Copper-catalyzed synthesis of valuable heterocyclic compounds using a tandem oxidation process approach

Article abstract of DOI:10.1080/00397911.2015.1022660

The synthesis of quinoxalines via a tandem oxidation process using a copper acetate monohydrate/2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) oxidative system has been described. Using this approach, a series of quinoxaline derivatives were formed in good yields within short reaction times under microwave irradiation. The oxidative system was also extended to the selective synthesis of dihydropyrazines and pyrazines.

Full text of DOI:10.1080/00397911.2015.1022660

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Copper Catalyzed Synthesis of Valuable Heterocyclic
Compounds Using a Tandem Oxidation Process
Approach
Vineet Jeenaa, Siphamandla Sithebea & Ross S. Robinsona
a School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville,
Pietermaritzburg, South Africa
Accepted author version posted online: 16 Mar 2015.
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To cite this article: Vineet Jeena, Siphamandla Sithebe & Ross S. Robinson (2015): Copper Catalyzed Synthesis of Valuable
Heterocyclic Compounds Using a Tandem Oxidation Process Approach, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1022660
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Copper Catalyzed Synthesis of Valuable Heterocyclic Compounds Using a Tandem
Oxidation Process Approach
Vineet Jeena1, Siphamandla Sithebe1, Ross S. Robinson1
1School of Chemistry and Physics, University of KwaZulu-Natal, Scottsville,
Pietermaritzburg, South Africa
Address Correspondance to Vineet Jeena, School of Chemistry and Physics, University
of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209, South Africa.
Email: Jeenav1@ukzn.ac.za
Abstract
The synthesis of quinoxalines via the tandem oxidation process using a copper acetate
monohydrate/TEMPO oxidative system has been described. Using this approach, a series
of quinoxaline derivatives were formed in high yields and short reaction times under
microwave irradiation. The oxidative system was also extended to the selective synthesis
of dihydropyrazines and pyrazines.
KEYWORDS: tandem oxidation process; quinoxalines; copper; microwave
1

INTRODUCTION
The tandem oxidation process (TOP) has developed into an innovative addition to
synthetic organic chemistry as it is characterized by high yields and short reaction times.1
This procedure consists of mixing an alcohol, nucleophile and oxidant in a one pot
process, in which the alcohol is oxidized to the aldehyde which is immediately trapped by
the nucleophile, leading to a variety of synthetically useful compounds.2 The quinoxaline
moiety is synonymous with TOP and continues to garner interest from synthetic chemists
the world over due to its activity against pancreatic cancer3 and malaria cell lines4 as well
as displaying exciting luminescence5 and photoinduced DNA cleaving applications6 to
name but a few. The most common oxidative method to access these quinoxaline
compounds, using the TOP, is through the use of transition metal catalysts such as
manganese,7 iron,8 ruthenium,9 palladium,10 mercury11 and titanium.12 However, these
methods suffer from cost, time and in some cases practicality limitations as elaborate
metal catalysts are prepared using long and tedious procedures. As an example, our
previous work using a titanium dioxide mediated system produced the desired
quinoxalines in excellent yields although a stoichiometric quantity of metal catalyst was
required.12 Thus, we set our sights on developing a simple, transition metal based
quinoxaline synthesis using the tandem oxidation process.
RESULTS AND DISCUSSION
We were particularly interested in a copper based system as previous research, towards
the synthesis of quinoxalines, using this metal was carried out using highly specialized
equipment with long reaction times although good yields were observed.13 Recently, Kan
2

and co-workers, in their manuscript on the synthesis of indolizines, reported the use
copper acetate monohydrate as a cheap and efficient oxidant.14 They vehemently argue
the merits of copper acetate monohydrate as an oxidant based on its price and ease of
handling. In addition, Stahl and co-worker have reviewed the use of copper catalysts in
combination with 2,2,6,6,-tetramethyl-piperidine-1-oxyl radical (TEMPO) for the
selective oxidation of alcohols to their carbonyl derivatives in excellent yields.15
However, an analysis of this review revealed that these systems used intricate copper
complexes and required the addition of specific ligands and additives. Thus, we set about
assembling a copper acetate monohydrate/TEMPO oxidative system under aerobic
conditions by monitoring the test reaction between 2-hydroxyacetophenone and o-
phenylenediamine. The results of this investigation into determining the optimum
reaction conditions for the copper catalyzed quinoxaline synthesis are summarized in
Table 1.
The copper acetate monohydrate/TEMPO system was initially evaluated using
conventional heating and ultrasonic irradiation and, in both cases, satisfactory yields were
observed (Table 1, entries i – ii). In an effort to improve the yields and decrease the
reaction times, the remaining set of test reactions were conducted under microwave
irradiation. The best result was observed using DMF as a solvent which produced the
desired quinoxaline in an excellent isolated yield of 94% (Table 1, entry v) and the
omission of either copper acetate monohydrate or TEMPO resulted in the formation of
only trace amounts of product (Table 1, entries vi – vii). The exclusion of copper acetate
monohydrate and TEMPO resulted in no product formation and only the starting
3

materials were detected (Table 1, entry viii). With the optimized procedure in hand, we
explored the scope and limitations of the copper acetate monohydrate/TEMPO system
using a diverse range of alcohols and nucleophiles (Table 2).
The second substrate that was analyzed was the aliphatic keto alcohol whose successor,
the aliphatic keto aldehyde is especially difficult to isolate due to its “hyper-reactivity”.7
Under our copper acetate monohydrate/TEMPO conditions, the desired quinoxaline was
isolated in a satisfactory yield of 63% (Table 2, entry ii) which was lower than expected.
The decrease in yield was presumably due to the volatility of the intermediate keto-
aldehyde at the elevated temperatures10 and this was confirmed as an excellent yield of
88% was observed when the reaction was conducted at room temperature. The copper
acetate monohydrate/TEMPO system was effective on a variety of alcohols and
nucleophiles (Table 2, entries iii – viii) although a decrease in yield was observed in the
case of bulkier substrates (Table 2, entries vi – vii).
Next, we turned our attention towards the synthesis of 2,3-diphenylpyrazine as it has
been shown to display promising activity against a variety of cancer cell lines.16 A
retrosynthetic study revealed that the precursor to the pyrazine was the dihydropyrazine
which was derived from benzil and ethylenediamine. Benzil, as expected, could be
derived from benzoin using our copper acetate monohydrate/TEMPO system (Scheme
1). The retrosynthetic analysis revealed an interesting point as two valuable heterocyclic
compounds were part of this synthetic approach (namely the dihydropyrazine and
pyrazine). Dihydropyrazines and pyrazines are important moieties as they have found
4

applications such as pollinator sex pheromones,17 antiviral applications18 as well as alarm
pheromones in ponerine ants.19
Previous research within the TOP mediated pyrazine synthesis has been divided into two
main oxidative systems. The first system, commencing from the alcohol would result
directly in the pyrazine being formed without the dihydropyrazine being detected and the
second system, commencing from the alcohol, would result in the dihydropyrazine which
would then require the addition of reagents to effect the aromatization. For example,
Shinde and co-workers have reported a TOP mediated synthesis of pyrazines directly
from the alcohol20 (no dihydropyrazine in final mixture) while Taylor and co-workers
have reported a TOP mediated pyrazine synthesis from the alcohol which initially formed
the dihydropyrazine which subsequently aromatized when concentrated base/MeOH was
added.7 To the best of our knowledge, there has not been a TOP oxidative system devised
which will selectively form the dihydropyrazine or the pyrazine (without the addition of
further reagents) and, with this in mind, we set about the synthesis of the potential cancer
antagonist, 2,3-diphenylpyrazine.
As the diphenylpyrazine compound was formed in excellent yield (Table 2, entry viii),
we sought to effectively aromatize the ring. Firstly, the reaction time was simply doubled
to determine if under prolonged microwave irradiation the desired pyrazine would form.
However, even after 30 additional minutes of microwave irradiation the 2,3-
diphenlpyrazine was not detected (Table 3, entry ii) and thus, we began to determine
possible reagents to effectively aromatize the ring. In this case, elemental sulfur was
5

chosen to aromatize the ring as it is cheap, easy to handle and non-toxic.21 Once again
we carried out the coupling of benzoin and ethylenediamine in the presence of copper
acetate monohydrate and TEMPO in DMF under microwave irradiation for 30 minutes,
and to the crude mixture was added elemental sulfur and the mixture was irradiated for an
additional 30 minutes. Under these conditions, the desired pyrazine was isolated in an
excellent yield of 88% as well as minute amounts of the dihydropyrazine (Table 3, entry
iii). Finally, a one pot synthesis of the pyrazine compound was verified by mixing
benzoin, ethylenediamine, copper acetate monohydrate/TEMPO and elemental sulfur in
DMF under microwave irradiation for 30 minutes and, to our delight, only the pyrazine
derivative was isolated (Table 3, entry iv). Thus, by the addition (or exclusion) of
elemental sulfur, two valuable heterocycles can be exclusively formed and in high yield
in a one pot synthesis.
EXPERIMENTAL
General Procedure For The Synthesis Of Quinoxalines
Alcohol (0.5 mmol), diamine (0.5 mmol), copper acetate monohydrate (0.05 mmol) and
TEMPO (0.05 mmol) in 2ml DMF was irradiated under open vessel microwave (150 W)
conditions for 30 minutes at 110oC. The cooled mixture was diluted with water and
extracted with dichloromethane, to produce the crude product, which was subsequently
purified using radial chromatography to afford the desired quinoxalines.
6

CONCLUSION
In conclusion, we have reported the one pot synthesis of quinoxalines using a copper
acetate monohydrate/TEMPO system. The developed oxidative system is simple and
produces the desired products in high yields in short reaction times. The copper acetate
monohydrate/TEMPO system was further extended to the synthesis of 2,3-
diphenylpyrazine, a known cancer antagonist and the dihyropyrazine and pyrazine
derivatives can be formed exclusively and in high yield through the addition or exclusion
of elemental sulfur. Further studies are underway to expand the scope of this
methodology to other coupling reactions and will be reported in due course.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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8

Table 1: Optimization study towards the synthesis of
quinoxalinesa
Entry
i
Metal
Additive
Solvent
Toluene
Toluene
Toluene
Water
DMF
Condition
CHc
USd
Yieldb
77
Cu(OAc)2∙H2O TEMPO
Cu(OAc)2∙H2O TEMPO
Cu(OAc)2∙H2O TEMPO
Cu(OAc)2∙H2O TEMPO
ii
62
iii
mw
30
iv
mw
38
v
TEMPO
mw
94e
trace
trace
0
Cu(OAc)2∙H2O
vi
Cu(OAc)2∙H2O
–
DMF
mw
vii
viii
–
–
TEMPO
DMF
mw
–
DMF
mw
aAlcohol (0.5 mmol), diamine (0.5 mmol), Cu(OAc)2.H2O (0.05 mmol) and TEMPO
(0.05 mmol) under open vessel conditions using microwave irradiation. b Yields
estimated using 1H NMR spectroscopy. C CH = conventional heating, reflux for 12h. d
US = ultrasound irradiation for 12 h. e Isolated yield.
9

Table 2. Evaluation of the copper acetate monohydrate/TEMPO system using a range of
keto-alcohols and diaminesa
Entry Alcohol
i
Nucleophile
Quinoxalines
Yieldb (%)
94
ii
63c
91
iii
iv
v
96
85
vi
69
59
vii
10

viii
92
aAlcohol (0.5 mmol), diamine (0.5 mmol), Cu(OAc)2.H2O (0.05 mmol), TEMPO (0.05
b
mmol) in 2 ml DMF under open vessel conditions using microwave irradiation.
Isolated yield. c the observed yield may be due to the volatility of the intermediate
aldehyde at elevated temperatures, under room temperature, 88% was obtained. See
supporting information for a detailed experimental.
11

Table 3: Synthesis of a dihydropyrazine and pyrazine using a copper acetate
monohydrate/TEMPO TOP approacha
Entry
Additive
Time (min)
Yield (%)b
3h
92
89
7
3i
i
–
30
60
60
30
ndc
ndc
88
94
ii
–
iiic
iv
sulfur
sulfur
nd
a Alcohol (0.5 mmol), diamine (0.5 mmol), copper acetate monohydrate (0.05 mmol),
TEMPO (0.05 mmol) in 2ml DMF under microwave irradiation. b Isolated yield. c Not
detected. See supporting information for a detailed experimental.
12

Scheme 1. Retrosynthetic study towards 2,3-diphenyl pyrazine showing two valuable
heterocycles
13