Visible-light-induced, copper(i)-catalysed C-N coupling between o-phenylenediamine and terminal alkynes: One-pot synthesis of 3-phenyl-2-hydroxy-quinoxalines

Article abstract of DOI:10.1039/c3pp50186h

Visible-light-initiated aerobic direct C-N coupling between o-phenylenediamines and terminal acetylenes was performed using simple copper(i) chloride as a catalyst for the synthesis of quinoxaline derivatives. The current method works well for a wide range of electron rich as well as electron poor group-substituted o-phenylenediamines and phenylacetylenes. The key component in the reaction is the direct photo-excitation of in situ generated copper arylacetylide (λ_abs = 420-480 nm). Moreover, as compared to the literature reports (thermal process), the current photochemical method is simple, mild, high yielding, and more viable towards the construction of biologically important quinoxaline derivatives from easily accessible raw materials, without the need of ligands and strong oxidants.

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ARTICLE TYPE
Visible-Light-Induced, Copper(I)-Catalysed C-N Coupling Between o-
Phenylenediamine and Terminal Alkynes: One-Pot Synthesis of 3-Phenyl-2-
Hydroxy-Quinoxalines
5
Arunachalam Sagadevan, Ayyakkannu Ragupathi and Kuo Chu Hwang*
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Visibleꢀlightꢀinitiated aerobic direct CꢀN coupling between oꢀphenylenediamines and terminal acetylenes was developed by
10 using simple copper (I) chloride as a catalyst for the synthesis of quinoxaline derivatives. The current method works well
for a wide range of electron rich as well as electron poor groupꢀsubstituted oꢀphenylenediamines and phenylacetylenes.
The key component in the reaction is the direct photo excitation of inꢀsitu generated copper arylacetylide (λabs= 420ꢀ480
nm). Moreover, as compared to the literature reports (thermal process), the current photochemical method is simple, mild,
high yields, and more viable towards the construction of biologically important quinoxaline derivatives from easily
15 accessible raw materials, without the need of ligands and strong oxidants.
Introduction
New synthetic approach for construction of nitrogen
20 containing natural products and heterocyclic molecules
from readily accessible starting material is an important
in which 1, 2ꢀdicarbonyl precursors have to be prepared in
55 advance using several oxidation methods and metallic/nonꢀ
research topic in organic synthesis. Quinoxaline scaffolds
are important building blocks in organic synthesis because
many of them exhibit biological activities,1ꢀ5 including,
25 antiꢀviral,6 antiꢀbacterial,7 antiꢀinflammatory,8ꢀ11 antiꢀ
metallic complex catalysts.34,37ꢀ46
Apart from these
classical approaches, many other methods have also been
developed for oxidative cyclization of alphaꢀhydroxy
ketones or alphaꢀhalide ketones with 1, 2ꢀ diamines.47ꢀ52
60 One of the major drawbacks for the above reported
methods is that specially designed substrates/ precursors
13
14
protozoal,12,
antiꢀcancer (colon cancer therapies),9,
antidepressant, antiꢀHIV,15 and as kinase inhibitors.11
Furthermore, quinoxaline derivatives have also been found
17
to have several applications in dyes,16,
organic
30 semiconductor,18, 19 organic luminescent materials,18, 20, 21
OLED,22, 23 synthesis of anion receptors, and in macroꢀ
cyclic receptors for molecular recognition (see Scheme
1).24
Due to their biomedical activities and ability to serve as
35 valuable intermediates in organic synthesis, many efforts
have been devoted to develop new methodologies for the
synthesis of substituted quinoxaline derivatives.25ꢀ27
Conventionally, quinoxalines can be synthesized by direct
thermal condensation reaction between 1,2ꢀdicarbonyl
40 compound and oꢀphenylenediamine (see, equation 1),28ꢀ36
[∗] Mr. A. Sagadevan, Mr. A. Ragupathi and professor Kuo Chu Hwang*
Department of Chemistry
National Tsing Hua University
45 Hsinchu, Taiwan, R. O. C.
Fax: (+886) 35711082
65
Scheme 1. Biologically active qiunoxaline derivatives.
Eꢀmail: kchwang@mx.nthu.edu.tw
† This article is dedicated to the late professor Nicholas J. Turro (1938ꢀ
2012)
are not readily available from the commercial sources. In
addition, most of these oxidation methods require usage of
toxic oxidants (stoichiometric amounts), excess additives
50
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or high reaction temperatures. To improve the overall
aliphatic alkynes without the need of any metal catalyst at
Recently, photoactive copper
product yields, direct oxidative addition of oꢀ 50 room temperature.69
phenylenediamine to terminal acetylene was developed
with the aid of less expensive catalyst (i.e. copper) for the
synthesis of quinoxaline derivatives.53
complexes have emerged as a novel and powerful catalysts
for alkyneꢀazide cycloꢀaddition (CuAAC) click reaction
and coupling reactions.70ꢀ72 Meanwhile, in 2012, Jonas C.
Peters and coꢀworkers reported the photoꢀinduced copper
5
74
55 (I) catalysed Ullman type CꢀN coupling reaction.73,
Recently, the same group also demonstrated the substrate
scope for alkylation of amines with alkyl halides by using
photoꢀinduced copper (I) catalyst at 0o C.75 These methods
are considered to be a versatile and novel protocol for the
60 synthesis of Nꢀalkylated carbazoles derivatives under mild
conditions. These methods, however, work only for
coupling between carbazoles and alkyl/aryl halides
derivatives under uvꢀlight irradiation and in the presence of
a strong base (LiOtBu), and do not work for preparation of
65 quinoxaline type of CꢀN coupling. Previously, we have
reported an visible light mediated the Sonogashira CꢀC
crossꢀcoupling reaction using simple Cu(I)Cl without any
palladium and ligands,76 where the key photoꢀcatalyst is
copper phenylacetylide.
Scheme 2. Comparison of the literature reported theramal process
10 and the current photo initiated/Cu(I) catalyzed synthesis of
quinoxaline derivatives
70
In the present work, we report that the same copper
phenylacetylide can also catalyse the direct oxidative
diamination of terminal alkynes with high yields (80ꢀ99 %)
and good selectivity under blue LED light irradiation at
room temperature. The copper phenylacetylide can be
Since it is inexpensive, one of the most abundant metals on
15 earth, and is also nonꢀtoxic, copper has been extensively
investigated as a catalyst for organic reactions, such as,
crossꢀcoupling reactions, 1,4ꢀasymmetric addition and
75 formed inꢀsitu via addition of simple Cu(I)Cl salt to
phenylacetyleneꢀcontaining solution in the absence of Pd,
ligands and additives. To the best of our knowledge, this is
the first report using light to initiate and Cu(I) to catalyse
oxidation reactions,69,70
Copper catalysed oxidative
coupling of 1,2ꢀdiamine to terminal alkynes or internal
20 alkynes has emerged as powerful tool for the
a
direct
CꢀN
coupling
between
substituted
oꢀ
construction of quinoxaline derivatives. In 2011, Baohua
et. al. have reported that copper (II) catalysed synthesis of
quinoxaline derivatives by the reaction of oꢀ
phenylenediamine and terminal alkynes using 4ꢀ
80 phenylenediamines and terminal alkynes for synthesis of 3ꢀ
phenylꢀ2ꢀhydroxyꢀquinoxalines without the need of any
ligands and additives at room temperatures.
o
25 dimethylaminopyridine (DMAP) as a ligand at 70 C (see
Scheme 2).53 Several other reports have documented the
thermal induced diamination of terminal alkynes/internal
alkynes to afford the corresponding products using copper
(II) as a catalyst.54ꢀ56 However, these reported reactions do
30 not work well for electron deficient terminal alkynes under
Results and discussion
85
Visibleꢀlight irradiation (blue lightꢀemitting diode
(LED), 420ꢀ490 nm, 40 mW/cm2) of a mixture of oꢀ
phenylenediamine (1a) (0.5 mmol) and phenylacetylene
(2a) (0.6 mmol) in acetonitrileꢀmethanol (1:1 v/v) solution
90 containing Cu(I)Cl (3 mol% relative to 1a) and K2CO3
(1.05 eqv. relative to 1a) in the presence of molecular
oxygen at 25 °C results in the formation of the coupling
product, 3ꢀphenylꢀ2ꢀhydroxyꢀquinoxaline (3a), in 96%
o
thermal conditions (above 70 C). In addition, excessive
amounts of ligands or additives are usually required (see
Scheme 2). Despite of the increasing attention, all of these
reactions absolutely require copper (II) catalyst, high
35 reaction temperature, excessive ligands, additives and/or
longer reaction times. Thus, it is highly desirable and
challenging to develop more efficient, environmentally
benign and atomꢀeconomical approach for direct aerobic
coupling of oꢀphenylenediamines with terminal acetylenes
40 by using simple copper (I) halide salt as a catalyst without
the need of any ligands under photoꢀirradiation
condition.74,75 Such type of photoꢀinitiated reactions have
been successful in the synthesis of asymmetric alkylation
of aldehyde,57ꢀ60 [2+2] and [3+2] cycloaddition of enone,
45 aryl cyclopropyl ketones,61ꢀ64 reductive dehalogenation,65,
66 and coupling reactions.67, 68 In addition, there is a report
on the strong uvꢀlight (254 or 310 nm) induced crossꢀ
coupling reaction between electron rich aryl chlorides and
1
isolated yield. The product (3a) was confirmed by H/13C
95 NMR spectroscopy and mass spectrometry (see
supplementary information).
Optimization studies
The reaction of 1,2ꢀoꢀphenylenediamine (1a) and
100 phenylacetylene (2a) was chosen as the model system for
optimization of experimental parameters. In the screening
of bases, K2CO3 was found to be the most effective one,
which gives a high yield of 96 % in the formation of the
quinoxaline product (3a). Other bases, such as, amine,
105 Cs2CO3, Na2CO3 and KOAc, are also active, but lead to the
2
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formation of slightly lower product yields of 90%, 92 %,
and 87%, respectively (Table 1, entries 7ꢀ9).
highest product yield of 96% (Table 1, entries 3, 5 & 6),
and the use of Cu(II)Cl2 results in a slightly lower yield of
90% (Table 1, entry 10). Other catalysts, such as,
Table 1: Effects of catalyst, solvent, and base on the yield 70 Cu(I)OAc and Cu(II)SO4, lead to 88% and 24 % yield of
5
of the coupling product (3a) from phenylacetylene (2a)
(3a), respectively (Table 1, entries 12 & 13). Interestingly,
the use of copper phenylacetylide as a catalyst for coupling
between (1a) and (2a) also results in the isolation of (3a) in
95 % yield (Table 1, entry 11). This result clearly
75 indicates that the inꢀsitu generated copper phenylacetylide
might be the key catalyst responsible for the visible light
initiated, catalytic coupling reaction between terminal
alkynes and oꢀphenylenediamine (see supplementary
information for the uvꢀvisible absorption spectra of a few
80 copper arylacetylides).
and oꢀphenylenediamine (1a) [a]
10
15
20
25
30
35
40
45
Table 2: Control experiments to the diamination reaction
of phenylacetylene (2a) using oꢀphenylenediamine (1a) [a]
85 [a] Reaction conditions: 0.083 M (1a), 0.1 M (2a), 1.05 eqv. of
base and 5 mol% of Cu(I)Cl in ACNꢀMeOH (1:1 v/v). The
solution was irradiated with blueꢀLED for 2 h in presence of O2
atmosphere. [b] Yields were determined by the 1H NMR
integration method using mesitylene as an internal standard.
90
[a] Reaction conditions: 0.083 M (1a), 0.1 M (2a), 1.05 eqv. of
Control Experiments
base and 5 mol% of Cu(I)Cl in solvent. The solution was
50 irradiated with blueꢀLED for 2 h in presence of O2 atmosphere.
1
Meanwhile, control experiments also reveal that removal
of either light, Cu(I)Cl, base or molecular oxygen leads to
failure to produce the quinoxaline product (3a) at room
95 temperature (Table 2). Notably, no product was obtained
by thermal heating of the reactantsꢀcontaining solutions at
[b] Yields were determined by the H NMR integration method
using mesitylene as an internal standard. (Note: entries 6-17, 3
mol% catalyst used)
55
o
Noticeably, it takes a longer reaction time to achieve
moderate product yield of 80%, when organic bases were
used (Table 1, entry 1). In addition to bases, the choice of
solvents can also affect the product yields. For example,
60 one can still obtain the product (3a), when CH3CN, MeOH,
or DMF was used, but it fails to afford complete
conversion of reactants (see Table 1, entries 14ꢀ16).
Mixture of CH3CNꢀCH3OH (1:1 v/v) was found to be the
best solvent, which leads to the highest yields of 96%
65 within a short photo irradiation time (Table 1, entry 3). In
the screening of catalysts, Cu(I)X (X= Cl, Br, I) gives the
80ꢀ90 C for 10 h in dark in presence of 10 mol% Cu(I)Cl
(see the equation (4) in Scheme 3). These results support
the necessity of the light and Cu(I)Cl as a catalyst in the
100 oxidative coupling reactions.
Substrates scope
The scope of the visible light induced copper catalysed
diamination
of
terminal
alkynes
by
1,2ꢀoꢀ
105 phenylenediamine reaction was summarized in Tables 3-5
with optimized reaction conditions. We examined the
reactions of various substituted oꢀphenylenediamines with
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a wide range of acetylenes including electron withdrawing
and electron rich substituent groups. Satisfactorily,
substituted oꢀphenylenediamines react well with
phenyleneacetylene to generate the corresponding
excellent yields and higher reactivities were generally
observed for most of the substrates.
35
Table 4. Results of visibleꢀlightꢀinduced Cu(I)Cl catalyzed
diamination reaction of terminal acetylenes (2) and oꢀ
phenylenediamines (1a) [a]
5
Table 3. Results of visibleꢀlightꢀinduced Cu(I)Cl catalyzed
diamination reaction of phenylacetylene (2a) and various
oꢀphenylenediamines (1) [a]
3 mol% CuCl
K2CO3 (1.05 eq)
NH2
N
+
NH2
CH3CN-CH3OH, O2
blue LED
N
OH
R
R
2a
1
3
yield [%] [b]
entry
1
t [h]
2
2
1
product
3
NH2
N
3a
96
2a
1a
NH2
N
OH
OH
NH2
NH2
MeO
N
N
2
1b 2a
1c 2a
3b
+ isomer
98
2
MeO
N
N
NH2
NH2
3c
+ isomer
97
99
2
2
3
4
OH
OH
N
N
NH2
NH2
3d
2a
1d
N
N
NH2
NH2
3
2
3e
3f
1e
1f
2a
2a
93
94
5
6
OH
OH
Cl
N
N
NH2
NH2
NH2
NH2
+ isomer
Cl
N
N
3g
+ isomer
1g
2a
74
5
Ph
O
7
Ph
OH
O
10 [a] Reaction conditions: 0.083 M (1), 0.1 M (2a), 1.05 eqv. of
K2CO3 and 5 mol % of Cu(I)Cl in ACNꢀMeOH (1:1 v/v) and the
reaction mixture was irradiated under blueꢀLED light for 2ꢀ5 h in
presence of O2 atmosphere. [b] Isolated yield after silica column
purification. (Note: trace amount of homocoupling product was
15 obtained in all reactions)
40
[a] Reaction conditions: 0.083 M (1a), 0.1 M terminal acetylene
(2), 1.05 eqv of K2CO3 and 5 mol % of Cu((I)Cl in ACNꢀMeOH
(1:1 v/v) and the reaction mixture was irradiated under blueꢀLED
light for 2ꢀ5 h in presence of O2 atmosphere. [b] Isolated yield
45 after silica column purification. (Note: trace amount of
homocoupling product was obtained in all reactions).
Reactivity of substituted o-phenylenediamines with
phenylacetylene:
20 As shown in Table 3, oꢀphenylenediamines bearing
neutral, electronꢀdonating and electronꢀwithdrawing
substituents all are reactive towards phenylacetylene to
accomplish the corresponding quinoxaline derivatives.
Electron rich and neutral group substituted oꢀ
quinoxaline products (3g) with 85% yield over a period of
50 3 h reaction time (Table 3, entry 7). This slow reactivity is
due to the fact that electronꢀwithdrawing groups easily pull
the electrons from nitrogen lone pair and make the diamine
moieties less reactive.
Thus the phenylenediamines
25 phenylenediamines
couple
effectively
with
become less nucleophilic towards the photoꢀexcited,
55 electron deficient copper phenylacetylides.
phenylacetylene over a short period of 2 h to generate the
corresponding quinoxaline products (Table 3, entries 1ꢀ6).
But in the case of single substituted oꢀphenylenediamines,
two regioisomers were obtained (Table 3, entries 2, 3 & 6,
30 7). This is due to unsymmetric nature of substituted oꢀ
phenylenediamines which react equally well to the CꢀC
Reactivity of substituted phenylacetylenes with o-
phenylenediamine:
In a similar manner, we examined the substrates scope
for various substituted phenylacetylenes with oꢀ
triple bond of phenylacetylene.
Electronꢀdeficient
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phenylenediamine, which generally gives good yields. The
difficult to achieve by traditional copper catalysed thermal
electron rich groupꢀsubstituted phenylacetylenes readily 65 diamination of terminal acetylene.53 Moreover, the current
react with oꢀphenylenediamine to afford corresponding
quinoxaline products (3h-3k) with yields of 97, 95, 97, and
97 %, respectively (Table 4, entries 1ꢀ4). Also, halogen
atomꢀsubstituted phenyl acetylenes (X= F, Cl, Br, or I)
photochemical method works very well with both electron
rich and electron deficient groups (Tables 3ꢀ5).
Some important mechanistic evidences for oxidative
5
coupling
between
terminal
alkynes
and
oꢀ
react very well with oꢀphenylenediamine to give the 70 phenylenediamines were collected from a few key control
corresponding quinoxaline products (3l-3o) in high yields
experiments (Scheme 3).
of 99, 97, 95, and 94%, respectively (Table 4, entries 5ꢀ8).
10 In general, electron rich substitution groups at the
phenylacetylenes will favour the homocoupling reaction to
generate 1,3ꢀdiyne more efficiently in the presence of O2,
since these groups have more πꢀbasicity on the CꢀC triple
bond to promote the reaction in the presence of soft Lewis
78
15 acids, such as Cu(I) ion.77,
We found that the
homocoupling process can be significantly suppressed by
lowering down the concentration of phenylacetylene
substrates in the reaction mixture. Under our reaction
condition, the amount of homocoupling product is
20 negligible (Tables 3 & 4).
Table 5. Visible lightꢀinduced Cu(I)Cl catalyzed
diamination reaction of terminal acetylenes (2) and oꢀ
phenylenediamine (1a) [a]
25
30
35
40
45
75 Scheme 3: Mechanistic control experiments.
Firstly, 3 h photo irradiation of a solution containing 3
mol% of Cu(I)Cl or Cu(II)Cl2 in the absence of any base
does not result in the formation of any product at all
80 (equation (1) in Scheme 3). This is probably due to the
fact that Cu(I)Cl or Cu(II)Cl2 can form complexes easily
with either oꢀphenylenediamines or phenylacetylenes to
form the light absorbing intermediate/catalyst. This result
suggests that base is required for the observed coupling
85 reaction in order to promote the formation of the catalyst,
i.e., copper phenylacetylide. In another experiments,
addition of copper phenylacetylide, instead of Cu(I)Cl, as a
catalyst could also result in the formation of quinoxaline
products (3a) in 95% isolated yield (equation (2) in
90 Scheme 3). Furthermore, copper phenylacetylide (2a')
(1.2 eqv.) could efficiently react with oꢀphenylenediamines
to give 92% yield of quinoxaline products (3a) without the
need of phenyl acetylenes, Cu(I)Cl and base (equation 3 in
Scheme 3). These two control experiments clearly reveal
95 that copper phenylacetylide is the key light absorbing
intermediate, which reacts with oꢀphenylenediamine to
generate the quinoxaline products (3a) upon blue LED
light irradiation. Finally, in order to examine whether the
key intermediate, i.e., copper phenylacetylide, can react
100 with oꢀphenylenediamine under thermal condition, we heat
the reaction mixture to 80ꢀ90 oC for 10 h in the presence of
10 mol% Cu(I)Cl and base. However, no product was
formed under such thermal condition (equation (4) in
50
[a] Reaction conditions: 0.083 M (1a), 0.1 M terminal acetylene
(2), 1.05 eqv. of K2CO3 and 5 mol % of Cu(I)Cl in ACNꢀMeOH
(1:1 v/v) and the reaction mixture was irradiated under blueꢀLED
55 light for 2ꢀ5 h in presence of O2 atmosphere. [b] Isolated yield
after silica column purification.
In the case of electron deficient groupsꢀsubstituted
phenylacetylenes, they react with oꢀphenylenediamine
60 effectively over a period of 2.5 h to generate quinoxaline
products (3p-3t) in high yields of 98, 96, 97, 94, and 95%,
respectively (Table 5, entries 9ꢀ13). More importantly, no
undesired homocoupling product was formed, which is
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Scheme 3), indicating that the key intermediate, copper
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75
80
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biologically important quinoxaline derivatives. To the best
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25 effective nature of catalyst (Cu(I)Cl), avoidance of toxic
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30 accessible starting materials.
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Experimental Section
General procedure: A dry test tube (20 mL) with a rubber
septum and a magnetic stirrer bar was charged with K2CO3
(0.52 mmol, 1.05 eqv.) and 5 mol% Cu(I)Cl and then
35 added dry CH3CN and CH3OH (1:1 v/v) via syringe, added
terminal acetylenes (0.1 M) and finally added 1,2ꢀoꢀ
phenylenediamines (0.083 M). The yellowish suspension
solution (see Figure S3 in the Supplementary Information
for optical pictures) was stirred and irradiated with blue
40 LED light (power density 40 mW/cm2 at 460 nm) at room
temperature in 1 atm. oxygen atmosphere for 2ꢀ5 h until
completion of coupling reaction (it was determined by thin
layer chromatography). The reaction mixture was diluted
with 40 % ethyl acetate in hexane and stirred for 10 min.
45 The mixture was filtered through celite and silica gel pads
and washed with ethyl acetate. The filtrate was
concentrated and the residue was purified by flash column
chromatography on silica gel to afford desired quinoxaline
product.
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50 Acknowledements
14. G. Vitale, P. Corona, M. Loriga and G. Paglietti, Quinoxaline
chemistry Part 10. Quinoxaline 10ꢀoxaꢀanalogues of
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The aurthors are grateful to the finanical support from
the the Frontier Research Center on Fundamental and
Applied Sciences of Matters, National Tsing Hua
55 University as well as from the National Science Council,
Taiwan.
6
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Table of Content
Visible-Light-Induced, Copper(I)-Catalysed C-N
Coupling Between o-Phenylenediamine and
Terminal Alkynes: One-Pot Synthesis of 3-Phenyl-
2-Hydroxy-Quinoxalines
5
Arunachalam Sagadevan, Ayyakkannu Ragupathi and Kuo
Chu Hwang*
10
Visibleꢀlightꢀinitiated direct double CꢀN coupling
reaction of oꢀphenylenediamines and terminal acetylenes
were achieved at room temperature by using simple
Cu(I)Cl as a catalyst, towards the synthesis of biologically
15 important 3ꢀPhenylꢀ2ꢀhydroxyꢀquinoxalines.
20
25
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