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CH‐Acidität in α‐Stellung zum N‐Atom in N,N ‐dialkylamiden mit sterisch geschützter Carbonylgruppe zur nucleophilen minoalkylierung
Author(s) -
Schlecker Rainer,
Seebach Dieter,
Lubosch Winfried
Publication year - 1978
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19780610144
Subject(s) - chemistry , steric effects , deprotonation , alkylation , medicinal chemistry , electrophile , diastereomer , stereochemistry , conformational isomerism , nucleophile , triflic acid , benzoic acid , organic chemistry , molecule , ion , catalysis
CH‐Acidity in α‐position to the N‐Atom of N, N ‐Dialkylamides with Sterically Protected Carbonyl Groups Contribution to the Nucleophilic Amino Alkylation Sterically protected amides 1 such as the 2,4,6‐triisopropyl‐benzoic acid derivatives 3, 8b and 10 undergo readily H/Li‐exchange with s ‐butyllithium at the CH 3 N‐ or CH 2 N‐groups. The resulting organolithium compounds ( cf . 9, 11 ) are alkylated and hydroxyalkylated with primary haloalkanes, aldehydes, and ketones under chain elongation in the amine position of the amides. The ( E / Z )‐rotamers of the dialkylamides 7 and 8 are separated by chromatography; the amides 4 – 6 , 12 , and 13 formally derived from β‐hydroxyamines are obtained in the ( Z )‐form only. The configurational ( E / Z )‐assignments follow from NMR. and IR. data. The erythro and threo configuration of the two diastereomeric amides 12a and 12b are tentatively concluded from Eu(fod) 3 ‐ 1 H‐NMR.‐shift experiments. The results strongly suggest that the H/Li‐exchange takes place regioselectively at the CHN group which is in cis ‐position to the CO double bond (→ 14 ). The methyl 2,4,6‐tri( t ‐butyl)benzoate ( 18 ) can also be deprotonated to the lithium acyloxymethanide 19 which is trapped by alkylation with 1‐iodooctane (→ 20 ). – The steric protection of the carbonyl groups in the products 4 – 8, 10, 12, 13 , and 20 prevents their ready hydrolysis to amines and alcohols, respectively. Therefore, triphenylacetic acid derivatives 21 rather than 2,4,6‐triisopropylbenzoic acid derivatives for use in the electrophilic substitution of equation (1) are recommended. The trityl group in 21 may be considered a C‐leaving‐group ( C C protective group, cf. 22, 23 ). The acetamide 25 reacts readily (→ 26 ) and then with electrophiles to give products 27a – c . As shown in the Table , the amides 27 are cleaved under a variety of conditions with formation of triphenylmethane. LiAlH 4 produces a tertiary amine, CH 3 Li a secondary amine, and dissolving alkali metals/naphthalene under aprotic conditions mixtures of secondary amine and its formamide (hydrolysed by acid treatment). Thus the overall process (2) is feasible.