Facile synthesis of 1-substituted 4,5-diaminopyrazoles and its application toward the synthesis of pyrazolo[3,4-b]pyrazines

Article abstract of DOI:10.1016/j.tetlet.2004.03.142

1-Substituted 5-aminopyrazole-4-carbonylazides were prepared from the appropriate 5-aminopyrazole-4-carboxylates. The acyl azides undergo a Curtius rearrangement followed by quenching with alcohols to form the corresponding carbamates. The 1-substituted 5

Full text of DOI:10.1016/j.tetlet.2004.03.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4105–4108
Facile synthesis of 1-substituted 4,5-diaminopyrazoles and
its application toward the synthesis of pyrazolo[3,4-b]pyrazines
Tun-Cheng Chien,a Ronald A. Smaldonea,ꢀ and Leroy B. Townsenda,b,
*
aDepartment of Chemistry, College of Literature, Science and Arts, The University of Michigan, Ann Arbor, MI 48109-1065, USA
bDepartment of Medicinal Chemistry, College of Pharmacy, The University of Michigan, Ann Arbor, MI 48109-1065, USA
Received 24 February 2004; revised 22 March 2004; accepted 24 March 2004
Abstract—1-Substituted 5-aminopyrazole-4-carbonylazides were prepared from the appropriate 5-aminopyrazole-4-carboxylates.
The acyl azides undergo a Curtius rearrangement followed by quenching with alcohols to form the corresponding carbamates. The
1-substituted 5-amino-4-benzyloxycarbonylaminopyrazoles were unblocked by catalytic hydrogenolysis to give the desired 4,5-
diaminopyrazoles. These 4,5-diaminopyrazoles were immediately condensed with glyoxal to afford 1-substituted pyrazolo[3,
4-b]pyrazines.
Ó 2004 Published by Elsevier Ltd.
Aromatic or heteroaromatic compounds possessing
ortho-diamino groups are versatile building blocks for
the synthesis of fused 1,4-diaza heterocycles such as
fused [d]imidazoles, [b]pyrazines, and [b]diazepines. Our
group had a particular interest in a facile synthesis of
4,5-diaminopyrazoles since they could then be used as
precursors for the synthesis of pyrazolo[3,4-b]pyrazines.
A perusal of the literature revealed that there are only a
limited number of synthetic routes available for the
preparation of 4,5-diaminopyrazoles.1–7 The most com-
mon approach has used an electrophilic nitrosation of 4-
unsubstituted 5-aminopyrazoles followed by a reduction
of the 4-nitroso group to afford the 4,5-diaminopyraz-
oles.1;4;6;7 Although this approach is effective, there are a
few limitations: (1) both the nitroso intermediates and
the resulting 4,5-diaminopyrazoles are unstable and can not
be stored for an extended period of time; (2) some of the
4-unsubstituted 5-aminopyrazoles are not readily avail-
able by the usual synthetic procedures. In our pre-
liminary studies, we encountered some difficulties in our
attempts to prepare 4,5-diaminopyrazole nucleosides
through the nitrosation-reduction approach. The con-
densation of ribosylhydrazone8 with 1,3-dielectrophiles
such as benzoylacetonitrile9 or 3-aminocrotononitrile10
did not afford the expected 4-unsubstituted 5-aminopyr-
azole nucleosides. The 4-unsubstituted 5-aminopyrazole
nucleosides could be prepared from the corresponding
ethyl 5-aminopyrazole-4-carboxylate nucleosides11;12 by
saponification followed by thermal decarboxylation.13
However, nitrosation of the 5-aminopyrazole nucleo-
sides gave the desired nitroso product only in low yields
and was accompanied by undesired side products. These
circumstances prompted us to look for an alternative
route for the preparation of 4,5-diaminopyrazoles. We
now report the preparation of 4,5-diaminopyrazoles
from the 5-aminopyrazole-4-carbonylazides via a Cur-
tius rearrangement strategy.
Non-nucleoside models were investigated first in order
to explore and establish the reaction conditions. Ethyl
esters of 5-aminopyrazole-4-carboxylates 1a–c can be
easily prepared by a condensation of alkylhydrazines
with 2-cyano-3-ethoxyacrylate derivatives.14;15 Reac-
tions of the esters 1a–c with hydrazine monohydrate
gave the carbonyl hydrazides 2a–c in quantitative yields.
Treatment of 2a–c with sodium nitrite in a 10% aqueous
acetic acid solution at 0 °C afforded the acyl azides 3a–c.
These compounds were characterized by their significant
IR absorptions around 2150 cmꢀ1. The acyl azides 3a–c
underwent Curtius rearrangements in the presence of
excess amounts of primary alcohols to give the corre-
sponding carbamates 4b and 5a–c, respectively. Since
Keywords: 4,5-Diaminopyrazole; Curtius rearrangement; Pyrazolo[3,
4-b]pyrazine.
* Corresponding author. Address: Department of Medicinal Chem-
istry, College of Pharmacy, The University of Michigan, 428 Church
St. Rm. 4567 CCL, Ann Arbor, MI 48109-1065, USA. Tel.: +734-
764-7547; fax: +734-763-5633; e-mail: ltownsen@umich.edu
ꢀ
Present address: Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, IL 61801, USA.
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.142

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T.-C. Chien et al. / Tetrahedron Letters 45 (2004) 4105–4108
Table 1
R3
R3
H
O
N
Reactant
Product
R1
R3
Yield (%)
c
R
ROOC
H2N
N
N
1a
1b
1c
2a
2b
2c
Ph
Bn
Bn
H
65a
73a
44a
N
N
H2N
H
Me
R1
R1
1 R = OEt
2 R = NHNH2
3 R = N3
4b R = Et
a
b
5a-c R = Bn
2a
2b
2c
3a
3b
3c
Ph
Bn
Bn
H
88a
82a
78b
H
Me
R3
R3
H2N
H2N
N
N
e
3b
4bc
Bn
H
71a
d
N
N
R = Bn
5ad
5be
5cd
Ph
Bn
Bn
H
33b
71b
35b
N
N
3a
3b
3c
R1
R1
H
Me
7a-c
6a-c
a: R1 = Ph, R3 = H
b: R1 = Bn, R3 = H
c: R1 = Bn, R3 = Me
5a
5b
5c
7a
7b
7c
Ph
Bn
Bn
H
83b;f
55b;f
71b;f
H
Me
Scheme 1. Reagents and conditions: (a) hydrazine monohydrate,
EtOH, reflux; (b) NaNO2, 10% acetic acid in H2O, 0 °C, 30 min; (c)
ROH, xylenes, reflux, (d) 10% Pd/C, H2, MeOH, rt, 90 min; (e) 40% wt
glyoxal, EtOH, rt.
a Yields are isolated yields after recrystallization.
b Yields are isolated yields after flash column chromatography.
c Ethanol was used as co-solvent, EtOH–xylenes ¼ 1:9 (v/v).
d Benzyl alcohol (4 equiv) was used.
e Benzyl alcohol (10 equiv) was used.
f Yields are after two-step reactions from 5a–c.
carbamates are widely used protecting groups for
amines,16 a removal of the carbamates should occur to
give the desired 1-substituted 4,5-diaminopyrazoles.
Catalytic hydrogenolysis of the Cbz-masked diamino-
pyrazoles 5a–c gave the desired 1-substituted 4,5-di-
aminopyrazoles (6a–c) in situ. The diamine intermediates
were immediately condensed with glyoxal to afford the
pyrazolo[3,4-b]pyrazines (7a–c) in good yields (Scheme 1
and Table 1).
propylidene group was removed and the three hydroxy
groups were then fully protected with acetyl esters to
provide compound 11. Compound 11 then underwent a
Curtius rearrangement in the presence of excess benzyl
alcohol to give 5-amino-4-benzyloxycarbonylamino-1-
(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)pyrazole (12) in
51% yield. Catalytic hydrogenolysis of 12 afforded the
diamine 13 in situ and compound 13 was immediately
condensed with glyoxal or 2,3-butanedione to furnish
the peracetylated pyrazolo[3,4-b]pyrazine nucleosides
14a–b. The acetyl groups were removed with methanolic
ammonia to afford the desired nucleosides 15a–b
(Scheme 2 and Table 2).
A conversion of the nucleoside precursor, ethyl 5-amino-
1-(2,3-O-isopropylidene-b-D-ribofuranosyl)pyrazole-4-
carboxylate8;11;12 (8), into the corresponding acyl azide
10 was accomplished by the same procedures as
described earlier for the model compounds. The iso-
O
O
H
N
R
N3
H2N
Cbz
N
N
N
N
N
N
H2N
O
H2N
b
d
HO
R5O
AcO
O
O
O
O
R3O
OR2
AcO
12
OAc
8 R = OEt
9 R = NHNH2
10 R5 = H, R2,R3 = C(Me)2
11 R2 = R3 = R5 = Ac
a
c
H2N
H2N
R
N
N
N
N
N
N
R
f
e
AcO
R5O
O
O
AcO
13
OAc
R3O
OR2
14a-b R2 = R3 = R5 = Ac
15a-b R2 = R3 = R5 = H
a: R = H
b: R = Me
g
Scheme 2. Reagents and conditions: (a) hydrazine monohydrate/EtOH (2:1, v/v), reflux; (b) NaNO2, 10% acetic acid in H2O, 0 °C, 20 min, 71% from
8; (c) (i) TFA/H2O ¼ 9:1, rt, 1 h; (ii) Ac2O, pyr, rt, 1 h, 73% from 10 ; (d) 10 equiv BnOH, xylenes, reflux, 5 h, 51%; (e) 10% Pd/C, H2, MeOH, rt,
90 min; (f) glyoxal or 2,3-butandione, EtOH, rt; (g) NH3/MeOH, rt, 1 h.

T.-C. Chien et al. / Tetrahedron Letters 45 (2004) 4105–4108
4107
Table 2
Reactant Product R2
Organic Synthesis; Wiley: New York, 1999; pp 503–
550.
17. Korbukh, I. A.; Preobrazhenskaya, M. N.; Dorn, H.;
Kondakova, N. G.; Kostyuchenko, N. P. J. Gen. Chem.
USSR (Engl. Transl.) 1974, 10, 1108–1113.
18. Korbukh, I. A.; Yakunina, N. G.; Preobrazhenskaya, M.
N. 1-b-D-Ribofuranosylpyrazolo[3,4-b]pyrazine. Isomeri-
R3
R5
R
Yield
(%)a
12
12
14a
14b
Ac
Ac
Ac
Ac
Ac
Ac
H
Me
68b
44b
14a
14b
15a
15b
H
H
H
H
H
H
H
Me
76
71
zation of 2-Glycosyl Derivatives of Fused Pyrazoles to 1-
Glycosyl Derivatives. In Nucleic Acid Chemistry: Improved
and New Synthetic Procedures, Methods and Techniques;
Townsend, L. B., Tipson, R. S., Eds.; Wiley: New York,
1978; Vol. 2, pp 745–747.
a The reported yields are isolated yields.
b Yields are after two-step reactions from 12.
Our success in these Curtius rearrangement reactions
has provided a viable alternative route for the prepara-
tion of 4,5-diaminopyrazoles. The synthesis of pyraz-
olo[3,4-b]pyrazine nucleosides from the pre-formed
pyrazole nucleosides has established that the ribose is
located at the N1-position and avoids the formation of
possible regioisomers by the Vobruggen or the fusion
method.17;18 Synthesis of the 4,5-diaminopyrazole
nucleoside 13 and the nucleosides 15a–b19–23 also illus-
trates the potential for the synthesis of other nucleosides
with pyrazole-fused bicyclic heterocycles.
19. General procedure for the preparation of 1-substituted 5-
aminopyrazole-4-carbonylazides 3a–c and 10: A solution of
sodium nitrite (11 mmol, 1.1 equiv) in H2O (5 mL) was
added dropwise to a suspension of the 1-substituted 5-
aminopyrazole-4-carboxhydrazide (2a–c or 9, 10 mmol) in
10% aqueous acetic acid (50 mL) at 0 °C for 15 min. The
mixture was stirred for an additional 15 min then extracted
with EtOAc. The organic layer was collected and washed
with saturated Na2CO3 solution, saturated NaCl solution,
and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the product was
purified by recrystallization or column chromatography.
20. General procedure for the preparation of 1-substituted 5-
amino-4-benxyloxycarbonylaminopyrazoles 5a–c and 12: A
mixture of 1-substituted 5-aminopyrazole-4-carbonylazide
(3a–c or 11, 10 mmol) and benzyl alcohol (100 mmol,
10 equiv) in xylenes (125 mL) was heated at reflux
temperature under an argon atmosphere. After cooling
to room temperature, the solvent was evaporated under
reduced pressure and the product was purified by column
chromatography.
Acknowledgements
This work was supported by Research Grant 5-PO1-
AI46390 from the National Institutes of Health.
21. 5-Amino-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)pyraz-
ole-4-carbonylazide (10): mp 119–121 °C (dec.) (Hex/
EtOAc). 1H NMR (CDCl3, 500 MHz) d 7.63 (s, 1H, 3-
H), 5.76 (d, 1H, J ¼ 2:3 Hz, 10-H), 5.73 (br s, 2H, NH2),
5.24 (dd, 1H, 20-H), 5.02 (dd, 1H, 30-H), 4.49 (br s, 1H, 50-
OH), 4.46 (dd, 1H, 40-H), 3.84 (dt, 1H, 50-H), 3.68 (ddd,
1H, 50-H), 1.60 (s, 3H, CH3), 1.39 (s, 3H, CH3); 13C NMR
(CDCl3, 125 MHz) d 168.1, 151.1, 140.9 (3-CH), 113.9,
98.6, 92.7 (CH), 88.7 (CH), 84.9 (CH), 82.2 (CH), 64.0 (50-
CH2), 27.4 (CH3), 25.4 (CH3); IR (KBr, cmꢀ1) 3434, 3333,
2139, 1664, 1630, 1546; MS (CI, NH3) m=z 83 (27), 125
(93), 297 (100) (MþꢀN2þ1), 325 (24) (Mþþ1); HRMS
calcd for C12H17N6O5 (Mþ1): 325.1260. Found: 325.1246.
Anal. Calcd for C12H16N6O5: C, 44.44; H, 4.97; N, 25.91.
Found: C, 44.52; H, 5.09; N, 25.74.
References and notes
1. Musante, C. Gazz. Chim. Ital. 1943, 73, 355–365.
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5451–5452.
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Soc. 1958, 80, 421–427.
4. Vicentini, C. B.; Ferretti, V.; Veronese, A. C.; Guarneri,
M.; Manfrini, M.; Giori, P. Heterocycles 1995, 41, 497–
506.
5. Vicentini, C. B.; Veronese, A. C.; Manfrini, M.
J. Heterocycl. Chem. 1997, 34, 629–632.
6. Blass, B. E.; Srivastava, A.; Coburn, K. R.; Faulkner,
A. L.; Seibel, W. L. Tetrahedron Lett. 2003, 44, 3009–3011.
7. Holschbach, M. H.; Wutz, W.; Olsson, R. A. Tetrahedron
Lett. 2003, 44, 41–43.
8. Acevedo, O. L.; Krawczyk, S. H.; Townsend, L. B. J. Org.
Chem. 1986, 51, 1050–1058.
9. Snyder, H. R., Jr. J. Heterocycl. Chem. 1975, 12, 1303–
1304.
10. Ganesan, A.; Heathcock, C. H. J. Org. Chem. 1993, 58,
6155–6157.
22. 5-Amino-4-benzyloxycarbonylamino-1-(2,3,5-tri-O-acetyl-
b-D
-ribofuranosyl)pyrazole (12): 1H (DMSO-d6, 500 MHz)
d 8.56 (br s, 1H, NH), 7.41–7.35 (m, 6H, Ph and 3-H), 6.01
(d, 1H, J ¼ 2:7 Hz, 10-H), 5.74 (dd, 1H), 5.58 (t, 1H), 5.29
(br s, 2H, NH2), 5.10 (s, 2H, CH2), 4.32–4.25 (m, 2 H),
3.99 (dd, 1H, 50-H), 2.10 (s, 3H, CH3), 2.08 (s, 3H, CH3),
2.00 (s, 3H, CH3); 13C NMR (DMSO-d6, 125 MHz) d
170.9, 170.3, 170.2, 155.4, 141.1, 137.7, 136.9 (3-CH),
129.3 (CH), 128.9 (CH), 128.8 (CH), 103.8, 86.9 (CH),
79.4 (CH), 73.9 (CH), 71.7 (CH), 66.7 (CH2), 64.3 (CH2),
21.4 (CH3), 21.2 (2 ꢁ CH3); MS (ESI) m=z 513 (100)
(MþNa); HRMS calcd for C22H26N4O9ÆNa: 513.1597.
Found: 513.1597.
11. Bhattacharya, B. K.; Robins, R. K.; Revankar, G. R.
J. Heterocycl. Chem. 1990, 27, 787–793.
12. Schmidt, R. R.; Guilliard, W.; Karg, J. Chem. Ber. 1977,
110, 2445–2455.
13. Sanghvi, Y. S.; Larson, S. B.; Robins, R. K.; Revankar,
G. R. J. Chem. Soc., Perkin Trans. 1 1990, 2943–2950.
14. Xia, Y.; Chackalamannil, S.; Hsingan, C.; Tsai, H.;
Vaccaro, H.; Cleven, R.; Cook, J.; Fawzi, A.; Watkins,
R.; Zhang, H. J. Med. Chem. 1997, 40, 4372–4377.
15. Dorn, H.; Zubek, A. Chem. Ber. 1968, 101, 3265–3277.
16. Greene, T. W.; Wuts, P. G. M. 7. Protection for the
Amino Group––Carbamates. In Protective Groups in
23. 1-(b-D-Ribofuranosyl)pyrazolo[3,4-b]pyrazine (15a): mp
187–189 °C (dec.) (EtOH) [lit.18 180–181 °C (MeOH)]; H
NMR (DMSO-d6, 500 MHz) d 8.74 (d, 1H, J ¼ 2:0 Hz),
8.68 (d, 1H, J ¼ 2:0 Hz), 8.62 (s, 1H, 3-H), 6.30 (d, 1H,
J ¼ 4:7 Hz, 10-H), 5.46 (d, 1H, OH), 5.23 (d, 1H, OH),
4.77–4.73 (m, 2H, 1 ꢁ OH and 1 ꢁ CH), 4.28 (dd, 1H),
3.96 (dd, 1H), 3.62–3.57 (m, 1H, 50-H), 3.47–3.43 (m, 1H,
50-H); 13C NMR (DMSO-d6, 125 MHz) d 144.3, 144.1
1

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T.-C. Chien et al. / Tetrahedron Letters 45 (2004) 4105–4108
(CH), 142.8 (CH), 135.3 (CH), 135.0, 89.5 (CH), 86.2
(CH), 73.9 (CH), 71.7 (CH), 63.0 (CH2); MS (EI, 70 eV)
m=z 121 (100), 133 (27), 149 (43), 163 (21), 175 (13), 252 (3)
(Mþ); HRMS calcd for C10H12N4O4: 252.0859. Found:
252.0857. Anal. Calcd for C10H12N4O4: C, 47.62; H, 4.80;
N, 22.21. Found: C, 47.57; H, 4.92; N, 22.28.