Visible-light initiated copper(i)-catalysed oxidative C-N coupling of anilines with terminal alkynes: One-step synthesis of α-ketoamides

Article abstract of DOI:10.1039/c4gc01623h

Development of C-N coupling processes is fundamentally important and challenging for the synthesis of biologically active molecules and drugs. Herein, we report a highly atom efficient green process for the synthesis of α-ketoamides via visible-light induced copper(i) chloride catalysed direct oxidative C_sp-N coupling reactions using commercially available alkynes and anilines at room temperature without the use of hazardous chemicals and harsh reaction conditions. Forty-seven examples are presented using a broad range of substrates including electron deficient anilines and various terminal alkynes. The current photochemical process is able to achieve epoxide hydrolase inhibitors in one step with high yield (92-95%). This transformation is highly efficient and highly selective for the synthesis of α-ketoamides. This journal is

Full text of DOI:10.1039/c4gc01623h

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Sagadevan, A.
Ragupathi, C. Lin, J. R. Hwu and K. C. Hwang, Green Chem., 2014, DOI: 10.1039/C4GC01623H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Page 1 of 9
Green Chemistry
View Article Online
DOI: 10.1039/C4GC01623H
79x29mm (150 x 150 DPI)

Green Chemistry
Page 2 of 9
View Article Online
DOI: 10.1039/C4GC01623H
Green Chemistry
RSCPublishing
ARTICLE
VisibleꢀLight Initiated Copper(I)ꢀCatalysed Oxidative
CꢀN Coupling of Anilines with Terminal Alkynes: Oneꢀ
Step Synthesis of αꢀKetoamides
Cite this: DOI: 10.1039/x0xx00000x
Arunachalam Sagadevan, Ayyakkannu Ragupathi, ChunꢀCheng Lin, Jih Ru Hwu,
and Kuo Chu Hwang*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Development of CꢀN coupling processes is fundamentally important and challenging for the synthesis of
biologically active molecules and drugs. Herein, we report highly atomic efficient green process for the
synthesis of αꢀketoamides via visibleꢀlight induced copper(I) chloride catalysed direct oxidative CspꢀN
coupling reactions using commercially available alkynes and anilines at room temperature without the
use of hazardous chemicals and harsh reaction conditions. Forty seven examples are presented using a
broad range of substrates including electron deficient anilines and various terminal alkynes. The current
photochemical process is able to achieve epoxide hydrolase inhibitors in one step with high yield
(92~95%). This transformation is highly efficient and highly selective for the synthesis of αꢀketoamides.
www.rsc.org/
quinoxalines10 at room temperature, where the key
photocatalyst involved is copper(I) phenylacetylide. In this
Introduction
work, we further extend our methodology to catalyse CspꢀN
coupling reaction of anilines with terminal alkynes, in the
presence of molecular oxygen, to form biologically active αꢀ
ketoamides at room temperature, upon irradiation with blue
LEDs and without the need of any base.
The development of novel and highly efficient strategies for the
formation of carbonꢀnitrogen bonds are fundamentally
important reactions for the synthesis of nitrogen containing
heterocyclic molecules and pharmaceuticals drugs.1 Apart from
the conventional Ullmann and BuchwaldꢀHartwig CꢀN
coupling process,2 the development of novel methods for
different types of CꢀN bond forming reactions under mild
conditions remains a very challenging subject. In recent years,
visibleꢀlightꢀmediated metal/organic dye based photoredox
catalysis has emerged as one of the most attractive and
powerful alternative to thermal mediated metalꢀcatalyzed
reactions.3 Recently, photoredox Cuꢀbased complexes have
been demonstrated as an inexpensive catalytic system for CꢀC
coupling, allylic substitution and atom transfer radical addition
(ATRA) reactions.4 In addition, photoinduced copper(II)
complex was also demonstrated as a powerful catalyst for
spatial and temporal control of the alkyneꢀazide cycloaddition
(CuAAC) click reactions,5 where the catalyst Cu(I) can be
generated by either direct photoreduction of Cu(II) or indirect
reduction of Cu(II) using a photoinitiator. Recently, Fu et al.,
has reported photoinduced copper(I) catalysed CꢀN coupling
reactions of hetrocyclic nucleophiles with aryl halides as well
as aliphatic halides.6 This strategy was also extended to the
alkylation of amides7 and reactions of arylthiols with
arylhalides.8 This method is considered to be versatile and
utilized as a novel protocol for CꢀN and CꢀS crossꢀcoupling
reactions under mild conditions. Moreover, this reaction
proceeds under UV light irradiation and also requires a strong
base (LiOtBu or NaOtBu) for the formation of CꢀN coupling
product. We recently reported a visibleꢀlightꢀinduced strategy
for copper(I)ꢀcatalysed Sonogashira CꢀC crossꢀcoupling
reaction9 and oxidative coupling reactions of oꢀ
phenylenediamine with terminal acetylene for the synthesis of
αꢀKetoamides are important building blocks in organic
synthesis and frequently found in a variety of natural products,
pharmaceuticals and biologically important compounds, such
as, FK506, cyclotheonamide, RARγ agonist, enzyme, protease
and epoxide hydrolase inhibitors.11 αꢀKetoamides can also
serve as an important starting material or intermediate for the
synthesis of medicinally useful compounds, such as,
tetrasubstituted 2ꢀoxindoles and 2ꢀoxazolidinꢀ4ꢀone.12 To
realize their bioactivities, a considerable number of synthetic
approaches have been developed.13ꢀ17 Despite the utility of such
processes, the previous methods suffer the following factors; a)
starting materials are needed to be prepared in advance or are
not commercially available, b) usage of oxidants or ligands, and
c) an elevated reaction temperature is required.
Scheme 1 Copper catalysed synthesis of αꢀketoamides.
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1

Page 3 of 9
ARTICLE
Green Chemistry
View Article Online
Green Chemistry
DOI: 10.1039/C4GC01623H
It was reported that copper(II) can also catalyse the oxidative The reaction between aniline (2a) and phenylacetylene (1a
)
amidation/diketonation of terminal alkynes with anilines in the was chosen as the model reaction for optimization of the
presence of pyridine (4.0 equiv.) and TEMPO at elevated experimental parameters. In an initial study (Table 1), reaction
temperature (60 oC) (see Scheme
1
, thermal process).18 of aniline (2a) (0.5 mmol) and phenylacetylene (1a) (0.6 mmol)
However, the above reaction is limited to electronꢀrich and in the presence of K2CO3 (1.05 equiv) and CuCl (5 mol%) in
electron neutralꢀaryl terminal alkynes, and does not work for CH3CNꢀCH3OH (1:1 v/v) affords αꢀketoamide (3aa) in 10%
linear aliphatic alkynes, as well as electronꢀdeficient yield. The use of weak bases, such as, K(OAc) (0.25 equiv),
substrates.18 The aerobic oxidative cross dehydrogenative dramatically improves the yield to 84 % (Table 1, entry 3).
coupling (CDC)19 reactions of terminal alkynes with Complete removal of the base affords the product 3aa in 93 %
nucleophiles (Nu= N, P & S) are also reported by using yield, indicating that base is not required for the observed
Cu(I)/Cu(II) complexes or Cuꢀacetylide as a substrate and air or reaction. However, unreacted/free aniline may acts as base to
O2 as the sole oxidant to form CꢀN, CꢀP and CꢀS acetylenes at promote the formation of copper(I) phenylacetylide in the
o
elevated temperatures (50~110 C).20 Although this thermal current reaction.
In the solvent screening, a mixture of
method can be used to synthesize acetylene CspꢀN, CspꢀP and CH3CNꢀCH3OH (1:1 v/v) gave the best yield of the αꢀ
CspꢀS coupling products, subsequent oxidation reaction cannot ketoamide product (Table 1, entry 4). The presence of water
be achieved. Herein, we report a facile visibleꢀlightꢀmediated slightly decreases the yield of 3aa from 93 to 80% (see Table
copper(I) chloride catalysed amidation/diketonation reaction of S1, entry 13). Other solvents were also tested, but yields are
terminal alkynes by anilines for the synthesis of αꢀketoamides poor (Table S1, entries 11ꢀ15). In the screening of metal salts,
at room temperature (see scheme 1, photoinduced approach). CuX (X: Cl, Br, I) affords the highest yield (93 %) of the
The significance of the present work includes the following product 3aa (Table 1, entries 4, 6 & 7). In contrast, CuCl2 turns
features: 1) an unprecedented visibleꢀlightꢀinduced strategy for out to be ineffective to catalyse the formation of product (Table
copper(I)ꢀcatalysed amidation/ diketonation of terminal alkynes 1, entry 5). Therefore, the catalyst responsible for this reaction
by anilines to give αꢀketoamides at room temperature; 2) as might be the copper(I)ꢀrelated species. Meanwhile, control
compared to copper(II) catalysed thermal process, the current experiments also reveal that the reaction did not proceed upon
photoinduced strategy does not require the use of any bases, or exclusion of light, CuCl or O2 (Table S2).
additional oxidants (Scheme
1); 3) inꢀsitu generated Cu(I)ꢀ
phenylacetylide act as the key light absorbing species, which is Table 2 Scope of aniline substrates (2) and phenylacetylene
different from the previously reported photoinduced Cuꢀ
(
1a) under Cuꢀcatalyzed visible light irradiationa
catalyzed click reaction5 and CꢀN coupling process6.
O
H
H2N
N
5 mol% CuCl
Results and discussion
+
CH3CN-CH3OH, O2
O
R
R
blue LEDs
RT,
3
1a
2
Table 1. Optimization studies on coupling reaction of (1a) and (2a)a
O
H
O
O
H
O
H
5 mol% catalyst
N
H
N
N
Ph
N
H2N
+
Ph
O
3aa
CH3CN-CH3OH, O2
10 h, RT, blue LEDs
O
O
O
1a
2a
3aa 93% (10 h)
3ab
3ae
93% (10 h)
3ac
94% (10 h)
Yield [%]b
Entry Catalyst
Base
Solvent
O
OMe
O
H
O
H
H
N
N
N
10
78
84
K2CO3 (1.05 eq) CH3CN-MeOH
1
2
CuCl
CuCl
CuCl
CuCl
O
O
O
OMe
tBu
95% (8 h)
3ad 96% (8 h)
3af 96% (8 h)
CH3CN-MeOH
KOAc (1.2 eq)
O
H
O
H
O
H
3
4
KOAc (0.25 eq)
CH3CN-MeOH
N
OMe
OMe
N
N
O
O
O
Br
I
no base
CH3CN-MeOH
93
3ah
3ag 96% (8 h)
80% (10 h)
3ai
74% (10 h)
no base
trace
CH3CN-MeOH
CuCl2
5
O
O
H
O
H
H
N
CF3
N
Br
N
no base
no base
93
93
6
7
CuBr
CuI
CH3CN-MeOH
CH3CN-MeOH
O
O
O
CF3
CF3
3aj
83% (10 h)
3ak
3an
66% (24 h)
3al
68% (24 h)
O
H
O
83
no base
CH3CN
8
CuCl
O
H
H
N
N
N
CF3
Cl
O
O
9
O
no base
no base
CuCl
CuCl
67
88
MeOH
O
CN
Ph
10c
3am 62% (24 h)
3ao
45% (24 h)
69% (24 h)
CH3CN-MeOH
aStandard condition. Isolated yield after purification by column
chromatography on silica gel. b1.0 mmol of 1a (0.125 M), 10 mol% CuCl and
5 mol% of NaOAc were used.
a0.6 mmol of 1a (0.1 M), 0.5 mmol of 2a (0.083 M), and 5 mol% of
CuCl in 8 ml of solvent. The solution was irradiated with blue LEDs
for 10 h in the presence of 1 atm O2 (in balloon). bYields were
1
determined by the H NMR integration method using mesitylene as an
internal standard. c1 atm air (in balloon) was used in the reaction.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Green Chemistry
Page 4 of 9
Green Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4GC01623H
Under the optimized conditions (see Table 1, entry 4), the scope of
the anilines (2) were further investigated (see Table 2). In general,
both electronꢀrich and electronꢀneutral substituted anilines result in
high yields of αꢀketoamide products (Table 2, 3aaꢀ3ag). Notably,
the current approach also works well for electronꢀwithdrawing
substituted groups with product yields in the range of 45ꢀ68 % over
a period of 15ꢀ24 h reaction (Table 2, 3akꢀ3ao). The slow reactivity
In a similar manner, the scope of various terminal alkynes was also
investigated (see Table 3). Electronꢀrich phenylacetylenes (1bꢀ1f)
can easily react with aniline to afford the corresponding αꢀketoamide
products (3baꢀ3fa) in good yields (88ꢀ96 %) (Table 3). In general,
electronꢀrich phenylacetylenes favor the formation of 1, 3ꢀdiynes in
the presence of O2, since these groups have more πꢀbasicity on the
C≡C triple bond and will certainly promote the reaction in the
presence of soft Lewis acids, such as Cu(I) ion.21 The homocoupling
(or the need of a longer reaction time) is due to the insufficient reaction can be effectively suppressed in the current process by
diluting the concentration of phenylacetylene in the reaction mixture.
In addition, aryl alkynes bearing haloꢀsubstituted groups (1gꢀ1i) as
well as naphthalene moieties (1jꢀ1l) readily react with aniline to
generate the corresponding αꢀketoamides 3gaꢀ3la (Table 3). The
electronꢀdeficient phenylacetylenes (1mꢀ1q) can also react with
aniline (2a) over a period of 15ꢀ20 h to afford the corresponding αꢀ
ketoamide products 3maꢀ3qa in good yields of 82ꢀ88 % (see Table
3). Moreover, heteroarylalkyne (1r) and aliphatic terminal alkynes
(including linear chain alkynes (1tꢀ1v) and cyclohexylacetylene (1s))
can also effectively couple with aniline to result in the formation of
corresponding products (Table 3). Thus, the current
amidation/diketonation reaction can occur for a broad range of
electronꢀdeficient phenylacetylenes/aliphatic linear chain terminal
alkynes, and is a powerful method for the synthesis of αꢀketoamides
with no/negligible amount of formation of homocoupling products.
Furthermore, many aryl acetylenes are also reactive with 4ꢀmethoxyꢀ
aniline 2d to afford the αꢀketoamide products in good to excellent
yields (see Table S3). Unfortunately, the current strategy does not
work for aliphatic amines and Nꢀsubstituted anilines.
nucleophilic nature of anilines bearing electronꢀwithdrawing groups.
As a result, 5 mol% of a weak base NaOAc was added to promote
the formation of Cu(I) phenylacetylide in all electron withdrawing
substituted anilines (2kꢀ2o) reactions. The reaction proceeds well
also for haloꢀsubstituted anilines. Good product yields were obtained
(see (Table 2, 3ahꢀ3aj). Note that the haloꢀsubstituted groups in αꢀ
ketoamides can provide good reactive sites for further synthetic
modifications.
Table 3 Scope of terminal acetylenes (1) and aniline (2a) under
Cuꢀcatalysed visible light irradiationa
O
H
H2N
5 mol% CuCl
N
R
+
R
CH3CN-CH3OH, O2
RT, blue LEDs
O
2a
3
1
O
O
O
H
H
H
N
N
N
To extend our current visibleꢀlightꢀinduced Cu(I)ꢀcatalyzed
strategy for the synthesis of biologically active αꢀketoamides,11 we
have synthesized epoxide hydrolase inhibitors (3np & 3sp) with a
high yields (92~95 %) in a single step using commercially available
substrates (see Scheme 2). Previously, both epoxide hydrolase
inhibitors (3np & 3sp) were prepared in five steps with an overall
yield of less than 5 % using preꢀsynthesized starting materials.11b
Recently, it was also reported that epoxide hydrolase inhibitor (3np)
can also be synthesized in single step with a yield of 58 % using a
modified process and preꢀsynthesized starting material, αꢀcarbonyl
aldehyde.15b In addition, the current synthesis of epoxide hydrolase
inhibitor (3sp) could be readily scaled up gram scale, and 1.15 g of
3sp (or 86% isolated yield) ca be obtained after 12 h irradiation in
blue LEDs at room temperature (see, Scheme S1 & Figure S15).
The structures of 3am and 3sp were confirmed by singleꢀcrystal Xꢀ
ray diffraction.22
O
O
O
Et
tBu
3da
O
3ba 95% (8 h)
3ca
94% (8 h)
96% (8 h)
Ph
O
H
O
H
H
N
N
MeO
N
O
O
O
MeO
F
3fa
3ia
3ea 88% (8 h)
95% (8 h)
3ga
O
96% (8 h)
O
H
O
H
H
N
N
N
O
O
O
Cl
Br
3ha
92% (10 h)
82% (15 h)
3ja
93% (8 h)
O
CF3
O
O
H
H
H
N
N
N
O
O
O
MeO
3ka
92% (10 h)
3ma
O
3la
88% (15 h)
89% (10 h)
O
O
H
H
N
H
N
N
O
O
O
MeO2C
F3C
O2N
NC
3pa
O
85% (20 h)
3na 86% (15 h)
3oa 82% (20 h)
O
H
O
H
H
N
N
N
O
S
O
O
3sa
91% (12 h)
3qa 86% (20 h)
3ra 88% ( 12 h)
O
H
O
H
O
H
N
N
N
Scheme 2 One step synthesis of inhibitors (3np & 3sp). a Standard condition:
1n or 1s (0.6 mmol), 2p (0.5 mmol), 5 mol% CuCl in 8 mL dry CH3CN and
CH3OH (1:1), irradiated with blue LEDs at room temperature under 1 atm O2
(in balloon). Isolated yield after purification by column chromatography on
silica gel. bThe reaction was performed on a 4 mmol scale (preparative scale).
4
5
O
O
O
3va
78% (15 h)
3ta 70% (15 h)
3ua 73% (15 h)
aStandard condition. Isolated yield after purification by column
chromatography on silica gel
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

Page 5 of 9
ARTICLE
Green Chemistry
View Article Online
Green Chemistry
DOI: 10.1039/C4GC01623H
We have evaluated the green chemistry metrics23 for the synthesis of
epoxide hydrolase inhibitor (3sp) in a preparative scale. Atom
economy is defined as “how much of the reactants remain in the
final desired product” (see equation (1)). Reaction mass efficiency
(RME) is defined as “the percentage of the mass of the reactants that
remain in the product” (see equation (2)).
Aniline + CuCl
0.5
0.4
0.3
0.2
0.1
0.0
Molecular mass of desired product
Aniline + CuCl + phenylacetylene
Aniline + CuCl + phenylacetylene
(Isolated yellow precipitate)
(1)
(2)
Atom economy (%) =
(AE)
X 100
Molecular mass of all reactants
476 nm
mass of desired product
X 100
=
Reaction mass efficiency (%)
(RME)
mass of all reactants
Table 4. Evaluation of Green chemistry metrics for the synthesis of
inhibitors (3sp)
360
400
440
480
520
560
600
Wavelength (nm)
Figure 1 UVꢀvisible spectra of reaction mixture in CH3CN and CH3OH (1:1
v/v). Black line indicates mixture of aniline and CuCl, red line indicates
mixture of aniline, CuCl and phenylacetylene, green line indicates isolation
of yellow suspension of copper(I) phenylacetylide.
Overall, our green process can enable to synthesis the Epoxide
hydrolase inhibitors (3sp) in preparative scale with a E factor or 47.7,
95% atom economy, 81.7% atom efficiency, 100% carbon efficiency,
and 76.6% reaction mass efficiency, which are far better than those
for previously reported multiꢀstep synthesis of epoxide hydrolase
inhibitor with low yield (less than 5 % total yield) (Patent literature,
see page 5, ref 11b in the main text).
Figure 2 EPR spectra (X band, 9.8 GHz, room temperature) of (a) Cu(I)
phenylacetylide (1a') in ACNꢀMeOH under blueꢀLED light irradiation in the
presence of O2 and a radical trapping reagent, DMPO (2.5 x 10ꢀ2 M). The
parameters used in the simulation are the followings: gav= 2.0059, aN= 14.9 G
(1N), and aβH= 8.5 G (1H). b) The same reaction solution as in (a) with
addition of superoxide dismutase (SOD), (1x10ꢀ2 M). c) The same reaction
solution as in (a), but in the dark. All measurements were done at 25 oC
In order to prove that the in situ generated copper(I)
phenylacetylide is the key light absorbing photocatalyst, we used
commercial copper(I) phenylacetylide (Alfa Aesar) to replace CuCl
and phenylacetylene as a substrate and to check whether the same
coupling product, 3aa, can be formed or not. The yields of 3aa were
80 and 32% in the presence and absence of CuCl, respectively (Eq.
(1)). Such a result seems to be reasonable since isolated copper(I)
phenylacetylide is known to exist in highly aggregated forms (higher
order polynuclear Cu(I) phenylacetylide)24 which may diminish the
reaction rate.24a Addition of free CuCl could coordinate to the side of
acetylene moiety via πꢀbonding, and activate the polynuclear Cu(I)
phenylacetylide,25 leading to the improved product yield.25 As a
supporting evidence, the binding constant (Ka ~ 6550 µMꢀ1) of free
CuCl to polynuclear Cu(I) phenylacetylide 1a' was determined by
isothermal titration caloriemetry (ITC) experiment26 (see more
details in Figure S16). This control experiment (Eq. (1)) supports
that the in situ generated copper(I) phenylacetylide may be the light
absorbing photocatalyst in the reaction.
Overall, the reaction mechanism is proposed in Scheme 3. First,
weak Cu(I)ꢀaniline complex 4 is initially formed27 and upon
addition of phenylacetylene, copper(I) phenylacetilyde (1a') is
preferentially formed. This was evidenced by (a) the formation of
yellow suspension of copper(I) phenylacetylide (see optical picture
in Figure S14); (b) the rise in the 476 nm absorption in the uvꢀvisible
absorption spectra (see Figure 1 and more details see Figure. S13);
and (c) the observation of characteristic yellow fluorescence
emission (λem at 524 & 583 nm) of copper(I) phenylacetilyde (see
Figures S10
& S11). Direct photoexcitation of copper(I)
phenylacetylide by blue LEDs (λmax = 476 nm) leads to the
formation of partial positive charge on the acetylene ligand and
partial negative charge on the metal center via ligand to metal charge
transfer (LMCT).28 It is believed that the excited state of copper(I)
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Green Chemistry
Page 6 of 9
View ArticAle ROnTliInCeLE
Green Chemistry
DOI: 10.1039/C4GC01623H
phenylacetylides undergo facile intersystem crossing (ISC),9b,28 and synthesis of biologically important αꢀketoamides via oxidative
hence undergoes single electron transfer (SET) to molecular oxygen CꢀN coupling of anilines with terminal alkynes without the
to generate superoxide29 and electron deficient Cu(II) need of base, ligands, and external oxidant. The current
phenylacetylide 6. Supporting evidences include, a) the lifetime of method is green, and highly atomic efficient without the use of
excited state of copper(I) phenylacetylide 5 shortens from 15.95 ꢁs hazardous chemicals, and harsh conditions. The current method
in the absence of molecular oxygen to 10.47 ꢁs in the presence of works well for a wide range of substrates including electron
molecular oxygen (see Figure S12); b) the formation of superoxide deficient anilines and various terminal alkynes.
The
free radical was detected by EPR measurements (see Figure 2 and importance of the current photoinduced Cu(I) catalysed process
Figure S1ꢀS9) using 5,5ꢀdimethylꢀ1ꢀpyrroline Nꢀoxide (DMPO) as a has been applied to the rapid syntheses of two prominent
selective superoxide trapping reagent. The EPR signal of the epoxide hydrolase inhibitors (3np & 3sp) in a single step with
DMPOꢀsuperoxide adduct (gav= 2.006) matches with the simulated high yields (92~95%) in preparative scale using commercially
one (see Figure 2(a)), as well as in well agreement with the available substrates. The costꢀeffective nature and availability
literature,30 which can be significantly suppressed in the presence of of the catalyst (CuCl), no requirement of base or ligands,
superoxide dismutase (SOD) (see Figure 2(b)) or removal of light practical feasibility and reaction under visibleꢀlight irradiation
(see Figure 2(c)).
make this methodology a very efficient and green process for
the synthesis of various biologically active αꢀketoamides.
A
(2a)
PhNH2
CuCl
Acknowledgements
H
N
H
This work was supported by the Ministry of Science and
Technology, Taiwan.
H
Ph
CuCl
Ph
C N
Ph
Ph
I
4
O
10
(1a)
PhNH3
CuI
Cu
O
Notes and references
Cl
Cl
Department of Chemistry, National Tsing Hua University,
Hsinchu, Taiwan, ROC. Eꢀmail: kchwang@mx.nthu.edu.tw;
Fax: (+886) 35711082.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
H
Ph
Cu
9
C N
Ph
abs : 476 nm)
(
Ph
II
.
1a'
5
O
O
blue-LEDs
O2
- Cl
*
H
Ph
CuI
Ph
N
Ph
CuI Cl
1,3-diyne
8
1
(a) A. Muci and S. Buchwald, in Cross-Coupling Reactions, ed. N.
Miyaura, Springer Berlin Heidelberg, 2002, vol. 219, pp. 131ꢀ209;
(b) The Alkaloids: Chemistry and Biology, ed. H. ꢀJ. Knölker,
Elsevier, San Diego, 2011, vol. 70.
O2
H
.
-
2H+
CuIII
O2
Ph
N
CuII
H2O2 + O2
Ph
Ph
(Disproportionation)
7
6
2
(a) Y. Jiang and D. Ma, in Catalysis without Precious Metals, ed. R.
M. Bullock, WileyꢀVCH, Weinheim, 2010, pp. 213ꢀ233; (b) D. S.
PhNH2 + 1/4 O2
1/2 H2O
O
H
Surry and S. L. Buchwald, Chem. Sci. 2011, 2, 27; (c) J. F.
Ph
HN Ph
N
Ph
Ph
Hartwig, S. Shekhar, Q. Shen and F. BarriosꢀLanderos in Chemistry
of Anilines, Ed. Z. Rapaport, Wiley, New York, 2007, vol. 1, pp.
455–536; (d) G. Evano, N. Blanchard and M. Toumi, Chem. Rev.
O
3aa
O O
A
Scheme 3 Proposed mechanism for visibleꢀlight induced Cu(I)ꢀcatalyzed
reaction of anilines and terminal alkynes.
2008, 108, 3054; (e) G. D. Vo and J. F. Hartwig, J. Am. Chem. Soc
2009, 131, 11049; (f) S. R. Chemler, Science 2013, 341, 624.
.
In the next step, nucleophilic addition of aniline to complex 6 (Cu(II)
phenylacetylide) results in the formation of the complex 7 (Cu(III)
species).31 Subsequent reductive elimination of Cu(III) leads to the
formation of the Cu(I)ꢀcoordinated ynamine complex 8.32 At this
stage, it is difficult to isolate the highly reactive ynamine (aniline
type ynamine).33 Based on the additional control experiments,34 the
electron rich ynamine could readily coordinate to Cu(I) ion35 and
3
For selected examples on the visibleꢀlight photoredox catalyst, see: (a)
C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322; (b) D. M. Schultz and T. P. Yoon, Science 2014, 343,
10.1126/science.1239176; (c) J. M. R. Narayanam and C. R. J.
Stephenson, Chem. Soc. Rev. 2011, 40, 102; (d) T. P. Yoon, M. A.
Ischay and J. Du, Nat. Chem. 2010, 2, 527; (e) J. Xuan and W.ꢀJ.
subsequently, react with O2 at the later stage.
Indeed, Cu(I)
Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828; (f) D. Prasad Hari, T.
Hering and B. König, Angew. Chem. Int. Ed. 2014, 53, 725; (g) D. A.
containing complex 8 readily reacts with the molecular oxygen to
form copper(II) peroxo complex 9.36 Isomerization of the resulting
copper(II) peroxo complex 9 to copper(I) species 10 with concurrent
formation of a carbon–oxygen bond.37 Finally, this complex can
undergo transformation to reꢀgenerate CuCl and formation of
intermediate (A).15a Subsequent cleavage15a,38 of (A) will produce
the desired αꢀketoamide product (3aa).
Nicewicz and T. M. Nguyen, ACS Catalysis 2013,
4, 355; (h) Y.ꢀQ.
Zou, J.ꢀR. Chen and W.ꢀJ. Xiao, Angew. Chem. Int. Ed. 2013, 52
,
11701; (i) M. Reckenthäler and A. G. Griesbeck, Adv. Synth. Catal.
2013, 355, 2727; (j) X.ꢀz. Shu, M. Zhang, Y. He, H. Frei and F. D.
Toste, J. Am. Chem. Soc. 2014, 136, 5844; (k) D. Ravelli and M.
Fagnoni, ChemCatChem 2012, 4, 169.
Conclusions
4
Selected examples on the lightꢀinduced copperꢀredox catalyst, see: (a)
M. Pirtsch, S. Paria, T. Matsuno, H. Isobe and O. Reiser, Chem. Eur.
J. 2012, 18, 7336; (b) A. Baralle, L. Fensterbank, J.ꢀP. Goddard and
In summary, we have demonstrated a visibleꢀlightꢀinitiated
copper(I) catalysed strategy to achieve a facile oneꢀstep
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Page 7 of 9
Green Chemistry
View Article Online
ARTICLE
Green Chemistry
DOI: 10.1039/C4GC01623H
C. Ollivier, Chem. Eur. J. 2013, 19, 10809; (c) A. C. Hernandezꢀ 18 Only one example was reported with a low yield of 22 % by using
Perez and S. K. Collins, Angew. Chem. Int. Ed. 2013, 52, 12696.
electronꢀdeficient aniline (ethyl 4ꢀaminobenzoate) as a substrate,
5
6
For selected examples on the lightꢀinduced click reaction, see: (a) M.
see: C. Zhang and N. Jiao, J. Am. Chem. Soc. 2010, 132, 28.
A. Tasdelen and Y. Yagci, Angew. Chem. Int. Ed. 2013, 52, 5930; (b) 19 C.ꢀJ. Li, Acc. Chem. Res. 2008, 42, 335.
J. A. Brian, T. Youhua, J. K. Christopher, A. D. Cole, S. A. Kristi 20 For examples on the copperꢀcatalyzed aerobic oxidative crossꢀ
and N. B. Christopher, Nat. Chem. 2011,
3, 256.
dehydrogenation reactions, see: (a) L. Wang, H. Huang, D. L.
Priebbenow, F.ꢀF. Pan and C. Bolm, Angew. Chem. Int. Ed. 2013,
52, 3478; (b) S. E. Allen, R. R. Walvoord, R. PadillaꢀSalinas and M.
C. Kozlowski, Chem. Rev. 2013, 113, 6234; (c) T. Hamada, X. Ye
and S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 833; (d) K. Jouvin, R.
Veillard, C. Theunissen, C. Alayrac, A.ꢀC. Gaumont and G. Evano,
Org. Lett. 2013, 15, 4592; (e) Y. Gao, G. Wang, L. Chen, P. Xu, Y.
Zhao, Y. Zhou and L.ꢀB. Han, J. Am. Chem. Soc. 2009, 131, 7956;
(a) S. E. Creutz, K. J. Lotito and G. C. Fu, J. C. Peters, Science 2012,
338, 647; (b) A. C. Bissember, R. J. Lundgren, S. E. Creutz, J. C.
Peters and G. C. Fu, Angew. Chem. Int. Ed. 2013, 52, 5129; (c) D. T.
Ziegler, J. Choi, J. M. MuñozꢀMolina, A. C. Bissember, J. C. Peters
and G. C. Fu, J. Am. Chem. Soc. 2013, 135, 13107.
7
8
9
H.ꢀQ. Do, S. Bachman, A. C. Bissember, J. C. Peters and G. C. Fu, J.
Am. Chem. Soc. 2014, 136, 2162.
C. Uyeda, Y. Tan, G. C. Fu and J. C. Peters, J. Am. Chem. Soc. 2013,
135, 9548.
(f) K. Jouvin, J. Heimburger and G. Evano, Chem. Sci. 2012, 3, 756;
(g) Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev. 2012,
41, 3381.
(a) A. Sagadevan and K. C. Hwang, Adv. Synth. Catal. 2012, 354
,
3421; (b) M. Majek and A. Jacobi von Wangelin, Angew. Chem. Int. 21 R. Chinchilla and C. Najera, Chem. Soc. Rev. 2011, 40, 5084.
Ed. 2013, 52, 5919. 22 CCDC 966115 3am) and CCDC 966320 (3sp) contains the
(
10 A. Sagadevan, A. Ragupathi and K. C. Hwang, Photochem.
Photobiol. Sci. 2013, 12, 2110.
supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallographic
11 (a) A. Ovat, Z. Z. Li, C. Y. Hampton, S. A. Asress, F. M. Fernández,
J. D. Glass and J. C. Powers, J. Med. Chem. 2010, 53, 6326; (b) R.
D. J. G. D. V. Patel, H. Webb, K. Heather, S. K. Anandan and B. R.
Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.
23. R. Turgis, I. Billault, S. Acherar, J. Augé and M.ꢀC. Scherrmann, Green
Chem., 2013,15, 1016
24 For selected examples on the structure of copper(I) phenylacetylide,
see: (a) J. E. Hein and V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1302;
(b) R. Buschbeck, P. J. Low and H. Lang, Coord. Chem. Rev. 2011,
255, 241; (c) B. R. Buckley, S. E. Dann, D. P. Harris, H. Heaney and
E. C. Stubbs, Chem. Commun. 2010, 46, 2274; (d) S. S. Y. Chui, M.
F. Y. Ng and C.ꢀM. Che, Chem. Eur. J. 2005, 11, 1739.
Aavula, PCT Int. Appl. WO 2008073623, 2008; (c) Y.ꢀH. Chen, Y.ꢀ
H. Zhang, H.ꢀJ. Zhang, D.ꢀZ. Liu, M. Gu, J.ꢀY. Li, F. Wu, X.ꢀZ.
Zhu, J. Li and F.ꢀJ. Nan, J. Med. Chem. 2006, 49, 1613; (d) M. L.
Stein, H. Cui, P. Beck, C. Dubiella, C. Voss, A. Krüger, B. Schmidt
and M. Groll, Angew. Chem. Int. Ed. 2014, 53, 1679; (e) N.
Fusetani, S. Matsunaga, H. Matsumoto and Y. Takebayashi, J. Am.
Chem. Soc. 1990, 112, 7053.
25 B. T. Worrell, J. A. Malik and V. V. Fokin, Science 2013, 340, 457.
26 For principle and experimental procedure of isothermal titration
calorimetry (ITC), see: M. W. Freyer and E. A. Lewis, in Methods
in Cell Biology, ed. J. C. Dr. John, Dr. H. William Detrich, III,
Academic Press, 2008, vol. 84 pp. 79ꢀ113.
12 (a) F. R. BouꢀHamdan and J. L. Leighton, Angew. Chem. Int. Ed.
2009, 48, 2403; (b) L. Yang, D.ꢀX. Wang, Z.ꢀT. Huang and M.ꢀX.
Wang, J. Am. Chem. Soc. 2009, 131, 10390; (c) J. L. Jesuraj, and J.
Sivaguru, Chem. Commun. 2010, 46, 4791; (d) L. Yin, M. Kanai
and M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 7620; (e) T.
27 (a) C. Tang and N. Jiao, J. Am. Chem. Soc. 2012, 134, 18924; (b) T.
Tsuda, K. Watanabe, K. Miyata, H. Yamamoto and T. Saegusa,
Inorg. Chem. 1981, 20, 2728.
Shirai, H. Ito and Y. Yamamoto, Angew. Chem. Int. Ed. 2014, 53
,
2658.
28 V. W.ꢀW. Yam, K. KamꢀWing Lo and K. ManꢀChung Wong, J.
Organomet. Chem. 1999, 578, 3.
13 (a) J. Chen and R. F. Cunico, J. Org. Chem. 2004, 69, 5509; (b) R. P.
Singh and J. n. M. Shreeve, J. Org. Chem. 2003, 68, 6063.
29 The byꢀproduct superoxide radical anion will undergo facile
disproportionation reaction to form hydrogen peroxide (H2O2) and
O2, see: L. Kussmaul and J. Hirst, Proc. Natl. Acad. Sci. U. S. A.
2006, 103, 7607.
14 (a) J. Liu, R. Zhang, S. Wang, W. Sun and C. Xia, Org. Lett. 2009,
11, 1321; (b) E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L.
Buchwald and K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 1734.
15 (a) C. Zhang, Z. Xu, L. Zhang and N. Jiao, Angew. Chem. Int. Ed.
2011, 50, 11088; (b) C. Zhang, X. Zong, L. Zhang and N. Jiao, Org.
30 (a) M. Danilczuk, F. D. Coms and S. Schlick, J. phys. Chem. B 2009,
113, 8031; (b) S.ꢀU. Kim, Y. Liu, K. M. Nash, J. L. Zweier, A.
Lett. 2012, 14, 3280; (c) F.ꢀT. Du and J.ꢀX. Ji, Chem. Sci. 2012, 3,
Rockenbauer and F. A. Villamena, J. Am. Chem. Soc. 2010, 132
,
460. (d) D. Li, M. Wang, J. Liu, Q. Zhao and L. Wang, Chem.
Commun. 2013, 49, 3640.
17157.
31 Example on the CuIII oxidation state, see: (a) A. King, L. M.
Huffman, A. Casitas, M. Costas, X. Ribas and S. Stahl, J. Am.
Chem. Soc. 2010, 132, 12068; (b) A. E. Wendlandt, A. M. Suess
and S. S. Stahl, Angew. Chem. Int. Ed. 2011, 50, 11062.
16 (a) W.ꢀP. Mai, H.ꢀH. Wang, Z.ꢀC. Li, J.ꢀW. Yuan, Y.ꢀM. Xiao, L.ꢀR.
Yang, P. Mao and L.ꢀB. Qu, Chem. Commun. 2012, 48, 10117; (b)
Z. Zhang, J. Su, Z. Zha and Z. Wang, Chem. Commun. 2013, 49
,
8982.
32 J. Li and L. Neuville, Org. Lett. 2013, 15, 1752.
17 (a) R. Mossetti, T. Pirali, G. C. Tron and J. Zhu, Org. Lett. 2010, 12
,
33 The high reactivity of yanamine caused much difficulty toward
isolation from reaction mixture, see: (a) J. Ficini, Tetrahedron 1976,
32, 1449. (b) K. A. DeKorver, H. Li, A. G .Lohse, R. Hayashi, Z.
Lu, Y. Zhang and R. P. Hsung, Chem. Rev. 2010, 110, 5064.
820; (b) J.ꢀM. Grassot, G. Masson and J. Zhu, Angew. Chem. Int.
Ed. 2008, 47, 947.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Green Chemistry
Page 8 of 9
Green Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4GC01623H
34 We prepared a stable carbazole type ynamine (sꢀ2r), which can
further react with molecular oxygen to generate the corresponding
αꢀketoamide in the presence of CuCl under both thermal heating and
photoirradiation condition. Therefore, our proposed reaction steps
from 8, 9, and 10 to the intermediate A are reasonable (Scheme 3).
See the details in Scheme S3 in the supporting information.
35 Due to the high reactivity of ynamine with electrophiles, in situ
generated electron rich yanmine easily coordinated to Cu(I) ion, see:
Z. Chen, W. Zeng, H. Jiang and L. Liu, Org. Lett. 2012, 14, 5385.
See also ref. 30.
36 (a) C. Zhang and N. Jiao, Angew. Chem. Int. Ed. 2010, 49, 6174; (b)
K. K. Toh, Y.ꢀF. Wang, E. P. J. Ng and S. Chiba, J. Am. Chem. Soc.
2011, 133, 13942.
37 H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew.
Chem. Int. Ed. 2011, 50, 5678.
38 K. Schank, H. Beck and F. Werner, Helv. Chim. Acta. 2000, 83
,
1611.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

Page 9 of 9
ARTICLE
Green Chemistry
View Article Online
Green Chemistry
DOI: 10.1039/C4GC01623H
Graphical Abstract
VisibleꢀLight Initiated Copper(I)ꢀCatalysed Oxidative CꢀN Coupling of
Anilines with Terminal Alkynes: OneꢀStep Green Synthesis of αꢀ
Ketoamides
Arunachalam Sagadevan, Ayyakkannu Ragupathi, ChunꢀCheng Lin, Jih Ru Hwu, and Kuo Chu Hwang*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
Eꢀmail: kchwang@mx.nthu.edu.tw; Fax: (+886) 35711082.
A green photochemical method was reported for synthesis of biologically active αꢀketoamides at room temperature
using commercially available substrates.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012