Metal-Free Radical Borylation of Alkyl and Aryl Iodides

Article abstract of DOI:10.1002/anie.201810782

A metal-free radical borylation of alkyl and aryl iodides with bis(catecholato)diboron (B₂cat₂) as the boron source under mild conditions is introduced. The borylation reaction is operationally easy to conduct and shows high functional group tolerance and broad substrate scope. Radical clock experiments and density functional theory calculations provide insights into the mechanism and rate constants for C-radical borylation with B₂cat₂ are disclosed.

Full text of DOI:10.1002/anie.201810782

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Accepted Article
Title: Metal-Free Radical Borylation of Alkyl and Aryl Iodides
Authors: Ying Cheng, Christian Mück-Lichtenfeld, and Armido Studer
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Metal-Free Radical Borylation of Alkyl and Aryl Iodides
Ying Cheng , Christian Mꢀck-Lichtenfeld[a][b], and Armido Studer*[a]
[
a]
Abstract: A metal-free radical borylation of alkyl and aryl iodides with
bis(catecholato)diboron (B cat ) as the boron source under mild
of alkyl halides.[2] The Ito group reported a similar reaction with
diboron using a CuCl/Xantphos catalyst and stoichiometric
2
2
t
[3]
conditions is introduced. The borylation reaction is operationally easy
to conduct and shows high functional group tolerance and broad
substrate scope. Radical clock experiments and density functional
theory calculations provide insights into the mechanism and rate
KO Bu. Fu reported borylation of various alkyl electrophiles with
a NiBr /N-
/pybox catalyst,[4] and Marder introduced a ZnCl
heterocyclic carbene catalyst system for the borylation of
unactivated alkyl halides.[5] Recently, Cook disclosed
MnBr /tetramethylethylenediamine-catalyzed borylation of alkyl
2
2
a
constants for C-radical borylation with B
2
cat
2
are disclosed.
2
halides using EtMgBr as a stoichiometric activator.[ However, all
these valuable methods require a transition metal catalyst, a
ligand and a stoichiometric amount of a base. To our knowledge,
metal and additive-free radical borylation of alkyl halides with
diborons is unknown.[7]
6]
Boronic esters are highly valuable synthetic precursors, since
the boronic ester moiety can be transformed into a wide range of
useful functional groups.[1] Therefore, methods that allow to
efficiently prepare alkyl and aryl boronates are demanded.
Arylboronates can be obtained from haloarenes and diborons
via reactive aryl radicals[8-13] (Scheme 1B). Along these lines,
Marder developed a zinc(II)-catalyzed borylation of aryl halides
using a stoichiometric base[8] and photoinduced aryl halide
[
9]
[10]
[11]
borylation was reported by Larionov , Li and Fu . Recently,
a pyridine-catalyzed radical borylation of aryl halides was
disclosed by Jiao.[12] We present herein mild radical borylation of
both
alkyl
and
aryl
iodides
with
commercial
bis(catecholato)diboron as the boron source (Scheme 1C).
We first explored the reaction of 1-iodooctane (1a) with
bis(catecholato)diboron (2a) to alkyl boronate 3a under blue LED
irradiation at ambient temperature using different solvents (Table
1).
Table 1: Optimization of the reaction conditions.[a]
Entry
1
n
2
2
2
2
2
2
2
2
4
4
Solvent
1,2-DCE
MeCN
THF
Yield [%]
2 2
Scheme 1. Borylation of alkyl and aryl halides with diboron reagents [B pin =
bis(pinacolato)diboron].
0
2
trace
trace
8
3
In recent years, various processes for transition metal
catalyzed borylation of alkyl halides with diborons to access alkyl
boronate esters have been developed (Scheme 1A).[2-6] Steel,
Marder, and Liu disclosed a CuCl/Xantphos-catalyzed borylation
4
MeOH
DMF
5
71
0
6[b]
7[c]
8[d]
9
DMF
DMF
0
DMF
7
[
a]
b]
Dr. Y. Cheng, Dr. C. Mꢀck-Lichtenfeld, Prof. Dr. A. Studer
Westfälische Wilhelms-Universität
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Dr. C. Mꢀck-Lichtenfeld
DMF
88
15
0[e]
1
DMF
[
a] Reaction conditions: 1a (0.2 mmol), 2a (n x 0.2 mmol), solvent (0.6 mL), 10
W blue LED, Ar, rt, 24 h; pinacol (0.8 mmol), NEt (0.7 mL), 1 h, isolated yields.
b] B pin was used. [c] B neo was used. [d] B (OH) was used. [e] In the dark.
[
3
Westfälische Wilhelms-Universität
Center for Multiscale Theory and Computation (CMTC)
Corrensstrasse 40, 48149 Münster (Germany)
[
2
2
2
2
2
4
Due to instability of n-octylcatecholborane, the crude product
was transesterified with pinacol and NEt to give 3a. In 1,2-
dichloroethane (1,2-DCE), borylation did not proceed and 1a was
Supporting information for this article is given via a link at the end of
the document.
3
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recovered (Table 1, entry 1). In acetonitrile or tetrahydrofuran
(
THF), trace amounts of 3a were detected (entries 2, 3), but in
methanol an encouraging 8% yield was obtained (entry 4).
Significant improvement of the yield to 71% was achieved by
using N,N-dimethylformamide (DMF)[14] (entry 5). Replacing
B
2
cat
glycolato)diboron (B
did not lead to any product formation (entries 6, 7). Using
tetrahydroxydiboron [B (OH) ] as the trapping reagent and
subsequent treatment with pinacol and magnesium sulfate, only
% of 3a was obtained (entry 8). Increasing the amount of B cat
2
2
by bis(pinacolato)diboron (B
2 2
pin ) or bis(neopentyl-
2
neo ) under otherwise identical conditions
2
2
4
7
2
to 4 equivalents led to a further improvement (88%, entry 9). A
control experiment in the absence of light irradiation proceeded in
low yield (entry 10).
Under optimized conditions, substrate scope was investigated.
Borylation of 3-methylbutyliodide (1b) to 3b proceeded in 80%
yield (Scheme 2). With 1-chloro-6-iodohexane (1c) containing
both an iodine and a chlorine atom, the borylation occurred
chemoselectively by replacing the I-atom (3c, 94%). The primary
alkyl iodide 1d bearing a perfluoroalkyl chain worked well (see 3d)
and an alkyl iodide containing a carbazole moiety participated to
provide 3e (70%). (2-Iodoethyl)benzene (1f) and 4-
(
iodomethyl)cyclohex-1-ene (1g) were also borylated in good
yields (91% and 82%). Alkynyl- (1h), nitrile- (1i), ester- (1j),
ketone- (1k), and aldehyde-functionalities (1l) are tolerated and
the products 3h-l were isolated in good yields (56-80%).
Borodeiodination of secondary alkyl iodides worked well, as
shown for 2-iodoheptane (1m) and 6-iodo-2-methylhept-2-ene
(
1n) to provide 3m and 3n in 91% and 89% yield. Iodides
containing cyclohexane, tetrahydropyran, Boc-protected
piperidine (Boc = tert-butoxycarbonyl), arene and phenyl alkyl
ether (1o-s) turned out to be good substrates for the borylation.
Compound 1t with both naphthyl and perfluorobutyl groups
performed well to give 3t in 86% yield. 1-Iodoadamantane (1u)
was smoothly converted to 3u (90%), but tert-butyliodide could
not be borylated under the standard conditions.
Scheme 2. Scope of alkyl iodides. Reaction conditions: 1a-u (0.2 mmol), 2a (0.8
mmol), DMF (0.6 mL), 10 W blue LED, Ar, rt, 24 h; pinacol (0.8 mmol), NEt (0.7
3
mL), 1 h, isolated yields. [a] 2 equiv of 2a was used.
We were very pleased to find that under the same conditions
aryl iodides can also be borylated (Scheme 3). However, as
compared to the alkyl iodides slightly lower yields are generally
achieved. Iodobenzene (4a) afforded phenyl pinacolboronate (5a,
61%) and iodoarenes 4b-g bearing para-substituents performed
well to give the aryl boronates 4b-g in 46-71% yield. Meta and
ortho-substituted aryl iodides 4h and 4i provided 5h and 5i in
good yields (73% each). Borylation of 1-iodonaphthalene (4j), 9-
iodophenanthrene (4k) and 3-iodothiophene (4l) was also
successful (5j-l). Our method, albeit less efficiently, is also
applicable to the preparation of vinyl boronates, as documented
by the borylation of 1-iodocyclohex-1-ene (5m, 32%).
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Scheme 4. Mechanistic experiments, isolated yields. [a] Yield was determined
1
by H NMR spectroscopy with 1,1,2,2-tetrachloroethane as the internal standard.
Scheme 3. Scope of aryl iodides. Reaction conditions: 4a-m (0.2 mmol), 2a (0.8
mmol), DMF (0.6 mL), 10 W blue LED, Ar, rt, 24 h; pinacol (0.8 mmol), NEt
3
(0.7
mL), 1 h, isolated yields.
The facts that light was required and that conditions are similar
to those reported by us and Aggarwal for alkyl radical
borylations[7a,7d,14a] indicated that these transformations are likely
radical in nature. We therefore carried out radical clock
experiments (Scheme 4). Cyclopropylmethyl iodide (6) gave
exclusively the ring opening product 7, but 6-Iodo-1-hexene (8)
reacted mainly to the uncyclized boronate 9a. Still, formation of
small amounts of the cyclized product 9b indicated that radicals
are involved. Moreover, this experiment revealed that trapping of
2 2
a primary C-radical with B cat to be very fast. Successful
cyclizing borylation of aryl iodide 10 to 11b further supported the
radical mechanism. Such cyclizing borylations cannot be
achieved using ionic type borylation processes.
The radical clock experiment with iodide 8 was chosen to
estimate the rate constant for trapping of a primary C-radical with
2 2
B cat . To this end, a series of reactions with 6-iodo-1-hexene (8)
were conducted varying the concentration of diboron 2a. Using
the ratio of non-cyclized 9a to cyclized product 9b at a given
diboron concentration and considering the known rate constant
Scheme 5. Proposed mechanism.
Based on these experiments and previous results,[14a]
plausible mechanism is depicted in Scheme 5. Initiation proceeds
via light mediated C−I bond homolysis of iodide 1 to generate the
2 2
alkyl/aryl radical A which adds to B cat to give the radical B. We
a
2.3 x 10 s at 25 °C[15]) for the 5-exo-cyclization of the 5-hexenyl
radical, the second order rate constant for the borylation of the
primary C-radical derived from 8 with B cat was estimated to be
.8 x 10 M •s (for details, see the Supporting Information (SI)).
5
-1
(
2
2
6
-1 -1
3
found that for radicals B derived from secondary alkyl radicals,
In analogy, we estimated the rate constant for trapping of the aryl
radical derived from 1-(3-butenyl)-2-iodo-benzene (10) with
B−B bond homolysis is higher in energy than degenerate B−C
2 2
bond homolysis to give B cat
and the starting radical A.[14a] The
7
-1 -1
B
B
2
cat
cat
2
to lie at 7.4 x 10 M •s . Hence, alkyl radical trapping with
unusual large solvent effect can readily be understood involving
the solvent. Hence, the radical B is trapped by DMF in an
exothermic process to give C, best described by a weak B−B one
electron σ-bond,[14] which readily homolyzes to give product
boronate 3 along with the DMF−complexed boryl radical D/E. The
2
2
is a very fast process and its rate constant lies in the region
of that for the reduction of a primary alkyl radical with Bu
However, the rate constant for the reaction of B cat with the aryl
SnH.[15]
3
2
2
radical derived from 10 is around one order of magnitude smaller
than that of the tin hydride reduction of a phenyl radical.[16] Likely,
steric effects exerted by the ortho-substituent and the bulky
diborane play a role. Notably, kinetic data on radical borylation
are currently unavailable in the literature.
[17]
chain is closed by an I−atom transfer reaction of the iodide 1
via F to eventually give G and radical A.
The I-atom transfer was further investigated using DFT
calculations (see SI for details). We looked at the spin density
plots of the DMF-complexed boryl radical D and found highest
spin density at the C-atom and only little spin at the boron atom
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(
Figure 1). Therefore, the complexed boryl radical D is best Acknowledgements
described by resonance structure E, which certainly also
influences its reactivity. In fact, I-transfer from CH I to the C-atom
3
We thank the European Research Council (ERC Advanced Grant
agreement No. 692640) for financial support.
in E to give F proceeds via a low barrier (9.5 kcal/mol), whereas
the barrier for I-transfer to the B-atom leading directly to G occurs
at significantly higher barrier (18.3 kcal/mol) (Figure 2). In a polar
solvent, however, iodide F is not stable and easily isomerizes (ΔG
Keywords: borylation • metal-free • alkyl Iodides • aryl iodides •
radical process
=
3
-8 kcal/mol) to the zwitterion G. The barrier in vacuum is only
.7 kcal/mol, but becomes negative when solvation energies are
included. Thus, F is most likely not a minimum structure under
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isosurface value: 0.01 a.u.).
1685.
In summary, a method for metal and additive-free borylation
of alkyl and aryl iodides was introduced. The reaction proceeds
under very mild conditions in good to excellent yields with a broad
range of alkyl and aryl iodides. As compared to the reactions with
aryl iodides, alkyl iodides generally lead to higher yields. Radical
clock experiments and DFT calculations support the suggested
radical chain mechanism.
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3
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(
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Layout 2:
COMMUNICATION
Y. Cheng, C. Mꢀck-Lichtenfeld, A.
Studer*
Page No. – Page No.
Metal-free Radical Borylation of Alkyl
and Aryl Iodides
I to B: A metal and additive-free radical borylation using a commercial diboron
reagent is introduced. Alkyl and aryl iodides are borylated under very mild
conditions in good to excellent yields.
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