Ni(II) salts and 2-propanol effect catalytic reductive coupling of epoxides and alkynes

Article abstract of DOI:10.1021/ol201702a

A Ni-catalyzed reductive coupling of alkynes and epoxides using Ni(II) salts and simple alcohol reducing agents is described. Whereas previously reported conditions relied on Ni(cod)₂ and Et₃B, this system has several advantages incl

Full text of DOI:10.1021/ol201702a

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4140–4143
Ni(II) Salts and 2-Propanol Effect Catalytic
Reductive Coupling of Epoxides and
Alkynes
Matthew G. Beaver and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
tfj@mit.edu
Received June 24, 2011
ABSTRACT
A Ni-catalyzed reductive coupling of alkynes and epoxides using Ni(II) salts and simple alcohol reducing agents is described. Whereas previously
reported conditions relied on Ni(cod)2 and Et3B, this system has several advantages including the use of air-stable and inexpensive Ni(II)
precatalysts (e.g., NiBr2 3H2O) as the source of Ni(0) and simple alcohols (e.g., 2-propanol) as the reducing agent. Deuterium-labeling
3
experiments are consistent with oxidative addition of an epoxide CÀO bond that occurs with inversion of configuration.
The development of methods for transition-metal-cata-
lyzedCÀC bond formation using air-stable and inexpensive
reagents continues to offer a challenge to synthetic che-
mists. Recent improvements in the scope and utility of Ni-
catalyzed CÀC bond forming reactions present a signifi-
cant advance toward this goal.1,2 The advent of methods
employing Ni(II) precatalysts, for example, has obviated
the need to handle air-sensitive Ni(0) sources.3 In many
cases, however, Ni-catalyzed coupling protocols are lim-
ited by the inclusion of air- and moisture-sensitivereducing
agents. Herein, we describe a practical method for the Ni-
catalyzed reductive coupling of alkynes and epoxides using
air-stable and inexpensive Ni(II) salts as the precatalysts
and 2-propanol (i-PrOH) as the reducing agent.4,5 Me-
chanistic analysis of the reductive coupling process via
(1) For reviews, see: (a) Montgomery, J. Angew. Chem., Int. Ed. 2004,
43, 3890–3908. (b) Montgomery, J.; Sormunen, G. J. Top. Curr. Chem.
2007, 279, 1–23. (c) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F.
Chem. Commun. 2007, 4441–4449. (d) Kimura, M.; Tamaru, Y. Top.
Curr. Chem. 2007, 279, 173–207. (e) Rosen, B. M.; Quasdorf, K. W.;
Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V.
Chem. Rev. 2011, 111, 1346–1416.
(2) For selected examples of recent advances in Ni-catalyzed CÀC
bond forming reactions, see: (a) Malik, H. A.; Sormunen, G. J.;
Montgomery, J. J. Am. Chem. Soc. 2010, 132, 6304–6305. (b) Matsu-
bara, R.; Jamison, T. F. J. Am. Chem. Soc. 2010, 132, 6880–6881. (c)
Cho, H. Y.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 7576–7577. (d)
Zhou, C.-Y.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc.
2010, 132, 10955–10957. (e) Li, W.; Chen, N.; Montgomery, J. Angew.
Chem., Int. Ed. 2010, 49, 8712–8716. (f) Ho, C.-Y.; He, L. Angew. Chem.,
Int. Ed. 2010, 49, 9182–9186. (g) Taylor, B. L. H.; Swift, E. C.; Waetzig,
J. D.; Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389–391. (h) Hoshimoto,
Y.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 4668–4671.
(3) For selected examples of CÀC bond forming methods employing
Ni(II) precatalysts, see: (a) Watson, M. P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 12594–12595. (b) Quasdorf, K. W.; Tian, X.; Garg, N. K.
J. Am. Chem. Soc. 2008, 130, 14422–14423. (c) Williams, C. M.; Johnson,
J. B.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14936–14937. (d) Everson,
D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920–
921. (e) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11027–
11029. (f) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11908–
11909.
(4) Alcohols bearing β-hydrogen atoms have proven to be competent
reducing agents in Ni-catalyzed reductive couplingreactions: (a) Herath,
A.; Li, W.; Montgomery, J. J. Am. Chem. Soc. 2008, 130, 469–471. (b) Li,
W.; Herath, A.; Montgomery, J. J. Am. Chem. Soc. 2009, 131, 17024–
17029. (c) Phillips, J. H.; Montgomery, J. Org. Lett. 2010, 12, 4556–4559.
(5) For additional examples of i-PrOH-mediated reductive CÀC
bond-forming reactions, see: (a) Bower, J. F.; Skucas, E.; Patman,
R. L.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 15134–15135. (b)
Bower, J. F.; Patman, R. L.; Krische, M. J. Org. Lett. 2008, 10, 1033–
1035. (c) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 6338–6339. (d) Patman, R. L.; Chaulagain, M. R.; Williams,
V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066–2067.
r
10.1021/ol201702a
Published on Web 06/30/2011
2011 American Chemical Society

deuterium-labeling studies provides evidence that oxida-
tive addition of the epoxide CÀO bond occurs with inver-
sion of configuration.
In this manner, simple alcohols (e.g., i-PrOH) could
serve as mild, air-stable, and inexpensive alternatives
to Et3B.
Our laboratory has previously demonstrated that al-
kynes and epoxides undergo reductive coupling in the
presence of Ni(cod)2, Bu3P, and Et3B.6À8 For example,
Ni-catalyzed reductive coupling of epoxide 1 provided
homoallylic alcohol 2 in 50% yield (Scheme 1). The
combination of Ni(cod)2 and Bu3P, both of which are
exceedingly prone to air oxidation, was found to provide
optimal results. In addition, the inclusion of Et3B, a highly
pyrophoric reducing agent, was critical for the desired
transformation to proceed. We hypothesize that Et3B
may serve as a Lewis acid to facilitate oxidative addition
of the epoxide, in addition to its standard role as a reducing
agent.
Table 1. Influence of Reaction Parameters on the Ni-Catalyzed
Reductive Coupling of an Alkyne and Epoxide
entry
variation from standard conditions
yield (%)a Z/Eb
1
2
3
4
5
nonec
82
82
76
74
75
90:10
95:5
Ni(cod)2 instead of NiBr2 3H2Od
3
NiBr2 diglyme instead of NiBr2 3H2O
88:12
89:11
95:5
3
3
NiCl2 6H2O instead of NiBr2 3H2O
3
3
5 mol % NiBr2 3H2O and 20 mol %
3
Scheme 1. Previously Reported Conditions for the Ni-Catalyzed
PhMe2P instead of standard
catalyst/phosphine loading
THF instead of i-PrOH
Reductive Couping of Alkynes and Epoxides6
7
<5e
<5e
76
---
8
no NiBr2 3H2O
---
3
9
30 mol % PhMe2P instead of 40 mol %
20 mol % PhMe2P instead of 40 mol %
no PhMe2P
90:10
91:9
---
10
11
52
<5e
a Isolated yield of the mixture of olefin isomers. b Determined by 1H
NMR spectroscopy of the crude reaction mixture. c Complete conver-
sion of starting material observed within 3 h. d Phosphine loading was 20
mol % instead of 40 mol %. e Determined by 1H NMR spectroscopy
relative to mesitylene as an internal standard.
In light of our recent studies involving regioselective
epoxide-opening cascades promoted by hydroxylic
solvents,9 we envisioned that alcohol solvents might
promote the Ni-catalyzed reductive coupling of alkynes
and epoxides. In this setting, the role of the alcohol
solvent would be twofold. First, oxidative addition of
the epoxide CÀO bond could be facilitated by hydro-
gen-bonding interactions between the epoxide oxygen
and the alcohol solvent.9b,10 Second, the appropriate
alcohol could serve as a reducing agent to provide the
desired homoallylic alcohol product (2) and regenerate
the active Ni(0) catalyst (vide infra, Scheme 2).4,5,11
Our investigations revealed that i-PrOH was an effective
reducing agent for the Ni-catalyzed reductive coupling
of alkynes and epoxides. For example, employing i-PrOH
as the solvent in the presence of PhMe2P and either
NiBr2 3H2O (Table 1, entry 1) or Ni(cod)2 (entry 2)
provided high yields of the desired homoallylic alcohol
3
2a.12À14 The use of air-stable Ni(II) precatalysts and
reducing agents(i.e., NiBr2 3H2O and i-PrOH, as opposed
3
to previous conditions employing Ni(cod)2 and Et3B),6
allowed us to setup and perform the coupling reac-
tions outside of a glovebox. Furthermore, all reactions
listed in Table 1 could be performed without drying of
the reagents or glassware. Of note, reactions employing
(6) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 8076–
8077.
(7) For examples of the utility of Ni-catalyzed alkyneÀepoxide
reductive coupling in the context of natural product synthesis, see: (a)
O’Brien, K. C.; Colby, E. A.; Jamison, T. F. Tetrahedron 2005, 61, 6243–
6248. (b) Woodin, K. S.; Jamison, T. F. J. Org. Chem. 2007, 72, 7451–
7454. (c) Sparling, B. A.; Simpson, G. L.; Jamison, T. F. Tetrahedron
2009, 65, 3270–3280. (d) Trenkle, J. D.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2009, 48, 5366–5368.
inexpensive NiX2 hydrate salts (entries 1 and 4) were
of comparable efficiency to reactions performed with
3
(8) Reductive opening of epoxides has also been observed under
€
Chem., Int. Ed. 1998, 37, 101–103. (b) Gansauer, A.; Bluhm, H.;
(11) For selected reviews describing transition-metal-catalyzed trans-
fer hydrogenation, see: (a) Zassinovich, G.; Mestroni, G.; Gladiali, S.
Chem. Rev. 1992, 92, 1051–1069. (b) Noyori, R.; Hashiguchi, S. Acc.
Chem. Res. 1997, 30, 97–102. (c) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34–46.
(12) Details of substrate synthesis are provided as Supporting
Information.
(13) Subjecting enantioenriched epoxide 1a (88% ee) to the standard
conditions for Ni-catalyzed reductive coupling provided homoallylic
alcohol 2a (88% ee) with complete preservation of optical purity. See
Supporting Information for details.
titanocene catalysis: (a) Gansauer, A.; Pierobon, M.; Bluhm, H. Angew.
€
Pierobon, M. J. Am. Chem. Soc. 1998, 120, 12849–12859.
(9) For example, see: (a) Vilotijevic, I.; Jamison, T. F. Science 2007,
317, 1189–1192. (b) Byers, J. A.; Jamison, T. F. J. Am. Chem. Soc. 2009,
131, 6383–6385. (c) Morten, C. J.; Byers, J. A.; Van Dyke, A. R.;
Vilotijevic, I.; Jamison, T. F. Chem. Soc. Rev. 2009, 38, 3175–3192.
(10) (a) Hine, J.; Linden, S.-M.; Kanagasabapathy, V. M. J. Am. Chem.
Soc. 1985, 107, 1082–1083. (b) Hine, J.; Linden, S.-M.; Kanagasabapathy,
V. M. J. Org. Chem. 1985, 50, 5096–5099. (c) Yamada, T.; Morisseau, C.;
Maxwell, J. E.; Argiriadi, M. A.; Christianson, D. W.; Hammock, B. D. J.
Biol. Chem. 2000, 275, 23082–23088. (d) Omoto, K.; Fujimoto, H. J. Org.
Chem. 2000, 65, 2464–2471. (e) Fleming, E. M.; Quigley, C.; Rozas, I.;
Connon, S. J. J. Org. Chem. 2008, 73, 948–956. (f) Wurst, J. M.; Liu, G.;
Tan, D. S. J. Am. Chem. Soc. 2011, 133, 7916–7925.
(14) Preliminary investigation of the reaction conditions indicated
that i-PrOH was the optimal alcohol reducing agent. See Supporting
Information for additional details of reaction optimization including
alcohol reducing agent, Ni(II) precatalyst, and temperature.
Org. Lett., Vol. 13, No. 15, 2011
4141

anhydrous NiBr2 diglyme (entry 3). Decreasing the cata-
conditions for reductive coupling did not result in forma-
tion of the desired product (entry 5).18 Terminal alkynes
are a particularly difficult class of substrates in Ni(0)-
catalyzed coupling reactions, as this moiety often suc-
cumbs to deleterious cyclotrimerization.19 Under these
conditions for reductive coupling, however, terminal
alkyne 1g underwent reductive coupling in 55% yield
(entry 6).
3
lyst loading to 5 mol % was tolerated and provided the
desired homoallylic alcohol 2a in only slightly lower yields
(entry 5). No product formation was observed in the
absence of i-PrOH, the nickel catalyst, or phosphine ligand
(entries 7, 8, 11).
Increased phosphine loadings were found to provide
the highest yields of homoallylic alcohol 2a for reactions in
which NiX2 salts were employed as the catalyst. Pre-
viously, a 2:1 (R3P/Ni) ratio was determined to be the
optimal loading for reductive coupling reactions of epox-
ides and alkynes using Ni(cod)2 (Table 1, entry 2).6 When
Table 2. Investigation of Reaction Scope
NiBr2 3H2O was employed as the catalyst, however, a
3
phosphine loading of 20 mol % did not result in complete
conversion of starting material (entry 10). Increasing the
phosphine loading to 30 mol % led to complete consump-
tion of the starting material and increased yields (entry 9).
Finally, a phosphine loading of 40 mol % was found
to provide the highest yield of homoallylic alcohol 2a
(entry 1). We attribute the requirement for excess phos-
phine ligand to its involvement in the reduction of the
Ni(II) precatalyst to the active Ni(0) species, which has
been observed previously for both Ni(II)15 and Pd(II)16
precatalysts. Alternatively, excess phosphine may be ne-
cessary to suppress the formation of catalytically inactive
Ni(Oi-Pr)2 species.17
In all cases examined, reductive coupling of epoxide 1a
proceeded to provide the desired tetrahydropyran product
(2a) asasingleregioisomerwithrespecttoboth the epoxide
and the alkyne. Stereospecific cis addition to the alkyne
occurred to provide the trisubstituted olefin (Z-2a);6 how-
ever, isomerization of the olefin geometry was observed to
a limited extent under the standard conditions for reduc-
tive coupling. The amount of undesired isomerization
product (E-2a) could be minimized by judicious choice of
catalyst identity and loading (entries 1, 2, and 5).
entry
X
R
product
yield (%)a
Z/Eb
1
2
3
4
5
6
CH2
Ph
Ph
Ph
2b
2c
2d
2e
2f
70
88:12
>95:5
88:12
>95:5
---
C(CO2Me)2
76
NBn
O
74
n-C5H11
CO2Me
H
75
O
<5c
55d
O
2g
---
a Isolated yield of the mixture of olefin isomers. b Determined by 1H
NMR spectroscopy of the crude reaction mixture. c Determined by 1H
NMR spectroscopy relative to mesitylene as an internal standard.
d Dropwise addition of substrate via syringe pump.
The proposed mechanism for Ni-catalyzed reductive
coupling of epoxides and alkynes involves initial oxidative
addition of the epoxide CÀO bond to form nickella(II)-
oxetane 5 (Scheme 2).6 Previous reports have demon-
strated that oxidative addition of epoxides with group 10
metals occurs with either inversion (Pd and Pt)20,21 or
scrambling (Ni)22 of configuration, corresponding to SN2
The mild conditions for Ni-catalyzed reductive coupling
were found to effect product formation for substrates
containing variation within the epoxideÀalkyne tether.
Both substituted cyclohexane (Table 2, entries 1 and 2)
and piperidine (entry 3) derivatives could be prepared in
this manner.12
Varying the substituent on the alkyne had a more
significant impact on the efficiency of reductive coupling.
Alkyl-substitution was tolerated and provided the desired
homoallylic alcohol (2e) in yields comparable to those
observed for phenyl-substituted alkynes (Table 2, entries
1À4). Conversely, subjecting alkynoate 1f to the standard
(19) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901–2916.
(20) (a) Aye, K.-T.; Gelmini, L.; Payne, N. C.; Vittal, J. J.; Puddephatt,
€
R. J. J. Am. Chem. Soc. 1990, 112, 2464–2465. (b) Backvall, J.-E.;
€
Bokman, F.; Blomberg, M. R. A. J. Am. Chem. Soc. 1992, 114, 534–
538. (c) Kulasegaram, S.; Kulawiec, R. J. Tetrahedron 1998, 54, 1361–
1374.
(21) Oxidative addition of epoxides with [Lewis acid][Co(CO4)]
complexes has also been observed to occur with inversion of configura-
tion: Church, T. L.; Getzler, Y. D. Y. L.; Coates, G. W. J. Am. Chem.
Soc. 2006, 128, 10125–10133.
€
(22) Backvall, J.-E.; Karlsson, O.; Ljunggren, S. O. Tetrahedron Lett.
1980, 21, 4985–4988.
(23) Oxidative addition of tosyl-aziridines with Ni(0) has been ob-
served to occur with inversion of configuration: Lin, B. L.; Clough,
C. R.; Hillhouse, G. L. J. Am. Chem. Soc. 2002, 124, 2890–2891.
(24) The relative stereochemistry of monodeuterated tetrahydropyr-
an 4 was confirmed by synthesis of the tert-butyldiphenyl silyl ether
(TBDPS-4) and comparison to the protio-congener (TBDPS-2a). See
Supporting Information for complete experimental details and stereo-
chemical analysis.
(25) The mechanism of migratory insertion is generally accepted to
occur with retention of configuration at the metal-bonded carbon. For
the seminal study, see: Bock, P. L.; Boschetto, D. J.; Rasmussen, J. R.;
Demers, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 2814–2825.
For further discussion of migratory insertion as it pertains to the
stereochemical outcome of transition-metal-mediated processes, see:
(a) Lau, K. S. Y.; Wong, P. K.; Stille, J. K. J. Am. Chem. Soc. 1976,
98, 5832–5840. (b) Spencer, J.; Pfeffer, M. Tetrahedron: Asymmetry
1995, 6, 419–426. (c) Malinakova, H. C. Chem.ÀEur. J. 2004, 10, 2636–
2646. (d) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 4701–4715.
(15) Ananikov, V. P.; Gayduk, K. A.; Starikova, Z. A.; Beletskaya,
I. P. Organometallics 2010, 29, 5098–5102.
(16) (a) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics
1992, 11, 3009–3013. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett.
1992, 2177–2180. (c) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald,
S. L. Org. Lett. 2008, 10, 3505–3508.
(17) (a) Sacco, A.; Mastrorilli, P. J. Chem. Soc., Dalton Trans. 1994,
2761–2764. (b) Hubert-Pfalzgraf, L. G.; Kessler, V. G.; Vaissermann, J.
Polyhedron 1997, 16, 4197–4203.
(18) Phosphine-catalyzed conjugate addition of i-PrOH to the al-
kynoate was observed, which has been reported previously: (a) Inanaga,
J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241–244. (b) Methot, J. L.;
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4142
Org. Lett., Vol. 13, No. 15, 2011

ring opening or homolytic CÀO bond cleavage, respec-
tively. To the best of our knowledge, there is no experi-
mental evidence describing oxidative addition of an epoxide
CÀO bond with Ni(0) that occurs with inversion of
configuration.23
Scheme 2. Deuterium-Labeling Experiment and Proposed Me-
chanism for Ni-Catalyzed Reductive Coupling
To gain insight into the oxidative-addition process, we
prepared monodeuterated epoxide 3 and observed the
relative configuration of the deuterated carbon center after
subjection to the standard conditions for Ni-catalyzed re-
ductive coupling (Scheme 2). Monodeuterated epoxide 3
was prepared with 83% deuterium incorporation at the
terminal epoxide site bearing a cis relationship to the
alkyne tether.12 Subjecting epoxide 3 to the standard
conditions for reductive coupling provided homoallylic
alcohol 4 with complete inversion of configuration at the
deuterated carbon center.24 This result is consistent with
inversion of configuration in the oxidative addition step
to afford the nickella(II)oxetane intermediate (5), followed
by migratory insertion that occurs with retention of
configuration.25 We propose that inversion of configura-
tion in the oxidative addition step occurs via SN2 attack by
the nucleophilic Ni(0) species facilitated by hydrogen-
bond activation of the epoxide.10 Importantly, identical
results were obtained when epoxide 3 was subjected to
the previously described conditions for reductive coupl-
ing (Scheme 1, PhMe2P instead of Bu3P) indicating that
the active Ni(0) catalyst is responsible for the inversion
process.
Following CÀC bond formation, i-PrOH serves as a mild
reducing agent to complete the catalytic cycle. Protonolysis
of the NiÀO bond of strained bicyclic oxanickellacycle 6
results in formation of the LnNi(Oi-Pr) species (7) necessary
for catalytic turnover. Subsequent β-H elimination occurs
to liberate acetone, which is inert under the reaction condi-
tions, followed by reductive elimination to afford homo-
allylic alcohol 4 and regenerate the active Ni(0) catalyst.
In summary, we have developed novel conditions for the
Ni-catalyzed reductive coupling of alkynes and epoxides
that employ air-stable and inexpensive reagents. These
reaction conditions are significantly milder and more
convenient than those previously used for similar reductive
coupling reactions in which a combination of Ni(cod)2 and
Et3B was necessary to effect CÀC bond formation.
Further investigation of the electrophile/π-nucleophile
scope is warranted in an effort to improve the efficiency
of previously developed methods and for the invention of
novel reductive coupling procedures.
Acknowledgment. This research was supported by the
National Institutes of Health (NIH), National Institute of
General Medical Sciences (GM72566 and GM63755). M.
G.B. is grateful to the NIH for a postdoctoral fellowship
(F32GM095014). We thank Dr. Christopher J. Morten
(MIT) for helpful discussions. We thank Dr. Jeff Simpson
(MIT) for assistance with NMR spectroscopy and Li Li
(MIT) for obtaining mass spectrometric data.
Supporting Information Available. Complete experi-
mental procedures and characterization data of novel
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
4143