Indian Journal of Chemistry Vol. 43B, June 2004, pp . 1275-1281

Ceric ammonium nitrate (CAN) catalyzed Baeyer-Villiger oxidation of carbonyl compounds, specially 20-oxosteroids

Papori Goswami, Saroj Hazarika, Archana M Das & Pritish Chowdhury*

Natural Products Chemistry Division, Regional Research Laboratory, Jorhat 785006, India e-mail: pritishchowdhury@yahoo.com

Received 4 February 2003; accepted (revised) 10 December 2003

The role of ceric ammonium nitrate (CAN) as an effective catalyst in the peracid induced Baeyer-Villiger oxidation of carbonyl compounds with special reference to steroids has been demonstrated .

IPC: Int.C1.7 C 07 K 1/00

Ceric ammonium nitrate (CAN) finds application in synthetic organic chemistry for various chemical transformations, viz., nitration 1, nitroacetamidation2

,

complex formation with various alcohols3 etc. Its role as single electron oxidant has been reported in a num­ber of publications including some recent reviews4

-8

.

CAN-induced oxidative radical transformations of steroids have also been reported9

. We too have re­ported lO the catalytic action of CAN in the esterifica­tion of carboxylic acids in very high yie ld . This in conjugation with our interest on steroid transforma­tions ll

-14 persuaded us to study its role in 8aeyer­

Villiger oxidation 1S-16 of 20-oxopregnanes to 17-

acetoxysteroids of potent sex hormones l7 and a lso of the formation of the steroidal D-ring lactones many of which are biologically active l8

.

Thus several steroidal carbonyl compounds 1-11 (Table I) which are available in our laboratory un­derwent Baeyer-Villiger oxidation to furnish their respective oxidation products 1a-lla (Table I) in high yield, when treated with m-chloroperbenzoic acid (m-CPBA) in the presence of catalytic amount of CAN in dichloromethane keeping just for 4-6 hr at room temperature. The method has been found to be effective for some non-steroidal carbonyl compounds 12-15 also (Table II) which give respective esters 12a-15a Cfable II) .

It is pertinent to note that although Andre et all ~ . have earlier reported the Baeyer-Villiger oxidation of some 20-oxopregnanes lIsing peracid alone, the reac­tion mixture had to be kept for 3 weeks in dark for completion . In the present case we did not find Baeyer­Villiger oxidation of 20-oxopregnanes 1-4 (Table I) when treated with either CAN or peracid alone at room

temperature even when kept for more than 48 hr. Fur­ther, GLC experiment confirmed 40-55 % conversion of benzophenone 12 to phenyl benzoate 12a in 5 hr when CAN was used as a catalyst along with peracid whereas only 8% conversion was observed in the ab­sence of CAN when kept for more than 24 hr. During our investigation, we also found that for all the cases (substrates 5-8, 10, 11, 13-15) the oxidation furni shed only one isomer viz. 5a-8a, lOa, lla, 13a-15a as con­firmed by TLC as well as analytical and spectral data.

The stereochemistry at C-17 position (17 Ha) in case of C-17 acetox y steroids fonned was confirmed by comparing the specific rotational value of products viz. 1a and 2a with those of the authentic compounds2112

when those were found to be completely identical. Earlier Mehta et al.2o reported the Baeyer-Villiger

oxidation of some carboxylic system by using slurry of CAN in acetonitrile. However, no Baeyer-Villiger oxidation occurred in our hands when the carbonyl compounds as listed in Table I were subjected to similar reaction conditions . T herefore, the present CAN catalyzed Baeyer-Villiger oxidation provides a useful way specially in the conversion of 20-oxopregnanes to 17-acetoxy steroids (C- 19 steroids) of sex hormone series and synthesis of steroidal ring­A and ring-D lactones.

Regarding thi s interesting observation about CAN which can act both as a Lewi s acid or as a SET ox i­dant , it seems to be reasonable that CAN co-ordinates with the ketone carbony l to facilitate nucleophilic attack of the peracid to form a complex which breaks­down to the products after the rearrangement steps. Recently , a nice modification of the 8aeyer-Villiger oxidation of some non-reactive substrates throu gh

1276

S.No.

1.

AcO

2 .

3 .

CI

4.

HO

5.

6 .

AcO

INDIAN 1. CHEM., SEC B, JUN E 2004

Table I - CAN catalyzed BV oxidation of carbonyl compounds in the presence of peracids.

Substrate Product

1a

2a

o

CI

4a

Sa

6a

Yield a (% )

80

75

91

80

77

78

376

318

352

354(M++2)

334

290

348

--Col1ld

GOSWAMI ('I a/.: CATALYZED BAEYER-VILLlG ER OXIDATION OF 20-0XOSTEROIDS

Table 1- CA N catalyzed BV oxidation of carbonyl co mpound s in the presence of peracids-Collld

S.No. Substrate Product Yielda mlz(M+)

(%)

0

83 324

326(M++2)

7. CI H

C H 7a b

0 79 306

8.

0 0

0 8a

78 .8 390

9.

Ac

9ac SH 17

82 402

10.

10a sH 17.;., "

78 388

11 .

11 a

(a) Yie lds refer to the isolated products which were fully characterised by spectral analys is. (b) The compounds shown has two molecular ion peak clue to J5C1 and ,17C1 isotopes. (c) The stereochemi stry of the epoxide was tentatively confirmed as Sa, 6a, o n the basis of the comparison of tr. ':! physi cal data of with that o f authentic 5u, 6u-epoxy cho lesterol: I nl D -9 .20 (c2, EtOH) [lit 20 I a) D -10.40 (c2, EtO H)J, mp 132-36°C ll it 21l mp 136°C).

1277

their hemi ketals or ketals was reported~ l, wherein il was the acti on of a Lewis acid that promoted the gen­eration of the reactive oxycarbonium ion to which the peracid added smooth ly. It is reported that CAN oxi-

dizes ketones as SET oxidant leading to radi cal cations, which usually undergo fragmentation~~. In situ generation of nitric acid from CAN may also be responsi ble for the observed BY oxidation reactions.

1278 INDIAN 1. CHEM ., SEC B, JUNE 2004

Table II-CAN c<ltalysed BY oxid<lt ion of non-steroid carbonyl compounds in the presence of peracids

S .No . Substrate Product Yield a m/z(M+)

(%)

12 . o°-U 56 198

12a d

13. ~o ~0'10 66 212

13a d

0 0

72 170 14 .

14ad

15 . ~CH3 :)-Jl [: CH 3 66

16. ~ t(d

16ae

(<I) Yields refer to the isolated products which were fully ch<lracterised by spectral analysis. (b) Yield c<llculated on the basis of GLC. (c) No re<lction W<lS observed and substrate was recovered gU<lntitatively.

The following points are to be noted: (i) only catalytic amount of CAN is necessary in

the reaction (CAN:Substrate:: 0.10: 1.5 mmole) . Oi) oxidation is complete within 4-6 hr at room

temperature. (iii) the yield of product is high, specially in the ster­

oids. (iv) the method is also applicable to the regioselec­

tive transformation of acyclic ketones to esters.

Experimental Section

Melting points were determined with an electro­thermal melting point apparatus and are uncorrected. All the chemicals used were of reagent grade of AI-

drich Chemical Co. and were used without further purification. m-CPBA used was purchased from Merck-Schuchardt, Germany and its purity was 55 %. Freshly distilled dichloromethane was used. The pro­gress' of the reactions were monitored by TLC using silica gel (E Merck) and the plates were activated at 100°C before use. IR spectra (in cm-!) were recorded on a Perkin-Elmer model 2000 series FT IR spec­trometer in CHCI3; 'H NMR spectra on a Bruker DPX (300 MHz) spectrometer with TMS as internal standard (chemical shifts in 0, ppm); and mass spectrometric analysis was performed by positive mode electro spray ionization with Bruker Esquire 3000 LC-MS instrument. Specific rotations (a\) were recorded on a Perkin-Elmer Polarimeter 343

GOSW AM! et al.: CATALYZED BAEYER-V!LLIGER OXIDA nON OF 20-0XOSTEROTDS 1279

corded on a Perkin-Elmer Polarimeter 343 instru­ment. Elemental analysis was carried out in Varian CHN Analyzer.

Cerie ammonium nitrate (CAN) induced selec­tive Baeyer-Villiger oxidation of carbonyl com­pounds with m-CPBA: General method. To the so­lution of a substrate (1.5 mmoles) in 10 mL of di ­chloromethane was added CAN (0.10 mmole) and m­

CPBA (Merck-Schuchardt, Germany, 55% pure) (2.0 mmoles). The reaction mixture was kept at room tem­perature for 4-6 hr. The reaction mixture was worked up by pouring into cold water (150 mL) and was ex­tracted with petroleum ether (60-80°C). The organic extract was first treated with aqueous solution of po­tassium iodide and the liberated iodine was neutral­ized with sodium thiosulfate and finally washed with sodium bicarbonate solution . The organic extract was evaporated under reduced pressure after drying over anhydrous sodium sulfate to get the desired oxidation product, which was further purified by preparative TLC (EtOAc-pet. ether). Since the reaction with all the substrates were carried out on a small scale with minimum amount of CAN, the catalyst could not be recycled and went into the aqueous phase during work-up.

5a-Androstan-3~, 17~-diol diacetate 1a. Com­pound 1 (500 mg) furnished 17-acetoxy compound la, yield 80% (420 mg) ; {a}D25-1.4° (c 2, CHCI3) [lit21 {a}o25- 1.5°; mp 124-28°C (Jit21 mp 128-29°C); IR (CHCI3): 1735, 1400, 1250, 950 cm-I; 'H NMR (300M Hz, CDCI3): 0.70 (s,3H), 1.1 (s, 3H), 2.0 (s, 6H,), 4.5 (m, 2H); MS (m/z) : 376(M+). Anal. Calce! for C23 H360 4: C, 73.40; H, 9.57. Found: C, 73 .25 ; H, 9.29%.

5a-Androstane-17~-acetate 2a. Compound 2 (500 mg) furnished 17-acetoxy compound 2a, yield 74% (380 mg); {a}D25 + 4.0° (c 2, CHCI3) [li e 2 (a}D25 + 5°); mp: 78-80°C (Jie 2 mp 82°C); IR (CHCI3): 1732, 1400, 1250, 950 cm-I; ' H NMR (300MHz, CDCI3): 0.70 (s,3 H), I.l (s, 3H), 2.1 (s , 3H), 4.5 (m, I H) ; MS (mlz) : 3 18 (M +). Anal. Calcd for C21H3402: C, 79.25 ; H, 10.69. Found: C, 79.53; H, 10.82%.

5a-Androstan-3J3-chloro-17J3-acetate 3a. Com­pound 3 (500 mg) furnished 17-acetoxy compound 3a, yield 91 % (450 mg); mp 95-98°C; IR (CHCI3): 1735 , 1400, 1252, 950 cm-I; 'H NMR (300 MHz, CDCb): 0.70 (s,3H), 1.1 (s, 3H), 2.1 (s, 3H), 4.5 (m, 2H); MS (mlz): 352 (M+);354 (M+ +2). Anal. Calcd for C21H330 2 CI: C, 71.59; H, 9.37. Found: C, 71.87 ; H, 9.55%.

5a-Androstan-3-~ol-17~-acetate 4a. Compound 4 (500 mg) furni shed 17 -acetoxy compound 4a, yield 80% (400 mg); {a}D25-O.9° (c 2, CHCI3); mp 143-46°C (Jit23 mp 148°C); IR (CHCb) : 3300, 1730, 1400, 1250, 950 cm· l

; 'H NMR (300 MHz, CDCI3): 0.70 (s, 3H), 1.1 (s, 3H), 2.0 (s, 3H), 4.5 (m, 1 H) , 4.1 (m,lH); MS (mlz): 334 (M+). Anal. Calcd for C21H340 3: C, 75.45 ; H, 10.18. Found : C, 75.76; H, 10.22%.

13a-Hydroxy-13,17, 5a-androstan-17-oie acid lactone Sa. Compound 5 (500 mg) furnished ring-8-lactone Sa, yield 77% (400 mg) ; mp 109-1 1°C; IR (CHCI3): 1735, 1400, 1250, 950 cm- I; 'H NMR (300MHz, CDCI3): 0.80 (s, 3H), 1.0 (s, 3H), 4.1 (q, 1=3 .5 Hz,2H); MS (mlz): 290 (M+) . Anal. Calcd for C19H300 2: C, 78.62; H, 10.34. Found: C, 78 .73 ; H, 10.62%.

3~-Acetoxy-13a-hydroxy-13,17, 5a-androstan-17-oie acid lactone 6a. Compound 6 (500 mg) furnished ring-8-lactone 6a, yield 79% (410 mg) ; {a}D25-47° (c 2, CHCI3); mp 129-31 °C; IR (CHCI3): 1735 , 1400, 1250, 950 cm-I; ' H NMR (300M Hz, CDCI3): 0.80 (s,3H), 1.0 (s, 3H), 2.1 (s, 3H), 4.1 (q, 1=3 .5 Hz,2H), 4.3 (m, IH) ; MS ( mlz): 348 (M+). Anal. Calcd for C21H320 4: C, 72.41; H, 9.19 . Found: C, 72 .63; H, 9.30%.

3~-Chloro-13a-hydroxy-13,17, 5a-androstan-17-oie acid lactone 7a. Compound 7 (500 mg) fur­ni shed ring-8-lactone 7a, yield 82% (430 mg); {a}D25-25° (c 2, CHCI3); mp 98-lOl oC; IR (CHCl 3):

1735, 1400, 1250, 950 cm- I; IH NMR (300MHz, CDCI 3): 0 .80 (s,3 H) , 1.0 (s, 3H), 4.1 (q, 1=3 .5 Hz, 2H), 4.3 (m, 1 H); MS (mlz): 324 (M+), 326(M+ +2). Anal. Calcd for C'9H290 2CI: C, 70.37 ; H, 8.95 . Found: C, 70.14; H, 8.77%.

3~, 13a-Dihydroxy-13,17 ,5a-androstan-17 -oic acid lactone 8a. Compound 8 (500 mg) furnished ring-8-lactone 8a, yield 79% (430 mg); {a}D25-40° (c 2, CHCb) [ lit 24 {a}D25-43°J; mp 164-68°C [ lit 24 mp 169°J; IR (CHCJ )): 3200, 1735, 1400, 1250,950 crn-I; IH NMR (300M Hz, CDCl3): 0.80 (s,3 H), 1.0 (s, 3H), 3.8 (m, I H), 4.1 (q, 1=3.5 Hz, 2H); MS (mlz):

306(M+). Anal. Calcd for C19H300 3: C, 74.51; H, 9.80. Found: C, 74.38; H, 9.96%.

3~,17~-Diacetoxy-5a, 6a-epoxy androstane 9a. Compound 9 (500 mg) furnished 17 -acetoxy com­pound 9a, yield 79% (400 mg); {a}D25-1 8. 1° (c 2, CHCI3); mp ISO-54°C; IR (CHCI3): 1730, 1400, 1250, 950 cm-I; IH NMR (300MHz, CDCI3): 0.70 (s ,3H),

1280 INDIAN J. C HEM. , SEC B, JUN E 2004

1.1 (s, 3H), 2.1 (bs, 6H), 4.5 (m, 2H ), 3.8 (m, I H); MS (mlz): 390 (M+). Anal. Ca lcd for C23H340 .'i : C, 70.77; H, 8.72. Found: C, 70.51; H, 8.60%.

£-Lactone of cholesterol lOa. Compound 10 (500

mg) furni shed the ring A £-Iactone lOa, yie ld 82% (430 mg); {a}D25 + 11.2° (c 2, CHCI3) I lit25 {a}1)25 + 12. 1°]; mp IS7-60°C JR (CHCI3) : 1735 , 1400, 1250, 9 ~i O cm-I; I H NMR (300M Hz, CDCI3) : 0.80-1.1 ( rn , ISH), 2.6 (b, 4a BH), 2A (d, 1=3.5 Hz,4 a a H), 4. 1 (q, 1=3.5 Hz, 2H).; MS (mlz): 402 (M +). Ana l. Calcd fo r Cn H460 2: C, 80.60; H, 11.44. Found : C, 80A3 ; H, 11 .24%.

3-0xo-4-oxa-5a-cholestane 11a. Compound 11 (500 mg) furni shed the ring A 8-lactone 11a, yield 79% (380 mg); {a}D25 + 78° (c 2, CHCI3) [ lit

26 {a}D25

+ 81.4°]; mp 11 3-16°C (Iit26 mp 1 16-1 8°C) ; lR (CHCI3) : 1735, 1400, 1250, 950 cm-I ; IH NMR (300MHz, CDCI 3): 0.80-1.1 (m,lSH), 4.1 (q, 1=3.5 HZ,2 H); MS (mlz):388(M+). Anal. Calcd for C26H440 2: C, 80A l ; H, 11.34. Found: C, 80.24; H, 11 .39%.

Phenyl benzoate 12a. Compound 12 (500 mg) fu rni shed phenyl benzoate 12a, yield 55 % (GLC) (300 mg); mp 63-69°C (I it27 mp 69-72 0C) ; IR (CHCI,).: 1735, 1400, 1250, 950 cm-I; IH NMR (300M Hz, CDCI3): 6.8-7.2 (m,SH) , 7.6-8.2 (m, SH ); MS (mlz): 198 (M+). Anal. Calcd for CI3H IO0 2: C, 78.79; H, 5.05. Found: C, 78.96; H, 5.27%.

2-(2,2,6-Trimethylcyclohexyl) ethyl acetate 13a. Compound 13, (500 mg) furnished ethyl acetate de­rivative 13a, yield 66% (GLC) (350 mg); IR (CHCI 3):

1730, 1400, 1250, 950 cm-I; IH NMR (300 MH z, CDCl3): 0.7-1.1 (m,9H), 2.1 (s, 3H), 4.97-5 .1 (q , 1=3.5 Hz, 2H); MS (mlz): 2 12 (M+) .

1-Methyl-4-isopropyl-£ -lactone 14a. Compound 141 (500 mg) furni shed the E-Iactone 14a, yield 71 % (GLC) (390 mg) ; IR (CHCl3) : 1736, 1400, 1250, 950 cm-'; 'H NMR (300MHz, CDCI3): 0.80-1.1 (m,9H), 3.7-4.1 (q, 1=3.5 Hz, 2H) ; MS (mlz): 170 (M+) .

Phenyl acetate 15a. Compound 15 (500 mg) fur­nished the £-Iactone 15a, yield 71 % (390 mg); JR (CHCI3): 1766, 1250,950 cm-'; 'H NMR (300MHz, CDCI3): 6.2-7.3 (m,SH), 2.1 (s, 3H); MS (mlz): 136 (M+).

Acknowledgement

The authors thank Director of the Insti tute for pro­viding necessary facilities for thi s work. One of the authors (PG) thanks CSlR, New Delhi for the award

of a Senior Research Fell owship. The Quality Control Center of our laboratory is thankfull y acknowledged for lR , NMR, mass and GLC experimen ts.

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