Cyclization–endoperoxidation cascade reactions of dienes mediated by a pyrylium photoredox catalyst

Summary Triarylpyrylium salts were employed as single electron photooxidants to catalyze a cyclization–endoperoxidation cascade of dienes. The transformation is presumed to proceed via the intermediacy of diene cation radicals. The nature of the diene component was investigated in this context to determine the structural requirements necessary for successful reactivity. Several unique endoperoxide structures were synthesized in yields up to 79%.


4,4'-(Hexa-1,5-diene-2,5-diyl)bis(methoxybenzene) (2b)
Prepared according to a published procedure; spectral data were in agreement with the literature values. 2 (5-Methylhexa-1,5-dien-2-yl)benzene (2c) 1.05 equiv of sodium hydride were dispensed into a flame-dried round bottom flask, which was subsequently purged with N 2 . The sodium hydride was suspended in dry THF (0.4 mmol/mL) and the stirred suspension was cooled to 0 °C in an ice bath. At 0 °C, ethyl acetoacetate was added dropwise with stirring. The solution was stirred at 0 °C for 30 minutes after effervescence ceased. At 0 °C, (3-bromoprop-1-en-2-yl)benzene (1.05 equiv) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours overnight. The reaction was then quenched with concentrated NH 4 Cl solution and diluted with DI water and diethyl ether. The organic layer was separated and aqueous layer extracted three times with diethyl ether in a separatory funnel. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil, which was taken on to the next step without further purification.
Decarboxylation of the crude alkylation product was carried out as follows: sodium hydroxide (5.2 equiv) was weighed into a round bottom flask containing a 2:1 water/ethanol mixture (approx. concentration 0.3 mmol/mL) and stirred to dissolution. At room temperature the crude alkylation product was introduced dropwise, then the reaction was heated to 70 °C overnight. The reaction was cooled to room temperature and quenched with concentrated NH 4 Cl. The organic phase was separated and the aqueous phase extracted three times with diethyl ether. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil, which was taken on to the next step without further purification.
The crude aryl ketone was converted to the diene product by Wittig olefination. Olefination procedure for this substrate was identical to the Wittig olefination procedure in General procedure A below (step 2). The final product was purified using silica gel column chromatography (20% EtOAc/hexanes) to furnish 0.78 g of pure product (47% overall) as a colorless oil. Spectral data were in agreement with the reported literature values. 3  Carried out using the procedure above for synthesis of 2c. In the initial alkylation, ethyl benzoyl acetate was used in place of ethyl acetoacetate and 3,3-dimethylallyl bromide in place of (3-bromoprop-1-en-2-yl)benzene. The remaining steps were carried out without alteration. The final product was purified using silica gel column chromatography (20% Et 2 O/hexanes) to furnish 0.67 g of pure product (50% overall) as a colorless oil. Spectral data were in agreement with the reported literature values. 3

General procedure A: Preparation of substrates with geminal dimethyl tether
A flame-dried round bottom flask equipped with magnetic stirbar containing potassium tert-butoxide (1.2 equiv) was purged with nitrogen. Dry THF was added via syringe (approximate concentration 0.4 mmol/mL) and the solution was cooled to 0 °C in an ice bath with stirring. At 0 °C, 1-(4-methoxyphenyl)-2-methylpropan-1-one (prepared according to literature procedure 4 ) was added to the stirring solution via syringe dropwise and stirred for 1 hour. At 0 °C, the appropriate allylic bromide was added dropwise via syringe and stirred at room temperature for 16 hours. The reaction was then quenched with concentrated NH 4 Cl solution and diluted with DI water and diethyl ether. The organic layer was separated and aqueous layer extracted three times with diethyl ether in a separatory funnel. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil, which was taken on to the next step without further purification (acceptable purity confirmed by TLC and 1 H NMR).

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The crude allylation product was converted to the desired diene by Wittig olefination. Potassium tert-butoxide (1.3 equiv) and methyltriphenylphosphonium bromide (1.4 equiv) were dispensed into a flame-dried round bottom flask equipped with a magnetic stirbar. The flask was purged with nitrogen and cooled to 0 °C with stirring. At 0 °C, dry THF was added via syringe (approximate concentration 0.4 mmol/mL) and the solution was stirred at 0 °C for 1 hour. At 0 °C, the crude allylation product was added via syringe (in THF) dropwise. The reaction was warmed to room temperature and stirred overnight. Upon completion, the reaction was quenched with concentrated NH 4 Cl solution and then diluted with DI water and diethyl ether. The organic layer was separated and aqueous layer extracted three times with diethyl ether in a separatory funnel. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford the crude product. The product was purified by silica gel column chromatography.

1-Methoxy-4-(3,3,6-trimethylhepta-1,5-dien-2-yl)benzene (2a)
Diene prepared according to general procedure A using 3,3-dimethylallyl bromide as the electrophile in the first step. The final product was purified by silica gel column chromatography (20% diethyl ether/hexanes) to furnish 2.16 g of pure product (88%) as a colorless oil. Analytical data for 2a: 1  Diene prepared according to general procedure A using cinnamyl bromide as the electrophile in the first step. The final product was purified by silica gel column chromatography (20% diethyl ether/hexanes) to furnish 2.73 g of pure product (93%) as a yellow oil. Analytical data for 2m: 1

General procedure B: Preparation of substrates with methylene tether
Freshly activated and dried magnesium turnings (1.38 equiv relative to aldehyde) were weighed into a flame-dried round bottom flask equipped with a stir bar. The flask was purged with nitrogen, cooled to 0 °C, and diethyl ether dispensed (to approximate concentration 0.6 mmol/mL). Seventy microliters 1,2-dibromoethane were added to activate the magnesium and stirred for 15 minutes. At 0 °C, 5-bromo-2-methyl-2-pentene (1.25 equiv relative to aldehyde) was added dropwise to the stirring magnesium turnings and stirred for 2 hours (consumption of magnesium observed). After formation of the Grignard reagent, the necessary aldehyde (freshly distilled to ensure purity), in diethyl ether, was added to the reaction mixture dropwise at 0 °C and stirred for 18 hours. The reaction was quenched with concentrated NH 4 Cl solution dropwise and diluted with DI water and diethyl ether. The organic layer was separated and aqueous layer extracted three times with diethyl ether in a separatory funnel. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil, which was taken on to the next step without further purification (acceptable purity confirmed by TLC and 1 H NMR).
The crude alkenol product was then converted to the aryl ketone via Swern oxidation. A flame-dried round bottom flask containing a stir bar was charged with dry DCM (to approximate concentration of 0.25 mmol/mL) and cooled to −78 °C. At −78 °C, the flask was charged with oxalyl chloride (1.2 equiv) and stirred. After 10 minutes, DMSO (2.4 equiv) was added to the flask dropwise then stirred for 25 minutes at −78 °C. The alkenol substrate was next added to the reaction mixture dropwise and stirred for additional 25 minutes at −78 °C. Finally, triethylamine (5 equiv) was added to the reaction dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was quenched with concentrated NH 4 Cl, the organic layer was separated, and the aqueous layer extracted three times with DCM. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford the crude aryl ketone, which was further purified by silica gel column chromatography. The purified aryl ketone was converted to the desired unconjugated diene by Wittig olefination. Wittig olefination procedure for general procedure B is identical to Wittig olefination procedure in general procedure A (step 2).

benzene (2i)
Diene prepared according to general procedure B using o-anisaldehyde in the Grignard addition step. The aryl ketone product from oxidation was purified by silica gel column chromatography (10% EtOAc/hexanes). The final product was purified using silica gel column chromatography (hexanes) to furnish 1.58 g of the desired diene (47%) as a colorless oil. Spectral data were in agreement with the reported literature values. 7 Analytical data for 2i: 1

1-Methyl-4-(6-methylhepta-1,5-dien-2-yl)benzene (2j)
Diene prepared according to general procedure B using 4-tolualdehyde in the Grignard addition step. The aryl ketone product from oxidation was purified by silica gel column chromatography (10% Et 2 O/hexanes). The final product was purified using silica gel column chromatography (hexanes) to furnish 1.27 g of the desired diene (52%) as a colorless oil. Spectral data were in agreement with the reported literature values. 7 Analytical data for 2j: 1

2,4-Dimethoxy-1-(6-methylhepta-1,5-dien-2-yl)benzene (2g)
A flame-dried round bottom flask, containing 2,4-dimethoxybenzoic acid (1.0 equiv) and N,O-dimethylhydroxylamine hydrochloride (1.2 equiv) dissolved in anhydrous dichloromethane (0.2 M), was cooled to 0 °C with stirring. At 0 °C, triethylamine (1.2 equiv) was added to the solution dropwise via syringe and stirred for 15 minutes. Next, at 0 °C, 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (EDCI•HCl, 1.2 equiv) was added to the stirring solution in one portion. The reaction was allowed warm to room temperature and stir overnight. The reaction was then quenched with 2 N HCl and diluted with DCM. The organic layer was separated and washed twice with DI water. The combined organics were then washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil, which was taken on to the Grignard addition without further purification.
Grignard addition into the Weinreb amide and Wittig olefination were carried out according the equivalent procedures in general procedure B. The aryl ketone produced from Grignard addition into the Weinreb amide was purified by column chromatography (20% EtOAc/hexanes) to yield a colorless oil (1.76 g, 47%). The Wittig olefination product was purified by column chromatography (20% Et 2 O/hexanes) to give 1.42 g (81%) of the desired unconjugated diene as a colorless oil. Analytical data for 2g: 1

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The reaction was allowed to warm to room temperature and stirred for 15 hours overnight. The reaction was then quenched with concentrated NH 4 Cl solution, and diluted with DI water and diethyl ether. The organic layer was separated and aqueous layer extracted three times with diethyl ether in a separatory funnel. The combined organics were washed with brine, dried with anhydrous MgSO 4 , filtered, and concentrated to afford a crude oil. The crude allylic ether was purified by silica gel column chromatography (20% Et 2 O/hexanes) to yield 2.16 g (70%) of the desired product as an off-white oil. Analytical data for 2t: 1

Procedure for synthesis of bicyclic endoperoxide 3a from diene 2a
A flame dried 1-dram vial equipped with a magnetic stir bar and 0.25 mg and 2,4,6-tris(4methoxyphenyl)pyrylium tetrafluoroborate catalyst, then sealed with a septum cap. 0.5 mL dry acetonitrile was then added via syringe under an atmosphere of nitrogen. Finally, 30 mg diene 3a was added to the stirring reaction mixture in 0.5 mL acetonitrile. A balloon of oxygen was fitted to the vial and bubbled through the stirring solution for 2 minutes. After bubbling was suspended, an atmosphere of oxygen was maintained over the solution and the reaction was irradiated for two hours at ambient temperature using 470 LEDs. Upon completion, the desired product was isolated using silica gel column chromatography (33% Et 2 O/hexanes). Spectral data were in agreement with the literature values. 12 General procedure for endoperoxidation of unconjugated dienes under oxygen atmosphere.
A flame dried flask (2-dram vial, scintillation vial, or round-bottom flask) was equipped with a magnetic stir bar and 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate catalyst (1c, 4-MeO-TPT, see conditions above for catalyst loading), then sealed with a septum. The solvent (DCM for conditions A and C, DCE for condition B, see conditions above for concentration) was then added to the flask via syringe under an atmosphere of nitrogen. Substrate was then added to the flask via microsyringe and stirred to ensure a homogeneous reaction mixture. A balloon of oxygen was fitted to the reaction flask and oxygen was bubbled through the stirring solution for 3 minutes to ensure oxygen saturation in the solvent. After bubbling was suspended the reaction was fitted with a balloon of oxygen to ensure an oxygen atmosphere and submerged in a temperature-controlled bath (−41 °C for conditions A and C, −10 °C for condition B). The reaction was irradiated with 470 nm LEDs until completion (as monitored by TLC). Upon completion, the reaction mixture was concentrated under reduced pressure and the products isolated by silica gel column chromatography.

1-(2-methoxyphenyl)-4,4-dimethyl-2,3-dioxabicyclo[3.2.1]octane (3i)
The average yield for the title compound was 16% (2 trials) at the 0.5 mmol scale, using condition B, and an irradiation time of 5 hours. The title compound was purified by column chromatography on silica gel (20% EtOAc/hexanes) to yield a white solid. Analytical data for 3i: 1   and The average yield for the title compound was 64% (2 trials) at the 0.5 mmol scale, using condition C, and an irradiation time of 4 hours. The polycyclic product was isolated as 6.5:1 mixture of inseparable diastereomers (shown above, left thought to be major diastereomer). The title compound was purified by column chromatography on silica gel (10% Et 2 O/pentane) to yield a colorless oil. Analytical data for 3n: 1

1-(4-Methoxyphenyl)-4-methylpent-4-en-1-one (3p)
The yield for the title compound was 37% (1 trial) at the 0.5 mmol scale, using condition C, and an irradiation time of 23 hours (-41 °C to rt). The title compound was purified by column chromatography on silica gel (20% Et 2 O/pentane) to yield a colorless oil. Spectral data were in agreement with the literature values. 13

1-(4-Methoxyphenyl)pent-4-en-1-one (3q)
The yield for the title compound was 27% (1 trial) at the 0.5 mmol scale, using condition C, and an irradiation time of 23 hours (−41 °C to rt). The title compound was purified by column chromatography on silica gel (20% Et 2 O/pentane) to yield a colorless oil. Spectral data were in agreement with the literature values. 13 Analytical data for 3q: 1

1-(4-Methoxyphenyl)-4-phenyltetrahydro-1H,4H-furo[3,4-d][1,2]dioxine (3u)
The average yield for the title compound was 79% (2 trials, 5.7:1 mixture of diastereomers) at the 0.5 mmol scale, using condition C, and an irradiation time of 3 hours. The title compound was purified by column chromatography on silica gel (33% to 50% EtOAc/hexanes) to yield a colorless oil. Spectral data were in agreement with the literature values. 11 Analytical data for 3u: 1  The yield for the title compound was 65% (1 trial) at the 0.36 mmol scale, using modified condition A, and an irradiation time of 3.5 hours. Rose Bengal was used in place of catalyst 1c and dry MeOH as solvent in place of DCM. The reaction was carried out at ambient temperature. The title compound was purified by column chromatography on silica gel (20% Et 2 O/hexanes) to yield a colorless oil. It should be noted that the shown tertiary allylic hydroperoxide was the major product in a transformation possibly producing multiple oxidation products (complete consumption of starting material was observed by 1 H NMR