Synthesis of 2,6′-dioxo-1′,5′,6′,7′- tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-5′- carbonitriles via a one-pot, three-component reaction in water

Article abstract of DOI:10.1021/co300047j

A one-pot, three-component condensation reaction of an isatin, aminopyrazole, and alkyl cyanoacetate in water to give 2,6′-dioxo- 1′,5′,6′,7′-tetrahydrospiro[indoline-3, 4′-pyrazolo[3,4-b]pyridine]-5′-carbonitrile with good yields, at 90 C, using a Et₃N as catalyst, is described.

Full text of DOI:10.1021/co300047j

Research Article
pubs.acs.org/acscombsci
Synthesis of 2,6′-Dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-
pyrazolo[3,4‑b]pyridine]-5′-carbonitriles via a One-Pot, Three-
Component Reaction in Water
Abbas Rahmati,* Tahmineh Kenarkoohi, and Hamid Reza Khavasi
,
†
†
‡
†
Department of Chemistry, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran
‡
Departement of Chemistry, Shahid Beheshti University, General Campus, Evin, Tehran 1983963113, Iran
S Supporting Information
*
ABSTRACT: A one-pot, three-component condensation
reaction of an isatin, aminopyrazole, and alkyl cyanoacetate
in water to give 2,6′-dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-
3
,4′-pyrazolo[3,4-b]pyridine]-5′-carbonitrile with good yields,
at 90 °C, using a Et N as catalyst, is described.
3
KEYWORDS: spirooxindole, isatin, 1,4-dihydropyridines
2
2
INTRODUCTION
component reactions (Figure 1). The substructures (I) and
II) in Scheme 1 may be homocyclic and/or heterocyclic rings
■
(
Multicomponent reactions (MCRs) are chemical transforma-
tions in which three or more different starting materials
combine together via a one-pot procedure to give a final
complex product. Such reactions are one of the best tools in
modern organic synthesis because they can generate a product
as well as substituents. Although many structures like A−D
have been synthesized by various groups, there are no reports
for the preparation of spirooxindoles like E.
In continuation of our previous work and the preparation of
new heterocyclic compounds, we have utilized isatins instead of
with most of the atoms incorporating in the starting materials
this is important from the atom economic standpoint). Also
23
1
aldehydes; therefore we wish to report the synthesis of 2,6′-
(
dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]-
pyridine]-5′-carbonitriles 4 via one-pot three-component
condensation reaction.
these reactions have received considerable attention in
synthetic chemistry for the production of a broad spectrum
of organic molecules. Water has emerged as a versatile solvent
for organic reactions in the past two decades since it is available,
inexpensive, environmentally benign, neutral, and natural
RESULTS AND DISCUSSION
■
2
solvent. For these reasons, water has been used for MCRs as
For the synthesis of 2,6′-dioxo-1′,5′,6′,7′-tetrahydrospiro-
[indoline-3,4′-pyrazolo[3,4-b]pyridine]-5′-carbonitriles 4, the
ethyl cyanoacetate 1{1}, 3-amin-5-methylpyrazole 2{1}, and
simple isatin 3{1} were selected as model reactants during the
optimization process. Initially, this transformation was carried
out in methanol under reflux conditions in the absence of
catalyst. It was found that no product was detected even after
3
well. MCRs in water are of outstanding value in organic
synthesis and green chemistry.
Pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]pyridinones are
attractive condensed heterocyclic compounds and are being
extensively investigated because of their wide range of
4
biological and pharmaceutical activities such as hypotensives,
5
6
7
2 h (entry 1, Table 1). Different acidic and basic catalysts (40
antitumor, antibacterial, anti-inflammatory against TNF-α8
7
mol %) were screened. Results showed that reaction proceeds
in the presence of both series of catalysts and also reaction
yields were better with basic catalysts (entries 2−9, Table 1)
and IL-6, antichagasic new drugs against Trypanosoma cruzi,
9
inhibitors of protein kinase, cyclin-dependent kinase 1
1
0
11
(
3
CDK1), p38α Kinase, glycogen synthase kinase-3 (GSK-
1
2
13
14
and with Et N proved better than the others. To increase the
), PDE4B and HIV reverse transcriptase.
Spirooxindoles have received more attention because of the
wide range of useful pharmacological properties and biological
3
yield, different solvents were tested at reflux (entries 10−15,
Table 1). Water at 90 °C proved to be the best solvent. It is
important to note that in nonprotic solvents, compound
15
16
activities such as antimicrobial, antitumoral, antibiotic
1
7
18
5
{-,1,1} formed in 20 min as major product. Also, after 24 h
agents, inhibitors of human NK-1 receptor, CRTH2
19
20
this product did not change. However, after isolation of
compound 5{-,1,1} and treating with ethyl cyano acetate in
water and/or ethanol, it was transformed to compound
receptor antagonist and microtubule assembly. Also, in
some of bioactive naturally alkaloids, the spirooxindole ring is
2
1
the main core of structure. For these reasons, there have been
numerous investigations on the synthesis of spirooxindoles
annulated in the 3-position with different fused-heterocyclic
rings such as spiro[oxindole-3:4-dihydropyridines] (A,B) and
spiro[oxindole-3:4′-pyrans] (C,D) via various three and four
Received: April 27, 2012
Revised: November 5, 2012
Published: November 28, 2012
́
©
2012 American Chemical Society
657
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ACS Combinatorial Science
Research Article
Figure 1. Various structures of spirooxindoles.
Scheme 1. Two Different Diastereomers (Each of Products
as One Pair of Enantiomers)
loading with values of 10, 20, 30, and 40 mol % of catalyst,
respectively. The results indicated that 20 mol % of catalyst was
optimal. Higher amounts of catalyst did not lead to a significant
change in yield.
To explore the scope and limitations of this reaction, the
optimized reaction conditions (water solvent, Et N catalyst, 90
3
°
C) were used for the construction of a library from two alkyl
cyanoacetates 1 {1−2}, four aminopyrazoles 2 {1−4}, and six
isatins 3 {1−6} (Figure 2 and Table 2).
The reaction proceeded equally well with either electron-
withdrawing or electron-donating substituted isatins (entries1−
4
also 6 and 7, Table 2). Similar to the isatins, the reaction was
performed with various aminopyrazoles. The effect of pyrazole
structure was more pronounced compared to substituted
isatins. We concluded that the reaction yields were better in
the presence of aryl pyrazoles compared to alkyl pyrazoles.
Also, 5-hydroxy-3-amino pyrazole 2{4} afforded no product.
Finally, the effect of alkyl cyanoacetate stucture was investigated
in this process. Although, final reaction products using ethyl
4
{1,1,1}. In addition, it was found that compound 5{-,1,1} in
the absence of ethyl cyanoacetate converted to the starting
materials in protic solvents. When 2{3} was used instead of
2
NMR spectrum of compound 5{-,1,1} clearly showed that
ethyl cyanoacetate was not incorporated in its structure.
Subsequently, we further turned to testing the effect of catalyst
1
{1} the corresponding product was not observed. The H
a
Table 1. Solvent, Catalyst, and Temperature Optimization for the One-Pot Synthesis of 4 {1,1,1}
b
c
d
entry
solvent
MeOH
catalyst
time/temperature
yield (%)
yield (%)
1
2
3
4
5
6
7
8
9
24,72 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/reflux
24 h/90 °C
48 h/90 °C
24 h/90 °C
18 h/90 °C
12 h/90 °C
6 h/90 °C
24 h/70 °C
24 h/90 °C
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
ethanol
water
p-TsOH
21
22
10
70
61
61
52
69
61
89
15
12
73
59
89
89
89
88
84
37
25
H SO4
2
AcOH
Et N
3
NaOH
Na CO3
2
NaHCO3
pyridine
10
11
12
13
14
15
16
17
18
19
20
21
22
Et N
3
Et N
3
ethyl acetate
Et N
3
40
72
CH CN
Et N
3
3
water/ethanol(1:1)
Et N
3
e
Choline chloride
Et N
3
water
water
water
water
water
water
water
Et N
3
Et N
3
Et N
3
Et N
3
Et N
3
Et N
3
a
b
c
Isatin (1 mmol), ethyl cyanoacetate (1 m mol), 3-amin-5-methylpyrazole (1 m mol) in solvent (5 mL). 40 mol % of catalyst. Isolated yield of
{1,1,1}. Isolated yield of 5{-,1,1}. RTIL.
d
e
4
6
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ACS Combinatorial Science
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Figure 2. Diversity of reagents.
a
Table 2. One-Pot Synthesis of 2,6′-Dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-5′-carbonitrile
b
c
entry
alkyl cyanoacetate
aminopyrazole
isatin
product
4{1,1,1}
yield(%)
major:minor
1
2
3
4
5
6
7
8
9
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{2}
1{2}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{2}
2{2}
2{3}
2{3}
2{3}
2{3}
2{3}
2{3}
2{1}
2{1}
3{1}
3{7}
3{2}
3{3}
3{4}
3{6}
3{1}
3{2}
3{1}
3{2}
3{3}
3{4}
3{5}
3{6}
3{1}
3{7}
89
92
57
56
67
63
83
89
83
71
78
72
72
74
61
62
79:21
81:19
76:24
85:15
83:17
82:18
66:34
62:38
76:24
72:28
81:19
77:23
77:23
75:25
82:18
d
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,2,1}
4{1,2,2}
4{1,3,1}
4{1,3,2}
4{1,3,3}
4{1,3,4}
4{1,3,5}
4{1,3,6}
4{2,1,1}
4{2,1,7}
1
1
1
1
1
1
1
0
1
2
3
4
5
6
e
e
81:19
a
b
c
Isatin (1 mmol), alkyl cyanoacetate (1 m mol), 3-aminpyrazole (1 m mol) in water (5 mL), Et N (20 mol %), 6−12 h. Isolated yield. Ratio of
3
1
d
e
isomers based on average of CH , CH and NH groups signals in H NMR. Product obtained from N-acylisatin. Products 4{2,1,1} and 4{2,1,7}
3
obtained from methyl cyanoacetate are the same as 4{1,1,1}.
1
cyanoacetate and methyl cyanoacetate were the same, the
results revealed that ethyl cyanoacetate yields were better than
methyl cyanoacetate (Table 2, entries1−2 also 15 and 16).
Furthermore, the last column in Table 2 represents the ratio of
the two diastereomers generated during the reaction. These
were given as minor and major isomers, and the amount of
(C−N), and 708 (C−Cl) cm− indicating the presence of these
functional groups at the proposed structure. The mass
spectrum of 4{1,1,4} displayed the molecular ion peaks at
37
35
m/z = 329 ( Cl) and 327 ( Cl), which were in agreement
with the 1:1:1 adduct of starting materials with loss of water
and ethanol. The H NMR and C NMR spectra of 4{1,1,4}
1
13
them was obtained according to the CH , CH, and NH
functional group signals in H NMR. However, each of them
exhibit duplication of signals because of the presence of one
pair of diasteriomers. The H NMR spectrum to major isomer
3
1
1
exists as a pair of enantiomers (Scheme 1). It is worthy to
mention that N-acylisatin products hydrolyzed during this
process, and its products were similar to simple isatin (Table 2,
entry 2). The same result was obtained under neutral
conditions indicating the labiality of the N-acyl group.
exhibited a singlet for −CH group at δ = 1.44 ppm and
3
another singlet at δ = 5.38 ppm for the CH group. Two
independent doublets for two aromatic hydrogens appeared at
3
4
δ = 7.02 and 7.53 ppm with J = 8.0 Hz and JHH= 1.6 Hz,
HH
respectively, and a doublet of doublet for other aromatic
3
4
The structures of all derivatives of compound 4 were
hydrogen at δ = 7.43 ppm with J = 8.4 Hz and J = 2.0
HH HH
1
13
deduced from their IR, H NMR, C NMR, mass spectra, and
elemental analysis.
Hz. Signals for the NH-group of amides and pyrazole ring
appeared as three singlet at δ = 10.90, 11.01 and δ = 12.43 ppm,
1
13
The IR spectrum of 4{1,1,4} showed absorptions at 3633,
respectively. The H decoupled C NMR spectrum for major
isomer of 4{1,1,4} showed 15 distinct resonances in agreement
with the suggested structures. Signals for the minor stereo-
3
418, 3322 (NH), 2906 (CH ), 2254 (CN), 1716, 1690 (C
3
O), 1619 (bending NH), 1477 (bending CH ), 1306, 1174
3
6
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Research Article
Scheme 2. Possible Four Different Products (Regioisomers) during the Reaction
isomer in amount up to between 13 and 19% were observed as
follows: two singlets for −CH and CH groups corresponding
3
at δ = 1.82 and 5.38 ppm. Two aromatic hydrogen appeared at
4
3
δ = 6.94 and 7.04 ppm with J = 2.0 and J = 8.8 Hz; and a
HH
HH
doublet of doublet for other aromatic hydrogen at δ = 7.38
3
4
ppm with J = 8.4 Hz and J = 2.0 Hz. One of the aromatic
HH
HH
hydrogen signals from a minor isomer at δ = 7.04 was
embedded at a major isomer signal. Signals for the NH-group
of amides and pyrazole ring were similar to the signals of the
major isomer and were appeared at δ = 11.24, 11.27 and δ =
1
13
1
2.28 ppm, respectively. The H decoupled C NMR spectrum
for the minor isomer showed 15 distinct resonances. All J values
were given as real values without correction and average.
In this reaction besides the product 4, compounds 6, 7, and 8
could potentially be formed because of the presence of two
nucleophilic sites close to the amine group (nitrogen and
Figure 3. X-ray crystal structure of major isomer from 4{1,1,1}.
4{1,1,1} was converted to final product via tautomerization
(Scheme 4).
1
carbon of pyrazole ring) (Scheme 2). However, the H NMR
Interesting results were obtained by stopping the reaction of
entry 7 in Table 2 after one hour. The reaction mixture was
filtered immediately and the solid residue washed with water,
and after drying, the ratio of A′,A′′ and B′,B′′ isomers (Scheme
spectrum of the product straightforwardly specified that the
NH signal appeared while the CH signal of pyrazole ring did
not appear. Therefore, these results indicated that products 7
and 8 were not generated. In addition, spectral data obtained
for the product may correspond for two regioisomers 4 and 6
which is shown in Scheme 2. ROSEY and HMBC spectra of
product (4{1,1,2}) proved that only 4 was generated. Also, the
ROSEY spectrum indicated that in the minor isomer, the
hydrogen of the pyrimidine ring was close to the aromatic
hydrogen. In addition, the HMBC spectrum indicated that
among the two tautomeric forms (III) and (IV) in Scheme 3
only form (IV) was generated.
1
1) in the products were determined by H NMR spectrum. As a
consequence, the amount of B′,B′′ isomers were higher than
A′,A′′ isomers (Figures 4). Therefore, B′,B′′ isomers were
kinetically products and A′,A′′ isomers were thermodynami-
cally products. These results were confirmed by comparing the
two spectra in Figures 4 and 5. B′,B′′ isomers were not
observed upon heating of the isolated A′,A′′ isomers in the
absence of catalyst in water. Meanwhile addition of triethyl-
amine catalyst led to the production of B′,B′′ after 48 h.
However, the equilibrium was established slowly. In addition, in
a separate experiment the isolated product 4{1,2,1} (after 1 h
in Figure 4) was heated in water in the absence of catalyst.
Results showed that the ratio of isomers remains unchanged
during 24 h, whereas in the presence of catalyst the obtained
isomer ratio was similar to that of obtained for the experimental
condition of Figure 5. No further change of isomers ratio was
observed with increasing heating time. Therefore, these results
showed that these isomers were in equilibrium in the presence
of catalyst, but were not in equilibrium in the absence of
catalyst.
Scheme 3. Two Tautomeric Forms 4{1,1,2}
The major isomer of product 4{1,1,1} was separated by
column chromatography and established by H NMR. Then a
single crystal of it was obtained from ethanol, and the
1
CONCLUSION
■
In summary, a novel, green, and efficient three-component
domino reaction of some typical isatins, 3-aminopyrazoles, and
alkyl cyanoacetate was developed for the synthesis of 2,6′-
dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]-
pyridine]-5′-carbonitrile. The simple one-pot nature of the
reaction makes it an interesting approach. One of the main
advantages of the proposed method is its good reaction yields.
Also, the reactions were carried out in water which is
considerably safer, nontoxic, environmentally friendly, and
inexpensive. Furthermore, the existence of three different
important heterocyclic moieties such as oxindole, pyridinone,
and pyrazole rings in one molecule is fantastic because of the
stereochemistry of its structure was confirmed by a single
24
crystal X-ray analysis (Figure 3).
There is no established mechanism for the formation of 2,6′-
dioxo-1′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]-
pyridine]-5′-carbonitrile; a reasonable possibility is shown in
Scheme 4. The reaction presumably proceeds via Knoevenagel
condensation between ethyl cyanoacetate 1{1} and the isatin
{1} to give α,β-unsaturated compound 11. Then, compound
1 converts to intermediate 13 through a Michael addition of
-aminopyrazole 2{1}. Then, product 14 was obtained by a
3
1
5
cyclization process from compound 13. Finally, compound
6
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Research Article
Scheme 4. Mechanism of Reaction
1
Figure 4. H NMR of 4{1,2,1} after 1 h.
potential applications of these rings in biological and
pharmacological activities.
(1 mmol) was added in a balloon and stirred for 5−12 h at 90
°C in an oil bath. After the completion of the reactions, which
has been followed by TLC (EtOAc:n-hexene, 1:2), the reaction
mixture was filtered while warm. The residue was washed with
water and then recrystallized from ethanol, and pure product
was obtained.
EXPERIMENTAL PROCEDURES
■
1
General Procedure for the Synthesis of 2,6′-Dioxo-
′,5′,6′,7′-tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]-
3
′,5-Dimethyl-2,6′-dioxo-1′,5′,6′,7′-tetrahydrospiro-
indoline-3,4′-pyrazolo[3,4-b]pyridine]-5′-carbonitrile 4-
{1,1,2}. White powder (57%); IR (KBr): 3639, 3313, 3256,
pyridine]-5′-carbonitriles 4. A solution of isatin (1 mmol),
[
ethyl cyanoacetate (1 mmol), and Et N (0.1 mmol) in water
3
−1
(
10 mL) in a balloon (25 mL) was stirred for 1 h at 60−70 °C
3039, 2912, 2254, 1707, 1605, 1530 cm ; MS (EI, 70 eV): m/z
+
in an oil bath. After production of intermediate 3-amin-pyrazole
(%): 307 (M , 100), 280 (49), 252 (82), 77 (75), 63 (53), 42
6
61
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1
Figure 5. H NMR of 4{1,2,1} after completion.
(
61); Anal. Calcd for C H N O : C 60.53, H 4.26, N 22.79;
126.48, 129.77, 130.81, 134.99, 139.84, 148.04, 161.42, 174.93
ppm.
1
6
13
5
2
1
Found: C 60.29, H 4.29, N 22.65. (major isomer)) H NMR
400 MHz, DMSO-d ) δ: 1.38 (s, 3H, CH ), 2.29 (s, 3H,
(
6
3
3
ASSOCIATED CONTENT
CH ), 5.31(s, 1H, CH), 6.87 (d, J = 7.6 Hz, 1H, CHarom), 7.16
3
■
3
(
1
d, J = 7.6 Hz, 1H, CHarom), 7.24 (s, 1H, CHarom), 10.64 (s,
H, NHamide), 10.97 (s, 1H, NHamide), 12.11 (s, 1H, NHpyrazole
*
S
Supporting Information
1
13
)
Experimental procedure, IR, H NMR, C NMR, mass spectra,
13
1
ppm. C NMR (100 MHz, DMSO-d ) δ: 8.90, 20.73, 42.54,
4
and elemental analysis data to all products; also IR, H NMR,
C NMR, mass spectra for all products presented. Only the H
6
13
1
8.88, 97.39, 109.96, 115.24, 125.06, 127.57, 130.05, 131.36,
34.96, 140.12, 148.15, 162.15, 176.04 ppm. (minor isomer)
1
NMR spectrum is given for the repetitive product. In addition,
ROSEY and HMBC spectra of product 4{1,1,2}. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
H NMR (400 MHz, DMSO-d ) δ: 1.82 (s, 3H, CH ), 2.22 (s,
6
3
3
3
7
H, CH ), 4.88 (s, 1H, CH), 6.79 (s, 1H, CH ), 6.89 (d, J =
3 arom
3
.6 Hz, 1H, CHarom), 7.10 (d, J = 7.6 Hz, 1H, CHarom), 11.01
(
s, 1H, NHamide), 11.23 (s, 1H, NHamide), 12.22 (s, 1H,
AUTHOR INFORMATION
Corresponding Author
*E-mail: a.rahmati@sci.ui.ac.ir or abbass_rahmati@yahoo.com.
■
1
3
NHpyrazole) ppm. C NMR (100 MHz, DMSO-d ) δ: 9.07,
2
1
6
0.61, 43.41, 48.41, 98.61, 110.28, 114.74, 123.45, 129.19,
29.96, 131.61, 134.18, 138.35, 147.57, 161.74, 175.27 ppm.
Funding
5
-Chloro-3′-methyl-2,6′-dioxo-1′,5′,6′,7′-
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan.
Notes
tetrahydrospiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-
5
′-carbonitrile 4{1,1,4}. White powder (57%); IR (KBr):
3
1
3
633, 3418, 3323, 2906, 2254, 1716, 1690, 1619, 1529, 1477,
The authors declare no competing financial interest.
−
1
+
306, 1174, 708 cm ; MS (EI, 70 eV): m/z (%): 329 (M +2,
+
1), 327 (M , 79), 166 (91), 75 (93), 69(95), 67 (90), 57
REFERENCES
■
(100), 44 (87). Anal. Calcd for C H ClN O : C 54.97, H
15 10 5 2
(
1) Zhu, J., Bienayme, H., Eds.; Multicomponent Reactions; Wiley-
VCH: Weinheim, Germany, 2005.
3
.08, N 21.37; Found: C 55.09, H 4.11, N 21.26. (major
1
isomer) H NMR (400 MHz, DMSO-d ) δ: 1.44 (s, 3H, CH ),
6
3
(2) (a) Li, C. J., Chan, T. H., Eds.; Organic Reactions in Aqueous
3
5
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4
4
J = 8.4 Hz, J = 2.0 Hz, 1H, CHarom), 7.54 (d, J = 1.6 Hz, 1H,
CHarom), 10.90 (s, 1H, NHamide), 11.01 (s, 1H, NHamide), 12.16
1
3
2
009, 109, 725−748. (d) Pirrung, M. C.; Sarma, K. D. Multi-
(
s, 1H, NHpyrazole)ppm. C NMR (100 MHz, DMSO-d ) δ:
6
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8
1
.94, 42.22, 49.09, 96.66, 111.86, 114.95, 154.80, 126.48,
2
004, 126, 444−445.
29.44, 129.89, 134.99, 141.49, 148.04, 161.77, 175.74 ppm.
1
(3) Kandhasamy, K.; Gnanasambandam, V. Multi-Component
(
minor isomer): H NMR (400 MHz, DMSO-d ) δ: 1.82 (s,
6
Reactions in Water. Curr. Org. Chem. 2009, 13, 1820−1841.
4
3
7
H, CH ), 4.92 (s, 1H, CH), 6.94 (d, J = 2.0 Hz, 1H, CHarom),
.04 (d, J = 8.8 Hz, 1H, CH ), 7.38 (dd, J = 8.4 Hz, J = 2.0
3
(4) Straub, A. S.; Alonso-Alija, J. P. C. NO-Independent Stimulators
3
3
4
arom
of Soluble Guanylate Cyclase. Bioorg. Med. Chem. Lett. 2001, 11, 781−
784.
(5) (a) Lin, R.; Connolly, P. J.; Lu, Y.; Chiu, G.; Li, S.; Yu, Y.; Huang,
S.; Li, X.; Emanuel, S. L.; Middleton, S. A.; Gruninger, R. H.; Adams,
Hz, 1H, CHarom), 11.24 (s, 1H, NH
NHamide), 12.28 (s, 1H, NHpyrazole) ppm. C NMR (100 MHz,
DMSO-d ) δ: 9.04, 43.17, 48.43, 97.69, 112.26, 114.57, 122.85,
), 11.26 (s, 1H,
amide
1
3
6
6
62
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̈
ufern der Hetero- und
monoclinic system, space group C2/c, a = 24.154(8) Å, b =
3
7.5150(15) Å, c = 16.506(5) Å, β = 110.27(2)°, V = 2810.6(14) Å ,
−
3
−1
1
Z = 8, Dc = 1.386 g cm , μ(Mo Kα)= 0.097 mm , crystal dimension:
6
63
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ACS Combinatorial Science
Research Article
0
.22 × 0.21 × 0.20 mm. The structure was solved by using SHELXS.
The structure refinement and data reduction was carried out with
SHELXL of the X-Step32 suite of programs. (REF: X-STEP32, version
1.07b, X-ray structure evaluation package; Stoe & Cie: Darmstadt,
Germany, 2000). The non-hydrogen atoms were refined anisotropi-
2
cally by full matrix least-squares on F values to final R = 0.0847, wR
1
2
=
0.1777, and S = 1.084 with 199 parameters using 2768 independent
reflection (θ range = 2.62−26.00°). Hydrogen atoms were located
from expected geometry and were not refined. Crystallographic data
for 4{1,1,1} have been deposited with the Cambridge Crystallographic
Data Centre. Copies of the data can be obtained, free of charge, on
application to The Director, CCDC 904326, Union Road, Cambridge
CB2 1EZ, U.K. Fax: +44 1223 336033. E-mail: deposit@ccdc.cam.ac.
uk.
6
64
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