Metal-free C–H alkylation of heteroarenes with alkyltrifluoroborates: a general protocol for 1°, 2° and 3° alkylation
A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts.Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by 1 H and 13 C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF 3 . Fig. 1 Complex heteroarenes poised for diversification.
Introduction<!>Results and discussion<!>Practical applications<!>Mechanistic investigations<!>Conclusions
<p>Heteroaryl subunits are among the most commonly employed, privileged structures in medicinal chemistry. 1 Unfortunately, the synthesis of many of these structures is oen predicated on cyclization reactions 2 from simple starting materials (e.g., aldehydes, hydrazines, alkynes, etc.). Although these methods oen prove advantageous when the precursors needed for a particular molecular target are inexpensive and commercially available, these sequences are untenable when attempting to access a diverse library of structurally rich heteroarenes with a common core (Fig. 1).</p><p>To overcome this challenge, two predominant anionic strategies have emerged for diversifying common heteroaryl motifs (Scheme 1): uorination to enable facile S N Ar-based chemistry 3 and halogenation (bromination, 4 chlorination 5 ) to provide a site for cross-coupling. 6 These methods are highly effective for many systems, but in numerous cases installation of the halide at the desired site is unselective or impossible, requiring re-evaluation of the synthetic strategy. Furthermore, when successful incorporation of halides has occurred, heteroarenes are oen obstinate partners in cross-coupling chemistry, 7 requiring careful screening to achieve fruitful union.</p><p>Most importantly, from an efficiency standpoint, these strategies are sub-optimal as they rst require a functional handle to be installed, only to be immediately replaced in a subsequent displacement reaction.</p><p>Radical alkylations of heteroarenes (Minisci reactions) 8 represent a more direct functionalization of specic C-H bonds. For this reason, radical alkylation strategies have recently risen to prominence for the late-stage functionalization of heteroaryl systems. Although Minisci and coworkers initially used silver oxidants at elevated temperatures to generate alkyl radicals from the corresponding carboxylic acids, 9 advances in alkyl radical generation have enabled much milder methods to be developed (Scheme 1). These have included methods using boronic acids, 10 peresters, 11 and other precursors 12 under much less forcing conditions. Most notably, the Baran laboratory has pioneered the use of sulnate salts 13 that have enabled the extremely facile introduction of functionalized alkyl radicals into an impressive array of heteroarenes. These methods allow the formal C-H alkylation of heterocycles in a mild, metal-free mannerdrawing rapid adoption by medicinal chemists for the late stage diversication of pharmaceutically relevant compounds. 14 Unfortunately, even with these advances, current methods are not without their limitations, particularly with regard to the continued requirement for high loadings of both the radical partner and oxidant. Even the milder methods employing sul-nate salts oen require a signicant excess of an expensive and synthetically demanding precursor (3-6 equiv.) and oxidant (5-10 equiv.) to achieve good yields. 13 To date, methods grounded on stoichiometric radical generation have been continually limited by parasitic reactivity (e.g., homocoupling, H-atom abstraction, and chain processes) that appear to outcompete the desired Minisci alkylation. As such, oen the only solution has been to push reactions to completion with increased reagent loadings or successive dosing (Scheme 1A).</p><p>To combat the disproportionate stoichiometry and typically harsh conditions, other groups have turned to photoredox catalysis for the efficient generation of radical. 15 Contributions by the MacMillan, 16 DiRocco, 17 Chen, 18 and Barriault 19 groups have all highlighted the advantages afforded under this paradigm. Although a variety of alkyl radicals precursors were presented in these photoredox contributions, each method exhibits some inherent limitations. For example, the MacMillan group targets weak C-H bonds, limited to a-heteroatom bonds. Barriault and coworkers demonstrated that alkyl bromides could be reduced to generate the corresponding alkyl radicals, but 3 equivalents of these precursors and a UVA LED light source were required. Additionally, MacMillan and Barriault used expensive iridium or gold photocatalysts, respectively. The recent report by Chen addressed many of these issues with the use of sustainable boronic acid partners and inexpensive Ru(bpy) 3 , but their method employs the use of a stoichiometric iodine oxidant that seems uniquely required for activation.</p><p>In light of these advances, we recognized the potential to marry photoredox Minisci chemistry with our laboratory's interest in alkyltriuoroborate reagents, especially given reports by our laboratory and others 20 on the favorable single electron oxidation potentials of these salts to form alkyl radicals (E red ¼ +1.10 V vs. SCE for 1 benzylic 20a and +1.50 V vs. SCE for 2 alkyltriuoroborates 20b ). Here, with appropriate organic photocatalyst selection (for 1: *E red ¼ +2.06 V vs. SCE 21 ), all representative radical classes could be activated under identical reaction conditions (Scheme 1B). In this scenario, one can envision photocatalyst excitation serving as a chaperone for steady, synchronized, catalytic radical generation. Such a protocol ensures that an excess of radicals are not generated, minimizing at least some of the byproducts formed through stoichiometric processes. The photoredox catalyst-coordinated generation of radicals in this manner leads to improvement in reagent and oxidant loading, thus enhancing the efficiency and sustainability of these methods. Serendipitously, these aforementioned concepts, in conjunction with the generation of Lewis acidic BF 3 byproduct, also led to enhanced reactivity and selectivity in these transformations.</p><!><p>Mechanistically, we anticipated that visible light irradiation of organic photocatalyst 1 would generate the excited complex 1*, which is highly oxidizing and capable of oxidizing an alkyltri-uoroborate to release the desired alkyl radical 3 and BF 3 (Scheme 2). The generated radical 3 can then intercept the protonated heteroarene to form the radical cation 5. Reduction of persulfate (E red ¼ >+0.35 V vs. SCE 22 ) by the reduced form of the photocatalyst 4 (E red ¼ +0.49 V vs. SCE 21 ) generates the sulfate dianion and sulfate radical anion, regenerating photocatalyst 1. 21 Finally, H-atom abstraction of 5 by the sulfate radical anion leads to rearomatization, affording the desired alkylated heteroarene 6. 16 Quantum yield studies indicate this is not a radical chain process as evidenced by a f of 0.31 (see ESI †). Furthermore, addition of excess allyl acetate (a known sulfate radical anion trap 23 ) did not interfere with reaction efficiency or conversion.</p><p>To begin this optimization, we keyed in on tertiary radical partners for our initial studies. In particular, tert-butyltri-uoroborate as the appropriate radical precursor and isoquinoline carboxylate as the heteroaryl partner. Before screening various photocatalysts, controls probing the need for oxidant (Table 1, entry 2), light (entry 3), and photocatalyst (entry 4) were completed. Additionally, the absence of acid (entry 5) afforded 30% conversion to product, although as alkyl radical 3 is generated, BF 3 (an electron-decient Lewis acid) is concomitantly being formed. Performing the reaction in air provided a comparable yield (entry 6) to a reaction carried out under inert conditions (entry 1).</p><p>The mesityl acridinium photocatalyst was then compared to other photocatalysts (entries 7-10). Noting the need for a relatively high oxidizing potential of the photocatalyst, it was expected that ruthenium photocatalysts (with signicantly lower oxidation potentials than the acridinium dyes) would experience diminished yields, which proved to be the case (entries 7 and 8). During the period that photoredox catalysis has gained traction in the organic chemistry community, one major criticism has been the high cost of the key metal-based photocatalysts (i.e., those based on iridium and ruthenium). Nicewicz 24 and Zhang 25 have explored alternative organophotocatalysts that have been shown to exhibit similar reactivity to their metal-based counterparts. Surprisingly, 4CzIPN (entry 10) signicantly outperformed MesAcr over a 12 h period. Neither excess alkyltriuoroborate (entry 11) nor excess oxidant (entry 12) provided any perceived advantages.</p><p>In view of their low cost and ease of access, going forward we focused on the two organophotocatalysts, MesAcr and 4CzIPN. To determine the most suitable organic photocatalyst for our purposes, we scaled up the reactions described in entries 1 and 10, and discovered that running the reaction for 16 h afforded similar yields, consistent with the small scale reactions. It was important for this protocol to be general for primary, secondary, and tertiary alkyltriuoroborates. Because primary alkyltri-uoroborates have a markedly higher oxidation potential (E red ¼ +1.90 V vs. SCE 20k ) than secondary or tertiary alkyltri-uoroborates, MesAcr and 4CzIPN were compared with a primary alkyltriuoroborate (Scheme 3). In this assay, MesAcr outperformed CzIPN with 76% versus <10% isolated yields, respectively.</p><p>Tricoordinate organoboron compounds are isoelectronic with carbocations, and thus would not be expected to be easily Scheme 2 Proposed mechanism.  oxidized by single electron transfer (SET) processes. To conrm that this chemistry was unique to alkyltriuoroborates, a variety of organoboron reagents were synthesized and analyzed by cyclic voltammetry to determine their relative oxidation potentials (Table 2). As expected, the trivalent organoboron variants exhibit very high oxidation potentials as compared to their tetravalent, "ate" complex analogues. Consequently, under the reaction conditions, no radical formation from the boronic acids and/or esters was observed. For the tetravalent species, triolborates exhibit comparatively low reduction potentials.</p><p>Unfortunately, the swi hydrolysis of triolborates under the acidic, aqueous reaction conditions forms the redox inactive boronic acid. 26 By contrast, alkyltriuoroborates are both stable to the reaction conditions and redox amenable, resulting in an excellent 72% yield with methyl isoquinoline carboxylate aer 16 h. tert-Butyltriuoroborate was selected to examine the amenability of various heteroarene partners (Table 3). Regioselectivity was probed using quinoline itself, leaving both the C2 and C4 positions available for alkylation. Currently there are two methods for installing tertiary radicals regioselectively into the quinoline core structure. Namgoong and coworkers reported the use of excess TMP-zincate to deprotonate selectively at the C2 position, followed by incorporation of the tert-butyl substituent. 27 This was a singular transformation, with no demonstrated scope. Additionally, Minisci and coworkers have reported selective C2 C-H substitution on quinolines using a 3fold excess of alkyl iodide radical precursors. 8b Although efficient, drawbacks of this approach included using peroxide as the oxidant, thereby limiting functional group tolerance, and the limited number of commercially available, complex alkyl iodides. Therefore, we were pleased to observe regioselective addition to the C2 position of the heteroarene in 72% yield (1a). With substitution at the C4 position of quinoline, the reaction reached full conversion to product within 16 h as determined by GC-MS analysis (1b). When isolated, a 95% yield of the desired product was achieved. Beyond alkyl substituents, halides and triuoromethyl groups incorporated within the heteroaromatics allowed excellent conversion to product (1c, 1d).  In addition to quinoline cores, indazole (1e), isoquinoline (1g), and quinoxaline (1h, 1i) moieties were successful partners under standard conditions. Indazole 1e is particularly notable because of the prevalence in medicinal chemistry 1 and, to the best of our knowledge, the absence of Minisci examples in the literature. As expected, the use of the benzimidazole core resulted in no conversion (1f) because of the electron-rich nature of the C2 site. Additionally, N-methyl benzimidazole was similarly unreactive. Pyridines also exhibited selective mono-addition (1j-1l, 1n). There has appeared only one report of nicotinamide alkylation via Minisci chemistry, wherein three equiv. of the corresponding carboxylic acid were necessary under silver catalyzed conditions. 28 A medicinally relevant core, quinazolinone 1p, afforded product in 90% yield. Purine 1q contains two sites of potential radical addition, but substitution was observed only on the pyrimidine subunit. Overall, this method is broadly tolerant of a wide range of functional groups as demonstrated with quinine 1r (possessing alkene, alcohol, tertiary amine groups). Notably, the tertiary amine embedded within quinine did not interfere with the photocatalytic cycle despite its propensity for competitive oxidation.</p><p>Currently, there are a limited number of tertiary alkylboranes commercially available and no alkyltriuoroborates. Presumably, this is a result of narrow synthetic utility compared to their primary and secondary counterparts. Although we demonstrated that tert-butyltriuoroborate was viable, more highly elaborated systems could also be incorporated. Cook and coworkers recently reported a manganese-catalyzed borylation of alkyl bromides. Using Cook's procedure, 29 >1 g of pinacolborane intermediate 1t was synthesized from the corresponding alkyl bromide 1s. This borylation was followed by treatment with saturated KHF 2 to afford the corresponding alkyltriuoroborate 1u (Scheme 4).</p><p>With tertiary alkyltriuoroborate 1u in hand, radical addition to caffeine 1v and benzothiophene 1w was carried out. The development of the Cook approach to 3 alkyltriuoroborates thus allows access to an even greater array of coupling partners.</p><p>In further studies, a wide range of alkyltriuoroborates were found to be suitable partners in the developed photoredox Minisci conditions (Table 4). First, a benzyl protected a-alkox-yalkyltriuoroborate afforded 2a in 58% yield. Additional examples of unactivated, secondary alkyl radical precursors could be appended as in 2b-2j. For 2b, the successful addition of uorinated isosteres is encouraging, given the welldocumented propensity these subunits have for modulating solubility and binding affinity in medicinal chemistry. 30 For 2c-2e, the tetrahydropyranyl and piperidinyl moieties are commonly introduced ring structures that serve as useful probes for H-bond donors/acceptors in SAR efforts. 31 To the best of our knowledge, primary alcohols appended to the radical coupling partner have not been reported in Miniscitype reactions, perhaps owing to their propensity to undergo Hatom abstraction alpha to the hydroxyl group. Therefore, we were pleased to obtain 2f, albeit in low yield. Of note, this  selectivity is complementary to the MacMillan group's work on alcohols as radical precursors in photoredox-Minisci couplings. 16a A further exploration of 5-and 4-membered heterocycles (2g-2i) was conducted with promising results, where tetrahydrofuran 2g was afforded in 34% yield, but access to pyrrolidine 2h was not successful. For azetidine 2i, standard solvent conditions provided only trace amounts of product, but switching to DCE/H 2 O (1 : 1) proved to be benecial. Cyclo-propyltriuoroborate, although unproductive in previously reported photoredox/Ni dual cross-coupling methods, 20b afforded 2j, albeit in 20% yield. 1-Adamantyltriuoroborate has never been used in Minisci-type alkylations. Using the standard conditions, 2k was isolated in 45% yield. Lastly, chemoselective radical addition to the isoquinoline was observed for 2l despite containing an alternate site for alkylation within the alkyltri-uoroborate partner.</p><p>Moving forward, this Minisci process was anticipated to be broadly applicable even to primary alkyltriuoroborates, which possess relatively high oxidation potentials (Table 5). As an initial foray, we rst investigated whether stabilized primary a-alkoxymethyltriuoroborates could be competent partners in this process (3a-3d). Non-stabilized alkyl radicals were also demonstrated in examples 3e-3l. Notably, 3j contains an ortho bromide functional handle for further elaboration. Unfortunately, electron decient 3,3,3-triuoropropyltriuoroborate afforded 3l in diminished yield, likely because of its high oxidation potential and resultant destabilization of the generated radical. These trends track with other recent reports specically targeting more electrophilic radicals. 13e,16b   As would be anticipated for the radical-based mechanism of the transformation, cyclopropylcarbinyltriuoroborate 3m formed the corresponding radical 3o aer SET oxidation and subsequent rearrangement. Following radical addition to the activated heteroaromatic, 3p was isolated in 55% yield.</p><p>The diversity of the process was expanded to underline the potential for widespread utility (Table 6). Lepidine was coupled with a variety of stabilized a-alkoxy (4a-4c) and unstabilized (4d-4f) radicals. With quinoline, C2 regiospecicity was again observed (4d, 4e), albeit in diminished yields. This is particularly noteworthy given the challenges associated with avoiding complex mixtures of isomers in prior Minisci-type reaction reports. 32 With heteroarene cores such as pyridine (4f), benzothiazole (4g), indazole (4h), and quinazolinone (4i, 4j), exceptional yields were observed. When exploring reactivity with caffeine, methylcyclopentyltriuoroborate afforded 4k in 37% yield. Additionally, a secondary alkyl radical was successfully appended to functionally rich quinine as demonstrated in 4l.</p><!><p>Given the success of this method, the use of this technology for selective ligand modications was envisioned (Scheme 5). As a case study, difunctionalization of a bipyridine-based ligand was selected for further investigation. Commonly these ligands are synthesized through the S N Ar reaction of strong nucleophiles (e.g., tert-butyllithium) to a uorinated bipyridine precursor, which is unfortunate given the popularity of these ligands in Cu and Ni catalysis. 33 In contrast to the use of such pyrophoric alkylating agents, bench-stable alkyltriuoroborates represent an attractive alternative. Gratifyingly, unfunctionalized substructures 5a and 5c were converted to the desired products in 84% and 68% yields, respectively. Pyridine ligands are also valuable for the synthesis of iridium photocatalysts. Under the same reaction conditions, heteroarene 5e afforded mono-alkylated product 5f in 82% yield. When tridentate ligand terpyridine 5g was subjected to the standard conditions with two equivalents of tert-butyltriuoroborate, mono-alkylated 5h was formed exclusively. 34 Although medicinal chemists have principally capitalized on late-stage Minisci heteroarene alkylation, 9 it can be advantageous to introduce alkyl substitution earlier in a synthetic sequence. 35 Using the present protocol, the installation of alkyl subunits on brominated heteroarenes provides an excellent opportunity to highlight divergency in molecular synthesis. Furthermore, the halides installed within a variety of heteroarenes can serve a dual purpose: they may serve as an electronic Table 6 Demonstration of diversity a a Reactions were run with heteroarene (1.0 equiv.), alkyltriuoroborate (1.0 equiv.), MesAcr (5 mol%), K 2 S 2 O 8 (2.0 equiv.), triuoroacetic acid (1.0 equiv.) in MeCN/H 2 O (1 : 1) on 0.3 mmol scale.</p><p>Scheme 5 Mild alternative for ligand synthesis. a Reactions were run with heteroarene (1.0 equiv.), alkyltrifluoroborate (1.0 or 2.0 equiv.), MesAcr (5 mol%), K 2 S 2 O 8 (2.0 equiv.), trifluoroacetic acid (1.0 equiv.) in MeCN/H 2 O (1 : 1) on 0.3 mmol scale.</p><p>bias for regioselective alkylations ortho to the halide, 13d and they provide a functional handle for cross-coupling reactions, etc. 6 To initiate studies to explore these concepts, a number of brominated heteroarenes were selected (Table 7). First, pyrimidine 6a was paired with an a-alkoxyalkyltriuoroborate to yield exclusively the C4-substituted product. When moving to pyridines, a mixture of C2 and C6 alkylation occurred with tosylprotected piperidinyltriuoroborate (6b). Conversely, with primary alkyltriuoroborates, only the C2-substituted products were observed in examples 6c and 6d. Chloride substitution was also well tolerated as demonstrated in 6d. When 4-bromoisoquinoline was utilized as a substrate, a mixture of regioisomers 6e and 6f was generated. Based on these studies, 6a and 6c contrast favorably with previous ndings in the Baran laboratory wherein regiomeric isomers were observed for heteroaryl bromides and chlorides. 13d As a nal highlight of the potential for late-stage functionalization, camptothecin (CPT) was selected as an appropriate, complex heteroarene. In medicinal chemistry, CPT was identi-ed as an anti-cancer drug candidate because of its cytotoxic activity in a number of cancer cell lines. Unfortunately, poor solubility was a systemic issue and prevented moving it forward as a drug candidate. 36 To tackle this challenge, various alkyl substitutions on the C7 position of the natural alkaloid were introduced, resulting in a more highly-active clinical candidate. 37 Although SAR studies were conducted to conrm the promising properties of alkyl decoration, the alkyl substituents were primarily limited to simple alkyl groups (e.g., methyl, ethyl) using the corresponding alkyl bromides, peroxide, and acid under thermal conditions. 38 To demonstrate the advantages of using the currently developed, mild photoredox conditions, secondary and primary alkyltriuoroborates were selected as reagents for generation of analogues. As displayed in Scheme 6, primary a-alkoxyalkyl subunits could be incorporated, along with secondary alkyl moieties (7a, 7b).</p><!><p>From our previous reports on Minisci chemistry 12 and the results provided herein, it became clear that the use of alkyl-triuoroborates provided clear advantages in terms of both reactivity (permitting a single equivalent of radical precursor to be employed) and regioselectivity in heteroarene alkylation. Given these observations, it seemed that there might be some inherent advantage to the generation of BF 3 byproduct during the course of the reaction. Two distinct possibilities were considered: (1) the BF 3 produced was intimately involved with the generated radical, providing a shepherding effect in delivering the radical with enhanced selectivity, or (2) the BF 3 was coordinating to the heteroarene prior to the radical addition, activating the heteroaryl substrate and enhancing preference for one site beyond the activation provided by the added protic acid.</p><p>To assess the rst hypothesis, DFT calculations were performed to determine the effective "bond order" for radical association with BF 3 in solution. This potential interaction was of particular interest as this escorting effect has little precedent in the chemical literature; currently, there are only examples of nitrogen-and oxygen-centered radicals interacting with BF 3 in solution. 39 Indeed, preliminary calculations suggest that a strong preference exists for the free radical over a BF 3 -bound complex in solution (see ESI †). Noting this lack of association, we were quick to investigate an alternative hypothesis.</p><p>To probe each of the possible heteroarene complexes, we prepared stoichiometric solutions of one of our successful, selective substrates, quinoline, with no additive, triuoroacetic acid (TFA) alone, BF 3 alone, and nally TFA with added BF 3 , hoping to probe the effect of coordination on the proton and carbon shis of heteroarene and provide some rationale for the differences between our chemistry and previously established protocols.</p><p>For triuoroacetic acid, a clear downeld shi was observed in the C2 and C4 protons of quinoline (Fig. 2). Likewise, for the addition of BF 3 , a slightly less pronounced, but clear, downeld shi was also observed for the same protons. However, the combination of both additives together produced a wholly different shi in resonances to a unique heteroarene species.</p><p>Most importantly, the carbon shis of C2 relative to C4 (the best indicator of relative radicophilicity) possess enhanced differentiation in relative downeld shi (3 ppm) in comparison to the BF 3 and triuoroacetic acid complexes alone (1 ppm) (Fig. 3). Based on these chemical shis, it is reasonable to suggest the C2 position is preferentially activated over the C4 position 40 under the reaction conditions, resulting in the enhanced regioselective mono-alkylation observed for the quinoline system and, by analogy, many of the other systems in which alkyltriuoroborates appear uniquely reactive and selective (vida infra).</p><p>To probe these ndings further, we hoped that the use of alternative radical precursors (e.g., sulnate salts or carboxylic acids) could be used in the presence and/or absence of BF 3 to achieve the same desired regioselectivity. Unfortunately, under our standard conditions, sulnate salts were universally ineffective, and carboxylic acids gave the same regiomixture, even with added BF 3 . Given this current ambiguity, this enhanced reactivity and regioselectivity appears to remain unique to the triuoroborate precursors (see ESI †).</p><p>At this time, although it is impossible to propose a structure for this distinct, activated species, we speculate that BF 3 activation of either the heteroarene p-cloud 41 or polarization of the triuoroacetic acid 42 to increase its effective pK a may be responsible. Intriguingly, this type of dual activation could perhaps be more broadly operative in the selective alkylation of other heteroaryl cores.</p><!><p>In summary, a mild, room temperature method for the introduction of a diverse palette of alkyl groups has been developed. Under a set of unied reaction conditions, primary, secondary, and tertiary alkyltriuoroborates can be employed in photoredox Minisci chemistry for the rst time. This chemistry makes use of an inexpensive, mild oxidant, organic photocatalyst, and requires only one equivalent of alkyl radical partner, providing one of the most cost efficient and sustainable approaches to date. Additionally, enhanced regioselectivity was observed compared to current "state of the art" Minisci-type alkylations. Both of these phenomena may be related to the synchronized, catalytic generation of radicals in conjunction with the in situ generation of BF 3 during the course of the reaction. The resultant method has been demonstrated broadly with respect to the heteroarene and alkyltriuoroborate partners. Furthermore, access to bipyridine-type ligands as well as the late stage diversication of medicinally relevant substructures has been showcased. Finally, NMR studies provided support for a unique, highly activated species caused by the formation of BF 3 upon the single-electron oxidation of alkyltriuoroborates. Currently, further mechanistic studies are underway to elucidate the nature of this complex.</p><p>Given the wide array of commercially available alkyltri-uoroborates, in addition to those synthesized by our laboratory and emerging from other groups, this approach provides a valuable contribution to the Minisci-type alkylation literature that is both highly competitive with, and complementary to, existing protocols. As alkyltriuoroborates are well behaved, bench stable salts, these reagents will continue to serve as useful "radicals in a bottle" for synthetic chemists.</p>