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Odachowski, M., Bonet, A., Essafi, S., Conti-Ramsden, P., Harvey, J. N.,Leonori, D., & Aggarwal, V. K. (2016). Development of EnantiospecificCoupling of Secondary and Tertiary Boronic Esters with AromaticCompounds. Journal of the American Chemical Society, 138(30), 9521-9532.https://doi.org/10.1021/jacs.6b03963
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Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds.
Marcin Odachowski,a Amadeu Bonet,a$ Stephanie Essafi,a Philip Conti-Ramsden,a Jeremy N. Harvey,a†* Daniele Leonori, a,b,‡* and Varinder K. Aggarwala*
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom. b School of Chemis-try, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.
KEYWORDS stereospecific, organoboron, boronic ester, synthetic methods, transition metal–free coupling, quater-nary centres, computational chemistry, DFT
ABSTRACT: The stereospecific cross-coupling of secondary boronic esters with sp2 electrophiles (Suzuki-Miyaura reac-tion) is a long-standing problem in synthesis but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. In order to address this general prob-lem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel-Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C-C bond. Elimination (preceded by further oxida-tion in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, ethers). The reaction also worked well with other electron rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found in which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp2)-C(sp3) and an adjacent C-B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.
1. Introduction
The cross coupling of organoboron derivatives with C-sp2 electrophiles, the Suzuki-Miyaura reaction, is one of the most broadly used reactions with applications that span materials, pharmaceuticals and agrochemicals.1,2 Its mild reaction conditions, functional group tolerance, broad scope and scalability are features which have contributed to its extensive use in both academic and industrial set-tings.2 There is currently a strong impetus to extend this reaction to sp3–sp2 cross-coupling as it offers new strate-gic disconnections for the rapid assembly of chiral (3D) molecules.3,4 However, such a coupling reaction has proved challenging.5,6 This is because the desirable fea-tures of the high configurational stability of the C–B bond which enables boronic esters to be isolated and purified also renders them relatively unreactive and further activa-tion is required in order to engage them in the key transmetalation step of the catalytic cycle.7,8 Furthermore, competing β-hydride elimination can also occur from the aliphatic organo-Pd(II) species which can have an impact on both yield and stereoselectivity.
SCHEME 1. The Suzuki-Miyaura Cross-Coupling of Aliphatic Organoborons
[Pdº(L)]Ar–X
oxidativeaddition
transmetalation
reductiveelimination
b-hydrideelimination
Ar–PdII–X
RR1
BR2 R2
RR1
Ar
RR1
PdII
Ar
Ar–H
RR1
BR2 R2
X
+
Despite these inherent difficulties, examples of Pd-catalyzed sp2–sp3 cross-coupling of chiral organoborons have been reported.5,6,9-20 Pioneering work by Crudden showed that benzylic pinacol boronic esters and diben-zylic neopentyl boronic esters could be coupled with high stereospecificity with retention of configuration with aryl iodides.21-23 Liao found that the stereospecific coupling of dibenzylic organoborons could be rendered invertive us-ing the potassium trifluoroborate salt in place of the neo-pentyl boronic ester (which occurred with retention).24 Molander and Hall employed internal activating groups to promote the coupling of chiral potassium trifluorobo-rates with inversion of configuration.25-28 Suginome devel-
oped a unique stereospecific cross-coupling of benzylic -amino boronic esters that, depending on the addition of a Bronsted or a Lewis acid, occurred with inversion or re-tention of configuration.29-32 More recently, Biscoe report-ed the first stereoinvertive cross-coupling of unactivated secondary potassium trifluoroborates.33
SCHEME 2. The Suzuki-Miyaura Stereospecific Cross-Coupling of Aliphatic Secondary Organoborons
CruddenStereoretentive coupling of chiral benzylic and di-benzylic boronic esters
Ar1 Me
B(pin)+ Ar2–I
Ar1 Me
Ar2
Ar1 Ar2
B(neo)+ Ar3–I
Ar1 Ar2
Ar3
[Pdº]
[Pdº]
Molander and HallStereoinvertive coupling of chiral b-C=O trifluoroborates
X
O
R
BF3K [Pdº]+ Ar–I
X
O
R
Ar
SuginomeStereoretentive and invertive coupling of chiral benzylic a-amino boronic esters
Ar1 NHAc
B(pin)
[Pdº]
PhOH
[Pdº]
Zr(OiPr)4•iPrOH+ Ar2–Br
Ar1 NHAc
Ar2
Ar1 NHAc
B(pin)+ Ar2–Br
Ar1 NHAc
Ar2
BiscoeStereoinvertive coupling of chiral trifluoroborates
Me Et
BF3KAr–Cl
Me Et
Ar[Pdº]
LiaoStereoinvertive coupling of chiral di-benzylic boronic esters
Ar1 Ar2
BF3K+ Ar3–I
Ar1 Ar2
Ar3[Pdº]
+
Single electron processes have also been used for the con-struction of sp2-sp3 bonds and Molander successfully ex-plored the application of dual photoredox and Niº cataly-sis for the coupling of secondary benzylic trifluoroborates and aryl bromides.34,35 Despite the moderate enantioselec-tivity achieved in the single example reported (52% yield, 75:25 e.r.), this exciting approach opens new avenues for exploration.
SCHEME 3. Molander’s Stereoselective Cross-Coupling of Aliphatic Organoborons
Ph Me
BF3K+ Ar–Br
[Ir-photocatalyst][Niº-catalyst]visible light
N
OO
N PhPh
Ph Me
Ar
racemic 52%75% ee
None of the transition metal-based processes have been applied to tertiary boronic esters and their application to secondary boronic esters are rather substrate specific, limiting the applicability of the methodology. This is be-cause the transition metal-catalyzed processes are espe-cially sensitive to steric effects. Indeed, the assembly of all-carbon quaternary stereogenic centres by Suzuki-Miyaura cross-coupling has not been reported.5,6
We have recently developed an alternative non-transition metal-mediated strategy for the stereospecific cross-coupling of secondary and tertiary boronic esters with complete retention of configuration (Scheme 4).36 Our protocol relies on the formation of a chiral boronate complex that upon addition of N-bromo-succinimide (NBS) undergoes a reaction cascade comprising SEAr, 1,2-metallate rearrangement and elimination. This chemistry was inspired by reactions developed more than 40 years ago on simple and symmetrical boranes.37-43 In this paper we provide a full account of this work, describing its gen-esis, mechanistic and DFT studies as well as illustrating the full scope of the coupling reaction.
SCHEME 4. Planned Coupling Protocol
R R1
B(pin)R2
+
R R1
R2
LiNBS
Ar
Ar
chiral boronic ester• secondary
• teriary
electron richaryllithium
arylated product• tertiary centres
• quaternary centres
RR1
R2
Ar
[Br+]
B(pin)
via stereospecificSEAr–1,2-metallate
rearrangement
2. Design Plan
At the outset, we reasoned that a possible way to achieve a transition metal-free stereospecific cross-coupling of boronic esters would be to exploit the inherent nucleo-philicity of an aryl-boronate complex I (Scheme 5A - left). These species are very easy to prepare by the addition of aryllithiums (e.g. 2-lithiofuran) to boronic esters and are both chemically and configurationally stable. In order to trigger a stereospecific 1,2-metallate rearrangement, a positive charge needs to be generated at the aromatic B-bearing carbon. Inspired by the work of Suzuki, Negishi and Levy on the coupling of symmetrical boranes,37-45 we reasoned that addition of a suitable electrophile would generate the cation II by SEAr. This was expected to trig-ger a 1,2-migration and following elimination would give the aryl-coupled product III stereospecifically. However, whilst feasible, this approach was not without concern since our previous studies on the reactivity of related aryl
boronates towards electrophilic reagents (e.g. NBS, I2,46 iminium ions,47 Selectfluor48) showed that they efficiently serve as chiral nucleophiles and undergo electrophilic substitution with inversion of stereochemistry (SE2inv) at the sp3 carbon (Scheme 5B).49 We therefore considered an alternative mode of activation. In particular, we envisaged that treatment of I with an appropriate oxidant would deliver the radical cation IV by SET oxidation (Scheme 5A - right).50,51 This was expected to trigger a 1,2-migration, and, following a 2nd oxidation (from the radical interme-diate V) and elimination, would deliver the arylated product III again with retention of stereochemistry. SCHEME 5. Proposed Pathways for Coupling (A) and Potential Competing Reactions (B)
O B(pin) Li
O
R1
O B(pin)O B(pin)
O
O
E
B(pin)
E O
B(pin)
ox ox•–
E+
1,2-Shift
1,2-Shift
SEAr oxidation
elimination elimination
B(pin)
R
R1
R
R1
R
R1
IVII
V
R1RR1R
R
R1R
O LiR R1
B(pin)+
Nu– Nu–
chiral boronatecomplex (I)
2e– 1e–
ox
ox•–
oxidation
StereospecificTransitionMetal-FreeCoupling
A) Proposed pathways for stereospecific coupling of boronic esters
B) Reaction of aryl boronate complexes with electrophiles
Ph
B(pin) Li
CF3
F3CPh
BrNBS
SE2inv (R)-2185%, 100% es
Ph
B(pin) LiPh
BrNBS
SE2inv/SET(R)-21
50%, 90% es
MeOPh
B(pin)
3,5-(CF3)2-C6H3Li
4-(MeO)-C6H4Li
(S)-1a
III
3. Synthesis of Boronic Esters
All of the required boronic esters were prepared using five general protocols as described in Scheme 6 and the Sup-porting Information. (1) Secondary and tertiary boronic esters 1a-k were prepared by lithiation-borylation meth-odology developed by us.52-55 (2) Benzylic boronate 1l was prepared by enantioselective hydroboration as reported by Yun,56 whereas carene -, pinene- and cholesterol-based substrates (1m-n and 1o-p) were prepared by diastereose-lective hydroboration as described by Renaud57 and in situ trans-esterification with pinacol. (3A) Menthyl and ox-
etane boronic ester 1q and 1r were obtained by Cu(I)-catalyzed borylation as reported by Ito58 and Marder.59 (3B) Nitrile 1s was synthesized according to Yun’s β-boration protocol.60 (4) 2-B(pin)-N-Boc-pyrrolidine 1t was prepared by asymmetric lithiation of N-Boc-pyrrolidine and quenching with i-PrOB(pin) as described by Whiting.61 (5) 1,2-Bis-boronic ester 1u was prepared by asymmetric Morken-Nishiyama diboration.62,63
SCHEME 6. Synthesis of Secondary and Tertiary Bo-ronic Esters.
N
Boc
B(pin)
RO
B(pin)H
B(pin)B(pin)
1t[er 95:5]
1m [dr >99:1]
1n [dr >99:1]
Secondary:1a [er 98:2] :1
1b [er 96:4] :1
1c [er 97:3] :1d [er 96:4] :1e [er 92:8] :1f [er 96:4] :
Tertiary:1g [er 99:1] :1
1h [er 99:1] :1
1i [er 99:1] :1j [er 99:1] :1k [er 99:1] :
R1 = PhCH2CH2
R1 = MeR1 = PhCH2CH2
R1 = (CH2)2CHC(CH3)2
R1 = CH2CH2CO2t-BuR1 = (CH2)4N3
R1 = PhCH2CH2
R1 = PhR1 = PhR1 = PhR1 = Ph
R3 = MeR3 = CH2CH2-p-OMe-PhR3 = i-PrR3 = CH2CH2-p-OMe-PhR3 = PhCH2CH2
R3 = CH2CH2-p-OMe-Ph
R3 = EtR3 = EtR3 = i-BuR3 = p-Br-PhR3 = Me
1o: R = H [dr >99:1]1p: R = TBS [dr >99:1]
H
H H
H
R1 R2
(pin)B R3 (pin)B
OCb
R3 R2R1
boronate complex
1. Lithiation-borylation
1q [dr >99:1]
B(pin)
1a-d, 1f-g, 1p-t
4. Asymmetric lithiation
N
Boc
sec-BuLi, (–)-sparteine, Et2O, –78 ºC
then i-PrOB(pin)88%
3. Cu(I)-catalyzed borylation
2. Hydroboration
R
Method 1HB(cat) then pinacol
Method 2HBBr2•DMS then pinacol
R1 R2
O
O
i-Pr2Nasymmetric lithiation
then R3–B(pin)
via
R2 = HR2 = HR2 = HR2 = HR2 = HR2 = H
R2 = MeR2 = MeR2 = MeR2 = MeR2 = CH(CH2)2
R
B(pin)
1m-n, 1o-p
R R1
XMethod 1
B2(pin)2, Cu(I)X, Xantphos, KOt-Bu
Method 2B2(pin)2, Cu(I)I, PPh3, LiOMe
O
B(pin)
1rX = Cl, I
Ph
HB(pin), CuCl(R,R,S,S)-TangPhos, NaOt-Bu
toluene, rt, 12h71 %
Ph
B(pin)
1l[er 93:7]
A)
B)
B2(pin)2, CuCl, NaOt-Bu (S,R)-JosiPhos, MeOH
THF, rt, 18 h
85%
PhCN
B(pin)
PhCN
1s[er 98:2]
A)
B)
5. Enantioselective diboration
B2(pin)2, Pt(dba)3, L*
MeCN, 60 °C
79%
O
P
O
Ph
ArAr
O
O
Ar = 3,5-(i-Pr)2-C6H3
L*
Ph Ph
Bpin
Bpin
1u[er 97:3]
ArAr
4. Results and Discussion
4.1 Oxidative couplings
We began our studies with the addition of 2-lithiofuran to secondary boronic ester 1a and explored a variety of oxi-dants covering a wide range of electrochemical potential (Scheme 7A). Out of all the oxidants tested, DDQ (2,3-dichloro-5,6-dicyano-1,4-benozquinone) was found to be uniquely effective, resulting in complete reaction after just 5 min at –78 ºC (entry 1). Furthermore the process was completely stereospecific (100% es). At this point a range of enantioenriched secondary and tertiary boronic esters were tested under the optimized reaction condi-tions (Scheme 7B). In general, secondary dialkyl boronic esters 1a, 1c and 1e reacted well and the corresponding products 2a, 2c and 2e were obtained in high yields and complete stereospecificity. This initial screening showed that the process tolerated increased steric hindrance on the boronic ester and ester functional groups. The meth-odology was also applied to hindered cyclic terpene-derived boronic esters 1m-n giving the desired products 2m-n in high yields and complete diastereospecificity.
However, secondary benzylic, -amino and tertiary bo-ronic esters 1l, 1t and 1g failed. Furthermore the boronate
SCHEME 7. Reaction Optimization and Substrate Scope with DDQ.a
O
Ph
B(pin) O B(pin) Li O
(R)-1a[er 98:2]
Oxidantn-BuLi, THF, –78 ºCgrt
then , –78 °C 2a
Entry
1
2
3
4
5
6
7
8
Oxidant
DDQ
DDQ
chloranil
Mn(OAc)3
Cu(OAc)2
CAN
WCl6(p-Br-Ph)3N
•+
Yield (%)
82
20
0
0
0
0
0
0
es (%)b
100
100
–
–
–
–
–
–
O
Ph
O
Ph
O
Ph
O O
2a82%
er 98:2100% es
2m58%
dr > 20:1100% ds
2n62%
dr > 20:1100% ds
2c67%
er 97:3100% es
2e71%
er 96:4100% es
T (ºC)
–78
0
–78grt
–78grt
–78grt
–78grt
–78grt
–78grt
time
5 ming1 h
5 min
5 ming16 h
5 ming16 h
5 ming16 h
5 ming16 h
5 ming16 h
5 ming16 h
A) Oxidant screening
B) Scope and limitations of the process• Successful couplings: • secondary non-benzylic boronic esters
• Unsuccessful couplings:• a-N, benzylic, tertiary boronic esters and other electron rich aromatics
CO2t-Bu
PhPh
O B(pin)
Ph
O B(pin) O B(pin)
NBoc
B(pin)
PhPh
MeO
ate-1l ate-1g ate-1t 22
a Reaction conditions: furan (1.2 equiv.), n-BuLi (1.2 equiv.) in THF (0.3 M) at –78 ºC→rt for 1 h, then 1a (1.0 equiv.) in THF (0.3 M) at –78 ºC then oxidant (1.5 equiv.) in THF (0.3 M).b
Determined by chiral HPLC analysis.
complex 22 obtained by addition of p-MeO-phenyllithium to 1a also failed to deliver the desired product. This was particularly surprising as (i) boronic ester 1a efficiently underwent intramolecular arylation with 2-lithiofuran (2a) and (ii) the p-MeO-phenyl group can be readily oxi-dized by DDQ.64
4.1.1 DFT Calculations & Proposed Mechanism of Oxidative Couplings
The surprising difference in behavior of these boronate complexes prompted us to try to understand the cause of the unsuccessful couplings (Scheme 8). Analysis of the different failed reactions revealed that 2-B(pin)-furan [or p-MeO-C6H4-B(pin)] was the major product and using boronic ester 1g, we were able to isolate olefin 23 (as a mixture of regioisomers) (Scheme 8A). The formation of these products suggested to us that preferential SET oxi-dation of the sp3-C–B bond over the aromatic unit was occurring which would generate the 2-B(pin)-furan, the radical anion of DDQ and a stable tertiary (or secondary benzylic) radical which could ultimately give the olefins 23. This proposed mechanism implied a surprising chemoselectivity in the DDQ oxidation step whereby sec-ondary (non-benzylic) boronate complexes react at the furyl unit (Scheme 8B, Path A), whereas the sp3 C–B bond is oxidized in the cases of secondary benzylic and tertiary substrates (Path B). In order to analyze this further we performed computational studies. DFT calculations based on model i-Pr boronate 24 showed the HOMO, and hence the site for SET, in species such as the boronate complex I to be mostly localized on the sp3 C–B bond. DFT geome-try optimization of the radical produced by SET led to spontaneous C–B bond breaking with formation of a radi-cal. While it does provide an explanation for the unsuc-cessful couplings, this predicted behavior is inconsistent with (i) the observed stereospecific coupling with the di-alkyl secondary boronic esters and (ii) the retention of the cyclopropane unit in example 2m. This led us to consider a different mechanism that did not involve SET. In fact, DDQ is known to be a strong electrophile with a Mayr reactivity parameter of –3.59, comparable to a tropylium ion.65
Thus, a mechanism similar to the one delineated for
the electrophilic quench in Scheme 5A might be opera-tive. As described in Scheme 8C, SEAr from the boronate complex ate-1a with DDQ would give intermediate 25, which, upon stereospecific 1,2-rearrangement and elimi-nation would account for the successful formation of 2a with retention of stereochemistry. DFT studies showed that DDQ could indeed react via this pathway after initial formation of the encounter complex 26•DDQ. The low calculated barriers for this mechanism are consistent with the fact that reaction with DDQ is complete in minutes at –78 °C and it is proposed that in the successful arylation cases this pathway is followed (see SI for more details).
While this mechanism would fully explain the successful couplings reported in Scheme 8B, a unified mechanistic picture would still imply a remarkable ability of DDQ to serve as an electrophile or a one-electron oxidant depend-ing on the furyl-boronate substitution pattern: secondary
non-benzylic substrates would undergo SEAr (Path C) while secondary benzylic and tertiary would undergo sp3 C–B bond SET oxidation (Path D). We believe that in the latter cases Path D operates owing to the greater ease of removal of an electron from the benzylic sp3 C–B bond leading to a more stable benzylic or tertiary radical and we performed further calculations using the model iso-propyl and benzylic boronate complexes 24 and ate-1l. We estimated the free energy of activation ΔG* for one-electron oxidation of the boronate in the encounter com-plex 26•DDQ with Marcus theory, 66,67 using DFT (B3LYP) calculations to obtain the parameters needed (see the SI for details of this Marcus theory modeling and other computations). This yielded ΔG* of 4.7 kcal mol–1 for R = Me, and 2.5 kcal mol for R = Ph (Scheme 8E)). Also, regu-
lar B3LYP-D2 calculations were used to predict free ener-gies of activation ΔG* for SEAr starting from 26•DDQ, which were 3.7 kcal mol–1 in both cases. Hence, as shown in Scheme 8D, reaction through Path C in the encounter complex 26•DDQ is favored by 1.0 kcal mol–1
for the iso-
propyl case (consistent with the successful coupling with secondary alkyl substrates), whereas reaction through Path D is favored by 1.2 kcal mol–1 for the benzylic sub-strate (accounting for the lack of coupling in such cases). The uncertainties in the Marcus theory calculations mean that this agreement with experiment is in part fortuitous, but the conclusion that both SEAr and SET are facile, and that the latter proceeds more readily from 26•DDQ, is more robust.
SCHEME 8. Experimental observations and proposed mechanism for unsuccessful couplings
A) C–B Bond oxidation – Experimental evidences and Proposed mechansim for not succesful couplings
D) SET vs SEAr pathway – DFT studies
O B(pin)
CNO
OCl
Cl
CN
DGTHF, –78 °C
kcal mol–1
O
O CNNC
Cl
Cl
OB(pin)
MeR
DG‡
Path CPath D
R = Me
R = Ph
DG*
4.7
2.5
3.7
0.0
26•DDQO B(pin)
R Me R Me
B(pin)OE
H
O B(pin)
O
O CNNC
Cl
Cl
OB(pin)
MeR
26•DDQ
CN
CNCl
Cl
O
O
Ph Me
R = Me (24)R = Ph (ate-1l)
DDQ
–78 ºC
R = Me
SEAr (Path C)
R = PhSET (Path D)
MeR
MeMe
B) C–B Bond oxidation – DFT studies
O B(pin)
MeMe
O B(pin)+
Me Me
O B(pin)
MeMe
not detected
furyl ring oxidationPath A
sp3 C–B bond oxidationPath B
furyl boronate complex HOMO
possible oxidation
sites
DDQ
Ph
B(pin)Et
2-Li-furanTHF, –78 ºC
then DDQ–78 ˚C, 5 min
O B(pin)Ph
+
C) Proposed mechanism for successful couplings – SEAr
CN
CNCl
Cl
O
O
O B(pin)
CNO
OCl
Cl
CN
Me
O B(pin)
Ph Ph
OB(pin)
Ph
O
OCl
Cl
CNCN
O
Ph
Nu–
O B(pin)
MeMe
DDQ
O B(pin)
MeMe
DDQ
SEAr 1,2-shift elimination
1g 23
O B(pin)
O B(pin)• oxidation• H-atom abstraction
[DDQ]•–
+
Ph DDQPh
via
E) SET vs SEAr pathway – energy diagram
24
ate-1g
ate-1a 252a
4.2 Electrophile-mediated couplings
Our initial study on the DDQ-mediated arylation of chiral boronic esters revealed that the electrophile-promoted pathway was feasible and so we decided to evaluate this
strategy further. As described in Scheme 9, we subjected boronate complex ate-1a (obtained by addition of 2-lithiofuran to boronic ester 1a) to a range of electrophiles and identified NBS to be highly effective at both –78 and 0 ºC (entries 3 and 4). Under these reaction conditions
product 2a was obtained in 92% yield and complete ste-reospecificity with retention of configuration.
SCHEME 9. Optimization of Reaction Conditions for Electrophile-Promoted Couplings.a
Ph
B(pin) B(pin) O
(R)-1a[er 98:2]
E+n-BuLi, THF, –78 ºC to rt
then , –78 °C 2a
PhPh
Entry
1
2
3
4
5
6
E+
I2
NIS
NBS
NBS
NCS
TCCA
Yield (%)
39
42
91
92
61
trace
es (%)b
nd
nd
100
100
nd
nd
T (ºC)
–78
–78
–78
0
–78
–78
time
1 h
1 h
1 h
1 h
1 h
1 h
OO
ate-1a
a Reaction conditions: furan (1.2 equiv.), n-BuLi (1.2 equiv.) in THF (0.3 M) at –78 °C→rt for 1 h, then 1a (1.0 equiv.) in THF (0.3 M) at –78 °C then electrophile (1.2 equiv.) in THF (0.3 M).b Determined by chiral HPLC analysis. TCCA = trichloroi-socyanuric acid.
4.2.1 Couplings between chiral secondary boronic esters with 5-membered ring heterocycles
We then decided to evaluate the scope of this transition metal-free cross-coupling strategy. As described in Scheme 10, a broad range of boronic esters was evaluated with electron rich 5-membered ring aryllithiums. In gen-eral, secondary dialkyl substituted boronic esters reacted very well with 2-furyllithium giving the desired products in high yields and complete es. Pleasingly, secondary ben-zylic and pyrrolidinyl boronic esters 1l and 1t also reacted
well and afforded the desired products in high yields and with complete retention of stereochemistry (2l-2t). Fur-thermore, we found that the stereospecific coupling was compatible with the following functional groups: ester 2e, azide 2f, nitrile 2s, a trisubstituted double bond 2d and an unprotected hydroxyl group 2o. The oxetanyl organobo-ronic ester 1r also coupled effectively under our standard conditions providing the first example of an oxetanyl or-ganoboron being engaged in a C–C coupling reaction.68 This moiety is gaining in popularity as it is emerging as a privileged pharmacophore in medicinal chemistry. In par-ticular, Carreira has shown that 3,3-disubstituted oxetanes are effective polar replacements for carbonyl and gem-dimethyl groups in drug-like molecules.69
Finally, we evaluated the use of other electron rich het-eroaromatics as coupling partners and found that the re-action scope was quite broad. Thus, the coupling reaction was applicable to the following lithiated heterocycles: C-3 furan 3e, C-2 benzofuran 4e, C-2 N-methyl pyrrole 5b, C-2 N-methyl indole 6a and 6q, C-2 thiophene 7a and 7q, and C-2 benzothiophene 8b. In some cases, N-iodosuccinamide (NIS) was found to be superior to NBS as the latter caused the bromination of the electron rich aromatic ring of the reaction product. However, attempts to carry out the coupling with indoles bearing other groups on nitrogen failed, as did coupling of C-3 N-methyl indole. Moreover, reaction with 2-lithio-5-methylfuran resulted in low yield. The power of this ap-proach for the simple modification of natural products was showcased by the successful coupling of cholesterol-B(pin) 1o with 2-lithiofuran and 2-lithio-N-methyl-indole (2o and 6p). Furthermore, by using 1,2-bis-boronic ester 1u a stereospecific di-arylation process was developed affording 2u in 58% yield and complete es.
SCHEME 10. Scope of Electrophile-Mediated Coupling of Secondary Alkylboronic Esters with 5-Membered Het-eroaromatics.a
O
Ph
O
Ph
O O
2ab
92%er 98:2
100% es
2nc
82%dr 99:1
100% ds
2rb
38%
2cc
92%er 97:3
100% es
2ec
90%er 96:4
100% es
O
2mb
77%dr 99:1
100% ds
X X
lithiation (see SI)
then , 0 ºCR1 R2
B(pin)
ON
Boc
X B(pin)
NBS
1 h
2tc
74%er 93:796% es
R1
R2R1
O
PMP
O
PMP
N3
OPh
O
CO2t-Bu
2lc
93%er 93:7
100% es
2fb
71%er 96:4
100% es
2qc
80%dr 99:1
100% ds
2db
94%er 92:8
100% es
N
Ph
S
6ac,e
86%er 98:2
100% es
7ac
92%er 98:2
100% es
3ec
85%er 96:4
100% es
O
Ph
CO2t-Bu
4ec
66%er 96:4
100% es
Ph
S
N
7qc
65%dr 99:1
100% ds
6qc,e
65%dr 99:1
100% ds
6pc,e
75%dr 99:1
100% ds
2oc
78%dr 99:1
100% ds
S
PMP
N
PMP5bc,e
47%er 96:4
100% es
8bc
55%er 96:4
100% es
HOH
H
H H
H
O
TBSOH
H
H H
H
N
OPh
CN
2sd
90%er 98:2
100% es
O
R2
O
Ph
CO2t-Bu
Ph
O O
2ub
58%er 97:3
100% es
O
Ph
a Reaction conditions: see Scheme 9. b NBS added at 0 ºC. c NBS added at –78 ºC. d NBS added at –100 ºC. e NIS was used instead of NBS. $ Electrophile added at –100 °C.
4.2.2 Couplings between chiral secondary boronic esters with 6-membered ring aromatics
Having evaluated the ability of chiral secondary bo-ronic esters to undergo the stereospecific NBS-coupling with electron rich heteroaromatics, we moved on to the more challenging 6-membered ring electron rich aromat-ics. As their corresponding boronate complexes are com-petent sp3-nucleophiles (SE2inv, see Scheme 5B),46-49 the reactions conditions had to be modified to promote reac-tion on the aromatic ring (Scheme 11A).
We started our investigation using the 3,5-(MeO)2-C6H3–Li, taking advantage of the synergistic effect of all 3 donor groups of the boronate complex promoting bro-mination on the aromatic ring at the para position.70 This would be followed by stereospecific 1,2-metallate rear-rangement and elimination. As shown in Scheme 11A when the reaction was performed using the standard conditions a mixture of the desired product 9a, the B(pin)-incorporated product 9aa (see Section 4.3) and the alkyl bromide 21 was obtained in a 81:6:13 ratio as deter-mined by crude GC analysis (entry 1). As compound 9aa arises from an incomplete nucleophilic elimination step, we repeated the reaction adding NBS in MeOH, in order to promote the elimination pathway (MeOH could act as the nucleophile). Pleasingly, this simple modification of the reaction conditions completely suppressed the for-mation of both 9aa and 21 (entry 2). As SEAr can be mod-
ulated by the reaction media, we now believe that the increased polarity of the mixed solvent system to be the reason for the improved selectivity.71 Under these reaction conditions 9a was isolated in 83% yield. When the reac-tion was tested with a single methoxy group in the aro-matic unit (using 3-MeO-C6H4–Li) no product 11a was observed under standard reaction conditions (entry 3) but following addition of NBS in MeOH, a mixture of 11a, 11aa and 21 in 69:29:3 ratio was obtained (entry 4). We there-fore reasoned that in order to maximize the beneficial effect of MeOH a complete solvent exchange was re-quired. Thus, after formation of the boronate complex in THF at –78 ºC the solvent was removed under high vacu-um at 0 ºC. MeOH was then added and the mixture was cooled to –78 ºC prior to NBS addition. Under these con-ditions the desired product 11a was obtained with com-plete selectivity and isolated in 72% yield (entry 5). As shown in Scheme 11B, a broad range of electron rich benzene derivatives was evaluated. The following lithiat-ed benzene derivatives coupled successfully with both secondary dialkyl as well as benzylic boronic esters fur-nishing products in high yield and complete stereospeci-ficity: 3,5-dimethoxy (9a, 9q, 9l), 3-N,N-dimethylamino (10a, 10q), and 3-methoxy (11a, 11l). Disubstituted elec-tron rich aromatics e.g. 2,3- or 3,4-dimethoxy (12b and 13b) aryllithiums also worked but lower yields were ob-served in these cases as a result of competing ipso substi-tution (giving the aryl bromide and starting boronic ester)
and competing reaction at the sp3 carbon (giving bromide 21). Pleasingly Br substitution e.g. at C-5 was tolerated giving 14b in good yield and complete es. The coupling was successful with the weakly nucleophilic naphthyl (both at C-1 and C-2) and the phenanthryl moiety giving products 15a, 16b and 17b. Furthermore, the coupling was also successful with weakly donating aromatics e.g. 3,5-dimethylphenyl and 2-lithio-6-methoxypyridine, giving products 18b and 20b, respectively. However, not all aromatics worked, due to competing processes. If bromination occurs on the aromatic ring, the desired arylation takes place but competing reaction can also occur at the sp3 carbon of the boronate complex. Substitution on the aromatic ring which pushes electron density onto boron (i.e. o- and p-donor groups) favors the latter process. This explains why 2- or 4- methoxyphenyl-lithium were not effective whereas 3-methoxyphenyllithium, giving 11a, was successful. With-
out a meta donor group, e.g. phenyllithium, bromination at the sp3 carbon dominated and no arylation was ob-served. With a weak meta donor group, e.g. 3-methylphenyllithium, a ~3:1 mixture of 2-bromo-4-phenylbutane and the desired coupled product were ob-tained showing the lower limit of the aromatic group that can be employed. We have previously found that benzylic boronate com-plexes are better nucleophiles at the sp3 carbon of the boronate than their non-benzylic counterparts. This competing undesired reaction could account for the lower yields of the desired arylation obtained in the benzylic versus the non-benzylic substrates e.g. compare 9a/9l, 11a/11l, 18b/18l. The cholesterol B(pin) 1o reacted well with the electron rich aryllithiums giving products 9o and 10p in high yield and complete diastereospecificity.
SCHEME 11. Optimization (A) and Scope (B) for Coupling of Secondary Boronic Esters to 6-Membered Electron Rich Aromatics.a
A) NBS coupling with 6-membered ring heterocycles: Optimizationa,b
B) Scope of the process with secondary boronic esters
Ph
RMeO
Br
B(pin)
Nu–
Ph
RMeO
Br
B(pin)Ph
RMeO
H
B(pin)9aa11aa
9a11a
1,2-shift
OMeMeO
Ph
9a83%
er 98:2100% es
Ph
10ac
65%er 98:2
100% es
Ph
15a89%
er 98:2100% es
PMP
18b83%
er 96:4100% es
Ph
11a72%
er 98:2100% es
H/Br
lithiation (see SI)
then , –78 ºCR1 R2
B(pin)
R1 R2
(pin)B R3
R1 R2
R
R
OMe NMe2
OMeBr
Ph
NMe2 OMe
OMe
PMP
OMe
OMe
PMP
OMe
PMP PMP
10qc
70%dr 99:1
100% ds
9q84%
dr 99:1100% ds
MeO
12b46%
er 96:4100% es
17b53%
er 96:4100% es
16bd
62%er 96:4
100% es
13b51%
er 96:4100% es
14b81%
er 98:2100% es
9o91%
dr 99:1100% ds
10pc
68%dr 99:1
100% ds
TBSOH
H
H H
HN
OMe
PMP
20be
58%er 96:4
100% es NMe2
ROH
H
H H
H
OMeMeO
Ph
OMeMeO
9l64%
er 97:3100% es
11l43%
er 97:3100% es
18l21%
19b17%
Ph
OMe
Ph PMP
RNBS
MeOH, –78 ºC, 1h
9a11a 21
: R = OMe: R = H
Ph
RMeO
BrPh
B(pin)
(R)-1a[er 98:2]
n-BuLi, THF, –78 ºC to rt
then , –78 ºC
OMeR
Ph
OMeR
Br
Ph
B(pin)B(pin)
Ph
R
MeO
NBS
solvent, –78 ºC, 1 h
9aa11aa
: R = OMe: R = H
Solvent
THFTHF, NBS
added in MeOH
THFTHF, NBS added in MeOH
THF then solvent switch to MeOH
9a
8199 (83%)
11a
<168
99 (72%)
9aa
6<1
11aa
<129<1
21
13<1
21
<13
<1
Entry
12
345
R
OMeOMe
HHH
B(pin)MeO
R
Ph
[Br+]
B(pin)MeO
R
Ph
BrSEAr
vs
B–
a Re-action conditions: for lithiation conditions see SI; boronic ester (1.0 equiv.) in THF (0.3 M) at –78 °C then solvent switch to MeOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78 °C, 1h. b Optimization perfomed with GC-MS, isolated yields in parentheses. c NIS used instead of NBS. d Reaction performed at –15 °C, e DBDMH (1,3-dibromo-5,5-dimethylhydantoin) used instead of NBS.
4.2.3 Couplings of chiral tertiary boronic esters
Having evaluated the use of secondary boronic esters in the NBS-mediated stereospecific cross-couplings meth-odology, we moved to the more challenging tertiary bo-ronic esters, a class of substrates for which transition metal–based methodologies are currently not available.5,6 As our approach goes through a distinct mechanistic pathway, we were keen to explore if our methodology had
the potential to solve this unmet synthetic challenge. As shown in Scheme 12, a range of tertiary alkyl and benzylic boronic esters with both 5- and 6-membered ring aryllith-iums were found to work well. Trialkyl, benzylic, and di-benzylic boronic esters 1g–k were coupled with 2-furyllithium in high yields and complete es furnishing products 2g–k. The chemistry was also extended to 2-lithiobenzofuran giving 4g and 4h. Electron rich 6-membered aryllithiums were evaluated next. In the case
of the 3,5-dimethoxy-phenyllithium both alkyl and ben-zylic substrates were successful and the desired products 9g and 9h were obtained in high yield and complete es. The coupling was successful with other electron rich ar-omatics such as 3-methoxy-phenyllithium (11h), 1- and 2-naphthyllithium (15g and 16g), 6-methoxy 2-lithio-pyridine (20g) and 3,5-dimethyl-phenyllithium (18g). A remarkable example is the successful coupling with the weakly electron rich aromatic, 3-methyl-phenyllithium which gave product 19g in 46% yield and complete es. We rationalized the success of this example with the in-creased steric congestion offered by the three alkyl groups that slows down the rate of sp3 halogenation enabling reaction at the aromatic ring to compete more favorably.
SCHEME 12. Coupling of Tertiary Boronic Esters.a
Ph
9h63%
er 99:1100% es
Ph
18g66%
er 98:2100% es
Ph
9g78%
er 99:1100% es
OMe
MeO
OMe
MeO
15g75%
er 99:1100% es
Ph
Ph
20gc
60%er 99:1
100% es
N
OMe
2h83%
er 99:1100% es
2i76%
er 99:1100% es
2g89%
er 99:1100% es
2j94%
er 99:1100% es
2k53%
er 98:299% es
19g46%
er 99:1100% es
11hc
47%er 99:1
100% es
18h24 %
R R1
B(pin)R2
lithiation (see SI)
then R R1
B(pin)R2Ar
Ar–Br/HNBS
MeOH, –78 ºC, 1h R R1
ArR2
Ph
O O
Ph
O
Ph
O
Ph
O
Ph
Br
Ph
Ph Ph
MeO
4g66%
er 99:1100% es
4h64%
er 99:1100% es
16gb
49%er 99:1
100% es
Ph
PhPh
OO
a Reaction conditions: for lithiation conditions see SI; bo-
ronic ester (1.0 equiv.) in THF (0.3 M) at –78 °C then solvent switch to MeOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78 °C, 1h. b Reaction performed at -15 °C, c DBDMH (1,3-dibromo-5,5-dimethylhydantoin) used instead of NBS.
4.3 Stereospecific arylation-B(pin) incorporations
During the optimization of the NBS-mediated coupling of secondary boronic esters and 6-membered ring aryllithi-ums we observed the unexpected formation of products where the B(pin) group was incorporated into the aro-matic ring (Scheme 11A, see entry 1 and 4). This observa-tion set the stage for the development of a unique ortho-borylation- -coupling reaction. Mechanistically we believe this product arises from an incomplete nucleophilic B(pin)-elimination reaction from intermediate 27 (Scheme 13A). This would lead to a nucleophilic 1,2-Wagner-Meerwein shift of the B(pin) moiety forming the more stable carbocation 28. Final deprotonation would furnish the B(pin)-incorporated product 18aa. Based on this mechanism, we speculated that whilst a polar solvent (e.g. MeOH) was required to facilitate the SEAr we needed to reduce its ability to serve as a nucleophile in order to favor the 1,2-Wagner-Meerwein shift.71 We therefore test-ed the sterically hindered alcohol i-PrOH in place of MeOH and the ratio of 18a:18aa:21 was improved to 5:88:7 as determined by GC-MS. Furthermore by using a 1:1 i-PrOH–CH3CN solvent mixture we were able to selectively obtain product 18aa and to isolate it in 90% yield. With the optimized reaction conditions we evaluated the scope of this novel coupling reaction. As described in Scheme 13B, a variety of aryllithiums reacted well providing the desired products in good yields and complete es (9ba, 11ba, 15ba, 18aa,). We were pleased to see that tertiary groups were compatible as well and delivered remarkably high yields furnishing very sterically congested quater-nary scaffolds (9ga, 18ga). It was also possible to perform this reaction on heterocyclic substrate such as benzothio-phene (8ba). We believe that this particular result is a very attractive tool for introducing neighboring function-alities in a single transformation. Moreover, the B(pin) moiety serves as a useful handle for further functionaliza-tion either by transition metal catalysis or the protocol described herein.
SCHEME 13. Method for Retaining the Boronic Ester in the Coupling Reaction
OMeMeO
PMP
9ba38%
er 96:4100% es
PMPPMP
15ba72%
er 96:4100% es
Ph
18aa90%
er 98:2100% es
11ba55%
er 96:4100% es
PhPh
9ga46%
er 99:1100% es
OMe
MeO
PhBr
Ph
B(pin)
1a
n-BuLi, THF, –78 ºC to rt
then , –78 ºCPh
Br
Ph
B(pin)B(pin)
Ph18a 18aa 21
H/Br
lithiation (see SI)
then , –78 ºCR1 R2
(pin)B R3
R1 R2
(pin)B R3
R1 R2
R3R
RR
OMe
18ga83%
er 99:1100% es
solvent switch
then NBS
solvent switch toCH3CN–i-PrOH (1:1)
then NBSCH3CN–i-PrOH (1:1)
0 ºC, 1h
B(pin)
B(pin) (pin)B (pin)BB(pin)B(pin)
B(pin)2.7 1
Solvent switch to
– MeOHi-PrOHCH3CN
CH3CN–MeOH (1:1)CH3CN–i-PrOH (1:1)
18aa
<160 (60%)
53422
18aaa
<137
88 (55%)55 (47%)
5394 (90%)
21a
99374754
Ph
Br
B(pin)
Ph
H
B(pin)
BasePh
Br
B(pin)
Nu–
Ph
vs
Entry
123456
B) Scope of the stereospecific arylation-B(pin) incorporation processb
A) Optimization of the arylation-B(pin) incorporation process
S
PMP
B(pin)
8ba46%
er 96:4100% es
27 28
a GC conversion, isolated yield in brackets. b Reaction conditions: for lithiation conditions see SI; boronic ester (1.0 equiv.) in THF (0.3 M) at –78 °C then solvent switch to CH3CN–i-PrOH then NBS (1.2 equiv.) in MeOH (0.2 M), –78 °C, 1h.
4.4 Trends in reactivity
The successful outcome of the coupling reaction is de-pendent on a number of factors but the extent of compet-ing reactions at the sp3 carbon versus the aromatic ring appears to dominate in many cases. Considering these two factors only, trends in reactivity can be readily un-derstood (Scheme 14). For tertiary and secondary non-benzylic boronates, as the aromatic becomes less electron rich, the yield for the coupled product declines since re-action of NBS at the less electron rich aromatic becomes increasingly less favored. Comparing benzylic secondary 2l, 9l, 11l and 18l) and tertiary (2h, 9h, 11h and 18h) prod-ucts the same trend is observed. In addition, the in-creased resistance to reactions at the sp3 carbon of the tertiary alkyl substrates leads to increased yields of cou-pled products compared to the corresponding secondary substrates (cf. 19g and 19b).
SCHEME 14. Main Competing Processes which De-termine the Outcome of the Coupling Reaction Illus-trate Trends in Reactivitya
Ph
OB(pin)
incre
ase
d s
teri
c h
ind
ran
ce
at
sp
3-C
18g66%
19g46%
2a92%
9a83%
18b83%
19b17%
R R1
Ar
B(pin)
[Br+]
vs
R R1
Ar
B(pin)
[Br+]
• highly electron rich Ar• not influenced by sterics
• not influenced by Ar• sterically accessible sp3-C
electron-richness of aromatic group
SEAr
SE2inv – not affected
B(pin)
Ph
MeO
MeO
B(pin)
Ph
B(pin)
Ph
B(pin)
Ph
B(pin)
PhEt Et
SE2
inv
SE
Ar
- n
ot
affe
cte
d
Ph
OB(pin)
Et
2g89%
9g78%
B(pin)
Ph
MeO
MeO
Et
SEAr – Path A SE2inv – Path B
a Yields for arylation process.
4.5 DFT and React-IR studies
Additional DFT calculations were performed for the elec-trophilic reactions with NBS. Using the same model iso-propyl boronate anionic complex 24, two mechanisms were considered: one involves electrophilic addition at the aromatic ring (Path A, SEAr), whereas the other in-volves electrophilic attack at the sp3 C–B bond (Path B – SE2inv) (Scheme 15A). In both cases, transition states were located (Scheme 15B), involving near-linear N–Br–C arrangements corresponding to nucleophilic substitution at bromine. For Path B, the TS leads directly to succin-imide anion and the bromoalkyl species with release of boronate ester. For Path A, electrophilic attack of the bromine triggered migration of the alkyl group in the same reaction step, without further barrier. The migra-tion is already well under way at the TS. The discrete cat-ionic intermediate II (Scheme 5A) is never actually formed but is nevertheless a useful species to consider when formulating the overall process. This TS is the sig-nificantly more stable one with the furyl model boronate complex, consistent with the observed high yields for alkylated furan. Additional calculations were performed using 3,5-dimethylphenyl and phenyl substrates. The TS for Path B has almost the same free
SCHEME 15. DFT Calculations of the Main Compet-ing Processes Illustrating Trends in Reactivity
OB(pin)
[Br+]
[Br+]
B(pin) B(pin)O
B(pin)
Path B
SE2inv
Path A
SEArO
Br
O B(pin)+
A) Reaction of boronate complex 24 with NBS
B) Transition state analysis – B3LYP-D2/6-31+G(d)
Path A: concerted SEAr and 1,2-shift
OB(pin)
Br
N OO N OO
OBrB(pin)
+
Path B
OB(pin)
Br
N OO
N OO
+
Br
O B(pin)
+
C) Activation energies and solvent effects – B3LYP-D2/6-31+G(d)
Solvent
Path A
Path B
THF
6.7
15.3
THF
17.8
15.4
MeOH
16.0
16.2
THF
21.7
13.9
Boronate complexes
24
energy in all three cases, but the barrier height for Path A increases sharply for these less nucleophilic aryl groups (Scheme 15C). In the case of phenyl, the barrier is now much higher than for oxidation of the C–B bond – con-sistent with experiment. For 3,5-dimethylphenyl, the SE2inv (Path B) is predicted to be strongly favored in THF as observed. However, in MeOH the two barriers are al-most the same, although experimentally Path A is fa-vored. The TS for path A is much more polar than the reactants, so the solvation free energy for the TS is large compared to that for reactants. This helps to explain why more polar solvents favor path A over path B. Also, con-sidering the uncertainties in continuum models of solva-tion free energy, one must bear in mind that the calculat-ed free energy for this TS is likely somewhat inaccurate. In previous work,72 we have shown based on calibration with very accurate coupled cluster calculations that B3LYP with dispersion corrections, as used here, yields reasonably accurate results for similar boronate chemis-try. However, it should also be noted that conformational complexity, treatment of the lithium counterion, and modeling of solvation introduces further sources of error.
The boronate reaction with NBS could be followed by React-IR.73 The boronate complex was prepared and cooled to –78 °C and the mixture monitored by React-IR.74 Addition of NBS in MeOH over 60 seconds resulted
in rapid consumption of the ate complex ate-9a, essen-tially instantaneously, indicating that the reaction was extremely rapid (Scheme 16). The low free energy barrier calculated for the reaction with the furan boronate com-plex suggests that reaction with NBS should be very rapid at –78 °C, and indeed, reaction was observed to occur in less than a minute for the dimethoxyphenyl boronate, which should have a similar reactivity.
SCHEME 16. React-IR Studies of Reaction at –78 °C
Ph
B(pin)
OMe
MeONBS
MeOH, –78 ºCPh
OMeMeO
ate-9a
IR band: 1588 cm–1
9a
IR band: 1570 cm–1
ate-9a – 1588 cm–1
9a – 1570 cm–1addition of NBS
5. Conclusions
We set out to explore two different pathways by which boronate complexes derived from an aliphatic secondary or tertiary boronic ester and 2-furyllithium could react with either an oxidant or an electrophile to give a coupled product stereospecifically. Of the oxidants tested, DDQ was uniquely effective but it only worked with a limited range of secondary boronic esters; benzylic and tertiary boronic esters were ineffective. From analysis of the products obtained from the unsuccessful reactions and from DFT studies we concluded that in those cases DDQ oxidized the aliphatic C-B bond leading to a relatively stable (benzylic or tertiary) radical. In the cases of non-benzylic aliphatic secondary boronic esters which did react successfully, DDQ acted as an electrophile – not an oxidant, triggering 1,2-migration and subsequent elimina-tion. NBS was a better electrophile than DDQ as it was less prone to oxidize the aliphatic C-B bond. This reagent was applicable to a broad range of secondary and tertiary boronic esters with very different steric demand and tol-erated a range of functional groups (esters, azides, ni-triles, alcohols, and ethers). It was also applicable to a range of electron rich heteroaromatics including pyrrole, indole, thiophene, benzofuran and benzothiophene. It was important that the NBS-mediated bromination oc-curred at the ortho or para position of the aromatic ring in relation to the boronate; if the electronics favored reac-
tion at the ipso position then competing ipso bromina-tion occurred returning the boronic ester (e.g. 2-lithioindole was successful but the 3-lithioindole failed) (Scheme 17).
SCHEME 17. Reactions with 5-Membered Ring Aromatics
X XB(pin)
(pin)B
R
R1
R
R1
[Br+]
[Br+]
X R
R1
X
Br
[Br+]
ipso-substitution
vs
The coupling reaction was also applicable to 6-membered ring aromatics provided they had donor groups in the meta position. The meta donor group together with the (electron rich) boronate worked synergistically, promot-ing bromination on the aromatic ring. If the donor group was para to the boronate it promoted bromination at the sp3 carbon instead and no coupled product was obtained. This competing reaction was increasingly observed when weaker meta donors on the 6-membered ring were em-ployed e.g. using 3-methylaryllithium. The coupling reac-tions with 6-membered ring aromatics required different conditions: it was found that solvent exchange from THF to MeOH led to improved yields of the desired coupling product. Using these conditions, a range of 6-membered ring aromatics, including 1- and 2-naphthalenes were suc-cessfully coupled to secondary and tertiary boronic esters. Solvent choice played a major role in the outcome of the coupling reaction. Using MeCN-iPrOH, we found that the B(pin)- moiety was retained in the product, ortho to the boron substituent. We believe this arises from a 1,2-Wagner-Meerwein shift of the B(pin) group which re-lieves steric hindrance followed by loss of a proton. Again this protocol, which created a new C(sp2)-C(sp3) and an adjacent C-B bond, was applicable to a range of secondary and tertiary boronic esters.
SCHEME 18. Reactions with 6-Membered Ring Aromatics.
R R1
B(pin)EDG
m-EDG and boronatepromote reaction
on aromatic
[Br+]
R1R
EDG
Br
B(pin)
MeOH
R1R
EDG
Br
B(pin)
MeOH
promotes reaction at aromatic
promotes reactionat aromatic but doesnot capture B(pin)
i-PrOH
R1R
EDG
R1R
EDG
B(pin)
R R1
B(pin)
EDG
[Br+]
p-EDG promotesreaction at sp3-C
vs
All of the coupling reactions occurred with complete ste-reospecificity.
DFT calculations supported the mechanistic scenario put forward and the very low barriers calculated for addition of NBS to electron rich aromatics were commensurate with the almost instantaneous reaction observed by Re-act-IR at -78 °C. Interestingly, no cationic intermediates are involved during the process; the 1,2-migration occurs as the NBS reacts with the aromatic ring.
The methodology described provides a new way of cou-pling secondary and tertiary boronic esters with electron rich aromatics. Since there are a growing number of prac-tical methods for making aliphatic secondary and tertiary boronic esters with very high enantioselectivity, this new stereospecific method should find wide application. Even in the cases where racemic or achiral substrates are used the absence of costly or difficult-to-remove transition metals, which are often avoided at late stage processes of drug manufacture, are further attractive features of the methodology.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures, 1H and 13C NMR spectra, HPLC traces, React-IR plots (PDF). DFT calculations (PDF).
AUTHOR INFORMATION
Corresponding Author
[email protected]; [email protected] [email protected]
Current Addresses
† JNH: Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Heverlee, Belgium. ‡ DL: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK. $ AB: Department of Chemistry, University of Hull, Cotting-ham Road, Hull, HU6 7RX, UK.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank EPSRC (EP/I038071/1) and the European Research
Council (FP7/2007-2013, ERC grant no. 246785) for financial
support. A. B. thanks the Marie Curie Fellowship program (EC
FP7 No 329578).
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TOC:
R R1
B(pin)R2
+
R R1
R2
Li
chiralboronic ester
• high ee• stable
• easy to make• high modularity
aryllithium
• easy to make• many available
chiralarylated product
• high ee• widespread motif
• all C-stereogenic centres• incorporation of B(pin)
stereospecifictransition metal-free
coupling
• full scope• DFT studies
• React-IR studies
R R1
R2or
B(pin)
NBSAr
Ar Ar
