Sunlight photocatalyzed regioselective b-alkylation and acylation of cyclopentanones †

Scheme 1 Concept: photocatalyzed b-selective alkylation of cyclopentanone based on the radical polar effect. Introduction The site-selective conversion of sp C–H bonds into C–C bonds remains a challenge in synthetic organic chemistry and in recent years, much attention has been directed to both transition metal-catalyzed and radical approaches to this goal. Of special note is a unique method to selectively convert b-C–H bonds (rather than a-C–H bonds) in ketones, reported by MacMillan and coworkers. This method employed radical generation from enamines formed via an organocatalytic reaction between the ketone and an amine. Alternatively, the ketone can be converted in situ to the corresponding a,b-unsaturated derivative and then functionalized. We hypothesized that a photocatalyzed radical approach based on the use of tetrabutylammonium decatungstate (TBADT) as the catalyst, would be promising to promote the bregioselective alkylation of cyclopentanones. In cyclopentanone (1a), the a-C–H bond is weaker than the b-C–H bond. However, we reasoned that b-selective C–H bond cleavage would be promoted by polar effects in a system requiring a highly polar SH2 (bimolecular homolytic substitution) transition state, as in the case of hydrogen abstraction by TBADT. When electronegative oxygen-centered radicals, such as those present in the excited decatungstate anion (cat*), abstract hydrogen from C–H bonds, the transition state should be polar in order to balance the positively charged carbon atom. Therefore, TS-a (Scheme 1), leading to A via a-C–H cleavage from cyclopentanone, has to create an unstabilized electron-decient a-carbon that can be


Introduction
The site-selective conversion of sp 3 C-H bonds into C-C bonds remains a challenge in synthetic organic chemistry 1 and in recent years, much attention has been directed to both transition metal-catalyzed 2 and radical approaches to this goal. 3Of special note is a unique method to selectively convert b-C-H bonds (rather than a-C-H bonds) in ketones, reported by Mac-Millan and coworkers.This method employed radical generation from enamines formed via an organocatalytic reaction between the ketone and an amine. 4Alternatively, the ketone can be converted in situ to the corresponding a,b-unsaturated derivative and then functionalized. 5e hypothesized that a photocatalyzed radical approach 6 based on the use of tetrabutylammonium decatungstate (TBADT) as the catalyst, [7][8][9] would be promising to promote the bregioselective alkylation of cyclopentanones.In cyclopentanone (1a), the a-C-H bond is weaker than the b-C-H bond. 10However, we reasoned that b-selective C-H bond cleavage would be promoted by polar effects 11 in a system requiring a highly polar S H 2 (bimolecular homolytic substitution) transition state, as in the case of hydrogen abstraction by TBADT.When electronegative oxygen-centered radicals, such as those present in the excited decatungstate anion (cat*), abstract hydrogen from C-H bonds, the transition state should be polar in order to balance the positively charged carbon atom.Therefore, TS-a (Scheme 1), leading to A via a-C-H cleavage from cyclopentanone, has to create an unstabilized electron-decient a-carbon that can be regarded as an Umpolung type, 12 rendering b-selective C-H bond cleavage to give B via TS-b more feasible.Thus, we assumed that regioselective C-H cleavage would be followed by C-C bond formation which would be suitable for the straightforward b-C-H functionalization of cyclopentanone (1a).In this paper, we report that using TBADT as the photocatalyst, the reaction of cyclopentanones with electron-decient alkenes proceeds with complete regioselectivity to give b-alkylated cyclopentanones.Interestingly, in most cases replacing articial xenon light with sunlight irradiation led to similar or even better results.In addition, we also achieved TBADT-catalyzed bacylation of cyclopentanone under CO pressurized conditions.

Results and discussion
We screened the reaction between cyclopentanone (1a) and several electron-decient alkenes as radical acceptors, including acrylonitrile (2a), methyl vinyl ketone (2b) and ethyl acrylate (2c).All these reactions resulted in an exclusive selectivity for b-C-H/C-C conversion (Scheme 2).As an example, when an acetonitrile solution of 1a (5 mmol), 2a (1 mmol) and TBADT (2 mol%) was irradiated for 24 h using a SolarBox equipped with a 1.5 kW xenon lamp (500 W m À2 ), b-alkylated ketone 3a was obtained in 61% yield.Not even trace amounts of 3a 0 were detected in the 1 H NMR spectrum of the crude product.With these favorable results in hand, we then examined the b-regioselective C-H/C-C reaction of cyclopentanones 1 with a variety of electron-decient olens 2, and the results obtained are summarized in Table 1.The reaction of cyclopentanone (1a) with methyl vinyl ketone (2b) gave the expected 1,6-diketone 3b in 41% yield aer isolation by silica gel chromatography (entry 2).Interestingly, direct sunlight irradiation of the reaction mixture (3 days, ca.24 h) gave 3b in a higher yield (58%, entry 3).The reaction of 1a with ethyl acrylate (2c) or tert-butyl acrylate (2d) gave moderate yields of keto esters 3c and 3d, respectively (entries 4 and 5).The reaction between 1a and dibutyl maleate (2e) gave the corresponding ketone 3e in 61% yield as a mixture of 1.1/1 diastereomers (entry 6).The direct sunlight-promoted reaction of 1a with vinyl sulfone 2f and fumaronitrile (2g) gave b-alkylated products 3f and 3g in 70 and 73% yield, respectively (entries 7 and 8).Reaction of 1a with methylene norbornanone (2h) gave the corresponding 1,6-diketone 3h exclusively as the endo-isomer in a 1.7/1 diastereomer ratio (entry 9).Gratifyingly, the reaction of 3-methylcyclopentanone (1b), which has one methine, one methyl, and three different methylene carbons, with 2b proceeded with high selectivity for the abstraction of the b-methine C-H hydrogen, to afford 1,6-diketone 3i having a quaternary carbon (entry 10).Similarly, 1b reacted with vinyl sulfone 2f to give 3j in 62% yield (entry 11).We also examined the reaction of 2-methylcyclopentanone with 2b; however, it yielded an inseparable 2 : 1 mixture of 4-and 3-alkylated products (see ESI †).
For comparison, we examined the regioselectivities for cyclohexanone (1c), 4-methylcyclohexanone (1d) and cycloheptanone (1e) in the reaction with 2b (Scheme 3).As a result, when both band g-hydrogens were present, H-abstraction by TBADT showed a slight preference for g-C-H cleavage (statistically corrected g : b ratio ca. 1 : 0.8) with cyclohexanone (1c) and cycloheptanone (1e) and, as expected, no a-C-H/C-C conversion took place.On the other hand, the presence of a methine group in compound 1d led to preferential selectivity (16 : 1, again statistically corrected) for the more hindered/labile g-C-H  bond, despite the bulkiness of the photocatalyst.This behavior is quite similar to that observed above in the case of 1b.In the reaction of 2-pentanone (1f) with methyl acrylate (2i), a selectivity for b-C-H over g-methyl C-H was found (statistically corrected g : b ratio ca. 1 : 8.5).
The approach described here compares favorably with related radical processes previously described for C-H functionalization in cycloalkanones.Sparse examples have been reported dealing with the reaction of ketones with hetero-atom radicals. 14Among them, there is only one report of selective bchlorocarbonylation of carbonyl derivatives, which took place by irradiation in the presence of oxalyl chloride via hydrogen abstraction by chlorine (Clc) radicals.14a A plausible mechanism is depicted in Scheme 4 for the photocatalyzed b-acylation of 1a.We expected that excited polyoxotungstate anion [W 10 O 32 ] 4À* would have an electronegoxygen character as the reactive site, 15 and therefore the observed selectivity is in favor of b-C-H abstraction (at least for 1a). 16The b-keto radical thus formed then undergoes consecutive addition to CO (when present) and to the electron-decient olen (e.g.acrylonitrile 2a) to form an adduct radical.Backhydrogen atom transfer from the reduced form of the tungstate anion to the latter radical gives the desired product 4a, restoring the TBADT catalyst.
We can then assume that a-C-H abstraction in cyclic ketones is inefficient, as previously demonstrated in related studies on the reactivity of excited TBADT with acetone. 17In fact, acetone was safely used as a solvent in TBADT photocatalyzed reactions.8e, 17 The simplicity of the procedure is another advantage of the method, since it requires merely exposing the solution to the sun in a glass vessel on a window ledge (Fig. 1).8e This 100% atom economical process has several benets from the environmental point of view, because no articial energy is required for irradiation, heating, cooling or stirring in order to carry out selective C-H/C-C conversion. 18

Conclusions
In summary, we have developed a simple straightforward strategy for b-alkylation and acylation of cyclopentanones using electron-decient alkenes as alkylating reagents under irradiation in the presence of TBADT as the catalyst.Interestingly, sunlight irradiation gave good results.The differentiation of favorable and unfavorable polar radical transition states has been exploited successfully in order to direct the regioselectivity.b-Acylation of cyclopentanone, which uses a threecomponent system comprising cyclopentanone, CO and electron-decient alkenes, was also achieved.We believe that the radical polar effect provides a powerful strategy to induce selective catalytic C-H functionalization and we are now pursuing further studies along this line.

Typical procedure for b-acylation of cyclopentanone
A magnetic stir bar, CH 3 CN (10 mL), TBADT (66.4 mg, 0.02 mmol), cyclopentanone (1a, 1262 mg, 15 mmol) and acrylonitrile (2a, 53.1 mg, 1 mmol) were placed in a stainless steel autoclave equipped with a Pyrex glass liner to permit irradiation of the contents.The autoclave was closed, purged three times with carbon monoxide, pressurized with 200 atm of CO and then irradiated by a xenon arc lamp (300 W) with stirring for 20 h.Aer the reaction, excess CO was discharged at room temperature.The solvent was removed under reduced pressure.The residue was puried by ash column chromatography on silica gel (hexane/ethyl acetate ¼ 1/2) to afford 95.8 mg of 4-oxo-4-(3-oxocyclopentyl)butanenitrile 4a (58%).

Scheme 4
Scheme 4 mechanism for the photocatalyzed b-C-H/C-C conversion in cyclopentanone and ensuing carbonylation.

Fig. 1
Fig. 1 Pyrex glass vessel (20 mL capacity) used for the sunlight photocatalyzed b-C-H/C-C conversion of 1a.

Table 2
Three-component b-acylation of cyclopentanone (1a) using TBADT as the photocatalyst a