Ring-chain tautomerism in the products of the reaction between 5-substituted furfurylamines and anhydrides of α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1007/s10593-016-1868-9

[Figure not available: see fulltext.] The reactions of 5-substituted furfurylamines with anhydrides of α,β-unsaturated carboxylic acids (acryloyl chloride and maleic anhydride) were studied. The first step of the reaction mechanism involved acylation of furfurylamine nitrogen atom, followed by a stereospecific, spontaneous intramolecular Diels–Alder reaction at the furan ring of the N-furfurylamide intermediates. When the starting materials were 5-alkyl-substituted furfurylamines, the expected 1-oxo-2,3,7,7a-hexahydro-1H-3a,6-epoxyisoindoles or the corresponding 7-carboxylic acids were obtained in up to 98% yields. The acylation of 5-aryl-substituted furfurylamines with maleic anhydride led to N-furfurylmaleic amides, which formed a dynamic equilibrium in solutions with adducts formed by intramolecular [4+2] cycloaddition, 3a,6-epoxyisoindole-7-carboxylic acids, as proved by NMR spectroscopy. X-ray structural analysis results show that these mixtures crystallized in the form of the cyclic tautomer.

Full text of DOI:10.1007/s10593-016-1868-9

DOI 10.1007/s10593-016-1868-9
Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Ring-chain tautomerism in the products of
the reaction between 5-substituted furfurylamines
and anhydrides of α,β-unsaturated carboxylic acids
Fedor I. Zubkov1*, Victor D. Golubev1, Vladimir P. Zaytsev1, Olga V. Bakhanovich1,
Evgeniya V. Nikitina1, Victor N. Khrustalev1,2, Rinat R. Aysin2, Tatiana V. Timofeeva3,
Roman A. Novikov4, Aleksey V. Varlamov1
1 People’s Friendship University of Russia,
6 Miklukho-Maklaya St., Moscow 117198, Russia; е-mail: fzubkov@sci.pfu.edu.ru
2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova St., Moscow 119991, Russia; е-mail: vnkhrustalev@gmail.com
3 Department of Chemistry & Biology, New Mexico Highlands University,
803 University Ave., Las-Vegas, NM 87701, USA; е-mail: tvtimofeeva@nmhu.edu
4 V. A. Engel'gardt Institute of Molecular Biology, Russian Academy of Sciences,
32 Vavilova St., Moscow 119991, Russia; е-mail: novikovfff@bk.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(4), 225–236
Submitted November 29, 2015
Accepted after revision April 6, 2016
The reactions of 5-substituted furfurylamines with anhydrides of α,β-unsaturated carboxylic acids (acryloyl chloride and maleic
anhydride) were studied. The first step of the reaction mechanism involved acylation of furfurylamine nitrogen atom, followed by a
stereospecific, spontaneous intramolecular Diels–Alder reaction at the furan ring of the N-furfurylamide intermediates. When the starting
materials were 5-alkyl-substituted furfurylamines, the expected 1-oxo-2,3,7,7a-hexahydro-1Н-3а,6-epoxyisoindoles or the corresponding
7-carboxylic acids were obtained in up to 98% yields. The acylation of 5-aryl-substituted furfurylamines with maleic anhydride led to
N-furfurylmaleic amides, which formed a dynamic equilibrium in solutions with adducts formed by intramolecular [4+2] cycloaddition,
3а,6-epoxyisoindole-7-carboxylic acids, as proved by NMR spectroscopy. X-ray structural analysis results show that these mixtures
crystallized in the form of the cyclic tautomer.
Keywords: furan, isoindole, [4+2] cycloaddition, dynamic stereochemistry, intramolecular Diels–Alder reaction, ring-chain
tautomerism.
The tandem acylation/intramolecular [4+2] cyclo-
addition reaction between anhydrides of α,β-unsaturated
carboxylic acids and furfurylamines, known as IMDAF
(the IntraMolecular Diels–Alder Reaction of Furan), was
thoroughly studied,1 and recently reviewed.2 This reaction
has become a classic method for the construction of 3а,6-
epoxyisoindoles, isoindoles, and their analogs fused with
other heterocycles.3 The patterns of cycloaddition were
studied mainly with furfurylamines lacking substituents in
the furan ring or in fewer cases with furfurylamines
substituted in the furan ring,3a,4 but 5-arylfurfurylamines
have practically never been used in this reaction.5
Thus, the main purpose of this work was to study the
sequence of acylation/intramolecular cycloaddition
reactions between anhydrides of α,β-unsaturated carboxylic
acids and 5-arylfurfurylamines I (Scheme 1). The most
commonly available anhydrides, maleic anhydride and
acryloyl chloride were used as model compounds. The aryl
substituent at position 6 of 3а,6-epoxyisoindolo-7-carb-
oxylic acids II was planned for use in a subsequent
modification of the heterocyclic skeleton.
The nearly complete lack of reports about the
possibility of obtaining isoindoles of type II bearing aryl
substituents at position 6 by using IMDAF reactions may,
0009-3122/16/52(4)-0225©2016 Springer Science+Business Media New York
225

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Scheme 1
Scheme 2
Table 1. Substituents and yields of furfurylamines 1a–k
Com-
pound
R1
R2
Yield, %
in our opinion, be linked to the loss of conjugation between
the aryl substituent and the furan ring in the transition state
of intramolecular Diels–Alder reaction, thus increasing its
energy and creating obstacles to the intramolecular [4+2]
cycloaddition.
Initially we performed synthesis of the 5-aryl- and
5-alkylfurfurylamines 1a–k with aryl substituents and
substituents of various steric bulk at the nitrogen atom
(Scheme 2) and then studied their interaction with maleic
anhydride and acryloyl chloride. The 5-phenylfurfuryl-
amines 1a–g, 5-ethyl- and 5-propylfurfurylamines (1h,i)
were obtained by the standard procedure from 5-phenyl- or
5-alkylfurancarbaldehydes and the appropriate primary
amines without isolation of the azomethine intermediates.
The 5-aryl-substituted furans 1j,k were synthesized from
the respective 5-bromo derivatives via a Suzuki–Miyaura
reaction6 (Scheme 2, Table 1).
The reaction sequence of one-pot acylation and [4+2]
cycloaddition of 5-alkyl- and 5-aryl-substituted furfuryl-
amines 1b,c,e,f,h,i was performed in refluxing benzene by
using acryloyl chloride in the presence of triethylamine
(Scheme 3). As a result, 3а,6-epoxyisoindolones 2a–f were
isolated in moderate yields (Table 2). The lowest yield of
the target adduct 2f (28%) was obtained from acylation of
the sterically hindered tert-butyl[(5-phenylfuran-2-yl)
methyl]amine (1f).
Ph
Ph
Ph
80
67
42
58
53
58
35
55
51
50
77
1a
1b
1c
1d
1e
1f
Bn
Ph
i-Pr
Ph
Cyclopentyl
Ph
(CH2)2OMe
Ph
t-Bu
Et
Ph
1g
1h
1i
Et
i-Pr
Ph
n-Pr
4-MeC6H4
3-ClC6H4
Ph
1j
Ph
1k
Scheme 3
The analogous reaction of 5-aryl-N-phenylfurfuryl-amines
1а,j,k (R1 = Ar, R2 = Ph) ended with the formation of N-
furfurylacrylamides 3a–c (Scheme 3). The attempts to achieve
thermal cyclization of amide 3a (R1 = R2 = Ph) did not result
in isolation of the target 3а,6-epoxyisoindolone 2. Thus,
increasing the reaction temperature to 140°С (refluxing in o-
xylene, 8 h) or using microwave irradiation (benzene, 200°С,
9 bar, 30 min) led to partial resinification of the reaction
mixtures, from which only the starting amide 3a could be
chromatographically isolated in a low yield. It should be noted
that the presence of cyclic form in trace amounts along with
the starting material 3а and intractable products was revealed
Table 2. Substituents and yields of acylation products 2a–f and
3a–c
Starting
material
R1
R2
Product
Yield, %
Et
n-Pr
i-Pr
45
45
32
43
47
28
57
84
67
1h
2a
2b
2c
2d
2e
2f
Ph
(CH2)2OMe
Bn
1i
1e
1b
1c
1f
Ph
Ph
Ph
i-Pr
1
by Н NMR analysis of the reaction mixture obtained after
Ph
t-Bu
Ph
refluxing in o-xylene. A system of coupled 7-CH2 and 7а-CH
protons characteristic for 3а,6-epoxyisoindole system was
observed in the upfield region at δ 2.16 ppm (1Н, dd, J = 9.0,
11.8 Hz), 2.45 ppm (1Н, dd, J = 3.3, 11.8 Hz), and 2.89 ppm
(1Н, dd, J = 3.3, J = 9.0 Hz) ppm.
Ph
1a
1j
3a
3b
3c
4-MeC6H4
3-ClC6H4
Ph
Ph
1k
226

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Scheme 4
The decreased reactivity of N-arylamides 3a–c
compared to their N-alkyl-substituted analogs towards
intramolecular [4+2] cycloaddition remains unexplained
and requires further study. On one hand, it has been
previously shown4a,7 that the reaction between phenyl-
furfurylamines 1 and acryloyl chloride, metacryloyl
chloride, or maleic anhydride proceeds without compli-
cations, leading to 3а,6-epoxyisoindolones 2. In this work
we demonstrate that N-(5-propylfurfuryl)aniline (1i) can be
transformed to the isoindole 2b (Table 2). On the other
hand, (5-phenylfurfuryl)alkylamines 1b,c,e,f also cyclize
under relatively mild conditions in the presence of acryloyl
chloride (Scheme 3, Table 2), and only the amines 1a,j,k
bearing aryl substituents both at the nitrogen atom and
position 5 of the furan ring give the acyclic amides 3a–c,
which practically can not undergo further intramolecular
[4+2] cycloaddition.
The thermodynamic parameters of [4+2] cycloaddition reac-
tion calculated by us for the model amides 3a (R1 = R2 = Ph)
and 3d (R1 = Ph; R2 = Bn) at the B3LYP/6-311+G(d,p)
level of theory did not show substantial differences
between these compounds. Equilibrium can be observed for
both reactions, and it can be shifted by solvation effects
and/or packing in the crystal structure (Scheme 4, Table 3).
The reaction of 5-alkylfurfurylamines 1h,i with maleic
anhydride as a more reactive dienophile occurred at room
temperature, providing high yields of the expected
3а,6-epoxyisoindole-7-carboxylic acids 4a,b (Scheme 5).
H2C
O
O
Ph
Ph
O
N
Ph
Bn
N
N
Ph
Ph
O
3a
2g
H2C
O
O
O
N
Bn
Ph
O
3d
2d
Table 3. The thermodynamic parameters of [4+2] cycloaddition
reaction of amides 3a and 3d at the B3LYP/6-311+G(d,p) level of
theory
Structures
Parameters**
TS (i525 cm–1)
3а
2g
Etot, a.u.
–977.47095
–977.45028
–977.52408
–977.42477
–977.40596
–977.47212
3.61
2.07
7.5
29.00
27.81
32.60
–977.46518
–977.44697
–977.51210
H0, a.u.
G0, a.u.
ΔEtot, kcal/mol
ΔEtot, kcal/mol
ΔEtot, kcal/mol
ΔEtot, kcal/mol
ΔEtot, kcal/mol
ΔEtot, kcal/mol
TS (i536 cm–1)
–1016.72308
–1016.70284
–1016.77406
5.90
3d
2d
Etot, a.u.
–1016.77142
–1016.74962
–1016.82616
–1016.76202
–1016.74233
–1016.81235
H0, a.u..
G0, a.u.
Scheme 5
ΔEtot, kcal/mol
ΔH0, kcal/mol
ΔG0, kcal/mol
ΔE≠, kcal/mol
ΔH≠, kcal/mol
ΔG≠, kcal/mol
4.58
8.66
30.33
29.35
32.69
* Geometry optimization and calculations of thermodynamic parameters
for isolated molecules was performed with the Gaussian 09 D.01 program
package. The results of normal coordinate analysis were used to verify
whether the optimized structures correspond to local minima (no
imaginary frequencies) or transition states (one imaginary frequency) on
the potential energy surface.
The reaction of 5-phenylfurfurylamines 1a–e,g with
maleic anhydride also proceeded easily, and the reaction
products crystallized from ether. The precipitates formed at
** The values of total energy Etot, enthalpy H0, and Gibbs energy G0 of
compounds 2d,g, 3a,d and the corresponding TS, the total energy Etot,
enthalpy H0, Gibbs energy G0, activation full energy E≠, activation
enthalpy H≠, and Gibbs energy of activation G≠ for reactions according
to Scheme 4.
1
room temperature were identified from Н NMR data as
mixtures of maleic amides 5a–f and epoxyisoindolone-
carboxylic acids 6a–f (Scheme 6). The attempts to separate
these mixtures by fractional crystallization or column
chromatography were not successful. The fraction of cyclic
adduct 6 also could not be increased by heating these
The composition of tautomeric mixtures 5 ⇄ 6 was
determined by the integral intensity ratio of 1H NMR
signals due to the protons at the double bond of maleic
amide moiety (for tautomers 5) or in the oxabicycloheptene
fragments (for tautomers 6) (Table 4). The presence of
atropoisomers 5A and 5B and their spatial structure were
studied in detail by NOESY NMR experiments by using
the isomers 5с ⇄ 6с as a reference mixture. The amide
bond rotamers 5A, 5B were determined by the most
characteristic signals of the CH2 group at the furan ring and
the H-2 protons of the maleic amide moiety (Fig. 1,
Table 5). The key parameter used for the assignment of
atropoisomers to series А or B was the difference between
the chemical shifts of analogous protons, instead of the
1
mixtures in benzene or o-xylene. The analysis of Н NMR
spectra showed that the ratio of isomers 5 and 6 remained
practically the same after all manipulations. Thus, we
concluded that a tautomeric equilibrium 5 ⇄ 6 existed in
the solutions of these amides.
Detailed analysis of NMR spectra obtained for the
tautomeric mixtures revealed the presence of three sets of
all proton and carbon signals in the molecules 5a–f and
6a–f. The reason for this was the existence of the open-
chain tautomer 5 in solution phase as a mixture of
conformers 5A and 5B differing by rotation around the
amide bond.
227

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Table 4. The characteristic chemical shifts in 1Н NMR spectra
Scheme 6
(DMSO-d6) of rotamers 5А/5B (ppm)
Products
R2
Ratio5A/5B/6*
4/43/53
Yield, %
Ph
Bn
5Aa/5Ba/6a
5Ab/5Bb/6b
5Ac/5Bc/6c
5Ad/5Bd/6d
5Ae/5Be/6e
5Af/5Bf/6f
52
38
47
46
42
71
22/37/41
10/32/58
13/24/63
30/37/33
32/36/32
i-Pr
Cyclopentyl
(CH2)2OMe
Et
* The ratio of tautomers in mixtures was determined from 1Н NMR
spectra in DMSO-d6 at 23–27°С.
The second conclusion that follows from the data of
Table 4 concerns the population of conformers 5A and 5B,
which also depends on the substituent R2 at the nitrogen
atom. The dominant conformer in solution phase in all
cases was 5B, the spatial structure of which did not favor
intramolecular Diels–Alder reaction. The content of
rotamer 5A was especially low in the equilibrium mixture
of N-phenyl-substituted compounds 5a ⇄ 6a (R2 = Ph,
5Aa/5Ba= 4/43).
The existence of dynamic equilibrium between the
tautomers 5 ⇄ 6 was also confirmed by NMR experiments
performed at different temperatures. The fraction of cyclic
form 6 in tautomeric mixtures gradually decreased upon
raising the temperature, which was demonstrated by
detailed 1Н NMR spectral study of isomers 5с/6с in
DMSO-d6 solutions over the temperature range from 30°C
to 110°C (Table 6). The tautomeric equilibrium dynamics
for compounds 5Ac, 5Bc, and 6c depending on the
temperature are shown in Figure 2.
absolute chemical shift value, which varied widely
depending on the nature of substituent at the nitrogen atom.
For example, the CH2 proton signals of the furfuryl group
in rotamers 5B were always observed at lower field than
the respective signals for rotamers 5A. This difference was
0.06–0.10 ppm for the amides 5a,b,e,f and 0.01–0.04 ppm
for compounds 5c,d. In the latter two cases the chemical
shift differences were small, therefore the rotamers were
additionally characterized by the CH protons of isopropyl
and cyclopentyl groups.
The data from Table 4 suggests that the position of ring-
chain tautomerism in compounds 5 ⇄ 6 substantially
depends on the steric bulk of substituent at the nitrogen
atom. For example, the sufficiently bulky and sterically
similar phenyl (in 5а ⇄ 6а), isopropyl (5c ⇄ 6c), and
cyclopentyl substituents (5d ⇄ 6d) shifted the equilibrium
towards the formation of cyclic form 6. The fraction of
cycloadducts 6a,c,d in DMSO solutions was in range of 53–
63%. On the other hand, the open-chain form dominated in
tautomeric mixtures of compounds 5e ⇄ 6e and 5f ⇄ 6f
containing small n-alkyl substituents at the nitrogen atom,
while the content of cyclic forms 6e,f was as low as 32–
33%. This observation was in a good agreement with the
well-known Thorpe–Ingold effect (the enthropy of
transition state in intramolecular reactions decreases with a
larger number and steric bulk of substituents in the chain).8
According to Figure 3 and the data of Table 6, the ratio
of open-chain forms 5Ac/5Bc shifted towards higher
content of rotamer 5Ac upon increasing the temperature.
When the temperature exceeded 80°C, the rotation of
substituents around the amide bond became too fast on
NMR timescale, therefore the signals of both rotamers 5Ac
and 5Bc merged into one, while significant broadening of
all 1Н NMR signals was observed.
It was proved by additional experiments that the
tautomers 5 ⇄ 6 existed exclusively in cyclic form in the
Table 5. The characteristic chemical shifts in 1Н NMR spectra
(DMSO-d6) of rotamers 5А/5B, ppm
Rotamers
5Aa/5Ba
5Ab/5Bb
5Ac/5Bc
5Ad/5Bd
5Ae/5Be
5Af/5Bf
CH2Fur
4.90/4.98
4.48/4.54
4.47/4.51
4.49/4.50
4.58/4.67
4.47/4.57
NCНAlk
∆, ppm
+0.08
+0.06
+0.04
+0.01
+0.09
+0.10
–
–
4.56/4.17
4.52/4.15
–
–
Figure 1. The most significant NOE cross peaks in 2D NOESY
NMR spectra of the amide rotamers 5Ac and 5Bc.
228

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Table 6. Tautomeric mixture compositions for products 5Ac, 5Bc,
6c at different temperatures
Temperatura, °C
Ratio 5Ac/5Bc/6c*
30
50
70
90
110
15/20/65
28/27/45
35/34/31
82/18**
88/12**
1
* The tautomeric ratio in mixtures was measured by Н NMR spectra of
DMSO-d6 solutions.
** The signals of rotamers 5Ac and 5Bc were averaged due to the
accelerated rotation of substituents relative to amide bond at higher
temperatures.
once, and the Diels–Alder reaction in alkenylfurfuryl-
amines has been found to be reversible4b,10 during
analogous transformations. However, to the best of our
knowledge, there has been no definite proof of
interconversion between both tautomeric forms in either
solution or solid phase.
In conclusion, the interaction of acryloyl chloride and
maleic anhydride with 5-arylfurfurylamines was described
for the first time. The reaction does not stop at the acylation
stage and followed by spontaneous intramolecular Diels–
Alder reaction leading to the formation of a 1-oxo-2,3,7,7a-
hexahydro-1H-3a,6-epoxyisoindole system. The results of
dynamic NMR experiments showed that ring-chain tauto-
merism of the products of the reaction of 5-aryl-
furfurylamines with maleic anhydride takes place in
solution. According to X-ray structural analysis results,
these products in crystals exist exclusively as the cyclic
3a,6-epoxyisoindole form.
Figure 2. Fragments of 1H NMR spectra for tautomeric mixtures
of compounds 5Ac, 5Bc, 6c at different temperatures (solutions in
DMSO-d6).
crystalline state. For example, recrystallization of
compounds 5с ⇄ 6с from a mixture of solvents EtOAc/
EtOH completely shifted the tautomeric equilibrium
towards the cyclic form – the mixture crystallized as
isoindolonecarboxylic acid 6с, the molecular structure of
which was established by X-ray structural analysis (Fig. 3).
Compound 6с crystallized in triclinic space group P–1
with the unit cell containing two crystallographically
independent molecules of similar geometry. All the five-
membered rings in the molecule (pyrrolidone, 2,5-dihydro-
furan, and tetrahydrofuran) assumed the regular envelope
conformation. The N(2) nitrogen atom had a slightly
pyramidalized configuration (the sum of valence angles for
the two crystallographically independent molecules was
equal to 358.5(4) and 358.9(4)°). The dihedral angle
between the planes of substituent and 3a,6-epoxy bridge
was 12.50(15) and 16.55(16)°, respectively.
Crystals of compound 6с were racemic and consisted
of enantiomeric pairs of molecules with the relative
configuration of rac-3ARS,6SR,7RS,7ASR at the indicated
centers. Molecules of compound 6с formed a crystal
structure featuring centrosymmetric dimers linked by two
intermolecular O–H···O hydrogen bonds (Table 7). The
crystal packing of dimers was stacked along the direction a.
We should note that incomplete intramolecular [4+2]
cycloaddition has been reported previously9 more than
Figure 3. The molecular structure of compound 6с (one of the
two crystallographically independent molecules is shown). The
atoms are represented by thermal vibration ellipsoids of 50%
probability.
Table 7. The hydrogen bond parameters in compound 6с
D–H···A*
Symmetry operation**
d(D–H), Å
d(H···A), Å
d(D···A), Å
Angle (D–H···A), deg
O(3)–H(3)···O(1)
(–x+1, –y+1, –z)
0.88(2)
0.89(2)
1.83(2)
1.73(2)
2.6932(2)
2.6177(2)
170.6(2)
174.7(2)
O(3B)–H(3B)···O(1B)
(–x+1, –y+2, –z+2)
* D – proton donor; A – proton acceptor.
** For the generation of equivalent atoms.
229

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
Experimental
6.56 (1H, d, J = 3.4, H-3,4 Fur); 6.69 (2H, d, J = 7.6, H-2,6
Ph); 6.74 (1H, tt, J = 7.6, J = 2.1, H-4 Ph); 7.19 (2H, t, J =
7.6, H-3,5 Ph); 7.23 (1H, t, J = 8.3, H-4 Ph); 7.35 (2H, dd,
J = 8.3, J = 7.6, H-3,5 Ph); 7.63 (2H, d, J = 7.6, H-2,6 Ph).
13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 41.8
(NCH2); 105.9, 109.3 (С-3,4 Fur); 113.3, 118.2, 123.7,
127.4, 128.8, 129.4, 130.9, 147.7 (С Ph); 152.5, 153.5 (C-
2,5 Fur). Mass spectrum (EI, 70 eV), m/z (Irel, %): 249 [М]+
(9), 157 (100), 128 (20), 115 (3), 77 (14), 65 (5), 51 (7), 39
(4). Found, %: С 81.78; Н 6.12; N 5.74. С17H15NO.
Calculated, %: С 81.90; Н 6.06; N 5.62.
IR spectra were recorded on an Infralum FT-801 FT-IR
spectrometer in KBr pellets. 1H NMR spectra were
acquired on Bruker AMX-400 (400 MHz) or JEOL JNM-
ECA600 (600 MHz) instruments, the internal standard for
1H NMR spectra was TMS. 13C NMR spectra were
acquired on Bruker Avance 600 (150 MHz) or Bruker
AMX-400 (100 MHz) instruments, the central signals of
CDCl3 triplet (77.4 ppm) or DMSO-d6 multiplet (40.0 ppm)
were used as internal standards. Mixing time for NOESY
NMR experiment was 800 ms. Mass spectra were recorded
on a Thermo Trace DSQ mass spectrometer (EI ionization
at 70 eV, source temperature 200°C, direct introduction of
sample) or a Thermo DSQ II – Focus GC GC-MS system
(EI ionization at 70 eV, source temperature 200°C, carrier
gas – helium, Rtx-5MS column). Chromato-mass spectra
1-Phenyl-N-[(5-phenylfuran-2-yl)methyl]methan-
amine (1b). Yield 8.81 g (67%), viscous yellow oil.
1
IR spectrum, ν, cm–1: 3318 (N–H). H NMR spectrum
(600 MHz, CDCl3), δ, ppm (J, Hz): 3.80 (4H, s,
CH2NHCH2); 6.22 (1H, d, J = 3.4) and 6.54 (1H, d, J = 3.4,
H-3,4 Fur); 7.18–7.33 (8H, m, H Ar); 7.61 (2H, d, J = 7.6,
H-2,6 Ph). 13C NMR spectrum (100 MHz, CDCl3), δ, ppm:
45.6 (NCH2); 52.8 (NCH2); 105.8, 109.5 (С-3,4 Fur);
123.8, 127.3 (2С), 128.5, 128.6, 128.8, 131.1, 139.9 (С Ar);
153.4, 153.6 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 263 [М]+ (2), 172 (6), 157 (28), 128 (26), 115
(21), 104 (16), 91 (100), 77 (25), 65 (14), 51 (14), 39 (5).
Found, %: С 82.18; Н 6.57; N 5.22. C18H17NO. Calculated,
%: С 82.10; Н 6.51; N 5.32.
were recorded on
a
system including
a
liquid
chromatograph Agilent 1100 Series, a mass spectrometer
Agilent Technologies LC/MSDVL (electrospray ionization
(ESI)), a detector Sedex 75 ELSD. Elemental analysis was
performed on a EuroVectorEA 3000 CHNS-analyzer.
Melting points of the synthesized compounds were
determined on SMP 10 and SMP 30 instruments and were
not corrected. TLC analysis was performed on Sorbfil
PTSH-AF-A-UF-254 plates, visualization with iodine
vapor or KMnO4 solution. The ratio of products in isomeric
mixtures was determined by 1Н NMR spectra as the
integral ratio for the signals of analogous protons. Reagents
were purchased from Acros Organics and Alfa Aesar and
were used without additional purification, while solvents
were distilled before use.
N-[(5-Phenylfuran-2-yl)methyl]propan-2-amine (1с).
Yield 4.52 g (42%), viscous yellow oil. IR spectrum, ν, cm–1:
1
2964 (N–H). H NMR spectrum (600 MHz, CDCl3), δ,
ppm (J, Hz): 1.13 (6H, d, J = 6.2, CH3); 2.91 (1H, heptet,
J = 6.2, NCH); 3.87 (2H, s, NCH2); 6.28 (1H, d, J = 2.7)
and 6.57 (1H, d, J = 2.7, H-3,4 Fur); 7.23 (1H, t, J = 7.8,
H-4 Ph); 7.36 (2H, t, J = 7.8, H-3,5 Ph); 7.65 (2H, d,
J = 7.8, H-2,6 Ph). 13C NMR spectrum (100 MHz, CDCl3),
δ, ppm: 22.8 (2СH3); 44.0 (CH); 47.6 (CH2); 105.7, 109.0
(C-3,4 Fur); 123.7, 127.2, 128.7, 131.1 (С Ph); 153.2,
154.0 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z (Irel, %):
215 [М]+ (10), 172 (4), 157 (100), 128 (17), 110 (11), 100
(4), 77 (10), 71 (26), 51 (7), 43 (10). Found, %: С 78.15;
Н 7.91; N 6.59. C14H17NO. Calculated, %: С 78.10; Н 7.96;
N 6.51.
Synthesis of [(5-aryl- or 5-alkylfuran-2-yl)methyl]-
amines 1a–i (General method). Anhydrous MgSO4 powder
(18 g, 0.15 mol) and the appropriate amine (0.05 mol) were
added to a solution of 5-substituted furfurol (8.6 g,
0.05 mol) in СН2Cl2 (100 ml). The reaction mixture was
stirred for 48 h at room temperature (control by TLC), the
drying agent was removed by filtration, and the solvent was
distilled off at reduced pressure. The residue was dissolved
in methanol (50 ml), cooled in ice bath, and treated with
sodium borohydride (1.90 g, 0.05 mol). The reaction
mixture was refluxed for 4 h (control by TLC), poured into
water (250 ml), and extracted with СН2Cl2 (3×70 ml). The
organic extract was dried over anhydrous Na2SO4, the
drying agent was removed by filtration, the solvent was
distilled off at reduced pressure, and the residue was
dissolved in acetone (5 ml). The obtained solution was
treated with oxalic acid (4.5 g, 0.05 mol) in acetone (10 ml),
the obtained oxalate was filtered off, washed with ether,
decomposed with ammonia, and the product was extracted
with ether (3×70 ml). The ethereal extract was dried over
anhydrous Na2SO4, the drying agent was removed by
filtration, and the solvent was distilled off at reduced
pressure.
N-[(5-Phenylfuran-2-yl)methyl]cyclopentanamine (1d).
Yield 7.01 g (58%), viscous yellow oil. IR spectrum, ν, cm-1:
1
2952 (N–H). H NMR spectrum (600 MHz, CDCl3), δ,
ppm (J, Hz): 1.31–1.84 (8H, m, CH2); 3.11 (1H, q, J = 6.9,
NCH); 3.79 (2H, s, NCH2); 6.21 (1H, d, J = 2.8) and 6.53
(1H, d, J = 2.8, H-3,4 Fur); 7.19 (1H, t, J = 7.6, H-4 Ph);
7.32 (2H, dd, J = 8.3, J = 7.6, H-3,5 Ph); 7.61 (2H, d,
J = 8.3, H-2,6 Ph). 13C NMR spectrum (150 MHz, CDCl3),
δ, ppm: 24.2, 33.2 (4CH2); 45.2 (NCH); 58.8 (NCH2);
105.7, 108.9 (С-3,4 Fur); 123.7, 127.1, 128.7, 131.1 (С Ph);
153.1, 154.2 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 241 [М]+ (14), 172 (3), 157 (100), 136 (8), 128
(23), 115 (6), 97 (13), 77 (10), 51 (6), 41 (9). Found, %:
С 79.52; Н 8.04; N 5.69. C16H19NO. Calculated, %:
С 79.63; Н 7.94; N 5.80.
N-[(5-Phenylfuran-2-yl)methyl]aniline (1а). Yield
(2-Methoxyethyl)[(5-phenylfuran-2-yl)methyl]amine
(1e). Yield 6.09 g (53%), viscous yellow oil. IR spectrum,
ν, cm–1: 3329 (N–H). 1H NMR spectrum (600 MHz,
CDCl3), δ, ppm (J, Hz): 1.88 (1H, br. s, NH); 2.85 (2H, t,
9.96 g (80%), viscous yellow oil. IR spectrum, ν, cm–1:
1
3400 (N–H). H NMR spectrum (600 MHz, CDCl3), δ,
ppm (J, Hz): 4.35 (2H, s, NCH2); 6.28 (1H, d, J = 3.4) and
230

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
J = 5.3, NCH2); 3.34 (3H, s, CH3); 3.51 (2H, t, J = 5.3,
(2H, s, NCH2); 5.91 (1H, d, J = 2.9) and 6.13 (1H, d, J = 2.9,
H-3,4 Fur); 6.68 (2H, dd, J = 8.4, J = 1.1, H-2,6 Ph); 6.75
(1H, t, J = 7.3, H-4 Ph); 7.19 (2H, dd, J = 8.4, J = 7.3,
H-3,5 Ph). 13C NMR spectrum (150 MHz, CDCl3), δ, ppm:
13.9 (CH3); 21.4 (CH2); 30.2 (CH2); 41.7 (NCH2); 105.5,
107.7 (C Fur); 113.3, 118.0, 129.3, 147.9 (С Ph); 150.7,
156.1 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z (Irel, %):
215 [М]+ (15), 123 (100), 94 (7), 81 (11), 77 (10), 65 (6),
57 (7), 51 (6), 39 (5). Found, %: С 78.00; Н 8.11; N 6.39.
C14H17NO. Calculated, %: С 78.10; Н 7.96; N 6.51.
OCH2); 3.86 (2H, s, NCH2); 6.26 (1H, d, J = 3.4) and 6.56
(1H, d, J = 3.4, H-3,4 Fur); 7.23 (1H, t, J = 7.6, H-4 Ph);
7.35 (2H, t, J = 7.6, H-3,5 Ph); 7.65 (2H, d, J = 7.6, H-2,6
Ph). 13C NMR spectrum (100 MHz, CDCl3), δ, ppm: 46.4
(NCH2); 48.5 (NCH2); 58.7 (OCH3); 72.0 (OCH2); 105.7,
109.4 (C-3,4 Fur); 123.6, 127.1, 128.7, 131.1 (C Ph);
153.1, 153.8 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 231 [М]+ (6), 172 (14), 157 (100), 128 (24), 115
(6), 105 (5), 77 (9), 51 (6), 45 (17). Found, %: С 72.61;
Н 7.35; N 6.16. C14H17NO2. Calculated, %: С 72.70;
Н 7.41; N 6.06.
Preparation of N-[(5-arylfuran-2-yl)methyl]anilines
1j,k (General method). The appropriate arylboronic acid
(12.8 mmol) and Pd(PPh)4 (0.37 g, 0.32 mmol) were added
to a solution of N-(5-bromofurfuryl)aniline13 (1.6 g,
6.4 mmol) in a 1:1 mixture of THF (20 ml) and 1 M KОН
aqueuos solution. The reaction mixture was stirred under
argon atmosphere for 4–8 h at 65°C (control by TLC,
eluent hexane– AcOEt, 4:1), poured into water (100 ml),
extracted with EtOAc (3×30 ml). The organic fractions
were combined and dried over anhydrous MgSO4. The
solvent was removed by distillation and the product was
purified by chromatography on a 1.8×28 cm silica gel
column, eluent heptane).
t-Butyl[(5-phenylfuran-2-yl)methyl]amine (1f). Yield
6.62 g (58%), viscous yellow oil. IR spectrum, ν, cm–1:
1
3302 (N–H). H NMR spectrum (600 MHz, CDCl3), δ,
ppm (J, Hz): 1.18 (9H, s, С(CH3)3); 3.81 (2H, s, NCH2);
6.26 (1H, d, J = 3.4) and 6.56 (1H, d, J = 3.4, H-3,4 Fur);
7.22 (1H, t, J = 7.6, H-4 Ph); 7.35 (2H, t, J = 7.6, H-3,5
Ph); 7.64 (2H, dd, J = 7.6, J = 1.4, H-2,6 Ph). 13C NMR
spectrum (150 MHz, CDCl3), δ, ppm: 29.0 (2С), 29.1
(3СН3); 40.3 (NC); 50.8 (NCH2); 105.9, 108.4 (C-3,4 Fur);
123.6, 127.1, 128.6, 131.1 (С Ph); 153.1, 154.5 (C-2,5
Fur). Mass spectrum (EI, 70 eV), m/z (Irel, %): 229 [М]+
(14), 214 (6), 157 (100), 128 (13), 115 (4), 77 (6), 51 (3),
41 (4). Found, %: С 78.44; Н 8.31; N 6.23. C15H19NO.
Calculated, %: С 78.56; Н 8.35; N 6.11.
N-[(5-(4-Methylphenyl)furan-2-yl]methyl)aniline (1j).
Yield 0.85 g (50%), light-yellow powder. IR spectrum, ν,
1
cm–1: 3420 (N–H). H NMR spectrum (600 MHz, CDCl3),
N-[(5-Phenylfuran-2-yl)methyl]ethanamine (1g). Yield
δ, ppm (J, Hz): 2.36 (3Н, s, CH3); 4.37 (2H, s, NCH2); 6.29
(1H, d, J = 3.3) and 6.51 (1H, d, J = 3.3, H-3,4 Fur); 6.71
(2H, d, J = 7.4, H-2,6 Ph); 6.75 (1H, t, J = 7.4, H-4 Ph);
7.17–7.22 (4H, m, HAr); 7.54 (2H, d, J = 8.2, H-2,6 Ar).
13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 21.2
(СН3); 41.6 (NCH2); 104.9, 109.1 (С-3,4 Fur); 113.1 118.0,
123.6, 128.1, 129.2, 129.3, 137.1, 147.6 (С Ar); 151.9,
153.6 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z (Irel, %):
263 [М]+ (4), 171 (100), 141 (5), 128 (23), 115 (5), 91 (4),
77 (4), 65 (4). Found, %: С 81.98; Н 6.47; N 5.54.
С18H17NO. Calculated, %: С 82.10; Н 6.51; N 5.32.
3.53 g (35%), viscous yellow oil. IR spectrum, ν, cm–1: 3317
1
(N–H). H NMR spectrum (600 MHz, CDCl3), δ, ppm
(J, Hz): 1.11 (3H, t, J = 6.9, CH3); 2.68 (2H, q, J = 6.9,
NCH2); 3.80 (2H, s, NCH2); 6.23 (1H, d, J = 3.4) and 6.55
(1H, d, J = 3.4, H-3,4 Fur); 7.20 (1H, t, J = 7.6, H-4 Ph);
7.33 (2H, dd, J = 8.3, J = 7.6, H-3,5 Ph); 7.63 (2H, dd,
J = 8.3, J = 1.4, H-2,6 Ph). 13C NMR spectrum (150 MHz,
CDCl3), δ, ppm: 15.2 (CH3); 43.4 (NCH2); 46.2 (NCH2);
105.7, 109.1 (С-3,4 Fur); 123.7, 127.2, 128.7, 131.0
(С Ph); 153.3, 153.8 (C-2,5 Fur). Mass spectrum (EI, 70 eV),
m/z (Irel, %): 201 [М]+ (37), 184 (21), 157 (100), 128 (27),
105 (14), 96 (32), 77 (20), 57 (19), 51 (14), 39 (6). Found,
%: С 77.67; Н 7.59; N 6.87. C13H15NO. Calculated, %:
С 77.58; Н 7.51; N 6.96.
N-{[5-(3-Chlorophenyl)furan-2-yl]methyl}aniline (1k).
Yield 1.40 g (77%), viscous yellow oil. IR spectrum, ν, cm–1:
3408 (N–H). 1H NMR spectrum (400 MHz, CDCl3), δ, ppm
(J, Hz): 4.40 (2H, s, NCH2); 6.33 (1H, d, J = 3.4) and 6.62
(1H, d, J = 3.4, H-3,4 Fur); 6.74 (2H, d, J = 7.5, H-2,6 Ph);
6.82 (1H, t, J = 7.5, H-4 Ph); 7.24–7.33 (4H, m, HAr); 7.53
(1H, dt, J = 8.1, J = 1.9, H-4 Ar); 7.67 (1H, t, J = 1.9, H-2
Ar). 13C NMR spectrum (100 MHz, CDCl3), δ, ppm: 41.6
(NCH2); 106.9, 109.3 (С-3,4 Fur); 113.3, 118.2, 121.7,
123.6, 127.2, 129.3, 130.0, 132.5, 134.7, 147.5 (С Ar);
151.9, 153.2 (C-2,5 Fur). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 283 [М]+ (10), 191 (100), 128 (42), 111 (11), 92
(9), 77 (29), 65 (27), 51 (25), 39 (17). Found, %: С 72.16;
Н 5.09; N 4.78. С17H14ClNO. Calculated, %: С 71.96;
Н 4.97; N 4.94.
Preparation of 3a,6-epoxyisoindol-1-ones 2a–f and
N-[(5-arylfuran-2-yl)methyl]-N-phenylacrylamides 3а–с
(General method). A solution of the appropriate furfuryl-
amine 1a–c,e,f,h–k (5 mmol), acryloyl chloride (0.45 ml,
5.5 mmol), and triethylamine (1.39 ml, 10 mmol) in
benzene (50 ml) was refluxed for 2–4 h (control by TLC),
cooled, and poured into water (100 ml). The organic layer
N-[(5-Ethylfuran-2-yl)methyl]propan-2-amine (1h).
Yield 4.61 g (55%), yellow oil. IR spectrum, ν, cm–1: 3312
1
(N–H). H NMR spectrum (600 MHz, CDCl3), δ, ppm
(J, Hz): 1.08 (6H, d, J = 6.2, 2CH3); 1.21 (3H, t, J = 7.6,
CH3); 2.61 (2H, q, J = 7.6, CH2); 2.83 (1H, heptet, J = 6.2,
NCH); 3.73 (2H, s, NCH2); 5.88 (1H, d, J = 3.4) and 6.04
(1H, d, J = 3.4, H-3,4 Fur). 13C NMR spectrum (150 MHz,
CDCl3), δ, ppm: 12.2 (CH3); 21.4 (CH2); 22.8 (2CH3); 44.1
(NCH); 47.7 (NCH2); 104.3, 107.1, 152.3, 157.1 (C Fur).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 167 [М]+ (17),
152 (6), 109 (100), 96 (13), 71 (6), 43 (24). Found, %:
С 71.72; Н 10.21; N 8.52. C10H17NO. Calculated, %:
С 71.81; Н 10.25; N 8.37.
N-((5-Propylfuran-2-yl)methyl)aniline (1i). Yield
5.44 g (51%), viscous yellow oil. IR spectrum, ν, cm–1:
3413 (N–H). 1H NMR spectrum (600 MHz, CDCl3), δ, ppm
(J, Hz): 0.97 (3H, t, J = 7.5, CH3); 1.67 (2H, sextet, J = 7.5,
CH2); 2.58 (2H, t, J = 7.5, CH2); 3.97 (1Н, br. s, NH); 4.26
231

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
was separated, while the aqueous layer was extracted with
90.9, 89.6 (С-3а,6); 125.9, 128.2, 128.6, 133.9, 138.5,
140.0 (С Ph, С-4,5); 174.0 (С-1). Mass spectrum (EI, 70 eV),
m/z (Irel, %): 285 [М]+ (20), 230 (57), 210 (29), 172 (23),
157 (100), 128 (37), 105 (13), 77 (17), 55 (44), 45 (16).
Found, %: С 71.44; Н 6.82; N 4.83. C17H19NO3.
Calculated, %: С 71.56; Н 6.71; N 4.91.
EtOAc (3×30 ml). The organic fractions were combined
and dried over anhydrous MgSO4. The extract was
evaporated and the residue was recrystallized from a
suitable solvent (products 2b–f, 3a,b) or purified by
chromatography (products 2а and 3с, 1.8×28 cm silica gel
column, elution with a gradient from hexane to 10:1 hexane–
EtOAc), giving the respective epoxyisoindolones 2a–f or
N-furfuryl-N-phenylacrylamides 3a–c.
(3aRS,6RS,7aSR)-2-Benzyl-6-phenyl-2,3,7,7a-tetra-
hydro-1Н-3a,6-epoxyisoindol-1-one (2d). Yield 0.68 g
(43%), colorless needles, mp 130–130.5°С (hexane–
EtOAc). IR spectrum, ν, cm–1: 1676 (NCO). 1H NMR
spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 2.06 (1H, dd,
J = 11.8, J = 9.0) and 2.37 (1H, dd, J = 11.8, J = 3.7,
7-CH2); 2.71 (1H, dd, J = 9.0, J = 3.7, 7a-СН); 3.66 (1H, d,
J = 11.6) and 3.86 (1H, d, J = 11.6, 3-CH2); 4.39 (1H, d,
J = 15.0) and 4.71 (1H, d, J = 15.0, NCH2); 6.48 (2H, s,
4,5-СН); 7.25–7.47 (10H, m, H Ar). 13C NMR spectrum
(100 MHz, CDCl3), δ, ppm: 34.3 (C-7); 46.8, 49.3 (NCH2,
C-3); 50.7 (C-7a), 89.2 (C-6), 90.9 (С-3a); 125.8, 127.7,
128.1, 128.2, 128.6, 128.8, 133.7, 136.3, 138.5, 140.1
(С Ph, С-4,5); 173.9 (С-1). Mass spectrum (EI, 70 eV), m/z
(Irel, %): 317 [М]+ (9), 226 (41), 172 (100), 157 (16), 128
(20), 91 (25), 77 (11), 55 (44). Found, %: С 79.61; Н 6.11;
N 4.37. C21H19NO2. Calculated, %: С 79.47; Н 6.03;
N 4.41.
(3aRS,6RS,7aSR)-6-Ethyl-2-isopropyl-2,3,7,7a-tetra-
hydro-1Н-3a,6-epoxyisoindol-1-one (2a). Yield 0.50 g
(45%), orange oil. IR spectrum, ν, cm–1: 1680 (NCO).
1H NMR spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 1.05
(3H, t, J = 7.6, CH3); 1.14 (3H, d, J = 6.9, CH3); 1.18 (3H,
d, J = 6.9, CH3); 1.61 (1H, dd, J = 11.7, J = 8.9) and 1.91
(1H, dd, J = 11.7, J = 4.1, 7-CH2); 1.95 (2H, q, J = 7.6,
CH2); 2.52 (1H, dd, J = 8.9, J = 4.1, 7a-СН); 3.65 (1H, d,
J = 11.0) and 3.79 (1H, d, J = 11.0, 3-CH2); 4.41 (1H,
heptet, J = 6.9, NCH); 6.29 (1H, d, J = 5.5) and 6.42 (1H,
d, J = 5.5, 4,5-СН). 13C NMR spectrum (150 MHz,
CDCl3), δ, ppm: 9.3 (CH3); 19.6, 20.1 (2CH3); 25.8 (CH2);
32.1 (С-7); 42.5, 44.4, 51.0 (С-3,7a, NCH); 88.5 (C-6);
91.3 (С-3a); 134.0, 139.0 (C-4,5); 173.5 (С-1). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 221 [М]+ (30), 178 (25),
164 (11), 124 (100), 109 (45), 94 (10), 77 (11), 55 (55), 43
(32). Found, %: С 70.54; Н 8.60; N 6.42. C13H19NO2.
Calculated, %: С 70.56; Н 8.65; N 6.33.
(3aRS,6RS,7aSR)-2-Isopropyl-6-phenyl-2,3,7,7a-tetra-
hydro-1Н-3a,6-epoxyisoindol-1-one (2e). Yield 0.63 g
(47%), colorless prisms, mp 112–113°С (hexane–EtOAc).
1
(3aRS,6RS,7aSR)-2-Phenyl-6-propyl-2,3,7,7a-tetra-
hydro-1Н-3a,6-epoxyisoindol-1-one (2b). Yield 0.60 g
(45%), light-yellow powder, mp 92–93°С (pentane). IR spect-
IR spectrum, ν, cm–1: 1671 (NCO). H NMR spectrum
(400 MHz, CDCl3), δ, ppm (J, Hz): 1.13 (3H, d, J = 6.9,
CH3); 1.17 (3H, d, J = 6.9, CH3); 1.99 (1H, dd, J = 11.8,
J = 8.7) and 2.28 (1H, dd, J = 11.8, J = 3.7, 7-CH2); 2.63
(1H, dd, J = 8.7, J = 3.7, 7a-СН); 3.73 (1H, d, J = 11.6) and
3.85 (1H, d, J = 11.6, 3-CH2); 4.41 (1H, heptet, J = 6.9,
NCH); 6.46 (1H, d, J = 5.5) and 6.51 (1H, d, J = 5.5,
4,5-СН); 7.28–7.45 (5H, m, H Ph). 13C NMR spectrum
(100 MHz, CDCl3), δ, ppm: 19.5, 20.0 (2CH3); 34.0 (C-7);
42.5 (C-7a); 44.4 (C-3); 51.2 (NCH); 89.1 (C-6); 90.7
(С-3a); 125.9, 128.1, 128.5, 133.8, 138.5, 140.0 (С Ph,
С-4,5); 173.0 (С-1). Mass spectrum (EI, 70 eV), m/z (Irel,
%): 269 [М]+ (26), 226 (19), 172 (100), 157 (37), 128 (22),
115 (9), 77 (13), 55 (46). Found, %: С 75.66; Н 7.24;
N 5.41. C17H19NO2. Calculated, %: С 75.81; Н 7.11;
N 5.20.
1
rum, ν, cm–1: 1699 (NCO). H NMR spectrum (600 MHz,
CDCl3), δ, ppm (J, Hz): 0.98 (3H, t, J = 7.4, CH3); 1.45–
1.56 (2H, m, CH2); 1.72 (1H, dd, J = 11.6, J = 8.3) and
2.06 (1H, dd, J = 11.6, J = 3.3, 7-CH2); 1.91–1.94 (2H, m,
CH2); 2.72 (1H, dd, J = 8.3, J = 3.3, 7a-СН); 4.13 (1H, d,
J = 11.6) and 4.39 (1H, d, J = 11.6, 3-CH2); 6.33 (1H, d,
J = 5.8) and 6.47 (1H, d, J = 5.8, 4,5-СН); 7.14 (1H, t,
J = 7.4, H-4 Ph); 7.38 (2H, t, J = 7.4, H-3,5 Ph); 7.63 (2H, d,
J = 7.4, H-2,6 Ph). 13C NMR spectrum (150 MHz, CDCl3),
δ, ppm: 14.7 (CH3); 18.6 (CH2); 33.6, 35.2 (CH2, С-7); 51.2,
51.6 (С-3,7a); 87.6, 91.1 (С-3a,6); 120.2, 124.7, 128.9,
133.6, 139.6, 139.7 (С Ph, C-4,5); 173.8 (С-1). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 269 [М]+ (6), 123 (100),
94 (4), 81 (6), 77 (5), 55 (7). Found, %: С 75.93; Н 6.99;
N 5.31. C17H19NO2. Calculated, %: С 75.81; Н 7.11; N 5.20.
(3aRS,6RS,7aSR)-2-(2-Methoxyethyl)-6-phenyl-2,3,7,7a-
tetrahydro-1Н-3a,6-epoxyisoindol-1-one (2c). Yield
0.46 g (32%), colorless needles, mp 79–80°С (petroleum
(3aRS,6RS,7aSR)-2-tert-Butyl-6-phenyl-2,3,7,7a-tetra-
hydro-1Н-3a,6-epoxyisoindol-1-one (2f). Yield 0.40 g
(28%), colorless needles, mp 120–122°С (petroleum ether–
ether). IR spectrum, ν, cm–1: 1671 (NCO). 1H NMR
spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 1.43 (9H, s,
С(CH3)3); 1.96 (1H, dd, J = 11.7, J = 8.9) and 2.31 (1H, dd,
J = 11.7, J = 3.4, 7-CH2); 2.62 (1H, dd, J = 8.9, J = 3.4,
7a-СН); 3.90 (1H, d, J = 11.7) and 4.00 (1H, d, J = 11.7,
3-CH2); 6.46 (1H, d, J = 5.5) and 6.50 (1H, d, J = 5.5,
4,5-СН); 7.33 (1H, t, J = 7.6, H-4 Ph); 7.39 (2H, t, J = 7.6,
H-3,5 Ph); 7.47 (2H, d, J = 7.6, H-2,6 Ph). 13C NMR
spectrum (150 MHz, CDCl3), δ, ppm: 27.8 (3СН3); 34.2
(C-7); 48.2, 51.7, 54.3 (С(CH3)3, C-3,7a); 88.4 (С-6); 90.8
(С-3a); 126.1, 128.2, 128.6, 134.1, 138.6, 140.0 (С Ph,
С-4,5); 174.2 (С-1). Mass spectrum (EI, 70 eV), m/z (Irel,
%): 283 [М]+ (7), 226 (56), 172 (100), 157 (96), 141 (14),
1
ether–ether). IR spectrum, ν, cm–1: 1678 (NCO). H NMR
spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 2.03 (1H, dd,
J = 11.7, J = 8.9) and 2.31 (1H, dd, J = 11.7, J = 3.4,
7-CH2); 2.67 (1H, dd, J = 8.9, J = 3.4, 7a-СН); 3.36 (3H, s,
CH3); 3.27–3.31 (1H, m), 3.51–3.57 (2H, m), and 3.77–
3.82 (1H, m, OCH2, NCH2); 3.85 (1H, d, J = 12.4) and 4.17
(1H, d, J = 12.4, 3-CH2); 6.48 (1H, d, J = 5.5) and 6.55
(1H, d, J = 5.5, 4,5-СН); 7.33 (1H, t, J = 7.6, H-4 Ph); 7.39
(2H, t, J = 7.6, H-3,5 Ph); 7.47 (2H, d, J = 7.6, H-2,6 Ph).
13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 34.0 (C-7);
43.0, 50.6, 51.4, 58.8, 71.2 (С-3,7a, OCH2, NCH2, CH3);
232

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
128 (39), 115 (29), 105 (14), 77 (29), 55 (63), 41 (37).
appropriate amine 1a–e,g–i (5 mmol) in ether (40 ml) at 20°
С and the reaction mixture was maintained for 1–3 days until
the completion of reaction (control by TLC). The precipitate
was filtered off and washed with ether (2×15 ml). The
carboxylic acids 4a,b and acids 6a–f as colorless crystals
were obtained. Acids 6a–f are in ring-chain tautomerism with
the respective N-furfuryl-N-phenylmaleic amides 5a–f.
Found, %: С 76.38; Н 7.35; N 5.08. C18H21NO2.
Calculated, %: С 76.29; Н 7.47; N 4.94.
N-Phenyl-N-((5-phenylfuran-2-yl)methyl)acrylamide
(3a). Yield 0.86 g (57%), colorless needles, mp 110–111°С
(petroleum ether–ether). IR spectrum, ν, cm–1: 1656 (NCO).
1H NMR spectrum (600 MHz, CDCl3), δ, ppm (J, Hz): 5.00
(2H, s, NCH2); 5.54 (1H, dd, J = 10.3, J = 2.1, CH2=CH cis);
6.03 (1H, dd, J = 16.5, J= 10.3, CH2=CH); 6.29 (1H, d,
J = 3.4) and 6.54 (1H, d, J = 3.4, H-3,4 Fur); 6.42 (1H, dd,
J = 16.5, J = 2.1, CH2=CH trans); 7.14 (2Н, dd, J = 7.6,
J = 1.4, H-2,6 Ph); 7.23 (1H, t, J = 7.6, H-4 Ph), 7.33–7.39
(5H, m, H Ph); 7.56 (2H, dd, J = 8.3, J = 1.4, H-2,6 Ph).
13C NMR spectrum (150 MHz, CDCl3), δ, ppm: 45.0 (NCH2);
105.9, 111.2 (С-3,4 Fur); 123.7, 127.3, 128.1 (2С), 128.5,
128.6, 128.7, 129.6, 130.8, 141.8 (C Ar, CH=CH2); 150.3,
153.5 (C-2,5 Fur); 165.5 (С=О). Mass spectrum (EI, 70 eV),
m/z (Irel, %): 303 [М]+ (6),157 (100), 128 (31), 115 (9), 105
(7), 77 (27), 55 (39), 51 (12). Found, %: С 79.25; Н 5.61;
N 4.69. C20H17NO2. Calculated, %: С 79.19; Н 5.65; N 4.62.
N-((5-(4-Methylphenyl)furan-2-yl)methyl)-N-phenyl-
acrylamide (3b). Yield 1.33 g (84%), pinkish prisms, mp
147–148°С (pentane–EtOAc). IR spectrum, ν, cm–1: 1688,
(3aRS,6SR,7RS,7aSR)-6-Ethyl-2-isopropyl-1-oxo-2,3,7,7a-
tetrahydro-1Н-3a,6-epoxyisoindole-7-carboxylic acid (4a).
Yield 1.13 g (85%), colorless powder, mp 178.0–178.5°С
(EtOAc–EtOH). IR spectrum, ν, cm–1: 1740 (CO2), 1669
1
(NCO). H NMR spectrum (600 MHz, DMSO-d6), δ, ppm
(J, Hz): 0.95 (3H, t, J = 7.6, CH3); 1.05 (3H, d, J = 6.9,
CH3); 1.09 (3H, d, J = 6.9, CH3); 1.82–1.94 (2H, m, CH2);
2.48 (1H, d, J = 8.9) and 2.75 (1H, d, J = 8.9, 7,7a-СН);
3.57 (1H, d, J = 11.7) and 3.82 (1H, d, J = 11.7, 3-CH2);
4.13 (1H, heptet, J = 6.9, NCH); 6.36 (1H, d, J = 5.5) and
6.63 (1H, d, J = 5.5, 4,5-СН); 12.06 (1H, br. s, CO2H).
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 9.3
(CH3); 19.3, 19.6 (2CH3); 22.2 (CH2); 41.8 (NCH); 43.2
(С-3); 46.8, 54.1 (С-7,7a); 87.5, 92.6 (С-3a,6); 137.2,
137.5 (C-4,5); 169.7, 171.7 (С-1, CO2). Mass spectrum
(ESI), m/z: 266 [М+Н]+ (100), 288 [М+Na]+ (24), 304
[М+K]+ (12). Found, %: С 63.43; Н 7.27; N 5.15.
C14H19NO4. Calculated, %: С 63.38; Н 7.22; N 5.28.
1
1655 (NCO). H NMR spectrum (600 MHz, CDCl3), δ,
ppm (J, Hz): 2.34 (3Н, s, СН3); 5.01 (2H, s, NCH2); 5.55
(1H, br. dd, J = 10.7, J = 1.7, CH2=CH cis); 6.03 (1H,
br. dd, J = 17.3, J = 10.7, CH2=CH); 6.28 (1H, d, J = 3.3)
and 6.48 (1H, d, J = 3.3, H-3,4 Fur); 6.43 (1H, dd, J = 17.3,
J = 1.7, CH2=CH trans); 7.14–7.17 (4Н, m, H Ar); 7.33–
7.40 (3H, m, H Ar); 7.46 (2Н, d, J = 8.3, H Ar). 13C NMR
spectrum (150 MHz, CDCl3), δ, ppm: 21.2 (СН3); 45.9
(NCH2); 105.0, 111.1 (С-3,4 Fur); 123.6, 128.0, 128.1,
128.4, 128.5, 129.3, 129.4, 137.1, 141.7, 145.7 (C Ar,
CH=CH2); 149.7, 153.6 (C-2,5 Fur); 164.0 (С=О). Mass
spectrum (EI, 70 eV), m/z (Irel, %): 317 [М]+ (3), 171 (100),
141 (5), 128 (26), 115 (5), 91 (6), 77 (5), 55 (6). Found, %:
С 79.31; Н 5.92; N 4.56. C21H19NO2. Calculated, %:
С 79.47; Н 6.03; N 4.41.
(3aRS,6SR,7RS,7aSR)-1-Oxo-2-phenyl-6-propyl-2,3,7,7a-
tetrahydro-1Н-3a,6-epoxyisoindole-7-carboxylic acid (4b).
Yield 1.33 g (98%), colorless powder, mp 146–147°С
(EtOAc–EtOH). IR spectrum, ν, cm–1: 1743 (CO2), 1666
1
(NCO). H NMR spectrum (600 MHz, DMSO-d6), δ, ppm
(J, Hz): 0.88 (3H, t, J = 7.4, CH3); 1.35–1.44 (2H, m, CH2);
1.76–1.90 (2H, m, CH2); 2.59 (1H, d, J = 8.3) and 3.04 (1H,
d, J = 8.3, 7,7a -CH); 4.01 (1H, d, J = 11.6) and 4.47 (1H, d,
J = 11.6, 3-CH2); 6.37 (1H, d, J = 5.8) and 6.65 (1H, d,
J = 5.8, 4,5-CH); 7.10 (1H, t, J = 7.4, H-4 Ph); 7.34 (2H, t,
J = 7.4, H-3,5 Ph); 7.62 (2H, d, J = 7.4, H-2,6 Ph); 12.23
(1H, br. s, CO2H). 13C NMR spectrum (150 MHz, DMSO-d6),
δ, ppm: 15.0 (CH3); 18.7 (CH2); 32.0 (CH2); 48.5, 50.2,
55.2 (С-3,7,7a); 87.2, 92.8 (С-3a,6); 120.0, 124.5, 129.2,
137.3, 138.7, 140.1 (С Ph, C-4,5); 171.3, 172.3 (СО2, С-1).
Mass spectrum (ESI), m/z: 314 [М+Н]+ (100), 336 [М+Na]+
(46), 352 [М+K]+ (16). Found, %: С 69.06; Н 5.98; N 4.59.
C18H19NO4. Calculated, %: С 68.99; Н 6.11; N 4.47.
N-((5-(3-Chlorophenyl)furan-2-yl)methyl)-N-phenyl-
acrylamide (3c). Yield 1.13 g (67%), pale-yellow needles,
mp 90–91°С (pentane–EtOAc). IR spectrum, ν, cm–1: 1654
1
(NCO). H NMR spectrum (400 MHz, CDCl3), δ, ppm
(J, Hz): 5.00 (2H, s, NCH2); 5.53 (1H, dd, J= 10.6, J = 1.9,
CH2=CH cis); 6.03 (1H, dd, J = 16.8, J = 10.6, CH2=CH);
6.29 (1H, d, J = 3.1) and 6.54 (1H, d, J = 3.1, H-3,4 Fur);
6.42 (1H, br. dd, J = 16.8, J = 1.9, CH2=CH trans); 7.12–
7.42 (8Н, m, H Ar); 7.49 (1H, t, J = 1.9, H-2 Ar). 13C NMR
spectrum (100 MHz, CDCl3), δ, ppm: 45.9 (NCH2); 106.9,
111.2 (С-3,4 Fur); 121.7, 123.6, 127.1, 128.1 (2С), 128.4,
128.5, 129.6, 129.9, 132.4, 134.7, 141.7 (C Ar, CH=CH2);
151.0, 151.9 (C-2,5 Fur); 165.4 (С=О). Mass spectrum (EI,
70 eV), m/z (Irel, %): 337 [М]+ (7), 191 (100), 139 (7), 128
(43), 111 (9), 91 (6), 77 (25), 55 (91), 51 (20), 39 (7).
Found, %: С 70.98; Н 4.90; N 4.01. C20H16ClNO2.
Calculated, %: С 71.11; Н 4.77; N 4.15.
(2Z)-4-Oxo-4-{phenyl[(5-phenylfuran-2-yl)methyl]-
amino}but-2-enoic acid (5а) and (3aRS,6SR,7RS,7aSR)-
1-oxo-2,6-diphenyl-2,3,7,7a-tetrahydro-1Н-3a,6-epoxy-
isoindole-7-carboxylic acid (6а). Yield 0.91 g (52%),
colorless powder, mp 134.5–135.5°С (EtOAc–EtOH). The
ratio of tautomers 5Аa/5Ba/6a = 4/43/53. IR spectrum, ν,
cm–1: 1676 (NCO), 1745 (CO2).
1
Compound 5Аа. The majority of Н NMR signals due
to the minor rotamer 5Аa overlapped with the proton
signals of other tautomeric forms. Signal assignment was
not performed.
Compound 5Bа. 1H NMR spectrum (600 MHz, DMSO-d6),
δ, ppm (J, Hz): 4.98 (2H, s, NCH2); 5.78 (1H, d, J = 11.7,
CH); 6.38 (1H, d, J = 3.4) and 6.81 (1H, d, J = 3.4, H-3,4
Fur); 6.41 (1H, d, J = 11.7, CH); 7.26–7.43 (8H, m, H Ph),
7.70 (2H, d, J = 7.6, H-2,6 Ph); 12.72 (1H, br. s, CO2H).
Preparation of 3a,6-epoxyisoindole-7-carboxylic acid
4a,b, 6a–f and [(5-phenylfuran-2-yl)methyl]amino-4-oxo-
but-2-enoic acids 5a–f (General method). Maleic
anhydride (0.49 g, 5 mmol) was added to a solution of the
233

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
1
Compound 6а. 1H NMR spectrum (600 MHz, DMSO-d6),
Compound 5Ас. H NMR spectrum (400 MHz, 30°C,
DMSO-d6), δ, ppm (J, Hz): 1.15 (6H, d, J = 6.9, 2CH3);
4.48 (2H, s, NCH2); 4.57 (1H, heptet, J = 6.9, NCH); 6.00
(1H, d, J = 11.7, CH=CHCO2H); 6.43 (1H, d, J = 2.8, H-3
Fur); 6.71 (1H, d, J = 11.7, CH=CHCO2H); 6.87 (1H, d,
J = 2.8, H-4 Fur); 7.25–7.43 (3H, m, H-3,4,5 Ph); 7.66 (2H,
br. d, J = 7.6, H-2,6 Ph); 12.02 (1H, br. s, CO2H).
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 20.5
(2CH3); 36.3 (NCH2); 49.4 (NCH); 106.5 (C-4 Fur); 110.1
(C-3 Fur); 123.0 (2C, C-3,5 Ph); 127.3 (C-4 Ph); 128.8
(3C, C-2,5 Ph, СН=СНCO2H); 130.1 (C-1 Ph); 137.6
(CH=CHCO2H); 151.6 (C-2 Fur); 152.4 (C-5 Fur); 165.9
(NCO), 166.8 (СO2H).
δ, ppm (J, Hz): 3.13 (1H, d, J = 8.9) and 3.28 (1H, d, J = 8.9,
7,7a-CH); 4.23 (1H, d, J = 11.7) and 4.64 (1H, d, J = 11.7,
3-CH2); 6.53 (1H, d, J = 5.5) and 6.82 (1H, d, J = 5.5, 4,5-CH);
7.16 (1Н, t, J = 7.6, H-4 Ph); 7.26–7.43 (7H, m, HPh); 7.69
(2Н, dd, J = 8.1, J = 1.3, H-2,6 Ph); 11.89 (1H, br. s, CO2H).
Mixture of compounds 5Bа and 6а. 13C NMR
spectrum (100 MHz, DMSO-d6), δ, ppm: 44.4 (NCH2);
49.5 (C-3); 49.7, 54.7 (C-7,7a); 87.0, 92.7 (C-3а,6); 106.3,
110.6 (C-3,4 Fur); 119.3, 123.2, 123.9, 125.2, 127.2 (2С),
127.8, 127.9, 128.6, 128.7, 129.0, 130.1 136.3, 136.4,
136.6, 139.5, 140.2, 140.9 (C Ph, 2CH, С-4,5); 150.0,
152.4 (C-2,5 Fur); 165.5, 166.1, 170.5, 170.6 (NCO, СO2).
Mass spectrum (EI, 70 eV), m/z (Irel, %): 347 [М]+ (10),
249 (49), 157 (100), 127 (28), 115 (20), 104 (13), 77 (41),
51 (33), 43 (22). Found, %: C 72.50; H 4.98; N 4.07.
C21H17NO4. Calculated, %: С 72.61; Н 4.93; N 4.03.
1
Compound 5Вс. H NMR spectrum (400 MHz, 30°С,
DMSO-d6), δ, ppm (J, Hz): 1.17 (6H, d, J = 6.9, 2CH3);
4.04 (1H, heptet, J = 6.9, NCH); 4.51 (2H, s, NCH2); 5.97
(1H, d, J = 12.4, CH=CHCO2H); 6.44 (1H, d, J = 2.8, H-3
Fur); 6.80 (1H, d, J = 12.4, CH=CHCO2H); 6.83 (1H, d,
J = 2.8, H-4 Fur); 7.25–7.43 (3H, m, H-3,4,5 Ph); 7.66 (2H,
br. d, J = 7.6, H-2,6 Ph); 12.02 (1H, br. s, CO2H). 13C NMR
spectrum (100 MHz, DMSO-d6), δ, ppm: 19.3 (2CH3); 40.4
(NCH2); 44.9 (NCH); 106.5 (C-4 Fur); 109.4 (C-3 Fur);
123.1 (2C, C-2,6 Ph); 123.6 (CH=CHCO2H); 127.0 (C-4
Ph); 128.7 (2C, C-3,5 Ph); 130.4 (C-1 Ph); 138.4
(CH=CHCO2H); 151.3 (C-5 Fur); 152.1 (C-2 Fur); 166.0
(NСO); 166.4 (CO2H).
(2Z)-4-{Benzyl[(5-phenylfuran-2-yl)methyl]amino}-
4-oxobut-2-enoic acid (5b) and (3aRS,6SR,7RS,7aSR)-
2-benzyl-1-oxo-6-phenyl-2,3,7,7a-tetrahydro-1Н-3a,6-
epoxyisoindole-7-carboxylic acid (6b). Yield 0.69 g
(38%), colorless powder, mp 101.5–102°С (EtOAc–EtOH).
The ratio of tautomers 5Аb/5Bb/6b
=
22/37/41.
IR spectrum, ν, cm–1: 1663 (NCO), 1745 (CO2).
Rotamers 5Ab and 5Bb. 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).
1
Compound 6с. H NMR spectrum (400 MHz, 30°C,
DMSO-d6), δ, ppm (J, Hz): 1.11 (3H, d, J = 6.9, CH3); 1.13
(3H, d, J = 6.9, CH3); 2.94 (1H, d, J = 8.9, H-7a); 2.97 (1H,
d, J = 8.9, H-7); 3.74 (1H, d, J = 11.7) and 3.95 (1H, d,
J = 11.7, 3-CH2); 4.17 (1H, heptet, J = 6.9, NCH); 6.43
(1H, d, J = 5.2, H-5); 6.73 (1H, d, J = 5.2, H-4); 7.25–7.43
(5H, m, H Ph); 12.02 (1H, br. s, CO2H). 13C NMR
spectrum (100 MHz, DMSO-d6), δ, ppm: 19.2 (CH3); 19.5
(CH3); 41.9 (NCH); 43.2 (С-3); 48.7 (C-7); 54.1 (C-7a);
87.9 (C-6); 92.4 (C-3a); 125.2 (2C, C-2,6 Ph); 127.0 (C-4
Ph); 127.7 (2C, C-3,5 Ph); 136.7 (C-4); 137.3 (C-1 Ph);
140 (C-5); 169.5 (NСO); 170.6 (CO2H). Mass spectrum
(EI, 70 eV), m/z (Irel, %): 313 [М]+ (58), 295 (19), 268 (45),
252 (27), 215 (56), 210 (13), 198 (38), 172 (40), 157 (100),
127 (29), 115 (27), 99 (26), 77 (19), 71 (11), 55 (19), 51
(12), 43 (20). Found, %: С 69.09; Н 6.18; N 4.32.
C18H19NO4. Calculated, %: С 68.99; Н 6.11; N 4.47.
(2Z)-4-Oxo-4-{[(5-phenylfuran-2-yl)methyl](cyclopentyl)-
amino}but-2-enoic acid (5d) and (3aRS,6SR,7RS,7aSR)-
2-cyclopentyl-1-oxo-6-phenyl-2,3,7,7a-tetrahydro-1Н-
3a,6-epoxyisoindole-7-carboxylic acid (6d). Yield 0.78 g
(46%), colorless powder, mp 154°С (EtOAc–EtOH). Ratio
of tautomers 5Аd/5Bd/6d = 13/24/63. IR spectrum, ν, cm–1:
1742 (CO2), 1664 (NCO).
Compound 6b. 1H NMR spectrum (600 MHz, DMSO-d6),
δ, ppm (J, Hz): 3.03 (1H, d, J = 8.9) and 3.08 (1H, d, J = 8.9,
7,7a-CH); 3.66 (1H, d,
J
= 11.7) and 3.96 (1H, d,
J
= 11.7,
= 15.1,
= 5.5,
3-CH2); 4.43 (1H, d,
NCH2); 6.45 (1H, d,
J
= 15.1) and 4.53 (1H, d,
= 5.5) and 6.74 (1H, d,
J
J
J
4,5-CH); 7.23–7.42 (10H, m, H Ph); 11.78 (1H, br. s, CO2H).
Mixture of rotamers 5Ab and 5Bb and compound
6b. 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 (C-3,7,7a,
NCH2); 88.1, 92.5 (C-3a,6); 106.3, 106.4, 110.5, 111.1
(C-3,4 Fur); 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 (C Ph, C-4,5, 2CH); 149.6, 150.0, 152.4, 153.0
(C-2,5 Fur); 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 3.70. C22H19NO4. Calculated, %: С 73.12; Н 5.30; N 3.88.
(2Z)-4-(Isopropyl((5-phenylfuran-2-yl)methyl)amino)-
4-oxobut-2-enoic acid (5с) and (3aRS,6SR,7RS,7aSR)-
2-isopropyl-1-oxo-6-phenyl-2,3,7,7a-tetrahydro-1Н-3a,6-
epoxyisoindole-7-carboxylic acid (6с). Yield 0.74 g
(47%), colorless powder, mp 139–140°С (EtOAc–EtOH).
Ratio of tautomers 5Аc/5Bc/6c = 10/32/58 (tautomer ratio
was measured using 1H NMR spectra in DMSO-d6 at 22°C).
IR spectrum, ν, cm–1: 1664 (NCO), 1745 (CO2).
Rotamers 5Ad and 5Bd. 1H NMR spectrum (600 MHz,
DMSO-d6), δ, ppm (J, Hz): 1.46–1.76 (8H, m, 4CH2); 4.14,
4.52 (1H, quin, J = 8.2, NCH); 4.49, 4.49 (2H, s, NCH2);
5.98, 5.99 (1H, d, J = 12.0, CH); 6.42, 6.43 (1H, d, J = 3.4)
and 6.84, 6.89 (1H, d, J = 3.4, H-3,4 Fur); 6.71, 6.82 (1H,
d, J = 12.0, CH); 7.25–7.43 (3H, m, HPh); 7.64–7.66 (2H,
m, HPh); 12.70 (1Н, br. s, СО2Н).
Compound 6d. 1H NMR spectrum (600 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.46–1.76 (8H, m, 4CH2); 2.95 (1H, d,
234

Chemistry of Heterocyclic Compounds 2016, 52(4), 225–236
J = 8.9) and 2.97 (1H, d, J = 8.9, 7,7a-CH); 3.75 (1H, d,
3.40 (2H, q, J = 7.0, NCH2); 4.51, 4.61 (2H, s, NCH2);
6.01, 6.06 (1H, d, J = 12.1, CH); 6.50 (1H, d, J = 3.3) and
6.88, 6.90 (1H, d, J = 3.3, H-3,4 Fur); 6.81, 6.83 (1H, d,
J = 12.1, CH); 7.26–7.43 (3H, m, H Ph), 7.66–7.69 (2H, m,
H Ph); 12.76 (1H, br. s, CO2H).
J = 11.7) and 4.00 (1H, d, J = 11.7, 3-CH2); 4.32 (1H, quin,
J = 7.6, NCH); 6.43 (1H, d, J = 5.5) and 6.74 (1H, d, J = 5.5,
4,5-CH); 7.25–7.43 (5H, m, H Ph); 11.67 (1Н, br. s, СО2Н).
Mixture of rotamers 5Ad, 5Bd and compound 6d.
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 14.0,
20.7, 23.2, 23.5, 23.9, 28.1, 28.3, 28.6, 29.1, 37.6, 42.2,
44.4, 48.8, 52.0, 54.1, 55.5, 59.2, 59.7 (4CH2, C-3,7,7a,
NCH, NCH2); 87.9, 92.4 (C-3a,6); 106.5, 106.6, 109.3,
109.9 (C-3,4 Fur); 123.0, 123.2, 123.7, 124.3, 125.3, 127.1,
127.4, 127.8, 128.8, 130.1, 130.5, 136.7, 137.3, 138.3,
140.0 (C Ph, C-4,5, 2CH); 151.4, 151.5, 152.0, 152.5
(C-2,5 Fur); 165.9, 166.0, 166.8, 167.1, 170.0, 170.7 (СO2,
NCO). Mass spectrum (EI, 70 eV), m/z (Irel, %): 339 [М]+ (10),
241 (24), 172 (23), 157 (100), 136 (11), 128 (24), 105 (14), 97
(21), 76 (21), 54 (36), 43 (41). Found, %: С 70.56; H 6.28;
N 4.18. C20H21NO4. Calculated, %: С 70.78; Н 6.24; N 4.13.
(2Z)-4-{(2-methoxyethyl)[(5-phenylfuran-2-yl)methyl]-
amino}-4-oxobut-2-enoic acid (5е) and (3aRS,6SR,7RS,7aSR)-
2-(2-methoxyethyl)-1-oxo-6-phenyl-2,3,7,7a-tetrahydro-
1Н-3a,6-epoxyisoindole-7-carboxylic acid (6е). Yield
0.69 g (42%), colorless powder, mp 86–87°С (EtOAc–
EtOH). Ratio of tautomers 5Аe/5Be/6e = 30/37/33.
IR spectrum, ν, cm–1: 1744 (CO2), 1669 (NCO).
Compound 6f. 1H NMR spectrum (600 MHz, DMSO-d6),
δ, ppm (J, Hz): 1.03 (3H, t, J = 7.0, CH3); 2.94 (1H, d,
J = 9.2) and 2.97 (1H, d, J = 9.2, 7,7a-CH); 3.33 (2H, q,
J = 7.0, CH2); 3.73 (1H, d, J = 11.7) and 4.08 (1H, d,
J = 11.7, 3-CH2); 6.44 (1H, d, J = 5.5) and 6.75 (1H, d,
J = 5.5, 4,5-CH); 7.26–7.43 (3H, m, H Ph), 7.66–7.69 (2H,
m, H Ph); 11.72 (1H, br. s, CO2H).
Mixture of rotamers 5Af, 5Bf and compound 6f.
13C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 11.9,
12.3, 13.4, 36.6, 40.0, 42.3, 44.1, 47.5, 48.7, 53.7 (СН3,
C-3,7,7a, 2NCH2); 88.0, 92.5 (C-3a,6); 106.4, 106.5, 110.3,
110.7 (C-3,4 Fur); 123.2, 123.3, 124.5, 124.9, 125.2, 127.1,
127.3, 127.4, 127.8, 128.8 (2С), 130.1, 130.3, 136.7, 137.0,
137.2 (2С), 140.0 (C Ph, C-4,5, 2CH); 150.3, 150.7 (C-2,5
Fur); 165.9, 166.1, 169.9, 170.7 (СO2, NCO). Mass
spectrum (ESI), m/z: 300 [М+Н]+ (100), 322 [М+Na]+
(18), 338 [М+K]+ (9). Found, %: С 68.14; H 5.61; N 4.82.
C17H17NO4. Calculated, %: С 68.21; Н 5.72; N 4.68.
X-ray structural study of compound 6c. The unit cell
parameters and intensities of reflections for monocrystal of
compound 6с were measured on a Bruker SMART APEX
II CCD automated three-circle diffractometer (MoKα
radiation, graphite monochromator, φ- and ω-scanning).
The absorption of X-ray radiation was accounted for by
semiempirical method using the SADABS software.11 The
structures were determined by direct method and refined
according to full matrix method of least squares by F2 in
anisotropic approximation for non-hydrogen atoms. The
hydrogen atoms of OH group in compound 6с were revealed
objectively from differential Fourier syntheses and refined
isotropically with fixed shift parameters (Uiso(H) = 1.2Ueq(N)
and Uiso(H) = 1.5Ueq(O)). The rest of the hydrogen atom
positions were calculated geometrically and included in the
refinement with fixed positional parameters (the "rider"
model) and isotropic shift parameters (Uiso(H) = 1.5Ueq(C)
for CH3 groups and Uiso(H) = 1.2Ueq(C) for the rest of the
groups). All calculations were performed by using the
SHELXTL software suite.12 The tables of atomic
coordinates, bond lengths, valence and torsion angles, and
anisotropic temperature parameters for compound 6с were
deposited at the Cambridge Crystallographic Data Center as
deposit CCDC 1023933. The data are available by request
from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk).
Rotamers 5Aе and 5Bе. 1H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 3.21, 3.29 (3H, s, CH3); 3.44–
3.64 (4H, m, CH2CH2); 4.57, 4.66 (2H, s, NCH2); 6.02,
6.08 (1H, d, J = 11.9, CH); 6.49, 6.50 (1H, d, J = 3.2) and
6.88, 6.90 (1H, d, J = 3.2, H-3,4 Fur); 6.74, 6.85 (1H, d,
J = 11.9, CH); 7.26–7.43 (3H, m, H Ph); 7.67–7.69 (2H, m,
H Ph); 12.56 (1H, br. s, CO2H).
Compound 6е. 1H NMR spectrum (400 MHz, DMSO-d6),
δ, ppm (J, Hz): 2.96 (1H, d, J = 9.2) and 2.99 (1H, d,
J = 9.2, 7,7a-CH); 3.24 (3H, s, CH3); 3.44–3.64 (4H, m,
CH2CH2); 3.80 (1H, d, J = 11.9) and 4.13 (1H, d, J = 11.9,
3-CH2); 6.44 (1H, d, J = 5.5) and 6.76 (1H, d, J = 5.5,
4,5-CH); 7.26–7.43 (3H, m, H Ph); 7.67–7.69 (2H, m,
H Ph); 12.56 (1H, br. s, CO2H).
Rotamers 5Ae, 5Be and compound 6e. 13C NMR
spectrum (100 MHz, DMSO-d6), δ, ppm: 41.1, 41.8, 43.6,
45.5, 47.1, 48.8, 49.2, 53.4, 57.9, 58.1, 58.2, 69.4, 69.6,
69.8 (СН3, ОCH2, C-3,7,7a, 2NCH2); 88.2, 92.5 (C-3a,6);
106.4, 106.5, 110.2, 110.7 (C-3,4 Fur); 123.2, 123.3, 124.5,
125.2, 125.3, 127.1, 127.3, 127.5, 127.8, 128.8, 128.9,
130.1, 130.3, 136.7 (2С), 137.2, 137.3, 140.0 (C Ph, C-4,5,
2CH); 150.2, 150.7, 152.4, 153.0 (C-2,5 Fur); 166.0 (2С),
166.7, 166.9, 170.4, 170.7 (СO2, NCO). Mass spectrum
(ESI), m/z: 330 [М+Н]+ (100), 352 [М+Na]+ (26), 368
[М+K]+ (12). Found, %: С 65.52; H 5.76; N 4.40.
C18H19NO5. Calculated, %: С 65.64; Н 5.81; N 4.25.
(2Z)-4-Oxo-4-{[(5-phenylfuran-2-yl)methyl](ethyl)-
amino}but-2-enoic acid (5f) and (3aRS,6SR,7RS,7aSR)-
2-ethyl-1-oxo-6-phenyl-2,3,7,7a-tetrahydro-1Н-3a,6-epoxy-
isoindole-7-carboxylic acid (6f). Yield 1.06 g (71%),
colorless powder, mp 103.5–104.5°С (EtOAc–EtOH).
Ratio of tautomers 5Аf/5Bf/6f = 32/36/32. IR spectrum, ν,
cm–1: 1747 (CO2), 1664 (NCO).
The Supplementary information file, containing the
complete X-ray structural analysis data for compound 6c
and NMR spectra copies for tautomeric mixture of
compounds 5Ac, 5Bc, 6c, is available online at http://
link.springer.com/journal/10593.
Rotamers 5Af and 5Bf. 1H NMR spectrum (600 MHz,
DMSO-d6), δ, ppm (J, Hz): 1.07 (3H, t, J = 7.0, CH3); 3.14,
The work was performed with support from the Russian
Foundation for Basic Research, project No. 13-03-00105
235

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