Photoinduced NaI-Promoted Radical Borylation of Alkyl Halides and Pseudohalides

Article abstract of DOI:10.1002/cjoc.202100115

A method for photoinduced NaI-promoted radical borylation of aliphatic halides and pseudohalides with bis(catecholato)diboron (B₂cat₂) as the boron source is introduced. The borylation reaction is operationally simple and shows high

Full text of DOI:10.1002/cjoc.202100115

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Title: Photoinduced NaI-Promoted Radical Borylation of Alkyl Halides and
Pseudohalides
Authors: Chenglan Wang, Lu Zhou, Kai Yang, Feng Zhang, and Qiuling Song *
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Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Photoinduced NaI-Promoted Radical Borylation of Alkyl Halides
and Pseudohalides
Chenglan Wang,a Lu Zhou,b Kai Yang,b Feng Zhang,b and Qiuling Song *, a, b, c
a Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou,
Zhejiang 310000 (China)
b Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University Fuzhou,
Fujian, 350108 (China)
c Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University 668 Jimei Boulevard,
Xiamen, Fujian, 361021 (China)
Keywords
Alkylboronate | Borylation | Radical | Metal-catalyst free | Aliphatic halide
Main observation and conclusion
A method for photoinduced NaI-promoted radical borylation of aliphatic halides and pseudohalides with bis(catecholato)diboron (B2cat2)
as the boron source is introduced. The borylation reaction is operationally simple and shows high functional group tolerance and broad
substrate scope. Preliminary mechanistic studies suggest that the reaction proceeds through SN2-based radical-generation strategy.
Comprehensive Graphic Content
N
DMF
NaI
O
O
O
O
O
+
B
B
R
R
B B
R
X
or
O
O
O
=
Br,
Cl,
OMs)
(X
O
O
examples
O
Bpin
Bpin
Bpin
Bpin
=
=
=
=
X
OMs
X
91%
X
Br 80%
,
X
Br 73%
,
Cl
,
,
41%
mmol,
63%)
from
(5
naproxen
O
Bpin
N
Bpin
O
Cl
H
H
O
N
S
H
X
BMIDA
O
H
O
=
=
=
OMs
X
91%
X
36%
52%
,
OMs
OMs
,
,
acid
from lithocholic
from
from idometacin
probenecid
*E-mail: qsong@hqu.edu.cn
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Supporting Information
Chin. J. Chem. 2021, 39, XXX－XXX©
2021
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CAS,
Shanghai,
&
WILEY-VCH
GmbH
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Running title
Chin. J. Chem.
in DMF (0.2 M) at ambient temperature under irradiation of blue
LEDs, alkylboronate 3a was obtained in 90% yield from benzyl bro-
mide (1a) (Table 1, entry 1). Control experiments established that in
the absence of light irradiation or NaI, the reaction proceeded in
low yields (entries 2 and 3). In the absence of light irradiation and
NaI, only trace amounts of the borylation product 3a were observed
(entry 4). Switching the solvent from DMF to the DMA slightly low-
ered the reaction efficiency (entry 5), while further solvent screen-
ing (MeCN, CH2Cl2) did not lead to the desired product 3a (entries
6 and 7). Other boron sources were evaluated as well, such as B2pin2
(bis(pinacolato)diboron) and B2(OH)2 ((dihydroxyboranyl)boronic
acid), both of them did not render any product formation under the
identical conditions (entries 8 and 9).
Background and Originality Content
Alkylboronates are versatile synthetic building blocks due to the
fact that the C-B bond is readily transformed into a great variety of
useful functional groups.[1] Therefore, the construction of alkyl-
boronates is the subject of substantial synthetic efforts.[2]
Classical approaches to prepare alkylboronates include hydrob-
oration of alkenes[3] and electrophilic substitution of suitable boron
compounds with organometallic reagents.[4] Organohalides are
commercially abundant, with diverse structures and stable proper-
ties. They are commonly used as raw materials in organic synthe-
sis.[5] In the past several years, numerous novel strategies for con-
structing C-B bonds from alkyl halides with diboron reagents have
emerged. Significant progress on transition-metal-catalyzed boryla-
tion of alkyl halides has been achieved by Marder,[6] Liu,[7] Ito,[8] Fu[9]
and Cook[10] and many others.[11] However, these highly efficient
methods inevitably use transition-metals, ligands and bases. Re-
cently, photoinduced radical borylation reaction has become a
powerful platform for the synthesis of alkylboronates.[12] For exam-
ple, in 2018, Studer group reported a radical borylation of alkyl io-
dides with B2cat2 (bis(catecholato)diboron) as the boron source
(Scheme 1a).[13] Subsequently, Melchiorre et al. reported a visible-
light-mediated organocatalytic system for the synthesis of alkyl-
boronates (Scheme 1b).[14] In addition, the base-promoted radical
borylations of alkyl halides were developed by Mo[15] and Jiao
(Scheme 1c),[16] respectively. Despite the clear improvement, these
methods still require highly reactive and unstable iodide derivatives
or benzylic and allylic compounds, while the transition-metal-free
borylation of alkyl chlorides or pseudohalides are rarely reported.
Therefore, simple and reliable synthetic routes for the synthesis of
alkylboronates from less reactive alkyl halides or pseudohalides, es-
pecially alkyl chlorides in the absence of transition-metal catalysts
are still worth exploring.
Table 1 Optimization studiesa
NaI
DMF,
1.
2.
(0.5 equiv),
blue LEDs, 36 h
Br
+
cat2
B2
Bpin
equiv)
overnight
(2
pinacol (4 equiv),
1a
3a
Entry
Deviation from the standard conditions
none
Yield of 3a ( % )b
1
2
3
4
5
6
7
8
9
90
28
dark
no NaI
34
dark and no NaI
5
DMA instead of DMF
MeCN instead of DMF
CH2Cl2 instead of DMF
B2pin2 instead of B2cat2
B2(OH)2 instead of DMF
85
NR
NR
NR
trace
Herein, we report a visible-light-mediated catalytic system for
the synthesis of alkylboronic acid derivatives from alkyl chlorides,
bromides and mesylates with commercially accessible bis(cate-
cholato)diboron as the boron source. This strategy demonstrated
good functional group tolerance for rapid access to various alkyl-
boronates.
a Isolated yields. b Reaction conditions: 1a (0.2 mmol), NaI (0.1mmol), B2cat2
(2) (0.4 mmol), DMF (0.5 mL), blue LEDs, Ar, rt, 36 h; then, pinacol (4 equiv),
rt, overnight.
With the optimized reaction conditions in hand, we examined
the generality of this radical borylation (Table 2). Previous methods
worked well with alkyl iodides and bromides, so this radical boryla-
tion of alkyl chlorides was firstly investigated. Since benzyl pinacol
esters are unstable on silica gel, leading to varying yield loss during
the purification process,[17] and methyliminodiacetyl (MIDA) boro-
nate showed some advantages in terms of stability and ease of pu-
rification, so we preferentially used MIDA as chelating agents for
boron. Benzyl chlorides (1c, 1d, 1e) were also tolerated, and the
substituent position on benzene ring has no obvious influence on
the efficiency of this transformation. Meanwhile, the substrates
with an electron-rich group (1f, 1g, 1h, 1i) also provided moderate
yields. Gratifyingly, our system displayed outstanding selectivity:
aryl fluoride (1j), aryl bromide (1k), and aryl iodide (1l, 1m) were all
tolerated and only the desired benzylboron products were ob-
tained. High conversions and excellent yields were obtained for the
substrates with electron-withdrawing group, such as -CF3 (1n) and
-OCF3 (1o). Naphthyl-chlorides were borylated under the standard
conditions with excellent yields (1p-1q). Olefin was compatible in
our system and only product 1r was obtained in 73% yield while
leaving C-C double bond intact. Moreover, we were very pleased to
find that when the amount of NaI was increased, the non-benzylic
primary alkyl bromides (1s-1u) can also smoothly undergo this rad-
ical borylation to deliver the corresponding products 3s-3u in mod-
erate to good yields (56-80%).
Scheme 1 Photoinduced borylation of alkyl (pseudo)halides
of alkyl iodides
(a) Borylation
Alkyl
cat2
B2
DMF, blue LEDs
,
B
I
Alkyl
of alkyl
(b) Organocatalytic borylation
(pseudo)halides
DMF, blue LEDs
X
B
Het
Het
cat2
B2
,
dithiocarbonyl anion
X
B
=
Br,
Cl,
OMs)
(X
and
of alkyl bromides
organocatalytic
(c) Base-promoted
Alkyl Br
borylation
cat2
B2
DMF, blue LEDs
,
B
Alkyl
MeONa
,
4-Phenylpyridine
work
This
(d)
B
X
Het
Het
cat2
B2
DMF, blue LEDs
,
NaI
B
Alkyl
X
Alkyl
=
Br,
Cl,
OMs)
(X
Results and Discussion
N-Heterocyclic moieties are ubiquitous motifs in natural prod-
ucts and active pharmaceutical ingredients.[18] However, for com-
mon synthetic methods, the borylation of substrates containing N-
heterocycles was a big challenge owing to the compatibility.
We evaluated the conditions for this borylation reaction and
found out that in the presence of 50 mol% NaI and B2cat2 (2 equiv)
Chin. J. Chem. 2021, 39, XXX－XXX
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First author et al.
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Table 2 Scope of the dehalogenative borylation reactiona,b
.
1 NaI
DMF, blue LEDs, 36 h
overnight
(0.5 equiv),
+
cat2
B2
R
X
R
B
.
2
pinacol (4 equiv),
1
2
or
3
MIDA
90 o 4 h
C,
(4 equiv),
and
Scope of
alkyl
aryl
BMIDA
BMIDA
BMIDA
BMIDA
Bpin
3a
3b
3c
3d
3e
=
=
=
=
=
=
X
X
Br 90%
,
X
Br 82%
,
X
71%
X
61%
X
F
Cl
,
Cl
,
Cl
72%
,
Cl
,
82%
MeO
BMIDA
BMIDA
O
BMIDA
Bpin
BMIDA
MeO
tBu
O
OMe
3f
3g
3h
3i
3j
=
=
=
=
=
X
Cl
X
50%
X
Br 57%
,
X
60%
X
40%
63%
,
Cl
,
Cl
,
Cl
,
BMIDA
BMIDA
BMIDA
Bpin
Bpin
F
F
3C
3CO
Br
I
I
3k
3l
3m
3n
3o
=
=
=
=
=
X Br 81%
,
X
64%
X
Br 61%
,
X
Br 40%
,
X
Br 88%
,
Cl
,
Bpin
Bpin
N
=
Bpin
Bpin
Bpin
3p
3q
3r
3sc
3tc
=
Br 63%
,
=
=
=
X
90%
X
X
Br 73%
,
X
Br 56%
,
X
Cl
,
Cl
91%
,
mmol,
63%)
(5
Scope of heterocycle
O
N
Bpin
N
BMIDA
N
BMIDA
BMIDA
N
N
O
BMIDA
Cl
X
N
O
3uc
3aa
3ab
3ac
3ad
=
=
=
=
=
Cl
X
Br 80%
,
X
60%
X
Cl 50%
X
62%
55%
,
Cl
Cl
,
,
O
O
,
O
O
BMIDA
S
O
BMIDA
O
O
Bpin
BMIDA
from
naproxen
3ae
3af
3ag
3ahc,d
=
=
=
=
OMs
X
53%
X
42%
X
58%
X
41%
,
Cl
,
Cl
,
Cl
,
and
Natural
pharmacal prouducts
O
O
Bpin
Bpin
N
N
S
H
H
O
Cl
BMIDA
O
H
H
O
acid
from
from idometacin
from lithocholic
probenecid
3aic,d
3ajc,d
3akc,d
=
=
=
X
OMs
X
91%
X
36%
52%
,
OMs
OMs
,
,
a Reaction conditions: 1a-1ak (0.2 mmol), NaI (0.1mml), B2cat2 (2) (0.4 mmol), DMF (0.5 mL), blue LEDs, Ar, rt, 36 h; then, pinacol (4 equiv), rt, overnight, or
MIDA (4 equiv), 90 oC, 4 h. b Isolated yields. c 1 equiv NaI was used, and the reaction time was extended to 48 h. d Reaction was performed at 40 oC
Gratifyingly, our approach displayed a high level of tolerance to-
wards N-heterocycles, such as oxazole (1aa), N-(chloromethyl)
phthalimide (1ab), benzotriazole (1ac) and pyridine (1ad). In addi-
tion, borylation of other heterocyclic compounds, for instance, fu-
ran (1ae), vinylene carbonate (1af) and benzothiophene (1ag) were
also successfully proceeded, and the desired products were pro-
cured in moderate to good yields. The utility of this method was
further demonstrated by applying it to the borylation of pharma-
ceutical derivatives, such as naproxen (1ah), probenecid (1ai),
lithocholic acid (1aj) and indomethacin (1ak), and the correspond-
ing target molecules were obtained in satisfactory to excellent
yields.
Meanwhile, we also explored the synthetic utility of our boryla-
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Running title
Chin. J. Chem.
tion method, through the further diversification of naphthylmethyl-
boronate products 3q and 3q'. Firstly, the boronates were subjected
to Suzuki-Miyaura coupling, giving the corresponding products 4a
and 4b respectively. Secondly, amination of 3q under reaction con-
ditions developed by Kuninobu et al[19] delivered the corresponding
aminated product 4c in 86% yield. Product 3q' could be readily
transformed to a series of α-functionalized alkyl boronates 4d and
4e with Wang’s photochemical radical C-H halogenations.[20] Finally,
potassium trifluoroborate salt 4f could be prepared in excellent
yield by treating 3q with KHF2 in MeOH.
Scheme 3 Mechanistic experiments
b
a,
Radical Clock
(a)
Experiment
standard condition
Bpin
yield
(1)
Br
5
37%
6,
standard condition
+
Br
Bpin
Bpin
(2)
7
8a,
8b
61%
yield
detected
GCMS
by
Control
(b)
Experiment
Scheme 2 Functionalization of boronate products
NaI
equiv)
(1
DMF, blue LEDs, 36 h
(1)
X
I
n
=
n =
X
Br,
OMs
3
Cl,
1,
N
N
n = and
=
=
X
X
Cl
Br,
1,
n = and
OMs
3,
detected
GCMS
by
4c
, 86%,
3q
from
4b
3q
a
from
, 56%,
n =
=
not
X
detected
Cl.
3,
b
cat
1. B2
DMF
2 (2 equiv),
Cl
blue LEDs 36 h
Bpin
(2)
B
a
c
overnight
2.
pinacol (4 equiv),
BF3K
NR
,
OMe
=
3q B
Bpin
BMIDA
4a
, 90%,
3q
from
4d
3q
from
, 85%,
Br
=
B
,
3q'
a Reaction conditions: alkyl halides (0.2 mmol), NaI (0.2 mmol), B2cat2 (2)
(0.4 mmol), DMF (0.5 mL), blue LEDs, Ar, rt, 48 h; then, pinacol (4 equiv), rt,
overnight. b Isolated yields.
e
d
SCN
BMIDA
BMIDA
(DMF) to afford intermediate C. Subsequently, the radical C col-
lapses to form the desired product alkyl boronic ester 3 and DMF-
stabilized boryl radical D which can be tautomerized to carbon rad-
ical E. Finally, the cycle is closed by an I-atom transfer reaction of
the alkyl iodide via E to eventually give G and radical A. And for the
thermal process, the 2:1 DMF/B2cat2 complex H undergoes thermal
homolytic fragmentation to give two DMF-stabilized boryl radical D,
which can be tautomerized into carbon radical E to propagate the
cycle as described above. In addition, benzyl bromide is a highly re-
active alkyl halide that could occur a Br-atom transfer reaction via E
to give G and radical A in the absence of NaI, and then allow the
reaction to proceed.
4e
from
, 72%,
3q'
4f
from
, 73%,
3q'
Reaction conditions: (a) Aryl bromide (0.3 mmol), 3q (0.2 mmol),
Pd(P(tBu)3)2 (5 mmol%), Cs2CO3 (0.6 mmol), dioxane (1 mL), H2O (0.25 mL),
100 oC, overnight. (b) N-methylaniline (0.138mmol), 3q (0.125 mmol),
(tBu)2O (0.25 mmol), Cu(OAc)2 (5 mmol%), toluene (0.5 mL), 50 oC, overnight.
(c) KHF2 (0.9 mmol), MeOH (2mL). (d) NBS (0.11 mmol), 3q' (0.1 mmol), BPO
o
(3 mol%), DCE (1.0 mL), 100 C, 3 h. (e) NBS (0.11 mmol), 3q' (0.1 mmol),
BPO (3 mol%), DCE (1.0 mL), 100 C, 3 h; then change the solvent to DMF
o
(1.0 mL), add KSCN (0.12 mmol), 60 oC, 6 h.
To shed light on the mechanism of the borylation reaction, we
conducted two radical cascade experiments. Cyclopropylmethyl
bromide (5) gave exclusively the ring opening product 6 when it was
subjected to the standard conditions (Scheme 3a-1). In terms of 6-
bromo-1-hexene (7), the uncyclized boronate 8a was mainly ob-
tained under the standard conditions with small amount of the cy-
clized product 8b detected by GCMS (Scheme 3a-2). These results
all support the involvement of an aliphatic radical and its further
reaction with the boron species. In the control experiments, phe-
nylpropyl bromide or mesylate, and benzyl chloride could convert
into corresponding iodide in the presence of NaI (Scheme 3b-1).
Phenylpropyl chloride cannot be converted, which was consistent
with the fact that the non-benzylic primary alkyl chlorides cannot
participate in this borylation reaction. In addition, benzyl chloride
did not produce any products in the absence of NaI (Scheme 3b-2).
These results indicated that iodide might be the key reaction inter-
mediate and a part of iodide ions in the reaction were reused.
Based on these experiments and previous reports,[2a, 13] we pro-
posed that the reaction involves a radical mechanism that is initi-
ated by both a photoinduced event and a less efficient thermal
event, and the proposed mechanism is shown in Scheme 4. For the
photoinduced process, alkyl electrophile reacts with NaI through an
SN2 pathway to generate alkyl iodide. Then, under excitation by vis-
ible light, the C−I bond homolyzes to generate the radical A which
could react with B2cat2 to obtain a radical B. The ensuing boron-
centered radical B is then intercepted by dimenthylformamide
Scheme 4 Proposed mechanism
O
B
O
X
O
I
N
I
N
O
I
H
G
R
I
R
X
1
SN2
X
X
O
B
O
O
O
hv
B
B
O
2
O
O
N
O
R
H
I
H
A
F
N
R
O
O
R
I
B
B
event
thermal
O
O
DMF
B
O
B
O
O
O
O
H
B
O
H
N
R
B
N
O
O
E
B
D
O
O
O
C
O
H
B
O
N
O
N
H
D
O
B
O
3
R
Conclusions
Chin. J. Chem. 2021, 39, XXX－XXX
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First author et al.
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moted radical borylation of alkyl halides and pseudohalides. This
approach proceeds under mild conditions and features a broad sub-
strate scope. This method can be a privileged alternative to current
known catalytic methods for the construction of alkylboron deriva-
tives from less reaction alkyl halides and pseudohalides.
Experimental
General procedure for the borylation reaction
A 25 mL Schlenk tube was charged with a mixture of B2cat2 (2)
(95 mg, 0.4 mmol, 2 equiv), NaI (15 mg, 0.1 mmol, 0.5 equiv, or 30
mg, 0.2 mmol, 1 equiv), alkyl halides 1 (0.2 mmol, 1 equiv). The tube
was evacuated and backfilled with Argon for three times. Dimethyl-
formamide (DMF) 0.50 mL was added, then the tube was quickly
evacuated and backfilled with Argon for four times (IMPORTANT!)
(If the alkyl halides are a liquid, add it after degassing). The reaction
mixture was stirred under blue LEDs irradiation for 36 or 48 h. Then,
methyliminodiacetic acid (118 mg, 0.8 mmol, 4 equiv) was added
and the reaction mixture heated to 90 °C for 4 hours, after which
the solvent was removed in vacuo. The reaction mixture was diluted
with ethyl acetate (20 mL) and saturated NaHCO3 solution (10 mL),
then organic phase was separated and the aqueous layer was ex-
tracted with ethyl acetate (20 mL) for three times. Alternatively, pi-
nacol (95 mg, 0.8 mmol, 4 equiv) was added to the reaction vessel
and the mixture was stirred overnight at ambient temperature, af-
ter which water was added, and the aqueous layer was extracted
with ethyl acetate (20 mL). Then organic phase was separated and
the aqueous layer was extracted with ethyl acetate (20 mL) for
three times. The combined organic layers were dried over Na2SO4,
filtered and concentrated. The crude product was purified by flash
column chromatography to give the corresponding product 3.
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
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philes, Including Unactivated Tertiary Halides, To Generate Carbon-Boron
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Acknowledgement
Financial support from the National Natural Science Foundation
of China (21772046, 2193103, 22001038) are gratefully
acknowledged.
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Entry for the Table of Contents
Photoinduced NaI-Promoted Radical Borylation of Alkyl Halides and Pseudohalides
Chenglan Wang, Lu Zhou, Kai Yang, Feng Zhang, Qiuling Song*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
DMF
NaI
N
O
O
O
O
O
+
B
R
B B
B
R
R
X
or
O
O
O
=
Br,
Cl,
OMs)
(X
O
O
A method for photoinduced NaI-promoted radical borylation of aliphatic halides and pseudohalides has been developed that enables synthesis of a
series of alkylboronates.
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim