Three-component condensation of methoxyarenes with isobutyraldehyde and α-substituted benzyl cyanides

Article abstract of DOI:10.1134/S1070428008090133

Three-component condensation of anisole with isobutyraldehyde and substituted benzyl cyanides gives 1-benzyl-3,3-dimethyl-2-azaspiro[4.5]deca-6,9- dien-8-ones which undergo dienone-phenol rearrangement during the reaction. Analogous condensation of 1-meth

Full text of DOI:10.1134/S1070428008090133

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 9, pp. 1327–1331. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © Yu.V. Shklyaev, M.A. El’tsov, O.A. Maiorova, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 9,
pp. 1343–1347.
Three-Component Condensation of Methoxyarenes with
Isobutyraldehyde and α-Substituted Benzyl Cyanides
Yu. V. Shklyaev, M. A. El’tsov, and O. A. Maiorova
Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences,
ul. Akad. Koroleva 3, Perm, 614013 Russia
e-mail: yushka@newmail.ru
Received January 15, 2008
Abstract—Three-component condensation of anisole with isobutyraldehyde and substituted benzyl cyanides
gives 1-benzyl-3,3-dimethyl-2-azaspiro[4.5]deca-6,9-dien-8-ones which undergo dienone–phenol rearrange-
ment during the reaction. Analogous condensation of 1-methoxynaphthalene leads to the formation of
2′-benzyl-5′,5′-dimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-ones.
DOI: 10.1134/S1070428008090133
We previously showed that anisole reacts with
isobutyraldehyde or 1,2-epoxy-2-methylpropane and
methyl or benzyl thiocyanate to give spiro-fused di-
hydropyrrole derivatives [1–3] and that analogous
reactions with acetonitrile and ethyl cyanoacetate are
accompanied by dienone–phenol rearrangement of the
primary spiro-fused pyrroles [4, 5]. It is also known
that steric load at the cyano group does not affect the
formation of 1-benzyl-3,4-dihydroisoquinolines [6].
It was interesting to study the behavior in analogous
reaction of benzyl cyanide and its α-substituted
derivatives.
action involves intermediate formation of (1Z)-1-ben-
zylidene-3,3-dimethyl-2-azaspiro[4.5]deca-6,9-dien-
8-one (II) which then undergoes dienone–phenol rear-
rangement.
As we showed previously [7], if the α-position in
the nitrile component is occupied by an alkyl group
larger than ethyl, the resulting 3,4-dihydroisoquinoline
derivatives exist exclusively in the imino form; there-
fore, their protonation and subsequent dienone–phenol
rearrangement should occur in statu nascendi, as was
reported in [4]. With a view to elucidate the possibility
for isolating spiro-fused products from α-substituted
benzyl cyanides, we examined the reaction of anisole
with butyraldehyde and 2-phenylhexanenitrile (IV).
We succeeded in isolating 3,3-dimethyl-1-(1-phenyl-
pentylidene)-2-azaspiro[4.5]deca-6,9-dien-8-one (V)
as an inseparable mixture of isomers at the exocyclic
Three-component reaction of anisole with benzyl
cyanide (I) and isobutyraldehyde led to the formation
of N-[1-(4-hydroxyphenyl)-2-methylpropan-2-yl]phen-
ylacetamide (III) in a satisfactory yield (Scheme 1). In
keeping with the results of our previous studies, the re-
Scheme 1.
Me
Me
OMe
CHO
O
H2SO4
NH
+
+
Ph
CN
Me
Me
Ph
I
II
H
N
Me
Me
O
HO
III
1327

SHKLYAEV et al.
1328
Scheme 2.
Me
Me
Me
Me
OMe
O
O
CHO
Me
Bu
NH
NH
+
+
+
Me
Ph
CN
Bu
Ph
Ph
Bu
IV
V
Me
Bu
Me
H
N
O
N
V
Me
Me
O
Ph
HO
Bu
VI
VIa
double bond at a ratio of 3 : 2 (according to the
1H NMR data; Scheme 2). In the IR spectrum of V we
observed an absorption band at 3350 cm–1, which cor-
responds to stretching vibrations of the NH bond, and
δ 6.23 and 6.26 ppm with a coupling constant J of
10 Hz. A complex multiplet in the region δ 7.18–
7.29 ppm was assigned to the aromatic protons. Quan-
tum-chemical calculation (AM1, Hyperchem 6.0) of
the enthalpies of formation of the two possible isomers
gave a difference of 4.3 kcal/mol (187.3387 and
182.9905 kcal/mol), which is consistent with the ex-
perimentally observed isomer ratio. Treatment of iso-
mer mixture V with sulfuric acid in acetic acid resulted
in tautomeric transformation to dihydropyrrole VIa in-
stead of the expected dienone–phenol rearrangement
into amide VI (Scheme 2).
Compound VIa displayed in the 1H NMR spectrum
signals from two methyl groups at δ 0.97 and
1.17 ppm, while neither triplet signal from the α-meth-
ylene group in the butyl radical (δ 3.07 ppm in the
spectrum of V) nor NH proton signal (δ ~5 ppm) were
1
carbonyl absorption at 1650 cm–1. The H NMR spec-
trum of V contained four signals from methyl groups
at δ 1.11, 1.18, 1.20, and 1.24 ppm (intensity ratio
2:3:2:3), the methylene protons on C4 gave rise to
2
a typical AB system (δ 2.69, 2.90 ppm; J = 12 Hz),
methyl protons in the butyl group resonated as a triplet
at δ 0.79 ppm, the α-methylene group in the butyl
radical gave a signal at δ 3.07 ppm, and signals from
the other methylene protons were complex multiplets
at δ 1.67 and 2.07 ppm. Protons of the NH group reso-
nated at δ 4.86 and 4.96 ppm (intensity ratio 2:3), and
protons in the cyclohexadiene fragment also appeared
as a double set of almost indistinguishable signals at
Scheme 3.
Me
Me
Ph
H
N
OMe
O
CHO
Me
N
+
+
Me
Me
O
Me
Ph
CN
HO
Ph
VII
VIII
IX
Scheme 4.
Me
Me
7
6
O
OMe
CHO
Me
Ac
N
+
+
H
9
10
·
·
Me
Ph
CN
·
Ph
O
Me
XI
X
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

THREE-COMPONENT CONDENSATION OF METHOXYARENES
1329
Scheme 5.
Me
Me
Me
Me
NH
N
OMe
Ph
COMe
Me2CHCHO, X
Me2CHCHO, I
Ph
O
O
XII
XIII
Scheme 6.
Me
Me
Me
Me
N
N
OMe
Bu
Ph
Me2CHCHO, IV
Me2CHCHO, VII
Ph
O
O
XIV
XV
present. The benzylic proton resonated as a triplet at
δ 3.37 ppm, and signals from the 4-H protons consti-
tuted a typical AB system (δ 2.56, 2.89 ppm; J =
12 Hz). The α-methylene protons in the butyl group
gave two complex multiplets at δ 1.52 and 1.90 ppm
each having an intensity corresponding to one proton;
this may be due to anisotropic effect of the lone elec-
tron pair on the nitrogen atom. Protons in the cyclo-
hexadiene fragment appeared as doublets of doublets
at δ 6.38 and 6.57 ppm (J = 10 Hz), and aromatic
proton signals were observed in the region δ 7.18–
7.26 ppm.
ized in terms of considerable reduction of basicity of
the nitrogen atom due to formation of intramolecular
hydrogen bond; as a result, its protonation is hampered
(Scheme 4).
According to our previous data [11], spirocyclic
systems obtained by three-component condensation
with methoxynaphthalenes are considerably more
stable toward dienone–phenol rearrangement. In fact,
1-methoxynaphthalene reacted with isobutyraldehyde
and nitrile X to give (2′Z)-5′,5′-dimethyl-2′-(2-oxo-1-
phenylpropylidene)-4H-spiro[naphthalene-1,3′-
pyrrolidin]-4-one (XII) (Scheme 5). The reaction of
1-methoxynaphthalene with isobutyraldehyde and ben-
zyl cyanide produced 2′-benzyl-5′,5′-dimethyl-4′,5′-di-
hydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one (XIII),
and the corresponding spiro-fused compounds XIV
and XV were formed from substituted benzyl cyanides
IV and VII (Scheme 6).
The reaction of anisole with isobutyraldehyde and
1-phenylcylopentanecarbonitrile (VII) [8] gave a prod-
1
uct whose H NMR spectrum lacked signal from
methoxy group, while signals in the aromatic region
corresponded to a para-substituted benzene ring rather
than to cyclohexadienone fragment. The IR spectrum
of this compound contained absorption bands assign-
able to a phenolic hydroxy group (3220 cm–1) and
amide carbonyl (1640 cm–1). These data led us to iden-
tify the product as N-[1-(4-hydroxyphenyl)-2-methyl-
prop-2-yl)-1-phenylcyclopentane-1-carboxamide (IX)
formed via dienone–phenol rearrangement of interme-
diate 1-(1-phenylcyclopentyl)-3,3-dimethyl-2-azaspiro-
[4.5]deca-1,6,9-trien-8-one (VIII) (Scheme 3).
Our results showed that the presence of an electron-
withdrawing group in the α-position of benzyl cyanide
is favorable for the formation of spiro-fused systems;
such systems are also formed on the basis of 1-meth-
oxynaphthalene; however, in all the examined reac-
tions, the size of the nitrile component is not signif-
icant for the ipso attack to occur.
As shown in [9], 3-oxo-2-phenylbutanenitrile (X)
can also be used as nitrile component in the Ritter
reaction. By reaction of anisole with isobutyraldehyde
and nitrile X [10] we obtained spriocyclic compound
XI. The relative stability of the latter may be rational-
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Varian Mercury
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

SHKLYAEV et al.
1330
Plus 300 instrument at (300 MHz) using DMSO-d6 as
solvent and tetramethylsilane as internal reference. The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates using
chloroform–acetone (9:1) as eluent; spots were visual-
ized by treatment with a 0.5% solution of chloranil in
toluene. The mass spectra (electron impact, 70 eV)
were obtained on an Agilent GC 6890N–MSD 5975B
system. The elemental compositions were determined
on a LECO CHNS-932 analyzer.
thesized as described above for compound III from
10.8 g (0.1 mol) of anisole, 7.2 g (0.1 mol) of isobutyr-
aldehyde, and 17.1 g (0.1 mol) of 1-phenylcyclopen-
tanecarbonitrile. Yield 63%, mp 118–119°C. IR spec-
trum, ν, cm–1: 1520, 1540, 1600, 1640, 3220, 3400.
1H NMR spectrum, δ, ppm: 1.13 s (6H, Me); 1.55 m,
1.73 m, 1.93 m, and 1.91 m [2H each, (CH2)4], 2.71 s
(2H, CH2), 4.95 s (1H, NH), 6.65–6.71 m (4H, C6H4),
6.80 s (1H, OH), 7.12–7.24 m (5H, Ph). Found, %:
C 78.43; H 8.18; N 4.10. C22H27NO2. Calculated, %:
C 78.30; H 8.06; N 4.15.
N-[1-(4-Hydroxyphenyl)-2-methylpropan-2-yl]-
phenylacetamide (III). A mixture of 10.8 g (0.1 mol)
of anisole, 7.2 g (0.1 mol) of isobutyraldehyde, and
11.7 g (0.1 mol) of benzyl cyanide was added dropwise
under stirring over a period of 15–20 min to 50 ml of
96% sulfuric acid cooled to 0–5°C. The mixture was
stirred for 30 min, poured into 300 ml of water, and
extracted with 100 ml of toluene, the extract was
washed with aqueous ammonium carbonate and dried
over sodium sulfate, the solvent was removed on
a rotary evaporator, and the residue was recrystallized
from alcohol. Yield 25%, mp 195–197°C. IR spectrum,
ν, cm–1: 1550, 1640, 3360. 1H NMR spectrum, δ, ppm:
1.11 s (6H, Me), 2.75 s (2H, CH2), 6.52 d (2H, 6-H,
10-H, J = 10 Hz), 6.68 d (2H, 7-H, 9-H, J = 10 Hz),
7.15–7.29 m (5H, Ph), 7.34 s (1H, OH), 9.07 s (1H,
NH). Found, %: C 76.43; H 7.38; N 4.81. C18H21NO2.
Calculated, %: C 76.30; H 7.47; N 4.94.
(1Z)-3,3-Dimethyl-1-(2-oxo-1-phenylpropyli-
dene)-2-azaspiro[4.5]deca-6,9-dien-8-one (XI).
A mixture of 10.8 g (0.1 mol) of anisole, 7.3 g
(0.1 mol) of isobutyraldehyde, and 15.9 g (0.1 mol) of
3-oxo-2-phenylbutanenitrile in 30 ml of methylene
chloride was added dropwise under stirring over
a period of 15–20 min to 50 ml of 96% sulfuric acid
cooled to 0–5°C. The mixture was stirred for 30 min,
poured into 300 ml of water, and neutralized to pH 8–9
with aqueous ammonium carbonate. The precipitate
was filtered off, washed with water, dried, and recrys-
tallized from propan-2-ol. Yield 32%, mp 168–170°C.
IR spectrum, ν, cm–1: 1550, 1600, 1660, 3300. 1H NMR
spectrum, δ, ppm: 1.43 s (6H, Me), 1.76 s (3H,
MeCO), 1.97 s (2H, CH2), 5.72 d (2H, 6-H, 10-H, J =
10 Hz), 6.68 d (2H, 7-H, 9-H, J = 10 Hz), 6.93–7.12 m
(5H, Harom), 10.87 s (1H, NH). Found, %: C 78.10;
H 6.98; N 4.67. C20H21NO2. Calculated, %: C 78.15;
H 6.89; N 4.56.
3,3-Dimethyl-1-[(1E)-1-phenylpentylidene]-2-
azaspiro[4.5]deca-6,9-dien-8-one (V) was syn-
thesized in a similar way from 17.3 g (0.1 mol) of
2-phenylhexanenitrile, 7.3 g (0.1 mol) of isobutyralde-
hyde, and 10.8 g (0.1 mol) of anisole. Yield 57%,
mp 186–188°C (from ethyl acetate). The spectral pa-
rameters of compound V are given in text. Found, %:
C 82.34; H 8.49; N 4.41. C22H27NO. Calculated, %:
C 82.20; H 8.47; N 4.36.
(2Z)-5,5-Dimethyl-2′-(2-oxo-1-phenylpropyli-
dene)-4H-spiro[naphthalene-1,3′-pyrrolidin]-4-one
(XII) was synthesized in a similar way from 1.58 g
(0.01 mol) of 1-methoxynaphthalene, 0.73 g (0.01 mol)
of isobutyraldehyde, and 1.59 g (0.01 mol) of 3-oxo-2-
phenylbutanenitrile using 30 ml of methylene chloride.
Yield 30%, mp 220–222°C. IR spectrum, ν, cm–1:
3,3-Dimethyl-1-(1-phenylpentyl)-2-azaspiro[4.5]-
deca-1,6,9-trien-8-one (VIa). Compound V, 0.5 g
(1.6 mmol), was dissolved in 15 ml of acetic acid, one
drop of concentrated sulfuric acid was added, and the
mixture was heated to the boiling point and was kept
boiling for 3 min. It was then poured into 100 ml of
water and adjusted to pH 8 with aqueous ammonia,
and the precipitate was filtered off, dried, and recrys-
tallized from ethyl acetate. mp 179–181°C. The spec-
tral parameters of compound VIa are given in text.
Found, %: C 82.23; H 8.40; N 4.51. C22H27NO. Cal-
culated, %: C 82.20; H 8.47; N 4.36.
1
1550, 1600, 1660, 3300. H NMR spectrum, δ, ppm:
1.49 s (3H, Me), 1.53 s (3H, Me), 1.62 s (3H, MeCO),
2.25 d.d (2H, CH2, J = 12 Hz), 5.83 d (1H, 2-H, J =
10 Hz), 5.96 d (1H, 3-H, J = 10 Hz), 6.46–7.89 m
(5H, Ph), 7.20–7.76 m (4H, Harom), 11.33 s (1H, NH).
Found, %: C 80.76; H 6.40; N 4.07. C24H23NO2. Cal-
culated, %: C 80.64; H 6.49; N 3.92.
2′-Benzyl-5′,5′-dimethyl-4′,5′-dihydro-4H-spiro-
[naphthalene-1,3′-pyrrol]-4-one (XIII) was syn-
thesized in a similar way from 1.17 g (0.01 mol) of
benzyl cyanide. Yield 27%, mp 141–142°C (from hex-
ane). IR spectrum, ν, cm–1: 1590, 1650. 1H NMR spec-
trum, δ, ppm: 1.78 s (3H, Me), 1.87 s (3H, Me), 2.53 s
N-[1-(4-Hydroxyphenyl)-2-methylprop-2-yl]-1-
phenylcyclopentane-1-carboxamide (IX) was syn-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

THREE-COMPONENT CONDENSATION OF METHOXYARENES
1331
(2H, PhCH2), 3.61 d and 4.24 d (1H each, 4′-H, J =
12 Hz), 6.17 d (1H, 2-H, J = 10 Hz), 6.39 d (1H, 3-H,
J = 10 Hz), 6.85–7.12 m (6H, Harom), 7.51 m (2H,
Russian Federation (project no. MK 3014.2007.3), by
the Presidium of the Russian Academy of Sciences
(program “New Principles and Methods of Target-
Oriented Synthesis of Substances with Specified
Properties”), and by the Russian Foundation for Basic
Research (project no. 07-03-00001).
Harom), 8.17 m (1H, Harom). Found, %: C 83.82; H 6.83;
N 4.55. C22H21NO. Calculated, %: C 83.78; H 6.71;
N 4.44.
5′,5′-Dimethyl-2′-(1-phenylpentyl)-4′,5′-dihydro-
4H-spiro[naphthalene-1,3′-pyrrol]-4-one (XIV) was
synthesized in a similar way from 1.73 g (0.01 mol) of
2-phenylhexanenitrile. The product was identified as
the corresponding hydrobromide (the free base was
dissolved in diethyl ether, and dry gaseous hydrogen
bromide was passed through the solution until it
became perfectly transparent). Yield 60%, mp 101–
103°C (from ethyl acetate). IR spectrum, ν, cm–1:
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1.80 s (3H, Me), 2.02 s (3H, Me), 2.17–2.38 m (2H,
PhCHCH2), 2.53 d.d (2H, 4′-H, J = 12 Hz), 3.11 t (1H,
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J = 10 Hz), 6.99–8.29 m (9H, Harom). Found, %:
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C 84.06; H 7.87; N 3.77.
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(XV) was synthesized in a similar way from 17.1 g
(0.1 mol) of 1-phenylcyclopentane-1-carbonitrile.
Yield 57%, mp 137–139°C (from ethyl acetate). IR
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1
spectrum, ν, cm–1: 1590, 1620, 1650. H NMR spec-
trum, δ, ppm: 1.18–2.31 m (8H, CH2), 1.39 s (3H, Me),
1.48 s (3H, Me), 2.13–2.20 d.d (2H, 4′-H, J = 12 Hz),
5.80 d (1H, 2-H, J = 10 Hz), 6.27 d (1H, 3-H, J =
10 Hz), 6.89–7.29 m (8H, Harom), 8.03–8.06 m (1H,
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Harom). Found, %: C 84.13; H 8.01; N 3.75. C27H31NO.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008