Catalyst-Free Singlet Oxygen-Promoted Decarboxylative Amidation of α-Keto Acids with Free Amines

Article abstract of DOI:10.1021/acs.orglett.6b01296

A novel catalyst-free decarboxylative amidation of α-keto acids with amines under mild conditions has been developed. Advantages of the new protocol include avoidance of metal catalysts and high levels of functional group tolerance. In addition, the reaction can be scaled up and shows high chemoselectivity. Preliminary mechanistic studies suggest that singlet oxygen, generated from oxygen under irradiation, is the key promoter for this catalyst-free transformation.

Full text of DOI:10.1021/acs.orglett.6b01296

Letter
pubs.acs.org/OrgLett
Catalyst-Free Singlet Oxygen-Promoted Decarboxylative Amidation
of α‑Keto Acids with Free Amines
Wen-Tao Xu, Bei Huang, Jian-Jun Dai, Jun Xu, and Hua-Jian Xu*
School of Biological and Medical Engineering, Hefei University of Technology, Key Laboratory of Advanced Functional Materials and
Devices of Anhui Province, Hefei 230009, P. R. China
S
* Supporting Information
ABSTRACT: A novel catalyst-free decarboxylative amidation of α-keto acids
with amines under mild conditions has been developed. Advantages of the new
protocol include avoidance of metal catalysts and high levels of functional group
tolerance. In addition, the reaction can be scaled up and shows high
chemoselectivity. Preliminary mechanistic studies suggest that singlet oxygen,
generated from oxygen under irradiation, is the key promoter for this catalyst-free
transformation.
mides are ubiquitous organic functional groups, especially
as components of natural products and pharmaceuticals.1
Wang’s,7,10 Chen’s,8 MacMillan’s,9 and Fu’s work.11 Although
decarboxylative coupling of α-keto acids has been proven to be a
powerful method for forming C−C bonds, oxidative coupling of
α-keto acids with amines for forming C−N bonds has been less
explored, especially with weakly nucleophilic aromatic amines. In
2014, Lei et al. disclosed decarboxylative amidation by employing
[Ru(phen)3]Cl2 as the photocatalyst (Scheme 1, eq 2).12 In
contrast to Bode’s work, Lei developed a new photoredox
process for synthesis of amides. Herein, we found that α-keto
acids could react with amines in the presence of O2 and H2O and
underwent a decarboxylative oxidation process to produce
amides (Scheme 1, eq 3). The reaction can proceed smoothly
without adding any photocatalyst.
A
The most prevalent strategy for preparing amides is the
interconversion of amines with carboxylic acids or carboxylic
acid derivatives, but due to the need to protect other functional
groups fully, the lability of activated carboxylic acid derivatives
and the low chemoselectivity makes a new generation of bond-
forming reactions using acyl anion equivant increasingly
attractive.2,3 The development of new amide linkage methods
using stable acyl synthon equivalents has received considerable
attention. In 2012, Bode reported that O-benzoyl hydroxyl-
amines underwent rapid amide formation in aqueous solvents
without the need for reagents or catalysts (Scheme 1, eq 1).3 An
Mechanistic investigations revealed that, in contrast to a
previous report,12 this reaction proceeds through an α-imino
acid13 intermediate, and the key enabler of this catalyst-free
process is attributed to the involvement of singlet oxygen,
generated under irradiation under our reaction conditions. This
reaction provides an easy-to-handle protocol for production of
amides and also demonstrates a new application of decarbox-
ylative carbon−heteroatom coupling reactions promoted by
photoexcited singlet oxygen.
Scheme 1. Recent Amide Linkage Methods Using Stable Acyl
Synthon Equivalents
We started our investigation with benzoylformic acid (1a) and
4-methylaniline (2a) as the standard substrates in the presence of
O2 exposed to two 23 W household bulbs at room temperature
(Table 1). First, based on Bode’s work,14 we were pleased to find
that a solution of these two reactants in dimethylformamide
(DMF) produced the desired amide product in 26% yield (entry
1). The screening of solvents showed that 1,4-dioxane/H2O (5:1,
v:v) was the optimal solvent (entries 2−9). Changing the ratio of
1a and 2a from 1.0/1.5 to 1.5/1.0 resulted in a 75% GC yield (in
68% isolated yield, entry 10). Further studies showed that the
yield of 3a was slightly decreased with the addition of a base or an
acid (entries 11−13). Finally, extending the reaction time to 48 h
effective aryl donor, potassium acyltrifluoroborate, has been
reported in the literature. The reactions are chemoselective, high
yielding, and operationally simple and provide a green method
for synthesis of amides.
Recently, α-keto acids have emerged as a new acyl anion
reagent.4 Significant progress has been made in the development
of photoredox catalysis,5 and photocatalysis has been widely
applied in organic synthesis because of the mild and green
conditions.6 Decarboxylative acylation for construction of Csp2−
Csp bonds, Csp2−Csp2 bonds, and Csp2−Csp3 bonds in
photochemistry has attracted considerable attention, such as
Received: May 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of α-Keto Acids
c
entry
solvent
DMF
additive
yield (%)
1
2
3
4
5
6
7
8
9
26
tBuOH
15
1-Butanol
CH3OH
4
8
CH3CN
trace
20
DMSO
dioxane
45
DCM
2
b
b
b
b
b
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
dioxane/H2O
67
d
10
75 (68)
45
11
12
13
Et3N
CH3COONa
CH3COOH
56
63
d
,
e
b
14
dioxane/H2O
87 (80)
trace
nd
d
,
,
f
b
15
16
dioxane/H2O
dioxane/H2O
d
g
b
a
Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), irradiation
with two 23 W household light bulbs in solvent (3 mL) at room
temperature for 24 h under O2 atmosphere, unless otherwise noted.
b
c
The ratio is 5:1 (v:v). GC yields. The number in parentheses is the
d
e
f
isolated yield. 1a (0.375 mmol), 2a (0.25 mmol). 48 h. Reaction
was carried out in the dark for 48 h. Reaction was carried out under
g
N2 for 48 h. DMF = dimethylformamide; DMSO = dimethyl sulfoxide;
DCM = dichloromethane; n.d. = not detected. CFL = compact
fluorescent light.
a
Reaction conditions: 1 (0.375 mmol), 2a (0.25 mmol), 1,4-dioxane/
H2O (2.5:0.5 v/v) irradiation with two 23 W household light bulbs at
room temperature for 48 h under O2 atmosphere, unless otherwise
resulted in an optimal yield of 3a (80% isolated yield, entry 14).
In addition, two control experiments indicated that visible light
and O2 were necessary for the success of this reaction (entries 15
and 16).
b
noted. Yield of isolated product. 1 (0.5 mmol), 2a (0.25 mmol), tert-
c
butyl hydroperoxide (TBHP, 0.5 mmol). 1 (0.5 mmol), 2a (0.25
The optimized reaction conditions were applied to the
decarboxylative amidation of a variety of α-keto acids (1) with
modest to good yields (Scheme 2). The present reaction can
tolerate electron-donating groups (3b, 3c, 3i) well and electron-
withdrawing groups (3g, 3h). Notably, this reaction also showed
satisfactory tolerance of halogens (3d, 3e, 3f, 3j, 3k), which
provide available protocols for cross-coupling reactions. In
addition, a 2-naphthyl-substituted substrate worked well to
deliver the product in 74% yield (3l). However, an acetal-
substituted substrate resulted in slightly lower yields (3r).
Furthermore, aliphatic α-keto acids and heterocyclic α-keto acid
were also compatible with this reaction (3m−o and 3p).
Notably, 2-oxoacetic acid produced the corresponding amide
product (3q) in 91% yield.
The scope of amines was next investigated in reaction with
benzoylformic acid, as shown in Scheme 3. The reaction can
tolerate electron-donating groups such as tert-butyl (3u),
isopropyl (3v), and methoxy (3t, 3ac, 3ae) well as well as
electron-neutral groups (3s). To our delight, halide groups were
also found to be well compatible with the amidation reaction
(3w, 3x, 3ad, 47−71% yield). Anilines containing electron-
withdrawing groups such as acetyl (3y, 58%) and trifluoromethyl
(3z, 40%) groups reacted efficiently. In addition, aniline with an
unprotected carboxyl group in the para position gives the desired
amide (3ab) in 60% yield, illustrating that carboxyl functional
groups are tolerated and the reaction can avoid dehydration
condensation of 4-aminobenzoic acid itself. In addition, 4-
mmol).
morpholinoaniline could also afford the corresponding product
3af in 43% yield. Furthermore, reaction with benzylamine was
achieved in the presence of 2 equiv of tert-butyl hydroperoxide
(TBHP), but in lower yield (3ag). Encouraged by the results, we
proceeded to employ this decarboxylative amidation of
benzoylformic acids with the secondary amine pyrrolidine, and
the reaction gave the desired product 3ah in moderate yield
under the modified conditions.
We next focused our attention on the synthetic application of
the N-(p-tolyl)benzamide product (Scheme 4). A gram-scale
reaction between benzoylformic acid (2.25 g) and 4-methylani-
line (1.07 g) provided the N-(p-tolyl)benzamide (1.34 g) in 64%
yield.
Note that the present reaction permits a compatible reaction
profile. Under the reaction conditions described in this study, a
chemoselective amidation of 2-oxopentanedioic acid with 4-
methylaniline in the presence of an unprotected carboxyl group
could be accomplished in 60% yield without 4a′ and 4a″
(Scheme 5a). When the reaction of pyruvic acid with 4-
aminophenols was performed, we were pleased to find that the
amino group in 4-aminophenols was selectively acetylated,
affording 4-acetamidophenol 4b, without hydroxyl acetylated
product 4b′ (Scheme 5b).
B
DOI: 10.1021/acs.orglett.6b01296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
From the two control experiments (Table 1, entries 15 and
16), we know that visible light and O2 are necessary for the
success of this reaction. However, we wondered about the key
enabling factor featuring this catalyst-free process. One
possibility is that singlet oxygen is produced and is responsible
for the oxidative procedure coupling process under our standard
conditions.15 We carried out control experiments trying to verify
the presence of photoexcited singlet oxygen. Trapping experi-
ments using 1,3-diphenylisobenzofuran 516,17 and 9,10-dime-
thylanthracene 718,19 under the standard conditions afforded 6, a
dicarbonyl compound formed through an endoperoxide, and the
endoperoxide product 8 formed through [4 + 2] cycloaddition
involving 1O2, while the corresponding oxidation products 6 and
8 were not detected in the dark (Scheme 6). These trapping
Scheme 3. Scope of Amines
Scheme 6. Trapping Experiments of 1O2
a
Reaction conditions: 1a (0.375 mmol), 2 (0.25 mmol), 1,4-dioxane/
H2O (2.5:0.5, v-v) irradiation with two 23 W household light bulbs at
room temperature for 48 h under O2 atmosphere, unless otherwise
experiments of 1O2 and the quenching experiments of 1O2 by 1,4-
diazabicyclo[2.2.2]octane (DABCO)20 (see the Supporting
Information) clearly indicate that O2 is produced from O2
b
noted. Yield of isolated product. 2 equiv (0.5 mmol) of TBHP was
1
c
added. 1a (0.25 mmol) and 2 (2.5 mmol) were added in 1,4-dioxane
under irradiation in our reaction system.
(3 mL).
According to Gooßen’s work,21 2-phenyl-2-(p-tolylimino)-
acetic acid was successfully obtained and converted to the amide
product 3a in 65% yield under the standard conditions (Scheme
7).
Scheme 4. Gram-Scale Reaction
Scheme 7. Transformation of the Key Intermediate α-Imino
Acid
Scheme 5. Chemoselectivity Profile in Amidation
Based on the mechanistic investigations above, a possible
pathway for this decarboxylative amidation process is proposed
(Scheme 8). We reasoned that mixing α-keto acid 1 with primary
amine 2 first leads to condensation via the hemiaminal to α-
iminoacids 9.21 Then singlet oxygen, generated from oxygen
under illumination in our reaction system, abstracts an electron
from α-imino acids 9 to generate 10 and 11, which next undergo
decarboxylation to deliver N-arylimidoyl radicals22 (12) followed
by subsequently reacting with water to give enol compounds 13.
Compound 13 undergoes tautomerization to afford amides.3,14
The mechanism involving hydrolysis of 12 by water was further
supported by an H218O labeling experiment, in which 18O was
detected in the final amide product (see the Supporting
Information).
In summary, a novel catalyst-free oxidative decarboxylativea-
midation of α-keto acids with free amines under mild conditions
C
DOI: 10.1021/acs.orglett.6b01296
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
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4830−4833.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01296.
(12) Liu, J.; Liu, Q.; Yi, H.; Qin, C.; Bai, R.; Qi, X.; Lan, Y.; Lei, A.
Angew. Chem., Int. Ed. 2014, 53, 502−506.
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Experimental procedures and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
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1757. (b) Wang, H.; Yang, X.; Shao, W.; Chen, S.; Xie, J.; Zhang, X.;
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(16) The trapping experiment with 1,3-diphenylisobenzofuran was
successfully conducted to test the formation of singlet oxygen; see:
(a) Braun, A. M.; Maurette, M. T.; Oliveros, E. in Technologie
Photochimique; Press Polytechnique Romandes: Lausanne, 1986; p
453. (b) Facchin, G.; Minto, F.; Gleria, M.; Bertani, R.; Bortolus, P. J.
Inorg. Organomet. Polym. 1991, 1, 389−395.
*E-mail: hjxu@hfut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21272050, 21371044,
21472033). We thank Dr. Yu-Feng Liang from the University of
Goettingen for valuable discussions on the reaction mechanism.
We also thank Jian Jiang and Yu-Yang Sun in this group for
reproducing the results of compounds 3e, 3w, and 3ag.
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successfully conducted to verify the presence of singlet oxygen, see:
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Org. Lett. XXXX, XXX, XXX−XXX