Heterocyclic ketones in the pfitzinger reaction

Article abstract of DOI:10.1134/S1070363211020198

By the reaction of isatin with heterocyclic ketones (N-tert-butoxycarbonyl derivatives of pyrrolidin-3-one, piperidin-4-one, piperidin-3-one, 1,2,3,4-tetrahydroquinolin-4-one, 8-azabicyclo[3.2.1]octan-3-one, tetrahydropyran-4-one, tetrahydrobenzopyran-4-one) in the presence of KOH (the Pfitzinger reaction) were synthesized quinoline-4-carboxylic acids [4,3]fused with the respective heterocycles. These acids were involved in the reactions with diazomethane and amines at the carboxy group leading to methyl esters and amides, respectively. The esters obtained reacted with hydrazine hydrate affording the acid hydrazides, which entered in the condensation with benzaldehyde to form phenylhydrazones. The esters and amides containing N-tert-butoxycarbonyl fragment lost the tert-butoxycarbonyl group easily to form the secondary amines dihydrochlorides, the [4,3]fused quinoline-4-carboxylic acid derivatives.

Full text of DOI:10.1134/S1070363211020198

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 2, pp. 397–404. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.I. Moskalenko, A.V. Boeva, V.I. Boev, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 2, pp. 299–306.
Heterocyclic Ketones in the Pfitzinger Reaction
A. I. Moskalenko, A. V. Boeva, and V. I. Boev
Lipetsk State Pedagogical University,
ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
Received February 2, 2010
Abstract—By the reaction of isatin with heterocyclic ketones (N-tert-butoxycarbonyl derivatives of pyrrolidin-
3-one, piperidin-4-one, piperidin-3-one, 1,2,3,4-tetrahydroquinolin-4-one, 8-azabicyclo[3.2.1]octan-3-one,
tetrahydropyran-4-one, tetrahydrobenzopyran-4-one) in the presence of KOH (the Pfitzinger reaction) were
synthesized quinoline-4-carboxylic acids [4,3]fused with the respective heterocycles. These acids were
involved in the reactions with diazomethane and amines at the carboxy group leading to methyl esters and
amides, respectively. The esters obtained reacted with hydrazine hydrate affording the acid hydrazides, which
entered in the condensation with benzaldehyde to form phenylhydrazones. The esters and amides containing N-
tert-butoxycarbonyl fragment lost the tert-butoxycarbonyl group easily to form the secondary amines
dihydrochlorides, the [4,3]fused quinoline-4-carboxylic acid derivatives.
DOI: 10.1134/S1070363211020198
The Pfitzinger reaction consists in the interaction of
isatin or its derivatives with α-hydrogen-containing
ketones in strongly alkaline medium to form the
corresponding cinchoninic acids [1, 2]. These com-
pounds and their derivatives, apart from their research
significance, are also of great practical interest, since
among them drugs were found with a broad spectrum
of biological activity [3–7]. In particular, it is
established [4] that 2-(4-bromophenyl)quinoline-4-
carboxylic acid is a selective inhibitor of the C.
albicans prolyl tRNA synthetase, and 2-phenyl-
quinolin-4-carboxamides may be used as analgesics,
tranquilizers, antitumor and tuberculocidal drugs [6, 7].
(IV), and 8-azabicyclo[3.2.1]octan-3-one (V), as well
as ketones with the oxygen-containing rings:
tetrahydropyran-4-one (VI) and tetrahydrobenzopyran-
4-one (VII) . While selecting these heterocycles, we
accounted for their biological significance as a
pharmacophore fragments contributing to the structure
of many pharmaceuticals [20, 21].
We found that the Pfitzinger reaction proceeds
smoothly at boiling ketones I–VII taken in a small
excess (5–10%) with isatin in the presence of a tenfold
excess of KOH in a dioxane–water 1:1 mixture for 10–
12 h. However, the composition of the formed reaction
products significantly depended on the structure of the
parent ketones. With compounds II, IV–VII individual
heterocycles VIII–XII formed. Their composition and
structure were confirmed by elemental analysis,
Analysis of published data [8–19] shows that in the
Pfitzinger reaction α-hydrogen ketones can be used
with a variety of substituents, including carbocyclic
derivatives: cyclohexanone [16–18], 1-indanone, and
α-tetralone [17]. As a result of these reactions the 2-
substituted, 2,3-disubstituted and [2,3]fused with carbo-
cycles quinoline-4-carboxylic acids were obtained.
1
GC–MS spectra (Table 1), IR and H NMR spectra
(Table 2) (Scheme 1).
Reaction of ketones I and III with isatin under the
conditions of the Pfitzinger reaction led to a mixture
(according to GC–MS and 1H NMR spectra) of
isomeric products XIII–XVI, due to the possibility of
the condensation of intermediately formed isatinic acid
potassium salt A at both α-methylene groups
contiguous to the carbonyl carbon atom of these
ketones (Scheme 2).
In this study, we first involved in the Pfitzinger reac-
tion a number of heterocyclic compounds containing in
the ring the –CH2–CO– fragment. For this purpose we
used N-tert-butoxycarbonyl-substituted (Boc-subs-
tituted) pyrrolidin-3-one (I), piperidin-4-one (II),
piperidin-3-one (III), 1,2,3,4-tetrahydroquinolin-4-one
397

398
MOSKALENKO et al.
Table 1. Yields, melting points, data of elemental analysis and gas chromatography–mass spectrometry of compounds VIII–
XXXVIII
mp,
Yield,
%
Found, %
Calculated, %
Mass spectrum, m/z
M + 1 M – 101 + 1
Comp.
no.
Calculated
°С
Formula
С
Н
N
С
Н
N
М
C
8.54
6.11
7.45
5.05
7.91
8.92
8.54
8.19
5.76
7.18
4.81
7.61
2.84
329
230
377
278
355
315
329
343
244
391
292
369
328
229
354
372
273
398
343
244
369
431
332
457
243
291
269
228
254
228
276
328
229
376
277
354
314
328
342
243
390
291
368
327
228
353
371
272
397
342
243
368
430
331
456
242
290
268
227
253
86
45
78
27
82
54
55
86
83
85
81
78
56
48
60
78
64
62
98
96
98
80
81
86
99
96
98
98
99
178–179 65.58 5.93
201–202 68.23 4.75
230–232 70.04 5.59
252–254 73.42 4.06
161–162 67.73 6.34
170–176 65.12 5.87
148–154 65.68 5.94
8.47
18H20N2O4
65.82 6.10
68.12 4.80
70.21 5.32
73.65 3.97
67.80 6.21
64.97 5.73
65.85 6.10
66.67 6.43
69.14 5.35
70.77 5.64
74.23 4.47
68.48 6.52
66.06 6.42
VIII
6.18 C13H11NO3
7.38 C22H20N2O4
4.96 C17H11NO3
7.85 C20H22N2O4
8.96 C17H18N2O4
8.62 C18H20N2O4
8.06 C19H22N2O4
5.83 C14H13NO3
7.03 C23H22N2O4
4.67 C18H13NO3
7.69 C21H24N2O4
12.93 C18H21N3O3
12.17 C13H12N2O2
11.85 C20H23N3O3
11.26 C20H25N3O4
10.40 C15H16N2O3
10.73 C22H27N3O4
16.28 C18H22N4O3
17.43 C13H13N3O2
15.08 C20H24N4O3
13.26 C25H26N4O3
12.61 C20H17N3O2
12.13 C27H28N4O3
IX
X
XI
254
214
228
242
XII
XIII+XI
V
61–62
oil
66.52 6.31
69.28 5.17
70.61 5.46
74.28 4.39
68.24 6.41
XV+XVI
XVII
92–93
54–55
65–66
290
XVIII
XIX
268
227
XX
161–162 65.86 6.34
136–138 68.41 5.18
156–157 68.09 6.43
136–137 64.52 6.78
XXI
68.42 5.26 12.28
67.99 6.52 11.90
64.69 6.74 11.32
66.18 5.88 10.29
66.50 6.80 10.58
63.16 6.43 16.37
64.20 5.35 17.28
65.22 6.52 15.22
69.77 6.05 13.02
72.51 5.14 12.69
71.05 6.14 12.28
XXII
253
271
XXIII
XXIV
XXV
96–97
66.36 5.96
112–113 66.38 6.67
181–182 63.17 6.52
148–149 64.32 5.21
155–156 65.14 6.39
198–200 69.63 5.93
158–160 72.37 5.24
181–182 70.83 6.02
223–225 53.62 4.85
287–289 59.38 4.26
273–275 56.17 5.34
293–295 51.87 5.08
301–304 55.43 5.16
297
242
XXVI
XXVII
XXVIII
XXIX
XXX
268
330
XXXI
XXXII
XXXIII
XXXIV
XXXV
XXXVI
XXXVII
XXXVIII
356
8.73 C14H14N2O2·2 HCl 53.33 5.08
7.61 C18H14N2O2·2 HCl 59.50 4.41
8.89
7.71
8.26 C16H16N2O2·2 HCl 56.30 5.28 8.21
14.11 C13H13N3O·2 HCl
12.74 C15H15N3O·2 HCl
52.00 5.00 14.00
55.21 5.21 12.88
Table 2. Spectral data of compounds VIII–XXXVIII
Comp. no.
IR spectrum, ν, cm–1
1Н NMR spectrum, δ, ppm
1681, 1704 (C=O), 2948 (OH)
1.40 s (9Н, 3 СН3), 3.12 d (2Н, СН2), 3.74 d (2Н, NСН2), 4.76 s (2Н, NСН2), 7.65 t (1Н,
Н6 quinoline), 7.75 t (1Н, Н7), 7.86 d (1Н, Н5), 7.97 d (1Н, Н8), 13.95 br.s (1Н, СООН)
3.15 d (2Н, СН2), 4.09 d (2Н, ОСН2), 4.90 s (2Н, ОСН2), 7.59 t (1Н, Н6 quinoline), 7.74
t (1Н, Н7), 7.91 d (1Н, Н5), 7.96 d (1Н, Н8), 13.92 br.s (1Н, СООН)
1.41 s (9Н, 3 СН3), 4.72 s (2Н, NСН2), 7.02–7.21 m (4Н, С6Н4), 7.64 t (1Н, Н6
quinoline), 7.78 t (1Н, Н7), 7.88 d (1Н, Н5), 7.97 d (1Н, Н8), 13.92 br.s (1Н, СООН)
4.92 s (2Н, ОСН2), 7.04–7.23 m (4Н, С6Н4), 7.61 t (1Н, Н6 quinoline), 7.75 t (1Н, Н7),
7.91 d (1Н, Н5), 7.98 d (1Н, Н8), 13.92 br.s (1Н, СООН)
VIII
1708 (C=O), 2936 (OH)
IX
X
1682, 1702 (C=O), 2945 (OH)
1700 (C=O), 2938 (OH)
XII
XII
1685, 1705 (C=O), 2893 (OH)
1.38 s (9Н, 3СН3), 1.46–1.85 m (4Н, 2СН2), 3.06 d (2Н, СН2), 4.53 m (1Н, Н), 4.83 s
(1Н, СН), 7.66 t (1Н, Н6 quinoline), 7.75 t (1Н, Н7), 7.85 d (1Н, Н5), 7.98 d (1Н, Н8),
14.03 br.s (1Н, СООН)
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HETEROCYCLIC KETONES IN THE PFITZINGER REACTION
Table 2. (Contd.)
Comp. no.
IR spectrum, ν, cm–1
1Н NMR spectrum, δ, ppm
XIII+XI 1684, 1702, 1707 (C=O),
1.39–1.43 d (9Н, 3 СН3), 3.31 d (0.65 СН2), 3.75–4.58 m (2Н, NСН2), 4.82 s (0.35 NСН2),
7.52–7.98 m (4Н, quinoline), 13.87 br.s (1Н, СООН)
2924, 2954, 3002 (OH)
1682, 1700, 1708 (C=O),
2932, 2968 (OH)
V
1.40–1.45 d (9Н, 3
СН3), 1.93 m (0.6 СН2), 2.92–3.05 m (2Н, СН2), 3.52–3.68 m (2Н,
NСН2), 4.74 s (0.4 NСН2), 7.48–8.01 m (4Н, quinoline), 13.95 br.s (1Н, СООН)
1.40 s (9Н, 3 СН3), 3.11 d (2Н, СН2), 3.74 d (2Н, NСН2), 3.96 s (3Н, ОСН3), 4.78 s (2Н,
NСН2), 7.64 t (1Н, Н6 quinoline), 7.75 t (1Н, Н7), 7.87 d (1Н, Н5), 7.98 d (1Н, Н8)
3.16 d (2Н, СН2), 4.01 s (3Н, ОСН3), 4.12 d (2Н, ОСН2), 4.91 s (2Н, ОСН2), 7.48 t (1Н,
Н6 quinoline), 7.73 t (1Н, Н7), 7.92 d (1Н, Н5), 7.98 d (1Н, Н8)
1.41 s (9Н, 3 СН3), 3.95 s (3Н, ОСН3), 4.73 s (2Н, NСН2), 7.01–7.20 m (4Н, С6Н4), 7.63 t
(1Н, Н6 quinoline), 7.78 t (1Н, Н7), 7.89 d (1Н, Н5), 7.98 d (1Н, Н8)
4.02 s (3Н, ОСН3), 4.94 s (2Н, ОСН2), 7.03–7.24 m (4Н, С6Н4), 7.61 t (1Н, Н6 quinoline),
7.78 t (1Н, Н7), 7.94 d (1Н, Н5), 8.00 d (1Н, Н8)
XV+XVI
XVII
XVIII
XIX
1683, 1715 (C=O)
1718 (C=O)
1685, 1716 (C=O)
1718 (C=O)
XX
1682, 1714 (C=O)
1.39 s (9Н, 3 СН3), 1.44–1.86 m (4Н, 2СН2), 3.07 d (2Н, СН2), 3.98 s (3Н, ОСН3), 4.73 s
(3Н, ОСН3), 4.23 m (1Н, СН), 4.84 s (1Н, СН), 7.66 t (1Н, Н6 quinoline), 7.74 t (1Н, Н7),
7.84 d (1Н, Н5), 7.98 d (1Н, Н8)
XXI
1688, 1702, 1710 (C=O),
1.41 s (9Н, 3 СН3), 3.12 d (2Н, СН2), 3.75 d (2Н, NСН2), 4.77 s (2Н, NСН2), 7.63–7.98 m
(4Н, quinoline), 8.14 m (2Н, СОNH2)
3410–3428 (NH
XXII
)
2
1700, 1714 (C=O),
3412–3438 (NH2)
3.15 d (2Н, СН2), 4.08 d (2Н, ОСН2), 4.90 s (2Н, ОСН2), 7.58–7.96 m (4Н, quinoline),
8.16 m (2Н, СОNH2)
XXIII
XXIV
XXV
1685, 1698, 1712 (C=O),
3410–3432 (NH2)
1682, 1702, 1715 (C=O)
1.38 s (9Н, 3 СН3), 1.47–1.84 m (4Н, 2СН2), 3.07 d (2Н, СН2), 4.24 m (1Н, СН), 4.85 s
(1Н, СН), 7.64–7.98 m (4Н, quinoline), 8.09 m (2Н, СОNH2)
1.40 s (9Н, 3 СН3), 3.10 d (2Н, СН2), 3.19 s (3Н, NСН3), 3.65 s (3Н, ОСН3), 3.76 d (2Н,
NСН2), 4.78 s (2Н, NСН2), 7.63–7.95 m (4Н, quinoline)
1703, 1715 (C=O)
3.14 d (2Н, СН2), 3.18 s (3Н, NСН3), 3.71 s (3Н, ОСН3), 4.10 d (2Н, ОСН2), 4.92 s (2Н,
ОСН2), 7.58–7.96 m (4Н, quinoline)
XXVI
XXVII
XXVIII
XXIX
XXX
1686, 1700, 1712 (C=O)
1.39 s (9Н, 3СН3), 1.45–1.86 m (4Н, 2 СН2), 3.05 d (2Н, СН2), 3.20 s (3Н, NСН3), 3.72 s
(3Н, ОСН3), 4.22 m (1Н, СН), 4.83 s (1Н, СН), 7.68–8.01 m (4Н, quinoline)
1.40 s (9Н, 3 СН3), 3.10 d (2Н, СН2), 3.70 d (2Н, NСН2), 4.78 s (2Н, NСН2), 5.72 s (2Н,
NН2), 7.68–8.03 m (4Н, quinoline), 9.38 s (1Н, NH)
3.17 d (2Н, СН2), 4.09 d (2Н, ОСН2), 4.93 s (2Н, ОСН2), 5.81 s (2Н, NН2), 7.61–8.04 m
(4Н, quinoline), 9.43 s (1Н, NH)
1684, 1698, 1705 (C=O),
3415–3486 (N–H)
1701, 1712 (C=O),
3418–3508 (N–H)
1682, 1704 (C=O),
3420–3497 (N–H)
1.39 s (9Н, 3 СН3), 1.48–1.87 m (4Н, 2СН2), 3.08 d (2Н, СН2), 4.25 m (1Н, СН), 4.85 s
(1Н, СН), 5.64 s (2Н, NН2), 7.68–8.02 m (4Н, quinoline), 9.26 s (1Н, NH)
1628 (C=N), 1684, 1708 (C=O), 1.41 s (9Н, 3 СН3), 3.11 d (2Н, СН2), 3.73 d (2Н, NСН2), 4.77 s (2Н, NСН2), 7.12–7.33 m
3436 (N–H)
(5Н, С6Н5), 7.66–7.98 m (4Н, quinoline), 9.12 s (1Н, =СH), 9.36 s (1Н, NH)
1632 (C=N), 1702, 1714 (C=O), 3.15 d (2Н, СН2), 4.08 d (2Н, ОСН2), 4.92 s (2Н, ОСН2), 7.14–7.36 m (5Н, С6Н5), 7.61–
3442 (N–H)
7.98 m (4Н, quinoline), 9.12 s (1Н, =СH), 9.31 s (1Н, NH)
1630 (C=N), 1682, 1705 (C=O), 1.38 s (9Н, 3 СН3), 1.47–1.86 m (4Н, 2СН2), 3.05 d (2Н, СН2), 4.24 m (1Н, СН), 4.85 s
3456 (N–H)
(1Н, СН), 7.10–7.28 m (5Н, С6Н5), 7.64–8.02 m (4Н, quinoline), 9.08 (1Н, =СH), 9.28
1720 (C=O), 3520–3640 (+NH2) (1Н, NH)
3.18 d (2Н, СН2), 3.91 m (2Н, NСН2), 4.08 s (3Н, ОСН3), 4.97 d (2Н, NСН2), 7.84–8.63 m
1722 (C=O), 3528–3654 (+NH2) (4Н, quinoline), 12.08 br.s (2Н, +NH2)
4.10 s (3Н, ОСН3), 4.96 d (2Н, NСН2), 7.24–7.36 m (4Н, С6Н4), 7.86–8.63 m (4Н,
1720 (C=O), 3534–3684 (+NH2) quinoline), 12.12 br.s (2Н, +NH2)
XXXI
XXXII
XXXIII
XXXIV
XXXV
XXXVI
s
s
1.52–1.98 m (4Н, 2 СН2), 3.18 d (2Н, СН2), 4.08 s (3Н, ОСН3), 4.86 m (1Н, СН), 5.29 m
(1Н, СН), 7.84–8.53 m (4Н, quinoline), 12.15 br.s (2Н, +NH2)
1710 (C=O), 3248 (N–H),
XXXVII 3564–3648 (+NH2)
1712 (C=O), 3265 (N–H),
XXXVIII 3568–3664 (+NH2)
3.31 d (2Н, СН2), 4.13 m (2Н, NСН2), 5.03 m (2Н, NСН2), 7.86–8.54 m (4Н, quinoline),
8.44 m (2Н, СОNН2), 12.16 br.s (2Н, +NH2)
1.56–1.97 m (4Н, 2 СН2), 3.20 d (2Н, СН2), 4.91 m (1Н, СН), 5.31 m (1Н, СН), 7.83–8.56
m (4Н, quinoline), 8.51 m (2Н, СОNН2), 12.11 br.s (2Н, +NH2)
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MOSKALENKO et al.
Scheme 1.
O
COOH
N
X
II, VI
X
X
−2 H2O
O
O
X
O
V
IX
III,
KOH
O
C
O
COOH
N
H
OK
NH2
IV, VII
A
O
−2 H2O
N
COOH
X, XI
N
Boc
Boc
N
V
−2 H2O
N
XII
X = N–Boc (II, IV, VIII, X), О (VI, VII, IX, XI).
Scheme 2.
COOH
1 N
Boc
COOH
1 N
Boc
6
5
2
2
5
3
4
3
N
4
O
O
XIII
XV
+ A +
−2 H2O
−2 H2O
COOH
COOH
N
N
1
4
1
Boc
III
6
Boc
I
N5
4
2
2
Boc
5 N
3
3
N
XIV
N
XVI
Boc
Unfortunately, we were unable to separate
individual compounds from the resulting mixtures of
the products, as they have almost the same
chromatographic mobility. Nevertheless, we identified
the quantitative content of the isomers XIII, XIV and
XV, XVI, respectively, on the basis of GC–MS and 1H
NMR spectra. The latter for the individual compounds
VIII–XII are characterized by distinct multiplets that
related uniquely to the corresponding protons of the
structural fragments (Table 2). At the same time in the
1H NMR spectra of the mixtures of compounds XIII,
XIV and XV, XVI the signals of the quinoline
skeleton are present as doubled signals, and in the
resonance region of aliphatic protons there are signals
related to both structures of the corresponding
individual compounds XIII–XVI. In particular, the
spectrum of a mixture of compounds XIII and XIV
contains a doublet in the strong magnetic field at
3.31 ppm, which characterizes the β-protons (2H) in
the CH2CH2N fragment of compound XIII with
relative integral intensity ~0.65. This spectrum contains
also a singlet in a weaker field at 4.82 ppm attributable
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HETEROCYCLIC KETONES IN THE PFITZINGER REACTION
to the protons (2H) in the fragment of N=C–CH2–N of
compound XIV with relative integral intensity ~0.35.
Consequently, the ratio of compounds XIII:XIV in the
mixture is 65:35. This result was also confirmed by the
GC–MS spectrum containing two peaks with the
integral intensities reflecting the quantitative ratio of
substances with similar molecular weight 32:18. A
of condensation of aryloxymethylene group with the
carbonyl group of the intermediate A.
Next, we studied some chemical transformations of
the synthesized acids VIII–XII confirming their
structures. In particular, by the reaction with
diazomethane they were easily converted into the
corresponding methyl esters XVII–XXI (Scheme 3).
The reaction of acid VIII, IX, and XII with amines
(ammonia and N-methyl-N-methoxyamine) in the
presence of a dehydrating reagent, benzotriazol-1-
yloxy-tris(di-methylamino)phosphonium hexafluoro-
phosphate (BOF), leads to the primary (XXII–XXIV)
and tertiary (XXV–XXVII) amides respectively,
prossessing the scientific and practical interest
(Scheme 4). The boiling of ethers XVII, XVIII, and
XXI with hydrazine-hydrate in ethanol produces hyd-
razides XXVIII–XXX, which condense with
benzaldehyde affording the cor-responding phenylhyd-
razones XXXI–XXXIII (Scheme 3).
1
similar analysis of H NMR spectrum (Table 2) of a
mixture of compounds XV and XVI leads to the ratio
of the isomers ~3:2. Thus, in the course of the
Pfitzinger reaction the condensation of compounds I
and III at the carbonyl group of the intermediate A
proceeds predominantly with the participation of
hydrogen atoms in the N–CH2–C=O fragment. This is
probably due to the higher mobility of these hydrogen
atoms because at the negative inductive effect of the
nitrogen atom. A similar effect of oxygen was
observed in the case of reaction of methyl
aryloxymethylene ketones with isatin under the
conditions of the Pfitzinger reaction [22]: 2-Methyl-3-
aryloxyquinoline-4-carboxylic acids formed as a result
Scheme 3.
NHNH2
X
O
COOMe
C
N
H2O
H2NNH2
X
−MeOH
N
XXVII, XXVIII
XXVIII, XXIX
OH
−H2O
PhCHO
CH2N2
X
VIII−XII
−N2
NHN CHPh
O
N
C
X
XIX, XX
COOMe
N
Boc
XXXI, XXXII
N
N
XXI
H2NNH2
−MeOH
H2O
NHN CHPh
NHNH2
O
O
C
N
C
Boc
N
Boc
PhCHO
−H2O
N
N
XXXIII
XXX
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MOSKALENKO et al.
Scheme 4.
VIII−XII
R1
NH
BOF
R2
NR1R2
NR1R2
NR1R2
O
O
O
C
N
C
N
C
N
Boc
Boc
O
N
N
XXIV, XXVII
XXIII, XXVI
XXII, XXV
X = N–Boc (XVII, XIX, XXVIII, XXXI), O (XVIII, XX, XXIX, XXXII); R1 = R2 = H (XXII–XXIV); R1 = Me, R2 =
OMe (XXV–XXVII).
Finally, at treating esters XVII, XIX, and XXI, and
amides XXII and XXIV, containing the Boc group,
with hydrogen chloride in anhydrous dioxane this
group was removed to afford the secondary amine
dihydrochlorides XXXIV–XXXVIII in almost
quantitative yields (Scheme 5).
1-tert-Butoxycarbonylpiperidino[4,3-c]quinoline-
4-carboxylic acid (VIII). A mixture of 1.47 g of isatin
and 5.6 g of KOH in 20 ml of 50% aqueous dioxane
was stirred for 20 min, then 2.40 g of N-tert-
butoxycarbonylpiperidin-4-one (II) in 10 ml of the
same solvent was added, and the reaction mixture was
refluxed for 11 h. Then 60 ml of water was added, and
aqueous solution was washed with 30 ml of benzene,
30 ml of diethyl ether, and acidified with concentrated
hydrochloric acid (~ 7.4 ml) to pH 2–3. The precipitate
formed was filtered off, washed with 40 ml of water,
and dried to a constant weight. 2.82 g (86%) of
compound VIII was obtained. By the same procedure
were synthesized compounds IX, X, and XII.
The composition and structure of compounds
XVII–XXXVIII were confirmed by elemental
1
analysis, GC–MS spectra (Table 1), IR and H NMR
spectra (Table 2).
It should be noted in conclusion that the
compounds obtained containing functional groups can
be used as reagents in combinatorial organic syntheses
of new substances of the quinoline series with a view
to their total screening for revealing biological activity.
1,2,3,4-Tetrahydrobenzopyrano[4,3-c]quinoline-
4-carboxylic acid (XI). A mixture of 7.5 g of isatin
and 28 g of KOH in 70 ml of 50% aqueous dioxane
was stirred for 20 min, then to the mixture was added
7.40 g of N-tert-butoxycarbonyl-1,2,3,4-tetrahydro-
quinolin-4-one (IV) in 20 ml of the same solvent, and
the reaction mixture was refluxed for 12 h. 200 ml of
water was added, and aqueous solution was acidified
with concentrated hydrochloric acid (~ 34 ml) to pH
2–3, extracted with ethyl acetate (5×150 ml), and the
extract was dried over anhydrous sodium sulfate. After
distilling off the solvent in vacuo the residue was
purified by chromatography on silica gel, eluting the
title substance with methanol. 3.65 g (27%) of
compound XI was isolated. Similarly were synthesized
compounds XIII–XVI as mixtures of isomers.
EXPERIMENTAL
IR spectra of the compounds were recorded on a
Specord 75 IR spectrometer from the mulls in mineral
1
oil. H NMR spectra were recorded on a Varian
Mercury Plus-400 spectrometer (400 MHz) from solu-
tions in CDCl3 (XVII–XXXIII) or in DMSO-d6 (VIII–
XVI, XXXIV–XXXVIII), internal reference HMDS.
The GC–MS spectra were recorded on a Surveyor
MSQ Thermo Finnigan (USA) instrument using
chemical ionization at atmospheric pressure. Identity
and purity of the compounds obtained was monitored
by TLC on Silufol UV-254 plates, eluent hexane–ethyl
acetate, 1:2, development under the UV light.
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403
HETEROCYCLIC KETONES IN THE PFITZINGER REACTION
Scheme 5.
Y
O
C
N
NH
2 HCl
XXXIV, XXXVII
OMe
O
C
NH
HCl
2 HCl
XVII, XIX, XXI, XXII, XXIV
tert-BuCl
N
CO2
XXXV
Y
C
O
NH
2 HCl
N
XXXVI, XXXVIII
Y = OMe (XXXIV, XXXVI), NH2 (XXXVII, XXXVIII).
Methyl cinchoninates (XVII–XXI). To a solution
of 5 mmol of an acid VIII–XII in 15 ml of methanol
was added with stirring an ether solution of
diazomethane prepared from 1.3 g of N-nitroso-
methylurea as described in [23]. Nitrogen evolved. The
mixture was stirred for 1 h (TLC monitoring), the
excess diazomethane was quenched by adding acetic
acid, then the solvent was evaporated in a vacuum, the
residue was dissolved in ethyl acetate–hexane (2:1)
mixture and subjected to chromatography on silica gel,
affording respective compounds XVII–XXI. The data
on these compounds are listed in Tables 1 and 2.
XXII was obtained. Similarly were synthesized amides
XXIII–XXVII, their characteristics are listed in
Tables 1 and 2. For the synthesis of tertiary amides
XXV–XXVII were used N-methyl-N-methoxyamine
and equimolar amount of triethylamine as an acceptor
of HCl.
Cinchoninic acids hydrazides (XXVIII–XXX). A
mixture of 3 mmol of methyl ester XVII, XVIII, or
XXI and 1 ml of hydrazine hydrate in 5 ml of ethanol
was heated at reflux with stirring for 2 h (TLC
monitoring). The solvent was then removed in vacuo,
15 ml of water was added, and the mixture was kept in
a refrigerator at 6–7°C for 10 h. The precipitate of
compound XXVIII–XXX, respectively, was filtered
off, washed with water, and crystallized from ethanol.
1-tert-Butoxycarbonylpiperidino[4,3-c]quinoline-
4-carboxamide (XXII). To a mixture of 3.28 g of acid
VIII, 5.32 g of BOF in 30 ml of dimethyl sulfoxide
(DMSO) was added 1.6 ml of triethylamine, and the
mixture was stirred for 1 h at 50°C. Then 3.5 g of
ammonium carbonate was added, and the reaction
mixture was stirred at room temperature for 50 h. The
mixture was poured into 200 ml of water, extracted
with ethyl acetate (3×100 ml), washed twice with
water, and dried over anhydrous sodium sulfate. After
distilling the solvent off in vacuo, the residue was
crystallized from ethanol. 1.84 g (56%) of compound
Benzaldehyde hydrazones with cinchoninic acids
hydrazides (XXXI–XXXIII). A mixture of 2 mmol of
a hydrazide XXVIII–XXX, 0.22 g of freshly distilled
benzaldehyde, and 0.2 g of molecular sieve 4A (8–
12 mesh) in 5 ml of anhydrous ethanol was refluxed
with stirring for 4 h (TLC monitoring), then cooled,
filtered, the solvent was distilled off in a vacuum and
the residue was crystallized from ethyl acetate–hexane
(3:1) to give respective compound XXXI–XXXIII.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 2 2011

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MOSKALENKO et al.
pounds), Elderfield, R., Ed., Moscow: Inostrannaya
Methyl piperidino[4,3-c]quinolin-4-carboxylate
Literatura, 1955, vol. 4, p. 36.
dihydrochloride (XXXIV). To a solution of 3.42 g of
methyl ester XVII in 15 ml of anhydrous methanol
was added 30 ml of saturated solution of HCl in
dioxane, the mixture was stirred for 15 h at room
temperature and then for 2 h at 50°C. The solvent was
removed in a vacuum, the residue was dissolved in a
minimum amount of isopropanol at heating, the
solution was cooled, 50 ml of anhydrous diethyl ether
was added, and the mixture was left for 15 h in a
refrigerator at 6–7°C. The precipitate formed was
filtered off, washed with 20 ml of ether, and dried in a
vacuum over anhydrous CaCl2. 3.11 g (99%) of
compound XXXIV was isolated. Similarly were
synthesized compounds XXXV–XXXVIII, their
characteristics are listed in Tables 1 and 2.
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pounds, Quinoline, Jones, G., Ed., New York: Wiley,
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