Ligand-guided pathway selection in nickel-catalyzed couplings of enals and alkynes

Article abstract of DOI:10.1039/c2cc17073f

Nickel-catalyzed couplings of enals and alkynes utilizing triethylborane as the reducing agent illustrate a significant dependence on ligand structure. Simple variation of monodentate phosphines allows selective access to alkylative couplings or reductive

Full text of DOI:10.1039/c2cc17073f

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COMMUNICATION
Ligand-guided pathway selection in nickel-catalyzed couplings of enals
and alkyneswz
Wei Li and John Montgomery*
Received 15th November 2011, Accepted 30th November 2011
DOI: 10.1039/c2cc17073f
Nickel-catalyzed couplings of enals and alkynes utilizing
triethylborane as the reducing agent illustrate a significant
dependence on ligand structure. Simple variation of monodentate
phosphines allows selective access to alkylative couplings or
reductive cycloadditions, while further variation of reaction
conditions provides clean access to reductive couplings and
redox-neutral couplings.
Under these conditions, [3+2] reductive cycloaddition product
3a, alkylative coupling product 4a, reductive coupling product
5a, and ester product 6a were seen in varying proportions. Our
previously reported conditions for [3+2] reductive cycloaddition
involved PBu3 as ligand,3a,b and under these conditions,
cyclopentenol 3a was obtained in 85% isolated yield as an
87 : 13 mixture of diastereomers (Table 1, entry 1). A series of
triarylphosphine ligands were next examined, with an eye
towards developing more user-friendly procedures, given the
ease of handling these more stable ligands. Couplings with
PPh3 provided mixtures of cyclopentenol 3a in 46% yield
along with alkylative coupling product 4a in 14% yield and
reductive coupling product 5a in 25% yield (Table 1, entry 2).
Use of the bulkier P(1-naphthyl)3 produced alkylative coupling
product 4a in 57% yield along with reductive coupling product 5a
in trace quantities (Table 1, entry 3). Similarly, the use of P(o-tol)3
also favored product 4a in 76% yield, along with 19% isolated
yield of 5a and trace quantities of product 3 (Table 1, entry 4).
In contrast to the general preference for product 4a when
using substituted triarylphosphines, the use of P(p-methoxy-
phenyl)3 and P(2,4,6-trimethoxyphenyl)3 afforded cyclopentenol
3a as the major product, in 72% and 79% yields respectively
(Table 1, entries 5 and 6). Diastereoselectivities were slightly
lower than observed with PBu3 and PPh3. Examination of more
hindered trialkylphosphines PCy3 and P(t-Bu)3 afforded lower
conversions (Table 1, entries 7 and 8) although a new product,
methyl ester 6a, was observed in moderate quantity when PCy3
was employed. As described below, mechanistic considerations
in the production of ester 6a suggested a simple modification for
optimization of this product.
A broad range of nickel-catalyzed reductive coupling processes
have been developed, including procedures that involve couplings
of aldehydes, a,b-unsaturated carbonyls, imines, alkynes, dienes,
allenes, and nitriles as the reactive p-components.1 The coupling
of enals or enones with alkynes is one of the more extensively
studied variants, and within this specific set of substrates, a
number of different reaction manifolds have been disclosed,
including reductive couplings,2 reductive cycloadditions,3
alkylative cycloadditions,3b and three-components couplings that
proceed without formal substrate reduction.2d,4 Our prior reports
in this area have described modifications in substrates, ligands,
reducing agents, additives, solvents, and metal stoichiometry to
select between the various possible reaction pathways. To better
illustrate the most important features in selecting individual
reaction pathways, we describe herein that simple modification
of monodentate phosphine structure, while leaving all other
reaction variables unchanged, can dramatically alter reaction
outcomes. As part of this study, we demonstrate that catalytic
alkylative enal-alkyne couplings with organoboranes can also be
accessed in addition to the previously reported pathways, and
we also disclose that stable, crystalline, electron-rich triaryl-
phosphine ligands can duplicate the reactivity characteristics of
the more sensitive and more easily oxidized trialkylphosphine
ligands.
Obtaining the [3+2] reductive cycloaddition products using
a stable triarylphosphine ligand (Table 1, entry 6) provides a
To illustrate the unique impact of ligand modifications in
enal-alkyne couplings, we examined couplings of aldehyde 1a
and phenylpropyne (2a), using 10 mol% Ni(COD)2, 20 mol% of
a monodentate phosphine, and 3.0 equiv. of triethylborane, in
an 8 : 1 methanol : THF cosolvent system (Scheme 1, Table 1).
Department of Chemistry, 930 N. University Ave. University of
Michigan, Ann Arbor, MI 48109-1055
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and copies of NMR spectra. See DOI: 10.1039/c2cc17073f
Scheme 1 Products from enal-alkyne couplings under reductive
conditions.
c
1114 Chem. Commun., 2012, 48, 1114–1116
This journal is The Royal Society of Chemistry 2012

Table 1 Ligand effects in reductive couplingsa
% 3a (dr)b % 4a % 5a % 6a
Table 3 Examination of alkylative couplingsa
Entry Ligand
1
2
3
4
5
6
7
8
PBu3
PPh3
P(1-naphthyl)3
P(o-tol)3
P[4-(MeO)C6H4]3
P[2,4,6-(MeO)3C6H2]3 79 (36 : 64)
PCy3
P(t-Bu)3
85 (87 : 13)
46 (87 : 13)
14
57
76
25
o10
19
o10
o10
72 (65 : 35) o10
Entry
R1
R2
R3
% 4
12
18
45
1
2
3
4
n-Pr
n-Pr
H
Me
Ph
Ph
Et
Ph
Ph
Ph
Et
76
52
53
57
o10
17
a
Conditions: Ni(COD)2 (10 mol%), PR3 (20 mol%), Et3B (3.0 equiv),
n-Pr
b
MeOH/THF (8 : 1), rt. Isolated yields shown. Diastereomeric ratio
of 3a is reported as cis : trans ratio.
a
Conditions: Ni(COD)2 (10 mol%), P(o-tol)3 (20 mol%), Et3B
(3.0 equiv), MeOH/THF (8 : 1), rt. Isolated yields shown. Only a
single regio- and stereoisomer was observed.
useful preparative simplification over the previously reported use
of PBu3. Additionally, the use of a hindered triarylphosphine
such as P(o-tolyl)3 to obtain product 4a involving ethylation
during the coupling process (Table 1, entry 4) has not been
previously reported. Therefore, a brief examination of the scope
of these two proceses was examined (Table 2 and 3). First,
the efficiency of [3+2] reductive cycloadditions employing
P[2,4,6-trimethoxyphenyl]3 as ligand was examined (Table 2).
Using b-substituted enal 1a, couplings with symmetrical
(Table 2, entries 1-2), unsymmetrical (Table 2, entry 3), and
terminal alkynes (Table 2, entry 4) were successful, albeit with
low levels of diastereocontrol. Additionally, an alkyne possessing
an unprotected hydroxyl could be effectively coupled (Table 2,
entry 5). Couplings with acrolein, however, proceeded only in
low yield (Table 2, entry 6).
agent with H-atom transfer in reactions of this type,1c,10 although
ethyl transfer was previously described in imine-alkyne couplings.11
We interpret the ligand effects described above (Table 1) by
the following analysis (Scheme 2). Following the production of
metallacycle intermediate 7,12 enolate protonation occurs to
generate common intermediate 8. The use of a small basic
phosphine (PBu3) allows direct addition of the vinyl nickel
fragment to the coordinated aldehyde of 8 while electronically
disfavoring ethyl transfer to 9 due to the strong s-donating
capability of the ligand. This addition produces cyclopentenol
derivative 10 leading to product 3a. By employing less basic
aryl phosphines, ethyl transfer to 9 is facilitated, and reductive
elimination to produce 4a occurs. While PPh3 provides a mixure
of products 3a and 4a, the increased sterics of P(o-tol)3 and
P(1-naphthyl)3 disfavor addition to the aldehyde and provide
superior entries to product 4a. In contrast, P(p-methoxyphenyl)3
and P(2,4,6-trimethoxyphenyl)3 are considerably more s-donating
than the other triarylphosphines, and these ligands duplicate the
electronic biases of PBu3, favoring the production of cyclopentenol
3. It is noteworthy that these electron-rich triaryl phosphines
display the crystallinity and stability of other triaryl phosphines,
and provide considerable practical advantanges over the use of
more sensitive trialkyl phosphines.
Alkylative couplings with ethyl transfer were briefly examined
using P(o-tol)3 as ligand. Using b-substituted enal 1a, couplings
with phenylpropyne and diphenylacetylene were effective
(Table 3, entries 1 and 2). A coupling of acrolein with diphenyl-
acetylene proceeded in moderate yield (Table 3, entry 3).
Additionally using a simple non-aromatic alkyne was effective
(Table 3, entry 4). Alkylative couplings of enals or enones with
alkynes were previously reported with organozinc,5 organo-
zirconium,6 organostannane,7 organoaluminum,8 and alkenyl-
borane reagents,9 but to our knowledge the corresponding
process with simple trialkyl boranes has not been previously
reported. Triethylborane more commonly functions as a reducing
While simple variation of phosphine structure does not
allow efficient production of products 5a and 6a, one can
readily visualize solutions to these optimizations according to
the mechanistic analysis described above. These previously-
reported advances complement the ligand control strategies
reported in this contribution and are summarized here to
provide a complete analysis of the products described in
Scheme 1. Using Et3B with a protic solvent medium, the
generation of product 5 could not be readily optimized.
However, by employing a trialkylsilane as the reducing agent
in an aprotic solvent, metallacycle 13 is converted directly to
intermediate 14, which does not release the electrophilic aldehyde
(Scheme 3). Additionally, direct transfer of a hydrogen atom from
the silane removes the complexity of C–Et vs. C–H reductive
elimination. Therefore, the enol silane 15 (corresponding to
product 5a) is obtained by this procedure.2c
Table 2 Examination of [3+2] reductive cycloadditionsa
Entry
R1
R2
R3
% 3 (dr)
1
2
3
4
5
6
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
H
Et
Ph
Me
H
(CH2)3OH
Me
Et
51 (48 : 52)b
70 (53 : 47)b
79 (36 : 64)b
71 (64 : 36)c
65 (62 : 38)c
31
Ph
Ph
Ph
Ph
Ph
For the production of compound 6a, the mechanistic scheme
above (Scheme 2) illustrates that methanol addition to 8, followed
by a formal 1,5 shift of the hemiacetal proton of 12 leads to the
production of compound 6a without involvement of an external
reducing agent. Therefore, simple omission of the reducing agent
a
Conditions: Ni(COD)2 (10 mol%), P[2,4,6-(MeO)3C6H2]3 (20 mol%),
Et3B (3.0 equiv), MeOH/THF (8 : 1), rt. Isolated yields shown.
b
Diastereomeric ratio of 3a is reported as cis :trans ratio. c Stereochemistry
of the diastereomeric mixture was not determined.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1114–1116 1115

Scheme 2 Mechanistic rationale for ligand control in enal-alkyne couplings.
2 (a) J. Montgomery and A. V. Savchenko, J. Am. Chem. Soc., 1996,
118, 2099–2100; (b) A. Herath, B. B. Thompson and J. Montgomery,
J. Am. Chem. Soc., 2007, 129, 8712–8713; (c) A. Herath and
J. Montgomery, J. Am. Chem. Soc., 2008, 130, 8132–8133;
(d) W. Li, A. Herath and J. Montgomery, J. Am. Chem. Soc., 2009,
131, 17024–17029; (e) For related cobalt-catalyzed processes:
H. T. Chang, T. T. Jayanth, C. C. Wang and C. H. Cheng, J. Am.
Chem. Soc., 2007, 129, 12032–12041.
3 (a) A. Herath and J. Montgomery, J. Am. Chem. Soc., 2006, 128,
14030–14031; (b) A. D. Jenkins, A. Herath, M. Song and
J. Montgomery, J. Am. Chem. Soc., 2011, 133, 14460–14466;
(c) H. T. Chang, T. T. Jayanth and C. H. Cheng, J. Am. Chem.
Soc., 2007, 129, 4166–4167; (d) V. M. Williams, J. R. Kong, B. J. Ko,
Y. Mantri, J. S. Brodbelt, M. H. Baik and M. J. Krische, J. Am.
Chem. Soc., 2009, 131, 16054–16062; (e) M. Ohashi, T. Taniguchi and
S. Ogoshi, J. Am. Chem. Soc., 2011, 133, 14900–14903.
Scheme 3 Alternate pathways for accessing products 5a and 6a.
(BEt3) allows clean production of the methyl ester product 6a,
likely involving the intermediacy of 13 and 12 (Scheme 3).4,13
Formation of product 6a was futher optimized by the use of
N-heterocyclic carbene ligands.4
4 A. Herath, W. Li and J. Montgomery, J. Am. Chem. Soc., 2008,
130, 469–471.
5 (a) S. Ikeda, H. Yamamoto, K. Kondo and Y. Sato, Organo-
metallics, 1995, 14, 5015–5016; (b) J. Montgomery, E. Oblinger and
A. V. Savchenko, J. Am. Chem. Soc., 1997, 119, 4911–4920.
6 (a) Y. Ni, K. K. D. Amarasinghe and J. Montgomery, Org. Lett.,
2002, 4, 1743–1745; (b) Y. Ni, R. M. Kassab, M. V. Chevliakov
and J. Montgomery, J. Am. Chem. Soc., 2009, 131, 17714–17718.
7 S. Ikeda and Y. Sato, J. Am. Chem. Soc., 1994, 116, 5975–5976.
8 M. V. Chevliakov and J. Montgomery, Angew. Chem., Int. Ed.,
1998, 37, 3144–3146.
9 (a) C. M. Yang, M. Jeganmohan, K. Parthasarathy and C. H. Cheng,
Org. Lett., 2010, 12, 3610–3613; (b) T. T. Jayanth and C. H. Cheng,
Angew. Chem., Int. Ed., 2007, 46, 5921–5924.
10 M. Kimura, A. Ezoe, K. Shibata and Y. Tamaru, J. Am. Chem.
Soc., 1998, 120, 4033–4034.
In conclusion, an interesting array of cyclic and acyclic
products are obtained by the nickel-catalyzed coupling of
enals and alkynes. Simple variation of ligand structure has a
major impact on the reaction outcome, and a mechanistic
scheme formulated allowed rational optimization of each of
the possible reaction outcomes. A noteworthy feature of this
study is the use of stable electron-rich triaryl phosphines that
serve as a convenient replacement for more sensitive trialkyl-
phosphines in reductive cycloadditions.
This work was supportedby NSF grant CHE-1012270.
11 S. J. Patel and T. F. Jamison, Angew. Chem., Int. Ed., 2003, 42,
1364–1367.
12 K. K. D. Amarasinghe, S. K. Chowdhury, M. J. Heeg and
J. Montgomery, Organometallics, 2001, 20, 370–372.
Notes and references
1 (a) J. Montgomery, Acc. Chem. Res., 2000, 33, 467–473;
(b) J. Montgomery, Angew. Chem., Int. Ed., 2004, 43, 3890–3908;
(c) R. M. Moslin, K. Miller-Moslin and T. F. Jamison, Chem.
Commun., 2007, 4441–4449; (d) M. Jeganmohan and C. H. Cheng,
Chem.–Eur. J., 2008, 14, 10876–10886.
13 For other examples of catalytic processes that proceed by transfer
hydrogenation: (a) J. F. Bower, E. Skucas, R. L. Patman and
M. J. Krische, J. Am. Chem. Soc., 2007, 129, 15134–15135;
(b) J. F. Bower, I. S. Kim, R. L. Patman and M. J. Krische,
Angew. Chem., Int. Ed., 2009, 48, 34–46.
c
1116 Chem. Commun., 2012, 48, 1114–1116
This journal is The Royal Society of Chemistry 2012