Bis(pinacolato)diboron‐Enabled Ni‐Catalyzed Reductive Arylation/Vinylation of Alkyl Electrophiles

Abstract Herein, the use of economically and environmentally friendly bis(pinacolato)diboron (B2Pin2) is described as a non‐metallic reductant in mediating Ni‐catalyzed C(sp3)–C(sp2) reductive cross‐coupling of alkyl electrophiles with aryl/vinyl halides. This method exhibits excellent suitability for heteroaryl halides and alkyl halides/Katritzky salts. The present study is compatible with an in situ halogenation of alcohol method, allowing for selective mono‐functionalization of diols and bio‐relevant alcohols (e.g., carbohydrates). The use of B2Pin2 shows potential for easy scalability without introducing additional metal impurities into the products. It is observed for the first time in the realm of cross‐electrophile coupling chemistry that B2Pin2 can sever as a reductant to reduce NiII to Ni0. This mechanistic insight may inspire the development of new reductive bond‐forming methodologies that can otherwise be difficult to achieve with a metal reductant.


Introduction
[3][4][5] In this vein, metal reductants, notably Zn and Mn, have been predominantly used in developing methodologies for transforming unusual electrophiles, [6][7][8][9] (For carbonylation, see ref. [9]) forging challenging bonds, (For DOI: 10.1002/advs.5a,11,12] However, the drawbacks associated with metal reductants, including scalability issues and the introduction of metallic impurities in pharmaceuticals, are well recognized. [13]o date, only meager efforts have been dedicated to the development of non-metal reductants that can outcompete Zn and Mn.A noteworthy example is the use of tetra(dimethylamino)ethylene (TDAE) as the 1e SET reductant in Ni-catalyzed aryl-alkyl XEC coupling. [14]Unfortunately, the laborious and costly preparation of moisture-and air-sensitive TDAE hampers its application (Figure 1a). [15]Recently, photoredox/electrochemical protocols have emerged as important alternatives to (thermal) XEC chemistry (For leading reviews, see ref. [16]).However, the requirements for high operational efficiency, easy scalability, and convenience for mechanistic studies continue to fuel demand for the development of new reductants in the realm of XEC chemistry.
We initially discovered that using B 2 Pin 2 as a cost-effective and environmentally friendly reductant significantly enhances the chemoselectivity of Ni-catalyzed C(sp 3 )-C(sp 3 ) coupling of primary with secondary alkyl halides compared to that using Zn (Figure 1b), [5a,17,18] (For other examples of B 2 Pin 2 -mediated C(sp 3 )-C(sp 3 ) bond formation, see ref. [18], For a recent Fecatalyzed alkyl-aryl coupling, see ref.
[18d]).However, achieving an equivalent version of C(sp 3 )-C(sp 2 ) XEC chemistry has proven elusive.In a broader context, the XEC chemistry mediated by the Ni/B 2 Pin 2 platform has received surprisingly less attention, and the reaction mechanisms of the disclosed methods remain unexplored.This challenge is attributed to the distinctive nature of B 2 Pin 2 in mediating Ni-catalyzed XEC chemistry.First, the 1e SET process associated with Zn/Mn is not applicable to B 2 Pin 2 , and thus far, the mechanism of reducing Ni intermediates with B 2 Pin 2 remains poorly understood.Second, the competitive formation of alkyl-Bpin could become problematic, as observed as a primary pathway by simply varying the solvents and bases in Ni-catalyzed C(sp 3 )-C(sp 3 ) XEC process (Figure 1b), [19] The profound impact of bases on Ni/B 2 Pin 2 -mediated reactions has also been demonstrated in fine-tuning the regioselectivity for borylation and arylation of cyclohexenes with B 2 Pin 2 and aryl halides. [20]erein, we present an unprecedented Ni/B 2 Pin 2 -reductive coupling protocol for the arylation/vinylation of alkyl halides/Katritzky salts with aryl/vinyl halides, effectively furnishing C(sp 3 )-C(sp 2 ) bonds.The present studies encompass three noteworthy aspects.First, it showcases that B 2 Pin 2 is a comparably versatile reductant to Zn/Mn for reductive C─C coupling.Second, it provides new mechanistic insight, revealing that B 2 Pin 2 is capable of reducing L n Ni II X 2 to L n Ni 0 in the XEC framework.This contradicts our initial proposal of L n Ni I Bpin involved in the C(sp 3 )-C(sp 3 ) XEC. [17] It should be noted that the reduction of NiX 2 (X = Br, Cl) to Ni(0) via in situ formation of Ni(OMe) 2 with B 2 (OR) 4 in the presence of 2 equiv of (iPr) 2 NEt in methanol has been disclosed.However, given the sophisticated effect of bases and solvents on the mechanism of Ni/B 2 Pin 2 reactions, [21] our finding could be critical for future development of B 2 Pin 2 -mediated XEC chemistry (Figure 1c).Finally, a homogeneous reaction could be attained based on a combination of B 2 Pin 2 /LiOMe/TBAI (tetrabutylammonium iodide), which holds promise for practical large-scale Ni-catalyzed XEC process (The use of metal reductant (e.g., Mn, Zn and Mg), can lead to handling and waste disposal issues when employed on a large scale, see ref. [22]).Notably, the boron residue can be easily removed during work-up, avoiding the introduction of extra metal impurities into the products. [23]
More importantly, we noticed that the reaction mixture with method A remained heterogeneous throughout the reaction suggesting likely due to the use of K 2 CO 3 .Thus, slight modifications to method A were implemented using LiOMe as the base, TBAI as the additive and DMA/THF (1/1, v/v, THF: tetrahydrofuran) as the solvent.The resulting reaction mixture remained homogeneous throughout the reaction course.Utilizing 1.2 equiv and 1.5 equiv of S2 gave 1a in 80% and 91% yields, respectively (Method B, Equation (1); Equation S2, Supporting Information).To the best of our knowledge, a homogeneous Ni-catalyzed crosselectrophile coupling reaction using an economical reductant has not been disclosed in the literature.
Next, the compatibility of aryl halides was assessed using Method A (Figure 2A), with (3-bromopropyl)benzene (S2) as the coupling partner.A brief screening of electron-deficient arenes suggested that aryl bromides decorated with ester, cyano, phosphoryl, aldehyde, and ketone functionalities were all competent substrates, affording products 2-7 in moderate to excellent yields.Notably, meta-ester 2 exhibited a lower yield compared to its para-counterpart 1a.Efficient alkylation of a bromoanalog of fenofibrate gave 7 in 82% yield.The method proved highly effective for heteroarenes.Coupling of the 2-, 3-, 4-, and 8bromoquinolines was satisfactory, giving products 8-11 in good results.Similarly, 4-, 3-, and 2-bromopyridines and their deriva-tives performed well, giving products 12-21 in good results.Noteworthy is the otherwise easy dimerization of 2-bromopyridine in Zn/Mn conditions to form bipyridine was not problematic as evidenced in 17-21. [25]The present method was also suitable for vinyl bromides as manifested by the examples of 22 and 23.For electron-rich arenes, the use of aryl iodides was necessary, with the assistance of 2 equiv of NaI and 50 mol% of tetrabutylammonium iodide (TBAI) (Figure 2C).Good to excellent yields were obtained for 24-30.Comparable results were observed for 4-and 2-methoxy arenes 25 and 29, indicating that ortho-substitution pattern for MeO has only a minor impact on the coupling efficiency.The chloro-and Bpin-groups were well-tolerated as exemplified by 27-28.Heteroarenes such as 6-iodo-2-methoxyquinoline, iodoindole, 9H-carbazole, 2-CF 3 -5-iodopyridine and 1-iodo-4-(trifluoromethyl)benzene were all compatible with the method, as shown by examples 32-35.Finally, alkylation of the iodo analog of bioactive deschloroclofibrate and iodo-(fluorophenyl)methylbenzyl)thiophene gave 36 and 37 in 85% and 56% yields, respectively.
Next, we studied the coupling efficiencies for the reactions of methyl 4-bromobenzoate with a wide range of alkyl electrophiles (Figure 3).Primary and secondary alkyl bromides, iodides and mesylates were generally effective as evident in the examples of 38-49.The method was also suitable for a range of alkyl-Katritzky pyridinium salts, generating 1a, 46, 50 and 51 in moderate to good yields (Figure 3).
Additionally, we integrated our previously reported in situ halogenation of alcohols method with the diboron-mediated coupling process to develop a protocol for in situ arylation of alcohols. [26]The use of CEBO/TBAB (CEBO = 2-chloro-3ethylbenzoxazolium tetrafluoroborate) has proven to be a powerful handle to convert primary and secondary alcohols into their bromide counterparts within 1-5 min, exhibiting high monoselectivity for halogenation of polyols at the less-hindered site.This technique facilitated a quick screening of various primary and secondary alcohols to couple with S1, giving 52-56 and 45 in synthetically useful yields (Method C, Figure 4).The unprotected diols were also compatible with method C, offering 57-59 in mono-and stereoselective manners.The utility of the method was also showcased by facile functionalization of uridine and diacetone-D-glucose to yield 60 and 61, respectively.
14c] This was previously unsuccessful when Zn was employed as the reductant.This outcome suggests that B 2 Pin 2 may function as a complementary reductant to enable reactions that have failed with reductants Zn and Mn.

Mechanistic Studies
To understand the details of the reaction process, we first evaluated whether the in situ formation of organoboron followed  b) for heteroaryl bromide, a similar procedure to the standard method A was used, except that dtbbpy (2.7 mg, 10 mol %) and NiCl 2 (Py) 4 (3.6 mg, 8 mol %) displaced (dtbbpy)NiBr 2 , and NaI (30 mg, 2 equiv) and TBAI (18 mg, 0.5 equiv) were employed; c) for electron rich aryl iodides, a similar procedure to the standard method A was used except that NaI (30 mg, 2 equiv), TBAI (18 mg, 0.5 equiv) and alkyl bromide (1.5 equiv) were employed.
by Suzuki coupling was a viable process.The reactions of (4methoxycarbonyl)phenyl-Bpin with the alkyl bromide S2, as well as phenylpropyl-Bpin with the aryl bromide S1 did not yield the coupling product 1a (Figure 5a), thus a mechanism of in situ Suzuki coupling was excluded.
Next, we established that the reaction accommodated a radical process, as suggested by the coupling of bromocyclopropyl methane with S1, which furnished the ring-opening product 62 (Figure 5b).The coupling of S1 with 6-bromohex-1-ene as a radical clock was examined to give a mixture of the cyclized and OMs, and Figure 3. Scope of alkyl electrophiles.Note: a) unless otherwise noted, standard method A was used; b) for the coupling of aryl halides with secondary alkyl bromides, a similar procedure to the standard method A was used, except that Ni(OTf) 2 (8 mol %) and dtbbpy (10 mol %) displaced (dtbbpy)NiBr 2 , and NaI (2 equiv), TBAI (0.5 equiv) and alkyl bromide (1.5 equiv) were employed; c) for the coupling of alkyl-pyridinium salts, a similar procedure to the standard method A was used, except that NaI (1 equiv) and alkyl-pyridinium salt (1.5 equiv) were employed.

Figure 4.
Formal coupling of alcohols and diols with aryl halides.Method C was used: alcohol (1.5 equiv) was treated with CEBO (1.5 equiv) and TBAB (tetrabutylammonium bromid1.5 equiv) in CH 3 CN (0.2 mL) for 5 min, before addition of the rest of ingredients as described in method A including 8 mol% NiBr 2 (dtbbpy), 180 mol% B 2 Pin 2 , 180 mol% K 2 CO 3 , 200 mol% NaI, DMA (0.4 mL).The reactions were run at 60 °C.linear products 54 and 63.A linear dependence of their ratios on the concentration of Ni catalyst was observed, indicative of a radical-chain process featuring diffusion of alkyl radical into the bulk solution, followed by trapping the radical with a Ni species (Figure 5c). [27]erhaps a more instructive result came from the detection of reduction of L n Ni II Br 2 (Ni-a) to L n Ni 0 by B 2 Pin 2 under the conditions similar to method A. First, a near-quantitative amount of of (dtbbpy)Ni 0 (COD) (COD: 1,5-cyclooctadiene) was observed upon exposure of (dtbbpy)NiBr 2 (Ni-a, 0.2 equiv) to B 2 Pin 2 in the presence of COD after 3 h (Figure 5d; Figure S6, Supporting Information).Next, the formation of Ni 0 was also evidenced by observation of (dtbbpy)Ni II (Ar 1 ) (Ni-b, dtbbpy = L1) in the reaction mixture of 2-methyl iodobenzene (Ar 1 -I, 1.0 or 0.2 equiv) with or without 1-bromododecane in the presence of (dtbbpy)Ni II Br 2 (Nia, 0.2 equiv) and stoichiometric amount of B 2 Pin 2 , K 2 CO 3 and NaI in DMA after 3-5 h (Figure 5e; Figures S1-S4, Supporting Information). [28]We reasoned that reduction of L n Ni II X 2 (I-1) to L n Ni 0 (I-3) under the present reductive coupling conditions, [21] likely through reductive omission of Bpin-X from a putative L n Ni II (Bpin)X species (I-2) (Scheme 1).
As illustrated above, a radical-chain mechanism (Figure 5c) is proposed in the present method, which likely involves the trapping of an alkyl radical with L n Ni II (Ar)X (I-4, path 1, Scheme 1) or L n Ni 0 (I-3, path 2, Scheme 1) to yield L n Ni III (Ar)(alkyl)X (I-5) or L n Ni I (alkyl) (I-6), respectively. [27,29]Whereas path 1 represents the most wildly accepted mechanism in the literature, path 2 has recently emerged as an important alternative pathway in certain methods. [29]In path 2, the oxidative addition of ArX to I-6 also leads to I-5.In both pathways, reductive elimination of I-5 affords the product along with L n Ni I (I-7).Subsequent halide abstraction of alkyl halide with I-7 produces an alkyl radical and L n Ni II (I-1).
Scheme 1. Possible reaction paths for the reductive coupling event.
To discern the more advantageous process between the two mechanisms, we conducted a control experiment wherein an equimolar mixture of Ni-b and 1-iodo-2,4-dimethylbenzene (Ar 2 -I) (0.5 equiv) was introduced to the catalytic reaction containing 1.2 equiv of hexyl bromide (Figure 5f).We observed a slight preference for the formation of product 65b arising from Ar 2 -I over 65a derived from Ni-b.Further, a control study indicated that Ni-b remained reasonably stable under the same reaction conditions without Ar 2 -I and n-hexyl bromide within 4 h (Figure S8, Supporting Information).In Path 1, the oxidative addition of ArX to L n Ni 0 (I-3) giving L n Ni II (Ar)X (I-4) is crucial.Therefore, if Path 1 is the sole reaction pathway, the formation of 65a would significantly exceed that of 65b.This is because the concentration of preformed Ni-b should be higher than that of in situ formed (dttppy)Ni II (Ar2)I (Ni-b') via the oxidative addition of Ar 2 -I to (dtbbpy)Ni 0 .However, the contrary observations suggest that Path 1 alone should not determine the predominance of the catalytic process (Scheme 1).This inference aligns with the significant observation of Ni-b in the coupling reaction (Figure 5e), potentially representing a catalyst resting state.Based on the collective mechanistic studies, we propose that paths 1 and 2 may concurrently operate in our B 2 Pin 2 -mediated reductive coupling event.The preference between the two pathways may vary depending on the stereoelectronic nature of the coupling electrophiles.
The kinetic profiles of the reaction, built upon initial rate models, were collected using Ni(COD) 2 /dtbbpy to substitute NiBr 2 /dtbbpy.This substitution was made in order to avoid errors induced by long induction periods (Figures S10-S28, Supporting Information). [30,31]The results revealed a first-order dependence on the concentration of B 2 Pin 2 , suggesting that B 2 Pin 2 may merely participate in the reduction of Ni(II) to Ni(0), which likely accounts for a rate-determining step.In addition, a positive rate dependence on Ni(COD) 2 /dtbbpy was observed (k obs = 0.2), indicating Ni may engage in multiple transformations (e.g., paths 1 and 2), including formation of Ar-L n Ni II X (I-4) species observed in the reaction.Finally, inverse reaction rate orders in both alkyl bromide S1 and aryl bromide S2 were noted, likely due to off-cycle mechanism for the two electrophiles.The off-cycle consumption of alkyl halides at elevated concentration could come from side reactions including formation of alkyl-Bpin and alkyl-alkyl dimers.Moreover, the undesired reaction of L n Ni I X with ArX (Figure S9, Supporting Information), and decomposition of Ar-L n Ni II X may account for the negative rate dependence on the concentration of aryl halides. [20]

Conclusion
In summary, we have demonstrated that B 2 Pin 2 serves as an effective terminal reductant to mediate the Ni-catalyzed C(sp 3 )-C(sp 2 ) cross-electrophile coupling of alkyl electrophiles with aryl/vinyl halides.The method circumvents the need for metal reductants, rendering it more environmentally benign and easily scalable, as the reaction can be adjusted to homogeneous.The versatility of the reaction was illustrated by a broad array of examples, encompassing electron-rich aryl iodides, electrondeficient aryl bromides, and various heteroarenes.Alkyl electrophiles ranging from halides, mesylates, Katritzky salts, to alcohols/diols derived from sugars were successfully employed.
Our mechanistic investigations revealed that B 2 Pin 2 effectively reduces Ni(II) salt to Ni(0), a departure from the electrontransfer reduction by metallic reductants.Furthermore, the reaction mechanism suggests the involvement of a radical chain process, emphasizing the trapping of the alkyl radical with L n Ni 0 .However, the well-established mechanism involving the interception of an alkyl radical with L n Ni II (Ar)X may operate concurrently.The utilization of diboron ester as the reductant opens avenues for novel reductive coupling approaches, addressing challenges posed by traditional metal reductants, and holds promise for industrial applications.

Figure 1 .
Figure 1.Brief summary of the current focuses of Ni-catalyzed cross-electrophile coupling with emphasis on the reductants.

Figure 5 .
Figure 5. Mechanistic considerations.a) 1 H NMR yields estimated using triazine as an internal standard (see Figures S1-S4, Supporting Information, for details).