Visible light-mediated transition metal-free esterification of amides with boronic acids

Article abstract of DOI:10.1016/j.tetlet.2020.152444

A novel strategy for visible light-mediated esterification of amides with boronic acids in air has been described. This method is characterized by mild reaction conditions and low cost owing to no need of any catalyst, which implies high potential utility in late-stage functionalization of amide drugs and materials.

Full text of DOI:10.1016/j.tetlet.2020.152444

Tetrahedron Letters 61 (2020) 152444
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible light-mediated transition metal-free esterification of amides
with boronic acids
b,
Hao Ding a, Wan-Ying Qi b, Jing-Song Zhen b, Qiuping Ding a, , Yong Luo
⇑
⇑
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi Normal University, Nanchang 330022, China
b School of Pharmaceutical Science (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 May 2020
Revised 31 August 2020
Accepted 1 September 2020
Available online 10 September 2020
A novel strategy for visible light-mediated esterification of amides with boronic acids in air has been
described. This method is characterized by mild reaction conditions and low cost owing to no need of
any catalyst, which implies high potential utility in late-stage functionalization of amide drugs and
materials.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Esterification
Sulfonamide
Boronic acids
Visible light-mediated
Transition metal-free
Introduction
with high yields. Transition metal-free esterification of amides
with alcohols and phenol has also been achieved in the presence
Amides are ubiquitous in natural products, pharmaceuticals,
fine chemicals, and polymer materials [1]. Many amide group-
embedded biological compounds as well as drugs like penicillin
and paracetamol play critical roles in life systems [2]. The wide
presence of amide group makes it a good building block for the
synthesis of other chemicals. However, the inertness of C(O)-N
bond hampered the conversion of amide group in a mild manner
[3]. Although enzyme-catalyzed cleavage of CAN bond in amides
is one of the most fundamental transformation in life processes,
synthetic transformation of amides to other functional groups,
such as esters and ketones, is quite challenging, typically requiring
harsh reaction conditions [4]. The employment of strong acids or
bases is incompatible with sensitive functional groups [5]. There-
fore, exploration of mild and versatile reaction conditions for the
transformation of amide groups is in highly demand.
of bases (Scheme 1a) [7]. CsF, K3PO4, and Cs2CO3 catalyzed or pro-
moted esterification of amides have been utilized to synthesize
diverse aryl and alkyl esters. Despite these achievements of con-
version of amides to esters using alcohols and phenols, esterifica-
tion of amide with other reagents is rare. Recently, Zeng reported
palladium-catalyzed oxidative coupling of amides with boronic
acids to synthesize esters (Scheme 1b) [8], which expanded the
esterification reagents from phenols to aryl boronic acids.
Visible light irradiation has been proved to be an efficient, reli-
able, and mild strategy in many organic transformations [9].
Herein, we report a novel visible light-mediated esterification of
amides with boronic acids without any catalyst (Scheme 1c). This
method provides an alternative synthetic route toward esters from
air stable and easy-handling boronic acids. The electron-deficient
boronic acid group would result in different reactivity and regios-
electivity from phenols in the pre-functionalization step. Further-
more, subsequent functionalization of hydroxy group and
esterification of boronic acid unit in substituted hydroxyphenyl
boronic acids could install two different groups specifically on
the aryl ring, which are unattainable with using dihydroxyarenes.
Our initial study commenced with the reaction of sulfonamide
1a and boronic acid 2a in the presence of Cs2CO3 under blue LEDs
irradiation in air (Table 1). Various solvents were screened firstly.
CH3CN and DMF only provided trace amount of product 3a (entries
1 and 2). And no desired product was detected with using DCE,
In recent years, several remarkable achievements for esterifica-
tion of amides provide a new insight to the conversion of amides.
With activation of amide groups by introducing sulfonyl or car-
bonyl group on nitrogen atom, the C(O)-N bond could be activated
by transition metals (Scheme 1a) [6]. Followed by cross-coupling
with alcohols and phenols, diverse esters could be synthesized
⇑
Corresponding authors.
E-mail addresses: dingqiuping@jxnu.edu.cn (Q. Ding), luoyong5@mail.sysu.edu.
cn (Y. Luo).
https://doi.org/10.1016/j.tetlet.2020.152444
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

H. Ding et al.
Tetrahedron Letters 61 (2020) 152444
Table 2
The scope of amides.a
Scheme 1. Esterification of amides.
Table 1
Optimization of the reaction conditions.a
aReaction condition: 1a (0.4 mmol), 2a (0.2 mmol), K3PO4 (0.5 mmol), DME (2 mL),
50 W Blue LEDs, air, 24 h, 40 ℃.
Entry
Base
Solvent
Yield
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
LiOtBu
NaOH
Na2CO3
K2CO3
Na3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CH3CN
DMF
DCE
PhCF3
DMSO
MeOH
1.4-dioxane
DME
THF
THF
THF
THF
trace
trace
n.r.
n.r.
n.r.
The scope of amides was investigated in the next step (Table 2).
2-Naphthamide provided good yield (72%) of the corresponding
ester 3b. Halide groups were compatible in this system. para-Fluo-
rine-substituted ester (3c) could be synthesized with 83% yield.
meta- or ortho-Chlorobenzamides furnished 3d and 3e with 64%
and 62% yield, respectively. However, 3,5-difluorobenzamide only
gave 30% yield of the desired product 3f. Other electron-withdraw-
ing groups like trifluoromethyl and cyano units could be tolerated,
affording ester products 3 g and 3 h with moderate yields. Elec-
tron-donating substrates, such as ortho- methyl group attached
amides also proceeded smoothly under the optimized reaction
conditions (3k). Aliphatic amides could also be employed in this
transformation. Ester 3 l was obtained with 74% yield, implying
the wide substrate scope of this methodology.
n.r.
33%
36%
36%
trace
33%
n.r.
54%
trace
63%
38%
64%
70%
82%
80%
9
10
11
12
13
14
15
16
17
18b
19c
20c,d
THF
THF
THF
THF + H2O (0.1 mL)
DME
DME
DME
DME
K3PO4
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (0.5 mmol), solvent
Various boronic acids were tested to examine the generality of
our protocol. However, only 39% yield was obtained with using 4-
methylphenyl boronic acid (Table S1 in Supplementary data). After
screening of serval additives and photocatalysts, DMAP was found
to be able to improve the yield to 64% yield (3m, Table 3). A stron-
ger electron-rich substrate 4-methoxyphenyl boronic acid pro-
vided lower yield of desired product (3n, 50% yield). And 4-
phenyl substituted ester 3o could be synthesized with 75% yield
in this reaction system. 2-Naphthylboronic acid resulted in the
desired product 3p with 65% yield. Electron with-drawing groups
gave moderate yields. 57% and 66% yields of 3n and 3o were iso-
lated with using para-methylsulfonyl and cyano phenylboronic
acids, respectively. The installation of ester group on the meta
position didn’t affect the efficiency, 70% yield of 3 s was obtained
without employment of DMAP. Bulky substrates like 2-methyl
and 2-phenyl substituted phenyl boronic acids could also be
employed in this system, providing 72% and 68% yields, respec-
tively (3 t and 3u).
(2 mL), 50 W Blue LEDs, air, 12 h, 40 ℃, Isolated yield.
b
24 h.
c
1a (0.4 mmol), 2a (0.2 mmol), 24 h.
36 h.
d
PhCF3, DMSO, or MeOH (entries 3–6). Only ether solvents provided
the desired product with 33–36% yields (entries 7–9). DME and
THF furnished a slightly better result (36%) than 1,4-dioxane
(33%). Various bases were tested in the next step. The substrates
possibly can’t be survived in strong base like LiOtBu, affording only
trace amount of 3a (entry 10). Weak bases, such as Na2CO3 and
Na3PO4 also couldn’t promote this transformation (entries 12 and
14). Finally, K3PO4 gave the best result (63% yield) among the bases
screened (entry 15). A small amount of water (0.1 mL) typically
employed in boronic acids involved reactions decreased the iso-
lated yield of 3a to 38% (entry 16). DME also provided comparable
result in the presence of K3PO4 (64% yield, entry 17). Prolonging the
reaction time could increase the yield of 3a to 70% (entry 18). At
the same time, reversion of the ratio of 1a and 2a to 2:1 elevated
the yield to 82% (entry 19). A longer reaction time wasn’t helpful
for this transformation, giving 80% yield of 3a after 36 h (entry 20).
The protecting groups of amides were explored (Table 4).
Mono- or di-t-butyloxy carbonyl group attached benzamide 1b
and 1c couldn’t afford the desired product 3a. With using
1-benzoylpiperidine-2,6-dione 1d, 50% yield of 3a was isolated,
probably owing to the less steric hinderance of the protecting
2

H. Ding et al.
Tetrahedron Letters 61 (2020) 152444
Table 3
Scope of boronic acids
Scheme 2. Control experiments.
aReaction condition:1a (0.4 mmol), 2a (0.2 mmol), K3PO4 (0.5 mmol), DMAP
(0.4 mmol), DME (2 mL), 50 W Blue LEDs, air, 24 h, 40 ℃. bWithout DMAP.
Table 4
Scope of protecting groups on the nitrogen atom.a
aReaction condition: 1 (0.4 mmol), 2a (0.2 mmol), K3PO4 (0.5 mmol), DME (2 mL),
50 W Blue LEDs, air, 24 h, 40 ℃.
Scheme 3. UV–vis absorption of solutions.
group. Substrate 1f containing both acyl and sulfonyl groups
afforded better result, providing product 3a with 62% yield.
To investigate the mechanism of this reaction, serval control
experiments were performed (Scheme 2). When the model reac-
tion was conducted either in argon atmosphere or in dark, no
desired product was detected, which implied that visible light-
mediated oxidation by air was critical for the esterification of
amides (Scheme 2a and 2b). Reaction of sulfulamide 1a and phenol
4 proceeded smoothly to furnish ester 3 m with 95% yield, indicat-
ing that phenol might be the key intermediate in our reaction sys-
tem (Scheme 2c). However, without participation of sulfulamide
1a, only trace amount of phenol was detected under the reaction
conditions, suggesting that aryl boronic acid couldn’t be excited
directly with blue light (Scheme 2d).
The UV–vis absorption spectrum of reaction solutions provided
a deeper insight into the reaction mechanism (Scheme 3). The 1,2-
dimethoxyethane solution of sulfonamide 1a, boronic acid 2b, or
mixture of 1a and 2b exhibited very low absorption at 460 nm
(blue light). However, with addition of K3PO4, a significant increase
of the absorption was observed. And a further red shift occurred
after the addition of DMAP, implying that a base-coordinated and
visible light-excitable complex was formed. (Scheme 4).
After carefully examining the references about oxidation of
boronic acids [10] and esterification of amides [7] with alcohols,
Scheme 4. Proposed mechanism.
3

H. Ding et al.
Tetrahedron Letters 61 (2020) 152444
16409;
a proposed mechanism was depicted in Scheme 3. The red shift in
UV–vis absorption spectrum indicated that the assembly of sulfon-
amide 1, boronic acid 2, and K3PO4/DMAP occurred to form a visi-
ble light-excitable complex A. In this intermediate, base-
coordinated boron anion was paired with cationic potassium-coor-
dinated sulfulamide [11]. Photoactivation of complex A was fol-
lowed to reduce molecular oxygen to superoxide radical anion
and radical cation intermediate B. Boronic acid reacted with the
radical anion to produce the intermediate C. Abstraction of hydro-
gen atom from D generated from complex B and solvent occurred
to afford the superoxide E and cation F. Nucleophilic addition to
amide 1 by H stemmed from rearrangement of E and subsequent
hydrolysis produced intermediate I. Finally, thermodynamic col-
lapse of I gave rise to the ester product 3.
In summary, we have developed a novel transition metal-free
methodology for visible light-mediated esterification of amide.
This protocol utilizing commercially available boronic acids
expanded the diversity of ester products derived from phenols.
The mild reaction conditions employed in this method had a high
potential utility in late-stage transformation of amide drugs and
materials.
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Declaration of Competing Interest
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(q) X. Li, G. Zou, J. Organomet. Chem. 794 (2015) 136–145;
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The authors declare that they have no known competing finan-
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to influence the work reported in this paper.
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