Visible-light-mediated direct access to α-ketoamides by dealkylative amidation of tertiary amines with benzoylformic acids

Article abstract of DOI:10.1016/j.tetlet.2019.151191

A visible-light induced direct amidation of benzoylformic acids with tertiary amines has been explored. Tertiary amines underwent N-dealkylative amidation with α-keto acid in the presence of [Ir{dFCF₃ppy}₂(bpy)]PF₆ and Cs<

Full text of DOI:10.1016/j.tetlet.2019.151191

Journal Pre-proofs
Visible-light-mediated direct access to α-ketoamides by dealkylative amidation
of tertiary amines with benzoylformic acids
Zhiguo Zhang, Fangnan Liu, Jingwen Chen, Kai Zhou, Zongbi Bao, Baogen Su,
Qiwei Yang, Qilong Ren, Yiwen Yang
PII:
S0040-4039(19)30967-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151191
TETL 151191
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 July 2019
19 September 2019
20 September 2019
Please cite this article as: Zhang, Z., Liu, F., Chen, J., Zhou, K., Bao, Z., Su, B., Yang, Q., Ren, Q., Yang, Y., Visible-
light-mediated direct access to α-ketoamides by dealkylative amidation of tertiary amines with benzoylformic acids,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151191
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Visible-light-mediated direct access to α-ketoamides by dealkylative amidation of
tertiary amines with benzoylformic acids
Zhiguo Zhang, Fangnan Liu, Jingwen Chen, Kai Zhou, Zongbi Bao, Baogen Su, Qiwei Yang, Qilong Ren,
and Yiwen Yang*
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering
Zhejiang University, Hangzhou 310027, China
E-mail: ceywyang@zju.edu.cn
previous work
Abstract:
A
visible-light induced direct amidation of
a) phenyl thiocyanate
benzoylformic acids with tertiary amines has been explored.
Bu3P
Tertiary amines underwent N-dealkylative amidation with α-keto
acid in the presence of [Ir{dFCF ppy} (bpy)]PF and Cs CO ,
3 2 6 2 3
b) primary/secondary amine
coupling reagent/boride
O
O
R'
affording the corresponding α-ketoamides in good yields under
mild conditions. This transformation exhibits a wide substrate
scope and provides a facile synthetic approach to α-ketoamides.
R
N
R
OH
c) formamides
transition metal
R''
amide
carboxylic acids
our work
d) tertiary amine
Cu, Ag salt
R', R'' = H or alkyl
Key words: Amidation, Photoredox, α-Ketoamides, Visible-light
α-Ketoamides are important functional motifs for the
synthesis of pharmaceuticals, chemistry and bioactive natural
products [1]. Thus, the development of mild and versatile
synthetic methods for generating α-ketoamides has become a
field of intense research effort. As carboxylic acids are stable,
inexpensive and environmentally benign, a vast number of
methods for the synthesis of α-ketoamides via coupling
carboxylic acid with amine have been developed [2]. The first
direct amidation of carboxylic acid is reported by Grieco group in
which they employ phenyl thiocyanate as nitrogen source
O
O
R'
R' photoredox
mild condition
+
N
R'
N
R
R
OH
R'
R'
Scheme 1. Methods of direct amidation
At the initial investigation, we selected benzoylformic acid 1a
and triethylamine 1b as model substrate to optimize the reaction.
Several conventional photocatalysts were screened in the
(Scheme 1, a) [3]. Conventional protocols for amidation of
presence of BrCCl under blue LEDs irradiation. In general, the
3
carboxylic acid mostly depend on coupling reagent, which can
first transform the acid into active species thus easy to couple
with amines (Scheme 1, b) [4]. Later, further exploration
indicates that formamides can also be used as a starting material
in oxidative conversion of carboxylic acids to amines (Scheme 1,
c) [5].
Tertiary amines are ubiquitous functionalities in nature,
which can also serve as a source of nitrogen in the direct
amidation of carboxylic acid. Wang’s group first reported the
Ag-catalyzed direct synthesis of α-ketoamide using tertiary
amines as nitrogen source at high temperature (120 °C) [6]. Later,
Yin’s group disclosed the copper-catalyzed amidation of acids
with tertiary amines through C-N bond cleavage with the
reactivity of iridium catalysts (Ir(ppy) , [Ir(dtbbpy)(ppy) ]PF ,
3
2
6
[Ir{dFCF ppy} (bpy)]PF ) were better than [Ru(bpy) Cl ]·6H O,
3
2
6
3
2
2
organic dye (eosin Y and Rose Bengal) and acridinium salt (9-
mesityl-10-methylacridinium perchlorate) (Table 1, entries 1-6).
Remarkably, [Ir{dFCF ppy} (bpy)]PF gave 44% yield after 20
3
2
6
hours reaction. Encouraged by these results, we then embarked
on screening different solvents, the results showed that the direct
amidation proceeded best in DCM, whereas 7-24 % yield
detected in MeCN, DMF, MeOH and only trace products were
found in DMSO and THF (Table 1, entries 7-13). Having
optimized catalyst and solvent in hand, we intentionally
investigated the performance under a variety of base salts such as
Cs CO , CsF, CsOAc, Na CO , NaHCO , K HPO and K PO
2
3
2
3
3
2
4
3
4
assistance of large excess amount of toxic CCl
4
at a lower
2 3
(Table 1, entries 14-20). To our delight, Cs CO was found to be
temperature (60 °C) [7]. Nevertheless, the development of energy
efficient, environmental benign catalytic system for the direct
synthesis of α-ketoamides through C-N bond cleavage under mild
condition is highly desirable. In recent years, photosynthesis that
converting the infinite solar energy to chemical energy have
attracted tremendous research interest. Rueping’s group reported
the aerobic dealkylation of amines via Ir catalyst [8]. In addition,
our group has developed a new protocol to dealkylative addition
using tertiary amine as a starting material [9]. We envisaged that
the application of tertiary amines as starting reactant through
photoredox cycle is a favorable alternative for direct amidation.
As part of our ongoing efforts on photoredox C-N cleavage
coupling, we herein report the visible-light-mediated direct
amidation of benzoylformic acids with tertiary amines through C-
N bond cleavage under mild condition.
an effective additive that generated product in 62% yield. Control
experiments showed that only trace product was observed in the
absence of iridium catalyst or light. No product was found
without oxidant BrCCl , which indicated the oxidative reaction
3
cycle is important for this reaction.

With the optimal conditions in hand, the investigation of
carboxylic acid scope is under evaluation (Table 2). Initially,
benzoylformic acids substituted with methyl group were
examined in the reaction. For the carboxylic acid bearing ortho-
position methyl group exhibited somewhat steric effect, and
lower yields were observed (3b). Carboxylic acid bearing meta-
position or para-position methyl group underwent amidation
smoothly to give moderate yield 67-60% (3c-d). Gratifyingly,
various functional groups were well tolerated, both electron
donating- and electron withdrawing substituents at the para
position of the phenyl moiety proceeded smoothly (Table 2).
Halogen functional groups such as F, Cl and Br were well-
tolerated, leading to 50-55% yields (3e-h). In addition,
benzoylformic acids substituted with tBu and OMe gave
corresponding product in 61% and 63% yields (3i-j). Moreover,
Table 1. Optimization of Reaction Conditionsa
O
photocatalyst, additive
O
N
CO2H
visible light
+
N
solvent, r.t. 20 h
O
1a
2a
3a
0.4 mmol
0.8 mmol
PF6
PF6
N
N
F3C
N
Ir
tBu
tBu
N
N
N
N
Ir+
N
Ir+
F
N
F
N
N
F
F
F3C
Ir(ppy)3
Ir[(dtbbpy)(ppy)2]PF6
[Ir{dFCF ppy} (bpy)]PF
3
2
6
Yieldb
17%
2
-naphthyl(oxo)acetic acid 1k and 1-naphthyl(oxo)acetic acid 1l
Entry
Catalyst
Eosin Y
Solvent
Base
also underwent amidation to generate α-ketoamines in 61% and
60% yields, respectively.
1
2
3
4
CH
CH
CH
CH
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
-
-
-
-
Rose Bengal
Trace
Trace
28%
Table 2. Substrates scope of α-keto acidsa
3 2 2
[Ru(bpy) Cl ]·6H O
O
[
Ir{dFCF3ppy}2(bpy)]PF6 3 mol%
O
Ir(ppy)
3
N
R1
BrCCl3 (2 equiv), Cs2CO3 (2 equiv)
CO2H +
R1
N
BLED, DCM, r.t.
9
-Mesityl-10-
O
5
methylacridinium
perchlorate
CH
2
Cl
2
-
26%
1a-l
0.4 mmol
2a
0.8 mmol
3
a-l b
6
7
8
9
[Ir(dtbbpy)(ppy)
[Ir{dFCF ppy} (bpy)]PF
[Ir{dFCF ppy} (bpy)]PF
2
]PF
6
CH
2
2
Cl
Cl
2
2
-
-
-
-
-
-
-
-
36%
44%
24%
17%
19%
Trace
Trace
7%
O
O
N
O
N
N
3
2
6
6
6
6
6
6
6
CH
O
O
O
MeCN
DMF
3
2
3a, 60%
3b, 62%
3c, 57%
O
N
O
[Ir{dFCF ppy} (bpy)]PF
3
2
O
N
N
1
1
1
1
0
1
2
3
[Ir{dFCF ppy} (bpy)]PF
toluene
DMSO
THF
3
2
O
O
O
Br
F
[Ir{dFCF ppy} (bpy)]PF
3
2
3
d, 60%
3e, 52%
3f, 53%
[Ir{dFCF ppy} (bpy)]PF
3
2
O
O
O
N
N
N
N
[Ir{dFCF ppy} (bpy)]PF
3
2
MeOH
O
O
O
t-Bu
6
2%
c
Cl
1
4
[Ir{dFCF ppy} (bpy)]PF
CH
2
Cl
2
Cs
2
CO
3
Br
3
2
6
(
60%)
32%
46%
16%
43%
27%
42%
3g, 50%
3h, 55%
3i, 61%
1
1
1
1
1
2
2
5
6
7
8
9
0
1
[Ir{dFCF ppy} (bpy)]PF
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
Na
NaHCO
HPO
PO
2
CO
3
O
O
3
2
6
6
6
6
6
6
O
N
N
[Ir{dFCF ppy} (bpy)]PF
3
2
3
O
O
MeO
O
[Ir{dFCF ppy} (bpy)]PF
3
2
K
2
4
3
j, 63%
3k, 61%
3
l, 60%
[Ir{dFCF ppy} (bpy)]PF
3
2
K
3
4
aReaction conditions: benzoylformic acids 1 (0.4 mmol), tertiary amine 2 (0.8
mmol), [Ir{dFCF ppy} (bpy)]PF (0.012 mmol), BrCCl (0.8 mmol), Cs CO
3
3
2
6
3
2
[Ir{dFCF ppy} (bpy)]PF
3
2
CsOAc
CsF
(0.8 mmol), H O (0.4 mmol), DCM (2.0 mL), room temperature, using Blue
2
b
LEDs as the visible light source, 20 h. Isolated yield.
[Ir{dFCF ppy} (bpy)]PF
3
2
To determine the possible intermediate of the reaction, we
performed the reaction of benzoylformic acids with secondary
amine under optimized reaction conditions. No desired amidation
product was generated, and therefore the pathway involved
dealkylation to secondary amine for amidation can be ruled out.
On the basis of literature reports [8] and our experimental results,
-
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
Trace
Trace
n.r.
2
2d
3e
[Ir{dFCF ppy} (bpy)]PF
3
3
3
2
6
6
2
[Ir{dFCF ppy} (bpy)]PF
3
2
aReaction conditions: Benzoylformic Acids (0.2 mmol), TEA (2.0 equiv),
photocatalyst (3.0 mol%), base (2.0 equiv), solvent (2.0 mL), room a plausible mechanism was proposed (Scheme 2). Initially,
temperature, using blue LEDs as the visible light source, 20 h. Determined by iridium catalyst was excited to generate the excited state under
b
1
c
d
2 2
H NMR yield using CH Br as internal standard. Isolated yield. Performed in
the dark. Without BrCCl .
3
irradiation, which then undergoes single electron transfer (SET)
with tertiary amine 2a to generate the radical cation 4 and Ir
e
II
metal complex. Meanwhile, the radical cation 4 undergoes
dehydrogenation to afford iminium ion 5. Next, the iminium ion
5
was attacked by deprotonated carboxylic anions to the
intermediate 6, which undergo a rearrangement to give the

desired α-ketoamines 3.
(f) H. Lundberg, F. Tinnis, H. Adolfsson, Chem. - Eur. J. 18 (2012) 3822-
3826.
O
R
[3] P.A. Grieco, D.S. Clark, G.P. Withers, J. Org. Chem. 44 (1979) 2945-
N
2
947.
O
CH3CHO
[4] E. Valeur, M. Bradley, Chem. Soc. Rev. 38 (2009) 606-631.
3
N
[5] (a) P.S. Kumar, G.S. Kumar, R.A. Kumar, N.V. Reddy, K. Rajender
hn
Ir(III)*
Ir(II)
2a
Reddy, Eur. J. Org. Chem. 2013 (2013) 1218-1222;
O
(
b) Y.X. Xie, R.J. Song, X.H. Yang, J.N. Xiang, J.H. Li, Eur. J. Org.
Chem. 2013 (2013) 5737-5742;
c) D. Saberi, S. Mahdudi, S. Cheraghi, A. Heydari, J. Organomet. Chem.
72 (2014) 222-228;
d) H.-Q. Liu, J. Liu, Y.-H. Zhang, C.-D. Shao, J.-X. Yu, Chin. Chem.
- e
O
N
Ir(III)
R
(
7
(
O 6
CCl3
O
BrCCl3
N
Lett. 26 (2015) 11-14;
4
(e) X. Bi, J. Li, E. Shi, H. Wang, R. Gao, J. Xiao, Tetrahedron 72 (2016)
R
CO2
N
8
210-8214.
CCl3
5
[6] B. Xiong, L. Zhu, X. Feng, J. Lei, T. Chen, Y. Zhou, L.B. Han, C.T. Au,
S.F. Yin, Eur. J. Org. Chem. 2014 (2014) 4244-4247.
7] X. Zhang, W. Yang, L. Wang, Org. Biomol. Chem. 11 (2013) 3649-3654.
8] M. Rueping, C. Vila, A. Szadkowska, R.M. Koenigs, J. Fronert, ACS
Catal. 2 (2012) 2810-2815.
CHCl3
Scheme 2. Proposed plausible mechanism
[
[
In summary, we have developed an operationally convenient
visible-light induced direct amidation of benzoylformic acids
with tertiary amines under mild conditions. This protocol
tolerates a variety of functional groups and provides an
alternative procedure for the synthesis of α-ketoamide derivatives.
Further studies on the mechanism and applications of the reaction
are currently underway in our laboratory.
[9] (a) F. Liu, Z. Zhang, Z. Bao, B. Su, H. Xing, Q. Yang, Y. Yang, Q. Ren,
Synlett 28 (2017) 1116-1120;
(b) F. Liu, Z. Zhang, Z. Bao, H. Xing, Y. Yang, Q. Ren, Tetrahedron Lett.
5
8 (2017) 2707-2710.
Experimental Section
The 10-mL round-bottom flask was equipped with a magnetic
stirrer bar. Afterwards, tertiary amine
benzoylformic acids 2 (0.2 mmol), [Ir{dFCF
1
(0.4 mmol),
ppy} (bpy)]PF
(0.4 mmol) and DCM
2 mL) were added. Then, the reaction mixture was sealed with
3
2
6
3 2 3
(0.006 mmol), BrCCl (0.6 mmol), Cs CO
(
stopper and placed in room temperature. A 5 w blue LED was
placed at a distance of about 5 cm from the reaction vessel. After
the reaction was complete (as monitored by TLC), the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography on silica gel to afford the
desired product 3.
Highlights
Acknowledgements
We are grateful for financial support from the National Key R&D
Program of China (grant number 2016YFA0202900), the
National Natural Science Foundation of China (grant numbers
(1) First example of operationally convenient
2
1878266, 21776240, 21722609), the Fundamental Research
visible-light induced direct amidation of
benzoylformic acids with tertiary amines.
Funds for the Central Universities (grant number 2019FZA4021)
References and notes
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(
2) Direct synthesis of a series of α-ketoamide
derivatives under mild condition.
3) The developed photocatalytic system can be
(
b) N. Fusetani, S. Matsunaga, H. Matsumoto, Y. Takebayashi, J. Am.
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(
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(
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(
applied to a variety of benzoylformic acids bearing
different substitutes.
[
2] (a) M.J. Litjens, A.J. Straathof, J.A. Jongejan, J.J. Heijnen, Tetrahedron
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5 (1999) 12411-12418;
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(
(
(
(
(
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386-8400;

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Visible-light-mediated direct amidation of
benzoylformic acids with tertiary amines:
access to α-ketoamine
Leave this area blank for abstract info.
Zhiguo Zhang, Fangnan Liu, Jingwen Chen, Kai Zhou, Zongbi Bao, Baogen Su, Qiwei Yang, Qilong Ren, and
Yiwen Yang*
[
Ir{dFCF ppy} (bpy)]PF 3 mol%
O
3 2 6
O
R'
N
BrCCl (2 equiv), Cs CO (2 equiv)
R'
N
3
2
3
+
CO H
R'
2
R
R'
R'
BLED, DCM, r.t.
R
O
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