Search

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 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.

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.

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

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 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

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)

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

Chiral 1,3-oxathiane from (+)-pulegone: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin intermediate: cis- and trans-5-Methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone reactant: 202.0 g (1.33 mol) of (+)-pulegone intermediate: 2-(1-Mercapto-1-methylethyl)-5-methylcyclohexanol product: Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin. Keywords: addition, to CC; annulation, heterocyclic-[6]; cyclization, condensation; reduction, CO CHOH; reduction, miscellaneous; reduction, miscellaneous; mercaptans, stench; apparatus, for condensing liquid ammonia

trans-4-t-Butylcyclohexanol product: trans-4-t-Butylcyclohexanol solvent: 150 ml. of hot petroleum ether Keywords: reduction, CO CHOH; lithium aluminum hydride, disposal

Diethyl tert-butylmalonate reactant: 400 g. (2.50 moles) of diethyl malonate intermediate: diethyl isopropylidenemalonate product: diethyl tert-butylmalonate Keywords: addition, to CC; condensation, ester-active methylene condensation; esterification, of dicarboxylic acids; Grignard and related reactions; lithium dimethylcuprate (solution); lithium dimethylcuprate (solution), preparation of; methyl iodide

La lithiation du perhydro-4,4,7-trimethyl-«1,3»-benzooxatkine [A] suivie d'une reaction avec un nitrile puis d'une hydrolyse conduit a des 2-acyl [A]

This paper embodies the belated publication of a thesis submitted by JJE to the Free University of Amsterdam in 1955; heretofore the data (heat of sublimation of cyclotetradecane, 21.34+/-0.10 kcal/mol or 89.33+/-0.42 kJ/mol; heat of sublimation of trans-stilbene, 20.68+/-0.08 kcal/mol or 86.57+/-0.33 kJ/mol) were available only in a printed version of the thesis. In conjunction with a subsequent determination of the heat of combustion of solid cyclotetradecane, this led to the conclusion that the compound was strain-free. That these data were not published at the time had unfortunate consequences: The strain energy of cyclotetradecane was susequently computed to be 12.6 kcal/mol (52.7 kJ/mol) on the basis of an erroneous value of the heat of sublimation determined independently in 1964. This was corrected only in 1992 through a third determination which gave a value for the strain energy close to that found in 1955, i.e. near zero.The heat of formation of trans-stilbene is of interest in connection with ...

Metallation of the acetal (H-2) proton in 1,3-dioxolanes, 1,3-dioxanes and open chain acetals is possible only if the proton can occupy an “equatorial-like” conformation.

Reduction of the previously prepared1 chiral 2-acyl-l,3-oxathianes derived from (+)-pulegone with various metal hydride combinations proceeds stereoselectively, with diastereomer excess (d.e.) of as much as 97% in the case of reduction of phenyl ketones with lithium tri-sec.butylborohydride. Lesser selectivity (maximum 82% d.e.) is achieved with primary or tertiary alkyl ketones: the predominant diastereomer is readily purified by chromatography. The major product in these cases is that predicted by Cram's chelate rule. The product ratio is reversed with diiasobutylaluminum hydride and also in the reduction of secondary alkyl ketones with lithium sec. butylborohydride, where stereoselectivity is low. The 2-hydroxyalkyl-l,3-oxathianes are cleaved to α-hydroxyaldehydes with N-chlorosuccinimide-silver nitrate and the aldehydes reduced to glycols, RCHOHCH2OH with sodium borohydride with little or no racemization. Esters, RCHOHCO2CH3, are obtained in high enantiomeric purity by O-benzylating the 2-hydroxyalkyl-l,3-oxathianes prior to cleavage, oxidizing with sodium chlorite following cleavage, esterifying and debenzylating. A method for measuring the enantiomeric purity of glycols RCHOHCH2OH by conversion to 2-phenyl-l,3-dioxolanes with benzaldehyde, followed by proton NMR analysis of the resulting 2-phenyl-4-alkyl-l,3-dioxolane diastereomer pair in the presence of a chiral europium shift reagent is described.

17O NMR spectra of fifteen cyclohexane-derived tertiary alcohols and related ethers and acetals, six 1,3-dioxane-derived orthoesters, four cyclohexane- and 1,3-dioxane-derived sulfones and the four corresponding sulfoxides, three acyclic sulfones, six alcohols derived from norbornane and 1,3-dithiane and two esters have been recorded. Attention is drawn to δ-compression effects and saturation effects in several of these compounds.

Uncatalyzed reaction between cyclopentadiene and (E)-3,4,5,6,7-pentaacetoxy-1-nitrohept-1-enes having the d -manno, d -galacto, and d -gluco configurations at C-3—C-7 led, in each case, to the four stereoisomeric 5-nitro-6-(1,2,3,4,5-penta-O-acetylpentitol-1-yl)bicyclo[2.2.1]hept-2-enes. Face selectivity is discussed in terms of the sugar-chain configuration. The structures assigned the adducts are based on their n.m.r. spectra, and, in the case of the d -manno compounds, on X-ray data. Also described are the 13C-n.m.r. spectra of the starting nitroalkenes. The crystal structures of (5S,6S)1,2,3,4,5-penta-O-acetyl-1-C-(5-exo-nitrobicyclo[2.2.1]hept-2-en-6-endo-yl- d -manno-pentitol (3a) and (5S,6S)1,2,3,4,5-penta-O-acetyl-1-C-(5-endo-nitrobicyclo[2.2.1]hept-2-en-6-exo-yl- d -manno-pentitol (5a) were determined from three-dimensional, X-ray data. Crystals of 3a are monoclinic, space group P21, with two molecules in a cell of dimensions a = 9.054(3), b = 15.580(11), c = 10.138(4) A, β = 116.27(3)°. The structure was refined to an R-factor of 0.050 on the basis of 1485 observations. Crystals of 5a are triclinic, space group P1, with one molecule in a cell of dimensions a = 8.680(4), b = 9.760(4), c = 8.695(7) A, α = 98.69(5), β = 103.13(5), γ = 112.09(3)°. The structure was refined to an R-factor of 0.074 based on 970 observations.

A chiral, conformationally locked 1,3-oxathiane has been prepared by 1,4-addition of benzyl, mercaptan to (+)-pulegone followed by Na/NH3 reduction and condensation of the resulting hydroxythiol with paraformaldehyde. The utility of this chiral adjuvant is exemplified by the asymmetric synthesis of the title compound in 93% e.e.

The 13C NMR spectra of 17 methyl- and ethyl-substituted tetrahydrofurans and 58 alkyl- and aryl- substituted 1,3-dioxolanes are reported. For the cases in which substituents recur, additive substituent parameters are calculated and compared with similar parameters in cyclopentanes and in 6-membered rings. Considering the conformational flexibility of 5-membered ring systems, additivity of the parameters is surprisingly good.

Addition of Grignard and organolithium reagents to as well as hydride reduction of 2α-benzoyl-N-benzyl-4,4,7α-trimethyl- trans -octahydro-1 ,3-benzoxazine (2, Y = C6H5CO) and addition of phenylmagnesium bromide to the corresponding 2-acetyl analog (11) proceed in highly diastereoselective fashion to produce virtually exclusively the diastereomer predicted on the basis of Cram's chelate rule if chelation involves the ring oxygen atom. Mild acid hydrolysis of the adducts followed by selective oxidation produces highly enantiomerically pure ρa-hydroxyacids with clean recovery of the chiral adjuvant.

Etude par diffraction RX des structures cristallines des dimethyl-3,4 phenyl-4 cyclohexanone; phenyl-1 methyl-1 nitrobenzoyloxy-2 cyclohexane et methyl-4 phenyl-1 cyclohexanol

The barriers to phenyl rotation in 2-lithio-2-phenyl-cis-4,6-dimethyl-, 2-lithio-2-phenyl-4,4,6-trimethyl- and 2-lithio-2-phenyl-trans-4,6-dimethyl-1,3-dithiane are compared in tetrahydrofuran (THF) and hexamethylphosphortriamide (HMPA). In the first two cases, the barriers in THF are lower than those in HMPA, presumably because the lithio compound exists as a tight ion pair in THF but as a solvent-separated ion pair (with more delocalization of charge into the phenyl ring) in HMPA. However, in the trans-4,6-dimethyl compound the barriers are the same in the two solvents and nearly equal to the barriers for ring reversal. It is concluded that in this compound the rate-determining step for phenyl rotation may actually be ring reversal, at least in solvent HMPA.

The configurations of the title compounds are reassigned, based on stereoselective syntheses of the hydroxyacid and corresponding glycol and application of Cram's, Prelog's and Sharpless' rules.

(+)- and (−)-Frontalin have been obtained from a chiral 1,3-oxathiane precursor in a short (3-step) synthesis in moderate (70%) enantiomeric excess (e.e.). A longer (6-step) modification gives the ...

17O chemical shifts of axial hydroxyl groups in cyclohexanols are upfield of those of corresponding equatorial groups, but in 5-hydroxy-1,3-dioxanes the opposite is observed: the axial OH resonates downfield of the equatorial OH. The situation is the same in the corresponding methyl ethers and is, thus, not a result of intramolecular hydrogen bonding in the axial 5-hydroxy-1,3-dioxane, but appears to parallel the effect on 13C and 19F shifts observed in corresponding equatorial and axial 5-methyl- and 5-fluoro-1,3-dioxanes, which has been attributed to an upfield shifting effect of the antiperiplanar γ-located heteroatoms. Surprisingly, the reciprocal effect is not seen in the ring 17O shifts of the 5-hydroxy-1,3-dioxanes. A δ compression shift is seen in the 17O spectrum of trans-3,3,5-trimethylcyclohexanol (syn-axial OH and CH3), analogous to the effect earlier reported in 13C spectra. Conversion of four of the alcohols to methyl ethers produces a large upfield effect on the 17O shift, larger in the cyclohexanols than in the 1,3-dioxane-5-ols. Similar upfield shifts have been recorded in the literature; their extent depends on whether the alcohols are primary, secondary or tertiary.

8β- t -Butyl- trans -decahydroquinoline picrate crystallizes a double chair with an axial t -butyl group. Except for a 16.2° torsion of the t -butyl group way from the staggered conformation, the molecule displays only minor conformation deformations.

The enantiomeric purity of primary-secondary glycols, RCHOHCH 2 OH, is conveniently determined by conversion to a pair of epimeric 1,3-dioxolanes through condensation with benzaldehyde, followed by NMR spectroscopy in presence of a chiral shift reagent with observation of the benzylic protons.

Etude de la diastereoselectivite des reactions d'acyl ou aroyl-2 trimethyl-4,4,6- ou -4,6,6 oxathiannes-1,3 avec des organometalliques (RMgX, R 2 Mg ou RLi) en fonction des variables suivantes: substitution (4,6,6 ou 4,4,6), nature du groupe acyl-2, nature de l'organometallique et de l'halogene dans le cas de RMgX, solvant, temperature; conditions optimales d'obtention d'un diastereoisomere

Treatment of the lithium derivative of cis-4,6-dimethyl-1,3dithiane (1) with DCl gives nearly exclusively (over 99%) the equatorial 2-deuterio compound (1a), treatment with methyl iodide gives exclusively the equatorial methyl compound (r-2,cis-6,cis-4trimethyl-1,3-dithiane, 2), and treatment with carbonyl compounds (formaldehyde, acetone, and pivalic aldehyde) gives the equatorial carbinols (4) in at least 99.8% isomeric purity. Treatment of the lithium derivative of the equatorial 2-methyl compound 2 with HCl yields exclusively the corresponding axial isomer 3 (r-2, trans-4,trans-G-trimethyl-1,3-dithiane); a similar contrathermodynamic'' equilibration occurs with the equatorial carbinols mentioned, above, with r-2-tert-butyl-cis-4,cis-6-dimethyl-1,3dithiane and with cis-2,4,4,6-tetramethyl-1,3-dithiane, suggesting a very large preference of the intermediate 2-dithianyl-lithium compound to have the metal in the equatorial position. The high degree of this preference (over 6 kcal/mol) suggests operation of a stereoelectronic rather than a simple steric effect. Carboxylation of the lithium derivative of 2 gives exclusively the equatorial carboxy derivative, r-2,cis-4,cis-6-dimethyl-1,3-dithianecarboxylic acid (6), whereas methylation of the lithium derivative of 2-carbinetgixy-cis-4,6-dimethyl- 1,3-dithiane with methyl iodide leads exclusively to the diastereoisomer 7. Lithiation followed by methylation of othe two diastereoisomeric 2-deuterio-cis- 4,8dimethyl-1,3-dithianes indicates that the kinetic stereoselectivity of the lithiation is only by a factor of 8.6 plus or minus 1.3 with an isotope effect of 2.5 plus ormore » minus 0.1. The preference of the lithium derivative or carbanion to be equatorial is thus largely thermodynamically controlled. (auth)« less

Part 1 of this account deals with the conformational analysis of the diastereomers of RCHXCHXR (R=CH 3 , X=Cl, Br; R=C 6 H 5 X=Br) and of compounds of the type R 2 CHCHR 2 and RR′CHCHRR′ (R and R′ alkyl). These studies are closely related to Mizushima's pioneering work. In part 2, conformational equilibria of geminally substituted phenylcyclohexanes are discussed, including that of phencyclidine [1-phenyl-1(N-piperidino)cyclohexane] as a function of solvent, temperature and protonation and that of the chromium tricarbonyl complexes of phenylcyclohexane and of 1-methyl-1-phenylcyclohexane.

In contrast to other α- and β-alkoxy substituents the triisopropylsilyloxy group does not depress the high diastereomer excess normally realized in nucleophilic addition to 2-acyl-1,3-oxathianes.

The 13C NMR spectra of cyclobutane and seven methylated homologs and of ethyl cyclobutanecarboxylate and five isomeric diethyl cyclobutanedicarboxylates are reported and substituent parameters for methyl groups in methylcyclobutanes are calculated. Of note is a sizeable and nearly configuration-independent upfield shifting γ-effect.

The conformational equilibrium of phencyclidine [1-phenyl-1-(N-piperidyl) cyclohexane or 1-(1-phenylcyclohexyl) piperidine, PCP] is strongly dependent on solvent and in the hydrogen-bonding solvent methanol also on temperature.

The 13C nmr spectra of 4 cis-2,4-diphenyl-3-azabicyclo[3.3.1]nonanes, 11 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ones, 26 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ols or acetates thereof, 5 cis-2,4-diaryl-3-azabi-cyclo[4.3.1]decan-10-ones or -10-ols and 5 cis-2,4-diphenyl-3-aza-7-thiabicyclo[3.3.1]nonan-9-ones, -9-ols or 9-yl acetates have been recorded. Except for the 7-thia compounds, which appear to exist mainly in the configuration and conformation with the nitrogen-containing ring in the boat form, these compounds seem to exist overwhelmingly in chair-chair conformations. The configuration of the 9-ols and their acetates (syn or anti to the nitrogen-containing ring) has been deduced from the spectra. In a number of cases, the structures assigned differ from those earlier postulated. Broadening of one set of aryl signals (probably those due to the ortho carbons) in the case of N-methyl (but not N-H) compounds without ortho substituents is ascribed to restricted phenyl rotation.