Photoredox-mediated Minisci C–H alkylation of N-heteroarenes using boronic acids and hypervalent iodine† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc02653b Click here for additional data file.

A photoredox-mediated Minisci C–H alkylation of N-heteroarenes with easily accessible primary and secondary alkyl boronic acids has been developed.

Introduction N-Heteroarenes are common structural motifs in natural products, drug molecules, organic materials and ligands for metal catalysts. 1 Synthetic methods which enable the selective functionalization of the C-H bonds of N-heteroarenes could greatly facilitate their applications in these areas. 2 Among the different types of C-H functionalizations, C-H alkylations could provide more stereochemically diverse modications. 3 Over the past few years, the C-H functionalization of electron-decient heteroarenes via addition of carbon-centered radicals under oxidative conditions, known as the Minisci reaction, has undergone a remarkable renaissance, offering increasingly powerful methods for synthesizing alkyl-substituted heteroarenes (Scheme 1). 4 While the classical Minisci alkylation reaction involves alkyl carboxylic acids and halides, Baran recently demonstrated that aryl boronic acids are also viable reagents in Minisci-type C-H arylation reactions using Ag(I)/ S 2 O 8 2À oxidant. 5 Molander demonstrated that alkyl tri-uoroborates, particularly secondary alkyl triuoroborates, can effect efficient Minisci alkylation using Mn(OAc) 3 oxidant. 6 In addition, Minisci C-H alkylation transformations have been achieved using a variety of other alkylating reagents, including sulnates, aldehydes, and even simple alkanes, using different radical initiators and oxidants. 7 More recently, DiRocco reported the rst photoredox-mediated Minisci alkylation reaction of N-heteroarenes using peroxides as the alkylating reagent. 8 MacMillan demonstrated a Minisci alkylation reaction of N-heteroarenes using primary alcohols as the alkylation reagent, via photoredox-and organocatalysis. 9a However, despite these signicant advances, practical and broadly applicable methods for Minisci C-H alkylation of N-heteroarenes capable of coupling complex alkyl groups are still lacking. Herein, we report a photoredox-mediated Minisci C-H alkylation reaction of N-heteroarenes with a variety of easily accessible primary and secondary alkyl boronic acids. Its high efficiency, broad substrate scope, excellent functional Scheme 1 Minisci C-H alkylation of N-heteroarenes. a State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative group tolerance, and mild operation conditions make it particularly suitable for late-stage functionalization of complex substrates such as drug molecules.

Results and discussion
Although alkyl boron reagents are readily available and are wellknown precursors for alkyl radicals, they have been rarely applied in photoredox-mediated C-C coupling reactions. 10-13 In 2012, Akita reported that alkyl triuoroborates or cyclic triolborates can couple with 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) or Michael acceptors under Ru or Ir photoredox catalysis. 11 In 2015, Chen reported a decarboxylative alkenylation of alkyl triuoroborates with vinyl carboxylic acids using a hypervalent iodine oxidant, acetoxybenziodoxole (BI-OAc), under Ru photoredox catalysis. 12a More recently, Molander achieved coupling of alkyl triuoroborates with aryl halides by merging photoredox with Ni cross-coupling catalysis. 13 During our recent investigation of radical-mediated sp 3 C-H azidation reactions, we discovered that azidobenziodoxole (Bl-N 3 ) can be readily activated by visible light in the presence of [Ru(bpy) 3 ]Cl 2 , initiating a radical chain reaction. 14 Intrigued by the unique radical reactivity of benziodoxole reagents with photocatalysts, we questioned whether they can facilitate Minisci C-H alkylation with alkyl boron reagents under photoredox-mediated conditions. [15][16][17] We commenced our investigation with C-H butylation of 4chloroquinoline 1, a common model substrate for Minisci reactions, using butyl boronic acid 2a or triuoroborate 2b under the visible light (VL) irradiation (Table 1). We were delighted to nd that the desired C2-alkylated product 3a can be formed in excellent yield with 2a using [Ru(bpy) 3 ]Cl 2 photocatalyst and BI-OAc oxidant under optimized conditions (entry 5). Alkylation with 2b proceeded in lower yield (entry 6). In comparison with Bl-OAc, hydroxylbenziodoxole (BI-OH) gave slightly lower yield, methoxylbenziodoxole (Bl-OMe) was notably less effective, BI-N 3 gave low yield, chlorobenziodoxole (Bl-Cl) and PhI(OAc) 2 showed little reactivity (entries 7-11). Hexauoroisopropanol (HFIP) solvent is critical for obtaining high yield (entries [3][4][5]. No 3a was formed in the absence of either Ru catalysis or light irradiation (entries 13-14). Formation of 3a was completely suppressed when 2 equiv of TEMPO was added, forming side product O-butyl TEMPO in 16% yield (entry 15).
With the optimized conditions in hand, we next explored the substrate scope (Scheme 2). As seen in 3c-3l, a range of primary alkyl boronic acids reacted with 4-chloroquinoline 3 to give C2alkylated products in good to excellent yield. Methylation with MeB(OH) 2 gave moderate yield (see 3b). Primary alkyl radicals are more challenging reactants in Minisci reactions than secondary alkyl radicals due to their lower stability and nucleophilicity. 18 We were pleased to observe that primary alkyl substituents carrying various functional groups, including alkyl bromide, aryl iodide, ester, amide, carbamate, terminal alkyne, and benzyl chloride, can be incorporated in good yield (see 3g-3l). As seen in 3m-3r, the alkylation reactions of secondary alkyl boronic acids are much faster than the primary and typically proceed in good to excellent yield under the standard conditions. In contrast to alkylation, arylation with PhB(OH) 2 gave product 3s in low yield (21%).
As seen in 4-11, alkylation of pyridines and pyridine-based heteroarenes selectively took place at C2 and/or C4 positions. A mixture of C2-substituted 4a and C4-substituted 4b was obtained for unsubstituted quinoline. Alkylation of 2-methylquinoline selectively occurred at C4 to give 9 in excellent yield. In general, electron-decient N-heteroarenes show higher reactivity toward alkylation. For instance, cyclohexylation of 4-tbutylpyridine predominantly resulted in mono-alkylation (see 5b) while cyclohexylation of 4-CF 3 -pyridine gave 2,6-dialkylated 8 in excellent yield using 3 equiv. of boronic acid. A variety of other N-heteroarenes can also be alkylated in good yield and regioselectivity (see [12][13][14][15][16][17][18][19][20]. For instance, a purine riboside substrate was selectively alkylated at C6 to give 12 in excellent selectivity; 7d and a pyrrole-fused pyrimidine was selectively alkylated on the electron-decient pyrimidine ring to give 14 in good yield. Without protection of the NH group, benzimidazole can be alkylated at C2 to give 20 in good yield. As shown in Scheme 3, this Minisci C-H alkylation can be readily applied to functionalize complex natural products and drug molecules. 2c, 8,9a For instance, quinine with a free OH and vinyl group can be selectively alkylated at C2 position with both ethyl and cyclohexyl groups in excellent yield (see 21). Camptothecin can be selectively alkylated at the C4 position of the pyridine ring (see 23). Caffeine, a challenging substrate for previous Minisci reactions, can be selectively alkylated at C2 (see 22). 7b Alkyl chains carrying an alkynyl or alkyl bromide group can be installed at C6 of Famciclovir in good yield (see 24a, 24b). Fasudil carrying a free secondary NH group was selectively alkylated at C1 in good yield (see 26).
Control experiments and density functional theory (DFT) calculations have been carried out to probe the mechanism of this photoredox-mediated Minisci alkylation with alkyl boronic acids and Bl-OAc oxidant. 19 As shown in Scheme 4A, we were surprised to observe that reaction of 1 with BuB(OH) 2 and 1 equiv. of benzoyl peroxide in HFIP under visible light irradiation without photocatalyst also gave the alkylated product 3a in 20% yield along with 11% yield of arylated side product 3s, which is presumably formed from Phc via the decarboxylation of BzOc. In comparison with BuB(OH) 2 , BuBF 3 K showed much lower reactivity. Furthermore, 3a was formed as the only C-H functionalized product in 38% yield when ortho-iodobenzoyl peroxide 27 (highly explosive) was used as the oxidant for Scheme 2 Substrate scope of photoredox-mediated C-H alkylation of N-heteroarenes. (a) Isolated yield on 0.2 mmol scale; (b) 2 equiv. of MeB(OH) 2 , 48 h; (c) 2 equiv. of RB(OH) 2 ; (d) 1.5 equiv. of PhB(OH) 2 ; (e) 1 equiv. of RB(OH), 2,4-dialkylated product was formed in <5% yield; (f) 2,6-dialkylated product was formed in <3% yield; (g) 2,2 0 -dialkylated product was formed in <5% yield; (h) 4.5 equiv. of CyB(OH) 2 ; (i) 3 equiv. of CyB(OH) 2 . (j) other alkylated regioisomer was formed in <5% yield. reaction of 1 with BuB(OH) 2 under the same conditions. 20 These experiments suggest that benzoyloxy radicals can react with alkyl boronic acids to generate the requisite alkyl radical for the subsequent C-H alkylation. As shown in Scheme 4B, our DFT calculation showed that oxidant Bl-OAc can be readily reduced by photoexcited Ru(II)* via single electron transfer (SET) to form a radical anion intermediate Bl-1, which then can undergo I-O bond cleavage to form radical Bl-2 and acetate anion via pathway a or form Bl-3 and acetoxy radical AcOc via pathway b. 21 Formation of Bl-2 is considerably more thermodynamically favorable than formation of AcOc. Although a pair of interconvertible radical species, I-centered radical Bl-4 and O-centered radical Bl-2, have been invoked in a number of previous studies, 22 the postulated cyclic structure of Bl-4 with a typical I-O bond length of ca. 2.1-2.2Å cannot be located in our DFT calculation (Scheme 4C). 23 Instead, the acyclic radical intermediate Bl-2 is stabilized by a secondary I-O bonding interaction ($2.6Å) and its spin density is distributed between the O and I atoms. 24 Calculation also revealed that Bl-2 is notably more stable than benzoyloxy radical BzOc and is much less prone to undergo decarboxylation to form the corresponding aryl radical, which could cause the C-H arylation side reaction. 25 Similar to the nucleo-homolytic substitution reaction of more reactive alkylboranes with O-centered radicals, Bl-2 could react with the less Lewis-acidic boronic acids to form an alkyl radical Rc via a radical "ate" transition state. [26][27][28] The DFT calculation showed that this is a facile process at ambient temperature and highly exothermic (Scheme 4D).
Based on the above studies, we propose that the reaction with boronic acid substrates is initiated with the SET from photoexcited Ru(II)* to Bl-OAc (Scheme 5). The resulting Bl-2 reacts with boronic acid to form a Rc, which then undergoes nucleophilic addition reaction with protonated N-heteroarenes to form a s-complex. Single-electron oxidation of this intermediate by Ru(III) and deprotonation gives the nal C-H alkylated product and closes the photoredox cycle. 29

Conclusions
In summary, we have developed a photoredox-mediated Minisci C-H alkylation reaction of N-heteroarenes with easily accessible alkyl boronic acids. A broad range of alkyl groups, including challenging primary alkyl groups, can be readily incorporated into various N-heteroarenes with high efficiency under mild conditions. These reactions exhibit excellent substrate scope and functional group tolerance, and offer a broadly applicable method for the late-stage functionalization of complex substrates. Mechanistic studies have revealed that acetoxybenziodoxole serves as a facile precursor for an ortho-iodobenzoyloxy radical intermediate under photoredox catalysis. The unique property of this intramolecularly stabilized benzoyloxy radical might be critical for the efficient transformation of usually less reactive alkyl boronic acids to form alkyl radicals. Further mechanistic studies and application of benziodoxole reagents in other photoredox-mediated reaction systems are currently underway.