Synthesis of N-allyl and N-acyl-2-vinylindoline

Article abstract of DOI:10.1134/S1070363214040112

Heating a mixture of (2R*,3R*)- and (2R*,3S*)-2- [(1S*)-1-iodoethyl]-3,5-dimethyl-1-[(2-nitrophenyl) sulfonyl]indolines with N-isopropylpiperidine in xylene resulted in (2S*,3R*)-3,5- dimethyl-1-[(2-nitrophenyl) sulfonyl]-2-vinylindoline. The latter reacted with thiophenol to afford (2S*,3R*)-3,5-dimethyl-2-vinylindoline, whose reaction with allyl halides or acetyl bromide gave rise to N-allyl-, N-propenyl-, or N-acetyl derivatives. Nitration of 1-acetyl-3,5-dimethyl-2- vinylindoline yielded ortho-nitro derivative.

Full text of DOI:10.1134/S1070363214040112

ISSN 1070-3632, Russian Journal of General Chemistry, 2014, Vol. 84, No. 4, pp. 672–675. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © G.G. Mazgarova, R.R. Gataullin, 2014, published in Zhurnal Obshchei Khimii, 2014, Vol. 84, No. 4, pp. 592–595.
Synthesis of N-Allyl- and N-Acyl-2-vinylindoline
G. G. Mazgarova and R. R. Gataullin
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Russia
e-mail: gataullin@anrb.ru
Received July 15, 2013
Abstract―Heating a mixture of (2R*,3R*)- and (2R*,3S*)-2-[(1S*)-1-iodoethyl]-3,5-dimethyl-1-[(2-nitro-
phenyl)sulfonyl]indolines with N-isopropylpiperidine in xylene resulted in (2S*,3R*)-3,5-dimethyl-1-[(2-nitro-
phenyl)sulfonyl]-2-vinylindoline. The latter reacted with thiophenol to afford (2S*,3R*)-3,5-dimethyl-2-vinyl-
indoline, whose reaction with allyl halides or acetyl bromide gave rise to N-allyl-, N-propenyl-, or N-acetyl
derivatives. Nitration of 1-acetyl-3,5-dimethyl-2-vinylindoline yielded ortho-nitro derivative.
Keywords: 2-vinylindoline, elimination, acylation
DOI: 10.1134/S1070363214040112
2
-Vinylindole derivatives have drawn considerable
by recrystallization; they were isolated as 4 : 1 mixture
[23]. Therefore, we investigated of the mixture of these
compounds. We found that the rate of dehydro-
halogenation of isomers I and II depends on the
temperature. Refluxing a mixture of heterocycles I and
II in xylene leads to the reaction of only trans-indoline
I resulting in trans-2-vinylindoline III with a yield of
attention [1–5] due to their wide use as intermediates
in the synthesis of some alkaloids [6–8], carbazoles of
various hydrogenation degree [9–17] or pyrrolo[1,2-a]-
indoles [6, 7].
Vinylindolines and their dehydrogenated analogs
can be obtained by various methods. For example, 2-
vinylindoline derivatives have been synthesized by
reacting conjugated dienes with a 2-haloanilines [13,
3
6%. Prolonged boiling of the mixture of I and II in
pseudocumene in the presence of 4 eq of N-iso-
propylpiperidine resulted in trans- and cis-vinyl-
indolines III, IV in a ratio of ~ 4 : 1 (see Scheme 1).
Probably, it is due to the steric factor. We assumed that
different orientation of the methyl and iodoethyl
fragments does not prevent such mutual arrangement
of the molecules of I and amine relative to each other
as is required for dehydroiodination; whereas cis-
orientation of these substituents and spatial orientation
of iodine atoms and methyl group create probably
some difficulties for dehydroiodination process.
Perhaps this obstacle is overcome when the tempera-
ture rises by another 15–20°C, which is impossible in
the case of xylene.
1
8] and by oxidative cyclization of 2-alkenylanilines
under metal complex catalysis [19–21]. Vinylindoles
have been prepared by Wittig methylenation of 2-
indolylcarbaldehyde [7, 22 ] and Hofmann elimination
of N-[2-(2-indolyl)ethyl-N,N,N-trimethylammonium
quaternary salts in the presence of wet silver oxide [1].
This work presents the results of our studies on the
synthesis of 2-vinylindolines starting from ortho-
alkenylanilines. We have already made some attempts
to obtain compounds of this series via dehydro-
halogenation of 2-(1'-iodoethyl)-substituted indolines
N-arylsulfonates by heating in an amine base [23].
Despite the fact that 2-vinylindoline N-tosylates can be
isolated only by fractional recrystallization of the
reaction products, further removal of tosyl group is a
challenging task. Aiming to select more easily re-
movable group, we continued research in this direction.
Since compounds I and II cannot be separated by
the column chromatography, we assumed that their
refluxing in xylene in the presence of an amine to from
vinyl derivative III and halogen derivative II allows us
to facilitate this task. Therefore, the heating time was
increased to 20 h. However we failed to isolate isomer
II in pure form, since it was eluted together with the
Previously it was shown that the heterocycles I and
II resulting from iodocyclization cannot be separated
6
72

SYNTHESIS OF N-ALLYL- AND N-ACYL-2-VINYLINDOLINE
673
Scheme 1.
N
H C
CH3
3
Pri
H C
CH3
H
3
H
CH3
+ II
Xylene, reflux
N
CH2
N
H
I
SO2
Ns
NO2
III, 36%
I
H C
CH3
H
3
CH3
N
H
I
SO2
H C
CH3
N
3
NO2
Pri
III +
H
CH2
N
Pseudocumene,
reflux
Ns
II
IV
Scheme 2.
H C
3
CH3
H C
3
H C
3
CH3
CH3
H
PhSH, K CO3
R
Br
H
2
H
o
DMSO, 20 С
K CO
2
3
N
o
N
acetone, 20 С
N
Ns
III
H
R
V (86%)
VI (86%)
VII (86%)
AcBr, K CO
2
3
o
Me COMe, 20 С
3
CH3
H
CH3
H
CH
3
H
H C
H C
H
3
C
3
3
Zn, NH Cl
NH NO , (F CCO) O
4
4
3
3
2
_
o
CH Cl , 30 C
MeOH, H O
2
2
2
N
N
N
NO2
NH
2
CH3
CH3
CH3
O
O
O
VIII (81%)
IX (72%)
X (55%)
R = H (VI), Me (VII).
isomer I when chromatographed. Vinylindoline III can
be obtained in pure form by column chromatography
and subsequent recrystallization from ethanol.
indoline V [23] with allyl or crotyl bromide in the
presence of K CO afforded the corresponding N-
2
3
alkenyl derivatives VI or VII. The acylation of
indoline V with acetyl bromide gave rise to compound
VIII [21]. The nitration of indoline VIII with
trifluoroacetyl nitrate under mild conditions yielded
nitro derivative IX. The reduction of the latter with
The removal of nitrophenylsulfonyl group was
carried out by stirring compound III with thiophenol
in DMSO in the presence of K CO . The reaction of
2
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014

6
74
MAZGAROVA, GATAULLIN
zinc in the presence of ammonium chloride in
methanol resulted in amine X. Relative orientation of
the methyl and vinyl groups in the five-membered ring
was established by NOESY NMR experiments (see
Scheme 2).
temperature for 4 h, 20 mL of petroleum ether and
7 mL of water were added to the reaction mixture. The
organic layer was separated and dried over MgSO4.
Then the solvent was evaporated, and the residue was
chromatographed on a silica gel column (benzene–
petroleum ether, 1 : 4). The first fraction yielded
In summary, we found dependence of elimination
of (2R*,3R*)- and (2R*,3S*)-2-[(1S*)-1-iodoethyl]-
0
.384 g of 1-nitro-2-(phenylsulfanyl)benzene. In the
subsequent fractions 0.267 g (86%) of compound V
was obtained as a light-brown liquid. Spectral
characteristics were identical to the data in [23].
3
,5-dimethyl-1-[(2-nitrophenyl)sulfonyl]indulines on
the spatial orientation of the substituents at the
nitrogen-containing ring and the boiling point of the
solvent. New 2-vinylindoline derivatives were obtained.
(
2R*,3S*)-1-[(2E)-But-2-en-1-yl]-3,5-dimethyl-2-
vinylindoline (VII). To a suspension of 0.220 g
1.3 mmol) of compound V and 0.439 g (3.18 mmol)
of K CO in 5 mL of acetone was added 0.181 g
EXPERIMENTAL
(
IR spectra were recorded on an IRPrestige-21
2
3
1
13
Shimadzu Fourier-spectrophotometer. H and
C
(1.34 mmol) of crotyl bromide. The reaction progress
was monitored by TLC (eluent benzene). When V was
consumed, the residue was filtered off and washed
with petroleum ether. After the solvent removal, the
filtrate was chromatographed on a short column filled
NMR spectra were taken on a Bruker AM-300
spectrometer operating at 300.13 and 75.47 MHz,
respectively. Mass spectrum of compound X was
obtained on a Therm-Finnigan MAT 95 XP instrument
using direct input mode under standard conditions.
Elemental analysis was performed on a CHNS
Elemental Analyzer EURO EA-3000. Column
chromato-graphy was performed on silica gel
Lankaster LS (40/100 μ). TLC analysis was carried out
using Sorbfil PTLC-AF-B plates (Sorbpolimer,
Krasnodar) detecting with iodine vapors.
with silica gel (eluent diethyl ether). Yield 0.177 g
1
(61%), R
ppm: 1.30 d (3Н, СН
J 0.7, 6.5 Hz), 2.28 s (3Н, СН
0.7 (C
H
). H NMR spectrum (CDCl
3
), δ,
f
6
6
3
, J 6.7 Hz), 1.70 d.d (3Н, СН ,
3
3
), 2.91 d. q (1Н, Н , J
3
2
6.7, 10.5 Hz), 3.42 d.d (1H, Н , J 8.5, 10.5 Hz), 3.47
d.d (1Н, Н , J 7.6, Jgem 15.9 Hz), 3.78 d.d. q (1Н,
Н , Jgem 15.5, J 3.0, 1.5 Hz), 5.25 d.d (1Н, Н , J 2.0,
.0 Hz), 5.28 d.d (1Н, Н , J 2.0, 16.5 Hz), 5.44–5.49
m (1Н, Н ), 5.63 d. q (1Н, Н , J 6.5, 15.2 Hz), 5.87
d.d.d (1Н, Н , J 8.5, 10.5, 16.5 Hz), 6.41 d (1Нarom,
J 7.9 Hz), 6.82 s (1Н, Н ), 6.85 d (1Нarom, J 7.9 Hz).
1
''А
1
''В
2'А
2
'В
8
(
2R*,3S*)-3,5-Dimethyl-1-[(2-nitrophenyl)sul-
2
''
3''
fonyl]-2-vinylindoline (III). A mixture of isomers I
and II (2.58 g, 5.3 mmol) and 3.2 mL (21.2 mmol) of
isopropylpiperidine in 11 mL of xylene was refluxed
for 20 h. After cooling to room temperature, 50 mL of
xylene and 50 mL of 5% aqueous HCl were added to
the mixture. Then the organic phase was separated,
1
'
4
Found, %: C 84.41; H 9.25; N 5.98. C H N.
1
6
21
Calculated, %: C 84.53; H 9.31; N 6.16.
(2R*,3S*)-1-Acetyl-3,5-dimethyl-2-vinylindoline
(VIII). To a suspension of 0.17 g (1 mmol) of indoline
washed with water, and dried over MgSO . The
4
solvent was removed, and the residue was chromato-
graphed on a silica gel column (benzene–petroleum
ether, 1 : 4). The first fractions yielded 0.104 g of a
mixture of isomers I and II in a ratio of ~1 : 2 (4%).
Recrystallization of the subsequent fractions from
ethanol gave 0.559 g (36%) of compound III as
colorless crystals. R 0.7 (C H ), mp 136°C (EtOH).
V and 0.28 g (2 mmol) of K CO in 5 mL of CHCl
2 3 3
was added at stirring dropwise 0.16 g (1.3 mmol) of
acetyl bromide. The reaction progress was monitored
by TLC (eluent benzene). After the reaction comple-
tion 5 mL of water was added to the mixture. After
stirring for 30 min the mixture was extracted with
50 mL of CHCl
. The organic layer was dried over
f
6
6
3
1
Data of H NMR spectra were identical to those
described in [21]. Found, %: C 60.24; H 5.01; N 7.79;
S 8.86. C H N O S. Calculated, %: C 60.32; H 5.06;
MgSO . Then the solvent was removed, and the
4
residue was chromatographed on silica gel (eluent
benzene). Yield 0.19 g (88%). Physicochemical charac-
teristics were identical to those described in [21].
1
8
18
2
4
N 7.82; S 8.95.
(
2R*,3S*)-3,5-Dimethyl-2-vinylindoline (V). To a
(2R*,3S*)-1-Acetyl-3,5-dimethyl-7-nitro-2-vinyl-
indoline (IX). To a solution of 0.226 g (1.24 mmol) of
suspension of 0.647 g (1.807 mmol) of compound III
and 1.243 g (9.035 mmol, 5.00 eq) of K CO in 2.5 mL
of DMSO was added 0.542 mL (5.403 mmol,
.00 equiv) of thiophenol. After stirring at room
compound VIII in 1 mL of CH
added triftoracetyl nitrate [prepared by stirring 0.48 g
(6 mmol) of NH NO and 4.3 g (20.4 mmol) of
Cl at –30°С was
2
3
2 2
3
4
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014

SYNTHESIS OF N-ALLYL- AND N-ACYL-2-VINYLINDOLINE
675
trifluoroacetic anhydride in 1 mL of CH Cl ]. After
3. Uchuskin, M.G., Molodtsova, N.V., Abaev, V.D.,
Trushkov, I.A. and Butin, A.V., Tetrahedron, 2012,
vol. 68, p. 8933.
2
2
1
h, the reaction mixture was poured into ice (20 g)
and extracted with 50 mL of CH Cl . The organic layer
2
2
4
. Gataullin, R.R., Ishberdina, R.R., Antipin, A.V.,
Suponitskii, K.Yu., Kabal’nova, N.N., Shitikova, O.V.,
Spirikhin, L.V., Antipin, M.Yu., and Abdrakhmanov, I.B.,
Chem. Heterocycl. Comp., 2006, no, 9, p. 1130.
was washed with water (10 mL) and dried over
Na SO . After the solvent removal the residue was
2
4
chromatographed on a silica gel column (eluent C H ).
6
6
Yield 0.234 g (72%), yellow viscous liquid, R 0.45
f
1
5. Gataullin, R.R., Ishberdina, R.R., Shitikova, O.V.,
Minnigulov, F.F., Spirikhin, L.V., and Abdrakhmanov, I.B.,
Chem. Heterocycl. Comp., 2006, no. 8, p. 1025.
(
C H –EtOAc, 8 : 1). H NMR spectrum (CDCl ), δ,
6 6 3
ppm: 1.35 d (3Н, СН , J 7.2 Hz), 2.20 s (3Н, СН ),
3
3
3
2
(
5
1
.39 s (3Н, СН ), 3.02 q (1Н, Н , J 7.2 Hz), 4.51 d. t
1Н, Н , J 1.5, 2.7 Hz), 5.20 d (1Н, Н , J 10.1 Hz),
.49 d (1Н, Н , J 17.1 Hz), 5.87 d.d.d (1Н, Н , J 4.4,
0.1, 17.1 Hz), 7.17 s (1Нarom), 7.48 s (1Нarom).
3
6
. Molander, G.A. and Schmitt, M.H., J. Org. Chem.,
000, vol. 65, no. 12, p. 3767.
2
2'А
2
2
'В
1'
7
. Gonzalez-Perez, P., Perez-Serrano, L., Casarrubios, L.,
Dominguez, G., and Perez-Castells, J., Tetrahedron
Lett., 2002, vol. 43, no. 27, p. 4765.
1
3
C
NMR spectrum (CDCl ), δ , ppm: 20.65, 21.26, 21.94
3
С
3
2
2'
(
3СН ), 42.94 (С ), 70.72 (С ), 115.42 (С ), 122.71,
3
8
. Orr, S.T.M., Tian, J., Niggemann, M., and Martin, S.M.,
1
'
4
6
1
1
6
6
29.03, 135.11 (С , С , С ), 130.65, 134.97, 140.17,
Org. Lett., 2011, vol. 13, no. 19, p. 5104.
3
а
5
7
7а
40.43 (С , С , С , С ), 167.96 (С=О). Found, %: С
5.41; Н 6.14; N 10.69. C H N O . Calculated, %: С
9
. Lebold, T.P. and Kerr, M.A., Org. Lett., 2007, vol. 9,
14
16
2
3
no. 10, p. 1883.
4.60; H 6.20; N 10.76.
1
0. Anthes, R., Bello, O., Benoit, S., Chen, C.K., Corbett, E.,
Corbett, R.M., DelMonte, A.J., Gingras, S., Livingston, R.,
Sausker, J., and Soumeillant, M., Org. Proc. Res.
Develop., 2008, vol. 12, no. 2, p. 168.
(2R*,3S*)-7-Amino-1-acetyl-3,5-dimethyl-2-vinyl-
indoline (X). To a solution of 0.211 g (0.81 mmol) of
compound IX in 5 mL of MeOH was added a solution
1
1
1
1
1
1. Chen, C.-B., Wang, X.-F., Cao, Y.-J., Cheng, H.-G., and
Xiao, W.-J., J. Org. Chem., 2009, vol. 74, no. 9, p. 3532.
2. Çаvdar, H. and Saraçoğlu, N., J. Org. Chem., 2006,
vol. 71, no. 20, p. 7793.
3. Back, T.G., Bethell, R.J., Parvez, M., and Taylor, J.A.,
of 0.045 g (0.83 mmol) of NH Cl in 1.5 mL of water.
4
Then 0.26 g (4.05 mmol) of zinc dust was added in
portions with vigorous stirring. The reaction progress
was monitored by TLC (C H –EtOAc, 8:1). The
6
6
precipitate was filtered off and washed with methyl
tert-butyl ether (30 mL). The organic layer was dried
over Na SO . The solvent was evaporated in a vacuum,
J. Org. Chem., 2001, vol. 66, no. 25, p. 8599.
4. Back, T.G., Pandyra, A., and Wulff, J.E., J. Org. Chem.,
2
4
2
003, vol. 68, no. 8, p. 3299.
and the residue was chromatographed on silica gel
eluent – C H ). Yield 0.102 g (55%), R 0.4 (C H –
5. Biolatto, B., Kneeteman, M., Paredes, E., and Man-
(
6
6
f
6
6
1
cini, P.M.E., J. Org. Chem., 2001, vol. 66, no. 11, p. 3906.
EtOAc, 4 : 1). H NMR spectrum (CDCl ), δ, ppm:
3
1
.22 d (3Н, СН , J 7.0 Hz), 2.14 s (3Н, СН ), 2.16 s
16. Chataigner, I., Hess, E., Toupet, L., and Pietre, S.R.,
3
3
3
2
Org. Lett., 2001, vol. 3, no. 4, p. 515.
(
3Н, СН ), 2.74 q (1Н, Н , J 7.0 Hz), 4.22 d.d (1Н, Н ,
3
2'А
J 0.9, 6.0 Hz), 4.60 br.s (2Н, NH ), 5.02 d. t (1Н, Н ,
J 10.1, 1.0 Hz), 5.10 d. t (1Н, Н , J 17.0, 1.0 Hz),
5
17. Chretien, A., Chataigner, I., Helias, N.L., and Pietre, S.R.,
2
2
'В
J. Org. Chem., 2003, vol. 68, no. 21, p. 7990.
1
'
.70 d.d.d (1Н, Н , J 6.0, 10.1, 17.0 Hz), 6.27 s
18. O’Connor, J.M., Stallman, B.J., Clark, W.G., Shu, A.Y.L.,
Spada, R.E., Stevenson, T.M., and Dieck, H.A., J. Org.
Chem., 1983, vol. 48, no. 6, p. 807.
13
(
1Нarom), 6.29 s (1Нarom). C NMR spectrum (CDCl ),
3
3
δ , ppm: 19.80, 21.12, 21.48 (3СН ), 43.23 (С ), 72.20
С
3
2
2'
6
7а
(С ), 115.52 (С ), 118.19 (С ), 125.65 (С ), 125.86
19. Rogers, M.M., Wendlandt, J.E., Guzei, I.A., and Stahl, S.S.,
4
1'
3а
5
7
(
1
С ), 135.74 (С ), 129.63, 136.64, 138.74 (С , С , С ),
68.04 (С=О). Mass spectrum, m/z (I , %): 230.1
Org. Lett., 2006, vol. 8, no. 11, p. 2257.
rel
20. Larock, R.C., Hightower, T.R., Hasvold, L.A., and
Peterson, K.R., J. Org. Chem., 1996, vol. 61, no. 11,
p. 3584.
+
+
[M] (100), 187.1 [M – CH CO] (45). Found, %: С
3
7
7
2.92; Н 7.84; N 12.08. C H N O. Calculated, %: С
14 18 2
3.01; H 7.88; N 12.16.
21. Mazgarova, G.G., Skladchikov, D.A., Nikolaev, V.P.,
and Gataullin, R.R., Chem. Heterocycl. Comp., 2013,
no. 5, p. 689.
REFERENCES
1
. Sapi, J., Grebille, Y., Laronze, J.P. and Levy, J.,
22. Amat, M., Llor, N., Checa, B., Molins, E., and Bosh, J.,
Synthesis, 1992, no. 4, p. 383.
J. Org. Chem., 2010, vol. 75, no. 1, p. 178.
2
. Butin, A.V., Abaev, V.T., Stroganova, T.A. and Gut-
23. Mazgarova, G.G., Absalyamova, A.M., and Gataullin, R.R.,
nov, A.V., Molecules, 1997, vol. 2, no. 4, p. 62.
Russ. J. Org. Chem., 2012, vol. 48, no. 9, p. 1200.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 84 No. 4 2014