Synthesis and Characterization of Multiple Functionalized Cyclohexanone Using Diels–Alder Reaction of -Nitrocinnamate

A systematic study of the Diels–Alder reaction of α-nitrocinnamate was performed. The reaction of p-substituted α-nitrocinnamate with 2,3-dimethyl-1,3-butadienes smoothly proceeded regardless of the p-substituent, which was either an electron-donating or -withdrawing group. A control reaction revealed that α-nitrocinnamate isomerized during the reaction. Danishefsly’s diene (1-methoxy-3-trimethylsiloxy-1,3-butadiene) facilitated cycloaddition under mild conditions to afford a cycloadduct without the alternation of the diastereomeric ratio. Moreover, the desilylation of the cycloadduct furnished multiple functionalized cyclohexanones.


Results and Discussion
When a toluene solution of ethyl α-nitrocinnamate 1a was heated with 1,3-butadiene 2 at 150 • C under microwave irradiation, product 3a was isolated in a 13% yield (Table 1, Entry 1). In the 1 H NMR of 3a, two singlet signals were inequivalently observed at around 1.7 ppm, indicating that symmetrical butadiene was converted into an unsymmetrical structure. Other spectral data also supported the idea that difunctionalized cyclohexene 3a was successfully obtained. To increase the yield of 3a, several solvents were tested, Table 1. Optimal conditions of the Diels-Alder reaction with ethyl α-nitrocinnamate 1a and 2,3dimethyl-1,3-butadiene (2).
Reactions 2022, 3, FOR PEER REVIEW 2 1.7 ppm, indicating that symmetrical butadiene was converted into an unsymmetrical structure. Other spectral data also supported the idea that difunctionalized cyclohexene 3a was successfully obtained. To increase the yield of 3a, several solvents were tested, and acetonitrile was found to be the most suitable (Entries 1-4). Though six hours were necessary to consume 1a at 150 °C (Entry 5), the reaction was completed within two hours when the reaction temperature was elevated to 180 °C (Entry 6). The optimal conditions were applied to several ethyl α-nitrocinnamates 1b-f possessing different substituent at the para position (Scheme 1). Each reaction used two diastereomeric products with different positions of the nitro and ethoxycarbonyl groups at the 3 position. Reactions efficiently proceeded, with substrates substituting either the electron-donating or -withdrawing group to afford the corresponding products 3b-e; however, the reaction of nitro-substituted substrate 1f was complicated due to overreactions such as the elimination of a nitrous acid and subsequent oxidation. This disadvantage was overcome by reducing the reaction temperature to 150 °C, and cycloadduct 3f was quantitatively obtained. Among substrates 1a-f, methoxy-and bromo-substituted cinnamates 1b and 1d were the least reactive, which was presumably due to the electron-donating resonance effect that increased the single bond character of the double-bond moiety. Systematic studies showed that the diastereomeric ratio of products 3a-f was about 60/40 even when only a Z isomer was used as a starting material, which means that isomerization occurred during the reaction. To reveal this phenomenon, only the Z isomer of 1a was heated at 180 °C, which afforded a Z/E mixture of 1a with a 60/40 ratio (Scheme 2). This result indicated that the isomerization of 1 occurred under reaction conditions and not during the Diels-Alder reaction.  The optimal conditions were applied to several ethyl α-nitrocinnamates 1b-f possessing different substituent at the para position (Scheme 1). Each reaction used two diastereomeric products with different positions of the nitro and ethoxycarbonyl groups at the 3 position. Reactions efficiently proceeded, with substrates substituting either the electron-donating or -withdrawing group to afford the corresponding products 3b-e; however, the reaction of nitro-substituted substrate 1f was complicated due to overreactions such as the elimination of a nitrous acid and subsequent oxidation. This disadvantage was overcome by reducing the reaction temperature to 150 • C, and cycloadduct 3f was quantitatively obtained. Among substrates 1a-f, methoxy-and bromo-substituted cinnamates 1b and 1d were the least reactive, which was presumably due to the electron-donating resonance effect that increased the single bond character of the double-bond moiety. Systematic studies showed that the diastereomeric ratio of products 3a-f was about 60/40 even when only a Z isomer was used as a starting material, which means that isomerization occurred during the reaction. To reveal this phenomenon, only the Z isomer of 1a was heated at 180 • C, which afforded a Z/E mixture of 1a with a 60/40 ratio (Scheme 2). This result indicated that the isomerization of 1 occurred under reaction conditions and not during the Diels-Alder reaction.
Next, α-cyano and α-acetylcinnamates 4 and 5 were employed as dienophiles instead of α-nitro derivative 1 (Scheme 3). Even when the nitro group was replaced with less electron-withdrawing acetyl groups, the cycloaddition proceeded to furnish the corresponding cycloadduct 6 with a 87/13 diastereomeric ratio. In the case of substrate 5 with a less hindered cyano group, cycloadduct 7 was quantitatively produced as a single isomer because the E isomer was not converted into an unstable Z isomer, even under conditions of progressive isomerization. When cyclopenta-1,3-diene 8 was subjected to the reaction with 1a, cycloadduct 9 was obtained in a 81% yield as a mixture of four diastereomers. Reactions 2022, 3, FOR PEER REVIEW 3 Scheme 1. Diels-Alder reactions of ethyl α-nitrocinnamates possessing a para-substituent.
Next, α-cyano and α-acetylcinnamates 4 and 5 were employed as dienophiles instead of α-nitro derivative 1 (Scheme 3). Even when the nitro group was replaced with less electron-withdrawing acetyl groups, the cycloaddition proceeded to furnish the corresponding cycloadduct 6 with a 87/13 diastereomeric ratio. In the case of substrate 5 with a less hindered cyano group, cycloadduct 7 was quantitatively produced as a single isomer because the E isomer was not converted into an unstable Z isomer, even under conditions of progressive isomerization. When cyclopenta-1,3-diene 8 was subjected to the reaction with 1a, cycloadduct 9 was obtained in a 81% yield as a mixture of four diastereomers.  Next, α-cyano and α-acetylcinnamates 4 and 5 were employed as dienophiles instead of α-nitro derivative 1 (Scheme 3). Even when the nitro group was replaced with less electron-withdrawing acetyl groups, the cycloaddition proceeded to furnish the corresponding cycloadduct 6 with a 87/13 diastereomeric ratio. In the case of substrate 5 with a less hindered cyano group, cycloadduct 7 was quantitatively produced as a single isomer because the E isomer was not converted into an unstable Z isomer, even under conditions of progressive isomerization. When cyclopenta-1,3-diene 8 was subjected to the reaction with 1a, cycloadduct 9 was obtained in a 81% yield as a mixture of four diastereomers. So far, nitrocinnamate 1 was found to serve as an excellent dienophile that could efficiently undergo the Diels-Alder reaction, which led to multiple substituted cyclohexene 3 products. Our next challenge was focused on the synthesis of more densely functionalized cyclohexenes. For this purpose, 1-methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky's diene, CAS No. 54125-02-9) 10 was employed because its silyl enol ether moiety can be converted into a carbonyl group upon desilylation and two electron-donating groups can improve its reactivity. The Diels-Alder reaction of 1a with diene 10 efficiently proceeded without heating to yield cycloadduct 11 regardless of the Z/E ratio of 1a (Scheme 4). The diastereomeric ratio of 11 was consistent with the Z/E ratio of 1a, and close to a single isomer (95/5) was obtained when only the Z form of 1a was used. So far, nitrocinnamate 1 was found to serve as an excellent dienophile that could efficiently undergo the Diels-Alder reaction, which led to multiple substituted cyclohexene 3 products. Our next challenge was focused on the synthesis of more densely functionalized cyclohexenes. For this purpose, 1-methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky's diene, CAS No. 54125-02-9) 10 was employed because its silyl enol ether moiety can be converted into a carbonyl group upon desilylation and two electron-donating groups can improve its reactivity. The Diels-Alder reaction of 1a with diene 10 efficiently proceeded without heating to yield cycloadduct 11 regardless of the Z/E ratio of 1a (Scheme 4). The diastereomeric ratio of 11 was consistent with the Z/E ratio of 1a, and close to a single isomer (95/5) was obtained when only the Z form of 1a was used. Cycloadduct 11 easily underwent desilylation to afford cyclohexanone 12 in air or during treatment with chromatography on silica gel. The formation of 12 was confirmed by NMR and IR measurements. In the 1 H NMR spectra, a doublet at 5.2 ppm assigned to an alkenyl proton of 11 disappeared, and the absorption of a carbonyl group newly appeared in the IR spectrum. So far, nitrocinnamate 1 was found to serve as an excellent dienophile that could efficiently undergo the Diels-Alder reaction, which led to multiple substituted cyclohexene 3 products. Our next challenge was focused on the synthesis of more densely functionalized cyclohexenes. For this purpose, 1-methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky's diene, CAS No. 54125-02-9) 10 was employed because its silyl enol ether moiety can be converted into a carbonyl group upon desilylation and two electron-donating groups can improve its reactivity. The Diels-Alder reaction of 1a with diene 10 efficiently proceeded without heating to yield cycloadduct 11 regardless of the Z/E ratio of 1a (Scheme 4). The diastereomeric ratio of 11 was consistent with the Z/E ratio of 1a, and close to a single isomer (95/5) was obtained when only the Z form of 1a was used. Cycloadduct 11 easily underwent desilylation to afford cyclohexanone 12 in air or during treatment with chromatography on silica gel. The formation of 12 was confirmed by NMR and IR measurements. In the 1 H NMR spectra, a doublet at 5.2 ppm assigned to an alkenyl proton of 11 disappeared, and the absorption of a carbonyl group newly appeared in the IR spectrum. Since cyclohexanone 12 is an oil, it was converted into solid hydrazone 13 to determine its stereochemistry with single X-ray crystallography. A single diastereomer of cyclohexanone 12 obtained from the Z isomer of 1a was reacted with 2,4-dinitrophylhydrazine in ethanol in the presence of hydrochloric acid, which afforded hydrazone 13 without any stereochemical isomerization. During the reaction, methanol was eliminated. The recrystallization of 13 from toluene-hexane successfully yielded orange needles as a single crystal, and X-ray crystallography revealed that the nitro group and 4-methylphenyl group were substituted in the cis form, which was the same relationship as the Z form in 1a (Figure 1, Supplementary Materials). These results confirmed that the Diels-Alder reaction concertedly proceeded. Since cyclohexanone 12 is an oil, it was converted into solid hydrazone 13 to determine its stereochemistry with single X-ray crystallography. A single diastereomer of cyclohexanone 12 obtained from the Z isomer of 1a was reacted with 2,4-dinitrophylhydrazine in ethanol in the presence of hydrochloric acid, which afforded hydrazone 13 without any stereochemical isomerization. During the reaction, methanol was eliminated. The recrystallization of 13 from toluene-hexane successfully yielded orange needles as a single crystal, and X-ray crystallography revealed that the nitro group and 4-methylphenyl group were substituted in the cis form, which was the same relationship as the Z form in 1a (Figure 1, Supplementary Materials). These results confirmed that the Diels-Alder reaction concertedly proceeded.

Conclusions
A systematic study of the Diels-Alder reactions of α-nitrocinnamate 1 was performed. Cinnamate 1 efficiently reacted with 2,3-dimethyl-1,3-butadiene 2 to afford cyclohexene 3 in high yields. This reaction was not influenced by the p-substituent of the phenyl group. Cycloadduct 3 was obtained as a mixture of stereoisomers, which was found to be due to E/Z isomerization at high temperatures. In the case of the more electron-rich Danishefsly's diene 10, cycloaddition efficiently proceeded under mild conditions, which furnished highly functionalized cyclohexene 11. Multiple functionalized cyclohexanones 12 were obtained via the subsequent desilylation of 11. The insights obtained in this study are surely valuable in the field of organic synthesis.

Conclusions
A systematic study of the Diels-Alder reactions of α-nitrocinnamate 1 was performed. Cinnamate 1 efficiently reacted with 2,3-dimethyl-1,3-butadiene 2 to afford cyclohexene 3 in high yields. This reaction was not influenced by the p-substituent of the phenyl group. Cycloadduct 3 was obtained as a mixture of stereoisomers, which was found to be due to E/Z isomerization at high temperatures. In the case of the more electron-rich Danishefsly's diene 10, cycloaddition efficiently proceeded under mild conditions, which furnished highly functionalized cyclohexene 11. Multiple functionalized cyclohexanones 12 were obtained via the subsequent desilylation of 11. The insights obtained in this study are surely valuable in the field of organic synthesis.

Experimental Section
All reagents were purchased from commercial sources and used without further purification. 1 H and 13 C NMR spectra were recorded with Bruker DPX-400 and JEOL JMN-ECZ400S spectrometers (400 MHz and 100 MHz, respectively) using TMS as an internal standard. The assignments of the 13 C NMR spectra were performed with DEPT experiments. IR spectra were recorded with a JASCO FT/IR-4200 spectrometer equipped with an ATM detector. High-resolution mass spectra were obtained with an AB SCEIX Triplet TOF 4600 mass spectrometer. Microwave heating was performed with an Anton Paar Microwave 300 (850 W, 2455 MHz) and an Anton Paar Microwave 400 (850 W, 2450 MHz) using a 10 mL glass vessel. Diffraction data were collected at 93 K under a cold N 2 gas stream with a Rigaku XtaLAB Synergy-S/Mo system (λ = 0.71073 Å (Mo-Kα)). The integrated data were analyzed by using a Yadokari-XG software package. The structures were solved with the ShelXT structure solution program using intrinsic phasing and refined with the ShelXL refinement package using least-squares minimization. Anisotropic refinement was performed for all non-hydrogen atoms, and all the hydrogen atoms were put in calculated positions.
Synthesis of α-nitrocinnamate 1a. α-Nitrocinnamate 1 was synthesized using a somewhat modified method previously described in the literature. Aniline (0.91 mL, 10.0 mmol) and magnesium sulfate (400 mg) were added to a solution of 4-methylbenzaldehyde (10.0 mmol) in THF (5 mL), and the mixture was stirred at room temperature for 5 h. After filtrations of magnesium sulfate, the filtrate was concentrated under reduced pressure to afford imine (2.0 g, 9.7 mmol, 97%) as a brown solid, which was used for the next step without further purification. A solution of imine (2.0 g, 9.7 mmol) and nitroacetate (1.08 mL, 9.7 mmol, CAS No. 626-35-7) in acetic anhydride (5 mL) was heated at 60 • C for 18 h. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (50 mL × 3). Organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was treated with flash column chromatography on silica gel (hexane/ethyl acetate = 9/1) to afford α-nitrocinnamate 1a (1520 mg, 6.5 mmol, 65%) as a yellow oil. When the aldehyde could not be completely separated, distillation was performed to remove it. The recrystallization of the product using hexane/chloroform afforded (Z) isomer. Other cinnamates 1b-f, 4, and 5 were synthesized in the same way.  Diels-Alder reaction of α-nitrocinnamate. 2,3-dimethyl-1,3-butadiene 2 (0.28 mL, 2.5 mmol) was added to a solution of α-nitrocinnamate 1a (117 mg, 0.5 mmol) in MeCN (1 mL), and the resultant solution was heated at 180 • C for 2 h under microwave irradiation. After the removal of the solvent under reduced pressure, the residue was subjected to flash column chromatography on silica gel (hexane/ethyl acetate = 95/5) to afford cycloadduct 3a (151 mg, 0.475 mmol, 95%) as a pale-yellow oil. When other substrates were used or conditions were changed, the reaction was conducted in the same way.