LHMDS mediated tandem acylation-cyclization of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl acetates: A short and efficient route to the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2005.11.113

We herein describe the discovery of a mild, one-pot tandem acylation-cyclization for the synthesis of 4-amino-3-benzimidazol-2- ylhydroquinolin-2-ones from 2-aminobenzenecarbonitriles and ethyl 2-benzimidazol-2-yl acetates.

Full text of DOI:10.1016/j.tetlet.2005.11.113

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 657–660
LHMDS mediated tandem acylation–cyclization
of 2-aminobenzenecarbonitriles with 2-benzymidazol-2-yl
acetates: a short and efficient route to the synthesis of
4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones
William R. Antonios-McCrea, Kelly A. Frazier, Elisa M. Jazan, Timothy D. Machajewski,
Christopher M. McBride, Sabina Pecchi,* Paul A. Renhowe,
Cynthia M. Shafer and Clarke Taylor
Small Molecule Drug Discovery, Medicinal Chemistry Department, Chiron Corporation, 4560 Horton Street,
Emeryville, CA 94608, USA
Received 8 November 2005; revised 22 November 2005; accepted 22 November 2005
Available online 9 December 2005
Abstract—We herein describe the discovery of a mild, one-pot tandem acylation–cyclization for the synthesis of 4-amino-3-benz-
imidazol-2-ylhydroquinolin-2-ones from 2-aminobenzenecarbonitriles and ethyl 2-benzimidazol-2-yl acetates.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
physicochemical and pharmacokinetic properties and
significant efficacy in murine and human xenograft
tumor models.10 In the course of our RTK inhibitor
program, we encountered the need for an efficient and
scalable synthetic route to 4-amino-3-benzimidazol-2-
ylhydroquinolin-2-ones.
Receptor tyrosine kinases (RTK) and their ligands are
involved in important signal transduction pathways
within the cell. In particular, vascular endothelial
growth factor (VEGF), basic fibroblast growth factor
(bFGF), platelet derived growth factor (PDGF) and
their receptors play a fundamental role in cell prolifera-
tion, differentiation (i.e., vasculogenesis and angiogene-
sis) and cell death.1–4 These kinases are overexpressed
in several malignancies in vivo and their pathways are
deregulated.5,6 Inhibition of growth factor receptor
tyrosine kinases represents an attractive therapeutic
modality in oncology, and several RTK inhibitors are
currently being evaluated preclinically or in clinical tri-
als.7–9
Two main approaches to 3-substituted-4-aminohydro-
quinolin-2-ones are described in the literature. The most
widely used is based on nucleophilic substitution on 4-
chlorohydroquinolin-2-ones with ammonia, ammonia
equivalents or amines.11–14 More direct transformations
begin with a 2-aminobenzenecarbonitrile and an active
methylene compound and are promoted with either
Lewis acids15–18 or bases.14,19–21 These two methods
incorporate esters, nitriles or aryl groups at the C-3
position of the hydroquinolin-2-one. The only reported
method incorporating a benzimidazole in the C-3 posi-
tion of a 4-hydroxyhydroquinolin-2-one involves high
temperatures (130–140 ꢁC).22–24
4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones (e.g., 4)
are a class of potent RTK inhibitors with attractive
In the course of our work, these synthetic routes were
examined for the synthesis of 4-amino-3-benzimidazol-
2-ylhydroquinolin-2-ones but were not optimal due to
lengthy reaction sequences, harsh reaction conditions,
or inability to accommodate various functionalities. This
paper describes a one pot, tandem acylation–cyclization
Keywords: Receptor tyrosine kinases (RTK); 4-Amino-3-benzimidazol-
2-ylhydroquinolin-2-one; Tandem acylation–cyclization; LHMDS.
*
Corresponding author. Tel.: +1 510 923 7812; fax: +1 510 923
3360; e-mail: sabina_pecchi@chiron.com
Present address: Pfizer Corporation, 2800 Plymouth Road, Ann
Arbor, MI 48105, USA.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.113

658
W. R. Antonios-McCrea et al. / Tetrahedron Letters 47 (2006) 657–660
Table 1.
sequence to obtain 4-amino-3-benzimidazol-2-ylhydro-
quinolin-2-ones with mild conditions and in good
yields.
Base (3 equiv)a
Temp. (ꢁC)
% Conversionb
Ratio 3:4b
KOtBuc
NaOEtd
NaH
80
80
25
20
10
10
50
4
50:50
70:30
10:90
30:70
95:5
s-BuLi
LDA
LHMDS
À78 to 25
À78 to 25
À78 to 25
2. Results and discussion
100
45:55
The reported synthesis of the 3-ethyl ester 4-
aminohydroquinolin-2-one used NaOEt in EtOH
(1 equiv at 80 ꢁC).14,25,26 Our attempts to reproduce this
work for the 3-benzimidazole analog, starting from ethyl
2-benzimidazol-2-ylacetate 132 and 2-aminobenzenecar-
bonitrile 2 (Scheme 1), gave a very low conversion (Ta-
ble 1). Moreover, the reaction afforded a mixture of the
desired cyclized product 4 together with the uncyclized
2-benzimidazol-2-yl-N-(2-cyanophenyl)acetamide 3.
a In THF unless otherwise indicated.
b % Conversions and ratios determined by HPLC.
c In PhMe.
d NaOEt in EtOH.
and freshly prepared LDA gave similarly disappointing
and unexplainable results.
Having found LHMDS to be the optimal base for
obtaining the desired product 4, the effect of tempera-
ture on the reaction was then assessed (Table 2). At
low temperature, cyclized product 4 did not form at
all. Warming to room temperature gave approximately
a 1:1 ratio of 3:4, while heating to 40 ꢁC for 2–4 h
resulted in complete conversion to 4.
Changing the base from NaOEt to LHMDS (1 equiv)
led exclusively to the formation of the uncyclized amide
3.27 Earlier literature reports28–31 suggest that similar
amide intermediates containing an acidic methylene
group can be cyclized to hydroquinolinones in the pres-
ence of bases such as NaH in DMF or NaOEt in EtOH,
albeit in poor yields. When the crude amide 3 was trea-
ted with NaOEt in EtOH, the desired product 4 could be
obtained in very low yields and was contaminated by
numerous impurities.
For compound 4, the optimal reaction conditions em-
ployed 3 equiv of LHMDS at 40 ꢁC resulting in a 61%
yield (Table 3).33 However, most 2-benzimidazol-2-yl-
acetates were sensitive to temperatures above 25 ꢁC,
and extensive decarboxylation to 2-methylbenzimidazole
occurred prior to reaction with the 2-aminobenzonitriles.
Lowering the temperature and increasing the equiva-
lents of LHMDS led to better yields, and the most gen-
eral reaction conditions are 5 equiv of LHMDS at room
temperature for 2–3 h. Under these conditions, yields
typically range from 30% to 80%. Table 3 highlights sev-
eral examples synthesized by this method.
The deprotonation of the benzimidazole NH in com-
pound 3 may in fact deactivate the a methylene, slowing
down the cyclization step and favoring undesired side
reactions. These preliminary results, however, prompted
us to optimize the reaction conditions to obtain 4 exclu-
sively and in one step.
A number of inorganic and organometallic bases were
surveyed. In general, when a mixture of ethyl 2-benz-
imidazol-2-ylacetate 132 and 2-aminobenzenecarbo-
nitrile 2 was treated with 3 equiv of base, the formation
of the desired cyclized 4 together with variable amounts
of uncyclized 3 was observed (Table 1). Alkoxides gave
low conversion of starting material to products and an
unfavorable ratio of 3 and 4. The main side product
was 2-methyl benzimidazole, derived from hydrolysis
and decarboxylation of the ethyl ester. The use of
NaH at room temperature gave mostly cyclized product
4, but the conversion was also very low. Attempts to im-
prove the reaction conversion by heating to reflux led to
decomposition. s-BuLi and LHMDS gave better results,
with the conversion of starting material to 3 and 4 being
superior with LHMDS. LDA gave very poor conversion
of starting material to products with the undesired 3
being the predominant product. Commercially available
A variety of functional groups, including halo, nitrile,
ester, aniline, and ether substituents, on either the
hydroquinolinone or the benzimidazole, are tolerated
using the optimized reaction conditions, and several
hundred 4-amino-3-benzimidazol-2-ylhydroquinolin-2-
ones have been synthesized by this method.
Table 2.
Temperature (ꢁC)a
Ratio 3:4b
À78
100:0
45:55
0:100
À78 to 25
40
a 3 equiv LHMDS in THF.
b Ratios determined by HPLC.
Scheme 1.

W. R. Antonios-McCrea et al. / Tetrahedron Letters 47 (2006) 657–660
659
Table 3.
R2
NH2
N
R2
CO2Et
CN
N
LHMDS,THF
R1
N
H
+
N
H
R1
rt or 40°C
NH2
N
H
O
5
Compound
R1
R2
Yield
5a
5b
5-F
H
–CO2Me
–CN
O
45a
63a
34b
61c
49a
87a
60a
N
5c
4
H
H
N
N
N
N
O
5d
5e
5f
5-NH2
5-OMe
5-F
N
N
N
N
5g
5h
6-Cl
7-F
63a
80a
N
N
N
a Yield after sonication in a solution of 94.5:5:0.5 Et2O/acetone/MeOH and filtration.
b Yield after reverse phase HPLC.
c Yield after column chromatography.
10. Lee, S. H.; Vora, J.; Lopes de Menezes, D.; Wiesmann,
M.; Garrett, E.; Aukerman, L.; Heise, C. Proc. AACR,
94th AACR Annual Meeting, Washington, DC, United
States, 11–14 July 2003, Vol. 44, p 934.
11. Shridhar, D. R.; Sastry, C. V. R.; Mehrotra, A. K.; Rao,
C. S.; Taneja, V. Ind. J. Chem. Sect. B: Org. Chem. Includ.
Med. Chem. 1979, 17B, 488–490.
3. Conclusions
In conclusion, LHMDS promotes a one-pot tandem
acylation–cyclization of 2-aminobenzene carbonitriles
and 2-benzimidazolyl acetates under very mild condi-
tions and in moderate to good yields.
12. Coppola, G. M.; Hardtmann, G. E. J. Heterocycl. Chem.
1981, 18, 917–920.
13. Stadlbauer, W.; Kappe, T. Monatsh. Chem. 1982, 113,
751–760.
Supplementary data
14. Santilli, A. A.; Scotese, A. C.; Bauer, R. F.; Bell, S. C. J.
Med. Chem. 1987, 30, 2270–2277.
15. Isowa, Y. In U.S.; (Mitsui Toatsu Chemicals Co., Ltd.).
US3663606, 1972, 3pp.
16. Veronese, A. C.; Callegari, R.; Salah, S. A. A. Tetrahedron
Lett. 1990, 31, 3485–3488.
Supplementary data (1H and 13C NMR) are available
for compound 4. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.11.113.
17. Veronese, A. C.; Callegari, R.; Morelli, C. F. Tetrahedron
1995, 51, 12277–12284.
References and notes
´
´
18. Charvat, T.; Potacek, M.; Marek, J. Monatsh. Chem. 1995,
126, 333–340.
1. Karkkainen, M. J.; Petrova, T. V. Oncogene 2000, 19,
5598–5605.
19. Schaefer, H.; Sattler, K.; Gewald, K. J. Prakt. Chem.
1979, 321, 695–698.
2. Carmeliet, P. Nat. Med. 2000, 6, 389–395.
3. List, A. F. Oncologist 2001, 6, 24–31.
20. Gewald, K.; Schaefer, H.; Bellmann, P.; Mueller, H.
Chem. Ber. 1991, 124, 1237–1241.
4. Zwick, E.; Bange, J.; Ullrich, A. Trends Mol. Med. 2002, 8,
17–23.
5. Graeven, U.; Fiedler, W.; Karpinski, S.; Ergun, S.; Kilic,
N.; Rodeck, U.; Schmiegel, W.; Hossfeld, D. K. J. Cancer
Res. Clin. Oncol. 1999, 125, 621–629.
6. Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57–70.
7. Traxler, P. Expert Opin. Ther. Targets 2003, 7, 215–234.
8. Laird, A. D.; Cherrington, J. M. Expert Opin. Invest.
Drugs 2003, 12, 51–64.
21. Rybakov, V. B.; Chernyshev, V. V.; Ukrainets, I. V.;
Bezugly, P. A.; Sidorenko, L. V.; Skaif, N. Acta Crystal-
logr. Sect. E: Struct. Reports Online 2003, E59, o412–o414.
22. Ukrainets, I. V.; Bezuglyi, P. A.; Treskach, V. I.; Turov,
A. V. Khim. Geterot. Soedin. 1992, 239–241.
23. Ukrainets, I. V.; Taran, S. G.; Turov, A. V. Khim. Geterot.
Soedin. 1993, 1105–1108.
24. Ukrainets, I. V.; Bezugly, P. A.; Taran, S. G.; Gorokhova,
O. V.; Turov, A. V. Tetrahedron Lett. 1995, 36, 7747–
7748.
9. Fischer, P. M. Current Med. Chem. 2004, 11, 1563–1583.

660
W. R. Antonios-McCrea et al. / Tetrahedron Letters 47 (2006) 657–660
25. Diethyl malonate and NaOEt in EtOH followed by the
addition of 2-aminobenzenecarbonitrile and heating for
51/2 h.
26. Santilli, A. A. In U.S.; (American Home Products Corp.,
USA). US4284768, 1981, 5pp.
32. Church, T. J.; Cutshall, N. S.; Gangloff, A. R.; Jenkins, T.
E.; Linsell, M. S.; Litvak, J.; Rice, K. D.; Spencer, J. R.;
Wang, V. R. In PCT Int. Appl.; (Axys Pharmaceuticals
Corporation, USA). WO9845275A1, 1998, 108pp.
33. 4-Amino-3-(6-morpholin-4-ylbenzimidazol-2-yl)hydro-
quinolin-2-one 4. To a flame dried 500 mL round-
bottomed flask were added ethyl 2-(5-morpholin-4-ylbenz-
imidazol-2-yl)acetate 1 (5.0 g, 17 mmol), anthranilonitrile
2 (2.0 g, 17 mmol), and anhydrous THF (50 mL). To the
resulting solution was added LHMDS (1.0 M solution in
THF, 50 mL, 50 mmol), via a syringe, over 10 min. The
reaction mixture was heated at 40 ꢁC for 2 h, cooled to
room temperature, and then poured into a vigorously
stirred mixture of satd aq NH4Cl (30 mL) and EtOAc
(200 mL). The two phases were separated, and the
aqueous phase was extracted with EtOAc (3 · 100 mL).
The organic extracts were collected, dried (Na2SO4), and
evaporated under reduced pressure. The residue was
triturated with Et2O, and the resulting greenish-brown
powder was purified by chromatography on silica gel (10%
MeOH in CH2Cl2), to afford the desired product 4 (3.7 g,
61% yield) as a light yellow solid.
27. Compound 3 can be distinguished by a diagnostic signal of
the methylene protons at 4.3 ppm.
28. Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.;
Stevenson, G. I.; Carling, R. W.; Baker, R.; Marshall, G.
R.; Kemp, J. A.; Foster, A. C.; Grimwood, S.; Hargreaves,
R.; Hurley, C.; Saywell, K. L.; Tricklebank, M. D.;
Leeson, P. D. J. Med. Chem. 1997, 40, 4053–4068.
29. Carling, R. W.; Leeson, P. D.; Moore, K. W.; Moyes, C.
R.; Duncton, M.; Hudson, M. L.; Baker, R.; Foster, A.
C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.;
Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1997,
40, 754–765.
30. Kreimeyer, A.; Laube, B.; Sturgess, M.; Goeldner, M.;
Foucaud, B. J. Med. Chem. 1999, 42, 4394–4404.
31. Tsuji, K.; Spears, G. W.; Nakamura, K.; Tojo, T.; Seki,
N.; Sugiyama, A.; Matsuo, M. Bioorg. Med. Chem. Lett.
2002, 12, 85–88.