Visible light-mediated synthesis of amides from carboxylic acids and amine-boranes

Article abstract of DOI:10.1039/d1gc01157j

Here, a photocatalytic deoxygenative amidation protocol using readily available amine-boranes and carboxylic acids is described. This approach features mild conditions, moderate-to-good yields, easy scale-up, and up to 62 examples of functionalized amides with diverse substituents. The synthetic robustness of this method was also demonstrated by its application in the late-stage functionalization of several pharmaceutical molecules.

Full text of DOI:10.1039/d1gc01157j

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Visible light-mediated synthesis of amides from
carboxylic acids and amine-boranes†
Cite this: DOI: 10.1039/d1gc01157j
a,b
Yu-Qi Miao,a Jia-Xin Kang, a Yan-Na Ma
*
a,b and Xuenian Chen
*
Received 5th April 2021,
Accepted 22nd April 2021
DOI: 10.1039/d1gc01157j
rsc.li/greenchem
Here, a photocatalytic deoxygenative amidation protocol using most of these cases, a high temperature is needed. During the
readily available amine-boranes and carboxylic acids is described. preparation of our work, Ramachandran and co-workers
This approach features mild conditions, moderate-to-good yields, reported the amidation of carboxylic acids using amine-borane
easy scale-up, and up to 62 examples of functionalized amides (NH3BH3) as a dual-purpose reagent in xylenes under reflux.17
with diverse substituents. The synthetic robustness of this method This method was highly efficient because other reagents
was also demonstrated by its application in the late-stage were not needed, but the high temperature may limit the sub-
functionalization of several pharmaceutical molecules.
strate scope. Therefore, searching for more universal and
“green” methods for the synthesis of amides is highly
desired.18,19
The amide motif is an essential and intriguing structure
present in many crucial compounds, such as natural products,
pharmaceuticals, agrochemicals, and some synthetic
structures.1,2 More importantly, the amide motif has a remark-
able role in biological and natural peptides.3 In 2016, Brown
and colleagues analyzed the chemical reactions used in medic-
inal chemistry and natural products from 1984 to 2014. They
revealed that formation of the amide bond was involved in
most commonly used reactions.4 Hence, preparation of
amides, as a fundamental and significant reaction in synthetic
and pharmaceutical chemistry, is of great demand and interest
to chemists.5,6
Recently, use of photoredox catalysis enabled by visible
light has emerged as a valuable synthetic method that allows
the invention of novel chemical reactions under mild and
environmentally benign conditions.20–27 This strategy has also
been applied to the activation of carboxylic acids by the for-
mation of acyl radicals via single electron transfer (SET). In
2015, Wallentin and coworkers reported the first photocatalytic
tandem acylarylation of olefins using aromatic carboxylic acids
as starting materials under visible light.28 They also achieved
the photoredox-catalyzed multicomponent 1,2-acylalkylation of
The seemingly “ideal” synthetic method of amides should
be the direct condensation of carboxylic acids and amines.
However, the harsh conditions needed to suppress the for-
mation of carboxylate-ammonium salts limit its application.7,8
To solve this problem, coupling reagents have been developed
to activate carboxylic acids, which enable this transformation
to be achieved at room temperature (Scheme 1a).9,10 However,
use of coupling agents greatly decreases the atom economy. As
a response to these disadvantages, several metal-catalyzed11–13
or boron-catalyzed14–16 methods to form amide bonds have
emerged as an alternative protocol (Scheme 1b). However, in
aHenan Key Laboratory of Boron Chemistry and Advanced Energy Materials, School
of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
453007, China. E-mail: xnchen@htu.edu.cn, mayanna@htu.edu.cn
bGreen Catalysis Center and College of Chemistry, Zhengzhou University, Zhengzhou,
450001, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc01157j
Scheme 1 Synthetic approaches to amide formation.
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Table 1 Optimization of the reaction conditionsa
olefins.29 Subsequently, the teams of Zhu and Xie developed a
hydroacylation reaction of alkenes using carboxylic acids and
hydrosilanes,30 or H2O,31 and deoxygenative reduction or deu-
teration of carboxylic acids by hydrosilanes32 or D2O33 under
visible-light photoredox catalysis. However, applications of
visible light-mediated reactions of acyl radicals have been
limited to direct addition of acyl radicals onto carbon–carbon
multiple bonds to produce aldehydes or deuterated alde-
hydes.34 Direct transformation of carboxylic acids to amides by
photoredox catalysis has not been reported. Here, we report
the first example of direct formation of an amide bond
through a suitable amine source capturing acyl radicals pro-
duced via the SET pathway.
Organoboron reagents have been used widely in organic
synthesis.35–37 Our team has focused on the study of boron
chemistry for a long time.38–44 Hence, we selected NH3BH3 as
the amine source to verify the feasibility of our proposed
photoredox catalytic strategy. We employed 4-methoxybenzoic
acid and NH3BH3 as the standard substrates in the presence of
di-tert-butyl dicarbonate (Boc2O), which forms a mixed anhy-
dride intermediate to serve as oxidative and photocatalytic
quenchers.28–33 First, diverse solvents were evaluated using fac-
Ir(ppy)3 as the photocatalyst, and K2HPO4 as the base under
blue-light irradiation at room temperature. MeCN was found
to be the optimal solvent (entries 1–7). Screening of different
bases, such as NaOAc, NaHCO3, K2CO3, K3PO4, and 2,4,6-luti-
dine, did not produce better results (entries 8–12). Other
amine sources, such as NH4Cl, (NH4)2CO3 and NH4OAc, were
also examined: NH3BH3 was found to be the best choice
(entries 13–15). We also found that the reaction yield was
related to catalyst loading (entries 16–18). Control experiments
verified the requirement of a photocatalyst, visible light,
(Boc)2O and MgCl2 in this deoxygenative amidation reaction
(entries 19–21). Specifically, the Lewis acid MgCl2 could acti-
vate Boc2O in the reaction28 and a control experiment verified
that the reaction did not work without MgCl2.
Amine
source
Entry Photocatalyst Base
Solvents Yieldb
1
2
3
4
5
6
7
8
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
None
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
NaOAc
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
THF
DCE
20
55
Acetone 30
DMF
i-PrOH
35
34
Dioxane 12
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
75
Trace
41
13
40
47
25
34
30
64
43
34
13
10
0
9
NaHCO3
K2CO3
K3PO4
10
11
12
13
14
15
16c
17d
18e
19f
20g
21h
2,4,6-Lutidine NH3BH3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
NH4Cl
(NH4)2CO3
NH4OAc
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
NH3BH3
fac-Ir(ppy)3
fac-Ir(ppy)3
a The reactions conditions, unless noted otherwise, were: 4-methoxy-
benzoic acid (0.4 mmol, 2 eq.), NH3BH3 (0.2 mmol, 1 eq.), (Boc)2O
(1.2 mmol, 6 eq.), MgCl2 (0.4 mmol, 2 eq.), photocatalyst (4 mol%),
base (0.8 mmol, 4 eq.), and solvents (2 mL) were irradiated with 10 W
blue LEDs at room temperature under air for 36 h. b Yields were deter-
mined by 1H NMR using anisic aldehyde as the internal standard.
c Photocatalyst (3 mol%). d Photocatalyst (2 mol%). e Photocatalyst
(1 mol%). f Reaction was carried out in the absence of a photocatalyst.
g Reaction was done in the absence of light. h Reaction was undertaken
in the absence of (Boc)2O or MgCl2.
substrates with severe steric hindrance, such as 2,4,6-tri-
Once the optimized conditions had been confirmed methylbenzoic acid and triphenylacetic acid, the reactions did
(Table 1, entry 7), we evaluated the other substrates of this not work (Scheme 2). Finally, aliphatic carboxylic acids were
deoxygenative amidation transformation of carboxylic acids explored and the corresponding products were obtained in
with NH3BH3. We discovered that a wide array of aryl and alkyl 52%–71% yields (39–42).
carboxylic acids were appropriate substrates to give the desired
Bolstered by these encouraging data, we further evaluated
products 1–42 in 34%–89% yields. Functional groups (e.g., other amine-borane complexes,45–47 which included coordi-
methyl, methoxy, halo, nitrile, nitro, trifluoromethyl, tertiary nation to gaseous or low-boiling-point amines, and the results
butyl, phenoxy, alkynyl and heterocycles) were tolerated in are summarized in Scheme 3. A series of borane complexes
these reactions. Different types of aryl carboxylic acids, includ- with various substituents on the amine were found to be appli-
ing electron-donating and electron-withdrawing substituents cable substrates to give the desired amides in moderate-to-
at ortho-, meta- and para-positions of phenyl rings, were trans- good yields. Borane complexes of two gaseous amines, methyl-
formed to target amides. The electronic property of the substi- amine and dimethylamine, reacted with 4-methylbenzoic acid
tuents had only a slight effect on this reaction. Steric hin- to offer the corresponding 2°- (43) and 3°- (47) amides in 77%
drance of the substituents on aryl groups affected the deoxy- and 68% yields, respectively. Aliphatic 1°-amines with 1°- (44),
genative amidation slightly. Substrates with an ortho substitu- 2°- (45), or 3°- (46) alkyl substituents, as well as acyclic and
ent on the aryl group (24–31) gave relatively lower yields than cyclic 2°-amines, were suitable for this transformation. In
substrates with a meta or para substituent on the aryl group addition, 2°-amines containing alkyl and aryl substituents
(1–23). Polysubstituted aryl, naphthyl and heteroaryl carboxylic could also be used for this reaction. Also, the electronic prop-
acids could also undergo this transformation to give the erty greatly influenced the reactivity, with electron-withdrawing
desired amides 32–38 in moderate-to-good yields. However, for aniline giving a low yield (51, 52).
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Scheme 4 Late-stage functionalization of drug molecules.
to-good yields. In addition, secondary and tertiary alkyl car-
boxylic acids were compatible with this system. The success of
this photoredox deoxygenative amidation of complicated car-
boxylic acids indicated that this methodology could be used in
the design and development of drug molecules.
Scheme 2 Scope of carboxylic acids.
To evaluate the scalability of this method, a scaled-up reac-
tion between 4-methoxybenzoic acid and NH3BH3 was con-
ducted and the corresponding product, 4-methoxybenzamide,
was obtained in 65% yield (Scheme 5).
To obtain insight into the reaction mechanism, several
control experiments were carried out (Scheme 6). First, when
the frequently used radical scavenger TEMPO (2,2,6,6-tetra-
methylpiperidin-1-oxyl) was added to the model reaction, the
desired amidation reaction ceased completely. The corres-
ponding acyl radical-trapping product 63 was isolated and
1
determined by H, 13C NMR and HRMS. The tert-butyl radical
adduct 64 was also detected by HRMS (Scheme 6a), which indi-
cated the formation of an acyl radical and tert-butyl radical.
Second, the anhydride 65 was synthesized by the reaction of
4-methoxybenzoic acid with (Boc)2O, MgCl2, and K2HPO4 in
MeCN at room temperature (Scheme 6b). Interestingly, we iso-
lated the radical-trapping product 63 in 50% yield when
TEMPO was subjected to a mixture of anhydride 65 and photo-
Scheme 3 Scope of amine-boranes.
To further underscore the generality of this protocol, late-
stage modification of drug molecules was conducted
(Scheme 4). Various structurally complex carboxylic acids con-
taining different sensitive functional groups (e.g., amide,
ketone, and heterocycle) underwent this transformation effec-
tively with NH3BH3 to afford the desired amides in moderate- Scheme 5 Gram-scale reaction.
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In conclusion, we designed a mild, general, and efficient
program for visible light-mediated photoredox deoxygenation
amidation reactions between carboxylic acids and amine-
boranes. This photoredox protocol is suitable for aromatic
acids, heteroaromatic acids, and aliphatic acids containing
different functional groups (e.g., alkyl, alkoxy, halogen, –CN,
–NO2, –CF3, alkynyl, carbonyl, amide) as well as free, primary,
secondary, cyclic, and heterocyclic amines. The mild con-
ditions and excellent tolerance of functional groups means
that this methodology has broader substrate scope than that
in existing methods. Our method could be applicable for late-
stage functionalization of drug molecules.
Conflicts of interest
Scheme 6 Mechanism studies.
There are no conflicts to declare.
catalyst in MeCN under blue LEDs, which illustrated that the
photocatalyst had been recycled (Scheme 6c). We hypothesized
that the tert-butoxy anion played an important part in this
reaction. In addition, NH3BH3 reacted with 65 and a photo-
catalyst under modified conditions to produce the desired
amide in 60% yield, and we also detected the production of
tert-butanol by NMR and GC-MS (Scheme 6d).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21771057 and 21801065).
Notes and references
On the basis of experimental evidence and literature
reports,28–33,48,49 we proposed a plausible reaction mechanism
(Scheme 7). Initially, the mixed anhydride A is generated
in situ from carboxylic acid, (Boc)2O, and MgCl2 in the pres-
ence of K2HPO4. The photocatalyst fac-Ir(ppy)3 provides a long-
lived excited state Ir*III under visible-light irradiation. Then,
the SET step between this strong reducing species Ir*III and
anhydride A provides the radical precursor B and IrIV. After
fragmentation, B generates the acyl radical C along with the
tert-butoxy anion and CO2. Another SET process between the
tert-butoxy anion and IrIV produces the ground-state photo-
catalyst and tert-butoxy radical to complete the catalytic cycle.
The acyl radical C reacts with NH3BH3 and the tert-butoxy
radical to generate the amide-borane complex D, which further
delivers the desired amide.
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