Radical Aryl Migration from Boron to Carbon

Article abstract of DOI:10.1021/jacs.1c04217

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 generatedin situby 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.

Full text of DOI:10.1021/jacs.1c04217

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Radical Aryl Migration from Boron to Carbon
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Dinghai Wang, Christian Muck-Lichtenfeld, Constantin G. Daniliuc, and Armido Studer*
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ABSTRACT: 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 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 trans-
formations, the α-C-radical anion intermediate 3 is oxidized
by single electron transfer (SET) to generate the zwitterion 4
(Scheme 1, 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 complex66
would allow for an unprecedented radical aryl migration
(Scheme 1, b-ii). First, the reaction of an alkenylboronic acid
ester 6 with an aryl lithium compound will give boronate
complex 7 (Scheme 1, 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.
adical aryl migration reactions are valuable trans-
Rformations 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-aryl19,24−26
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 1, a). Although intensively
studied and applied in synthesis, radical aryl migration
generally19−23,26,45,46 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.
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 group54 and
us55 (Scheme 1, 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 1, 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
Received: April 22, 2021
Published: June 20, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/jacs.1c04217
J. Am. Chem. Soc. 2021, 143, 9320−9326
9320

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a
Scheme 1. Radical Aryl Migrations
Table 1. Reaction Optimization
variation from the standard
Ph-
entry
1
condition
8a
Bpin
conv
365 nm LED (3 W)
77%
(71% )
4%
100%
b
2
3
fac-Ir(ppy)3, 465 nm LED (3 W)
Ru(bpy)3(PF6)2, 465 nm LED (3
W)
72%
66%
8%
13%
100%
100%
4
rhodamine B base, 465 nm LED (3 72%
W)
11%
100%
5
6
eosin Y, 465 nm LED (3 W)
no photo catalyst, 465 nm LED (3 42%
W)
68%
14%
3%
100%
100%
7
8
−20 °C
no light irradiation
64%
0%
4%
0%
100%
100%
a
Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL),
conversion determined based on recovered 6a, yields determined by
b
GC analysis with n-tetradecane as the internal standard. Isolated
yield. Pin = pinacolato.
a
Table 2. Variation of the Aryl Lithium Reagent
Considering the prevalence 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 1, 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 temper-
ature to −20 °C also provided a worse result (64%, Table 2,
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 2, entry 8). Notably, the corresponding
catechol boronic ester did not engage in the phenyl migration
reaction.
a
Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL).
Reaction conducted with nonafluorobutyl bromide (1.5 equiv).
b
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 2). Aryl lithium reagents were generated in situ by
lithium/halogen exchange of the corresponding aryl iodides/
bromides and n-butyllithium. Boronate complexes derived
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Communication
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% hydro-
deiodination 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.
Table 3. Substrate Scope: Varying the Alkylboronic Acid
Pinacol Ester and Carbon Radical Precursor
a
We then studied the scope with respect to the alkenylbor-
onic acid pinacol ester and also varied the C-radical precursor
(Table 3). 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 diastereose-
lectivity was very high (17:1).
It is obvious that the aryl migration is slower for substrates
lacking the two geminal substituents in the backbone (Thorpe
Ingold effect). In these cases, iodine atom transfer out-
competed 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 stereo-
induction 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 form80 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).
a
Reactions conducted on a 0.2 mmol scale in CH3CN (2 mL).
Corresponding alkyl iodide (0.3 mmol, 1.5 equiv) was used.
b
c
Corresponding alkyl bromide (0.3 mmol, 1.5 equiv) was used.
d
e
Relative configuration could not be assigned. Products isolated as
corresponding alcohols after treatment with H2O2/NaOH.
Aryl migration to a tertiary C-radical is not efficient, 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
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Communication
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, penta-
fluoroethyl 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).
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).
To document the synthetic value of the method, various
follow-up transformations on aryl migration products were
conducted (Scheme 2). Oxidation of the C−B bond in 8ad
= 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).
a
Scheme 2. Follow-up Chemistry
In summary, radical aryl migration from 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 com-
plexes. 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.
a
a. (1) H2O2/NaOH in THF/H2O, 0 °C, then rt; (2) DMAP, DCC,
n
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).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04217.
■
sı
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 homologation50,81 of 8v afforded the boronic ester
12 (53%). Oxidative coupling of 8x with 2-thiophenyl lithium
gave 13 (68%),82 and oxidative amination83 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
Experimental details and characterization data, NMR
spectra of new compounds, DFT calculations, X-ray data
(PDF)
Accession Codes
CCDC 2078808 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
To get a better picture on the mechanism 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 1). 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′
AUTHOR INFORMATION
Corresponding Author
■
Armido Studer − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität, 48149 Munster, Germany;
̈
orcid.org/0000-0002-1706-513X; Email: studer@uni-
muenster.de
Authors
Dinghai Wang − Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität, 48149 Munster, Germany;
orcid.org/0000-0002-9863-8031
̈
9323
https://doi.org/10.1021/jacs.1c04217
J. Am. Chem. Soc. 2021, 143, 9320−9326

Journal of the American Chemical Society
Christian Muck-Lichtenfeld − Organisch-Chemisches Institut,
pubs.acs.org/JACS
Communication
catalyzed one-pot trifluoromethylation/aryl migration/carbonyl for-
mation with homopropargylic alcohols. Angew. Chem., Int. Ed. 2014,
53, 7629−33.
̈
Westfälische Wilhelms-Universität, 48149 Munster,
̈
Germany; orcid.org/0000-0002-9742-7400
(17) Thaharn, W.; Soorukram, D.; Kuhakarn, C.; Tuchinda, P.;
Reutrakul, V.; Pohmakotr, M. Radical Cyclization/ipso-1,4-Aryl
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propanoylbicyclo[3.3.0]octanes. Angew. Chem., Int. Ed. 2014, 53,
2212−2215.
Constantin G. Daniliuc − Organisch-Chemisches Institut,
Westfälische Wilhelms-Universität, 48149 Munster,
̈
Germany; orcid.org/0000-0002-6709-3673
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04217
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Long-Distance Aryl Migration from Carbon Center to Nitrogen
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Alexander von Humboldt Foundation
(postdoctoral fellowship to D.W.) and the European Research
Council (ERC) (advanced grant agreement no. 692640) for
supporting this work.
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