Pyrazoline analogs

Very recently, Solvay Pharmaceuticals (Lange et al. 2004) reported a novel class of 3,4-disubstituted pyrazoline analogs exhibiting high CBi selectivity (e.g., 51, Fig. 12). Another novel class of CBi antagonists that has received only limited attention includes the 3-alkyl-5-arylhydantoins (Ooms et al. 2002). 

The photorearrangement of pyrazoles to imidazoles is probably analogous, proceeding via iminoylazirines (82AHC(30)239) indazoles similarly rearrange to benzimidazoles (67HCA2244). 3-Pyrazolin-5-ones (56) are photochemically converted into imidazolones (57) and open-chain products (58) (70AHC(ll)l). The 1,2- and 1,4-disubstituted imidazoles are interconverted photochemically. 

Tautomerism has been discussed in Section 4.04.1.5.2. It concerns prototropic tautomerism and the decreasing order of stability is (hydrazone) >A (azo)> A (enehydrazine). The isomerization A -> A occurs via a A -pyrazoline (65BSF769). Pyrazolidones and amino-A -pyrazolines exist as such. The only example of non-prototropic tautomerism deals with the isomerization (403) —> (404) (74CJC3474). This intramolecular process is another example (Section 4.04.1.5) of the thermodynamic analogy between prototropy and metallotropy. 

Analogous to the oxidation of hydrazones to azo compounds, A-unsubstituted pyrazolidines are oxidized to A -pyrazolines. For example, the blcyclic pyrazolidine (415) when treated with silver oxide yields the pyrazoline (416) (65JA3023). Pyrazolidine (417) is transformed into the perchlorate of the pyrazolium salt (411) by reaction with mercury(II) acetate in ethanol followed by addition of sodium perchlorate (69JOU1480). 

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. 

Similar behavior was also observed for analogous 3-oxopyrazolidines 282 (X = O) and pyrazoline-3-thiones 282 (X = S) (Scheme 101). 

The pyrazole analog 140 has been prepared from the reaction of the alkynyl phosphonate with ethyl diazoacetate, whereas the pyrazoline 139 was obtained under similar conditions with diediyl vinylphosphonate (78). 

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... 

The ambiguity of infrared criteria for the identification of protonation sites in imidazoles and 2-pyrazolines has been discussed by Elguero et al. (1967a), who have also provided new information on the infrared spectra of the hydrochloride of 3,5,5-trimethyl-2-pyrazoline in chloroform solution. There is a shift of the stretching vibration of the C=N bond from 1624 cm in the base to 1649 cm" in the hydrochloride salt in chloroform, i.e., in the N-1 protonated cation. This is analogous to similar shifts of the carbonyl frequency in some amide salts (see page 338). 

When l,4-dihydronaphthalen-l,4-imine (2) was first obtained via the hydrobromide (113), it was shown to react with phenyl azide to give an adduct (127). The analogous phenyl azide adduct (128) from compound 103 has been better characterized. Naphthalen-l,4-imines also add diazomethane across the 2,3-double bond, forming pyrazolines, e.g., 104 -> 129, two of which have been photolyzed to give the corresponding cyclopropane derivatives (130) with extrusion of nitrogen. ... 

The azapenam derivatives 122 were isolated as single diastereomers from the irradiation of (dibenzylaminocarbene)pentacarbonylchromium [78] in the presence of imidazolines 121. The relative configuration of the new stereocenters at C-3 and C-4 was predicted as being exo, exo from MMX calculations, and this configuration was proven by X-ray structure analysis [59]. High stereoselectivity was also observed in the analogous transformation of pyrazoline 25b, but... 

Diazo compounds also undergo cycloaddition with fullerenes [for reviews, see (104),(105)]. These reactions are HOMO(dipole)-LUMO(fullerene) controlled. The initial A -pyrazoline 42 can only be isolated from the reaction of diazomethane with [60]fullerene (106) (Scheme 8.12) or higher substituted derivatives of Ceo (107). Loss of N2 from the thermally labile 42 resulted in the formation of the 6,5-open 1,2-methanofullerene (43) (106). On the other hand, photolysis produced a 4 3 mixture of 43 and the 6,6-closed methanofullerene (44) (108). The three isomeric pyrazolines obtained from the reaction of [70]fullerene and diazomethane behaved analogously (109). With all other diazo compounds so far explored, no pyrazoline ring was isolated and instead the methanofullerenes were obtained directly. As a typical example, the reaction of Cgo with ethyl diazoacetate yielded a mixture of two 6,5-open diastereoisomers 45 and 46 as well as the 6,6-closed adduct 47 (110). In contrast to the parent compound 43, the ester-substituted structures 45 and 46, which are formed under kinetic control, could be thermally isomerized into 47. The fomation of multiple CPh2 adducts from the reaction of Ceo and diazodiphenylmethane was also observed (111). The mechanistic pathway that involves the extrusion of N2 from pyrazolino-fused [60]fullerenes has been investigated using theoretical methods (112). 

Other analogous photodecompositions of 1-pyrazolines are known,72 73 while the photolysis74 of 3,3a,5 ,6,6a,66-hexahydro-3,6-ethenocycloprop[gf]indazole gives rise to products resulting from bond cleavage and further rearrangement [Eq. (20)]. 

Diazomethane and its simple analogs undergo cycloaddition to unsaturated compounds both directly and after conversion to carbenes. The direct cycloadditions are 1,3-dipolar for the most part and provide access to pyrazolines and pyrazoles. Intramolecular cyclizations were recognized as early as 1965 95 The two main methods used in generation of diazo compounds for subsequent intramolecular cycloaddition include thermolysis of tosylhydrazone salts and thermolysis of iminoaziridines. Decomposition of nitros-amines has also been employed. 

Some azocane-substituted pyrazoline compounds have been reported as cannabinoid receptor modulators <2007W00009723, 2007WO131538>. An azocane derivative with a 3,3-diphenylpentane skeleton was reported to be an inhibitor of human 5a-reductase 1 <2007BMCL5414>. A dipyridamole analog having a bis-azocane structure was identified as a highly potent Nucleoside Transporter 1 inhibitor <2007JMC3906>. 

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