Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp3)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp3)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp3)–H functionalization.


Introduction
The sulfonyl group is one of the most important functional groups in organic synthesis, 1 materials science, 2 and medicinal chemistry. 3 However, methods are lacking for the direct installation of the sulfonyl group by harnessing the abundant aliphatic C-H bonds with high potential for a rapid build-up of the structural diversity. The introduction of the sulfonyl group into organic molecules by the C-S bond formation is instead typically accomplished in a stepwise fashion via pregenerated reactive intermediates, 4,5 while the direct installation of the sulfonyl group by reactions with C-H bonds remains underdeveloped (Fig. 1A). Currently available methods for the introduction of the sulfonyl group by means of C-H functionalization largely comprise sulfonylations (e.g., reactions producing sulfones and sulfonamides) of aromatic substrates proceeding by transition metal-catalyzed pathways that either require a directing group or exploit the innate reactivity of the aromatic ring. 6 The scope of the reactions that engage aliphatic C-H bonds remains limited, and only few examples of C(sp 3 )-H sulfonylation have been described to date. 7 Importantly, no C(sp 3 )-H sulnation, i.e., a reaction that can enable direct access to sulnate salts by the functionalization of aliphatic C-H bonds is currently available. Sulnates have recently emerged as highly versatile synthetic intermediates that can be used to access all major classes of organosulfur compounds 1a,4 and as coupling partners in new regio-and stereoselective C-C bond-forming cross-coupling reactions (Fig. 1B). 5 Given the central position of the sulfonyl group in medicine and the growing recognition of the importance of increasing the fraction of saturated residues (Fsp 3 ) in compounds that enter screening as a way of improving success rates of drug discovery campaigns, 8 new methods are required that selectively install the sulfonyl group by the functionalization of C(sp 3 )-H bonds. In addition, to be broadly synthetically useful these methods should enable facile access to a variety of classes of organosulfur compounds. Due to the synthetic versatility of sulnates, C-H sulnation will satisfy these requirements. However, sul-nates are generally incompatible with the oxidative conditions that are required for transition metal-catalyzed C-H functionalization, and a broad scope synthesis of sulnates directly from C-H bonds has remained elusive.
Recent studies of photoinduced transformations have resulted in the development of new and efficient methods, enabling construction of a variety of carbon-carbon and carbon-heteroatom bonds under mild conditions and in the absence of precious and toxic metals that are typically required to effect the bond formation. 9 Sulfur dioxide is known to produce sulfonyl groupcontaining mixtures of products that include sulnic acids in a photoinduced gas-phase reaction with C 1 -C 4 alkanes. The reaction proceeds via the excitation of sulfur dioxide that undergoes intersystem crossing (ISC) to the reactive triplet state (Fig. 1C). The triplet sulfur dioxide then abstracts a hydrogen atom from the substrate generating alkyl and hydroxysulnyl (S(O)OH) radicals. Subsequent radical combination or trapping of the alkyl radical by sulfur dioxide and hydrogen abstraction from S(O)OH produce the sulnic acid product (Fig. 1) that is prone to decomposition under the reaction conditions. 10 Despite the signicant synthetic potential, the reaction has not found synthetic applications because of the harsh gas phase conditions, the use of pressurized toxic sulfur dioxide gas and mercury vapors, formation of many by-products, low yields (typically #10%), and a narrow substrate scope.
Due to the instability of sulfurous acid (H 2 SO 3 ) in aqueous solutions, sulte salts (e.g., sodium hydrogen sulte) exist in an equilibrium with dissolved sulfur dioxide. 11 We hypothesized that the quantities of sulfur dioxide that are present in the solution ($0.003M in a 1M solution of NaHSO 3 ) will be sufficient to effect the photoinduced C(sp 3 )-H sulnation, producing stable sulnate salts. Sulfur dioxide is well soluble in organic solvents, and we expected biphasic solvent mixtures also to be suitable for reactions with water-insoluble organic substrates. Given the mild conditions, the absence of reactive oxidants and transition metals, the low concentration of the highly reactive photoexcited sulfur dioxide, and the in situ formation of stable sulnates, thus obviating the isolation of unstable sulnic acids, it was also expected that the method would solve the challenges that have hitherto prevented the development of a broadly useful photoinduced C(sp 3 )-H sulnation.
We report herein an efficient photoinduced direct sulnation of aliphatic C-H bonds, producing sulnates that serve as versatile synthetic linchpins and provide access to other key classes of organosulfur compounds. Remarkably, and in contrast to other radical C-H functionalizations, the reaction produces only monosulnation products, while the regioselectivity of the C-H sulnation can be controlled by the solvent, enabling for the rst time a regiodivergent sulnation of distal C-H bonds.

Results and discussion
Initial optimization studies with cyclohexane revealed that a clean C-H sulnation can be achieved in the presence of sodium metabisulte in aqueous acetonitrile under UV-B light (l ¼ 300 nm), producing sulnate salt 1 in 89% yield (Table 1). Sodium metabisulte is a bench stable and inexpensive reagent that is used as a pharmaceutical and food preservative. In aqueous solutions sodium metabisulte rapidly hydrolyzes to sodium hydrogen sulte. Sodium metabisulte has one of the highest SO 2 equivalent contents (65.4%) and is one of the most atom-economical sulfur dioxide precursors. 11a,12 Shorter-(254 nm) or longer-(350 nm) wavelength light afforded the product in lower yields. Other solvents (e.g., dichloromethane,  hexauoroisopropanol (HFIP), entries 5 and 6) were less suitable for the C-H sulnation of a hydrocarbon substrate but could be used for other types of reactants (vide infra). Sodium bisulte also mediated the sulnation, albeit with a lower yield than the freshly prepared solution from metabisulte, while no reaction was observed with sodium sulte (entries 7 and 8). The inuence of structural and electronic effects on the photoinduced C-H sulnation was examined next with a variety of substrates and using methyl and allyl sulfone products as readouts to facilitate the analysis (Scheme 1). Cycloalkanes of various ring sizes 2-5 reacted smoothly, including on a gram scale (e.g., 5). Acyclic substrates 6 and 7 were equally suitable, providing an opportunity to study the selectivity of the hydrogen abstraction by triplet sulfur dioxide. The k(2 ) : k(1 ) and k(3 ) : k(1 ) ratios were 15 : 1 and 30 : 1 respectively, indicating that the hydrogen abstraction selectivity of triplet sulfur dioxide is comparable to that of the tert-butoxy radical that is commonly used in synthetic radical chemistry. 13 b-Sulfonylketones 8 and 9 were readily formed as sole products, highlighting the deactivating effect of the carbonyl group. Other solvents, in particular, hexauoroisopropanol (HFIP), and pH adjustment had a bene-cial effect on the reaction efficiency with deactivated substrates. The C-H sulnation proceeded with b-selectivity for sulfone 10 and substantial g-selectivity for sulfones 11-13.
Notably, the observed g-selectivity could be attributed to the selectivity-modulating effect of HFIP (vide infra) that was also previously observed for other photoinduced regiodivergent transformations. 9d Unexpectedly, 2-adamantanone reacted with high selectivity at the a position (14). This selectivity is unprecedented, as it stands in contrast to the distal (d) selectivity observed with other HAT-inducing radicals and the distal selectivity observed for other ketones in the present system. Given the presence of hydrogen-bonded sulfur dioxide 11b,c and the conformational rigidity of 2-adamantanone, the a selectivity can be facilitated by hydrogen bonding of the carbonyl group with triplet sulfur dioxide with water or protic solvent as a hydrogen bonding linchpin, indicating that directing groupenabled functionalization of specic C-H bonds may be possible with conformationally constrained substrates using the sulnation reaction. Similarly, b-sulfonylesters 15 and 16b were produced as major products. Notably, b-isomer 16b was produced as a single diastereomer, pointing to the stereoselectivity of the sulnation step. An ester alkyl group can also be sulnylated (17), with the carboxylic group exerting a deactivating effect on the proximal C-H bonds. The strongly deactivating character of the nitrile group resulted in a higher gselectivity (18 and 19) with the trans preference for the distal C-H sulnation in 19a, despite the remote position and the small size of the nitrile group. Benzylic C-H bonds can also be readily sulfonylated (20). Interestingly, the reaction can be used to access the sultine framework in a trans-selective fashion (21). Sultines have signicant potential as emerging structural units for drug discovery, 3 yet they remain underexplored, as few methods are available for their selective and efficient construction. 14 N-Protected amines and amino acids can also serve as suitable substrates, favoring functionalization in the gposition (22 and 23). In addition, functionalization of the remote side chain in ibuprofen highlighted the synthetic potential for the late-stage diversication of medicinal targets (24). In contrast to the electron-decient substrates, the functionalization of cyclic alkyl ethers afforded a-sulfones as sole products (25)(26)(27)(28)(29)(30). Notably, facile sulnation of crown ethers (29 and 30) provides a straightforward approach to appending functionalized side chains that can be used for conjugation and graing in materials science applications. 15 In another demonstration of the facility of the C-H sulnation-enabled structural diversication, isosorbide methyl ether that is used in drug delivery applications, 16 was readily converted to a set of sulfonyl derivatives 31a and 31b,c, formed as single diastereomers. Importantly, only monosulnation was observed in all cases, in contrast to other radical processes, e.g., halogenation, that tend to suffer from polyhalogenation. The high g-selectivity observed for products 11-13, 18, 19, 22, and 23 in HFIP indicated that the regioselectivity of the C-H sulnation is controlled by the solvent. Indeed, while b-selective sulnation of the tertiary position in ketone 32 was observed in dichloromethane, the selectivity switched in favor of the distal primary g position in HFIP (34, Scheme 2), enabling solventcontrolled regiodivergent C-H functionalization in the absence of directing groups and catalysts that are typically required to achieve regiodivergent distal C-H functionalizations. 17 The solvent controlled regioselectivity was also observed for substrates 35 and 36, with the selectivity shiing from b in aprotic solvents (dichloromethane and acetonitrile) in favor of the distal g-sulnation in HFIP. Notably, the b-sulnation of ester 36 proceeded with exclusive cis-selectivity both in acetonitrile and HFIP.
In addition to sulnates (e.g., 37, Scheme 3), other classes of sulfonyl compounds can also be accessed using the photoinduced C-H sulnation. For example, aliphatic sulnic acids are typically difficult to access, due to facile disproportionation and oxidation, but can be readily synthesized using the reported method following aqueous work-up (38). Furthermore, a simple post-sulnation S-N coupling affords sulfonamides that play important roles in medicinal and synthetic chemistry (39-43). Sulfonyl uorides have recently emerged as versatile probes with applications in chemical biology and materials science. 18 Pleasingly, the photoinduced C-H functionalization of two ketone substrates in conjunction with the Selectuor-induced sulnate uorination afforded sulfonyl uorides 44 and 45. Notably, sulfonamides 42 and 43 and sulfonyl uorides 44 and 45 were formed as single regioisomers with no polysulnation by-products, highlighting the efficiency of the reaction and the excellent HFIP-induced regiocontrol, enabling for the rst time exclusive distal C-H amidosulfonation and uorosulfonation. Sulfones are also readily accessible (46) by a metal-free, persulfate-mediated coupling reaction. 4e Isotopically labeled compounds, e.g., 18 O-labeled sulfonylcontaining small molecule probes, play increasingly important roles in drug discovery. 19 However, the installation of the 18 O-labeled sulfonyl groups remains challenging, because sulfonyl compounds do not undergo a facile 16 O/ 18 O exchange. 20 Given the mildly acidic (pH 3.9) medium of the C-H sulnation reaction and the propensity of sulnic acids to undergo an 16 18 O-labeled sulnate salt 47 and sulfone 48 were readily produced with 95% 18 O isotopic purity, following the simple protocol. These results further highlight the broad synthetic potential of the photoinduced C-H sulnation reaction.
The photoinduced C-H sulnation exhibits several remarkable features, e.g., a high preference for monosulnation that contrasts other radical processes, and a protic solvent-induced distal g-functionalization whose understanding is impeded by a lack of mechanistic knowledge of the triplet sulfur dioxidemediated hydrogen atom transfer from C-H substrates. To gain insights into the mechanism of the C-H sulnation that accounts for the observed selectivity, computational studies were carried out. The C-H sulnation of cyclohexane proceeded with a relatively small kinetic isotope effect of k H /k D ¼ 2.6 ( Fig. 2A, see also S1 †), pointing to a signicantly asymmetrical transition state 21 in the hydrogen atom transfer step. Indeed, computational studies of the reaction with methane as the C-H substrate show that the hydrogen abstraction by triplet sulfur dioxide proceeds exergonically via an early transition state ( Fig. 2B) with the interaction of the lowest SOMO-1 of SO 2 with the s orbital of the C-H substrate, forming a doubly occupied s bonding orbital and an antibonding SOMO-1 in the transition state 3 TS A . The activation barrier has a relatively small enthalpic contribution (DG s ¼ 11.0 kcal mol À1 , and DH s ¼ 1.7 kcal mol À1 ), as was previously observed for other reactive oxygen-centered radical-mediated hydrogen atom transfers. 13 The activation strain model (ASM) 22 analysis further indicates that the distortion energy is higher for the sulfur dioxide fragment than for the C-H substrate, while both the overall distortion energy and the interaction energy remain relatively small (Fig. 3A).
Further insights into the electronic effects inuencing the interaction energy of the transition state were derived from the second-generation energy decomposition analysis based on absolutely localized molecular orbitals (ALMO-EDA2). 23 Pauli repulsion was the major contributor to the interaction energy, however, charge transfer and dispersion also played signicant roles, nearly compensating for the Pauli repulsion, in combination with the electrostatic component (Fig. 3B). The complementary occupied-virtual pair (COVP) 24 analysis indicated that the most signicant charge transfer takes place between a s orbital of the C-H substrate and the lowest SOMO-1 of the triplet sulfur dioxide in the beta space with substantially smaller a-SOMO-1/s C-H * contribution in the alpha space (Fig. 3C), pointing to the electrophilic character of triplet sulfur dioxide, and is further corroborated by the second order perturbation theory (SOPT) analysis 25 (see the ESI †). These results underscore the delicate balance of the various stabilizing and destabilizing effects that contribute to the low-barrier hydrogen atom transfer and clarify interfragment interactions that enable the process.
We further proceeded with the investigation of the high preference for monosulnation observed for all substrates even in the presence of a large excess of sodium metabisulte (e.g., 4-12 equiv.). We hypothesized that triplet sulfur dioxide can engage in an unproductive single electron transfer/back electron transfer (SET/BET) process with the sulnate product. Indeed, triplet sulfur dioxide is a strong oxidant with a calculated reduction potential E red ¼ 2.30 V vs. SCE that can readily oxidize sulnate salts (e.g., E ox ¼ À0.30 V vs. SCE for CH 3 SO 2 -NBu 4 ), producing the corresponding sulfonyl radical and sulfur dioxide anion radical. 26 The latter (E ox ¼ 0.70 V vs. SCE) can reduce the sulfonyl radical to sulnate by a back electron transfer, resulting in net deactivation of photoexcited sulfur dioxide by the C-H sulnation product (Fig. 4A), thus preventing the installation of additional sulfonyl groups and leading to exclusive monosulnation. This conclusion is supported by the observation of the inhibitory effect of the added sulnate on the  reaction performance (Fig. 4B), underscoring the autoinhibitory role of the sulnate products. Additionally, since the O-H bond in sulnic acids is substantially weaker (BDE $78 kcal mol À1 ) 27 than C-H bonds, the deactivation of photoexcited sulfur dioxide can also readily proceed via a hydrogen atom abstraction by triplet SO 2 that is followed by back-HAT (Fig. 4A). Both steps are near barrierless and exergonic, indicating that monosulnation can also be effected by the HAT pathway with sulnic acids present in the acid-base equilibrium. We next explored the origin of the solvent-induced divergence in the b/g-regioselectivity that is observed in dichloromethane and HFIP. Given the strong hydrogen bond donor ability of HFIP (a ¼ 1.96) 28 and the effects of hydrogen bonding and polar medium on HAT processes, 29 we hypothesized that hydrogen bonding interactions of HFIP with the carbonyl group substrate amplied by the high polarity (E T (30) ¼ 65.3) 28 and very low nucleophilicity (N OTs ¼ À4.23) 28 of the HFIP solvent medium result in the deactivation of the proximal C-H positions in favor of the distal g-C-H functionalization. Computational studies with ketone 32 as the substrate revealed that the C-H sulnation proceeds with bselectivity in dichloromethane (DG s ¼ 11.0 kcal mol À1 for 3 TS B , DG s ¼ 9.8 kcal mol À1 for 3 TS C , and DDG s 3 /1 ¼ À1.2 kcal mol À1 ) in line with the experimental observations (DDG s 3 /1 ¼ À1.3 kcal mol À1 , Fig. 5). Both the HAT step and the subsequent cross-termination of the alkyl and hydrox-ysulnyl radicals were substantially exergonic, resulting in an overall thermodynamically favorable C-H functionalization process facilitated by the high triplet energy of sulfur dioxide (73.4 kcal mol À1 ). 30 Interestingly, when the C-H sulnation of the HFIP-32 hydrogen bond complex was studied with HFIP as a solvent, the regioselectivity inverted in favor of the g-functionalization (DG s ¼ 11.9 kcal mol À1 for 3 TS D , DG s ¼ 12.3 kcal mol À1 for 3 TS E , and DDG s 3 /1 ¼ 0.4 kcal mol À1 ) in agreement with the experiment (DDG s 3 /1 ¼ 0.3 kcal mol À1 ). Notably, both the b (3 ) and the g (1 ) HAT pathways suffered from higher barriers in HFIP, however, the b HAT pathway was more sensitive to the deactivating effect of the HFIP ligation, due to the proximity of the carbonyl group. These results indicate that HFIP-mediated hydrogen-bonding interactions can be successfully used to modulate the regioselectivity of synthetically important radical C(sp 3 )-H functionalization reactions.

Conclusions
In conclusion, we have developed a direct photoinduced C-H sulnation of abundant C(sp 3 )-H bonds mediated by sodium metabisulte in aqueous organic solvent mixtures. The reaction proceeds under ambient and mild conditions and does not require pressurized toxic sulfur dioxide gas. Remarkably, only monosulnation products are formed, and a clean conversion to sulnates is achieved without disproportionation and oxidation by-products that typically complicate sulnic acid synthesis. In addition to high chemoselectivity, the reaction allows for the functionalization of distal C-H positions with moderate to good regioselectivity and with solvent effects playing a key role in establishing the regiocontrol. The new method enables a simple and direct conversion of aliphatic C-H bonds to other classes of organosulfur compounds, including sulfonamides, sulfonyl uorides, and sulfones, and can be used for the facile introduction of 18 O-labeled sulfonyl groups.

Data availability
Experimental and computational data associated with this work are provided in the accompanying ESI. †

Author contributions
SJ and VDN carried out the experiments, GCH and RT performed the computational studies. HDA performed the X-ray crystallography studies. OVL conceived the project, wrote the manuscript, and co-wrote and edited the ESI. SJ, VDN, GC, and RT co-wrote the ESI and contributed to writing the manuscript.

Conflicts of interest
There are no conicts to declare.