Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

Eco-friendly and facile synthesis of 2-substituted-1H-imidazo[4,5-b]pyridine in aqueous medium by air oxidation

We report a new environmentally-benign, convenient, and facile methodology for the synthesis of 2-substituted-1H-imidazo[4,5-b]pyridine. The reaction of 2,3-diaminopyridine with substituted aryl aldehydes in water under thermal conditions without the use of any oxidative reagent has been studied. The reaction has yielded 1H-imidazo[4,5-b]pyridine derivatives by an air oxidative cyclocondensation reaction in one step in an excellent yield. Furthermore, a series of compounds were synthesized and characterized by melting point, EI-MS, NMR, and IR tools. For comparison, the reference samples were prepared by the reported method. Utilization of aqueous medium, easy reaction conditions, isolation, and purification make this manipulation very interesting from an economic and environmental perspective.     

Synthesis of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives via a one-pot four-component reaction

A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyrazol-5-amine in the presence of p-toluenesulfonic acid as a catalyst has been developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives is produced under mild reaction conditions and in good yields at ambient temperature.     

Synthesis of new steroidal derivatives by the reaction of steroid-amino acid conjugates with N,N′-dicyclohexyl-carbodiimide. Unusual formation of steroidal imide derivatives

Several new steroid derivatives have been synthesised by the reaction of steroid-amino acid conjugates with N,N′-dicyclohexyl-carbodiimide. Selectivity of the reaction was found to depend greatly on the properties of the amino acid moiety. While the reaction of the glycine derivative led to the corresponding 5(4H)-oxazolone, an unusual imide formation together with an N-acylurea side product was observed in the case of conjugates of l-alanine, l-phenylalanine and l-methionine. The structures of the new products, steroidal imide and N-acylurea derivatives, were determined by various spectroscopic methods.     

A theoretical investigation on the mechanism of the α,α-diphenylprolinol trimethylsilyl ether-catalyzed oxyamination reaction

A theoretical investigation on the reaction mechanism of a chiral prolinol silyl ether-catalyzed oxyamination reaction strongly suggests that the reaction proceeds via an enol intermediate and not via an enamine intermediate. The catalyst generates the enol and forms an enol-catalyst complex. Nitrosobenzene subsequently reacts with the enol-catalyst complex to afford the (S)-N-nitroso aldol product. The proposed mechanism is able to account for the experimentally observed enantioselectivity.     

A novel and facile stereocontrolled synthetic method for polyhydro-quinolines and pyridopyridazines via a diene-transmissive Diels-Alder reaction involving inverse electron-demand hetero Diels-Alder cycloaddition of cross-conjugated azatrienes

Cross-conjugated azatrienes bearing an electron-withdrawing sulfonyl or benzoyl group on the nitrogen atom underwent, on heating or in the presence of a Lewis acid (TMSOTf), an initial inverse electron-demand hetero Diels-Alder reaction with electron-rich dienophiles (vinyl ether, vinyl thioether, and allenyl ether) to produce 1:1 cycloadducts with high endo selectivity. The initial cycloadducts thus obtained underwent a second Diels-Alder reaction stereoselectively on the newly formed diene unit with electron-deficient dienophiles to give the crossed bis-cycloadducts, octahydroquinolines, with high diastereo-π-facial selectivity. The N-sulfonylazatrienes tethering an ortho-cinnamyloxyphenyl dienophile at the triene terminal underwent an initial intramolecular hetero Diels-Alder reaction of the inverse electron-demand type. The subsequent second Diels-Alder reaction of the formed mono-cycloadducts completed the diene-transmissive hetero Diels-Alder protocol to give benzopyrano[3,4-c]quinolines in a highly stereoselective manner.     

Ferric nitrate-promoted oxidative esterification of toluene with N-hydroxyphthalimide: Synthesis of N-hydroxyimide esters

A ferric nitrate-promoted cross-dehydrogenative coupling reaction of N-hydroxyphthalimide (NHPI) with toluene derivatives is reported. The reaction proceeded smoothly using molecular oxygen as an oxidant, providing an efficient method for the synthesis of N-hydroxyimide esters. Furthermore, a plausible mechanism was proposed.     

Organocatalyzed stereoselective construction of N-formylpiperidines via a Michael-aza-Henry-hemiaminalization reaction cascade

An efficient asymmetric synthesis of N-formylpiperidines via an organocatalytic Michael-aza-Henry-hemiaminalization reaction cascade of an aldehyde, a nitroalkene, and an N-arylideneformamide is reported. The reaction is triggered by diphenylprolinol trimethylsilyl ether and creates two C-C and one C-N bonds leading to the formation of highly enantio-enriched N-formylpiperidines with five contiguous chiral centers in a one-pot operation.     

Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: kinetics and application

N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.     

An unexpected route toward the synthesis of spiro-benzo[b]acridine-furan derivatives

A facile and straightforward procedure for the synthesis of spiro-benzo[b]acridine-6,2′-furan derivatives via the reaction between benzo[b]acridine-6,11-dione, electron-deficient acetylenic compounds, and an isocyanide is described. The benzo[b]acridine-6,11-dione is obtained from the reaction between 2-(aminomethyl)aniline and 2-hydroxynaphthalene-1,4-dione via an unexpected reaction pathway. The products are synthesized in medium to high yields and no complicated purification is required.     

E-selective isomerization of stilbenes and stilbenoids through reversible hydroboration

Hydroboration of a mixture of E and Z stilbenes and stilbenoids is followed by an elimination reaction to yield the E isomer with high stereoselectivity. The reaction tolerates aromatic substituents with varying stereoelectronic properties, occurs in one pot, and requires only commercially available reagents. An illustration of the isomerization reaction in a synthesis of resveratrol, a biologically active antioxidant, is presented.     

Asymmetric Mannich reactions catalyzed by proline and 4-hydroxyproline derived organocatalysts in the presence of water

The ability of amphiphilic catalysts based on proline and 4-hydroxyproline to catalyze the Mannich reaction in aqueous media is reported. With a 4-tert-butyldimethylsiloxy-substituted organocatalyst derived from N-prolylsulfonamide, the reaction of cyclohexanone with iminoglyoxylate proceeds with high enantioselectivity (>99% ee for the syn-diastereomer). This catalyst was also successfully applied in a reaction of an iminoglyoxylate with an aqueous tetrahydro-2H-pyran-2,6-diol to give the corresponding 2,3-disubstituted tetrahydropyridine with up to 95:5 dr and 98% ee.     

An efficient Darzens reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

An efficient DBU promoted Darzens reaction utilising α-haloketones containing an enolizable α′-hydrogen is reported. This method diastereoselectively afforded the corresponding α,β-epoxy ketones good to excellent yields in an one-pot reaction without using any transition metals or additives. Furthermore, haloketones without an α′-hydrogen are also applicable in this reaction.     

Cascade synthesis of selective dihydro pyridazino fused acridinone derivatives via MCM-41 catalyzed ring-opening/ring-closure reaction

An enhanced one-pot synthesis of new functionalized 5,6-dihydro-5,5-dimethyl-2-phenyl-2H-pyridazino[3,4,5-kl]acridin-1(4H)-one derivatives with different substituted patterns by using mesoporous MCM-41 catalyst via a ring opening/ring closure reaction process has been established. This MCM-41 silica catalyst has been synthesized and characterized using an array of sophisticated analytical techniques like BET, XRD, UHRTEM, etc. This reaction could be conducted from inexpensive substrates within short period under neat reflux conditions. Compared with the usual methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times and an environmentally friendly procedure.     

C-N bond formation followed by N-Cl bond breaking. One more and unexpected case of the formation of a hydroxamic group via heterolytic bond cleavage

An unexpected and previously unknown reaction sequence in the interactions of the acyl halides with nitrosobenzenes, which involves carbon-nitrogen bond formation followed by heterolytic nitrogen-chlorine bond cleavage giving the corresponding unsubstituted N-phenylalkylhydroxamic acids (or N-phenylarylhydroxamic acids) and chlorine as the products has been observed. The kinetic and other evidence obtained suggest that the carbon-nitrogen bond formation is the consequence of a nucleophilic interaction of an N-phenylchlorohydroxylamine intermediate, formed in the first reaction step, with the acyl halide in the second step of the complex sequence, which leads to an N-acyl-N-chlorophenylhydroxylamine cation intermediate. The key reaction step involves the interaction of an N-acyl-N-chlorophenylhydroxylamine cation intermediate with chloride ion, which leads to the N-Cl heterolytic bond cleavage and the final formation of the hydroxamic group and a molecule of chlorine.     

Stereospecific deoxydichlorocyclopropanation of expoxides by dichlorocarbene generated in an emulsifying system

The reaction of epoxides with dichlorocarbene generated in an emulsifying system was investigated. The products were the corresponding dichlorocyclopropane derivatives. The reaction of cis- and trans-β-methylstyrene oxides showed the reaction was completely stereospecific. Styrene oxide gave the corresponding dichlorocyclopropane and styrene, where the concentration of the latter was kept in the nearly stationary state during the reaction. Further the competitive reaction of α- and β-methylstyrene oxide showed that introduction of an additional Me group at the α-position accelerated the reaction only 12 times. From these observations the reaction was concluded to involve the two step process, namely, the deoxygenation process and dichlorocyclopropanation process, both of which were stereospecific and practically concerted.     

New opinions on the amidoalkylation of hydrophosphorylic compounds

A new and milder version of the procedure for the synthesis of N-protected α-aminoalkylphosphorylic compounds by reaction of alkyl carbamates, aldehydes and hydrophosphorylic compounds in acetic anhydride/acetyl chloride and a new mechanism for this type of reaction are described. The isolation, for the first time, of N,N′-benzylidene- and N,N′-alkylidenebiscarbamates as intermediates from the reaction medium and studies of the direct reaction of pre-obtained biscarbamates and hydrophosphorylic compounds in acetic anhydride are reported. A new version of the mechanism for this reaction which includes an Arbuzov-type reaction is proposed.     

Competitive thermal ene reaction and Diels-Alder reactions of 2-[N-(alk-2-enyl)benzylamino]-3-vinylpyrido[1,2-a]pyrimidin-4(4H)-ones

Thermal reaction of 2-[N-(alk-2-enyl)benzylamino]-3-(2-substituted and 2,2-disubstituted)vinylpyrido[1,2-a]pyrimidin-4(4H)-ones gave azepine, the desired ene products, and/or pyran derivatives. The formation of the latter was responsible for the [4+2] cycloaddition reaction between the α,β-unsaturated ester carbonyl moiety as a diene part and the alkenylamino moiety as an ene one. The reaction features depended upon the kinds of substituents both on the vinyl and alkenyl counterparts; strongly electron-withdrawing substituents on the vinyl moiety or an electron-donating substituent on the alkenyl one changed the reaction feature from the ene reaction to the hetero Diels-Alder reaction.     

Synthesis of pyrimidine-containing 3-aminobutenolides

An efficient synthesis of pyrimidine-containing butenolides is reported, starting from C-alkoxycarbonyl isoxazolidines. Two competitive reaction routes are operating: the pathway leading to homo-N,O-nucleosides, based on the reduction of an ester group at C₃, and the reaction channel leading to butenolides promoted by the removal of the hydrogen atom at C₃. The two reaction pathways can be easily controlled according to the adopted experimental conditions