Continuous-flow catalytic hydrogenation of 3a,6-epoxyisoindoles

Article abstract of DOI:10.1007/s11172-015-0829-2

Selective catalytic (10% Pd/C) hydrogenation of the double bond in the oxabicyclo[2.2.1]heptene fragment of substituted fused 1-oxo-3a,6-epoxyisoindoles is described. A continuous-flow hydrogenation device that incorporates in situ hydrogen generation by

Full text of DOI:10.1007/s11172-015-0829-2

Russian Chemical Bulletin, International Edition, Vol. 64, No. 1, pp. 112—126, January, 2015
112
Continuousꢀflow catalytic hydrogenation of 3a,6ꢀepoxyisoindoles
V. P. Zaytsev,a,b F. I. Zubkov,a D. F. Mertsalov,a D. N. Orlova,a E. A. Sorokina,a E. V. Nikitina,a and A. V. Varlamova
aDeparment of Organic Chemistry, People´s Friendship University of Russia,
6 ul. MiklukhoꢀMaklaya, 117198 Moscow, Russian Federation.
Fax: +7 (495) 955 0779. Eꢀmail: vzaitsev@sci.pfu.edu.ru
bShared Research and Educational Center of PhysicoꢀChemical Studies
of New Materials, Substances, and Catalytic Systems",
3 ul. Ordzhonikidze, 115419 Moscow, Russian Federation.
Fax: +7 (495) 952 2644. Eꢀmail: ckp_fhi@sci.pfu.edu.ru
Selective catalytic (10% Pd/C) hydrogenation of the double bond in the oxabicycloꢀ
[2.2.1]heptene fragment of substituted fused 1ꢀoxoꢀ3a,6ꢀepoxyisoindoles is described. A conꢀ
tinuousꢀflow hydrogenation device that incorporates in situ hydrogen generation by electrolysis
of water was used. Changing the hydrogen source from water to deuterium oxide provides
possibility to synthesize deuterated oxoepoxyisoindolones. Hydrogenation is stereoselective to
give exclusively exoꢀcis deuterated derivatives.
Key words: continuousꢀflow reactor, heterogeneous catalytic hydrogenation, reduction,
3a,6ꢀepoxyisoindoles, deuteration.
Addition of the molecular hydrogen to multiple bonds
of the organic compounds occurring on metal surfaces is
widely used in the organic synthesis.1—7
Only four works devoted to the conventional hydrogeꢀ
nation of the double bond in epoxyisoindoles are availꢀ
able.23—26 Hydrogenation of these compounds under conꢀ
tinuousꢀflow conditions has not been studied.
Recently, a great attention was paid to continuousꢀ
flow hydrogenation technology. An HꢀCube ProTM conꢀ
tinuousꢀflow hydrogenation reactor combining in situ hyꢀ
drogen generation with a disposable cartridge system preꢀ
loaded with a metal catalyst gives the possibility to fast
and safe hydrogenation of various compounds.8—10 In the
present work, we describe the results of the selective hyꢀ
drogenation of the double bond in the 7ꢀoxabicyclo[2.2.1]ꢀ
heptene fragment fused with different azaheterocycles.
Continuousꢀflow hydrogenation was studied on the exꢀ
amples of readily available adducts of intramolecular [2+4]
cycloaddition between unsaturated acid derivatives and
compounds bearing the furfurylamine moiety, namely,
3a,6ꢀepoxyisoindolꢀ1ꢀones,11—15 6b,9ꢀepoxyisoindoloꢀ
[2,1ꢀa]quinolines,16,17 11,13aꢀ or 12,14aꢀepoxyisoindoꢀ
lo[3,2ꢀc]quinolines,16,18 10,12aꢀepoxyisoindolo[1,2ꢀa]ꢀ
isoquinolines,19 8,10aꢀepoxy[1,3]oxazino[2,3ꢀa]isoꢀ
indoles,20,21 and 2,4aꢀepoxyisoindolo[1,2ꢀb]quinazolꢀ
ines.21 The main structural motif of all mentioned heteroꢀ
cycles is the oxabicyclo[2.2.1]heptene fragment. This
moiety undergoes aromatization under both basic and
acidic conditions,11,13,14,17,18,22 its reaction with comꢀ
plex hydrides can lead to a retro Diels—Alder reacꢀ
tion giving the starting furfurylamines.23 Moreover,
the conventional hydrogenation techniques with hydroꢀ
gen gas are time consuming and require high pressure of
hydrogen.
Reactions of furfurylamines 1a—l with acid anhydrides
(acid halides) of ,ꢀunsaturated carboxylic acids11,12,14,15
and allylfurfurylamine 1g (R1 = All, R2 = H) with arylsulꢀ
fonyl chlorides27,28 carried out following the known proꢀ
cedures produced 3a,6ꢀepoxyisoindoles 2—5 (Scheme 1).
To increase the solubility, the corresponding carboxylic
acids were transformed into methyl esters 3g—j.
The conditions of continuousꢀflow hydrogenation (solꢀ
vent, reaction temperature, catalyst) of the C=C bond
using the HꢀCube ProTM reactor were optimized. It was
found that the double bond in the oxabicycloheptene fragꢀ
ment of epoxyisoindoles 2—5 is completely hydrogenated
under continuousꢀflow conditions (TLC and GC/MS
monitoring); while, other functional groups remain intact
(Scheme 2). The optimum conditions for the synthesis are
as follows: H2 (full mode); disposable cartridge packed
with 10% Pd/C; 0.025 M solution of isoindole in either
EtOH (for 2a—g, 3g—j) or CH2Cl2 (for 3a—f, 4a—d, 5a,b,
8—13); room temperature; atmosphere pressure; flow rate
of 1 mL min–1. All perhydroepoxyisoindoles 6a—w were
obtained in nearly quantitative yields as wellꢀshaped crysꢀ
tals and viscous or glassy oils (Table 1).
It is known that deuterated compounds are widely used
for the study of the reaction mechanisms, for structural
characterization of compounds by NMR spectroscopy,
and as standards for both mass spectrometry and monitorꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0112—0125, January, 2015.
1066ꢀ5285/15/6401ꢀ0112 © 2015 Springer Science+Business Media, Inc.

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
113
Scheme 1
R1 = Ph (1a—c, 2a—d, 3g,h, 4a,b), Bn (1d, 2e,f, 3f,i,j, 4c), ꢀfurfuryl (1e, 4d), 3,4ꢀ(MeO)2C6H3(CH2)2 (1f, 2g), All (1g), Me (1h, 3a),
Et (1i, 3b), cyclopropyl (1j, 3c), (CH2)2OMe (1k, 3d), 2ꢀMeC6H4 (1l, 3e)
R2 = H (1a,d—l, 2a,d—g, 3a—g,i,j, 4a,c,d), Me (1b, 2b, 3h, 4b), Et (1c, 2c); R3 = H (2a—c,e,g, 3a—i), Me (2d,f, 3j)
R
4 = H (3a—f), Me (3g—j); R5 = Ph (5a), 4ꢀMeC6H4 (5b)
Scheme 2
ing of pharmacokinetics of the biologically active subꢀ
stances. However, labeling compounds using deuterium
gas is fraught with difficulties such as high cost of D2 and
possible exchange reaction to give H—D, etc. At the same
time, in the HꢀCube ProTM continuousꢀflow hydrogenaꢀ
tion reactor hydrogen is generated in situ by electrolysis of
deionized water, consequently, the replacement of H2O
by D2O provides possibility to generate D2.29,30
Deuteration of oxoepoxyisoindolones 2—4 using heavy
water at room temperature results in target 4,5ꢀdideuteroꢀ
isoindolones 7a—c in high yields (see Scheme 2). The exo
orientation of the deuterium atoms in the 7ꢀoxabicycloꢀ
heptane fragment and, consequently, their cis arrangeꢀ
ment are unambiguously followed from the spinꢀspin couꢀ
pling constant values for the H(4), H(5), and H(6) proꢀ
Table 1. Yields, physicochemical characteristics, and IR spectral data for 3a,6ꢀepoxyisoindoles 2c—e,g, 3e,i, 4a,b,d, 6a—w, and 7a—c
Comꢀ
pound
R1
X
R2 R3
R4
R5 Yield
(%)
M.p./C
(solvent)
Found
Calculated
Molecular
formula
IR,
/cm–1
(%)
С
Н*
N
2c
2d
2e
Ph
Ph
Bn
O
O
Et
H
H
H
H
H
H
35
25
81
100—102
(hexane— 75.27 6.71 5.49
AcOEt)
117—119
(hexane— 74.67 6.27 5.81
AcOEt)
75.40 6.92 5.63 C16H17NO2 1688 (NCO)
Me
74.42 6.07 5.99 C15H15NO2 1686 (NCO)
O
O
H
H
H
H
H
H
H
H
—
74.78 6.39 5.60 C15H15NO2 1687 (NCO)
74.67 6.27 5.81
2g 3,4ꢀ(MeO)2ꢀ
31 114.5—115.5 68.71 6.52 4.30 C18H21NO4 1675 (NCO)
C6H3(CH2)2
(hexane— 68.55 6.71 4.44
AcOEt)
(to be continued)

114
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
Table 1 (continued)
Comꢀ
pound
R1
X
R2 R3
R4
R5
Yield
(%)
M.p./C
(solvent)
Found
Calculated
Molecular
formula
IR,
/cm–1
(%)
С
Н*
N
3e
2ꢀMeC6H4
O
H
H
CO2H
H
H
85
79
178—179
(EtOH—
DMF)
—
67.51 5.12 5.03
67.36 5.30 4.91
C16H15NO4 1738 (СО2H),
1673 (NCO)
3i
Bn
Ph
O
O
H
H
H
H
CO2Me
H
68.38 6.01 4.51
68.21 5.72 4.68
C17H17NO4 1736 (СО2Ме),
1688 (NCO)
C17H17NO4 1731 (СО2Et),
1683 (NCO)
4a
CO2Et 57
CO2Et 46
CO2Et 70
108—109.5 68.02 5.59 4.55
(hexane—
AcOEt)
82—84
68.21 5.72 4.68
4b
4d
6a
6b
Ph
ꢀFurfuryl
Ph
O
O
O
O
Me
H
H
H
H
H
H
H
H
H
68.70 5.89 4.58
68.99 6.11 4.47
C18H19NO4 1720 (СО2Et),
1695 (NCO)
(hexane—
AcOEt)
105—107
(hexane—
AcOEt)
119—120
(hexane—
AcOEt)
127—128
(hexane—
AcOEt)
96—97
63.10 5.49 4.71
63.36 5.65 4.62
C16H17NO5 1736 (СО2Et),
1674 (NCO)
H
H
H
87
86
73.84 6.72 5.71
73.34 6.59 6.11
C14H15NO2 1682 (NCO)
C15H17NO2 1682 (NCO)
Ph
Me
73.90 7.49 5.33
74.05 7.04 5.76
6c
6d
6e
6f
Ph
Ph
Bn
Bn
O
O
O
O
O
O
Et
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
88
93
87
94
64
99
75.00 7.75 5.36
74.68 7.44 5.44
74.16 7.21 5.92
74.05 7.04 5.76
74.23 6.89 5.70
74.05 7.04 5.76
74.41 7.25 5.38
74.68 7.44 5.44
67.76 7.37 4.11
68.12 7.30 4.41
66.57 5.62 5.15
66.89 5.96 4.88
C16H19NO2 1694 (NCO)
C15H17NO2 1701 (NCO)
C15H17NO2 1687 (NCO)
C16H19NO2 1688 (NCO)
C18H23NO4 1686 (NCO)
(hexane)
—
H
H
—
—
—
Me
H
H
6g 3,4ꢀ(MeO)2ꢀ
H
C6H3(CH2)2
6h
6i
Ph
H
CO2Me
167—168
(hexane—
AcOEt)
156—158
(hexane—
AcOEt)
—
C16H17NO4 1731 (СО2Me),
1702 (NCO)
Ph
O
Me
H
H
CO2Me
CO2Me
H
91
67.48 6.27 4.34
67.76 6.36 4.65
C17H19NO4 1728 (СО2Me),
1696 (NCO)
6j
Bn
Bn
O
O
H
H
H
H
81
96
68.00 6.53 4.66
67.76 6.36 4.65
68.05 6.29 4.33
68.55 6.71 4.44
C17H19NO4 1736 (СО2Me),
1688 (NCO)
C18H21NO4 1748 (СО2Me),
1691 (NCO)
6k
Me CO2Me
114—115
(hexane—
AcOEt)
6l
Ph
Ph
O
O
O
O
H
Me
H
H
H
H
H
H
H
H
H
CO2Et 71
CO2Et 46
CO2Et 57
CO2Et 72
120—121
(hexane—
AcOEt)
127—128
(hexane—
AcOEt)
67.82 6.48 4.60
67.76 6.36 4.65
C17H19NO4 1734 (СО2Et),
1703 (NCO)
6m
6n
6o
68.72 6.58 4.51
68.55 6.71 4.44
C18H21NO4 1729 (СО2Et),
1696 (NCO)
Bn
160.5—161.5 68.32 6.89 4.52
C18H21NO4 1735 (СО2Et),
1674 (NCO)
(hexane—
AcOEt)
94—95
(hexane—
AcOEt)
68.55 6.71 4.44
ꢀFurfuryl
H
63.11 6.09 4.71
62.94 6.27 4.59
C16H19NO5 1737 (СО2Et),
1678 (NCO)
(to be continued)

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
115
Table 1 (continued)
Comꢀ
pound
R1
X
R2 R3
R4
R5
Yield
(%)
M.p./C
(solvent)
Found
Calculated
Molecular
formula
IR,
/cm–1
(%)
С
Н*
N
6p
6q
Me
Et
O
O
H
H
H
H
CO2H
CO2H
H
H
64
68
183
56.55 6.35 6.78
56.86 6.20 6.63
58.42 6.55 6.35
58.66 6.71 6.22
C10H13NO4 1724 (СО2H),
1644 (NCO)
C11H15NO4 1712 (СО2H),
1634 (NCO)
(EtOH)
150—151
(AcOEt—
EtOH)
6r Cyclopropyl
6s (CH2)2OMe
O
H
H
CO2H
H
63
181—182
(AcOEt—
EtOH)
167—168
(AcOEt)
209
60.60 6.56 6.12
60.75 6.37 5.90
C12H15NO4 1737 (СО2H),
1667 (NCO)
O
O
H
H
H
H
H
H
H
H
CO2H
CO2H
CO2H
H
H
H
H
H
55
66
87
70
56.52 6.78 6.62
56.46 6.71 5.49
66.69 6.12 5.01
66.89 5.96 4.88
66.98 6.08 4.72 C16H17NO4
66.89 5.96 4.88
C12H17NO5 1694 (NCO,
СО2H)
C16H17NO4 1744 (СО2H),
1677 (NCO)
6t
2ꢀMeC6H4
Bn
(EtOH)
205—206
(EtOH)
131—132
(hexane—
AcOEt)
123—124
(hexane—
AcOEt)
121—123
(hexane—
AcOEt)
168—169
(hexane—
AcOEt)
6u
O
1715 (СО2H),
1695 (NCO)
6v**
PhSO2
H, H
60.01 6.32 5.26 C14H17NO3S 1169 ( (SO2)),
60.19 6.13 5.01
s
1339 ( (SO2))
as
6w**
7a
Ts
Ph
Ph
Ph
H, H
O
H
H
H
H
H
H
H
H
H
H
H
H
H
94
92
95
61.66 6.41 4.56 C15H19NO3S 1159 ( (SO2)),
61.41 6.53 4.77
s
1343 ( (SO2))
as
72.87 7.54 6.28 C14H13D2NO2 1682 (NCO)
72.70 7.41 6.06
7b
O
CO2Me
H
66.65 6.35 4.99 C16H15D2NO4 1731 (СО2Me),
66.42 6.62 4.84
1703 (NCO)
7c
O
CO2Et 77
120.5—121.5 67.51 6.69 4.34 C17H17D2NO4 1734 (СО2Et),
(hexane—
AcOEt)
67.31 6.98 4.62
1702 (NCO)
* Calculated for D (7a—c).
** Found (%): S, 11.36 (6v) and 11.07 (6w). Calculated (%): S, 11.48 (6v) and 10.93 (6w).
tons (J4,5 = 8.9 Hz). Lack of the noticeable vicinal spinꢀ
spin coupling constants 3J for the bridgehead H(6) proton
room temperature and atmosphere pressure (see Scheme 3,
Table 5). The catalytic hydrogenation is affected neither
by the nature nor by the size of the fused heterocycle (see
Scheme 2), the 1H NMR spectroscopy and mass spectroꢀ
metry data indicate that only the C=C double bond are
hydrogenated with other functional groups remaining inꢀ
tact (see Table 4). Only in the case of compound 12a,
hydrogenation is accompanied by simultaneous reduction
of acrylamide fragment to propionamide group. Removal
of the solvent afforded target heteroarylꢀfused perhydroꢀ
epoxyisoindoles 14—19 in good yields as colorless wellꢀ
shaped crystals. The products do not require further puriꢀ
fication (purity of the products was monitored by TLC,
GC/MS, and elemental analysis).
in the oxabicyclic moiety of isoindoles 7a—c (J5,6
=
= J6,7ꢀendo = 0 Hz) is indicative of exo orientation of all
substituents (Table 2). The C(4) and C(5) atoms in
13C NMR spectra resonate in the strong fields as triplets
with the spinꢀspin coupling constants of ~20—21 Hz
(Table 3). The presence of the functional groups and moꢀ
lecular weight of compounds 7a—c are also in complete
agreement with IR spectroscopy and mass spectrometry
data (see Tables 1 and 4).
The flow hydrogenation first applied and optimized for
the model epoxyisoindoles 2—5 was then employed for
hydrogenation of more complicated epoxyisoindoles comꢀ
pounds 8—13, i.e., epoxyisoindoles fused with different
heterocycles bearing the alkaloidꢀlike moieties and bioꢀ
logically active fragments (Scheme 3).
In summary, we suggested an efficient procedure for
selective hydrogenation and deuteration of the oxabiꢀ
cycloheptene double bond in the substituted fused 1ꢀoxoꢀ
3a,6ꢀepoxyisoindoles using a continuousꢀflow hydrogeꢀ
nation reactor incorporating in situ hydrogen generation.
The double bond of the oxabicycloheptene fragment in
compounds 8—13 underwent selective hydrogenation at

116
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
Table 2. 1H NMR spectral data for 3a,6ꢀepoxyisoindoles 2g, 6a,b,f—h,k,m—o (CDCl3, 400 MHz), 2c—e, 3i, 4a,b,d, 6c—e,i,j,l,s,v,w, 7a—c
(CDCl3, 600 MHz), and 3e, 6p—r,t,u (DMSOꢀd6, 400 MHz)
Comꢀ
poꢀ
und
 (J/Hz)
Н(7)
Н(3A) Н(3B)
d
Н(4)
Н(5)
Н(6)
—
Н(7a)
NꢀR
Other protons
2c
4.39 4.13
6.34, 6.47
(both d, 1 Н each,
2.04 (dd, J = 3.4,
J = 12.0); 1.72
(dd, J = 8.9,
J = 12.0)
2.72 (dd, 7.13 (t, 1 Н, J = 7.6);
J = 3.4,
J = 8.9)
1.06 (t, СH2СН3,
J = 7.6); 1.98 (dq,
СH2СН3, J = 2.0,
J = 7.6)
(J =
(J =
7.36 (t, 2 Н, J = 7.6);
7.63 (d, 2 Н, J = 7.6)
11.4) 11.4)
J = 5.8)
2d
2e
4.33 4.07
6.42 (d, 6.49 (dd, 4.98 (dd, 2.55 (dd, J = 4.8,
—
7.11 (t, 1 Н, J = 7.6);
7.34 (t, 2 Н, J = 7.6);
7.62 (d, 2 Н, J = 7.6)
1.10 (s, Me)
(J =
(J =
J = 6.2) J = 2.1,
J = 6.2)
J = 2.1,
J = 4.8)
J = 11.7); 1.18
(d, J = 11.7)
11.4) 11.4)
3.81 3.54
6.33 (d,
J = 6.0)
6.49
(dd,
J = 1.4,
J = 6.0)
5.05 (dd, 2.21 (ddd, J = 3.5,
2.46
(dd,
J = 3.5,
J = 8.8)
4.44, 4.64 (both d,
1 Н each, CH2Ph,
J = 15.1); 7.21—7.32
(m, Ph)
—
(J =
(J =
J = 1.4,
J = 4.4)
J = 4.4, J = 12.1);
1.58 (dd, J = 8.8,
J = 12.1)
11.5) 11.5)
2g
3.83 3.57
6.35 (d,
J = 5.6)
6.37
(dd,
J = 1.3,
J = 5.6)
5.05 (dd, 2.17 (ddd, J = 3.7,
2.37
(dd,
J = 3.7,
J = 9.0)
2.77—2.87 (m, 2 H,
NСH2СН2); 3.42—3.49,
3.64—3.71 (both m,
1 Н each, NСH2СН2);
3.86, 3.87 (both s,
—
(J =
(J =
J = 1.3,
J = 4.7)
J = 4.7, J = 11.8);
1.56 (dd, J = 9.0,
J = 11.8)
11.5) 11.5)
OMe); 6.76—6.82
(m, 3 Н, С6Н3)
3e
3i
4.49 3.77
6.47, 6.63
(both d, 1 Н each,
5.06 (s)
2.98 (d, J = 9.4)
2.81 (d, J = 8.9)
2.55
(d,
J = 9.4)
2.14 (s, Me);
7.22—7.25
(m, 4 H, Ar)
12.2 (s, CO2H)
(J =
(J =
11.4) 11.4)
J = 5.4)
3.80 3.63
6.42 (d,
J = 6.2)
6.45
(dd,
5.17 (d,
J = 2.1)
2.75
(d,
4.35, 4.64 (both d, 1 Н 3.79 (s, OMe)
each, CH2Ph, J = 15.1);
(J =
(J =
11.7) 11.7)
J = 2.1,
J = 6.2)
J = 8.9)
7.24—7.34 (m, Ph)
4a
4b
4.42 4.09
6.57
(d,
6.33
(dd,
5.25 (dd, 3.54 (dd, J = 3.4,
3.08 (d,
J = 3.4)
7.12 (t, 1 Н, J = 7.6);
7.33 (dd, 2 Н,
J = 7.6, J = 8.9);
7.62 (dd, 2 Н,
1.22 (t,
(J =
(J =
J = 1.8,
J = 4.8)
J = 4.8)
OСH2СН3,
J = 7.6); 4.11
(dq, OСH2СН3,
J = 1.4, J = 7.6)
11.7) 11.7) J = 5.5) J = 1.8,
J = 5.5)
J = 1.4, J = 8.9)
4.36 4.05
(J = (J =
11.7) 11.7)
6.16, 6.55
(both d, 1 Н each,
J = 5.5)
—
3.18 (d, J = 3.4)
3.16 (d,
J = 3.4)
7.10 (t, 1 Н, J = 7.6);
7.32 (t, 2 Н, J = 7.6);
7.57 (d, 2 Н, J = 7.6)
1.22 (t,
OСH2СН3,
J = 7.6); 1.62
(s, Me);
4.06—4.13
(m, OСH2СН3)
4d
3.94 3.64
6.51
(d,
6.30
(dd,
5.23
(dd,
J = 1.4,
J = 4.8)
3.45 (dd, J = 3.8,
J = 4.8)
2.91 (d,
J = 3.8)
4.34, 4.68 (both d,
1 Н each, CH2(Fur),
J = 15.1); 6.24 (br.d,
1 Н, J = 3.0); 6.30
(dd, 1 Н, J = 2.1,
J = 3.0); 7.36 (br.d,
1 Н, J = 2.1)
1.24 (t,
(J =
(J =
OСH2СН3,
J = 7.6); 4.12
(dq, OСH2СН3,
J = 2.1,
11.7) 11.7) J = 5.5) J = 1.4,
J = 5.5)
J = 7.6)
6a
6b
4.11 4.10 1.58—1.65 (m, 1 Н); 4.64
(J = (J = 1.75—1.88 (m, 2 Н); (t,
11.2) 11.2) 1.90—2.01 (m, 1 Н) J = 5.7)
1.90—2.01 (m, 1 Н); 2.79
2.18—2.22 (m, 1 Н) (dd,
J = 4.7,
7.11 (t, 1 Н, J = 7.5);
7.34 (dd, 2 Н, J = 7.5,
J = 8.7); 7.62 (dd, 2 Н,
J = 1.3, J = 8.7)
—
J = 9.3)
4.08 4.03 1.67—2.08 (m, 4 Н)
(J = (J =
11.5) 11.5)
—
1.67—2.08 (m, 2 Н) 2.87
7.12 (t, 1 Н, J = 7.6);
7.34 (t, 2 Н, J = 7.6);
7.62 (d, 2 Н, J = 7.6)
1.51 (s, Me)
(dd,
J = 4.6,
J = 9.6)
(to be continued)

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
117
Table 2 (continued)
Comꢀ
poꢀ
und
 (J/Hz)
Н(3A) Н(3B)
d
Н(4)
Н(5)
Н(6)
—
Н(7)
Н(7a)
NꢀR
Other protons
6c
4.06
(J =
4.03 1.69—1.78 (m, 2 Н);
(J = 1.91—1.98 (m, 2 Н)
2.03 (dd, J = 9.6,
J = 11.7);
1.83—1.89 (m)
2.86
(dd,
J = 4.8,
J = 9.6)
7.12 (t, 1 Н, J = 7.6);
7.34 (dd, 2 Н, J = 7.6,
J = 8.9); 7.63 (dd,
0.99 (t, СH2СН3,
J = 7.6);
1.83—1.89
11.7) 11.7)
2 Н, J = 1.4, J = 8.9)
(m, СH2СН3)
6d
6e
4.00 (s, 2 Н)
1.58—1.62 (m, 1 Н); 4.53
1.71—1.76 (m, 1 Н); (t,
1.93—1.98 (m, 2 Н) J = 4.8)
2.46 (ddd, J = 2.1,
J = 4.8, J = 12.4);
1.47 (d, J = 12.4)
—
7.12 (t, 1 Н, J = 7.5);
7.35 (dd, 2 Н, J = 7.5,
J = 8.2); 7.64 (d, 2 Н,
1.28 (s, Me)
J = 8.2)
3.50
(J =
3.46 1.52—1.58 (m, 1 Н); 4.59
(J = 1.63—1.70 (m, 1 Н); (t,
1.88 (dd, J = 9.6,
J = 12.4);
1.63—1.70
(m, 1 Н)
2.63
(dd,
J = 4.6,
J = 9.6)
4.41, 4.52 (both d, 1 Н
each, CH2Ph, J = 14.9);
7.20—7.32 (m, Ph)
—
11.5) 11.5) 1.85—1.92 (m, 1 Н); J = 5.5)
2.06—2.12 (m, 1 Н)
6f
3.42
(J =
11.5) 11.5)
3.38 1.54—1.63 (m, 2 Н); 4.53
2.38 (ddd, J = 2.3,
J = 5.0, J = 12.1);
1.42 (d, J = 12.1)
—
4.39, 4.60 (both d, 1 Н
each, CH2Ph, J = 14.9);
7.21—7.35 (m, Ph)
1.23 (s, Me)
—
(J =
1.83—1.93 (m, 2 Н)
(t,
J = 5.0)
6g
3.51 (s, 2 Н)
1.52—1.58 (m, 1 Н); 4.57
1.63—1.74 (m, 1 Н); (t,
1.82—1.91 (m, 1 Н); J = 5.0)
1.85 (dd, J = 9.2,
J = 12.4);
1.63—1.74
(m, 1 Н)
2.54
(dd,
J = 4.6,
J = 9.2)
2.73—2.85 (m, 2 H,
NСH2СН2); 3.39—3.48,
3.59—3.66 (both m,
1 Н each, NСH2СН2);
3.84, 3.86 (both s,
2.01—2.06 (m, 1 Н)
OMe); 6.73—6.80
(m, 3 Н, С6Н3)
6h
6i
4.15
(J =
4.12 1.62—1.68 (m,1 Н); 4.80
(J = 1.80—1.94 (m, 2 Н); (d,
3.16 (d, J = 9.6)
3.14 (d, J = 9.6)
3.03 (d, J = 9.6)
2.57 (s)
3.10
(d,
J = 9.6)
7.13 (t, 1 Н, J = 7.6);
7.34 (t, 2 Н, J = 7.6);
7.56 (d, 2 Н, J = 7.6)
3.75 (s, OMe)
11.5) 11.5) 2.00—2.06 (m, 1 Н) J = 5.5)
4.13
(J =
11.5) 11.5)
4.09 1.77—1.90 (m, 3 Н);
(J = 1.98—2.03 (m, 1 Н)
—
3.12
(d,
J = 9.6)
7.12 (t, 1 Н, J = 7.6);
7.33 (t, 2 Н, J = 7.6);
7.56 (d, 2 Н, J = 7.6)
1.52 (s, Me);
3.75 (s, OMe)
6j
3.56
(J =
3.48 1.56—1.60 (m, 1 Н); 4.74
(J = 1.68—1.76 (m, 2 Н); (d,
2.97
(d,
J = 9.6)
4.40, 4.54 (both d, 1 Н
each, CH2Ph, J = 14.7);
7.23—7.33 (m, Ph)
3.73 (s, OMe)
1.37 (s, Me);
11.7) 11.7) 1.93—1.99 (m, 1 Н) J = 5.5)
6k
6l
3.50
(J =
11.5) 11.5)
3.34 1.55—1.68 (m, 2 H); 4.70
—
4.30, 4.67 (both d, 1 Н
each, CH2Ph, J = 14.7); 3.77 (s, OMe)
7.23—7.36 (m, Ph)
(J =
1.85—2.02 (m, 2 Н)
(d,
J = 5.8)
4.10
(J =
11.7) 11.7)
4.01 1.66—1.70 (m, 1 Н); 5.21
3.13 (ddd, J = 1.5,
J = 4.2, J = 5.5)
3.26
(d,
J = 4.2)
7.11 (t, 1 Н, J = 7.6);
7.32 (dd, 2 Н,
J = 7.6, J = 8.9);
7.62 (dd, 2 Н,
1.26 (t,
OСH2СН3,
J = 7.6);
4.12—4.29
(m, OСH2СН3)
(J =
1.83—1.89 (m, 3 Н)
(dd,
J = 4.8,
J = 5.5)
J = 1.4, J = 8.9)
6m
6n
4.08
(J =
11.5) 11.5)
4.01 1.56—1.65 (m, 1 Н);
(J = 1.85—2.02 (m, 3 Н)
—
3.13 (dd, J = 1.8,
J = 4.1)
3.40
(d,
J = 4.1)
7.13 (t, 1 Н, J = 7.8);
7.35 (t, 2 Н, J = 7.8);
7.62 (d, 2 Н, J = 7.8)
1.29 (t,
OСH2СН3,
J = 7.3); 1.62
(s, Me);
4.16—4.26
(m, OСH2СН3)
3.51
(J =
3.45 1.62—1.86 (m, 4 Н) 4.77 (t,
(J = J = 5.2)
3.37 (ddd, J = 1.4,
J = 4.5, J = 5.2)
3.14
(d,
4.42, 4.56 (both d, 1 Н
each, CH2Ph, J = 15.1); OСH2СН3,
1.28 (t,
11.9) 11.9)
J = 4.5)
7.21—7.35 (m, Ph)
J = 7.3);
4.14—4.22
(m, OСH2СН3)
(to be continued)

118
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
Table 2 (continued)
Comꢀ
 (J/Hz)
Н(7)
poꢀ
Н(3A) Н(3B)
und
Н(4)
Н(5)
Н(6)
Н(7a)
NꢀR
Other protons
d
6o
3.60 3.54 1.60—1.88 (m, 4 Н) 4.73
3.31 (dt, J = 1.8,
J = 4.8)
3.09
(d,
J = 4.8)
4.31, 4.62 (both d,
1 Н each, CH2(Fur),
J = 15.6); 6.24 (dd,
1.25 (t,
OСH2СН3,
J = 7.3); 4.14
(J =
(J =
(t,
11.5) 11.5)
J = 4.8)
1 Н, J = 0.9, J = 3.2); (dq, OСH2СН3,
6.30 (dd, 1 Н, J = 1.8, J = 1.8, J = 7.3)
J = 3.2); 7.34 (dd, 1 Н,
J = 0.9, J = 1.8)
6p
6q
6r
6s
3.62 3.49 1.53—1.79 (m, 4 Н) 4.53
2.98 (d, J = 9.6)
2.99 (d, J = 9.6)
2.99 (d, J = 9.6)
2.83
(d,
J = 9.6)
2.71 (s, Me)
11.9 (s, CO2H)
11.9 (s, CO2H)
11.9 (s, CO2H)
(J =
(J =
(d,
11.5) 11.5)
J = 5.0)
3.64 3.49 1.53—1.78 (m, 4 Н) 4.53
2.82
(d,
J = 9.6)
1.01 (t, 3 Н, J = 7.3);
3.04—3.13, 3.25—3.33
(both m, 2 Н)
(J =
(J =
(d,
11.5) 11.5)
J = 5.0)
3.39 3.54 1.51—1.77 (m, 4 Н) 4.51
2.81
(d,
J = 9.6)
0.57—0.69 (m, 4 Н);
2.62—2.68 (m, 2 Н)
(J =
(J =
(d,
11.2) 11.2)
J = 5.0)
3.83 3.85 1.59—1.63 (m, 1 Н); 4.87
(J = (J = 1.74—1.81 (m, 2 Н); (d,
11.7) 11.7) 1.96—2.01 (m, 1 Н) J = 5.5)
3.12 (s, 2 Н)
3.35 (s, OMe); 3.32—3.36,
3.70—3.73 (both m,
1 Н each, OСH2СН2N);
3.51—3.57 (m, 2 Н,
OСH2СН2N)
—
6t
6u
6v
3.70 4.14 1.60—1.87 (m, 4 Н) 4.62
3.22 (d, J = 9.6)
3.12 (d, J = 9.6)
2.92
(d,
J = 9.6)
1.37 (s, Me);
7.18—7.27
(m, 4 H С6Н4)
12.0 (s, CO2H)
(J =
(J =
(d,
11.5) 11.5)
J = 5.0)
3.42 3.53 1.53—1.78 (m, 4 Н) 4.57
2.89
(d,
J = 9.6)
4.42, 4.56 (both d, 1 Н 12.0 (s, CO2H)
each, CH2Ph, J = 15.1);
7.25—7.35 (m, Ph)
(J =
(J =
(d,
11.5) 11.5)
J = 5.5)
3.63 3.55 1.45—1.79 (m, 4 Н) 4.49
1.45—1.79
(m, 2 Н)
2.24—2.29 7.52 (t, 2 Н, J = 7.6);
2.65 (t, 1 Н,
Н(1А), J = 9.6);
3.72 (t, 1 Н,
(J =
(J =
(t,
(m)
7.58 (t, 1 Н, J = 7.6);
7.81 (d, 2 Н, J = 7.6)
11.7) 11.7)
J = 5.2)
Н(1В), J = 9.6)
6w
7a
3.61 3.52 1.39—1.80 (m, 4 Н) 4.49
1.39—1.80
(m, 2 Н)
2.23—2.28 7.29 (d, 2 Н, J = 8.2); 2.41 (s, Me);
(J =
(J =
(dd,
(m)
7.69 (d, 2 Н, J = 8.2)
2.63 (t, 1 Н,
Н(1А), J = 9.6);
3.69 (dd, 1 Н,
Н(1В), J = 8.2,
J = 9.6)
12.0) 12.0)
J = 4.8,
J = 5.5)
4.12 4.05
1.60, 1.76
(both d, 1 Н each,
J = 8.9)
4.64
(d,
J = 4.8)
2.19 (dt, J = 4.8,
J = 12.4); 1.95 (dd,
J = 9.6, J = 12.4)
2.79
(dd,
J = 4.8,
J = 9.6)
7.12 (t, 1 Н, J = 7.6);
7.35 (t, 2 Н, J = 7.6);
7.61 (dd, 2 Н,
—
(J =
(J =
11.0) 11.0)
J = 1.4, J = 7.6)
7b
7c
4.14 4.11
1.61, 1.80
(both d, 1 Н each,
J = 8.9)
4.78 (s)
3.15 (d, J = 9.6)
3.09
(d,
J = 9.6)
7.12 (t, 1 Н, J = 7.6);
7.33 (t, 2 Н, J = 7.6);
7.56 (d, 2 Н, J = 7.6)
3.75 (s, OMe)
(J =
(J =
11.0) 11.0)
4.14 4.04
1.68, 1.86
(both d, 1 Н each,
J = 8.9)
4.73
(d,
J = 5.4)
3.45 (dd, J = 4.1,
J = 5.4)
3.29
(d,
J = 4.1)
7.14 (t, 1 Н, J = 7.6);
7.36 (t, 2 Н, J = 7.6);
7.61 (dd, 2 Н, J = 1.4, J = 7.3);
1.29 (t,
OСH2СН3,
(J =
(J =
11.7) 11.7)
J = 7.6)
4.17—4.23
(m, OСH2СН3)

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
119
Table 3. 13C NMR spectral data for 3a,6ꢀepoxyisoindoles 2c,e,g, 3i, 4b,d, 6c,m—o,v,w (CDCl3, 100 MHz), 2d, 4a, 6a,b,d—l,p—u, 7a—c
(CDCl3, 150 MHz), 3e, 6p,t (DMSOꢀd6, 100 MHz), and 6q,r,u (DMSOꢀd6, 150 MHz)
Comꢀ
pound

C(1)
C(3a) C(4), C(5)
C(6)
C(3)
51.2
C(7a)
51.7
C(7)
33.2
NꢀR
Other C atoms
2c
2d
2e
2g
173.7
91.7 133.7, 139.3 87.7
90.3 131.4, 137.9 79.1
89.1 133.3, 137.2 79.1
88.9 133.0, 136.9 78.9
120.2, 124.6, 128.9,
139.6
120.1, 124.6, 128.9,
139.7
46.7, 127.6, 128.0,
128.8, 136.3
33.3, 47.5, 55.8 (2×ОМе),
111.2, 111.8, 120.5, 131.1,
147.5, 148.8
9.3 (СH2СН3),
25.8 (СH2СН3)
20.7 (Ме)
177.2
174.1
174.0
49.5, 53.5
36.8
28.2
27.9
49.0
44.4
47.7
50.0
—
—
3e
3i
172.8
172.2
171.9
88.8 135.5, 136.9 81.3
88.5 135.4, 136.8 81.4
89.5 135.0, 135.3 80.6
51.3
48.1
45.0, 50.1
44.8, 51.1
17.4 (Ме), 126.4, 126.7,
127.5, 130.7, 136.0, 137.6
46.7, 127.6, 127.9, 128.8,
136.0
120.2, 124.9, 129.0, 139.3 14.3 (OСH2СН3),
61.3 (OСH2СН3),
169.8 (CO2)
52.1 (ОМе),
170.7 (CO2)
4a
47.6, 50.8, 52.7
170.4 (CO2)
4b
4d
172.1
172.3
89.6 135.1, 138.6 88.4
90.4 135.0, 135.1 80.5
51.0
49.3
52.5, 56.0
46.8, 51.4
120.3, 124.9, 129.0, 139.4 14.3 (OСH2СН3),
18.5 (Ме), 61.2
(OСH2СН3),
170.4 (CO2)
39.7, 108.5, 110.5, 142.6,
149.8
14.2 (OСH2СН3),
61.2 (OСH2СН3),
170.4 (CO2)
—
6a
6b
6c
174.5
174.8
174.8
85.6
85.5
88.4
29.5, 30.0
31.1, 36.1
27.9, 30.8
77.1
85.1
85.1
50.9, 51.8
51.3, 53.3
36.2
41.6
39.2
120.0, 124.5, 128.9, 139.5
120.0, 124.5, 128.9, 139.6 20.8 (Ме)
119.9, 124.5, 128.9, 139.6 9.3 (СH2СН3),
33.8 (СH2СН3)
51.3
52.9
6d
6e
178.3
175.1
88.4
86.7
25.4, 29.9
29.5, 30.0
77.0
77.0
49.6, 54.8
46.7, 50.6
44.1
35.6
119.9, 124.5, 128.9, 139.7 20.1 (Ме)
49.1, 127.6, 128.0, 128.8,
136.3
—
6f
178.8
175.0
89.4
86.8
25.3, 29.8
29.6, 30.0
76.8
77.0
46.5, 53.5
44.5, 50.6
43.3
35.6
47.8, 127.6, 127.9, 128.8,
136.4
33.5, 50.2, 56.0 (2×ОМе),
111.3, 112.0, 120.7,
131.4, 147.7, 149.0
20.0 (Ме)
—
6g
6h
6i
171.6
171.2
85.2
86.7
29.2, 29.7
31.8, 37.3
79.5
84.6
50.3, 50.3, 52.4
50.9, 51.8, 56.3
120.3, 124.9, 128.9, 139.2 55.6 (ОМе),
170.8 (CO2)
120.4, 124.8, 128.9, 139.2 18.3 (Ме), 56.5
(ОМе),
170.7 (CO2)
6j
171.6
175.2
86.1
88.9
29.1, 29.7
24.8, 29.6
79.2
78.6
48.5, 51.7, 52.0
46.6, 52.0, 58.6
46.7, 127.6, 128.0, 128.8,
136.1
47.2, 127.7, 128.0, 128.9,
136.3
54.5 (ОМе),
171.5 (CO2)
20.8 (Ме),
59.6 (ОМе),
172.1 (CO2)
6k
6l
173.0
173.3
87.2
87.2
26.5, 28.9
30.5, 32.6
78.6
86.0
50.9, 52.9, 54.3
120.0, 124.7, 129.0, 139.4 14.3 (OСH2СН3),
61.3 (OСH2СН3),
170.9 (CO2)
119.9, 124.7, 128.9, 139.4 14.3 (OСH2СН3),
20.7 (Ме), 61.3
6m
51.1
49.1
56.1, 57.3
(OСH2СН3),
171.1 (CO2)
6n
173.6
88.3
26.5, 28.9
78.5
52.3, 53.1
46.7, 127.7, 128.0, 128.8,
136.1
14.3 (OСH2СН3),
61.3 (OСH2СН3),
170.9 (CO2)
(to be continued)

120
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
Table 3 (continued)
Comꢀ

pound
C(1)
C(3a) C(4), C(5)
C(6)
78.4
C(3)
49.5
C(7a)
C(7)
NꢀR
Other C atoms
6o
173.3
88.3
26.5, 28.9
52.2, 52.8
39.6, 108.4, 110.5, 142.6,
149.9
14.3 (OСH2СН3),
61.2 (OСH2СН3),
170.8 (CO2)
6p
6q
172.3
172.7
86.3
86.3
29.0, 29.7
29.0, 29.7
79.3
79.2
50.7, 51.5, 53.8
48.0, 51.6, 54.1
29.8
12.8, 37.0
171.6 (CO2)
171.1 (CO2)
6r
6s
6t
172.8
173.0
172.8
86.1
86.6
86.7
29.0, 29.7
29.1, 29.6
29.0, 29.8
79.2
79.9
79.4
48.5, 51.6, 54.7
50.9, 52.3, 54.2
51.9, 52.1, 54.0
4.8, 4.9, 25.8
43.1, 58.7, 70.7
18.0 (Ме), 126.9, 127.1,
127.9, 131.2, 136.5, 138.2
45.8, 127.6, 127.9, 129.0,
137.3
172.6 (CO2)
173.0 (CO2)
171.1 (CO2)
6u
172.8
86.3
29.0, 29.7
79.3
48.5, 51.7, 53.9
171.9 (CO2)
6v
6w
50.5
50.4
92.7
92.8
29.9, 30.3
29.9, 30.3
78.5
78.5
54.4
54.4
46.7
46.6
36.9
36.9
127.5, 129.1, 132.8, 137.1
21.6 (Ме), 127.6, 129.8,
134.1, 143.5
—
—
7a
7b
7c
174.6
171.5
173.1
85.7
85.1
87.2
29.1, 29.6
(both t)
28.9, 29.3
(both t)
26.2, 28.5
(both t)
85.6
79.4
78.6
50.9, 51.8
36.3
120.0, 124.6, 128.9, 139.6
—
50.3, 50.3, 52.3
50.9, 52.9, 54.3
120.2, 124.9, 128.9, 139.2 55.6 (ОМе),
170.8 (CO2)
120.0, 124.8, 129.0, 139.4 14.3 (OСH2СН3),
61.4 (OСH2СН3),
170.9 (CO2)
Table 4. Mass spectral data for 3a,6ꢀepoxyisoindoles 2c—e,g, 3e,i, 4a,b,d, 6a—w, 7a—c, 6b,9ꢀepoxyisoindolo[2,1ꢀa]quinolines 14a,b,
11,13aꢀ or 12,14aꢀepoxyisoindolo[3,2ꢀc]quinolines 15a,b, 10,12aꢀepoxyisoindolo[1,2ꢀa]isoquinolines 16a—d, 8,10aꢀepoxy[1,3]ꢀ
oxazino[2,3ꢀa]isoindoles 17a,b, 2,4aꢀepoxyisoindolo[1,2ꢀb]quinazolines 18a,b, and 7b,10ꢀepoxyisoindolo[2,1ꢀa]perimidine 19
Compound
m/z (Irel (%))
2c
2d
2e
2g
3e
3i
255 [M]+ (7), 198 (2), 109 (100), 94 (4), 77 (10), 55 (13), 43 (16), 27 (7)
241 [M]+ (39), 212 (5), 172 (4), 148 (10), 104 (6), 81 (100), 69 (16), 53 (18), 41 (37)
241 [M]+ (38), 160 (23), 150 (37), 106 (48), 96 (100), 91 (34), 81 (20), 65 (10), 55 (46), 39 (4)
315 [M]+ (4), 164 (100), 151 (29), 149 (6), 107 (15), 96 (9), 81 (84), 65 (7), 55 (25)
285 [M]+ (9), 268 (26), 241 (8), 186 (100), 131 (9), 118 (9), 100 (14), 81 (25), 69 (13), 53 (18), 43 (55)
299 [M]+ (5), 240 (4), 218 (37), 208 (32), 186 (26), 113 (100), 106 (26), 96 (43), 91 (62), 81 (61),
65 (15), 53 (23), 39 (8)
4a
4b
4d
6a
299 [M]+ (6), 253 (3), 226 (8), 172 (87), 128 (5), 104 (5), 99 (8), 81 (100), 77 (11), 53 (24), 39 (4)
313 [M]+ (9), 267 (9), 240 (8), 186 (71), 104 (5), 95 (100), 77 (9), 43 (11)
303 [M]+ (2), 258 (2), 222 (13), 176 (4), 127 (13), 96 (37), 81 (100), 53 (44), 39 (6)
229 [M]+ (52), 200 (35), 172 (19), 156 (15), 146 (14), 119 (23), 104 (68), 91 (22), 81 (17), 77 (100),
68 (28), 55 (33), 51 (29), 39 (32)
243 [M]+ (46), 200 (45), 186 (13), 172 (34), 156 (19), 119 (16), 104 (51), 95 (19), 81 (20), 77 (82),
55 (24), 43 (100), 39 (19)
6b
6c
6d
257 [M]+ (80), 200 (76), 186 (18), 172 (35), 124 (18), 106 (49), 81 (24), 77 (58), 67 (16), 57 (100), 41 (19)
243 [M]+ (90), 214 (13), 200 (12), 170 (15), 158 (14), 119 (18), 106 (62), 104 (81), 96 (22), 91 (32),
81 (36), 77 (100), 67 (36), 53 (24), 41 (44), 39 (30)
6e
6f
6g
6h
243 [M]+ (28), 214 (3), 186 (3), 160 (9), 132 (10), 106 (32), 91 (100), 81 (9), 65 (28), 55 (16), 39 (17)
257 [M]+ (29), 242 (4), 228 (4), 174 (4), 152 (4), 109 (8), 95 (10), 91 (100), 81 (12), 65 (23), 55 (9), 41 (25)
317 [M]+ (2), 164 (100), 151 (65), 135 (6), 107 (16), 91 (11), 81 (16), 77 (11), 55 (12), 42 (11)
287 [M]+ (18), 228 (3), 200 (6), 156 (10), 146 (12), 119 (31), 104 (67), 91 (24), 81 (41), 77 (100),
59 (47), 51 (20), 39 (16)
301 [M]+ (68), 270 (10), 241 (12), 198 (17), 184 (28), 173 (12), 119 (28), 113 (13), 106 (40), 95 (21), 77 (65),
59 (30), 53 (13), 43 (100)
6i
(to be continued)

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
121
Table 4 (continued)
Compound
m/z (Irel (%))
6j
301 [M]+ (30), 270 (11), 241 (18), 213 (11), 198 (12), 185 (34), 157 (38), 132 (11), 106 (16), 91 (100),
81 (12), 65 (16), 53 (7)
6k
6l
315 [M]+ (12), 284 (5), 255 (8), 226 (9), 212 (7), 199 (33), 171 (9), 106 (7), 91 (100), 79 (11), 65 (20),
59 (10), 41 (13)
301 [M]+ (100), 256 (13), 227 (41), 212 (12), 199 (26), 184 (12), 171 (12), 146 (15), 127 (16), 119 (33),
106 (54), 95 (14), 77 (51), 67 (16), 53 (20), 41 (17)
6m
6n
315 [M]+ (36), 241 (31), 226 (23), 220 (26), 198 (25), 184 (41), 173 (32), 127 (37), 119 (20), 104 (34),
96 (29), 79 (23), 43 (100)
315 [M]+ (11), 270 (3), 241 (9), 220 (12), 198 (13), 184 (23), 173 (17), 139 (11), 127 (32), 119 (23),
104 (35), 96 (28), 77 (53), 53 (15), 43 (100)
6o
6p
6q
6r
305 [M]+ (19), 260 (3), 231 (6), 202 (10), 175 (8), 136 (5), 122 (8), 109 (14), 96 (13), 81 (100), 53 (40), 39 (7)
211 [M]+ (25), 193 (11), 167 (100), 152 (12), 138 (92), 110 (54), 98 (16), 82 (18), 77 (24), 67 (16), 55 (18), 43 (51)
225 [M]+ (100), 210 (65), 182 (29), 152 (33), 125 (34), 112 (27), 97 (19), 80 (40), 67 (14), 56 (33), 43 (35), 33 (14)
237 [M]+ (48), 208 (19), 191 (57), 164 (47), 148 (22), 135 (46), 120 (15), 107 (16), 95 (23), 81 (50), 70 (98),
53 (38), 41 (100)
6s
6t
255 [M]+ (20), 223 (12), 210 (40), 166 (32), 155 (12), 138 (14), 122 (12), 110 (21), 94 (47), 80 (36), 67 (39),
59 (100), 43 (97)
287 [M]+ (100), 269 (14), 259 (12), 241 (33), 225 (33), 214 (29), 197 (29), 187 (22), 170 (29), 149 (10), 106 (13),
91 (81), 81 (44), 69 (31), 43 (77)
287 [M]+ (37), 241 (12), 187 (9), 132 (18), 119 (13), 106 (33), 91 (100), 81 (18), 65 (25), 43 (66)
279 [M]+ (3), 260 (3), 221 (5), 208 (3), 138 (100), 120 (32), 103 (7), 94 (28), 77 (47), 67 (14), 51 (12),
41 (18), 27 (5)
6u
6v
6w
7a
7b
293 [M]+ (6), 235 (5), 155 (23), 138 (100), 120 (42), 103 (6), 91 (63), 80 (12), 65 (21), 55 (11), 41 (17), 29 (5)
231 [M]+ (100), 202 (40), 172 (19), 119 (22), 105 (52), 91 (20), 77 (69), 68 (32), 55 (24), 42 (14), 39 (19)
289 [M]+ (100), 258 (15), 230 (17), 146 (16), 119 (25), 106 (53), 97 (15), 91 (19), 81 (17), 77 (53), 69 (16),
59 (14), 51 (16)
303 [M]+ (100), 258 (14), 229 (44), 201 (23), 171 (14), 146 (13), 119 (22), 106 (31), 77 (36), 69 (10), 51 (9), 29 (20)
7c
14a
338 [M]+ (25), 309 (7), 253 (100), 235 (79), 224 (16), 209 (70), 196 (19), 180 (21), 167 (17), 130 (34),
103 (7), 77 (13), 55 (10), 41 (16)
14b
15a
15b
16a
16b
16с
16d
17a
17b
18a
18b
19
396 [M]+ (11), 311 (33), 279 (36), 251 (46), 234 (22), 223 (19), 213 (81), 208 (28), 195 (20), 180 (31),
167 (34), 145 (19), 130 (100), 59 (41), 41 (20)
355 [M]+ (100), 324 (9), 310 (7), 252 (7), 214 (13), 174 (17), 156 (9), 144 (12), 130 (19), 115 (10),
91 (7), 77 (9), 41 (8)
369 [M]+ (100), 310 (15), 281 (8), 266 (8), 207 (12), 186 (15), 158 (12), 144 (20), 130 (28), 128 (15),
117 (12), 91 (16), 81 (15), 77 (22), 55 (13), 41 (18)
255 [M]+ (91), 254 (100), 237 (17), 226 (14), 210 (14), 198 (20), 184 (13), 130 (55), 115 (21), 103 (28),
77 (28), 55 (23), 39 (18)
313 [M]+ (85), 312 (61), 281 (62), 252 (29), 224 (25), 197 (37), 141 (21), 130 (100), 123 (20), 115 (36),
103 (35), 77 (29), 67 (19), 59 (22), 41 (21)
315 [M]+ (100), 314 (95), 300 (28), 284 (66), 272 (7), 258 (7), 242 (7), 190 (28), 176 (21), 146 (9),
115 (12), 91 (13), 77 (12), 67 (13), 55 (15), 41 (11)
373 [M]+ (100), 372 (91), 342 (36), 284 (37), 207 (45), 190 (89), 176 (56), 133 (31), 129 (28),
115 (33), 81 (31), 77 (40), 67 (31), 59 (57), 53 (27), 44 (54)
253 [M]+ (13), 252 (36), 209 (73), 194 (12), 180 (100), 178 (52), 152 (26), 139 (11), 123 (26),
95 (14), 86 (17), 67 (9), 56 (8), 41 (6)
267 [M]+ (56), 221 (34), 194 (50), 178 (24), 166 (35), 153 (48), 123 (34), 109 (25), 94 (30),
86 (100), 56 (23), 43 (37)
312 [M]+ (12), 256 (100), 238 (32), 212 (34), 199 (15), 183 (14), 132 (90), 117 (12), 106 (30),
91 (17), 77 (40), 57 (83), 41 (18)
314 [M]+ (79), 283 (17), 268 (21), 254 (8), 211 (10), 198 (16), 183 (12), 171 (13), 158 (17), 131 (100),
106 (20), 96 (8), 77 (8)
350 [M]+ (100), 319 (6), 245 (4), 235 (6), 219 (5), 207 (4), 194 (4), 168 (48), 159 (4), 140 (6),
115 (5), 44 (12)

122
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
Scheme 3
R = H (8a, 10a,c, 11a, 12a, 14a, 16a,c, 17a, 18a), CO2Me (8b, 10b,d, 12b, 14b, 16b,d, 18b), Me (11b, 17b)
n = 1 (9a, 15a), 2 (9b, 15b)
R´ = H (12b, 18b), COCH=CH2 (12a), COEt (18a)
X = H (10a,b, 16a,b), OMe (10c,d, 16c,d)
Table 5. Yields, physicochemical characteristics, and IR spectral data for 6b,9ꢀepoxyisoindolo[2,1ꢀa]quinolines 14a,b, 11,13aꢀ or
12,14aꢀepoxyisoindolo[3,2ꢀc]quinolines 15a,b, 10,12aꢀepoxyisoindolo[1,2ꢀa]isoquinolines 16a—d, 8,10aꢀepoxy[1,3]oxazino[2,3ꢀa]ꢀ
isoindoles 17a,b, 2,4aꢀepoxyisoindolo[1,2ꢀb]quinazolines 18a,b, and 7b,10ꢀepoxyisoindolo[2,1ꢀa]perimidine 19
Comꢀ
pound
Yield
(%)
M.p./C
(solvent)
Found
Calculated
Molecular
formula
IR, /cm–1
(%)
С
Н
N
14a
14b
15a
15b
16a
86
99
88
97
82
225—226
(AcOEt—EtOH)
~250
(EtOH—DMF)
~250
(EtOH—DMF)
~250
(EtOH—DMF)
143—144
70.80
70.99
66.48
66.65
67.81
67.59
68.37
68.28
75.31
75.27
6.71
6.55
6.31
6.10
5.74
5.96
6.33
6.28
6.92
6.71
8.39
8.28
6.89
7.07
3.89
3.94
3.53
3.79
5.35
5.49
C20H22N2O3
C22H24N2O5
C20H21NO5
C21H23NO5
C16H17NO2
1699 (NCO), 1677 (NCO)
1735 (СО2Me), 1678 (NCO)
1731 (СО2Me), 1684 (NCO)
1736 (СО2Me), 1688 (NCO)
1679 (NCO)
(AcOEt—EtOH)
(to be continued)

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
123
Table 5 (continued)
Comꢀ
pound
Yield
(%)
M.p./C
(solvent)
Found
Calculated
Molecular
formula
IR, /cm–1
(%)
С
Н
N
16b
16с
16d
17а
17b
18a
18b
19
96
88
99
92
56
88
95
95
212 (decomp.)
(AcOEt—EtOH)
174—175
(AcOEt—EtOH)
217—218 (decomp.)
(AcOEt—EtOH)
244—246
69.23
68.99
68.32
68.55
64.42
64.33
56.73
56.91
58.75
58.42
69.02
69.21
64.80
64.96
68.40
68.56
6.28
6.11
6.85
6.71
6.33
6.21
6.12
5.97
6.38
6.41
6.67
6.45
5.59
5.77
5.28
5.18
4.56
4.47
4.32
4.44
3.51
3.75
5.66
5.53
5.41
5.24
9.11
8.97
8.78
8.91
7.89
8.00
C18H19NO4
C18H21NO4
C20H23NO6
C12H15NO5
C13H17NO5
C18H20N2O3
C17H18N2O4
C18H20N2O4
1721 (СО2Me), 1695 (NCO)
1677 (NCO)
1738 (СО2Me), 1690 (NCO)
1731 (СО2Н), 1710 (NCO)
1741 (СО2Н), 1666 (NCO)
1649 (NCO), 1703 (NCO)
(EtOH—DMF)
225—226
(EtOH)
223—224
(AcOEt—EtOH)
278—279
(AcOEt—EtOH)
238—239
3323 (NH), 1732 (СО2Me),
1674 (NCO)
3280 (NH), 1745 (СО2Me),
1687 (NCO)
(AcOEt—EtOH)
3a,6ꢀEpoxyꢀ2,3,7,7aꢀtetrahydroisoindolꢀ1ꢀones 2c—e,g and
Experimental
ethyl 1ꢀoxoꢀ1,2,3,6,7,7aꢀhexahydroꢀ3a,6ꢀepoxyisoindoloꢀ7ꢀcarꢀ
boxylates 4a—d (general procedure). A solution of the correꢀ
sponding amine 1a—f (0.06 mol), acryloyl chloride (7.31 mL,
0.09 mol) (for 2c,e,g) or metacryloyl chloride (8.79 mL,
0.09 mol) (for 2d), or monoethyl fumaroyl chloride (0.09 mol)
(for 4a—d), and triethylamine (16.7 mL, 0.12 mol) in toluene
(100 mL) was refluxed for 6—10 h (TLC monitoring). Monoꢀ
ethyl fumaroyl chloride was prepared by stirring monoethyl fumaꢀ
rate (12.96 g, 0.09 mol) and thionyl chloride (38.83 mL, 0.54 mol)
in anhydrous benzene (100 mL) for 7 days followed by removal
of the solvent and thionyl chloride excess in vacuo. The organic
layer was separated, the aqueous layer was extracted with ethyl
acetate (3×50 mL). The combined organic layers was dried with
magnesium sulfate and the solvent was removed in vacuo. Reꢀ
crystallization of the residue from hexane—AcOEt afforded
epoxyisoindolones 2c,d,g, 4a—d as colorless crystals. Comꢀ
pound 2e is a yellow viscous oil.
(3aRS,6SR,7RS,7aSR)ꢀ2ꢀ(2ꢀMethylphenyl)ꢀ1ꢀoxoꢀ1,2,3,
6,7,7aꢀhexahydroꢀ3a,6ꢀepoxyisoindoloꢀ7ꢀcarboxylic acid (3e). To
a solution of Nꢀ(2ꢀfurylmethyl)ꢀ2ꢀmethylaniline (1l) (0.02 mol)
in benzene (50 mL), a solution of maleic anhydride (2.24 g,
0.023 mol) in benzene (50 mL) was added at 20 C and the
mixture was held at this temperature until the reaction was comꢀ
pleted (TLC monitoring). The precipitate formed was collected
by filtration and washed with diethyl ether (2×15 mL). Recrysꢀ
tallization of the precipitate from EtOH—DMF afforded 4.84 g
(85%) of acid 3e as colorless powder.
Commercially available reagents (Acros Organics, Alfa Aesar)
were used as purchased; all solvents were distilled prior to use.
Hydrogenation was performed using apparatus comprising a high
pressure Knauer Pump 100 and an HꢀCube ProTM continuousꢀ
flow hydrogenation reactor (two electrolytic cells, a 70 mm disꢀ
posable catalyst cartridge (CatCart®) preloaded with 10% Pd/C).
Melting points of the synthesized compounds were measured
with SMP 10 and SMP 30 apparatuses and were uncorrected.
Elemental analysis was carried out using a EuroVector EA 3000
CHNS analyzer. IR spectra were recorded on an Infralum FTꢀ801.
The samples were run neat (compounds 2e, 3i, 6d—g,j) or dilutꢀ
ed with KBr. 1H NMR spectra were run on Bruker AMXꢀ400
(working frequency of 400 MHz) and JEOL JNMꢀECA600
(working frequency of 600 MHz) instruments at 26 C for ~3%
solutions of the samples in CDCl3 or DMSOꢀd6; the signals are
given in the  scale relative to the residual signals of CHCl3
( 7.26) and DMSO ( 2.49) as internal standards. 13C NMR
spectra were obtained with Bruker Avance 600 (working freꢀ
quency of 150 MHz) and Bruker AMXꢀ400 (working frequency
of 100.6 MHz) spectrometers; the central signal of the CDCl3
triplet ( 77.4) and the DMSOꢀd6 multiplet ( 40.0) were used as
internal standards. Mass spectra were obtained using either
a Thermo Trace DSQ instrument (electron impact, 70 eV, source
temperature of 200 C, direct inlet) or a Thermo DSQ II—Focus
GC instrument (electron impact, 70 eV, source temperature of
200 C, carrier gas was helium, an RTXꢀ5MS column). For TLC,
precoated Sorbfil PTSKhꢀAFꢀAꢀUFꢀ254 plates were used; the
spots of the compounds were visualized by iodine vapors. Synꢀ
thesis, spectral data, physicochemical parameters, and elemenꢀ
tal analysis data for compounds 2a,b,f, 3a—d,f,g,h,j, 4c, 5a,b,
and 8—13 have been published earlier.11,12,14—22,27,28,31
Methyl (3aRS,6SR,7RS,7aSR)ꢀ2ꢀbenzylꢀ1ꢀoxoꢀ1,2,3,6,7,7aꢀ
hexahydroꢀ3a,6ꢀepoxyisoindoloꢀ7ꢀcarboxylate (3i). To a suspenꢀ
sion of (3aRS,6SR,7RS,7aSR)ꢀ2ꢀbenzylꢀ1ꢀoxoꢀ1,2,3,6,7,7aꢀ
hexahydroꢀ3a,6ꢀepoxyisoindoloꢀ7ꢀcarboxylic acid11 (3.0 g,
0.01 mol) in MeOH (50 mL), concentrated H2SO4 (1 mL) was
added and the mixture was refluxed for 12 h (TLC monitoring,
clear solution was formed). The reaction mixture was cooled
down, poured into water (100 mL), and extracted with CHCl3
(3×50 mL). The combined organic layers was dried with anhyꢀ
Yields, elemental analysis data, physicochemical parameters,
1H and 13C NMR spectra, and mass spectra of compounds synꢀ
thesized in the present work are given in Tables 1—5.

124
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Zaytsev et al.
drous magnesium sulfate and the solvent was removed in vacuo.
Purification of the residue by column chromatography (Al2O3,
40×100 cm, elution with diethyl ether) afforded compound 3i as
lightꢀyellow oil.
C(13b), OMe); 67.5 (C(2)); 76.5, 78.7 (C(3a), C(11)); 87.8
(C(13a)); 120.7, 125.2, 128.2, 128.9, 130.5 (C(3b), C(4)—C(7));
135.5 (C(7a)); 170.3 (CO2); 171.7 (NCO).
Methyl (4aRS,10aRS,11SR,12RS,14aSR,14bRS,14cRS)ꢀ
10ꢀoxoꢀ2,3,10,10a,11,12,13,14,14b,14cꢀdecahydroꢀ1H,4aHꢀ
12,14aꢀepoxyisoindolo[2,1ꢀa]pyrano[3,2ꢀc]quinolineꢀ11ꢀcarbꢀ
oxylate (15b). 1H NMR (600 MHz, CDCl3), : 1.34—1.41,
1.50—1.52, 1.62—1.68, 1.72—1.80, 1.84—1.92, 2.02—2.08 (all m,
8 H, C(1)H2, C(2)H2, C(13)H2, C(14)H2); 2.35—2.38 (m, 1 H,
H(14c)); 3.01, 3.11 (both d, 1 H each, H(10a), H(11), J = 9.6 Hz);
3.26—3.30, 3.60—3.63 (both m, 1 H each, C(3)H2); 3.77 (s, 3 H,
OMe); 4.34 (d, 1 H, H(14b), J = 2.1 Hz); 4.74 (d, 1 H, H(12),
J = 5.5 Hz); 5.11 (d, 1 H, H(4a), J = 5.5 Hz); 7.16 (t, 1 H, H(6),
J = 7.6 Hz); 7.27 (t, 1 H, H(7), J = 7.6 Hz); 7.53 (d, 1 H, H(5),
J = 7.6 Hz); 8.08 (d, 1 H, H(8), J = 7.6 Hz). 13C NMR (150 MHz,
CDCl3), : 19.7, 24.5, 27.2, 29.6 (C(1), C(2), C(13), C(14));
33.7 (C(14c)); 52.1, 52.8, 54.9 (C(10a), C(11), OMe); 60.8 61.9
(C(3), C(14b)); 72.3, 78.7 (C(4a)); 78.6 (C(12)); 87.3 (C(14a));
121.2, 125.1, 125.4, 127.4, 128.2 (C(4b), C(4)—C(8)); 136.4
(C(8a)); 169.6 (CO2); 171.2 (NCO).
Hydrogenation (general procedure). A 0.025 M solution of
the corresponding isoindole in EtOH (for 2a—g and 3g—j) or
CH2Cl2 (for 3a—f, 4a—d, 5a,b, and 8—13) was introduced into
the continuousꢀflow hydrogenation HꢀCube ProTM device unꢀ
der the following condition: 100% H2 production (full mode),
room temperature (20—25 C), atmospheric pressure, flow rate
of 1 mL min–1. Removal of the solvents afforded perhydroisoꢀ
indoles 6, 7, 14—19 as colorless crystals or weakly colored heavy
oils (2e, 3i, 6d—g,j). Deuteration was carried out similarly using
D2O (99.8%) as a hydrogen source and CH2Cl2 as a solvent.
(5RS,6aRS,6bRS,9SR,10aSR)ꢀ5ꢀ(2ꢀOxopyrrolidinꢀ1ꢀyl)ꢀ
6,6a,8,9,10,10aꢀhexahydroꢀ5Hꢀ6b,9ꢀepoxyisoindolo[2,1ꢀa]ꢀ
quinolinꢀ11(7H)ꢀone (14a). 1H NMR (600 MHz, CDCl3),
: 1.62—1.66, 1.70—1.74, 1.79—1.84, 1.92—1.96, 1.99—2.04,
2.15—2.22 (all m, 10 H, NCH2CH2CH2, C(6)H2, C(7)H2,
C(8)H2, C(10)H2); 2.45—2.57 (m, 2 H, NCH2CH2CH2); 2.82
(dd, 1 H, H(10a), J = 4.8 Hz, J = 9.6 Hz); 3.07—3.10, 3.21—3.25
(both m, 1 H each, NCH2CH2CH2); 4.29 (dd, 1 H, H(6a),
J = 4.9 Hz, J = 9.6 Hz); 4.61 (dd, 1 H, H(9), J = 4.8 Hz, J = 5.5 Hz);
5.62 (t, 1 H, H(5), J = 8.9 Hz); 6.98 (d, 1 H, H(4), J = 7.6 Hz);
7.04 (t, 1 H, H(2), J = 7.6 Hz); 7.24 (t, 1 H, H(3), J = 7.6 Hz);
8.69 (d, 1 H, H(1), J = 7.6 Hz). 13C NMR (150 MHz, CDCl3), :
18.3 (NCH2CH2CH2); 25.1, 28.0, 29.9, 31.4, 35.5 (NCH2CH2CH2,
C(6), C(7), C(8), C(10)); 42.3, 48.1, 51.7, 57.1 (NCH2CH2CH2,
C(5), C(6a), C(10a)); 76.9 (C(9)); 87.1 (C(6b)); 119.4, 123.2,
123.8, 126.6, 128.5 (C(1)—C(4), C(4a)); 137.4 (C(12a)); 173.4
(CO2); 176.1 (NCO).
(8aRS,10RS,12aSR,12bSR)ꢀ5,9,10,11,12,12bꢀHexahydroꢀ
6Hꢀ10,12aꢀepoxyisoindolo[1,2ꢀa]isoquinolineꢀ8(8aH)ꢀone (16a).
1H NMR (600 MHz, CDCl3), : 1.57—1.61, 1.87—1.98, 2.07—2.10,
2.16—2.21 (both m, 5 H, H(9A), C(11)H2, C(12)H2); 1.89 (dd,
1 H, H(9B), J = 9.6 Hz, J = 12.4 Hz); 2.67—2.70 (m, 1 H,
H(5B)); 2.83 (dd, 1 H, H(8a), J = 4.8 Hz, J = 9.6 Hz); 2.90—2.99
(m, 2 H, H(5A), H(6B)); 4.34—4.37 (m, 1 H, H(6A)); 4.52 (t, 1 H,
H(10), J = 5.5 Hz); 5.11 (s, 1 H, H(12b)); 7.15—7.29 (m, 4 H,
Ar). 13C NMR (150 MHz, CDCl3), : 29.3, 29.6, 29.8, 35.3
(C(5), C(9), C(11), C(12)); 37.6 (C(6)); 51.8 (C(8a)); 57.9
(C(12b)); 76.7 (C(10)); 90.0 (C(12a)); 125.7, 126.6, 127.3, 129.6
(C(1)—C(4)); 132.1, 135.3 (C(4a), C(12c)); 174.2 (NCO).
Methyl (8aRS,9SR,10RS,12aSR,12bSR)ꢀ8ꢀoxoꢀ5,8,8a,9,
10,11,12,12bꢀoctahydroꢀ6Hꢀ10,12aꢀepoxyisoindolo[1,2ꢀa]isoꢀ
quinolineꢀ9ꢀcarboxylate (16b). 1H NMR (600 MHz, CDCl3), :
1.58—1.62, 1.92—2.01, 2.20—2.24, 2.65—2.71, 2.92—2.96 (all m,
7 H, H(6A), C(5)H2, C(11)H2, C(12)H2); 3.03, 3.17 (both d,
1 H each, H(8a), H(9), J = 9.6 Hz); 3.68 (s, 3 H, ОMe);
4.32—4.34 (m, 1 H, H(6A)); 4.66 (d, 1 H, H(10), J = 5.5 Hz);
5.10 (s, 1 H, H(12b)); 7.15—7.28 (m, 4 H, Ar). 13C NMR
(150 MHz, CDCl3), : 29.4, 29.5, 29.5 (C(5), C(11), C(12));
37.8 (C(6)); 51.7, 51.9, 55.8, 57.5 (ОMe, C(8a), C(9), C(12b));
78.9 (C(10)); 89.6 (C(12a)); 125.6, 126.6, 127.4, 129.7 (C(1)—C(4));
131.7, 135.6 (C(4a), C(12c)); 170.5 (CО2); 171.6 (NCO).
(8aRS,10RS,12aSR,12bSR)ꢀ2,3ꢀDimethoxyꢀ5,9,10,11,12,
12bꢀhexahydroꢀ6Hꢀ10,12aꢀepoxyisoindolo[1,2ꢀa]isoquinolineꢀ
Methyl (5RS,6aRS,6bRS,9SR,10RS,10aSR)ꢀ11ꢀoxoꢀ5ꢀ(2ꢀ
oxopyrrolidinꢀ1ꢀyl)ꢀ6,6a,7,8,9,10,10a,11ꢀoctahydroꢀ5Hꢀ6b,9ꢀ
1
epoxyisoindolo[2,1ꢀa]quinolineꢀ10ꢀcarboxylate (14b). H NMR
(600 MHz, DMSOꢀd6), : 1.61—1.74 (m, 4 H, C(7)H2, C(8)H2);
1.91—2.08 (m, 4 H, NCH2CH2CH2, C(6)H2); 2.30—2.41 (m, 2 H,
NCH2CH2CH2); 2.91—2.94, 3.20—3.23 (both m, 1 H each,
NCH2CH2CH2); 3.07, 3.41 (both d, 1 H each, H(10), H(10a),
J = 9.6 Hz); 3.53 (s, 3 H, OMe); 4.50 (dd, 1 H, H(6a), J = 2.8 Hz,
J = 11.7 Hz); 4.61 (d, 1 H, H(9), J = 4.1 Hz); 5.62 (br.s, 1 H,
H(5)); 6.92 (d, 1 H, H(4), J= 7.6 Hz); 7.04 (t, 1 H, H(2), J= 7.6 Hz);
7.21 (t, 1 H, H(3), J = 7.6 Hz); 8.55 (d, 1 H, H(1), J = 7.6 Hz).
13C NMR (150 MHz, DMSOꢀd6), : 18.4 (NCH2CH2CH2);
24.9, 26.7, 29.5, 31.1 (NCH2CH2CH2, C(6), C(7), C(8)); 42.3
(NCH2CH2CH2); 48.0, 51.0, 51.7, 55.6, 56.3 (OMe, C(5),
C(6a), C(10), C(10a)); 78.9 (C(9)); 87.1 (C(6b)); 118.6, 123.9,
124.1, 126.8, 128.4 (C(1)—C(4), C(4a)); 137.7 (C(12a)); 171.0
(CO2); 172.2, 175.5 (both NCO).
Methyl (3aRS,9aRS,10SR,11RS,13aSR,13bRS,13cRS)ꢀ9ꢀ
oxoꢀ1,2,9,9a,10,11,12,13,13b,13cꢀdecahydroꢀ3aHꢀ11,13aꢀepꢀ
oxyfuro[3,2ꢀc]isoindolo[2,1ꢀa]quinolineꢀ10ꢀcarboxylate (15a).
1H NMR (600 MHz, DMSOꢀd6), : 1.44—1.51, 1.61—1.65,
1.75—1.84, 1.93—1.98 (all m, 6 H, C(1)H2, C(12)H2, C(13)H2);
2.89—2.93 (m, 1 H, H(13c)); 3.08, 3.33 (both d, 1 H each,
H(9a), H(10), J = 9.6 Hz); 3.57 (s, 3 H, OMe); 3.61—3.64,
3.69—3.73 (both m, 1 H each, C(2)H2); 4.39 (d, 1 H, H(13b),
J = 2.8 Hz); 4.61 (d, 1 H, H(11), J = 4.8 Hz); 5.22 (d, 1 H, H(3a),
J = 8.2 Hz); 7.11 (dt, 1 H, H(5), J = 1.4 Hz, J = 7.6 Hz); 7.23
(ddd, 1 H, H(6), J = 1.4 Hz, J = 7.6 Hz, J = 8.2 Hz); 7.32 (d, 1 H,
H(4), J = 7.6 Hz); 7.71 (dd, 1 H, H(7), J = 1.4 Hz, J = 8.2 Hz).
13C NMR (150 MHz, DMSOꢀd6), : 25.6, 27.4, 29.6 (C(1),
C(12), C(13)); 39.4 (C(13c)); 51.7, 52.0, 54.6, 59.0 (C(9a), C(10),
1
8(8aH)ꢀone (16c). H NMR (600 MHz, CDCl3), : 1.57—1.61,
1.85—1.92, 1.95—1.99, 2.06—2.14 (all m, 5 H, H(9A), C(11)H2,
C(12)H2); 1.87 (dd, 1 H, H(9B), J = 9.6 Hz, J = 12.4 Hz);
2.56—2.59 (m, 1 H, H(5B)); 2.81 (dd, 1 H, H(8a), J = 4.1 Hz,
J = 9.6 Hz); 2.83—2.93 (m, 2 H, H(5A), H(6B)); 3.82, 3.84
(both s, 3 H each, ОMe); 4.34—4.37 (m, 1 H, H(6A)); 4.53 (t, 1 H,
H(10), J = 5.5 Hz); 5.04 (s, 1 H, H(12b)); 6.63, 6.72 (both s,
1 H each, H(1), H(4)). 13C NMR (150 MHz, CDCl3), : 28.8,
29.7, 29.8, 35.3 (C(5), C(9), C(11), C(12)); 37.6 (C(6)); 51.8,
55.9, 56.1, 57.7 (2 ОMe, C(8a), C(12b)); 76.7 (C(10)); 90.0
(C(12a)); 108.8, 112.3 (C(1), C(4)); 123.6, 127.7 (C(4a), C(12c));
147.8, 148.3 (C(2), C(3)); 174.1 (NCO).
Methyl (8aRS,9SR,10RS,12aSR,12bSR)ꢀ2,3ꢀdimethoxyꢀ8ꢀ
oxoꢀ5,8,8a,9,10,11,12,12bꢀoctahydroꢀ6Hꢀ10,12aꢀepoxyisoindoꢀ
lo[1,2ꢀa]isoquinolineꢀ9ꢀcarboxylate (16d). 1H NMR (600 MHz,
CDCl3), : 1.58—1.64, 1.92—2.02, 2.13—2.18, 2.55—2.61,

Flow catalytic hydrogenation of epoxyisoindoles
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
125
2.86—2.92 (all m, 7 H, H(6A), C(5)H2, C(11)H2, C(12)H2);
3.02, 3.15 (both d, 1 H each, H(8a), H(9), J = 9.6 Hz); 3.68 (s, 3 H,
ОMe); 3.84 (s, 6 H, ОMe); 4.32—4.34 (m, 1 H, H(6A)); 4.67
(d, 1 H, H(10), J = 5.5 Hz); 5.03 (s, 1 H, H(12b)); 6.63, 6.71 (both s,
1 H each, H(1), H(4)). 13C NMR (150 MHz, CDCl3), : 29.0,
29.5, 29.6 (C(5), C(11), C(12)); 37.9 (C(6)); 51.8, 51.8, 55.7,
55.9, 56.2, 57.2 (3 ОMe, C(8a), C(9), C(12b)); 78.9 (C(10));
89.6 (C(12a)); 108.9, 112.4 (C(1), C(4)); 123.2, 128.1 (C(4a),
C(12c)); 147.9, 148.4 (C(2), C(3)); 170.4(CО2); 174.1 (NCO).
(6aRS,7SR,8RS,10aSR,10bRS)ꢀ6ꢀOxooctahydroꢀ2Hꢀ8,10aꢀ
epoxy[1,3]oxazino[2,3ꢀa]isoindoloꢀ7ꢀcarboxylic acid (17a).
1H NMR (400 MHz, DMSOꢀd6), : 1.44—1.81 (m, 6 H, C(3)H2,
C(9)H2, C(10)H2); 2.89, 3.00 (both d, 1 H each, H(6a), H(7),
J = 9.5 MHz); 3.06 (dt, 1 H, H(4A), J = 3.2 Hz, J = 12.7 Hz);
3.79—4.06 (m, 3 H, C(2)H2, H(4B)); 4.62 (d, 1 H, H(8), J = 5.1 Hz);
5.05 (s, 1 H, H(10b)); 12.0 (s, 1 H, CО2H). 13C NMR (100 MHz,
DMSOꢀd6), : 24.9, 27.1, 28.6 (C(3), C(9), C(10)); 38.0 (C(4));
50.9, 52.0 (C(6a), C(7)); 66.5 (C(2)); 79.7 (C(8)); 86.1 (C(10b));
87.3 (C(10a)); 171.0 (CО2); 171.7 (NCO).
(6aRS,7SR,8RS,10aSR,10bRS)ꢀ8ꢀMethylꢀ6ꢀoxooctahydroꢀ
2Hꢀ8,10aꢀepoxy[1,3]oxazino[2,3ꢀa]isoindoloꢀ7ꢀcarboxylic acid
(17b). 1H NMR (600 MHz, CDCl3), : 1.48—1.50 (m, 1 H, H(3A));
1.55 (s, 3 H, Me); 1.73—1.97 (m, 5 H, H(3B), C(9)H2, C(10)H2);
3.07, 3.09 (both d, 1 H each, H(6a), H(7), J = 9.4 Hz); 3.12 (dt,
1 H, H(4A), J = 3.4 Hz, J = 13.1 Hz); 3.81 (dt, 1 H, H(2A),
J = 2.1 Hz, J = 12.4 Hz); 4.14—4.23 (m, 2 H, H(2B), H(4B)); 5.13
(s, 1 H, H(10b)). 13C NMR (100 MHz, CDCl3), : 18.2 (Me);
25.0, 29.3, 36.4 (C(3), C(9), C(10)); 39.0 (C(4)); 54.1, 55.0
(C(6a), C(7)); 67.5 (C(2)); 87.3, 87.5, 87.6 (C(8), C(10a),
C(10b)); 172.2 (CО2); 173.0 (NCO).
(2RS,4aSR,4bSR,12aRS)ꢀ5ꢀPropionylꢀ1,3,4,5,10,12aꢀhexaꢀ
hydroꢀ4bHꢀ2,4aꢀepoxyisoindolo[1,2ꢀb]quinazolinꢀ12(2H)ꢀone
(18a). 1H NMR (600 MHz, CDCl3), : 1.13 (t, 3 H, CОCH2CH3,
J = 7.3 Hz); 1.50 (ddd, 1 H, H(1A), J = 4.8 Hz, J = 9.6 Hz,
J = 11.9 Hz); 1.74 (dd, 1 H, H(1B), J = 9.6 Hz, J = 11.9 Hz);
1.83—1.95, 2.13—2.21 (both m, 4 H, C(3)H2, C(4)H2); 2.32—2.42,
2.61—2.69 (both m, 2 H, CОCH2CH3); 2.80 (dd, 1 H, H(12a),
J = 4.8 Hz, J = 9.6 Hz); 3.78, 4.88 (both d, 1 H each, C(10)H2,
J = 14.7 Hz); 4.41 (t, 1 H, H(2), J = 4.8 Hz); 6.53 (s, 1 H, H(4b));
7.17—7.31 (m, 4 H, H(6)—H(9)). 13C NMR (150 MHz, CDCl3),
: 9.7 (CОCH2CH3); 28.4, 28.4, 29.7, 35.1 (CОCH2CH3, C(1),
C(3), C(4)); 40.4 (C(10)); 52.1 (C(12a)); 68.7 (C(4b)); 76.7
(C(2)); 90.3 (C(4a)); 126.0, 126.2, 126.4, 128.0, 132.7 (C(6)—C(9),
C(9a)); 137.2 (C(5a)); 174.1, 174.5 (both NCO).
(s, 3 H, ОMe); 4.64 (br.s, 1 H, NH); 4.83 (d, 1 H, H(10),
J = 4.8 Hz); 5.34 (s, 1 H, H(7a)); 6.71, 7.33, 7.56, 7.70 (all d,
1 H each, H(1), H(3), H(4), H(6), J = 7.6 Hz); 7.28, 7.43
(both t, 1 H each, H(2), H(5), J = 7.6 Hz). 13C NMR (150 MHz,
CDCl3), : 27.4, 29.2 (C(8), C(9)); 51.8, 52.2, 53.8 (ОMe, C(11),
C(11a)); 69.1 (C(7a)); 80.0 (C(10)); 87.2 (C(7b)); 109.6, 116.4,
120.0, 124.4, 126.5, 126.6, 127.8, 130.9, 134.4, 139.8 (C(1)—C(6),
C(3a), C(6a), C(13a), C(13b)).
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 13ꢀ03ꢀ00105,
13ꢀ03ꢀ90400_Ukr_f_a, and 12ꢀ03ꢀ31088 mol_a).
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