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This chapter is a review of those reactions of compounds containing labile amino groups in which a carbon-carbon bond is formed by amine replacement as, for example, in the alkylation of diethyl malonate by 1-dimethylamino-3-butanone. Attention has been given primarily to reactions of amines prepared by the Mannich reaction (Mannich bases), but for comparison, analogous reactions of simpler quaternary ammonium salts have been included. Keywords: carbon-carbon alkylations; amines; ammonium salts; cyanide; replacements; active methyl groups; active methylene groups; indole; quaternary salts; organometallic compounds; related reactions; experimental conditions

The first question the reader might ask Why only organic chemistry? and why only the second half of the 20th century? One answer is to say that 1 am an organic chemist and that, since my independent career started in 1948, 1 arn a professional witness only to what happened in the second half of this century. But there are more cogent answers to the two questions. Were 1 to try to cover al1 of chemistry of the entire century with its many advances, for example in chemical instrumentation, this article would become entirely unwieldy.

The previously described chiral 2-acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ-butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH2OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ-lactones. A modification of this synthesis (Scheme I) leads to optically active α-methylene-γ-lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β-hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α- or β-hydroxy-γ-lactones.

Conformational equilibria in 1-, 3-, and 4-methyl-1,2,3,4-tetrahydroisoquinolines (THIQs) and the diastereomeric pairs of their 1,3- and 1,4-dimethyl homologs have been determined by measurement of H3/H4(trans) coupling constants and have been confirmed by molecular mechanics [MMP2(85)] calculations. The experimental −ΔG° values (a → e) for the monomethyl compounds (computed values in parentheses) in kcal mol-1 are Me-1, 0.56 (0.46); Me-3, 1.63 (1.53); and Me-4, −0.32 (−0.22). Agreement of experimental and calculated values is very good as is the additivity of values for the dimethyl compounds (Table 1). Values for the corresponding hydrochlorides are Me-1, 0.19 (−0.34); Me-3, l.15 (1.46); and Me-4, 0.35 (0.10) kcal mol-1. The less than satisfactory agreement of experimental with computed data here is probably due to neglect of solvation. The very small or negative ΔG° values for Me-1 and Me-4 were ascribed not only to the pseudoaxial (rather than axial) nature of Me(ax) and the absence of a syn-axial hyd...

The configurational descriptors at C(1) and C(4) of (−)-quinic acid are given incorrectly in at least four reference compendia. The stereogenic centers C(1) and C(4) as a pair are reflection invariant and are thus not chiral centers. The correct name, according to the 1982 amendment to the CIP system, is (1 s n ,3 R ,4 s n ,5 R )-tetrahydroxycyclohexanecarboxylic acid.

Results of IR and 1 H, 13 C, and 31 P NMR studies of the anancomeric title compounds (2‐5) and compound 1 (Scheme 1) are analyzed to search for the existence of high-energy boat or twist-boat conformations in the equatorial epimers. While the difference in frequencies (Dm)P4O between the axial and equatorial compounds and 13 C NMR JPOCC and anti JPOCCH3 values suggest the participation of twist-boat conformations for the equatorial isomers, coupling constants in 1 H NMR JH4H5a or JH6H5a and JH4H5e or JH6H5e of the equatorial isomers 2e‐4e along with the lack of a large 3 JPH in 31 P NMR are consistent with predominant chair conformations. In addition, an X-ray structure of the equatorial 2-p-nitrophenoxy-2-oxo-cis-4,6-dimethyl-1,3,2dioxaphosphorinane (4e) showed that the molecule adopts a chair conformation with no severe ring flattening in the OPO region in the solid state. X-ray structures of trans-4 and trans-5 displayed chair conformations with mild ring flattening especially in the axial methyl region, presumably as a result of the steric

The position of conformational equilibria in 2- and 3-methyl-1,4-thiazanes and cis- and trans-2,3-dimethyl-1,4-thiazanes, their N-methyl derivatives, and several of the correSponding sulfoxides and sulfones have been measured. The ΔG o values for the methyl groups are generally in agreement with what one would expect on the basis of known conformational equilibria in methylthianes, methylpiperidines, and N-methylated homologs of the latter; however, the differences in ΔG o between the 2-methyl and N,2-dimethyl homologs are even larger than in the piperidine series

The synthesis of (R)-2,3-dihydro-2,5-dimethyl-2-isopropylfuran (1), an insect pheromone, via a 1,3-oxathiane is reported. Key steps are the preparation of (S)-2,3-dimethylbutane-1,2-diol (7) from isobutyryloxathiane 5 and reaction of lithiated acetone dimethylhydrazone with tosylated diol 8. NMR spectra of the key tautomeric precursors, 2/2'/3, to 1 have been analyzed in detail, and the enantiomeric excess of these precursors was determined by a chiral shift 13 C NMR experiment

The alkaline hydrolysis of the title compounds 1-5 (Chart II) with 17 OH − has been studied. The labeled cyclic phosphate salts produced by hydrolysis of 1-5 were converted to a mixture of the corresponding methyl esters by treatment with diazomethane. The resulting mixture was analyzed by 31 P NMR or GC for the epimeric OCH 3 ratio and by 17 O NMR for the 17 O axial to equatorial ratio in the P= 17 O moiety. Nucleophilic displacement of ArO − by 17 OH − at phosphorus is nonstereospecific. The results can be rationalized by postulating that the direct displacement process involving inversion completes with pseudorotation of pentocoordinate intermediates involving retention

Chelates have been considered intermediates in the often highly stereoselective reactions of α-alkoxy and similarly substituted ketones for over 30 years, 10 but without mechanistic evidence

The addition of methyl- and phenylmagnesium bromide and phenyllithium to 2-(methoxyacetyl)-, 2-[(tri-isopropylsiloxy)acetyl]-, and 2-[(methylthio)acetyl]hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin and the corresponding 2'-methyl, 2'-(triisopropylsiloxy)propionyl, and 2'-(methylthio)butyryl homologs has been studied

In contrast to simple esters, α-alkoxy, α-alkylthio, and α-dimethylamino esters react with lithiooxathiane 1-Li in good yield to give the corresponding α-functionalized 2-acetylhexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin 2. In some cases, mixtures of diastereomers (2,2') are obtained. The reaction has been extended to α-methoxy- and α-[(triisopropylsilyl)oxy]propanoyl and α-(methylthio)butanoyl homologs which have chiral centers at C(α)

The addition of methyl- and phenylmagnesium bromide and phenyllithium to 2-(methoxyacetyl)-, 2-[(tri-isopropylsiloxy)acetyl]-, and 2-[(methylthio)acetyl]hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin and the corresponding 2'-methyl, 2'-(triisopropylsiloxy)propionyl, and 2'-(methylthio)butyryl homologs has been studied

The syntheses of the title 1,4-thiazanes (thiamorpholines) by reduction of the 5-oxa-1,4-thiazanes resulting from the lactamization of the appropriate acyclic phenyl derivatives of 5-amino-3-thiapentanoic acid are reported. The oxidation reactions at sulfur yielded the corresponding sulfoxides and sulfones. The stereochemistry of all these compounds was unequivocally established from their 1 H-NMR spectroscopic parameters

Crystal-structure studies of cis-4-tert-butyl-1-(tert-butylsulfonyl)cyclohexane (cis-9), cis-4-tert-sulfonyl)cyclohexane (cis-10), trans-4-tert-butyl-1-(tert-butylsulfonyl)cyclohexane (trans-9), and trans-2-butylsulfonyl)-1,3-dioxane (trans-4) were performed in order to determine the preferred rotational conformation of these compounds in the solid state. These structures were compared with the most stable conformations predicted by MMP2 calculations

Chelates have been considered intermediates in the often highly stereoselective reactions of α-alkoxy and similarly substituted ketones for over 30 years, 10 but without mechanistic evidence

The alkaline hydrolysis of the title compounds 1-5 (Chart II) with 17 OH − has been studied. The labeled cyclic phosphate salts produced by hydrolysis of 1-5 were converted to a mixture of the corresponding methyl esters by treatment with diazomethane. The resulting mixture was analyzed by 31 P NMR or GC for the epimeric OCH 3 ratio and by 17 O NMR for the 17 O axial to equatorial ratio in the P= 17 O moiety. Nucleophilic displacement of ArO − by 17 OH − at phosphorus is nonstereospecific. The results can be rationalized by postulating that the direct displacement process involving inversion completes with pseudorotation of pentocoordinate intermediates involving retention

A synthesis of 3-alkylsulphenyl-, 3-alkylsulphinyl- and 3-alkylsulphonyl-1-methylpiperidinium hydrochlorides has been carried out starting from 3-hydroxypyridine and alkanethiols. These piperidyl derivatives described herein are monoconformational compounds in solution and their magnetic parameters can be used as reference standards for the conformational analysis of related cyclic and acyclic compounds with sulphur and nitrogen heteroatoms in a 1,3-relationship.

The asymmetric synthesis based on a chiral 1,3-oxathiane developed some years ago (ref. 1.4) has been applied (ref. 6 ) to an efficient synthesis of the sex attractant pheromone of the bark beetle hyelocoerus dermestoides L., (R)-2,3-dihydro-2,5-dimethyl-2-isopropylfuran (Scheme 1). This work raised the question as to whether the intermediacy of chelates in Cram's "chelate rule" (ref. 15) is real. This question was answered (ref. 23) in the affirmative by kinetic and stereochemical studies of the reaction C2H5COCH(R)CH3 + (CH3)2Mg. The rate of this bimolecular reaction was measured by rapid injection nmr (ref. 24) and it was found for a variety of R's [OS~(~FY)~,OS~(C~H~)~~-BU, OSiMe2t-Bu, OSiEtj, OSiMej, OCH3J that stereoselectivity parallels rate qualitatively and quantitatively, with the non-chelating (ref. 17) OSi(iFr)g derivative reacting slowest (and at the same rate as propiophenone, R = H) and the chelating OCH3 compound reacting ca. 2000 times faster. The results are interpreted in terms of a competition between a non-chelating and a highly organized chelating transition state, with the R=OCH3 compound which chelates extensively reacting fastest and with over 99% stereoselectivity giving the Cram product. Some years ago we developed a method of enantioselective synthesis of tertiary (ref. 1) and secondary (ref. 2) hydroxyaldehydes, RRC(0H)CHO (R = alkyl or H) which have served as synthons for a variety of chiral, nearly enantiomerically pure target molecules. The chiral auxiliary in this method is the oxathiane 1 derived from naturally occurring enantiomencally pure (+)-pulegone (Scheme 1) (ref. 3). Two earlier reviews (ref. 4) as well as a number of more recent publications (ref. 5) have dealt with this synthesis. Scheme 1 SCH2CeHS Na, CH,W N-l3 6 I YE?& I 80-82% (+) P u leg on e (major isomer) I I I I I (Crystallizes; overall yield of crystalline product: 25%) (major isomer)

Previously studied highly stereoselective additions of Grignard, organolithium, and hydride reagents to the 2-benzoyl derivative of compound 1a have been extended to other 2-alkanoyl derivatives (1,R'=methyl, ethyl, isopropyl) and to the 2-benzoyl derivative with R=methyl. High diastereoselectivity is attained in most of the products

Misuse of current stereochemical terms is discussed, including terms that should be avoided altogether and replaced by other, standard ones. The reasons for using the proper terms and avoiding the infelicitous ones are pointed out. Chirality 9:428–430, 1997. © 1997 Wiley-Liss, Inc.

α-Chlorophenylacetic acid intermediate: ethyl mandelate intermediate: ethyl α-chlorophenylacetate product: α-Chlorophenylacetic acid Keywords: esterification, of substituted monobasic acids; replacement reactions, hydroxy by halogen; replacement reactions, hydroxy by halogen; hydrogen chloride, anhydrous, preparation and drying