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The first objective of this investigation was to conduct a systematic study into the reactions of chloroketenes with ketene acetals. The second objective was to explore the synthetic utility of these reaction products and offer a rational explanation for these reaction products.

Thesis. 1978. Ph.D.--Massachusetts Institute of Technology. Dept. of Chemistry. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Vita. / Includes bibliographical references. / Ph.D.

Cyclic ketene-N,N-acetal chemistry was explored. 2-Methylimidazoline and 2-methyl-1,4,5,6-tetrahydropyrimidine derivatives were prepared from the condensation reactions of diamines with nitriles under Lewis acid catalysis and used as the precursors of cyclic ketene-N,N-acetals including the N-methyl and N-acyl cyclic ketene-N,N-acetals. The reactions of 2-methylimidazoline with excess benzoyl chlorides in THF or MeCN in the presence of triethylamine generate N,N'-diacyl-beta-keto-cyclic ketene-N,N-acetals. The corresponding reactions of 1,2-dimethylimidazoline under the same conditions form the ring-opened (Z)-3-((2-benzamidoethyl)(methyl)amino)-3-oxo-1-phenylprop-1-enyl benzoates. The latter reactions feature the formation of carbon-carbon bonds, carbon-nitrogen bonds, and carbon-oxygen bonds in one operation. The reactions of 2-methyl-1,4,5,6-tetrahydropyrimidine with excess acid chlorides in Et3N/THF generate N,N-diacyl-cyclic ketene-N,N-acetals, with no further acylation on the exocyclic beta-carbons. In contrast, the reactions of 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine under the same conditions form N-acyl-N'-methyl-beta,beta-diketo-cyclic ketene-N,N-acetals, with the dual acylations on the exocyclic beta-carbons. Significant double bond torsion and elongation were observed by the X-ray analysis of an example compound from the latter reactions. The reactions of 2-methylimidazoline and 2-methyl-1,4,5,6-tetrahydropyrimidine with 1,3-diacid chlorides, in the presence of Et3N in refluxing MeCN give highly functionalized potentially bioactive 1,8-naphthyridinetetraones. 2-Methylimidazoline and 2-methyl-1,4,5,6-tetra-hydropyrimidine can be viewed as tridentate nucleophiles which give four consecutive tandem nucleophilic attacks on electrophiles. The reactions of 1,2-dimethylimidazoline and 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine with isocyanates in refluxing MeCN gave bicyclic pyrimidinediones. The reactions of N,N'-dimethyl cyclic ketene-N,N-acetals with various isocyanates generated push-pull alkenes which have never been reported. Significant elongations and torsions of the polarized carbon-carbon double bonds in the novel push-pull alkenes were observed using the X-ray crystallography. The stronger pushing effect of the six-membered cyclic ketene acetal portion in a push-pull alkene, versus the five-membered analog, was detected by reactivity differences for the first time.

Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.

The research presented in this dissertation focuses on chiral BINOL metal phosphatephosphoric acid catalyzed enantioselective additions of phosphorus and sulfur nucleophiles to imines and epoxides. In chapter 2, we reported a new method to synthesize chiral amino phosphine oxides. The reaction combines N-substituted imines and diphenylphosphine oxide catalyzed by chiral magnesium 9-antryl phosphate. A wide variety of aliphatic and aromatic aldimines substituted by electron neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The imines protected with dibenzocycloheptene protecting group provided better enantioselectivity than those protected with benzhydryl group, while both imines gave comparable yields. Also, the substituted diphenylphosphine oxides were excellent nucleophiles obtaining chiral α-amino phosphine oxides in good yields and enantioselectivities. In chapter 3, we reported the first catalytic asymmetric method to prepare enantioenriched N,S-acetals catalyzed TRIP phosphoric acids. The reaction combined N-acyl imines with thiols to generate products in excellent yield and enantioselectivity. Electron-rich and electron-deficient aromatic N-acyl imines were excellent substrate for the addition reaction. A wide range of aliphatic and aromatic thiols obtained the N,S-acetals in excellent yields and enantioselectivities. The TRIP phosphoric acid was found to be an extremely efficient catalyst for the transformation, resulting in asymmetric induction at extremely low catalyst loading. In chapter 4, a highly enantioselective method for desymmetrization of meso-epoxides using thiols catalyzed by substituted BINOL lithium phosphate is reported. This is the first example of epoxide activation using metal phosphate is reported. Various five and six membered aliphatic cyclic meso-epoxides were excellent substrates for the desymmetrization reaction; aromatic acyclic epoxides also reacted with excellent yield and asymmetric induction. Similarly electron rich and electron deficient aromatic thiols obtained the β-hydroxyl sulfides in excellent yields and enantioselectivities.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The use of ionic liquids 1-butyl-3-methylimidazolium tetrafluorborate ([BMIM] [BF4]) and 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) as catalytic solvent in the synthesis of 1,1,1-trichloro(fluoro)-3-alken-2-onas [CX3C(O)C(R2)=C(R1)OR] from the reaction of enolethers or acetals with acyl halides is reported. The results obtained in the presence of ionic liquids were compared with those obtained in the conventional condition already developed in our laboratory, and they demonstrated great improvement in the reaction times, with maintenance of the good yields. Ionic liquids also were used in the reactions of enolethers with poor reactive acylants, as acetyl chloride and benzoyl chloride, proving its efficiency as catalytic media in this reaction type. The ionic liquids were still used as medium in the synthesis of β-enaminones bearing a trifluoro[chloro]methyl starting from the 1,1,1-trichloro(fluoro)-3-alken-2-ones. It was also evaluated the reutilization of the ionic liquids (recharge) after the reactions mentioned above. In all of the cases of recharge there was the maintenance of the times reacionais without significant loss of yield. / Esta tese descreve a utilização dos líquidos iônicos tetrafluorborato de 1-butil-3-metilimidazolium ([BMIM] [BF4]) e hexafluorfosfato de 1-butil-3-metilimidazolium ([BMIM][PF6]) como solventes catalíticos na síntese de 1,1,1-tricloro(fluor)-3-alquen-2-onas [CX3C(O)C(R2)=C(R1)OR] a partir da reação de enoléteres ou acetais com haletos de acila. Os resultados obtidos com líquidos iônicos foram comparados com os obtidos por método convencional já desenvolvido em nosso laboratório, e demonstraram grande melhora nos tempos reacionais e manutenção dos bons rendimentos. Os líquidos iônicos também foram utilizados em reações de enoléteres com acilantes menos reativos como cloreto de acetila e cloreto de benzoíla, provando ser bons meios catalíticos neste tipo de reação. Os líquidos iônicos foram utilizados como meio para a síntese de trifluoro[cloro]metil β-enaminonas a partir de 1,1,1-tricloro(fluor)-3-alquen-2-onas. Também foi avaliada a reutilização dos líquidos iônicos (recarga) após as reações mencionadas. Em todos os casos, após a recarga os tempos reacionais foram mantidos sem perda significativa nos rendimentos.

The thesis entitled “Enantioselective synthesis of bio-active bicyclic acetals, cyclic ethers and lactones” demonstrates the utility of chiral pool tartaric acid as the source in the synthesis of natural products. The results are discussed in three chapters; 1) Enantioselective synthesis of bio-active bicyclic acetals, 2) Enantioselective synthesis of bio-active cyclic ethers and 3) Enantioselective synthesis of bio-active lactones. A brief introduction is provided in each chapter to keep the present work in proper perspective. Compounds (in bold) and references (in superscripts) are sequentially numbered differently for each chapter and references are given as foot notes. Experimental procedures are given differently for each chapter and placed at the end of chapter. Scanned 1H and 13C NMR spectras are given with description of signals. Chapter 1 describes the enantioselective synthesis of bicyclic acetal containing insect pheromones. First part of this chapter deals with the enantiodivergent synthesis of both enantiomers of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin starting from a single chiral compound, bis-Weinreb amide derived from L-(+)-tartaric acid. Controlled addition of Grignard reagent to bis-Weinreb amide followed by diastereoselective reduction of the resultant ketone was employed as the key step for the enantiodivergent synthesis of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin. In the second part, enantioselective synthesis of exo-brevicomin, iso-exo-brevicomin and formal synthesis of frontalin comprising similar framework is demonstrated, utilizing á -benzyloxy aldehydes derived from L-(+)-tartaric acid as chiral building block. Second Chapter describes the enantioselective synthesis of bio-active cyclic ethers, disparlure, centrolobine and isolaurepan. Employing á-benzyloxy aldehydes derived from L-(+)-tartaric acid as the chiral building block, synthesis of both enantiomers of insect pheromone disparlure is achieved involving the diastereoselective addition of allyltributyl tin to the á-benzyloxy aldehyde and cross metathesis of the resultant homoallylic alcohol with 4-methyl-1-pentene. Formal synthesis of centrolobine and isolaurepan are accomplished. Pivotal step involved in the synthesis of centrolobine is iron(III) mediated cyclization of 1,5-diol derived from L-(+)-tartaric acid, while Lewis acid mediated reductive cyclization of the hydroxy ketone derived from á-benzyloxy aldehyde is the key step in the synthesis of isolaurepan. Third chapter in the thesis deals with the enantioselective synthesis of bio-active lactones muricatacin, 6-acetoxy-5-hexadecanolide and boronolide. Utilizing á-benzyloxy aldehyde as the building block, synthesis of five and six membered lactones, muricatacin and 6-acetoxy-5-hexadecanolide were accomplished via the diastereoselective addition of 3-butenylmagnesium bromide and allyltributyl tin to á-benzyloxy aldehyde, respectively. Stereoselective formal synthesis of boronolide was described, starting from D-(–)-tartaric acid. Key reaction sequence includes the elaboration of ã-hydroxy amide obtained by a combination of controlled Grignard addition and diastereoselective reduction from bis- Weinreb amide derived from D-(–)-tartaric acid.

The development of heterocyclic chemistry is important for various science areas and for the industry. The main task of this branch of chemistry is the search for the new, more effective synthetic methods for obtaining heterocyclic derivatives. That covers not only the formation of heterocycles, but also their functionalization, which leads to the creation of compounds having various chemical and physical properties. The accomplishments of this area are applied in biochemistry, pharmacochemistry, photophysics and other branches of science and industry. The creation of effective heterocycles synthesis methods, that may be applied for the formation of heterosystems based on pyrazolo[3,4-d]pyrimidine was the main aim in this work. During this work, three hitherto unknown peri-fused heterocyclic systems based on pyrazolo[3,4-d]pyrimidine scaffold were synthesized. The suitable conditions for the cyclization of 4-(2,2-diethoxyethyl)aminopyrimidines to 2,3-dihydroimidazo[1,2-c]pyrimidines were found. The influence of functional groups in pyrimidine moiety for the course of this reaction was investigated. It has been shown that functional groups including alkylthio, cyano, amino, formyl are tolerated in this type of reaction. The method for the replacement of ethoxy group with benzyl mercaptan in 3-ethoxy-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidines has been found. / Heterociklų chemijos vystymasis turi didelę reikšmę įvairioms mokslo sritims ir pramonės raidai. Pagrindinis šios chemijos srities uždavinys – kurti naujus heterociklinių junginių sintezės metodus, leidžiančius paprasčiau, efektyviau gauti norimos struktūros junginius. Tai apima ne tik heterociklų formavimo būdus, bet ir jų funkcionalizavimą, leidžiantį sukurti įvairiomis cheminėmis ir fizikinėmis savybėmis pasižyminčių junginių įvairovę. Šios mokslo srities pasiekimai pritaikomi biochemijoje, farmacijoje, fotofizikoje ir kitose mokslo ir pramonės šakose. Šiame darbe buvo siekiama sukurti efektyvius heterosistemų sintezės būdus, kuriuos galima pritaikyti pirazolo[3,4-d]pirimidino fragmentą turinčių heterociklų formavimui. Šio darbo metu buvo susintetintos trys iki šiol neaprašytos heterociklinės sistemos atliekant peri-kondensuotų heterosistemų sintezę iš 3-amino-4-chlor-1-metil-6-metiltio-1H-pirazolo[3,4-d]pirimidino. Surastos tinkamos sąlygos 4-(2,2-dietoksietilmino)pirimidinų ciklizacijai į 3-etoksi-2,3-dihidroimidazo[1,2-c]pirimidinus. Ištirta pirimidino žiede esančių pakaitų įtaka šiai reakcijai. Parodyta, kad ši reakcija yra suderinama su tokiomis funkcinėmis grupėmis, kaip alkiltio-, cian-, amino-, formilgrupės. Surastas metodas 3-etoksi-2,3-dihidroimidazo[1,2-c]pirazolo[4,3-e]pirimidinų etoksigrupės pakeitimui benziltiogrupe.

Heterociklų chemijos vystymasis turi didelę reikšmę įvairioms mokslo sritims ir pramonės raidai. Pagrindinis šios chemijos srities uždavinys – kurti naujus heterociklinių junginių sintezės metodus, leidžiančius paprasčiau, efektyviau gauti norimos struktūros junginius. Tai apima ne tik heterociklų formavimo būdus, bet ir jų funkcionalizavimą, leidžiantį sukurti įvairiomis cheminėmis ir fizikinėmis savybėmis pasižyminčių junginių įvairovę. Šios mokslo srities pasiekimai pritaikomi biochemijoje, farmacijoje, fotofizikoje ir kitose mokslo ir pramonės šakose. Šiame darbe buvo siekiama sukurti efektyvius heterosistemų sintezės būdus, kuriuos galima pritaikyti pirazolo[3,4-d]pirimidino fragmentą turinčių heterociklų formavimui. Šio darbo metu buvo susintetintos trys iki šiol neaprašytos heterociklinės sistemos atliekant peri-kondensuotų heterosistemų sintezę iš 3-amino-4-chlor-1-metil-6-metiltio-1H-pirazolo[3,4-d]pirimidino. Surastos tinkamos sąlygos 4-(2,2-dietoksietilmino)pirimidinų ciklizacijai į 3-etoksi-2,3-dihidroimidazo[1,2-c]pirimidinus. Ištirta pirimidino žiede esančių pakaitų įtaka šiai reakcijai. Parodyta, kad ši reakcija yra suderinama su tokiomis funkcinėmis grupėmis, kaip alkiltio-, cian-, amino-, formilgrupės. Surastas metodas 3-etoksi-2,3-dihidroimidazo[1,2-c]pirazolo[4,3-e]pirimidinų etoksigrupės pakeitimui benziltiogrupe. / The development of heterocyclic chemistry is important for various science areas and for the industry. The main task of this branch of chemistry is the search for the new, more effective synthetic methods for obtaining heterocyclic derivatives. That covers not only the formation of heterocycles, but also their functionalization, which leads to the creation of compounds having various chemical and physical properties. The accomplishments of this area are applied in biochemistry, pharmacochemistry, photophysics and other branches of science and industry. The creation of effective heterocycles synthesis methods, that may be applied for the formation of heterosystems based on pyrazolo[3,4-d]pyrimidine was the main aim in this work. During this work, three hitherto unknown peri-fused heterocyclic systems based on pyrazolo[3,4-d]pyrimidine scaffold were synthesized. The suitable conditions for the cyclization of 4-(2,2-diethoxyethyl)aminopyrimidines to 2,3-dihydroimidazo[1,2-c]pyrimidines were found. The influence of functional groups in pyrimidine moiety for the course of this reaction was investigated. It has been shown that functional groups including alkylthio, cyano, amino, formyl are tolerated in this type of reaction. The method for the replacement of ethoxy group with benzyl mercaptan in 3-ethoxy-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidines has been found.