Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-dien-8-ones and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones by condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles

Article abstract of DOI:10.1134/S1070428012010101

1-Substituted 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones and 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized by three-component condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles in concentrated

Full text of DOI:10.1134/S1070428012010101

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 1, pp. 69–77. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © Yu.S. Rozhkova, K.A. Khmelevskaya, Yu.V. Shklyaev, M.A. Ezhikova, M.I. Kodess, 2012, published in Zhurnal Organicheskoi
Khimii, 2012, Vol. 48, No. 1, pp. 75–82.
Synthesis of 1-Substituted 2-Azaspiro[4.5]deca-6,9-dien-8-ones
and 2-Azaspiro[4.5]deca-1,6,9-trien-8-ones by Condensation
of 2,6-Dimethylphenol with Isobutyraldehyde and Nitriles
Yu. S. Rozhkovaa, K. A. Khmelevskayaa, Yu. V. Shklyaeva, M. A. Ezhikovab, and M. I. Kodessb
a Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences,
ul. Akad. Koroleva 3, Perm, 614013 Russia
e-mail: rjs@mail.ru
b Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
Received May 30, 2011
Abstract—1-Substituted 3,3,7,9-tetramethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones and 3,3,7,9-tetramethyl-2-
azaspiro[4.5]deca-1,6,9-trien-8-ones were synthesized by three-component condensation of 2,6-dimethylphenol
with isobutyraldehyde and nitriles in concentrated sulfuric acid.
DOI: 10.1134/S1070428012010101
Compounds having a 2-azaspiro[4.5]decane skele-
ton rarely occur in nature. Examples of such structures
are annosqualine isolated from the Stems of Annona
squamosa [1], spirostaphylotrichins produced by
Staphylotrichum coccosporum [2–4], triticones (spiro-
cyclic lactams from the fungal plant pathogen
Drechslera tritici-repentis [5]), and spiro-arogenate
(a spiro-γ-lactam produced by Neurospora crassa from
prephenic acid [6, 7]). Some 2-azaspiro[4.5]decanes
attract certain interest from the viewpoints of medici-
nal and synthetic organic chemistry. Some synthetic
analogs of natural 2-azaspirane derivatives showed high
immunosupressive activity [8]. Kazmierski et al. [9]
proposed novel HIV-1 protease inhibitors on the basis
of a spirocyclic pyrrolidone. It was also found that
2-azaspiranes are formed as intermediate products in
the Bischler–Napieralski [10, 11] or Ritter [12] syn-
theses of isoquinolines and phenanthridines.
carboxamides in the presence of Mn(OAc)3 [14] or of
2-bromo-substituted diene amides, e.g., N-benzyl-2-
bromo-N-[1-(cyclohex-1-en-1-yl)vinyl]propanamide,
in the presence of CuBr–(C5H5N)3N [15]. A group of
methods for the preparation of 2-azaspirane systems is
based on dearomatization of arenes with simultaneous
construction of pyrrolidinone fragment. Acid-catalyzed
intramolecular ipso-cyclization of electron-rich aro-
matic diazoacetamides [16] or thionium ions generated
by reaction of N-benzylglyoxamides with thiols [17]
leads to the formation of spirocyclic lactams. 2-Aza-
spiranes can also be obtained by oxidative radical ipso-
cyclization of N-[p-methoxy(hydroxy)benzyl]acet-
amides [18] and substituted N-benzyltrichloroacet-
amides [19]. Pigge et al. [20–24] developed a proce-
dure for the synthesis of 2-azaspiranes via aromatic
nucleophilic substitution in the presence of
(η6-arene)RuCp+ complexes. Another possible way to
2-azaspiranes is based on the reaction of tricarbonyl
(η5-1-alkyl-4-methoxycyclohexadienylium)iron with
difunctional nucleophiles [25]. Intramolecular ene-type
[6+2]-cyclization of Fe(CO)3–(cyclohexa-1,3-diene)
complexes having a pendant double bond was reported
to afford spirocyclic systems [26–28]. 2-Azaspiro[4.5]-
deca-6,9-diene-3,8-diones were synthesized by tandem
Ugi reaction and intramolecular Michael 5-exo-
addition [29].
Several synthetic approaches to 2-azaspiro[4.5]-
decane derivatives have been reported. Some proce-
dures imply building of 2-azaspiro[4.5]decane skeleton
from cyclohexanone or cyclohexene fragments. 2-Aza-
spiranes can be synthesized according to Buchwald–
Hartwig via intramolecular cyclization of the corre-
sponding cyclohexanone derivatives [13] and by
radical cyclization of N,N-diallyl-2-oxocyclohexane-
69

ROZHKOVA et al.
70
Scheme 1.
Me
Me
Me
OH
O
O
N
Me
Me
OH
Me
Me
R
CHO
Me
Me
Me
H2SO4
R
IIa–IIg
+
+
R
N
Me
N
Me
Me
Me
Me
NH
Ia–Im
A
Me
R'
IIh–IIm
I, R = MeS (a), Ph (b), 3,4-(MeO)2C6H3 (c), pyridin-2-yl (d), PhCH2 (e), 3,4-(MeO)2C6H3CH2 (f), Me (g), pyridin-2-ylmethyl (h),
MeOCOCH2 (i), EtOCOCH2 (j), H2NCOCH2 (k), 1H-benzimidazol-2-ylmethyl (l), 1,3-benzothiazol-2-ylmethyl (m); II, R′ =
MeS (a), Ph (b), 3,4-(MeO)2C6H3 (c), pyridin-2-yl (d, h), PhCH2 (e), 3,4-(OMe)2C6H3CH2 (f), Me (g), MeOCO (i), EtOCO (j),
H2NCO (k), 1H-benzimidazol-2-yl (l), 1,3-benzothiazol-2-yl (m).
However, most of the above syntheses of 2-aza-
component condensation of isobutyraldehyde with
phenols and nitriles, catalyzed by concentrated sulfuric
acid. Clearly, the use of phenol instead of anisoles as
aromatic component should ensure higher reactivity in
electrophilic substitution and is attractive from the
viewpoint of accessibility of initial reactants.
spiro[4.5]decane systems include a number of steps;
therefore, development of simpler and more general
procedures for the preparation of such compounds is
an important problem.
We previously proposed a procedure for the syn-
thesis of 2-azaspiro[4.5]deca-6,9-dien-8-ones and
2-azaspiro[4.5]deca-1,6,9-trien-8-ones on the basis of
three-component condensation of anisole [30] or sub-
stituted anisoles [31–34] with an α-branched aldehyde
and a nitrile under acid catalysis. In continuation of
these studies in the present work we examined three-
Reactions of isobutyraldehyde with nitriles and
such hydroxy aromatics as phenol, 2-methylphenol, or
4-methylphenol resulted in the formation of tarry mix-
tures which were difficult to separate, and we failed to
isolate spirane systems. Obviously, the reason is
a number of side processes, such as acid-catalyzed
polymerization of phenol and aldehyde [35] and
Baeyer reaction with formation of diarylmethane
derivatives [35–37]. To exclude the possibility for ortho
attack on phenol molecule by aldehyde and suppress
side reactions we used 2,6-dimethylphenol as aromatic
component in the three-component condensation.
C13
C1
C2
C12
C14
C10
We found that 2,6-dimethylphenol reacts with iso-
butyraldehyde and nitriles Ia–Im in 92% sulfuric acid
to give 2-azaspiro[4.5]deca-6,9-dien-8-ones IIa–IIg
and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones IIh–IIm
(Scheme 1). Compounds IIa–IIm displayed in the
1H NMR spectra singlets from geminal methyl groups
on C3 (δ 1.37–1.49 ppm), methyl groups on C7 and C9
(δ 1.76–1.94 ppm), methylene protons on C4 (δ 2.00–
2.20 ppm), and olefinic protons on C6 and C10 (δ 6.23–
6.93 ppm). The structure of IIg was proved by X-ray
analysis (Fig. 1). In the spectra of IIi–IIm we observed
a singlet at δ 3.91–4.69 ppm from vinylic proton and
a broadened singlet at δ 8.26–8.90 ppm from the NH
proton, which indicated their enamine structure.
N1
C4
C9
C3
C6
C8
C5
C7
O1
C11
Fig. 1. Structure of the molecule of 1,3,3,7,9-pentamethyl-2-
azaspiro[4.5]deca-1,6,9-trien-8-one (IIg) according to the
X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

SYNTHESIS OF 1-SUBSTITUTED 2-AZASPIRO[4.5]DECA-6,9-DIEN-8-ONES
71
O
O
O
Me
S
Me
Me
Me
Me
Me
δN 288.5 ppm
δN 313.5 ppm
N
N
Me
N
HN
N
Me
Me
Me
Me
Me
Me
δN 323.6 ppm
δN 119.8 ppm
δN 349.2 ppm
IIa
IIh
Fig. 2. 15N chemical shifts of model 3,3,7,9-tetramethyl-1-methylsulfanyl-2-azaspiro[4.5]deca-1,6,9-trien-8-one (IIa) and 3,3,7,9-
tetramethyl-1-(pyridin-2-ylmethylidene)-2-azaspiro[4.5]deca-6,9-dien-8-one (IIh).
1
According to the H NMR data, compound IIh in
tron-rich phenyl fragment on intermediate spiro-σ-
complex. The formation of compound IIf in the three-
component condensation with 2,6-dimethylphenol may
be rationalized in terms of both reduced positive
charge on σ-complex A due to effect of the phenolic
hydroxy group and stabilization of σ-complex A via
abstraction of proton from the phenolic hydroxy group,
which prevents subsequent cyclization to neospiro-
dienone system (Scheme 3).
CDCl3 exists as a mixture of enamino and imino
tautomers at a ratio of 4:1 (Scheme 2). The H NMR
1
spectrum contained two sets of signals from the methyl
groups on C3 (δ 1.49 and 1.44 ppm), C7-CH3 and
C9-CH3 (δ 1.93 and 1.78 ppm), and C4H2 (δ 2.13 and
2.04 ppm) and two sets of signals from protons in the
pyridine ring. Enamino tautomer A gave rise to a sin-
glet at δ 4.70 ppm from the C1=CH proton and
a broadened singlet at δ 8.86 ppm from the NH group.
Tautomer B was characterized by a singlet at
δ 3.61 ppm due to protons in the C1-CH2 group.
As in the reaction with anisole [39], we failed to
isolate spirane system in the three-component con-
densation with chloroacetonitrile due to fast dienone–
phenol rearrangement, leading to the formation of only
amide III as formal classical Ritter reaction product.
The corresponding spirane was detected only by
GC–MS analysis of the reaction mixture immediately
after the reaction was complete (Scheme 4).
Scheme 2.
O
O
Me
Me
Me
Me
The reaction with malononitrile as nitrile compo-
nent gave compound IV as a result of condensation
involving both cyano groups (Scheme 5). The structure
N
N
HN
N
Me
Me
Me
Me
1
15
of compound IV was confirmed by H, 13C, and N
A
IIh
B
NMR spectroscopy, including two-dimensional 1H–13C
1
In the condensation with 3,4-dimethoxyphenyl-
acetonitrile (If) as nitrile component we succeeded in
isolating for the first time spirane IIf. We previously
showed [38] that three-component reaction of anisole
or p-methylanisole with isobutyraldehyde and 3,4-di-
methoxyphenylacetonitrile leads to the formation of
neospiroenone systems as a result of attack by elec-
HSQC and HMBC and H–15N HMBC techniques.
The 1H and 13C NMR spectra contained only one set of
signals corresponding to “symmetric” structure IV.
The intensity of the methyl protons signals at δ 1.42
(3-CH3) and 1.85 ppm (7-CH3, 9-CH3) was equivalent
to 12 protons, and the singlet at δ 2.02 ppm (methylene
protons) had an intensity of 4H with respect to the CH
Scheme 3.
O
OH
Me
Me
N
MeO
MeO
Me
Me
Me
Me
MeO
MeO
Me
OMe
N
N
Me
Me
Me
Me
O
Me
OMe
IIf
A
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

ROZHKOVA et al.
72
Scheme 4.
Me
Me
Me
Me
OH
HO
Me
CHO
Me
H2O
Me
Me
Me
Cl
Me
NH
O
+
+
ClCH2CN
N
Me
Me
Cl
O
III
Scheme 5.
OH
CHO
Me
Me
+
+ NCCH2CN
Me
Me
Me
Me
Me
7
6
5
4
Me
3
Me
Me
Me
Me
O
O
O
8
Me
9
1
N2
N
N
N
10
Me
Me
Me
Me
Me
Me
H
H
H
N
N
Me
Me
Me
Me
Me
Me
O
O
O
Me
Me
Me
IV
signal at δ 3.80 ppm. The NH signal in the spectrum
recorded from a solution of IV in CDCl3 appeared in
the δ range from 2 to 6 ppm; it was so broadened that it
was difficult to distinguish it from the baseline. Com-
pound IV in DMSO-d6 displayed a broadened signal
centered at δ ~9 ppm with a width of ~200 Hz. The
chemical shift of the CH carbon atom (δC 78.87 ppm)
indicates its average hybridization between sp2 and sp3.
125.76 MHz, respectively; TMS as internal reference).
The 15N NMR spectra were measured on a Bruker
Avance-500 spectrometer at 50.7 MHz using liquid
ammonia as external reference. The mass spectra were
obtained on an Agilent Technologies 6890N/5975B
GC–MS system [HP-5ms column, 30 m×0.25 mm,
film thickness 0.25 μm; carrier gas helium; electron
impact, 70 eV; ion source temperature 200°C] and on
a Varian MAT 311A spectrometer (electron impact,
70 eV). The elemental compositions were determined
on a Leco CHNS-932 analyzer. The IR spectra were
recorded on a Bruker IFS-66 spectrometer with Fourier
transform from samples dispersed in mineral oil. The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates; spots
were visualized by treatment with a 0.5% solution of
tetrachloro-1,4-benzoquinone in toluene. Silica gel
(0.06–0.20 mm, 70–230 mesh; Lancaster) was used for
preparative column chromatography. The melting
points were measured on a PTP melting point appa-
ratus and are uncorrected.
1
The H–15N HMBC spectrum contained only one
signal from nitrogen atom coupled through three bonds
with the CH proton and protons in the C4H2 and
C3(CH3)2 groups. The chemical shift of the nitrogen
(δN 220.2 ppm) can also be interpreted as an average
value between enamine and imine nitrogen atoms. This
15
is confirmed by the N chemical shifts measured for
structurally related compounds IIa and IIh (Fig. 2).
Thus the above spectral data indicate that com-
pound IV in solution exists as symmetric structure
with delocalized electron density (fast interconversion
of one enaminoazomethine tautomer into another).
EXPERIMENTAL
X-Ray analysis of compoun IIg. Single crystals of
IIg were obtained by crystallization from ethyl acetate.
The X-ray diffraction data were acquired at 295(2) K
on an Xcalibur-3 diffractometer equipped with a CCD
1
The H and 13C NMR spectra were recorded on
Varian Mercury Plus (300.06 and 75.46 MHz, HMDS)
and Bruker Avance-500 spectrometers (500.13 and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

SYNTHESIS OF 1-SUBSTITUTED 2-AZASPIRO[4.5]DECA-6,9-DIEN-8-ONES
73
Crystallographic data for 1,3,3,7,9-pentamethyl-2-azaspiro-
[4.5]deca-1,6,9-trien-8-one (IIg) and parameters of X-ray
diffraction experiment
detector (MoKα irradiation, graphite monochromator,
ω-scanning). The structure was solved by the direct
method using SHELXS-97 and was refined in aniso-
tropic approximation (isotropic for hydrogen atoms)
using SHELXL-97. The crystallographic data and
parameters of X-ray diffraction experiment are given
in table.
Parameter
Value
Formula
C14H19NO
217.31
Molecular weight
Crystal system
Space group
a, Å
Monoclinic
C2/c
Compounds IIa–IIj, III, and IV (general proce-
dure). A mixture of 5 mmol of 2,6-dimethylphenol,
5 mmol of isobutyraldehyde, and 5 mmol of nitrile Ia–
Ih in 1 ml of methylene chloride was added dropwise
under stirring to 6 ml of 92% sulfuric acid cooled with
ice water. The mixture was stirred for 20 min at room
temperature, poured into a mixture of ice and 25 ml
of aqueous ammonia, and extracted with methylene
chloride (3×25 ml). The combined extracts were dried
over MgSO4, the solvent was distilled off, and the
residue was crystallized from appropriate solvent or
purified by chromatography.
11.5115(10)
11.1898(10)
20.184(3)00
90.0000()
94.537(9)
90.0000()
2591.8(5)
8
b, Å
c, Å
α, deg
β, deg
γ, deg
V , Å3
Z
d
calc, g/cm–3
1.114
μ, mm–1
0.069
3,3,7,9-Tetramethyl-1-methylsulfanyl-2-azaspiro-
[4.5]deca-1,6,9-trien-8-one (IIa). Yield 0.43 g (35%),
mp 95.5–97.5°C (from hexane–ethyl acetate). IR spec-
Scan range, deg
2.79–26.36
4450
Total number of reflections
1
trum, ν, cm–1: 1665, 1637, 1588. H NMR spectrum
Number of independent reflections
2561
(CDCl3), δ, ppm: 1.42 s (6H, 3-CH3), 1.92 s (6H,
7-CH3, 9-CH3), 2.15 s (2H, CH2), 2.36 s (3H, SMe),
6.50 (2H, 6-H, 10-H). 13C NMR spectrum (CDCl3), δC,
ppm: 13.89 (SMe), 16.06 (7-CH3, 9-CH3), 31.01
(3-CH3), 48.97 (C4), 61.78 and 74.06 (C3, C5), 134.93
(C7, C9), 144.81 (C6, C10), 168.32 (C1), 186.15 (C8).
15N NMR spectrum (CDCl3): δN 323.6 ppm. Mass
spectrum, m/z (Irel, %): 249 (0.6) [M]+, 234 (4.7) [M –
Me]+, 176 (100) [M – MeSCN]+, 161 (66.6) [M –
MeSCN – Me]+, 146 (3.4), 134 (16.5), 121 (36), 106
(3.1), 91 (16.6), 65 (5.2), 41 (8.1). Found, %: C 67.25;
H 7.80; N 5.74; S 12.93. C14H19NOS. Calculated, %:
C 67.47; H 7.63; N 5.62; S 12.90.
Number of refined parameters
0150
Rint
0.0331
R, %
4.3500
R1 for reflections with I > 2(I)
0.0435
wR2
0.0898
R1 for all reflections
0.1170
wR2
0.0990
91.1 (14), 77 (11.2), 65 (3.4), 51 (3.9), 41 (4.2). Found,
%: C 81.42; H 7.44; N 5.04. C19H21NO. Calculated, %:
C 81.68; H 7.58; N 5.01.
1-(3,4-Dimethoxyphenyl)-3,3,7,9-tetramethyl-
2-azaspiro[4.5]deca-1,6,9-trien-8-one (IIc). Yield
0.98 g (58%), mp 118–120°C (from propan-2-ol). IR
spectrum, ν, cm–1: 3000, 1662, 1633, 1603, 1578,
1514. 1H NMR spectrum (CDCl3), δ, ppm: 1.48 s (6H,
3-CH3), 1.94 s (6H, 7-CH3, 9-CH3), 2.18 s (2H, CH2),
3.79 s (3H, OMe), 3.86 s (3H, OMe), 6.71 d (1H, 5′-H,
3J = 8.6 Hz), 6.78 s (2H, 6-H, 10-H), 7.19 d.d (1H,
3,3,7,9-Tetramethyl-1-phenyl-2-azaspiro[4.5]-
deca-1,6,9-trien-8-one (IIb). Yield 0.80 g (57%),
mp 125–127°C (from hexane–ethyl acetate). IR spec-
trum, ν, cm–1: 3055, 1661, 1623, 1606, 1574, 1540.
1H NMR spectrum (CDCl3), δ, ppm: 1.49 s (6H,
3-CH3), 1.94 s (6H, 7-CH3, 9-CH3), 2.19 s (2H, CH2),
6.75 s (2H, 6-H, 10-H), 7.30 m (3H, Ph), 7.63 m (2H,
Ph). 13C NMR spectrum (CDCl3), δC, ppm: 16.15
(7-CH3, 9-CH3), 30.66 (3-CH3), 49.63 (C4), 60.85,
72.18 (C3, C5), 127.53, 128.16, 130.36 (Ph), 133.74,
134.43 (Ph, C7, C9), 146.90 (C6, C10), 166.46 (C1),
186.26 (C8). Mass spectrum, m/z (Irel, %): 279 (0.2)
[M]+, 176 (100) [M – PhCN]+, 161 (64.8) [M – PhCN –
Me]+, 145 (5.3), 134 (13.0), 121 (28.7), 103 (27.5),
3
4
4
6′-H, J = 8.6, J = 1.9 Hz), 7.34 d (1H, 2′-H, J =
13
1.9 Hz). C NMR spectrum (CDCl3), δC, ppm: 16.03
(7-CH3, 9-CH3), 30.66 (3- CH3), 49.56 (C4), 55.49
(OMe), 55.60 (OMe), 60.69 and 71.88 (C3, C5), 110.07
and 110.22 (C2′, C5′), 120.76 (C6′), 126.41 (C1′), 134.02
(C7, C9); 147.43, 148.23, 150.71 (C6, C10, C3′, C4′),
165.25 (C1), 186.14 (C8). Mass spectrum, m/z (Irel, %):
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

ROZHKOVA et al.
74
3
4
339 (1. 7) [M]+, 205 (1. 0), 176 (100) [M –
(MeO)2C6H3CN]+, 161 (58.6) [M – (MeO)2C6H3CN –
Me]+, 148 (11.9), 134 (8.4), 121 (19.5), 105 (8.1), 91
(12.6), 77 (10.7), 65 (7.3), 51 (2.7), 41 (3.9). Found,
%: C 73.92; H 7.32; N 4.13. C21H25NO3. Calculated,
%: C 74.31; H 7.42; N 4.13.
(2H, 6-H, 10-H), 6.57 d.d (1H, 6′-H, J = 8.3, J =
4
1.9 Hz), 6.69 d (1H, 2′-H, J = 1.9 Hz), 6.72 d (1H,
5′-H, J = 8.3 Hz). 13C NMR spectrum (CDCl3), δC,
3
ppm: 15.69 (7-CH3, 9-CH3), 30.66 (3-CH3), 36.18
(CH2), 47.94 (C4), 55.71 (OMe), 55.91 (OMe), 62.61
and 73.36 (C3, C5); 111.68, 112.47, 121.39 (C2′, C5′,
C6′); 129.32 (C1′), 134.96 (C7, C9), 144.98 (C6, C10),
147.94 and 149.07 (C3′, C4′), 169.16 (C1), 185.96 (C8).
Mass spectrum, m/z (Irel, %): 353 (1.1) [M]+, 177 (100)
[M – (MeO)2C6H3CH2CN + H]+, 161 (49.1) [M –
(MeO)2C6H3CH2CN – Me]+, 146 (10.3), 135 (14.6),
121 (14.3), 107 (19.2), 91 (15.9), 77 (10), 65 (6.4), 51
(4.3), 41 (2.6). Found, %: C 74.35; H 7.60; N 3.95.
C22H27NO3. Calculated, %: C 74.76; H 7.70; N 3.96.
3,3,7,9-Tetramethyl-1-(pyridin-2-yl)-2-azaspiro-
[4.5]deca-1,6,9-trien-8-one (IId). Yield 0.50 g (36%),
mp 136–137°C (from hexane–ethyl acetate). IR spec-
trum, ν, cm–1: 3059, 3009, 1667, 1633, 1611, 1581,
1534. 1H NMR spectrum (CDCl3), δ, ppm: 1.52 s (6H,
3-CH3), 1.91 s (6H, 7-CH3, 9-CH3), 2.19 s (2H, CH2),
3
6.68 s (2H, 6-H, 10-H), 7.21 d.d.d (1H, 5′-H, J = 7.7,
4
3
4
4.8, J = 0.9 Hz), 7.61 t.d (1H, 4′-H, J = 7.7, J =
3
1,3,3,7,9-Pentamethyl-2-azaspiro[4.5]deca-1,6,9-
trien-8-one (IIg) was synthesized from 5 mmol of
2,6-dimethylphenol, 5 mmol of isobutyraldehyde, and
15 mmol of acetonitrile. Yield 0.47 g (43%), mp 95–
97°C (from ethyl acetate). IR spectrum, ν, cm–1: 1644,
1.8 Hz), 7.76 br.d (1H, 3′-H, J = 7.0 Hz), 8.45 br.d
3
13
(1H, 6′-H, J = 4.8 Hz). C NMR spectrum (CDCl3),
δ, ppm: 16.15 and 16.03 (7-CH3, 9-CH3), 30.64
(3-CH3), 48.92 (C4), 60.50 and 72.98 (C3, C5), 122.47
and 124.48 (C3′, C5′), 134.04 (C7, C9), 135.91 (C4′),
146.17 (C6, C10), 149.18 (C2′), 167.34 (C1), 186.83
(C8). Mass spectrum, m/z (Irel, %): 280 (15.1) [M]+, 237
(1.2), 197 (1.5), 176 (100) [M – C5H4NCN]+, 161
(76.3) [M – C5H4NCN – Me]+, 146 (4.5), 134 (17.1),
121 (36.4), 105 (30.2), 91 (18.1), 77 (14.4), 65 (4.4),
51 (6.3), 41 (6.1). Found, %: C 76.89; H 7.01; N 9.93.
C14H19NO. Calculated, %: C 77.11; H 7.19; N 9.99.
1
1630, 1543. H NMR spectrum (CDCl3), δ, ppm:
1.40 s (6H, 3-CH3), 1.72 s (3H, 1-CH3), 1.93 s (6H,
7-CH3, 9-CH3), 2.06 s (2H, CH2), 6.47 s (2H, 6-H,
10-H). 13C NMR spectrum (CDCl3), δC, ppm: 15.18
and 15.74 (1-CH3, 7-CH3, 9-CH3), 30.48 (3-CH3),
47.13 (C4), 62.34 and 73.12 (C3, C5), 135.03 (C7, C9),
144.94 (C6, C10), 167.36 (C1), 185.81 (C8). Mass spec-
trum, m/z (Irel, %): 217 (0.4) [M]+, 202 (2.1) [M –
Me]+, 176 (100) [M – MeCN]+, 161 (85) [M – MeCN –
Me]+, 147 (5.7), 134 (21.2), 121 (45.3), 105 (11.7), 91
(22.7), 77 (10), 65 (6.2), 41 (13.2). Found, %: C 77.39;
H 8.54; N 6.46. C14H19NO. Calculated, %: C 77.38;
H 8.81; N 6.45.
1-Benzyl-3,3,7,9-tetramethyl-2-azaspiro[4.5]-
deca-1,6,9-trien-8-one (IIe). Yield 0.56 g (38%),
mp 95–106°C (from ethyl acetate). IR spectrum, ν,
1
cm–1: 3032, 1665, 1647, 1626. H NMR spectrum
(CDCl3), δ, ppm: 1.43 s (6H, 3-CH3), 1.76 s (6H,
7-CH3, 9-CH3), 2.00 s (2H, CH2), 3.37 s (2H, CH2),
6.23 s (2H, 6-H, 10-H), 7.16 m (5H, Ph). 13C NMR
spectrum (CDCl3), δC, ppm: 15.82 (7-CH3, 9-CH3),
30.63 (3-CH3), 36.61 (CH2), 47.50 (C4), 62.43 and
73.35 (C3, C5); 126.40, 128.10, 128.75 (Ph); 134.90,
136.44 (C7, C9, Ph); 145.11 (C6, C10), 168.91 (C1),
186.06 (C8). Mass spectrum, m/z (Irel, %): 293 (0.2)
[M]+, 176 (100) [M – PhCH2CN]+, 161 (64) [M –
PhCN – Me]+, 146 (4.2), 134 (13.9), 121 (31.8), 117
(28.3), 105 (9), 91 (31.3), 77 (8.4), 65 (7.1), 51 (4.4),
41 (5.4). Found, %: C 81.67; H 7.74; N 4.79.
C20H23NO. Calculated, %: C 81.87; H 7.90; N 4.77.
3,3,7,9-Tetramethyl-1-(pyridin-2-ylmethylidene)-
2-azaspiro[4.5]deca-6,9-dien-8-one (IIh). Yield
0.40 g (27%), mp 166–167.5°C (from propan-2-ol).
IR spectrum, ν, cm–1: 3283, 3023, 1663, 1624, 1587,
1537. 1H NMR spectrum (CDCl3), δ, ppm: tautomer A:
1.49 s (6H, 3-CH3), 1.93 s (6H, 7-CH3, 9-CH3), 2.13 s
(2H, CH2), 4.70 s (1H, =CH), 6.72 s (2H, 6-H, 10-H),
3
4
6.74 d.d.d (1H, 5′-H, J = 7.7, 5.3, J = 1.0 Hz),
3
6.74 d.m (1H, 3′-H, J = 7.7 Hz), 7.39 t.d (1H, 4′-H,
3J = 7.7, 4J = 1.6 Hz), 8.37 d.d (1H, 6′-H, 3J = 5.3, 4J =
1.6 Hz), 8.86 br.s (1H, NH); tautomer B: 1.44 s (6H,
3-CH3), 1.78 s (6H, 7-CH3, 9-CH3), 2.04 s (2H, 4-H),
3.61 s (2H, CH2), 6.33 s (2H, 6-H, 10-H), 7.08 d.d.d
1-(3,4-Dimethoxybenzyl)-3,3,7,9-tetramethyl-
2-azaspiro[4.5]deca-1,6,9-trien-8-one (IIf). Yield
1.13 g (64%), mp 106–112°C (from ethyl acetate). IR
spectrum, ν, cm–1: 3001, 1664, 1634, 1591, 1514.
1H NMR spectrum (CDCl3), δ, ppm: 1.43 (6H, 3-CH3),
1.78 s (6H, 7-CH3, 9-CH3), 2.00 s (2H, CH2), 3.30 s
(2H, CH2), 3.81 s (3H, OMe), 3.83 s (3H, OMe), 6.24 s
3
4
(1H, 5′-H, J = 7.7, 5.0, J = 1.0 Hz), 7.14 d.m (1H,
3
3
4
3′-H, J = 7.7 Hz), 7.57 t.d (1H, 4′-H, J = 7.7, J =
3
4
1.8 Hz), 8.47 d.d (1H, 6′-H, J = 5.0, J = 1.8 Hz).
13C NMR spectrum (CDCl3), δC, ppm: tautomer A:
16.10 (7-CH3, 9-CH3), 31.62 (3-CH3), 47.22 (C4),
52.90 and 60.18 (C3, C5), 87.68 (CH=), 116.35 and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

SYNTHESIS OF 1-SUBSTITUTED 2-AZASPIRO[4.5]DECA-6,9-DIEN-8-ONES
75
120.71 (C3′, C5′), 132.77 (C7, C9), 135.36 (C4′); 147.33,
147.67, 151.89 (C6, C10, C2′, C6′); 159.65 (C1), 187.15
(C8). 15N NMR spectrum (CDCl3), δN, ppm: A: 119.8
(N2), 288.5 (N1′); B: 349.2 (N2), 313.5 (N1′). Mass
spectrum, m/z (Irel, %): 294 (9.3) [M]+, 176 (100) [M –
NHCH=CHC5H4N]+, 161 (76.3), 146 (8.2), 135 (15.9),
119 (59.1), 105 (11.4), 91 (26.6), 78 (23.8), 65 (10.5),
51 (9.2), 41 (7.7). Found, %: C 81.67; H 7.74; N 4.79.
C20H23NO. Calculated, %: C 81.87; H 7.90; N 4.77.
2-Chloro-N-[1-(4-hydroxy-3,5-dimethylphenyl)-
2-methylpropan-2-yl]acetamide (III). Yield 0.47 g
(35%), mp 125–126°C (from ethyl acetate). IR spec-
trum, ν, cm–1: 3385, 3291, 2995, 1659, 1598, 1536.
1H NMR spectrum (CDCl3), δ, ppm: 1.36 s [6H,
C(CH3)2], 2.22 s (6H, 3′-CH3, 5′-CH3), 2.83 s (2H,
CH2), 3.93 s (2H, CH2Cl), 4.64 br.s (1H, OH), 6.31 br.s
13
(1H, NH), 6.74 s (2H, 2′-H, 6′-H). C NMR spectrum
(CDCl3), δC, ppm: 15.94 (3′CH3, 5′-CH3), 26.56
[C(CH3)2], 42.98 and 44.98 (CH2Cl, CH2); 54.11
[C(CH3)2], 122.97 and 128.35 (C1′, C3′, C5′), 130.48
(C2′, C6′), 151.10 (C4′), 165.22 (C=O). Mass spectrum,
m/z (Irel, %): 269 (2) [M]+, 176 (57) [M –
NH(CO)CH2Cl – H]+, 161 (11), 147 (6), 134 (100),
121 (6), 115 (4), 105 (4), 91 (14), 77 (8), 58 (94), 42
(4). Found, %: C 62.25; H 7.53; N 5.14. C14H20ClNO2.
Calculated, %: C 62.33; H 7.47; N 5.19.
Methyl 2-(3,3,7,9-tetramethyl-8-oxo-2-azaspiro-
[4.5]deca-6,9-dien-1-ylidene)acetate (IIi). Yield
0.72 g (52%), mp 155–156°C (from ethanol). IR spec-
trum, ν, cm–1: 3360, 3256, 1661, 1633, 1602. 1H NMR
spectrum (DMSO-d6), δ, ppm: 1.41 s (6H, 3-CH3),
1.81 s (6H, 7-CH3, 9-CH3), 2.11 s (2H, CH2), 3.47 s
(3H, OCH3), 3.91 s (1H, =CH), 6.79 s (2H, 6-H,
10-H), 8.26 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 15.60 (7-CH3, 9-CH3), 30.36
(3-CH3), 45.56 (C4), 49.60 (OCH3), 52.78 and 61.66
(C3, C5), 75.30 (=CH), 132.63 (C7, C9), 146.36 (C6,
C10), 162.34 (C1), 169.11 (C=O), 185.78 (C8). Mass
spectrum, m/z (Irel, %): 275 (87.5) [M]+, 260 (24.9)
[M – Me]+, 243 (26.6), 228 (56.9), 216 (57.1)
[M – COOMe]+, 200 (22.4), 188 (20.2), 176 (91.3)
[M – NHCH=CHCOOMe]+, 161 (100) [M –
NHCH=CHCOOMe – Me]+, 148 (9.1), 134 (23.5), 121
(47.5), 105 (14.4), 91 (27.7), 77 (13), 68 (13.3),
55 (10.8). Found, %: C 69.47; H 7.57; N 5.05.
C16H21NO3. Calculated, %: C 69.79; H 7.69; N 5.09.
3,3,7,9-Tetramethyl-1-[(3,3,7,9-tetramethyl-
8-oxo-2-azaspiro[4.5]deca-1,6,9-trien-1-yl)methyli-
dene]-2-azaspiro[4.5]deca-6,9-dien-8-one (IV) was
synthesized from 5 mmol of 2,6-dimethylphenol,
5 mmol of isobutyraldehyde, and 2.5 mmol of malono-
nitrile. Yield 0.26 g (22%), mp 221–224°C (from ethyl
acetate). IR spectrum, ν, cm–1: 1664, 1634, 1600, 1536.
1H NMR spectrum, δ, ppm: in CDCl3: 1.42 s (12H,
3-CH3, 3′-CH3), 1.85 s (12H, 7-CH3, 7′-CH3, 9-CH3,
9′-CH3), 2.02 s (4H, 4-H, 4′-H), 3.80 s (1H, CH),
6.53 s (4H, 6-H, 6′-H, 10-H, 10′-H); in DMSO-d6:
1.37 s (12H, 3-CH3), 3′-CH3), 1.72 s (12H, 7-CH3,
7′-CH3, 9-CH3, 9′-CH3), 2.02 s (4H, 4-H, 4′-H), 3.58 s
(1H, CH), 6.72 s (4H, 6-H, 6′-H, 10-H, 10′-H),
Ethyl 2-(3,3,7,9-tetramethyl-8-oxo-2-azaspiro-
[4.5]deca-6,9-dien-1-ylidene)acetate (IIj). Yield
0.82 g (57%), mp 157–158.5°C (from ethanol). IR
spectrum, ν, cm–1: 3364, 3246 w, 1663, 1631, 1602.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.11 t (3H,
CH2CH3, 3J = 7.1 Hz), 1.41 s (6H, 3-CH3), 1.81 s (6H,
7-CH3, 9-CH3), 2.11 s (2H, CH2), 3.90 s (1H, =CH),
13
8.95 br.s (1H, NH). C NMR spectrum (CDCl3), δC,
ppm: 16.07 (7-CH3, 7′-CH3, 9-CH3, 9′-CH3), 31.75
(3-CH3, 3′-CH3), 47.89 (C4, C4′), 56.93 (C3, C3′), 66.26
(C5, C5′), 78.87 (CH), 133.63 (C7, C7′), 146.51 (C6,
C6′), 162.12 (C1, C1′), 186.73 (C8, C8′). 15N NMR spec-
trum (CDCl3): δN 220.2 ppm (N2, N2′). Mass spectrum,
m/z (Irel, %): 418 (6.8) [M]+, 243 (66.3), 227 (12), 212
(2.3), 176 (100), 161 (33), 146 (3.8), 135 (17.7), 121
(13.9), 105 (6.1), 91 (9.1), 77 (4.4), 77 (4.4), 55 (9).
Found, %: C 77.06; H 8.11; N 6.63. C27H34N2O2. Cal-
culated, %: C 77.48; H 8.19; N 6.69.
3
3.98 q (2H, OCH2, J = 7.1 Hz), 6.79 s (2H, 6-H,
10-H), 8.26 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 14.58 (CH2CH3), 15.59 (7-CH3,
9-CH3), 30.39 (3-CH3), 45.56 (C4), 57.78 (OCH2),
52.76 (C5), 61.63 (C3, C5), 75.56 (=CH), 132.60 (C7,
C9), 146.37 (C6, C10), 162.33 (C1), 168.83 (C=O),
185.78 (C8). Mass spectrum, m/z (Irel, %): 289 (59.5)
[M]+, 274 (14.6) [M – Me]+, 244 (21.9) [M – OEt]+,
228 (40.2), 216 (43.5) [M – COOEt]+, 200 (15.9), 188
(13.4), 176 (100) [M – NHCH=CHCOOEt]+, 161
(87.6) [M – NHCH=CHCOOEt – Me]+, 148 (8.2), 134
(20.9), 121 (42.8), 114 (16.5), 105 (13.2), 91 (23), 86
(14.6), 77 (10.3), 55 (10). Found, %: C 70.30; H 7.83;
N 4.79. C17H23NO3. Calculated, %: C 70.56; H 8.01;
N 4.84.
Compounds IIk–IIm (general procedure). Nitrile
Ik–Im, 5 mmol, was dissolved in 6 ml of 92% sulfuric
acid, a mixture of 5 mmol of 2,6-dimethylphenol and
5 mmol of isobutyraldehyde in 1 ml of methylene
chloride was added, the mixture was stirred for 20 min
at room temperature and poured into a mixture of ice
and 25 ml of aqueous ammonia. The precipitate was
filtered off, washed with methylene chloride, dried,
and recrystallized from DMSO to isolate compounds
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 1 2012

ROZHKOVA et al.
(1H, Harom, J = 7.9 Hz), 7.32 br.t (1H, Harom, J =
76
3
3
IIk and IIl; to isolate compound IIm, the mixture was
extracted with methylene chloride (3×25 ml), the com-
bined extracts were dried over MgSO4, the solvent was
distilled off, and the residue was purified by chroma-
tography using chloroform–acetone (25:1) as eluent.
3
4
7.9 Hz), 7.67 d.d (1H, Harom, J = 7.9, J = 0.9 Hz),
3
4
7.76 d.d (1H, Harom, J = 7.9, J = 0.9 Hz), 8.90 br.s
(1H, NH). 13C NMR spectrum (CDCl3), δC, ppm: 16.03
(7-CH3, 9-CH3), 31.28 (3-CH3), 47.27 (C4), 52.48 and
60.92 (C3, C5), 82.17 (CH=); 120.04, 120.86, 122.58,
125.37 (C4′, C5′, C6′, C7′); 132.51 and 133.43 (C7a′, C7,
C9), 145.78 (C6, C10), 154.07 and 154.53 (C2′, C3a′),
167.83 (C1), 186.50 (C8). Mass spectrum, m/z (Irel, %):
350 (34.4) [M]+, 335 (2.8) [M – Me]+, 201 (2.9), 176
(100) [M – NHCH=CHC7H5NS]+, 161 (37.5), 149
(22.7), 135 (13.2), 121 (18.9), 108 (8.3), 91 (11.8), 77
(6.7), 55 (8.6). Found, %: C 71.15; H 6.54; N 8.08;
S 9.04. C21H22N2OS. Calculated, %: C 71.97; H 6.33;
N 7.99; S 9.15.
2-(3,3,7,9-Tetramethyl-8-oxo-2-azaspiro[4.5]-
deca-6,9-dien-1-ylidene)acetamide (IIk). Yield
0.63 g (48%), mp 178–179°C. IR spectrum, ν, cm–1:
3429, 3311, 3280, 3186, 1673, 1654, 1625, 1562.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.37 s (6H,
3-CH3), 1.80 s (6H, 7-CH3, 9-CH3), 2.05 s (2H, CH2),
4.10 s (1H, =CH), 6.15 br.s (2H, NH2), 6.79 s (2H,
6-H, 10-H), 8.37 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 15.70 (7-CH3, 9-CH3), 30.78
(3-CH3), 45.82 (C4), 52.46 and 60.45 (C3, C5), 79.92
(CH=), 131.96 (C7, C9), 147.44 (C6, C10), 158.54 (C1),
171.52 (C=O), 186.09 (C8). Mass spectrum, m/z (Irel,
%): 260 (23.5) [M]+, 245 (2.6) [M – Me]+, 228 (10),
216 (5) [M – CONH2]+, 200 (4.8), 176 (100) [M –
NHCH=CHCONH2], 161 (82.2), 146 (5.9), 134 (19.6),
121 (37.6), 105 (11.3), 91 (21.8), 85 (19.8), 77 (10.1),
55 (8.5). Found, %: C 69.30; H 7.73; N 10.76.
C15H20N2O2. Calculated, %: C 69.20; H 7.74; N 10.76.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 11-03-00 367-a) and by the Presidium of the
Russian Academy of Sciences (program no. 18).
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1530. H NMR spectrum (DMSO-d6), δ, ppm: 1.48 s
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(IIm). Yield 0.47 g (27%), mp 178–179°C (from ethyl
acetate). IR spectrum, ν, cm–1: 3260, 1662, 1625, 1598.
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3-CH3), 1.93 s (6H, 7-CH3, 9-CH3), 2.19 s (2H, CH2),
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SYNTHESIS OF 1-SUBSTITUTED 2-AZASPIRO[4.5]DECA-6,9-DIEN-8-ONES
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