Spirocyclohexadienones: IX. Synthesis of 1-alkoxycarbonylmethylidene-6,10- dimethoxy-8-[(alkoxycarbonyl)cyanomethylidene]-3,3-R2-2-azaspiro[4.5] deca-6,9-dienes by four-component condensation of 1,3,5-trimethoxybenzene with α-branched aldehydes and alkyl cyanoacetates

Article abstract of DOI:10.1134/S107042800812004X

Four-component condensation of 1,3,5-trimethoxybenzene, a C ₂-synton, and alkyl cyanoacetate in the presence of concentrated sulfuric acid gave the corresponding 1-alkoxycarbonylmethylidene-6,10-dimethoxy- 8-[(alkoxycarbonyl)cyanomethylidene]-3,3-R₂-2-azaspiro[4.5]deca-6,9- dienes.

Full text of DOI:10.1134/S107042800812004X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1752–1755. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © O.G. Stryapunina, I.V. Plekhanova, O.A. Maiorova, V.A. Glushkov, Yu.V. Shklyaev, 2008, published in Zhurnal Organicheskoi
Khimii, 2008, Vol. 44, No. 12, pp. 1778–1781.
Spirocyclohexadienones: IX.* Synthesis of 1-Alkoxycarbonyl-
methylidene-6,10-dimethoxy-8-[(alkoxycarbonyl)cyano-
methylidene]-3,3-R2-2-azaspiro[4.5]deca-6,9-dienes by Four-
Component Condensation of 1,3,5-Trimethoxybenzene
with α-Branched Aldehydes and Alkyl Cyanoacetates
O. G. Stryapunina, I. V. Plekhanova, O. A. Maiorova, V. A. Glushkov, and Yu. V. Shklyaev
Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences,
ul. Akademika Koroleva 3, Perm, 614013 Russia
e-mail: glusha@nm.ru
Received February 7, 2008
Abstract—Four-component condensation of 1,3,5-trimethoxybenzene, a C2-synton, and alkyl cyanoacetate in
the presence of concentrated sulfuric acid gave the corresponding 1-alkoxycarbonylmethylidene-6,10-dimeth-
oxy-8-[(alkoxycarbonyl)cyanomethylidene]-3,3-R2-2-azaspiro[4.5]deca-6,9-dienes.
DOI: 10.1134/S107042800812004X
Multicomponent reactions are widely used in the
chemistry of nitrogen-containing heterocyclic com-
pounds due to their practicability, simplicity, and short
reaction time [2]. We previously described three-com-
ponent electrophilic condensation of 1,3,5-trimethoxy-
benzene with 1,2-epoxy-2-methylpropane and methyl
thiocyanate in the presence of concentrated sulfuric
acid, which led to the formation of 6,10-dimethoxy-
3,3-dimethyl-1-methylsulfanyl-2-azaspiro[4.5]deca-
1,6,9-trien-8-one [3] (Scheme 1). The reaction in-
volved intermediate formation of resonance-stabilized
carbocation A which reacted with water during the
isolation procedure [4, 5].
cyanoacetate molecule to give 3,3-disubstituted 1-alk-
oxycarbonylmethylidene-6,10-dimethoxy-8-[(alkoxy-
carbonyl)cyanomethylidene]-2-azaspiro[4.5]deca-6,9-
dienes I–IV (Scheme 2). Here, alkyl cyanoacetate acts
as both C1–N2 synthon and nucleophile which attacks
carbocation A. The yields of condensation products I–
IV were fairly poor (14–24%). The optimal reactant
ratio (arene–aldehyde–alkyl cyanoacetate) was 1:1:2;
however, even at an equimolar ratio of the reactants,
compounds I–IV were formed as the major products.
1
Among by-products we identified by H NMR spec-
troscopy 1,1-bis(2,4,6-trimethoxyphenyl)-2-methyl-
propane; the other by-products were unidentified low-
melting oligomeric compounds.
We found that analogous reaction with methyl or
ethyl cyanoacetate instead of methyl thiocyanate
occurs as four-component condensation in which inter-
mediate carbocatione A reacts with the second alkyl
The reactions were carried at room temperature
(0.5–1 h), and the mixture was then neutralized with
aqueous ammonia to avoid hydrolytic dienone–phenol
Scheme 1.
Me Me
N
Me Me
N
OMe
Me
Me
O
O
O
H2SO4
H2O
+
+ MeSCN
Me
–MeOH, –H+
Me
SMe
OMe
SMe
OMe
MeO
OMe
Me
O
O
A
* For communication VIII, see [1].
1752

SPIROCYCLOHEXADIENONES: IX.
1753
Scheme 2.
R1 R1
Me
O
NH
OMe
O
O
CHO
R1
H2SO4
+
+
NC
Me
NC
OR2
R1
OR2
O
O
MeO
OMe
Me
OR2
O
A
R1 R1
Me
O
10
3
H
N
4
1
9
O
5
8
6
–MeOH, –H+
NC
O
11
OR2
O
7
Me
OR2
I–IV
I, R1 = R2 = Me; II; R1 = Me, R2 = Et; III, R1R1 = (CH2)5, R2 = Me; IV, R1R1 = (CH2)5, R2 = Et.
rearrangement of substituted 2-azaspiro[4.5]deca-
1,6,9-trien-8-ones, which is known to occur in dilute
acids [6]. In the condensation with cyclohexanecarbal-
dehyde we obtained dispiro compounds III and IV.
group. After recrystallization, only one isomer was
obtained, but we failed to determine its configuration
on the basis of the NMR data. The configuration of the
other exocyclic double bond in I–IV is fixed due to
formation of intramolecular hydrogen bond between
the ester carbonyl oxygen atom and proton of the
endocyclic NH group (Z configuration), as reported
previously for spirocyclohexadienones derived from
anisole [7]. This structure is also confirmed by the IR
(reduced ester carbonyl vibration frequency, 1650–
1670 cm–1, and NH absorption at 3310–3355 cm–1) and
1H NMR data (olefinic proton signal at δ 3.79–
3.83 ppm and NH signal at δ 8.30–8.37 ppm). In the
13C NMR spectra of I–IV, the spiro carbon atom (C5)
resonated at δC 57.75–58.59 ppm, and signal from the
β-carbon atom with respect to the NH group appeared
in a fairly strong field, δC 73.00–73.71 ppm. Stretching
vibrations of the cyano group in molecules I–IV gave
rise to a weak band at 2155–2175 cm–1 in the IR
spectra. The mass spectra of compounds I–IV lacked
molecular ion peaks, but their fragmentation pattern
involved successive elimination of the alkyl cyano-
acetate residue and hydrocarbon fragment on C3.
No analogous products were detected in analogous
three-component condensations with anisole [7] and
1,3-dimethoxybenzene [8]. Presumably, the observed
four-component condensation is favored by increased
ability of 1,3,5-trimethoxybenzene to undergo dearo-
matization [9]. On the other hand, capture of carbo-
cationic intermediates by the initial arene was reported
by us previously in three-component reactions with
substituted anisoles [10].
Alternatively, compounds I–IV could be synthe-
sized by Knoevenagel condensation. However, our
attempts to obtain analogous products by Knoevenagel
condensation of 3,3-dimethyl-1-ethoxycarbonylmeth-
ylidene-2-azaspiro[4.5]deca-6,9-dien-8-one [7] and
ethyl cyanoacetate were unsuccessful despite variation
of the reaction conditions. We also failed to trap inter-
mediate cation A with such 1,3-dicarbonyl compounds
as diethyl malonate and dimedone.
The structure of compounds I–IV was confirmed
1
by elemental analyses and IR, H and 13C NMR, and
EXPERIMENTAL
mass spectra. The products were isolated as mixtures
of E and Z isomers with respect to the exocyclic
double bond C=C(CN)COOAlk; their 13C NMR spec-
tra contained double sets of signals from the ester
The elemental compositions were determined on
a Leco CHNS analyzer. The IR spectra were recorded
on a Specord M80 spectrometer from samples dis-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

STRYAPUNINA et al.
1754
1
persed in mineral oil. The H and 13C NMR spectra
were obtained from solutions in DMSO-d6 on a Varian
Mercury Plus instrument (300 and 75 MHz, respec-
tively); the chemical shifts were measured relative to
HMDS as internal reference (1H) or solvent signal
(13C). Analytical thin-layer chromatography was
performed on Sorbfil plates using chloroform–acetone
(9:1) as eluent; spots were detected by spraying with
a 1% solution of chloranil in toluene. The mass spectra
(electron impact, 70 eV) were recorded on an Agilent
6890N–5975B GC–MS system.
and 5.60 g (2.13 ml, 50 mmol) of ethyl cyanoacetate
using 20 ml of methylene chloride and 15 ml of con-
centrated sulfuric acid. After removal of the solvent,
the residue was recrystallized from methanol. Yield
1.95 g (24%), bright yellow crystals, mp 167–169°C,
Rf 0.64. IR spectrum, ν, cm–1: 3310 (NH); 2175 (C≡N);
1700 sh, 1670 (C=O); 1600 (C=C); 1265, 1170, 1075,
1
860. H NMR spectrum, δ, ppm: 1.12 t and 1.27 t (3H
each, Me, J = 7.8 Hz), 1.38 s (6H, Me), 2.18 s (2H,
CH2), 3.79 s (4H, OMe, CH=), 3.82 s (3H, OMe),
3.93 q and 4.21 q (2H each, OCH2, J = 7.8 Hz), 5.95 s
and 7.33 s (1H each, 7-H, 9-H), 8.30 s (1H, NH).
13C NMR spectrum, δC, ppm: 14.12 (CH2CH3), 14.45
(CH2CH3), 29.79 (3-CH3), 45.14 (C4), 56.71 (OCH3),
57.80 (OCH3), 58.40 (C5), 60.70 (OCH3), 62.72
(OCH3, C3), 73.00 (CH=), 88.88 (C11), 93.44 (C7),
95.09 (C9), 117.55 (C≡N), 158.00 (C6), 161.77 (C10),
163.44 (C8), 168.94 (C1), 169.87 (C=O), 169.94
(C=O). Mass spectrum, m/z (Irel, %): 416 (15) [M]+,
303 (100) [M – NCCH2CO2Et]+, 261 (46), 189 (15),
114 (14). Found, %: C 63.22; H 6.64; N 6.75.
C22H28N2O6. Calculated, %: C 63.45; H 6.78; N 6.73.
Methyl cyano[6,10-dimethoxy-1-(2-methoxy-2-
oxoethylidene)-3,3-dimethyl-2-azaspiro[4.5]deca-
6,9-dien-8-ylidene]acetate (I). A mixture of 1.68 g
(10 mmol) of 1,3,5-trimethoxybenzene, 0.95 g (1.2 ml,
13.2 mmol) of freshly distilled isobutyraldehyde,
1.98 g (1.76 ml, 20 mmol) of methyl cyanoacetate, and
3 ml of methylene chloride was added dropwise to
6 ml of 96% sulfuric acid on cooling with water. The
mixture was stirred for 0.5 h and poured into a mixture
of 200 g of ice and 20 ml of 25% aqueous ammonia
(pH ~7–8), the organic layer was separated, and the
aqueous layer was extracted with methylene chloride
(3 ×20 ml). The extracts were combined with the
organic phase, washed with 30 ml of water and 20 ml
of a saturated solution of sodium chloride, and dried
over anhydrous MgSO4. The solvent was removed
under reduced pressure, and the residue was purified
by column chromatography on silica gel using chloro-
form as eluent. Yield 0.81 g (18%), pale yellow crys-
tals, mp 185.5–187.0°C, Rf 0.57. IR spectrum, ν, cm–1:
3320 (NH); 2155 (C≡N); 1690, 1660 (C=O); 1630,
Methyl cyano[1,5-dimethoxy-15-(2-methoxy-2-
oxoethylidene)-14-azadispiro[5.1.5.2]pentadeca-1,4-
dien-3-ylidene]acetate (III) was synthesized in
a similar way from 0.59 g (3.5 mmol) of 1,3,5-tri-
methoxybenzene, 0.42 ml (0.39 g, 3.5 mmol) of cyclo-
hexanecarbaldehyde, and 0.66 ml (0.75 g, 7 mmol) of
methyl cyanoacetate using 2 ml of concentrated sul-
furic acid. After removal of the solvent, the residue
was recrystallized from ethanol. Yield 0.22 g (14%),
pale yellow crystals, mp 208–209°C, Rf 0.62. IR spec-
trum, ν, cm–1: 3355 (NH); 2155 (C≡N); 1690, 1650
1
1580 (C=C). H NMR spectrum, δ, ppm: 1.38 s (6H,
1
Me); 2.17 s (2H, 4-H); 3.45 s, 3.74 s, and 3.78 s (3H
each, OCH3); 3.81 m (4H, OCH3, CH=); 5.94 s and
7.35 s (1H each, 7-H, 9-H); 8.36 s (1H, NH). 13C NMR
spectrum, δC, ppm: 29.97 (3-CH3), 45.46 (C4), 49.58
(OCH3), 51.93 (OCH3), 56.75 (OCH3), 56.79 (OCH3),
58.59 (C5), 62.70 (C3), 73.25 (CH=), 88.96 (C11), 93.70
(C7), 95.36 (C9), 117.52 (C≡N), 158.25 (C6), 161.97
(C10), 164.00 (C8), 169.46 (C1), 170.01 (C=O), 170.07
(C=O). Mass spectrum, m/z (Irel, %): 289 (95) [M –
NCCH2CO2Me]+, 247 (100) [M – NCCH2CO2Me –
C3H6]+, 230 (15), 216 (18). Found, %: C 61.20;
H 6.10; N 7.21. C20H24N2O6. Calculated, %: C 61.85;
H 6.23; N 7.21.
(C=O); 1625, 1595 (C=C). H NMR spectrum,** δ,
ppm: 1.29–1.69 m (10H, CH2); 2.14 s (2H, 4-H);
3.46 s, 3.74 s, 3.77 s, and 3.80 s (3H each, OCH3);
3.83 s (1H, CH=); 5.95 s and 7.35 s (1H each, 7-H,
9-H); 8.37 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
23.45 (C3′, C5′), 24.59 (C4′), 38.22 (C2′, C6′), 42.52 (C4),
49.70 (OCH3), 51.96 (OCH3), 56.80 (OCH3), 56.84
(OCH3), 57.82 (C5), 65.18 (C3), 73.52 (CH=), 88.82
(C11), 93.65 (C7), 95.31 (C9), 117.54 (C≡N), 158.22
(C6), 162.05 (C10), 163.97 (C8), 169.67 (C1), 169.93
(C=O), 169.99 (C=O). Mass spectrum, m/z (Irel, %):
329 (50) [M – NCCH2CO2Me]+, 247 (100) [M –
NCCH2CO2Me – C6H10]+, 216 (10). Found, %:
C 64.40; H 6.51; N 6.54. C23H28N2O6. Calculated, %:
C 64.47; H 6.59; N 6.54.
Ethyl cyano[1-(2-ethoxy-2-oxoethylidene)-6,10-
dimethoxy-3,3-dimethyl-2-azaspiro[4.5]deca-6,9-
dien-8-ylidene]acetate (II) was synthesized in a simi-
lar way from 4.2 g (25 mmol) of 1,3,5-trimethoxyben-
zene, 1.90 g (2.4 ml, 26.4 mmol) of isobutyraldehyde,
** For atom numbering in the NMR spectra of III and IV, see
Scheme 2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SPIROCYCLOHEXADIENONES: IX.
1755
Ethyl cyano[15-(2-ethoxy-2-oxoethylidene)-1,5-
dimethoxy-14-azadispiro[5.1.5.2]pentadeca-1,4-di-
en-3-ylidene]acetate (IV) was synthesized in a similar
way from 1.68 g (10 mmol) of 1,3,5-trimethoxyben-
zene, 1.2 ml (1.12 g, 10 mmol) of cyclohexanecarbal-
dehyde, and 2.12 ml (2.26 g, 20 mmol) of ethyl cyano-
acetate using 8 ml of concentrated sulfuric acid. After
removal of the solvent, the residue was recrystallized
from ethanol. Yield 0.94 g (21%), yellow crystals,
mp 138–139°C, Rf 0.66. IR spectrum, ν, cm–1: 3350
(NH); 2170 (C≡N); 1700, 1660 (C=O); 1640, 1605
Target-Oriented Synthesis of Substances with Speci-
fied Properties”) and by the joint program of the Ural
and Siberian Divisions of the Russian Academy of
Sciences “Target-Oriented Synthesis and Optimization
of Properties of Biologically Active Compounds.”
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1
2. Orru, R.V.A. and de Greef, M., Synthesis, 2003, p. 1471.
(C=C). H NMR spectrum, δ, ppm: 1.06 t and 1.21 t
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(3H each, CH2CH3, J = 6.9 Hz), 1.26–1.63 m (10H,
CH2), 2.09 s (2H, 4-H), 3.72 s and 3.75 s (3H each,
OCH3), 3.78 s (1H, CH=), 3.88 q and 4.15 q (2H each,
OCH2, J = 6.9 Hz), 5.90 s and 7.30 s (1H each, 7-H,
9-H), 8.33 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
14.17 (CH2CH3), 14.49 (CH2CH3), 23.48 (C3′, C5′),
24.60 (C4′), 38.22 (C2′, C6′), 42.46 (C4), 56.77 (OCH3),
56.82 (OCH3), 57.75 (C5), 58.02 (OCH2), 60.75
(OCH2), 65.16 (C3), 73.71 (CH=), 89.28 (C11), 93.68
(C7), 95.32 (C9), 117.55 (C≡N), 157.98 (C6), 162.04
(C10), 163.54 (C8), 169.41 (C1), 169.78 (C=O), 169.83
(C=O). Mass spectrum, m/z (Irel, %): 343 (28) [M –
NCCH2CO2Et]+, 262 (20), 261 (100) [M – NCCH2-
CO2Et – C6H10]+, 216 (12), 189 (17). Found, %:
C 65.71; H 7.02; N 6.10. C25H32N2O6. Calculated, %:
C 65.77; H 7.07; N 6.14.
The authors thank A.A. Gorbunov for recording the
mass spectra. This study was performed under finan-
cial support by the Presidium of the Russian Academy
of Sciences (program “New Principles and Methods of
10. Shklyaev, Yu.V., Nifontov, Yu.V., Shashkov, A.S., and
Firgang, S.I., Izv. Ross. Akad. Nauk, Ser. Khim., 2002,
p. 2075.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008