Alkene-Directed, Nickel-Catalyzed Alkyne Coupling Reactions

Article abstract of DOI:10.1021/ja0491735

In alkene-directed, nickel-catalyzed coupling reactions of 1,3-enynes with aldehydes and epoxides, the conjugated alkene dramatically enhances reactivity and uniformly directs regioselectivity, independent of the nature of the other alkyne substituent (ar

Full text of DOI:10.1021/ja0491735

Published on Web 03/16/2004
Alkene-Directed, Nickel-Catalyzed Alkyne Coupling Reactions
Karen M. Miller, Torsak Luanphaisarnnont, Carmela Molinaro, and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received February 14, 2004; E-mail: tfj@mit.edu
Table 1. Alkene-Directed, Nickel-Catalyzed Coupling Reactions of
As carbon-carbon double bonds can be transformed into a vast
array of other functional groups, alkenes are among the most
important and versatile organic compounds. While many simpler
alkenes are commodity chemicals, those that are highly substituted
are generally less available.1 The controlled addition of two groups
across an alkyne triple bond is an important strategy for the
synthesis of these olefins,1d and low-valent nickel complexes
catalyze several of these transformations.2 In intermolecular cases,
regioselectivity, one of the chief challenges in all alkyne addition
reactions, is generally governed by electronic and/or steric differ-
ences between the two alkyne substituents.3,4 We now report a new
strategy for selective olefin synthesis, whereby a transient interaction
between a conjugated alkene and a transition metal5 dramatically
enhances reactivity and uniformly directs regioselectivity (eq 1,
Table 1).
Alkynes with Aldehydes and Epoxidesa
In Ni-catalyzed coupling reactions of alkynes of the general form
Ar-CtC-alkyl the regioselectivity is generally very high (>95:
5), favoring carbon-carbon bond formation distal to the aromatic
group.3d,g-i It was therefore quite unexpected that an electronically
similar and smaller vinyl group caused a complete reVersal in the
sense of regioselectivity, favoring C-C bond formation proximal
to the aryl substituent (entry 1). This regioselectivity is also opposite
that observed by Montgomery in intramolecular aldehyde-enyne
couplings.6,7,8
The alkene substituent not only imparts exquisite regioselectivity
but, as demonstrated by t-Bu-CtC-CHdCH2 (1b, entry 2), also
provides a remarkable increase in reactivity. Other alkynes with
tert-alkyl substituents (t-Bu-CtC-alkyl and Ar-CtC-t-Bu) do
not undergo reductive coupling under similar conditions.9 Of even
further significance is that few examples of catalytic carbon-carbon
bond-forming reactions of tert-alkyl-CtC-R alkynes are known,3a,10
and in none of these, Ni-catalyzed or otherwise, is C-C bond
formation favored adjacent to a tert-alkyl group.11
The directing ability of the alkene depends neither on the nature
or size of the other alkyne substituent (aryl, alkyl (1°, 2°, 3°)) nor
on the degree of alkene substitution (entries 1-9). Terminal
epoxides also undergo coupling3i in similarly high regioselectivity
and with retention of configuration (entries 10-11). The availability
of epoxides in >99% ee12 makes this strategy attractive for
preparing enantiomerically pure 3,5-dienols. It is also noteworthy
that the product dienes do not react with another molecule of
aldehyde2,13 or epoxide under these conditions.
a See eq 1. Standard procedure (see Supporting Information): To a
solution of Ni(cod)2 (0.05 mmol), tricyclopentylphosphine (Cyp3P) (0.10
mmol), and Et3B (1.0 mmol) in EtOAc (0.5 mL) at 0 °C were added
i-PrCHO (1.0 mmol) and the enyne (0.5 mmol). Upon consumption of the
enyne, purification by chromatography provided dienes 2a-2k. b Regio-
selectivity determined by 1H NMR. c (+)-Neomenthyldiphenylphosphine
used as ligand. d Bu3P and (+)-octene oxide (>99% ee) used in place of
Cyp3P and i-PrCHO. EtOAc omitted. e Yield over two steps.
exhibit all the hallmarks of directed reactions14 and can be explained
by complexation of the alkene to the metal center during the
regioselectivity-determining step.5,15
In conjunction with a rhodium-catalyzed, site-selective hydro-
genation (eq 2, Table 2), the above couplings address two gen-
eral problems observed in catalytic additions to alkynes, namely
control of regioselectivity with unsymmetrical dialkylacetylenes
(alkyl-CtC-alkyl′)16 and inaccessibility of disfavored regioisomers.
Wilkinson’s catalyst [(Ph3P)3RhCl] under H2 smoothly converted
dienes 2a-f into allylic alcohols 3a-f (entries 1-6)17,18 and dienes
2j-k into homoallylic alcohols 3g-h (entries 7-8).19,20
The dramatic enhancement of reactivity (e.g., entry 2) and the
invariant sense and degree of regioselectivity (in particular the
complete turnover vs Ph, entry 1) are not consistent with a purely
steric and/or electronic phenomenon. Conversely, these trends
Substrate-directed reactions are of tremendous importance to
selective chemical synthesis.14 In the case of Ni-catalyzed alkyne-
coupling reactions, an alkenyl group dramatically enhances reactiv-
9
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J. AM. CHEM. SOC. 2004, 126, 4130-4131
10.1021/ja0491735 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Site-Selective, Catalytic Hydrogenation of 1,3- Dienesa
Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc.
2004, 126, 3698-3699.
Supporting Information Available: Experimental procedures and
data for compounds 1a-e, 1g-i, 2a-k, and 3a-h (PDF). This
information is available free of charge via the Internet at http://
pubs.acs.org
1
2
entry
diene
R
R
n
R
alkenol
yield (%)
1
2
3
4
2a
2b
2c
2d
2e
2f
Ph
t-Bu
Cy
i-Pr
n-Hex
Et
H
0
0
0
0
0
0
1
1
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-Hex
n-Hex
3a
3b
3c
3d
3e
80
83
87
76
92
96
94
85
References
H
H
H
H
Me
Me
H
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5
6
3f
7b
8b
2j
2k
Et
i-Pr
3gc
3hc
a See eq 2. Standard procedure (see Supporting Information): A solution
of the diene (0.12 mmol) and RhCl(PPh3)3 (12 µmol) in toluene (1 mL)
was stirred under H2 until the diene was consumed. Purification (chroma-
tography) provided alkenols 3a-3h. b TBS ether of alcohol used; see Table
1. c TBS ether isolated in >99% ee.
ity and completely controls regioselectivity, (Table 3), enabling the
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1,3-dienes.2,13 A novel, site-selective hydrogenation yields allylic
and homoallylic alcohols that cannot be obtained in high regiose-
lectivity (or at all) from the corresponding alkynes with these
methods.3d,g-i Finally, the alkene-directing effect presented herein
may be of broad utility in catalytic reactions of alkynes, a possibility
that we are currently investigating.
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and Reactivity in Nickel-Catalyzed Alkyne Coupling Reactionsa
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a Numbers indicate typical regioselectivity (Table 1 and refs 3d,
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Acknowledgment. We thank the FQRNT (fellowship to C.M.)
and Boehringer-Ingelheim (New Investigator Award to T.F.J.) for
postdoctoral support, the MIT Undergraduate Research Opportuni-
ties Program (T.L.), and the National Institute of General Medical
Sciences (GM-063755) for support of part of this work. We also
thank the NSF (CAREER CHE-0134704), Merck Research Labo-
ratories, Johnson & Johnson, Amgen, Pfizer, and GlaxoSmithKline
for generous financial support. The MIT Department of Chemistry
Instrumentation Facility is supported in part by the NSF (CHE-
9809061 and DBI-9729592) and the NIH (1S10RR13886-01).
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(17) As is often observed with hindered alkenes, (Ph3P)3RhCl did not catalyze
effective hydrogenation of 2g-i under any conditions evaluated.
(18) TBS ethers of dienols are equally effective and site-selective.
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Note Added in Proof. Recently Montgomery reported two
examples of intermolecular, nickel-catalyzed, enyne-aldehyde
reductive coupling reactions that proceed with the same sense
of regioselectivity as that which we observe (Table 1). See
(20) Low regioselectivity is observed in the coupling of i-Pr-CtC-Et and
(+)-octene oxide (3g:3h ) 2:1). See Supporting Information.
JA0491735
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