Interaction of 4-hydroxymethyl- 2-(3,4-dimethoxybenzyl)isoindoline with methyl propiolate

Full text of DOI:10.1007/s10593-009-0261-3

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
INTERACTION OF 4-HYDROXYMETHYL-
2-(3,4-DIMETHOXYBENZYL)ISOINDOLINE
WITH METHYL PROPIOLATE
L. G. Voskressensky1*, L. N. Kulikova1, A. V. Kleimenov1, T. N. Borisova1,
E. V. Nikitina1, A. V. Listratova1, and A. V. Varlamov1
Keywords: benzo[c]azepine, isoindoline.
We showed previously that tetrahydropyrrolopyridines and hexahydroazepinoindoles, under the action
of alkynes activated by electron-withdrawing substituents, undergo, depending on the type of solvent, either
expansion of the hydrogenated aza fragment, or its decomposition. In this way tetrahydropyrroloazocines and
hexahydroazoninoindoles or substituted pyrroles and indoles [1, 2] respectively are formed. This reaction is an
efficient method of synthesizing condensed azocines and azonines.
Transformation of isoindolines by alkynes have not previously been studied. We synthesized
2-dimethoxybenzyl-4-hydroxymethylisoindoline (1) by the reduction of 2-dimethoxybenzyl-3-oxoisoindoline-
4-carboxylic acid [3] with lithium aluminum hydride and studied its conversion under the action of methyl
propiolate in acetonitrile and methanol at 20 and -10oC.
O
OH
OH
OMe
N
N
MeOH
MeCN
O
2
OMe
MeO
OMe
O
1
O
OH
OMe
OMe
MeOH
N
OMe
OMe
3
_______
* To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Russian Peoples' Friendship University, Moscow 117198, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 456-458, March, 2009. Original
article submitted March 12, 2009.
372
0009-3122/09/4503-0372©2009 Springer Science+Business Media, Inc.

Debenzylation of compound 1 occurs in methanol and acetonitrile at 20oC with the formation of
methoxycarbonylvinyl-substituted derivative 2. At a temperature from -5 to -10oC the competing processes of
debenzylation and expansion of the isoindoline fragment leads to a mixture of isoindoline 2 and benzoazepine 3.
The observed conversions of isoindoline 1 under the action of methyl propiolate occur through the
formation of a zwitterion.
O
OH
OMe
MeOH
C
2
3
OMe
+
N
–
OMe
OMe
MeO
OMe
A
The high capability of the dimethoxybenzyl radical towards cationic fission causes the formation of the
debenzylation product 2. Nucleophilic attack of the anionic center of A at position 3 leads to the ring expansion
product azepine 3. It is possible that the formation of compound 3 at low temperature is caused by the fact that
the energy of activation of the expansion process is less than that of debenzylation.
The possibility has therefore been shown for the first time of expanding the tetrahydropyrroline ring to
an azepine under the action of activated alkynes.
1
The H NMR spectra were obtained on a Jeol JNM-ECA 600 instrument (600 MHz) in CDCl3, internal
standard was TMS.
[2-(3,4-Dimethoxybenzyl)-2,3-dihydro-1H-isoindol-4-yl]methanol (1). 2-(3,4-Dimethoxybenzyl)-
3-oxoindoline-4-carboxylic acid (5 g, 15.3 mmol) was added in portions to a suspension of lithium aluminum
hydride (2.32 g, 62 mmol) in dioxane (100 ml) and the mixture was boiled. A check on the progress of the
reaction was effected by TLC. The reaction mixture was cooled to 20oC and decomposed by adding
sequentially, dropwise, ethyl acetate (30 ml) and a 5% sodium hydroxide solution (100 ml), and the mixture was
extracted with ethyl acetate (3×100 ml). The extract was dried over sodium sulfate. After distillation of the ethyl
acetate in vacuum the residue was crystallized from a mixture of hexane and ethyl acetate. Isoindole 1 (3.14 g,
1
70%) of mp 134oC was obtained. H NMR spectrum, δ, ppm (J, Hz): 3.73 (2H, s, NCH2); 3.79 (3H, s, OCH3);
3.85 (3H, s, OCH3); 3.82 (2H, s, NCH2); 4.77 (2H, s, CH2OH); 6.78-7.32 (6H, m, arom.). Found, %: C 72.22;
H 7.07; N 4.68. M+ 299. C18H21NO3. Calculated, %: C 72.28; H 7.04; N 4.70.
Interaction of Isoindoline 1 with Methyl Propiolate. A solution of isoindoline 1 (0.51 g, 1.7 mmol)
and methyl propiolate (0.2 g, 2.5 mmol) in methanol or acetonitrile (10 ml) was maintained at 20oC or -5oC until
the disappearance of the starting material (check on the progress of the reaction by TLC). The solvent was
evaporated in vacuum, and the residue obtained was chromatographed on silica gel, eluent was ethyl acetate–
hexane, 1:20 to 1:1. Compounds 2 and 3 were obtained.
2-(3,4-Dimethoxybenzyl)-6-(hydroxymethyl)-2,5-dihydro-1H-2-benzoazepine-4-carboxylic
Acid
Methyl Ester (3). Yield was 40%, white crystals of mp 129oC. 1H NMR spectrum, δ, ppm (J, Hz): 3.69 (3H, s,
CO2CH3); 3.84 (3H, s, OCH3); 3.87 (3H, s, OCH3); 3.89 (2H, s, NCH2); 4.61 (2H, d, J = 4.6, CH2OH); 4.85 (2H,
s, NCH2); 4.91 (2H, s, NCH2); 6.78 (3H, m, arom.); 7.09-7.32 (3H, m, arom.); 7.87 (1H, s, H-3). Found, %:
C 68.74; H 6.41; N 3.71. M+ 383. C22H25NO5. Calculated, %: C 68.91; H 6.57; N 3.65.
3-[4-(Hydroxy)-1,3-dihydro-2H-isoindolyl]acrylic Acid Methyl Ester (2). Yield was 19%, yellowish
1
crystals, mp 116oC. H NMR spectrum, δ, ppm (J, Hz): 3.67 (3H, s, CO2CH3); 3.82 (2H, s, NCH2); 3.84 (2H, s,
NCH2); 4.65 (1H, d, J = 13.1, =CHCO2CH3); 4.9 (2H, s, CH2OH); 7.19-7.34 (3H, m, arom.); 7.73 (1H, d, J = 13.1,
NCH=). Found, %: C 66.71; H 6.63; N 6.12. M+ 233. C13H15NO3. Calculated, %: C 66.95; H 6.44; N 6.00.
373

The work was carried out with the financial support of the Russian Fund for Fundamental Investigations
(RFFI) (grant No. 08-03-90451 Ukr-a).
REFERENCES
1.
2.
3.
L. G. Voskresensky, T. N. Borisova, T. A. Vorob′eva, A. I. Chernyshev, and A. V. Varlamov, Izv. Akad.
Nauk, Ser. Khim., 2513 (2005).
L. G. Voskressensky, S. V. Akbulatov, T. N. Borisova, and A. V. Varlamov, Tetrahedron, 62, 12392
(2006).
F. I. Zubkov, E. V. Boltukhina, K. E. Turdin, R. S. Borisov, and A. V. Varlamov, Tetrahedron, 61, 4009
(2005).
374