A general strategy for regiocontrol in nickel-catalyzed reductive couplings of aldehydes and alkynes

Full text of DOI:10.1021/ja102262v

Published on Web 04/15/2010
A General Strategy for Regiocontrol in Nickel-Catalyzed Reductive Couplings
of Aldehydes and Alkynes
Hasnain A. Malik, Grant J. Sormunen, and John Montgomery*
930 North UniVersity AVenue, Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
Received March 17, 2010; E-mail: jmontg@umich.edu
Table 1. Ligand Effects in Couplings of 2-Hexyne
The reductive coupling of aldehydes and alkynes has been widely
studied as an entry to stereodefined allylic alcohols.1 While broad
scope has been demonstrated for several variants, the control of
regiochemistry is consistently a major hurdle.2 Indeed, the challenge
of controlling regiochemistry plagues nearly every class of alkyne
addition reactions. In most classes of addition processes, alkynes
that possess either a strong electronic or steric bias often participate
with good to excellent regiocontrol, but only a single regiochemical
outcome is typically available. Alternatively, alkynes that lack a
strong electronic or steric bias generally participate in addition
processes with poor regioselectivity. These characteristics generally
hold true for aldehyde-alkyne reductive coupling processes.
Aromatic alkynes, terminal alkynes, silyl alkynes, ynamides, and
conjugated diynes and enynes are among the biased substrate classes
that participate in highly regioselective reductive couplings with
aldehydes, with a single regiochemical outcome typically being
possible.3 Additionally, remote directing functionality such as
alkenes and alcohols have proven to be effective in Ni-catalyzed
and Ti-promoted variants.2,4
entry
L·HX
Regioselectivity (1:2)
% Yield
1
2
3
4
5
6
7
8
9
10
3a
6
87:13
86:14
75:25
67:33
61:39
44:56
29:71
20:80
7:93
18
29
22
83
73
64
86
84
85
69
5a
3b
4a
3c
5b
3d
4b
5c
6:94
Despite these impressive advances with biased alkynes and
directed processes, we envisioned that a strategy for regiochemical
control that overrides inherent substrate biases and that does not
require installation of a directing functional group would be the
ideal solution to regiocontrol in this group of reactions. Previous
results from our lab illustrated that regioselectivities may be
moderately impacted by ligand structure, but the effects were too
small to be broadly useful.5 A recent computational study described
the minimal impact that ligand structure has on regioselectivity in
aldehyde-alkyne reductive couplings with Ni(0)-phosphine cata-
lysts and organoborane reducing agents,6 thus highlighting the
complexity of designing a ligand-controlled regioselective process.
Herein, we describe that carefully selected carbene ligands com-
plexed with nickel provide a general solution to regiocontrol in
silane-mediated aldehyde-alkyne reductive couplings with a broad
range of alkynes.
Our studies began with an evaluation of ligand effects in
reductive couplings of heptaldehyde with 2-hexyne, since this
alkyne provides a relatively unbiased case (Table 1).7 Initial
couplings were evaluated with carbene ligands paired with (i-
Pr)3SiH.3d The catalysts were generated in situ, by treating the
carbene HCl or HBF4 salt with Ni(COD)2 and KO-t-Bu in THF.
Substantial regiocontrol favoring either product was exerted across
the range of ligands examined, although chemical yields were
typically poor with less hindered carbenes. As the examples
illustrate, ligand 6 (i-Pr-BAC), recently developed by Bertrand,8
and ligand 3a (ITol) provided the best selectivities for product 1,
whereas ligands 4b (SIPr) and 5c9 provided the best selectivities
for product 2.
favor the formation of product 1. Extensive experimentation
illustrated that the use of BuLi as base and (t-Bu)2SiH2 as reducing
agent provided much improved chemical yields when using ligand
6, with negligible effect on regioselectivity.10 Thus, in choosing
reaction conditions, the following guidelines may be adopted: To
generate products when C-C bond formation at the less hindered
alkyne terminus is desired, ligand 3b (IMes) is a good commercial
ligand to employ, and ligand 6 (i-Pr-BAC) provides even higher
selectivity, especially with internal doubly aliphatic substituted
alkynes. To generate products when C-C bond formation at the
more hindered alkyne terminus is desired, ligand 4b (SIPr) is a
good commercial ligand to employ, and ligand 5c provides even
higher selectivity, especially with terminal alkynes (Vide infra).
The above guidelines are illustrated with a broad range of biased
and unbiased alkynes (Table 2). Couplings of 2-hexyne with
unbranched, branched, or aromatic aldehydes are accomplished with
good to excellent regioselectivity for either desired regioisomer 7
or 8 (entries 1-3). Increasing the steric differences between the
two alkyne substituents (Me vs i-Pr) is cleanly tolerated and
provides high regioselectivity for either isomer (entry 4). We next
considered the possibility of applying these findings to reductive
couplings of alkynes that possess considerable electronic bias and
that typically provide highly regioselective access to only one of
the two possible regioisomeric products. We chose to examine
aromatic alkynes, conjugated enynes, and terminal alkynes, which
uniformly provide highly selective access to regioisomer 7 using
previously reported R3SiH-NHC or Et3B-PR3 Ni-catalyzed pro-
While substantial changes in regioselectivity of 2-hexyne addition
reactions were observed from the above studies, an obvious
limitation is the low yield observed with unhindered ligands that
9
6304 J. AM. CHEM. SOC. 2010, 132, 6304–6305
10.1021/ja102262v  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ligand-Controlled Regioselectivity Reversal
conjugated enynes provides useful substructures, several of which
were previously inaccessible by aldehyde-alkyne reductive cou-
pling. Either regiochemical outcome of the alkyne addition may
be selectively accessed with each of these substrate classes. The
extent of regiochemical reversal seen across the broad range of
alkynes studied rivals that seen for any class of alkyne addition
reactions. While improvements in ligand structure can be envisioned
to provide further enhancements in selectivity and scope, the above
study illustrates the special role that stable carbene ligands can play
in governing catalytic reactions that are sensitive to steric controlled
regioselection.
entry
R1
R2
R3
7:8 (% yield)a
7:8 (% yield)a
1
2
3
4
5
6
7
8
9
n-Hex
c-Hex
Ph
Ph
Ph
n-Hex
Ph
Ph
Me
Me
Me
Me
Me
Me
H
n-Pr
n-Pr
n-Pr
i-Pr
Ph
c-Hexenyl
CH2OTBS
n-Hex
A, 88:12 (78)
A, 82:18 (75)
A, 84:16 (72)
A, 97:3 (85)
C, >98:2 (84)
C, 97:3 (99)
C, 93:7 (88)
C, 97:3 (82)
C, >98:2 (74)
B, 7:93 (85)
B, 5:95 (91)
B, 2:>98 (86)
B, 10:90 (89)
B, 19:81 (99)
B, 9:91 (77)
D, 15:85 (86)
D, 12:88 (71)
D, 5:95 (76)
Acknowledgment. The authors wish to acknowledge receipt
of NIH Grant GM-57014 in support of this work. G.J.S. acknowl-
edges training grant support from NIH Grant GM-007767. Mani
Raj Chaulagain is thanked for helpful discussions.
H
H
n-Hex
i-Pr
a Conditions: A: L·HX ) 6, BuLi, (t-Bu)2SiH2; B: L·HX ) 4b,
KO-t-Bu, (i-Pr)3SiH; C: L·HX ) 3b, KO-t-Bu, (i-Pr)3SiH or Et3SiH; D:
L·HX ) 5c, BuLi, Et3SiH. Ligand structures are given in Table 1.
Supporting Information Available: Full experimental details and
copies of NMR spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
cedures. Coupling of phenyl propyne with benzaldehyde, as
anticipated, provided regioisomer 7 with high selectivity under
standard conditions with ligand 3b (IMes) (entry 5). However, the
use of ligand 4 (SIPr) reverses selectivity, favoring regioisomer 8
with 81:19 regioselectivity. We next examined a conjugated enyne,
knowing that this substrate class is one of the most biased alkyne
classes in reductive couplings.3d-f,6 Standard coupling with ligand
3b (IMes) provided highly selective coupling at the aliphatic
substituted alkyne terminus to produce isomer 7 as anticipated (entry
6). However, the use of ligand 4 (SIPr) cleanly reversed selectivity,
providing regioisomer 8 with excellent regiocontrol. Finally, three
different terminal alkyne-aldehyde combinations were examined
(entries 7-9). As anticipated, standard couplings with ligand 3b
(IMes) cleanly and selectively provided the trans-1,2-disubstitution
pattern (isomer 7). Unfortunately, this bias could not be overcome
with ligand 4 (SIPr), and isomers 7 and 8 were obtained with poor
regiocontrol. However the use of ligand 5c provided an important
breakthrough, providing the 1,1-disubstitution pattern (isomer 8)
with excellent regiocontrol, ranging from 12:88 to 5:95 for the three
examples studied.11
References
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Figure 1. Ligand steric control of regiochemistry.
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regiochemistry, provides a possible rationale for the observed
regiochemical outcome.12 This model had previously been presented
as part of a synergistic picture to explain how ligand size effects
supplement inherent substrate biases.5a However, the current study
illustrates that, with careful optimization of ligand structure, the
impact of ligand size effects is substantial and can override
substrate-derived influences with a broad range of both biased and
unbiased alkynes.
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Soc. 2010, 132, 4249.
In summary, the complementary use of cyclopropenylidene
ligands and highly hindered N-heterocyclic carbene ligands provides
dramatic regiochemical reversal in nickel-catalyzed aldehyde-alkyne
reductive couplings. The participation of relatively unbiased internal
alkynes or strongly biased terminal alkynes, aryl alkynes, and
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