A copper- and amine-free Sonogashira reaction employing aminophosphines as ligands

Article abstract of DOI:10.1021/jo049379o

An efficient Pd-catalyzed Sonogashira coupling reaction was achieved in the absence of a copper salt or amine with an inorganic base and easily prepared, air-stable aminophosphine ligands in commonly used organic solvents; good to excellent yields were ob

Full text of DOI:10.1021/jo049379o

A Cop p er - a n d Am in e-F r ee Son oga sh ir a Rea ction Em p loyin g
Am in op h osp h in es a s Liga n d s
†
†
‡
‡
†
†
J iang Cheng, Yanhui Sun, Feng Wang, Minjie Guo, J ian-Hua Xu, Yi Pan, and
Zhaoguo Zhang*,
‡
Department of Chemistry, Nanjing University, 22 Hankou Road, Nanjing 210093, and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
zhaoguo@mail.sioc.ac.cn
Received April 14, 2004
An efficient Pd-catalyzed Sonogashira coupling reaction was achieved in the absence of a copper
salt or amine with an inorganic base and easily prepared, air-stable aminophosphine ligands in
commonly used organic solvents; good to excellent yields were obtained. Under optimized reaction
conditions, the Sonogashira coupling reaction occurred selectively when an enyne substrate was
employed and no Heck reaction product was detected; acetone-masked acetylene and trimethylsi-
lylacetylene can also be efficiently coupled, providing a method to make terminal alkynes.
In tr od u ction
SCHEME 1
Palladium-catalyzed coupling of terminal alkynes with
aryl or alkenyl iodides, which was described for the first
time by Sonogashira et al. in 1975, is one of the most
straightforward methods for the preparation of aryl-
1
alkynes and conjugated enynes (Scheme 1). Generally,
the Sonogashira coupling is carried out in the presence
of a catalytic amount of a palladium complex as well as
copper iodide in an amine as the solvent to obtain a good
2
yield. Numerous applications in natural product syn-
thesis have been reported, for example, in the construc-
tion of the complex unsaturated framework of the ene-
3
diyne antibiotics. Recently, the use of aryl bromide and
aryl chloride has been explored, and good results were
achieved. Muller et al. reported a method to synthesize
4
Although an impressive variety of modifications have
been reported for this reaction, including phase-transfer
reaction conditions6 and aqueous,7 and solvent-free
versions, a copper cocatalyst is still needed. The coppper-
(I) acetylides formed in situ could undergo oxidative
R,â-unsaturated alkynones by the cross-coupling of aroyl
4
h
8
chloride with trimethylsilylacetylene. In addition to
traditional palladium-catalyzed methods, the nickel-
catalyzed Sonogashira reaction was also reported.5
†
Nanjing University.
Chinese Academy of Sciences.
(4) For recent examples, see: (a) Choudary, B. M.; Madhi, S.;
Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J . Am. Chem. Soc. 2002,
124, 14127-14136. (b) Eberhard, M. R.; Wang, Z.; J ensen, C. M. Chem.
Commun. 2002, 818-819. (c) Hundertmark, T.; Littke, A. F.; Buch-
wald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-1731. (d) Alami, M.;
Crousse, B.; Ferri, F. J . Organomet. Chem. 2001, 624, 114-123. (e)
Ansorge, M.; M u¨ ller, T. J . J . J . Organomet. Chem. 1999, 585, 174-
178. (f) Thorand, S.; Krause, N. J . Org. Chem. 1998, 63, 8551-8553.
(g) K o¨ llhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. 2003,
42, 1056-1058. (h) Karpov, A. S.; Muller, T. J . J . Org. Lett. 2003, 5,
3451-3454.
‡
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1
2
2
975, 4467-4470. (b) Cassar, L. J . Organomet. Chem. 1975, 93, 253-
57. (c) Dieck, H. A.; Heck, F. R. J . Organomet. Chem. 1975, 93, 259-
63.
(
2) For reviews, see: (a) Sonogashira, K. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
991; Vol. 3, pp 521-549. (b) Rossi, R.; Carpita, A.; Bellina, F. Org.
1
Prep. Proced. Int. 1995, 27, 129-169. (c) Tsuji, J . Palladium Reagents
and Catalysts; Wiley: Chichester, U.K., 1995; pp 168-171. (d) Nico-
laou, K. C.; Sorensen, E. J . Classics in Total Synthesis; VCH: Wein-
heim, Germany, 1996; pp 582-586. (e) Brandsma, L.; Vasilevsky, S.
F.; Verkruijsse, H. D. Application of Transition Metal Catalysts in
Organic Synthesis; Springer: Berlin, 1998; pp 179-225. (f) Sonogash-
ira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 203-
(5) Beletskaya, I. P.; Latyshev, G. V.; Tsvetkov, A. V.; Lukashev,
N. V. Tetrahedron Lett. 2003, 44, 5011-5013.
(6) Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J . Org. Chem.
2001, 66, 1910-1913.
(7) (a) Bong, D. T.; Ghadiri, M. R. Org. Lett. 2001, 3, 2509-2511.
(b) Dibowski, H.; Schmidtchen, F. P. Tetrahedron Lett. 1998, 39, 525-
528. (c) Genet, J .-P.; Blart, E.; Savignac, M. Synlett 1992, 715-717.
(d) Casalnuovo, A. L.; Calabrese, J . C. J . Am. Chem. Soc. 1990, 112,
4324-4330.
2
29.
(
3) (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl.
1
991, 30, 1387-1416. (b) Maier, M. E. Synlett 1995, 13-26. (c)
Grissom, J . W.; Gunawardena, G. U.; Kingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453-6518.
(8) Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.
Tetrahedron Lett. 2000, 41, 5151-5154.
1
0.1021/jo049379o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/07/2004
5
428
J . Org. Chem. 2004, 69, 5428-5432

Copper- and Amine-Free Sonogashira Reaction
dimerization to give diaryldiacetylenes when they are
exposed to air or an oxidant (a reaction known as the
Glaser coupling). These byproducts are generally dif-
TABLE 1. Effect of Ba ses in th e Son oga sh ir a
Cr oss-Cou p lin g Rea ction a
9
ficult to separate from the desired products. Furthermore,
the copper acetylide is a potential explosive reagent.
Some examples of “palladium-only” catalysts have been
reported in this cross-coupling reaction.10
Trivalent aminophosphines that contain one or more
P-N bonds have been recently employed as ligands in
yieldb
(%)
yieldb
(%)
1
1
transition-metal-catalyzed cross-coupling reactions.
A
entry
base
Et3N
entry
base
few reports on the coordination chemistry of aminophos-
phine compounds revealed that the function of amino
groups was more diversified than that of alkoxy groups
in phosphites.12 In mono- and diaminophosphines, alkyl-
and/or arylamino groups served as strong electron-
donating groups, making the phosphines stronger σ-do-
nor ligands. In our previous work, we found phosphina-
mides L1, L4, and L5 (Scheme 1) were highly efficient
ligands in the Suzuki cross-coupling reaction.13 We
attempted to extend the use of this type of ligand to the
Sonogashira reaction. Herein, we report a copper- and
amine-free Sonogashira reaction employing aminophos-
phine ligands.
1
2
3
4
5
83c
21
NR
24
6
7
8
9
10
Na2CO3
NaHCO3
K3PO4‚3H2O
KOH
25 (88)d
Et3N
23
90
NR
7
pyridine
morpholine
K2CO3
97
KF
a
All reactions were run with p-bromoanisole (374 mg, 2 mmol),
phenylacetylene (245 mg, 2.4 mmol), Pd(OAc)2 (11 mg, 0.05 mmol),
and L1 (43 mg, 0.15 mmol) with the indicated base (6 mmol) in 5
mL of THF at 65 °C for 8 h. b Isolated yield. c Et N was employed
3
as solvent. d 30 h.
TABLE 2. Effects of Liga n d s a n d Solven ts in th e
Son oga sh ir a Rea ction betw een p-Br om oa n isole a n d
P h en yla cetylen ea
3
a a yieldb
(%)
Resu lts a n d Discu ssion
entry
ligand
solvent
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L1
L1
L1
L1
THF
THF
THF
THF
97
91
67
9
11
80
77
93
95
We first chose p-bromoanisole (2a ) and phenylacetyl-
ene (1a ) as substrates and L1 as ligand to investigate
the Sonogashira reaction in the absence of a copper salt.
Treatment of a mixture of 1a (245 mg, 2.4 mmol), 2a
THF
dioxane
toluene
DMF
(374 mg, 2 mmol), Pd(OAc)
2
(11 mg, 0.05 mmol), and L1
(
43 mg, 0.15 mmol) in Et N (5 mL) at 65 °C under an
3
inert atmosphere for 8 h produced the desired product
CH3CN
a
All reactions were run with p-bromoanisole (374 mg, 2 mmol),
(
9) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632-2657.
10) Copper-free Sonogashira coupling reactions are not common.
See: (a) B o¨ hm, V. P.; Hermann, W. A. Eur. J . Org. Chem. 2000, 3679-
681. (b) Pal, M.; Parasuraman, K.; Gupta, S.; Yaleswarapu, K. R.
phenylacetylene (245 mg, 2.4 mmol), Pd(OAc)2 (11 mg, 0.05 mmol),
K2CO3 (828 mg, 6 mmol), and ligand (0.15 mmol) in 5 mL of the
indicated solvent at 65 °C for 8 h. b Isolated yield.
(
3
Synlett 2002, 12, 1976-1982 and references therein. (c) Fu, X.; Zhang,
S.; Yin, J .; Schumacher, D. Tetrahedron Lett. 2002, 43, 6673-6676.
3a a in 83% yield. This is a promising result, since no
copper salt was required. If we can reduce the amount
of the base, or realize the reaction in a commonly used
organic solvent, the reaction would be more attractive.
However, only a 21% yield of product was obtained when
(
d) Alonso, D. A.; N a´ jera, C.; Pacheco, M. C. Tetrahedron Lett. 2002,
3, 9365-9368. (e) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato,
4
M.; Ryu, I. Org. Lett. 2002, 4, 1691-1694 and references therein. (f)
M e´ ry, D.; Heuz e´ , K.; Astruc, D. Chem. Commun. 2003, 1934-1935.
(
g) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 2, 1729-1731. (h) Heuz e´ , K.; M e´ ry, D.; Gauss, D.; Astruc,
D. Chem. Commun. 2003, 2274-2275. (i) Soheili, A.; Albaneze-Walker,
J .; Murry, J . A.; Dormer, P. G., Hughes, D. L. Org. Lett. 2003, 5, 4191-
3
the reaction was performed in THF (5 mL) with Et N (6
mmol) as the base (Table 1, entries 1 and 2). To improve
the efficiency of the reaction in a common organic solvent
other than triethylamine, we investigated the effect of
the commonly used organic and inorganic bases in THF.
The results are summarized in Table 1.
A significant effect of bases was found in the reaction.
With a strong base such as KOH, no desired product was
isolated (Table 1, entry 9). Morpholine, which is com-
monly employed to accelerate the Sonogashira reaction,
and KF failed to give good yields under this reaction
4
194. (j) Ma, Y.; Song, C.; J iang, W.; Wu, Q.; Wang, Y.; Liu., X.; Andrus,
M. B. Org. Lett. 2003, 5, 3317-3319. (k) N a´ jera, C.; Gil-Molt o´ , J .;
Karlstr o¨ m, S.; Falvello, L. R. Org. Lett. 2003, 5, 1451-1454. (l) Alonso,
D. A.; N a´ jera, C.; Pacheco, M. C. Adv. Synth. Catal. 2003, 345, 1146-
1
158. (m) Buchmeiser, M. R.; Schareina, T.; Kempe, R.; Wurst, K. J .
Organomet. Chem. 2001, 634, 39-46. (n)Uozumi, Y.; Kobayashi, Y.
Heterocycles 2003, 59, 71-74.
(11) (a) Clarke, M. L.; Cole-Hamilton, D. J .; Woollins, J . D. J . Chem.
Soc., Dalton Trans. 2001, 2721-2723. (b) Schareina, T.; Kempe, R.
Angew. Chem., Int. Ed. 2002, 41, 1521-1523. (c) Urgaonkar, S.;
Nagarajan, M.; Verkade, J . G. Tetrahedron Lett. 2002, 43, 8921-8924.
(d) Clarke, M. L.; Cole-Hamilton, D. J .; Slawin, A. M. Z.; Woollins, J .
D. Chem. Commun. 2000, 2065-2066. (e) Urgaonkar, S.; Nagarajan,
M.; Verkade, J . G. J . Org. Chem. 2003, 68, 452-459. (f) Urgaonkar,
S.; Nagarajan, M.; Verkade, J . G. Org. Lett. 2003, 5, 815-818. (g) You,
J .; Verkade, J . G. J . Org. Chem. 2003, 68, 8003-8007. (h) Urgaonkar,
S.; Xu, J .-H.; Verkade, J . G. J . Org. Chem. 2003, 68, 8416-8423.
condition (Table 1, entries 4 and 10). K
high efficiency, giving the product in 90% yield (Table 1,
entry 8). However, the best base was K CO , which
3
PO
4
‚3H
2
O showed
2
3
(
12) (a) Rømming, C.; Songstad, J . Acta Chem. Scand., Ser. A 1978,
provided a 97% yield of the desired product (Table 1,
entry 5).
We then turned our attention to ligand and solvent
effects. The results are summarized in Table 2.
Both L1 and L2 are highly effective ligands in this
reaction (Table 2, entries 1 and 2), while other ligands
3
2, 689-699. (b) Rømming, C.; Songstad, J . Acta Chem. Scand., Ser.
A 1979, 33, 187-197. (c) Rømming, C.; Songstad, J . Acta Chem. Scand.,
Ser. A 1982, 36, 665-671. (d) Moloy, K. G.; Petersen, J . L. J . Am. Chem.
Soc. 1995, 117, 7696-7710. (e) Socol, S. M.; J acobson, R. A.; Verkade,
J . G. Inorg. Chem. 1984, 23, 88-94.
(
13) Cheng, J .; Wang, F.; Xu, J .; Pan, Y.; Zhang, Z. Tetrahedron Lett.
2
003, 44, 7095-7098.
J . Org. Chem, Vol. 69, No. 16, 2004 5429

Cheng et al.
TABLE 3. Rea ction of Ar yl Br om id es a n d
TABLE 4. Son oga sh ir a Rea ction betw een Ar yl
Br om id es a n d Alk yn esa
a
P h en yla cetylen e
aryl
yieldb
(%)
entry
alkyne
1-hexyne (1b)
1b
1b
1b
1b
1b
bromide
product
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2h
2i
3ba
3bb
3bc
3bd
3bh
3bi
3cb
3d c
3ec
3ej
96
93 (94)
86 (91)
88
yieldb
(%)
entry
2
3
c
93
1
2
3
4
5
6
7
8
p-bromoanisole (2a )
2a
3a a
3a a
3a b
3a c
3a d
3a e
3a f
3a i
97 (91)
92
72
93
96
88
c
1-naphthylacetylene (1c)
benzyl propargyl ether (1d ) 2c
1-cyclohexenylacetylene (1e) 2c
2b
p-bromotoluene (2b)
bromobenzene (2c)
2,6-dimethylphenyl bromide (2d )
o-bromotoluene (2e)
1-bromonaphthalene (2f)
3-bromopyridine (2i)
65 (94)
78 (95)
15 (88)
86 (99)
68 (80)
(95)
c
1
1
0
1
1e
2j
95
benzylacetylene (1f)
2c
2a
2b
2c
2f
3fc
83
86
92
94
78
12 2-methyl-3-butyn-2-ol (1g)
13 1g
3ga
3gb
3gc
3gf
3gg
1
1
1
4
5
6
1g
1g
1g
a
All reactions were run with aryl bromide (2 mmol), phenyl-
acetylene (245 mg, 2.4 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and
L1 (43 mg, 0.15 mmol) with K2CO3 (828 mg, 6 mmol) in 5 mL of
d
1,4-dibromo-
benzene (2g)
2c
88
b
THF at 65 °C for 8 h. Isolated yield. The yields in parentheses
1
7
3-methoxy-3-methyl-1-
butyne (1h )
3h c
96
c
refer to reaction when L2 was employed as ligand. Yield obtained
at room temperature for 24 h.
18 trimethylsilylacetylene (1i) 2b
3ib
3ic
87
94
1
9
1i
2c
a
All reactions were run at 65 °C for 8 h with aryl bromide (2
are inferior. L3, L4, and L5 are workable ligands in the
Suzuki-Miyaura cross-coupling reaction;13 however, they
mmol), alkyne (2.4 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and L1
43 mg, 0.15 mmol) with K2CO3 (828 mg, 6 mmol) in 5 mL of THF.
(
gave poor yields in the Sonogashira reaction (Table 2,
entries 3-5).
The reaction proceeded well in polar solvents, such as
THF, dioxane, DMF, and acetonitrile; 97%, 80%, 93%,
and 95% isolated yields were obtained, respectively
b
Isolated yield. The yields in parentheses refer to reaction when
L2 was employed as ligand. c The reaction was complete in 3 h.
d
2.4 mol of 1g/mol of 2g was used.
SCHEME 2
(Table 2, entries 1, 6, 8, and 9). The yields decreased in
less polar solvents such as toluene. Simple primary and
secondary alcohols are not proper solvents for this
reaction, since they would react with the ligands to give
alkoxyphosphines.14
On the basis of these results, we employed the follow-
ing optimized reaction conditions: 2 mmol of aryl bro-
uents were considered reluctant to oxidative addition to
Pd(0); however, a 96% isolated yield of product 3ba was
obtained for the coupling reaction of hexyne (1b ) and
p-bromoanisole (2a ) (Table 4, entry 1). The ortho group
in the aryl bromide had hardly any effect in the reaction;
the yield reached 88% for 1b and 2,6-dimethylphenyl
bromide (2d ) (Table 4, entry 4). As the primary alcohol
will react with the phosphinamide ligands, prop-2-yn-1-
ol is not a proper substrate in the procedure.14 However,
if the hydroxy group was protected with a benzyl group
mide, 2.4 mmol of alkyne, 0.05 mmol of Pd(OAc)
mmol of L1, 6 mmol of K CO , and 5 mL of THF as sol-
vent. In fact, even if the reaction was performed at rt for
4 h, the product was obtained in an excellent yield (92%)
Table 3, entry 2). However, when p-bromotoluene (2b)
2
, 0.15
2
3
2
(
and bromobenzene (2c) were employed as substrates, the
yields decreased to 65% and 78%, respectively (Table 3,
entries 3 and 4). Fortunately, the yields increased to 94%
and 95%, respectively, when the ligand L2 was employed
instead of L1 (Table 3, entries 3 and 4). The results using
L1 and L2 as ligands are summarized in Table 3. In
general, L2 showed higher efficiency toward the Sono-
gashira reaction of aryl bromides and phenylacetylene.
The reaction is not sensitive to steric hindrance; for 2d
and 2e, which have ortho substituent groups, the coup-
ling reactions were still realized in 88% and 99% yields,
respectively (Table 3, entries 5 and 6). When bromonaph-
thalene (2f) was employed as substrate, a good isolated
yield could also be obtained (Table 3, entry 7).
If we perform this reaction with aryl bromides and
hexyne, no obvious difference is found between L1 and
L2 (Table 4, entries 2 and 3). Since L1 is easier to prepare
and handle (L1 is stable in air; no change was detected
when it was exposed in air for 3 days), we employed
ligand L1 in the reaction of aryl bromides and other
alkynes. The results are summarized in Table 4.
(1d ), the coupling reaction could be realized with 2c,
providing a 96% isolated yield of 3d c (Table 4, entry 8).
It is worth noting that with unprotected tertiary alcohol
2
-methyl-3-butyn-2-ol (1g), the coupling reaction may be
realized, giving the coupling product in 94% isolated
yield. The product could be further converted to the
terminal alkyne in the presence of a strong base (Scheme
1
5
2
). Because 1g is a large-volume industrial product, the
successful coupling of this compound is of great signifi-
cance; it provides a possible entry to large-scale produc-
tion of terminal aryl alkynes by the Sonogashira coupling
reaction. The commonly used substitute for 1g, trimeth-
ylsilylacetylene, is a good reactant (Table 4, entries
1
8,19). For substrate 1e, which possesses both a C-C
double bond and a C-C triple bond, only the Sonogashira
(
14) Mukaiyama, T.; Kikuchi, W.; Shintou, T. Chem. Lett. 2003, 32,
00-301.
15) Havens, S. J .; Hergenrother, P. M. J . Org. Chem. 1985, 50,
1763-1764.
All of the alkyne substrates worked well under the
reaction conditions in the absence of Cu and amine. The
aryl bromides which contain electron-donating substit-
3
(
5
430 J . Org. Chem., Vol. 69, No. 16, 2004

Copper- and Amine-Free Sonogashira Reaction
i
SCHEME 3
stirred for 1 h at this temperature, and then Pr
1
2 2
NPCl (2.0 g,
0 mmol) in dry ether (15 mL) was added dropwise in 2 h.
The reaction mixture was stirred overnight. Then the solvent
was evaporated under reduced pressure, and the residue was
purified by flash chromatography on Al
3%) as a colorless oil.
Da ta for L1. White solid. Mp: 69-70 °C. 1H NMR (300
MHz, CDCl ): δ 7.53-7.47 (m, 4H), 7.34-7.30 (m, 6H), 3.39
m, 2H), 1.08 (d, J ) 6.3 Hz, 12H). 13C NMR (75 MHz, CDCl
):
δ 140.5 (d, J ) 19.8 Hz), 132.4 (d, J ) 20.3 Hz), 127.9, 127.9,
7.4 (d, J ) 8.3 Hz), 23.8 (d, J ) 7.1 Hz). 31P NMR (121 MHz,
CDCl ): δ 38.2. MS (EI): m/z 285, 270, 242, 228, 194, 183,
2 3
O to give L2 (1.53 g,
4
3
(
3
4
3
-
1
1
1
08, 100. IR (KBr, cm ): 3067, 2981, 2965, 1433, 1360, 1178,
120.
Da ta for L2. Oil. H NMR (300 MHz, CDCl
m, 2H), 6.82-6.79 (m, 2H), 6.82-6.79 (m, 2H), 5.97 (s, 4H),
.38 (m, 2H), 1.13 (d, J ) 6.0 Hz, 12H). 13C NMR (75 MHz,
CDCl ): δ 147.5, 126.7, 126.4, 111.9, 111.6, 108.2, 100.8, 47.1,
3.8. 31P NMR (121 MHz, CDCl
): δ 40.1. MS (EI): m/z (rel
intens) 373, 316, 273, 238. HRMS: m/z calcd for C20
1
3
): δ 7.03-6.97
(
3
3
2
3
cross-coupling product 3ec was isolated in 88% yield and
no Heck reaction product was detected (Table 4, entry
H
4
24NO P
-
1
3
1
73.1443, found 373.1466. IR (neat, cm ): 2965, 2893, 1502,
473, 1413, 1362, 1234, 1042.
9
). As expected, aryl halides with electron-withdrawing
groups are more reactive than those with electron-
donating groups; when bromoacetone and methyl 2-bro-
mobenzoate were employed, the reaction was complete
in 3 h (Table 4, entries 5 and 10).
The mechanism of the reaction is suggested as in
Scheme 3. The first step is the oxidative addition of Pd-
Gen er a l P r oced u r e for P a lla d iu m -Ca ta lyzed Cop p er -
a n d Am in e-F r ee Son oga sh ir a Cr oss-Cou p lin g Rea ction .
Under a nitrogen atmosphere, a Schlenk reaction tube was
charged with alkyne substrate 1 (2.4 mmol), aryl bromide 2
(
2 mmol), K
mmol), ligand (0.15 mmol), and THF (5 mL). The reaction tube
was purged with N in a dry ice bath. After the mixture was
2 3 2
CO (828 mg, 6 mmol), Pd(OAc) (11 mg, 0.05
2
(0) with aryl halide. The application of electron-rich
heated at 65 °C for 8 h, the solvent was evaporated under
reduced pressure and the residue was purified by flash column
chromatography on silica gel to give the product 3.
Da ta for Hex-1-yn yl-2,6-d im eth ylben zen e (3bd ). 1H
aminophosphine ligands makes this step easier. The
second step is the activation of the terminal alkyne.
Because no copper salt was employed, and the bases are
not strong enough to subtract a proton from the alkyne,
a transmetalation step could be excluded. The terminal
alkyne C-H bond activation is acomplished by the
coordination of the alkyne to the ArPdX complex. Upon
coordination, the C-H bond is weakened, and HX is
removed from I in the presence of a base to form
arylalkynylpalladium species II, which undergoes reduc-
tive elimination to afford the product III and regenerates
the catalyst. The electron-rich, and bulky, aminophos-
phine ligands may play key roles in facilitating the
reductive elimination step.
In conclusion, we have developed an efficient, copper-
and amine-free Sonogashira reaction with easily pre-
pared, air-stable aminophosphines as the ligands. The
mild reaction conditions, the obviation of copper salt as
cocatalyst and amine as solvent, and the utilization of
inorganic base are the most attractive features of the
reaction.
NMR (300 MHz, CDCl ): δ 7.03-7.01 (m, 3H), 2.50 (t, J )
3
7.2 Hz, 2H), 2.54 (s, 6H), 1.62-1.52 (m, 4H), 0.95 (t, J ) 7.2
Hz, 3H). 13C NMR (75 MHz, CDCl
): δ 139.9, 126.8, 126.5,
3
1
23.7, 98.9, 78.1, 31.1, 22.0, 21.1, 19.4, 13.6. MS (EI): m/z (rel
intens) 186, 157, 143, 142, 141, 129, 115. HRMS: m/z calcd
-1
for C14
H18 186.1409, found 186.1396. IR (neat, cm ): 3022 (m),
2
(
980 (s), 2924 (s), 2874 (m), 2226 (m), 1467 (s), 1378 (m), 769
s), 734 (m).
Da ta for 2-Meth yl-4-(1′-n a p h th a len -2-yl)bu t-3-yn -2-ol
1
(3gf). H NMR (300 MHz, CDCl ): δ 8.35-8.31 (m, 1H), 7.85-
3
7.79 (m, 2H), 7.67-7.65 (m, 1H), 7.58-7.50 (m, 2H), 7.42-
7.37 (m, 1H), 2.70 (s, br, 1H), 1.76 (s, 6H). 13C NMR (75 MHz,
CDCl
3
): δ 133.2, 133.0, 130.3, 128.6, 128.2, 126.7, 126.3, 125.9,
1
2
(
2
(
25.0, 120.2, 98.8, 80.1, 65.8, 31.6. MS (EI): m/z (rel intens)
+
10 (M , 67), 209 (28), 195 (98), 165 (24), 152 (33), 86 (28), 84
14O 210.1045, found
10.1029. IR (neat, cm ): 3368 (s), 3060 (m), 2983 (s), 2248
41), 43 (100). HRMS: m/z calcd for C15H
-1
m), 1396 (s), 1164 (s), 908 (s), 808 (s), 774 (s), 733 (s).
Da ta for 1,4-Bis(3-h yd r oxy-3-m eth ylbu t-1-yn yl)ben -
1
zen e (3gg). H NMR (300 MHz, CD
3
COCD
3
): δ 7.35 (s, 4H),
4
.53 (s, br, 2H), 1.53 (s, 12H). 13C NMR (75 MHz, CD
3
-
COCD ): δ 131.6, 123.2, 97.2, 80.6, 64.5, 31.3. MS (EI): m/z
3
Exp er im en ta l Section
+
(
rel intens) 242 (M , 12), 227 (47), 135 (15), 107 (47), 92 (17),
Ma ter ia ls. THF was distilled from sodium-benzophenone
91 (24), 59 (16), 46 (21), 43 (100). HRMS: m/z calcd for
C H O 242.1307, found 242.1329. IR (KBr, cm ): 3339 (s),
16 18 2
2981 (s), 2983 (s), 1508 (m), 1362 (s), 1273 (s), 1187 (m), 1143
(s), 960 (s), 905 (s), 836 (s), 788 (m).
Dep r otection of Aceton e-Ma sk ed Alk yn es.17 To a solu-
tion of 3gf (2.2 g, 10.5 mmol) in dry toluene (50 mL) was added
sodium hydroxide powder (400 mg, 10 mmol). The suspension
was refluxed till the starting material was consumed com-
pletely (8 h). Brine (15 mL) was added, and the separated
-
1
prior to use. K
2
CO
3
, K
3
PO
4
‚3H
2
O, KF, Pd(OAc)
2
, KOH, aryl
bromides, phenylacetylene, and hexyne were used directly as
obtained commercially unless otherwise noted. Other alkynes
were prepared according to the literature.
P r ep a r a tion of Liga n d s. Caution: The aminophosphine
ligands may be toxious, no MSDS available. L1 was prepared
1
6
according to the literature, while L2 was prepared according
to the process mentioned as follows: Under a nitrogen
atmosphere, a 100 mL three-necked flask was charged with
toluene layer was dried (MgSO ). The solvent was evaporated
4
5
-bromobenzo[1,3]dioxole (4.0 g, 20 mmol) in dry ether (15 mL)
under reduced pressure, and the residue was purified by flash
and n-BuLi (15 mL, 1.6 M in hexanes, 24 mmol) was added
dropwise at -20 °C with stirring. The mixture was further
(17) (a) Havens, S. J .; Hergenrother, P. M. J . Org. Chem. 1985, 50,
1
763-1764. (b) Pourjavadi, A.; Marandi, G. B. J . Chem. Res., Synop.
(
16) Contreras, R.; Grevy, J . M.; Garcia-Hernandez, Z.; Gueizado-
2002, 11, 552-555. (c) Takalo, H.; Kankare, J .; H a¨ enninen, E. Acta
Chem. Scand., Ser. B 1988, 42, 448-454.
Rodriguez, M.; Wrackmeyer, B. Heteroat. Chem. 2001, 12, 542-550.
J . Org. Chem, Vol. 69, No. 16, 2004 5431

Cheng et al.
column chromatography on a silica gel to give 1-naphthyl-
acetylene (4gf) as a colorless liquid (1.17 g, yield 73%). H NMR
Sciences, and Science and Technology Commission of
Shanghai Municipality for financial support.
1
(
3
300 MHz, CDCl ): δ 8.42 (d, J ) 8.1 Hz, 1H), 7.87 (d, J ) 8.1
Hz, 2H), 7.80-7.76 (m, 1H), 7.62-7.54 (m, 2H), 7.46-7.42 (m,
1
1
H), 3.52 (s, 1H). 1 C NMR (75 MHz, CDCl
3
Su p p or tin g In for m a tion Ava ila ble: Analytical data and
copies of spectra for the ligands and the cross-coupling
products (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
3
): 133.4, 133.0,
31.2, 129.2, 128.2, 126.9, 126.4, 126.0, 125.0, 119.7, 82.0, 81.7.
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, Chinese Academy of
J O049379O
5
432 J . Org. Chem., Vol. 69, No. 16, 2004