Metal-free borylation of electron-rich aryl (pseudo)halides under continuous-flow photolytic conditions

Abstract

A metal-free borylation reaction of electron-rich aryl chlorides, fluorides, mesylates and phosphates under continuous-flow photolytic conditions is reported. The flow setup was designed to facilitate this process efficiently in comparison with the batch mode. Owing to its unique chemical selectivity, mild reaction conditions, good functional group tolerance and substrate scope, this reaction adds a complementary protocol to the current synthetic methods for boronic acid derivatives. The proposed reaction mechanism involves a photolytically generated triplet aryl cation, and DFT calculations suggest that the borylation product is formed in an anion-mediated single step process passing a minimum energy crossing point.

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Arylboronic acid derivatives are essential synthetic building blocks and are widely used in the syntheses of pharmaceuticals, materials, and other functional molecules, due to their versatile transformations, broad availability, air and/or moisture stability, and ease of handling.¹ Conventionally, arylboronic acid derivatives can be prepared by treatment of arylmagnesium or lithium reagents with trialkyl borates, followed by transesterification or hydrolysis. However, these reactions suffer from limited functional group tolerance. Over the past two decades, transition metal-catalyzed reactions have been developed for the conversion of aryl iodides, bromides, and triflates to the corresponding boronates.^2,3 Nevertheless, only a few catalyst systems are effective for the borylation of the less reactive aryl chlorides and mesylates, and no general methods are available for aryl fluorides. Recently, direct aromatic C–H borylation methods have been developed using precious transition metal catalysts.⁴ These catalytic approaches possess tremendous versatility and functional group compatibility, and thus have been widely used in the syntheses of arylboronic acid derivatives. To lower the costs and reduce heavy metal residues in the products, however, transition metal-free methods should be more desirable. In this regard, borylation reactions from arylamine derivatives have been developed.⁵ Alternatively, aryl iodides or bromides could be effectively borylated with alkali metal alkoxides as promoters.^6,7 Mild borylation of diaryliodonium salts has also been reported.⁸ Additionally, useful methods for direct transition metal-free C–H borylation of electron-rich arenes and heteroarenes have been developed.^9,10

Despite these advancements, new methods for syntheses of functional aryl boronates in a chemoselective and environmentally friendly fashion from broadly available starting materials under mild reaction conditions are still attractive. Moreover, new reactions that are complementary to the current methods in terms of substrate scope and reaction conditions are highly desirable. Very recently, we discovered an efficient borylation reaction of aryl iodides and bromides under photochemical conditions (Scheme 1a).¹¹

Scheme 1 Previous photochemical borylation and the outline of this work.

Preliminary mechanistic studies indicated an aryl radical intermediate that reacted with activated diboron species to generate the borylation product and a boron-centered radical.^11b,c Under the same conditions, however, aryl chlorides and fluorides were less reactive. In a set of related photochemical C–C coupling reactions, Fagnoni, Albini and their co-workers have demonstrated that electron-rich aryl chlorides and fluorides were particularly more effective than the corresponding bromides and iodides, and the key intermediate was a photochemically generated triplet aryl cation (Scheme 1b).¹² Herein, we describe our recently obtained results in the development and computational mechanistic studies of a photochemical C–B bond-forming reaction of electron-rich aryl chlorides, fluorides and phenol derivatives (Scheme 1c).

4-Chlorophenol (1a) was used as a model substrate for initial investigations (Table 1). A solution of 1a and bis(pinacolato)diboron (B₂pin₂, 2) (1 : 1 molar ratio) was placed in a quartz test tube and irradiated with UV light. Encouragingly, the desired borylation product could be observed when the reactions were conducted in polar solvents such as acetonitrile, methanol and trifluoroethanol for 10 hours under irradiation with a 300 W high pressure mercury lamp (Table 1, entries 1–3). Using water and acetone as co-solvents slightly increased the yields (entries 4 and 5). Addition of bases led to remarkable effects (entries 6–8) and among them, tetramethylethylenediamine (TMEDA) gave a somewhat higher yield (28%, entry 6). Using two equivalents of B₂pin₂ could further improve the yield to 37% (entry 9) and reducing the amount of TMEDA to 0.5 equivalents resulted in comparable yield (entry 10).

Table 1 Reaction optimization under batch and continuous-flow conditions

Entry	Ratio (1a/2)	Solvent	Additive [mol %]	Time	Yield^c [%]
a Batch conditions: 1a (c = 0.05 M), 2 (1.0–3.0 equiv.), RT, 10 h. b Flow conditions: 1a (c = 0.05 M), 2 (1.5–2.0 equiv.), −5 °C. c Determined by ^1H NMR with 1,3,5-trimethoxybenzene as an internal standard. d Isolated yield. TEA: triethylamine, TMEDA: tetramethylethylenediamine, TBAF: tetrabutylammonium fluoride.
Batch conditions
1	1 : 1	MeCN	None	10 h	11
2	1 : 1	MeOH	None	10 h	10
3	1 : 1	TFE	None	10 h	14
4	1 : 1	MeCN/H2O	None	10 h	19
5	1 : 1	MeCN/H2O	None	10 h	23
		Acetone
6	1 : 1	MeCN/H2O	TMEDA (100)	10 h	28
		Acetone
7	1 : 1	MeCN/H2O	K2CO3 (100)	10 h	0
		Acetone
8	1 : 1	MeCN/H2O	TEA (100)	10 h	17
		Acetone
9	1 : 2	MeCN/H2O	TMEDA (100)	10 h	37
		Acetone
10	1 : 2	MeCN/H2O	TMEDA (50)	10 h	40
		Acetone
Continuous-flow conditions
11	1 : 2	MeCN/H2O	TMEDA (50)	26 min	77
		Acetone
12	1 : 2	MeCN/H2O	TMEDA (50)	26 min	87(85^d)
		Acetone	TBAF (10)
13	1 : 2	MeCN/H2O	TMEDA (50)	16 min	61
		Acetone	TBAF (10)
14	1 : 1.5	MeCN/H2O	TMEDA (50)	26 min	47
		Acetone	TBAF (10)

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Based on the batch conditions and our previous experience in continuous-flow reactions,^11,13 we designed and assembled a continuous-flow photochemical reactor and further optimized this borylation reaction.¹⁴ Thus, transparent fluorinated ethylene propylene (FEP) tubing was coiled outside of a cooled quartz immersion well in which the mercury lamp was situated (see the ESI†). A stock solution containing all reactants and reagents was introduced into the tubing using a syringe pump. We were delighted to find that when the reaction was conducted in a continuous-flow fashion, the yield was significantly improved (40% to 77%, entry 11 vs. entry 10) with a residence time of only 26 minutes. The yield further increased to 87% when 0.1 equivalents of tetrabutylammonium fluoride (TBAF) were used as an additive (entry 12). A shorter reaction time and a smaller amount of B₂pin₂ both led to diminished yields (entries 13 and 14).

With the optimized reaction conditions in hand, the substrate scope of this photolytic borylation reaction was examined (Table 2). A series of electron-rich aryl halides or phenol derivatives were subjected to the reaction conditions. All continuous-flow reactions were run with less than 60 minutes of residence time. Aryl chlorides with para- or ortho-electron-donating substituents including both protic and non-protic O-, N-, and S-based groups were all viable substrates in these reactions to produce the corresponding boronates in moderate to good yields. Substituents at the ortho- (for 3b–3d, 3f, 3m and 3n) and/or meta- (for 3g and 3w) positions to the leaving group were also compatible. Aryl boronates containing saturated (3j–3l) and aromatic N-heterocycles (3p and 3q) that are interesting for drug synthesis could be prepared by this reaction. In addition, a few representative aryl fluorides (for 3a, 3e, 3v), phosphates (for 3t–3w) and mesylates (for 3t–3w) could be used as substrates in the borylation reaction. Aryl triflates (3w) were ineffective under the same conditions due to hydrolytic decomposition. Furthermore, the neopentanediolato boronates (3r and 3s) were similarly prepared when bis(neopentanediolato)diboron (B₂neop₂) was used in place of B₂pin₂. Remarkably, these electron-rich aryl chlorides, fluorides and mesylates are typically challenging substrates in transition-metal catalyzed borylation reactions. The present work, therefore, offers a complementary method for aryl boronate preparation. To demonstrate the stability and usefulness of this process in an automated system, the borylation of p-chlorophenol (1a) was carried out on a gram scale employing a commercial flow chemistry system (see the ESI†). With no further optimization, the reaction produced the desired boronate 3a in 87% isolated yield. Finally, attempts of this photolytic borylation reaction with electron-neutral aryl chlorides such as p-chlorotoluene and electron-poor substrates such as methyl 2-chlorobenzoate under the same conditions were not successful and only small amounts of hydrodechlorination products were observed.

Table 2 Substrate scope of the continuous-flow photolytic borylation reaction^a

a Reaction conditions: 1 (c = 0.05 M), 2 or 4 (2.0 equiv.), TMEDA (0.5 equiv.), TBAF (0.1 equiv.), acetone/H₂O/CH₃CN. b 2 (3.0 equiv.), and TBAF (1.0 equiv.). TMEDA: tetramethylethylenediamine, TBAF: tetrabutylammonium fluoride.

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Based on our experimental results, we conducted computational mechanistic studies to understand this new borylation reaction, especially the roles of σ-nucleophiles as previously proposed. The results are summarized in Fig. 1. p-Chloroanisole was used as the model substrate. In analogy to Fagnoni and Albini's work,^12c we proposed that this reaction begins with a sensitizer-mediated excitation of the substrate to its triplet state, followed by a heterolytic C–Cl bond cleavage to generate the triplet aryl cation (³Ar⁺) and a chloride anion. A DFT study pointed out that the ³Ar⁺ lies 1.4 kcal mol⁻¹ lower than the ¹Ar⁺. To form the singlet borylation product from the triplet intermediate ³Ar⁺, a state crossing point must be involved. We therefore employed a code developed by Harvey and co-workers to optimize the geometry of minimum energy crossing points (MECPs) between potential energy surfaces of different spin states (Fig. 1).¹⁵ As shown in Fig. 1, a three-component interaction of ³Ar⁺, chloride anions and B₂pin₂ is taking place until the MECP is achieved. After the MECP, the reaction can be completed directly through TS_singlet (ΔE_a = 11.0 kcal mol⁻¹) to form the final product ArBpin.

Fig. 1 Proposed mechanism for the photolytic borylation and energy profiles of the product formation step via a singlet and/or triplet aryl cation. All molecular geometries were optimized without constraints via DFT calculations using the UB3LYP functional with the Lanl2DZ basis set for Cl, 6-311G* for B and those C atoms involved in bond breaking/forming processes, and 6-31G for all other atoms (see the ESI† for the computational details). The relative solvation- and entropy-corrected free energies (298 K) are given in kcal mol⁻¹.

In conclusion, we have described a metal-free, photochemical C–B bond formation reaction from readily available electron-rich aryl chlorides, fluorides, mesylates and phosphates under continuous-flow conditions. The current method is complementary to the conventional transition metal-based approaches in terms of substrate scope and reactions conditions. Based on both the experimental and computational results, a reaction mechanism was proposed, which involves a triplet aryl cation intermediate and an anion-mediated facile one-step formation of the borylation product.

Acknowledgements

This work was financially supported by the Department of Science and Technology of Shaanxi Province (no. 2015KJXX-02), the National Science Foundation of China (no. 21472146) and the Research Grants Council of Hong Kong (HKUST 603313). We thank Prof. Wenxiu Que's group (XJTU) and Vapourtec Ltd for generously sharing with us the batch and flow photochemistry equipment.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Materials including experimental procedures, and copies of ¹H and ¹³C NMR spectra of all new products. See DOI: 10.1039/c6qo00109b

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