Benzylic Lithiation Research Articles

Mechanisms of Competitive Ring-Directed and Side-Chain-Directed Metalations in Ortho-Substituted Toluenes

Heteroatom-directed metalation reactions of aromatic compounds are complicated by the presence of an ortho CH3 group or side chain as a second possible metalation site. We have employed ab initio calculations (Becke3LYP 6-311++G**//HF 6-31G* + ΔZPE (6-31G*) to study the preferred site of lithiation of three ortho-substituted toluenes (o-CH3C6H4OH (13), o-CH3C6H4NH2 (21), and o-CH3C6H4F (28)) with LiH as a model metalation reagent. The results are compared with the ring and side chain lithiations of toluene (7). The acidity of the hydrogen which undergoes exchange does not explain the regiochemistry. The preferred site for lithiation is governed by the stabilization of the transition state, rather than by the initial complexation: electrostatic dipole effects and enhanced intramolecular interaction of the metalating reagent with the substituent groups in the transition states are responsible. The complexation energies of lithium hydride with toluene, o-hydroxytoluene, o-aminotoluene, and o-fluorotoluene are −11.8 kcal/mol (8; C6H5CH3−LiH π-complex), −14.6 kcal/mol (14, o-CH3C6H4OH-LiH, coordinated to O), −15.6 kcal/mol (15, o-CH3C6H4OH−LiH, coordinated to O with agostic interaction to −CH3), and −11.9 kcal/mol (16; o-CH3C6H4OH−LiH π-complex). We could only locate one type of σ complex, both for o-fluorotoluene and o-aminotoluene (o-toluidine). The binding energies are −15.9 kcal/mol (22; o-CH3C6H4NH2−LiH) and −10.8 kcal/mol (29; o-CH3C6H4F−LiH), respectively. The related π complexes are less stable than the σ structures with energies of −14.1 kcal/mol (23; o-CH3C6H4NH2−LiH) and −9.2 kcal/mol (30; o-CH3C6H4F−LiH). The activation barriers for toluene, relative to the separated species, are as follows: for ortho metalation (9), 15.5 kcal/mol; for methyl lithiation (10), 4.4 kcal/mol. When substituents are present, the activation barriers are reduced significantly: for X = OH, 4.4 kcal/mol (17; TSortho) and 1.3 kcal/mol (18; TSCH3); for X = NH2, 6.6 kcal/mol (24; TSortho), and −1.3 kcal/mol (25; TSCH3); for X = F, 6.6 kcal/mol (31; TSortho) and 3.4 kcal/mol (32; TSCH3). Benzylic lithiation of toluene is calculated to be −2.0 kcal/mol exothermic (12); however, ortho metalation is 6.8 kcal/mol endothermic (11). Both ortho and side chain lithiations in substituted toluenes are exothermic: X = OH, ortho −5.9 kcal/mol (19), −6.7 kcal/mol (20; CH3); X = NH2, −3.8 kcal/mol (26; ortho), −8.9 kcal/mol (27; CH3); X = F, −7.5 kcal/mol (33; ortho), −4.1 kcal/mol (34; CH3). Since benzyl derivatives with different alkali metals have different structural preferences, substituent interactions vary. The effects of ortho substituents X (X = NH2, OH, F) in benzyl and in phenyl alkali-metal compounds (M = Li, Na, K) were computed with the 6-31G* basis set for Li, Na, H, C, N, O, and F and the pseudopotential method (9 VE ECP) for K. Becke3LYP 6-311++G**//6-31G* +ΔZPE (6-31G*) calculations emphasize the importance of electrostatic interactions in phenyl alkali-metal compounds (the stabilization energies follow the electronegativity: N < O < F). The reverse order is calculated for the benzyl series, where the intramolecular interactions between the metal and X are most important.

A comparison of secondary and tertiary amides as directors of ortho and adjacent benzylic lithiation and of asymmetric induction in ortho lithiated benzamides

Comparisons are made between the influence of secondary and tertiary amides on ortho and adjacent benzylic metallations of benzamides. In the intramolecular competition offered by N,N-diethyl-N-ethylterephthalamide ( 1) the tertiary amide is the more effective director of ortho lithiation, while the secondary amide is better in the intermolecular competitions offered by the pairs N-ethyl-(9): N,N-diethylbenzamide( 10) and N-isopropyl-( 11):N,N-diisopropylbenzamide( 12). Both secondary and tertiary amides are found to direct metallation ortho to the amide in the 2-isopropylbenzamides 25 and 26; however, benzylic metallation is observed with secondary 2-ethyl- and 2-methylbenzamides 21 and 22 and with the tertiary 2-ethylbenzamide 19. Magnetic non-equivalence is noted for the anti-N-methylene group of 19. The reaction of an ortho lithio (S)-O-methyl-N-benzoylleucinol ( 34) with 1-naphthaldehyde-1-d gives, after lactonization, 3-(1-naphthyl-1-d)-phthalide with 10% enantiomeric excess. The phthalide can be obtained in high enantiomeric purity by separation of the diastereoisomers prior to cyclization. Control experiments establish that the observed asymmetric induction is attributable to diastereomeric transition states. The corresponding tertiary benzamide is ineffective in inducing asymmetry. Structural and mechanistic rationales are offered for these observations.