s t e r o i d s 7 1 ( 2 0 0 6 ) 632–638

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Short communication

A simple, convenient and chemoselective formylationof sterols by Vilsmeier reagent

Vandana Srivastava, Arvind Singh Negi ∗, J.K. Kumar, M.M. GuptaCentral Institute of Medicinal and Aromatic Plants (CIMAP)1, P.O. CIMAP, Kukrail Road, Lucknow 226 015, India

a r t i c l e i n f o

Article history:

Received 2 February 2006

a b s t r a c t

Vilsmeier reagent (DMF-POCl3) was used as an efficient formylating agent. Several sterols

having sec-hydroxyl group at 3/17-position have been modified into respective formate

Received in revised form 16 March

2006

Accepted 26 March 2006

Published on line 15 May 2006

Keywords:

Formylation

Vilsmeier reagent

Chemoselective

Protection

esters. The method is simple, mild, chemoselective and provides sec-alcoholic protection

in good yields.

© 2006 Elsevier Inc. All rights reserved.

1. Introduction

Generally, during a multistep synthesis of a natural prod-uct, several groups are first protected and then deprotectedafter the completion of desired reactions. Formylation of alco-hols is one of the most useful and versatile reactions inprotective organic chemistry [1]. In the recent years, sev-eral methodologies have been developed by using HCOOH [2],HCOOH-HClO4 [3], HCOOH-BF3·2MeOH [1], HCOOH-Al(HSO4)3[4], Ph3P-CBr4 in ethyl formate [5], potassium dodecatungsto-cobaltate trihydrate (K5CoW12O40·3H2O) in ethyl formate [6],chloral-K2CO3 [7], 2,2,2-trifluoroethyl formate [8], DMF-2,4,6-trichloro-1,3,5-triazine in acetone [9]. Formate esters have alsobeen found quite useful in developing other transformations[10–15]. Formylation has been thought of as a better protec-tive group for sterols in several transformations [16]. However,

∗ Corresponding author. Tel.: +91 522 2717529x327; fax: +91 522 2342666.E-mail address: arvindcimap@rediffmail.com (A.S. Negi).

1 CIMAP Communication No. 2005-58J.

formylation of alcohols has been less preferred in syntheticstrategies. It might be due to drastic reaction conditions, unde-sirable side products, poor yields and use of uncommon andunstable reagents [1,17].

Vilsmeier reagent has been used for the formylation of elec-tron rich aromatic systems to introduce an aldehyde groupin the ring system [18–21]. Use of this reagent as a formy-lating agent for alcohols was found to be ineffective [22].However, conversion of O-silyl protected sugars into theircorresponding formates by using dimethyl formamide (DMF)-phosphorus oxychloride (POCl3) complex has been reportedrecently [23,24]. Morimura et al. [25] used this reagent for theformylation of phenols to obtain the corresponding aryl for-mates in good yields. We herein report the use of this reagentfor the formylation of sec-sterols. We found that dimethyl for-mamide and phosphorus oxychloride is an effective reagent

0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.steroids.2006.03.005

s t e r o i d s 7 1 ( 2 0 0 6 ) 632–638 633

Scheme 1 – Chemoselective formylation of sec-sterols by Vilsmeier reagent.

for synthesizing formate esters of sterols even in the presenceof phenolic hydroxyls. The reaction is simple, efficient andundergoes in mild reaction conditions (10 ◦C to room temper-ature) to give formate esters in good yields (40–91%).

We have synthesized formate esters of different sterolshaving sec-alcoholic hydroxyls at 3- or 17-positions as shownon Scheme 1 and Table 1 (entries 1–10).

2. Experimental

2.1. General procedures

Starting material substrates 1–4 were purchased from SigmaBiochemicals, USA. For substrates 5–10, estrone was used asa starting material, which was also purchased from SigmaBiochemicals. Substrate 5 was synthesized by methylatingestrone with dimethyl sulphate/anhydrous K2CO3 in dry ace-tone under refluxing conditions and subsequent sodiumborohydride reduction in methanol at 50 ◦C. Substrate 6was obtained from estradiol, 3-methyl ether, 17�-acetate byperforming formylation using phosphorus oxychloride anddimethyl formamide at 80 ◦C [26] and then saponifying with1N aqueous methanolic KOH. Substrate 7 was synthesizedby reducing estrone with sodium borohydride in methanolat room temperature. Substrate 8 was synthesized from 2-formyl-estradiol, 3-methyl ether-17�-acetate on stirring withd[Kw

Substrate 10 was obtained on Baeyer–Villiger oxidation of 2-formyl, 3-methoxyestra-1,3,5(10)-trien,17�-acetate by stirringit with dry dichloromethane-m-chloro perbenzoic acid for 18 hat room temperature and subsequent hydrolysis with aqueousmethanolic-KOH. Dry solvents were prepared as per standardmethods [28]. Acetone was first treated with KMnO4 and thendried over fused CaCl2. Dichloromethane was also dried overfused CaCl2, while DMF was dried over CaH2. All the reac-tions were performed as per standard procedures. Reactionswere monitored on Merck aluminium thin layer chromatog-raphy (TLC, UV254 nm) plates. Visualization was accomplishedby spraying TLC plates with 2% ceric sulphate-10% aqueoussulphuric acid solution and charring them at higher temper-atures (100–120 ◦C). Column chromatography was carried outon silica gel (60–120 mesh, LOBA chemicals). 1H NMR, 13C NMRand DEPT experiments were obtained on a Bruker Avance-300 MHz instrument with tetramethyl silane as an internalstandard. Chemical shifts are given in ı ppm values. All the1H and necessary 13C spectral data are reported. Electrospraymass spectra were recorded on API-3000, LC-MS/MS (AppliedBiosystem) after dissolving the compounds in acetonitrile. Ele-mental analysis was carried out in Heraus CHN analyser.

2.2. Typical experimental procedure: synthesis offormylated products of entries 1–10

ry dichloromethane-anhydrous AlCl3 at room temperature27] and subsequent hydrolysis with 1N aqueous-methanolicOH. Substrate 9 was obtained on reduction of substrate 8ith sodium borohydride in methanol at room temperature.

2.2.1. Synthesis of 3-methoxyestra-1,3,5(10)-trien-17ˇ-ylformate [entry 5 (product), Table 1]In a 25 ml round bottom flask, estra 1,3,5 (10)-trien-3,17�-diol-3-methyl ether [entry 5 (substrate), 100 mg, 0.35 mmol] was

634s

te

ro

ids

71

(20

06

)632–638

Table 1 – Formylation of sterols by Vilsmeier reagent (DMF-POCl3)

Entrya Substrate Product Temperatureb Time (h) Isolated yield (%) Molar ratios(substrate:DMF:POCl3)

1 RT 3.0 64 1:5.2:4.5

2 RT 4.0 91 1:5.6:4.9

3 RT 3.5 48 1:5.1:4.5

4 RT 3.5 67 1:5.4:4.7

5 RT 4.5 79 1:5.2:4.5

6 RT 4.0 73 1:4:3.5

7 RT 3.0 52 1:3.5:3.1

st

er

oid

s7

1(2

00

6)

632–638635

Table 1 – (Continued )

Entrya Substrate Product Temperatureb Time (h) Isolated yield (%) Molar ratios(substrate:DMF:POCl3)

8 RT 4.0 59 1:3.8:3.3

9 RT 4.0 42 1:3.8:3.4

10 RT 3.5 40 1:3.8:3.4

a (1) 5-cholesten-3�-ol (cholesterol), (2) 8,24,(5�)-cholestadien-4,4,14-trimethyl-3�-ol (lanosterol), (3) (22E) ergosta-5,7,22-trien-3�-ol (ergosterol), (4) 5-cholesten-24�-ethyl-3�-ol (�-sitosterol), (5) estra-1,3,5(10)-trien-3,17�-diol,3-methyl ether, (6) 2-formyl-estra-1,3,5(10)-trien-3,17�-diol,3 methyl ether (2-formyl,17�-estradiol 3-methyl ether), (7) estra-1,3,5(10)-trien-3,17�-diol (17�-estradiol), (8)2-formyl,estra-1,3,5(10)-trien-3,17�-diol, (9) 2-hydroxymethyl,estra-1,3,5(10)-trien-3,17�-diol and (10) estra-1,3,5(10)-trien-2,3,17�-triol,3-methyl ether.

b Initial temperature of the reaction mixture was 5–10 ◦C at the time of addition of POCl3 and later on it went up to 30–35 ◦C.

636 s t e r o i d s 7 1 ( 2 0 0 6 ) 632–638

stirred in dry DMF (0.2 ml, 2.59 mmol). The reaction mixturewas cooled to 5–10 ◦C by using ice bath. After 10 min, phos-phorus oxychloride (0.2 ml, 2.26 mmol) was added drop wiseto the reaction mixture. The reaction mixture was kept atthis temperature for next 30 min and then further stirred atroom temperature for 4 h. After completion of the reaction, itwas poured into crushed ice and extracted with chloroform(25 ml × 3). The organic layer was washed with water, driedover anhydrous sodium sulphate and concentrated in vacuo.The residue thus obtained was column chromatographed oversilica gel (60–120 mesh) and eluted with hexane-ethyl acetate.The formate was obtained in 2% ethyl acetate-hexane frac-tion. It was recrystallised with hexane-chloroform (4:1) to geta white crystalline solid (87 mg, 79%).

Yield 79%. m.p. 102–104 ◦C. 1H NMR (CDCl3, 300 MHz): ı

0.85 (s, 3H, 18-CH3), 1.32–2.28 (m, 13H), 2.84–2.86 (bs, 2H, 6-CH2), 3.78 (s, 3H, OCH3), 4.79 (t, 1H, 17-CH, J = 8.39 Hz), 6.63(d, 1H, 4-CH, J = 8.5 Hz), 7.18 (d, 1H, 1-CH, J = 8.5 Hz), 8.10 (s,1H, not exchangeable, O–CHO, formate). 13C NMR (CDCl3,75.47 MHz): ı 12.38, 23.64, 26.41, 27.41, 28.05, 37.37, 39.15, 43.50,44.25, 50.55, 68.61, 83.03, 110.98, 114.46, 126.52, 132.92, 138.17,158.19, 161.40. Electrospray mass (CH3CN): 315.3 [M + H]+, 353.3[M + K]+. Elemental analysis calcd for C20H26O3: C, 76.40; H,8.33. Found: C, 75.98; H, 8.52.

2.2.2. 5-Cholesten-3ˇ-yl formate (3ˇ-cholesterylformate, 1)

23.36, 28.53, 28.53, 30.01, 33.49, 37.01, 37.51, 38.24, 39.48, 40.63,43.23, 43.27, 46.52, 54.96, 56.28, 73.22, 116.69, 120.88, 132.49,135.91, 138.45, 141.97, 160.83. Electrospray mass (CH3CN): 425.3[M + H]+, 447.4 [M + Na]+, 463.4 [M + K]+. Elemental analysiscalcd for C29H44O2: C, 82.02; H, 10.44; Found: C, 81.77; H, 10.82.

2.2.5. (24R)-24-Ethyl-5-cholesten-3ˇ-yl formate(3ˇ-sitosteryl formate; 4)Yield 67. m.p. 113–116 ◦C. 1H NMR (CDCl3, 300 MHz): ı 0.61 (s,3H, 18-CH3), 0.76 (d, 6H, C-28 and C-29 CH3, J = 6.36 Hz), 0.86(distorted t, 3H, C-26 CH3), 0.95 (d, 3H, C-21 CH3), 1.18 (bs, 3H, C-19 CH3), 2.30 (bd, 2H, 7-CH2, J = 7.62 Hz), 5.32 (bs, 1H, 6-CH), 7.96(s, 1H, not exchangeable, O–CHO, formate). Electrospray mass(CH3CN): 445.4 [M + H]+, 465.4 [M + Na]+, 481.3 [M + K]+. Elemen-tal analysis calcd for C30H50O2: C, 81.39; H, 11.38. Found: C,80.97; H, 11.74.

2.2.6. 2-Formyl-3-methoxyestra-1,3,5(10)-trien-17ˇ-ylformate (6)Yield 73%. m.p. oil. 1H NMR (CDCl3, 300 MHz): ı 0.78 (s, 3H,18-CH3), 1.185–2.31 (m, 13H), 2.85 (bs, 2H, 6-CH2), 3.82 (s, 3H,OCH3), 4.71 (t, 1H, 17-CH, J = 8.46 Hz), 6.61 (s, 1H, 4-CH), 7.68(s, 1H, 1-CH), 8.03 (s, 1H, not exchangeable, O–CHO, formate),10.32 (s, 1H, CHO, aldehyde). Electrospray mass (CH3CN):329.3 [M + H]+, 351.2 [M + Na]+, 367.4 [M + K]+. Elemental anal-ysis calcd for C21H26O4: C, 73.66; H, 7.65. Found: C, 74.14;H, 6.76.

Yield 64%. m.p. 112–113 ◦C. 1H NMR (CDCl3, 300 MHz): ı 0.61(s, 1H, 18-CH3), 0.78–1.92 (m, 36H), 0.96 (s, 3H, 19-CH3), 2.30(d, 2H, 7-CH2, J = 7.12 Hz), 4.65 (bs, 1H, 3-CH), 5.32 (s, 1H, 6-CH), 7.97 (s, 1H, not exchangeable, O–CHO, formate). 13C NMR(CDCl3, 75.46 MHz): ı 12.19 (18-Me), 19.09 (C-21), 19.53 (C-19),21.48 (C-11), 22.75 (C-26), 22.94 (C-27), 24.27 (C-23), 24.62 (C-15), 28.26 (C-12), 28.30 (C-25), 28.45, 29.57, 32.29, 32.42 (C-8),36.08 (C-20), 36.66 (C-22), 37.06 (C-1), 37.42, 38.56 (C-24), 39.94(C-16), 40.27 (C-4), 42.85, 50.70, 56.83, 57.24, 74.39 (C-3), 123.20(C-5), 139.91 (C-4), 160.56 (O–CHO, formate). Electrospray mass(CH3CN): 415.3 [M + H]+, 437.4 [M + Na]+. Elemental analysiscalcd for C28H46O2: C, 81.10; H, 11.18. Found: C, 81.62; H,11.36.

2.2.3. Lanosta-8,24-dien-3ˇ-yl formate (3ˇ-lanosterylformate; 2)Yield 91%. m.p. oil. 1H NMR (CDCl3, 300 MHz): ı 0.62 (s, 3H,18-CH3), 0.79 (d, 3H, 27-CH3), 0.83 (d, 3H, 26-CH3), 1.08 (d, 3H,21-CH3), 1.18 (s, 3H, 19-CH3), 1.96 (bs, 6H, 28-CH3 and 29-CH3),4.56 (bs, 1H, 3-CH), 5.05 (bt, 1H, 24-CH, J = 6 Hz), 8.05 (s, 1H, notexchangeable, O–CHO, formate). Electrospray mass (CH3CN):455.3 [M + H]+. Elemental analysis calcd for C31H50O2: C, 81.88;H, 11.08. Found: C, 82.34; H, 10.66.

2.2.4. (22E) Ergosta 5,7,22-trien-3ˇ-yl formate(3ˇ-ergosteryl formate; 3)Yield 48%. m.p. 141–144 ◦C. 1H NMR (CDCl3, 300 MHz): ı 0.56 (s,3H, 18-CH3), 0.78 (d, 6H, 21 and 25-CH3), 0.89 (d, 6H, 27 and 28-CH3), 1.18 (s, 3H, 19-CH3), 0.74–1.96 (m, 16H), 2.34–2.44 (m, 2H,2-CH2), 4.72–4.80 (distorted quintet, 1H, 3-CH), 5.13–5.15 (t, 2H,22 and 23-CH, J = 5.67 Hz), 5.32 (bs, 1H, 6-CH), 5.51 (bs, 1H, 7-CH), 7.98 (s, 1H, not exchangeable, O–CHO, formate). 13C NMR(CDCl3, 75.46 MHz): ı 12.42, 16.55, 17.92, 19.97, 20.24, 21.47,

2.2.7. 3,17ˇ-Dihydroxyestra-1,3,5(10)-trien-17ˇ-ylformate (7)Yield 52%. m.p. 108–110 ◦C. 1H NMR (CDCl3, 300 MHz): ı 0.63(s, 3H, 18-CH3), 1.04–2.06 (m, 13H), 2.59 (bs, 2H, 6-CH2), 4.57(t, 1H, 17-CH, J = 8.3 Hz), 6.36 (s, 1H, 4-CH), 6.42 (d, 1H, 2-CH,J = 8.3 Hz), 6.92 (d, 1H, 1-CH, J = 8.3 Hz), 7.89 (s, 1H, not exchange-able, O–CHO, formate). 13C NMR (CDCl3, 75.47 MHz): ı 12.41,23.64, 26.59, 27.56, 28.01, 29.87, 37.30, 39.06, 43.47, 44.20, 50.35,83.13, 113.20, 115.70, 126.77, 138.48, 153.93, 161.47. Electrospraymass (CH3CN): 301.1 [M + H]+, 323.2 [M + Na]+. Elemental anal-ysis calcd for C19H24O3: C, 75.97; H, 8.05. Found: C, 76.27; H,8.42.

2.2.8. 2-Formyl-3,17ˇ-dihydroxyestra-1,3,5(10)-trien-17ˇ-yl formate (8)Yield 59%. m.p. 93–94 ◦C. 1H NMR (CDCl3, 300 MHz): ı 0.79 (s,3H, 18-CH3), 1.18–2.23 (m, 13H), 2.73 (bs, 2H, 6-CH2), 4.77 (bs,1H, 17-CH), 6.62 (s, 1H, 4-CH), 7.36 (s, 1H, 1-CH), 7.94 (s, 1H,not exchangeable, O–CHO, formate), 10.71 (s, 1H, CHO, alde-hyde). Electrospray mass (CH3CN): 329.1 [M + H]+. Elementalanalysis calcd for C20H24O4: C, 73.15; H, 7.37. Found: C, 73.48;H, 7.94.

2.2.9. 2-Hydroxymethyl-3,17-dihydroxyestra-1,3,5(10)-trien-17ˇ-yl formate (9)Yield 42%. m.p. oil. 1H NMR (CDCl3, 300 MHz): ı 0.78 (s, 3H,18-CH3), 1.18–2.28 (m, 13H), 2.53 (bs, 2H, 6-CH2), 3.36 (s, 2H,CH2OH), 4.74 (t, 1H, 17-CH, J = 8.63 Hz), 6.55 (s, 1H, 1-CH), 6.84(s, 1H, 4-CH), 8.04 (s, 1H, not exchangeable, O–CHO, formate).Electrospray mass (CH3CN): 331.1 [M + H]+. Elemental anal-ysis calcd for C20H26O4: C, 72.70; H, 7.93. Found: C, 73.06;H, 8.24.

s t e r o i d s 7 1 ( 2 0 0 6 ) 632–638 637

Scheme 2 – An alternate strategy for the demonstration of chemoselective formylation. Reagents and conditions: (i) Me2SO4,K2CO3, dry acetone, reflux, 5 h, 89%; (ii) NaBH4, MeOH, 50 ◦C, 2 h, 92%; (iii) DMF-POCl3, 0–10 ◦C for 30 min, then RT, 4.5 h, 79%;(iv) DMF-POCl3, 0–10 ◦C for 30 min, then RT, 3 h, 52% and (v) Me2SO4, K2CO3, dry acetone, reflux, 6 h, 78%.

2.2.10. 2,17-Dihydroxy-3-methoxyestra-1,3,5(10)-trien-17ˇ-yl formate (10)Yield 40%. m.p. oil. 1H NMR (CDCl3, 300 MHz): ı 0.78 (s, 3H,18-CH3), 1.18–2.28 (m, 13H), 2.72 (bs, 2H, 6-CH2), 3.78 (s, 3H,OCH3), 4.71 (t, 1H, 17-CH, J = 8.38 Hz), 6.49 (s, 1H, 1-CH), 6.79(s, 1H, 4-CH), 8.03 (s, 1H, not exchangeable, O–CHO, formate).Electrospray mass (CH3CN): 331.1 [M + H]+. Elemental analysiscalcd for C20H26O4: C, 72 .70; H, 7.93. Found: C, 72.97; H, 7.36.

3. Results and discussion

Vilsmeier reagent has been found ineffective for the formy-lation of alcohols when dimethyl formamide-phosphorusoxychloride (DMF-POCl3) was used. However, cholesterolcould be formylated with dimethyl formamide-benzoyl chlo-ride (DMF-BzCl) [22]. But, now we were able to formy-late cholesterol by dimethyl formamide-phosphorus oxychlo-ride at room temperature and the method was successfullyextended to some other sec-sterols like lanosterol, ergosterol,�-sitosterol and estradiol 3-methyl ether. It is reported thatthis reagent has also been used for the formylation of phe-nolic hydroxyls to get corresponding aryl formates [23]. Butin case of substrates 7–10, exclusively alcoholic formateswere formed and phenolic hydroxyls were intact by thismethodology.

The formylation of sec-alcohols was found to be very effec-twop

trospray mass spectrometry. In 1H NMR, the chemical shiftof formate protons was found between ı 7.9 and 8.1 ppmwhere as, in 13C NMR the corresponding formate carbonylswere resonated between ı 160 and 161 ppm. Alternatively, thechemoselectivity of the reaction was confirmed by anothersynthetic strategy (Scheme 2), which proved the formylationpossibility at alcoholic hydroxyl only. However, benzylic alco-hols could not be converted to corresponding formates andin few cases, multiple products were obtained with very pooryields (<10%). This might be due to the reduced nucleophilicityof alcoholic oxygen as it is attached to the benzylic methylene.This reaction did not respond to ter-alcohols, e.g. menthol andnor-ethindrone.

In conclusion, it is demonstrated that Vilsmeier reagent(DMF-POCl3) is a very effective formylating agent for sec-steroidal alcohols. This is a simple, mild and straightforwardreaction, which completes in a short span of time. Otherfunctional groups such as phenol, aldehyde, acetate and arylmethyl ether were found rigid under the reaction conditions.Thus, this reaction may be of much helpful in the syntheticsteroidal chemistry where the protection of secondary alco-holic group is required.

Acknowledgements

Authors are thankful to the Director, CIMAP for the constant

ive in steroidal systems by this reagent. The formylationas chemoselective, as in the presence of phenolic hydroxylnly sec. alcoholic group got formylated (substrates 7–10). Theroducts have been identified by 1H NMR, 13C NMR and Elec-

encouragement and providing necessary facilities. The awardof Research Internship to one of the authors (V.S.) fromCouncil of Scientific and Industrial Research (CSIR) is dulyacknowledged.

638 s t e r o i d s 7 1 ( 2 0 0 6 ) 632–638

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