Table 3 Microwave-assisted Pd catalyzed Negishi cross-coupling reactions
Table 4 Microwave assisted Negishi cross-coupling reaction of arylchloride
bound to Merrifield resin
Catalysta
(mol %)
Yield
(%)b
Entry ArCl
Ar–ZnX
Solvent
1
2
3
4
4-Cl–C6H4–NO2 o-Tol–ZnCl 1/4
2-Cl–C6H4–CN p-Tol–ZnCl 0.015/0.06 THF/NMP 90
4-Cl–C6H4–OMe o-Tol–ZnCl 1/4 THF/NMP 90
THF/NMP 85
2-Cl–C6H4–CN
3-MeO–
C6H4–ZnI 2.5/10
THF
THF
THF
83c
73
75
5
6
7
4-Cl–C6H4–CN
2-Py–ZnCl
1.5/6
1.5/6
Entry
Ar–ZnX
Solvent
Yield (%)
Puritya
4-Cl–C6H4–NO2 2-Py–ZnCl
4-Cl–Py 4-MeO–
C6H4–ZnCl 1.5/6
4-Cl–C6H4–NO2 Bu–ZnCl 1/4
1
2
Ph–ZnCl
3-MeO–C6H4–ZnIb
THF/NMP
THF
90
87
96
90
THF
THF
77
84
8d
a HPLC purity b prepared by Rieke zinc insertion (Table 1, entry 6)
a Pd2(dba)3/tBu3P.HBF4 (mol ratio 1/4). b Isolated yields after chromatog-
raphy. c GC-MS conversion. d Run at 120°C for 30 minutes.
exception of entry 4) showed complete conversion after 10 min of
microwave irradiation, comparing very favourably with reaction
times of 2–24 h observed under conventional conditions.6,13 We
also report here that the use of microwaves facilitates the Grignard
reaction as shown in Scheme 1 and the so obtained arylmagnesium
bromide can be subjected to subsequent high yielding Kumada
cross-coupling1 with an aryl chloride under the same conditions as
used in the Negishi reactions.
It has to be noted, however, that typically a higher amount of
homocoupling product is formed using microwave irradiation as
compared with ultrasound-promoted Grignard reactions performed
at ambient temperature.
Notes and references
1 For reviews see: V. Snieckus, Chem. Rev., 1990, 90, 879; S. P.
Stanforth, Tetrahedron, 1998, 54, 263; J. Hassan, M. Sévignon, C.
Gozzi, E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359.
2 For a review, see: E.-I. Negishi, in Metal-Catalyzed Cross-Coupling
Reactions, ed. F. Diederich, P. J. Stang, Wiley-VCH, New York,
1998.
3 M. Larhed, C. Moberg and A. Hallberg, Acc. Chem. Res., 2002, 35,
717.
4 (a) L. Öhberg and J. Westman, Synlett, 2001, 1893; (b) P. Stanetty, M.
Schnürch and M. D. Mihovilovic, Synlett, 2003, 1862; (c) See also: B.
Hayes, Microwave Synthesis. Chemistry at the Speed of Light, CEM
Publishing, Matthews, 2002.
Finally we wish to report that microwave-assisted Negishi cross-
coupling reactions can also be carried out employing a resin-bound
aryl chloride (Table 4).
5 For an excellent review, see: A. F. Littke and G. C. Fu, Angew. Chem.
Int. Ed., 2002, 41, 4176.
6 C. Dai and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 2719.
7 (a) L. Zhu, R. M. Wehmeyer and R. D. Rieke, J. Org. Chem., 1991, 56,
1445; (b) L. Zhu, K. H. Shaughnessy and R. D. Rieke, Synth. Commun.,
1993, 23, 525; (c) R. D. Rieke, M. V. Hanson and J. D. Brown, J. Org.
Chem., 1996, 61, 2726.
8 (a) P. Lidström, J. Tierney, B. Wathey and J. Westman, Tetrahedron,
2001, 57, 9225; (b) A. Stadler and C. O. Kappe, J. Comb. Chem., 2001,
3, 624; (c) For online resources on microwave-assisted organic
9 V. P. W. Böhm, T. Weskamp, C. W. K. Gstöttmayr and W. A.
Herrmann, Angew. Chem. Int. Ed., 2000, 39, 1602.
10 D. Zim and A. L. Monteiro, Tetrahedron Lett., 2002, 43, 4009 and
references therein.
Applying the optimized Pd2(dba)3/tBu3P.HBF4 catalyst system a
solid-phase protocol was realized, applying microwave-assisted
reactions in all three steps of the synthesis.14 For two model
arylzinc halides (Table 4), complete conversions were achieved
within 10 minutes employing 5 mol% of the Pd catalyst, providing
the desired biaryl carboxylic acids in high yield and high purity.
These are the first reported transition metal-catalyzed C–C
coupling reactions on solid-phase involving aryl chlorides.15
In conclusion, we have developed a general and efficient
protocol for high-speed microwave-assisted Negishi cross-cou-
pling reactions in solution- and solid-phase applied to aryl
chlorides. Similarly, Grignard, Kumada and Rieke zinc insertion
reactions could be easily conducted under microwave conditions in
sealed vessels without the need for inert atmosphere.
11 S. Saito, S. Oh-tani and N. Miyaura, J. Org. Chem., 1997, 62, 8024 and
references therein.
12 M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295.
13 Note that here the use of microwave irradiation provides very high
turnover frequencies for Pd-catalyzed C–C cross-coupling reactions of
aryl chlorides (TOF 270 h21, Table 3, entry 3), for Pd-catalyzed cross-
couplings of aryl chlorides in general (36 3 104 h21, entry 2) and for Ni-
catalyzed cross-couplings (328 h21, Table 2, entry 4). For comparison,
see: B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam and B.
Sreedhar, J. Am. Chem. Soc., 2002, 124, 14127.
This work was supported by the Austrian Science Fund (FWF, P-
15582). We thank Personal Chemistry AB (Uppsala) for providing
single-mode microwave technology.
14 For literature precedent regarding the microwave-assisted coupling and
cleavage of arylcarboxylic acids to Merrifield resins, see: A. Stadler and
C. O. Kappe, Eur. J. Org. Chem., 2001, 919.
15 J. Hassan, M. Sévignon, C. Gozzi, E. Schulz and M. Lemaire, Chem.
Rev., 2002, 102, 1359 see in particular p. 1429.
Scheme 1 Microawave-assisted Grignard and Kumada reactions.
C h e m . C o m m u n . , 2 0 0 4 , 5 6 4 – 5 6 5
565