Bromine as a Visible-Light-Mediated Polarity-Reversal Catalyst for the Functionalization of Aldehydes

Polarity-reversal catalysts enable otherwise sluggish or completely ineffective reactions which are characterized by unfavorable polar effects between radicals and substrates. We herein disclose for the rst time that when irradiated by visible light, bromine can behave as a polarity-reversal catalyst. Hydroacylation of vinyl arenes, a three-component cascade transformation and deuteration of aldehydes were each achieved in a metal-free manner without initiators by using N-bromosuccinimide as the precatalyst. Light is essential to generate and maintain the active bromine radical during the reaction process. Another key to success is that HBr can behave as an effective hydrogen-donor to turn over the catalytic cycles.


Introduction
The "polar effect" is one of the paramount factors that determine the reactivity of radicals. It has been widely exploited in radical chemistry to obtain desired reactivity and selectivity. [1][2][3] This is especially important in the domain of radical-based C-H functionalization, which can differentiate the various C-H bonds in organic molecules. [4][5][6][7][8] In this context, the emergence of photocatalysis has provided enormous opportunities for C-H functionalization through direct photo hydrogen atom transfer (HAT) catalysis or by the synergistic combinations of photoredox with HAT catalysis. [9][10][11][12][13][14][15][16][17][18] Aldehydes, one of the most abundant and readily available feedstocks, are enabled to generate acyl radicals to achieve umpolung reactivity by photo-induced HAT in a step-and atom-economic fashion. [19][20] However, the acceptors of acyl radicals were limited to electron-de cient alkenes and radical trappers containing electron-withdrawing leaving groups, [21][22][23][24][25] to result in an electrophilic radical intermediate to turn over the redox-neutral photocatalytic cycle (Fig. 1a). On the other hand, polarity reversal catalysis (PRC), established decades ago, has found broad applications in radical hydrogen atom transfer (HAT) processes. [26][27][28] Otherwise sluggish or completely ineffective reactions could, therefore, be accomplished by replacing a polarity-mismatched step with a two-step process in which the radicals and substrates are polarity-matched. In contrast to redox-neutral photocatalysis, the resulting radical adduct from the reaction between the acyl radical and radical trappers needs to be nucleophilic to nish the PRC catalytic cycle. Thiols and Nhydroxyphthalimide (NHPI) have been employed as PRCs for hydroacylation with electron-rich alkenes. [29][30][31][32] However, catalytic or stoichiometric radical initiators are required to generate the active thiyl and oxy radicals to induce the PRC. The discovery of new polarity-reversal catalysts that can avoid the use of radical initiators will enable greener radical transformations.
Bromine and sulfur are diagonal relationships in the periodic table which possess many similar characters. Thiol is the most common PRC catalyst with notorious toxic and odiferous characters (Fig.  1b). In stark contrast, bromine reagents have not been utilized in PRC reactions, but bromine radical (Br·) is well known as a moderately electrophilic HAT agent, which can abstract hydrogen atoms from C-H bonds to form nucleophilic carbon radicals. 11,[33][34][35][36][37] In this context, Ryu et al. have developed various attractive bromine-radical mediated transformations. [35][36][37] Very recently, the Miyake group described an excellent study of bromine radical catalysis promoted by energy transferring photosensitization. 38 Our group has reported photo-induced selective tertiary C(sp 3 )-H alkylation and amination using CH 2 Br 2 as a bromine radical precursor. 11 Published work has indicated that both Br 2 (with a bond dissociation energy, BDE = 194 kJ/mol) and NBS (N-bromosuccinimide, BDE = 243 kJ/mol) undergo reversible homolytic cleavage by visible-light photolysis (470 nm blue photon energy = 254 kJ/mol) to reversibly generate active bromine radicals. [39][40] We envisioned that by taking advantage of visible-light promoted homolysis of bromine reagents, bromine radical formed may behave as an effective polarity-reversal catalyst without the requirement of an external radical initiator, and result in a complementary substrate scope to photoredox catalysis.
Herein, we report that bromine acts as an e cient polarity-reversal catalyst for radical transformations with aldehydes (Fig. 1c). This strategy features a broad scope of applications, including hydroacylation of vinyl arenes, a three-component cascade transformation, and deuteration of aldehydes. The bromine radical will promote a HAT from an aldehyde substrate to deliver hydrogen bromide and an acyl radical which will subsequently react with a radical trapper to give another transient nucleophilic radical adduct.
Finally, the polarity-matched HAT between the nucleophilic radical adduct and HBr will furnish the nal product, with the regeneration of the active bromine radical which can participate in another polarity reversal catalytic cycle.

Results
Reaction optimization. The feasibility of this concept was rst investigated in a bromine-catalyzed hydroacylation of styrene with two equivalents of hexanal. After an extensive evaluation (Supplementary Table S1), we established that a combination of NBS (15 mol%) in PhF (0.025 M) at 80 o C under blue LED irradiation was optimal and produced the desired ketone product 3a in 66% isolated yield. No decarbonylated product was detected at this elevated temperature (80 o C). Other bromine sources such as Br 2 , 40 CBr 4 41 , and BnBr 42 also generated the desired product, albeit with lower e ciency. However, (n-Bu) 4 N-Br failed to promote this transformation. The solvent has a large impact on the reaction outcome and the formation of the product was observed only in aromatic organic solvents (e.g., PhCl, 33% yield; benzene, 46% yield). Use of other non-aromatic solvents such as MeCN, DMF, and EtOAc gave no product.
A lower reaction temperature (50 o C) resulted in a signi cantly decreased yield of 16%. The yield of product can be improved to 71% by adding NBS in two portions sequentially (10 mol% NBS followed by additional 5 mol% NBS after 36 hours). Control experiments showed that light was essential for this transformation. Replacing NBS with PhSSPh could not lead to the formation of product under the optimized conditions (Supplementary Table S1).
Substrate scope. With the optimal conditions in hand, we investigated the substrate scope of the hydroacylation of vinyl arenes 2. As demonstrated in Fig. 2a, a broad scope of aliphatic aldehydes was effective and provided the ketone products in moderate to good yields. Primary aldehydes which are readily available feedstocks, participated smoothly in hydroacylation reactions (3a-3f). Some sensitive functionalities such as a terminal ester (3e) and alkyne (3f) were tolerated in this radical transformation.
Multi-component radical cascade reactions play a privileged role in organic synthesis and enable direct construction of complex and diverse molecular scaffolds. 7,[43][44] The failure of hydroacylation with acrylates 4 and the radical nature of this PRC led us to search for a possible bromine-catalyzed threecomponent coupling reaction. We speculated that the bromine-induced nucleophilic acyl radicals from aldehydes would preferentially add to electron-de cient acylates in the presence of vinyl arenes. The generated a-acyl radical was relatively electrophilic and would be expected to couple with vinyl arenes instead of undergoing an unfavorable HAT with HBr. The intended three-component PRC reactions were realized effectively with coupling aldehydes 1, unsaturated esters 4 and vinyl arenes 2, generating densely functionalized 1,4-dicarbonyl compounds in a highly selective manner (Fig. 2b). Such useful products would be di cult to access otherwise, and related reports usually require excess oxidants for quenching the nucleophilic radical adduct. [45][46] Primary (5a-5c), secondary (5d-5f), and aromatic (5g-5j) aldehydes were all effective substrates for this cascade transformation, leading to 1,4-dicarbonyl products in moderate to good yields (41-79%). To further demonstrate the diversity of this transformation, acrylates 4 containing various functionalities, such as benzyl, tri uoromethyl, ether, chloride, and isobornyl groups participated smoothly to afford the corresponding products (5k-5p) in good yields (64-75%). Various vinyl arenes were applied in this protocol which illustrated good tolerance of functionalities (5q-5v). Functional groups such as the aryl chloride (5q) and bromide (5u) provided handles for further diversi cation.
In addition, we hypothesized that the bromine-induced nucleophilic acyl radicals may trap a deuterium atom from D-Br in a polarity-matched manner, thus realizing deuteration of aldehydes. The D-Br could be irradiation. All electron-de cient and electron-rich aromatic aldehydes delivered products in generally good to excellent isolated yields and deuterium incorporation (Fig. 2c). Functionalities ranging from electron-withdrawing substituents such as halides, tri uoromethyl groups, and boronate esters (6a-6e), to electron-donating substituents, such as phenyl (6f), alkyloxy (6g-6j, 6n), diphenylamino (6k), tert-butyl (6l), and methylthio (6m) groups, were tolerated well. However, aliphatic aldehydes were less effective in the H/D exchange process, and only low deuterium incorporations in the aldehyde C-H bond (6r-6t) were achieved. This may be due to the keto-enol tautomerization of aliphatic aldehydes in the presence of excess D 2 O, 47 which was suggested by the deuteration of the α-positions of the formal groups. The successful H/D exchange also con rmed the formation of acyl radicals under light-promoted conditions. Notably, no deuteration was detected at the benzylic positions.
Further synthetic applications. Encouraged by the broad substrate scope of the bromine-based PRC protocols, the potential of this strategy for the late-stage site-selective functionalization of complex molecules was subsequently investigated (Fig. 3a). Aldehydes derived from natural products such as (+)fenchol and lithocholic acid, participated in hydroacylation smoothly to afford products 7 and 8 in moderate yields. H/D exchange of derivatives from L-menthol, epiandrosterone, and cholesterol resulted in high deuterium incorporation with excellent chemoselectivity of the aldehydic C-H bonds. No tertiarycarbon functionalization could be detected in above transformations, even though Br radical has been reported as a suitable HAT agent for tertiary C-H bonds. 11,37 The synthetic value of this method was further demonstrated by the diversi cation of the synthesized products (Fig. 3b). D-labeled alkenes can be easily obtained from deuterated benzaldehydes by Horner-Wadsworth-Emmons ole nation. 48 Treatment of 1,4-diketones that generated from the radical cascade reaction with NaBH 4 followed by TsOH produced lactones 12 in good yields albeit in low diastereoselectivity. 49 Mechanistic elucidation with supporting evidence. A series of control experiments were performed to reveal more hints concerning the mechanisms of the aforementioned transformations (Fig. 4a). A deuterium-labeling experiment was conducted by adding D 2 O to the hydroacylation reaction. This resulted in a 55% yield of deuterium-containing 1-phenyl-3-octanone 3a', where deuteration took place at the α-positions of the carbonyl group and benzylic positions. When 3a was treated with D 2 O under the same conditions, deuteration was only detected at the α-positions of the carbonyl group (3a''). These results indicate that keto-enol tautomerism 47 promoted the deuteration at the α-positions of the carbonyl group, and this is consistent with the results of deuterated aldehydes 6r-6t (Fig. 2c). The 26% deuteration of 3a' at the benzylic positions suggested a HAT between a generated benzylic radical and H/D-Br. No product could be detected under the standard hydroacylation conditions in the presence of TEMPO, supporting a radical pathway. The light on/off experiment indicated that photolysis is essential for the reformation of Br radicals to sustain the radical chain process. UV-Vis measurements indicate that both NBS and Br 2 absorb and can be activated by light in the range of 400 to 600 nm ( Supplementary Fig. S7 and S8).
In light of all experimental data and previous literature reports, [35][36][37][38]50 plausible mechanistic pathways for photo-mediated bromine-catalyzed PRC reactions are proposed and illustrated in Fig. 4b. Even though the homolysis of NBS to bromine radicals could be induced by blue light irradiation, 37 this process might be accelerated by heating under our optimal conditions. The generated bromine radicals can recombine to form Br 2 , which explains the requirement of constant light irradiation for the homolysis of Br 2 back to the desired Br radicals. The Br radical abstracts a hydrogen atom from aldehyde 1 to produce an acyl radical I. When vinyl arenes 2 were utilized to trap the acryl radical, the resulting benzylic radical II can subsequently undergo a polarity-favored HAT with HBr to produce ketone product 3. Alternatively, in the presence of acrylate 4, the nucleophilic acyl radical I will preferentially add to electron-de cient acrylates rather than to vinyl arenes. In this way, an electrophilic radical adduct III is formed, which is polaritymismatched with H-Br and will couple instead with vinyl arene 2. The resulting benzylic radical IV nally can trap a hydrogen atom from HBr to give the 1,4-dicarbonyl product 5. In the deuteration reaction, the acyl radical I will abstract the deuterium atom from D-Br, which is generated from the rapid H/D exchange between D 2 O and HBr.
Density functional theory (DFT) calculations were conducted to further support the proposed mechanism of hydroacylation. The calculated potential energy surface (PES) was illustrated in Fig. 5a. The reaction started with a process of bromine radical abstracting the hydrogen atom from propionaldehyde to deliver INT1, which was an easy process without transition state (Fig. 5b). The subsequent radical addition to styrene led to a radical adduct INT2 with an energy barrier of 11.6 kcal/mol. The HAT between hydrogen bromide and INT2 gave an energy barrier of 7.0 kcal/mol to deliver the product. The pathway of INT2 abstracting the hydrogen atom from propionaldehyde was unlikely due to a higher energy barrier of 23.6 kcal/mol.
In summary, we have disclosed for the rst time, to the best of our knowledge, that bromine can be utilized as a polarity-reversal catalyst under visible-light irradiation. Hydroacylation of vinyl arenes, a three-component 1,2-difunctionalization of acrylates, and a deuteration of aldehydes were achieved in an atom-and step-economic and highly selective manner. The key to the success relies on the constant lightirradiation which induces and maintains bromine radicals for an active chain process. Compared to conventional PRC, this photo-mediated bromine-based PRC is distinguished by its green characters which stem from its no requirement of any chemical initiators.

Methods
General procedure for hydroacylation of vinyl arenes. In the glovebox, aldehyde 1 (0.4 mmol, 2 equiv) and alkene 2 (0.2 mmol, 1 equiv), PhF (8 mL), and NBS (0.02 mmol, 0.1 equiv) were added to a sealed tube equipped with a magnetic stirring bar. Then, the reaction mixture was irradiated by blue LED lamps (2 x 40 W) and magnetically stirred at 80 o C. After 36 hours, NBS (0.01 mmol, 0.05 equiv) was added and the reaction mixture was stirred and irradiated for an additional period of 36 hours. The reaction was quenched with water (5 mL), extracted with EtOAc (3 x 5mL) and the combined organic layers were dried over Na 2 SO 4 and concentrated. The product was puri ed by column chromatography (SiO 2 ).
General procedure for three-component cascade transformation. In the glovebox, aldehyde 1 (0.4 mmol, 2 equiv) and alkene 2 (0.2 mmol, 1 equiv), acrylate 4 (0.6 mmol, 3 equiv), PhF (8 mL), and NBS (0.02 mmol, 0.1 equiv) were added to a sealed tube equipped with a magnetic stirring bar. Then, the reaction mixture was irradiated by blue LED lamps (2 x 40 W) and magnetically stirred at 80 o C. After 36 hours, NBS (0.01 mmol, 0.05 equiv) was added and the reaction mixture was stirred and irradiated for an additional period of 36 hours. The reaction was quenched with water (5 mL), extracted with EtOAc (3 x 5 mL) and the combined organic layers were dried over Na 2 SO 4 and concentrated. The product was puri ed by column chromatography (SiO 2 ).
General procedure for deuteration of aldehydes. In the glovebox, aldehyde 1 (0.2 mmol, 1 equiv), D 2 O (5 mmol, 25 equiv), PhF (4 mL), and NBS (0.02mmol, 0.1 equiv) were added to a sealed tube equipped with a magnetic stirring bar. Then, the reaction mixture was irradiated by blue LED lamps (2 x 40 W) and magnetically stirred at 80 o C. After 72 hours, the reaction solution was concentrated, and the product was puri ed by column chromatography (SiO 2 ).
Computational details. All density functional theory (DFT) calculations were conducted with the Gaussian 09 program, 51 using the popular functionals of (U)B3LYP-D3(BJ). [52][53][54][55] Geometry optimizations were carried out with the basis set of 6-31+G(d, p) basis set for all atoms. Structures were optimized with Truhlar's SMD method (Solvation Model based on the Quantum Mechanical Charge Density) and Benzene was chosen as the solvent. Vibrational frequency analysis con rmed that the structure was either a minimum or a transition state. The calculation of single-point energy using SMD model (Benzene) and (U)B3LYP-D3(BJ) method (with the 6-311++G(3df, 3pd) basis set for all atoms). All relative enthalpy and Gibbs free energies (at 298.15K and 1 atm) are reported in kcal mol -1 .
Declarations Figure 1 Development of bromine radicals as visible-light-mediated polarity-reversal catalysts. a Functionalization of aldehydes through photo-promoted HAT catalysis. b Functionalization of aldehydes through traditional PRC. c Development of bromine radicals as polarity-reversal catalysts (this work).  Proposed mechanism and supporting evidence. a Supporting experiments for mechanism elucidation. b Proposed visible-light-mediated PRC mechanism.

Supplementary Files
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