Isobutyraldehyde in the synthesis of isopropyl-substituted 4H-pyrans, 1,4-dihydropyrano[2,3-c]pyrazole, 1,4-dihydropyridines, and cyclobutane

Article abstract of DOI:10.1007/s11176-005-0351-6

Condensation of isobutyraldehyde with CH acids, such as acetoacetanilide, dimedone, acetoacetamide, ethyl benzoylacetate, resorcinol, cyanoacetic acid, malononitrile, 3-methyl-1-ethyl-2-pyrazolin-5-one, benzoylacetone, and cyanoacetamide, in the presence of amines gave isopropyl-substituted 4H-pyrans, 1,4-dihydropyrano[2,3-c]pyrazole, 4H-benzo[b]pyranes, 1,4-dihydropyridines, and 1,1-dicyano-2-(1-cyano-1-ethoxycarbonyl)methyl-4-isopropyl-3, 3-dimethylcyclobutane. The structure of the latter product was studied by X-ray diffraction analysis.

Full text of DOI:10.1007/s11176-005-0351-6

Russian Journal of General Chemistry, Vol. 75, No. 6, 2005, pp. 952 960. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 6, 2005,
pp. 1007 1016.
Original Russian Text Copyright
2005 by Dyachenko, Chernega.
Isobutyraldehyde in the Synthesis
of Isopropyl-substituted 4H-Pyrans,
1,4-Dihydropyrano[2,3-c]pyrazole, 1,4-Dihydropyridines,
and Cyclobutane
V. D. Dyachenko* and A. N. Chernega**
* Shevchenko National Pedagogical University, Lugansk, Ukraine
** Institute of Organic Chemistry, National Academy of Sciences, Kiev, Ukraine
Received October 22, 2003
Abstract Condensation of isobutyraldehyde with CH acids, such as acetoacetanilide, dimedone, acetoacet-
amide, ethyl benzoylacetate, resorcinol, cyanoacetic acid, malononitrile, 3-methyl-1-ethyl-2-pyrazolin-5-one,
benzoylacetone, and cyanoacetamide, in the presence of amines gave isopropyl-substituted 4H-pyrans, 1,4-
dihydropyrano[2,3-c]pyrazole, 4H-benzo[b]pyranes, 1,4-dihydropyridines, and 1,1-dicyano-2-(1-cyano-1-
ethoxycarbonyl)methyl-4-isopropyl-3,3-dimethylcyclobutane. The structure of the latter product was studied
by X-ray diffraction analysis.
Aromatic aldehydes are widely used in the syn-
thesis of 4-aryl-substituted pyridine-2-chalcogenones
and pyrans [1 4] that are fairly thoroughly studied and
used in practice [5, 6]. At the same time, alkyl-
substituted analogs still remain poorly explored, on
account of their enhanced reactivity and low selec-
tivity of reactions with aliphatic aldehydes, as well as
susceptibility of certain of them to polymerization [7].
(X), or 2-ethyl-5-methyl-2,4-dihydro-3H-pyrazol-3-
one (XV), instead of dimedone (IV), gave 6-amino-5-
cyano-4-isopropyl-2-methyl-4H-pyran-3-carboxamides
IXa and IXb, ethyl 6-amino-5-cyano-4-isopropyl-2-
phenyl-4H-pyran-3-carboxylate (XI), and 6-amino-1-
ethyl-4-isopropyl-3-methyl-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitrile (XVI). The condensations of
aldehyde I with such CH acids as resorcinol XII and
cyanoacetic acid (XIII) provided ethyl 2-amino-7-
hydroxy-4-isopropyl-4H-chromene-3-carboxylate
(XIV). Compounds IX, XI, XIV, and XVI are
probably formed by the same scheme as pyran VI.
Proceeding with the research into the synthesis of
novel pyridin-2-chalcogenones and pyrans by multi-
component condensation involving aliphatic al-
dehydes [8 15], we turned to reactions of isobutyral-
dehyde (I) with CH acids, such as malononitrile (II),
dimedone (IV), acetoacetanilide (VIIIa), acetoacet-
amide (VIIIb), ethyl benzoylacetate (X), resorcinol
(XII), cyanoacetic acid (XIII), 2-ethyl-5-methyl-2,4-
dihydro-3H-pyrazol-3-one (XV), and cyanothioacet-
amide (XVII), in the presence of amines. We showed
that the three-component condensation of isobutyral-
dehyde (I) with malononitrile (II) and dimedone (IV)
in ethanol in the presence of morpholine gives rise to
2-amino-4-isopropyl-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydro-4H-chromene-3-carbonitrile (VI). The reaction
probably involves intermediate formation of substi-
tuted acrylonitrile III that takes up dimedone (IV) by
the Michael reaction [16]. Adduct V undergoes
cyclization into compound VI under reaction condi-
tions.
The structures of compounds VI, IX, XI, XIV, and
XVI were proved by their physicochemical and spec-
tral characteristics (Tables 1 and 2). Thus, the IR
spectra contain characteristic absorption bands of the
1
conjugated cyano group at 2167 2210 cm , as well
as absorption bands due to stretching and bending
vibrations of the amino group at 3088 3448 and
1
1642 1656 cm , respectively. Furthermore, by
treatment of compound VI with a solution of bromine
in aqueous methanol at 20 C the cyano group was
hydrolyzed into amide. Therewith, the pyran ring re-
cyclized into pyridine and, as a result, 4-isopropyl-
7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,7,8-octahydroqui-
noline-3-carboxamide (VII) was obtained.
With acetoacetanilide (VIIIa) and cyanothioacet-
amide (XVII) as CH-acid components in condensation
with aldehyde I in the presence of N-methylmorpho-
line with subsequent introduction of -bromoacetyl-
The above condensation with acetoacetanilide
(VIIIa), acetoacetamide (VIIIb), ethyl benzoylacetate
1070-3632/05/7506-0952 2005 Pleiades Publishing, Inc.

ISOBUTYRALDEHYDE IN THE SYNTHESIS OF ISOPROPYL-SUBSTITUTED 4H-PYRANS
953
O
Me
Me
Me
CN
Me
Me
O
O
(IV)
Me
Me
CN
O
Me
NC
III
Me
Me
Me
Me
OH C
CN
NH2
O
VI
<
N
V
MeOH H2O Br2
(II), B
CN
NC
H2O
Me
Me
O
O
NH2
Me
Me
N
O
O
O
O
Me
CN
Me
H
VII
O
(VIIIa, VIIIb), II, B
Me
Me
RHN
Me
H2O
Me
N
RHN
CHO
NH2
IXa, IXb
(XV), B
Me
O
II,
O
O
N
I
(X), II, B
Ph
Me
OEt
H2O
H2O
(XII),
H2O
HO
OH
Me
CN
Me
EtOOC
OEt
(XIII), B
NC
O
Me
CN
Me
Me
CN
Me
N
Me
NH2
Ph
O
XI
NH2
N
O
NH2
HO
O
Me
XIV
XVI
B = morpholine; VIII, IX, R = Ph (a), H (b).
thiophene (XXI) into the reaction mixtures, 4-iso-
propyl-6-methyl-2-thenoylmethylsulfanyl-5-phenyl-
carbamoyl-3-cyano-1,4-dihydrolyridine (XXII) was
isolated. The reaction is likely to involve formation
of alkene XVIII (Knoevenagel condensation [16]),
followed by the Michael addition of acetoacetanilide
VIIIa to compound XVIII, leading to adduct XIX.
The latter undergoes regioselective cyclocondensation
into substituted N-methylmorpholinium 1,4-dihydro-
pyridine-2-thiolate (XX) that is further alkylated with
compound XXI into derivative XXII.
the dihydropyridine nucleus. This result can be ex-
plained in terms of hydrogen bonding between the
anilide oxygen and N1H hydrogen atoms. The same
reason is likely to underlie the resistance of 1,4-di-
hydropyridine XXII to oxidation. The preservation of
the boat conformation of the 1,4-dihydropyridine
nucleus [17, 18] and the lack of conformational iso-
merism make compound XXIV fairly resistant to
oxidants [19]. Thus, the two-component oxidation of
aldehyde I with cyanothioacetamide (XVII) in the
presence of N-methylmorpholine provides a dehydro-
genation product, 6-amino-4-isopropyl-2-thioxo-1,2-
dihydropyridine-3,5-dicarbonitirile (XXV). It is reaso-
nable to suggest that the reaction involves formation
of alkene XVII that reacts with amide XVII to form
adduct XXIII whose heterocyclocondensation affords
The above condensation without CH acid VIIIa
and -chloroacetanilide (XXVI) instead of alkylating
agent XXI gave N-phenyl-2-[(6-amino-3,5-dicyano-4-
isopropylidene-1,4-dihydropyridin-2-yl)sulfanyl]acet-
amide (XXVII). Note that this condensation involves
oxidation, probably, with atmospheric oxygen, of
structure XXIV, that results in formation of an iso-
propylidene fragment, rather than in aromatization of
N-methylmorpholinium
dihydropyridinethiolate
(XXIV). Treatment of the reaction mixture with dilute
HCl gives substituted pyridine-2(1H)-thione XXV that
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 6 2005

954
DYACHENKO, CHERNEGA
Me
Me
Me
Me
CN
O
CN
CN
VIIIa
I, VIIIa, B
PhHN
..
H2N
S
Me
O H2N
S
H2N
XVIII
S
XVII
XIX
I, B
XVII
Me
CN
Me
O
Me
Me
CN
S BH+
Me
Me
NC
RHN
CN
NC
H2N
S BH+
H2S
N
H
Me
..
H2N
N
S H2N
S
H
XXIII
XXIV
XX
NHPh
O
(XXVI)
Cl
(XXI)
H+
Br
2[H]
O
2[H]
S
Me
CN
Me
Me
CN
Me
Me
CN
Me
NC
NC
NC
S
H2N
N
S
H2N
S
N
H2N
N
H
O
H
H
O
XXV
NHPh
S
XXVII
XXII
B = N-methylmorpholine.
was previously prepared via recyclization of 2,6-di-
amino-3,5-dicyano-4-isopropyl-4H-thiopyran [14].
The two-component condensation of aldehyde I
with malononitrile (II) in ethanol in the presence of
morpholine at 20 C formed substituted cyclobutane
XXXII, rather than expected cyclohexene XXX
[20 23]. Thus, isopropylmethylenemalononitrile (III)
formed by the Knoevenagel condensation dimerizes
by the Michael scheme to give adduct XXVIII that
undergoes regioselective intramolecular cyclization
into cyclobutane XXIX. The formation of the latter is
a result of three reactions: Knoevenagel condensation
and two Michael additions, inter- and intramolecular.
Further on alcoholysis of one of the nitrile group in
compound XXIX occurs, yielding imidoester XXXI.
Note that malononitrile [24] and other aliphatic
nitriles [25] readily form imidoesters like XXXI in
The structure of compounds XXII and XXVII was
proved by their physicochemical and spectral charac-
teristics (Tables 1 and 2). Evidence for the presence
of a hydrogen bond in XXII and XXVII comes from
1
1
their H NMR spectra. The H NMR spectrum of di-
hydropyridine XXII contains, along with character-
istic dihydropyridine and substituent signals in the
expected ranges (Table 2), signals of nonequivalent
protons of the SCH2 group as doublets at 4.42 and
4.67 ppm (2J 17.32 Hz). Such a splitting of the me-
thylene proton signals suggests lack of free rotation
of the thenoyl fragment.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 6 2005

ISOBUTYRALDEHYDE IN THE SYNTHESIS OF ISOPROPYL-SUBSTITUTED 4H-PYRANS
955
Table 1. Yields, melting points, and elemental analyses of octahydroquinolin-2-one VII, pyrans IXa, XIb, XI, XIV,
XXXVI, and XXXVII, pyrano[2,3-c]pyrazole XVI, dihydropyridines XXII and XXVII, and cyclobutane XXXII
Found, %
Calculated, %
H N
mp,
C
Formula
(solvent for crystallization)
C
H
N
C
VII
IXa
IXb
XI
XIV
XVI
XXII
XXVII
XXXII
XXXVI,
XXXVII
41
82
65
89
83
71
72
66
77
65
227 229 (EtOH)
221 222 (i-PrOH)
243 245 (BuOH)
168 169 (EtOH)
171 172 (EtOH)
177 178 (MeOH)
158 160 (BuOH)
191 193 (AcOH)
118 119 (EtOH)
177 179 (EtOH)
64.60
68.51
59.62
69.10
65.12
63.44
62.95
61.40
66.72
72.19
8.11
6.32 14.00
6.71 19.08
6.34
7.06
7.20 22.58
5.15 9.71
4.72 20.15
7.25 14.54
6.50 10.08
9.88
C15H22N2O3
C17H19N3O2
C11H15N3O2
C18H20N2O3
C15H19NO4
C13H18N4O
C23H23N3O2S2
C18H17N5OS
C16H21N3O2
C17H18N2O2
64.73
68.67
59.71
69.21
64.97
63.39
63.13
61.52
66.88
72.32
7.97
6.44
6.83
6.45
6.91
7.37
5.30
4.88
7.37
6.43
10.06
14.13
18.99
8.97
5.05
22.75
9.60
19.93
14.62
9.92
9.15
4.85
1
Table 2. IR and H NMR spectra of octahydroquinolin-2-one VII, pyrans IXa, XIb, XI, XIV, XXXVI, and XXXVII,
pyrano[2,3-c]pyrazole XVI, dihydropyridines XXII and XXVII, and cyclobutane XXXII
1
IR spectrum, cm
1H NMR spectrum, , ppm
Comp.
no.
(C N),
(C=O),
(NH2);
(NH2)
NH2, br.s; CH(CH3)2,
CH(CH3)2, m two d
C4H, d
other signals
VII
1710, 1678 3305,
3.07 m 6.79 and 7.20; 0.78, 0.83 1.05 s (6H, 2CH3), 2.12 s (2H, C8H2),
3390;
1655
1.65
(J 6.92 Hz) 2.11 d and 2.29 d (at 1H, C6H2, 2J
18.4 Hz), 2.95 d (1H, C3H, J 5.46 Hz),
9.91 br.s (1H, N1H)
IXa
IXb
XI
2167, 1680 3192, 3340,
3.79
5.67; 1.28 0.98, 1.12, 2.27 s (3H, CH3), 7.14 m (2H, Harom),
3448; 1656 (J 4.0 Hz)
(J 6.87 Hz) 7.46 m (3H, Harom), 8.85 br.s (1H, CONH)
2210, 1642 3214, 3356,
3.42
6.06; 1.60 0.69, 0.93
2.13 s (3H, CH3)
3444; 1653 (J 3.96 Hz)
(J 6.90 Hz)
2188, 1694 3091, 3213,
3.23
6.69; 1.92 0.88, 1.01
0.99 t (3H, CH3CH2O), 3.94 q (2H, CH2,
3298; 1642 (J 4.11 Hz)
(J 7.02 Hz) J 6.20 Hz), 7.42 br.s (5H, Harom
7.15; 1.76 0.62, 0.81 1.28 t (3H, CH3CH2O), 4.10 q (2H, CH2,
(J 6.18 Hz) J 6.14 Hz), 6.39 s (1H, Harom), 6.48 d
(1H, Harom), 8.83 d (1H, Harom
)
XIV
1714
3115, 3302,
3.51
3407; 1644 (J 3.86 Hz)
,
J 7.98 Hz), 9.01 br.s (1H, OH)
0.74, 0.80 1.25 t (3H, CH3CH2), 2.24 s (3H, CH3),
(J 6.85 Hz) 4.15 q (2H, CH2, J 6.21 Hz)
XVI
2197
3088, 3241,
3415; 1649 (J 3.95 Hz)
3.19
6.61; 1.70
1.70
XXII
2190, 1713;
1668
3315
3.45
(J 4.1 Hz)
0.85, 0.92 2.18 s (3H, C2CH3), 4.42 d and 4.67 d (at
2
(J 7.03 Hz) 1H, SCH2, J 17.32 Hz), 7.26 m (3H,
Harom), 7.02 t (1H, thienyl C4H), 7.68 d
(2H, Harom, J 5.16 Hz), 8.03 d (1H, thi-
enyl C3H, J 5.2 Hz), 8.09 d (1H, thienyl
C5H, J 3.8 Hz), 8.40 br.s (1H, NH),
9.15 br.s (1H, NHCO)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 6 2005

956
DYACHENKO, CHERNEGA
Table 2. (Contd.)
1
IR spectrum, cm
1H NMR spectrum, , ppm
NH2, br.s; CH(CH3)2,
Comp.
no.
(C N),
(C=O),
(NH2);
(NH2)
C4H, d
other signals
CH(CH3)2, m
two d
XXVII 2200 sh;
3240, 3330,
3412; 1645
5.81
1.21 s
3.86 s (2H, SCH2), 7.12 d.d (1H, Harom,
1673
J 6.14 Hz), 7.35 d.d (2H, Harom), 7.58 d
(2H, Harom, J 5.20 Hz), 9.41 br.s (1H,
NH), 10.32 br.s (1H, NHCO)
XXVII 2255 sh;
2.03 m
0.92, 1.03, 1.06 s (3H, CH3), 1.27 s (3H, CH3),
(J 6.84 Hz) 1.39 t (3H, CH3CH2O), 2.43 d (1H, C4H,
J 6.80 Hz), 3.39 d (1H, C2H, J 7.22 Hz),
1718
4.30 m (3H, CH2 and C1H)
XXXVI, 2196,
XXXVII 1715
3184, 3319,
3420; 1647 (J 4.0 Hz)
3.19
6.56a and 6.69; 0.80a and 1.79 s and 1.83a s (3H, CH3), 7.42
1.65 0.92a, 0.83 7.79 m (5H, Harom
)
and 1.11
(J 6.92 Hz)
a
Signals of isomer XXXVI.
basic media. Under reaction conditions, adduct XXXI
is hydrolyzed to ester XXXII that is a promising
candidate for medical applications [26, 27].
Fig. 1. The central four-membered carbocycle
C1C2C3C4 is appreciable nonplanar (the atomic devia-
tions from the mean plane attain 0.13 ) and has a
butterfly shape: The fold along the C2 C4 line is
26.5 . All bond lengths and bond angles in molecule
XXXII are normal values [28].
The structure of compound XXXII was proved by
X-ray diffraction analysis. The molecular structure
and its principal geometric parameters are given in
NC
Me
Me
Me
Me Me
Me
O
NH
III
Me
CN
NC
Me
Me
Me
I + II
III
H2O
NC
NC
NH
XXVIII
XXX
Me Me
Me Me
Me Me
Me
Me
Me
NC
EtO
NC
NC
EtO
EtOH
H2O
NH3
NC
Me
Me
XXIX
Me
XXXII
CN
NC
NH
CN
NC
CN
NC
O
XXXI
The crystal packing of compound XXXII is shown
in Fig. 2.
XXXIII provides a 2:1 mixture of structural isomers
XXXVI and XXXVII. This conclusion follows from
the H NMR spectrum of this mixture (Table 2). The
1
The three-component condensation of aldehyde I,
malononitrile (II), and unsymmetrical 1,3-diketone
proton signals were assigned with account for data of
Marchalin et al. [29] for analogs of pyrans XXXVI
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 6 2005

ISOBUTYRALDEHYDE IN THE SYNTHESIS OF ISOPROPYL-SUBSTITUTED 4H-PYRANS
957
and XXXVII, viz. 5-acetyl-2-amino-3-cyano-4-(2-
furyl)-6-methyl-4H-pyran derivatives.
that forms can undergo prototropic isomerization into
enol XXXV. Intramolecular cyclization of adducts
XXXIV and XXXV under the action of morpholine
gives corresponding structural isomers XXXVI and
XXXVII.
It is reasonable to suggest that the condensation
gives rise to alkene III that enters the Michael reac-
tion with benzoylacetone (XXXIII). Adduct XXXIV
Me
Me
O
I, II, O
NH
O
O
XXXIII
CN
Ph
Me
III
Me
Ph
OH C
XXXIII
<
N
XXXIV
Me
O
Me
Me
CN
Me
CN
Me
Me
O
O
CN
Me
Ph
Me
+
Ph
Ph
OH C
Me
NH2
XXXVII
NH2
O
O
<
XXXVI
N
XXXV
Thus, isobutyraldehyde in mild conditions smooth-
ly condenses with various CH acids to form unstable
alkenes that further react with a new CH component
or dimerize into corresponding isopropyl-substituted
4H-pyranes, 4H-benzo[b]pyranes, 1,4-dihydropyrano-
[2,3-c]pyrazoles, 1,4-dihydropyridines, and cyclo-
butanes.
radiation, 2 /
segment 0
total of 2466 reflections were measured, of which
2180 were symmetrically independent (averaging R
factor 0.019). Crystals of compound XXXII, triclinic,
1.2 scanning,
8, 11
24 , sphere
12). A
h
k
11, ma1x2
l
a 7.738(2), b 10.421(2), c 11.127(2)
;
75.23(3),
74.90(3), 83.65(3) ; V 840.96 3, M 287.36, Z 2,
EXPERIMENTAL
N1
C15
C16
The IR spectra were measured on an IKS-29 in-
C6
1
strument in mineral oil. The H NMR spectra were
C13
C5
C2
C3
recorded on Bruker WP-100SY (100 MHz) (for VI,
IXa, IXb, XXV, and XXVII), Gemini200
(199.975 MHz) (for VII), Bruker WM-250
(250.13 MHz) (for XI, XXXVI, and XXXVII),
Varian Mercury-400 (400.397 MHz) (for XXII and
XXXII), and Bruker DR-500 (500.13 MHz) (for XIV
and XVI) instruments in DMSO-d6, internal reference
TMS. The mass spectra were obtained on a Kratos
MS-890 instrument, ionizing energy 70 eV. The
melting points were determined on a Kofler hot stage.
Reaction progress was followed by TLC (Silufol UV-
254, acetone hexane, 3:5, developer iodine vapor).
C1
O2
C9
C12
C7
N2
C4
C8
C10
N3
O1
C11
C14
Fig. 1. Molecular structure of compound XXXII with
atom numbering (hydrogen atoms are not shown). Prin-
cipal geometric parameters: l(C C ) 1.563(11),
l(C C ) 1.610(10),
1.580(10), l(C C ) 1.593(11)
C C C 90.8(6), C C C 85.2(6), and C C C
90.8(6) .
1
2
1
4
1
5
2
3
X-ray diffraction analysis of a single crystal
(0.20 0.25 0.30 mm) of compound XXXII was per-
formed at room temperature on an Enraf Nonius
CAD-4 automated four-circle diffractometer (MoK
l(C C ) 1.497(11), l(C C )
3
4
1 2 3
;
C C C 87.2(6),
2
3
4
1
4
3
2 1 4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 6 2005

958
DYACHENKO, CHERNEGA
c
a
b
Fig. 2. Crystal packing of compound XXXII.
3
1
Table 3. Atomic coordinates and equivalent isotropic
thermal parameters Ueq in structure XXXIIaa
1.13 g cm , 0.713 cm , space group P1 (N 2).
Tchaelc structure was solved by the direct method and
refined by full-matrix least squares in the anisotropic
approximation using the CRYSTALS program
package [30]. The refinement included 1004 reflec-
tions with I > 4 (I) (170 refined parameters, reflec-
tions per parameter 5.9, singular weight scheme). All
hydrogen atoms were refined geometrically and in-
cluded in the calculation with fixed positional and
thermal parameters. Final divergence factors: R 0.073
and RW 0.074, and residual electron density from the
Fourier difference series 0.32 and 0.19 e 3. The
atomic coordinates are given in Table 3.
2
Atom
x
y
z
Ueq,
O1
O2
N1
N2
N3
C1
0.240(1)
0.2379(8)
1.0108(7)
0.8783(6)
0.8875(8)
1.3508(9)
1.1890(8)
1.1253(8)
1.2252(8)
1.3210(8)
1.2422(8)
1.0429(8)
0.9507(9)
0.9751(9)
0.8106(12)
0.7093(15)
1.3019(9)
1.2107(8)
1.4668(8)
1.5287(9)
1.5324(9)
1.2768(9)
1.170(1)
0.9143(8)
0.7855(6)
0.5806(7)
0.744(1)
1.0650(9)
0.7531(9)
0.6521(8)
0.7467(8)
0.8201(9)
0.7141(8)
0.6395(8)
0.8162(9)
0.1202
0.0826
0.0778
0.1007
0.0926
0.0674
0.0524
0.0652
0.0538
0.0590
0.0593
0.0648
0.6593(11)
0.1815(14)
0.4130(13)
0.5594(12)
0.6924(11)
0.6368(12)
0.4600(12)
0.4464(11)
0.5669(12)
0.2957(12)
0.0868(15)
0.0426(19)
0.3048(15)
0.4297(12)
0.6233(12)
0.7984(13)
0.5374(14)
0.6465(15)
0.8833(14)
C2
C3
C4
2-Amino-4-isopropyl-7,7-dimethyldimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(VI). To a solution of 0.91 ml of isobutyraldehyde (I)
in 20 ml of ethanol at 20 C, malononitrile (II), 0.66 g,
and 1 drop of morpholine were added, and the result-
ing mixture was stirred for 15 min. Dimedone (IV),
was then added, and the mixture was stirred for 1 h
and left to stand for 1 day. A precipitate formed and
was filtered off, washed with ethanol and hexane, and
recrystallized from ethanol to obtain 2.34 g (90%) of
C5
C6
C7
C8
0.8777(14) 0.1394
0.8440(18) 0.2002
C9
C10
C11
C12
C13
C14
C15
C16
0.7787(9)
0.957(1)
0.7042(8)
0.627(1)
0.815(1)
0.525(1)
0.0597
0.0587
0.0616
0.0835
0.0862
0.0874
1
compound VI whose melting point, H NMR spec-
trum, and chromatographic parameters were similar
to those reported in [15].
0.6395(12) 0.1023
a
For atom numbering, see the legend to Fig. 1.
4-Isopropyl-7,7-dimethyl-2,5-dioxo-1,2,3,4,5,6,-
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ISOBUTYRALDEHYDE IN THE SYNTHESIS OF ISOPROPYL-SUBSTITUTED 4H-PYRANS
959
7,8-octahydroquinolin-3-carboxamide (VII). To a
solution of 5 ml of water in 20 ml of methanol, pyran
VI, 2.6 g, was added, and a solution of 0.51 ml of
bromine in 5 ml of methanol was added to the result-
ing suspension dropwise over the course of 10 min.
The mixture was allowed to stand for 1 day and then
diluted with equal volume of water. The precipitate
was filtered off and washed with water, ethanol, and
hexane to obtain compound VII whose characteristics
are given in Tables 1 and 2. Mass spectrum, m/z
(Irel, %): 278 (4) [M]+; 234 (100), 192 (79), 178 (10),
135 (14), 118 (10), 108 (7), 55 (9).
2.05 g of -bromoacetophenone (XXI) was added,
and stirring was continued for an additional 3 h. The
mixture was then diluted with equal volume of water,
and the precipitate that formed was separated and
washed in succession with water, ethanol, and hexane
to obtain compound XXII (Tables 1 and 2.)
6-Amino-4-isopropyl-2-thioxo-1,2-dihydropyri-
dine-3,5-dicarbonitrile (XXV). To a mixture of
0.91 ml of isobutyraldehyde (I) and 1.0 g of cyanothio-
acetamide (XVII) at 20 C, N-methylmorpholine,
1 drop, was added, and the mixture was stirred for 1 h.
Cyanothioacetamide (XVII), 1.0 g, and 1.1 ml of
N-methylmorpholine were then added, and stirring
was continued for an additional 5 h. The mixture was
diluted with 10% hydrochloric acid to pH 7 and
allowed to stand for 3 day. The precipitate that formed
was separated and washed in succession with water,
ethanol, and hexane to obtain 1.72 g (79%) of com-
6-Amino-5-cyano-4-isopropyl-2-methyl-4H-
pyran-3-carboxamides IXa and IXb were prepared
similarly to VI, replacing dimedone (IV) by 10 mmol
of CH acid VIIIa or VIIIb (Tables 1 and 2).
Ethyl 6-amino-5-cyano-4-isopropyl-2-phenyl-
4H-pyran-3-carboxamide (XI) was prepared si-
milarly to compound VI, replacing dimedone IV by
1.73 ml of ethyl benzoylacetate (X) (Tables 1 and 2).
Mass spectrum, m/z (Irel, %): 312 (4) [M]+; 269 (100),
241 (13), 197 (10), 168 (11), 115 (7), 105 (12), 77 (9),
43 (8).
1
pound XXV, whose melting point and H NMR spec-
tra were the same as those reported in [14, 31].
N-Phenyl-2-[(6-amino-3,5-dicyano-4-isopropyl-
idene-1,4-dihydropyridin-2-yl)sulfanyl]acetamide
(XXVII). To a solution of 0.91 ml of isobutyralde-
hyde (I) in 20 ml of ethanol at 20 C, cyanothioacet-
amide (XVII), 1.0 g, and 1 drop of N-methylmor-
pholine were added, and the mixture was stirred for
25 min, after which 1.0 g of CH acid XVII and 1.1 ml
of N- methylmorpholine were added, and stirring was
continued for 2 h. -Chloroacetanilide (XXVI) was
then added, and the mixture was stirred for 4 h, di-
luted with equal volume of water, and allowed to
stand for 1 day. The precipitate that formed was se-
parated and washed in succession with water, ethanol,
and hexane to obtain compound XXVII (Tables 1
and 2).
Ethyl 2-amino-7-hydroxy-4-isopropyl-4H-
chromene-3-carboxamide (XIV). To a solution of
0.91 ml of isobutyraldehyde (I) in 20 ml of ethanol at
20 C, cyanoacetic ester (XIII), 1.06 ml, and 1 drop
of morpholine were added, and the resulting mixture
was stirred for 30 min. Resorcinol (XII), 1.1 g, was
then added, and the mixture was stirred for 3 h, and
then allowed to stand for 2 days at room temperature.
A precipitate formed and was washed with ethanol
and hexane (Tables 1 and 2). Mass spectrum, m/z (Irel,
%): 277 (3) [M]+; 235 (13), 234 (100), 206 (8), 189
(7), 188 (67), 161 (6), 134 (8), 43 (6).
6-Amino-1-ethyl-4-isopropyl-3-methyl-1,4-di-
hydropyrano[2,3-c]pyrazol-5-carbonitrile (XVI)
was prepared similarly to compound VI, replacing
dimedone (IV) by 1.26 g of CH acid XV (Tables 1
and 2). Mass spectrum, m/z (Irel, %): 246 (4) [M]+;
235 (11), 221 (15), 209 (26), 208 (50), 207 (100),
180 (29), 179 (68), 163 (25), 162 (47), 161 (55), 134
(48), 119 (21), 106 (22), 105 (36), 67 (41), 58 (30).
Ethyl (4,4-dicyano-3-isopropyl-2,2-dimethyl-
cyclobutyl)cyanoacetate (XXXII). To a solution of
0.91 ml of isobutyraldehyde (I) in 10 ml of ethanol at
20 C, malononitrile (II), 0.66 g, and 0.87 ml of
morpholine were added. The mixture was stirred for
2 h and allowed to stand for 4 days. The precipitate
that formed was filtered off and washed with ethanol
and hexane to obtain compound XXXII (Tables 1
and 2).
N-Phenyl-5-cyano-4-isopropyl-2-methyl-6-[[2-
oxo-2-(2-thienyl)ethyl]sulfanyl]-1,4-dihydropyri-
dine-3-carboxamide (XXII). To a solution of
0.91 ml of isobutyraldehyde (I) in 20 ml of ethanol at
20 C, cyanothioacetamide (XVII), 1.0 g, and 1 drop
of N-methylmorpholine were added, and the mixture
was stirred for 25 min. Acetoacetanilide (VIIIa),
1.77 g, and 1.1 ml of N-methylmorpholine were then
added, the mixture was stirred for 2 h, after which
2-Amino-5-benzoyl-4-isopropyl-6-methyl-4H-
pyran-3-carbonitrile (XXXIV) and 5-acetyl-2-
amino-4-isopropyl-6-phenyl-4H-pyran-3-carbo-
nitrile (XXXVII) were obtained as a 2:1 mixture by
the procedure for compound VI, replacing dimedone
(IV) by 1.62 g of benzoylacetone (XXXIII) (Tables 1
and 2).
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960
DYACHENKO, CHERNEGA
and Litvinov, V.P., Khim. Geterotsikl. Soedin., 1997,
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