Nitrogen-containing molecules are ubiquitous in both natural products and pharmaceutical drugs, thus an efficient method for the formation of these motifs is of great importance. Hydroamination, that is the addition of an N-H bond across an unsaturated carbon-carbon bond of an alkene or alkyne, stands out as a potential approach to obtain such molecules. To date, most research in this area relies on transition-metal catalysis to enable such reactivity. In efforts directed towards metal-free alternatives, we have developed a simple, metal-free hydroamination of alkenes using hydrazides. Further investigation into the corresponding reactivity of alkynes with hydrazides has provided access to novel azomethine imine products. In Chapter 2, expansion of the substrate scope with respect to the intramolecular hydroamination of alkenes using hydrazides, as well as studies directed towards elucidation of the mechanism of this reaction will be presented. The intramolecular hydroamination of alkynes using hydrazides and methods to access and isolate the azomethine imine products formed will be discussed in Chapter 3.

The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate. The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines. In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones. Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to the enantioselective synthesis of nitrogen-substituted polycyclic heterocycles. By using a cationic Rh(I) triflate catalyst in the presence of the chiral Josiphos ligand PPF-PtBu2, the ring opening reactions on dihydrooxaquinoline and dihydrooxaisoquinoline using different nucleophiles afford access to multiple dihydroquinolines and dihydroisoquinolones in high yield and high enantioselectivity (up to 99% total yield and >99%ee). A variety of nucleophiles were shown to be compatible with the catalytic system. The electronic effects in the new ring opening reactions were investigated using a variety of nucleophiles. It was found that reactivity and enantioselectivity of the ring opening products depends on the electronic effects as well as the position of the substituents on the substrates. Good yields and high ee of regioisomeric products are obtained using electron donating substituents, whereas electron withdrawing substituents decelerate the reactions.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

We report the application of our rhodium-catalyzed nucleophilic ring-opening methodology to the enantioselective synthesis of nitrogen-substituted polycyclic heterocycles. By using a cationic Rh(I) triflate catalyst in the presence of the chiral Josiphos ligand PPF-PtBu2, the ring opening reactions on dihydrooxaquinoline and dihydrooxaisoquinoline using different nucleophiles afford access to multiple dihydroquinolines and dihydroisoquinolones in high yield and high enantioselectivity (up to 99% total yield and >99%ee). A variety of nucleophiles were shown to be compatible with the catalytic system. The electronic effects in the new ring opening reactions were investigated using a variety of nucleophiles. It was found that reactivity and enantioselectivity of the ring opening products depends on the electronic effects as well as the position of the substituents on the substrates. Good yields and high ee of regioisomeric products are obtained using electron donating substituents, whereas electron withdrawing substituents decelerate the reactions.

The development of a novel palladium-catalyzed domino reaction with indole-based gem-dibromoolefin substrates is described. The reaction allowed access to a new class of polycyclic nitrogen heterocycles: N-fused benzo[c]carbazoles. A key feature of this domino reaction was the participation of both bromides in C–H functionalization processes, a hitherto unprecedented reactivity. Various substituents and substitution patterns were tolerated in this reaction, allowing for a highly modular approach to these challenging synthetic targets. Mechanistic studies were performed to gain further insight into the reactivity of these systems and elucidate the sequence of reaction steps. The results indicate that isomerization of reaction intermediates likely played a key role in promoting a successful reaction.

The Lautens group has a long-standing interest in developing novel approaches to heterocycle synthesis. One such approach is a Pd-catalyzed, norbornene-mediated domino reaction which can form up to three carbon-carbon bonds in one synthetic sequence. The key additive is norbornene which acts similar to a catalyst by assembling the scaffold to enable the formation of a carbon-carbon bond, though is not incorporated into the final compound. The reaction involves C-H bond functionalization as a key step and a Pd(IV) complex as a key intermediate. The goal of the current thesis was to introduce reactive heteroatoms to this domino reaction for the first time, with particular focus on the introduction of nitrogen. Methodologies were developed to present novel syntheses of heterocycles with high pharmaceutical interest. Our initial study focused on the selective functionalization of thiophenes to give multi-substituted sulfur compounds. To synthesize pharmaceutically important nitrogen heterocycles, we demonstrated for the first time that an amination reaction was compatible with the domino reaction. This development led to novel approaches to synthesize substituted indolines, indoles, tetrahydroquinolines, benzomorpholines, phenoxazines, dihydrodibenzoxazepines, tetrahydroisoquinolines, tetrahydroisoquinolinones and tetrahydrobenzazepines. In contrast to the use of norbornene in a catalytic manner, we demonstrated that heterocycles could also be synthesized by the incorporation of strained alkenes. We developed a conceptually novel approach to generate nitrogen heterocycles by using norbornadiene as an acetylene synthon. A palladium-catalyzed annulation of substituted haloanilines with norbornadiene led to functionalized indolines. These indolines could be rapidly converted to benzenoid-substituted indoles and tricyclic indolines, which form the core of many biologically active compounds. Extension to the use of substituted halobenzamides led to functionalized isoquinolinones. Finally, we embarked on a study to perform selective palladium-catalyzed C-H functionalization reactions with N-iodoarylpyrroles and strained alkenes. We will present the reaction conditions necessary to favour aryl C-H functionalization over pyrrole C-H functionalization.

Nitrogen-containing molecules are ubiquitous in both natural products and pharmaceutical drugs, thus an efficient method for the formation of these motifs is of great importance. Hydroamination, that is the addition of an N-H bond across an unsaturated carbon-carbon bond of an alkene or alkyne, stands out as a potential approach to obtain such molecules. To date, most research in this area relies on transition-metal catalysis to enable such reactivity. In efforts directed towards metal-free alternatives, we have developed a simple, metal-free hydroamination of alkenes using hydrazides. Further investigation into the corresponding reactivity of alkynes with hydrazides has provided access to novel azomethine imine products. In Chapter 2, expansion of the substrate scope with respect to the intramolecular hydroamination of alkenes using hydrazides, as well as studies directed towards elucidation of the mechanism of this reaction will be presented. The intramolecular hydroamination of alkynes using hydrazides and methods to access and isolate the azomethine imine products formed will be discussed in Chapter 3.

Natural products and small molecules play a major role in drug development. However, using natural products as a source of medicine comes with many challenges, such as lack of natural abundance and difficulty in isolation. Consequently, synthetic organic chemistry is a solution in order to access these compounds in usable quantities. However, synthetic chemisty comes with its own challenges such as efficiency, chemoselectivity, stereoselectivity and enantioselectivity. Therefore, synthetic tools that addresses these challenges are required solve these limitations. This thesis discusses new methodologies using strained carbocycles (cyclopropanes and cyclopropenes) as the reactive subunit for the construction of different carbocyclic and heterocyclic compounds. The homo-Nazarov cyclization of alkenyl and heteroaryl cyclopropyl ketones was used in order to construct cyclohexenones, cyclohexenols, heteroaryl ring-fused cyclohexenones, dihydrofurans, furans and furanones in a mild and efficient manner. Benzofused heteroaromatic compounds were achieved via the Lewis acid-catalyzed cycloisomerization of cyclopropene-3,3-dicarbonyls and furan-3-carboxylates. These heteroaromatic compounds can be applied to medicinal chemistry and material science.

The main aims of this investigation were to investigate cyclization reactions of electron–deficient 6–alkynylpyrimidine–5–carbaldehydes and 2–alkynylquinoline–3–carbaldehydes, and electron–rich 2–alkynylindole–3–carbaldehydes and 2–alkynylthiophene–3–carbaldehydes with N–, S–. O–, C– and P–nucleophiles. It was found, that 6–arylethinylpyrimidine–5–carbaldehydes under the treatment with tert–butylamine underwent thermal or microwave–induced cyclization reaction to form pyrido[4,3–d]pyrimidines. A novel and fast synthetic method for preparation of 1,2,3–trisubstituted 1,2–dihydrobenzo[b][1,6]naphthyridines by means of a three–component reaction between 2–alkynylquinoline–3–carbaldehydes, primary amines and C– or P–pronucleophiles was developed. It was showed, that methyl mercaptoacetate was able to trigger a novel benzannulation reaction of the starting materials. Novel, concise and regioselective synthetic methods of 5,7–dihydrofuro[3,4–d]pyrimidine, 5H–pyrano[4,3–d]pyrimidine, 1,3–dihydrofuro[3,4–b]quinolines and 1H–pyrano[4,3–b]quinolines frameworks via regioselective acetalisation/cyclization reactions of 2,4–disubstituted 6–phenylethynylpyrimidine–5–carbaldehydes and 2–alkynylquinoline–3–carbaldehydes were developed. A relatively short and efficient synthesis of 2–(2–oxoethyl)–1H–indole–3–carbaldehydes via tandem 6–endo–dig cyclization from 2–alkynylindole–3–carbaldehydes was developed. It was found that 2–alkynylquinoline–3–carbaldehydes react with dimethylphosphite in... [to full text] / Darbo tikslas – ištirti heterociklinių junginių, gretimose padėtyse turinčių etinil– ir formilfragmentus, ciklizacijos reakcijas su įvairiais nukleofiliniais reagentais. Darbo metu buvo rastas naujas ir efektyvus pirido[4,3–d]pirimidinų sintezės būdas kurio esmė yra 4–ariletinil–5–pirimidinkarbaldehidų terminė ar mikrobangų inicijuojama reakcija su tret–butilaminu. Parodyta, kad 2–alkinilchinolin–3–karbaldehidai dalyvauja trikomponentinėse reakcijose su pirmininiais aminais ir C– bei P-pronukleofilais sudarydami 1,2–dihidrobenzo[b][1,6]naftiridinus. Pasiūlytas naujas, universalus ir efektyvus būdas benzanuliuotoms sistemoms sintetinti panaudojant metilmerkaptoacetato kalio druską metanolyje. Rasti regioselektyvūs 5,7–dihidrofuro[3,4–d]pirimidinų, 5(H)–pirano[4,3–d]pirimidinų, 1,3–dihidrofuro[3,4–b]chinolinų ir 1H–pirano[4,3–b]chinolinų sintezės būdai tandeminių 5–egzo–dig ir 6–endo–dig ciklizacijos reakcijų pagalba. Rastas efektyvus būdas 2–(2–aril(alkil)–2–oksoetil)–1H–indol–3–karbaldehidams sintetinti iš 2–alkinil–1H–indol–3–karbaldehidų ir metanolio katalizuojant sidabro druskoms. Parodyta, kad 2–alkinilchinolin–3–karbaldehidai reaguodami su dimetilfosfitu bazinėje terpėje sudaro prisijungimo produktus dimetilhidroksi– (2–pakeistus-chinolin–3–il)metilfosfonatus. Pastarieji, esant bazės pertekliaus, persigrupuoja į atitinkamus dimetil–(2–pakeistus-chinolin–3–il)metilfosfatus. Nustatyta, kad 2–(2–piridinil)etinilchinolin–3–karbaldehidas ir 6–ariletinilpirimidin–... [toliau žr. visą tekstą]