Synthesis and Structure of Esterification Products of 6-aryl-1,2,3,6,7,7a-hexahydro-3а,6-epoxyisoindole-7-carboxylic Acids

Article abstract of DOI:10.1007/s10593-019-02528-z

[Figure not available: see fulltext.] It was found that the reaction of 5-arylfurfurilamines with maleic anhydride leads to the formation of 6-aryl-3a,6-epoxyisoindole-7-carboxylic acids (the cyclic form), which in solution are in dynamic equilibrium with N-furfurylmaleinamides (the open form). During the esterification of these tautomeric mixtures with methanol in the presence of a catalytic amount of sulfuric acid, methyl esters of 5-aryl-7a-hydroxy-7-methoxy-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-4-carboxylic acids, unexpected cleavage products of the 3a,6-oxo bridge of the cyclic form, are formed diastereospecifically. The structure of the obtained products was confirmed by X-ray structural analysis.

Full text of DOI:10.1007/s10593-019-02528-z

DOI 10.1007/s10593-019-02528-z
Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Synthesis and structure of esterification products of
6-aryl-1,2,3,6,7,7a-hexahydro-3а,6-epoxyisoindole-
7-carboxylic acids
Maryana А. Nadirova1, Kuz'ma M. Pokazeev2, Irina А. Kolesnik2,
Pavel V. Dorovatovskii3, Nikolay А. Bumagin4*, Vladimir I. Potkin2
1 Institute of Organic and Macromolecular Chemistry, Heinrich Heine University Düsseldorf,
1 Universitäts St., Düsseldorf 40225, Germany; е-mail: mariannanadirova17@gmail.com
2 Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
13 Surganova St., Minsk 220072, Belarus; e-mail: potkin@ifoch.bas-net.by
3 National Research Center ''Kurchatov Institute'',
1 Akademika Kurchatova Sq., Moscow 123182, Russia; e-mail: paulgemini@mail.ru
4 M. V. Lomonosov Moscow State University,
1 Build. 3, Leninskie Gory, Moscow 119991, Russia; e-mail: bna51@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(8), 729–738
Submitted February 20, 2019
Accepted March 7, 2019
It was found that the reaction of 5-arylfurfurilamines with maleic anhydride leads to the formation of 6-aryl-3a,6-epoxyisoindole-
7-carboxylic acids (the cyclic form), which in solution are in dynamic equilibrium with N-furfurylmaleinamides (the open form). During
the esterification of these tautomeric mixtures with methanol in the presence of a catalytic amount of sulfuric acid, methyl esters of 5-aryl-
7a-hydroxy-7-methoxy-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-4-carboxylic acids, unexpected cleavage products of the 3a,6-oxo
bridge of the cyclic form, are formed diastereospecifically. The structure of the obtained products was confirmed by X-ray structural
analysis.
Keywords: furan, isoindole, 7-oxabicyclo[2.2.1]heptene, [4+2] cycloaddition, esterification, IMDAF reaction, intramolecular Diels–
Alder reaction.
Scheme 1
In 2016, the phenomenon of ring-chain tautomerism in
solutions of the products of acylation of 5-aryl-
furfurylamines with maleic anhydride was discovered.1 The
authors showed that, unlike other well-known examples2 of
equilibrium intramolecular Diels–Alder reactions involving
furans (the IMDAF reaction3,4), the process proceeds
spontaneously when the cyclic form dissolves in a polar
solvent and does not require the use of catalysts or heating
(Scheme 1).
tautomeric form entered. The evaluation of the possibility
of selective modification of tautomers was the reason for
the present study.
The precursor furfurylamines 1a–h were obtained by
known methods5 from 5-arylfurfurals6 and primary amines
(Scheme 2). The acylation of secondary amines 1a–h with
an equimolar amount of maleic anhydride was carried out
at room temperature for 2 days. The reaction products
Reliable evidence of the existence of both tautomeric
forms in solution, including density functional theory
calculations and dynamic H NMR spectra, was presented.
Using X-ray structural analysis, it was demonstrated that
only the cyclic form crystallizes from solutions.1 In this
case, not a single reaction was given (by analogy with the
chemistry of sugars), in which either one or the other
1
0009-3122/19/55(8)-0729©2019 Springer Science+Business Media, LLC
729

Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Scheme 2
which crystallized from diethyl ether were confirmed to be
6-aryl-3a,6-epoxyisoindole-7-carboxylic acids 2a–h, by
1H NMR spectra recorded one minute after the sample was
dissolved in DMSO-d6 at room temperature. When these
samples were held in the vial of the NMR spectrometer at
room temperature, a gradual formation and accumulation of
the retro-Diels–Alder products 3a–h was observed, which
is in good agreement with the literature data1 (Scheme 2).
The equilibrium between the cyclic (compound 2) and the
open (compound 3) tautomeric forms was achieved after 8–
12 h. Table 1 shows the ratio of tautomeric forms 2/3 after
keeping the solutions in the NMR vial for 1 day. The NMR
spectra of tautomeric mixtures are complicated by the
presence of Z/E-isomerism with respect to the C(O)–N
bond in maleinamides 3. Thus, NMR spectroscopy reveals
the presence of three mutually interchanging forms
2/3A/3B in solutions. The assignment of signals in the
NMR spectra to the 3A/3B rotamers is insignificant for
subsequent experiments and was not performed.
Table 1. Yields of adducts 2 and compositions of tautomeric
mixtures 2 + 3 in DMSO-d6 solutions after 1 day at room
temperature
Com-
pound
2/3A/3B
ratio*, %
R1
Ar
Yield, %
i-Pr
Bn
Ph
Ph
72/13/15
41/22/37
59/41**
62/25/13
69/14/17
64/36**
80/10/10
44/22/34
88
38
75
95
55
50
90
44
2a
2b
2c
2d
2e
2f
Ph
p-Tol
Ph
2-MeOC6H4
4-MeOC6H4
4-ClC6H4
2-O2NC6H4
4-O2NC6H4
i-Pr
Ph
i-Pr
Bn
2g
2h
* The ratio of tautomers and rotamers in the mixture is determined by
1H NMR spectra by analogy with the literature data.1
** Signals of only one amide rotamer 3A or 3B were detected in the
1H NMR spectra in DMSO solution.
It should be noted that the acylation products 2a–h are
white powders, moderately soluble only in DMF and
DMSO at room temperature. To improve the solubility of
the obtained samples, esterification of a highly polar
carboxyl group was carried out (Scheme 3). The products
of esterification, esters 4, should be better soluble in
organic solvents compared to starting acids 2 or 3, which
would allow, for example, selective epoxidation reactions
of cyclic tautomeric form 2 via the Prilezhaev reaction or
Simmons–Smith cyclopropanation. In addition, the corres-
ponding esters 4 can be used as multifunctional acyl
modifiers of amino(hydroxy)-1,2-azoles and to obtain new
potential N-ligands for catalysis in aqueous media.7
When esterifying acids 2a,b or 3a,b under classical
conditions in MeOH medium using catalytic amounts of
H2SO4 (the tautomeric forms 2 and 3 were completely
dissolved), mixtures of products were formed, which,
according to 1H NMR spectroscopy, did not contain neither
the target esters of isoindolecarboxylic acids 4, nor esters
of their chain tautomers (Scheme 3). Unexpected
heterocycles 5a,b were isolated as the reaction products.
The formation of such structures in such simple
experimental conditions was the basis for this publication.
Indeed, analysis of the literature data showed that in the
case of esterification of 3a,6-epoxyisoindole-7-carboxylic
acids containing a hydrogen, halogen atom, or alkyl
substituent in position 6 under similar conditions, the
expected esters are formed in good yields,2d,4h,5b,6c,8 and no
cleavage of the oxo bridge is observed.
Note that in heterocycles containing 7-oxabicyclo[2.2.1]-
heptenic fragment, the epoxy bridge is cleaved by the
action of strong mineral acids (H3PO4, HCl, PPA) or Lewis
acids, and depending on the conditions, various types of
compounds are formed, including products of the Wagner–
Meerwein rearrangement.9 The main direction of the
opening of the 7-oxabicycloheptene fragment by the action
of acids and bases is usually the aromatization of the six-
membered ring via dehydration, resulting in 2,3-dihydro-
isoindoles.5b,10
Optimization of the synthesis conditions (changing the
concentration of the catalyst within 0.05–0.5 ml H2SO4 per
10 ml of solvent, varying the heating time from 2 to 24 h)
allowed us to achieve about 50% yield of test isoindolones
5a,b. The optimal conditions were 0.15 ml of concd H2SO4
in 10 ml of MeOH and boiling for 4–8 h. The use of higher
boiling EtOH or i-PrOH in the reaction led to the formation
of multicomponent mixtures. Examination of their 1Н NMR
spectra revealed no signals related to the homologs of
compounds 5. Probably, in these cases, the products of the
cleavage of the oxo bridge undergo further transformations,
accompanied by the elimination of oxygen-containing
substituents from the cyclohexane fragment of the
molecule. Chromatographic separation and detailed
analysis of the products obtained in these experiments were
not carried out. Thus, under the conditions described
above, three more representatives of the series were
obtained, compounds 5c–e (Table 2).
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Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Scheme 3
The conversion of bridged compounds 2 to isoindoles 5
Table 2. Yields of esterification products –
compounds 5a–e
should include esterification steps, the cis/trans
isomerization of the double bond of the maleinamide
moiety most likely in the open tautomeric form 3, and the
acid-catalyzed opening of the oxo bridge of the cyclic
tautomer (Scheme 3). Presumably, after protonation of the
carboxylic fragment of tautomer 3 with a double bond in
the cis configuration, the resulting carbocation (represented
by the resonance forms A and B) turns into a more stable
trans-isomer C. The reversible IMDAF reaction of the
latter and the esterification of the endocyclic form D leads
to the formation of methyl esters of 3a,6-epoxyisoindolone
acids E. The opening of the oxo bridge in the protonated
form F can occur through two alternative carbocations G
and H. Both cations are tertiary and resonantly stabilized,
but the carbocation G is preferred due to the positive
mesomeric effect of the aryl substituent. Its subsequent
stabilization with the MeOH molecule leads to the target
product 5. Interestingly, the elimination of the tertiary
alcohol group and the subsequent aromatization of the
cyclohexene ring in isoindoles 5 are not observed under the
chosen conditions.
The structure of isoindoles 5 could not be unambi-
guously established using only the NMR spectroscopy
method. The difficulty was determining the configuration
of the node carbon atom C-7a bonded with the hydroxyl
group. To eliminate this uncertainty, X-ray structural
analysis of single crystals of samples 5b,d was performed
(Figs. 1 and 2).
The X-ray structural analysis data allowed us to
determine the absolute configuration of all asymmetric
centers in products 5. In particular, the protons at the
carbon atoms C-3a/C-4 have the trans arrangement relative
to each other, which proves the cis/trans isomerization of
the maleinamide moiety of acids 2 or 3 during the course of
the reaction (Scheme 3). The hydroxyl group (7a-OH) and
the methoxy moiety (7-OMe) have the trans configuration
in the cyclohexene ring.
Compound
R1
Ar
Yield, %
i-Pr
Bn
Ph
Ph
Ph
50
50
42
35
42
5а
5b
5c
5d
5e
p-Tol
Ph
2-MeOC6H4
4-MeOC6H4
i-Pr
Compounds 5b,d crystallize, respectively, in the
monoclinic C2/c or P21/n space group with eight or four
molecules in the unit cell as a racemate with the
asymmetric centers having the configuration of
3aRS,4RS,7RS,7aSR.
Phenyl and cyclohexene fragments of both molecules are
not coplanar: torsion angles C(6)–C(5)–C(1)(Ph)–C(2)(Ph)
are 113.6° (compound 5b) and 104.9° (compound 5d). The
cyclohexene ring adopts the conformation of a slightly
twisted "boat" in which the hydroxyl and methoxy groups
occupy pseudoaxial positions, whereas the methoxy-
carbonyl group occupy the pseudoequatorial position.
In the crystal cell, the carbonyl group of the pyrrolidine
ring (C(3)=O) acts as a hydrogen bond acceptor toward the
CH groups of the cyclohexene ring of the neighboring
molecule, which leads to the formation of C(7)–H···O
intermolecular hydrogen bonds (2.687 Å, compound 5b)
and C(6)–H···O (2.640 Å, compound 5e).11 The interaction
of the hydroxyl and methoxy groups of the benzene ring
stabilizes isoindolone 5b conformation due to the
formation of an intramolecular noncovalent bond with a
length of 2.706(3) Å. In addition, many noncovalent
interactions are observed in the solid state, such as
intermolecular hydrogen bonds CH···π and bonds π···π.12
It should be noted that products 5 are formed in the
conditions described in Scheme 3 only in the case when the
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Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Figure 1. The molecular structure of isoindole 5b.
Figure 2. The molecular structure of isoindole 5d.
aryl substituent in the furan ring of amides 2 or 3 contains
an electron-donating group (H, Me, OMe). Electron-
withdrawing groups (Cl, NO2) in compounds 2f–h or 3f–h
probably destabilize the carbocation G, which offers the
opportunities for other transformations to take place, and
ultimately leads to the formation of a multicomponent
mixture from which individual products cannot be isolated.
To conclude, the paper describes the unusual opening of
an epoxy bridge in 6-aryl-3a,6-epoxyisoindole-7-carb-
oxylic acids. The key role of a 6-aryl substituent in the
precursor compounds in this process is shown, and the
reaction mechanism is proposed based on the structure of
the products formed.
well as certain characteristics of compounds 2, 3 have been
described earlier.1,5,6
Synthesis of [(5-arylfuran-2-yl)methyl]amines 1a–h
(General method). Anhydrous MgSO4 powder (18 g,
0.15 mol) and the corresponding amine (aniline) (0.05 mol)
were added to a solution of 5-substituted furfural (8.6 g,
0.05 mol) in СН2Cl2 (100 ml). The reaction mixture was
stirred for 48 h at room temperature (TLC control), and the
drying agent was filtered off through a layer of SiO2 (2×3 cm),
which was then washed with СН2Cl2 (2×30 ml). The
solvent was evaporated under reduced pressure. The
residue was dissolved in MeOH (50 ml), and NaBH4
(1.90 g, 0.05 mol) was added with stirring and cooling in
ice bath. The reaction mixture was then heated under
reflux for 4 h, poured in water (250 ml), and the organic
products were extracted with СН2Cl2 (3×70 ml). The
combined organics were dried over Na2SO4, the drying
agent was filtered off, and the solvent was evaporated
under reduced pressure. The residue was purified by flash
chromatography on silica gel, using hexane–EtOAc system
with increasing polarity as the eluent. Amines 1a–h were
obtained as oils or colorless crystals, making it possible to
record satisfactory spectral data. Crystalline samples were
additionally recrystallized from the solvent indicated
below.
Experimental
IR spectra were registered on
a Nicolet 8700
spectrometer with the sample as a thin film (for oils) or in
KBr pellets (for crystalline samples). 1H NMR spectra were
acquired on Bruker Avance III HD 400 NanoBay (400 MHz)
and JEOL JNM-ECA600 (600 MHz) spectrometers for
sample solutions, using residual solvent signals (7.26 ppm
in CDCl3 or 2.50 ppm in DMSO-d6) or TMS as internal
standard. 13C NMR spectra were acquired on Bruker
Avance 600 (151 MHz) and Bruker Avance III HD 300
NanoBay (100 MHz) spectrometers, using the triplet signal
of CDCl3 (77.4 ppm) or septet signal of DMSO-d6
(40.5 ppm) as internal standard. Mass spectra were recorded
on Agilent Technologies LCMS6230B mass (electrospray
ionization) and Thermo Trace DSQ (electron ionization
70 eV, source temperature 200°C, direct input)
spectrometers. High-resolution mass spectra were recorded
on a Bruker AutofleX Speed mass spectrometer (matrix-
assisted laser desorption/ionization). Elemental analysis of
new compounds (С, H, N) was performed on a Carlo Erba
NA 1500 Elemental analyzer. Melting points were
determined on a Stuart SMP 30 apparatus in open glass
capillaries and are uncorrected. TLC was performed on
Merck Silica gel 60 F254 plates, visualization under UV
light or in the iodine chamber. Silica gel 60 (60–200 mesh)
was used for column chromatography, eluent hexane →
hexane–EtOAc, 2:1. The composition of tautomeric
N-[(5-Phenylfuran-2-yl)methyl]propan-2-amine (1a).
Yield 8.6 g (80%). Yellow oil. IR spectrum, ν, cm–1: 3127
1
(NH). H NMR spectrum (600 MHz, CDCl3), δ, ppm
(J, Hz): 1.13 (6Н, d, J = 6.2, 2CH3); 1.73 (1H, br. s, NH);
2.91 (1H, sep, J = 6.2, NCH); 3.86 (2H, s, NCH2); 6.27
(1H, d, J = 3.2, H-4 Fur); 6.59 (1H, d, J = 3.2, H-3 Fur);
7.25 (1H, t, J = 7.6, H-4 Ph); 7.38 (2H, t, J = 7.6,
H-3,5 Ph), 7.67 (2H, dd, J = 7.6, J = 1.1, H-2,6 Ph).
13C NMR spectrum (151 MHz, CDCl3), δ, ppm (J, Hz):
21.9 (2C); 43.0; 47.9; 105.9; 110.6; 123.8; 127.4; 128.8
(2C); 130.8, 151.4; 153.7.
N-Benzyl-1-[(5-phenylfuran-2-yl)methyl]methanamine
(1b). Yield 12.6 g (95%). Yellow oil. IR spectrum, ν, cm–1:
3412 (NH). 1H NMR spectrum (600 MHz, CDCl3), δ, ppm
(J, Hz): 1.96 (1H, br. s, NH); 3.87 (4Н, br. s, CH2NHCH2);
6.30 (1H, d, J = 3.1, H-3 Fur); 6.62 (1H, d, J = 3.1, H-4
Fur); 7.25–7.44 (8H, m, H Ph); 7.69 (2H, d, J = 7.3, H Ph).
13C NMR spectrum (151 MHz, CDCl3), δ, ppm: 45.4; 52.7;
105.5; 109.1; 123.5 (2C); 126.9; 127.0; 127.8; 128.2 (2C);
128.5 (2C); 130.8; 139.8; 153.1; 153.5.
1
mixtures 2/3 was determined by H NMR in DMSO-d6 at
22–25°С from the ratio of the integral intensities of signals
of similar protons. Signal assignments were made by
analogy with related compounds,1 identification of
rotamers A or B was not carried out. Spectral and
physicochemical characteristics of compounds 1a–c, as
N-([5-(4-Methylphenyl)furan-2-yl]methyl)aniline (1c).
Yield 11.2 g (85%). Light-brown plates. Mp 50–51°C
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Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
(EtOH). IR spectrum, ν, cm–1: 3330 (NH). 1H NMR
N-Benzyl-1-[5-(4-nitrophenyl)furan-2-yl]methan-
amine (1h). Yield 11.4 g (74%). Dark-yellow thin oil.
spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 2.40 (3Н, s,
СН3); 4.10 (1H, br. s, NH); 4.42 (2H, s, NCH2); 6.34 (1H,
br. s, H-4 Fur); 6.56 (1H, br. s, H-3 Fur); 6.75–6.82 (3H,
m, H Ar); 7.22–7.30 (4H, m, H Ar); 7.59 (2H, d, J = 7.0, H
Ar). 13C NMR spectrum (151 MHz, CDCl3), δ, ppm: 21.3;
41.7; 105.0; 109.1; 113.2; 118.1; 123.6; 128.2; 129.3;
129.4; 137.1; 147.7; 152.0; 153.7.
N-{[5-(2-Methoxyphenyl)furan-2-yl]methyl}aniline
(1d). Yield 7.0 g (50%). Viscous yellow oil. IR spectrum,
ν, cm–1: 3412 (NH). 1H NMR spectrum (600 MHz, CDCl3),
δ, ppm (J, Hz): 1.59 (1Н, br. s, NH); 3.94 (3H, s, OCH3);
4.40 (2H, s, NCH2); 6.35 (1H, d, J = 3.3, H-4 Fur); 6.73
(2H, dd, J = 8.6, J = 1.0, H Ph); 6.75–6.78 (1H, m, H Ar);
6.89 (1H, d, J = 3.3, H-3 Fur); 6.97 (1H, d, J = 8.1, H Ar);
7.03–7.04 (1H, m, H Ar); 7.21–7.27 (3H, m, H Ar); 7.84
(1H, dd, J = 8.1, J = 1.8, H Ar). 13C NMR spectrum
(151 MHz, CDCl3), δ, ppm: 41.8; 55.5; 109.4; 111.0;
111.2; 113.4; 118.1; 120.0; 120.9; 125.9; 128.1; 129.4;
147.9; 149.9; 151.6; 155.5. Found, %: С 77.29; Н 6.16;
N 4.99. C18H17NO2. Calculated, %: C 77.40; H 6.13;
N 5.01.
N-{[5-(4-Methoxyphenyl)furan-2-yl]methyl}propan-
2-amine (1e). Yield 8.6 g (70%). Colorless rhombs. Mp 60–
62°C (EtOH). IR spectrum (KBr) ν, cm–1: 3150 (NH).
1H NMR spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 1.11
(6H, d, J = 6.2, 2CH3); 1.66 (1H, br. s, NH); 2.89 (1H, sep,
J = 6.2, NCH); 3.82 (3H, s, OCH3); 3.84 (2H, s, NCH2),
6.22 (1H, d, J = 3.3, H-3 Fur); 6.43 (1H, d, J = 3.3, H-4
Fur); 6.91 (2H, d, J = 8.8, H-2,6 Ar); 7.58 (2H, d, J = 8.8,
H-3,5 Ar). 13C NMR spectrum (151 MHz, CDCl3), δ, ppm:
22.8 (2C); 44.0; 47.6; 55.3; 104.1; 108.8; 114.2 (2C);
124.2; 125.1 (2C); 153.3; 156.7; 159.0. Found, %: C 73.09;
H 7.63; N 5.62. C15H19NO2. Calculated, %: C 73.44;
H 7.81; N 5.71.
N-{[5-(4-Chlorophenyl)furan-2-yl]methyl}aniline (1f).
Yield 12.0 g (85%). Fine white plates. Mp 67–69°C
(EtOH). IR spectrum, ν, cm–1: 3328 (NH). 1H NMR
spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 4.08 (1H, br. s,
NH); 4.42 (2H, s, NCH2); 6.35 (1H, d, J = 2.8, H-4 Fur);
6.61 (1H, d, J = 2.8, H-3 Fur); 6.74–6.82 (3H, m, H Ar);
7.23–7.29 (2H, m, H Ar); 7.38 (2H, d, J = 8.3, H Ar); 7.60
(2H, d, J = 8.3, H Ar). 13C NMR spectrum (151 MHz,
CDCl3), δ, ppm: 41.6; 106.3; 109.3; 113.2 (2C); 118.2;
124.9; 125.1; 128.9 (2C); 129.3 (4C); 132.9; 147.6; 152.4;
152.8. Found, %: C 72.10; H 4.69; N 4.87. C17H14ClNO.
Calculated, %: C 71.96; H 4.97; N 4.94.
1
IR spectrum, ν, cm–1: 3324 (NH). H NMR spectrum
(400 MHz, CDCl3), δ, ppm (J, Hz): 2.11 (1H, br. s, NH);
3.86 (2Н, s, NCH2); 3.88 (2H, s, NCH2); 6.36 (1H, d,
J = 3.1, H-3 Fur); 6.82 (1H, d, J = 3.1, H-4 Fur); 7.27–7.35
(5H, m, H Ph); 7.76 (2H, d, J = 8.6, H Ar); 8.23 (2H, d, J = 8.6,
H Ar). 13C NMR spectrum (151 MHz, CDCl3), δ, ppm:
45.7; 53.2; 110.1; 110.3; 123.9 (2C); 124.6 (2C); 127.5;
128.5 (2C); 128.8 (2C); 136.7; 139.7; 146.4; 151.2; 156.3.
Found, %: C 69.85; H 5.37; N 9.00. C18H16N2O3.
Calculated, %: C 70.12; H 5.23; N 9.09.
Synthesis of 3a,6-epoxyisoindole-7-carboxylic acids
2a–h and their tautomeric forms, [(5-phenylfuran-2-yl)-
methyl]amino-4-oxobutyl-2-enoic acids 3a–h (General
method). Maleic anhydride (0.49 g, 5 mmol) was added to a
solution of amine 1a–h (5 mmol) in PhH (40 ml), and the
reaction mixture was kept at room temperature for 1–3 days
until the completion of the reaction (no more precipitate
formed). The formed crystalline adduct was filtered off and
washed with Et2O (2×15 ml). Compounds 2a–h were
obtained as colorless or light-yellow crystals. In solution in
organic solvents acids 2a–h (cyclic form) are in equilibrium
with the corresponding tautomeric N-substituted N-furfuryl-
maleinamides 3a–h (open form).
(3aRS,6SR,7RS,7aSR)-2-Isopropyl-1-oxo-6-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2a) and (2Z)-4-{isopropyl[(5-phenylfuran-2-yl)-
methyl]amino}-4-oxobut-2-enoic acid (3а).1 Yield 0.85 g
(88%). Colorless powder. Mp 139–140°С (EtOAc–EtOH,
1:1). The ratio of tautomers in DMSO-d6 at room
temperature according to 1Н NMR was 2а/3Аа/3Bа =
72/13/15. IR spectrum, ν, cm–1: 1649 (NСО), 1754
(СО2Н).
Compound 2a. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.11 (3H, d, J = 6.7, 2СН3); 1.13 (3H, d,
J = 6.7, СН3); 2.94 (1H, d, J = 9.1, 7a-СН); 2.97 (1H, d,
J = 9.1, 7-СН); 3.74 (1H, d, J = 11.8) and 3.94 (1H, d,
J = 11.8, 3-СН2); 4.16 (1Н, sep, J = 6.7, NСH); 6.43 (1H,
d, J = 5.1, 4-СН); 6.75 (1H, d, J = 5.1, 5-СН); 7.25–7.42
(5H, m, H Ph); 11.71 (1H, br. s, CO2H).
Rotamer 3Aa. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.10–1.19 (6H, m, 2CH3); 4.46 (2H, s,
NCH2); 4.57 (1H, sep, J = 6.7, NCH); 5.99 (1H, d,
J = 12.1, CH=CHCO2H); 6.42–6.44 (1H, m, H-3 Fur); 6.70
(1H, d, J = 11.8, CH=CHCO2H); 6.88 (1H, J = 3.5,
H-4 Fur); 7.25–7.42 (3H, m, H Ph); 7.65–7.67 (2H, m,
H-4,6 Ph); 11.71 (1H, br. s, CO2H).
N-[5-(2-Nitrophenyl)furan-2-yl]propan-2-amine (1g).
Yield 13.2 g (86%). Viscous dark-yellow oil. IR spectrum,
ν, cm–1: 3328 (NH). 1H NMR spectrum (400 MHz, CDCl3),
δ, ppm (J, Hz): 1.01 (6H, br. d, J = 6.2, 2CH3); 1.45 (1H,
br. s, NH); 2.77 (1H, sep, J = 6.2, NCH); 3.73 (2H, s,
NCH2); 6.21 (1H, d, J = 3.3, H-3 Fur); 6.52 (1H, d, J = 3.3,
H-4 Fur); 7.27–7.30 (1H, m, H Ph); 7.46 (1H, ddd, J = 8.8,
J = 7.7, J = 1.5, H Ph); 7.57 (1H, dd, J = 8.8, J = 1.5,
H Ph); 7.61 (1H, dd, J = 7.7, J = 1.5, H Ph). 13C NMR
spectrum (151 MHz, CDCl3), δ, ppm: 22.7 (2C); 43.7;
47.4; 109.0; 110.4; 123.8; 124.2; 128.0; 128.6; 131.8;
147.3; 147.5; 156.2. Found, %: C 64.45; H 5.96; N 10.61.
C14H16N2O3. Calculated, %: C 64.60; H 6.20; N 10.76.
1
Rotamer 3Ba. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.10–1.19 (6H, m, 2CH3); 4.04 (1H, sep,
J = 6.7, NCH); 4.50 (2H, s, NCH2); 5.98 (1H, d, J = 12.1;
CH=CHCO2H); 6.42–6.44 (1H, m, H-3 Fur); 6.81 (1H, d,
J = 12.1, CH=CHCO2H); 6.83 (1H, d, J = 3.5, H-4 Fur);
7.25–7.42 (3H, m, H Ph); 7.65–7.67 (2H, m, H-4,6 Ph);
11.71 (1H, br. s, CO2H).
Tautomeric mixture of compound 2a and rotamers
3Aa and 3Ba. 13C NMR spectrum (151 MHz, DMSO-d6),
δ, ppm: 19.9 (2C); 20.0; 20.2 (2C); 21.2; 36.9; 41.0; 42.5;
43.8; 45.4; 49.3; 50.0; 54.7; 88.5; 93.0; 107.1; 107.2;
110.1; 110.7, 123.6 (2C); 123.8; 124.2; 124.5; 125.9 (2C);
733

Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
127.7 (2C); 127.9; 128.4 (2C); 129.4 (2C); 129.5 (2C);
d, J = 3.3, H-4 Fur); 7.11–7.38 (7H, m, H Ar); 7.45 (2H, d,
J = 8.1, H-2,6 Ph); 12.64 (1H, br. s, CO2H).
139.2; 130.7; 131.0; 137.4; 137.9; 138.2; 139.1; 140.6;
151.9; 152.2; 152.7; 153.0; 166.6; 166.7; 167.0; 167.5;
170.3; 171.3. Found, %: С 69.08; Н 6.23; N 4.39.
C18H19NO4. Calculated, %: С 69.00; Н 6.11; N 4.47.
Tautomeric mixture of compounds 2с and 3с.
13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 20.7;
20.8; 44.5; 49.6; 49.8; 54.8; 87.0; 93.0; 105.6; 110.6; 119.4
(2C); 124.0 (2C); 125.2; 127.6 (2C); 127.9; 128.0; 128.4;
128.7 (2C); 129.1 (2C); 129.3 (2C); 130.0 (2C); 134.0
(2C); 136.4 (2C); 136.7 (2C); 139.5; 140.1; 140.2; 140.9;
149.6; 152.6; 165.5; 166.2; 170.6; 170.7. Found, %:
С 73.26; Н 5.03; N 3.97. C22H19NO4. Calculated, %:
С 73.12; Н 5.30; N 3.88.
(3aRS,6SR,7RS,7aSR)-2-Benzyl-1-oxo-6-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2b) and (2Z)-4-{benzyl[(5-phenylfuran-2-yl)-
methyl]amino}-4-oxobut-2-enoic acid (3b).1 Yield 0.69 g
(38%). Colorless powder. Mp 101.5–102°С (EtOAc–EtOH,
1:1). The ratio of tautomers in DMSO-d6 at room
1
temperature according to Н NMR was 2b/3Аb/3Bb =
(3aRS,6SR,7RS)-6-(2-Methoxyphenyl)-1-oxo-2-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2d) and its tautomeric form (2Z)-4-[{[5-(2-
methoxyphenyl)-2-furyl]methyl}(phenyl)amino]-4-oxo-
but-2-enoic acid (3d). Yield 1.8 g (95%). Beige powder.
Mp 147–148°С (EtOAc–EtOH, 1:1). The ratio of tautomers
41/22/37. IR spectrum, ν, cm–1: 1663 (NCO), 1745
(CO2H).
Compound 2b. 1H NMR spectrum (600 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.03 (1H, d, J = 8.9, 7-CH); 3.08 (1H, d,
J = 8.9, 7a-CH); 3.66 (1H, d, J = 11.7) and 3.96 (1H, d,
J = 11.7, 3-СН2); 4.43 (1H, d, J = 15.1) and 4.53 (1H, d,
J = 15.1, NCH2); 6.45 (1H, d, J = 5.5, 4-СН); 6.74 (1H, d,
J = 5.5, 5-СН); 7.23–7.42 (10H, m, H Ph); 11.78 (1H, br. s,
CO2H).
1
in DMSO-d6 at room temperature according to Н NMR was
2d/3Ad/3Bd = 62/25/13. IR spectrum, ν, cm–1: 1640
(NСО), 1732 (СО2Н).
Compound 2d. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.07 (1H, d, J = 9.2, 7а-СН); 3.19 (1H, d,
J = 9.2, 7-СН); 3.68 (1H, d, J = 11.7, 3-СН2); 3.84 (3H, s,
OCH3); 3.97 (1H, d, J = 11.7, 3-СН2); 6.50 (1H, d, J = 5.5,
4-СН); 6.71 (1Н, d, J = 5.5, 5-СН); 7.25–7.41 (9H, m,
H Ar); 12.20 (1H, br. s, CO2H).
Rotamers 3Ab and 3Bb. 1H NMR spectrum (600 MHz,
DMSO-d6), δ, ppm (J, Hz): 4.43, 4.49, 4.52, 4.58 (2H, s,
NCH2); 6.05 (1H, d, J = 11.7, CH); 6.15 (1H, d, J = 12.4,
CH); 6.44 (1H, d, J = 3.4) and 6.84, 6.87 (1H, d, J = 3.4,
H-3,4 Fur); 6.82 (1H, d, J = 11.7, CH); 6.94 (1H, d,
J = 12.4, CH); 7.23–7.42 (8H, m, H Ph); 7.62–7.66 (2H, m,
H-2,6 Ph); 12.83 (1H, br. s, CO2H).
Compound 3Ad. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.91 (3H, s, OCH3); 4.38–4.59 (2H, m,
NCH2); 6.18 (1H, d, J = 12.1, НС=СНCO2H); 6.44 (1H, d,
J = 3.3, H-3 Fur); 6.92 (1H, d, J =12.1, НС=СНCO2H);
6.95 (1H, d, J = 3.3, H-4 Fur); 7.25–7.41 (8H, m, Н Ar);
7.69 (1H, dd, J = 7.7, J = 1.5, H Ph); 12.20 (1H, br. s,
CO2H).
Mixture of rotamers 3Ab and 3Bb and compound 2b.
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 40.4;
43.9; 45.4; 46.8; 48.0; 48.9; 50.9; 53.5; 88.1; 92.5; 106.3;
106.4; 110.5; 111.1; 123.2; 123.3; 125.0; 125.3; 126.9;
127.1; 127.2; 127.4 (2С); 127.5; 127.7; 127.8; 128.2;
128.4; 128.5; 128.7; 128.8; 130.0; 130.2; 136.4; 136.6;
136.7 (2С); 136.9; 137.0; 137.1; 139.9; 149.6; 150.0;
152.4; 153.0; 166.0 (2С); 166.8; 166.9; 170.6; 170.7 (СO2,
NCO). Mass spectrum (EI, 70 eV), m/z (Irel, %): 361 [М]+
(6), 270 (23), 263 (100), 246 (19), 186 (20), 172 (49), 158 (66),
128 (24), 119 (64), 106 (27), 91 (66), 79 (27), 65 (17), 55
(20), 51 (22), 44 (23). Found, %: С 73.24; Н 5.36; N 3.61.
C22H19NO4. Calculated, %: С 73.12; Н 5.30; N 3.88.
(3aRS,6SR,7RS)-6-(4-Methylphenyl)-1-oxo-2-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2с) and (2Z)-4-[{[5-(4-methylphenyl)-2-furyl]
methyl}(phenyl)amino]-4-oxobut-2-enoic acid (3с).
Yield 1.4 g (75%). Colorless needles. Mp 224–225°С
(EtOAc–EtOH). The ratio of tautomers in DMSO-d6 at
room temperature according to 1Н NMR was 2с/3с = 59/41.
IR spectrum, ν, cm–1: 1647 (NСО), 1729 (СО2).
Compound 3Bd. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.91 (3H, s, OCH3); 4.38–4.59 (2H, m,
NCH2); 6.08 (1H, d, J = 12.1, НС=СНCO2H); 6.44 (1H, d,
J = 3.3, H Fur); 6.83 (1H, d, J =12.1, НС=СНCO2H); 6.84
(1H, d, J = 3.3, H-4 Fur); 7.25–7.41 (8H, m, Н Ph);
7.63 (1H, dd, J = 7.7, J = 1.5, H Ph); 12.20 (1H, br. s,
CO2H).
Tautomeric mixture of rotamers 3Ad and 3Bd and
compound 2d. 13C NMR spectrum (151 MHz, DMSO-d6),
δ, ppm: 44.3; 45.0; 49.3; 50.2; 55.2; 56.0; 56.3; 86.7; 91.8;
111.2 (2C), 111.6 (2C), 112.1 (2C); 113.7 (2C); 114.8;
115.0; 119.3, 119.8 (2C); 120.5 (2C); 121.1; 124.5 (2C);
125.5 (2C); 125.8; 126.6; 127.7; 127.9 (2C); 128.4; 128.5;
128.8 (2C); 128.9 (2C); 129.2 (2C); 129.3; 129.6; 129.7;
136.5 (2C); 140.0; 140.1; 141.5 (2C); 155.4; 156.1 (2C);
156.4 (2C); 156.6 (2C); 156.9; 166.1; 166.8; 166.9; 167.4;
171.3; 171.4. Found, %: С 70.18; Н 5.31; N 3.78.
C22H19NO5. Calculated, %: С 70.02; Н 5.07; N 3.71.
(3aRS,6SR,7RS)-2-Isopropyl-6-(4-methoxyphenyl)-
1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carb-
oxylic acid (2е) and (2Z)-4-(isopropyl{[5-(4-methoxy-
phenyl)furan-2-yl]methyl}amino)-4-oxobut-2-enoic acid
(3е). Yield 0.94 g (55%). Colorless powder. Mp 140–141°С
(EtOAc–EtOH, 1:1). The ratio of tautomers in DMSO-d6 at
room temperature according to 1Н NMR was 2e/3Ae/3Be =
69/14/17. IR spectrum, ν, cm–1: 1647 (NСО), 1760
(СО2Н).
1
Compound 2c. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 2.25 (3H, s, CH3); 3.06 (1H, d, J = 9.1,
7а-СН); 3.22 (1H, d, J = 9.1, 7-СН); 4.18 (1H, d, J = 11.6)
and 4.59 (1H, d, J = 11.6, 3-СН2); 6.47 (1H, d, J = 5.4,
4-СН); 6.77 (1H, d, J = 5.4, 5-СН); 7.11–7.38 (7H, m,
H Ar); 7.66 (2H, dd, J = 9.1, J = 1.0, H-2,6 Ph); 11.78
(1H, br. s, CO2H).
Compound 3с. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 2.27 (3H, s, CH3); 4.93 (2H, s, NCH2);
5.74 (1H, d, J = 12.1, CH=CHCO2H); 6.32 (1H, d, J = 3.3,
H-3 Fur); 6.38 (1H, d, J = 12.1, CH=CHCO2H); 6.69 (1H,
734

Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Compound 2e. 1H NMR spectrum (400 MHz, DMSO-d6),
(3aRS,6SR,7RS)-2-Isopropyl-6-(2-nitrophenyl)-1-oxo-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2g) and its tautomeric form (2Z)-4-(isopropyl-
{[5-(2-nitrophenyl)-2-furyl]methyl}amino)-4-oxobut-2-en-
oic acid (3g). Yield 1.61 g (90%). Yellow powder. The
ratio of tautomers in DMSO-d6 at room temperature
according to 1Н NMR was 2g/3Аg/3Bg = 80/10/10.
IR spectrum, ν, cm–1: 1640 (NСО), 1738 (СО2Н).
δ, ppm (J, Hz): 1.11 (3H, d, J = 6.5, CH3); 1.13 (3H, d,
J = 6.5, CH3); 2.92 (2H, АВ system, J = 9.0, 7,7a-СН);
3.72 (1H, d, J = 11.7, 3-СН2); 3.74 (3H, s, OCH3); 3.93 (1H,
d, J = 11.7, 3-СН2); 4.17 (1H, sep, J = 6.5, NCH); 6.42 (1H,
d, J = 5.3, H-4); 6.73 (1H, d, J = 5.3, H-5); 6.90–6.91 (2H,
m, H Ar); 7.30–7.33 (2H, m, H Ar); 11.94 (1H, br. s, CO2H).
Rotamer 3Аe. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.14 (6Н, d, J = 6.6, 2СН3); 3.77 (3H, s,
OCH3); 4.04 (1H, sep, J = 6.6, NCH); 4.45 (2H, s, NCH2);
5.98 (1H, d, J = 11.9, CH=CHCO2H); 6.38 (1H, d, J = 3.3,
H-3 Fur); 6.67 (1H, d, J = 3.3, H-4 Fur); 6.70 (1H, d,
J = 11.9, CH=CHCO2H); 6.97–6.99 (2H, m, H Ph); 7.58–
7.61 (2H, m, H Ph); 11.94 (1H, br. s, CO2H).
1
Compound 2g. H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.00–1.28 (6H, m, 2CH3); 3.05 (1H, d,
J = 9.2, 7-CH); 3.19 (1H, d, J = 9.2, 7a-CH); 3.74 (1H, d,
J = 11.9) and 3.99 (1H, d, J = 11.9, 3-СН2); 4.17 (1H, sep,
J = 6.6, NCH); 6.58 (1H, d, J = 5.5, 4-СН); 6.84 (1H, d,
J = 5.5, 5-СН); 7.53–7.87 (3H, m, H Ar); 8.05 (1H, d,
J = 7.3, H-3 Ar); 11.90 (1H, br. s, CO2H).
Rotamer 3Вe. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.15 (6H, d, J = 6.8, 2CH3); 3.77 (3H, s,
OCH3); 4.49 (2H, s, NCH2); 4.57 (1H, sep, J = 6.8, NCH);
6.00 (1H, d, J = 12.1, CH=CHCO2H); 6.40 (1H, d, J = 3.3,
H-3 Fur); 6.71 (1H, d, J = 3.3, H-4 Fur); 6.82 (1H, d,
J = 12.1, CH=CHCO2H); 7.03–7.04 (2H, m, H Ph); 7.68–7.71
(2H, m, H Ph); 11.94 (1H, br. s, CO2H).
Tautomeric mixture of rotamers 3Ae and 3Be and
compound 2e. 13C NMR spectrum(151 MHz, DMSO-d6),
δ, ppm: 19.3; 19.8; 19.9; 20.2; 21.2; 36.9; 42.5; 43.8; 49.4;
50.0; 54.9; 55.6; 55.7; 55.8; 88.4; 92.8; 105.2; 105.3; 110.1;
110.6; 113.8; 114.8; 114.9; 123.7; 124.0; 125.1; 125.3;
127.1; 128.9; 129.8; 137.2; 140.6; 151.3; 151.7; 152.1;
153.2; 158.9; 150.0; 166.6; 167.0; 167.4; 170.2; 171.4.
Found, m/z: 366.1317 [М+Na]+. C22H19NNaO5. Calculated,
m/z: 366.1312.
Rotamer 3Ag. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.00–1.28 (6H, m, 2CH3); 4.43 (2H, s,
NCH2); 4.54 (1H, sep, J = 6.9, NCH); 5.97 (1H, d,
J = 12.1, CH=CHCO2H); 6.50–6.53 (1H, m, H-3,4 Fur);
6.57–6.61 (1H, m, CH=CHCO2H); 6.77–6.89 (1H, m,
H-3,4 Fur); 7.53–7.87 (3H, m, H Ar); 8.05 (1H, d, J = 7.3,
H-3 Ar); 11.90 (1H, br. s, CO2H).
Rotamer 3Bg. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.00–1.28 (6H, m, 2CH3); 4.05 (1H, sep,
J = 6.9, NCH); 4.45 (2H, s, NCH2); 6.01 (1H, d, J = 12.1,
CH=CHCO2H); 6.80 (1H, d, J = 12.1, CH=CHCO2H); 6.81
(1H, d, J = 3.3, H-3 Fur); 6.88 (1H, d, J = 3.3, H-4 Fur);
7.53–7.87 (3H, m, H Ar); 8.05 (1H, d, J = 7.3, H-3 Ar);
11.90 (1H, br. s, CO2H).
Tautomeric mixture of rotamers 3Ag and 3Bg and
compound 2g.13C NMR spectrum (151 MHz, DMSO-d6),
δ, ppm: 19.9; 20.0; 21.0; 36.7; 40.8; 42.5; 43.8; 45.4; 48.9;
50.0; 54.4; 87.5; 91.8; 110.2; 110.8; 111.2; 111.3; 122.9;
123.2; 124.3 (2C); 124.4 (2C); 125.2; 128.7; 128.9; 129.1;
129.5; 129.6; 130.3; 132.2; 132.7; 132.8; 133.8; 137.8;
138.0; 138.7; 139.2; 146.7; 147.2; 147.3: 148.0; 154.2;
154.7; 166.5; 166.6; 167.0; 167.4; 169.9; 171.1 (3C).
Found, m/z: 381.1051 [М+Na]+. C18H18N2NaO6.
Calculated, m/z: 381.1057.
(3aRS,6SR,7RS)-6-(4-Chlorophenyl)-1-oxo-2-phenyl-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxy-
lic acid (2f) and its tautomeric form (2Z)-4-(phenyl-
{[5-(4-chlorophenyl)furan-2-yl]methyl}amino)-4-oxobut-
2-enoic acid (3f). Yield 0.95 g (50%). Colorless powder.
The ratio of tautomers in DMSO-d6 at room temperature
1
according to Н NMR was 2f/3f = 64/36. IR spectrum,
ν, cm–1: 1647 (NСО), 1760 (СО2Н).
Compound 2f. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.10 (1H, d, J = 9.1, 7-CH); 3.26 (1H, d,
J = 9.1, 7a-CH); 4.19 (1H, d, J = 11.6) and 4.60 (1H, d,
J = 11.6, 3-СН2); 6.50 (1H, d, J = 5.6, 4-СН); 6.80 (1H, d,
J = 5.6, 5-СН); 7.31–7.42 (7H, m, H Ar); 7.66 (2H, d,
J = 7.4, H Ph); 11.97 (1H, s, CO2H).
(3aRS,6SR,7RS)-2-Benzyl-6-(4-nitrophenyl)-1-oxo-
1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic
acid (2h) and its tautomeric form (2Z)-4-(benzyl{[5-(4-
nitrophenyl)-2-furyl]methyl}amino)-4-oxobut-2-enoic
acid (3h). Yield 0.89 g (44%). Light-yellow powder. The
ratio of tautomers in DMSO-d6 at room temperature
according to 1Н NMR was 2h/3Аh/3Bh = 44/22/34.
IR spectrum, ν, cm–1: 1640 (NСО), 1738 (СО2Н).
Compound 3f. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 4.95 (2H, s, NCH2); 5.74 (1H, d, J = 12.1,
CH=CHCO2H); 6.36 (1H, d, J = 3.0, H-3 Fur); 6.38 (1H, d,
J = 12.1, CH=CHCO2H); 6.84 (1H, d, J = 3.0, H-4 Fur);
7.12 (1H, t, J = 7.4, H Ph); 7.22 (2H, d, J = 7.1, H Ph); 7.27–
7.42 (4H, m, H Ar); 7.58 (2H, d, J = 8.6, H Ph); 12.67 (1H,
s, CO2H).
Compound 2h. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.16 (2H, s, NCH2); 3.69 (1H, d, J = 11.8)
and 4.00 (1H, d, J = 11.8, 3-СН2); 4.41–4.61 (2H, m,
7,7a-CH); 6.51–6.55 (1H, m, 4-CH); 6.80 (1H, d, J = 5.5,
5-CH); 7.24–7.40 (5H, m, H Ph); 7.73 (2H, d, J = 8.8,
H-2,6 Ar); 8.26 (2H, d, J = 8.8, H-3,5 Ar); 12.43 (1H, s,
CO2H).
Tautomeric mixture of compounds 2f and 3f.
13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 19.1;
45.1; 50.1; 50.3; 55.3; 56.6; 87.8; 92.8; 107.8; 111.4; 119.9
(2C); 124.6; 125.5; 125.7; 127.9 (2C); 128.4 (2C); 128.5
(2C); 128.6 (2C); 129.3 (2C); 129.4 (2C); 129.6; 129.7;
132.2; 132.6 (2C); 136.5; 137.2; 140.0; 140.3; 141.5;
151.1; 151.8; 166.2; 166.8; 171.0; 171.3. Found, %:
С 66.27; Н 4.04; N 3.74. C21H16ClNO4. Calculated, %:
С 66.06; Н 4.22; N 3.67.
Rotamer 3Аh. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 4.41–4.61 (4H, m, 2NCH2); 6.08 (1H, d,
J = 12.1, CH=CHCO2H); 6.84 (1H, d, J = 12.1, CH=CHCO2H);
6.51–6.55 (1H, m, H-3 Fur); 7.20 (1H, d, J = 3.3, H-4 Fur);
7.24–7.40 (5H, m, H Ph); 7.85 (2H, d, J = 8.8, H Ar); 8.26
(2H, d, J = 8.8, H Ar); 12.43 (1H, s, CO2H).
735

Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
Rotamer 3Bh. 1H NMR spectrum (400 MHz, DMSO-d6),
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 42.0;
45.2; 46.0; 51.3; 53.5; 56.9; 72.8; 74.9; 125.5; 126.5 (2C);
127.1; 127.5 (2C); 127.6; 128.0 (2C); 128.5 (2C); 136.9;
139.5; 139.9; 170.7; 172.4. Mass spectrum (EI, 70 eV), m/z
(Irel, %): 407 [M]+ (91), 316 (23), 299 (21), 209 (23), 167
(35), 106 (22), 91 (100), 42 (36). Found, %: C 70.48;
H 6.04; N 3.32. C24H25NO5. Calculated, %: C 70.75;
H 6.18; N 3.44.
δ, ppm (J, Hz): 4.41–4.61 (4H, m, 2NCH2); 6.15 (1H, d,
J = 11.8, CH=CHCO2H); 6.80 (1H, d, J = 5.5, H-3 Fur);
6.96 (1H, d, J = 11.8, CH=CHCO2H); 7.20 (1H, d, J = 3.3,
H-4 Fur); 7.24–7.40 (5H, m, H Ph); 7.88 (2H, d, J = 8.8,
H Ar); 8.26 (2H, d, J = 8.8, H Ar); 12.43 (1H, s, CO2H).
Tautomeric mixture of rotamers 3Ah and 3Bh and
compound 2h. 13C NMR spectrum (151 MHz, DMSO-d6),
δ, ppm: 44.6 (2С); 46.0; 47.6; 48.4; 51.7; 53.7; 89.2; 92.5;
111.4; 111.6; 111.8; 112.4; 123.6 (2С); 124.3 (2С); 124.5
(4С); 124.8; 124.9; 125.5 (4C); 125.8 (4C); 127.3; 127.5
(4С); 127.7 (4С); 128.0 (2С); 128.1; 128.2; 128.7; 129.0;
136.2; 136.5; 136.9; 137.1; 137.2; 137.4; 137.6; 137.7; 139.5;
145.3; 146.2; 146.4; 147.3; 150.8; 151.4; 152.6; 153.2; 166.6;
167.4; 167.6; 170.9; 171.1. Found, %: С 65.09; Н 4.40;
N 6.85. C22H18N2O6. Calculated, %: С 65.02; Н 4.46; N 6.89.
Synthesis of methyl esters of isoindole-4-carboxylic acids
5a–e (General method). Concentrated H2SO4 (0.15 ml) was
added to a suspension of compounds 2a–e/3a–e (5 mmol)
in MeOH (10 ml), and the mixture was heated under reflux
for 4–8 h (TLC control, suspension of the starting material
completely turned into a solution). The reaction mixture
was cooled, poured into water (100 ml), and extracted with
CHCl3 (3×50 ml). The combined organics were dried over
MgSO4. The residue after filtration of the drying agent and
evaporation of CHCl3 under reduced pressure was recrystal-
lized from hexane–AcOEt, 1:6 mixture (for compound 5b–e),
or purified by column chromatography on silica gel (com-
pound 5a), eluent hexane–AcOEt with increasing polarity.
(3aRS,4RS,7RS,7aSR)-7a-Hydroxy-2-isopropyl-7-methoxy-
3-oxo-5-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-
4-carboxylic acid methyl ester (5a). Yield 0.89 g (50%).
Colorless rhombs. Mp 134.5–135.5°С (MeOH). IR spect-
rum, ν, cm–1: 1665 (NCO), 1734 (СО2H). 1H NMR
spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 1.15 (3H, d,
J = 6.9) and 1.18 (3H, d, J = 6.9, CH(CH3)2); 1.95 (1Н,
br. s, OH); 3.23 (1H, d, J = 10.1) and 3.29 (1H, d, J = 10.1,
1-СН2); 3.51 (3H, s, OCH3); 3.55 (3H, s, CO2CH3); 3.78
(1H, d, J = 11.8, 3а-CH); 3.82 (1H, d, J = 4.9, 7-CH); 3.97
(1H, dd, J = 11.8, J = 2.0, 4-CH); 4.43 (1H, sep, J = 6.9,
CH(CH3)2); 6.14 (1H, dd, J = 4.9, J = 2.0, 6-CH); 7.28–7.36
(5H, m, H Ph). 13C NMR spectrum (151 MHz, CDCl3),
δ, ppm: 20.0; 20.1; 42.3; 42.6; 46.9; 48.9; 52.2; 57.2; 74.8;
75.0; 124.6; 127.0 (2C); 128.0; 128.3 (2C); 139.4; 142.3;
170.4; 172.5. Mass spectrum (EI, 70 eV), m/z (Irel, %): 359
[M]+ (68), 344 (32), 268 (100), 188 (29), 183 (100), 147
(27), 141 (54), 115 (50), 59 (40), 57 (45), 42 (67). Found,
m/z: 382.1627 [М+Na]+. C20H25NO5. Calculated, m/z:
382.1625.
(3aRS,4RS,7RS,7aSR)-7a-Hydroxy-7-methoxy-5-(4-methyl-
phenyl)-3-oxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-
4-carboxylic acid methyl ester (5c). Yield 0.85 g (42%).
Colorless powder. Mp 139–140°С (MeOH). IR spectrum,
1
ν, cm–1: 1670 (NCO), 1737 (CO2H). H NMR spectrum
(600 MHz, DMSO-d6), δ, ppm (J, Hz): 2.29 (3Н, s, CH3);
3.15 (1H, d, J = 11.1, 3a-CH); 3.39 (3H, s, OCH3); 3.52
(3H, s, CO2CH3); 3.70 (1H, d, J = 10.1, 1-СН2); 3.81 (1H,
d, J = 5.1, 7-CH); 3.89 (1H, dd, J = 11.1, J = 1.0, 4-CH);
4.24 (1H, d, J = 10.1, 1-СН2); 5.58 (1H, s, OH); 6.13 (1H,
dd, J = 5.1, J = 2.5, 6-CH); 7.12–7.16 (3H, m, H Ar, H-4
Ph); 7.23 (2H, d, J = 8.1, H Ar); 7.37 (2H, m, H-3,5 Ph); 7.68
(2H, d, J = 8.1, H-2,6 Ph). 13C NMR spectrum (100 MHz,
DMSO-d6), δ, ppm: 15.7; 21.3; 31.2; 40.6; 42.6; 48.2; 52.0;
55.8; 57.6; 65.5; 72.6; 75.5; 119.6; 124.2; 125.4; 127.0;
129.3; 137.1; 137.6; 140.1; 140.4; 171.4; 173.0. Found, %:
C 70.81; H 6.20; N 3.48. C24H25NO5. Calculated, %: C 70.75;
H 6.18; N 3.44. Mass spectrum (ESI), m/z: 407 [M+H]+.
Found, %: C 70.89; H 6.25; N 3.69. C24H25NO5. Calculated,
%: C 70.75; H 6.18; N 3.44.
(3aRS,4RS,7RS,7aSR)-7a-Hydroxy-7-methoxy-5-(2-meth-
oxyphenyl)-3-oxo-2-phenyl-2,3,3a,4,7,7a-hexahydro-1H-iso-
indole-4-carboxylic acid methyl ester (5d). Yield 0.71 g
(35%). Colorless needles. Mp 145–146°С (MeOH). IR spect-
rum, ν, cm–1: 1668 (NCO), 1768 (СO2H). 1H NMR
spectrum (600 MHz, DMSO-d6), δ, ppm (J, Hz): 3.08 (1H,
d, J = 11.6, 3a-CH); 3.19 (3H, s, OCH3); 3.46 (3H, s,
CO2CH3); 3.66 (1H, d, J = 10.0, 1-СН2); 3.73 (3H, s,
PhOCH3); 3.76 (1H, dd, J = 4.5, J = 0.8, 7-CH); 4.00 (1H,
dd, J = 11.1, J = 2.5, 4-CH); 4.21 (1H, d, J = 10.0, 1-СН2);
5.51 (1Н, br. s, OH); 5.90 (1H, dd, J = 4.5, J = 2.5, 6-CH);
6.85 (1H, dt, J = 7.4, J = 1.2, H Ar); 6.93–6.96 (2H, m,
H Ar); 7.08 (1H, tt, J = 7.4, J = 1.2, H-4 Ph), 7.24 (1H,
ddd, J = 8.3, J = 7.4, J = 1.7, H Ar); 7.32–7.34 (2H, m,
H-3,5 Ph); 7.65 (2H, dd, J = 8.3, J = 1.2, H-2,6 Ph).
13C NMR spectrum (100 MHz, CDCl3), δ, ppm: 43.2; 46.9;
52.0; 54.7; 55.7; 57.1; 74.2; 74.8; 110.4; 119.4 (2C); 120.6;
124.2; 125.1; 128.5; 128.8 (2C); 129.5; 129.8; 139.6;
141.5; 156.6; 171.2; 171.8. Mass spectrum (ESI), m/z: 424
[M+H]+ (100). Found, %: C 67.84; H 5.90; N 3.37.
C24H25NO6. Calculated, %: C 68.07; H 5.95; N 3.31.
(3aRS,4RS,7RS,7aSR)-2-Benzyl-7a-hydroxy-7-methoxy-
3-oxo-5-phenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole-
4-carboxylic acid methyl ester (5b). Yield 1.0 g (50%).
Colorless rhombs. Mp 150–151°С (MeOH). IR spectrum,
(3aRS,4RS,7RS,7aSR)-7a-Hydroxy-2-isopropyl-7-meth-
oxy-5-(4-methoxyphenyl)-3-oxo-2,3,3a,4,7,7a-hexahydro-
1H-isoindole-4-carboxylic acid methyl ester (5e). Yield
0.85 g (42%). Colorless powder. Mp 129–130°С (MeOH).
IR spectrum, ν, cm–1: 1663 (NCO), 1766 (CO2H). 1H NMR
spectrum (600 MHz, DMSO-d6), δ, ppm (J, Hz): 1.06 (3H,
d, J = 6.9) and 1.08 (3H, d, J = 6.9, CH(CH3)2); 2.83 (1H,
d, J = 10.6, 3a-СН); 3.20 (1H, d, J = 9.9, 1-СН2); 3.36 (3H,
s, OCH3); 3.46 (3H, s, CO2CH3); 3.56 (1H, d, J = 9.9,
1-СН2); 3.71 (1H, d, J = 5.1, 7-СН); 3.73 (1Н, dd, J = 10.6,
J = 1.0, 4-CН); 3.75 (3H, s, OCH3); 4.16 (1H, sep, J = 6.9,
1
ν, cm–1: 1674 (NC=O), 1746 (CO2H). H NMR spectrum
(600.2 MHz, DMSO-d6), δ, ppm (J, Hz): 2.92 (1H, d,
J = 11.0, 3a-CH); 3.14 (1H, d, J = 9.8, 1-СН2); 3.36 (3H, s,
OCH3); 3.42 (3H, s, CO2CH3); 3.64 (1H, d, J = 9.8,
1-СН2); 3.73 (1H, d, J = 5.1, 7-CH); 3.86 (1H, dd, J = 11.0,
J = 2.0, 4-CH); 4.42 (2H, s, CH2Ph); 5.44 (1H, s, OH); 6.12
(1H, dd, J = 5.1, J = 2.0, 6-CH); 7.26–7.38 (10H, m, H Ph).
736

Chemistry of Heterocyclic Compounds 2019, 55(8), 729–738
CH(CH3)2); 5.27 (1H, s, OH); 6.04 (1H, dd, J = 5.1, J = 2.5,
Supplementary information file containing 1H and
13C NMR spectra for synthesized compounds 1a–h, 2a,c–h/
3a,c–h, and 5a–e is available at the journal website at
http://link.springer.com/journal/10593.
6-СН); 6.89 (2H, d, J = 9.1, H-3,5 Ar); 7.24 (2H, d, J = 8.9,
H-2,6 Ar). 13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm:
19.9; 20.3; 41.9; 42.5; 47.1; 49.1; 51.9; 55.6; 57.4; 73.3;
75.7; 114.0 (2C); 124.8; 128.3 (2C); 132.5; 140.1; 159.3;
170.3; 173.2. Mass spectrum (ESI), m/z: 390 [M+H]+.
Found, %: C 64.87; H 6.72; N 3.82. C21H27NO6.
Calculated, %: C 64.77; H 6.99; N 3.60.
This work was financially supported by the Russian
Foundation for Basic Research (grants 18-58-00013-
Bel_a, 19-53-04002) and the Belarusian Republican
Foundation for Fundamental Research (grants Х18Р-010,
Х19РМ-003).
X-ray structural analysis of compounds 5b,d. Single
crystals of compounds 5b,d were obtained by slow
crystallization of samples from hexane–EtOAc mixtures
(see below). Unit cell parameters and reflection intensities
for compounds 5b,d were measured respectively on a
Bruker SMART APEX-II CCD automatic three-circle
diffractometer with a two-coordinate detector (100 K,
MoKα radiation, λ 0.71073 Å, graphite monochromator,
φ- and ω-scan) and at the synchrotron station ''BELOK'' of
the National Research Center ''Kurchatov Institute'', using a
Rayonix SX165 CCD two-coordinate detector (100 K,
λ 0.96990 Å, φ-scan with 1.0 step). The data was indexed
and integrated using programs SAINT13 (compound 5b)
and iMOSFLM (compound 5d), included in the CCP413
program complex. Absorption correction for the obtained
data was performed by the SADABS14 program for
compound 5b and Scala16 program for compound 5d. The
structures for both compounds were solved with the direct
method and refined against F2 by the least-squares
technique in the full-matrix anisotropic approximation
for all non-hydrogen atoms. H atom positions were
calculated geometrically and included in the refinement
according to the "rider" model with fixed isotropic
displacement parameters (Uiso(H) = 1.5Ueq(C) for CH3
groups and Uiso(H) = 1.2Ueq(C) for all other groups). All
calculations were performed using the SHELXTL17
program set.
Compound 5b (C24H25NO5, M 407.45): colorless
monoclinic crystals, spatial symmetry group C2/c, at
100(2) K: a 36.133(12), b 9.881(3), c 12.064(4) Å;
β 102.225(4)°; V 4210(2) Å3; Z 8; dcalc 1.286 g/cm3;
F(000) 1728; μ 0.090 mm–1. A total of 20331 reflections
were collected, of which 5015 were independent
(Rint 0.0368). Final probability factor values R1 0.0933 for
4281 independent reflections with I ≥ 2σ(I) and wR2 0.2078
for all independent reflections, S 1.006. Values of residual
electron density peaks ρmin/ρmax –0.594 /0.554 e·Å–3.
Compound 5d (C24H25NO6, M 423.45): light-yellow
monoclinic crystals, spatial symmetry group P21/n, for
100(2) K: a 10.914(2), b 15.915(3), c 12.885(3) Å;
β 102.00(3)°; V 2189.2(8) Å3; Z 4; dcalc 1.285 g/cm3;
F(000) 896; μ 0.195 mm–1. A total of 25952 reflections were
collected, of which 4450 were independent (Rint 0.0562).
Final probability factor values R1 0.0593 for 3331
independent reflections with I ≥ 2σ(I) and wR2 0.1569 for
all independent reflections, S 1.009. Values of residual
electron density peaks ρmin/ρmax –0.259/0.244 e·Å–3.
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