Efficient metal-free photochemical borylation of aryl halides under batch and continuous-flow conditions

Article abstract of DOI:10.1039/c5sc04521e

A rapid, chemoselective and metal-free C-B bond-forming reaction of aryl iodides and bromides in aqueous solution at low temperatures was discovered. This reaction is amenable to batch and continuous-flow conditions and shows exceptional functional group tolerance and broad substrate scope regarding both the aryl halide and the borylating reagent. Initial mechanistic experiments indicated a photolytically generated aryl radical as the key intermediate.

Full text of DOI:10.1039/c5sc04521e

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A metal-free C-B bond forming reaction from the corresponding aryl halides in batch and continuous-flow
conditions is described.

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Efficient Metal-Free Photochemical Borylation of Aryl Halides
under Batch and Continuous-Flow Conditions
Cite this: DOI: 10.1039/c0sc00000x
Kai Chen, Shuai Zhang, Pei He and Pengfei Li*
A rapid, chemoselective and metal-free C–B bond-forming reaction of aryl iodides and bromides in
aqueous solution at low temperatures was discovered. This reaction is amenable to batch and
continuous-flow conditions and shows exceptional functional group tolerance and broad substrate
scope regarding both the aryl halide and the borylating reagent component. Initial mechanistic
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/c0sc00000x
experiments indicated
a
photolytically generated aryl radical as the key intermediate.
www.rsc.org/chemicalscience
Introduction
under mild conditions.7 Using aryl amines as the starting material,
Wang developed a mild and efficient Sandmeyer-type borylation
process.8a-c Borylation of aryl diazonium salts8d-f and aryl triazenes8g
were also reported. In addition, innovative methods for direct C-H
borylation under transition metal-free conditions have been
reported,9 although the substrates were limited to either electron rich
arenes or heterocycles, and air and moisture sensitive reagents were
needed. Consequently, a practical, metal-free method that is rapid
and effective, works under mild conditions with various readily
available borylating reagents, shows high functional group tolerance
and avoids strong acids, bases and hazardous reagents, is still highly
desirable. Herein, we wish to report our discovery and development
of a new borylation reaction of aryl halides using light as a clean
reagent (Scheme 1e).10
Arylboronic acids or esters have found broad applications in
chemical, medicinal and materials sciences. In synthetic organic
chemistry, in particular, they are versatile synthons for the formation
of carbon-carbon or carbon-heteroatom bonds.1 The conventional
methods to generate arylboron compounds involved reactions of
arylmetallic intermediates with trialkyl borates, followed by
transesterification or hydrolysis. These reactions suffer some major
drawbacks such as limited functional group tolerance as well as
rigorous anhydrous conditions (Scheme 1a).2 In the past decades,
transition metal-catalyzed borylation reactions using palladium,
nickel, copper and zinc have emerged as highly useful methods for
conversion of a C-X bond to a C-B bond (Scheme 1b).3 More
recently, direct C-H borylation methods based on transition-metal
catalysts have also been developed.4 In order to reduce the costs and
the heavy metal residues in the final products, several transition-
metal-free methods toward C-B bond formation have been
developed. Ito and coworkers discovered an alkali alkoxide-
mediated borylation of aryl halides with a silylborane as the unique
borylating reagent (Scheme 1c).5, Zhang and coworkers reported that
aryl iodides could be borylated with 4.0 equivalents of
bis(pinacolato)diboron in refluxing methanol using 2.0 equivalents of
Ce2CO3 as the promoter. The reaction time ranged from several hours to
days and the yields were generally moderate (Scheme 1d).6 Fernándes
and Muñiz transformed diaryliodonium acetates to arylboronates
Scheme 1 Summary of borylation reactions of aryl halides and the outline of this
work.
Results and discussion
Initially, a solution of 4-iodoanisole (1a) and bis(pinacolato)-
diboron (2) in acetonitrile was placed in a quartz test tube and
a Center for Organic Chemistry, Frontier Institute of Science and Technology
(FIST), Xi’an Jiaotong University 99 Yanxiang Road, Xi’an, Shaanxi, 710054
(China) E-mail: lipengfei@mail.xjtu.edu.cn
irradiated with a 300 W high pressure mercury lamp (maximum
at 365 nm) for 4 hours. Encouragingly, the desired aryl-B(pin)
1
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization for new compounds are provided. See
DOI:10.1039/c0sc00000x
product 3a was formed in 29% yield based on H NMR analysis
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of the crude product (Table 1, entry 1). Other polar solvents such developed by Booker-Milburn11a and our own experience in flow
as methanol and trifluoroethanol did not improve the reaction chemistry,14 we designed and assembled a continuous-flow
(entries 2 and 3). Adding water and acetone as co-solvents were photochemical reactor. Thus, transparent fluorinated ethylene
both beneficial and increased the yields to 46% (entries 4 and 5). propylene (FEP) tubing (reaction volume 780 μL) was coiled
Screening of various organic and inorganic additives revealed around a jacketed quartz immersion well in which the mercury
that an organic base, N,N,N',N'-tetramethyldiaminomethane lamp was situated. The reaction temperature was regulated by a
(TMDAM), could further improve the outcome to 58% yield cooling liquid circulating pump (see SI). A stock solution
(entry 9). For comparison, other bases led to inferior results containing all reactants and reagents was introduced into the
(entry 6-8). Interestingly, more amount of TMDAM led to tubing using a syringe pump. To our delight, running the reaction
significantly lower yield (entry 10). Using two equivalents of under conditions same as entry 12 but using a continuous-flow
B2(pin)2 could improve the yield to 72% (entry 11). Further mode gave 3a in excellent yield (87%, entry 15) with a residence
optimization by changing the reaction concentrations of 1a time of only 15 minutes. Indeed, the amount of B2(pin)2 could be
resulted in higher yield (c = 0.1 M, 81% yield) (entry 12 vs. 11 reduced to 1.5 equivalent without affecting the reaction
and 13).
efficiency (88% yield, entry 16).
Table 1 Reaction optimization under batch and continuous-flow conditions
Table 2 Substrate scope of the photolytic borylation.a
Entry
2 (eq.)
Solvent
Additive
(mol %)
Yield [%]c
Batch conditionsa
1
2
3
4
1.0
1.0
1.0
1.0
MeCN
TFE
MeOH
MeCN/H2O
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
none
none
none
none
29
26
15
42
5
6
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
none
46
16
12
52
58
39
72
81
55
Cs2CO3
(100)
KOtBu
(100)
7
TMEDA
(50)
TMDAM
(50)
TMDAM
(100)
TMDAM
(50)
TMDAM
(50)
TMDAM
(50)
8
9
10
11
12d
13e
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
MeCN/H2O/
Acetone
Flow conditionsb
MeCN/H2O/
Acetone
TMDAM
(50)
14
2.0
87
MeCN/H2O/
Acetone -
TMDAM
(50)
15
1.5
88
a
batch conditions: 1a (0.1-0.2 mmol, c = 0.05 M/0.1 M),
2
(0.1-0.4 mmol),
RT, 4 h; flow conditions: 1a (c = 0.1 M), -5 oC, residence time 15 min;
b
c
determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal standard;
a Batch conditions: 1a (0.2 mmol, c = 0.1 M), 2 (0.4 mmol, 2.0 eq.), TMDAM (0.5
d
e
c = 0.1 M; c = 0.2 M; TMEDA: N,N,N,N-tetramethylethylenediamine;
eq.), RT, 4 h; Flow conditions: 1a (c = 0.1 M), 2 (1.5 eq.), TMDAM (0.5 eq.), -5
TMDAM: N,N,N',N'-tetramethyldiaminomethane.
b
oC, residence time 15-30 min;
determined by 1H NMR with 1,3,5-
trimethoxybenzene as an internal standard; TMDAM: N,N,N',N'-
tetramethyldiaminomethane.
During the study, we observed gradual decomposition of
B2(pin)2. We felt that continuous-flow photolytic conditions
might help in reducing the amount of B2(pin)2 by competitively
accelerating the desired reaction. In comparison with a typical
batch photoreactor, microchannel photochemical reactors have
significant benefits on reaction efficiency, yield, reproducibility,
material throughput and scaling-up.11-13 Based on the method
With the optimized conditions in hand, we examined the
substrate scope of the current borylation reaction under batch and/or
continuous-flow conditions, as summarized in Table 2. Iodoarenes
with various electron-donating, -neutral and -withdrawing groups at
the para-, meta-, or ortho-positions, including hydroxyl, amino,
2 | Chem. Sci., 2015, 00, 1-5
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amide, ester, acid, ketone, cyano, fluorine, boronate and the solvent. Due to the inconvenience to isolate the pure arylboronic
trifluoromethyl groups, were all efficiently converted to the acid, aqueous KHF2 was added and the resulting potassium
corresponding aryl pinacol boronates in good to excellent yields (3a- aryltrifluoroborate 8a was obtained in 93% yield. Other aryl and
3r). Potentially reactive groups under UV light such as aryl ketone heteroaryl iodides and a bromide were also transformed to the
(for 3i) and biaryl (for 3h) were compatible. Interestingly, a substrate boronates in good to excellent yields in this manner (Table 3).
containing allyl ether group was also viable (3r), considering the
To gain insights into the reaction mechanism, particularly to
reaction might involve reactive carbon-based radical and the double probe the roles of additives and light, we conducted a series of
bond might be attacked. In addition, the borylation of 2-amino-5- control experiments (Table 4). When the batch reaction of 1f with
iodopyridine was also possible and moderate yield of the B2(pin)2 was run under the standard conditions, 7% of deiodination
1
corresponding boronate 3s was observed by H NMR spectroscopic product 9 was formed accompanying the borylation product 3f (entry
analysis. Attempts to purify 3s were not successful due to its 1). In the absence of both TMDAM and light (entry 2), no
decomposition on silica gel. Furthermore, when aryl bromides were conversion was observed. However, the reaction with 0.5 equivalent
subjected to the same reaction conditions, the desired products could of TMDAM in dark led to small amount of 3f (entry 3); higher
be produced in comparable or slightly lower yields in comparison reaction temperatures and prolonged reaction time had little
with the iodides (3c, 3f, 3k, 3l and 3t-3x). Finally, different influence on the outcome. A hydrogen atom donor Bu3SnH
borylating reagents were utilized under the otherwise identical increased the conversion but led to 9 as the major product (entry 4).
conditions. Thus, the reactions using bis(neopentanediolato)diboron Furthermore, the reaction with Bu3SnH afforded 9 in high yield
B2(neop)2 successfully afforded the desired products in good yields under UV irradiation (entry 5). Similarly using 9,10-dihydro-
(3y and 3z). Interestingly, when an unsymmetrical diboron (pin)B- anthracene instead of Bu3SnH, 9 (26%) and concomittant anthracene
B(dan) was employed, selective introduction of the B(dan) moiety (11%) were observed (entry 6). Finally, when TEMPO was added as
was realized (3aa and 3ab) and no aryl pinacol boronate was a radical scavenger, the conversion was low and four products
observed.15 To demonstrate the stability and usefulness of this including 3f (15%), 9 (11%), the aryl-TEMPO adduct 10 (14%) and
reaction in larger scale preparation, the borylation of iodobenzene ethyl 4-hydroxybenzoate 11 (26%) were formed (entry 7).
and 4-iodophenol were carried out in grams scale (10.0 mmol)
Table 4 Control experiments for preliminary mechanistic studya
employing a commercial automated flow chemistry system (with a
reactor volume of 7.8 mL, see SI). Without any further optimization,
the reactions produced the desired arylboronate products in excellent
isolated yields (3b 90% and 3c 93%) and the productivity
corresponded to ~3 mmol h-1.
Table 3 Continuous-flow photolytic borylation with B2(OH)4
TMD
Conver-
sion [%]
100
0
Yield of
3f [%]
81
Yield of
Entry
Light
Additive
AM
+
9 [%]
7
1
2
3
4
5
6
7
+
-
-
-
-
0
0
-
+
-
13
13
0
-
+
Bu3SnH
Bu3SnH
DHA
TEMPO
46
17
26
80
26b
11
+
+
+
+
100
68
18
+
42
+
69
15
a
Reactions were run in batch and yields were determined by 1H NMR
b
spectroscopic analysis with 1,3,5-trimethoxybenzene as an internal standard;
11% of anthracene was formed. TMDAM: N,N,N',N'-tetramethyldiaminomethane;
DHA: 9,10-dihydroanthracene; TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxyl.
Encouraged by the above results, we further investigated the
possibility of using a more atom economical borylating reagent bis-
boronic acid (BBA, 6). Largely because its polar protic property may
not be amenable to most known borylation methods, this reagent has
only recently been successfully used in palladium or nickel-
catalyzed Miyaura borylation by Molander and coworkers.16 In the
present borylation, pleasingly, we were able to convert 4-iodoanisole
1a to the corresponding boronic acid 7a under continuous-flow
conditions in quantitative yield based on 1H NMR analysis
(residence time 10 minutes). The key variation from the previous
conditions was using aqueous methanol (MeOH : H2O = 4:1 v/v) as
Based on the experimental results and related reports on
photolytic reactions of aryl iodides,17 we propose two pathways both
involving an aryl radical intermediate as the possible reaction
mechanism (Scheme 2). Thus, the excited state 12 may be generated
by UV irradiation of aryl iodide 1. In path A, 12 can undergo
homolytic C-I bond cleavage to form aryl radical 13 and an iodine
atom. Under aqueous conditions, TMDAM might activate water
molecule, with B2(pin)2 (2), to form a sp3-sp2 diboron species
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14.18,7a,7b,8f Aryl radical 13 then might react with 14 to produce
arylboronate 3 and a boryl radical anion 15.19 15 can also be viewed
Pintaric, S. Olivero, Y. Gimbert, P. Y. Chavant, E. Duñach, J. Am.
Chem. Soc. 2010, 132, 11825.
as an anionic base-stabilized boryl radical.20 Alternatively, in path B, 3 For selected references, see: a) T. Ishiyama, M. Murata, N. Miyaura, J.
the excited state 12 or the starting aryl iodide 1 (when in dark
although in low efficiency) might be reduced by TMDAM via a
single electron transfer (SET) process to form radical anion 16 and
TMDAM-derived radical cation 17. 16 should then undergo C-I
bond cleavage to generate aryl radical 13 and iodine anion. Finally,
15 could be oxidized by the iodine atom from path A or TMDAM-
derived radical cation 17 from path B to form borate 18 as a
byproduct.
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4
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Scheme 2 Proposed reaction mechanism
Conclusions
In summary, we have discovered a novel and efficient photolytic
borylation reaction of aryl halides using diboron reagents. This
metal-free reaction features very mild conditions, short reaction
times, generally high yields and broad functional group tolerance.
Considering the reaction conditions, borylating reagent types and
possible reaction mechanism, this work represents an important
complementary approach to the existing C-B bond formation
methods. Further studies on the mechanism and synthetic
applications of this reaction are ongoing.
Acknowledgements
This work was financially supported by the NSFC (No. 21472146),
the Department of Science and Technology of Shaanxi Province (No.
2015KJXX-02) and the Ministry of Science and Technology (No.
2014CB548200). We thank Prof. Que (Xi’an Jiaotong University)
and Dr. Duncan Guthrie (Vapourtec) for their generous sharing of
the batch and flow photochemistry equipment.
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