Chemistry Letters Vol.36, No.4 (2007)
523
Table 1. Synthesis of 3-bromoflavone 6 from 1 and 2
R4
References and Notes
1
a) A. M. Khattab, M. H. Grace, E. A. El-Khrisy, Pharmazie
2001, 56, 661. b) T. Horie, H. Tominaga, Y. Kawamura, T.
M. M. Haenen, W. J. F. van der Vijgh, A. Bast, W. M. P. B.
J. F. A. Molfetta, K. M. Honorio, R. H. A. Santos, A. B. F. Silva,
R3
R2
R1
O
O
CuBr2
t-BuOK
1 + 2
3
4
pyridine
THF
Br
DMF
130 °C, 10 min.
6
Yield of Yield of CuBr2
4/%a (equiv.)
Yield of
6/%a
R1 R2
R3 R4
3/%a
H
H
H
H
3a 60 4a 60
2.2
3.0
4.0
4.0
4.0
6a 53(30)b
54(22)b
68
6b 70
6c 75
2
a) M. Pal, V. Subramanian, K. Parasuraman, K. R. Yeleswarapu,
Subramanian, R. Dakarapu, K. R. Yeleswarapu, Tetrahedron
Me
Cl
H
Cl
Me
Cl
Br
Br
H
H
MeO
H
H
H
H
H
H
t-Bu
H
F
H
H
H
H
3b 91 4b 54
3c 89 4c 53
3d 96 4d 68
3e 91 4e 77
4.0c 6d 49
3
4
A. Takechi, H. Takikawa, H. Miyake, M. Sasaki, Chem. Lett.
T. G. C. Bird, B. R. Brown, I. A. Stuart, A. W. Tyrrell, J. Chem.
4.0
4.0
4.0
4.0
4.0
6e 57
6f 55
6g 50
6h 82
6i 66
Cl 3f 99 4f 85
H
H
3g 82 4g 84
3h 96 4h 84
5
6
H
H
H
H
Cl 3i 91 4i 78
aIsolated yield. bYield of 5 is in parentheses. cReaction conditions:
7
8
110 ꢁC, 25 min.
a) J. K. Makrandi, Shashi, S. Kumar, Surender, Indian J. Chem.,
Sect. B 2004, 43B, 895. b) R. E. Hadange, A. G. Doshi, A. W.
Raut, Asian J. Chem. 2002, 14, 509. c) S. Garg, M. P. S. Ishar,
R. Sarin, R. P. Gandhi, Indian J. Chem., Sect. B 1994, 33B,
1123. d) K. N. Wadodkar, K. B. Doifode, Indian J. Chem., Sect.
B 1979, 18B, 458.
O
O
O
R−NH2
THF
Br
NHR
Br
Br
O
9
6h
Entry 1 R = Et (70% aqueous solution)
r. t., 12 h
r. t., 12 h
r. t., 3.5 h
60 °C, 6 h
r. t., 12 h
8a 90%
8b 98%
8c 88%
8d 85%
8e 57%
2
3
4
5
6
R = n-Pr
10 T. S. Wheeter, Org. Synth. 1963, Coll. Vol. IV, 478.
R = n-Bu
R = c-Hex
R = H (28% aqueous solution)
12 Typical procedures are as follows.
R = H (28% aqueous solution, DMF 50 °C, 15 h 8e 86%
Synthesis of 3b. Benzoyl chloride (4.5 g, 32 mmol) was added
to a pyridine (10 mL) solution of 5-methyl-2-hydroxyacetophe-
none (4.5 g, 30 mmol). The mixture was heated at 70 ꢁC for
10 min. The mixture was poured into cool 3 M HCl (40 mL)
and extracted with ethyl acetate. The extract was dried over
anhydrous MgSO4, and the solvent was removed under reduced
pressure. The residue was recrystallized from methanol to give
3b (6.9 g, 27 mmol) in 91% yield.
Synthesis of 4b. Potassium t-butoxide (90% purity, 3.7 g,
30 mmol) was added to a THF (30 mL) solution of 3b (6.9 g,
27 mmol). The mixture was stirred at r.t. for 10 min. The mixture
was poured into cool 3 M HCl (30 mL) and extracted with ethyl
acetate. The extract was dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The residue was
recrystallized from methanol to give 4b (3.7 g, 15 mmol) in
54% yield.
was used as solvent)
Scheme 4.
unidentified products were obtained.
The effectiveness of DMF can be explained as follows
(Scheme 3). When 4 was treated with CuBr2, bromination of 4
proceeded smoothly to give 7 and HBr, and the latter catalyzed
the cyclization of 7 to give 5. However, HBr also catalyzed the
cyclization of 4 to give the undesired product 5. When a solvent
other than DMF was used, acid (HBr)-catalyzed cyclization
proceeded more smoothly than the bromination of 4, and in
that case, 5 was obtained as a major product. On the other hand,
because of its basisity, DMF trapped Hþ to some extent and
moderately suppressed the acid-catalyzed cyclization.
The ammonia and primary amines shown in Scheme 4 react-
ed with 6h, which was prepared by the procedures described
above, to give 3-aminoflavones 8 in a good yield.13 In the
cases of ethylamine (Entry 1) and ammonia (Entries 5 and 6), an
aqueous solution of amines can be used. Using DMF as a solvent
for the reaction with aqueous NH3 is effective for improving the
yield of 8. The reaction of aqueous NH3 with 6h gave 8e in an
86% yield (Entry 6), whereas the corresponding reaction in
THF gave 8e in only a 57% yield (Entry 5). Probably because
of its poor nucleophilicity, aniline did not react with 6h even
under reflux conditions for 15 h.
Synthesis of 6b. A DMF (6 mL) solution of 4b (0.76 g,
3.0 mmol) was heated to 130 ꢁC. Copper(II) bromide (2.68 g,
12 mmol) was added to the solution and stirred for 10 min.
The mixture was poured into water and extracted with ethyl
acetate. After the usual workup, the crude product was purified
by column chromatography on silica gel to give 6b (0.66 g,
2.1 mmol) in 70% yield.
13 Typical procedures are as follows.
Synthesis of 8c. A THF (1.5 mL) solution of 6h (0.114 g,
0.30 mmol) and butylamine (0.55 g, 0.75 mmol) was stirred at
r.t. for 3.5 h. The mixture was poured into water (10 mL) and
extracted with ethyl acetate. After the usual workup, the crude
product was recrystallized from CHCl3 to give 8c (0.098 g,
0.26 mmol) in 88% yield. In the cases of 8a and 8e (Entries 1,
5, and 6), a large excess (10–20 equiv.) of amines was used.
In conclusion, the reaction of 4 with CuBr2 in DMF is an
effective method for the synthesis of 6. Furthermore, 6 is as good
a precursor of 8 as 3-tosyloxy- or 3-mesyloxyflavone.3