A single-step synthesis of enynes: Pd-catalyzed arylalkynylation of aryl iodides, internal alkynes, and alkynylsilanes

Article abstract of DOI:10.1021/ol100180j

"Chemical Equation Presented" An unprecedented single-step synthesis of enyne derivatives through Pd-catalyzed arylalkynylation of aryl iodides, internal alkynes, and alkynylsilanes is described.

Full text of DOI:10.1021/ol100180j

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1300-1303
A Single-Step Synthesis of Enynes:
Pd-Catalyzed Arylalkynylation of Aryl
Iodides, Internal Alkynes, and
Alkynylsilanes
Norio Sakai,* Ryosuke Komatsu, Naoki Uchida, Reiko Ikeda, and
Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo
UniVersity of Science (RIKADAI), Noda, Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
Received January 25, 2010
ABSTRACT
An unprecedented single-step synthesis of enyne derivatives through Pd-catalyzed arylalkynylation of aryl iodides, internal alkynes, and
alkynylsilanes is described.
Conjugated enynes, especially 1,1,2-trisubstituted conjugated
enynes, constitute basic units of naturally occurring com-
pounds, related biologically active substances, and organic
electronic materials.1 A number of approaches for the
synthesis of the enyne skeleton have been extensively
studied.2,3 Among these approaches, the Sonogashira-type
coupling reaction of terminal alkynes with vinyl halides4 and
metal-catalyzed coupling reactions between various alky-
nylmetals containing B,5 Mg,6 Zn,7 Si,8 Sn,9 Ag,10 Au,11
and In12 and vinyl halides/triflates are most frequently used.13
On the other hand, we have reported that InBr3 functions as
a cocatalyst in Sonogashira-type coupling reactions between
aryl iodides and a terminal alkyne.14 Our ongoing studies
(4) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46. (b)
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
(c) Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1991, 32, 6109. (d)
Uenishi, J. i.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353. (e) Chen, L.;
Li, C.-J. Tetrahedron Lett. 2004, 45, 2771. (f) Shi, M.; Liu, L.-P.; Tang, J.
Org. Lett. 2005, 7, 3085. (g) Feuerstein, M.; Chahen, L.; Doucet, H.; Santelli,
M. Tetrahedron 2006, 62, 112. (h) Hatakeyama, T.; Yoshimoto, Y.; Gabriel,
T.; Nakamura, M. Org. Lett. 2008, 10, 5341.
(5) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Yamada,
K.; Miyaura, N.; Itoh, M.; Suzuki, A. Tetrahedron Lett. 1975, 16, 1961.
(6) Dang, H. P.; Linstrumelle, G. Tetrahedron Lett. 1978, 19, 191.
(7) (a) King, A. O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc., Chem.
Commun. 1977, 683. (b) Andreini, B. P.; Carpita, A.; Rossi, R.; Scamuzzi,
B. Tetrahedron 1989, 45, 5621. (c) See also ref 3.
(8) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. (b) Hatanaka,
Y.; Matsui, K.; Hiyama, T. Tetrahedron Lett. 1989, 30, 2403. (c) Ito, H.;
Arimoto, K.; Sensui, H.-o.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977. (d)
Nishihara, Y.; Ikegashira, K.; Mori, A.; Hiyama, T. Chem. Lett. 1997, 26, 1233.
(e) Koseki, Y.; Omino, K.; Anzai, S.; Nagasaka, T. Tetrahedron Lett. 2000, 41,
2377. (f) Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.-i.; Mori, A.;
Hiyama, T. J. Org. Chem. 2000, 65, 1780. (g) Halbes, U.; Bertus, P.; Pale, P.
Tetrahedron Lett. 2001, 42, 8641. (h) Marshall, J. A.; Chobanian, H. R.; Yanik,
M. M. Org. Lett. 2001, 3, 4107. (i) Yang, C.; Nolan, S. P. Organometallics
2002, 21, 1020. (j) Halbes, U.; Pale, P. Tetrahedron Lett. 2002, 43, 2039. (k)
Nishihara, Y.; Inoue, E.; Ogawa, D.; Okada, Y.; Noyori, S.; Takagi, K.
Tetrahedron Lett. 2009, 50, 4643. (l) Sakai, N.; Uchida, N.; Konakahara, T.
Tetrahedron Lett. 2008, 49, 3437.
(1) (a) Diederich, F.; Stang, P. J.; Tykwinski, R. R. Acetylene Chemistry,
Chemistry, Biology and Material Science; Wiley-VCH: Weinheim, Ger-
many, 2005. (b) El-Jaber, N.; Estevez-Braun, A.; Ravelo, A. G.; Munoz-
Munoz, O.; Rodriguez-Afonso, A.; Murguia, J. R. J. Nat. Prod. 2003, 66,
722. (c) Gobbi, L.; Seiler, P.; Diederich, F. Angew. Chem., Int. Ed. 1999,
38, 674. (d) Saito, S. Chem. Pharm. Bull. 2005, 53, 1069.
(2) (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons,
Ltd: Chichester, England, 2004; pp 201-265. (b) de Meijere, A.; Diederich,
F., Eds. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2004; Vols. 1 and 2
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(3) (a) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (b)
Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834. (c)
Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874. (d) Yamamoto, Y.
Chem. ReV. 2008, 108, 3199
.
10.1021/ol100180j  2010 American Chemical Society
Published on Web 02/25/2010

of metal-catalyzed coupling reactions that use the alkyne
derivatives produced unique results. We found that employ-
ment of an alkynylsilane instead of a terminal alkyne as the
coupling partner permits a three-component coupling reaction
of an aryl iodide and two alkynylsilanes, producing an enyne
skeleton. Use of alkynylsilanes is of considerable interest,
owing to their commercial availability, relatively low toxicity,
high tolerance to functional groups, and common utilization
as a convenient reactant in previously described common
organic reactions.15 In this paper we report a palladium-
catalyzed arylalkynylation of aryl iodides, internal alkynes,
and alkynylsilanes, leading to the preparation of 1,1,2-
trisubstituted enyne derivatives. To our knowledge, direct
preparation of an enyne and a related alkene derivative
through trapping of an in situ generated alkenylpalladium
intermediate with organosilicon compounds has not been
previously reported.16
First, when the reaction of 4-iodotoluene, diphenylacety-
lene (3 equiv), and 1-phenyl-2-trimethylsilylacetylene (1.5
equiv) was conducted in dimethylacetamide (DMA) at 100
°C in the presence of 2 mol % of Pd(OAc)2 and 3 equiv of
K2CO3 as a model reaction, the 1,1,2-trisubstituted enyne
derivative 1 was obtained in 42% yield along with the
Sonogashira product 2 in 16% yield (run 1 in Table 1).17
The geometric structure of 1 was determined from NOE and
H-H COSY measurements.18 To improve the yield and
selectivity of the product 1, the effects of several additives
were examined. The phosphine ligand t-Bu3P was highly
effective for this reaction (runs 2-4). The addition of a
cosolvent was also an important determinant of product
yield. Thus, when MeOH (0.5% of solvent volume) was
Table 1. Optimization of Reaction Conditions
yield (%)c
run
molar ratioa
ligand
cosolvb
1
2
1
2
3
4
5
6
1:3:1.5
1:3:1.5
1:3:1.5
1:3:1.5
1:3:1.5
2:3:1
42
53
46
60
67
68
(80)
17
16
20
23
26
24
18
(17)
80
DPEPhos
Ph3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
t-Bu3P
MeOH
MeOH
MeOH
MeOH
7
2:4:1
2:4:1
8d
a Molarratio)p-iodotoluene:diphenylacetylene:alkynylsilane.b DMA/MeOH
) 99.5/0.5 (v/v). c NMR yield of runs 1-4 based on p-iodotoluene. NMR
(Isolated) yield of runs 6-8 based on an alkynylsilane. d Reaction was
carried out with phenylacetylene instead of alkynylsilane.
added, the reaction mixture was clean, and the yield
increased to 67% (run 5). Moreover, examination of
variation in the substrates molar ratio (aryl iodide:alkyne:
alkynylsilane ) 2:4:1) improved the selectivity and gave
the highest yield of the desired enyne 1 (run 7). In contrast,
use of phenylacetylene produced the Sonogashira-coupling
product 2 as the major product in 80% yield without
insertion of the alkyne (run 8).
To extend the generality of the coupling reaction, the
reaction with alkynylsilanes, aryl iodides, and symmetrical
internal alkynes was then carried out under the optimal
conditions (Table 2). For example, when the reaction was
(9) (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630. (b) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109,
2138.
(10) (a) Dillinger, S.; Bertus, P.; Pale, P. Org. Lett. 2001, 3, 1661. (b)
Le´tinois-Halbes, U.; Pale, P.; Berger, S. J. Org. Chem. 2005, 70, 9185.
(11) (a) Jones, L. A.; Sanz, S.; Laguna, M. Catal. Today 2007, 122,
403. (b) Gonzalez-Arellano, C.; Abad, A.; Corma, A.; Garcia, H.; Iglesias,
M.; Sanchez, F. Angew. Chem., Int. Ed. 2007, 46, 1536. (c) Panda, B.;
Sarkar, T. K. Tetrahedron Lett. 2010, 51, 301.
Table 2. Synthesis of Tetraarylsubstituted Enynes
(12) (a) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999, 1,
1267. (b) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc.
2001, 123, 4155.
(13) For selected papers for metal-catalyzed dimerizations with two
alkynes, see: (a) Barluenga, J.; Llorente, I.; Alvarez-Garcia, L. J.; Gonzalez,
J. M.; Campos, P. J.; Diaz, M. R.; Garcia-Granda, S. J. Am. Chem. Soc.
1997, 119, 6933. (b) Shirakawa, E.; Yoshida, H.; Kurahashi, T.; Nakao,
Y.; Hiyama, T. J. Am. Chem. Soc. 1998, 120, 2975. (c) Chang, S.; Yang,
S. H.; Lee, P. H. Tetrahedron Lett. 2001, 42, 4833. (d) Liu, Y.; Zhong, Z.;
Nakajima, K.; Takahashi, T. J. Org. Chem. 2002, 67, 7451. (e) Weng, W.;
Guo, C.; Celenligil-Cetin, R.; Foxman, B. M.; Ozerov, O. V. Chem.
Commun. 2006, 197. (f) Suginome, M.; Shirakura, M.; Yamamoto, A. J. Am.
Chem. Soc. 2006, 128, 14438. (g) Tsukada, N.; Ninomiya, S.; Aoyama,
Y.; Inoue, Y. Org. Lett. 2007, 9, 2919.
(14) Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6, 1527.
(15) For selected recent papers on organic reactions with alkynylsilanes,
see: (a) Lettan, R. B., II.; Scheidt, K. A. Org. Lett. 2005, 7, 3227. (b) Yadav,
J. S.; Raju, A. K.; Sunitha, V. Tetrahedron Lett. 2006, 47, 5269. (c)
Kitazawa, T.; Minowa, T.; Mukaiyama, T. Chem. Lett. 2006, 35, 1002.
(16) For selected recent papers on related three-component coupling
reactions, see: (a) Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4317.
(b) Zhou, C.; Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579. (c)
Zhang, X.; Larock, R. C. Org. Lett. 2003, 5, 2993. (d) Shibata, K.; Satoh,
T.; Miura, M. Org. Lett. 2005, 7, 1781. (e) Zhou, C.; Larock, R. C. J. Org.
Chem. 2005, 70, 3765. (f) Shibata, K.; Satoh, T.; Miura, M. AdV. Synth.
Catal. 2007, 349, 2317. See also ref 13d.
entry
Ar1
Ar2
Ar3
yield (%)a
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3, 75
4, 60
5, 70
6, 62
7, 60
8, 62
9, 80
10, 80
11, 40
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
3-pyridinyl
2-thiopheyl
4-F-C6H4
Ph
4-F-C6H4
4-F-C6H4
4-Me-C6H4
4-F-C6H4
4-F-C6H4
4-Me-C6H4
Ph
a Isolated yield based on an alkynylsilane.
(17) See the experimental details in the Supporting Information.
(18) Correlation between two benzene rings derived from an internal
alkyne was observed. See details in the Supporting Information.
run with alkynylsilanes derived from 1-(4-substituted-phen-
yl)-2-(trimethylsilyl)acetylene, the corresponding enyne de-
Org. Lett., Vol. 12, No. 6, 2010
1301

rivatives 3-6 were obtained in practical yields. When
alkynylsilanes containing a pyridine and thiophene ring were
used, the heterocycle-containing enynes 7 and 8 were
obtained in 60% and 62% yield. The electronic effect of the
substituted group on the benzene ring may not affect the
reactivity of the coupling reaction. Reactions with 4-fluor-
inated diphenylacetylene gave the corresponding enynes 9
and 10 in good yields. On the other hand, the use of an
internal alkyne containing a methyl group reduced the yield
of the desired product 11 to 40%.
phenyl group from iodobenzene favored the less-hindered
side (Me group) of the internal alkyne, and the alkynyl
moiety favored the more-hindered end (Ph group) of the
unsymmetrical alkyne. In addition, when a similar reaction
was carried out with an internal alkyne with a strong electron-
withdrawing group, the single coupling compound 18 with
the stereostructure shown in Scheme 2 was obtained in 58%
Similar reactions were then performed with several aryl
iodides under the optimal conditions (Table 3). Use of aryl
Scheme 2
Table 3. Synthesis of Tetrasubstituted Enynes
yield. Thus, the p-tolyl group was preferentially added to
the more electron-deficient side of the alkyne. The regiose-
lectivity of the reaction observed in the present study was
consistent with the results reported by several groups.16b,e
On the other hand, geometrical selectivity was not consistent
with the previous reports.16b,e,19 In Scheme 1, we observed
formation of cis-trans geometrical isomers 16 and 17, due
to isomerization of the alkenylpalladium intermediate.2
entry
Ar1
R
yield (%)a
1
2
3
4
2-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Me-C6H4
Ph
Ph
Ph
C3H7
12, 36 (10)b
13, 60 (E:Z ) 2:5)c
14, 50 (30)b
15, 60
a Isolated yield based on an alkynylsilane. b Yield of the Sonogashira-
type product is in parentheses. c Ratio of E:Z was determined by NOE and
H-H COSY.
When bis(trimethylsilylacetylene) was used under optimal
conditions, a corresponding enyne product was produced,
in which the other terminal trimethylsilyl group remained
intact. Thus, when an excess of iodobenzene was added
without isolation of the product and the reaction mixture was
further heated at 100 °C for 2 h, the four-component coupling
product 3 was obtained in 62% yield (Scheme 3).
iodides with an electron-donating group repressed the So-
nogashira-type reaction to afford the corresponding triaryl-
substituted enyne derivatives 13 and 15 in relatively good
yields. Use of aryl iodides with an electron-withdrawing
group gave the enyne derivative 14 and the Sonogashira-
type product in 30% yield. When an aryl iodide with an
ortho-substituted group was used, the product 12 was
obtained in low yield due to steric hindrance by the methyl
group.
Scheme 3
Moreover, to evaluate the regioselectivity of this type of
coupling reaction, we attempted the reaction with the
unsymmetrical alkyne 1-phenylpropyne. When the reaction
was carried out under our standard conditions, the Z-adduct
16 and the E-adduct 17 were isolated in 44% and 17% yields,
respectively, after standard purification (Scheme 1). The
Scheme 1
We then applied the present method for preparation of a
1,3-diene derivative using vinylsilane instead of alkynylsi-
lane. When a similar reaction of 4-iodoanisole, dipheny-
(19) Wu, M.-J.; Wei, L.-M.; Lin, C.-F.; Leou, S.-P.; Wei, L.-L.
Tetrahedron 2001, 57, 7839
.
1302
Org. Lett., Vol. 12, No. 6, 2010

lacetylene, and vinylsilane was performed, the (E,Z)-diene20
19, which is a Tamoxifen precursor, was directly obtained
in 65% yield through a single step (Scheme 4).16e,21
Scheme 5
Scheme 4a
a Ratio of E:Z was determined by NOE and H-H COSY.
To understand the reaction path, we performed several
control experiments. For instance, iodobenzene and alky-
nylsilane were used as reactants under the following
reaction conditions: 2 mol % of Pd(OAc)2, 8 mol % of
t-Bu3P, and 3 equiv of KF in DMA. As a result of this
reaction, the Sonogashira-type product diphenylacetylene
(20) was isolated in 74% yield (Scheme 5). In contrast,
when a similar reaction was conducted under our standard
conditions with K2CO3 and MeOH, diphenylacetylene (20)
was obtained in only 18% yield and a mixture of two
enyne derivatives 3 and 21 was simultaneously isolated.
Thus, we assumed that use of an activating reagent that
permits facile cleavage of a C-Si bond, such as fluoride
ion, favors transmetalation of an acetylide ion over
insertion of an internal alkyne on the Pd center, resulting
in the formation of an internal alkyne derivative as well
as the products obtained from a sila-Sonogashira-type
(Hiyama-type) coupling reaction.8
We demonstrated an unprecedented single-step synthesis
of enyne derivatives through a Pd-catalyzed arylalkynylation
of aryl iodides, internal alkynes, and alkynylsilanes. In
particular, we found that when the coupling reaction was
performed under relatively mild conditions, which consisted
of a methanol solution containing K2CO3, the formation of
an enyne derivative from an aryl iodide, an internal alkyne,
and an alkynylsilane preferentially formed a Sonogashira-
type product.
Acknowledgment. This work was partially supported by
a grant from the Japan Private School Promotion Foundation
supported by MEXT. The authors deeply thank Shin-Etsu
Chemical Co., Ltd., for the gift of the organosilicon com-
pounds.
Supporting Information Available: The experimental
procedures, spectroscopic data for the prepared compounds,
and ORTEP drawings of compounds 7, 12, and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Because a trace amount of the byproduct involving a TMS group
on the terminal carbon was isolated, this reaction may proceed through a
Heck-type reaction path.
(21) Shao, L.-X.; Shi, M. Org. Bimol. Chem. 2005, 3, 1828
.
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