Enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylheteroarenes

Article abstract of DOI:10.1021/ja106809p

In the presence of a rhodium complex containing a newly developed chiral diene ligand, alkenes activated by a range of π-deficient or π-excessive heteroarenes engage in highly enantioselective conjugate additions with various arylboronic acids.

Full text of DOI:10.1021/ja106809p

Published on Web 09/29/2010
Enantioselective Rhodium-Catalyzed Addition of Arylboronic Acids to
Alkenylheteroarenes
Graham Pattison, Guillaume Piraux, and Hon Wai Lam*
School of Chemistry, UniVersity of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road,
Edinburgh, EH9 3JJ, United Kingdom
Received July 30, 2010; E-mail: h.lam@ed.ac.uk
Table 1. Evaluation of Chiral Dienes for the Arylation of 1aa
Abstract: In the presence of a rhodium complex containing a
newly developed chiral diene ligand, alkenes activated by a range
of π-deficient or π-excessive heteroarenes engage in highly
enantioselective conjugate additions with various arylboronic
acids.
Heteroarenes are of widespread chemical significance, being
present in numerous biologically active natural products, and serving
as building blocks for the discovery of new medicines, agrochemi-
cals, and functional molecules. Consequently, synthetic methods
that enable functionalization of heteroarenes and their derivatives
are of prime importance. Although metal-catalyzed cross-coupling
reactions1 and their modern equivalents involving C-H bond
functionalization2 have revolutionized this area, new methods that
open up previously little explored pathways are of high value. In
this regard, the addition of nucleophiles to ꢀ-substituted alkenyl-
heteroarenes has captured our attention.3 Despite the potential utility
of catalytic asymmetric variants of these processes for generating
chiral heteroarene-containing building blocks, such reactions have,
until recently,4,5 remained elusive.6 We have demonstrated that
alkenes conjugated to a CdN moiety in an adjacent heteroarene
undergo highly enantioselective copper-catalyzed hydride addi-
tions.4 Due to issues of convergency, analogous processes involving
C-C bond formation are inherently of much greater value. Herein
we report the catalytic enantioselective addition of arylboronic acids
and an alkenyl MIDA boronate to alkenylheteroarenes.
Rhodium-catalyzed asymmetric 1,4-addition of arylboron com-
a Reactions were conducted using 0.10 mmol of 1a (0.1 M).
pounds to alkenes activated by electron-withdrawing groups has
emerged as a versatile method for the construction of chiral
compounds.7-9 However, examples where heteroarenes are em-
ployed in alkene activation are limited to ꢀ-unsubstituted vinyla-
zines, which provide achiral products.10-12 Although the possibility
of future asymmetric variants was mentioned,10a such a report has
not appeared, presumably due to the relatively poor reactivity of
ꢀ-substituted alkenylheteroarenes.
Undeterred, we first studied the racemic addition of PhB(OH)2
(2 equiv) to (E)-2-alkenylquinoline 1a using [Rh(cod)Cl]2 (2.5 mol
%) and KOH in 9:1 dioxane/H2O at 80 °C for 30 min under
microwave (µw) irradiation. These experiments highlighted the
importance of the amount of KOH in promoting the reaction; rac-
2a was obtained in 43% and 14% NMR yield when 2.5 and 0.5
equiv of KOH were used, respectively. The remaining mass balance
in these reactions was unreacted 1a, along with traces (ca. 3-6%)
of the reduction product 3a.13 Next, a variety of chiral diene ligands,
which are known to exhibit high activities in related processes,14,15
were evaluated (Table 1). Using [Rh(C2H4)2Cl]2 (2.5 mol %) in
the presence of 2.5 equiv of KOH, the commercial ligand L116
provided 2a in good conversion and a promising 79% ee (entry
b Determined by 1H NMR analysis. c Enantioselectivities of 2a were
determined by chiral HPLC analysis.
1).17 While (R)-R-phellandrene-derived diene L218,19 gave 2a in
similar enantioselectivity, the conversion was much lower (entry
2). New derivatives of L2 were then prepared for evaluation.
Although morpholine amide L3 offered no improvement (entry 3),
diene L4, constructed from (S,S)-2-(2,5-dimethyl)pyrrol-1-ylcyclo-
hexylamine, provided 2a in high enantioselectivity, though in
incomplete conversion (entry 4). The chiralities of the diene and
cyclohexyl fragments of L4 appear to be a matched combination,
as suggested by the inferior results obtained using diastereomeric
ligand L5 (entry 5). On the basis of the high enantioselectivity
imparted by L4, this ligand was selected for further experimentation.
Table 2 presents the results of the investigation of the scope of
the reaction using L4. Higher conversions into the products were
realized by doubling the concentrations of the reactions to 0.2 M
with respect to the alkenylheteroarene and by employing 2.4 equiv
of the arylboronic acid.20 Under these conditions, arylboronic acids
containing various substituents (including methyl, chloro, fluoro,
and alkoxy) underwent highly enantioselective addition to a range
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J. AM. CHEM. SOC. 2010, 132, 14373–14375 14373

C O M M U N I C A T I O N S
Table 2. Asymmetric Rh-Catalyzed Arylation of
Scheme 1. Possible Catalytic Cycle
Alkenylheteroarenesa
conditions, only small quantities of the desired 1,4-addition products
were observed, with protodeboronation of the alkenylboronic acid
being the dominant outcome. Recently, N-methyliminodiacetic acid
(MIDA) boronates22 have emerged as promising alternatives to
boronic acids in transition-metal-catalyzed reactions23-25 by virtue
of their high benchtop stability and their capacity to gradually
release unstable boronic acids in situ under carefully controlled
aqueous basic conditions, thus minimizing decomposition pathways.
These features are especially valuable for 2-heterocyclic23 and
alkenylboronic acids,24 which generally exhibit lower stability than
simple arylboronic acids.
Fortunately, in this study, alkenyl MIDA boronates also proved
to be superior to their boronic acid counterparts in delivering the
desired products.24 For example, alkenylquinoxaline 1b reacted with
(E)-2-phenylvinyl MIDA boronate in 5:1 dioxane/H2O in the
presence of K3PO4 (2.0 equiv) at 60 °C for 16 h to provide 4 in
58% yield, though in a modest 61% ee (eq 1).
a Unless otherwise stated, reactions were conducted using 0.50 mmol
of 1a-1f (0.2 M). b Isolated yield. c Determined by chiral HPLC
analysis. d Isolated as a 14:1 inseparable mixture of 2a and 3a. e Using
2.0 equiv of PhB(OH)2. f Isolated as a 16:1 inseparable mixture of 2d
and the reduction product 3d (see Supporting Information). g Reaction
performed using 2.0 mmol of 1b (0.2 M) at 80 °C under thermal heating
for 1 h, using 3 mol % Rh and 3.6 mol % of L4.
of (E)-alkenylheteroarenes.17,21 In addition to 2-alkenylquinoline
1a (entries 1-3), substrates that are effective include alkenes
activated by π-deficient heteroarenes such as quinoxaline (entries
4-8) and pyrimidine (entries 9 and 10), as well as π-excessive
heteroarenes such as benzoxazole (entries 11 and 12), 4,5-
diphenyloxazole (entry 13), and 3-phenyl-1,2,4-oxadiazole (entry
14). Regarding the ꢀ-position of the alkene, both aliphatic (entries
1-10, 13, and 14) and aromatic (entries 11 and 12) substituents
are tolerated. Microwave irradiation is not necessary for the reaction
to proceed. For example, reaction of 2-alkenylquinoxaline 1b with
4-fluorophenylboronic acid on a 2.0 mmol scale was readily
accomplished under thermal heating using only 1.5 mol % of
[Rh(C2H4)2Cl]2 and 3.6 mol % of L4, which provided 2g in 91%
yield and 91% ee (entry 7).
In accordance with the accepted catalytic cycle of conjugate
addition of arylboronic acids to enones26 and the stereochemical
model proposed for arylation of acyclic substrates,14a,18 a possible
mechanism for the reactions described herein, using an alkenylpy-
rimidine for illustrative purposes, is presented in Scheme 1.
Treatment of [Rh(C2H4)2Cl]2 and L4 with KOH results in formation
of chiral diene-ligated rhodium hydroxide 5, which can undergo
transmetalation with the arylboronic acid to form rhodium aryl
species 6, where the rhodium-aryl linkage is positioned trans to
the more electron-deficient alkene. Coordination of the alkenyl-
heteroarene 1 to the remaining binding site of 6 then occurs as
depicted in 7 to minimize unfavorable nonbonding interactions
between the heteroarene and the amide substituent of the ligand.
Arylrhodation of the bound substrate results in the formation of
aza-π-allylrhodium intermediate 8, which then undergoes hydrolysis
to regenerate the rhodium hydroxide 5 and liberate the product 2.
The lower reactivity of alkenylheteroarenes compared with
established substrates for Rh-catalyzed 1,4-arylation may be at-
tributed, at least in part, to the loss of aromaticity that accompanies
the formation of aza-π-allylrhodium species 8. Therefore, structural
features in the heteroarene that reduce this energetic penalty would
Attempts to expand the scope of the nucleophile to encompass
alkenylboronic acids were largely unsuccessful. Under various
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C O M M U N I C A T I O N S
(6) For Ni-catalyzed addition of organometallics to 4-alkenylpyridines proceed-
ing with low (e15% ee) enantioselectivities, see: Houpis, I. N.; Lee, J.;
Dorziotis, I.; Molina, A.; Reamer, B.; Volante, R. P.; Reider, P. J.
Tetrahedron 1998, 54, 1185–1195.
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4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
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Figure 1. Poorly reactive substrates.
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be expected to result in more reactive substrates.27 Such features
include benzannulation (Table 1, entries 1-8, 11, and 12), the
presence of a second CdN moiety (entries 4-10 and 14), and
conjugation with aryl substituents (entry 13). The importance of
these features is underscored by attempted arylation of substrates
that lack them. For example, under our standard conditions,
2-alkenylpyridine 1g and 2-alkenylthiazole 1h (Figure 1) remain
largely unchanged, providing only small quantities (<30%) of
arylation products and other unidentified side products. Work is
underway to identify improved conditions to arylate these less
reactive substrates.
In summary, by employing a new chiral diene ligand L4, highly
enantioselective Rh-catalyzed additions of arylboronic acids to
ꢀ-monosubstituted alkenylheteroarenes have been developed. This
work further exemplifies the capacity of CdN-containing heteroare-
nes, chemotypes of relevance to chemists in the medicinal and
agrochemical industries, to activate alkenes toward catalytic asym-
metric conjugate addition reactions.4,5 Further exploration of this
reaction in more depth, along with the development of related
processes, is ongoing in our laboratory.
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organometallic compounds, see: Fagnou, K.; Lautens, M. Chem. ReV. 2003,
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cobalt-catalyzed addition of an alkenylboronic acid to 2-[(E)-prop-1-
enyl]pyridine was reported: Kobayashi, T.; Yorimitsu, H.; Oshima, K.
Chem.sAsian J. 2010, DOI: 10.1002/asia.201000275.
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Michelet, V.; Geneˆt, J.-P. J. Organomet. Chem. 2004, 23, 3820–3830.
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(17) The absolute configurations of the products obtained herein were assigned
by analogy with that of 2g, which was determined by X-ray crystallography.
See Supporting Information for details. The sense of enantioinduction
obtained using L4 is consistent with reported examples of 1,4-arylation of
acyclic enones (ref 18).
(18) Okamoto, K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10, 4387–4389.
(19) For the synthesis of a range of other (R)-R-phellandrene-derived chiral
dienes using an improved route, see: Okamoto, K.; Hayashi, T.; Rawal,
V. H. Chem. Commun. 2009, 4815–4817.
Acknowledgment. This work was supported by the EPRSC and
the Erasmus student exchange program. We thank Charlene Fallan,
Benoit Gourdet, and Yi Wang for assistance in the preparation of
ligands and substrates and Dr. Fraser J. White for assistance with
X-ray crystallography. We thank the EPSRC National Mass
Spectrometry Service Centre at the University of Wales, Swansea,
for providing high resolution mass spectra.
(20) With these modestly reactive substrates, competing Rh-catalyzed protode-
boronation is the likely side reaction, necessitating the use of an excess of
arylboronic acid for acceptable yields.
Supporting Information Available: Experimental procedures, full
spectroscopic data for new compounds, and crystallographic data in
cif format. This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) (Z)-Alkenylheteroarenes are also competent substrates in these reactions
but provide the same major enantiomer of product as the corresponding
(E)-isomers, using the same enantiomeric series of the chiral diene. For
example, arylation of (Z)-1a with PhB(OH)2 using ligand L1 gave (S)-2a
in 80% ee. We attribute this observation to isomerization of (Z)-substrates
to the (E)-isomers under the reaction conditions, prior to arylation.
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