A new stereoselective method for the preparation of allylic alcohols

Full text of DOI:10.1021/ja9719182

J. Am. Chem. Soc. 1997, 119, 9065-9066
Table 1. Ynal Alkylative Cyclizations
9065
A New Stereoselective Method for the Preparation
of Allylic Alcohols
Eric Oblinger and John Montgomery*
Department of Chemistry, Wayne State UniVersity
Detroit, Michigan 48202-3489
ReceiVed June 11, 1997
Allylic alcohols are useful building blocks in many synthetic
applications including Claisen rearrangements and related
sigmatropic processes,1 enantio-2 and diastereoselective3 hy-
droxyl-directed additions to alkenes, SN2′ displacements with
cuprates,4 palladium-catalyzed π-allyl chemistry,5 and cationic
cyclizations.6 Allylic alcohols with a tri- or tetrasubstituted
alkene component are efficient substrates in many of these
applications, and the stereochemical integrity of the alkene is
critical to issues involving the creation of stereogenic centers.
Prior synthesis of a stereochemically-defined alkenyl iodide
followed by metalation/addition or Nozaki/Kishi coupling7 with
an aldehyde are the most commonly employed strategies for
the stereoselective preparation of allylic alcohols. However,
few general methods exist that allow creation of a tri- or tetra-
substituted alkene and incorporation of an aldehyde in a single
operation. In order to address this synthetic challenge, we have
initiated the development of a general protocol for the nickel-
catalyzed cyclization/alkylation of ynals with organozincs to
produce cyclic allylic alcohols and the three-component coupling
of alkynes, aldehydes, and organozincs to produce acyclic allylic
alcohols with complete control of alkene stereochemistry.
Many powerful methods for reductive and alkylative cycliza-
tions of dienes, enynes, and diynes employing transition metal
catalysis have been developed.8 The corresponding transforma-
tions employing enals and ynals to produce alcohol derivatives
are also potentially useful. Early transition metal catalysis has
proven to be most efficient in cyclizations involving a carbonyl
component through the involvement of oxametallacycles, al-
though the strength of the metal-oxygen bond renders catalytic
sequences difficult.9 Recent developments by Buchwald10 and
Crowe11 demonstrated that σ-bond metathesis of early transition
metal oxametallacycles with silyl hydrides provides an efficient
mechanism for catalytic turnover in this important class of
reactions.12 Based on our earlier developments in cyclizations
of alkynyl enones,13 we envisioned that nickel-catalyzed cou-
plings of ynals with organozincs could provide an efficient and
general entry to allylic alcohols with tri- and tetrasubstituted
1
a Products were obtained as single stereoisomers by 500 MHz H
NMR analysis. b Isolated as the benzoate ester (two-step yield is
reported).
alkenes. These studies provide, to our knowledge, the first
examples of transition metal catalyzed alkylative cyclizations
of ynals and related three-component couplings.
Derivatives of 5-hexynal were first examined in alkylative
cyclizations. Upon treatment of 5-hexynal and organozincs with
catalytic Ni(COD)2 (5 mol %) at 0 °C in THF, efficient
cyclization with stereoselective introduction of the exocyclic
trisubstituted alkene was observed (Table 1). The organozincs
were generated in situ from organolithiums or organomagne-
siums and anhydrous zinc chloride. Both sp2- and sp3-
hybridized organozincs, including those that possess â-hydro-
gens, were efficiently incorporated without competing â-hydride
elimination. Pyrrolidines could also be efficiently prepared by
incorporating nitrogen in the tether chain. As expected, the
organozinc substituent was always introduced exclusively cis
to the alcohol functionality. Direct addition of the organozinc
to the aldehyde was not observed. Functionalization of the ter-
minal alkyne (by acetylide alkylation or Sonogashira coupling14)
followed by nickel-catalyzed alkylative cyclization led to the
stereoselective introduction of tetrasubstituted exocyclic alkenes,
again with complete and predictable stereocontrol (Table 1).
Both isomers of the tetrasubstituted allylic alcohols were con-
veniently prepared by simply switching the order of substituent
introduction. Direct addition of the organozinc to the aldehyde
was initially problematic with internal alkynes; however, since
the 1,2-addition likely does not involve nickel catalysis, this
side reaction could be essentially completely suppressed by
employing higher catalyst loadings (20 mol % Ni(COD)2).
Although competing â-hydride elimination was not observed
in Ni(COD)2-catalyzed cyclizations employing diethylzinc and
dibutylzinc, a complete crossover to reductive cyclization with
hydrogen atom introduction was observed simply by pretreating
the Ni(COD)2 with PBu3 (Table 2).15 Reductive cyclizations
were efficient with both terminal and internal alkynes, with the
latter allowing completely selective introduction of trisubstituted
alkenes of the opposite configuration as those obtained from
alkylative cyclizations of terminal alkynes.16
(1) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, p 827.
(2) (a) Johnson, R. A.; Sharpless, K. B. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 7, p 389.
(b) Charette, A. B.; Marcoux, J. F. Synlett 1995, 1197. (c) Denmark, S. E.;
O’Connor, S. P. J. Org. Chem. 1997, 62, 584.
(3) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(4) Lipshutz, B. H.; Sengupta, S. In Organic Reactions; Wiley: New
York, 1992; Vol. 41, p 135.
(5) Godleski, S. A. In ComprehensiVe Organic Synthesis; Trost, B. M.,
The above procedures were also extrapolated to three-
component couplings of alkynes, aldehydes, and organozincs
Ed.; Pergamon Press: Oxford, 1991; Vol. 4, p 585.
(6) Overman, L. E. Acc. Chem. Res. 1992, 25, 352.
(7) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.;
Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
(8) (a) For a general review: Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. ReV. 1996, 96, 635. (b) For a palladium-catalyzed
procedure: Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem.
Soc. 1992, 114, 1923. (c) For a zirconium-catalyzed procedure: Knight,
K. S.; Wang, D.; Waymouth, R. M. Ziller, J. J. Am. Chem. Soc. 1994, 116,
1845.
(9) (a) Hewlett, D. F.; Whitby, R. J. J. Chem. Soc., Chem. Commun.
1990, 1684. (b) For a mid transition metal promoted cyclization, see: Bryan,
J. C.; Arterburn, J. B.; Cook, G. K.; Mayer, J. M. Organometallics 1992,
11, 3965.
(12) Related late transition metal cyclizations were reported by Mori,
although a mechanism not involving oxametallacycles was proposed: (a)
Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M.
J. Am. Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto, M.; Mori, M.
Tetrahedron Lett. 1996, 37, 887.
(13) (a) Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996,
118, 2099. (b) Montgomery, J.; Seo, J.; Chui, H. M. P. Tetrahedron Lett.
1996, 37, 6839. (c) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J.
Am. Chem. Soc. 1997, 119, 4911. (d) Montgomery, J.; Chevliakov, M. V.;
Brielmann, H. L. Tetrahedron 1997, in press.
(14) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(10) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182, and references therein.
(11) Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787.
(15) Tributylphosphine was found to be far more effective in promoting
reductive cyclization than was triphenylphosphine, which was extensively
used in our earlier studies with alkynylenones (ref 13).
S0002-7863(97)01918-5 CCC: $14.00 © 1997 American Chemical Society

9066 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Communications to the Editor
Scheme 1. Proposed Mechanism for Ynal Cyclizations and
Three-Component Couplings
both the alkyne and aldehyde components, although yields were
significantly lower with enolizable aldehydes. sp3-Hybridized
organozincs were tolerated, but diisopropenylzinc underwent
direct addition to the aldehyde without alkyne incorporation.
In contrast to the efficient reductive cyclizations of ynals in
the presence of PBu3, hydrogen atom incorporation was not
observed in intermolecular three-component couplings in the
presence of phosphines. The allylic alcohols that would be
obtained by intermolecular reductive couplings involving â-hy-
dride elimination are easily obtained by the Wipf procedure
involving alkene transfer from hydrozirconation-derived orga-
nometallics.20 The Wipf procedure, however, is not amenable
to intramolecular reductive cyclizations (as in Table 2) since
aldehyde hydrozirconation proceeds faster than hydrozirconation
of alkynes.21 Thus the Wipf procedure and the methods reported
herein are completely complementary.
We speculate that oxametallacycles are involved in the
transformations described above and that both reductive and
alkylative cyclization products are derived from a common
intermediate (Scheme 1).22 Oxidative cyclization of Ni(0) with
an alkyne and an aldehyde would directly afford oxametallacycle
1.23,24 Transmetalation of the organozinc would produce vinyl
nickel species 2. Reductive elimination of 2 would afford
alkylative cyclization products, whereas â-hydride elimination
prior to reductive elimination in the presence of tributylphos-
phine would afford reductive cyclization products.25
Table 2. Ynal Reductive Cyclizations
In summary, an efficient, general, and stereoselective syn-
thesis of cyclic and acyclic allylic alcohols that possess tri- and
tetrasubstituted alkenes has been developed. Significantly, both
E and Z isomers of the alkenes may be obtained in a completely
stereoselective fashion from a common intermediate. The above
procedures are direct and experimentally simple and are carried
out at 0 °C with thermally-stable and readily-accessible reagents.
Further methodological refinements, catalytic asymmetric vari-
ants, and mechanistic studies are under investigation.
1
a Products were obtained as single stereoisomers by 500 MHz H
NMR analysis. b Isolated as the benzoate ester (two-step yield is
reported). c Isolated as a mixture with 9% of the ethyl-substituted
alkylative cyclization product.
Table 3. Three-Component Couplings
Acknowledgment. J.M. acknowledges receipt of a National Science
Foundation CAREER Award (1996-2000) and a New Faculty Award
from 3M Pharmaceuticals. Acknowledgment is made to the Donors of
The Petroleum Research Fund, administered by the American Chemical
Society, for partial support of this research.
Supporting Information Available: Experimental procedures for
all reported compounds and copies of 1H NMR spectra of all new
compounds (25 pages). See any current masthead page for ordering
and Internet access instructions.
a Products were obtained as single regio- and stereoisomers by 500
1
MHz H NMR analysis. b Isolated as the acetate ester (two-step yield
JA9719182
is reported). c The alcohol derived from isopropenyl addition to
benzaldehyde was isolated in 90% yield.
(19) See Supporting Information for further details.
(20) (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197. (b) Wipf,
P.; Xu, W. Org. Synth. 1996, 74, 205.
(21) For a discussion of competing reactivity of alkynes and aldehydes
with Schwartz’s reagent, see: Lipshutz, B. H.; Lindsley, C.; Bhandari, A.
Tetrahedron Lett. 1994, 35, 4669.
(22) A closely related mechanism was proposed by Buchwald and Crowe
in titanium-mediated reductive cyclizations, refs 10 and 11.
(23) We are unaware of any fully characterized oxametallacycles of nickel
that are exactly analogous to those proposed as intermediates in Scheme 1.
However, related nickelacycles prepared from Ni(0), CO2, and alkenes or
alkynes are known. (a) Walther, D.; Dinjus, E.; Sieler, J.; Andersen, L.;
Lindqvist, O. J. Organomet. Chem. 1984, 276, 99. (b) Walther, D.;
Bra¨unlich, G.; Kempe, R.; Sieler, J. J. Organomet. Chem. 1992, 436, 109.
(c) Hoberg, H.; Peres, Y.; Kru¨ger, C.; Tsay, Y. Angew. Chem., Int. Ed.
Engl. 1987, 26, 771.
(Table 3).17,18 Highly chemo-, regio-, and stereoselective addi-
tion directly afforded the desired allylic alcohols. Yields were
typically highest when the alkyne was introduced as the limiting
reagent.19 Aromatic and aliphatic substitution was tolerated in
(16) To our knowledge, only one other method allows cyclization and
selective formation of either isomer of an exocyclic alkylidene from a
common precursor: (a) Martinez-Grau, A.; Curran, D. P. J. Org. Chem.
1995, 60, 8332. (b) Martinez-Grau, A.; Curran, D. P. Tetrahedron 1997,
53, 5679. Also, see: (c) Molander, G. A.; Harris, C. R. Chem. ReV. 1996,
96, 307. (d) Cossy, J.; Pete, J. P.; Portella, C. Tetrahedron Lett. 1989, 30,
7361.
(17) For related three-component couplings of enones, alkynes, and
organozincs, see: (a) Reference 13b. (b) Ikeda, S.; Sato, Y. J. Am. Chem.
Soc. 1994, 116, 5975. (c) Ikeda, S.; Yamamoto, H.; Kondo, K.; Sato, Y.
Organometallics 1995, 14, 5015. (c) Ikeda, S.; Kondo, K.; Sato, Y. J. Org.
Chem. 1996, 61, 8248.
(18) Alkyne carbometalation followed by aldehyde addition accomplishes
the same transformation as the three-component couplings reported herein,
although chemoselectivity issues generally preclude intramolecular variants
(as in Table 1). (a) Okukado, N.; Negishi, E. Tetrahedron Lett. 1978, 2357.
(b) Normant, J. F.; Alexakis, A. Synthesis 1981, 841.
(24) For allylic alcohol syntheses based on the stoichiometric generation
of early transition metal oxametallacycles: (a) Kataoka, Y.; Miyai, J.;
Oshima, K.; Takai, K.; Utimoto, K. J. Org. Chem. 1992, 57, 1973. (b)
Takayanagi, Y.; Yamashita, K.; Yoshida, Y.; Sato, F. Chem. Commun. 1996,
1725. (c) Takagi, K.; Rousset, C. J.; Negishi, E. J. Am. Chem. Soc. 1991,
113, 1440. (d) Van Wagenen, B. C.; Livinghouse, T. Tetrahedron Lett.
1989, 30, 3495.
(25) A sequence involving alkyne hydro- or carbometalation followed
by addition to the aldehyde cannot be rigorously excluded. Stu¨demann, T.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 93.