Synthesis of 2-aryl-substituted 3-allyl-7-carboxyphthalamidines - New synthones for the construction of isoindolo[2,1-a]quinolines [1]

Full text of DOI:10.1023/A:1016047809349

Chemistry of Heterocyclic Compounds, Vol. 38, No. 4, 2002
LETTERS TO THE EDITOR
SYNTHESIS OF 2-ARYL-SUBSTITUTED
3-ALLYL-7-CARBOXYPHTHALAMIDINES –
NEW SYNTHONES FOR THE CONSTRUCTION
OF ISOINDOLO[2,1-a]QUINOLINES
A. V. Varlamov, N. V. Sidorenko, F. I. Zubkov, and A. I. Chernyshev
Keywords: homoallylamines, isoindolinones, furfurylamines, intramolecular [4+2] cycloaddition.
The major synthones for the construction of isoindolo[2,1-a]quinolines are 1-hydroxy- and
1
-carboxymethyl-2,3-dihydro-2-aryl-3-oxoisoindoles obtained from N-arylphthalimides [1, 2]. We have
developed an original method for the synthesis of 3-allyl-2-aryl-7-carboxy-1-isoindolinones, which are new
synthones for the construction of this heterocyclic system, by means of transformations of furan
homoallylamines. Homoallylamines 1a,b were obtained by the reaction of the corresponding Schiff bases with
allylmagnesium bromides [3].
COOH
COOH
O
O
O
O
O
6
4
5
1
7
3
+
H
O
N
N
O
2
N
C
2
6
H
5°C
,
6
R
9
R
H
R
1
a,b
3a,b
2
a,b
a R = H; b R = Me
The reaction of allylamines 1a,b with maleic anhydride was carried out in benzene at 25°C and gave
3
a,6-epoxyisoindolinones 2a,b, in 88 and 95% yield, respectively. Adducts 2a,b are the products of the
1
acylation and subsequent exo-[4+2] cycloaddition of the amide fragment to the furan ring [4]. H NMR
spectroscopy showed that adducts 2a,b are obtained as 1:1 mixtures of isomers differing in the position of allyl
substituent relative to the epoxide bridge. Aromatization of these compounds to the desired dihydroisoindolones
3
a,b was carried out by the action of excess phosphoric acid.
2
-Allyl-3-aryl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic Acids (2a,b). A mixture
of maleic anhydride (0.1 mol) and homoallylamine 1a or 1b (0.1 mol) in benzene (100 ml) was stirred for 24 h
at 25°C. The crystalline precipitate was filtered off, washed with benzene, and dried at 90°C to constant mass.
_
_________________________________________________________________________________________
Russian People's Friendship University, 117198 Moscow, e-mail: avarlamov@sci.pfu.edu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 556-557, April, 2002. Original article submitted
November 23, 2001.
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90
0009-3122/02/3804-0490$27.00©2002 Plenum Publishing Corporation

Adduct 2a (mixture of isomers) was obtained in 88% yield as white crystals with mp 149-152°C.
H NMR spectrum (CDCl , 200 MHz), δ, ppm, J (Hz): isomer A: 10.06 (1H, br. s CO H); 7.45-7.20 (5H, m,
1
3
2
3
3
H-Ph); 6.62 (1H, d, J98 = 5.8, 9-H); 6.49 (1H, dd, J89 = 5.8, J78 = 1.8, 8-H); 5.77 (1H, m, J = 9.3, J = 18.0, 2-H);
3
3
3
3
5
.33 (1H, d, J78 = 1.8, 7-H); 5.19 (1H, dd, J = 9.3, J = 1.3, 1'-H-cis); 5.17 (1H, dd, J = 18.0, J = 1.3,
'-H-trans); 4.63 (1H, t, J23'A = J23'B = 4.8, 2-H); 3.10 (1H, d, J56 = 9.2, 5-H); 2.86 (1H, d, J56 = 9.2, 6-H); 2.62
1
(
2H, m, 3'A-H and 3'B-H). Isomer B: 10.06 (1H, br. s, CO
2
H); 7.45-7.20 (5H, m, H-Ph); 6.47 (1H, d, J89 = 5.8,
3
3
9
7
-H); 6.39 (1H, dd, J89 = 5.8, J78 = 1.8, 8-H); 5.71 (1H, m, J = 10.4, J = 18.5, 2'-H); 5.27 (1H, d, J78 = 1.8,
3 3 3 3
-H); 5.09 (1H, dd, J = 10.4, J = 1.3, 1'-H-cis); 5.07 (1H, dd, J = 18.5, J = 1.3, 1'-H-trans); 4.59 (1H, dd,
J
23'A = 5.2, J23'B = 9.8, 2-H); 3.02 (1H, d, J56 = 9.2, 5-H); 2.84 (1H, d, J56 = 9.2, 6-H); 2.41 (2H, m, 3'A-H and
-1
3
'B-H). IR spectrum (KBr), ν, cm : 1689, 1756 (C=O), 2610, 3390 (OH). Found, %: C 69.55; H 5.74; N 4.53;
+
M 311. C18
H17NO
4
. Calculated, %: C 69.45; H 5.47; N 4.50; M 311.
Adduct 2b (mixture of isomers) was obtained in 95% yield as white crystals; mp 139-141°C. H NMR
spectrum (DMSO-d , 200 MHz), δ, ppm, J (Hz): Isomer A: 7.45-7.20 and 7.15-6.95 (4H, m, H-Ar); 6.73 (1H, d,
89 = 6.1, 9-H); 6.52 (1H, dd, J89 = 6.1, J78 = 1.8, 8-H); 5.77 (1H, m, J = 10.1, J = 18.0, 2'-H); 5.15 (1H, m,
1
6
3
3
J
3
3
J = 18.0, 1'-H-trans); 5.13 (1H, m, J = 10.1, 1'-H-cis); 5.02 (1H, d, J78 = 1.8, 7-H); 4.66 (1H, dd, J23'A = 6.4,
23'B = 4.3, 2-H); 3.04 (1H, d, J56 = 9.2, 5-H); 2.58 (1H, d, J56 = 9.2, 6-H); 2.65-2.57 (2H, m, 3'-H); 2.32 (3H, s,
CH -Ar). Isomer B: 7.45-7.20 and 7.15-6.95 (4H, m, H-Ar); 6.56 (1H, d, J89 = 5.8, 9-H); 6.42 (1H, dd, J89 = 5.8,
J
3
3
3
J
78 = 1.8, 8-H); 5.77 (1H, m, J = 10.1, J = 18.0, 2'-H); 5.09 (1H, d, J78 = 1.8, 7-H); 5.10-5.00 (2H, m, 1'-H);
4
.81 (1H, dd, J23'A = 10.1, J23'B = 4.6, 2-H); 2.95 (1H, d, J56 = 9.2, 5-H); 2.59 (1H, d, J56 = 9.2, 6-H); 2.32 (2H, s,
-1
CH
3
-Ar); 2.65-2.55 (2H, m, 3'-H). IR spectrum (KBr), ν, cm : 1660, 1700, 1743 (C=O), 2600, 3400 (OH).
+
Found, %: C 69.89; H 5.80; N 4.39; M 325. C19
H19NO
4
. Calculated, %: C 70.15; H 5.85; N 4.31; M 325.
3
-Allyl-2-aryl-7-carboxy-1-isoindolinones (3a,b). A sample of epoxyisoindolinone 2 (16.6 mmol) in
8
5% phosphoric acid (40 ml) was heated at 60°C for 1 h with monitoring by thin-layer chromatography. The
mixture was cooled and poured into water. The crystalline precipitate was filtered off, washed with water until
the wash water was neutral, dried, and recrystallized from ethyl acetate.
1
Dihydroisoindolone 3a was obtained in 80% yield as white crystals; mp 132-134°C. H NMR spectrum
(
CDCl , 400 MHz), δ, ppm, J (Hz): 8.47 (1H, dd, 6-H); 7.80-7.75 (2H, m, 5-H and 4-H); 7.53-7.37 (5H, m,
3
3 3 3
H-Ph); 5.41 (1H, dd, J33'A = 3.7, J33'B = 6.1, 3-H); 5.26 (1H, m, J = 10.4, J = 17.1, 2'-H); 5.00 (1H, dd, J = 10.4,
3
J
J
11' = 1.2, 1'-H-cis); 4.86 (1H, dd, J = 17.1, J11' = 1.2, 1'-H-trans); 2.80 (1H, m, J3'A3 = 3.7, 3'A-H); 2.62 (1H, m,
-1
3'B3 = 6.1, 3'B-H). IR spectrum (KBr), ν, cm : 1652, 1728, 1745 (C=O), 2580 (OH). Found, %: C 73.51;
+
H 5.48; N 4.41; M 293. C18
H15NO
3
. Calculated, %: C 73.78; H 5.12; N 4.79; M 293.
Dihydroisoindolone 3b was obtained in 81% yield as colorless crystals; mp 122-125°C. H NMR spectrum
, 400 MHz), δ, ppm, J (Hz): 15.75 (1H, br. s, CO H); 8.47 (1H, dd, 6-H); 7.83-7.76 (2H, m, 5-H and
1
(
CDCl
3
2
3
3
3
4
-H); 7.41 (1H, t, J = 7.3, 5"-H); 7.35 (1H, br. s, 2"-H); 7.28 (1H, br. d, J = 7.3, 4"-H); 7.20 (1H, br. d, J = 7.3,
3 3
6
"-H); 5.37 (1H, dd, J33'A = 3.5, J33'B = 5.6, 3-H); 5.30 (1H, m, J = 9.7, J = 16.2, J3'B2' = 6.2, 2'-H); 5.01 (1H,
3
br. d, 3J = 9.7, 1'-H-cis) 4.87 (1H, br. d, J = 16.2, 1'-H-trans); 2.80 (1H, m, J3'A3 = 3.5, J3'3' = 13.7, 3'A-H); 2.63
-1
(
(
1H, m, J3'B3 = 5.6, J3'3' = 13.7, J3'2' = 6.2, 3'B-H), IR spectrum (KBr), ν, cm : 1610, 1713 (C=O), 2290, 3430
+
3
OH). Found, %: C 74.31; H 5.73; N 4.72; M 307. C19H17NO . Calculated, %: C 74.27; H 5.54; N 4.56; M 307.
This work was carried out with the financial support of the Russian Basic Research Fund (Grant No. 01-
0
3-32844).
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