Indian Journal of Chemistry VoI.4IB,June2002,pp.125l-l256

An efficient method for selective deprotection of trimethylsilyl ethers, tetrahydropyranyl ethers, ethylene acetals and ketals under solvent-free conditions

Abdol R Hajipour*; Shadpour E Mallakpour*;I Mohammadpoor-Baltorkb & S Khoee'

'Phannaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan, 84156, I.R. IRAN; E-mail: Haji@cc.iut.ac.ir

bDepartment of Chemistry, Isfahan University, Isfahan, 81744, I.R. IRAN

Received 16 October 2000; accepted (revised) 9 October 2001

I-Benzyl-4-aza-I-azoniabicyclo[2.2.2]octane dichromate (BAABOD) is a useful reagent for the selective cleavage of trimethylsilyl ethers, tetrahydropyranyl ethers, ethylene acetals and ketals to their corresponding alcohols, aldehydes and ketones. This method is very simple and efficient and the reaction has been carried out under solvent-free conditions in the presence of anhydrous aluminium chloride.

Development of a mild and selective method for the protection of functional groups and then deprotection of the protected derivatives continues to be a significant aspect in the synthetic organic chemistry of polyfunctional molecules including the total synthesis of natural products. Thus a large variety of protective groups have been developed along with numerous methods for their removal.

Trimethylsilyl ether, tetrahydropyranyl ether, ethylene acetals and ketals are widely used as protective groups during the synthesis of natural compounds. 1·3

A wide variety of methods are available for the conversion of alcohols to their trimethylsilyl ether and tetrahydropyranyl ether and to deprotect these derivatives to the parent alcohol or to their corresponding carbonyl compounds via oxidative cleavage of the protected groupS.4.18 Deprotection of ethylene acetals and ketals to their carbonyl compounds under non aqueous and aprotic conditions is of practical importance. 19.23 In the course of studies on the synthesis of interesting biological natural products, a mild, fast and efficient method was required for the selective removal of protecting groups and carbonyl and alcohol moieties without affecting the other polyfunctional groups present in the molecule.

Heterogeneous reactions that are facilitated by supported reagents on various inorganic surfaces have recently attracted attention.24 The advantage of these methods over conventional and classical methods is that they show cleaner reactions, decreased reaction

times and easier work-up. In continuation of our ongoing program to develop environmentally benign

25 methods using solid supports, recently we have introduced 1-benzyl-4-aza-l-azoniabicyclo[2.2.2] octane dichromate 3 for the oxidation of alcohols to their corresponding carbonyl compounds.26

In this article we wish to report that under same reaction conditions this reagent is able to deprotect TMS- and THP-protected molecules to their corresponding alcohols without over oxidation to their aldehydes, ketones or carboxylic acids. The effects of several Lewis acids such as ZnC~, FeCl3 6~O, AICl3 and BiCl3 were thoroughly investigated. Surprisingly,

only anhydrous AlCl3 was found to be an effective

catalyst. The optimum molar ratio of anhydrous aluminium chloride for this purpose was 0.1 molar ratio. One equimolar of TMS- or THP-protected alcohols 4a-41 were mixed with 3 in the presence of 0.1 molar ratio of aluminium chloride in a mortar and ground with a pestle until TLC showed complete disappearance of starting TMS or THP derivatives (Scheme I). The reaction followed by TLC clearly indicates simultaneous disappearance OTMS and OTHP derivatives and

Rl 3/ AlCl3

~OM .. (1 :0.1)

Rl

~OH 4a-1 5a-1

, -Si(C~b

Scheme I

1252 INmAN J. CHEM .• SEC B. JUNE 2002

appearance of corresponding alcohols as the only product without any by-product formation. The reactions were completed within 0.5-1 min and the pure alcohols were obtained by a simple work-up. The results illustrated in Table I indicate that the reaction can be

used for a variety of TMS- and THP- protected primary and secondary benzylic alcohols.

Deprotection of ethylene acetals and ketals to their carbonyl compounds were also performed under same conditions. The reactions were completed within

Table 1- Deprotection of tetrahydropyranyl (THP) and trimethylsilyl (TMS) ethers 4a-4l with reagent 3 in the presence of anhy­drous AICI)·

4a

4b

4c

4d

4c

4f

4g

4h

4i

4j

4k

41

Substrate

Q-CH:PlMS

0Me

MIlO

Q-CH:PlMS

OMe

o-CH:PlMS

o~

~OlMS

0v

~H:P1HP

Sa

Sb

Sc

Sd

Se

5g

5h

5i

5j

5k

5c

Product

Q-CH:PH

OMe

o-CH:PH

0i'I

_ OH

Q-OCH-CH3

~OH

0v

~CH:PH

Reaction Period (sec)

35

57

35

40

35

45

45

60

60

55

45

30

Yield (%)

93

95

96

98

95

97

93

91

96

95

92

94

Reported2J Found

248-50n6O 248-51 n60

122-2511 381-83110

30-32 29-31

119/10 118-19110

20 18-20

94-96

102-04/2 161-63110

122-23 120-21

235n60 231n60

65-67 63-65

23-5 22-24

30-32 29-31

"All of the compounds were characterized by comparing with known compounds and their IR and 'H NMR spectra

HAJIPOUR et al. : DEPROTECfION OF SUBSTlTUTED ETHERS, ACETALS AND KETALS 1253

0.5-1 min and the pure aldehydes and ketones were obtained by a simple work-up (Scheme II and Table II).

In order to see, that the reactions are completed un­der solid state or during the extraction, we carried out the IR spectra of the reaction mixture after grinding the reaction mixture for the time being specified in Tables using KBr pellets. To evaluate the synergy between aluminium chloride and BAABOD in this reaction, several experiments were tried. The reaction of TMS ether 4c with 3 without aluminium chloride was unsuccessful and the TMS ether 4c was recov­ered unchanged after 45 min grinding in a mortar. The

_3_' A_I_CI......,3 .. ~ A:3>=o (1:0.1) R4

6a-i 7a-i

Scheme II

reaction of aluminium chloride with TMS ether 4c without 3 was unsuccessful and the yield of corre­sponding alcohol after 45 min grinding in a mortar was only 10% yield. As we have reported in our pre­vious work, adding a catalytical amount of anhydrous AICb to reaction media is very effective to convert

Table II - Deprotection of ethylene acetals and ketals 6a-i with reagent 3 in the presence of anhydrous AICI3Q

6a

6b

6c

6d

6e

6f

6g

6h

6i

Substrate Product Reaction Yield mp(°C) or bp (0C) {fOIT

Period (%) Reported26 Found

o-HC(~ MaO

CI-o-HC<~

0-1:> CH3

~CH=CH-HC~

7a

7b

7c

7d

7e

7f

7g

7h

7i

o ~.H

MaO

o ~.H

0Me

o C~-H

o ~II ~CH=CH-C'H

(sec)

30 86 178-79 n60 177-78 n60

55 93 43-46 42-46

35 97 57-59 56-58

30 96 143/5 141/5

45 92 37-39 36-39

40 97 47-50 46-48

35 95 19-20 19

40 91 116-18 115-18

35 93 248n60 246n60

a All of the compounds were characterized by comparing with known compounds and their IR and I H NMR spectra

1254 INDIAN 1. CHEM .• SEC B. JUNE 2002

benzylic alcohols to benzylic aldehydes and ketones26•

herein our new findings show that under the same condition TMS-. THP- ether, ethylene acetals and ketals were deprotected to their corresponding alco­hols and carbonyl compounds respectively but failed completely or gave less yields in the absence of anhy­drous AICh. So, it is interesting to investigate the competitive reaction of alcohols and the mentioned protected compounds with this reagent. When we treated an equimolar amount of ethylene ketal 6h with 3 in the presence of 3,4-dimethoxybenzyl alcohol, the ketal 6h was selectively deprotected and 3,4-dimethoxybenzyl alcohol was unchanged CEq 1). When an equimolar amount of THP ether 4k in the presence of 3,4-dimethoxybenzyl alcohol was treated

M'~CH'OH MeO 3: A1UJ (1 : 0.1)

2 min grinding

•

MeO

v1e~CH20H 3: AICI3 (1 : 0.1)

2 min. grinding

Meo-Q-CH20THP

M'0-y-CH,(JH

MeO

?1MS ~CH--CH3

VCH201HP

2 min grinding

with reagent 3, only the THP ether was selectively deprotected to its corresponding alcohol CEq 2). Treatment of TMS ether 4f in the presence of 3,4-dimethoxybenzyl alcohol, led to exclusive deprotec­tion of TMS ether 4f to the corresponding alcohol in 100% yield CEq 3).

Another noteworthy advantage of this reagent lies in the selective deprotection of TMS- and THP-ethers in the presence of ethylene ketals and TMS ether irrespective of the presence of THP ether. When an equimolar amount of THP ether 41 in the presence of ethylene ketal 6c was treated with reagent 3, only the THP ether 41 was selectively deprotected to its corresponding alcohol CEq 4). When we treated an equimolar amount of TMS ether 4c with 3 in the

unchanged

(Eq 1)

100%

unchanged

(Eq 2)

100%

unchanged

(Eq 3)

?H Q-OCH-.CIh 100%

V CH20H 100%

<hN 3: AI03 ~N (Eq 4) •

VH(~) (1 : 0.1) V HC

) 3min unchanged

~N ~N

HAJIPOUR ef al. : DEPROTECTION OF SUBSTITUTED ETHERS, ACETALS AND KETALS 1255

VCH10TMS VCH10H 100%

0 2N 3 :AICI3 OlN (Eq 5) ~

(1 : 0.1)

V H<) 3min

V HC::) unchanged

OlN OlN

VCH10TMS V

CH10H 100%

OlN 3 : AI03 OlN (Eq 6) ~

(1 : 0.1)

Me o-Q-CH lOT HP 3min

Me o-O-CHlOTHP unchanged

presence of ethylene ketal 6c, the TMS ether 4c was selectively deprotected and ethylene ketal 6c was unchanged (Eq 5). Treatment of TMS ether 4c in the presence of THP ether 4k led to exclusive deprotection of TMS ether 4f to the corresponding alcohol in quantitative yield (Eq 6). Interestingly in the deprotection of a, fJ unsaturated ketal only the ketal group was deprotected and C=C group remained intact.

In conclusion, we have developed a mild, fast and efficient method for the cleavage of TMS-, THP­ether, ethylene acetals and ketals under solvent-free conditions, which is superior to previously reported methods27 in terms of selecti vity, high yield, purity of the products, simple and rapid work-up. This method does not require a large excess of reagent and long reaction times. Notably ether, nitro, halogen and double bond functional groups present in the molecules were found to be resistant under the employed conditions.

Experimental Section Trimethylsilyl ethers, tetrahydropyranyl ethers,

ethylene acetals were prepared according to described procedures. 17.18 All of the products were characterized by comparison of their spectral (JR, IH NMR and TLC) and physical data (melting and boiling points) with those of authentic samples.5.13.22 All IH NMR spectra were recorded at 90 MHz in COCl3 and CCl

4

relative to TMS (0.00 ppm). All of the reactions were carried out in a hood with strong ventilation. IR spectra were recorded on Shimadzu 435 IR spectro­photometer (spectra of solids were taken usi ng KBr pellets).

General procedure Deprotection of TMS-, THP- ether. The

deprotection of 2-nitrobenzyl alcohol TMS ether is representative of the general procedure employed. In a mortar a mixture of the protected derivative 4c (0.39 g, 1.6 mmole), 1-benzyl-4-aza-l-azoniabicyclo­[2.2.2]octane dichromate (1.00g, 1.6 mmole) and aluminium chloride (2l.7 mg, 0.16 mmole) was added in one portion. The mixture was ground with a pestle for the specified time (Table I). After completion of the reaction (followed by TLC), CCl4 (15 mL) was added to the reaction mixture and after vigorous stirring the mixture was filtered off and the solvent was evaporated by rotary evaporator when the pure 2-nitrobenzyl alcohol was obtained .

Deprotection of ethylene acetals and ketals. The deprotection of 3-nitrobenzyl ethy lene acetal 6c is representative of the general procedure employed. The protected derivative 6c (0.28 g, 1.61 mmole), 1-benzyl-4-aza-l-azoniabicyclo[2.2.2] octane dichro­mate (l.00 g, 1.61 mmole) and aluminium chloride (21.7 mg, 0.16 mmole) was crushed with a mortar and pestle until TLC showed complete disappearance of starting materials which required 35 sec (Table II). CCl4 (15 mL) was added to the reaction mixture and after vigorous stirring, the mixture was filtered off and evaporated the solvent when the pure 3-nitrobenzaldehyde was obtained.

Acknowledgement

We are thankful to Research Council of the Isfahan University of Technology (lUT) for the partial support of this work.

1256 INDIAN J. CHEM., SEC B, JUNE 2002

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