Stereocontrolled synthesis of branched enyne by stepwise cross-coupling reactions of 1,1-dibromo-1-alkenes

Article abstract of DOI:10.1016/S0040-4039(01)00749-3

Geometrically pure alkynyl, alkenyl and alkyl substituted branched enynes were prepared by the Sonogashira coupling followed by Sonogashira, Suzuki-Miyaura, and Kumada-Tamao-Corriu coupling reactions.

Full text of DOI:10.1016/S0040-4039(01)00749-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4353–4355
Stereocontrolled synthesis of branched enyne by stepwise
cross-coupling reactions of 1,1-dibromo-1-alkenes
Jun’ichi Uenishi* and Katsuaki Matsui
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Received 2 April 2001; revised 1 May 2001; accepted 2 May 2001
Abstract—Geometrically pure alkynyl, alkenyl and alkyl substituted branched enynes were prepared by the Sonogashira coupling
followed by Sonogashira, Suzuki–Miyaura, and Kumada–Tamao–Corriu coupling reactions. © 2001 Elsevier Science Ltd. All
rights reserved.
Enyne is an important structural unit for biologically
active organic compounds, including anticancer anti-
biotics,1 and other natural products,2 and also for new
functional materials.3 The functional unit has been
prepared by the cross-coupling reaction of haloalkene
with terminal alkyne,4 Wittig olefination of aldehyde
with alkynylmethylidene ylide,5 or homologation of
enal to terminal enyne.6 However, such synthetic meth-
ods are sometimes not so effective for the stereoselec-
tive preparation of branched enynes, I–III and there
have been few efforts made to develop a general
method for the synthesis of branched enynes (Fig. 1).7
A differentiation of two carbonꢀhalogen bonds of 1,1-
dihalo-1-alkene under metal-catalyzed reactions has
been successfully performed in Kumada–Tamao–Corriu
coupling,8 Suzuki coupling,9 Stille coupling,10 and
hydrogenolysis11 (Scheme 1). However, a few stereose-
lective Sonogashira couplings of 1,1-dibromo-1-alkene
were reported, in which a combination of Pd(PPh3)4
and alkynyl metals were employed.12 The couplings
using free terminal alkyne were poorly chemoselec-
tive,13 and the next cross coupling reaction of the
resultant trisubstituted bromoenyne (Scheme 2) has not
been examined. If the second cross-coupling reaction of
the resultant bromoenyne occurs with alkynyl, alkenyl
and alkyl reagents under Sonogashira, Suzuki–Miyaura
and Kumada–Tamao–Corriu conditions,4,14 a variety of
branched enynes will be obtained.
Sonogashira
Coupling
R'
i)
Br
R'
R
ii)
Br
Second
Cross-coupling
III
R
I
II
A
A
= alkynyl, alkenyl , or alkyl
Figure 1.
Stereoselective
Cross Coupling
Scheme 2.
X
R'
R
R
X
X
In this paper, we describe the synthesis of some
branched (E)- and (Z)-enynes in geometrically pure
form by stereoselective Sonogashira coupling reaction
of 1,1-dibromo-1-alkenes using terminal alkyne, and
the successive cross-coupling reaction of the resultant
bromoenyne.
R' = aryl, alkenyl, H
Scheme 1.
Keywords: enyne; cross coupling; stereocontrolled synthesis.
* Corresponding author. Fax: +81-75-595-4763; e-mail: juenishi
@mb.kyoto-phu.ac.jp
Sonogashira coupling of 1,1-dibromo-1-alkene 1 with
(trimethylsilyl)acetylene in the presence of
a
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00749-3

4354
J. Uenishi, K. Matsui / Tetrahedron Letters 42 (2001) 4353–4355
SiMe3
cat. PdCl2(dppf)
CuI, Pri2NH
PdCl2(dppf) catalyst, copper iodide and diisopropyl-
amine gave enyne 2 in 87% yield stereoselectively along
with 1,1-dialkynyl-1-alkene in less than 10% yield.15
The same coupling reaction of 1,1-dibromo-1,3-diene 3
also proceeded very well to give dienyne 4 in 79% yield
and dialkynyldiene in 15% yield. Since the Sonogashira
reaction of 1,1-dibromo-1-alkene gave a mixture of
1-alkynyl-1-bromo-1-alkene, 1,1-dialkynyl-1-alkene and
some recovery of starting material13 under typical con-
ditions,16 the use of PdCl2(dppf) largely improved the
chemoselective formation of bromoenyne 2 or 4. In
fact, Pd catalysts such as Pd(PPh3)4, PdCl2(PPh3)2,
Pd(dppe)2 and other commercial catalysts provided a
mixture of bromoenyne, enediyne and the starting
dibromoalkene with poor selectivity (Scheme 3).
Br
Ph
Ph
n
n
Br
SiMe3
Br
benzene, rt
1 (n = 0)
3 (n = 1)
2 (n = 0)
4 (n = 1)
Scheme 3.
C4H9
SiMe3
cat. Pd(PPh3)4
2
Ph
CuI, Pri2NH
benzene, reflux, 4h
5
C4H9
C4H9
(HO)2B
The second coupling reactions of 2 can take place
stereospecifically to give the corresponding substituted
enynes. Thus, 1,1-dialkynyl-1-alkene 5 was obtained as
a single stereoisomer in 95% yield by the second Sono-
gashira coupling of 2 with hexyne. Suzuki–Miyaura
coupling of 2 with 1-hexenylboronic acid provided
dienyne 6E exclusively in 82% yield, though the termi-
nal trimethylsilyl group was removed under the reaction
conditions. On the other hand, Kumada–Tamao–Cor-
riu coupling with ethylmagnesium bromide in the pres-
ence of NiCl2(dppp) gave (E)-alkene 7a exclusively in
71% yield. The coupling reaction of 2 with trimethyl-
silylmethyl Grignard reagent gave the corresponding
coupling products 7b in 53% yields. These three sp-,
sp2- and sp3-carbon coupling reactions occur to give a
single stereoisomer with retention of the configuration,
respectively (Scheme 4).
cat. PdCl2(PPh3)2
Ph
2
2
aq. NaOH, THF
rt, 30 min
6E
C4H9
RCH2MgCl
SiMe3
cat. NiCl2(dppp)
Ph
THF, rt, 50 min
7a,b
R
a; R = Me
b;
R = SiMe3
Scheme 4.
R
(HO)2B
C4H9
cat. Pd(PPh3)4
Ph
1
Pd-catalyzed cross-coupling reaction of 1 with 1-hex-
enylboronic acid took place smoothly to give bromo-
diene 8 stereoselectively in 85% yield.9 Although Roush
et al. noted that 2-bromo-1,3-diene was poorly reactive
for the second Suzuki coupling reactions,9a Sonogashira
coupling of 8 with trimethylsilylacetylene in the pres-
ence of PdCl2(dppf), CuI and diisopropylamine at 65°C
in benzene gave dienyne in 81% yield. Desilylation of
the product by Bu4NF afforded dienyne 6Z quantita-
tively, corresponding to the stereoisomer of 6E, which
was obtained in Suzuki coupling of 2 with hexynyl-
boronic acid shown in Scheme 4. Combinations of
Sonogashira and Suzuki cross-coupling reactions in
either order can provide either 6Z or 6E in stereochem-
ically pure form (Scheme 5).
aq. NaOH, THF
rt, 35 min
Br
8
i)
SiMe3
C4H9
cat. PdCl2(dppf)
Ph
CuI, Pri2NH
benzene, 65°C
ii) Bu4NF, THF
6Z
Scheme 5.
enyne 11 in 58% yield. Manipulation of the terminal
enyne to (Z,E)-iododiene was performed in two steps.
First, iodination with iodine in the presence of morpho-
line and then cis-reduction of the idodoalkyne with
diimide eventually gave 12 in 58% yield.18 Since there
have been no reports on the synthesis of 13-substituted
derivatives for (11Z)-retinal, this method should be
valuable for the stereocontrolled preparation of the
corresponding fragment (Scheme 6).
We have demonstrated this methodology for the syn-
thesis of (2E,4Z)-3-ethyl-5-iodopentadienyl silyl ether
12. This iododiene is a C11–C15 part of a 13-ethyl
substituted analogue of (11Z)-retinal, which is an
important chromophore for the visual system. A silyl
ether of 3-hydroxy-1,1-dibromo-1-propene 917 having a
protected hydroxymethyl group, which can be trans-
formed to other functional groups and elongate a car-
bon chain in a later stage, was first coupled with
(trimethylsilyl)acetylene to give 10 in 81% yield. The
coupling reaction of 10 with ethylmagnesium bromide
followed by desilylation with Bu4NF gave branched
In conclusion, we have demonstrated a novel and
efficient preparation of geometrically pure branched
enynes from 1,1-dibromo-1-alkene by Pd- or Ni-cata-
lyzed cross-coupling reactions.

J. Uenishi, K. Matsui / Tetrahedron Letters 42 (2001) 4353–4355
4355
SiMe3
4. Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
5. Ogawa, H.; Mukae, J. Tetrahedron Lett. 1978, 4929.
6. Michel, P.; Gennet, D.; Rassat, A. Tetrahedron Lett.
1999, 40, 8575.
Br
a
Br
Br
OSIButPh2
OSiButPh2
7. (a) Ikeda, S. Acc. Chem. Res. 2000, 33, 511; (b) Hara, R.;
Liu, Y.; Sun, W.-H.; Takahashi, T. Tetrahedron Lett.
1997, 38, 4103; (c) Trost, B. M.; McIntosh, M. C. Tetra-
hedron Lett. 1997, 38, 3207.
8. (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc.
1987, 109, 1257; (b) Minato, A. J. Org. Chem. 1991, 56,
4052.
9
10
I
b, c
d, e
OSiButPh2
Et
Et
OSiButPh2
9. (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetra-
hedron Lett. 1990, 31, 6509; (b) Roush, W. R.; Koyama,
K.; Curtin, M. L.; Moriarty, K. J. J. Am. Chem. Soc.
1996, 118, 7502.
10. Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873.
11. (a) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J.
J. Org. Chem. 1996, 61, 5716; (b) Uenishi, J.; Kawahama,
R.; Shiga, T.; Yonemitsu, O.; Tsuji, J. Tetrahedron Lett.
1996, 37, 6759.
12. (a) Neidlein et al. reported the reaction using alkynyl-
magnesium bromide in which dibromoalkene was recov-
ered in all the cases, see: Bryant-Friedrich, A.; Neidlein,
R. Synthesis 1995, 1506; (b) The reaction using alkynylz-
inc chloride was recently reported by Hayashi et al, see:
Ogasawara, M.; Ikeda, H.; Ohtsuki, K.; Hayashi, T.
Chem. Lett. 2000, 776.
13. Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J.
Org. Chem. 1998, 63, 8965. Exceptionally, Meyers
recently reported selective alkynylation in specific sub-
strate: Meyers, A. G.; Goldberg, S. D. Angew. Chem., Int.
Ed. 2000, 39, 2732.
14. Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: New York, 1991; Vol. 3, by
Sonogashira, K. p. 521, by Knight, D. W., p. 481 and by
Tamao, K., p. 435.
15. General procedure: To a mixture of 1,1-dibromo-1-alkene
(2 mmol) and trimethylsilylacetylene (3 mmol) in anhy-
drous benzene (20 mL) were added PdCl2(dppf)·CH2Cl2
(5 mol%), CuI (0.08 mmol), and EtNPri2 (4–6 mmol), and
the mixture was stirred for 10–20 min at rt. After a work
up, purification by flash column chromatography (eluted
12
11
Scheme 6. Reagents and conditions: (a) (trimethylsilyl)-
acetylene, cat. PdCl2(dppf), CuI, Pri2NH, benzene, rt; (b)
ethylmagnesium bromide, cat. NiCl2 (dppp), THF, rt; (c)
Bu4NF, THF, −20°C; (d) iodine, morpholine, benzene, 50°C;
(e) diimide, THF, rt.
Acknowledgements
This work was financially supported by the Grant-in-
Aid for Scientific Research on Priority Areas (A) from
the Ministry of Education, Science, Sports and Culture,
Japan, and a Special Grant for Cooperative Research
administered by the Japan Private School Promotion
Foundation.
References
1. (a) Maier, M. E. Synlett 1995, 13; (b) Grissom, J. W.;
Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetra-
hedron 1996, 52, 6453; (c) Nicolaou, K. C.; Smith, A. L.
Acc. Chem. Res. 1992, 25, 497.
2. (a) Kuhnt, D.; Anke, T.; Besl, H.; Bross, M.; Herrmann,
R.; Mocek, U.; Steffan, B.; Steglich, W. J. Antibiot. 1990,
43, 1413; (b) Kusumi, T.; Ohtani, I.; Nishiyama, K.;
Kakisawa, H. Tetrahedron Lett. 1987, 28, 3981; (c) Ohta,
T.; Uwai, K.; Kikuchi, R.; Nozoe, S.; Oshima, Y.;
.
Sasaki, K.; Yoshizaki, F. Tetrahedron 1999, 55, 12087;
(d) Trowitsch-Kienast, W.; Forche, E.; Wray, V.;
Riechenbach, H.; Hunsmann, G.; Ho¨fle, G. Liebigs Ann.
Chem. 1992, 659.
with hexane for
bromoenyne.
1 and 3) gave the corresponding
16. Sonogashira, K.; Tohda, Y.; Hagiwaha, N. Tetrahedron
Lett. 1975, 4756.
17. Francesch, A.; Alvarez, R.; Lo¨pez, S.; De Lera, A. R. J.
Org. Chem. 1997, 62, 310.
18. The corresponding 13-methyl derivative was used for the
synthesis of (11Z)-9-demethylretinal. De Lera, A. R.;
Torrado, A.; Iglesias, B.; Lo¨pez, S. Tetrahedron Lett.
1992, 33, 6205.
3. (a) Boldi, A. M.; Anthony, J.; Gramlich, V.; Knobler, C.
B.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M.; Diederich,
F. Helv. Chim. Acta 1995, 78, 779; (b) Hynd, G.; Jones,
G. B.; Plourde, II, G. W.; Wright, J. M. Tetrahedron
Lett. 1999, 40, 4481; (c) Shimada, S.; Masaki, A.;
Hayamizu, K.; Matsuda, H.; Okada, S.; Nakanishi, H.
Chem. Lett. 2000, 11, 1128; (d) Ciulei, S. C.; Tykwinski,
R. R. Org. Lett. 2000, 2, 3607.