S. G. Johnson et al. / Tetrahedron Letters 47 (2006) 4853–4856
4855
not an issue with the synthon 14. Alkylation and cycliza-
Ar
Ar
X
N
X
N
tion of 2 with 14 proceeded uneventfully to give 15 in
excellent yield. Treatment of 15 with DMF dimethyl-
acetal at elevated temperatures led directly to intermedi-
ate 12c. In lieu of isolation, the reaction was cooled and
treated with thionyl chloride to directly give intermedi-
ate 13.9 This shortened route was more conducive to
scale-up, improved the overall yield to 27%, and was
carried through without chromatography.
CN
CN
R
HN
S
N
S
N
a
b
MeS
13
16
17
Scheme 5. Reagents and conditions: (a) ArXH, IPA, 120–160 °C
(sealed reactor) or ArXH, LHMDS, DMF; (b) (1) MCPBA, CHCl3,
NaHCO3(aq); (2) RNH2, DCM.
The differentially activated intermediate 13 was sequen-
tially derivatized on C-7 and C-2 to give the compounds
in Tables 1 and 2, respectively. The synthesis of these
compounds was performed as outlined in Scheme 5
without optimization for any given analog. First, the
C-7 chloride of 13 was displaced by nucleophiles such
as anilines, phenols, and thiophenols to provide 16
(Table 1).10 The sterically more congested nucleophiles
required the addition of base and correspondingly gave
lower yields; for instance 16a–b versus 16c–d. The
methyl mercapto group of 16 was then oxidized with
MCPBA to activate it for subsequent displacement with
amines, giving the products 17 (Table 2). Oxidation with
MCPBA generally gave a mixture of sulfoxide and sul-
fone intermediates, with the sulfoxide as the major prod-
uct. When adding anilines in the subsequent step the
sulfoxides proved to be kinetically more reactive than
the sulfones. Complete reaction of the sulfoxides, based
on LCMS monitoring, was routinely seen prior to con-
sumption of the sulfones. Displacements with aliphatic
amines were always low yielding (17a,e) with hydrolysis
the major product of the reaction.
Table 1. Substitution on C-7 of thiazolo[4,5-b]pyridine-6-carbonitrile
Ar
X
CN
S
In summary, we have developed a concise route for
synthesis of the versatile intermediate 13. Masking the
cyano group as a t-butylamide provided a convenient
means of improving the yield and shortening the syn-
thetic route. The orthogonal activity of the C-2 and C-
7 positions on 13 allowed for selective substitution at
these two sites on the bicyclic ring.
MeS
N
N
Compound
Ar
X
Yield (%)
16a
16b
16c
3-Cl, 4-FPh
3-HCCPh
NH
NH
NH
70
67
53
2,4-DiCl, 5-MeOPh
O
Acknowledgements
16d
NH
45
O
The authors thank Dr. Xun Li and Yongzheng Zhang
for the scale-up of advanced intermediates.
Cl
16e
16f
16g
16h
3-CF3OPh
2,4-DiClPh
3-BrPh
O
O
S
76
52
73
40
2-Cl, 4-FPh
S
References and notes
1. Artyomov, V. A.; Ivanov, V. L.; Shestopalov, A. M.;
Litvinov, V. P. Tetrahedron 1997, 53, 13351–13360.
2. Ismail, N. A.; Khalifa, F. A.; Fekry, R. M.; Abdel Azim,
Y. N. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 66, 29–
35.
Table 2. Substitution on C-2 of thiazolo[4,5-b]pyridine-6-carbonitrile
R
3. Leysen, D. C.; Haemers, A.; Bollaert, W. J. Heterocycl.
Chem. 1984, 21, 1361–1366.
X
R'
HN
CN
S
4. Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M.
B., Jr.; Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.;
Mamuya, N.; Nilakantan, R.; Reich, M. F.; Shen, R.;
Tsou, H.; Upeslacis, E.; Wang, Y. F.; Wu, F.; Zhang, N.
J. Med. Chem. 2000, 43, 3244–3256.
N
N
Compound
R
X
R0
Yield
(%)a
5. Hayakawa, I.; Tanaka, Y. Heterocycles 1984, 22, 1697–
1700.
6. Dahn, H.; Hauth, H. Helv. Chim. Acta 1964, 47, 1424–
1428.
7. (a) Claisen, L. Chem. Ber. 1909, 42, 59–68; (b) Sauers, R.
R.; Van Arnum, S. D. J. Heterocycl. Chem. 2003, 40, 655–
658.
8. (a) Benary, E. Chem. Ber. 1908, 41, 2399–2411; (b)
Boosen, K. J. Helv. Chim. Acta 1977, 60, 1256–1261.
9. Representative synthesis: Example 13: Commercially avail-
able 2 (21.3 g, 125 mmol) was added to a solution of 14
(23.9 g, 125 mmol) at 0 °C in acetone (300 mL). The
reaction was stirred for 1 h at 0 °C and then at rt for 18 h.
17a
17b
17c
17d
17e
17f
3-Cl, 4-F NH (CH2)3-morpholin-4-yl
3-Cl, 4-F NH 6-Cl-pyridin-3-yl
3-Cl, 4-F NH 4-(CH2-morpholin-4-yl)Ph 27
3-Cl, 4-F NH 6-MeO-pyridin-3-yl
3-CCH NH (CH2)2-morpholin-4-yl
2,4-DiCl, NH 4-(CH2-morpholin-4-yl)Ph 19
5-OMe
4
16
50
10
17g
17h
2,4-DiCl
O
4-OCH2-(1-CH3)-
piperidin-3-yl-Ph
4-OCH2-(1-CH3)-
piperidin-3-yl-Ph
29
2-Cl, 4-F
S
38
a Overall isolated yield from methylsulfanyl intermediate, 16; 2 steps.