Mononuclear heterocyclic rearrangement: Synthesis of [5:5] bicyclic [c]-fused 3-aminopyrazoles via the N-N bond formation strategy

Article abstract of DOI:10.3987/com-04-10144

The formation of [5:5] bicyclic heterocyclic ring systems containing [c]pyrazoles, i.e. imidazo[4,5-c]pyrazole, pyrazolo[3,4-c]pyrazole, pyrrolo-[2,3-c]pyrazole, and pyrazolo[3,4-d][1,2,3]triazole, was accomplished by mononuclear heterocyclic rearrangemen

Full text of DOI:10.3987/com-04-10144

HETEROCYCLES, Vol. 63, No. 11, 2004, pp. 2475 - 2494
Received, 8th June, 2004, Accepted, 3rd September, 2004, Published online, 7th September, 2004
MONONUCLEAR HETEROCYCLIC REARRANGEMENT: SYNTHESIS
OF [5:5] BICYCLIC [c]-FUSED 3-AMINOPYRAZOLES via THE N-N
BOND FORMATION STRATEGY
David A. Berry,b† Tun-Cheng Chien,a and Leroy B. Townsend*a,b
Department of Chemistry, College of Literature, Science and Arts;a
Department of Medicinal Chemistry, College of Pharmacy;b
The University of Michigan, Ann Arbor, Michigan 48109-1065, USA
Abstract – The formation of [5:5] bicyclic heterocyclic ring systems containing
[c]pyrazoles, i.e. imidazo[4,5-c]pyrazole, pyrazolo[3,4-c]pyrazole, pyrrolo-
[2,3-c]pyrazole, and pyrazolo[3,4-d][1,2,3]triazole, was accomplished by
mononuclear heterocyclic rearrangement (MHR). The core pyrazole ring was
formed based on a N-N bond formation strategy. The ring transformation of
5-substituted 3-(2-aminoaryl)-1,2,4-oxadiazoles (14, 15a-b, 16b and 33) under
thermal conditions to the corresponding [5:5] bicyclic [c]-fused 3-aminopyrazole
ring systems (17a, 18a-b, 20 and 34 respectively) was promoted by sodium
hydride in DMF or DMSO. The ring transformation by MHR has provided a
practical and general synthetic method for the derivatives of 3-aminoimidazo-
[4,5-c]pyrazole (4), 3-aminopyrazolo[3,4-c]pyrazole (5), 3-aminopyrrolo[2,3-c]-
pyrazole (6) and 6-aminopyrazolo[3,4-d][1,2,3]triazole (7).
INTRODUCTION
Naturally occurring [6:5] bicyclic heterocycles, i.e. purines, indoles, benzimidazoles et al., and [6:6]
bicyclic heterocycles, i.e. pteridines, quinazolines et al., have received significant attention in the past
half century because of their chemical and especially their biological properties.1 A number of
ring-structural analogs have also been discovered in nature or synthesized in various laboratories.2 Many
of these analogs have demonstrated interesting biological activities and stimulated interest in the
preparation of other bicyclic heterocycles.3-5 Most of the studies have involved modifications of the
† Current Address: Berry & Associates, Inc., Dexter, MI 48130, USA

heterocyclic ring system by replacing ring carbon atoms with nitrogen atoms, or vice versa, to form the
bicyclic ring analogs.2,6,7
In contrast to the [6:5] and [6:6] bicyclic heterocycles, the ring-contracted [5:5] bicyclic aromatic rings,
with the same number of π-electrons, have significant differences in the distribution of ring electron
densities as well as in spatial orientation. These properties could change the binding affinity of these
compounds to the biological targets as well as alter their biological responses. The [5:5] azapentalene
[c]pyrazole ring systems were of special interest to us because of their close structural resemblance to the
[6:5] ring systems (1, 2 and 3) and the inherent potential for biological activities.8-12 Based on the
chemical and biological interest in this series of heterocycles, we initiated studies to investigate feasible
synthetic strategies to prepare the [5:5] bicyclic [c]-fused 3-aminopyrazole ring systems (4, 5, 6 and 7).
Figure 1 [6:5] bicyclic heterocycles and proposed [5:5] azapentalene [c]pyrazole ring systems
NH2
N
NH2
Y
Y
N
X
X
N
H
N
R
N
R
N
1 X = CH, Y = N
4 X = CH, Y = N
adenine
2 X = N, Y = CH
3-aminoimidazo[4,5-c]pyrazole
5 X = N, Y = CH
4-aminopyrazolo[3,4-d]pyrimidine
3 X = Y = CH
3-aminopyrazolo[3,4-c]pyrazole
6 X = Y = CH
4-aminopyrrolo[2,3-d]pyrimidine
3-aminopyrrolo[2,3-c]pyrazole
7 X = Y = N
6-aminopyrazolo[3,4-d][1,2,3]triazole
A literature survey showed a paucity of feasible routes for the synthesis of the [5:5] bicyclic [c]-fused
3-aminopyrazole ring systems.13-18 Two general pathways may be amenable for the construction of the
[c]-fused 3-aminopyrazole ring system from existing 5-membered heterocycles.19,20 (Scheme 1)
Scheme 1 Synthetic Strategies for [c]-fused 3-aminopyrazoles
R
N
NH2
N
O
A
B
C N
X
N
N
NH2
H
X = halogen,
NO2, NH2
A. hydrazine annulation; B. N-N bond formation

The most straightforward approach involves a condensation of hydrazine with a heterocycle possessing a
cyano group and an adjacent leaving group to afford the fused pyrazole rings. This approach has been
widely utilized in the synthesis of fused pyrazoles from various aromatic rings (A).21 However, its
application toward the [5:5] bicyclic [c]-fused 3-aminopyrazole ring systems was rarely reported in the
literature. Our preliminary studies resulted in no success with the hydrazine annulation methods. We then
elected to study an alternative approach (B) based on the mononuclear heterocyclic rearrangement (MHR)
(or Boulton-Katritzky rearrangement).22 It has been reported that the [c]-fused 3-aminopyrazole ring can
be prepared by the ring transformation of an aromatic ring bearing adjacent 5-substituted
1,2,4-oxadiazol-3-yl and amino groups.18-20,23-26 This approach was initially used on π-electron deficient
heterocyclic and carbocyclic aromatic ring systems to furnish the [c]-fused 3-aminopyrazoles. Korbonits
et al. demonstrated that 5-amino-1-phenyl-4-(5-phenyl-1,2,4-oxadiazol-3-yl)pyrazole would undergo the
MHR to give the bicyclic pyrazolo[3,4-c]pyrazole ring.18 This was the only azapentalene congener which
has been synthesized via the MHR of an appropriately substituted pyrazole derivative. We reasoned that
the ring transformation, in this case, was facilitated by the electron withdrawing property of the phenyl
groups. Therefore, the generality of this methodology has still remained unexploited. Our group has
previously used this approach to synthesize 3-aminopyrazolo[3,4-c]pyrazole nucleosides as [5:5] bicyclic
adenosine analogs.17 Herein, we wish to report our studies which were designed to expand the application
of this methodology for the preparation of a series of azapentalene derivatives including 3-amino-
imidazo[4,5-c]pyrazole (4), 3-aminopyrazolo[3,4-c]pyrazole (5), 3-aminopyrrolo[2,3-c]pyrazole (6) and
6-aminopyrazolo[3,4-d][1,2,3]triazole (7).
RESULTS AND DISCUSSION
The 5-substituted 3-(2-aminoaryl)-1,2,4-oxadiazole derivatives of 5-membered heterocycles were
synthesized to explore and establish the reaction conditions. 1-Benzylated 5-membered heterocyclic
1,2-aminonitriles (8,27 9a,28,29 9c,30 and 1031) which were prepared by literature procedures, were selected
for the initial investigation. Reactions of the 1,2-aminonitriles (8, 9a, 9c and 10) with hydroxylamine in
ethanol at reflux temperature gave the carboxamidoximes (11, 12a, 12c and 1332) in excellent yields.
Treatment of the carboxamidoximes (11, 12a, 12c and 13) with ethyl acetate or ethyl benzoate in an
ethanolic solution of sodium ethoxide at reflux temperature afforded the 3-(2-aminoaryl)-1,2,4-
oxadiazoles (14, 15a-c, and 16a-b).
Several attempts to treat 14, 15a-c, and 16a-b under the reported conditions18,20,23,25 were unsuccessful in
obtaining the desired [5:5] bicyclic products. These attempts included various reaction conditions such as
different bases (KOH, NaOH, NaOEt), different solvents (MeOH, EtOH, DMF) and different reaction
temperatures (75 oC, 100 oC, 150 oC). However, it was subsequently found that the rearrangement would

proceed with sodium hydride as a base.17 The pyrazole derivative (14) was treated with sodium hydride in
o
N,N-dimethylformamide at 100 C to give the ring-transformed 3-acetamido-6-benzylpyrazolo[3,4-c]-
pyrazole (17a) in 40% yield. A similar set of reaction conditions was then applied to the imidazole
derivatives (15a-c). When 15a-c was treated with sodium hydride in DMF, only 15a underwent the
rearrangement to give the desired 3-acetamido-6-benzylimidazo[4,5-c]pyrazole (18a) in 36% yield. It was
1
of some interest that the chemical shifts for the methyl groups had significant upfield shifts in the H
NMR spectrum from 2.58 and 2.60 ppm for 14 and 15a to 2.07 and 2.03 ppm for 17a and 18a,
respectively. These shifts indicated that the exocyclic methyl groups of the 1,2,4-oxadiazoles were
transformed to the corresponding acetyl groups. The amide NH resonances of 17a and 18a were also
observed approximately at 11 – 12 ppm by 1H NMR spectrum. The rearrangement of 15b was facilitated
o
by using sodium hydride in dimethyl sulfoxide at 120 C and afforded 3-benzamido-6-benzylimidazo-
[4,5-c]pyrazole (18b) in 27% yield. (Scheme 2)
Scheme 2
R
NH2
N
N
O
CN
OH
Y
Y
Y
N
c
b
X
X
X
N
N
N
NH2
NH2
NH2
Bn
Bn
Bn
8 X = N, Y = CH
9a X = CH, Y = N
9c X = CCl, Y = N
10 X = N, Y = N
11 X = N, Y = CH (83%)
12a X = CH, Y = N (96%)
12c X = CCl, Y = N (92%)
13 X = N, Y = N (95%)
14 X = N, Y = CH, R = Me (56%)
15a X = CH, Y = N, R = Me (56%)
15b X = CH, Y = N, R = Ph (53%)
15c X = CCl, Y = N, R = Me (38%)
16a X = N, Y = N, R = Me (80%)
16b X = N, Y = N, R = Ph (69%)
a
O
HN
R
Y
d
N
X
N
H
N
reagents and conditions
a) NCS, THF, rt, 5 h, 45%
Bn
b) NH2OH, EtOH, reflux
c) (i) Na / EtOH, rt; (ii) RCOOEt, EtOH, reflux
d) NaH, DMF or DMSO, ∆
17a X = N, Y = CH, R = Me (40%)
18a X = CH, Y = N, R = Me (36%)
18b X = CH, Y = N, R = Ph (27%)
The triazole derivatives (16a-b) were also subjected to a wide variety of reaction conditions but did not
form the desired rearranged products (19a-b). However, when the 5-amino group of 16b32 was first
acetylated and then the compound was treated with sodium hydride in DMF, it did undergo the MHR to
form 3-benzyl-4-acetyl-6-benzamidopyrazolo[3,4-d][1,2,3]triazole (20) in 42% yield. (Scheme 3)
Studies designed to explore the chemical behavior of azapentalene (17a) were also investigated.
Compound (17a) was readily brominated with N-bromosuccinimide to give 3-acetamido-6-benzyl-4-

bromopyrazolo[3,4-c]pyrazole (17b) in 91% yield. Bromination occurred exclusively at the 4-position of
the bicyclic heterocycle as determined by 1H NMR spectrum. Debenzylation of 17a was accomplished by
dissolving metal reduction to give 3-acetamidopyrazolo[3,4-c]pyrazole (22).14,33 The acetyl group in 22
was removed by acid hydrolysis to afford 3-aminopyrazolo[3,4-c]pyrazole hydrochloride (23).14,33
(Scheme 4)
Scheme 3
R
N
O
O
N
HN
R
HN
N
Ph
O
N
N
N
a,b
N
N
N
N
N
N
H
N
N
N
NH2
Ac
Bn
Bn
Bn
19a R = Me
19b R = Ph
20
16a R = Me
16b R = Ph
reagents and conditions
a) Ac2O, cat. DMAP, pyridine, 100 oC, 7 h
b) NaH, DMF, 100 oC, 35 min, 42% from 16b
Scheme 4
R
R4
NHAc
N
HN
b
N
N
N
R4 = H
N
N
H
reagents and conditions
a) NBS, THF, rt, 2 h, 91%
b) Na / NH3, -50 oC - rt, 49%
c) 1N HCl, reflux, 2 h, 69%
N
N
H
H
Bn
17a R4 = H
17b R4 = Br
22 R = Ac
23 R = H (HCl salt)
a
c
Our initial approach for the synthesis of the bicyclic pyrrolo[2,3-c]pyrazole ring system was based on the
successful synthesis of some pyrazolo[3,4-c]pyrazoles and imidazo[4,5-c]pyrazoles. However, the
anticipated carboxamidoxime was not obtained when 2-amino-1-benzyl-3-cyanopyrrole34 was treated
with hydroxylamine. This result prompted us to look for a different route to prepare the 5-substituted
3-(2-aminopyrrol-3-yl)-1,2,4-oxadiazole derivatives. Instead of the 1,2-aminonitrile approach, ethyl
1-benzyl-3-cyanopyrrole-2-carboxylate35 (24) was selected as the starting material. The carboxylate was
first converted to the amide (25) with ammonia. Compound 25 was then reacted with hydroxylamine in
ethanol to give 2-carboxamido-1-benzylpyrrole-3-carboxamidoxime (26) in 54% yield. Formation of the
1,2,4-oxadiazoles (28a-b) from 26 was accomplished by a base-promoted condensation with ethyl acetate,
or acylated at the oxime oxygen by p-nitrobenzoyl chloride followed by an acid-catalyzed condensation.
The amides were hydrolyzed by nitrosylsulfuric acid to give the corresponding carboxylic acids (29a-b).

Compound (29a) was treated with ethyl chloroformate in the presence of triethylamine followed by
sodium azide to form the acyl azide in situ. The acyl azide underwent a Curtius rearrangement and was
subsequently trapped with ethanol to afford the carbamate (30a) in 19% yield. An improved procedure
was also developed. Compound (29b) was treated with diphenylphosphoryl azide followed by heating
with methanol to give the carbamate (30b) in 46% yield. (Scheme 5)
Scheme 5
R5'
R5'
NH2
N
N
N
O
O
CN
OR
N
N
b
g or h
d or e
N
N
N
N
COR
CONH2
COR
NHR
Bn
Bn
Bn
Bn
30a R5' = Me,
24 R = OEt
25 R = NH2
26 R = H
27 R = p-NO2C6H4CO
28a R5' = Me,
R = NH2 (90%)
29a R5' = Me,
R = OH (50%)
a
c
R = CO2Et (19%)
30b R5' = p-nitrophenyl,
f
f
R = CO2Me (46%)
28b R5' = p-nitrophenyl,
R = NH2 (55%)
reagents and conditions
a) NH3, 100 oC, 4 days, 96%
29b R5' = p-nitrophenyl,
R = OH (57%)
b) NH2OH, MeOH, reflux, 18 h, 93%
c) p-nitrobenzoyl chloride, Et3N, THF, rt, 5 h, 54%
d) (i) Na / EtOH, rt; (ii) EtOAc, EtOH, reflux, 18 h, 90%
e) (i) p-nitrobenzoyl chloride, Et3N, THF, rt, 5 h; (ii) AcOH, toluene, reflux, 16 h, 55% from 26
f) nitrosylsulfuric acid, AcOH, rt
g) (i) ClCOOEt, Et3N, DMF, rt, 2 h; (ii) NaN3, 3 h, rt; (ii) EtOH, 85 oC, 2 h, 19% from 29a
h) (i) diphenylphosphoryl azide, DMF, rt, 70 min; (ii) MeOH, 65 oC, 70 min, 46% from 29b
Ring transformations of 30a-b under various basic conditions were unsuccessful. It was noticeable that
30a-b were completely consumed in the reaction when the compounds were heated with sodium hydride
in DMF or DMSO. We interpreted that the ring transformations might occur but the highly
electronegative rings may cause the decomposition of the unstable products. Therefore, a cyano group
was introduced to the pyrrole ring in order to reduce the electron density and stabilize the [5:5] bicyclic
ring. Compound (30b) was treated with chlorosulfonyl isocyanate followed by quenching with
N,N-dimethylformamide to afford 32 in 66% yield. The position of the cyano group on the pyrrole ring
1
13
was determined by extensive NMR spectroscopic studies including H, C, DEPT135, proton coupled
13C, HETCOR, and COLOC NMR. A long-range coupling between the methylene protons of the benzyl
13
group and C-5 on the pyrrole ring was observed while the proton-coupled C NMR spectrum showed
multiplet splitting at C-5 position due to the three-bond coupling. This long range coupling was also

confirmed by the 2D COLOC NMR spectroscopy. (Table 1) Attempts to catalyze the ring transformation
of 32 to the [5:5] bicyclic ring also failed. While exploring possible conditions for the rearrangement, it
was found that treatment of 32 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in anisole at reflux
resulted in a clean removal of the methoxycarbonyl group to afford 33. Compound (33) was then
subjected to sodium hydride in DMSO at 125 oC to give the desired product (34) in 29%. (Scheme 6)
Scheme 6
R5'
O
R5'
N
HN
O
N
N
N
R
N
N
NHR
Bn
Bn
30a R5' = Me, R = CO2Et
30b R5' = p-nitrophenyl,
R = CO2Me
31
a
p-NO2Ph
O
N
N
O
HN
N
c
NO2
NC
NC
N
H
N
N
NHR
Bn
Bn
34
32 R = CO2Me
33 R = H
b
reagents and conditions
a) (i) chlorosulfonyl isocyanate, MeCN, 0 oC - rt, 16 h;
(ii) 1 eq. DMF, MeCN, reflux, 2 h, 66% from 30b
b) DBU, anisole, reflux, 1.5 h, 70%
c) NaH, DMSO, 15 min, 29%
CONCLUSION
This investigation has successfully extended the use of the mononuclear heterocyclic rearrangement to the
[5:5] bicyclic [c]-fused pyrazole ring systems which were not achievable by the widely used hydrazine
annulation approach. Our success has established a viable route toward several derivatives of the [5:5]
bicyclic [c]-fused 3-aminopyrazole ring systems. Our efforts, thus far, in the removal of the acyl groups
from the ring-transformed products (17a, 18a-b, 20 and 34) have been unsuccessful. We have attributed

this to the fact that these [5:5] bicyclic [c]-fused 3-aminopyrazole derivatives are relatively unstable due
to the highly π-electron excess properties on the ring atoms. In certain examples, such as 20 and 34, the
heterocycles required some stabilization by extra electron-withdrawing substituents.
Table 1 13C NMR Spectral Assignments for 30b, 32, and 33
Assignment
30b
128.0
32
132.8
33
145.9
2-
3-
4-
5-
CH2
1-b,d
2-a,b
3-a,b
4-a
105.0
106.8
90.3
Pyrroleb,c
107.5a
120.9a
49.4
119.7a
102.7
120.1a
97.4
a
49.1
136.5
127.9
129.6
128.8
113.5
156.0
53.4
47.6
137.2
127.5
129.6
128.5
115.5
-----
-----
138.4
128.3
129.3
128.3
-----
156.6
53.0
129.8
Benzyl
CNd
C=Od
MeOa
1-d
Methoxycarbonyl
129.4
129.6
130.4, 125.4
150.8
2-,3-d
4-d
130.0, 125.5
150.7
166.0, 173.1
130.1, 125.6
150.8
164.6, 173.8
p-Nitrophenyl
1,2,4-Oxadiazole 3-,5-d
165.4, 173.1
The peak was assigned by: a)DEPT135 NMR and 2D HETCOR NMR; b)Proton-coupled 13C NMR;
c)2D COLOC NMR; d)Empirical and/or Calculation
EXPERIMENTAL
General chemical procedures. Melting points were taken on a Thomas-Hoover Unimelt capillary
melting point apparatus and are uncorrected. NMR spectra were obtained by Bruker WP270SY, DPX300,
or DRX500 instruments. The chemical shift values are reported in δ values (parts per million, ppm)
relative to the standard chemical shift of tetramethylsilane (TMS). The coupling constant values are
expressed in Hertz (Hz). UV spectra were recorded on a Hewlett-Packard model 8450A UV/VIS
spectrophotometer. IR spectra were recorded on a Nicolet 5DXB FT-IR spectrophotometer. Elemental
analyses were performed by M-H-W Laboratories, Phoenix, AZ, or by the Analytical Laboratory,
Department of Chemistry, University of Michigan, MI. MS spectrometry was performed by the
Analytical Laboratory, Department of Chemistry, University of Michigan, MI. TLC was performed on
silica gel GHLF-254 plates (Merck Reagents). Compounds on TLC were visualized by illumination under
UV light (254 nm), or dipped into 10% methanolic sulfuric acid followed by charring on a hot plate.
Solvent systems are expressed as a percentage of the more polar component with respect to total volume
(v/v%). E. Merck silica gel (230 - 400 mesh) was used for flash column chromatography and this
technique has been described by Still et al.36 The reported yields have not been optimized. Evaporations

were carried out under reduced pressure (water aspirator) with the bath temperature below 50 oC unless
specified otherwise. Materials obtained from commercial suppliers were used without further purification.
5-Amino-1-benzylpyrazole-4-carboxamidoxime (11)
A solution of 5-amino-1-benzylpyrazole-4-carbonitrile27 (8, 31.7 g, 0.16 mol) and hydroxylamine37 (8.3 g,
0.25 mol) in ethanol (650 mL) was heated at reflux temperature under nitrogen for 4.5 h. The mixture was
concentrated under reduced pressure to give the crude product. This material was recrystallized from
o
acetonitrile to give 11 (30.6 g, 0.13 mol, 83%). mp 134 – 137 C; IR (KBr, cm-1) 3480 – 3000, 1637,
1602, 1574; 1H NMR (DMSO-d6, 270 MHz) δ 8.90 (s, 1 H, OH), 7.58 (s, 1 H, 3-H), 7.38 - 7.22 (m, 3 H,
Ph), 7.20 – 7.10 (m, 2 H, Ph), 5.95 (br s, 2 H, NH2), 5.60 (br s, 2 H, NH2), 5.13 (s, 2 H, CH2); UV λmax
nm (ε) (MeOH): 248 (9270). Anal. Calcd for C11H13N5O: C, 57.13; H, 5.67; N, 30.28. Found: C, 56.93; H,
5.63; N, 30.25.
5-Amino-1-benzylimidazole-4-carboxamidoxime (12a)
Compound (12a) (12.58 g, 54.41 mmol, 89%) was prepared from 5-amino-1-benzylimidazole-4-
carbonitrile28,29 (9a, 12.14 g, 61.25 mmol) using 50%wt aqueous hydroxylamine solution (5.6 mL,
containing 3.04 g of hydroxylamine (91.88 mmol)) and ethanol (300 mL) by the method described for 11,
o
o
and purified by recrystallization. mp 184 – 189 C (decomp) (EtOH / H2O) [lit.,38 193 – 201 C
1
(decomp)]; H NMR (DMSO-d6, 300 MHz) δ 8.88 (s, 1 H, OH), 7.38 – 7.19 (m, 5 H, Ph), 7.22 (s, 1 H,
2-H), 5.37 (br s, 2 H, NH2), 5.31 (br s, 2 H, NH2), 5.07 (s, 2 H, CH2). Anal. Calcd for C11H13N5O: C,
57.13; H, 5.67; N, 30.28. Found: C, 56.98; H, 5.73; N, 30.66.
5-Amino-1-benzyl-2-chloroimidazole-4-carboxamidoxime (12c)
Compound (12c) (5.54 g, 20.85 mmol, 92%) was prepared from 5-amino-1-benzyl-2-chloroimidazole-4-
carbonitrile30 (9c, 5.25 g, 22.56 mmol) using 50%wt aqueous hydroxylamine solution (2.3 mL, containing
1.24 g of hydroxylamine (37.5 mmol)) and ethanol (175 mL) by the method described for 11, and purified
o
by recrystallization. mp 145 C (decomp) (EtOH); IR (KBr, cm-1) 3493, 3458 - 1946, 1637, 1616, 1574;
1H NMR (DMSO-d6, 270 MHz) δ 8.95 (s, 1 H, OH), 7.40 – 7.10 (m, 5 H, Ph), 5.60 (br s, 2 H, NH2), 5.35
(br s, 2 H, NH2), 5.10 (s, 2 H, CH2); UV λmax nm (ε) (MeOH): 263 (11200). Anal. Calcd for
C11H12N5OCl: C, 49.72; H, 4.55; N, 26.36. Found: C, 49.56; H, 4.50; N, 26.12.
5-Amino-1-benzyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazole (14)
Compound (11) (9.50 g, 41.1 mmol) was added to an ethanolic solution of sodium ethoxide (9.50 g of
sodium (413.2 mmol) in 300 mL ethanol) followed by the addition of EtOAc (10.1 mL, 9.09 g, 103.2

mmol). The mixture was heated at reflux temperature under nitrogen for 2 h. After the reaction mixture
was cooled to rt, the solution was neutralized with acetic acid, and then concentrated under reduced
pressure. The resulting residue was partitioned between CHCl3 and H2O. The organic partition was
washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and then concentrated under
reduced pressure to give the crude product. This material was recrystallized in acetonitrile to give 14
o
1
(5.90 g, 23.1 mmol, 56%). mp 146 – 148 C; IR (KBr, cm-1) 3480, 3222, 1630, 1600, 1560; H NMR
(DMSO-d6, 270 MHz) δ 7.59 (s, 1 H, 3-H), 7.32 - 7.24 (m, 3 H, Ph), 7.17 – 7.15 (m, 2 H, Ph), 6.11 (br s,
2 H, NH2), 5.22 (s, 2 H, CH2), 2.58 (s, 3 H, CH3); UV λmax nm (ε) (MeOH): 264 (6535). Anal. Calcd for
C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.19; H, 5.04; N, 27.80.
5-Amino-1-benzyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)imidazole (15a)
Compound (15a) (7.79 g, 30.5 mmol, 56%) was prepared from 12a (12.58 g, 54.41 mmol) using sodium
ethoxide (3.13 g of sodium (136.02 mmol) in 500 mL of ethanol) and then EtOAc (81 mL, 71.9 g, 816
o
mmol) by the method described for 14, and purified by recrystallization from ethanol. mp 198 – 200 C;
IR (KBr, cm-1) 3416, 3282, 1630, 1595; 1H NMR (CDCl3, 500 MHz) δ 7.42 – 7.35 (m, 3 H, Ph), 7.30 (s,
13
1 H, 2-H), 7.21 – 7.19 (m, 2 H, Ph), 5.07 (s, 2 H, CH2), 4.36 (br s, 2 H, NH2), 2.60 (s, 3 H, CH3); C
NMR (CDCl3, 125 MHz) δ 175.7, 165.2, 139.7, 135.2, 133.2 (CH), 129.7 (CH), 128.9 (CH), 127.2 (CH),
110.9, 48.1 (CH2), 12.6 (CH3); UV λmax nm (ε) (MeOH): 280 (9530). MS (CI, NH3) m/z 91 (100), 256
(75) (M + 1); HRMS (CI) Calcd for C13H14N5O (M + 1): 256.1198. Found: 256.1199. Anal. Calcd for
C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.07; H, 5.38; N, 27.50.
5-Amino-1-benzyl-4-(5-phenyl-1,2,4-oxadiazol-3-yl)imidazole (15b)
Compound (15b) (7.25 g, 22.9 mmol, 53%) was prepared from 12a (10.0 g, 43.24 mmol) using sodium
ethoxide (2.5 g of sodium (108.7 mmol) in 225 mL of ethanol) and then ethyl benzoate (15.0 mL, 15.7 g,
104.4 mmol) by the method described for 14, and purified by recrystallization from ethanol. mp 205 –
240 oC (decomp); IR (KBr, cm-1) 3420, 3280, 1630, 1600, 1545; 1H NMR (DMSO-d6, 270 MHz) δ 8.20
(m, 2 H), 7.80 – 7.60 (m, 2 H), 7.40 – 7.20 (m, 7 H), 5.87 (br s, 2 H, NH2), 5.2 (s, 2 H, CH2); UV λmax nm
(ε) (MeOH): 266 (31450). Anal. Calcd for C18H15N5O: C, 68.13; H, 4.76; N, 22.07. Found: C, 68.05; H,
4.81; N, 21.97.
5-Amino-1-benzyl-2-chloro-4-(5-methyl-1,2,4-oxadiazol-3-yl)imidazole (15c)
Compound 15c (830 mg, 2.86 mmol, 38%) was prepared from 12c (2.0 g, 7.53 mmol) using sodium
ethoxide (0.50 g of sodium (21.7 mmol) in 150 mL of ethanol) and then EtOAc (40.0 mL, 36.0 g, 408.6
mmol) by the method described for 14, and purified by recrystallization from methanol. mp 184 – 187 oC;

IR (KBr, cm-1) 3423, 3310, 1616, 1567, 1553, 1454; 1H NMR (DMSO-d6, 270 MHz) δ 7.40 – 7.10 (m, 5
H, Ph), 6.00 (br s, 2 H, NH2), 5.20 (s, 2 H, CH2), 2.57 (s, 3 H, CH3); UV λmax nm (ε) (MeOH): 247 (8540),
281 (10200). Anal. Calcd for C13H12N5OCl: C, 53.89; H, 4.17; N, 24.17. Found: C, 54.03; H, 4.26; N,
24.05.
5-Amino-1-benzyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,3-triazole (16a)
Compound (16a) (17.6 g, 68.7 mmol, 80%) was prepared from 5-amino-1-benzyl-1,2,3-triazole-4-
carboxamidoxime32 (13, 20.0 g, 86.1 mmol) using sodium ethoxide (20 g of sodium (0.87 mol) in 600 mL
ethanol) and then EtOAc (25 mL, 22.6 g, 0.256 mmol) by the method described for 14, and purified by
o
1
recrystallization from ethanol and H2O. mp 236 - 239 C; H NMR (DMSO-d6, 270 MHz) δ 7.39 - 7.30
(m, 3 H, Ph), 7.25 – 7.22 (m, 2 H, Ph), 6.37 (br s, 2 H, NH2), 5.49 (s, 2 H, CH2), 2.64 (s, 3 H, CH3). MS
(EI, 70 eV) m/z 91 (43), 137 (43), 185 (47), 227 (44), 256 (100) (M+); HRMS (EI) Calcd for C12H12N6O
(M): 256.1073. Found: 256.1075.
3-Acetamido-6-benzylpyrazolo[3,4-c]pyrazole (17a)
Compound (14) (5.0 g, 19.6 mmol) was added to a mixture of sodium hydride (50% in mineral oil, 2.0 g,
o
41.7 mmol) in N,N-dimethylformamide (100 mL). The mixture was heated at 100 C under nitrogen for
45 min. The mixture was then cooled (ice bath) and concentrated in vacuo. The resulting residue was
dissolved in water (50 mL) and neutralized with acetic acid. The precipitate was collected by filtration.
o
This material was recrystallized from ethanol to give 17a (2.0 g, 7.8 mmol, 40%). mp 212 – 215 C; IR
(KBr, cm-1) 3320, 1705, 1550, 1485; 1H NMR (DMSO-d6, 270 MHz) δ 11.44 (br s, 1 H, NH), 11.39 (br s,
1 H, NH), 7.32 - 7.19 (m, 5 H, Ph), 7.15 (s, 1 H, 4-H), 5.29 (s, 2 H, CH2), 2.07 (s, 3 H, CH3); UV λmax nm
(ε) (MeOH): 264 (16720). Anal. Calcd for C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.06; H,
5.12; N, 27.28.
3-Acetamido-6-benzyl-4-bromopyrazolo[3,4-c]pyrazole (17b)
To a solution of 17a (0.25 g, 1.0 mmol) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (220
mg, 1.2 mmol) and the mixture was stirred at rt for 2 h. The solution was concentrated under reduced
pressure and the resulting residue was purified by column chromatography (EtOAc) to give 17b (303 mg,
0.91 mmol, 91%). mp 240 – 243 oC (EtOAc); IR (KBr, cm-1) 3311, 3057, 2755, 1764, 1694, 1574, 1518;
1H NMR (DMSO-d6, 270 MHz) δ 11.92 (br s, 1 H, NH), 11.45 (br s, 1 H, NH), 7.34 - 7.21 (m, 5 H, Ph),
5.27 (s, 2 H, CH2), 2.08 (s, 3 H, CH3); Anal. Calcd for C13H12N5OBr: C, 46.72; H, 3.62; N, 20.96. Found:
C, 46.80; H, 3.64; N, 20.76.

3-Acetamido-6-benzylimidazo[4,5-c]pyrazole (18a)
Sodium hydride (60% in mineral oil, 0.16 g, 4 mmol) was placed in a 100 mL round bottom flask
equipped with a rubber septum and an inert gas (argon) inlet. N,N-Dimethylformamide (20 mL) was
o
added and the mixture was stirred at rt. The suspension mixture was heated in a 75 C oil bath and 15a
(0.511 g, 2 mmol) was added to the mixture. The reaction temperature was gradually raised to 100 oC in
15 min. The reaction was then cooled to rt and neutralized with acetic acid (0.12 mL, 0.12 g, 2 mmol).
The solvent was evaporated in vacuo. The residue was partitioned between CHCl3 (150 mL) and H2O (50
mL). The aqueous layer was further extracted with CHCl3 (2 x 150 mL). The organic partitions were
washed with saturated aqueous NaCl solution, combined, dried over anhydrous MgSO4, and then
concentrated under reduced pressure. The crude product was recrystallized in ethanol to give 18a (0.183 g,
o
1
0.72 mmol, 36%). mp 207 - 210 C (decomp); H NMR (DMSO-d6, 500 MHz) δ 11.70 (br s, 1 H, NH),
11.09 (br s, 1 H, NH), 7.52 (s, 1 H, 5-H), 7.35 – 7.27 (m, 5 H, Ph), 5.24 (s, 2 H, CH2), 2.03 (s, 3 H, CH3);
13C NMR (DMSO-d6, 125 MHz) δ 168.8, 141.5, 137.8, 134.8 (CH), 134.1, 133.4, 129.0 (CH), 128.1
(CH), 128.0 (CH), 48.8 (CH2), 23.3 (CH3); MS (CI, NH3) m/z 91 (33), 256 (100) (M + 1); UV λmax nm (ε)
(MeOH): 202 (21383), 272 (14566), 279 (14489). HRMS (CI) Calcd for C13H14N5O (M + 1): 256.1198.
Found: 256.1206. Anal. Calcd for C13H13N5O: C, 61.16; H, 5.13; N, 27.43. Found: C, 61.08; H, 5.17; N,
27.38.
3-Benzamido-6-benzylimidazo[4,5-c]pyrazole (18b)
Sodium hydride (50% in mineral oil, 480 mg, 10.0 mmol) was added to dimethyl sulfoxide (50 mL) and
the mixture was heated at 75 oC until a cessation of hydrogen gas evolution. Compound 15b (1.50 g, 4.73
o
mmol) was added and the mixture was heated at 100 C under argon for 15 min. The solvent was
removed by distillation and the resulting residue was added to ice / water. The precipitated solid was
collected by filtration. This material was purified by column chromatography (acetone) to give 18b (410
o
mg, 1.29 mmol, 27%). mp 200 – 240 C (decomp) (acetone); IR (KBr, cm-1) 3557 – 2579, 3275, 1672,
1602, 1574; 1H NMR (DMSO-d6, 270 MHz) δ 12.02 (br s, 1 H, NH), 11.45 (br s, 1 H, NH), 8.00 (m, 2 H),
7.60 – 7.40 (m, 4 H), 7.30 – 7.20 (m, 5 H), 5.25 (s, 2 H, CH2); UV λmax nm (ε) (MeOH): 228 (15250),
307 (13410); MS (EI) m/z 212, 317 (M+); Anal. Calcd for C18H15N5O: C, 68.13; H, 4.76; N, 22.07.
Found: C, 68.08; H, 5.01; N, 22.15.
3-Benzyl-4-acetyl-6-benzamidopyrazolo[3,4-d][1,2,3]triazole (20)
To a mixture of 5-amino-1-benzyl-4-(5-phenyl-1,2,4-oxadiazol-3-yl)-1,2,3-triazole32 (16b, 0.50 g, 1.57
mmol) and N,N-dimethylaminopyridine (19.2 mg, 0.157 mmol) in pyridine (20 mL) was added acetic
anhydride (0.30 mL, 0.321 g, 3.14 mmol). The reaction mixture was heated at 100 oC for 7 h. The solvent

was evaporated under reduced pressure. The residue was dissolved in EtOAc and the solution was washed
with H2O, saturated aqueous NaCl solution, and then dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give the crude product of 5-acetamido-1-benzyl-4-(5-phenyl-
1,2,4-oxadiazol-3-yl)-1,2,3-triazole that was used without further purification. This compound was added
to a mixture of sodium hydride (50% in mineral oil, 0.10 g, 2.08 mmol) in N,N-dimethylformamide (5
mL). The mixture was heated at 100 oC under nitrogen for 35 min. The mixture was then cooled (ice bath),
neutralized with acetic acid, and then poured onto ice. The resulting precipitate was collected by filtration.
This material was recrystallized from methanol to give 20 (0.24 g, 0.67 mmol, 42% from 16b). mp 192 -
196 oC; 1H NMR (DMSO-d6, 270 MHz) δ 10.50 (br s, 1 H, NH), 8.20 (m, 2 H, Ph), 7.80 - 7.60 (m, 3 H,
Ph), 7.40 – 7.20 (m, 5 H, Ph), 5.55 (s, 2 H, CH2), 2.10 (s, 3 H, CH3). Anal. Calcd for C19H16N6O2: C,
63.32; H, 4.48; N, 23.32. Found: C, 63.02; H, 4.46; N, 23.11.
3-Acetamidopyrazolo[3,4-c]pyrazole (22)
o
To a solution of 17a (2.0 g, 7.83 mmol) in liquid ammonia (125 mL) at –50 C was added sodium
portionwise with vigorous stirring until a blue color persisted. Ammonia was allowed to evaporate and
the resulting residue was placed under vacuum to remove a trace amount of ammonia. Methanol (100
mL) was added and the solution was neutralized with acetic acid. The precipitate was collected, washed
with water, methanol and ether, and then dried in vacuo to give 22 (640 mg, 3.88 mmol, 49%). The
compound was recrystallized from 75% aqueous ethanol to give the analytical sample of 22 (100 mg,
0.61 mmol, 8%). mp 297 - 300 oC (decomp); IR (KBr, cm-1) 3663 - 2389, 3360, 2938, 1686, 1602, 1525;
1H NMR (DMSO-d6, 270 MHz) δ 12.40 - 11.00 (br s, 3 H, 3 x NH), 7.30 (s, 1 H, 4-H), 2.14 (s, 3 H,
CH3); MS (EI) m/z 165 (65), 123 (100) (M+ – CH3CO); Anal. Calcd for C6H7N5O . 0.25 H2O: C, 42.48; H,
4.46; N, 41.28. Found: C, 42.45; H, 4.23; N, 40.89.
3-Aminopyrazolo[3,4-c]pyrazole hydrochloride (23)
A solution of 22 (473 mg, 2.9 mmol) in 1 N HCl (25 mL) was heated at reflux temperature for 2 h. The
solution was concentrated under reduced pressure and the residue was coevaporated with ethanol. The
o
crude product was recrystallized from ethanol, washed with ether, and then dried in vacuo at 100 C
o
1
overnight to give 23 (323 mg, 2 mmol, 69%). mp 282 – 285 C (decomp); H NMR (DMSO-d6, 270
MHz) δ 13.65 (br s, 1 H, NH), 12.00 (br s, 1 H, NH), 8.35 (br s, 2 H, NH2), 7.58 (d, 1 H, 4-H); 13C NMR
(DMSO-d6, 68 MHz) δ 154.9, 146.0, 114.8, 110.5 (4-CH); MS (El): m/z 43 (100), 123 (84) (M+); Anal.
.
Calcd for C4H5N5 HCl: C, 30.11; H, 3.79; N, 43.89. Found: C, 30.17; H, 3.73; N, 43.73.
1-Benzyl-3-cyanopyrrole-2-carboxamide (25)

To ethyl 1-benzyl-3-cyanopyrrole-2-carboxylate35 (24, 20.0 g, 78.7 mmol) in a high-pressure vessel was
o
added liquid ammonia (300 mL). The vessel was sealed and heated at 100 C for 4 days. The pressure
vessel was allowed to cool to rt with venting to release the ammonia. The solid residue was suspended in
o
ether and the solid was collected by filtration to give 25 (17.0 g, 75.5 mmol, 96%). mp 141 – 145 C
1
(EtOAc); IR (KBr, cm-1) 3400, 3300, 3250, 3200, 2224, 1665, 1610, 1480; H NMR (DMSO-d6, 270
MHz) δ 8.00 - 7.70 (d, 2 H, NH2), 7.40 - 7.15 (m, 6 H), 6.56 (d, 1 H), 5.45 (s, 2 H, CH2); UV λmax nm (ε)
(MeOH): 244 (7020), 265 (6820). Anal. Calcd for C13H11N3O: C, 69.32; H, 4.92; N, 18.66. Found: C,
69.29; H, 4.83; N, 18.79.
1-Benzyl-2-carboxamidopyrrole-3-carboxamidoxime (26)
Compound 25 (45.0 g, 200 mmol) was added to a solution of sodium methoxide (54.0 g, 1.0 mol) in
methanol (1 L) and the solution was stirred for 30 min. Hydroxylamine sulfate (82.8 g. 0.50 mol) was
added to the solution portionwise with stirring and then the mixture was heated at reflux temperature
under argon for 18 h. The solids were removed by filtration and the filtrate was concentrated under
reduced pressure to approx. 250 mL. This solution was poured onto ice (500 g) with stirring and the pH
was adjusted to 6 with acetic acid. The mixture was stirred for 30 min, and the precipitate formed was
collected by filtration, washed with cold water and dried to give 26 (48.0 g, 186 mmol, 93%). mp 144 –
o
1
147 C (H2O); IR (KBr, cm-1) 3528 - 2657, 3458, 1651, 1588, 1496; H NMR (DMSO-d6, 270 MHz) δ
9.55 (s, 1 H, OH), 9.50 (br s, 2 H, NH2), 7.40 – 7.10 (m, 6 H), 6.38 (d, 1 H), 5.90 (br s, 2 H, NH2), 5.62 (s,
2 H, CH2); UV λmax nm (ε) (MeOH): 267 (7230); Anal. Calcd for C13H14N4O2: C, 60.45; H, 5.46; N,
21.69. Found: C, 60.27; H, 5.32; N, 21.70.
1-Benzyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrole-2-carboxamide (28a)
Compound 28a (6.88 g, 24.4 mmol, 90%) was prepared from 26 (7.0 g, 27.1 mmol) using sodium
ethoxide (610 mg of sodium (26.5 mmol) in 250 mL of ethanol) and then EtOAc (7.6 mL, 6.86 g, 77.8
mmol) by the method described for 14, and purified by recrystallization from acetonitrile. mp 141 – 144
oC; IR (KBr, cm-1) 3370, 3190, 1645, 1622, 1587, 1562; 1H NMR (DMSO-d6, 270 MHz) δ 8.10 (br s, 1 H,
NH), 7.54 (br s, 1 H, NH), 7.34 - 7.24 (m, 3 H), 7.16 - 7.13 (m, 3 H), 6.52 (d, 1 H), 5.00 (s, 2 H, CH2),
2.60 (s, 3 H, CH3); UV λmax nm (ε) (MeOH): 261 (4340), 277 (sh, 3760). Anal. Calcd for C15H14N4O2: C,
63.82; H, 5.00; N, 19.85; O, 11.34. Found: C, 63.68; H, 4.92; N, 19.96.
1-Benzyl-3-[5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl]pyrrole-2-carboxamide (28b)
To a mixture of 26 (10.0 g, 38.7 mmol) and triethylamine (30 mL, 21.6 g, 213 mmol) in THF (800 mL)
was added p-nitrobenzoyl chloride (9.2 g, 49.6 mmol). The mixture was stirred at rt for 5 h. The solvent

was removed under reduced pressure. The resulting residue was dissolved in EtOAc (200 mL). The
solution was washed with H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried over
anhydrous Na2SO4, and then evaporated to dryness. The resulting solid was recrystallized from
acetonitrile to give 27 (8.5 g, 20.9 mmol, 54%) that was used without further characterization. Anal.
.
Calcd for C20H17N5O5 H2O: C, 56.47; H, 4.50; N, 16.46. Found: C, 56.57; H, 4.54; N, 16.39.
A mixture of 27 (obtained from 38.7 mmol of 26) and acetic acid (1 mL) in toluene (300 mL) was heated
at reflux temperature for 16 h in a flask equipped with a Dean-Stark apparatus. The solution was
o
concentrated under reduced pressure to approx. 250 mL. The solution was placed in the freezer (0 C)
overnight. Crystals were collected by filtration and washed with pentane to give 28b (8.3 g, 21.3 mmol,
55% from 26). mp 215 - 219 oC (toluene); IR (KBr, cm-1) 3381, 3205, 1658, 1623, 1567, 1525; 1H NMR
(DMSO-d6, 270 MHz) δ 8.45 - 8.35 (m, 4 H, p-NO2C6H4), 7.93 (br s, 1 H, NH), 7.60 (br s, 1 H, NH),
7.38 - 7.20 (m, 6 H), 6.60 (d, 1 H), 5.45 (s, 2 H, CH2); UV λmax nm (ε) (MeOH): 274 (34070). Anal.
Calcd for C20H15N5O4: C, 61.69; H, 3.88; N, 17.99. Found C, 61.79, H, 4.14, N, 18.04.
1-Benzyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrole-2-carboxylic Acid (29a)
To a solution of nitrosylsulfuric acid (3.1 g, 24.4 mmol) in acetic acid (50 mL) was added 28a (4.13 g,
14.6 mmol) portionwise with vigorous stirring. After 1 h, the room temperature solution was diluted with
ether (50 mL) and the precipitated white solid was collected by filtration. This material was dried and
then a solution of sodium acetate (1.20 g, 14.6 mmol) in water was added. The mixture was stirred for 30
min. The crude product was collected and dried, and then suspended in ether to remove the reddish
o
impurities. The solid was collected by filtration to give 29a (2.06 g, 7.27 mmol, 50%). mp 154 – 156 C
(acetone); IR (KBr, cm-1) 3600 - 2400, 2938, 2593, 1700, 1596, 1510; 1H NMR (DMSO-d6, 270 MHz) δ
12.75 (br s, 1 H, CO2H), 7.37 - 7.20 (m, 5 H), 7.10 (s, 1 H), 6.40 (d, 1 H), 5.55 (s, 2 H, CH2), 2.57 (s, 3 H,
CH3); UV λmax nm (ε) (MeOH): 266 (9630). Anal. Calcd for C15H13N3O3: C, 63.60; H, 4.63; N, 14.83.
Found: C, 63.71; H, 4.51; N, 15.08.
1-Benzyl-3-[5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl]pyrrole-2-carboxylic Acid (29b)
Compound 29b (570 mg, 1.46 mmol, 57 %) was prepared from 28b (1.0 g, 2.57 mmol) using
nitrosylsulfuric acid (560 mg, 4.4 mmol) and acetic acid (40 mL) by the method described for 29a, and
o
purified by recrystallization from acetone. mp 232 – 235 C; IR (KBr, cm-1) 3600 - 2400, 1715, 1574,
1539; 1H NMR (DMSO-d6, 270 MHz) δ 12.85 (br s, CO2H), 8.45 - 8.35 (m, 4 H, p-NO2C6H4), 7.38 - 7.11
(m, 6 H), 6.53 (d, 1 H), 5.58 (s, 2 H, CH2); MS (EI) m/z 91 (100), 374, 391 (M + 1); UV λmax nm (ε)
.
(MeOH): 273 (19060). Anal. Calcd for C20H14N4O5 0.5 H2O: C, 60.15; H, 3.79; N, 14.03. Found: C,
60.10; H, 3.84; N. 14.15.

1-Benzyl-2-ethoxycarbonylamino-3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrrole (30a)
To a solution of 29a (1.0 g, 3.53 mmol) and triethylamine (0.5 mL, 0.36 g, 3.56 mmol) in
N,N-dimethylformamide (75 mL) was added ethyl chloroformate (0.84 mL, 0.95 g, 8.79 mmol) in one
portion with vigorous stirring. After 2 h, sodium azide (0.34 g, 5.23 mmol) was added and the mixture
was stirred for an additional 3 h. Ethanol (20 mL) was added and the mixture was heated at 85 oC for an
additional 2 h. The dark mixture was then concentrated under reduced pressure and the residue was
partitioned between H2O (40 mL) and EtOAc (50 mL). The organic layer was washed with H2O,
concentrated to dryness and then purified by column chromatography (toluene / EtOAc = 10 : 3) to give
30a (216 mg, 0.66 mmol, 19%). mp 156 – 160 oC (ether). IR (KBr, cm-1) 3233, 3198, 3142, 3121, 2980,
1700, 1580; 1H NMR (DMSO-d6, 270 MHz) δ 9.00 and 8.75 (both br s, total = 1 H, NH), 7.35 - 7.15 (m,
5 H), 6.80 (d, 1 H), 6 43 (d, 1 H), 5.00 (s, 2 H, CH2), 4.05 and 3.80 (both br s, total = 2 H, CH2), 2.57 (s, 3
H, CH3), 1.15 and 0.85 (both br s, total = 3 H, CH3); UV λmax nm (ε) (MeOH): 241 (8920), 262 (sh, 6305).
Anal. Calcd for C17H18N4O3: C, 62.57; H, 5.56; N, 17.17. Found: C, 62 49; H, 5.36; N, 16.96.
1-Benzyl-2-methoxycarbonylamino-3-[5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl]pyrrole (30b)
To a solution of 29b (7.44 g, 19.1 mmol) and triethylamine (3.5 mL, 2.52 g, 24.9 mmol) in
N,N-dimethylformamide (300 mL) was added diphenylphosphoryl azide (6.54 g, 23.7 mmol) and the
solution was stirred at rt for 70 min. MeOH (65 mL) was added and the mixture was heated at 65 oC for
an additional 70 min. The reaction mixture was concentrated under reduced pressure to afford a dark solid
residue. The crude product was purified by column chromatography (toluene : EtOAc = 7 : 3) to give the
product which was contaminated by a trace amount of orange impurity. This material was recrystallized
from EtOAc to give 30b (3.65 g, 8.7 mmol, 46%). mp 187 - 192.5 oC; IR (KBr, cm-1) 3282, 1707, 1567,
1532; 1H NMR (DMSO-d6, 500 MHz) δ 9.24 (br s, 0.7 H, NH), 8.99 (br s, 0.3 H, NH), 8.48 (d, J = 8.7 Hz,
2 H, p-NO2C6H4 3-H), 8.37 (d, J = 8.7 Hz, 2 H, p-NO2C6H4 2-H), 7.36 – 7.33 (m, 2 H, Ph 3-H), 7.30 –
7.27 (m, 1 H, Ph 4-H), 7.24 – 7.22 (m, 2 H, Ph 2-H), 6.89 (br s, 1 H, pyrrole 5-H), 6.60 (d, J = 3.1 Hz, 1
13
H, pyrrole 4-H), 5.09 (s, 2 H, CH2), 3.68 (br s, 3 H, CH3); C NMR (DMSO-d6, 125 MHz) δ 173.1
(oxadiazole 5-C), 166.0 (oxadiazole 3-C), 156.6 (C=O), 150.7 (p-NO2C6H4 4-C), 138.4 (Ph 1-C), 130.0
(p-NO2C6H4 2-CH), 129.8 (p-NO2C6H4 1-C), 129.3 (Ph 3-CH), 128.3 (Ph 2- and 4-CH), 128.0 (pyrrole
2-C), 125.5 (p-NO2C6H4 3-CH), 120.9 (pyrrole 5-CH), 107.5 (pyrrole 4-CH), 105.0 (pyrrole 3-C), 53.0
(CH3), 49.4 (CH2); UV λmax nm (ε) (MeOH): 276 (23700). Anal. Calcd for C21H17N5O5: C, 60.14; H,
4.09; N, 16.70. Found: C, 60.42; H, 4.04; N, 16.47.

1-Benzyl-2-methoxycarbonylamino-3-[5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl]pyrrole-5-carbonitrile
(32)
To a solution of 30b (0.10 g, 0.24 mmol) in acetonitrile (15 mL) in an ice bath was added a solution of
chlorosulfonyl isocyanate (24 µL, 39 mg, 0.27 mmol) in acetonitrile (5 mL) dropwise with stirring. The
ice bath was removed after the addition was completed and the reaction mixture was allowed to stir for an
additional 16 h at rt. N,N-Dimethylformamide (22 µL, 20 mg, 0.27 mmol) was added and the mixture was
heated at reflux temperature for an additional 2 h. The solvent was removed under reduced pressure and
the resulting residue was suspended in EtOAc (2 mL). The yellow solid was collected by filtration and
o
then recrystallized from methanol to give 32 (70.0 mg, 0.16 mmol, 66%). mp 198 – 201 C (MeOH); IR
(KBr, cm-1) 3250, 2227, 1743, 1708, 1602, 1567; 1H NMR (DMSO-d6, 500 MHz) δ 9.85 (br s, 1 H, NH),
8.47 (d, J = 8.9 Hz, 2 H, p-NO2C6H4 3-CH), 8.36 (d, J = 8.9 Hz, 2 H, p-NO2C6H4 2-CH), 7.57 (s, 1 H,
pyrrole 4-H), 7.40 – 7.37 (m, 2 H, Ph 3-CH), 7.34 – 7.31 (m, 1 H, Ph 4-CH), 7.21 – 7.20 (m, 2 H, Ph
13
2-CH), 5.32 (s, 2 H, CH2), 3.71 (br s, 3 H, CH3); C NMR (DMSO-d6, 125 MHz) δ 173.8 (oxadiazole
5-C), 164.6 (oxadiazole 3-C), 156.0 (C=O), 150.8 (p-NO2C6H4 4-C), 136.5 (Ph 1-C), 132.8 (pyrrole 2-C),
130.1 (p-NO2C6H4 2-CH), 129.6 (Ph 3-CH), 129.4 (p-NO2C6H4 1-C), 128.8 (Ph 4-CH), 127.9 (Ph 2-CH),
125.6 (p-NO2C6H4 3-CH), 119.7 (pyrrole 4-CH), 113.5 (CN), 106.8 (pyrrole 3-C), 102.7 (pyrrole 5-C),
.
53.4 (CH3), 49.1 (CH2); UV λmax nm (ε) (MeOH): 274 (29500). Anal. Calcd for C22H16N6O5 0.5 H2O: C,
58.28; H, 3.78; N, 18.53. Found: C, 58.17; H, 4.00; N, 18.25.
2-Amino-1-benzyl-3-[5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl]pyrrole-5-carbonitrile (33)
To a solution of 32 (150 mg, 0.34 mmol) in anisole (10 mL) was added 1,8-diazabicyclo-
[5.4.0]undec-7-one (15 µL, 40.0 mg, 0.26 mmol) and the mixture was heated at reflux temperature for 1.5
h. The reaction mixture was concentrated in vacuo to afford a solid residue. This material was
recrystallized from methanol to give 33 (92 mg, 0.24 mmol, 70%). mp 245 – 250 oC (decomp); IR (KBr,
cm-1) 3430, 3346, 2207, 1623, 1525; 1H NMR (DMSO-d6, 500 MHz) δ 8.45 (s, 4 H, p-NO2C6H4), 7.41 –
7.38 (m, 2 H, Ph 3-CH), 7.35 (s, 1 H, pyrrole 4-H), 7.33 – 7.30 (m, 1 H, Ph 4-CH), 7.18 – 7.16 (m, 2 H,
13
Ph 2-CH), 6.67 (s, 2 H, NH2), 5.27 (s, 2 H, CH2); C NMR (DMSO-d6, 125 MHz) δ 173.1 (oxadiazole
5-C), 165.4 (oxadiazole 3-C), 150.8 (p-NO2C6H4 4-C), 145.9 (pyrrole 2-C), 137.2 (Ph 1-C), 130.4
(p-NO2C6H4 2-CH), 129.6 (2 C, p-NO2C6H4 1-C + Ph 3-CH), 128.5 (Ph 4-CH), 127.5 (Ph 2-CH), 125.4
(p-NO2C6H4 3-CH), 120.1 (pyrrole 4-CH), 115.5 (CN), 97.4 (pyrrole 5-C), 90.3 (pyrrole 3-C), 47.6
(CH2); MS (EI) m/z 386 (100) (M+); UV λmax nm (ε) (MeOH): 306 (29100), 275 (sh, 22150). Anal. Calcd
for C20H14N6O3: C, 62.17; H, 3.65; N, 21.75. Found: C, 62.41; H, 3.81; N, 21.58.
6-Benzyl-5-cyano-3-(p-nitrobenzamido)pyrrolo[2,3-c]pyrazole (34)

To a suspension of sodium hydride (50% in mineral oil, 62 mg, 1.29 mmol) in dimethyl sulfoxide (40
mL) was added 33 (0.50 g, 1.29 mmol) and the mixture was heated at 75 °C under argon for 15 min. The
reaction mixture was then cooled (ice bath) to rt and neutralized with acetic acid (80 mg, 1.33 mmol). The
solvent was removed by distillation to give a dark residue. The residue was partitioned between EtOAc
(150 mL) and H2O (100 mL). The organic layer was washed with saturated aqueous NaCl solution, and
then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was
purified by column chromatography (toluene / EtOAc = 3 : 1) to give a dark orange solid. The solid was
suspended in a small amount of ether and then collected by filtration to give 34 (146 mg, 0.38 mmol,
o
1
29%). mp 245 – 250 C (decomp) (EtOAc); IR (KBr, cm-1) 3346, 3297, 2214, 1680, 1602, 1546; H
NMR (DMSO-d6, 270 MHz) δ 12.34 (br s, 1 H, NH), 12.03 (br s, 1 H, NH), 8.34 - 8.22 (m, 4 H,
p-NO2C6H4), 7.36 - 7 18 (m, 5 H), 6.78 (s, 1 H, 4-H), 5.30 (s, 2 H, CH2); MS (FAB) m/z 91 (100), 150,
386 (7) (M+). Anal. Calcd for C20H14N6O3: C, 62.17; H, 3.65; N, 21.75. Found. C, 62.11; H, 3.87; N,
21.51.
ACKNOWLEDGMENT
This work was supported by Research Grant 5-PO1-AI46390 from the National Institutes of Health.
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