Indian Journal of Chemistry Vol. 40B, October 200 1 , pp. 1 007- 1 0 1 0

Note

A new approach to reductive deprotection of thioethers with a low-valent titanium reagentt

U Shadakshari, S Talukdar & S Chattopadhyay*

Bio-Organic Division, Bhabha Atomic Research Centre, . Mumbai 400 085, India

Fax: 9 1 -22-5505 1 5 1 ; E. Mail : schatt@apsara.barc.ernet.in

Received 24 January 2001 .. accepted 23 May 2001

Low-valent titanium mediated cleavage of carbon-sulphur bond is reported. This has resulted in an efficient and mild proto­col for the deprotection of allyl/benzyl thioethers under reductive condition and with good yields. Deprotection can be performed regio- and chemo-selectively in the presence of acid, ester and N-benzyllallyl functionalities and is general for aliphatic and aro­matic precursors.

Low-valent titanium reagents have occupied pride of place in organic synthesisl -3 . These have been suc­cessfully used for the construction of cycloalkanes, heterocycles, macrocylic rings as well for the synthe­sis of several complex natural products4.6. In view of the importance, several new variants of the L VT rea­gents3,7 including instantS and catalytic formulations5,9

have also been developed. Considering the utility of selective cleavage of carbon-heteroatom (0, N, S) bonds in organic synthesis, several useful synthetic methodologies involving C-O and C-N bond cleavage have been reportedlO. 12 from our laboratory. These include deprotection of alcohols/phenols 10 and amines I I , reductive cleavage of acetals 1 2 etc. Al­though many methods are available l3 for the cleavage of C-O and C-N bonds, the C-S bond cleavage in thioethers has received scanty attention. Protection of thiols finds innumerable applications in multistep or­ganic syntheses, particularly in protein chemistry in­cluding the synthesis of coenzyme A. Of the two classes of protections, viz. ester and ether types, the latter is preferred because of their inertness to nucleo­philic, acidic or basic reaction conditions. For thiols, deprotection under a reducing environment would be of importance over oxidative approach due to the in­herent tendency of thiol towards dimerization. Amongst the thioethers, the S-benzyl derivatives are most frequently used, although very few methods are

tDedicated to Prof. U.R. Ghatak on his 70'h birthday

lli. TiClyLilTHF R-:5'-P � R-S-P + p-p . . . Equation 1 R = alkyl, aryl

P = allyl, benzyl ©CNHR1 Ph-S-R

SR

1 a: R = Bn, R1 = H; 1 b: R = R1 = H 8a: R = Bn

2a: R = allyl, R 1 = H 8b: R = H

3a: R = R1 = Bn; 3b: R = H, R1 = Bn

4a: R = R1 = allyl; 4b: R = H, R1 = allyl

5a: R = cinnamyl, R1 = H

6a: R = Me, R1 = H

7a: R = Et, R1 = H

9a: R = Bn, R1 = Et

1 0a: R = Bn, R1 = Me

H2N1C02R

SH

9b: R = Et

1 0b: R = Me

Scheme I

�SR

1 1 a: R = allyl

1 1 b: R = H

known for their deprotection 1 3. These include both photolytic l4 and some chemical routes. Amongst the latter, the more frequently used protocol 1 3. 1 5 with Na/NH3 is not selective, while reagents like Hg(I1)/HCI 16 are not of general utility. Use of corro­sive and strong acid viz. HF in combination with scavangers produces 1 7 side products due to drastic conditions, thereby, limiting their synthetic utility for sensitive polyfunctional compounds. Therefore, a need for a better and selective strategy for this trans­formation was felt. To this end, we have developed a convenient approach for the selective removal of al­lyl/benzyl thioethers to the corresponding thiols via a L VT mediated single electron transfer (SET) reaction (Scheme I). Herein, we present the same.

In a model experiment, the reaction was carried out by refluxing a mixture of S-benzyl-2-aminothiophenol la and LVT, prepared from TiCliLi in THF. The re­action was complete (cf TLC) in 20 hr under reflux­ing condition affording 2-aminothiophenol Ib in good yield (Table I, entry 1 ) . The scope of the methodol­ogy has been illustrated (Table I) by the deprotection of a variety of S-allyl and S-benzyl thioethers of both

1 008 INDIAN J CHEM, SEC B, OCTOBER 2001

Table I-Deprotection of thioethers with L VT

Entry Substrate Temp (°C)I Product time

I la reflux/20 lb 2 2a 25/2 lb 3 la + 2a 25/18 la + lb

4 3a 25122 3b 5 4a 25118 4b 6 5a 25/18 Ib 7 6a reflux122 8 7a refluxl22 9 8a 25/16 8b 1 0 9a 2.5/25 9b I I lOa 2.5/25 lOb 1 2 lla 1 8/25 lIb

"The starting materials were recovered quantitatively, byield based on GLC.

Yield (%) 55 47 45 49 45 40

55 20 22 94b

aromatic (entries 1 -6 and 9) and aliphatic (entries 1 0-1 2) origins. Selective protection of polyfunctional molecule constitutes a challenging task in organic synthesis. In the present study, both chemo- and re­gio-selectives were achieved. In general, the method was very effective for the cleavage of the S-benzyl and S-allyl bonds but did not affect S-alkyl groups (entries 7 and 8). Hence, the former can be cleaved selectively in presence of the latter. Allyl group ap­peared to be removed easily (entry 2) as compared to the benzyl counterpart. Hence, to study any selectivity of cleavage between S-allyl and S-Bn, a model reac­tion was carried out with a mixture ( 1 : 1 molar prepa­rations) of S-allyl and S-benzyl-2-aminothiophenols la and 2a with L VT. The S-allyl bond was found to be cleaved even at room temperature along with the quantitative recovery of la (entry 3). In addition, the reagent ensured chemo-selecti ve deprotection of both allyl and benzyl thioethers in preference to the N­benzyl and N-allyl bonds thus, allowing selective protection of aminothiols (entries 4 and 5).

The lability of the S-C bond cleavage was further augmented by replacing the benzyl group with the cinnamyl component. In fact, S-cinnamyl group was cleaved in 1 8 hr at room temperature (entry 6) com­pared to S-benzyl group which required 20 hr at reflux temperature. The preferential cleavage of S-cinnamyl > S-benzyl > S-alkyl groups is in tune with the rela­tive stabilities of the respective radicals generated in the cleavage I 8. In case of the cleavage of S-benzyl bond, bibenzyl was also isolated (Equation 1) which is indicative of an electron transfer process l •2•

Since most of the above chosen substrates pos­sessed a protected or free amino functionality ortho to

the thioether group, it was of interest to investigate any influence of the former on the course of the deprotection route. For this, the reaction was also car­ried out, with a simple unsubstituted aryl thioether, 8a. This furnished the expected thiol 8b and in identical yield (entry 9) as that of the corresponding ortho­amino compound la. Thus, the method appeared to have general applicability with a wide substrate toler­ance.

In the synthesis of biologically important cystein­based compounds, the thiol group is often protected by benzylation. Hence, we attempted regeneration of the thiol group from two benzylated cystein esters with the above reagent. It was gratifying to note that deprotection of S-benzyl thioethers 9a and lOa pro­ceeded smoothly even in the presence of the reducible ester functionlaity in the substrates (entries 10 and 1 1 ). In the case of the cystein derivatives, 9b and lOb, the product recovery was poor possibly due to their high solubility in water. Hence, the yield is reported based on the amount of equimolar proportion of bibenzyl isolated. Finally, the reaction was also appli­cable with aliphatic thioethers as is reflected with re­sult with the substrate 11a (entry 1 2).

In conclusion, an efficient and selective protocol for the deprotection of allyl and benzyl derivatives of thiols has been developed with LVT. The S-benzyl bond can be cleaved chemoselectively in the presence of N-benzyl, N-allyl, S-alkyl and ester functionalities and is general for both aliphatic and aromatic precur­sors. Regioselective cleavage of S-allyl bond in pre­ference to their benzyl counterpart is an additional feature of the method.

Experimental Section Reagents are used as received. The LVT reactions

were carried out under Ar atmosphere and using freshly dried solvent. Lithium rods cut into small pieces were used for the reduction of titanium chlo­ride. All the extracts were dried over anhyd. Na2S04. The IR spectra were scanned with a Nicolet FT-IR spectrophotometer model 4 10 and only pertinent val­ues are shown. The IH NMR spectra were recorded with a Bruker AC-200 200 MHz spectrometer using CDCh as the solvent. The GLC analyses were carried out with a Shimadzu GC- 1 6A chromatogram.

Preparation of the substrates Alkylation of thiols. A suspension of the thiol

(0.0 16 mole), suitable halide (0.0 1 8 mole) and K2CO) (0.064 mole) in anhyd. EtOH (25 mL) was stirred at

NOTES 1 009

o DC till the reaction was complete (cf TLC). The re­action mixture was filtered, the filtrate concentrated in vacuo and the residue dissolved in ether. The ether extract was washed with water and brine and dried (Na2S04)' Removal of solvent followed by coloumn chromatogrpahy (silica gel) gave the pure product.

2-Amino-S-benzylthiophenol la: Yield 68%; IH NMR: 8 3.73 (s, 2H, SCH2), 4. 1 (bs, 2H, 020 ex­changeable, NH2), 6.3-7 . 1 (m, 9H, ArH).

2-Amino-S-aUylthiophenol 2a: Yield 58%; IH NMR: 8 3.36 (d, J = 6 Hz, 2H, SCH2), 4.2 (bs, 2H, D20 exchangeable, NH2), 4.88 (d, J = 4 Hz, 2H, ole­finic CH2), 5 .6-6.25 (m, I H, olefinic CH), 7.0-7 .47 (m, 4H, ArH).

2-Amino-S-cinnamylthiophenol Sa: In this case, the alkylation was carried out at 25 DC. Yield: 4 1 %; IH NMR: 8 3.52 (d, J = 6 Hz, 2H, SCH2), 4.2 (bs, 2H, 020 exchangeable, NH2), 6.23-6.37 (m, 3H, CH=CH2), 6.78-7.47 (m, 9H, ArH).

2-Amino-S-methylthiophenol 6a: Yield: 48%; IH NMR: 8 2.33 (s, 3H, CH3) , 4. 1 (bs, 2H, 020 ex­changeable, NH2), 6.47-7.4 (m, 4H, ArH).

2-Amino-S-ethylthiophenol 7a: Yield: 45%; IH NMR: 8 1 .22 (t, J = 7.2 Hz, 3H, CH3), 2.76 (q, J = 7.2 Hz, 2H, CH2), 4.23 (bs, 2H, 020 exchangeable, NH2), 6.63-7.5 1 (m, 4H, ArH).

S-Allyithiobutanol 11a: The alkylation was car­ried at 25 DC in THF using NaOH as the base. Yield 40%; IH NMR: 8 0.9 (dist. t, 3H, CH3), 1 .5 (m, 4H, CH2CH2), 2.4 (t, J = 6 Hz, 2H, SCH2), 3 . 1 (d, J = 4.5 Hz, 2H, allylic CH2), 4.9-5.2 (m, 2H, olefinic CH2), 5.5-6.2 (m, I H, olefinic CH).

N-Alkylation of protected thiols 2-(N-Benzyl)Amino-S-benzylthiophenol 3a. A

suspension of la ( 1 .0 g, 4.7 mmole), BnBr ( 1 .22 mL, 10.2 mmole) and NaOH (0.744 g, 1 8.6 mrnole) in an­hyd. toluene (25 mL) was refluxed for 48 hr. The re­action mixture was filtered, the filtrate concentrated in vacuo and the residue dissolved in ether. The ether extract was washed with water and brine and dried (Na2S04)' Removal of solvent followed by column chromatography (silica gel) gave pure 3a. Yield. 0.5 g (35%); IH NMR: 8 3.73 (s, 2H, SCH2), 4.03 (d, J = 6 Hz, NCH2), 4. 1 7 (bs, lH, 020 exchangeble, NH), 6.9-7.2 (m, 14H, ArH).

2-(N-AlIyl)Amino-S-allylthiophenol 4a. A sus­pension of 2a (0.6 g, 3 .7 mmole), allyl bromide ( 1 .4 mL, 16.5 mmole) and NaOH ( 1 .7 1 g, 29.3 mmole) in anhyd. benzene (25 mL) was refluxed for

48 hr. The reaction mixture was filtered, the filtrate concentrated in vacuo and the residue dissolved in ether. The ether extract was washed with water and brine and dried (Na2S04)' Removal of solvent fol­lowed by column chromatography (silica gel) gave pure 4a, yield 0.25 g (33%); IH NMR: 8 3.33 (d, J = 4 Hz, 2H, SCH2), 3.7 (m, 3H, partially 020 exchange­able, NCH2, NH), 4.7 (d, J = 4 Hz, 2H, olefinic CH2), 4.83 (d, J = 4 Hz, 2H, olefinic CH2), 5 . 1 -6.3 (m, 2H, olefinic CH), 6.43-7.47 (m, 4H, ArH).

General procedure for deprotection of thioeth­ers. A dry argon-filled three-necked round-bottom flask was charged with anhyd. THF (70 mL), TiCh ( 1 1 .2 mmole) and Li (37 mmole). The mixture was refluxed for 3 hr with stirring, during which the col­our of the reaction mixture changed from violet to black. To the L VT reagent thus prepared, was added the appropriate thiophenol (2.5 mrnole) in THF (5 mL) and the reaction mixture was stirred at suitable temperature for a specific period as mentioned in Table I. After the completion of the reaction (cf TLC), the reaction mixture was diluted with petro­leum ether-ethyl acetate mixture (3:2) and passed through Celite. The organic layer was washed with water and brine and dried (Na2S04)' Removal of sol­vent followed by preparative thin layer chromatogra­phy (silica gel) furnished the respective products.

2-Aminothiophenol Ib: IH NMR: 8 3.6 (bs, 3H, 020 exchangeable, NH2, SH), 6.4-7.4 (m, 4H, ArH).

2-(N-Allylamino)thiophenol 3b: IH NMR: 8 3 .7 (m, 3H, partially 020 exchangeable, NCH2, SH), 4.23 (bs, l H, 020 exchangeable, NH), 4.83 (d, J = 4 Hz, 2H, olefinic CH2), 6.33-6.7 (m, 1 H, olefinic CH), 6.9-7:2 (m, 4H, ArH).

2-(N-Benzylamino)thiophenoI 4b: IH NMR: 8 3.8 (s, 1 H, 020 exchangeable, SH), 4.23 (bs, 1 H, 020 exchangeable, NH), 4.36 (m, 2H, NCH2), 6.4-7.3 (m, 9H, ArH).

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