Ritter reaction. Synthesis of 1-substituted 3,3,7,9-tetramethyl-2- azaspiro[4.5]deca-6,9-dien- and -1,6,9-trien-8-ones and 7-methoxy-3,3,6,8- tetramethyl-3,4-dihydroisoquinolines

Article abstract of DOI:10.1134/S1070428013070166

1-(4-Methoxy-3,5-dimethylphenyl)-2-methylpropan-1-ol reacted with nitriles [MeSCN, PhCN, MeCN, EtOC(O)CH₂CN] in the presence of concentrated sulfuric acid to give both 1-R-3,3,7,9-tetramethyl-2-azaspiro[4,5]deca-6,9-dien- and -1,6,9-trien-8-one

Full text of DOI:10.1134/S1070428013070166

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 1055–1061. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © Yu.S. Rozhkova, K.A. Galata, T.S. Vshivkova, Yu.V. Shklyaev, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49,
No. 7, pp. 1070–1076.
Ritter Reaction. Synthesis of 1-Substituted
3,3,7,9-Tetramethyl-2-azaspiro[4.5]deca-6,9-dien-
and -1,6,9-trien-8-ones and 7-Methoxy-3,3,6,8-tetramethyl-
3,4-dihydroisoquinolines
Yu. S. Rozhkova, K. A. Galata, T. S. Vshivkova, and Yu. V. Shklyaev
Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences,
ul. Akad. Koroleva 3, Perm, 614013 Russia
e-mail: rjs@mail.ru
Received December 14, 2012
Abstract—1-(4-Methoxy-3,5-dimethylphenyl)-2-methylpropan-1-ol reacted with nitriles [MeSCN, PhCN,
MeCN, EtOC(O)CH2CN] in the presence of concentrated sulfuric acid to give both 1-R-3,3,7,9-tetramethyl-2-
azaspiro[4,5]deca-6,9-dien- and -1,6,9-trien-8-ones and 1-R-7-methoxy-3,3,6,8-tetramethyl-3,4-dihydroiso-
quinolines. The reaction with 3,4-dimethoxyphenylacetonitrile afforded 10,11-dimethoxy-1,3,6,6-tetramethyl-
1,5,6,12b-tetrahydrodibenzo[d,f]indole-2,8-dione. Three-component condensation of 2-methoxy-1,3-dimethyl-
benzene with isobutyraldehyde and nitriles led to the formation of spirocyclic systems and 3,4-dihydroiso-
quinoline derivatives in lower yield.
DOI: 10.1134/S1070428013070166
The Ritter reaction is widely used in the synthesis
of various nitrogen-containing heterocycles [1–6]. We
previously proposed [7–10] a convenient procedure for
the synthesis of 3,4-dihydroisoquinoline derivatives by
the Ritter reaction of 1-aryl-2-methylpropan-1- and
-2-oles with nitriles. However, alcohols containing
an alkoxy group in the para-position of the aromatic
fragment, e.g., 1-(4-methoxyphenyl)-2-methylpropan-
1-ol [11] and (4-methoxyphenyl)cyclohexylmethanol
[12], gave rise to 1-substituted 3,3-dimethyl-2-aza-
spiro[4,5]deca-6,9-dien- and -1,6,9-trien-8-ones in-
stead of 1-R-3,4-dihydroisoquinolines.
Scheme 1.
Me
Me
Me
Me
Me
Me
O
NH
+
NH
MeO
OH
Me
IVa
COOEt
COOEt
RCN (IIa–IId)
H2SO4
Me
Me
Me
IIIa
Me
MeO
Me
Me
Me
Me
N
Me
Me
I
Me
O
N
R
+
MeO
Me
R
Me
IIIb–IIId
IVb, IVc
R = EtOC(O)CH2 (a), MeS (b), Me (c), Ph (d).
1055

ROZHKOVA et al.
1056
In continuation of our systematic studies on hetero-
δ 6.81 ppm from the aromatic proton (5-H). The
enamine structure of IVa was confirmed by the pres-
ence of a vinylic proton singlet at δ 4.82 ppm and
a broadened singlet from the NH proton at δ 9.06 ppm.
cyclizations of 1-aryl-2-methylpropan-1-ols in the
Ritter reaction, depending on the nature and position of
substituents in the aromatic ring of the initial alcohol,
in the present work we examined the reaction of
1-(4-methoxy-3,5-dimethylphenyl)-2-methylpropan-1-
ol (I) with nitriles II under catalysis by concentrated
sulfuric acid.
A probable reaction mechanism includes protona-
tion of alcohol I, elimination of water molecule to
generate secondary carbocation A which occurs in
equilibrium with tertiary carbocation B, and addition
of nitrile to the latter (Scheme 2). Spirocyclic system
III is formed via ipso-cyclization of iminocarbenium
ion C (path a) due to para-orientating effect of the
methoxy group. 3,4-Dihydroisoquinoline derivatives
are likely to be formed as a result of ortho-cyclization
of ion C, which is favored by the consistent effects of
the two methyl groups (path b).
The reaction of I with 3,4-dimethoxyphenylaceto-
nitrile (IIe) produced neospirodienone V which was
isolated in 18% yield by column chromatography
(Scheme 3). We also detected by GC/MS the corre-
sponding 3,4-dihydroisoquinoline derivative, but we
failed to isolate it as individual substance because of
strong tarring during the isolation procedure.
Alcohol I reacted with nitriles IIa–IIc to produce
both 2-azaspiro[4.5]decane derivatives IIIa–IIIc and
previously unknown 1-R-3,3-dimethyl-3,4-dihydroiso-
quinolines IVa–IVc (Scheme 1, Table 1). In the reac-
tion with benzonitrile (IId) the major product was
spirocyclic pyrrole IIId, whereas only traces of the
corresponding isoquinoline derivative were detected
by GC/MS analysis of the reaction mixture. Com-
pounds IIIa–IIId were identical to those reported pre-
viously [13]. The structure of IVa–IVc was determined
1
on the basis of their H and 13C NMR, IR, and mass
1
spectra and elemental analyses. The H NMR spectra
of IVa–IVc contained singlets at δ 1.14–1.19 ppm
from the geminal methyl groups on C3, at δ 2.27–
2.48 ppm from the methyl groups on C6 and C8, at
δ 2.49–2.65 ppm from the C4H2 methylene group, at
δ 3.69–3.71 ppm from the methoxy group, and at
Presumably, the formation of V involves intramo-
lecular cyclization of intermediate spiro-σ-complex D to
enol ether E whose hydrolysis yields neospiroenone F.
Scheme 2.
Me
Me
a
b
Me
Me
Me
Me
Me
IIIa–IIId
IVa–IVc
H+
a
I
Me
Me
RCN
N
–H2O
MeO
MeO
MeO
b
Me
Me
Me
R
A
B
C
Scheme 3.
MeO
OMe
Me
CN
Me
Me
Me
MeO
MeO
I
+
MeO
Me
Me
OMe
Me
Me
N
N
MeO
OMe
IIe
D
E
O
O
Me
Me
3
2
Me
Me
1
12
11
H2O
–MeOH, –H+
O2
4
MeO
MeO
4a
12a
Me
Me
12b
MeO
MeO
5
Me
Me
6
8a 7a
8
7
N
10
9
N
O
F
V
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

RITTER REACTION. SYNTHESIS OF 1-SUBSTITUTED 3,3,7,9-TETRAMETHYL-...
1057
The latter is unstable (as free base), and it readily
undergoes oxidation at C8 [14] with atmospheric
C21
oxygen to form dienone V (Scheme 3). The structure
O3
1
13
of V was confirmed by H and C NMR and IR spec-
O2
troscopy, mass spectrometry, and elemental analysis.
1
C22
C6
The H NMR spectrum of V in CDCl3 contained
signals from aromatic protons (9-H and 12-H) as two
singlets at δ 7.63 and 6.85 ppm; protons on C5 reso-
nated as two doublets at δ 2.41 and 2.46 ppm (AB spin
system, 2J = 13.5 Hz), and the 4-H signal was a broad-
ened one-proton singlet at δ 1.45 ppm. The 1-H and
12b-H signals overlapped each other to give a multi-
plet at δ 3.46 ppm. In addition, two singlets from the
geminal methyl groups on C6 (δ 1.45, 1.47 ppm), a sin-
glet from 1-CH3 (δ 1.51 ppm), and a doublet from
C5
C7
C8
O4
C4
C11
C10
C9
C3
C20
C19
C2
C14
C15
C12
O1
C1
C13
4
C3H2 were present (δ 1.64 ppm, J = 1.2 Hz). The
N1
structure of V was unambiguously proved by X-ray
analysis (see figure).
C16
C18
C17
Apart from the reaction of 1-aryl-2-methylpropan-
1-ols with nitriles, 1-substituted 3,3-dialkyl-3,4-dihy-
droisoquinoline and 3,3-dimethyl-2-azaspiro[4.5]-
deca-6,9-dien- and -1,6,9-trien-8-one derivatives can
also be obtained by three-component condensation of
an activated arene with isobutyraldehyde and nitriles
[10, 15–20]. Unlike the classical Ritter reaction where
carbocation is generated by protonation of alcohol, the
corresponding carbocationic species in the three-com-
ponent condensation is formed in situ by reaction of
activated arene with protonated isobutyraldehyde.
As an alternative to the reaction of 1-(4-methoxy-
3,5-dimethylphenyl)-2-methylpropan-1-ol (I) with
nitriles II we examined the reaction of 2-methoxy-1,3-
dimethylbenzene with isobutyraldehyde and nitriles II
under catalysis by concentrated sulfuric acid. Like the
reaction with alcohol I, the three-component condensa-
tion with nitriles IIa and IIb afforded mixtures of
2-azaspiro[4.5]decane derivative IIIa and IIIb with
1-R-3,4-dihydroisoquinolines IVa and IVb, respec-
tively, but in lower yields. The reaction of 2-methoxy-
1,3-dimethylbenzene with isobutyraldehyde and ben-
zonitrile (IId) gave only traces of isoquinoline deriv-
atives (cf. the results of the reaction of alcohol I with
nitrile IId), whereas the major product was spiro com-
pound IIId (Scheme 4, Table 1).
Structure of the molecule of 10,11-dimethoxy-1,3,6,6-tetra-
methyl-1,5,6,12b-tetrahydrodibenzo[d,f]indole-2,8-dione (V)
according to the X-ray diffraction data.
Among the examined nitriles, acetonitrile (IIc)
turned out to be the least reactive in the three-com-
ponent condensation. In this case, we succeeded in
isolating from the reaction mixture only 3% of IIIc,
and traces of IVc were detected (Scheme 5). The major
product was diaryl(isopropyl)methane VI (yield 19%).
The three-component condensation of 3,4-dimethoxy-
phenylacetonitrile (IIe) afforded 7% of V and 8% of
Table 1. Yields of compounds IIIa–IIId and IVa–IVd in
the reactions of alcohol I with nitriles IIa–IId (A) and in
the three-component condensation of 2-methoxy-1,3-di-
methylbenzene with isobutyraldehyde and IIa–IId (B)
Yield, % (III/IV)
Nitrile no.
A
B
IIa
IIb
IIc
IId
46/15
20/11
47/21
15/17
03/tracesa
19/tracesb
Scheme 4.
40/13
42/tracesb
Me
Me
a
O
According to the GC/MS data, the concentration of IVc in the
reaction mixture was 2%. The major product was diaryl(iso-
propyl)methane VI (Scheme 5).
+
+ IIa, IIb, IId
Me
MeO
H
Me
b
According to the GC/MS data, the concentration of IVd in the
H2SO4
IIIa, IIIb, IIId
+
IVa, IVb
reaction mixture was 2%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

ROZHKOVA et al.
1058
Scheme 5.
Me
Me
Me
Me
Me
Me
H2SO4
O
+
+
IIc
+
IIIc
Me
MeO
MeO
OMe
H
Me
Me
Me
VI
Scheme 6.
MeO
O
Me
Me
H2SO4
O
NH
+
+
IIe
V +
Me
MeO
MeO
H
Me
Me
VII
Me
isoquinolinone VII (Scheme 6). Presumably, the latter
is formed via reaction of isobutyraldehyde with 3,4-di-
methoxyphenylacetonitrile (IIe), which was confirmed
by independent synthesis where compound VII was
obtained in 58% yield. Examples of the synthesis of
analogous systems via reaction of unsubstituted
phenylacetonitrile with some aliphatic and aromatic
aldehydes in the presence of polyphosphoric acid were
reported in [21].
Table 2. Crystallographic data and parameters of the X-ray
diffraction experiment for compound V
EXPERIMENTAL
Parameter
Value
1
The H and 13C (DEPT) NMR spectra were
Formula
C22H25NO4
367.43
recorded on a Varian Mercury Plus spectrometer at
300.06 and 75.46 MHz using hexamethyldisiloxane as
internal reference. The mass spectra were obtained on
an Agilent Technologies 6890N/5975B GC/MS system
(HP-5ms capillary 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 mass spectrometer (electron impact,
70 eV). The elemental compositions were determined
on a Leco Corporation CHNS-932 analyzer. The IR
spectra were measured from thin films on a Bruker
IFS-66 instrument with Fourier transform. The prog-
ress of reactions and the purity of products were
monitored by TLC on Sorbfil plates (UF-254); spots
were detected by treatment with a 0.5% solution of
p-chloranil in toluene. Silica gel (0.06–0.20 mm, 70–
230 mesh, Lancaster) was used for column chromatog-
raphy. The melting points were determined using
a PTP melting point apparatus. The physical constants
of compounds IIIa–IIId coincided with those reported
previously [13].
Molecular weight
Crystal system
Monoclinic
P21/c
Space group
Unit cell parameters
a, Å
b, Å
c, Å
β, deg
V , Å3
Z
0008.4773(12)
13.129(3)
17.565(3)
094.649(12)
1948.6(6)
4
d
calc, g/cm3
1.252
μ, mm–1
0.086
Scan range, deg
Total number of reflections
Number of independent reflections
Number of variables N
Rint
2.80–26.37
7635
3981
0244
0.0326
R1, %
4.1000
X-Ray analysis of compound V. Single crystals of
V suitable for X-ray analysis were obtained by crystal-
lization from ethyl acetate. The X-ray diffraction data
were acquired at 295(2) K on an Xcalibur-3 diffrac-
tometer equipped with a CCD detector (MoKα irradia-
R1 [I > 2(I)]
0.0410
wR2 [I > 2(I)]
0.0827
R1 (all reflections)
wR2 (all reflections)
0.1106
0.0870
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

RITTER REACTION. SYNTHESIS OF 1-SUBSTITUTED 3,3,7,9-TETRAMETHYL-...
1059
tion, graphite monochromator, ω-scanning). The struc-
ture was solved by the direct method using SHELXS-
97 and was refined using SHELXL-97 in anisotropic
approximation (isotropic for hydrogen atoms). The
crystallographic data and parameters of X-ray diffrac-
tion experiment are given in Table 2.
59.42 (OMe), 79.61 (CH), 126.82 (C2′, C6′), 130.08 and
139.02 (C1′, C3′, C5′), 155.76 (C4′). Mass spectrum, m/z
(Irel, %): 208 (6.7) [M]+, 190 (8.9) [M – H2O]+, 175
(8.0), 165 (100) [M – C3H7]+, 149 (2.5), 137 (48.6),
122 (21.1), 105 (8.3), 91 (10.5), 77 (7.5), 65 (2.3), 43
(2.8). Found, %: C 74.81; H 9.76. C13H20O2. Calculat-
ed, %: C 74.96; H 9.68. M 208.30.
1-(4-Methoxy-3,5-dimethylphenyl)-2-methylpro-
pan-1-one was synthesized from 20.4 g (150 mmol)
of 2-methoxy-1,3-dimethylbenzene and 16.8 g
(158 mmol) of isobutyryl chloride in the presence of
23.9 g (180 mmol) of AlCl3 as catalyst according to the
procedure described in [22]. Appropriate treatment of
the reaction mixture gave an oily product which con-
tained more than 95% of 1-(4-methoxy-3,5-dimethyl-
phenyl)-2-methylpropan-1-one (GC/MS). The product
was used without additional purification. Yield 28.1 g
(91%). IR spectrum, ν, cm–1: 2970, 2932, 2872, 1678,
Reaction of 1-(4-methoxy-3,5-dimethylphenyl)-2-
methylpropan-1-ol (I) with nitriles IIa–IId (general
procedure). A mixture of 5 mmol of compound I and
5 mmol of nitrile IIa–IId in 1 ml of methylene
chloride was added dropwise to 6 ml of 92% H2SO4
under vigorous stirring and cooling with ice water. The
mixture was then stirred for 20 min at room tempera-
ture, poured into a mixture of ice with 25 ml of
aqueous ammonia, and extracted with methylene chlo-
ride (3×25 ml). The combined extracts were dried over
MgSO4, the solvent was distilled off, and the residue
was subjected to chromatography or recrystallization.
1
1595, 1466. H NMR spectrum (CDCl3), δ, ppm:
3
1.08 d [6H, CH(CH3)2, J = 7.2 Hz], 2.21 s (6H,
3′-CH3, 5′-CH3), 3.42 m (1H, CH), 3.63 s (3H, OCH3),
7.55 s (2H, 2′-H, 6′-H). 13C NMR spectrum (CDCl3),
δC, ppm: 15.72 (3′-CH3, 5′-CH3), 18.81 [CH(CH3)2],
34.53 (CH), 59.00 (OMe), 128.87 (C2′, C6′), 130.57 and
131.42 (C1′, C3′, C5′), 160.59 (C4′), 203.03 (C=O). Mass
spectrum, m/z (Irel, %): 206 (7.3) [M]+, 163 (100) [M –
C3H7]+, 120 (2.2), 105 (10.4), 91 (8.8), 79 (3.4), 65
(1.8), 41 (1.3). Found, %: C 75.97; H 8.95. C13H18O2.
Calculated, %: C 75.69; H 8.80. M 206.28.
Ethyl 2-(7-methoxy-3,3,6,8-tetramethyl-3,4-dihy-
droisoquinolin-1-ylidene)acetate (IVa) was obtained
from compounds I and IIa. After removal of the
solvent from the extract, the residue was crystallized
from ethanol, the precipitate (0.40 g of IIIa) was
filtered off, the mother liquor was evaporated, and the
residue was subjected to chromatography using
hexane–acetone (15:1) as eluent. Two fractions were
collected. The first fraction contained 0.22 g (15%) of
isoquinoline IVa, and the second fraction, 0.26 g of
IIIa. Overall yield of IIIa 0.66 g (46%).
1-(3,5-Dimethyl-4-methoxyphenyl)-2-methylpro-
pan-1-ol (I). A solution of 26.9 g (130 mmol) of
1-(4-methoxy-3,5-dimethylphenyl)-2-methylpropan-1-
one in 20 ml of ethanol was added under stirring and
cooling with ice water to a suspension of 5 g
(130 mmol) of sodium tetrahydridoborate in 70 ml of
ethanol. The mixture was stirred for 2 h at room tem-
perature, the solvent was distilled off under reduced
pressure, the dry residue was treated with 80 ml of
water, and the mixture was extracted with diethyl ether
(3×20 ml). The extracts were combined, washed with
water, and dried over MgSO4, the solvent was distilled
off, and the residue was distilled under reduced pres-
sure. Yield 19.2 g (71%), colorless liquid, bp 115–
120°C (2 mm), which crystallized on prolonged stor-
age, mp 44–45°C (from hexane). IR spectrum, ν, cm–1:
Compound IVa. mp 91–92°C (from hexane). IR
spectrum, ν, cm–1: 3270, 3183, 2971, 2897, 1647,
1599, 1562, 1476. 1H NMR spectrum (CDCl3), δ, ppm:
1.19 s (6H, 3-CH3), 1.28 t (3H, CH2CH3, 3J = 7.1 Hz),
2.28 s (3H, CH3), 2.48 s (3H, CH3), 2.65 s (2H, CH2),
3
3.71 s (3H, OCH3), 4.14 q (2H, OCH2, J = 7.1 Hz),
4.82 s (1H, =CH), 6.81 s (1H, 5-H), 9.06 s (1H, NH).
13C NMR spectrum (CDCl3), δC, ppm: 14.68 (CH2CH3),
15.49 and 16.18 (6-CH3, 8-CH3), 28.13 (3-CH3), 43.71
(C4), 49.03 (C3), 58.51 (OCH2), 59.68 (OCH3), 83.14
(=CH), 128.54 (C5); 129.10, 129.41, 132.12, 132.28
(C6, C8, C4a, C8a); 155.75 and 156.80 (C1, C7), 171.02
(C=O). Mass spectrum, m/z (Irel, %): 303 (45.3) [M]+,
288 (75.8) [M – CH3]+, 260 (11.4), 258 (21.7) [M –
OCH2CH3]+, 242 (100) [M – 2CH3 – OCH2CH3]+, 230
(18.5) [M – C(O)OCH2CH3]+, 216 (38.1), 198 (19.8),
184 (20.9), 174 (11.9), 158 (10.8), 144 (8.5), 128
(18.1), 115 (20.5), 103 (4.2), 91 (9.8), 77 (7.2), 65
(4.9). Found, %: C 71.09; H 8.21; N 4.63. C18H25NO3.
Calculated, %: C 71.26; H 8.31; N 4.62. M 303.40.
1
3426, 2955, 2873, 1480. H NMR spectrum (CDCl3),
3
δ, ppm: 0.75 d (3H, CH3, J = 6.8 Hz), 0.98 d (3H,
3
CH3, J = 6.8 Hz), 1.87 m (1H, CH), 2.10 br.s (1H,
OH), 2.24 s (6H, 3′-CH3, 5′-CH3), 3.67 s (3H, OCH3),
3
4.16 d (1H, CH, J = 6.9 Hz), 6.90 s (2H, 2′-H, 6′-H).
13C NMR spectrum (CDCl3), δC, ppm: 15.97 (3′-CH3,
5′-CH3), 18.40 and 19.02 [CH(CH3)2], 34.97 (CH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

ROZHKOVA et al.
1060
4
7-Methoxy-3,3,6,8-tetramethyl-1-methylsulfanyl-
(3H, 3-CH3, J = 1.2 Hz), 2.41 d and 2.46 d (1H each,
2
3,4-dihydroisoquinoline (IVb) was synthesized from
compounds I and IIb. The residue was separated using
hexane–acetone (30:1) as eluent. The first fraction
contained 0.28 g (21%) of IVb, and the second, 0.59 g
(47%) of IIIb. mp 72–73°C (from hexane). IR spec-
trum, ν, cm–1: 2967, 2928, 2880, 1583, 1550. 1H NMR
spectrum (CDCl3), δ, ppm: 1.14 s (6H, 3-CH3), 2.27 s
(3H, CH3), 2.40 s (3H, CH3), 2.49 s (2H, CH2), 2.59 s
(3H, SCH3), 3.69 s (3H, OCH3), 6.81 s (1H, 5-H).
13C NMR spectrum (CDCl3), δC, ppm: 14.03 (SCH3),
15.16 and 16.27 (8-CH3, 6-CH3), 27.61 (3-CH3), 40.73
(C4), 55.30 (C3), 59.89 (OCH3), 127.93 and 128.73
(C6, C8), 128.20 (C5), 132.66 and 132.69 (C4a, C8a),
159.32 (C7), 161.72 (C1). Mass spectrum, m/z (Irel, %):
263 (0.3) [M]+, 248 (100) [M – CH3]+, 232 (2.2) [M –
OCH3]+, 218 (4.3), 202 (3.1), 174 (8.9), 158 (1.2), 116
(1.9), 89 (1.3), 41 (1.3). Found, %: C 68.16; H 8.05;
N 5.34; S 12.19. C15H21NOS. Calculated, %: C 68.40;
H 8.04; N 5.32; S 12.17. M 263.40.
5-H, J = 13.5 Hz), 3.46 m (2H, 1-H, 12b-H), 3.92 s
(3H, OCH3), 3.95 s (3H, OCH3), 6.31 br.s (1H, 4-H),
6.85 s (1H, 12-H), 7.63 s (1H, 9-H). 13C NMR spec-
trum (CDCl3), δC, ppm: 15.71 (1-CH3), 18.33 (3-CH3),
29.08 and 31.23 (6-CH3), 45.34 and 50.82 (C1, C12b),
53.09 (C5), 55.96 and 56.02 (9-OCH3, 10-OCH3),
58.06 and 73.59 (C4a, C6), 109.12 and 109.32 (C9, 12);
127.29, 133.47, 138.14 (C3, C8a, C12a); 143.34 (C4),
148.39 and 154.78 (C10, C11), 167.45 (C7a), 181.69 and
199.16 (C8, C2). Mass spectrum, m/z (Irel, %): 367
(100) [M]+, 352 (24.7) [M – CH3]+, 324 (19.5) [M –
CH3 – CO]+, 310 (12.5), 296 (13.8), 284 (13.7), 270
(21.1), 258 (18.2), 243 (6.8), 215 (11.0), 165 (4.2), 141
(3.7), 115 (5.1), 91 (5.0), 65 (2.9), 41 (5.8). Found, %:
C 71.79; H 6.60; N 3.85. C22H24NO4. Calculated, %:
C 71.91; H 6.86; N 3.81. M 367.44.
Three-component condensation of 2-methoxy-
1,3-dimethylbenzene with isobutyraldehyde and
nitriles IIa–IId. A mixture of 5 mmol of 2-methoxy-
1,3-dimethylbenzene, 5 mmol of isobutyraldehyde, and
5 mmol of nitrile IIa–IId was added dropwise under
stirring and cooling with ice water to 6 ml of
92% H2SO4. The mixture was then poured into a mix-
ture of ice with 25 ml of aqueous ammonia and ex-
tracted with methylene chloride (3×25 ml). The com-
bined extracts were dried over MgSO4, the solvent was
distilled off, and the residue was subjected to chroma-
tography or crystallization.
7-Methoxy-1,3,3,6,8-pentamethyl-3,4-dihydro-
isoquinoline (IVc) was synthesized from compounds I
and IIc. The products were isolated by chromatog-
raphy using chloroform–hexane (20:1) as eluent. The
first fraction contained 0.43 g (40%) of IIIc, and the
second fraction, 0.15 g (13%) of IVc. Oily substance.
1
IR spectrum, ν, cm–1: 2965, 2865, 1604, 1556. H NMR
spectrum (CDCl3), δ, ppm: 1.14 s (6H, 3-CH3), 2.28 s
(3H, 1-CH3), 2.42 s (3H, CH3), 2.43 s (3H, CH3),
2.50 s (2H, CH2), 3.69 s (3H, OCH3), 6.81 s (1H, 5-H).
13C NMR spectrum (CDCl3), δC, ppm: 14.95 and 16.16
(6-CH3, 8-CH3), 26.92 and 27.81 (1-CH3, 3-CH3),
39.78 (C4), 53.02 (C3), 59.78 (OCH3), 128.18 (C5),
128.29 and 128.93 (C6, C8), 133.01 and 133.07 (C4a,
C8a), 156.18 (C7), 163.48 (C1). Mass spectrum, m/z
(Irel, %): 231 (80.9) [M]+, 216 (100) [M – CH3]+, 201
(20.1), 174 (51.7), 159 (15.4), 131 (6.0), 115 (15.2), 91
(12.1), 65 (5.0), 42 (9.4). Found, %: C 77.51; H 8.91;
N 5.97. C15H21NO. Calculated, %: C 77.88; H 9.15;
N 6.05. M 231.33.
The residue obtained in the three-component con-
densation with IIa was recrystallized from ethanol.
The precipitate, 0.17 g of IIIa, was filtered off, and the
residue was subjected to chromatography using hex-
ane–acetone (15:1) to isolate 0.17 g (11%) of IVa
from the first fraction and 0.12 g of IIIa from the
second fraction. Overall yield of IIIa 0.29 g (20%).
The residue obtained in the condensation with IIb
was separated by chromatography using hexane–
acetone (30:1) as eluent. From the first fraction we
isolated 0.17 g (13%) of IVb, and from the second,
0.19 g (15%) of IIIb.
In the reaction of alcohol I with nitrile IId, crys-
tallization of the residue from hexane–ethyl acetate
gave 0.59 g (42%) of spiro compound IIId.
The residue obtained in the condensation with IIc
was separated by chromatography using methylene
chloride–acetone (7:1) as eluent. From the first frac-
tion we isolated 0.31 g (19%) of diaryl(isopropyl)-
methane VI, and from the second, 0.03 g (3%) of IIIc.
10,11-Dimethoxy-1,3,6,6-tetramethyl-1,5,6,12b-
tetrahydrodibenzo[d,f]indole-2,8-dione (V) was syn-
thesized from compounds I and IIe. The product was
isolated by chromatography using petroleum ether–
acetone (2:1) as eluent. Yield 0.33 g (18%), mp 236–
237°C. IR spectrum, ν, cm–1: 2971, 2870, 1674, 1597,
The residue obtained in the condensation with IId
was subjected to chromatography using chloroform–
hexane (20:1) as eluent to isolate 0.26 g (19%) of
compound IIId.
1
1514. H NMR spectrum (CDCl3), δ, ppm: 1.45 s and
1.46 s (3H each, 6-CH3), 1.51 s (3H, 1-CH3), 1.64 d
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RITTER REACTION. SYNTHESIS OF 1-SUBSTITUTED 3,3,7,9-TETRAMETHYL-...
1061
2. Shome, M., Smith, P.W., Southam, R.M., and Ox-
ford, A.W., Tetrahedron Lett., 1980, vol. 21, p. 2927.
3. Van Emelen, K., De Wit, T., Hoornaert, G.J., and
The residue obtained in the condensation with IIe
was subjected to chromatography using petroleum
ether–acetone (2:1 to 1:1) as eluent. From the first
fraction we isolated 0.17 g (13%) of V, and from the
second, 0.19 g (15%) of VII.
Compernolle, F., Org. Lett., 2000, vol. 2, p. 3083.
4. Davies, I.W., Senanayake, C.H., Larsen, R.D.,
Verhoeven, T.R., and Reider, P.J., Tetrahedron Lett.,
1996, vol. 37, p. 813.
5. Toshimitsu, A., Hirosawa, C., and Tamao, K., Tetra-
hedron, 1994, vol. 50, p. 8997.
5,5′-(2-Methylpropane-1,1-diyl)bis(2-methoxy-
1,3-dimethylbenzene) (VI). Colorless oily substance.
1H NMR spectrum (CDCl3), δ, ppm: 0.81 d [6H,
3
CH(CH3)2, J = 6.0 Hz], 2.22 s (12H, 1-CH3, 3-CH3,
6. Huang, J. and Shi, M., Synlett, 2004, p. 2343.
1′-CH3, 3′- CH3), 2.32 m [1H, CH(CH3)2], 3.11 d (1H,
7. Aleksandrov, B.B., Dormidontov, M.Yu., Shklya-
ev, V.S., and Shklyaev, Yu.V., Khim. Geterotsikl.
Soedin., 1990, p. 995.
8. Aleksandrov, B.B., Dormidontov, M.Yu., Shklya-
ev, V.S., and Shklyaev, Yu.V., Khim. Geterotsikl.
Soedin., 1991, p. 657.
3
CH, J = 10.8 Hz), 3.63 s (6H, 2-OCH3, 2′-OCH3),
6.87 s (4H, 4-H, 4′-H, 6-H, 6′-H). 13C NMR spectrum
(CDCl3), δC, ppm: 16.23 (1-CH3, 3-CH3, 1′-CH3,
3′-CH3), 21.96 [CH(CH3)2], 32.12 [CH(CH3)2], 59.51
and 59.79 (CH, 2-OCH3, 2′-OCH3), 128.07 (C4, C4′,
C6, C6′), 130.25 (C5, C5′), 140.43 (C1, C1′, C3, C3′),
154.96 (C2, C2′). Mass spectrum, m/z (Irel, %): 326
(4.1) [M]+, 283 (100) [M – C3H7]+, 268 (5.4), 253
(2.8), 210 (2.3). Found, %: C 81.15; H 9.36. C22H30O2.
Cal-culated, %: C 80.94; H 9.26. M 326.47.
9. Glushkov, V.A., Karmanov, V.I., and Shklyaev, Yu.V.,
Izv. Akad. Nauk, Ser. Khim., 2002, p. 1204.
10. Shklyaev, Yu.V., Ismagilov, R.R., Rozhkova, Yu.S.,
Fatykhov, A.A., Abdarakhmanov, I.B., and Tolsti-
kov, A.G., Izv. Akad. Nauk, Ser. Khim., 2004, p. 869.
11. Ausheva, O.G., Glushkov, V.A., Shurov, S.N., and
Shklyaev, Yu.V., Izv. Akad. Nauk, Ser. Khim., 2001,
p. 1571.
1-Isopropyl-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinolin-3-one (VII). a. mp 136–137°C (from
EtOAc–hexane). IR spectrum, ν, cm–1: 3296, 3207,
12. Glushkov, V.A., Ausheva, O.G., and Shklyaev, Yu.V.,
1
2961, 2838, 1662, 1518. H NMR spectrum (CDCl3),
Khim. Geterotsikl. Soedin., 2000, p. 693.
δ, ppm: 0.78 d and 1.02 d (3H each, CH3, 3J = 6.8 Hz),
2.03 m [1H, CH(CH3)2], 3.43 d and 3.61 d (1H each,
4-H, 2J = 20.6 Hz), 3.86 s and 3.87 s (3H each, OCH3),
4.29 br.s (1H, 1-H), 6.58 s (1H, Harom), 6.60 s (1H,
13. Rozhkova, Yu.S., Khmelevskaya, K.A., Shklyaev, Yu.V.,
Ezhikova, M.A., and Kodess, M.I., Russ. J. Org. Chem.,
2012, vol. 48, p. 69.
14. Shklyaev, Yu.V., El’tsov, M.A., Rozhkova, Yu.S.,
Kharitonova, A.V., and Maiorova, O.A., Izv. Akad.
Nauk, Ser. Khim., 2010, p. 1222.
15. Glushkov, V.A., Ausheva, O.G., Shurov, S.N., and
Shklyaev, Yu.V., Izv. Akad. Nauk, Ser. Khim., 2002,
p. 822.
16. Nifontov, Yu.V., Glushkov, V.A., Ausheva, O.G., and
Shklyaev, Yu.V., Russ. J. Org. Chem., 2002, vol. 38,
p. 1386.
H
arom), 7.11 br.s (1H, NH). 13C NMR spectrum
(CDCl3), δC, ppm: 16.25 and 19.23 [CH(CH3)2], 35.45
(C4), 36.80 [CH(CH3)2], 55.87 and 55.97 (6-OCH3,
7-OCH3), 61.73 (C1), 109.36 and 110.09 (C5, C8),
123.61 and 125.63 (C4a, C8a), 147.52 and 148.21 (C6,
C7), 172.17 (C3). Mass spectrum, m/z (Irel, %): 249
(1.6) [M]+, 206 (100) [M – C3H7]+, 178 (21.9), 162
(4.8), 147 (7.3), 104 (2.2), 77 (1.5), 41 (1.2). Found,
%: C 67.38; H 7.51; N 5.53. C22H24NO4. Calculated,
%: C 67.45; H 7.68; N 5.62. M 249.31.
17. Shklyaev, Yu.V., Nifontov, Yu.V., Shashkov, A.S., and
Firgang, S.I., Izv. Akad. Nauk, Ser. Khim., 2002, p. 2075.
18. Shklyaev, Yu.V., Glushkov, V.A., Nifontov, Yu.V.,
Stryapunina, O.G., Firgang, S.I., Sokol, V.I., and Sergi-
enko, V.S., Mendeleev Commun., 2003, p. 80.
19. Glushkov, V.A., Stryapunina, O.G., Gorbunov, A.A.,
Mayorova, O.A., Slepukhin, P.A., Ryabukhina, S.Ya.,
Khorosheva, E.V., Sokol, V.I., and Shklyaev, Yu.V.,
Tetrahedron, 2010, vol. 66, p. 721.
20. Shklyaev, Yu.V. and Nifontov, Yu.V., Izv. Akad. Nauk,
Ser. Khim., 2002, p. 780.
21. Barbry, D., Sokolowski, G., and Champagne, P., Synth.
Commun., 2002, vol. 32, p. 1787.
b. A mixture of 5 mmol of 3,4-dimethoxyphenyl-
acetonitrile (IIe) and 5 mmol of isobutyraldehyde was
added dropwise under stirring and cooling with ice
water to 4 ml of 92% H2SO4. The residue was recrys-
tallized from ethyl acetate. Yield 0.72 g (58%).
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 11-03-00367-a).
REFERENCES
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1. Pich, K.C., Bishop, R., Craig, D.C., and Scudder, M.L.,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013