Thesis (M.Sc.(Chemistry))--University of Pretoria, 2000. / Includes abstract in English. Includes bibliographical references. Also available online.

New Carbanion Rearrangement of Sulfur Compounds and Its Application Abstract This thesis reports the investigation of an unusual reversal in the metalation selectivity of alkyl aryl sulfones and sulfoxides and its application. Such compounds undergo initial directed ortho-metalation at −78 řC despite having an acidic α-hydrogen atom and the resulting aryllithiums rearrange subsequently completely to the initially expected α-sulfonyllithiums on warming. The scope and the limitations for this process were identified. Both carbanion types of sulfones were applied in reactions with various electrophiles. α-Lithiated sulfones generated upon the transmetalation process were used in Julia olefinations. A mechanistic study of the course of the transmetalation reaction is presented. The kinetics of the transmetalation were determined. Investigations concerning the concentration dependence, proton transfer equilibria between the different ortho-sulfonyllithium intermediates and crossover experiments provided the evidence that a concerted intermolecular pathway prevails. On this basis a new integrated synthetic approach to naturally occurring iridoids was developed. It is based on a tandem alkoxycarbonylation/oxidative radical cyclization of the olefins synthesized by the Julia reaction after the investigated...

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The use of sulfoxide ligands for transition metal catalyzed transformations has recently been brought to the forefront in organic chemistry. The synthesis of a series of tri- and disulfoxides will be presented, and their applications investigated. Their use in rhodium catalyzed 1,4-additions of phenylboronic acid to 2-cyclohexen-1-one result in enantioselectivities up to 80%. The incorporation of β-amino acid residues into polypeptides has resulted in new foldamers whose structures and enhanced stability provide interesting opportunities for new biological applications. A novel strategy for an iterative peptide synthesis involving β-amino acids will be proposed. Lastly, a hydroamidation-type strategy for the construction of β3-amino acids, or more specifically of β-(N-acylamino)acrylates, will be presented as preliminary work towards the goal of dipeptide synthesis.

The use of sulfoxide ligands for transition metal catalyzed transformations has recently been brought to the forefront in organic chemistry. The synthesis of a series of tri- and disulfoxides will be presented, and their applications investigated. Their use in rhodium catalyzed 1,4-additions of phenylboronic acid to 2-cyclohexen-1-one result in enantioselectivities up to 80%. The incorporation of β-amino acid residues into polypeptides has resulted in new foldamers whose structures and enhanced stability provide interesting opportunities for new biological applications. A novel strategy for an iterative peptide synthesis involving β-amino acids will be proposed. Lastly, a hydroamidation-type strategy for the construction of β3-amino acids, or more specifically of β-(N-acylamino)acrylates, will be presented as preliminary work towards the goal of dipeptide synthesis.

Thesis (Ph. D.)--Uppsala University, 1983. / Description based on print version record. Bibliography: p. 35-36.

The previously unreported 3-methyltetrahydrothiophene I-oxide (<u>1</u>) and 3-methyl-2, 5-dihydrothiophene I-oxide (<u>2</u>) have been prepared by oxidation of the corresponding sulfides. The structure of these unsymmetric sulfoxides was established by chemical and physical methods. Nuclear magnetic resonance analyses have provided significant information concerning some stereochemical aspects of these molecules. In the case of <u>1</u>. which has four possible configurations, both <u>cis</u> and <u>trans</u> isomers were shown to exist in the synthetic material. A study on the temperature dependence of the nuclear magnetic resonance spectrum of <u>2</u> between -34° and 100°, suggested little or no association of a dimeric nature between molecules of this unsaturated sulfoxide. The rapid and clean reduction of <u>2</u> to the corresponding sulfide was carried out using hydriodic acid and detected by gas chromatographic analysis. The partial base catalyzed isomerization of <u>2</u> to 3-methyl-4, 5- dihydrothiophene 1-oxide (<u>13</u>) was carried out in sodium hydroxide solution and detected by gas chromatographic analysis of the reduced products. Maximum isomerization occurred after 96 hours when <u>2</u> and <u>13</u> were present in a ratio of 1.78:1 respectively. This finding is similar to the previously observed isomerization of the corresponding sulfone, but is in contrast to the lack of isomerization of the olefinic bond of the related 2, 5-dihydrothiophene l-oxide. A plausible mechanism has been proposed for this interesting isomerization of <u>2</u>. Sulfoxide <u>1</u> was reacted with various Grignard reagents and shown to undergo a substitution reaction at the α-carbon atoms. Predominant reaction occurred at position-5 of <u>1</u> and binary sulfide mixtures composed of 2-substituted-4-methyl- and 2-substituted-3-methyltetrahydrothiophenes were obtained in yields ranging from 17-31%. The ratio of isomeric sulfides ranged from 1.50:1, in the case of phenylmagnesium bromide, to 8.09:1 when using neopentylmagnesium chloride. The binary sulfide mixtures were desulfurized and the hydrocarbon products were identified. In this manner, the structure and composition of the components of the sulfide mixtures was established. Preparative-scale gas chromatography was used to separate two binary sulfide mixtures. Desulfurization of the individual sulfides led to the discovery of isomerization reactions which occurred during desulfurization. By-products of the Grignard reaction were identified as 3-methyltetrahydrothiophene, 3-methyl-2, 3- and 3-methyl-4, 5-dihydrothiophene, and, in some cases the alkene and alcohol derived from the Grignard reagent. A reaction pathway, by which these products and by-products may conceivably be formed has been proposed. Results of the reaction of the unsaturated sulfoxide <u>2</u> with Grignard reagents were quite different than with sulfoxide <u>1</u>. Sulfoxide <u>2</u> underwent reaction at the sulfur atom with a subsequent cleavage of the ring yielding single dienyl sulfides. These novel compounds were formed by a stereospecific ring cleavage of <u>2</u>, a reaction similar to that previously observed with the corresponding sulfone. The dienyl sulfides, 1-phenylthio- and 1-n-propylthio-2-methyl-1, 3-butadiene, were isolated in good yield and characterized by their spectral properties and by conversion to known compounds. The only detectable by-product of this reaction was a trace amount of 3-methyltetrahydrothiophene. A mechanism, consistant with the data obtained, has been suggested. / Ph. D.

A finalidade deste trabalho é o estudo de reações de carbânions de sulfóxidos funcionalizados com reagentes sulfenilantes, pelo emprego de dois métodos: fase homogênea e transferência de fases. A revisão bibliográfica apresentada demonstra que trata-se de reações novas e que, entretanto, outras reações de carbânions de sulfóxidos funcionalizados, tais como alquilações, acilações, condensações com compostos carbonílicos e adições de Michael, já tinham sido descritas. Por outro lado, poucas reações de sulfinil carbânions tinham sido efetuadas pelo emprego do método de transferência de fases. As reações de sulfenilação em fase homogênea de &#945;-sulfinil cetonas aromáticas (Ia-d), e cíclicas (II), &#945;-sulfinil ésteres (IIIa,b) e tioéster (IV) foram efetuadas pelo emprego de NaH/DMSO e de dimetildissulfeto ou metanotiossulfonato de metila (MeSO2SMe). Com exceção do composto (IIIb) que não reagiu, em todos os casos foram obtidos compostos monossulfenilados ainda não descritos na literatura. Os rendimentos variavam entre 25-90%, na ordem: Ib > Ia > IVa > Ic > Id > IIIa > II. As reações de sulfenilação em transferência de fases foram efetuadas pelo emprego de dois procedimentos distintos: o de extração do íon-par (A) e o sistema Sólido-líquido (B). Os compostos Ia, IIIa e IVb foram submetidos à sulfenilação pelo procedimento A, em que usou-se NaOH/CH2Cl2/Bu4NHSO4 e MeSO2SMe. Enquanto Ia e IIIa renderam produtos monossulfenilados em baixos rendimentos, IVb não reagiu. As reações de sulfenilação pelo procedimento B, usando-se K2CO3/&#934;H/TEBA e MeSO2SMe foram efetuadas com os compostos Ia-d, IIIa e IVb e mostraram-se mais satisfatórias do que pelo procedimento A, pois todos reagiram, rendendo produtos monossulfenilados. O rendimento do composto IIIa era apenas de 20% , mas os rendimentos dos outros derivados variavam entre 40-67%. Observou-se, através da análise de RMN-1H, em todos os derivados sulfenilados, a presença de dois diastereoisômeros em quantidades iguais. Entretanto, substituindo-se o TEBA por um sal de quinínio quirálico, no caso de duas sulfinil cetonas (Ia e Ic) os compostos sulfenilados correspondentes mostraram uma relação diastereomérica de 4:1. O trabalho apresenta também os resultados de decomposição térmica de sulfinil cetonas monossulfeniladas, efetuado com a finalidade de investigar a aplicabilidade sintética destes compostos. A obtenção de &#945;-cetotioésteres é interpretada como uma reação de Pummerer não catalisada e se constitui em um método alternativo de preparação destes compostos. A decomposição térmica de sulfinil cetonas não sulfeniladas, efetuada para fins de comparação, mostrou-se mais complexa e de difícil interpretação. / The scope of this work consists of a study of reactions of carbanions of functionalyzed sulfoxides with sulfenylating reagents, employing two methods: in the homogeneous phase and by the phase transfer. The literature review, which is presented, shows that although these reactions are new, some other reactions of the carbanions of the functionalyzed sulfoxides, such as alkylations, acylations, condensations with carbonyl compounds and Michael addition, have been already reported. Furthermore, a small number of reactions of sulfinyl carbanions by phase transfer method has been described. The sulfenylation reaction, in the homogeneous phase of the &#945;-sulfinyl aromatic (Ia-d) and cyclic (II) ketones, &#945;-sulfinyl esters (IIIa,b) and thioesters (IVa,b) were performed employing NAH/DMSO and dimethyldissulfide or methyl methanethiosulfonate (MeSO2SMe). Except for the compound (IIb), which showed to be unreactive, in all other cases the monosulfenylated derivatives, not reported previously in the literature, were obtained. The yields of these compounds of 25-90% follow the order: Ib > Ia > IVa > Ic > Id > IIIa > II. The sulfenylation reactions by the phase transfer method were performed employing two different procedures: ion-pair extraction (A) and solid-liquid system (8). The procedure (A) was applied to the compounds Ia, IIIa and IVb, using NaOH/CH2Cl2/Bu4NHSO4 and MeS02SMe. While Ia and IIIa yielded the monosulfenylated derivatives in good yields, IVb remained unchanged. The sulfenylation reactions by procedure (B), using K2CO3/&#934;H/TEBA and MeSO2SMe, carried out with the compounds Ia-d, IIIa and IVb, showed to be more satisfactory than by procedure (A), as all compounds afforded the monosulfenylated derivatives. The yield of compound IIIa was only of 20%, but those for other compounds were of 40-67%. The 1H-NMR analysis of the sulfenylated derivatives showed the presence of two diastereomers in equal quantities. It was possible, by replacement of TEBA by a quiral quininium salt, for the case of two sulfinyl ketones (Ia and Ic), to obtain the corresponding sulfenylated derivatives of diastereomeric ratio 4:1. This work presents also, having in application, the thermal decomposition monosulfenylated sulfinyl ketones. The mind the synthetic reaction of the obtention of the &#945;-ketothioesters is interpreted as a non catalyzed Pummerer reaction and may be considered as an alternative method for preparation of these compounds. The thermal decomposition of the non-sulfenylated sulfinyl ketones performed for comparison, showed to be more complex and hardly to be interpreted.

A finalidade deste trabalho é o estudo de reações de carbânions de sulfóxidos funcionalizados com reagentes sulfenilantes, pelo emprego de dois métodos: fase homogênea e transferência de fases. A revisão bibliográfica apresentada demonstra que trata-se de reações novas e que, entretanto, outras reações de carbânions de sulfóxidos funcionalizados, tais como alquilações, acilações, condensações com compostos carbonílicos e adições de Michael, já tinham sido descritas. Por outro lado, poucas reações de sulfinil carbânions tinham sido efetuadas pelo emprego do método de transferência de fases. As reações de sulfenilação em fase homogênea de &#945;-sulfinil cetonas aromáticas (Ia-d), e cíclicas (II), &#945;-sulfinil ésteres (IIIa,b) e tioéster (IV) foram efetuadas pelo emprego de NaH/DMSO e de dimetildissulfeto ou metanotiossulfonato de metila (MeSO2SMe). Com exceção do composto (IIIb) que não reagiu, em todos os casos foram obtidos compostos monossulfenilados ainda não descritos na literatura. Os rendimentos variavam entre 25-90%, na ordem: Ib > Ia > IVa > Ic > Id > IIIa > II. As reações de sulfenilação em transferência de fases foram efetuadas pelo emprego de dois procedimentos distintos: o de extração do íon-par (A) e o sistema Sólido-líquido (B). Os compostos Ia, IIIa e IVb foram submetidos à sulfenilação pelo procedimento A, em que usou-se NaOH/CH2Cl2/Bu4NHSO4 e MeSO2SMe. Enquanto Ia e IIIa renderam produtos monossulfenilados em baixos rendimentos, IVb não reagiu. As reações de sulfenilação pelo procedimento B, usando-se K2CO3/&#934;H/TEBA e MeSO2SMe foram efetuadas com os compostos Ia-d, IIIa e IVb e mostraram-se mais satisfatórias do que pelo procedimento A, pois todos reagiram, rendendo produtos monossulfenilados. O rendimento do composto IIIa era apenas de 20% , mas os rendimentos dos outros derivados variavam entre 40-67%. Observou-se, através da análise de RMN-1H, em todos os derivados sulfenilados, a presença de dois diastereoisômeros em quantidades iguais. Entretanto, substituindo-se o TEBA por um sal de quinínio quirálico, no caso de duas sulfinil cetonas (Ia e Ic) os compostos sulfenilados correspondentes mostraram uma relação diastereomérica de 4:1. O trabalho apresenta também os resultados de decomposição térmica de sulfinil cetonas monossulfeniladas, efetuado com a finalidade de investigar a aplicabilidade sintética destes compostos. A obtenção de &#945;-cetotioésteres é interpretada como uma reação de Pummerer não catalisada e se constitui em um método alternativo de preparação destes compostos. A decomposição térmica de sulfinil cetonas não sulfeniladas, efetuada para fins de comparação, mostrou-se mais complexa e de difícil interpretação. / The scope of this work consists of a study of reactions of carbanions of functionalyzed sulfoxides with sulfenylating reagents, employing two methods: in the homogeneous phase and by the phase transfer. The literature review, which is presented, shows that although these reactions are new, some other reactions of the carbanions of the functionalyzed sulfoxides, such as alkylations, acylations, condensations with carbonyl compounds and Michael addition, have been already reported. Furthermore, a small number of reactions of sulfinyl carbanions by phase transfer method has been described. The sulfenylation reaction, in the homogeneous phase of the &#945;-sulfinyl aromatic (Ia-d) and cyclic (II) ketones, &#945;-sulfinyl esters (IIIa,b) and thioesters (IVa,b) were performed employing NAH/DMSO and dimethyldissulfide or methyl methanethiosulfonate (MeSO2SMe). Except for the compound (IIb), which showed to be unreactive, in all other cases the monosulfenylated derivatives, not reported previously in the literature, were obtained. The yields of these compounds of 25-90% follow the order: Ib > Ia > IVa > Ic > Id > IIIa > II. The sulfenylation reactions by the phase transfer method were performed employing two different procedures: ion-pair extraction (A) and solid-liquid system (8). The procedure (A) was applied to the compounds Ia, IIIa and IVb, using NaOH/CH2Cl2/Bu4NHSO4 and MeS02SMe. While Ia and IIIa yielded the monosulfenylated derivatives in good yields, IVb remained unchanged. The sulfenylation reactions by procedure (B), using K2CO3/&#934;H/TEBA and MeSO2SMe, carried out with the compounds Ia-d, IIIa and IVb, showed to be more satisfactory than by procedure (A), as all compounds afforded the monosulfenylated derivatives. The yield of compound IIIa was only of 20%, but those for other compounds were of 40-67%. The 1H-NMR analysis of the sulfenylated derivatives showed the presence of two diastereomers in equal quantities. It was possible, by replacement of TEBA by a quiral quininium salt, for the case of two sulfinyl ketones (Ia and Ic), to obtain the corresponding sulfenylated derivatives of diastereomeric ratio 4:1. This work presents also, having in application, the thermal decomposition monosulfenylated sulfinyl ketones. The mind the synthetic reaction of the obtention of the &#945;-ketothioesters is interpreted as a non catalyzed Pummerer reaction and may be considered as an alternative method for preparation of these compounds. The thermal decomposition of the non-sulfenylated sulfinyl ketones performed for comparison, showed to be more complex and hardly to be interpreted.