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Practical and Scalable Synthesis of Borylated Heterocycles using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts Arumugam Jayaraman, Luis Carlos Misal Castro, and Frédéric-Georges Fontaine Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00248 • Publication Date (Web): 04 Oct 2018 Downloaded from http://pubs.acs.org on October 5, 2018

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Organic Process Research & Development

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

ABSTRACT: A practical and scalable metal-free catalytic method for the borylation and borylative dearomatization of heteroarenes has been developed. This synthetic method uses inexpensive and conveniently synthesizable bench-stable precatalysts of the form 1-NHR2-2-BF3-C6H4, commercially and synthetically accessible heteroarenes as substrates, and pinacolborane as borylation reagent. Preparation of several borylated heterocycles in 2 and 50 grams was achieved under solvent-free conditions without the use of Schlenk techniques or a glove box. A kilogramscale borylation of one of the heteroarene substrates was also achieved using this cost-effective green methodology to exemplify the fact that our methodology can be conveniently implemented in fine chemical industries.

INTRODUCTION For the fine-chemical industries, including pharmaceutical and organic electronic (OE) industries, the development of straightforward methods to prepare highly valuable synthetic intermediates from commercial and easily synthesizable chemicals without using any expensive laboratory equipment is of enormous interest.1 Improvements in the selective and direct functionalization of organic compounds, while avoiding toxic intermediates, hazardous reagents and solvents, and equimolar by-product wastes, are an incessant focus for the synthetic chemistry community.2 To date, highly expensive precious transition metals, including Ru, Rh, Pd, Ir and Pt, and special ligands as well as several additives, have often been used as catalysts by synthetic chemists.3 These systems can notably be used for the highly efficient and atomeconomic regioselective functionalization of unactivated C(sp2)–H and C(sp3)–H bonds in a myriad of organic compounds.3a, 3b, 3f, 4 Nevertheless, the presence of trace amount of transition metals in the end-product raises serious concerns such as toxicity issues in the case of pharmaceuticals5 and reduced performances in the case of OEs.6 Thus, complete removal of metals from end-products becomes compulsory, adding additional steps in processes, such as treatments with metal scavengers. As a result, the production of metal-free synthetic intermediates using transition metal catalysts in industrial applications becomes over-costly.7 Less-expensive and more abundant first-row transition metals such as Mn, Fe, Co,

Placeholder

Ni, and Cu, instead of noble metals is an emerging area that provides entries to circumvent the cost problems;8 however, several of these elements remain toxic.5 Among a variety of products that can be prepared via C–H bond functionalization and/or reduction of unsaturated C-C bonds, hydrocarbons with a C-B functionality serve as versatile reagents. These reactive C(sp2)–B or C(sp3)–B bond-containing reagents provide several synthetic possibilities to access numerous functional groups.9 Of the widely accepted synthetic utilities of organoboronate reagents are the Pd-catalyzed Suzuki-Miyaura and the Cu-catalyzed Chan-Lam cross-coupling reactions for the construction of C–C and C-N bonds, respectively.10 Preparation of a wide variety of organoborane reagents through C-H borylation was achieved efficiently by utilizing transition metal catalysts, particularly the noble metals,11 and extending such reactions by using earth-abundant transition metal catalysts has also emerged.12 In recent years, main-group compounds have been shown to promote catalysis processes classically performed by transition metal catalysts.13 Among those, the 2006 finding by Stephan and coworkers of the heterolytic splitting of molecular H2 under the cooperative effect of a Lewis acid and a Lewis base center has disregarded the belief that the H-H bond activation of molecular H2 was only possible using transition metals.14 This discovery has initiated the field of frustrated Lewis pair (FLP) chemistry and exploration of such chemistry has rapidly expanded from curious stoichiometric synthetic transformations to useful catalysis,13h, 15 mainly in the hydrogenation of unsaturated compounds.16 In 2015, we have established that an intramolecular B/N FLP, 1TMP-2-BH2-C6H4 (1, Scheme 1a), can be used as a catalyst for the direct C-H borylation of heteroarenes with pinacolborane (HBpin), via a C-H activation/σ-bond metathesis mechanism (Figure 1a).17 Due to the high atom-efficiency of this metal-free method, this method was highlighted as potentially interesting to processing research and development chemists.18 Following our work on the C-H activation using a B/N FLP, such reactivity pattern was found to be common for other more reactive B/N FLPs.19 Despite some metal-free electrophilic borylation methods for borylation of heteroarenes and arenes disclosed before our discovery,20 there have been many reports appearing on this topic 21 after our work was published.19,

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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 atom-efficiency under mild conditions in good to excellent yields, catalyst 1 was found to be highly sensitive to the ambient conditions; hence, its synthesis, storage, manipulation, and experimental setup for catalysis should be performed under strict inert conditions, which may restrict industries in adopting this synthetic methodology. Previously, Buchwald and coworkers have brought up an elegant encapsulation method to introduce air and moisturesensitive transition metal catalysts to the reaction flask without using air-sensitive operation conditions, leading to easier application in an industrial set-up.22 In order to simplify the use of our B/N FLP catalyzed borylation reactions, we reported in 2016 the synthesis of the air and water-stable zwitterionic compound 1TMP(H)-2-BF3-C6H4 (1F, Scheme 1), which acts as a precatalyst for borylation reactions.23 From this precatalyst, the active catalyst 1 is generated in-situ by a reduction reaction with HBpin and provided a similar catalytic activity as 1 after an induction period. Later, in 2017, our group also demonstrated that the less sterically-hindered ambiphilic aminoboranes 1-piperidyl-2-BH2-C6H4 (2, 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 species generate stable Lewis adducts.24 In addition, a preliminary study was made on the synthesis of fluoride derivatives of 2 and 3, 1-piperidyl(H)-2-BF3-C6H4 (2F, Scheme 1) and 1-Et2NH-2-

BF3-C6H4 (3F, Scheme 1), and their use as precatalysts for C-H borylation reactions. In a subsequent report, we have demonstrated that all these catalysts and BH3.SMe2 can promote the borylative dearomatization reaction when using electron-poor arylsulfonyl indoles as substrates and HBpin as reagent, leading to the formation of 3-boronyl indoline products (Scheme 1b), through a 1,2-hydroboration/backbone redistribution mechanism (Figure 1b).25 Such products can be viewed as potential synthetic intermediates for several pharmaceuticals, natural products, and materials.26 Herein we report the progress we made in optimizing our metal-free methodology for borylation and borylative dearomatization of heteroarenes suitable for an industrial environment. RESULTS AND DISCUSSION Synthesis and scale-up of fluoroborate precatalysts. In our previous preliminary study, we have described the synthetic protocols for four different fluoroborate salts (1F-4F) that have different alkyl substituents on the ammonium nitrogen center.24, 27 Yet, these precatalysts were synthesized only on a smaller scale (2-5 grams) to explore their catalytic activity towards borylation. As the preliminary study showed that the piperidyl precatalyst 2F is more efficient for the borylation and borylative dearomatization of heteroarenes (vide infra), its synthesis on a 100-gram scale was


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attempted. The synthetic protocol for 2F involves three steps (Scheme 2): (i) the formation of the 1-Br-2-piperidyl-C6H4 intermediate (A) through an amine-promoted cyclocondensation between 2-bromoaniline and 1,5-dibromopentane, (ii) formation of the boronic acid 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 dibromopentane can be recovered by simple distillation. Among the three synthetic steps to 2F, only for step 2, i.e., for lithiation of A and the later addition of B(OMe)3, is the inert atmosphere needed. The precatalyst 2F was purified conveniently by recrystallization in CH2Cl2/hexanes. In total, three 100 g batches

chloroform, first the borylation of 1-methyl pyrrole in three different dried Table 1. Conversions (%) of catalytic borylation of 1-Me-pyrrole (5a) under different conditions using precatalysts 1F-4F.

Entry

Time (h)

1F

2F

3F

4F

4

7 (86:14)

64 (98:2)

63 (98:2)

3 (100:0)

16

97 (88:12)

94 (98:2)

91 (98:2)

31 (100:0)

Toluene

16

91 (89:11)

93 (98:2)

90 (98:2)

34 (100:0)

2-MeTHF

16

95 (90:10)

95 (98:2)

90 (98:2)

33 (100:0)

THF

16

93 (88:12)

93 (98:2)

92 (99:1)

39 (100:0)

1

41 (95:5)

80 (99:1)

75 (99:1)

9 (100:0)

2

57 (95:5)

97 (98:2)

96 (98:2)

23 (100:0)

Solvent

1 CDCl3

2

3

4

5 Neat

In parenthesis: 6a to 6a’ ratio.

Scheme 2. Synthetic steps to precatalyst 2F in 100 grams. of 2F were synthesized with consistent overall reaction yields (55 – 59%). While the piperidyl precatalyst 2F is more active for the borylation of most heteroarenes, precatalyst 3F is the second best in catalyzing borylation reactions. However, the TMP-containing precatalyst 1F appears to be better for a minority of heteroarenes (vide infra). Therefore, to compare their catalytic activity with that of 2F and to study their stability under ambient conditions, the syntheses of precatalysts 1F and 3F in a 10 gram-scale were achieved by following our previously established procedure (see Supporting Information).24 Choice of solvent. In our earlier C-B bond forming reactions, we used dry dichloromethane and chloroform. However, for practical considerations these solvents should be avoided.28 Thus, we confined our investigations to certain criteria in choosing the solvent, including: (i) should be non-chlorinated, (ii) should have a boiling point higher than 70 °C, and (iii) must be compatible with our catalysts, substrates and end-products. To find out the suitable solvent that provides a catalytic conversion as high as observed in

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 excellent and similar to what was observed in chloroform. However, to our delight, this reaction works better and with improved selectivity 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 reaction in chloroform gave only a 7% conversion in that time. This outcome is very important for the industrial scale production since it removes reaction solvent from the production costs. Borylation and borylative dearomatization of heteroarenes on a 2-gram scale. To show the versatility of our catalytic system towards producing metal-free borylated heterocycles, borylated heterocycles that are of interest for pharmaceutical or OE industries were produced on a 2 gram-scale through either C-H borylation or borylative dearomatization reactions. For C-H borylation reactions, N, O and S-containing heteroarene substrates were explored (Scheme 3). More emphasis was placed on N-based heteroarenes. From Table 1, it became apparent that the precatalyst 4F and its active catalyst 4 show lower catalytic efficiency. Therefore, only precatalysts 1F-3F were screened further to find a better catalyst for borylation of some intended substrates (see Supporting Information for the catalysis screening results). From screening, it was found that the precatalysts 2F and 3F are more efficient for the N and O-based heteroarenes. In addition, these precatalysts also exhibited an



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Scheme 3. Catalytic borylation of heteroarenes on 2 gram-scale using HBpin reagent and the appropriate bench-stable fluoroborate precatalyst under solvent-free conditions. “n” signifies the equivalents of HBpin with respect to the substrate. 1 Celite column using ethyl ether as eluent. 2 Silica gel column purification using petroleum ether/ethyl ether as eluent.3 Partially decomposed upon silica gel column purification.4 Recrystallization in CH2Cl2/hexanes. improved regioselectivity with heteroarenes having multiple nucleophilic sites. For example, with 1-methyl pyrrole under neat conditions, a 98:2 ratio of C2-substituted to C3-substituted isomers was respectively observed with precatalysts 2F and 3F, while a 95:5 ratio was formed when using precatalyst 1F. Although both precatalysts 2F and 3F were found to be quite active, the easier synthetic protocol for 2F explains our choice of catalyst for the 2 gram-scale borylation reactions. For thiophene deriva-

tives, precatalyst 1F and its active form, 1, were found to be better than our other catalysts. In these systems it was shown that 2 undergoes two consecutive C-H activation steps which prevents the metathesis reaction to occur, and thus catalytic activity.24 Despite some heteroarenes and all precatalysts being in the solid state, the liquid HBpin reagent together with the reaction temperatures of 80 -100


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Scheme 4. Catalytic borylative dearomatization of arylsulfonyl indoles on 2 gram-scale using HBpin reagent and precatalyst 2F under solvent-free conditions. “n” signifies the equivalents of HBpin with respect to the substrate. 1 CH2Cl2/H2O extraction. 2 Celite column using ethyl ether as eluent. 3 Derivatized as alcohol using NaOCl. °C bring the reaction mixture to a liquid phase and facilitates the desired reaction. Only for the 1,2-dimethyl indole substrate such process proved to be a concern, since the solution solidifies after 15 minutes at 80 °C, stopping the reactivity. Therefore, a minimal amount of 2-methyl-THF was added to push the reaction forward. The reaction time for the borylation reactions generally varies with respect to the nucleophilicity of the heteroarenes. More nucleophilic ones such as 1-methyl pyrrole (5a), 1-benzyl pyrrole (5b), 3,4-ethylenedioxythiophene (EDOT, 5d), 1-methyl indole (5j), 1,2-dimethyl indole (5k) and 5-methoxy-1-methyl indole (5s) require less than 10 h at 80 °C, while others require 16 h at this temperature. Using stoichiometric or excess HBpin with respect to the amount of substrate leads to the formation of a significant amount of diborylated products in the cases of 5d and 5f-5i. Therefore, 0.8 equiv HBpin with respect to the substrate was added. The substrate 1-TBDMS-7-azaindole (5t), which bears a highly exposed basic pyridine nitrogen, required a longer reaction time (48 h) and extra precatalyst and HBpin loadings to achieve > 80% conversion. Purification of most borylated heteroarenes was straightforward as it involves mainly removal of excess HBpin,

FBpin and other volatiles in vacuo, followed by passing the ethereal solution of the crude product through a short column of Celite using ethyl ether as eluent, which scrubs the residual catalyst. The borylated furan derivatives 6f-6i, however, were found be less stable under the chromatographic conditions, partially decomposing during purification, which was identified through phosphomolybdic acid staining of the eluted silica gel TLC plate. Consequently, to obtain two grams of these products higher substrate loadings were used. Up to this point, several electron-rich heteroarenes can be conveniently borylated using this methodology. Many N-heteroarenes including indoles and pyrroles protected at N with BOC, Cbz or phosphinyl group, derivatives of pyridine, pyrimidine, oxazole, thiazole, imidazole, triazole, isoxazole and selenophene, and electro-rich arenes were not successful toward borylation. For the borylative dearomatization reactions, 1-arylsulfonyl indoles were used as substrates. The catalytic reactions were tested using all four precatalysts, 1-tosyl indole as substrate, in the presence of 1.5 equiv of HBpin at 100 °C. All reactions gave a



quantitative conversion to 3-Bpin-1-tosyl indoline (8a), suggest-

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ing

that

Table 2. Comparison of the catalytic activity between iridium catalyst and metal-free fluoroborate precatalysts

entry

1

substrate

conv. (%) using Ir/dtbipy catalyst

conv. (%) using precatalyst 2F

94.4 (92:8, C2/C3 regioisomers)

97 (98:2, C2/C3 regioisomers)

63 (C2 regioisomer)

conv. (%) using Ir/dtbipy catalyst

conv. (%) using precatalyst 2F

5

51

96

91 (C2 regioisomer)

6

94 (C2 regioisomer)

99 (C3 regioisomer)

48 (67:33, mono and disubstituted)

96 (disubstituted)a

7

89 (C2 regioisomer)

72 (C3 regioisomer) c

88 (C2 regioisomer)

> 99 (C3 regioisomer)

69 (C2 regioisomer)

89 (C3 regioisomer)

2

3

4

a

entry

substrate

8

Precatalyst 1F was used.

any of the precatalysts among 1F-4F can be used for the borylative dearomatization transformation. A total of 15 arylsulfonyl indoles were transformed quantitatively in a 2 gram-scale using precatalyst 2F (10 – 20 mol%) and HBpin reagent (1.5 – 2.6 equiv) at 100 °C under solvent-free condition over 16 h of reaction time (Scheme 4). Substrates containing either an electrondonating substituent or an electron-withdrawing substituent at different positions on the benzene ring of 1-arylsulfonyl indoles undergo solely the desired borylative dearomatization reaction. In this transformation, the Bpin group added exclusively to the C3position of indoles while the H substituent simultaneously added to the C2-position. Thus, the borylative dearomatized products obtained were highly regioselective. Moreover, this 1,2-addition occurs on the same face of the aromatic C-C double bond, which leads to highly diastereoselective products. The syn addition and related high diastereoselectivity was previously evidenced from the X-ray crystallographic characterization of the products derived from the borylative dearomatization of 2-methyl substituted 1phenylsulfonyl indoles such as 7n and 7o.25 Despite all substrates and the precatalyst 2F being solids, none of the catalytic reactions needed a solvent medium. The 100 °C was found to be an optimal temperature for this transformation since the reactions conducted at 80 °C required a longer reaction time (~ 36 h). The purification procedure to isolate the products was similar to that of the borylated heteroarenes. However, some products were found to be quite sensitive to air and moisture; therefore, they were sequentially derivatized to alcohol and silyl ethers respectively through stereoretentive oxidation, using the household bleach composed of 6% sodium hypochlorite, and silylation using TBDMS-

chloride. Unlike C-H borylation reactions, borylative dearomatization reactions do not produce any H2 by-product except for the generation of active catalyst from the fluoride precatalyst. Therefore, this atom-efficient reaction can also be carried out in a sealed reaction flask at the 2-gram scale. Comparison of catalytic activity with metal catalysts. Most procedures to synthesize borylated heteroarenes from the respective heteroarenes through C-H activation use expensive iridium catalysts, which were notably developed by Miyaura-Hartwig.11a, 11c, 29 The capability of our metal-free ambiphilic aminoboranes to catalyze the borylation of heteroarenes has drawn us to compare their catalytic activity with that of the iridium catalyst. The comparison was made with a set of substrates under similar reaction conditions on a millimole scale (Table 2) using catalyst loadings typically used in the respective transformations. The exception is the presence of solvent with the iridium catalysts. Comparing the catalytic results, it was found that: (i) the catalytic efficiency of both catalysts is more or less similar only when 10 – 20 mol% of the FLP catalyst is used in relationship to the 3 mol% iridium catalyst, and (ii) the regioselectivity pattern for the pyrrole and thiophene derivatives remains the same whereas it differs with the indole derivatives, i.e., the iridium catalyst promotes C2borylation while our metal-free catalysts facilitate the C3borylation. Nevertheless, it should be pointed out that the low cost of precatalyst 2F makes the metal-free approach economically viable. Stability of the precatalysts. As the stability of the precatalysts was marked as an indispensable criterion for the application of


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this synthetic method in fine chemical industries, the stability of precatalysts 1F-3F towards air and moisture at room temperature, Table 3. Stabilities of the bench-top kept precatalysts 1F-3F examined periodically through their catalytic activity

Period

conv. using 1F

(%) precat

conv. using 2F

(%) precat

conv. using 3F

(%) precat

1st week

73 (88:12)

84 (98:2)

88 (98:2)

3rd month

74 (89:11)

80 (98:2)

82 (98:2)

6th month

69 (87:13)

86 (97:3)

95 (98:2)

12th month

71 (89:11)

83 (98:2)

86 (98:2)

Numbers in parenthesis denote the ratio of products A and B.

keeping them under ambient conditions of the lab, was checked four times over a 12-month period, starting from their syntheses (1st week, 3rd, 6th and 12th month). Two ways have been followed to examine their stability: (i) through inspecting the purity of these precatalysts by NMR spectroscopy (1H, 13C, 11B, and 19F nuclei), and (ii) by studying their catalytic activity with one of the heteroarene substrates, 1-methyl pyrrole. Over the one yearperiod, all three precatalysts kept their original white color, and the purity of all these precatalysts, as inspected through NMR spectroscopy, stayed the same with a purity of >99%. To check the stability of the precatalysts 1F-3F through catalytic activity studies, the borylation of 1-methyl pyrrole (5a) on a 1 mmol-scale using 1.3 equiv of HBpin and a 5 mol% loading of the precata-

by lysts was carried out in 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 regioselectivity. Additionally, using commercially available HBpin having 1% of triethylamine stabilizer did not halt the borylation reaction when tested with the sixmonth old precatalysts. All these results clearly show that the stability of the precatalysts 1F-3F is excellent towards air and moisture at room temperature for up to a year. Furthermore, as noted previously, the thermal stability of the in situ generated catalysts is adequate since they can withstand temperatures of 100 °C and 120 °C for the catalytic borylation and borylative dearomatization reactions. 50 gram-scale trials. Given the excellent stability towards the ambient condition by these precatalysts and the adequate thermal stability by the active aminoborane catalysts, we next aimed at preparing some of the borylated heteroarenes and borylative dearomatized heterocycles in an intermediate scale (about 50 grams). The representative N, O and S-based heterocycles such as 1-methyl pyrrole, 2-methyl furan and EDOT were borylated and more emphasis was placed on the N-heteroarenes. Purification of products at this scale involves either recovery or removal of excess HBpin respectively through distillation or evaporation in vacuo, followed by dissolution of the crude product in a minimum amount of ethyl ether and filtration through a short Celite column using another equivalent of ethyl ether eluent. Evaporation of the solvent from resulting solution yields pure borylated heterocycles. 1-kilogram trial. We attempted to synthesize one of the borylated heteroarenes on a kilogram-scale. For this, we chose to prepare 3-



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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 purification using petroleum ether/ethyl ether as eluent. 4 Partially decomposed. 5 CH2Cl2/H2O extraction. 6 Derivatized to alcohol.

Figure 2. Few experimental stages for the metal-free kilogram-scale borylation of 1-methyl indole; left: initial experimental setup with 1methyl 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 equiv) and precatalyst 2F (10 mol%) (Scheme 5). The experimental setup is shown in Figure 2. The hot reactor setup was initially flushed with nitrogen, followed by charging the substrate 1-methyl indole and the reagent HBpin, heating the solution at 60 °C, and adding the precatalyst 2F in portions using a powder addition funnel. The reaction temperature was kept at 60 °C until all precatalyst was introduced and the dramatic brisk effervescence developed within minutes due to evolution of H2, to generate active catalyst, is reduced to a normal rate. During this 1 kilogram-scale trial, the addition of the precatalyst in small portions allows controlling the liberation of H2, which is mostly generated from the catalyst generation from precatalyst, to reduce the risk of explosion hazard. Afterwards, the reaction temperature was raised and maintained at 80 °C for 8 h, which led the conversion to 96%. After purification by first recovering the excess HBpin through distillation followed by passing the crude product precatalyst 2F (10 mol%) HBpin (1.5 equiv) N 5j, 4.1 mmol

80 °C, neat, 8 h

Bpin

N 6j

conv: 96% yield: 1006g, 95% purity: > 98%

Scheme 5. Catalytic borylation of 1-methyl indole in 1 kilogram using HBpin reagent and precatalyst 2F under the solvent-free condition. through a short Celite column using ethyl ether gave ~1 kilogram (1006 grams) of the product (isolated yield = 95%) in >98% purity. As this metal-free methodology involves the liberation of a stoichiometric amount of H2, a good outlet for H2 liberation is required. Furthermore, the solution becomes more viscous as the catalytic reaction proceeds. Therefore, we customized our reaction setup to have a constant stirring rate with the help of a mechanical stirrer in a 2L three-neck round bottom flask (Figure 2(left)). The preservation of constant stirring of the reaction solution provided an excellent conversion within a reasonable reaction time (8 h). CONCLUSIONS

A straightforward and practical metal-free synthetic methodology was developed for the borylation and borylative dearomatization of heteroarenes. This method uses bench-stable precatalysts of the form 1-NHR2-2-BF3-C6H4, commercial and easily-synthesizable heteroarene substrates and the pinacolborane (HBpin) reagent. The strategy of this methodology first involves the generation of ambiphilic organocatalysts of structure 1-NR2-2-BH2-C6H4 from the precatalysts and HBpin. Then the organocatalysts can undergo C-H activation of an heteroarene, H2 elimination and transmetallation with HBpin through σ-bond metathesis to afford highly regioselective borylated heteroarene products, or 1,2-dearomative hydroboration and transmetallation of electron-poor indoles to afford C3-borylated indolines with a high regio- and diasteroselectivity. Several borylated N, O and S-containing heterocyles were produced under solvent- and additive-free conditions in good to excellent yields in 2 and 50 gram-scales. Additionally, the synthesis of one of the heteroarylboronates, 3-boryl-1-Me indole, was successfully scaled up to 1 kilogram under the solvent-free reaction condition. Although our metal-free methodology demonstrated here does present some substrate scope limitations compared to transition metal 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 endproducts, the absence of solvent, an easy purification process using ethereal solvents for column chromatography, 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 ways.

ASSOCIATED CONTENT Supporting Information The following files are available free of charge on the ACS Publications website at DOI: Experimental details and NMR spectra (PDF). AUTHOR INFORMATION Corresponding Author *E-mail for F.-G.F.: [email protected]


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Author Contributions

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‡These authors contributed equally. Notes The technology presented within this article is patent pending. ACKNOWLEDGMENT We gratefully acknowledge National Sciences and Engineering Research Council of Canada (NSERC) and Centre de Catalyse et Chimie Verte (Quebec) for funding, BASF for the generous supply of pinacolborane. F.G.F. also thanks NSERC for a Canada Research Chair. REFERENCES 1. (a) Rodrigues, T.; Schneider, P.; Schneider, G., Accessing New Chemical Entities through Microfluidic Systems. Angew. Chem. Int. Ed. 2014, 53, 5750-5758; (b) Gutmann, B.; Cantillo, D.; Kappe, C. O., Continuous-Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem. Int. Ed. 2015, 54, 66886728. 2. (a) Wang, G.-W., Mechanochemical Organic Synthesis. Chem. Soc. Rev. 2013, 42, 7668-7700; (b) Gawande, M. B.; Bonifácio, V. D. B.; Luque, R.; Branco, P. S.; Varma, R. S., Solvent-Free and Catalysts-Free Chemistry: A Benign Pathway to Sustainability. ChemSusChem 2014, 7, 24-44; (c) Anastas, P. T.; Warner, J. C., Green Chemistry: Theory and Practice. Oxford University Press: New York, 1998. 3. (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H., Ruthenium(II)Catalyzed C–H Bond Activation and Functionalization. Chem. Rev. 2012, 112, 5879-5918; (b) Wencel-Delord, J.; Glorius, F., C–H Bond Activation Enables the Rapid Construction and Late-Stage Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369; (c) Magano, J.; Dunetz, J. R., Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177-2250; (d) Busacca Carl, A.; Fandrick Daniel, R.; Song Jinhua, J.; Senanayake Chris, H., Transition Metal Catalysis in the Pharmaceutical Industry. In Applications of Transition Metal Catalysis in Drug Discovery and Development, 2012; (e) Watson, W., Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry. Org. Process Res. Dev. 2014, 18, 277-277; (f) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K., C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960-9009. 4. (a) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L., Weakly Coordinating Directing Groups for Ruthenium(II)-Catalyzed C-H Activation. Adv. Syn. Catal. 2014, 356, 1461-1479; (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q., Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788-802. 5. (a) Egorova, K. S.; Ananikov, V. P., Which Metals are Green for Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and Au Salts. Angew. Chem. Int. Ed. 2016, 55, 12150-12162; (b) Egorova, K. S.; Ananikov, V. P., Toxicity of Metal Compounds: Knowledge and Myths. Organometallics 2017, 36, 4071-4090. 6. (a) Usluer, Ö.; Abbas, M.; Wantz, G.; Vignau, L.; Hirsch, L.; Grana, E.; Brochon, C.; Cloutet, E.; Hadziioannou, G., Metal Residues in Semiconducting Polymers: Impact on the Performance of Organic Electronic Devices. ACS Macro Lett. 2014, 3, 1134-1138; (b) Nikiforov, M. P.; Lai, B.; Chen, W.; Chen, S.; Schaller, R. D.; Strzalka, J.; Maser, J.; Darling, S. B., Detection and Role of Trace Impurities in HighPerformance Organic Solar Cells. Energy Environ. Sci. 2013, 6, 15131520; (c) Camaioni, N.; Tinti, F.; Franco, L.; Fabris, M.; Toffoletti, A.; Ruzzi, M.; Montanari, L.; Bonoldi, L.; Pellegrino, A.; Calabrese, A.; Po, R., Effect of Residual Catalyst on Solar Cells Made of a FluoreneThiophene-Benzothiadiazole Copolymer as Electron-Donor: A Combined Electrical and Photophysical Study. Org. Electron. 2012, 13, 550-559; (d) Urien, M.; Wantz, G.; Cloutet, E.; Hirsch, L.; Tardy, P.; Vignau, L.; Cramail, H.; Parneix, J.-P., Field-Effect Transistors Based on Poly(3Hexylthiophene): Effect of Impurities. Org. Electron. 2007, 8, 727-734. 7. Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; DaSilva, J.; Henderson, D.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.; Wang, T., Adsorbent Screening for Metal Impurity Removal in Pharmaceutical Process Research. Org. Process Res. Dev. 2005, 9, 198-205. 8. (a) Su, B.; Cao, Z.-C.; Shi, Z.-J., Exploration of Earth-Abundant Transition Metals (Fe, Co, and Ni) as Catalysts in Unreactive Chemical Bond Activations. Acc. Chem. Res. 2015, 48, 886-896; (b) Liu, W.;

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