Mild and selective palladium-catalyzed dimerization of terminal alkynes to form symmetrical (Z,Z)-1,4-dihalo-1,3-dienes

Article abstract of DOI:10.1021/jo0486645

A regioselective and stereoselective palladium-catalyzed dimerization of terminal alkynes method for the synthesis of symmetrical (Z,Z)-1,4-dihalo-1,3- dienes is presented. In the presence of a catalytic amount of PdX₂ and 3 equiv of CuX_2<

Full text of DOI:10.1021/jo0486645

SCHEME 1
Mild and Selective Palladium-Catalyzed
Dimerization of Terminal Alkynes To Form
Symmetrical (Z,Z)-1,4-Dihalo-1,3-dienes
Jin-Heng Li,* Yun Liang, and Ye-Xiang Xie
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research, College of Chemistry and Chemical
Engineering, Hunan Normal University, Changsha 410081,
China
jhli@hunnu.edu.cn
selectively construct diene skeletons is a promising area
for exploration. Here, we report a novel and selective
palladium-catalyzed dimerization of alkynes method for
the synthesis of symmetrical 1,3-dienes. Furthermore,
there are two halides at the 1,4-position of these 1,3-
dienes, which provides an attractive and useful route to
introduce new groups for synthesizing natural products
(Scheme 1).
Received August 2, 2004
Abstract: A regioselective and stereoselective palladium-
catalyzed dimerization of terminal alkynes method for the
synthesis of symmetrical (Z,Z)-1,4-dihalo-1,3-dienes is pre-
sented. In the presence of a catalytic amount of PdX2 and 3
equiv of CuX2 (X ) Cl and Br), terminal alkynes were
dimerized to afford (Z,Z)-1,4-dihalo-1,3-dienes in good yields.
The results showed that the effect of solvent had a funda-
mental influence on the chemoselectivity of the dimerization
reaction. The mechanism of the palladium-catalyzed dimer-
ization reaction is also discussed.
We have recently reported the palladium-catalyzed
cyclotrimerization of alkynes to form benzenes, and the
effect of solvent was found to play a crucial role in the
chemoselectivity.7 For example, in BuOH/C6H6, treat-
ment of phenylacetylene (1a) with PdCl2 and CuCl2
formed only a red oil,7a whereas in H2O, 1,3,5-diphenyl-
benzene was isolated in addition to the red oil.7b Interest-
ingly, 60% yield of a diene 2a [(Z,Z)-1,3-dichloro-1,4-
diphenylbuta-1,3-diene] was obtained from the cor-
responding substrate 1a when MeCN was used as the
solvent in the presence of 5 mol % of PdCl2 and 2 equiv
of CuCl2 (entry 1 in Table 1). The results showed that
both CuCl2 and solvent affected the reaction (entries
1-4). The yield of 2a was increased to 85% with increas-
ing the loading of CuCl2 to 3 equiv (entry 2). Further
increasing the loading of CuCl2 to 4 equiv resulted in a
slight decrease in the yield (entry 3). No desired product
was isolated in benzene (entry 4). For PdBr2- and CuBr2-
catalyzed dimerization of 1a, however, only 1,2-dibro-
mostryrene was observed in 100% yield when MeCN was
used as the solvent (entry 5). After a series of attempts
(entries 5-8), MeCN/C6H6 (1:50) was observed as the
most effective solvent. With 5 mol % of PdBr2 and 3 equiv
of CuBr2 as the catalytic system, 91% yield of (Z,Z)-1,3-
dibromo-1,4-diphenylbuta-1,3-diene (3a) was obtained in
MeCN/C6H6 (1:50) (entry 7). The results also demon-
strated that both PdBr2 and CuBr2 were necessary for
the reaction (entries 9 and 10). Noteworthy was that
similar results were found in the presence of 3 equiv of
CuBr2 when 5 mol % of PdCl2 was used to replace the
expensive PdBr2 (entry 11).
1,3-Dienes are useful building blocks in organic syn-
thesis1 and a recurring functional group in many natural
products and bioactive compounds.2 For these reasons,
the development of efficient and selective methods for the
synthesis of 1,3-dienes remains an area of current
interest.3-6 A particularly effective approach to the
synthesis of functionalized dienes is through the pal-
ladium-catalyzed transformations including cross-cou-
pling reactions4,5 and oligomerization reactions.4e,6 How-
ever, few reports on the palladium-catalyzed oligomeri-
zation of an alkyne to a substituted diene have been
described.4e,6 Thus, the development of novel palladium-
catalyzed oligomerization of alkyne transformations to
(1) Luh, T.-Y.; Wong, K.-T. Synthesis 1993, 349.
(2) (a) Rappoport, Z. The Chemistry of Dienes and Polyenes; John
Wiley & Sons: Chichester, 1997; Vol. 1. (b) Rappoport, Z. The
Chemistry of Dienes and Polyenes; John Wiley & Sons: Chichester,
2001; Vol. 2.
(3) (a) Yamaguchi, S.; Jin, R.-Z.; Tamao, K.; Sato, F. J. Org. Chem.
1998, 63, 10060 and references therein. (b) Fukuhara, K.; Takayama,
Y.; Sato, F. J. Am. Chem. Soc. 2003, 125, 6884.
(4) For reviews, see: (a) Larock, R. C. Comprehensive Organic
Transformations, 2nd ed.; Wiley-VCH: New York, 1999; Chapter 2.
(b) Vasil’ev, A. A.; Sterebryakov, E. P. Russ. Chem. Rev. 2001, 70, 735.
(c) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reac-
tions; Wiley-VCH: Weinheim, 1998. (d) Miyaura, N. Cross-Coupling
Reaction; Springer: Berlin, 2002. (e) Negishi, E., Ed. Handbook of
Organopalladium Chemistry for Organic Synthesis; Wiley-Inter-
science: New York, 2002.
A number of terminal alkynes underwent the dimer-
ization reaction smoothly in the presence of a catalytic
amount of PdX2 and 3 equiv of CuX2, and the results are
summarized in Table 2. The results showed that both
aromatic alkynes 1b and aliphatic alkynes 1c-e were
dimerized to afford the corresponding (Z,Z)-1,4-dihalo-
1,3-alkadienes 2b-e and 3b-e in excellent yields. For
example, in the presence of 5 mol % of PdCl2, 3 equiv of
(5) For recent palladium-catalyzed cross coupling reactions to
synthesize 1,3-dienes, see: (a) Zeng, F.; Negishi, E. Org. Lett. 2002, 4,
703. (b) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D.
Org. Lett. 2003, 5, 1597. (c) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E. J.
Am. Chem. Soc. 2003, 125, 13636. (d) Qian, M.; Huang, Z.; Negishi, E.
Org. Lett; 2004, 6, 1531. (c) Zeng, X.; Qian, M.; Hu, Q.; Negishi, E.
Angew. Chem., Int. Ed. 2004, 43, 2259 and references therein.
(6) For palladium-catalyzed oligomerization of alkynes to synthesize
1,3-dienes, see: (a) Kawanami, Y.; Yamamoto, K. Synlett 1995, 1232.
(b) Wang, Z.; Lu, X.; Lei, A.; Zhang, Z. J. Org. Chem. 1998, 63, 3806.
(c) Zhao, L.; Lu, X. Org. Lett. 2002, 4, 3903 and references therein. (d)
Uno, T.; Wakayanagi, S.; Sonoda, Y.; Yamamoto, K. Synlett 2003, 1997
and references therein.
(7) (a) Li, J.-H.; Jiang, H.-F.; Chen, M.-C. J. Org. Chem. 2001, 66,
3627. (b) Li, J.-H.; Xie, Y.-X. Synth. Commun. 2004, 34, 1737.
10.1021/jo0486645 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/07/2004
J. Org. Chem. 2004, 69, 8125-8127
8125

TABLE 1. Palladium-Catalyzed Dimerization of
Phenylacetylene 1aa
CuX2
t
yield
(%)
As outlined in Scheme 2, we have formulated a working
mechanism for the palladium-catalyzed dimerization of
terminal alkynes that is based on the proposed mecha-
nism of the cyclotrimerization reaction.4e,7-9 The cis-
addition of alkyne and PdX2 proceeded to form cis-
halopalladation intermediate 5. Then intermediate 5
underwent a consecutive cis-addition of an alkyne to
afford new halopalladation intermediate 6. With the aid
of CuX2, both the cleavage of C-Pd σ-bond of intermedi-
ate 610 and the addition of bromide atom occurred to
afford Pd(0) and the desired product 2 or 3. Finally, the
active Pd(II) species were regenerated by the oxidation
reaction of Pd(0) with CuX2 to start a new catalytic cycle.
entry
PdX2
(equiv)
solvent
MeCN
MeCN
MeCN
benzene
(h)
1b
PdCl2
PdCl2
PdCl2
PdCl2
CuCl2 (2)
CuCl2 (3)
CuCl2 (4)
CuCl2 (3)
12 60 (2a)
10 85 (2a)
10 81 (2a)
2b
3b
4b
12
4
0
0
5c
PdBr2 CuBr2 (3) MeCN
PdBr2 CuBr2 (3) benzene
6b
12 35 (3a)
7d
PdBr2 CuBr2 (3) MeCN/benzene
PdBr2 CuBr2 (3) MeCN/benzene
8
8
4
91 (3a)
63 (3a)
0
8e
9d,f
10b,d
11d
0
CuBr2 (3) MeCN/benzene
PdBr2
PdCl2
0
MeCN/benzene 12 trace (3a)
CuBr2 (3) MeCN/benzene 90 (3a)
8
a Under otherwise indicated, the reaction conditions were as
follows: 1a (1 mmol), PdX2 (5 mol %), and CuX2 in the indicated
solvent (5 mL) at room temperature. bRed oils were obtained. The
structure of the red oils cannot be confirmed by 1H NMR, 13C NMR,
SCHEME 2
c
and MS analysis. A mixture of (E)- and (Z)-1,2-dibromostyrene
was obtained in 100% yield, and the ratio is 1:1. dMeCN/benzene
e
(1:50, 5 mL). MeCN/benzene (1:10, 5 mL). A 1:1 mixture of (E)-
and (Z)-1,2-dibromostyrene was obtained in 35% yield. fOnly (E)-
1,2-dibromostyrene was obtained in 100% yield.
TABLE 2. Palladium-Catalyzed Dimerization of
Terminal Alkynesa
In summary, we have developed a novel PdX2-catalyzed
dimerization of alkynes with 1,4-dihalo addition protocol,
providing an efficient, highly regio- and stereoselective
route to synthesize symmetrical (1Z,3Z)-1,4-dihalo-1,3-
dienes. Because a variant of terminal alkynes can be
readily available, the palladium-catalyzed dimerization
a Conditions A: 1 (1 mmol), PdCl2 (5 mol %), and CuCl2 (3 equiv)
in MeCN (5 mL) at room temperature. Conditions B: 1 (1 mmol),
PdBr2 (5 mol %), and CuBr2 (3 equiv) in MeCN/benzene (1:50, 5
mL) at room temperature. bIsolated yield.
(8) For reviews on the synthesis of benzenes by using palladium
catalysts, see: (a) Schore, N. E. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Elmsford,
New York, 1991; Vol. 5, p 1129. (b) Grotijahn, D. B. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Hegedus, L. S., Eds.; Pergamon: Tarrytown, NY, 1995; Vol. 12, p
741. (c) Gevorgyan, V.; Yamamoto, Y. J. Organomet. Chem. 1999, 576,
232. (d) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. (e) Rubin
M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003, 2265.
(9) For representative papers on the synthesis of benzenes using
palladium catalysts, see: (a) Zingales, F. Ann. Chem. 1962, 52, 1174.
(b) Dietl, H.; Reinheimer, H.; Moffat, J.; Maitlis, P. M. J. Am. Chem.
Soc. 1970, 92, 2276. (c) Reinheimer, H.; Moffat, J.; Maitlis, P. M. J.
Am. Chem. Soc. 1970, 92, 2285. (d) Maitlis, P. M. Acc. Chem. Res. 1976,
9, 93. (e) Kelley, E. A.; Maitlis, P. M., J. Chem. Soc., Dalton Trans.
1979, 167. (f) Maitlis, P. M. J. Organomet. Chem. 1980, 200, 161. (g)
Canziani, F.; Allevi, C.; Garlaschelli, L.; Malatesta, M. C.; Albinati,
A.; Ganazzoli, F. J. Chem. Soc., Dalton Trans. 1984, 187.
CuCl2, and 5 mL of MeCN, the dimerization reaction of
1e, a bulky aliphatic alkyne, was carried out smoothly
to afford (Z,Z)-3,6-dichloro-2,2,7,7-tetramethylocta-3,5-
diene (2e) in quantitative yield (entry 7). Similarly, a
100% yield of (Z,Z)-3,6-dibromo-2,2,7,7-tetramethylocta-
3,5-diene (3e) was obtained by using 5 mol % of PdBr2, 3
equiv of CuBr2, and 5 mL of MeCN/C6H6 (1:50) as the
reaction conditions (entry 8).
For palladium-catalyzed reaction of 4-octyne (1f), a
mid-alkyne, 90% yield of the corresponding cyclotrimer-
ization product 4 was obtained exclusively in the presence
of PdCl2 (5 mol %), CuCl2 (3 equiv), and MeCN (5 mL) at
room temperature (eq 1).7a
(10) It has been reported that Cu(II) as an oxidant could cleave the
C-Pd σ-bond; see: (a) Ba¨ckvall, J, E.; Nordberg, R. E. J. Am. Chem.
Soc. 1980, 10, 02, 393. (b) Ji, J.; Zhang C.; and Lu, X. J. Org. Chem.
1995, 60, 1160. (c) Zhu, G.; Ma, S.; Lu, X.; Huang, Q. J. Chem. Soc.,
Chem. Commun. 1995, 271. (d) Li, J.-H.; Jiang, H.-F.; Feng A.-Q.; Jia,
L.-Q. J. Org. Chem. 1999, 64, 5984.
8126 J. Org. Chem., Vol. 69, No. 23, 2004

(Z,Z)-1,3-Dibromo-1,4-diphenylbuta-1,3-diene (3a): white
solid; mp 120-122 °C (lit.3a mp 121-123 °C); 1H NMR (300 MHz)
δ 7.69 (d, J ) 8.2 Hz, 4H), 7.44-7.35 (m, 8H); 13C NMR (75 MHz)
of terminal alkynes represents an attractive means for
the synthesis of (1Z,3Z)-1,4-dihalo-1,3-dienes. Further
applications of this reaction and these products in organic
synthesis are underway in our laboratory.
δ 139.3, 130.0, 129.2, 128.5, 128.1, 127.7; IR (CH2Cl2) 1606, 1568,
81
1487, 1444, 863, 779 cm-1; LRMS (EI, 20 eV) m/z 366 (M+
(
-
Br), 5), 364 (M+ 79Br), 16), 205 (M+ - Br, 25), 204 (M+ - 2Br,
(
100); HRMS (EI) for C16H1279Br2 (M+) calcd 363.9286, found
363.9312.
Experimental Section
Typical Experimental Procedure for the Palladium-
Catalyzed Dimerization of Terminal Alkynes. A mixture
of alkyne 1 (1.0 mmol), PdX2 (5 mol %), CuX2 (3 equiv), and the
indicated solvent (5 mL) was stirred at room temperature until
complete consumption of starting material as judged by TLC.
After the mixture was filtered and evaporated, the residue was
purified by flash column chromatography to afford 2, 3, or 4
(hexane).
(Z,Z)-1,3-Dibromo-1,4-di(p-methylphenyl)buta-1,3-di-
ene (3b): white solid; mp 124-127 °C; 1H NMR (400 MHz) δ
7.58 (d, J ) 8.4 Hz, 4H), 7.31 (s, 2H), 7.18 (d, J ) 8.0 Hz, 4H),
2.38 (s, 6H); 13C NMR (100 MHz) δ 139.4, 129.2, 129.0, 127.6,
127.5, 127.4, 21.2; IR (CH2Cl2) 1606, 1568, 1487, 1444, 863, 779
cm-1; LRMS (EI, 20 eV) m/z 392 (M+ 81Br), 3), 390 (M+ 79Br),
( (
2), 313 (M+ - Br, 23), 232 (M+ - 2Br, 100); HRMS (EI) for
C18H1679Br2 (M+) calcd 389.9641, found 389.9619.
(Z,Z)-5,8-Dibromododeca-5,7-diene (3c): colorless oil; 1H
NMR (300 MHz) δ 6.55 (s, 2H), 2.52 (t, J ) 7.5 Hz, 4H), 1.63-
1.53 (m, 4H), 1.40-1.30 (m, 4H), 0.93 (t, J ) 7.3 Hz, 6H); 13C
NMR (75 MHz) δ 131.9, 125.7, 41.8, 30.4, 21.6, 13.8; IR (CH2-
Cl2): 1604, 1551, 1421, 896 cm-1; LRMS (EI, 20 eV) m/z 324
(Z,Z)-1,3-Dichloro-1,4-diphenylbuta-1,3-diene (2a): white
solid; mp 117-118 °C; 1H NMR (300 MHz) δ 7.74 (d, J ) 8.4
Hz, 4H), 7.44-7.36 (m, 6H), 7.34 (s, 2H); 13C NMR (75 MHz) δ
136.2, 129.2, 128.5, 126.6, 122.0, 118.2; IR (CH2Cl2) 1605, 1566,
37
1489, 1445, 864, 782 cm-1; LRMS (EI, 20 eV) m/z 276 (M+
(
-
Cl), 31), 274 (M+ 35Cl), 48), 241 (M+ - Cl, 15), 239 (M+ - 2Cl,
(
(M+ 81Br), 100), 322 (M+ 79Br), 52), 243 (M+ - Br, 25), 201 (16),
( (
55), 204 (100); HRMS (EI) for C16H1235Cl2 (M+) calcd 274.0316,
found 274.0316.
163 (M+ - 2Br, 10); HRMS (EI) for C12H2079Br2 (M+) calcd
321.9932, found 321.9922.
(Z,Z)-9,12-Dibromoeicosa-9,11-diene (3d): colorless oil; 1H
NMR (400 MHz) δ 6.54 (s, 2H), 2.51 (t, J ) 7.2 Hz, 4H), 1.29-
1.28 (m, 24H), 0.88 (t, J ) 7.9 Hz, 6H); 13C NMR (100 MHz) δ
132.0, 125.7, 42.1, 31.8, 29.3, 29.2, 28.5, 28.3, 22.7, 14.1; IR (CH2-
Cl2) 1605, 1551, 1421, 896, 704 cm-1; LRMS (EI, 20 eV) m/z 436
(Z,Z)-1,3-Dichloro-1,4-di(p-methylphenyl)buta-1,3-di-
ene (2b): white solid; mp 124-125 °C; 1H NMR (400 MHz) δ
7.62 (d, J ) 8.2 Hz, 4H), 7.29 (s, 2H), 7.20 (d, J ) 8.0 Hz, 4H),
2.38 (s, 6H); 13C NMR (100 MHz) δ: 139.3, 136.0, 134.9, 129.2,
126.5, 121.2, 21.2; IR (CH2Cl2) 1605, 1566, 1489, 1445, 864, 782
cm-1; LRMS (EI, 20 eV) m/z 304 (M+ 37Cl), 3), 302 (M+ 35Cl),
( (
(M+ 81Br), 100), 434 (M+ 79Br), 43), 357 (M+ - Br, 5), 275 (M+
( (
7), 267 (M+ - Cl, 100), 232 (M+ - 2Cl, 96); HRMS (EI) for
C18H1635Cl2 (M+) calcd 302.0629, found 302.0626.
- 2Br, 21); HRMS (EI) for C20H3681Br2 (M+) calcd 436.1165,
found 436.1163.
(Z,Z)-5,8-Dichlorododeca-5,7-diene (2c): colorless oil; 1H
NMR (300 MHz) δ 6.40 (s, 2H), 2.40 (t, J ) 7.2 Hz, 4H), 1.62-
1.52 (m, 4H), 1.40-1.32 (m, 4H), 0.92 (t, J ) 7.9 Hz, 6H); 13C
NMR (75 MHz) δ 137.7, 120.3, 39.6, 29.6, 21.8, 13.8; IR (CH2-
Cl2): 1605, 1466, 1430, 780 cm-1; LRMS (EI, 20 eV) m/z 236
(Z,Z)-3,6-Dibromo-2,2,7,7-tetramethyl-octa-3,5-diene
1
(3e): white solid; mp 74-76 °C; H NMR (400 MHz) δ 6.71 (s,
2H), 1.25 (s, 18H); 13C NMR (75 MHz) δ: 144.7, 123.6, 40.3, 29.6;
IR (CH2Cl2) 1605, 1551, 1421, 896, 763 cm-1; LRMS (EI, 20 eV)
m/z 324 (M+ 81Br), 100), 322 (M+ 79Br), 47), 245 (M+ - Br, 16),
( (
(M+
(
37Cl), 62), 234 (M+
(
35Cl), 100), 199 (M+ - Cl, 9), 191 (31),
79
201 (12), 181 (22), 163 (M+ - 2Br, 33); HRMS (EI) for C12H20
-
163 (M+ - 2Cl, 8); HRMS (EI) for C12H2035Cl2 (M+) calcd
234.0942, found 234.0929.
Br2 (M+) calcd 321.9932, found 321.9925.
Hexapropylbenzene (4): white solid; mp 98-101 °C (lit.7a
mp 102 °C); 1H NMR (300 MHz) δ 2.47 (t, J ) 8.4 Hz, 12H),
1.54-1.52 (s, 12H), 1.04 (t, J ) 7.2 Hz, 18H); 13C NMR (75 MHz)
δ: 136.7, 32.2, 24.8, 15.2.
(Z,Z)-9,12-Dichloroeicosa-9,11-diene (2d): colorless oil; 1H
NMR (300 MHz) δ 6.40 (s, 2H), 2.39 (t, J ) 7.8 Hz, 4H), 1.29-
1.28 (m, 24H), 0.88 (t, J ) 6.9 Hz, 6H); 13C NMR (75 MHz) δ
137.7, 120.3, 39.9, 31.8, 29.5, 29.2, 28.7, 27.5, 22.7, 14.1; IR (CH2-
Cl2) 1605, 1551, 1421, 896, 703 cm-1; LRMS (EI, 20 eV) m/z 348
Acknowledgment. We thank the National Natural
Science Foundation of China (No. 20202002), Hunan
Province Department of Education (No. 02C211), and
Hunan Normal University for financial support.
(M+ 37Cl), 51), 346 (M+ 35Cl), 100), 311 (M+ - Cl, 3), 275 (M+
( (
- 2Cl, 7); HRMS (EI) for C20H3635Cl2 (M+) calcd 346.2194, found
346.2194.
(Z,Z)-3,6-Dichloro-2,2,7,7-tetramethylocta-3,5-diene
1
(2e): white solid; mp 67-68 °C; H NMR (300 MHz) δ 6.55 (s,
Supporting Information Available: Experimental pro-
cedure and spectra (1H and 13C NMR) for products 2 and 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2H), 1.23 (s, 18H);13C NMR (75 MHz) δ: 148.0, 117.9, 39.2, 28.9;
IR (CH2Cl2) 1589, 1421, 896, 738 cm-1; LRMS (EI, 20 eV) m/z
236 (M+ 37Cl), 40), 234 (M+ 35Cl), 62), 199 (M+ - Cl, 100), 163
( (
(M+ - 2Cl, 12); HRMS (EI) for C12H2035Cl2 (M+) calcd 234.0942,
found 234.0937.
JO0486645
J. Org. Chem, Vol. 69, No. 23, 2004 8127