Synthesis of 1,3-diynes via palladium-catalyzed reaction of 1,1-dibromo-1-alkenes

Article abstract of DOI:10.1021/ol006282p

Both symmetric and unsymmetric 1,3-diynes were prepared from the palladium-catalyzed reaction of 1,1-dibromo-1-alkenes. The formation of symmetric 1,3-diynes 2 (homocoupling) was catalyzed by a weak ligand, tris(2-furyl)phosphine (TFP), and the addition of catalytic amount of Cul accelerated the reaction. The synthesis of unsymmetric 1,3-diynes 4 (the Sonogashira reaction) required a highly electron rich tris(4-methoxyphenyl)phosphine as the ligand, and Cul promotes the formation of byproduct 1,1-diynyl-1-alkenes 5.

Full text of DOI:10.1021/ol006282p

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2857-2860
Synthesis of 1,3-Diynes via
Palladium-Catalyzed Reaction of
1,1-Dibromo-1-alkenes
Wang Shen* and Sheela A. Thomas
Department D4N6, Cancer Research, Pharmaceutical Products DiVision,
Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101
wang.shen@abbott.com
Received June 30, 2000
ABSTRACT
Both symmetric and unsymmetric 1,3-diynes were prepared from the palladium-catalyzed reaction of 1,1-dibromo-1-alkenes. The formation of
symmetric 1,3-diynes 2 (homocoupling) was catalyzed by a weak ligand, tris(2-furyl)phosphine (TFP), and the addition of catalytic amount of
CuI accelerated the reaction. The synthesis of unsymmetric 1,3-diynes 4 (the Sonogashira reaction) required a highly electron rich tris(4-
methoxyphenyl)phosphine as the ligand, and CuI promotes the formation of byproduct 1,1-diynyl-1-alkenes 5.
1,1-Dibromo-1-alkenes1 are versatile in palladium chemistry.
They can form (Z)-1-aryl(alkenyl)-1-bromo-1-alkenes, ste-
reospecifically trisubstituted alkenes, and disubstituted cis-
1-bromo-1-alkenes through coupling with organoboronic
acids (Suzuki reaction),2 organostannanes (Stille reaction),3
organozinc and Grignard reagents,4 organozirconium re-
agents5 and tributyltin hydride.6 1,1-Dibromo-1-alkenes can
also be used as equivalents of 1-bromo-1-alkynes in pal-
ladium catalyzed reactions. This reaction was first reported
by Zapta7 and was recently investigated in detail by us.3a In
this letter, we wish to report an extension of this methodology
to the synthesis of both symmetric8,9 and unsymmetric 1,3-
diynes.8e,10
The homocoupling of methyl 4-(2′,2′-dibromovinyl)-
benzoate (1a) is summarized in Table 1. With tris(dibenz-
Table 1. Optimization of the Homocoupling of 1aa
entry CuI (%)
base
T (°C) t (h) productsb (yield, %)
1
2
3
4
5
0
0
20
100
20
TEA
TEA
TEA
TEA
K2CO3
80
100
80
80
80
36
12
4
1
48
2a (73)
2a (61)c
2a (83), 3a (5.6)
2a (57), 3a (28)
2a (15)d
(1) Preparation: (a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972,
3769. (b) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745.
(2) (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509. (b) Shen, W. Synlett 2000, 737.
(3) (a) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. (b) Wang,
L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625.
a Reaction conditions: 1a (1.0 mmol), Pd2dba3 (2.5%), TFP (15%), and
base (2.5 equiv) in DMF. b Yields are isolated. c 1a was recovered (2%).
d 1a was recovered (9%).
(4) (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc. 1987, 109,
1257. (b) Minato, A. J. Org. Chem. 1991, 56, 4052. (c) Panek, J. S.; Hu,
T. J. Org. Chem. 1997, 62, 4912.
(5) Xu, C.; Negishi, E. Tetrahedron Lett. 1999, 40, 431.
(6) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem.
1998, 63, 8965.
ylideneacetone)dipalladium(0) (Pd2dba3) as the palladium
source, tris(2-furyl)phosphine (TFP) is found to be the most
effective ligand for the homocoupling reaction. Though
reducing agents were shown to facilitate the homocoupling
(7) Zapata, A. J.; Ruiz, J. J. Organomet. Chem. 1994, 479, C6.
10.1021/ol006282p CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/08/2000

of aryl halides,11 they either had no effect on the reaction
(2-propanol11a), resulted in partial reduction of diyne 2a
(Zn11b,c and HCO2Na11d), or complicated the reaction
(hydroquinone11e and Me6Sn211f). The best results were
obtained with triethylamine (TEA),12 without using another
reducing reagent (entry 1, Table 1). The reductant in this
reaction is believed to be the tertiary amine, which was
proposed previously in other palladium-mediated reactions.11a,13
A controlled experiment also showed that the reaction
required TEA, as the reaction proceeded very poorly with
K2CO3 (entry 5, Table 1). The addition of CuI greatly
accelerates the reaction, though it also introduces byproduct
3a. The ratio of byproduct 3a to product 2a increases with
increased amount of CuI used, while the reaction time
decreases (entries 3 and 4, Table 1).
a good yield of the desired unsymmetric diyne 4a was
obtained without CuI (entry 4, Table 2).
These optimized conditions for the preparation of both
symmetric (entry 3, Table 1) and unsymmetric 1,3-diynes
(entry 4, Table 2) were used to synthesize a wide variety of
1,3-diynes, as summarized in Tables 3 and 4.15 Moderate to
Table 3. Homocoupling of 1,1-Dibromo-1-alkenes
When these optimized homocoupling conditions were
applied to the Sonogashira reaction,14 a mixture of products
(entry 1, Table 2) was obtained, with the major product being
Table 2. Optimization of the Sonogashira Reaction of 1a
entry
CuI
20% TFP
TFP
20% (4-MeOPh)3P
(4-MeOPh)3P
ligand
t (h)
productsa (yield, %)
1
2
3
4
2
4
4
4
4a (26), 5a (58), 2a (13)
4a (39), 5a (51), 2a (9)
4a (29), 5a (26), 2a (25)
4a (78), 5a (18)
0
0
a Yields are isolated.
1,1-diynyl-1-alkene 5a. However, when the very electron-
rich tris(4-methoxyphenyl)phosphine was used as the ligand,
(8) Representative syntheses of symmetric 1,3-diynes: (a) Liu, Q.;
Burton, D. J. Tetrahedron Lett. 1997, 38, 4371. (b) Sarkar, A.; Okada, S.;
Nakanishi, H.; Matsuda, H. HelV. Chem. Acta 1999, 82, 138. (c) Takai, K.;
Kuroda, T.; Nakatsukasa, S.; Oshima, K.; Nazuki, H. Tetrahedron Lett.
1985, 26, 5585. (d) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D.
B.; Pak, J. J.; Wan, W. B. Tetrahedron Lett. 1997, 38, 7483. (e) Nishihara,
Y.; Ikegashira, K.; Hirabayashi, K.; Ando, J.; Mori, A.; Hiyama, T. J. Org.
Chem. 2000, 65, 1780.
a Pd(OAc)2 (5 mol %) was used in place of Pd2dba3.38
(9) 1,1-Dibromo-1-alkenes formed 1,3-symmetric diynes (a) under “CO”
atmosphere with a strong base (5 N NaOH): Galamb, V.; Gopal, M.; Alper,
H. Organometallics 1983, 2, 801. (b) As byproducts in the Suzuki
reaction: Soderquist, J. A.; Leon, G.; Colberg, J. C.; Martinez, I.
Tetrahedron Lett. 1995, 36, 3119.
good yields of the homocoupling products 2 were obtained
with both 2-aryl- and 2-alkyl-1,1-dibromoethenes (Table 3).
Para or meta substitutions (1a, 1c, 1d) on the aromatic rings
do not affect the homo-coupling. However, ortho substituents
might participate in the reaction.3b When 2-(o-methoxy-
phenyl)-1,1-dibromoethene (1e) was subjected to the homo-
coupling reactions, byproduct 6 was isolated along with the
desired diyne 2e.
(10) Representative palladium-catalyzed synthesis of unsymmetric 1,3-
diynes: (a) Kang, S. K.; Lee, H. W.; Jang, S. B.; Ho, P. S. Chem. Commun.
1996, 835. (b) Cai, C.; Vasella, A.; HelV. Chim. Acta 1996, 79, 255.
(11) (a) Penalva, V.; Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron Lett. 1998, 39, 2559. (b) Venkatraman, S.; Li, C.-J. Org. Lett.
1999, 1, 1133. (c) Jutand, A.; Mosleh, A. Synlett 1993, 568. (d) Bamfield,
P.; Quan, P. M. Synthesis 1978, 537. (e) Hennings, D. D.; Iwama, T.; Rawal,
V. H. Org. Lett. 1999, 1, 1205. (f) Iyoda, M.; Miura, M.; Sasaki, S.; Kabir,
S. M. H.; Kuwatani, Y.; Yoshida, M. Tetrahedron Lett. 1997, 38, 4582.
(12) Tertiary amines were also used in homocoupling of aryl halides
without the addition of other reductants: (a) Clark, F. R. S.; Norman, R.
O. C.; Thomas, C. B. J. Chem. Soc., Perkin Trans. 1 1975, 121. (b) Boger,
D. L.; Goldberg, J.; Andersson, C.-M. J. Org. Chem. 1999, 64, 2422. (c)
Boger, D. L.; Jiang, W.; Goldberg, J. J. Org. Chem. 1999, 64, 7094. (d)
Hassan, J.; Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1999,
40, 857.
As shown in Table 4, the reactions of 1,1-dibromo-1-
alkenes 1 with both aryl and alkyl terminal alkynes afforded
moderate to good yields of the desired unsymmetric 1,3-
(14) Sonogashira, K. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
5, p 203.
(13) (a) Stokker, G. E. Tetrahedron Lett. 1987, 28, 3179. (b) Konopelski,
J. P.; Chu, K. S.; Negrete, G. R. J. Org. Chem. 1991, 56, 1355.
(15) All the 1,3-diynes (2, 4), 1,1-diynyl-1-alkenes (3, 5) and compound
1
6 gave satisfactory mass (DCI) and H and 13C NMR spectra.
2858
Org. Lett., Vol. 2, No. 18, 2000

solvent such as DMF and in the presence of a base,
intermediate 7 transforms into alkynylpalladium 8.3a In the
absence of CuI and a terminal alkyne, intermediate 8 would
yield homocoupling product 2, with a mechanism similar to
the homocoupling of aryl halides. In the presence of CuI,
the palladium in intermediate 8 may interchange with copper-
(I) to give alkynylcopper 9, which couples with 8 at a much
faster rate to give product 2. This may explain the catalytic
role of CuI. Because alkynylcopper 9 couples fast with
organopalladium species, formation of monobromide 10 from
the coupling of 7 and 9 becomes competitive to the
transformation of 7 to 8. Further coupling of 10 with 9 results
in product 3. The homocoupling also produces Pd(II) species,
which is reduced by triethylamine to Pd(0) species to
complete the palladium cycle.13
Table 4. Synthesis of Unsymmetric 1,3-Diynes
A parallel mechanism could be derived for the formation
of unsymmetric 1,3-diynes 4, and the byproducts 5, as also
shown in Scheme 1. The palladium cycle in these reactions
ends with Pd(0) species, so that no reduction of Pd(II) species
is necessary.
Further proof of the mechanism is obtained with the
reaction of alkynyl bromide 11,16 as illustrated in Scheme
2. Under the homocoupling conditions developed for 1,1-
Scheme 2
a Yield after recovered 1a (13%). b 1a (8%) was recovered.
diynes 4. The homocoupling products 2 were usually isolated
in minor amounts, and the bis-coupled products 5 were
observed in a few cases (entries 3 and 9, Table 4). The
electronic characteristics and the substitution patterns of 1,1-
dibromo-1-alkenes 1 do not affect the Sonogashira reaction,
as both 1a and 1e afforded good yields of unsymmetric 1,3-
diynes 4. However, the reaction is much slower with electron
deficient alkynes, as the coupling of 1a with 2-pyridylethyne
gave low yield of 4f after long reaction time (entry 5, Table
4), and no desired unsymmetric 1,3-diyne was found in the
coupling of 1a with ethyl propiolate (entry 6).
dibromo-1-alkenes, a comparable yield of 2a was obtained
from 11 in 0.5 h. Similarly, unsymmetric 1,3-diyne 4a was
obtained in good yield from 11 under the optimal conditions
developed for the Sonogashira reaction of 1,1-dibromo-1-
alkenes 1, though the byproduct is 2a instead of 5a.
In summary, we have developed convenient methods for
the preparation of both symmetric17 and unsymmetric18 1,3-
diynes from easily accessible 1,1-dibromo-1-alkenes 1. Both
A possible mechanism for the reactions is proposed in
Scheme 1. 1,1-Diboromo-1-alkene 1 undergoes normal
palladium insertion to give intermediate 7. In a highly dipolar
(16) Compound 11 was prepared in quantitative yield according to the
protocol in: Ratovelomanana, V.; Rollin, Y.; Gebehenne, C.; Gosmini, C.;
Perichon, J. Tetrahedron Lett. 1994, 35, 4777.
(17) Typical Procedure for Preparation of Symmetric 1,3-Diynes 2.
A mixture of 1a (320 mg, 1.0 mmol), Pd2(dba)3 (23 mg, 0.025 mmol),
TFP (35 mg, 0.15 mmol), CuI (38 mg, 0.20 mmol), and triethylamine (0.42
mL, 3.0 mmol) in DMF (3 mL) was flushed with nitrogen and heated at 80
°C for 4 h. The reaction mixture was cooled, filtered through Celite and
rinsed with ethyl acetate. The filtrate was partitioned between ethyl acetate
(50 mL) and water (10 mL), and the organic layer was washed with water
(10 mL, twice), dried over MgSO4, filtered, and concentrated. The residue
was purified by flash chromatography, eluting with 0-5% ethyl acetate in
hexanes/dichloromethane (1: 1) to give 2a (132 mg), followed by 3a (8.8
mg).
Scheme 1
(18) Typical Procedure for Preparation of Unsymmetric 1,3-Diynes
4. A solution of 1a (320 mg, 1.0 mmol), phenylacetylene (153 mg, 2.0
mmol), Pd2dba3 (9.0 mg, 0.010 mmol), tris(4-methoxyphenyl)phosphine (14
mg, 0.040 mmol), and triethylamine (0.41 mL, 3.0 mmol) in anhydrous
DMF (3.0 mL) was flushed with nitrogen and heated at 80 °C for 4 h.
Usual aqueous work up was followed by column chromatography purifica-
tion with hexanes/dichloromethane/ethyl acetate (70:25:5) to give 4a as the
first fraction (204 mg, 78%) and 5a as the second fraction (65 mg, 18%).
Org. Lett., Vol. 2, No. 18, 2000
2859

methods are relatively mild and appear to be broadly
applicable. These reactions again demonstrate the utility of
1,1-dibromo-1-alkenes as synthons for alkynyl bromides and
the importance of ligands, additives, and solvents in pal-
ladium catalyzed reactions of 1,1-dibromo-1-alkenes.
Acknowledgment. We thank Dr. Saul Rosenberg and
Abbott Laboratories for the permission and financial support
to carry out this work. We are very grateful to a reviewer
for the suggestions and insightful mechanistic comments, in
particular to the work in Scheme 2.
(19) A comparable yield (43%) of 2h was obtained with Pd2dba3 as the
palladium source, after purification with silica gel column twice (dba and
2h have similar Rf values). As a comparison, 2a (79%) and 3a (6.1%)
were resulted from the homocoupling of 1a with Pd(OAc)2 in place of Pd2-
dba3.
OL006282P
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