1,1-enediamines and β-substituted enamines in heterocyclic synthesis

The work in this thesis mainly deals with l,l-enediamines and ~ -substituted enamines (push-pull olefines) and their reactions, leading to the formation of a number of heterocycles. Various ~-substituted enamines were prepared by a 'one pot synthesis' in which a l,l-enediamine presumably acts as an intermediate. These enamines, various substituted crotonamides and propenamides, were made by using two different orthoesters, various secondary and primary amines and cyanoacetamide. Their structures, mechanism of formation and geometry are discussed. A synthetic route to various unsymmetrically substituted pyridines was examined. Two substituted pyridinones were obtained by using two different ~-substituted enamines and cyanoacetamide. In one case a dihydropyridine was isolated. This dihydropyridine, on heating in acidic conditions, gave a pyridinone, which confirmed this dihydropyridine as an intermediate in this pyridine synthesis. A new synthetic method was used to make highly substituted pyridinones, which involved the reaction of l,l-enediamines with the ~-substituted enamines. A one pot synthesis and an interrupted one pot synthesis were used to make these pyridinones. Two different orthoesters and three different secondary amines were used. Serendipitous formation of a pyrimidinone was observed when pyrrolidine was used as the secondary amine and triethyl orthopropionate was used as the orthoester. In all cases cyanoacetamide was used as the carbon acid. This pyridine synthesis was designed with aI, l-enediamine as the Michael donor and the ~ -substituted enamines as Michael acceptors. Substituted ureas were obtained in two cases, which was a surprise. Some pyrimidines were made by reacting two substituted enamines with two different amidines. When benzamidine was used, the expected pyrimidines were obtained. But, when 2-benzyl-2-thiopseudourea (which is also an amidine) was used, of the two expected pyrimidines, only one was obtained. In the other case, an additional substitution reaction took place in which the S-benzyl group was lost. An approach to quinazolone and benzothiadiazine synthesis is discussed. Two compounds were made from 1, I-dimorpholinoethene

ortho-Bromo(propa-1,2-dien-1-yl)arenes : substrates for domino reactions

o-Bromo(propa-1,2-dien-1-yl)arenes exhibit novel and orthogonal reactivity under Pd catalysis in the presence of secondary amines to form enamines (concerted Pd insertion, intramolecular carbopalladation, and terminative Buchwald–Hartwig coupling) and of amides to form indoles (addition, Buchwald–Hartwig cyclization, and loss of the acetyl group). The substrates for these reactions can be accessed in a reliable and highly selective two-step process from 2-bromoaryl bromides.

手性有机小分子催化烯胺不对称还原

手性胺是合成天然产物和手性药物的重要中间体，亚胺和烯胺的不对称催化还原是制备手性胺最直接有效的方式之一。手性有机小分子催化的亚胺不对称还原已取得了可喜的进展，但到目前为止，有机小分子催化的烯胺不对称还原，尤其是环状烯胺的不对称还原还少有报道。 本研究从手性叔丁基亚磺酰胺出发，设计并合成了一系列含有叔丁基亚磺酰基的新型脲类及硫脲类催化剂，并将其用于催化三氯硅烷对烯胺的不对称还原，尤其是1, 4-二氢吡啶酯类环状烯胺的不对称还原。通过对催化反应条件的优化，发现当添加1eq H2O时，反应收率和对映选择性明显提高，获得高达99% 的收率和88% ee，同时也取得了很好的非对映选择性（dr = 8:92）。首次实现了三氯硅烷对1, 4-二氢吡啶酯类环状烯胺的高立体选择性还原。 通过机理方面的研究，我们推测反应过程中可能是：首先，底物1, 4-二氢吡啶酯与催化剂形成氢键而被活化，当加入添加剂后，添加剂与三氯硅烷反应释放出一个质子，然后受活化的1, 4-二氢吡啶酯捕获该质子转变成更活泼的亚胺正离子的中间体。随后，在催化剂上的手性硫氧的活化下，三氯硅烷的负氢加成到受活化的亚胺正离子的中间体上，最后生成比较有利的反式产物1, 4, 5, 6-四氢吡啶乙酯。 Calalytic enantioselective reduction of imines and enamines represents one of the most straightforward and efficient methods for the preparation of chiral amines, which is an important class of intermediates for the synthesis of natural products and chiral drugs. Significant progresses have been made in organocatalytic enantioselective reduction of imines. However, asymmetric reduction of enamines, especially of cyclic enamines catalyzed by small organocatalysts has scarcely been reported. In this study, starting from chiral tert-butanesulfinamide, a series of structurally simple tert-butanesulfinyl urea and thiourea organocatalysts were developed and employed in asymmetric reduction of enamines by triclorosilane, particularly in the reduction of cyclic enamines such as Hantzsch 1, 4-dihydropyridines. During the optimization of reaction condictions, we found that the addition of one equivalent of H2O could significantly improve the yields and enatioselectivities. Under optimal condictions, 99% yield, up to 88% ee, and 8:92 diastereomeric ratio were obtained. Thus, we have for the first time realized the highly stereoselective reduction of Hantzsch 1, 4-dihydropyridines catalyzed by triclorosilane. As for the mechanism, we speculate that the Hantzsch 1, 4-dihydropyridine was firstly engaged with the catalyst through hydrogen bond. The proton released from the reaction of the additive and triclorosilane next added to one of the C=C bond to make an active iminium intermediate, which was then attacked by the nucleophlic hydrogen of HSiCl3 activated by the Lewis basic sulfinyl function of the catalyst to provide superior trans-1, 4, 5, 6-tetrahydropyridine products.

路易斯碱催化的烯胺不对称还原研究

手性胺不仅是许多天然产物和手性药物的重要结构单元，而且也是非常有用的拆分试剂、手性配体和手性催化剂。亚胺和烯胺的不对称催化还原是制备手性胺的最直接有效的方式之一，手性有机小分子催化的亚胺不对称还原已取得了很大的进展，但到目前为止，有机小分子催化的烯胺不对称还原极少见文献报道。 本研究以廉价的三氯氢硅为氢源、DMF 等路易斯碱为催化剂实现了烯胺的高效还原。通过反应条件的优化，各种烯胺底物在0.1 eq. DMF 催化下、12 个小时内可以获得非常高的收率（>93%）。 在本课题组前期研究的基础上，我们筛选并设计了一系列以手性哌啶酸和叔丁基亚磺酰胺为母体的有机小分子路易斯碱催化剂，它们能催化三氯氢硅对(Z)-N-苄氧羰基-1-苯基丙烯胺的不对称还原，获得很高的收率和中等的对映选择性，并且具有很好的底物普适性。另外，通过机理方面的研究，我们推测在反应过程中一分子烯胺先捕获一个质子而转变为亚胺正离子，然后受到路易斯碱活化的三氯氢硅中的富电氢原子进攻该亚胺正离子得到还原产物。 另外，本文列出了在此课题进展中所发现的一些新反应，并且试图去阐释这些反应的作用机理。 Catalytic enantioselective reduction of imines and enamines represents one of the most straightforward and efficient methods for the preparation of chiral amines, which are not only important building blocks of many natrural products and chiral drugs, but also can serve as useful resolution reagents, chiral ligands and chiral catalysts. By now, asymmetric reduction of enamines catalyzed by organocatalysts has scarcely been reported, although organocatalyzed enantioselective reduction of imines has already gained great progress. In this study, we report the DMF-catalyzed reduction of enamines with high yields using HSiCl3 as the reducing agent. Under the optimized reaction conditions, various enamines can be reduced in the presence of 0.1 eq. DMF with high yields (>93%) in 12 hours. We screened a set of Lewis base organocatalysts derived from chiral pipecolinic acid and tert-butanesulfinamide for the reduction of (Z)-N-Cbz-1- phenylpropenamine, including newly designed ones and some of those previously developed in our lab. However, only moderate stereoselectivities, albeit high yields were obtained. As for the mechanism, we speculate that the enamine firstly engages a proton to form an iminium species, which is then attacked by the nucleophlic hydrogen of HSiCl3 activated by Leiws base. During the above studies, we have also discovered some new reactions, for which feasible mechanisms were proposed.

吲哚生物碱Desbromoarborescidine A 的全合成及烯胺C-亚磺酰化反应研究

从新几内亚核桃木的树皮中分离得到的吲哚类喹诺里西定生物碱10-Desbromoarborescidine A，因发现其具有阻滞钙离子通道的活性而倍受关注。10-Desbromoarborescidine A由A、B、C、D四个环组成，只有一个手性中心，是吲哚生物碱中结构较简单的一种，常作为此类生物碱全合成方法的模型化合物。但迄今为止，能高效而简便的实现手性10-Desbromoarborescidine A不对称全合成方法线路不多，大多数以不对称诱导的方式建立其手性中心，手性催化的方式仅有一例金属催化。从逆合成分析可知，Desbromoarborescidine A的全合成可以通过亚胺不对称催化还原进行关键的手性中心构建，而本课题组在之前的研究中通过手性有机小分子催化剂的发展，已将三氯硅烷氢转移还原亚胺发展成了一类简便实用、高效、高对映选择性并具有优良底物适应范围的不对称催化反应，我们希望以这一反应作为关键手段，发展一条Desbromoarborescidine A及其类似物不对称合成新路线。 根据我们设计的新路线，首先成功合成了其关键中间体，然后我们进行了关键的不对称催化尝试。用本实验室已有的高性能有机小分子催化剂虽得到了较好的对应选择性，但是产率很低。同时，为了验证整条线路的可行性，我们也用消旋的中间体进行拉通线路的尝试。但不幸的是，在脱除保护基时遇到了很大困难。尝试换不同的保护基，或改变脱保护基的顺序，都未能成功合成目标产物。究其原因可能是由于吲哚的特殊性造成的，吲哚类亚胺与常规的芳香亚胺有较大的差异，其NH基团无论保护还是不保护，对与其2位相联接的C=N双键均有很大的影响，导致其不对称催化还原难以进行。另外，由于所设计的还原产物含有处在吲哚苄位的胺基，稳定性较差，造成保护基脱除困难。 烯胺C-亚磺酰化反应是本课题组最近发现的一个新反应，之前未见文献报道。本研究对该反应进行了反应条件优化和底物扩展，发现带Cbz，Ac，COt-Bu，CO2Et，Bz等保护基的一系列环状和非环状烯胺在亚磺酸钠、DMAc和MeSiCl3的共同作用下能高效高产率生成β-胺基烯基亚砜类新化合物，为合成多官能团化的烯基亚砜新化合物提供了一条简便实用的途径。 The main constituent of Dracontomelum mangiferum B1, indoloquinolizidine alkaloid 10-Desbromoarborescidine A, has drawn great attention due to its calcium channel blocking activity. Its molecular structure is relatively simple compared with the other alkaloids of the same type, which has only one chiral center, albeit with four cycles A, B, C, and D. This compound is often used as a model target for exploring different strategies for the total synthesis of indole alkaloids. Nevertheless, so far there still lack practical and highly efficient methods for the asymmetric total synthesis of 10-Desbromoarborescidine A. Most of the current available methods rely on stoichiometric asymmetric synthesis for the construction of the chiral center. There is only one example reporting utilization of asymmetric catalysis, but with transition metal complex as the catalyst. Our retrosynthetic analysis shows that catalytic asymmetric reduction of imine could be used as the key step for the construction of the chiral center of Desbromoarborescidine A. Since in the previous studies our group has developed the asymmetric reduction of imines by trichlorosilane into a practical and highly efficient and enantioselective method using newly designed chiral organocatalysts, we hope to apply this method to develop a novel synthetic route for the total synthesis of Desbromoarborescidine A and its analogues in this study. According to the newly designed synthetic route, we first accomplished the synthesis of the key intermediates which was then examined for the critical asymmetric catalysis. The asymmetric reduction using the highly efficient organocatalysts, developed in our lab afforded high ee but poor yield. We tried different reaction conditions to improve the yield, but failed to get any good results. Simultaneously, to vertify the feasibility of the synthetic route we designed, we also tired to go through the route toward the racemic synthesis of Desbromoarborescidine A. But unfortunately, protection and deprotection proved to be big hurdles. All the different protection groups and different sequences of protection and deprotection we tried failed to get us through the designed synthetic sequence and furnish the final product. Most likely, the indole part is the culprit behind the failures.The NH group of the indole, no matter protected or not, may impact the catalytic asymmetric reduction of C-N double bond connected with 2-C. Additionally, the reduction product we designed contains an amino group in the β-position of the indole, which may cause problems due to its instability. C-sulfenylation of enamines is a novel reaction discovered recently by our group, which has not been seen before in the literature. In this study, optimization of the reaction conditions and exploration of the substrate scope were further undertaken for this reaction, which reveal that a series of enamines with N-Cbz, Ac, COt-Bu, CO2Et protection groups could all undergo smooth C-sulfinylations with the comined use of sodium benzene sulphinate, DAMc and MeSiCl3, efficiently furnishing the β-amino vinylsulfoxide products in high yield, affording a practical and highly efficient methods for synthesis of functional vinylsulfoxides.

Aza-annulation of enaminones with itaconic anhydride:kinetic preference for exocyclic enamide products

Enaminones react with itaconic anhydride in methylene chloride at room temperature to give exocyclic enamides sis the major products. These can be readily equilibrated to the thermodynamically more stable endocyclic enamides. In substrates where the exocyclic isomer could not be formed only intractable materials were produced from this reaction. An intermediate in this two step process was detected and identified by proton and C-13 NMR spectroscopy. In two cases chiral enaminones were employed and the relative stereochemistry at the new chiral centre in the product was established by a crystal structure of compound 27.

Rearranjos 3-aza-cope de N-alil-N-sililoxi enaminas

O rearranjo [3,3]-sigmatrópico térmico (180ºC) de diferentes N-alil-N-sililoxi enaminas foi estudado. Os respectivos produtos de rearranjo (éteres de óxima) foram obtidos com rendimentos elevados (80%). A regiosselectividade, [3,3] vs [1,3], e a diastereosselectividade do processo foram elevadas, superior a 99% e aproximadamente 80%, respectivamente. Foi demonstrada a importância do grupo sililoxilo na promoção do rearranjo face a substratos sem este tipo de substituição. Posteriormente, foi estudada a possibilidade de aceleração aniónica deste tipo de rearranjo por formação de oxianião ligado ao átomo de azoto. A estratégia seguida para a formação do mesmo, consistiu na O-dessililação de diferentes N-alil-N-sililoxi enaminas tendo-se obtido as nitronas correspondentes ou produtos de ciclização. Num exemplo envolvendo um derivado de isoxazole-5-(2H)-ona foi observado um aumento de velocidade do rearranjo por reacção com ião etoxilo. Este aumento de velocidade foi atribuído à abertura de anel do N-O éster cíclico para o N-oxianião, seguida de rearranjo e posterior fecho. Métodos alternativos de aceleração do rearranjo por geração de carga positiva, parcial ou completa, no átomo de azoto levaram apenas à dessililação das N-alil-N-sililoxi enaminas. ABSTRACT - [3,3]-sigmatropic rearrangement of a variety of N-allyl-N-silyloxy enamines was studied. The corresponding rearrangement products (oxime-ethers) were obtained in high yields (80%). High regioselectivity, [3,3] vs [1,3] (> 99%) and in appropriate cases, diastereoselectivity (80%) were observed. The importance of the silyloxy group in promoting the rearrangement, in relation to substrates lacking this functionality, is underlined. The possible anionic acceleration of the rearrangements was next examined by O-desilylation the N-silyloxy group bonded to the nitrogen. Attempted generation of these species however, was found to lead either to the corresponding nitrones or to cyclization products. In one particular example involving an isoxazol-5-(2H)-one derivative rate enhancement of rearrangement was indeed observed with ethoxide ion. It is tentatively attributed to ring opening of the cyclic N-O ester to the N-oxyanion ethyl ester followed by rearrangement and subsequent reclosure. Alternative methods to accelerate the process by generating a partial or complete positive charge on the nitrogen atom led only to desilylation.

Studies of some cocondensations of nickel atoms with unsaturated organic ligands and with mixed ligand systems

The cocondensation of nickel with a number of unsaturated ligands was studied, as was the cocondensation with a number of mixed ligand systems. Enamines were found not to react with nickel while acrylonitrile was polymerized. In the mixed ligand syst.ems different products were obtained than when the ligands were cocondensed individually. Cocondensations of benzyl halide/allyl halide mixtures gave unstable products that were not observed when the halides were cocondensed individually. The effect of Kao-Wool insulation on nickel/benzyl halide cocondensations was found to be significant. Kao-Wool caused the bulk of the benzyl halide to be polymeri zed to a number of poly-benzylic species. An alkali metal reactor was designed for the evaporation of sodium and potassium atoms into cold solutions of metal halide and an or ganic substrate. This apparatus was used to synthesize Ni(P¢3 )3' but proved unsuccessful for synthesizing a nickel-enamine compound.

DFT Studies of the Organocatalytic Aldol Reaction and a Frustrated Lewis Pair

The computational study, and in particular the density functional theory (DFT) study of the organocatalytic α-chlorination-aldol reaction and the chiral backbone Frustrated Lewis Pair (FLP) system served as a valuable tool for experimental purposes. This thesis describes methods to consider different transition states of the proline- catalyzed α-chlorination aldol reaction to determine the reasonable transition state in the reaction between the enamine and α-chloro aldehydes. Moreover, the novel intramolecular Frustrated Lewis pair based on a chiral backbone for the asymmetric hydrogenation of imines and enamines was designed and the ability of hydrogen splitting by this new FLP system was examined by computational modeling and calculating the hydrogen activation energy barrier.

Estudo sobre o uso do pentacloreto de nióbio, como ácido de Lewis, na síntese de enaminas através da reação de adição de Michael

The NbCl5 being a strong electrophile, is a potential candidate to act as a Lewis acid, and therefore it mediates various organic reactions. For this reason, it has received continuous attention by Brazilian researchers, especially in recent decades, since Brazil holds the largest reserves of niobium, besides being the largest producer of this element. The Michael addition reaction is one of the most widely used for forming carbon-carbon bonds and takes place by the addition of nucleophiles to activated olefins. Although this type of reaction is usually catalyzed by base, there are reports in the literature on the use of various Lewis acids in this type of reaction. The synthesis of enamines based acetilenodicarboxilates and amines, aromatic or alkyl, by Michael addition reaction is quite interesting, since these are valuable synthetic intermediates for the synthesis of heterocyclic and they are used in multicomponent reactions. The derivatives of anilino-fumarate also have a great potential for medical application. In this study we investigated the use of niobium pentachloride as Lewis acid to catalyze the Michael additions between the derivatives of aniline and acetilenodicarboxilates the synthesis of enamines

Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters

Carbon-carbon and carbon-heteroatom bond formations constitute the central events in organic synthesis. In view of this, much of the research in organic synthesis has been focused on devising novel and efficient methods for such bond constructions. In general, polar, pericyclic and radical methodologies are employed for this purpose. The polar and radical reactions proceed via reactive intermediates such as carbanions, enols/enolates, enamines, carbocations, radical cations, radical anions, carbenes, zwitterions etc. In recent years, there has been enormous interest in the chemistry of zwitterionic species largely from the standpoint of their applications in multicomponent reactions (MCRs) and organocatalytic reactions. Zwitterions formed by the addition of nucleophiles to electrophilic π-systems such as acetylenic esters and azoesters have been the subject of extensive investigations; their synthetic utility, however, remained largely unexplored. Investigations in a number of laboratories, including our own, have shown that zwitterions of the type mentioned above on reaction with electrophiles give rise to carbo- and heterocyclic products by 1,3- or 1,4-dipolar cycloadditions. Recently, allenoates, another class of active π-systems were introduced to this field. Against this background, a systematic investigation of the reactions of various zwitterions derived from allenoates with different electrophiles especially 1,2-diones, were carried out. The results of these studies are embodied in the thesis entitled “Novel Synthesis of Carbocycles and Heterocycles Employing Zwitterions Derived from Allenic Esters”.