Chemistry Letters Vol.35, No.3 (2006)
271
References and Notes
´
For examples, see: a) J. Gerencser, G. Panka, T. Nagy, O. Egyed, G.
1 equiv.
1
N
N
R1
HBr
O
¨
Dorman, L. Urge, L. Darvas, J. Comb. Chem. 2005, 7, 530. b) J.-Y.
´
Kazock, C. Enguehard-Gueiffier, I. Thery, A. Gueiffier, Bull. Chem.
Br
N
NH2
R1
´
OCH2Ph
11'
OCH2Ph
Soc. Jpn. 2005, 78, 154. c) J. M. Chezal, E. Moreau, O. Chavignon,
C. Lartigue, Y. Blache, J. C. Teulade, Tetrahedron 2003, 59, 5869.
d) C. Enguehard, H. Allouchi, A. Gueiffier, S. L. Buchwald, J.
Org. Chem. 2003, 68, 5614.
O
O
DMSO
O
S
Br
R1
R1
Br
2
a) K. F. Byth, J. D. Culshaw, S. Green, S. E. Oakes, A. P. Thomas,
Bioorg. Med. Chem. Lett. 2004, 14, 2245. b) C. Hamdouchi, H.
Keyser, E. Collins, C. Jaramillo, J. E. De Diego, C. D. Spencer,
J. A. Dempsey, B. D. Anderson, T. Leggett, N. B. Stamm, R. M.
Schultz, S. A. Watkins, K. Cocke, S. Lemke, T. F. Burke, R. P.
Beckmann, J. T. Dixon, T. M. Gurganus, N. B. Rankl, K. A. Houck,
F. Zhang, M. Vieth, J. Espinosa, D. E. Timm, R. M. Campbell,
B. K. R. Patel, H. B. Brooks, Mol. Cancer Ther. 2004, 3, 1. c) M.
Anderson, J. F. Beattie, G. A. Breault, J. Breed, K. F. Byth, J. D.
Culshaw, R. P. A. Ellston, S. Green, C. A. Minshull, R. A. Norman,
R. A. Pauptit, J. Stanway, A. P. Thomas, P. J. Jewsbury, Bioorg. Med.
Chem. Lett. 2003, 13, 3021.
S. L. Colletti, J. L. Frie, E. C. Dixon, S. B. Singh, B. K. Choi, G.
Scapin, C. E. Fitzgerald, S. Kumar, E. A. Nichols, S. J. O’Keefe,
E. A. O’Neill, G. Porter, K. Samuel, D. M. Schmatz, C. D. Schwartz,
W. L. Shoop, C. M. Thompson, J. E. Thompson, R. Wang, A. Woods,
D. M. Zaller, J. B. Doherty, J. Med. Chem. 2003, 46, 349.
11'
Attack to Br
Attack to S
S
1
Base
Base
Br
Bromosulfonium salt
12
demethylation
Scheme 2. A plausible mechanism for the formation of 3-bro-
moimidazo[1,2-a]pyridine derivatives.
obtained in 11 and 5% yields, respectively (Entries 1 and 2).13
Elongation of the reaction time led to the increase of unfavorable
product 12a while compound 11a disappeared (Entries 2–4).
Further addition of ꢀ-bromoketone (five equivalents) was not
effective for improving yield of products (Entries 5 and 6). In-
creasing temperature resulted in a decrease in the yield of 1a,
as compared with synthesis of compound 1a under the condition
of room temperature (Entries 7–9). This result would be due to
the lower thermal stability of 1a. Consequently, the conditions
shown in Entry 4 were adopted as the optimum conditions.14
The reaction of compound 10 with ꢀ-bromoketone derivatives
3–9 under this optimum conditions directly gave the desired
products 1b–1h in 40–63% yields, though unfavorable products
12a–12h were also obtained, respectively (Entries 10–16). The
lower yield for 1b would be due to its instability and to the rapid
decomposition of 3.
A plausible mechanism for the reaction in this study is illus-
trated in Scheme 2. The reaction of 2-aminopyridine with an
equimolar amount of ꢀ-bromoketone first yields salts of 3-
non-substituted IP derivative 110. The reaction of an excess
amount of ꢀ-bromoketone with DMSO as a solvent generates
a bromosulfonium salt via an alkoxysulfonium salt. Attack by
110 on the Br side of this reactive salt leads to the formation of
1, along with dimethyl sulfide. On the other hand, attack on
the S side and subsequent demethylation by bromide leads to the
formation of 12. Formation of dimethyl sulfide and ꢀ-hydroxy-
acetophenone during the experiment under the conditions shown
in Entry 4 was confirmed. Reaction of 110 in DMSO in the pres-
ence of 2 gave 1 and 12 in 73 and 9% yields, respectively.
In conclusion, we have demonstrated that the reaction of 2-
aminopyridine derivatives with an excess amount of ꢀ-bromoke-
tones proceeds smoothly to directly produce 3-bromoimidazo-
[1,2-a]pyridine derivatives in moderate yields, along with
corresponding 3-methylthio derivatives. Therefore, our method
would be advantageous in terms of mild reaction at room tem-
perature and one-pot procedure, compared with previous reports
for the construction of title compounds.9 Further study of the
details of the reaction mechanism in this study and application
of this method to other 2-amino-substituted heterocyclic com-
pounds and ꢀ-haloketones, and their biological activities are
now in progress.
3
4
5
Z.-P. Zhuang, M.-P. Kung, A. Wilson, C.-W. Lee, K. Plossl, C. Hu,
¨
D. M. Holtzman, H. F. Kung, J. Med. Chem. 2003, 46, 237.
J. J. Kaminski, J. A. Bristol, C. Puchalski, R. G. Lovey, A. J. Elliott,
H. Guzik, D. M. Solomon, D. J. Conn, M. S. Domalski, S.-C. Wong,
E. H. Gold, J. F. Long, P. J. S. Chiu, M. Steinberg, A. T. McPhail,
J. Med. Chem. 1985, 28, 876.
6
7
K. J. Holm, K. L. Goa, Drugs 2000, 59, 865.
D. J. Keeling, A. G. Taylor, C. Schudt, J. Biol. Chem. 1989, 264,
5545.
´
´
Y. Kawakami, A. Raya, R. M. Raya, C. Rodrıguez-Esteban, J. C.
8
9
´
Izpisua Belmonte, Nature 2005, 435, 165.
For examples, for construction of IP framework, see Refs. 1–8. For
bromination, see: a) E. Moreau, J.-M. Chezal, C. Dechambre, D.
Canitrot, Y. Blache, C. Lartigue, O. Chavignon, J.-C. Teulade, Het-
erocycles 2002, 57, 21. b) T. Ikemoto, M. Wakimasu, Heterocycles
2001, 55, 99. c) A. P. Thomas, C. P. Allott, K. H. Gibson, J. S. Major,
B. B. Masek, A. A. Oldham, A. H. Ratcliffe, D. A. Roberts, S. T.
Russell, D. A. Thomason, J. Med. Chem. 1992, 35, 877.
10 Bromoketone derivatives 2 and 3 were purchased from Wako Pure
Chemical Industries, Ltd.
11 S. Kajigaeshi, T. Kakinami, T. Okamoto, S. Fujisaki, Bull. Chem.
Soc. Jpn. 1987, 60, 1159.
12 J. A. Bristol, I. Gross, R. G. Rovey, Synthesis 1981, 971.
13 General procedure: To a solution of 10 (152 mg, 0.75 mmol) in dry
DMSO (3.0 mL) was added 2 (447 mg, 2.25 mmol) at room temper-
ature. The reaction mixture was stirred overnight at the same temper-
ature, and then poured into ice-water. After being adjusted to pH 9
with saturated aqueous sodium carbonate, the reaction mixture was
extracted with ethyl acetate. The organic layer was washed with
H2O and brine, and then dried over anhydrous MgSO4. After remov-
al of the solvent, the residue was purified by column chromatography
(silica gel, hexane–ethyl acetate, 4:1, v/v) to give 1a (173 mg, 61%)
as colorless needles, along with 12a (29 mg, 11%) as yellow crystals.
Selected data for 1a: mp 98.5–99.0 ꢁC (dec). 1H NMR (400 MHz,
CDCl3) ꢃ 8.17 (2H, d, J ¼ 7:0 Hz), 7.82 (1H, d, J ¼ 6:6 Hz), 7.51–
7.46 (4H, m), 7.40–7.31 (4H, m), 6.74 (1H, dd, J ¼ 6:6 Hz, 7.9
Hz), 6.53 (1H, d, J ¼ 7:9 Hz), 5.43 (2H, s). FAB-MS (NBA) m=z
380 ½M þ Hꢂþ. 12a: mp 98.5–99.0 ꢁC. 1H NMR (400 MHz, CDCl3)
ꢃ 8.33 (2H, d, J ¼ 7:0 Hz), 8.10 (1H, d, J ¼ 6:6 Hz), 7.50–7.45
(4H, m), 7.39–7.31 (4H, m), 6.74 (1H, dd, J ¼ 6:6 Hz, 7.9 Hz),
6.55 (1H, d, J ¼ 7:9 Hz), 5.42 (2H, s), 2.24 (3H, s). FAB-MS
(NBA) m=z 347 ½M þ Hꢂþ.
14 Compounds 1 and 12 can be easily separated by column chromatog-
raphy, though compounds 11 and 12 were difficult to separate due to
comparable Rf value.
We thank the Materials Analysis Center of ISIR-Sanken,
Osaka University for assisting us with FAB-MS analysis.