The Piloty-Robinson reaction of N-substituted piperidin-4-one azines. A novel route for the synthesis of 3,6-diazacarbazole

Article abstract of DOI:10.1007/s10593-011-0802-4

The possibility of preparing 1,2,3,4,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4, 5-c']dipyridines using the Piloty-Robinson reaction has been studied under various conditions. A novel method is proposed for the synthesis of the aromatic 3,6-diazacarbazole (5H-pyrrolo[3,2-c:4,5-c']dipyridine) from 2,8-dibenzoyl-1,2,3,4,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4,5-c']dipyridine obtained for the first time by the Piloty- Robinson method under thermal conditions.

Full text of DOI:10.1007/s10593-011-0802-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 5, August 2011 (Russian original Vol. 47, No. 5, May, 2011)
THE PILOTY-ROBINSON REACTION OF
N-SUBSTITUTED PIPERIDIN-4-ONE AZINES.
A NOVEL ROUTE FOR THE SYNTHESIS OF
3,6-DIAZACARBAZOLE
R. S. Alekseyev1, A. V. Kurkin1, and M. A. Yurovskaya1*
The possibility of preparing 1,2,3,4,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4,5-c']dipyridines using the
Piloty-Robinson reaction has been studied under various conditions. A novel method is proposed for the
synthesis of the aromatic 3,6-diazacarbazole (5H-pyrrolo[3,2-c:4,5-c']dipyridine) from 2,8-dibenzoyl-
1,2,3,4,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4,5-c']dipyridine obtained for the first time by the Piloty-
Robinson method under thermal conditions.
Keywords: 8-aza--carboline, 2',3a',4',5',6',7'-hexahydrospiro[piperidine-4,3'-pyrazolo[4,3-c]pyridines],
3,6-diazacarbazole, 5H-pyrrolo[3,2-c:4,5-c'']dipyridine, Piloty-Robinson synthesis of pyrroles, [3,3] sig-
matropic rearrangement.
In 1960 O. Piloty discovered that diethyl ketone azine with an excess of anhydrous zinc chloride was
converted to 2,5-diethyl-3,4-dimethylpyrrole at 230ºC in 25% yield [1]. G. and R. Robinson reported in 1918
that heating desoxybenzoin azine at 180ºC in a stream of hydrogen chloride gave 2,3,4,5-tetraphenylpyrrole in
88% yield [2]. This method of preparing pyrroles by heating the corresponding carbonyl compound azines in the
presence of an acidic reagent has since been called the Piloty-Robinson reaction [3]. In a series of studies [1, 2,
4, 5] there were undertaken unsuccessful attempts to extend this synthetic route to azines of other carbonyl com-
pounds, viz: butyric and isovaleric aldehydes, acetone, cyclopentanone, butyrone, and acetophenone. However,
cyclohexanone azine (1) could be successfully cyclized to 2,3,4,5,6,7,8,9-octahydro-1H-carbazole (2) by reflu-
xing in tetralin in an HCl atmosphere in 28% yield [6]. A. N. Kost and I. I. Grandberg reported [5] that
compound 2 could be prepared in 79% yield by heating the azine 1 with anhydrous zinc chloride and also that
the N-acetyloctahydrocarbazole could be prepared in 82% yield by refluxing in dioxane with acetyl chloride.
It was thought that the mechanism of the Piloty-Robinson reaction is similar to that of the Fischer syn-
thesis of indoles. Acid causes a tautomeric conversion of the azine to the bisenehydrazine which undergoes a
[3,3] sigmatropic rearrangement accompanied by formation of a novel C–C bond and cleavage of the N–N bond
with closure to a pyrrole ring via loss of a molecule of ammonia [2, 7].
_______________
Dedicated to Academician V. N. Charushin on his 60th birthday.
* To whom correspondence should be addressed, e-mail: yumar@org.chem.msu.ru.
1 M. V. Lomonosov Moscow State University, 1–3 Leninskiye Gory, Moscow 199991, Russia.
______________________________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 706–720, May, 2011. Original
article submitted February 3, 2011.
0009-3122/11/4705-0584©2011 Springer Science+Business Media, Inc.
584

R 1
R1
R1
R1
R1
R1
R1
R1
[3,3] Sigmatropic
rearrangement
H+
R
R
R
R
R
R
R
R
–NH3
N
N
H
N
N
N N
N
H
H
H
H
R, R1 = Ar, Alk, H
The Piloty-Robinson method remained quiescent for a long time but modifications have appeared in
recent years. Thus methods for preparing pyrroles containing both symmetrically [8] and unsymmetrically
placed substituents have been proposed [9, 10]. In addition, variants of the Piloty-Robinson synthesis have been
reported using microwave irradiation [11], solid-phase synthesis [12] or base catalysis [13] conditions.
In the first stage of this work we decided to develop a preparative method for obtaining the octahydro-
carbazole 2 from azine 1 using acid catalysts such as p-toluenesulfonic acid and PPA (Table 1).
From the data obtained it is clear that use of 2 equivalents of p-toluenesulfonic acid gives the target oc-
tahydrocarbazole 2 in maximum yield. It should be noted that the Piloty-Robinson reaction can be accompanied
by the formation of a side compound (the spiropyrazole 3), the structure of which was proposed in studies [14,
15] but established by the authors only from elemental analytical data and from a chain of chemical reactions
which finally led to 1-cyclohexylcyclohexene. In fact, from our data, the spiropyrazoline 3 is indeed formed in a
1
significant amount in the case of p-toluidine hydrochloride. Characteristic for the H NMR spectrum of
compound 3 (compared with that of compound 2) is the appearance of a multiplet signal for the H-3a proton at
2.61 and a broadened NH proton signal at 4.79 ppm while the signal for the proton of the NH group in
compound 2 is found at 7.35 ppm.
4
5
3
6
3a'
2
4'
7'
Acid
5'
6'
+
2' NH

N
H
N
1'
N
N
1
2
3
H+
AdN
H+

2
3
1
'
–NH3
N
N
N
N
H
H
H
A
B
TABLE 1. Conditions for Cyclization of Azine 1 and Yields of Compo-
unds 2 and 3
Yield, %
Method
Conditions
2
3
A
B
C
D
PPA, 180°С, 5 min
85
95
85
60
–
–
TsOH (2 eq.), toluene, refluxing, 4 h, Ar atmosphere
TsOH (1.5 eq.), toluene, refluxing, 4 h, Ar atmosphere
p-Toluidine hydrochloride (1.5 eq.), dioxane, refluxing, 4 h
5
35
585

According to the data in Table 1 a decrease in the acidity of the medium leads to an increase in the con-
tent of the spiro compound 3 in the reaction mixture. This may be due to the fact that, under conditions of
insufficient acidity, takes place the shift in the equilibrium concentration to the enamino-imine form A which
cyclizes to the spiropyrazoline 3 while the biseneamine form B serves as the intermediate for formation of
carbazole 2.
Up to this time there has been no evidence for the potential use of azines of heterocyclic ketones in the
Piloty-Robinson reaction. Hence we have studied the reaction of the azines of 1-substituted piperidin-4-ones 4 in
the presence of an acid catalyst with a view to preparing the corresponding 1,2,3,4,6,7,8,9-octahydro-5H-
pyrrolo[3,2-c:4,5-c']dipyridines 5. At this time only one synthetic method has been reported [16] and this is
based on the annelation of two tetrahydropyridine rings onto a pyrrole ring. Our method, based on the Piloty-
Robinson reaction, involves the construction of the tricyclic diazacarbazole system 5 via formation of the
pyrrole ring. The starting azines 4 (Table 2) were prepared from the corresponding piperidin-4-ones 6 by the
following sequence of reactions:
R
R
NH2NH2·H2O
+
H2N
R
N
N
RCl
(0.5 eq.)
N
–
OH
OH
EtOH,

Cl
K2CO3,
H2O–CHCl3
O
N
N
4a–f
6a–d
4,6 a R = Ac, b R = Bz, c R = Ms, d R = Ts; 4 e R = Me, f R = Bn
We have carried out the cyclization of the azines 4 under the conditions developed in the case of the
cyclohexylideneazine (1). For the azines 4a–d two equivalents of TsOH were used while, for the azines 4e,f, it
was necessary to use four equivalents of TsOH so that both tertiary nitrogen atoms occurred in the protonated
form. We also carried out the reaction with 1.5 equivalents of p-toluidine hydrochloride in order to study the
effect of the nature of the catalyst on the course of the cyclization of azines 4a–d (Table 3).
TABLE 2. Characteristics of the Synthesized Piperidin-4-ones 4
Found, %
Calculated, %
Com-
pound
Empirical
formula
mp., °С
Yield, %
C
H
N
4a
С14H22N4O2
С24H26N4O2
С12H22N4O4S2
С24H30N4O4S2
С12H22N4
60.36
60.41
7.92
7.97
20.00
20.13
172–173
210–211
78
93
77
79
59
90
4b
4c*
71.63
71.62
6.58
6.51
13.91
13.92
41.44
41.13
6.46
6.33
16.01
15.99
281–282
(decomp.)
4d*2
57.52
57.35
6.14
6.02
11.06
11.15
289–290
(decomp.)
4e
64.64
64.83
10.05
9.97
25.31
25.20
65–66
4f
С24H30N4
77.14
76.97
7.97
8.06
14.85
14.96
109–110
_______
* Found, %: S 17.99; calculated, %: S 18.30.
*2 Found, %: S 12.70; calculated, %: S 12.76.
586

TABLE 3. Cyclization Conditions for Azines 4a–f and Yields of
Pyrazolo[4,3-c]pyridines 7
Ketazine
Method
Compound 7
Yield, %
4а
А (p-toluidine hydrochloride)
B (2 eq. TsOH)
7а
7а
66
43
62
4b
4c
4d
А (p-toluidine hydrochloride)
B (2 eq. TsOH)
7b
tarring
7c
А (p-toluidine hydrochloride)
B (2 eq. TsOH)
0*
0*2
0*
7c
А (p-toluidine hydrochloride)
B (2 eq. TsOH)
7d
7d
0*2
4e
4f
C (4 eq. TsOH)
7е
79
C (4 eq. TsOH)
7f
77
_______
* Starting azine isolated in quantitative yield.
*2 Isolated products could not be identified.
R
N
R
N
N
H
5a–f
R
TsOH or
4a–f
N 1
6
3
5
R
Me
NH2 · HCl
4'
2
3a'
N
5'
3'(4)
6'
NH
2'
7'
7a'
N
1'
7a–f
a R = Ac, b R = Bz, c R = Ms, d R = Ts, e R = Me, f R = Bn
It should be noted that, in contrast to the cyclohexylideneazine, the cyclization of the azines 4a,b,e,f in
acid conditions gives the corresponding pyrazolopyridines 7 (Tables 3 and 4), the octahydrodiazacarbazoles 5
not being observed amongst the reaction products. For the azines 4c,d the use of two equivalents of the TsOH
gave compounds which structures could not be determined.
The 1H NMR spectra of compounds 7a and 7b appeared as mixtures of amidine rotamers, characterized
by the existence of several sets of signals in different ratios due to the presence of the acetyl and benzyl
substituents respectively. The 13C NMR spectra were uninformative for the same reason. The derivative 7f gave
1
a H NMR spectrum with a rather complex pattern of multiplet signals for the aliphatic protons. In order to
achieve an exact assignment of the proton and carbon atom signals for the aliphatic region, we carried out
additional homo- (COSY 1H–1H NMR) and heteronuclear (1H−13C) 2D NMR experiments (Table 5) on the basis
of which we have made the signal assignments for the analogous compound 7e. The structure of the spiro
compounds 7 was confirmed by X-ray analytical data for the N-methyl substituted derivative 7e (Figure 1,
Tables 6 and 7).
587

TABLE 4. Characteristics of the 2',3a',4',5',6',7'-Hexahydrospiro-
[piperidine-4,3'-pyrazolo[4,3-c]pyridines] 7
Found, %
Calculated, %
Com-
pound
m/z
Empirical formula
mp., °С
[М]+
C
H
N
7a
7b
7e
7f
С14H22N4O2
С24H26N4O2
С12H22N4·3HCl
С24H30N4
60.61
60.41
7.85
7.97
20.15
20.13
193–194
162–163
278
402
222
374
71.46
71.62
6.53
6.51
13.69
13.92
43.51
43.45
7.66
7.60
16.95
16.89
225–227
(decomp.)
77.25
76.97
8.10
8.07
14.81
14.96
124–125
1
1
TABLE 5. Results of the COSY H–1H and H–13C Experiments for
Compound 7f
1H NMR
Spectrum,
δ, ppm
Cross peaks in the
13C measurement,
δ, ppm
Chemical shifts of the correlated
Atom groups
protons, δ, ppm
H-5
H-7'
1.57–1.62
1.65–1.71
1.81
2.11–2.23, 2.67–2.76
1.81, 2.11–2.23, 2.67–2.76
1.65–1.71, 2.11–2.23, 2.67–2.76
31.46
37.58
H-7'
37.58
Н-2 and H-4'
2.02–2.09
2.41–2.50, 2.51–2.56, 2.67–2.76,
2.97, 3.04–3.09
50.92 and 53.51
Н-6 and H-6'
2.11–2.23
1.57–1.62, 1.65–1.71, 1.81,
2.67–2.76
53.38 and 53.51
Н-3
2.41–2.50
2.51–2.56
2.67–2.76
2.02–2.09, 2.51–2.56, 3.04–3.09
2.02–2.09, 2.41–2.50, 3.04–3.09
27.94
27.94
H-3
H-6, Н-4'
and H-6'
1.57–1.62, 1.65–1.71, 1.81,
2.02–2.09, 2.11–2.23, 2.97
50.92, 53.38
and 53.51
H-3а'
2.97
3.04–3.09
3.50
2.02–2.09, 2.67–2.76
53.85
53.51
63.23
62.64
62.64
H-2
2.02–2.09, 2.41–2.50, 2.51–2.56
PhCH2N(1)
PhCH2N(5')
PhCH2N(5')

3.59
3.62
3.59
3.62
Figure 1. Molecular structure of the compound 7e.
588

TABLE 6. Individual Bond Lengths (l) in the Structure 7e
Bond
l, Å
Bond
l, Å
C(1)–N(2)
C(1)–C(5)
C(1)–C(9)
N(2)–N(3)
N(3)–C(4)
C(4)–C(41)
C(4)–C(5)
C(4)–C(45)
C(41)–C(42)
1.257(10)
1.492(11)
1.556(12)
1.434(9)
C(42)–N(43)
N(43)–C(43)
N(43)–C(44)
C(44)–C(45)
C(5)–C(6)
1.501(9)
1.476(9)
1.525(9)
1.478(10)
1.464(11)
1.534(10)
1.462(10)
1.603(10)
1.500(11)
1.565(10)
1.515(10)
1.547(12)
1.531(11)
1.473(10)
C(6)–N(7)
N(7)–C(7)
N(7)–C(8)
C(8)–C(9)
It follows from the mechanism of the Piloty-Robinson reaction given above that a necessary condition
for the occurrence of the key [3,3] sigmatropic rearrangement stage is the presence of a reasonable equilibrium
concentration of the bisenehydrazine form. Evidently it is the inadequate concentration of such a form in acid
catalysis conditions that serves as the reason for the absence of the dicarbazole 5 among the reaction products.
With the bis acylated azines the needed formation of the bisenehydrazine form is achieved [9] and this cyclizes
to the corresponding N-acylpyrrole when refluxed in xylene. Based on this data we have studied the potential
cyclization of the dibenzoyl azine derivative 4f under thermal conditions.
1
NBn
2
NBn
6
NBn
BnN
3
2'
5'
1'
BnN
3'
5
BnN
2.1 eq. BzCl
Py

4
4f
4'
N
N
Bz
N
o-Xylene
6'
N
N H
Bz
Bz
Bz
Bz
9
8
TABLE 7. Individual Valence Angles () in the Structure 7e
Angle
, deg
Angle
, deg
N(2)–C(1)–C(5)
N(2)–C(1)–C(9)
C(5)–C(1)–C(9)
C(1)–N(2)–N(3)
N(2)–N(3)–C(4)
C(41)–C(4)–C(5)
C(41)–C(4)–C(45)
C(5)–C(4)–C(45)
C(41)–C(4)–N(3)
C(5)–C(4)–N(3)
C(45)–C(4)–N(3)
C(42)–C(41)–C(4)
C(41)–C(42)–N(43)
C(43)–N(43)–C(42)
120.2(9)
119.9(9)
119.8(9)
102.5(8)
111.3(7)
114.7(8)
111.3(8)
112.7(8)
108.8(8)
96.8(8)
C(43)–N(43)–C(44)
C(42)–N(43)–C(44)
C(45)–C(44)–N(43)
C(44)–C(45)–C(4)
C(6)–C(5)–C(1)
C(6)–C(5)–C(4)
C(1)–C(5)–C(4)
C(5)–C(6)–N(7)
C(7)–N(7)–C(6)
C(7)–N(7)–C(8)
C(6)–N(7)–C(8)
C(9)–C(8)–N(7)
C(8)–C(9)–C(1)
112.9(6)
111.7(7)
112.8(7)
112.2(8)
114.5(8)
118.6(8)
101.4(8)
110.4(8)
110.9(7)
109.2(7)
106.3(6)
108.8(7)
108.7(8)
111.8(7)
112.5(7)
113.5(7)
114.7(7)
589

It was found, however, that treatment of azine 4f with 2.1 equivalents of benzoyl chloride in the pres-
ence of pyridine as a base and subsequent refluxing in xylene for 36 h did not give the expected carbazole 9, the
single reaction product 8 (in 92% yield) being the result of a sigmatropic rearrangement. In our view this result
is of considerable interest from the viewpoint of confirming the route of the Piloty-Robinson reaction as a [3,3]
sigmatropic rearrangement occurring with the formation of a C–C bond and cleavage of the N–N bond.
Attempts to cyclize compound 8 by heating in diphenyl oxide at 180–200ºC did not yield the carbazole 9 but led
to its thermal degradation. However, on study of the mass spectrum of compound 8, it was found that it does not
show a molecular ion but undergoes cyclization under EI conditions to compound 9 as indicated by subsequent
fragment [the m/z (Irel, %) values for the fragments are reported]:
+
+
.
.
Ph
Ph
Ph
CH2
N
N
N
EI
8
– BzNH2
– CH2=NCH2Ph
CH2
N
N
m/z 119
O
O
Ph
Ph
9
m/z
342 (13%)
m/z 461(3%)
.
– Ph–C=O
m/z
105
+
Ph
CH2
CH2
O
N
+
Ph+
+
N
– CO
m/z 91 (94%)
m/z 237 (8%)
m/z 77 (52%)
m/z
105 (100%)
Since the Piloty-Robinson reaction takes place via a [3,3] sigmatropic rearrangement mechanism, we
considered that it might occur at high temperature without a catalyst and this has not been reported previously in
the literature. In fact, a positive result (i.e. the preparation of the target octahydro-3,6-diazacarbazole 5) was
achieved under thermal conditions and in 95% yield without an acid catalyst by using the dibenzoylazine 4b at
210–220ºC in diphenyl oxide over 4–6 h.
O
O
Ph
Ph
Ph2O
N
N
4b
200–210oC
N
H
4–6 h, Ar atm.
5b
The cyclization does not occur at lower temperatures (160–170ºC) and the starting azine 4b is isolated
in 96% yield. The cyclization of azines 4a,c–f under thermal conditions could not be achieved. Hence at 160–
170ºC all of the azines returned the starting materials: 4a (80%), 4c,d (quantitative), 4e (84%), 4f (65%).
Increasing the temperature to 210–220ºC for the azines 4a,e,f led to tarring of the reaction mixtures and the
azines 4c,d were separated unchanged.
590

Because the ultimate aim of our work is the preparation of the aromatic 3,6-diazacarbazole (10) we have
studied the possible aromatization of the octahydro derivative 5b by various routes. The first consists of
simultaneous debenzoylation and oxidation using Pd/C in diphenyl oxide at 160–170ºC in an argon atmosphere
(method A). In the second, initial reduction by LiAlH4 was assumed to give the dibenzyl derivative 5f with its
subsequental debenzylation and aromatization in the presence of Pd/C by heating in diphenyl oxide in an inert
atmosphere (method B) or by refluxing in mesitylene (method C).
N
N
Pd/C
Ph2O, Ar, 160–170oC,
6 h (22%)
N
H
10
Ph2O, Ar,160–170oC, 6 h (37%) or
5b
Pd/C
mesitylene,  , 90 min (74%)
Ph
N
Ph
N
LiAlH4
THF,

N
H
5f (86%)
The yield of compound 10 by method C proved to be optimal hence we are able to propose a novel route
for preparation of the 3,6-diazacarbazole 10 in five stages in overall 55% yield based on the starting piperidin-
4-one hydrochloride monohydrate.
EXPERIMENTAL
13
1H and C NMR spectra were recorded on a Bruker-400 (400 and 100 MHz respectively) with the use
1
of double resonance (1H–1H), APT, and 2D COSY (1H–1H and H–13C) spectroscopic methods. The chemical
shifts were measured relative to the signals of the remaining solvent protons in the DMSO-d6 and CDCl3 (2.51
and 7.27 ppm respectively). Mass spectra were taken on a Finnigan MAT ITD-700 instrument using EI, 70 eV
ionization energy, and mass spectral range m/z 45 to 400. Monitoring of the reaction course and the purity of the
compounds prepared was carried out by TLC on Silufol UV-254 plates in the system ethyl acetate–methanol (2:1).
X-ray Structural Analysis of Compound 7e. Crystals of 7e were grown in methanol at 22ºC and are
monoclinic with a = 11.258(3), b = 6.8667(12), c = 25.039(5) Å,  = 98.56(2)º, V = 1914.1(7) Å3, Mr = 331.71,
Z = 4, space group P21/n, dcalc = 1.151 g/cm3, (AgK) = 0.245 mm–1, F(000) = 704. The unit cell parameters
and intensities of 2766 reflections (2439 independent, Rint = 0.0341) were measured on a CAD4 diffractometer
[17] (AgK radiation, point scintillation detector, graphite monochromator, -scanning, max = 18º).
The structure was solved by the direct method using the SHELXS97 program package [18]. The posi-
tions of all of the hydrogen atoms were revealed in electron density difference synthesis and the refinement was
carried out using the “riding” model. The structure was refined by F2 full matrix least squares analysis in the
anisotropic approximation for non-hydrogen atoms to wR2 = 0.0607 for 4205 reflections (R1 = 0.0421 for 2439
reflections with F2 ˃ 2(F2)) with S = 0.562 using the SHELXL97 program package [18]. The numbering of the
atoms in the compound studied and its geometric structure are illustrated in Figure 1 using the ORTEP-3
program [19]. The full crystallographic information has been placed in the Cambridge Structural Database as
deposit CCDC 812271.
591

Cyclohexylideneazine (1) was prepared by method [6]. Yield 72%; mp 32–33ºC (mp 33ºC [6]).
1H NMR spectrum, , ppm: 1.58–1.65 (8H, m, Ha-3(5) and H-4); 1.70–1.76 (4H, m, He-3(5)); 2.31–2.34 (4H,
m, Ha-2(6)); 2.37–2.40 (4H, m, He-2(6)).
2,3,4,5,6,7,8,9-Octahydro-1H-carbazole (2). A. A mixture of azine 1 (8.0 g, 41.7 mmol) and PPA
(40 g) [20] was heated to 150–160ºC with stirring and the reaction mixture self heated to about 200ºC. The
product was held at 180ºC for a further 5 min, cooled, dissolved in cold water, and extracted with chloroform
(4×50 ml). The extract was washed with saturated sodium bicarbonate solution, dried over sodium sulfate,
evaporated to dryness, and a further twice evaporated with toluene (10 ml) to constant weight to give the product
as a yellow oil (6.2 g, 85%) which crystallized in the cold; mp 95ºC (mp 96ºC [5]). The compound obtained was
unstable to storage in air. 1H NMR spectrum, , ppm: 1.77–1.89 (8H, m, H-2,3,6 and 7); 2.43–2.46 (4H, m, H-4
and H-5); 2.58–2.61 (4H, m, H-1 and H-8); 7.35 (1H, br s, NH).
B. A solution of p-toluenesulfonic acid monohydrate (15.9 g, 83.7 mmol) was dehydrated by azeotropic
distillation using toluene. Azine 1 (8.0 g, 41.7 mmol) was added to the solution obtained (of volume ~ 50 ml)
and the reaction mixture was refluxed for 4 h under an argon atmosphere, cooled, diluted with water, and
basified using ammonia solution (25%). The organic phase was separated and the aqueous phase was extracted
with chloroform (3×50 ml). The combined extracts were dried over sodium sulfate and evaporated to dryness to
1
give light-yellow oil which crystallized in the cold; mp 96ºC (petroleum ether). The H NMR spectrum was
identical to that obtained using method A.
C. Similarly to method B but using p-toluenesulfonic acid monohydrate (11.9 g, 62.6 mmol) to give brown
oil (6.8 g), which was chromatographed on silica gel. Octahydrocarbazole 2 (6.2 g, 85%) was obtained as a yellow
oil (eluent benzene) which crystallizes in the cold (mp 94–95ºC) and also the 2',3a',4',5',6',7'-hexahydro-
spiro[cyclohexane-1,3'-indazole] (3) (eluent chloroform) as a gray, crystalline material with mp 62–63ºC (mp
1
63ºC [5]). H NMR spectrum, , ppm: 1.27–1.57 (13H, m, H-2,3,4,5,6 and H-5',6'); 1.76–1.94 (3H, m, H-4' and
H-6'); 2.08–2.16 (1H, m, Ha-7'); 2.33–2.38 (1H, m, He-7'); 2.59–2.63 (1H, m, H-3a'); 4.97 (1H, br. s, NH).
D. A suspension of azine 1 (8.0 g, 41.7 mmol) and p-toluidine hydrochloride (9.0 g, 62.6 mmol) in di-
oxane (50 ml) was refluxed for 4 h. The product was cooled, the dioxane was evaporated, water (50 ml) was
added followed by ammonia solution (25%), and then extracted with chloroform (4×50 ml). The extract was
dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel as in method C to give the
octahydrocarbazole 2 (4.4 g, 60%) and the indazole 3 (2.8 g, 35%). The physicochemical characteristics of
compounds 2 and 3 were identical to those given above.
N-Acyl- and N-Sulfonylpiperidin-4-ones (6a–d) (General Method). Potassium carbonate (33.0 g,
240 mmol) was added portionwise to a solution of piperidin-4-one hydrochloride monohydrate (15.4 g,
100 mmol) in water (100 ml) followed by dichloromethane (100 ml). A solution of the acyl- or sulfonyl chloride
(105 mmol) in dichloromethane (60 ml) was then added dropwise with stirring. The reaction mixture was stirred
for 3 h at 25ºC. The organic phase was separated, washed with a solution of sodium bicarbonate, dried over
1
sodium sulfate, and evaporated to dryness. As judged from H NMR data the N-substituted piperidin-4-ones
6a–d obtained in this way were satisfactory for further use without additional purification.
N-Acetylpiperidin-4-one (6a). Colorless oil. Yield 94%. 1H NMR spectrum, , ppm: 2.13 (3H, s, CH3);
2.39–2.46 (4H, m, H-3(5)); 3.70–3.73 (2H, m, H-2); 3.80–3.83 (2H, m, H-6).
N-Benzoylpiperidin-4-one (6b). Light-yellow, viscous oil, crystallizing over 4–5 weeks in the cold.
Yield 97%; mp 50–51ºC (49–52ºC [21]). 1H NMR spectrum, , ppm: 2.32–2.59 (4H, m, H-3(5)); 3.62–4.03 (4H,
m, H-2(6)); 7.38–7.45 (5H, m, Ph).
N-(Methylsulfonyl)piperidin-4-one (6c). White crystalline material. Yield 52%; mp 102–103ºC (102–
1
104ºC [22]). H NMR spectrum, , ppm: 2.57–2.61 (4H, m, H-3(5)); 2.90 (3H, s, CH3); 3.58–3.61 (4H, m,
H-2(6)).
N-[(4-Methylphenyl)sulfonyl]piperidin-4-one (6d). White crystalline material. Yield 98%; mp 129–
1
130ºC (129–131ºC [23]). H NMR spectrum, , ppm (J, Hz): 2.45 (3H, s, CH3); 2.53–2.56 (4H, m, H-3(5));
3.38–3.41 (4H, m, H-2(6)); 7.36 (2H, d, J = 8.2, H-3(5) Ar); 7.69 (2H, d, J = 8.2, H-2(6) Ar).
592

Ketazines 4a–f (General Method). Hydrazine hydrate (1.5 g, 30 mmol) was added dropwise with vigo-
rous stirring to a solution of the corresponding piperidin-4-one (60 mmol), refluxed for 5 min, and left to cool in
the fridge. The precipitated crystals were filtered off and dried in air.
1
N-Acetylpiperidin-4-ylideneazine (4a). White crystalline material. H NMR spectrum, , ppm: 2.16
(6H, s, 2CH3); 2.49–2.55 (4H, m, Ha-3(5)); 2.59–2.71 (4H, m, He-3(5)); 3.55–3.79 (8H, m, H-2(6)).
N-Benzoylpiperidin-4-ylideneazine (4b). White crystalline material. 1H NMR spectrum, , ppm: 2.38–
2.83 (8H, m, H-3(5)); 3.48–4.01 (8H, m, H-2(6)); 7.38–7.49 (10H, m, 2Ph).
1
N-(Methylsulfonyl)piperidin-4-ylideneazine (4c). White crystalline material. H NMR spectrum
(DMSO-d6), , ppm: 2.48–2.51 (4H, m, Ha-3(5)); 2.61–2.64 (4H, m, He-3(5)); 2.92 (6H, s, 2CH3); 3.23–3.26
(4H, m, H-2(6)); 3.34–3.37 (4H, m, H-2(6)).
1
N-[(4-Methylphenyl)sulfonyl]piperidin-4-ylideneazine (4d). White crystalline material. H NMR spec-
trum, , ppm (J, Hz): 2.44 (6H, s, 2CH3); 2.50–2.53 (4H, m, Ha-3(5)); 2.66–2.69 (4H, m, He-3(5)); 3.11–3.14 (4H,
m, H-2(6)); 3.21–3.24 (4H, m, H-2(6)); 7.32 (4H, d, J = 8.2, H-3(5) Ar); 7.65 (4H, d, J = 8.2, H-2(6) Ar).
1
N-Methylpiperidin-4-ylideneazine (4e). Cream-colored crystalline material. H NMR spectrum, ,
ppm: 2.33 (6H, s, 2CH3); 2.46–2.50 (8H, m, H-3(5)); 2.56–2.62 (8H, m, H-2(6)).
N-Benzylpiperidin-4-ylideneazine (4f). White crystalline material. 1H NMR spectrum, , ppm: 2.47–2.50
(4H, m, Ha-3(5)); 2.53–2.65 (12H, m, He-3(5) and H-2(6)); 3.57 (4H, s, 2CH2Ph); 7.26–7.37 (10H, m, 2Ph).
2',3a',4',5',6',7'-Hexahydrospiro(piperidine-4,3'-pyrazolo[4,3-c]pyridines 7a–f (General Method). A.
p-Toluidine hydrochloride (1.5 mmol) was added to a suspension of the azine 4 (1 mmol) in anhydrous dioxane
(10 ml) and refluxed for 4 h, the solvent evaporated, and water (20 ml) was added. The product was basified
using ammonia solution (25%) and, for azines 4a,b, extracted with chloroform (3×30 ml), dried over sodium
sulfate, and evaporated to dryness. In the case of the azines 4c,d the precipitate was filtered, washed with water,
and dried in air. In both cases the unpurified compound was washed with ether to remove p-toluidine, the
solution decanted, and the residue was recrystallized from methanol.
B. A solution of p-toluenesulfonic acid monohydrate (0.38 g, 2.0 mmol) was dehydrated by azeotropic
distillation of toluene. The azine 4a–d (1.0 mmol) was added to the solution obtained (volume ~ 30 ml) and the
reaction mixture was refluxed for 4 h in an argon atmosphere, evaporated to dryness, diluted with water, basified
by ammonia solution (25%), and extracted with chloroform (4×20 ml). The extracts were combined, dried over
sodium sulfate, and evaporated to dryness. The residue was recrystallized from methanol.
C. The method was similar to B but, in the case of azines 4e,f, toluenesulfonic acid monohydrate
(0.76 g, 4.0 mmol) was used.
1,5'-Diacetyl-2',3a',4',5',6',7'-hexahydrospiro[piperidine-4,3'-pyrazolo[4,3-c]pyridine] (7a). Light-
1
yellow, crystalline material. H NMR spectrum (mixture of two rotamers in the ratio 3:7), , ppm: 1.55–1.88
(4Н, m, Н-3,5); 2.12 and 2.13 (3Н, 2s, 1-CONCH3); 2.15 and 2.18 (3Н, 2s, 5'-CONCH3); 2.32–2.44 (1Н, m,
Н-7'); 2.49–2.56 (1Н, m, Н-7'); 2.60–2.72 (2Н, m, Н-2(6)); 2.91–3.22 (2Н, m, H-2(6)); 3.29–3.40 (1Н, m,
Н-3а'); 3.57–3.78 (1H, m, Н-6'); 3.86–3.93 and 4.28–4.42 (1Н, 2m, Н-6'); 4.01–4.08 and 4.10–4.16 (1Н, 2m,
Н-4'); 4.79–4.84 and 4.88–4.93 (1Н, 2m, Н-4'); 5.52 (1Н, br. s, NH). Mass spectrum, m/z (Irel, %): 278 [M]+
(3.1), 235 [M–Ac]+ (6.4), 191 (20.4), 164 (5.5), 137 (14.9), 120 (31.4), 97 (11.7), 82 (11.2), 80 (26.1), 58 (15.4),
56 (16.1), 44 (16.4), 43 (100), 42 (51.8).
1,5'-Dibenzoyl-2',3a',4',5',6',7'-hexahydrospiro[piperidine-4,3’-pyrazolo[4,3-c]pyridine]
(7b).
1
Cream, crystalline material. H NMR spectrum (mixture of several rotamers), , ppm: 1.55–2.58 (6Н, m,
Н-3,5,7')); 2.60–3.75 (6Н, m, Н-2,6,3a',6'); 3.80–5.09 (3Н, 2m, Н-4',6'); 5.52 (1Н, br. s, NH); 7.36–7.52 (10H,
m, 2Ph). Mass spectrum, m/z (Irel, %): 402 [M]+ (8.1), 401 [M–H]+ (11.6), 297 [M–Bz]+ (6.2), 283 [M–NBz]+
(26.3), 255 (6.2), 241 (8.9), 148 (6.3), 134 (12.4), 120 (15.9), 106 (12.8), 105 [Bz]+ (100), 78 (5.8), 77 [Ph]+
(75.5), 51 (11.2), 42 (7.6).
1,5'-Dimethyl-2',3a',4',5',6',7'-hexahydrospiro[piperidine-4,3'-pyrazolo[4,3-c]pyridine] (7e). White
crystalline material. 1H NMR spectrum, , ppm (J, Hz): 1.59–1.62 (2Н, m, Н-5); 1.64–1.69 (1Н, m, Н-7'); 1.81
(1Н, ddd, J1 = 13.2, J2 = 11.0, J3 = 4.1, H-7'); 1.95–2.02 (2Н, m, Н-2 and Н-4'); 2.09–2.20 (2Н, m, Н-6 and
593

Н-6'); 2.26 (3Н, s, 5'-NCH3); 2.33 (3Н, s, 1-NCH3); 2.38–2.54 (2Н, m, Н-3); 2.55–2.67 (2Н, m, H-6 and Н-6');
2.72 (1Н, dd, J1 = 11.5, J2 = 6.1, Н-4'); 2.87 (1Н, ddd, J1 = 10.4, J2 = 6.1, J3 = 1.7, H-3а'); 2.93–3.00 (1Н, m,
Н-2); 5.23 (1Н, br. s, NH). 13C NMR spectrum, , ppm: 27.84 (3-СH2); 31.37 (5-СH2); 37.51 (7'-СH2); 46.16
(5'-NCH3); 46.23 (1-NCH3); 52.61 (С-4); 52.89 (2-СH2 and 6-СH2); 55.64 (4'-CH2); 55.82 (6'-CH2); 61.79 (3a'-
СH); 155.19 (7a'-С). Mass spectrum, m/z (Irel, %): 222 [M]+ (3.7), 464 [M–H]+ (20.6), 152 (9.8), 151 (100), 108
(16.1), 107 (5.9), 77 (5.1), 58 (15.7), 44 (32.2), 43 (15.0), 42 (40.7), 36 (40.4).
1,5'-Dibenzyl-2',3a',4',5',6',7'-hexahydrospiro[piperidine-4,3'-pyrazolo[4,3-c]pyridine] (7f). Cream
1
crystalline material, trihydrobromide – white colored; mp of trihydrobromide of 7f 216–217ºC (decomp.). H
NMR spectrum, , ppm (J, Hz): 1.57–1.62 (2Н, m, Н-5); 1.65–1.71 (1Н, m, Н-7'); 1.81 (1Н, ddd, J1 = 13.2,
J2 = 11.0, J3 = 4.2, H-7'); 2.02–2.09 (2Н, m, Н-2 and H-4'); 2.11–2.23 (2Н, m, Н-6,6'); 2.41–2.50 (1Н, m, Н-3);
2.51–2.56 (1Н, m, H-3); 2.67–2.76 (3Н, m, Н-6, Н-4',6'); 2.97 (1Н, ddd, J1 = 10.3, J2 = 6.1, J3 = 1.8, Н-3а');
3.04–3.09 (1Н, m, Н-2); 3.50 (2Н, s, 1-PhCH2N); 3.59 and 3.62 (2H, 2d, J = 13.3, 5'-PhCH2N); 5.41 (1Н, br. s,
NH); 7.26–7.36 (10Н, m, 2Ph). 13C NMR spectrum, , ppm: 27.94 (3-СH2); 31.46 (5-СH2); 37.58 (7'-СH2);
50.41 (С-4); 50.92 (4'-CH2); 53.38 (6'-CH2); 53.51 (2-СH2 and 6-СH2); 53.85 (3a'-СH); 62.64 (5'-PhCH2N);
63.23 (1-PhCH2N); 127.28 and 127.32 (4''-СH Ph); 128.39 and 128.45 (3''(5'')-СH Ph); 128.99 and 129.28
(2''(6'')-СH Ph); 138.16 and 138.28 (С-1'' Ph); 156.01 (7a'-С). Mass spectrum, m/z (Irel, %): 374 [M]+ (1.0), 283
[M–Bn]+ (5.8), 241 (8.2), 240 (18.0), 227 (43.7), 148 (12.6), 134 (21.6), 109 (21.6), 91 [Bn]+ (100), 65 (16.4),
42 (35.4), 41 (13.2).
N-(3-[4-(Benzoylamino)-1-benzyl-1,2,5,6-tetrahydropyridin-3-yl]-1-benzylpiperidin-4-ylidene)benz-
amide (8). Pyridine (2 ml) and then, dropwise, benzoyl chloride (1.2 g, 8.5 mmol) were added to a solution of
the azine 4f (1.5 g, 4.0 mmol) in o-xylene (10 ml). The mixture was stirred at room temperature for 30 min and
then refluxed for 36 h under an argon atmosphere. The reaction mixture was evaporated to dryness and the
residue was washed with sodium bicarbonate solution and extracted with methylene chloride (3×30 ml). The
extracts were dried over sodium sulfate, evaporated to dryness, and the residue was then chromatographed on
silica gel (ethyl acetate−methanol, 25:1) to give a yellowish, crystalline product (1.7 g, 92%); mp 152–153ºC.
1H NMR spectrum, , ppm (J, Hz): 1.40–1.44 (1Н, m, На-5); 1.63–1.71 (1Н, m, Не-5); 2.20–2.26 (1Н, m,
На-6'); 2.28–2.34 (1Н, m, На-6); 2.38 (1Н, dd, J1 = 12.5, J2 = 4.5, На-2'); 2.41–2.47 (1Н, m, Не-6'); 2.56–2.60
(1Н, m, Не-6); 2.61–2.67 (1Н, m, На-5'); 2.79 (1Н, dd, J1= 12.5, J2 = 2.0, Не-2'); 2.83–2.87 (1Н, m, Не-5');
3.00 (1Н, m, На-2); 3.06 (1Н, m, Не-2); 3.41 and 3.64 (2Н, 2 d, J = 16.2, 1'-PhCH2N); 3.59 (2Н, s, 1-PhCH2N);
4.42 (1Н, m, H-3'); 7.09 (1Н, br. s, NH); 7.25–7.49 (16H, m, Ph); 7.57 (2Н, dd, Jo = 7.1, Jm = 1.3, Н-o PhCO);
7.81 (2Н, dd, Jo = 7.1, Jm = 1.3, Н-o PhCO). 13C NMR spectrum, , ppm: 27.15 (5-СН2); 34.83 (5'-СН2); 42.92
(3'-СН2); 49.56 (6-СН2); 49.90 (2-СН2); 49.92 (6'-СН2); 50.41 (2'-СН2); 62.40 (1'-PhCH2N); 63.08 (1-PhCH2N);
120.86 (С-3); 127.29; 127.34; 128.39; 128.62; 129.15; 129.28; 130.82; 132.34 (С-1 PhCON=); 135.35 (С-1
PhCONH); 137.37 (С-4); 138.17 (С-1 Bn); 138.62 (С-1 Bn); 167.55 (CO PhCONH); 168.42 (C-4'); 171.01 (CO
PhCON=). Mass spectrum, m/z (Irel, %): 461 [M–BzNH2]+ (3.0), 342 (13.5), 237 (7.7), 122 (5.2), 105 [PhCO]+
(100), 91 [Bn]+ (94.5), 77 [Ph]+ (51.9), 65 (9.5), 51 (14.1). Found, %: С 78.33; Н 6.41; N 9.48. C38H38N4O2.
Calculated, %: С 78.32; Н 6.57; N 9.61.
2,8-Dibenzoyl-2,3,4,5,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4,5-c']dipyridine (5b). A solution of
azine 4b (21.7 g, 54.0 mmol) in diphenyl oxide (30 ml) was heated for 4–6 h at 210–220ºC under an argon
atmosphere. The reaction mixture was cooled, benzene (50 ml) was added with stirring, and petroleum ether
(80 ml) was added slowly. The precipitate formed was stirred for 20–30 min, filtered, washed with a mixture
of benzene and petroleum ether (1:3, 100 ml), and dried in air to give a light-cream, crystalline material
(19.7 g, 95%) with mp 237–238ºC. 1H NMR spectrum, , ppm (J, Hz): 2.60–2.81 (4Н, m, H-4(6)); 3.55–4.09
(4Н, m, H-3(7)); 4.27–4.80 (4Н, m, H-1(9)); 7.32–7.51 (10Н, m, 2Ph); 8.00 (1H, br. s, NH). 13C NMR
spectrum, , ppm: 23.88 and 22.93 (4-СН2 and 6-СН2); 40.25 and 40.68 (1-СН2 and 9-СН2 ); 45.39 and 45.64
(3-СН2 and 7-СН2); 110.26 and 110.73 (С-9а,9b); 123.10 and 123.30 (С-4а,5а); 126.86 (2-СН and 6-СН Ph);
128.61 (3-СН and 5-СН Ph); 129.82 (4-СН Ph); 136.12 (C-1 Ph); 171.12 (C=O). Mass spectrum, m/z (Irel, %):
385 [M]+ (3.4); 280 [M–Bz]+ (4.0), 264 (12.2), 251 (16.9), 159 (22.8), 147 (16.3), 132 (15.3), 119 (15.2), 105
594

[Bz]+ (100), 78 (13.8), 77 [Ph]+ (85.1), 51 (25.8). Found, %: С 74.72; Н 5.97; N 11.00. C24H23N3O2.
Calculated, %: С 74.78; Н 6.01; N 10.90.
2,8-Dibenzyl-1,2,3,4,6,7,8,9-octahydro-5H-pyrrolo[3,2-c:4,5-c']dipyridine (5f). Compound 5b
(19.7 g, 51.0 mmol) was added portionwise with vigorous stirring to a suspension of lithium aluminum hydride
(3.8 g, 100 mmol) in anhydrous THF (300 ml) and the mixture was refluxed for 8 h. The product was cooled and
water (4 ml) was added followed by NaOH solution (15%, 5 ml) and further water (4 ml). The reaction product
was then filtered and the precipitate on the filter was washed several times with hot THF (3×40 ml). The filtrate
obtained was dried over sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (70 ml),
evaporated to constant weight, and recrystallized from ethanol to give a white or cream colored material (15.6 g,
1
86%); mp 177–178ºC. H NMR spectrum, , ppm: 2.66 (4Н, t, J = 5.5, H-4(6)); 2.77 (4Н, t, J = 5.5, H-3(7));
3.37 (4Н, s, H-1(9)); 3.71 (4H, s, PhCH2); 7.25–7.28 (2Н, m, H-4 Ph); 7.31–7.35 (4Н, m, H-3(5) Ph); 7.38–7.42
(4Н, m, H-2(6) Ph); 7.46 (1H, br. s, NH). 13C NMR spectrum, , ppm: 23.46 (4-СН2 and 6-СН2); 50.21 (3-СН2
and 7-СН2); 50.48 (1-СН2 and 9-СН2); 112.53 (C-9а,9b); 123.58 (C-4а,5а); 127.09 (4-СН Ph); 128.36 (3-СН
and 5-СН Ph); 129.14 (2-СН and 6-СН Ph); 139.13 (C-1 Ph). Mass spectrum, m/z (Irel, %): 357 [M]+ (4.0); 238
[M–BnN=CH2]+ (38.3), 146 (7.1), 145 (7.1), 120 (13.7), 119 [M-2BnN=CH2]+ (48.7), 91 [Bn]+ (100), 65 (15.1).
Found, %: С 80.56; Н 7.43; N 11.74. C24H27N3. Calculated, %: С 80.63; Н 7.61; N 11.75.
5H-Pyrrolo[3,2-c:4,5-c']dipyridine (3,6-Diazacarbazole, 8-Aza--carboline) (10). A. Compound 5b
(0.5 g, 1.30 mmol) was added to a suspension of palladium on carbon (10%, 0.2 g) in diphenyl oxide (10 ml)
and the mixture was heated for 6 h at 160–170ºC under an argon atmosphere. The product was cooled and
toluene (20 ml) and hydrochloric acid (1 N, 20 ml) were added. The aqueous phase was washed with more
toluene (10 ml) and basified to pH 9.0 with aqueous potassium hydroxide solution. The mixture obtained was
evaporated to dryness and the residue was extracted with ethanol (3×10 ml). The alcohol solution was
evaporated to dryness and the residue was recrystallized from water to give a light-gray, crystalline material
(0.048 g, 22%) with mp 312–313ºC (subl.) (mp ˃ 300ºC [24]), mp 344–347ºC [25], mp 328ºC [26]).
B. The conditions and separation process for the target compound were similar to method A but using
palladium on carbon (10%, 0.13 g) in diphenyl oxide (7 ml) and compound 5f (0.24 g, 0.67 mmol) to give a
light-gray, crystalline material with mp 314–315ºC (subl.).
C. Compound 5f (0.8 g, 2.0 mmol) was added to a suspension of palladium on carbon (10%, 0.4 g) in
mesitylene (15 ml) and refluxed for 90 min. The product was cooled and toluene (15 ml) and hydrochloric acid
(2 N, 15 ml) were added. The aqueous phase was separated, washed with toluene (10 ml) and basified to pH 9.0
with an aqueous solution of potassium hydroxide. The precipitated material was filtered off and recrystallized
1
from water to give a light-gray, crystalline material (0.25 g, 74%); mp 315–316ºC (subl.). H NMR spectrum
(DMSO-d6), , ppm (J, Hz): 7.56 (2Н, d, J = 5.7, Н-4,6); 8.51 (2Н, d, J = 5.7, Н-3,7); 9.45 (2Н, s, Н-1,9); 12.05
(1Н, br. s, NH). 13C NMR spectrum, , ppm: 107.40 (4-СН and 6-СН); 117.83 (C-9a,9b); 143.10 (3-СН and
7-СН); 144.00 (C-4а,5а); 145.39 (1-СН and 9-СН). Mass spectrum, m/z (Irel, %): 169 [M]+ (100); 142
[M–HCN]+ (10.0), 141 (9.5), 115 [M–2HCN]+ (8.5), 114 (12.6), 88 (12.5), 87 (12.2), 75 (16.8), 74 (14.8), 63
(19.3), 62 (18.1), 52 (29.1), 51 (11.3), 50 (14.2), 40 (23.6), 39 (12.4), 38 (12.5). Found, %: С 68.07; Н 4.30;
N 23.75. C10H7N3·0.4H2O. Calculated, %: С 68.09; Н 4.46; N 23.82.
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