Synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives via Aza-Diels-Alder reaction: Evaluation of torsion effect of pyrazoylimines

Article abstract of DOI:10.1016/j.tet.2014.08.013

A modified method for the synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine was developed through an Aza-Diels-Alder reaction of pyrazoylimines with maleimides in the sealed tube. Based on the control experiment, the yields for the Aza-Diels-Alder reaction seemed proportional to the suitable torsion conformation of pyrazoylimine, which was modulated by N,N-disubstituted amidinyl moiety. The versatile sealed tube technique was also proved to promote the higher isolated yields in the Aza-Diels-Alder reaction.

Full text of DOI:10.1016/j.tet.2014.08.013

Tetrahedron 70 (2014) 7439e7444
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives via
Aza-DielseAlder reaction: evaluation of torsion effect of
pyrazoylimines
,d,
Li-Ya Wang a, Naoto Uramaru b, Fung Fuh Wong c
*
a The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Environmental Science, Nihon Pharmaceutical University, 10281, Komuro, Ina-machi, Kitaadachi-gun, Saitama, Japan
c School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
d Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A modified method for the synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine was developed through an
Aza-DielseAlder reaction of pyrazoylimines with maleimides in the sealed tube. Based on the control
experiment, the yields for the Aza-DielseAlder reaction seemed proportional to the suitable torsion
conformation of pyrazoylimine, which was modulated by N,N-disubstituted amidinyl moiety. The ver-
satile sealed tube technique was also proved to promote the higher isolated yields in the Aza-DielseAlder
reaction.
Received 19 July 2014
Accepted 8 August 2014
Available online 14 August 2014
Keywords:
Pyrazolopyrrolopyridines
Aza-DielseAlder reaction
Pyrazoylimines
Ó 2014 Elsevier Ltd. All rights reserved.
Leaving group effect
1. Introduction
pyrrolidinylamidinyl, and piperidinylamidinyl groups. On the other
hand, we also tried to carry out the Aza-DielseAlder reaction of
New
functionalized
pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine
pyrazoylimine with maleimides under sealed tube condition to
promote the reaction.
derivatives1e6 were originally designed and synthesized by using
zolpidem as the lead model compound. They act as a benzodiaze-
pine receptor agonist and are commonly used to treat anxiety dis-
2. Results and discussion
orders related to the neuronal inhibition induced by g-aminobutyric
acid (GABA).7e9 Pyrazolopyrrolopyridines have been synthesized
generally by cyclization reactions starting from specific heterocyclic
reagents.10,11 Most of the methods involved the hetero-DielseAlder
cycloaddition of pyrazoylimines with maleimides and subsequent
oxidation under the conventional heating condition4 or microwave-
assisted synthetic methodology.5,6 However, these methods could
not provide the satisfactory results due to the low yields (20e60%)
were obtained even under harsh conditions and long reaction
time.4e6 Herein, we explored the suitable torsion conformation of
pyrazoylimine10 as the dienes for hetero-DielseAlder reaction,
which was possessed various of N,N-disubstituted amidinyl func-
tional groups including N,N-dimethylamidinyl, N,N-dieth-
ylamidinyl, N,N-diisopropylamidinyl, N,N-di(n-propyl)amidinyl,
All of pyrazoylimine starting materials 1aef containing various
of N,N-dimethylamidinyl, N,N-diethylamidinyl, N,N-diisopropyla-
midinyl, N,N-di(n-propyl)amidinyl, pyrrolidinylamidinyl, and
piperidinylamidinyl groups were prepared following our pre-
viously developed procedures.12 To evaluate and study the torsion
conformations, various N,N-disubstituted amidinyl pyrazoylimine
compounds 1aef were treated with 3.0 equiv of N-phenyl-
maleimide 2 in acetic acid at 50e90 ꢀC (see Scheme 1). Preliminary,
compound 1a was allowed to react with 3.0 equiv of N-phenyl-
maleimide 2 under normal atmosphere and monitored by TLC for
48 h. After the work-up and purification, the corresponding pyr-
azolo[3,4-b]pyrrolo[3,4-d]pyridine 3 was isolated in 48% yield (see
the Entry 1 of Table 1). Consequently, we prolonged the reaction
time to 120 h, the desired product 3 was obtained in 49% yield (see
the Entry 2 of Table 1). Otherwise, we tried to carry out the same
reaction at w50 ꢀC with 100 W of microwave energy for 1.5 h, the
yield was promoted to 38% (see the Entry 3 of Table 1). Our ex-
perimental results were consistence with the previous literature
* Corresponding author. Tel.: þ886 4 2205 3366x5603; fax: þ886 4 2207 8083;
e-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F. Wong).
http://dx.doi.org/10.1016/j.tet.2014.08.013
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

7440
L.-Y. Wang et al. / Tetrahedron 70 (2014) 7439e7444
H
O
N
NR1R2
O
N
N
Ph
+
N
N Ph
AcOH, 50~90 o
C
N
N
O
N
Ph
O
Ph
2
3
1a-f
Scheme 1. Synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines from N,N-disubstitutedamidinyl pyrazoylimines with N-phenylmaleimide via Aza-DielseAlder reaction.
Table 1
The result of pyrazoylimines 1aef with N-phenylmaleimide 2 via Aza-DielseAlder reaction in various reaction conditions
Entry
Pyrazoylimines 1aef
Reaction temp (ꢀC)
Reaction time (h)
Pyrazolo[3,4-b]pyrrolo-[3,4-d]pyridines 3
S.M.
R1
R2
Products
Yields (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Et
i-Pr
Me
Me
Me
Me
Me
Me
Et
50
50
50
50
50
50
50
50
50
50
50
90
90
90
90
48
120
1.5
48
72
120
48
48
48
48
48
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
48a
49a
38b
57c
65c
78c
76c
85c
81c
80c
78c
91c
24c
dd
dd
i-Pr
n-Pr
9
n-Pr
10
11
12
13
14
15
Pyrrolidinyl
Piperidinyl
i-Pr
n-Pr
Pyrrolidinyl
Piperidinyl
1c
1d
1e
1f
i-Pr
n-Pr
24
24
24
24
a
The conventional heating under normal atmosphere.
The heating under microwave-assisted synthesis condition.
The heating in sealed tube.
b
c
d
Non-detectable.
reported data.4e6 Due to use of the sealed tube technique allowed
the reaction system to prevent the intrusion of moisture and
vaporization of solvents,13 we tried to employ compound 1a with
N-phenylmaleimide 2 at the same reaction temperature in the
sealed tube condition. When we monitored the reaction result at
the different reaction times including 48 h, 72 h, and 120 h, the
isolate yields of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine 3 were im-
proved from 57% to 78% (see the Entry 4e6 in Table 1). As a result,
we believed that the sealed tube technique would be able to opti-
mize this Aza-DielseAlder reaction of pyrazoylimines with mal-
eimide. Furthermore, compound
spectroscopic methods. For example, it presented one singlet peaks
at
9.23 ppm for pyrazolopyrrolopyridine ring N]CHeC]C in 1
NMR and two peaks at
3 were fully identified by
d
H
d
164.88 and 166.48 ppm for maleimide
moiety carbon O]13CeN in 13C NMR spectrum. The structure of
pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine 3 was also characterized by
X-ray crystallographic analyses and the single-crystal X-ray dif-
fraction study (ORTEP) was presented in Fig. 1.
Fig. 1. The ORTEP diagram of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine 3.
Díaz-Ortiz et al. reported that a suitable torsion angle between
the exocyclic double bond and the pyrazole ring can provide the
more stable conformation of pyrazoylimines for the optimization of
the Aza-DielseAlder reaction.10 Therefore, we investigated the
torsion conformation of pyrazoylimine by modulating the N,N-di-
substituted amidinyl moiety. We employed the new reaction con-
dition to a series of pyrazoylimine compounds 1bef containing
different N,N-disubstituted amidinyl moieties, including N,N-
dimethyl, N,N-diethyl, N,N-diisopropyl, N,N-di(n-propyl), piper-
idinyl, and pyrrolidinylamidinyl groups (see the Entry 7e11 in Table
1). We found that the bulky amidinyl pyrazoylimine reactants 1cef
containing N,N-diisopropyl, N,N-di(n-propyl), piperidinyl, and pyr-
rolidinyl can provide the better reaction results at 50 ꢀC for 48 h,
especially for N,N-diisopropylamidinyl pyrazoylimine 1c in 85%
yield (see the Entry 7e11 in Table 1).

L.-Y. Wang et al. / Tetrahedron 70 (2014) 7439e7444
7441
Simultaneously, we also searched for the optimum reaction
temperature to reduce the reaction time. We reacted pyr-
azoylimines 1cef with 3.0 equiv of N-phenylmaleimide 2 at 90 ꢀC
for 24 h. Based on the experimental results, most of the pyr-
azoylimines 1bef were decomposed to 5-amino-1-3-
diphenylpyrazole, except for N,N-diisopropylamidinyl pyr-
azoylimine 1c (see the Entry 12e15 in Table 1). As a result, the
reliable procedure for the new developed Aza-DielseAlder cyclo-
addition reaction involved the treatment of N,N-diisopropylami-
dinyl pyrazoylimine 1c with 3.0 equiv of N-phenylmaleimide 2 in
acetic acid solution in the sealed tube at 90 ꢀC for 24 h. After
aqueous worked-up and purified by column chromatography on
silica gel, the corresponding pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine
3 was obtained in the best 91% isolated yield (see Scheme 1 and the
Entry 12 of Table 1).
For further investigation of the substitution effect on the pyr-
azole ring, we synthesized a series of N,N-diisopropylamidinyl
pyrazoylimine 4aef with various substituents, including m-Me, m-
Cl, p-Me, p-Cl, p-Br, and p-COOH groups on N1-phenyl ring of
pyrazole moiety (see Scheme 2). Those N,N-diisopropylamidinyl
pyrazoylimines 4aef were reacted with 3.0 equiv of N-phenyl-
maleimide 2 in sealed tube at 90 ꢀC for 24 h under the same re-
action condition. The corresponding pyrazolo[3,4-b]pyrrolo[3,4-d]
pyridines 9aef were also successfully obtained in 77e94% yields
(see Scheme 2 and the Entry 2e8 in Table 2). Furthermore, we
applied this reliable procedure to N,N-diisopropylamidinyl pyr-
azoylimine 5aee bearing various substituents including methyl, t-
butyl, p-MeePh, p-ClePh, and p-OMeePh groups at the C-3 po-
sition of pyrazolic ring. The Aza-DielseAlder reaction also
smoothly took place using compounds 5aee as the reactants to
give the corresponding pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine
products 10aee in 79e92% yields under the optimal condition (see
Entry 9e13 of Table 2). Based on the above substituent study, we
found that the electron donating methoxy group at the para-po-
sition of C3-phenyl of pyrazolic ring would activate the azadiene.
In general, most of substituents such as methyl, chloro, bromo, or
carboxylic groups on the meta- or para-position of N1 or C3-
phenyl of pyrazolic ring did not show significant effects. All of
pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines 9aef and 10aee were fully
identified by conventional spectroscopic methods to confirm their
structures. In comparison with the published data from Fraga
et al., the yield of compound 10a has been remarkably promoted
from 25%5 to 82% under our conditions (see Scheme 2 and the
Entry 9 in Table 2).
To evaluate the reactivity of N-substituted maleimide de-
rivatives as the dienophile and establish a reproducible procedure,
N,N-diisopropylamidinyl pyrazoylimine 1c was selected as the
model diene to react with 3.0 equiv of maleimide 6, N-methyl-
maleimide 7, or N-(n-propyl)maleimide 8 in acetic acid solution at
w90 ꢀC for 24 h. When maleimide 6 or N-methylmaleimide 7 were
H
O
X
N
X
O
N
N
N
Z
N
N
+
N
N
N Z
AcOH, 90 oC, sealed-tube
O
Y
Y
O
1c, 4a-f, 5a-e
2. Z = Ph,
6. Z = H,
3, 9a-f, 10a-e. Z = Ph,
11. Z = H,
X = H, m-Me, m-Cl, p-Me,
12. Z = Me,
7. Z = Me,
8. Z = n-Pr
p-Cl, p-Br, p-COOH
13. Z = n-Pr
Y = Me, t-Bu, p-MePh,
p-OMePh, p-ClPh
Scheme 2. Synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines from N,N-diisopropylamidinyl pyrazoylimines with maleimides via Aza-DielseAlder reaction.
Table 2
The result of pyrazoylimines (1c, 4aef, and 5aee) with maleimide (2 and 6e8) via Aza-DielseAlder reaction in the sealed tube
Entry
Pyrazoylimines 1aef
Maleimide 2 and 6e8
Pyrazolo[3,4-b]pyrrolo-[3,4-d]pyridines 3
S.M.
X
Y
Maleimide
Z
Products
Yields (%)
1
2
3
4
5
6
7
8
1c
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
1c
1c
1c
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
t-Bu
p-MePh
p-ClPh
p-OMePh
Ph
2
2
2
2
2
2
2
2
2
2
2
2
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
3
9a
9b
9c
9d
9e
91
82
88
77
94
77
85
82
81
79
86
92
19
52
76
m-Me
m-Cl
p-Me
p-Cl
p-Br
p-COOH
H
H
H
H
H
9f
10a
10b
10c
10d
10e
11
9
10
11
12
13
14
15
H
H
H
Ph
Ph
Me
n-Pr
12
13

7442
L.-Y. Wang et al. / Tetrahedron 70 (2014) 7439e7444
used as the dienophile substrates, the corresponding pyrazolo[3,4-
b]pyrrolo[3,4-d]pyridine products 11 and 12 were obtained in 19%
and 52% low yields, respectively (see Scheme 2 and the Entry 12
and 13 in Table 2). Large amount of starting materials 7 and 8 were
recovered. While we tried to prolong the reaction time to 120 h, the
yields were not improved. When N-(n-propyl)maleimide 8 was
used as the dienophile substrate, the optimized method gave the
corresponding pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine products 13
in 76% yield. Following the above experimental results, maleimide 6
and N-methylmaleimide 7 were considered as the less reactive
dienophiles than N-(n-propyl)maleimide 8 due to they favored the
C(Oꢁ)]NþeC]O configuration more than N-(n-propyl)maleimide
8.14 In comparison with N-phenylmaleimide 2, we found that N-
phenylmaleimide 2 is the best the dienophile to give the good
isolated yields for new improved Aza-DielseAlder reaction
according to the resonance distortions did not smoothly take place
to give the expected fused pyrimidine product.
4.2. Standard procedure for synthesis of pyrazolo[3,4-b]pyr-
rolo[3,4-d]pyridines (3, 9aef, 10aee, and 11e13)5
The reliable procedure involved the treatment of pyr-
azoylimines (1c, 4aef, and 5aee, 1.0 equiv), maleimide (2 and 6e8,
3.0 equiv), in AcOH solution (10 mL) at w90 ꢀC within 24 h. When
the reaction was completed, the reaction mixture was added to
water (10 mL) for precipitation. The precipitation was filtered,
washed with cold water (5 mLꢂ2), and rinsed with EtOH to give the
corresponding pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines (3, 9aef,
10aee, and 11e13) in 19e94% yields.
4.3. 1,3,7-Triphenylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-
6,8(3H,7H)-dione (3)
Orange solid; mp 150e151 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.47e7.49 (m, 4H, ArH), 7.50e7.51 (m, 5H, ArH), 7.57e7.58 (m, 2H,
ArH), 7.88e7.89 (m, 2H, ArH), 8.27e8.29 (m, 2H, ArH), 9.23 (s, 1H);
13C NMR (CDCl3, 125 MHz)
Recently, Insuasty et al.15 reported the catalyst-free and one-
pot Aza-DielseAlder reaction for the synthesis of pyrazolo[3,4-b]
pyrrolo[3,4-d]pyridine derivatives using 5-aminopyrazoles, DMF-
DMA (or TMOF), and N-arylmaleimides in xylene solution. In our
investigation, we focused on evaluating the torsion conformations
of N,N-disubstituted amidinyl pyrazoylimines 1bef12 with N-
phenylmaleimide for the improvement of Aza-DielseAlder re-
action. Consequently, we searched the optimum conditions in-
cluding the conventional heating condition,4 microwave-assisted
synthesis,5,6 and sealed-tube technique. The use of the ‘sealed-
tube’ technique allowed us to obtain the suitable quantitative
yields. On the other hands, this efficient method can be applied to
1,3-disubstituted pyrazoylimines 4aef and 5aee to give the cor-
responding pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines 9aef and
10aee in good yields.
d
109.07, 110.00, 120.94, 120.48 (2ꢂCH),
126.81 (2ꢂCH), 127.49 (2ꢂCH), 128.04, 128.52, 129.25 (2ꢂCH),
129.27, 129.56 (2ꢂCH), 129.91, 131.19, 131.62, 134.54, 138.49, 144.07,
146.38, 153.96, 164.88, 166.48; IR (diffuse reflectance) 1714e1614
(br, C]O), 1371 (m), 1286 (m), 1222 (m) mꢁ1; MS (ESI) m/z: 416
(Mþ, 100), 371 (19), 268 (5), 242 (2), 77 (12); HRMS (ESI) calcd for
C26H16N4O2: 416.1273; found: 416.1279.
4.4. 3-(3-Methylphenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9a)
Yellow solid; mp 223e224 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 2.49
(s, 3H, CH3), 7.39e7.47 (m, 4H, ArH), 7.48e7.51 (m, 6H, ArH),
7.87e7.89 (m, 2H, ArH), 8.04e8.07 (m, 2H, ArH), 9.21 (s, 1H); 13C
NMR (CDCl3, 125 MHz)
d 21.59, 108.95, 119.75, 120.84, 123.16,
126.80, 128.02 (2ꢂCH), 128.38 (2ꢂCH), 128.50, 129.05, 129.24,
129.53 (2ꢂCH), 129.90 (2ꢂCH), 131.16, 131.63, 134.48, 138.31,
139.39, 144.04, 146.24, 153.91, 164.90, 166.51; IR (diffuse re-
flectance) 2922 (m), 2360 (m), 1728e1633 (br, C]O), 1375 (m),
1242 (m) cmꢁ1; MS (ESI) m/z: 430 (Mþ, 9), 396 (5), 302 (100), 219
(9), 203 (37), 193 (77), 178 (16), 164 (50), 155 (10), 121 (15); HRMS
(ESI) calcd for C27H19N4O2: 431.1503; found: 431.1498.
3. Conclusions
We have successfully developed an improved Aza-DielseAlder
reaction for the synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines
by modulating N,N-disubstituted amidinyl moiety to control the
suitable torsion conformation of pyrazoylimines as azadiene re-
actants. Based on the results from control experiment, we found
N,N-diisopropylamidinyl pyrazoylimines is the best azadiene sub-
strates and N-phenylmaleimide was the better dienophile. On the
other hand, the sealed tube technique can also promote this Aza-
DielseAlder cycloaddition reaction.
4.5. 3-(3-Chlorophenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9b)
Yellow solid; mp 101e102 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.36e7.41 (m, 4H, ArH), 7.47e7.51 (m, 6H, ArH), 7.87e7.87 (m, 2H,
ArH), 8.31e8.33 (m, 1H, ArH), 8.43 (s, 1H, ArH), 9.23 (s, 1H); 13C
NMR (CDCl3, 125 MHz) 109.39, 119.86, 121.18, 122.01, 126.76
(2ꢂCH), 127.22, 128.06 (2ꢂCH), 128.54, 129.24 (2ꢂCH), 129.73
(2ꢂCH), 129.88, 130.22, 131.11, 131.30, 134.59, 135.00, 139.54, 144.19,
146.77, 154.00, 164.67, 166.27; IR (diffuse reflectance) 1768e1620
(br, C]O), 1494 (m), 1384 (m), 1238 (m) cmꢁ1; MS (ESI) m/z: 452
(35), 450 (Mþ, 100), 405 (16), 382 (19), 380 (54), 337 (37), 269 (18),
268 (11), 77 (18), 58 (61); HRMS calcd for C26H15ClN4O2: 450.0884;
found: 450.0891.
4. Experimental section
4.1. General procedure
d
All chemicals were reagent grade and used as purchased. All
reactions were carried out under nitrogen atmosphere and mon-
itored by TLC analysis. Commercially available reagents were used
without further purification unless otherwise noted. 1H NMR were
recorded at 200, 400, or 500 MHz, and 13C NMR recorded at 50,
100, or 125 MHz, respectively, in CDCl3, CH3OD, and DMSO-d6 as
solvent. The standard abbreviations s, d, t, q, and m refer to singlet,
doublet, triplet, quartet, and multiplet, respectively. Coupling
constant (J), whenever discernible, have been reported in Hertz.
Infrared spectra (IR) were recorded as neat solutions or solids; and
mass spectra were recorded using electron impact or electrospray
ionization techniques. The wavenumbers reported are referenced
to the polystyrene 1601 cmꢁ1 absorption. Flash column chroma-
tography purification of compounds was carried out by gradient
elution using hexanes in ethyl acetate (EA) unless otherwise
stated.
4.6. 3-(4-Methylphenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9c)
Brown solid; mp 129e130 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 2.44
(s, 3H, CH3), 7.36e7.41 (m, 5H, ArH), 7.47e7.92 (m, 5H, ArH), 7.88 (d,
2H, J¼8.50 Hz, ArH), 8.11 (d, 2H, J¼8.50 Hz, ArH), 9.19 (s, 1H); 13C
NMR (CDCl3,125 MHz)
d
21.11,108.79,120.75,122.45 (2ꢂCH),126.76
(2ꢂCH), 127.98, 128.44 (2ꢂCH), 128.54, 129.20, 129.45 (2ꢂCH),
129.78 (2ꢂCH), 129.87, 131.18, 131.65, 134.44, 135.97, 137.50, 143.95,
146.06, 153.79, 164.88, 166.48; IR (diffuse reflectance) 1724e1624

L.-Y. Wang et al. / Tetrahedron 70 (2014) 7439e7444
7443
(br, C]O), 1516 (m), 1373 (m), 1261 (m) cmꢁ1; MS (ESI) m/z: 430
NMR (CDCl3, 125 MHz)
d
29.27 (3ꢂCH), 34.94, 108.43, 119.85, 122.10
(Mþ,100), 385 (13), 309 (3), 282 (6), 220 (3), 215 (4),128 (7), 77 (16);
HRMS calcd for C27H18N4O2: 430.1430; found: 430.1429.
(2ꢂCH), 126.78, 126.87 (3ꢂCH), 128.48, 129.09 (2ꢂCH), 129.23,
131.27, 133.78, 138.66, 143.50, 154.31, 154.94, 165.98, 166.30; IR
(diffuse reflectance) 2353 (m), 2320 (m), 1730e1633 (br, C]O),
1506 (m), 1454 (m), 1394 (m) cmꢁ1; MS (ESI) m/z: 396 (Mþ, 6), 381
(13), 266 (70), 264 (53), 144 (66), 119 (100), 77 (44), 57 (13); HRMS
(ESI) calcd for C24H21N4O2: 397.1659; found: 397.1653.
4.7. 3-(4-Chlorophenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9d)
Orange solid; mp 205e206 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.39e7.40 (m, 3H, ArH), 7.47e7.54 (m, 7H, ArH), 7.86e7.87 (m, 2H,
4.12. 1-(4-Methylphenyl)-3,7-diphenyl-pyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (10c)
ArH), 8.32 (d, 2H, J¼8.50 Hz, ArH), 9.21 (s, 1H); 13C NMR (CDCl3,
125 MHz)
d
109.24, 121.07, 123.21 (2ꢂCH), 126.76, 128.06 (2ꢂCH),
Yellow solid; mp 105e106 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 2.42
128.55, 129.25, 129.34 (2ꢂCH), 129.69, 129.86, 131.10 (3ꢂCH),
131.37, 132.85 (2ꢂCH), 134.60, 137.08, 144.12, 146.61, 153.86, 164.72,
166.32; IR (diffuse reflectance) 2378 (m), 1716e1624 (br, C]O),
1541 (m), 1489 (m), 1373 (m) cmꢁ1; MS (ESI) m/z: 452 (36), 450
(Mþ, 100), 405 (15), 370 (6), 225 (4), 152 (5), 77 (27); HRMS (ESI)
calcd for C26H16ClN4O2: 451.0956; found: 451.0949.
(s, 3H, CH3), 7.31 (d, 2H, J¼8.00 Hz, ArH), 7.39e7.42 (m, 4H, ArH),
7.47e7.50 (m, 2H, ArH), 7.56e7.59 (m, 2H, ArH), 7.78 (d, 2H,
J¼8.00 Hz, ArH), 8.27e8.28 (m, 2H, ArH), 9.21 (s, 1H); 13C NMR
(CDCl3, 125 MHz)
d
21.50, 109.11, 120.80, 122.44 (2ꢂCH), 126.83
(2ꢂCH), 127.41, 128.50 (2ꢂCHþCH), 128.77, 129.25 (2ꢂCHþ2ꢂCH),
129.76 (2ꢂCH),131.18,134.54,138.49,139.56,143.99,146.44,153.94,
164.92, 166.51; IR (diffuse reflectance) 1714e1633 (br, C]O), 1539
(m), 1465 (m), 1373 (m) cmꢁ1; MS (ESI) m/z: 430 (Mþ, 100), 385
(13), 281 (5), 207 (7), 141 (8), 129 (6), 91 (11), 77 (12); HRMS calcd
for C27H18N4O2: 430.1430; found: 430.1425.
4.8. 3-(4-Bromophenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9e)
Orange solid; mp 245e246 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.39e7.42 (m, 3H, ArH), 7.47e7.50 (m, 5H, ArH), 7.69 (d, 2H,
J¼8.50 Hz, ArH), 7.86e7.87 (m, 2H, ArH), 8.23 (d, 2H, J¼8.50 Hz,
ArH), 9.22 (s, 1H); 13C NMR (CDCl3, 125 MHz)
109.36, 119.82,
4.13. 1-(4-Chlorolphenyl)-3,7-diphenyl-pyrazolo[3,4-b]pyr-
rolo[3,4-d]pyridine-6,8(3H,7H)-dione (10d)
d
121.15,121.95,126.74 (2ꢂCH),127.19, 128.05, 128.54 (2ꢂCH), 129.24,
129.73 (2ꢂCH), 129.86, 130.22 (2ꢂCH), 131.07, 131.27, 134.56, 137.97,
139.51,144.17,146.73,153.96,164.66,166.26; IR (diffuse reflectance)
2351 (m), 2318 (m), 1728e1622 (br, C]O), 1490 (m), 1373 (m)
cmꢁ1; MS (ESI) m/z: 496 (100), 494 (Mþ, 96), 451 (12), 294 (6), 128
(5), 77 (23); HRMS (ESI) calcd for C26H16BrN4O2: 495.0451; found:
495.0453.
Yellow solid; mp 228e229 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.39e7.44 (m, 4H, ArH), 7.47e7.52 (m, 4H, ArH), 7.57e7.60 (m, 2H,
ArH), 7.84 (d, 2H, J¼8.00 Hz, ArH), 8.26 (d, 2H, J¼8.00 Hz, ArH), 9.23
(s, 1H); 13C NMR (CDCl3, 125 MHz)
108.81, 121.00, 122.49, 126.07
d
(2ꢂCH), 127.65 (2ꢂCH), 128.63 (2ꢂCH), 129.15 (2ꢂCHþCH), 129.32,
130.06, 131.05 (2ꢂCH), 131.18, 134.21, 134.46, 135.78, 138.33, 144.21,
145.19, 153.93, 165.04, 166.37; IR (diffuse reflectance) 1722e1624
(br, C]O), 1504 (m), 1489 (m), 1386 (m) cmꢁ1; MS (ESI) m/z: 452
(37), 450 (Mþ,100), 405 (14), 77 (13); HRMS calcd for C26H15ClN4O2:
450.0884; found: 450.0893.
4.9. 3-(4-Carboxyphenyl)-1,7-diphenylpyrazolo[3,4-b]pyrrolo
[3,4-d]pyridine-6,8(3H,7H)-dione (9f)
Yellow solid; mp 178e179 ꢀC; 1H NMR (DMSO-d6, 500 MHz)
d
5.73 (s, 1H), 7.45e7.48 (m, 3H, ArH), 7.52e7.56 (m, 5H, ArH),
4.14. 1-(4-Methoxylphenyl)-3,7-diphenyl-pyrazolo[3,4-b]pyr-
rolo[3,4-d]pyridine-6,8(3H,7H)-dione (10e)
7.94e7.96 (m, 2H, ArH), 8.17 (d, 2H, J¼8.00 Hz, ArH), 8.40 (d, 2H,
J¼8.00 Hz, ArH), 9.32 (s, 1H); 13C NMR (DMSO-d6, 125 MHz)
d
108.83, 121.16 (2ꢂCH), 121.85, 127.56 (2ꢂCH), 127.91 (3ꢂCH),
Yellow solid; mp 151e152 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.85
128.46, 129.05, 129.49 (2ꢂCH), 129.94 (2ꢂCHþCH), 130.50, 131.52,
131.64 (2ꢂCH), 135.74, 144.34, 146.19, 153.62, 164.75, 166.46
(2ꢂCH); IR (diffuse reflectance) 1714e1633 (br, C]O), 1530 (m),
1465 (m), 1373 (m) cmꢁ1; MS (ESI) m/z: 460 (Mþ, 100), 415 (18), 371
(6), 77 (12); HRMS calcd for C27H16N4O4: 460.1172; found: 460.1175.
(s, 3H, OCH3), 7.02 (d, 2H, J¼8.50 Hz, ArH), 7.40e7.41 (m, 4H, ArH),
7.47e7.50 (m, 2H, ArH), 7.54e7.57 (m, 2H, ArH), 7.83 (d, 2H,
J¼8.50 Hz, ArH), 8.26e8.28 (m, 2H, ArH), 9.18 (s, 1H); 13C NMR
(CDCl3, 125 MHz)
d
55.27, 109.02, 113.51 (2ꢂCH), 120.68, 122.30,
123.99 (2ꢂCH), 126.77, 127.30, 128.47 (2ꢂCH), 129.20
(2ꢂCHþ2ꢂCH), 131.20 (2ꢂCHþCH), 134.48, 138.48, 143.92, 146.11,
153.87, 160.75, 164.95, 166.44; IR (diffuse reflectance) 1720e1616
(br, C]O), 1502 (m), 1458 (m), 1377 (m) cmꢁ1; MS (ESI) m/z: 446
(Mþ, 100), 403 (4), 223 (4); HRMS calcd for C27H18N4O3: 446.1379;
found: 446.1376.
4.10. 1-Methyl-3,7-diphenylpyrazolo[3,4-b]pyrrolo[3,4-d]pyri-
dine-6,8(3H,7H)-dione (10a)5
Yellow solid; mp 210e211 ꢀC (lit. mp 228e230 ꢀC); 1H NMR
(CDCl3, 500 MHz)
d 2.96 (s, 3H, CH3), 7.24e7.36 (m, 1H, ArH),
7.44e7.47 (m, 3H, ArH), 7.52e7.56 (m, 4H, ArH), 8.19 (d,1H, J¼1.00 Hz,
ArH), 8.21 (d, 1H, J¼1.00 Hz, ArH), 9.13 (s, 1H); 13C NMR (CDCl3,
4.15. 1,3-Diphenyl-pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-
6,8(3H,7H)-dione (11)
125 MHz)
d
15.04, 110.75, 119.54, 121.86 (2ꢂCH), 126.61, 127.03
(2ꢂCH),128.50,129.25 (2ꢂCH),129.27 (2ꢂCH),131.25,134.73,138.54,
143.86, 143.92, 153.70, 165.62, 166.64; IR (diffuse reflectance)
1728e1633(br, C]O),1504(m),1489(m),1375(m)cmꢁ1;MS(ESI)m/
z: 354 (Mþ, 48), 266 (100),146 (11),119 (86),118 (43), 91 (11), 77 (16).
Red solid; mp 232e233 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.40e7.42 (m, 1H, ArH), 7.52e7.54 (m, 3H, ArH), 7.56e7.59 (m, 1H,
ArH), 7.86e7.88 (m, 2H, ArH), 8.25 (d, 2H, J¼7.50 Hz, ArH), 9.14 (s,
1H); 13C NMR (CDCl3, 125 MHz)
d
109.03, 121.86 (2ꢂCH), 122.49,
4.11. 1-tert-Butyl-3,7-diphenyl-pyrazolo[3,4-b]pyrrolo[3,4-d]
pyridine-6,8(3H,7H)-dione (10b)
127.51, 128.01 (2ꢂCH), 129.27 (2ꢂCH), 129.61, 129.84 (2ꢂCH),
131.56, 135.18, 138.43, 143.94, 146.22, 153.83, 165.07, 166.64; IR
(diffuse reflectance) 2920 (m), 1782e1735 (br, C]O), 1593 (m),
1496 (m), 1377 (m), 1303 cmꢁ1; MS (ESI) m/z: 340 (Mþ, 100), 315
(17), 263 (9), 242 (33), 228 (23), 207 (59), 200 (18), 165 (28), 111
(12); HRMS calcd for C20H12N4O2: 340.0960; found: 340.0956.
Yellow solid; mp 209e210 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 1.66
(s, 9H, 3ꢂCH3), 7.35e7.38 (m, 1H, ArH), 7.44e7.49 (m, 3H, ArH),
7.52e7.56 (m, 4H, ArH), 8.34e8.25 (m, 2H, ArH), 9.15 (s, 1H); 13C

7444
L.-Y. Wang et al. / Tetrahedron 70 (2014) 7439e7444
4.16. 1,3-Diphenyl-7-methyl-pyrazolo[3,4-b]pyrrolo[3,4-d]
pyridine-6,8(3H,7H)-dione (12)
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.08.013.
Yellow solid; mp 124e125 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.17
(s, 3H), 7.38e7.40 (m, 1H, ArH), 7.53e7.56 (m, 5H, ArH), 7.86e7.88
(m, 2H, ArH), 8.24e8.26 (m, 2H, ArH), 9.09 (s, 1H); 13C NMR (CDCl3,
References and notes
125 MHz)
d
24.23, 109.02, 121.40, 122.23 (2ꢂCH), 127.29 (2ꢂCH),
127.92, 129.18 (2ꢂCH), 129.54, 129.84 (2ꢂCH), 131.58, 134.88,
138.45, 143.39, 146.08, 153.71, 165.88, 167.44; IR (diffuse re-
flectance) 2924 (m), 2358 (m),1714e1624 (br, C]O),1558 (m),1456
(m),1381 (m) cmꢁ1; MS (ESI) m/z: 354 (Mþ,100), 277 (9), 251 (6), 77
(13); HRMS calcd for C20H12N4O2: 354.1117; found: 354.1115.
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pyridine-6,8(3H,7H)-dione (13)
Yellow solid; mp 178e179 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 0.93 (t,
3H, J¼7.50 Hz, CH3), 1.69 (sex, 2H, J¼7.50 Hz, CH2), 3.65 (t, 2H,
J¼7.50 Hz, CH2), 7.40e7.53 (m, 1H, ArH), 7.53e7.58 (m, 5H, ArH),
7.88e7.90 (m, 2H, ArH), 8.25e8.27 (m, 2H, ArH), 9.11 (s,1H); 13C NMR
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316e320.
(CDCl3,125 MHz)
d
11.24, 21.82, 40.00,109.03,121.36,122.40 (2ꢂCH),
ꢀ
ꢀ
10. Draz-Ortiz, A.; Carrillo, J. R.; Cossío, F. P.; Gomez-Escalonilla, M. J.; de la Hoz, A.;
Moreno, A.; Prieto, P. Tetrahedron 2000, 55, 1569e1577.
127.36, 127.95 (2ꢂCH), 129.23 (2ꢂCH), 129.56 (2ꢂCH), 129.88,
131.69, 134.95, 138.49, 143.50, 146.15, 153.82, 165.90, 167.59; IR
(diffuse reflectance) 1714e1635 (br, C]O),1541 (m), 1456 (m), 1396
(m) cmꢁ1; MS (ESI) m/z: 382 (Mþ,100), 353 (29), 340 (23), 268 (9), 77
(34); HRMS (ESI) calcd for C23H19N4O2: 383.1503; found: 383.1499.
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Acknowledgements
We are grateful to the Tsuzuki Institute for Traditional Medicine
and the National Science Council of Republic of China for financial
support (NSC-102-2113-M-039-003).