Indian Journal of Chemistry Vol. 38B, March 1999, pp. 274 - 282

Synthesis of ~-formylsteroidal enamides and their conversion into geminal dichlorides

Romesh C Boruah,* Shahadat Ahmed, Utpal Sharma & Jagir S Sandhu

Organic Chemistry Division, Regional Research Laboratory, 10rhat 785 006, India.

Received 9 September 1998; accepted 18 December '1998

A novel class of ~-formyl s teroidal enamides has been prepared from l6-dehydropregnenolone-20-oxime. Reaction of these enamides with Vilsmeier reagent affords steroidal geminal dichlorides in good yields. Rea€tion of the corresponding C-16 formylidenemalononitrile derivative with chloromethyleneimin ium sal t, however, leads to a ring-D fused pyridosteroid.

The chemistry of enamide is an area of intense interest owing to the key role played by this functionality in the synthesis of natural products I as well as heterocycles .2 Vilsmeier formy lations of secondary and tertiary enamides are considered to be useful strategies for pyridine and quinoline synthesis.' Recently C-17 aza-steroids have received renewed interests because of their profound activities against prostate cancer.4 . However, little attention5 has been paid to the study of ring-D steroidal enamides despite their enormous synthetic and biological potentials. On the other hand, geminal dichlorides are chemically important synthones bearing rich chemistry.6 Although geminal difluorides7 are easi ly accessible, the synthesis of the corres-ponding geminal dichlorides is limited to specific substrates or resul ts in poor yie lds.8. lo Recent ly, we have reported the convers ion of steroidal y-formyl oxime in to a novel class of steroidal geminal dihalides that have proved to be excellent precursors I 1.12 to steroidal alkynes . In this paper we describe a fac ile preparation of a novel class of steroidal 16-formyl- 17-enamides and thei r utility in the preparation of geminal dichlorides under Vilsmeier condition.

Result and Discussion

n preliminary model experiments directed towards ring-D steroidal enamides, 16-dehydropregnenolone-acetate-20-oxime 2a, prepared from 16-DPA (Ia), was added to a mixture of POCI, and DMF ( I: 10: 10

eq) at IS °c to obtain 3-~ -acetoxy-17-acetamido-16-formylandrosta-5,16-diene 3a in 88% yield. The formation of 3a may be proposed as a result of Beckmann rearrangement imd formylation. Beckmann rearrangement might lead to the in termediate enamide 4 which upon subsequent electrophilic attack of chloromethyleneiminium salt on the enamide terminal carbon and tautomerism resulted in the intermediate salt A. The latter hydrolysed to 3a (Scheme I). The IH NMR spectra of 3a showed a singlet for a formyl proton at 8 9.25 and amide -NH at 8 10.30, exchangeable with D20 and absence of a C-16 olefinic proton signal near 8 5.20. However, we failed in our attempt to isolate the enamide 4 from the reaction mixture probably due to strong in situ electrophilic attack of chloromethyleneiminium salt at the terminal vinyl carbon atom at C-16 pos ition of 3a.

To substantiate our proposed mechani sm of en amide intermediacy, 3~-acetox y-1 7 -acetamido-androsta-5, l6-diene 4 was prepared independentl y by treating 2a with POCI , in pyridine at 0 DC. Treatment of 4 with chloromethyleneimin ium salt at 15 °C led to the same product 3a in 92% yield. A comparison of I H NMR data between 3a and 4 showed that the low field amjde proton signal which appeared in the case of 3a was absent in 4, thus ind icating a strong hydrogen bonding between amide -NH and formyl group in 3a. Further support for the intermediacy of the salt A was achieved when a portion of this salt was heated at 65 DC for 2hr to give the pyridosteroid 5

BORUAH et al. : CONVERSION OF p-FORMYLSTEROIDAL ENAMIDES INTO GEMINAL DICHLORIDES 275

RO

1a, R=Ac 1b, R=CHO 1c, R= PhCO

N~OH .. RO

~,-Py. "'C

NHCOCH,

.. RO

2a-c 3a-c

COCH3

1 ~.1&C

NHCOCH3 I P02CI2 NHCOCHs

RO

4 R=Ac

V.R.

RO

AcO

CI

5

R=Ac

+ ........ Me _N "-Me

..

RO

RO

..

(A)

(8)

+ ........ Me -N

'Me

Scheme I

as the sole product13 . The formation of 5 can thus be due to cyclocondensation of the iminium salt B at an elevated temperature.

In order to investigate the behaviour of formyl enamides towards electrophiles, Vi lsmeier reaction was carried on en amide 3a. The action of chloromethyleneiminium salt on 3a at 65 °C led to 3 ~acetoxy-17, 17-dichloro-l 6(E) .. chloromethyleneandro-st-5-ene 6a and 3~-acetoxy-16(E)-chloromethyleneandrost-5 -en-17-one 7a in 60% and 10% yields, respectively. The IH NMR spectra of 6a showed the absence of a formyl proton signal at 8 9.25 and

appearance of a singlet at 8 6.40 due to C-16 vinylic proton . The mass spectra showed molecular ion peaks at mlz 370 (M+, 98%), 372 [(M+ + 2), 100%] and 374 [(M+ + 4), 33%] which is a characteristic pattern for trich loro compounds. The IH NMR spectra of 7a however exhibited a characteristic l4 triplet signal for olle proton at 8 6.86 and molecular ion peaks at 316 (M+, 100%) and 318[(M+ + 2), 33%)] that are diagonistic of monochloro compounds . The fo rmation of 6a and 7a may be proposed via an initial tautomerism of 3a to an azadiene intermediate C followed by vinylic chlorination to the intermediate D. Subsequent chlorination of C-17 imine bond of the

276 INDIAN J CHEM, SEC. B, MARCH 1999

intermediate D led to 6a as major product whereas hydrolysis yielded 7a as a minor product (Scheme II) . Similarly, compounds 3b-c, prepared from 2b-c, afforded 6b-c and 7b-c as major and minor products, respectively. The products were characterised by their physical and spectral data and elemental analysis (Table I).

To study the reactivity of steroidal enamides towards Vilsmeier reagent in general, compound 7-amino- 16-formyl-3~-hydroxyandrost-5 , 16-diene 8 was prepared from 3a by the action of methanolic KOH. Treatment of 8 with Vilsmeier reagent under similar reaction condition afforded 3~-formyloxy-16 E)-chloromethylene-5-androsten-17 -one 9 as the sole product. Tertiary enamine 3~-acetoxy-16-formylI 7-pyrroli -dinoandrosta-5, I 6-diene 11, prepared from 17-formyl-16-chloroandrosta-5 , 16-diene 10, analo-gously reacted with chloromethyleneiminium salt resulting in 6a and 7a as major and mjnor products, respectively . The tert iary en amide 3~-acetoxy-16-formyl - I 7-(N-acetyl-N-ethyl)androsta-5, 16-diene 12, prepared from 3a by alkylation with ethyl bromide under phase transfer catalysis, on reaction with Vilsmeier reagent similarly produced 6a and 7a under

identical condition (Scheme III) .

The steroidal ~ -formylenamide 3a was found to be fairly table under ac idic condition in contrast to steroidal enamide 4 which is susceptible to hydrolysis. The stability of 3a may be due to participation of C-17 amido group in enolization with formyl group substituted at C- J6 position. An attempt to prepare steroidal geminal dich lorides from 3 utilizing PCls or POCI, was unsuccessful and afforded polychlorinated materials ..

Consistent with the invol vement of ~-formyl group in these novel rearrangements, there was no reaction of steroidal C-1 6 fo rmylidienemalononitrile 13 upon treatment with excess of Vilsmeier reagent even on prolonged heating at 65 DC. However, elevation of the reaction temperature to .110 DC for I hr led to the substituted pyridosteroid 14 in 72% yield . The structure of the product 14 was assigned on the basis of spectral data l 5 including IH NMR spectrum which ex ibited three one-proton singlets due to a formyl, an aromatic and an olefinic protons, respectively. The C-6 proton appeared at 0 5.43 as a broad singlet. The mass spectrum showed the molecular ion peak at mlz 487 . The product gave sati sfactory microanalytical

BORUAH el aL. : CONVERSION OF ~-FORMYLSTEROIDAL ENAMIDES INTO GEMINAL DICHLORIDES 277

.+ Table I - Physical data of various compounds prepared Compd mt' Yield Mol. formula Calcd (Found) (%)

(0C) (%) (mol.wt) C H N

Ib 176 50 Cn H!(P3 77.19 ' 8.77 (342) (77 .05 8.62 -)

Ie 220 56 CZSH340 3 80.38 8.13 (418) (80.25 8.20 -)

2a 225 63 CZ3H33N03 74.39 8.99 3.77 (371) (74.45 8.92 3.70)

2b 176 68 Cn H31N03 73.95 8.68 3.92 (357) (74.05 8 .77 3.88)

2c 220 66 CZSH3SN03 77.60 8.08 3.23 (433) (77 .52 8.25 3.18)

3a 236 88 CZ4H33N04 72.18 8.27 3.51 (399) (72.25 8.30 3.40)

3b 190 76 C23H31 N04 71.69 8.05 3.64 (385) (71.80 8.00 3.50)

3e 245 70 CZ9H3SN04 76.49 7.59 3.04 (461) (76.38 7.50 2.99)

4 205 81 CZ3H33N03 74.39 8.89 3.77 (371) (74.56 8.80 3.64)

5 200 67 Cz4HmNOzCI 72.18 7.52 3.51 (399) (72.38 7.41 3.40)

.~ 6a 155 60 C22Hz90zC13 61.40 6.74 (430) (61 .35 6.82 -)

6b 176 66 CZIHz70zCI3 60.58 6.49 (416) (60.48 6.60 - )

6e 169 67 C27H3IOzCI) 65.85 6.30 (492) (65.61 6.46 -)

7a 170 10 CZZ HZ903CI 70.21 7.71 (376) (70.12 7.82 -)

7b 186 9 CZIH2703CI 69.61 7.47 (362) (69 .51 7.55 -)

7e 192 8 CZ7 H3103CI 73 .97 7.08 (438) (73.80 7.18 -)

8 185 65 CZOHZ9N02 76.19 9.21 4.44 (315) (76.02 9.10 4.25)

9 165 54 C2IH27CIO) 69.61 7.45 (362) (69 .70 7.23)

11 227 69 C26HJ7N03 75 .91 9.00 3.41 (411 ) (75 .99 9.20 3.57)

12 168 46 C26HJ7 N04 73 .07 8.67 3.28 (427) (73 .29 8.55 3. 11 )

13 201 78 C27 H33N)OJ 72.48 7.38 9.39 (447) (72.29 7.52 9.25)

14 240 72 C30H37N30 3 73.92 7.60 8.62 (487) (73 .60 7.72 8.87)

data. The mechanism for the formation of 14 may be and electron withdrawing cyano group at the ortho-attributed to the initial tautomerism and chlorination position (Scheme IV). of 13 under Vilsmeier condition leading to C-17

Conclusion chloroimine intermediate E followed by cycloconden-sation to the intermediate F . Subsequent reaction of In summary we have made an access to a novel two chloromethyleneiminium salts with activated C-2 class of ~-formyl steroidal enamides and showed their methyl of pyridosteroid intermediate F and hydrolysi s utility as key precursor of geminal dichlorides . would lead to product 14. Reactivity of C-2 methyl Notably, Vilsmeier reagent has been employed as presumably enhanced due to extended conjugation Beckmann as well as chlorinating agent in a one-pot

278 INDIAN J CHEM, SEC. B, MARCH 1999

H

OH 3a

HO OHCO

8 9

CI

Q Q

H .. AcO AcO

-10 11 PO,CI, ~w-

CH3 CI w-I Sa + 7a

0=\ /~2H5 N

EII/PTC 3a ..

AcO

12

Scheme III

react ion . Introduction of a formyl group at ~-pos ition renders steroidal C-17 enamide group to participate in enolization providing more stability to this new class of ~-formyl steroidal enamides.

Experimental Section

General. IR spectra were recorded on a Perkin-Elmer 580B spectrophotometer in KBr di sks . 'H NMR spectra were recorded on Varian T -60 and Brucker 300 MHz spectrometers using tetramethyl-silane as internal standard . Mass spectra were recorded on an Incos 50 mass spectrometer. Melting points were determined on a Buchi glass capillary melting point apparatus and are uncorrected . Elemental analyses were carried out on a Perkin-Elmer Series II 2400 machine. All chemicals were procured from Aldrich Chemical Company and all anhydrous reactions were performed under nitrogen

atmosphere. Solvent Dfv[F was dried over CaH2 and both DMF and POCI, were freshly distilled. All reactions were monitored by TLC over silica gel.

Preparation of 16-dehydropregnenoloneacetate-20-oxime 2a. To a stirred solution of commercial 16-DPA (la, 1.06g, 3 mmoles) in dry ethanol (50 mL) at room temperature was added hydroxylamine hydrochloride (420 mg, 6 mmo\es) and KH2P04 (8 16 mg, 6 mmoles). The reaction mixture was heated to reflux for 0 .5hr. Removal of the solvent under reduced pressure gave a thick sol id which was treated with ice cold water. The aqueous solution was neutralized with powered NaHCO" extracted with CH2CI2 (2 x 50 mL) and dried over Na2S04. Removal of the solvent gave 2a as a white solid, yield 700 mg, Rr 0.6 (TLC in CHCb); IR (KEr) : 3400, 2945, 1720; 1600, 1250 cm-I; IH NMR (CDCI,): 6 6.45 (bs, I H), 5.22 (bs, IH), 4.45 (m, 1H), 2. 12 (s, 3H), 1.90 (s, 3H), 0.98 (s, 3H), 0.80 (s, 3H), 2.30-1.10 (m, 17H); Mass

BORUAH et at. : CONVERSION OF ~-FORMYLSTEROIDAL ENAMIDES INTO GEMINAL DICHLORIDES 279

H

VR I .. 3a ~ 1200C CN AcO

AcO 14

13

1 0>1 ~ H

N.J:C)

~e Me

N

'-'::C-CN -CNC) VR

I ..

CN

AcO AcO AcO

(E) (F)

Scheme IV

spect rum (EI): rnJz 3 11,294,279,264,253. I6-Dehydropregnenoloneformate-20-oxime 2b.

An oven dried flask was charged wi th POCI3 (0.93 mL, 10 mmoles) and DMF ( 0.78 mL 10 mmoles) and the mi xture sti rred for 0 .5hr under nitrogen atmosphere . A solut ion of 16-dehydropregnenolone (3 14 mg, I mmole) in chloroform (30 mL) was added dropwise at 10 DC Lo the mixture . After the add ition was over, the reaction mixture was stirred at 15 DC for 2hr and then poured into ice-co d wa ter. Removal of the so lvent under reduced pressure gave an aqueous layer which was basified with powdered KOH Lo pH 10 and stirred at 60 °C fo r 0 .5hr. The product was extracted with dic hloromethane (2 x 20 mL), washed with water (2 x 50 mL) and finall y dried over Na2S04. On re moval of the sol vent the product 1 b was iso lated as a white sol id. yield 170 mg; Rr 0 .9 (TLC in CHC b ); IR (KE r): 2900, 1700, 1650, 1575 cm- I; IH NMR (CDCb): 8 7.82 (s, I H), 6 .52 (01, I H), 5.25 (m, I H), 4.56 (m, 1 H), 2.20 (s , 3H), 1.08 (s, 3H), 0.92 (s, 3H), 2.40-1 .20 (m, 17H); Mass spec trum (El): rnJz 296, 28 1, 253.

Oximation of Ib afforded 2b in 785 mg yie ld ; Rr 0.5 (TLC in CHCI3); IR (KBr): 3390, 2950, 1730, 16 10, 1265 cm- I; IH NMR (CDC,,): 87.80 (s, IH),

6 .40 (bs, I H), 5.20 (m, I H, C-5), 4.40 (m, I H), 2.15 (s, 3H), 1.80 (s , 3H), 0.90 (s, 3H), 0.80 (s, 3H). 2.20-1.1 5 ( 17H, 01); Mass spectrum (EI): rnJz 3 11, 294, 279,264.

16-Dehydropregnenolonebenzoate-20-oxime 2e. A so luti on of benzoy l chl oride (0.58 mL, 5 mmoles) was added to a mix ture of 16-dehydropregnenol one (942 mg, 3 mmoles) in dry pyrid ine (10 mL) and stirred at room temperature for 12hr. The reaction mi xture was treated with ice-cold water, acidified with dilu te hydrochloric acid (10 mL, 30%) and extracted with chl oroform (3 x 30 mL). The organic so lvent was washed with di lute sodium bicarbonate so lu tion (2 x 20 mL, 10 %) and dried over Na2S04. Removal of the organic so lvent gave the product Ie as a white solid. in 700 mg yie ld ; Rr 0 .9 (TLC in chloroform): lR ( KBr): 2925, 1700 , 1650, 1575 c m- I; IH NMR

(CDCl J) : 87.55-7. 12 (m, 5H), 6 .25 (bs, IH), 5 .22 (01, I H), 4 .45 (m, I H), 2.25 (s , 3H), 1.05 (5, 3H), 1.00 (s , 3H), 2 .40- 1.30 (m, 17H ); Mass spectrum (El): mlz 296, 28 1, 253.

Oximati on of Ie afforded 2c in 926 mg yield ; RI 0.5 (TLC in CHCI3); lR (KBr): 3380, 2950, 1725 , 1600, 1260 cm- I; IH NMR (CDCl 3): 87 .65-7. 12 (m, 5H), 6.30 Cbs, I H) 5 .25 (m, I H), 4 .35 (m, I H). 2.20 (s.

280 INDIAN J CHEM. SEC. B. MARCH 1999

3H), 1.90 (s, 3H), 0.95 (s, 3H), 0.85 (s, 3H), 2.25-1.10 (m, 17H); Mass spectrum (EI): mJz 311, 294, 279, 264.

Synthesis of 3~-acetoxy-17-acetamido-16-formylandrosta-5,16-diene 3a. To an oven-dried flask was added a solution of POCh (11.2 mL, 12 mmoles) and DMF (10 mL, 13 mmoles) at 0 °c and flushed with nitrogen. The reaction mixture was stirred vigorously until a white chloromethylene-minium salt separated out. A cold solution of 2a (1.16 g, 3.12 mmoles) in chloroform (100 mL) was prepared and added to this salt at -5°C under nitrogen atmosphere. Stirring was continued for 3 hr when the temperature gradually rose to 15° C. The reaction mixture was immediately poured into ice-cold water and stirred vigorously. Removal of the solvent under reduced pressure at 20°C gave an aqueous mixture which was basified with powered KOH to pH 10 and then warmed on a water-bath at 60°C for 2 hr. Extraction with dichloromethane (3 x 20 mL) and washing with water (2 x 50 mL) gave a light yellow solution which was dried over Na2S04. Removal of the solvent gave 3a as a white solid in 760 mg yield; Rr 0.3 (TLC in chloroform); IR (KBr): 3250, 2940, 1725, 1625, 1500 cm-I; IH NMR (CDCI,): 8 10.75 (s, IH), 9.08 (s, IH) , 5.10 (m, IH), 4.33 (m, I H), 2.05 (s, 3H), 1.80 (m, 3H), 0 .98 (s, 3H), 0.85 (s, 3H), 2.55-1.15 (m, 17H); Mass spectrum (EI): mJz 339,311,297,282,269.

17 -Acetamid6-16-fonnyl-3~-fonnyloxyandrosta-5,16-diene 3b: Yield 91 1 mg ; Rr 0.5 (TLC in chloroform); IR (KBr): 3350,2950, 1725, 1630, 1260 cm-I; IH NMR (CDCl,): 8 11.03 (s, IH), 9.23 (s, IH) , 7.72 (s, 1 H), 5.28 (bs, I H), 4.55 (s, I H), 2.09 (s, 3H), 1.10 (s, 3H), 1.00 (s, 3H), 2.45-1.25 (m, 17H); Mass spectrum (EI): mJz 385,357,339,311,297,282.

3~-Benzoyloxy-17 -acetamido-16-fonnylandrosta-5,16-diene 3c: Yield 1.0 I g; Rr 0.2 (TLC in chloroform); IR (KBr): 3345,2945, 1730, 1625, 1255 cm-I; IH NMR (CDCh): 8 7.60-7 .10 (m, 5H), 5.20 (bs, I H), 4.30 (m, IH), 2.15 (s, 3H), 1.85 (s, 3H), 0.92 (s, 3H), 0.78 (s, 3H), 2.20-1 .10 (m, 17H); Mass spectrum (EI): mJz 339,311,297,282.

3~-Acetoxy-17 -acetamidoandrosta-5,16-diene 4. To a cold solution of phosphorous oxychloride (0.931 mL, 1 mmole) in pyridine (2 mL) was added slowly under nitrogen atmosphere a solution of 2b (371 mg, I mmole) in dry pyridine (3 mL) and stirred at 0 °c . The reaction mixture was stirred at this temperature for 0.75 hr and poured into ice-cold water. The aqueous layer was extracted with chloroform (2 x 25 mL) and the organic layer washed with dilute HCI to remove pyridine. Drying over Na2S04 and removal of the · solvent in rotavapor at 30 °C gave 4 as a white

solid in 300 mg yield; Rr 0.1 (TLC in chltlroform); IR(KBr): 3300, 2900, 1715, 1680, 1520 1260 cm-I. I " H NMR (CDCh): 06.42 (s, IH), 5.72 (m, IH), 5.25

(m, IH), 4.45 (m, IH), 1.92 (s, 3H,), 1.88 (s, 3H), 0.92 (s, 3H), 0.72 (s, 3H), 2.25-1.05 (m, 17H); Mass spectrum (EI): mJz 311,296,269.

Vilsmeier reaction of 3~-acetoxy-17 -acetamido-androsta-5,16-diene 4. To a solid white chi oro-methyleneiminium sail, prepared from phosphorous oxychloride (8.37 mL, 9.0 mmoles) and dimethyl-formamide (7 mL, 9.0 mmoles) at -5 °C, was slowly added a solution of 4 (371 mg, 1.0 mmole) under nitrogen atmosphere. The temperature of the reaction was allowed to rise to 25 DC in 0.5hr and then refluxed at 65 DC for 2.5hr. The reaction mixture was poured into ice-cold water, basified with powdered KOH to pH 10, extracted with dichloromethane (3 x 30 mL) and dried over Na2S04. Removal of the solvent gave a solid material consisting of two products which were separated by column chromatography using toluene as eluant: (a) 3-~-acetoxy-2°-chloropyrido[ 17, 16-b ]andro-st-5-ene 5, yield 267 mg; Rr 0.9 (TLC in chloroform); IR (KBr): 3340,2940,1730,1625,1500,1240 em-I; IH NMR (CDCh): 87.11 (d, J = 8.0 Hz, d), 6.76 (d, J = 8.0 Hz, d), 5.20 (bs, I H), 4.35 (m, IH, C-3), 1.90 (3H, s), 1.05 (3H, s), 0 .90 (3H, s), 2.67-1.15 (17H, m); Mass spectrum (EI) : mJz 339 (100%),341(33%),324, and (b) 3a, yield 39 mg, Rr 0.2 (TLC in chloroform); IR (KBr) : 3340,2940,1730,1625,1500,1240 em-I; IH NMR (CDCl,): 8 10.75 (s, IH,), 9.08 (s, IH), 5.10 (m, I H) , 4.33 (m, I H), 2.05 (s, 3H), 1.80 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H), 2.55-1.25 (m, 17H); Mass spectrum (EI): mJz 339, 311 , 297,282.

3~-Hydroxy-17 -amino-16-formylandro-sta-5: 16- diene 8. A 30% KOH (1 mL) solution was added slowly to 3a (399 mg, I mmole) in ethanol (25 mL) at room temperature and the mixture stirred for 3.5 hr. On completion of the reaction, the solvent was removed in a rota vapor at 40 DC. t was treated with water (50 mL) and extracted with hloroform (2 x 40 mL) . The organic solution was ashed with water, dried over Na2S04 and solvent rem ved to afford 8 as a white solid, yield 205 mg; Rr O. (TLC in MeOH-CHCI, ); JR (KBr) : 3350, 1625, 15 0 em-I; 'H NMR (DMSO-d6): 89.45 (s, IH), 5.30 bs, IH), 3.52 (m, I H), 1.12 (s , 3H), 0.93 (s, 3H), 2. 5-1 .30 (m, 17H); Mass spectrum (EI) : mlz 297 , 282.

Acetylation was carried by addi g a solution of 8 (357 mg, I mmole) to a mixture f dry pyridine (5 mL) and acetic anhydriqe (0.37 mL, 4 mmoles) under nitrogen atmosphere. After stirring for 12hr at room temperature the reaction mixture wa. poured into cold

BORUAH et al. : CONVERSION OF p-FORMYLSTEROIDAL ENAMIDES INTO GEMINAL D1CHLORIDES 281

water (50 mL), acidified with dil. HCI, extracted with CHCh (3 x 30 mL), washed with water and dried over Na2S04. Removal of the solvent yielded 3a as a white solid, yield 298 mg (75%); Rf O.3 (TLC in CHCh); mp 236-37 0c. The product was characterized by comparison of spectral data and mixed melting point with a standard sample.

3~-Acetoxy-16-formyl-17-pyrrolidinoandrost-5,

16-diene 11. The required 3~-acetoxy-17 -chloro-16-formylandrosta-5,16-diene 10 was prepared according to the literature method.4d

To a solutiQn of 10 (1 g, 2.65 mmoles) in ethanol (100 mL) was added pyrrolidine (0.5 mL, 3 mmoles) under stirring and then refluxed for 2hr. On completion of reaction, the reaction mixture was concentrated in a rota vapor and poured into cold water. It was extracted with chloroform (3 x 30 mL), washed with dilute hydrochloric . acid and then with water. Drying over Na2S04 and removal of the solvent gave a red semisolid mass which was purified by column chromatography over silica gel using chloroform-MeOH (99: 1) as eluant to yield 11 as a white solid, yield 751 mg; Rf 0.3 (TLC in chloroform-methanol, 99:1); IR (KBr): 2940, 1725, 1630 cm- ' ; 'H NMR (CDCI): ~ 9.34 (s, IH), 5.25 (bs, IH), 4.30 (m, I H), 3.48 (m, 4Hj, 1.92 (s, 6H), 1.0 (s, 6H), 2.55-1.10 (m, 2IH); Mass spectrum (EI): mlz 351,336.

$-Acrtoxy-17-(N-acetyl-N-ethyl)-l6-fonnyIandro-sta-5,16-diene 12 To a stirred solution of 3a (300 mg, 0.75 mmole) and ethyl bromide (112 mg, 1.5 mmoles) in dichloromethane (100 mL) was added a solution of aqueous KOH (30%, 20 mL) and tetrabutylammo-nium bromide (644 mg, 0 .75 mmole) at room temperature. The reaction was monitored by TLC using ethyl acetate-hexane (20:80) as eluant. After stirring for 12 hr, the organic layer was separated and the basic aqueous layer extrated with dichloromethane (2 x 20 mL). The combined organic extract was washed with water (3 x 30 mL), dried over Na2S04 and the solvent removed to afford 12 as a white solid, yield 150 mg; Rr 0.3 (TLC in ethyl acetate-hexane, 20:80); IR (KBr): 2900, 1730, 1650, 1600, 1250 cm- ' ; 'H NMR (CDCI -): 89.35 (s, IH), 5.20 (bs, IH), 4.35 (m, I H), 3.80 (q, 1H), 2.00 (bs, 6H), 1.08 (bs, 6H) , 2.30-1.25 (m, 20I-L; Mass spectrum (EI) : mlz 367 , 352.

General Procl~ .ilJre for Synthesis of 3~-acetoxy-17,17 -dichloro- 1 Ii ,E)-chloromethyleneandrost-S-ene 6a. To a freshly prepared chloromethylene-iminium sa 1 (, prepared from freshly distilled phosphorous oxychloride (8 .37 mL, 9.0 mmoles) and dimethylformamide (7 mL, 9.0 mmoles), was added a solution of 3a (1.2 g, 3.0 mmoles) in chloroform (100

mL) under nitrogen atmosphere. The reaction was stirred first at room temperature for 0.25 hr and then at 65 °C for 3hr and subsequently poured into ice-cold water. The organic solvent was removed in a rotavapor at 25 °C and basified with powdered sodium bicarbonate to pH 6.5 at 15 °C. Extraction with ethyl acetate (3 x 30 mL), washing with water, drying and removal of the solvent gave a white solid product. Column chromatography of the product .using toluene as eluant afforded: (a) 6a as white crystals, yield 774 mg; Rf O.6 (TLC in toluene) ; IR (KBr): 2950,1735 cm-' ; 'H NMR (CDCI): 8 6.40 (s, IH), ~ .20 (bs, I H), 4.35 (m, IH), 1.85 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H), 2.30-1.10 (m, 17H); Mass spectrum (EI) : mlz 370 (98%), 372 (100%), 374 (33%), and (b) 3~-acetoxy-16-(E)chloromethyleneandrost-5-ene-17-one 7a, yield 112 mg; IR (KBr) : 2945 , 1740, 1700 cm-'; 'H NMR (CDCh): 8 6.86 (t, J = 2Hz, I H), 5.15 (bs, 1 H), 4.30 (m, 1 H) , 1.90 (s, 3H), 0.85 (s, 3H), 2.30-1 .10 (m, 17H); Mass spectrum (EI): mlz 316 (100%,) 318 (33%).

17,17 -Dichloro-16(E)-chloromethylene-3~-formyloxyandrost-5-ene 6b: Yield 831 mg; Rf 0.7 (TLC in toluene) ; IR (KBr) : 2950, 1730 cm- ' ; 'H NMR(CCI4): 8 7.82 (s, IH), 6.48 (s, IH), 5.30 (m, IH), 4 .62 (m, I H), 1,12 (s, 3H), 0.98 (s, 3H), 2.48-1.20 (m, 17H); Mass spectrum (EI): mlz 370 (98%),372 (100%),374 (33%).

3~-Formyloxy- 16-(E)-chloromethyleneandrost-S-ene-17-one 7b: Yield 98 mg, Rf 0.4 (TLC in toluene); IR (KBr) : 2940, 1730, 1700 cm-'; 'H NMR (CDCh) : 8 7.80 (s, I H), 6.90 (s, I H), 4.60 (m, I H), 1.10 (s, 3H), 0.94 (s, 3H), 2.40-1.20 (m, 17H); Mass spectrum (EI): mlz 316(100%), 318(33%).

17 , 17 - Dichloro ~ 16 ( E ) - chloromethylene-3~-benzoyl-oxyandrost-5-ene 6c: Yield 998 mg; Rr 0.7 (TLC in toluene) : IR (KBr): 2950, 1740 cm- ' ; 'H NMR (CDCb): 87.82-7 .35 (m, 5H, aromatic), 6.38 (s, IH), 5.25 (bs, IH), 4.65 (m, IH), 1.02 (s, 3H), 0 .85 (s, 3H, Me), 2.45-1.10 (m, 17H); Mass spectrum (EI): mlz 370 (98%),372 (100%), 374 (33%).

3~ - Benzoyloxy - 16 - ( E ) - chloromethylene-androst-5-ene-17-one 7c: Yield 105 mg; Rf 0.4 (TLC in toluene); IR (KBr): 2950, 1740, 1700 cm-I; 'H NMR (CDCI) : 8 7.82-7 .35 (m, 5H, aromatic), 5.20 (bs, I H), 4 .60 (m, I H), 1.06 (s, 3H), 0.85 (s, 3H), 2.48-1.15 (m, 17H); Mass spectrum (EI): mlz 3 16 (100%),3 18 (33%) .

3~-Formyloxy-16(E)-chloromethylene- 5-andro-sten-17-one9: Yield 634 mg; Rr 0.4 (TLC in toluene); IR (KBr): 2950, 1730 em-I; IH NMR (CDCI, ): 87.78 (s, I H) , 6.92 (t, J = 2Hz, I H), 5.32 (bs, 1 H), 4.55 (m,

282 INDIAN J CHEM, SEC. B, MARCH 1999

IH), 1.02 (s, 3H), 0.90 (s, 3H), 2.40-1.15 (m, 17H); Mass spectrum (ED: rnIz 316 000%),318 (33%).

3p~Acetoxy-17 -acetamidoandrosta-S,16-diene-16-formylidenemalononitrile 13. To a solution of 3a (400 mg, 0.001 mole) in ethanol (40 mL) below 5° C were added malononitrile (264 mg, 0.004 mole) and powdered KOH (500 mg) and the reaction mixture was stirred at 10 °C for 1 hr. It was treated with ice-cold water, neutralised with dilute hydrochloric acid (PH 7.6) and stirred for 15 min. when a solid yellowish product separated out. The product was filtered, washed with water and dried. Recrystallisation from hexane-diethyl ether (8 :2) afforded 365 mg (78% yield) of the product 13 as yellowish white flakes; Rr O. I (TLC in toluene-acetone, 95 :5); IR (KEr): 3280, 2910, 2230, 1710, 1650, 1585,1270 cm- I; IH NMR (DMSO-d6): 89.31 (bs, I H), 7.79 (s, 1 H), 5.23 (bs, I H), 4.45 (m, I H) , 2. 10 (s, 3H), 1.89(s, 3H), 1.00 (s, 6H), 2.3-1 .5 (m, 17 H); Mass spectrum (ED: rnIz 387 (M+ - CH3COOH), 372 [(M+ - CH3COOH) - 15], 345 [(M+ -CH3COOH) - 42], 330 [{ (M+ - CH3COOH) - 42} -15], 237,121.

Preparation of steroida1[17,I6-b ]pyridine derivative 14. A solution of 3a (447 mg, 0.001 mole) in DMF (25 mL) was poured into 0.0 I mole of Vilsmeier reagent (prepared from 0.93 mL of POCI3 and 0.78 mL of DMF) at O°C under nitrogen atmosphere in a 150 mL round bottomed fl ask. The reaction mixture was stirred at room temperature for I hr and then at I 10°C for 1.5hr. It was worked-up by pouring the reaction mixture into ice-cold water, basified to pH 9, and stirred at '45 °C for 0.5 hr when a sol id product separated out. It was fi ltered through Whatmann 40 fil ter paper under suction, washed with water, dried and purified by silica gel column chromatography using toluene-acetone (90: 10) as eluting sol vent to afford 14, yield 350 mg; Rr 0.3 (TLC in toluene:acetone, 95:5); IR(NaCI) : 2960, 2240, 1735, 1650, 1590, 1540, 1385, 1260, 1125, 1050, 780 cm-I; IH NMR (acetone-d6): 8 8.70 (s, I H), 8.01 (s , 3H), 7.68 1 (s, IH), 5.43 (bs, IH), 4.5 1 (m, IH), 3.19 (s, 3H), 3.11 (s, 3H), 1.97 (s, 3H), 1.14 (s, 3H), 0.97 (s , 3H), 2.52- 1.29 (m, 17 H); Mass spectrum (EI): mJz 487 (M+), 461 (M+ - 26) , 425 , 380, 300, 288, 260.

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