Intermolecular Approach

7 Cycloaddition Reactions with Azides for the Synthesis of Tetrazoles 9.7.1 Intermolecular Approaches 

Tetrazoles with a similar structure to triazoles tolerate various chemical environments. They are stable under oxidizing and reducing conditions as well as strongly acidic and basic media. Thus, this class of heterocycles presently plays a crucial role in the field of coordination chemistry, material science application and medicinal chenustry. The pharmacokinetic potential of tetrazoles, frequently used as metabolically stable surrogates of carboxylic acids, makes the synthesis of this nitrogen-rich heterocycle particularly fascinating. 

In the case of acyltetrazoles (55), a slight excess (1.5 equiv.) of nitrile was used for the full conversion of the cycloaddition. 

The 5-substitntents of the resulting snlfonyl (53) and acyl tetrazoles (55) are known to be replaceable with a wide range of 0-, N- and C-nncleophiles through an addition-elimination pathway, leading to a variety of 1,5-disnbstitnted tetrazoles hardly accessible by a direct Huisgen azide-nitrile cycloaddition. ° 

A further synthesis of acyltetrazoles was reported in 2007, in which acyl cyanides (10 equiv.), bearing a hydrogen at the -position, were transformed into tetrazoles in higher yield and purity in the presence of ZnBr2 as a catalyst (1 equiv.) at room temperature.  

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis 06OL5837 . For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles 06OPRD899 . The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

Following the communcation in 2004, a full report appeared that described type Ilac cyclocondensation reactions between dihydroisoquinolines and a-nitrocinnamates leading to complex fused pyrroles 06JOC9440 . The latter were converted into the lamellarin alkaloids and related analogues. 

An oxidative radical coupling promoted by tetra-ra-butylammonium cerium(IV) nitrate (TB ACN) between P-aminocinnamate 22 and enamine 23 provided pyrrole-3,4-dicarboxylate 24 06T2235 . Dimerization of the P-aminocinnamates provided symmetrical pyrroles. 

Two unique type Had syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles 06SL2339 . In the event, treatment of stannylcyclopropane 25 with -BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 

A review of the Bartoli indole synthesis (type Ilac cyclization) has appeared 05COC163 . The Bartoli indole synthesis involves the addition of vinyl Grignards to nitroarenes. 

A three-component type Ilae indole synthesis has been developed involving 1,2-dihaloarenes, arylaUcynes, and anilines 05OL439, 05T11311 . For example, iodoarene 114 was converted to indole 116 in one-pot utilizing this three-step sequence Sonogashira coupling, amination, and 

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As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

The furyl- and benzofurylstannanes can be coupled with a variety of electrophiles including aryl [53] and heteroaryl halides [54, 55]. In their synthetic studies towards lophotoxin and pukalide, Paterson and coworkers explored both intermolecular and intramolecular Stiile coupling reactions [56], The intermolecular approach between vinyl iodide 54 and furylstannane 55 was... 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

Pyrrole syntheses have been organized systematically into intramolecular and intermolecular approaches as well as by the location of the new bonds that describe the pyrrole ring forming step (two examples are illustrated below). Multi-component reactions appear at the end of the section on intermolecular approaches. The final section includes pyrrole syntheses that arise from transformations of other heterocycles. 

Intramolecular Approaches (type I) Intermolecular Approaches (type II)... 

A type Ilae reaction has been reported by Willis and co-workers who prepared N-substituted indoles via Pd-catalyzed coupling of 2-(2-haloalkenyl)-aryl halides with a variety of amines <06ASC851>. In an alternative intermolecular approach to ring construction, Tang and Hu have reported a Pd-catalyzed coupling of o-alkynylhalobenzenes with amines to afford 1,2-disubstituted indoles <06ASC846>. 

For the intermolecular approach, lithiation of 26 and trapping, under standard condi-... 

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