Photochemical Radical C–H Halogenation of Benzyl N-Methyliminodiacetyl (MIDA) Boronates: Synthesis of α-Functionalized Alkyl Boronates

Article abstract of DOI:10.1002/anie.202011872

α-Haloboronates are useful organic synthons that can be converted to a diverse array of α-substituted alkyl borons. Methods to α-haloboronates are limiting and often suffer from harsh reaction conditions. Reported herein is a photochemical radical C-H halogenation of benzyl N-methyliminodiacetyl (MIDA) boronates. Fluorination, chlorination, and bromination reactions were effective by using this protocol. Upon reaction with different nucleophiles, the C?Br bond in the brominated product could be readily transformed to a series of C?C, C?O, C?N, C?S, C?P, and C?I bonds, some of which are difficult to forge with α-halo sp²-B boronate esters. An activation effect of B(MIDA) moiety was found.

Full text of DOI:10.1002/anie.202011872

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Accepted Article
Title: Photochemical Radical C-H Halogenation of Benzyl N-
methyliminodiacetyl (MIDA) boronates as Versatile Platform for α-
Functionalized Alkyl Boronates Synthesis
Authors: Honggen Wang, Ling Yang, Dong-Hang Tan, Wen-Xin Fan,
Xu-Ge Liu, Jia-Qiang Wu, Zhi-Shu Huang, and Qingjiang Li
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COMMUNICATION
Photochemical Radical C-H Halogenation of Benzyl N-
Methyliminodiacetyl (MIDA) Boronates: Synthesis of -
Functionalized Alkyl Boronates
[
a]
[a]
[a]
[a]
[a]
[a]
Ling Yang, Dong-Hang Tan, Wen-Xin Fan, Xu-Ge Liu, Jia-Qiang Wu, Zhi-Shu Huang,
[
a]
[a]
Qingjiang Li and Honggen Wang*
[
a]
L. Yang, D.-H. Tan, W.-X. Fan, X.-G. Liu, J.-Q. Wu, Z.-S. Huang, Q. Li, H. Wang
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University
Guangzhou 510006 (China)
E-mail: wanghg3@mail.sysu.edu.cn
Abstract: -Haloboronates are useful organic synthons which can be
converted to a diverse array of -substituted alkyl borons. Methods to
reaction is feasible and the substrate scope was mainly limited to
secondary alkylboronate esters (Figure 1d).
-haloboronates are limiting and often suffer from harsh reaction
conditions. Reported herein is photochemical radical C-H
a
halogenation of benzyl N-methyliminodiacetyl (MIDA) boronates.
Fluorination, chlorination as well as bromination reactions were
effective by using this protocol. Upon reaction with different
nucleophiles, the C-Br bond in the brominated product could be
readily transformed to a series of C-C, C-O, C-N, C-S, C-P and C-I
2
bonds, some of which are difficult to forge with -halo sp -B boronate
esters. An activation effect of B(MIDA) moiety was found.
The -halogenated alkyl borons represent an interesting class of
amphoteric compounds, which have found intriguing
applications.[ For instances, the famous Matteson homologation
1]
reaction
of
-haloboronates
with
organolithium
or
organomagnesium reagents is a reliable route to prepare
secondary alkylboronate esters.[2] Fu’s nickel-catalyzed coupling
reaction of racemic -haloboronates with organozincs provides
straightforward access to enantioenriched alkylboronate esters.[3]
The displacement of the halogen with amines leads to valuable -
amino boronate esters,[4] which are key pharmacophores for
several drugs such as Bortezomib and Ixazomib.[5] Traditionally,
the Matteson homologation could be applied to the synthesis of
-halogenated alkyl borons by using dihaloalkyl metallic reagent
2
such as (dichloromethyl)lithium (LiCHCl ) as the key reagent
Figure 1a).[
2a,6]
The need of low temperature and the intrinsic high
limits its widespread synthetic applications.
(
basicity of LiCHCl
2
The rhodium-catalyzed regioselective hydroboration of 1-halo-1-
alkenes provided another valuable route to α-halogenated alkyl
borons (Figure 1b).[7] Alternatively, the hydrozirconation of alkenyl
boronate esters followed by the treatment with electrophilic
halogen sources was also useful for the synthesis of these
compounds (Figure 1c).[8] Arguably, the most straightforward and
appealing synthesis might be the selective radical halogenation of
the C-H of the parent alkylboronates esters. On one hand, the
boron moiety tends to stabilize an adjacent carbon radical through
Scheme 1. Synthesis of -haloborons.
The displacement of the C-X bond in -haloboronates
typically occurs through the formation of an intermediate boronate
complex followed by a concerted 1,2-metallate rearrangement,
and direct nucleophilic substitution is in fact rare.[13] Besides,
[12]
[
2]
nucleophiles were typically limited to organometallic reagents,
alkoxides,[
2b,14]
sulfides
[2b,14e,14f,15]
and amides anions.
[4,16]
The use
p -p
 
interaction,[9] thus making a site-selective C-H abstraction
of phosphite, sulfinate or cyano as nucleophiles was not
established (Figure 1e). One possible challenge is that the formed
possible. On the other hand, however, free radicals may attack
the low-lying p orbital of boron atom and leads to the undesired
displacement of an alkyl group, which was indeed the case in the
reactions with oxygen and nitrogen based free radicals.[10]
Nevertheless, some success was achieved by using
-functionalized
alkyl
alkylboronates
esters
are
thermodynamically unstable. They are prone to undergo facile
protodeborylation reaction due to the electro-withdrawing nature
of the phosphoryl, sulfinyl and cyano group.[17]
[
11]
photochemical radical reaction conditions, but only bromination
1
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COMMUNICATION
3
As a protecting form of organoboronic acids, sp -B organo N-
methyliminodiacetyl (MIDA) boronates showed some advantages
in terms of stability, ease of purification and automated
well applicable (2l). While aliphatic primary alkyl MIDA-boronate
showed no reactivity under the standard reaction conditions (2m),
secondary alkyl MIDA-boronate did provided the -brominated
product (2n), but in low yield. The bromiation of an allyl MIDA
boronate gave an alkene transposition product 2o.
[18]
synthesis. Besides, they can serve as valuable boron-retentive
building blocks for synthetically challenging organoboron
synthesis.[19,20] We have long been interested in the late-stage
functionalization of organo MIDA boronates.[21] We envisioned the
employment of alkyl MIDA boronates in direct radical C-H
halogenation reaction may show some advantages. First, the
coordination saturation on the B(MIDA) moiety should prevent the
above-mentioned radical attack on boron atom, thereby enabling
a
higher chemoselectivity. Second, previous studies have
3
suggested that organoboron compounds with a sp -B sitting  to
the electron-withdrawing group are more stable compared to their
2
[21c,19c,22]
sp -B congeners.
Thus, the -halogenated alkyl borons
3
derived from C-H halogenation of alkyl sp -B MIDA boronates
should find broader applications. Herein, we report
photochemical benzylic C(sp )-H halogenation (F, Cl and Br) of
a
3
benzyl MIDA boronates.
A telescoped direct nucleophilic
substitution reaction (compared to the conventional 1,2-metallate
rearrangement) with diverse nucleophiles allowed a one-pot
synthesis of structurally intriguing organoborons. Competition
experiments revealed an activating effect of B(MIDA) for this
radical process.
Scheme 3. Synthesis of -bromo benzyl MIDA boronates. Reaction conditions:
1
(0.2 mmol), NBS (1.1 equiv.), MeCN, Ar, 13 W CFL.
To start, we explored the direct bromination reaction of benzyl
MIDA boronate 1a. This class of compounds could be readily
prepared via a two-step synthesis comprising of a catalytic
borylation of benzyl bromides and a subsequent ligand exchange
with N-methyliminodiacetic acid. Two reaction systems were
identified to be effective for the desired reaction. First, the use of
benzoyl peroxide (BPO, 3 mol%) as radical initiator and N-
The above success encouraged us to explore the more
challenging chlorination and fluorination reactions. Using a similar
photochemical protocol, the reaction of 1b with N-
Chlorosuccinimide (NCS) did provide the -chlorinated benzyl
MIDA boronate 3b, but in low yield of 26% (Scheme 4). To
improve the yield, ketone 9-fluorenone was chosen as a photo
catalyst.[24] The employment of 5 mol% 9-fluorenone in the
reaction significantly improved the yield to 89%. Thus, under the
modified protocol, the chlorination of several representative
benzyl MIDA boronates gave the corresponding products in
reasonable yields. Unexpectedly, the use of unsubstituted benzyl
MIDA boronate 1a in this reaction led to chlorination on the phenyl
ring at the para position (formation of 1e). Similarly, under the
assistance of ketone catalyst, the benzylic fluorination of benzyl
MIDA boronates was also feasible by using 1-Chloromethyl-4-
o
Bromosuccinimide (NBS 1.1 equiv.) as halogen donor at 90 C
led to selective formation of the benzylic bromination product 2a
in 82% yield (eq 1). The displacement of the benzyl radical, a
typical side reaction when oxygen-based radical initiator is used,
was not found, which could be a result of coordination saturation
of the boryl moiety in the substrate. Alternatively, the simple
irradiation of a mixture of 1a and NBS (1.1 equiv.) in acetonitrile
using a 13 W household compact fluorescence lamp (CFL)[23] at
room temperature gave a higher yield of 89% yield, thus providing
a greener photochemical route to the target molecule. No reaction
occurred in dark.
fluoro-1,4-diazoniabicyclo[2.2.2]octane
Selectfluor) as the fluorine donor (4a-c).
bis(tetrafluoroborate
(
Scheme 2. Model reaction. DCE = 1,2-dichloroethane.
The scope of the direct bromination reaction was then explored
under the photochemical reaction conditions. As shown in
Scheme 3, a diverse array of substituted benzyl MIDA boronates,
regardless of electron nature of the substituents on the aryl ring,
were good substates for the reaction. A number of valuable and
commonly encountered functional groups such as halides (2c, 2d,
Scheme 4. Synthesis of -halo benzyl MIDA boronates. Reaction conditions:
a] 1 (0.2 mmol), NCS (1.5 equiv.), 9-fluorenone (5 mol %), acetonitrile, Ar, 13
2e, 2i, 2j, 2k), ester (2f) and cyano (2h) were well tolerated,
[
affording the corresponding products in generally good yields.
The reactivity was not hampered by sterically hindered ortho-
substituent (2i, 2j). A secondary benzyl MIDA boronate was also
W CFL. [b] without 9-fluorenone. [c] 1 (0.2 mmol), Selectfluor (2 equiv.), 9-
fluorenone (5 mol %), MeCN, Ar, 13 W CFL.
2
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COMMUNICATION
We were also quite interested in the synthetic utility of the
formed product (Scheme 5). The high reactivity of C-Br bond
toward nucleophilic substitution should offer valuable opportunity
to forge other chemical bonds. Besides, the simplicity of the
reaction conditions and the high efficiency for the bromination
step should permit a two-step telescoped synthesis. Thus, after
the completion of the first step, solvent MeCN was evacuated, and
the corresponding nucleophile, base and solvent were introduced.
We are delighted to find that the two-step procedure allowed the
efficient construction of a series of C-N, C-O, C-S, C-P, C-I and
C-C bond in overall high yields. It should be noted the cyanation
parent structure 6 were conducted. It was found that upon
B(MIDA) substitution, a higher reactivity was found, although the
B(MIDA) moiety may confer steric hindrance to the benzylic site
(Scheme 6a). In other word, the C-H bond  to the B(MIDA) is
weakened, thus providing higher reaction rate. The kinetic isotope
effect studies were also performed (Scheme 6b). A smaller KIE
value of 2.1 was found for benzyl MIDA boronate, as compared
to the toluene derivatives (KIE = 3.3). This is consistent with a
lower activation barrier for the hydrogen abstraction step for
benzyl MIDA boronate. Taking together, an activating effect of
B(MIDA) for radical substitution reaction was involved.
(
5ba), phosphorylation (5aj), and sulfinylation (5ah) products with
In summary, the photochemical radical C-H substitution
reaction of benzyl MIDA boronates allowed the facile synthesis of
the boron atom substituted  to the electron-withdrawing group,
were also formed efficiently. Finally, a copper-catalyzed radical
substitution reaction of 2a with olefin was also feasible, providing
an allylboron compound 5ak in good yield.
-F, -Cl and -Br alkyl MIDA boronates. The brominated products
serve as useful synthons, enabling the divergent and modular
synthesis of nine types of -functionalized benzyl MIDA
boronates. Mechanistic studies showcased an activating effect of
B(MIDA) on reactivity. The B(MIDA) moiety also allowed the
successful use of phosphite, sulfinate and cyano as nucleophiles
for C-Br bond substitution reaction, expanding the chemical space
of -substituted alkyl borons.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21971261, 21801256 and 81930098), the
Key Project of Chinese National Programs for Fundamental
Research and Development (2016YFA0602900), the Guangdong
Basic
and
Applied
Basic
Research
Foundation
Scheme 5. Synthesis of -functionalized benzyl MIDA boronates. Reaction
(2019A1515011170 and 2020A1515010624), the Fundamental
Research Funds for the Central Universities (19ykpy133 and
condition: [a] PhNH
KSCN; [f] PhSNa; [g] sodium benzo[d]thiazole-2-thiolate; [h] sodium 4-
methylbenzenesulfinate; [i] NaI; [j] P(OEt) ; [k] TMSCN, TBAF; [l] 2a (1 mmol
scale), CuCl, 1,10-phenanthroline, Na CO ethene-1,1-diyldibenzene. For
2 3 4
; [b] NaN ; [c] PhCOOK, 18-crown-6; [d] AgBF , DMF; [e]
20ykzd12).
3
2
3
,
more details, see the Supporting Information. Ts = tosyl, TMS = trimethylsilyl,
TBAF = tetrabutylammonium fluoride.
Keywords: halogenation • ketone catalysis • organoboron •
photochemistry • radical reaction
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Angewandte Chemie International Edition
10.1002/anie.202011872
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Entry for the Table of Contents
A photochemical radical C-H halogenation of benzyl N-methyliminodiacetyl (MIDA) boronates is described. Fluorination, chlorination and
bromination reactions were all effective by using this protocol. The brominated products serve as versatile platforms for various -functionalized
alkyl borons synthesis. By virtue of coordination saturation of the MIDA boron moiety, some synthetically challenging -substituted alkyl borons
are also accessible.
5
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