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CrO3/NHPI Adsorbed onActivated Clay: A NewSupported Reagent for AllylicSelective Oxidation of Δ5-SterolsJin Liu a , Hong-You Zhu a & Xiao-Hong Cheng aa Department of Chemistry , Key Laboratory ofMedicinal Chemistry for Natural Resources (Ministryof Education), Yunnan University , Kunming, ChinaPublished online: 25 Feb 2009.

To cite this article: Jin Liu , Hong-You Zhu & Xiao-Hong Cheng (2009) CrO3/NHPI Adsorbed on Activated Clay: A New Supported Reagent for Allylic SelectiveOxidation of Δ5-Sterols, Synthetic Communications: An International Journalfor Rapid Communication of Synthetic Organic Chemistry, 39:6, 1076-1083, DOI:10.1080/00397910802484114

To link to this article: http://dx.doi.org/10.1080/00397910802484114

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CrO3/NHPI Adsorbed on Activated Clay: A NewSupported Reagent for Allylic Selective

Oxidation of D5-Sterols

Jin Liu, Hong-You Zhu, and Xiao-Hong ChengDepartment of Chemistry, Key Laboratory of Medicinal Chemistry for

Natural Resources (Ministry of Education), Yunnan University,Kunming, China

Abstract: Chromium trioxide and N-hydroxyphthalimide (NHPI) supported onactivated clay could serve as an efficient and mild oxidant for allylic selective oxi-dation of D5-sterols. Thus, a ketone group could be easily introduced into theallylic position of D5-sterols with the existence of a sensitive 3b-hydroxyl group.The oxidant residue can be removed easily from the reaction mixture by filtrationand reused after reactivation at 120 �C for 4–6 h.

Keywords: Activated clay, allylic oxidation, CrO3=NHPI, 7-keto-D5-sterols,supported reagents

7-Keto-D5-sterols are found in animal tissues, food products, and certainfolk medicines and are reported as inhibitors of sterol biosynthesis,HMG-CoA reductates, and cell replication.[1] Therefore, a great numberof oxidants for allylic oxidation of D5-sterols are developed to obtain 7-keto-D5-sterols. The most common allylic oxidants used are CrO3

complexes, such as Collins reagent,[2] pyridinium chlorochromate(PCC),[3] pyridinium dichromate (PDC),[4] CrO3-3,5-dimethylpyrazole,[5]

Received June 24, 2008.Address correspondence to Xiao-Hong Cheng, Department of Chemistry,

Key Laboratory of Medicinal Chemistry for Natural Resources (Ministry ofEducation), Yunnan University, Kunming, Yunnan 650091, China. E-mail:xhcheng@ynu.edu.cn

Synthetic Communications1, 39: 1076–1083, 2009

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print=1532-2432 online

DOI: 10.1080/00397910802484114

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pyridinium fluorochromate (PFC),[6] and so on. However, a large excessof oxidants (about 10–30 equiv.) must be applied in this process, whichled to a difficult workup process and production of environmentallyhazardous chromium residues. Recently, low molar ratios of the oxidantsare realized by using CrO3=NHPI in a cosolvent system of water andorganic solvents[7] however, the complicated separation procedure anddifficult disposal of the toxic chromium residues remained unsolved.

Many supported reagents were studied, and some provided particu-larly environmentally friendly mild procedures in acceptable yields,[8]

Among them, Cr(VI)-supported reagents were used as efficient oxidantsfor the transformation of hydroxyl compounds to carbonyl com-pounds;[9] unfortunately only few are related to the allylic oxidation.[10]

In this article, we report that CrO3 and N-hydroxyphthalimide (NHPI)adsorbed on activated clay could be applied as a new supported reagentfor allylic selective oxidation of D5-sterols. The reactions were carried outunder room temperature, the chromium residues could be easily removedfrom reaction mixture by filtration and reused by reactivation at 120 �Cfor 4–6 h. The structures of the products were characterized by infrared(IR) and NMR. The sensitive 3b-hydroxyl groups in the D5-sterolsremained uninfluenced.

As far as we know, reported oxidants, including CrO3 complexes ort-butyl hydroperoxide (TBHP), combined with different types of catalystsor cooxidations,[11] when used as allylic oxidants of 3b-hydroxylD5-sterols. In most cases, the 3b-hydroxyl group should be protectedbefore oxidation, usually as the acetate or benzoate ester[1]; if not, 3b-hydroxyl group would be oxidized to a ketone group. For example,oxidation of steroidal 5-en-3b-ol (via intermediate 5-en-3b-one) yielded4-en-3,6-diones instead of 7-one-5-en-3b-ol using of Jones reagent[12] orPCC.[13]

To demonstrate the validity and regioselectivity of theCrO3=NHPI-activated clay system developed herein, some model com-pounds were tested, and the results are summarized in Table 1. In allcases, the 7-keto-D5-sterols were synthesized successfully in acceptableyields by using this supported oxidizing system; the 3b-hydroxyl groupremained uninfluenced as concluded from the IR and NMR spectra ofthe corresponding oxidized products (compounds 1a–1e) (Scheme 1).For D5-steroid with the protected 3b-hydroxyl group (compound 1f),the allylic oxidation remained similar, but increasing reaction rate andoxidizing yield were observed (Scheme 2). The oxidant residue can berecovered by reactivation at 120 �C for 4–6 h and reused for thenew oxidizing reaction. For example, oxidizing compound 1f with therecovered oxidant still gave 2f in good yield (60%). Note that for com-pound 1g, after the oxidizing reaction, the acetal protecting group was

Allylic Selective Oxidation of D5-Sterols 1077

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Ta

ble

1.

All

yli

co

xid

ati

on

sw

ith

CrO

3=N

HP

I-a

ctiv

ate

dcl

ay

Su

bst

rate

aP

rod

uct

1H

-NM

Rb

d(p

pm

)

13C

-NM

Rb

d(p

pm

)IR

c

(cm�

1)

Mp

(�C

)Y

ield

d

(%)

1a

2a

5.7

1(s

,1

H,

H-6

),2

19

.7(C

-17

),2

00

.33

47

7.9

,2

36

–2

38

67

3.6

6(m

,1

H,

H-3

),(C

-7),

16

5.7

(C-5

),1

72

6.2

,1

.23

(s,

3H

,H

-19

),1

24

.8(C

-6),

69

.2(C

-3),

16

55

.4,

0.8

8(s

,3

H,

H-1

8).

16

.5(C

-19

),1

2.8

(C-1

8).

10

67

.0.

1b

2b

5.6

3(s

,1

H,

H-6

),2

09

.9(C

-20

),2

01

.63

49

5.9

,2

00

–2

01

54

3.6

0(m

,1

H,

H-3

),(C

-7),

16

6.1

(C-5

),1

70

7.9

,2

.07

(s,

3H

,H

-21

),1

25

.7(C

-6),

70

.2(C

-3),

16

58

.6,

1.1

4(s

,3

H,

H-1

9),

31

.6(C

-21

),1

7.3

10

70

.0.

0.5

9(s

,3

H,

H-1

8).

(C-1

9),

13

.2(C

-18

).1

c2

c5

.69

(s,

1H

,H

-6),

20

2.6

(C-7

),1

67

.23

51

9.2

,1

62

–1

66

52

3.6

8(m

,1

H,

H-3

),(C

-5),

12

5.8

(C-6

),7

0.2

16

63

.7,

1.2

3(s

,3

H,

H-1

9),

(C-3

),2

2.8

(C-2

6),

22

.61

06

1.3

.0

.88

(d,

3H

,H

-21

),(C

-27

),1

8.9

(C-2

1),

0.8

5(m

,6

H,

H-2

6,

17

.3(C

-19

),1

2.0

27

),0

.68

(s,

3H

,H

-18

).(C

-18

).1

d2

d5

.72

(s,

1H

,H

-6),

20

3.0

(C-7

),1

66

.03

42

9.2

,1

49

–1

54

40

5.2

0(d

d,

1H

,H

-22

),(C

-5),

13

9.0

(C-6

),1

67

0.1

,5

.05

(dd

,1

H,

H-2

3),

13

0.5

(C-2

2),

12

7.0

10

54

.9.

3.7

0(m

,1

H,

H-3

),(C

-23

),7

1.4

(C-3

).

1078

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1.17(d,3H,H-21),

0.87(d,3H,H-26),

0.85(t,3H,H-29),

0.84(d,3H,H-27).

1e

2e

5.70(s,1H,H-6),

201.6

(C-7),165.4

3506.8,

198–203

58

4.47(m

,1H,H-16),

(C-5),125.9

(C-6),

1667.9,

3.67(m

,1H,H-3),

109.2

(C-22),81.0

1066.0.

1.22(s,3H,H-19),

(C-16),70.4

(C-3),66.8

1.10(d,3H,H

-27),

(C-26),17.3

(C-19,17.1

0.80(d,3H,H-21),

(C-27),16.4

(C-18),

0.79(s,3H,H-18).

14.6

(C-21).

1f

2f

5.72(s,1H,H-6),

219.3

(C-17),199.8

1734.9,

184–186

75

4.69(m

,1H,H-3),

(C-7),169.3

(CO,

1670.4

60e

2.02(s,3H,

acetate),163.9

(C-5),

1630.9,

–O–CO–CH3),1.21(s,

125.5

(C-6),71.0

(C-3),

1026.9

3H,H-19),0.86(s,

19.6

(CH

3,acetate),16.4

3H,H-18).

(C-19),12.8

(C-18).

1g

2a

40

aAllsubstratesare

commerciallyavailable.

b1H-N

MR

and

13C-N

MR

spectrawererecorded

onaBruker–DRX-500spectrometer

inCDCl 3.

c IR

wasrecorded

onThermoNicoletAvatar360.

dIsolated.

e Yield

withtherecovered

oxidant.

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cleaved to 2a (as concluded from 1H NMR and 13C NMR). Probablythe oxidizing conditions used here are not mild enough for the acid-sen-sitive acetal protecting group in 1g to survive the transformation(Scheme 3).

In summary, CrO3=NHPI-activated clay in CH2Cl2 proved to be aneffective oxidant for allylic oxidation of D5-sterols. In this way, allylichydrogen atoms of D5-sterols could be oxidized to a ketone group withthe existence of the sensitive 3b-hydroxyl group, and the chromiumresidues can be removed easily by filtration after the reaction and reusedafter reactivation at 120 �C for 4–6 h.

Scheme 1. Allylic selective oxidation of compounds 1a–e to compounds 2a–e.

Scheme 2. Allylic selective oxidation of compound 1f with protected 3b-hydroxylgroup to compound 2f.

1080 J. Liu, H.-Y. Zhu, and X.-H. Cheng

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The reactions can be carried out under mild condition with moderateyields. This procedure expands the utility of supported reagents as anefficient method for allylic selective oxidation of D5-sterols.

EXPERIMENTAL

Preparation of CrO3/NHPI-Activated Clay-Supported Oxidant

Solid chromium trioxide (10 g, 100 mmol) was dissolved in water (15 ml)at 40 �C; NHPI (5 g, 260 mmol) was added. The mixture was stirred for20 min; then water (15 ml) and activated clay (/< 75 mm) (45 g) wereadded. The mixture was further stirred for 10 min and then dried invacuum. The dry mixture was ground with a mortar and obtained finallyas a kind of brown powder.

Oxidation of 3b-Hydroxyl-D5-Sterols: Typical Procedure

To a solution of 3b-hydroxyl-D5-sterols (5 mmol) in CH2Cl2 (120 ml), theCrO3=NHPI-activated clay-supported oxidant (5.8 g, CrO3 content,8 mmol) was added at rt with stirring. After 10 h to 24 h, an additionalamount of CrO3=NHPI-activated clay-supported oxidant (5.8 g, CrO3

content, 8 mmol) was added portionwise during a period of 10 h. Afterthat, the reaction mixture was further stirred until the reaction completed(thin-layer chromatography, TLC, control) (about 24 h to 48 h). The mix-ture was filtered through a bed of activated clay and washed with dichlor-omethane. The combined filtrate was washed repetitively with saturatedNa2CO3 solution until no orange color was observed in the organic layer(at this moment, almost all the NHPI residues were removed). Theorganic layers were then washed with brine and water and dried overMgSO4; the solvent was evaporated in vacuum. Purification of the

Scheme 3. Allylic selective oxidation of compound 1g to compound 2a

accompanied by cleavage of the acetal protecting group.

Allylic Selective Oxidation of D5-Sterols 1081

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product was done by column chromatography (eluent: petroleum=ethylacetate 3=1).

ACKNOWLEDGMENTS

Thanks are due to Prof. Fu-Chu Liu (Yunnan University) for helpfulcriticism of the manuscript. This work was supported by the NationalNatural Science Foundation of China (No. 20472070) and the YunnanScience Foundation (No. 2005E008M).

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