A. S. Kiselyov, L. Smith, II / Tetrahedron Letters 47 (2006) 2611–2614
2613
The described transformations is likely to proceed via
Saloutin, V.; Stepanchikova, A.; Stingaci, E.; Tkach, N.;
Vlad, L.; Voronina, T. Bioorg. Med. Chem. Lett. 2005, 12,
6559.
. (a) Zimmermann, P. J.; Palmer, A.; Brehm, C.; Klein, T.;
Senn-Bilfinger, J.; Simon, W.-A.; Postius, S.; Chiesa, M.
V.; Buhr, W.; Kromer, W. PCT Int. Appl. 2004, WO
the initial formation of the respective a,b-unsaturated
1
0–12
imines
3 that undergo nucleophilic attack at C3 by
3
the exocyclic amino group of the heterocycle. This step
is then followed by cyclization and aromatization to
1
4
yield the observed products 4a–l. Optimized reaction
conditions include application of dry THF or dioxane
as solvents, as well as thorough temperature control.
The latter is particularly important at the earlier stages
of reagent addition, during the formation of a,b-unsatu-
rated imines. The reason could be high reactivity of
the intermediate species 2a/2b and 3. Addition of dry
freshly distilled DMF (ca. 20%) to the reaction mixtures
at the heterocyclization stage was found to increase the
overall yields of the targeted molecules by ca. 25–30%.
This is presumably due to the increased solubility of
the amino heterocycle component and higher reaction
temperature that both facilitate condensation and aro-
matization steps. We further extended the described pro-
cedure to the synthesis of fused tricyclic systems 4j–l by
reaction of the intermediate 3 with 2-amino benzimid-
azole derivatives (Scheme 2).
2
004071391; (b) Mueller, B.; Zimmermann, P.; Scheufler,
C.; Kohl, B. PCT Int. Appl. 2004, WO 2004101566; (c)
Fernstroem, P.; Hasselgren, G. PCT Int. Appl. 2005, WO
2005041961.
4. (a) Olivier, A.; Sevrin, M.; Durant, F.; George, P. Bioorg.
Med. Chem. Lett. 1997, 7, 2277; (b) Sanger, D. J. Behav.
Pharm. 1995, 6, 116; (c) Harrison, T. S.; Keating, G. M.
CNS Drugs 2005, 19, 65.
5
. (a) Miwa, S.; Mizokami, A.; Keller, E. T.; Taichman, R.;
Zhang, J.; Namiki, M. Cancer Res. 2005, 65, 8818; (b) Cui,
N.; Nomura, T.; Noma, H.; Yokoo, K.; Takagi, R.;
Hashimoto, S.; Okamoto, M.; Sato, M.; Yu, G.; Guo, C.;
Shibahala, T. Clin. Cancer Res. 2005, 11, 2713; (c) Ling,
Y.; Sahota, G.; Odeh, S.; Chan, J. M. W.; Araujo, F. G.;
Moreno, S. N. J.; Oldfield, E. J. Med. Chem. 2005, 48,
3130; (d) Yuasa, T.; Nogawa, M.; Kimura, S.; Yokota, A.;
Sato, K.; Segawa, H.; Kuroda, J.; Maekawa, T. Clin.
Cancer Res. 2005, 11, 853.
. Hamdouchi, C.; Zhong, B.; Mendoza, J.; Collins, E.;
Jaramillo, C.; De Diego, J. E.; Robertson, D.; Spencer, C.
D.; Anderson, B. D.; Watkins, S. A.; Zhang, F.; Brooks,
H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1943.
. Xia, G.; Li, J.; Peng, A.; Lai, S.; Zhang, S.; Shen, J.; Liu,
Z.; Chen, X.; Ji, R. Bioorg. Med. Chem. Lett. 2005, 15,
6
Additional components of the reaction mixtures
included the corresponding a,b-unsaturated ketones
(
25–40% by LC MS analysis, 20–35% isolated yields)
7
that likely originated from the intermediate imines 3.
Our attempts to reduce formation of these side products
by thorough moisture control (dry box), increasing the
temperature of the reaction (ca. 140 °C, sealed tube),
microwave irradiation of the reaction mixtures or by
addition of an alternative polar solvents at the conden-
sation stage (N-methylpyrrolidone, dimethoxyethane)
were unsuccessful. Regioselective nature of the cycliza-
2
790.
8. Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.;
MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, Sandra
L.; DeMartino, J. A.; Springer, M. S.; Hazuda, D.; Miller,
M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.;
Henry, K.; Lineberger, J.; Schleif, W. A.; Emini, E. A.
Boorg. Med. Chem. Lett. 2005, 15, 2129.
9. (a) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4487; (b)
Gerencser, J.; Panka, G.; Nagy, T.; Egyed, O.; Dorman,
G.; Uerge, L.; Darvas, F. J. Comb. Chem. 2005, 7, 530; (c)
Huang, H.-Y.; Hou, R.-S.; Wang, H.-M.; Chen, L.-C. J.
Chin. Chem. Soc. 2004, 51, 1377.
1
3
tion has been confirmed by NOE experiments.
In summary, we have described a convenient regio-
specific one-pot approach to pyrazolo[1,5-a]- and
imidazo[1,2-a]pyrimidine derivatives from a,b-unsatu-
rated imines generated in situ and amino heterocycles.
Reaction is general with respect to all three components,
namely (i) nitrile, (ii) aldehyde, and (iii) amino hetero-
cycle reagents. Good yields (52–77%), convenient isola-
tion of the targeted heterocycles 4a–l are the distinct
characteristics of the developed protocol. Currently,
we are in the process of investigating both scope and
limitations of the procedure.
10. (a) Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 9297; (b)
Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 1663.
11. (a) Shin, W. S. S.; Lee, K.; Oh, D. Y. Tetrahedron Lett.
1
995, 36, 281; (b) Palacios, F.; Garcia, J.; Ochoa de
Retana, A. M.; Oyarzabal, J. Heterocycles 1995, 41, 1915,
and references cited therein.
1
1
2. Lee, K.; Oh, D. Y. Synthesis 1991, 213.
3. General experimental procedure: n-BuLi (2.5 M solution in
hexanes, 4 mL, 10 mmol) was added by syringe to a
vigorously stirred solution of methyl phosphonate
(
10 mmol) in dry THF or dioxane (10 mL) under Ar at
À78 °C. A solution of nitrile (10 mmol) in 5 mL of the
same solvent was slowly added by syringe. The resulting
colorless mixture was slowly warmed to À50 °C and
stirred for additional 30 min. A solution of aldehyde
(10 mmol) in 5 mL of dry solvent (THF or dioxane) was
slowly added (5 min), and the resulting mixture was
allowed to warm up to room temperature (45 min). A
solution of amino heterocycle (10 mmol) in freshly dis-
tilled dry DMF (5 mL) was added to the a,b-unsaturated
imine 3 generated in situ at 0 °C. The reaction mixture was
brought to rt (20 min) and, subsequently to reflux
(20 min). Further, it was refluxed for additional 8 h until
TLC (hexanes/ether, 1:1) or LC MS analyses indicated
absence of starting materials (nitrile and aldehyde). The
mixture was then concentrated on rotavap, the residue was
re-dissolved in EtOAc (50 mL) and filtered. The organic
References and notes
1
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2
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2