Transition-Metal-Free DMAP-Mediated Aromatic Esterification of Amides with Organoboronic Acids

Article abstract of DOI:10.1002/ejoc.202100478

A new, transition-metal-free, effective method for aromatic esterification of amides with organoboronic acids has been developed. A wide range of benzoate derivatives were obtained with yields ranging from moderate to good. The catalytic reaction shows a broad substrate scope and excellent functional group tolerance. Conceptually, DMAP mediates the reaction and is crucial for this transformation.

Full text of DOI:10.1002/ejoc.202100478

Communications
doi.org/10.1002/ejoc.202100478
Transition-Metal-Free DMAP-Mediated Aromatic
Esterification of Amides with Organoboronic Acids
Tao Wang,*[a, b] Yanqing Wang,[a] Kai Xu,[a, b] Yuheng Zhang,[a, b] Jiarui Guo,[a, b] and
Lantao Liu*[a, b, c]
A new, transition-metal-free, effective method for aromatic
esterification of amides with organoboronic acids has been
developed. A wide range of benzoate derivatives were obtained
with yields ranging from moderate to good. The catalytic
reaction shows a broad substrate scope and excellent functional
group tolerance. Conceptually, DMAP mediates the reaction
and is crucial for this transformation.
Amides are versatile building blocks existing in natural prod-
ucts, proteins and various other organic molecules of
importance.[1] During the past decades, the development of
methods to construct amides have been well studied. In
contrast, the conversion of amides to other functional groups is
an important task in organic synthesis, which is also
challenging.[2] The main reason stems from the strength of the
amides CÀ N bond, which benefit from well-known resonance
stabilization.[3] With this longstanding challenge in mind, recent
attentions have turned to the cleavage of amide CÀ N bonds.[4,5]
Among, a significant breakthrough has been made in the use of
amides as benign reactants to synthesize esters. For instance,
the groups of Garg[6] and Danoun[7] reported the amide to ester
interconversion using transition-metal-catalyzed activation of
the amide CÀ N bond via a versatile acyl-metal intermediate
Scheme 1. Different strategies for the conversion of amides into esters.
and co-workers (Scheme 1A, right).[10] Besides these advances,
Zeng and co-workers[11] showed a new protocol for the aerobic
oxidative coupling of amides with arylboronic acids using the
fluoride and palladium as cooperative catalysis (Scheme 1B).
Despite the impressive progress made so far in the trans-
formations, the optimization and development of new con-
ceptual methods to convert amides to esters are still an
attractive research topic.[12] In our previous work, we have
developed efficient catalytic systems for the Suzuki-Miyaura
cross-coupling of N-acylsuccin imides with arylboronic acids via
CÀ N bond activation.[13] These leading results encourage us to
develop new synthetic methods based on CÀ N bond cleavage
of amides under exceedingly mild conditions. In addition,
contrast phenol derivatives, arylboronic acids are less toxic,
highly stable under air and moisture, commercially available
and cost effective.[14] Herein, we describe esterification of
arylamides with arylboronic acids under transition-metal-free
conditions (Scheme 1C). This operationally simple, mild, and
practical method exhibits functional group compatibility and
represents a practical alternative to existing the aromatic
esterification of amides with organoboronic acids.
(Scheme 1A, left). Later, Szostak[8] and Lei[9] developed
a
remarkable esterification of amide under transition-metal free
condition using excess base, which widely expand the scope of
amide substrates (Scheme 1A, right). Very recently, a general
transition-metal-free hydrogen bond assisted base-catalyzed
esterification of diverse amides has also been realized by Tu
[a] T. Wang, Y. Wang, K. Xu, Y. Zhang, J. Guo, Prof. L. Liu
School of Chemistry and Chemical Engineering,
Henan Engineering Laboratory of Green Synthesis for Pharmaceuticals
Shangqiu Normal University
Shangqiu, Henan 476000, China
E-mail: liult05@iccas.ac.cn
wt67751726@126.com
[b] T. Wang, K. Xu, Y. Zhang, J. Guo, Prof. L. Liu
School of Chemistry and Chemical Engineering,
Henan Key Laboratory of Biomolecular Recognition and Sensing
Shangqiu Normal University
Shangqiu, Henan 476000, China
https://hxhgxy.sqnu.edu.cn/info/1099/2448.htm
[c] Prof. L. Liu
The transition-metal-free aromatic esterification of amide
1a with phenylboronic acid 2a using TBHP as oxidant in the
dry xylenes was first examined. As shown in Table 1, no reaction
occurred with different types of bases (entries 1–5). Gratifyingly,
when DMAP was employed, product 3a was generated in 82%
yield (entry 6). The reaction did not occur when air has been
tested as an oxidant (entry 7). Other oxidants such as K2S2O8, m-
CPBA, Ag2O, and H2O2 gave inferior results (entry 6 vs entries 8–
College of Chemistry
Zhengzhou University
Zhengzhou, Henan 450001, China
https://hxhgxy.sqnu.edu.cn/info/1099/2477.htm
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100478
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Table 1. Optimization of reaction conditions.[a]
Table 2. Evaluating of amide substrates.[a]
Entry
Base
Oxidant
Solvent
Yield [%] [b]
1
2
3
4
5
6
7
8
K2CO3
Na2CO3
Cs2CO3
K3PO4
Et3N
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Air
K2S2O8
m-CPBA
Ag2O
H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
Xylenes
THF
–
–
–
–
–
82
–
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
–
9
18
trace
62
79
88
88
91
82
85
20
36
91
[a] All reactions were carried out using 1 (0.20 mmol), 2a (0.60 mmol),
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
20[f]
°
DMAP (2.0 equiv), TBHP (1.0 equiv) in toluene (2.0 mL) at 100 C for 12 h.
[b] Isolated yields.
CH3CN
DCE
Toluene
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
Table 3. Scope of the amide substrates.[a]
[a] All reactions were carried out using 1a (0.20 mmol), 2a (0.60 mmol),
°
base (2.0 equiv), oxidant (2.0 equiv), solvent (2.0 mL) at 100 C for 12 h. [b]
Isolated yields. [c] DMAP (1.0 equiv). [d] DMAP (0.2 equiv). [e] DMAP
(1.0 equiv), TBHP (1.0 equiv). [f] TBHP (1.0 equiv).
11). Next, the solvents of THF, CH3CN, DCE, toluene and 1,4-
dioxane were investigated (entries 12–16). Toluene showed the
best result and afforded desired product in 91% yield (entry 15).
The loading of DMAP and TBHP on the catalytic reactions was
also checked (entries 15 and 17–20). With 2.0 equivalent of
DMAP and 1.0 equivalent of TBHP, the corresponding phenyl 4-
methoxybenzoate 3a was isolated in excellent yield (up to
91%) (entry 20). Eventually, the screening efforts, which
involved testing base, oxidant, solvent as well as the amount of
base and oxidant, led to the suitable reaction conditions of this
approach.
[a] All reactions were carried out using 1 (0.20 mmol), 2a (0.60 mmol),
°
DMAP (2.0 equiv), TBHP (1.0 equiv) in toluene (2.0 mL) at 100 C for 12 h.
[b] Isolated yields.
By applying these suitable reaction conditions, the other
four classes of amides, including N-acylphthalimides, N-acyl-
glutarimides, N-acyl-5,5-dimethylhydantoins and N-acylsacchar-
ins were tested. As summarized in Table 2, it is evident that the
transformation is sensitive to the choice of N-substituents. N-
Acylphthalimides 1b gave a slightly lower yield (85%). When
the N-Acyl-glutarimides 1c and N-Acylsaccharins 1e were
tested, the yield of the products decreased to 17% and 29%,
respectively. Additionally, it was observed that N-Acyl-5,5-
Dimethylhydantoins 1d was completely unreactive. This result
suggested that an attempt to focus on the esterification of N-
acylsuccinimides with arylboronic acids will be highlighted.
The substituents effect of N-Acylsuccinimides 1f–1o were
investigated by their reactions with phenylboronic acid 2a
(Table 3). We were delighted to find that all the reactions
proceeded smoothly to generate benzoate derivatives under
the optimal condition. Roughly, the electron-donating group in
the phenyl ring of N-Acylsuccinimides are benefit to the yields
of the desired products (3b–3h). Sterically hindered substitu-
ents on the N-Acylsuccinimides component resulted in a slightly
decrease in yield (3c and 3f). Gratifyingly, heterocyclic amide
such as thiophene derivative 1o could proceed smoothly with
phenylboronic acid 2a, and the product 3k was isolated in 73%
yield.
Next, the scope of arylboronic acids was explored through
their reactions with 1-(4-methoxybenzoyl)pyrrolidine-2,5-dione
1a (Table 4). Substituents including methyl, methoxy, tertiary
butyl, trimethylsilyl, fluoro, phenyl, trifluoromethyl and nitro
groups were perfectly tolerated regardless of their position on
phenyl ring (4a–4m). The esterification reactions of 1-(4-meth-
oxybenzoyl)pyrrolidine-2,5-dione 1a with 4-nitrophenylboronic
acid resulted in a slight decrease of yield (4m, 52% yield).
Furthermore, 1-naphthylboronic acid, 2-naphthylboronic acid,
9-phenanthreneboronic acid and 1-pyrenylboronic acid were
employed in this approach, and the corresponding products
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Table 4. Scope of the arylboronic acids.[a]
°
[a] All reactions were carried out using 1a (0.20 mmol), 2 (0.60 mmol), DMAP (2.0 equiv), TBHP (1.0 equiv) in toluene (2.0 mL) at 100 C for 12 h. [b] Isolated
yields.
were generated in good yield (4n–4q). Pleasingly, this new
method is also compatible with heteroatom-containing arylbor-
onic acids to give the corresponding esterification products in
moderate to good yield yields (4r–4t). However, a slightly lower
Scheme 2. Scale-up experiment.
yield of 4u–4v was obtained when aliphatic boronic acids such
as isopropyl boronic acid and cyclopentyl boronic acid were
used as the substrates. The present strategy may open the door
for further application in the modification of natural product
synthesis.
To demonstrate the synthetic utility of this method, the
reaction was performed on 1 mmol scale, producing phenyl 4-
methoxybenzoate 3a in 81% yield (Scheme 2).
To understand the reaction mechanism, some control
experiments were performed (Scheme 3). Firstly, trace amount
of phenol was detected when the reaction between phenyl-
corresponding phenol was generated in 35% yield (Scheme 3B).
Next, the esterification of amide 1a with phenol proceeds in
excellent 89% yield using DMAP as a base and toluene as a
°
solvent at 100 C for 12 h (Scheme 3C). Therefore, phenol may
be an intermediate for the transformation of amides with
arylboronic acids to esters.
A putative reaction mechanism was then proposed as
outlined in Scheme 4 base on the previous reports[8,15] and the
control experiments. First, DMAP was oxidized to form N-oxide
intermediate I, which can be detected by GC-MS. Subsequently,
aryl boronic acid was converted to phenol by nucleophilic
°
boronic acid 2a and TBHP was carried out in toluene at 100 C
for 12 h (Scheme 3A). Subsequently, when phenylboronic acid
was employed under the optimal reaction conditions, and the
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Henan Province (192102110222), the Program for Science &
Technology Innovation Talents in Universities of Henan Province
(14HASTIT016) and the Program of Science and Technology
Innovation Talents of Henan Province (No. 184100510011).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Amides · Esterification · Organoboronic acids ·
Transition-metal-free
Scheme 3. Control experiments of the aromatic esterification of amides with
arylboronic acids.
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Acknowledgements
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 21572126), the Key
Science Research of Education Committee in Henan Province
(19A150035), the Key Scientific and Technological Project of
Manuscript received: April 17, 2021
Revised manuscript received: May 25, 2021
Accepted manuscript online: May 27, 2021
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