Synthesis of N-tosyl-5-methyl-3-methylidene-2-ethylindole

Full text of DOI:10.1134/S107036321302028X

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 2, pp. 400–403. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © D.A. Skladchikov, R.R. Gataullin, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 2, pp. 345–348.
LETTERS
TO THE EDITOR
Synthesis of N-Tosyl-5-methyl-3-methylidene-2-ethylindole
D. A. Skladchikov 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 June 21, 2012
DOI: 10.1134/S107036321302028X
The 3-methylideneindole derivatives are convenient
starting materials for obtaining some heterocyclic com-
pounds with biological activity [1–3]. Therefore these
structure attract high interest of synthetic chemists.
Such structures can be obtained via the palladium-
catalyzed heterofusion reaction of ortho- haloanilines
with 1,2-octadiene [4], cyclization of N-tosyl-2-(1-
propen-2-yl)aniline into N-tosyl-3-methylideneindole
[5], of organotin precursors into a mixture of N-acetyl-
3-methylideneindole and 3-methylindole [6], respec-
tively. Several 3-methylideneindole derivatives, in-
cluding N-Ac-, N-Bz-, N-Boc- and N-Cbz-2-ethyl-3-
methylideindole as a mixture with the 3-methyl-
substituted analog, N-tosylates of 4-, 5-, 6-methoxy-,
4-, 5-, 6-chloro-, and 4-methyl-3-methylidene-2-ethyl-
indoles were obtained via the olefins metathesis
reactions catalyzed by ruthenium complexes [2, 7, 8]
(Grubbs catalyst of the II second generation [9]).
Scholl et al. also obtained 3-methylidene-2-propyl-, 3-
methylidene-2-(2-methoxycarbethyl-1)-, and 3-
methylidene-2-(3-methoxycarbpropyl-1)indoles mixed
with the acyclic structures. At the same time, the
ortho-methyl- or ortho-methoxy-substituted analog
could not be synthesized in this way [7]. The
palladium-catalyzed heterocyclization of 2-chloro-(α-
aminomethyl)styrene can also be used to obtain the
unsubstituted 3-methylideneindole [9]. The N-benzyl-
containing 3-methylideneindole had previously been
obtained via the dehydroiodination of the
corresponding N-benzyl-3-iodomethylindole at heating
with DBU [11]. The research in this area is still actual.
Earlier we developed a synthesis of ortho-methyl-
3-methylideneindole I by the reaction of mesylates II
and III with Br2. This reaction occurs through the
formation of a relatively stable allyl halide IV [12]. In
MsNH Me
MsNH Me
MsNH
R1
Et
Me
Me
Br
Br2
Br2
NaHCO3
NaHCO3
Et
Et
III
IV
R2
II, VI, VII
Br2
Amine base
20оС
_HBr
NaHCO3
MsNH Me
Br
HBr
Et
Et
Et
N
N
R2
VIII, IХ
Me
Me
Ms
Ms
V
I
II, R1 = Me, R2 = H; VI, R1 = R2 = H; VII, R1 = H, R2 = Me; VIII, R2 = H; IX, R2 = Me.
400

401
SYNTHESIS OF N-TOSYL-5-METHYL-3-METHYLIDENE-2-ETHYLINDOLE
the presence of NH3 or Et2NH bromide IV easily
transforms into the indoline I containing an exo-
methylidene group. In the absence of amine compound
IV underwent spontaneous cyclization into indole V in
a quantitative yield. The treatment of I with HBr
solution also results in indole V.
In this work we present the approaches to the
synthesis of 3-methylideneindole starting from some
alkenylanilines. We found that an analog of I with a
para-positioned methyl group, 2-ethyl-5-methyl-3-
methylene-1-[(4-methylphenyl)sulfonyl]indoline
X,
can be obtained via the oxidative cyclization of N-
tosylate XI [12] in the presence of palladium acetate.
One of the possible transformations of 3-
methylideneindole is obtaining 3-oxoindoles, the
application scope of which is quite diverse, including
using them as starting materials for the preparation of
compounds with photochrome properties [13].
But this method has some limitations, since it was
not possible to synthesize a similar 3-methylidene-
indole from the aniline derivative VI or p-toluidine
VII. Unlike sulfonyltoluidines II and III, the reaction
of methanesulfonylanilines VI or VII with Br2 gives
rise only to vinyl bromides VIII or IX [12].
CH3
CH2
H3C
H3C
Pd(OAc)2 (5 mol %)
CH3
Pyridine/toluene (1:5),
air, 80оС, 4 h
N
NHTs
Ts
ХI
Х, 53%
The composition and structure of compound X was
proved by the elemental analysis and spectral data. In
the 1H NMR spectrum of compound X a methyl group
of CH3CH2 fragment is represented as a triplet at 0.88
ppm (J 7.5 Hz). The methylene protons of this
fragment are magnetically non-equivalent, as
evidenced by the nature of their splitting. Thus, the
proton Н1'А appears as a doublet of doublets of quartets
at 1.80 ppm (J1 4.0, J1 7.5, Jgem 14.0 Hz). A doublet of
doublets of quartets at 2.15 ppm (J1 5.3, J1 7.5, Jgem
14.0 Hz) belongs to the proton Н1'B. These protons
differ in the coupling constants with the Н2 proton of
indole ring. The latter appears at δ 4.58 ppm as a
complex multiplet due to the long-range coupling
constants (J 2.0 Hz). The coupling constants of the
protons of terminal double bond, observed at 4.84 and
5.34 ppm, are small (2.0 Hz) and consistent with the
literature data. The location of the methyl protons of
aromatic fragments (δ 2.32 and 2.34 ppm) corresponds
to the calculated values. The aromatic protons of tosyl
groups are represented as the doublets at 7.15 and
7.54 ppm (J 8.2 Hz). The protons ortho-positioned
relative to the sulfonyl group have a small long-range
spin-spin coupling constant. The aromatic ring protons
appear at 7.08 (Н7, d. d, J1 2.0, J2 8.0 Hz), 7.11 (H4),
and 7.64 ppm (H6, d, J 8.0 Hz).
In order to obtain an analog of X containing readily
leaving N-acetyl or N-ethoxycarbonyl groups, we tried
to carry out the cyclization of compound XIIa, XIIb
under action of Pd(OAc)2. Both attempts were
unsuccessful. The cyclization product was not formed.
EtO2C_Cl,
CH3
CH3
H3C
H3C
K2CO3, CH2Cl2
CH3
CH3
or Ac2O, 20оС
NH2
NHR
ХIIa, XIIb
CH2
H3C
Pd(OAc)2 (5 mol %)
Pyridine/toluene (1:5),
N
air, 80оС, 4 h
R
R = EtO2C (a), Ac (b).
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SKLADCHIKOV, GATAULLIN
The heating of a mixture of atropisomers syn-XIII
that the formed intermediate C is unstable, therefore
the exocyclic double bond undergoes migration as a
result of a 1,3-H-shift to form the aromatic structure
XIV, which is more favorable by the energy.
and anti-XIII [14] in the presence of Pd(OAc)2 results
in 1-acetyl-3-ethyl-2-methyl-1H-indole XIV in 62%
yield after chromatographic purification. We believe
I
I
PdLn
CH3
CH3
CH3
Pd(OAc)2/PPh3
Et3N, K2CO3
I
PdLn
CH3
CH3
toluene, reflux, 10 h
N
N
CH3
N
H3C
O
H3C
O
H3C
O
ХIII
syn-/anti-
B
А
CH3
CH3
CH3
CH3
N
N
H3C
O
H3C
O
C
ХIV, 62%
The composition and the structure of resulting
indole XIV were determined on the basis of the
elemental analysis and spectral data. The presence of
(4.4 mmol) of tosylamide XI in 1 ml of toluene and
0.2 ml of pyridine was added 0.096 g (0.5 mmol) of
Pd(OAc)2. The reaction mixture was heated at 80°C
with blowing air through the solution for 5 h, cooled to
room temperature, transferred to a column filled with
30 g of silica gel and eluted with benzene to yield
1.34 g of crude product. The latter was recrystallized
from ethanol. Yield 0.76 g (53%), white crystals, mp
113–116°C. The spectral characteristics are discussed
in the text. Chromatography of the mother liquor on
silica gel gave an additional 0.41 g of the starting
amide XI and the cyclization product X in equal ratios.
1
the ethyl group was proved by the presence in the H
NMR spectrum of a triplet signal at 1.10 ppm and a
quartet at 2.58 ppm (coupling constant ≈ 7.5 Hz). In
addition, there are two singlet signals of two methyl
groups at 2.45 and 2.62 ppm. The signals of aromatic
protons are shifted downfield.
The IR spectra were recorded on a FT IR Presstige-
1
21 (Shimadzu) spectrophotometer. The H and 13C
NMR spectra were recorded on a Bruker AM 300
instrument operating at 300.13 and 75.45 MHz and
Bruker Avance III 500 spectrometer operating at
500.13 and 125.73 MHz, internal reference TMS. The
elemental analysis was performed on a CHN Analyzer
M-185B. The mass spectra (APCI) were taken on a
LCMS-2010EV spectrometer (mobile phase methanol–
water, 50:50). The purity of the samples was
determined on a Chromos GC-1000 complex using
helium as a carrier gas, flame-ionization detector,
column of 1 m × 3 mm, 5% SE 30 on a Chromaton N-
AW carrier. TLC analysis was performed using Sorbfil
plates (Sorbpolimer, Krasnodar) and detecting with
UV irradiation (λ 254 nm) or iodine vapor.
1-Acetyl-3-ethyl-2,5-dimethyl-1H-indole (XIV).
To a solution of 0.009 g (0.04 mmol) of Pd(OAc)2,
0.02 g (0.08 mmol) of PPh3 in 3 ml of toluene was
added 0.011 ml (0.12 mmol) of triethylamine, 0.017 g
(0.12 mmol) of K2CO3, and 0.14 g (0.04 mmol) of the
atropisomers XIII mixture. The reaction mixture was
refluxed for 10 h, then cooled to room temperature,
transferred into a column filled with 3 g of silica gel,
and eluted with benzene. Yield 0.05 g (62%), Rf 0.74
1
(C6H6–EtOAc, 10:1). H NMR spectrum (CDCl3), δ,
ppm: 1.10 t (3H, CH3, J 7.5 Hz), 2.45 s (3H, CH3),
2.58 q (2H, CH2, J 7.5 Hz), 2.62 s (3H, CH3), 7.12–
7.16 m (2НAr), 7.36–7.38 m (1НAr), 7.85–7.89 m
(1НAr). Mass spectrum, m/z: 202 [M + H]+.
2-Ethyl-5-methyl-3-methylene-1-[(4-methylphenyl)-
sulfonyl]indoline (X). To a solution of 1.435 g
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SYNTHESIS OF N-TOSYL-5-METHYL-3-METHYLIDENE-2-ETHYLINDOLE
8. Ogawa, T., Nakamura, T., Araki, T., Yamamoto, K.,
Shuto, S., and Arisawa, M., Eur. J. Org. Chem., 2012,
p. 3084.
REFERENCES
1. Ma, J., Yin, W., Zhou, H., Liao, X., and Cook, J.M.,
J. Org. Chem., 2009, vol. 74, p. 264.
2. Terada, Y., Arisawa, M., and Nishida, A., J. Org.
Chem., 2006, vol. 71, p. 1269.
3. Azotsoderzhashchie geterotsikly (Nitrogen-Containing
Heterocycles), Karstev, V.G., Ed., Moscow: Iridium-
Press, 2006, vol. 1, p. 353.
9. Scholl, M., Ding, S., Lee, C.W., and Grubbs, R.H., Org.
Lett., 1999, vol. 1, no. 6, p. 953.
10. Baxter, C.A., Cleator, E., Alam, M., Daves, A.J.,
Goodyear, A., and O’Hagen, M., Org. Lett., 2010,
vol. 12, p. 668.
11. Tidwell, J.H. and Buchwald, S.L., J. Am. Chem. Soc.,
1994, vol. 116, p. 11797.
4. Larock, R.C., Berrios-Pena, N.G., and Fried, C.A.,
J. Org. Chem., 1991, vol. 56, p. 2615.
5. Larock, R.C., Hightower, T.R., Hasvold, L.A., and
12. Gataullin, R.R., Sotnikov, A.M., Spirikhin, L.V., and
Abdrakhmanov, I.B., Zh. Org. Khim., 2005, vol. 41,
no. 5, p. 730.
Peterson, K.R., J. Org. Chem., 1996, vol. 61, p. 3584.
13. Matsumoto, S., Samata, D., Akazome, M., and Ogura, K.,
6. Lin, H. and Kazmaier, U., Eur. J. Org. Chem., 2009,
Tetrahedron Lett., 2009, vol. 50, p. 111.
p. 1221.
14. Skladchkov, D.A. and Gataullin, R.R., Zh. Obshch.
Khim., 2013, vol. 83, no. 2, p. 313.
7. Arisawa, M., Terada, Y., Takahashi, K., Nakagawa, M.,
and Nishida, A., J. Org. Chem., 2006, vol. 71, p. 4255.
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