New N-heterocyclic carbene ligand and its application in asymmetric nickel-catalyzed aldehyde/alkyne reductive couplings

Article abstract of DOI:10.1021/ja072992f

A new chiral N-heterocyclic carbene ligand has been prepared and examined in nickel-catalyzed, asymmetric reductive couplings of aldehydes and alkynes. In comparison with related structures that have been largely examined in asymmetric ring-closing metath

Full text of DOI:10.1021/ja072992f

Published on Web 07/12/2007
New N-Heterocyclic Carbene Ligand and Its Application in Asymmetric
Nickel-Catalyzed Aldehyde/Alkyne Reductive Couplings
Mani Raj Chaulagain, Grant J. Sormunen, and John Montgomery*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received April 28, 2007; E-mail: jmontg@umich.edu
Table 1. Examination of Ligand Structurea
Allylic alcohols are integral subunits of a variety of biologically
interesting natural products as well as key building blocks for a
number of important synthetic transformations. Among the numer-
ous strategies for the preparation of allylic alcohols, the reductive
coupling of aldehydes and alkynes in either an inter- or intramo-
lecular sense arguably provides the most direct access to this
important substructure from simple precursors.1,2 Whereas several
asymmetric approaches to the reductive coupling of aldehydes and
alkynes have been reported,3 our recent studies involving the use
of achiral N-heterocyclic carbene complexes of nickel illustrated
several important features including broad scope with both internal
and terminal alkynes, direct incorporation of a silyl protecting group,
and the ability to tune alkyne regioselection in macrocyclizations
based on ligand sterics.4 In order to capitalize upon these advan-
tages, we have now examined the asymmetric coupling of aldehydes
and alkynes using chiral N-heterocyclic carbene complexes.
Pioneering studies from Grubbs illustrated that N-heterocyclic
carbenes derived from C2 symmetric diamines and mono-ortho-
substituted aryl halides were excellent participants in asymmetric
a Below each structure in the table is the given the compound number
ring-closing metathesis reactions.5 Members of this structural class
of the imidazolium salt, % yield for the production of 2 using the ligand,
of N-heterocyclic carbenes appeared to be promising candidates
and the % ee (in parenthesis) of compound 2 produced with the ligand.
b This entry employed 2 mol % of 1f, KO-t-Bu, and Ni(COD)2.
for asymmetric nickel-catalyzed reductive couplings. We thus
examined the reductive coupling of benzaldehyde and 1-phenyl-
propyne under a variety of conditions to provide a lead ligand
structure for further optimization. The known N-heterocyclic
carbene ligands, generated in situ from 1a and 1b in THF with
KO-t-Bu, allowed the production of the desired protected allylic
alcohol 2a in modest yield and poor enantioselectivity (Table 1).
New ligands 1c and 1d, which incorporate an ortho-phenyl or ortho-
cyclohexyl substituent, were then prepared from the commercially
available aryl bromides. A reaction involving ligand 1c afforded
product 2a with slightly improved enantioselectivity, whereas a
reaction with ligand 1d proceeded with significantly improved
enantioselectivity, affording compound 2a in 76% ee in 60% yield.
Despite the encouraging enantioselectivity with ligand 1d, examina-
tion of additional starting material combinations illustrated that
yields were often poor to modest. Given the requirement of steric
hindrance to stabilize free N-heterocyclic carbenes (by preventing
dimerization), we next considered ortho,ortho-disubstituted carbene
ligands. Ligand 1e was thus prepared, which did indeed allow
improved chemical yields but with low enantioselectivities. Rec-
ognizing that ortho,ortho-disubstitution was optimal from the
standpoint of chemical yield, whereas steric differentiation of the
two ortho substituents was optimal from the standpoint of enanti-
oselectivity, we next prepared ligand 1f. Under the same conditions
described for the above experiments, chemical yields in couplings
of benzaldehyde and 1-phenylpropyne improved to 98% with lower
catalyst loading (2 mol %) in 78% ee. Whereas ligand 1f was
primarily designed for enantioselectivity optimization, the catalytic
activity of the nickel catalyst derived from this ligand surprisingly
exceeded that of the commonly employed IMes and IPr N-
heterocyclic carbene ligands in catalytic aldehyde/alkyne reductive
couplings. We therefore anticipate that this new ligand may be
useful in various metal-catalyzed5,6 or organocatalytic7 processes
that rely on N-heterocyclic carbene species.
Upon identifying the excellent catalytic activity and promising
enantioselectivity in a reaction with the catalyst derived from ligand
1f, we sought to explore its generality across a range of substrates.
As illustrated (Table 2), the yields and enantioselectivities are
relatively uniform across a broad range of substrates. Key functional
groups cleanly tolerated in the procedure include aromatic as well
as branched and unbranched aldehydes, internal alkynes that either
possess or lack an aromatic substituent, terminal alkynes, and
unprotected alcohols, wherein the trialkylsilyl group is regioselec-
tively installed on the newly formed hydroxyl. Regioselection of
alkyne insertion is high with the exception of internal alkynes that
possess two aliphatic substituents (entries 4 and 11). Notably, the
regioselectivity in one of these cases was found to undergo reversal
with ligand 1d (compare entries 11 and 12). Therefore, ligand 1d
may be useful in some applications due to this complementary
regioselection. The reversal of regioselectivity is consistent with
the steric-based model for regioselectivity reversal proposed in
macrocyclizations involving achiral ligands.4b
Given that macrocyclizations of ynal substrates provide an
important entry to substructures found in many bioactive natural
products, this new procedure was applied in an asymmetric
macrocyclization of ynal 3 (eq 1). In this example, 14-membered
macrocycle 4a and 13-membered macrocycle 4b were produced
in 76% combined yield as an 86:14 mixture of regioisomers (79%
9
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J. AM. CHEM. SOC. 2007, 129, 9568-9569
10.1021/ja072992f CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Asymmetric Couplings
cyclohexyl substituent anti to the backbone phenyl group and distal
to nickel as depicted. This orientation would then position the ortho-
methyl substituent syn to the backbone phenyl group and proximal
to nickel. It is the ortho-methyl substituent that thus dictates the
selectivity of aldehyde binding according to this model. Oxidative
cyclization of structure 5 to metallacycle 6 would then lead to the
formation of 2, which is the major enantiomer observed.9
In summary, an efficient approach to synthesis of allylic alcohols
involving the catalytic asymmetric coupling of aldehydes and
alkynes has been developed. A new chiral N-heterocyclic carbene
ligand was prepared that provides improved reaction efficiencies
and enantioselectivities compared with known, structurally related
N-heterocyclic carbene ligands. Although prior studies established
good to excellent enantioselectivities with specific substrate com-
binations,3 the simple experimental protocol (fast reactions at rt
with a stable reducing agent) provides significant preparative
advantages of this new procedure, and the range of participating
substrates is the broadest of any single method to date. The
development of new generations of ligands, synthetic applications,
and mechanistic studies are in progress.
entry
R1
R2
R3
% yield (% ee)a
regioselectivity
1
2
Ph
Ph
Me
Et
Ph
Et
98 (78)b
82 (70)
86 (70)
86 (75)
84 (85)c
75 (78)
78 (81)
64 (65)
70 (73)
99 (79)
79 (76)
47 (79)d
10:1
3
4
5
i-Pr
i-Pr
Cy
Me
(CH2)3Ph
Et
Ph
Me
Et
>19:1
3:1
6
7
(CH2)2Ph
Cy
Et
Me
Et
Ph
>19:1
>19:1
10:1
9:1
8
9
10
11
12
Cy
n-hex
Cy
Cy
Cy
H
Me
(CH2)4OH
n-pent
Me
n-hex
Ph
Ph
Me
n-pent
3:1e
6:1
a The % ee is given for the major regioisomer. b We used 2 mol % of
1f, Ni(COD)2, and KO-t-Bu. c Ligand (S,S)-1f was used, and the enantiomer
of the configuration shown for product 2 was obtained. d Ligand 1d was
used. e Minor regioisomer of entry 11 is of the S configuration produced in
76% ee.
Acknowledgment. The authors wish to acknowledge receipt
of NIH grant GM57014 in support of this work. Dr. Scott Bader is
kindly acknowledged for helpful suggestions.
Scheme 1. Model for Enantioselection
Supporting Information Available: Full experimental details and
copies of NMR spectral data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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(9) Absolute stereochemistry of 12 of the 14 examples (Table 2 and eq 1)
was established by Mosher’s ester analysis. See Supporting Information
for details.
In analogy to the proposal from Grubbs in asymmetric ring-
closing metathesis reactions involving members of the ligand class
1,5 we propose that the reaction proceeds via generation of a three-
coordinate complex 5 (Scheme 1).8 Tilting of the N-aryl ring of 5
relative to the imidazolidine ring would position the ortho-
JA072992F
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