Facile synthesis of 2-alkynyl buta-1,3-dienes via Sonogashira cross-coupling methodology

Article abstract of DOI:10.1021/jo051434l

2-Alkynyl buta-1,3-dienes 4 can be synthesized in moderate to high yields by the reactions of the corresponding diiodides 1 derived from methylenecyclopropanes with substituted alkynes 2 via Sonogashira cross-coupling in the catalysis of Pd(PPh₃

Full text of DOI:10.1021/jo051434l

architectures.8 Previously, we synthesized some interest-
ing molecules with a buta-1,3-diene structure by various
coupling reactions with 1,1-disubstituted 2,4-diiodo-but-
1-enes 1 derived from methylenecyclopropanes (MCPs)
and substituted alkenes, boronic acids, or Grignard
reagents as the substrates since buta-1,3-dienes and its
derivatives are important in organic synthesis, especially
as starting materials in Diels-Alder reactions.9 These
interesting results led us to a further detailed study of
the synthesis of 2-alkynyl buta-1,3-dienes10-12 by a
Sonogashira-type reaction because enynes are also in-
teresting compounds that can be found in many naturally
occurring and biologically active compounds.13 Herein, we
report the synthesis of 2-alkynyl buta-1,3-dienes from 1,1-
disubstituted 2,4-diiodo-but-1-dienes and alkynes via a
Sonogashira-type reaction in the catalysis of Pd(PPh3)4/
CuI.
Facile Synthesis of 2-Alkynyl
Buta-1,3-dienes via Sonogashira
Cross-Coupling Methodology
Li-Xiong Shao and Min Shi*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032 China
mshi@pub.sioc.ac.cn
Received July 11, 2005
Results and Discussion
2-Alkynyl buta-1,3-dienes 4 can be synthesized in moderate
to high yields by the reactions of the corresponding diiodides
1 derived from methylenecyclopropanes with substituted
alkynes 2 via Sonogashira cross-coupling in the catalysis of
Pd(PPh3)4/CuI.
As a first try, we searched for a protocol for the cross-
coupling reaction of 1,1-diphenyl-2,4-diiodo-but-1-ene 1a
(5) (a) Mongin, O.; Porres, L.; Moreaux, L.; Merta, J.; Blanchard-
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Introduction
The palladium-catalyzed coupling of terminal alkynes
with aryl and vinyl halides in the presence of catalytic
CuI and an amino base (the Sonogashira reaction) is one
of the important and widely used carbon-carbon bond-
forming reactions in organic synthesis.1,2 This method has
been successfully applied in the synthesis of natural
compounds,3 biologically active molecules,4 new organic
materials for optical and microelectronic application,5
dendrimeric, oligomeric, polymeric materials,6 macro-
cycles with acetylene links,7 polyalkynylated molecules,
and, generally, as a route to new intriguing molecular
* Corresponding author. Fax: 86-21-64166128.
(1) For selected reviews and articles on the Sonogashira alkynyla-
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Lett. 1975, 16, 4467. (b) Sonogashira, K. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, Chapter 2.4, p 521 and references therein. (c) Sonogashira,
K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (d) Sonogashira,
K. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., de Meijere, A., Eds.; Wiley-VCH: New York, 2002. (e)
Burnagin, N. A.; Sukhomlinova, L. I.; Luzikova, E. V.; Tolstaya, T. P.;
Beletskaya, I. P. Tetrahedron Lett. 1996, 37, 897. (f) Hundertmark,
T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
(g) Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.
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Chem. 1998, 63, 5568. (b) Tobe, Y.; Utsumi, N.; Nagano, A.; Naemura,
K. Angew. Chem., Int. Ed. 1998, 37, 1285. (c) Onitsuka, K.; Fujimoto,
M.; Ohshiro, N.; Takahashi, S. Angew. Chem., Int. Ed. 1999, 38, 689.
(9) (a) Shi, M.; Shao, L.-X. Synlett 2004, 807 and references therein.
(b) Shao, L.-X.; Shi, M. Org. Biomol. Chem. 2005, 3, 1828 and
references therein.
(10) (a) Maier, M. E. Synlett 1995, 13. (b) Grissom, J. W.; Gunawar-
dena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453. (c)
Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497.
(11) (a) Kuhnt, D.; Anke, T.; Besl, H.; Bross, M.; Herrmann, R.;
Mocek, U.; Steffan, B.; 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.
(12) (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, G. W., II;
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.
(2) For a recent review, see: Negishi, E.; Anastasia, L. Chem. Rev.
2003, 103, 1979.
(3) (a) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew. Chem.,
Int. Ed. 2001, 40, 603. (b) Toyota, M.; Komori, C.; Ihara, M. J. Org.
Chem. 2000, 65, 7110. (c) Ioshimura, F.; Kawata, S.; Hirama, M.
Tetrahedron Lett. 1999, 40, 8281.
(4) (a) Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith,
N. D.; Anderson, J.; Bristow, L.; Brodkin, J.; Jiang, X.; McDonald, I.;
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10.1021/jo051434l CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/17/2005
J. Org. Chem. 2005, 70, 8635-8637
8635

TABLE 1. Sonogashira Coupling Reaction of Diiodide
1a and Phenylacetylene 2a under Various Reaction
Conditions
TABLE 2. Sonogashira-type Reaction of Diiodides 1
(0.25 mmol) and Aryl-Substituted Alkynes 2 (0.30 mmol)
under the Optimized Reaction Conditions
entry
1 (R1/R2)
2 (R3)
yield (%)a
yield (%)c
1
2
3
4
5
6
7
8
9
1b (p-MeOC6H4/p-MeOC6H4) 2a (C6H5)
4b, 91
4c, 87
4d, 97
4e, 71
entrya
catalyst
baseb
temp (°C)
3
4a
1c (p-MeC6H4/p-MeC6H4)
2a
2a
2a
1d (p-ClC6H4/p-ClC6H4)
1
2
Pd(PPh3)4/CuI
Pd(PPh3)4/CuI
Pd(PPh3)4/CuI
Pd(PPh3)4/CuI
Pd(PPh3)4/CuI
iPr2NH
Et2NH
reflux
reflux
reflux
100
-
-
-
-
-
-
-
-
60
1e (Me/p-EtOC6H4)
90
1b
2b (p-MeOC6H4) 4f, 82
3
Et3N
85
1a (C6H5/C6H5)
2b
2b
4g, 99
4h, 99
4i, 78
4j, 56
4k, 60
4l, 76
4
pyridine
morpholine
Pd(OAc)2/CuI/PPh3 Et2NH
trace
24
1d
1b
1a
5
100
d
2c (p-ClC6H4)
6
reflux
reflux
reflux
reflux
reflux
64
2c
2c
2c
7
PdCl2(PPh)3/CuI
Pd(OAc)2/CuI
CuIe
Et2NH
Et2NH
Et2NH
Et2NH
76
10 1d
11 1e
a Isolated yields.
8
51
9
40 30
60 22
10
NiCl2(PPh3)2/CuI
a Unless otherwise specified, all the reactions were carried out
using 1a (0.25 mmol), 2a (0.3 mmol) in the catalysis of Pd(PPh3)4
(0.1 equiv) or NiCl2(PPh3)2 and CuI (0.2 equiv) at the appropriate
temperatute for 24 h. b As the base and solvent. c Isolated yields.
d A quantity of 0.4 equiv of PPh3 was used. e A quantity of 0.2 equiv
of CuI was used.
TABLE 3. Sonogashira-type Reaction of Diiodides 1
(0.25 mmol) and Alkyl-Substituted 2 (0.30 mmol) under
the Optimized Reaction Conditions
(0.25 mmol) with phenylacetylene 2a (0.30 mmol). We
were pleased to find that diiodide 1a could react with
phenylacetylene 2a in the presence of 10 mol % of
i
Pd(PPh3)4, 20 mol % of CuI and Pr2NH as the base and
entry
1 (R1/R2)
2 (R3)
yield (%)a
solvent under reflux temperature to give the desired
product 4a within 24 h with a 60% yield as the sole
product (Table 1, entry 1).
1
2
3
4
5
6
7
8
9
1b (p-MeOC6H4/p-MeOC6H4) 2d (CH2OH)
4m, 30
4n, 49
4o, 28
4p, 92
4q, 78
4r, 57
4s, 51
4t, 47
4u, 29
1c (p-MeC6H4/p-MeC6H4)
2d
1a (C6H5/C6H5)
2d
The structure of 4a was determined by 1H and 13C
NMR spectroscopic data and X-ray diffraction (Support-
ing Information).14
1b
1c
1a
1b
1c
1a
2e (CH2OBn)
2e
2e
2f (n-C4H9)
The reaction conditions were further optimized, and
some typical results are listed in Table 1. In a second
experiment, we found that when Et2NH was used as the
base and solvent, the coupling product 4a was obtained
with a 90% yield also as a sole product (Table 1, entry
2). When Et2NH was replaced by Et3N or morpholine,
4a was similarly obtained as the sole product as well but
in somewhat lower yields (Table 1, entries 3 and 5). When
pyridine was used as the base and solvent, no desired
product was obtained (Table 1, entry 4). In addition, the
coupling product 4a was obtained in lower yields using
mixed palladium(II) catalysts such as Pd(OAc)2/CuI/PPh3,
PdCl2(PPh3)2/CuI, and Pd(OAc)2/CuI (Table 1, entries
6-8). In the case of some other catalysts such as CuI or
NiCl2(PPh3)2, the coupling product 4a was obtained in
much lower yields along with the elimination product 3
(Table 1, entries 9 and 10). Thus, the optimized reaction
conditions for this Sonogashira-type reaction are
Pd(PPh3)4/CuI as the catalyst and Et2NH as the base and
solvent under reflux temperature (Table 1, entry 2).
2f
2f
a Isolated yields.
To survey the generality of this Sonogashira-type
reaction, we next investigated the reactions using some
other diiodides 1 with 2a or other aryl-substituted
alkynes 2b and 2c as the substrates under the optimized
conditions. The results are shown in Table 2. As can be
seen from Table 2, the corresponding 2-alkynyl buta-1,3-
dienes 4 were obtained in moderate to excellent yields
in most cases (Table 2). For substrates 1 in which both
R1 and R2 are aromatic groups such as 1a, 1b, 1c, and
1d, the cross-coupling reactions with alkynes 2a and 2b
proceeded very well to give the desired products 4 in good
to excellent yields (Table 2, entries 1-3, 5-7). For aryl-
substituted alkyne 2c with an electron-withdrawing
group (Cl-) on the benzene ring, the corresponding
products 4 were obtained in relatively lower yields (Table
2, entries 8-10). For substrate 1e in which R1 is a methyl
group and R2 is an aryl group, the reactions also
proceeded smoothly to give the desired products in good
yields (Table 2, entries 4 and 11).
(14) The X-ray data of 4a have been deposited in CCDC with the
number 227450. Empirical formula: C24H18; formula weight: 306.38;
crystal color, habit: colorless, prismatic; crystal system: triclinic;
lattice type: primitive; lattice parameters: a ) 9.8838(18) Å, b )
10.5056(18) Å, c ) 10.8938(19) Å, R ) 117.681(3)°, â ) 99.163(4)°, γ )
108.395(4)°, V ) 885.3(3) Å3; Space group: P1h; Z ) 2; Dcalcd ) 1.149
g/cm3; F000 ) 324; diffractometer: Rigaku AFC7R; residuals: R; Rw
) 0.0480, 0.0881.
We next explored some alkyl group substituted alkynes
2d-f for this transformation. The results are sum-
marized in Table 3. The reactions proceeded smoothly
8636 J. Org. Chem., Vol. 70, No. 21, 2005

alkyne 2 (0.30 mmol), Pd(PPh3)4 (0.025 mmol), and CuI (0.05
mmol) were added into a Schlenk tube with degassed Et2NH
(1.0 mL). The reaction mixture was stirred under reflux for about
24 h. The solvent was removed under reduced pressure, and then
the residue was purified by a flash column chromatography.
but gave the desired products in somewhat lower yields
in contrast to the aryl-substituted alkynes 2a-c (Table
3). For substrate 1, in which both R1 and R2 are aromatic
groups such as 1a, 1b, and 1c, the Sonogashira cross-
coupling reactions with alkyne 2d furnished the corre-
sponding products 4 in 28-49% yields (Table 3, entries
1-3). For alkyl-substituted alkyne 2e in which the
hydroxyl group was protected by a benzyl group, the
yields of the corresponding products 4 were raised
dramatically for the reactions with diiodides 1a-c to 57-
92% (Table 3, entries 4-6). For alkyne 2f, the Sonogash-
ira cross-coupling products 4 were obtained in moderate
yields (Table 3, entries 7-9).
Product 4a: A yellow solid, mp 117-120 °C; 1H NMR (CDCl3,
300 MHz, TMS) δ 5.31 (dd, 1H, J ) 1.8, 10.5 Hz), 5.95 (dd, 1H,
J ) 1.8, 16.8 Hz), 6.59 (dd, 1H, J ) 10.5, 16.8 Hz), 7.19-7.36
(m, 13H, Ar), 7.49-7.53 (m, 2H, Ar). 13C NMR (CDCl3, 75 MHz,
TMS) δ 87.8, 94.8, 117.2, 119.9, 123.6, 127.5, 127.8, 127. 9, 128.0,
128.1, 128.3, 130.5, 130.6, 131.4, 134.6, 140.6, 141.90, 149.13.
IR (CH2Cl2) ν 3058, 3055, 2911, 2837, 1948, 1819, 1596, 1485,
1441 cm-1
.
MS (%) m/e 306 (M+, 100). Anal. Calcd for
C
24H18: C, 94.08%; H, 5.92%. Found: C, 93.98%; H, 5.91%.
Thus, the novel Sonogashira-type reaction of diiodides
1 and alkynes 2 to give 2-alkynyl buta-1,3-dienes 4 in
moderate to high yields has been developed.
Acknowledgment. We thank the State Key Project
of Basic Research (Project 973) (No. G2000048007),
Shanghai Municipal Committee of Science and Technol-
ogy, and the National Natural Science Foundation of
China for financial support (203900502, 20472096, and
20272069).
Conclusions
Some 2-alkynyl buta-1,3-dienes were synthesized by
the Sonogashira-type reaction of diiodides 1, derived from
the ring-opening reaction of MCPs with iodine, with some
substituted alkynes 2 in the catalysis of Pd(PPh3)4/CuI.
A range of alkynes has been examined. Efforts are in
progress to investigate the reaction mechanism and the
subsequent transformation thereof.
Supporting Information Available: Spectroscopic data
of the compounds shown in Tables 1-3, X-ray crystal data of
4a, and detailed descriptions of experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
General Reaction Procedure for the Sonogashira-type
Reaction. Under an argon atmosphere, diiodide 1 (0.25 mmol),
JO051434L
J. Org. Chem, Vol. 70, No. 21, 2005 8637