Proc. Nati. Acad. Scd. USA Vol. 75, No. 1, pp. 4-6, January 1978 Chemistry Silane/iodine-based cleavage of esters and ethers under neutral conditions* (ester cleavage/ether cleavage/dealkylation/iodotrimethylsilane/phenyltrimethylsilane-iodine) TSE-LOK HO AND GEORGE A. OLAH Institute of Hydrocarbon Chemistry, Department of Chemistry, University of Southern California, Los Angeles, California 90007 Contributed by George A. Olah, September 26, 1977

ABSTRACT New, efficient cleavage of carboxylic esters physical constants and spectral data that were in good agree- with iodotrimethylsilane or a mixture of phenyl imethylsilane ment with literature data or those of authentic samples. and iodine is described. Essentially neutral conditions can be maintained throughout the reactions. Ethers can be dealkylated Cleavage of Esters and Ethers by Phenyltrimethylsil- by the latter method in high yields. The mechanism of the ane/lodine. A mixture of the ester or ether (5 mmol), phen- cleavage reactions is considered to include six-membered ring yltrimethylsilane (1.0 g, 7.5 mmol), and iodine (1.91 g, 15 mg homopolar transition states. atom) was heated to 1100 for 2-6 hr (see Tables 3 and 4). It was then cooled and quenched with water, and the organic material The most commonly used and convenient method for pro- was extracted with benzene and washed with dilute sodium tecting carboxylic acids is esterification. In view of the frequent hydroxide. The aqueous phase was acidified, deiodinated with incompatibility, during ester hydrolysis, of alkaline conditions Na2S203, and extracted with benzene. Pure carboxylic acids with many sensitive functional groups, esters that permit and phenols were isolated from the benzene solution. They had cleavage by other means are of great value. Benzyl, benzhydryl, satisfactory physical constants and spectral data. and trityl esters are such cases in which hydrogenolysis and acid treatment provide alternative routes to regenerate the car- RESULTS AND DISCUSSION boxylic acids (1). (Methylthio)methyl esters (2) can be cleaved under acidic (CF3COOH) or essentially neutral (Mel/aqueous Cleavage reactions with iodotrimethylsilane acetone) conditions. Among the most widely used carboxylic Consideration of the nature of esters RCOOR' indicates that protecting groups is the 2,2,2-trichloroethyl group which can the O-R' bond is essentially a hard base-soft acid combination be removed by zinc dust (3) or electrolysis (4). Photosensitive (23-25). To cleave this bond effectively, one should consider esters have also been developed (5-8). The point of scission a reagent or a combination of reagents incorporating a hard acid during deblocking of these special esters is generally the 0-alkyl and soft base center such as suggested by Saville's rule (26). bond as contrasted to 0-acyl cleavage in saponification. The well-known "hardness" of silicon (27-29) suggests the For deblocking methyl esters, Taschner and Liberek (9) used usefulness of silyl groups as the acidic portion of effective re- lithium iodide, and the method has been refined by Eschen- agents. Soft ligands such as I-,RS-, and CN- are suitable as the moser and coworkers (10) and later by others (11-13). Thiolate basic moieties. ions are more effective but, like iodide, they induce cleavage Based on the above-mentioned considerations, we have of the C-O bond of methyl esters (14) and of some of the more chosen iodotrimethylsilane as the cleavage reagent. This silyl active esters such as phenacyl (15). 9-anthrylmethyl (16), and iodide can be conveniently prepared by halogen exchange of benzyl esters (17). However, the high nucleophilicity of the chlorotrimethylsilane with anhydrous magnesium iodide ac- thiolate ion has been utilized in deblocking w-haloalkyl esters cording to the procedure of Kruerke (30). When methyl esters by anchoring strategy (18-20). were heated with iodotrimethylsilane at 1000, a smooth reaction Despite these intensive studies, there is still need for a general, took place. Methyl iodide was formed along with the trimeth- neutral method for ester hydrolysis. We reported, in two pre- ylsilyl esters. liminary communications (21,- 22), our work in this regard and now describe our results in full. RCOOMe + Me3SiI - RCOOSiMe3 + Mel Aqueous work-up of the cooled reaction mixture afforded the EXPERIMENTAL SECTION carboxylic acid. Judging from the high isolated yields, the re- General Procedure of Ester Cleavage with Iodotrimeth- action proceeds nearly quantitatively. Data are summarized ylsilane. A mixture of an appropriate ester (5 mmol) and io- in Table 1. dotrimethylsilane (2.0 g, 10 mmol) was heated to 1000, with The cleavage of ethyl and benzyl esters can be achieved exclusion of atmospheric moisture, for the time period specified. equally successfully. In the case of methyl esters, heating for The cooled reaction mixture was diluted with ether (25 ml) and 2 hr suffices to complete the demethylation, except for highly washed with 0.5 M sodium hydroxide (twice with 30-ml posi- hindered systems such as methyl pivalate (21). The excellent tions). The alkaline solutions were acidified and extracted with results in similar cleavage of ethyl esters indicate that the chloroform (twice with 30-ml portions). After removal of sol- method is conceivably of general use in cleaving unactivated vent, the dried extracts gave carboxylic acids that were pure primary alkyl esters. On the other hand, phenyl esters are inert on thin-layer chromatography. All acids were identified by to the reagent, as expected. Commercially available bromotrimethylsilane was found to be of little use. Methyl benzoate gave less than 10% cleavage The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate * This work was carried out in part at Case Western Reserve University, this fact. Cleveland, OH. 4 Downloaded by guest on September 25, 2021 Chemistry: Ho and Olah Proc. Natl. Acad. Sci. USA 75 (1978) 5 Table 1. Cleavage of esters with iodotrimethylsilakze Table 2. Cleavage of esters with phenyltrimethylsilane/12 Carboxylic Reaction time, Carboxylic acid Reaction acid yield,* Ester hr yield,* % Ester time, hr % Methyl benzoate 2 95 Methyl Methyl o-bromobenzoate 2 98 Benzoate 2 80 Methyl decanoate 2 90 o-Bromobenzoate 2 81 Ethyl phenylacetate 4 96 Phenylacetate 2 78 Isopropyl benzoate 4 88 n-Decanoate 2 75 n-Butyl benzoate 4 90 Cyclohexanecarboxylate 2 80 Benzyl benzoate 2 92 Pivalate 18 55 Ethyl * Isolated yield. Benzoate 4 72 Phenylacetate 4 70 Benzyl cannot be taken as firm support for the suggested ionic cleavage Benzoate 2 86 path. Because iodotrimethylsilane is extremely sensitive to Cyclohexanecarboxylate 2 90 hydrolysis (fumes in air), the adventitious presence of hydrogen iodide might have caused the cleavage of such acid-sensitive * Isolated yield. esters. after heating for 18 hr. Chlorotrimethylsilane was totally in- In situ cleavage with silane/iodine reagent effective. It is of interest to note that McKenna et al. (31). Re- After conclusion of our work with the iodotrimethylsilane re- cently reported that dialkyl phosphonates undergo dealkylation agent, we devoted our effort toward finding an improved with bromotrimethylsilane under exceptionally mild conditions. procedure. The preparation and handling of iodotrimethylsi- This dichotomous behavior of phosphonates versus carboxylates lane require strictly anhydrous conditions and, at best, are in- can be explained by considering the ready formation of phos- convenient. On the other hand, the facile iodolysis of phenyl- phonium ion intermediates in the former case trimethylsilane (34), which produces iodotrimethylsilane and iodobenzene, appeared amenable to being adopted for in situ O OSiMe:3 OSiMe, 11 1 cleavage of esters. R-P-OR' + Me.,SiBr -- R-P-OR'Br- - R-P-OR' + R'Br After equivalent quantities of phenyltrimethylsilane, 12, and l 11 the appropriate esters were heated at 1100 and then subjected OR' OR' 0 to aqueous quenching, carboxylic acids were obtained in high whereas a homopolar pathway for the reaction with carboxylic yields. The generality of the method was demonstrated by the esters is more likely. The efficiency of this latter pathway is equally efficient cleavage of methyl, ethyl, isopropyl, n-butyl, directly related to the "softness" of the nucleofugal group (I and benzyl esters. This method obviates the need for prepara- versus Br or Cl) linking to silicon. tion of the reactive iodotrimethylsilane shortly prior to its use (iodotrimethylsilane turns purple on standing and thus storage for a long period is not recommended). Moreover, higher yields were obtained (see Table 2) in the in situ method than with iodotrimethylsilane. The mechanism of the in situ reaction does not necessarily involve the prior formation of iodotrimethylsilane. The sig- nificantly increased efficiency in cleaving alkyl aryl ethers with Shortly after our preliminary communication appeared, Jung this procedure in comparison with reactions with iodotri- and Lyster (32) reported their independent work on the same methylsilane is noteworthy (Tables 3 and 4). On the basis of this reaction. In contrast to us, they suggested that the reaction an alternative proceeds via rapid, reversible formation of silyloxy alkoxy observation, it seems reasonable to suggest carbenium iodides followed by a slow elimination of iodoal- pathway involving a six-centered transition state: kanes: Ar\ 0 O R 11 _ OSiMe3 OSiMe, u + Me3SiI = RC' + I - R- C + R'I. Me3Si P) NC-,OR' OR' O The greatly different reactivities observed in our work between c5 j iodotrimethylsilane and bromotrimethylsilane are, however, _ 0 _~~~~ rather difficult to rationalize on this basis. In addition, the collapse of intermediate dioxycarbenium iodides to products A similar six-membered ring transition state can be attained should be more rapid than their reversion to starting materials, during ester cleavage, with iodotrimethylsilane but only a rel- when considering the strongly nucleophilic nature of iodide and atively unfavorable four-membered ring transition state or the hard-soft acids and bases principle (23, 24). Ample prece- alternative ionic mechanism is possible in ether cleavage, dents are known for the regioselective attack on ambident thereby accounting for the low reactivity in the latter case. The cations (25, 33). experimental observations are thus not consistent with the as- In the absence of experimental details, the observation that sumption that both processes involve iodotrimethylsilane as the tert-butyl and benzyl esters were dealkylated in the work of reagent or that ionic pathways are followed. Jung and Lyster at higher rates than n- and iso-alkyl esters (32) The role of HI, which might be present in the iodotrimeth- Downloaded by guest on September 25, 2021 6 Chemistry: Ho and Olah Proc. Natl. Acad. Sci. USA 75 (1978) Table 3. Demethylation of aryl methyl ethers with nucleophilic iodide efficiently displacing at the methyl carbon iodotrimethylsilane* atom of the developing oxonium ion. It should be emphasized Yield,t that demethylation with HI often requires forceful "digestion" Ether Phenol conditions. Anisole Phenol 48 Support of our work by the National Science Foundation and the o-Cresyl methyl ether o-Cresol 22 National Institutes of Health is gratefully acknowledged. 1-Naphthyl methyl ether 1-Naphthol 40 1. Harslam, E. (1973) in Protective Groups in Organic Chemistry, * At 1000, 24 hr. ed. McOmie, J. F. W. (Plenum, New York), pp. 183-215 and t Isolated yield. references given therein. 2. Ho, T. L. & Wong, C. M. (1973) Chem. Commun., 224-225. 3. Woodward, R. B., Heusler, K., Gosteli, J., Naegeli, P., Oppolzer, ylsilane samples as a contaminant or generated during ma- W., Ramage, R., Ranganathan, S. & Vorbruggen, H. (1966) J. nipulation, cannot be of significance (with the exception of Am. Chem. Soc. 88, 852-853. highly reactive tertiary systems) because for example, in the 4. Semmelhack, M. F. & Heinsohn, G. E. (1972) J. Am. Chem. Soc. case of ethyl esters, the addition of tertiary amines (e.g., pyri- 94,5139-5140. 5. Sheehan, J. C., Wilson, R. M. & Oxford, A. W. (1971) J. Am. dine) hardly affected the outcome of the cleavage reactions. Chem. Soc. 93,7222-7228. During the relatively short reaction times used by us, no 6. Patchornik, A., Amet, B. & Woodward, R. B. (1970) J. Am. formation of acyl iodide (32), by further reaction of the inter- Chem. Soc. 92, 6333-6335. mediate silyl esters with excess iodotrimethylsilane, was ob- 7. Barltrop, J. A., Plant, P. J. & Schofield, P. (1966) Chem. Com- served. This reaction proceeds under conditions described by mun., 822-823. Jung and it has to be an ionic process. 8. Barton, D. H. R., Chow, Y. L., Cox, A. & Kirby, G. W. (1965) J. Chem. Soc., 3571-578. 9. Taschner, E. & Liberek, B. (1956) Rocz. Chem. 30,323-325. RCOOSiMe, + Me;SiI - R-C FI- RCOI + (Me3Si)20 10. Elsing, E., Schreiber, J. & Eschenmoser, A. (1960) Helv. Chim. +O(SiMe,)2 Acta 43, 113-118. In the role of an acid (electrophile), tetracoordinated silicon 11. McMurry, J. E. & Wong, G. B. (1972) Synth. Commun. 2, 389-394. is generally "harder" than the carbonyl carbon. Thus, formation 12. Dean, P. D. G. (1965) J. Chem. Soc., 6655-6655. of acyl iodide is, in fact, anticipated upon prolonged exposure 13. Feutrill, G. I. & Mirrington, R. N. (1970) Tetrahedron Lett. of an ester to excess iodotrimethylsilane. 1327-1328. The cleavage of aryl alkyl ethers by the phenyltrimethyl- 14. Bartlett, P. A. & Johnson, W. S. (1970) Tetrahedron Lett., silane/iodine reagent is synthetically valuable because most 4459-4462. existing procedures (10) require harsher conditions (higher 15. Sheehan, J. C. & Daves, G. D., Jr. (1964) J. Org. Chem. 29, temperatures, strongly acidic or basic reagents) and their utility 2006-2008. is mainly limited to methyl ethers. As expected from a homo- 16. Kornblum, N. & Scott, A. (1974), J. Am. Chem. Soc. 96,590- polar mechanism, cleavage of unsymmetrical dialkyl ethers is 591. 17. Ho, T. L. & Wong, C. M. (1975), Synth. Commun. 5, 305- not regiospecific. 307. The long-known ability of HI to demethylate various methyl 18. Ho, T. L. (1974) Synthesis, 715. ethers can now be better understood through a similar mech- 19. Ho, T. L. (1975) Synthesis, 510-511. anism: 20. Ho, T. L. & Wong, C. M. (1974) Synth. Commun. 4, 302- 309. R-O-CH3 21. Ho, T. L. & Olah, G. A. (1976) Angew. Chem. 88,847-848. R-O-CH3 + HI - 4 t ROH + CH.J. 22. Ho. T. L. & Olah, G. A. (1977) Synthesis, 417-418. H-I 23. Pearson, R. G. (1963) J. Am. Chem. Soc. 85,3533-5S9. L _ 24. Pearson, R. G. & Songstad, J. (1967) J. Am. Chem. Soc. 89, Because 1827-1836. four-membered transition states are unfavorable, the 25. Ho, T. L. (1977) Hard and Soft Acids and Bases Principle in reactions are not considered to be completely concerted and Organic Chemistry (Academic Press, New York). could involve a somewhat stepwise process with the soft, highly 26. Saville, B. (1967) Angew. Chem. Int. Ed. Engl. 6,928-939. 27. Evans, D. A. & Wong, R. Y. (1977) J. Org. Chem. 42, 350- 351. Table 4. Cleavage of alkyl aryl ethers 28. Klebe, J. F. (1972) Adv. Organomet. Chem. 8,97-132. with phenyltrimethylsilane/12 29. Birkofer, L. & Ritter, A. (1965) Angew. Chem. 77,414-426. Reaction time, Phenol 30. Kruerke, U. (1962) Chem. Ber. 95, 174-182. Ether hr yield,* % 31. McKenna, C. E., Higa, M. T., Cheung, N. H. & McKenna, M. (1977) Tetrahedron Lett., 155-158. Anisole 4 90 32. Jung, M. E. & Lyster, M. A. (1977) J. Am. Chem. Soc. 99, Phenetole 4 84 968-969. Phenyl n-propyl ether 6 50 33. Burton, D. J. & Briney, G. C. (1970) J. Org. Chem. 35, 3036- Benzyl phenyl ether 4 80 3045. Methyl 2-naphthyl ether 4 86 34. Pray, B. O., Sommer, L. H., Goldberg, G. M., Kerr, G. T., Di- Giorgio, P. A. & Whitmore, F. C. (1948) J. Am. Chem. Soc. 70, * Isolated yield. 433-434. Downloaded by guest on September 25, 2021