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Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Pharmacy 244
_____________________________ _____________________________
Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry
BY
KRISTOFER OLOFSSON
ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2001
2
Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in OrganicPharmaceutical Chemistry presented at Uppsala University in 2001.
Abstract
Olofsson, K. 2001. Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry.Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Pharmacy 244. 74 pp. Uppsala. ISBN 91–554–4883–6
The palladium-catalysed Heck-reaction has been utilised in organic synthesis, where theintroduction of aryl groups at the internal, β-carbon of different allylic substrates hasbeen performed with high regioselectivity.
The β-stabilising effect of silicon enhances the regiocontrol in the internal arylation ofallyltrimethylsilane, while a coordination between palladium and nitrogen induces veryhigh regioselectivities in the arylation of N,N-dialkylallylamines and the Boc-protectedallylamine, producing β-arylated arylethylamines, which are of interest for applicationsin medicinal chemistry. Phthalimido-protected allylamines are arylated with poor tomoderate regioselectivity.
Single-mode microwave heating can reduce the reaction times of Heck-, Stille- andradical mediated reactions drastically from approximately 20 hours to a few minuteswith, in the majority of cases, retained, high regioselectivity.
The use of heavily fluorinated tin reagents, which proved to be unreactive under thermalheating, is shown to be applicable with microwave-heating and the high fluorouscontent of the products is utilised with the aim of improving and simplifying the work-up procedure.
Kristofer Olofsson, Organic Pharmaceutical Chemistry, Department of PharmaceuticalChemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden
© Kristofer Olofsson 2000
ISSN 0282–7484ISBN 91–554–4883–6
Printed in Sweden by Lindbergs Grafiska HB, Uppsala 2000
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List of Papers
The thesis is based on the following papers:
I. Kristofer Olofsson, Mats Larhed and Anders HallbergHighly Regioselective Palladium-Catalyzed Internal Arylation ofAllyltrimethylsilane with Aryl Triflates.J. Org. Chem. 1998, 63, 5076-5079.
II. Kristofer Olofsson, Sun-Young Kim, Mats Larhed, Dennis P. Curran and AndersHallbergHigh-Speed, Highly Fluorous Organic Reactions.
J. Org. Chem. 1999, 64, 4539-4541.
III. Kristofer Olofsson, Mats Larhed and Anders HallbergHighly Regioselective Palladium-Catalyzed β-Arylation of N,N-Dialkylallylamines.J. Org. Chem. 2000, 65, 7235-7239.
IV. Kristofer Olofsson, Helena Sahlin, Mats Larhed and Anders HallbergRegioselective Palladium-Catalysed Synthesis of β-Arylated PrimaryAllylamine Equivalents.J. Org. Chem. Accepted.
Reproduced in part with permission from Journal of Organic Chemistry, AmericanChemical Society. Copyright 1998-2000.
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CONTENTS
LIST OF PAPERS......................................................................................................................................3
ABBREVIATIONS.....................................................................................................................................6
1 INTRODUCTION.............................................................................................................................7
1.1 PALLADIUM(0) CATALYSED ORGANIC REACTIONS ........................................................................71.1.1 The Heck-Reaction ...............................................................................................................81.1.2 The Stille-Reaction ...............................................................................................................9
2 THE CATALYTIC CYCLE AND REACTANTS OF THE HECK-REACTION....................10
2.1 THE CATALYTIC CYCLE................................................................................................................102.1.1 Catalyst Formation.............................................................................................................102.1.2 Oxidative Addition..............................................................................................................102.1.3 π-Complex Formation and σ-Complex Formation (Insertion) ..........................................122.1.4 Elimination and Palladium(0) Regeneration .....................................................................17
2.2 REACTION CONDITIONS ................................................................................................................182.2.1 Palladium ...........................................................................................................................182.2.2 The Ligand (dppf) ...............................................................................................................182.2.3 The Base .............................................................................................................................212.2.4 The Solvent .........................................................................................................................22
2.3 REGIOCONTROL IN THE HECK-REACTION .....................................................................................232.3.1 The β-Effect of Allylsilanes.................................................................................................232.3.2 The Chelation of Palladium to Allylamines and Allylamides. ............................................26
3 RECENT DEVELOPMENTS........................................................................................................30
3.1 MICROWAVE CHEMISTRY .............................................................................................................303.1.1 The Microwave Oven..........................................................................................................303.1.2 General Physics..................................................................................................................313.1.3 Rate Enhancements with Microwave Chemistry.................................................................33
3.2 FLUOROUS CHEMISTRY.................................................................................................................353.2.1 History ................................................................................................................................353.2.2 Applications in Modern Chemistry .....................................................................................35
4 AIMS OF THE PRESENT STUDY ..............................................................................................38
5 RESULTS AND DISCUSSION .....................................................................................................39
5.1 HIGHLY REGIOSELECTIVE INTERNAL ARYLATION OF ALLYLTRIMETHYLSILANE (PAPER I) ..........395.2 HIGHLY REGIOSELECTIVE INTERNAL ARYLATION OF N,N-DIALKYLALLYLAMINES AND PRIMARY
ALLYLAMINE EQUIVALENTS (PAPER III AND IV). ........................................................................455.3 INTERNAL ARYLATION OF FLUOROALLYLAMINES (APPENDIX) ....................................................585.4 MICROWAVE HEATED FLUOROUS STILLE-COUPLINGS AND RADICAL REACTIONS (PAPER II) ......60
6 CONCLUDING REMARKS .........................................................................................................64
7 APPENDIX......................................................................................................................................65
8 SUPPLEMENTARY MATERIAL................................................................................................66
9 REFERENCES................................................................................................................................70
10 ACKNOWLEDGEMENTS............................................................................................................74
6
AbbreviationsAc acetylAIBN azobisisobutyronitrileAr arylBINAP 2,2´-bis(diphenylphosphino)-1,1´-binaphthylBoc tert-butoxycarbonylBTF benzotrifluorideBu butylcbz carbobenzyloxyDABCO 1,4-diazabicyclo[2.2.2]octanedisoppf (diisopropylphosphino)-ferroceneDMA dimethylacetamideDMF dimethylformamidedmpe bis(dimethyl-phosphino)ethaneDMSO dimethylsulfoxidedppb 1,4-bis(diphenylphosphino)butanedppe 1,2-bis(diphenylphosphino)ethanedppf 1,1´-bis(diphenylphosphino)ferrocenedppm 1,1-bis(diphenylphosphino)methanedppp 1,3-bis(diphenylphosphino)propaneEDG electron-donating groupequiv equivalentsEt ethylEWG electron-withdrawing groupFBS fluorous biphase systemFC-84 a perfluorinated solventFRP fluorous reverse phaseGC gas chromatographyL ligandMAO monoamine oxidaseMe methylMS mass spectroscopyNMR nuclear magnetic resonanceNR no reactionPh phenylPht (NPht) phthalimidoPMP 1,2,2,6,6-pentamethylpiperidineref referenceSSAO semicarbazide-sensitive amine oxidaset tertiaryTBAF tetrabutylammonium fluoridetemp temperatureTf trifluoromethanesulfonylTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographytriflate trifluoromethanesulfonylX halide or pseudohalide
7
1 Introduction
Palladium was discovered by William Hyde Wollaston in 1803 and was named after theasteroid Pallas, the second largest in the asteroid belt, that had been discovered the yearbefore. The name Pallas itself can be traced to the Grecian goddess Pallas Athena.Palladium is nowadays produced mainly in Russia and South Africa and although thisthesis will concentrate on the chemical applications of palladium is only 5% of theworld’s palladium stock used in chemistry, while 50% is used in electric componentsand 10% for car-exhaust catalysts.
1.1 Palladium(0) Catalysed Organic Reactions
The ability to create new carbon-carbon bonds is of paramount importance in medicinal-and organic chemistry and there are today a number of methods available for thatpurpose. Palladium(0) catalysed organic reactions (e. g. Heck-,1-9 Stille-,10,11 andSuzuki-couplings12,13) belong to the most versatile and popular of these methods.
One explanation for the popularity of palladium chemistry is the wide array offunctionalities that is compatible with the reaction conditions and the fact that thepalladium metal, which is expensive, can be used in catalytic amounts. The Heck-coupling, which in most cases attaches a vinyl or aryl group to an olefin, is widely usedtoday, particularly with electron-poor olefins, where the regiocontrol of the reactiongenerally is very good. However, some unsymmetrical olefins suffer from poorregioselectivity at the insertion step. The lack of regioselectivity can easily give amixture of product regioisomers that can reduce yields and hamper work-upsignificantly (Scheme 1).
The development of methods where the regioselectivity of the Heck-coupling can becontrolled should be of great importance both for the general understanding of themechanism of the Heck-reaction as well as for broadening the applicability of themethod.
XY+
Y Y+
Y
Pd
Scheme 1: Example of Low Regioselectivity in Heck-Reactions.
+
8
1.1.1 The Heck-ReactionThe palladium-catalysed coupling known as the Heck-reaction was first reported byMoritani,14 Fujiwara15 and Heck16,17 in the late 1960s. The reaction was stoichiometricat first but has been refined into a catalytic reaction.The standard model for the catalytic cycle, as described in Scheme 2, has recently beenaugmented with alternative mechanisms (e. g. Jutand’s new version of the catalyticcycle)6 and although these in many cases are valid only under special circumstances,there is today a growing awareness that the standard model for the Heck-reactionmechanism is not general.
If the catalytic cycle is investigated in detail it is clear that one source of the confusionover the mechanism is the poor understanding of the individual steps. To gainknowledge thereof is a great challenge as there is an inherent difficulty in identifyingthe catalytically active complexes in a given reaction mechanism. The most stablestructures, i. e. those that can be isolated and characterised, are in many cases not theconformations responsible for the success of the reaction.6 The difficulty of coming toterms with the details of the catalytic cycle is highlighted by the comparatively large
Pd(0)L4
Pd(0)L3
Pd(0)L2
Pd(II)RL
LX
Pd(II)RL
X
Y
Pd(II)LL
X
Pd(II)HL
LX
RX
LY
L
Y
R
Base
BaseHX
Scheme 2: The Classical Heck-Coupling Mechanism.
Oxidative Addition
ππππ-Complex Formation
Insertion
ββββ-Elimination
Pd(0) Regeneration
Y
R
9
number of papers on the Heck-reaction mechanism that still, approximately thirty yearsafter the first report of the coupling, are published in respected journals.
1.1.2 The Stille-ReactionThe Stille-reaction is a cross-coupling reaction where an alkynyl, vinyl, aryl or alkylgroup is transferred from a tin reagent to an organohalide (Scheme 3).
The stability of the organotin starting materials makes the Stille-reaction a popular andgenerally very reliable method for carbon-carbon bond formation. The toxicity of the tincompounds and the relative sluggishness of the method, where reaction temperatures ofup to 100 °C are not uncommon, reduce the synthetic usefulness of the coupling.18 LiClis frequently added to stabilise the palladium catalyst10 and Cu(I) salts have also beenutilised to improve the selectivity at the rate-determining transmetallation step. Coppersalts may function both as phosphine scavengers, when PPh3 is used as ligand, and as ameans of converting the stannane to an organocopper species.18
Pd(II)
Pd(II)R3
XPd(II)
R3
R1
Pd(0)Ln R3-X
Oxidative Addition
Transmetallation
R1-Sn(R2)3X-Sn(R2)3
ReductiveElimination
R1-R3
Reduction
LnLn
Scheme 3: The Mechanism of the Stille-Reaction.
10
2 The Catalytic Cycle and Reactants of the Heck-Reaction
2.1 The Catalytic Cycle
2.1.1 Catalyst FormationPalladium is usually administered in its Pd(II) oxidation state and is reduced in thereaction medium to the catalytically active Pd(0) form (Scheme 2). There are at leastfour possible reducing agents in the typical Heck-coupling: the phosphine ligand,19-21
the base,22 the olefin23,24 or, in some cases, the solvent.25 There has been someuncertainty over which reducing agent predominates over the other, but convincingevidence has emerged that phosphine ligands, when they are present, are the most activeof the four and the agent most likely to reduce Pd(II).26 The mechanism depicted inScheme 4 has been proposed for the reduction of Pd(II) species.20
2.1.2 Oxidative AdditionIn the oxidative addition step is Pd(0) oxidised to Pd(II) and an aryl- or vinyl group isadded with its X–-counterpart, which usually is a halide or a pseudohalide (Scheme 5).Examples of pseudohalides that have been used in Heck-reactions include triflates,27
nonaflates,28 aryldiazonium salts7 and iodonium salts.7
The rate of the oxidative addition29 is quite sensitive to the choice of halide orpseudohalide with the reactivity falling in the series ArN2X > I– >> OTf– > Br– >> Cl–.Reactions with aryldiazonium salts are not very common but aryl- and vinyl iodides
PPh3AcO
O
Me O
PAcO O
2 PPh3
H
Pd(II)(OAc)2 + PdAcO OAc
Ph3P PPh3
(II) Pd(0)Ph3P
AcO+ AcO-PPh3
AcO-PPh3
+AcO Ac2O + O=PPh3
+H2O
-HAcOH + O=PPh3
Scheme 4: Reduction of Pd(II) to Pd(0) by Phosphine Ligands.
1
Ph3
Pd(0)L2 + ArX Pd(II)L
LAr
X
Scheme 5: Oxidative Addition of Palladium(0) to ArX.
2
11
have been studied extensively. Iodides are usually reactive at room temperature evenwithout the addition of phosphine ligands. Aryl- or vinyl triflates, nonaflates andbromides typically need phosphine ligands, if the reactions are not run under phasetransfer conditions,5 but are usually quite reactive. It is interesting to note thatselectivity between aryl triflates and -bromides has been attained under certain reactionconditions.30 Aryl chlorides react only with difficulty and at elevated temperatures instandard Heck-couplings and considerable effort is at present made to explore thisreaction.31-36 One incentive for this exertion is the relative cheapness and availability ofaryl chlorides, when compared to aryl triflates and the other aryl halogens, which makethe chloro-compounds attractive for industrial-scale synthesis. The development ofwater-soluble catalysts7 is another research area that is highly interesting for industrialapplications.
The choice of organic moiety that is to be coupled (–R, Scheme 2) is limited as it shouldnot have a cis-hydrogen on an sp3-hybridised carbon in the position β to the palladium.The desired reaction may be ineffective if this prerequisite is not fulfilled since Pd–Helimination of the cis-hydrogen occurs more readily than addition to olefins.1 Suitable –R groups can be e. g. aryl,1 alkenyl,1 benzyl,1 allyl,37 alkynyl37 or alkoxycarbonyl-methyl37 groups.
Although the 14 e--complex 2 (Scheme 5) is commonly referred to as the reactivespecies in the oxidative addition of monodentate phosphine-ligated palladiumcomplexes has the 16 e--complex Pd(0)(PPh3)2(OAc)- 3 (Scheme 6) recently beenpresented as a contender.6 Complex 3 is formed from complex 1 (Scheme 4) byequilibrium with one equivalent of phosphine ligand. The oxidative addition may thenproceed through a short-lived pentacoordinated palladium species 4, yielding 5, theproduct of the oxidative addition (Scheme 6).
The oxidative addition of bidentate-ligated palladium complexes has recently beenreported to go through the full dissociation of one of the chelated bidentate ligands (PathA, Scheme 7)38 or alternatively through the reversible dissociation of one of the arms ofone bidentate ligand in consequence of the association of ArX through a combination ofassociative and dissociative steps (Path B, Scheme 7), finally generating the same Pd(0)complex 6 as Path A. These mechanisms were found to be applicable to BINAP as well
PhI Pd
PPh3
PPh3
Ph IOAc PhPd(PPh3)2(OAc)
-I
Scheme 6: Oxidative Addition via a Pentacoordinated Palladium Species.
4 53
Pd(PPh3)2(OAc)
12
as dppf.38 Notable is that one equivalent of bidentate ligand is in both mechanismsligated to the palladium through all intermediate steps of the oxidative addition.
2.1.3 π-Complex Formation and σ-Complex Formation (Insertion)It is vital to control the π-complex formation and insertion39,40 steps in order to controlthe regioselectivity of the Heck-reaction, that is if the –R group will be added to theinternal carbon of the olefin, yielding 7, or the terminal, yielding 8 (Scheme 8).
The literature has described two slightly different mechanisms of the Heck-reaction,depending on if the leaving group is a tightly coordinating halide, typically bromides(the neutral pathway), or a weakly coordinating pseudohalide, typically triflates (thecationic pathway). There are a number of reaction parameters that can be chosen toensure that only one, or mostly one, of the pathways is active in a certain reaction. If thereaction parameters are set ambiguously can both the neutral and cationic pathway beactive simultaneously and mixtures of regioisomers may be produced ifunsymmetrically substituted olefins are used. Some previously reported regio-selectivities for the arylation of vinyl- and allyl substrates are summarised in Scheme 9.3
PdL
L LL Pd
L
L+ L L ArX Pd
L
L
Ar
XA:
B: PdL
L LL Pd
L
L L L
ArX PdL
L Ar-XPd
L
L
Ar
X
Scheme 7: Mechanism for Oxidative Addition with Bidentate Ligands.
6
6
Pd(0) Pd(0) Pd(II)
Pd(II)RL
LX
Scheme 8: Internal and Terminal Insertion in the Heck-Reaction.
Y
Pd(II)RL
X YPd(II)
LL
XY
Pd(II)LL
XY
R
R Y
RR
Y
-L
+L
7
8
π-Complex Formation Insertion
Pd(II)RL
X
Y
+L
13
The neutral pathway: The choice of an aryl- or vinyl halide as substrate results in aneutral oxidative addition complex, e. g. 9 (Scheme 10), where the anion (–X) is tightlycoordinated to the palladium. When the olefin coordinates to the complex is one of thephosphine ligands lost rather than the halide –X, which is why monodentate ligands areused in neutral-pathway Heck-reactions; they coordinate more weakly to palladium thanbidentate ligands.
Factors governing the regiochemical outcome of Heck-reactions going through theneutral pathway are largely sterical. The neutral complex 9 will preferably give thelinear, terminally arylated product 8 (Scheme 8) as the organic moiety (the –R group)usually is larger than the palladium moiety and will be inserted on the less substitutedcarbon.1 When electron-withdrawing substituents are present on the olefin is theelectronic effect inducing the insertion to the same position as the steric effect, that isstimulating terminal substitution (e. g. entry 1, Scheme 9). With electron-rich groupspresent on the olefin, may the electronic factors favour insertion at the carbon with thehighest electron density (the internal, secondary carbon in the case of electron-rich,terminal alkenes) instead of the carbon with the lowest degree of substitution (theterminal carbon of the olefin), which may give a mixture of products (entries 3–4,
Pd(II)L X
Ar9
Pd(II)L L
Ar10
Scheme 10: Neutral and Cationic π-Complexes.
R R
COOMe
N
O
OH
OH
OBu OH
OAc
Olefin PathwayNeutral Cationic
0/100 0/100
40/60 100/0
Mixture ofIsomers
100/0
Mixture of Isomers
95/5
0/100 100/0
10/90 95/5
20-25/80-85
90/10
20/80 80-85/20-25
Scheme 9: Regioselectivity in the Neutral and Cationic Heck-Reaction.
Ratio Internal/Terminal Insertion
Olefin PathwayNeutral Cationic
Ratio Internal/Terminal Insertion
1. 5.
2.
3.
4.
6.
7.
8.
Entry Entry
14
Scheme 9). Olefins with electron-withdrawing groups are thus favoured in reactionsgoing through the neutral mechanism.41
Even though the electronic influences of the reactants generally are lower in the neutralpathway than in the cationic has an unmistakable change in regioselectivity betweenelectron-poor and electron-rich or -neutral aryl halides been reported in the arylation ofenol ethers (Scheme 11).42 Butyl vinyl ether that easily gives a mixture of regioisomerscould with a relatively high regioselectivity be arylated at the terminal carbon with p-nitrophenyl halides.42
All in all, the electronic properties of the olefin are of less importance in the neutralpathway than in the cationic, as the neutral complex is associated with a reducedpolarisation of the double bond, but can in some instances influence the regiochemistryof the insertion.3,43
The cationic pathway: The most popular pseudohalide in Heck-reactions going throughthe cationic pathway is the triflate. A high selectivity for internal arylation of butyl vinylether in coordinating solvents was reported by our group in the late eighties.44 Cabri hassince then published several seminal papers on the use of aryl triflates in combinationwith palladium catalysts ligated to bidentate ligands in reactions with electron-richolefins.3 Triflate groups will, especially in polar solvents such as DMF,45 easilydissociate from the oxidative addition complex and produce a cationic complex 10(Scheme 10). As the triflate anion is to be exchanged upon coordination to the olefin arebidentate ligands such as dppf or dppp used, which are not as easily exchanged asmonodentate ligands and thus indirectly favour the dissociation of the triflate group.
The electronic properties of the olefin are in the cationic pathway important not only forthe reactivity but also, to a higher degree than the neutral pathway, for theregiochemical outcome of the insertion. The coordination of the olefin in a cationiccomplex increases the polarisation of the π-system of the olefin, easing the migration ofthe aryl moiety onto the internal carbon because of the lower charge density withrespect to the terminal carbon.43 This is not to say that steric factors are to be ignored in
Br
O2N
OBu
Br
62
38OBu
23
77
Scheme 11: Ratio of Arylation of Butyl Vinyl Ether with Electron-Poor and -Neutral Aryl Bromides.
15
the cationic mechanism. In fact, several studies indicate that there is, in many cases, abalance between electronic and steric factors that influences the regioselectivity inreactions going through the cationic pathway;7,41 a manifestation that adds to thedifficulty of finding, or expressing, a simple model for the mechanism of the Heck-reaction.
The mechanism of the cationic Heck-reaction is described in Scheme 12. Electron-richolefins generally function better than electron-poor olefins.3 One factor behind thisphenomenon may be the disfavoured interaction between an electron-poor olefin andthe cationic palladium complex,41 as depicted in complex 10, Scheme 12, leading to aslow insertion. The insertion step has been suggested to be the rate-determining step inthe cationic Heck-mechanism.6,43
The reaction (and the regioselectivity) can in many cases, when vinyl- or aryl halidesare used, be changed from the neutral- to the cationic pathway by adding halide“scavengers”, such as silver46-48 and thallium43,49 salts (Scheme 13).
ArOTf
R
Base
BaseHOTf
Pd(II)LL
OTfAr
Pd(0)LL
OTf
Pd(II)LL
ArPd(II)
LL
Ar R
Scheme 12: The Cationic Heck-Reaction Mechanism.
10
Pd(II)LL
OTfH
Oxidative Addition
ππππ-ComplexFormation
Insertion
ββββ-Elimination
Pd(0) Regeneration
OTf
RR
Ar
Pd(II)L
LAr
X
Scheme 13: Scavenging of Halide Anions by Silver- or Thallium-Salts.
Ag- or Tl-saltsPd(II)
L
LAr+ AgX or TlX
16
There may also be other connections between the neutral and cationic pathways asJutand has reported the dissociation of the halide in neutral palladium complexes 11 incoordinating solvents such as DMF, yielding cationic complexes 12 (Scheme 14).50
Overman has studied the insertion of bidentate-ligated neutral- as well as cationicpalladium species and found proof that a temporary dissociation of one of the arms ofBINAP is unlikely, even in the neutral pathway, as this should have a negative effect onthe stereoinduction; a result that was not seen. A mechanism involving a transientneutral, pentavalent palladium complex 13 was proposed with aryl halides in the neutralmechanism, while a cationic complex 14 could be formed directly from aryl triflates(Scheme 15).51
ArPdL2X ArPdL2(DMF)
Scheme 14: Equilibrium Between Neutral and Cationic Arylpalladium Complexes in DMF.
11 12
ArX PdL L
PdL L
X ArPd
LL
XAr
PdL L
ArPd
L L
X
Ar
Scheme 15: Neutral and Cationic Pathways with Palladium-BINAP Complexes.
ArOTf PdL L
PdL L
ArPd
L L
solv
Ar
Neutral
Cationic
13
14
-X
X
OTf OTf
17
2.1.4 β-Elimination and Palladium(0) RegenerationThe β-hydride elimination is the step yielding the final product of the Heck-reaction.For this process to occur must the insertion complex be able to rotate to a positionwhere a β-hydrogen is placed cis to the palladium. The elimination will then result in areconstituted alkene and a palladium hydride species. The β-elimination is reversibleand the preferred formation of the thermodynamically more stable trans products is thusexplained (Scheme 16).37
There is today no precise knowledge of how Pd(II) is reduced to Pd(0). A recentlypublished mechanism favouring a base-promoted elimination of Pd(II) to Pd(0)(Scheme 17) is suggested to be more energetically favoured than a mechanism where aβ-elimination yields a free HPdL2 species.52
R
H PdL2
R´3N R´3NHX
R
PdL2PdL2 + R
Scheme 17: Base-Promoted Elimination.
X
Pd
Y
R
Pd
Y
H
R
H H
H
Pd
Y
H
HR
Scheme 16: β-Elimination in the Heck-Reaction.
Y R
Y
R
Y R
Y
R
PdH
PdH
H
H
H
-PdH
-PdH
18
2.2 Reaction Conditions
Evidently, it is difficult to analyse the precise importance of every ingredient of areaction and the Heck-reaction has proven to be a tough nut to crack, as has been notednot without humour in a recent review by Beletskaya,7 where it is amply demonstratedthat even small variations in the reaction conditions can have considerable effects on theoverall performance of the system. Some of the components37 of the Heck-reaction arereviewed below.
2.2.1 PalladiumThere is at present an abundance of different palladium complexes available.37 It isdifficult to predict how a certain catalytic system will work under given reactionconditions and it is not uncommon to test several different catalyst/ligand pairs when anew reaction is to be optimised. However, mechanistic investigations have suggested arole for the –OAc anion in the catalytic cycle6,19 and the relatively moisture insensitivePd(OAc)2 catalyst is perhaps the first choice today.
2.2.2 The Ligand (dppf)The choice of ligand can have a considerable effect on the outcome and selectivity ofthe Heck-coupling. Phosphine ligands are regularly used as they stabilise reactiveintermediates and influence the reactivity and selectivity through electronic and stericeffects.7,53,54 The presence of phosphine ligands can reduce the rate of readdition, andincrease the rate of dissociation, of the hydridopalladium to the double bond in a Pd–olefin π-complex intermediate.1 This would tend to decrease double-bond migration andthe formation of unwanted β-elimination products.
One of the most commonly used bidentate ligands is 1,1´-bis(diphenylphosphino)-ferrocene (dppf).55,56 Dppf is a sandwich-complex and is known to be flexible in three-dimensional space,55,57 probably more so than the other most ordinarily used bidentateligands, such as dppp and BINAP. Several studies support the idea that ligands with alarge bite angle54,58 (Scheme 18) can increase the rate of palladium elimination, as thelarge bite angle induces a stress in the structure of the intermediate complex that will bereleased by the elimination.26,54,55,59,60
Pd
Scheme 18: Representation of the Bite Angle (θ) of a Bidentate Ligand.
L Lθ
Bridge
19
Analogues of dppf that have an even larger bite angle, e. g. (diisopropylphosphino)-ferrocenes (disoppf), are known to give very high regioselectivities. Too large biteangles, on the other hand, are known to be deleterious for the Heck-reaction.54
LIGAND BITE ANGLE
dppp54 91°
BINAP61 92.7°
dppf56 99.1°
disoppf60 103.4°
If dppf is added in more than two equivalents to the amount of palladium can thecomplex 15 be formed (Scheme 19). It was previously assumed that a dissociation ofone of the pairs of the bidentate ligands was necessary in order for a Heck-reaction totake place62 but recent results, where the complex 15 was found to have catalyticactivity with aryl halides,38 put doubt on this suggestion. Instead, it has been suggestedthat 15 might be the dominating resting state of the active catalyst in the reactionmedium.38,63
Another explanation for the success of bidentate ligands in catalysis might be formationof the palladacyclic intermediate 16, which was identified after 6 h at 100 °C in DMA(Scheme 20).38
The importance of palladacyclic complexes in palladium-catalysed reactions withbidentate ligands is at present poorly understood but palladacycles are known for theirstability64 and the formation of 16 could protect the catalytic system fromdecomposition at high reaction temperatures and during prolonged reactions.
Pd(0)L L
L LPd(0)
L L+ L L
Scheme 19: The Equilibrium of PdL4 and PdL2 with Bidentate Ligands.15
Scheme 20: Formation of Palladacycle Intermediates with Pd-dppf Complexes.
+Br
Pd(dppf)2 FePPh2
PdFe
PPh2
PPh2
PdBr
Br
PPh316
20
The electronic influences of dppf on palladium are somewhat unclear. Electrochemicalstudies of iridium complexes indicate that dppf is at least a stronger electron donor thandppm or dppe.65 The possibility of dative bonding between the iron centre of dppf andpalladium has been implied as well.55,66
A side reaction that can be seen in some Heck-couplings is the generation of olefinsarylated with an aromatic ring from the ligand system. This process is also called arylmigration or aryl scrambling42,64,67 and stems from the proximity of the palladium-bound aryl group and the aryl groups of the ligand in complexes such as 17 (Scheme21). This proximity might result in the insertion of one of the aryl groups from theligand instead of the desired aryl group. In Scheme 21 have the aryl groups in the dppf-complex been pictured as lying flat in the dimension of the paper for the sake of aneasier overview.
Palladium complexes with electron-donating ligands seem more prone to aryl exchangethan those with electron-withdrawing ligands.67-69 The migration of alkyl groups69 hasalso been noted, although the mechanism may be different than that for aryl migration,which has been elucidated by Novak.67 The mechanism of the aryl migration mayinvolve the dissociation of a phosphine from the palladium centre as the addition of 1equivalent of PPh3 in mechanistic studies suppresses the scrambling almost totally,67
while 0.1 equivalent of PPh3 did not influence the reaction at all.70 This could beexplained by a mechanism encompassing reductive elimination of the Pd(II)L2Ar´Xspecies to Pd(0) (Scheme 22).67,71,72 The addition of excess PPh3 could lead to theformation of Pd(PPh3)n from Pd(0), preventing subsequent oxidative addition.
Scheme 21: Aryl Migration in the Pd/dppf Complex.
MeO
Fe
P P
Y
OTf
Fe
P P
MeO
Fe
P P
YMeO
Y+
+
Pd
Pd
Pd
17
-OTf
21
Recent studies indicate that aryl migration is dependent both on the nature of X inArX,73 where the ease of scrambling is I- > Br- > Cl-, and the nature of the solvent, withhighly polar solvents giving more scrambling than less polar. These results wouldsupport the theory that Pd–X ionisation is a requirement for the exchange to occur.67,73
As many studies in which aryl migration is investigated are conducted with GC–MS it isworth noting that no aryl exchange seem to occur during the process of massmeasurement.70
2.2.3 The BaseThe role of the base in the Heck-coupling has been debated and although some clarityhas been added, it is nonetheless safe to say that our knowledge of the details of thefunctions of bases in the reaction medium is unsatisfactory. It was suggested from anearly point that bases were needed to deprotonate the hydridopalladium complex formedat the β-elimination step in order to regenerate Pd(0) (Scheme 2). This mechanism hasbeen corroborated recently.74 Jutand has suggested that nitrogen bases may be involvedin the abstraction of protons that otherwise would interact with the –OAc anion incomplex 3 (Scheme 6), and produce the proton-coordinated complex 18 (Scheme 23).Complex 18, where the acetate is more weakly coordinated to the palladium than in 3would result in a more naked and reactive palladium species.6 The proton abstractionwould occur less readily when bases are added and bases may thus slow the oxidativeaddition.
Inorganic bases have in several papers been used successfully in couplings where alower degree of reduction of the aryl precursors was needed.75 This could be explained,when aryl bromides are used, by the neutralisation of the HBr formed during thereaction.76 Nitrogen bases have also been suggested to act as a source of hydrides in thedeoxygenation of triflates, which would explain the low degree of deoxygenation wheninorganic bases are used in favour of organic (Scheme 24).75,77
Pd(0)Ph3P
Ph3POAc H
Scheme 23: Abstraction of Palladium-Ligated Acetate by Protons in the Reaction Medium.
18
Pd(II)XAr3P
PAr3Ar'Ar'PAr3 + X + Pd(0) Pd(II)
XAr2P
PAr3Ar
Ar'
L
Pd(0)Ln
Scheme 22: Aryl Migration by Reductive Elimination.
22
The base can also affect an equilibrium that influences the concentration of the keyreactive species of the insertion, ArPd(II)(OAc)(PPh3)2 5, as illustrated in Scheme 25.The abstraction of hydrogens is thought to shift the equilibrium to favour the reactive 5over the less reactive cationic complex ArPd(II)(PPh3)2
+ 19.6
The base has thus at least two roles; one that impedes the fast oxidative addition(Scheme 23) and one that speeds the slow π-coordination and insertion (Scheme 25).This is suggested to be beneficial for the catalytic cycle as the oxidative addition andinsertion steps then can take place with comparable rates.6
2.2.4 The SolventPolar, aprotic solvents such as acetonitrile and DMF are often used in Heck reactions.37
The possible effects of trace amounts of water in the reaction medium have beendiscussed, with varying conclusions. Brown indicated that just traces of water couldalter the composition of the palladium complexes in reactions with bis(phosphane)-palladium complexes,74 while Overman found no noticeable effect of up to 5% (v/v)water in couplings with Pd/BINAP systems.51 Poorly degassed reaction solutions wereon the other hand clearly shown to have a negative effect on the stereoselectivity due tooxidation of phosphine ligands to phosphine oxides by oxygen.51 Jutand has noted thatthe presence of water does not affect the rate of reduction of Pd(II) to Pd(0).20 Crispsuggested that water might be a source for hydroxide ligands that in reactions with arylchlorides temporarily can replace the halogen and produce a more reactive species.78
Traces of water may also increase the degree of aryl scrambling (especially whenreactions are run with relatively unpolar solvents) by making the reaction medium morepolar.67
NEt2H
H3CH
PdL2Ar
NEt2
PdL2ArH
HH PdL2HAr + Et2N
Scheme 24: Organic Bases as a Source of Hydrides.
TfO
TfOH
ArPd(OAc)(PPh3)2 ArPd(PPh3)2 + OAc
HOAc
H NEt3
Scheme 25: Equilibrium Shift due to Abstraction of Hydrides by a Base.
5 19
23
2.3 Regiocontrol in the Heck-Reaction
2.3.1 The β-Effect of AllylsilanesThe carbon–silicon bond is in a number of ways different from the carbon–carbon bondand these differences are reflected in the unique chemistry of organosiliconcompounds.79-81 Silicon is one of the few elements routinely used in synthetic organicchemistry that are more electropositive than carbon (Pauling electronegativity for Si: 1.8and C: 2.5)82 and the C–Si bond is also longer (typically 25%)82 than the C–Ccounterpart and relatively easy to polarise.83 Silicon also forms stronger bonds withelectronegative elements than with carbon and the addition of fluoride salts such asTBAF can often be used for the removal of silicon groups. Electrophilic substitution ofthe silyl functionality has also frequently been taken advantage of in preparativechemistry.79,84,85 Another peculiarity of silicon that can be put to synthetic use is theability of organosilicon compounds to stabilise a cation in a β-position, the so-called β-effect of silicon (Scheme 26).
The basis of the β-effect is thought to be the σ–π hyperconjugation (Scheme 27).86-88
Another form, the p–d homoconjugation87 (Scheme 27) is also discussed in the literatureand uncertainty in the denomination of the two systems is encountered from time totime.
Si
C C
π
σ−π Hyperconjugation
CC Si
p d
p−d Homoconjugation
Scheme 27: Hyper- and Homoconjugation with Allylsilanes.
σ
SiMe3αγ β
Scheme 26: Denomination of the α, β and γ -Positions.
24
A number of studies have been made to shed light on the underlying mechanism of theβ-stabilisation. Basically, the stabilisation can be explained by three factors:1. induction effects from the Si-atom2. hyperconjugation through vertical stabilisation3. hyperconjugation through nonvertical stabilisation.
Induction can be seen as a lowering of energy from through-bond delocalisation ofelectrons and hyperconjugation as energy lowering by through-space delocalisation. Themagnitude of induction should depend on the bond length but not the bond angle, whilehyperconjugation should vary according to the dihedral angle between the vacant p-orbital and the C–Si bond. The inductive effect was from an early stage found not toinfluence the β-stabilisation markedly.86,89,90 Hyperconjugation, on the other hand, hasbeen demonstrated to be the main source of the β-effect in ab initio studies.86 This waslater corroborated in solvolysis experiments, where the direction dependence of the β-effect was beautifully illustrated with comparisons of molecules where the leavinggroup was placed either in a gauche 20 or antiperiplanar 21 position89,91 to thetrimethylsilyl group (Scheme 28).
The conformer with the trimethylsilyl group in the antiperiplanar position 21 lost theleaving group 1012 times faster and the one with the gauche trimethylsilyl 20 group3.3×104 times faster than the molecule without trimethylsilyl substitution, which amplydemonstrates the importance of the dihedral angle for an effective β-stabilisation. Thehyperconjugative factor for the stabilisation of the antiperiplanar compound wasestimated to 1010 and the inductive factor to 102.89 The substituents of the silicon atomcan also influence the β-effect. The presence of electronegative elements (e. g. –Cl) onthe silicon atom leads to a lower degree of stabilisation.92
There has been a debate during the last fifteen years over the structure of the β-silylallyl cation, where some proponents argue for an open, vertical structure88 22 and somefor a bridged, nonvertical structure93,94 23 (Scheme 29).
SiMe3t-Bu
O(CO)CF3
t-Bu
O(CO)CF3
SiMe3
Antiperiplanar ConformationGauche Conformation
Scheme 28: Gauche and Antiperiplanar Conformations in Solvolysis Experiments.
20 21
25
If sufficient proof of the existence of the hyperconjugative effect has been easy to comeby has the differentiation between vertical and nonvertical stabilisation been difficult toexamine experimentally. A partially bridged system has been argued for in gas-phaseexperiments.93,94 Lambert has argued convincingly for the vertical mode of stabilisationin several papers88 where NMR-95 and dihedral angle studies90 were made in solution.The additional stabilisation of a second silyl group has been found to strengthen the β-effect as well.96 This would support the open structure as additive stabilisation shouldnot be allowed in bridged structures.
The β-effect is also prominent in germanium and tin systems.92,95,97 The β-effects ofgermanium-stabilised allyl compounds are slightly higher than the corresponding siliconcompounds, while the β-effect of tin is considerably higher than both. In fact, the rate-enhancement due to β-stabilisation of tin was so high that it could only be approximatedwith a weaker leaving group (OAc) and a gauche conformation in solvolysis studies.97
A couple of examples of where the β-stabilising effect of silicon has been appliedsynthetically include the generation of the relatively stable cation 24,98 which is 15kcal/mol more stable than the corresponding dimethyl derivative and the higherstabilisation of the five-membered ring 25 compared to the six-membered 26,99 wherethe overlap of the lone pairs of the oxygen is more favourable in 25 than in 26. The rateof protonation was also found to be higher in the alkyne 27100 when X is –SiMe3 thanwhen X is –H (kSiMe3/kH= 54,300) (Scheme 30).
SiMe3Me3Si
24
O
R3Si
H
R3SiO
Si
H
R3Si= =
25 26
Me X H+Me
H
X
27
Scheme 30: Reactions where β−Stabilisation has been Utilised.
R3
R3Si
CH2
CR´2
Open/Vertical
H2C CR´2
R3Si
Bridged/Nonvertical
Scheme 29: Vertical and Nonvertical Modes of β-Stabilisation.
22 23
26
The stabilisation due to hyperconjugation is not limited to the β-position and a fewcases of γ-stabilisation83,101 have been reported as well.
2.3.2 The Chelation of Palladium to Allylamines and Allylamides.The palladium(II)–nitrogen chelation has been reported on many occasions; for examplein conjunction with nucleophilic attacks on palladium-coordinated allylamines such as28102-106 and Heck-couplings with vinyl ethers, such as in 29107 and 30108 (Scheme 31).
Complexes such as 28 are reported to be quite stable and no decomposition wasdiscovered at 100 °C in NMR studies.102 The palladium–nitrogen coordination can alsobe strong enough to allow the analysis of crystal structures such as 31109,110 (Scheme32).
In complex 32 was the formation of 33, instead of the anticipated 34, explained by acoordination of the palladium moiety to the anilic, primary nitrogen, which hindered β-elimination and readdition and further migration of the double bond111 (Scheme 33).
O
NPd
Me2
ArX
NPdL
LMe2
Nu
NMe2 Li2PdCl4Nu
NMe2
Nu
28
29 30
Scheme 31: Examples of Coordination between Palladium and Allylamines or Vinyl Amine Ethers.
O
NPdArI
MeO
NPd
Me2Cl
Cl
Scheme 32: Crystal Structure of a Palladium-Homoallylamine Complex.
31
N
MeO O
NH2
PdH I
N
MeO O
NH2
N
MeO O
Ar
32 33 34
Scheme 33: Suppression of Double-Bond Migration through Palladium-Nitrogen Coordination.
27
The ring sizes of the chelated complexes are known to be important and a preference forfive-membered rings over six-membered rings is well established.106 In sulphur-coordination experiments were complexes such as 36 spontaneously formed from six-membered intermediates 35 (Scheme 34).112
Chelation of palladium to amines has also been investigated with IR spectroscopy,113,114
where the N–H stretching vibrations appeared at lower frequencies in palladium-coordinated than in free amines. Coordination has in some experiments been shown toincrease in non-polar solvents.115
The electron density of the heteroatom in palladium–heteroatom coordinationcomplexes may influence the strength of the chelation. In complex 37 was coordinationstronger with a nitrogen substituent capable of electron donation, such as propane ormethane, than with the electron withdrawing methyl ester (Scheme 35).116 In addition,the imine-substituted complex 38 underwent a transmetallation reaction via a Pd–Ncoordinated five-membered ring easier than the acetyl substituted 39, where resonancedelocalisation in the amide group was reported to reduce the chelating ability of thenitrogen (Scheme 35).117
PdS CH2CH2C6F6
HBr2 36
R
Scheme 34: Preferred Five-Membered Ring Size of a Palladium-Sulphur Complex.
PdS CH2C6F6
HBr2
R
35
NR
ArX, Ag+
Pd(0)NR
Pd
Ar NR
Ar
R = COOMe, Alk
Scheme 35: Influence of the Electron Density of Nitrogen on Palladium-Nitrogen Coordination.
37
NPh
Ph
Pd
Bu3Sn Br
Transmetallation-Bu3SnBr Pd
N Ph
PhH3CO2C H3CO2C
NHAc
PdBu3Sn Br
H3CO2C
38
39
28
Similarly was complex 36 in Scheme 34 more stable with n-Bu than with Ph as sulphursubstituent (–R).112 Electron-withdrawing substituents in general facilitate ring openingin palladium–carbonyl complexes118 and an electron-poor palladium centre has beensuggested to be more sensitive for coordination than electron-rich.115
Equilibrium studies with palladium chelated to the bidentate ligand bis(dimethyl-phosphino)ethane (dmpe) 40 (Scheme 36) revealed the following binding order fordifferent degrees of nitrogen substitution NH2Et > NHEt2 > NH3 >> NEt3 and fordifferent substituents NH2Et > NH2i-Pr > NH3 > 1-adamantamine > NH2t-Bu >NH2Ph.119 The effect of the basicity of the amine ligand appeared to be negligible foramines with cone angles54,58 smaller than 120°.119 The same report found a strongercoordination when the nitrogen was enclosed in a ring system, which was explained bysteric effects. Pyridine had an anomalously strong binding to palladium, where theplanarity of the ring system was suggested to favour π-back bonding to the metal centre.All in all were both steric and electronic effects found to affect the binding of nitrogento palladium.119
In the case of allylamides can the situation be more complex, as chelation is possibleboth to the nitrogen and the carbonyl group. Studies on small peptides indicate thatwhen a transition metal coordinates to the nitrogen of a secondary amide can adeprotonation of the nitrogen occur more readily, which would generate an anionicnitrogen, possibly more capable of coordination to Pd2+ than a neutral nitrogen.120 Theease of deprotonation is dependent on the metal and representative pKa values for anumber of transition metals have been reported (Pd2+=2; Cu2+=4; Ni2+=8; Co2+=10).120
If the metal–N coordination can generate a five-membered ring is deprotonation easierthan with six-membered intermediates. Furthermore, the charge of the amide isimportant for the mode of coordination, as anionic, deprotonated forms of amides insmall peptides coordinate at the nitrogen and neutral forms at the carbonyl.120
Pd(H3C)2P P(CH3)2
H3C NR2
Scheme 36: Equilibrium Study of Nitrogen Ligands to Palladium.
40
29
Palladium–carbonyl coordination has been suggested on many occasions.106,118,121-123
Hegedus has suggested structure 41 as an intermediate in nucleophilic attacks on vinylcarbamates121 and Alvisi and Blart presented the six-membered Pd–carbonylcoordinated structure 42 and the five-membered Pd–N coordinated 43 as alternativeintermediates in the arylation of Boc-protected allylamines with a vinylic trimethylsilylgroup (Scheme 37).122
Impressive reports of rhodium–carbonyl coordination also support the importance offive-membered structures.124
HN O
OBn
PdL
L
HN O
Pd
OBn
NuNu-L L
SiMe3
NH Boc
Pd ArI
LLPd
N
ArMe3Si
BocHLL
SiMe3
Pd ArI
LL NHO
Ot-Bu
PdLL
NHO
Ot-Bu
41
43
Scheme 37: Examples of Palladium Coordination to Carbonyls and Nitrogen.
42
ArSiMe3
I
I
30
3 Recent Developments
3.1 Microwave Chemistry
3.1.1 The Microwave OvenThe first examples of the use of microwaves to enhance reaction rates in organicchemistry date as far back as when the first household microwave ovens wereintroduced, but the difficulty of controlling the reactions lead to unreproduciblereactions and explosions. Domestic ovens have been developed to meet differentstandards than what is needed in chemistry and use rotating dishes or other mechanismsto spread the microwaves in the oven to reduce the risk of unevenly heated food ratherthan trying to focus the radiation. When doing chemistry in multi-mode ovens there isthus a risk of getting poorly reproducible results as the heating is not uniform and this,in turn, accounts for the risk of explosions.
Several factors can account for the momentum gained in the development of microwavechemistry during the last few years. One reason is the advent of combinatorial chemistryand high-throughput screening, where there is a need for high-speed synthetic methods.Another is the development of single-mode microwave ovens, where not only the powerinput can be controlled but also, what is perhaps more important, the focusing of themicrowave irradiation. Single-mode reactors found one of their first applications in thesynthesis of radiopharmaceuticals, where a fast, controlled synthesis of radioactivecompounds were of paramount importance.125,126
The possibility of controlling the power input in single-mode ovens is a greatimprovement for the synthetic chemist, as even though it appears as if the temperaturecan be controlled in the domestic oven, it is mostly not the power input that is changedbut only the length of the heating cycles. Even so, in spite of the differences between thefocused single-mode and domestic multi-mode ovens have the latter been used in mostof the papers published as of today. The danger of explosion is minimised by severalmethods, some of which are running the reactions without solvents in open vessels,although the use of solvent-free conditions is reported with single-mode reactors aswell,127 and modifying the domestic oven with pressure valves. The popularity ofdomestic microwave ovens is an effect of the considerably higher prices for the single-mode apparatus combined with the availability of the multi-mode ovens. In fact, thereare not many companies that manufacture single-mode ovens commercially, but theneed for controlled and fast synthetic processes has lately created a substantially higherdemand for single-mode ovens in combinatorial chemistry.128 There is also a possibilitythat microwave chemistry can be used to reduce the environmental damage that often isassociated with chemistry at an industrial scale.129 The development of single-mode
31
microwave chemistry is still dynamic and it is at present difficult to predict its precisedevelopment in the future.
3.1.2 General PhysicsElectromagnetic radiation, such as ultraviolet light, is well known to be able to transferenergy. Microwaves, which is a form of electromagnetic radiation with a frequencyrange of 0.3–300 GHz (Scheme 38),130 is no exception and can be used to transferenergy as long as the medium that is to be heated is able to absorb radiation in themicrowave range.
In order to avoid disturbance with telecommunications and radar, which both utilisefrequencies in the microwave range, have two frequencies been allotted for microwaveoven use: 900 MHz (λ = 33.3 cm) and 2.45 GHz (λ = 12.2 cm). Most commercialovens, both single- as well as multi-mode, use the 2.45 GHz frequency.
The term “dielectric heating” is frequently used when microwave heating is discussed.A dielectric material contains either permanent or induced dipoles, which can functionas a capacitor that can store charge when placed between two electrodes.131 Heating canbe induced, mainly through polarisation and ion conductance, when microwaveirradiation is applied. The polarisation consists of several parameters:130
Scheme 38: The Electromagnetic Spectrum.
32
αt = αe + αa + αd + αi
where the total polarisation (αt) is described by the sum of the electronic (αe), atomic(αa), dipolar (αd) and interfacial (αi) polarisations. These different forms of polarisationhave different speeds with which they can be realigned in an oscillating microwavefield. The electronic and atomic polarisations are not of interest in microwave chemistryas the response time, or lag factor τ, due to αe and αa is considerably faster than thefrequency of the field and as a consequence is no, or very little, energy transferred to themedium as a result of these effects. The lag time for the dipolar polarisation (αd) is, onthe other hand, similar to the microwave frequency. The polarisation can then lagbehind the oscillation of the field and electromagnetic radiation can be converted intoheat.130,131
The efficacy with which a certain medium can be heated by means of microwaveirradiation can be described by the factor tan δ, the dielectric loss tangent, which isdefined as the quota of the dielectric loss ε’’ (the efficiency with which electromagneticradiation can be converted into heat) and the dielectric constant ε’ (the ability of amolecule to be polarised by an electric field).
tan δ = ε’’/ε’
The tan δ value can thus describe the ability of a material to convert electromagneticenergy into heat at a given frequency and temperature.130 It should be noted that the tanδ value could in some liquids vary markedly with temperature. In the examples of waterand ethanol is the tan δ value considerably smaller at higher temperatures. A list of thetan δ values of some common solvents has been published by Mingos.131 The choice ofsolvent can, as a consequence, be of great importance when the reaction conditions formicrowave-heated reactions are considered and nonpolar solvents, with low tan δvalues, should in most cases be avoided.
The other mechanism through which heating can be transferred to a reaction medium isionic conductance. The addition of salts to increase the ionic conductance or a minoramount of polar solvent can in many cases suffice to raise the ability of the reactionmedium to absorb microwave irradiation if unpolar solvents are vital for the reaction.131
When an oscillating microwave field is irradiated through a solvent with ions will theions also oscillate and transfer heat to the reaction medium through friction. It shouldfor safety reasons be pointed out that the heating due to ionic conductance has atendency to increase with higher temperatures and if care is not taken can thetemperature rise unpredictably fast (the so called “thermal runaway effect”) with aconcomitant risk of reaction vessel rupture and explosion.
33
Interfacial polarisation (αi) can occur as a build-up of charges takes place betweenliquid-liquid interfaces; the so-called Maxwell-Wagner effect. This effect is not as wellunderstood as the dipolar polarisation but in an examination of interfaces betweensoybean oil and water has αi been suggested to be important.132 Microwave irradiationhas also proved to be of use in phase-transfer catalysis,133 where the interface areashould be large.
3.1.3 Rate Enhancements with Microwave ChemistryThe sometimes remarkable rate enhancements reported with microwave-heatedreactions have fuelled a debate whether there is a specific effect on the reactingmolecules from the microwaves, apart from the increase in temperature, that speeds thereaction (the so called non-thermal microwave effect). This effect could be explained,for example, by storage of microwave energy in the vibrational energy of a molecule(enthalpic effect) or by an alignment of molecules (entropic effect).134 An increasingamount of reports135,136 seem to disfavour the non-thermal microwave effect as theenergy transmitted by the microwaves is too weak to cleave a chemical bond(approximately 1 J/mol,135 0.3 kcal/mol137). Stuerga and Gaillard have presented anumber of conclusions for why the non-thermal microwave effect is non-existent.135
The three most important of which are:1. The energy of the microwave photon is too low to break chemical bonds (10-5
eV135).2. The electric field strength in microwave ovens cannot induce shifting in chemical
equilibria.3. The electric field strength is too low to induce organisation. Dipolar moments
remain randomly distributed due to thermal convection.
If we are to assume that the non-thermal microwave effect is imaginary there must beother important factors that can account for the rate-enhancements of microwavechemistry (thermal microwave effects). Mingos has presented four advantages ofmicrowave heating, compared to conventional, thermal heating, which are discussedbelow:131
1. A very high heating rate, compared to thermal reactions, can be achieved if themicrowaves can interact with at least one component in the reaction mixture.
2. The nature of the electromagnetic radiation allows for heating where there is nocontact between the heating medium and the heated material. For the syntheticchemist this phenomenon is most importantly embodied in the absence of wall-effects with microwave heating. The wall-effect is created when a reaction vessel of,in most cases, low temperature is put in a reaction medium, such as an oil-bath, with
34
high temperature. A temperature gradient will be created in the reaction mixture,where the temperatures closest to the walls of the vessel may be considerably higherthan the temperatures in the bulk of the reaction mixture.129 In palladiumchemistry,138 this has been suggested to be a source of catalyst deactivation and theprospect of doing chemistry without wall-effects is thus promising for applicationsin organometallic chemistry.
3. Selective heating can be attained when different materials or reactants interact to adifferent degree with microwave irradiation. In the specific case of organometallic-and palladium chemistry has the possibility of hot spots136 around the metalcatalyst136 been discussed. The local higher temperatures around the catalyticallyactive species should, if the complex can withstand the higher temperatures, result infaster reactions.
4. The selective interactions mentioned above also imply that microwave chemistry iswell suited for reactions conducted under high pressure. “The pressure cookereffect” is frequently hailed as one of the main factors behind the rate enhancementof reactions performed in closed vessels. A dramatic increase in turnover numbershas been reported in palladium-catalysed reactions conducted under high-pressureconditions.139 Running a reaction in a closed vessel under increased pressurepresents the opportunity of heating the reaction medium above the normal boilingpoint of the solvent. Depending on the solvent used can the boiling point be raisedsignificantly over the boiling point at atmospheric pressure140,141 and the highertemperatures in themselves are capable of inducing faster reactions. Gedye and Weihave investigated the rate enhancement of microwave irradiation at atmosphericpressure142 and draw the conclusion that rate-enhancements of synthetic reactions donot occur as easily under microwave heating in open vessels and that no non-thermal microwave effect can be discerned. The same authors refer the slight rateenhancements that at some instances were found to the presence of local hot spots inthe reaction medium.
35
3.2 Fluorous Chemistry
3.2.1 HistoryThe characteristic of fluorine that is taken advantage of in fluorous chemistry is theinability of perfluorinated or highly fluorinated compounds to be dissolved in organicsolvents or water.143 A separation in an ordinary separation funnel with a perfluorinatedsolvent, such as FC-84, dichloromethane and water gives rise to a three-phase systemwith the fluorinated phase at the bottom. The physical bases for the poor solubility offluorinated solvents are their low surface tensions, low intermolecular interactions, highdensities and low dielectric constants. They are also nontoxic, stable (due to the stabilityof the C–F bond) and, unlike the freons, relatively environment-friendly.144 Horváth andRabái introduced the term “Fluorous Biphasic Systems” (FBS) where fluorinatedrhodium catalysts were used in the hydroformylations of olefins.145,146 The concept wasfurther developed by Curran, who presented synthetic strategies where fluorinated tagswere used to introduce samples in the fluorous phase with the aim of ameliorating thepurification step (Scheme 39).147-149
One further benefit of this strategy is the possibility of recycling expensive ligands andlikewise expensive metal catalysts bound to the ligands.150,151 Once the tag or ligand isisolated in the fluorous phase can the fluorous solvent, which has a low boiling pointdue to its low polarisability and low intermolecular forces, easily be removed underreduced pressure and collected. Fluorinated solvents have other interesting properties aswell, such as a high ability to dissolve oxygen gas. This has been taken advantage of inmedicinal technology, where fluorinated solvents have been used as oxygen carriers inthe treatment of lung failure.152
3.2.2 Applications in Modern ChemistryDue to the insolubility of highly fluorinated compounds in water or organic solventshave various synthetic strategies been used in order to allow the full mixing, aprerequisite for successful chemistry, of the fluorous with the non-fluorous reagents.Fully fluorinated compounds are thus for solubility reasons seldom used but rather tagswith a varying degree of fluorination.149,153-155 Large compounds with a high molecular
F Substrate+ F Substrate Reagents F Product + excess Reagents
Purification F Product Detachment F Product+
Scheme 39: Example of Curran's Fluorous Synthetic Strategy.
36
weight need a higher fluorine content in the attached tag in order to be fully distributedto the fluorous phase than small compounds with low molecular weights.156,157 Indeed,the mass percentage of fluorine atoms compared to the total amount of non-fluorousatoms can usually give a good approximation of the solubility in fluorous media.Horváth has recommended a fluorine content of at least 60% in order to ensure a goodpartitioning to the fluorous phase.146 A recent addition to the discussion is a report byGladysz where the fluorous phase affinities for a number of benzenoid compounds withvarying degrees of fluorination are investigated.158
Different methods have also been used in the measurement of how fluorous a compoundis. Rabái introduced the term fluorophilicity (f),159 where f = lnP and P is the partitioncoefficient of the compound over perfluoro(methylcyclohexane) and toluene at 25 °Cwhile Horváth and Hughes have analysed fluorous partition coefficients PFBS = cFluorous
phase/cOther phase, where the perfluorinated heptane was used as the fluorous phase andtoluene as the organic.160
It has been found that, when fluorous tags are used, the inductive power of the fluorousatoms can influence the reactivity of the tagged molecule. In order to prevent this isoften a spacer introduced at the end of the tag, where it connects with the reactant orproduct (Scheme 40).146
Fluorinated alkyl tails separated from the rest of the tag with a spacer have been provento be more advantageous than fluorinated aryl groups, partly due to the risk of aromaticinteractions when the latter is used.161 The ideal length of the spacers has been thesubject of several papers.153,154,162 Some reports question if the ethylene spacer is longenough to insulate properly154 and other have found the propylene spacer moreunstable.162 The use of longer spacers does not seem to be of value and may increase therisk of micelle creation.146 The inductive effect of the perfluorinated tail has also beenused in reactions where fluorous tags were found to react faster than non-fluoroustags,163,164 although there are other reports where the reactivity is similar162 or lower165
with fluorous compounds.
R-Sn(CH2CH2C10F21)3
Scheme 40: Stille Reactant with Three Fluorous Tags.
Spacer Fluorous Tag
37
Another parameter that can be adjusted to improve the solubility and mixing offluorinated and non-fluorinated molecules is the solvent. Hybrid solvents, such as BTF(C6H5CF3)166 with fluorous as well as organic properties, can dissolve organic as well asmost fluorinated molecules, especially at elevated temperatures. One effect that isregularly noted in fluorous chemistry is the insolubility of the fluorous phase with thehybrid or non-fluorous phases at room temperature. When heating is applied will thesolubility of the two phases increase and a one-phase system appears that upon coolingto room temperature will recreate the two-phase system. If the solubility of thefluorinated phase is too poor, most often due to a high degree of fluorination, may theintermixing of the phases not occur, with an ensuing synthetic failure.
It is from this discussion possible to reach the conclusion that in order for a successfulfluorous synthetic strategy to be realised must the fluorine content of the tags becontrolled; too high a degree of fluorination may result in an insoluble fluorous phasethat cannot react with non-fluorinated reagents and a too low degree will, on the otherhand, give leaching of the fluorinated content into the organic phase. An important andinteresting application of lightly fluorinated tags has been applied by Curran in the useof fluorous reverse phase (FRP) chromatography.167-169 In this context are moleculeswith a low degree of fluorination beneficial, as a good separation can be fulfilled byeluting non-fluorous compounds with 80% MeOH/H2O and later the fluorouscompounds with acetonitrile.169
If the reaction conditions and choice of reagents can be controlled to ensure a smoothseparation can fluorous chemistry be used to good effect in synthetic strategy.149 Whentoxic compounds, for example the tin reagents used in the palladium-catalysed Stille–reactions, have to be used, it would be not only convenient but also environmentallyadvantageous if the toxic compounds could be easily separated from the reactionmixture. Curran has used fluorous tags on tin reagents that enable not only theseparation of the tin compounds but also the possibility of recycling them for furthersynthesis.151 This is of importance as tin compounds are difficult to isolate from thereaction mixture.170 In radical-mediated reactions has the use of catalytic amounts (10%) of tin hydride in combination with the reducing agent NaBH3CN171 been shown togive full conversion in a coupling of adamantyl bromide with acrylonitrile.151
38
4 Aims of the Present Study
The aims of the present study were:a) To study and improve the regiocontrol in the Heck-reaction by developing novelsynthetic methods of arylation at the internal carbon of selected allylic systems ofparticular interest for medicinal chemistry. The allyltrimethylsilane compounds werechosen due to their synthetic usefulness and the allylamine substrates for their potentialas bioactive compounds. Furthermore, the heteroatoms of the two types of olefins,encompassing C=C–C–Si and C=C–C–N fragments respectively, were foreseen to exertan impact on the regiocontrol of the Heck-reaction that was thought to be important toassess.
b) To use the internal arylation of allylic substrates to develop short and attractivesynthetic strategies for MAO-B and SSAO inhibitors.
c) To investigate the effects of single-mode microwave heating on chemical reactionswith the aim of reducing the reaction times without compromising the regioselectivityand efficacy of the reactions.
d) To explore the use of heavily fluorinated tags and their applications in microwave-heated reactions.
39
5 Results and Discussion
5.1 Highly Regioselective Internal Arylation of Allyltrimethylsilane (Paper I)
β-Arylated compounds of the type 45 had previously been synthesised using mono-dentate ligands and aryl iodides, e. g. by regioselective phenylation of 44 at 120 °C inthe presence of silver salts (Scheme 41).46
Allyltrimethylsilane was arylated terminally, producing mainly 46, by palladium andmonodentate ligands with aryl halides as aryl precursors. The addition of silver salts,which was thought to produce a cationic palladium by halide scavenging (Scheme 13),produced the double-bond isomer 47 and small amounts of 45 (Scheme 41).46 A studywas undertaken to investigate if the direct synthesis of compounds 45 could be broughtabout through a regioselective Heck-coupling of aryl triflates with allyltrimethylsilaneand a palladium/bidentate ligand catalytic system (Scheme 42).
Several bidentate ligands were investigated (dppp, BINAP, dppb, dppe) but none gavethe same high and reproducible regioselectivities as dppf.55,56 Monodentate ligandsinvariably produced very poor regioselectivities. The reaction can due to the choice ofaryl triflates as aryl precursors and a bidentate ligand be taken to go through the cationicpathway. The polarisation of the double bond of the allyltrimethylsilane would lead to apreferred arylation at the internal carbon of the olefin, partly due to the greater ability ofthe internal, secondary carbon compared to the primary, terminal carbon to stabilise a
OTf SiMe3
R R+
Pd(OAc)2dppf
45
SiMe3 +R
46
SiMe3
Scheme 42: Palladium/dppf-Catalysed Internal Arylation of Allyltrimethylsilane.
48
ISiMe3Me3Si Pd(OAc)2, PPh3
AgNO3, 120 oC
SiMe3+
44
Scheme 41: Previous Syntheses of Arylallyltrimethylsilanes.
46 47
SiMe3 SiMe3
45
40
burgeoning positive charge and partly due to the documented β-stabilising effect of thesilicon group (Scheme 43). The transition state 49 in Scheme 43 is depicted to underlinethe β-stabilising effect and is not a true estimation of the insertion process, which isbelieved to be concerted.39,40
Aryl triflates with a wide range of functionalities could be coupled with high regio-selectivity and moderate to high isolated yield (Scheme 44). The electron-poor aryltriflates 48g and 48h and the ortho-substituted 48c needed a higher reaction temperature(80 °C vs. 60 °C for the other aryl triflates) to reach full conversion in over-nightreactions. Most couplings produced a small amount of the terminally, γ-arylated 46, inaddition to the desired 45 (Scheme 42).
The yields were lowered due to formation of side-products by a) aryl migration, b)deoxygenation of the aryl triflates and c) desilylation of the products.
Aryl migration occurred mainly with the electron-rich aryl triflates (48a and 48b). Itwas also noted in line with earlier results67 that the ortho-substituted electron-rich aryltriflate 48c gave a lower degree of aryl migration compared to the para-substitutedelectron-rich 48a and 48b.
Deoxygenation of the aryl triflates occurred particularly with the electron-poor aryltriflates. This side reaction could be reduced by switching from an organic base (Et3N)to an inorganic (K2CO3)75 as one source of hydrides for the deoxygenation of triflatescould be amine bases (Scheme 24).77 The triethylammonium formate-catalyseddeoxygenation of triflates has been found to occur more easily when electron-poor aryltriflates and non-coordinating solvents are used.172 Aryl triflates are also more readilyreduced by electrochemical reactions when substituted by electron-withdrawinggroups.173
Desilylation of the product to the corresponding α-methyl-styrene derivatives was notedespecially in the reactions conducted at 80 °C (entries 3, 7–8; Scheme 44).
LL
XAr
LL
Ar
SiMe3
Me3Si
PdLL
Ar
Me3Si
PdLL
-X
X = OTf, OAcMe3Si
Pd
Ar
Pdγβ
α
ArSiMe3
Scheme 43: Internal Arylation of Allyltrimethylsilane.49
41
SiMe3
MeO
SiMe3
t-Bu
SiMe3Me
MeSiMe3
SiMe3
SiMe3
Cl
SiMe3
SiMe3
O
Me
NC
Me
Cl
ProductIsolated Yieldb
45+46
97/3
94/6
100/0d
95/5
98/2
98/2
94/6
100/0d
42%
47%
60%
67%
77%
85%
31%
59%
45a
45b
45c
45d
45e
45f
Selectivitya
45/46
45g
45h
Temp. (oC)
60
60
80
60
60
60
80
80
Reaction Time/Microwave Powerc
Selectivitya
45/46 GC-MS Yield 45+46
5 min/50 W
5 min/50 W
5 min/50 W
5 min/50 W
5 min/50 W
7 min/50 W
10 min/50 W
78/22e
88/12f
93/7e
92/8
97/3
97/3
34%
69%
66%
62%
66%
54%
28%100/0d
7 min/60 W 48%100/0d
Scheme 44: Internal Arylation of Allyltrimethylsilane with Aryl Triflates 48.
Thermal Reactions Microwave-Heated Reactions
Entry
1.
2.
3.
4.
5.
6.
7.
8.
The thermal reactions were run in 2.5 mmol scale under nitrogen atmosphere at 60 oC (entries 1-2, 4-6) or 80 °C (entries 3, 7-8) with 1 equiv of 48a-h; 0.03 equiv of Pd(OAc)2, 0.132 equiv of dppf, 5 equiv of allyltrimethylsilane; 2 equiv of base (Et3N for entries 1-5, K2CO3 for entries 6-8) and 10 mL of fresh acetonitrile. All reactions were completed after 20 h. The microwave reactions were run in 1.0 mmol scale in sealed Pyrex tubes with septa under nitrogen atmosphere and heated by means of microwave irradiation. The microwave heated reactions were run in 1.5 mL of fresh acetonitrile with 1 equiv of 48a-h, 2.5 equiv of allyltrimethylsilane, 0.03 equiv of Pd(OAc)2, 0.132 equiv of dppf and 2 equiv of base (Et3N for entries 1-5, K2CO3 for entries 6-8) aSelectivity internal β-arylation/terminal γ-arylation. Determined by GC-MS and 1H-NMR. b>95% by GC-MS. cContinuous irradiation at 2450 MHz. dOnly product 45 detected byGC-MS. eThree isomeric products detected by GC-MS. fFour isomeric products detected by GC-MS.
42
The regioselectivities of the arylation of allyltrimethylsilane were found to be high anda comparison with 4-methyl-1-pentene, an olefin where the β-effect of silicon does notinfluence the regioselectivity, indicated a higher tendency in the case of allyltrimethyl-silane to favour arylation at the internal β-carbon (Scheme 45). The arylation of 4-metyl-1-pentene generated four products with the right m/z as analysed by GC–MS andthe selectivity for internal arylation was gauged by hydrogenation of the double bondswith Pd/C and H2 and subsequent analysis of the two resulting internally and terminallyarylated isomers by GC–MS and 1H–NMR.
In a competitive experiment where one equivalent each of allyltrimethylsilane and 4-methyl-1-pentene were added to the reaction mixture was the allyltrimethylsilanearylated 5.5 times more easily than the alkene, which might indicate a reduced energybarrier, presumably due to β-stabilisation, in the rate-determining insertion step.
A series of single-mode microwave heated reactions was also performed (Scheme 44).The reaction times could be effectively reduced from thermally heated over-nightreactions (<20 h) to 5–10 minutes with microwave heating; a truly dramatic reduction inreaction time without far-reaching consequences for the outcome of the reaction. Theregioselectivities under microwave heating were generally slightly lower than thecorresponding thermal reactions, except for the synthesis of 45g, where theregioselectivity was raised from 94/6 (thermal heating) to 100/0 (microwave heating).The electron-poor aryl triflates needed longer reaction times and higher microwaveinput than the electron-rich aryl triflates, which is reminiscent of the tendency in thethermal reactions, where the electron-poor aryl triflates also needed highertemperatures.
The lower regioselectivity noted in many of the microwave-heated reactions could becaused by the problem of controlling the reaction temperature. Under microwave-irradiation can the reaction temperature be raised high above the boiling point of thesolvent and in many cases were visible signs of catalyst decomposition present in thereaction mixtures (palladium-black, palladium-mirror). It could be seen in thermalreactions, where the temperature could be controlled more easily, that when the reactiontemperature was raised from 60 °C to 80 °C was also the regioselectivity in many casesbetter. There are thus reasons to assume that there is a delicate balance between a faster
SiMe3
Scheme 45: Comparative Regioselectivities in the Phenylation of Allyltrimethylsilane and 4-Methyl-1-Pentene.
5
95
14
86
43
and more efficient Heck-coupling with a higher regioselectivity (by a moderately highertemperature) and catalyst decomposition (due to too high temperatures) and,presumably in the case of microwave-heated reactions, hot-spots around the catalystmetal. This balance was difficult to control with the present microwave cavity, wherethe reaction temperature could not be controlled by any other means than by themicrowave power input and reaction time.
To further evaluate the influence of the β-effect on the regioselectivity in the Heck-reaction were couplings made where the nature of the olefin and the triflate were subjectto variation (Scheme 46).
Couplings with phenyl triflate and a Pd(OAc)2/dppf system with vinyl silane and 3,3-dimethyl-1-butene resulted in the formation of 50 and 51 in poor regioselectivities; thesynthesis of 50 also produced a considerable amount of styrene. The arylation of 50could be expected to result in a mixture of regioisomers as the polarisation of the olefinshould favour internal- and the β-stabilisation terminal arylation. The 3,3-dimethyl-1-butene induced a somewhat higher ratio of internal arylation. The terminallydisubstituted 1,1-dimethyl-3-(trimethylsilyl)-1-propene was unreactive and no trace of52 could be detected by GC–MS even at elevated reaction temperatures. The use ofvinyl triflates, such as the cyclohexenyl triflate, produced 53 along with a mixture ofproducts (Scheme 46) and changing the bidentate ligand dppf to four equivalents of themonodentate ligand PPh3 did not result in a regioselective synthesis of 46d but in acomplex mixture of stereo- and regioisomers. Couplings under our standard reactionconditions with aryl bromides in the presence of thallium- or silver salts43 instead of aryltriflates also resulted only in complex mixtures of stereo- and regioisomers. If twoequivalents of bidentate ligand was used instead of 4.4 equivalents were the reactionsconsiderably slower (2–3 days) and the yields tended to be lower although theregioselectivities were largely unchanged.
SiMe3
SiMe3
SiMe3 NR50
51
52
Selectivity (Internal/Terminal)
71/29
89/11 75/2553
Product Selectivity (Internal/Terminal)Product
Scheme 46: Regioselectivity in the Heck Reaction.
44
A highly regioselective method for the synthesis of the terminally arylated 46 underphase-transfer conditions at room temperature was recently published, where smallchanges in the reaction conditions could allow the formation of the desilylated product54 in high yield with no detectable production of 46 (Scheme 47).174
We made a considerable effort to synthesise the internally arylated allyltrimethyl-stannane 55 (Scheme 48) from aryl triflates and allyltrimethylstannane as the β-stabilisation of tin is reported to be considerably higher than that of silicon.97
The present reaction conditions were evidently not suitable for the synthesis ofinternally arylated allylstannanes as no product formation was seen by GC–MSanalyses. A high degree of destannylation and formation of α-methylstyrene was noted.The product 55 could easily be synthesised by lithiation175 as in Scheme 49, provingthat the instability of 55 was not the only reason for the failure of the palladium-coupledreaction.
In short, the bidentate-controlled arylation of allyltrimethylsilane with aryl triflates wasshown to produce the internally arylated 45 with good regioselectivity. This reactioncomplements our previously published syntheses of the isomers 46 and 47, usingmonodentate ligands.
I+ SiMe3
Pd(dba)2, DABCOn-Bu4NCl
Pd(dba)2, cat. PPh3n-Bu4NOAc
SiMe3
46
54
Scheme 47: Synthesis of 46 and 54 by Heck-Arylation under Phase-Transfer Conditions.
SnR3
OTf SnR3+ Pd(OAc)2, dppf
K2CO3, CH3CN55
Scheme 48: Failed Internal Arylation of Allyltrimethylstannane.
SnMe31. BuLi, KOt-Bu
2. ClSnMe3
Scheme 49: Synthesis of Internally Arylated Allyltrimethylstannanes by Lithiation.
55
45
5.2 Highly Regioselective Internal Arylation of N,N-Dialkylallylamines andPrimary Allylamine Equivalents (Paper III and IV)
The success of the internal arylation of allyltrimethylsilanes encouraged theinvestigation of internal arylation of other allylic substrates. In our medicinal chemistryprogram we had had the need to insert amine functionalities with different chain lengthsfrom an aryl backbone and the synthesis of compounds 56 (Scheme 50) appeared to beof high interest as primary allylamines had been reported to yield chiefly polymers inHeck-couplings.176
It was soon apparent that the regioselectivities in the arylations of N,N-dialkyl-allylamines were higher than the regioselectivities encountered with allyltrimethyl-silanes and a different reaction mechanism was anticipated. The internal arylation ofN,N-dialkylallylamines could go through an energetically favoured five-membered ringsystem 57, generating compounds 56 in excellent regioselectivity (Scheme 51).
A number of different aryl triflates were coupled with N,N-dimethylallylamine withvery high regioselectivities and moderate to high isolated yields under thermal as wellas single-mode microwave heating; the latter method proved efficient, just as in thereactions with allyltrimethylsilane, to reduce the reaction times to a couple of minutes(Scheme 52). The deoxygenation of the aryl triflates that occurred under the arylation ofallyltrimethylsilane hampered the reactions with N,N-dimethylallylamine as well. Theuse of 1,2,2,6,6-pentamethylpiperidine (PMP) as base resulted in higher isolated yieldsin a few cases, but when deoxygenation occurred was the inorganic potassium carbonatesuperior (Scheme 52). When a change of base did not increase the yield was a higheramount of catalyst effective, although this, in turn, resulted in a higher degree of arylmigration, especially with the electron-rich aryl triflates.
NR2
Pd
Ar
L L
57
ArNR2
56
PdL L
Ar X
NR2Pd
NR2
Ar
LL
X=OTf, OAc, SolventR= Alkyl
Scheme 51: Coordination-Controlled Internal Insertion of N,N-Dialkylallylamines.
-X
OTfNR2+
80 oC, 20 h or microwave 3-5 min
NR2
56R=Alkyl
Pd(OAc)2, dppf, Base, CH3CN or DMF
Scheme 50: Internal Arylation of N,N-Dialkylallylamines.
R R48
46
NMe2
MeO
NMe2
NMe2Me
Me
NMe2
NMe2
NMe2
Cl
NMe2
O
Me
NMe2
NC
NMe2
MeO
NMe2
MeO
OMe
Me
Cl
A
A
A
B
C
C
B
D
B
D
t-Bu
Scheme 52: Internal Arylation of N,N-Dimethylallylamine with Aryl Triflates 48.
Entry Product Isolated Yield 56 (%)d
1.
4.
5.
6.
7.
8.
9.
10.
40
35
81
42
71
38
48
50
56i
56b
56c
56d
56e
56f
56g
56h
β/γc
94/656a
56j
4192/8
49
93/7
100/0e
100/0e
100/0e
100/0e
100/0e
100/0e
2.
3.
Microwave Heatingb
Isolated Yield 56 (%)d
30
21
48
24
42
β/γc
95/5
3592/8
46
84/16
96/4
88/12
100/0e
Time (min)/ Effect (W)
3/20
5/20
5/20 100/0e
5/15
5/15
5/15
5/15
Thermal Heatinga
f
f
f
99/1
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
Et3N
PMP
PMP
Method
aThe thermal reactions were run in 2.5 mmol scale under nitrogen atmosphere at 80 oC with 1 equiv of 48a-j; Pd(OAc)2, see Methods below; dppf, see Methods below; 5 equiv of N,N-dimethylallylamine; base, see Methods below; and 10 mL of acetonitrile. Method A (entries 1-3): 0.03 equiv of Pd(OAc)2, 0.132 mmol of dppf, 1.5 equiv of K2CO3. Method B (entries 4, 7, 9): 0.06 equiv of Pd(OAc)2, 0.264 equiv of dppf, 1.5 equiv of K2CO3. Method C (entries 5-6): As Method A but with 2 equiv of triethylamine instead of K2CO3. Method D (entries 8, 10); As Method A but with 2 equiv of PMP instead of K2CO3. All reactions were completed after 20 h. bContinuous irradiation at 2450 MHz. The microwave heated reactions were run in 1.0 mmol scale in septum-sealed Pyrex tubes with 1 equiv of 48a-j, 3 equiv of N,N-dimethylallylamine, 0.03 equiv of Pd(OAc)2, 0.132 equiv of dppf and 1.2 equiv of K2CO3 in 1.0 mL of DMF. cSelectivity internal β−arylation/terminal γ-arylation. Determined by GC-MS and 1H-NMR.d>95% by GC-MS. eOnly one product detected by GC-MS. fNot isolated.
47
The allylamines 3-piperidino-1-propene and 3-morpholino-1-propene were phenylatedwith excellent (>99.5/0.5) and moderate (88/12) regioselectivity, respectively, withphenyl triflate giving the products 58 and 59 in 50% and 56% isolated yield (Scheme53). The lower regioselectivity of 59 might be the result of a competing coordination ofpalladium to the oxygen in the morpholino moiety.
The internal arylation of N,N-dialkylallylamines was found to be sensitive of hightemperatures and the raising of the reaction temperature above 80 °C invariably resultedin poorer yields due to formation of palladium-black and tar. Polymers have previouslybeen noted as a side-product in palladium-catalysed reactions with allylamine.176
The microwave-heated reactions with the electron-poor aryl triflates were difficult tooptimise compared to the thermally heated couplings due to the poor control of thereaction temperature. Temperature curves were made with fluoroptic probes in reactionsrun under microwave irradiation with DMF as solvent, indicating a reaction temperatureclose to 200 °C at 15 W, microwave power (Scheme 54).
Scheme 54: Temperature Curve for Entry 5, Scheme 52.
N NO
58β/γ >99.5/0.5Isolated Yield: 50%
Scheme 53: Internal Phenylation of 3-Piperidino-1-Propene and 3-Morpholino-1-Propene.
59β/γ = 86/14Isolated Yield: 56%
0
50
100
150
200
250
0 60 120 180 240 300 360 420 480
Seconds
Deg
rees
Cen
tigra
de
48
A tendency for the thermally heated internal arylations of N,N-dimethylallylamines toyield higher regioselectivities with sterically unhindered electron-poor aryl triflates(entries 9–10, Scheme 52) than with sterically unhindered electron-rich aryl triflates(entries 1–2, 4; Scheme 52) could tentatively be explained by an inductive effect fromthe aryl group (Scheme 55). Partially sterically hindered aryl triflates (entries 3, 5, 7–8;Scheme 52) generally give higher regioselectivities than unhindered aryl triflates.Substrates with a high degree of steric hindrance (e. g. 2,6-dimethylphenyl triflate) giveno product.
The higher regioselectivities for couplings with electron-poor aryl triflates are difficultto explain. Aryl groups with electron-withdrawing substituents 60 might throughinduction produce a slightly more electropositive palladium that would rather add to theterminal carbon as the internal position of the olefin easier could support a lower chargedensity than the terminal. Aryl groups with electron-donating substituents 61 wouldcreate the opposite effect. Alternatively could the electropositive palladium in 60coordinate tighter to the nitrogen and create a more stable intermediate than 61 and thusinduce a slightly higher regioselectivity. This inclination of electron-poor aryl triflatesto give a higher regioselectivity is not as clear in the microwave-heated reactions due tothe difficulty of controlling the reaction temperature under microwave irradiation. Theinternal arylations of allyltrimethylsilanes do not show any marked difference in regio-selectivities between electron-rich and electron-poor aryl triflates.
Compounds with the general structure 62 have in the search for new anti-tumour agentsreceived attention as protein tyrosine kinase inhibitors177 and epidermal growth factor-receptor inhibitors178 (Scheme 56).
Pd2+L L
NMe2 Pd2+L L
NMe2
Scheme 55: The Effect of the Electron Density of the Aryl Triflate on the Regioselectivity.
EWG EDG60 61
O
R
NR2
62Scheme 56: General Structure of a Group of Anti-Tumour Agents.
49
Although carbonylative Heck-couplings with allylamines to the best of our knowledgehave not been reported, we nevertheless decided to test the reaction as it, if it were tosucceed, would be a very convenient synthesis of 62. Instead of 62, which was notformed, we found a relatively high formation of 63 (30% isolated yield, non-optimised).The exact mechanism for this deallylation is not known to us, but a suggestedmechanism is presented in Scheme 57. A similar deallylation has been publishedpreviously.179
The internal arylation was also successfully applied on allyl alcohol 64, as haspreviously been published by Cabri,41 and with lower regioselectivity on allyl ethylether 65 (Scheme 58). A similar coordination between palladium and the oxygen,resulting in a five-membered intermediate, might be envisioned in these couplings, aswas suggested in the case of the internal arylation of N,N-dialkylallylamines.
Scheme 58: Regioselectivities with Allyl Alcohol and Allyl Ethyl Ether.
OH
>99.5
<0.5O
88
12
64 65
PdLL
TfO Ph
CO PdLL
C Ph-OTfPd
LL
PhO
NMe2Pd
LL
Me2N
PdLL
O
Me2NPh
OPh
PdLL
+ Ph NMe2
O
Scheme 57: Suggested Mechanism for the Formation of N,N-Dimethylbenzamide.
63
O
50
A direct comparison between allyl alcohols and allylamines may not be appropriate.The primary allylamine does not yield any product under the present reaction conditions(see below) in contrast to the primary allyl alcohol and the regioselectivity falls when anethyl substituent is added to the allyl alcohol, while the tertiary N,N-dimethylallylaminecouples readily with excellent regioselectivity. Whether the poor regioselectivity of allylethyl ether is due to changes in the electron density or steric hindrance is unclear but ithas been suggested that primary alcohols can be deprotonated in the reaction medium ofpalladium-catalysed reactions (Scheme 59).180 The deprotonated anionic allyl alcohols66–67, as reported by Kang, may coordinate more efficiently to the palladium and thismay well lead to a better regioselectivity compared to the ether, which cannot bedeprotonated.
Partly inspired by Blart and Ricci’s success with the internal arylation of 68122 (Scheme60),
we anticipated that a direct synthesis of internally arylated protected allylamines, suchas 69 and 70 (Scheme 61), might be possible without the vinylic trimethylsilyl group of68.
OPd
ROH
I
Ph
HH O
Pd
ROH
H
HHPh I
Scheme 59: Five- or Four-Membered Intermediates Formed Through Coordination Between Palladium and an Anionic Oxygen.
66 67
HN
BocHN
Boc
I
+ Pd(OAc)2, DppbMe3Si
Scheme 60: Synthesis of 69 by Internal Arylation of 68.
68 69MeO MeOEt3N
ArOTf
HN
Boc ArHN
BocPd(OAc)2, dppf
NPht ArNPhtPd(OAc)2, dppf48
+
βγ K2CO3, CH3CN
80−90 oC, <20 h
90 oC, 2−4 daysK2CO3, DMF
Scheme 61: Internal Arylation of Allylamides and Allylimides.
69
70
51
The ability to synthesise internally arylated allylamides and –imides through a one-stepHeck-reaction would open a new and very convenient synthetic route to primaryallylamine equivalents. The primary allylamine 71 (MDL-72274)181 (Scheme 62) hasbeen evaluated as an SSAO-inhibitor,182 a new and very interesting class of compoundsthat recently has found applications in several fields of medicinal chemistry.183-187 Asynthesis of MDL-72274 from 70 has been published.188 3-Halo-2-phenylallylamines ingeneral are well characterised as irreversible enzyme inhibitors189-191 and 70 has beenused in several other syntheses of enzyme inhibitors.188,192,193 The (E)-3-chlorosubstituent is vital for the selectivity for SSAO-receptors over MAO-B receptors.181
Other structural analogues of 71 have also been tested for MAO-B activity, although thecompounds with the highest selectivity for the MAO-B receptor seem to be the (E)-3-fluoro-substituted compounds, such as MDL-72145 72. The latter compound wasevaluated as an MAO-B inhibitor but was never marketed due to reports of haemolyticanaemia190 and was later further developed into Mofegiline 73, a drug registered foruse against Parkinson’s disease (Scheme 62).
A number of couplings between aryl triflates and Boc- (Scheme 63) and phthalimido-protected allylamines (Scheme 64) were made with thermal as well as microwaveheating.
The regioselectivities were excellent with the secondary Boc-protected allylamine,especially with thermal heating, although the microwave-heated reactions also gave avery high preference for arylation at the internal carbon. One interesting result was therelatively high yield for the microwave-heated reaction with Boc-protected allylamineand 48f (entry 6, Scheme 63) as compared to the thermal reaction. The tertiaryphthalimido-protected allylamines needed longer reaction times and resulted inmoderate to very poor regioselectivities, although a few aryl triflates (entries 3 and 5,Scheme 64) could be coupled with good regioselectivity.
NH2
F
MeOMDL-72145
MeONH2
Cl
ClMDL-7227471 72
F
NH2
FMofegiline73
Scheme 62: SSAO- and MAO-B Inhibitors.
52
Scheme 63: Internal Arylation of Boc-Protected Allylamine with Aryl Triflates 48.
Product Isolated Yield 69 (%)d
Me
Me
Cl
O
Me
41
68
70
70
7
45
69c
69d
69e
69f
69g
Selectivity β/γc
>99.5/0.5MeO 69a
69jOMe 74
>99.5/0.5
>99.5/0.5
>99.5/0.5
>99.5/0.5
>99.5/0.5
Microwave Heatingb
Isolated Yield 69 (%)d
34
68
40
56
β/γc
>99.5/0.5
64
98/2
93/7
>99.5/0.5
Time (min)/ Effect (W)
6/20
6/20 95/5
3/20
4/20
5/20
Thermal Heatinga
63
64
>99.5/0.5
Me
Cl >99.5/0.5
>99.5/0.5
6/35
5/20
aThe thermal reactions with Boc-protected allylamine were run in 2.5 mmol scale under nitrogen atmosphere at 80 oC (entries 3-6) or 90 °C (entries 1-2, 7) with 1 equiv of aryl triflate 48; 0.03 equiv of Pd(OAc)2; 0.132 equiv of dppf; 3 equiv of Boc-protected allylamine; 1.2 equiv of K2CO3 and 10 mL of acetonitrile. All reactions were completed within 20 h. bContinuous irradiation at 2450 MHz. The microwave heated reactions were run in 1.0 mmol scale in septum-sealed Pyrex tubes with 1 equiv of aryl triflate 48, 3 equiv of Boc-protected allylamine, 0.03 equiv of Pd(OAc)2, 0.132 equiv of dppf and 1.2 equiv of K2CO3 in 1.0 mL of DMF. cSelectivity internal β-arylation/terminal γ-arylation. Determined by GC-MS and 1H-NMR. d>95% by GC-MS.
Entry
1.
2.
3.
4.
5.
6.
7.
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
NHBoc
53
Isolated Yield 70 (%)d
18e
65
34
40
9
17g
Selectivity β/γc
57/43
57
96/4
88/12
96/4
>99.5/0.5f
50/50
Microwave Heatingb
Isolated Yield 70 (%)d
21e
42
18e
23
β/γc
67/33
24
89/11
45/55
60/40
Time (min)/ Effect (W)
5/20
6/20 86/14
6/20
5/20
6/20
Thermal Heatinga
6
13g
86/14
>99.5/0.5f
50/50
5/20
5/20
Me
Me
Cl
O
Me
70c
70d
70e
70f
70g
MeO 70a
70jOMe
Me
Cl
Product
Scheme 64: Internal Arylation of Phthalimido-Protected Allylamine with Aryl Triflates 48.
aThe thermal reactions with phthalimido-protected allylamine were run in 2.5 mmol scale under nitrogen atmosphere at 90 °C with 1 equiv of aryl triflate 48; 0.03 equiv of Pd(OAc)2; 0.132 equiv of dppf; 3 equiv of phthalimido-protected allylamine; 1.2 equiv of K2CO3 and 10 mL of DMF as solvent. The reactions were completed after 2 days (entries 1-2, 7), 3 days (entries 4-6) or 4 days (entry 3). bContinuous irradiation at 2450 MHz. The microwave heated reactions were run in 1.0 mmol scale in septum-sealed Pyrex tubes with 1 equiv of aryl triflate 48, 3 equiv of phthalimido-protected allylamine, 0.03 equiv of Pd(OAc)2, 0.132 equiv of dppf and 1.2 equiv of K2CO3 in 1.0 mL of DMF. cSelectivity internal β-arylation/terminal γ-arylation. Determined by GC-MS and 1H-NMR. d>95% by GC-MS, except where otherwise indicated. e92-93% pure. Mixture of internally and terminally arylated products. f Ratio uncertain due to low yield. g91-93% pure. Mixture of internally and terminally arylated products. No elemental analysis made.
Entry
1.
2.
3.
4.
5.
6.
7.
NPht
NPht
NPht
NPht
NPht
NPht
NPht
54
A deprotonation of secondary amides similar to the deprotonation of alcohols (Scheme59) could explain the very high regioselectivities attained with the secondary Boc-allylamide. An efficient coordination between the anionic nitrogen and palladium cantake place as in structure 74 (Scheme 65), which would lead to the formation of thefive-membered ring intermediate 75 and the internally arylated product 69 (Scheme 65).A structure similar to 75 has been suggested by Blart and Ricci in a palladium catalysedarylation, e. g. 43 (Scheme 37).
There are no clear indications that might prove if palladium–carbonyl coordinationoccurs under our reaction conditions, but it might be argued that the tertiaryphthalimido-protected amine, which cannot be deprotonated and thus cannot form ananionic intermediate, could coordinate to the palladium via one of the carbonyl groupsas illustrated in structure 76, Scheme 66.
The insertion of the aryl group would then have to go through a seven-ring intermediate77, which when compared to the five-membered 75 should be energetically unfavoured,in order to form the internally arylated product 70 (Scheme 66). However, it cannot beruled out that the poorer regioselectivities encountered with tertiary N-protectedallylamines might reflect an insertion with no palladium–heteroatom coordination at all.
N
Pd
ArO
Ot-Bu
L L
75
ArHN
Boc
69
PdL L
Ar X
HN
Boc
-X, -H
Pd
N
Ot-BuO74
Ar
LL
Scheme 65: Suggested Mechanism for the Internal Arylation of Boc-Protected Allylamine.
H
PdL L
Ar
Pd
N
76
Ar
L L
PdL L
Ar OTf
NPhtO
O N
O
O
ArNPht
70
77Scheme 66: Coordination of Palladium to the Carbonyl of an Uncharged Tertiary Allylimide.
-OTf
55
To estimate the reactivity of secondary Boc-protected allylamines in comparison withtertiary Boc-protected allylamines, we investigated the internal arylation of the tertiaryN-methyl substituted Boc-protected amine 81, yielding product 78 (Scheme 67).
The tertiary 81 was in pilot studies evaluated with a number of aryl triflates and thereaction times were in most cases similar to the phthalimido-protected allylamines, i. e.longer than those of the secondary 79 (Scheme 68), although a few couplings with 81were finished over night. The regioselectivities with 81 were moderate and more in linewith the phthalimido-protected allylamine 80 than with 79. This indicates that thereactivity and regioselectivity of a secondary allylamide can be profoundly changed if athird nitrogen substituent is added, possibly by preventing coordination betweenpalladium and an anionic nitrogen as in Scheme 65.
To bring more light on the mechanism underlying the regioselectivity in the palladium-catalysed internal arylation of heteroatom-containing olefins were eleven olefinsinvestigated in competitive couplings (Scheme 68).
In each reaction were five equivalents of two different olefins added to the reactionmixture and the relative ratio of arylation with phenyl triflate of the two olefins wasmeasured. To ensure that the response factors for the different compounds werecomparable were equimolar amounts of the arylated olefins, when the pure, isolatedinternally arylated olefins were obtainable, injected on GC–MS and their respectivepeaks measured by GC–MS integration. When pure samples were not at hand were thereaction mixtures analysed by 1H-NMR and GC–MS. The only compound that had adiffering response factor was the phenylated phthalimido-protected allylamine, whichhad a 1.9 times higher response factor than the other phenylated olefins. The results ofthe competitive couplings are summarised in Scheme 69.
NMe
Boc
78
NBoc
Pd(OAc)2, dppf+
OTf Me
K2CO3, CH3CN 80 oC, <20 h 67% Isolated Yield
Regioselectivity 89/11
Scheme 67: Internal Arylation of the Tertiary N-Methyl, Boc-Protected Allylamine.
81
56
The secondary Boc-amide 79 has in the competitive reactions a slight advantage overthe tertiary imide 80, the tertiary amide 81 and the heteroatom-lacking alkene 87 and ahigh reactivity compared to the tertiary amine 82. The reactivity of the phthalimidocompound 80 was comparable with 81. The oxygen containing alcohol derivatives 88–89 and the trimethylsilyl compound 86 are all slightly more reactive than 79.
The primary 83 and secondary, methyl-substituted 84 allylamines suppress the reactionin competition with 79, giving only traces of 69 and no arylated 83 or 84 that could bedetected by GC–MS analyses. Strong palladium–nitrogen coordination can thus causecatalyst poisoning with a primary or a secondary allylamine lacking electronwithdrawing substituents on the nitrogen. The electron density of the amine moiety haspreviously been found to influence its coordinating ability.112,116 Interestingly, allylalcohol 88 was arylated to the same extent as allyl ethyl ether 89, which may imply thatother factors besides deprotonation of the oxygen influences the regioselectivity whenoxygen-containing olefins are used in the Heck-reaction (Scheme 58).
SiMe3
86 87Me
Me
HN
Boc79
N
O
O80
NBoc
Me
81
NMe
Me
82
OEt
89
OH
88
NBoc
Boc
85
NH2
83
HN
Me84
Scheme 68: Olefins Evaluated in Competitive Heck-Couplings.
79/82
79/81
91/9
63/37
79/80
79/87
79/83-84
60/40a
69/31
NR
88/89
79/88
79/89
35/65
38/62
79/86
86/89
51/49
57/43
87/89
79/85 >99.5/0.5
33/67
28/72
80/81 55/45a
82/87 35/65
Scheme 69: Product Distribution in Competitive Arylations.
aCalculation based on a 1.9 times larger response factor for 80.
81/82 90/10
57
The data suggest that there is a balance between coordination and deactivation of thepalladium catalyst that must be controlled in order to ensure the formation of a Heck-coupling product. The primary allylamine 83 and the secondary N-methylallylamine 84deactivate the catalyst, while the tertiary N,N-dimethylallylamine 82 is coupled withexcellent regioselectivity, although it is at a disadvantage to the other tested olefins incompetitive couplings. Even the non-coordinating 87 is favoured over 82 (65/35) incompetitive phenylations. This may be explained by a partial deactivation of palladiumby electron donation from the amine moiety in 82. A tight coordination of palladium tothe heteroatom may result in slower ligand dissociation and a slower rate for the overallreaction.194 This deactivation may be stronger in the primary and secondary analogues83–84 due to reduced steric hindrance.119 Furthermore, it cannot be ruled out that ananionic amine is formed when primary and secondary allylamines are used, as aminehydrogens may be more acidic when the nitrogen is coordinated to palladium,195
although no pKa values for this hydrogen dissociation have been reported.
When comparing the tertiary allylamine to the secondary or tertiary allylamides or thetertiary allylimide is the reactivity in competitive couplings higher with the amides andimide, possibly due to a weaker coordination and deactivation from the amide or imidenitrogen as the carbonyl decreases the electron density around the nitrogen as comparedto the amine nitrogen. Another explanation could be a weaker coordination of acarbonyl group of the amide or imide to palladium compared to the nitrogencoordination of amines. The secondary amide 79 is more reactive in competitivecouplings than the tertiary amide 81 and –imide 80 and may coordinate more efficientlyto the palladium through an anionic intermediate.120 It is in this context interesting tonote that the relatively electron-poor 79 is at a disadvantage to the β-stabilising 86(33/67) in competitive experiments (Scheme 69).
A large steric bulk on the olefin may hamper the reaction as a loss of reactivity is notedwhen an additional Boc group is added to 79, giving the di-Boc protected 85. Couplingswith 85 yield no product and the presence of 85 in a competitive coupling with 79 doesnot disturb the product formation of 69, indicating that the reason for the lack ofreactivity of 85 is not deactivation of the catalyst (Scheme 69). The synthesis of theterminally arylated 85, which should not be as sensitive to steric hindrance, appears torun smoothly with vinyl triflates and monodentate ligands.196
In short, very high regioselectivities, which can partly be explained by Pd2+–Ncoordination, could be induced with N,N-dialkylallylamines and Boc-protectedallylamines with thermal as well as microwave heating. Phthalimido-protectedallylamines resulted in arylations with lower and less reproducible regioselectivities,especially under microwave heating.
58
5.3 Internal Arylation of Fluoroallylamines (Appendix)
As was discussed in chapter 5.2 was a synthetic route to SSAO-inhibitors, such as MDL72274 71, open through the phthalimido-protected allylamine 70 but the (E)-3-fluoro-2-arylallylamines, such as MDL-72145 72, Scheme 62, were not accessible by the samemethod.
We realised that if the methodology of highly regioselective internal arylation ofprotected allylamines could be taken advantage of in a direct internal arylation of 90,this would result in a highly interesting and very short synthetic route to 91 and 92(Scheme 70).
We synthesised 90, largely following McCarthy’s method of producing terminallyfluorinated olefins,197,198 as described in Scheme 71.
ArOTfNR2
ArNR2Pd(OAc)2, dppf
K2CO3, CH3CN
F
+
Scheme 70: Envisioned Synthesis of Irreversible MAO-B Inhibitors.
90 91
DeprotectionAr
NH2
F
92
R=Boc and H or Pht
F
N
O
O
OEtEtO
N
O
O
O
H N
O
O
S FPh O
O
N
O
O
FH
HCl/H2O PhSO2CH2F
N
O
O
Bu3Sn FHSnBu3
AIBNMeONaMeOH
93 94 95
96 90
Scheme 71: Synthesis of Terminally Fluorinated N-Allylimide Compounds.
ClP(O)(OEt)278%60%
41% 65%
59
Deprotection of the acetal 93 followed by a fluoro-Pummerer reaction of 94199 withPhSO2CH2F200,201 resulted in compound 95, where the regioisomers could be separatedby circular chromatography, although it was found to be unnecessary as the radicalinduced substitution of the PhSO2- by the Bu3Sn-group resulted in regiochemicalscrambling of the vinylic fluorous atom. Separation by circular chromatography of thetwo regioisomers of 96 could be performed as well. The removal of the Bu3Sn-groupwas most easily made in refluxing NaOMe/MeOH198 although heating with CsF wasalso effective,198,202 yielding 90. Compounds 90 and 95 were evaluated as olefins inHeck-couplings with phenyl-, 1-naphthyl- and 2,3,5-trimethylphenyl triflates, under thesame reaction conditions used for the internal arylation of protected allylamines,without any trace of the desired internally arylated products 91. The deprotection of 90with a subsequent mono-protection with Boc was planned but abandoned when it wasclear that no Heck-coupling could be discerned with 90 or 95. One explanation for thelack of success of Heck-couplings with terminally fluoro-substituted allylic compoundscould be the low electron density of the olefin, which plausibly might lead to anunfavoured coordination with the cationic palladium complex and a suppressedreaction. Vinylic fluoroolefins have previously been reported to be compatible withStille-203-205 (as in product 97)203,204 and Suzuki-coupling205,206 (98)206 conditions(Scheme 72).
In short, the direct internal arylation of terminally fluorinated protected allylaminesfailed, possibly due to an unfavoured interaction between the cationic palladium and theelectron-poor olefin.
SnBu3
F+
I
O
Pd(PPh3)2CuI
F
O
97
Br
F+
Pd(PPh3)2F
98
90%
86%
Scheme 72: Palladium-Catalysed Synthesis of Fluoroolefins.
(HO)2B
60
5.4 Microwave Heated Fluorous Stille-Couplings and Radical Reactions(Paper II)
Curran has in a series of papers taken advantage of the insolubility of fluorouscompounds in standard organic and aqueous phases in separations and presented severalelegant methods where the tagging of tin reagents with fluorous tails, such as 99 and100, improved the purification process (Scheme 73).
The C10F21-tags used in 99 and 100 were introduced in fluorous Ugi- and Biginellireactions were the normally used fluorous tags (C6F13) did not have the power topartition large compounds fully to the fluorous phase.156 The further use of C10F21-tagsin thermal reactions resulted in poor yields and irreproducible result, most likely a resultof the very poor solubility of the highly fluorinated compounds.207 In this context wasmicrowave-heated chemistry138,208 evaluated with great success in chemical reactionswith compounds 99 and 100. It was shown that the high temperatures reached in themicrowave vessels allowed the dissolution of 99 and 100 in either a mixture of TBF andt-BuOH (for radical-mediated reactions) or in DMF (for Stille-couplings), which waseasily ascertained as the fluorous compounds were insoluble solids before microwave-heating was applied and fully dissolved after a couple of minutes in the single-modemicrowave oven.
R1Sn(CH2CH2C10F21)3+R2X
R1 R2
R1Sn(CH2CH2C10F21)3+
inorganic
Reaction organic
fluorous
water
Partitioning
XSn(CH2CH2C10F21)3
Scheme 73: Work-Up Procedure with Fluorous Reagents.
R1= Ph 99R1= H 100
61
A number of Stille-couplings with 99 were performed in moderate to high isolatedyields under microwave irradiation (Scheme 74). The experiments are summarised inScheme 75.
Products 101–103 were formed in moderate to high yields, while the isolated yield of104 was lowered by formation of sideproducts, mainly diphenylmethane. The isolatedyield of 102 could be raised marginally by switching to a water-soluble catalyst209,210
(entry 5, Scheme 75). Side products arising from aryl scrambling could thus be removedby extraction.
Time (min)/Effect (W)a Product
Isolated Yield (%)b
I Ph6/50 78
Br
O
Me
Ph
O
Me
6/50 71
Br
O2N
Ph
O2N6/50 69
Ph6/50 46
1.
2.
3.
4.
6/50 75c5.
101
102
103
104
OrganoHalide
102
Br
Entry
Br
O
Me
Ph
O
Me
Scheme 75: Microwave Promoted Stille-Couplings with F-21 Compound 99.
aContinuous irradiation at 2450 MHz. b>95% by GC/MS. cPd(OAc)2 and P(m-PhSO3Na)3 instead of Pd(PPh3)2Cl2 as precatalyst.
Br Ph
Pd(PPh3)2Cl2, LiCl
Scheme 74: Stille-Couplings with Highly Fluorinated Tin Reagents.
99
R R
62
A number of radical-mediated reactions211 were successfully executed as well in good toexcellent isolated yields (Scheme 76). Reduction of adamantyl bromide, yieldingadamantane 105, and ring-closures, yielding 106 and 107 could be performed in high toexcellent yields. Notably was the use of a catalytic amount of the fluorous tin hydride100, in combination with NaBH3CN, used in the addition of adamantyl bromide toacrylonitrile, yielding the product 108. This result is interesting not only as the amountof expensive (in this case commercially unavailable) tin compound could be reduced byat least 90% but also because the amount of tin reagents, which are toxic, can beminimised. The yield of this addition could actually be increased when the insolubilityof the tin-containing by-products was taken advantage of in a simplified work-upprocedure, where the reaction mixture simply was filtered through a plug of silica toyield >95% pure product 108 in 77% isolated yield. The corresponding isolated yieldfrom the standard purification procedure, with three-phase extraction and silicachromatography was 64% (Scheme 76).
Time (min)/Effect (W)a Product
Isolated Yield (%)b
Br 5/35 H 81
Ncbz
I
Ncbz
93100 5/35
Br
Ph Ph PhPh
785/50100
1.
2.
3.
105
106
107
Organo Halide
100
Entry
CN CN4. 0.1 equiv 100c10/60 64/77d
108+
Reagents
Scheme 76: Microwave Promoted Radical Reactions with F-21 Compound 100.
Br
aContinuous irradiation at 2450 MHz. b>95% by GC/MS. cNaBH3CN added to recycle the tin hydride. d64% isolated yield by extraction, 77% isolated yield by filtration.
63
The removal of by-products of 100 by filtration at room temperature could be seen as ahybrid solid phase/liquid phase technique. The filtration allows for a work-up procedurereminiscent of solid-phase techniques at the purification step while enjoying theadvantages of homogenous reactions in solution at the reaction step. The fluorousapproach can thus be said to be a means of integrating synthetic and purificationstrategy.
The first example of a microwave heated one-pot hydrostannylation of an alkyne 109and subsequent Stille-coupling of the resulting vinylic stannane, yielding 110, could beperformed under microwave irradiation in 44% overall isolated yield (Scheme 77). Thismethod was subsequently adopted and further developed by Maleczka.212
In short, the highly fluorinated tags 99 and 100, which were difficult to use underthermal heating, proved to be efficient in synthesis under microwave irradiation. Thehigh fluorous content of the reactants could be used to improve the purification step.High yields for Stille- and radical-mediated reactions are reported, as well as a one-potprocedure for hydrostannylation and subsequent Stille-coupling of alkynes undermicrowave heating.
OO
EtO OEt
109
1. 100, AIBN, BTF 10 min/60 W
2. PhI, Pd(OAc)2, CuO, DMF/BTF 8 min/60 W
H
EtOO
110E/Z 5:1
Ph
OOEt
Scheme 77: One-Pot Hydrostannylation and Stille-Coupling.
44%
64
6 Concluding Remarks
The results of the aims of the thesis are summarised below.
a) Regioselectivities that in most cases are high to excellent have been reported in novelpalladium-catalysed Heck-arylation reactions with various allylic substrates.The β-stabilising effect of silicon enhances the regiocontrol in the internal arylation ofallyltrimethylsilane, while a coordination between palladium and nitrogen induces veryhigh regioselectivities in the arylation of N,N-dialkylallylamines and the Boc-protectedallylamine, producing β-arylated arylethylamines, which are of interest for applicationsin medicinal chemistry. Phthalimido-protected allylamines are arylated with poor tomoderate regioselectivity. Furthermore, considerable effort has been laid down toexplain the bases for the high regioselectivities attained. The results of these studiesshould improve the understanding of the regiocontrol in the Heck-reaction.
b) The internal arylation of protected allylamines presented a shorter and more attractivesynthesis of a precursor to SSAO-inhibitors than the previously published syntheticroute. The direct synthesis of MAO-B inhibitors, through the internal arylation of aterminally fluorinated, protected allylamine, failed under the present reactionconditions.
c) Single-mode microwave heating has been applied on a number of Heck-, Stille- andradical-mediated reactions. The reactions were in all instances completed in three to tenminutes and the regioselectivities were in most cases comparable with those performedunder thermal heating, with the exception of the microwave-heated internal arylation ofphthalimido-protected allylamines, where the regiocontrol was poor.
d) Fluorous chemistry with highly fluorinated tags that are inert under thermal heatingcould be performed with microwave heating. The insolubility of highly fluorinatedcompounds in ordinary organic solvents at room temperature was utilised in the rapidand efficient purification of reaction mixtures.
Corrections to the original publications:
Paper I: In the texts to Table 1 and Table 2 should the amount of dppf be 0.132mmol.
Paper III: The numbers of the products in Table 1 should be 2.
65
7 Appendix
2-Phthalimido-1-ethanal (93). 50 g of phthalimidoacetaldehyde diethylacetal was added to 1M HCl andheated at 100 °C in 6 h. The reaction was monitored by GC–MS and the GC–MS samples wereprepurified by extraction between diethyl ether and water and dried over potassium carbonate beforeanalysis. After full conversion of the starting material had been achieved was the reaction mixture cooledto –4 °C over night and the white crystals was collected by filtration and washed with cold water. Theisolated yield after recrystallisation with CHCl3/isohexane was 78% and the melting point 114 °C. 1HNMR (270 MHz, CDCl3) δ 9.65 (s, 1H), 7.90-7.74 (m, 4H), 4.56 (s, 2H); 13C NMR (67.8 MHz, CDCl3) δ193.5, 167.5, 134.3, 131.9, 123.6, 47.3. MS m/z (relative intensity 70 eV) 189 (M+, 2), 160 (100), 133(12), 104 (14), 77 (18).1-Fluoro-1-phenylsulfonyl-3-phthalimido-1-propene (94). Fluoromethyl phenyl sulfone200 (20.4 g,118 mmol) and diethylchlorophosphate (17.1 mL, 118 mmol) was mixed in 200 ml of dry THF undernitrogen atmosphere in a 1L three-necked round-bottom flask with magnetic stirring. The reactionmixture was cooled to –78 °C and 250 mL LiHMDS (1M in THF) was added. The reaction was stirred at–78 °C for 30 min and 93 (15.0 g, 84 mmol) dissolved in 20 mL dry THF was added and the reactionmixture was allowed to reach room temperature. The reaction was monitored with GC–MS and stirringwas continued for 30 h before the aldehyde had been consumed. The reaction was quenched withsaturated aq. NH4Cl and extracted with CH2Cl2, dried with MgSO4, filtrated and the solvent was removedunder reduced pressure. The product 94 was purified by silica flash chromatography (eluents:isohexane/ethyl acetate 2:1) and by circular chromatography (eluents: isohexane/ethyl acetate 4:1) andisolated in 60% (E/Z 4:1): 1H NMR (270 MHz, CDCl3) (E)-1-Fluoro-1-phenylsulfonyl-3-phthalimido-1-propene: δ 8.0-7.6 (m, 9H), 6.33 (dt, J = 7, 31 Hz, 1H), 4.49 (dd, J = 2, 7 Hz, 2H). 13C NMR (67.8 MHz,CDCl3) δ 167.5, 155.9, 151.5, 137.3, 134.9, 131.8, 129.5, 129.0, 123.5, 114.9, 32.4. (Z)-1-Fluoro-1-phenylsulfonyl-3-phthalimido-1-propene: δ 8.1-7.6 (m, 9H), 5.84 (dt, J = 7, 20 Hz, 1H), 5.05 (dd, J = 3, 7Hz, 2H); 13C NMR (67.8 MHz, CDCl3) δ 167.5, 155.9, 151.5, 137.3, 134.9, 131.8, 129.5, 129.0, 123.5,114.7, 32.3. MS m/z (relative intensity 70 eV) 204 (100), 175 (7), 160 (5), 147 (8), 130 (57).1-Fluoro-3-phthalimido-1-tributylstannyl-1-propene (95). 94 (5.2 g, 15 mmol), HSnBu3 (9 mL, 33mmol) and AIBN (150 mg) was mixed in 100 mL toluene and refluxed for 6 h. The reaction wasmonitored with TLC (isohexane/ethyl acetate 2:1). The reaction was not completed after 6 h, but theisolated yield did not improve with longer reaction times. The reaction mixture was extracted withCH2Cl2/water, dried over MgSO4 and the solvent was removed under reduced pressure. Excess HSnBu3was removed by bulb-to-bulb distillation (~180 °C/1 mm Hg) and the residue was separated by circularchromatography (isohexane/ethyl acetate 10:1), where 10% unreacted starting material was recovered.The (E) and (Z) isomers were isolated in 41% yield, (E/Z) 5:2. 1H NMR (270 MHz, CDCl3) (E)- 1-Fluoro-3-phthalimido-1-tributylstannyl-1-propene: δ 7.9-7.5 (m, 4H), 4.99 (dt, J = 7, 51 Hz, 1H), 4.43(dd, J = 2, 8 Hz, 2H), 1.8-0.8 (m, 27H). 13C NMR (67.8 MHz, CDCl3) δ 167.8, 133.9, 132.2, 123.2,118.7, 117.5, 31.7, 28.9, 27.2, 13.6, 9.9. (Z)- 1-Fluoro-3-phthalimido-1-tributylstannyl-1-propene: δ 7.9-7.7 (m, 4H), 6.00 (dt, J = 8, 35 Hz, 1H), 4.16 (dd, J = 2, 8 Hz, 2H), 1.7-0.8 (m, 27H); 13C NMR (67.8MHz, CDCl3) δ 167.7, 133.8, 132.2, 123.2, 118.6, 117.5, 31.4, 28.7, 27.1, 13.6, 9.9.1-Fluoro-3-phthalimido-1-propene (90). 95 (81 mg, 0.16 mmol) was mixed with a fresh 1M NaOMesolution (220 µL) and dry THF (5 mL). The mixture was heated at 60 °C for 2 h and was monitored byTLC (isohexane/ethylacetate 10:1). The product was purified by circular chromatography (ethyl acetateelutes side-products, methanol elutes the product). The product 90 was isolated in 65% yield as a 5:2mixture of (Z) and (E) isomers. 1H NMR (270 MHz, CDCl3) (Z)- 1-Fluoro-3-phthalimido-1-propene: δ7.8-7.7 (m, 4H), 6.61 (dd, J = 85, 5 Hz, 1H), 5.07 (dddd, J = 43, 8, 8, 5 Hz, 1H), 4.07 (d, J = 8 Hz, 2H).13C NMR (67.8 MHz, CDCl3) δ 176.2, 152.3, 148.5, 137.7, 130.5, 108.7, 29.2. (E)- 1-Fluoro-3-phthalimido-1-tributylstannyl-1-propene: δ 7.8-7.7 (m, 4H), 6.85 (dd, J = 84, 11 Hz, 1H), 5.52 (dddd, J=18, 11, 8, 8 Hz, 1H), 3.87 (d, J = 8 Hz, 2H); 13C NMR (67.8 MHz, CDCl3) δ 173.8, 154.5, 151.4, 137.7,128.4, 109.4, 34.3. MS m/z (relative intensity 70 eV) 205 (100), 187 (10), 176 (17), 160 (8), 104 (22).
66
8 Supplementary Material
Paper I2-(4-Methoxyphenyl)-3-(trimethylsilyl)-1-propene (3a).5c Compound 3a was obtained in 42% yield(3a+1a) at 60 ºC. The eluent was isohexane/diethyl ether 19:1 and the products were further purified bybulb-to-bulb distillation (∼ 100 ºC at 10 mm Hg).2-(4-t-Butylphenyl)-3-(trimethylsilyl)-1-propene (3b). Compound 3b was obtained in 47% yield(3b+1b) at 60 ºC. An alumina column was used for chromatography. The eluent was isohexane and theproducts were further purified by bulb-to-bulb distillation (∼ 110 ºC at 10 mm Hg). 1 H NMR (270 MHz,CDCl3) δ 7.32 (app d, J = 1.7 Hz, 4 H), 5.13 (s, 1 H), 4.82 (m, 1 H), 2.00 (d, J = 0.7 Hz, 2 H), 1.31 (s, 9H), -0.09 (s, 9 H); 13 C NMR (67.8 MHz, CDCl3) δ 150.1, 146.2, 139.7, 125.9, 124.9, 109.3, 34.4, 31.3,25.9, -1.4; MS m/z (relative intensity 70 eV) 246 (M+, 12), 189 (61), 73 (100). Anal. calcd for C16 H26 Si:C, 78.0; H, 10.6. Found: C, 77.9; H, 10.4.2-(2,3,5-Trimethylphenyl)-3-(trimethylsilyl)-1-propene (3c). Compound 3c was obtained in 69% yield(3c+1c) after 10 days at 60 ºC and in 60% after 16 h at 80 ºC. The eluent was isohexane and the productswere further purified by bulb-to-bulb distillation (∼ 100 ºC at 10 mm Hg). 1H NMR (270 MHz, CDCl3) δ6.87 (s, 1 H), 6.78 (s, 1 H), 4.98 (m, 1 H), 4.73 (d, J = 2.3 Hz, 1H), 2.26 (s, 3 H), 2.23 (s, 3 H), 2.19 (s, 3H), 1.88 (d, J = 1.0 Hz, 2H), -0.08 (s, 9 H); 13 C NMR (67.8 MHz, CDCl3) δ 148.5, 144.7, 136.7, 134.1,129.7, 129.0, 126.8, 111.9, 29.1, 20.8, 20.4, 16.3, -1.7; MS m/z (relative intensity 70 eV) 232 (M+, 47),217 (60), 73 (100). Anal. calcd for C15 H24 Si: C, 77.5; H, 10.4. Found: C, 77.4; H, 10.0.2-Phenyl-3-(trimethylsilyl)-1-propene (3d).5c Compound 3d was obtained in 67% yield (3d+1d) at 60ºC. The eluent was isohexane and the products were further purified by bulb-to-bulb distillation (∼ 105 ºCat 10 mm Hg).2-(1-Naphthyl)-3-(trimetylsilyl)-1-propene (3e).5c Compound 3e was obtained in 77% yield (3e+1e) at60 ºC. The eluent was isohexane. No bulb-to-bulb distillation was needed.2-(4-Acetylphenyl)-3-(trimethylsilyl)-1-propene (3g). Compound 3g was obtained in 31% yield(3g+1g) at 80 ºC. The eluent was isohexane/diethyl ether 9:1 and the products were further purified bybulb-to-bulb distillation (∼ 135 ºC at 6 mm Hg). 1 H NMR (270 MHz, CDCl3 ) δ 7.89 (m, 2 H), 7.47 (m, 2H), 5.21 (d, J = 1.3 Hz, 1 H), 4.96 (dd, J = 1.0 Hz, 1.3 Hz, 1 H), 2.81 (s, 3 H), 2.03 (d, J = 1.0 Hz, 2 H), -0.13 (s, 9 H); 13C NMR (67.8 MHz, CDCl3) δ 197.6, 147.5, 145.7, 135.8, 128.3, 126.4, 112.1, 26.5, 25.9,-1.5; MS m/z (relative intensity 70 eV) 232 (M+, 65), 217 (8), 73 (100). Anal. calcd for C14H20OSi: C,72.4; H, 8.7. Found: C, 72.7; H, 8.6.2-(4-Cyanophenyl)-3-(trimethylsilyl)-1-propene (3h). Compound 3h was obtained in 59% yield(3h+1h) at 80 ºC. The eluent was isohexane/diethyl ether 19:1 and the products were further purified bybulb-to-bulb distillation (∼ 115 ºC at 10 mm Hg). 1H NMR (270 MHz, CDCl3 ) δ 7.58 (m, 2 H), 7.47 (m, 2H), 5.20 (d, J = 1.0 Hz, 1 H), 4.99 (dd, J = 1.0 Hz, 1.0 Hz, 1 H), 2.00 (d, J = 1.0 Hz, 2 H), -0.11 (s, 9 H);13C NMR (67.8 MHz, CDCl3) δ 147.3, 145.1, 131.9, 126.8, 118.9, 112.9, 110.7, 25.4, -1.5; MS m/z(relative intensity 70 eV) 215 (M+, 32), 200 (7), 73 (100). Anal. calcd for C13H17NSi: C, 72.5; H, 8.0; N,6.5. Found: C, 72.7; H, 7.9; N, 6.7.
Paper III
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2-(3,4-Dimethoxyphenyl)-3-N,N-dimethylamino-1-propene (2a). Compound 2a was isolated in 41%yield at 80 °C and 35% yield after microwave irradiation (3 min/20 W). The boiling point at bulb-to-bulbdistillation was ~115 °C at 5 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.09-7.05 (m, 2H), 6.85-6.81 (m,1H), 5.37 (d, J = 2 Hz, 1H), 5.14 (q, J = 1 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.26 (d, J = 1 Hz, 2H), 2.24(s, 6H); 13C NMR (67.8 MHz, CDCl3) δ 148.7, 148.6, 144.7, 133.0, 118.6, 114.0, 110.9, 109.5, 64.7,55.84, 55.76. 45.3. MS m/z (relative intensity 70 eV) 221 (M+, 2), 206 (0.4), 178 (25), 58 (100). Anal.Calcd for C13H19NO2: C, 70.6; H, 8.65; N, 6.33. Found: C, 70.5; H, 8.8; N, 6.1.3-N,N-Dimethylamino-2-(4-methoxyphenyl)-1-propene (2b).3a Compound 2b was isolated in 40% yield at80 °C and 30% yield after microwave irradiation (5 min/20 W). The boiling point at bulb-to-bulb distillationwas ~115 °C at 8 mm Hg.3-N,N-Dimethylamino-2-(2-methoxyphenyl)-1-propene (2c). Compound 2c was isolated in 49% yieldat 80 °C and 46% yield after microwave irradiation (5 min/20 W). The boiling point at bulb-to-bulbdistillation was ~105 °C at 6 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.29-7.18 (m, 2H), 6.96-6.86 (m,2H), 5.33 (m, 1H), 5.19 (d, J = 2 Hz, 1H), 3.83 (s, 3H), 3.32 (s, 2H), 2.21 (s, 6H); 13C NMR (67.8 MHz,CDCl3) δ 156.7, 146.0, 130.9, 130.1, 128.5, 120.6, 117.0, 110.7, 64.9, 55.3, 45.4. MS m/z (relativeintensity 70 eV) 191 (M+, 3), 176 (1), 160 (3), 146 (5), 58 (100). Anal. Calcd for C12H17NO: C, 75.4; H,8.96; N, 7.32. Found: C, 75.2; H, 9.2; N, 7.3.2-(4-t-Butylphenyl)-3-N,N-dimethylamino-1-propene (2d). Compound 2d was isolated in 35% yield at80 °C and 21% yield after microwave irradiation (5 min/15 W). The boiling point at bulb-to-bulbdistillation was ~105 °C at 8 mm Hg. Further purification of contaminating 2f was made by applyingreduced pressure. 1H NMR (270 MHz, CDCl3) δ 7.45 (m, 2H), 7.36 (m, 2H), 5.45 (d, J = 2 Hz, 1H), 5.19(q, J = 1 Hz, 1H), 3.28 (s, 2H), 2.25 (s, 6H), 1.32 (s, 9H); 13C NMR (67.8 MHz, CDCl3) δ 150.3, 144.8,137.0, 125.7, 125.2, 114.6, 64.5, 45.4, 34.4, 31.3. MS m/z (relative intensity 70 eV) 217 (M+, 10), 174(31), 159 (9), 128 (7), 58 (100). Anal. Calcd for C15H23N: C, 82.9; H, 10.7; N, 6.44. Found: C, 82.9; H,10.8; N, 6.4.3-N,N-Dimethylamino-2-(2,3,5-trimethylphenyl)-1-propene (2e). Compound 2e was isolated in 81%yield at 80 °C and 48% yield after microwave irradiation (5 min/15 W). 1H NMR (270 MHz, CDCl3) δ6.90 (s, 1H), 6.80 (s, 1H), 5.40 (m, 1H), 5.03 (m, 1H), 3.10 (m, 2H), 2.26 (s, 6H), 2.23 (s, 3H), 2.15 (s,3H); 13C NMR (67.8 MHz, CDCl3) δ 147.4, 141.8, 136.8, 134.3, 130.2, 129.6, 126.8, 115.6, 66.1, 45.8,20.8, 20.4, 16.0. MS m/z (relative intensity 70 eV) 203 (M+, 8), 158 (13), 129 (5),128 (5), 58 (100). Anal.Calcd for C14H21N: C, 82.7; H, 10.4; N, 6.9. Found: C, 82.8; H, 10.2; N, 6.7.3-N,N-Dimethylamino-2-phenyl-1-propene (2f).3a Compound 2f was isolated in 42% yield at 80 °C and24% yield after microwave irradiation (5 min/15 W). The boiling point at bulb-to-bulb distillation was ~90°C at 10 mm Hg.2-(2,4-Dichlorophenyl)-3-N,N-dimethylamino-1-propene (2h). Compound 2h was isolated in 38% yield at80 °C. The boiling point at bulb-to-bulb distillation was ~120 °C at 8 mm Hg. 1H NMR (270 MHz, CDCl3) δ7.37 (m, 1H), 7.26-7.14 (m, 2H), 7.5 (m, 4H), 5.45 (q, J = 2 Hz, 1H), 5.17 (m, 1H), 3.23 (s, 2H), 2.22 (s,6H); 13C NMR (67.8 MHz, CDCl3). 144.5, 139.0, 133.4, 132.8, 131.2, 129.5, 126.9, 118.9, 65.0, 45.4. MSm/z (relative intensity 70 eV) 228 (0.3), 194 (9), 115 (5), 58 (100). Anal. Calcd for C11H13Cl2N: C, 57.4; H,5.69; N, 6.08. Found: C, 57.3; H, 5.8; N, 6.2.2-(4-Acetylphenyl)-3-N,N-dimethylamino-1-propene (2i). Compound 2i was isolated in 48% yield at80 °C. The boiling point at bulb-to-bulb distillation was ~130 °C at 1 mm Hg. 1H NMR (270 MHz,CDCl3) δ 7.92 (m, 2H), 7.58 (m, 2H), 5.54 (d, J = 1 Hz, 1H), 5.31 (q, J = 1 Hz, 1H), 3.29 (s, 2H), 2.58, (s,3H), 2.21 (s, 6H); 13C NMR (67.8 MHz, CDCl3) δ 197.7, 144.7, 144.5, 136.0, 128.4, 126.4, 117.3, 64.3,45.2, 26.6. MS m/z (relative intensity 70 eV) 203 (M+, 7), 160 (1), 145 (2), 115 (4), 58 (100). Anal. Calcdfor C13H17NO: C, 76.8; H, 8.43; N, 6.89. Found: C, 76.8; H, 8.3; N, 6.9.2-(4-Cyanophenyl)-3-N,N-dimethylamino-1-propene (2j). Compound 2j was isolated in 50% yield at 80°C. The boiling point at bulb-to-bulb distillation was ~105 °C at 8 mm Hg. 1H NMR (270 MHz, CDCl3) δ7.60 (s, 4H), 5.53 (d, J = 1Hz, 1H), 5.34 (q, J = 1.3 Hz, 1H), 3.27 (d, J = 1 Hz, 2H), 2.20 (s, 6H); 13C NMR(67.8 MHz, CDCl3) δ 144.5, 143.9, 132.0, 126.9, 119.0, 118.1, 110.9, 64.2, 45.1. MS m/z (relative intensity70 eV) 186 (M+, 6), 169 (1), 140 (3), 58 (100). Anal. Calcd for C12H14N2: C, 77.4; H, 7.58; N, 15.0. Found:C, 77.2; H, 7.6; N, 14.7.2-Phenyl-3-piperidino-1-propene (2k). Compound 2k was isolated in 50% yield at 80 °C. The boilingpoint at bulb-to-bulb distillation was ~90 °C at 1 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.57-7.52 (m,
68
2H), 7.37-7.23 (m, 3H), 5.46 (d, J = 2 Hz, 1H), 5.25 (q, J = 2 Hz, 1H), 3.30 (d, J = 1Hz, 2H), 2.42 (m,4H), 1.56 (m, 4H), 1.42 (m, 2H); 13C NMR (67.8 MHz, CDCl3) δ 144.5, 140.8, 128.0, 127.3, 126.3,114.8, 63.7, 54.6, 26.0, 24.5. MS m/z (relative intensity 70 eV) 201 (M+, 8), 158 (1), 118 (4), 115 (7), 98(100). Anal. Calcd for C14H19N: C, 83.5; H, 9.5; N, 7.0. Found: C, 83.2; H, 9.5; N, 6.9
Paper IV
Thermal Internal Phenylation of 3-N-t-Butoxycarbonylamino-N-Methyl-1-propene 6c (Eq 3). Asdescribed under General Procedure for the Thermal Internal Arylation of 3-N-t-Butoxycarbonylamino-1-propene 6a but with 6c as olefin and 5d as aryl triflate. The reaction was completed within 18 h at 80 °C.Eluents for chromatography of 4d were isohexane–ethyl acetate 9:1.Microwave Heated Arylation of 3-Phthalimido-1-propene 6b (Table 1). To a heavy-walled, oven-dried Pyrex tube were added: 1.00 mmol of aryl triflate 5a–g; 0.03 mmol (6.7 mg) of Pd(OAc)2, 0.132mmol (73 mg) of dppf, 3.0 mmol (0.26 g) of 3-phthalimido-1-propene (0.57 g), 1.2 mmol (173 mg) ofK2CO3 and 1.0 mL of DMF bubbled with N2 for 5 minutes. Otherwise as under Microwave HeatedInternal Arylation of 3-N-t-Butoxycarbonylamino-1-propene 6a (Table 1).3-N-t-Butoxycarbonylamino-2-(4-methoxyphenyl)-1-propene (2a).122 Compound 2a was obtained in41% yield at 90 °C and 34% yield after microwave irradiation (6 min/20 W). The boiling point at bulb-to-bulb distillation was ~160 °C at 2 mm Hg.3-N-t-Butoxycarbonylamino-2-(2-methoxyphenyl)-1-propene (2b). Compound 2b was obtained in74% yield at 90 °C and 64% yield after microwave irradiation (6 min/20 W). The boiling point at bulb-to-bulb distillation was ~ 140 °C at 2 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.19-7.17(m, 1H), 6.96-6.85 (m, 2H), 5.30 (s, 1H), 5.15 (s, 1H), 4.71 (br s, 1H), 4.12 (d, J = 6 Hz, 2H), 3.82 (s,3H), 1.41 (s, 9H); 13C NMR (67.8 MHz, CDCl3) δ 156.5, 155.8, 145.7, 130.4, 129.5, 128.9, 120.6, 114.7,110.5, 79.0, 55.4, 45.0, 28.3. MS m/z (relative intensity 70 eV) 263 (M+, 0.4), 207 (100), 190 (15), 121(60), 57 (40). Anal. Calcd for C15H21NO3: C, 68.4; H, 8.04; N, 5.32. Found: C, 68.2; H, 8.0; N, 5.4.3-N-t-Butoxycarbonylamino-2-(2,3,5-trimethylphenyl)-1-propene (2c). Compound 2c was obtained in68% yield at 80 °C and 68% yield after microwave irradiation (3 min/20 W). The boiling point at bulb-to-bulb distillation was ~ 160 °C at 2 mm Hg. 1H NMR (270 MHz, CDCl3) δ 6.93 (s, 1H), 6.79 (br s, 1H),5.32 (d, J = 1.7 Hz, 1H), 4.97 (d, J = 1.7 Hz, 1H), 4.74 (br s, 1H), 3.91 (d, J = 5.3 Hz, 2H), 2.28 (s, 3H),2.26 (s, 3H), 2.18 (s, 3H), 1.45 (s, 9H); 13C NMR (67.8 MHz, CDCl3) δ 155.8, 147.2, 140.4, 136.9, 134.5,130.7, 129.8, 126.9, 113.1, 79.5, 46.2, 28.3, 20.7, 20.4, 15.9. MS m/z (relative intensity 70 eV) 275 (M+, 2),219 (31), 174 (100), 158 (53), 143 (42). Anal. Calcd for C17H25NO2: C, 74.1; H, 9.15; N, 5.09. Found: C,74.1; H, 9.0; N, 5.2.3-N-t-Butoxycarbonylamino-2-(1-naphthyl)-1-propene (2e). Compound 2e was obtained in 70% yield at80 °C and 56% yield after microwave irradiation (5 min/20 W). The boiling point at bulb-to-bulbdistillation was ~165 °C at 2 mm Hg. 1H NMR (270 MHz, CDCl3) δ 8.10-8.00 (m, 1H), 7.88-7.78 (m, 2H),7.52-7.42 (m, 3H), 7.33-7.30 (m, 1H), 5.57 (s, 1H), 5.21 (s, 1H), 4.76 (br s, 1H), 4.11 (d, J = 5.6 Hz, 2H),1.43 (s, 9H); 13C NMR (67.8 MHz, CDCl3) δ 155.8, 145.3, 138.5, 133.6, 131.4, 128.2, 127.7, 126.1, 125.8,125.5, 125.4, 125.2, 115.3, 79.4, 46.7, 28.3. MS m/z (relative intensity 70 eV) 283 (M+, 5) , 227 (6), 183
Table 1, Product 2e
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(36), 166 (100), 153 (99). Anal. Calcd for C18H21NO2: C, 76.3; H, 7.47; N, 4.94. Found: C, 76.1; H, 7.5; N,4.9.3-N-t-Butoxycarbonylamino-2-(2,4-dichlorophenyl)-1-propene (2f). Compound 2f was obtained in 7%yield at 90 °C and 63% yield after microwave irradiation (6 min/35 W). The boiling point at bulb-to-bulbdistillation was ~ 175 °C at 2 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.39-7.38 (m, 1H), 7.23-7.13 (m,2H), 5.41 (s, 1H), 5.11 (s, 1H), 4.70 (bs, 1H), 4.02 (d, J = 6 Hz, 2H), 1.40 (s, 9H); 13C NMR (67.8 MHz,CDCl3) δ 155.7, 144.2, 137.9, 133.8, 133.1, 131.5, 129.3, 127.0, 116.4, 79.3, 45.0, 28.3. MS m/z (relativeintensity 70 eV) 247 (63), 245 (97), 210 (27), 166 (65), 57 (100). Anal. Calcd for C14H17Cl2NO2: C, 55.6;H, 5.67; N, 4.63. Found: C, 55.6; H, 5.8; N, 4.7.2-(4-Acetylphenyl)-3-N-t-butoxycarbonylamino-1-propene (2g). Compound 2g was obtained in 45%yield at 90 °C and 64% yield after microwave irradiation (5 min/20 W). The boiling point at bulb-to-bulbdistillation was ~175 °C at 1 mm Hg. 1H NMR (270 MHz, CDCl3) δ 7.95-7.86 (m, 2H), 7.51 (d, J = 8.4Hz, 2H), 5.53 (s, 1H), 5.34 (s, 1H), 4.66 (br s, 1H), 4.21 (d, J = 5.4 Hz, 2H), 2.60 (s, 3H), 1.43 (s, 9H);13C NMR (67.8 MHz, CDCl3) δ 197.8, 155.6, 144.2, 143.5, 136.5, 128.5, 126.3, 115.2, 79.4, 44.1, 28.3,26.6. MS m/z (relative intensity 70 eV) 219 (77), 204 (44), 186 (62), 175 (55), 146 (100). Anal. Calcd forC16H21NO3: C, 69.8; H, 7.69; N, 5.09. Found: C, 70.0; H, 7.3; N, 4.9.2-(4-Methoxyphenyl)-3-phthalimido-1-propene (3a). Compound 3a was obtained in 18% yield (mixtureof internally and terminally arylated products) at 90 °C and 21% yield (mixture of internally and terminallyarylated products) after microwave irradiation (5 min/20 W). Melting point: 106 °C. 1H NMR (270 MHz,CDCl3) δ 7.88-7.68 (m, 4H), 7.46-7.42 (m, 2H), 6.89-6.80 (m, 2H), 5.37 (s, 1H), 5.09 (t, J = 1 Hz, 1H),4.68 (t, J = 1 Hz, 2H), 3.80 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 167.9, 141.6, 133.9, 132.1, 127.7,127.5, 123.2, 120.4, 113.7, 112.5, 55.2, 41.5. MS m/z (relative intensity 70 eV) 293 (M+, 77), 278 (4), 260(4), 160 (7), 133 (100). High resolution MS (EI) calcd for C18H15NO3 (M+) 293.1048, found 293.1048.Anal. Calcd for C18H15NO3: C, 73.7; H, 5.15; N, 4.78. Found: C, 73.2; H, 5.0; N, 4.2.3-Phthalimido-2-(2,3,5-trimethylphenyl)-1-propene (3c). Compound 3c was obtained in 65% yield at90 °C and 42% yield after microwave irradiation (6 min/20 W). Melting point: 152 °C. 1H NMR (270MHz, CDCl3) δ 7.90-7.70 (m, 4H), 6.97-8.85 (m, 2H), 5.08 (s, 1H), 4.98 (s, 1H), 4.43 (s, 2H), 2.26 (m,9H); 13C NMR (67.8 MHz, CDCl3) δ 167.9, 144.2, 139.6, 137.0, 134.6, 134.0, 132.0, 131.0, 130.1, 127.1,123.4, 113.1, 43.0, 20.7, 20.4, 15.8. MS m/z (relative intensity 70 eV) 305 (M+, 78), 290 (100), 262 (22),158 (87), 143 (59). Anal. Calcd for C20H19NO2: C, 78.7; H, 6.27; N, 4.59. Found: C, 78.5; H, 6.4; N, 4.5.2-Phenyl-3-phthalimido-1-propene (3d).188 Compound 3d was obtained in 34% yield at 90 °C and 18%yield (mixture of internally and terminally arylated products) after microwave irradiation (5 min/20 W).2-(1-Naphthyl)-3-phthalimido-1-propene (3e). Compound 3e was obtained in 40% yield at 90 °C and23% yield after microwave irradiation (6 min/20 W). Melting point: 115 °C. 1H NMR (270 MHz, CDCl3) δ8.27-8.23 (m, 1H), 7.90-7.69 (m, 6H), 7.58-7.39 (m, 4H), 5.36 (t, J = 1 Hz, 1H), 5.24 (m, 1H), 4.65 (t, J = 2Hz, 2H) ; 13C NMR (67.8 MHz, CDCl3) δ 167.9, 142.4, 137.7, 134.0, 133.6, 132.0, 131.4, 128.2, 128.0,126.3, 125.9, 125.8, 125.5, 125.2, 123.4, 115.3, 43.4. MS m/z (relative intensity 70 eV) 313 (M+, 12), 166(100), 152 (38), 104 (5), 77 (9). Anal. Calcd for C21H15NO2: C, 80.5; H, 4.82; N, 4.47. Found: C, 80.3; H,5.1; N, 4.4.2-(4-Acetylphenyl)-3-phthalimido-1-propene (3g). Compound 3g was obtained in 17% yield (mixtureof internally and terminally arylated products) at 90 °C and 13% yield (mixture of internally andterminally arylated products) after microwave irradiation (5 min/20 W). Melting point: 135 °C. 1H NMR(270 MHz, CDCl3) δ 7.93-7.68 (m, 6H), 7.60-7.39 (m, 2H), 5.54 (s, 1H), 5.13 (t, J = 1 Hz, 1H), 4.72 (s,2H), 2.57 (s, 3H) ; 13C NMR (67.8 MHz, CDCl3) δ 197.5, 167.8, 140.8, 136.5, 134.0, 132.0, 128.6, 126.6,125.7, 123.3, 116.3, 39.5, 26.6. MS m/z (relative intensity 70 eV) 305 (M+, 94), 290 (100), 272 (5), 160(37), 115 (16). Anal. Calcd for C19H15NO3: C, 74.7; H, 4.95; N, 4.59. Found: C, 74.4; H, 5.0; N, 4.4.
70
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10 Acknowledgements
This investigation was carried out at the Institution of Organic PharmaceuticalChemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Uppsala.
The author would like to express his sincere gratitude to the following:
My supervisor, professor Anders Hallberg for invaluable help and for surroundinghimself and the department with empathy and positive energy.
Hà for everything…
Elsa and Per-Ivan for neverending support and for letting me do things my way.
My four new sisters, their families and my mother-in-law for spring-rolls and sympathy.
Dr Mats Larhed for help and assistance during the writing of our papers and the thesis,Sun-Young Kim for help with the synthesis of the fluorous starting materials andHelena Sahlin for help with the synthetic work.
My colleagues at the department, especially my room mates Susanna Lindman, UlrikaRosenström and Karl Vallin.
Mathias Alterman, Professor Anders Hallberg, Docent Anette Johansson, Dr MatsLarhed, Peter Nilsson, Ulrika Rosenström and Karl Vallin for proof-reading andconstructive criticism.
Arne Andersson, Björn Carlsson and Marianne Åström for assistance whenever neededand Lotta Wahlberg for kind help with the chemicals.
George Paul John and Ringo, Monty Python, Norrbotten, Liljeborns Trafikskola.
