1.3- Dipolarophiles, enamines

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

The types of cycloadditions discovered for enamines range through a regular sequence starting with divalent addition to form a cyclopropane ring, followed by 1,2 addition (i) of an alkene or an alkyne to form a cyclo-cyclobutane or a cyclobutene, then 1,3-dipolar addition with the enamine the dipolarophile 4), and finally a Diels-Alder type of reaction (5) with the enamine the dienophile. 

Azides can use enamines as dipolarophiles for ],3 cycloadditions to form triazolines. These azides can be formate ester azides (186), phenyl azides (187-195), arylsulfony] azides (191-193,196), or benzoylazides (197,198). For example, the reaction between phenyl azide (138) and the piperidine enamine of propionaldehyde (139) gives 1 -phenyl-4-methy l-5-( 1 -piperidino)-4,5-dihydro-l,2,3-triazole (140), exclusively, in a 53% yield (190). None of the isomeric l-phenyl-5-methyl product was formed. This indicates that the... 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

Apart from the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity norbornene, for example, is consistently more reactive than cyclohexene in 1,3-DCA reactions. Conjugated functional groups usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enol ethers, enamines, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with several 1,3-dipoles are given in Table 10.6 of Part A. Additional discussion of these reactivity trends can be found in Section 10.3.1 of Part A. 

During the course of a study of the cycloaddition of azidomethyldiethylphospho-nate with acetylenes and enamines leading to alkyltriazoles under solvent-free conditions we observed that specific effects can be involved, depending on the nature of the substituents on the dipolarophiles [50] (Eq. (7) and Tab. 3.4). 

Ir and nmr analysis of the condensation products of primary amines with aldehydes and ketones are in favor of the Schiff-base structure (46a). Nevertheless, these substances react with aryl azides in chloroform solution in the tautomeric enamine form (46b) yielding aminotriaiolines.206 225- 227 It proves that the dipolarophilic activity of an enamine olefin bond is much greater than that of an azomethine bond. 

Azidoadamantane fails to react with enamines (see Scheme 18).155 The FMO of phenyl azide and 1-azidoadamantane suggests that the latter may be as reactive as phenyl azide toward electron-poor dipolarophiles but less reactive toward electron-rich dipolarophiles because of its relatively higher LUMO energy.155... 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

Carbonyl compounds and other dipolarophiles containing heteroatoms react with miinch-nones. Thus benzaldehyde forms the betaine (245) which suffers ring-cleavage to yield the enamine (246 equation 65). Thiocarbonyl compounds and nitrosobenzene behave in an analogous manner. The action of dipolarophiles containing cumulative double bonds results in the formation of new mesoionic systems. Thus carbon disulfide and phenyl isothiocyanate afford a zwitterionic thiazole and imidazole, respectively (Scheme 25). 

In the absence of dipolarophiles the intermediate loses sulfur to give the carbodiimide however, the intermediate may be trapped with a number of alkenes, heterocumulenes and other reagents such as ynamines, ketenes, isocyanates, isothiocyanates, carbodiimides, ketenimines, sulfonylimines, imines, nitriles, thiocarbonyl compounds, Wittig reagents and the already mentioned enamines (80AG277). Contemporary knowledge of the chemistry of these sulfonyliminothiatriazolines is mainly due to the meticulous work of L abbe and his coworkers (80AG277). 

Azine approach. Enamines when used as dipolarophiles with nitrile oxides form isoxazoles. With cyclic enamines such as (89) fused isoxazoles are formed the nitrile oxide in this reaction is generated in situ from benzhydroxamoyl chloride (64JOC1582). 

Enamines, enol ethers and related compounds again encompass one-site nucleophiles and two-site dipolarophiles. Where the adducts are acyclic or where a coelectrophile is involved these appear to be examples of equation (1). In equations (217)-(219), the paths to the major products seem straightforward. While a competing... 

Alkylidene imidazoles are best described as either ketene acetals or enamines, depending on the positions of substitution. 2-(2-Propylidene)imidazoles such as 787 (Scheme 195) react with azides to form spiroheterocycles 788. The reaction rates vary widely depending on the hybridization of C(4)-C(5) bond of the dipolarophiles dihydroimidazoles react in days while imidazoles take only hours <2005HCA1589>. 

The mechanistic details of this reaction have been examined by several workers. Absorption of a photon produces the enamine excited singlet state EA, which undergoes inter system crossing to the excited triplet state EA. Cyclization leads to an excited zwitterion ZW, which relaxes to the zwitterionic ground state (Scheme 8) . A suprafacial hydride shift produces the observed product. The presence of the zwitterionic intermediate has been detected by laser flash photolysis . In studies on the related sulfide ring closure, the zwitterion was trapped by a dipolarophile ... 

Dipolar cycloadditions can, of course, only produce five-membered rings. Addition of dipolarophiles can generate tetrahydro, dihydro or aromatic oxidation level heterocycles, as illustrated above. Alkene dipolarophiles, with a group that can be eliminated following cycloaddition, give the same result as equivalent alkyne dipolarophiles, for example enamines as the dipolarophile, interact with azides, as the 1,3-dipole, with subsequent elimination of the amine, affording 1,2,3-triazoles. ... 

The reaction of /7-nitrophenyl azide with the furanones 168,157, and 181a under the same reaction conditions was also studied (00H237). This dipolarophile reacted in a nonregiospecific manner with 5-methoxyfuranone 168 to give a mixture of the epimeric triazolines 261a and 261b. After flash chromatography, a diazo compound 262 and an enamine 263 were also isolated in poor yield (6 and 4%,... 

Other reactive olefins, such as enamines and vinyl ethers also participate as dipolarophiles in their reaction with thiocarbonyl 5-imides. Even fulvenes undergo [3+2] cycloaddition reactions. 

Enamines as 1,3-dipolarophiles 5-Amino-z] -isoxazolines from nitrile oxides and enamines... 

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