3
Supplementary Material
Scheme 2. Synthesis of PhIP.
Supplementary data (experimental procedures and spectral
data for all new compounds) associated with this article can be
found in the online version.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP,
a
20) is
known carcinogen produced amino acid
condensations during high temperature cooking of meat
and fish.10 Previous syntheses of 20 have required steps at
high temperatures and proceeding in low yields.11 We
applied our CBZ-protected imidoyl dichloride reagent 6 as
the penultimate step (Scheme 2) and were able to produce
20 from the inexpensive 2-chloro-3-nitropyridine in >60 %
yield over 6 steps.
Acknowledgments
Research support is granted from the National Institutes of
Health (PHS 5R37DK015556 to J.A.K). J.A.P. was supported by
training fellowship from the National Institutes of Health
(T32ES007326).
References and notes
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Dallas-Yang, Q.; Ding, V.; Dragovic, J.; Iliff, S.; Jiang, G. Q.;
Mock, S.; Qureshi, S.; Saperstein, R.; Szalkowski, D.;
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Scheme 3. Synthesis of Boc-protected Imidoyl Dichloride,
22.
2. Kubicek, S.; O'Sullivan, R. J.; August, E. M.; Hickey, E. R.;
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Initially, we chose a carboxybenzyl protecting group for
our imidoyl dichloride reagent for ease of monitoring the
reactions by TLC and removal by hydrogenation. However,
we predicted the chemistry could be amenable to additional
protecting groups. Indeed, we were able to prepare a t-
butyloxycarbonyl protected imidoyl dichloride (22) through
reaction of the S,S’-dimethyliminiothiocarbonate (4) with
phosgene followed by t-butanol and finally the displacement
of the thioethers with chlorine. Similar to 6, reaction of 22
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with
1,2-phenylenediamines
afforded
the
2-
aminobenzimidazoles (Table 4) rapidly and in good yields
regardless of the electronic nature of the ring substituents
(entries b-c) and the N-substitution (entry d). In addition,
reaction of 22 with 2-aminophenol afforded the
corresponding benzoxazole in good yield (entry e). We
predict that the imidoyl dichoride reagents would be
amenable, as well, to alternative amine protecting groups,
allowing for the rapid production of 2-aminobenzimidazoles
and related azoles that could be further derivatized as
desired.
7. Nawrocka, W.; Sztuba, B.; Kowalska, M. W.; Liszkiewicz, H.;
Wietrzyk, J.; Nasulewicz, A.; Pełczyńska, M.; Opolski, A. Il.
Farmaco. 2004, 59, 83.
Table 4. Scope of reaction with 22.
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Felton, J. S. Fd. Chem. Toxic. 1989, 27, 667. (b) Perkins, J. J.;
Zartman, A. E.; Meissner, R. S. Tet. Lett. 1999, 40, 1103. (c) Car-
penter, R. D.; Deberdt, P. B.; Lam, K. S.; Kurth, M. J. J. Comb.
Chem. 2006, 8, 907-914.
entry
R
H
X
Yield (%)
9. Lee, J. H.; An, M. H.; Choi, E. H.; Choo, H. Y. P.; Han, G.
Heterocycles 2006, 70, 571.
a
b
c
NH
81
70
93
88
57
10. (a) Felton, J. S.; Knize, M. G.; Shen, N. H.; Lewis, P. R.;
Andresen, B. D.; Happe, J.; Hatch, F. T. Carcinogenesis, 1986, 7,
1081. (b) Felton, J. S.; Knize, M. G.; Shen, N. H.; Lewis, P. R.;
Andresen, B. D.; Bjeldanes, L. F.; Hatch, F. T. Environ. Health
Perspect. 1986, 67, 17.
OCH3
NO2
H
NH
NH
N(CH2CH2CH3)
O
d
e
11. (a) Knize, M. G.; Felton, J. S. Heterocycles 1986, 24, 1815. (b)
Choshi, T.; Tonari, A.; Yoshioka, H.; Harada, K.; Sugino, E.;
Hibino, S. J. Org. Chem. 1993, 58, 7952. (c) Nguyen, T.M.;
Novak, M. J. Org. Chem. 2007, 72, 4698. (d) Chrisman, W.;
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H
3. Conclusions
Overall, we have developed a robust reagent tolerant of
multiple functional groups that allows for the rapid formation of
benzimidazole or alternative azole rings at room temperature.