and satisfactory method for the Pd-catalyzed alkynylation
than the other known methods.
(iii) acylation,15 as well as (c) selective synthesis of
conjugated diynes.11c,12c,13a Along with these favorable results,
however, some unsatisfactory results, both understandable
and inexplicable, have also been reported.5b,11a,16 For example,
we recently reported the synthesis of 3-aryl-2-propynoic
esters by the Pd-catalyzed reaction of 3-zinco derivatives of
ethyl propynoate with aryl iodides only in modest yields.11a
The corresponding reaction of 2-propynone derivatives was
even less satisfactory. We judged that the difficulty observed
with these alkynes must be associated with the use of highly
nucleophilic bases, such as n-BuLi, routinely used by us and
others.2, 9-16
Currently, the method most widely used by far is a hybrid
of the Cu-promoted Castro-Stevens reaction3 and the alkyne
version of the Heck reaction,4 commonly known as the
Sonogashira reaction1 (eq 3 in Scheme 1). Despite its overall
excellence, however, various difficulties have also been
noted. One widely reported is that, under the standard
conditions, electron-deficient alkynes, such as HCtCCOOR,5
where R is Me, Et, and so on, 1-propyn-3-ones,5h and
HCtCCF3,6 tend to give their arylated and alkenylated
derivatives in unacceptably low yields. Various modifications
have been devised to overcome this difficulty. They include
the use of (a) propynoic acid readily convertible in situ to
electron-rich propynoate anion,5a,b (b) 3,3,3-tris(ethoxy)-1-
Accordingly, “non-nucleophilic” bases, LDA17 in particu-
lar, were used to generate alkynyllithiums to be converted
to the Zn derivatives (eq 1 in Scheme 1).18
5d,e,g,h
As the results summarized in Table 1 indicate, the yields
obtained with HCtCCOOMe are uniformly excellent, while
the use of n-BuLi in place of LDA led only to traces of the
desired cross-coupling products. Furthermore, LDA also
permits the use of intrinsically more sensitive 1-propyn-3-
ones without noticeable difficulties. We believe that this
method (Procedure A) is generally more satisfactory than
any of the known methods, including the most recently
reported reaction of iodonium salts5h for the Pd-catalyzed
alkynylation.
As the requirement for rigorous exclusion of moisture by
flame drying or other forms of heating at reduced pressures
(3 mmHg) has been considered to be an inconvenience in
the Pd-catalyzed alkynylzinc coupling as compared with the
Sonogashira reaction, we sought an operationally simpler
procedure by the use of amines as bases for the Pd-catalyzed
alkynylation (Procedure B, eq 2 in Scheme 1),19 and the
following new, simple, and efficient procedure was devel-
oped. To premixed ZnBr2 and Et3N (1:4 ratio) in THF were
propyne in place of ethyl propynoate, and (c) K2CO3
or Na2CO35f as a base in place of amines. These modifications
are, however, indirect5a,b,7 and hence somewhat cumbersome
and/or of unpredictable and limited applicability.5d-f The
most recent modification5h published during the course of
this investigation does appear to represent an exception, but
the use of preformed iodonium salts requiring both aryl
iodides and sulfonates8 adds an extra step and poses a
question of how to attain the aryl/alkyne ratio of 1:1.
We discovered and developed in the 1977-1978 period
the Pd-catalyzed alkynylation with alkynylmetals containing
Zn,2 B,2c Sn,2c Mg,2c and Al2c a` la that with alkynylsodium
of limited applicability reported by Cassar.9 Of these metals,
Zn has repeatedly been shown to be generally of superior
reactivity leading to higher selectivity and product yields.2c,10
Thus, the Pd-catalyzed alkynylation with alkynylzincs has
been successfully applied to (a) direct ethynylation2a,b,10,11
that cannot be achieved by the Sonogashira reaction, (b)
synthesis of internal alkynes via (i) arylation and hetero-
arylation,2b,c,10a,b,11a,b,12 (ii) alkenylation,2a,10a,c,11b,c,12c,13,14 and
(12) (a) Negishi, E.; Luo, F. T.; Frisbee, R.; Matsushita, H. Heterocycles
1982, 18, 117. (b) Negishi, E.; Akiyoshi, K.; Takahashi, T. J. Chem. Soc.,
Chem. Commun. 1987, 477. (c) Negishi, E.; Hata, M.; Xu, C. Org. Lett.
2000, 2, 3687.
(13) (a) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
1984, 49, 2629. (b) Negishi, E.; Ay, M.; Gulevich, Y. V.; Noda, Y.
Tetrahedron Lett. 1993, 34, 1437. (c) Negishi, E.; Liu, F.; Choueiry, D.;
Mohamud, M. M.; Silveira, A., Jr.; Reeves, M. J. Org. Chem. 1996, 61,
8325. (d) Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Tetrahedron 2000, 56,
10197. (e) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719.
(14) (a) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini, P.
Tetrahedron 1998, 54, 135. (b) Abarbri, M.; Parrain, J. L.; Cintrat, J. C.;
Ducheˆne, A. Synthesis 1996, 82.
(15) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F. T.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(2) (a) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem.
Commn. 1977, 683. (b) King, A. O.; Negishi, E.; Villani, F. J., Jr.; Silveira,
A., Jr. J. Org. Chem. 1978, 43, 358. (c) Negishi, E. In Aspects of Mechanism
and Organometallic Chemistry; Brewster, J. H., Ed.; Plenum Press: New
York, 1978; p 285. See also: Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(3) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163.
(4) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259.
(5) (a) Cacchi, S.; Morera, E.; Ortar, G. Synthesis 1986, 320. (b)
Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.;
Yamanaka, H. Synthesis 1992, 746. (c) Hsung, R. P.; Babcock, J. R.;
Chidsey, C. E. D.; Sita, L. R. Tetrahedron Lett. 1995, 36, 4525. (d) Yu, K.
L.; Chen, S.; Ostrowski, J.; Tramposch, K. M.; Reczek, P. R.; Mansuri, M.
M.; Starrett, J. E., Jr. Bioorg. Med. Chem. Lett. 1996, 6, 2859. (e) Eckert,
T.; Ipaktschi, J. Synth. Commun. 1998, 28, 327. (f) Barabanov, I. I.; Fedenok,
L. G.; Shvartsberg, M. S. Russ. Chem. Bull. 1998, 47, 2256. (g) de Kort,
M.; Luijendijk, J.; van der Marel, G. A.; van Boom, J. H. Eur. J. Org.
Chem. 2000, 3085. (h) Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 3,
859.
(16) Passarella, D.; Lesma, G.; Deleo, M.; Martinelli, M.; Silvani, A. J.
Chem. Soc., Perkin Trans. 1 1999, 2669.
(17) We have previously used LDA to effect both elimination of
haloalkenes and generation of alkynyllithiums in the synthesis of conjugated
diynes (ref 11c, 12c).
(6) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara, T.; Suzuki, A.
Bull. Chem. Soc. Jpn. 1990, 63, 2124.
(7) Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997, 1367.
(8) (a) Koser, G. F.; Wettach, R. H.; Smith, C. S. J. Org. Chem. 1980,
45, 1543. (b) Stang, P. J.; Zhdankin, V. V.; Tykwinski, R.; Zefirov, N. S.
Tetrahedron Lett. 1991, 32, 7497.
(18) Procedure A. Methyl 3-(4-Methoxyphenyl)propiolate. Repre-
sentative Example. To a solution of N,N-diisopropylamine (0.57 g, 5.6
mmol) in 5 mL of THF was added n-BuLi (2.5 M solution in hexanes, 2.2
mL) at 0 °C in a flame-dried flask under Ar atmosphere. After 10 min, the
reaction mixture was successively treated with methyl propiolate (0.5 mL,
5.6 mmol) in 2 mL of THF (-78 °C, 10 min), dry ZnBr2 (1.26 g, 5.61
mmol) in 3 mL of THF (-78 °C, 10 min), 4-iodoanisole (1.09 g. 4.67
mmol), and Pd(PPh3)4 (0.25 g, 0.23 mmol). The temperature was raised to
23 °C. After 3 h, the reaction mixture was diluted with Et2O, washed with
aqueous NH4Cl and then with aqueous NaHCO3, dried over MgSO4, filtered,
and concentrated. Chromatography on silica gel (95/5 hexane/EtOAc, v/v)
gave methyl 3-(4-methoxyphenyl)propiolate as light yellow crystals (0.77
g, 87%), mp 41-42 °C.
(9) Cassar, L. J. Organomet. Chem. 1975, 93, 253.
(10) (a) Negishi, E.; Kotora, M.; Xu, C. J. Org. Chem. 1997, 62, 8957.
(b) Negishi, E.; Xu, C.; Tan, Z.; Kotora, M. Heterocycles 1997, 46, 209.
(c) Negishi, E. J. Organomet. Chem. 1999, 576, 179.
(11) (a) Kotora, M.; Negishi, E. Synthesis 1997, 121. (b) Liu, F.; Negishi,
E. J. Org. Chem. 1997, 62, 8591. (c) Negishi, E.; Alimardanov, A.; Xu, C.
Org. Lett. 2000, 2, 65.
3112
Org. Lett., Vol. 3, No. 20, 2001