Practical and Scalable Synthesis of Borylated Heterocycles using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts

Arumugam Jayaraman, Luis C. Misal Castro and Frédéric-Georges Fontaine† a

a Département de Chimie, Centre de Catalyse et Chimie Verte, Université Laval, 1045 Avenue de

la Médecine, Québec (Québec), Canada, G1V 0A6.

† Canada Research Chair in Green Catalysis and Metal-Free Processes

Email : [email protected]

This is the peer reviewed version of the following article: [Practical and Scalable Synthesis of Borylated Heterocycles

Using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts. Org. Process Res. Dev. 2018, 22, 11, 1489-1499],

which has been published in final form at [10.1021/acs.oprd.8b00248].

Practical and Scalable Synthesis of Borylated Heterocycles using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts Arumugam Jayaraman,‡ Luis C. Misal Castro‡ and Frédéric-Georges Fontaine†*

Département de Chimie, Centre de Catalyse et de Chimie Verte (C3V), Université Laval, Quebec City, Québec, Canada G1V 0A6 † Canada Research Chair in Green Catalysis and Metal-Free Processes.

KEYWORDS. Borylation, Heteroarylboronates, Metal-free synthesis, Frustrated Lewis pair catalysis, C-H activation, Organocatalysis.

Supporting Information Placeholder

ABSTRACT: A practical and scalable metal-free catalytic transition metals such as Mn, Fe, Co, Ni, and Cu, instead of noble method for the borylation and borylative dearomatization of het- metals is an emerging area that provides entries to circumvent the eroarenes has been developed. This synthetic method uses inexpen- cost problems;8 however, several of these elements remain toxic.5 sive and conveniently synthesizable bench-stable precatalysts of Among a variety of products that can be prepared via C–H bond the form 1-NHR2-2-BF3-C6H4, commercially and synthetically ac- functionalization and/or reduction of unsaturated C-C bonds, hy- cessible heteroarenes as substrates, and as borylation drocarbons with a C-B functionality serve as versatile reagents. reagent. Preparation of several borylated heterocycles in 2 and 50 These reactive C(sp2)–B or C(sp3)–B bond-containing reagents pro- grams was achieved under solvent-free conditions without the use vide several synthetic possibilities to access numerous functional 9 of Schlenk techniques or a glove box. A kilogram-scale borylation groups. Of the widely accepted synthetic utilities of organoboro- of one of the heteroarene substrates was also achieved using this nate reagents are the Pd-catalyzed Suzuki-Miyaura and the Cu-cat- cost-effective green methodology to exemplify the fact that our alyzed Chan-Lam cross-coupling reactions for the construction of methodology can be conveniently implemented in fine chemical in- C–C and C-N bonds, respectively.10 Preparation of a wide variety dustries. of organoborane reagents through C-H borylation was achieved ef- ficiently by utilizing transition metal catalysts, particularly the no- ble metals,11 and extending such reactions by using earth-abundant transition metal catalysts has also emerged.12 INTRODUCTION In recent years, main-group compounds have been shown to pro- For the fine-chemical industries, including pharmaceutical and or- mote catalysis processes classically performed by transition metal 13 ganic electronic (OE) industries, the development of straightfor- catalysts. Among those, the 2006 finding by Stephan and cowork- ward methods to prepare highly valuable synthetic intermediates ers of the heterolytic splitting of molecular H2 under the coopera- from commercial and easily synthesizable chemicals without using tive effect of a Lewis acid and a Lewis base center has disregarded any expensive laboratory equipment is of enormous interest.1 Im- the belief that the H-H bond activation of molecular H2 was only 14 provements in the selective and direct functionalization of organic possible using transition metals. This discovery has initiated the compounds, while avoiding toxic intermediates, hazardous rea- field of frustrated Lewis pair (FLP) chemistry and exploration of gents and solvents, and equimolar by-product wastes, are an inces- such chemistry has rapidly expanded from curious stoichiometric 13h, 15 sant focus for the synthetic chemistry community.2 To date, highly synthetic transformations to useful catalysis, mainly in the hy- 16 expensive precious transition metals, including Ru, Rh, Pd, Ir and drogenation of unsaturated compounds. Pt, and special ligands as well as several additives, have often been In 2015, we have established that an intramolecular B/N FLP, 1- 3 used as catalysts by synthetic chemists. These systems can notably TMP-2-BH2-C6H4 (1, Scheme 1a), can be used as a catalyst for the be used for the highly efficient and atom-economic regioselective direct C-H borylation of heteroarenes with pinacolborane (HBpin), 17 functionalization of unactivated C(sp2)–H and C(sp3)–H bonds in a via a C-H activation/σ-bond metathesis mechanism (Figure 1a). myriad of organic compounds.3a, 3b, 3f, 4 Nevertheless, the presence Due to the high atom-efficiency of this metal-free method, this of trace amount of transition metals in the end-product raises seri- method was highlighted as potentially interesting to processing re- ous concerns such as toxicity issues in the case of pharmaceuticals5 search and development chemists.18 Following our work on the C- and reduced performances in the case of OEs.6 Thus, complete re- H activation using a B/N FLP, such reactivity pattern was found to moval of metals from end-products becomes compulsory, adding be common for other more reactive B/N FLPs.19 Despite some additional steps in processes, such as treatments with metal scav- metal-free electrophilic borylation methods for borylation of het- engers. As a result, the production of metal-free synthetic interme- eroarenes and arenes disclosed before our discovery,20 there have diates using transition metal catalysts in industrial applications be- been many reports appearing on this topic after our work was pub- comes over-costly.7 Less-expensive and more abundant first-row lished.19, 21 Scheme 1. Metal-free catalytic method developed by us towards the C-H borylation (a) and borylative dearomatization (b) of heteroarenes.

Figure 1. Mechanisms proposed for C-H borylation (a) and borylative dearomatization (b) reactions.

While our methodology affords heteroaryl boronates with high C6H4 (3F, Scheme 1), and their use as precatalysts for C-H boryla- atom-efficiency under mild conditions in good to excellent yields, tion reactions. In a subsequent report, we have demonstrated that catalyst 1 was found to be highly sensitive to the ambient condi- all these catalysts and BH3.SMe2 can promote the borylative tions; hence, its synthesis, storage, manipulation, and experimental dearomatization reaction when using electron-poor arylsulfonyl in- setup for catalysis should be performed under strict inert condi- doles as substrates and HBpin as reagent, leading to the formation tions, which may restrict industries in adopting this synthetic meth- of 3-boronyl indoline products (Scheme 1b), through a 1,2-hydrob- odology. Previously, Buchwald and coworkers have brought up an oration/backbone redistribution mechanism (Figure 1b).25 Such elegant encapsulation method to introduce air and moisture-sensi- products can be viewed as potential synthetic intermediates for sev- tive transition metal catalysts to the reaction flask without using air- eral pharmaceuticals, natural products, and materials.26 Herein we sensitive operation conditions, leading to easier application in an report the progress we made in optimizing our metal-free method- industrial set-up.22 In order to simplify the use of our B/N FLP cat- ology for borylation and borylative dearomatization of het- alyzed borylation reactions, we reported in 2016 the synthesis of eroarenes suitable for an industrial environment. the air and water-stable zwitterionic compound 1-TMP(H)-2-BF3- C6H4 (1F, Scheme 1), which acts as a precatalyst for borylation re- actions.23 From this precatalyst, the active catalyst 1 is generated RESULTS AND DISCUSSION in-situ by a reduction reaction with HBpin and provided a similar Synthesis and scale-up of fluoroborate precatalysts. In our pre- catalytic activity as 1 after an induction period. vious preliminary study, we have described the synthetic protocols Later, in 2017, our group also demonstrated that the less sterically- for four different fluoroborate salts (1F-4F) that have different al- kyl substituents on the ammonium nitrogen center.24, 27 Yet, these hindered ambiphilic aminoboranes 1-piperidyl-2-BH2-C6H4 (2, precatalysts were synthesized only on a smaller scale (2-5 grams) Scheme 1) and 1-Et2N-2-BH2-C6H4 (3, Scheme 1) can be used as borylation catalysts with faster reaction rates than 1, even if these to explore their catalytic activity towards borylation. As the prelim- species generate stable Lewis adducts.24 In addition, a preliminary inary study showed that the piperidyl precatalyst 2F is more effi- study was made on the synthesis of fluoride derivatives of 2 and 3, cient for the borylation and borylative dearomatization of het- 1-piperidyl(H)-2-BF3-C6H4 (2F, Scheme 1) and 1-Et2NH-2-BF3- eroarenes (vide infra), its synthesis on a 100-gram scale was at- that provides a catalytic conversion as high as observed in chloro- tempted. The synthetic protocol for 2F involves three steps form, first the borylation of 1-methyl in three different dried (Scheme 2): (i) the formation of the 1-Br-2-piperidyl-C6H4 inter- mediate (A) through an -promoted cyclocondensation be- Table 1. Conversions (%) of catalytic borylation of 1-Me-pyrrole tween 2-bromoaniline and 1,5-dibromopentane, (ii) formation of (5a) under different conditions using precatalysts 1F-4F. the 1-B(OH)2-2-piperidyl-C6H4 (B) via lithiation of A followed by nucleophilic substitution with B(OMe)3 and hydrolysis with water, and (iii) formation of fluoroborate salt 2F from the treatment of boronic acid with KHF2 under acidic conditions. In the first step, after the reaction comes to completion, the excess dibro- mopentane can be recovered by simple distillation. Among the three synthetic steps to 2F, only for step 2, i.e., for lithiation of A En- Time Solvent 1F 2F 3F 4F and the later addition of B(OMe)3, is the inert atmosphere needed. try (h) The precatalyst 2F was purified conveniently by recrystallization in CH2Cl2/hexanes. In total, three 100 g batches 1 7 64 63 3 4 (86:14) (98:2) (98:2) (100:0)

CDCl3 97 94 91 31 16 (88:12) (98:2) (98:2) (100:0)

2 Tolu- 91 93 90 34 16 ene (89:11) (98:2) (98:2) (100:0)

3 2-Me- 95 95 90 33 16 THF (90:10) (98:2) (98:2) (100:0)

4 93 93 92 39 THF 16 (88:12) (98:2) (99:1) (100:0)

5 41 80 75 9 1 (95:5) (99:1) (99:1) (100:0) Neat 57 97 96 23 2 (95:5) (98:2) (98:2) (100:0)

In parenthesis: 6a to 6a’ ratio.

solvents, toluene, THF and 2-Me-THF, were explored using all four precatalysts. The results obtained and displayed in Table 1 show that the catalytic conversions with all three solvents are ex- cellent and similar to what was observed in chloroform. However, to our delight, this reaction works better and with improved selec- tivity under solvent-free (neat) conditions (entry 5). Moreover, the reactions were faster under neat conditions. For example, the borylation of 1-methyl pyrrole (5a) using precatalyst 1F under neat conditions gave a conversion of 41% after 4 h, while the same re- action in chloroform gave only a 7% conversion in that time. This Scheme 2. Synthetic steps to precatalyst 2F in 100 grams. outcome is very important for the industrial scale production since it removes reaction solvent from the production costs. of 2F were synthesized with consistent overall reaction yields (55 Borylation and borylative dearomatization of heteroarenes on – 59%). While the piperidyl precatalyst 2F is more active for the a 2-gram scale. To show the versatility of our catalytic system to- borylation of most heteroarenes, precatalyst 3F is the second best wards producing metal-free borylated heterocycles, borylated het- in catalyzing borylation reactions. However, the TMP-containing erocycles that are of interest for pharmaceutical or OE industries precatalyst 1F appears to be better for a minority of heteroarenes were produced on a 2 gram-scale through either C-H borylation or (vide infra). Therefore, to compare their catalytic activity with that borylative dearomatization reactions. For C-H borylation reactions, of 2F and to study their stability under ambient conditions, the syn- N, O and S-containing heteroarene substrates were explored theses of precatalysts 1F and 3F in a 10 gram-scale were achieved (Scheme 3). More emphasis was placed on N-based heteroarenes. by following our previously established procedure (see Supporting From Table 1, it became apparent that the precatalyst 4F and its Information).24 active catalyst 4 show lower catalytic efficiency. Therefore, only Choice of solvent. In our earlier C-B bond forming reactions, we precatalysts 1F-3F were screened further to find a better catalyst used dry dichloromethane and chloroform. However, for practical for borylation of some intended substrates (see Supporting Infor- considerations these solvents should be avoided.28 Thus, we con- mation for the catalysis screening results). From screening, it was fined our investigations to certain criteria in choosing the solvent, found that the precatalysts 2F and 3F are more efficient for the N including: (i) should be non-chlorinated, (ii) should have a boiling and O-based heteroarenes. In addition, these precatalysts also ex- point higher than 70 °C, and (iii) must be compatible with our cat- hibited an alysts, substrates and end-products. To find out the suitable solvent

Scheme 3. Catalytic borylation of heteroarenes on 2 gram-scale using HBpin reagent and the appropriate bench-stable fluoroborate precata- lyst under solvent-free conditions. “n” signifies the equivalents of HBpin with respect to the substrate. 1 Celite column using ethyl as eluent. 2 Silica gel column purification using petroleum ether/ethyl ether as eluent.3 Partially decomposed upon silica gel column purifica- 4 tion. Recrystallization in CH2Cl2/hexanes. improved regioselectivity with heteroarenes having multiple nucle- borylation reactions. For derivatives, precatalyst 1F and ophilic sites. For example, with 1-methyl pyrrole under neat condi- its active form, 1, were found to be better than our other catalysts. tions, a 98:2 ratio of C2-substituted to C3-substituted isomers was In these systems it was shown that 2 undergoes two consecutive C- respectively observed with precatalysts 2F and 3F, while a 95:5 H activation steps which prevents the metathesis reaction to occur, ratio was formed when using precatalyst 1F. Although both precat- and thus catalytic activity.24 Despite some heteroarenes and all alysts 2F and 3F were found to be quite active, the easier synthetic precatalysts being in the solid state, the liquid HBpin reagent to- protocol for 2F explains our choice of catalyst for the 2 gram-scale gether with the reaction temperatures of 80 -100

Scheme 4. Catalytic borylative dearomatization of arylsulfonyl indoles on 2 gram-scale using HBpin reagent and precatalyst 2F under sol- 1 2 vent-free conditions. “n” signifies the equivalents of HBpin with respect to the substrate. CH2Cl2/H2O extraction. Celite column using ethyl ether as eluent. 3 Derivatized as using NaOCl.

°C bring the reaction mixture to a liquid phase and facilitates the involves mainly removal of excess HBpin, FBpin and other vola- desired reaction. Only for the 1,2-dimethyl indole substrate such tiles in vacuo, followed by passing the ethereal solution of the crude process proved to be a concern, since the solution solidifies after product through a short column of Celite using ethyl ether as eluent, 15 minutes at 80 °C, stopping the reactivity. Therefore, a minimal which scrubs the residual catalyst. The borylated derivatives amount of 2-methyl-THF was added to push the reaction forward. 6f-6i, however, were found be less stable under the chromato- The reaction time for the borylation reactions generally varies with graphic conditions, partially decomposing during purification, respect to the nucleophilicity of the heteroarenes. More nucleo- which was identified through phosphomolybdic acid staining of the philic ones such as 1-methyl pyrrole (5a), 1-benzyl pyrrole (5b), eluted silica gel TLC plate. Consequently, to obtain two grams of 3,4-ethylenedioxythiophene (EDOT, 5d), 1-methyl indole (5j), these products higher substrate loadings were used. Up to this 1,2-dimethyl indole (5k) and 5-methoxy-1-methyl indole (5s) re- point, several electron-rich heteroarenes can be conveniently quire less than 10 h at 80 °C, while others require 16 h at this tem- borylated using this methodology. Many N-heteroarenes including perature. Using stoichiometric or excess HBpin with respect to the indoles and protected at N with BOC, Cbz or phosphinyl amount of substrate leads to the formation of a significant amount group, derivatives of pyridine, pyrimidine, oxazole, thiazole, imid- of diborylated products in the cases of 5d and 5f-5i. Therefore, 0.8 azole, triazole, isoxazole and selenophene, and electro-rich arenes equiv HBpin with respect to the substrate was added. The substrate were not successful toward borylation. 1-TBDMS-7-azaindole (5t), which bears a highly exposed basic For the borylative dearomatization reactions, 1-arylsulfonyl in- pyridine nitrogen, required a longer reaction time (48 h) and extra doles were used as substrates. The catalytic reactions were tested precatalyst and HBpin loadings to achieve > 80% conversion. Pu- using all four precatalysts, 1-tosyl indole as substrate, in the pres- rification of most borylated heteroarenes was straightforward as it ence of 1.5 equiv of HBpin at 100 °C. All reactions gave a quanti- tative conversion to 3-Bpin-1-tosyl indoline (8a), suggesting that Table 2. Comparison of the catalytic activity between iridium catalyst and metal-free fluoroborate precatalysts

conv. (%) using conv. (%) using conv. (%) using conv. (%) using entry substrate entry substrate Ir/dtbipy catalyst precatalyst 2F Ir/dtbipy catalyst precatalyst 2F

1 94.4 (92:8, C2/C3 97 (98:2, 5 51 96 regioisomers) C2/C3 regioisomers)

63 (C2 91 (C2 94 (C2 99 (C3 2 regioisomer) regioisomer) 6 regioisomer) regioisomer)

48 (67:33, mono 96 89 (C2 72 (C3 3 and di- (disubstituted)a 7 regioisomer) regioisomer) c substituted)

4 88 (C2 > 99 (C3 8 69 (C2 89 (C3 regioisomer) regioisomer) regioisomer) regioisomer)

a Precatalyst 1F was used. any of the precatalysts among 1F-4F can be used for the borylative tion reactions do not produce any H2 by-product except for the gen- dearomatization transformation. A total of 15 arylsulfonyl indoles eration of active catalyst from the fluoride precatalyst. Therefore, were transformed quantitatively in a 2 gram-scale using precatalyst this atom-efficient reaction can also be carried out in a sealed reac- 2F (10 – 20 mol%) and HBpin reagent (1.5 – 2.6 equiv) at 100 °C tion flask at the 2-gram scale. under solvent-free condition over 16 h of reaction time (Scheme 4). Comparison of catalytic activity with metal catalysts. Most pro- Substrates containing either an electron-donating substituent or an cedures to synthesize borylated heteroarenes from the respective electron-withdrawing substituent at different positions on the ben- heteroarenes through C-H activation use expensive iridium cata- zene ring of 1-arylsulfonyl indoles undergo solely the desired lysts, which were notably developed by Miyaura-Hartwig.11a, 11c, 29 borylative dearomatization reaction. In this transformation, the The capability of our metal-free ambiphilic aminoboranes to cata- Bpin group added exclusively to the C3-position of indoles while lyze the borylation of heteroarenes has drawn us to compare their the H substituent simultaneously added to the C2-position. Thus, catalytic activity with that of the iridium catalyst. The comparison the borylative dearomatized products obtained were highly regiose- was made with a set of substrates under similar reaction conditions lective. Moreover, this 1,2-addition occurs on the same face of the on a millimole scale (Table 2) using catalyst loadings typically used aromatic C-C double bond, which leads to highly diastereoselective in the respective transformations. The exception is the presence of products. The syn addition and related high diastereoselectivity was solvent with the iridium catalysts. Comparing the catalytic results, previously evidenced from the X-ray crystallographic characteriza- it was found that: (i) the catalytic efficiency of both catalysts is tion of the products derived from the borylative dearomatization of more or less similar only when 10 – 20 mol% of the FLP catalyst 25 2-methyl substituted 1-phenylsulfonyl indoles such as 7n and 7o. is used in relationship to the 3 mol% iridium catalyst, and (ii) the Despite all substrates and the precatalyst 2F being solids, none of regioselectivity pattern for the pyrrole and thiophene derivatives the catalytic reactions needed a solvent medium. The 100 °C was remains the same whereas it differs with the indole derivatives, i.e., found to be an optimal temperature for this transformation since the the iridium catalyst promotes C2-borylation while our metal-free reactions conducted at 80 °C required a longer reaction time (~ 36 catalysts facilitate the C3-borylation. Nevertheless, it should be h). The purification procedure to isolate the products was similar to pointed out that the low cost of precatalyst 2F makes the metal-free that of the borylated heteroarenes. However, some products were approach economically viable. found to be quite sensitive to air and moisture; therefore, they were sequentially derivatized to alcohol and silyl respectively Stability of the precatalysts. As the stability of the precatalysts through stereoretentive oxidation, using the household bleach com- was marked as an indispensable criterion for the application of this posed of 6% sodium hypochlorite, and silylation using TBDMS- synthetic method in fine chemical industries, the stability of precat- chloride. Unlike C-H borylation reactions, borylative dearomatiza- alysts 1F-3F towards air and moisture at room temperature, by

Table 3. Stabilities of the bench-top kept precatalysts 1F-3F exam- HBpin and a 5 mol% loading of the precatalysts was carried out in ined periodically through their catalytic activity a sealed 5 mL vial at 80 °C for 4 h. The outcome of these studies, as shown in Table 3, indicates that over a one-year aging, all these precatalysts still keep excellent catalytic efficacy and similar regi- oselectivity. Additionally, using commercially available HBpin having 1% of triethylamine stabilizer did not halt the borylation re- action when tested with the six-month old precatalysts. All these results clearly show that the stability of the precatalysts 1F-3F is conv. (%) us- conv. (%) us- conv. (%) us- excellent towards air and moisture at room temperature for up to a Period ing precat 1F ing precat 2F ing precat 3F year. Furthermore, as noted previously, the thermal stability of the in situ generated catalysts is adequate since they can withstand tem- 1st week 73 (88:12) 84 (98:2) 88 (98:2) peratures of 100 °C and 120 °C for the catalytic borylation and 3rd month 74 (89:11) 80 (98:2) 82 (98:2) borylative dearomatization reactions. 6th month 69 (87:13) 86 (97:3) 95 (98:2) 50 gram-scale trials. Given the excellent stability towards the am- bient condition by these precatalysts and the adequate thermal sta- 12th month 71 (89:11) 83 (98:2) 86 (98:2) bility by the active aminoborane catalysts, we next aimed at pre- Numbers in parenthesis denote the ratio of products A and B. paring some of the borylated heteroarenes and borylative dearoma- tized heterocycles in an intermediate scale (about 50 grams). The keeping them under ambient conditions of the lab, was checked representative N, O and S-based heterocycles such as 1-methyl pyr- four times over a 12-month period, starting from their syntheses (1st role, 2-methyl furan and EDOT were borylated and more emphasis week, 3rd, 6th and 12th month). Two ways have been followed to was placed on the N-heteroarenes. Purification of products at this examine their stability: (i) through inspecting the purity of these scale involves either recovery or removal of excess HBpin respec- precatalysts by NMR spectroscopy (1H, 13C, 11B, and 19F nuclei), tively through distillation or evaporation in vacuo, followed by dis- and (ii) by studying their catalytic activity with one of the het- solution of the crude product in a minimum amount of ethyl ether eroarene substrates, 1-methyl pyrrole. Over the one year-period, all and filtration through a short Celite column using another equiva- three precatalysts kept their original white color, and the purity of lent of ethyl ether eluent. Evaporation of the solvent from resulting all these precatalysts, as inspected through NMR spectroscopy, solution yields pure borylated heterocycles. stayed the same with a purity of >99%. To check the stability of the 1-kilogram trial. We attempted to synthesize one of the borylated precatalysts 1F-3F through catalytic activity studies, the borylation heteroarenes on a kilogram-scale. For this, we chose to prepare 3- of 1-methyl pyrrole (5a) on a 1 mmol-scale using 1.3 equiv of

Chart 1. Borylated and borylative dearomatized products obtained in 50 grams using bench-stable fluoroborate precatalysts. “n” signifies the equivalents of HBpin with respect to the substrate. 1 Celite column using ethyl ether as eluent. 2 Washed with hexanes. 3 Silica gel column 4 5 6 purification using petroleum ether/ethyl ether as eluent. Partially decomposed. CH2Cl2/H2O extraction. Derivatized to alcohol.

Figure 2. Few experimental stages for the metal-free kilogram-scale borylation of 1-methyl indole; left: initial experimental setup with 1- methyl indole substrate and HBpin reagent charged in the reaction flask and the precatalyst loaded in the powder addition funnel attached to the right-side condenser, center: reaction mix at the start of the reaction at 80 °C, right: reaction mix at the end of the reaction at 80 °C.

Bpin-1-Me indole (6j) from 1-methyl indole (5j), HBpin (1.6 heteroarene substrates and the pinacolborane (HBpin) reagent. The equiv) and precatalyst 2F (10 mol%) (Scheme 5). The experimental strategy of this methodology first involves the generation of am- setup is shown in Figure 2. The hot reactor setup was initially biphilic organocatalysts of structure 1-NR2-2-BH2-C6H4 from the flushed with nitrogen, followed by charging the substrate 1-methyl precatalysts and HBpin. Then the organocatalysts can undergo C- indole and the reagent HBpin, heating the solution at 60 °C, and H activation of an heteroarene, H2 elimination and transmetallation adding the precatalyst 2F in portions using a powder addition fun- with HBpin through σ-bond metathesis to afford highly regioselec- nel. The reaction temperature was kept at 60 °C until all precatalyst tive borylated heteroarene products, or 1,2-dearomative hydrobo- was introduced and the dramatic brisk effervescence developed ration and transmetallation of electron-poor indoles to afford C3- within minutes due to evolution of H2, to generate active catalyst, borylated indolines with a high regio- and diasteroselectivity. Sev- is reduced to a normal rate. During this 1 kilogram-scale trial, the eral borylated N, O and S-containing heterocyles were produced addition of the precatalyst in small portions allows controlling the under solvent- and additive-free conditions in good to excellent liberation of H2, which is mostly generated from the catalyst gener- yields in 2 and 50 gram-scales. Additionally, the synthesis of one ation from precatalyst, to reduce the risk of explosion hazard. Af- of the heteroarylboronates, 3-boryl-1-Me indole, was successfully terwards, the reaction temperature was raised and maintained at 80 scaled up to 1 kilogram under the solvent-free reaction condition. °C for 8 h, which led the conversion to 96%. After purification by Although our metal-free methodology demonstrated here does pre- first recovering the excess HBpin through distillation followed by sent some substrate scope limitations compared to transition metal passing the crude product catalysts (Ir, Rh, Pd and others), the introduction of boronyl group on heteroarenes using this process has several advantages. These include the use of inexpensive metal-free catalysts, the absence of trace metals in the end-products, the absence of solvent, an easy purification process using ethereal solvents for column chromatog- raphy, complementary reactivity to the most efficient catalysts (iridium complexes), and a moderate reaction temperature range (80–120 °C). Adopting this green methodology by pharmaceutical and other fine chemical industries may well benefit them in many Scheme 5. Catalytic borylation of 1-methyl indole in 1 kilogram ways. using HBpin reagent and precatalyst 2F under the solvent-free con- dition. ASSOCIATED CONTENT Supporting Information through a short Celite column using ethyl ether gave ~1 kilogram (1006 grams) of the product (isolated yield = 95%) in >98% purity. The following files are available free of charge on the ACS Publi- As this metal-free methodology involves the liberation of a stoichi- cations website at DOI: Experimental details and NMR spectra ometric amount of H2, a good outlet for H2 liberation is required. (PDF). Furthermore, the solution becomes more viscous as the catalytic reaction proceeds. Therefore, we customized our reaction setup to AUTHOR INFORMATION have a constant stirring rate with the help of a mechanical stirrer in Corresponding Author a 2L three-neck round bottom flask (Figure 2(left)). The preserva- tion of constant stirring of the reaction solution provided an excel- *E-mail for F.-G.F.: [email protected] lent conversion within a reasonable reaction time (8 h). Author Contributions ‡These authors contributed equally. CONCLUSIONS Notes A straightforward and practical metal-free synthetic methodology The technology presented within this article is patent pending. was developed for the borylation and borylative dearomatization of heteroarenes. This method uses bench-stable precatalysts of the ACKNOWLEDGMENT form 1-NHR2-2-BF3-C6H4, commercial and easily-synthesizable

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