Dipolar cycloadditions 1,2,3,4-tetrazoles from

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

The presence of the propionamide fragment in the stmcture of the anti-inflammatory agent broperamole (125-1) is reminiscent of the heterocycle-based NSAID propionic acids. The activity of this agent may trace back to the acid that would result on hydrolysis of the amide. Tetrazoles are virtually always prepared by reaction of a nitrile with hydrazoic acid or, more commonly, sodium azide in the presence of acid in a reaction very analogous to a 1,3-dipolar cycloaddition. A more recent (and safer) version of the reaction noted later (see losartan, 77-4) uses tributyltin azide. In the case at hand, reaction of the anion of mefa-bromobenzonitrile (125-1) with sodium azide and an acid affords the tetrazole (125-2). Condensation of the anion from that intermediate with ethyl acrylate leads to the product from Michael addition saponiflcation gives the corresponding carboxylic acid (125-3). This is then converted to the acid chloride reaction with piperidine affords broperamole (125-4) [136]. 

Fleet and co-workers (75a) synthesized various tetrazoles from manno- and rhamnopyranoses, as well as furanoses, based on the intramolecular 1,3-dipolar cycloadditions of azides with nitriles (Scheme 9.75). All of these tetrazoles were tested for their inhibitory activities toward both glycosidases and other sugarprocessing enzymes. D-Mannopyranotetrazole (397) was prepared from L-gluono-lactone (393). Azide 394 on ring opening with ammonia followed by dehydration with trifluoroacetic anhydride gave the azido nitrile 395. Intramolecular 1,3-dipolar cycloaddition of 395 in refluxing toluene followed by deprotection produced the D-mannopyranotetrazole 397 in 86% overall yield. 

Complexes of the heteroaromatic compounds may be prepared by building up the heterocyclic ligand. The most effective method for the N (10, E = N) and C (11) derivatives is 1,3-dipolar cycloaddition from the metal azides. The N and C derivatives of triazole (67) and (68), tetrazole (69-72) and other azoles, e.g., 73, were prepared.The transformations leading to the complexes are summarized later. 

As nitriles are generally readily available this is the main route to simple tetrazoles. More complicated ones are made by alkylation of the product of a cycloaddition. The tetrazole substitute for indomethacin that we mentioned in Chapter 43 is made by this approach. First, the nitrile is prepared from the indole. The 1,3-dipolar cycloaddition works well by the azide route we have just discussed, even though this nitrile will form an enoF rather easily. 

Thermolysis of triazole 520 in acetonitrile affords imidazole 521 in 75% yield. Its formation was rationalized in terms of a 1,3-dipolar cycloaddition of the intermediate a-cyaniminocarbene 522 to the C=N bond of the solvent [81AG(E)113], although the mechanism of ylide formation with concomitant cyclization must not be ruled out. The similar nitrile with carbene 523, generated from diazo tetrazole 524, leads to imidazotetrazolic systems 525 (R = Me, Ph) in 42 and 51% yield, respectively (85T4621). 

If there is functionality directly attached to the carbon atom of the tetrazole, a problem may seem to arise. Thus many drugs are made from 5-aminotetrazole 97 and our disconnection requires the unlikely looking molecule H2N-CN. This is in fact cyanamide available as a mixture with water and stabilisers to prevent dimerisation to dicyandiamide 98. The dimer is 50 times cheaper and can be used in the 1,3-dipolar cycloaddition under slightly different conditions.10... 

Tetrazole synthesis from azides by dipolar cycloaddition with activated nitriles or intramolecularly with nitriles in the presence of acids (see 1st edition). 

A facial synthesis of tetrazole 62 as an intermediate for the synthesis of 1-deoxymannojirimycin (2) has been reported (Scheme 11). The azide 54, obtained from L-gulonolactone 53, " was treated with ammonia in methanol to produce 59, which was reacted with trifluoroacetic anhydride in pyridine to give the nitrile 60. When the azidonitrile 60 was heated in toluene for 3 days, an efficient 1,3-dipolar cycloaddition took place, resulting in the formation of the tetrazole 61. Removal of both the silyl and acetonide groups in... 

Reactions of heterocycles ch29 How to make pyridazines and pyrazoles How to make pyrimidines from 1,3-dicarbonyl compounds and amidines How to make thiazoles How to make isoxazoles and tetrazoles by 1,3-dipolar cycloadditions The Fischer indole synthesis Making drugs Viagra, sumatriptan, ondansetron, indomethacin How to make quinolines and isoquinolines ... 

Demko, Z.P. Sharpless, K.B. A click chemistry approach to tetrazoles by huisgen 1,3-dipolar cycloaddition Synthesis of 5-sulfonyl tetrazoles from azides and sulfonyl cyanides. Angew. Chem. Int. Ed. 2002,... 

Majumdar and coworkers [83] synthesized fused thiopyran derivatives 150 in 83-98% yields through a three-component domino reaction of 71a, 69, and indoline-2-thione 136 or 4-hydroxy-2H-thiochromene-2-thione in water at 100 °C (Scheme 12.59). The resulting heterocyclic products could be conveniently separated from the reaction mixture without the use of any volatile organic solvent. In the reaction, three new bonds and one stereocenter were formed. When indoline-2-thione was replaced with sodium azide 151, the three-component domino reaction provided 5-substituted-tetrazoles 152 in 67-88% yields through a Knoevenagel condensation/1,3 dipolar cycloaddition sequence (Scheme 12.60) [84]. 

Dabiri has developed a catalyst-free three-component synthesis of a series of stmc-turally diverse 5-substituted tetrazoles 24 and 25 in good yields under mild conditions from caiboityl compounds (including benzaldehydes, isatin and ninhydrin), malononitrile and sodium azide in water [19], This process can be assumed to proceed through a domino Knoevenagel condensation/l,3-dipolar cycloaddition sequence (Scheme 1.13). 

Figure 2.16 Kinetics of the photoinducible cycloaddition between 2,5-diaryl tetrazoles and alkenes (Song et al., 2008). (Reproduced with permission from W. Song, Y. Wang, J. Qu et al., A photoinducible 1,3-dipolar cycloaddition reaction for rapid, selective modification of tetrazole-containing proteins, Angewandte Chemie International Edition, 2008,47,15,2832-2835. Wiley-VCH Verlag GmbH Co. KGaA.)...

From the results of control experiments, the actual mechanism of the present reaction might be as follows The [5+1] cycloaddition of isocyanide 35a and C,N-cyclic N -acyl azomethine imine 34A first proceeded very quickly to afford 36Aa, whose imin-l,3,4-ozazin-6-one ring was cleaved by TMSCl to generate the corresponding nitrilium intermediate (A, Z = TMS) in Scheme 11.9 in situ. Subsequent 1,3-dipolar cycloaddition between the nitrilium intermediate (A) and an azide ion proceeded to afford the corresponding tetrazole 39. 

The energetic 1,3,4-oxadiazole (22) is synthesized from the reaction of the tetrazole (20) with oxalyl chloride. In this reaction the tetrazole (20) undergoes a reverse cycloaddition with the expulsion of nitrogen and the formation of the 1,3-dipolar diazoalkane (21) which reacts with the carbonyl groups of oxalyl chloride to form the 1,3,4-oxadiazole rings. 

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