Synthesis of 2-alkyl-3-(indol- 2(or 3)-yl)-1,3-dihydroisoindol- 1-ones by amidoalkylation

Article abstract of DOI:10.1007/s10593-009-0333-4

2-Alkyl-3-(indol-3-yl)-1,3-dihydroisoindol-1-ones have been obtained in good yield on amidoalkylation of indoles with 2-alkyl-3-hydroxyphthalides in chloroform at room temperature in the presence of catalytic quantities of boron trifluoride etherate. When

Full text of DOI:10.1007/s10593-009-0333-4

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
SYNTHESIS OF 2-ALKYL-3-(INDOL-
2(OR 3)-YL)-1,3-DIHYDROISOINDOL-
1-ONES BY AMIDOALKYLATION
N. P. Andryukhova1, O. A. Pozharskaya1, G. A. Golubeva1,
L. A. Sviridova1, and A.V. Sadovoy1*
2-Alkyl-3-(indol-3-yl)-1,3-dihydroisoindol-1-ones have been obtained in good yield on amidoalkylation
of indoles with 2-alkyl-3-hydroxyphthalides in chloroform at room temperature in the presence of
catalytic quantities of boron trifluoride etherate. When a substituent is present at position 3 of the
indole, attack is directed to position 2 of the indole nucleus.
Keywords: 2-alkyl-3-hydroxyphthalides, 2-alkyl-3-(indol-3-yl)-1,3-dihydroisoindol-1-ones, indoles,
amidoalkylation, rotational isomerism.
The amidoalkylation reaction is widely applied in synthetic organic chemistry [1]. In the indole series
this reaction leads, depending on the structure of the substrate, the reactant, and the reaction conditions, to
substitution in position 1 [2], 2 [3-5], or 3 [1-3] of the indole molecule, and in strongly acidic medium
amidoalkylation is directed to position 5 or 6 [6].
We have found that both indole itself and its 1- and/or 2-substituted derivatives 1 react with 2-alkyl-
3-hydroxyphthalides 2 in chloroform at room temperature in the presence of catalytic amounts of boron
trifluoride etherate, and attack is directed to position 3 of the indole nucleus.
The obtained compounds 3 are stable crystalline substances, in the 1H NMR spectra of which the signal
of the proton in position 3 of the indole nucleus has disappeared and a signal for a benzhydryl proton appears.
The properties and spectral characteristics of the obtained compounds are correlated in Tables 1 and 2.
1
In the H NMR spectra of compounds 3a-d,h-j a double set of portions of signals of comparable
intensity was observed, and the greatest difference in values of the chemical shifts of the two sets of signals was
observed for the protons in position 3 of the isoindolone and the methyl group in position 2 of the indole (see
Table 2). In the spectra of compounds 3k-o the intensity of the second set of signals was significantly less, and
in the spectra of the remaining compounds only one set of signals was present. This doubling is impossible to
explain by a competing attack at position 1 of indole, since it is also observed in the case of N-methyl
derivatives of indole (compounds 3i-k,m,o).
_______
* To whom correspondence should be addressed, e-mail: sadovoy@mail.ru.
1Moscow M. V. Lomonosov State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 847-852, June, 2009. Original
article submitted March 11, 2008.
672
0009-3122/09/4506-0672©2009 Springer Science+Business Media, Inc.

R2
O
O
O
R1
N
R3
N
R3
N
R3
R2
+
or
N
R
OH
1a–i
R1
R N
2a–d
N
R
3a–o
4
R
R1
R2
R3
1a
1b
1c
1d
1e
1f
H
Me
H
H
H
H
H
H
H
H
Me
H
H
H
Me
H
Me
p-MeC6H4
p-MeC6H4
p-ClC6H4
Ph
Me
H
1g
1h
1i
Me
H
H
Me
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
(CH2)2CHMe2
c-C6H11
(CH2)3OBu
CH2CH2Ph
(CH2)2CHMe2
c-C6H11
H
Me
H
Me
H
Me
(CH2)3OBu
CH2CH2Ph
(CH2)2CHMe2
(CH2)2CHMe2
(CH2)3OBu
(CH2)2CHMe2
c-C6H11
H
Me
Me
H
H
H
3g
3h
3i
H
H
Me
Me
Me
H
Me
Me
3j
Me
CH2CH2Ph
(CH2)2CHMe2
c-C6H11
3k
3l
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-ClC6H4
Ph
H
3m
3n
3o
4
Me
H
(CH2)2CHMe2
c-C6H11
Me
H
c-C6H11
Me
CH2CH2Ph
It is known that in a series of indole derivatives a rearrangement of the Wagner-Meerwein type may take
place in acidic media, occasionally under very mild conditions, as a result of which migration occurs of a group
from position 3 to position 2 of indole, and a substituent from position 2 may transfer to position 3 [3]. To check
this hypothesis we carried out the interaction of the isomeric 2-methylindole (1a) and 3-methylindole (1i), and
1
also 1,2-dimethylindole (1d), with 3-hydroxy-2-phenylethylphthalide (2d). In the H NMR spectra of the
obtained compounds 3d,j two sets of signals were observed, but in the spectrum of compound 4 there was only
one set of signals. The spectra of isoindolones 3d and 4 differed significantly from one another and contained no
common signals (see Table 2). The sole signal for the methyl group in the spectrum of compound 4 was found at
2.15-2.45 ppm (br. s), and in the spectra of compounds 3d,j the methyl group was displayed as two signals at
1.60-1.65 and 2.50-2.55 ppm. Therefore isomerization does not occur in the course of the reaction being studied.
673

TABLE 1. Characteristics of the Obtained Compounds 3, 4
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
3a
3b
3c
3d
3e
3f
C22H24N2O
79.69
79.48
7.08
7.28
8.31
8.43
182-185
244-245
140-142
192-195
125-127
158-160
128-130
137-139
176-178
149-151
267-269
302-304
138-140
297-298
181-182
198-201
48
70
34
55
32
62
46
66
40
84
56
70
50
58
64
54
C23H24N2O
C24H28N2O2
C25H22N2O
C22H24N2O
C21H22N2O
C23H26N2O2
C23H26N2O
C24H26N2O
C26H24N2O
C28H28N2O
C29H28N2O
C29H30N2O
C28H25ClN2O
C29H28N2O
C25H22N2O
80.04
80.20
7.24
7.02
8.00
8.13
76.77
76.56
7.30
7.50
7.32
7.44
82.03
81.94
6.15
6.05
7.75
7.64
79.75
79.48
7.05
7.28
8.37
8.43
79.54
79.21
7.10
6.96
8.78
8.80
3g
3h
3i
76.54
76.21
7.37
7.23
7.71
7.73
79.75
79.73
7.92
7.56
8.13
8.09
80.50
80.41
7.27
7.31
7.86
7.81
3j
82.40
82.07
6.57
6.36
7.28
7.36
3k
3l
82.14
82.32
6.99
6.91
6.85
6.86
83.02
82.82
6.59
6.71
6.60
6.66
3m
3n
3o
4
82.52
82.43
7.30
7.16
6.60
6.63
76.10
76.27
5.52
5.71
6.40
6.35
82.99
82.82
6.97
6.71
6.58
6.66
82.02
81.94
6.28
6.05
7.64
7.64
Probably in this case we are dealing with inhibition of internal rotation around the indole C-3 and
isoindolone C-3 σ-bond. In reality in the spectra of the compounds in which there is no substituent in position 2
of the indole nucleus (3e-g) steric difficulties are insignificant and we are observing the sole set of signals in the
spectra. If there is a bulky aryl group in position 2 of the indole (compounds 3k-o), rotation is impeded or
impossible, and probably as a result of significant steric hindrance one of the possible rotational isomers exists
preferentially. Consequently the intensity of the signals of the second rotational isomer in the 1H NMR spectra is
small. In the presence of a methyl group in position 2 of the indole (compounds 3a-d,h-j) the existence of both
rotational isomers is possible, but the internal rotation is hindered or impossible, and both rotational isomers are
clearly displayed in the spectra in comparable amounts.
There was no temperature dependence in the spectra of compounds 3a,b,d,h,j obtained in DMSO-d6 at
temperatures of 20, 40, and 60oC, therefore the barrier to rotation around the σ-bond from C-3 in the indole to
C-3 in the indolone is fairly high.
We were unsuccessful in reacting 2-(m- and p-nitrophenyl)indoles under the given conditions due to
their low reactivity, and in the case of 2-(m- and p-methoxyphenyl)indoles the reaction products proved to be
contaminated to a significant extent by starting indoles due to the low solubility of the reaction products and of
the starting materials.
674

TABLE 2. 1H NMR Spectra of Compounds 3, 4 at 20oC
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3a
3b
3c
0.8-0.9 (6H, 2d, J ≈ 7, CH(CH3)2); 1.3-1.5 (2H, m, CCH2C); 1.5-1.6 (1H, m, CH(CH3)2);
1.65, 2.65 (3H, 2s, ~1:4, CH3); 2.7-2.9 (1H, m, NCH2); 3.6-3.8 (1H, m, NCH'2);
5.8, 6.1 (1H, 2s, ~ 4:1, H-3); 6.2-7.8 (8H, m, arom.); 11.0 (1H, br. s, NH)
0.8-2.0; 1.7 (10 + 0.6H, br. m, 5CH2 + high field portion CH3C);
2.7 (2.4H, s, low field portion CH3C); 3.6-3.8 (1H, br. m, NCH(CH2)5);
5.9, 6.15 (1H, 2 s, ~4:1, H-3); 6.3-7.8 (8H, m, arom.); 10.9 (1H, br. s, NH)
0.85 (3H, t, J ≈ 7, CH3); 1.1-1.5 (4H, m, 2CH2);
1.5-1.85, 1.7 (~2.5H, m, CH2 + high field portion H-3);
2.6 (~2.5H, s, low field portion CH3); 2.8-3.0 (1H, m, NCH2); 3.2-3.4 (4H, m, 2CH2O);
3.6-3.9 (1H, m, NCH'2); 5.8, 6.1 (1H, 2s, ~5:1, H-3); 6.2-7.8 (8H, m, arom.);
11.0 (1H, br. s, NH)
3d
3e
3f
1.65, 2.5 (3H, 2s, ~1:5, CH3C); 2.7 (1H, m, CH2C6H5); 3.0 (1H, m, CH'2C6H5);
3.4 (1H, m, NCH2); 3.9 (1H, m, NCH'2); 5.5, 5.8 (1H, 2s, ~5:1, H-3);
6.2 - 7.9 (13H, m, arom.); 10.8 (1H, br. s, NH)
0.8-0.9 (6H, 2d, J ≈ 7, CH(CH3)2); 1.4 (2H, m, CCH2C); 1.5 (1H, m, CH(CH3)2);
2.7-2.9 (1H, m, NCH2); 3.7-3.8 (1H, m, NCH'2); 3.85 (3H, s, CH3N); 5.85 (1H, s, H-3);
6.55-7.8 (9H, m, arom.)
0.8-0.9 (6H, 2d, J ≈ 7, CH(CH3)2); 1.4 (2H, m, CCH2C); 1.45-1.6 (1H, m, CH(CH3)2);
2.7-2.9 (1H, m, NCH2); 3.7-3.9 (1H, m, NCH'2); 5.85 (1H, s, H-3);
6.5-7.8 (9H, m, arom.); 11.1 (1H, br. s, NH)
3g
3h
3i
0.85 (3H, t, J ≈ 7, CH3,); 1.1-1.5 (4H, m, 2CH2); 1.5-1.85 (2H, m, CH2);
2.8-3.0 (1H, m, NCH2); 3.2-3.4 (4H, m, 2CH2O); 3.6-3.9 (1H, m, NCH'2);
5.9 (1H, s, H-3); 6.5-7.8 (9H, m, arom.); 11.1 (1H, br. s, NH)
0.8, 0.9 (6H, 2d, J ≈ 7, CH(CH3)2); 1.4 (2H, m, CCH2C); 1.5 (1H, m, CH(CH3)2);
1.7, 2.7 (3H, 2s, ~1:4, CH3C); 2.75 (1H, m, NCH2); 3.75 (1H, m, NCH'2);
3.6, 3.8 (3H, 2 s, ~ 1:4, CH3N); 5.9, 6.1 (1H, 2 s, ~4:1, H-3); 6.2-7.8 (8H, m, arom.)
0.8-2.0; 1.7 (10 + 0.6H, br. m + s, 5CH2 + high field portion CH3C);
2.7 (2.4H, s, low field portion CH3C); 3.6, 3.8 (3H, 2s, ~1:4, CH3N);
3.7 (1H, br. m, NCH(CH2)5); 5.9, 6.15 (1H, 2s, ~4:1, H-3); 6.3-7.8 (8H, arom.)
3j
1.6, 2.55 (3H, 2s, ~1:4, CH3C), 2.65-2.8 (1H, m, CH2C6H5), 2.85-3.0 (1H, m, CH'2C6H5),
3.05-3.2 (1H, m, NCH2), 3.6-3.85 (3H, 2s, ~1:4, CH3N), 3.85-3.95 (1H, m, NCH'2),
5.7, 6.0 (1H, 2s, H-3); 6.2-7.8 (13H, m, arom.)
3k
0.6-0.7 (6H, 2t, J ≈ 7, CH(CH3)2); 0.85-1.2 (2H, m, CCH2C); 1.2-1.4 (1H, m, CH(CH3)2);
2.45 (3H, s, CH3); 2.55-2.65 (1H, m, NCH2); 3.55-3.75 (1H, m, NCH'2);
5.9, 6.2 (1H, 2 s, ~6:1, H-3); 6.3-7.9 (12H, m, arom.); 11.4 (1H, br. s, NH)
3l
0.7-1.6 (10H, br. m, 5CH2); 2.4 (3H, s, CH3); 3.6-3.8 (1H, br. m, NCH(CH2)5);
5.95, 6.2 (1H, 2s, ~ 40:1, H-3); 6.4-7.8 (12H, m, arom.); 11.3 (1H, br. s, NH)
3m
0.7-0.8 (6H, 2d, J ≈ 7, CH(CH3)2); 0.9-1.2 (2H, m, CCH2C); 1.2-1.4 (1H, m, CH(CH3)2);
2.45 (3H, s, CH3C); 2.55-2.7 (1H, m, NCH2); 3.7 (3H, s, CH3N); 3.7-3.8 (1H, m, NCH'2);
5.55, 6.1 (1H, 2s, ~20:1); 6.3-7.8 (12H, m, arom.)
3n
3o
4
0.7-1.6 (10H, br. m, 5CH2); 3.6-3.8 (1H, br. m, NCH(CH2)5);
5.95, 6.25 (1H, 2 s, ~20:1, H-3); 6.4-7.8 (12H, m, arom.); 11.4 (1H, br. s, NH)
0.8-1.7 (10H, br. m, 5CH2); 3.6-3.8 (4H, br. m + s, NCH(CH2)5) + CH3);
5.6, 6.25 (1H, 2 s, ~40:1), 6.5-7.8 (13H, br. m, arom.)
2.15-2.45 (3H, br. s, CH3); 2.7-2.8 (1H, m, CH2C6H5); 2.9-3.0 (1H, m, CH'2C6H5);
3.05-3.15 (1H, m, NCH2); 3.95-4.1 (1H, m, NCH'2); 5.7 (1H, s, H-3);
6.9-7.8 (13H, m, arom.); 10.3 (1H, br. s, NH)
EXPERIMENTAL
1
The H NMR spectra were obtained on a Bruker AM 360 instrument (360 MHz) in DMSO-d6, internal
standard was TMS. A check on the progress of reactions was effected by TLC on Merck Silicagel 60 F254 plates.
The initial 2-alkyl-3-hydroxyphthalides 2a-d were obtained by the procedure of [7].
675

Preparation of Compounds 3 and 4 (General Method). A small excess (~5%) of 2-alkyl-
3-hydroxyphthalide 2a-d was added to a solution or suspension of indole 1a-i (1 mmol) in CHCl3 (10ml) at
room temperature in one batch with stirring. Boron trifluoride etherate (~10 mol %) was then added. The
suspension of the initial indole, if still present, dissolved after several minutes, the solution became colored, and
water separated as an emulsion. The mixture was stirred for 2-3 h, then left overnight. If the reaction product
separated as a solid it was filtered off, washed with CHCl3, with alcohol, with ether, and dried. Otherwise the
reaction mixture was passed through a layer of silica gel (Merck, for column chromatography, 0.035-0.070 nm,
pore diameter 6 nm, 500 m2/g) (eluent CHCl3), the eluate was evaporated in vacuum, the residue was triturated
with ether (in the case of N-methylindoles with hexane), the solid was filtered off, washed with ether or hexane,
and dried.
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676