Reaction of Steroidal Ketones with Substituted Alkylazide
1Steroidal Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh-202002 India.
2Somany Institute of Technology and Management, Rewari.
*Corresponding Author E-mail: mmushfiqs@gmail.com.
ABSTRACT:
A series of steroidal N-2-phenylethenyl-7a-aza-B-homo-3b-acetoxycholest-5-en-7-one were prepared by the reaction of 2-hydroxy-2-phenylethylazide with steroidal a, b-unsaturated ketones in dichloromethane. Structures of all the synthesized compounds are supported by elemental analysis IR, 1HNMR and Mass Spectral studies and chemical evidences.
KEYWORDS: Steroids, Steroidal ketones, N-substituted lactams, substituted alkylazide.
Lactam are particular important molecules owing to their versatility as synthesis intermediates and widespread occurring in Biological important compound.1-8 In continuation with this, Aube et al. and co-worker9-25 have reported the synthesis of N-hydroxy alkyl lactams utilizing the slightly modified version of Schmidt reaction where hydrazoic acid was replaced by hydroxy alkyl azide. Recent reports of obtaining various N-hydroxy lactam and our continued interest in synthesis of modified steroids prompted us to study the similar rection with steroidal substrate. In connection with this, we wish to report synthesis of N-2-phenylethenyl-7a-aza-B-homo-3b-acetoxy -5-en-7-one and its analogues.
EXPERIMENTAL:
All the melting points are uncorrected infrared spectra (I.R.) were measured in KBr with Perkin-Elmer 237 and Unichem SP 300 spectrophotometers. The I.R. values were given in cm-1 (s-strong m-medium w-weak br-broad).
1HNMR spectra were run in CDCl3 and Bruker AC 300 (300 MHz). These values were given in ppm (s-singlet d-doublet t-triplet b-broad m-multipletγ centered at), using TMS as internal standard. The Mass spectra were measured as a JMSD-100 Mass Spectrometry at 70eV using direct insertion technique at a source temperature 250o. Thin layer chromatography plates were coated with silica gel G and developed in iodine chamber light petroleum refers to fraction b. p. 60-80o.
Synthesis of Steroidal Lactams (General Procedure): A mixture of the ketones (I, II, III and IV) (0.45 mmol) was mixed with 2-hydroxy-2-phenylethylazide (1.54 mmol) in dichloromethane (25 ml) reaction mixture was cooled to 0oC. BF3-etherate (0.5 ml) was added drop-wise over five minutes; immediate gas was evaluation was noticed upon addition. The reaction mixture stirred for four hours. The progress of the reaction was determined by TLC. After completion of the reaction, organic matter was extracted with ether and ethereal layer was washed with water, (5%) sodium hydrogen carbonate solution and again with water and dried over anhydrous (Na2SO4). Evaporation of the solvents, gave oil furnished V and VI as crystallized product from methanol while VII and VII failed to crystallize from usual solvents. The yield m. p. and spectral data are given in Table-1.
RESULTS AND DISCUSSION:
In the continuation to the work reported26-33from our laboratories earlier work26 the purpose of this investigation is to extend the scope of these reactions in the preparation of N-substituted lactams. Therefore, easily accessible steroidal α, β-unsaturated ketones such as 3β-acetoxycholest-5-en-7-one (I) 3β-chlorocholest-5-en-7-one (II) 3β-hydroxycholest-5-en-7-one (III) and cholest-4-en-3-one (IV). Thus ketones (I-IV) were treated with 2-hydroxy-2-phenylethylazide, the products (V-VIII) respectively were characterized on the basis of elemental analysis spectral and chemical methods.
The Compound (V) m.p. 110o was analysed for C37H53NO3 indicating that the reagent 2-hydroxy-2-phenylethylazide is incorporated. The I.R. spectrum of the compound showed weak absorption band at 3033 and 1626 cm-1 for the aromatic ring. Bands at 1715 and 1248 cm-1, were assigned for (acetate, β-oriented) and at cm-1 1660 for (CONH). Other bands were exhibited at 1605 for (C=C) and 1350 cm-1 for (C–N) and absence of a band around 3100-3300 for N-H. These values supported the presence of N-substituted lactam moiety.
On the basis of elemental analysis and I.R. two isomeric structure (V) and (Va) are possible for compound m. p. 110o. The distinction between the two structures (V) and (Va) could be made on the basis of its 1HNMR spectral study which showed a multiplet at δ δ7.46 integrating for the five protons which can be assigned to the protons of aromatic ring. Another multiplet ranging δ 6.30-6.39 integrating for two protons could be assigned to the protons of N–CH and =CH–Ar. A singlet at δ 5.8 integrating for one proton indicated the presence of another vinylic hydrogen at C6-H as in structure (V). A multiplet centered at δ 2.6 integrating for one proton is assigned to C8-βH as in (V) although one expected it to be at ~δ 3.311 but in the alternate structure the same proton would not be shifted down beyond δ 2.3 as C8-βH in structure (Va). Slight up field shift (d3.3 to 2.6) may be due the field generated by the aromatic ring. A multiplet was observed, integrating for one proton at δ3.9 (W½ = 16Hz) which could be attributed to C3-αH. The acetate methyl protons were observed at δ 2.1 as sharp singlet. The angular and side chain methyls were observed at δ 1.16, 1.14, 1.10 and 0.94.
X= (I) OAc (II) Cl (III) OH
(IV)
X= (I) OAc (II) Cl (III) OH
X= (I) OAc (II) Cl (III) OH
(Va)
(VIII)
(VIIIa)
In the light of forgoing discussion and the mechanism proposed for such conversion15 the compound, m. p. 110o, is tentatively characterized as N-2-phenylethenyl-7a-aza-B-homo-3β-acetoxycholest-5-en-7-one (V). Similarly the synthesized compound (VI and VII) are characterized on the same grounds and these find support from the fact that (VII) can be easily converted to (V) or (VI) by conventional methods.
PHYSICAL, SPECTRAL AND ANALYTICAL DATA FOR THE COMPOUNDS V TO VIII
|
Compound |
M. P. oC |
Formula (M+) |
Found required of |
vmax/cm-1 |
mc dH |
||
|
C |
H |
N |
|||||
|
V. |
110 |
C37H53NO3
|
80.39 (80.41) |
10.98 (11.12) |
6.05 (6.06) |
3033, 1626 (aromatic), 1715 aromatic 1248 (acetate, b-oriented), 1660 (CONH) 1605 (C=C) and 1350 (C– N) |
7.46 mc (5H), 6.30-6.39 mc (2H, N-CH and =CH-Ar) 5.8 s(H, C6-H, vinylic-H) 2.6 mc (C8-bH), 3.9 mc (H, C3-aH). 2.1 s (3H, OAc-) 1.16, 1.14, 1.10, 0 .94 (Me) |
|
VI. |
103 |
C35H50NOCl
|
80.94 (80.99) |
10.79 (10.81) |
6.09 (6.11) |
3024, 1623 (aromatic), 1665 (CONH) 1597 (C=C), 1360 (C-N) and 708 (C-Cl) |
7.40 mc (5H), 6.07-6.16 (2H, N-CH and =CH-Ar), 5.6 s(H, C6-H, vinylic-H) 2.3 mc (H, C8-bH), 3.4 mc (H, C3-aH). 1.11, 1.02, 0.93, 0.91, 0.87 and 0.71 (Me) |
|
VII. |
Oil |
C35H51NO2
|
81.12 (81.19) |
11.01 (11.13) |
6.17 (6.18) |
3185-3366 (-OH), 3070, 1631 (aromatic), 1662 (CONH), 1615(C=C) 1348 (C– N). |
7.18 mc (5H), 6.23-6.31 (2H, N-CH and =CH-Ar), 5.2 s(H, C6-H, vinylic-H) 3.7 mc (H, C3-aH), 4.2 br (OH) 1.0, 0.96, 0.91, 0.84 and 0.72 (Me) |
|
VIII. |
Oil |
C35H49NO |
81.12 (81.19) |
11.01 (11.13) |
6.21 (6.23) |
3050, 1630 (aromatic), 1658 (CONH) 1600 (C=C) and 1352 (C-N) |
6.92-7.35 mc (5H), 6.07-6.15 (2H, N-CH and =CH-Ar), 5.5 s(H, C4a-H, vinylic-H) 1.18, 1.11, 1.06, 0.91, 0.87, 0.85, 0.80 and 0.7 (Me) |
The ketone (IV) when allowed to react with 2-hydroxy-2-phenylethylazide in dichloromethane afforded N-2-phenylethenyl-4-aza-A-homocholest-4a-en-3-one as oil.
The compound (VIII) was analysed for C35H49NO indicating that the reagent 2-hydroxy-2-phenylethylazide is incorporated. The I.R. spectrum of the compound showed bands at 3050, 1630 cm-1 which could be assigned for aromatic ring. Bands at 1658 cm-1 is ascribed to (CONH). Other bands were exhibited at the 1600 (C=C) and 1352 cm-1 (C-N). These values supported the presence of lactam moiety.
On the basis of the elemental analysis and I.R. two possible isomeric structures (VIII) and (VIIIa) can be written for the oil. The distinction is based on its 1HNMR spectral study. 1HNMR spectrum showed a multiplet at δ92-7.35 integrating for five protons which can be assigned to the protons of aromatic moiety. Another multiplet ranging δ 6.07-6.15 integrating for two protons could be assigned to the proton of N-CH and =CH-Ar. A singlet at δ5.5 integrating for one proton indicated the presence of a vinylic proton at C4a-H. The angular and side chain methyl protons were observed at δ1.18, 1.11, 1.06, 0.91, 0.87, 0.85, 0.8 and 0.71. These values discarded the structure (VIIIa) in favor of (VIII).
In the light of forgoing discussion the oil is tentatively characterized as N-2-phenylethenyl-4-aza-A-homocholest-4a-en-3-one (VIII).
ACKNOWLEDGEMENT:
We are grateful to the Chairman of Department of Chemistry Aligarh Muslim University Aligarh for providing necessary facilities.
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Received on 17.04.2010 Modified on 02.05.2010
Accepted on 22.05.2010 © AJRC All right reserved
Asian J. Research Chem. 3(3): July- Sept. 2010; Page 747-750