Photocatalytic borylcyclopropanation of α-boryl styrenes

Tsuyoshi Ohtani a, Yuto Tsuchiya a, Daisuke Uraguchi a and Takashi Ooi *ab
aInstitute of Transformative Bio-Molecules (WPI-ITbM) and Department of Molecular and Macromolecular Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8601, Japan. E-mail:
bCREST, Japan Science and Technology Agency (JST), Nagoya University, Nagoya 464-8603, Japan

Received 4th February 2019 , Accepted 15th March 2019

First published on 20th March 2019

A diastereoselective borylcyclopropanation of α-MIDA-boryl styrenes with 1,1-diiodoborylmethane is developed using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a catalyst under visible-light irradiation. The scope of this photocatalytic method is explored, and the utility of the resulting doubly borylated cyclopropanes is demonstrated by the selective transformation of one of the two boryl groups.


Cyclopropane is a key structural motif in biologically relevant molecules; hence, numerous efforts have been devoted to developing convenient and efficient protocols for the construction of this strained three-membered carbocycle.1 Among the previously established methods, direct carbene transfer to a carbon–carbon double bond is one of the most straightforward processes to install the cyclopropane framework. However, the reliable methods, such as the Simmons–Smith and metal–carbenoid-mediated reactions, are not necessarily ideal as they usually accompany a considerable amount of metal wastes. Therefore, development of more practical and sustainable protocols for cyclopropyl ring formation is in high demand. This problem could potentially be addressed by the recently introduced photocatalytic cyclopropanation using diiodomethane, although the scope and limitations of this system are yet to be fully explored.2,3

Because the boryl group can be converted into hydroxyl and amino groups and can serve as a valuable synthetic handle for bond formation with various coupling partners, such as aromatic/aliphatic halides, CO2, and olefins, extensive efforts have been undertaken to enlarge the repertoire of preparative routes to borylated organic compounds.4 Borylated cyclopropanes have garnered particular attention as they are useful building blocks to integrate a cyclopropane subunit onto complex molecular architectures through the Suzuki–Miyaura cross-coupling reaction. As a means of accessing this class of functionalized carbocycles, simultaneous installation of the cyclopropane framework and the boryl functionality is more direct and advantageous than the common approaches, including cyclopropanation of borylalkenes with metal carbenoids.5,6 In this context, chromium-mediated and Simmons–Smith borylcyclopropanations of simple alkenes have been developed by Takai and Charette, respectively.7,8 In consideration of the importance of strategies for rapidly increasing molecular complexity in a step-economical manner, we became interested in developing a method for the preparation of doubly borylated compounds featuring two differently protected boryl groups as an effective tool to provide a precursor for multiply functionalized molecular entities.9 Herein, we report a photocatalytic borylcyclopropanation of α-boryl styrenes.

Results and discussion

From the outset of this study, we employed diiodoborylmethane 1 as a source of the requisite borylmethyl radical, which could be generated from 1 under visible-light irradiation in the presence of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN)10 as a catalyst. Considering the reaction mechanism, we reasoned that the photoexcited 4CzIPN (image file: c9qo00197b-t1.tifversus saturated calomel electrode (SCE))11 would transfer an electron to 1 (E1/2 = −1.01 V vs. SCE)12 to generate the corresponding radical anion, which would irreversibly undergo cleavage of one of its carbon–iodine bonds to form the borylmethyl radical. The subsequent addition of the resulting radical to the carbon–carbon double bond of the boryl styrene would give rise to a benzylic radical that would engage in the cyclopropyl ring closure. Actual investigation was initiated with α-MIDA-boryl styrene 2a13 as a model alkene and 1 as the “carbene” precursor under illumination with blue LED lights (456 nm) at an ambient temperature (Table 1). Extensive optimization of the reaction conditions revealed that the combined use of Na2S2O3 as a terminal reductant and 2,6-di-tert-butyl-4-methylpyridine as a scavenger of acidic species with 5 mol% of 4CzIPN in MeCN led to the production of the desired diborylcyclopropane 3a in 67% NMR yield (500 MHz) with virtually complete diastereoselectivity after 10 h of stirring (entry 1). Other common solvents, such as dichloromethane and N,N-dimethylformamide (DMF), were not suitable and a considerable decrease in reactivity was observed (entries 2 and 3). Only a trace amount of 3a was obtained in the absence of Na2S2O3 presumably because concomitantly formed iodine acted as a quencher of the excited photocatalyst (entry 4), and Na2SO3 was found to be a less effective reductant than Na2S2O3 (entry 5). The addition of a base was beneficial for improving the chemical yield, and 2,6-di-tert-butyl-4-methylpyridine was superior to other representative organic and inorganic bases (entries 6–8). It should be noted that direct excitation of 1 by visible light irradiation appeared feasible, although the conversion was rather low (entry 9).14 The reaction efficiency slightly decreased when tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)- or tetrakis(3,6-di-bromo-9H-carbazol-9-yl)-IPN was used as the photocatalyst in place of 4CzIPN (entries 10 and 11).15 While none of the product formation was detected under dark conditions, white LEDs were a useful light source, but not as effective as blue LEDs (entries 12 and 13). Extending the reaction time also delivered improvements in the chemical yield (entry 14).
Table 1 Optimization of the borylcyclopropanation of 1-MIDA-boryl styrene 2a with diiodoborylmethane 1 under photoredox catalysisa

image file: c9qo00197b-u1.tif

Entry Modification of the standard conditions Yieldb (%)
a Standard conditions: The reaction was performed with 0.1 mmol of 2a and 0.5 mmol of 1 with 5 mol% of 4CzIPN, 0.3 mmol of 2,6-tBu2-4-Me-pyridine, and 0.5 mmol of Na2S2O3·5H2O in 5.0 mL of MeCN under irradiation with 456 nm LEDs for 10 h at ambient temperature (cooling with a fan). Diastereomeric ratio was determined by 1H NMR analysis (500 MHz) of crude aliquot to be >20[thin space (1/6-em)]:[thin space (1/6-em)]1. b NMR yield (500 MHz) was reported by use of 1,3,5-trimethoxybenzene as an internal standard. c Isolated yield is indicated in the parenthesis.
1 None 67
2 In CH2Cl2 18
3 In DMF Trace
4 Without Na2S2O3 Trace
5 Na2S2O3 → Na2SO3 0
6 Without 2,6-tBu-4-Me-pyridine 47
7 2,6-tBu2-4-Me-pyridine → 2,6-lutidine 66
8 2,6-tBu2-4-Me-pyridine → K2CO3 0
9 Without 4CzIPN 8
10 4CzIPN → 4CztBuIPN 58
11 4CzIPN → 4CzBrIPN 26
12 Without light 0
13 Blue LEDs → white LEDs 48
14 18 h 69 (58)c

With the optimal conditions in hand, we examined the scope of this borylcyclopropanation with a variety of α-MIDA-boryl styrenes (Table 2). The reactions with styrenes having an electron-donating substituent at the para or meta position of the aryl group afforded the products in moderate to good yields (entries 1–5). Incorporation of an electron-deficient aromatic substituents was also possible without detrimental effects on the reaction profile (entries 6–8). In addition, naphthyl and 3,4-methylenedioxyphenyl MIDA-borylethenes were well tolerated (entries 9 and 10).

Table 2 Substrate scope of the photocatalyzed borylcyclopropanationa

image file: c9qo00197b-u2.tif

Entry Ar (2) Yieldb (%) 3
a The reaction was performed with 0.1 mmol of 2 and 0.5 mmol of 1 with 5 mol% of 4CzIPN, 0.3 mmol of 2,6-tBu2-4-Me-pyridine, and 0.5 mmol of Na2S2O3·5H2O in 5.0 mL of MeCN under irradiation with 456 nm LEDs for 18 h at ambient temperature (cooling with a fan). Diastereomeric ratio was determined by 1H NMR analysis (500 MHz) of crude aliquot to be >20[thin space (1/6-em)]:[thin space (1/6-em)]1. b Isolated yield was reported.
1 4-MeOC6H4 (2b) 55 3b
2 3-MeOC6H4 (2c) 64 3c
3 4-MeC6H4 (2d) 65 3d
4 3-MeC6H4 (2e) 48 3e
5 4-tBuC6H4 (2f) 53 3f
6 4-ClC6H4 (2g) 45 3g
7 3-ClC6H4 (2h) 53 3h
8 4-FC6H4 (2i) 58 3i
9 2-Naphthyl (2j) 62 3j
10 3,4-Methylenedioxyphenyl (2k) 65 3k

To better understand this transformation, we prepared geometrically enriched β-deuterated boryl styrene dZ-2a from (E)-2-deuterio-1-bromostyrene16 and exposed it to the standard reaction conditions (Scheme 1). This experiment gave d-3a as a mixture of nearly equal amounts of two diastereomers with respect to the deuterium-bearing stereocenter, indicating that the olefin geometry of the starting styrene was not reflected in the stereochemistry of the product. We also confirmed that the diastereomeric ratio of the remaining dZ-2a was not changed. These observations allow us to exclude the possibility of a concerted cyclopropanation of a singlet-carbene intermediate and suggest that the present photocatalytic cyclopropanation proceeds in a stepwise manner.

image file: c9qo00197b-s1.tif
Scheme 1 Mechanistic insight.

The synthetic utility of the doubly borylated cyclopropane 3 possessing two differently protected boryl groups was demonstrated by submitting it to the oxidation reaction illustrated in Scheme 2.9 The pinacol boronate moiety of 3b was selectively converted into a hydroxyl group by simple treatment with magnesium monoperoxyphthalate hexahydrate (MMPP) in DMF and the corresponding alcohol 4 was obtained in good yield without erosion of the stereochemical integrity. 4 could be further modified through the procedure established for the transformation of MIDA-boronates,17 enhancing the versatility of this borylcyclopropanation protocol.

image file: c9qo00197b-s2.tif
Scheme 2 Selective oxidation of the pinacol-borate moiety.


In conclusion, we have developed a borylcyclopropanation of α-MIDA-boryl styrenes under visible-light photoredox catalysis, which proceeded with complete diastereocontrol and was applicable to a range of α-MIDA-boryl styrenes. The resulting doubly borylated cyclopropanes could serve as useful building blocks, as demonstrated by the selective oxidation of one of the two boryl groups.


Representative procedure for the borylcyclopropanation of 1-MIDA-boryl styrenes 2 with diiodoborylmethane 1 under photoredox catalysis

In a flame and vacuum dried test tube, 1-MIDA-boryl-1-phenyl-ethene (2a, 25.9 mg, 0.10 mmol), 2-(diiodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1, 196.9 mg, 0.50 mmol), 4CzIPN (3.9 mg, 0.005 mmol), 2,6-tBu2-4-Me-pyridine (61.6 mg, 0.30 mmol), and Na2S2O3·5H2O (79.1 mg, 0.50 mmol) were placed under argon atmosphere. After addition of MeCN (5.0 mL), evacuation of the tube followed by backfill with argon was conducted three times. The test tube was then illuminated with blue LED lights (456 nm) for 18 hours at ambient temperature with fans. (Fans are employed to maintain the temperature below 40 °C.) The reaction was quenched by adding a water (5.0 mL) and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The diastereomeric ratio of the product 3a was determined to be >20[thin space (1/6-em)]:[thin space (1/6-em)]1 by 1H NMR (500 MHz) analysis of the crude aliquot and relative stereochemistry of 3a was determined by the NOE experiment. Purification of the crude residue was performed by column chromatography on silica gel twice (hexane/ethyl acetate = 1[thin space (1/6-em)]:[thin space (1/6-em)]1 to 0[thin space (1/6-em)]:[thin space (1/6-em)]1 as eluent for the first purification, CH2Cl2/MeCN = 5[thin space (1/6-em)]:[thin space (1/6-em)]1 as eluent for the second one) to afford the diastereomerically pure product 3a in 58% yield (23.2 mg, 0.058 mmol). 3a: 1H NMR (500 MHz, (CD3)2CO) δ 7.42 (2H, d, J = 7.7 Hz), 7.19 (2H, t, J = 7.7 Hz), 7.11 (1H, t, J = 7.7 Hz), 4.15 (1H, d, J = 16.5 Hz), 3.97 (1H, d, J = 16.5 Hz), 3.92 (1H, d, J = 16.5 Hz), 3.09 (3H, s), 3.01 (1H, d, J = 16.5 Hz), 1.35 (1H, dd, J = 6.6, 3.0 Hz), 1.07 (1H, dd, J = 8.9, 3.0 Hz), 1.01 (6H, s), 0.77 (6H, s), 0.51 (1H, dd, J = 8.9, 6.6 Hz); 13C NMR (126 MHz, (CD3)2CO) δ 168.9, 168.1, 144.2, 132.2, 128.5, 126.2, 83.1, 63.6, 63.1, 46.5, 25.3, 24.8, 13.5, two carbon atoms were not detected due to quadrupolar broadening; 11B NMR (160 MHz, (CD3)2CO) δ 31.7, 11.0; IR (film) 2977, 1766, 1408, 1324, 1286, 1242, 1146, 1028, 1001, 865 cm−1; HRMS (ESI) Calcd for C20H27O6NB2Na+ ([M + Na]+) 422.1917. Found 422.1915.

Conflicts of interest

There are no conflicts to declare.


Financial support was provided by CREST-JST, Program for Leading Graduate Schools “Integrative Graduate Education and Research Program in Green Natural Sciences” in Nagoya University, WISE Program (Doctoral Program for World-leading Innovative & Smart Education) “Graduate Program of Transformative Chem-Bio Research” in Nagoya University, and Grants of JSPS for Scientific Research. TOhtani acknowledges JSPS for financial support.

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c9qo00197b

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