1782
B. Liu et al. / Tetrahedron Letters 46 (2005) 1779–1782
Table 1 (continued)
Entry
Aryl halide
NH2
Boronic acid
Product
NH2
Solvent/temp (°C)
Base (equiv)
KF (5)
Yielda (%)
51
OH
B
OH
13
THF/80
Br
NH2
Cl
NH2
OH
B
OH
14
Dioxane/110
K3PO4 (2)
91
NC
NC
Reaction conditions: 1 equiv of aryl halide, 1.0–1.5equiv of aryl boronic acid, 5mol% of Pd catalyst 1. Reaction time: 4–16 h.
a All the yields were isolated yields and all the products gave satisfactory 1H NMR and MS.
mides were used as substrate, milder reaction conditions
could be used (entries 2a, and 5–13). For example, both
2-chloro-6-methyl-aniline and 2-bromo-6-methyl-aniline
provided 3-methyl-biphenyl-2-ylamine in good yields
(entries 2a and 2b). Not surprisingly, even at a lower
reaction temperature (60 °C in THF) the bromide sub-
strate gave a better yield compared with the chloride
substrate at a higher reaction temperature (110 °C in
dioxane). Heteroaryl substituted anilines and phenols
were also obtained in good yield (entries 1, 6, 7, 8). In
addition, at a lower reaction temperature, Suzuki cou-
pling was successful between 2-bromo-6-methyl-phenyl-
amine and phenyl boronic acids with chloro
substitutions (entries 10–12). The R3 group was not just
limited to aryl or heteroaryl moieties. For example,
when cyclohexen-1-ylboronic acid was used, the corre-
sponding substituted aniline was obtained in moderate
yield (entry 13). This coupling reaction can be easily
scaled up. We have carried out reaction 2a at 5g scale
and obtained 88% isolated yield.
Acknowledgements
We thank Mr. Brandon Campbell and Dr. Robert
Schiksnis for their analytical assistance, and Dr. Enrique
Michelotti for his helpful suggestions.
References and notes
1. Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39,
2887.
2. For a nice review on aryl-aryl bond formation, see:
Hassen, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359.
3. (a) Zhu, S.; Shi, S.; Gerritz, S. W.; Sofia, M. J. J. Comb.
Chem. 2003, 5, 205; (b) Caron, S.; Massett, S. S.; Bogle, D.
E.; Castaldi, M. J.; Braish, T. F. Org. Process Res. Dev.
2001, 5, 254.
4. Lisowski, V.; Robba, M.; Rault, S. J. Org. Chem. 2000,
65, 4193.
5. Shen, W. Tetrahedron Lett. 1997, 38, 5575.
6. For an excellent review, see: Fu, G. C.; Littke, A. F.
Angew. Chem. Int. Ed. 2002, 41, 4176.
Suzuki coupling with Pd catalyst 1 was easily carried out
according to the following representative experimental
procedure for synthesizing compound 10: To a mixture
of 2-chloro-6-methyl-phenol (1.00 g, 7.0 mmol), phenyl
boronic acid (0.85g, 7.0 mmol) and KF (2.0 g,
35.0 mmol) in a flask was added catalyst 1 (150 mg,
5% mol). The flask was then flushed with nitrogen and
10.0 mL of degassed dioxane was added. The flask was
then sealed and heated at 120 °C overnight. The reaction
mixture was cooled to room temperature, filtered
through CeliteÒ, and concentrated under vacuum. The
residue was then purified by flash chromatography (hex-
anes to 30% ethyl acetate) to afford the desired product
as pale yellow oil (0.70 g, 54%).
7. Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H.-U.
Angew. Chem. Int. Ed. 2002, 41, 3668.
8. Purchased from Strem Chemicals, Inc.
9. Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125.
10. Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron
Lett. 1998, 39, 3985.
11. Analytical data for compound 5: 1H NMR (400 MHz,
CD3OD): d 7.52 (d, J = 8.0 Hz, 1H), 7.46–7.42 (m, 2H),
7.38–7.34 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 6.69 (t, J = 8
Hz, 1H); 13C (100 MHz, CD3OD): d 172.6, 146.2, 139.2,
133.4, 129.4, 129.1, 128.8, 128.1, 127.4, 115.9, 115.4; MS
(APCI+): 214.5(M+H +).
12. Analytical data for compound 9: 1H NMR (400 MHz,
C2D6CO): d 7.50–7.28 (m, 7H), 7.25 (d, J = 8.0 Hz, 1H),
7.09 (d, J = 7.8 Hz, 1H), 6.59 (s, 1H), 4.58 (s, 2H); 13C
NMR (100 MHz, C2D6CO): d 168.7, 145.1, 139.6, 134.8,
130.2, 129.6, 129.0, 128.9, 127.5, 116.4, 114.9; MS
(APCI+): 213.2 (M+H+).
In conclusion, we have reported Suzuki coupling reac-
tion conditions amenable to prepare substituted biaryl
anilines or phenols without protection of amino or hy-
droxyl groups. Using preformed catalyst 1, these biaryl
building blocks with multiple diversity points were
efficiently obtained from commercially available aryl
chlorides or aryl bromides.
13. Analytical data for compound 10: 1H NMR (400 MHz,
CDCl3): d 7.50–7.37 (m, 5H), 7.13 (d, J = 8 Hz, 1H), 7.07
(d, J = 8.0 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 2.24 (s, 3H).
14. Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37,
3387.