Aromatic heterocycles as activating groups for asymmetric conjugate addition reactions. Enantioselective copper-catalyzed reduction of 2-alkenylheteroarenes

Article abstract of DOI:10.1021/ja904365h

(Chemical Equation Presented) The versatility of chiral copper hydride catalysis has been demonstrated through development of highly enantioselective 1,4-reductions of 2-alkenylheteroarenes, substrates that have been rarely considered for asymmetric conju

Full text of DOI:10.1021/ja904365h

Published on Web 07/09/2009
Aromatic Heterocycles as Activating Groups for Asymmetric Conjugate
Addition Reactions. Enantioselective Copper-Catalyzed Reduction of
2-Alkenylheteroarenes
Leszek Rupnicki, Aakarsh Saxena, 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 May 29, 2009; E-mail: h.lam@ed.ac.uk
Table 1. Ligand Optimization for the Asymmetric Reduction of 1aa
The 1,4-addition of a nucleophile to an alkene conjugated to an electron-
withdrawing group is a fundamental reaction in organic chemistry, and
numerous catalytic asymmetric variants (eq 1) of this process are now
routinely employed in the synthesis of molecules of interest.1,2 The most
common functional groups used to activate alkenes toward asymmetric
conjugate additions include carbonyls, nitriles, sulfones, phosphonates, and
nitro groups. We recently questioned whether other rarely considered yet
common functional groups might also be employed in this capacity, and
our attention focused on nitrogen-containing aromatic heterocycles. Given
that heteroarenes such as oxazoles, thiazoles, pyridines, and others are
ubiquitous in biologically active natural products, pharmaceuticals, and
agrochemicals, the ability to functionalize these privileged structures
through a diverse set of asymmetric conjugate additions of 2-alkenyl
derivatives (eq 2) would open up broad-ranging applications.
a Reactions were conducted using 0.20 mmol of 1a in toluene (1 mL).
Conversions were determined by GC analysis. Enantioselectivities were
determined by chiral HPLC analysis. b Reactions complete after 2 h.
SEGPHOS ligands L3 and L4, with 91% ee obtained using (S)-SEGPHOS
(L3). The Josiphos ligands L5 and L6 were also effective, providing 2a
in 89% and 87% ee, respectively. Of all the ligands, the highest reaction
rates were observed with L4 and L5 (reactions were complete in 2 h).
However, the superior selectivity provided by L5 prompted us to select
Although conjugate additions to 2-vinylheteroarenes (R1, R2 ) H in
eq 2) are relatively common,3 the corresponding reactions of substrates
containing a ꢀ-substituent are much rarer, presumably for steric reasons.4,5
Furthermore, the only report of a catalytic enantioselective variant is limited
this ligand for further optimization and investigation of the reaction scope.
to poorly selective (e15% ee) Grignard additions to 4-alkenylpyridines.5
Using 5 mol % each of Cu(OAc)2 ·H2O and L5, PhSiH3 (1.5 equiv),
and t-BuOH (2.0 equiv) at an initial temperature of 0 °C, a range of ꢀ,ꢀ′-
disubstituted 2-alkenylheteroarenes underwent conjugate reduction with
generally excellent levels of enantioselection (Table 2).11 In addition to
benzoxazole (entries 1-4), other effective nitrogen-containing hetero-
arenes in this process included 5-phenyloxazole (entry 5), benzothiazole
(entry 6), pyridine (entries 7-9), quinoline (entry 10), and pyrazine (entry
11). Tolerated functionality at the ꢀ-positions of the alkene included simple
aliphatic groups, a phenyl group (entry 4), a benzyl group (entry 9), various
oxygenated alkyl groups (entries 2, 3, 7-9, and 11), and a cyclopropane
(entry 10). The process is tolerant of lower loadings of copper and ligand.
For example, reduction of 1g on a 1.0 mmol scale using 2 mol % each of
Cu(OAc)2 ·H2O and L5 provided 2g in 92% yield and 96% ee (entry 7,
values in parentheses).
Therefore, we recently initiated a program targeted at addressing these
deficiencies, and in this communication, our preliminary findings involving
highly enantioselective copper-catalyzed reductions6 of ꢀ,ꢀ’-disubstituted
2-alkenylheteroarenes are presented.
The asymmetric copper-catalyzed conjugate reduction of activated
alkenes is a well-established method for the synthesis of various useful
chiral building blocks.6-10 Whether a nitrogen-containing heteroarene
would provide sufficient activation to an adjacent alkene in an analogous
reaction was, however, uncertain. In addition, it seemed likely that
coordination of the Lewis basic nitrogen of the heteroarene to the copper
catalyst would occur in such a process, and whether this interaction would
be beneficial, inconsequential, or detrimental was not easy to predict.
Our investigations began with a survey of chiral bisphosphines L1-L6
using 2-alkenylbenzoxazole 1a as a test substrate (Table 1). Using 10 mol
% of Cu(OAc)2 ·H2O, 10 mol % of ligand, and 4 equiv each of PhSiH3
and t-BuOH in toluene at room temperature, biaryl-based ligands L1-L4
proved competent in promoting conjugate reduction.11 With (R)-BINAP
(L1), both conversion and enantioselectivity were only moderate. However,
improved results were observed using (R)-MeO-BIPHEP (L2) and the
Experiments to explore the origins of reactivity were then conducted.
Reduction of 4-alkenylpyridine 3 provided 4 in 60% yield and 94% ee,
albeit in a slower reaction that was incomplete even after 4 days (eq 3).
This result suggests that alkene reduction by copper hydride can occur
without assistance of a directing effect from the nitrogen atom. In contrast,
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10.1021/ja904365h CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Cu-Catalyzed Asymmetric Conjugate
(Takasago), Rudolf Schmid (Hoffmann-La Roche), and Matthias Lotz
(Solvias AG) are gratefully acknowledged for supplying the SEGPHOS,
MeO-BIPHEP, and Josiphos ligands, respectively, used in this study. We
thank the EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea, for providing high resolution mass spectra.
Dr. Fraser J. White is thanked for assistance with X-ray crystallography.
Reductiona
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.
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a Reactions were conducted using 0.20 mmol of 1a-1k unless
otherwise stated. b Isolated yield. c Determined by chiral HPLC analysis.
d Using 0.155 mmol of 1d. e Values in parentheses refer to a reaction
conducted using 1.0 mmol of 1g, 2 mol % Cu, and 2 mol % L5. f Using 0.10
mmol of 1h and 2.0 equiv of PhSiH3.
3-alkenylpyridine 5 was unreactive (eq 4), demonstrating the importance
of conjugation of the alkene to a CdN moiety for reactivity.
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In summary, copper-catalyzed asymmetric conjugate reductions of ꢀ,ꢀ′-
disubstituted 2-alkenylheteroarenes are reported. In addition to serving as
a further demonstration of the power of chiral copper hydride catalysis,6
this work has shown nitrogen-containing aromatic heterocycles can provide
effective activation of an adjacent alkene for highly enantioselective
catalytic conjugate addition reactions. Extension of the general concept
to other classes of asymmetric reactions should provide a range of useful
tools for chemists working with heteroarenes. Future studies from our
laboratory will be directed toward this goal.
(11) The stereochemistries of the products obtained herein were assigned
tentatively by analogy with that of 2c, which was secured through X-ray
crystallography of a derivative. See Supporting Information for details.
Acknowledgment. This work was supported by the European
Commission (Project No. MEST-CT-2005-020744). Drs. Izuru Nagasaki
JA904365H
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