Pyrazolines cycloaddition

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). 

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). 

Burger s criss-cross cycloaddition reaction of hexafluoracetone-azine (76S349) is also a synthetic method of the [CNN + CC] class. In turn, the azomethines thus produced, (625) and (626) (79LA133), can react with alkenes and alkynes to yield azapentalene derivatives (627) and (628), or isomerize to A -pyrazolines (629) which subsequently lose HCF3 to afford pyrazoles (630 Scheme 56) (82MI40401). 

The stereochemistry of the 1,3-dipolar cycloaddition reaction is analogous to that of the Diels-Alder reaction and is a stereospecific syn addition. Diazomethane, for example, adds stereospecifically to the diesters 43 and 44 to yield the pyrazolines 45 and 46, respectively. 

In general, reaction of diazomethane with a, -unsaturated carbonyl compounds affords pyrazolines in which the nucleophilic methylene group is attached to the carbon atom of the carbonyl compound. According to Huisgen, the reactions belong to the general class of 1,3-dipolar cycloadditions. 

The cycloaddition product derived from 3-crotonoyl-2-oxazolidinone was identified to be the 4S,51 -enantiomer of 2-pyrazoline cycloadduct, meaning that the re,si-enan-... 

In general, nitrilimines are generated in the presence of a suitable dipo-larophile. Thus, heating an equimolar mixture of hydrazone 313, alkene 314, and chloramine-T trihydrate in ethanol under reflux for 3 h provided pyrazolines 315 in 68-90% yield [81]. The cycloaddition in all the cases was regiospecific as indicated by NMR (Table 23). 

Simple criss-cross cycloadditions described so far are in fact limited to aromatic aldazines and cyclic or fluorinated ketazines. Other examples are rather rare, including the products of intramolecular criss-cross cycloaddition. The criss-cross cycloadditions of hexafluoroacetone azine are probably the best studied reaction of this type. It has been observed that with azomethine imides 291 derived from hexafluoroacetone azine 290 and C(5)-C(7) cycloalkenes < 1975J(P 1)1902, 1979T389>, a rearrangement to 177-3-pyrazolines 292 competes with the criss-cross adduct 293 formation (Scheme 39). 

Thermolysis of 6-substituted l,5-diazabicyclo[3.1.0]hexanes 326, easily available from 325, leads to a diaziridine ring opening and to the intermediate formation of labile azomethine imines 327. These compounds can be stabilized by a proton shift to form 1-substituted 2-pyrazolines 328. However, when the thermolysis is carried out in the presence of a 1,3-dipolarophile, the corresponding products of dipolar cycloaddition can be obtained. For example, iV-arylmaleimides provide mixtures of the major trans- and minor air-products 329 and 330, respectively (Scheme 47) C1999RJO110, 2001RJ0841, 2003RJ01338, 2004RJ067>. 

Diazocarbonyl compounds readily undergo [3 + 2] cycloaddition to electron-poor alkenes 139). The 1-pyrazolines thus formed usually tautomerize to 2-pyrazolines if there is a hydrogen in an a-position to one of the nitrogen atoms otherwise, thermally induced ring contraction with evolution of nitrogen to give cyclopropanes can occur (Scheme 18). 

EvenPd(OAc)2 is not effective in catalyzing the cyclopropanation of a,P-unsaturated nitriles by ethyl diazoacetate. Instead, vinyloxazoles 92 are formed from acrylonitrile or methacrylonitrile by carbenoid addition to the CsN bond 143 Diethyl maleate and diethyl fumarate as well as polyketocarbenes are by-products in these reactions the 2-pyrazoline which would result from initial [3 + 2] cycloaddition at the C=C bond and which is the sole product of the uncatalyzed reaction at room temperature, can be avoided completely by very slow addition of the diazoester... 

Based on a detailed investigation, it was concluded that the exceptional ability of the molybdenum compounds to promote cyclopropanation of electron-poor alkenes is not caused by intermediate nucleophilic metal carbenes, as one might assume at first glance. Rather, they seem to interfere with the reaction sequence of the uncatalyzed formation of 2-pyrazolines (Scheme 18) by preventing the 1-pyrazoline - 2-pyrazoline tautomerization from occurring. Thereby, the 1-pyrazoline has the opportunity to decompose purely thermally to cyclopropanes and formal vinylic C—H insertion products. This assumption is supported by the following facts a) Neither Mo(CO)6 nor Mo2(OAc)4 influence the rate of [3 + 2] cycloaddition of the diazocarbonyl compound to the alkene. b) Decomposition of ethyl diazoacetate is only weakly accelerated by the molybdenum compounds, c) The latter do not affect the decomposition rate of and product distribution from independently synthesized, representative 1-pyrazolines, and 2-pyrazolines are not at all decomposed in their presence at the given reaction temperature. 

Cycloadditions are in general an effective way of constructing cyclobutane rings. A wide variety of heterocyclic systems dimerize in this way. 1,3-Diacetylindole, for example, affords the head-to-tail dimer 242 on irradiation in ethanol.185 Ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxy-late is similarly converted in diethyl ether into the trans head-to-head dimer.186 Notable among many analogous photodimerizations are those reported in 1,4-dihydropyridines,187 in furo[3,2-b]pyridin-2(4//)-ones,188 in 8-methyl-s-triazolo[4,3-a]pyridine,189 and in 2H-2-benzazepine-1,3-diones.190 The [ 2 + 2] dimerization of amidopyrine is the first reported example of a photocycloaddition in a 4-pyrazolin-3-one.191... 

Photoelimination of nitrogen from 1-pyrazolines has also been employed in the synthesis of tricyclo[3.2.1.02,4]oct-6-ene,338 prismane,339 quadri-cyclane,340 snoutene ,341 and marasmic acid.342 The trimethylenemethanes 414 have been prepared by photolysis of azoalkanes 415 and characterized spectroscopically.343 Dimerization and cycloaddition to alkenes of these biradicals have been reported.344... 

Pyrazoles can be synthesized by thermal cycloreversion of adducts formed in the 1,3-dipolar cycloaddition of alkyldiazoacetates with norbornadiene. The rate of the primary process of cycloaddition is accelerated by iron pentacarbonyl (Scheme 88)155 a similar catalytic effect has been observed during the formation of ethyl 5-phenyl-A2-pyrazoline-3-carboxylate from cycloaddition of ethyl diazoacetate and styrene.155 Reactions of this type are catalyzed presumably because of coordination of one or both reactants to the transition metal, and a wider study of the effect of a variety of complexes on 1,3-dipolar cycloaddition processes would be valuable. 

Moffett and coworkers203 reported the synthesis of several 4-/3-D-ribofuranosylpyrazoles, such as 284(a-c), by 1,3-dipolar cycloaddition of diazoalkanes to the alkenic C-glycosyl compound 283, followed by dehydrogenation of the resulting pyrazolines. In view of the known biological activities of several nucleosides containing the... 

Reaction of isatin or thioisatin 263 with (R)-(—)-thiaproline afforded thiazolo-oxazolidinones 264 as precursor of azomethine ylides, obtained by decarboxylation, for 1,3-dipolar cycloadditions (Equation 116) <2002SC435, 2004PS2549>. Condensation of 5-(alkylamino)methyl-2-pyrazolines 265 with ketones or aldehydes led to tetrahy-dro-imidazo[l,5-7]pyrazoles 266 (Equation 117) <1998JCCS375>. 

The 1,3-dipolar cycloaddition of diazomethane to MFA (24) occurred exclusively at the C2-C3 Jt-bond to give 4-(fluoromethylene)pyrazolines. The methylene group of diazomethane was regioselectively attached to the C2 carbon atom of 24 with a syw.anti ratio of 88 12 [72b], DFA (25) similarly reacted with diazomethane to give 4-(difluoromethylene)pyrazoline 89 selectively [72b, 86], The cycloaddition reaction of bulkier 2-diazopropane with DFA was less regioselective. 

Not much is known about the reactivity of the phosphinocarbene 2i. Problems arise, at least in part, from the high 1,3-dipolar reactivity of the diazo precursor li, which hides any carbene reactivity. Indeed, although li is stable in a toluene solution at 60°C for hours, the addition of an electron-poor olefin, such as a perfluoroalkyl-monosubstituted alkene, induces the exclusive formation of the thermodynamically more stable anti-isomer of the cyclopropane 14 (see Section V,B,3,a).36 This clearly demonstrates that the cyclopropanation reaction does not involve the carbene 2i, but that an initial [2 + 3]-cycloaddition occurs leading to the pyrazoline 13, which subsequently undergoes a classical N2 elimination.37... 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

Cyclohexadiene 45 was converted to 46 by what has proven to be a general method for preparation of the cyclohexa-2,4-dien-l-one ring system.2 Fragmentation of the aziridinyl imine in 46 at 110 °C gave an intermediate diazoalkane which underwent an intramolecular 1,3-dipolar cycloaddition to give the pyrazoline 47. At 140 °C, pyrazoline 47 expelled N2 and rearranged to the tricyclic ketone 48. The development of this and related bicyclizations29 illustrated a practical synthetic equivalence of an intramolecular diene-carbene 4-1-1 cycloaddition in the cyclohexa-2,4-dien-l-one series. 

The carbon-carbon double bond of an unsaturated AA reacts with 1,3-dipoles to give derivatives of pyrazole or isoxazole. When methanol is used as a solvent, the 1-pyrazolines primarily formed are tautomerized into 2-pyrazolines, which may eliminate benzamide or acetamide to give aromatic pyrazoles (Scheme 19) (88JHC851). Aromatization may also be affected with BF3 Et20. The cycloadditions are stereospecific (85JOC3167). In a... 

Figure 9. Preparation of some carbohydrate pyrazolines by cycloaddition of diazomethane to nitroalkenic sugars.

Dipolar cycloadditions are an important means of synthesis of a wide variety of heterocyclic molecules, some of which are useful intermediates in multistage synthesis. Pyrazolines, which are formed from alkenes and diazo compounds, for example, can be pyrolyzed or photolyzed to give cyclopropanes. 

Extension of the linkage to hve atoms as in 285 provides routes to pyrazolines or pyrazoles 286, or 1,2,4-triazoles 287, fused to a seven-membered ring. The products are potentially biologically active and examples have been reported for X=N (177-181), X = 0 (181-185) and for a pyrazolo fused analogue (186) and X = S (187). In some cases, [e.g., (183)], these reactions are accompanied by tandem intramolecular-intermolecular reactions leading to the formation of macrocycles (see the section Tandem Intermolecular-Intramolecular Cycloaddition Reactions). 

Due to space limitations, it is not possible to provide a comprehensive coverage of all 1,3-dipolar cycloaddition chemistry carried out using diazo compounds over the past two decades. Rather, attention will be given to the most significant developments, including the synthesis of novel heterocyclic systems, the preparation of well-established heterocycles (such as pyrazoles and pyrazolines) with novel functionalities, as well as stereoselective cycloadditions. A discussion of the theoretical, mechanistic, and kinetic aspects of these 1,3-dipolar cycloaddition reactions will be kept to a minimum, but references to important work in these areas will be given at appropriate places. Authoritative reviews dealing with the... 

The use of 3 also allows for [3 + 2] cycloaddition with enaminoketones (38) (Scheme 8.3). When the morpholine-derived enaminoketon 6 was used, a mixture of A -pyrazoline 7 and pyrazole 8 was obtained. Complete transformation of 7 into 8 was achieved by treatment with water. In the case of the pyrrohdine-derived enaminoketone 9, pyrazole 11 and diazabicycloheptadiene 10 are formed competitively. In the formation of the latter compound, reaction of a second equivalent of 3 with the carbonyl group of 9 is involved. Reaction of uracil as... 

Diazoacetaldehyde dimethylacetal (12) has been used as a substitute for diazoacetaldehyde in 1,3-dipolar cycloadditions with l-benzopyran-2(//)-ones (40), styrene, methyl methacrylate, 1-cyanocyclopentene, and methyl cyclohexene-1-carboxylate (41). The resulting A -pyrazolines were readily transformed in two steps into cyclopropanecarbaldehydes [e.g., 13 —> 14 (Scheme 8.4)]. In a similar manner, 3-phenylcyclopropane-l,2-dicarbaldehyde was obtained from the reaction of 12 with dimethyleneketal of cinnamic aldehyde. 

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