Radical Aryl Migration from Boron to Carbon.

Radical aryl migration reactions represent a unique type of organic transformations that involve the intramolecular migration of an aryl group from a carbon or heteroatom to a C- or heteroatom-centered radical through a spirocyclic intermediate. Various elements, including N, O, Si, P, S, Sn, Ge, and Se, have been reported to participate in radical aryl migrations. However, radical aryl migration from a boron center has not been reported to date. In this communication, radical 1,5-aryl migration from boron to carbon in aryl boronate complexes is presented. C-radicals readily generated through radical addition onto alkenyl aryl boronate complexes are shown to engage in 1,5-aryl migration reactions to provide 4-aryl-alkylboronic esters. As boronate complexes can be generated in situ by the reaction of alkenylboronic acid esters with aryl lithium reagents, the aryl moiety is readily varied, providing access to a series of arylated products starting from the same alkenylboronic acid ester via divergent chemistry. Reactions proceed with high diastereoselectivity under mild conditions, and also the analogous 1,4-aryl shifts are feasible. The suggested mechanism is supported by DFT calculations.

Radical aryl migration reactions are valuable transformations involving the intramolecular translocation of an aryl group from a carbon or heteroatom to a radical center through a three-, four-, five-, or six-membered spirocyclic intermediate or transition state.[1−6] Various synthetic methods have been developed for C–C σ-bond formation through radical 1,2-,[7−13] 1,3-,[14,15] 1,4-,[16−24] and 1,5-aryl[19,24−26] migration. Such reactions are not restricted to the “all-carbon” case, and various elements, such as N,[27,28] O,[29−31] Si,[32−36] P,[37] S,[38−46] Sn,[47] Ge, and Se,[39] have been reported as origins in radical aryl migrations (Scheme , a). Although intensively studied and applied in synthesis, radical aryl migration generally[19−23,26,45,46] suffers from the need to preinstall the transferable aryl group onto the substrate. Considering the aryl translocation step, only one aryl migration product is accessible from the functionalized starting material. In that regard, a divergent approach would be desirable.

Scheme 1

Radical Aryl Migrations

Organoboron compounds are important intermediates,[48−51] and their radical chemistry has gained great attention recently.[52,53] Surprisingly, aryl migration from a boron center to a C-radical has not yet been reported. Considering an sp2-hybridized boron compound bearing an aryl moiety, it is more likely that the whole boron group migrates rather than the aryl group, due to the interaction of the empty p orbital at boron with the C-radical. Indeed, 1,2-boron shifts of β-boryl radicals of type 1 were recently reported by Aggarwal’s group[54] and us[55] (Scheme , b-i). We envisioned that aryl migration from sp3 boron intermediate 2 would be feasible, as the p orbital of boron is no longer vacant, rendering a radical–aryl interaction possible (Scheme , b-ii). Accordingly, we assumed that boronate complexes should be eligible substrates for radical aryl migration from an sp3 boron center, as they can be easily generated by the reaction of organoboronic acid esters with organometallic reagents.[56−59]

Radical pan> class="Chemical">chemistry on boronate complexes is an emerging area in synthesis.[59] For example, radical-induced 1,2-aryl migrations of boronate complexes to access benzylic boronic acid esters 5 in radical/polar crossover processes were reported by us,[60−62] Aggarwal,[63,64] and Renaud.[65] In such transformations, the α-C-radical anion intermediate 3 is oxidized by single electron transfer (SET) to generate the zwitterion 4 (Scheme , c).[60] An ionic 1,2-aryl migration eventually provides the product 5. We supposed that the interaction of a distal C-radical and an aryl group in a boronate complex[66] would allow for an unprecedented radical aryl migration (Scheme , b-ii). First, the reaction of an alkenylboronic acid ester 6 with an aryl lithium compound will give boronate complex 7 (Scheme , d). Radical addition of R• to 7 will generate the distal radical anion 9. Intramolecular radical 1,5-aryl migration should lead to the radical anion 10, which could finally be SET oxidized to the targeted product 8 by the radical precursor R–X sustaining the chain reaction. Initiation could be achieved by LED irradiation of the corresponding halide R–X. As the boronate complex 7 is formed in situ and various aryl lithium reagents can be accessed by lithium/halogen exchange reaction of aryl halides and n-BuLi or deprotonation of heteroarenes with a strong base, various arylated products could be formed from a single starting alkenylboronic acid ester in a divergent manner. Moreover, also the radical precursor R–X should be varied, further enlarging the number of potential products from the same substrate.

Considering the prevalenpan> class="Chemical">ce of the CF3 group in pharmaceutical compounds and bioactive molecules,[67−69] we first tested the CF3-radical addition induced aryl migration reaction of boronate complex 7a,[7,9,16,43,70−74,20,42,75−78] which was in situ generated by reaction of pinacol ester 6a and PhLi. Pleasingly, upon 365 nm LED light irradiation of a solution of 7a and CF3I in acetonitrile, 8a was obtained in 77% yield (Table , entry 1). With photocatalysts as smart initiators,[79] lower yields were noted (66–72%, entries 2–5), and 465 nm LED irradiation in the absence of a catalyst provided 8a in a lower yield (42%, entry 6). Decreasing the reaction temperature to −20 °C also provided a worse result (64%, Table , entry 7). In all cases, the PhBpin (3–14%) was identified as the side product, which was likely formed by direct SET oxidation of 7a by oxidizing species such as the CF3-radical or CF3I. No product was obtained upon conducting the reaction in the dark (Table , entry 8). Notably, the corresponding catechol boronic ester did not engage in the phenyl migration reaction.

Table 1

Reaction Optimizationa

entry	variation from the standard condition	8a	Ph-Bpin	conv
1	365 nm LED (3 W)	77% (71%b)	4%	100%
2	fac-Ir(ppy)3, 465 nm LED (3 W)	72%	8%	100%
3	Ru(bpy)3(PF6)2, 465 nm LED (3 W)	66%	13%	100%
4	rhodamine B base, 465 nm LED (3 W)	72%	11%	100%
5	eosin Y, 465 nm LED (3 W)	68%	14%	100%
6	no photo catalyst, 465 nm LED (3 W)	42%	3%	100%
7	–20 °C	64%	4%	100%
8	no light irradiation	0%	0%	100%

Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL), conversion determined based on recovered 6a, yields determined by GC analysis with n-tetradecane as the internal standard.

Isolated yield. Pin = pinacolato.

Table 2

Variation of the Aryl Lithium Reagenta

Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL).

Reaction conducted with nonafluorobutyl bromide (1.5 equiv).

Isolated yield. Pin = pinan class="Chemical">colato.

Reactionpan>s conducted on a 0.2 mmol scale in CH3CN (2 mL).

Reactionpan> conducted with nonafluorobutyl bromide (1.5 equiv).

With the optimized reaction condition in hand, we first tested the scope with respect to the aryl lithium reagent, keeping 6a as the acceptor and CF3I as the C-radical precursor (Table ). Aryl lithium reagents were generated in situ by lithium/halogen exchange of the corresponding aryl iodides/bromides and n-butyllithium. Boronate complexes derived from para-substituted aryl lithium reagents reacted with moderate to good yields to the corresponding 4-arylalkyl boronic esters (57–86%). Various para-substituents are tolerated, such as methyl (8b), tert-butyl (8c), phenyl (8d), methoxy (8e), benzyloxy (8f), trimethylsilyl (8g), iodide (8h), and fluoride (8i). For the reaction of 7h, 7% hydrodeiodination product 8a was formed. Notably, both para-bromo and para-chloro phenyl lithium provided 8h as the major product, likely derived from a halogen/iodide exchange in the targeted products (see SI for detailed discussion). Fluoride/iodide exchange was detected by crude GC analysis for the reaction of the F-substituted substrate 7i (5% 8h). Meta-substituted aryl lithium compounds were found to be eligible aryl donors, providing the products 8j–m in 57–69% yield. Hydrodeiodination (4% 8a) was also observed for 7m. Migration of the ortho-tolyl group was less efficient (8n, 30%), likely for steric reasons. Reactions of boronate complexes generated with 3,5-dimethylphenyl lithium (7o), 3-naphthyl lithium (7p), and benzo[d][1,3]dioxol-5-yl lithium (7q) also worked (45–57%). Heteroarenes such as dibenzofuran (8r), benzothiophene (8s), dibenzothiophene (8t), and quinoline (8u) are compatible with the reaction conditions.

We then studied the scope with respect to the alkenylboronic acid pinacol ester and also varied the C-radical precursor (Table ). These experiments were mostly conducted with para-tert-butylphenyl lithium as the aryl donor. The 2,2-diethyl and 2,2-dipropyl alkenyl boronic esters 6v and 6w delivered the trifluoromethylarylated products 8v and 8w in 85% and 74% yield, respectively. Substrates 6x–6aa, bearing five- to seven-membered rings, also displayed good reactivity (76–79%). The boronic ester 6ab, bearing a stereocenter, afforded the product 8ab in 59% yield with good diastereoselectivity (dr = 5.8:1). The stereochemical outcome of the aryl migration will be discussed below. For the 2-isopropylalkenyl boronic ester 6ad, the yield was lower (50%), but the diastereoselectivity was very high (17:1).

Table 3

Substrate Scope: Varying the Alkylboronic Acid Pinacol Ester and Carbon Radical Precursora

Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL).

Corresponding alkyl iodide (0.3 mmol, 1.5 equiv) was used.

Corresponding alkyl bromide (0.3 mmol, 1.5 equiv) was used.

Relative configuration could not be assigned.

Products isolated as corresponding alcohols after treatment with H2O2/NaOH.

Reactionpan>s conducted on a 0.2 mmol scale in CH3CN (2 mL).

Corresponpan>ding pan> class="Chemical">alkyl iodide (0.3 mmol, 1.5 equiv) was used.

Corresponpan>ding pan> class="Chemical">alkyl bromide (0.3 mmol, 1.5 equiv) was used.

Relative n class="Chemical">conpan>figurationpan> n class="Chemical">could not be assigned.

It is obvious that the aryl migration is slower for substrates lacking the two geminal substituents in the bapan> class="Chemical">ckbone (Thorpe Ingold effect). In these cases, iodine atom transfer outcompeted the aryl migration. To slow down the I atom transfer, we switched to the nonafluorobutyl bromide as the C-radical precursor. Pleasingly, the yield could be improved to 76% and 8ae was obtained with complete stereoselectivity. Hence, switching from CF3I to C4F9Br not only improved the yield but also led to an improved diastereoselectivity. Benefiting from these effects, 8ac and 8af were isolated in 53% and 59% yield and high diastereoselectivity (>20:1). As 1,6-aryl migration was not efficient, 1,5-aryl migration product 8ag (50%) was the only isolated product with excellent diastereoselectivity (dr > 20:1) starting from the linear internal alkene 6ag (E/Z = 3:1). As expected for the cyclic system 6ah, an excellent diastereoselectivity was noted for the aryl migration (see 8ah). Yield was low, likely due to non-diastereoselective initial addition of the C4F9-radical to the substituted cyclopentene. After having shown that stereoinduction can be high for acceptors with a chirality center in the backbone, we studied the aryl migration in the chiral boronate complex 7ai bearing a chirality center at the diol moiety of the boronic ester. 7ai was generated in diastereoisomerically pure form[80] from alkenylboronic acid (1S,2S,3R,5S)-(+)-pinanediol ester 6ai and 4-t-BuC6H4Li. Reaction with CF3I afforded 8ai in 64% yield but moderate diastereoselectivity (71:29).

Aryl migration to a tertiary C-radical is not effipan> class="Chemical">cient, likely for steric reasons (see 8aj). We found a substituent in the backbone that renders the substrate conformationally less flexible to be important for getting acceptable yields. Thus, the unsubstituted boronic ester 6ak provided the migration product 8ak in 3% yield only. We also tested whether radical 1,4-aryl migration is feasible, by studying the lower homologues 6al and 6am. Both reactions worked, and as expected, a methyl substituent in the backbone increasing rigidity of the system improves the yield (8al–8am). However, as compared to the 1,5-aryl migration, the corresponding 1,4-translocation is far less efficient.

Other perfluoroalkyl halides also performed well in the radical addition/1,5-aryl migration sequence using acceptor 6a and 4-t-BuC6H4Li as the reaction partners. Hence, pentafluoroethyl iodide (8ao, 74%), heptafluoropropyl iodide (8ap, 64%), perfluorohexyl bromide (8an, 68%), and perfluorooctyl bromide (8aq, 75%) engaged in this cascade. Less electrophilic alkyl halides reacted with significantly lower efficiencies (14–43% yield, 8ar–8au).

To document the synpan>thetipan> class="Chemical">c value of the method, various follow-up transformations on aryl migration products were conducted (Scheme ). Oxidation of the C–B bond in 8ad and esterification provided the ester 11 with overall 57% yield. X-ray structure analysis on 11 showed that the aryl and isopropyl groups in the backbone are anti to each other, which agrees with the relative configuration of the major aryl migration isomer deduced by DFT calculations (see below). Matteson homologation[50,81] of 8v afforded the boronic ester 12 (53%). Oxidative coupling of 8x with 2-thiophenyl lithium gave 13 (68%),[82] and oxidative amination[83] of the C–B bond in 8y was achieved using standard protocols (14, 57%). Insertion of an isopropyl moiety into the C–B bond in 8c was realized applying a radical homologation sequence (15, 50%).[62]

Scheme 2

Follow-up Chemistry

a. (1) H2O2/NaOH in THF/H2O, 0 °C, then rt; (2) DMAP, DCC, 6-bromo-2-naphthoic acid; b. CH2Br2, BuLi; c. 2-thiophenyllithium, then NBS; d. BCl3 in CH2Cl2, then BnN3; e. isopropyl lithium, then CF3I in CH3CN/DMSO (10:1), 365 nm (3 W).

a. (1) H2O2/pan> class="Chemical">NaOH in THF/H2O, 0 °C, then rt; (2) DMAP, DCC, 6-bromo-2-naphthoic acid; b. CH2Br2, BuLi; c. 2-thiophenyllithium, then NBS; d. BCl3 in CH2Cl2, then BnN3; e. isopropyl lithium, then CF3I in CH3CN/DMSO (10:1), 365 nm (3 W).

To get a better picture on the mepan> class="Chemical">chanism of the aryl migration reaction, the cascade was investigated by DFT (for details, see the SI). For the 1,5-aryl migration in the radical anion 9a (R = CF3, Ar = Ph, R′ = 2,2-Me,Me), we find a transition structure with chair conformation, in which the CH2Rf group attains an equatorial position (Figure ). The low barrier (10.9 kcal/mol) agrees with the facile transformation and can be rationalized with the spin delocalization in the aryl ring. In the intermediate radical anion then formed, the B atom/aryl interaction remains (see the SI). The subsequent SET-oxidation terminates the aryl translocation. The prevalent formation of anti products with a chiral precursor (e.g., 8ad, R′ = i-Pr,H) is qualitatively confirmed by a barrier that is 0.5 kcal/mol lower than that of the syn pathway. This difference is determined by the equatorial position of the isopropyl group in the anti transition structure, which is axial in the syn TS (Figures S3–S5).

Figure 1

Transition structure (PBE0-D3/def2-TZVP) of Ph migration in 9a. Spin density (ρα–ρβ) isosurface at ρSD = 0.005 au (PW6B95-D3/def2-TZVP).

Transition strun class="Chemical">cture (PBE0-D3/def2-TZVP) of Ph migrationpan> in 9a. Spin density (ρα–ρβ) isosurfapan> class="Chemical">ce at ρSD = 0.005 au (PW6B95-D3/def2-TZVP).

In summary, radical aryl migration from pan> class="Chemical">boron in boronate complexes to carbon was introduced as an efficient route for arylation of secondary alkyl radicals that are generated by perfluoroalkyl radical addition onto alkenyl boronate complexes. These complexes derive from boronic esters by addition of aryl lithium reagents. The migrating aryl moiety is readily varied upon changing the aryl lithium reagent allowing for divergent chemistry. The 1,5-aryl shift occurs with high diastereoselectivity. The cascade also works on the lower homologous alkenylboronic esters comprising a 1,4-aryl migration step, albeit less efficiently. The potential of the method was convincingly documented by a series of valuable follow-up transformations.