Nucleophilic Azide Research Articles

Azidoindolines—From Synthesis to Application: A Review

Azide-containing compounds, organic azides, showcases a variety of reactivities, making them highly convenient and chameleonic intermediates. An indoline derivative has been proven to be of great significance in drug discovery due to its sp3-rich property. In this context, it is interesting to perform such vigorous azidation on medicinal-relevant indoles/indolines, resulting in the production of sp3-rich azidoindolines. The potential biological activity, in combination with the sp3-rich indoline bearing the azido moiety, makes azidoindolines an attractive synthetic target for medicinal and synthetic chemists. This review describes recent advances in the synthesis and application of azidoindolines: (1) iodine-mediated azidations, (2) metal-catalyzed azidations, (3) electrochemical azidations, (4) photochemical azidations, (5) azidation using a combination of an oxidant and an azide source, and (6) nucleophilic azidation.

Simple, catalytic C(sp3)-H azidation using the C-H donor as the limiting reagent.

C-N bonds play a critical role in pharmaceutical, agrochemical, and materials sciences, necessitating ever-better methods to forge this linkage. Here we report a simple procedure for direct C(sp3)-H azidation using iron or manganese catalysis and a nucleophilic azide source. All reagents are commercially available, the experimental procedure is simple, and we can use the C-H donor substrate as the limiting reagent, a challenge for many C-H azidation methods. Preliminary experiments are consistent with a hydrogen atom transfer (HAT)/radical ligand transfer (RLT) radical cascade mechanism and a wide variety of substrates can be azidated in moderate to high yields.

Cobalt-catalyzed regioselective hydroazidation of 1-aryl-1,3-dienes: facile access to allylic azides

A new cobalt-catalyzed hydroazidation of 1-aryl-1,3-dienes by using TMSN3 as a nucleophilic azide source under mild conditions has been reported, leading to the synthesis of a wide range of allylic azides with moderate to good yields.

Hypervalent silicate-assisted azidation approach for the substituted azepane motif

An efficient and stereospecific azidation of a cis-disubstituted azepane is described as the first example of hypervalent silicate-assisted nucleophilic azidation on a substituted seven-membered azepane ring. DFT calculations suggest an SN2-like mechanism whereby the azido nucleophile coordinated to the hypervalent silicate presents flexible geometries for the nucleophilic approach. The method provides a viable alternative to the classical Mitsunobu-based approaches in substituted seven-membered N-heterocycles with complex conformational properties.

Continuous-Flow Direct Azidation of Alcohols and Peroxides for the Synthesis of Quinoxalinone, Benzooxazinone, and Triazole Derivatives.

Continuous-flow reactors provide an ideal tool for the synthesis of potentially explosive but synthetically useful organic substances like organic azides due to their intrinsically small volume leading to very effective collision and highly controlled reaction conditions. Herein, we report the continuous-flow direct azidation of various alcohols by using TMSN3 as an azide transfer reagent in the presence of Amberlyst-15 as a recyclable catalyst. Numerous 3-hydroxy-2-oxindoles effectively undergo azide transfer to afford azide-functionalized quaternary stereocenters in a continuous-flow module. Interestingly, peroxyoxindole undergoes sequential skeletal rearrangement to generate a carbocation followed by nucleophilic azidation to afford a library of substituted 2-azido-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives under continuous flow. Furthermore, a continuous-flow Cu-catalyzed click reaction afforded triazole-functionalized deivatives. Next, reduction of azide in the presence of PPh3 affords the amine derivatives in good yields. The continuous-flow application was extended further for the thermolytic skeletal rearrangement of 3-azide-2-oxindole for the synthesis of biologically important quinoxalin-2(1H)-ones without any reagents. Furthermore, this continuous-flow direct azidation reaction is scaled up to 6.144 g of azides with a turnover number of 9.24 under safer conditions.

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols.

The efficient synthesis of two new stereoisomeric 3-aminocyclooctanetriols and their new halocyclitol derivatives starting from cis,cis-1,3-cyclooctadiene are reported. Reduction of cyclooctene endoperoxide, obtained by photooxygenation of cis,cis-1,3-cyclooctadiene, with zinc yielded a cyclooctene diol followed by acetylation of the hydroxy group, which gave dioldiacetate by OsO4/NMO oxidation. The cyclooctane dioldiacetate prepared was converted to the corresponding cyclic sulfate via the formation of a cyclic sulfite in the presence of catalytic RuO4. The reaction of this cyclic sulfate with a nucleophilic azide followed by the reduction of the azide group provided the target, 3-aminocyclooctanetriol. The second key compound, bromotriol, was prepared by epoxidation of the cyclooctenediol with m-chloroperbenzoic acid followed by hydrolysis with HBr(g) in methanol. Treatment of bromotriol with NaN3 and the reduction of the azide group yielded the other desired 3-aminocyclooctanetriol. Hydrolysis of the epoxides with HCl(g) in methanol gave stereospecifically new chlorocyclooctanetriols.

Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7-Deazapurine Ribonucleosides

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts.

Synthesis of (Z)-fluoroallyl azides through aluminium-mediated defluorinative functionalization reactions

The reaction of difluorohomoallyl alcohols with Me2AlCl in CH2Cl2 selectively gave (Z)-fluoroallyl chlorides via SN2′ type defluorinative chlorination. These chlorides were easily converted to the corresponding (Z)-fluoroallyl azides by the sequential nucleophilic azidation reaction using NaN3. Direct defluorinative azidation of the difluorohomoallyl alcohols was also achieved by treating with Me3SiN3 in the presence of Al(Oi-Pr)3. Fluoroallyl azides thus obtained successfully applied to the Huisgen 1,3-dipolar cycloaddition chemistry.

Unexpected Cyclization During the Mitsunobu Reaction of d-Talose ­Derivatives

A d -talose derivative underwent unexpected cyclization during a Mitsunobu reaction. A plausible pathway for the reaction involves an attack of the nucleophilic azide on the benzyl ring by intramolecular cyclization with loss of the benzyl group. These newly formed, unexpected compounds may be used in the synthesis of ­derivatives of C-nucleosides.

Zwitterionic biphenyl quinone methides in photodehydration reactions of 3-hydroxybiphenyl derivatives: laser flash photolysis and antiproliferation study

In aqueous media, photochemical excitation to S(1) of 3-phenylphenols 4-8 leads to deprotonation of the phenol OH, coupled with protonation of the benzyl alcohol and overall dehydration that delivers zwitterions 17-21. The zwitterions react with nucleophiles (CH(3)OH, CF(3)CH(2)OH and ethanolamine) converting them in high quantum yields to the corresponding adducts and photosolvolysis products (for photomethanolysis Φ~0.1-0.5). Zwitterions 20 and 21 were characterized by laser flash photolysis in CH(3)CN-H(2)O (τ~7.5 and 25 μs, respectively) and the associated quenching rate constants with nucleophiles azide and ethanolamine determined. In vitro studies of antiproliferative activity of the photochemicaly generated QMs and zwitterions formed from 2-, 3- and 4-phenylphenols were carried out on three human cancer cell lines HCT 116 (colon), MCF-7 (breast), and H 460 (lung). Irradiation of cells incubated with 3, 6, and 26 showed enhanced antiproliferative activity compared to the cells that were not irradiated.

ChemInform Abstract: Click to a Focused Library of Benzyl 6‐Triazolo(hydroxy)benzoic Glucosides: Novel Construction of PTP1B Inhibitors on a Sugar Scaffold.

AbstractAzides (III) bearing alkyl chain lengths ranging from 3 to 5C are synthesized from methyl hydroxylbenzoates, e.g. (I), via a straightforward two‐step sequence involving O‐alkylation followed by nucleophilic azide substitution.

1,4,7-Trimethyloxatriquinane: SN2 Reaction at Tertiary Carbon

The synthesis of 1,4,7-trimethyloxatriquinane (1), a 3-fold tertiary alkyl oxonium salt, is described. Compound 1 is inert to solvolysis with alcohols, even at elevated temperatures, but undergoes facile substitution with the strongly nucleophilic azide anion. Since an S(N)1 pathway is excluded, the only reasonable mechanistic interpretation for the reaction between 1 and N(3)(-) is S(N)2, despite the fact that substitution is occurring at a tertiary carbon center. This finding is supported by computational modeling and a study of the reaction kinetics, and is also consistent with observed solvent and salt effects.

Catalytic Mechanism of Retaining α-Galactosidase Belonging to Glycoside Hydrolase Family 97

Glycoside hydrolase family 97 (GH 97) is a unique glycoside family that contains inverting and retaining glycosidases. Of these, BtGH97a (SusB) and BtGH97b (UniProtKB/TrEMBL entry Q8A6L0), derived from Bacteroides thetaiotaomicron, have been characterized as an inverting α-glucoside hydrolase and a retaining α-galactosidase, respectively. Previous studies on the three-dimensional structures of BtGH97a and site-directed mutagenesis indicated that Glu532 acts as an acid catalyst and that Glu439 and Glu508 function as the catalytic base in the inverting mechanism. However, BtGH97b lacks base catalysts but possesses a putative catalytic nucleophilic residue, Asp415. Here, we report that Asp415 in BtGH97b is the nucleophilic catalyst based on the results of crystal structure analysis and site-directed mutagenesis study. Structural comparison between BtGH97b and BtGH97a indicated that OD1 of Asp415 in BtGH97b is located at a position spatially identical with the catalytic water molecule of BtGH97a, which attacks on the anomeric carbon from the β-face (i.e., Asp415 is poised for nucleophilic attack on the anomeric carbon). Site-directed mutagenesis of Asp415 leads to inactivation of the enzyme, and the activity is rescued by an external nucleophilic azide ion. That is, Asp415 functions as a nucleophilic catalyst. The multiple amino acid sequence alignment of GH 97 members indicated that almost half of the GH 97 enzymes possess base catalyst residues at the end of β-strands 3 and 5, while the other half of the family show a conserved nucleophilic residue at the end of β-strand 4. The different positions of functional groups on the β-face of the substrate, which seem to be due to “hopping of the functional group” during evolution, have led to divergence of catalytic mechanism within the same family.

An Epoxide Ring‐Opening Reaction via Hypervalent Silicate Intermediate: Synthesis of Statine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Epoxide Ring-Opening Reaction via Hypervalent Silicate Intermediate: Synthesis of Statine

The azide- and cyanide-opening reaction of epoxide with TBAF and TMSN3 in THF or TBAF and TMSCN in MeCN occurred regioselectively to afford β-hydroxy azides and cyanides in good yield. These hypervalent silicates have been shown to be highly effective as nucleophilic azide and cyanide donors under mild conditions. This methodology has been applied to the preparation of statine.

Chemistry of Substituted Quinolinones IV. Regioselective Nucleophilic Substitution of 1,3-Dichlorobenzo[f]quinoline

1,3-Dichlorobenzo[f]quinoline 2 was obtained from 1-hydroxybenzo[f]quinolin-3-one 1. Nucleophilic substitution, hydrolysis, hydrazinolysis and azidation reactions of compound 2 have been studied and found regioselective. Also, 1-aminobenzo[f]quinolinone 11 was obtained and used to prepare the benzoquinolinylthiourea derivative 12, naphthonaphthyridinedione 13, benzoquinolinylhydrazonoquinoline 15 and benzo[f]-quinolinyl enamine 17.

Acid-catalyzed solvolytic elimination (aromatization) of allylic ethers and alcohols

Acid-catalyzed solvolysis of 1-methoxy-1-methyl-1,4-dihydronaphthalene (1-OMe) in 50 vol% acetonitrile in water yields exclusively the elimination product 1-methylnaphthalene (3). Neither intramolecular rearrangement giving 2-methoxy-4-methyl-1,2-dihydronaphthalene (2-OMe), nor nucleophilic substitution with water giving the corresponding alcohols (1-OH) or (2-OH), was observed. However, addition of the strongly nucleophilic azide ion gives rise to competing substitution. The 2-N33 adduct rapidly looses HN3, affording 3 as the final product. These results are consistent with a carbocation relatively stable towards trapping with nucleophiles, but which easily loses a hydron. This process has a rate constant of about ke = 6 × 108 s−1, which is more than an order of magnitude slower than the dehydronation of the corresponding unsubstituted benzallylic carbocation (J. Am. Chem. Soc., 1998, 129, 6512). The heat of reaction of 1-OH in 25 vol% glycerol in water, measured by microcalorimetry, is ΔH = −21.7 ± 0.9 kcal mol−1.

Studies on the origin of stereoselectivity in the synthesis of 1,2-trans glycofuranosyl azides

The stereoselectivity of the 1,2-trans directed, Lewis acid-catalysed azidation of peracylated furanoses was found to depend on the reactivity of the azide donor (azide nucleophilicity) and the configuration at the anomeric centre relative to the neighbouring 2- O-acyl group. Reactions of 1,2-trans glycosyl esters with highly nucleophilic azide donors, generated from SnCl 4 and Me 3SiN 3, were stereospecific. The results are interpreted in terms of the rapid reaction of the azide species with bicyclic 1,2-acyloxonium (1,2- O-alkyliumdiyl- d-glycofuranose) ions, which were the primarily formed reactive intermediates. When using 1,2-cis glycosyl esters as starting materials the selectivity was reduced (90–94% de); the same is true with 1,2-trans counterparts if less nucleophilic Me 3SiN 3 in combination with Me 3SiOTf catalyst was used. This occurred due to the appearance of the more reactive but less selective oxocarbenium (glycofuranoxonium) ions either as primarily formed reactive intermediates in the former case or after equilibration with acyloxonium ions in the latter case. Protected 1,2-trans β- d-glycofuranosyl azides with ribo, xylo and 3-deoxy-erythro-pento configurations were best prepared from the corresponding glycosyl esters using 0.05 equivalents of SnCl 4, i.e., under anomerization-free conditions. Azidation of methyl glycofuranosides proceeds with inferior (80–90% de) and less predictable selectivity irrespective of the starting anomeric configuration.

Azide and Cyanide Displacements via Hypervalent Silicate Intermediates.

Hypervalent azido- and cyanosilicate derivatives, prepared in situ by the reaction of trimethylsilyl azide or trimethylsilyl cyanide, respectively, with tetrabutylammonium fluoride, are effective sources of nucleophilic azide or cyanide. Primary and secondary alkyl halides and sulfonates undergo rapid and efficient azide or cyanide displacement in the absence of phase transfer catalysts with the silicate derivatives. Application of these reagents to the stereoselective synthesis of glycosyl azide derivatives is reported.

Epoxide ring opening catalysed by imidochromium complexes ‡

tert-Butylimidochromium complexes catalysed ring opening of epoxides by SiMe3(N3) to give azidohydrins in good yields. The proposed mechanism for the chromium-mediated epoxide azidolysis involves the intermediacy of a chromium–azide species which delivers nucleophilic azide to the epoxide substrate. The azido complexes [{Cr(NBut)2Cl}2µ-N3)2] 1 and [Cr(ButNNNNSiMe3)(N3)Cl2] 2 have been isolated in the reactions of SiMe3(N3) with [Cr(NBut)2Cl2] and [Cr(NBut)Cl3(dme)] (dme = 1,2-dimethoxyethane), respectively. The structure of complex 1 has been established by X-ray crystallography. The mean Cr–N (imide) and Cr–N (azide) distances are 1.605 and 2.061 A, respectively. Reaction of [Cr(NBut)Cl3(thf)2] (thf = tetrahydrofuran) with (S,S)-diop {4,5-[bis(diphenylphosphino)methyl]-2,2-dimethyl-1,3-dioxolane} gave the dimeric complex [{Cr(NBut)Cl3}2{µ-(S,S)-diop}], which has been characterised by X-ray crystallography. The Cr–N and Cr–P distances are 1.593(9) and 2.449(4) A, respectively.