The photochemistry of some pyranopyrazoles

Irradiation of 1,3,6-trimethylpyrano [2,3-c ] pyrazole-4 (1 H )-one ( 1 ) or 3,6-dimethyl-1-phenylpyrano [2,3-c ]pyrazole-4-(1 H )-one ( 2 ) in acetonitrile solution at 254 nm resulted in the formation of the cis-head-to-tail [2+2] dimers 5 or 13 respectively. When the irradiation was carried out in ethanol solvent 1 or 2 underwent dimerization to yield 5 or 13 respectively and also photocleavage to provide ethyl 5-hydroxy-1,3-dimethyl-1 H -pyrazole-4-carboxylate ( 10 ) or ethyl 5-hydroxy-3-methyl-1-phenyl-1 H -pyrazole-4-carboxylate ( 14 ) respectively.


Introduction
The photochemical properties of pyranopyrazoles are intriguing because the molecule can be viewed as a 4-pyrone ring fused on to a pyrazole ring.9][20][21] Although the photochemistry of the individual ring systems have been studied, we are unaware of any reports concerning the photochemistry of the pyranopyrazole ring system.Because of our interest in these compounds, we have undertaken a study of the photochemistry of 1,3,6-trimethylpyrano [2,3-c] pyrazole-4(1H)-one (1) and of 3,6-dimethyl-1-phenylpyrano [2,3-c] pyrazole-4(1H)-one (2).The results of that study are the subject of this manuscript.

Results and Discussion
Pyranopyrazoles 1 and 2 were synthesized in two steps from the methyl-or phenylhydrazone 3a or 3b via the diketopyrazoles 4a or 4b respectively, according to a modification of the method developed by Gelin and colleagues 22,23 (Scheme 1).The UV-absorption spectra of 1 and 2 in acetonitrile solution exhibited absorption maxima at 250 nm (ε = 9,068 L mol -1 cm -1 ) and 206.0 nm (ε = 14,764 L mol -1 cm -1 ) and at 242.5 nm (ε = 24,646 L mol -1 sec -1 ) respectively.Considering the magnitude of these extinction coefficients, these absorptions were assigned to S 0 to S 1 (π, π*) and S 0 to S 2 ( π,π*) in the case of 1 and to S 0 to S 1 (π,π*) in the case of 2. 25 A solution of 1 (3.0 mL, 2.0 x 10 -2 M) in acetonitrile was irradiated at 254 nm.HPLC analysis as a function of irradiation time showed a continuous decrease in the peak area at 7.3 minutes due to the consumption of the reactant and the appearance of a new peak at 6.7 minutes due to the formation of a photoproduct 5. Analysis revealed, however, that the rate of reactant consumption decreased after 45 minutes of irradiation.Analysis also revealed that the area of the photoproduct 5 peak at 6.7 minutes increased during the first 45 minutes of irradiation and then slowly decreased upon longer irradiation time.This indicates that after 45 minutes of irradiation the product competes with the reactant for the incident light and begins to be consumed in a secondary photoreaction.
A solution of 1 was also irradiated at 254 nm on a preparative scale (20.0 mL, 2.0 x 10 -2 M) in acetonitrile until HPLC analysis indicated maximum formation of 5. Preparative-layer chromatography of the resulting solution allowed isolation of a white crystalline product, mp 229-230˚C.HPLC analysis of this solid showed a single peak with a retention time identical to the retention time of photoproduct 5 observed during the analytical-scale irradiation.This confirms that the isolated product is the observed photoproduct 5.
The mass spectrum of 5 exhibited a molecular ion at m/z = 356, exactly twice the mass of the reactant 1, indicating that 5 is a dimer of 1.The molecular mass and elemental analysis are consistent with the molecular formula C 18 H 20 N 4 O 4 , the correct formula for a dimer.
The 1 H NMR spectrum of 5 shows singlets at δ1.78, 2.28, 3.41, and 3.22 with an integrated ratio of 3:3:3:1.Thus, although the molecular formula is consistent with the presence of six methyl groups, the 1 H NMR spectrum exhibits three different sets of methyl protons.Each set must therefore contain two methyl groups.Similarly, the 13 C NMR spectrum shows the presence of nine different sets of carbon atoms.Since the molecular formula shows that 5 contains18 carbon atoms, each set must contain two identical carbon atoms.The 1 H and 13 C NMR spectra indicate that the dimer 5 must have a symmetrical structure.Structures consistent with this include the cis or trans-head-to-head (5a or 5b) or head-to-tail (5c or 5d) [2 + 2] cycloaddition adducts shown in Scheme 2.

Scheme 3
Single crystal X-ray diffraction analysis allowed distinction among these possibilities and confirmed that the structure of the photoproduct 5 is the cis-head-to-tail [2 + 2] cycloaddition dimer shown as 5c in Scheme 2. The crystal structure of 5c is shown in Figure 1.The conformations and structures of the cyclobutane ring and dihydropyranone rings in 5c are consistent to those reported for 7 and 9. HPLC analysis as a function of irradiation time showed that the yield of the dimer 5 reached a maximum of 35% after 45 minutes of irradiation and then slowly decreased upon longer irradiation.This indicates that after 45 minutes of irradiation the dimer 5 was being consumed faster than it was being formed.Irradiation of a pure sample of photodimer 5 revealed that it underwent a retro [2 + 2] reaction leading back to 1.
A solution of pyranopyrazole 1 (20.0 mL, 2.0 x 10 -2 M) in ethanol was also irradiated at 254 nm.The 1 H NMR spectrum of the crude product mixture revealed singlets at δ1.78, 2.28, 3.41, and 3.22 due to formation of dimer 5 and additional signals due to the formation of a second product 10 which was not observed after irradiation of 1 in acetonitrile solvent.Preparativelayer chromatography led to the isolation of the dimer 5 and to 10 as a white crystalline compound, mp 124-125˚C.
The 1 H NMR spectrum of 10 revealed a 2H quartet and a 3H triplet (J = 7.1 Hz) at δ4.28 and 1.24 respectively.Thus, it appears that a molecule of ethanol has been incorporated into the photoproduct 10.The spectrum also shows a 3H singlet at δ3.58, consistent with an N-methyl group, and a 3H singlet at δ2.29, consistent with an allyl methyl group.Significantly, although pyranopyrazole 1 has three methyl groups, the product has only two.One methyl group has been lost.In addition, the 1H singlet due to the α-proton in the 4-pyrone ring in the reactant is not observed in the product.This suggests that the α and β carbons of the pyrone ring have been lost during the photoreaction.Finally, the 1 H NMR spectrum exhibits a broad peak at δ9.24 (D 2 O exchangeable) due to the presence of a hydroxyl proton in the structure.The 13 C NMR spectrum shows the presence of eight sets of carbon atoms.These include the three methyl groups absorbing at δ14.6, 14.8, and 33.3, and the methylene carbon of the ethoxy group absorbing at δ60.7.Significantly, the 13 C NMR spectrum also exhibits a signal for a quaternary carbon at δ167.2, consistent with an ester carbonyl carbon, and signals for quaternary carbon atoms at δ157.7, 147.8, and 92.7, consistent with the C3, C5, and C4 atoms respectively of a pyrazole ring.
Taken together, the spectroscopic data suggests that photoproduct 10 is ethyl 5-hydroxy-1, 3dimethyl-1H-pyrazole-4-carboxylate. 27This proposed structure for 10 was confirmed by direct comparison of the spectroscopic properties of the isolated photoproduct with an authentic sample of ester 10 synthesized by acetylation of diethyl malonate 11 to provide acetyldiester 12 and treatment of the latter with methylhydrazine as shown in Scheme 4. The photoreaction of pyranopyrazole 1 in ethanol solvent is summarized in Scheme 5.The photochemistry of N-phenylpyranopyrazole 2 was analogous to the photochemistry of Nmethylpyranopyrazole 1.Thus, as shown in Scheme 6, irradiation of 2 at 254 nm in acetonitrile solvent led to the formation of a single photoproduct 13, shown by mass spectroscopy, elemental analysis, and 1 H and 13 C NMR spectroscopy to be the cis-head-to tail dimer 13 formed in 58% yield.

Scheme 6
Irradiation of 2 in ethanol, however, led to the formation of dimer 13 in 22% yield and to the formation of ethyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate 14. 28 The structure of ester 14 was confirmed by comparison of the photoproduct with an authentic sample of 14 synthesized in this laboratory.
The formation of photodimers 5 and 13 from 1 and 2 respectively is viewed as [2+2] cycloaddition reactions occurring from the S 1 (π, π*) state of the pyranopyrazole in which the excitation energy is localized within the 4-pyrone ring.In alcohol solvent, it is suggested that the excited state partitions between [2+2] dimerization and 2,6-bridging, as shown in Scheme 7, to yield zwitterionic species 15.Such 2,6-bridging is a well-established photochemical pathway for 4-pyrones and is known to be enhanced by the use of polar protic solvents. 7Although such photochemically generated zwitterions are generally trapped by nucleophilic solvents, such as alcohols, with simultaneous opening of the epoxide ring, 10,11 in the present case it is suggested that 15 undergoes cleavage to yield ketene 17 via intermediate 16.Whereas such cleavage is not a known pathway for zwitterions photochemically generated from monocyclic 4-pyrones, in the present case it is plausible that the strain associated with two fused five-membered rings in 15 provides the driving force for cleavage of 16 to yield ketene 17.The latter species is then trapped by the alcohol solvents to yield the observed esters.As expected by this mechanistic suggestion, irradiation of pyranopyrazole 1 in methanol solvent led to the formation of dimer 5 and the methyl ester 18, analogous to 10, as shown in Scheme 8. Experimental Section General Procedures.All melting points were determined using a MEL-TEMP apparatus and are uncorrected. 1H NMR spectra (400 MHz) and 13 C NMR spectra (100 MHz) were recorded on a Bruker FT-NMR system. 1 H and 13 C chemical shifts were measured relative to internal TMS (0 ppm) and CDCl 3 (77.0ppm) respectively.UV absorption spectra were recorded in 1.0 cm matched quartz cells using a Hitachi U-2000 spectrometer.HPLC analyses were carried out on a Waters Model 510 system equipped with a C-18 90Ǻ 5µm 3.9 x 300 mm column.Analysis of the photoreactions of 1 or 2 were carried out using a mobile phase of 75% methanol-25% water ( 0.50 ml min -1 ) or 65% methanol-35% water ( 0.5 ml min -1 ) respectively.Preparative layer chromatography was carried out on 20-cm x 20-cm glass plates coated with 2mm Kieselgel 60 F 254 (Merck).

Irradiation procedures
Analytical scale.A solution of the pyranopyrazole 1 or 2 (3.0 mL, 2.0 x 10 -2 M) in either acetonitrile or ethanol was placed in a quartz tube (7.0 mm i.d.x 10.0 cm long), sealed with a rubber septum, purged with argon for 10 minutes and irradiated in a Rayonet reactor equipped with 14 low pressure mercury lamps.Aliquots (5.0 microliters) were removed periodically for analysis by HPLC.
Preparative scale.A solution of the pyranopyrazole 1 or 2 (20.0 mL, 2.0 x 10 -2 M) in either acetonitrile or ethanol was placed in a quartz tube (1.0 cm i.d.x 22.0 cm long), sealed with a rubber septum, purged with argon for 20 minutes and irradiated in a Rayonet reactor equipped with 14 low pressure mercury lamps.Aliquots (5.0 microliters) were removed periodically for analysis by HPLC.

Determination
Scheme 1

Figure 1 .
Figure 1.Crystal structure of the cis-head-to-tail [2 + 2] cycloaddition dimer 5c viewed from above (a) and from the sides (b and c) of the cyclobutane ring.