Photocatalytic Boryl Radicals Triggered Sequential B─N/C─N Bond Formation to Assemble Boron‐Handled Pyrazoles

Abstract Vinyldiazo compounds are one of the most important synthons in the construction of a cyclic ring. Most photochemical transformations of vinyldiazo compounds are mainly focusing on utilization of their C═C bond site, while reactions taking place at terminal nitrogen atom are largely unexplored. Herein, a photocatalytic cascade radical cyclization of LBRs with vinyldiazo reagents through sequential B─N/C─N bond formation is described. The reaction starts with the addition of LBRs (Lewis base–boryl radicals) at diazo site, followed by intramolecular radical cyclization to access a wide range of important boron‐handled pyrazoles in good to excellent yields. Control experiments, together with detailed mechanism studies well explain the observed reactivity. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.


Introduction
Radical cascade cyclization reactions are highly valued in organic synthesis as robust strategies to the de novo construction of ring systems omnipresent in various biologically important structures. [1]Bearing with conjugated functionalities of both alkene and diazo groups, vinyldiazo compounds have proven to be one of the most versatile building blocks in contemporary chemical synthesis. [2]Typically, decomposition of vinyldiazo reagents in presence of transition metals (Rh, Au, Cu, Ag, etc.) forms electrophilic metallo-vinylcarbenes as dipolar adducts which have been wellapplied in many cyclization processes to access diverse carbo-and heterocycles. [3]n the contrary, compared with those widely explored in polar chemistry, reaction of vinyldiazo compounds with radicals and related active species remains largely unexplored.In 2018, Ferreira and co-workers [4a] found that vinyldiazo compounds could serve as nucleophiles to intercept the photogenerated radical cations, thus providing a powerful approach to access cyclopentenes (Scheme 1a, left).Subsequently, Kang et al. [4b] realized a similar light-mediated radical cation [3+2]cycloaddition of electron-rich alkenes and vinyl diazoesters with Fe(phen) 3 (PF 6 ) 3 as photoredox catalyst.Later, Ferreira group further expanded the strategy to dearomative photocatalyzed [3+2]cycloaddition between indoles and vinyldiazo reagents using a novel oxidizing [Cr(PMP 2 phen) 3 ](BF 4 ) 3 photocatalyst. [5]Very recently, Zhou, Koenigs et al. [6] realized the photocatalytic self-[3+2]-cycloaddition of vinyldiazo reagents leading to a variety of cyclopentenyl -diazo compounds in good yields.7b] Despite these impressive advances provided very effective value-added downstream transformations, the initial step of those reactions all occurred at C═C bond site of vinyldiazo reagents.Moreover, diazo moiety released through nitrogen gas extrusion, thus could not conserve the N 2 function into the product structure.Further exploration of novel and synthetic useful radical transformation of vinyldiazo compound, especially with the utilization of its terminal nitrogen reaction site to facile synthesis biologically active nitrogencontaining heterocycles, is still attractive, yet a challenge goal.Organoboron compounds are versatile building blocks in chemical society, with applications that span natural isolates, pharmaceuticals, as well as functional materials. [8]In the past years, tremendous progresses have been made on radical borylation reactions with the formation of boron centered radicals as the key intermediates, especially the relative stable Lewis base-boryl radicals (LBRs), e.g.NHC-boryl radicals (NHC─BH 2 • ). [9,10]These active species are formed either through catalytic hydrogen atom abstraction or photoredoxmediated single-electron oxidation. [10]To date, the photogenerated nucleophilic LBRs [11] have been widely applied in the formation of new B─C bonds through radical addition to C═Y bonds (Y═C, N). [12] Remarkably, they can also be used to trigger hydrogen-atom transfer (HAT) [13] from electrophilic C─H bonds or halogen-atom transfer (XAT) [14] from alkyl halides, enabling access to the corresponding alkyl radicals for further photochemical transformations.In the latter scenario, new B─H or B─X bonds are formed during the catalytic cycle.In sharp contrast, application of boryl radicals for the construction of B─N bonds are largely overlooked.Some sporadic reported examples have been so far invariably relied on thermal strategy. [15]To the best of our knowledge, photochemical application of LBRs into the formation of new B─N bond is still unknown.
Against this background, we questioned whether a borylative radical cascade strategy, that is, LBRs-trigged chemoselective addition/cyclization with vinyldiazo compounds, could serve as a handle to overcome present limitations.As shown in Scheme 1b, the designed reaction starts with chemo-selective addition of LBRs to the terminal nitrogen atom of vinyldiazo reagents, followed by radical resonation and intramolecular cyclization, yielding a boron-handled pyrazoles.Significantly, the formed boronhandled pyrazoles would be of great interest in medicinal chemistry and material science, due to the fact that pyrazole is a core motif in numerous biologically relevant molecules. [16]In addition, B─N bonds are also widely employed in various materials with intriguing electronic and optoelectronic properties. [17]o achieve this goal, the following challenges should be considered: 1) identification of a suitable LBRs that can selectively add to unsaturated N─N bonds while being compatible with C═C bonds, and 2) exploitation of a photoredox catalytic system that maintains an efficient radical cascade cyclization over the vinyldiazo self-1,5-electrocyclization [7,18] or self-[3+2] cycloaddition. [6]erein, we disclose the successful execution of this design plan.

Evaluation of Reaction Conditions
At the outset of our investigation, N-heterocyclic carbene (NHC)borane 1a and vinyldiazoacetate 2a were used as model substrates in CH 3 CN under irradiation of 24 W blue LEDs at room temperature (Table 1).Note that, all reactions were performed with a commercial light source to ensure reproducibility of the data.To our delight, the anticipated boron-handled pyrazole 3 could  be obtained in 71% isolated yield when using a combination of 2.0 mol% Ir(ppy) 2 (dtbbpy)PF 6 as photocatalyst, and 1.0 equivalent DABCO (1,4-diaza[2.2.2]bicyclooctane) as the base (entry 1).
A slightly decrease of the yield was observed when the model reaction was carried out in 5 mmol scale.We further examined the influence of different reaction media, including DMC (dimethyl carbonate), EtOH and H 2 O, but no significant improvement of yield (22-60%) was achieved (entries 2-4).Replacement of Ir(ppy) 2 (dtbbpy)PF 6 to other commonly used photoredox catalysts, such as Ru(bpy) 3 Cl 2 •6H 2 O and fac-Ir(ppy) 3 did not give better results (entries 5 and 6).The yield of 3 decreased to 15% when the reaction was performed in argon atmosphere (entry 7).It was found that the yield of 3 can still increase up to 54% without the addition of DABCO, which demonstrated the major function of DABCO should be as a base to accurate the deprotonation (Table 1, entry 8).Notably, control experiments confirmed that visible light irradiation and photoredox catalyst were all indispensable (entries 9 and 10).

Reaction Scope
Having finalized the optimal reaction conditions, the scope of this photocatalytic boron-handled pyrazole formation protocol was explored (Scheme 2).The reaction was quite general for a wide range of vinyldiazo compounds bearing various ester moieties, including primary alkyl (3-6), secondary alkyl (7), tertiary alkyl (8, 9) and unsaturated alkene and alkyne functional groups (10, 11), thus giving the desired pyrazoles in 65-78% yields.To our delight, the reaction was not limited to diazoesters; the process was also effective using an acylpyrazole-, amide or ketonebased vinyldiazo species (12-14).Next, we investigated the reactivity of  -or -substituted vinyldiazo esters.It was found that diazoacetate with -methyland cyclopropyl-substitution could also participate in the cascade radical cyclization, affording the target heterocyclic products in 54% and 87%, respectively (15,16).Incor-poration of different alkyl (17-19), silyl ether (20) and aryl groups (21, 22) at□-position of vinyldiazo esters also proved to be successful.Note that, the method could be further extended to the synthesis of fully substituted pyrazole by using 23 as an example.More complex bioactive molecules, as well as drug derivatives were examined with no influence on this pyrazole formation reaction, including naturally occurring alcohols such as cholesterol (24), tetrahydrogeraniol (25), stigmasterol (26) and a protected glucose derivative (27) as well as derivatives of drugs such as vitamin E (28), and quinine (29).
Next, we tested the reactivity of other types of LBRs through different commonly used Lewis base boranes.As shown in Scheme 3, either structure modification of the N,N-alkyl substituents or incorporation of two chlorine atoms on the imidazole ring of NHC-BH 3 complexes proved to be compatible with the present reaction conditions (31-34).Note that, reduced efficiency was observed by the introduction of two isopropyl groups which should be attributed to the steric effect.We also studied the reaction of NHC-BH 3 with cyclopropanation of the imidazolium backbone, [19] yielding product 35 with 55% yield.Importantly, the current method allowed the construction of different kind of Lewis base borane-modified pyrazoles, such as products derived from triazole borane (36), benzimidazole borane (37), and DBUborane (38).Adding a phenyl group on boron site still could give the target heterocycle, albeit with relatively low yield (39).

Mechanism Studies
To elucidate the mechanism of this photocatalytic B─N bond formation process, some mechanistic investigations were conducted in Scheme 4. It was found that the reaction could be intercepted by a radical capturing experiment with the addition stoichiometric amount of TEMPO.The adduct of TEMPO and NHC-boryl radical could be detected by HRMS (Scheme 4A).The result indicated that the reaction should proceed through Scheme 2. Scope of vinyldiazo compounds.a 1 (0.3 mmol), 2 (0.9 mmol), DABCO (0.3 mmol), and Ir(ppy) 2 (dtbbpy)PF 6 (2.0 mol%) in MeCN (1.0 mL), with 24 W blue LEDs irradiation at rt under air atmosphere.b isolated yield.
transfer to pyrazole 40 through 1,5-electrocyclization. [7,18] When vinyldiazo compound 2a was irradiated with blue LED for 2 h under the best reaction conditions with or without the addition of DABCO, no 40 was detected (Scheme 4D, entry 1 and entry 2).Only 10% of 40 was isolated when 2a was irradiated under sole blue LED irradiation without any photoredox catalyst and base (Scheme 4D, entry 3).In addition, 3 was not observed by reacting of 40 with NHC-BH 3 under standard reaction conditions.These results suggested that 40 should not be the intermediate for the formation of the final boron-handled pyrazoles.
Base on the above mechanistic investigations, a plausible reaction mechanism was proposed in Scheme 4G.

DFT Calculation
Density functional theory (DFT) calculations were also performed to provide further understanding of the reaction mechanism.As shown in Figure 1, the reaction starts with the radical addition process.NBO charge analysis indicates that the terminal carbon atom of the C═C bond is more negative charged compared to the terminal N atom, rendering the high reactivity of N atom with the nucleophilicity boryl radical, [11] in accordance with the calculated favorable B─N bond formation process via transition state TS1.A lower Gibbs free energy barrier of 5.9 kcal mol −1 is needed for this process to supply the stable intermediate B, which is an exothermic process of −18.5 kcal mol −1 .Then, the intramolecular radical addition with C─N bond formation process takes place via TS3 to afford the more stable intermediate F. The reaction barrier for this step is 17.3 kcal mol −1 , which is the rate-determining transition state.From F, the barrierless oxidation and deprotonation process take place to produce the final product 3.In summary, the rate-determining step for this reaction is the intramolecular radical cyclization process, with a Gibbs free energy barrier of 17.3 kcal mol −1 , in accordance with the current reaction conditions.

Evaluation of the In Vitro Antitumor Activities of Boron-Handled Pyrazoles
Considering the potential bioactivity of the formed boronhandled pyrazoles, [8,16] we investigated the antitumor activities of those obtained compounds against HeLa cells (human cervical cancer cells), a typical human cervical cancer cell line.Here, IC 50 (the half maximal inhibitory concentration) was selected to evaluate the antitumor activity.As shown in Figure 2, the obtained pyrazole 25 had excellent antitumor ability with IC 50 = 20.3μg mL −1 , better than the performance of antitumor drug etoposide.In order to verify the universality of its antitumor ability, we further chose two other cell lines, Hep G2 (human liver cancer) and A549 (human lung cancer) cells (Figure 2), and the results showed that IC 50 values were 15.68 and 17.98 μg mL −1 for Hep G2 and A549 cells, respectively.indicating the excellent antitumor activity of compound 25.In contrast, IC 50 values of compound 25 for HL-7702 (normal hepatic) cells was 36.62 μg mL −1 , approximately two folds for cancer cells (Figure S2, Supporting Information), suggesting the selectivity towards cancerous cells.

Conclusion
In summary, we have developed a photoredox-mediated cascade radical cyclization of LBRs with vinyldiazo compounds.The reaction started with the addition of LBRs at diazo site, followed  by intramolecular radical cyclization to access a wide range of boron-handled pyrazoles in good to excellent yields.This was a significant advancement comparing to previous report where photochemical transformation of vinyldiazo compounds mainly occurred at C═C bond site, where diazo moiety leaved as nitrogen gas.The detailed mechanism studies and computational studies were performed to elucidate the reaction mechanism and to rationalize the observed reaction outcome.The scale-up reaction, and the discovery of hit compounds for potential antitumor drugs further rendered the method attractive and valuable.

Scheme 1 .
Scheme 1. Background and evolution of a strategy for radical B─N bond formation.
After photoexcitation of Ir(III) photoreodx catalyst, the formed Ir(III)* [E 1/2 ox (III*/IV) = − 0.96 V vs. SCE)] [21] was quenched by O 2 [E 1/2 red (O 2 /O 2 •− ) = −0.75V vs. SCE] to generate Ir(IV) and superoxide radical anion.Then, single electron oxidation of NHC-BH 3 (E 1/2 ox = + 0.76 V vs. SCE) was electronically matched oxidative state Ir(IV) [E 1/2 red (IV/III) = + 1.21 V vs. SCE)] to close the photoredox catalytic cycle and generate the NHC-boryl radical cation, subsequently deprotonation to give NHC-boryl radical A. Selective radical addition of A to the N-atom of vinyldiazoacetate 2a afforded intermediate B which resonated to terminal radical species D.Then, the intramolecular radical cyclization with C-N bond formation process took place to afford intermediate F. Rapid oxidation of F provided the cation intermediate G, which subsequently underwent deprotonation process to produce the final product 3.

Scheme 4 .
Scheme 4. Mechanism studies and the proposed reaction mechanism.A) Radical trapping experiment with TEMPO.B) Superoxide radical anion quenching experiment with 1,4-benzoquinone.C) Probing involvement of O 2 • ¯species by EPR studies.D) Stern−Volmer experiments with photoexcited Ir(ppy) 2 (dtbbpy)PF 6 in CH 3 CN.I 0 and I are the respective luminescence intensities in the absence and presence of the indicated concentrations of the corresponding quencher.E) Pyrazole 40 isolation and control experiments.F) Plausible reaction mechanism.

Figure 1 .
Figure 1.A) The calculated Gibbs energy profiles for the reaction mechanism (in kcal mol −1 ), spin density in blue and NBO charge in orange; B) 3D structures and spin density diagrams of key transition states.

Figure 2 .
Figure 2. The antiproliferative activity of the obtained boron-handled pyrazoles in cancer cell lines.

Table 1 .
Optimization of reaction condition.