Several diarylamines in the benzo[b]thiophene series were
prepared in good to high yields by palladium-catalysed amination
of ethyl 3-bromobenzo[b]thiophene-2-carboxylate
with anilines and 5-aminoindole in the presence of Pd(OAc)2,
BINAP and Cs2CO3 in toluene. The presence of the ester
group at the 2-position of the benzo[b]thiophene moiety increases
the yields and lowers the heating times relative to the
reactions performed with 3-bromobenzo[b]thiophene. When
aminopyridines were used instead of anilines, the ligand and
the solvent need to be changed to XANTHPHOS and dioxane
in the amination reaction. With 2-aminopyridine a onepot
C−N coupling and intramolecular cyclization involving
the nitrogen atom of the pyridine ring occurred, with loss of ethanol, giving an interesting fluorescent tetracyclic heteroaromatic
compound. The antimicrobial activity, the minimal
inhibitory concentrations (MICs) and the structure-activity
relationships (SARs) were evaluated. A selectivity with
low MICs was observed against Bacillus Cereus, and good
results were also obtained against Candida albicans. The acids
obtained by hydrolysis of the ester group, as non-proteinogenic
α,β-unsaturated β-amino acids, can be incorporated
into peptide chains to induce conformational constraints.
Compostos heterociclos estão muito presentes em nossas vidas, desde processos biológicos até em fármacos. Dentre esses compostos, os carbazóis, vem ultimamente se mostrando promissores como alternativa terapêutica para diversas doenças, principalmente para o câncer. Muitos carbazóis são produtos naturais, como é o caso das Claurailas A-D. Baseando-se na estrutura da Clauraila A, esse trabalho propôs o desenvolvimento de uma biblioteca de análogos desse alcaloide a fim de prospecção biológica. Para a síntese da Clauraila A foram estudadas condições ideais da ciclodeidrogenação da diarilamina precursora desse alcaloide, através da reação de Åkermark-Knölker. Para a obtenção dessa diarilamina, foi realizado uma otimização da reação de aminação de Buchwald-Hartwig. Com o processo otimizado, foram obtidos diversos carbazóis, com diferentes padrões de substituição, em rendimentos bons à moderados, entre eles estão os produtos naturais 6-metoximurraianine e Clausenal. O rendimento global obtido na síntese desses produtos naturais e da Clauraila A são semelhantes aos previamente descritos na literatura, no entanto, em nosso trabalho foi realizada a síntese deste alcaloide em número reduzido de etapas. Durante o processo de otimização da reação de Åkermark-Knölker foi demonstrado...
Several diarylamines in the benzo[b]thiophene series were prepared by palladium catalyzed amination of ethyl 3-bromobenzo[b]thien-2-yl carboxylate with anilines and 5-aminoindole, in good to high yields using Pd(OAc)2, BINAP, Cs2CO3 in toluene. The presence of the ester group in the position 2 of the benzo[b]thiophene moiety increases the yields and lowers the heating times when compared with reactions using 3-bromobenzo[b]thiophene. When aminopyridines, instead of anilines, were used the ligand and the solvent need to be changed to XANTHPHOS and dioxane in the amination reaction. From 2-aminopyridine a one pot C-N coupling and intramolecular cyclization involving the nitrogen of the pyridine, with lost of ethanol, occurred giving an interesting fluorescent tetracyclic heteroaromatic compound. The antimicrobial activity, the minimal inhibitory concentration (MIC) and structure-activity relationships (SAR) were evaluated. A selectivity with low MICs was observed against Bacillus Cereus and good results were also obtained against Candida albicans. The acids obtained by hydrolysis of the ester group, as non proteinogenic alpha,beta-unsaturated beta-amino acids can be incorporated in a peptide chain to induce conformational constraints.; Fundação para a Ciência e Tecnologia.
The present study was designed to determine: (i) the role of the reductive amination of alpha-ketoglutarate via the glutamate dehydrogenase reaction in furnishing mitochondrial glutamate and its transamination into aspartate; (ii) the relative incorporation of perfusate 15NH4Cl, [2-15N]glutamine or [5-15N]glutamine into carbamoyl phosphate and aspartate-N and, thereby, [15N]urea isotopomers; and (iii) the extent to which perfusate [15N]aspartate is taken up by the liver and incorporated into [15N]urea. We used a liver-perfusion system containing a physiological mixture of amino acids and ammonia similar to concentrations in vivo, with 15N label only in glutamine, ammonia or aspartate. The results demonstrate that in perfusions with a physiological mixture of amino acids, approx. 45 and 30% of total urea-N output was derived from perfusate ammonia and glutamine-N respectively. Approximately two-thirds of the ammonia utilized for carbamoyl phosphate synthesis was derived from perfusate ammonia and one-third from glutamine. Perfusate [2-15N]glutamine, [5-15N]glutamine or [15N]aspartate provided 24, 10 and 10% respectively of the hepatic aspartate-N pool, whereas perfusate 15NH4Cl provided approx. 37% of aspartate-N utilized for urea synthesis...
Carbohydrate-protein conjugates are utilized extensively in basic research and as immunogens in a variety of bacterial vaccines and cancer vaccines. As a result, there have been significant efforts to develop simple and reliable methods for the construction of these conjugates. While direct coupling via reductive amination is an appealing approach, the reaction is typically very inefficient. In this paper, we report improved reaction conditions providing an approximately 500% increase in yield. In addition to optimizing a series of standard reaction parameters, we found that addition of 500 mM sodium sulfate improves the coupling efficiency. To illustrate the utility of these conditions, a series of high mannose BSA conjugates were produced and incorporated into a carbohydrate microarray. Ligand binding to ConA could be observed and apparent affinity constants (Kds) measured using the array were in good agreement with values reported by surface plasmon resonance. The results show that the conditions are suitable for microgram scale reactions, are compatible with complex carbohydrates, and produce biologically active conjugates.
A highly selective and general Pd/sulfoxide-catalyzed allylic C—H amination reaction en route to syn-1,3-amino alcohol motifs is reported. Key to achieving this reactivity under mild conditions is the use of electron-deficient N-nosyl carbamate nucleophiles that are thought to promote functionalization by furnishing higher concentrations of anionic species in situ. The reaction is shown to be orthogonal to classical C—C bond forming/reduction sequences as well as nitrene-based C—H amination methods.
Copper and germanium complexes of β-substituted nitrocorroles were reacted with 4-amino-4H-1,2,4-triazole to give the corresponding β-amino-β-nitro derivatives, in moderate to good yields. This is the first successful example of a vicarious nucleophilic substitution performed on corrole derivatives, because the same reaction carried out on silver complexes afforded the corresponding 6-azahemiporphycenes by way of corrole ring expansion. The first step of this work is related to the modification of a synthetic protocol for preparation of the β-substituted nitro corroles. The nitration reaction was carried out on a copper corrole using NaNO2 as the primary source of NO2− coupled with AgNO2 used as oxidant. By variation of the molar ratio of the reagents it was possible to direct the product distribution towards mono- and di-nitro derivatives. The reaction between mono- and di-nitro derivatives of (TtBuCorrCu) with 4-amino-4H-1,2,4-triazole gave good results, leading to the isolation of 2,3-(NH2)(NO2)-TtBuCorrCu and 2,18-(NH2)2-3,17-(NO2)2-TtBuCorrCu in moderate yields. To elucidate factors that influence the reaction, and to highlight the different behavior observed for different metal complex substrates, the electrochemistry of three copper complexes...
Intermolecular Ritter-type C–H amination of unactivated sp3 carbons has been developed. This new reaction proceeds under mild conditions using readily available reagents and an inexpensive source of nitrogen (acetonitrile). A broad scope of substrates can be aminated with this method since many functional groups are tolerated. This reaction also allows for the direct, innate C–H amination of a variety of hydrocarbons such as cyclohexane without the need of prefunctionalization or installation of a directing group.
We have applied an ambient ionization technique, desorption electrospray ionization MS, to identify transient reactive species of an archetypal C–H amination reaction catalyzed by a dirhodium tetracarboxylate complex. Using this analytical method, we have detected previously proposed short-lived reaction intermediates, including two nitrenoid complexes that differ in oxidation state. Our findings suggest that an Rh-nitrene oxidant can react with hydrocarbon substrates through a hydrogen atom abstraction pathway and raise the intriguing possibility that two catalytic C–H amination pathways may be operative in a typical bulk solution reaction. As highlighted by these results, desorption electrospray ionization MS should have broad applicability for the mechanistic study of catalytic processes.
We recently reported that the aldehyde residue of an abasic (Ap) site in duplex DNA can generate an interstrand cross-link via reaction with a guanine residue on the opposing strand. This finding is intriguing because the highly deleterious nature of interstrand cross-links suggests that even small amounts of Ap-derived cross-links could make a significant contribution to the biological consequences stemming from the generation of Ap sites in cellular DNA. Incubation of 21-bp duplexes containing a central 5′-CAp sequence under conditions of reductive amination (NaCNBH3, pH 5.2) generated much higher yields of cross-linked DNA than reported previously. At pH 7, in the absence of reducing agents, these Ap-containing duplexes also produced cross-linked duplexes that were readily detected on denaturing polyacrylamide gels. Cross-link formation was not highly sensitive to reaction conditions and, once formed, the cross-link was stable to a variety of work-up conditions. Results of multiple experiments including MALDI-TOF mass spectrometry, gel mobility, methoxyamine capping of the Ap aldehyde, inosine-for-guanine replacement, hydroxyl radical footprinting, and LCMS/MS were consistent with a cross-linking mechanism involving reversible reaction of the Ap aldehyde residue with the N2-amino group of the opposing guanine residue in 5′-CAp sequences to generate hemiaminal...
Enamines and enamides are useful synthetic intermediates and common components of bioactive compounds. A new protocol for their direct synthesis by a net alkene C–H amination and allylic amination by using catalytic CuII in the presence of MnO2 is reported. Reactions between N-aryl sulfonamides and vinyl arenes furnish enamides, allylic amines, indoles, benzothiazine dioxides, and dibenzazepines directly and efficiently. Control experiments further showed that MnO2 alone can promote the reaction in the absence of a copper salt, albeit with lower efficiency. Mechanistic probes support the involvement of nitrogen-radical intermediates. This method is ideal for the synthesis of enamides from 1,1-disubstituted vinyl arenes, which are uncommon substrates in existing oxidative amination protocols.
A series of copper(I) alkylamide complexes have been synthesised; copper(I) dicyclohexylamide (1), copper(I) 2,2,6,6-tetramethylpiperidide (2), copper(I) pyrrolidide (3), copper(I) piperidide (4), and copper(I) benzylamide (5). Their solid-state structures and structures in [D6]benzene solution are characterised, with the aggregation state in solution determined by a combination of DOSY NMR spectroscopy and DFT calculations. Complexes 1, 2 and 4 are shown to exist as tetramers in the solid state by X-ray crystallography. In [D6]benzene solution, complexes 1, 2 and 5 were found by using 1H DOSY NMR to exist in rapid equilibrium between aggregates with average aggregation numbers of 2.5, 2.4 and 3.3, respectively, at 0.05 m concentration. Conversely, distinct trimeric, tetrameric and pentameric forms of 3 and 4 were distinguishable by one-dimensional 1H and 1H DOSY NMR spectroscopy. Complexes 3–5 are found to react stoichiometrically with iodobenzene, in the presence or absence of 1,10-phenanthroline as an ancillary ligand, to give arylamine products indicative of their role as potential intermediates in the modified Ullmann reaction. The role of phenanthroline has also been explored both in the stoichiometric reaction and in the catalytic Ullmann protocol.
Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2010.; Part I. Asymmetric Diels-Alder Reaction of Cyclic Isoimidium Salts
The asymmetric Diels-Alder reaction of cyclic isoimidium salts are described. The corresponding cycloadducts are obtained with high regioselectivity and excellent diastereoselectivity (> 99:1). In addition the chiral amine can be efficiently recovered by converting the cycloadducts to enantiomerically pure y-lactones.
Part II. Total Synthesis of a Camphor Derived Dimer
A short and efficient synthesis of a potentially potent anticancer agent, a Camphor Derived Dimer, from (+)-camphoric anhydride is described. The synthesis was accomplished in eleven steps employing key reactions of a Curtius rearrangement, a mono-alkylation, a reductive amination and a coupling transformation between a camphor derived aziridine and a camphor derived secondary amine.
Part III. Asymmetric Cyclopropanation Catalyzed by Chiral Camphor-based Dirhodium(II) Complex:
A series of novel camphor-based dirhodium(II) complexes have been synthesized efficiently. Asymmetric cyclopropanation using chiral camphor-based dirhodium(II) complex as catalyst was described. Promising enantioselectivity (up to 60%) have been achieved by ligand modifications in preliminary studies.
Retro-peptides are peptidomimetics that present the direction of the amino acidic sequence reversed. A classical retro modification can be obtained by the introduction of the malonyl unit followed by a gem-diaminic unit, that can result in an increase of proteolysis resistance of the related parent peptide, retarding degradation and consequently enhancing therapeutic efficacy.This thesis aims at developing synthetic stategies to synthesize new interesting building blocks for the construction of peptidomimetics containing a retro modification.In this field Meldrum’s acid is recently reported as a useful scaffold to obtain non-symmetric disubstituted malonamides rAA-mGly-AA′ as building blocks for the synthesis of retro-peptides. The attention has been turned towards the synthetic elaboration of different rAA-mGly-AA′ with the aim of introducing, into the malonamide backbone, the olefinic moiety by a Knoevenagel condensation, obtaining correspondig malonyl dehydro peptides MDHPs.The investigation of a further elaboration was carried out to obtain the corresponding epoxy and aziridino peptides,interesting building blocks containing electrophilic sites known to react with nucleophilic amino acids within the active site of proteases. Starting from L-amino acids...
Src homology 3 (SH3) domains are highly conserved protein-protein interaction domains that mediate important biological processes and are considered valuable targets for the development of therapeutic agents. In this paper, we report the preparation of a range of new 6-heterocyclic substituted 2-aminoquinolines using Buchwald-Hartwig chemistry. 6-Heterocyclic substitution of the 2-aminoquinoline has provided ligands with increased binding affinity for the SH3 domain relative to the lead compound, 2-aminoquinoline, that are the highest affinity ligands prepared to date. The key step in the synthesis of these compounds required a selective Buchwald-Hartwig amination of an aryl bromide in the presence of an activated heteroaryl chloride. The optimization of reaction conditions to achieve the selective amination is discussed and has allowed for cross-coupling with a range of cyclic amines. Introduction of the amino functionality of the 6-heterocyclic 2-aminoquinolines involved additional Buchwald-Hartwig chemistry utilizing lithium bis(trimethylsilyl)amide as an ammonia equivalent.; Jessica A. Smith, Rhiannon K. Jones, Grant W. Booker and Simon M. Pyke
A number of 2-chlorobenzophenones, containing
electron releasing groups (e.g. hydroxy, thiomethoxy and
methoxy) in the 4' - position, were prepared by the Friess
rearrangement, or the Friedel-Crafts reaction. These
ketones, when treated with potassamide in liquid ammonia,
underwent partial Haller-Bauer scission, unlike 2-chlorobenzophenone
which is known to undergo complete scission.
Under similar conditions 4-nitrobenzophenone
also underwent partial scission, but the main reaction in
this case was nucleophilic amination of the nitro containing
ring. This amination reaction was shown not to be a useful
general reaction for aromatic nitro compounds.
3-Methylxanthone was then prepared by treatment
of 2- and 3- chloro-2'-hydroxy-5'-methylbenzophenone with
. little, if any, attendant scission. The corresponding 2fluoro-
compound also gave the xanthone, but as the 3-fluoro
compound did not, it was concluded that the 2-fluoro compound
reacted through a nucleophilic substitution mechanism, rather
than the benzyne mechanism invoked for the chloro and bromo
3-Methylthioxanthone was synthesised by treatment
of methyl 4-tolyl sulphide and 2-chlorobenzoyl chloride
with aluminum chloride in carbon disu1phide, followed.by heating.
This compound was also prepared by treatment of 3-chloro-2'thiomethoxy-
5'-methylbenzophenone with potassamide in liquid
Developing new catalyst systems for cross-coupling reactions such as Buchwald-Hartwig aminations has been one of the remarkable topics in the palladium-catalyzed, cross-coupling reaction research area.
In this thesis, the use of the easily synthesized and handled Pd(η3-1-Ph-C3H4)(η5-C5H5) (I) as a catalyst precursor for Buchwald-Hartwig amination of aryl halides was investigated utilizing various phosphines (PtBu3, Xphos and Mor-Dalphos), different phosphine (L) to Pd ratios (L:Pd = 2:1 and 1:1) and different procedures; in situ generation of PdLn prior to addition of other reactants (Method A) and in situ generation of PdLn in the presence of aryl halide but prior to the addition of other reactants (Method B). The reaction profiles are monitored by gas chromatography (GC) and the effect of each of the mentioned parameters on the reaction rate is determined. The reaction profiles of I with various phosphines are also compared with those of other precursors, Pd2(dba)3, Pd(OAc)2 and [Pd(η3-1-Ph-C3H4)Cl]2 (IV).
In spite of a large number of studies involving modification of Buchwald-Hartwig amination reactions by developing new precursors and phosphines, fewer studies have been carried out on catalytic mechanisms and there is still ambiguity about the catalytically active species in these palladium-catalyzed reactions. This study on a representative Buchwald-Hartwig amination finds that...
Direct amination of heteroarenes and arenes has been achieved in a one-pot C–H zincation/copper-catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using C–H amination methods. The mild reaction conditions and good functional-group compatibility demonstrate its great potential for the synthesis of important and complex amines.
Allylic amines are important and fundamental building blocks due to their wide-spread occurrence in many natural products and the ability to further functionalize them by transformations on the double bond to generate a diverse range of compounds. Transition-metal catalyzed allylic substitution represents an attractive and efficient approach towards the synthesis of these allylic amines. However, limitations associated with the traditional methods developed for such allylic amination in terms of regiospecificity, atom economy and generality in these transformations, combined with the importance of allylic amination, prompted us to develop novel atom efficient and regiospecific methods for their synthesis.
A 1:1 mixture of AuCl[P(t-Bu)2o-biphenyl] (5 mol %) and AgSbF6 (5 mol %) catalyzed the intermolecular amination of underivatized allylic alcohols with 1-methyl-2-imidazolidinone and related nucleophiles. The first examples of intermolecular allylic amination was developed that in the case of gamma-unsubstituted and gamma-methyl-substituted allylic alcohols, occurred with high gamma-regioselectivity and syn-stereoselectivity.
A 1:1 mixture of AuCl[P(t-Bu)2o-biphenyl] (5 mol %) and AgSbF6 (5 mol %) also served as a very efficient catalytic system for the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. The protocol was effective for a range of secondary as well as primary alkylamines as nucleophiles with different substitutions on the alkyl chain tethering the nucleophile to the allylic alcohol. The method was also extended towards the total synthesis of the naturally occurring alkaloid (S)-(+)-coniine in two steps from the starting (R...
Preparation of a small library of secondary amino acids was achieved by
solution-phase organic synthesis using reductive amination reactions with
selected cc-amino acids and aromatic aldehydes. Reductive amination employing
sodium triacetoxyborohydride instead of sodium cyanoborohydride was found to
give shorter reaction times and much safer byproducts. With less sterically
hindered a-amino acids, direct reductive amination generally yielded the
bisalkylated product. However, monoalkylation was achieved by adopting an
indirect reductive amination route. Reaction mixtures were characterized by
HPLC and LC-MS, resulting in the synthesis of a 21 compound library.