Synthesis of some steroidal oxazolines

Article abstract of DOI:10.1135/cccc20011831

Steroidal oxazolines 4a-4d and 5a-5f were synthesized. The acid-catalyzed reactions of 21-azido-20-hydroxy- and 21-hydroxy-20-azidosteroids with substituted aromatic aldehydes led to the formation of androst-5-en-3β-ols substituted in position 17β with oxazoline residues.

Full text of DOI:10.1135/cccc20011831

Steroidal Oxazolines
1831
SYNTHESIS OF SOME STEROIDAL OXAZOLINES
1
2
János WÖLFLING , Erzsébet MERNYÁK , Melinda SEBŐK
3,
and Gyula SCHNEIDER *
Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, Hungary;
1
2
3
e-mail: wolfling@chem.u-szeged.hu, bobe@chem.u-szeged.hu, schneider@chem.u-szeged.hu
Received October 5, 2001
Accepted Novem ber 5, 2001
This paper is dedicated to the memory of Professor Václav Černý, DrSc.
Steroidal oxazolin es 4a–4d an d 5a–5f were syn th esized. Th e acid-catalyzed reaction s of
21-azido-20-h ydroxy- an d 21-h ydroxy-20-azidosteroids with substituted arom atic aldeh ydes
led to th e form ation of an drost-5-en -3β-ols substituted in position 17β with oxazolin e
residues.
Keyw ord s: Steroids; Vicinal-azidoalcoh ols; Oxazolin es; Sch m idt reaction .
Prostatic can cer is th e secon d leadin g cause of can cer-related m ortality
worldwide. Con siderable atten tion h as been devoted to th e developm en t of
drugs active again st prostate can cer th at in terven e in th e processes of tu-
m our growth , an d especially in th e steroid m etabolism path ways leadin g to
testosteron e1. An drogen deprivation by th e in h ibition of h um an cyto-
ch rom e P45017α (17α-h ydroxylase/C17,20-lyase), th e en zym e respon sible for
th e con version of th e C21 steroids to th e C19 an drogen s, h as been devised as
a poten tial th erapeutic approach to th e treatm en t of th is disease, wh ich is
frequen tly an drogen depen den t2. Th e syn th eses of Abirateron e [(17-(3-
pyridyl)an drosta-5,16-dien -3β-ol] an d its 4-en -3-on e an alogue were re-
ported recen tly; th ese displayed a h igh in h ibitory activity toward P45017α
.
It h as been suggested th at th is activity is related to th e presen ce of th e
h eterocyclic m oiety in th e rin g D, with th e n itrogen atom lon e pair coordi-
n atin g to th e h em e iron atom at th e active site of th e en zym e3. A broad
class of steroid derivatives substituted at C-17 with h eterocyclic rin gs such
as im idazole or triazole are also good in h ibitors of th is en zym e4.
We set out to syn th esize a n ovel series of steroidal oxazolin es, con tain in g
th e h eterocycle with two h eteroatom s at position 17β of an drost-5-en -3β-ol.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi:10.1135/cccc20011831

1832
Wölfling et al.:
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. Optical rotation s
were m easured in ch loroform (c 1.0) on a Polam at-A (Zeiss, Jen a) polarim eter at 23 °C an d
[α]D values are given in 10–1 deg cm 2 g–1. NMR spectra were recorded on Bruker AM 400 an d
Bruker DRX 500 in strum en ts. Ch em ical sh ifts are reported in ppm (δ-scale), couplin g con -
stan ts (J) in Hz. For determ in ation of m ultiplicities, th e J-MOD pulse sequen ce was used. Ele-
m en tal an alysis data were determ in ed with a Perkin –Elm er CHN an alyser m odel 2400. Th e
reaction s were m on itored by TLC (Merck Silica gel 60 F225). Products were isolated by flash
ch rom atograph y (Merck Kieselgel 60, 40–63 µm ). In deacetylation reaction s, alkalin e alu-
m in a (pH 8–9) of activity I–II, stan dardized accordin g to Brockm an n (Aldrich Ch em ical Co.
Ltd.), was used. All solven ts were distilled prior to use.
3β,21-Diacetoxypregn -5-en -20-on e (1)
To a stirred solution of 3β-acetoxypregn -5-en -20-on e (1.8 g, 5 m m ol) in ben zen e (50 m l), a
solution of m eth an ol (5 m l) in ben zen e (50 m l), a solution of BF3·OEt2 (12 m l) in ben zen e
(50 m l) an d powdered Pb(OAc)4 (3.5 g, 8 m m ol) were added sim ultan eously in th e course of
4 h . Th e m ixture was diluted with dieth yl eth er (100 m l), an d successively wash ed with 5%
h ydroch loric acid an d water. Th e organ ic ph ase was evaporated an d th e resultin g crude
product was ch rom atograph ed on silica gel with tert-butyl m eth yl eth er–ligh t petroleum
(20 : 80), yieldin g pure 1 (2 g, 90%), m .p. 164–165 °C, [α]D +35 (ref.5 gives 166–167.5 °C,
[α]D +29.3). 1H NMR (CDCl3): 0.67 s, 3 H (18-H3); 1.00 s, 3 H (19-H3); 2.02 s, 3 H
(3-OAc-CH3); 2.16 s, 3 H (21-OAc-CH3); 2.50 m , 1 H; 4.53 d, 1 H, J = 16.8 an d 4.71 d, 1 H, J =
16.8 (21-H2); 4.60 m , 1 H (3-H). 13C NMR (CDCl3): 13.0 (C-18); 19.2 (C-19); 20.3 an d 21.3
(2 × Ac-CH3); 21.0, 22.8, 24.6, 27.7, 31.7, 31.8, 36.6, 37.1, 38.0, 38.5, 44.6, 49.8, 56.9, 59.2,
69.1 (C-21); 73.7 (C-3); 122.1 (C-6); 139.7 (C-5); 170.1 an d 170.3 (2 × Ac-CO); 203.6 (C-20).
For C25H36O5 (416.6) calculated: 72.08% C, 8.71% H; foun d: 72.16% C, 8.83% H.
3β,21-Diacetoxypregn -5-en -20β-ol (2b)
Com poun d 1 (2.1 g, 5 m m ol) was suspen ded in eth an ol (100 m l), an d KBH4 (1.5 g, 30 m m ol)
was added in sm all portion s wh ile coolin g th e m ixture in ice. pH of th e reaction m ixture
was m ain tain ed between 6.5 an d 7.5 by addition of acetic acid in th e presen ce of
Brom oth ym ol Blue as in dicator. At th e en d of th e reduction , th e reaction m ixture was acidi-
fied with dilute h ydroch loric acid. Th e resultin g solution was diluted with water, an d th e
precipitate was filtered off, wash ed un til n eutral, dissolved in ch loroform an d subjected to
ch rom atograph ic separation on silica gel with a m ixture of eth yl acetate–ch loroform (2.5 :
97.5). Th e product was 2b (1.7 g, 80%), m .p. 134–136 °C, [α]D –50 (ref.6 gives m .p. 136–137 °C,
[α]D –46). 1H NMR (CDCl3): 0.77 s, 3
H (18-H3); 1.02 s, 3 H (19-H3); 2.02 s, 3 H
(3-OAc-CH3); 2.09 s, 3 H (21-OAc-CH3); 2.31 m , 2 H; 3.77 m , 1 H (20-H); 3.90 dd, 1 H, J =
11.5, 7.1 an d 4.15 dd, 1 H, J = 11.5, 2.1 (21-H2); 4.58 m , 1 H (3-H); 5.36 m , 1 H (6-H).
13C NMR (CDCl3): 12.2, 19.3, 20.8, 20.9 an d 21.4 (2 × Ac-CH3); 24.6, 24.8, 27.7, 31.6, 31.9,
36.6, 37.0, 38.1, 39.5, 42.5, 50.0, 52.3, 55.8, 68.8 (C-21); 72.6, 73.9, 122.3 (C-6); 139.7 (C-5);
170.5 (3-OAc-CH3); 171.2 (21-OAc-CH3). For C25H38O5 (418.6) calculated: 71.74% C, 9.15% H;
foun d: 71.85% C, 9.02% H.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Steroidal Oxazolines
1833
3β,21-Diacetoxy-20β-tosyloxypregn -5-en e (2c)
Com poun d 2b (2.09 g, 5 m m ol) was dissolved in pyridin e (20 m l) an d a solution of tosyl
ch loride (1.05 g, 5.5 m m ol) dissolved in pyridin e (5 m l) was added wh ile coolin g th e m ix-
ture in ice. Th e reaction m ixture was allowed to stan d at room tem perature for 24 h an d
th en saturated with water. Th e resultin g precipitate was filtered off, wash ed an d dried. Th e
product was crystallized from m eth an ol givin g 2c (2.5 g, 83%), m .p. 147–149 °C, [α]D –41
(ref.6 gives m .p. 149–150 °C, [α]D –36). 1H NMR (CDCl3): 0.76 s, 3 H (18-H3); 1.00 s, 3 H
(19-H3); 1.95 s, 3 H (21-OAc-CH3); 2.02 s, 3 H (3-OAc-CH3); 2.30 m , 2 H; 2.43 s, 3 H
(tosyl-CH3); 3.95 dd, 1 H, J = 12.8, 4.5 an d 4.22 dd, 1 H, J = 12.8, 2.3 (21-H2); 4.59 m , 1 H
(3-H); 4.86 m , 1 H (20-H); 5.35 m , 1 H (6-H); 7.31 d, 2 H, J = 8.0 (3′-H an d 5′-H); 7.79 d, 2 H,
J = 8.0 (2′-H an d 6′-H). 13C NMR (CDCl3): 11.7 (C-18); 19.3 (C-19); 20.6, 21.4 an d 21.6
(tosyl-CH3 an d 2 × Ac-CH3); 20.7, 24.1, 24.9, 27.7, 31.7, 31.8, 36.6, 37.0, 37.7, 37.9, 42.1,
49.9, 50.1, 56.0, 64.6 (C-21); 73.9 (C-3); 82.2 (C-20); 122.2 (C-6); 127.5 (2 C, C-2′ an d C-5′);
129.6 (2 C, C-3′ an d C-5′); 135.2 (C-1′); 139.8 (C-5); 144.4 (C-4′); 170.5 (2 C, 2 × Ac-CO). For
C
32H44O7S (572.8) calculated: 67.11% C, 7.74% H; foun d: 67.28% C, 7.55% H.
3β-Acetoxypregn -5-en e-20β,21-diol (2a)
Com poun d 2b (4.18 g, 10 m m ol) was dissolved in dich lorom eth an e (25 m l) an d th e solu-
tion was added to alkalin e alum in a (200 g). Th e solven t was evaporated in vacuo at am bien t
tem perature. Th e dry residue was placed in a Pyrex tube an d irradiated at 90 W for 12 m in
in side a MAXIDIGEST-350 m icrowave oven . Th e product was eluted with eth yl acetate
(500 m l) an d th e eluate was evaporated to dryn ess. Th e residual yellow oil was subjected to
ch rom atograph ic separation on silica gel with a m ixture of eth yl acetate–ch loroform (2.5 :
87.5). Th e product was crystallized from m eth an ol yieldin g 2a (3.2 g, 76%), m .p. 174–175 °C,
[α]D –63 (ref.6 gives m .p. 163–164 °C, [α]D –49). 1H NMR (CDCl3): 0.79 s, 3 H (18-H3); 1.03 s,
3 H (19-H3); 2.03 s, 3 H (Ac-CH3); 3.40 m , 1 H (20-H); 3.67 m , 2 H (21-H2); 4.63 m , 1 H
(3-H); 5.35 m , 1 H (6-H). 13C NMR (CDCl3): 12.3, 19.3, 20.9, 21.4, 24.6, 24.7, 27.7, 31.7,
31.9, 36.6, 37.0, 38.1, 39.6, 42.4, 50.1, 52.4, 55.9, 66.4 (C-21); 74.0, 74.6, 122.4 (C-6); 139.7
(C-5); 170.6 (Ac-CH3). For C23H36O4 (376.5) calculated: 73.37% C, 9.64% H; foun d: 73.10% C,
9.82% H.
3β-Acetoxy-21-iodopregn -5-en -20β-ol (2d )
To dry dich lorom eth an e (20 m l) were successively added triph en ylph osph in e (1.57 g, 6 mmol),
im idazole (408 m g, 6 m m ol), iodin e (760 m g, 6 m m ol) an d a solution of com poun d 2a in
dich lorom eth an e (20 m l), an d th e m ixture was stirred at room tem perature. Th e disappear-
an ce of th e startin g m aterial was followed by TLC. Wh en th e reaction was com plete, m ost of
th e solven t was rem oved in vacuo an d th e residual oil was dissolved in ch loroform for ch ro-
m atograph ic separation with ch loroform on silica gel. Th e product was 2d (2.1 g, 72%),
m .p. 169–170 °C, [α]D –72. 1H NMR (CDCl3): 0.79 s, 3 H (18-H3); 1.03 s, 3 H (19-H3); 2.03 s,
3 H (Ac-CH3); 3.20 dd, 1 H, J = 10.1, 6.5 an d 3.47 dd, 1 H, J = 10.1, 2.3 (21-H2); 3.29 m , 1 H
(20-H); 4.60 m , 1 H (3-H); 5.37 m , 1 H (6-H). 13C NMR (CDCl3): 12.6 (C-18); 19.2, 19.3
(C-19); 20.7, 21.3, 24.5, 25.0, 27.5, 31.8, 36.5, 37.3, 38.1, 39.2, 42.6, 49.9, 55.7 (2 C); 72.8,
73.8 (C-39); 122.3 (C-6); 139.7 (C-5); 170.4 (Ac-CO). For C23H35IO3 (486.4) calculated:
56.79% C, 7.25% H; foun d: 56.88% C, 7.36% H.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1834
Wölfling et al.:
3β-Acetoxy-21-azidopregn -5-en -20β-ol (2e)
Com poun d 2d (973 m g, 2 m m ol) was dissolved in dim eth ylform am ide (25 m l), NaN3 (520 m g,
8 m m ol) was added, th e m ixture was stirred at 80 °C for 3 h an d th en poured in to water
(250 m l). Th e resultin g precipitate was filtered off, dissolved in ch loroform an d
ch rom atograph ed on silica gel with tert-butyl m eth yl eth er–ligh t petroleum (20 : 70), wh ich
afforded 2e (650 m g, 81%), m .p. 170–171 °C, [α]D –57. 1H NMR (CDCl3): 0.78 s, 3 H (18-H3);
1.03 s, 3 H (19-H3); 2.04 s, 3 H (Ac-CH3); 3.21 dd, 1 H, J = 12.4, 7.1 an d 3.88 dd, 1 H, J =
12.4, 2.4 (21-H2); 3.70 m , 1 H (20-H); 4.60 m , 1 H (3-H); 5.37 m , 1 H (6-H). 13C NMR
(CDCl3): 12.1 (C-18); 19.2 (C-19); 20.7 (Ac-CH3); 21.3, 24.5, 24.8, 27.6, 31.6, 31.8, 36.5,
42.4, 49.9, 53.1, 55.8, 57.1 (C-21); 73.3, 73.8 (C-3); 122.2 (C-6); 139.6 (C-5); 170.5 (Ac-CO).
For C23H35O3N3 (401.5) calculated: 68.80% C, 8.79% H; foun d: 68.92% C, 8.65% H.
3β,21-Diacetoxy-20α-azidopregn -5-en e (3a)
Method A. Com poun d 2c (2.86 g, 5 m m ol) was dissolved in dim eth ylform am ide (50 m l),
NaN3 (1.3 g, 20 m m ol) was added, th e m ixture was stirred at 80 °C for 4 h an d th en poured
in to water (500 m l). Th e precipitate was filtered off, dissolved in ch loroform an d
ch rom atograph ed on silica gel with eth yl acetate–ch loroform (2.5 : 97.5) to afford 3a (1.9 g,
86%).
Method B. Com poun d 2b (420 m g, 1 m m ol) was dissolved in toluen e (15 m l), th en
triph en ylph osph in e (510 m g, 2 m m ol) an d Zn (N3)2·(pyridin e)2 (230 m g, 0.75 m ol) were
added as a suspen sion . To th is stirred m ixture, dieth yl diazen edicarboxylate (0.4 m l, 2 m m ol)
was added dropwise at room tem perature, wh ich resulted in a sligh tly exoth erm ic reaction .
Stirrin g was con tin ued un til th e disappearan ce of th e startin g com poun d (TLC m on itorin g).
Th e h eterogen eous m ixture was filtered th rough a Celite pad, con cen trated in vacuo an d
ch rom atograph ed on silica gel as described in m eth od A yieldin g 3a (280 m g, 63%), m .p.
141–143 °C, [α]D –38. 1H NMR (CDCl3): 0.75 s, 3 H (18-H3); 1.02 s, 3 H (19-H3); 2.05 s, 3 H
(3-OAc-CH3); 2.11 s, 3 H (21-OAc-CH3); 2.32 m , 2 H; 3.47 m , 1 H (20-H); 3.99 dd, 1 H, J = 11.6,
8.2 an d 4.41 dd, 1 H, J = 11.6, 2.9 (21-H2); 4.61 m , 1 H (3-H); 5.37 m , 1 H (6-H). 13C NMR
(CDCl3): 12.3 (C-18); 19.2 (C-19); 20.6 an d 21.3 (2 × Ac-CH3); 20.7, 24.1, 26.1, 27.7, 31.6,
31.7, 36.6, 36.9, 38.1, 38.4, 41.8, 49.9, 50.9, 56.2, 63.4 (C-20); 66.3 (C-21); 73.8 (C-3); 122.3
(C-6); 139.7 (C-5); 170.4 an d 170.6 (2 × Ac-CO). For C25H37N3O4 (443.6) calculated: 67.69% C,
8.41% H; foun d: 67.52% C, 8.50% H.
3β,21-Dih ydroxy-20α-azidopregn -5-en e (3b)
Com poun d 3a (443 m g, 1 m m ol) was dissolved in m eth an ol (20 m l) con tain in g MeONa
(11 m g, 0.2 m m ol) an d th e solution was left stan din g at am bien t tem perature for 24 h . It
was then diluted with water, the formed precipitate was filtered off and crystallized from acetone–
water yielding pure 3b, m .p. 140–143 °C, [α]D –38. 1H NMR (CDCl3): 0.74 s, 3 H (18-H3); 1.01 s,
3 H (19-H3); 3.38 m , 1 H (20-H); 3.52 m , 1 H (3-H); 3.55 dd, 1 H, J = 11.5, 7.9 an d 3.85 dd,
1 H, J = 11.5, 3.0 (21-H2); 5.35 m , 1 H (6-H). 13C NMR (CDCl3): 12.4 (C-18); 19.4 (C-19);
20.8, 24.2, 26.1, 31.6, 31.7, 31.8, 36.5, 37.3, 38.6, 41.9, 42.1, 50.1, 51.3, 56.3, 64.9 (C-21);
67.6 (C-20); 71.7 (C-3); 121.4 (C-6); 140.8 (C-5). For C21H33N3O2 (359.5) calculated: 70.16% C,
9.25% H; foun d: 70.02% C, 9.34% H.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Steroidal Oxazolines
1835
Gen eral Procedure for Preparation of Com poun ds 4a, 4c, 4e an d 5b, 5d
A solution of com poun d 2e or 3b (l m m ol) an d a 4-substituted ben zaldeh yde (1.1 equiva-
len t) in dich lorom eth an e (20 m l) was cooled to 0 °C, followed by dropwise addition of
BF3·OEt2 (2.0 equivalen ts); th e addition of acid was accom pan ied by gas evolution . Th e reac-
tion m ixture was allowed to warm to room tem perature an d th e solution was stirred for 2 h .
Saturated NaHCO3 solution was added slowly an d th e m ixture was stirred un til bubblin g
ceased. Th e reaction m ixture was extracted with dich lorom eth an e, th e organ ic layer was
wash ed with brin e, dried an d con cen trated in vacuo to afford th e crude product, wh ich was
purified by ch rom atograph y on silica gel; 4a, 4c an d 4e were eluted with eth yl acetate–
ch loroform (30 : 70), an d 5b an d 5d with eth yl acetate–ch loroform (2.5 : 97.5).
17β-[2-(4-Bromophenyl)-4,5-dihydrooxazol-4-yl]androst-5-en-3β-ol (4a). Yield 358 m g (72%),
m .p. 178–180 °C, [α]D –27. 1H NMR (CDCl3): 0.77 s, 3 H (18-H3); 1.02 s, 3 H (19-H3); 3.52 m ,
1 H (3-H); 4.02 t, 1 H, J = 8.4 an d 4.50 t, 1 H, J = 8.4 (21-H2); 4.15 q, 1 H, J = 9.4 (20-H);
5.35 m , 1 H (6-H); 7.52 d, 2 H, J = 8.4 (3′-H an d 5′-H); 7.79 d, 2 H, J = 8.4 (2′-H an d 6′-H).
13C NMR (CDCl3): 13.3 (C-18); 19.4 (C-19); 20.8, 24.4, 26.5, 31.6, 31.7 (C-8); 31.8, 36.8,
37.3, 38.9, 42.1, 42.3, 50.2, 56.0, 56.5, 69.2 (C-20); 71.7 (C-3); 72.3 (C-21); 121.5 (C-6);
125.7 (C-4′); 127.0 (C-1′); 129.7 (2 C, C-2′ an d C-6′); 131.5 (2 C, C-3′ an d C-5′); 140.7 (C-5);
162.2 (C(N,O)). For C28H36BrNO2 (498.5) calculated: 67.46% C, 7.28% H; foun d: 67.50% C,
7.12% H.
17β-[2-(4-Nitrophenyl)-4,5-dihydrooxazol-4-yl]androst-5-en-3β-ol (4c). Yield 292 m g (63%),
m .p. 196–198 °C, [α]D –29. 1H NMR (CDCl3): 0.79 s, 3 H (18-H3); 1.03 s, 3 H (19-H3); 3.52 m ,
1 H (3-H); 4.08 dd, 1 H, J = 9.7, 8.1 an d 4.57 dd, 1 H, J = 9.2, 8.1 (21-H2); 4.22 q, 1 H, J =
9.5 (20-H); 5.36 m , 1 H (6-H); 8.09 d, 2 H, J = 8.5 (2′-H an d 6′-H); 8.24 d, 2 H, J = 8.5 (3′-H
an d 5′-H). 13C NMR (CDCl3): 13.4 (C-18); 19.4 (C-19); 20.8, 24.4, 26.5, 31.6, 31.7 (C-8);
31.8, 36.6, 37.3, 38.9, 42.2, 42.3, 50.2, 56.0, 56.4, 69.5 (C-20); 71.7 (C-3); 72.7 (C-21); 121.5
(C-6); 123.4 (2 C, C-3′ an d C-5′); 129.2 (2 C, C-2′ an d C-6′); 133.9 (C-1′); 140.7 (C-5); 149.4
(C-4′); 161.2 (C(N,O)). For C28H36N2O4 (464.6) calculated: 72.39% C, 7.81% H; foun d:
72.45% C, 7.92% H.
17β-[2-(4-Methoxyphenyl)-4,5-dihydrooxazol-4-yl]androst-5-en-3β-ol (4e). Yield 247 m g (55%),
m .p. 160–163 °C, [α]D –26. 1H NMR (CDCl3): 0.77 s, 3 H (18-H3); 1.02 s, 3 H (19-H3); 3.52 m ,
1 H (3-H); 3.83 s, 3 H (OCH3); 4.00 t, 1 H, J = 8.1 an d 4.48 t, 1 H, J = 8.1 (21-H2); 4.14 q, 1 H,
J = 9.4 (20-H); 5.36 m , 1 H (6-H); 6.89 d, 2 H, J = 8.6 (3′-H an d 5′-H); 7.87 d, 2 H, J = 8.6,
(2′-H an d 6′-H). 13C NMR (CDCl3): 13.3 (C-18); 19.4 (C-19); 20.8, 24.5, 26.5, 31.6, 31.7, 31.8
(C-8); 36.6, 37.3, 38.9, 42.1, 42.3, 50.2, 55.3, 56.0, 56.6, 69.0 (C-20); 71.7 (C-3); 72.0 (C-21);
113.6 (2 C, C-3′ an d C-5′); 120.6 (C-1′); 121.6 (C-6); 129.9 (2 C, C-2′ an d C-6′); 140.7 (C-5);
161.9 an d 162.7 (C(N,O) an d C-4′). For C29H39NO3 (449.6) calculated: 77.47% C, 8.74% H;
foun d: 77.56% C, 8.82% H.
3β-Acetoxy-17β-[2-(4-bromophenyl)]-4,5-dihydrooxazol-5-yl]androst-5-ene (5b). Yield 464 m g
(86%), m .p. 103–105 °C, [α]D –40. 1H NMR (CDCl3): 0.86 s, 3 H (18-H3); 1.05 s, 3 H (19-H3);
2.02 s, 3 H (Ac-CH3); 3.62 dd, 1 H, J = 14.5, 8.1 an d 4.03 dd, 1 H, J = 14.5, 9.4 (21-H2); 4.61 m ,
2 H (3 H an d 20-H); 5.37 m , 6 H; 7.53 d, 2 H, J = 8.4 (3′-H an d 5′-H); 7.78 d, 2 H, J = 8.4
(2′-H an d 6′-H). 13C NMR (CDCl3): 12.7 (C-18); 19.3 (C-19); 20.8, 21.4 (Ac-CH3); 23.7, 27.8,
31.7, 31.9, 36.7, 37.0, 38.1, 39.0, 42.7, 50.1, 54.9, 55.9, 59.8 (C-21); 73.9 (C-3); 82.0 (C-20);
122.4 (C-6); 125.8 (C-4′); 127.1 (C-1′); 129.6 (2 C, 2-C′ an d C-6′); 131.6 (2 C, C-3′ an d C-5′);
139.8 (C-5); 163.4 (C(N,O)); 170.5 (Ac-CO). For C30H38BrNO3 (540.5) calculated: 66.66% C,
7.09% H; foun d: 66.53% C, 7.22% H.
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1836
Wölfling et al.:
3β-Acetoxy-17β-[2-(4-nitrophenyl)-4,5-dihydrooxazol-5-yl]androst-5-ene (5d ). Yield 445 m g
(88%), m .p. 111–113 °C, [α]D –34. 1H NMR (CDCl3): 0.88 s, 3 H (18-H3); 1.06 s, 3 H (19-H3);
2.03 s, 3 H (Ac-CH3); 3.69 dd, 1 H, J = 14.9, 8.2 an d 4.11 dd, 1 H, J = 14.9, 9.4 (21-H2);
4.58 m , 1 H (3-H); 4.72 dd, 1 H, J =17.9, 8.8 (20-H); 5.38 m , 1 H (6-H); 8.08 d, 2 H, J = 8.8
(2′-H an d 6′-H); 8.25 d, 2 H, J = 8.8 (3′-H an d 5′-H). 13C NMR (CDCl3): 12.6 (C-18); 19.3
(C-19); 20.7, 21.3, 23.6, 24.6, 27.7, 31.6, 31.8, 36.6, 36.9, 38.4, 38.9, 42.6, 50.0, 54.9, 55.8,
60.0 (C-21); 73.8 (C-3); 82.4 (C-20); 122.2 (C-6); 123.4 (2 C, C-3′ an d C-5′); 129.0 (2 C, C-2′
an d C-6′); 133.9 (C-1′); 139.7 (C-4′); 149.3 (C-5); 162.2 (C(N,O)); 170.4 (Ac-CO). For
C
30H38N2O5 (506.6) calculated: 71.12% C, 7.56% H; foun d: 71.25% C, 7.65% H.
Gen eral Procedure for Acetylation of Com poun ds 4a, 4c an d 4e
Com poun d 4a, 4c or 4e (1 m m ol) was dissolved in a m ixture of pyridin e (5 m l) an d acetic
an h ydride (3 m l, 0.03 m ol), th e solution was left stan din g for 24 h an d th en poured on to
ice (50 g). Th e resultin g precipitate was filtered off, wash ed an d dried. Th e crude products
4b, 4d or 4f were crystallized from m eth an ol.
4-β-Acetoxy-17β-[2-(4-bromophenyl)-4,5-dihydrooxazol-4-yl]androst-5-ene (4b). After acetylation
of 4a by th e gen eral m eth od, yield 486 m g (90%), m .p. 185–189 °C, [α]D –30. 1H NMR
(CDCl3): 0.77 s, 3 H (18-H3); 1.04 s, 3 H (19-H3); 2.03 s, 3 H (Ac-CH3); 2.33 m , 2 H; 4.02 dd,
1 H, J = 9.5, 8.1 an d 4.50 dd, 1 H, J = 9.0, 8.1 (21-H2); 4.15 q, 1 H, J = 9.4 (20-H); 4.62 m , 1 H
(3-H); 5.38 m , 1 H (6-H); 7.52 d, 2 H, J = 8.4 (3′-H an d 5′-H); 7.79 d, 2 H, J = 8.4 (2′-H an d
6′-H). 13C NMR (CDCl3): 13.3 (C-18); 19.3 (C-19); 20.7, 21.4 (Ac-CH3); 24.4, 26.4, 27.7, 31.7
(C-8); 31.8, 36.6, 37.0, 38.1, 38.8, 42.1, 50.1, 55.9, 56.5, 69.1 (C-20); 72.3 (C-21); 73.9 (C-3);
122.5 (C-6); 125.7 (C-4′); 127.0 (C-1′); 129.7 (2 C, C-2′ an d C-6′); 131.5 (2 C, C-3′ an d C-5′);
139.6 (C-5); 162.2 (C(N,O)); 170.5 (Ac-CO). For C30H38BrNO3 (540.5) calculated: 66.66% C,
7.09% H; foun d: 66.52% C, 6.98% H.
3β-Acetoxy-17β-[2-(4-nitrophenyl)-4,5-dihydrooxazol-4-yl]androst-5-ene (4d ). After acetylation
of 4c by th e gen eral m eth od, yield 466 m g (92%), m .p. 78–80 °C, [α]D –32. 1H NMR (CDCl3):
0.79 s, 3 H (18-H3); 1.00 s, 3 H (19-H3); 2.03 s, 3 H (Ac-CH3); 2.34 m , 2 H; 4.10 t, 1 H, J = 8.6
an d 4.57 t, 1 H, J = 8.6 (21-H2); 4.22 q, 1 H, J = 9.5 (20-H); 4.60 m , 1 H (3-H); 5.39 m , 1 H
(6-H); 8.10 d, 2 H, J = 8.5 (2′-H an d 6′-H); 8.24 d, 2 H, J = 8.5 (3′-H an d 5′-H). 13C NMR
(CDCl3): 13.4 (C-18); 19.3 (C-19); 20.7, 21.4 (Ac-CH3); 24.4, 26.4, 27.8, 31.7 (C-8); 31.8,
36.6, 37.0, 38.1, 38.8, 42.1, 50.1, 55.9, 56.4, 69.5 (C-20); 72.7 (C-21); 73.9 (C-3); 122.5 (C-6);
123.4 (2 C, C-3′ an d C-5′); 129.2 (2 C, C-2′ an d C-6′); 133.9 (C-1′); 139.6 (C-5); 149.4 (C-4′);
161.2 (C(N,O)); 170.5 (Ac-CO). For C30H38N2O5 (506.6) calculated: 71.12% C, 7.56% H;
foun d: 71.28% C, 7.62% H.
3β-Acetoxy-17β-[2-(4-methoxyphenyl)-4,5-dihydrooxazol-4-yl]androst-5-ene (4f). After acetylation
of 4e by th e gen eral m eth od, yield 432 m g (96%), m .p. 188–190 °C, [α]D –28. 1H NMR
(CDCl3): 0.77 s, 3 H (18-H3); 1.02 s, 3 H (19-H3); 2.03 s, 3 H (Ac-CH3); 2.33 m , 2 H; 3.83 s, 3 H
(OCH3); 4.00 t, 1 H, J = 8.5 an d 4.47 t, 1 H, J = 8.5 (21-H2); 4.14 q, 1 H, J = 9.3 (20-H); 4.47 m ,
1 H (3-H); 5.38 m , 1 H (6-H); 6.88 d, 2 H, J = 8.6 (3′-H an d 5′-H); 7.87 d, 2 H, J = 8.6 (2′-H
an d 6′-H). 13C NMR (CDCl3): 13.3 (C-18); 19.3 (C-19); 20.7, 21.4, 24.4 (Ac-CH3); 26.5, 27.7,
31.7 (C-8); 31.8, 36.6, 37.0, 38.1, 38.8, 42.0, 50.1, 55.3, 55.9, 56.6, 68.9 (C-20); 72.0 (C-21);
73.9 (C-3); 113.5 (2 C, C-3′ an d C-5′); 120.6 (C-1′); 122.5 (C-6); 129.9 (2 C, C-2′ an d C-6′);
139.6 (C-5); 161.9 an d 162.7 (C(N,O) an d C-4′); 170.5 (Ac-CO). For C31H41NO4 (491.7) cal-
culated: 75.73% C, 8.41% H; foun d: 75.92% C, 8.26% H.
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Steroidal Oxazolines
1837
Gen eral Procedure for Deacetylation of Com poun ds 5b, 5d
Com poun d 5b or 5d (1 m m ol) was dissolved in m eth an ol (20 m l) con tain in g MeONa (11 m g,
0.2 m m ol), th e solution was left stan din g for 24 h an d th en poured in to water (50 m l). Th e
form ed precipitate of 5a or 5c was filtered off an d crystallized from aceton e–ligh t petroleum .
17β-[2-(4-Bromophenyl)-4,5-dihydrooxazol-5-yl]androst-5-en-3β-ol (5a). After deacetylation of
5b by th e gen eral m eth od, yield 463 m g (93%), m .p. 202–203 °C, [α]D –38. 1H NMR
(CDCl3): 0.87 s, 3 H (18-H3); 1.04 s, 3 H (19-H3); 3.52 m , 1 H (3-H); 3.62 dd, 1 H, J = 14.1,
8.0 an d 4.04 dd, 1 H, J = 14.1, 9.6 (21-H2); 4.65 m , 1 H (20-H); 5.35 m , 1 H (6-H); 7.54 d, 2 H,
J = 7.6 (3′-H an d 5′-H); 7.78 d, 1 H, J = 7.6 (2′-H an d 6′-H). 13C NMR (CDCl3): 12.7 (C-18);
19.4 (C-19); 20.9, 23.7 (Ac-CH3); 24.7, 31.7, 31.8, 31.9, 36.6, 37.3, 39.1, 42.3, 42.7, 50.3,
55.0, 56.0, 59.9 (C-21); 71.7 (C-3); 82.0 (C-20); 121.4 (C-6); 125.8 (C-4′); 127.1 (C-1′); 129.6
(2 C, C-2′ an d C-6′); 131.6 (2 C, C-3′ an d C-5′); 140.9 (C-5); 163.4 (C(N,O)). For
C
28H36BrNO2 (498.5) calculated: 67.46% C, 7.28% H; foun d: 67.35% C, 7.36% H.
17β-[2-(4-Nitrophenyl)-4,5-dihydrooxazol-5-yl]androst-5-en-3β-ol (5c). After deacetylation of
5d by th e gen eral m eth od, yield 427 m g (92%), m .p. 236–238 °C, [α]D –48. 1H NMR
(CDCl3): 0.88 s, 3 H (18-H3); 1.05 s, 3 H (19-H3); 3.52 m , 1 H (3-H); 3.69 dd, 1 H, J = 14.6,
8.1 an d 4.11 dd, 1 H, J =14.6, 7.7 (21-H2); 4.73 dd, 1 H, J =17.9, 8.9 (20-H); 5.35 m , 1 H (6-H);
8.09 d, 2 H, J = 8.2 (2′-H an d 6′-H); 8.26 d, 2 H, J = 8.2 (3′-H an d 5′-H). 13C NMR (CDCl3):
12.7 (C-18); 19.4 (C-19); 20.9, 23.7, 24.7, 31.6, 31.7, 31.9, 36.6, 37.3, 39.1, 42.3, 42.7, 50.2,
54.9, 56.0, 60.0 (C-21); 71.6 (C-3); 82.5 (C-20); 121.3 (C-6); 123.5 (2 C, C-3′ an d C-5′); 129.1
(2 C, C-2′ an d C-6′); 133.9 (C-1′); 140.9 (C-4′); 149.2 (C-5); 162.4 (C(N,O)). For C28H36N2O4
(464.6) calculated: 72.39% C, 7.81% H; foun d: 72.55% C, 765% H.
RESULTS AND DISCUSSION
Th e reaction between a carbon yl com poun d (keton e or aldeh yde) an d
h ydrazoic acid is a m eth od for th e in sertion of an NH group between th e
carbon yl group an d an alkyl group, con vertin g th e startin g com poun d in to
an am ide7. In an exten sion of th is classic Sch m idt reaction , Boyer an d
Ham m er foun d th at th e reaction s of alkyl azides with arom atic aldeh ydes
could be carried out with H2SO4 in ben zen e to afford am ides in m oderate
yields. In con trast, th e use of β- or γ-azidoalcoh ols un der sim ilar con dition s
afforded oxazolin es or dih ydrooxazin es, respectively, with m uch greater ef-
ficien cy8. Later on , a variety of Lewis acids were exam in ed, of wh ich
BF3·OEt2 was foun d to be th e m ost con ven ien t9.
Th is observation provides a possibility for th e preparation of com poun ds
con tain in g various substituted oxazolin es con den sed to rin g D of th e
an drostan e skeleton , wh ich are poten tially biologically active com poun ds.
In our syn th esis, 3β,21-diacetoxypregn -5-en -20-on e (1) was used as startin g
m aterial. Reduction with KBH4 gave two com poun ds, 3β,21-diacetoxypregn --
5-en -20β-ol (2b) an d its 20α epim er, in a ratio of 9 : 1. Th e required pure
epim er 2b was obtain ed by flash ch rom atograph y. Th e 20β-tosyloxy com -
poun d 2c, prepared with tosyl ch loride in pyridin e, was reacted with NaN3
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1838
Wölfling et al.:
in dim eth ylform am ide to furn ish 3a. For th e preparation of 3a, we also
used a sim ple on e-step reaction 10. Treatm en t of 2b with th e zin c
azide/bis-pyridin e com plex, triph en ylph osph in e an d dieth yl diazen e-
dicarboxylate afforded th e correspon din g azide 3a in m oderate yield. Com -
poun d 3b for cyclization was obtain ed after deacetylation of 3a by th e
Zem plen m eth od. Th e oth er startin g com poun d for cyclization to obtain
steroids with th e 20β con figuration was 2b. Th eir selective deacetylation
was carried out at th e secon dary acetoxy group by an earlier developed
m eth od11. Com poun d 2b was subjected to m icrowave irradiation at 90 W
on alkalin e alum in a in a h ouseh old m icrowave apparatus. After irradiation
of 2b, 2a was obtain ed in 86% yield. Iodin ation by th e Appel reaction 12
produced th e iodoh ydrin 2d . Nucleoph ilic exch an ge with NaN3 in
dim eth ylform am ide led to th e required 21-azido-20β-ol 2e. Com poun d 2e
was suitable for th e cyclization of h eterocycles with th e 20β con figuration ,
wh ile 3b resulted in th e 20α con figuration (Sch em e 1).
H2C R2
H2C OAc
R1
R2
R1
C
H
C
O
a
b
c
d
e
OH
OH
OTs
OH
OH
OH
OAc
OAc
I
(i)
AcO
N3
1
AcO
2
(ii)
H2C OR2
H C N3
(iii)
R1
Ac
H
R2
Ac
H
a
b
R1O
3
(iii)
R2
R2
O
R1 R2
4-bromophenyl
Ac 4-bromophenyl
4-nitrophenyl
Ac 4-nitrophenyl
4-methoxyphenyl
O
N
N
H
a
b
c
d
e
f
H
H
R1O
R1O
Ac 4-methoxyphenyl
4a-4f
5a-5d
O
C
(i) KBH4/MeOH; (ii) NaN3/DMF, 80 oC or (NCOOEt)2·P(Ph)3·pyridine·Zn(N3)2; (iii)
R
H
·BF3·Et2O
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Steroidal Oxazolines
1839
Mech an istically, it can be presum ed13 th at th e first step in th e Sch m idt
reaction in volves h em iacetal form ation between th e arom atic aldeh yde an d
th e steroid azidoalcoh ol 6, wh ich un dergoes elim in ation to afford a ben zyl
carbocation 7. In tram olecular attack of th e azide group on th e carbocation
furn ish es in term ediate 8, an d subsequen t proton elim in ation an d N2 de-
tach m en t give th e product 9 (Sch em e 2).
O
C
H
R
R
N
O
N N
R
R
N3
H
C
OH
H
- H2O
7
6
N2
C
R
R
N
O
R
R
N
O
H
- N2
- H
8
9
SCHEME 2
Financial support by the National Research Foundation (grant OTKA T 032265) and by the Hun-
garian Ministry of Education (FKFP 0110/2000) is gratefully acknowledged. We also thank P. Forgó
(University of Szeged) for the measurement of NMR spectra.
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11. Vass A., Tapolcsányi P., Wölfling J., Schneider Gy.: J. Chem. Soc., Perkin Trans. 1 1998,
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