Facile three-component synthesis of macrocyclane-fused pyrazolo[3,4-b] pyridine derivatives

Article abstract of DOI:10.1002/ejoc.201100127

A series of new functionalized macrocyclane-fused pyrazolo[3,4-b]pyridine derivatives with an aryl group at the 2-position of the pyridine nucleus have been synthesized by microwave-assisted three-component reactions of aldehydes, aminopyrazole and cyclok

Full text of DOI:10.1002/ejoc.201100127

FULL PAPER
DOI: 10.1002/ejoc.201100127
Facile Three-Component Synthesis of Macrocyclane-Fused
Pyrazolo[3,4-b]pyridine Derivatives
Bo Jiang,*[a] Yin-Ping Liu,[a] and Shu-Jiang Tu*[a]
Keywords: Multicomponent reactions / Microwave reactions / Fused ring systems / Nitrogen heterocycles / Ketones
A series of new functionalized macrocyclane-fused pyra-
zolo[3,4-b]pyridine derivatives with an aryl group at the 2-
position of the pyridine nucleus have been synthesized by
microwave-assisted three-component reactions of aldehydes,
aminopyrazole and cycloketones in HOAc using 1.0 equiv. of
TFA as a promoter. The procedure is facile, avoiding time-
consuming and costly syntheses, tedious work-ups and puri-
fications of precursors as well as protection/deprotection of
functional groups. This method is very efficient due to short
reaction times and easy work-up and provides an efficient
and promising synthetic strategy for the construction of the
macrocyclane-fused pyrazolo[3,4-b]pyridine skeleton.
fertility.[10] They have also been reported as potent and se-
lective inhibitors of A1 adenosine receptors,[11] phosphodi-
esterase 4 (PDE4) inhibitors in immune and inflammatory
cells,[12] glycogen synthase kinase-3 (GSK-3) inhibitors[13]
and kinase inhibitors of p38 as anti-inflammatory drugs.[14]
Because of the biological activities they exhibit, these com-
pounds have distinguished themselves as heterocycles of
profound chemical and biological significance. Thus, the
preparation of these molecules has attracted considerable
attention.[15] Many pyrazolo[3,4-b]pyridines have been syn-
thesized through the reactions of 5-aminopyrazoles, alde-
hydes and appropriate cycloketones by various methods.[16]
However, most of these compounds are pyrazolo[3,4-b]pyr-
idines I or II (Figure 1) with the aryl group at the 4-position
of pyridine ring. Recently, Chebanov and co-workers syn-
thesized unexpected pyrazolopyridine III by similar three-
component reactions under strong basic conditions.[17] In
this reaction, the aryl group was also located at the 4-posi-
tion of the pyridine ring (Figure 1). To the best of our
knowledge, the regioselective construction of pyrazolopyr-
idines of type IV, macrocyclane-fused pyrazolo[3,4-b]pyr-
idines with an aryl group at the 2-position of the pyridine
nucleus, has not been reported.
Introduction
The use of combinatorial chemistry has tremendously
changed the theory and practice of the design and synthesis
of new substances for pharmaceutical research. Great effort
has been focused on synthesizing libraries of small hetero-
cyclic molecules because of their high degree of structural
diversity and widespread use as therapeutic agents.[1] How-
ever, the range of suitably functionalized heterocyclic build-
ing blocks for the synthesis of structurally diverse libraries
is rather limited. The development of new, rapid and clean
synthetic routes towards focused libraries of such com-
pounds is therefore of great importance to both medicinal
and synthetic chemists.[2] Undoubtedly, synthetic strategies
involving multicomponent reactions (MCRs) have mani-
fested themselves as powerful tools for the rapid introduc-
tion and expansion of molecular diversity.[3] Consequently,
the design and development of new MCR routes for the
generation of heterocycles attracts ever increasing inter-
est.[4,5]
Nitrogen-containing heterocycles are abundant in nature
and exhibit diverse and important biological properties.
The pyrazolo[3,4-b]pyridine system as a key heterocycle
represents the core skeleton of a pharmaceutically impor-
tant class of heterocyclic compounds that possess a broad
range of biological activities,[6] such as anxiolytic activity,[7]
and can be used in the inhibition of xanthine oxidases[8] and
cholesterol formation[9] and in the treatment of Alzheimer’s
disease, gastrointestinal diseases, anorexia nervosa, drug
and alcohol withdrawal symptoms, drug addiction and in-
Figure 1. Different substituent patterns in the condensation of 5-
aminopyrazoles, aldehydes and cycloketones.
[a] School of Chemistry and Chemical Engineering, Xuzhou
Normal University,
Xuzhou, 221116, P. R. China
Fax: +86-516-83500065
E-mail: laotu@xznu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100127.
In the past several years, our group and others have de-
veloped various multicomponent reactions (MCRs) that
provide easy access to useful functionalized multiple ring
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Macrocyclane-Fused Pyrazolo[3,4-b]pyridine Derivatives
structures of chemical and pharmaceutical interest.[18–21] promoter in this reaction, the yield of the product 4ad in-
For example, a new four-component domino reaction has creased from 72 to 88% at 140 °C (Table 1, entry 8;
been established that provides an easy access to the synthe- Scheme 2).
sis of multifunctionalized quinazoline derivatives.[18a] The
reaction is easily performed by simply mixing readily avail-
Table 1. Optimization of the conditions for the synthesis of 4ad.
able starting materials, aromatic aldehydes, cyclopentanone
and cyanoacetamide with K2CO3 in ethylene glycol, under
microwave (MW) irradiation. When aliphatic aldehydes re-
placed their aromatic counterparts in the above multicom-
ponent reaction, the reaction was found to proceed along
another pathway leading to the formation of multifunction-
alized tricyclo[6.2.2.01,6]dodecanes.[18b] Recently, we also
found that the multicomponent reaction of Meldrum’s acid,
aromatic aldehydes and electron-rich heteroarylamines in
aqueous solution under MW irradiation led to the multi-
functionalized spiro{[1,3]dioxane-pyridine}-4,6-dione with
high chemo-, regio- and stereoselectivity and good
yields.[18d]
Entry Solvent
TFA [equiv.] T [°C]
Time
[min]
Yield
[%][a]
1
2
3
4
5
6
7
8
CH3CN
DMF
ethylene glycol
HOAc
HOAc
HOAc
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
80
80
80
15
15
15
15
15
15
15
15
trace
11
19
33
47
51
72
88
80
100
120
140
140
HOAc
HOAc
[a] Isolated yield.
As a continuation of our research devoted to the devel-
opment of multicomponent reactions,[18–20] we report
herein another new three-component approach to the re-
gioselective construction of macrocyclane-fused pyr-
azolo[3,4-b]pyridine derivatives that are of chemical and
biomedical importance (Scheme 1). This reaction was
achieved by reacting aromatic aldehydes, aminopyrazole
and cycloketones as starting materials in acidic conditions
under microwave irradiation.
Scheme 2. Synthesis of macrocyclane-fused pyrazolo[3,4-b]pyr-
idines 4ad.
With this result in hand, we went on to study the scope
of the methodology. Using the optimized reaction condi-
tions, a variety of structurally diverse aromatic aldehydes
were investigated and a series of new macrocyclane-fused
pyrazolo[3,4-b]pyridines were afforded in good yields, with
Table 2. Three-component synthesis of products 4aa–4az.[a]
Entry
n
Product 4 Ar
Time Yield
[min] [%][b]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
3
3
3
3
3
7
7
7
7
7
7
7
7
7
7
7
7
7
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
phenyl (1a)
4-tolyl (1b)
12
14
15
11
12
14
12
15
13
12
11
14
13
12
11
13
12
11
12
14
13
15
13
12
13
77
80
86
80
70
88
70
76
76
75
85
85
76
75
70
70
88
72
88
72
78
70
78
82
80
80
4-methoxyphenyl (1c)
4-bromophenyl (1d)
2-chlorophenyl (1e)
3,4,5-trimethoxyphenyl (1f)
4-nitrophenyl (1g)
2-thienyl (1h)
Scheme 1. The synthesis of macrocyclane-fused pyrazolo[3,4-b]pyr-
idines.
9
phenyl (1a)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4aj
4ak
4al
2-chlorophenyl (1e)
3,4,5-trimethoxyphenyl (1f)
2-thienyl (1h)
2,3-dimethoxyphenyl (1i)
phenyl (1a)
4am
4an
4ao
4ap
4aq
4ar
4as
4at
4au
4av
4aw
4ax
4ay
4az
Results and Discussion
4-tolyl (1b)
We started this study by treating 4-bromobenzaldehyde
(1d) and cycloheptanone (2a) with 3-methyl-1-phenyl-1H-
pyrazol-5-amine (3a) in the presence of 0.5 equiv. of tri-
fluoroacetic acid (TFA) under microwave irradiation at
80 °C using different solvents, including acetonitrile, ethyl-
ene glycol, DMF and HOAc. Of these, HOAc proved to be
the best solvent (Table 1, entry 4). Subsequently, the reac-
tion was performed in HOAc and repeated many times at
different temperatures in a sealed vessel under microwave
irradiation for 15 min. The yield of the product 4ad in-
creased from 33 to 72% as the temperature was raised from
4-methoxyphenyl (1c)
4-bromophenyl (1d)
2-chlorophenyl (1e)
3,4,5-trimethoxyphenyl (1f)
4-nitrophenyl (1g)
2-thienyl (1h)
2,3-dimethoxyphenyl (1i)
4-chlorophenyl (1j)
4-fluorophenyl (1k)
3,4-dimethoxyphenyl (1l)
4-(dimethylamino)phenyl (1m) 14
[a] Reagents and conditions: TFA (1.0 equiv.), 140 °C, HOAc,
80 to 140 °C. When 1.0 equiv. of TFA was employed as a microwaves. [b] Isolated yield.
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B. Jiang, Y.-P. Liu, S.-J. Tu
FULL PAPER
the aryl group at the 2-position of the pyridine nucleus. As idines. The structures of cycloalka[d]pyrazolo[3,4-b]pyr-
1
shown in Table 2, at the beginning, we explored the alde- idines 4aa–4az were deduced from their IR, H NMR, 13C
hyde substrate scope, using cycloheptanone (2a) and 3- NMR and mass spectra. Furthermore, the structure of 4ao
methyl-1-phenyl-1H-pyrazol-5-amine (3a) as model sub- was further confirmed by single-crystal X-ray crystallogra-
strates (Table 2, entries 1–8). The results indicate that aro- phy (Figure 2).[22]
matic aldehydes bearing either electron-donating or -with-
To expand further the scope of the reaction, 3-amino-
drawing functional groups, such as nitro, bromo, chloro or 1H-pyrazol-5-ol (3b) was employed with cycloheptanone,
methoxy, were able to affect the synthesis of compound 4a. cyclooctanone and cyclododecanone (Scheme 3). Under the
Moreover, the heterocyclic aldehyde thiophene-2-carbal- above optimized conditions, all the reactions proceeded to
dehyde (Table 2, entry 8) still displayed high reactivity un- generate the corresponding macrocyclane-fused pyr-
der the standard conditions. Note that this result is signifi- azolo[3,4-b]pyridin-1-ol derivatives 4ba–4br in good-to-
cant because there is no literature precedent for the synthe- excellent yields (Table 3, entries 1–18).
sis of highly functionalized cyclohepta[d]pyrazolo[3,4-b]pyr-
idines.
To further expand the scope of the reaction, different
aldehydes and 3-methyl-1-phenyl-1H-pyrazol-5-amine (3a)
were used as substrates with cyclooctanone (2b) and cyclo-
dodecanone (2c). In all these cases, the reactions proceeded
smoothly to give the corresponding cycloocta- and cyclodo-
deca[d]pyrazolo[3,4-b]pyridines in good yields of 70–88%
Scheme 3. Synthesis of products 4ba–4br.
(Table 2, entries 9–26). Indeed, the protocol provides a
straightforward pathway for the construction of highly
functionalized macrocyclane-fused pyrazolo[3,4-b]pyr-
Table 3. Three-component synthesis of products 4ba–4br.[a]
Entry
n
Product Ar
Time
[min]
Yield
[%][b]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
3
3
3
3
3
3
7
7
7
7
7
4ba
4bb
4bc
4bd
4be
4bf
4bg
4bh
4bi
4bj
4bk
4bl
4bm
4bn
4bo
4bp
4bq
4br
4-tolyl (1b)
15
13
12
11
14
13
80
86
80
70
88
70
76
76
75
85
85
76
75
70
70
80
86
80
4-methoxyphenyl (1c)
4-bromophenyl (1d)
2-chlorophenyl (1e)
2-thienyl (1h)
2,3-dimethoxyphenyl (1i)
4-(dimethylamino)phenyl (1m) 12
4-tolyl (1b)
11
13
12
11
12
14
13
15
13
12
15
9
4-methoxyphenyl (1c)
4-bromophenyl (1d)
2-chlorophenyl (1e)
2-thienyl (1h)
3,4-dimethoxyphenyl (1l)
4-tolyl (1b)
2-chlorophenyl (1e)
2-thienyl (1h)
2,3-dimethoxyphenyl (1i)
3,4-dimethoxyphenyl (1l)
10
11
12
13
14
15
16
17
18
[a] Reagents and conditions: TFA (1.0 equiv.), 140 °C, HOAc,
microwaves. [b] Isolated yield.
Figure 2. X-ray crystallographic structure of product 4ao.
Scheme 4. Proposed mechanism for the formation of products 4a.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3026–3035

Macrocyclane-Fused Pyrazolo[3,4-b]pyridine Derivatives
monitored by TLC, the reaction mixture was cooled to room tem-
perature. The solid product was collected by Büchner filtration and
subsequently washed with ethanol to give the pure white solid
The formation of pyrazolo[3,4-b]pyridines I or II by
Knoevenagel-type condensation, intermolecular Michael
addition and intramolecular cyclization has been reported
previously.[16] Compared with compounds of type I or II,
pyrazolo[3,4-b]pyridines IV with different aryl substitution
patterns should be formed by another reaction process.
Based on an analysis of the literature and experimental re-
sults, we reasoned that the reaction occurred by a [4+2] cy-
cloaddition process. This type of [4+2] cycloaddition is well
(yield: 0.38 g, 88%), m.p. 202–205 °C. IR (KBr): ν = 3079, 2980,
˜
2918, 2850, 2843, 1582, 1507, 1414, 1382, 1305, 1252, 1205, 1136,
1108, 1070, 1008, 964, 839, 748, 685 cm–1 1H NMR (CDCl3,
.
400 MHz): δ = 8.34 (d, J = 8.0 Hz, 2 H, ArH), 7.62 (d, J = 8.0 Hz,
2 H, ArH), 7.49–7.43 (m, 4 H, ArH), 7.23 (t, J = 7.2 Hz, 1 H,
ArH), 3.36–3.33 (m, 2 H, CH2), 2.96–2.93 (m, 2 H, CH2), 2.82 (s,
3 H, CH3), 1.98–1.93 (m, 2 H, CH2), 1.86–1.80 (m, 2 H, CH2),
precedented.[23] Thus, a plausible mechanism for the forma- 1.72–1.63 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
157.1, 149.5, 149.1, 141.9, 140.7, 139.9, 31.2, 130.2, 128.9, 124.9,
122.2, 120.4, 115.1, 32.0, 30.1, 30.1, 27.8, 26.6, 16.4 ppm. HRMS
(ESI): calcd. for C24H23BrN3 432.1070; found 432.1072.
tion of the type IV compounds is proposed in Scheme 4.
Presumably, in the presence of HOAc, cycloketone 2 (cyclo-
heptanone, cycloctanone and cyclododecanone) is in equi-
librium with the enol form 2Ј. The condensed intermediate
A undergoes a [4+2] cycloaddition with the enol form 2Ј to
form intermediate B. The subsequent dehydration of B and
aromatization results in 4a. This type of reaction is similar
to the Povarov reaction.[24]
1-Methyl-3,5-diphenyl-3,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo-
[3,4-b]pyridine (4aa): White solid, m.p. 153–154 °C. IR (KBr): ν =
˜
3056, 3028, 2979, 2927, 2856, 1584, 1508, 1492, 1441, 1411, 1380,
1295, 1204, 1141, 969, 756, 692 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 8.38–8.35 (m, 2 H, ArH), 7.59–7.56 (m, 2 H, ArH), 7.52–7.44
(m, 5 H, ArH), 7.23–7.20 (m, 1 H, ArH), 3.36–3.34 (m, 2 H, CH2),
2.98–2.96 (m, 2 H, CH2), 2.82 (s, 3 H, CH3), 1.97–1.93 (m, 2 H,
CH2), 1.88–1.83 (m, 2 H, CH2), 1.72–1.67 (m, 2 H, CH2) ppm. 13
C
Conclusions
NMR (CDCl3, 100 MHz): δ = 158.5, 149.6, 148.8, 141.9, 141.8,
140.0, 130.4, 129.5, 128.9, 128.0, 127.8, 124.8, 120.4, 114.9, 32.1,
30.1, 27.9, 26.6, 16.4 ppm. HRMS (ESI): calcd. for C24H24N3
354.1965; found 354.1961.
We have reported herein a one-pot three-component het-
erocyclization reaction (aminopyrazole, cyclic ketones and
aldehydes) as an approach to the annulation of pyr-
azolo[3,4-b]pyridines with concomitant formation of three
new σ bonds. The reaction proceeds by a selective [4+2]
heterocyclization reaction to give pyrazolo[3,4-b]pyridines
in good yields, which shows that the synthetic route allows
us to build blocks of macrocyclane-fused pyrazolo[3,4-b]-
pyridine derivatives with a wide range of substituents. This
1-Methyl-3-phenyl-5-(p-tolyl)-3,6,7,8,9,10-hexahydrocyclohepta[d]-
pyrazolo[3,4-b]pyridine (4ab): White solid, m.p. 184–186 °C. IR
(KBr): ν = 2976, 2917, 2854, 1586, 1569, 1508, 1490, 1439, 1410,
˜
1379, 1296, 1253, 1201, 1137, 1107, 964, 918, 828, 793, 759,
692 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.35–8.33 (m, 2 H,
ArH), 7.46–7.41 (m, 4 H, ArH), 7.28 (d, J = 7.6 Hz, 2 H, ArH),
7.20–7.16 (m, 1 H, ArH), 3.33–3.30 (m, 2 H, CH2), 2.96–2.94 (m,
methodology is simple, practical and an alternative regiose- 2 H, CH2), 2.79 (s, 3 H, CH3), 2.44 (s, 3 H, CH3), 1.94–1.90 (m, 2
H, CH2), 1.84–1.79 (m, 2 H, CH2), 1.69–1.64 (m, 2 H, CH2) ppm.
13C NMR (CDCl3, 100 MHz): δ = 153.3, 144.3, 143.5, 136.6, 134.8,
133.8, 132.3, 125.2, 124.2, 123.6, 123.5, 119.5, 115.1, 109.6, 26.9,
24.9, 22.6, 21.4, 16.1, 11.1 ppm. HRMS (ESI): calcd. for
C25H25N3Na 390.1941; found 390.1938.
lective synthetic route to the formation of macrocyclane de-
rivatives in good yields under microwave irradiation. This
method is very efficient due to short reaction times and easy
work-up.
5-(4-Methoxyphenyl)-1-methyl-3-phenyl-3,6,7,8,9,10-hexahydro-
cyclohepta[d]pyrazolo[3,4-b]pyridine (4ac): White solid, m.p. 190–
Experimental Section
191 °C. IR (KBr): ν = 2973, 2915, 2855, 1583, 1509, 1414, 1370,
˜
General: Microwave irradiation was carried out with a Biotage ap-
paratus from Personal Chemistry, Uppsala, Sweden. Melting
points were determined in open capillaries. IR spectra were re-
corded with a FT-IR-Tensor 27 spectrometer using KBr pellets.
The 1H NMR spectra were recorded with a Bruker DPX 400 MHz
spectrometer in CDCl3 or [D6]DMSO (13C NMR, 100 MHz) with
the chemical shifts (δ) given in ppm relative to TMS as internal
standard. HRMS (ESI) were recorded with a microTOF-QII
HRMS/MS instrument (Bruker). The X-ray crystallographic analy-
sis was performed with a Siemens SMART CCD and a Siemens
P4 diffractometer.
1299, 1251, 1174, 1028, 965, 836, 752, 645 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 8.37 (dd, J1 = 1.2, J2 = 8.0 Hz, 2 H, ArH), 7.53 (d,
J = 8.8 Hz, 2 H, ArH), 7.49–7.45 (m, 2 H, ArH), 7.23–7.20 (m, 1
H, ArH), 7.03 (d, J = 4.8 Hz, 2 H, ArH), 3.91 (s, 3 H, OCH3),
3.35–3.32 (m, 2 H, CH2), 3.01–2.98 (m, 2 H, CH2), 2.81 (s, 3 H,
CH3), 1.97–1.93 (m, 2 H, CH2), 1.87–1.83 (m, 2 H, CH2), 1.73–
1.67 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.4,
158.2, 149.6, 148.8, 141.8, 140.0, 134.4, 130.9, 130.4, 128.9, 124.8,
120.4, 114.7, 113.5, 55.4, 32.1, 30.2, 30.1, 27.9, 26.7, 16.4 ppm.
HRMS (ESI): calcd. for C25H26N3O 384.2071; found 384.2071.
5-(2-Chlorophenyl)-1-methyl-3-phenyl-3,6,7,8,9,10-hexahydrocyclo-
Typical Procedure for the Preparation of 5-(4-Bromophenyl)-1-meth- hepta[d]pyrazolo[3,4-b]pyridine (4ae): White solid, m.p. 149–150 °C.
yl-3-phenyl-3,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo[3,4-b]-
pyridine (4ad): In a 10 mL Emrys reaction vial, 4-bromobenzalde-
IR (KBr): ν = 3057, 2970, 2923, 2854, 1583, 1507, 1440, 1412, 1383,
˜
1297, 1209, 1135, 1115, 1052, 963, 753, 690, 675 cm–1. 1H NMR
hyde (0.18 g, 1 mmol), cycloheptanone (0.12 g, 1 mmol), 3-methyl- (CDCl3, 400 MHz): δ = 8.32–8.30 (m, 2 H, ArH), 7.53–7.50 (m, 1
1-phenyl-1H-pyrazol-5-amine (0.17 g, 1 mmol), TFA (0.11 g,
1 mmol) and HOAc (2.0 mL) were mixed and stirred at room tem-
perature for 3 min. Then the mixture was heated for 15 min at
140 °C under microwave irradiation. The automatic stirring mode
helped to mix and uniformly heat the reactants. Upon completion,
H, ArH), 7.47–7.43 (m, 2 H, ArH), 7.41–7.36 (m, 3 H, ArH), 7.23–
7.19 (m, 1 H, ArH), 3.42–3.28 (m, 2 H, CH2), 2.83 (s, 3 H, CH3),
2.79–2.68 (m, 2 H, CH2), 1.93–1.85 (m, 3 H, CH2), 1.80–1.66 (m,
2 H, CH2), 1.53–1.46 (m, 1 H, CH2) ppm. 13C NMR (CDCl3,
100 MHz): δ = 156.1, 149.4, 148.4, 141.9, 140.7, 139.8, 133.2, 131.1,
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B. Jiang, Y.-P. Liu, S.-J. Tu
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130.8, 129.4, 129.1, 128.9, 126.6, 125.0, 120.6, 115.5, 32.2, 30.2,
30.1, 27.5, 26.5, 16.4 ppm. HRMS (ESI): calcd. for C24H23ClN3
388.1566; found 388.1579.
7.41–7.38 (m, 3 H, ArH), 7.21 (t, J = 7.2 Hz, 1 H, ArH), 3.38–3.32
(m, 1 H, CH2), 3.26–3.20 (m, 1 H, CH2), 2.83 (s, 3 H, CH3), 2.73–
2.67 (m, 1 H, CH2), 2.03–1.81 (m, 2 H, CH2), 1.71–1.31 (m, 7 H,
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 156.9, 149.6, 146.3,
141.9, 140.6, 139.8, 133.1, 130.7, 129.5, 129.1, 128.9, 128.2, 126.4,
125.0, 120.6, 115.2, 31.2, 30.4, 27.9, 26.8, 26.3, 25.9, 15.7 ppm.
HRMS (ESI): calcd. for C25H25ClN3 402.1732; found 402.1716.
1-Methyl-3-phenyl-5-(3,4,5-trimethoxyphenyl)-3,6,7,8,9,10-hexa-
hydrocyclohepta[d]pyrazolo[3,4-b]pyridine (4af): White solid, m.p.
172–173 °C. IR (KBr): ν = 2982, 2919, 2849, 1584, 1508, 1456,
˜
1413, 1384, 1237, 1170, 1130, 1006, 749, 689 cm–1 1H NMR
.
(CDCl3, 400 MHz): δ = 8.34 (d, J = 7.6 Hz, 2 H, ArH), 7.44 (t, J
= 8.0 Hz, 2 H, ArH), 7.20 (t, J = 7.6 Hz, 1 H, ArH), 6.77 (s, 2 H,
ArH), 3.93 (s, 3 H, OCH3), 3.90 (s, 6 H, OCH3), 3.34–3.32 (m, 2
H, CH2), 2.99–2.96 (m, 2 H, CH2), 2.79 (s, 3 H, CH3), 1.98–1.93
(m, 2 H, CH2), 1.86–1.82 (m, 2 H, CH2), 1.73–1.62 (m, 2 H,
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 158.2, 152.8, 149.3,
141.9, 139.8, 138.0, 137.1, 130.3, 128.9, 125.1, 120.7, 120.6, 115.0,
113.2, 106.8, 61.0, 56.2, 32.1, 30.2, 30.1, 27.9, 26.7, 16.3 ppm.
HRMS (ESI): calcd. for C27H30N3O3 444.2282; found 444.2268.
1-Methyl-3-phenyl-5-(3,4,5-trimethoxyphenyl)-6,7,8,9,10,11-hexahy-
dro-3H-cycloocta[d]pyrazolo[3,4-b]pyridine (4ak): White solid, m.p.
190–193 °C. IR (KBr): ν = 3059, 2958, 2924, 2856, 1597, 1579,
˜
1
1506, 1409, 1380, 1301, 1253, 1140, 1119, 1086, 755, 691 cm–1. H
NMR (CDCl3, 400 MHz): δ = 8.35 (d, J = 8.0 Hz, 2 H, ArH), 7.46
(t, J = 8.0 Hz, 2 H, ArH), 7.22 (t, J = 7.2 Hz, 1 H, ArH), 6.75 (s,
2 H, ArH), 3.96 (s, 3 H, OCH3), 3.91 (s, 6 H, OCH3), 3.29–3.26
(m, 2 H, CH2), 2.94–2.92 (m, 2 H, CH2), 2.83 (s, 3 H, CH3), 1.98–
1.90 (m, 2 H, CH2), 1.71–1.65 (m, 3 H, CH2), 1.53–1.43 (m, 3 H,
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.2, 152.8, 149.4,
146.4, 141.8, 139.9, 137.8, 137.6, 128.9, 128.0, 125.0, 120.5, 114.9,
106.6, 61.0, 56.3, 32.0, 31.1, 27.8, 27.2, 26.2, 15.7 ppm. HRMS
(ESI): calcd. for C28H32N3O3 458.2439; found 458.2432.
1-Methyl-5-(4-nitrophenyl)-3-phenyl-3,6,7,8,9,10-hexahydrocyclo-
hepta[d]pyrazolo[3,4-b]pyridine (4ag): Light-yellow solid, m.p. 216–
218 °C. IR (KBr): ν = 2972, 2917, 2850, 1581, 1515, 1507, 1412,
˜
1343, 1205, 1134, 1103, 967, 843, 759, 694 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 8.37–8.34 (m, 2 H, ArH), 8.32–8.29 (m, 2 H, ArH),
7.74–7.71 (m, 2 H, ArH), 7.49–7.45 (m, 2 H, ArH), 7.26–7.22 (m,
1 H, ArH), 3.38–3.36 (m, 2 H, CH2), 2.94–2.91 (m, 2 H, CH2),
2.83 (s, 3 H, CH3), 2.00–1.95 (m, 2 H, CH2), 1.89–1.84 (m, 2 H,
CH2), 1.73–1.67 (m, 2 H, CH2) ppm. 1 3C NMR (CDCl3,
100 MHz): δ = 155.8, 149.6, 149.4, 148.3, 147.5, 142.0, 140.6, 139.7,
130.5, 130.1, 129.0, 125.2, 123.3, 120.4, 115.5, 32.0, 30.1, 30.1, 27.8,
26.5, 16.3 ppm. HRMS (ESI): calcd. for C24H23N4O2 399.1816;
found 399.1819.
1-Methyl-3-phenyl-5-(2-thienyl)-6,7,8,9,10,11-hexahydro-3H-cyclo-
octa[d]pyrazolo[3,4-b]pyridine (4al): Grey solid, m.p. 137–139 °C.
IR (KBr): ν = 2920, 2850, 1594, 1574, 1505, 1408, 1297, 1252, 1138,
˜
826, 753, 691, 647 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.38 (d,
J = 8.0 Hz, 2 H, ArH), 7.54–7.50 (m, 3 H, 2ϫ ArH, thienyl-H),
7.26 (d, J = 7.6 Hz, 1 H, thienyl-H), 7.21–7.18 (m, 1 H, ArH), 7.05
(d, J = 3.2 Hz, 1 H, thienyl-H), 3.21–3.18 (m, 2 H, CH2), 2.87–2.84
(m, 2 H, CH2), 2.07 (s, 3 H, CH3), 2.00–1.89 (m, 2 H, CH2), 1.75–
1.58 (m, 2 H, CH2), 1.54–1.37 (m, 4 H, CH2) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 162.7, 149.4, 142.6, 140.0, 136.6, 136.2,
130.0, 128.9, 128.1, 126.9, 126.2, 125.0, 120.6, 115.7, 36.2, 32.5,
31.3, 27.6, 26.6,26.1, 13.4 ppm. HRMS (ESI): calcd. for C23H23N3S
374.1686; found 374.1685.
1-Methyl-3-phenyl-5-(2-thienyl)-3,6,7,8,9,10-hexahydrocyclohepta-
[d]pyrazolo[3,4-b]pyridine (4ah): Grey solid, m.p. 126–127 °C. IR
(KBr): ν = 3070, 2979, 2924, 2842, 1579, 1506, 1441, 1414, 1299,
˜
1
1229, 1205, 1135, 958, 904, 838, 756, 704, 693, 659, 633 cm–1. H
NMR (CDCl3, 400 MHz): δ = 8.42–8.40 (m, 2 H, ArH), 7.53–7.51
(m, 1 H, ArH), 7.49–7.47 (m, 2 H, ArH, thienyl-H), 7.33 (dd, J1 =
1.2, J2 = 4.0 Hz, 1 H, thienyl-H), 7.27–7.23 (m, 1 H, ArH), 7.15
(dd, J1 = 3.6, J2 = 7.6 Hz, 1 H, thienyl-H), 3.35–3.32 (m, 2 H,
CH2), 3.31–3.21 (m, 2 H, CH2), 2.79 (s, 3 H, CH3), 2.01–1.96 (m,
2 H, CH2), 1.87–1.76 (m, 4 H, CH2) ppm. 13C NMR (CDCl3,
100 MHz): δ = 150.9, 149.4, 149.3, 145.1, 141.9, 139.9, 130.0, 128.9,
127.5, 127.3, 127.2, 124.8, 120.1, 114.8, 32.0, 30.0, 29.7, 27.3, 26.7,
16.3 ppm. HRMS (ESI): calcd. for C22H22N3S 360.1529; found
360.1527.
5-(2,3-Dimethoxyphenyl)-1-methyl-3-phenyl-6,7,8,9,10,11-hexa-
hydro-3H-cycloocta[d]pyrazolo[3,4-b]pyridine (4am): White solid,
m.p. 168–171 °C. IR (KBr): ν = 2922, 2852, 1599, 1578, 1509, 1474,
˜
1414, 1352, 1260, 1126, 1071, 1056, 1010, 795, 761, 695, 676 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 8.36 (d, J = 8.0 Hz, 2 H, ArH),
7.43 (t, J = 8.0 Hz, 2 H, ArH), 7.21–7.14 (m, 2 H, ArH), 7.03 (d,
J = 7.6 Hz, 1 H, ArH), 6.91 (d, J = 7.2 Hz, 1 H, ArH), 3.96 (s, 3
H, OCH3), 3.68 (s, 3 H, OCH3), 3.36–3.30 (m, 1 H, CH2), 3.25–
3.18 (m, 1 H, CH2), 2.83 (s, 3 H, CH3), 2.80–2.73 (m, 2 H, CH2),
2.03–1.85 (m, 2 H, CH2), 1.64–1.54 (m, 1 H, CH2), 1.51–1.32 (m,
5 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 151.6, 147.6,
144.4, 141.2, 140.4, 136.6, 134.8, 131.6, 123.6, 123.6, 119.5, 118.4,
17.0, 115.1, 109.8, 106.7, 56.1, 50.6, 26.0, 25.3, 22.6, 21.8, 21.0,
20.8, 10.4 ppm. HRMS (ESI): calcd. for C27H30N3O2 428.2333;
found 428.2336.
1-Methyl-3,5-diphenyl-6,7,8,9,10,11-hexahydro-3H-cycloocta[d]-
pyrazolo[3,4-b]pyridine (4ai): White solid, m.p. 174–176 °C. IR
(KBr): ν = 3059, 2959, 2917, 2850, 1601, 1579, 1506, 1413, 1380,
˜
1251, 1136, 1080, 1030, 772, 748, 704, 688 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 8.35 (d, J = 8.0 Hz, 2 H, ArH), 7.54–7.43 (m, 7 H,
ArH), 7.21 (t, J = 7.2 Hz, 1 H, ArH), 3.29–3.26 (m, 2 H, CH2),
2.92–2.89 (m, 2 H, CH2), 2.83 (s, 3 H, CH3), 1.98–1.90 (m, 2 H,
CH2), 1.79–1.68 (m, 3 H, CH2), 1.59–1.47 (m, 3 H, CH2), 1.45–
1.37 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.5,
149.6, 146.2, 142.2, 141.8, 139.9, 129.0, 128.9, 127.9, 127.9, 127.7,
124.9, 120.4, 114.8, 31.4, 31.2, 29.7, 27.9, 26.9, 26.3, 26.0,
15.7 ppm. HRMS (ESI): calcd. for C25H26N3 368.2122; found
368.2126.
1-Methyl-3,5-diphenyl-6,7,8,9,10,11,12,13,14,15-decahydro-3H-
cyclododeca[d]pyrazolo[3,4-b]pyridine (4an): White solid, m.p. 186–
187 °C. IR (KBr): ν = 2925, 2849, 1600, 1572, 1505, 1410, 1378,
˜
1352, 1294, 1266, 1199, 1134, 1029, 909, 749, 699, 689, 671 cm–1.
1H NMR (CDCl3, 400 MHz): δ = 8.33–8.31 (m, 2 H, ArH), 7.54–
7.52 (m, 2 H, ArH), 7.50–7.42 (m, 5 H, ArH), 7.22–7.18 (m, 1 H,
ArH), 3.21–3.16 (m, 2 H, CH2), 2.84 (s, 1 H, CH2), 2.82 (s, 3 H,
CH3), 2.80 (s, 1 H, CH2), 1.94–1.85 (m, 2 H, CH2), 1.72–1.62 (m,
5-(2-Chlorophenyl)-1-methyl-3-phenyl-6,7,8,9,10,11-hexahydro-3H- 5 H, CH2), 1.59–1.50 (m, 3 H, CH2), 1.49–1.39 (m, 4 H, CH2),
cycloocta[d]pyrazolo[3,4-b]pyridine (4aj): White solid, m.p. 149–
1.35–1.27 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
150 °C. IR (KBr): ν = 3059, 2958, 2924, 2856, 1597, 1579, 1506, 160.4, 149.4, 146.0, 142.4, 141.8, 139.9, 128.9, 127.9, 127.7, 127.7,
˜
1435, 1409, 1301, 1253, 1140, 1086, 1031, 755, 691, 635, 509 cm–1. 124.9, 120.5, 115.5, 30.9, 30.4, 28.6, 28.3, 28.2, 27.8, 27.7, 27.1,
1H NMR (CDCl3, 400 MHz): δ = 8.30 (d, J = 8.4 Hz, 2 H, ArH),
26.8, 22.5, 22.5, 15.5 ppm. HRMS (ESI): calcd. for C29H34N3
7.52 (d, J = 6.0 Hz, 1 H, ArH), 7.44 (t, J = 8.0 Hz, 2 H, ArH), 424.2748; found 424.2740.
3030
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3026–3035

Macrocyclane-Fused Pyrazolo[3,4-b]pyridine Derivatives
1-Methyl-3-phenyl-5-(p-tolyl)-6,7,8,9,10,11,12,13,14,15-decahydro-
3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4ao): White solid, m.p.
(s, 2 H, ArH), 3.93 (s, 3 H, OCH3), 3.88 (s, 6 H, OCH3), 3.18–3.14
(m, 2 H, CH2), 2.80 (s, 3 H, CH3), 2.84–2.81 (m, 1 H, CH2), 1.91–
1.84 (m, 2 H, CH2), 1.68–1.43 (m, 13 H, CH2), 1.40–1.33 (m, 2 H,
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 160.0, 152.8, 149.2,
146.2, 141.8, 139.8, 137.8, 128.9, 127.7, 125.0, 120.6, 120.6, 115.6,
203–204 °C. IR (KBr): ν = 2922, 2900, 2866, 2845, 1597, 1578,
˜
1564, 1504, 1487, 1411, 1379, 1357, 1115, 812, 761, 692 cm–1. 1H
NMR (CDCl3, 400 MHz): δ = 8.30 (d, J = 7.6 Hz, 2 H, ArH),
7.43–7.39 (m, 4 H, ArH), 7.26 (s, 1 H, ArH), 7.24 (s, 1 H, ArH), 113.2, 106.4, 61.0, 56.3, 31.0, 30.4, 29.1, 28.3, 28.3, 27.8, 27.7, 27.1,
7.17 (t, J = 7.6 Hz, 1 H, ArH), 3.17–3.13 (m, 2 H, CH2), 2.82–2.79 22.6, 22.5, 15.5 ppm. HRMS (ESI): calcd. for C32H40N3O3
(m, 1 H, CH2), 2.79 (s, 3 H, CH3), 2.44 (s, 3 H, CH3), 1.92–1.82 514.3065; found 514.3060.
(m, 2 H, CH2), 1.76–1.72 (m, 2 H, CH2), 1.72–1.68 (m, 4 H, CH2),
1-Methyl-5-(4-nitrophenyl)-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4at): Pale-yel-
1.64–1.38 (m, 7 H, CH2), 1.35–1.27 (m, 2 H, CH2) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 155.2, 144.1, 140.7, 136.5, 134.7, 134.2,
132.1, 123.6, 123.5, 123.4, 122.6, 119.6, 115.2, 112.7, 110.2, 25.1,
23.4, 23.1, 23.0, 22.6, 22.5, 21.8, 21.6, 17.4, 17.3, 16.1, 10.2 ppm.
HRMS (ESI): calcd. for C30H36N3 438.2904; found 438.2919.
low solid, m.p. 221–224 °C. IR (KBr): ν = 2928, 2857, 1599, 1578,
˜
1571, 1507, 1416, 1347, 1132, 864, 854, 753, 691 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 8.36 (d, J = 8.8 Hz, 2 H, ArH), 8.26 (d, J
= 8.8 Hz, 2 H, ArH), 7.71 (d, J = 8.8 Hz, 2 H, ArH), 7.45 (t, J =
5-(4-Methoxyphenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15- 8.0 Hz, 2 H, ArH), 7.23 (t, J = 7.2 Hz, 1 H, ArH), 3.22–3.18 (m,
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4ap): White
2 H, CH2), 2.83 (s, 3 H, CH3), 2.81–2.78 (m, 1 H, CH2), 1.94–1.85
(m, 2 H, CH2), 1.72–1.63 (m, 4 H, CH2), 1.63–1.49 (m, 5 H, CH2),
1.48–1.44 (m, 2 H, CH2), 1.41–1.37 (m, 2 H, CH2), 1.35–1.30 (m,
solid, m.p. 212–217 °C. IR (KBr): ν = 2933, 2919, 2864, 2844, 1575,
˜
1
1519, 1506, 1411, 1380, 1291, 1251, 1175, 1032, 753, 688 cm–1. H
NMR (CDCl3, 400 MHz): δ = 8.30 (d, J = 7.6 Hz, 2 H, ArH), 7.46 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 157.7, 149.1,
(d, J = 7.6 Hz, 2 H, ArH), 7.42 (t, J = 7.6 Hz, 2 H, ArH), 7.18 (t, 148.8, 147.4, 146.8, 141.9, 139.6, 130.0, 128.9, 127.3, 125.2, 123.4,
J = 6.8 Hz, 1 H, ArH), 6.98 (d, J = 7.2 Hz, 2 H, ArH), 3.89 (s, 3 120.5, 116.1, 31.0, 30.4, 28.8, 28.2, 28.1, 27.7, 27.7, 27.0, 26.6, 22.4,
H, OCH3), 3.18–3.13 (m, 1 H, CH2), 2.86–2.81 (m, 1 H, CH2), 2.79 15.5 ppm. HRMS (ESI): calcd. for C29H33N4O2 469.2599; found
(s, 3 H, CH3), 1.90–1.83 (m, 1 H, CH2), 1.67–1.61 (m, 4 H, CH2), 469.2600.
1.60–1.56 (m, 5 H, CH2), 1.55–1.48 (m, 3 H, CH2), 1.47–1.38 (m,
1-Methyl-3-phenyl-5-(2-thienyl)-6,7,8,9,10,11,12,13,14,15-deca-
3 H, CH2), 1.34–1.29 (m, 2 H, CH2) ppm. 13C NMR (CDCl3,
hydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4au): White solid,
100 MHz): δ = 159.2, 145.9, 141.8, 139.9, 134.9, 130.1, 128.9, 27.9,
m.p. 180–181 °C. IR (KBr): ν = 2921, 2861, 2842, 1575, 1505, 1409,
˜
126.7, 124.8, 120.5, 115.4, 113.4, 55.3, 31.0, 30.4, 28.6, 28.3, 28.2,
27.8, 27.7, 27.0, 26.8, 22.6, 15.5 ppm. HRMS (ESI): calcd. for
C30H36N3O 454.2853; found 454.2833.
1
1380, 1231, 1130, 905, 852, 751, 705, 691 cm–1. H NMR (CDCl3,
400 MHz): δ = 8.38–8.36 (m, 2 H, ArH), 7.50–7.48 (m, 3 H, ArH),
7.46–7.44 (m, 2 H, thienyl-H), 7.24–7.20 (m, 1 H, ArH), 7.14–7.11
(m, 1 H, thienyl-H), 3.16–3.12 (m, 2 H, CH2), 3.10–3.05 (m, 2 H,
CH2), 2.77 (s, 3 H, CH3), 1.85–1.84 (m, 2 H, CH2), 1.75–1.68 (m,
2 H, CH2), 1.69–1.62 (m, 4 H, CH2), 1.61–1.63 (m, 2 H, CH2),
1.57–1.50 (m, 6 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
5-(4-Bromophenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4aq): White
solid, m.p. 218–220 °C. IR (KBr): ν = 2929, 2864, 2849, 1594, 1576,
˜
1
1506, 1415, 1382, 1352, 1124, 1012, 752, 689, 619 cm–1. H NMR
(CDCl3, 400 MHz): δ = 8.26 (d, J = 7.6 Hz, 2 H, ArH), 7.59 (d, J 151.9, 149.0, 146.6, 145.8, 141.9, 139.8, 128.9, 127.6, 127.5, 127.2,
= 8.0 Hz, 2 H, ArH), 7.44–7.38 (m, 4 H, ArH), 7.19 (t, J = 7.6 Hz, 126.7, 124.9, 120.2, 115.6, 113.2, 30.1, 28.4, 28.2, 28.2, 27.8, 27.5,
1 H, ArH), 3.18–3.14 (m, 2 H, CH2), 2.79 (s, 3 H, CH3), 2.79–2.76 27.4, 26.8, 22.5, 22.4, 15.4 ppm. HRMS (ESI): calcd. for C27H32N3
(m, 1 H, CH2), 1.90–1.82 (m, 2 H, CH2), 1.74–1.61 (m, 6 H, CH2), 430.2312; found 430.2293.
1.57–1.29 (m, 9 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
5-(2,3-Dimethoxyphenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,
159.0, 156.7, 149.2, 146.3, 141.8, 141.3, 139.8, 131.2, 130.6, 128.9,
14,15-decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4av):
127.6, 125.0, 122.0, 120.5, 115.7, 31.0, 30.4, 28.7, 28.3, 28.2, 27.8,
White solid, m.p. 180–181 °C. IR (KBr): ν = 2929, 2860, 2843,
˜
27.7, 27.0, 26.7, 22.5, 22.5, 15.5 ppm. HRMS (ESI): calcd. for
C29H33BrN3 502.1853; found 502.1828.
1568, 1507, 1475, 1412, 1380, 1360, 1265, 1227, 1126, 1074, 1054,
1
1011, 748, 689 cm–1. H NMR (CDCl3, 400 MHz): δ = 8.32–8.30
5-(2-Chlorophenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4ar): White
(m, 2 H, ArH), 7.42–7.38 (m, 2 H, ArH), 7.18–7.12 (m, 2 H, ArH),
7.01–6.99 (m, 1 H, ArH), 6.91–6.89 (m, 1 H, ArH), 3.94 (s, 3 H,
OCH3), 3.64 (s, 3 H, OCH3), 3.24–3.07 (m, 2 H, CH2), 2.80 (s, 3
H, CH3), 2.77–2.73 (m, 1 H, CH2), 2.64–2.54 (m, 1 H, CH2), 1.90–
1.82 (m, 2 H, CH2), 1.67–1.37 (m, 12 H, CH2), 1.27–1.25 (m, 2 H,
CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 157.9, 152.7, 149.4,
146.4, 145.4, 141.8, 140.0, 136.9, 129.0, 128.8, 124.8, 123.6, 122.6,
120.4, 115.8, 111.9, 61.4, 55.8, 30.4, 28.5, 28.4, 28.2, 27.8, 27.8,
27.2, 26.8, 22.4, 22.3, 15.5 ppm. HRMS (ESI): calcd. for
C31H38N3O2 484.2959; found 484.2958.
solid, m.p. 183–184 °C. IR (KBr): ν = 2921, 2844, 1598, 1576, 1567,
˜
1505, 1411, 1353, 1136, 1118, 757, 691 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 8.25 (d, J = 8.0 Hz, 2 H, ArH), 7.49–7.47 (m, 1 H,
ArH), 7.43–7.37 (m, 5 H, ArH), 7.19–7.16 (t, J = 7.2 Hz, 1 H,
ArH), 3.26–3.17 (m, 1 H, CH2), 3.16–3.08 (m, 1 H, CH2), 2.80 (s,
3 H, CH3), 2.53–2.45 (m, 1 H, CH2), 1.98–1.78 (m, 2 H, CH2),
1.72–1.57 (m, 5 H, CH2), 1.51–1.36 (m, 8 H, CH2), 1.30–1.22 (m,
2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 157.8, 149.2,
148.0, 146.0, 141.8, 140.6, 139.7, 133.0, 130.9, 129.4, 129.1, 128.9,
128.4, 126.4, 125.1, 120.7, 116.0, 31.0, 30.4, 28.5, 28.4, 28.1, 27.8,
27.2, 26.7, 22.4, 22.2, 15.4 ppm. HRMS (ESI): calcd. for
C29H33ClN3 458.2358; found 458.2355.
5-(4-Chlorophenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4aw): White
solid, m.p. 225–226 °C. IR (KBr): ν = 2929, 2859, 1598, 1566, 1505,
˜
1414, 1381, 1353, 1130, 1116, 747, 687, 619 cm–1 1H NMR
.
1-Methyl-3-phenyl-5-(3,4,5-trimethoxyphenyl)-6,7,8,9,10,11,12,13, (CDCl3, 400 MHz): δ = 8.27 (d, J = 8.0 Hz, 2 H, ArH), 7.47–7.40
14,15-decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4as):
White solid, m.p. 205–208 °C. IR (KBr): ν = 2929, 2860, 2842,
(m, 6 H, ArH), 7.19 (t, J = 7.2 Hz, 1 H, ArH), 3.18–3.14 (m, 2 H,
CH2), 2.79 (s, 3 H, CH3), 2.79–2.76 (m, 1 H, CH2), 1.90–1.82 (m,
˜
1583, 1507, 1412, 1379, 1238, 1170, 1130, 1001, 826, 750, 691 cm–1. 2 H, CH2), 1.68–1.58 (m, 6 H, CH2), 1.53–1.37 (m, 7 H, CH2),
1H NMR (CDCl3, 400 MHz): δ = 8.30 (d, J = 8.0 Hz, 2 H, ArH),
1.33–1.28 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
7.43 (t, J = 8.0 Hz, 2 H, ArH), 7.19 (t, J = 7.6 Hz, 1 H, ArH), 6.73 159.0, 149.3, 146.3, 141.8, 140.8, 139.8, 133.7, 130.3, 128.9, 128.2,
Eur. J. Org. Chem. 2011, 3026–3035
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3031

B. Jiang, Y.-P. Liu, S.-J. Tu
FULL PAPER
127.6, 125.0, 120.5, 115.7, 31.0, 30.4, 28.7, 28.3, 28.1, 27.8, 27.7,
27.0, 26.7, 22.5, 22.5, 15.5 ppm. HRMS (ESI): calcd. for
C29H33ClN3 458.2358; found 458.2342.
1290, 1249, 1189, 1035, 959, 877, 828, 814, 638, 589 cm–1. 1H NMR
([D6]DMSO, 400 MHz): δ = 11.70 (s, 1 H, NH), 7.19 (d, J = 8.8 Hz,
2 H, ArH), 7.00 (d, J = 8.8 Hz, 2 H, ArH), 3.82 (s, 3 H, OCH3),
3.05–3.03 (m, 2 H, CH2), 2.64–2.61 (m, 2 H, CH2), 1.83–1.73 (m,
2 H, CH2), 1.73–1.63 (m, 2 H, CH2), 1.57–1.47 (m, 2 H, CH2) ppm.
HRMS (ESI): calcd. for C18H20N3O2 310.1551; found 310.1550.
5-(4-Fluorophenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4ax): White
solid, m.p. 173–174 °C. IR (KBr): ν = 2928, 2859, 2848, 1599, 1577,
˜
1504, 1414, 1380, 1356, 1294, 1226, 1157, 1117, 845, 820, 746,
687 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.31–8.28 (m, 2 H,
ArH), 7.53–7.49 (m, 2 H, ArH), 7.47–7.43 (m, 2 H, ArH), 7.23–
7.14 (m, 3 H, ArH), 3.20–3.16 (m, 2 H, CH2), 2.82 (s, 3 H, CH3),
2.82–2.79 (m, 1 H, CH2), 1.94–1.84 (m, 2 H, CH2), 1.67–1.33 (m,
15 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 163.7, 161.2,
159.3, 149.3, 146.2, 141.8, 139.8, 138.4, 138.4, 130.6, 130.6, 128.9,
127.7, 125.0, 120.5, 115.6, 115.0, 114.8, 30.9, 30.4, 28.6, 28.3, 28.2,
27.8, 27.7, 27.0, 26.8, 22.5, 15.4 ppm. HRMS (ESI): calcd. for
C29H33FN3 442.2654; found 442.2646.
5-(4-Bromophenyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo-
[3,4-b]pyridin-1-ol (4bc): White solid, m.p. Ͼ300 °C. IR (KBr): ν =
˜
3048, 2923, 2853, 1596, 1540, 1504, 1393, 1349, 1271, 1252, 1190,
1072, 1011, 961, 878, 820, 810, 634 cm–1. 1H NMR ([D6]DMSO,
400 MHz): δ = 11.77 (s, 1 H, NH), 10.41 (s, 1 H, OH), 7.64 (d, J
= 8.4 Hz, 2 H, ArH), 7.22 (d, J = 8.4 Hz, 2 H, ArH), 3.06–3.04
(m, 2 H, CH2), 2.59–2.57 (m, 2 H, CH2), 1.83–1.73 (m, 2 H, CH2),
1.72–1.68 (m, 2 H, CH2), 1.57–1.47 (m, 2 H, CH2) ppm. HRMS
(ESI): calcd. for C17H17BrN3O 358.0550; found 358.0541.
5-(2-Chlorophenyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo-
5-(3,4-Dimethoxyphenyl)-1-methyl-3-phenyl-6,7,8,9,10,11,12,13,
14,15-decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridine (4ay):
[3,4-b]pyridin-1-ol (4bd): White solid, m.p. Ͼ300 °C. IR (KBr): ν =
˜
3137, 2925, 2856, 1589, 1543, 1439, 1398, 1280, 1252, 1218, 1184,
1053, 959, 878, 815, 749, 637 cm–1 1H NMR ([D6]DMSO,
.
White solid, m.p. 182–183 °C. IR (KBr): ν = 2927, 2902, 2864,
˜
2842, 1600, 1576, 1566, 1508, 1412, 1381, 1354, 1255, 1230, 1167,
1138, 1021, 851, 814, 756, 690 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 8.34 (d, J = 7.6 Hz, 2 H, ArH), 7.44 (t, J = 1.6 Hz, 2 H, ArH),
7.20 (t, J = 7.6 Hz, ArH), 7.13–7.09 (m, 2 H, ArH), 6.98 (d, J =
8.4 Hz, 2 H, ArH), 3.98 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 3.20–
3.16 (m, 2 H, CH2), 2.87–2.83 (m, 2 H, CH2), 2.81 (s, 3 H, CH3),
1.90–1.88 (m, 2 H, CH2), 1.71–1.63 (m, 4 H, CH2), 1.63–1.57 (m,
2 H, CH2), 1.55–1.51 (m, 2 H, CH2), 1.40–1.42 (m, 4 H, CH2),
1.39–1.31 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ =
160.0, 149.3, 148.7, 148.3, 146.0, 141.8, 139.9, 135.2, 128.9, 127.8,
124.9, 121.3, 120.4, 115.4, 112.5, 110.7, 56.0, 56.0, 30.4, 28.8, 28.3,
27.8, 27.7, 27.1, 27.0, 22.5, 15.5 ppm. HRMS (ESI): calcd. for
C31H38N3O2 484.2959; found 484.2959.
400 MHz): δ = 11.76 (s, 1 H, NH), 10.31 (s, 1 H, OH), 7.57–7.54
(m, 1 H, ArH), 7.46–7.38 (m, 2 H, ArH), 7.26–7.24 (m, 1 H, ArH),
3.12–3.00 (m, 2 H, CH2), 2.48–2.42 (m, 2 H, CH2), 1.78–1.58 (m,
4 H, CH2), 1.56–1.40 (m, 2 H, CH2) ppm. 13C NMR ([D6]DMSO,
100 MHz): δ = 164.6, 154.6, 153.5, 151.3, 139.5, 135.4, 132.0, 130.6,
129.4, 128.9, 127.2, 126.7, 101.4, 31.3, 28.5, 27.7, 26.4 ppm. HRMS
(ESI): calcd. for C17H17ClN3O 314.1055; found 314.1062.
5-(2-Thienyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo[3,4-b]-
pyridin-1-ol (4be): Brown solid, m.p. Ͼ300 °C. IR (KBr): ν = 3109,
˜
2924, 2854, 1590, 1541, 1451, 1386, 1268, 1250, 1174, 961, 876,
829, 795, 724, 709 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ =
11.83 (s, 1 H, NH), 10.39 (s, 1 H, OH), 7. 70 (dd, J1 = 0.8, J2 =
5.2 Hz, 1 H, thienyl-H), 7. 16 (dd, J1 = 3.2, J2 = 5.2 Hz, 1 H,
thienyl-H), 7. 06 (dd, J1 = 0.8, J2 = 3.6 Hz, 1 H, thienyl-H), 3.07–
3.04 (m, 2 H, CH2), 2.73–2.71 (m, 2 H, CH2), 1.84–1.74 (m, 2 H,
CH2), 1.72–1.62 (m, 2 H, CH2), 1.59–1.50 (m, 2 H, CH2) ppm.
HRMS (ESI): calcd. for C15H16N3OS 286.1009; found 286.1008.
N,N-Dimethyl-4-(1-methyl-3-phenyl-6,7,8,9,10,11,12,13,14,15-
decahydro-3H-cyclododeca[d]pyrazolo[3,4-b]pyridin-5-yl)aniline
(4az): White solid, m.p. 246–249 °C. IR (KBr): ν = 2919, 2900,
˜
2859, 2843, 1612, 1569, 1524, 1505, 1408, 1361, 1269, 1205, 1132,
1029, 815, 755, 692, 640 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
8.36 (dd, J1 = 0.8, J2 = 8.0 Hz, 2 H, ArH), 7.48 (dd, J1 = 0.8, J2
= 7.2 Hz, 2 H, ArH), 7.23–7.20 (m, 1 H, ArH), 7.14 (d, J = 8.0 Hz,
2 H, ArH), 6.82 (s, 2 H, ArH), 3.05 (s, 6 H, NCH3), 3.00–2.95 (m,
2 H, CH2), 2.69–2.65 (m, 2 H, CH2), 2.11–2.04 (m, 2 H, CH2), 1.94
(s, 3 H, CH3), 1.66–1.60 (m, 2 H, CH2), 1.57–1.50 (m, 4 H, CH2),
1.48–1.42 (m, 6 H, CH2), 1.33–1.27 (m, 2 H, CH2) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 161.5, 152.2, 142.6, 141.5, 140.5, 140.0,
138.2, 137.2, 134.8, 133.1, 131.7, 129.3, 129.3, 129.1, 129.0, 128.6,
125.1, 124.3, 120.8, 115.3, 31.0, 29.5, 26.8, 21.4, 21.4, 15.0 ppm.
HRMS (ESI): calcd. for C31H39N4 467.3170; found 467.3164.
5-(2,3-Dimethoxyphenyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]-
pyrazolo[3,4-b]pyridin-1-ol (4bf): Pink solid, m.p. 262–263 °C. IR
(KBr): ν = 3109, 2933, 2854, 1594, 1545, 1473, 1425, 1349, 1264,
˜
1231, 1196, 1174, 1060, 1001, 958, 879, 813, 771 cm–1. 1H NMR
([D6]DMSO, 400 MHz): δ = 11.62 (s, 1 H, NH), 7.11–7.06 (m, 2
H, ArH), 6.63 (dd, J1 = 2.4, J2 = 6.4 Hz, 1 H, ArH), 3.85 (s, 3 H,
OCH3), 3.46 (s, 3 H, OCH3), 3.10–2.98 (m, 2 H, CH2), 2.50–2.47
(m, 2 H, CH2), 1.81–1.67 (m, 3 H, CH2), 1.66–1.57 (m, 1 H, CH2),
1.55–1.45 (m, 1 H, CH2), 1.43–1.35 (m, 1 H, CH2) ppm. HRMS
(ESI): calcd. for C19H22N3O3 340.1656; found 340.1671.
5-[4-(Dimethylamino)phenyl]-2,6,7,8,9,10-hexahydrocyclohepta-
[d]pyrazolo[3,4-b]pyridin-1-ol (4bg): Yellow solid, m.p. Ͼ300 °C. IR
5-(p-Tolyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo[3,4-b]-
pyridin-1-ol (4ba): Pink solid, m.p. Ͼ300 °C. IR (KBr): ν = 3189,
˜
(KBr): ν = 3042, 2911, 2852, 1611, 1594, 1541, 1524, 1441, 1400,
˜
3141, 3055, 2948, 2923, 2854, 2683, 1596, 1542, 1394, 1274, 1190,
960, 877, 819, 637 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ =
11.71 (s, 1 H, NH), 10.30 (s, 1 H, OH), 7.24 (d, J = 7.6 Hz, 2 H,
ArH), 7.14 (d, J = 8.0 Hz, 2 H, ArH), 3.05–3.03 (m, 2 H, CH2),
2.61–2.59 (m, 2 H, CH2), 2.37 (s, 3 H, CH3), 1.82–1.77 (m, 2 H,
1350, 1273, 1225, 1182, 959, 875, 837, 812, 728, 636 cm–1. 1H NMR
([D6]DMSO, 400 MHz): δ = 11.63 (s, 1 H, NH), 10.45 (s, 1 H, OH),
7.10 (d, J = 8.4 Hz, 2 H, ArH), 6.77 (d, J = 8.8 Hz, 2 H, ArH),
3.04–3.01 (m, 2 H, CH2), 2.96 (s, 6 H, NCH3), 2.68–2.66 (m, 2 H,
CH2), 1.83–1.74 (m, 2 H, CH2), 1.72–1.64 (m, 2 H, CH2), 1.59–1.51
(m, 2 H, CH2) ppm. HRMS (ESI): calcd. for C19H23N4O 323.1867;
found 323.1842.
CH2), 1.74–1.64 (m, 2 H, CH2), 1.56–1.47 (m, 2 H, CH2) ppm. 13
C
NMR ([D6]DMSO, 100 MHz): δ = 164.6, 154.7, 151.3, 142.9,
136.6, 133.1, 129.1, 128.2, 127.1, 112.7, 101.2, 31.3, 28.2, 28.1, 26.5,
20.8 ppm. HRMS (ESI): calcd. for C18H20N3O 294.1601; found
294.1609.
5-(p-Tolyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta[d]pyrazolo[3,4-
b]pyridin-1-ol (4bh): Pink solid, m.p. Ͼ300 °C. IR (KBr): ν = 3124,
˜
5-(4-Methoxyphenyl)-2,6,7,8,9,10-hexahydrocyclohepta[d]pyrazolo-
[3,4-b]pyridin-1-ol (4bb): Light-yellow solid, m.p. Ͼ300 °C. IR
3052, 2932, 2853, 2682, 1594, 1542, 1475, 1396, 1358, 1275, 1252,
1
1211, 1162, 1135, 1072, 912, 839, 819, 802, 778, 691, 647 cm–1. H
(KBr): ν = 3136, 3052, 2926, 2853, 1595, 1543, 1518, 1442, 1394, NMR ([D6]DMSO, 400 MHz): δ = 11.62 (s, 1 H, NH), 11.04 (s, 1
˜
3032
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3026–3035

Macrocyclane-Fused Pyrazolo[3,4-b]pyridine Derivatives
H, OH), 7.23 (d, J = 8.0 Hz, 2 H, ArH), 7.14 (d, J = 8.0 Hz, 2 H,
1.71 (m, 2 H, CH2), 1.48–1.26 (m, 6 H, CH2) ppm. 13C NMR ([D6]-
ArH), 3.00–2.97 (m, 2 H, CH2), 2.66–2.63 (m, 2 H, CH2), 2.37 (s,
DMSO, 100 MHz): δ = 162.6, 148.1, 147.8, 128.7, 125.2, 121.1,
3 H, CH3), 1.80–1.71 (m, 2 H, CH2), 1.43–1.23 (m, 6 H, CH2) ppm. 113.0, 110.9, 55.5, 55.4, 35.3, 31.6, 30.7, 26.3, 25.9, 25.5 ppm.
13C NMR ([D6]DMSO, 100 MHz): δ = 162.7, 144.0, 136.4, 133.5, HRMS (ESI): calcd. for C20H24N3O3 354.1813; found 354.1798.
128.5, 128.2, 125.0, 112.7, 102.4, 35.4, 31.3, 30.7, 26.0, 25.9, 25.3,
20.9 ppm. HRMS (ESI): calcd. for C19H21N3NaO 330.1577; found
330.1573.
5-(p-Tolyl)-6,7,8,9,10,11,12,13,14,15-decahydro-2H-cyclododeca[d]-
pyrazolo[3,4-b]pyridin-1-ol (4bn): White solid, m.p. Ͼ300 °C. IR
(KBr): ν = 3198, 3147, 3055, 2921, 2861, 1598, 1537, 1519, 1475,
˜
5-(4-Methoxyphenyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta[d]-
pyrazolo[3,4-b]pyridin-1-ol (4bi): White solid, m.p. 283–284 °C. IR
1410, 1320, 1077, 1206, 1179, 1129, 1020, 863, 815, 723 cm–1. 1H
NMR (CDCl3, 400 MHz): δ = 11.59 (s, 1 H, NH), 10.21 (s, 1 H,
(KBr): ν = 3124, 2921, 2851, 1594, 1537, 1518, 1467, 1449, 1395, OH), 7.23 (d, J = 8.0 Hz, 2 H, ArH), 7.15 (d, J = 8.4 Hz, 2 H,
˜
1358, 1308, 1289, 1248, 1209, 1180, 1137, 1038, 838, 804, 648,
595 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 11.56 (s, 1 H,
NH), 10.27 (s, 1 H, OH), 7.18 (d, J = 8.4 Hz, 2 H, ArH), 6.98 (d,
J = 8.4 Hz, 2 H, ArH), 3.81 (s, 3 H, OCH3), 3.00–2.97 (m, 2 H,
CH2), 2.75–2.65 (m, 2 H, CH2), 1.80–1.70 (m, 2 H, CH2), 1.43–
1.24 (m, 6 H, CH2) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ =
162.7, 158.5, 155.0, 152.1, 143.8, 129.9, 128.5, 125.1, 113.0, 102.6,
55.0, 35.5, 31.3, 30.7, 26.0, 26.0, 25.4 ppm. HRMS (ESI): calcd. for
C19H21N3NaO2 346.1526; found 346.1520.
ArH), 2.87–2.83 (m, 2 H, CH2), 2.59–2.55 (m, 2 H, CH2), 2.38 (s,
3 H, CH3), 1.92–1.83 (m, 2 H, CH2), 1.57–1.35 (m, 10 H, CH2),
1.34–1.27 (m, 2 H, CH2), 1.22–1.14 (m, 2 H, CH2) ppm. HRMS
(ESI): calcd. for C23H30N3O 364.2384; found 364.2382.
5-(2-Chlorophenyl)-6,7,8,9,10,11,12,13,14,15-decahydro-2H-cyclo-
dodeca[d]pyrazolo[3,4-b]pyridin-1-ol (4bo): White solid, m.p.
Ͼ300 °C. IR (KBr): ν = 3100, 2931, 2846, 1601, 1539, 1505, 1284,
˜
1254, 1208, 1052, 808, 748 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
11.63 (s, 1 H, NH), 10.28 (s, 1 H, OH), 7.55 (d, J = 7.2 Hz, 1 H,
5-(4-Bromophenyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta[d]- ArH), 7.46–7.39 (m, 2 H, ArH), 7.33–7.31 (m, 1 H, ArH), 2.95–
pyrazolo[3,4-b]pyridin-1-ol (4bj): Pink solid, m.p. Ͼ300 °C. IR 2.78 (m, 2 H, CH2), 2.67–2.57 (m, 1 H, CH2), 2.42–2.32 (m, 1 H,
(KBr): ν = 3049, 2928, 2854, 1595, 1541, 1492, 1395, 1358, 1276, CH2), 1.92–1.82 (m, 2 H, CH2), 1.57–1.28 (m, 12 H, CH2), 1.23–
˜
1208, 1163, 1136, 1075, 1012, 841, 821, 720, 683, 643 cm–1
.
1H
1.15 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 162.3,
NMR ([D6]DMSO, 400 MHz): δ = 11.68 (s, 1 H, NH), 10.43 (s, 1 151.8, 141.4, 135.4, 132.0, 130.7, 129.5, 128.9, 126.5, 125.2, 102.1,
H, OH), 7.63 (d, J = 8.4 Hz, 2 H, ArH), 7.24 (d, J = 8.0 Hz, 2 H,
ArH), 3.04–2.95 (m, 2 H, CH2), 2.70–2.59 (m, 2 H, CH2), 1.81–
1.69 (m, 2 H, CH2), 1.43–1.24 (m, 6 H, CH2) ppm. 13C NMR ([D6]-
DMSO, 100 MHz): δ = 162.9, 152.0, 142.4, 135.7, 130.9, 130.6,
124.7, 120.9, 112.7, 79.5, 35.4, 31.2, 30.7, 26.0, 25.9, 25.3 ppm.
HRMS (ESI): calcd. for C18H19BrN3O 372.0706; found 372.0702.
32.8, 28.5, 27.7, 27.1, 26.7, 26.3, 25.8, 22.7, 22.3 ppm. HRMS
(ESI): calcd. for C22H27ClN3O 384.1839; found 384.1841.
5-(2-Thienyl)-6,7,8,9,10,11,12,13,14,15-decahydro-2H-cyclododeca-
[d]pyrazolo[3,4-b]pyridin-1-ol (4bp): Brown solid, m.p. Ͼ300 °C. IR
(KBr): ν = 3118, 2927, 2845, 1596, 1537, 1473, 1442, 1271, 1196,
˜
1128, 858, 820, 796, 695 cm–1. 1H NMR (CDCl3, 400 MHz): δ =
11.79 (s, 1 H, NH), 10.32 (s, 1 H, OH), 7.67 (d, J = 5.2 Hz, 1 H,
thienyl-H), 7.16–7.14 (m, 1 H, thienyl-H), 7.09 (d, J = 2.8 Hz, 1 H,
5-(2-Chlorophenyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta[d]-
pyrazolo[3,4-b]pyridin-1-ol (4bk): Pink solid, m.p. Ͼ300 °C. IR
(KBr): ν = 3066, 2933, 2856, 1655, 1589, 1541, 1473, 1437, 1395, thienyl-H), 2.87–2.83 (m, 2 H, CH2), 2.70–2.67 (m, 2 H, CH2),
˜
1275, 1249, 1207, 1167, 1130, 1078, 1053, 855, 835, 808, 759, 1.91–1.82 (m, 2 H, CH2), 1.52–1.36 (m, 12 H, CH2), 1.27–1.23 (m,
635 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 11.67 (s, 1 H,
2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 162.0, 154.2,
NH), 10.32 (s, 1 H, OH), 7.55–7.54 (m, 1 H, ArH), 7.44–7.41 (m, 151.4, 136.9, 135.8, 128.1, 127.0, 126.7, 126.6, 102.4, 32.8, 29.5,
2 H, ArH), 7.32–7.31 (m, 1 H, ArH), 3.05–2.98 (m, 2 H, CH2),
2.68–2.61 (m, 1 H, CH2), 1.82–1.71 (m, 2 H, CH2), 1.46–1.24 (m, 7
H, CH2) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 163.0, 140.6,
135.4, 134.2, 132.0, 130.5, 129.5, 128.9, 126.6, 124.8, 105.9, 102.4,
35.4, 30.8, 30.4, 26.3, 25.9, 25.3 ppm. HRMS (ESI): calcd. for
C18H19ClN3O 328.1212; found 328.1196.
27.7, 27.1, 26.9, 26.6, 26.4, 25.8, 22.8, 22.4 ppm. HRMS (ESI):
calcd. for C20H26N3OS 356.1792; found 356.1793.
5-(2,3-Dimethoxyphenyl)-6,7,8,9,10,11,12,13,14,15-decahydro-2H-
cyclododeca[d]pyrazolo[3,4-b]pyridin-1-ol (4bq): Yellow solid, m.p.
281–283 °C. IR (KBr): ν = 3118, 2934, 2854, 1641, 1595, 1536,
˜
1
1475, 1427, 1267, 1234, 1194, 1099, 1061, 1008, 809, 743 cm–1. H
5-(2-Thienyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta[d]pyrazolo-
NMR (CDCl3, 400 MHz): δ = 11.54 (s, 1 H, NH), 10.40 (s, 1 H,
[3,4-b]pyridin-1-ol (4bl): Brown solid, m.p. Ͼ300 °C. IR (KBr): ν = OH), 7.11–7.06 (m, 2 H, ArH), 6.68 (dd, J1 = 2.8, J2 = 6.0 Hz, 1
˜
3109, 2923, 2856, 1591, 1545, 1474, 1450, 1390, 1359, 1274, 1248,
H, ArH), 3.85 (s, 3 H, OCH3), 3.47 (s, 3 H, OCH3), 2.98–2.88 (m,
1 H, CH2), 2.80–2.69 (m, 1 H, CH2), 2.61–2.53 (m, 2 H, CH2),
1213, 1162, 1132, 1064, 840, 781, 698 cm–1. 1H NMR ([D6]DMSO,
400 MHz): δ = 11.81 (s, 1 H, NH), 7. 68 (d, J = 4.8 Hz, 1 H, 2.40–2.31 (m, 1 H, CH2), 1.91–1.82 (m, 2 H, CH2), 1.63–1.15 (m,
thienyl-H), 7. 15 (t, J = 3.6 Hz, 1 H, thienyl-H), 7. 09 (d, J =
3.2 Hz, 1 H, thienyl-H), 3.01–2.98 (m, 2 H, CH2), 2.78–2.75 (m, 2
H, CH2), 1.80–1.71 (m, 2 H, CH2), 1.58–1.48 (m, 2 H, CH2), 1.41–
1.28 (m, 4 H, CH2) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ =
162.5, 154.3, 151.6, 136.1, 135.6, 128.2, 126.8, 126.7, 126.7, 102.7,
35.2, 32.1, 30.6, 26.6, 25.8, 25.5 ppm. HRMS (ESI): calcd. for
C16H18N3OS 300.1166; found 300.1159.
13 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 161.8, 152.0,
145.3, 141.6, 130.8, 125.9, 123.2, 121.8, 112.4, 102.7, 102.2, 59.5,
55.5, 32.8, 28.6, 27.7, 27.2, 26.8, 26.5, 26.5, 25.8, 22.8, 22.2 ppm.
HRMS (ESI): calcd. for C24H32N3O3 410.2439; found 410.2427.
5-(3,4-Dimethoxyphenyl)-6,7,8,9,10,11,12,13,14,15-decahydro-2H-
cyclododeca[d]pyrazolo[3,4-b]pyridin-1-ol (4br): White solid, m.p.
284–285 °C. IR (KBr): ν = 3341, 2930, 2843, 1588, 1545, 1518,
˜
5-(3,4-Dimethoxyphenyl)-6,7,8,9,10,11-hexahydro-2H-cycloocta-
[d]pyrazolo[3,4-b]pyridin-1-ol (4bm): Pink solid, m.p. Ͼ300 °C. IR
1464, 1412, 1368, 1317, 1254, 1233, 1204, 1139, 1017, 849, 810,
762, 669 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 11.58 (s, 1 H,
(KBr): ν = 3100, 2929, 2852, 1600, 1545, 1518, 1463, 1415, 1382, NH), 10.20 (s, 1 H, OH), 7.00 (d, J = 8.0 Hz, 1 H, ArH), 6.85 (s,
˜
1359, 1324, 1260, 1233, 1212, 1170, 1140, 1028, 959, 855, 840, 797,
1 H, ArH), 6.80 (d, J = 9.6 Hz, 1 H, ArH), 3.81 (s, 3 H, OCH3),
762, 694, 619 cm–1. 1H NMR ([D6]DMSO, 400 MHz): δ = 11.62 (s, 3.72 (s, 3 H, OCH3), 2.89–2.82 (m, 2 H, CH2), 2.67–2.59 (m, 2 H,
1 H, NH), 7.00 (d, J = 8.0 Hz, 1 H, ArH), 6.84 (s, 1 H, ArH), 6.79
(d, J = 8.0 Hz, 1 H, ArH), 3.81 (s, 3 H, OCH3), 3.73 (s, 3 H,
OCH3), 3.00–2.97 (m, 2 H, CH2), 2.75–2.65 (m, 2 H, CH2), 1.82–
CH2), 1.92–1.82 (m, 2 H, CH2), 1.52–1.32 (m, 12 H, CH2), 1.26–
1.18 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 100 MHz): δ = 162.0,
151.8, 148.0, 147.7, 144.6, 128.8, 125.5, 121.1, 113.0, 110.8, 102.2,
Eur. J. Org. Chem. 2011, 3026–3035
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3033

B. Jiang, Y.-P. Liu, S.-J. Tu
FULL PAPER
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22.5 ppm. HRMS (ESI): calcd. for C24H32N3O3 410.2439; found
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of all the compounds.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (grant numbers 21072163 and
21002083), the Xuzhou Normal University (Science Foundation of
Interdisciplinary Major Research Projects, grant number
09XKXK01 and Doctoral Research Foundation, grant number
10XLR20).
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Published Online: April 12, 2011
Eur. J. Org. Chem. 2011, 3026–3035
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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