Photocatalytic three-component asymmetric sulfonylation via direct C(sp3)-H functionalization

The direct and selective C(sp3)-H functionalization of cycloalkanes and alkanes is a highly useful process in organic synthesis owing to the low-cost starting materials, the high step and atom economy. Its application to asymmetric catalysis, however, has been scarcely explored. Herein, we disclose our effort toward this goal by incorporation of dual asymmetric photocatalysis by a chiral nickel catalyst and a commercially available organophotocatalyst with a radical relay strategy through sulfur dioxide insertion. Such design leads to the development of three-component asymmetric sulfonylation involving direct functionalization of cycloalkanes, alkanes, toluene derivatives or ethers. The photochemical reaction of a C(sp3)-H precursor, a SO2 surrogate and a common α,β-unsaturated carbonyl compound proceeds smoothly under mild conditions, delivering a wide range of biologically interesting α-C chiral sulfones with high regio- and enantioselectivity (>50 examples, up to >50:1 rr and 95% ee). This method is applicable to late-stage functionalization of bioactive molecules, and provides an appealing access to enantioenriched compounds starting from the abundant hydrocarbon compounds.


Introduction
−4 For example, remikiren is a renin inhibitor used for the treatment of hypertension, 5 apremilast has been approved by FDA as an oral drug to treat active psoriatic arthritis and plaque psoriasis. 6Chiral sulfones play important roles in organic synthesis as auxiliaries, ligands and synthetic intermediates. 7,8Great efforts have been devoted to the development of practical synthesis of enantioenriched sulfones. 9However, there are few asymmetric catalytic approaches to chiral sulfones with α-carbon stereocenters, and those typically rely on noble-metal-catalyzed asymmetric hydrogenation.
−14 The direct C(sp 3 )-H functionalization of cycloalkanes and alkanes is a highly useful process due to the low-cost starting materials, the high step and atom economy (Fig. 1b). 15,16Methods to control siteselectivity towards C-H bonds at the speci c positions of unactivated cycloalkanes or alkanes (without the assistance of any directing group), 17−30 at the same time combine with asymmetric catalysis, provide appealing opportunities for construction of high value-added chiral molecules, but remains a remarkable challenge. 31−37 Recently, we found a photocatalytic enantioselective alkylation reaction of N-sulfonylimines with benzylic or alkyl C(sp 3 )-H precursors enabled by copper-based asymmetric catalysis and organophotocatalysis.This radical-mediated method however relies on very speci c reaction partners and is extremely ineffective for conversions of cycloalkanes. 38Practical methods which can be applied to common substrates are still undeveloped.To achieve this goal, suppression of the side reactions such as selfcoupling or elimination of radical intermediates and powerful stereocontrol in the radical process are required.−46 The resulting sulfonyl radicals have longer life time which might be bene cial for asymmetric induction. 47Hence, we questioned whether incorporation of sulfur dioxide insertion with appropriate dual asymmetric photocatalysis 48−51 would allow us nd an effective approach for stereoselective transformations starting from most abundant hydrocarbon compounds.On the basis of these considerations, a photocatalytic asymmetric threecomponent sulfonylation reaction of a cycloalkane (an alkane, a toluene derivative or an ether), a SO 2 surrogate, and a common Michael acceptor was developed, whose stereochemistry was governed by a nickel catalyst of a well-tailored chiral bisoxazoline ligand.This method provides a straightforward and economic access to biologically interesting α-C chiral sulfones (> 50 examples, up to 50:1 rr and 95% ee, Fig. 1c).

Results
Reaction development.α,β-Unsaturated carbonyl compounds are one class of common Michael acceptors in organic synthesis.Initially, we chose cyclohexane (1a) as the model substrate, α,βunsaturated carbonyl compound bearing an N-acylpyrazole moiety (2a) as the reaction partner, 5,7,12,14pentacenetetrone (PC1) as the HAT photocatalyst, 38,52 and the bisoxazoline nickel complex generated in situ ([L1-Ni]) as the chiral catalyst (Table 1).The reaction of 1a and 2a failed to produce an addition product under visible light conditions (entry 1).We next tested several SO 2 surrogates in the photochemical system, and found that DABCO•(SO 2 ) 2 was the appropriate reaction component (entries 2,3).Under irradiation with a 24 W blue LEDs lamp (λ max = 455 nm) at 20°C under argon, the reaction of 1a, 2a and DABCO•(SO 2 ) 2 in dichloroethane delivered the chiral sulfone product (3a) in 58% conversion and with only 3% ee (entry 3).α,β-Unsaturated carbonyl substrates bearing a different auxiliary group (Z) were examined, and it was found that N-acylpyrazole (2a) was a suitable substrate (entries 4-7).Other photocatalysts (PC2-PC4) failed to catalyze this transformation (entries 8-10).In order to improve the reaction e ciency and enantioselectivity, a range of chiral ligands (L2-L11) were screened (entries 11-20).Chiral bis(oxazoline) ligands (L2-L4) and a tridentate ligand (L5), which have been successfully used for asymmetric induction in some radical-mediated transformations, 53−56 were found to be ineffective in this photocatalytic reaction (entries 11-14), but replacement of L1 with an indane-derived BOX ligand (L6) led to a full conversion and signi cantly increased enantiomeric excess (82% ee) (entry 15).Based on this observation, we modi ed this type of ligands and synthesized several sterically more bulky analogs for creation of more precise chiral environment (L7-L9).One of these, L7 was identi ed as the best ligand with regard to the yield and enantioselectivity (86% ee) (entry 16).Finally, the reaction was further improved by reducing the reaction temperature and increasing the loading of chiral catalyst, which provided 3a with a full conversion and 95% ee (entry 23).The reaction with only 1.0 equiv. of cyclohexane also proceeded smoothly at a lower but reasonable reaction rate (52% conversion within 96 h) and the similar enantioselectivity of 93% ee (entry 24).Such conditions would be useful with more expensive C(sp 3 )−H precursors such as natural products or drug molecules.
Mechanistic studies.Several control experiments were conducted to gain insight into the reaction mechanism (Fig. 4).For example, addition of a radical quencher (2,2,6,6-tetramethylpiperidine-1-oxyl, TEMPO, 3 equiv.)to the photochemical reaction 1v+DABCO•(SO 2 ) 2 +2a®3v was found to completely inhibit the transformation to 3v, instead affording a TEMPO-carbon radical cross-coupling product (4)  detected by HRMS analysis.The three-component sulfonylation reaction of 4-(cyclopropylmethyl)-1,1'biphenyl (1zp) under the standard conditions provided a ring-opened product (5) in 63% yield and with 95% ee, which further con rmed the reaction pathway via benzylic radicals.Employing cyclopropylsubstituted N-acylpyrazole (2p) as a substrate for the radical clock experiment provided product 6 in 65% yield and did not give any ring-opened product, thus excluding mechanisms involving the β-carbon radicals of N-acylpyrazole complexes. 60The reaction of 2a with sodium cyclopentanesul nate was examined under the standard conditions, and failed to produce any desired product 3b (Fig. 4b).This result indicated that the reaction might not proceed through sulfonyl anion intermediates.Moreover, removal of the nickel catalyst in the reaction of 1v+DABCO•(SO 2 ) 2 +2a®3v led to the failure of product formation, while replacing the nickel catalyst by other Lewis acids such as a copper, zinc, iron or cobalt complex of the same chiral ligand (L7) still afforded product 3v in a moderate yield (17−31%).The cobalt complex with similar octahedral con guration even gave good enantioselectivity of 80% (Fig. 4c).These results suggested that the nickel complex most likely only provided Lewis acid activation for α,βunsaturated N-acylpyrazoles.Finally, luminescence quenching experiments quenching experiments revealed that the C(sp 3 )-H precursors such as toluene (1v) was capable of quenching the excited state of PC1 and initiating the radical process (Fig. 4d).
Mechanistic proposal.On the basis of the initial experiments and mechanistic studies, we propose a plausible reaction mechanism (Fig. 5a).The chiral nickel catalyst ([L*-Ni]) undergoes fast ligand exchange with the α,β-unsaturated N-acylpyrazole (2) to generate an intermediate complex (A).On the other hand, the organophotocatalyst (PC) is excited to its triplet state (B), which performs hydrogen atom abstraction from the C(sp 3 )-H precursor (1) to give the semiquinone-type radical intermediate (C) and the transient carbon radical (D). 52The radical (D) is rapidly trapped by the sulfur dioxide released in situ to produce the stabilized sulfonyl radical (E). 41Owing to the electronic and steric effects, E reacts with the metal-coordinated Michael acceptor (A) through an outer-sphere rather than an inner-sphere pathway, affording the radical complex (F). 61−66 Such an outer-sphere attack might be critical to avoid side reactions such as self-coupling or elimination and to achieve a high level of asymmetric induction in the photochemical reaction. 67−80 Subsequent single electron transfer and proton transfer among intermediates C, F and small amount of water in the solution lead to formation of the neutral complex (G) and the organophotocatalyst (PC).Ultimately, ligand exchange between intermediate G and the substrate (2) gives the chiral sulfone product (3) and regenerates the coordinated α,β-unsaturated N-acylpyrazole (A).
A crystal structure of nickel complex [L6-Ni] exhibits an octahedral geometry, in which the six coordination sites are occupied by one chiral ligand and four water molecules (Fig. 5b, left).Accordingly, an intermediate [L7-Ni-2a] is simulated by Gaussian 09, and a proposed transition state is modeled by CYLview 1.0 (Fig. 5b, middle). 81The sulfonyl radical (E) interacts with the C=C double bond of the coordinated α,β-unsaturated N-acylpyrazole from Re-face with less steric hindrance, that is consistent with an observed R-con guration in product 3b (Fig. 5b, right).The modeled transition state structure also illustrated that the extended phenyl substituents on the chiral ligand (L7) were critical for a high level of asymmetric induction.Synthetic utility.A mmol-scale reaction was performed to demonstrate the synthetic utility of the reaction.A mixture of toluene (1v, 533 μL, 5.0 mmol), 2a (164 mg, 1.0 mmol) and DABCO•(SO 2 ) 2 (180 mg, 0.75 mmol) was irradiated with a blue LEDs lamp under the standard conditions (Fig. 6a), leading to the production of 227 mg of 3v (71% yield, 91% ee).The yield and enantioselectivity were basically the same as in the small-scale reaction.Next, we investigated further transformations of the reaction product.For example, an alcohol derivative (7) was obtained in 93% yield and with 91% ee by treatment of the chiral sulfone (3v, 91% ee) with NaBH 4 in a mixed solvent of THF and H 2 O at 0 °C to room temperature.3v could also be converted into the corresponding ester (8) or amide (9) in good yield and with retention of enantiomeric excess by substitution of the pyrazole moiety with an ethoxy or an amino group, respectively (Fig. 6b).Finally, the photochemical reaction was applied to the late-stage modi cation of bioactive molecules (Fig. 6c).Under the standard conditions, the reaction of a lopid derivative afforded its chiral sulfone derivative (10) as a single regioisomer in 64% yield and with 86% ee.Such precise recognition of two very similar benzylic C(sp 3 )-H bonds further con rmed the powerful catalyst-control of selectivity in the photochemical reaction.Using the similar protocol, celestolide and a synthetic

Figure 1 Overview
Figure 1

Figure 5 Proposed
Figure 5