Copper(i)-catalysed oxidative C-N coupling of 2-aminopyridine with terminal alkynes featuring a CC bond cleavage promoted by visible light

Article abstract of DOI:10.1039/c6cc05506k

Facile visible-light promoted copper-catalyzed aerobic oxidative C-N coupling between 2-aminopyridine and terminal alkynes at room temperature via CC triple bond cleavage is described. This reaction allows direct synthesis of biologically important pyridy

Full text of DOI:10.1039/c6cc05506k

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Copper(I)-Catalysed Oxidative C-N Coupling of 2-aminopyridine
with Terminal alkynes featuring an C≡C bond Cleavage promoted
by Visible Light
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Ayyakkannu Ragupathi, Arunachalam Sagadevan, Chun-Cheng Lin, Jih Ru Hwu, and Kuo
Chu Hwang*
www.rsc.org/
4
Facile visible-light promoted copper-catalyzed aerobic oxidative C- peptides, proteins and organic materials. Typically, pyridyl
N coupling between 2-aminopyridine and terminal alkynes at benzamides are frequently found in a diverse array of bioactive
room temperature via C≡C triple bond cleavage is described. This molecules, such as; luciferase inhibitor, antiulcer activity, antifungal
5
reaction allows direct synthesis of biologically important pyridyl activity, glucokinase activator, etc. (see Scheme 2).
amides by utilization of commercially available starting materials
NH
2
without the need of bases/external oxidants.
H
H
H
N
N
N
N
N
O
N
Reactions involving C≡C triple bond cleavage is of great challenge
O
O
R
O
Ph
antiulcer activity
R=I, CF
3
and fundamentally important in the construction of targeted
luciferase inhibitor
F
1
molecules in organic synthesis. In this regard, most of reports
H
N
2
N
H
focused on the use of stoichiometric organometallic complexes
N
N
O
F
O
and catalytic amounts of transition metal complexes (Scheme 1) to
O
O
GKA-60
glucokinase activator
1
,3
antifungal activity
HOOC
cleave the tough C≡C triple bond. Despite increasing attention of
these processes, these methods often suffer from the following
drawbacks, such as; a) requirement of specific (stoichiometric)
Scheme 2. Pyridyl benzamides in pharmaceuticals
3
a
organometallic complex with strong oxidants, b) often needs of
As a result, over years many efforts have been devoted to the
6
additional promotors (such as; 2-aminopyridine or 2-
preparation of pyridyl-amides.
Conventionally, preparation of
3
b,g
aminophenol),
of reactions, which sometimes lead to poor control in the selectivity groups and amines.
of required products. Although metal-catalysed C≡C triple bond other methods have also been developed, including; 1) coupling of
and c) requirement of high temperature in most
pyridyl-amides heavily relies on reaction of activated carbonyl
6
d
Apart from this classical approach, many
7
8
(
terminal and internal alkynes) cleavage reaction has been alkynes with azides, 2) Staudinger reaction, 3) direct oxidative
6
,9
reported, the direct oxidative coupling of 2-aminopyridine with amidation of benzyl alcohols, ketones, aldehyde, and 4) other
1
0
methods. Recently, copper and silver-catalysed coupling reactions
involving 2-aminopyridine with alkynes (including activated alkynes)
have been reported for the construction of imidazo[1,2-α]pyridines
terminal alkynes for the synthesis of heterocyclic amides via C≡C
triple bond cleavage remains unexplored.
[
Cu] [Pd] [Ru] [Au] or [Ag]
oxidants, >90 o
11
R
1
R
oxidized products
(cyclic products) under harsh conditions. Despite several elegant
C
(
formation of oxidized products via
examples have been described, the alternative platform with
combination of copper and light may provide a new opportunity for
developing effective process to synthesize N-(pyridine-2-yl)amides
through C≡C triple bond cleavage. Recently, photoredox copper-
complexes have been proven as an inexpensive catalyst for various
coupling reactions, including C-C, C-N, C-S, and C-O cross-coupling
R= H or alkyl/aryl
C
C bond cleavage)
Scheme 1 Transition metal-catalysed oxidative C≡C triple bond
cleavage
.
Nitrogen containing heterocyclic amides represent an important
building block in numerous natural products, pharmaceutical,
1
2
reactions. Previously, we reported several examples on visible
light-mediated CuCl-catalysed efficient C-C, C-N cross-coupling, and
13
C-H annulation reactions. We demonstrated that these coupling
reactions may proceed through the photoexcitation of copper(I)
13d
acetylides. Herein, we report a novel and effective oxidative
coupling of terminal alkynes with 2-aminopyridine through C≡C
triple bond cleavage under low energy visible light irradiation. The
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significance of the present chemistry is threefold; a) it is the first aminopyridine (1a) (0.5 mmol) and phenylacetylene (2a) (0.6
mmol) in the presence CuCl (5 mol%) in CH
benzamide (3a) in 92% yield and 5% pyridyl α-ketoamide (3aa
after 10 h irradiation under blue-LEDs. It is worthy to note that,
short time irradiation (3-4 h) or reaction in the presence of 0.5
equivalents of base (K CO ) accomplished 70% pyridyl α-
2 3
ketoamide (3aa) and trace amount of pyridyl benzamide (3a),
thus the reaction pathway goes through formation of pyridyl
3
CN affords pyridyl
example involving both oxidative coupling and cleavage reaction of
terminal alkynes, b) this C≡C triple bond cleavage occurs selectively
and provides pyridyl-amides, and c) mechanistic investigation
illustrates that in-situ formation of copper(II)-superoxo or -peroxo
complex might be the key catalyst responsible for oxidative
cleavage of terminal alkynes.
)
α-ketoamide. In the solvent screening, CH CN gives the best
3
yield of the pyridyl-amides (Table 1, entry 1). Other solvents
were also tested, but yields are poor (Table 1, entries 4-7). The
presence of water dramatically decreases the product yield to
3
6% (entry 10). In the screening of copper salts, CuX (X: Cl or
Br) turns out to be an effective catalyst and affords 3a in 92%
entries 1 & 2). But, CuCl2 is ineffective for the current
(
reaction (entry 3) and thus copper(I)-salt is responsible for the
observed coupling reaction. Control experiments also reveal
that the reaction does not occur upon exclusion of light, CuCl
or O
conducted using other light sources (ambient white light; entry
1), however, this light source provided lower yields as
2
(entries 12-14). Meanwhile, the reaction can be
1
compared to blue-LEDs.
a
Scheme 3 Transition metal-catalysed oxidative coupling reactions of
Table 2. Scope of 2-aminopyridines (1).
2
-aminopyridine.
O
5
mol% CuCl
R
R
a
+
Table 1 Optimization of reaction conditions.
N
NH2
O
CH CN, O2
N
N
H
3
3
RT,
blue LEDs
O
1
2a
5
mol% CuCl
+
Ph
N
N
H
3a
Ph
N
1
NH2
CH CN,RT, 10h
O2 blue LEDs
O
O
3
a
2a
N
N
N
N
N
N
H
H
H
Yield (%)b
Entry
[Cu] Catalyst
CuCl
Solvent
3
a 92% (10 h)
3
b 90% (10 h)
3c 92% (10 h)
1
2
CH CN
92
92
3
F
O
O
O
CuBr
CH CN
3
N
N
N
N
N
N
3
4
CuCl2
CuCl
CH CN
trace
84
H
H
3
H
CH CN/MeOH (1:1)
3d 87% (12 h)
3f 89% (12 h)
3
3e 86% (12 h)
Br
NC
5
CuCl
CuCl
CuCl
CH OH
64
O
MeO2C
O
3
O
6
DMF
THF
32
N
N
N
N
H
N
N
H
7
trace
H
3
g 78% (15 h)
3h
3i 70% (18 h)
8c
72% (15 h)
CuCl
CuCl
CH CN
3
10
10
a
Standard condition. Isolated yield after purification by column
9d
CH CN
chromatography on silica gel.
3
1
0e
1f
2g
3h
4i
CuCl
CuCl
CuCl
CuCl
CuCl
CH CN
36
80
n.r
3
With the optimized reaction conditions in hand (see Table 1,
entry 1), we have investigated the substrate scope of the 2-
aminopyridine derivatives (1) with 2a as a coupling partner
(see Table 2). Both electron-rich and electron-neutral groups
on 2-aminopyridine ring were well tolerated and produced
1
CH3CN
1
CH CN
3
1
CH CN
n.r
3
1
CH CN
trace
3
a
corresponding amides in good yields 86-92%
Importantly, electron-withdrawing groups, such as, ester and
mixture was irradiated with blue LEDs (power density: 40 mW/cm at nitrile-containing 2-aminopyridines 1h 1i), are also
atmosphere (1 atm.). Yield of compatible with phenylacetylene (1a), and result in 72 & 70%
the isolated product. Reaction conducted in the short time irradiation yields of the corresponding amides (3h
3i). It was found that
current protocol can well tolerate halo-substituted (X= F, Br) 2-
aminopyridines, and affords desired amides (3f 3g) in good
yields (89 & 78%), which can be used for further synthetic
(3a-3e).
Unless otherwise noted, reaction conditions are as follows; 1a (0.5
mmol), 2a (0.6 mmol) [Cu] catalyst (5 mol%), and solvent (7 mL). The
,
2
(
&
b
4
60 nm) for 10 h in the presence of O
2
c
&
d
e
(3h) Reaction conducted with 0.5 equivalent of K
2
CO
3
0.25 mL water
f
was added. Reaction irradiated with an ambient white light bulb for
&
2
g
1
5h (power density: 8 mW/cm at 460 nm). Reaction conducted in the
o
h
i
dark at 80 C with O
2
of O . n.r = No reaction, DMF= N, N-dimethylformamide.
2
. In the absence of [Cu] catalyst. In the absence
1
4
modification.
Next, the substrate scope of various terminal alkynes was
also investigated using 1a as a coupling partner (see Table 3).
Electron-rich phenylacetylenes (2b-2d) effectively couple with
2-aminopyridine (1a) to afford the corresponding amide
products (4b-4d) in good yields (Table 3). In addition,
The coupling between 2-aminopyridine (1a) and phenyl-
acetylene (2a) was chosen as a model reaction for all
optimization studies. In an initial study (Table 1), reaction of 2-
2
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naphthalene moieties (2e-2g) as well as aryl alkynes bearing used 3aa as the starting material and conducted experiments
fluoro-substituted group (2h) also proceeds with the coupling with 5 mol% CuCl in presence of light and O along with 5
2
reaction to furnish the corresponding products 4e-4h (Table 3). mol% of 2-aminopyridine or phenanthroline produce the
It is worthy to note that the current reaction produces trace or desired product 3a in 92% yield [Eq. (4)] However, no 3a
negligible amount of homocoupling 1,3-diyene by-product, in product was observed in the dark [Eq. (3)]. In contrast, 5 mol%
view that most of literature reported reactions involving of pyridine used in the reaction (3aa, O
2
& light) leads to no
terminal alkynes always produce 1,3-diynes as homocoupling reaction, only starting materials were collected [Eq. (5)]. Thus,
by-product under aerobic condition.
1
4b
The electron-deficient the in-situ generated bidentate ligand coordinated copper(II)-
phenylacetylenes 2i-2m effectively couple with 2- superoxo or -peroxo complex is most probably the key catalyst
(
)
aminopyridine (2a) to afford the desired amide products 4i-4m responsible for oxidative cleavage of pyridyl α-ketoamide to
in good yields of 78-85%. Moreover, other terminal alkynes, pyridyl benzamide. Indeed, copper(II)-superoxo or peroxo
including heteroaryl, cyclohexyl, and octyl alkynes, also complex could be easily generated by reaction of copper (I)-
1
7
successfully underwent the reaction to produce the salt with molecular oxygen in presence of bidentate ligands.
corresponding pyridyl-amide products (4n 4p), without any Moreover, coupling of 1a and 2a in the presence of 2,2,6,6-
side products. In addition, we have evaluated the green tetramethylpiperidine 1-oxyl (TEMPO, 50 mol%) was examined
-
1
3c
chemistry metrics for the synthesis of the pyridyl benzamide under the standard condition. The formation of pyridyl
(
single-crystal X-ray diffraction.
4b) (see details in S.I.). The structures of 4k was confirmed by benzamide (3a) was completely inhibited [Eq. (6)], suggesting
that a radical process might be involved in this reaction.
1
5
Table 3. Scope of terminal alkynes (2)
CH3CN, O2
3a
+
Ph
2a' (1. 2 eq)
Cu
(1)
N
NH2
4 h, RT, blue LEDs
2
58%
O
1a
5
mol% CuCl
CH3CN,O2
RT, blue LEDs
R
+
Ph
Cu 2a'
N
N
N
1
NH2
O
or
CuCl
(5 mol%)
H
5 mol% 1a or phen.
mol%CuCl, O2
-8 h, rt,
(
4) 3a
trace (2)
a
2
4
R
5
5-8 h, rt, O2
blue LEDs
9
2%
5
O
O
blue LEDs
O
Ph
N
N
N
N
N
N
N
N
H
H
H
H
O
OMe
tBu
3aa
4b 91% (10 h)
4c 92% (10 h)
4d 92% (10 h)
5 mol% CuCl or 2a' or
1a or pyridine or phen.
O2,10 h, rt or 80 oC,
(
isolated)
5
mol% CuCl, O2
(
5) n.r.
n.r.
(3)
(6)
O
O
O
5 mol% pyridine
8
-12 h, rt, blue LEDs (phen.= phenanthroline)
Dark condition
N
N
N
N
N
N
H
H
H
CH3CN, O2
1
a
+
Ph
+
TEMPO
3a
OMe
2a
(50 mol%) 24 h, RT, blue LEDs
0%
4e 88% (12h)
4f 90% (12 h)
4g 90% (12 h)
O
O
O
With respect to mechanistic control experiments and our
N
N
N
N
N
N
1
3c, d
H
H
H
previous studies, a plausible mechanism was proposed in
scheme Direct Photo-excitation of the in-situ generated
CO2Me
F
CO2Me
4
h 86% (12 h)
4i 85% (15 h)
4j 82% (18 h)
4.
copper(I) phenylacetylide by blue LEDs (see, uv-visible spectra
in figure-S3) generates a long lived triplet photoexcited Cu(I)-
O
O
O
NO2
1
3c,d
N
N
H
N
N
N
N
phenylacetylide
(LMCT).
via ligand to metal charge transfer
The photo-excited Cu(I)-phenylacetylide would
H
H
Ph
18
CF3
4
k 84% (18 h)
4l 81% (18 h)
4m 78% (18 h) O
undergo a single electron transfer (SET) process to donate an
electron to molecular oxygen to generate the Cu(II)-
O
O
O
1
3c,19
S
N
N
H
N
N
N
N
phenylacetylide and superoxide radical anion,
which is
H
H
5
evidenced by EPR measurements (see, supporting
information).
4
n 86% (15 h)
4o 86% (12 h)
4p 84% (12 h)
a
Standard condition. Isolated yield after purification by column
chromatography on silica gel.
.-
O2
O2
Ph
H
N
NH2
NH2
CuI
*
CuII
+
Ph
CuI
Ph
SET Ph
To gain insights regarding the reaction mechanism, a set of
control experiments were carried out [Eq. (1)-(5)]. First, the
CuCl
6
2
a'
5
N
H
blue-LEDs
Ref. 13c
1
3d
N
NH
2
pre-synthesized copper(I) phenylacetylide (2a'
)
(1.2 eqv)
Cl
O.
1a, O2
O2
1
a
[
Cu]
O
N
NH2
CuCl
could react with 1a and afford the amide product (3a) in 58%
isolated yield [Eq. (1)]. The reduced yield was attributed to
polymeric form of isolated copper(I) phenylacetylide
hv
CuII
O
O.
O
Cl
O
3
a
N
N
Ph
Ph
H
N
3
N
1
3c,16
H
aa
O
powder.
generated copper(I) phenylacetylide might be the
This control experiments show that in-situ
CuI
[Cu]
O
O
O.
[
Cu]
O
OH
1
3d
[Cu]
O
OH
photocatalyst involved in the oxidative coupling reaction.
We have isolated pyridyl α-ketoamide (3aa) (after short time
irradiation, 3h) and conducted some key control experiments
O
.
Ph
Ph
.
.
N
N
N
N
Ph
N
N
O
.
.
7
CO
O
8
6
for
presence of light and O
trace amount of pyridyl benzamide 3a [Eq. (2)]. Second, we
C
≡
C
triple bond cleavage; first, 5 mol% of CuCl or 2a' in
along with 3aa leads to formation of
radical-radical coupling
2
Scheme 4. Proposed reaction mechanism.
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Afterward, nucleophilic addition of 2-aminopyridine to Cu(II)
phenylacetylide results in the formation of the complex Cu(III)
7
8
9
1
3c,20
species.
and reaction with molecular oxygen afford pyridine
Subsequent reductive elimination of Cu(III) to Cu(I)
M. Kohn and R. Breinbauer, Angew. Chem., Int. Ed., 2004, 43
3
,
106.
1
3c,21
ketoamides and regenerate CuCl.
aminopyridine (as a bidentate ligand) could coordinate to Cu .
Residual (free) 2-
For amidation of benzylalcohol; (a) S. Selvamurugan, R.
Ramachandran, G. Prakash, P. Viswanathamurthi, J. G.
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I
I
Further photo excitation of the Cu -aminopyridine complex and
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chelated
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superoxo/-peroxo
1
7,22
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1
2a,23
3
aa) to form N-centred radical.
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monoxide elimination and recombination of N-centered
1
2
radical and carbon centered radical leads to formation of the
4
Wang, J. Liu, G. Li and M. Yuan, Green Chem., 2016, 18
604.
,
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2
In conclusion, we have demonstrated for the first time that C≡C 11 Cyclic product; (a) J. Zeng, Y. J. Tan, M. L. Leow and X.-W. Liu,
triple bond cleavage and facile synthesis of biologically important
pyridyl-amides can be acheived via visible light-initiated copper(I)
catalyzed oxidative C-N coupling of 2-aminopyridine with terminal
alkynes at room temperature. The current method works well for a
wide range of substrates including electron deficient 2-
aminopyridines and various terminal alkynes. The mechanistic
investigation illustrates that copper(II)-superoxo or -peroxo
complex is most probably responsible for oxidative cleavage of C≡C
triple bond in terminal alkynes. From the synthetic point of view,
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Acknowledgments; this work was supported by the Ministry of
Science and Technology, Taiwan.
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,
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DOI: 10.1039/C6CC05506K
ChemComm
COMMUNICATION
Graphical Abstract
Copper(I)-Catalysed Oxidative C-N Coupling of 2-aminopyridine with Terminal
alkynes featuring an C≡C bond Cleavage promoted by Visible Light
Ayyakkannu Ragupathi, Arunachalam Sagadevan, Chun-Cheng Lin, Jih Ru Hwu, and Kuo Chu Hwang*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
kchwang@mx.nthu.edu.tw; Fax: (+886) 35711082.
E-mail:
An efficient and eco-friendly approach to aerobic oxidative C-N coupling of 2-aminopyridine with terminal alkynes
for preparation of biologically important priydyl- amides via C C triple bond cleavage at room temperature.
≡
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This journal is © The Royal Society of Chemistry 20xx
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