Nickel-catalyzed reductive coupling of alkynes and epoxides

Article abstract of DOI:10.1021/ja0361401

Nickel-catalyzed, intramolecular and intermolecular reductive coupling of alkynes and epoxides affords synthetically useful homoallylic alcohols of defined alkene geometry. Very high regioselectivity is generally observed, and cyclizations proceed with complete selectivity for endo epoxide opening. This catalytic reaction represents the first use of a non-π-based electrophile in a growing class of nickel-catalyzed, multicomponent coupling reactions, and is the first catalytic method of reductive coupling of alkynes and epoxides that is effective for both intermolecular and intramolecular cases, and mechanistically distinct from these, possibly involving a nickella(II)oxetane. Copyright

Full text of DOI:10.1021/ja0361401

Published on Web 06/17/2003
Nickel-Catalyzed Reductive Coupling of Alkynes and Epoxides
Carmela Molinaro and Timothy F. Jamison*
Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139
Received May 14, 2003; E-mail: tfj@mit.edu
Table 1. Intermolecular Reductive Coupling of Alkynes and
The development of catalytic reactions that effect carbon-carbon
Epoxidesa
bond formation by uniting readily available functional groups is a
major research area. We and others have recently reported several
examples of such methods that are catalyzed by nickel(0)-ligand
complexes,1 and all of these involve the union of two π-electron
systems (e.g., alkyne-aldehyde,2 alkyne-imine,3 1,3-diene-alde-
hyde,4 alkyne-R,â-unsaturated carbonyl,1a,e and allene-aldehyde5).6
Herein, we describe the first member of this family that deviates
from this requirement, wherein the π-system of one molecule
(alkyne) combines with a functional group that has no multiple
bonds (epoxide), affording synthetically useful, chiral homoallylic
alcohols (eqs 1 and 2). Other metal salts catalyze an intramolecular
form of this reaction by way of a single-electron-transfer mecha-
nism,7 but catalytic intermolecular alkyne-epoxide reductive
coupling is without precedent. To our knowledge, there are no
examples of nickel-catalyzed carbon-carbon bond-forming reac-
tions of epoxides.8
In our initial investigations, we discovered that this process is
quite sensitive to the nature of the phosphine and that the use of
Bu3P and Et3B as reducing agent is the optimum combination for
intermolecular reductive coupling (Table 1).9 Only (n-Oct)3P (entry
3) is of comparable efficacy, whereas Et3P (or any of 15 other
phosphines evaluated) provides less than 5% yield of the desired
homoallylic alcohol (entry 1). While there is little dependence of
yield upon solvent choice (entries 2, 4, 5), maximum yield is
obtained without an added solvent (entries 6-9). Stereospecific cis
addition10 to the alkyne is observed in every case, and most notable
is the complete (>95:5) regioselectivity with respect to both the
alkyne and the epoxide in all cases except for styrene oxide (entry
9).11,12
regioselectivity
yield
product (%)
1
2
3
entry
R
R
R
additive
Et3P
Bu3P
(n-Oct)3P
Bu3P
alkyne
epoxide
1b Ph
2b Ph
3b Ph
4c Ph
5d Ph
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
1a
1a
1a
1a
1a
1a
1b
1c
1d
0
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
83:17
36 >95:5
35 >95:5
25 >95:5
34 >95:5
71 >95:5
68 >95:5
Bu3P
Bu3P
6
7
8
9
Ph
Ph
Ph
Me n-Hex Bu3P
Me Ph
Bu3P
Bu3P
50e
35e
88:12
na
n-Pr n-Pr Et
>95:5
a See eq 1, ref 9, and Supporting Information. b Ether used as solvent.
c Toluene used as solvent. d Ethyl acetate used as solvent. e Overall yield
after conversion to TBDPS ether.
Table 2. Catalytic, Reductive Alkyne-Epoxide Cyclizationsa
yield
(%)
regioselectivity
(endo:exo)
entry
X
n
product
1b
2
3
4
5
CH2
O
NBn
C(CO2Me)2
CH2
1
1
1
1
0
3a
3b
3c
3d
3e
45
50
65
88c
54
>95:5
>95:5
>95:5
>95:5
>95:5
Intramolecular cases display an especially noteworthy sense and
degree of regioselectivity (eq 2, Table 2). The exo mode of epoxide
ring-opening is typically favored in the absence of a significant
electronic bias,13 and the existing catalytic alkyne-epoxide reduc-
tive cyclizations follow this trend.7 However, we observe complete
(>95:5) endo opening in every case we have examined, regardless
of the nature of the linking group or ring size.10 The tolerance of
heteroatoms allows for rapid transformation of glycidol into
important tetrahydropyranyl and piperidinyl heterocycles possessing
a stereogenic center and an exocyclic, trisubstituted olefin of defined
geometry (entries 2 and 3).
a See eq 2 and Supporting Information. b Toluene used as solvent.
c Isolated as a 3:1 mixture of homoallylic alcohol and lactone (loss of
MeOH).
Scheme 1. Reductive Cyclization via a Proposed
Nickella(II)oxetane
The very high “endo” epoxide-opening regioselectivity in these
cyclizations suggests a mechanistic framework very different from
those we and others have proposed for Ni-catalyzed alkyne/π-
electrophile couplings.1-6 As shown in Scheme 1, a possible
explanation involves the intermediacy of A, a metallaoxetane
(oxametallacyclobutane) corresponding to a regioselective oxidative
addition of a phosphine-nickel(0) complex into the less hindered
C-O bond of the epoxide,8c,d,14,15 followed by exo-dig cyclization
onto the alkyne. Installation of the vinylic hydrogen atom could
arise from transfer of Et to Ni from Et3B, â-H elimination, and
finally reductive elimination. This mechanism requires formation
of cyclopentyl product 3e to occur by way of a 3-nickella-4-
oxabicyclo[3.2.1]oct-1-ene that would be classified as an “anti-
Bredt” alkene if Ni were replaced with CR2. However, the longer
9
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J. AM. CHEM. SOC. 2003, 125, 8076-8077
10.1021/ja0361401 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Chem. Res. 2000, 33, 511-519. (d) Houpis, I. N.; Lee, J. Tetrahedron
2000, 56, 817-846. (e) Montgomery, J.; Amarasinghe, K. K. D.;
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Chem. 2002, 74, 129-133.
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9066. (b) Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221-
4223. (c) Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156-166.
(d) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003,
125, 3442-3443. (e) Takai, K.; Sakamoto, S.; Isshiki, T. Org. Lett. 2003,
5, 653-655.
(3) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364-1367.
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1998, 120, 4033-4034. (b) Sato, Y.; Saito, N.; Mori, M. J. Org. Chem.
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Tamaru, Y. Angew. Chem., Int. Ed. 2002, 41, 2784-2786.
Ni-C and Ni-O bonds might be expected to accommodate the
bridgehead olefin.16
(5) (a) Montgomery, J.; Song, M. Org. Lett. 2002, 4, 4009-4011. (b) Kang,
S.-K.; Yoon, S.-K. Chem. Commun. 2002, 2634-2635.
Further support for A and the mechanistic proposal in Scheme
1 is the isolation of products of epoxide isomerization such as
acetophenone and 2-octanone (Table 1, entries 7 and 8, respec-
tively), which can be attributed to collapse of the metallaoxetane
to a nickel(II) enolate14c,16 and subsequent reductive elimination.
The experiment shown in Scheme 2 confirms that optical purity
is preserved in the Ni-catalyzed alkyne-epoxide reductive coupling
and is a further demonstration of the utility of this method. Using
only commercially available reagents and catalysts, this procedure
is an alternative to enantioselective addition of allylmetal reagents
to aldehydes17 and, after further elaboration, affords in >99% ee18
a â-silyloxyketone (4) that corresponds to an asymmetric acetone-
acetaldehyde aldol addition reaction.
The catalytic reaction described here represents the first use of
a non-π-based electrophile in a growing class of nickel-catalyzed,
multicomponent coupling reactions. It is also the first catalytic
method of reductive coupling of alkynes and epoxides that is
effective for both intermolecular and intramolecular cases and may
also be mechanistically unique among these (nickella(II)oxetane).
Another feature that is unprecedented in existing methods is the
complete selectivity for the usually disfavored endo epoxide-
opening product in alkyne-epoxide reductive cyclizations. Finally,
the utility and ease of implementation of this method are direct
results of the availability of terminal epoxides in >99% ee.19 We
continue to investigate the mechanistic details and potential
applications of this method to the synthesis of carbocyclic and
heterocyclic natural products.
(6) Other Ni-catalyzed π-π reactions: (a) Lozanov, M.; Montgomery, J. J.
Am. Chem. Soc. 2002, 124, 2106-2107. (b) Takimoto, M.; Mori, M. J.
Am. Chem. Soc. 2002, 124, 10008-10009.
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M. F. J. Am. Chem. Soc. 1967, 89, 2755-2757. (b) Hegedus, L. S.;
Wagner, S. D.; Waterman, E. L.; Siirala-Hansen, K. J. Org. Chem. 1975,
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carbonates via C-O bond formation): Tascedda, P.; Dunach, E. J. Chem.
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of epoxides: Yang, Z.-Y. J. Am. Chem. Soc. 1996, 118, 8140-8141.
(9) Standard procedure: To a mixture of Ni(cod)2 (0.50 mmol), Bu3P (1.00
mmol), Et3B (2.00 mmol), the epoxide (10.0 mmol), and the alkyne (5.00
mmol) at room temperature was added additional Et3B (8.00 mmol) via
syringe pump over 4 h, and the resulting solution was stirred 24 h.
Treatment with NaOH/H2O2 and purification (SiO2) afforded the homo-
allylic alcohol.
(10) Alkene geometry confirmed by NOE experiments. See Supporting
Information.
(11) Terminal alkynes afforded 15-20% yields of homoallylic alcohols due
to competing alkyne cyclotrimerization, and disubstituted epoxides did
not undergo reductive coupling under these conditions.
(12) The selectivity trends in ring-opening reactions of aryloxiranes often differ
from those of alkyloxiranes: (a) Winstein, S.; Henderson, R. B. Ethylene
and Trimethylene Oxides. In Heterocyclic Compounds; Elderfield, R. C.,
Ed.; Wiley: New York, 1950; Vol. 1. (b) Parker, R. E.; Isaacs, N. S.
Chem. ReV. 1959, 59, 737-799. (c) Wohl, R. A. Chimia 1974, 28, 1-5.
(13) Coxon, J. M.; Hartshorn, M. P.; Swallow, W. H. Aust. J. Chem. 1973,
26, 2521-2526.
(14) Nickella(II)oxetanes have not been isolated in pure form but have been
proposed as intermediates in catalytic reactions: (a) De Pasquale, R. J. J.
Chem. Soc., Chem. Commun. 1973, 157-158. (b) Ba¨ckvall, J.-E.;
Karlsson, O.; Ljunggren, S. O. Tetrahedron Lett. 1980, 21, 4985-4988.
(c) Miyashita, A.; Shimada, T.; Sugawara, A.; Nohira, H. Chem. Lett.
1986, 1323-1326. Computational studies: (d) Ba¨ckvall, J.-E.; Bo¨kman,
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Mavrikakis, M.; Doren, D. J.; Barteau, M. A. J. Phys. Chem. B 1998,
102, 394-399. (f) Medlin, J. W.; Mavrikakis, M.; Barteau, M. A. J. Phys.
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E.; Hauge, R. H.; Margrave, J. L.; Zakya. H. High Temp. Sci. 1990, 30,
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(15) X-ray structures of related complexes: Pd(II)- and Pt(II)-metallaoxet-
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Chem. Soc. 1974, 96, 6893-6900. (b) Lenarda, M.; Ros, R.; Traverso,
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(II)azetidine: Lin, B. L.; Clough, C. R.; Hillhouse, G. L. J. Am. Chem.
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(16) (a) Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics
1990, 9, 30-44. (b) Ni(II)-O-enolate: Amarasinghe, K. K. D.; Chowdhury,
S. K.; Heeg, M. J.; Montgomery, J. Organometallics 2001, 20, 370-372.
(17) Roush, W. R. Allyl Organometallics. In ComprehensiVe Organic Synthesis;
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(19) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936-938. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
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Acknowledgment. Postdoctoral support was provided by the
Fonds Que´be´cois de la Recherche sur la Nature et les Technologies
(FQRNT, fellowship to C.M.) and Boehringer-Ingelheim (New
Investigator Award to T.F.J.). We also thank the National Institute
of General Medical Sciences (GM-063755), the NSF (CAREER
CHE-0134704), the donors of the Petroleum Research Fund,
Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Johnson &
Johnson, Merck Research Laboratories, Pfizer, 3M, and MIT for
financial support. The NSF (CHE-9809061 and DBI-9729592) and
NIH (1S10RR13886-01) provide partial support for the MIT
Department of Chemistry Instrumentation Facility.
Supporting Information Available: Experimental procedures and
data for 1a-d, 2a-e, 3a-e, and 4 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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Montgomery, J. Acc. Chem. Res. 2000, 33, 467-473. (c) Ikeda, S.-i. Acc.
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