Silylstannylation of highly functionalized acetylenes. Synthesis of precursors for annulations via radical or heck reactions

Article abstract of DOI:10.1021/ol048265w

(Chemical Equation Presented) Pd-catalyzed silylstannylation of acetylenes tolerates a variety of reactive functional groups (aldehydes, nonterminal acetylenes, epoxides, activated and unactivated olefins), providing easy access to precursors that can be

Full text of DOI:10.1021/ol048265w

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4053-4056
Silylstannylation of Highly
Functionalized Acetylenes. Synthesis of
Precursors for Annulations via Radical
or Heck Reactions
Sandeep Apte, Branko Radetich, Seunghoon Shin,† and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received August 30, 2004
ABSTRACT
Pd-catalyzed silylstannylation of acetylenes tolerates a variety of reactive functional groups (aldehydes, nonterminal acetylenes, epoxides,
activated and unactivated olefins), providing easy access to precursors that can be converted into carbocyclic and heterocyclic compounds
via free radical or Heck reactions. Examples of the synthesis of pyrrolidines, bicyclic â-lactams, hydrindanes, and tetrahydrofurans are described.
While trying to expand the scope of the trialkylsilyltrialkyl-
stannane-mediated cyclization of 1,6-diynes,1, 2 (Scheme 1,
Scheme 1. Selectivity in the Silylstannylation of Acetylenes
1 f 4), we have found that some individual steps of the
reaction are remarkably selective for monosubstituted acety-
lenes. As illustrated in Scheme 1, neither the putative initial
1,2-silylpalladation (e.g., 1 f 2) nor the subsequent carbo-
palladation (e.g., 2 f 3) takes place at the more substituted
acetylene (R ) TMS or Me). Such chemoselectivity results
in the formation of a (Z)-1,2-silylstannyl olefin 5 as the only
product when one of the acetylenes is nonterminal. The
reaction at the terminal acetylene proceeds with excellent
regio- and stereoselectivity, leading to the olefin with a
† Current address: Department of Chemistry, Hanyang University, Seoul
133-791, Korea.
(1) (a) Gre´au, S.; Radetich, B.; RajanBabu, T. V. J. Am. Chem. Soc.
2000, 122, 8579. (b) Warren, S.; Chow, A.; Fraenkel, G.; RajanBabu, T.
V. J. Am. Chem. Soc. 2003, 125, 15402.
(2) For other reports dealing with the silylstannylation of acetylenes,
see: (a) Chenard, B. L.; Laganis, E. D.; Davidson, F.; RajanBabu, T. V. J.
Org. Chem. 1985, 50, 3666. (b) Mitchell, T. N.; Wickenkamp, R.; Amamria,
A.; Diecke, R.; Schneider, U. J. Org. Chem. 1987, 52, 4868. (c) Chenard,
B. L.; Van Zyl, C. M. J. Org. Chem. 1986, 51, 3561. (d) Casson, S.;
Kocienski, P.; Reid, G.; Smith, N.; Street, J. M.; Webster, M. Synthesis
1994, 1301. (e) Hada, M.; Tanaka, Y.; Ito, M.; Murakami, M.; Amii, H.;
Ito, Y.; Nakatsuji, H. J. Am. Chem. Soc. 1994, 116, 8754. (f) Murai, S.;
Chatani, N. J. Synth. Org. Chem. Jpn. 1993, 51, 421. (g) Mori, M.; Isono,
N.; Wakamatsu, H. Synlett 1999, 269. (h) Neilsen, T. E.; Le Quement, S.;
Tanner, D. Synthesis 2004, 1381.
terminal SiR3 group and an internal SnR3 group. Instead of
a nonterminal acetylene, the second functional group can also
be an activated or unactivated olefin, a 1,3-diene, an
aldehyde, or even an epoxide. Because of the presence of
unsaturation on the appendage and the facility with which a
C-Sn bond can be replaced by a C-X bond (e.g., 6a, 6b),
10.1021/ol048265w CCC: $27.50
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alternate strategies for cyclization of these adducts can now
be envisioned. In this paper we report several examples of
such applications of the silylstannyl olefins for the synthesis
of highly functionalized carbocyclic and heterocyclic com-
pounds. These include (a) cyclizations of vinyl radicals, (b)
intramolecular Heck additions of vinyl iodides to acetylenes
and olefins, and (c) additions of â-alkoxyradicals (generated
from epoxides and Cp2TiCl) to vinylstannanes.
Table 1. Silylstannylation of Functionalized Acetylenesa
Examples of the exquisite selectivity in the silylstanny-
lation of substrates with terminal acetylenes are shown in
Table 1. Typically the reaction is run in a hydrocarbon
solvent such as benzene with a slight excess of the silyl-
stannane in the presence of 5 mol % of a Pd(0) source such
as (Ph3P)4Pd or Pd2(dba)3 and a phosphine.3 Depending on
the substrate, temperatures between 25 and 80 °C are
employed. Optimization of the reaction for a new substrate
is best accomplished by mixing the reagents and the catalyst
1
in a deuterated solvent and following the reaction by H
NMR. Conditions have been found where nonterminal
acetylenes (entries 1 and 2), activated or unactivated olefins4
(entries 3-8), 1,3-dienes (entry 7), epoxides (entry 9), and
aldehydes3 are also not affected. The proline-derived acety-
lenic alcohol derivative 13, which is a potential source of
bicyclic alkaloid intermediates, is readily converted into a
silylstannyl olefin (entry 5). The corresponding allyl alcohol
from which 13 was derived underwent the reaction, albeit
in a lower yield (21%). Several epoxyacetylenes,3 exempli-
fied by 19a,b (entry 9), gave the silylstannyl olefin in
surprisingly good yields.
The vinyl-stannane substrates are useful intermediates for
further synthesis. For example, the acetylenes 5a and 5b upon
treatment with iodine in CH2Cl2 give very high yields of
the vinyl iodides 6a and 6b with complete retention of
stereochemistry at the double bond (Scheme 1). Treatment
of the iodide 6b with Bu3SnH in refluxing benzene gives
the (Z,Z)-bis-alkylidenecyclopentane 21b in 48% yield (eq
1). An interesting application of this sequence for the
a See Scheme 1 and the text for a typical procedure. See Supporting
Information for other examples, including aldehyde and acetylenic ester
substrates, and specific experimental details. b Yield of two steps.
synthesis of a bicyclic â-lactam is shown in eq 2. Precursors
such as 8 are easily synthesized via Hart’s imine-ester enolate
cycloaddition5 followed by N-propargylation and silylstan-
nylation. Treatment of 8 with iodine in CH2Cl2 followed by
cyclization mediated by Bu3SnH at 90 °C in toluene give
the bicyclic â-lactam 23 in 61% yield.
4054
Org. Lett., Vol. 6, No. 22, 2004

Employing this strategy, readily available dimethyl 2-(3-
propynyl)malonate can be used as a cyclopentane-annulation
reagent. The two prototypical substrates shown in Table 1,
entry 8 were readily prepared from a mixture of (()-carveol
mesylate and sodium dimethyl 2-(3-propynyl)malonate using
a procedure similar to what has been reported by Trost.6 The
cis-adduct 17a undergoes the silylstannylation (to 18a)
followed by iodination to give the vinyl iodide 24, which
when subjected to radical cyclization gives a mixture of
alkylidenecyclopentanes, 25 (eq 3). Note that a highly
congested ring junction with a quaternary carbon is produced
in this key step in a very respectable 75% yield. Not
surprisingly, a mixture of Z- and E-vinylsilanes is obtained
in the reaction.7 The configuration of the ring junction has
been assigned as cis on the basis of ample precedents for
the formation of bicyclo[4.3.0]-nonane skeletons under
similar situations.8
The trans-malonate adduct 17b, upon silylstannylation
followed by iodination, give a surprisingly high 86% yield
(two steps) of the vinyl iodide 26. Under Heck reaction
conditions 26 gives 82% of a vinylsilane 27 with the
formation of an endocyclic olefin. Unlike the radical reaction,
the configuration of the vinylsilane (Z) is maintained in the
Heck reaction. However, upon treatment with catalytic
amounts of p-toluenesulfonic acid, the Z-vinylsilane 27
rearranges to a more stable E-vinylsilane 28 in nearly
quantitative yield. A similar strategy can also be used for
propargyl bromide and trans-cinnamyl alcohol in three steps
and was subjected to intramolecular Heck reactions to give
the product as a mixture of two isomers in a ratio of 9:1,
with the (Z,E)-product predominating.3,9
Titanium(III)-mediated epoxide opening as a method of
generation of functionalized radicals has become a powerful
tool for the synthesis of carbon-carbon bonds, homolytic
reductions, and deoxygenations.10 The vinylstannane adducts
derived from the epoxy acetylenes (e.g., 20a,b) undergo
facile cyclization upon treatment with Cp2TiCl in THF (eq
5).11 The product was isolated as a mixture of E and Z-olefins
(31a 1.0:0.2; 31b 1.0:0.6).12
In summary, in this communication we demonstrate the
remarkable functional group compatibility of the silylstan-
nylation of acetylenes that permits the preparation of
polyfunctional molecules that are difficult if not impossible
to synthesize by conventional methods. Applications for the
synthesis of highly functionalized carbocyclic and hetero-
cyclic compounds through free radical or Heck cyclization
protocols illustrate the myriad possibilities of using these
building blocks for further synthesis.
Scheme 2. Cyclopentane Annulation via Heck Reaction
(6) Trost, B. M.; Lautens, M.; Chan, C.; Jebaratnam, D. J.; Mueller, T.
J. Am. Chem. Soc. 1991, 113, 636.
(7) The inversion barrier for a vinyl radical is very low (∼2 kcal). For
a leading references to a discussion of stereochemistry of vinyl radicals,
see: (a) Bentrude, W. G. Annu. ReV. Phys. Chem. 1967, 18, 283. (b) Jenkins,
P. R.; Symons, M. C. R.; Booth, S. E.; Swain, C. J. Tetrahedron Lett. 1992,
33, 3543. For early examples of vinyl radicals in organic synthesis, see:
(c) Stork, G.; Mook, J. R. J. Am. Chem. Soc. 1983, 105, 3720. (d) Choi,
J.-K.; Hart, D. J. Tetrahedron 1985, 41, 3959 and references therein.
(8) Stork, G.; Reynolds, M. E. J. Am. Chem. Soc. 1988, 110, 6911 and
earlier papers in this series.
the synthesis of bis-alkylidenetetrahydrofurans as shown in
eq 4. The vinyl iodide 29 was prepared starting from
(9) A dienyl-propargyl ether derived from sorbyl alcohol and propargyl
bromide also undergoes silylstannylation followed by iodination in overall
60% yield (entry 7, Table 1). See footnote 3.
(3) See Supporting Information for specific details of experimental
conditions. A more complete table with other examples, including acetylenic
aldehydes and propiolate esters, can also be found there.
(10) (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116,
986. (b) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem.
Soc. 1990, 112, 6408. (c) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem.
Soc. 1989, 111, 4525. (d) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem.
Soc. 1988, 110, 8561. For a catalytic version of the reaction see: Gansa¨uer,
A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120, 12849.
(11) For related C-C bond-forming reactions involving homolytic
substitution via addition-fragmentation, see: (a) Baldwin, J. E.; Kelly, D.
R.; Ziegler, C. B. J. Chem. Soc., Chem. Commun. 1984, 133. (b) Keck, G.
E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron 1985, 41, 4079.
(c) Lowinger, T. B.; Weiler, L. Can. J. Chem. 1990, 68, 1636.
(12) Note that the E and Z-isomers of 31a and 31b have different
vinylsilane configurations because the priorities of groups around the double
bond change with the nature of X.
(4) Some eneynes with terminal olefins do undergo competitive silyl-
stannylative cyclization depending on the catalyst and reaction conditions.
For example, see: Mori, M.; Hirose, T.; Wakamatsu, H.; Imakuni, N.; Sato,
Y. Organometallics 2001, 20, 1907. See also: Lautens, M.; Mancuso, J.
Synlett 2002, 394. We found that 4,4′-dicarboethoxy-6-ene-1-yne under
catalysis of Pd2(dba)3/(C6F5)3P leads to predominant silylstannylation-
cyclization, whereas with (Ph3P)4Pd simple addition to the terminal is
observed. Radetich, B. Ph.D. Thesis, The Ohio State University, 1999. See
Supporting Information.
(5) Ha, D.-C.; Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc. 1984, 106,
4819 and references therein.
Org. Lett., Vol. 6, No. 22, 2004
4055

Acknowledgment. This work was supported by the NSF
(CHE-0308378).
full characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures for the synthesis of all new compounds and their
OL048265W
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Org. Lett., Vol. 6, No. 22, 2004