Transformations of mono- and bisphenylhydrazones of aliphatic-aromatic 1,5-diketones under the conditions of the fischer reaction

Article abstract of DOI:10.1023/A:1021725312271

The mono- and bisphenylhydrazones of 3-R-1,5-diphenylpentane-1,5-diones were obtained, and their transformations in the Fischer indole synthesis under various conditions were studied. It was shown that 4-R-2,6-diphenylpyridines, 2-phenylindole, and 5-R-1,-3-diphenyl-Δ²-pyrazolines are formed as the main products in addition to the 3-R-1-phenyl-3-(2-phenyl-3-indolyl)propan-1-ones or their phenylhydrazones produced as a result of indolization. The ways of formation of these compounds are discussed. Some transformations of the obtained ketones were studied.

Full text of DOI:10.1023/A:1021725312271

Chemistry of Heterocyclic Compounds, Vol. 38, No. 10, 2002
TRANSFORMATIONS OF MONO- AND
BISPHENYLHYDRAZONES OF ALIPHATIC-
AROMATIC 1,5-DIKETONES UNDER THE
CONDITIONS OF THE FISCHER REACTION
T. V. Moskovkina
The mono- and bisphenylhydrazones of 3-R-1,5-diphenylpentane-1,5-diones were obtained, and their
transformations in the Fischer indole synthesis under various conditions were studied. It was shown
that 4-R-2,6-diphenylpyridines, 2-phenylindole, and 5-R-1,3-diphenyl-∆2-pyrazolines are formed as the
main products in addition to the 3-R-1-phenyl-3-(2-phenyl-3-indolyl)propan-1-ones or their
phenylhydrazones produced as a result of indolization. The ways of formation of these compounds are
discussed. Some transformations of the obtained ketones were studied.
Keywords: bisphenylhydrazones, 1,5-diketones, 5-R-1,3-diphenyl-∆2-pyrazolines, 4-R-2,6-diphenyl-
pyridines, phenylhydrazones, 3-R-1-phenyl-3-(2-phenyl-3-indolyl)propan-1-ones, Fischer reaction.
Earlier we showed that substituted indoloacridines are obtained from alicyclic 1,5-diketones [di(2-
oxocyclohexyl)-R-methanes] in reaction with an equimolar amount of phenylhydrazine in an acidic medium [1].
Under analogous conditions substituted pyridocarbazoles are obtained from the semicyclic 1,5-diketones
[phenacyl(2-oxocyclohexyl)-R-methanes] [2]. The products result from transformations of the initially formed
monophenylhydrazones, i.e., Fischer indolization followed by cyclodehydration.
In a continuation of a study of the reactions of 1,5-dicarbonyl compounds with hydrazines [1,2] and
diamines [3] we investigated the reaction of the familiar 3-R-1,5-diphenyl-1,5-pentanediones 1a-c [4, 5] with
phenylhydrazine (Scheme 1) and the subsequent transformations of the obtained mono- and
bisphenylhydrazones (Scheme 2).
Scheme 1
R
R
R
β
α
α
2NH2NHPh
4NH2NHPh
Ph
Ph
Ph
Ph
Ph
Ph
N
N
O
O
N
O
1a–c
HNPh
2a–c
HNPh
PhNH
3a,c
a R = H, b R = Me, c R = Ph
__________________________________________________________________________________________
Far-Eastern State University, Vladivostok 690600, Russia; e-mail: piboc@stl.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1355-1363, October, 2002. Original article submitted
November 30, 2000; revision submitted February 22, 2002.
1190
0009-3122/02/3810-1190$27.00©2002 Plenum Publishing Corporation

It was possible to obtain the monophenylhydrazones 2a-c with good yields in the reaction of the
diketones 1a-c with twice the amount of phenylhydrazine in a mixture of acetic acid and ethanol (5:2) at room
temperature. Their composition and structure were confirmed by the results of elemental analysis, by data from
1
the IR spectra and mass spectra, and also by the H NMR spectra. Thus, in the IR spectra of compounds 2a-c
there are absorption bands at 1680 (νC=O) and 3300 cm-1 (νN–H), while in the mass spectra there are peaks for the
molecular ions with m/z 342, 356, and 418 respectively. The strongest peaks in the mass spectra correspond to
ions formed during the McLafferty rearrangement (m/z 222, 336, and 298 respectively) and to the C6H5CO+ ions
(m/z 105).
Scheme 2
X
Ph
R
(1)
Ph
N
H
4a–c; 15a
R
R
R
R
2
(2)
1
+
Ph
PhNH2
Ph
Ph
Ph
N
5a–c
Ph
N
X
Ph
N
NHPh
7a–c
Ph
Ph
NH
NHPh
X
NHPh
2a–c, 3a,c
6a–c, 17a,c
R
R
Me
Ph
(3)
C
N
+
+
PhCOMe
+
Ph
Ph
O
8a–c
Ph
N
NHPh
11
10
NHPh
9a–c
R
R
11
9a–c
N
N
N
N
N
H
Ph
Ph
Ph
Ph
14a–c
13a–c
12
2–8, 9, 13–15, 17 a R = H, b R = Me, c R = Ph; 2, 6, 4 X = O; 3, 15, 17 X = NNHPh
The reaction of the diketones 1a,c with a fourfold excess of phenylhydrazine under conditions similar to
those used for the synthesis of the monohydrazones gave the bisphenylhydrazones 3a,c, which are labile
compounds that are soon oxidized in air, particularly in chloroform solutions. Their IR spectra do not contain
the absorption of carbonyl groups, while the bands of the stretching vibrations of the N–H groups are observed
at 3360 cm-1. In the mass spectra there are peaks for the molecular ions with m/z 432 (for 3a) and m/z 508 (for
3c). The characteristics of the synthesized compounds are presented in greater detail in Table 1.
The transformations of the monohydrazones 2a-c under various conditions of Fischer indolization (see
the Experimental, methods A-D) took place ambiguously. The formation of 4-R-substituted
2,6-diphenylpyridines 5a-c through the intermediate compounds 6a-c and 7a-c (path 2), retro-Michael cleavage
1191

leading to 3-R-1-phenyl-2-propen-1-ones 8a-c, their phenylhydrazones 9a-c, acetophenone 10, and its
phenylhydrazone 11 (path 3), and also the associated formation of 2-phenylindole 12 and 5-R-1,3-diphenyl-∆2-
pyrazolines 13a-c were probably observed in addition to the desired transformation to 3-R-1-phenyl-3-(2-
phenyl-3-indolyl)propan-1-ones (β-indolylpropiophenones) 4a-c (path 1). The indole 12 (the product from
Fischer cyclization of the phenylhydrazone 11) and the pyrazolines 13a-c are formed as a result of
intramolecular addition of the NH group of the hydrazones 9a-c at the double bond.
The above-mentioned transformation products 4b, c, 5a-c, 12, 13a-c were isolated, and this included
isolation by column chromatography on silica gel. Their structures were confirmed by the spectra and, for the
previously known substances, by comparison of their physical constants with published data (Tables 2 and 3).
In addition, the unsaturated ketones 8a-c, acetophenone 10, and the products from aromatization of the
pyrazolines 13a-c (the 5-R-1,3-diphenylpyrazoles 14a-c), identified by comparison of their mass spectra with
the mass spectra of the authentic compounds, were detected in the reaction mixtures by chromato-
massspectrometric analysis. The mass spectra of compounds 8a-c contain peaks of molecular ions with m/z 132,
146, and 208, and the mass spectra of compounds 14a-c contain peaks with m/z 220, 234, and 296 respectively.
The desired transformation (1) and the side transformations (2, 3) took place to different degrees,
depending on the employed conditions and on the structure of the initial hydrazone. The highest yields of the
required β-indolylpropiophenones 4b,c (30-36%) were obtained when the reaction was carried out in absolute
methanol saturated with hydrogen chloride (method A). The ketone 4a could not be isolated in the individual
state, but chromato-mass-spectrometric analysis demonstrated its presence in the respective reaction mixtures at
the rate of 15-20%. The retro-Michael dissociation of the hydrazone 2c was more intense than for the
hydrazones 2a,b. The yield from conversion to pyridines was greatest for the hydrazone 2a (Table 3).
The obtained ketones 4b,c were previously unknown, and the method proposed here for their synthesis
from aliphatic-aromatic 1,5-diketones is new. At the same time other methods for the production of analogous
substances, e.g., by the addition of indole derivatives to α,β-unsaturated carbonyl compounds [6, 7] and by the
reaction of compounds of the gramine type with derivatives of acetoacetic ester followed by decarboxylation
[8, 9], have been described in the literature.
Some derivatives of the products 4b,c were obtained in order to confirm their structure: The
phenylhydrazones 15b,c by reaction with phenylhydrazine; the stereoisomeric 3-R-3-(2-phenyl-3-indolyl)-1-
phenyl-1-propanols (the α- and β-isomeric forms 16b and 16c respectively) by treatment of the ketones with
sodium borohydride (see Scheme 3). The isomers 16b and 16c were separated by high-pressure HPLC on a
column of Silasorb. The IR spectra of the phenylhydrazones 15b,c do not contain absorption bands for the
carbonyl group, but there are bands at 3450 and 3330 cm-1, corresponding to the absorption of the NH group in
the indole and hydrazone fragments. In the IR spectra of the stereoisomeric alcohols 16b,c instead of the
absorption band of the carbonyl group there is an absorption band for the OH group at 3597 cm-1. Their
structure is also confirmed by the 1H NMR spectra (Table 2).
Scheme 3
NHPh
HO
N
R
Ph
Ph
R
NaBH4
PhNHNH2
Ph
Ph
4b,c
N
N
H
H
α,β−16b
α,β−16c
15b,c
b R = Me, c R = Ph
1192

TABLE 1. The Characteristics of Mono- and Bisphenylhydrazones 2a-c and 3a,c
Found, %
IR
Mass
1H NMR spectrum (CDCl3),
——————
Com-
Empirical
formula
Yield,
%
spectrum,
spectrum,
Calculated, %
mp, °C
Rf*
0.39
0.45
δ, ppm,*2 SSCC (J), Hz
pound
M+, m/z
ν, cm-1
С
Н
N
C23H22N2O
C24H24N2O
80.70
80.70
6.25
6.43
8.35
8.19
108-109
3298 (NH),
1675 (CO),
1602 (C=N)
3293 (NH),
1676 (CO),
1602 (C=N)
342
356
82
85
2а
2.05 (2H, m, β-СН2); 2.70 (2H, m, γ-СН2);
3.20 (2H, m, α-СH2.); 6.70 (1H, t, J = 7.5, p-HPhNH);
7.00-8.00 (14H, m, HPh); 9.45 (1H, s, NH)
(decomp.)
80.75
80.90
6.92
6.74
8.00
7.86
132-133
151-153
1.00 (3H, d, J = 7.0, СH3); 2.85 (2H, m, γ-CH2);
2b
3.25 (3H, m, α-CH2 and β-СH);
6.80 (1H, t, J = 7.5, p-H PhNH);
7.20-8.00 (14H, m, HPh); 9.50 (1H, s, NH)
C29H26N2O
83.50
83.25
6.37
6.22
6.90
6.70
0.43
3294 (NH),
1676 (CO),
1602 (C=N)
418
3.65 (1H, m, β-СH); 3.20 (2H m, 2α-СH2);
2.50 (2H, m, γ-СH2); 6.80 (1H, t, J = 7.5, p-H PhNH);
7.00-8.00 (19H, m, HPh); 9.40 (1H, s, NH)
88
2c
C29H28N4
C35H32N4
80.75
80.55
6.30
6.48
13.10
12.96
114-116
(decomp.)
118-120
0.30
0.27
3359 (NH),
432
508
2.00 (2Н, m, β-СH2), 2.60-3.30 (4Н, m, 2α-СH2);
70
75
3а
1602 (C=N)
6.70-8.10 (20Н, m, HPh); 9.40 (1H, s, NH)
82.48
6.20
10.85
3343 (NH),
1602 (C=N)
3.05 (2Н, dd, J1 = 8.0, J2 = 14.0, HА АВХ-system);
3.28 (2Н, dd, J1 = 6.0, J2 = 14.0, HВ);
3.40 (1Н, m, HХ); 6.60-7.00 (25H, HPh);
9.65 (2H, s, NH)
3c
82.68
6.30
11.02
(decomp.)
_______
* On plates with Sorbfil, petroleum ether–ethyl acetate, 5:1.
*2 The signals were assigned on the basis of comparison with the 1H NMR spectra of the initial diketones.

TABLE 2. The Characteristics of β-(3-Indolyl) Ketones 4b,c and Their Derivatives: Phenylhydrazones 15a-c and
Alcohols 16b,c
Found, %
Mass
spectrum,
m/z
——————
IR spectrum
Com-
Empirical
formula
Yield, %
(method)
Calculated, %
mp, °C
6
Rf*
1Н NMR spectrum (CDCl3), δ, ppm, SSCS, (J), Hz
(CHCl3), ν, cm-1
pound
С
3
Н
4
N
5
1
2
7
8
9
10
11
C24H21NO 85.10
84.95
6.30
6.19
4.30 146-147 0.35
4.13
339
3455(NH);
1685(C=O)
1.55 (3H, d, J = 7.0, СH3,);
30 (A); 20 (B);
18 (C); 10 (D)
4b
3.45 (1H, dd, J1 = 7.0, J2 = 16.0, HA ABX-system);
3.65 (1H, dd, J1 = 7.0, J2 = 16.0, HB);
4.00 (1H, m, HX); 7.10-7.90 (14H, m, H arom);
7.95 (1H, s, NH)
C29H23NO 86.90
86.78
5.60
5.73
3.60 112-114 0.44
3.49
401
3454 (NH);
3.85 (1H, dd, J1 = 7.0, J2 = 18.0, HA ABX-system),
3.95 (1H, dd, J1 = 7.0, J2 = 18.0, HB );
5.30 (1H, t, J = 7.0, HX);
36 (A); 24 (B);
20 (C); 8 (D)
4c
1687 (С=O)
7.10-7.80 (19H, m, H arom); 8.0 (1H, s, NH)
C29H25N3
C30H27N3
84.05
83.85
6.11
6.02
10.30 166-167 0.40
10.12
415
429
3480 (NH indole);
3.07 (2H, m, CH2); 3.21 (2H, m, CH2);
70 (F)
93
15а
3350 (NH hydrazole) 6.55-7.80 (19H, m, H arom); 7.90 (2Н, br. s, NH)
83.80
6.40
9.95 176-178 0.42
3451 (NH indole);
1.67 (3Н, d, J = 7.0, CH3);
15b
83.91
6.29
9.79
3333 (NH hydrazole) 3. 07 (1H, dd, J1 = 9.5, J2 = 19.0, HA ABX-system);
3.55 (1H, m, HB); 3.55 (1H, m, HX);
6.16-8.10 (19Н, m, H arom); 7.90 (2H, br. s, NH)
C35H29N3
85.30
85.54
6.10
5.90
8.70 210-211 0.55
8.55
491
3453 (NH indole);
3.64 (1Н, dd, J1 = 3.5, J2 = 14.0, HA ABX-system);
90
15c
3330 (NH hydrazole) 3.82 (1Н, dd, J1 = 12.5, J2 = 14.0, HB);
4.72 (1H, dd, J1 = 3.5, J2 = 12.0, HX);
6.85-7.65 (24Н, m, H arom); 7.96 (2Н, br. s, NH)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
9
10
11
50
С24H23NO
54-56
0.17
341
3450 (NH indole);
3596 (OH)
1.48 (3Н, d, J = 7.1, СН3);
α-16b
2.09 and 2.39 (1Н, m and 1H, m, СН2);
3.50 (1Н, m, СНСН3); 4.43 (1Н, m, СНОН);
7.10-7.52 (14Н, m, Н arom); 7.94 (1Н, br. s, NH)
β-16b
α-16c
β-16c
С24H23NO
144-146 0.19
341
403
403
3450 NH indole);
3596 (OH)
1.47 (3H, d, J = 7.1, СН3);
17
45
15
2.12 and 2.56 (1Н, ddd, J1 = 6.0, J2 = 7.0, J3 = 14.4
and 1Н, ddd, J1 = 6.8, J2 = 9.1, J3 = 14.4, СН2);
3.17 (1Н, m, CHCH3); 4.47 (1Н, t, J = 6.9, СНОН);
7.00-7.72 (14H, m, Н arom); 8.05 (1Н, br. s, NH)
С29H25NO 86.20
6.40
6.20
3.60
3.47
70-72
0.28
3454 (NH indole);
3597 (OH)
2.65 and 2.91 (1H, ddd, J1 = 6.0, J2 = 7.4, J3 = 13.5
and 1H, ddd, J1 = 13.5, J2 = 6.4, J3 = 9.4, СН2);
4.30 (1H, dd, J1 = 6.0, J2 = 9.4, CHOH);
4.49 (1H, t, J = 7.0, CHPh);
86.35
6.60-7.75 (19H, m, H arom); 8.10 (1H, br. s, NH)
С29H25NO 86.12
6.06
6.20
3.30 197-198 0.32
3.47
3450 (NH indole);
3597 (OH)
2.56 and 2.71 (1H, ddd, J1 = 5.4, J2 = 9.7, J3 = 14.2
and 1H, ddd, J1 = 3.5, J2 = 10.8, J3 = 14.2, CH2);
4.46 (1H, dd, J1 = 3.5, J2 = 9.7, CHOH);
86.35
4.79 (1H, dd, J1 = 5.4, J2 = 10.8, CHPh);
7.05-7.67 (19H, m, H arom); 8.10 (1H , br. s, NH)
_______
* On plates with Sorbfil, petroleum ether–ethyl acetate, 3:1.

TABLE 3. The Characteristics of Side Processes Accompanying the Indolization of Phenylhydrazones 2a-c and 3a,c
Com-
IR spectrum,
mp, °C
[publ.]
Mass spectrum,
Yield, %
(method)
mp, °C
1Н NMR spectrum (CDCl3), δ, ppm, CCSS, (J), Hz
M+, m/z
ν,cm-1
pound
79-80
80-82
80-81 [10]
81-82 [11]
1598; 1489
1596; 1502
1596; 1500
3463; 1606
231
245
307
193
—
—
—
12 (A); 15 (B);
11 (C); 8 (D)
5a
5b
5c
12
10 (A); 13 (B);
5 (C); 6 (D)
134-136
188-189
136-137 [12, 13]
188-189 [14]
12 (A); 9 (B);
10 (C); 5 (D)
6.82 (1H, s, Н-3); 6.98-7.80 (9H, m, Н arоm);
8.35 (1Н, br. s, NH)
5-7* (from 2a);
10-12* (from );
2b
15-20* (from 2с)
154-156
103-105
158 [15, 16]
104-106 [17]
—
222
236
—
5-7*
5-7*
13a
13b
1596; 1504; 1494
1.35 (3H, d, J = 6.6; CH3); 2.90 (1H, dd, J1 = 18.0,
J2 = 5.0, HA ABX-system); 3.55 (1H, dd, J1 = 18.0,
J2 = 11.5, HB); 4.50 (1Н, m, HX); 6.85 (1H, t, J1 = 7.0,
p-H PhN); 7.20-7.80 (9H, m, HPh
)
134-136
134-135 [18]
1598; 1504; 1496
298
3.15 (1H, dd, J1 = 18.0, J2 = 7.0, HA ABX-system);
3.85 (1H, dd, J1 = 18.0. J2 = 13.0, HB); 5.30 (1H, dd,
J1 = 13.0, J2 = 7.0, HX); 6.80 (1H, t, J = 7.0, p-HPhN);
7.00-7.80 (14Н, m, HPh)
10-14*
13c
_______
* In all the investigated cases.

We also investigated the transformations of the bishydrazones 3a,c under the conditions of the Fischer
indole synthesis (methods A-D) and with heating in ethylene glycol (method E). According to theoretical ideas
the formation of the respective derivatives of 3,3'-bisindolylmethane (analogs of certain marine antibiotics) was
expected from these compounds. However, analysis of the obtained reaction mixtures by chromato-mass
spectrometry showed that they are hardly formed at all under the indicated conditions. The pyridines 5a,c
(probably through the intermediates 17a,c and 7a,c), 2-phenylindole 12, and ∆2-pyrazolines 13a,c were obtained
by methods A-D, and the phenylhydrazone 15a and the ketone derivative 4a were obtained by heating the
bishydrazone in ethylene glycol (Scheme 2). All these compounds were isolated from the reaction mixture and
identified by direct comparison with authentic samples (TLC, mixed melting tests, comparison of the spectra).
According to the obtained data, the bisphenylhydrazones 3a,c are transformed in an acidic medium like the
corresponding monophenylhydrazones 2a,c (scheme 2). They undergo retro-Michael dissociation and
conversion to pyridines extremely readily (paths 2 and 3 in the scheme). Indolization usually stops at the
formation of one indole ring and takes place more effectively not in an acidic medium (A-D) but under the
conditions of the thermal indole synthesis (E). Partial transformation of the diphenylhydrazones into the initial
1,5-diketones was observed on heating in acetic acid.
The obtained data show that the phenylhydrazones of the various types of 1,5-diketones differ
appreciably from each other in their behavior under the conditions of the Fischer reaction. Thus, for the above-
mentioned derivatives of aliphatic-aromatic 1,5-diketones, in contrast to their alicyclic and semicyclic analogs,
cyclodehydration of the indolization products formed from them was not observed, but a significant tendency
toward retro-Michael dissociation in an acidic medium was detected. At the same time partial pyridinization was
characteristic of hydrazones of all types.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker WM-250 instrument (250 MHz) in deuterochloroform
with the subsequent addition of deuteromethanol and with TMS as internal standard. The IR spectra were
recorded on a Spectrum BX-II FT-IR System spectrophotometer (Perkin-Elmer) in chloroform, vaseline oil, and
tablets with potassium bromide. The mass spectra were obtained on an LKB 9000s instrument with direct
injection into the ion source at 70 eV. In individual cases the reaction mixtures were analyzed by chromato-mass
spectrometry on an HP 5972 MSD/HP 5890 series II GC instrument (Hewlett-Packard); CPB-5 column,
140→280°C, 5 deg/min, carrier gas helium, ionizing potential 70 eV.
The melting points were determined on a Boetius bench. Silica gel L (Chemapol, former
Czechoslovakia) was used for low-pressure column chromatography. The reactions and the separation of the
reaction mixtures were monitored by TLC with detection of the spots with iodine vapor. To separate the
stereoisomeric alcohols we used high-pressure HPLC on an Ultrasphere-Si column (25 cm × 10 mm) in 7:1
petroleum ether–ethyl acetate; Du Pont 8800 chromatograph, RIDK-2 refractometric detector.
Monophenylhydrazones of 1,5-Diketones 1a-c (2a-c). To a solution of phenylhydrazine (20 mmol) in
a 5:4 mixture of acetic acid and ethanol (2.2 ml) we added a solution of the diketone 1a-c (10 mmol) in acetic
acid (10 ml). The reaction mixture was kept at room temperature for 2-4 h. The precipitated product 2a-c was
filtered off, washed on the filtered with alcohol, and dried under vacuum.
Bisphenylhydrazones of 1,5-Diketones 1a,c (3a,c). To a solution of phenylhydrazine (40 mmol) in a
5:4 mixture of acetic acid and ethanol (4.4 ml) while stirring we added a solution of the diketone 1a,c (10 mmol)
in acetic acid (5 ml). The reaction mixture was kept at room temperature for 3-5 h until a precipitate of the
product 3a,c had formed. The precipitate was filtered off, washed with alcohol, and recrystallized from alcohol.
1197

Heterocyclization of Monophenylhydrazones 2a-c. A. The compound 2a-c (10 mmol) was boiled in
absolute methanol (30 ml) saturated with hydrogen chloride for 1.5-2 h. The solution was yellow and then
became dark-green. The precipitated ammonium chloride was filtered off. The methanol was distilled from the
filtrate, and water (20 ml) and ethyl acetate (20 ml) were added to the oily residue. The ethyl acetate extract was
washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated. A
mixture of reaction products was obtained (TLC) in the form of a thick oil, which was stirred with ether (20 ml).
After 2-3 h the precipitated chromatographically individual ketone 4b (0.7 g, 20%) or 4c (1.0 g, 25%) was
filtered off. The filtrate was evaporated, and the residue was separated by column chromatography with silica
gel. The substances were eluted with petroleum ether and a mixture of petroleum ether and ethyl acetate
(100:1 → 100:7). Here the ∆2-pyrazoline 13a-c (fraction with violet fluorescence), pyridine 5a-c,
2-phenylindole 12, and further amounts of the ketone 4b,c were isolated in succession. The total yield amounted
to 30% of 4b and 36% of 4c. Compounds 4b,c were washed with ether and recrystallized from alcohol.
B. A mixture of the compound 2a-c (10 mmol) and polyphosphoric acid (2 g) was heated to 180°C for
1 h. It was then kept at this temperature for 15 min and cooled to room temperature. To the reaction mass we
added a 5% solution of sodium hydroxide to pH 8. The product was extracted with ethyl acetate (3 × 10 ml), and
the extract was dried over magnesium sulfate and evaporated. The reaction products were isolated from the
residue as described in method A.
C. The compound 2a-c (10 mmol) was heated in acetic acid (10 ml) to boiling point for 30 min and kept
at this temperature for 2.5 h. The reaction mixture was cooled to room temperature, neutralized with a saturated
solution of sodium carbonate, and extracted with ethyl acetate (3 × 10 ml). The extract was dried over magnesium
sulfate and evaporated. The reaction products were isolated from the residue as described in method A.
D. A mixture of the compound 2a-c (10 mmol) and boron trifluoride etherate (2 ml) in benzene (10 ml)
was boiled for 3 h. The benzene was then distilled from the reaction mixture, a saturated solution of sodium
bicarbonate (25 ml) was added to the residue, and the product was extracted with ethyl acetate (3 × 10 ml). The
extract was dried over magnesium sulfate and evaporated. The reaction products were extracted from the
residue (method A).
Heterocyclization of Bisphenylhydrazones 3a,c. A-D. The products 5a,c, 12, 13a,c were obtained as a
result of treatment of compounds 3a,c by methods A-D described above and were identified by comparison with
authentic samples.
E. The bisphenylhydrazone 3a (1 mmol) was kept in freshly distilled ethylene glycol (10 ml) at 190°C
for 6 h. After the reaction mixture had cooled the precipitate was filtered off and washed with ethanol, and
0.29 g (70%) of β-(2-phenyl-3-indolyl)propiophenone phenylhydrazone (15a) was obtained.
Phenylhydrazones of β-Indolylpropiophenones 4b,c (15b,c). A mixture of 4b,c (1 mmol) with
phenylhydrazine (2 mmol) was boiled in ethanol (10 ml) for 4-6 h. After the reaction mass had cooled the
precipitate of the respective phenylhydrazone 15b,c was filtered off and recrystallized from alcohol.
The α and β Stereoisomers of 3-Methyl-1-phenyl-3-(2-phenyl-3-indolyl)-1-propanol (16b) and
1,3-Diphenyl-3-(2-phenyl-3-indolyl)-1-propanol (16c). A mixture of the ketone 4b,c (1 mmol) and sodium
borohydride (0.2 g) in THF (15 ml) and water (2 ml) was stirred at room temperature for 2 h. The organic layer
was separated, washed to a neutral reaction with water, and dried over magnesium sulfate. The solvent was
distilled, and 0.30 and 0.35 g respectively of a caramel-like mass was obtained. Analysis of the reaction
products by chromato-mass spectrometry showed the presence of two substances with identical molecular mass
equal to 341 (in the case of 16b) and 403 (in the case of 16c). The individual α- and β-diastereoisomers 16b or
16c (in a ratio of ~1:3) were isolated by HPLC on a column of Silasorb and were recrystallized from hexane.
The work was carried out with financial support from the Russian Fund of Fundamental Research
(Grant 98-03-32891) and grant REC-003 from the US CRDF fund and the Ministry of Education of the Russian
Federation.
1198

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