Opening of the epoxide bridge in 3a,6-epoxyisoindol-1-ones by the action of bf3et2o in acetic anhydride

Article abstract of DOI:10.1007/s10593-012-1024-0

The opening of the epoxide bridge in N-substituted 2,3,7,7a-tetrahydro-3a, 6-epoxyisoindol-1-ones by the action of BF3Et2O in acetic anhydride at 25°C over 1 h proceeds through an SN1 mechanism. The allylic type cation formed in the first step is stabiliz

Full text of DOI:10.1007/s10593-012-1024-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
OPENING OF THE EPOXIDE BRIDGE IN
3a,6-EPOXYISOINDOL-1-ONES BY THE ACTION
OF BF3·Et2O IN ACETIC ANHYDRIDE*
F. I. Zubkov1**, V. P. Zaytsev1, E. S. Puzikova1, E. V. Nikitina1,
V. N. Khrustalev2, R. A. Novikov3, and A. V. Varlamov1
The opening of the epoxide bridge in N-substituted 2,3,7,7a-tetrahydro-3a,6-epoxyisoindol-1-ones by
the action of BF3·Et2O in acetic anhydride at 25°C over 1 h proceeds through an SN1 mechanism. The
allylic type cation formed in the first step is stabilized by the addition of an acetoxy group at C-5 in the
isoindole system to give a mixture of cis and trans isomers of 5,6-diacetoxy-2,3,5,6,7,7a-hexa-
hydroisoindol-1-ones, which are aromatized under these conditions over 24 h to give 2,3-dihydro-
1H-isoindol-1-ones.
Keywords: 3a,6-epoxyisoindole, furan, furfurylamine, isoindole, 7-oxabicyclo[2.2.1]heptene, aromati-
zation, intramolecular Diels-Alder reaction.
The nucleophilic opening of 7-oxabicyclo[2.2.1]heptenes is known to proceed with high regio- and
stereoselectivity, predominantly through an SN2' mechanism (accompanied by migration of the double bond)
[1, 2] and, as a consequence, is commonly used for stereodirected synthesis of polysubstituted cyclohexenes
[3, 4]. The regularities of the electrophilic opening of the epoxide bridge in 7-oxabicyclo[2.2.1]heptenes has not
been studied as extensively. In this case, depending on the conditions, the formation of an often unpredicted
variety of products is possible [5-7].
In the present work, we continue our systematic investigation of the transformations of the
oxabicycloheptene ring in 3a,6-epoxyisoindol-1-ones 1 in acidic media [8, 9]. Previous results [10-14] have
indicated that these reactions even for similar reagents under similar experimental conditions may lead to
different products. Some examples of such transformations are given below. However, most frequently, the
action of electrophiles such as H3PO4 [8], HCl [15], p-TsOH [16], and BF3·Et2O [17] on oxabicycloheptenes
_______
*Dedicated to the memory of Prof. N. S. Prostakov, Honored Science Worker of the Russian Federation,
founder of the organic chemistry department at the Peoples' Friendship University of Russia.
**To whom correspondence should be addressed, e-mail: fzubkov@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
GSP-1, Moscow 119991, Russia; e-mail: vkh@xrlab.ineos.ac.ru.
3V. A. Engel'gardt Institute of Molecular Biology, 32 Vavilova St., Russian Academy of Sciences, Moscow
119991, Russia; e-mail: novikovfff@bk.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 549-560, March, 2012. Original
article submitted January 17, 2012.
514
0009-3122/12/4803-0514©2012 Springer Science+Business Media, Inc.

leads to a tandem sequence involving opening of the oxa bridge, dehydration, and aromatization, which finally
leads to 2,3-dihydroisoindoles.
Br
Br
TiCl4
O
NCH2Ph
NCH2Ph
98% [10]
OH
O
O
Cl
NO2
O
NO2
AcO
AcO
.
BF3 Et2O–Ac2O
38% [11]
NO2
NO2
AcO
NMe
O
Ac2O, 
NMe
O
O
83% [12]
Cl
O
O
O
Cl
I2–AgOAc
AcOH–H2O
NCH2Ph
Me
O
NCH2Ph
Me
61% [13]
I
OAc
.
BF3 Et2O–CH2Cl2
1) –78 – 0°C, 3 h
O
O
O
O
2) 25°C, 4 h
51% [14]
NO2
NO2
OAc
AcO
O
.
BF3 Et2O–Ac2O
O
NPh
O
NPh
75% [9]
O
MeO2C
CO2Me
O
In recent work [9], we have shown that the reaction of perhydro-3a,6:4,5-diepoxyisoindoles with
BF3·Et2O in acetic anhydride is accompanied not only by opening of the oxirane fragment, but also a previously
unreported Wagner-Meerwein skeletal rearrangement. In this communication, we report on the transformations
of 3a,6-epoxyisoindoles 1 under similar conditions.
Starting 3a,6-epoxyisoindolones 1a-f used in this study were prepared according to reported procedures
[8, 9, 18] from furfurylamines and -unsaturated acid anhydrides. The corresponding carboxylic acids were
converted into methyl esters 1c,d,f to improve solubility in acetic anhydride. Starting isoindolones 1a-f were
used as individual diastereomers with relative configuration as shown on the following scheme.
Prolonged maintening of derivatives 1a,c in acetic anhydride at room temperature does not lead to any
marked change. Increasing the reaction temperature leads to the gradual formation of a multicomponent product
mixture. The addition of two or three equivalents of boron trifluoride etherate produces a rapid selective
conversion of epoxyisoindolones 1 even at room temperature. These reactions are usually complete in not more
than 2 h.
515

R2
R2
Cl
O
H2C
R
O
NR1
O
Et3N, PhMe, 
NHR1
1a (48%), b (45%), e (46%)
R2
R
CO2Me
O
R2
O
1.
O
O
O
R
PhH, 25°C
2. MeOH, H+
NR1
O
1c (83%), d (74%), f (32%)
a,c,e,f R = H, b R = Me, d R = Br; a–d R1 = Ph, R2 = H, e,f R1 = CH2Ph, R2 = Me
The oxabicyclic fragment in compounds 1a,b is readily cleaved by the action of the acetyl cation, and
an allylic cation 1' forming in the first step. This cation is stabilized by the addition of the acetoxy anion at
C-5 carbon atom of resonance structure 1". This direction of the addition is probably due to steric reasons.
O
O
R
R
O
7
AcO
AcO
.
AcO
AcO
7a
BF3 Et2O–Ac2O
R
1
6
+
O
NPh
2
NPh
NPh
25°C, 15–30 min
5
3a
3
4
1a,b
2aA,bA
2aB
+
Ac
2aA : 2aB = 80:20
.
BF3 Et2O–Ac2O
25°C, 24 h
+
– Ac
Ac2O
O
O
R
R
AcO
AcO
O
O
R
NPh
NPh
+
+
HC
C
NPh
1'
1''
3a (68%), b (41%)
Me
+
C
NPh
OAc
C
a R = H, b R = Me
The attack of the acetoxy anion on the cationic site in intermediate 1" proceeds with formation of a pair
of diastereomers A and B. In the case of isoindole 1a (R = H), trans-5,6-diacetoxy isomer 2aA predominates in
the isolated mixture, possibly due to steric repulsion of the carbonyl fragments of the OAc group and acetoxy
anion in the transition state. In the case of isoindole 1b (R = Me), the reaction proceeds less smoothly to give a
multicomponent mixture, from which only trans-5,6-diacetoxy isomer 2bA was isolated with 43% yield. The
formation of the multicomponent mixture in this case is probably related to the possibility of an alternative
cleavage of the epoxide bridge in isoindole 1b to give a tertiary carbon cation C, leading to side products with
different positions of the acetoxy groups.
We should note that even after 15 min maintening of epoxy derivative 1a under the conditions indicated
in the above scheme, the reaction mixture already contains up to 22% aromatization product 3a as indicated by
1
the H NMR spectrum of the isolated mixture prior to fractional crystallization. The loss of the acetic acid
fragments most likely occurs by the action of BF3·Et2O through a step involving formation of carbocation of
516

type 1' (1") with subsequent elimination of a proton. When the reaction time is extended, the latter pathway
becomes predominant. Thus, maintaining epoxyisoindolones 1a,b or the corresponding diacetoxy derivatives
2a,b in the reaction mixture for 24 h is accompanied by aromatization of the bicyclic fragment and formation of
isoindoles 3a,b.
Isomeric isoindoles 2aA and 2aB were isolated as pure compounds by column chromatography with
62% overall yield. Their structure was proved by X-ray structural analysis. This finding permits the unequivocal
13
assignment of the signals in their 1H or C NMR spectra and determination of the stereochemistry of the other
synthesized isoindole products 2.
Analogous transformations by the action of boron trifluoride etherate also occur in the case of esters
1c,d. Epoxyisoindolone 1c (R = H) is converted over 1.5 h at room temperature into trans-5,6-diacetoxy-
hexahydroisoindole 2cA in 37% yield.
CO2Me
CO2Me
O
R
O
O
.
BF3 Et2O, Ac2O
AcO
AcO
R
NPh
NPh
1c,d
2cA,dA
c R = H, d R = Br
Epoxyisoindolone 1d (R = Br) reacts extremely slowly at room temperature in the presence of a two-
fold excess of Lewis acid. Extensive tar formation is observed when this reaction is carried out at 50°C with a
fivefold molar excess of BF3·Et2O for 48 h. Analysis of the 1H NMR spectrum of the mixture obtained (20% of
a products mixture was isolated by standard work-up) showed the presence of the isoindolone 3 (the product of
the aromatization of the oxabicycloheptene fragment) in addition to starting ester 1d and desired cyclohexene
2dA. From a preparative point of view, a detailed analysis of this mixture does not seem appropriate. In our
opinion, the low reactivity of epoxyisoindolone 1d may be attributed either to steric hindrance to attack of the
bridging oxygen atom due to the bromine atom at C-6 or reduced electron density on this oxygen atom.
R
R
O
O
.
R
O
BF3 Et2O
Me
Me
O
Me
AcO
AcO
AcO
AcO
Ac2O
+
NCH2Ph
NCH2Ph
NCH2Ph
25°C
0.5–2 h
2eA,fA
2eB,fB
1e,f
2e (39%), 2eA : 2eB = 75:25
2f (74%), 2fA : 2fB = 90:10
e R = H; f R = CO2Me
The methyl substituent at C-7a in 3a,6-epoxyisoindolones 1e,f as in the case of the ester group at C-7 in
compound 1c does not have a significant effect on the rate or direction of the opening of the 3a,6-oxygen
bridge. Diacetoxy derivatives 2e,f are formed in moderate yields as pairs of diastereomers A and B. In contrast
to analogs 2a-c, aromatization of derivatives 2e,f to give isoindolones of type 3 at room temperature is not
observed even after one week. This failure is apparently due to the impossibility of eliminating the methyl
radical at C-7a.
Major isomers 2eA and 2fA were isolated as pure compounds by fractional crystallization and column
chromatography, respectively. Minor isomers 2eB and 2fB could not be isolated as pure compounds and these
products were characterized using the 1H and 13C NMR spectra of the corresponding mixtures.
517

The three-dimensional structures of isomers 2aA and 2aB were established by X-ray structural analysis
(Figs. 1 and 2). We should note that the crystal of isomer 2Aa studied in this work contained a cocrystallized
molecule of isoindole 3a in 3:1 ratio, that is, the crystal unit cell had three crystallographically independent
molecules of major product 2aA and one molecule of isoindole 3a. The three crystallographically independent
molecules of 2aA had similar geometry and were a 2:1 mixture of different enantiomers with relative
configurations of the asymmetric centers 5R*, 6R*, 7aS*. We could not determine which of the enantiomers
predominates due to the lack of a heavy atom in the molecule with Z > 14. Furthermore, the cocrystallized
molecule of 3a proved disordered at two positions related to rotation of 180° in the molecular plane such that a
pseudo center of inversion arises in the crystal of isomer 2aA, which greatly complicates the solution of its
crystal structure.
The crystal of cis-5,6-diacetoxyisoindolone 2aB is a racemate consisting of an enantiomeric pair with the
following relative configurations of the three asymmetric centers at carbon atoms C-5, C-6, and C-7a: 5S*, 6R*, 7aS*.
Product 2a, which was identified as 5,6-diacetoxy-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-isoindol-1-one,
contains two trans-fused rings, namely 2-pyrrolidine and cyclohexene rings. The pyrrolidine ring in the
molecules of both diastereomers 2aA and 2aB has "envelope" conformation, in which carbon atom C-3a
deviates from the mean-square plane traversing the other ring atoms. On the other hand, the cyclohexene ring
has asymmetric "half-chair" conformation, in which carbon atoms C-6 and C-7 deviate in opposite directions
from the mean-square plane traversing the other ring atoms to a greater or lesser extent, respectively. The angle
between the planar segments of these rings is 20.1(1), 25.5(1), and 27.1(1)° for the three crystallographically
independent molecules in diastereomer 2aA and 26.4(2)° in diastereomer 2aB. The dihedral angle between the
planes of the phenyl substituent and the planar segment of the pyrrolidine fragment is 18.2(1), 18.7(1), and
14.9(1)° for the three crystallographically independent molecules in diastereomer 2aA and 11.0(2)° in
diastereomer 2aB. The greatest geometrical differences between the diastereomer molecules of compound 2a
are the different conformations of the acetoxy groups at C-5 and C-6 positions. The range of torsion angles
(C=)C–C–O–C(=O) and (H2)C–C–O–C(=O) for the three crystallographically independent molecules in
diastereomer 2aA is 86.5(2)-97.3(2)°, while these angles in diastereomer 2aB are 95.0(4)/121.8(4)° for the two
alternative positions and -155.6(2)°, respectively.
Fig. 1. Molecular structure of diastereomer 2aA. The atoms are represented by 50%-probability anisotropic shift
ellipsoids (one of the three crystallographically independent molecules is shown).
Of the other geometrical parameters of diastereomers 2aA and 2aB of practical importance, we should
note torsion angles H–C(OAc)–C(OAc)–H between the acetoxy groups at C-5 and C-6: 159.6, 157.1, and
156.0° for the three crystallographically independent molecules in diastereomer 2aA and 42.4° in diastereomer
3
2aB. Thus, the J5,6 coupling constant for major trans isomers A should be close to 8 Hz, while the same
3J5,6 coupling constant for cis isomers B should be about 3 Hz. These data help us to distinguish these
1
diastereomers by H NMR spectroscopy. In the 13C NMR spectra, the most informative are the well-identified
518

signals for the C-5 atoms at 71-73 ppm and for the C-6 atoms at 70-73 ppm for major isomers A and for the C-5
atoms at 64-65 ppm and for the C-6 atoms at 68-69 ppm for minor isomers B.
Fig. 2. Molecular structure of diastereomer 2aB. The atoms are represented by 50%-probability anisotropic shift
ellipsoids. The alternative position of the disordered carboxylate substituent is not shown.
Thus, we have shown that opening of the oxygen bridge in N-substituted hydrogenated 3a,6-epoxy-
isoindol-1-ones proceeds readily at room temperature in acetic anhydride using BF3·Et2O. Mixtures of cis- and
trans-5,6-diacetoxy-2,3,5,6,7,7a-hexahydroisoindol-1-ones, which are isomeric relative to the position of the
acetoxy groups, are rapidly formed in moderate to high yields with short reaction times from 15 min to 2 h. The
trans isomer predominates in the product mixture. Extending the reaction time leads to aromatization of the
bicyclic fragment and formation of 2-R-isoindolin-1-ones in moderate yield. The observed transformations
significantly expand the synthetic potential of readily available 3a,6-epoxyisoindol-1-ones and permit their use
for the preparation of polyfunctional hydrogenated isoindole derivatives.
EXPERIMENTAL
The IR spectra were recorded on an IR Fourier spectrometer Infralum FT-801 using KBr pellets. The 1H
NMR spectra were recorded on a Bruker AMX-400 spectrometer at 400 MHz and JEOL JNM-ECA600
spectrometer at 600 MHz for ~3% solutions in CDCl3. The residual solvent protons ( 7.26 ppm) served as
internal standard. The 13C NMR spectra were recorded on a Bruker Avance 600 spectrometer at 150 MHz and a
Bruker AMX-400 spectrometer at 100 MHz with the central signal of the CDCl3 triplet ( 77.4 ppm) as the
standard. The mass spectra were obtained on a Thermo Trace DSQ mass spectrometer (70 eV electron ionization
and direct inlet into the ion source, the temperature in the source was 200°C) or a Finnigan MAT-95-XL
GC/MS with direct introduction of the sample into the ion source. The melting points of the products were
determined on an SMP 30 melting points apparatus and were not corrected. The thin-layer chromatography was
carried out on Sorbfil plates with 1:2 ethyl acetate–hexane as the eluent with iodine vapor development. Column
chromatography was carried out on activated neutral alumina (50-200 mesh) with 1:2 ethyl acetate–hexane as
1
the eluent. The isomer ratio in the reaction products was determined in the H NMR spectra as the ratio of the
integral intensities of signals of monotypic protons and by GC/MS.
Reagents obtained from Acros Organics were used without further purification. Freshly-prepared
solvents were used for the syntheses. The synthesis, spectral data, physicochemical characteristics, and
elemental analysis results for compounds 1a-d [9] and 1e* have already been published.
_______
*F. I. Zubkov, V. P. Zaytsev, I. K. Airiyan, V. D. Golubev, E. S. Puzikova, E. A. Sorokina, E. V. Nikitina, and
A. V. Varlamov, Izv. Akad. Nauk, Ser. Khim. (2012), in press.
519

TABLE 1. The Principal Crystallographic Data and Refinement Parameters
for Compounds 2aA and 2aB
Parameters
Empirical formula
2aА·⅓C14H11NO
2аB
C18H19NO5
3(C18H19NO5)·C14H11NO
Molecular mass
1197.26
100
329.34
296
T, K
System
Triclinic
P1
Monoclinic
P21/c
Space group
a, Å
8.246(2)
11.297(3)
15.997(5)
95.190(6)
103.399(6)
90.346(7)
1443.1(7)
1
8.2172(8)
6.1754(6)
34.190(3)
90
b, Å
c, Å
, deg
, deg
96.590(3)
90
, deg
V, Å3
1723.5(3)
4
Z
dc, g·cm–3
1.378
1.269
F(000)
, mm1
632
696
0.099
0.093
2max, deg
56
52
Number of measured reflections
Number of independent reflections
Number of reflections with I > 2(I)
Number of refined parameters
R1 (I > 2(I))
14983
15782
3362 (Rint = 0.032)
2377
12900 (Rint = 0.024)
10098
811
217
0.058
0.062
wR2 (all data)
0.157
0.173
GOOF
1.004
1.002
Monocrystals of isomers 2aA and 2aB were obtained by slow crystallization from ethyl acetate–hexane
of samples obtained after chromatographic separation (see below). The unit cell parameters and reflection
intensities for 2aA and 2aB were measured on an automatic three-circle Bruker SMART IK CCD diffractometer
using MoK radiation, graphite monochromator, and - and -scanning for compound 2aA and automatic
three-circle Bruker SMART APEX-II CCD diffractometer with MoK radiation, graphite monochromator,
and - and -scanning for compound 2aB. The principal crystal structure data are given in Table 1. The
structures of both compounds were determined by the direct method and refined anisotropically by the full-
matrix method of least squares relative to F2 for the non-hydrogen atoms. The crystal of compound 2aA
contains a cocrystallized molecule of 2-phenylisoindolin-1-one (3a); the 2aA:3a ratio is 3:1. The molecule of
compound 3a is disordered over two positions related by a 180° rotation in the molecular plane with
occupancies 0.6:0.4. One of the two carboxylate substituents in 2aB is disordered over two positions with equal
occupancies. In both compounds, the positions of the hydrogen atoms were calculated geometrically and
included in the refinement isotropically with fixed positions ("horse rider" model) and thermal parameters
(Uiso(H) = 1.5Uequ(C) for the CH3 groups and Uiso(H) = 1.2Uequ(C) for the other groups). All the calculations
were carried out using the SHELXTL software package [19]. Tables for the atomic coordinates, bond lengths,
bond and torsion angles, and anisotropic temperature parameters for compounds 2aA·⅓C14H11NO and 2aB have
been deposited at the Cambridge Crystallographic Data Center (CCDC 8600029 and 860030).
(3aRS,6SR,7RS,7aSR)-2-Benzyl-7a-methyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carb-
oxylic Acid Methyl Ester (1f). Concentrated sulfuric acid (1 ml) was added to a suspension of
(3aRS,6SR,7RS,7aSR)-2-benzyl-7a-methyl-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylic acid
[20] (3 g, 0.01 mol) in methanol (50 ml) and heated at reflux for 10-12 h with monitoring by thin-layer
chromatography. The suspension was completely converted to a solution. The reaction mixture was cooled and
poured into water (100 ml); the mixture was extracted with chloroform (3x50 ml). The extract was dried over
520

anhydrous magnesium sulfate. The residue after distilling off chloroform was recrystallized from ethyl acetate–
hexane to give colorless plates. Yield 0.90 g (32%); mp 103-104°С. IR spectrum, ν, cm–1: 1681 (N–C=O), 1734
1
(О–C=O). Н NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.15 (3Н, s, СН3); 2.24 (1Н, s, Н-7); 3.52 (1Н, d,
J = 11.5, H-3); 3.62 (1Н, d, J = 11.5, Н-3); 3.76 (3Н, s, OСН3); 4.20 (1Н, d, J = 15.1) and 4.70 (1Н, d, J = 15.1,
NCH2Ph); 5.05 (1Н, d, J = 1.7, Н-6); 6.37 (1Н, d, J = 5.7, Н-4); 6.47 (1Н, dd, J = 1.7, J = 5.7, Н-5); 7.19 (2Н, d,
J =7.7, Н-2,6 Ph); 7.22 (1Н, t, J = 7.7, Н-4 Ph); 7.29 (2Н, t, J = 7.7, Н-3,5 Ph). Mass spectrum, m/z (Irel, %): 313
[M]+ (2), 232 (6), 222 (6), 186 (36), 127 (100), 99 (13), 91 (63), 81 (53), 53 (19), 39 (10). Found, %: С 68.63; Н
6.35; N 4.65. С18H19NO4. Calculated, %: С 69.00; Н 6.11; N 4.47.
1-Oxo-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Diacetates 2a-f (General Method). BF3·Et2O
(0.70 ml, 5.5 mmol) was added to a solution of the corresponding 3a,6-epoxyisoindolone 1a-f (2.2 mmol) in
acetic anhydride (10 ml) and stirred for from 15 min to 2 h at room temperature with monitoring by thin-layer
chromatography. At the end of the reaction, the mixture was poured into water (50 ml), made basic by adding
aqueous sodium bicarbonate, and extracted with chloroform (3×20 ml). The extract was dried over anhydrous
magnesium sulfate. The residue after the removal of chloroform was purified either by column chromatography
or fractional crystallization as indicated below to give isoindoles 2a-e as colorless crystals or, in the case of 2f, a
pale-yellow oil.
(5RS,6RS,7aSR)-1-Oxo-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Diacetate (2aA) and
(5RS,6SR,7aRS)-1-Oxo-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Diacetate (2aB). Removal
1
of chloroform gave 0.44 g of a ~73:18:9 mixture of products 2aA, 2aB, and 3a as indicated by H NMR
spectroscopy. Column chromatography gave two major fractions.
1
Fraction 1, 0.36 g (~50%) of a 92:8 mixture of 2aA and 3a as indicated by H NMR spectroscopy.
Recrystallization from ethyl acetate–hexane gave crystals suitable for X-ray structural analysis containing
compounds 2aA and 3a in 3:1 ratio. Pure isomer 2aA was obtained after repeated recrystallization from the
same mixed solvent as a powder unsuitable for X-ray structural analysis. Mp 154-156°С. IR spectrum, ν, cm-1:
1689 (N–C=O), 1736 (О–C=O). 1Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.75 (1Н, q, J = 12.4, Н-7); 2.07
(6Н, s, СОСН3); 2.57 (1Н, ddd, J = 4.1, J = 5.1, J = 12.4, Н-7); 3.39-3.43 (1Н, m, Н-7а); 4.23 (1Н, dq, J = 0.9,
J = 12.8, Н-3); 4.52 (1Н, dq, J = 2.3, J = 12.8, Н-3); 5.20 (1Н, ddd, J = 4.1, J = 7.7, J = 12.4, Н-6); 5.53-5.57
(1Н, m, Н-5); 5.74-5.76 (1Н, m, Н-4); 7.16 (1Н, t, J = 7.8, Н-4 Ph); 7.37 (2Н, t, J = 7.8, Н-3,5 Ph); 7.61 (2Н, d,
J = 7.8, Н-2,6 Ph). 13С NMR spectrum (100 MHz), δ, ppm: 21.12 and 21.14 (CH3); 29.4 (C-7); 43.3 (C-7a);
51.7 (C-3); 72.3 (C-6); 72.6 (C-5); 119.2 (C-4); 119.8 (C-2,6 Ph); 125.0 (C-4 Ph); 129.1 (C-3,5 Ph); 136.7
(C-3a); 138.8 (C-1 Ph); 170.4 and 170.8 (OC=O); 171.0 (NC=O). Mass spectrum, m/z (Irel, %): 329 [M]+ (5),
281 (23), 207 (100), 181 (37), 133 (15), 91 (17), 73 (25), 43 (91). Found, %: С 65.79; Н 6.01; N 4.14. С18H19NO5.
Calculated, %: С 65.64; Н 5.81; N 4.25.
Fraction 2, 0.09 g (12%) isomer 2aB as colorless needles. IR spectrum, ν, cm–1: 1687 (N–C=O), 1740
1
(О–C=O). Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.92 (1Н, q, J = 12.0, Н-7); 2.05 (3Н, s, СОСН3);
2.09 (3Н, s, СОСН3); 2.30 (1Н, ddd, J = 3.3, J = 5.9, J = 12.0, Н-7); 3.32-3.37 (1Н, m, Н-7а); 4.26 (1Н, d,
J = 12.8, Н-3); 4.55 (1Н, dq, J = 2.3, J = 12.8, Н-3); 5.08 (1Н, dt, J = 3.3, J = 12.0, Н-6); 5.60-5.63 (1Н, m,
Н-5); 5.77-5.80 (1Н, m, Н-4); 7.16 (1Н, t, J = 7.6, Н-4 Ph); 7.37 (2Н, t, J = 7.6, Н-3,5 Ph); 7.62 (2Н, d, J = 7.6,
Н-2,6 Ph). 13С NMR spectrum (100 MHz), δ, ppm: 20.9 and 21.0 (CH3); 24.3 (C-7); 44.4 (C-7a); 52.0 (C-3);
65.3 (C-5); 69.4 (C-6); 118.3 (C-4); 119.8 (C-2,6 Ph); 125.0 (C-4 Ph); 129.1 (C-3,5 Ph); 137.5 (C-3a); 139.0
(С-1 Ph); 170.1 and 170.4 (OC=O); 171.0 (NC=O). Mass spectrum, m/z (Irel, %): 329 [M]+ (12), 209 (83), 181
(22), 156 (5), 104 (9), 91 (15), 77 (26), 43 (100). Found, %: С 65.37; Н 5.56; N 4.01. С18H19NO5. Calculated,
%: С 65.64; Н 5.81; N 4.25.
(5RS,6RS,7aSR)-6-Methyl-1-oxo-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Diacetate
(2bA). Removal of chloroform and recrystallization from ethyl acetate–hexane gave 0.32 g (43%) pure
isomer 2bA as colorless needles. Mp 217-218°С (EtOAc–hexane). IR spectrum, ν, cm–1: 1708 (N–C=O), 1750
(О–C=O). 1Н NMR spectrum (600 MHz), δ, ppm (J, Hz): 1.84 (3Н, s, СН3); 1.95 (3Н, s, СОСН3); 2.10 (3Н, s,
СОСН3); 2.36 (1Н, dd, J = 6.2, J = 17.2, Н-7); 2.45 (1Н, ddq, J = 1.4, J = 11.0, J = 17.2, Н-7); 3.11 (1Н, dd,
521

J = 6.2, J = 11.0, Н-7а); 4.11 (1Н, d, J = 11.7, Н-3); 4.52 (1Н, d, J = 11.7, Н-3); 5.59 (1Н, dq, J = 1.6, J = 5.5,
Н-5); 5.74 (1Н, d, J = 5.5, Н-4); 7.14 (1Н, t, J = 7.6, Н-4 Ph); 7.36 (2Н, dd, J = 7.6, J = 8.9, Н-3,5 Ph); 7.61
(2Н, d, J = 8.9, Н-2,6 Ph). 13С NMR spectrum (100 MHz), δ, ppm: 21.2; 21.8 and 23.6 (CH3); 26.4 (С-7); 44.7
(С-7a); 51.5 (C-3); 65.3 (C-5); 80.4 (C-6); 117.5 (C-4); 119.4 (C-2,6 Ph); 124.5 (C-4 Ph); 129.1 (C-3,5 Ph);
139.3 (C-3a); 141.8 (С-1 Ph); 169.4 and 170.4 (OC=O); 171.4 (NC=O). Mass spectrum, m/z (Irel, %): 343 [M]+
(4), 223 (32), 208 (53), 196 (29), 122 (16), 104 (49), 91 (25), 77 (28), 43 (100). Found, %: С 66.66; Н 6.37;
N 4.10. С19H21NO5. Calculated, %: С 66.46; Н 6.16; N 4.08.
(5RS,6RS,7SR,7aSR)-5,6-Bis(acetoxy)-1-oxo-2-phenyl-2,3,5,6,7,7a-hexahydro-1H-isoindole-
7-carboxylic Acid Methyl Ester (2c). Removal of chloroform and recrystallization from ethyl acetate–hexane
gave 0.31 g (37%) pure isomer 2c as colorless plates. Mp 189-190°С (EtOAc–hexane). IR spectrum, ν, cm–1:
1686 (N–C=O), 1741 (О–C=O). 1Н NMR spectrum (600 MHz), δ, ppm (J, Hz): 2.05 (3Н, s, СОСН3); 2.09 (3Н,
s, СОСН3); 3.57-3.60 (1Н, m, Н-7а); 3.68 (3Н, s, OСН3); 3.79 (1Н, t, J = 5.5, Н-7); 4.32 (1Н, d, J = 13.1, Н-3);
4.52 (1Н, dq, J = 2.8, J = 13.1, Н-3); 5.26 (1Н, dd, J = 5.5, J = 8.3, Н-6); 5.60 (1Н, dq, J = 2.8, J = 8.3, Н-5);
5.76-5.78 (1Н, m, Н-4); 7.13 (1Н, t, J = 7.3, Н-4 Ph); 7.34 (2Н, t, J = 7.3, Н-3,5 Ph); 7.58 (2Н, d, J = 7.3, Н-2,6
Ph). 13С NMR spectrum (100 MHz), δ, ppm: 21.0 and 21.1 (CH3); 43.4 (С-7а); 45.4 (С-7); 51.6 (С-3); 52.3
(OСН3); 70.8 (С-6); 71.9 (С-5); 118.8 (С-4); 120.0 (C-2,6 Ph); 125.1 (C-4 Ph); 129.1 (C-3,5 Ph); 133.8 (С-3а);
138.8 (С-1 Ph); 169.7; 169.9 and 170.4 (OC=O); 170.5 (NC=O). Mass spectrum, m/z (Irel, %): 387 [M]+ (52),
327 (26), 285 (37), 267 (73), 224 (38), 208 (100), 166 (19), 107 (66), 91 (27), 77 (36), 59 (21), 43 (40). Found, %:
С 62.48; Н 5.15; N 4.01. С20H21NO7. Calculated, %: С 62.01; Н 5.46; N 3.62.
(5RS,6SR,7SR,7aSR)-5,6-Bis(acetoxy)-6-bromo-1-oxo-2-phenyl-2,3,5,6,7,7a-hexa-hydro-1H-isoin-
dole-7-carboxylic Acid Methyl Ester (2d). Removal of chloroform gave 0.18 g of a mixture of products,
containing about 40% of the desired product. The composition of the mixture was not studied in detail. The
1H NMR spectrum for compound 2d (400 MHz), , ppm (J, Hz): 2.39 (3Н, s, СОСН3); 2.40 (3Н, s, СОСН3);
3.12 (1Н, d, J = 8.7, Н-7а); 3.29 (1Н, d, J = 8.7, Н-7); 3.83 (3Н, s, OСН3); 4.32 (1Н, d, J = 11.5, Н-3); 4.43 (1Н,
d, J = 11.5, Н-3); 6.49-6.54 (1Н, m, Н-5); 6.68 (1Н, d, J = 5.5, Н-4); 7.77 (2Н, d, J = 9.2, Н-2,6 Ph); 8.02–8.10
(3Н, m, H-3,4,5 Ph).
(5RS,6RS,7aSR)-2-Benzyl-7a-methyl-1-oxo-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Diacetate
(2eA) and (5RS,6SR,7aRS)-2-Benzyl-7a-methyl-1-oxo-2,3,5,6,7,7a-hexahydro-1H-isoindole-5,6-diyl Di-
acetate (2eB). Removal of chloroform gave 0.31 g (39%) of a ~75:25 mixture of 2eA and 2eB as indicated by
1H NMR spectroscopy. The major isomer 2eA was isolated as a pure compound by fractional crystallization
from ethyl acetate–hexane as colorless needles. Mp 110-110.5°С. IR spectrum, ν, cm–1: 1677 (N–C=O), 1736
1
(О–C=O). Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.37 (3Н, s, СН3); 1.77 (1Н, t, J = 12.4, Н-7); 2.04
(3Н, s, СОСН3); 2.05 (3Н, s, СОСН3); 2.23 (1Н, dd, J = 4.1, J = 12.4, Н-7); 3.56 (1Н, d, J = 12.4, Н-3); 3.86
(1Н, dt, J = 1.8, J = 12.4, Н-3); 4.35 (1Н, d, J = 15.1, NCH2); 4.59 (1Н, d, J = 15.1, NCH2); 5.35 (1Н, ddd,
J = 4.1, J = 7.3, J = 12.4, Н-6); 5.43–5.45 (1Н, m, Н-5); 5.50-5.51 (1Н, m, Н-4); 7.19-7.35 (5Н, m, H Ph). 13С
NMR spectrum (100 MHz), δ, ppm: 21.1 and 21.2 (CH3); 21.8 (CH3); 35.1 (C-7a); 44.6 (C-7); 46.4 (NCH2);
48.9 (C-3); 70.5 (C-6); 73.0 (C-5); 118.3 (C-4); 128.0; 128.2; 129.0 (C Ph); 136.0 (C-3a); 142.4 (С-1 Ph); 170.5
and 170.9 (OC=O); 176.0 (NC=O). Mass spectrum, m/z (Irel, %): 357 [M]+ (2), 297 (4), 237 (45), 222 (5), 146
(17), 121 (16), 105 (17), 91 (100), 77 (9), 65 (13), 43 (85). Found, %: С 67.55; Н 6.68; N 4.13. С20H23NO5.
Calculated, %: С 67.21; Н 6.49; N 3.92.
Isomer 2eB. 1Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.30 (3Н, s, СН3); 1.92-1.95 (1Н, m, Н-7);
2.02 (3Н, s, СОСН3); 2.06 (3Н, s, СОСН3); 2.02-2.06 (1Н, m, Н-7); 3.59 (1Н, d, J = 12.8, Н-3); 3.87 (1Н, d,
J = 12.4, Н-3); 4.20 (1Н, d, J = 14.7, NCH2); 4.74 (1Н, d, J = 14.7, NCH2); 5.20-5.25 (1Н, m, Н-6); 5.44-5.46
13
(1Н, m, Н-5); 5.52-5.53 (1Н, m, Н-4); 7.19-7.35 (5Н, m, H Ph). С NMR spectrum (100 MHz), δ, ppm: 20.9
and 21.1 (CH3); 21.5 (CH3); 30.0 (C-7a); 44.9 (C-7); 46.3 (NCH2); 49.2 (C-3); 65.2 (C-5); 67.3 (C-6); 117.4
(C-4); 127.8; 128.0; 128.8 (C Ph); 135.9 (C-3a); 142.8 (С-1 Ph); 170.1 and 170.3 (OC=O); 175.8 (NC=O).
Mass spectrum, m/z (Irel, %): 357 [M]+ (2), 297 (3), 272 (5), 237 (48), 164 (3), 146 (7), 121 (19), 105 (23), 91
(100), 77 (9), 65 (12), 43 (83).
522

Methyl Esters of (5RS,6RS,7RS,7aSR)-5,6-Bis(acetoxy)-2-benzyl-7a-methyl-1-oxo-2,3,5,6,7,7a-hexa-
hydro-1H-isoindole-7-carboxylic Acid (2fA) and (5RS,6SR,7SR,7aRS)-5,6-Bis(acetoxy)-2-benzyl-
7a-methyl-1-oxo-2,3,5,6,7,7a-hexahydro-1H-isoindole-7-carboxylic Acid (2fB). Removal of chloroform gave
1
0.67 g (74%) of a yellow oil consisting of a ~90:10 mixture of esters 2fA and 2fB as indicated by H NMR
spectroscopy. The major isomer 2fA was isolated chromatographically as a light-yellow oil. IR spectrum, ν, cm–1:
1687 (N–C=O), 1737 (О–C=O). 1Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.39 (3Н, s, СН3); 2.11 (6Н, s,
2СОСН3); 3.40 (1Н, d, J = 5.5, Н-7); 3.64 (3Н, s, OСН3); 3.65 (1Н, d, J =12.8, Н-3); 3.84 (1Н, dt, J = 2.3,
J = 12.8, Н-3); 4.38 (1Н, d, J = 14.7) and 4.48 (1Н, d, J = 14.7, NCH2); 5.39 (1Н, dd, J = 5.5, J = 7.8, Н-6);
13
5.48–5.50 (1Н, m, Н-5); 5.52-5.54 (1Н, m, Н-4), 7.15–7.31 (5Н, m, H Ph). С NMR spectrum (100 MHz), δ,
ppm: 21.0 and 21.1 (CH3); 23.1 (CH3); 46.3 (С-7); 47.3 (NCH2); 48.7 (С-7а); 49.0 (С-3); 52.2 (OСН3); 70.2 (С-
6); 71.2 (С-5); 118.2 (С-4); 127.8; 128.0; 128.9 (C Ph); 135.8 (С-3а); 139.2 (С-1 Ph); 170.4; 170.5 and 170.6
(OC=O); 174.7 (NC=O). Mass spectrum, m/z (Irel, %): 415 [M]+ (4), 355 (3), 313 (11), 296 (8), 254 (13), 236
(11), 163 (6), 121 (17), 91 (100), 65 (9), 43 (81). Found, %: С 63.79; Н 6.15; N 3.11. С22H25NO7. Calculated,
%: С 63.61; Н 6.07; N 3.37.
1
Isomer 2fB. Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 1.34 (3Н, s, СН3); 1.99 (3Н, s, СОСН3);
2.03 (3Н, s, СОСН3); 3.20 (1Н, d, J = 5.5, Н-7); 3.63 (3Н, s, OСН3); 3.54-3.62 (1Н, m, Н-3); 3.79-3.83 (1Н, m,
Н-3); 4.35 (1Н, d, J = 14.9) and 4.58 (1Н, d, J = 14.9, NCH2); 4.96 (1Н, q, J = 5.5, Н-6); 5.47-5.50 (1Н, m, Н-5);
13
5.52-5.54 (1Н, m, Н-4); 7.15-7.31 (5Н, m, H Ph). С NMR spectrum (100 MHz), δ, ppm: 20.8 and 20.9 (CH3);
22.5 (CH3); 46.4 (С-7); 47.6 (NCH2); 49.1 (С-7а); 51.8 (С-3); 52.5 (OСН3); 64.7 (С-5); 67.8 (С-6); 119.1 (С-4); 128.4;
128.8; 128.9 (C Ph); 135.8 (С-3а); 139.2 (С-1 Ph); 170.1; 170.2 and 170.4 (OC=O); 174.7 (NC=O). Mass spectrum,
m/z (Irel, %): 415 [M]+ (3), 355 (5), 296 (5), 280 (4), 254 (11), 236 (7), 163 (3), 121 (11), 91 (100), 77 (6), 43 (96).
Phenylisoindoline-1-ones 3a,b (General Method). BF3·Et2O (1.1 ml, 8.7 mmol) was added to a
solution of 3a,6-epoxyisoindolone 1a,b (3.5 mmol) in acetic anhydride (10 ml) and stirred for 24 h at room
temperature with monitoring by thin-layer chromatography. The reaction mixture was poured into water (50 ml),
neutralized by addition of aqueous sodium bicarbonate, and extracted with chloroform (3×20 ml). The extract
was dried over anhydrous magnesium sulfate. The residue after distilling off the chloroform was triturated in
ether. The powder formed was filtered off and recrystallized from hexane–ethyl acetate to give 2-phenyl-
isoindolones 3a,b as colorless crystals.
2-Phenylisoindolin-1-one (3a). Yield 0.50 g (68%). Colorless fibrous crystals; mp 143-144°С
1
(EtOAc–hexane). IR spectrum, ν, cm–1: 1689 (N–C=O). Н NMR spectrum (400 MHz), δ, ppm (J, Hz): 4.86
(2Н, s, H-3); 7.18 (1Н, t, J = 7.3, Н-4 Ph); 7.43 (2Н, dd, J = 7.3, J = 8.5, Н-3,5 Ph); 7.50 (1Н, t, J = 7.3, Н-6);
7.52 (1Н, d, J = 8.2, Н-4); 7.59 (1Н, ddd, J = 0.9, J = 7.3, J = 8.2, Н-5); 7.87 (2Н, dd, J = 0.9, J = 8.5, Н-2,6
Ph); 7.92 (1Н, d, J = 7.3, Н-7). 13С NMR spectrum (150 MHz), δ, ppm: 50.8 (С-3); 119.6 (С-2,6 Ph); 122.7 (С Ar);
124.3 (С-4 Ph); 124.6 (С Ar); 128.5 (С Ar); 129.3 (С-3,5 Ph); 132.2; 132.8; 139.6; 140.2 (С Ar); 167.6 (С-1 Ph).
Mass spectrum, m/z (Irel, %): 209 [M]+ (85), 180 (42), 152 (21), 132 (10), 104 (53), 89 (57), 77 (100), 63 (33),
51 (31), 39 (18). Found, %: С 80.49; Н 5.08; N 6.91. С14H11NO. Calculated, %: С 80.36; Н 5.30; N 6.69.
6-Methyl-2-phenylisoindolin-1-one (3b) was obtained as colorless fibrous crystals. Yield 0.32 g (41%);
mp 190-191°С (EtOAc–hexane). IR spectrum, ν, cm–1: 1680 (N–C=O). NMR spectrum 1Н (600 MHz), δ, ppm
(J, Hz): 2.45 (3Н, s, СН3); 4.78 (2Н, s, H-3); 7.16 (1Н, t, J = 7.6, Н-4 Ph); 7.38 (2Н, s, Н-4,5); 7.41 (2Н, t,
13
J = 7.6, Н-3,5 Ph); 7.71 (1Н, s, Н-7); 7.85 (2Н, d, J = 7.6, Н-2,6 Ph). С NMR spectrum (100 MHz), δ, ppm:
21.5 (СН3); 50.6 (С-3); 119.4 (С-2,6 Ph); 122.4 (С Ar); 124.3 (С-4 Ph); 124.4 (С Ar); 129.2 (С-3,5 Ph); 133.2;
133.4; 137.4; 138.5; 139.7 (С Ar); 167.8 (С-1 Ph). Mass spectrum, m/z (Irel, %): 223 [M]+ (100), 208 (29), 194
(43), 165 (6), 130 (7), 104 (16), 91 (15), 77 (40), 63 (8), 51 (9). Found, %: С 80.99; Н 5.55; N 6.69. С15H13NO.
Calculated, %: С 80.69; Н 5.87; N 6.27.
This work was carried out with the financial support of the Russian Foundation for Basic Research
(Grants 10-03-00177-a, 11-03-90416Ukr_f_a, 11-04-01537-a, and 10-04-90044-Bel_a) and the Program of the
Presidium of the Russian Academy of Sciences "Molecular and cell biology".
523

The authors express their gratitude to the laboratory staff of the Precision instrumental methods of
analysis department "PRIMA" of the Shared Research and Education Center of the Peoples' Friendship
University of Russia for carrying out the spectral studies.
REFERENCES
1.
2.
3.
4.
5.
6.
S. Woo and B. A. Keay, Synthesis, 669 (1996).
M. Lautens and E. Fillion, J. Org. Chem., 63, 647 (1998).
C. O. Kappe, S. S. Murphree, and A. Padwa, Tetrahedron, 53, 14179 (1997).
C. S. Schindler and E. M. Carreira, Chem. Soc. Rev., 38, 3222 (2009).
Y.-P. Xue and W.-D. Z. Li, J. Org. Chem., 76, 57 (2011).
A. D. Mance, B. Borovička, K. Jacopčić, G. Pavlović, and I. Leban, J. Heterocycl. Chem., 39, 277
(2002).
7.
8.
A. Ilyin, V. Kysil, M. Krasavin, I. Kurashvili, and A. V. Ivachtchenko, J. Org. Chem., 71, 9544 (2006).
A. V. Varlamov, E. V. Boltukhina, F. I. Zubkov, N. V. Sidorenko, A. I. Chernyshev, and
D. G. Grudinin, Khim. Geterotsikl. Soedin., 27 (2004). [Chem. Heterocycl. Compd., 40, 22 (2004)].
F. I. Zubkov, V. P. Zaytsev, E. V. Nikitina, V. N. Khrustalev, S. V. Gozun, E. V. Boltukhina, and A. V.
Varlamov, Tetrahedron, 67, 9148 (2011).
9.
10.
A. Padwa, K. R. Crawford, C. S. Straub, S. N. Pieniazek, and K. N. Houk, J. Org. Chem., 71, 5432
(2006).
11.
12.
13.
14.
15.
16.
L. Sader-Bakaouni, O. Charton, N. Kunesch, and F. Tillequin, Tetrahedron, 54, 1773 (1998).
A. Padwa and T. S. Reger, Can. J. Chem., 78, 749 (2000).
M. E. Jung and L. J. Street, Tetrahedron Lett., 26, 3639 (1985).
I. N. N. Namboothiri, M. Ganesh, S. M. Mobin, and M. Cojocaru, J. Org. Chem., 70, 2235 (2005).
J. E. Hernández, S. Fernández, and G. Arias, Synth. Commun., 18, 2055 (1988).
P. S. Sarang, A. A. Yadav, P. S. Patil, U. M. Krishna, G. K. Trivedi, and M. M. Salunkhe, Synthesis,
1091 (2007).
17.
18.
A. A. Mir, V. V. Mulwad, and G. K. Trivedi, J. Heterocycl. Chem., 47, 214 (2010).
F. I. Zubkov, E. V. Nikitina, and A. V. Varlamov, Usp. Khim., 74, 707 (2005) [Russ. Chem. Rev., 74,
639 (2005)].
19.
20.
G. M. Sheldrick, Acta Crystallogr., A64, 112 (2008).
V. P. Zaitsev, N. M. Mikhailova, I. K. Airiyan, E. V. Galkina, V. D. Golubev, E. V. Nikitina,
F. I. Zubkov, and A. V. Varlamov, Khim. Geterotsikl. Soedin., 538 (2012). [Chem. Heterocycl. Compd.,
48, 505 (2012)].
524