Annelation of the pyrrole to the steroid skeleton using the Trofimov reaction

Article abstract of DOI:10.1023/A:1014803325701

The product of annelation of the N-vinyl pyrrole ring with steroid skeleton of 5-cholestene was obtained in a single regioselective step by the reaction of 5-cholesten-3-one oxime with acetylene in KOH-DMSO by the Trofimov reaction.

Full text of DOI:10.1023/A:1014803325701

Chemistry of Heterocyclic Compounds, Vol. 38, No. 1, 2002
ANNELATION OF THE PYRROLE
TO THE STEROID SKELETON
USING THE TROFIMOV REACTION*
A. M. Vasil'tsov, A. B. Zaitsev, A. I. Mikhaleva, E. Yu. Shmidt, and A.V.Afonin
The product of annelation of the N-vinyl pyrrole ring with steroid skeleton of 5-cholestene was obtained
in a single regioselective step by the reaction of 5-cholesten-3-one oxime with acetylene in KOH-DMSO
by the Trofimov reaction.
Keywords: acetylene, N-vinylpyrroles, ketosteroids, Trofimov reaction, KOH–DMSO system.
The reaction of ketoximes, containing a methylene group in the α-position to the oxime function, with
acetylene in strongly basic conditions (the Trofimov reaction [1-7]) is an effective and universal method for the
construction of 1H- and N-vinylpyrrole systems. The expected interest in the biological properties of the desired
products led us to investigate the use of this reaction for modification of ketosteroids, using 5-cholesten-3-one
(1) as an example, particularly since pyrrole rings had been introduced into other isopropenoids by this reaction
[8]. Including in a single molecule the steroid skeleton and the pyrrole structure, units which are connected with
biological activity in many natural and synthetic compounds, has great potential for the creation of new
medicinals, among them polymers (via polymerization of the N-vinyl group) with prolonged activity.
26
Me
21
24
22
Me
Me
Me
25
Me
20
18 Me
23
Me
19
Me
12
17
16
15
13
14
11
9
27
Me
Me
HC CH
, ~25 atm
HA
HB
1
2
3
8
10
β
KOH–DMSO, 120°C, 30 min
5
7
α
6
4
2'
HON
3
1'
HX
N
3'
2
25%
4'
E:Z ~ 1:1
5'
In this paper we report the first successful attempt at annelation of the steroid skeleton with the
N-vinylpyrrole unit by the interaction 5-cholesten-3-one oxime (2) with acetylene in the strongly basic
KOH–DMSO system. The reaction occurs regioselectively with the formation of a single product of
pyrrolisation of the methylene group at position 4 (compound 3) in a preparative yield of 25%.
_______
* Presented to Academician of the Russian Academy of Sciences M. G. Voronkov on his 80th birthday.
__________________________________________________________________________________________
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk
664033, Russia; e-mail: mikh@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1,
66-70, January 2002. Original paper submitted April 27, 2001.
60
0009-3122/02/3801-0060$27.00©2002 Plenum Publishing Corporation

The oxime 2 was prepared from ketone 1 as a mixture of the E- and Z-configurational isomers. This is
most clearly apparent from the presence of two signals for each of atoms C(2) and C(4) differing by 5-7 ppm
13
(Table 1) in the C NMR spectrum of oxime 2, caused by the different spatial orientation of the OH groups
relative to these carbon atoms [9]. The purity of compound 3 is indicated by the presence of a single set of
1
signals for the vinyl group and the pyrrole ring in the H and 13C NMR spectra (Tables 1 and 2), although
hypothetically the two isomers 4 and 5 could have been formed.
A correlation between protons H-6 and H-4' was observed in the 2D NOESY spectrum of 3 which
shows the structure unambiguously (similar correlations in the structures of 4 and 5 are not possible because of
the long distance between proton H-4' and H-6 and H-5 respectively).
Me
Me
N
N
5
4
Apart from the resonances of C(3) and C(4), which form part of the pyrrole ring, the signals of the carbon
atoms of the steroid residue are changed little on formation of the pyrrole ring. The strong field shift of the
signal for C(6) (~7 ppm) in the vinylpyrrolocholestene 3 (in comparison with the ketone 1 and the oxime 2) is
explained by conjugation of the ∆5 bond with the pyrrole unit.
TABLE 1. Chemical Shifts in the 13C NMR Spectra of Compounds 1-3*
Carbon
atom
δ, ppm
2
Carbon
atom
δ, ppm
2
1
3
1
3
С(1)
С(2)
36.19
36.74
36.38
34.69
19.13
C(17)
C(18)
56.68
11.92
56.87
12.09
57.04
12.05
20.95 (E)
27.91 (Z)
С(3)
С(4)
С(5)
С(6)
208.70
49.21
159.97
160.39
126.67
120.45
137.32
115.30
C(19)
C(20)
C(21)
C(22)
19.17
35.74
18.74
36.92
19.14
19.24
35.98
18.81
35.90
18.50
36.15
32.08 (Z)
37.10 (E)
138.61
122.71
138.62
139.73
18.91
122.13
37.99
38.08
122.78
С(7)
С(8)
С(9)
С(10)
С(11)
31.78
31.98
48.13
37.43
21.36
31.26
31.98
49.70
37.69
31.75
31.83
48.24
36.29
21.63
C(23)
C(24)
C(25)
C(26)
C(27)
23.84
39.74
27.96
22.76
22.55
24.02
39.92
28.21
23.01
22.75
23.94
39.97
28.09
22.90
22.65
21.31
21.38
С(12)
С(13)
С(14)
С(15)
С(16)
39.52
42.42
56.23
24.25
28.17
39.71
42.53
56.33
24.46
28.42
39.61
42.45
56.30
24.36
28.35
C(3')
C(4')
Cα
105.57
116.65
130.33
96.38
Cβ
_______
* Data from [10] were partially used to assign the signals.
61

TABLE 2. Chemical Shifts (δ, ppm) and Coupling Constants (J, Hz) in the
1H NMR Spectra of Compounds 1-3
Com-
Н-6
Н-4'
H-5'
HA
HВ
HХ
pound
5.33 (1H, m)
1
2
5.42 (1H, m)
5.37 (1H, m)
5.69 (1H, m) 6.25 (1H, d, 6.86 (1H, d) 4.58 (1H, dd, 5.01 (1H, dd, 6.77 (1H, dd)
3
3J4', 5' = 3.1)
2JAB = 1.3,
3JAX = 6.7)
3JBX = 13.7)
Com-
pound
Me(18)
Me(19)
Me(21)
Me(26*)
Me(27*)
0.70 (3H, s)
0.69 (3H, s)
0.71 (3H, s)
1.18 (3H, s)
1.10 (3H, s)
0.98 (3H, s)
0.92 (3H, s)
0.90 (3H, s)
0.92 (3H, s)
0.87 (3H, d)
0.86 (3H, d)
0.86 (3H, d)
0.86 (3H, d)
0.85 (3H, d)
0.85 (3H, d)
1
2
3
_______
* 3J = 1.8 Hz.
According to the mechanism of the Trofimov reaction [2, 3], which includes the initial formation of the
O-vinylketoxime A with subsequent [3,3] sigmatropic rearrangement of its N-vinylhydroxylamine tautomer B,
the such nature of this process may be explained by the greater stabilization of intermediates A and B by
conjugation (in comparison with the possible isomeric structures). Decreasing the reaction temperature from
120° to 100°C and lower led to a considerable deceleration of pyrrolisation in comparison with the rates of side
processes, the most probable of which there are prototropic isomerization of the bond ∆5 → ∆4 in the ketoxime 2
and followed partial deoximation. It was shown by HPLC that only 50% of the initial oxime 2 remained after 1h
in KOH–DMSO at 90°C in the absence of acetylene. Only traces of N-vinylpyrrolocholestene 3 were detected in
the reaction mixture by 1H NMR spectroscopy along with 4-cholestene-3-one oxime (an isomer of 5-cholesten-
3-one oxime) after carrying out the reaction for 5 h at 100°C. One of the most likely reasons for the low rate of
reaction under the given conditions may be the liquid crystalline state of the starting oxime, which specifically
interacts with DMSO. We have previously observed unusual behavior of steroids in the KOH–DMSO system
during the vinylation of cholestene with acetylene [11] when a remarkably narrow range of temperature for
successful completion of the reaction was noted. When the temperature was raised above 120°C a considerable
amount of oily impurity was produced which made isolation of the required products difficult. How many
difficulties may have the alternative step-wise annelation of steroids with a pyrrole units is illustrated by the
synthesis of N-phenylpyrrolo[2,3-b]cholestanes from derivatives of cholestan-2,3-dione [12]. Our synthesis of
N-vinylpyrrolocholestene 3, despite its moderate yield of the required product, in view of the simplicity of the
process and the availability of the reagents may serve as a method for obtaining the basic structural unit for
preparing a library of promising candidates for medicinal use by combinatorial chemical methods.
EXPERIMENTAL
1H (400.13 MHz) and 13C (101.61 MHz) NMR spectra were recorded on a Bruker 400-DPX
spectrometer in CDCl3 with HMDS as internal standard. Infrared spectra of KBr disks were recorded with a
Bruker ISF 25 machine. Molecular masses and elemental compositions were determined from the exact mass of
molecular ions on a Finnigan MAT-8200 mass spectrometer. Chromatographic experiments were carried out
62

with a Milikhrom A-02 (ZAO "EkoNova", Novosibirsk, Russia) microcolumn liquid chromatograph with a
column (2 × 75 mm) filled with Nucleosil 100-5 C18 AB (Machery-Nagel, Germany) with an efficiency of
5000-6000 plates according to the chrysene peak in acetonitrile.
The cholesterol starting material is a commercial product from ICN Pharmaceuticals, Inc. Pyridinium
chlorochromate, used as an oxidizing agent was synthesized by a known method [13].
5-Cholesten-3-one (1) was obtained by oxidation of the cholesterol with pyridinium chlorochromate in
CH2Cl2 by a known method [14]. The product was purified by recrystallisation from aqueous acetone.
5-Cholesten-3-one oxime (2). A suspension of NaOAc (0.56 g, 6.8 mmol) and NH2OH·HCl (0.47 g,
6.8 mmol) in ethanol (40 ml) was added over 20 min with stirring to a mixture of ketone 1 (1.74 g, 4.5 mmol)
and pyridine (25 ml). After stirring for 25 min the reaction mixture was poured into cold water (100 ml), the
precipitate was filtered off, washed with water, and dried in air to give the oxime 2. Yield 1.67 g (4.2 mmol,
93%).
b
N-Vinylcholesteno[3,4- ]pyrrole (3).
2
A mixture of oxime (0.82 g, 2.1 mmol), KOH·0.5H O (0.7 g,
2
10.8 mmol) and DMSO (50 ml) was placed in a half liter steel rotating autoclave, charged with acetylene (initial
pressure 14 atm, maximum pressure during the reaction 25 atm). The temperature was raised to 120°C with
stirring and the mixture was stirred at this temperature for 30 min. After cooling, water (50 ml) was added to the
reaction mixture which was then extracted with ether (4 × 40 ml). The extract was washed with water
(4 × 30 ml) and dried over calcined potassium carbonate. After removal of the ether the residue was placed on a
column (deactivated basic aluminum oxide, hexane). Vinylpyrrole 3 (0.23 g, 25%) was obtained as colorless
transparent needles after recrystallisation from acetone. At 136°C the crystals became brown and at 146°C they
melted to give a clear liquid. IR spectrum: ν, cm-1: 1639 (vs) (CH=CH2), 1570 (s) (C=CH), 1546 (sh) (pyrrole
ring), 1491 (s) (pyrrole ring), 1465 (pyrrole ring), 1442, 1381 (s) ( pyrrole skeleton), 1323 (m) (C-N), 1301 (m)
(C–N), 1230 (s), 1168 (m), 1101, 1074, 1030 (m) (CH, planar def. pyrrole), 957 (m) (HC=CH rotation), 917
(m), 860 (s) (=CH2 twist), 831 (m), 799 (m), 742 (m), 717 (s) (CH, out of plane def.), 677 (m), 614, 581 (m)
(HC=CH twist). Mass spectrum, m/z (rel. intensity, %): 433 (100, M), 418 (9, M-CH3), 320 (1, M-C8H17), 305
(1, M-CH3-C8H17), 279 (2, M-CH3-HC≡CH-C8H17), 278 (2, M-H-CH3-HC≡CH-C8H17), 264 (1,
M-2CH3-HC≡CH-C8H17), 224 (6), 210 (6). Found: m/z = 433.7234. C31H47N. Calculated 433.7237. Found, %:
C 85.11; H 11.56; N 3.48. C31H47N. Calculated, %: C 85.85; H 10.92; N 3.23.
REFERENCES
1.
B. A. Trofimov, Heteroatomic Derivatives of Acetylene: New Polyfunctional Monomers, Reagents, and
Intermediates [in Russian], Nauka, Moscow (1981).
B. A. Trofimov and N. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Novosibirsk (1984).
B. A. Trofimov, in: A. R. Katritzky (ed.), Adv. Heterocycl. Chem., Acad. Press, San Diego (1990),
Vol. 51, 177.
2.
3.
4.
5.
6.
7.
8.
B. A. Trofimov, in: R. A. Jones (ed.), Pyrroles. The Synthesis, Reactivity, and Physical Properties of
Substituted Pyrroles, Intersci., Wiley, New York (1992), Pt. 2, 131.
A. F. Pozharskii, V. A. Anisimova, and E. B. Tsupak, Prakticum on the Chemistry of Heterocycles
[in Russian], Rostov University Press, Rostov (1988), 9.
R. J. Tedeshci, in: Encyclopedia of Physical Science and Technology, Acad. Press, San Diego (1992),
Vol. 1, 27.
G. P. Bean, in: R. A Jones (ed.), Pyrroles. The Synthesis and the Chemical and Physical Properties of
the Pyrrole Ring, Intersci. Wiley, New York (1992), Pt. 1, 105.
B. A. Trofimov, A. M. Vasil'tsov, E. Yu. Shmidt, O. V. Petrova, and A. I. Mikhaleva, Zh. Org. Khim.,
30, 576 (1994).
63

9.
A. V. Afonin, I. A. Ushakov, O. A. Tarasova, E. Yu. Schmidt, A. I. Mikhaleva, and V. K. Voronov, Zh.
Org. Khim., 36, 1831 (2000).
10.
11.
S. S. Korde, R. Katoch, R. A. Udasi, and G. K. Trivedi, Magn. Res. Chem., 37, 594 (1999).
B. A. Trofimov, A. M. Vasil'tsov, E. Yu. Schmidt, A. B. Zaitsev, A. I. Mikhaleva, and A. V. Afonin,
Synthesis, 1521 (2000).
12.
13.
14.
B. M. Trost and E. Keiman, J.Org.Chem., 45, 2741 (1980).
E. J. Corey and J. W. Suggs, Tetrahedron Lett., 2647 (1975).
E. J. Parish and S. Chitrokorn, Org. Prep. Proc. Int., 15, 365 (1983).
64