Pyrazole cycloaddition

Thieno[3,4-c]pyrazoles.—Cycloaddition of dibenzoylacetylene to N-phenyl-sydnone (78) afforded the pyrazole (79), which, when thionated (P2Ss Pyridine), gave in high yield the stable triphenylthieno[3,4-c]pyrazole (80), the first reported member of this class." Compound (80) enters into cycloaddition reactions, notably with dibenzoylacetylene, with loss of sulphur, giving the diketone (81). Thionation of compound (81) gives, in high yield, the stable blue-black quadricovalent species (82). The mass spectra of... 

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 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. 

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. 

The different possibilities for the creation of the pyrazole ring according to the bonds formed are shown in Scheme 46. It should be noted that this customary classification lacks mechanistic significance actually, only two procedures have mechanistic implications the formation of one bond, and the simultaneous formation of two bonds in cycloaddition reactions (disregarding the problem of the synchronous vs. non-synchronous mechanism). 

Hart and Brewbaker have described the cyclization of l,3-bis(diazopropane) to pyrazole (Scheme 49) by a concerted, intramolecular 1,3-dipolar cycloaddition (69JA711). 

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). 

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). 

The following compounds have been obtained from thiete 1,1-dioxide Substituted cycloheptatrienes, benzyl o-toluenethiosulfinate, pyrazoles, - naphthothiete 1,1-dioxides, and 3-subst1tuted thietane 1,1-dioxides.It is a dienophile in Diels-Alder reactions and undergoes cycloadditions with enamines, dienamines, and ynamines. Thiete 1,1-dioxide is a source of the novel intermediate, vinylsulfene (CH2=CHCH=SQ2). which undergoes cyclo-additions to strained olefinic double bonds, reacts with phenol to give allyl sulfonate derivatives or cyclizes unimolecularly to give an unsaturated sultene. - Platinum and iron complexes of thiete 1,1-dioxide have been reported. 

Nitrilimines can be produced by treating halogenated hydrazones with a base such as triethylamine. These nitrilimines undergo 1,3 cycloaddition with enamines to form pyrazoles (181-183). This is shown by the reaction of the pyrrolidine enamine of cyclohexanone with diphenyinitrilimine to... 

Another possibility is observed upon cyclization of hydrazides of pyrazole-carboxylic acids in the presence of CuCl in an inert atmosphere in DMF. When acetylenylcarboxylic acids are heated in the presence of CuCl in DMF, the orientation of the cycloaddition of the hydrazide group differs from that observed for cyclization in basic conditions. The cycloisomerization of hydrazides 78 in boiling DMF leads to the corresponding pyrazolopyridazines 79 in 60-71 % yields (Scheme 134 Table XXIX) (85IZV1367 85MI2). 

Dipolar cycloaddition of 2-diazopropane and 1,3-diphenyldinitrilimine to E- and Z-methoxybutenynes occurs at the triple bond to form 3,3-dimethyl-5-(2-methoxyvinyl)pyrazole (168) and a mixture of , Z-l,3-diphenyl-4- (169) and -5-(2-methoxyvinyl)pyrazole (170) [70CR(C)80]. 

The cycloaddition reaction of compound 6 with N-aryl- and N-aralkylazides 23 was also investigated (967(52)7183). Thiadiazabicyclo[3.1.0]hexene derivatives 25 were obtained from the labile triazoline intermediate 24 through nitrogen elimination. This bicyclic system underwent thermal transformation, producing thiadiazine dioxides 26 as the main product together with thiazete dioxides 27 and pyrazoles 28. 

The diazepines 13 react with dimethyl acetylenedicarboxylate to yield mixtures of the pyrazole 19 and the benzene derivatives 18. The reaction proceeds by cycloaddition to yield 14, followed by valence isomerization to the 1,2-diazonines 15, a further valence isomerization to 16, a Second cycloaddition to give 17 and, finally, fragmentation."... 

Cycloaddition of azirines 5 to 1.2,4,5-tetrazines 6 is followed by loss of nitrogen and ring enlargement to yield 5//-1,2,4-triazepines 7, which tautomerize spontaneously by a [1,51-hydrogen shift to the 2/7-1,2,4-triazepines 8. The triazepinesare accompanied by variable amounts of pyrimidines and pyrazoles.335 - 338... 

Diazoalkanes add to 3-p-toluenesulphinylcoumarin 580 to give the cycloaddition products 581, which after elimination of p-toluenesulphenic acid afford 3-H-pyrazole derivatives 582677 (equation 368). 

The first [3S+2C] cycloaddition reaction using a Fischer carbene complex was accomplished by Fischer et al. in 1973 when they reported the reaction of the pentacarbonyl(ethoxy)(phenylethynyl)carbene complex of tungsten and diazomethane to give a pyrazole derivative [45]. But it was 13 years later when Chan and Wulff demonstrated that in fact this was the first example of a 1,3-dipolar cycloaddition reaction [46,47a]. The introduction of a bulky trime-thylsilyl group on the diazomethane in order to prevent carbene-carbon olefi-nation leads to the corresponding pyrazole carbene complexes in better yields (Scheme 15). 

In 2000, it was proposed that the regioselectivity of the [3 + 2] cycloaddition of fullerenes could be modified under microwave irradiation. Under conventional heating, N-methylazomethine yhde and fullerene-(C7o) gave three different isomeric cycloadducts because of the low symmetry of C70 vs. Ceo. Using microwave irradiation and o-dichlorobenzene as a solvent, only two isomers were obtained, the major cycloadduct 114 being kinetically favored (Scheme 39) [75]. The same authors had previously reported the 1,3-dipolar cyclo addition of pyrazole nitrile oxides, generated in situ, to Geo under either conventional heating or microwave irradiation. The electrochemical characteristics of the cycloadduct obtained with this method made this product a candidate for photophysical apphcations [76]. 

Syntheses of fluoro-substituted pyrazoles continue to be of interest. Both 3- and 5-fluoropyrazoles (44 and 45, respectively) can be prepared from 43 <96JOC2763>. Treatment of 43 with hydrazine followed by N-alkylation provides 44, whereas reactions with monosubstituted hydrazines afford 45. The 4-(trifluoromcthyl)pyrazoles 47 are obtained from J-trifluoromethyl vinamidinium salt 46 <96TL1829>. The 5-trifluoromethyl-3-carboethoxypyrazoles 49 are obtained from the 1,3-dipolar cycloadditions of trifluoromethyl alkenes 48 with ethyl diazoacetate <96T4383>. 

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

We now report the synthesis of new antibacterial 3H-pyrazoles by regioselective 1,3-dipolar cycloaddition of the versatile 2-diazopropane to nonprotected disubstituted propargyl alcohols and that the unsubstituted propar-gyl alcohol allows the double addition of 2-diazopropane and gives a 3H-pyrazole with formal insertion of the dimethylcarbene into a carbon-carbon bond. We also show that the photolysis of the 3H-pyrazoles leads to new alcohols containing the cyclopropenyl unit. 

Dipolar cycloaddition reaction of suitable dipolarophiles to azomethine imines is a well-known method leading to the pyrazolo[l,2-tf]pyrazole ring system and the methodology was duly reviewed in CHEC-II(1996) <1996CHEC-II(8)747>. During the covered period, some new applications have appeared. 

A library of fifteen 6,7,9,9a-tetrahydro-57/-pyrazolo[l,2-tf]pyrrolo[3,4-ir]pyrazole-l,3,5(2/7,3a7/)-triones 712 was prepared by combinatorial stereoselective cycloadditions of compounds 320 to A-substituted maleimides. 

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. 

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