Insight into the solvation and isomerization of 3-halo-1-azaallylic anions from ab initio metadynamics calculations and NMR experiments.
In organic synthesis, it is observed experimentally that the nature of the solvent can influence tremendously the reactivity and overall product selectivity. In this communication, we report on the E/Z isomerization of a typical solvated species, that is, the stable lithiated 3-chloro-3-methyl-1azaallylic anion readily accessible from the N-isopropylACHTUNGTRENNUNGimine of a-chloropropiophenone, from a theoretical and a subsequent NMR study. To date, the configurational properties of these 3-chloro-3-methyl-1-azaallylic anions are poorly understood. Our main emphasis is devoted to the monomeric species as these are believed to be the most important for further reactivity studies (see below). It will be shown that the investigated species is a particular example in which the inclusion of the solvent in the modeling study is of the utmost importance to determine the proper chemical ACHTUNGTRENNUNGbehavior. The 3-chloro-3-methyl-1-azaallylic anion was chosen as a model compound to obtain a deeper insight into the structural features of 3-halo-1-azaallylic anions and to get a better understanding, and eventually a better control, of the stereochemical outcome of the reactions in which these anions are involved. Since their first use in the early 1960s, non-halogenated 1-azaallylic anions have gained a predominant role in organic synthesis due to their ability to form new C C bonds with a lack of side products. The chemistry of 1-azaallylic anions leads to basic heterocyclic systems such as aziridines, azetidines, pyrrolidines, pyrroles, piperidines, oxiranes, oxolanes, and higher functionalized ring systems, currently of interest for pharmaceutical chemistry and agrochemistry. The application of certain halogenated counterparts, that is, the 3-chloro-3-methyl-1azaallylic anions, in particular by the group of De Kimpe and more general by the group of Florio, which incorporated the 3-chloro-3-methyl-1-azaallylic moiety into heterocyclic structures, has led to the synthesis of various important classes of compounds such as cyclopropanes, tetrahydrofurans, tetrahydropyrans, oxiranes, aziridines, chloroimines, pyrroles and pyridines, steroids, alkenylheterocycles, and oxazetidines. As mentioned, 3-chloro3-methyl-1-azaallylic anions can be used for the synthesis of functionalized oxiranes and aziridines since the former anions behave as nucleophiles in Darzensand aza-Darzenstype reactions with carbonyl compounds and imines. One of the determining factors in the stereochemical outcome of these Darzens-type reactions is the E/Z stereochemistry of the starting 1-azaallylic anion. Therefore, it is important to know and understand the configurational properties of 3chloro-3-methyl-1-azaallylic anions in order to perform aldoland Mannich-type reactions with these intermediates in a stereocontrolled manner. NMR investigation and semiempirical calculations on the stereochemistry of (2-(a-chloroethyl)benzothiazolyl)lithium and (4,4-dimethyl-2-(a-chloroethyl)oxazolinyl)lithium have demonstrated that internal coordination between lithium and chlorine stabilizes the corresponding isomer with nitrogen and chlorine at the same side of the C=C double bond. The lack of such structural investigations on 3chloro-3-methyl-1-azaallylic anions in sensu stricto urged us to study their stereochemical properties. The E/Z isomerism for non-halogenated 1-azaallylic anions has been observed and investigated quite frequently. The facile carbon carbon bond rotation in simple lithiated 1-azaallylic anions was investigated using H NMR spectros[a] Dr. R. Declerck, B. De Sterck, T. Verstraelen, Prof. Dr. M. Waroquier, Prof. Dr. V. Van Speybroeck Center for Molecular Modeling, Ghent University Proeftuinstraat 86, 9000 Gent (Belgium) Fax: (+32) 9-264-6697 E-mail : Veronique.VanSpeybroeck@UGent.be [b] Dr. G. Verniest, Dr. S. Mangelinckx, J. Jacobs, Prof. Dr. N. De Kimpe Department of Organic Chemistry, Faculty of Bioscience Engineering Ghent University, Coupure links 653, 9000 Gent (Belgium) Fax: (+32) 9-264-6243 E-mail : Norbert.DeKimpe@UGent.be Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200800948.
Diastereoselective aldol reaction of zincated 3-chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-tetrasubstituted 3-chloroazetidines.
Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-β-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-β-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.
Understanding the high diastereofacial discrimination in nucleophilic additions to nitrones: the first ab initio study on the nucleophilic addition reactions of chiral nitrones with Grignard reagents
Abstract The nucleophilic addition of methyl magnesium bromide to a C-(2-pyrrolidinyl) nitrone has been studied by ab initio molecular orbital (HF/6-31+G∗) and density functional theory (B3LYP/6-31+G∗//HF/6-31+G∗) calculations via location of the two diastereomeric transition states. The overall reaction is exothermic and proceeds via precomplexation of the nitrone with the organometallic reagent. The calculations confirm that chelation is the main factor governing the experimentally confirmed preference for the Si attack leading to syn adducts.