Highly selective synthesis of (E)-3-methyl-1-trialkylsilyl-3-en-1-ynes via trans-selective alkynylation catalyzed by Cl2Pd(DPEphos) and stereospecific methylation with methylzincs catalyzed by Pd(tBu3P)2.

Article abstract of DOI:10.1021/ol030017x

[reaction: see text] trans-Selective (>or=98%) monoalkynylation of 1,1-dibromo-1-alkenes and 1,1-dichloro-1-alkenes catalyzed by Cl(2)Pd(DPEphos) followed by stereospecific methylation with Me(2)Zn or MeZnX (X= Cl or Br) catalyzed by Pd((t)()Bu(3)P)(2) pr

Full text of DOI:10.1021/ol030017x

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1825-1828
Highly Selective Synthesis of
(E)-3-Methyl-1-trialkylsilyl-3-en-1-ynes via
trans-Selective Alkynylation Catalyzed
by Cl2Pd(DPEphos) and Stereospecific
Methylation with Methylzincs Catalyzed
t
by Pd( Bu3P)2
Ji-cheng Shi, Xingzhong Zeng, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received February 5, 2003
ABSTRACT
trans-Selective (g98%) monoalkynylation of 1,1-dibromo-1-alkenes and 1,1-dichloro-1-alkenes catalyzed by Cl2Pd(DPEphos) followed by
t
stereospecific methylation with Me2Zn or MeZnX (X) Cl or Br) catalyzed by Pd( Bu3P)2 provides an efficient and stereoselective (g98%) route
to 5, convertible to a wide variety of enynes and conjugated dienes. In the cases of 1,1-dibromo-1-alkenes, the Sonogashira alkynylation may
also be satisfactory, but it is distinctly less satisfactory than the alkynylzinc reaction in cases where 1,1-dichloro-1-alkenes are used.
Reported herein is a highly selective synthesis of (E)-3-
methyl-3-en-1-ynes via two-stage Pd-catalyzed cross-
coupling1 of 1,1-dihalo-1-alkenes (1) containing Br or Cl (eq
2 in Scheme 1, where M is a Zn group and R4 is a Si group).
Although various protocols for the trans-selective substitution
of 1 to 2 and/or 3 have been known since 1987,2-7 selective
conversion of 1 to 5 via 4 appears to be unprecedented, the
only reported example of Pd- or Ni-catalyzed methylation
of 2 to produce 3 being that of (Z)-bromostilbene with Me4-
Sn.5c In more recent papers,7a,b trans-selective Sonogashira
alkynylation7c of PhCH2CH2CHdCBr2 with HCtCSiMe3
Scheme 1
(1) For recent reviews of the Pd-catalyzed cross-coupling in general,
see: (a) Negishi, E., Ed. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: New York, 2002; Vol. I, Part III,
pp 215-1119. (b) Diederich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross
Coupling Reactions; VCH: Weinheim, Germany, 1998; p 517.
(2) For papers involving Grignard reagents, see: (a) Minato, A.; Suzuki,
K.; Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257. (b) Bryant-Friedrich,
A.; Neidlein, R. Synthesis 1995, 1506. (c) Braun, M.; Rahematpura, J.;
Bu¨hne, C.; Paulitz, T. C. Synlett 2000, 1070.
10.1021/ol030017x CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003

followed by alkylation with a couple of alkylmagnesium
chlorides catalyzed with Cl2Ni(dppp)2a was reported, but
methylation was not achieved. Also known are a few
alkylation reactions of (Z)-3-bromo-3-en-1-ynes not involving
Pd or Ni catalysts.8 Interestingly, these reactions predomi-
nantly produced the stereoinverted (Z)-3-alkyl-3-en-1-ynes.
Table 1. Methylation or Ethylation of
(Z)-3-Halo-1-trimethylsilyl-3-en-1-ynes with Me2Zn, MeZnX (X
) Cl or Br), or Et2Zn in the Presence of Pd Catalysts
Conjugated oligoenes and oligoenynes containing stereo-
and regiodefined methyl-branched trisubstituted alkenes
represent a large number of natural products and related
compounds of biological and medicinal significance. We
recently reported an efficient and selective “head-to-tail” (H-
to-T)9 route to carotenoids involving Zr-catalyzed carboalu-
mination and Pd-catalyzed alkenyl-alkenyl coupling.10
However, it is also very desirable to develop complementary
“tail-to-head” (T-to-H)9 routes to cope with various structural
features, including the presence of proximal asymmetric
carbon and heterofunctional groups. One such protocol11 that
has been used with considerable success involves regiose-
lective hydrozirconation of 2-alkynes followed by Pd-
catalyzed cross-coupling, and the required alkynes are often
prepared via Corey-Fuchs reaction12 of aldehydes followed
by elimination and methylation. In such cases, however,
stereoselective two-stage substitution of 1,1-dihaloalkenes
would be more straightforward.
(3) For papers involving organoboranes, see: (a) Roush, W. R.; Moriarty,
K. J.; Brown, B. B. Tetrahedron Lett. 1990, 31, 6509. (b) Roush, W. R.;
Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am. Chem. Soc. 1996, 118,
7502 and pertinent references therein. (c) Wong, L. S. M.; Sharp, L. A.;
Xavier, N. M. C.; Turner, P.; Sherburn, M. S. Org. Lett. 2002, 4, 1995.
(4) For papers involving organozincs, see: (a) ref 2a. (b) Minato, A. J.
Org. Chem. 1991, 56, 4052. (c) Xu, C.; Negishi, E. Tetrahedron Lett. 1999,
40, 431. (d) Ogasawara, M.; Ikeda, H.; Ohtsuki, K.; Hayashi, T. Chem.
Lett. 2000, 776. (e) Ogasawara, M.; Ikeda, H.; Hayashi, T. Angew. Chem.,
Int. Ed. 2000, 39, 1042.
(5) For papers involving organotins, see: (a) Uenishi, J.; Kawahama,
R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716. (b) Uenishi, J.;
Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965 and
pertinent references therein. (c) Shen, W.; Wang, L. J. Org. Chem. 1999,
64, 8873. (d) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000,
39, 2732.
(6) For a paper involving organozirconium derivatives, see ref 4c.
(7) For papers involving Sonogashira alkynylation, see: (a) Uenishi, J.;
Matsui, K. Tetrahedron Lett. 2001, 42, 4353. (b) Uenishi, J.; Matsui, K.;
Ohmaya, H. J. Organomet. Chem. 2002, 653, 141. (c) For a recent review
of the Sonogashira alkynylation, see: Sonogashira, K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; p 493.
(8) (a) Miller, J. A.; Leong, W.; Zweifel, G. J. Org. Chem. 1988, 53,
1839. (b) For a synthesis of (E)-3-methyl-1-trimethylsilyl-3-decen-1-yne
by Cu-promoted methylation of (Z)-(n-Hex)CHdC(AlBu3Li)CtCSiMe3
with MeI, see: Miller, J. A.; Zweifel, G. J. Am. Chem. Soc. 1983, 105,
1383.
a By GLC with isolated yields in parentheses. b Two other byproducts
were formed. c From MeLi and ZnCl2. d From MeMgBr and ZnCl2. e Z )
tert-butyldimethylsilyl.
As implied by a related investigation mentioned above,8
stereospecific methylation of (Z)-3-halo-3-en-1-ynes (4)
proved to be very challenging. Methylation of (Z)-(n-C9H19)-
CHdC(Br)CtCSiMe3(4a) with MeMgBr in the presence of
either 5 mol % Cl2Ni(dppp) or 5 mol % Pd(PPh3)4 was not
clean in our hands. It was hence not a practically useful
reaction. On the other hand, the Pd-catalyzed reaction of 4a
with Me2Zn proceeded to give the methylated product in high
yields. As indicated by the results summarized in Table 1,
however, all catalysts tested except Pd(tBu3P)2,13,14 namely,
Pd(PPh3)4, Cl2Pd(dppf), Cl2Pd(DPEphos) [DPEphos ) bis-
(2-diphenylphosphinophenyl) ether],15 and Cl2Pd(TFP)2 [TFP
(9) “Head-to-tail” (H-to-T) and “tail-to-head” (T-to-H) directions in
methyl-branched trisubstituted alkenes may be conveniently defined as
shown below (Negishi, E.; Liou, S. Y.; Xu, C.; Huo, S. Org. Lett. 2002, 4,
261).
(13) For the use of Pd(tBu3P)2 in the Pd- or Ni-catalyzed C-C cross
coupling, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998,
37, 3387. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38,
2411. (c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020. (d) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719. (e) Littke,
A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343.
(14) For trans-selective alkylation of 1,1-dichloro-1-alkenes with Pd (t-
Bu3P)2 as a catalyst, see: Tan, Z.; Negishi, E. Manuscript in preparation.
(15) (a) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje J. Organometallics 1995, 14,
3081. (b) Kranenburg, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Eur. J. Inorg. Chem. 1998, 155 (c) Frid, M.; Perez, D.; Peat, A. J.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9469.
(10) (a) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719. (b) See also: Hoye,
T.; Tennakoon, M. A. Org. Lett. 2000, 2, 1481, for a H-to-T stereocontrolled
alkylation of a â-methylalkenyl derivative.
(11) For a few representative papers, see: (a) Panek, J. S.; Hu, T. J.
Org. Chem. 1997, 62, 4912. (b) Panek, J. S.; Hu, T. J. Org. Chem. 1997,
62, 4914. (c) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999,
121, 456. (d) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3,
3281. (e) For a seminal paper on regioselective hydrozirconation, see: Hart,
D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679.
(12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
1826
Org. Lett., Vol. 5, No. 11, 2003

Table 2. Pd-Catalyzed Alkynylation of 1,1-Dihalo-1-alkenes with M-t-SiR3
i
a N ) Negishi alkynylation in THF. S ) Sonogashira alkynylation in benzene with CuI (5 mol %) and Pr2NH (2 equiv). b By GLC. Isolated yields in
parentheses. c Formation of 1% of this product requires 2% of the starting alkyne.
) tris(2-furyl)phosphine],16 led to stereoisomerization to
extents ranging from 28 to 89%. It is also noteworthy that
the reaction of 4a with Me4Sn5c in the presence of Pd2(dba)3
and TFP also led to extensive stereoisomerization. Thus, the
use of Pd(tBu3P)2 was crucial in achieVing stereospecific
methylation in high yields with nearly 100% retention of
configuration.
The results summarized in Table 1 also indicate the
following. (1) Methylzinc derivatives generated in situ by
treating either MeMgBr or MeLi with dry ZnCl2 or ZnBr2
in a molar ratio of 1:1 to 2:1 are comparably satisfactory.
(2) On the other hand, MeMgBr without the addition of a
Zn salt converted 4a into a mixture of (E)-5a and its (Z)-
isomer in 31 and 21% yields, respectively, along with a
byproduct produced in a significant amount even in the
presence of Pd(tBu3P)2. (3) The methylation of 1,1-dichloro-
1-alkenes with methylzincs in the presence of Pd(tBu3P)2 is
slower than but as satisfactory as the corresponding reaction
of the dibromo derivatives. (4) The methylation procedure
appears to be of wide scope with respect to R1 in 4. Thus,
not only alkyl groups, e.g., n-Hex, n-C9H19, and TBSOCH2-
(Me)CH- but also aryl groups, e.g., Ph, and alkynyl groups,
e.g., Me3SiCtC-, can serve satisfactorily as the R1 group
in 4. Although the current scope of our investigation is
largely limited to methylation, the use of Et2Zn was similarly
satisfactory with little or no complication due to the presence
of â hydrogens.
Having developed a highly selective and high-yielding
methylation of 4 to give 5, we then focused our attention on
the trans-selective alkynylation of 1 to produce the requisite
4. Prior to our study, this transformation was achieved
exclusively by Pd-catalyzed alkynylation of 1,1-dibromo-1-
alkenes with alkynylmetals containing Mg or Zn2b,4d and with
terminal alkynes7a,b only in modest yields (e68%).17
In view of these results, an extensive study was undertaken
to develop superior procedures. Two main side reactions,
i.e., competitive dialkynylation and formation of (E)- and
(17) In an earlier paper,7a the alkynylation with HCtCSiMe3 in the
presence of Cl2Pd(dppf) was reported to give the desired product in 87%
yield, but a subsequent full paper7b changed the yield to 68%.
(16) Farina, V.; Baker, S. R.; Sapino, C., Jr. Tetrahedron Lett. 1988,
29, 6043.
Org. Lett., Vol. 5, No. 11, 2003
1827

(Z)- stereoisomeric mixtures, were observed. The results
summarized in Table 2 indicate the following. First, the
reaction of either 1,1-dibromo- or 1,1-dichloro-1-alkenes with
ClZnCtCSiMe3 in the presence of 5 mol % Cl2Pd-
(DPEphos)15 proved to be the most satisfactory procedure,
leading to the desired monoalkynylation products in g84%
yields except in the reaction of 1,1-dichloro-1-octene, where
the product yield was 65%. Second, the reaction of 1,1-
dibromo-1-alkenes is nearly 100% stereoselective. The extent
of dialkynylation in each case is <10%, corresponding to
the consumption of 0.2 molar equiv of ClZnCtCSiMe3
relative to the dibromide.
variety of their derivatives, as exemplified by the conversion
of 5f to 6 via desilylation with K2CO3-MeOH and then to
7 via lithiation with n-BuLi and methylation with MeI both
in nearly quantitative yields. Conversion of 6 into a trienonic
ester 8 in one pot in 94% yield as a single stereoisomer
(g98%) is also noteworthy (Scheme 3). The potential
Scheme 3
On the other hand, alkynylation of 1,1-dichloro-1-alkenes
displays more widely varied results. Even with Cl2Pd-
(DPEphos), the Sonogashira alkynylation using HCtCSiMe3
(1.2-1.3 molar equiv), CuI (5 mol %), Cl2Pd(DPEphos) (5
i
mol %), and Pr2NH (2 equiv) proceeded slowly at 23 °C
and was accompanied by detectable formation of the (E)-
isomer. Third, dppf may be nearly as effective as DPEphos
in some cases but is at least somewhat inferior to the latter,
synthetic value of the method reported herein is further
demonstrated by the five-step synthesis of enyne 9 (g98%
(E)- and 92% ee) from 1-heptene in 65% overall yield
(Scheme 4). This enyne can potentially serve as a convenient
t
while PPh3, TFP, dppb, and Bu3P are distinctly inferior to
DPEphos with some exceptions. Fourth, the use of bulky
i
silyl groups, e.g., Ph3Si and Pr3Si, is effective in avoiding
dialkynylation, even with highly demanding substrates such
as 4f.
Scheme 4
Despite the favorable results presented above, the trans-
selective monoalkynylation protocol reported herein is still
of limited scope with respect to R4 in 4 and 5. In contrast,
with the favorable results observed with silyl-substituted
alkynes, extensive dialkynylation has been observed with
other alkynes and their zinc derivatives, including those
containing Me, Ph, PhCHdCH, and TBSOCH2 under various
conditions, even though favorable results such as those shown
in Scheme 2 were also observed in some exceptional cases.
Scheme 2
intermediate for the synthesis of a recently reported potent
topoisomerase inhibitor, topostatin.18
Acknowledgment. We thank the National Science Foun-
dation (CHE-0080795), the National Institutes of Health (GM
36792), and Purdue University for support of this research.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Further development is clearly desirable. In the meantime,
however, various 3-bromo- and 3-methyl-substituted 1-tri-
alkylsilyl-3-en-1-ynes preparable by the process reported
herein may be desilylated and further converted into a wide
OL030017X
(18) Suzuki, K.; Yahara, S.; Kido, Y.; Nagao, K.; Hatano, Y.; Uyeda,
M. J. Antibiot. 1998, 51, 999.
1828
Org. Lett., Vol. 5, No. 11, 2003