Cycloaddition of furfurylamines to maleic anhydride and its substituted derivatives

Article abstract of DOI:10.1007/s10593-012-1023-1

The regio- and stereoselectivity of the [4+2] cycloaddition of maleic, citraconic, dichloromaleic, and dibromomaleic anhydrides to difurfuryl amines and secondary furfurylamines were studied. N-Furfuryl-, N-phenyl-, and N-benzylhexahydrooxoepoxyisoindole-7-carboxylic acids were synthesized. An approach was developed for obtaining hexahydroepoxyoxoisoindole-7-carboxylic acid unsubstituted at the nitrogen atom. Aromatization of the oxabicycloheptene fragment of the dihaloepoxyiso-indolonecarboxylic acids gave a series of 7-carboxy-2-R-isoindol-1-ones.

Full text of DOI:10.1007/s10593-012-1023-1

×Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
CYCLOADDITION OF FURFURYLAMINES TO MALEIC
ANHYDRIDE AND ITS SUBSTITUTED DERIVATIVES
V. P. Zaytsev1*, N. M. Mikhailova1, I. K. Airiyan1, E. V. Galkina1,
V. D. Golubev1, E. V. Nikitina1, F. I. Zubkov1, and A. V. Varlamov1
The regio- and stereoselectivity of the [4+2] cycloaddition of maleic, citraconic, dichloromaleic, and
dibromomaleic anhydrides to difurfuryl amines and secondary furfurylamines were studied. N-Furfuryl-,
N-phenyl-, and N-benzylhexahydrooxoepoxyisoindole-7-carboxylic acids were synthesized. An
approach was developed for obtaining hexahydroepoxyoxoisoindole-7-carboxylic acid unsubstituted at
the nitrogen atom. Aromatization of the oxabicycloheptene fragment of the dihaloepoxyiso-
indolonecarboxylic acids gave a series of 7-carboxy-2-R-isoindol-1-ones.
Keywords: furfurylamines, isoindolones, maleic anhydride, [4+2] cycloaddition.
Functionally substituted epoxyisoindolones hold interest for use in organic synthesis. Pseudo-sugars
annelated with azaheterocycles [1-3], and various condensed heterocyclic compounds containing an isoindole
fragment may be obtained on the basis of these compounds [4-10]. A recently developed method for the
synthesis of isoindol-1-ones holds considerable promise in this regard. This method is based on the acylation of
N-aryl- or N-alkylfurfurylamines by unsaturated acid derivatives with subsequent intramolecular [4+2]
cycloaddition of the resultant unsaturated amides [11-19].
The development of this approach is an elaboration of the two-step preparative method for the synthesis
of 7-carboxy-2-R-isoindol-1-ones [20] based on [4+2] cycloaddition of maleic anhydride to N-substituted
furfurylamines. We studied the scope of this reaction and showed the effect of the substituent at the furfuryl-
amine nitrogen atom on the cycloaddition. Conditions were found for the aromatization of the oxabicyclo-
heptene fragment to give 7-carboxyphthalimidines [21].
In the present work, we have studied the regio- and stereoselectivity of the cycloaddition of maleic,
citraconic, dibromomaleic, and dichloromaleic anhydrides to difurfurylamines as well as to phenyl- and benzyl-
furfurylamines. An attempt was made to evaluate the effect of substituents in the oxabicycloheptene fragment
on the capacity of the Diels-Alder adducts to undergo aromatization.
Starting furfurylamines 1a-h were obtained as light, mobile oils by the reduction of the corresponding
Schiff bases using sodium borohydride in ethanol.
_______
*To whom correspondence should be addressed, e-mail: vzaitsev@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, pp. 538-548, March, 2012. Original article
submitted April 26, 2011.
0009-3122/12/4803-0505©2012 Springer Science+Business Media, Inc.
505

R1
R1
NaBH4
EtOH
O
O
R
R
N
N
H
1a–h
a-d R = furfuryl, e,f R = Ph, g,h R = Bn;
a,e,g, R1 = H, b,f,h R1 = Me, c R1 = Br, d R1 = I
Difurfurylamines 1a-d readily undergo cycloaddition with maleic anhydride at room temperature to
give a mixture of isomeric N-furfurylisoindolonecarboxylic acids 2a-d. The addition takes place through the
intermediate formation of the maleic acid furfurylamide 2' and subsequent exo-[4+2] cycloaddition of the
unsaturated fragment to a furan ring [20].
O
O
R1
6
CO2H
O
R1
CO2H
O
7
5
O
O
O
O
4
1
exo-[4+2]
3
N2
N
N
O
1a–d
+
50–87%
C6H6
O
O
O
O
R1
OH
2'
A
B
2a–d
a R1 = H, b R1 = Me, c R1 = Br, d R1 = I
The cycloaddition to furfurylamines 1b-d at room temperature proceeds nonselectively at both furan
fragments to give a mixture of isomeric N-furfuryloxoepoxyisoindolonecarboxylic acids 2b-dA and 2b-dB. In
the case of 5-methyl- and 5-bromofurylamines 1b,c, isomers 2b,cB with substituent R1 in the oxabicycloheptene
fragment predominate in the product mixture, while isomer 2dA is the major component of the product mixture
in the case of iodine derivative 1d. In the case of difurfurylamine 1b (R1 = Me), we showed that lowering the
reaction temperature from 25°C to 0-5°C slightly increases the regioselectivity (the fraction of the isomer 2Bb
increases from 1:2.3 to 1:3). Isomer 2bB is probably the kinetic reaction product (the 5-methylfuran ring is a
better diene than its analog lacking a substituent at C-5), while isomer 2bA is the thermodynamic product (see
below). The cycloaddition of maleic anhydride to amines 1a-d in benzene at reflux proceeds both stereo- and
regioselectively. In the case of compounds 1c,d, the maleimide fragment undergoes cycloaddition to the
halofuran fragment to give isomers 2c,dB, while, in the case of methylfurfurylamine 1b, the reaction proceeds
at the unsubstituted furan fragment to give acid 2bA.
The ratio of isomers A and B was established by measuring the integral intensities of the signals for
1
H-4, H-5, and H-6 protons in the H NMR spectra of the air-dried reaction mixtures (the crystalline adducts
precipitated during the reaction were filtered off and washed with ether). The 1H NMR spectra of products 2a-d
show three characteristic signals from coupled protons H-4, H-5, and H-6 with chemical shifts 6.48-6.55, 6.41-
6.74, and 4.98-4.99 ppm, respectively, and coupling constants 3J5,6 = 1.5-1.7 and 3J4,5 = 5.6-5.7 Hz. The lack of
3
a J6,7 coupling constant in the oxabicycloheptene fragment unequivocally indicates endo arrangement of H-7
and H-7a protons (J7,7a = 8.7-9.3 Hz) and, thus, exo orientation of the carboxyl and amide substituents. The lack
3
of the characteristic signal for H-6 proton and coupling constant J5,6 indicate formation of acids 2 as the B
isomer. The protons of the 3-CH2 group in isoindolonecarboxylic acids 2a-d are chemically nonequivalent and
appear as an AB system with coupling constant 2JA,B = 11.2-11.8 Hz.
There is no description in the literature of methods of synthesis of epoxyisoindolonecarboxylic acids
lacking substituents at the nitrogen atom. The presence of a secondary nitrogen atom opens a broad range of
possibilities for modifying such isoindoles at the amide group. Previous attempts to synthesize such compounds
by the cycloaddition of maleic anhydride to furfurylamine in various solvents proved unsuccessful [22]. Only
acid 2e was obtained in 17% yield upon heating at reflux in water for 5 h with an equimolar amount of maleic
506

anhydride. An approach based on the reaction of salicylidenefurfurylamine 3 with maleic anhydride in
dichloromethane proved more convenient. In this case, elimination of salicylaldehyde leads to tricyclic product
2e in 51% yield.
H2O
O
O
O
O
H2N
N
CO2H
Ac
17%
6
O
7
2
5
N
BF3·Et2O
O
4
Ac2O
41%
O
1
3
CH2Cl2
51%
N
H
2e
O
CO2H
4a
OH
3
The mechanism of this unusual reaction, apparently, involves nucleophilic attack of the secondary
nitrogen atom of tautomeric form I of Schiff base 3 at the carbonyl group of maleic anhydride. A subsequent
intramolecular Diels-Alder exo reaction in resultant amide II leads to tricyclic system III. The addition of water
to compound III is accompanied by elimination of salicylaldehyde and finalize the formation of adduct 2e.
CO2H
O
O
O
O
O
N
O
N
H
O
3
O
I
II
HO2C
O
HO2C
O
O
N
O
exo-[4+2]
H2O
2e
N
O
–
OH
OH
OH
O
III
IV
This reaction, although proceeding under mild conditions (25°C), requires prolonged maintenance (3-5
days). This prolonged reaction time is probably necessary for completion of the hydrolysis of quinoid species
III by atmospheric moisture. Heating has hardly any effect on the reaction rate, while the addition of water to
the reaction mixture, likely, leads to hydrolysis of starting azomethine 3.
Citraconic anhydride also undergoes cycloaddition with secondary furfurylamines 1a,b,f-h. Formation
of epoxyisoindolonecarboxylic acids 5a-eA is observed upon heating in benzene at reflux for 4 h.
We might have expected that the reaction of furfurylamines 1a,b,f-h with citraconic anhydride would
lead to two regioisomeric acids A and B with geminal and vicinal arrangement of the methyl and carboxyl
groups. However, only carbonyl carbon C-2 undergoes aminolysis at 80°C such that the N-furfurylamide of
citraconic acid 5' is formed, which converts into adducts 5a-eA with vicinal arrangement of the methyl and
carboxyl groups through the exo transition state.
In the case of isoindolones 5aA (R = 5-furfuryl) and 5eA (R = Bn), the position of the methyl group at
1
C-7a is unequivocally indicated by a combination of NMR methods, including two-dimensional H-13C NMR,
NOE, HSQC, and HMBC spectra. The most complete information is obtained by the HMBC method, which
permits a reliable determination of the hydrocarbon skeleton using the strong cross peaks corresponding to
3
3
3
coupling JMe,C-1, JMe,C-3a, and JH-3,C-7a. In our view, measurement of the NOE in samples of these compounds
507

used for the same purpose by Murali et al. [15, 17] does not provide sufficiently reliable structural information
due to the low intensity of the H-7/Me-7a (H-7a/Me-7) cross peaks.
Thus, the position of the endo-7a-methyl group in the bicycloheptene fragment in adducts 5A is in
accord with the data of Murali et al. [15, 17] but differs from the corresponding position in the adducts obtained
from the cycloaddition of methylmaleic anhydride to 2-furyl heterocycles described in our previous work
[6, 23].
1
R
1
O
O
R
Me
O
4
3
CO2H
CO2H
Me
O
H
N
7
5
5
C6H6
N
[4+2]
R
2
H
O
R1
O
Me
O
4
O
+
O
R
O
1
50–88%
3
1
N
N2
B R
CO2H
Me
1a,b,f–h
R
A
5'
5a–e
O
Hal
Hal
1
7
O
R
O
1
6
CO2H
Hal
R
N
Zn, AcOH
40–62%
O
2
1e,g,h
O
R1
3
4
C6H6
50–76%
N
O
Hal
CO2H
4b–d
R
6a–d
1a,b, 5a R = furfuryl; 1e,f, 4b, 5c, 6a,d R = Ph; 1g,h, 4c,d, 5d,e, 6b,c R = Bn;
5b R = 5-methylfurfuryl; 1a,e,g, 4b,c, 5a,b,d, 6a,b,d R1 = H; 1f,h, 4d, 5c,e, 6c R1 = Me;
6a–c Hal = Cl; 6d Hal = Br
TABLE 1. Physicochemical Characteristics of Compounds 2a-e, 4a,d, 5a-c, and 6a-d
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, ºС
С
Н
N
C14H13NO5
C15H15NO5
C14H12BrNO5
C14H12INO5
C9H9NO4
61.38
61.09
62.44
62.28
47.13
47.48
42.13
41.92
4.50
4.76
5.07
5.23
3.56
3.42
2.67
3.02
5.64
5.09
4.59
4.84
4.22
3.95
3.15
3.49
150-151
2a
106-108
2bA
2cB
2dB
2e
>209 (decomp.)
>205 (decomp.)
152-154
55.72
55.39
4.47
4.65
8.11
7.18
C11H9NO4
59.91
60.27
72.81
72.58
62.42
62.28
63.11
63.36
68.01
68.21
52.53
52.96
54.42
54.26
55.72
55.45
4.49
4.14
5.49
5.37
5.68
5.23
5.33
5.65
5.65
5.72
3.19
3.26
3.54
3.70
4.37
4.11
6.53
6.39
5.13
4.98
4.35
4.84
5.82
4.62
4.16
4.68
4.27
4.12
4.26
3.95
3.65
3.80
188-190 (decomp.)
153-154 (decomp.)
106-107
4a
C17H15NO3
C15H15NO5
C16H17NO5
C17H17NO4
C15H11Cl2NO4
C16H13Cl2NO4
C17H15Cl2NO4
C15H11Br2NO4
4d
5a
145-146
5b
5c
133-134
160-161 (decomp.)
149-150 (decomp.)
131-132 (decomp.)
175-176
6a
6b
6c
6d
42.33
41.99
2.13
2.58
3.48
3.26
508

TABLE 2. IR and 1H NMR Spectra of Compounds 2a-e, 4a,d, 5a-c, and 6a-d
IR
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
spectrum,
, cm−1
1663 (NCO), 2.52 (1Н, d, J = 9.3, Н-7a); 2.79 (1Н, d, J = 9.3, Н-7); 3.58 (1Н, d, J = 11.2) and
1741 (СО2Н) 3.94 (1Н, d, J = 11.2, 3-CН2); 4.30 (1Н, d, J = 15.6) and
4.52 (1Н, d, J = 15.6, 2-CH2); 4.99 (1Н, d, J = 1.5, Н-6);
2a
6.31 (1Н, br. d, J = 3.2, Н-3'); 6.39 (1Н, dd, J = 1.9, J = 3.2, Н-4');
6.41 (1Н, dd, J = 1.5, J = 5.6, Н-5); 6.55 (1Н, d, J = 5.6, Н-4);
7.56 (1Н, br. d, J = 1.9, Н-5'); 12.11 (1Н, br. s, CO2H)
1675 (NCO), 2.22 (3H, s, СН3); 2.52 (1Н, d, J = 9.2, Н-7a); 2.79 (1Н, d, J = 9.2, Н-7);
1744 (СО2Н) 3.56 (1Н, d, J = 11.5) and 3.94 (1Н, d, J = 11.5, 3-CН2); 4.20 (1Н, d, J = 15.6)
and 4.45 (1Н, d, J = 15.6, 2-CH2); 4.97 (1Н, d, J = 1.7, Н-6);
2bA
2cB
2dB
2e
5.99 (1Н, dq, J = 0.7, J = 3.0, Н-4'); 6.18 (1Н, br. d, J = 3.0, Н-3');
6.41 (1Н, dd, J = 1.7, J = 5.7, Н-5); 6.55 (1Н, d, J = 5.7, Н-4)
1675 (NCO), 2.97 (1Н, d, J = 8.7, Н-7a); 3.01 (1Н, d, J = 8.7, Н-7); 3.64 (1Н, d, J = 11.8)
1750 (СО2Н) and 3.94 (1Н, d, J = 11.8, 3-CН2); 4.32 (1Н, d, J = 15.6) and
4.50 (1Н, d, J = 15.6, 2-CH2); 6.35 (1Н, dd, J = 0.9, J = 3.1, Н-3');
6.41 (1Н, dd, J = 1.9, J = 3.1, Н-4'); 6.48 (1Н, d, J = 5.6, Н-4);
6.74 (1Н, d, J = 5.6, Н-5); 7.59 (1Н, dd, J = 0.9, J = 1.9, Н-5')
1670 (NCO), 2.88 (1Н, d, J = 8.8, Н-7a); 2.93 (1Н, d, J = 8.8, Н-7); 3.62 (1Н, d, J = 11.8)
1745 (СО2Н) and 3.92 (1Н, d, J = 11.8, 3-CН2); 4.30 (1Н, d, J = 16.0) and
4.50 (1Н, d, J = 16.0, 2-CH2); 6.35 (1Н, dd, J = 0.8, J = 3.2, Н-3');
6.41 (1Н, dd, J = 1.8, J = 3.2, Н-4'); 6.54 (1Н, d, J = 5.6, Н-4);
6.55 (1Н, d, J = 5.6, Н-5); 7.58 (1Н, dd, J = 0.8, J = 1.8, Н-5')
1634 (NCO), 2.43 (1Н, d, J = 9.3, Н-7а); 2.67 (1Н, d, J = 9.3, Н-7);
1733 (СО2Н), 3.47 (1Н, dd, J = 11.7, J = 1.4) and 3.85 (1Н, d, J = 11.7, 3-CН2);
3355 (NH)
4.97 (1Н, d, J = 1.7, Н-6); 6.42 (1Н, dd, J = 5.7, J = 1.7, Н-5);
6.57 (1Н, d, J = 5.7, H-4); 7.64 (1Н, s, NH); 12.15 (1Н, br. s, CO2H)
1640 (NCO), 2.74 (3Н, s, CH3); 4.96 (2Н, s, 1-CН2); 7.79 (1Н, br. d, J = 7.9, Н-7);
1722 (CO2H) 7.89 (1Н, t, J = 7.9, Н-6); 8.54 (1Н, br. d, J = 7.9, Н-5); 14.31 (1Н, s, СО2Н)
4a
4d
5a
1602 (NCO), 2.33 (3Н, s, 5-CH3); 4.33 (2Н, s, 1-CН2); 4.70 (2Н, s, CH2Ph);
1712 (СО2Н) 7.26-7.46 (7Н, m, H Ar)
1667 (NCO), 1.03 (3H, s, 7a-CH3); 2.06 (1Н, s, Н-7); 3.53 (1Н, d, J = 11.8) and
1736 (СО2Н) 3.82 (1Н, d, J = 11.8, 3-CН2); 4.26 (1Н, d, J = 15.6) and
4.54 (1Н, d, J = 15.6, 2-CH2); 4.89 (1Н, d, J = 1.6, Н-6);
6.30 (1Н, br. d, J = 3.0, Н-3'); 6.39 (1Н, dd, J = 1.9, J = 3.0, Н-4');
6.51 (1Н, dd, J = 1.6, J = 5.6, Н-5); 6.53 (1Н, d, J = 5.6, Н-4);
7.56 (1Н, br. d, J = 1.9, Н-5'); 12.05 (1Н, br. s, CO2H)
1644 (NCO), 0.99 (3H, s, 7a-CH3); 2.02 (1Н, s, Н-7); 2.19 (3H, d, J = 0.8, 5'-CH3);
1722 (СО2Н) 3.49 (1Н, d, J = 11.7) and 3.77 (1Н, d, J = 11.7, 3-СН2); 4.13 (1Н, d, J = 15.6)
and 4.45 (1Н, d, J = 15.6, 2-CH2); 4.84 (1Н, d, J = 1.6, Н-6);
5b
5c
5.94 (1Н, dq, J = 0.8, J = 3.0, Н-4'); 6.11 (1Н, d, J = 3.0, Н-3');
6.47 (1Н, dd, J = 1.6, J = 5.7, Н-5); 6.50 (1Н, d, J = 5.7, Н-4)
1712 (NCO), 1.12 (3H, s, 7a-СН3); 1.52 (3H, s, 6-СН3); 2.21 (1Н, s, Н-7);
4.02 (1Н, d, J = 11.8) and 4.45 (1Н, d, J = 11.8, 3-СН2);
6.40 (1Н, d, J = 5.6, Н-4); 6.66 (1Н, d, J = 5.6, Н-5);
7.14 (1Н, br. t, J = 7.5, Н-4'); 7.38 (2Н, br. t, J = 7.5, Н-3',5');
7.65 (2Н, br. d, J = 7.5, Н-2',6')
1750 (СО2Н)
1701 (NCO), 4.26 (1Н, d, J = 12.5) and 4.66 (1Н, d, J = 12.5, 3-CН2);
1746 (СО2Н) 5.58 (1Н, d, J = 1.9, Н-6); 6.77 (1Н, dd, J = 1.9, J = 5.6, Н-5);
6.85 (1Н, d, J = 5.6, Н-4); 7.24 (1Н, br. t, J = 7.5, Н-4');
6a
6b
6c
6d
7.44 (2Н, br. t, J = 7.5, Н-3',5'); 7.65 (2Н, br. d, J = 7.5, Н-2',6')
1674 (NCO), 3.60 (1Н, d, J = 12.5) and 3.97 (1Н, d, J = 12.5, 3-CН2); 4.44 (1Н, d, J = 15.6)
1746 (СO2H) and 4.52 (1Н, d, J = 15.6, 2-CH2); 5.51 (1Н, d, J = 1.9, Н-6);
6.69 (1Н, dd, J = 1.9, J = 5.6, Н-5); 6.75 (1Н, d, J = 5.6, Н-4);
7.24-7.37 (5Н, m, H Ph)
1666 (NCO), 1.57 (3H, s, 6-CH3); 3.59 (1Н, d, J = 12.5) and 3.90 (1Н, d, J = 12.5, 3-CН2);
1751 (СO2H) 4.41 (1Н, d, J = 14.8) and 4.49 (1Н, d, J = 14.8, 2-CH2); 6.48 (1Н, d, J = 5.5, Н-5);
6.70 (1Н, d, J = 5.5, Н-4); 7.24 (2Н, br. d, J = 7.5, Н-2',6');
7.28 (1Н, br. t, J = 7.5, Н-4'); 7.33 (2Н, br. t, J = 7.5, Н-3',5')
1700 (NCO), 4.22 (1Н, d, J = 12.5) and 4.58 (1Н, d, J = 12.5, 3-CН2);
1739 (СO2H) 5.56 (1Н, d, J = 1.9, Н-6); 6.73 (1Н, dd, J = 1.9, J = 5.6, Н-5);
6.77 (1Н, d, J = 5.6, Н-4); 7.21 (1Н, t, J = 7.5, Н-4');
7.42 (2Н, br. t, J = 7.5, Н-3',5'); 7.63 (2Н, br. d, J = 7.5, Н-2',6')
509

Dibromo- and dichloromaleic anhydrides [24, 25] react with N-furfurylamines 1e,g,h even at room
temperature to give exo adducts 6a-d in good yields.
All adducts 2a-e, 5a-e, and 6a-d are colorless crystalline compounds with poor solubility in most
organic solvents. The IR spectra of these compounds have characteristic stretching vibrational bands for the
amide and carboxyl groups at 1634-1712 and 1722-1751 cm-1, respectively. The mass spectra of 2a-e, 5a-c, and
6a-d show weak molecular ion peaks corresponding to their chemical formulas.
The presence of an acidophobic furan fragment in acids 2a-d, free NH group in compound 2e, and
methyl group or halogen atoms in the oxabicycloheptene fragment in acids 5 and 6 significantly hinders
aromatization of the epoxy-containing ring or even makes this process impossible. Attempts to effect
aromatization of the 7-oxa-bicyclo[2.2.1]heptene fragment by the action of strong mineral acids such as HCl,
H3PO4, and H2SO4 at various concentrations [20] were unsuccessful. Acid 2e is aromatized at room temperature
by boron trifluoride etherate in acetic anhydride to give isoindolone 4a. Aromatization of dihaloacids 6a-c was
carried out using zinc in acetic acid. Acids 4b-d were obtained in satisfactory yields.
TABLE 3. 13C NMR Spectra of Compounds 2a-e, 4a,d, 5a-c, and 6a-d
Com-
pound
Chemical shifts, δ, ppm
38.8 (СH2); 44.5 (С-7а); 47.8 (C-3); 49.9 (C-7); 81.1 (C-6); 88.2 (C-3a); 107.8 (C-4');
110.5 (C-3'); 135.5 (C-5); 136.6 (C-4); 142.6 (C-5'); 150.0 (C-2');
170.1 (C-1); 172.7 (CO2H)
2a
13.3 (CH3); 38.9 (СH2); 44.6 (С-7а); 47.8 (C-3); 50.1 (C-7); 81.2 (C-6); 88.3 (C-3a);
106.5 (C-4'); 108.8 (C-3'); 135.6 (C-5); 136.7 (C-4); 148.2 (C-5'); 151.3 (C-2');
170.1 (C-1); 172.8 (CO2H)
2bA
2cB
2dB
38.8 (СH2); 47.7 (C-3); 51.1 (С-7а); 53.0 (C-7); 87.3 (C-3a); 90.5 (C-6); 108.8 (C-4');
110.6 (C-3'); 138.0 (C-5); 139.8 (C-4); 142.7 (C-5'); 149.8 (C-2'); 169.2 (C-1);
169.6 (CO2H)
38.8 (СH2); 47.3 (C-3); 52.0 (С-7а); 52.8 (C-7); 87.9 (C-3a); 88.3 (C-6); 108.0 (C-4’);
110.5 (C-3'); 135.5 (C-5); 137.2 (C-4); 142.7 (C-5'); 149.8 (C-2'); 169.3 (C-1);
170.4 (CO2H)
43.2 (C-3); 44.5 (C-7); 49.3 (C-7a); 81.2 (C-6); 91.3 (C-3a); 135.9 (C-5);
136.6 (C-4); 173.1 (C-1); 173.2 (CO2H)
2e
4a
4d
25.3 (COCH3); 49.0 (C-1); 127.8 (C-7); 128.4 (C-6); 130.8 (C-5); 134.8 (C-4);
135.2 (C-3a); 142.5 (C-7a); 164.1 (CO); 170.4 (CO2H); 171.1 (C-3)
18.1 (CH3); 45.4 (СH2); 48.8 (C-1); 123.5 (C-7); 127.3 (С-4'); 127.6 (С-4);
127.7 (C-3',5'); 128.0 (C-5); 128.6 (C-2',6'); 128.8 (C-1); 133.0 (C-6);
137.3 (C-3a); 139.4 (C-7a); 166.1 (C-3); 168.6 (CO2H)
21.5 (CH3); 38.9 (СH2); 46.4 (C-3); 52.6 (C-7); 55.7 (С-7а); 80.7 (C-6); 90.4 (C-3a);
107.8 (C-4'); 110.6 (C-3'); 133.5 (C-5); 137.6 (C-4); 142.7 (C-5'); 150.1 (C-2');
172.9 (C-1); 173.7 (CO2H)
5a
5b
5c
6a
6b
6с
6d
13.2 (CH3); 21.4 (CH3); 38.9 (СH2); 46.3 (C-3); 52.5 (C-7); 55.6 (С-7а); 80.6 (C-6);
90.3 (C-3a); 106.4 (C-4'); 108.5 (C-3'); 133.5 (C-5); 137.5 (C-4); 148.2 (C-5');
151.2 (C-2'); 172.8 (C-1); 173.6 (CO2H)
15.6 (CH3); 21.8 (CH3); 48.1 (C-3); 56.9 (C-7); 60.0 (С-7а); 88.0 (C-6); 88.9 (C-3a);
119.5 (C-2',6'); 123.9 (C-4'); 128.6 (C-3',5'); 134.3 (C-4); 139.6 (C-1'); 140.5 (C-5);
171.6 (C-1); 174.0 (CO2H)
48.4 (C-3); 72.5 (С-7а); 75.5 (C-7); 85.7 (C-6); 90.5 (C-3a); 120.7 (C-2',6');
125.9 (C-4'); 129.5 (C-3',5'); 133.9 (C-5); 138.9 (C-1'); 139.6 (C-4); 166.3 (C-1);
168.2 (CO2H)
46.2 (СH2); 46.7 (C-3); 71.9 (С-7а); 74.7 (C-7); 85.5 (C-6); 91.5 (C-3a);
127.9 (C-3',5'); 128.1 (C-4'); 129.2 (C-2',6'); 134.3 (C-5); 136.3 (C-1'); 139.2 (C-4);
167.3 (C-1); 168.2 (CO2H)
14.2 (CH3), 45.7 (СH2); 46.7 (C-3); 76.2 (С-7а); 77.7 (C-7); 90.1 (C-6); 93.0 (C-3a);
127.5 (C-3',5'); 128.4 (C-4'); 128.7 (C-2',6'); 134.5 (C-5); 135.8 (C-1'); 141.4 (C-4);
166.4 (C-1); 167.3 (CO2H)
47.8 (C-3); 65.8 (С-7а); 68.0 (C-7); 85.1 (C-6); 90.2 (C-3a); 120.0 (C-2',6');
125.1 (C-4'); 128.9 (C-3',5'); 133.1 (C-5); 138.5 (C-1'); 139.7 (C-4);
165.8 (C-1); 167.5 (CO2H)
510

TABLE 4. Mass Spectra of Compounds 2a-e, 4a,d, 5a-c, and 6a-d
Com-
pound
m/z (Irel, %)
275 [М]+ (3), 231 (2), 194 (47), 176 (31), 150 (18), 121 (12), 109 (64), 99 (61), 80 (100),
2a
69 (24), 54 (94), 43 (63)
289 [М]+ (22), 208 (87), 194 (54), 164 (13), 150 (21), 110 (100), 96 (83), 80 (92), 67 (13),
2b
55 (70), 43 (40)
353 [М]+ (for 79Br) (3), 274 (27), 254 (19), 228 (17), 194 (70), 176 (76), 159 (52),
2c
148 (29), 131 (47), 109 (38), 96 (72), 80 (100), 67 (26), 53 (88), 43 (65), 32 (34)
401 [М]+ (6), 320 (64), 276 (14), 222 (46), 207 (72), 194 (67), 179 (39), 147 (16), 128 (67),
2d
109 (38), 96 (73), 80 (100), 59 (54), 53 (85), 44 (49)
195 [М]+ (3), 177 (20), 96 (100), 81 (40), 69 (18), 53 (23), 39 (17)
2e
219 [М]+ (5), 191 (11), 175 (92), 145 (13), 133 (100), 104 (42), 89 (14), 76 (37),
4a
59 (47), 43 (78)
289 [М]+ (6), 208 (47), 176 (22), 122 (100), 113 (75), 96 (80), 80 (72), 69 (39), 53 (52),
5a
43 (35)
303 [М]+ (11), 222 (83), 204 (27), 190 (67), 136 (12), 123 (57), 109 (100), 95 (92),
5b
80 (96), 68 (41), 59 (42), 53 (43), 43 (52)
299 [M]+ (12), 254 (21), 187 (100), 143 (11), 106 (36), 95 (96), 77 (24), 68 (30),
5c
51 (21), 41 (56)
340 [M]+ (for 35Cl) (3), 304 (41), 260 (22), 224 (76), 196 (71), 172 (52), 140 (22),
6a
123 (48), 105 (47), 86 (100), 76 (94), 65 (44), 53 (82), 43 (47)
353 [M]+ (for 35Cl) (3), 318 (21), 274 (30), 238 (22), 218 (24), 182 (58), 146 (41),
6b
122 (78), 105 (43), 96 (100), 86 (97), 65 (72), 53 (68), 43 (31)
368 [M]+ (for 35Cl) (3), 332 (11), 276 (13), 252 (21), 232 (14), 196 (82), 160 (40),
6c
122 (79), 110 (69), 91 (100), 77 (43), 65 (67), 52 (87)
427 [М]+ (for 79Br) (2), 348 (4), 303 (7), 255 (13), 223 (24), 195 (28), 172 (34),
6d
143 (16), 130 (81), 104 (49), 80 (100), 65 (22), 53 (74), 43 (67)
EXPERIMENTAL
1
IR spectra were obtained on an IR Fourier spectrometer Infralum FT-801 using KBr pellets. H NMR
spectra were recorded on a Bruker WH-400 spectrometer at 400 MHz and JEOL JNM-ECA600 spectrometer at
600 MHz at 26°C in ~3% DMSO-d6 solutions using the residual solvent signal at 2.49 ppm as internal standard.
13
A Bruker AMX-400 spectrometer at 100 MHz was used to record the C NMR spectra with the central signal
of the DMSO-d6 multiplet at 39.96 ppm as the standard. The mass spectra were recorded on a Thermo Trace
DSQ spectrometer with direct sample inlet into the ion source. The ionization energy was 70 eV. The melting
points of the samples synthesized were determined SMP 30 melting points apparatus and were uncorrected.
Sorbfil plates were used for thin-layer chromatography with iodine vapor development. The reaction products
were purified by recrystallization from 2-propanol–DMF. The isomer ratio in the reaction products was
1
determined using the H NMR spectra as the ratio of integral intensities of monotypic protons. Activated,
neutral alumina (50-200 mesh) was used for column chromatography. Reagents from Acros Organics were used
without further purification. Freshly distilled solvents were used for the syntheses.
The physicochemical characteristics and elemental analysis data for all the new compounds are given in
Table 1, while the 1H NMR spectral data are given in Table 2, the 13C NMR spectral data are given in Table 3,
and the mass spectra are given in Table 4.
(3aS*,6R*,7S*,7aR*)-2-(Furylmethyl)-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
Acid (2a), (3aS*,6R*,7S*,7aR*)-2-[(5-Methyl-2-furyl)methyl]-1-oxo-1,2,5,6,7,7a-hexahydro-3a,6-epoxyisoindole-
7-carboxylic Acid (2bA), (3aS*,6R*,7S*,7aR*)-2-(2-Furylmethyl)-6-methyl-1-oxo-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisodindole-7-carboxylic Acid (2bB), (3aS*,6R*,7S*,7aR*)-2-[(5-Bromo-2-furyl)methyl]-1-oxo-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (2cA), (3aS*,6S*,7R*,7aR*)-6-Bromo-2-(2-furyl-
methyl)-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (2cB), (3aS*,6R*,7S*,7aR*)-
2-[(5-Iodo-2-furyl)methyl]-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (2dA),
511

and
(3aS*,6S*,7R*,7aR*)-2-(2-Furylmethyl)-6-iodo-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-
7-carboxylic Acid (2dB) (General Method). A. A solution of maleic anhydride (2.24 g, 0.023 mol) in benzene
(50 ml) was added to a solution of amine 1b-d (0.020 mol) in benzene (50 ml) at 20°C, and the mixture was
maintained until the end of the reaction as indicated by thin-layer chromatographic monitoring. The precipitate
was filtered off and washed with ether (2×15 ml) to give a mixture of isomers A and B of carboxylic acids 2b-d
as colorless crystals. The yields were 79% for 2b, 52% for 2c, and 50% for 2d. The A/B isomer ratio was 30:70
for 2b, 45:55 for 2c, and 60:40 for 2c.
B. A solution of amine 1a-d (0.020 mol) and maleic anhydride (2.24 g, 0.023 mol) in benzene (100 ml)
was heated at reflux for 10 h to give pure carboxylic acids 2a in 87% yield, 2bA in 86% yield, 2cB in 78%
yield, and 2dB in 70% yield as colorless crystals.
(3aS*,6R*,7S*,7aR*)-1-Oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (2e). A
solution of maleic anhydride (15.1 g, 0.154 mol) and salicylidenefurfurylamine 3 (15.5 g, 0.077 mol) in
CH2Cl2 (100 ml) was stirred for 72 h at 20°C. The fine crystalline powder precipitate was filtered off, washed
with CH2Cl2, (2×25 ml) and recrystallized from 2-propanol–DMF to give 11.1 g (51%) acid 2e as colorless
crystals.
2-Acetyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic Acid (4a). BF3·Et2O (6.6 ml, 0.05 mol) was
added to a solution of epoxyisoindolonecarboxylic acid 2e (10.42 g, 0.05 mol) in freshly distilled acetic
anhydride (70 ml). The reaction mixture was stirred for 24 h at 20°C with thin-layer chromatographic
monitoring, poured into water (100 ml), and extracted with methylene chloride (3×50 ml). The extract was dried
over anhydrous magnesium sulfate. The solvent was distilled off in vacuum. The dark oily residue was purified
by column chromatography on a 40×100-cm alumina column using 1:1 ethyl acetate–hexane as the eluent to
give 4.60 g (41%) acid 4a as pale-yellow crystals.
3-Oxo-2-phenyl-2,3-dihydro-1H-isoindole-4-carboxylic Acid (4b), 2-Benzyl-3-oxo-2,3-dihydro-
1H-isoindole-4-carboxylic Acid (4c), and 2-Benzyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic
Acid (4d) (General Method). Zinc dust (1.1 g, 16.90 mmol) was added to a solution of carboxylic acid 6a-c
(0.28 mmol) in glacial acetic acid (10 ml) and stirred for 2 h at 70°C. The reaction mixture was cooled and
water (100 ml) was added. The mixture was neutralized by adding ammonium hydroxide. Unreacted zinc was
filtered off. The filtrate was brought to pH 4-5 by adding concentrated hydrochloride acid. The crystalline
precipitate was filtered off and washed with ether (2×15 ml). Recrystallization from 2-propanol–DMF gave the
corresponding acids as colorless crystals: 4b in 45% yield, 4c in 62% yield, and 4d in 40% yield. The
physicochemical characteristics and spectral data for acids 4b,c were identical to the results reported in our
previous work [20].
(3aS*,6R*,7S*,7aR*)-2-(2-Furylmethyl)-7a-methyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-
7-carboxylic Acid (5a), (3aS*,6R*,7S*,7aR*)-7a-Methyl-2-[(5-methyl-2-furyl)methyl]-1-oxo-1,2,3,6,7,7a-hexa-
hydro-3a,6-epoxyisoindole-7-carboxylic Acid (5b), (3aS*,6R*,7S*,7aR*)-6,7a-Dimethyl-1-oxo-2-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (5c), (3aS*,6R*,7S*,7aR*)-2-Benzyl-7a-methyl-
1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (5d), and (3aS*,6R*,7S*,7aR*)-2-Benzyl-
6,7a-dimethyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
Acid
(5e)
(General
Method). Corresponding amine 1a,b,f-h (0.011 mol) and citraconic anhydride (1.1 ml, 0.012 mol) in benzene
(30 ml) were heated at reflux for 6 h with thin-layer chromatographic monitoring. The residue after distilling off
the solvent was recrystallized from 2-propanol–DMF to give the corresponding acids as colorless crystals: 5a in
88% yield, 5b in 50% yield, 5c in 59% yield, 5d in 65% yield, and 5e in 69% yield. The physicochemical
characteristics and spectral data for acids 5d,e were identical to the results obtained by Murali et al. [15, 17].
(3aR*,6R*,7R*,7aS*)-7,7a-Dichloro-1-oxo-2-phenyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-
7-carboxylic Acid (6a), (3aR*,6R*,7R*,7aS*)-2-Benzyl-7,7a-dichloro-1-oxo-1,2,3,6,7,7a-hexahydro-
3a,6-epoxyisoindole-7-carboxylic Acid (6b), (3aR*,6R*,7R*,7aS*)-2-Benzyl-7,7a-dichloro-6-methyl-
1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic Acid (6c), and (3aR*,6R*,7R*,7aS*)-
7,7a-Dibromo-1-oxo-2-phenyl-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid (6d) (General
512

Method). A solution of amine 1e,g,h (0.011 mol) and dichloro- (1.8 g, 0.011 mol) (for 6a-c) or
dibromomaleic anhydride (2.8 g, 0.011 mol) (for 6d) in benzene (20 ml) was stirred for 72 h at 20°C with
monitoring by thin-layer chromatography. The crystalline precipitate was filtered off and washed with ether
(2×15 ml). Recrystallization from 2-propanol–DMF gave colorless crystals of the corresponding acids: 6a in
51% yield, 6b in 50% yield, 6c in 55% yield, and 6d in 76% yield.
This work was carried out with the financial support of the Russian Foundation for Basic Research
(Grant 11-03-90416 Ukr_f_a).
The authors express their gratitude to the laboratory staff of the Precision instrumental methods of
analysis department "PRIMA" of the Shared Research and Education Center of the Peoples' Friendship
University of Russia.
REFERENCES
1.
2.
3.
4.
5.
6.
S. Ogawa, I. Kasahara, and T. Suami, Bull. Chem. Soc. Jpn., 52, 118 (1979).
I. N. N. Namboothiri, M. Ganesh, S. M. Mobin, and M. Cojocaru, J. Org. Chem., 70, 2235 (2005).
H. W. Gschwend, M. J. Hillman, B. Kisis, and R. K. Rodebaugh, J. Org. Chem., 41, 104 (1976).
A. Ilyin, V. Kysil, M. Krasavin, I. Kurashvili, and A. V. Ivachtchenko, J. Org. Chem., 71, 9544 (2006).
V. V. Kouznetsov, U. M. Cruz, F. I. Zubkov, and E. V. Nikitina, Synthesis, 375 (2007).
F. I. Zubkov, V. P. Zaitsev, A. M. Piskareva, M. N. Eliseeva, E. V. Nikitina, N. M. Mikhailova, and
A. V. Varlamov, Russ. J. Org. Chem., 46, 1192 (2010).
7.
8.
A. V. Varlamov, E. V. Boltukhina, F. I. Zubkov, E. V. Nikitina, and K. F. Turchin, J. Heterocycl.
Chem., 43, 1479 (2006).
A. V. Varlamov, F. I. Zubkov, E. V. Boltukhina, N. V. Sidorenko, and R. S. Borisov, Tetrahedron
Lett., 44, 3641 (2003).
9.
10.
F. I. Zubkov, E. V. Boltukhina, K. F. Turchin, and A. V. Varlamov, Tetrahedron, 60, 8455 (2004).
F. I. Zubkov, E. V. Boltukhina, K. F. Turchin, R. S. Borisov, and A. V. Varlamov, Tetrahedron, 61,
4099 (2005).
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
P. A. Jacobi and Y. Li, J. Am. Chem. Soc., 123, 9307 (2001).
R. A. Tromp, J. Brussee, and A. van der Gen, Org. Biomol. Chem., 1, 3592 (2003).
K. Paulvannan, T. Chen, and J. W. Jacobs, Synlett, 1609 (1999).
K. Paulvannan and J. W. Jacobs, Tetrahedron, 55, 7433 (1999).
R. Murali, H. S. Prakash Rao, and H. W. Scheeren, Tetrahedron, 57, 3165 (2001).
R. Paulvannan, Tetrahedron Lett., 40, 3029 (1999).
R. Murali and H. W. Scheeren, Tetrahedron Lett., 40, 3029 (1999).
D. Fokas, J. E. Patterson, G. Slobodkin, and C. M. Baldino, Tetrahedron Lett., 44, 5137 (2003).
K. L. Milkiewicz, I. B. Neagu, D. J. Parks, and T. Lu, Tetrahedron Lett., 44, 7341 (2003).
A. V. Varlamov, E. V. Boltukhina, F. I. Zubkov, N. V. Sidorenko, A. I. Chernyshev, and
D. G. Grudinin, Khim. Geterotsikl. Soedin., 27 (2004) [Chem. Heterocycl. Compd., 40, 22 (2004)].
P. S. Sarang, A. A. Yadav, P. S. Patil, U. M. Krishna, G. K. Trivedi, and M. M. Salunkhe, Synthesis,
109 (2007).
21.
22.
23.
F. I. Zubkov, E. V. Nikitina, and A. V. Varlamov, Russ. Chem. Rev., 74, 639 (2005).
F. I. Zubkov, E. V. Airiyan, A. A. Dzyubenko, N. I. Yudina, V. P. Zaytsev, E. V. Nikitina, A. V.
Varlamov, V. N. Khrustalev, and D. G. Grudinin, J. Heterocycl. Chem., 47, 400 (2010).
M. Dubernet, V. Caubert, J. Guillard, and M.-C. Viaud-Massuard, Tetrahedron, 61, 4585 (2005).
H. M. Relles, J. Org. Chem., 37, 3630 (1972).
24.
25.
513