Solution phase synthesis of imidazo[1,2-b]pyrazol-2-one, an interesting 5,5-fused heterocyclic ring system

Article abstract of DOI:10.1016/j.tetlet.2003.10.177

The solution phase synthesis of a series of imidazo[1,2-b]pyrazol-2-ones, a fused 5,5-ring system, based on diverse set of hydrazino acids and malononitriles is described. The method involves formation of 5-aminopyrazoles followed by intra-molecular cyclodehydration.

Full text of DOI:10.1016/j.tetlet.2003.10.177

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 619–621
Solution phase synthesis of imidazo[1,2-b]pyrazol-2-one,
an interesting 5,5-fused heterocyclic ring system
a,
Benjamin E. Blass, Anil Srivastava, Keith R. Coburn, Amy L. Faulkner,
b
a
a
*
a
a
John J. Janusz, James M. Ridgeway and William L. Seibel
a
a
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
b
ChemBiotek Research International, Salt Lake, Block BN, Sector V, Kolkata 700091, India
Received 30 September 2003; revised 14 October 2003; accepted 20 October 2003
Abstract—The solution phase synthesis of a series of imidazo[1,2-b]pyrazol-2-ones, a fused 5,5-ring system, based on diverse set of
hydrazino acids and malononitriles is described. The method involves formation of 5-aminopyrazoles followed by intra-molecular
cyclodehydration.
Ó 2003 Elsevier Ltd. All rights reserved.
The ability to generate large numbers of compounds
rapidly in parallel processes, rather than by sequential
reiteration of individual syntheses, is one of several
factors that contribute to the appeal of combinatorial
A brief literature search revealed only a limited number
of examples of 1H-imidazo[1,2-b]pyrazol-2-ones and re-
lated structures. 2,3-Dihydro-1H-imidazo[1,2-b]pyrazole
(IMPY, 1) has been found to reversibly inhibit DNA
synthesis without significantly affecting RNA or protein
synthesis. The antiviral and antitumor activities of many
agents depend, at least in part, on their ability to inhibit
1
chemistry for drug discovery. Solution phase organic
chemistry and combinatorial chemistry have been
widely used during the last few years in the continued
search for biologically active compounds. The synthesis
of vast libraries of structurally diverse compounds based
on heterocyclic scaffolds, including imidazoles, ben-
zodiazepines, diketopiperazines, oxazolidinones, and
5
DNA synthesis. IMPY has been shown to be active
6
against Herpes Simplex Virus type-1 (HSV-1). Several
derivatives of 1H-imidazo[1,2-b]pyrazoles, (e.g., N-
(tropanyl)imidazo[1,2-b]pyrazolecarboxamide, 2), have
2
7
quinolones have been disclosed. Our efforts in this area
have led to an investigation of several types of hetero-
been shown to have potential as CNS agents. Addi-
tionally, the pyrazolopyridine analog 3 has been shown
3
8
cycles, including 1,2,3-triazoles, and 1,2,4-triazin-6-
4
to inhibit both interluekin-1 and tumor necrosis factor,
while the pyrazole benzimidazolone derivative 4 is a
ones. Our continuing interest in this area has lead us to
investigate the synthesis of imidazo[1,2-b]pyrazol-2-
ones, an unusual 5,5-fused ring system.
9
MAP kinase inhibitor with anti-inflammatory activity.
In an effort to further explore this interesting scaffold, we
F
F
N
O
N
R2
N
R3
NH
N
N
O
N
N
N
NH
HN
N
N
N
NH
N
NH
O
N
NH
R1
O
N
1
2
3
4
7
O
Keywords: Pyrazole; Heterocycle; Imidazolone; Hydrazino acid; Aminopyrazole.
*
Corresponding author. Tel.: +1-513-622-3797; fax: +1-513-622-0086; e-mail: blass.be@pg.com
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.177

620
B. E. Blass et al. / Tetrahedron Letters 45 (2004) 619–621
R2
R3
R3
R2
O
NHNHBoc
N
a, b
NH2
c
N
HO
N
NH
O
N
R1
OH
R1
R1
O
5
6
(a-p)
7 (a-p)
Scheme 1. Solution phase synthesis of 1H-imidazo[1,2-b]pyrazol-2-ones. Reagents and conditions: (a) 50% TFA–DCM, rt, 1 h; (b) R
MeOH, rt, 18 h; (c) EDCIÆHCl, DCM, rt, 15–18 h.
2 3
COCHR CN,
11
Table 1. Representative examples of solution phase synthesis of bicyclic and tricyclic imidazopyrazolones (7)
Entry
R
1
R
2
R
3
Yield (%)
55
Entry
R
1
R
2
R
3
Yield (%)
55
7
a
b
H
H
7i
H
H
O
Cl
7
t-Bu
81
7j
Bn
t-Bu
H
60
7
7
c
Ph
H
H
60
54
7k
7l
Bn
Bn
Ph
H
H
67
69
d
Et
Et
t-Bu
F3C
O
7
e
f
H
H
55
55
7m
7n
–CH
2
2
SCH
2
2
–
–
19
22
O
7
t-Bu
Et
–CH
SCH
F3C
O
O
7
7
g
h
Ph
H
H
55
84
7o
7p
H
–CH
2
2
SCH
2
2
–
–
16
18
F3C
H
t-Bu
Bn
–CH
SCH
have developed a simple synthesis of imidazo[1,2-b]pyr-
azol-2-ones from commercially available malononitriles
and a-hydrazino acids.
b]pyrazol-2-one from readily available starting materials
in good to excellent yield. In addition, we have extended
the chemistry to the preparation of 5,5,5 fused tricyclic
systems.
As previously reported, a range of Boc-protected
a-hydrazino acids (5) can be readily prepared from
either the corresponding a-bromoacids or a-hydroxy-
References and Notes
10
acids. Standard Boc deprotection of the hydrazine
with TFA in methylene chloride followed by conden-
sation with commercially available malononitriles
provided the desired amino pyrazoles (6). EDCI med-
iated intramolecular cyclodehydration was then
achieved resulting in the formation of the desired 5,5-
ring system, imidazo[1,2-b]pyrazol-2-ones (7a–l) in
good to excellent yields (Scheme 1, Table 1). Interest-
ingly, this chemistry was able to provide fused tricycles
1
. Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63,
23–727.
7
2. (a) Gordon, E. W.; Gallop, M. A.; Barret, R. W.; Dower,
W. J.; Fodor, S. P. A. J. Med. Chem. 1994, 37, 1223–1252,
1386–1401; (b) Terret, N. K.; Gardner, M.; Gordon, D.
W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51,
8
135–8173; (c) Bunin, B. A. The Combinatorial Index;
Academic: 1998; (d) Czarnik, A. W.; DeWitt, S. H.
A Practical Guide to Combinatorial Chemistry; American
Chemical Society, 1997.
7
m–p, although the yields were relatively low, most
likely due to the highly strained nature of the 5,5,5-
fused tricyclic system.
3
. (a) Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Hunn, C.
L.; Natchus, M. G.; Parker, M. S.; Portlock, D. E.; Tullis,
J. S.; Wood, R. Tetrahedron Lett. 2002, 43, 4059–4061; (b)
Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seibel, W.
L.; Srivastava, A. Tetrahedron Lett. 2003, 44, 2153–2155.
In conclusion, we have developed a simple process for
the preparation of the 5,5 fused ring system, imidazo[1,2-

B. E. Blass et al. / Tetrahedron Letters 45 (2004) 619–621
621
þ
1
4
. Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Liu, S.;
Ogden, A.; Portlock, D. E.; Srivastava, A. Tetrahedron
Lett. 2002, 43, 8165–8167.
5.62 (s, 1H). (M H) 236. Entry 7c H NMR (300 MHz,
OD): d 0.97 (dd, J ¼ 6:50 Hz each, 6H), 1.92 (m, 1H),
CD
2.03 (m, 2H), 4.72 (t, J ¼ 6:41 Hz, 1H), 6.06 (s, 1H), 7.26–
3
þ
5
6
7
8
9
. Ennis, H. L.; Moller, L.; Wang, J. J.; Selawry, O. S.
Biochem. Pharmac. 1971, 20, 2539–2546.
. Pelling, J. C.; Shipman, C., Jr. Biochem. Pharmac. 1976,
5, 2377–2382.
. Vanotti, E.; Florentini, F.; Villa, M. J. Heterocyc. Chem.
994, 31, 737–743.
. Oku, T.; Kawai, Y.; Marusawa, H.; Yamazaki, H.; Abe,
Y.; Tanaka, H. E. P. 531901, 1993.
. Dombroski, M. A.; Letavic, M. A.; McClure, K. F. WO
7.42 (m, 3H), 7.75 (d, J ¼ 5:21 Hz, 2H). (M H) 256. Entry
1
7d H NMR (300 MHz, CD
3H), 1.32 (s, 9H), 2.08–2.19 (m, 2H), 4.63 (t, J ¼ 5:34 Hz,
þ
3
OD): d 0.77 (t, J ¼ 7:40 Hz,
1
2
1H), 5.65 (s, 1H). (M H) 208. Entry 7e H NMR
(300 MHz, CD
3
OD): d 0.86 (t, J ¼ 7:40 Hz, 3H), 2.07–
1
2.24 (m, 2H), 3.83 (s, 3H), 4.69 (t, J ¼ 5:15 Hz, 1H), 6.0 (s,
1H), 6.96 (d, J ¼ 4:70 Hz, 2H), 7.70 (d, J ¼ 4:70 Hz, 2H).
þ
1
3
(M H) 258. Entry 7f H NMR (300 MHz, CD OD): d
1.30 (s, 9H), 3.52 (d, J ¼ 4:90 Hz, 1H), 3.57 (d,
J ¼ 4:90 Hz, 1H), 4.90 (t, J ¼ 3:07 Hz, 1H), 5.40 (s, 1H),
0
2072576, 2002.
0. (a) Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett.
998, 39, 5135–5138; (b) Li, M.; Wilson, L. J.; Portlock, D.
þ
1
1
6.84–7.01 (m, 4H). (M H) 354. Entry 7g H NMR
(300 MHz, CD
1
3
OD): d 3.50 (d, J ¼ 4:76 Hz, 1H), 3.55
E.; Blass, B. E.; Harris, C.; Russell, A. Abstr. Pap. Am.
Chem. Soc. 2000, 220, 233; (c) Harris, C. L.; Blass, B. E.;
Wilson, L. J.; Li, M.; Chen, J. J.; Rupnik, K. J.; Portlock, D.
E.; Burt, T. M. Abstr. Pap. Am. Chem. Soc. 2000, 220,
(d, J ¼ 4:76 Hz, 1H), 4.95 (t, J ¼ 4:60 Hz, 1H), 5.82 (s,
1H), 6.93–7.03 (m, 4H), 7.24–7.34 (, 3H), 7.67 (d,
J ¼ 7:06 Hz, 2H). (M H) 374. Table 7h H NMR
þ
1
þ
(300 MHz, CD
3
1
OD): d 1.30 (s, 9H), 4.60 (s, 2H). (M H)
225.
180. Entry 7i H NMR (300 MHz, CD
3
OD): d 3.71 (s,
1
1. Representative procedure (entry 7b): Boc-protected hydra-
zine leucine (2.0 g) was deprotected under standard con-
ditions (TFA–methylene chloride, 50%, 50 mL, 2 h, rt).
3H), 4.54 (s, 2H), 5.86 (s, 1H), 6.81 (d, J ¼ 4:92 Hz, 2H),
þ
1
7.54 (d, J ¼ 4:64 Hz, 2H). (M H) 230. Entry 7j H NMR
(300 MHz, CD
OD): d 1.33 (s, 9H), 3.52 (d, J ¼ 4:80 Hz,
1H), 4.90 (t, J ¼ 3:2 Hz, 1H), 6.94 (m, 3H), 7.10 (m, 2H).
3
4
,4-Dimethyl-3-oxopentane nitrile (100 mg, 0.80 mmol)
þ
1
and hydrazine leucine (128.5 mg, 0.88 mmol) were stirred
in methanol for 18 h at room temperature to give the
(M H) 270. Entry 7k H NMR (300 MHz, CD OD): d
3
3.62 (dd, J ¼ 4:74 Hz each, 2H), 5.06 (t, J ¼ 3:50 Hz, 1H),
1
corresponding amino pyrazole (6b) in 32% yield, H NMR
5.91 (s, 1H), 7.06 (m, 3H), 7.16 (m, 2H), 7.44 (m, 3H), 7.81
(d, J ¼ 7:0 Hz, 2H). (M H) 290. Entry 7l H NMR
þ
1
(
(
1
0
0
300 MHz, CDCl
s, 9H, 1.92 (m, 1H), 2.09 (m, 2H), 5.42 (m, 1H), 5.65 (s,
H). (M H) 254. The amino pyrazole 6b (20 mg,
.08 mmol) was then treated with EDCI (22.7 mg,
.12 mmol) in methylene chloride at room temperature
3
): d 0.91 (dd, J ¼ 6:6 Hz each, 6H, 1.31
(300 MHz, CD OD): d 3.27 (m, 2H), 4.91 (t, 3.61 Hz, 1H),
3
þ
6.05 (s, 1H), 6.90 (m, 3H), 7.0 (m, 2H), 7.19 (d,
þ
J ¼ 8:10 Hz, 2H), 7.75 (d, J ¼ 6:7 Hz, 2H). (M H) 374.
1
Entry 7m H NMR (300 MHz, CD
3
OD): d 1.07 (dd,
for 18 h to give the cyclized product 7b (15 mg, 81%).
1
J ¼ 7:0 Hz each, 6H), 2.30 (m, 1H), 3.75 (s, 2H), 3.87 (s,
þ
1
Spectral data for Table 1: Entry 7a H NMR (300 MHz,
CD
2H), 4.74 (d, J ¼ 4:91 Hz, 1H) (M H) 224. Entry 7n H
NMR (300 MHz, CD
OD): d 0.91 (t, J ¼ 7:40 Hz, 3H),
2.23 (m, 2H), 3.87 (s, 2H), 3.98 (s, 2H), 4.63 (m, 1H).
3
OD): d 0.96 (dd, J ¼ 6:50 Hz each, 6H), 1.89 (m, 1H),
3
2
.08 (m, 2H), 4.70 (t, J ¼ 6:5 Hz, 1H), 6.06 (s, 1H), 7.37 (d,
þ
þ
1
J ¼ 4:70 Hz, 2H), 7.73 (d, J ¼ 4:70 Hz, 2H). (M H)
(M H) 210. Entry 7o H NMR (300 MHz, CD
þ
3
OD): 3.80
1
1
2
90.76. Entry 7b H NMR (300 MHz, CD
3
OD): d 0.91
(s, 2H), 3.85 (s, 2H), 4.62 (s, 2H). (M H) 182. Entry 7p H
OD): d 3.27 (m, 2H), 3.81 (s, 4H),
(
9
d, J ¼ 6:42 Hz, 3H), 0.99 (d, J ¼ 6:45 Hz, 3H), 1.31 (s,
NMR (300 MHz, CD
4.93 (m, 1H), 6.90–7.12 (m, 5H). (M H) 272.
3
þ
H), 1.93 (m, 1H), 2.01 (m, 2H), 4.58 (t, J ¼ 6:1 Hz, 1H),