COMMUNICATIONS PIERRE DESLONGCHAMPS,~ CLAUDE LEBREUX, AND ROLAND TAILLEFER

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1 The Importance of Conformation of the Tetrahedral Intermediate in the Hydrolysis of Amides. Selective Cleavage of the Tetrahedral Intermediate Controlled by Orbital Orientation1 PIERRE DESLONGCHAMPS,~ CLAUDE LEBREUX, AND ROLAND TAILLEFER Lnborntoire de Synthkse organique, Departernen1 de chimie, Universiie' de Sherbrooke, Sherbrooke, Q~cPbec Received January 24, 1973 The basic hydrolysis of N-disubstituted imidate salts proceeds via a hemi-orthoamide tetrahedral intermediate which can in principle give amide-alcohol or ester-amine products. Experimental evidence has been obtained which shows that the specific conformation of the tetrahedral intermediate determines products formation and it is further suggested that theorientation ofthe lone pair orbitals of the heteroatoms governs this remarkable selective decomposition. L'hydrolyse basique des sels d'imidate N-disubstitues passe par la formation d'un intermtdiaire tetrahedrique du type hemi-orthoamide qui peut conduire soit aux produits amide-alcool ou ester-amine. Les rksultats experimentaux obtenus dkmontrent que la conformation precise de I'intermediaire tttrahkdrique determine la formation des produits. 11 est de plus avancc que I'orientation des orbitales d'electrons non-lies des httcroatomes contrble la dtcomposition selective de l'intermkdiaire tetrahkdrique. Can. J. Chem (1973) We have recently demonstrated the importance of the conformation of the tetrahedral intermediate (hemi-orthoester) during the hydrolysis or the transesterification of esters (1). We now wish to report that the conformation of the tetrahedral intermediate (hemi-orthoamide) formed during the hydrolysis of ainide and related functions is equally important; speclfic cleavage of a carbon-oxygen or a carbon-nitrogen bond being allowed only if the other two heteroatoms (oxygen or nitrogen) of the tetrahedral intermediate have each an orbital oriented antiperiplanar to the leaving 0-alkyl or N-alkyl group. In order to verify this stereoelectronic theory, we have selected for study the basic hydrolysis of the N-disubstituted imidate salts 1 (2) (Scheme I), expecting that such salts would react very fast with hydroxide ion to yield a tetrahedral intermediate 2 which can give in principle the amide-alcohol products 3 or the ester-amine products 4.3 If the reaction gives the 'Support for this work by the National Research Council of Canada and by the "Ministere de I'Education" Quebec, is gratefully acknowledged. 2A. P. Sloan Fellow To whom inquiries should be addressed. 3Study of the decomposition in a basic medium is important in order to prevent the protonation of the basic nitrogen of the intermediate 2. amide-alcohol products 3 via a kinetically controlled reaction, no information on the orbital assisted decomposition of the tetrahedral intermediate can be obtained since the amide-alcohol products 3 are also the thermodynamically favored products of the reaction. However, the formation of the ester-amine products 4 can give useful information on the decomposition of the tetrahedral intermediate 2 since they are clearly the result of a kinetically controlled reaction. Thus, if products 4 are preferentially observed it means that the transition state leading to those products is of lower energy than the one leading to the formation of the much more stable amide-alcohol products 3. We disclose here experimental evidence which clearly establishes that the preferential formation of the ester-amine products 4 is possible in basic medium and proposed that whenever such products are formed, the low energy transition state is due to the formation of a specific conformation of the tetrahedral intermediate 2 in which the lone pair orbitals of the oxygens are properly oriented to permit the specific cleavage of the carbon-nitrogen bond. Imidate salts can exist into two different planar conformations, the anti (la) or the syn (lb) form. If the anti form la reacts with hydroxide ion (Scheme 2), it should give specifically

2 CAN. J. CHEM. VOL. 51, 1973 (9 $ KOH the conformer 2a in which the two new lone-pair orbitals on the oxygen of the OR' group and the nitrogen are both oriented antiperiplanar to the C-OH bond (I). In this tetrahedral intermediate, the oxygens of the OH and the OR' group each possess an orbital oriented antiperiplanar to the C-N bond so the cleavage of the C-N bond is possible by an orbital assisted mechanism yielding an ester and a secondary ami~~e.~ The nitrogen atom does not possess an orbital oriented antiperiplanar to the C-OR' bond, the cleavage of the C-OR' bond will therefore be a much higher energy process and should not be observed. Thus anti imidate 4The breakdown of the tetrahedral intermediate is certainly subject to complex general acid-base catalysis (3) which implies that the nitrogen will not be ejected as an amide ion but as a secondary amine. salt la should give specifically the conformer 2a which will immediately decompose in one specific direction giving the ester-amine products 4. Reaction of hydroxide ion on the syn form lb of the imidate (Scheme 3) should give specifically the conformer 26. In conformer 26, the nitrogen does not possess an orbital oriented antiperiplanar to the C-OR' bond and similarly the OR' oxygen does not possess an orbital anti- periplanar to the C-N bond. Therefore, we propose that intermediate 26 will not decompose before it undergoes rotational changes to give new intermediates such as 2a or c for example. In conformer 2c, the nitrogen atom and the oxygen of the OH group have each an orbital oriented antiperiplanar to the C-OR' bond, thus 2c, once fotmed should give immediately the amide-alcohol products 3. Consequently,

3 basic hydrolysis of syn imidate salt lb can in principle give both types of products 3 and/or 4 depending on the new conformers that will be formed by bond rotation of conformer 2b. Hydrolysis5 of S6 (CD3CN-D20, NaOH, 2 equiv) at room temperature for 2 min gave 2.95% of ester-amine 6 and -5% of amidealcohol 7. After 30 min, the reaction mixture consisted of 77 only, indicating that 6 is first formed and then converted into 7 under those conditions. Treatment5 of the ammonium salt g8 under identical basic conditions gave also the ester-amine 6 (-95% after 2 min) which was completely converted into the amide-alcohol 77 after 30 min. Hydrolysiss of 5 utilizing excess sodium carbonate (CD3CN-D20) gave exclu This reaction was followed by p.m.r. spectroscopy. 6Prepared by alkylation of the corresponding 5,6- dihydro-l,3-4h-oxazine (4) with (CH,),O+ BF4- (5). 'This product was isolated as its acetate derivative (AczO/pyridine) which was identified by comparison with an authentic sample. sprepared by reaction of the corresponding imidate salts with HzO (6). sively the ester-amine 6' which was not converted into 7 under these conditions. Similarly, hydrolysiss of 9'' with sodium carbonate gave exclusively the ester-amine 10.' Hydrolysis of 9 with sodium hydroxide (-2 min) gave exclusively the amide-alcohol 11.7 However, treatment of the ammonium salts 125,8 under similar conditions with sodium hydroxide also gave only the amide-alcohol 11.~ This result shows that the transformation of the ester-amine 10 into the amide-alcohol 11 is a very fast reaction in presence of sodium hydroxide. Hydrolysis5 of 13'' with sodium carbonate gave after -10 min the ester-amine 14' which is then transformed completely into the amide-alcohol 1S7 after standing for 1.5 h at room temperature. It has been reported (8) that the salts 16, 17, gthis product was isolated as its acetamide derivative (Ac,O/pyridine) which was identified by con~parison with an authentic sample. loprepared by alkylation of the corresponding 2-oxazoline (7) with (CH,),O+ BF4-. llprepared by alkylation of the corresponding 2-oxazoline with iodomethane.

4 1668 CAN. J. CHEM. VOL R = C6H5; R' = H CH3 14 R = CH3; R' = H 19 R = CH3; R' = CH3 11 R = C6H5 20 R = (CH3)3C; R' = CH3 15 R = CH; 21 R = C6H5; R' = CH3 18 gave the corresponding ester-amine 19, 20, and 21 on basic hydrolysis. Reaction of 22 with water has also been reported recently (9) and the ester-amine 23 was the only product isolated. In those cases (16, 17, 18, and 22) two factors direct the specific cleavage of the carbon-nitrogen bond as shown in the intermediate 24: the orbital orientation factor and a I,3-diaxial type interaction between the OH group and the pseudo axial methyl group. The importance of this steric compression factor was verified in the following way. Ozonolysis (10, 1 I) of the acetal 25 gave exclusively the primary ester 26." During this reaction the intermediate 27 is formed and the orientation of the orbitals favors the opening in both directions equally but the interaction between the OH group and the pseudo axial methyl group in 27 is strong enough to allow a specific cleavage in one direction. The lzunpublished result, R. Chcnevert, this laboratory. I preceding study was carried out with rigid anti imidate salts and the experimental results clearly demonstrate that in such case, the ester-amine products are the only products observed under kinetically controlled condition. We have also studied the basic hydrolysis of the imidate salts 2813 (R = H, CH3, C6Hll (cyclohexyl), (CH3),C and C6H,). Such salts can exist in principle in the anti (28a) or the syn (286) form. The extent of the electronic interactions in either of these two forms is as yet unknown. There is however a steric repulsion between the R group and the ethyl group in the syiz form 286. There is also a steric interaction between the ethyl and the methyl groups in the anti form 28a. Therefore, when R is a small - CH I3These salts were prepared from the corresponding amide and (CzH5)30+BF4- (12).

5 TABLE 1. Basic hydrolysis of irnidate salts 28 R % ester* % arnide* H CH C,H,, 50'1 507 (CH,),C CsHs > 98 - 'Y~elds were est~mated by p.m.r. spectroscopy analys~s. tylelds were estimated by v.p.c. analysis. group, one can postulate that the syn form 28b might be favored and when R is a large group (t-butyl and planar C,H,), the anti form 28a would predominate. If this assumption is correct, the stereoelectronic theory predicts that basic hydrolysis of 28 should give a mixture of products 3 and 4 when R is a small group and it should give mainly the ester amine products 4 when R is a large group. Table 1 described results which are in accord with the preceding discussion. Basic hydrolysis of the cyclic imidate salts 2913 and 3213 was also studied. Treatment of a solution of 29 in dichloromethane with a large excess of aqueous sodium carbonate at 0 "C for - 15 s (rapid mixing) gave a mixture of esteramine 30' (65%) and lactam 31 (35%). A similar experiment with 32 gave also a mixture of esteramine 33' (83%) and lactam 34 (17%). Work is now in progress to complete this study with various types of N-dialkylated imidate salts. I. P. DESLONGCHAMPS, P. ATLANI, D. FREHEL, and A. MALAVAL. Can. J. chern. 50, 3405 (1972). 2. R. ROGER and D. G. NEILSON. Chern. Rev (1960). 3. W. P. JENCKS. Chern. Rev. 72, 705 (1972). 4. W. SEELIGER, E. AUFDERHAAR, W. DIEPERS, R. FEINAUER, R. NEHRING, W. THIER, and H. HELLMAN. Angew. Chern. Int. Ed. 5, 875 (1966) and refs. therein. 5. H. MEERWEIN. Org. Synth. 46, 120 (1966). 6. S. WINSTEIN and R. BOSCHAN. J. Am. Chern. Soc. 72, 4669 (1950). 7. J. A. FRUMP. Chern. Rev. 71, 483 (1971). 8. P. ALLEN and J. GINOS. J. Org. Chern.28,2759(1963). 9. A. I. MEYERS and N. NAZARENKO. J. Am. Chern. Soc. 94, 3243 (1972). 10. P. DESLONGCHAMPS and C. MOREAU. Can. J. Chern. 49, 2465 (1971). 11. P. DESLONGCHAMPS, C. MOREAU, D. FREHEL, and P. ATLANI. Can. J. Chern. 20, 3402 (1972). 12. H. MEERWEIN, W. FLORIAN, N. SCHON, and G. STOPP. Ann. Chern. 641, 1 (1961).

THE IMPORTANCE OF CONFORMATION OF THE TETRAHEDRAL INTERMEDIATE IN THE HYDROLYSIS OF ESTERS AND AMIDES

THE IMPORTANCE OF CONFORMATION OF THE TETRAHEDRAL INTERMEDIATE IN THE HYDROLYSIS OF ESTERS AND AMIDES PIERRE DESLONGCHAMPS Département de Chimie, Université de Sherbrooke, Sherbrooke, Québec, Canada JJK