Neospiroenones. Synthesis of 10,11-dimethoxy-1,6,6-trimethyl-5,6,8,12b- tetrahydrobenzo[d,f]indol-4(3H)-one and 10,11-dimethoxy-6,6-dimethyl- 1,5,6,12b-tetrahydrobenzo[d,f]indol-2(8H)-one

Article abstract of DOI:10.1007/s11172-010-0229-6

The three-component condensation of isobutyraldehyde, 3,4- dimethoxyphenylacetonitrile, and p-methylanisole or anisole in the presence of concentrated sulfuric acid affords neospiroenone systems.

Full text of DOI:10.1007/s11172-010-0229-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 6, pp. 1248—1253, June, 2010
1248
Neospiroenones. Synthesis of 10,11ꢀdimethoxyꢀ1,6,6ꢀtrimethylꢀ5,6,8,12bꢀ
tetrahydrobenzo[d,f]indolꢀ4(3H)ꢀone and 10,11ꢀdimethoxyꢀ6,6ꢀdimethylꢀ
1,5,6,12bꢀtetrahydrobenzo[d,f]indolꢀ2(8H)ꢀone
Yu. V. Shklyaev, M. A. El´tsov, Yu. S. Rozhkova, A. V. Kharitonova, and O. A. Mayorova
Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
3 ul. Akad. Koroleva, 614013 Perm, Russian Federation.
Fax: +7 (342) 237 8262. Eꢀmail: yushka@newmail.ru
The threeꢀcomponent condensation of isobutyraldehyde, 3,4ꢀdimethoxyphenylacetonitrile,
and pꢀmethylanisole or anisole in the presence of concentrated sulfuric acid affords neoꢀ
spiroenone systems.
Key words: pꢀmethylanisole, anisole, isobutyraldehyde, phenylacetonitrile, 3,4ꢀdimethoxyꢀ
phenylacetonitrile, threeꢀcomponent condensation, neospiroenone, spiro σꢀcomplex, sulfuꢀ
ric acid.
The synthesis of neospiro systems, viz., neospiroꢀ
enones, neospirodienones, and their structural analogs,
has attracted interest in relation to investigation of the
biomimetic synthesis of such alkaloids as aporphines,
proaporphines, erythrinans, and morphinanodienones, as
well as because of the possibility of the preparation of new
synthetic analogs of these alkaloids.1—3 For example, it
was shown that the ( )ꢀNꢀmethylneospirodienone—BF3
complex can be transformed into dibenzazonine (eribiꢀ
dine) and the corresponding aporphines.4
One of the main approaches to the synthesis of tetraꢀ
cyclic neospiro systems is based on the intramolecular
nonphenol oxidative coupling of Nꢀsubstituted 1ꢀbenzylꢀ
1,2,3,4ꢀtetrahydroisoquinolines. Such compounds were
synthesized5 by the intramolecular nonphenol oxidative
coupling of ( )ꢀlaudanosine with vanadium oxytrifluoꢀ
ride in trifluoroacetic acid. More recently,6 it has been
shown that similar transformations can be performed not
only for 1ꢀbenzylꢀ1,2,3,4ꢀtetrahydroisoquinolines but also
for 1ꢀphenethylꢀ1,2,3,4ꢀtetrahydroisoquinolines. In furꢀ
ther studies, [IPh(CF3COO)2] (PIFA),7 PIFA—heteroꢀ
polyacid,8,9 and PIFA—BF3•Et2O (see Ref. 10) were used
as oxidizing systems for the intramolecular nonphenol oxꢀ
idative coupling of Nꢀsubstituted 1ꢀbenzylꢀ1,2,3,4ꢀtetraꢀ
hydroisoquinolines with the aim of preparing neospirodiꢀ
enones. The anodic oxidation of Nꢀtrifluoroacetylꢀ1ꢀbenꢀ
zylꢀ1,2,3,4ꢀtetrahydroisoquinolines in acetonitrile giving
the corresponding neospirodienones was also documented.11
In most of the aboveꢀconsidered cases, neospiro sysꢀ
tems are formed as a result of the intramolecular nonpheꢀ
nol oxidative coupling of Nꢀsubstituted 1ꢀbenzylꢀ1,2,3,4ꢀ
tetrahydroisoquinolines. An analysis of the possibilities of
the formation of such compounds led to the conclusion
that tetracyclic neospiro systems can be synthesized withꢀ
out the preliminary synthesis of 1ꢀbenzylꢀ1,2,3,4ꢀtetraꢀ
hydroisoquinoline.
It is known12 that the threeꢀcomponent reaction of
pꢀmethylanisole, isobutyraldehyde, and nitrile affords
1ꢀRꢀsubstituted 8ꢀ(2´ꢀmethoxyphenylꢀ5´ꢀmethyl)ꢀ3,3,9ꢀ
trimethylꢀ2ꢀazaspiro[4.5]decaꢀ1,7ꢀdienꢀ6ꢀones. This
is attributed to the fact that the spiro σꢀcomplex, which is
a precursor of 3,3ꢀdimethylꢀ2ꢀazaspiro[4.5]decꢀ8ꢀenꢀ
6ꢀone, is a stronger electrophile than the protonated
form of isobutyraldehyde, and this complex alkylates
unreacted pꢀmethylanisole to form the corresponding spiro
systems.
It would be expected that in the presence of particular
steric and electronic factors, a new C—C bond will be
formed via intramolecular electrophilic substitution with
the involvement of the electronꢀsaturated phenyl moiety
and the intermediate spiro σꢀcomplex giving rise to
neospiro systems.
The model reaction of pꢀmethylanisole, isobutyraldeꢀ
hyde, and phenylacetonitrile in concentrated sulfuric acid
(Scheme 1) afforded the only isolated product, viz.,
1ꢀbenzylꢀ8ꢀ(2´ꢀmethoxyꢀ5´ꢀmethylphenyl)ꢀ3,3,9ꢀtrimeꢀ
thylꢀ2ꢀazaspiro[4.5]decaꢀ1,7ꢀdienꢀ6ꢀone (1).
The threeꢀcomponent condensation of pꢀmethylaniꢀ
sole, isobutyraldehyde, and 3,4ꢀdimethoxyphenylacetoꢀ
nitrile occurs in a different way and gives tetracyclic sysꢀ
tem 2 (Scheme 2). The structure of heterocyclic comꢀ
pound 2 was confirmed by mass spectrometry, IR specꢀ
1
troscopy, and H and 13C NMR spectroscopy. Thus, the
1H NMR spectrum of compound 2 in CDCl3 has signals
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1222—1227, June, 2010.
1066ꢀ5285/10/5906ꢀ1248 © 2010 Springer Science+Business Media, Inc.

Threeꢀcomponent synthesis of neospiroenones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1249
2 was finally established based on the 2D 1H—13C HMBC
spectrum. The principal HMBC correlations confirming
the presence of the bond between the moieties in molecule
2 are as follows (see Table 1): H(12b)/C(12) 3.52/109.27,
H(12b)/C(12a) 3.52/124.84, H(12b)/C(1) 3.52/135.61,
and H(12b)/C(1)Me 3.52/25.80.
Scheme 1
According to Scheme 2, the reaction occurs as follows:
the initially formed spiro σꢀcomplex A intramolecularly
attacks the C(6) atom of the dimethoxyphenyl moiety to
form enol ether B, whose hydrolysis affords neospiroenone 2.
It should be noted that compound 2 in the freeꢀbase
form is unstable and is readily oxidized at the C(8) atom
by atmospheric oxygen, as in the case of 1ꢀbenzylꢀ3,4ꢀ
dihydroisoquinolines,13 to form neospiro system 3 (see
1
Scheme 2). In the H NMR spectrum of neospiro comꢀ
pound 3, the signals for the protons H(8A) and H(8B) at
δ 4.14 and 4.64, respectively, are absent. In the 13C NMR
spectrum, the signal for the C(8) atom is shifted downfield
and is observed at δ 181.14 (δC(8) 30.66 in the 13C NMR
spectrum of compound 2). Based on these facts, as well as
on the elemental analysis, mass spectrometry, and IR specꢀ
troscopic data, the structure 10,11ꢀdimethoxyꢀ1,6,6ꢀtriꢀ
methylꢀ5,6ꢀdihydrobenzo[d,f]indoleꢀ4,8ꢀ(3H,12bH)ꢀdiꢀ
one was assigned to compound 3.
Previously, it has been shown14 that the threeꢀcompoꢀ
nent condensation of anisole, isobutyraldehyde, and
αꢀsubstituted phenylacetonitriles affords 1ꢀRꢀsubstituted
3,3ꢀdimethylꢀ2ꢀazaspiro[4.5]decaꢀ6,9ꢀdienꢀ8ꢀones. This
reaction, like that with the use of pꢀmethylanisole, proꢀ
for the aromatic protons H(12) and H(9) as two singlets at
δ 6.57 and 6.64 with an integrated intensity of 1 H each.
The 2D COSY experiments showed that the signal for the
proton H(12b) correlates with the signals for the protons
of the methyl group at the C(1) atom and the aromatic
proton H(12). The presence of the singlet of the methyl
group C(1)Me at δ 2.22 indicates that the double bond in
compound 2 is at the C(1) atom. Taking into account the
2D HSQC 1H—13C spectroscopic data, the assignment of
the signals for all protonated carbon atoms in compound 2
was made (Table 1). The structure of neospiro compound
Scheme 2

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Shklyaev et al.
Table 1. NMR spectroscopic parameters for compound 2 (CDCl3, δ, J/Hz)
Atom,
group
1H NMR
13C NMR
(DEPT)
HSQC
HMBC
C(1)
—
135.61 (C)
25.80 (Me)
121.32 (CH)
36.90 (CH2)
—
—
C(1)Me
C(2)H
C(3)H2
2.22 (s, 3 Н)
5.87 (m, 1 Н)
2.70 (br.d, 1 Н,
J = 23.1); 3.01 (dd,
1 Н, J = 23.1, J = 4.2)
—
25.80
121.32
36.90
135.61 (C(1)); 121.32 (C(2)); 51.01 (C(12b))
204.35 (C(4)); 51.01 (C(12b)); 36.90 (С(3)); 25.80 (C(1)Me)
204.35 (C(4)); 121.32 (C(2)); 135.61 (C(1))
C(4)
C(4a)
C(5)H2
204.35 (C)
65.42 (C)
44.04 (CH2)
—
—
44.04
—
—
—
2.04, 2.26 (both d,
1 H each, J = 14.4)
—
1.54, 1.73 (both s,
3 Н each)
204.35 (C(4)); 65.42 (C(4a)); 70.96 (C(6)); 187.33 (C(7a));
51.01 (C(12b)); 28.21, 28.78 (C(6)Me2)
—
C(6)
C(6)Ме
70.96 (C)
28.21 (Me);
28.78 (Me)
187.33 (C)
30.66 (CH2)
—
28.21;
28.78
—
70.96 (C(6)); 44.04 (C(5))
C(7a)
C(8)H2
—
—
4.14, 4.64 (both d,
1 H each, J = 23.7)
—
6.64 (s, 1 Н)
—
30.66
187.33 (C(7a)); 111.40 (C(9)); 124.84 (C(12a));
122.17 (C(8a))
—
30.66 (C(8)); 124.84 (C(12a)); 148.66 (C(11))
—
149.37 (C(10))
—
148.66 (C(11))
51.01 (C(12b)); 122.17 (C(8a)); 149.37 (C(10))
—
135.61 (C(1)); 121.32 (C(2)); 204.35 (C(4)); 65.42 (C(4a));
44.04 (C(5)); 187.33 (C(7a)); 124.84 (C(12a));
109.27 (C(12)); 25.80 (C(1)Me)
C(8a)
C(9)H
C(10)
C(10)ОМе 3.84 (s, 3 Н)
C(11)
C(11)ОМе 3.82 (s, 3 Н)
C(12)H
C(12a)H
C(12b)H
122.17 (C)
111.40 (CH)
149.37 (C)
55.90 (Me)
148.66 (C)
56.01 (Me)
109.27 (CH)
124.84 (C)
51.01 (CH)
—
111.40
—
55.90
—
56.01
109.27
—
—
6.57 (s, 1 Н)
—
3.52 (s, 1 Н)
51.01
* The 1H NMR spectrum of compound 2 isolated as hydrochloride shows also a signal at δH 16.54 (br.s, HCl).
ceeds through the formation of the intermediate spiro
σꢀcomplex. Consequently, the use of 3,4ꢀdimethoxypheꢀ
nylacetonitrile as the nitrile component in the reaction
with anisole and isobutyraldehyde can lead to the formaꢀ
tion of the neospiroenone system.
Actually, the threeꢀcomponent condensation of aniꢀ
sole, isobutyraldehyde, and 3,4ꢀdimethoxyphenylacetoniꢀ
trile in concentrated sulfuric acid gives compound 4, whose
structure was determined by mass spectrometry, IR specꢀ
troscopy, and 1H and 13C NMR spectroscopy (Scheme 3).
O(4)
H(24A)
C(22)
C(24)
H(18B)
C(17)
H(17A)
H(14B)
H(18A)
C(14)
H(20A)
H(20B)
H(10A)
C(18)
C(4)
H(14C)
H(14A)
C(16)
C(10)
C(13)
C(20)
O(3)
O(2)
H(23A)
C(21)
H(4)
C(5)
C(11)
H(23C)
C(23)
H(23B)
N(1)
C(7)
C(8)
C(12)
C(6)
H(19B)
H(19A)
H(25B)
C(25)
H(25A)
H(6)
C(19)
H(19C)
O(1)
H(25C)
Fig. 1. Molecular structure of compound 5.

Threeꢀcomponent synthesis of neospiroenones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1251
Scheme 3
1
Thus, the H NMR spectrum of compound 4 in CDCl3
Experimental
has signals for the aromatic protons H(9) and H(12) as
two singlets at δ 6.66 and 6.62 with an integrated intensity
of 1 H each, which partially overlap with the signal for the
proton H(4). The 2D COSY experiment showed that the
signal for the proton H(12b) correlates with the signals for
the protons H(1A) and H(1B), as well as with the signal
for the proton H(12).
Like compound 2, 10,11ꢀdimethoxyꢀ6,6ꢀdimethylꢀ
1,5,6,12bꢀtetrahydrobenzo[d,f]indolꢀ2(8H)ꢀone (4) in the
freeꢀbase form is unstable in air and is readily oxidized at
the C(8) atom to form neospiro system 5 (see Scheme 3).
The structure of compound 5 was unambiguously estabꢀ
lished by Xꢀray diffraction (Fig. 1).
Although the stereochemistry of neospiroenones
2—5 remains unknown, the 1H NMR spectra of comꢀ
pounds 2—5 have one set of signals. This is evidence
that one of the possible diastereomers was isolated.
It should be noted that the GCꢀmass spectra of the reacꢀ
tion mixtures in the case of compounds 4 and 5 have exꢀ
clusively peaks at masses corresponding to the neospiro
systems. For compounds 2 and 3, the GCꢀmass spectra
of the reaction mixtures show major peaks at masses 339
and 353, respectively, and minor peaks (<5%) at the
same masses.
The 1H and 13C (DEPT) NMR spectra were recorded on
a Varian Mercury Plus spectrometer (300.06 MHz for 1H and
75.46 MHz for 13C) with HMDS as the internal standard in
CDCl3. The electron impact mass spectra (200 °C, 70 eV) were
obtained on an Agilent Technologies 6890N/5975B GCꢀmass
spectrometer equipped with an HPꢀ5ms column (30×0.25 mm,
0.25 μm) using helium as the carrier gas. The elemental analysis
was carried out on a CHNSꢀ932 Leco Corporation analyzer.
The IR spectra were recorded on a URꢀ20 instrument in Nujol
mulls. The course of the reactions was monitored and the purity
of the reaction products was checked by TLC on Silufol plates;
the spots were visualized with the use of a 0.5% chloranil soluꢀ
tion in toluene. The column chromatography was performed on
silica gel (0.06—0.20 mm, 70—230 mesh, Lancaster). The meltꢀ
ing points were measured on a PTP instrument and are unꢀ
corrected.
1ꢀBenzylꢀ8ꢀ(2´ꢀmethoxyphenylꢀ5´ꢀmethyl)ꢀ3,3,9ꢀtrimethylꢀ
2ꢀazaspiro[4.5]decaꢀ1,7ꢀdienꢀ6ꢀone hydrochloride (1). A mixꢀ
ture of pꢀmethylanisole (0.48 g, 4 mmol), isobutyraldehyde
(0.14 g, 2 mmol), and phenylacetonitrile (0.24 g, 2 mmol) in
dichloromethane (2 mL) was added dropwise with stirring and
cooling with ice water to concentrated H2SO4 (10 mL). The
reaction mixture was poured into crushed ice (50 g) and extractꢀ
ed with hexane (20 mL). The aqueous layer was adjusted with
aqueous ammonia to pH 7—8. The resulting oil was extracted
with hexane (2×10 mL), dried with MgSO4, and filtered. Dry
HCl was bubbled through the filtrate until the solution became
completely transparent. The precipitate that formed was sepaꢀ
rated and crystallized from ethyl acetate. Compound 1, m.p.
187—191 °C, was obtained in a yield of 0.18 g (21%). Found (%):
Therefore, the aboveꢀdescribed method can be used to
synthesize polyfunctional derivatives of neospiro systems,
four new covalent bonds being formed in the course
of the reaction.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
Shklyaev et al.
C, 73.89; H, 7.33; N, 3.24. C27H31NO2•HCl. Calculated (%):
C, 74.04; H, 7.36; N, 3.20. IR, ν/cm–1: 1590, 1660. 1H NMR, δ:
1.01 (d, 3 H, C(9)Me, J = 7.2 Hz); 1.70 and 1.75 (both s, 3 H
each, C(3)Me, C(3)Me); 1.82 (m, 1 H, H(10A)); 2.01 (d, 1 H,
H(4A), J = 13.7 Hz); 2.29 (s, 3 H, C(5´)Me); 2.66 (m, 2 H,
H(10B), H(4B)); 3.47 (m, 1 H, H(9)); 3.83 (s, 3 H, OMe); 4.25
and 4.39 (both d, 1 H each, CH(A)Ph, CH(B)Ph, J = 13.8 Hz);
5.98 (d, 1 H, H(7), J = 1.2 Hz); 6.86 (m, 2 H, H(Ar)); 7.26 (m, 6 H,
H(Ar)); 16.68 (br.s, 1 H, HCl). 13C NMR, δ: 20.18, 20.45
(C(9)Me, C(5´)Me); 27.87, 29.31 (C(3)Me2); 31.01 (C(9)); 35.83
(CH2Ph); 40.12 (C(10)); 47.60 (C(4)); 55.51 (OMe); 62.89, 69.86
(C(3), C(5)); 110.91, 125.89, 126.93, 128.05, 129.03, 129.44,
129.51, 130.20, 130.76, 131.35, 153.87, 167.89 (C(7), C(8),
C(Ar)); 186.32 (C(1)); 193.04 (C(6)). MS, m/z (Irel (%)): 401
[M – HCl]+ (72), 386 [M – HCl – Me]+ (6), 284 (100), 269
(18), 241 (14), 228 (13), 213 (8), 200 (8), 184 (6), 173 (15), 159
(20), 145 (10), 135 (11), 128 (10), 115 (9), 91 (31), 77 (6), 41 (5).
10,11ꢀDimethoxyꢀ1,6,6ꢀtrimethylꢀ5,6,8,12bꢀtetrahydrobenzoꢀ
[d,f]indolꢀ4(3H)ꢀone hydrochloride (2). A mixture of pꢀmethylꢀ
anisole (0.24 g, 2 mmol), isobutyraldehyde (0.14 g, 2 mmol), and
3,4ꢀdimethoxyphenylacetonitrile (0.35 g, 2 mmol) in dichloroꢀ
methane (2 mL) was added dropwise with stirring and cooling
with ice water to concentrated H2SO4 (10 mL). The reaction
mixture was stirred for 10 min, poured into crushed ice (50 g),
adjusted with aqueous ammonia to pH 7—8, and extracted with
dichloromethane (3×15 mL). After the extraction, the dichloroꢀ
methane solution was separated from the aqueous layer, and dry
HCl was bubbled through the dichloromethane solution. Then
ethyl acetate (20 mL) was added to the solution, and dichloꢀ
romethane was evaporated. The crystals that formed were sepaꢀ
rated. Compound 2, m.p. 212 °C (with decomp.), was obtained
in a yield of 0.42 g (56%). Found (%): C, 67.15; H, 7.04; N, 3.76.
C21H25NO3•HCl. Calculated (%): C, 67.10; H, 6.97; N, 3.73.
IR, ν/cm–1: 1520, 1612, 1708. MS, m/z (Irel (%)): 339 [M – HCl]+
(100), 324 [M – HCl – Me]+ (70), 296 [M – HCl – Me – CO]+
(23), 280 (3), 265 (3), 242 (4), 209 (3), 177 (5), 151 (5), 115 (4),
77 (3), 41 (2).
(C(9)); 121.99 (C(2)); 127.48, 136.03, 137.26 (C(1), C(8a),
C(12a)); 148.14, 154.45 (C(10), C(11)); 165.81 (C(7a)); 181.14
(C(8)); 208.16 (C(4)). MS, m/z (Irel (%)): 353 [M]+ (100), 338
[M – Me]+ (18), 324 (5), 310 [M – Me – CO]+ (37), 296 (10),
282 (6), 268 (30), 258 (17), 241 (5), 225 (5), 210 (6), 164 (9),
115 (7), 77 (4), 41 (4).
10,11ꢀDimethoxyꢀ6,6ꢀdimethylꢀ1,5,6,12bꢀtetrahydrobenzoꢀ
[d,f]indolꢀ2(8H)ꢀone hydrochloride (4). A mixture of anisole (0.22 g,
2 mmol), isobutyraldehyde (0.14 g, 2 mmol), and 3,4ꢀdimethꢀ
oxyphenylacetonitrile (0.35 g, 2 mmol) in dichloromethane
(2 mL) was added dropwise with stirring and cooling with ice
water to concentrated H2SO4 (10 mL). The reaction mixture
was stirred for 10 min, poured into crushed ice (50 g), adjusted
with aqueous ammonia to pH 7—8, and extracted with dichloroꢀ
methane (3×15 mL). Dry HCl was bubbled through the extract.
Then ethyl acetate (20 mL) was added to the solution, and dichloꢀ
romethane was evaporated. The crystals that formed were sepaꢀ
rated and recrystallized from ethanol. Compound 4, m.p. 220 °C
(with decomp.), was obtained in a yield of 0.08 g (11%).
Found (%): C, 66.32; H, 6.73; N, 3.90. C20H23NO3•HCl. Calꢀ
culated (%): C, 66.38; H, 6.69; N, 3.87. IR, ν/cm–1: 1524, 1612,
1684. 1H NMR, δ: 1.75 and 1.76 (both s, 3 H each, C(6)Me,
C(6)Me); 2.42 and 2.59 (both d, 1 H each, H(5A), H(5B),
J = 14 Hz); 2.93 (dd, 1 H, H(1A), J = 17.6 Hz, J = 4.1 Hz); 3.39
(br.d, 1 H, H(1B), J = 17.6 Hz); 3.60 (br.s, 1 H, H(12b)); 3.83
and 3.84 (both s, 3 H each, C(10)OMe, C(11)OMe); 4.10 and
4.74 (both d, 1 H each, H(8A), H(8B), J = 21.5 Hz); 6.03 (d, 1 H,
H(3), J = 11 Hz); 6.62 (s, 1 H, H(12)); 6.66 (s, 1 H, H(9)); 6.64
(d, 1 H, H(4), J = 11 Hz); 16.85 (br.s, 1 H, HCl). 13C NMR, δ:
29.08, 29.36 (C(6)Me2); 31.36 (C(8)); 38.26, 46.38 (C(1), C(5));
46.61 (C(12b)); 56.01, 56.09 (C(10)OMe, C(11)OMe); 54.65,
70.91 (C(4a), C(6)); 109.14, 111.58 (C(9), C(12)); 120.92, 124.48
(C(8a), C(12a)); 131.29, 143.18 (C(3), C(4)); 148.95, 149.34
(C(10), C(11)); 187.80 (C(7a)); 193.67(C(2)). MS, m/z (Irel (%)):
325 [M – HCl]+ (100), 310 [M – HCl – Me]+ (36), 282
[M – HCl – Me – CO]+ (9), 268 (5), 242 (6), 218 (10), 196 (2),
176 (10), 152 (3), 114 (4), 76 (3), 41 (2).
10,11ꢀDimethoxyꢀ1,6,6ꢀtrimethylꢀ5,6ꢀdihydrobenzo[d,f]ꢀ
indoleꢀ4,8ꢀ(3H,12bH)ꢀdione (3). A mixture of pꢀmethylanisole
(0.24 g, 2 mmol), isobutyraldehyde (0.14 g, 2 mmol), and
3,4ꢀdimethoxyphenylacetonitrile (0.35 g, 2 mmol) in dichloroꢀ
methane (2 mL) was added dropwise with stirring and cooling
with ice water to concentrated H2SO4 (10 mL). The reaction
mixture was stirred for 10 min, poured into crushed ice (50 g),
and adjusted with aqueous ammonia to pH 7—8. The precipitate
that formed after the neutralization was filtered off and kept in
ethyl acetate for 24 h in air. Then the product was filtered off,
dried, and purified by chromatography (chloroform—acetone,
35 : 1, as the eluent). Compound 3, m.p. 248 °C (with decomp.),
was obtained in a yield of 0.15 g (21%). Found (%): C, 71.42;
H, 6.48; N, 3.89. C21H23NO4. Calculated (%): C, 71.37; H, 6.56;
N, 3.96. IR, ν/cm–1: 1514, 1568, 1592, 1632, 1676, 1708.
1H NMR, δ: 1.26 and 1.52 (both s, 3 H each, C(6)Me, C(6)Me);
1.92 and 2.17 (both d, 1 H each, H(5A), H(5B), J = 13.5 Hz);
2.00 (s, 3 H, C(1)Me); 2.66 (br.d, 1 H, H(3A), J = 22.7 Hz); 2.99
(dd, 1 H, H(3B), J = 22.7 Hz, J = 1.3 Hz); 3.67 (s, 1 H, H(12b));
3.91 and 3.92 (both s, 3 H each, C(10)OMe, C(11)OMe); 5.85
(m, 1 H, H(2)); 6.65 and 7.63 (both s, 1 H each, H(9), H(12)).
13C NMR, δ: 25.52 (C(1)Me); 28.24, 30.76 (C(6)Me2); 37.48
(C(3)); 46.44 (C(5)); 52.00 (C(12b)); 55.95, 56.06 (C(10)OMe,
C(11)OMe); 70.09, 73.65 (C(4a), C(6)); 108.23 (C(12)); 110.15
10,11ꢀDimethoxyꢀ6,6ꢀdimethylꢀ1,5,6,12bꢀtetrahydrobenzoꢀ
[d,f]indoleꢀ2,8ꢀdione (5). A mixture of anisole (0.22 g, 2 mmol),
isobutyraldehyde (0.14 g, 2 mmol), and 3,4ꢀdimethoxyphenylꢀ
acetonitrile (0.35 g, 2 mmol) in dichloromethane (2 mL) was
added dropwise with stirring and cooling with ice water to conꢀ
centrated H2SO4 (10 mL). The reaction mixture was stirred for
10 min, poured into crushed ice (50 g), adjusted with aqueous
ammonia to pH 7—8, and extracted with dichloromethane
(3×15 mL). After the extraction, dichloromethane was dried with
anhydrous MgSO4. Then the solution was filtered, dichloroꢀ
methane was distilled off, and the residue was crystallized from
ethyl acetate. Compound 5 was obtained in a yield of 0.16 g
(24%), m.p. 244—247 °C. Found (%): C, 70.72; H, 6.20;
N, 4.17. C20H21NO4. Calculated (%): C, 70.78; H, 6.24; N, 4.13.
IR, ν/cm–1: 1516, 1568, 1596, 1672, 1688. 1H NMR, δ: 1.46 and
1.55 (both s, 3 H each, C(6)Me, C(6)Me); 2.35 and 2.44 (both d,
1 H each, H(5A), H(5B), J = 13.4 Hz); 2.95 and 3.29 (both dd,
1 H each, H(1A), H(1B), J = 16.8 Hz, J = 3.9 Hz, J = 2.4 Hz);
3.64 (br.s, 1 H, H(12b)); 3.93 and 3.94 (both s, 3 H each,
C(10)OMe, C(11)OMe); 5.84 (d, 1 H, H(3), J = 10.1 Hz); 6.66
(dd, 1 H, H(4), J = 10.1 Hz, J = 2.1 Hz); 6.75 and 7.66 (both s,
1 H each, H(9), H(12)). 13C NMR, δ: 29.21, 30.88 (C(6)Me2);
39.08, 49.45 (C(1), C(5)); 45.72 (C(12b)); 56.05, 56.14
(C(10)OMe, C(11)OMe); 60.12, 73.38 (C(4a), C(6)); 108.65,

Threeꢀcomponent synthesis of neospiroenones
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 6, June, 2010
1253
Table 2. Crystallographic parameters and the Xꢀray data collecꢀ
tion and structure refinement statistics for compound 5
my of Sciences, Ekaterinburg) for supplying the Xꢀray
diffraction data.
The present study was financially supported by the
Council on Grants at the President of the Russian Federaꢀ
tion (Program for State Support of Young Scientists, Grant
MKꢀ3014.2007.3), the Russian Foundation for Basic
Research (Project No. 07ꢀ03ꢀ00001), the Collaborative
Research Grant of the Ural Branch of the Russian Acadeꢀ
my of Sciences and the Siberian Branch of the Russian
Academy of Sciences (Program "Targeted Synthesis and
Optimization of Properties of Biologically Active Comꢀ
pounds"), and the Presidium of the Russian Academy of
Sciences (Program "Development of Methods for the Synꢀ
thesis of Chemical Substances and the Design of New
Materials").
Parameter
Characteristics
Molecular formula
Molecular weight
Crystal system
Space group
Unit cell parameters
a/Å
b/Å
c/Å
C20H21NO4
339.15
Monoclinic
P21/n
12.036 (2)
10.0103 (17)
14.243 (2)
90.00
95.41(1)
90.00
α/deg
β/deg
γ/deg
V/Å3
1708.41(216)
4
Z
dcalc/g cm–3
1.319
0.092
References
μ/mm–1
θꢀscan range/deg
Total number of reflections
Number of independent reflections
Number of refined parameters, N
Rint
R1 factor (%)
R factors based on reflections with I > 2(I)
R1
2.87—31.80
27365
5377
264
0.0867
4.71
1. K. W. Bently, J. W. Lewis, J. B. Taylor, J. Chem. Soc. C,
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0.0471
0.0689
wR2
R factors based on all reflections
R1
wR2
0.1744
0.0747
8. H. Hamamoto, Y. Shiozaki, H. Nambu, K. Hata, H. Tohma,
Y. Kita, Chem. Eur. J., 2004, 10, 4977.
109.89 (C(9), C(12)); 128.87, 149.86 (C(3), C(4)); 127.68
(C(12a)); 137.77, 148.64, 154.85 (C(8a), C(10), C(11)); 167.50
(C(7a)); 181.18 (C(8)); 194.83 (C(2)). MS, m/z (Irel (%)): 339
[M]+ (100), 324 [M – Me]+ (19), 296 [M – Me – CO]+ (23),
282 (2), 271 (17), 256 (31), 229 (12), 213 (7), 201 (7), 184 (3),
157 (4), 141 (4), 128 (4), 115 (5), 91 (2), 77 (6), 41 (4).
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Lett., 1982, 23, 4581.
Xꢀray diffraction study of compound 5. Single crystals of comꢀ
pound 5 were obtained by the crystallization from ethyl acetate.
The Xꢀray diffraction data were collected on a Xcaliburꢀ3 difꢀ
fractometer equipped with a CCD area detector at 295(2) К
(λ(MoꢀKα), graphite monochromator, ϕꢀ and ωꢀscanning mode).
The structure of compound 5 was solved by direct methods with
the use of the SHELXSꢀ97 program packages and refined anisoꢀ
tropically (isotropically for hydrogen atoms) with the use of the
SHELXLꢀ97 program package. Principal crystallographic paꢀ
rameters and the Xꢀray data collection and structure refinement
statistics for compound 5 are given in Table 2.
12. Yu. V. Shklyaev, Yu. V. Nifontov, A. S. Shashkov, S. I. Firꢀ
gang, Izv. Akad. Nauk, Ser. Khim., 2002, 2075 [Russ. Chem.
Bull., Int. Ed., 2002, 51, 2234].
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stikov, V. M. Dembitsky, Heteroat. Chem., 2004, 15, 486.
14. Yu. V. Shklyaev, M. A. El´tsov, O. A. Maiorova, Zh. Org.
Khim., 2008, 44, 1343 [Russ. J. Org. Chem. (Engl. Transl.),
2008, 44, 1343].
We thank P. A. Slepukhin (I. Ya. Postovsky Institute
of Organic Synthesis, Ural Branch of the Russian Acadeꢀ
Received June 31, 2009;
in revised form March 10, 2010