Stereoselective preparation of β-aryl-β-boronyl enoates and their copper-catalyzed enantioselective conjugate reduction

Article abstract of DOI:10.1021/ol301958x

A new methodology has been developed for the stereoselective preparation of β-aryl-β-boronyl α,β-unsaturated esters via Heck coupling, and their subsequent copper(I)-catalyzed enantioselective conjugate reduction. Various chiral secondary boronate derivatives can be accessed in excellent yields and good to high levels of enantioselectivity through the efficient copper-catalyzed process using polymethylhydrosiloxane (PMHS) as the hydride source.

Full text of DOI:10.1021/ol301958x

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4462–4465
Stereoselective Preparation of
β‑Aryl-β-Boronyl Enoates and Their
Copper-Catalyzed Enantioselective
Conjugate Reduction
Jinyue Ding, Jack Chang Hung Lee, and Dennis G. Hall*
Department of Chemistry, 4-010 Centennial Centre for Interdisciplinary Science,
University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
dennis.hall@ualberta.ca
Received July 15, 2012
ABSTRACT
A new methodology has been developed for the stereoselective preparation of β-aryl-β-boronyl R,β-unsaturated esters via Heck coupling, and
their subsequent copper(I)-catalyzed enantioselective conjugate reduction. Various chiral secondary boronate derivatives can be accessed in
excellent yields and good to high levels of enantioselectivity through the efficient copper-catalyzed process using polymethylhydrosiloxane
(PMHS) as the hydride source.
the groups of Yun,4a Fernandez,4b Hoveyda,4c Shibasaki,4d
Nishiyama,4e and McQuade4f (a, Figure 1). Our group has
developed a complementary conceptual approach where
the boronate group is preinstalled on a universal R,β-
unsaturated ester substrate, which is then subjected to a
catalytic asymmetric conjugate addition with unstabilized
carbanions5a or to an asymmetric conjugate borylation5b
that provides optically enriched boronates (b, Figure 1). As
part of our ongoing search for new ways to access chiral
secondary boronates, we reasoned that the corresponding
copper-catalyzed enantioselective conjugate reduction of
β-alkyl-β-boronyl R,β-unsaturated esters would provide a
useful alternative. Various chiral secondary boronate de-
rivatives were accessed in excellent yields and good to high
levels of enantioselectivities through this efficient copper
catalyzed process using polymethylhydrosiloxane (PMHS)
as a hydride source (c, Figure 1).6a However, with this
ꢀ
Optically enriched chiral organoboronate derivatives
are important synthetic intermediates,1,2 which may be
employed in cross-coupling chemistry or as precursors of
alcohols and amines following a CÀB bond oxidation.
Borylative conjugate addition3 provides an attractive metho-
dology to access chiral boronates, as recently demonstrated by
(1) Hall, D. G. Boronic Acids, 2nd ed.; Wiley-VCH: Weinheim, 2011.
(2) (a) Matteson, D. S. Tetrahedron 1998, 54, 10555–10607. (b) Gao,
X.; Hall, D. G. J. Am. Chem. Soc. 2003, 125, 9308–9309. (c) Crudden,
C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem. Soc. 2004, 126, 9200–
9201. (d) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629.
(e) Gao, X.; Hall, D. G.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni,
B. Chem.;Eur. J. 2006, 13, 3132–3142. (f) Carosi, L.; Hall, D. G. Can. J.
Chem. 2009, 87, 650–661. (g) Lessard, S.; Peng, F.; Hall, D. G. J. Am.
Chem. Soc. 2009, 131, 9612–9613. (h) Thomas, S. P.; French, R. M.;
Jheengut, V.; Aggarwal, V. K. Chem. Rec. 2009, 9, 24–39. (i) Thomas,
S. P.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48, 1896–1898. (j)
Smith, S. M.; Takacs, J. M. J. Am. Chem. Soc. 2010, 132, 1740–1741. (k)
Noh, D.; Yoon, S. K.; Won, J.; Lee, J. Y.; Yun, J. Chem.;Asian J. 2011,
6, 1967–1969. (l) Schuster, C. H.; Li, B.; Morken, J. P. Angew. Chem.,
Int. Ed. 2011, 50, 7906–7909. (m) Larouche-Gauthier, R.; Elford, T. G.;
Aggarwal, V. K. J. Am. Chem. Soc. 2011, 133, 16794–16797. (n) Pulis,
A. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2012, 134, 7570–7574. (o) Wu,
H.; Radomkit, S.; O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc.
2012, 134, 8277–8285. (p) Hall, D. G.; Lee, J. C. H.; Ding, J. Pure Appl.
Chem. 2012, ASAP. DOI: 10.1351/PAC-CON-12-02-04.
(4) (a) Chea, H.; Sim, H.-S; Yun, J. Adv. Synth. Catal. 2009, 351, 855–
ꢀ
ꢀ
858. (b) Bonet, A.; Gulyas, H.; Fernandez, E. Angew. Chem., Int. Ed.
2010, 49, 5130–5134. (c) Lee, K.-S.; Zhugralin, A. R.; Hoveyda, A. H.
J. Am. Chem. Soc. 2009, 131, 7253–7255. (d) Chen, I.-H.; Kanai, M.;
Shibasaki, M. Org. Lett. 2010, 12, 4098–4101. (e) Shiomi, T.; Adachi, T.;
Toribatake, K.; Zhou, L.; Nishiyama, H. Chem. Commun. 2009, 44,
5987–5989. (f) Park, J. K.; Lackey, H. H.; Rexford, M. D.; Kovnir, K.;
Shatruk, M.; McQuade, D. T. Org. Lett. 2010, 12, 5008–5011.
€
(3) (a) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem., Int.
Ed. 2010, 49, 1194–1196. (b) Hartmann, E.; Vyas, D. J.; Oestreich, M.
Chem. Commun. 2011, 47, 7917–7932.
r
10.1021/ol301958x
Published on Web 08/15/2012
2012 American Chemical Society

method, the R group on the enoate substrate was limited to
alkyl substituents because established methodologies for the
preparation of the substrates did not permit the use of aryl
groups (i, ii in Scheme 1). Herein, we have developed a new
method for the preparation of β-aryl-β-boronyl R,β-unsa-
turated esters via Heck coupling (iii, Figure 1), and their
subsequent copper-catalyzed enantioselective conjugate re-
duction with polymethylhydrosiloxane (PMHS) as a hy-
dride source.
1,8-diaminonaphthalene (dan) adduct 1a5a was utilized
as a test substrate (Table 1). When 5 mol % Pd(OAc)2
was applied as the catalyst with 10 mol % PPh3 as the
ligand, the desired coupling product 2a was obtained
in a decent yield as a single E stereoisomer, which was
verified by NOE experiments (Table 1).10 Further
optimization revealed that the Bu4NHSO4 additive
was highly beneficial,11 allowing better conversions and
yields of the desired products to be afforded (entry 4). When
bromobenzene instead of iodobenzene was employed as
the aryl halide substrate, an improved yield was observed
(entry 7). In terms of the reaction solvent, DMF and
acetonitrile were found to be optimal, while other solvents
such as toluene afforded lower yields (entries 9À11). Over-
all, the reaction conditions shown in entry 11 were found
to be optimal for the syntheses of various β-aryl-β-boronyl
enoates.
The scope of aryl halides toward the preparation of
β-aryl-β-boronyl R,β-unsaturated esters was examined
under the optimal reaction conditions. As shown in Table 2,
while bromobenzene and 4-bromotoluene can be used as
coupling partners to afford the desired coupling product 2a
and 2b with good yields, coupling of 2-bromotoluene failed to
occur (entries 1À3, Table 2). Presumably, steric hindrance
from the ortho-substituent inhibits the desired coupling. In
terms of electronic effects, both electron-rich and -deficient
aryl halides afforded the desired β-aryl-β-boronyl R,β-unsa-
turated esters as single stereoisomers with good yields
(entries 4À6). Oligoaryl halides such as 2-bromonaphthalene
were also tolerated, providing the desired enoate 2g with good
efficiency (entry 7).
Figure 1. Possible conjugate addition approaches to chiral second-
ary boronates.
β-Boronyl R,β-unsaturated esters are important syn-
thetic intermediates.1,7 To date, Miyaura’s borylation of
alkenyl triflates8 and Yun’s β-borylation of ynoates9a,6b
are the two main ways of preparing these compounds
(Scheme 1, i and ii). However, both methods are limited
to the preparation of β-alkyl-β-boronyl enoates, while the
preparation of β-aryl derivatives has not yet been reported.
A new method for the preparation of β-aryl-β-boronyl R,
β-unsaturated esterswould be valuable due tothe synthetic
applications associated with these boron compounds. We
surmised that this class of compounds could be accessed
through Heck coupling of previously reported β-boronyl
enoate 1 (Scheme 1, iii).5
Table 1. Optimization of Reaction Conditions for the
Preparation of β-Aryl-β-boronyl R,β-Unsaturated Esters via
Heck Couplinga
Scheme 1. Methods for Preparation of β-Boronyl R,
β-Unsaturated Esters
yield
entry
X
catalyst (mol %)
additive
solvent (%)b
1
l
5% Pd(OAc)2, 10% PPh3
5% Pd(OAc)2, 10% PPh3
10% Pd(OAc)2, 6% PPh3
À
DMF
DMF
DMF
52
24
58
63
20
55
75
76
75
2
l
l
l
l
À
À
3
4
10% Pd(OAc)2, 6% PPh3 Bu4NHSO4 DMF
5
10% Pd(PPh3)4
À
À
DMF
DMF
6
Br 10% Pd(OAc)2, 6% PPh3
7
Br 10% Pd(OAc)2, 6% PPh3 Bu4NHSO4 DMF
Br 5% Pd(OAc)2, 3% PPh3 Bu4NHSO4 DMF
Br 5% Pd(OAc)2, 3% PPh3 Bu4NHSO4 DMF
8
9c
10
11
Br 5% Pd(OAc)2, 3% PPh3 Bu4NHSO4 toluene 61
Br 5% Pd(OAc)2, 3% PPh3 Bu4NHSO4 MeCN 74
a Reaction conditions: 1a (1.0 mmol), PhX (2.0 mmol), Et3N (3.0
mmol), additive (1.0 mmol), solvent (5 mL), 80 °C for 10 h. b Isolated
yield, E/Z > 98% by 1H NMR. c DMF 1.0 mL.
With this idea in mind, optimal conditions were
first sought for the Heck coupling reaction, and
Org. Lett., Vol. 14, No. 17, 2012
4463

The Buchwald12 and Lipshutz13 groups have indepen-
dently developed efficient copper-catalyzed enantioselec-
tive methods for conjugate reduction of R,β-unsaturated
compounds with polymethylhydrosiloxane (PMHS) as a
mild hydride source. Recently, for the first time, our group
applied these methodologies to the reduction of β-alkyl-
β-boronyl R,β-unsaturated esters to access various corre-
sponding chiral secondary boronates in excellent yields
and good to high levels of enantioselectivity.6a To further
expand this methodology, we decided to explore the
scope of asymmetric conjugate reduction on β-aryl-β-
boronyl enoate substrates. With β-aryl-β-boronyl eno-
ates 2 now in hand (Table 2), their subsequent copper-
catalyzed asymmetric reductions were then tested. With
Josiphos as the chiral ligand,14 both (Ph3P)CuH13 and
Table 2. Scope of Preparation of β-Aryl-β-boronyl R,
β-Unsaturated Estersa
15
Cu(OAc)2 can be used as the copper salts to give the
desired product 3a with decent yields and enantioselec-
tivities (entries 1, 2). When CuCl was used as the copper
source, a slightly higher reactivity and enantioselectivity
were obtained (entry 3). In terms of chiral ligands, (R)-
Tol-BINAP was found to be optimal, while Josiphos and
Walphos ligands provided relatively lower enantiomeric
excesses (entries 3À5). The asymmetric conjugate reduc-
tion was equally efficient at rt (entry 6). As the reaction
solvent, both dichloromethane and toluene proved to be
effective, but no product was obtained when tetrahy-
drofuran was employed as the solvent (entries 6À8).
Interestingly, even though β-Bdan-β-phenyl enoate 2a
can be reduced to the chiral β-Bdan carboxyester 3a with
good yield and enantiomeric excess, the corresponding
β-Bpin-β-phenyl enoate showed no reactivity under the
same reaction conditions (entry 9). Thus, the reaction
conditions of entry 8 were found to be optimal to explore
the substrate scope.
a Reaction conditions: 1a (1.0 mmol) and ArX (2.0 mmol) in MeCN
(0.2 M) with 5 mol % Pd(OAc)2, 3 mol % PPh3, 3 equiv of Et3N (3.0 mmol),
and 1 equiv of Bu4NHSO4 (1.0 mmol) at 80 °C for 10 h. b Isolated yield,
E/Z > 98% by 1H NMR.
As shown in Table 4, both electron-rich and -poor
substrates afforded the desired products with moderate
to high yields. However, substrates bearing β-aryl groups
other than phenyl were reduced with lower enantiomeric
excesses (entries 2À4). Carbomethoxy-substituted 2f
(entry 5) afforded the corresponding protodeboronation
product. Ontheotherhand, naphthylsubstitutedsubstrate
2g showed excellent enantioselectivity (entry 6), possibly
due to its highly conjugate planar structure, which can lead
to enhanced interactions with the catalyst. To study the
influence of boron protecting groups on enantioselectivity,
the 1,8-diaminonaphthalene (dan) protecting group was
compared with the pinacol (pin) protecting group, which
was previously reported for the enantioselective reduction
of alkyl-substituted substrates6,10 (entries 7À10). Simi-
lar to the results observed for the β-Bdan-β-phenyl
enoate 2a (Table 3, compare entries 8 and 9), an im-
provement for the Bdan substrates was also observed for
β-Bdan-β-cyclohexyl enoate 2i16 (Table 4, entries 7, 8). The
key for the improved reactivity and enantioselectivity in the
reduction of these substrates is the utilization of 1,8-diamino-
naphthalene as a planar masking group over the bulky
pinacol protecting group. The same levels of reactivity and
enantioselectivity were obtained for β-Bdan-β-(n-hexyl) en-
oate 2k16 (entries 9, 10).
(5) (a) Lee, J. C. H.; Hall, D. G. J. Am. Chem. Soc. 2010, 132, 5544–
5545. (b) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3,
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894–899. (c) Gravel, M.; Toure, B. B.; Hall, D. G. Org. Prep. Proc. Intl.
2004, 36, 573–579.
(6) (a) Ding, J.; Hall, D. G. Tetrahedron 2012, 68, 3428–3434. (b)
Jung, H.-Y.; Feng, X.; Kim, H.; Yun, J. Tetrahedron 2012, 68, 3444–
3449.
(7) For reviews, see: (a) Suzuki, A. In Organoboranes in Syntheses;
ACS symposium series 783; Ramachandran, P. V., Brown, H. C.,
Eds.; American Chemical Society: Washington, DC, 2001; Chapter 6,
pp 80À93. (b) Miyaura, N. In Organoboranes in Syntheses, ACS
symposium series 783; Ramachandran, P. V., Brown, H. C., Eds.; American
Chemical Society: Washington, DC, 2001; Chapter 7, pp94À107. (c) Tusiji, J.
Palladium Reagents and Catalysts; John Wiley & Sons: Chichester, U.K., pp
218À227.
(8) Ishiyama, T.; Takagi, J.; Kamon, A.; Miyaura, N. J. Organomet.
Chem. 2003, 687, 284–290.
(9) (a) Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 43, 733–
734. (b) Mannathan, S.; Jeganmohan, M.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2009, 48, 2192–2195.
(10) See Supporting Information for details.
(11) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254–
278.
(12) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473–9474.
(13) (a) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem.
Soc. 2004, 126, 8352–8353. (b) Lipshutz, B. H.; Servesko, J. M.; Petersen,
T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273–1275.
(14) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108,
2916–2927.
(15) (a) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45,
2785–2787. (b) Lee, D.; Yang, Y.; Yun, J. Org. Lett. 2007, 9, 2749–2751.
(16) See Supporting Information for the syntheses of 2i and 2k.
Org. Lett., Vol. 14, No. 17, 2012
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Table 3. Possible Conjugate Addition Approaches to Chiral
Secondary Boronatesa
Table 4. Scope for the Copper-Catalyzed Enantioselective
Conjugate Reductiona
temp
yield
ee
entry X2 Cu catalyst ligand (°C) solvent (%)b (%)c
1
2
3
4
5
6
7
8
9
dan (Ph3P)CuH
dan Cu(OAc)2
dan CuCl
L1
L1
L1
L2
L3
L3
L3
L3
L3
0
toluene
toluene
DCM
67
71
83
83
87
88
0
71
70
75
72
85
84
À
0
0
dan CuCl
0
DCM
dan CuCl
0
DCM
dan CuCl
rt
rt
rt
rt
DCM
dan CuCl
THF
dan CuCl
toluene
toluene
88
0
85
À
pin CuCl
a Reaction conditions: 0.25 M 2a (1.0 mmol) in solvent with 4 equiv
of PMHS, 5 mol % catalyst, 10 mol % ligand, and 5 mol % NaOtBu.
b Isolated yields. c Measured by chiral HPLC; see Supporting Informa-
tion for details.
In summary, we have successfully developed a new
and efficient approach to access synthetically valuable
β-aryl-β-boronyl enoates through Heck coupling, and
the subsequent copper(I)-catalyzed enantioselective con-
jugate reduction of these enoates to produce various chiral
secondary boronate derivatives. This method consti-
tutes the first general approach for synthesizing β-aryl-
β-boronyl enoates in very high E/Z selectivity. In addi-
tion, these Bdan derivatives were asymmetrically reduced
with good to excellent enantiomeric excesses, affording
the desired optically enriched secondary boronates
with substantially improved reactivity and selectivity
compared to our previously reported conditions. These
improvements are attributed to the utilization of the
planar 1,8-diaminonaphthalene as a superior boron
masking group over the bulky pinacol group. Accord-
ingly, with chiral boronic acid derivatives emerging as
an important and versatile functional group in organic
synthesis, we believe that the synthetic methods re-
ported herein are valuable tools to access a variety of
important organic intermediates.
a Reaction conditions: 0.25 M of 2 (1.0 mmol) in toluene with
4 equiv of PMHS, 5 mol % CuCl, 5 mol % NaOt-Bu, and 10 mol % L3
at rt. b Isolated yield. c Measured by chiral HPLC; see Supporting
Information for details. Absolute configuration assigned by compar-
ison with optical rotation of known compound. d The Bdan derivative
3b could not be well resolved by chiral HPLC, so further derivatiza-
tion was applied for the measurement of enantiomeric excess; see
Supporting Information for details. e The protodeboronation prod-
uct was obtained exclusively.
Acknowledgment. This research was generously funded
by the Natural Sciences and Engineering Research Council
(NSERC) of Canada and the University of Alberta. J.C.H.
L. thanks the University of Alberta for a Queen Elizabeth
II Graduate Scholarship.
Supporting Information Available. Experimental pro-
cedures, NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4465