Domino reaction of arylglyoxals with pyrazol-5-amines: Selective access to pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes, and pyrroles

Article abstract of DOI:10.1021/jo500823z

New multicomponent domino reactions of arylglyoxals with pyrazol-5-amines have been established, providing selective access to unprecedented pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes, and pyrroles (up to 52 examples). The unreported dipyrazolo-fused 1,7-naphthyridines were regioselectively synthesized through a special double [3 + 2 + 1] heteroannulation accompanied by direct C-C formation between two electrophilic sites of arylglyoxals. The unusual [3 + 3 + 1 + 1] cyclization resulted in 20 examples of novel dipyrazolo-fused 1,3-diazocanes, whereas pyrrolo[2,3-c] pyrazoles were obtained in good yields by varying arylglyoxals 1 and pyrazol-5-amines 2 in the ratio 1:2. Mechanisms of formation of these three new types of heterocycles are also proposed.

Full text of DOI:10.1021/jo500823z

Article
pubs.acs.org/joc
Domino Reaction of Arylglyoxals with Pyrazol-5-amines: Selective
Access to Pyrazolo-Fused 1,7-Naphthyridines, 1,3-Diazocanes, and
Pyrroles
Bo Jiang,*,† Wei Fan,† Mu-Yan Sun,† Qin Ye,† Shu-Liang Wang,† Shu-Jiang Tu,*,† and Guigen Li‡,§
†School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou 221116, People’s Republic of China
‡Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
§Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093, People’s Republic of China
S
* Supporting Information
ABSTRACT: New multicomponent domino reactions of arylglyoxals
with pyrazol-5-amines have been established, providing selective access
to unprecedented pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes,
and pyrroles (up to 52 examples). The unreported dipyrazolo-fused 1,7-
naphthyridines were regioselectively synthesized through a special
double [3 + 2 + 1] heteroannulation accompanied by direct C−C
formation between two electrophilic sites of arylglyoxals. The unusual [3
+ 3 + 1 + 1] cyclization resulted in 20 examples of novel dipyrazolo-
fused 1,3-diazocanes, whereas pyrrolo[2,3-c]pyrazoles were obtained in
good yields by varying arylglyoxals 1 and pyrazol-5-amines 2 in the ratio
1:2. Mechanisms of formation of these three new types of heterocycles
are also proposed.
encouraged us to develop new methodologies for their
syntheses.
INTRODUCTION
■
The structural range and biological importance of functional
1,7-naphthyridines have made them attractive targets of
research for many years.1 Their derivatives are found in various
natural alkaloids such as eburnamonine,2 anisopusine,3 and
tacamonine4 (Figure 1), which have appreciable chemical and
Multicomponent domino reactions (MDRs) are some of the
most effective methods to improve synthetic efficiency, which
can realize reaction cascades, generating natural products or
natural-like analogues.12,13 Recently, we established a new four-
component reaction of arylglyoxals14 and electron-rich pyrazol-
5-amines in n-butyric acid, providing highly substituted
dipyrazolo-fused 2,6-naphthyridine derivatives (Scheme 1).14a
In this reaction, when the Brønsted acid promoter was changed
from n-butyric acid to p-TsOH, dipyrazolo-fused 1,7-naphthyr-
idines were unexpectedly obtained through different [3 + 2 + 1]
bis-cyclizations, whereas dipyrazolo-fused 2,6-naphthyridines
were not observed (Scheme 1). It can be inferred that the
acidity of the Brønsted acid promoter may control the direction
of the reaction. Further investigations illustrated that the
variation of substituents at pyrazole N1 or C3 positions can
lead to different products (Scheme 1). Herein, we report this
interesting discovery.
Figure 1. Several representative natural products.
biological importance. In addition, a variety of synthetic 1,7-
naphthyridine derivatives have possessed widespread biological
activities, including hypotensive activity,5 neurokinin NK1-
receptor antagonists,6 antimalarial agents,7 selective Tpl2 kinase
inhibitors,8 anti-inflammatory activity,9 and antagonistic
agents.10 The synthesis of functional 1,7-naphthyridines and
their derivatives has played an important role in organic and
medical chemistry due to their therapeutic and pharmacological
properties. However, only a few references exist concerning 1,7-
naphthyridine syntheses,11 and these synthetic procedures still
have several limitations involving poor yields, multiple steps,
and even metal catalysts. These alarming situations have
RESULTS AND DISCUSSION
■
To develop metal-free conditions for selective [3 + 2 + 1] bis-
cyclizations, we began our study with the reaction of 2,2-
dihydroxy-1-phenylethanone (1a) with 1,3-dimethyl pyrazol-5-
Received: April 12, 2014
© XXXX American Chemical Society
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Scheme 1. Synthesis of Pyrazolo-Fused 1,7-Naphthyridines, 1,3-Diazocanes, and Pyrroles
amines 2 in DMF solvent. In our previous report, this reaction
promoted by n-butyric acid gave tetracyclic dipyrazolo-fused
2,6-naphthyridines. To continue our efforts in this project, p-
toluenesulfonic acid (p-TsOH) was chosen as a Brønsted acid
promoter in this reaction system, due to its strong acidity, easy
availability, and wide utilization in heterocyclic synthesis.15
Delightedly, this bis-cyclization reaction proceeded smoothly to
generate unprecedented tetracyclic dipyrazolo-fused 1,7-naph-
thyridines in 63% yield. The relative structure of compound 3c
was determined by spectroscopic analysis and X-ray crystallo-
graphic study (see the Supporting Information).
Encouraged by the interesting results reported above, we
next optimized the reaction conditions for this protocol. We
screened different Brønsted acid and Lewis acid promoters for
the domino reaction using DMF as a solvent. As shown in
Table 1, the reaction did not proceed in the presence of
effective in pushing this reaction forward, resulting in product
3a in 70% yield (entry 9).
Various structurally diverse arylglyoxals 1 and 1-methyl
pyrazol-5-amines 2 were explored to establish the applicability
of this protocol. The results are summarized in Table 2. A
variety of functional groups in substituted arylglyoxal
monohydrates were well tolerated to give moderate to good
yields of dipyrazolo-fused 1,7-naphthyridines (3a−l). When the
substituents on arylglyoxal monohydrates 1 were electron-
withdrawing groups such as F, Cl, and Br, they showed weaker
reactivity in comparison to those containing electron-neutral or
electron-donating groups. Moreover, a cyclopropyl group at the
3-position of pyrazol-5-amines 2b participated successfully in
this reaction. Surprisingly, when an aryl group was placed at C3
of pyrazol-5-amines 2c, the reaction did not provide the
expected 1,7-naphthyridine but went in another direction to
form the multifunctionalized 1,3-diazocane derivatives 4 (Table
3). These experimental facts indicated that the steric hindrance
of substituents on the pyrazole ring may control the reaction
pathway.
Functional 1,3-diazocanes belong to another family of species
with an important framework, which have a nonplanar eight-
membered ring with two nitrogen atoms. These diazocine units
are expected to exhibit a boat (neutral state) to planar
(dianion) conformational change via a two-electron-transfer
process.16 Therefore, the derivatives of diazocines are a
significant class of synthons for biomimetic molecular
recognition and supramolecular compunds.17 Furthermore,
1,3-diazocane units commonly exist in natural products,
represented by N3,5′-cycloxanthosine18 and cottoquinazolines
A and D.19 In view of their importance, we then explored the
feasibility of this p-TsOH-promoted reaction for the formation
of fused 1,3-diazocanes. Various functional groups in
arylglyoxals 1 did not hamper the reaction process. Reactions
of Me-, MeO-, Cl-, F-, and Br-substituted arylglyoxals 1 with 2
all proceeded efficiently to give fused tricyclic 1,3-diazocanes in
65−79% yields. This reaction also tolerated the 4-nitro-
phenylglyoxal 1f, which was smoothly transformed into the
targeted 1,3-diazocane 4f in 74% yield. Moreover, 3-phenyl-, 3-
(4-chlorophenyl)-, and 3-(2-thienyl)-substituted pyrazol-5-
amines 2c−e all successfully participated in this reaction as
well, leading to the corresponding pyrazolo[3,4-b]pyridines 5
with good results (Table 4). It is noteworthy that the protocols
provide unusual pathways for the formation of unreported
dipyrazolo-fused 1,7-naphthyridine and 1,3-diazocane deriva-
tives, which are normally difficult to synthesize by other
methods.
Table 1. Optimization of Reaction Conditions
entry
promoter (amt (equiv))
solvent
temp (°C)
yield (%)
1
CF3SO3H (1.0)
CF3COOH (1.0)
ZnCl2 (1.0)
DMF
DMF
DMF
DMF
DMF
toluene
CH3CN
EtOH
DMF
DMF
DMF
DMF
100
100
100
100
100
100
100
100
120
130
120
120
trace
trace
trace
trace
63
2
3
4
InCl3 (1.0)
5
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (0.2)
p-TsOH (1.5)
6
12
7
29
8
45
9
70
10
11
12
62
39
41
CF3SO3H or CF3COOH or with Lewis acids such as InCl3 and
ZnCl2. Subsequently, different solvents were optimized. The
desired product 3a was isolated in low yield (12%) in toluene
solvent. Other polar solvents such as acetonitrile and EtOH
were inferior to DMF in terms of yield. Taking DMF as the
optimized solvent, we varied other parameters. To verify
whether the role of p-TsOH was catalytic or stoichiometric, we
carried out two reactions, where p-TsOH was used in amounts
of 1.5 equiv (entry 10; see the Supporting Information) and 20
mol % (entry 11; see the Supporting Information). The use of a
catalytic amount of p-TsOH decreased the yield of the product
3a, whereas a higher loading of p-TsOH also failed to improve
the yield of 3a. When the reaction temperature was elevated to
120 °C, the use of 1.0 equiv of p-TsOH in DMF was more
B
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Table 2. Domino Synthesis of 1,7-Naphthyridines 3
Furthermore, we were eager to see the outcome of the
reaction when pyrazol-5-amines 2 with an aryl group residing at
the N1 position were employed as a multicomponent partners
with arylglyoxals. Hence, we reacted 2,2-dihydroxy-1-phenyl-
ethanone (1a) with 1-phenyl-3-methylpyrazol-5-amine (2f) in
DMF using p-TsOH as a promoter; after 20 min the
unexpected pyrrolo[2,3-c]pyrazole 5a was formed in 34%
yield. In this reaction, 1a and 1-phenyl-3-methylpyrazol-5-
amine (2f) in a molar ratio of 1:2 were introduced to give the
pyrrolo[2,3-c]pyrazole 5a. Subsequently, the ratio of 1a and 2f
was changed to 1:2, and the corresponding product 5a was
generated in a chemical yield of 78% under the same microwave
irradiation conditions. The variation of substituents at pyrazole
N1 and C3 positions, including phenyl, methyl, and cyclo-
propyl groups, afforded good yields of pyrazolo[3,4-b]pyridines
5 within short times. It should be noted that arylglyoxals 1 and
the 3-(2-thienyl)-substituted pyrazol-5-amine 2e in the ratio 1:2
also resulted in pyrrolo[2,3-c]pyrazole products 5q−t in 70−
74% yields. However, in the present system, the domino
reaction between 1 and 2c,d in a 1:2 ratio still gave dipyrazolo-
fused 1,3-diazocanes predominantly, and pyrrolo[2,3-c]-
pyrazoles were not observed, owing to their stronger steric
hindrance. In general, these MDRs give new examples for
synthesizing three types of heterocycles in an efficient and
atom-economical strategy to discover new bioactive com-
pounds.
Information). The regioselective formation of new dipyrazolo-
fused 1,7-naphthyridines was easily achieved through a special
[3 + 2 + 1] bis-cyclization with concomitant formation of five
new σ bonds and direct C−C coupling between two
electrophilic sites of arylglyoxals under metal-free or carbine-
free conditions. The last two reactions readily resulted in an
eight-membered macrocyclic motif and a five-membered ring,
respectively, through a change of substituents on the pyrazole
ring in a one-pot operation. This observation illustrates the high
efficiency of bond formation, excellent selectivity, and
remarkable increase in complexity starting from simple
substrates.
We believe that this [3 + 2 + 1] bis-cyclization process is
unique and different from that in our previous report.14a
Electron-rich pyrazol-5-amines possessing strong 1,3-bis-
nucleophilic centers showed high reactivity in heterocyclic
synthesis, and both nucleophilic sites easily take part
simultaneously in the cyclization. Thus, it is difficult to capture
its uncyclized intermediate. We reasoned that a similar
uncyclized intermediate may be captured when the nucleophil-
icity of the 1,3-bis-nucleophile is softer. To understand this
domino process, we attempted to treat p-toluidine with soft
nucleophilicity to replace one molecule of pyrazol-5-amines.
Then, the four-component reaction of 1e with 2a and p-
toluidine 6 was performed in the presence of 1.0 equiv of p-
TsOH in DMF solvent at 120 °C under microwave irradiation
conditions. Fortunately, the pyrazolo[3,4-b]pyridine 7 was
generated in 62% yield (Scheme 2). It is indicated that the
mechanism for the synthesis of pyrazolo-fused 1,7-naphthyr-
idines 3 may undergo this similar process of formation of a
pyrazolo[3,4-b]pyridine intermediate.
The structural elucidation and attribution of regioselectivity
of three types of heterocycles were unambiguously determined
by their NMR spectroscopic analysis. The structures of 1,7-
naphthyridines 3c and 1,3-diazocanes 4a and 5b were further
confirmed by X-ray diffraction analysis (see the Supporting
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Table 3. Domino Synthesis of 1,3-Diazocanes 4
On the basis of experimental results, reasonable mechanisms
for three different domino reactions are postulated in Schemes
3 and 4. In the former, arylglyoxals 1 protonated by p-TsOH
underwent dehydration and subsequent addition with pyrazol-
5-amines 2 to intermediate A, followed by intermolecular C
O addition of intermediate B and dehydration to yield active
allenes E. Next, intramolecular 6π electrocyclization of allenes
E occurred, providing pyrazolo[3,4-b]pyridines G, similar to
product 7 above. The pyrazolo[3,4-b]pyridine intermediate G
was transformed into the final dipyrazolo-fused 1,7-naphthyr-
idines 3 through intramolecular second CO addition and
third dehydration. Similar to the former reaction, the second
reaction initially gave the imines B, which were involved in the
CN addition with intermediate C to generate adducts I. The
1,3-diazocanes were obtained through intramolecular Michael
addition and tautomerization. In both reactions, the key steps
of MDRs involve tandem formation of two different
condensation intermediates B and C that are trapped by two
different CO and CN additions, although the reason for
these selective additions is not clear to us. The third reaction
involved initial condensation, intermolecular Michael addition,
and cyclization.
In conclusion, we have discovered novel multicomponent
domino reactions (arylglyoxals and pyrazol-5-amines) for the
selective synthesis of fused 1,7-naphthyridines, 1,3-diazocanes,
and pyrazoles by varying the substituents on the pyrazol-5-
amine ring. The [3 + 2 + 1] bis-cyclization reaction
simultaneously installs two C−N and three C−C bonds
through a key 6π electrocyclization process, showing that the
procedure allows the efficient synthesis of diverse 1,7-
naphthyridine derivatives selectively. The latter [3 + 3 + 1 +
1] heteroannulation represents the first example for the
formation of this special fused 1,3-diazocane skeleton, which
provides a new insight into multicomponent reactions. The last
[3 + 2] heterocyclization reaction worked well with a broad
range of highly compatible substrates to afford pyrrolo[2,3-
c]pyrazoles with biological relevance in good yields. Further
investigations are in progress to probe the mechanism of these
transformations and to synthesize more complex products and
evaluate their biological activity.
EXPERIMENTAL SECTION
■
General Methods. Microwave irradiation was carried out with
Initiator 2.5 Microwave Synthesizers from Biotage, Uppsala, Sweden.
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Table 4. Domino Synthesis of 1,3-Diazocanes 5
ν, cm−1) 3046, 1586, 1544, 1501, 1483, 1446, 1406, 1384, 1344;
HRMS (ESI-TOF) m/z calcd for C26H23N6 419.1984 [M + H]+,
found 419.1963.
Scheme 2. Control Experiment
5, 10-Bis(4-fluorophenyl)-1, 3, 7, 9-tetramethyl-3, 7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3b). Yellow
solid: 0.322 g, yield 71%; mp >300 °C; 1H NMR (400 MHz,
CDCl3; δ, ppm) 8.29−8.26 (m, 2H), 7.53−7.49 (m, 2H), 7.32−7.27
(m, 4H), 4.20 (s, 3H), 4.12 (s, 3H), 1.98 (s, 3H), 1.56 (s, 3H); 13C
NMR (100 MHz, CDCl3; δ, ppm) 163.5 (1JCF = 247.6 Hz), 163.4
(1′JCF = 248.3 Hz), 159.1, 148.2, 146.7, 141.4, 140.9, 140.1, 139.9,
135.2 (4JCF = 3.5 Hz), 134.0 (4′JCF = 3.7 Hz), 133.5 (3JCF = 8.2 Hz),
The reaction temperatures were measured by infrared detector during
microwave heating.
Representative Synthesis of 3: 1,3,7,9-Tetramethyl-5,10-
diphenyl-3,7-dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]-
naphthyridine (3a). Typically, 2,2-dihydroxy-1-phenylethanone (1a;
2.2 mmol, 0.334 g, 1.1 equiv) and 1,3-dimethyl-1H-pyrazol-5-amine
(2a; 2.0 mmol, 0.222 g, 1.0 equiv) were introduced into a 10 mL
Initiator reaction vial, and p-TsOH (1.0 equiv), and DMF (1.5 mL)
were then added successively. Subsequently, the reaction vial was
closed and then prestirred for 10 s. The mixture was irradiated (time,
20 min; temperature, 120 °C; absorption level, high; fixed hold time)
until TLC (petroleum ether/acetone 3/1) revealed that conversion of
the starting material 2a was complete. After it was cooled to room
temperature, the reaction mixture was diluted with cold water (20 mL)
and neutralized with 10% NaOH solution. The solid product was
132.8 (3′JCF = 8.1 Hz), 122.1, 115.6 (2JCF = 21.3 Hz), 114.6 (2′JCF
=
21.3 Hz), 105.8, 100.0, 34.0, 33.6, 15.8, 15.0; IR (KBr, ν, cm−1) 2936,
1598, 1548, 1450, 1407, 1346; HRMS (ESI-TOF) m/z calcd for
C26H21F2N6 455.1796 [M + H]+, found 455.1783.
5,10-Bis(4-chlorophenyl)-1,3,7, 9-tetramethyl-3, 7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3c). Yellow
1
solid: 0.330 g, yield 68%; mp 288−289 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.21 (d, J = 8.4 Hz, 2H), 7.59−7.54 (m, 4H), 7.47 (d,
J = 8.0 Hz, 2H), 4.19 (s, 3H), 4.11 (s, 3H), 1.99 (s, 3H), 1.57 (s, 3H);
13C NMR (100 MHz, CDCl3; δ, ppm) 159.0, 148.2, 146.7, 141.3,
140.8, 140.0, 139.6, 137.6, 136.4, 135.6, 135.3, 132.9, 132.4, 128.7,
127.8, 121.8, 116.3, 105.8, 34.0, 33.6, 15.9, 15.1; IR (KBr, ν, cm−1)
2937, 1586, 1543, 1484, 1449, 1377, 1342; HRMS (ESI-TOF) m/z
calcd for C26H21Cl2N6 487.1205 [M + H]+, found 487.1198.
collected by Buchner filtration and was purified by flash column
̈
chromatography (silica gel, petroleum ether/acetone mixtures, 7/1, v/
v) to afford the desired pure 3a as a yellow solid (0.146 g, yield 70%,
mp 279−280 °C): 1H NMR (400 MHz, CDCl3; δ, ppm) 8.25 (d, J =
7.2 Hz, 2H), 7.60−7.51 (m, 8H), 4.19 (s, 3H), 4.11 (s, 3H), 1.94 (s,
3H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 160.2, 148.3,
146.8, 141.7, 141.1, 141.0, 140.2, 139.3, 138.1, 131.6, 131.1, 129.3,
129.0, 128.3, 127.6, 121.9, 116.4, 105.9, 34.0, 33.5, 15.4, 14.9; IR (KBr,
5,10-Bis(3,4-dichlorophenyl)-1,3,7,9-tetramethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3d). Yellow
1
solid: 0.399 g, yield 72%; mp 268−270 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.49 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.73−7.67 (m,
3H), 7.42 (d, J = 8.0 Hz, 1H), 4.24 (s, 3H), 4.17 (s, 3H), 2.07 (s, 3H),
1.67 (s, 3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 148.1, 146.5,
E
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Scheme 3. Proposed Mechanisms for the Synthesis of Products 3 and 4
Scheme 4. Proposed Mechanism for the Synthesis of Products 5
146.2, 143.0, 141.1, 140.5, 139.8, 138.8, 138.0, 134.0, 133.6, 133.4,
133.0, 132.8, 131.8, 130.8, 130.5, 130.4, 129.6, 121.6, 116.2, 100.0,
34.1, 33.6, 16.1, 15.3; IR (KBr, ν, cm−1): 2939, 1586, 1540, 1501,
1473, 1446, 1406, 1380, 1342; HRMS (ESI-TOF) m/z calcd for
C26H19Cl4N6 555.0425 [M + H]+, found 555.0405.
5,10-Bis(4-bromophenyl)-1,3,7,9-tetramethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3e). Yellow
solid: 0.397 g, yield 69%; mp >300 °C; 1H NMR (400 MHz,
CDCl3; δ, ppm) 8.14 (d, J = 8.0 Hz, 2H), 7.75−7.70 (m, 4H), 7.41 (d,
J = 8.0 Hz, 2H), 4.19 (s, 3H), 4.12 (s, 3H), 2.00 (s, 3H), 1.57 (s, 3H);
13C NMR (100 MHz, CDCl3; δ, ppm) 160.8, 148.2, 146.7, 141.3,
15.8, 15.1; IR (KBr, ν, cm−1) 2933, 1605, 1590, 1544, 1518, 1487,
1383; HRMS (ESI-TOF) m/z calcd for C28H27N6O2, 479.2195 [M +
H]+, found 479.2183.
1,9-Dicyclopropyl-3,7-dimethyl-5,10-diphenyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3h). Yellow
1
solid: 0.296 g, yield 63%; mp 209−210 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.25 (d, J = 7.2 Hz, 2H), 7.66−7.64 (m, 2H), 7.58−
7.54 (m, 3H), 7.52−7.49 (m, 3H), 4.16 (s, 3H), 4.08 (s, 3H), 1.22−
1.16 (m, 1H), 0.90−0.86 (m, 2H), 0.70−0.66 (m, 2H), 0.63−0.58 (m,
2H), 0.34−0.30 (m, 2H), 0.17−0.12 (m, 1H); 13C NMR (100 MHz,
CDCl3; δ, ppm) 159.8, 148.6, 146.6, 146.4, 145.9, 141.4, 140.3, 139.4,
138.7, 131.6, 130.8, 128.9, 128.8, 128.2, 127.5, 121.9, 116.6, 106.3,
34.1, 33.6, 10.2, 10.0, 9.3, 7.7; IR (KBr, ν, cm−1) 3056, 1543, 1487,
1443, 1387, 1354; HRMS (ESI-TOF) m/z calcd for C30H27N6
471.2297 [M + H]+, found 471.2283.
140.8, 140.0, 139.6, 138.0, 136.8, 133.2, 132.7, 132.2, 131.7, 131.6,
130.8, 121.7, 116.3, 105.8, 34.0, 33.6, 15.8, 15.1; IR (KBr, ν, cm−1)
2937, 1585, 1543, 1483, 1406, 1344; HRMS (ESI-TOF) m/z calcd for
C26H21Br2N6 577.0174 [M + H]+, found 577.0152.
1,9-Dicyclopropyl-5,10-bis(4-fluorophenyl)-3,7-dimethyl-3,7-
1,3,7,9-Tetramethyl-5,10-di-p-tolyl-3,7-dihydrodipyrazolo[3,4-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3i). Yellow
b:4′,3′-f ][1,7]naphthyridine (3f). Yellow solid: 0.343 g, yield 77%; mp
1
1
solid: 0.369 g, yield 73%; mp 231−232 °C; H NMR (400 MHz,
298−299 °C; H NMR (400 MHz, CDCl3; δ, ppm) 8.19 (d, J = 7.6
CDCl3; δ, ppm) 8.28−8.25 (m, 2H), 7.66−7.62 (m, 2H), 7.26−7.23
(m, 4H), 4.16 (s, 3H), 4.09 (s, 3H), 1.24−1.19 (m, 1H), 0.93−0.90
(m, 2H), 0.74−0.70 (m, 2H), 0.68−0.64 (m, 2H), 0.42−0.38 (m, 2H),
0.28−0.23 (m, 1H); 13C NMR (100 MHz, CDCl3; δ, ppm) 163.5 (1JCF
= 247.2 Hz), 163.2 (1′JCF = 247.8 Hz), 158.7, 148.5, 146.5, 146.2,
145.6, 140.2, 140.1(6), 135.3 (4JCF = 3.3 Hz), 134.6 (4′JCF = 3.4 Hz),
133.5 (3JCF = 8.1 Hz), 132.6 (3′JCF = 8.0 Hz), 122.0, 116.8, 115.4 (2JCF
= 21.3 Hz), 114.5 (2′JCF = 21.3 Hz), 106.2, 34.2, 33.6, 10.4, 10.1, 9.2,
7.7; IR (KBr, ν, cm−1) 3008, 1605, 1583, 1543, 1514, 1456, 1354;
HRMS (ESI-TOF) m/z calcd for C30H25F2N6 507.2109 [M + H]+,
found 507.2101.
Hz, 2H), 7.41−7.36 (m, 6H), 4.21 (s, 3H), 4.12 (s, 3H), 2.53 (s, 3H),
2.51 (s, 3H), 1.97 (s, 3H), 1.53 (s, 3H); 13C NMR (100 MHz, CDCl3;
δ, ppm) 148.4, 146.8, 141.7, 141.4, 141.3, 140.4, 140.0, 139.3, 139.2,
136.4, 135.0, 131.6, 131.0, 128.9, 128.4, 122.0, 116.5, 105.9, 33.9, 33.6,
21.5(2), 21.5(1), 15.4, 15.0; IR (KBr, ν, cm−1) 2932, 1585, 1543,
1505, 1449, 1341; HRMS (ESI-TOF) m/z calcd for C28H27N6
447.2297 [M + H]+, found 447.2286.
5,10-Bis(4-methoxyphenyl)-1,3,7,9-tetramethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3g). Yellow
1
solid: 0.344 g, yield 72%; mp 281−282 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.31 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H),
7.10 (t, J = 9.2 Hz, 4H), 4.20 (s, 3H), 4.13 (s, 3H), 3.95 (s, 6H), 2.01
(s, 3H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 160.5,
160.4, 159.5, 148.3, 146.9, 141.7, 141.2, 141.0, 140.4, 133.2, 132.3,
131.9, 130.4, 122.4, 116.8, 113.7, 113.1, 105.7, 55.5, 55.4, 33.9, 33.5,
5,10-Bis(4-chlorophenyl)-1,9-dicyclopropyl-3,7-dimethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3j). Yellow
1
solid: 0.409 g, yield 76%; mp 243−246 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.20 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H),
F
dx.doi.org/10.1021/jo500823z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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7.52 (t, J = 10.0 Hz, 4H), 4.16 (s, 3H), 4.08 (s, 3H), 1.28−1.23 (m,
1H), 0.94−0.90 (m, 2H), 0.75−0.72 (m, 2H), 0.70−0.65 (m, 2H),
0.42−0.39 (m, 2H), 0.34−0.29 (m, 1H); 13C NMR (100 MHz,
CDCl3; δ, ppm) 158.6, 148.5, 146.5, 146.2, 145.5, 140.1, 139.9, 137.6,
136.9, 132.9, 132.3, 131.3, 129.1, 128.6, 127.8, 121.8, 116.5, 106.2,
34.2, 33.6, 10.4, 10.2, 9.5, 7.7; IR (KBr, ν, cm−1) 3004, 1587, 1541,
1487, 1396, 1354; HRMS (ESI-TOF) m/z calcd for C30H25Cl2N6
539.1518 [M + H]+, found 539.1503.
1570, 1531, 1489, 1447, 1393; HRMS (ESI-TOF) m/z calcd for
C36H27F2N6O2 613.2164 [M − H]−, found 613.2143.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-chlorophenyl)-
methanone) (4c). Yellow solid: 0.452 g, yield 70%; mp 288−289 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.07 (d, J = 8.4 Hz, 2H),
7.80 (d, J = 8.4 Hz, 2H), 7.33−7.26 (m, 6H), 7.19 (t, J = 7.6 Hz, 4H),
7.11 (d, J = 7.2 Hz, 4H), 6.66 (t, J = 8.0 Hz, 1H), 6.20 (d, J = 8.0 Hz,
2H), 5.74 (s, 1H), 3.54 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 201.7, 192.0, 148.4, 145.6, 139.5, 138.7, 134.5, 133.8, 133.1,
131.0, 130.3, 129.8, 129.1, 129.0, 128.1, 127.9, 100.2, 67.9, 41.7, 35.4;
IR (KBr, ν, cm−1) 3344, 3173, 1696, 1587, 1570, 1533, 1489, 1447,
1399; HRMS (ESI-TOF) m/z calcd for C36H27Cl2N6O2 645.1567 [M
− H]−, found 645.1574.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((3,4-dichlorophenyl)-
methanone) (4d). Yellow solid: 0.521 g, yield 73%; mp 274−276 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.17 (s, 1H), 8.03−7.97 (m,
2H), 7.55 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.36−7.29 (m, 3H), 7.20
(t, J = 7.6 Hz, 4H), 7.12 (d, J = 7.6 Hz, 4H), 6.57 (t, J = 8.4 Hz, 1H),
6.24 (d, J = 8.0 Hz, 2H), 5.71 (s, 1H), 3.56 (s, 6H); 13C NMR (100
MHz, DMSO-d6; δ, ppm) 200.8, 191.2, 148.4, 145.6, 137.3, 136.8,
136.0, 134.7, 133.6, 132.5, 132.1, 132.0, 131.4, 131.0, 130.1, 129.6,
129.0, 128.4, 128.2, 127.9, 99.9, 68.4, 41.9, 35.4; IR (KBr, ν, cm−1)
3369, 3155, 1698, 1655, 1583, 1571, 1498, 1448, 1377; HRMS (ESI-
TOF) m/z calcd for C36H25Cl4N6O2 713.0788 [M − H]−, found
713.0789.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-bromophenyl)-
methanone) (4e). Yellow solid: 0.545 g, yield 74%; mp 290−292 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.07 (d, J = 8.4 Hz, 2H),
7.79 (d, J = 8.4 Hz, 2H), 7.33−7.24 (m, 6H), 7.19 (t, J = 7.6 Hz, 4H),
7.11 (d, J = 7.6 Hz, 4H), 6.66 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 8.0 Hz,
2H), 5.74 (s, 1H), 3.55 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 201.2, 191.6, 147.9, 145.1, 139.1, 138.2, 134.0, 133.4, 132.6,
130.5, 129.8, 129.3, 128.6, 128.5, 127.6, 127.4, 99.7, 67.4, 41.2, 34.9; IR
(KBr, ν, cm−1) 3342, 3182, 1697, 1587, 1490, 1448, 1399; HRMS
(ESI-TOF) m/z calcd for C36H27Br2N6O2 735.0542 [M − H]−, found
735.0529.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-nitrophenyl)-
methanone) (4f). Yellow solid: 0.468 g, yield 70%; mp 290−291 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.54 (d, J = 9.2 Hz, 2H),
1,9-Dicyclopropyl-5,10-bis(3,4-dichlorophenyl)-3,7-dimethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3k). Yellow
1
solid: 0.430 g, yield 71%; mp 240−242 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.45 (d, J = 2.0 Hz, 1H), 8.13−8.11 (m, 1H), 7.86 (d,
J = 1.6 Hz, 1H), 7.62 (t, J = 8.8 Hz, 2H), 7.47−7.45 (m, 1H), 4.16 (s,
3H), 4.11 (s, 3H), 1.29−1.23 (m, 1H), 1.02 (s, 1H), 0.90 (s, 2H),
0.79−0.66 (m, 3H), 0.45−0.37 (m, 3H); 13C NMR (100 MHz,
CDCl3; δ, ppm) 156.9, 148.5, 146.3, 146.1, 145.2, 139.8, 138.9, 138.4,
138.1, 133.5, 133.3, 133.2, 133.1, 132.8, 131.7, 130.7, 130.3, 130.2,
129.5, 121.5, 116.4, 106.2, 34.3, 33.7, 10.7, 10.3, 9.6, 8.7, 7.9, 7.2; IR
(KBr, ν, cm−1) 3003, 1584, 1537, 1475, 1391; HRMS (ESI-TOF) m/z
calcd for C30H23Cl4N6 607.0738 [M + H]+, found 607.0722.
5,10-Bis(4-bromophenyl)-1,9-dicyclopropyl-3,7-dimethyl-3,7-
dihydrodipyrazolo[3,4-b:4′,3′-f ][1,7]naphthyridine (3l). Yellow
1
solid: 0.471 g, yield 75%; mp 266−268 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.14 (d, J = 8.0 Hz, 2H), 7.71−7.66 (m, 4H), 7.55 (d,
J = 8.0 Hz, 2H), 4.16 (s, 3H), 4.09 (s, 3H), 1.30−1.24 (m, 1H), 0.93−
0.90 (m, 2H), 0.76−0.66 (m, 4H), 0.44−0.40 (m, 2H), 0.34−0.27 (m,
1H); 13C NMR (100 MHz, CDCl3; δ, ppm) 158.6, 148.5, 146.5, 146.3,
145.5, 140.0, 139.9, 138.1, 137.4, 133.2, 132.5, 131.5, 130.8, 123.6,
123.2, 121.7, 116.4, 106.2, 34.2, 33.7, 10.5, 10.2, 9.5, 7.7; IR (KBr, ν,
cm−1) 3087, 3009, 1590, 1543, 1485, 1392,1353; HRMS (ESI-TOF)
m/z calcd for C30H25Br2N6 629.0487 [M + H]+, found 629.0466.
Representative Synthesis of 4: (3,7-Dimethyl-1,9-diphenyl-
3,4,5,6,7,10-hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-
5,10-diyl)bis(phenylmethanone) (4a). Typically, 2,2-dihydroxy-1-
phenylethanone (1a; 2.2 mmol, 0.334 g, 1.1 equiv) and 1-methyl-3-
phenyl-1H-pyrazol-5-amine (2c; 2.0 mmol, 0.346 g, 1.0 equiv) were
introduced into a 10 mL Initiator reaction vial, and p-TsOH (1.0
equiv) and DMF (1.5 mL) were then added successively.
Subsequently, the reaction vial was closed and then prestirred for 10
s. The mixture was irradiated (time, 25 min; temperature, 120 °C;
absorption level, high; fixed hold time) until TLC (petroleum ether/
acetone 3/1) revealed that conversion of the starting material 2c was
complete. After it was cooled to room temperature, the reaction
mixture was diluted with cold water (20 mL) and neutralized with 10%
8.26 (d, J = 9.2 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz,
2H), 7.32 (t, J = 7.2 Hz, 2H), 7.21 (t, J = 8.0 Hz, 4H), 7.12 (t, J = 7.2
Hz, 4H), 6.61 (t, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 2H), 5.77 (s,
1H), 3.53 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 201.5,
191.5, 150.2, 149.7, 147.9, 145.0, 140.6, 138.9, 133.2, 129.9, 128.9,
128.5, 127.6, 127.4, 124.1, 123.4, 99.3, 68.1, 41.8, 34.8; IR (KBr, ν,
cm−1) 3366, 3178, 1697, 1603, 1568, 1520, 1444, 1378; HRMS (ESI-
TOF) m/z calcd for C36H27N8O6, 667.2052 [M − H]−, found
667.2031.
NaOH solution. The solid product was collected by Buchner filtration
̈
and was purified by flash column chromatography (silica gel,
petroleum ether/acetone mixtures, 8/1, v/v) to afford the desired
pure 4a. Yellow solid: 0.410 g, yield 71%; mp 269−270 °C; 1H NMR
(400 MHz, DMSO-d6; δ, ppm) 8.11 (d, J = 7.6 Hz, 2H), 7.77 (t, J =
7.2 Hz, 1H), 7.69 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 7.2 Hz), 7.35 (d, J =
7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 7.19 (t, J = 7.6 Hz, 6H), 7.13 (d,
J = 7.2 Hz, 4H), 6.76 (t, J = 8.0 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 5.83
(s, 1H), 3.53 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 202.7,
193.1, 148.4, 145.7, 135.9, 134.7, 134.3, 134.0, 133.8, 129.6, 129.2,
129.0, 128.9, 128.5, 128.1, 127.9, 100.5, 67.7, 41.6, 35.3; IR (KBr, ν,
cm−1) 3374, 3191, 1695, 1674, 1567, 1529, 1446, 1370; HRMS (ESI-
TOF) m/z calcd for C36H29N6O2 577.2347 [M − H]−, found
577.2346.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis(p-tolylmethanone) (4g).
1
Yellow solid: 0.424 g, yield 70%; mp 271−273 °C; H NMR (400
MHz, DMSO-d6; δ, ppm) 8.00 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz,
2H), 7.31−7.25 (m, 4H), 7.18 (t, J = 7.2 Hz, 4H), 7.12 (d, J = 7.2 Hz,
4H), 7.00 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 8.4 Hz, 1H), 6.14 (d, J = 8.4
Hz, 2H), 5.80 (s, 1H), 3.53 (s, 6H), 2.44 (s, 3H), 2.25 (s, 3H); 13C
NMR (100 MHz, DMSO-d6; δ, ppm) 201.6, 192.1, 147.9, 145.2,
144.9, 143.9, 133.5, 132.6, 131.2, 129.6, 129.0, 128.9, 128.4, 128.2,
127.5, 127.4, 100.1, 67.0, 40.9, 34.8, 21.3, 20.9; IR (KBr, ν, cm−1)
3368, 3187, 1694, 1606, 1568, 1528, 1446, 1378; HRMS (ESI-TOF)
m/z calcd for C38H33N6O2 605.2665 [M − H]−, found 605.2653.
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-methoxyphenyl)-
methanone) (4h). Yellow solid: 0.440 g, yield 69%; mp 263−265 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.09 (d, J = 8.8 Hz, 2H),
(3,7-Dimethyl-1,9-diphenyl-3,4,5,6,7,10-hexahydrodipyrazolo-
[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-fluorophenyl)-
methanone) (4b). Yellow solid: 0.424 g, yield 69%; mp 283−285 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.18−8.14 (m, 2H), 7.56 (t,
J = 8.8 Hz, 2H), 7.42−7.39 (m, 2H), 7.32−7.28 (m, 2H), 7.19 (t, J =
8.0 Hz, 4H), 7.13−7.11 (m, 4H), 7.03 (t, J = 8.8 Hz, 2H), 6.72 (t, J =
8.4 Hz, 1H), 6.18 (d, J = 8.4 Hz, 2H), 5.76 (s, 1H), 3.54 (s, 6H); 13C
NMR (100 MHz, DMSO-d6; δ, ppm) 201.2, 191.7, 165.9 (1JCF = 252.1
Hz), 165.3 (1′JCF = 251.4 Hz), 148.4, 145.6, 133.9, 132.5 (4JCF = 2.9
Hz), 132.2 (3JCF = 9.6 Hz), 131.4 (3′JCF = 9.4 Hz), 131.0 (4′JCF = 2.8
Hz), 128.9, 128.1, 127.9, 116.8 (2JCF = 22.2 Hz), 116.1 (2′JCF = 21.7
Hz), 100.4, 67.7, 41.6, 35.3; IR (KBr, ν, cm−1) 3347, 3175, 1699, 1584,
7.37 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 8.8 Hz,
3H), 7.18−7.13 (m, 7H), 6.78 (t, J = 8.4 Hz, 1H), 6.70 (d, J = 8.8 Hz,
G
dx.doi.org/10.1021/jo500823z | J. Org. Chem. XXXX, XXX, XXX−XXX

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2H), 6.13 (d, J = 8.4 Hz, 2H), 5.76 (s, 1H), 3.90 (s, 3H), 3.75 (s, 3H),
3.55 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 200.7, 191.5,
164.4, 163.6, 148.3, 145.7, 134.1, 131.7, 131.0, 128.9, 128.3, 128.0,
127.9, 126.9, 114.9, 114.2, 100.8, 67.2, 56.2, 56.0, 41.3, 35.3; IR (KBr,
ν, cm−1) 3374, 1684, 1655, 1601, 1570, 1528, 1443, 1377; HRMS
(ESI-TOF) m/z calcd for C38H33N6O4, 637.2558 [M − H]−, found
637.2528.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis-
(phenylmethanone) (4i). Yellow solid: 0.452 g, yield 70%; mp 283−
285 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.08 (d, J = 8.8 Hz,
2H), 7.78 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2
Hz, 1H), 7.36−7.34 (m, 2H), 7.30−7.25 (m, 6H), 7.12 (d, J = 8.4 Hz,
4H), 6.66 (t, J = 8.4 Hz, 1H), 6.23 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H),
3.53 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 202.8, 192.9,
147.2, 145.8, 135.9, 134.7, 134.2, 133.8, 132.9, 132.8, 129.6, 129.5(7),
129.2, 129.1, 129.0, 128.4, 100.6, 67.6, 41.8, 35.4; IR (KBr, ν, cm−1)
3354, 3187, 1696, 1634, 1595, 1580, 1564, 1446, 1373; HRMS (ESI-
TOF) m/z calcd for C36H27Cl2N6O2 645.1573 [M − H]−, found
645.1558.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
fluorophenyl)methanone) (4j). Yellow solid: 0.484 g, yield 71%; mp
280−282 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.16−8.12 (m,
2H), 7.56 (t, J = 8.8 Hz, 2H), 7.45−7.41 (m, 2H), 7.29 (t, J = 8.4 Hz,
4H), 7.15−7.10 (m, 6H), 6.62 (t, J = 8.0 Hz, 1H), 6.24 (d, J = 8.4 Hz,
2H), 5.55 (s, 1H), 3.54 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 201.3, 191.5, 166.0 (1JCF = 251.9 Hz), 165.4 (1′JCF = 251.4 Hz),
147.1, 145.7, 133.0, 132.7, 132.4 (4JCF = 2.8 Hz), 132.2 (3JCF = 9.8
Hz), 131.3 (3′JCF = 9.6 Hz), 131.0 (4′JCF = 2.8 Hz), 129.6, 129.1, 116.8
(2JCF = 22.1 Hz), 116.2 (2′JCF = 21.9 Hz), 100.6, 67.7, 41.9, 35.4; IR
(KBr, ν, cm−1) 3353, 3180, 1692, 1631, 1592, 1581, 1562, 1446, 1371;
HRMS (ESI-TOF) m/z calcd for C36H25Cl2F2N6O2 681.1382 [M −
H]−, found 681.1356.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
chlorophenyl)methanone) (4k). Yellow solid: 0.514 g, yield 72%; mp
294−296 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.05 (d, J = 8.8
Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.38−7.33 (m, 4H), 7.29 (d, J = 8.4
Hz, 4H), 7.11 (d, J = 8.4 Hz, 4H), 6.55 (t, J = 8.0 Hz, 1H), 6.25 (d, J =
8.4 Hz, 2H), 5.53 (s, 1H), 3.54 (s, 6H); 13C NMR (100 MHz, DMSO-
d6; δ, ppm) 201.8, 191.9, 147.2, 145.7, 139.6, 138.8, 134.5, 133.0,
132.9(7), 132.7, 131.0, 130.2, 129.8, 129.6, 129.2, 129.1, 100.4, 67.9,
41.9, 35.4; IR (KBr, ν, cm−1) 3347, 3183, 1693, 1633, 1587, 1567,
1446, 1399, 1374; HRMS (ESI-TOF) m/z calcd for C36H25Cl4N6O2
713.0764 [M − H]−, found 713.0761.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
bromophenyl)methanone) (4l). Yellow solid: 0.587 g, yield 73%; mp
288−290 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 7.98−7.93 (m,
4H), 7.51 (d, J = 8.8 Hz, 2H), 7.28 (t, J = 8.4 Hz, 6H), 7.12 (d, J = 8.4
Hz, 4H), 6.55 (t, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 2H), 5.52 (s,
1H), 3.54 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 202.0,
192.1, 147.1, 145.7, 134.8, 133.3, 133.0, 132.7, 132.6, 132.2, 131.0,
130.3, 129.6, 129.1, 128.9, 128.0, 100.4, 67.8, 41.9, 35.4; IR (KBr, ν,
cm−1) 3342, 3106, 1676, 1650, 1600, 1520, 1406, 1347; HRMS (ESI-
TOF) m/z calcd for C36H25Br2Cl2N6O2 802.9757 [M − H]−, found
802.9781.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis(p-
tolylmethanone) (4m). Yellow solid: 0.512 g, yield 76%; mp 298−300
°C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 7.98 (d, J = 8.0 Hz, 2H),
7.49 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 6H), 7.12−7.06 (m, 6H),
6.66 (t, J = 8.4 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 5.58 (s, 1H), 3.53 (s,
6H), 2.44 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 202.0, 192.4, 147.1, 145.8, 145.4, 144.5, 133.1, 132.9, 132.8(5),
131.7, 130.1, 129.6, 129.5(9), 129.3, 129.0, 128.6, 100.7, 67.4, 41.6,
35.4, 21.8, 21.4; IR (KBr, ν, cm−1) 3349, 3201, 1687, 1605, 1580,
1561, 1509, 1447, 1374; HRMS (ESI-TOF) m/z calcd for
C38H31Cl2N6O2 673.1880 [M − H]−, found 673.1882.
(1,9-Bis(4-chlorophenyl)-3,7-dimethyl-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
methoxyphenyl)methanone) (4n). Yellow solid: 0.522 g, yield 74%;
mp 298−299 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.07 (d, J
= 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 4H), 7.23
(d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 4H), 6.78 (d, J = 8.8 Hz, 2H),
6.69 (t, J = 8.4 Hz, 1H), 6.17 (d, J = 8.4 Hz, 2H), 5.55 (s, 1H), 3.90 (s,
3H), 3.77 (s, 3H), 3.54 (s, 6H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 200.2, 190.9, 164.0, 163.2, 146.6, 145.3, 132.4, 132.3(6), 131.2,
130.4, 129.1, 128.5, 127.7, 126.3, 114.4, 113.8, 100.5, 66.7, 55.7, 55.5,
41.0, 34.9; IR (KBr, ν, cm−1) 3351, 3188, 1688, 1601, 1575, 1510,
1444, 1420, 1373; HRMS (ESI-TOF) m/z calcd for C38H31Cl2N6O4,
705.1778 [M − H]−, found 705.1751.
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis-
(phenylmethanone) (4o). Yellow solid: 0.419 g, yield 71%; mp 268−
1
270 °C; H NMR (400 MHz, CDCl3; δ, ppm) 8.14 (d, J = 7.6 Hz,
2H), 7.69 (t, J = 7.6 Hz, 1H), 7.64−7.56 (m, 4H), 7.43 (t, J = 7.2 Hz,
1H), 7.30 (d, J = 5.2 Hz, 2H), 7.22 (t, J = 7.6 Hz, 2H), 6.95−6.93 (m,
2H), 6.84−6.78 (m, 3H), 6.34 (s, 1H), 4.68 (d, J = 8.4 Hz, 2H), 3.49
(s, 6H); 13C NMR (100 MHz, CDCl3; δ, ppm) 200.1, 193.1, 144.5,
143.4, 135.3, 134.8, 134.4, 133.3, 133.2, 129.4, 129.1, 128.8, 128.5,
127.6, 125.7, 125.3, 102.3, 67.8, 40.8, 34.7; IR (KBr, ν, cm−1) 3354,
3187, 1685, 1596, 1574, 1526, 1447, 1324; HRMS (ESI-TOF) m/z
calcd for C32H25N6O2S2, 589.1481 [M − H]−, found 589.1475.
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
fluorophenyl)methanone) (4p). Yellow solid: 0.495 g, yield 79%; mp
1
>300 °C; H NMR (400 MHz, CDCl3; δ, ppm) 8.21−8.18 (m, 2H),
7.66−7.62 (m, 2H), 7.32−7.30 (m, 2H), 7.29−7.26 (m, 2H), 6.96−
6.93 (m, 2H), 6.91−6.87 (m, 2H), 6.82−6.78 (m, 3H), 6.29 (s, 1H),
4.60 (d, J = 8.8 Hz, 2H), 3.53 (s, 6H); 13C NMR (100 MHz, CDCl3;
δ, ppm) 199.6, 191.0, 165.4 (1JCF = 251.9 Hz), 164.9 (1′JCF = 251.7
Hz), 145.3, 141.9, 135.2, 131.7 (4JCF = 2.7 Hz), 131.6 (3JCF = 9.6 Hz),
130.9 (3′JCF = 9.4 Hz), 130.4 (4′JCF = 2.7 Hz), 127.5, 126.2, 124.0,
116.3 (2JCF = 22.1 Hz), 115.7 (2′JCF = 21.7 Hz), 99.8, 67.6, 40.9, 34.8;
IR (KBr, ν, cm−1) 3356, 3176, 1688, 1599, 1574, 1526, 1444, 1334;
HRMS (ESI-TOF) m/z calcd for C32H23F2N6O2S2, 625.1292 [M −
H]−, found 625.1278.
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
chlorophenyl)methanone) (4q). Yellow solid: 0.494 g, yield 75%; mp
>300 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 8.02 (d, J = 8.4 Hz,
2H), 7.79 (d, J = 8.4 Hz, 2H), 7.56−7.53 (m, 4H), 7.37 (d, J = 8.4 Hz,
2H), 6.97−6.95 (m, 2H), 6.68 (d, J = 3.2 Hz, 2H), 6.54 (t, J = 8.0 Hz,
1H), 6.22 (d, J = 8.0 Hz, 2H), 6.13 (s, 1H), 3.51 (s, 6H); 13C NMR
(100 MHz, DMSO-d6; δ, ppm) 200.6, 191.9, 145.8, 142.5, 139.6,
138.9, 135.7, 134.4, 133.0, 130.9, 130.3, 129.8, 129.3, 128.1, 126.7,
124.6, 100.2, 68.3, 41.5, 35.4; IR (KBr, ν, cm−1) 3340, 3179, 1684,
1589, 1572, 1526, 1489, 1399, 1318; HRMS (ESI-TOF) m/z calcd for
C32H23Cl2N6O2S2, 657.0701 [M − H]−, found 657.0684.
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
bromophenyl)methanone) (4r). Yellow solid: 0.509 g, yield 68%; mp
1
>300 °C; H NMR (400 MHz, CDCl3; δ, ppm) 8.04−8.02 (m, 2H),
7.75−7.30 (m, 2H), 7.48−7.46 (m, 2H), 7.38−7.36 (m, 2H), 7.32−
7.31 (m, 2H), 6.95−6.93 (m, 2H), 6.82−6.81 (m, 2H), 6.78−6.76 (m,
1H), 6.29 (s, 1H), 4.51 (d, J = 8.8 Hz, 2H), 3.57 (s, 6H); 13C NMR
(100 MHz, DMSO-d6; δ, ppm) 200.8, 192.1, 145.8, 142.5, 135.7,
134.7, 133.4, 132.7, 132.2, 131.0, 130.4, 128.8, 128.1, 128.0, 126.7,
124.7, 100.2, 68.3, 41.5, 35.4; IR (KBr, ν, cm−1) 3328, 1688, 1604,
1574, 1527, 1513, 1459, 1422; HRMS (ESI-TOF) m/z calcd for
C32H23Br2N6O2S2, 746.9670 [M − H]−, found 746.9653.
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis(p-
tolylmethanone) (4s). Yellow solid: 0.476 g, yield 77%; mp 279−280
1
°C; H NMR (400 MHz, CDCl3; δ, ppm) 8.06 (d, J = 7.6 Hz, 2H),
7.54 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 4.8 Hz,
2H), 7.03 (d, J = 7.6 Hz, 2H), 6.94−6.92 (m, 2H), 6.84−6.81 (m,
3H), 6.32 (s, 1H), 4.64 (d, J = 8.8 Hz, 2H), 3.55 (s, 6H), 2.47 (s, 3H),
2.31 (s, 3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 199.7, 192.8,
H
dx.doi.org/10.1021/jo500823z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
145.7, 144.5, 144.1, 143.4, 134.8, 132.7, 130.8, 129.8, 129.6, 129.3,
128.9, 127.6, 125.7, 125.4, 102.3, 67.6, 40.7, 34.8, 21.9, 21.6; IR (KBr,
ν, cm−1) 3339, 1683, 1601, 1574, 1527, 1510, 1459, 1420; HRMS
(ESI-TOF) m/z calcd for C34H29N6O2S2 617.1794 [M − H]−, found
617.1787.
3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 148.4, 141.0, 140.9, 139.4,
132.2, 132.1, 130.1, 129.9, 129.7, 129.5, 129.3, 129.1, 127.4, 125.0,
123.3, 120.8, 118.8, 117.8, 103.3, 97.0, 13.2, 12.8; IR (KBr, ν, cm−1)
3437, 2923, 1596, 1573, 1522, 1458, 1350, 1284; HRMS (ESI-TOF)
m/z calcd for C28H22BrN6 521.1090 [M − H]−, found 521.1078.
3-Methyl-4-(3-methyl-5-(4-nitrophenyl)-1-phenyl-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-phenyl-1H-pyrazol-5-amine
(3,7-Dimethyl-1,9-bis(thiophen-2-yl)-3,4,5,6,7,10-
hexahydrodipyrazolo[3,4-d:4′,3′-g][1,3]diazocine-5,10-diyl)bis((4-
methoxyphenyl)methanone) (4t). Yellow solid: 0.423 g, yield 65%;
1
(5e). An red solid: 0.362 g, yield 74%; mp >300 °C; H NMR (400
1
mp >300 °C; H NMR (400 MHz, CDCl3; δ, ppm) 8.16 (d, J = 8.8
MHz, DMSO-d6; δ, ppm) 11.69 (s, 1H), 8.23 (d, J = 8.8 Hz, 2H), 7.89
(d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H),
7.56−7.48 (m, 4H), 7.31 (t, J = 7.6 Hz), 7.25 (t, J = 7.2 Hz), 5.11 (s,
2H), 2.31 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 147.2, 145.2, 145.1, 141.8, 140.9, 140.7, 139.9, 139.3, 131.3,
129.9, 129.6, 127.0, 126.3, 124.8, 124.1, 122.8, 119.7, 117.8, 105.4,
96.4, 13.4, 13.2; IR (KBr, ν, cm−1) 3378, 3062, 1594, 1570, 1499,
1375, 1320, 1272; HRMS (ESI-TOF) m/z calcd for C28H22N7O2
488.1835 [M − H]−, found 488.1860.
Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.30−7.28 (m, 2H), 7.05 (d, J = 8.8
Hz, 2H), 6.93−6.91 (m, 2H), 6.90−6.86 (m, 1H), 6.83−6.82 (m, 2H),
6.70 (d, J = 8.8 Hz, 2H), 6.30 (s, 1H), 4.55 (d, J = 8.8 Hz, 2H), 3.92
(s, 3H), 3.79 (s, 3H), 3.58 (s, 6H); 13C NMR (100 MHz, CDCl3; δ,
ppm) 198.7, 191.8, 164.7, 163.6, 144.4, 143.5, 135.1, 132.0, 131.2,
128.1, 127.6, 126.1, 125.6, 125.3, 114.4, 113.7, 102.4, 67.3, 55.7, 55.4,
40.5, 34.9; IR (KBr, ν, cm−1) 3326, 1675, 1610, 1578, 1525, 1510,
1459, 1428; HRMS (ESI-TOF) m/z calcd for C34H29N6O4S2 649.1692
[M − H]−, found 649.1678.
Representative Synthesis of 5: 3-Methyl-4-(3-methyl-1,5-
diphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-phenyl-1H-
pyrazol-5-amine (5a). Typically, 2,2-dihydroxy-1-phenylethanone
(1a; 1.0 mmol, 0.152 g, 1.0 equiv) and 1-phenyl-3-methylpyrazol-5-
amine (2f; 2.0 mmol, 0.346 g, 2.0 equiv) were introduced in a 10 mL
Initiator reaction vial, and p-TsOH (1.0 equiv) and DMF (1.5 mL)
were then added successively. Subsequently, the reaction vial was
closed and then prestirred for 10 s. The mixture was irradiated (time,
30 min; temperature, 120 °C; absorption level, high; fixed hold time)
until TLC (petroleum ether/acetone 3/1) revealed that conversion of
the starting material 2f was complete. After room temperature, the
reaction mixture was diluted with cold water (20 mL) and neutralized
3-Methyl-4-(3-methyl-1-phenyl-5-(p-tolyl)-1,6-dihydropyrrolo-
[2,3-c]pyrazol-4-yl)-1-phenyl-1H-pyrazol-5-amine (5f). White solid:
0.307 g, yield 67%; mp 296−298 °C; 1H NMR (400 MHz, CDCl3; δ,
ppm) 8.37 (s, 1H), 7.67−7.61 (m, 4H), 7.48−7.44 (m, 4H), 7.36−
7.29 (m, 3H), 7.22 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.2 Hz, 2H), 3.70
(s, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz,
DMSO-d6; δ, ppm) 147.5, 145.0, 140.7, 140.1, 140.0, 139.6, 136.0,
133.7, 131.3, 129.8, 129.5, 129.3, 127.2, 126.0, 124.3, 122.4, 118.9,
117.4, 100.6, 97.5, 21.3, 13.5, 13.2; IR (KBr, ν, cm−1) 3355, 3071,
2917, 1620, 1579, 1509, 1079; HRMS (ESI-TOF) m/z calcd for
C29H25N6 457.2141 [M − H]−, found 457.2157.
4-(5-(4-Methoxyphenyl)-3-methyl-1-phenyl-1,6-dihydropyrrolo-
[2,3-c]pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5-amine (5g).
1
with 10% NaOH solution. The solid product was collected by Buchner
White solid: 0.327 g, yield 69%; mp 270−273 °C; H NMR (400
̈
filtration and was purified by recrystallization from 95% EtOH to
afford the desired pure 5a. White solid: 0.346 g, yield 78%; mp 251−
254 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 8.35 (s, 1H), 7.68−7.62
(m, 4H), 7.51−7.45 (m, 6H), 7.37−7.30 (m, 3H), 7.25−7.21 (m, 2H),
3.72 (s, 2H), 2.45 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3;
δ, ppm) 148.5, 142.9, 141.0, 140.8, 139.5, 133.2, 132.4, 130.0, 129.7,
129.5, 129.0, 128.5, 127.1, 126.0, 124.9, 123.3, 118.7, 117.7, 105.6,
97.5, 13.3, 12.8; IR (KBr, ν, cm−1) 3287, 3059, 1624, 1596, 1499,
1387, 1268; HRMS (ESI-TOF) m/z calcd for C28H23N6 443.1984 [M
− H]−, found 443.2009.
MHz, CDCl3; δ, ppm) 8.81 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.61 (d, J
= 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 4H), 7.39 (d, J = 8.4 Hz, 2H), 7.30
(t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H),
3.80 (s, 3H), 3.70 (s, 2H), 2.43 (s, 3H), 2.07 (s, 3H); 13C NMR (100
MHz, CDCl3; δ, ppm) 148.7, 142.8, 140.7, 139.5, 134.8, 132.6, 129.6,
129.4, 128.8, 127.7, 126.7, 125.9, 124.6, 123.9, 123.2, 122.3, 118.5,
117.7, 100.4, 97.7, 55.3, 13.3, 12.9; IR (KBr, ν, cm−1) 3332, 2920,
1676, 1570, 1520, 1409, 1289, 1248; HRMS (ESI-TOF) m/z calcd for
C29H25N6O 473.2090 [M − H]−, found 473.2107.
3-Methyl-4-(3-methyl-5-phenyl-1-(p-tolyl)-1,6-dihydropyrrolo-
[2,3-c]pyrazol-4-yl)-1-(p-tolyl)-1H-pyrazol-5-amine (5h). White
4-(5-(4-Fluorophenyl)-3-methyl-1-phenyl-1,6-dihydropyrrolo[2,3-
c]pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5-amine (5b). White
1
solid: 0.349 g, yield 74%; mp 272−273 °C; H NMR (400 MHz,
1
solid: 0.356 g, yield 77%; mp 270−271 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 8.16 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.50−7.45 (m,
4H), 7.37−7.28 (m, 5H), 7.25−7.23 (m, 2H), 3.67 (s, 2H), 2.45 (s,
3H), 2.40 (s, 3H) 2.39 (s, 3H), 2.07 (s, 3H); 13C NMR (100 MHz,
CDCl3; δ, ppm) 147.1, 145.0, 141.2, 139.5, 137.1, 134.2, 133.7, 133.5,
132.4, 131.9, 130.2, 129.8, 128.5, 127.3, 126.9, 123.9, 118.0, 117.7,
101.4, 98.0, 21.2, 20.9, 13.3, 11.9; IR (KBr, ν, cm−1) 3364, 3079, 2917,
1659, 1567, 1509; HRMS (ESI-TOF) m/z calcd for C30H27N6
471.2297 [M − H]−, found 471.2332.
CDCl3; δ, ppm) 8.73 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6
Hz, 2H), 7.46−7.38(m, 6H), 7.30 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.2
Hz, 1H), 7.01 (t, J = 8.4 Hz, 2H), 3.71 (s, 2H), 2.42 (s, 3H), 2.04 (s,
3H); 13C NMR (100 MHz, CDCl3; δ, ppm) 161.7 (1JCF = 246.0 Hz),
148.4, 142.9, 140.9 (4JCF = 2.1 Hz), 139.4, 131.7, 129.9, 129.6, 129.5,
128.0 (3JCF = 7.9 Hz), 126.9, 124.9, 123.9, 123.8, 123.2, 120.5, 118.6,
117.7, 115.9 (2JCF = 21.5 Hz), 97.2, 13.2, 12.8; IR (KBr, ν, cm−1) 3286,
1629, 1598, 1509, 1454, 1353, 1225; HRMS (ESI-TOF) m/z calcd for
C28H22FN6 461.1890 [M − H]−, found 461.1914.
4-(5-(4-Chlorophenyl)-3-methyl-1-(p-tolyl)-1,6-dihydropyrrolo-
[2,3-c]pyrazol-4-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine (5i).
1
White solid: 0.344 g, yield 68%; mp 286−289 °C; H NMR (400
4-(5-(4-Chlorophenyl)-3-methyl-1-phenyl-1,6-dihydropyrrolo[2,3-
c]pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5-amine (5c). White
MHz, DMSO-d6; δ, ppm) 11.45 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.55
(t, J = 7.2 Hz, 4H), 7.42 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 9.2 Hz, 4H),
4.90 (s, 2H), 2.35 (s, 6H), 2.28 (s, 3H), 1.77 (s, 3H); 13C NMR (100
MHz, DMSO-d6; δ, ppm) 147.0, 144.9, 140.9, 139.7, 137.6, 137.3,
135.4, 133.5, 133.1, 132.1, 131.1, 130.2, 129.9, 128.8, 128.7, 122.7,
118.9, 117.5, 101.9, 96.7, 21.0, 20.9, 13.4, 13.2; IR (KBr, ν, cm−1)
3339, 3079, 2919, 1614, 1562, 1521, 1348; HRMS (ESI-TOF) m/z
calcd for C30H26ClN6 505.1908 [M − H]−, found 505.1935.
1
solid: 0.325 g, yield 68%; mp 297−300 °C; H NMR (400 MHz,
DMSO-d6; δ, ppm) 11.52 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.69 (d, J
= 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.53−7.42 (m, 6H), 7.29 (t, J
= 7.6 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 4.99 (s, 2H), 2.30 (s, 3H), 1.79
(s, 3H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 147.4, 145.1, 141.0,
140.2, 140.0, 139.5, 133.0, 132.3, 131.2, 129.8, 129.5, 128.8, 128.7,
126.1, 124.4, 122.6, 119.0, 117.5, 101.9, 96.9, 13.4, 13.2; IR (KBr, ν,
cm−1) 3437, 2923, 1596, 1573, 1522, 1458, 1350, 1284; HRMS (ESI-
TOF) m/z calcd for C28H22ClN6 477.1595 [M − H]−, found
477.1614.
4-(5-(4-Bromophenyl)-3-methyl-1-(p-tolyl)-1,6-dihydropyrrolo-
[2,3-c]pyrazol-4-yl)-3-methyl-1-(p-tolyl)-1H-pyrazol-5-amine (5j).
1
White solid: 0.413 g, yield 75%; mp 296−298 °C; H NMR (400
MHz, CDCl3; δ, ppm) 8.61 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.43 (t, J
= 9.2 Hz, 4H), 7.30 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 4H), 3.69
(s, 2H), 2.42 (s, 3H), 2.38 (s, 6H), 2.04 (s, 3H); 13C NMR (100 MHz,
CDCl3; δ, ppm) 148.0, 142.1, 141.0, 140.6, 137.0, 134.7, 132.3, 132.0,
131.3, 131.1, 131.0, 130.2, 130.0, 127.5, 123.4, 120.7, 118.6, 117.9,
4-(5-(4-Bromophenyl)-3-methyl-1-phenyl-1,6-dihydropyrrolo[2,3-
c]pyrazol-4-yl)-3-methyl-1-phenyl-1H-pyrazol-5-amine (5d). White
1
solid: 0.371 g, yield 71%; mp >300 °C; H NMR (400 MHz, CDCl3;
δ, ppm) 8.30 (s, 1H), 7.67−7.61 (m, 4H), 7.51−7.45 (m, 6H), 7.34−
7.32 (m, 3H), 7.24−7.22 (m, 1H), 3.74 (s, 2H), 2.44 (s, 3H), 2.07 (s,
I
dx.doi.org/10.1021/jo500823z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
102.5, 96.8, 21.1, 21.0, 13.2, 12.8; IR (KBr, ν, cm−1) 3356, 3036, 1611,
1574, 1522, 1466, 1381, 1285; HRMS (ESI-TOF) m/z calcd for
C30H26BrN6 549.1403 [M − H]−, found 549.1391.
1H); 13C NMR (100 MHz, CDCl3; δ, ppm) 153.7, 147.2, 140.7, 139.6,
136.7, 133.2, 130.3, 129.5(5), 129.4(8), 129.4, 128.3, 126.7, 126.1,
124.5, 123.4, 118.1, 117.7, 98.0, 21.2, 9.3, 8.6, 8.2, 7.9, 7.3, 6.7; IR
(KBr, ν, cm−1) 3419, 1595, 1567, 1455, 1359, 1336; HRMS (ESI-
TOF) m/z calcd for C33H29N6 509.2454 [M − H]−, found 509.2475.
4-(5-(4-Chlorophenyl)-1-methyl-3-(thiophen-2-yl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-methyl-3-(thiophen-2-yl)-1H-
pyrazol-5-amine (5q). White solid: 0.363 g, yield 74%; mp >300 °C;
1H NMR (400 MHz, DMSO-d6; δ, ppm) 11.46 (s, 1H), 7.49−7.46
3-Methyl-4-(3-methyl-5-(4-nitrophenyl)-1-(p-tolyl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-(p-tolyl)-1H-pyrazol-5-amine
1
(5k). An red solid: 0.377 g, yield 73%; mp >300 °C; H NMR (400
MHz, DMSO-d6; δ, ppm) 11.62 (s, 1H), 8.22 (s, 2H), 7.83−7.78 (m,
4H), 7.55 (s, 2H), 7.33−7.30 (m, 4H), 5.02 (s, 2H), 2.37 (s, 6H), 2.31
(s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 146.9,
145.0, 141.8, 141.0, 140.2, 137.5, 137.1, 135.6, 133.9, 131.2, 130.2,
130.0, 126.9, 124.1, 122.9, 119.6, 117.8, 105.5, 96.2, 21.0, 20.9, 13.4,
13.1; IR (KBr, ν, cm−1) 3335, 2921, 1592, 1522, 1461, 1338, 1269;
HRMS (ESI-TOF) m/z calcd for C30H26N7O2 516.2148 [M − H]−,
found 516.2174.
(m, 2H), 7.36−7.34 (m, 2H), 7.23−7.22 (m, 1H), 7.16−7.15 (m, 1H),
6.82−6.80 (m, 1H), 6.75−6.73 (m, 2H), 6.61−6.60 (m, 1H), 4.97 (s,
2H), 3.92 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz, DMSO-d6; δ,
ppm) 147.2, 145.1, 143.1, 138.0, 137.8, 135.4, 133.5, 133.0, 131.1,
128.8, 127.8, 127.7, 127.4, 124.3, 124.2(5), 124.2, 122.9, 114.9, 101.5,
93.8, 36.1, 35.2; IR (KBr, ν, cm−1) 3372, 3068, 1699, 1632, 1582,
1540, 1498, 1381; HRMS (ESI-TOF) m/z calcd for C24H18ClN6S2
489.0723 [M − H]−, found 489.0711.
3-Methyl-4-(3-methyl-1,5-di-p-tolyl-1,6-dihydropyrrolo[2,3-c]-
pyrazol-4-yl)-1-(p-tolyl)-1H-pyrazol-5-amine (5l). White solid: 0.345
g, yield 71%; mp 275−277 °C; 1H NMR (400 MHz, CDCl3; δ, ppm)
8.47 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.34
(d, J = 7.6 Hz, 2H), 7.26−7.24 (m, 4H), 7.12 (d, J = 8.0 Hz), 3.65 (s,
2H), 2.43 (s, 3H), 2.38 (s, 6H), 2.34 (s, 3H), 2.07 (s, 3H); 13C NMR
(100 MHz, CDCl3; δ, ppm) 148.3, 142.7, 140.8, 140.4, 137.2, 136.7,
136.4, 134.5, 132.4, 130.5, 130.3, 130.1, 129.9, 129.6, 125.9, 123.3,
118.5, 117.8, 101.3, 97.4, 21.2, 21.1, 20.9, 13.2, 12.9; IR (KBr, ν, cm−1)
3334, 3025, 1614, 1595, 1521, 1381, 1348; HRMS (ESI-TOF) m/z
calcd for C31H29N6 485.2454 [M − H]−, found 485.2483.
4-(5-(4-Chlorophenyl)-3-cyclopropyl-1-phenyl-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-3-cyclopropyl-1-phenyl-1H-pyra-
zol-5-amine (5m). White solid: 0.345 g, yield 65%; mp 289−291 °C;
1H NMR (400 MHz, CDCl3; δ, ppm) 8.65 (s, 1H), 7.65 (d, J = 8.0 Hz,
2H), 7.56 (d, J = 8.0 Hz, 2H), 7.46−7.38 (m, 6H), 7.30−7.26 (m,
3H), 7.19 (t, J = 7.2 Hz, 1H), 3.66 (s, 2H), 2.10−2.03 (m, 1H), 1.75−
1.70 (m, 1H), 0.98−0.92 (m, 3H), 0.90−0.86 (m, 2H), 0.78−0.71 (m,
2H), 0.65−0.60 (m, 1H); 13C NMR (100 MHz, CDCl3; δ, ppm)
153.5, 147.3, 143.0, 141.0, 139.4, 132.5, 132.0, 131.7, 129.6, 129.4,
128.9, 127.5, 126.9, 124.7, 123.5, 118.2, 117.8, 97.4, 9.3, 8.6, 8.3, 8.2,
7.9, 7.3; IR (KBr, ν, cm−1) 3412, 1597, 1574, 1516, 1454, 1403, 1382;
HRMS (ESI-TOF) m/z calcd for C32H26ClN6 529.1908 [M − H]−,
found 529.1915.
4-(5-(4-Bromophenyl)-3-cyclopropyl-1-phenyl-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-3-cyclopropyl-1-phenyl-1H-pyra-
zol-5-amine (5n). White solid: 0.442 g, yield 77%; mp 296−298 °C;
1H NMR (400 MHz, CDCl3; δ, ppm) 8.65 (s, 1H), 7.65 (d, J = 8.0 Hz,
2H), 7.56 (d, J = 8.0 Hz, 2H), 7.46−7.42 (m, 6H), 7.35−7.29 (m,
3H), 7.19 (t, J = 7.6 Hz, 1H), 3.67 (s, 2H), 2.09−2.04 (m, 1H), 1.75−
1.71 (m, 1H), 0.99−0.93 (m, 3H), 0.90−0.87 (m, 2H), 0.81−0.71 (m,
2H), 0.65−0.60 (m, 1H); 13C NMR (100 MHz, CDCl3; δ, ppm)
153.5, 147.3, 142.9, 141.0, 139.5, 132.2, 131.9, 131.8, 129.5, 129.4,
127.7, 126.8, 124.7, 123.4, 120.6, 118.3, 117.8, 97.4, 9.3, 8.6, 8.3, 8.2,
7.9, 7.2; IR (KBr, ν, cm−1) 3423, 1598, 1518, 1454, 1407, 1380, 1352;
HRMS (ESI-TOF) m/z calcd for C32H26BrN6 573.1403 [M − H]−,
found 573.1385.
4-(5-(3,4-Dichlorophenyl)-1-methyl-3-(thiophen-2-yl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-methyl-3-(thiophen-2-yl)-1H-
pyrazol-5-amine (5r). White solid: 0.372 g, yield 71%; mp 251−252
1
°C; H NMR (400 MHz, DMSO-d6; δ, ppm) 11.57 (s, 1H), 7.70 (s,
1H), 7.54 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 4.8
Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.82 (t, J = 4.4 Hz, 1H), 6.77−6.75
(m, 2H), 6.62 (d, J = 3.6 Hz, 1H), 5.05 (s, 2H), 3.93 (s, 3H), 3.67 (s,
3H); 13C NMR (100 MHz, DMSO-d6; δ, ppm) 147.2, 145.2, 143.0,
137.8, 137.6, 135.6, 134.7, 132.0, 131.5, 131.0, 128.6, 127.8, 127.5,
127.4, 125.8, 124.5, 124.4, 124.3, 122.9, 115.0, 102.7, 93.2, 36.1, 35.2;
IR (KBr, ν, cm−1) 3369, 3078, 1695, 1622, 1583, 1541, 1498, 1385;
HRMS (ESI-TOF) m/z calcd for C24H17Cl2N6S2 523.0333 [M − H]−,
found 523.0321.
4-(5-(4-Bromophenyl)-1-methyl-3-(thiophen-2-yl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-methyl-3-(thiophen-2-yl)-1H-
pyrazol-5-amine (5s). White solid: 0.391 g, yield 73%; mp 258−260
°C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 11.47 (s, 1H), 7.48 (d, J
= 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 5.2 Hz, 1H), 7.16
(t, J = 2.8 Hz, 1H), 6.81 (s, 1H), 6.75−6.74 (m, 2H), 6.60 (s, 1H),
4.98 (s, 2H), 3.92 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz, DMSO-
d6; δ, ppm) 147.2, 145.1, 143.0, 137.9, 137.8, 135.4, 133.5, 133.3,
131.7, 128.0, 127.8, 127.4, 124.3, 124.2(5), 124.2(0), 122.9, 119.6,
115.0, 101.5, 93.8, 36.1, 35.2; IR (KBr, ν, cm−1) 3372, 1664, 1613,
1544, 1505, 1487, 1397, 1328; HRMS (ESI-TOF) m/z calcd for
C24H18BrN6S2 535.0198 [M − H]−, found 535.0174.
Methyl-4-(1-methyl-3-(thiophen-2-yl)-5-(p-tolyl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-3-(thiophen-2-yl)-1H-pyrazol-5-
1
amine (5t). White solid: 0.375 g, yield 70%; mp 265−267 °C; H
NMR (400 MHz, DMSO-d6; δ, ppm) 11.31 (s, 1H), 7.37 (d, J = 8.0
Hz, 2H), 7.22−7.20 (m, 1H), 7.15−7.14 (m, 1H), 7.07 (d, J = 8.4 Hz,
2H), 6.81−6.79 (m, 1H), 6.75−6.73 (m, 2H), 6.59−6.58 (m, 1H),
4.88 (s, 2H), 3.91 (s, 3H), 3.65 (s, 3H), 2.23 (s, 3H); 13C NMR (100
MHz, DMSO-d6; δ, ppm) 147.2, 144.9, 143.2, 138.1, 138.0, 135.9,
135.2, 135.0, 131.3, 129.4, 127.7, 127.4, 126.2, 124.1, 124.0, 122.9,
114.8, 100.1, 94.4, 36.1, 35.2, 21.1; IR (KBr, ν, cm−1) 3367, 1625,
1533, 1486, 1454, 1421, 1380; HRMS (ESI-TOF) m/z calcd for
C25H21N6S2 469.1269 [M − H]−, found 469.1285.
3-Cyclopropyl-4-(3-cyclopropyl-5-(4-nitrophenyl)-1-phenyl-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-phenyl-1H-pyrazol-5-amine
1
(5o). White solid: 0.384 g, yield 71%; mp >300 °C; H NMR (400
MHz, CDCl3; δ, ppm) 8.57 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.68−
7.59 (m, 6H), 7.51−7.46 (m, 4H), 7.36−7.31 (m, 1H), 7.26−7.22 (m,
1H), 3.78 (s, 2H), 2.09−2.04 (m, 1H), 1.72−1.68 (m, 1H), 1.03−0.99
(m, 3H), 0.94−0.90 (m, 2H), 0.80−0.74 (m, 2H), 0.65−0.59 (m, 1H);
13C NMR (100 MHz, CDCl3; δ, ppm) 142.4, 140.4, 139.9, 137.0,
136.5, 134.5, 134.0, 132.4, 128.9, 124.4, 124.3, 121.85, 120.6, 119.8,
119.0, 118.2, 112.8, 96.6, 3.9, 3.2(3), 3.2(0), 3.1, 2.9, 2.1; IR (KBr, ν,
cm−1) 3423, 1596, 1502, 1454, 1407, 1330; HRMS (ESI-TOF) m/z
calcd for C32H26N7O2 540.2148 [M − H]−, found 540.2165.
3-Cyclopropyl-4-(3-cyclopropyl-1-phenyl-5-(p-tolyl)-1,6-
dihydropyrrolo[2,3-c]pyrazol-4-yl)-1-phenyl-1H-pyrazol-5-amine
(5p). White solid: 0.388 g, yield 76%; mp 286−288 °C; 1H NMR (400
MHz, CDCl3; δ, ppm) 8.39 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.60 (d, J
= 7.6 Hz, 2H), 7.48−7.42 (m, 4H), 7.37 (d, J = 7.6 Hz, 2H), 7.29 (d, J
= 7.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 3.64
(s, 2H), 2.34 (s, 3H), 2.12−2.05 (m, 1H), 1.82−1.77 (m, 1H), 1.00−
0.93 (m, 3H), 0.92−0.87 (m, 2H), 0.83−0.73 (m, 2H), 0.68−0.61 (m,
Synthesis of (4-Bromophenyl)(6-(4-bromophenyl)-1,3-di-
methyl-5-(p-tolylamino)-1H-pyrazolo[3,4-b]pyridin-4-yl)-
methanone (7). Typically, 1-(4-bromophenyl)-2,2-dihydroxyetha-
none (1e; 2.0 mmol, 0.462 g, 2.0 equiv) was introduced into a 10
mL Initiator reaction vial, and then 1,3-dimethyl-1H-pyrazol-5-amine
(2a; 1.0 mmol, 0.111 g), p-toluidine (3a; 1.0 mmol, 0.107 g), p-TsOH
(1.0 mmol, 0.172 g), and 1.5 mL of DMF were then added
successively. Subsequently, the reaction vial was capped and then
prestirred for 20 s. The mixture was irradiated (time, 20 min;
temperature, 115 °C; absorption level, high; fixed hold time) until
TLC (petroleum ether/ethyl acetate 3/1) revealed that conversion of
the starting materials 1a and 3a was complete. After room
temperature, the reaction mixture was diluted with cold water (20
mL) and neutralized with 10% NaOH solution. The solid product was
collected by Buchner filtration and was purified by flash column
̈
chromatography (silica gel, petroleum ether (bp 60−90 °C)/ethyl
acetate mixtures) to afford the desired pure pyrazolo[3,4-b]pyridine 7.
J
dx.doi.org/10.1021/jo500823z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Yellow solid: 0.366 g, yield 62%; mp >300 °C; H NMR (400 MHz,
CDCl3; δ, ppm) 7.61 (d, J = 8.0 Hz, 2H), 7.49 (s, 5H), 7.47 (s, 1H),
6.79 (d, J = 8.0 Hz, 2H), 6.27 (d, J = 8.0 Hz, 2H), 5.14 (s, 1H), 4.15
(s, 3H), 2.18 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3; δ,
ppm) 193.8, 159.5, 155.1, 149.2, 144.6, 143.2, 141.0, 139.4, 137.1,
132.0, 131.5, 130.7, 130.7, 129.6, 129.4, 126.3, 123.6, 117.8, 115.4,
33.8, 20.5, 13.8. IR (KBr, ν, cm−1) 3374, 1666, 1583, 1513, 1347, 1258,
1205, 1070, 1009, 812, 798. HRMS (ESI-TOF) m/z calcd for
C28H21Br2N4O 589.0062 [M − H]−, found: 589.0044.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Figures and CIF files giving H and 13C NMR spectra of all
pure products and X-ray crystal data for 3c, 4a, 5b, and 7. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
AUTHOR INFORMATION
Corresponding Authors
■
*B.J.: e-mail, jiangchem@jsnu.edu.cn.
*S.-J.T.: fax, 86-516-83500065; e-mail, laotu@jsnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (Nos.
21332005, 21232004, 21272095, and 21102124), the PAPD of
Jiangsu Higher Education Institutions, Jiangsu Science and
Technology Support Program (No. BE2011045), the Qing-Lan
Project (12QLG006), the Robert A. Welch Foundation (D-
1361), and the NIH (R33DA031860) for partial support.
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T.; Kirsch, S. F. J. Org. Chem. 2011, 76, 2145−2156. (d) Shi, Q.-Q.;
Fu, L.-P.; Shi, Y.; Ding, H.-Q.; Luo, J.-H.; Jiang, B.; Tu, S.-J.
Tetrahedron Lett. 2013, 54, 3176−3179. (e) Li, Y.; Li, Q.-Y.; Xu, H.-
W.; Fan, W.; Jiang, B.; Wang, S.-L.; Tu, S.-J. Tetrahedron 2013, 69,
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