Cycloaddition reactions 1,3-dipolar cycloadditions

Keywords Diels-Alder reactions, dipolar cycloadditions, electrocyclic reactions, ene reactions, pericyclic reactions, sigmatropic rearrangements... 

In contrast to the failure of Diels-Alder reactions, dipolar cycloadditions of indoles are much more successful, and the Boger group has reported a fascinating [4+2]/l,3-dipolar cycloaddition cascade involving indole as the dipolarophile in their impressive synthesis of vindoline (Scheme 4.8) [26]. After the initial... 

Arylglyoxals in synthesis of heterocychc compounds 13CRV2958. 1,2-Benzoquinones in Diels—Alder reactions, dipolar cycloadditions, nucleophihc additions, multicomponent reactions and more 12CSR1050. 

F. de Moliner, S. Crosignani, A. Galatini, R. Riva, A. Basso, ACS Comb. Sci. 2011, 13, 453-457. Novel application of a-azido aldehydes in multicomponent reactions synthesis of triazolo-fused dihydrooxazinones via a Passerini reaction-dipolar cycloaddition strategy. 

Vorobyeva DV, Sokolova NV, Nenajdenko VG, Peregudov AS, Osipov SN (2012) Synthesis of CF3-containing tetrapeptide surrogates via Ugi reaction/dipolar cycloaddition sequence. Tetrahedron 68 872-877... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van... 

The reaction of cyclohexene with the diazopyruvate 25 gives unexpectedly ethyl 3-cyclohexenyl malonate (26), involving Wolff rearrangement. No cyclo-propanation takes place[28]. 1,3-Dipolar cycloaddition takes place by the reaction of acrylonitrile with diazoacetate to afford the oxazole derivative 27[29]. Bis(trimethylstannyl)diazomethane (28) undergoes Pd(0)-catalyzed rearrangement to give the A -stannylcarbodiimide 29 under mild conditions[30]. 

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Ozonation ofAlkenes. The most common ozone reaction involves the cleavage of olefinic carbon—carbon double bonds. Electrophilic attack by ozone on carbon—carbon double bonds is concerted and stereospecific (54). The modified three-step Criegee mechanism involves a 1,3-dipolar cycloaddition of ozone to an olefinic double bond via a transitory TT-complex (3) to form an initial unstable ozonide, a 1,2,3-trioxolane or molozonide (4), where R is hydrogen or alkyl. The molozonide rearranges via a 1,3-cycloreversion to a carbonyl fragment (5) and a peroxidic dipolar ion or zwitterion (6). 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

Reaction of arninoacetonitrile hydrochloride with sodium nitrite provides diazoacetonittile (62). The product undergoes a 1,3-dipolar cycloaddition with diethyl fumarate to yield a pyrazoline intermediate, which without isolation reacts with ammonia in water to furnish the pyrazole [119741-54-7] (63) (eq. 14) (43). 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

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). 

In the alternative approach.the 1,3-dipolar system can be constructed in several ways. Treatment of a-chloroacylhydrazones of diaryl ketones and certain aralkyl and dialkyl ketones (382) with NaH in anhydrous THF gives l-(disubstituted methylene)-3-oxo-l,2-diazetidinium inner salts (383). Reaction of (383) with DMAD in methylene chloride gave (384), a 2 1 adduct with loss of CO. Double bond migration in (384) occurred on heating to give (385). The intermediate in the cycloaddition was found to be (386), which on heating lost CO to form a new ylide system which in turn underwent reaction with more DMAD <81JA7743). 

Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-membered rings. Their principal use in five-membered heterocycles is for ring annulations giving [5,6] ring-fused systems. 

In this section, reactivity studies will be emphasized while in those devoted to synthesis (Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles (mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the theoretical treatment of reactivity is a very complicated problem and for this reason, most of the calculations have been carried out on aromatic compounds, as they are the easiest to handle. In general, solvents are not taken into account thus, at the best, the situation described theoretically corresponds to reactions taking place in the gas phase. 

The synthesis of pyrazoles, indazoles and their derivatives generally follows classical methods, the two most important methods for practical purposes being the reaction between hydrazines and /3-difunctional compounds, and 1,3-dipolar cycloadditions (Section 4.04.3.1.2). Both procedures are well documented (64HC(20)l, 66AHC(6)327, 67HC(22)l) and thus the length of the sections in this part of the chapter reflects not only the number of publications dealing with a particular method but also its interest and novelty. 

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 theoretical interest that these reactions aroused was enormous. Presently 1,3-dipolar cycloadditions are one of the cornerstones of theoretical chemistry and many references are to be found in the publications quoted in Table 36. For some recent publications related to this chapter see (78JA5701, 79TL2621, JST(89)147). 

In these types of 1,3-dipolar cycloaddition only one of two possible isomers is obtained and the pyrazole functions have different orientations by the two methods. Another classical synthesis of pyrazoles (Section 4.04.3.2.l(ii)), the reaction between hydrazines and )3-diketones, has been used with success to prepare high molecular weight polypyrazoles (Scheme 65) (81MI40400). A-Arylation (Section 4.04.2.1.3(ix)) of 4,4 -dipyrazolyl with 1,4-diiodobenzene also yields polymeric pyrazoles (69RRC1263). 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

Nitrile ylides derived from the photolysis of 1-azirines have also been found to undergo a novel intramolecular 1,1-cycloaddition reaction (75JA3862). Irradiation of (65) gave a 1 1 mixture of azabicyclohexenes (67) and (68). On further irradiation (67) was quantitatively isomerized to (68). Photolysis of (65) in the presence of excess dimethyl acetylenedicar-boxylate resulted in the 1,3-dipolar trapping of the normal nitrile ylide. Under these conditions, the formation of azabicyclohexenes (67) and (68) was entirely suppressed. The photoreaction of the closely related methyl-substituted azirine (65b) gave azabicyclohexene (68b) as the primary photoproduct. The formation of the thermodynamically less favored endo isomer, i.e. (68b), corresponds to a complete inversion of stereochemistry about the TT-system in the cycloaddition process. 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

Two extreme mechanisms can be envisaged (Scheme 12), concerted [2 + 2] cycloaddition or the more generally accepted formation of a dipolar intermediate (164) which closes to a /3-lactam or which can interact with a second molecule of ketene to give 2 1 adducts (165) and (166) which are sometimes found as side products. In some cases 2 1 adducts result from reaction of the imine with ketene dimer. 

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