Organophotocatalytic Radical–Polar Cross-Coupling of Styrylbo-ronic Acids and Redox-Active Esters

We report the development of a radical–polar cross-coupling reaction using styrylboronic acids and redox-active esters under organophotoredox catalysis. The reaction proceeds through a formal polarity-mismatched radical addition. The use of an organic photocata-lyst permitted very low loadings of the electron-shuttle additive and accelerated reaction times compared with established processes. The scope of the reaction was explored, and the utility of the products is demonstrated.

C(sp 2 )-C(sp 3 ) coupled product Radical-polar cross-coupling reactions are broadly useful methods for synthesis. 1The addition of a radical species to an alkene forges an initial C-C or C-X bond and produces an intermediate radical that can, in turn, be used to access several different products, depending on the reaction conditions (Scheme 1a).For example, oxidation of the intermediate radical delivers a carbocation that can be intercepted by a nucleophile or can lose a proton to forge an alkene.Alternatively, reduction of the intermediate radical generates an anion that can undergo reaction with an electrophile.Extensions to this chemistry where the intermediate radical reacts with another substrate (e.g., a second alkene or hydrogen donor) or a transition metal to promote further bond formations have also been developed. 2The functionalization of the alkene starting material can be critical to the downstream reactivity of the intermediate radical.
Borylated alkenes have been used in radical-polar cross-coupling in three main approaches: (i) as -nucleophiles to intercept an intermediate carbocation, 3 (ii) to generate -boryl radicals for addition to alkenes or as SOMOphiles, 4,5 and (iii) as SOMOphiles where the boryl unit acts as a leaving group to facilitate formation of alkene products. 5he third approach has seen several applications, selected examples of which are shown in Scheme 1b.For example, Wu and co-workers developed a method for photocatalytic coupling of aryl radicals, generated from diazonium salts, with styrylboronic acids.5a The groups of Leonori and Akita have developed photocatalytic couplings of potassi-

Alkyl radicals
Cascade processes

Letter Synlett
um alkenyl(trifluoro)borates with radicals generated from -halocarbonyls or the Togni reagent, respectively.5b,c Yu and co-workers have shown how styrylboronic acids can react with C-centered radicals generated from cascade processes.5d,e We recently reported a method for coupling styrylboronic acids with redox-active N-hydroxyphthalimide (NHPI) esters using Ru photocatalysis.5f Here, we report an improved process based on organophotoredox catalysis that is metal-free and permits a faster reaction using lower loadings of the electron-shuttle additive (Scheme 1c).
The motivation for this work was to move away from noble-metal-based photocatalysts to improve the sustainability of coupling processes. 6Accordingly, we focused on the use of organic photocatalysts.The benchmark reaction between styrylboronic acid (1) and cyclohexyl (c-Hex) NHPI ester (2) to give the desired C(sp 2 )-C(sp 3 ) coupled product is shown in Table 1.The optimized reaction conditions required 1 mol% of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6dicyanobenzene (4CzIPN) 7 as a photocatalyst and 2 mol% of Ph 3 N as an electron shuttle (see below), with the reaction complete in one hour (Table 1, entry 1).This represented an improvement on previous conditions, which used 1 mol% of an Ru-based photocatalyst, 10 mol% of an electron-shuttle additive (PhNMe 2 ), and required three hours for a similar yield. 8Selected optimization data are provided.First, the re-action did not proceed with eosin Y 9 and PhNMe 2 under irradiation from blue LEDs (entry 2), but required green LEDs and an extended reaction time to give a low yield (entry 3).Using 4CzIPN with PhNMe 2 for an extended reaction time gave a good yield, but resulted in erosion of stereochemical integrity (entry 4).This extended reaction time resulted in photocatalytic alkene isomerization. 10Solvent variation was not tolerated (entries 6 and 7).Control reactions confirmed the requirement for blue LEDs (entries 8 and 9).Other additives were assessed, such as catechol (entry 10), but none an improvement on Ph 3 N.An increased loading of Ph 3 N offered no advantage compared with 1 mol% (entry 11).Finally, the reaction was more effective with the boronic acid: the equivalent Bpin, Bcat (cat = 1,2-O 2 C 6 H 4 ), and BF 3 K compounds were less effective or were unreactive (entries 12-14).
The generality of the benchmark reaction conditions was assessed by application to a range of NHPI esters and styrylboronic acids (Scheme 2).Variation of the NHPI component was generally well tolerated, with some fluctuations in the isolated yield (Scheme 2a).Cycloalkyl NHPI es-
A range of styrylboronic acids with various electronic and steric parameters were generally effective reactants (Scheme 2b).There was no clear electronic trend, with some electron-rich (24) or electron-deficient (33) examples providing diminished yields.
Lastly, the majority of products were isolated with >20:1 E/Z ratios; however, several examples notably displayed an erosion of stereochemical integrity through uncontrolled photocatalytic isomerization (noted in Scheme 2). 10 To showcase the synthetic utility of this photocatalytic coupling method, we used product 3 in a range of downstream derivatization processes (Scheme 3).Photocatalytic E→Z isomerization was achieved under the conditions reported by Gilmour and co-workers to give 35.10d Ru-catalyzed aziridination delivered 36. 11Catalytic dihydroxylation smoothly delivered diol 37, 12 whereas dibromination was also straightforward, giving 38. 13 Hydrogenation using a Pt catalyst gave the linear alkane 39 in a good yield. 14 (42/43) = 1.35 V vs SCE].8b This is capable of one-electron oxidation of Ph 3 N (E 1/2 = 0.98 V vs SCE) to give the reduced photocatalyst 43 and the aminium radical 48. 16Radical anion 43 [E 1/2 (41/43) = -1.21V vs SCE] 8b facilitates singleelectron transfer to 45 (E 1/2 = -1.26V vs SCE), 17 16 gives carbocation 50, which is primed for elimination of the boron unit to give the product 51.

Scheme 4 Proposed mechanism
In summary, a metal-free approach to radical-polar cross-coupling of styrylboronic and NHPI esters has been developed.The reaction conditions offer several advantages over established methods, including the avoidance of metals, lower loadings of catalytic additives, and shorter reaction This C(sp 3 )-C(sp 2 ) coupling is general and affords the desired products in typically good yields.

Table 1
Reaction Development.