Tetrahedron Letters, Vol. 33. No. 17, pp. 2299.2302. 1992 0040-4039/92 $5.00 + .OO Printed in Great Britain Pcrgamon Press Ltd

Chemoselective Deprotection of Benzyl Esters in the Presence of Benzyl Ethers, Benzyloxymethyl Ethers and N-Benzyl

Groups by Catalytic Transfer Hydrogenation

Joginder S. Bajwa

Sandoz Research Instibte, Sandoz Inc.,

East Hanover, New Jersey 07936

&Y K’ordr: Chemoselective; deprotectio~~ knzyl groups; catalytic transfer hydrogendm.

Abstract: -COOBn, -PO(OH)OBn. -O-CBr and -N-CBz groups are @iciently and chemoselectively deprorected in

the presence of Bn and BOM ethers and NBn groups by hydrogenolysis under catalytic trm@er hydrogenadon using 10

% palladiwn on carbon as the catalyst and cyclohexadiene as the hydrogen donor.

As the complexity of synthetic targets increases, the need for mild and selective methods to protect and deprotect functional groups in highly sensitive multifunctional systems expands. Benzyl esters, benzyl ethers, benzyl carbonates and benzyl carbamates are the most useful in the repert&e of 0- andN-protecting groups in synthetic organic chemistry, primarily because of their ease of formation, inherent stability and the variety of methods available for their deprotection. * Among the various methods, catalytic or chemical hydrogenation is frequently the method of choice for debenzylation under mild conditions. Although examples of selectivity in dekenzylations have been recorded in the literature,2-5 we know of only one example6 in which a benzyl ester was cleaved in the presence of a hindered benzyl ether. The literature also lacks any reports on selective hydrogenolysis of benzyl esters in the presence of benzyl amines and selective hydrogenolysis of N-Cbzs or O- Cbz groups in the presence of benzyl ethers. Felix and coworkers 7 have shown that catalytic transfer hydrogenation using l&cyclohexadiene as the hydrogen donor is a very mild and effective method for the deprotection of various kinds of benzyl groups in peptides. However, chemoselective deprotection of various benzyl-type groups when they are present in the same molecule, has not been demonstrated. In this letter is presented such a chemoselective deprotection of various benzyl-protected functional groups.

01 I I lO%Pd-c

COOBn COOH Etch. FIT, 30 min

9B%

1

Scheme 1

2

Selective hydrogenolysis of benzyl esters in the presence of a benzyl ether was initially examined. We observed that catalytic transfer hydrogenation using 1,4-cyclohexadiene7 as the hydrogen donor is a very general method for cleaving benzyl esters in the presence of benzyl ethers. For example, treatment of sterically hindered benzyl ester 1 under these conditions resulted only in the deprotection of the ester group to give a near quantitative yield of acid 2 (Scheme 1).

2299

2300

Table: Selecfive Deprotection of Benzyl Esters in the Presence of Benryl Ethersa

Benzyl Ester Reaction Time

PVAJCtb YieW (%.I

7

6

BnO,,COOBn

BnO

BnO,),/COOB”

BnO&COOBn

BOMO&OOB”

BnO&COOBn

OBn

COOBn

BnS,/COOBn

20 min BnO,,COOH

20 min BnO

B”O&COOH

20 min BnO&COOH g6

30 min BOMO&COOH

100

20 min BnO~COOH 94

80 mind BOMO

w:-

89

10 min

OBn

d- I

COOH

24 hr No Reaction

95

90

100

-

Bn - PhCH2-; BOM - PhCH20CH2-

aThe reaction was carried out following the general procedure described in the text. bAll products were fully characterized by spectroscopic methods. clsolated yields. Que to insolubility of the the atacting material in EMH, the reaction was carried out in a mixture of EtOH and THF.

2301

The Table lists several examples in which benzyl esters were selectively debenzylated. Deprotection of benzyl esters was usually complete in less than OShs as monitored by the disappearance of starting material and products of high purity were obtained in excellent yields by direct isolation. 9 Even prolonged reactin times (24- 48 h) failed to cleave any significant amount of the benzyl ethers. It is interesting to note that catalytic transfer hydrogenation using 20 % Pd(OH)z-C as the catalyst and cyclohexene as the hydrogen donor in refluxing ethanol has been used to cleave benzyl ethers. 3 Like benzyl ethers, benzyloxymethyl (BOM) ethers (entries 4

and 6) are stable under the present conditions. a&Unsaturated benzyl esters are also selectively deprotected, however, the double bond is reduced (entry 5). A p-nitrobenzyl ester (entry 6) is also cleaved selectively in the presence of a benzyl ether. Literature reportslOJ1 on inhibition of catalytic transfer hydrogenation by sulfur containing compounds are conflicting, but we observed no reaction when benzyl2benzylthio acetate (entry 8) was subjected to catalytic transferhydrogenation, likely due to poisoning of the palladium catalyst by sulfur.

Next we examined selective cleavage of benzyl esters in the presence of N-benzyl groups. A benzyl group attached to a nonbasic nitrogen, such as in indole 3, is found to be completely stable. Thus, N-benzyl indole3- carboxylic acid 4 was obtained in 88 % yield by selective hydrogenolysis of benzyl ester 3. N-Benzyl groups from tertiary benzyl amines however, are cleaved under the present conditions, Nevertheless, N-benzyl nipccotic acid 6 was obtained in 63 8 yield by hydrogenolysis of benzyl ester 5 indicating that Ndebenzylation is slower than O-debenzylation of an ester group (Scheme 2).

COOBn

O/ I I lD%Pd-c -

EKMRT,3Omh I

COOH

An 4 88%

COOBn

5 8 63% Nipemtii Aeii 30%

Scheme 2

The benzyloxycarbonyl (Cbz) group is one of the most common amino protecting group used in the synthesis of amino acids, amino sugars, alkaloids and peptides*. Occasionally, it has also been used for the protection of hydroxyl groups.1~2 We have observed that cleavage of both N-Cbz and O-Cbz groups under the present conditions is very rapid and highly selective (Scheme 3).

O/ I I lO%PbC

BnO-OCbz w EC)H,RT, 10min BnO-OH

7 8 93%

COOhA I I lO%WC COOMe BnO

01 c BnO

E(OH,RT,lOmin NHCbz N Hz

9

Scheme 3

10 90%

2302

Fiiy, monobenzyl phosphonate 11 can be selectively deprotected in the presence of a benzyl ether under the present conditions to give phosphonic acid 12 (Scheme 4).

01 I I lO%PIC

E!Oli-THF. Rl, 40 h BnO-‘;-oH

OH

Scheme 4

In conclusion, the chemoselectivity demonstrated in the deprotection of benzyl protected functional groups further enhances the use of these groups in organic synthesis. General Procedure: To a stirred solution of benzyl ester (1 mmol) in absolute ethanol (10 ml) was added, under nitrogen atmosphere, 10 8 Pd-C12 (1:l catalyst / substrate by weight) followed by 1,Ccyclohexadiene (0.43 ml, 10 mmol). The suspension was stirred at room temperature for the required period of time (T. L. C. monitoring). The catalyst is removed by filtration through Celite and the filtrate was evaporated to dryness under vacuum to give the product in >95 96 purity (NMR). Acknowledgement: Thanks arc due to Dr. R. C. Anderson for helpful discussions and to Drs. Michael J. Shapiro, Emil W. Fu and Mr. Lance Janaskie of the Physical Chemistry Department for their analytical services.

References and Notes 1.

2.

3.

4.

5.

6. 7.

8.

9.

10. 11. 12.

Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Chemistry; John Wiely & Sons; New York, 1991. For an isolated example of a selective cleavage of 0-benzyloxycarbonyl group in the presence of a benzyl ester, see: Shue, Y-K.; Camera Jr., G. M.; Tufano, M. D.; Nadzan, A. M. J. Org. Chem. 1991,56, 2107-2111. The reason for this unusual selectivity is presumed to be the steric shielding of the benzyl ester by the bulky tert-butyl protected amino acid Asp side chain in the molecule. For a selective cleavage of a benzyl ether in the presence of a benzylidene acetal group, see: Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis, 1981, 396-397. For a selective deprotection of benzyl amines in the presence of benzyl ethers, see: Bernotas, R. C.; Cube, R. V. Synth. Commun., 1990,20, 1209-1212. For an isolated example of selective deprotection (cyclohexenc/PdC/rt/2 days) of an N-Cbz group in the presence of benzyl ethers see: Liu, P. S. J. Org. Chem. 1987,52.4717-4721. Kelly, T. R.; McNutt, Jr., R. W.; Montury, M., Tosches, N. P. J. Org., Chem. 1979.44, 63-67. Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1978.43, 4194-4196. The only exception was that of entry 6 (Table). Insolubility of the starting material in EtOH necessitated the use of THF as a cosolvent. This however, decelerates the reaction. See reference 7. The product in enny 6 (Table), N-benzyl nipecotic acid 6 (Scheme 2) and phosphonic acid 12 (Scheme 4) required a short-path silica gel chromatography. Jackson, A. E.; Johnstone, R. A. W. Synthesis , 1976, 685-687. Anantharamaiah, G. M.; Sivanandaiah, K. M. J. Chem. Sot., Perkin Trans Z, 1977,4X)-491. The 10 % Pd-C catalyst used in these studies was recently purchased from Engelhard Inc. The rate of the transfer hydrogenation was found to be highly dependent upon the quality of the catalyst. For example, the reaction times required for the conversion of the benzyl ester 1 to the acid 2 (Scheme 1) varied from 30 min to 4h depending upon the source and age of the catalyst. Surprisingly, however, the chemoselectivity of the reaction was not affected.

(Received in USA 9 December 1991)