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Hemming, Karl

Heterocyclic chemistry

Original Citation

Hemming, Karl (2011) Heterocyclic chemistry. Annual Reports Section B Organic Chemistry, 107 (1). pp. 118-137. ISSN 0069-3039

This version is available at http://eprints.hud.ac.uk/id/eprint/11580/

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Heterocyclic Chemistry

Karl Hemming DOI: 11.1039/b000000x [DO NOT ALTER/DELETE THIS TEXT] Division of Chemistry, University of Huddersfield, Huddersfield, West Yorkshire, HD1 3DH, UK. 5

Fax: 44(0)1484472182; Tel: 44(0)1484472188; E-mail: [email protected]

2009 offered several significant advances in the field of heterocyclic chemistry, with particular highlights including several new approaches to pyrroles, indoles and pyrimidines. Major themes were hydroamination processes, the development of new multi-component reactions and 10

advances in the development of catalytic asymmetric electrocyclisations.

Introduction

This chapter contains a short review of the highlights in the synthesis of heterocycles published in 2009. The main focus is on synthesis rather than reactivity and the review looks at 3-, 4-, 5-, 6-, and 7-membered rings and larger containing 15

nitrogen, oxygen and sulfur. Other elements, as well as polymer and solid supported methodologies and combinatorial approaches are omitted for sake of brevity.

Three-membered rings

The use of surface organometallic chemistry has allowed the production of gold nanoparticles supported on silica, a catalytic system which allows an efficient, high-20

yielding aerobic liquid-phase epoxidation of trans-stilbene in the presence of a peroxide initiator and hydrocarbon solvent (Scheme 1).1

PhPh + O2

Au/SiO2tBuOOH (initiator)

PhPh

O

methylcyclohexane

Scheme 1 25

Optically pure epoxides are available via a highly diastereoselective and enantioselective Darzens reaction involving a chiral titanium complex which is generated in situ from titanium isopropoxide and (R)-binol, as shown in Scheme 2.2

The range of aldehydes includes aromatic, aliphatic and unsaturated substrates and hence allows access to a wide range of cis-glycidic amides. 30

R

O

H N2

O

NPh

H

+

(R)-binol/Ti(OiPr)4, (10 mol%)

CH2Cl2, 4A mol. sieves, 0 oCO

R

O

NH

Ph

30 examples, 52 - 95% yieldee 88 - >97%

Scheme 2

Work by Page has shown that epoxides can be produced in the absence of metal species using the new and highly selective organocatalytic iminium salt shown in 35

Scheme 3. The catalyst works at a relatively low loading, and the process could also


2 | [journal], [year], [vol], 00–00


be applied to other alkenes, a selection of which is shown in the Scheme.3

PhIminium salt (5 mol%), Oxone (2 equiv.)Na2CO3 (4 equiv.), MeCN/H2O (1:1), 2h

PhO

N

O

O

Ph4B

Catalyst:

Ph

69% yield91% ee

Ph

66% yield95% ee

PhPh

Me

58% yield49% ee

PhPh 58% yield

20% ee

Scheme 3

The reductive cyclisation of the 1,2-acetoxysulfenylnitroalkanes shown in Scheme 4 40

gave trans-aziridines in excellent yields. The starting materials were readily available from the copper catalysed 1,2-acetoxysulfenylation of nitroalkenes generated by an in-situ Henry reaction.4

ArNO2

OAc

SR

Fe, AcOH

40 - 50 oC

HN

H H

Ar SR

4 examples 79 - 84% yield

Scheme 4 45

An organocatalytic approach to aziridines using fluoronium ion as the catalyst in the reaction of imines with ethyl diazoacetate has been reported (Scheme 5).5 By using N-fluoropyridinium triflate as the F+ source, this process allows access to N-aryl systems, species that have attracted relatively few organocatalytic methods. The use 50

of N-(2,4-dimethoxybenzene) or N-TMS substituted imines allowed access to NH aziridines in good yield on large scale.

N2

O

OEt +

Ar/R

N

Ar1/R

1

N

Ar/R CO2Et

Ar1/R

1

11 examples15 - 100% yield

cis:trans up to 100%

N

FOSO2CF3

CH2Cl2, RT

Scheme 5 55

The use of the N-amino-tetrahydrophthalimide shown in Scheme 6 in the oxidative aminoaziridation of alkenes was found to give excellent yields of trans-aziridines from trans-alkenes, whereas lower reactivity was observed with cis-alkenes.6 This reaction is believed to proceed via an intermediate aminonitrene which arises from the action of the PhI(OAc)2 upon the N-aminophthalimide. 60

N

13 examples40 - 76%

[trans]5 examples

19 - 25%[cis]

PhI(OAc2)2, K2CO3

CH2Cl2, RTR

1

R2

O

N

O

O

NH2

+R

1

R2

O

N

O

O

Scheme 6

The use of 2-azido-1,3-thiazole as a nitrene source has been reported by Racioppi,




with the resulting nitrene giving aziridines upon reaction with enol ethers as shown 65

in Scheme 7, the first time that such a process has been observed (previous reactions of azides with enol ethers proceed via 1,3-dipolar cycloaddition).7 Aziridine formation via intramolecular 1,3-dipolar cycloaddition and nitrogen extrusion led to the aziridinopyrrolobenzodiazepines shown in Scheme 8, where the products are of interest as DNA-intercalating antitumour antibiotics.8 Finally, the use of the aza-70

Darzens reaction (Scheme 9) as an approach to aziridines has been reviewed.9

N4 examples

42 - 79%

OR1

N

S

N3

R2

OR1

hν

N

S

R3

R2

R3

Scheme 7

XN

N3

R1

R2

N

NX

H

R1

R2

N

NX

H

R1

R2

NN X = CO, SO2

R1, R

2 = H or OMe, OBn

44 - 60%

MeCN, reflux,20 hours

75

Scheme 8

R2

N

R3

R4

LGZ

R1

R3

N

R4

R1

Z

LGR2

N

R4

R3 R

1

R2 Z

- LG

LG = leaving group; Cl, N2 etc. Z = C(O)nR, S(O)nR, P(O)nR, CN

Scheme 9 80

Four-membered rings

The synthesis of β-lactams by thermal rearrangement of aminocyclobutenones leads to cis products in the presence of 1,4-dimethylpiperazine as base, but trans products in the presence of DBU as base, as shown in Scheme 10. The aminocyclobutenones were readily available from the reaction of alkynyl imines with ketene silyl acetals 85

and reduction of the resulting iminocyclobutenones.10

NOPMP

R2O

R1

R2

HN

PMP

base

octane, 110 oC, 48h

R1

NOPMP

R2

R1

+

N NMe MeN

Nbase:

59 - 99% yield

[cis selective98/2 : 82:18]

[trans selective98/2 : 97:3]

(DBU)

Scheme 10




The generation of ketene from acetone and subsequent [2+2] cycloaddition reaction 90

with an aldehyde in the presence of the highly active bifunctional Lewis acid-Lewis base Co(III) catalyst shown in Scheme 11 gave β-lactones with excellent ees and high yields. The ease with which the lactones can be converted into β-hydroxy esters makes a valuable alternative to aldol based approaches to these targets.11

N

OMe

N

O

N N

O O

Co+

tBu

tBu

tBu

tBu

O

- CH4

O

C

CH2

R H

O

catalystCH2Cl2, -78

oC

20 min to 1 h

OO

R

catalyst:


> 99% ee SbF6

95

Scheme 11

The reaction of aryl(alkyl)ketenes with trifluoromethyl ketones in the presence of a triazolium N-heterocyclic carbene has resulted in the asymmetric approach to the 4-trifluoromethyl-β-lactones shown in Scheme 12, which are typically formed in high 100

yield with good diastereoselectivity and excellent enantioselectivity.12

NN

N

OTBS

Ph

PhBF4

Ar1

C

O

RAr

2

O

CF3

+

catalyst (12 mol%), Cs2CO3 (10 mol%)

toluene, -40 oC

OO

Ar1

CF3

R Ar2

19 examples50 - 99% yielddr 4:1 to 23:1ee 91 - 99%

catalyst:

Scheme 12

A three-component, one pot approach to thietanes has been reported as shown in 105

Scheme 13, giving the products in high yield with high diastereoselectivety.13 The process relies upon the treatment of diethyl phosphorodithioate with sodium hydride, addition of the resulting anion to the Michael acceptor and subsequent reaction with an aldehyde to afford the thietane.

O

PEtO

OEt

SH EWG+

NaH, benzeneRT, 3 - 5 h

S 12 examples85 - 95% yield

93:7 to 96:4 trans/cis

+ O Ar

Ar

EWGO

PEtO

OEt

O_

NaH

O

PEtO

OEt

S

EWG O

PEtO

OEt

SEWG

O Ar O

PEtO

OEt

SEWG

O Ar

110

Scheme 13




At the very end of 2009, the formation of highly strained 1,2-diazetidines (see Scheme 14) was reported. This reaction proceeded in good yield when a soft leaving group such as iodide was used. Hard leaving groups tended to result in the formation 115

of almost equal amounts of 6-membered 1,3,4-oxadiazine rings when the R1 group was a carbonyl. When R1 was a sulfone, exclusive formation of diazetidines was observed.14

NHR1

NR

1X

R2

Cs2CO3, RT, MeCN, 5 h N N

R2

R1

R1

X = I5 examples

50 - 98%

Scheme 14 120

Five-membered rings

Several significant new syntheses of pyrroles appeared in 2009, and these are summarised in Scheme 15. Thus, Anary-Abbasinejad15 showed that the reaction of phosphoranes with arylglyoxals yields an intermediate dimethyl carboxylate that 125

cyclises to give pyrroles. The phosphoranes were easily formed from the reaction of a Ph3P-DMAD zwitterion with aniline. Work by Iwasawa showed that a rhodium(I)-catalysed [4+1] cycloaddition between an aza-diene and an alkyne allows access to substituted pyrroles via a rhodium vinylidene complex.16 Ackermann reported two related approaches to pyrroles, the first of which was based upon the titanium 130

catalysed hydroamination of chloroenynes. The development of this into a more useful dehydration-hydroamination of α-haloalkynols was reported in the same publication, hence avoiding the need to prepare chloroenynes.17 A titanium(IV) based synthesis has also been reported by Cież18 in which symmetric systems, including fused pyrrole derivatives, are available by oxidative dimerisation of α-135

azido esters. The reaction proceeds through a titanium(IV) enolate which loses nitrogen to generate a titanium-complexed iminoester. The gold-catalysed dehydrative cyclisation of propargyl amino alcohols was shown by Aponick to give pyrroles,19 a process also applicable to the synthesis of furans and thiophenes. The gold-catalysed cycloisomerisation of acetylene-substituted aziridines reported 140

by Hou20 gave generally high yields of 2,5-disubstituted pyrroles, particularly when carried out in the presence of a protic species. Wilson has reported an uncatalysed Paal-Knoor condensation pyrrole synthesis that utilises microwave irradiation in water, followed by isolation by filtration, an improved and significant ‘green’ addition to the field.21 The final reaction shown in Scheme 15 shows work by Opatz 145

which has shown that α-aminonitriles undergo cyclocondensation with enones to give carbonitrile substituted ∆1-pyrrolines (2H-pyrroles) which undergo a base-induced loss of HCN to give 2,3,5-trisubstituted pyrroles. Starting from aminoacetonitrile itself (R1 = H) allowed the ∆1-pyrroline-5-carbonitriles to be isolated after reaction in pyridine at reflux.22 The reaction of other α-aminonitriles 150

(R1 ≠ H) with enones in the presence of TiCl4/triethylamine allowed the isolation of pyrroles. Other new routes to pyrrolines also appeared in 2009. Thus, Wender and Strand23 used a formal [3+2] cycloaddition between aziridines and non-activated alkynes to give a range of ∆2-pyrrolines. The groups of Marinetti24 and Robina25 have also published new routes to ∆3-pyrrolines. 155




MeO2C

PPh3

NHPh

N

R1

CO2MeAr

CO2Me

CO2Me

O

HAr

O

MeO2CNHPh

CO2Me

HO

Ar

- H2O

- Ph3P=O

R1

N

R2

TMS

R3

R+

[{RhCl(coe)2}2]PCy3/additive (see text)

toluene, 110 oC, 9 - 24 h

N

R3

R2

R

R1


8 examples84 - 90%

R1

Cl

+ H2N R2

TiCl4 (20 mol%)

tBuNH2, PhMe

105 oC, 18 h

N

R2

R1


R3

+ H2N R4

1. TiCl4 (20 mol%), tBuNH2,

PhMe, 105 oC, 18 h

2. AcCl, TiCl4N

R4

R1


R1

X

R2HO

R2 Ac

R3

Anary-Abbasinejad

Iwasawa

Ackermann

Ciez

R1

N3

CO2R2

TiCl4, CH2Cl2, DIEA-96

oC to RT, 12 h

R1

N

CO2R2

TiCl3N

H

R2O2C


R1 R

1

CO2R2

R

OH

NHR1

Au[PtBu2(o-biphenyl)]Cl, AgOTf

THF, mol. sieves, 0 o

C

N

R1

R4 examples

90 - 92% yield

Aponick

N

R2

R1

R3

Hou PPh3AuCl (10 mol%)AgOTf (10 mol%)THF/MeOH, RT

N

R2

R1


Wilson

R1

NH2

OMeO OMe

+H2O

µW N

R1

18 examples

89 - 99% yield

[R1 = Ar or SO2Ar]

R3

Opatz

R1

NH2

CN

R2

O

R3

+

NR

2NC

R1

R3

N

H

R3

R1

R2

see text see text

R1 = H; 11 examples;

33 - 90% yield

R1 = H; 12 examples;

21 - 50% yield [2 steps]

.

Scheme 15 160

Highlights in the synthesis of the fully saturated pyrrolidine nucleus are shown in Scheme 16. Cheng and co-workers26 showed that pyrrolidinones were available via a one-pot, Co-catalysed reductive coupling cyclisation between a nitrile and an




acrylamide. Doye’s group reported27 a one-pot synthesis of pyrrolidines from the reaction of arylcyclopropylalkynes with primary amines. This synthesis proceeds 165

through an initial Ti-catalysed hydroamination to give a cyclopropylimine which rearranges in the presence of ammonium chloride to give a ∆2-pyrroline. Final addition of NaBH3CN, ZnCl2 and methanol gave the pyrrolidines. A catalyst-free intramolecular hydroamination/aminocarbonylation of a series of hydrazine derivatives also allowed access to pyrrolidines.28 Schneider and Enkisch showed that 170

a sequential Mannich aza-Michael process gives 2,3,5-trisubstituted pyrrolidines in enantiopure form when the Mannich process was performed in the presence of L-proline as an organocatalyst.29 Reduction and silylation of the Mannich adducts allowed a stereodivergent aza-Michael ring-closure with NaOEt as base giving excellent yields of 2,5-trans-products, whereas KOtBu gave 2,5-cis-products. 175

Also shown in Scheme 16, Beller and colleagues have developed a convenient one-pot process for the synthesis of succinimides by using commercially available alkynes and amines (including ammonia) in the presence of carbon monoxide and an iron carbonyl catalyst.30

Ar

Schneider and Enkisch

Doye

Cheng

NR

1R

2

NH

R3

O

+

Co(dppe)I2, Zn, ZnI2

H2O, 80 oC, 12 h NO

R1

H

R2

R3

18 examples58 - 91%

R NH2

Ind2TiMe2 (5 mol%)

toluene, 105 oC, 24 h

Ar

NR

NH4Cl

(20 mol%) N

Ar

R

NaBH3CN

ZnCl2, Zn, MeOH N

Ar

R

19 examples15 - 90%

[over 3 steps]

R1

NR

2

H CO2Et

O

1. L-Pro, MeCN

2. NaBH43. TBSCl

+CO2Et

OTBS

R1

NHR2

NR

1

R2

CO2Et

TBSO

base

8 examples, 44 - 97%, ee 82 - 99% 16 examples 81 - 93%

cis/trans: >90/10 (KOtBu)

cis/trans: <5:95 (NaOEt)

R2

R1 R NH2

+CO, Fe3(CO)12

THFN

R1

R2

O

O

R17 examples

37 - 84% yield

Beller

180

Scheme 16

Aponick’s gold-catalysed dehydrative cyclisation of pyrroles (previously shown in Scheme 15) was applied to the synthesis of furans, as shown in Scheme 17.19 185

R1

HO

OH

Au[PtBu2(o-biphenyl)]Cl, AgOTf

THF, mol. sieves, 0 o

C

OR

1

8 examples85 - 99% yieldR

3R

2

R2

R3

Scheme 17

Polysubstituted furans are also available from a Cu(I)-catalysed domino process




involving the rearrangement/dehydration oxidation/carbene oxidation cascade shown 190

in Scheme 18. The process starts with diethyl acetylenedicarboxylate and a alkynol, and proceeds through an intermediate 1,5-enyne.31

CO2Et

CO2Et

R1

HO R2

+

DABCOCH2Cl2, RT

EtO2C

OEtO2C

R1

R2

O2 / CuIDMF, 80

oC

O

EtO2C

EtO2C

R1

R2

O

12 examples, 45 - 78% Scheme 18

Scheme 19 shows that di- and tri-substituted furans can be accessed through a 195

palladium(II)-catalysed intramolecular carbonylation of an aryl iodide followed by cycloisomerisation of an activated alkyne-substituted 1,3-diketone.32

R1

O O

R2

+ CO + Ar I

Pd(PPh3)2Cl2 (6 mol%)

THF, Et3N, 30 - 100 oC

OR

1 Ar

O OR

2

> 25 examples27 - 84%

Scheme 19 200

The Rh(II)-catalysed cyclopropenation of a range of ynamides and sulfonamides results in a formal [3+2] cycloaddition, leading to a series of 2-amido/sulfonamido-furans when diazo dimethyl malonate or a phenyl iodonium ylide (see Scheme 20) were used as cyclopropenating agents. In all cases, better yields were observed with diazo dimethyl malonate.33 205

N

R

R1 R = COR

2 or SO2R

3

Rh2(OAc)2 (2 - 5 mol%)cyclopropenation agent

MeO

O

ONR

R1

R4

CO2Me

R4

O

N2

in toluene or MeO

O

R4

O

IPh

in CH2Cl2

cyclopropenation agent:

16 examples24 - 82%

[diazo dimethyl malonate]

22 - 55%[phenyl iodonium ylide]

Scheme 20

Zhang’s group34 have accessed furo[3,4-d][1,2]oxazines using a gold-catalysed 1,3-dipolar [3+3] cycloaddition between a nitrone and a 2-(1-alkynyl)-2-alken-1-one, as 210

shown in Scheme 21. This reaction probably proceeds through a gold-catalysed cyclisation of the 2-(1-alkynyl)-2-alken-1-one, followed by addition of the nitrone to the resultant furanyl gold complex. When performed in the presence of asymmetric gold catalysts, moderate enantioselectivities were observed (50 – 71% ee).

R3

O

R1

R2

NO R

5

R4

+

Ph3PAuOTf (2.5 mol%)

CH2Cl2, RT, 10 - 30 min.

O

NO

R1

R3

R5

R2

R4 15 examples

53 - 98%dr : 85:15 to > 99:1

215

Scheme 21

Furanones have attracted attention,35,36,37 and several approaches to these important synthetic building blocks are shown in Scheme 22. Thus, Kumar and co-workers35




have shown that 4-oxoalkenoic acids yield dihydrofuranones (X = H) under 220

cyclodehydrative conditions. Bromination of the 4-oxoalkenoic acids, cyclodehydration with P2O5, and dehydrobromination with DBU allowed the isolation of bromodihydrofuranones (X = Br). Blum and colleagues have shown that a combination of a carbophilic Lewis acid gold catalyst and a Lewis basic palladium catalyst allows the conversion of allenoates into furanones (butenolides) through an 225

initial gold-catalysed allenoate rearrangement. Palladium catalysed deallylation, transmetalation and C–C coulping are the other key mechanistic steps.36 Li’s group37 have demonstrated that the Cu(I)-catalysed O-vinylation of a series of vinylcarboxylic acids gave furanones after an Ullmann coupling process. Trost and co-workers have shown that a Ru/In-catalysed redox cycloisomerisation–230

O-conjugate addition process can be used for the atom efficient formation of tetrahydrofurans starting from the propargyl alcohols, also shown in Scheme 22.38

O

OH

OR O

R

O

8 examples (X = H)75 - 87%

8 examples (X =Br)50 - 83%

Kumar

Blum

Me

R2

R1

O

O PPh3AuCl / AgOTf (5 mol%)

Pd2dba3 (5 mol%), CD2Cl2, RT

OO

Me

R1

R2

10 examples68 - 91%

X[see text]

R3 R

3

Br

OH

R

O

Li

CuI (10 mol%), DMCHDA (20 mol%)

K2CO3 (200 mol%), THF, refluxOO

R


R1

R2

R1

R2

R1

OHR

OH

O

O

RR1

5 examples72 - 77%

RuCl

PPh3

PPh3

Catalyst [3 mol%]In(OTf)3 [3 mol%]

20% CSA, 90 minTHF, reflux

Catalyst:

Trost

Scheme 22 235

Alkynes can be used to form sulfur ylides from allylic sulfoxides under gold or platinum catalysis. When performed in an intramolecular fashion with a tether of appropriate length, as shown in Scheme 23, these sulfur ylides have been used to generate tetrahydrothiophenes.39

240

R4

R3

R2

S

R1

OPtCl2 or Au(III)

ClCH2CH2Cl70

oC, 18 - 24 h

S

OR

1

R4 R

3

R2

8 examples24 - 61% [Pt]

69 - 85% [Au(III)]

Au(III):

NO

OAuCl

Cl

Scheme 23

Pyrazoles, by virtue of their wide range of biological activities, attracted a number


10 | [journal], [year], [vol], 00–00


of interesting approaches in 2009. Harrity (Scheme 24)40 showed that cycloaddition 245

between a sydnone and an alkynylboronate was highly flexible and regioselective, allowing access to di-, tri- and tetrasubstituted pyrazole boronic esters. The process was extended to three bicyclic sydnones, allowing access to fused pyrazoles. Suzuki coupling of the boronic acids allowed access to further pyrazoles.

N

O

N

O

R1

R2

R3

B

O

O

+N

N

R1

R2

R3

B

O

O

reflux in xylenes oro-dichlorobenzene

16 - 48 h14 examples

>98:2 selectivety38 - 80%

250

Scheme 24

A simple one-pot route to N-arylpyrazoles from di-tert-butylazodicarboxylate (DBAD), aryl nucleophiles (derived from aryl halides in the presence of n-BuLi) and 1,3-dicarbonyls has been reported (Scheme 25). The process requires generation of 255

the nucleophile, addition of DBAD, and then addition of the carbonyl, and can be adapted to allow access to halogenated pyrazoles and to indazoles.41

R1

O O

R3

R2

R

X

N

N

Boc

Boc

+ +

N

N

R3

R2

R1

R

20 examples25 - 75%

nBuLi

(see text)

Scheme 25

260

List and Müller42 have developed an asymmetric synthesis of highly sought after 2-pyrazolines (e.g. as COX-2 inhibitors) using a chiral Brønsted acid (Scheme 26) to catalyse the cycloisomerisation of α,β-unsaturated hydrazones, the first example of a catalytic asymmetric 6π-electrocyclisation. The process was modified to allow the enantioselective synthesis of 2-pyrazolines starting from an unsaturated ketone and 265

phenylhydrazine, thus removing the need to isolate the hydrazone.

N

NAr114 examples

85 - 99%er 88:12 to 98:2

Ar1 N

HN

Ar2

Ar2

catalyst (10 mol%)

chlorobenzene30 oC, 75 - 96 h O

O

P

O

OH

catalyst:

Scheme 26

A notable advance in imidazole chemistry, shown in Scheme 27, has been described whereby a four-component domino reaction gives excellent yields in short reaction 270

times. The reaction is proposed to occur through an interesting condensation, nucleophilic addition, umpolung, intramolecular addition, dehydration sequence.43

Ar1

CN

O

Ar2

O

Ar2

NH4OAc+

µwave15 - 30 minutes

N

NAr1

Ar2

Ar2

25 examples70 - 90%

Scheme 27


[journal], [year], [vol], 00–00 | 11


The major advances in the synthesis of 1,2,3-triazoles are shown in Scheme 28. 275

Ley’s group used modular flow reactors in which alkynes are delivered by the use of the Bestmann-Ohira reagent. Excess aldehyde was removed using an amine resin, excess base was removed using a sulfonic acid resin, and acidic impurities were removed using a dimethylamine resin. The use of an immobilised copper(I) catalyst, followed by removal of excess copper by a thiourea resin allowed the alkyne to react 280

with an azide to produce 1,2,3-triazoles.44 Work by Fokin showed that 5-iodo-1,4-substituted-1,2,3-triazoles were available from the reaction of 1-iodoacetylenes with azides in the presence of Cu(I) and a tris(triazole) catalyst. The products are excellent substrates for further couplings.45 The use of a tris(triazolyl)methanol catalyst by Pericàs (see Scheme) for the ‘on water’ synthesis of 1,4-disubstituted-285

1,2,3-triazoles starting from benzyl or alkylbromides is a process that is significant in avoiding the manipulation of organic azides.46 The synthesis of 1-substituted triazoles under an atmosphere of acetylene gas47 or by the use of calcium carbide48 have been reported. Click processes have continued to offer significant advances in molecular biology, and the selective labeling of living or intact cells by Popik and 290

Boons and co-workers,49 and by Fast and co-workers50 are notable in this respect.

Me

O

POMe

O

OMeN2

N3 Ar

R H

O

KOtBu/MeOH

+

NH2

SO3HNMe2 NMe2.CuI

NH

S

NH2

N

N

N

R

Ar

see reference 44 for full details; 55 - 89% isolated yield of triazole

Ley

Fokin

IR2

R1

N3+

CuI, ligandTHF, RT, 2 h N

NN

R2

R1

I

N

NN

N

N

N

N

N

N N

tBu

tBu

tBu

Ligand(5 mol%):18 examples

73 - 99%

Pericas

R2

R1

Br +

NN

N

R2

R1

NN

N

N

N

N

N

N N

Bn Bn

Bn

Ligand (1 mol%):

13 examples38 - 99%

Ligand.CuCl, NaN3

H2O, 40 oC, 8 h OH

`

Scheme 28

The major highlights in indole synthesis are summarised in Scheme 29.51-56 Cacchi’s 295

approach uses a copper-catalysed C–H functionalisation of readily available N-aryl enaminones.51 Doyle52 has shown that intramolecular nucleophilic attack of imines by aryldiazoacetates is catalysed by Lewis acids, facilitating the formation of 2,3-disubstituted indoles in quantitative yields. Work from Dong’s laboratory has exploited the reactivity of nitroalkenes which were shown to undergo a Pd-catalysed 300

reductive cyclisation using carbon monoxide as the reductant during a novel C–H amination process.53 Pei and colleagues at Merck have shown that carbon nucleophiles add readily to a series of α-chloro acetophenones to give 2-substituted indoles after a [1,2]-aryl rearrangement.54 2-Substituted indoles are also available


12 | [journal], [year], [vol], 00–00


from the reduction/hydroamination of (2-nitroaryl)alkynes using iron oxide 305

supported gold nanoparticles.55 Sorensen56 has shown that an interrupted Ugi process allows cyclisation to give 3-aminoindoles when an aldimine is reacted with an isocyanide, and indoxyls when a ketimine is reacted. The triflyl phosphoramide shown in Scheme 29 was found to be the optimal acid. Oxindoles are recurrant motifs in natural products and Ackermann57 has developed a new approach that uses 310

an air-stable secondary phosphine oxide to catalyse the arylation of acidic C–H compounds, a process that also allowed the synthesis of azaoxindoles.

N

R

Ar1

O Ar2

X

CuI (5 mol%)phen (17.5 mol%)Li2CO3 (2 equiv)

DMF, 100 oC, air N

Ar1

R

X

Ar2

O

25 examples51 - 84%

phen: 1,10-phenanthroline

CO2Me

N2

N R

BF3.Et2O or Zn(OTf)2

CH2Cl2, RT N

R

H

9 examples100%

CO2Me

NO2

ArR Pd(OAc)2, phen

CO (1 atm.), DMF N

H

10 examples58 - 98%

Ar

OX RM

THF or toluene

-40 oC to RT N

H

17 examples45 - 91%

Cl

NH2

X

R

X = Hal, H or Me or OMe

Pei

Dong

Doyle

Cacchi

Sorensen

EDG

N

R1

O

PPhO

PhONH

S

O O

CF3

acid (1.1 eq.)

R2

NC

CH2Cl2, 2 h, RT

R = H

R

N

H

R1

EDGNHR

2acid (1.1 eq.)

R2

NC

R = alkyl

N

H

R1

EDGO

R

acid:

then K2CO3

17 examples12 - 96%

5 examples48 - 96%

Pd(OAc)2 [5 mol%]

(1-Ad)2P(O)H [10 mol%]

NaOtBu, 1,4-dioxane

100 o

C, 18h

X Cl

N

O

R3

R2

MeR

1

X

N

Me

O

R2

R3

R1 [Ad = adamantyl]

14 examples (X = CH)45 - 91%

3 examples (X = N)60 - 88%

Ackermann

Scheme 29 315


[journal], [year], [vol], 00–00 | 13


A catalytic asymmetric electrocyclisation for the generation of indolines has been developed and relies upon the use of the cinchona-derived ammonium salt shown in Scheme 30.58 Indolines are also available from a palladium-catalysed C–H amination using F+, the role of which is to ensure the oxidation of a C–H insertion intermediate 320

up to a Pd(IV) species whilst still allowing reductive elimination of the aminated product. The use of DMF as labile ligand was crucial to the process.59

R1

CO2iPr

NH2

CO2iPr 1. R

2CHO, MgSO4,

toluene, RT

2. catalyst (10 mol%)

toluene, -15 oC,

K2CO3/ H2O

R1

NH

R2

CO2iPr

CO2iPr

19 examples52 - 94% yield73 - 98% ee

N

N

OHPh

Cl

catalyst:

NHTf

R Pd(OAc)2 [10 mol%]

F+

source [2 eq.]

DMF [1.25 eq.]

DCE, 120 oC, 72 h

N

R

Tf

20examples53 - 91%

N F

OTfF source:

Scheme 30 325

New approaches to benzofurans are summarised in Scheme 31. Barluenga’s group60 showed that a non-heteroatom stabilised carbene complex underwent regioselective [3+3] benzannelation in the presence of 2-imino furans. Li’s group61 have used a Fe-catalysed oxidative Pechmann-type condensation to generate benzofurans rather than 330

coumarins from the reaction of phenols with β-keto esters. The group of Du and Zhao62 used an Fe-mediated intramolecular cyclisation of electron-rich α-aryl ketones in which direct oxidative aromatic C–O bond formation occurs.

(CO)5Cr

R2

R1

O

NR

3

+

THF-80

oC to RT O

NHR3

R2

R1

9 examples51 - 83%

Barluenga

OHR

1

O O

OR2

R+

FeCl3.6H2O (10 mol%)

tBuO OtBu

DCE, 100 o

C, 1h

O16 examples

20 - 75%

Li

Du and Zhao

O

R1

E

R

FeCl3 [2.5 eq.]DCE, RT, 1 - 6 h O

20 examples30 - 94%

CO2R2

R1R

R

E

R1

Scheme 31 335

A wide range of benzazoles has been made available using the transition-metal-catalysed hydrogen-transfer reactions shown in Scheme 32. Thus, benzimidazoles were synthesised from 1,2-aminoanilines and alcohols using crotononitrile as the hydride acceptor, a Ru catalyst, Xantphos and piperidinium acetate; benzoxazoles and benzothiazoles were synthesised using no acceptor, an aldehyde, a 1,2-340

aminophenol/thiophenol and an Ir catalyst with no further additives.63


14 | [journal], [year], [vol], 00–00


R

OHor

R

OHX

H2N

Ru or Ir catalyst

Ru: Ru(PPh3)3(CO)H2

Ir: [Cp*IrI2]2

R1

X

N

R R1

X = O, S, NH

24 examples36 - 85%+

Scheme 32

Six-membered rings

Notable syntheses of pyridines are shown in Scheme 33. Chiba and Wang have 345

developed a Mn(III)-induced reaction between vinyl azides and cyclopropanols. The initial product is a tetrahydropyridine, but this undergoes dehydration and oxidation in the presence of excess Mn(III), AcOH and oxygen to give the pyridines.64 Beauchemin and colleagues65 were able to access pyridines from an intramolecular Cope-type hydroamination, isomerisation, aromatisation sequence starting with the 350

alkynyl oximes shown in Scheme 33. It is of interest to note that the process was also adaptable to enable the synthesis of pyrazines, also shown in Scheme 33.65 Banerjee and Sereda used silica nanoparticles under mild, near neutral conditions to catalyse the formation of pyridines from aldehydes, malononitrile and thiols.66

Mn(acac)3 [1.7 eq.]then AcOH [2.0 eq.]

MeOH, RT

NR3

R1

R2

R4

24 examples30 - 84%

NH2N

NC

R

SR1

CN

12 examples60 - 85%

Chiba and Wang

Banerjee and Sereda

Beauchemin

R1

N3

R2 HO R

3

R4

+

N R1

R2

17 examples45 - 99%

R3

X

N

OH

R1

R2

R3

TsOH [2 mol%], iPrOH

160 - 180 oC, 5 - 8 h (µW)

TsOH [2 mol%], iPrOH

160 - 180 oC, 5 - 8 h (µW)N

N R1

R3

6 examples35 - 81%

X = NBoc X = CH2

R

O

H

CN

CN

+ R1SH+

Silica nanoparticles

EtOH, reflux, 2 - 6 h

355

Scheme 33

Chen and colleagues (Scheme 34) have disclosed an inverse-demand aza-Diels-Alder reaction in which N-tosyl-1-aza-1,3-butadienes react with α,β-unsaturated aldehydes in the presence of a dienamine catalyst, generated from the reaction of a 360

chiral amine with the aldehyde. The products are enantiomerically pure piperidines which can be isolated as hemiaminals or, after PCC oxidation, as lactams.67

R1

N

R2

Ts

R4

R3

O

H+N

R2

X Y

Ts R3

R4

R1


>97% ee

X = Y = Oor X = OH, Y = H

NH

Ph

PhOTMS

BzOH [10 mol%]MeCN/H2O, RT, 8 - 12 h

[10 mol%]

Scheme 34 365


[journal], [year], [vol], 00–00 | 15


The formation of a pyridine ring from the intramolecular inverse-demand Diels-Alder reaction of an alkyne with a 1,2,4-triazine has been used to make azachomans and azabenzofurans, as shown in Scheme 35.68

N

NN

O

NHCbzn

R1

N O

nNHCbz

R1

PhCl, µW, 200 - 220 oC 5 examples

65 - 95%(n = 0 or 1)

Scheme 35 370

Advances in the synthesis of pyrans are shown in Scheme 36. Jiang69 used a DABCO-induced [2+2+2]-cycloaddition cascade to synthesise 4-aryl-4H-pyrans from ethyl propiolate and aryl aldehydes. Gharpure and Reddy used a tandem SN2 alkylation-Michael addition to make tetrahydropyrans from the iodides shown and 375

active methylene compounds.70 This process was easily adapted to allow access to trans-fused bicylic tetrahydropyrans. Johnson and Parsons have developed a formal [4+2] cycloaddition using donor-acceptor cyclobutanes and aldehydes. Sc(OTf)3 was shown to be a useful catalyst for aryl aldehydes; alkyl aldehydes required the use of MADNTf2 (see Scheme) as catalyst. The methodolgy could be streamlined into a 380

[2+2+2] process so that some of the cyclobutanes were constructed in situ from dimethyl methylidene malonate and a styrene in the presence of Sc(OTf)3.71

CO2Et

+ ArCHO

DABCO [1 mol%]1,4-dioxane, 90

oC, 12 h

O

Ar

EtO2C CO2Et 7 examples30 - 82%

Jiang

Gharpure and Reddy

O

I

CO2EtR

E1

E2+

Cs2CO3, DMF, RT

O

R

H H

E1

E2

CO2Et

20 examples55 - 92%

dr - 7:1 to >19:1

Parsons and Johnson

CO2Me

CO2Me

Ar

R

O

H

+

O

Ar

H H

R

CO2Me

CO2Me

17 examples68 - 95%

dr - 77:23 to 99:1

catalyst [see text]

CH2Cl2, RTAr MeO2C CO2Me

+see text

MetBu

tBu

O)2AlNTf2

MADNTf2 (see text):

Scheme 36 385

Pyrimidines attracted several notable new syntheses in 2009, and these are summarised in Scheme 37. Reissig’s group reported a three-component approach using lithiated alkoxyallenes, nitriles and carboxylic acids as precursors. The reaction proceeds via an intermediate enamide which could be ring-closed with 390

ammonium salts to give the pyrimidine.72 Work from the Movassaghi group73 synthesised pyrimidines and quinazolines from the reaction of cyanic acid derivatives with N-vinyl or N-aryl amides in the presence of 2-chloropyridine and trifluoromethanesulfonic anhydride as electrophilic amide activators. Konakahara and colleagues74 used a ZnCl2-catalysed three-component coupling reaction in which 395


16 | [journal], [year], [vol], 00–00


a range of enamines were reacted with triethyl orthoformate and ammonium acetate to give 4,5-disubstituted pyrimidines. Ketones can be used in the place of the enamine, allowing access to 4-monosubstituted pyrimidines. Zhang, Xi and co-workers have shown that an organolithium-promoted three-component reaction between terminal alkynes, elemental sulfur and carbodiimides gives an easy route 400

through to 2,3-dihydropyrimidinthiones.75

N N 6 examples56 - 86%

. OR1

Li

R2

C N

R3

CO2H

R3

O

NH O

R2

OR1

R3

R2

OR1

NH4X, MeOH, sealed tube1.

2.

Reissig

R1

O

HNR

2

N

R4

R3

+

Tf2O,N Cl N N 18 examples

54 - 99%

R1

R4

R3

R2

Movassaghi

CH2Cl2

H2NR

1

R2 N N 20 examples

24 - 99%R

2

R1

Konakahara

CH(OEt)3 [3 eq.]+

NH4OAc [2 eq.]+

ZnCl2 [0.1 eq.]

PhMe, 100 oCO

R1

R2

N NH 14 examples52 - 83%

R

S

1. n-BuLi, THF, -78 o

C, 30 min

2. 80 oC, 4h, then H2O

Zhang and Xi

R H

S8

R1

H

R2

N C N R3

++

R3

R1

R2

OR

Scheme 37

Looking at other non-benzo-fused systems, a significant new synthesis of potentially antimalarial 1,2-dioxanes through the Pd(II)-catalysed cyclisation of readily 405

available unsaturated hydroperoxides has appeared (Scheme 38).76 White and Rice (also Scheme 38) have developed a Pd(II)-sulfoxide-catalysed allylic C–H amination that allows the synthesis of syn-oxazinanones.77 The products are valuable intermediates for the synthesis of syn-1,3-amino alcohols.

Pd(OAc)2 [5 mol%]pyridine [20 mol%]

Ag2CO3

dioxane, 80 oC, 3h

R1

R2

OOHR

3 O OR1

R2

R3

7 examples30 - 35%

de 75:25 to >97:3

R

O NHNs

O

O N

O

R

S SO O

Ph Ph

.Pd(OAc)2

[10 mol%]

PhBQ [2 eq.], DCE, 45 oC, 24 h

Ns

Ns - nosyl; PBQ - phenylbenzoquinone

12 examples67 - 87%dr >20:1

410

Scheme 38

Approaches to benzo-fused six-membered heterocycles are shown in Scheme 39. Thus, Dong and Lin78 have developed a Vilsmeier-Haack, cyclisation, aromatisation


[journal], [year], [vol], 00–00 | 17


approach to quinolines by reacting α-arylamino ketones with PBr3 in DMF. A 415

nickel-catalysed decarboxylative carboamination of alkynes using isatoic anhydrides was shown by Matsubara and Kurahashi to give quinolones.79 Gong has developed an enantioselective synthesis of tetrahydroquinolines starting from 2-(2-propynyl)anilines using a gold-catalysed hydroamination and Brønsted acid catalysed transfer hydrogenation.80 Guimond and Fagnou used a Rh(III)-catalysed 420

oxidative cross-coupling, cyclisation process to form isoquinolines in a regioselective manner from aldimines and alkynes. Rh species were shown to catalyse C–H bond-breaking and C–C and C–N bond-formation.81 Further work from Matsubara and Kurahashi82 showed that chromones are available from the nickel-catalysed cycloaddition of salicylic acid ketals with alkynes, a process which 425

was shown to involve the β-elimination of a ketone. Rueping’s group used asymmetric Brønsted acid catalysis to synthesise dihydroquinazolinones from aldehydes and 2-aminobenzamide.83

N 17 examples63 - 82%

PBr3 / DMFHN

R3

O

R3

R2 R

2

R1 R

1120 oC, 3 - 5 h

N

O

O

O

R1

R3

R2

R4

R5

+

Ni(cod)2 [5 mol%]PCy3 [5 mol%]


N R4

R3

R2

O

R1

R5

16 examples69 - 99%

NH2

R1

R2

NH

EtO2C CO2Et

+

Ph3PAuCH3 [5 mol%]Bronsted acid [15 mol%]


NH

16 examples82 - 99% yield94 - >99% ee

R1

R2

Bronsted acid structure: see Scheme 26

NR

1

R2

R3

+

[Cp*Rh(MeCN)3][SbF6]2Cu(OAc)2.H2O

DCE, 83 oC, 16 h

N

R3

R2

R1


O

O

O

R1

R2

+

Ni(cod)2 [10 mol%]PCy3 [10 mol%]

pyridine, toluene, 120 oC, 6 h

O R2

O

R1

14 examples38 - 99%

Ph

Ph

R3 R

3

NH2

O

NH2

R

O

H

+Bronsted acid catalyst

CHCl3, RT

Bronsted acid structure: see Scheme 26NH

NH

O

RH

10 examples85 - 93%

er 90:10 to 99:1

430

Scheme 39

Seven-membered rings and larger

An unexpected benzothiadiazocine formation occurred when the amino alkenes 435

shown in Scheme 40 were subjected to iodocyclisation conditions. The identical


18 | [journal], [year], [vol], 00–00


products were obtained from the corresponding azides upon intramolecular 1,3-dipolar cycloaddition and nitrogen extrusion from the intermediate triazoline.8

N

HN

O2

S

N3

HN

O2

S

NH2

HN

O2

SCCl4, refluxI2, NaHCO3

R2

R1R

1R

1

R2

R24 examples

30 - 49%

4 examples34 - 52%

440

Scheme 40

An enantioselective Rh-catalysed [4+2+2] cycloaddition between terminal alkynes and dienyl isocyanates gave bicyclo[6.3.0]azocines in the presence of a phosphoramidite ligand as shown in Scheme 41.84 445

R1

NCO

R2+

[Rh(C2H4)2Cl]2 [5 mol%]Phosphoramidite


N

O

H

R1

R2

Phosphoramidite

O

P

OO

O

Ar Ar

Ar Ar

N Ar:

12 examples35 - 82%

97 - 99% ee

Scheme 41

A variety of seven- and eight-membered heterocyclic rings is available in highly asymmetric fashion from the Rh-catalysed intramolecular hydroacylation of 450

alkenals, a rare example of transition-metal-catalysed asymmetric medium ring formation (Scheme 42).85

O

H

X

R1

n

[Rh(ligand)]BF4 [2.5 mol%]CH2Cl2, RT, 1 day

X

O

n

R1

R

X = O, S, S(O); n = 0, 1; R = H, Etligand = (R, R)- Me-DuPHOS

R

15 examples80 - 97% yieldee: 94 - 99%

Scheme 42 455

To conclude, the central role of heterocycles in medicinal chemistry and natural product chemistry, and the huge interest in C–heteroatom bond synthesis, have ensured that 2009 was a productive year with many novel and useful contributions to this most important field of organic chemistry. 460

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