Synthesis and photooxygenation of 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles: facial selectivity

Two 3-(p-substituted phenyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazoles were synthesized by 1,3-dipolar cycloaddition of the corresponding nitrile oxides with cycloheptatriene. Two endoperoxides were synthesized as facially selective and single products in high yields (93%–95%) from the reactions of isoxazole derivatives with singlet oxygen. The exact configurations of the endoperoxide with a methyl group in the phenyl ring and the diol synthesized from it were confirmed by X-ray analysis. To elucidate the mechanism, the formation energy of the endoperoxide was investigated by simulations using the software package Gaussian 09 and density functional theory calculations via the M06-2X/6-311+G(d,p) level method in dichloromethane. The results were consistent with experimental findings showing the formation of isoxazole products.


Synthesis
As described previously [7,11,12], oximes 4 and 5 were synthesized to obtain new compounds that are derivatives of compound 3. Therefore, the reactions of oximes 4 and 5 with cycloheptatriene (CHT) were carried out separately (Scheme 1).The products 7 and 8 obtained from each reaction were purified by column chromatography and obtained in high yields.Adducts 7 and 8 are structures in which five-and seven-membered rings are interlocked with each other.According to the 1 H-NMR spectra of these products, the double bonds in the seven-membered rings were conjugated.
Reactions such as Diels-Alder reactions can be performed with the conjugated diene in the seven-membered ring of compounds 7 and 8 and compounds with various functional groups, especially in its seven-membered ring, can be obtained.As a result of Diels-Alder reactions of conjugated dienes with singlet oxygen and PTAD (4-phenyl-1,2,4triazoline-3,5-dione), oxygen and nitrogen atoms are placed at the 1,4 positions of the diene [1,2,13,14].Compound 7 was reacted with both singlet oxygen and PTAD.Only one product from each of these reactions was isolated in high yield (Scheme 2).Since it is understood from their NMR spectra that there is only a double bond in their seven-membered ring, these products are adducts formed by Diels-Alder reactions.
A catalytic hydrogenation reaction is used in the reduction of many functional groups such as unsaturated endoperoxides [1,[15][16][17].The adduct, endoperoxide 9, was reacted with gaseous hydrogen (approximately 1.0 atm) in the presence of catalyst Pd/C at room temperature (RT) (Scheme 2).A product was obtained from the purification process of the reaction mixture on the silica gel column chromatography.This product should be a diol derivative because no double bond was present in its seven-membered ring when its NMR spectra were investigated and it was more polar than the corresponding endoperoxide.X-ray analysis of the diol derivative both explains its configuration as 10 and suggests that the structures of the adducts formed from the reactions of 7 with singlet oxygen and PTAD should be 9 and 11, respectively.Moreover, the proposed structure of endoperoxide 9 was confirmed by X-ray analysis of it.

DFT calculations
As mentioned above, the formation of a single product in the Diels-Alder reactions of compounds 7 and 8 with dienophiles indicated that there was facial selectivity in them during these reactions.We also focused on testing this selectivity with a theoretical study and examined the mechanism in detail.In our previous research, we used quantum chemical calculations including DFT in the M06-2X method to examine the structural properties of compounds and shed light on the formation mechanism of reactions and obtained quite consistent results [18][19][20].The fact that the method used in these studies yielded good results prompted us to use the same method in the quantum chemical calculations in the present study.

Computational details
The DFT studies were carried out with the software package Gaussian 09 [21].The visualizations of the geometric optimizations for all calculations were generated with the program CYLview v1.0.561BETA [22] and the software GaussView 5.0 [23].All calculations were performed using DFT with the M06-2X method at the 6-311+G(d,p) level in DCM, and the default polarizable continuum model (PCM) method was used [24,25].In the present study, we examined the reaction mechanism by optimizing the product (endoperoxide) and the reactant obtained from the intrinsic reaction coordinate (IRC) calculation of the transition state (TS).

Mechanistic calculations
There are two possible pathways for the [4+2] cycloaddition mechanism of 1 O 2 to 3-(p-tolyl)-3a,8a-dihydro-4Hcyclohepta[d]isoxazole (7), as shown in Scheme 3. We observed that the endoperoxides (9 and 9ꞌ) were formed when the products from IRC calculations of the TSs were optimized.In both TSs, the endoperoxide formation reaction occurred in an asynchronous concerted manner by the electrophilic attack of O2 on C1 and C4 on O1 with singlet oxygen approaching compound 7 from the same (path B) or opposite (path A) direction as H1 and H2.
The first transition state (TS1) corresponds to the electrophilic attack of the singlet oxygen molecule ( 1 O 2 ) on the carbon atom (C1) in the less sterically face of diene 7 from the opposite direction as H1 and H2.This transition state is shown as path A in Scheme 3 and Figure 4.In the case of path B, the alternative transition state (TS1′) corresponds to the electrophilic attack of O2 on the C1 atom from the same direction as H1 and H2.The optimized geometries of the transition structures for paths A and B are shown in Figure 4.
The relative Gibbs free energies of both mechanisms are presented in Table .While the TS1ꞌ energy barrier of path B (8.3 kcal/mol) is lower than the TS1 energy barrier of path A (9.1 kcal/mol), the relative energy value of the reactant complex  (RCꞌ) for path B is higher by 2.9 kcal/mol than the energy of the reactant complex (RC) for path A. This result shows that RC is more stable than RCꞌ.Considering the stability of the products obtained from both pathways, it was calculated that the relative Gibbs free energy of product 9 (product compound, PC) was lower by 0.2 kcal/mol than that of product 9ꞌ (PCꞌ).According to these results, since the relative energy values of the reactant complex (RC) and product (PC) of path A are lower than those of path B (RCꞌ and PCꞌ), the product to be formed is expected to be obtained from path A. For paths A and B, potential energy profiles in DCM are depicted in Figure 5.The TS1ꞌ energy barrier of path B is lower by 0.8 kcal/ mol than the TS1 energy value of path A. However, this value represents a very small energy difference for the transition state during the formation of the product.Here the most important driving force in the formation of the product is the relative energy values of the initially formed reactant complex.

Conclusion
As seen in Scheme 1, two new isoxazole derivatives (7 and 8) were synthesized from the reactions of CHT with oximes 4 and 5.It was observed that the endoperoxides 9 and 12 obtained during their reactions were formed as single products in high yields by the Diels-Alder reaction.Compound 7 was also reacted with PTAD and the adduct 11 was obtained quantitatively from this reaction.Diol 10 was obtained from the reaction of endoperoxide 9 with catalytic hydrogenation.
To determine the configurations of endoperoxides (9 and 12) and interpret the formation of adducts, X-ray diffraction analyses of compounds 10 and 12 were performed, respectively.Furthermore, the analyses indicated that the observation of facial selectivity in Diels-Alder reactions is the result of the approach of the dienophiles ( 1 O 2 and PTAD) to the diene moieties of 9 and 10 from only one side.Facial selectivity in the adducts was also investigated theoretically, taking into account the formation of endoperoxide 9.After the structure of compound 9 was elucidated by X-ray analysis, it was examined by the M06-2X/6-311+G(d,p) level method in DCM to understand the formation mechanism of the product.Our computational studies supported the experimental findings showing that benzoxazole products are formed in this reaction.This research will make significant contributions to the study of elucidating the structure of the products that will be formed during the photooxygenation of isoxazole derivatives in which the cyclic structures are adjacent.

Synthesis of 3-(p-tolyl)-3a,8a-dihydro-4H-cyclohepta[d]isoxazole (7)
A stirring solution of compound 4 (2.6 g, 1.0 equiv.)and 6 (5.0 equiv.) in CH 2 Cl 2 (30 mL) was cooled in the ice bath and then a solution of NEt 3 (2.98 g, 2.0 equiv.) in CH 2 Cl 2 (10 mL) was added dropwise to this solution.After the mixture was stirred for 2 days without further bath cooling, the reaction mixture was monitored by TLC and the reaction was completed.Water (15 mL) was added to the mixture and then the pH of the mixture was adjusted to 6-7 with dilute HCl solution.The mixture was extracted with CH 2 Cl 2 (2 × 15 mL) and after the organic phases were combined, the resulting solution was dried over Na 2 SO 4 , and the solvent was removed under low pressure.

Catalytic hydrogenation of endoperoxide 9
After compound 9 (300 mg, 1.17 mmol), Pd/C catalyst (6 mg), and EtOAc (30 mL) were placed in a flask (100 mL, twonecked) fitted with a spin bar at RT, the air in the flask was replaced 3 times by hydrogen gas (about 1 atm in the balloon attached to the flask).Subsequently, the reaction was started, checked from time to time by TLC, and terminated after 5 days.The reaction mixture was filtered through filter paper to remove the catalyst and EtOAc was removed by rotary evaporator at RT. Diol 10 (115 mg, 38%) was obtained from the purification of residue on silica gel column chromatography (25 g) with EtOAc/petroleum ether (2/3) and crystallized in the mixture of CHCl

Figure 2 .
Figure 2. (Top) X-ray structure of the molecule 9. Thermal ellipsoids are drawn at the 40% probability level.(Bottom) The crystal lattice and the unit cell viewed down along the c-, b-, and a-axis, respectively, with the square void motif.

Figure 3 .
Figure 3. (Top) Molecular structure of 10.Thermal ellipsoids are drawn at the 40% probability level.(Bottom) Consecutive tetramer chain structure with H-bonding geometry.

Scheme 3 .
Scheme 3. Paths A and B of the proposed mechanism for the endoperoxides.

Table .
Gibbs free energies and relative ΔG energies (kcal/mol) of the reactant complexes, transition states, and products for both mechanisms with M06-2X/6-311+G(d,p) level in DCM.

. Photooxygenation of compound 8
The reaction was carried out like the photooxygenation of compound 7 in 4.4.The reaction was realized according to procedure 1. Compound 8 (180 mg), CH 2 Cl 2 (70 mL), and TPP (catalytic) were used in the reaction.The reaction lasted 3 days and its crystallization was carried out like that of endoperoxide 9.