Cyclocondensation of lower aliphatic aldehydes with arylamines and cyclopentadiene

Article abstract of DOI:10.1007/s11172-013-0344-2

Three-component condensation of lower aliphatic aldehydes (C ₁-C₃) with arylamines and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]-quinolines. Ozonization of their N-trifluoroacetyl derivatives a

Full text of DOI:10.1007/s11172-013-0344-2

Russian Chemical Bulletin, International Edition, Vol. 62, No. 11, pp. 2377—2384, November, 2013
2377
Cyclocondensation of lower aliphatic aldehydes
with arylamines and cyclopentadiene
A. G. Tolstikov, R. G. Savchenko, E. S. Lukina, S. R. Afon´kina, D. V. Nedopekin, L. M. Khalilov, and V. N. Odinokov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
1
41 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
Fax: +7 (347) 284 2750. Eꢀmail: odinokov@anrb.ru
Threeꢀcomponent condensation of lower aliphatic aldehydes (C —C ) with arylamines
1
3
and cyclopentadiene (the Povarov reaction) gave 3a,4,5,9bꢀtetrahydroꢀ3Hꢀcyclopenta[c]ꢀ
quinolines. Ozonization of their Nꢀtrifluoroacetyl derivatives afforded the corresponding ozonides.
Cyclocondensation of 4ꢀfluoroaniline with formaldehyde and cyclopentadiene gave earlier
unknown 2ꢀfluoroꢀ3b,6,6a,7,9,9a,10,12aꢀoctahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.
Key words: threeꢀcomponent condensation, aldehydes, anilines, cyclopentadiene, cycloꢀ
penta[c]naphtho[1,2ꢀf]quinolines, ozonolysis, ozonides, 2ꢀfluoroꢀ3b,6,6a,7,9,9a,10,12aꢀ
octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine.
Heterocyclization of electronꢀrich olefins as dienoꢀ
precipitate of compound 4 (86% yield) identical with the
1
12
philes with Nꢀarylimines (the Povarov reaction ) is an
product obtained earlier (Xꢀray diffraction data, Fig. 1).
After separation of the precipitate, we additionally isolatꢀ
ed from the solution a 10 : 1 mixture of compound 4 and
its diastereomer (GCꢀMS data) and determined the inꢀ
tensity ratios of the signals at  7.04 and 7.37 in the
2
efficient route to substituted tetrahydroquinolines. In
3
,4
threeꢀcomponent cyclocondensation of an arylamine
with an aldehyde and an olefin, Nꢀarylimine is formed
in situ as an intermediate undergoing further transformaꢀ
tion into tetrahydroquinoline.5 Cyclocondensation of
arylamines with aromatic aldehydes and cyclopentadiene
,6
1
H NMR spectrum. Both the compounds have the same
+
molecular ion [M] 249.
(
CPD) affords tetrahydroquinolines fused to cyclopentaꢀ
For more complete spectroscopic characterization of
2
,7,8
1
13
diene.
The use of aliphatic aldehydes in the Povarov
compound 4, we recorded its H and C NMR spectra.
The spectra show identical signals in pairs because of
its symmetrical structure: C(1)H and C(3)H, C(3b)H
and C(12a)H, C(4)H and C(12)H, C(5)H and C(11)H,
C(6)H and C(10)H , C(6a)H and C(9a)H, and C(7)H
reaction is limited because selfꢀcondensation of aldehydes
and intermediate arylimines occurs as side processes leadꢀ
ing to byꢀproducts of the Doebner—Miller reaction.
In the present work, we studied cyclocondensation of
aliphatic aldehydes (formaldehyde, acetaldehyde, and proꢀ
panal) with arylamines and CPD (Scheme 1). The resultꢀ
ing tetrahydroquinolines fused to cyclopentene were Nꢀtriꢀ
fluoroacetylated and then transformed into the correꢀ
sponding ozonides, which are of interest as potential antiꢀ
malarial agents.1
2
,9
2
2
2
and C(9)H (Table 1).
2
The
diastereomer
with
the
relative
3bS*,6aR*,9aR*,12aS*ꢀconfiguration of the chiral center
corresponds to symmetrical structure 4 with the antiplanar
arrangement of the cyclopentene rings (Xꢀray diffraction
data, see Fig. 1). Accordingly, the minor diastereomer
with the synplanar of the cyclopentene rings should have
the 3bS*,6aR*,9aS*,12aR*ꢀconfiguration of the chiral
center.
0,11
Addition of a solution of aniline (1) and trifluoroacetic
acid (TFA) in acetonitrile to a mixture of formaldehyde
(
as a 37% aqueous solution) and cyclopentadiene (MeCN,
0
C, 1 : TFA : H CO : CPD = 1 : 1.4 : 5 : 5) has been
Under similar conditions, threeꢀcomponent condenꢀ
sation with 4ꢀcarboxyꢀ (2) and 4ꢀfluoroanilines (3) inꢀ
stead of aniline gave individual crystalline products, nameꢀ
ly, 2ꢀcarboxyꢀ (5) (95% yield) and 2ꢀfluoroꢀsubstituted
pentacyclic compounds (6) (85% yield) (see Scheme 1).
2
1
2
reported to lead to a 3.7 : 1 mixture of two isomeric penꢀ
tacyclic compounds in a total yield of 98%. The major
product isolated by column chromatography on silica gel
was structurally characterized by Xꢀray diffraction.
When carrying out this reaction under the same condiꢀ
tions,12 we observed the abundant formation of a white
1
13
The H and C NMR spectra of compounds 5 and 6 (see
Table 1) look like the spectra of compound 4, which sugꢀ
Dedicated to Academician of the Russian Academy of Sciences
M. P. Egorov on the occasion of his 60th birthday.
Molecular structure 4 determined from Xꢀray diffraction data
is not cited in Ref. 12.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2377—2384, Novemer, 2013.
066ꢀ5285/13/6211ꢀ2377 © 2013 Springer Science+Business Media, Inc.
1

2378
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Tolstikov et al.
Scheme 1
Compound
, 4
, 5
, 6
R
H
Compound
8, 16, 16´, 21
10, 17, 17´, 20
11, 18
R1
F
H
H
H
R2
H
H
Me
Et
1
2
3
CO H
2
F
1
5, 19
1
gests the antiꢀarrangement of the cyclopentene fragments
in their structures. The GCꢀMS profile of fluoride 6 shows
the sole peak ([M]+ 267). The F NMR spectrum of
compound 6 contains the sole singlet for the F atom
the C(2) ( 155.92, J
= 236 Hz), C(1) and C(3)
C—F
2
( 112.73, J
= 21 Hz), and C(3a) and C(12b) atoms
= 6 Hz). The H NMR spectrum shows
C—F
19
3
1
( 128.27, J
C—F
3
a distinct doublet ( J
= 9.2 Hz) due to couplings of
H—F
(
 –126.468). The 13C NMR spectrum shows doublets for
the H(1) and H(3) atoms ( 6.71) with the F atom. The

Lower aldehydes in the Povarov reaction
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2379
Table 1. H and 13C NMR spectra (, J/Hz) of compounds 4—6
1
A group
or an atom
С(1)Н
Compound 4
H
Compound 5
Compound 6
С
С
Н
С
H
126.71
7.04
d, JH(1),H(2) = 8.0)
2.80 (t,
125.37
7.34 (c)
—
112.73
6.71
(
(d, 2J
= 21)
(d, 3JH,F = 9.2)
С,F
—
С(2)Н
С(2)
118.49
—
—
—
JH(2),H(3) = 8.0)
—
117.65
125.37
129.17
146.22
—
155.92
d, 1JС,F = 236)
112.73
—
(
С(3)Н
С(3а)
С(3b)Н
126.71
126.71
146.60
7.04
d, JH(3),H(2) = 8.0)
—
7.34 (c)
—
6.71
(d, 3JH,F = 9.2)
—
(
(d, 2J
= 21)
С,F
128.27
(
d, 3J
= 6)
С,F
46.81
3.99 (br.s)
3.96 (s)
3.91
d, JH(3b),H(6а) = 7.6)
5.79 (m)
(
С(4)Н
С(5)H
С(6)H2
135.86
129.40
137.23
5.86 (br.s)
5.77 (br.s)
2.42
135.81
129.41
137.08
5.84 (s)
5.72 (s)
2.32 (m),
2.65 (m)
135.09
129.86
137.10
5.74 (m)
2.36 (m),
2.70 (m)
(
d, JН(6),Н(6a) = 16),
.69
2
(
dd, JН(6),Н(5) = 6)
С(6a)H
С(7)H2
С(9)Н2
С(9a)Н
С(10)H2
135.88
153.76
153.76
135.88
137.23
2.94 (m)
135.51
152.72
152.72
135.51
137.08
2.99
d, JН(6a),Н(3b) = 6.8)
2.85
(d, JН(7),Н(6a) = 6.8)
2.85
(d, JН(9),Н(9a) = 6.8)
2.99
d, JН(9a),Н(12a) = 6.8)
2.32 (m),
135.84
153.98
153.98
135.84
137.10
2.88 (m)
2.84
(d, JН(7),Н(6a) = 4.0)
2.84
(
2.82
(
d, JН(7),Н(6a) = 10)
2.82
d, JН(9),Н(9a) = 10)
2.94 (m)
(
(d, JН(9),Н(9a) = 4.0)
2.88 (m)
(
2.42
2.36 (m),
2.70 (m)
(
d, JН(10),Н(11) = 16),
.69
2.65 (m)
2
(
dd, JН(10),Н(9a) = 6)
5.77 (br.s)
С(11)Н
С(12)H
С(12a)Н
129.40
135.86
146.60
129.41
135.81
146.22
5.72 (c)
5.84 (c)
3.96 (c)
129.86
135.09
146.81
5.74 (m)
5.79 (m)
3.91
5.86 (br.s)
3.99 (br.s)
(
d, JH(12a),H(9а) = 7.6)
С(12b)
126.71
—
129.17
—
128.27
—
(
d, 3J
= 6)
С,F
С(13)
СООН
145.11
—
—
—
149.97
172.77
—
—
—
—
—
11.62 (br.s)
3
coupling constant ( J = 7.6 Hz) for the H(3b) and
H(6a) protons, as well as for the H(9a) and H(12a) proꢀ
tons, is characteristic of their cisꢀarrangement in the
above pairs.
C(1)
C(2)
C(3)
C(12b)
After the separation of the crystals of compound 6,
a mixture of products was additionally isolated from the
C(3a)
C(13)
N(8)
1
C(12)
C(11)
C(3b)
mother liquor. The H NMR spectrum of the mixture
C(12a)
C(9a)
C(4)
C(5)
shows both unidentified signals and those due to comꢀ
pound 6 and its diastereomer with the synꢀoriented cycloꢀ
pentene fragment. According to the intensity ratio of the
total signals at  6.74 and 6.93 for H(1) and H(3), the ratio
of the diastereomers in the mother liquor is ~1 : 2.
Therefore, the threeꢀcomponent condensation of both
aniline and its 4ꢀsubstituted analog in the presence of exꢀ
cess CPD and formaldehyde yields products containing
two fused cyclopentene molecules.
C(6a)
C(9)
C(10)
C(7)
C(6)
*
*
*
*
Fig. 1. Molecular structure of (3bS ,6aR ,9aR ,12aS )ꢀ
b,6,6a,7,9,9a,10,12aꢀoctahydrobenzo[i,j]dicyclopenta[b,g]ꢀ
3
quinolizine (4) in the crystal.

2380
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Tolstikov et al.
Table 2. H and 13C NMR spectra (, J/Hz) of compounds 8, 10, 11, and 15
1
An atom or
a group
Compound 8
H
Compound 10
Н
Compound 11
Н
Compound 15
С Н
С
С
С
С(1)Н
С(2)Н
С(3)Н2
128.94
5.78 (d,
JH(1),H(2) = 3.0)
5.88 (d,
JH(2),H(1) = 3.0)
2.26 (m),
128.68
5.85, (br.s)
130.11
5.75 (br.s)
130.22 5.91 (m)
134.64 5.78 (br.s)
135.49
137.16
136.07
137.43
5.99 (m)
2.31 (d,
134.47
31.03
5.85 (d,
JH(2),H(1) = 2.8)
2.29 (d,
JН(3),Н(2) = 8.8),
2.59 (m)
130.87 2.30 (m),
2.60 (m)
2
.75 (m)
JH(3),H(2) = 16),
.86 (m)
2
С(3а)Н
С(4)Н2
135.95
143.93
2.89 (m)
3.21 (dd,
JH(4),H(9b) = 4,
JH(4),H(3а) = 10)
136.26
144.83
2.85 (m)
44.16
48.83
2.82 (m)
3.58 (d,
JН(4),Н(3a) = 2.8)
142.23 2.94 (m)
155.30 3.33 (m)
3.18 (dd,
JH(4),H(9b) = 4,
JH(4),H(3а) = 10),
2.96 (t,
2
.93 (s)
JH(4),H(3а) = 10)
—
—
С(5а)
С(6)
135.51
—
—
146.18
—
145.76
1—
1—
1—
145.71
1—
—
—
151.25,
1
(
JСF = 237)
С(6)H
С(7)H
С(8)H
С(9)Н
—
—
115.33
126.45
118.37
129.77
6.68 (d,
JН(6),Н(7) = 8.0)
7.14 (t,
JН(6),Н(7) = 8.0)
6.89 (t,
JН(6),Н(7) = 8.0)
7.31 (d,
115.35
126.16
118.70
128.24
6.57 (d,
JН(6),Н(7) = 8.0)
6.98 (t,
JН(9),Н(7) = 7.6)
6.73 (t,
JН(6),Н(8) = 7.2)
7.04 (d,
115.48 6.98 (br.s)
126.22 7.08 (br.s)
118.80 7.04 (br.s)
129.50 7.27 (br.s)
111.80
117.06
124.67
6.89 (t,
JН(6),Н(7) = 8.0)
6.70 (m)
7.02 (d,
JН(9),Н(8) = 7.6)
—
3.98 (d,
JН(9),Н(8) = 8.0)
—
4.05 (br.s)
JН(9),Н(8) = 7.6)
—
4.02 (d,
С(9a)
С(9b)H
127.24
145.70
125.03
146.19
126.23
146.33
128.95
146.41 4.05 (d,
JН(9b),Н(1) = 8.4)
110.66 1.08 (t,
JН(10),Н(11) = 7.6)
—
JН(9b),Н(1) = 8.4)
—
JН(9b),Н(1) = 8.4)
1.24 (d,
JН(10),Н(4) = 6.4),
С(10)Н3
1—
1—
—
119.97
1
.30 (d,
JН(10),Н(4) = 5.2)
—
3.42 (br.s)
С(11)H2
NH
1—
1—
—
1—
1—
—
1—
1—
127.03 1.63 (m)
1— 3.56 (br.s)
4.11 (br.s)
3.81 (br.s)
It should be expected that orthoꢀsubstituted aniline will
form no pentacyclic compound in threeꢀcomponent conꢀ
densation. Indeed, the use of 2ꢀfluoroaniline 7 leads to
mixture—probably with isomeric compound 12´ (see
Schemes 1 and 2)—with m/z 213 [M]+ for both), and
compound 13 (a nearly equivalent mixture of three diasteꢀ
reomeric pentacyclic condensation products with m/z 277
6
ꢀfluorotetrahydrocyclopenta[c]quinoline 8 in 86% yield.
1
13
+
Its H and C NMR spectra (Table 2) are similar to those
of substituted tetrahydroquinolines obtained earlier. The
MALDIꢀTOF mass spectrum contains the molecular ion
[M] for each).
7,8
Individual tetrahydroquinoline 11 was obtained in 30%
yield by addition of a solution of CPD and acetaldehyde
to a solution of amine 1 and TFA (MeCN, 0 C,
CPD : MeCHO : 1 : TFA = 3 : 1 : 1 : 1; see Scheme 1).
Under the conditions of the synthesis of pentacyclic
compound 4 with propanal instead of formaldehyde, the
reaction gave 2ꢀethylꢀ3ꢀmethylquinoline (14) in 23% yield
+
peak [M] 189.
Tetrahydroquinoline 10 (90% yield; according to the
+
GCꢀMS data, [M] = 171) was obtained by the Povarov
1
reaction of phenylimine 9 with CPD. The H and
1
3
C NMR spectra of compound 10 (see Table 2) are typiꢀ
7
,8
1
13
cal of tetrahydroquinolines.
as the sole product (see Scheme 1); the H and C NMR
1
3
In contrast to the condensation of aniline and CPD
with formaldehyde, the use of acetaldehyde results in inꢀ
tense resinification of the reaction mixture. The reaction
products (see Scheme 1) were separated by column chroꢀ
spectra are identical with the literature data. Since CPD
remained inert, the reaction followed the Doebner—Millꢀ
1
4
er rather than Povarov pattern, with the aldol selfꢀconꢀ
densation product of propanal as a conjugated unsaturatꢀ
ed aldehyde. Tetrahydroquinoline 15 was obtained by
gradual addition of a solution of propanal in MeCN to
a mixture of amine 1 and CPD, to avoid as far as possible
the selfꢀcondensation of the aldehyde.5
matography on SiO . Using the GCꢀMS technique, we
2
identified compound 11 (the product of the Povarov reacꢀ
+
tion, m/z 185 [M] ), compound 12 (the product of further
condensation of compound 11 with MeCHO; it is a ~1 : 2

Lower aldehydes in the Povarov reaction
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2381
Table 3. H and 13C NMR spectra (, J/Hz) of compounds 16—19
1
An atom or
a group
Compound 16
Compound 17
Compound 18
Compound 19
С
H
С
Н
С
Н
С
Н
С(1)Н
С(2)Н
132.41
132.41
5.81 (br.s)
5.81 (br.s)
129.38
133.10
5.78 (m)
5.78 (m)
133.11
133.11
5.83 (br.s)
5.94 (d,
130.80
132.32
5.92 (br.s)
5.82 (br.s)
JH(2),H(1) = 2.8)
2.28 (br.s),
2.32 (m)
С(3)Н2
С(3а)Н
36.68
37.65
2.24 (br.s),
37.16
36.68
2.21 (m), 2.80
(d, JH(2),H(1) = 8)
2.96 (m)
36.16
50.19
35.83
44.92
3.20 (m)
2.34 (m),
2
.81 (br.s)
3.01 (br.s)
2.79, (br.s)
2
.85 (m)
С(4)Н2
С(5а)
С(6)
48.49
4.15 (m)
—
—
48.00
136.85
—
3.91 (m)
—
—
52.18
132.24
—
4.35, (br.s)
—
—
58.31
133.16
—
4. 83 (br.s)
—
—
130.50
155.38
(
1JCF = 256)
С(6)H
С(7)H
—
113.75
—
7.02 (t,
124.35
126.61
7.25 (m)
7.25 (m)
120.57
126.14
7.25 (br.s)
7.27 (br.s)
120.59
126.67
7.34 (br.s)
7.34 (br.s)
JН(9),Н(8) = 9.2)
7.26 (m)
7.15 (d,
С(8)H
С(9)Н
128.09
124.02
125.95
129.05
7.25 (m)
7.36 (d,
126.20
129.27
7.37 (br.s)
7.41 (d,
128.06
130.08
7.41, (br.s)
7.62 (d,
JН(9),Н(8) = 6.4)
—
4.15 (m)
JН(9),Н(8) = 6.8)
—
4.08 (d,
JН(9),Н(8) = 6.8)
—
4.04 (br.s)
JН(9),Н(8) = 7.2)
—
4.06 (br.s)
С(9a)
С(9b)H
130.50
46.52
132.54
46.53
132.24
44.56
132.32
45.28
JН(9b),Н(3a) = 7.2)
—
С(10)Н3
С(11)H2
—
—
—
17.58
1.23 (t,
JН(10),Н(9 = 7.2),
10.12
19.28
0.78 (t,
JН(10),Н(9) = 7.2)
1
.33 (br.s)
—
—
—
—
—
—
—
—
1.23 (m),
1
.40 (br.s)
CF C=O
155.00
155.46
154.01
—
154.90
—
3
(
q, C=O,
(q, C=O,
JC,F = 38)
(q, C=O,
JC,F = 38)
(q, C=O,
JC,F = 38)
2
2
2
2
JC,F = 38)
1
14.84
116.70
116.50
116.63
(
q,CF3,
(q, CF ,
JC,F = 289)
(q, CF ,
JC,F = 289)
(q, CF ,
JC,F = 289)
3
3
3
1
1
1
1
JC,F = 289)
According to the accepted mechanism, the threeꢀcomꢀ
ponent Povarov reaction involves in situ formation of Nꢀ
arylimine, which reacts with CPD in the azaꢀDiels—Alꢀ
der reaction leading diastereoselectively to an endo,cisꢀ
ring (as in 12´), the former cyclization pathway seeming
to be preferred.
Tetrahydroquinolines 8, 10, 11, and 15 were transꢀ
formed into the corresponding trifluoroacetamides 16—19
(see Scheme 1). Trifluoroacetylation of oily compound 10
gave crystalline trifluoroacetamide 17. Its structure became
clear from Xꢀray diffraction data (Fig. 2): the carbonyl group
in the crystal of compound 17 is oriented toward the aromatic
ring. This conformer (produced by rotation of the COCF3
group about the N—C bond) is predominant in solution as
2
,9
annulation product (substituted tetrahydroquinoline)
Scheme 2). The secondary amino group of the resulting
(
tetrahydroquinoline (A) can interact with an electrophilic
center of the protonated aldehyde to give the ammonium
cation B, which eliminates a water molecule to produce
the carbenium ion C. Its further transformations can probꢀ
ably follow two pathways. An interaction with the double
bond of CPD (much like that in the Prins reaction) gives
the carbenium cation D. Subsequent electrophilic aroꢀ
matic substitution of the H atom that is ortho to the N
atom leads to the corresponding pentacyclic compound E
1
9
well. The F NMR spectrum shows signals at  –68.55
and –66.02 for the fluorine atoms in the CF group. It
3
follows from their relative intensities that the ratio of the
rotamers in compound 17 is ~75 : 25. In rotamer 17´, in
which the trifluoromethyl group is oriented toward the
(
it is most characteristic when formaldehyde is used).
aromatic ring, the fluorine atoms of the CF group are
3
Alternatively, the carbenium ion C can be transformed in
the presence of acetaldehyde. This pathway involves posꢀ
sible reversible hydride migration15 leading to the isomeric
carbenium ion F. Subsequent electrophilic substitution at
the orthoꢀposition relative to the N atom can probably
involve both the carbenium ions F and C. This gives rise to
either a fiveꢀ (as in 12) or fourꢀmembered Nꢀcontaining
deshielded by the aromatic ring and thus resonate in the
lower field ( –66.02). In trifluoroacetamide 16, a stabiꢀ
lizing intramolecular interaction of the oꢀF atom with the
carbonyl group increases the percentage of the major rotaꢀ
mer up to 80%. This is evident from the signal intensity
ratio for the fluorine atoms of the CF group ( –69.21
3
and –70.67) or from that for the aromatic F atom

2382
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Tolstikov et al.
Scheme 2
R = H, Me
(
 –113.51 and –125.36) in conformers 16 and 16´, reꢀ
spectra of compounds 16, 18, and 19 are similar to those
of trifluoroacetamide 17, one can conclude that they all
have the relative 3aR*,9bS*ꢀconfiguration. Compounds
11, 15, 18, and 19 acquire an additional chiral center on
the C(4) atom. Inasmuch as the proton at this atom is cis
to the HC(3a) and HC(9b) protons, the relative configuꢀ
ration of the chiral atoms in compounds 11, 15, 18, and
19 is 3aR*,4R*,9bS*. The MALDIꢀTOF mass spectra of
compounds 8, 10, 11, and 15 and trifluoroacetamides 16—19
contain the corresponding molecular ion peaks. Ozonizaꢀ
tion of compounds 16 and 17 in CH Cl at 0 C occurs at
spectively (see Scheme 1).
The cisꢀorientation of the vicinal protons at the chiral
C(3a) and C(9b) atoms in compounds 10 and 17 is sugꢀ
gested by their low coupling constant (the signal for H(9b)
1
in the H NMR spectrum of compound 10 appears as
a broadened singlet at  4.05, while the spectrum of comꢀ
pound 17 shows a doublet at  4.08 (J9b,3a = 7.2 Hz)).
Thus, the relative configuration of the chiral C(3a) and
C(9b) atoms formed in compounds 10 and 17 upon the
1
cyclocondensation is 3aR*,9bS*. The signals in the H
2
2
and 1 C NMR spectra of compounds 10 and 17 were asꢀ
signed using 1D and 2D correlation experiments (see
Tables 2 and 3).
3
the C(1)—C(2) bond, yielding ozonides 20 and 21, respecꢀ
tively. The presence of the 1,2,4ꢀtrioxolane ring in these
ozonides is evident from narrow signals at  100.4—103.8
Since the H and 13C NMR spectra of compounds 8,
1
in their C NMR spectra (this range is characteristic of
13
7
,8,16
1
1, and 15 are similar to those of compounds 10 and the
ozonides
): these are the signals for the C(1) and C(4)
atoms rather than the signals for the C(1) and C(2) atoms
in the spectra of the starting trifluoroacetamides 17 and 16
C(8)
(
 129.4—136.9).
The similarity of the H and C NMR spectra of ozoꢀ
1
13
C(9)
C(7)
C(6)
8
nides 17 and 16 with those of documented ozonides sugꢀ
gests the identical relative configuration of their chiral
centers (1R*,4S*,5aR*,11bR*).
C(9a)
C(5a)
O
Experimental
C(9b)
C(3a)
C(1)
C(2)
N(5)
C(13)
1H and 13C NMR spectra were recorded on Bruker Avance
1
13
400 spectrometers (400.13 ( H) and 100.62 MHz ( C)) in CDCl
3
C(4)
C(14)
with Me Si as the internal standard. Homoꢀ and heteronuclear
4
experiments (COSY, HSQC, and HMBC) were performed acꢀ
cording to the Bruker standard procedures. Mass spectra were
measured on a Bruker Autoflex III spectrometer (MALDIꢀTOF
mode, positive ion detection, ꢀcyanoꢀ4ꢀhydroxycinnamic acid
(HCCA) matrix). GCꢀMS spectra were recorded on a Shimadzu
GC 2010 chromatograph equipped with a GCMSꢀQP2010 Ultra
C(3)
F
F
F
*
*
Fig. 2. Molecular structure of (3aR ,9bS )ꢀ5ꢀtrifluoroacetylꢀ
a,4,5,9bꢀtetrahydroꢀ3Hꢀcyclopenta[c]quinoline (17) in the
crystal.
3

Lower aldehydes in the Povarov reaction
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013 2383
MS detector (Shimadzu, Japan). The GCꢀMS facilities and settings
were as follows: ionizing energy 70 eV, ion source temperature
R 0.64 (hexane—ethyl acetate, 3 : 1), m.p. 94—96 C (from hexane).
MS, m/z (I (%)): 267 [M] (100). Found (%): C, 80.97; H, 6.93;
f
+
2
00 C, Supelco 5ms capillary column (60 m×0.25 mm×0.25 m),
N, 5.01. C H FN. Calculated (%): C, 80.90; H, 6.74; N, 5.24.
18
18
*
–1
*
helium as a carrier gas (10.8 mL min ), analysis duration 43 min.
Primary data were processed with the GCMSsolution program.
The products were identified by mass spectrometry. Melting
points were determined on a Boetiusꢀtype small hot stage. Eleꢀ
mental analysis was carried out on a Carlo Erba EAꢀ1108 CHNSꢀO
analyzer. For column chromatography, silica gel (KSKG grade,
(3aS ,9bS )ꢀ6ꢀFluoroꢀ3a,4,5,9bꢀtetrahydroꢀ3Hꢀcyclopentaꢀ
[c]quinoline (8). Freshly distilled CPD (0.25 mL, 3 mmol) and
37% aqueous formaldehyde (1 mL, 1.2 mmol) were successively
added at 0 C to a stirred (Ar) solution of 2ꢀfluoroaniline 7 (0.097 mL,
1 mmol) and TFA (0.08 mL, 1 mmol) in dry acetonitrile (30 mL).
The reaction mixture was stirred until the starting arylamine
was consumed completely (3—4 h, monitoring by TLC, hexꢀ
ane—ethyl acetate (3 : 1)) and neutralized with a saturated soluꢀ
1
00/200) was used. The course of the reactions was monitored by
TLC on SiO plates (Silufol); spots were visualized with a soluꢀ
2
tion of vanillin in ethanol acidified with H SO . Xꢀray diffracꢀ
tion of NaHCO (~5 mL). The solvent was removed, and organꢀ
2
4
3
tion studies of compounds 4 and 17 were performed on a Bruker
ic materials were extracted with ethyl acetate (20 mL). The exꢀ
Smart 1000 CCD diffractometer (graphite monochromator,
tract was dried with MgSO and concentrated. The residue was
4

= 0.71073 Å,  scan mode, 2 = 54). The crystals of 4 (C H N,
separated by column chromatography on SiO2 with hexane—
18
19
M = 249.34) grown in EtOAc—CHCl (1 : 1) are monoclinic; at
ethyl acetate (50 : 1) as an eluent. The yield of compound 8 was
3
1
00(2) K, a = 8.7409(7) Å, b = 17.9702(15) Å, c = 8.9818(8) Å,
0.16 g (86%), colorless viscous liquid, R 0.63 (hexane—ethyl
acetate, 3 : 1). MS (MALDIꢀTOF), m/z (I (%)): 189.229 [M] .
f
3
+

= 111.944(2), V = 1308.61(19) Å , space group P2(1)/n, Z = 4,
calc = 1.266 g cm–3, (MoK) = 0.073 mm . The colorless
–1
Found (%): C, 76.80; H, 6.73; N, 7.20. C H FN. Calculated (%):
12
12
crystals of 17 (C H F NO, M = 267.25) grown in EtOAc—
C, 76.19; H, 6.35; N, 7.41.
14
12 3
*
*
CHCl (1 : 1) are orthorhombic; at 120(2) K, a = 5.1174(6) Å,
(3aS ,9bS )ꢀ3a,4,5,9bꢀTetrahydroꢀ3Hꢀcyclopenta[c]quinolꢀ
ine (10). Aniline (0.27 mL, 3 mmol) was added at room temperꢀ
ature to a stirred 37% aqueous solution of formaldehyde (0.24 mL,
3 mmol). The reaction mixture was kept for 1 h. The precipitate
that formed was filtered off and washed with water. The yield of
3
3
b = 14.3064(15) Å, c = 16.0124(17) Å,  = 90.0, V = 1172.3(2) Å ,
space group P2(1)/n, Z = 4, 
0.128 mm . The structures were solved by the direct methods
= 1.514 g cm–3, (MoK) =
calc
–
1
=
and refined anisotropically (for all the nonꢀhydrogen atoms) by the
fullꢀmatrix leastꢀsquares method on F2hkl. The final R factors are
intermediate 9 was 0.22 g, R 0.61 (hexane—ethyl acetate, 5 : 1),
f
wR = 0.1199 and COOF = 1.007 for all unique reflections (refineꢀ
m.p. 194—196 C (from hexane). Compound 9 was dissolved in
dry acetonitrile (30 mL). Then freshly distilled CPD (0.65 mL,
8 mmol), TFA (1.0 mL, 13 mmol), and molecular sieves A4 (2 g)
were added. The reaction mixture was stirred (Ar) at room temꢀ
perature for 18 h (monitoring by TLC, hexane—ethyl acetate
(3 : 1)), concentrated, and neutralized with a saturated solution
of NaHCO3 (~5 mL). Organic materials were extracted with
ethyl acetate (3×15 mL). The extract was concentrated, and the
2
ment on Fhkl gives R = 0.0460 for 2148 measured reflections
1
with I > 2(I)). All PCꢀassisted calculations were performed with
the SHELXTL program package.14 The CIF files containing
comprehensive data on the structures studied have been deposited
with the Cambridge Structural Database (Nos 936640 (4) and
9
36639 (17)) and can be retrieved free of charge from www.ccdc.
1
13
cam.ac.uk/data_request/cif. The H and C NMR spectra of comꢀ
1
13
pounds 4—6 are given in Table 1. The H and C NMR spectra
of compounds 8, 10, 11, and 15—19 are given in Tables 2 and 3.
Synthesis of 3b,6,6a,7,9,9a,10,12aꢀoctahydrobenzo[i,j]diꢀ
cyclopenta[b,g]quinolizines (4—6) (general procedure). A soluꢀ
tion of appropriate arylamine 1—3 (1.4 mmol) and trifluoroacetic
acid (0.08 mL, 1 mmol) in dry acetonitrile (10 mL) was added at
residue was separated by column chromatography on SiO with
2
hexane—ethyl acetate (40 : 1) as an eluent. The yield of comꢀ
pound 10 was 0.26 g (83% with respect to the starting amine 1),
amorphous solid, R 0.50 (hexane—ethyl acetate, 1 : 1). MS, m/z
f
+
(I (%)): 171 [M] (80).
*
*
*
(3aR ,4R ,9bS )ꢀ4ꢀMethylꢀ3a,4,5,9bꢀtetrahydroꢀ3Hꢀcycloꢀ
penta[c]quinoline (11). Trifluoroacetic acid (0.308 mL, 4 mmol)
was added to a stirred solution of amine 1 (0.364 mL, 4 mmol) in
dry acetonitrile (50 mL). After 3 min, freshly distilled CPD
(0.99 mL, 12 mmol) and acetaldehyde (0.224 mL, 4 mmol) in
MeCN (10 mL) were added at 0 C. The reaction mixture was
stirred (Ar) until the starting amine was consumed completely
(3—4 h, monitoring by TLC, hexane—ethyl acetate (3 : 1)), neuꢀ
tralized with a saturated solution of NaHCO3 (~5 mL), and
concentrated. Organic materials were extracted with ethyl aceꢀ
0
(
5
C to a stirred (Ar) mixture of freshly distilled cyclopentadiene
0.410 mL, 5 mmol) and 37% aqueous formaldehyde (0.415 mL,
mmol). The reaction mixture was stirred for 1 h. The white preꢀ
cipitate that formed was filtered off and washed on the filter with
ethanol (2×5 mL) to give the corresponding compounds 4—6. The
filtrate was concentrated, and the residue was separated by column
chromatography on SiO with hexane—ethyl acetate (10 : 1) as an
2
eluent. This gave an additional crop (0.03 g) of compound 4 as
a 10 : 1 mixture with its diastereomer and an additional crop
(
0.025 g) of compound 6 as a 10 : 1 mixture with its diastereomer.
tate. The extract was dried with MgSO and concentrated. The
4
*
*
*
*
(
3bS ,6aR ,9aR ,12aS )ꢀ3b,6,6a,7,9,9a,10,12aꢀOctahydroꢀ
residue was separated by column chromatography on SiO with
2
benzo[i,j]dicyclopenta[b,g]quinolizine (4). Yield 86%, R 0.70
hexane—ethyl acetate (50 : 1) as an eluent. The yield of comꢀ
f
1
2
(
hexane—ethyl acetate, 3 : 1), m.p. 95—96 C (from hexane).
pound 11 was 0.3 g (30%), amorphous solid, R 0.68 (hexꢀ
f
+
+
MS, m/z (I (%)): 249 [M] (100).
ane—ethyl acetate, 3 : 1). MS, m/z (I (%)): 185 [M] (90).
*
*
*
*
*
*
*
(
3bS ,6aR ,9aR ,12aS )ꢀ3b,6,6a,7,9,9a,10,12aꢀOctahydroꢀ
benzo[i,j]dicyclopenta[b,g]quinolizineꢀ2ꢀcarboxylic acid (5). Yield
5%, R 0.52 (hexane—ethyl acetate, 1 : 1), m.p. 190—195 C
(3aR ,4R ,9bS )ꢀ4ꢀEthylꢀ3a,4,5,9bꢀtetrahydroꢀ3Hꢀcycloꢀ
penta[c]quinoline (15). Trifluoroacetic acid (0.308 mL, 4 mmol)
was added to a stirred (Ar) solution of amine 1 (0.364 mL,
4 mmol) in dry acetonitrile (25 mL). After 3 min, freshly distilled
CPD (0.99 mL, 12 mmol) was added at 0 C, whereupon a soluꢀ
tion of propanal (0.284 mL, 6 mmol) in MeCN (10 mL) was
added dropwise at room temperature for 4 h. The reaction mixture
9
f
(
from hexane). MS (MALDIꢀTOF), m/z (I (%)): 292.370
+
[
M – H] . Found (%): C, 77.96; H, 6.09; N, 4.82. C H NO .
19
18
2
Calculated (%): C, 78.08; H, 6.16; N, 4.79.
*
*
*
*
(
3bS ,6aR ,9aR ,12aS )ꢀ2ꢀFluoroꢀ3b,6,6a,7,9,9a,10,12aꢀ
octahydrobenzo[i,j]dicyclopenta[b,g]quinolizine (6). Yield 85%,
was neutralized with a saturated solution of NaHCO (~5 mL)
3

2384
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 11, November, 2013
Tolstikov et al.
and concentrated. Organic materials were extracted with ethyl
(0.3 g, 1.05 mmol) in dry CH Cl2 (10 mL) until the starting
2
acetate. The extract was dried with MgSO and concentrated.
The residue was separated by column chromatography on SiO2
with hexane—ethyl acetate (50 : 1) as an eluent. The yield of
compound was consumed completely (~3 min, monitoring by
TLC). The reaction mixture was purged with argon and evapoꢀ
rated to dryness. Ozonide 21 was isolated from the residue by
column chromatography on SiO with CHCl as an eluent. Yield
4
compound 15 was 0.14 g (17%), amorphous solid, R 0.48 (hexꢀ
f
2
3
+
ane—ethyl acetate, 3 : 1). MS, m/z (I (%)): 199 [M] (100).
0.2 g (60%), R 0.55 (CHCl —MeOH, 20 : 1), m.p. 56—58 C
f 3
Synthesis of Nꢀtrifluoroacetylꢀ3a,4,5,9bꢀtetrahydroꢀ3Hꢀ
cyclopenta[c]quinolines (16—19) (general procedure). Trifluoroꢀ
(from hexane). Found (%): C, 50.46; H, 3.33; F, 22.80; N, 4.20.
C H F NO . Calculated (%): C, 50.70; H, 3.60; F, 22.41;
14
11
4
1
4
acetic anhydride (0.21 mL, 1.5 mmol), Et N (0.20 mL, 1.5 mmol),
N, 4.80. H NMR (CDCl ), : 1.96 and 2.35 (both m, 2 H, H(5));
3
3
and DMAP (2 mg) were added to a solution of an appropriate
2.50 (m, 1 H, H(5a)); 3.42 (d, 1 H, H(11b), J = 6.4 Hz); 3.60 and
3.93 (both m, 2 H, H(6)); 5.86 (s, 1 H, H(4)); 6.27 (s, 1 H, H(1));
7.07 (d, 1 H, H(9), J = 5.7 Hz); 7.28 (d, 1 H, H(11), J = 7.6 Hz);
compound (8, 10, 11, or 15) (1 mmol) in CH Cl (1 mL). The
2
2
reaction mixture was stirred (Ar) at room temperature for 10—60 min
until the starting compound was consumed completely (moniꢀ
toring by TLC, hexane—ethyl acetate (3 : 1)) and concentrated.
The corresponding trifluoroacetamide (16—19) was isolated by
column chromatography on SiO2 with hexane—ethyl acetate
13
7.35 (m, 1 H, H(10)). C NMR (CDCl ), : 31.20 (C(5a));
3
31.94 (C(5)); 39.68 (C(11b)); 48.69 (C(6)); 100.51 (C(4)); 103.59
(C(1)); 114.84 (C(8)); 114.98 (C(9)); 117.71 (CF , J
= 286 Hz);
3
C—F
123.82 (C(11)); 125.29 (C(7a)); 128.41 (C(10)); 128.64 (C(9));
(
10 : 1) as an eluent.
156.72 (COCF ).
3
*
*
(
3aR ,9bS )ꢀ6ꢀFluoroꢀ5ꢀtrifluoroacetylꢀ3a,4,5,9bꢀtetrahydroꢀ
3
Hꢀcyclopenta[c]quinoline (16). Yield 98%, Rf 0.48 (hexꢀ
This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program "Basic Sciꢀ
ences to Medicine").
ane—ethyl acetate, 3 : 1), m.p. 71—72 C (from hexane). MS
+
(
MALDIꢀTOF), m/z (I (%)): 285 [M] . Found (%): C, 59.10;
H, 4.02; N, 4.85. C H F NO. Calculated (%): C, 58.95;
1
4
11 4
H, 3.86; N, 4.91.
References
*
*
(
3aR ,9bS )ꢀ5ꢀTrifluoroacetylꢀ3a,4,5,9bꢀtetrahydroꢀ3Hꢀ
cyclopenta[c]quinoline (17). Yield 86%, R 0.49 (hexane—ethyl
acetate, 3 : 1), m.p. 68—70 C (from hexane). Found (%): C, 62.70;
f
1
2
. L. S. Povarov, Russ. Chem. Rev. (Engl. Transl.), 1967, 36,
56 [Usp. Khim., 1967, 36, 1533].
. V. A. Glushkov, A. G. Tolstikov, Russ. Chem. Rev. (Engl.
Transl.), 2008, 77 (2), 137—159 [Usp. Khim., 2008, 77, 138].
. A. Dumling, I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168.
. A. Nefzi, J. M. Ostresh, R. A. Houghten, Chem. Rev., 1997,
6
H, 4.23; N, 5.08. C H F NO. Calculated (%): C, 62.92;
1
4
12 3
H, 4.49; N, 5.24.
*
*
*
(
3aR ,4R ,9bS )ꢀ4ꢀMethylꢀ5ꢀtrifluoroacetylꢀ3a,4,5,9bꢀtetraꢀ
3
4
hydroꢀ3Hꢀcyclopenta[c]quinoline (18). Yield 74%, R 0.69 (hexꢀ
f
ane—ethyl acetate, 3 : 1). MS (MALDIꢀTOF), m/z (I (%)):
9
7, 449.
+
2
81.273 [M] . Found (%): C, 63.98; H, 4.82; N, 4.81. C H F NO.
15
14 3
5. S. Kobayashi, H. Ishitani, S. Nagayama, Synthesis, 1995, 1195.
6. J. M. Mellor, G. D. Merriman, Tetrahedron, 1995, 51, 6115.
7. A. G. Tolstikov, L. M. Khalilov, R. G. Savchenko, D. V.
Nedopekin, V. A. Glushkov, G. F. Krainova, I. V. Glukhov,
M. Yu. Antipin, V. N. Odinokov, Russ. Chem. Bull. (Int. Ed.),
Calculated (%): C, 64.05; H, 4.98; N, 4.98.
*
*
*
(
3aR ,4R ,9bS )ꢀ4ꢀEthylꢀ5ꢀtrifluoroacetylꢀ3a,4,5,9bꢀtetraꢀ
hydroꢀ3Hꢀcyclopenta[c]quinoline (19). Yield 70%, R 0.63 (hexꢀ
f
ane—ethyl acetate, 3 : 1). MS (MALDIꢀTOF), m/z (I (%)):
+
2
95.300 [M] . Found (%): C, 65.29; H, 5.37; N, 4.85. C H F NO.
16
16 3
2
009, 58, 1991 [Izv. Akad. Nauk, Ser. Khim., 2009, 1929].
Calculated (%): C, 65.08; H, 5.42; N, 4.74.
8
. A. G. Tolstikov, G. Savchenko, D. V. Nedopekin, S. R.
Afon´kina, E. S. Lukina, V. N. Odinokov, Russ. Chem. Bull.
*
*
(
1R*,4S*,5aR ,11bR )ꢀ1,4ꢀEpoxyꢀ7ꢀtrifluoroacetylꢀ4,5,5a,
6
,7,11bꢀhexahydroꢀ1Hꢀ[1,2]dioxepino[5,4ꢀc]quinoline (20). An
(Int. Ed.), 2011, 60, 160 [Izv. Akad. Nauk, Ser. Khim., 2011, 153].
ozone—oxygen mixture produced by an ozonizer (30 mmol of
9
. D. A. Powell, R. A. Batey, Tetrahedron Lett., 2003, 44, 7569.
O /h) was bubbled at 0 C through a solution of compound 17
3
1
1
0. G. A. Tolstikov, A. G. Tolstikov, O. V. Tolstikova, Russ.
Chem. Rev. (Engl. Transl.), 1996, 65 [Usp. Khim., 1996, 65, 836].
1. Y. Tang, Y. Dong, S. Wittlin, S. A. Charman, J. Chollet, F. C. K.
Chiu, W. N. Charman, H. Matile, H. Urwyler, A. Dorn,
S. Bajpai, X. Wang, M. Padmanilayam, J. M. Karle, R. Brun,
J. L. Vennerstrom, Bioorg. Med. Chem. Lett., 2007, 17, 1260.
2. P. A. Grieco, A. Bahsas, Tetrahedron Lett., 1988, 29, 5855.
3. Y. Watanabe, S. C. Shim, T. Mitsudo, Bull. Chem. Soc. Jpn,
(
0.5 g, 1.87 mmol) in dry CH Cl2 (10 mL) until the starting
2
compound was consumed completely (~3 min, monitoring by
TLC). The reaction mixture was purged with argon and evapoꢀ
rated to dryness. Ozonide 20 was isolated from the residue by
column chromatography on SiO with CHCl as an eluent. Yield
2
3
0
.4 g (68%), R 0.54 (CHCl ), m.p. 58—60 C (from hexane).
f 3
1
1
Found (%): C, 53.34; H, 3.84; F, 18.08; N, 4.44. C H F NO .
1
4
12
3
4
1
Calculated (%): C, 53.60; H, 3.20; F, 18.00; N, 4.86. H NMR
1
981, 54, 3460.
(
CDCl ), : 1.94 and 2.36 (both m, 2 H, H(5)); 2.55 (m, 1 H,
3
1
1
1
4. K. V. Vatsuro, G. L. Mishchenko, Imennye reaktsii v organꢀ
icheskoi khimii [Named Organic Reactions], Khimiya, Mosꢀ
cow, 1976, 528 pp. (in Russian).
5. D. N. Kursanov, Z. N. Perness, M. I. Kalinkin, N. M. Loim,
Ionnoe gidrirovanie [Ionic Hydrogenation], Khimiya, Mosꢀ
cow, 1979, 192 pp. (in Russian).
H(5a)); 3.31 (d, 1 H, H(11b), J = 3.6 Hz); 3.64 and 3.94 (both m,
H, H(6)); 5.86 (s, 1 H, H(4)); 6.23 (s, 1 H, H(1)); 7.36 (m, 1 H,
H(9)); 7.37 (m, 1 H, H(10)); 7.55 (m, 1 H, H(11)); 7.81 (m,
2
13
H(8)). C NMR (CDCl ), : 30.07 (C(5a)); 32.11 (C(5)); 39.97
3
(
(
(
C(11b)); 48.36 (C(6)); 100.59 (C(4)); 102.74 (C(1)); 115.14
CF , J = 287 Hz); 124.47 (C(8)); 127.33 (C(11)); 127.77
3
C—F
6. Sh. Kawamura, R. Takeuchi, A. Masuyama, M. Nojima,
K. J. McCullough, J. Org. Chem., 1998, 63, 5617.
C(10)); 128.64 (C(9)), 137.43 (C(7a)); 156.14 (COCF ).
3
*
*
(
1R*,4S*,5aR ,11bR )ꢀ1,4ꢀEpoxyꢀ8ꢀfluoroꢀ7ꢀtrifluoroacetꢀ
ylꢀ4,5,5a,6,7,11bꢀhexahydroꢀ1Hꢀ[1,2]dioxepino[5,4ꢀc]quinoline
21). An ozone—oxygen mixture (ozonizer output 30 mmol of
O /h) was bubbled at 0 C through a solution of compound 16
(
Received May 28, 2013;
in revised form June 19, 2013
3