Synthesis of heterocyclic compounds from 4-formylpyrazoles

Article abstract of DOI:10.1007/s11172-014-0451-8

Formylation of pyrazole and 2,5-dimethylpyrazole gave a number of pyrazole-containing aldehydes, which can be used to obtain chromenes, tetrahydrochromenes, 1,4-dihydropyrano[2,3-c]pyrazoles, pyrano[3,2-c]chromenes, thiochromeno[4,3-b]pyrans, pyrano[3,2-c

Full text of DOI:10.1007/s11172-014-0451-8

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 443—456, February, 2014
443
Synthesis of heterocyclic compounds from 4ꢀformylpyrazoles*
V. Yu. Mortikov, L. A. Rodinovskaya, A. E. Fedorov, A. M. Shestopalov, and P. A. Belyakov†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: alf@server.ioc.ac.ru
Formylation of pyrazole and 2,5ꢀdimethylpyrazole gave a number of pyrazoleꢀcontaining
aldehydes, which can be used to obtain chromenes, tetrahydrochromenes, 1,4ꢀdihydropyrꢀ
ano[2,3ꢀc]pyrazoles, pyrano[3,2ꢀc]chromenes, thiochromeno[4,3ꢀb]pyrans, pyrano[3,2ꢀc]ꢀ
quinolines, and thiazolo[3,2ꢀa]pyridines.
Key words: pyrazole, 2,5ꢀdimethylpyrazole, 1ꢀalkylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde, "domino"
reactions, Knoevenagel condensation, dicyanomethylidene derivatives, chromenes, tetraꢀ
hydrochromenes, 1,4ꢀdihydropyrano[2,3ꢀc]pyrazoles, pyrano[3,2ꢀc]chromenes, thiochromꢀ
eno[4,3ꢀb]pyrans, pyrano[3,2ꢀc]quinolines, thiazolo[3,2ꢀa]pyridines.
A great number of publications concerned with 2ꢀamiꢀ
noꢀ3ꢀcyanoꢀ4Hꢀchromenes 1 (X = H) is due to the high
biological activity of heterocyclic compounds of this
class.1—24 Chromenes exhibit antibacterial,1—4,16 antituꢀ
berculosis,4 fungicidal,4—6 and anthelmintic7 activity;
some of them can act as antioxidants.8 Many 2ꢀaminoꢀ3ꢀ
cyanoꢀ4Hꢀchromenes show antitumor activity.9—24 Speꢀ
cifically, 4ꢀ(3ꢀtrifluoromethylphenyl)ꢀ4Hꢀchromene (2)
(chromeceptin) can trigger the apoptosis of cancer
cells.11—14 Some tests have revealed high anticancer activꢀ
ity of compounds 1 for X = OR and NR2 in low concenꢀ
trations.15—24 Some 6ꢀaminoꢀ4ꢀaryl(hetaryl)ꢀ5ꢀcyanoꢀ
1,4ꢀdihydropyrano[2,3ꢀc]pyrazoles 3 can act as bacteriꢀ
cides25,26 and inhibitors of kinases,27,28 Pꢀglycoprotein,29
Scrꢀhomologs of tyrosine phosphatase (SHPꢀ2),30 and
autotaxin (ATX).31
The most convenient routes to such compounds inꢀ
volve baseꢀcatalyzed reactions of condensation products
of malononitrile and aldehydes with appropriate carbonyl
compounds and metaꢀsubstituted phenols. These reactions
follow a "domino" pattern involving the Knoevenagel conꢀ
densation, the Michael addition, and the heteroꢀThorꢀ
pe—Ziegler reaction for two, three, and four reaction comꢀ
ponents.32 Using this approach, one can obtain libraries of
compounds with widely varied substituents. This has beꢀ
come of special interest since the discovery of a correlaꢀ
tion between the activity of 2ꢀaminoꢀ4ꢀaryl(hetaryl)ꢀ3ꢀ
cyanoꢀ7ꢀhydroxy(dimethylamino, diethylamino)ꢀ4Hꢀ
chromenes 1 and the structures of substituents in positions
7, 6, and 4.15—24
The literature data on 4ꢀpyrazolylpyrans of the type 1
(X = H) or 3 are scarce;33—42 some of them produce molꢀ
luscicidal,33 antibacterial, and fungicidal effects.36,38,40—42
Pyrans containing an Nꢀalkylpyrazole fragment virtually
have not been documented. However, the starting aldeꢀ
hydes for the synthesis of libraries of such compounds
are fairly accessible. NꢀAlkylpyrazoles 7 prepared by alkylꢀ
ation of pyrazole 4 or 3,5ꢀdimethylpyrazole (5) can be
transformed into Nꢀalkylꢀ4ꢀformylpyrazoles 8 in high
yields under the conditions of the Vilsmeier reaction43—45
(Scheme 1).
We obtained and characterized a number of new aldeꢀ
hydes 8a—g. Aldehydes 8a,c,d,f are colorless or faintly
yellowish liquids that are well soluble in water and comꢀ
mon organic solvents but hexane. Compounds 8b,e are
virtually odorless, colorless or slightly colored solids, while
aldehyde 8g is a viscous oil; the solubilities of the last three
1: R = Ar, Het; X = H, OH, OMe, OEt, Hal, NH2, NHEt, NMe2, NEt2
3: R = Ar, Het; R´ = Alk, Ar
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of Sciences.
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0443—0456, February, 2014.
1066ꢀ5285/14/6302ꢀ0443 © 2014 Springer Science+Business Media, Inc.

444
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
Scheme 1
(high intensity). The 1ꢀalkyl substituents produce no efꢀ
fect on the positions or intensities of the absorption bands
in the UVꢀVis spectra. However, introduction of two
methyl groups into positions 3 and 5 of the pyrazole
ring results in slight (4—7 nm) bathochromic shifts of
both bands.
We employed aldehydes 8 for the synthesis of heteroꢀ
cyclic compounds. Attempted threeꢀcomponent synthesis
of pyrans from an aldehyde, malononitrile, and a carbonyl
compound gave only resinous products. Using a twoꢀcomꢀ
ponent synthesis, we obtained Nꢀalkylpyrazolylmethylꢀ
idenemalononitriles 9a—g and determined their physicoꢀ
chemical characteristics. Compounds 9a—g are colorless
or faintly colored solids that are well soluble in most orꢀ
ganic solvents, moderately soluble in ethanol (the solubilꢀ
ity becomes much better when more alkyl groups are
present), and poorly soluble in water and hexane.
Like the 1H NMR spectra of compounds 8a,c,d,f, the
spectra of compounds 9a,c,d,f (Table 2) show characterisꢀ
tic signals for the 1ꢀalkyl(allyl) substituent and signals for
the H(3) and H(5) protons of the pyrazole ring. The signal
for the proton at the double bond of the dicyanoethenyl
substituent appears at  8.27—8.37. The IR spectra of comꢀ
pounds 9 feature a band at 2222—2234 cm–1 (CN). For
3ꢀ and 5ꢀunsubstituted pyrazoles 9, this band appears as
4: R1 = H; 5: R1 = Me; 6: R2 = Me, Et, Pri, All; X = Br, I
7, 8: R1 = H, R2 = Me (a); R1 = R2 = Me (b); R1 = H, R2 = Et (c);
R1 = H, R2 = Pri (d); R1 = Me, R2 = Pri (e);
R1 = H, R2 = All (f); R1 = Me, R2 = All (g)
compounds in water are appreciably lower. The 1H NMR
spectra of compounds 8a,c,d,f show characteristic signals
for the protons of the 1ꢀalkyl(allyl) substituent, signals for
the H(3) and H(5) protons at  7.96 and 8.41, and a signal
for the formyl proton at  9.78 (Table 1). In the 1H NMR
spectra of compounds 8b,e,g, the signals for the protons of
the methyl groups in positions 3 and 5 appear at  2.29—2.31
and 2.45—2.48. The IR spectra of compounds 8 feature
a band at 1660—1680 cm–1 (C=O); an increase in the numꢀ
ber of alkyl groups slightly increases (by 10—15 cm–1) the
wavenumber. The UVꢀVis spectra of these aldehydes show
two bands at 202—206 (low intensity) and 246—252 nm
Table 1. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of 4ꢀformylpyrazoles 8a—g
Comꢀ
pound
Found
Calculated
Molecular
formula
1H NMR (DMSOꢀd6),  (J/Hz)
IR, /cm–1
UVꢀVis,
max/nm ()
(%)

C
H
N
8а
8b
54.49 5.56 25.42
54.54 5.49 25.44
C5H6N2O
C7H10N2O
3.90 (s, 3 H, NCH3); 7.96, 8.41 (both s,
each 1 H, CH of pyrazole); 9.78 (s, 1 H, CHO)
1679 (CO), 1541, 246 (10900),
1459, 1385 202 (3600)
2956, 2848, 1660 252 (13800),
60.67 7.38 20.15
60.85 7.30 20.28
2.29, 2.45 (both s, each 3 H, CH3);
3.68 (s, 3 H, NCH3); 9.81 (s, 1 H, CHO)
(CO), 1556,
1544, 1508
206 (7700)
8c
8d
8e
8f
57.98 6.61 22.43
58.05 6.50 22.57
C6H8N2O
C7H10N2O
C9H14N2O
C7H8N2O
1.39 (t, 3 H, CH3, J = 7.0); 4.19 (q, 2 H,
NCH2CH3, J = 7.0); 7.97, 8.46 (both s,
each 1 H, CH of pyrazole); 9.78 (s, 1 H, CHO)
1680 (CO), 1540, 246 (9900),
1460, 1390 202 (3500)
60.80 7.34 20.19
60.85 7.30 20.28
1.43 (d, 6 H, (CH3)2CH, J = 6.6); 4.57
(m, 1 H, (CH3)2CHN); 7.98, 8.50 (both s,
each 1 H, CH of pyrazole); 9.78 (s, 1 H CHO)
1682 (CO), 1543, 247 (13200),
1456, 1418,
1394, 1371
202 (4400)
64.98 8.60 16.73
65.03 8.49 16.85
1.34 (d, 6 H, (CH3)2CH, J = 6.2); 2.31, 2.48
(both s, each 3 H, CH3); 4.52 (m, 1 H,
(CH3)2CHN); 9.83 (s, 1 H CHO)
2989, 2749, 1666 252 (14600),
(CO), 1541, 1485, 206 (6600)
1428, 1397
61.73 5.96 20.62
61.75 5.92 20.58
4.83 (d, 2 H, NCH2CHCH2, J = 5.7);
2846, 2814, 2799, 245 (13600),
2777, 1671 (CO), 202 (4300)
1545, 1465,
5.15 (d, 1 H, NCH2CHCHH, J = 17.2);
5.24 (d, 1 H, NCH2CHCHH, J = 10.3); 6.03
(m, 1 H, NCH2CHCH2); 8.00, 8.45 (both s,
each 1 H, CH of pyrazole); 9.84 (s, 1 H, CHO)
1419, 1393
8g
65.78 7.41 16.99
65.83 7.37 17.06
C9H12N2O
2.31, 2.41 (both s, each 3 H, CH3); 4.68
(d, 2 H, NCH2CHCH2, J = 4.4); 4.97 (d, 1 H,
NCH2CHCHH, J = 16.8); 5.17 (d, 1 H,
NCH2CHCHH, J = 9.9); 5.92 (m, 1 H,
NCH2CHCH2); 9.84 (s, 1 H, CHO)
1681 (CO), 1545, 252 (21000),
1495, 1435,
1404, 1397
206 (11200)

Formylpyrazoles in the synthesis of heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
445
Table 2. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of Nꢀalkylpyrazolylmethylidenemalononitriles 9a—g
Comꢀ
pound
Found
Calculated
Molecular
formula
1H NMR (DMSOꢀd6),  (J/Hz)
IR, /cm–1
UVꢀVis,
max/nm ()
(%)
N
C
H
9а
9b
9c
60.59 3.96 35.36
60.75 3.82 35.42
C8H6N4
3.96 (s, 3 H NCH3); 8.08 (s, 1 H,
CH of pyrazole); 8.37 (s, 1 H, CHC(CN)2);
8.47 (s, 1 H, CH of pyrazole)
3124, 3100, 3040, 2224
317 (30450),
(CN), 2232 (CN), 1600, 217 (6950)
1492, 1212, 1172, 1152,
1068, 1020
60.67 7.38 20.15
64.50 7.30 20.28
C10H10N4 2.27, 2.37 (both s, each 3 H, CH3); 3.73
(s, 3 H, NCH3); 8.27 (s, 1 H, CHC(CN)2)
3020, 2932, 2228 (CN),
1592, 1512, 1452, 1396,
1376, 1356, 1236,
1176, 1036
329 (3300),
218 (1100)
62.74 4.70 32.48
62.78 4.68 32.54
C9H8N4
1.39 (t, 3 H, CH3, J = 6.9); 4.26 (q, 2 H,
CH3CH2N, J = 6.9); 8.11 (s, 1 H,
CH of pyrazole); 8.35 (s, 1 H, CHC(CN)2);
8.49 (s, 1 H, CH of pyrazole)
3124, 3035, 2986, 2230
(CN), 2221 (CN), 1592, 217 (6200)
1532, 1522, 1476, 1448,
317 (28900),
1385, 1233, 1217, 1173,
1147, 1103, 1082, 1015
9d
64.45 5.44 30.06
64.50 5.41 30.09
C10H10N4 1.41 (d, 6 H, (CH3)2CH, J = 6.5); 4.65
(m, 1 H, (CH3)2CHN); 8.11 (s, 1 H, CH
of pyrazole); 8.32 (s, 1 H, CHC(CN)2);
8.46 (s, 1 H, CH of pyrazole)
3119, 3052, 2988, 2921,
2855, 2294, 2232, 2224
(CN), 1716, 1599, 1530,
1520, 1453, 1383, 1338,
1240, 1186, 1147,
320 (21200),
217 (5200)
1081, 1019
9e
9f
67.18 6.67 26.13
67.27 6.59 26.15
C12H14N4 1.36 (d, 6 H, (CH3)2CH, J = 6.5); 2.30, 2.40
(both s, each 3 H, CH3); 4.58 (m, 1 H,
2984, 2941, 2878, 2319,
2223 (CN), 1596, 1498,
1454, 1422, 1381, 1367,
1357, 1263, 1134, 1186,
1161, 1059
328 (22300),
217 (6000)
(CH3)2CHN); 8.27 (s, 1 H, CHC(CN)2)
65.22 4.40 30.38
65.21 4.38 30.42
C10H8N4 4.90 (d, 2 H, NCH2CHCH2, J = 5.1); 5.15
(d, 1 H, NCH2CHCHH, J = 17.2); 5.24
(d, 1 H, NCH2CHCHH, J = 10.3); 6.02
(m, 1 H, NCH2CHCH2); 8.13 (s, 1 H, CH
of pyrazole); 8.37 (s, 1 H, CHC(CN)2);
8.49 (s, 1 H, CH of pyrazole)
3123, 3036, 2986, 2903,
2230, 2222 (CN), 1876,
1714, 1594, 1528, 1469,
1435, 1420, 1384, 1337,
1290, 1224, 1195, 1167,
1146, 1118, 1015, 1003
320 (28300),
217 (5900)
9g
67.88 5.73 26.39
67.90 5.70 26.40
C12H12N4 2.28, 2.36 (both s, each 3 H, CH3); 4.99
2948, 2336, 2224 (CN),
327 (27500),
218 (11500)
(d, 2 H, NCH2CHCH2, J = 5.1); 5.19 (d, 1 H, 1644, 1564, 1508, 1456,
NCH2CHCHH, J = 17.9); 5.24 (d, 1 H,
NCH2CHCHH, J = 10.0); 6.02 (m, 1 H,
NCH2CHCH2); 8.30 (s, 1 H, CHC(CN)2)
1420, 1384, 1336, 1292,
1260, 1160, 1072, 1044,
1028, 988
two peaks (rather than one peak observed for the 3ꢀ and
5ꢀsubstituted derivatives). The intense band at 1600 cm–1 is
due to the stretching vibrations of the double bond of the
dicyanoethenyl group. The UVꢀVis spectra contain two
bands at 217 (low intensity) and 317—330 nm (high inꢀ
tensity). As with aldehydes 8, the 1ꢀalkyl(allyl) substituꢀ
ents do not affect the spectral pattern; however, introducꢀ
tion of two methyl groups into positions 3 and 5 of the
pyrazole ring results in a bathochromic shift (13—14 nm)
of the lowerꢀfrequency band.
NꢀAlkylpyrazolylmethylidenemalononitriles 9 were
used in reactions with carbonyl compounds and metaꢀ
substituted phenols (Scheme 2).
Reactions of compounds 9 with phenols 10 gave the
corresponding 4Hꢀchromenes 11. The highest yields were
achieved for resorcinol (X = OH), while the use of
3ꢀ(N,Nꢀdiethylamino)phenol (X = NEt2) provided the
lowest yields. Chromenes 11a—i are highꢀmelting colorꢀ
less (X = O), yellow (X = NH2), or dark brown solids
(X = NAlk2); their structures were confirmed by physicoꢀ
chemical data. The 1H NMR spectra of these compounds
(Table 3) show signals for the protons of the aliphatic
groups and the aromatic and pyrazole rings ( 7.18—7.20,
7.40—7.48) as well as broadened signals for the protons of
the 2ꢀamino substituent ( 6.69—6.75). The spectra of
chromenes 11b,e,h additionally contain signals for the proꢀ
tons of the 7ꢀamino substituent ( 6.65—6.67) and signals
for the C(4)H protons of the pyran ring ( 4.48—4.58).32
The higherꢀfield signals correspond to the chromenes conꢀ
taining the NH2 group in the benzene ring. For 7ꢀdialkylꢀ

446
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
Scheme 2
X = O (16), S (17), NH (18)
9
a
b
c
d
e
f
R1
H
Me
H
H
Me
H
R2
Me
Me
Et
Pri
Pri
All
All
11, 13 X (R)
R2
Pri
Pri
Pri
Et
15
a
b
c
d
e
f
g
h
R1
Me
Me
Me
Me
H
Me
Me
H
R2
Pri
Pri
Pri
All
All
Me
Me
Pri
R3
Pri
Ph
Me
Me
But
Pri
19—21
19a
19b
19c
19d
20a
20b
20c
20d
21a
21b
21c
21d
X
O
O
O
O
S
S
S
S
NH
NH
NH
NH
R1
H
Me
H
Me
Me
H
Me
H
R2
Me
Me
Et
Pri
Pri
Me
Me
Et
11a
11b
11c
11d
11e
11f
11g
11h
11i
OH
NH2
NMe2
OH
NH2
NEt2
NMe2
NH2
OH
Et
Et
g
Me
Me
Me
Me
All
Et
Et
But
H
Me
H
Me
Pri
Et
13a
13b
13c
Me
Me
H
Et
Me
Me
aminochromenes 11c,f,g, the signal for the C(4)H proton
is slightly (by ~0.06 ppm) shifted downfield. The downꢀ
field shift of this signal is also observed in the spectra of
7ꢀhydroxychromenes 11a,d,i.
The IR spectra of compounds 11 show a strong band at
2185—2196 cm–1 due to the nitrile group, which is charꢀ
acteristic of 2ꢀaminoꢀ3ꢀcyanopyrans.32 Such a frequency
decrease results from conjugation of the nitrile group with
the pyran ring.
The UVꢀVis spectra of 7ꢀhydroxychromenes 11a,d,i
consist of three wide absorption bands with max = 202—204
( = 55 200—35 400), 233—231 ( = 21 000—15 400), and
267—272 nm (low intensity). The absorption maximum
of the last band experiences a slight hypsochromic shift
when moving from the methyl through ethyl to isopropyl
substituent at the N atom of the pyrazole ring. The UVꢀVis
spectra of 7ꢀaminochromenes 11b,e,h additionally show
a lowꢀintensity band with max = 425–434 nm ( =
= 2400—300), which experiences a slight bathochromic
shift (6—9 nm) and becomes considerably more intense
for 7ꢀdialkylamino derivatives. Another absorption band
of 7ꢀaminochromenes 11b,e,h has max = 270—272 nm
and is virtually insensitive to the alkyl group at the N atom
of the pyrazole ring. For 7ꢀdialkylaminochromenes, this
band experiences a strong bathochromic shift (36—40 nm).
A similar but smaller bathochromic shift (12—15 nm) is obꢀ
served for the absorption band with max = 245—248 nm
in the spectra of 7ꢀaminochromenes 11b,e,h. The shortꢀ
estꢀwavelength band of 7ꢀaminochromenes 11b,e,h and
11c,f,g has max = 211—214 nm, and its position is virtuꢀ
ally affected by neither the alkyl group of the pyrazole ring
nor the alkyl groups of the 7ꢀamino substituent.
Reactions of compounds 9 with dimedone (12, R = Me)
and cyclohexaneꢀ1,3ꢀdione (12, R = H) gave hydrogenatꢀ
1
ed 4Hꢀchromenes 13a—c in good yields. The H NMR
spectra of compounds 13 (see Table 3) show signals for

Formylpyrazoles in the synthesis of heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
447
Table 3. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of 2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀpyrazolylꢀ4Hꢀchromenes 11a—i and 2ꢀ
aminoꢀ3ꢀcyanoꢀ4ꢀpyrazolylꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀchromenes 13a—c
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
IR,
/cm–1
UVꢀVis,
max/nm ()
(%)
N
 (J/Hz)

C
H
11а 64.79 5.51 19.01 C16H16N4O2 1.35 (d, 6 H, (CH3)2CH, J = 6.2); 4.40 (m, 1 H, 3421, 3338, 2980, 2806, 267 (8300),
64.85 5.44 18.91
(CH3)2CHN); 4.58 (s, 1 Н, СН of pyran); 6.35
(s, 1 H, CHAr); 6.51 (d, 1 H, CHAr, J = 8.1);
6.74 (s, 2 H, NH2); 6.93 (d, 1 H, CHAr,
J = 8.1); 7.19, 7.48 (both s, each 1 H,
2691, 2600, 2189 (CN),
1646, 1621, 1587, 1508, 204 (39000)
1463, 1406, 1347,
232 (15400),
1309, 1157
CH of pyrazole); 9.62 (br.s, 1 H, OH)
11b 65.02 5.87 23.75 C16H17N5O 1.35 (d, 6 H, (CH3)2CH, J = 5.5); 4.41 (m,
65.07 5.80 23.71
3440, 3368, 3315, 3234, 427 (560),
1 H, (CH3)2CHN); 4.48 (s, 1 Н, СН of pyran); 3191, 2979, 2933, 2874, 272 (8300),
5.19 (s, 2 H, NH2); 6.16 (s, 1 H, CHAr); 6.30
(d, 1 H, CHAr, J = 7.3); 6.65 (s, 2 H, NH2);
6.76 (d, 1 H, CHAr, J = 7.3); 7.18, 7.46
(both s, each 1 H, CH of pyrazole)
2195 (CN), 1652, 1604,
1572, 1512, 1463, 1407, 211 (50800)
1332, 1247, 1207, 1177
245 (22500),
11c 66.79 6.61 21.58 C18H21N5O 1.35 (d, 6 H, (CH3)2CH, J = 4.0); 2.85 (s, 6 H,
3429, 3318, 3235, 3220, 430 (1300),
3185, 2978, 2931, 2898, 308 (3200),
66.85 6.55 21.66
NMe2);, 4.40 (m, 1 H, (CH3)2CHN); 4.56
(s, 1 Н, СН of pyran); 6.19 (s, 1 H, CHAr);
6.48 (d, 1 H, CHAr, J = 7.0); 6.69 (s, 2 H,
NH2); 6.92 (d, 1 H, CHAr, J = 7.1); 7.19,
7.47 (both s, each 1 H, CH of pyrazole)
2815, 2632, 2196 (CN),
260 (31000),
1638, 1600, 1556, 1521, 214 (42000)
1443, 1397, 1367,
1316, 1291
11d 63.75 5.06 19.76 C15H14N4O2 1.31 (t, 3 H, CH3, J = 6.9); 4.00 (q, 2 H,
63.82 5.00 19.85
3487, 3398, 3346, 3216, 270 (11500),
CH3CH2N, J = 6.9); 4.57 (s, 1 Н, СН of pyran); 3196, 3108, 3038, 2991, 231 (21000),
6.36 (s, 1 H, CHAr); 6.51 (d, 1 H, CHAr,
J = 7.9); 6.75 (s, 2 H, NH2); 6.92 (d, 1 H,
CHAr, J = 8.1); 7.20, 7.47 (both s, each 1 H,
CH of pyrazole); 9.64 (br.s, 1 H, OH)
2936, 2816, 2717, 2686, 202 (55200)
2636, 2185 (CN), 1651,
1618, 1593, 1505, 1493,
1462, 1399, 1357, 1307
11e 64.11 5.37 24.83 C15H15N5O 1.31 (t, 3 H, CH3, J = 6.8); 4.05 (q, 2 H,
64.04 5.37 24.90
3451, 3363, 3323, 3159, 425 (300),
CH3CH2N, J = 6.8); 4.50 (s, 1 Н, СН of pyran); 2988, 2957, 2875, 2185
270 (4300),
(CN), 1662, 1632, 1611, 248 (16000),
1575, 1511, 1448, 1400, 214 (29900)
1359, 1325, 1275
5.20 (s, 2 H, NH2); 6.18 (s, 1 H, CHAr); 6.31
(d, 1 H, CHAr, J = 7.7); 6.67 (s, 2 H, NH2);
6.76 (d, 1 H, CHAr, J = 7.9); 7.20, 7.45
(both s, each 1 H, CH of pyrazole)
11f
67.62 6.90 20.81 C19H23N5O 1.05 (t, 6 H, CH3CH2N, J = 6.0); 1.31 (t, 3 H,
67.63 6.87 20.76
3363, 3321, 3264, 3190, 434 (1100),
CH3CH2N, J = 6.6); 3.31 (m, 2 H, CH3CH2N*); 3109, 2997, 2936, 2894, 310 (3000),
4.04 (q, 2 H, CH3CH2N, J = 6.5); 4.55 (s, 1 Н, 2873, 2684, 2602, 2187 262 (23000),
СН of pyran); 6.12 (s, 1 H, CHAr); 6.42 (d, 1 H, (CN), 1655, 1627, 1608, 213 (28300)
CHAr, J = 6.7); 6.68 (s, 2 H, NH2); 6.88
(d, 1 H, CHAr, J = 7.8); 7.21, 7.47
(both s, each 1 H, CH of pyrazole)
1557, 1515, 1441, 1409,
1378, 1282, 1271, 1251
11g 65.04 5.86 23.69 C16H17N5O 2.85 (s, 6 H, NMe2); 3.74 (s, 3 H, NCH3);
65.07 5.80 23.71
3353, 3309, 3139, 3114, 430 (2400),
4.55 (s, 1 Н, СН of pyran); 6.19 (s, 1 H, CHAr); 2941, 2872, 2807, 2632, 308 (3700),
6.48 (d, 1 H, CHAr, J = 7.3); 6.68 (s, 2 H,
NH2); 6.89 (d, 1 H, CHAr, J = 8.0);
7.18, 7.41 (both s, each 1 H, CH of pyrazole)
2188 (CN), 1661, 1626,
1561, 1518, 1444, 1408, 214 (79000)
1364, 1317, 1274
260 (26000),
11h 62.88 4.96 26.16 C14H13N5O 3.76 (s, 3 H, NCH3); 4.48 (s, 1 Н, СН of pyran); 3465, 3415, 3374, 3332, 425 (2100),
62.91 4.90 26.20
5.18 (s, 2 H, NH2); 6.16 (s, 1 H, CHAr); 6.30
(d, 1 H, CHAr, J = 8.1); 6.65 (s, 2 H, NH2);
6.73 (d, 1 H, CHAr, J = 8.1); 7.17, 7.40
(both s, each 1 H, CH of pyrazole)
3242, 3206, 3182, 3060, 270 (6400),
2973, 2945, 2872, 2664, 248 (16000),
2192 (CN), 1875, 1663,
1640, 1620, 1577, 1557,
1514, 1449, 1400, 1331,
1309, 1274, 1247, 1212
212 (35300)
(to be continued)

448
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
Table 3 (continued)
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
IR,
/cm–1
UVꢀVis,
max/nm ()
(%)
N
 (J/Hz)
C
H
11i
62.63 4.55 20.91 C14H12N4O2 3.75 (s, 3 H NCH3); 4.57 (s, 1 Н, СН of pyran); 3419, 3121, 3086, 3053, 272 (8900),
62.68 4.51 20.88
6.36 (s, 1 H, CHAr); 6.51 (d, 1 H, CHAr,
J = 6.6); 6.75 (s, 2 H, NH2); 6.91 (d, 1 H,
CHAr, J = 7.7); 7.19, 7.43 (both s, each 1 H,
CH of pyrazole); 9.63 (br.s, 1 H, OH)
3027, 2928, 2712, 2673, 233 (13400),
2626, 2196 (CN), 1656,
1621, 1588, 1561, 1503,
1481, 1467, 1405,
1352, 1308
202 (35400)
13a 66.59 6.24 17.32 C16H18N4O2 0.93, 1.02 (both s, each 3 H, CH3); 2.23 (m, 2 H, 3518, 3384, 3158, 2962, 290 (3500),
66.65 6.21 17.27 CH2); 2.43 (s, 2 H, CH2); 4.17 (s, 1 Н, СН 2926, 2892, 2877, 2194 236 (25300)
of pyran); 4.66 (d, 2 H, CHH=CHCH2, J = 4.0); (CN), 1679, 1662 (СО),
5.03 (d, 1 H, CHH=CHCH2, J = 16.9); 5.14 1607, 1555, 1452, 1410,
(d, 1 H, CHH=CHCH2, J = 9.9); 5.95 (m, 1 H, 1370, 1335, 1248
CHH=CHCH2); 6.93 (s, 2 H, NH2); 7.17,
7.40 (both s, each 1 H, CH of pyrazole)
13b 65.42 6.39 17.88 C16H17N5O 0.95, 1.03 (both s, each 3 H, CH3); 1.30 (t, 3 H, 3385, 2957, 2933, 2895, 291 (2500),
65.37 6.45 17.94 CH3CH2, J = 6.8); 2.22 (m, 2 H, CH2); 2.44 2872, 2195 (CN), 2185, 236 (25400)
(s, 2 H, CH2); 4.03 (q, 2 H, CH3CH2, J = 6.8); 1682, 1652 (СО), 1609,
4.16 (s, 1 Н, СН of pyran); 6.92 (s, 2 H, NH2);
7.14, 7.42 (both s, each 1 H, CH of pyrazole)
1556, 1463, 1408,
1368, 1248, 1215
13c 63.43 6.71 19.68 C15H16N4O2 1.31 (t, 3 H, CH3CH2, J = 6.8); 1.92, 2.30
3374, 2956, 2936, 2894, 290 (2800),
63.37 5.67 19.71
(both m, each 2 H, CH2); 2.50 (s, 2 H, CH2)**; 2662, 2188 (CN), 1680, 236 (21000)
4.03 (q, 2 H, CH3CH2, J = 6.8); 4.16 (s, 1 Н,
СН of pyran); 6.91 (s, 2 H, NH2); 7.16, 7.42
(both s, each 1 H, CH of pyrazole)
1650 (СО), 1609, 1557,
1453, 1422, 1409,
1366, 1246, 1252
* Masked by the signal of water.
** Overlap with the signal of the solvent.
the aliphatic protons, signals for the protons of the pyrꢀ
azole ring ( 7.17 and 7.42), and signals for the protons of
the amino group ( 6.91—6.92). The spectra of 7,7ꢀdiꢀ
methylꢀ5,6,7,8ꢀtetrahydrochromenes 13a,b reveal magꢀ
netic nonequivalence of the protons of the methyl groups
in position 7 ( 0.93 and 1.02, respectively), which results
from a special conformation of their molecules. The proꢀ
tons of the methylene group of the cyclohexane ring are
magnetically nonequivalent as well, which results in an
increased number of spectral lines. The IR spectra feature
absorption bands due to the nitrile group at 2194 (for 13a,b)
and 2188 cm–1 (for 13c) and absorption bands due to the
carbonyl group at 1650, 1652, and 1665 cm–1, respectiveꢀ
ly. The UVꢀVis spectra consist of two wide absorption
bands at 236 (high intensity) and 290 nm (low intensity).
Using 5ꢀsubstituted pyrazolꢀ3ꢀones 14 in reactions with
compounds 9, we obtained a number of 6ꢀaminoꢀ5ꢀcyanoꢀ
4ꢀpyrazolylꢀ1,4ꢀdihydropyrano[2,3ꢀc]pyrazoles 15 (see
Scheme 2). The structure of compounds 15a—d,f,g allows
intramolecular interactions between the methyl groups in
positions 3 and 5 of the 4ꢀpyrazolyl substituent and the group
at the C(3) atom of the annulated pyrazole ring. This is most
pronounced in the 1H NMR spectra of compounds 15a—c,f
(Table 4). Such interactions between the methyl groups
and a bulky substituent in position 3 of the pyranopyrazole
molecule make the rotation of the pyrazolyl substituent so
hindered that the signals for the methyl protons of the
isopropyl group become magnetically nonequivalent and
appear as two doublets. The structures of compounds 15
are confirmed by the characteristic signals at  4.59—4.91
for the C(4)H protons of the pyran ring and by the signals
at  6.67—6.77 for the protons of the amino group.41
The IR spectra of compounds 15 feature absorption
bands at 2206—2180 cm–1 (CN), which agrees well with
data for pyranopyrazoles.32 The UVꢀVis spectra show three
absorption bands of medium intensity. When the 4ꢀpyrꢀ
azolyl substituent contains two methyl groups, the middle
band experiences a slight bathochromic shift. For 3ꢀphenꢀ
yl derivative 15b, the lowestꢀfrequency band experiences
a hypsochromic shift by 10 nm and all the bands become
much more intense (the hyperchromic effect).
Reactions of compounds 9 with coumarin 16 and its
heteroanalogs (thiocoumarin 17 and 2,4ꢀdihydroxyquinꢀ
oline 18) afforded 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀoxoꢀ4ꢀpyrazolylꢀ
4H,5Hꢀpyrano[3,2ꢀc]chromenes 19, 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀ
oxoꢀ4ꢀpyrazolylꢀ4H,5Hꢀthiochromeno[4,3ꢀb]pyrans 20,
and 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀoxoꢀ4ꢀpyrazolylꢀ5,6ꢀdihydroꢀ
4Hꢀpyrano[3,2ꢀc]quinolines 21, respectively. The 1H NMR

Formylpyrazoles in the synthesis of heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
449
Table 4. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of 6ꢀaminoꢀ5ꢀcyanoꢀ4ꢀpyrazolylꢀ1,4ꢀdihydropyrano[2,3ꢀc]ꢀ
pyrazoles 15a—h
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6),
IR, /cm–1
UVꢀVis,
max/nm ()
(%)
N
 (J/Hz)

C
H
15a 63.49 7.13 24.81 C18H24N6O2 0.80, 0.94 (both d, each 3 H, (CH3)2CH, J = 6.2); 3505, 3395, 3362, 3119, 260 (6800),
63.51 7.11 24.69
1.28 (m, 6 H, (CH3)2CHN); 1.82, 2.05 (both s,
each 3 H, CH3); 2.50 (m, 1 H, (CH3)2CH)*;
4.37 (m, 1 H, (CH3)2CHN); 4.59 (s, 1 Н,
СН of pyran); 6.67 (s, 2 H, NH2);
2979, 2962, 2924, 2873, 231 (6100),
2196 (CN), 1638, 1603, 201 (10200)
1567, 1526, 1486, 1432,
1402, 1365, 1353, 1333,
12.02 (br.s, 1 H, NH)
1318, 1298, 1255, 1218
15b 65.02 5.87 23.75 C21H22N6O 1.09, 1.18 (both d, each 3 H, (CH3)2CH, J = 4.4); 3600, 3395, 3303, 3145, 250 (25500),
67.36 5.92 24.44 1.71, 2.07 (both s, each 3 H, CH3); 4.26 (m, 1 H, 2977, 2948, 2921, 2873, 230 (18700),
(CH3)2CHN); 4.91 (s, 1 Н, СН of pyran);
6.77 (s, 2 H, NH2); 7.31 (m, 5 H, CHAr);
12.76 (br.s, 1 H, NH)
2180 (CN), 1649, 1610, 201 (34500)
1563, 1503, 1488, 1449,
1435, 1401, 1384, 1371,
1346, 1325, 1259, 1221
15c 67.69 6.91 20.88 C16H20N6O 1.29 (m, 6 H, (CH3)2CH); 1.75, 1.83, 2.08 (all
67.63 6.87 20.76
3682, 3317, 3185, 3051, 260 (9800),
s, each 3 H, CH3); 4.38 (m, 1 H, (CH3)2CHN); 2978, 2933, 2875, 2346, 230 (9100),
4.56 (s, 1 Н, СН of pyran); 6.69 (s, 2 H, NH2);
12.01 (br.s, 1 H, NH)
2206 (CN), 1645, 1618, 201 (14300)
1597, 1558, 1487, 1434,
1398, 1350, 1316,
1280, 1258, 1215
15d 61.85 5.92 27.16 C15H14N4O2 1.77, 1.81, 2.03 (all s, each 3H, CH3); 4.57
3550, 3300, 3116, 3042, 259 (8000),
61.92 5.85 27.08
(m, 3 Н, СН of pyran and NCH2CHCH2); 4.70 2961, 2921, 2196 (CN), 229 (8100),
(d,1 H, NCH2CHCHH, J = 16.9); 5.07 (d, 1 H, 2182, 1650, 1616, 1601, 200 (13800)
NCH2CHCHH, J = 9.2); 5.89 (m, 1 H,
NCH2CHCH2); 6.69 (s, 2 H, NH2);
12.03 (br.s, 1 H, NH)
1564, 1534, 1490, 1432,
1393, 1356, 1331,
1314, 1303, 1214
15e 62.86 6.27 25.83 C17H20N6O 1.09 (s, 9 H, But); 4.64 (s, 1 Н, СН of pyran);
62.95 6.21 25.91 4.68 (d, 2 Н, NCH2CHCH2, J = 4.4); 5.00
3327, 3252, 3227, 3193, 260 (9000),
3095, 3077, 2971, 2940, 225 (9800),
(d, 1 H, NCH2CHCHH, J = 15.8); 5.13 (d, 1 H, 2913, 2879, 2198 (СN), 200 (15600)
NCH2CHCHH, J = 10.3); 5.94 (m, 1 H,
NCH2CHCH2); 6.68 (s, 2 H, NH2); 7.18, 7.41
(both s, each 1 H, CH of pyrazole);
12.09 (br.s, 1 H, NH)
1660, 1603, 1589, 1556,
1517, 1482, 1443, 1422,
1396, 1372, 1360, 1307,
1293, 1277, 1261, 1230
15f
67.62 6.90 20.81 C16H20N6O 1.76 (m, 3 H, CH3CH2, CH3); 2.04 (s, 3 H,
3440, 3318, 3152, 2973, 260 (11900),
2956, 2921, 2894, 2870, 231 (11200),
2191 (CN), 2141, 1657, 201 (18700)
1610, 1591, 1567, 1520,
67.63 6.87 20.76
CH3); 2.48 (m, 2 H, CH3CH2)*; 3.58 (s, 3 H,
CH3); 4.58 (s, 1 Н, СН of pyran); 6.67 (s, 2 H,
NH2); 12.04 (br.s, 1 H, NH)
1492, 1477, 1433, 1408,
1386, 1324, 1290, 1224
15g 60.34 6.16 28.09 C15H18N6O 1.29 (m, 6 H, (CH3)2CH); 1.75, 1.83, 2.08 (all s, 3336, 3312, 3253, 2967, 260 (9500),
60.39 6.08 28.17
each 3 H, CH3); 4.38 (m, 1 H, (CH3)2CHN);
4.56 (s, 1 Н, СН of pyran); 6.69 (s, 2 H, NH2);
12.01 (br.s, 1 H, NH)
2932, 2882, 2696, 2519, 231 (12400),
2353, 2345, 2192 (CN), 201 (13100)
2142, 1655, 1619, 1607,
1558, 1524, 1488, 1469,
1436, 1398, 1375,
1365, 1274, 1220
15h 62.48 6.86 25.66 C17H22N6O 1.05 (s, 9 H, But); 1.33 (m, 6 H, (CH3)2CH);
3650, 3476, 3264, 3137, 260 (12400),
3104, 3080, 2975, 2937, 225 (12400),
2871, 2819, 2666, 2196 200 (24100)
(CN), 1644, 1606, 1573,
62.56 6.79 25.75
4.42 (m, 1 H, (CH3)2CHN); 4.62 (s, 1 Н,
СН of pyran); 6.67 (s, 2 H, NH2); 7.14, 7.39
(both s, each 1 H, CH of pyrazole);
12.03 (br.s, 1 H, NH)
1508, 1484, 1447, 1401,
1367, 1291, 1263,
1228, 1213
* Masked by the signal of the solvent.

450
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
spectra of these compounds (Table 5) show signals for the
protons of the benzene ring, a signal for the amino group,
a signal for the C(4)H proton of the pyran ring, and signals
of the aliphatic substituents in the pyrazole ring. For comꢀ
pounds 21, the spectra additionally contain a wide signal
for the N(6)H proton. Note that although the spectral
regions relating to the protons of the benzene ring are
generally similar, the lowestꢀfield signals for these protons
in chromeno[3,2ꢀc]pyrans 19 and pyrano[3,2ꢀc]quinolines 21
appear at  7.85—7.89, while analogous signals in the spectra
of thiochromeno[4,3ꢀb]pyrans 20 appear at  8.34—8.37.
The UVꢀVis spectra of products 19—21 are rather comꢀ
plicated because of superposition of many absorption
bands. The positions of the absorption bands are virtually
insensitive to the number of alkyl substituents in the pyrꢀ
azole ring; however, an increase in their number produces
a hyperchromic effect on the band intensities. Chromenes 19
are characterized by max = 203 nm, while replacement of
the O atom by the S atom results in a strong bathochromic
shift of this band to max = 236 nm in the spectra of thioꢀ
chromenes 20. For pyranoquinolines 21, the maximum of
this band appears at 228 nm. In addition, the UVꢀVis
spectra of compounds 21 show three closely spaced lines
arranged in a nearly regular triplet with a center at 322 nm,
which is absent from the spectra of compounds 19 and 20.
The IR spectra of products 19—21 are also complicatꢀ
ed. The stretching vibrations of the carbonyl group are
manifested by a band at 1669—1679 cm–1 in the spectra of
compounds 19 and 20 and by two bands in the spectra of
compounds 21: one at 1670—1672 cm–1 (amide band I
due to the C=O stretching vibrations) and the other at
1648—1651 cm–1 (amide band II due to the NH bending
vibrations). A strong band at 2180—2198 cm–1 (conjuꢀ
gated CN) is also characteristic. In addition, each of
these heteroanalogs specifically absorbs at 1373—1375,
1553—1554, and 1378—1382 cm–1 (for 19—21, respectively).
Table 5. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀoxoꢀ4ꢀ(1Hꢀpyrazolyl)ꢀ4H,5Hꢀpyranoꢀ
chromenes 19a—d, 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀoxoꢀ4ꢀ(1Hꢀpyrazolyl)ꢀ4H,5Hꢀthiochromeno[4,3ꢀb]pyrans 20a—d, and 2ꢀaminoꢀ3ꢀcyanoꢀ
5ꢀoxoꢀ4ꢀpyrazolylꢀ5,6ꢀdihydroꢀ4Hꢀpyrano[3,2ꢀc]quinolines 21a—d
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6), (J/Hz)
IR, /cm–1
UVꢀVis,
max/nm ()
(%)
N

C
H
19а 63.81 3.80 17.51 C17H12N4O3 3.75 (s, 3 H, CH3N); 4.43 (s, 1 Н, СН
3419, 3307, 3281, 3249, 308 (6700),
3121, 3111, 2875, 2195 285 (8000),
(CN), 1711, 1678, 1644, 245 (12500),
1602, 1533, 1497, 1456, 213 (25600),
63.75 3.78 17.49
of pyran); 7.30 (s, 1 H, CH of pyrazole);
7.32 (s, 2 H, NH2); 7.47 (m, 2 H, CHAr);
7.58 (s, 1 H, CH of pyrazole);
7.70, 7.86 (both m, each 1 H, CHAr)
1405, 1373, 1302
203 (32000)
19b 65.43 4.66 15.99 C19H16N4O3 1.93, 2.13 (both s, each 3 H, CH3); 3.59 (s, 3 H, 3412, 3298, 3155, 2962, 307 (11800),
65.51 4.63 16.08
CH3N); 4.39 (s, 1 Н, СН of pyran);
7.25 (s, 2 H, NH2); 7.45 (m, 2 H, CHAr);
7.68, 7.87 (both m, each 1 H, CHAr)
3121, 3111, 2875, 2188 278 (11700),
(CN), 1699, 1677, 1647, 246 (22600),
1610, 1563, 1495, 1458, 211 (42500),
1438, 1374, 1326, 1305 205 (47400)
19c 66.97 5.35 14.81 C18H14N4O3 1.30 (t, 3 H, CH3, J = 7.2); 4.03 (q, 2 H,
67.01 5.36 14.88
3354, 3311, 3265, 3143, 307 (10700),
CH3CH2N, J = 7.2); 4.42 (s, 1 Н, СН of pyran); 3109, 2978, 2942, 2198 283 (12000),
7.31 (br.s, 3 H, CH of pyrazole, NH2); 7.48
(m, 2 H, CHAr); 7.61 (s, 1 H, CH of pyrazole);
7.69, 7.85 (both m, each 1 H, CHAr)
(CN), 1724, 1672, 1648, 245 (18700),
1609, 1555, 1494, 1456, 213 (38100),
1395, 1375, 1352,
1328, 1306
205 (46100)
19d 65.47 4.75 16.22 C19H16N4O3 1.29 (d, 6 H, (CH3)2CH, J = 5.9); 1.92,
3565, 3360, 3144, 3114, 308 (10100),
2962, 2979, 2949, 2934, 277 (10600),
2656, 2192 (CN), 1728, 245 (17600),
1712, 1671, 1642, 1610, 213 (39300),
1557, 1494, 1455, 1437, 203 (45000)
1374, 1326, 1310
65.51 4.63 16.08
2.15 (both s, each 3 H, CH3); 3.44 (m, 1 H,
(CH3)2CHN); 4.41 (s, 1 H, СН of pyran);
7.26 (br.s, 2 H, NH2); 7.47 (m, 1 H, CHAr);
7.70 (m, 2 H, CHAr);
7.89 (d, 1 H, CHAr, J = 7.0)
20a 63.19 5.24 14.17 C21H24N4O2S 1.33 (d, 6 H, (CH3)2CH, J = 5.9); 1.92, 2.15
3463, 3250, 3070, 2985, 330 (6300),
2938, 2832, 2194 (CN), 300 (10200),
1677, 1631, 1590, 1554, 260 (12600),
64.27 5.14 14.28
(both s, each 3 H, CH3); 4.38 (m, 1 H,
(CH3)2CHN, 4.56 (s, 1 H, СН of pyran); 7.26
(br.s, 2 H, NH2); 7.62 (m, 1 H, CHAr); 7.70
(m, 2 H, CHAr); 8.37 (d, 1 H, CHAr, J = 7.3)
1489, 1475, 1435,
1397, 1349, 1310
255 (15700),
236 (50600)
(to be continued)

Formylpyrazoles in the synthesis of heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
451
Table 5 (continued)
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6), (J/Hz)
IR, /cm–1
UVꢀVis,
max/nm ()
(%)
N
C
H
20b
60.59 3.71 16.49 C17H12N4O2S 3.73 (s, 3 H, CH3N); 4.59 (s, 1 Н, СН of pyran); 3396, 3315, 3273, 3198, 330 (5300),
60.70 3.60 16.66
7.22 (s, 1 H, CH of pyrazole); 7.38 (s, 2 H,
NH2); 7.50 (s, 1 H, CH of pyrazole);
7.60 (m, 1 H, CHAr); 7.69 (m, 2 H, CHAr);
8.34 (d, 1 H, CHAr, J = 7.3)
3110, 2940, 2197 (CN), 300 (6700),
1670, 1625, 1608, 1587, 260 (9400),
1483, 1436, 1405,
1360, 1309
255 (10700),
236 (51100)
20c 62.55 4.48 15.51 C19H16N4O2S 1.90, 2.11 (both s, each 3 H, CH3); 3.58 (s, 3 H, 3301, 3124, 3070, 2980, 330 (6600),
62.62 4.43 15.37 CH3N); 4.53 (s, 1 Н, СН of pyran); 7.27 (br.s, 2946, 2919, 2196 (CN), 300 (12300),
2 H, NH2); 7.61 (m, 1 H, CHAr); 7.69 (m, 2 H, 1672, 1623, 1603, 1558, 260 (14600),
CHAr); 8.36 (d, 1 H, CHAr, J = 7.3)
1554, 1510, 1479, 1432, 255 (19300),
1421, 1396, 1353, 1300 236 (62600)
20d 61.62 4.08 15.89 C18H14N4O2S 1.29 (t, 3 H, CH3, J = 7.2); 4.02 (q, 2 H,
61.70 4.03 15.99
3395, 3316, 3273, 3223, 330 (6300),
CH3CH2N, J = 7.2); 4.59 (s, 1 Н, СН of pyran); 3201, 3069, 2977, 2198 300 (11900),
7.23 (s, 1 Н, CH of pyrazole); 7.39 (br.s, 2 H,
NH2); 7.53 (s, 1 H, CH of pyrazole);
7.60 (m, 1 H, CHAr); 7.69 (m, 2 H, CHAr);
8.34 (d, 1 H, CHAr, J = 7.3)
(CN), 1670, 1624, 1610, 260 (14000),
1589, 1553, 1483, 1433, 255 (19600),
1408, 1358, 1309
236 (33700)
21a 63.93 4.15 21.87 C17H13N5O2 3.74 (s, 3 H, CH3N); 4.48 (s, 1 Н, СН
3353, 3284, 3131, 3075, 336 (6400),
3028, 2967, 2912, 2867, 322 (8300),
2748, 2183 (CN), 1679 310 (6400),
63.94 4.10 21.93
of pyran); 7.19 (s, 1 H, CH of pyrazole);
7.25 (s, 2 H, NH2); 7.34 (m, 2 H, CHAr); 7.49
(s, 1 H, CH of pyrazole); 7.56 (m, 1 H, CHAr);
7.86 (d, 1 H, CHAr, J = 6.6);
(СО, amide band I),
1652 (NH, amide
272 (6400),
243 (19200),
228 (53640),
11.78 (s, 1 H, NH)
band II), 1630, 1608,
1584, 1562, 1500, 1489, 215 (44700),
1437, 1414, 1401,
1380, 1323, 1294
202 (26800)
21b 67.09 5.73 18.58 C21H21N5O2 1.28 (d, 6 H, (CH3)2CH, J = 5.8);
3507, 3355, 3176, 3075, 336 (5300),
3020, 2973, 2930, 2899, 322 (7100),
2867, 2197 (CN), 1677 310 (5600),
67.18 5.64 18.65
1.93, 2.16 (both s, each 3 H, CH3);
3.44 (m, 1 H, (CH3)2CHN);
4.44 (s, 1 Н, СН of pyran); 7.07 (s, 2 H,
NH2); 7.29 (m, 2 H, CHAr);
(СО, amide band I),
1651 (NH, amide
band II), 1630, 1606,
272 (7500),
243 (16900),
228 (47300),
7.56, 7.89 (both m, each 1 H, CHAr);
11.62 (s, 1 H, NH)
1581, 1558, 1503, 1488, 215 (37500),
1434, 1382, 1352,
1327, 1309
202 (27300)
21c 64.67 4.63 20.89 C18H15N5O2 1.29 (t, 3 H, CH3, J = 7.2);
3322, 3290, 3204, 3146, 336 (4700),
2990, 2981, 2952, 2906, 322 (6000),
2893, 2735, 2190 (CN), 310 (4800),
1689, 1669 (СО, amide 272 (2900),
64.86 4.54 21.01
4.02 (q, 2 H, CH3CH2N, J = 7.2);
4.48 (s, 1 Н, СН of pyran);
7.19 (s, 1 H, CH of pyrazole);
7.26 (s, 2 H, NH2); 7.31 (m, 2 H, CHAr);
7.51 (s, 1 H, CH of pyrazole);
7.55, 7.85 (both m, each 1 H, CHAr);
11.78 (s, 1 H, NH)
band I), 1658 (NH,
amide band II),
243 (14700),
228 (40700),
1632, 1601, 1557, 1501, 215 (36000),
1469, 1431, 1413,
1382, 1319
202 (24000)
21d 65.48 5.07 20.09 C19H17N5O2 1.28 (d, 6 H, (CH3)2CH, J = 5.8);
3333, 3289, 3185, 3123, 336 (6950),
3072, 2979, 2953, 2919, 322 (10400),
2735, 2194 (CN), 1682, 310 (8300),
65.69 4.93 20.16
1.93, 2.16 (both s, each 3 H, CH3);
3.44 (m, 1 H, (CH3)2CHN);
4.44 (s, 1 H, СН of pyran); 7.07 (br.s,
2 H, NH2); 7.30 (m, 2 H, CHAr);
7.56, 7.88 (both m, each 1 H, CHAr);
11.62 (s, 1 H, NH)
1672 (СО, amide
band I), 1648 (NH,
amide band II),
1635, 1601, 1582, 1554, 215 (55600),
1498, 1430, 1408, 1378, 202 (27800)
1348, 1325
272 (10500),
243 (24300),
228 (63900),

452
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
The yields of pyrans 11, 13, 15, and 19—21 range from
4,5ꢀdihydroꢀ1,3ꢀthiazolꢀ2ꢀyl)acetonitrile (23) containing
two active methylene groups. These reactions reportedly
yield either 5ꢀaminoꢀ7ꢀarylꢀ6ꢀcyanoꢀ2ꢀcyanomethylꢀ7Hꢀ
pyrano[2,3ꢀd]thiazoles 24 (see Ref. 33) or the correspondꢀ
ing 2,3ꢀdihydroꢀ3ꢀoxoꢀ7Hꢀ[1,3]thiazolo[3,2ꢀa]pyridinꢀ
es 25 (Scheme 3).46—49
For this reason, we found it interesting to study reacꢀ
tions of pyrazolylmethylidenemalononitriles 9 with thiꢀ
azolone 23. Compounds 9 react with cyanomethylthiaꢀ
zolone 23 in EtOH in the presence of Et3N to give colored
(from lemon yellow to orange) products in low yields.
The highest yields were achieved when two equivalents of
compound 9 were used. This suggests that the reaction
follows pathway B (see Scheme 3) leading to thiazoloꢀ
pyridines 27 rather than pyranothiazoles 26 (Scheme 4).
One can assume that the formation of compounds 27 inꢀ
volves the following pattern of a "domino" reaction:
Michael addition  Thorpe—Ziegler reaction  retroꢀ
Michael reaction. The possible sequence of the last two
reactions remains a subject of debate.
moderate (25—45%) for phenols and pyrazolones to high
(60—80%) for coumarin and its heteroanalogs. This scatꢀ
ter is probably associated with the reversibility of the Thorꢀ
pe—Ziegler and Michael reactions.
Earlier, ambiguous results have been obtained in reacꢀ
tions of aryl(hetaryl)idenemalononitriles 22 with 2ꢀ(4ꢀoxoꢀ
Scheme 3
To optimize the synthetic procedure, we carried out
a threeꢀcomponent reaction between equimolar amounts of
aldehyde 8a, Nꢀmethylpyrazolylmethylidenemalononitrꢀ
ile 9a, and thiazolone 23. Thiazolopyridine 27c was obꢀ
tained in good yield. This reaction also follows the "domiꢀ
Scheme 4
27: R1 = H, R2 = Et (a); R1 = R2 = Me (b); R1 = H, R2 = Me (c); R1 = H, R2 = Pri (d); R1 = H, R2 = All (e)

Formylpyrazoles in the synthesis of heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
453
procedures.44,51,52 1ꢀMethylpyrazole (7a),51 b.p. 126 C; 1,3,5ꢀtriꢀ
methylpyrazole (7b),52 b.p. 171 C; 1ꢀethylpyrazole (7c), b.p.
137—138 C (cf. Ref. 44: b.p. 126 C). Pyrazole, 3,5ꢀdimethylꢀ
pyrazole, malononitrile, phenols 10, dimedone, cyclohexaneꢀ
1,3ꢀdione, pyrazolones 14, 4ꢀhydroxycoumarin (16), and 4ꢀhydrꢀ
oxyquinolinꢀ2ꢀone (18) were commercial chemicals (Acros).
4ꢀHydroxythiocoumarin (17) (m.p. 154 C) and 2ꢀ(4ꢀoxoꢀ4,5ꢀdiꢀ
hydroꢀ1,3ꢀthiazolꢀ2ꢀyl)acetonitrile (23) were synthesized as deꢀ
scribed earlier.53,54 Commercial DMF for the Vilsmeier reacꢀ
tion was kept over CaH2 (2 g per 100 mL) for at least 24 h and
distilled in vacuo immediately before use. Other solvents were
purified simply by distillation.
Synthesis of 1ꢀalkylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehydes 8a—f (genꢀ
eral procedure). Method A. A 500ꢀmL fourꢀneck flask equipped
with a mercuryꢀsealed mechanical stirrer, a thermometer, a dropꢀ
ping funnel, a gas inlet, and a reflux condenser capped with
a calcium chloride tube was purged two times with dry argon and
charged with a mixture of an appropriate Nꢀalkylpyrazole
(1 mol) and freshly distilled dry DMF (1.15 mol). The flask was
cooled on a bath filled with a mixture of ice and NaCl. Freshly
distilled POCl3 (1.15 mol) was added dropwise under argon at
0 C to the stirred mixture. The addition rate was such as to
prevent the temperature from rising above 20 C. After the addiꢀ
tion of POCl3 was completed, the cooling bath was removed.
The reaction mixture was stirred at room temperature for 1 h,
turning dark red. Then the reaction mixture was stirred for 18 h
on a boiling water bath, turning brown. On cooling, the resulting
thick mixture was poured with stirring into a 2ꢀL beaker filled
no" pattern: Michael addition  Thorpe—Ziegler reacꢀ
tion  Knoevenagel condensation (see Scheme 4).
Structures 27 were confirmed by spectroscopic data.
1
The H NMR spectra show signals for the protons of two
pyrazole fragments, a signal at  7.6—7.9 for the proton at the
exocyclic double bond, and no signal for the methylene
group (Table 6). The presence of absorption bands at 2212
and 2188—2200 cm–1 in the IR spectra indicates the conꢀ
jugation of the nitrile groups.32,50 This is evidence in favor
of structure 27 and so is the presence of strong absorption
bands at 1648—1662 cm–1 (C=O). Elemental analysis data
correspond to the molecular formulas of compounds 27.
The high degree of conjugation in structures 27 accounts
for their intense color. They strongly absorb at ~370 nm,
which is near the visible region of the UVꢀVis spectrum.
Experimental
1
H NMR spectra were recorded on a Bruker AMꢀ300 instruꢀ
ment in DMSOꢀd6. IR spectra were recorded on a Bruker
instrument (KBr pellets). UVꢀVis spectra were recorded on
a Specord M80ꢀ2 instrument in MeOH. Melting points were
measured on a Kofler hot stage and are given uncorrected.
1ꢀAlkylpyrazoles 7 used in the synthesis of 1ꢀalkylꢀ1Hꢀpyrꢀ
azoleꢀ4ꢀcarbaldehydes 8a—c were prepared according to known
Table 6. Elemental analysis data and 1H NMR, IR, and UVꢀVis spectra of 7Hꢀthiazolo[3,2ꢀa]pyridines 27a—e
Comꢀ Found
pound Calculated
Molecular
formula
1H NMR (DMSOꢀd6),  (J/Hz)
IR, /cm–1
UVꢀVis,
max/nm ()
(%)
N

C
H
27a 57.29 4.45 26.53 С20H18N8OS 1.38 (m, 6 H, CH3CH2); 4.12, 4.24 (both q,
3400 (NH2), 2212 (CN), 368 (20900),
57.40 4.34 26.78
each 2 H, CH3CH2, J = 6.4); 4.54 (s, 1 H,
CH of pyridine); 7.38 (s, 2 H, NH2); 7.44
(s, 1 H, CH of pyrazole); 7.76 (s, 2 H,
CH of pyrazole); 7.86 (s, 1 H, CH of pyrazole);
8.28 (s, 1 H, CH)
2196 (CN), 1700,
1652 (CO), 1612, 1568
297 (14600),
274 (17600),
221 (33400)
27b 59.12 5.03 24.87 С22H22N8OS 2.02, 2.16, 2.19, 2.28 (all s, each 3 H, CH3);
3440 (NH2), 2212 (CN), 371 (27300),
59.18 4.97 25.09
3.64, 3.70 (both s, each 3 H, NCH3); 4.58
(s, 1 H, CH of pyridine); 7.46 (s, 2 H, NH2);
7.63 (s, 1 H, CH)
2188 (CN), 1692,
1648 (CO), 1604, 1548
284 (19600),
221 (25000)
27c 55.29 3.68 28.59 С18H48N8OS 3.83, 3.94 (both s, each 3 H, NCH3); 4.53
3384 (NH2), 2212 (CN), 367 (20500),
55.37 3.61 28.70
(s, 1 H, CH of pyridine); 7.39 (s, 2 H,
NH2); 7.44, 7.71, 7.76, 7.85 (all s, each 1 H,
CH of pyrazole); 8.25 (s, 1 H, CH)
2200 (CN), 1700, 1662
(CO), 1608, 1540
299 (10800),
277 (122000),
221 (16600)
27d 59.05 5.08 24.93 С22H22N8OS 1.40 (m, 12 H, СH(CH3)2); 4.23 (q, 1 H,
3452 (NH2), 2208 (CN), 369 (316000),
59.18 4.97 25.09
NСH(CH3)2, J = 6.4); 4.53 (s, 1 H,
CH of pyridine); 4.65 (q, 1 H, NСH(CH3)2,
J = 6.4); 7.44 (m, 3 H, NH2, CH of pyrazole);
7.78, 7.87, 7.85 (all s, each 1 H, CH of pyrazole);
8.29 (s, 1 H, CH)
2192 (CN), 1708,
1652 (CO),
1608, 1540
300 (14700),
278 (16400),
230 (22200)
27e 59.64 4.15 25.22 С22H18N8OS 4.57 (s, 1 H, CH of pyridine); 4.75 (d, 2 H,
59.71 4.10 25.32 NCH2CH=CH2, J = 3.0); 4.88 (d, 2 H,
3420 (NH2), 2212 (CN), 367 (22100),
2196 (CN), 1700,
303 (8400),
278 (9700),
231 (14200)
NCH2CH=CH2, J = 3.0); 5.00—5.30 (m, 5 H, 1648 (CO), 1612, 1564
CH of pyridine, CH2CH=CH2); 6.00 (m, 2 H,
CH2CH=CH2); 7.45 (s, 2 H, NH2); 7.49, 7.75,
7.78, 7.91 (all s, each 1 H, CH of pyrazole);
8.29 (s, 1 H, CH)

454
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Mortikov et al.
with crushed ice (1 kg) (in some experiments, the mixture beꢀ
came too thick to be poured out, and its liquefaction by heating
was required). After the ice melted roughly by half, solidꢀstate
KOH was added in small portions with stirring to pH ~9 (to
avoid a temperature rise above 60 C, some ice was added to the
mixture). On cooling to 35—40 C, the product was extracted
with CHCl3 (6×100 mL). The extract was dried with anhydrous
Na2SO4 and concentrated on a rotary evaporator. The residue
was either distilled in vacuo or recrystallized from ethanol.
1ꢀMethylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8a). Yield 40%,
a yellowish liquid solidifying in storage, b.p. 90—92 C (10 Torr)
(cf. Ref. 43: b.p. 106—108 C (20 Torr)), m.p. 28 C (cf. Ref. 55:
m.p. 30 C).
1,3,5ꢀTrimethylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8b). Yield 86%,
colorless crystals, m.p. 81 C (EtOH) (cf. Ref. 45: m.p. 79 C),
b.p. 136—138 C (8 Torr) (cf. Ref. 45: b.p. 132 C (12 Torr)).
1ꢀEthylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8c). Yield 58%, yelꢀ
lowish liquid, b.p. 96—98 C (7 Torr) (cf. Ref. 44: b.p. 46—48 C
(5 Torr)), nD20 1.5179 (cf. Ref. 44: nD20 1.5183).
2ꢀ[(1ꢀMethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malononitrile
(9a). Yield 87%, colorless crystals, m.p. 136 C (EtOH).
2ꢀ[(1,3,5ꢀTrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malonoꢀ
nitrile (9b). Yield 83%, colorless crystals, m.p. 112 C (EtOH).
2ꢀ[(1ꢀEthylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malononitrile (9c).
Yield 58%, colorless crystals, m.p. 92 C (EtOH).
2ꢀ[(1ꢀIsopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malononitrile
(9d). Yield 75%, colorless crystals, m.p. 73 C (EtOH).
2ꢀ[(1ꢀIsopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ
malononitrile (9e). Yield 77%, colorless crystals, m.p. 115 C (EtOH).
2ꢀ[(1ꢀAllylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malononitrile (9f).
Yield 81%, colorless crystals, m.p. 90 C (EtOH).
2ꢀ[(1ꢀAllylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]malꢀ
ononitrile (9g). Yield 85%, colorless crystals, m.p. 52 C (EtOH).
The spectra and elemental analysis data for compounds 9a—g
are given in Table 2.
Synthesis of 2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀpyrazolylꢀ4Hꢀchromenes
11a—i, 2ꢀaminoꢀ3ꢀcyanoꢀ4ꢀpyrazolylꢀ5,6,7,8ꢀtetrahydroꢀ4Hꢀ
chromenes 13a—c, 6ꢀaminoꢀ5ꢀcyanoꢀ4ꢀpyrazolylꢀ1,4ꢀdihydroꢀ
pyranopyrazoles 15a—h, 2ꢀaminoꢀ3ꢀcyanoꢀ5ꢀoxoꢀ4ꢀ(1Hꢀpyrꢀ
azolyl)ꢀ4H,5Hꢀpyranochromenes 19a—d, and 2ꢀaminoꢀ3ꢀcyanoꢀ
5ꢀoxoꢀ4ꢀ(1Hꢀpyrazolyl)ꢀ4H,5Hꢀthiochromeno[4,3ꢀb]pyrans 20a—d
(general procedure). A mixture of Nꢀalkylpyrazolylmethylideneꢀ
malononitrile 9 (1 mmol), a carbonyl compound (or metaꢀsubꢀ
stituted phenol) (1.1 mmol), and Et3N (2—3 drops) was refluxed
in EtOH (10 mL) for 1 h. On cooling, the reaction mixture was
diluted with water (10 mL) and left at 0 C for 8 h. The precipiꢀ
tate that formed was filtered off, washed with cold (0 C) ethanol
and hexane, and dried in air. In most cases, the compounds
obtained were analytically pure. When needed, they were reꢀ
crystallized from a small amount of ethanol.
2ꢀAminoꢀ7ꢀhydroxyꢀ4ꢀ(1ꢀisopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀ
chromeneꢀ3ꢀcarbonitrile (11a). Yield 57%, colorless powder,
m.p. 169 C.
2,7ꢀDiaminoꢀ4ꢀ(1ꢀisopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀchromꢀ
eneꢀ3ꢀcarbonitrile (11b). Yield 53%, yellow powder, m.p. 198 C.
2ꢀAminoꢀ7ꢀdimethylaminoꢀ4ꢀ(1ꢀisopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
4Hꢀchromeneꢀ3ꢀcarbonitrile (11c). Yield 38%, brown powder,
m.p. 202 C (EtOH).
The spectra and elemental analysis data for compounds 8a—c
are given in Table 1.
Method B. In contrast to method A, intermediate Nꢀalkylꢀ
pyrazoles were not isolated in the individual state. A 500ꢀmL
roundꢀbottomed threeꢀneck flask equipped with a mercuryꢀ
sealed mechanical stirrer, a reflux condenser, and a thermomeꢀ
ter was charged with pyrazole or 2,5ꢀdimethylpyrazole (1 mol),
calcined K2CO3 (1 mol), DMF (150 mL), and an appropriate
alkyl halide (PriI or AllBr, 1.2 mol). The reaction mixture was
heated to 80 C with stirring and kept quiet at this temperature
for 24 h. On cooling, the reaction mixture was diluted with
CH2Cl2 (250 mL) and filtered. The filter cake was washed with
CH2Cl2 (150 mL). The combined filtrates were fractionated on
a heated Vigreux column (h = 70 cm), while collecting a fraction
with b.p. <100 C at atmospheric pressure. Then the still botꢀ
toms were evaporated almost to dryness under reduced pressure
(100—150 Torr) to collect a fraction with b.p. >100 C (with
reference to 760 Torr). This fraction consisting of Nꢀalkylpyrꢀ
azole and DMF was further treated with POCl3 (1.15 mol) as
described in method A.
1ꢀIsopropylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8d). Yield 65%,
a colorless liquid with a keen pyridine odor, b.p. 100—102 C
(7 Torr), nD20 1.5165.
1ꢀIsopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8e).
Yield 87%, colorless crystals, m.p. 115 C (EtOH).
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ7ꢀhydroxyꢀ4Hꢀchromꢀ
eneꢀ3ꢀcarbonitrile (11d). Yield 55%, colorless powder, m.p. 232 C.
2,7ꢀDiaminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀchromeneꢀ3ꢀ
carbonitrile (11e). Yield 47%, yellow powder, m.p. 179 C.
2ꢀAminoꢀ7ꢀdiethylaminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀ
chromeneꢀ3ꢀcarbonitrile (11f). Yield 41%, brown powder, m.p.
148 C (EtOH).
2ꢀAminoꢀ7ꢀdimethylaminoꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
4Hꢀchromeneꢀ3ꢀcarbonitrile (11g). Yield 35%, brown powder,
m.p. 208 C (EtOH).
2,7ꢀDiaminoꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀchromeneꢀ
3ꢀcarbonitrile (11h). Yield 49%, yellow powder, m.p. 142 C.
2ꢀAminoꢀ7ꢀhydroxyꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀ
chromeneꢀ3ꢀcarbonitrile (11i). Yield 45%, colorless powder, m.p.
253 C (EtOH).
1ꢀAllylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8f). Yield 61%, a colorꢀ
less liquid with a keen pyridine odor, b.p. 106—107 C (5 Torr),
20
nD 1.5298.
1ꢀAllylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde (8g). Yield
55%, yellowish viscous liquid, b.p. 138—139 C (6 Torr),
20
nD 1.5293.
The spectra and elemental analysis data for compounds 8d—g
are given in Table 1.
Synthesis of Nꢀalkylpyrazolylmethylidenemalononitriles 9a—g
(general procedure). Triethylamine (1 mL) was added to a solution
of an appropriate 1ꢀalkylpyrazoleꢀ4ꢀcarbaldehyde (0.1 mol) and
malononitrile (0.1 mol) in EtOH (100 mL). The reaction mixture
was refluxed for 30 min, cooled, diluted with water (100 mL),
and left at 0 C for 8 h. The precipitate that formed was filtered
off, washed on the filter with water, cold (0 C) 50% aqueous
EtOH (20 mL), and hexane, and dried in a desiccator over P2O5. In
most cases, the compounds obtained were analytically pure. When
needed, they were recrystallized from a small amount of EtOH.
The spectra and elemental analysis data for compounds 11a—i
are given in Table 3.
4ꢀ(1ꢀAllylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀaminoꢀ7,7ꢀdimethylꢀ5,6,7,8ꢀ
tetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile (13a). Yield 51%, colꢀ
orless powder, m.p. 94 C.
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ7,7ꢀdimethylꢀ5,6,7,8ꢀ
tetrahydroꢀ4Hꢀchromeneꢀ3ꢀcarbonitrile (13b). Yield 65%, colꢀ
orless powder, m.p. 158 C.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
455
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5,6,7,8ꢀtetrahydroꢀ
4Hꢀchromeneꢀ3ꢀcarbonitrile (13c). Yield 58%, colorless powder,
m.p. 157 C (EtOH).
The spectra and elemental analysis data for compounds 13a—c
are given in Table 3.
6ꢀAminoꢀ3ꢀisopropylꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrꢀ
azolꢀ4ꢀyl)ꢀ1,4ꢀdihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15a).
Yield 57%, colorless powder, m.p. 242 C.
6ꢀAminoꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ
phenylꢀ1,4ꢀdihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15b).
Yield 63%, colorless powder, m.p. 156 C.
6ꢀAminoꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ3ꢀ
methylꢀ1,4ꢀdihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15c).
Yield 58%, colorless powder, m.p. 154 C.
4ꢀ(1ꢀAllylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ6ꢀaminoꢀ3ꢀmethꢀ
ylꢀ1,4ꢀdihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15d). Yield
45%, colorless powder, m.p. 158 C.
water, cold (0 C) EtOH, and hexane, and dried in air. In most
cases, the compounds obtained were analytically pure. When needꢀ
ed, they were recrystallized from a small amount of ethanol.
2ꢀAminoꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ
4Hꢀpyrano[3,2ꢀc]quinolineꢀ3ꢀcarbonitrile (21a). Yield 85%,
creamꢀcolored powder, m.p. 247 C (EtOH).
2ꢀAminoꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀ
oxoꢀ5,6ꢀdihydroꢀ4Hꢀpyrano[3,2ꢀc]quinolineꢀ3ꢀcarbonitrile (21b).
Yield 82%, colorless powder, m.p. 262 C.
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ
4Hꢀpyrano[3,2ꢀc]quinolineꢀ3ꢀcarbonitrile (21c). Yield 79%,
creamꢀcolored powder, m.p. 265 C.
2ꢀAminoꢀ5ꢀoxoꢀ4ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5,6ꢀdiꢀ
hydroꢀ4Hꢀpyrano[3,2ꢀc]quinolineꢀ3ꢀcarbonitrile (21d). Yield
86%, creamꢀcolored powder, m.p. 330 C.
The spectra and elemental analysis data for compounds 19—21
are given in Table 5.
4ꢀ(1ꢀAllylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ6ꢀaminoꢀ3ꢀtertꢀbutylꢀ1,4ꢀdiꢀ
hydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15e). Yield 47%, colꢀ
orless powder, m.p. 206 C.
6ꢀAminoꢀ3ꢀisopropylꢀ4ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
1,4ꢀdihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15f). Yield
51%, colorless powder, m.p. 145 C (EtOH).
6ꢀAminoꢀ3ꢀethylꢀ4ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ1,4ꢀ
dihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15g). Yield 60%,
colorless powder, m.p. 256 C.
6ꢀAminoꢀ3ꢀtertꢀbutylꢀ4ꢀ(1ꢀisopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ1,4ꢀ
dihydropyrano[2,3ꢀc]pyrazoleꢀ5ꢀcarbonitrile (15h). Yield 55%,
colorless powder, m.p. 226 C.
Synthesis of 2,3ꢀdihydroꢀ7Hꢀthiazolo[3,2ꢀa]pyridines 27a—c
(general procedure). A. 2ꢀ(4ꢀOxothiazolꢀ2ꢀyl)acetonitrile 23
(1 mmol) was added to a hot (60 C) solution of appropriate
Nꢀalkylpyrazolylmethylidenemalononitrile 9 (2 mmol) in EtOH
(10 mL). The reaction mixture was refluxed to complete homoꢀ
genization. Then Et3N (2—3 drops) was added, and the reflux
was continued for an additional 30 min. On cooling, the precipꢀ
itate that formed was filtered off, washed with EtOH and hexꢀ
ane, and dried. In most cases, the compounds obtained were
analytically pure. When needed, they were recrystallized from
a small amount of EtOH. The spectra and elemental analysis
data for compounds 27a—e are given in Table 6.
The spectra and elemental analysis data for compounds 15a—h
are given in Table 4.
5ꢀAminoꢀ7ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ[(1ꢀethylꢀ1Hꢀpyrꢀ
azolꢀ4ꢀyl)methylidene]ꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ7Hꢀ[1,3]thiazoloꢀ
[3,2ꢀa]pyridineꢀ6,8ꢀdicarbonitrile (27a). Yield 81%, yellow powꢀ
der, m.p. 253 C (decomp.).
5ꢀAminoꢀ3ꢀoxoꢀ7ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ
[(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ2,3ꢀdihydroꢀ
7Hꢀ[1,3]thiazolo[3,2ꢀa]pyridineꢀ6,8ꢀdicarbonitrile (27b). Yield
81%, orange powder, m.p. 250 C (decomp.).
2ꢀAminoꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4H,5Hꢀpyrꢀ
ano[3,2ꢀc]chromeneꢀ3ꢀcarbonitrile (19a). Yield 87%, colorless
powder, m.p. 235 C.
2ꢀAminoꢀ5ꢀoxoꢀ4ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4H,5Hꢀ
pyrano[3,2ꢀc]chromeneꢀ3ꢀcarbonitrile (19b). Yield 83%, colorꢀ
less powder, m.p. 256 C (EtOH).
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4H,5Hꢀpyrꢀ
ano[3,2ꢀc]chromeneꢀ3ꢀcarbonitrile (19c). Yield 68%, colorless
powder, m.p. 225 C.
2ꢀAminoꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀ
oxoꢀ4H,5Hꢀpyrano[3,2ꢀc]chromeneꢀ3ꢀcarbonitrile (19d). Yield
75%, colorless powder, m.p. 246 C (EtOH).
2ꢀAminoꢀ4ꢀ(1ꢀisopropylꢀ3,5ꢀdimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀ
oxoꢀ4H,5Hꢀthiochromeno[4,3ꢀb]pyranꢀ3ꢀcarbonitrile (20a).
Yield 77%, colorless powder, m.p. 252 C (EtOH).
2ꢀAminoꢀ4ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4H,5Hꢀthioꢀ
chromeno[4,3ꢀb]pyranꢀ3ꢀcarbonitrile (20b). Yield 81%, faintly
colored bright leaflets, m.p. 260 C (EtOH).
5ꢀAminoꢀ7ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ[(1ꢀmethylꢀ1Hꢀ
pyrazolꢀ4ꢀyl)methylidene]ꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ7Hꢀ[1,3]thiazoꢀ
lo[3,2ꢀa]pyridineꢀ6,8ꢀdicarbonitrile (27c). Yield 76%, yellow
powder, m.p. 260 C (decomp.).
5ꢀAminoꢀ7ꢀ(1ꢀisopropylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ[(1ꢀisopropylꢀ
1Hꢀpyrazolꢀ4ꢀyl)methylidene]ꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ7Hꢀ[1,3]thiꢀ
azolo[3,2ꢀa]pyridineꢀ6,8ꢀdicarbonitrile (27d). Yield 58%, yellow
powder, m.p. 262—264 C.
7ꢀ(1ꢀAllylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ2ꢀ[(1ꢀallylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ
methylidene]ꢀ5ꢀaminoꢀ3ꢀoxoꢀ2,3ꢀdihydroꢀ7Hꢀ[1,3]thiazoloꢀ
[3,2ꢀa]pyridineꢀ6,8ꢀdicarbonitrile (27e). Yield 79%, orange powꢀ
der, m.p. 266 C.
2ꢀAminoꢀ5ꢀoxoꢀ4ꢀ(1,3,5ꢀtrimethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4H,5Hꢀ
thiochromeno[4,3ꢀb]pyranꢀ3ꢀcarbonitrile (20c). Yield 85%,
colorless powder, m.p. 237 C.
2ꢀAminoꢀ4ꢀ(1ꢀethylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ5ꢀoxoꢀ4H,5Hꢀthioꢀ
chromeno[4,3ꢀb]pyranꢀ3ꢀcarbonitrile (20d). Yield 80%, creamꢀ
colored powder, m.p. 216 C.
Synthesis of 2ꢀaminoꢀ5ꢀoxoꢀ4ꢀpyrazolylꢀ5,6ꢀdihydroꢀ4Hꢀ
pyrano[3,2ꢀc]quinolineꢀ3ꢀcarbonitriles 21 (general procedure). Amixꢀ
ture of Nꢀalkylpyrazolylmethylidenemalononitrile 9 (1 mmol),
4ꢀhydroxyquinolinꢀ2ꢀone (18) (1.1 mmol), and Et3N (2—3 drops)
was refluxed in EtOH (10 mL) for 1 h. On cooling, the reaction
mixture was stirred with 10% NaHCO3 (1 mL) for 10 min, dilutꢀ
ed with water (10 mL), and left at 0 C for 8 h. The precipitate
that formed was filtered off, washed with 10% NaHCO3 (5 mL), ice
B. Triethylamine (2—3 drops) was added to a hot solution of
compound 9a (158 mg, 1 mmol), 4ꢀformylꢀ1ꢀmethylpyrazole
(8a) (110 mg, 1 mmol), and thiazolone 23 (140 mg, 1 mmol) in
EtOH (10 mL). The reaction mixture was refluxed for 30 min.
On cooling, the precipitate that formed was filtered off, washed
with EtOH and hexane, and dried. The yield of compound 27c
was 320 mg (81%). The melting point and spectral characterisꢀ
tics of this sample are identical with those of compound 27c
obtained according to method A.
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Received December 19, 2013;
in revised form January 27, 2014