Reactions of N- and C-alkenylanilines: III. Synthesis and cyclization of substituted 2-(1-methyl-2-butenyl)anilines

Article abstract of DOI:10.1023/A:1015342406252

Reactions of substituted 2-(1-methyl-2-butenyl)anilines with iodine result in cyclization and formation of 3-iodo-1,2,3,4-tetrahydroquinolines; N-methylsulfonyl-2-(1-methyl-2-butenyl)anilines give rise exclusively to the corresponding 2-(1-iodoethyl)-3-methyl-2,3-dihydroindoles.

Full text of DOI:10.1023/A:1015342406252

Russian Journal of Organic Chemistry, Vol. 38, No. 1, 2002, pp. 31 37. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 1, 2002,
pp. 41 46.
Original Russian Text Copyright
2002 by Gataullin, Minnigulov, Fatykhov, Spirikhin, Abdrakhmanov.
Reactions of N- and C-Alkenylanilines: III.* Synthesis
and Cyclization of Substituted 2-(1-Methyl-2-butenyl)anilines
R. R. Gataullin, F. F. Minnigulov, A. A. Fatykhov,
L. V. Spirikhin, and I. B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 69, Ufa, 450054 Bashkortostan, Russia
fax: (3472)356066; e-mail: chemorg@anrb.ru
Bashkir State Agrarian University, Ufa, Bashkortostan, Russia
Received January 12, 2001
Abstract Reactions of substituted 2-(1-methyl-2-butenyl)anilines with iodine result in cyclization and
formation of 3-iodo-1,2,3,4-tetrahydroquinolines; N-methylsulfonyl-2-(1-methyl-2-butenyl)anilines give rise
exclusively to the corresponding 2-(1-iodoethyl)-3-methyl-2,3-dihydroindoles.
2-(1-Methyl-2-butenyl)aniline derivatives, which
are readily obtained from commercially available
piperylene [2], exhibit biological activity [3] and are
used in the synthesis of heterocyclic compounds [4].
Depending on the reagent nature, their cyclizations
give dihydroindoles and aminoindans [4], mixtures
indoles. In continuation of our studies on hetero-
cyclization of alkenylanilines [5], we have synthesized
substituted 2-(1-methyl-2-butenyl)anilines and
examined their reactions with iodine I2.
By alkenylation of p-toluidine (I) with piperylene
in benzene in the presence of AlCl3 at 130 C we
of dihydroindoles with tetrahydroquinolines [5], or obtained products II and III (Scheme 1). The reaction
Scheme 1.
I, II, III, R = Me; IV, VI, VIII, R = OMe.
____________
*
For communication II, see [1].
1070-4280/02/3801-0031$27.00 2002 MAIK Nauka/Interperiodica

32
GATAULLIN et al.
Scheme 2.
of p-anisidine (IV) with 2-chloro-3-pentene in triethyl-
amine gives N-(1-methyl-2-butenyl)-4-methoxyaniline
(V) [6] which undergoes Claisen rearrangement to
aniline VI [6]. Repeated alkylation of amine VI with
2-chloro-3-pentene in triethylamine [6] yields N-sub-
stituted derivative VII. The Claisen rearrangement of
the corresponding hydrochloride in o-xylene at 144 C
leads to formation of compound VIII (Scheme 1).
elimination of a proton from the latter yields dihydro-
quinoline XXI [11] which is sensitive to oxidants.
The structure of the resulting tetrahydroquinolines
suggests that the process occurs only as 6-endo-
cyclization [12] of two possible complexes A and
B (Scheme 4) in which intramolecular nucleophilic
attack by the nitrogen atom is directed exclusively at
the C3 atom of the alkenyl fragment.
2-Chloro-3-pentene reacts with excess o-anisidine
(IX) to give both mono- and dialkylated products X
and XI (Scheme 2). Due to the presence of a methoxy
group in the ortho position, the reaction time and
temperature (160 C) strongly increase, as compared
to aniline [2] and alkyl-substituted anilines. Products
II, III, VI VIII, X, and XI were reported by us
previously [6 9].
By reactions of amines II, VI, and X with iodine
[10] we obtained stereoisomeric 3-iodo-1,2,3,4-tetra-
hydroquinolines XII XVII (Scheme 3). The reactions
were carried out in various solvents, but in all cases
isomers XII XIV were the major products (Table 1).
From amines II and VI quinolines XVIII and XIX
were obtained. Probably, the aromatization of XII
XVII involves formation of intermediate ion XX;
Under analogous conditions, the reactions of
anilines III and VIII with iodine gave complex mix-
tures of products. Judging by the 13C NMR spectra,
the major products were isomers XXIIa (XXIIb) and
XXIIIa (XXIIIb) (Scheme 5). Presumably, the forma-
tion of compounds with cis-arrangement of the
4-methyl group and 3-iodine atom is preferred. We
failed to isolate pure isomers, and their structure was
assigned on the basis of characteristic signals from
C2 at
50.4 and 50.8 ppm and C4 at 36.6 and
C
37.0 ppm, by analogy with the 13C NMR spectra of
tetrahydroquinolines XII XIV.
Treatment of amines II and VI with methanesul-
fonyl chloride gave sulfonamides XXIV and XXV;
the latter reacted with iodine to afford dihydroindoles
XXVI XXIX among which trans isomers XXVI and
Scheme 3.
II, XII, XV, XVIII, XXa, XXIa, R = Me, R = H; VI, XIII, XVI, XIX, XXb, XXIb, R = OMe, R = H;
X, XIV, XVII, R = H, R = OMe.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002

REACTIONS OF N- AND C-ALKENYLANILINES: III.
33
Scheme 4.
R = Me, R = H; R = OMe, R = H; R = H, R = OMe.
Scheme 5.
XXII, XXIII, R = Me (a), R = OMe (b).
Scheme 6.
XXIV, XXVI, XXVIII, R = Me; XXV, XXVII, XXIX, R = OMe.
XXVII prevailed (Scheme 6). Analogous reaction
with iodine of enantiomeric methanesulfonamides
XXX and XXXI resulted in formation of four pairs
of diastereoisomeric dihydroindoles XXXII XXXV
(Scheme 7).
constants for the 3-H signal of XV XVII (10.4 and
10.3 Hz) indicates a double axial axial interaction,
i.e., these compounds are diastereoisomers with
trans,trans arrangement of the substituents at C2,
C3, and C4, and the conformational equilibrium is
displaced toward conformer E (Scheme 8). Isomers
XII XIV are characterized by different orientation of
the 4-methyl group. The chemical shift of the 4-CH3
protons changes from 1.69 1.72 ppm for equatorial
orientation to 1.41 1.44 ppm for axial orientation.
In going from the equatorial to axial isomer, the
3-H 4-H coupling constant decreases from 10.4 to
The structure of the products was unambiguously
1
proved by the data of elemental analysis and H
and 13C NMR spectroscopy. The configuration of
isomers XII XVII was established on the basis of the
NMR spectra. The 4-H and 2-H signals appear in the
1H NMR spectra as doublets of quartets, and the 3-H
signal is a doublet of doublets. The larger coupling
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002

34
GATAULLIN et al.
Scheme 7.
Scheme 8.
3.9 Hz, while the coupling constant between 3-H and
2-H remains large (J = 7.4 7.8 Hz); these data suggest
the occurrence of axial axial interactions. Hence com-
pounds XII XIV are diastereoisomers with trans,cis
arrangement of the substituents at C2, C3, and C4, and
the conformational equilibrium is displaced toward
conformer (C) (Scheme 8) [13].
The methyl groups on C2 and C4 are characterized
by different geminal coupling constants with 2-H and
4-H, respectively: J(2-H,2-CH3) = 6.3 6.4 Hz and
J(4-H,4-CH3) = 7.3 7.4 Hz. The signals were reliably
assigned on the basis of the C H correlation spectrum,
where the chemical shifts of C2 and C4 differ con-
siderably from each other. In the 13C NMR spectra
of these compounds the greatest change of chemical
shift is observed for C4: the C4 signal of stereoisomers
This is consistent with the known data [14] on the
upfield shift of signals due to 1,2-cis-interaction of
substituents at such carbon atoms.
The iodine atom in position 3 and 2-methyl group
in streoisomeric quinolines XII XIV and XV XVII
are arranged trans. Presumably, the difference in the
chemical shifts of C2 is determined by orientation of
the methyl group on C4, other conditions being equal.
It is known that equatorial substituents in cyclo-
hexanes exert a stronger deshielding effect on the
-
and -carbon atoms than do the corresponding axial
substituents. Therefore, the chemical shifts of C4 and
C3 in conformer C, where the 4-CH3 group occupies
the axial position, are smaller than those found for
conformer E with equatorial 4-methyl group. It is
also known that the presence of an axial substituent
in cyclohexane induces an upfield shift of the -carbon
XII XIV is located in a stronger field,
36 37 ppm
C
signal [15]. The C2 and C4 signals of 2,4-dimethyl-
tetrahydroquinolines with trans arrangement of the
(conformer C), relative to the corresponding signal of
isomers XV XVII, 42 43 ppm (conformer D).
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002

REACTIONS OF N- AND C-ALKENYLANILINES: III.
35
methyl groups appear in a stronger field relative to
those of the cis isomer [5, 16]. Therefore, the C2
signal of stereoisomers XII XIV (conformer C) with
trans arrangement of the 2-Me and 4-Me groups is
Table 1. Reactions of compounds II, IV, and X with
iodine in the presence of NaHCO3
Initial
comp.
no.
Molar
ratio
XII: XV
Time,
min
observed at
50 51 ppm, whereas the corresponding
Solvent
Ba
C
signal of isomers XV XVII (conformer E) is located
in a weaker field (
53 54 ppm).
C
In the 1H NMR spectra of cis-dihydroindoles
XXVIII and XXIX the 2-H signal appears as
II
II
II
II
II
CH2Cl2
C6H6
ClCH2CH2Cl
CCl4
MeCN
24
48
24
72
108
72
9.08
2.28
10.36
2.23
37.4
10.36
9.08
23
48
40
0
160
40
23
3: 2
4: 1
4: 3
3: 1
a doublet of doublets at 4.7 ppm (J = 8.4, J2,1
=
2,3
4.0 Hz). The large value of the first coupling constant
indicates cis arrangement of 2-H and 3-H. The signal
from 3-H is observed at 3.7 ppm as a doublet of
quartets (J3,2 = 8.4, J3, 3-Me = 7.3 Hz). In the spectra
of trans-isomers XXVI and XXVII the 2-H signal
2: 1
b
VI ClCH2CH2Cl
CH2Cl2
c
X
45
a
b
c
B is the solvent nucleophilicity.
Molar ratio XIII:XVI = 4:3.
Molar ratio XIV:XVIII = 4:1.
shifts upfield (
1.3 ppm) due to cis-effect of the
3-methyl group and is observed as a doublet at
3.4 ppm (J2, 3 = 3.0, J2,1 = 5.4 Hz). The low couling
constant is indicative of trans arrangement of the 2-H
and 3-H protons, their equatorial orientation, and shift
of the conformational equilibrium toward conformer
with axial substituents. The 3-H signal (due to cis-
effect of the 1-iodoethyl group) appears in a stronger
field ( 3.3 ppm) as a doublet of quartets (J3, 2 = 3.0,
J3, 2-Me = 7.2 Hz).
The trans isomers of methanesulfonamides XXVI
and XXVII are characterized by more downfield
signals from C2 and C3, as compared to cis isomers
XXVIII and XXIX in which cis-interaction of the
substituents exists.
The positions and splitting modes of the 2-H signal
of dihydroindoles XXVIII and XXIX and of the 3-H
signal of quinolines XII XIV are similar; therefore,
in order to perform a more reliable structural assign-
ment, quinoline XII was treated with methanesulfonyl
chloride with a view to obtain compound XXXVI and
compare its spectral parameters with those of dihydro-
indole XXVIII. The reaction of XII with MeSO2Cl
was carried out in pyridine (Scheme 9). It resulted in
formation of a mixture of 1-methylsulfonyl-2,4,6-tri-
methyl-1,2,3,4-tetrahydroquinoline (XXXVI) and
1-methylsulfonyl-2,4,6-trimethyl-1,2-dihydroquinoline
(XXXVII), which were identified without isolation
from the mixture.
The 1H NMR spectrum of quinoline mixture
XXXVI/XXXVII, recorded by the double-resonance
technique, contained 5 groups of signals in the region
3.7 5.8 ppm. The 2-H, 3-H, and 4-H signals of
XXXVI were located at 4.1, 4.55, and 3.7 ppm,
respectively. The signal from 3-H of dihydroquinoline
XXXVII appeared at 5.8 ppm as a doublet (J =
5.6 Hz), and the 2-H signal was observed as a doublet
of quartets at 4.75 ppm (J1 = 5.6, J2 = 7.2 Hz).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Scheme 9.
a Bruker AM-300 spectrometer at 300 and 75 MHz,
respectively, using CDCl3 as solvent and TMS as
internal reference. The IR spectra were measured on
a UR-20 spectrometer in mineral oil. The progress of
reactions was monitored by TLC on Silufol UV-254
plates; development with iodine vapor. The yields,
melting points, Rf values, and elemental analyses of
compounds XII XIX and XXIV XXXI are given
in Table 2.
Reactions of compounds II, III, and VI with
methanesulfonyl chloride. Methanesulfonyl chloride,
0.6 ml, was added dropwise to a solution of 3 mmol
of aniline II, III, or VI in 4 ml of pyridine. The mix-
ture was kept for 24 h at room temperature, 20 ml of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002

36
GATAULLIN et al.
Table 2. Yields, melting points, Rf values, and elemental analyses of compounds XII XIX and XXIV XXXI
Found, %
I
Calculated, %
Comp. Yield, Rf or
Formula
no.
%
mp,
C
C
H
N
S
C
H
I
N
S
XII
XIII
XIV
XV
37
33
53
30
29
12
20
26
91
88
0.4a
47.67 4.86 41.87 4.92
44.98 4.71 39.58 4.14
45.07 4.81 39.63 4.02
47.82 5.40 40.00 4.92
44.98 4.65 39.58 4.42
44.98 4.65 39.58 4.42
C12H16IN
C12H16INO
C12H16INO
C12H16IN
C12H16INO
C12H16INO
C12H13N
48.00 5.33 42.00 4.67
45.44 5.08 40.01 4.42
45.44 5.08 40.01 4.42
48.00 5.33 42.00 4.67
45.44 5.08 40.01 4.42
45.44 5.08 40.01 4.42
0.4a
110b
0.5a
0.4a
0.4a
125b
0.3c
0.5c
0.6c
XVI
XVII
XVIII
XIX
83.85 7.32
76.77 6.64
61.24 7.27
57.54 6.74
7.78
7.11
84.21 7.60
76.98 7.00
61.63 7.56
57.97 7.11
8.19
7.48
5.53 12.64
5.20 11.90
C12H13NO
XXIV
XXV
XXVI
XXVII
XXVIII
XXIX
XXX,
XXXI
5.15 12.25 C13H19NO2S
4.85 11.51 C13H19NO3S
42 119 120d 40.87 4.33 32.98 3.24 8.03 C13H18INO2S 41.17 4.78 33.46 3.69 8.45
43 116 117d 39.15 4.21 31.73 3.08 8.11 C13H18INO3S 39.50 4.59 32.11 3.54 7.69
12 121 122d 40.87 4.33 33.07 3.24 8.15 C13H18INO2S 41.17 4.78 33.46 3.69 8.45
11
90
0.4c
39.16 4.18 31.86 3.32 7.94 C13H18INO3S 39.50 4.59 32.11 3.54 7.69
67.32 8.47 4.01 9.62 C18H27NO2S 67.32 8.24 4.36 9.97
a
Eluent CCl4.
b
c
d
From CHCl3.
Eluent CHCl3.
From 2-propanol.
water was added, and the mixture was stirred for
30 min and treated with 40 ml of chloroform. The
organic phase was separated, washed with 20 ml of
a 10% aqueous solution of NaHCO3 and 20 ml of
water, and dried over Na2SO4. The solvent was dis-
tilled off under reduced pressure, and the residue
was passed through a thin layer of silica gel usig
carbon tetrachloride as eluent to isolate a mixture of
stereoisomeric N-methylsulfonyl-2,6-bis(1-methyl-
2-butenyl)-4-methylanilines XXVIII and XXIX as
a light yellow oily substance.
or XX) was filtered off, washed with CCl4, and dried
under reduced pressure. The filtrate was evaporated
to a minimal volume, and the residue was subjected
to chromatography on silica gel (10 g, eluent CCl4)
to isolate compounds XII XVII.
The cyclization of N-methylsulfonyl derivatives
XXIV and XXV was performed in a similar way.
After treatment with Na2S2O3 and drying over
Na2SO4, the solvent was evaporated under reduced
pressure, and the residue was recrystallized from 8 ml
of isopropyl alcohol to isolate dihydroindole XXVI
or XXVII. The mother liquor was evaporated under
reduced pressure, the residue was dissolved in 1 ml
of methylene chloride, and the solution was applied
to a column charged with 3 g of silica gel. Using
carbon tetrachloride as eluent, cis-dihydroindole
XXVIII or XXIX was isolated.
Cyclization of alkenylanilines II, VI, and X.
A mixture of 10 mmol of aniline II, VI, or X, 1.5 g
of NaHCO3, and 0.51 g of I2 in 10 ml of appropriate
solvent (Table 1) was shaken for 24 130 h at 20 C,
the progress of the reaction being monitored by TLC
(eluent hexane methanol, 9.8:0.2). When the reaction
was complete, the mixture was diluted with 50 ml of
methylene chloride, and the precipitate was filtered
off and washed with methylene chloride (3 10 ml).
The organic phase was treated with a 5% aqueous
solution of Na2S2O3 (3 10 ml) and water (20 ml),
dried over Na2SO4, and evaporated under reduced
pressure. Carbon tetrachloride was added to the
residue, and the crystalline product (quinoline XVIII
REFERENCES
1. Gataullin, R.R., Minnigulov, F.F., Fatykhov, A.A.,
Spirikhin, L.V., and Abdrakhmanov, I.B., Russ. J.
Org. Chem., 2001, vol. 37, no. 9, pp. 1289 1296.
2. Abdrakhmanov, I.B., Sharafutdinov, V.M., and Tol-
stikov, G.A., Zh. Org. Khim., 1984, vol. 20, no. 3,
pp. 620 622.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002

REACTIONS OF N- AND C-ALKENYLANILINES: III.
37
3. Gataullin, R.R., Kazhanova, T.V., Davydova, V.A.,
Ismagilova, A.F., Zarudii, F.S., and Abdrakhma-
nov, I.B., Khim.-Farm. Zh., 2000, no. 2, pp. 18 21.
9. Abdrakhmanov, I.B., Shabaeva, G.B., Musta-
fin, A.G., and Tolstikov, G.A., Zh. Org. Khim., 1984,
vol. 20, no. 3, pp. 663 664.
10. Cardillo, C. and Orena, M., Tetrahedron, 1990,
4. Abdrakhmanov, I.B., Mustafin, A.G., and Tolsti-
kov, G.A., Izv. Akad. Nauk SSSR, Ser. Khim., 1983,
no. 10, pp. 2171 2172.
vol. 46, pp. 3321 3407.
11. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 4.
Translated under the title Obshchaya organicheskaya
khimiya, Moscow: Khimiya, 1985, vol. 8, p. 201.
5. Gataullin, R.R., Kazhanova, T.V., Il’yasova, L.T.,
Fatykhov, A.A., Spirikhin, L.V., and Abdrakhma-
nov, I.B., Izv. Ross. Akad. Nauk, Ser. Khim., 1999,
no. 5, pp. 975 978.
12. Baldwin, J.E., J. Chem. Soc., Chem. Commun., 1976,
no. 18, p. 734.
6. Abdrakhmanov, I.B., Sharafutdinov, V.M., Dzhemi-
lev, U.M., Tal’vinskii, E.V., Sagitdinov, I.A., and
Tolstikov, G.A., Zh. Prikl. Khim., 1982, vol. 55, no. 9,
pp. 2121 2123.
13. Pretsch, E., Clerk, T., Seible, J., and Simon, W.,
Tables of Spectral Data for Structure Determination
of Organic Compounds, Berlin: Springer, 1983.
14. Jackman, L.M. and Sternhell, S., Application of
Nuclear Magnetic Resonance in Organic Chemistry,
Oxford: Pergamon, 1969, p. 236.
7. Abdrakhmanov, I.B., Sharafutdinov, V.M., Nigmatul-
lin, N.G., Sagitdinov, I.A., and Tolstikov, G.A.,
Zh. Org. Khim., 1982, vol. 18, no. 7, pp. 1466 1471.
15. Rajan, S.P. and Manimekalai, A., Magn. Reson.
Chem., 1991, vol. 29, no. 9, pp. 904 911.
8. Abdrakhmanov, I.B., Shabaeva, G.B., Nigmatul-
lin, N.G., and Tolstikov, G.A., Izv. Akad. Nauk SSSR,
Ser. Khim., 1985, no. 6, pp. 1372 1378.
16. Stothers, J.B. and Tan, C.T., Can. J. Chem., 1974,
vol. 52, no. 2, pp. 308 314.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 1 2002