Enantioselective copper-catalyzed reductive coupling of alkenylazaarenes with ketones

Article abstract of DOI:10.1021/ja3036916

Catalytic enantioselective methods for the preparation of chiral azaarene-containing compounds are of high value. By combining the utility of copper hydride catalysis with the ability of C=N-containing azaarenes to activate adjacent alkenes toward nucleophilic additions, the enantioselective reductive coupling of alkenylazaarenes with ketones has been developed. The process is tolerant of a wide variety of azaarenes and ketones, and provides aromatic heterocycles bearing tertiary-alcohol-containing side chains with high levels of diastereo- and enantioselection.

Full text of DOI:10.1021/ja3036916

Communication
pubs.acs.org/JACS
Enantioselective Copper-Catalyzed Reductive Coupling of
Alkenylazaarenes with Ketones
Aakarsh Saxena, Bonnie Choi, and Hon Wai Lam*
EaStCHEM, School of Chemistry, University of Edinburgh, The King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, United
Kingdom
S
* Supporting Information
ABSTRACT: Catalytic enantioselective methods for the
preparation of chiral azaarene-containing compounds are
of high value. By combining the utility of copper hydride
catalysis with the ability of CN-containing azaarenes to
activate adjacent alkenes toward nucleophilic additions, the
enantioselective reductive coupling of alkenylazaarenes
with ketones has been developed. The process is tolerant
of a wide variety of azaarenes and ketones, and provides
aromatic heterocycles bearing tertiary-alcohol-containing
side chains with high levels of diastereo- and enantiose-
lection.
he development of new catalytic reactions for the
functionalization of aromatic heterocycles and their
T
derivatives continues to be a valuable endeavor due to the
importance of these structures in natural products, pharma-
ceuticals, agrochemicals, and other molecules of interest. In this
regard, recent efforts from our laboratory have targeted the
development of processes that exploit the ability of a suitably
positioned CN moiety within azaarenes to activate adjacent
alkenes toward catalytic enantioselective nucleophilic addi-
tions.1−3 The first of these reports described copper-catalyzed
reductions4 of β,β-disubstituted 2-alkenylazaarenes, which
result in alkylazaarenes with a new stereogenic center at the
β-carbon (representative example in Figure 1A).1 Since these
reactions likely proceed via the intermediacy of organocopper
species that undergo protonation with t-BuOH, we questioned
whether these intermediates could be trapped in situ with an
alternative electrophile such as a ketone (Figure 1B). Such a
reductive coupling process would be synthetically more
valuable, delivering more complex tertiary-alcohol-containing
products with stereochemistry at both α- and β-carbons.
Although the proposed process is related to copper-catalyzed
Figure 1. Catalytic transformations of alkenylazaarenes.
This study began with examination of the enantioselective
reductive coupling of 2-vinylquinoline (1a) with acetophenone
(1.1 equiv) using PhSiH3 (1.2 equiv) as the hydride source, 5
mol % Cu(OAc)2·H2O, and 5 mol % of various chiral
bisphosphines in toluene (Table 1).4 Pleasingly, proof of
concept was quickly established, and all ligands evaluated led to
complete consumption of 1a to provide the coupling product
2a as a mixture of diastereomers, along with traces of the simple
reduction product 3.11 Enantioselectivities were modest using
ligands L1−L3 (entries 1−3), but high using (R,R)-Quinox-P*
(L4) (entry 4), the Josiphos ligand L5 (entry 5), and the
Taniaphos ligand L6 (entry 6). However, no diastereoselectiv-
ity was observed in most cases, with the notable exception
being the reaction using L6 which provided 2a in 5:1 dr and
reductive aldol reactions described previously,5−9 to our
knowledge, there are no reports of alkenylazaarenes being
employed as substrates in these reactions. To date, the only
report of catalytic reductive coupling reactions of alkenylazaar-
enes is that from the Krische group, who described racemic
rhodium-catalyzed hydrogenative coupling of vinylazines with
N-sulfonylaldimines (Figure 1C).10 The realization of enantio-
selective variants of this and related processes would therefore
be of obvious value. Herein, we report highly enantioselective
copper-catalyzed reductive coupling reactions of alkenylazaar-
enes with ketones.
Received: April 17, 2012
Published: May 7, 2012
© 2012 American Chemical Society
8428
dx.doi.org/10.1021/ja3036916 | J. Am. Chem. Soc. 2012, 134, 8428−8431

Journal of the American Chemical Society
Communication
a
a
Table 1. Evaluation of Chiral Bisphosphines
Chart 1. Reaction Scope with Vinylazaarenes
b
b
c
entry
bisphosphine
2a:3
dr
ee (%)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
11:1
13:1
24:1
17:1
12:1
7:1
1:1
1:1
1:1
1:1
1:1
5:1
43, 50
67, 67
27, 17
−60, −92
92, 93
93, 60
a
b
Reactions were conducted using 0.10 mmol of 1a. Determined by
c
1H NMR analysis of the unpurified reaction mixtures. Determined by
chiral HPLC analysis.
93% ee for the major isomer (entry 6). Accordingly, L6 was
selected for further experimentation.
Chart 1 presents results of reductive coupling of various
vinylazaarenes 1a−1h12 with a range of ketones. Gratifyingly,
the scope of the process is broad, and the enantioselectivities of
the products were uniformly high (89−>99% ee).11 Although
L6 provided the best results for products 2a−2i, this ligand
resulted in a low yield in the attempted synthesis of 2j, and
poor diastereo- and enantioselectivities in the attempted
syntheses of 2k and 2l. In these cases, (R,R)-Quinox-P* (L4)
was superior for 2j and 2k, and the Josiphos ligand L5 was
optimal for 2l. In addition to 1a, effective substrates include
those containing azines such as pyridines (products 2c and 2k),
isoquinoline (products 2d−2g), two different isomeric
dimethoxypyrimidines (products 2h and 2i), and quinoxaline
(product 2l). A vinylthiazole also smoothly underwent the
reaction (product 2j). With acyclic ketones, the diastereose-
lectivity of the reaction appears to be dependent on the steric
properties of the azaarene, with diastereoselectivity increasing
from pyridine to quinoline to isoquinoline (compare
diastereomeric ratios for products 2c, 2a, and 2d). In the
coupling of 2-vinylpyridine with acetophenone, the two
diastereomeric products 2ca and 2cb were isolated with high
enantioselectivities (>99% and 92% ee, respectively). Regarding
the electrophile, the process is tolerant of acyclic ketones
containing various alkyl, aryl, or heteroaryl substituents
(products 2a−2g). In addition, cyclic ketones are viable
substrates, as exemplified by the successful use of two
indanones (products 2h and 2i), 4-chromanone (product 2j),
4-thiochromanone (product 2k), and tetralone (product 2l).
a
Reactions were conducted using 0.30−0.40 mmol of 1a−1h. Cited
yields are of pure isolated major diastereomers. Diastereomeric ratios
were determined by 1H NMR analysis of the unpurified reaction
mixtures. Enantiomeric excesses were determined by chiral HPLC
analysis.
Interestingly, the absolute stereochemistries of isoquinoline-
containing products 2d−2g are opposite to those of quinoline-
containing products 2a and 2b, even though the same
enantiomer of ligand L6 was employed throughout.11 In
addition, the diastereochemical outcomes of the reactions
producing 2h−2l are different from those resulting in 2a, 2b,
and 2d−2g.11 Assuming that the reactions proceed via
Zimmerman−Traxler-type transition states where the larger
aryl group of the ketone occupies a pseudoequatorial
position,13 Figure 2 depicts conformations that are consistent
with these observations. The stereochemical outcomes of the
reactions producing 2a, 2b, and 2d−2g are consistent with the
participation of Z-azaallylcopper species14 (TS 1 and TS 2),
though the reasons for the opposite sense of enantioinduction
in TS 2 compared with TS 1 are not clear at this time.
Furthermore, while the preference for the Z-azaallylcopper
species in TS 2 is readily explained by the severe A1,3-strain15
that would disfavor the corresponding E-azaallylcopper species,
a similar argument cannot be used to explain the same
preference in TS 1. For reactions producing 2h−2l, reaction
8429
dx.doi.org/10.1021/ja3036916 | J. Am. Chem. Soc. 2012, 134, 8428−8431

Journal of the American Chemical Society
Communication
In summary, we have described the first examples of catalytic
enantioselective reductive couplings of alkenylazaarenes. The
scope of this process is broad, with 11 different types of
azaarenes and a range of acyclic and cyclic ketones having been
shown to be effective coupling partners. β-Substitution on the
alkene is tolerated, and the reactions proceed under mild
conditions to deliver products in good to high levels of
diastereo- and enantioselection. These features should be
advantageous for application of this process in the preparation
of novel enantioenriched chiral azaarene-containing building
blocks.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full spectroscopic data for all new
compounds, and crystallographic data in cif format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 2. Rationalization of stereochemical outcomes.
through the E-azaallylcopper species (or Z-azaallylcopper
species in the case of 2j) appears to be favored, as in TS 3
for the formation of 2i. The interplay between the steric and/or
electronic properties of the alkenylazaarene and the ligand and
the resulting effect on the stereochemical outcome are clearly
complex. In addition, while the preceding discussion has been
based upon the assumption that chairlike transition states are
operative, reaction through boatlike structures cannot be
excluded.
AUTHOR INFORMATION
■
Corresponding Author
h.lam@ed.ac.uk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Edinburgh, the
EPSRC, and the ERC (Starting Grant No. 258580). We thank
Matthias Lotz (Solvias AG) for kind donations of L5 and L6.
The EPSRC is gratefully acknowledged for the award of a
Leadership Fellowship to H.W.L. We thank Iain D. Roy and
Boris Michel (University of Edinburgh) for assistance in the
preparation of substrates, and Dr. Gary S. Nichol and Professor
Simon Parsons (University of Edinburgh) for assistance with X-
ray crystallography. We are grateful to the EPSRC National
Mass Spectrometry Service Centre at the University of Wales,
Swansea, for providing high resolution mass spectra.
Notably, the process is not limited to vinylazaarenes; β-
substituted alkenylazaarenes are also effective coupling partners
(Chart 2). For example, alkenylazaarenes 4a−4c12 containing
Chart 2. Reductive Coupling of β-Substituted
a
Alkenylazaarenes with Ketones
REFERENCES
■
(1) Rupnicki, L.; Saxena, A.; Lam, H. W. J. Am. Chem. Soc. 2009, 131,
10386−10387.
(2) Pattison, G.; Piraux, G.; Lam, H. W. J. Am. Chem. Soc. 2010, 132,
14373−14375.
(3) For related contributions from elsewhere, see: (a) Houpis, I. N.;
Lee, J.; Dorziotis, I.; Molina, A.; Reamer, B.; Volante, R. P.; Reider, P.
J. Tetrahedron 1998, 54, 1185−1195. (b) Baschieri, A.; Bernardi, L.;
Ricci, A.; Suresh, S.; Adamo, M. F. A. Angew. Chem., Int. Ed. 2009, 48,
9342−9345. (c) Sun, H.-W.; Liao, Y.-H.; Wu, Z.-J.; Wang, H.-Y.;
Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2011, 67, 3991−3996.
(4) For reviews of copper hydride chemistry, see: (a) Lipshutz, B. H.
Synlett 2009, 509−524. (b) Deutsch, C.; Krause, N.; Lipshutz, B. H.
Chem. Rev. 2008, 108, 2916−2927. (c) Rendler, S.; Oestreich, M.
Angew. Chem., Int. Ed. 2007, 46, 498−504. (d) Lipshutz, B. H. In
Modern Organocopper Chemistry; Wiley-VCH Verlag GmbH: Wein-
heim, 2002; pp 167−187.
a
Reactions were conducted using 0.30 mmol of 4a−4c. Cited yields
are of pure isolated major diastereomers. Diastereomeric ratios were
determined by H NMR analysis of the unpurified reaction mixtures.
Enantiomeric excesses were determined by chiral HPLC analysis.
1
(5) For intermolecular copper-catalyzed reductive aldol reactions,
see: (a) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2006, 47, 1403−1407. (b) Welle, A.; Diez-Gonzalez, S.; Tinant, B.;
Nolan, S. P.; Riant, O. Org. Lett. 2006, 8, 6059−6062. (c) Chuzel, O.;
Deschamp, J.; Chausteur, C.; Riant, O. Org. Lett. 2006, 8, 5943−5946.
(d) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292−1297. (e) Zhao, D.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440−14441.
methyl, phenethyl, or allylic ether groups smoothly underwent
reductive coupling to deliver products 5a−5c, respectively, in
high enantioselectivities.11 Furthermore, these products contain
additional examples of azaarenes not utilized in Chart 1, such as
diphenyloxazole (product 5a), a dimethoxytriazine (product
5b), and 1,3-pyrimidine (product 5c).
8430
dx.doi.org/10.1021/ja3036916 | J. Am. Chem. Soc. 2012, 134, 8428−8431

Journal of the American Chemical Society
Communication
(6) For intramolecular copper-catalyzed or -mediated reductive aldol
reactions, see: (a) Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org.
Lett. 2001, 3, 1901−1903. (b) Chiu, P.; Leung, S. K. Chem. Commun.
2004, 2308−2309. (c) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7,
4225−4228. (d) Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005,
7, 5743−5746. (e) Lipshutz, B. H.; Amorelli, B.; Unger, J. B. J. Am.
Chem. Soc. 2008, 130, 14378−14379. (f) Deschamp, J.; Riant, O. Org.
Lett. 2009, 11, 1217−1220. (g) Li, N.; Ou, J.; Miesch, M.; Chiu, P.
Org. Biomol. Chem. 2011, 9, 6143−6147. (h) Ou, J.; Wong, W.-T.;
Chiu, P. Tetrahedron 2012, 68, 3450−3456. (i) Deschamp, J.;
Hermant, T.; Riant, O. Tetrahedron 2012, 68, 3457−3467.
(7) Relevant reviews on the reductive aldol reaction: (a) Nishiyama,
H.; Ito, J.-i. Chem. Commun. 2010, 203−212. (b) Han, S. B.; Hassan,
A.; Krische, M. J. Synthesis 2008, 2669−2679. (c) Garner, S. A.; Han,
S. B.; Krische, M. J. In Modern Reduction Methods; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, 2008; pp 387−417. (d) Nishiyama,
H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105−137. (e) Ngai, M.-Y.;
Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063−1072. (f) Jang,
H.-Y.; Krische, M. J. Eur. J. Org. Chem. 2004, 3953−3958. (g) Jang, H.-
Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 653−661. (h) Chiu, P.
Synthesis 2004, 2210−2215. (i) Huddleston, R. R.; Krische, M. J.
Synlett 2003, 12−21. (j) Motherwell, W. B. Pure Appl. Chem. 2002, 74,
135−142.
(8) For enantioselective copper-catalyzed reductive Michael reac-
tions, see: Oswald, C. L.; Peterson, J. A.; Lam, H. W. Org. Lett. 2009,
11, 4504−4507.
(9) For enantioselective copper-catalyzed reductive Mannich
reactions, see: Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 16146−16147.
(10) Komanduri, V.; Grant, C. D.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 12592−12593.
(11) Where indicated, the relative and absolute stereochemistries of
the products obtained herein were assigned by analogy with those of
products 2a, 2b, 2d, 2e, 2j, and 5c, which were determined by X-ray
crystallography using a copper radiation source (see Supporting
Information for details). The stereochemistry of 2l (obtained using
ligand L5) was assigned by analogy with the product obtained using
ligand L6, which was the same major enantiomer of 2l but in 2:1 dr
and 73% ee.
(12) See Supporting Information for the structures of 1b−1h and
4a−4c.
(13) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920−1923.
(14) For a review of 1-azaallylic anions in heterocyclic chemistry, see:
Mangelinckx, S.; Giubellina, N.; De Kimpe, N. Chem. Rev. 2004, 104,
2353−2400.
(15) For a review of allylic 1,3-strain as a stereocontrolling element in
reactions, see: Hoffmann, R. W. Chem. Rev. 1989, 89, 1841−1860.
8431
dx.doi.org/10.1021/ja3036916 | J. Am. Chem. Soc. 2012, 134, 8428−8431