W. S. Chow, T. H. Chan / Tetrahedron Letters 50 (2009) 1286–1289
1289
the coupling reaction.16 We offer the following interpretation of
our results. In the reaction of 3a with imidazole (Figure 1), chela-
tion of the amino acid with Cu(I) facilitates the coupling reaction
as nearly all amino acids give a better yield of product 4a than
using CuI alone. However, because the reaction is carried out under
solventless conditions and an external base may not be in close
proximity, the rate determining step may well be the replacement
of the bromide by imidazole to give the intermediate C (Scheme 4).
If that is the case, the presence of the extra basic amino group in
lysine will assist in removing the proton from imidazole thus pro-
moting the substitution. Other factors may play a role as well. Argi-
nine which also has a basic amino group did not show comparable
result in this reaction. This may be due to the strong coordination
between the guanidine moiety of arginine and copper ion which
interferes with the formation of complex A.
R
R
O
O
ArBr
oxidative addition
H2N
Ar
O
H2N
O
Cu
Cu
reductive
elimination
Br
B
A
R
O
NuH
ArNu
H2N
Ar
O
HBr
Cu
HNu = imidazole
Nu
C
For the reaction of electron-deficient 3h (Figure 2), the
plexed mechanism proposed by Paine may be operative.19 Under
solventless conditions, the formation of the -complex D (Scheme
p-com-
Scheme 4.
p
R
5) may be the critical step. Hydrogen bonding between the gluta-
mine amide function and the carbonyl function of 3h may facilitate
bringing the Cu(I) species A and the aryl bromide together for such
complexation formation.
In conclusion, we have shown that microwave-assisted solvent-
free reactions can be used for the N-arylation of imidazole and
pyrazole.
O
Ar-Br
Ar-Nu
H2N
O
R
O
Cu
R
A
O
H2N
O
Acknowledgments
Cu
H2N
O
We acknowledge the support from the Hong Kong Polytechnic
University and the Research Grants Council Central Allocation
Fund (CityU 2/06C).
Cu
Br
R
O
Nu
π−complex D
References and notes
H2N
O
1. Metal-catalyzed Cross-Coupling Reactions; Diederich, F., de Meijere, A., Eds.;
Wiley-VCH: Weinheim, 2004.
Cu
(HNu)
2. Cozzi, P.; Carganio, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli, M.;
Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964–2972.
3. Gregory, E. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055–3057.
4. Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J. Med. Chem. 1996,
39, 3971–3979.
- Br-
Br
Nu
5. Martinez, G. R.; Walker, K. A. M.; Hirshfield, D. R.; Bruno, J. J.; Yang, D. S.;
Maloney, P. J. J. Med. Chem. 1992, 35, 620–628.
Scheme 5.
6. Gungor, T.; Fouquet, A.; Teulon, J. M.; Provost, D.; Cazes, M.; Cloavec, A. J. Med.
Chem. 1992, 35, 4455–4463.
7. Lo, Y. S.; Nolan, J. C.; Maren, T. H.; Welatead, W. J., Jr.; Gripshover, D. F.;
Shamblee, D. A. J. Med. Chem. 1992, 35, 4790–4794.
ers in promoting this reaction, with
L-lysine being the most effec-
tive for 3a (Figure 1) and -glutamine for 3 h (Figure 2). We have
L
8. (a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J. Org. Chem. 2004,
695–709; (b) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P.
W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers,
R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhange, Y. Y.; Tsakson, P. C. J. Med. Chem. 1997, 40, 1347–1365.
9. Corbet, I.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.
10. Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–
1470.
11. Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2007, 46, 8862–8865.
12. Ibata, T.; Isogami, Y.; Toyoda, J. Bull. Soc. Chem. Jpn. 1991, 64, 42–49.
13. Meciaerova, M.; Podlesna, J.; Toma, S. Monatsh. Chem. 2004, 135, 419–423.
14. (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–584; (b)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–796.
15. A Milestone MicroSYNTH microwave organic synthesis labstation was used for
the reaction. Aryl fluoride (1 mmol), imidazole (1 mmol), and potassium
phosphate tribase (2 equiv) were placed in a sealed vessel. After the reaction,
the mixture was cooled and the product was extracted by dichloromethane.
16. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164–5173.
17. Physical data of 4j: 1H NMR (CDCl3) d 4.64 (d, J = 5.0 Hz, 2H), 5.35 (d, J = 10.0 Hz,
1H), 5.46 (d, J = 17.0 Hz, 1H), 6.05–6.08 (m, 1H), 6.79 (s, 1H), 7.06 (d,
J = 10.0 Hz, 2H), 7.27 (s, 1H), 7.41 (s, 1H), 7.69–7.75 (m, 2H), 7.90 (d,
J = 9.0 Hz, 2H), 7.98 (s, 1H), 8.23 (s, 1H); 13C NMR (CDCl3) d 67.0, 106.0,
115.3, 117.4, 118.3, 120.0, 123.6, 124.9, 126.4, 128.1, 130.9, 132.4, 134.4, 154.7,
161.7, 163.9, 177.3; LRMS m/z (M+H+) 345; HRMS calcd for C21H16N2O3 (M+H+)
345.1239, found 345.1232.
therefore applied the CuI-promoted cross-coupling of imidazole
to a number of aryl bromides under microwave-assisted solvent-
free conditions using either L-lysine or L-glutamine (Table 2). The
results are summarized in Table 2. As one can see, the reaction
worked well for aryl bromides with electron-rich substituents.
For bromoanisoles, irrespective of the position of the methoxy
group, nearly quantitative yield of the product could be obtained
(Table 2, entries 1–3).
We were able to achieve C–N coupling for the complex flavone
3j with imidazole to give 4j (Table 2, entry 10), which was required
in the study of multidrug resistance.17,18 When the same reaction
was carried out in DMSO, no product was obtained. We have also
applied the microwave-assisted solvent-free conditions to the cou-
pling of pyrazole with aryl bromides (Scheme 3). The results are
summarized in Table 3. In all cases, the reaction worked and the
products were obtained in moderate yields.
It is interesting to compare our observation with that of Ma
et al.16 where they found
L-proline and glycine to be the most effec-
tive amino acids to promote the CuI catalyzed coupling reaction in
DMSO solution. It was suggested that chelation of Cu(I) with the
amino acid made the Cu(I) species (A, Scheme 4) more reactive to-
ward the oxidative addition step (B, Scheme 4), thereby promoting
18. Chan, K. F.; Zhao, Y.; Burkett, B. A.; Wong, I. L. K.; Chow, L. M. C.; Chan, T. H. J.
Med. Chem. 2006, 49, 6742–6759.
19. Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496–1502.