Spirocyclohexadienones 5. Synthesis of 2-R-7a-methyl-3-(spirocyclohexa-2,5-dien-4-one)perhydro-1-indolines

Article abstract of DOI:10.1023/A:1015888706390

2-R-7a-Methyl-3-(spirocyclohexa-2,5-dien-4-one)perhydro-1-indolines were obtained by the reactions of 1-(4-ethoxyphenyl)-2-methylcyclohexanol with nitriles (RCN) in dichloromethane in the presence of concentrated sulfuric acid.

Full text of DOI:10.1023/A:1015888706390

Russian Chemical Bulletin, International Edition, Vol. 51, No. 4, pp. 709—711, April, 2002
709
Brief Communications
Spirocyclohexadienones
5*. Synthesis of 2ꢀRꢀ7aꢀmethylꢀ
3ꢀ(spirocyclohexaꢀ2,5ꢀdienꢀ4ꢀone)perhydroꢀ1ꢀindolines
V. A. Glushkov,ꢀ O. G. Ausheva, and Yu. V. Shklyaev
Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
13 ul. Lenina, 614600 Perm´, Russian Federation.
Fax: +7 (342 2) 12 6237. Eꢀmail: cheminst@mpm.ru
2ꢀRꢀ7aꢀMethylꢀ3ꢀ(spirocyclohexaꢀ2,5ꢀdienꢀ4ꢀone)perhydroꢀ1ꢀindolines were obtained by
the reactions of 1ꢀ(4ꢀethoxyphenyl)ꢀ2ꢀmethylcyclohexanol with nitriles (RCN) in dichloroꢀ
methane in the presence of concentrated sulfuric acid.
Key words: spiro compounds, indole, cyclohexaꢀ2,5ꢀdienꢀ1ꢀone, nitriles, the Ritter
reaction.
Indole derivatives can be obtained in a variety of
ways,2 whereas the number of synthetic methods for the
construction of a perhydroindole system is limited.3—6
Earlier,1 we have proposed a synthetic route to spiroꢀ
pyrrolines, namely, 1ꢀsubstituted 3,3ꢀdimethylꢀ2ꢀazaꢀ
spiro[4.5]decaꢀ1,6,9ꢀtrienꢀ8ꢀones. The method is based
on the Ritter condensation of 2,2ꢀdialkylꢀ1ꢀ(4ꢀmethoxyꢀ
phenyl)ethanols with nitriles. In the present work, the
Ritter reaction was used to obtain 2ꢀRꢀ7aꢀmethylꢀ
3ꢀ(spirocyclohexaꢀ2,5ꢀdienꢀ4ꢀone)perhydroꢀ1ꢀindolines
3a—c from 1ꢀ(4ꢀethoxyphenyl)ꢀ2ꢀmethylcyclohexanol
(1) and nitriles RCN 2a—c (Scheme 1). During the conꢀ
densation, alcohol 1 undergoes dehydration to give a
tertiary benzyl carbocation A, which is in equilibrium
with tertiary carbocation B. Being more reactive, the
latter interacts with a nitrile to form a nitrilium ion C.
An intramolecular ipsoꢀattack in the nitrilium ion C is a
key stage of the synthesis, which affords the target
perhydroindolines 3a—c. Thus, the method affords
2ꢀRꢀ7aꢀmethylperhydroꢀ1ꢀindolines spiroꢀfused through
the C(3) atom with cyclohexaꢀ2,5ꢀdienꢀ1ꢀone.
The structures of compounds 3a—c were confirmed
1
by elemental analysis data and IR, H and 13C NMR,
and mass spectra. Correlation of 13C chemical shifts for
compounds 3b,c was performed using twoꢀdimensional
1H—13C NMR spectroscopy.
The IR spectra of compounds 3a—c show absorption
bands from the cyclohexadienone ring at 1660—1665
(C=O) and 1600—1625 cm–1 (C=C); the bands from the
indoline C=N bond (for 3a,b) appear at 1575—1600 cm–1
.
The 13C NMR spectra of compounds 3a,b contain a
signal from the spiro C atom at δ 72—77 (δ 57 for 3c).
* For Part 4, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 654—656, April, 2002.
1066ꢀ5285/02/5104ꢀ709 $27.00 © 2002 Plenum Publishing Corporation

710
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 4, April, 2002
Glushkov et al.
Scheme 1
2, 3: R = SMe (a); Ph (b); CH2CO2Et (c)
According to the 1H NMR data, compounds 3a—c
were isolated as a racemic mixture of diastereomers
(3aRS, 7aRS)ꢀ3 with cisꢀjuncture of the rings.
of 4ꢀethoxyphenylmagnesium bromide with 2ꢀmethylcycloꢀ
hexanone in ether in 53% yield, b.p. 155—165 °C (7 Torr)) and
MeSCN (3.44 mL, 0.05 mol) in 40 mL of CH2Cl2 was added
dropwise at ∼15 °C to vigorously stirred 96% H2SO4 (12 mL,
0.22 mol). The reaction mixture was stirred for 40 min and
poured into a mixture of ice (300 mL) and 20% aqueous amꢀ
monia (pH ∼8) (45 mL). The aqueous layer was separated, and
the organic material was extracted with CH2Cl2 (3×30 mL).
The combined organic layers were washed with water and dried
over MgSO4. The solvent was removed, and the residue was
treated with hexane. The precipitate that formed was recrystalꢀ
lized from hexane. Yield 4.42 g (34%), m.p. 86—88 °C. Rf 0.46
(a gray spot with a light blueꢀgreen contour). Found (%):
C, 68.89; H, 7.30; N, 5.18. C15H19NOS. Calculated (%):
C, 68.93; H, 7.33; N, 5.36. IR, ν/cm–1: 1665 (C=O); 1625
(C=C); 1575 (C=N); 1270, 1245, 1220 (w); 1200, 1180, 1140,
1H NMR spectrum of compound 3c, as distinct from
the spectra of other products, contains signals from the
olefin proton at δ 4.01 and from the NH group at δ 8.32,
which suggests its enamino form stabilized by an inꢀ
tramolecular hydrogen bond, as was earlier determined
for structurally close 1ꢀethoxycarbonylmethylideneꢀ(Z)ꢀ
3,3ꢀdimethylꢀ2ꢀazaspiro[4.5]decaꢀ6,9ꢀdienꢀ8ꢀone.7 Such
a structure of compound 3c is also confirmed by its IR
spectrum, in which the absorption band from the esꢀ
ter group is shifted toward the lowꢀfrequency range
(1640 cm–1). Because of this, compounds 3a—c follow
different fragmentation pathways in mass spectra. Thus,
indolines 3a,b easily lose the original nitrile under elecꢀ
tron impact, while the decomposition of compound 3c
includes gradual detachment of the ethoxycarbonyl group
and breaking of the cyclohexane ring (see Experimental).
1
1110, 1045, 920, 905, 890, 860. H NMR (DMSOꢀd6), δ: 1.20
(m, 2 H, CH2); 1.26 (m, 2 H, CH2); 1.35 (s, 3 H, Me); 1.38
(m, 1 H, CH); 1.55 (m, 1 H, CH); 1.65 (m, 1 H, CH); 1.88 (m,
1 H, CH); 2.34 (s, 3 H, SMe); 2.47 (d, 1 H, CH, J = 7 Hz);
3
4
6.27 (dd, 1 H, C(3´)H, J = 10 Hz, J = 2 Hz); 6.32 (dd, 1 H,
C(5´)H, 3J = 10 Hz, 4J = 2 Hz); 6.85 (dd, 1 H, C(2´)H, 3J =
10 Hz, 4J = 2 Hz); 7.40 (dd, 1 H, C(6´)H, 3J = 10 Hz, 4J =
2 Hz). 13C NMR (DMSOꢀd6), δ: 184.36 (C=O); 166.45 (C=N);
150.82 and 147.50 (C(2´) and C(6´), respectively), 129.50 and
129.21 (C(5´) and C(3´), respectively); 73.18 (C(3)); 65.23
(C(7a)); 53.62 (C(3a)); 36.47 (Me); 27.12, 21.80, 21.21, and
20.99 (C(7), C(4), C(5), and C(6)); 12.95 (SMe). MS (EI,
70 eV), m/z (Irel (%)): 261 [M]+ (7), 188 [M – MeSCN]+
(100), 173 (10), 159 (12), 145 (17), 131 (19), 121 (32), 107
(18), 91 (30).
Experimental
IR spectra were recorded on a URꢀ20 instrument (suspenꢀ
1
sions in Vaseline oil). H and 13C NMR spectra were recorded
on a Bruker DRX 500 instrument (500 and 125.76 MHz) with
HMDS and CDCl3 as the internal standards, respectively. The
mass spectra of compounds 3a—c were taken on a Finnigan
MAT instrument (EI, 70 eV). The course of the reactions was
monitored and the purity of the products was checked by TLC
on Silufol plates in toluene — AcOEt (1 : 1), spots were visualꢀ
ized with a 3% solution of chloranil in toluene with heating the
plates to 70 °C (the spot color was recognized immediately
during the heating). Methylene chloride (Lancaster Co., Great
Britain) was used.
7aꢀMethylꢀ2ꢀphenylspiro[3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀinꢀ
doleꢀ3,4´ꢀcyclohexaꢀ2´,5´ꢀdien]ꢀ1´ꢀone (3b) was obtained
analogously from alcohol 1 (11.7 g, 0.05 mol) and PhCN (5.15 g,
0.05 mol). The solvent was removed, and the residue was treated
with a small amount of cold MeOH and crystallized from
MeOH. Yield 2.34 g (16%), m.p. 165—166 °C. Rf 0.58 (a green
spot). Found (%): C, 82.40; H, 7.25; N, 4.62. C20H21NO.
Calculated (%): C, 82.44; H, 7.26; N, 4.81. IR, ν/cm–1: 1665
(C=O); 1625 (C=C); 1600 (C=N); 1320, 1270 (w), 1260,
7aꢀMethylꢀ2ꢀmethylthiospiro[3a,4,5,6,7,7aꢀhexahydroꢀ1Hꢀ
indoleꢀ3,4´ꢀcyclohexaꢀ2´,5´ꢀdien]ꢀ1´ꢀone (3a). A solution of
8
alcohol 1 (11.7 g, 0.05 mol) (obtained by the reaction

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 4, April, 2002
711
1240 (w), 1220, 1190, 1175, 1140, 1010, 915, 890, 860. 1H NMR
(DMSOꢀd6), δ: 1.25 (m, 2 H, CH2); 1.37 (m, 2 H, CH2); 1.48
(m, 1 H, CH); 1.50 (s, 3 H, Me); 1.56 (m, 1 H, CH); 1.68 (m,
1 H, CH); 1.95 (m, 1 H, CH); 2.45 (d, 1 H, CH, J = 7 Hz);
20.57 (C(7), C(4), C(5), and C(6)); 14.39 (CH2Me). MS (EI,
70 eV), m/z (Irel (%)): 301 [M]+ (97), 286 [M – Me]+ (22), 255
[M – EtOH]+ (32), 244 [M – C4H9]+ (86), 240 [M – Me –
OEt – H]+ (72), 228 [M – CO2Et]+ (28), 216 [M – CHCO2Et]+
(100), 212 (40), 200 (25), 184 (28), 170 (88), 144 (43), 132
(31), 117 (48), 107 (61), 91 (68).
4
6.32 (dd, 1 H, C(3´)H, 3J = 10 Hz, J = 2 Hz); 6.36 (dd, 1 H,
C(5´)H, 3J = 10 Hz, 4J = 2 Hz); 7.00 (dd, 1 H, C(2´)H, 3J =
4
10 Hz, J = 2 Hz); 7.33 (m, 3 H, Harom); 7.65 (m, 2 H, Harom);
7.40 (dd, 1 H, C(6´)H, 3J = 10 Hz, 4J = 2 Hz). 13C NMR
(DMSOꢀd6), δ: 184.18 (C=O); 165.08 (C=N); 152.88 and
149.10 (C(2´) and C(6´), respectively), 129.46 and 128.27 (C(3´)
and C(5´), respectively); 133.89, 130.36, 128.12, 127.14 (Ph);
72.18 (C(3)); 63.97 (C(7a)); 53.44 (C(3a)); 36.37 (Me); 26.93,
21.98, 21.28, and 20.46 (C(7), C(4), C(5), and C(6)). MS (EI,
70 eV), m/z (Irel (%)): 291 [M]+ (1), 189 [M + H – C6H5CN]+
(14), 188 [M – C6H5CN]+ (100), 173 (12), 159 (18), 152 (18),
146 (19), 131 (22), 121 (44), 107 (52), 91 (35).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
96479).
References
1. V. A. Glushkov, O. G. Ausheva, S. N. Shurov, and Yu. V.
Shklyaev, Izv. Akad. Nauk, Ser. Khim., 2001, 1571 [Russ.
Chem. Bull. Int. Ed., 2001, 50, 1648 (Engl. Transl.)].
2. R. T. Brown and G. A. Jouli, in Comprehensive Organic Chemꢀ
istry, Eds. D. Barton and W. D. Ollis, V. 4: Heterocyclic
Compounds, Ed. P. G. Sammes, Pergamon Press, Oxꢀ
ford—New York—Toronto—Sydney—Paris—Frankfurt, 1978.
3. B. A. Trofimov and A. I. Mikhaleva, NꢀVinilpirroly
[NꢀVinylpyrroles], Nauka, Novosibirsk, 1984, 260 pp. (in
Russian).
4. B. F. Kukharev, V. K. Stankevich, and V. A. Kukhareva,
Abstrs., I Vsesoyuznaya konferentsiya po "Khimii, biokhimii i
farmakologii proizvodnykh indola" [I AllꢀUnion Conf. on "The
Chemistry, Biochemistry, and Pharmacology of Indole Derivaꢀ
tives"], Tbilisi, 1986, 89 (in Russian).
5. D. Bland, G. Chambournier, V. Dragan, and D. J. Hart,
Tetrahedron, 1999, 55, 8953.
6. A. Padwa, M. A. Brodney, K. Satake, and C. S. Straub,
J. Org. Chem., 1999, 64, 4617.
7. V. A. Glushkov, O. G. Ausheva, S. N. Shurov, and Yu. V.
Shklyaev, Izv. Akad. Nauk, Ser. Khim., 2002, 822 [Russ.
Chem. Bull., Int. Ed., 2002, 51, No. 5].
2ꢀEthoxycarbonylmethylideneꢀZꢀ7aꢀmethylspiro[perhydroꢀ
indoleꢀ3,4´ꢀcyclohexaꢀ2´,5´ꢀdien]ꢀ1´ꢀone (3c) was obtained
analogously from alcohol
1 (11.7 g, 0.05 mol) and
CNCH2CO2Et (5.65 g, 0.05 mol). The solvent was removed,
and the residue was crystallized from EtOH. Yield 3.53 g (25%),
m.p. 177—179 °C. Rf 0.62 (a gray spot with a green contour).
Found (%): C, 71.68; H, 7.65; N, 4.52. C18H23NO3. Calcuꢀ
lated (%): C, 71.73; H, 7.69; N, 4.65. IR, ν/cm–1: 3340 (NH);
1660 (C=O); 1640 (O—C=O); 1600 (br, C=C and C=N);
1275 (w); 1260 (w); 1235, 1215 (w); 1195 (w); 1145, 1075,
1060, 1015, 925, 910, 865. 1H NMR (DMSOꢀd6), δ: 1.16 (t,
3 H, CH2Me, J = 7 Hz); 1.25 (m, 2 H, CH2); 1.32 (m, 1 H,
CH); 1.43 (s, 3 H, Me); 1.45 (m, 1 H, CH); 1.60 (m, 2 H,
CH2); 1.67 (m, 1 H, CH); 1.92 (m, 1 H, CH); 2.38 (d, 1 H,
CH, J = 7 Hz); 3.97 (t, 2 H, OCH2, J = 7 Hz); 4.01 (s, 1 H,
CH=); 6.17 (dd, 1 H, C(3´)H, 3J = 10 Hz, 4J = 2 Hz); 6.25
(dd, 1 H, C(5´)H, 3J = 10 Hz, 4J = 2 Hz); 6.80 (dd, 1 H,
C(2´)H, 3J = 10 Hz, 4J = 2 Hz); 7.20 (dd, 1 H, C(6´)H, 3J =
4
10 Hz, J = 2 Hz); 8.32 (s, 1 H, NH). 13C NMR (DMSOꢀd6),
δ: 184.39 (C=O); 168.44* (C(O)—O); 160.60* (=C—N); 151.13
(C(2´)) and 148.37 (C(6´)), 128.84 (C(5´)) and 127.48 (C(3´));
77.08 (=CHC(O)); 61.31 (C(7a)); 57.60* (C(3)), 57.24*
(OCH2); 49.35 (C(3a)); 37.19 (Me); 26.12, 21.57, 21.50, and
8. H. Bergs, Ber. Deutsch. Chem. Ges., 1934, 67, 238.
Received June 28, 2001;
* Assignments of the signals may have to be interchanged.
in revised form December 17, 2001