Ligand-switchable directing effects of tethered alkenes in nickel-catalyzed additions to alkynes

Article abstract of DOI:10.1021/ja0446799

Nickel-catalyzed reductive couplings of aldehydes with alkynes that contain tethered olefins are described, in which the degree and sense of regioselectivity are controlled by the length of the tether and the presence or absence of an additive. When the a

Full text of DOI:10.1021/ja0446799

Published on Web 11/04/2004
Ligand-Switchable Directing Effects of Tethered Alkenes in Nickel-Catalyzed
Additions to Alkynes
Karen M. Miller and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received September 2, 2004; E-mail: tfj@mit.edu
Table 2. Highly Regioselective, Catalytic Reductive Coupling
Substrate-directable reactions are a very important class of
selective organic transformations.1 A temporary dative bond
between a nonreacting functional group in the starting material and
a reagent or catalyst can amplify (or reverse) selectivity by
reinforcing (or changing) the low energy conformation of the
transition state of the selectivity-determining step. We recently
proposed that certain nickel-catalyzed additions to alkynes are
directed by a conjugated alkene.2,3,4 Herein we report not only that
a remote, unconjugated alkene dictates regioselectivity but also that
the sense of regioselectivity can be completely reVersed (from
>95:5 to 5:>95) by a substoichiometric amount of an additive.
Simply put, the degree of regioselectivity is due entirely to a
directing effect of an appropriately placed alkene, and the sense of
the regioselectivity is due entirely to the presence (or absence) of
a phosphine ligand.
Reactions Directed by a Remote Alkenea
In our initial investigations we examined reductive coupling
reactions between aldehydes and alkynes with two linear aliphatic
groups, one of which posessed a terminal alkene (Table 1, entries
1-4). In all cases a very low yield of the allylic alcohol products
was observed in the absence of a phosphine ligand, with one striking
exception (entry 3). Remarkably, a tether of three methylene groups
(1c) provides not only a dramatic increase in reactivity but also
complete selectivity for allylic alcohol regioisomer 2c.
Table 1. Directing Effects of Tethered Alkenesa
a See eq 1, Table 1, and Supporting Information. R ) (CH2)3CHdCH2.
regioselectivity
entry
alkyne
n
yield (%)
(2/3)b
1
Regioselectivity determined by H NMR and/or GC.
1
2
3
4
5
1a
1b
1c
1d
1
2
3
4
n.a.
<5
<5
53c
<5
28c
nd
nd
>95:5
nd
Table 2 illustrates the scope and utility of this directing effect,5
and several of the examples deserve further comment. In coupling
reactions of n-alkylsCtCsi-Pr alkynes, the steric demand of the
i-Pr group disfavors the regioisomer corresponding to 2h (∼1:2
ratio),2,6 while n-alkylsCtCsCH2OTBS alkynes exhibit a 2-fold
preference for the regioisomer corresponding to 2i, attributable to
an electron-withdrawing effect of the propargylic oxygen. A tethered
alkene, however, is sufficient to override (or reinforce) these
“inherent” regioselectivities. Heteroatoms that could compete with
the alkene for binding to nickel do not erode regioselectivity but
rather augment the versatility of this directable transformation
(alkynes 1f-i).
The results of a set of coupling reactions employing an
organophosphine were especially surprising and provide significant
insight into the mechanistic framework of not only these directed
reactions but also nickel-catalyzed reductive coupling reactions of
alkynes in general (eq 2).7 In contrast to the experiments sum-
marized in Table 1 (no phosphine), alkynes 1a, 1b, and 1d (n ) 1,
n-pentylsCtCsn-hexyl
50:50
a Standard procedure: The alkyne (0.50 mmol) was added to a 0 °C
solution of Ni(cod)2 (0.05 mmol), i-PrCHO (1.00 mmol), and Et3B (1.00
mmol) in EtOAc (0.5 mL), and the solution was allowed to stir 15 h at
room temperature. See Supporting Information for details. b Determined by
1H NMR and/or GC. c Some alkylative coupling (transfer of Et from Et3B)
also observed.
Because of the marked difference in reactivity and selectivity
for one (and only one) tether length, it is very unlikely that the
infinitesimal differences in the steric and electronic properties of
the alkyne substituents in 1c are responsible for this effect.
Consistent with this notion is a control experiment with the
corresponding alkyne lacking the pendant alkene, 1,2-dihydro-1c
(entry 5). As expected, product yield was significantly diminished,
and no regioselectivity was observed.
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10.1021/ja0446799 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
2, and 4, respectively) did undergo coupling with i-PrCHO when
tricyclopentylphosphine (Cyp3P)2,8 was employed, but in a non-
regioselective fashion (75% yield (54:46), 84% (47:53), and 50%
(50:50), respectively). However, with three carbon-carbon single
bonds between the alkene and the alkyne (1c), remarkably high
regioselectivity was observed as before, but in this case with
complete preference for the other regioisomer (3c, 45% yield).9 A
control experiment using 1,2-dihydro-1c also provided further
evidence for a temporary dative interaction between the remote
alkene and the metal center (77% (50:50)).
in this work not only resonate with the ligand-dependence observed
by Montgomery, but they also provide the first strong evidence
for which mechanism is operating in each case, carbon-carbon bond
formation prior to hydrometalation or vice versa.
The results of the studies described here have several other
important ramifications. A chiral tether between the alkyne and
alkene or alkene-containing ligands themselves may impart high
stereo- and/or regioselectivity in these reactions.16,17 These areas
and the use of ligand-switchable directed reactions in target-oriented
synthesis are under current investigation.
Acknowledgment. We thank Mr. Ryan T. Moslin for thought-
provoking discussions of his related studies. Support for this work
was provided by the National Institute of General Medical Sciences
(GM-063755). We also thank the NSF (CAREER CHE-0134704),
Amgen, Boehringer-Ingelheim, Bristol Myers-Squibb, GlaxoSmith-
Kline, Johnson & Johnson, Merck Research Laboratories, Pfizer,
the Sloan Foundation, Wyeth, and MIT for generous 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).
Our explanation of these observations is that the directed
reactions herein proceed by fundamentally distinct mechanisms
(Scheme 1). Intermediate A is consistent with the studies of
Po¨rschke, who showed that 1,6-heptadiene and 1,6-heptadiyne
chelate nickel in three-coordinate, approximately trigonal planar
complexes in the solid state and in solution.10 The exclusive
formation of regioisomer 3 when Cyp3P is employed can be
explained by installation of the alkenyl H prior to carbon-carbon
bond formation. Oxidative addition of a Ni-ligand complex into a
carbon-boron bond of Et3B and directed hydrometalation would
give alkenyl-nickel species B that undergoes carbonyl addition.
Supporting Information Available: Experimental procedures and
data for all new compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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(3) Other examples of catalytic reductive coupling reactions of 1,3-enynes
and aldehydes: (a) (Ni) Mahandru, G. M.; Liu, G.; Montgomery, J. J.
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(5) Aromatic aldehydes are of considerably reduced efficacy. An extended
reaction time (40 h) was required for a 26% yield (>95:5 regioselectivity)
in a coupling between 1h and PhCHO. See Supporting Information.
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(7) Details in Supporting Information.
Scheme 1
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(9) Alkynes with a heteroatom in the tether (1g-i) primarily afford products
of phosphine-promoted carbocyclization (i.e., not allylic alcohols 2j-l
or 3j-l). Under investigation is the scope of this process, which, as shown
below, may arise from a species akin to A (Scheme 1). See also Tamao,
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Conversely, in the absence of Cyp3P, the formation of regio-
isomer 2 is best accounted for by reversing the order of events
(C-C bond formation prior to alkenyl H introduction) possibly by
way of oxanickellacyclopentene (C).11,12,13
Although directing effects of tethered alkenes have been
demonstrated in other metal-mediated reactions,14 the only other
examples in which the sense of the effect was reversed by an
additive are Pd-catalyzed enyne isomerizations reported by Trost.15
However, high regioselectivity was observed in only one direction
(g15:1 vs 1:2.5), and the reversal was not the result of two different
alkene-directed mechanisms, but rather preferential binding to Pd
of the additive over the tethered olefin that was responsible for the
directing effect.
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Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628-1629.
Montgomery’s recent crossover labeling experiments elegantly
demonstrated that the pathways operating in related coupling
reactions depend strongly on the ligand used.3a The experiments
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