] Jack

Cathleen M Crudden

Emily Labine

Kazem Ghozati

L.-Y Chen

Laetitia Chausset-Boissarie

Varinder K Aggarwal

CiteSeerX

DOI: 10.1002/chem.201303683
Enantiospecific, Regioselective Cross-Coupling Reactions of Secondary
Allylic Boronic Esters
Laetitia Chausset-Boissarie,[a] Kazem Ghozati,[b] Emily LaBine,[b] Jack L.-Y. Chen,[a]
Varinder K. Aggarwal,*[a] and Cathleen M. Crudden*[b, c]
Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday
Asymmetric cross-coupling reactions in which stereo-
chemistry-bearing CC bonds are created are still in their
infancy. Considering the wealth of compounds that can be
prepared by cross-coupling methodologies, and the impor-
tance of synthetic methods leading to enantiomerically en-
riched products, this is a surprising reality. Advances in this
area have occurred in the past few years, in the realm of
enantioselective or enantiospecific cross-couplings of chiral
electrophiles.[1]
In the area of cross-coupling of stereodefined nucleo-
philes, Crudden originally reported the enantiospecific
cross-coupling of chiral enantiomerically enriched benzylic
boronic esters [Eq. (1)].[2,3]
Similar reaction conditions were shown by Aggarwal[4] to
be applicable to tertiary propargylic boronic esters [Eq. (2)]
and by Crudden to allylic boronates in racemic form
[Eq. (3)].[5] Elegant examples of stereospecific cross-cou-
plings of unrelated chiral organoboronic esters have fol-
lowed from Suginome, Hall and Molander,[6] and recent ad-
vances have been reported in the stereospecific Stille cross-
coupling reaction.[7,8]
Herein, we address the question of enantiospecificity, iso-
meric composition and mechanism in the coupling of enan-
tiomerically enriched versions of allylic boronic esters, such
as 6 and related derivatives. We demonstrate that the cou-
pling proceeds with almost perfect stereoretention in all
cases, and high g-selectivity with several classes of sub-
strates. The method provides a valuable addition to the
cross-coupling of allylic organometallics, such as organosi-
lanes,[9] in which the introduction of chirality in the starting
materials can be challenging. Remarkably, this is the first
report of the coupling of chiral, non-racemic allylic organo-
boron species,[10] a readily available class of substrates.[11]
After brief optimization, conditions for the cross-coupling
of allylic boronic esters were found, with small but signifi-
cant changes from the previously described coupling proce-
dure[2] for benzylic boronic esters. Most importantly, with
the addition of only two equivalents of PPh3 relative to Pd,
the reaction proceeded in high yield with virtually complete
enantiospecificity.
In addition to providing good yields and high g/a selectivi-
ties for substrates similar to those previously reported in
racemic form,[5] equally good results were obtained regard-
less of the geometry of the olefin (entries 1 and 2, Table 1)
and branched aliphatic substituents were well tolerated
(entry 3, Table 1). Interestingly, although yields were lower,
even trisubstituted allyl boronic esters were reactive
(entry 4, Table 1). Entry 5 describes the only example in
which there is an aromatic substituent on the vinyl group
and this is the only example in which the cross-coupling pro-
ceeds with (albeit moderate) a-selectivity. The same propen-
sity for styrene-containing substrates to react with a-selec-
tivity was observed in previous work, and in these cases, se-
[a] Dr. L. Chausset-Boissarie, Dr. J. L.-Y. Chen, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol, BS8 1TS (UK)
E-mail : V.aggarwal@bristol.ac.uk
[b] Dr. K. Ghozati, E. LaBine, Prof. C. M. Crudden
Department of Chemistry, Queens University
Kingston, Ontario, K7L 3N6 (Canada)
E-mail : Cathleen.crudden@chem.queensu.ca
[c] Prof. C. M. Crudden
Institute of Transformative Bio-Molecules (WPI-ITbM)
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303683.
 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 17698 – 1770117698
lectivities for a-arylation of 8:92 (nBu in place of
CH2CH2Ph) and 18:82 (nHex in place of CH2CH2Ph) were
observed.[5] The rationale for the a-selectivity in these cases
is discussed in an overall mechanistic context below.
We next embarked on the synthesis of enantiomerically
enriched versions of allylic boronic esters using Aggarwal
lithiation-borylation methodology. For example, (Z)-10 was
prepared in 80 % yield with a 98:2 e.r. [Eq. (4)].[11c,12]
Boronic esters (E)-10, (E)-13, and (E)-14 were prepared
in a similar manner in high yield and selectivity.[11c,12] How-
ever, the synthesis of (E)-15, which requires the lithiation
and homologation of a benzylic carbamate, is significantly
more challenging, as the lithiated derivative is configuration-
ally unstable even at low temperature, leading to racemic
products.[13]
Hoppe has shown that under thermodynamic control, bi-
soxazoline ligands are effective with this class of carbamate,
and we found that the combination of this ligand with the
more reactive neopentyl glycol boronic ester provided the
desired chiral allylic boronate (R,E)-15 with 96 % enantiose-
lectivity.[14]
Having secured access to all of our key substrate classes
in enantiomerically enriched form, we then examined the
enantiospecificity of the coupling reaction. All of the sub-
strate classes investigated reacted with virtually complete
enantiospecificity (Table 2). The (Z)-allylic boronates 10
and 13 gave the g-products with high E selectivity. In con-
trast, the (E)-allylic boronate 10 gave the g-product with
lower E selectivity, although high E selectivity was restored
with the more hindered iPr substituent. The E/Z selectivity
is governed by A1,3 strain between the R1 and R2 substitu-
ents in the conversion of A!B (Scheme 1).
Electronic effects with respect to the aryl halide were
then explored in the cross-coupling of allylic boronic ester
(R,Z)-13 (96:4 e.r.). As shown in Table 3, electron-neutral or
electron-rich aryl iodides gave the desired product in good
yield and high isomeric purity favoring the (E)-g-product
(Table 3, entries 1–3). Electron poor aryl iodides resulted in
decreased yields but still reacted with high enantiospecifici-
ties (Table 3, entries 4–6).
Similar to previous work with allyl silanes,[9] work by
Yamamoto and Miyaura[10f] showed—consistent with our re-
sults with boronic esters—that the cross-coupling of racemic
crotyl and methallyl trifluoroborates proceeds with SE’ re-
Table 1. Effect of substrate structure on regioselectivity of the cross-cou-
pling reaction.[a]
Entry Compound g/a[b] E/Z[c] Yield
[%][d]
1 (E)-6 97:3 99:1 65
2 (Z)-6 92:8 99:1 70
3 (Z)-7 91:9 99:1 77[e]
4 8 92:8 99:1 40
5 (E)-9 39:61 86:14 28[e]
[a] PhI (1 equiv), PdACHTUNGTRENNUNG(dba)2 (5 %), PPh3 (10 %), Ag2O (1.5 equiv), DME
(0.1 m), 90 8C, 16 h; [b] g/a ratio determined by GC and/or 1H NMR;
[c] E/Z ratio for the major regioisomer; [d] isolated yield of major regio-
isomer unless otherwise stated; [e] isolated as mixture of regioisomers.
Table 2. Regio- and enantiospecificity in the Suzuki–Miyaura cross-cou-
pling of enantiomerically enriched allylic boronic esters.[a]
Compound g/a[b] E/Z[b] Yield
[%][c]
e.r.ACHTUNGTRENNUNG(S.M.)[d] e.s.[%][e]ACHTUNGTRENNUNG(R,Z)-10 83:17 94:6 75[f] 98:2 96ACHTUNGTRENNUNG(R,E)-10 94:6 78:22 81 98:2 100ACHTUNGTRENNUNG(R,Z)-13 90:10 99:1 77[f] 96:4 96ACHTUNGTRENNUNG(R,E)-14 92:8 99:1 71 96:4 100ACHTUNGTRENNUNG(R,E)-15 98:2 99:1 78 98:2 100
[a] See Table 1 footnote for conditions; [b] g/a ratio determined by
1H NMR, and E/Z selectivity is given for the major regioisomer; [c] Iso-
lated yield of major isomer unless otherwise stated; [d] e.r. of the starting
material; [e] enantiospecificity =ee product/ee starting material; [f] isolat-
ed as mixtures of g and a products.
Table 3. Electronic effects in the Suzuki–Miyaura cross-coupling of aryl
iodides with boronic ester (R,Z)-13.[a]
Entry R g/a E/Z[a] Yield
[%][b]
e.s.
[%][c]
1 H 90:10 99:1 77 96
2 Me 91:9 99:1 72 93
3 OMe 85:15 99:1 72 96
4 COCH3 90:10 99:1 60 96
5 Br 90:10 99:1 42 93
6 CF3 91:9 99:1 42 93
[a] See notes to Table 1; [b] isolated as mixture of g and a products;
[c] enantiospecificity, determined by chiral HPLC analysis, ee product/ee
starting material.
Chem. Eur. J. 2013, 19, 17698 – 17701  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 17699
COMMUNICATION
giochemistry. Thus, it remained to be determined whether
transmetalation occurred through anti- or syn-SE’ type reac-
tions, which would lead to opposite stereoisomers of the
product.[9] Mechanistic studies on the Suzuki–Miyaura reac-
tion[15] point to likely pathways that involve a BOPd link-
age (A, Scheme 1) prior to transmetalation, such that the
syn-SE’ intramolecular transmetalation would be predicted.
This leads ultimately to organopalladium intermediate B,
which subsequently undergoes reductive elimination gener-
ating the g product.
In order to test this hypothesis, the absolute stereochemis-
try of the products was determined and was found to corre-
late with olefin stereochemistry.[16] Thus, (R,E)-10 was
shown to give (S,E)-17 a, whereas cross-coupling of the geo-
metrical isomer (R,Z)-10 gave (R,E)-17 a (Scheme 2). This is
consistent with syn-SE’ transmetalation.
The involvement of p-allyl intermediates in the transfor-
mation was considered next.[17] Isomerization of the
s-bonded transmetalated intermediate B to the isomeric or-
ganopalladium intermediate D, could occur prior to reduc-
tive elimination. If this isomerization occurred fully, the
ratio of g/a cross-coupled products would be solely depen-
dent on the relative rates of reductive elimination from in-
termediates B or D (Scheme 1).
To test the involvement of p-allyl intermediate C, we pre-
pared a selectively deuterated allylic boronic ester, 18, in
which the steric and electronic effects of the two substitu-
ents are equivalent. Subjecting 18 (90:10 mixture of g/a
d-isomers) to our standard conditions gave an 85:15 (5 %)
ratio in favor of g product 19 a, indicating that reductive
elimination is faster than isomerization via p-allyl intermedi-
ate C [Eq. (5)]. Indeed, it appears that on the order of 95 %
of the transmetalated intermediate A proceeds to product
without isomerization through C.
The synthesis of a deuterated diphenyl substituted version
of 18 was not possible due to facile borotropic shifts, making
a conclusive statement on the mechanism of the reaction of
diaryl substrates difficult. However, it was observed that
starting materials in which one aryl group is present on
either end of the allylic unit, that is, (E)-15 or (E)-20,[18] give
the same major isomer [Eqs. (6), (7)], which does suggest
a more significant role of p-allyl intermediates.[19]
Interestingly, however, the selectivity of the cross-coupling
starting from (E)-20 is markedly lower than that starting
from (E)-15. In the latter case, the high selectivity can be
explained if the reaction proceeds through the expected
SE’-transmetalation yielding organopalladium intermediate
B, in which the olefin and aromatic ring are in conjugation
(R1 =Ph). Direct reductive elimination (kre(B)) then gives the
g product in high selectivity, as observed with fully aliphatic
systems.[20] For (E)-20, SE’-transmetalation disrupts conjuga-
tion, forming intermediate B in which R3 =Ph. Isomeriza-
tion of this intermediate to D (via C) followed by reductive
elimination kre(D) appears to be preferred, presumably
driven by the conjugated styrene unit. The low selectivity
observed suggests that reductive elimination from B still
occurs to some extent, either directly from B, or after iso-
merization to C.[21]
In conclusion, we have described the first enantioselective
Suzuki–Miyaura cross-coupling of chiral, enantioenriched
secondary allylic boronic esters. The reaction proceeds with
high g-regioselectivity and high retention of chirality. Mech-
anistic studies show that the reactions proceed via g-selec-
tive transmetalation followed by reductive elimination; the
Scheme 2. Absolute configuration of products and the relationship to
mechanism of transmetalation.
Scheme 1. Mechanism for the formation of both the a- and g-isomers.
www.chemeurj.org  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 17698 – 1770117700
V. K. Aggarwal, C. M. Crudden et al.
latter process competes with isomerization to the p-allyl in-
termediate. Deuterium labeling studies show that direct re-
ductive elimination is faster than formation of p-allyl inter-
mediates for alkyl substituted allylic boronates. In addition
to the synthetic utility of this transformation, the reaction
provides the first independent confirmation that the trans-
metalation of boronic esters proceeds via a syn pathway, in
accord with mechanistic studies that show the importance of
the BOPd linkage for facile transmetalation.
Experimental Section
General procedure for cross-coupling reactions of secondary allylic bor-
onic esters : In a nitrogen-atmosphere glovebox, aryl iodide (1.0 equiv),
secondary allylic boronic ester (1.2 equiv), Ag2O (1.5 equiv), Pd ACHTUNGTRENNUNG(dba)2
(0.05 equiv), and PPh3 (0.1 equiv) were added to a 1 dram vial and taken
up in DME (0.1 m). The reaction solution was sealed in the glovebox, re-
moved, and heated to 90 8C in an oil bath for 18 h. Once cooled, the reac-
tion solution was passed through a silica plug and washed with copious
amounts of EtOAc then the solvents were removed under reduced pres-
sure with a rotary evaporator. GC or 1H NMR analysis was used to deter-
mine g/a and E/Z ratio of products. The crude mixture was purified by
silica gel chromatography to obtain desired product. Detailed procedures
for the individual substrates are provided in the Supporting Information.
Acknowledgements
C.M.C. acknowledges the Natural Sciences and Engineering Research
Council (NSERC) for support of this work in terms of a discovery grant,
an accelerator grant and a research tools grant. WPI-ITbM is acknowl-
edged for support of this work. The Canada Foundation for Innovation
(CFI) is acknowledged for a Leaders Opportunity Fund to C.M.C.
V.K.A. thanks the Swiss National Foundation for a fellowship (LCB),
and the European Research Council (ERC grant no. 246785) for finan-
cial support.
Keywords: allylboronate · cross-coupling · stereospecificity ·
Suzuki–Miyaura · synthetic methods
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[18] Derivatives of 20 in which the alkyl group are nBu and nHex also
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selective transmetalation.
Received: September 19, 2013
Published online: December 2, 2013
Chem. Eur. J. 2013, 19, 17698 – 17701  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org 17701
COMMUNICATIONSecondary Allylic Boronic Esters


Enantiospecific, regioselective crosscoupling reactions of secondary allylic boronic esters

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Enantiospecific, regioselective crosscoupling reactions of secondary allylic boronic esters

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