Spirocyclohexadienones 4. Synthesis and dienone-phenolic rearrangement of 1-r-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones

Article abstract of DOI:10.1023/A:1013051005590

The reactions of 1-(p-methoxyphenyl)-2-methylpropan-1-ol or α-cyclohexyl-p-methoxybenzyl alcohol with nitriles RCN in concentrated sulfuric acid afforded 1-R-3.3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones. The stability of the latter toward the dienone-phenolic rearrangement depends on the nature of the substituent R. The reaction mechanism was studied by the semiempirical quantum-chemical AMI method.

Full text of DOI:10.1023/A:1013051005590

1648
Russian Chemical Bulletin, International Edition, Vol. 50, No. 9, pp. 1648—1656, September, 2001
Spirocyclohexadienones
4.* Synthesis and dienone-phenolic rearrangement of
1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-trien-8-ones
O. G. Ausheva,a V. A. Glushkov,a« S. N. Shurov,b and Yu. V. Shklyaeva
aInstitute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences,
13 ul. Lenina, 614600 Perm, Russian Federation.
Fax: +7 (342 2) 12 6237. Å-mail: cheminst@mpm.ru
bDepartment of Chemistry, Perm State University,
15 ul. Bukireva, 614600 Perm, Russian Federation.
Fax: +7 (342 2) 39 6367. E-mail: info@psu.ru
The reactions of 1-(p-methoxyphenyl)-2-methylpropan-1-ol or α-cyclohexyl-p-methoxy-
benzyl alcohol with nitriles RCN in concentrated sulfuric acid afforded 1-R-3,3-dialkyl-2-aza-
spiro[4.5]deca-1,6,9-trien-8-ones. The stability of the latter toward the dienone-phenolic
rearrangement depends on the nature of the substituent R. The reaction mechanism was
studied by the semiempirical quantum-chemical AM1 method.
Key words: secondary alcohols, nitriles, Ritter reaction, cyclohexa-2,5-dien-4-one,
1-pyrrolines, spiro compounds, dienone-phenolic rearrangement, amides of carboxylic acids,
semiempirical quantum-chemical AM1 calculations.
Scheme 1
Heterocyclic systems spiro-fused at position 4 of
cyclohexa-2,5-dien-1-one occur in nature2,3 and serve
as intermediates in the synthesis of alkaloids of the
Amaryllidaceae family.4 Procedures were developed for
the synthesis of cyclohexa-2,5-dienospirolactams,5
-spiroisoxazolines,6 and -spirobenzofurans.7
Me
Me
ipso-
attack
X = OMe
X
O
Me
N
+
Me
N
C
R
R
Spiro derivatives of cyclohexa-2,5-dien-1-ones have
been described in the last few years.8,9 These com-
pounds were synthesized by intramolecular cyclization
catalyzed by Lewis acids through the electrophilic
ipso-attack on para-substituted anisoles. Recently, we
have developed a procedure for the synthesis of hetero-
cyclic spirocyclohexadienones, viz., 1-R-3,3-dimethyl-
2-azaspiro[4.5]deca-1,6,9-trien-8-ones, based on the
Ritter reaction.10 Possible ways of stabilizing the key
product of the Ritter reaction, viz., the nitrilium cation,
are shown in Scheme 1.
ortho-
attack
+H2O
(80% H2SO4)
(98% H2SO4)
X = H
H3O+
Me
Me
X
Me
N
Me
NHC(O)R
R
X = H, OH
Depending on the nature of the substituent in the
aromatic nucleus and on the concentration of the acid
used (in our case, H2SO4), the Ritter reaction can take
three pathways. Previously, it has been established that
if X = H, the reaction performed in 98% sulfuric acid
proceeded as the ortho-attack to form 3,4-dihydro-
isoquinolines;11,12 however, lowering of the H2SO4 con-
centration to 80% resulted in the nucleophilic attack of
water on the nitrilium cation to yield amides, which are
products of the normal Ritter reaction.13,14 The peculiar
reaction pathway was observed in the case of X = OMe:
the nitrilium cation was stabilized through the ipso-attack
to form 1-R-3,3-dimethyl-2-azaspiro[4.5]deca-1,6,9-
trien-8-ones.10 Analogous spiro compounds have been
postulated previously as intermediates in the synthesis of
methoxy-substituted isoquinolines;15,16 however, these
compounds have not been isolated. Intermediates with
the spiropyrroline structure can either be stabilized
through the 1,2-shift to generate 3,4-dihydroiso-
quinolines16 or undergo the dienone-phenolic rearrange-
ment to p-hydroxyphenylethylamides. In the present
study, we synthesized spiroheterocyclic compounds
3a—d, which were then subjected to the dienone-phe-
nolic rearrangement in an acidic medium to obtain
amides 4a—c,e—j. The synthesis of spiranes 3a—f is
detailed in Scheme 2.
* For Part 3, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1571—1579, September, 2001.
1066-5285/01/5009-1648 $25.00 ©ꢀ2001 Plenum Publishing Corporation

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001 1649
Scheme 2
R1
R1
+
MeO
CH CHMe2
1
2
MeO
CHOH
C1
1a,b
H+
–H3O+
H+
H+
c
Me
Me
+
+
CR1
MeO
CH2
MeO
CH
MeO
CH CHMe2
2
H+
1
2
N
Ph
I1
C2
R2CN
2a—f
+
CR1
MeO
CH2
MeO
CH CHMe2
2
R2
N
+N
Ph
I2
C3
3
2
Me
Me
CHMe2
b
4
1
CR1
CH2
+
+
MeO
2
N
N
+N
R2
5
6
MeO
MeO
H
H
Ph
Ph
I3
C4
B
–H+
–H+
a
CHMe2
R1
R1
Me
Me
+
MeO
N
N
N
MeO
MeO
A1
Ph
R2
Ph
5
6
H2O H+
R1 R1
NH
R1
R1
R1
7
6
4
R2
O
3
MeO
HO
H+
8
5
R1
O
2
HO
–MeOH
N
N
9
10
1
R2
R2
A2
3a—j
4a—c,e—j
Com-
pound
R1 or R1
Com-
pound
R2
Compound
3, 4:
R1 or R1
R2
2
2
1a
1b
Me
(CH2)5
2a
2b
2c
2d
2e
2f
SMe
SBn
3a, 4a
3b, 4b
3c, 4c
3d
3e, 4e
3f, 4f
3g, 4g
3h, 4h
3i, 4i
Me
Me
SMe
SBn
SMe
SBn
CH2CO2Et
Ph
Bn
(CH2)5
(CH2)5
Me
CH2CO2Et
Ph
CH2Cl
Me
(CH2)5
(CH2)5
(CH2)5
(CH2)5
CH2CO2Et
Ph
Bn
3j, 4j
CH2Cl
Note: only for I2—A2: R1 = Me, R2 = Ph.

1650
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001
Ausheva et al.
Table 1. Characteristics and data of elemental analysis of compounds 3, 4, and 7
Com-
pound(%)
YieldM.p./
(solvent
crystallization)
°C
Found
Calculated
Molecular
formula
(%)
for
Ñ
H
N
3a
3b
3c
3d
4a
4b
4c
4e
4f
52
13
14
17
97
27
17
64
58
15
38
29
28
72
95—97 [95—9710
(EtOH—water)
115—116
(ether)
]
65.33 6.74
65.12 6.83
72.58 6.36
72.69 6.44
69.12 7.40
68.93 7.33
74.47 7.08
74.74 6.87
60.19 7.16
60.22 7.16
68.44 6.56
68.54 6.71
64.67 7.49
64.48 7.58
64.75 7.39
64.50 7.58
75.88 7.05
75.81 7.11
67.54 7.85
67.69 7.89
77.77 7.33
77.64 7.49
78.05 7.83
77.98 7.79
64.09 7.17
63.94 7.15
76.52 7.40
76.27 7.47
6.41
6.33
5.15
4.71
5.25
5.36
4.38
4.15
5.77
5.85
4.60
4.44
5.09
5.01
5.18
5.01
5.27
5.20
4.60
4.38
4.50
4.52
4.62
4.33
5.11
4.97
5.16
4.94
C12H15NOS
C18H19NOS
C15H19NOS
C21H23NOS
Ñ12H17NO2S
C18H21NO2S
C15H21NO2S
C15H21NO4
C17H19NO2
C18H25NO4
C20H23NO2
C21H25NO2
C15H20ClNO2
C18H21NO2
104—106
(ether)
140—142
(ether)
139—140
(CH2Cl2—hexane)
131—132
(EtOH—water)
177—178.5
(AcOEt—hexane)
100—102
(toluene—hexane)
141—142
(dichloroethane)
119—121
(toluene)
148—150
(EtOH—water)
158—160
4g
4h
4i
(toluene)
140—141
(CH2Cl2—hexane)
109—110
4j
7
In these reactions, both carbinols 1a,b and
1-(p-methoxyphenyl)-2-methylprop-1-ene, which is gen-
erated from carbinol 1a in the course of the reaction in
the presence of 98% H2SO4, can be used as a source of
carbocations.
As can be seen from Scheme 2, the key stage of the
synthesis of spiropyrrolines 3a—d involves the ipso-attack
on the nitrilium cation at the para position with respect
to the MeO group in intermediate I3. The resulting
compounds 3a—d and 4a—c,e—j are presented in
Table 1. The low yields of spiropyrrolines 3b—d
(13—17%) are, apparently, accounted for by side pro-
cesses involving both the initial carbinols 1a,b and
thiocyanates 2a,b in acidic media.
It should be noted that only spiranes 3a—d with
sulfur-containing substituents can be prepared by these
reactions. Under the reaction conditions, spiropyrrolines
3e—h containing electron-withdrawing substituents at
the C(1) atom (Ph or CH2COOEt) and spiranes 3i,j
were found to undergo the dienone-phenolic rearrange-
ment even upon isolation giving rise to the correspond-
ing amides 4e—j. In this case, the dienone-phenolic
rearrangement can be considered as a peculiar kind of
hydrolysis of spiranes at the C(1)—C(5) bond. Appar-
ently, the fact that spiranes containing electron-with-
drawing groups at the C(1) atom of the pyrroline ring
readily underwent hydrolysis is associated with an in-
crease in the partial positive charge on the C(1) atom,
which promotes the attack of a water molecule
(Scheme 3). Spiranes 3a—c with sulfur-containing sub-
stituents appeared to be more stable toward hydrolysis
due, apparently, to the positive mesomeric effect of the
sulfur atom.
It has been possible to carry out the dienone-phe-
nolic rearrangement of sulfur-containing spiranes 3a,b
by heating their aqueous-ethanolic solutions with 10%
H2SO4. The reactions proceeded smoothly to form the
corresponding amides 4a,b (see the Experimental sec-
tion). Since p-methoxy-substituted amides of type 7 can
be normal products of the Ritter reaction (Scheme 1),
the question arose of whether amides 4a—c,e—j can be
formed by the classical Ritter reaction13,14 accompanied
by acidic elimination of the MeO group in the course of
treatment, i.e., by the direct reaction without intermedi-
ate formation of spiranes 3. According to the published
data, this is not possible;16 however, we carried out
methylation of compound 4f at the hydroxyl group of
the aryl fragment and treated the resulting amide 7 with
concentrated H2SO4 followed by dilution with water
and extraction with toluene, thus simulating the condi-

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001 1651
Scheme 3
R1
R1
R1
R1
R1
R1
H2O
O
O
O
–H+
+
NH
NH
NH
+
R2
R2 OH2
D2a—c
R2 OH
D3a—c
H+
D1a—c
3a—j
R1 R1
R1
R2
R1
+
HO
HO
N
+
OH2
N
R2
E1a—c
E2
H2O
–H+
I1 + 2d
R1 R1
Me Me
NHC(O)Ph
2
6
3
5
R2
O
H+
NaH, MeI
1
4
4f
MeO
HO
NH
4a—c,e—j
7
Only for D1—D3, E1, and E2: R1 = Me; R2 = Ph (a); R2 = SMe (b); R2 = CH2CO2Et (c).
tions of isolation of amides 4. The starting amide 7,
which was identified based on the TLC data, the melt-
ing point, and the IR spectrum, was regenerated in 73%
yield. Hence, the cleavage of the p-methoxy group by
acid hydrolysis in H2SO4 did not occur. We attempted
to direct the Ritter reaction toward the classical forma-
tion of amides of type 7 (see Scheme 1) by performing
the reaction in 90% or 70% H2SO4. However, the
reactions afforded exclusively p-hydroxyamides 4, i.e.,
elimination of the p-methoxy group from the aromatic
ring occurred through the formation of spiranes 3 fol-
lowed by their subsequent decomposition. In our opin-
ion, the results of the experiments provided support for
the conclusion that p-hydroxyamides 4 were formed
exclusively via spiranes 3 and their dienone-phenolic
rearrangement (Scheme 3).
The characteristics of spiranes 3a—d and amides
4a—c,e—j and 7 are given in Table 1. Their structures
were confirmed by the results of elemental analysis, the
IR and 1H NMR spectral data (Table 2), and by the
13C NMR and mass spectra (Tables 3 and 4).
The IR spectra of spiranes 3a—d in Nujol mulls have
strong absorption bands of the cyclohexadienyl fragment
at 1660—1700 (C=O) and 1620—1660 cm–1 (C=C) and
dilute solutions of compounds 4b,h in CCl4, this band is
observed at 3612 cm–1, which indicates that the OH
groups in the crystals are involved in intermolecular
association. In the spectra of solutions in CCl4, the NH
–1
stretching vibrations are observed at 3430—3445 cm
.
The spectra of amides 4a—c,e—j have also bands at
–1
1605—1615 cm (C=C of the aromatic ring). The IR
spectrum of amide 7 shows also asymmetric and sym-
metric stretching vibration bands of the C—O—CH3
bond at 1250 and 1070 cm–1, respectively.
The distinguishing feature of the 1H NMR spectra of
spiranes 3a—d is the presence of doublets of the H(7)
and H(9) protons of the cyclohexadiene ring at
δ 6.17—6.23. The NMR spectra of amides 4a—c,e—j
have doublets of the corresponding H(2) and H(6)
protons at δ 6.57—6.70. In the 1H NMR spectra, amides
4c,g—j containing the cyclohexane ring give, in addi-
tion to multiplets of the CH2 groups at δ 1.15—1.65, a
characteristic signal at δ 2.00—2.25. The latter can be
assigned to two protons of the CH2 groups, which are
adjacent to the quaternary carbon atom and experi-
ence the anisotropic influence of the amide carbonyl
group.
The 13C NMR spectra measured with complete sup-
pression of spin-spin 1H—13C coupling also confirmed
the structures of compounds 3 (Table 3) and 4 (Table 4).
The atomic numbering schemes for spiranes 3 and
amides 4 are shown in Schemes 2 and 3, respectively.
The 13C NMR spectra of compounds 3a,b,d have
a characteristic signal of the C(5) spiro-atom at
δ 74.4—77.8, which is absent in the spectra of com-
pounds 4c,f—h. The signals of the carbonyl groups
in the spectra of ketones 3a,b,d are observed at
–1
medium intensity bands at 1585—1620 cm
(the shoulder at 1630 cm
(C=N)
–1
in the spectrum of com-
pound 3b). The IR spectra of amides 4a—c,e—j have
–1
signals at 1620—1660 cm (C=O) along with a narrow
band at 3350—3405 cm–1 (NH) and a broad band of the
OH groups, which occur in the associated form in the
crystalline state, with the absorption maximum at
3150—3330 cm–1. The latter band is absent in the
spectrum of methoxy derivative 7. In the spectra of

1652
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001
Ausheva et al.
Table 2. IRa and 1H NMR spectra of spiranes 3a—d and amides 4a—c,e—j and 7
Com-
pound
IR,
ν/cm
1H NMR, δ (J/Hz)
–1
3a
3b
1700 (Ñ=Î), 1660 (Ñ=Ñ),
1620 (Ñ=N)
1660 (C=O),
1.43 (s, 6 H, 2 Ìå); 2.23 (s, 2 H, Ñ(4)H2); 2.38 (s, 3 H, SMe); 6.22
(d, 2 H, H(7), H(9), J = 10.0); 6.75 (d, 2 H, H(6), H(10), J = 10.0)
1.41 (s, 6 H, 2 Me); 2.21 (s, 2 H, C(4)H2); 4.19 (s, 2 H, SCH2); 6.17
(d, 2 H, H(7), H(9), J = 10.0); 6.81 (d, 2 H, H(6), H(10), J = 10.0);
7.20—7.35 (m, 5 H, Ph)
1630 (C=N and Ñ=Ñ)
3c
3d
1660 (C=O), 1620 (C=C),
1585 (C=N)
1660 (C=O), 1620 (C=C),
1585 (C=N)
1.34—1.83 (m, 10 H, (ÑH2)5); 2.19 (s, 2 H, Ñ(4)H2); 2.35 (s, 3 H, SMe);
6.23 (d, 2 H, H(7), H(9), J = 10.1); 6.92 (d, 2 H, H(6), H(10), J = 10.1)
1.40—1.85 (m, 10 H, (ÑH2)5); 2.20 (s, 2 H, Ñ(4)H2); 4.22 (s, 2 H, SCH2);
6.21 (d, 2 H, H(7), H(9), J = 10.0); 6.89 (d, 2 H, H(6), H(10), J = 10.0);
7.20—7.40 (m, 5 H, H arom.)
4a
4b
4c
4e
4f
3400 (NH), 3220 (OH),
1650 (C=O), 1610
1.24 (s, 6 H, 2 Me); 2.27 (s, 3 H, SMe); 2.85 (s, 2 H, CH2Ar); 5.46
(br.s, 1 H, NH); 6.70 (d, 2 H, H(2), H(6), J = 9.2); 6.92
(d, 2 H, H(3), H(5), J = 9.2); 8.62 (s, 1 H, OH)
1.20 (s, 6 H, 2 Me); 2.83 (s, 2 H, CH2Ar); 4.04 (s, 2 H, SCH2); 6.57
(d, 2 H, H(2), H(6), J = 9.3); 6.82 (d, 2 H, H(3), H(5), J = 9.3);
7.20—7.40 (m, 6 H, Ph + NH); 8.88 (s, 1 H, OH)
1.20—1.60 (m, 10 H), 1.95 and 2.05 (both s, 1 H each, (ÑH2)5); 2.22
(s, 3 H, SMe); 2.80 (s, 2 H, CH2Ar); 6.62 (d, 2 H, H(2), H(6), J = 9.0);
6.84 (d, 2 H, H(3), H(5), J = 9.0); 6.98 (br.s, 1 H, NH); 8.85 (br.s, 1 H, OH)
1.20 (s, 6 H, 2 Me); 1.27 (t, 3 H, Me, J = 7.0); 2.85 (s, 2 H, CH2Ar); 3.13
(s, 2 H, CH2CO); 4.13 (ê, 2 H, OCH2, J = 7.0); 6.62 (d, 2 H, H(2), H(6),
J = 9.0); 6.90 (d, 2 H, H(3), H(5), J = 9.0); 7.29 (s, 1 H, NH); 8.87 (s, 1 H, OH)
1.34 (s, 6 H, 2 Me); 3.00 (s, 2 H, CH2Ar); 6.60 (d, 2 H, H(2), H(6));
6.92 (d, 2 H, H(3), H(5), J = 10.0); 7.38—7.48 (m, 5 H, Ph); 7.73
(s, 1 H, NH); 8.84 (s, 1 H, OH)
3400 (NH), 3320 (OH),
1660 (C=O), 1605
3370 (NH), 3330 (OH),
1650 (C=O), 1610
3390 (NH), 3240 (OH),
1735 (O—C=O),
1640 (C=O), 1615
3405 (NH), 3385 (OH),
3190 (br., NH),
1630 (Ñ=O), 1610
4g
3350 (NH), 3150 (br., OH), 1.16—1.55 (m, 8 H), 1.95 and 2.05 (both s, 1 H each, (ÑH2)5); 1.28
1720 (O—C=O),
1660 (C=O), 1610
(t, 3 H, Me, J = 7.6); 2.80 (s, 2 H, CH2Ar); 3.18 (s, 2 H, CH2CO);
4.11 (q, 2 H, OCH2, J = 7.6); 6.60 (d, 2 H, H(2), H(6), J = 9.8);
6.88 (d, 2 H, H(3), H(5), J = 9.8); 7.00 (s, 1 H, NH); 8.80 (s, 1 H, OH)
4h
4i
4j
7
3365 (NH), 3170 (br., OH), 1.25—1.65 (m, 8 H), 2.20 and 2.25 (both s, 1 H each, (ÑH2)5); 2.98
1620 (Ñ=O), 1610
(s, 2 H, ÑH2Ar); 6.59 (d, 2 H, H(2), H(6), J = 10.1); 6.88 (d, 2 H, H(3), H(5),
J = 10.1); 6.96 (s, 1 H, NH); 7.35—7.50 (m, 5 H, Ph); 8.85 (s, 1 H, OH)
1.15—2.00 (m, 10 H, (CH2)5); 2.80 (s, 2 H, ÑH2Ar); 3.39 (s, 2 H, ÑH2Ph);
6.57 (d, 2 H, H(2), H(6), J = 10.0); 6.73 (d, 2 H, H(3), H(5), J = 10.0);
6.83 (s, 1 H, NH); 7.19—7.30 (m, 5 H, Ph); 8.83 (s, 1 H, OH)
3400 (NH), 3160 (OH),
1635 (C=O), 1610
3400 (NH), 3170 (br., OH), 1.15—2.02 (m, 10 H, (ÑH2)5); 2.83 (s, 2 H, CH2Ar); 3.93 (s, 2 H, CH2Cl);
1650 (C=O), 1610
6.62 (d, 2 H, H(2), H(6), J = 10.1); 6.85 (d, 2 H, H(3), H(5), J = 10.1);
7.10 (s, 1 H, NH); 8.87 (s, 1 H, OH)
3350 (NH), 1630 (C=O),
1605, 1575
1.37 (s, 6 H, 2 Me); 3.05 (s, 2 H, CH2); 3.75 (s, 3 H, OMe); 6.75
(d, 2 H, H(3), H(5), J = 10.0); 7.05 (m, 2 H, H arom.); 7.38 (s, 1 H, NH);
7.43 (m, 3 H, H arom.); 7.74 (d, 2 H, H(2), H(6), J = 10.0)
a For suspensions in Nujol mulls.
δ 183.9—184.3, whereas these signals in the spectra of
amides 4c,f—h are observed at δ 164.8—167.1. In addi-
tion, the spectra of the spiranes have signals of the C(1)
atom at the C=N bond at low field (δ 164.3—165.7).
The quaternary carbon atom adjacent to the nitrogen
atom gives a signal at δ 53.5—62.0, this signal in the
spectra of the spiranes being shifted downfield by
3—7 ppm. The same is true for the methyl groups at this
carbon atom (signals at δ 26.7—30.8). The penta-
methylene ring is manifested as three signals at
δ 21.0—23.0, 25.3—26.0, and 33.8—34.6. The 13C NMR
spectra of amides 4e,g containing the ethoxycarbo-
nyl groups have additional low-intensity signals at
δ 160.0—160.1, which are apparently attributable to one
of the rotational conformers with respect to the amide
C—N bond. The 13C NMR spectra of compounds 3 and
4 show also signals characteristic of the cyclohexadiene
ring (3a,b,d) and the p-hydroxy-substituted aromatic
ring (4c,e,f—h) as well as of the functional groups R2
(see Tables 3 and 4, respectively).
The structures of compounds 3 and 4 were con-
firmed by the mass spectra (see Tables 3 and 4, respec-
tively) although the fragmentation paths for spiranes 3
and amides 4 are somewhat different. All spectra have
low-intensity molecular ions peaks, which are in agree-
ment with the calculated values. Fragmentation of
spiranes 3a,b,d under the action of electron impact
occurred predominantly with the cleavage of the

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001 1653
Table 3. 13C NMR spectra (δ) and mass spectra of compounds 3a,b,d
Com-
pound
Ñ(5) C(6), C(10) C(7), C(9)
C(8)
C(1) C(4) C(3)
R1
R2
MS, m/z
(Irel (%))
3a
3b
3d
74.5
74.4
77.8
150.6
150.0
150.6
128.4
128.3
128.3
184.3
165.7 48.2
164.4 47.8
164.3 45.8
62.9
61.8
30.8
13.7 (SMe)
221 [M]+ (2), 149 (16),
148 (100), 133 (75),
107 (19), 106 (26),
105 (25)
184.0
184.1
30.5
137.1, 28.7,
128.2, 127.0 (Ph); 148 (24), 133 (14),
297 [M]+ (9), 197 (28),
34.5 (SCH2)
105 (10), 100 (12),
91 (100)
337 [M]+ (2), 197 (11),
188 (28), 107 (40),
91 (100), 81 (29)
61.0 23.0;
26.0;
137.5, 129.0,
128.8, 128.7,
127.1 (Ph)*
34.6;
* The signal of SCH2 overlaps with the signal of DMSO.
Table 4. 13C NMR spectra (δ) and mass spectra of compounds 4c,e—h
Com-
pound
Ñ(1) Ñ(2), C(6) Ñ(3), C(5)
Ñ(4)
C=O
164.8
CH2 NC(R1)2
R1
R2
MS, m/z
(Irel (%))
4c
155.7
155.6
114.6
114.5
127.6
128.2
131.2
42.8
42.7
57.6
53.5
21.3,
25.3,
34.0;
26.7
11.6 (SMe)
279 [M]+ (32), 172 (100),
144 (25), 129 (18),
107 (28), 75 (13)
4e
131.2
164.8
160.0 (C=O); 279 [M]+ (5), 172 (38),
168.0 (C=O); 148 (14), 107 (7),
60.2 (CH2O); 58 (100)
43.3 (CH2N);
14.0 (Me)
4f
155.7
155.6
114.6
114.5
*128.0*
127.6
131.1
131.2
166.8
164.9
43.0
42.3
53.9
55.8
26.9
136.1;
130.6; 128.4*; 148 (21), 105 (100),
127.3 (Ph)* 77 (22)
269 [M]+ (13), 162 (53),
4g
21.0,
25.3,
33.8;
160.1 (C=O); 319 [M]+ (23), 212 (85),
168.1 (C=O); 188 (25), 107 (23),
60.2 (CH2O); 98 (100)
43.3 (CH2N);
14.0 (Me)
136.5,
130.5,
4h
155.6
114.5
*127.9*
131.2
167.1
42.4
56.2
21.5,
25.5,
34.0;
309 [M]+ (23), 202 (65),
188 (18), 107 (10),
105 (100), 77 (28)
127.4 (Ph)*
* Assignments of the signals may be interchanged.
C(1)—C(5) and N—C(3) bonds and then of the
C(3)—C(4) bond in the pyrroline ring. Compounds 3b,d
are also characterized by the detachment of the benzyl
carbocation (m/z 91).
Under the action of electron impact, fragmentation
of amides 4c,e,g,i,j occurred at the amide C—N bond
with elimination of the p-hydroxybenzyl carbocation
(m/z 107). Compounds 4i,j containing the penta-
methylene ring produced additionally the (1H)- or
(3H)-tetrahydroazepinium cations (m/z 98). Substi-
tuted benzamides 4f,h eliminated the C6H5CO group
(m/z 105). The mass spectra of 4i,j are given in the
Experimental section.
Possible conversion pathways for carbinols 1a,b and
1-(p-methoxyphenyl)-2-methylprop-1-ene and the for-
mation of assumed intermediates I1—I3, A1, A2, B, and
C1—C4 under the reaction conditions via the paths a, b,
and c are presented in Scheme 2. Under the reaction
conditions, alcohol 1a was, evidently, dehydrated to
1-(p-methoxyphenyl)-2-methylprop-1-ene, which added
a proton to give cation I1 of the tert-butyl type. The
reaction of the latter with a molecule of nitrile R2CN
(2a—f) afforded initially ion-dipole complex I2 and
then intermediate I3. The latter underwent intramolecu-
lar cyclization through the electrophilic ipso-attack on
the aromatic ring to form intermediate A1, thus giving
rise to the spiro system. The subsequent stages involved
the addition of water to the C(8) atom and deprotonation.
The structure of compound 3a has been established
previously10 by X-ray diffraction analysis.

1654
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001
Ausheva et al.
Finally, elimination of methanol from neutral interme-
diate A2 afforded spirane 3.
barrier of 26.5 kJ mol–1. Hence, the conversion
I1 + PhCN
I3 is characterized by the lower
With the aim of confirming the proposed scheme,
we simulated particular reaction stages by the semi-
empirical AM1 SCF MO LCAO method17 and calcu-
lated the enthalpies of formation (∆Hf) and the total
energies (Etotal) of the possible intermediates, which can
be involved in the process under consideration. Accord-
ing to the results of our calculations, the C(1) and C(2)
atoms in 1-(p-methoxyphenyl)-2-methylprop-1-ene bear
the charges q = –0.135 and –0.095 a.u., respectively.
The attachment of a proton to the C(1) atom (according
to the Markovnikoff rule) gives rise to cation I1 of the
energy barrier (or the absence of this barrier) of the
forward reaction and the higher energy barrier of the
back reaction, which can provide accumulation of cat-
ions I3 in the reaction mixture. It is also probable that
under the conditions of the real process, the activation
barrier of the reaction I1 + PhCN → I3 decreases,
whereas the barrier of the reaction C1 + PhCN → C3
increases due to specific solvation, which was not taken
into account in calculations of the isolated species.
The possible path of the conversion of a cation of
type C3 (path c, Scheme 2) involves the intramolecular
electrophilic attack of the sp-hybridized carbon atom on
one of the ortho positions of the methoxyphenyl group,
which should give rise to a σ-adduct of type C4 (∆Hf =
934.4 kJ mol–1, Etotal = –3097.5 eV). However, on the
one hand, this species, is characterized by the large ∆Hf
and Etotal values and, hence, its formation requires
substantial expenditure of energy and, on the other
hand, its conversion into the reaction product, viz., into
indole 6, should involve the proton abstraction, which
does not occur in a strongly acidic reaction medium.
Apparently, it is because of these facts that the path c is,
on the whole, unfavorable.
In connection with the fact that cation I3 is the key
intermediate in both the paths a and b, we carried out
calculations of the geometry of I3 and the electron
density distribution. Intermediate I3 appeared to have
the structure of the nitrilium cation formed through the
unoccupied 2p orbital of the carbon atom of carbocation
I1 and the lone electron pair of the nitrogen atom of
nitrile, the hybridizations of the nitrogen and carbon
atoms of the C≡N group in I3 remaining virtually un-
changed compared to those in benzonitrile. The
Me2C—N≡C and N≡C—CPh bond angles are 176.4° and
179.4°, respectively. The N≡C and C—CPh bond lengths
(1.161 and 1.410 Å, respectively) are also similar to
those in the starting nitrile (1.163 and 1.422 Å).
tert-butyl type (∆Hf = 664.3 kJ mol–1, Etotal
=
–1927.1 eV), whereas the attachment of a proton to the
C(2) atom affords cation C1 of the benzyl type (∆Hf =
620.0 kJ mol–1, Etotal = –1927.6 eV). The subsequent
conversions of these cations are described by the
paths a, b, and c (Scheme 2). A comparison of the ∆Hf
and Etotal values demonstrated that benzyl cation C1
should be more stable than substituted tert-butyl cation
I1 and, hence, the formation of the former should be
considered as more favorable. However, we did not
detect products of the conversion of cation C1 (isoindoles
of type 6) (see Scheme 2) in the reaction mixture, i.e.,
the reaction did not actually take the path c.
To account for this fact, we simulated the addition
of benzonitrile (∆Hf = 223.5 kJ mol–1, Etotal
=
–1170.9 eV) to cations I1 and C1 by the reaction
coordinate method. We used the interatomic distances
lC(1)...N and lC(2)...N, respectively, as such a reaction
coordinate. The curves on the ∆Hf—lC(1 or 2)...N coordi-
nates each have two minima. One of them corresponds to
possible ion-dipole complexes I2 (∆Hf = 842.2 kJ mol
,
,
–1
Etotal = –3098.4 eV) and C2 (∆Hf = 813.3 kJ mol
–1
Etotal = –3098.7 eV), respectively, which are responsible
for the character of the approach of the reagents. The
second minimum corresponds to cations I3 (∆Hf
=
798.1 kJ mol–1, Etotal = –3098.9 eV) and C3 (∆Hf =
791.4 kJ mol–1, Etotal = –3099.0 eV), respectively. The
maxima in the curves are assigned to the reaction
The largest positive charge (q = +0.282 a.u.) in
cation I3 is localized on the sp-hybridized carbon
atom. The nitrogen atom bears a negative charge
(q = –0.060 a.u.). The carbon atoms of the aromatic
ring containing the methoxy group, except for the C(4)
atom, are electron-excessive. The charges on the C(1),
C(2), and C(6) atoms of the ring are –0.166, –0.073,
and –0.109 a.u., respectively. It is these reaction centers
that can be subjected to the electrophilic attack by the
sp-hybridized carbon atom (the corresponding inter-
atomic distances are 3.46, 4.33, and 3.41 Å). The attack
on the C(2) atom, which is more remote and bears a
lower negative charge, seems to be the least probable.
transition states I3TS (∆Hf = 887.4 kJ mol–1, Etotal
=
=
–3098.0 eV) and C3TS (∆Hf = 870.0 kJ mol–1, Etotal
–3098.2 eV). The activation barrier of the reaction
I2 → I3, which is determined as the difference between
the ∆Hf values for the activated and the starting ion-
dipole complexes, is 45.6 kJ mol–1; the activation bar-
rier of the reaction C2 → C3 is 56.7 kJ mol–1. However,
if the formation of cations I3 and C3 is reversible, the
activation barriers of the back reactions I3 → I2 and
C3 → C2 are equally important. According to the results
–1
of calculations, these barriers are 89.3 and 78.6 kJ mol
,
respectively. Assuming a supermolecule, whose ∆Hf is
equal to the sum of the enthalpies of formation of the
constituent species, as the starting point of the reaction,
the reaction I1 + PhCN → I3 is activationless to
within the accuracy of the AM1 method, whereas
the reaction C1 + PhCN → C3 has the activation
The attack on the C(1) atom should give rise to cation
–1
A1 with the spiro structure (∆Hf = 869.5 kJ mol
,
Etotal = –3098.2 eV), and the attack on the C(6) atom
should afford cation B (∆Hf = 870.6 kJ mol–1, Etotal
=
–3098.2 eV) whose deprotonation may produce substi-
tuted 3,4-dihydroisoquinoline 5 (in reality, compounds

Spirocyclohexadienones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001 1655
of type 5 were formed in trace amounts and were
detected in the reaction mixtures only by TLC; previ-
ously, it has been established that 3,3-dialkyl-substi-
tuted 3,4-dihydroisoquinolines, regardless of the sub-
stituent in the aromatic portion of the molecule, gave
characteristic bright colors with chloranil, the color of
the spot being dependent on the character of the sub-
stituent at position 1 of isoquinoline18). It follows from
the above-considered data that cations A1 and B have
similar energy characteristics. Simulation of their for-
mation by the reaction coordinate method and localiza-
tion of the corresponding transition states gave similar
activation barriers (99.1 and 101.6 kJ mol–1, respec-
tively). Apparently, the regioselectivity of the process
under study is governed by the low basicity of the
medium in which cation B does not undergo de-
protonation rather than is determined by the energies of
the formation of cations A1 and B.
Subsequent conversions of cation A1 are associated
with the irreversible addition of water to the electron-
deficient C(4) atom (q = +0.317 a.u.) followed by
deprotonation, which gives rise to neutral intermediate
A2, and elimination of methanol. Previously, it has been
demonstrated10 that the stability of spiropyrrolines 3a—f
toward hydrolysis depends on the nature of the substitu-
ent R2. If R2 = SMe (3a,c) or SBn (3b,d), the corre-
sponding compounds are stable under the experimental
conditions and can be isolated. On the contrary, 3,3-di-
methyl-1-R2-2-azaspiro[4.5]deca-1,6,9-trien-8-ones with
R2 = CH2COOEt (3e) or Ph (3f) underwent the dienone-
phenolic rearrangement accompanied by the addition of
water to the C(1) atom and the cleavage of the
C(1)—C(5) bond (Scheme 3). A priori both the neutral
molecule of compound 3 and its O- or N-protonated
form can be involved in the process.
trien-8-ones and studied their dienone-phenolic rear-
rangements in acidic media. The results of the present
investigation showed that compounds of this type must
be isolated under conditions precluding acid hydrolysis
to prevent their rearrangements.
Experimental
The IR spectra were measured on a UR-20 instrument in
Nujol mulls. The 1H NMR spectra were recorded on a Bruker
AM-300 instrument (300 MHz) in DMSO-d6 with HMDS as
the internal standard. The 13C NMR spectra were measured on
a Bruker AC-200 instrument (50.32 MHz) in DMSO-d6. The
mass spectra were obtained on a Finnigan MAT instrument
(EI, 70 eV). The course of the reactions and the purities of the
products were monitored by TLC on Silufol plates (Czech
Republic) using a toluene—AcOEt system (1 : 1); spots were
visualized with a 2% solution of chloranil in toluene. Ethyl
acetate was washed with water and a saturated NaHCO3 solu-
tion, dried over MgSO4, and distilled. Monoglyme was dried
over solid KOH and distilled over sodium. Dichloromethane
was purchased from Lancaster (UK). Toluene of analytical
grade, ClCH2CN, MeSCN, PhCN, and CNCH2CO2Et (all
compounds were domestic reagents), and BnSCN (Chemapol,
Czech Republic) were used without additional purification.
Carbinol 1a and 1-(p-methoxyphenyl)-2-methylprop-1-ene were
prepared according to a known procedure.19 Quantum-chemi-
cal calculations were carried out on a Pentium-133 computer
with the use of the MOPAC 7.0 program package.20
3,3-Dimethyl-1-methylthio-2-azaspiro[4.5]deca-1,6,9-trien-
8-one (3a). This compound was synthesized according to a
procedure reported previously.10
1-Benzylthio-3,3-dimethyl-2-azaspiro[4.5]deca-1,6,9-trien-
8-one (3b). A mixture of 1-(p-methoxyphenyl)-2-methylprop-
1-ene (4.05 g, 25 mmol) and BnSCN (2.98 g, 20 mmol) in
CH2Cl2 (50 mL) was added dropwise with intense stirring to
98% sulfuric acid (6 mL, 110 mmol) for 0.5 h at the tempera-
ture not exceeding –15 °C. The reaction mixture was stirred for
0.5 h and poured into a mixture of NH4Cl (25 g), a concen-
trated aqueous NH3 solution (25 mL), and ice (300 g). Then
the reaction mixture was stirred (pH ∼8), the organic layer was
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were washed with water (50 mL)
and dried with anhydrous MgSO4. The solvent was distilled off
and the residue was recrystallized from ether upon cooling to
–10 °C. Compound 3b was obtained in a yield of 0.8 g (13%).
1-Methylthio-3,3-(pentane-1,5-diyl)-2-azaspiro[4.5]deca-
1,6,9-trien-8-one (3c) was prepared analogously from racemic
We carried out simulation of the attack of water on
the C(1) atom in neutral molecules 3e,f and their
N- and O-protonated forms D1a—c and E1a—c by the
reaction coordinate method using the interatomic
lC(1)...OH distance as the coordinate (Scheme 3). It
2
appeared that only the attack on the O-protonated
forms is accompanied by an increase in the interatomic
C(1)—C(5) distance up to the cleavage of the bond in
the molecules of spiranes 3e,f as the nucleophile comes
closer. Therefore, only the O-protonated form can be
converted (through an intermediate of type E2) into
amide 4.
Hence, the results of semiempirical quantum-chemi-
cal calculations did not provide an unambiguous answer
to the question concerning the causes of the specific
formation of 1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-
trien-8-ones 3a—d in these reactions but demonstrated
that hydrolysis (accompanied by the dienone-phenolic
rearrangement) of compounds 3e,f containing electron-
withdrawing substituents can proceed through the for-
mation of the O-protonated forms.
α-cyclohexyl-p-methoxybenzyl alcohol 1b21 (5.5 g, 25 mmol)
–1
[m.p. 86—87.5 °C; cf. lit. data21: m.p. 92 °C); IR, ν/cm
:
3460 (OH). 1H NMR, δ: 0.85—1.73 (m, 10 H, (CH2)5); 1.90
(d, 1 H, CH); 3.75 (s, 3 H, OMe); 4.13 (t, 1 H, OCH,
J = 7.2 Hz); 4.70 (d, 1 H, OH); 6.80 (d, 2 H, H(3), H(5),
J = 9.1 Hz); 7.14 (d, 2 H, H(2), H(6), J = 9.1 Hz) and
MeSCN (1.46 g, 1.37 mL, 20 mmol). Compound 3c was
obtained in a yield of 0.73 g (14%).
1-Benzylthio-3,3-(pentane-1,5-diyl)-2-azaspiro[4.5]deca-
1,6,9-trien-8-one (3d) was prepared analogously from carbinol
1b (5.5 g, 25 mmol), BnSCN (2.98 g, 20 mmol), and concen-
trated H2SO4 (6 mL) in CH2Cl2 (30 mL). Compound 3d was
obtained in a yield of 1.15 g (17 %).
To summarize, we developed a procedure for the
synthesis of 1-R-3,3-dialkyl-2-azaspiro[4.5]deca-1,6,9-
Thiomethyl N-[1-(4-hydroxyphenyl)-2-methylprop-2-
yl]carbamate (4a). A. The synthesis from carbinol 1a was

1656
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 9, September, 2001
Ausheva et al.
carried out analogously to the synthesis of compound 4c; the
yield was 97%.
off to the volume of 10 mL. Then an equal volume of water was
added and the precipitate that formed was filtered off and
dried. Amide 5 was obtained in a yield of 0.75 g (72%).
B. Acid hydrolysis of compound 3a. Spirane 3a (0.3 g,
1.35 mmol) was refluxed in 10% H2SO4 (10 mL) for 1 h. Then
the reaction mixture was cooled and the precipitate that formed
was separated, washed with water (3 mL), dried, and recrystal-
lized. Amide 4a was obtained in a yield of 0.29 g (90%).
Thiobenzyl N-[1-(4-hydroxyphenyl)-2-methylprop-2-
yl]carbamate (4b). A. The synthesis from carbinol 1a was
carried out analogously to the synthesis of compound 4c; the
yield was 27%.
B. Acid hydrolysis of compound 3b. Spirane 3b (100 mg,
0.3 mmol) was refluxed in a mixture of 10% H2SO4 (10 mL)
and EtOH (3 mL) for 2.5 h. Then the reaction mixture was
poured into water (50 mL) and made alkaline with solid
(NH4)2CO3 to pH ∼7—8. The precipitate that formed was
separated, dried, and recrystallized. Amide 4b was obtained in a
yield of 38 mg (40%).
Thiomethyl N-[2-(4-hydroxyphenyl)-1,1-(pentane-1,5-
diyl)ethyl]carbamate (4c). A solution of carbinol 1b (11 g,
50 mmol) and MeSCN (3.66 g, 50 mmol) in toluene (100 mL)
was added with intense stirring to concentrated H2SO4 (50 mL)
at 20—25 °C. The reaction mixture was stirred for 1 h, poured
into cold water (300 mL), and neutralized with a 25% aqueous
NH3 solution to pH 7—8. The resulting resinous product was
triturated with CH2Cl2 and the precipitate of compound 4c that
formed was separated. The aqueous layer was extracted with
toluene (60 mL). The combined toluene extracts were washed
with water and dried with MgSO4. The toluene was distilled off
to 1/3 of the initial volume and the residue was kept in the cold
(–10 °C). The crystals that precipitated were combined with
the compound isolated previously and recrystallized. The total
yield of compound 4c was 2.42 g (17%).
Ethyl 2-{[1-(4-hydroxyphenyl)-2-methylprop-2-yl]amino-
carbonyl}acetate (4e), N-[1-(4-hydroxyphenyl)-2-methylprop-
2-yl]benzamide (4f), ethyl 2-{[2-(4-hydroxyphenyl)-1,1-
(pentane-1,5-diyl)ethyl]aminocarbonyl}acetate (4g), and
N-[2-(4-hydroxyphenyl)-1-(pentane-1,5-diyl)ethyl]benzamide
(4h) were prepared analogously from carbinols 1a,b and the
corresponding nitriles 2c,d.
N-[2-(4-Hydroxyphenyl)-1,1-(pentane-1,5-diyl)ethyl]phe-
nylacetamide (4i) was prepared analogously from carbinol 1b
(11 g, 50 mmol) and BnSCN (5.85 g, 5.75 mL, 50 mmol) in
concentrated H2SO4 (60 mL); the yield was 4.72 g (29%).
MS, m/z (Irel (%)): 323 [M–2]+ (1), 216 (43), 107 (20), 98
(100), 91 (25).
N-[2-(4-Hydroxyphenyl)-1,1-(pentane-1,5-diyl)ethyl]chlo-
roacetamide (4j) was prepared analogously from carbinol 1b
(11 g, 50 mmol) and ClCH2CN (3.78 g, 50 mmol) in H2SO4
(50 mL). MS, m/z (Irel (%)): 281 [M]+ (1), 188 (25), 177 (29),
174 (100), 107 (28), 98 (55), 81 (38). Unlike the remaining
amides, compound 4j was additionally isolated as a precipitate
from the aqueous layer; the total yield was 4.0 g (28%).
N-[1-(4-Methoxyphenyl)-2-methylprop-2-yl]benzamide (7).
Sodium hydride (90 mg; from 150 mg of a 60% suspension of
NaH in mineral oil) and MeI (0.55 mL, 8.3 mmol) in
monoglyme (3 mL) were successively added to a solution of
amide 4f (1 g, 3.7 mmol) in dry monoglyme (30 mL). The
reaction mixture was stirred for 2 h and the solvent was distilled
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Received April 24, 2000;
in revised form May 14, 2001