prate, generated from butylmagnesium bromide and CuBr,
significantly improved the yield of cis-5b from 5 to 58%
(entry 2). Furthermore, the reaction at -78 °C was found to
give the desired product cis-5b in 94% yield. Additional
studies focused on a copper salt such as CuI and CuCN,
both of which had proven to be good copper salts in our
preliminary studies on the carbocupration reaction using
organolithium reagents.8 Thus, changing the copper salt from
CuBr to CuI appreciably affected the yield (entry 4). Higher-
ordered cyanocuprates realized the satisfactory reaction,
resulting in the formation of cis-5b in 69% yield, although
lower-ordered cyanocuprate did not lead to good results. In
all cases, isomers such as trans-5b, cis-6b, and trans-6b were
not detected at all (Figure 2).
Scheme 1. Retrosynthesis of Panomifene
1 as illustrated in Scheme 1. Our strategy for the synthesis
of 1 is based on the possibility of using a carbometalation
reaction of trifluoromethylated internal alkyne 3a with
organocopper reagent, leading to the corresponding inter-
mediate 4a.5 The successive stereospecific cross-coupling
reaction of vinyl copper 4a with phenyl halide would provide
us with the target compound.6
In this communication, we wish to describe a highly regio-
and stereoselective carbocupration reaction of fluoroalkylated
internal alkynes and the following stereospecfic Suzuki-
Miyaura cross-coupling reaction, the utilization of which
realizes an efficient stereoselective total synthesis of pa-
nomifene 1.
Figure 2.
As preliminary studies, we examined the feasibility of the
carbometalation reaction with a series of organocopper
reagents (prepared from Grignard reagents) by using tri-
fluoromethylated alkyne 3b,7 in order to determine the
optimum linchpin (Table 1). Treatment of 3b with n-
To examine the scope and limitation of this carbocupration,
optimized reaction conditions were applied for various types
of fluoroalkylated alkynes 3 as shown in Table 2.
Primary and secondary Grignard reagents such as n-
BuMgBr and s-BuMgBr (entries 1 and 2), cyclohexyl,
benzyl, and allyl Grignard reagents (entries 3-5) could
participate well in the carbocupration reaction to give the
corresponding adducts cis-5 in good to excellent yields (69-
86% isolated yields). However, the yield was somewhat
eroded when vinyl Grignard reagent was employed (entry
6). Switching R in the Grignard reagent from aliphatic to
aromatic groups had no discernible effect on the yield,
although 2.4 equiv of copper reagents or CuCN instead of
CuBr were required for the smooth reaction (entries 7 and
Table 1. Investigation of the Reaction Conditions for the
Carbocupration
copper
temp time
yieldb
recoveryb
entry
reagenta
(°C)
(h)
of 5b (%) of 3b (%)
(5) For reviews on the carbocupration reaction, see: (a) Lipshutz, B.
H.; Sengupta, S. Org. React. 1992, 41, 135-631. (b) Lipshutz, B. H.
Synthesis 1987, 325-341. (c) Lipshutz, B. H. Synlett 1990, 119-128. (d)
Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984, 40,
5005-5038. (e) In Modern Organocopper Chemistry; Krause, N., Ed.;
Wiley-VCH: Weinheim, 2002.
1
2
3
4c
5
6
n-BuCu
n-Bu2CuX
n-Bu2CuX
n-Bu2CuX
n-BuCu(CN)X
n-Bu2Cu(CN)X2
-45
-45
-78
-78
-78
-78
4
4
2
2
2
2
5
58
48
0
94 (85)
31
24
0
68
76
28
(6) For reviews on the cross-coupling reaction, see Negishi cross-coupling
reaction: Negishi, E. Acc. Chem. Res. 1982, 15, 340-348. Stille cross-
coupling reaction: (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508-524. (b) Mitchel, T. N. Synthesis 1992, 803-815. Suzuki-Miyaura
cross-coupling reaction: (c) Suzuki, A. Acc. Chem. Res. 1982, 15, 178-
184. (d) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(7) Recently, we have developed convenient synthetic methods for
various types of fluoroalkylated alkynes and their synthetic applications:
(a) Konno, T.; Chae, J.; Kanda, M.; Nagai, G.; Tamura, K.; Ishihara, T.;
Yamanaka, H. Tetrahedron 2003, 59, 7571-7580. (b) Konno, T.; Chae,
J.; Tanaka, T.; Ishihara, T.; Yamanaka, H. Chem. Commun. Accepted. For
other synthetic methods, see: (c) Bunch, J. E.; Bumgaradner, C. L. J.
Fluorine Chem. 1987, 36, 313-317. (d) Kobayashi, Y.; Yamashita, T.;
Takahashi, K.; Kuroda, H.; Kumadaki, I. Tetrahedron Lett. 1982, 23, 343-
344. (e) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara, T.; Suzuki, A.
Bull. Chem. Soc. Jpn. 1990, 63, 2124-2126. (f) Hiyama, T.; Sato, K.; Fujita,
M. Bull. Chem. Soc. Jpn. 1989, 62, 1352-1354. (g) Brisdon, A. K.;
Crossley, I. R. Chem. Commun. 2002, 2420-2421.
69
a Copper reagents were prepared from Grignard reagent (n-BuX, X )
MgBr) and CuBr or CuCN, unless otherwise noted. b Determined by 19F
NMR. Value in parentheses is of isolated yield. c CuI was employed instead
of CuBr.
butylcopper at -45 °C for 4 h furnished the carbometalation
product cis-5b in only 5% yield, together with 48% of the
starting material, after quenching the reaction with NH3 (aq)/
MeOH at -45 °C. The product proved to be a cis-adduct as
a single isomer. This result encouraged us to investigate the
reaction in more detail. Use of a lower-ordered dibutylcu-
(8) Konno, T.; Noiri, A.; Ishihara, T.; Yamanaka, H. Unpublished results.
934
Org. Lett., Vol. 6, No. 6, 2004