Synthesis of polyhydroxylated 2H-azirines and 2-halo-2H-azirines from 3-azido-2,3-dideoxyhexopyranoses by alkoxyl radical fragmentation

The reaction of 3-azido-2,3-dideoxypyranose and 3-azido-2,3-dideoxy-2-halohexopyranose compounds with (diacetoxyiodo)benzene and iodine generated 2-azido-1,2-dideoxy-1-iodoalditols and 2-azido-1,2-dideoxy-1-halo-1-iodoalditols, respectively. These beta-iodo azides could be transformed by chemoselective dehydroiodination into 2-azido-1,2-dideoxy-4- O-formyl-pent-1-enitols and (Z, E)-2-azido-1,2-dideoxy-1-halo-4- O-formyl-pent-1-enitols in good yields. Thermolysis and photochemical studies of these vinyl azides and 1-halovinyl azides for the synthesis of polyhydroxylated 3-alkyl-2 H-azirines and the hitherto unknown 2-halo-3-alkyl-2 H-azirines have also been accomplished.     

Synthesis of highly functionalized chiral nitriles by radical fragmentation of beta-hydroxy azides. Convenient transformation of aldononitriles into 1,4- and 1,5-iminoalditols

The synthesis of highly functionalized nitriles by an alkoxyl radical fragmentation of cyclic beta-hydroxy azides is described. The alkoxyl radicals were generated by reaction of the alcohols with (diacetoxyiodo)benzene and iodine under mild conditions compatible with the presence of sensitive substituents and the protective groups most frequently used in carbohydrate chemistry. To explore the scope and limitations of this methodology, experiments were carried out using a variety of beta-hydroxy azides of the carbohydrate (1-6, 33, and 41), monoterpenoid (21 and 22), and steroid (23-25) families of natural products. Of special interest are the aldopentonitriles (15-18, 34, and 42) and aldotetrononitriles (19 and 20) synthesized from the corresponding 2-azido-2-deoxycarbohydrates. To demonstrate the versatility of these aldononitriles as chiral synthons, 1,4-imino-1-deoxysugar (37) and 1,5-imino-1-deoxysugar (43) analogues of the polyhydroxypyrrolidine and -piperidine types were prepared.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

Reactions of fullerene C60 with organometallic azides

Reactions of fullerene C₆₀ with organometallic azides [Et₂AlN₃, EtAl(N₃)₂ and Bu₃SnN₃] led to novel 1-azido-2-alkylfullerenes. The structures of the products were confirmed by IR, ¹Н and ¹³C NMR spectroscopy and MALDI TOF mass spectrometry.     

Orthogonal synthesis of pyrroles and 1,2,3-triazoles from vinyl azides and 1,3-dicarbonyl compounds

Tri- and tetrasubstituted N-H pyrroles were prepared by the simple treatment of vinyl azides with 1,3-dicarbonyl compounds in toluene at 100 °C via 2H-azirine intermediates generated in situ. When the reactions of vinyl azides and 1,3-dicarbonyl compounds were performed in DMF in the presence of a catalytic amount of K₂CO₃, 1-vinyl-1,2,3-triazoles were obtained via 1,3-dipolar cycloaddition. These methodologies exploited orthogonal modes of chemical reactivity of vinyl azides, which could be achieved by slight modification of the reaction conditions.     

C2-symmetric macrocyclic carbohydrate/amino acid hybrids through copper(I)-catalyzed formation of 1,2,3-triazoles

An efficient method was developed for the preparation of macrocyclic carbohydrate/amino acid hybrids by macrocyclization with copper(I)-catalyzed 1,2,3-triazole formation. Methyl 2-amino-6-azido-3,4-di-O-benzoyl-2,6-dideoxy-beta-D-glucopyranoside was prepared and coupled to two different N-propiolyl dipeptides (propiolyl-Tyr-Tyr-OH and propiolyl-Arg(Mtr)-Tyr-OH) to obtain bifunctional molecules carrying one azido group and one terminal alkyne. These bifunctional molecules were cyclodimerized using Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes to form macrocycles containing two 1,2,3-triazoles. Various cyclization methods were evaluated, and the most efficient conditions were found to be CuI and N,N-diisopropylethylamine in CH3CN.     

Synthesis of polysubstituted N-H pyrroles from vinyl azides and 1,3-dicarbonyl compounds

Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from alpha-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting from the same vinyl azides.     

Intermolecular [3 + 3]-cycloadditions of azides with the Nazarov intermediate

Tetrasubstituted 1,4-dien-3-ones undergo Nazarov cyclization at low temperature, followed by reaction with organic azides via an apparent [3 + 3]-cycloaddition to give bridged bicyclic triazenes. These products do not appear to be intermediates in the previously described Schmidt-type process to furnish dihydropyridones. The reaction typically occurs with high diastereoselectivity.     

Synthesis of aryl azides and vinyl azides via proline-promoted CuI-catalyzed coupling reactions

The coupling reaction of aryl halides or vinyl iodide with sodium azide under catalysis of CuI/L-proline works at relatively low temperature to provide aryl azides or vinyl azides in good to excellent yields.     

Asymmetric Schmidt reaction of hydroxyalkyl azides with ketones

An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed.     

A simple green procedure for the synthesis of 2H-azirines

An efficient and environmentally friendly method preparing 2H-azirines in good yield has been achieved by microwave irradiation of vinyl azides in solvent free conditions.     

Lewis acid-mediated reactions of alkyl azides with alpha,beta-unsaturated ketones

[reaction: see text] Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt reaction, but this reaction does not proceed when alpha,beta-unsaturated ketones are used. In this study, alkyl azides were reacted with enones in the presence of Lewis acids to give enaminones (vinylogous amides), which formally involve a ring contraction reaction. The mechanism and scope of this reaction is discussed.     

Efficient amidation from carboxylic acids and azides via selenocarboxylates: application to the coupling of amino acids and peptides with azides

A facile one-pot procedure for the coupling of carboxylic acid and azide via selenocarboxylate and selenatriazoline has been developed and successfully applied to the coupling of amino acids and peptides with azides. Selenocarboxylates are readily prepared by the reaction of the activated carboxylic acids with LiAlHSeH under mild conditions. The selenocarboxylates formed in situ are used to react directly with azides to form the corresponding amides via a selenatriazoline intermediate. Excellent yields were obtained for electron-deficient azides, and moderate to good yields were obtained for electron-rich azides. The selenocarboxylate/azide amidation reaction is clean and chemoselective. It provides an attractive alternative method to the conventional acylation of amines when an amide bond needs to be formed without going through an amine intermediate.     

Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins

The discovery, study, and implementation of the Co- and Mn-catalyzed hydrohydrazination and hydroazidation reactions of olefins are reported. These reactions are equivalent to direct hydroaminations of C-C double bonds with protected hydrazines or hydrazoic acid but are based on a different concept in which the H and the N atoms come from two different reagents, a silane and an oxidizing nitrogen source (azodicarboxylate or sulfonyl azide). The hydrohydrazination reaction using di-tert-butyl azodicarboxylate is characterized by its ease of use, large functional group tolerance, and broad scope, including mono-, di-, tri-, and tetrasubstituted olefins. Key to the development of the hydroazidation reaction was the use of sulfonyl azides as nitrogen sources and the activating effect of tert-butyl hydroperoxide. The reaction was found to be efficient for the functionalization of mono-, di-, and trisubstituted olefins, and only a few functional groups are not tolerated. The alkyl azides obtained are versatile intermediates and can be transformed to the free amines or triazoles without isolation of the azides. Preliminary mechanistic investigations suggest a rate-limiting hydrocobaltation of the alkene, followed by an amination reaction. Radical intermediates cannot be ruled out and may be involved.     

Revisiting the thermal decomposition of five <Emphasis Type="Italic">ortho</Emphasis>-substituted phenyl azides by calorimetric techniques

The thermal decomposition (TD) of 2-azidophenylmethanol (1), 2-azidobenzenecarbaldehyde (2), 1-(2-azidophenyl)-1-ethanone (3), (2-azidophenyl)(phenyl)methanone (4) and 1-azido-2-nitrobenzene (5) was analysed by DSC, TG and C80 calorimetric techniques under both oxidative and non-oxidative conditions. The TD of these azides in solution is well known to give the corresponding benzoxazoles, generally in good yields, with the exception of azide 1. When both the outcomes from the solid phase and in ‘solution phase’ TD reactions combined with the results from EI-MS experiments were considered, sufficient information was available to estimate the azides intrinsic molecular reactivity (MIR).     

Reactions of fluoroalkanesulfonyl azides with cyclic vinyl ethers

The addition reactions of fluoroalkanesulfonyl azides to dihydropyran or dihydrofuran were studied. These reactions do not give the corresponding N-fluoroalkanesulfonyl azilidines but N-fluoroalkanesulfonyl-tetrahydropyranon-2-imines or N-fluoroalkanesulfonyl-tetrahydro-furano-2-imines. The reaction mechanism is discussed.     

Studies in azide chemistry. Part 13 [1]. Intermolecular insertion of azide-derived polyfluorinated aryl- and heteroaryl-nitrenes into ring CH bonds of 1,3, 5-trimethyl- and 1,3,5-trimethoxy-benzene

Thermolysis of perfluoroazidobenzene, perfluoro-4- azidotoluene, perfluoro-4-azidopyridine, 4-azido-3- chlorotrifluoropyridine, and 4-azido-3, 5-dichlorodifluoropyridine (Ar_FN₃) in the presence of a large excess ($\text{ca}$. 10 molar) of 1,3,5-trimethyl- or 1,3,5-trimethoxy-benzene (ArH) gave the diarylamines expected from nitrene ‘insertions’ at nuclear CH bonds (Ar_FN₃ + ArH→Ar_FNHAr + N₂); product yields in the cases of the perfluorinated azides are the highest ever recorded for this type of reaction. By contrast, no recognisable products were obtained when either perfluoro-(2-azido-4-isopropylpyridine) or 2-azido- 4-chlorotrifluoropyridine were decomposed thermally in 1,3,5-trimethylbenzene.     

From azides to nitro compounds in a few seconds using HOF.CH3CN

HOF.CH3CN, a very efficient oxygen-transfer agent, was reacted with various azides to form the corresponding nitro compounds in excellent yields and in very short reaction times. The respective nitroso derivatives were found to be intermediates in this reaction. When the azides were reacted with MCPBA or DMDO, no reaction took place, and the starting materials were fully recovered.     

Amide bond formation from selenocarboxylates and aromatic azides

A new method of amide bond formation was developed through the reaction of potassium selenocarboxylates with aromatic azides at room temperature. Potassium selenocarboxylates were prepared in situ by the treatment of diacyl selenides with potassium methoxide at 5 °C under N₂. After the addition of azide, the reaction was allowed to gradually warm to room temperature and was stirred for 0.5-2 h. Excellent yields were obtained when electron deficient aromatic azides were used.     

Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones

New heterocyclic azides, ethyl 2-azido-4-R¹-5-R²-3-thiophenecarboxylates, were synthesized by diazotization of 2-aminothiophenes and subsequent treatment with sodium azide. The reactions of these heterocyclic azides with β-ketoesters and activated acetonitriles were studied. The derivatives of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine, a new ring system, were prepared in high yields via an anionic hetero-domino reaction.