A new and convenient synthesis of 13,16-diazaestrone analogs

Article abstract of DOI:10.1016/S0040-4039(03)00093-5

Imidazolidine-2,4-dione was chemoselectively N-alkylated at the imidic NH with several 2-(3,4-dihydro-1-naphthalenyl)ethyl-4-methylphenylsulphonates to give the corresponding imides for the first time which on selective reduction at one of the carbonyl groups followed by cyclization in PPA gave the corresponding title compounds.

Full text of DOI:10.1016/S0040-4039(03)00093-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1843–1845
A new and convenient synthesis of 13,16-diazaestrone analogs
J. A. Parihar and M. M. V. Ramana*
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai-400098, India
Received 3 November 2002; revised 20 December 2002; accepted 10 January 2003
Abstract—Imidazolidine-2,4-dione was chemoselectively N-alkylated at the imidic NH with several 2-(3,4-dihydro-1-naph-
thalenyl)ethyl-4-methylphenylsulphonates to give the corresponding imides for the first time which on selective reduction at one
of the carbonyl groups followed by cyclization in PPA gave the corresponding title compounds. © 2003 Elsevier Science Ltd. All
rights reserved.
Several azasteroids1–7 have been synthesised due to
their potential biological properties.8–10 Moreover some
of the diazasteroids exhibit analgesic2 and cardiotonic
and hypotensive activity.11 Though many azasteroids
have been reported, the title compounds have not yet
been synthesised. We now wish to report the first
syntheses of the title compounds.
ethanols 1a–c were converted to the corresponding
4-methylphenylsulphonates12 2a–c. Imidazolidine-2,4-
dione 3 was then chemoselectively N-alkylated at the
imidic NH with 2a–c using K2CO3 in DMF under
reflux for 90 min to give the corresponding seco-
azasteroids13 4a–c for the first time. Selective reduction
of 4a–c at one of the carbonyl groups employing
NaBH4 in MeOH under reflux for 6 h afforded the
corresponding hydroxy lactams14 5a–c which on heat-
Towards this end, 2-(3,4-dihydro-1-naphthalenyl)-
Scheme 1. Reagents and conditions: (1) p-TsCl, CHCl3, C5H5N; (2) K2CO3/DMF, reflux, 90 min; (3) NaBH4, MeOH, reflux, 6 h;
(4) PPA, stream bath, 6 h.
Keywords: 4-methylphenylsulphonylation; chemoselective N-alkylation; imide reduction; cyclization; 13,16-diazasteroids.
* Corresponding author. E-mail: mmvramana@indiatimes.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00093-5

1844
J. A. Parihar, M. M. V. Ramana / Tetrahedron Letters 44 (2003) 1843–1845
Table 1.
Compound
R1
R2
R3
mpa (°C)
Yieldb (%)
2a
2b
2c
4a
4b
4c
5a
5b
5c
6a
6b
6c
H
CH3
H
H
CH3
H
H
CH3
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
Cl
H
H
Cl
H
H
Cl
51 (lit1 mp 51.5–53)
85
84
84
76
72
67
Oil
Oil
98–100
74–76
Oil
Oil
126–128
Oil
48 (24)c
44 (22)c
44 (25)c
67
60
39
202
197–199
184–186
a Melting points are uncorrected.
b Yield refers to purified product.
c % of starting material recovered.
ing in PPA on a steam bath for 6 h underwent
intramolecular cyclization to afford the corresponding
title compounds15 6a–c (Scheme 1).
8. Martin-Smith, M.; Sugrue, M. F. J. Pharm. Pharmacol.
1964, 16, 569–589.
9. Allauddin, M.; Martin-Smith, M. J. Pharm. Pharmacol.
1962, 14, 325–345.
The required 2-(3,4-dihydro-1-naphthalenyl)ethanols
1a–c were prepared by the Reformatsky reaction1 on
the corresponding 2H-3,4-dihydro-1-naphthalenones
with ethyl bromoacetate followed by the reduction16 of
the b–g unsaturated esters with NaBH4 in PEG-400 at
65°C. The physical constants and yields of the com-
pounds synthesized are listed in Table 1.
10. Allauddin, M.; Martin-Smith, M. J. Pharm. Pharmacol.
1962, 14, 469–491.
11. Akherm, A. A.; Lakhvich, F. A.; Pshenichnyi; Lakhvich,
O. F.; Kuz,mitskii, B. B.; Gorbatenko, S. F. USSR
Patent 636235 (Cl. C07J73/00); Chem. Abstr. 1979, 90,
104211u.
12. General procedure for the synthesis of 4-methylphenyl-
sulphonates 2:
In conclusion, the present work provides the first syn-
thesis of the title compounds 6a–c starting from 2a–c
which involves chemoselective N-alkylation of 3 at the
imidic NH with 2a–c followed by selective reduction of
4a–c and finally cyclization of 5a–c in PPA. Thus the
method for the synthesis of title compounds 6a–c is
short, general and utilizes easily accessible materials.
To a well-stirred mixture of 4-methylphenylsulphonyl
chloride (1.045 g, 5.5 mmole) and dry pyridine (1.58 g, 20
mmole) in dry CHCl3 (25 cm3) was added alcohol 1 (5
mmole) in dry CHCl3 (10 cm3) at 10°C (for 1a) and at rt
(for 1b–c) during a period of 15 min. After the addition
was completed, the mixture was stirred for an additional
3 h at the same temperature. The reaction mixture was
then poured onto a mixture of ice and conc. HCl (50 cm3)
and the organic layer was separated. The aqueous layer
was extracted with CHCl3 (3×25 cm3) and the combined
CHCl3 layer washed with 10% Na2CO3 (2×25 cm3), water
(2×25 cm3) and then dried (anhyd. Na2SO4). After the
evaporation of the solvent, a brown residue was obtained
which was purified by column chromatography [silica gel,
pet. ether:CHCl3 (80:20)] to afford the corresponding
4-methylphenylsulphonate 2.
Acknowledgements
One of the authors (J.A.P.) is thankful to UGC, New
Delhi, for financial assistance.
References
2 - (3,4 - Dihydro - 1 - naphthalenyl)ethyl - 4 - methylphenyl-
sulphonate 2a:
1. Schleigh, W. R.; Catala, A.; Popp, F. D. J. Heterocycl.
Chem. 1965, 2, 379–384.
2. Talor, E. C.; Lenard, K. J. Chem. Soc., Chem. Comm.
IR (KBr): 1180, 1360 (S=O str.) cm−1; 1H NMR (CDCl3,
60 MHz): l=2.0–2.97 (9H, m), 4.15 (2H, t, J=7 Hz,
O–CH2), 5.8 (1H, t, J=5 Hz, CꢀCꢁH), 6.8–7.66 (8H, m,
Ar-H); UV (CHCl3): umax, nm (log m)=261 (3.90).
2-(3,4-Dihydro-7-methyl-1-naphthalenyl)ethyl-4-methyl-
phenylsulphonate 2b:
1967, 97–98.
3. Birch, A. J.; Subba Rao, G. S. R. J. Chem. Soc. 1965,
3007–3008.
4. Kessar, S. V.; Singh, M.; Kumar, A. Tetrahedron Lett.
1965, 3245–3247.
5. Hubert, J. C.; Speckamp, W. N.; Huisman, H. O. Tetra-
hedron Lett. 1969, 1553–1556.
IR (oil film): 1180, 1360 (SꢁO str.) cm−1 1H NMR
;
(CDCl3, 60 MHz): l=2.0–2.93 (12H, m), 4.1 (2H, t, J=7
Hz, OꢀCH2), 5.76 (1H, t, J=5 Hz, C=CꢀH), 6.8–7.6
(7H, m, Ar–H); UV (CHCl3): umax, nm (log m)=263
(3.91); Anal. calcd for C20H22O3S: C, 70.15; H, 6.48; S,
9.36. Found: C, 70.05; H, 6.53; S, 9.33.
6. Dijkink, J.; Speckamp, W. N.; Huisman, H. O. Tetra-
hedron 1978, 34, 173–178.
7. Trehan, I. R.; Bala, K.; Singh, J. B. Indian J. Chem. 1979,
18B, 295–297.
2-(5-Chloro-3,4-dihydro-1-naphthalenyl)ethyl-4-methyl-
phenylsulphonate 2c:

J. A. Parihar, M. M. V. Ramana / Tetrahedron Letters 44 (2003) 1843–1845
1845
IR (oil film): 1180, 1360 (SꢁO str.) cm−1
;
1H NMR
extract was washed with water (2×25 cm3) and then dried
(anhyd. Na2SO4). Evaporation of the solvent gave a
brown residue which was purified by column chromato-
graphy [alumina (basic), chloroform: MeOH (98:2)] to
furnish starting seco-steroid 4. Further elution with chlo-
roform:MeOH (96:4) (500 cm3) followed by recovery of
solvents gave hydroxy lactam 5.
(CDCl3, 60 MHz): l=2.0–3.0 (9H, m), 4.1 (2H, t, J=7
Hz, OꢀCH2), 5.79 (1H, t, J=5 Hz, CꢁCꢀH), 6.8–7.66
(7H, m, Ar–H); UV (CHCl3): umax, nm (log m)=263
(3.90); Anal. calcd for C19H19O3ClS: C, 62.89; H, 5.28;
Cl, 9.77; S, 8.84. Found: C, 62.80; H, 5.31; Cl, 9.80; S,
8.80.
13. General procedure for the synthesis of seco-azasteroids 4:
A mixture of 4-methylphenylsulphonate 2 (2 mmole),
imidazolidine-2,4-dione 3 (298 mg, 3 mmole), anhyd.
K2CO3 (1 g) and dry DMF (20 cm3) was refluxed with
stirring for 90 min. The reaction mixture was diluted with
water and extracted with EtOAc (4×50 cm3). The com-
bined EtOAc extracts were washed with water (3×50 cm3)
and then dried (anhydrous Na2SO4). Evaporation of the
solvent gave a brown residue which was purified by
column chromatography [alumina (neutral), CHCl3:
MeOH (98:2)] to afford the corresponding seco-azas-
teroid 4.
1-[2-(3,4-Dihydro-1-naphthalenyl)ethyl]-5-hydroxyimida-
zolidin-2-one 5a:
IR (oil film): 1680 (CꢁO str.), 3200-3500 (N–H and O–H
str.) cm−1; UV (CHCl3): umax, nm (log m)=263 (3.86);
Anal. calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84.
Found: C, 69.67; H, 6.98; N, 10.92.
1 - [2 - (3,4 - Dihydro - 7 - methyl - 1 - naphthalenyl)ethyl] - 5-
hydroxyimidazolidin-2-one 5b:
IR (KBr): 1670 (CꢁO str.), 3200-3500 (N–H str.) cm−1
;
UV (CHCl3): umax, nm (log m)=263 (3.86); Anal. calcd
for C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C,
70.47; H, 7.43; N, 10.24.
1 - [2 - (5 - Chloro - 3,4 - dihydro - 1 - naphthalenyl)ethyl] - 5-
hydroxyimidazolidin-2-one 5c:
3-[2-(3,4-Dihydro-1-naphthalenyl)ethyl]imidazolidine-2,4-
dione 4a:
IR (KBr): 1715,1780 (CꢁO str.), 3250 (N–H str.) cm−1; 1H
NMR (CDCl3, 500 MHz): l=2.24 (2H, m, H3 of dihy-
dronaphthalene ring), 2.72 (2H, t, J=6.7 Hz, H4 of
dihydronaphthalene ring), 2.77 (2H, t, J=7.0 Hz,
CꢁCꢀCH), 3.70 (2H, t, J=7.0 Hz, N–CH), 3.87 (2H, s,
CO–CH–N), 5.22 (1H, s, NH), 5.96 (1H, t, J=5.0 Hz, H2
of dihydronaphthalene ring), 7.13–7.23 (3H, m, H5–7 of
dihydronaphthalene ring), 7.38 (1H, d, J=7.9 Hz, H8 of
dihydronaphthalene ring); MS: m/z=256 (M+, 50%), 156
(65%), 155 (36%), 141 (70%), 128 (100%), 127 (48%),
115(24%); UV (CHCl3): umax, nm (log m)=264 (3.84);
Anal. calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93.
Found: C, 70.37; H, 6.24; N, 10.99.
IR (oil film): 1680 (CꢁO str.), 3200-3500 (N–H and O–H
str.) cm−1; UV (CHCl3): umax, nm (log m)=266 (3.90);
Anal. calcd for C15H17N2O2Cl: C, 61.54; H, 5.85; N, 9.57;
Cl, 12.11. Found: C, 61.49; H, 5.89; N, 9.53; Cl, 12.15.
15. General procedure for the synthesis of title compounds 6:
A mixture of hydroxy lactam 5 (50 mg) and PPA (10 g)
was heated on a steam bath for 5 h. The reaction mixture
was poured onto ice and allowed to stand overnight. It
was extracted with EtOAc (3×25 cm3). The combined
EtOAc extracts were washed with 10% Na2CO3 (2×25
cm3), water (2×25 cm3) and then dried (anhyd. Na2SO4).
Evaporation of the solvent gave a brown residue which
was purified by column chromatography [alumina (basic),
chloroform: MeOH (98:2)] to furnish title compounds 6.
5,6,10,10a,11,12 - Hexahydrobenzo[ f ]imidazo[5,1 - a]iso-
quinolin-8[9H]-one 6a:
3-[2-(3,4-Dihydro-7-methyl-1-naphthalenyl)ethyl]imidazoli-
dine-2,4-dione 4b:
IR (KBr): 1710, 1780 (CꢁO str.), 3300 (NꢀH str.) cm−1
;
1H NMR (CDCl3, 60 MHz): l=2.0–3.0 (9H, m), 3.66–
4.0 (4H, m, N–C–H), 5.9 (1H, t, J=5.0 Hz, C=CꢀH),
6.5 (1H, s, NꢀH), 7.0–7.5 (3H, m, ArꢀH); MS: m/z=270
(M+, 90%), 170 (85%), 155 (100%), 143 (67%), 142 (72%),
141 (75%), 128 (67%); UV (CHCl3): umax, nm (log m)=
263 (3.94); Anal. calcd for C16H18N2O2: C, 71.09; H,
6.71; N, 10.36. Found: C, 71.00; H, 6.76; N, 10.39.
3-[2-(5-Chloro-3,4-dihydro-1-naphthalenyl)ethyl]imidazo-
lidine-2,4-dione 4c:
IR (KBr): 1700 (CꢁO str.), 3200 (N–H str.) cm−1 1H
;
NMR (CDCl3, 60 MHz): l=2.33–4.6 (11H, m), 5.6 (1H,
s, NH), 6.9–7.4 (4H, m, Ar–H); UV (CHCl3): umax, nm
(log m)=264 (3.89); Anal. calcd for C15H16N2O: C, 74.97;
H, 6.71; N, 11.66. Found: C, 74.85; H, 6.76; N, 11.59.
5,6,10,10a,11,12 - Hexahydro - 3 - methylbenzo[ f ]imidazo-
[5,1-a]isoquinolin-8[9H]-one 6b:
IR (KBr): 1700 (CꢁO str.), 3300 (NꢀH str.) cm−1
NMR (CDCl3, 60 MHz): l=2.0–4.33 (14H, m), 5.33
(1H, s, NH), 6.5–7.2 (3H, m, ArꢀH); UV (CHCl3): umax
;
1H
IR (oil film): 1715, 1780 (CꢁO str.), 3300 (NꢀH str.) cm−1
;
1H NMR (CDCl3, 60 MHz): l=2.1–3.1 (6H, m), 3.75–
4.1 (4H, m, N–C–H), 5.9 (1H, t, J=5.0 Hz, CꢁCꢀH),
6.66 (1H, s, N–H), 7.1–7.4 (3H, m, ArꢀH); UV (CHCl3):
,
nm (log m)=263 (3.93); Anal. calcd for C16H18N2O: C,
75.76; H, 7.13; N, 11.03. Found: C, 75.87; H, 7.08; N,
11.07.
umax
,
nm (log m)=260 (3.94); Anal. calcd for
1 - Chloro - 5,6,10,10a,11,12 - hexahydrobenzo[ f ]imidazo-
[5,1-a]isoquinolin-8[9H]-one 6c:
C15H15N2O2Cl: C, 61.97; H, 5.20; N, 9.63; Cl, 12.19.
Found: C, 61.90; H, 5.24; N, 9.67; Cl, 12.23.
IR (KBr): 1690 (CꢁO str.), 3300 (N–H str.) cm−1 1H
;
14. General procedure for the synthesis of hydroxy lactams 5:
To a well-stirred solution of seco-azasteroid 4 (1 mmole)
in dry MeOH (50 cm3) was added gradually sodium
borohydride (76 mg, 2 mmole) in dry MeOH (20 cm3) at
rt and the mixture was refluxed with stirring for 6 h.
MeOH was removed by distillation and the residue was
decomposed with 5% NH4Cl solution (100 cm3). It was
extracted with CHCl3 (3×25 cm3). The combined CHCl3
NMR (CDCl3, 60 MHz): l=2.0–4.5 (11H, m), 5.5 (1H, s,
NH), 6.8–7.5 (3H, m, Ar–H); UV (CHCl3): umax, nm (log
m)=265 (3.88); Anal. calcd for C15H15N2OCl: C, 65.57;
H, 5.50; N, 10.20; Cl, 12.90. Found: C, 65.64; H, 5.46; N,
10.17; Cl, 12.94.
16. Santaniello, E.; Ferraboschi, P.; Sozzani, P. J. Org.
Chem. 1981, 46, 4584–4585.