Eucalyptol: A new solvent for the synthesis of heterocycles containing oxygen, sulfur and nitrogen

Article abstract of DOI:10.1039/c8gc04016h

We report here the first investigation of the use of eucalyptol as a new solvent for organic transformations. Heterocycles containing oxygen, sulfur and nitrogen were chosen as targets or as starting materials for widely used palladium-catalysed cross-cou

Full text of DOI:10.1039/c8gc04016h

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: J. F. CAMPOS, M.
Scherrmann and S. Berteina-Raboin, Green Chem., 2019, DOI: 10.1039/C8GC04016H.
Volume 18 Number
7
7
April 2016 Pages 1821–2242
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
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
author guidelines.
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, outlined
in our author and reviewer resource centre, 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.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Page 1 of 10
Please Gd roe en no tC ha ed mj u iss tt r my argins
View Article Online
DOI: 10.1039/C8GC04016H
Green Chemistry
ARTICLE
Eucalyptol : New solvent for the synthesis of heterocycles
containing oxygen, sulfur and nitrogen
Received 00th January 20xx,
Accepted 00th January 20xx
a
b*
a*
Joana F. Campos, Marie-Christine Scherrmann and Sabine Berteina-Raboin
DOI: 10.1039/x0xx00000x
Abstract: We reported here a first investigation of the use of eucalyptol as the new solvent for organic transformations.
Heterocycles containing oxygen, sulfur and nitrogen were chosen as targets or as starting materials for widely used
palladium-catalysed cross-coupling reactions, i.e. Suzuki-Miyaura and Sonogashira-Hagihara reactions. Eucalyptol turned
out to be a viable sustainable alternative to common solvents.
www.rsc.org/
Eucalyptol or 1,8-cineole is often described as contained up to
90% in Eucalyptus’ essential oils, depending on the species. For
example, the chemical composition determined by GCMS
Introduction
In a context of sustainable development, the need to find
alternatives to compounds from non-renewable resources is a
priority. In the field of organic synthesis, solvents often
constitute the major part of the reaction medium. This amount
was evaluated for active pharmaceutical ingredients
syntheses: it reaches 52% by mass, taking into account only
organic solvents, and more than 80% including water. As a
result of the high environmental impact caused by the
solvents, many studies have been devoted to the search for
analysis of E. cinerea’s oil isolated from fresh foliage has
showed three major constituents, Eucalyptol (84.39%),
Limonene (5.92%) and -Terpineol (5.55%) with 17 other
9
different compounds occurring in less than 0.5% each.
That is a very interesting proportion because the Eucalyptus forests
have been developed strongly, during the last decades, for their use
in the paper industry because of their rapid growth (7 to 10 years).
The producers of eucalyptus essential oils are mainly: Australia,
China, Portugal, Spain and South Africa without problems of supply
since Eucalyptus are very big trees with fast growth during which
the leaves can produce eucalyptol. The world production of
1
2
greener and sustainable alternatives and solvent selection
guides were published, that included bio-derived solvents.
Among the solvents derived from biomass, those produced
3
4
5
from food waste represents an interesting approach since eucalyptus essential oils from Eucalyptus globulus and Eucalyptus
their use could participate to a more circular economy. One of radiata was estimated, in 2015 at 4 000 tons per year by
those bio-solvents is limonene (Fig 1), a monoterpene FranceAgrimer.
unsaturated hydrocarbon with low polarity and weak
hydrogen bond basicity (Table 1), making it an alternative to
non-polar petroleum-based solvents used in extraction
6
,7
Eucalyptol
(R)-(+)-Limonene
processes or cleaning applications but rarely for organic
transformations.8 In this paper, we decided to compare
limonene and Eucalyptol or 1,8-cineole (Fig. 1) that we wanted
to use as new solvent. The latter is a saturated oxygenated
terpene widely distributed in many plants and their essential
oil fractions. Its use as green solvent is also related to its safety
and pharmacological profiles: Eucalyptol is considered to be a
safe chemical when taken in normal doses.
bp: 176-177 °C
d: 0.921
bp: 176-177 °C
d: 0.842
: 2.36

: 4.84
O
Figure 1. Structures of eucalyptol and limonene
Compared to limonene, this bicyclic ether exhibits higher
polarity and hydrogen bond basicity (Table 1). It is insoluble in
water but miscible with ether, ethanol and chloroform.
a. Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans UMR-
CNRS 7311, BP 6759, rue de Chartres 45067 Orléans cedex 2, France.
sabine.berteina-raboin@univ-orleans.fr
Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR CNRS 8182,
Université Paris-Sud, Bâtiment 420, 91400 Orsay, France.
marie-christine.scherrmann@u-psud.fr
b.
Eucalyptol could also be compared to the 2-
N
Methyltetrahydrofuran which has E
T
= 0.179, acidity () = 0,
1
0
Basicity () = 0,58, and Polarity (*) = 0,53. The 2-MeTHF is
†Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
mainly used as solvent to replace THF because of its higher
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 00, 1-3 | 1
Please do not adjust margins

Please Gd roe en no tC ha ed mj u iss tt r my argins
Page 2 of 10
ARTICLE
Green Chemistry
boiling point 78-80°C. Nevertheless it can, like THF, generate presence of several bases in limonene or eucalyptol as the
View Article Online
DOI: 10.1039/C8GC04016H
peroxides and require the addition of inhibitor such as solvents (Table 2).
butylated hydroxytoluene (BHT), a powerful antioxidant. In
addition Eucalyptol is cheaper than 2 Methyltetrahydrofuran.
Table 2. Optimization of the condensation from 2-aminopyridine 1 and
bromoacetophenone 2 in limonene or eucalyptol at 105 °C.
Entry
Base
2 equiv.)
Solvent
Time (h)
Yield (%)
Table 1. Solvatochromic parameters of limonene and eucalyptol
(
1
2
3
4
5
6
7
8
9
K
2
CO
KOAc
Cs CO
3
Eucalyptol
Eucalyptol
Eucalyptol
Eucalyptol
Eucalyptol
Eucalyptol
Limonene
Limonene
Limonene
Limonene
Limonene
Limonene
24
24
24
22
24
48
24
24
24
22
24
48
64
71
75
83
53
13
85
64
66
84
50
33
Limonene
Ref.
Eucalyptol
Ref.
2
3
N
E
T
0.102
0
0.61
0.36
[11]
[10]
[12]
[12]
NaHCO
CsOAc
KOH
3
Acidity ()
Basicity ()
Polarity ()
0
[10]
[10]
0.24
K
2
CO
KOAc
Cs CO
3
To the best of our knowledge, there is no report in the
literature to date on the use of Eucalyptol in organic synthesis.
In this context, our project aimed at evaluating limonene and
eucalyptol as solvents for some of the most prevalent
transformations at both process development and
manufacturing scale, i.e. the synthesis of heterocycles and
2
3
1
1
1
0
1
2
NaHCO
CsOAc
KOH
3
2
-phenylimidazo[1,2-a]pyridine 3a was obtained in good yield
after 22 h at 105°C in the presence of NaHCO (Table 1, Entries
and 10) both in limonene and eucalyptol whereas the use of
CO gave better results with limonene as solvent (Table 1,
3
1
3
cross-coupling reactions.
4
K
Based on our previous work in the development of new
methodologies and greener approaches in the synthesis of
we focussed on heterocycles containing
oxygen, sulfur or nitrogen.
2
3
Entries 1 and 7).
heterocycles,1
4-19
As the C-H activation at position C-3 of 2-phenylimidazo[1,2-
a]pyridine was more effective in eucalyptol (see below), and in
order to carry out a one pot procedure, we chose this solvent
to study the scope of the reaction with various 2-bromo
acetophenones 3b-c (Fig.3).
Results and discussion
A. Synthesis of Imidazo[1,2-a]pyridines
Imidazo[1,2-a]pyridine is one of the most potential bicyclic 5–6
heterocyclic rings that is recognized as a “drug prejudice”
scaffold due to its broad range of applications in medicinal
chemistry
such
as
anticancer,
antimycobacterial,
antileishmanial, anticonvulsant, antimicrobial, antiviral,
antidiabetic, proton pump inhibitor, insecticidal activities. This
scaffold has also been represented in various marketed
preparations such as zolimidine, zolpidem, alpidem. Therefore,
2
0
many works have been done to propose syntheses and
structural modifications of this scaffold with the aim to
2
1
discover and develop novel therapeutic agents. Greener
approaches involving one pot condensation and C-H activation
were also proposed by us and others. (Fig.2)
2
2
23
Figure 3. Condensation of 2-amino pyridine with a various 2-bromo
acetophenones 2b-e.
The various groups in position 4 on the aromatic ring had no
influence and the expected products were obtained in
moderate to excellent yields (Fig. 3).
We then studied the C-H activation at position C-3 of 2-
phenylimidazo[1,2-a]pyridine 3a using bromobenzene 4 (1.5
2
equiv.) and by varying the amount of Pd(OAc) in limonene or
eucalyptol (Table 3).
Figure 2. Greener approach for the synthesis of Imidazo[1,2-
2
2,23
a]pyridine
This work started with an optimization of condensation using
2
-aminopyridine 1 and 2-bromoacetophenone 2a (1 equiv.) in
2
| Green Chem., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 3 of 10
Green Chemistry
Green Chemistry
ARTICLE
The 2,3-diarylimidazol[1,2-a]pyridines 6a-f were VioewbtAartiincleedOnlinine
moderate to excellent yield, demonstratinDgOtIh: 1e0.g10e3n9e/rCa8liGtyC0o4f0t1h6His
Table 3. Optimization of C-H activation of 3a in eucalyptol and limonene as
solvents
method. Yields shown at Fig. 4 correspond to tests carried out on a
scale of 1 mmol of 2 aminopyridine 1. We verified that the results
were equivalent on a larger scale. Indeed, from 10.6 mmol of 1 (1.0
g), 2-(4-fluorophenyl)-3-(4-nitrophenyl)imidazol[1,2-a]pyridine 6c
was isolated in 98% yield (3.47 g). Analysing the mean values
obtained by the various teams in the development of the one-
pot approach for the synthesis of imidazo[1,2-a]pyridines, we
can conclude that Eucalyptol is a valid option (Graph 1)22,24,25.
The average yields were made, depending on published
examples, on 18 reactions in DMF, 20 reactions in PEG, 16
reactions in DMA and on the 7 reactions in Eucalyptol
described herein.
Entry
Pd(OAc)
2
(mol %)
Solvent
Yield (%)
1
2
3
4
5
2.5
5
10
2.5
5
Eucalyptol
Eucalyptol
Eucalyptol
Limonene
Limonene
42
60
61
Traces
Traces
Compound 5 was obtained in moderate yield in eucalyptol
Table 3, Entries 2 and 3). When the reaction was performed in
limonene the results were poor (Table 2, Entries 4 and 5). The
amount of Pd(OAc) was studied, and the improvement was
(
2
not sufficient to justify the use of 10 mol% in the last phase.
The one pot procedure was then performed with 2-bromo-4-
fluoroacetophenone 2c, aryl bromides and 2-aminopyridine 1
using eucalyptol as solvent (Fig. 4).
D M F
P E G
D M A
E U C A L Y P T O L
Graph 1. Average yield (%) reported for the synthesis of 2,3-
diarylimidazol[1,2-a]pyridines in different solvents
Encouraged by the good results obtained previously with
eucalyptol as solvent, we decided to use this solvent for
palladium catalyzed coupling reactions such as Suzuki-Miyaura
and Sonogashira-Hagihara reactions.
B. Suzuki-Miyaura coupling reaction
The Suzuki-Miyaura reaction belongs to the most powerful and
most applicable group of reactions for formation of C-C bonds.
Its use is effective for a wide range of substrates, which makes
this cross coupling reaction a versatile tool. Due to all of these
features and properties, efforts were done to find greener
2
6
conditions.
Scheme 1. Suzuki-Miyaura reaction
Figure 4. one pot procedure
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 00, 1-3 | 3
Please do not adjust margins

Please Gd roe en no tC ha ed mj u iss tt r my argins
Page 4 of 10
ARTICLE
Green Chemistry
In comparison with yields obtained for the sameVierweAartcictlieoOnnlionef
chlorothieno[3,2-d]pyrimidine in the mDO
solvents, eucalyptol proved to be a good alternative (Graph
).27-30 The average yields were made on 4 reactions in THF, 15
o
I
s
:
t
10
c
.1
o
0
m
39
m
/C
o
8Gnl
C
y
04
used
0
1
6H
2
reactions in Toluene, 5 reactions in DMF, 17 reactions in
Dioxane, 4 reactions in DME and on the 5 reactions in
Eucalyptol described herein.
Figure 5. A: Reaction medium at temperature below 100 °C; B:
reaction mixture at 100 °C.
Optimization of the Suzuki reaction was achieved starting from
4
-chlorothieno[3,2-d]pyrimidine
7
using 4-methylphenyl
boronic acid 8a and by varying the catalytic system and the
base (Scheme 1). After several attempts, we observed that the
complete dissolution of all the reactants and consequently the
reaction progress was achieved when the temperature was set
at 100 °C. (Fig. 5)Results are summarized in Table 1.
Compound 9a was obtained in moderate (Table 1, Entry 2) to
excellent yield (Table 1, Entries 1, 3 and 4). When the reaction
T H F
T O L U E N
E
D M F
D I O X A N
E
D M E
E U C A L Y P
T O L
was performed in the presence of Pd(PPh
3 4
) , yields were Graph 2. Average yield (%) reported for Suzuki-Miyaura coupling
higher. The base had a pronounced effect: when the reaction reaction of chlorothieno[3,2-d]pyrimidine
was carried out using Pd(PPh
quantitative yield was obtained.
3 4 2 3
) and Na CO as base,
Optimization of the Suzuki reaction with 7-chloro-5-methyl
1,2,4]triazolo[1,5-a]pyrimidine 10 was performed using 4-
[
methylphenyl boronic acid 8a as a model substrate.
Table 4. Optimization of the Suzuki-Miyaura reaction (Scheme 1)
Entry
Catalyst
0.1 eq.)
Pd(PPh
Pd(OAc)
Pd(PPh
Pd(PPh
Ligand
(0.2 eq.)
Base
(2 eq.)
Time
(h)
14
20
14
Yielda
(
(%)
99
65
97
90
1
2
3
4
3
)
4
Na
Cs
2
CO
CO
3
2
Xantphos
2
3
3
)
4
K
K
2
CO
CO
3
3
)
2
Cl
2
2
3
20
aisolated yields after purification by flash chromatography.
Scheme 2.
Based on our results (Table 4) the scope and limitations of the
Suzuki-Miyaura coupling reaction on 4-chlorothieno[3,2-
d]pyrimidine 7, were assessed using various boronic acids 8b-e
The use of different palladium sources as catalyst and sodium
bicarbonate, potassium carbonate or cesium carbonate as
base were examined. Best conditions were found using
(Fig. 6).
3 4 2 3
Pd(PPh ) and K CO (Table 5, entry 3).
Table 5. Optimization of the Suzuki-Miyaura reaction (Scheme 2)
Entry
Catalyst
0.1 eq.)
Pd(PPh
Pd(OAc)
Pd(PPh
Pd(PPh
Ligand
(0.2 eq.)
Base
(2 eq.)
Time
(h)
14
14
14
Yielda
(%)
49
71
73
(
1
2
3
4
3
)
2
4
Na
Cs
2
CO
CO
3
Xantphos
2
3
3
)
4
K
K
2
CO
CO
3
3
)
2
Cl
2
2
3
14
66
aisolated yield after purification by flash chromatography.
Different boronic acids 8b-e were then used to evaluate the
reaction scope. Several 5-methyl-7-(aryl)-[1,2,4]triazolo[1,5-
a]pyrimidines 11b-e were obtained in moderate yield. (Fig. 7)
Figure 6. Scope and limitations of the Suzuki-Miyaura coupling reaction on 7
4
| Green Chem., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 5 of 10
Green Chemistry
Green Chemistry
ARTICLE
View Article Online
DOI: 10.1039/C8GC04016H
Scheme 3. Conditions: 8a, 1.5 equiv., Pd(PPh
eucalyptol 100 °C, 20 h.
3 4 2 3
) 0.1 equiv., Na CO 2 equiv.,
Figure 7. Suzuki-Miyaura coupling reaction on 10
In this case the average yields were made on 3 reactions in
DME, 2 reactions in Dioxane (2015), 2 reactions in Dioxane
In comparison with the yields described for this reaction with
3
1-33
the same substrate in dioxane or DME,
those obtained
(2013) and in Eucalyptol on the reaction described herein for
using eucalyptol were generally lower (Graph 3). The average
yields were made on 8 reactions in Dioxane, 30 reactions in
DME (2011), 2 reactions in DME (2010) and on the 5 reactions
in Eucalyptol described herein. However, since dioxane and
each heterocycle.
8-chloro[1,2,4]triazolo[4,3-a]pyrazine
6-chloro[1,2,4]triazolo[4,3-a]pyrazine
3
4
DME are classified as hazardous, eucalyptol remains a good
alternative for this transformation.
D M E
D I O X A N E
2 0 1 5 )
D I O X A N E
( 2 0 1 3 )
E U C A L Y P T O L
(
Graph 4. Average yield (%) reported for Suzuki-Miyaura coupling reaction on
-chloro-[1,2,4]triazolo[4,3-a]pyrazine 12 and 6-chloro-[1,2,4]triazolo[4,3-
8
a]pyrazine 14.
Starting from 4-chlorofuro[3,2-c]pyridine 16 we obtained,
under the same conditions, compounds 17a-e with moderate
to excellent yield (Fig. 8).
D I O X A N E
D M E ( 2 0 1 1 )
D M E ( 2 0 1 0 ) E U C A L Y P T O L
Graph 3. Average yield (%) reported for Suzuki-Miyaura coupling reaction of
chloro[1,2,4]triazolo[1,5-a]pyrimidine
The 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine 12 and 6-chloro-
[
1,2,4]triazolo[4,3-a]pyrazine 14 were submitted to the same
reaction conditions (Scheme 3) affording 13 or 15 in good
yield. The yield obtained with 12 in eucalyptol as solvent was
3
5,36
similar to those obtained in dioxane or DME,
whereas with
1
4, a significant yield increase was obtained compared to
dioxane (Graph 4).
Figure 8. Suzuki-Miyaura coupling reaction on 16
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 00, 1-3 | 5
Please do not adjust margins

Please Gd roe en no tC ha ed mj u iss tt r my argins
Page 6 of 10
ARTICLE
Green Chemistry
Also in this case, eucalyptol gave better results compared to Sonogashira-Hagihara coupling reaction
View Article Online
DOI: 10.1039/C8GC04016H
DME (Graph 5).37,38 The average yields were made on 18
The coupling of aryl or vinyl halides with terminal acetylenes
catalysed by palladium and other transition metals, commonly
termed as Sonogashira cross-coupling reaction, is another
example of the most important and widely used sp2–sp
carbon–carbon bond formation reactions in organic synthesis,
frequently employed in the synthesis of natural products,
reactions in DME (2015), 4 reactions in DME (2010) and on the
5
reactions in Eucalyptol described herein
.
3
9,40
biologically active molecules and heterocyclic compounds.
Optimization of the Sonogashira reaction in eucalyptol was
achieved starting from 4-chlorothieno[3,2-d]pyrimidine 7 using
4
-methoxyphenyl acetylene 18a and by varying the catalytic
system and the base. The results obtained are summarized in
3
1
Table 8. In this case the conditions previously reported by us
i.e. Pd(PPh Cl (5 % mol), CuI (10 % mol) in a mixture of
solvent and Et N) were not the best option with eucalyptol.
(
)
3 2
2
3
D M E ( 2 0 1 5 )
D M E ( 2 0 1 0 )
E U C A L Y P T O L
Compound 19a was obtained in moderate (Table 8, Entries 1
and 2) to good yield (Table 8, Entry 3). When the reaction was
Graph 5. Average yield (%) reported for Suzuki-Miyaura coupling reaction of performed in the presence of Pd(PhCN)
2 2 3
Cl and P(Cy ), yield
4
-chlorofuro[3,2-c]pyridine 16.
was increased.
Furthermore, the optimized conditions are in line with other
reported conditions in which the use of CuI with aryl chlorides
Recyclability of the solvent
Reusability of the solvent being essential from the economic was not necessary.41-44 It was a curiosity, as it is well known
and environmental point of view, we were incited to that normally this coupling of terminal alkynes is performed
implement it during the reactions described above. To with a palladium catalyst, a copper(I) co catalyst and an amine
illustrate solvent reusability, we present in graph 6 an example
of one of the periods of time in which we had relayed a series
of 7 reactions, each being carried out in 3 mL eucalyptol/mmol
of substrate.
base.
Table 6. Optimization of the Sonogashira-Hagihara coupling reaction
After the reactions, eucalyptol was recovered by distillation
under reduced pressure, and then reused immediately for the
next run. We started with 21 mL of eucalyptol for 7 reactions,
1
5 mL were recovered by distillation and used to perform 5
reactions from which we could distillate 10 mL of solvent.
These operations were continued so that 21 mL of eucalyptol
were used to perform 19 reactions on 1 mmol scale without
noticeable loss of properties. The boiling point of Eucalyptol is
high but it is possible to evaporate it, in few minutes, with a normal
pump and cooling liquid like monoethyleneglycol into a classical
rotary evaporator system.
Entry
1
Catalyst
Base
Time
h)
Yield
(% )
a
(
Solvent used in the reactions
solvent recovered in the reactions
Stock of solvent
Pd(PPh ) Cl
CuI
Et N
20
16
24
57
64
75
3
2
2
2
3
(
0.01 eq.)
(0.02 eq.) (used as co-solvent
in 1/3 ratio)
2
3
Pd(PPh
3
)
2
Cl
CuI
(0.1 eq.)
3
Et N
(
0.05 eq.)
(used as co-solvent
in 1/2 ratio)
2
Pd(PhCN) Cl
2
P(Cy
3
)
Cs
2 3
CO
(0.1 eq.)
(0.2 eq.)
(2 eq.)
aisolated yields after purification by flash chromatography.
Based on our results (Table 6) the scope and limitations of the
Sonogashira coupling reaction on 4-chlorothieno[3,2-
d]pyrimidine 7, were assessed using several acetylenes 18b-e
1
2
3
4
5
6
(Fig. 9).
Graph 6. Recyclability of Solvent
6
| Green Chem., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 7 of 10
Green Chemistry
Green Chemistry
ARTICLE
good solvent for Sonogashira-Hagihara coupling rVeieawcAtritoicnle Ownilitnhe
starting material containing nitrogen on th in
D
O
e
I:
5
10-m.10
e
3
m
9/
b
C
e
8Gre
C
d
04
r
0
16H
g.
Scheme 4. Sonogashira-Hagihara coupling reaction on 4-chloro-7H-
pyrrolo[2,3-d]pyrimidine 21
Figure 9. aisolated yield after purification by flash chromatography.
bLimonene as solvent (28 h)
To the best of our knowledge, up to this day there is only one
reported case of Sonogashira applied to the thieno[3,2-
d]pyrimidine45 skeleton: Zhang's team reported the
preparation
d]pyrimidine in 51% yield using 4-chloro-7-phenylthieno[3,2-
d]pyrimidine, PdCl (PPh , CuI, Et N and phenylacetylene at
of
7-phenyl-4-(phenylethynyl)thieno[3,2-
2
)
3 2
3
reflux for 21 h. The use of eucalyptol as solvent allowed to
improve the yield and to work under Cu-free conditions.
The Sonogashira reaction was also tested in eucalyptol from 7-
chloro-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine 10 but poor
results were obtained (Table 7).
Table 7. Sonogashira reaction in eucalyptol starting from 7-chloro-5-methyl
[
1,2,4]triazolo[1,5-a]pyrimidine 10
Figure 10. Sonogashira-Hagihara coupling reaction on 23
Starting from 4-chlorofuro[3,2-c]pyridine 23 we obtained
better results, since compounds 24a,b,d,e were synthesized in
moderate yield (38% to 53%) under the same conditions (Fig.
Entry
1
Catalyst
Base
Et
(used as co-
solvent in 1/3
ratio)
Time
h)
24
Yieldc
(%)
-
1
0).
(
a
Pd(PPh
3
)
2
Cl
2
2
CuI
(0.02
eq.)
3
N
(
0.01 eq.)
Conclusion
24b
We demonstrated, for the first time, that eucalyptol could be
used as solvent for organic synthesis. Experiment results
described herein and dielectric constant of eucalyptol allow us
to think that it can advantageously replace a large number of
solvents in which: Anisole, Bromobenzene, chlorobenzene,
Chloroform, Diethyl ether, DMF, DMA, DME, 1,4-Dioxane,
Ethyl acetate, Ethyl benzoate, THF, Toluene. We have shown
that it could be an interesting alternative to conventional
solvents for the one-pot synthesis of 2,3-diarylimidazol[1,2-
a]pyridines involving a condensation between 2-aminopyridine
2
Pd(PPh
3
)
2
Cl
CuI
(0.1 eq.)
Et
3
N
-
(
0.05 eq.)
(used as co-
solvent in 1/2
ratio)
3
2
Pd(PhCN) Cl
2
3
P(Cy )
Cs
2
CO
3
16a
27
(0.1 eq.)
(0.2 eq.)
(2 eq.)
a
00 °C; b 70 °C; isolated yield after purification by flash chromatography.
c
1
Similarly, using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 21 gave
very poor yield (Scheme 4) showing that eucalyptol is not a
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 00, 1-3 | 7
Please do not adjust margins

Please Gd roe en no tC ha ed mj u iss tt r my argins
Page 8 of 10
ARTICLE
Green Chemistry
7
G. Paggiola, S. Van Stempvoort, J. BustamanteVi,ewJ.ArMtic.le VOnelginae
and bromoacetophenones, followed by a C-H activation at C-3.
This solvent, derived from biomass, was also effective for
Barbero, A. J. Hunt, and J. H. Clark, Biofuels, Bioprod.
DOI: 10.1039/C8GC04016H
Biorefin. 2016, 10, 686.
various
transformations
of
heteroatom-containing
8
9
1
J. H. Clark, D. J. Macquarrie and J. Sherwood, Green Chem.,
heterocycles such as oxygen, sulfur or nitrogen. A limitation
was found for the Sonogashira-Hagihara coupling reaction with
starting material containing nitrogen on the 5-membered ring.
However, it should be noted that, the use of eucalyptol as
solvent in Sonogashira coupling applied to the thieno[3,2-
d]pyrimidine allowed to improve the yield and work under Cu-
free conditions. Furthermore, we have shown that it was
possible to recover this solvent from the reaction media by
simple distillation, using a standard equipment, which is very
important from the environmental and also economic aspects.
As mentioned above, its use as green solvent is also related to
2
012, 14, 90–93.
G.D.K. Babu, and B. Singh, Biochem. Eng. J., 2009, 44, 226-
31.
0 P. G. Jessop, D. A. Jessop, D. Fu and L. Phan, Green Chem.,
012, 14, 1245.
2
2
1
1
1 Y. Marcus, Chem. Soc. Rev., 1993, 22, 409–416.
2 C. Laurence, P. Nicolet, M. T. Dalati, J.-L. M. Abboud and R.
Notario, J. Phys. Chem., 1994, 98, 5807–5816.
1
3 (a) R. W. Dugger, J. A. Ragan and D. H. B. Ripin, Org. Process
Res. Dev., 2005, 9, 253; (b) J. S. Carey, D. Laffan, C. Thomson
and M. T. Williams, Org. Biomol. Chem., 2006, 4, 2337.
4 N. Fresneau, M.-A. Hiebel, L. A. Agrofoglio, S. Berteina-
Raboin, Molecules,2012, 17, 14409
1
its safety and pharmacological profiles: Eucalyptol is 15 N. Fresneau, M.-A. Hiebel, L.A. Agrofoglio, S. Berteina-
Raboin, Tetrahedron Lett., 2012, 53, 1760
6 M.-A. Hiebel, Y. Fall, M.-C. Scherrmann, S. Berteina-Raboin,
Eur. J. Org. Chem, 2014, 21, 4643.
7 M.-A. Hiebel, S. Berteina-Raboin, Green Chem.,2015, 17, 937
8 G. Dumonteil, M.-A. Hiebel, M.-C. Scherrmann, S. Berteina-
Raboin, RSC Adv., 2016, 6, 73517.
considered to be a safe chemical when taken in normal doses.
It becomes hazardous via ingestion, skin contact or inhalation
at higher doses and does not show genotoxicity or
carcinogenicity.46
1
1
1
1
2
9 J. F. Campos, M. Loubidi, M.-C. Scherrmann, S. Berteina-
Raboin, Molecules, 2018, 23, 684.
0 See for instance: (a) S. El Kazzouli, S. Berteina-Raboin, A.
Mouaddib, and G. Guillaumet, Tetrahedron Lett., 2003, 44,
6265; (b) J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A.
Mouaddib, and G. Guillaumet, Synlett, 2006, 19, 3237; (c) J.
Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib,
and G. Guillaumet J. Org. Chem., 2007, 72, 7650; (d) J.
Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib,
and G. Guillaumet, J. Mar. Chim. Heterocycl., 2008, 7, 1; (e) J.
Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib,
and G. Guillaumet, Synthesis, 2008, 16, 2537; (f) J. Koubachi,
S. Berteina-Raboin, A. Mouaddib, and G. Guillaumet,
Synthesis, 2009, 2, 271; (g) J. Koubachi, S. Berteina-Raboin, A.
Mouaddib, and G. Guillaumet, Tetrahedron 2010, 66, 1937;
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
Notes and references
1
R. K. Henderson, C. Jiménez-González, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and
A. D. Curzons, Green Chem., 2011, 13, 854.
(
h) A. El Akkaoui, I. Bassoude, J. Koubachi, S.Berteina-Raboin,
A. Mouaddib, and G. Guillaumet, Tetrahedron, 2011, 67,
128; (i) S. El Kazzouli, A.G. du Bellay, S. Berteina-Raboin, P.
2
3
C. J. Clarke, W.-C. Tu, O. Levers, A. Bröhl, and J. P. Hallett,
Chem. Rev., 2018, 118, 747-800.
7
(a) C. Capello, U. Fischer, K. Hungerbühler, Green Chem.,
Delagrange, D.-H. Caignard, and G. Guillaumet, Eur. J. Med.
Chem., 2011, 46, 4252; (j) S. El Kazzouli, S. Berteina-Raboin,
A. Mouaddib, and G. Guillaumet, Lett. Org. Chem., 2012, 9,
2
007, 9, 927; (b) K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S.
Jennings, T. A. Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D.
A. Perry, and M. Stefaniak, Green Chem. 2008, 10, 31; (c) R. K
Henderson, C. Jiménez-González, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, and
A. D. Curzons, Green Chem., 2011, 13, 854; (d) D. Prat, O.
Pardigon, H. W. Flemming, S. Letestu, V. Ducandas, P.
Isnard, E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani, and P.
Hosek, Org. Process Res. Dev., 2013, 17, 1517; L. J. Diorazio,
D. R. J. Hose, and N. K. Adlington, Org. Process Res. Dev.,
1
18; (k) Z. Tber, M.-A. Hiebel, M. Akssira, G. Guillaumet, and
S. Berteina-Raboin, Synthesis 2015, 47, 1780.
2
1 (a) R. Goel, V. Luxami, and K. Paul, Curr Top Med
Chem.,2016, 16, 3590; (b) A. Deep, R.K. Bhatia, R. Kaur, S.
Kumar, U.K. Jain, H. Singh,S.Batra, D. Kaushik, and P.K. Deb,
Curr Top Med Chem.,2017, 17, 238.
2 M.-A. Hiebel, Y. Fall, M.-C. Scherrmann, and S. Berteina-
Raboin, Eur. J. Org. Chem., 2014, 21, 4643.
3 (a) V. M. Bangade, B. C. Reddy, P. B. Thakur, B. M. Babu, and
H. M. Meshram, Tetrahedron Lett., 2013, 54, 4767; (b) F.
Tufail, S. Singh, M. Saquib, J. Tiwari, J. Singh, and J. Singh,
ChemistrySelect 2017, 2, 6082.
4 M.A. Abarghooei, R. Mohebat, Z. Karimi-Jaberi, and M. H.
Mosslemina, Catal. Commun., 2018, 105, 59.
2
2
2
016, 20, 760.
4
(a) D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S.
Abou-Shehada, and P. J. Dunn, Green Chem. 2016, 18, 288;
(b) C. M. Alder, J. D. Hayler, R. K. Henderson, A. M.
Redman, L. Shukla, L. E. Shuster, and H. F. Sneddon, Green
Chem. 2016, 18, 3879.
2
5
6
Y. Gu and F. Jérôme, Chem. Soc. Rev., 2013, 42, 9550.
(a) M. Virot, V. Tomao, C. Ginies, F. Visinoni and F. Chemat, J.
Chromatogr., A, 2008, 147, 1196–1197; (b) A. Medvedovici,
S. Udrescu and V. David, Biomed. Chromatogr., 2013, 27, 48;
2
2
5 Y. Wang, B. Frett, and H.-y. Li, Org. Lett., 2014, 16, 3016.
6 (a) D. A. Pantess, C. V. Rich, Chem. Educ, 2009, 14, 258; (b)
M. Vafaeezadeh, M. M. Hashemi, J. Mol. Liq., 2015, 207, 73;
(
c) A. Ghorbani-Choghamarani, and M. Norouzi, New J.
(
c) P. K. Mamidipally and S. X. Liu, Eur. J. Lipid Sci. Technol.,
004, 106, 122 ; (d) M. Aissou, Z. Chemat-Djenni, E. Yara-
Varón, A.-S. Fabiano-Tixier, F. Chemat, C. R. Chim., 2016, 20,
46.
Chem., 2016, 40, 6299; (d) A. Chatterjee, T.R. Ward, Catal.
Lett., 2016, 146, 820; (e) K. L. Wilson, J. Murray, C. Jamieson,
and A. J. B. Watson, Synlett 2018, 29, 650.
2
3
2
7 Metal complexes and organic electroluminescent devices By
8
| Green Chem., 2018, 00, 1-3
This journal is © The Royal Society of Chemistry 2018
Please do not adjust margins

Page 9 of 10
Green Chemistry
Green Chemistry
ARTICLE
Boudreault, Pierre-Luc T. et al. From U.S. Pat. Appl. Publ.,
0160336520, 17 Nov 2016.
8 Preparation of thienopyrimidines and related compounds as
organic electroluminescentdevice materials By Kim, Hongsuk
et al From PCT Int. Appl., 2015047058, 02 Apr 2015.
View Article Online
DOI: 10.1039/C8GC04016H
2
2
2
3
9 Biheterocyclic amine-series Hedgehog signaling path
inhibitor By Xin, Minxing et al From Faming ZhuanliShenqing,
1
04177363, 03 Dec 2014.
0 A. Gopalsamy, M. Shi, Y. Hua, F. Lee, L. Feldberg, E. Frommer,
S. Kim, K. Collins, D. Wojciechowicz, and R. Mallon, Bioorg.
Med. Chem. Lett., 2010, 20, 2431.
3
3
3
1 M. Loubidi, A. Moutardier, J. F. Campos, and S. Berteina-
Raboin, Tetrahedron Lett., 2018, 59, 1050.
2 Novel antiviral compounds By Carlens, Gunter et al From PCT
Int. Appl., 2011076765, 30 Jun 2011.
3 Preparation of triazolopyrimidine derivatives or salts as
pesticides By Yamamoto, Kazuhiro et al From PCT Int. Appl.,
2
010018868, 18 Feb 2010.
3
4 (a) D. Prat, J. Hayler, and A. Wells, Green Chem., 2014, 16,
4
4
546; (b) T. Welton, Proc. Math. Phys. Eng. Sci., 2015,
71:20150502.
3
3
3
5 S. Mal, K.J. Prathap, S. C. Smith, and J. D. Umarye,
Tetrahedron Lett., 2015, 56, 2896.
6 C. S. Demmera, M. Jørgensen, J. Kehler, L. Bunch, and L. K.
Rasmussen, Synlett, 2015, 26, 519.
7 Preparation of carboxamide derivatives as antiviral
compounds By Wang, Guangyi et al From PCT Int. Appl.,
2
015026792, 26 Feb 2015.
3
8 Benzamides and related compounds asGPR52 agonists and
their preparation anduse in the treatment of schizophrenia
By Setoh, Masaki et al From PCT Int. Appl., 2010018874, 18
Feb 2010.
3
9 A. Biffis, P. Centomo, A. Del Zotto, and M. Zecca, Chem. Rev.,
2
018, 118, 2249.
4
4
4
0 R. Chinchilla, C. Najera, Chem. Soc. Rev., 2011, 40, 5084.
1 H. Hu, F. Yang, and Y. Wu, J. Org. Chem., 2013, 78, 10506.
2 H. Huang, H. Liu, H. Jiang, and K. Chen, J. Org. Chem., 2008,
7
3, 6037.
4
4
3 C. Yi, R. Hua, J. Org. Chem., 2006, 71, 2535.
4 D. Gelman, S. L. Buchwald, Angew. Chem. Int. Ed., 2003, 42,
5
993.
4
4
5 H. Zhang, M.S. Bednarz, N.-K. Lim, G. Hernandez, W. Wu,
Org. Lett., 2014, 16, 2522.
6 M. Bhowal and M. Gopal, RGUHS J Pharm Sci, 2015, 5, 125,
doi: 10.5530/rjps.2015.4.2.
This journal is © The Royal Society of Chemistry 2018
Green Chem., 2018, 00, 1-3 | 9
Please do not adjust margins

Green Chemistry
Page 10 of 10
S
uzuki
S
onogashira