Aryl Azides as Forgotten Electrophiles in the Van Leusen Reaction: A Multicomponent Transformation Affording 4-Tosyl-1-arylimidazoles

Article abstract of DOI:10.1021/acs.joc.9b02546

Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism

Full text of DOI:10.1021/acs.joc.9b02546

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Note
Aryl azides as forgotten electrophiles in the Van Leusen reaction: a
multicomponent transformation affording 4-tosyl-1-arylimidazoles
Cristiana Necardo, Antonella Ilenia Alfano, Erika Del Grosso, Sveva Pelliccia, Ubaldina
Galli, Ettore Novellino, Fiorella Meneghetti, Mariateresa Giustiniano, and Gian Cesare Tron
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02546 • Publication Date (Web): 29 Nov 2019
Downloaded from pubs.acs.org on November 29, 2019
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Aryl azides as forgotten electrophiles in the Van Leusen reaction: a multicomponent
transformation affording 4-tosyl-1-arylimidazoles
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Cristiana Necardo,a Antonella Ilenia Alfano,b Erika Del Grosso,a Sveva Pelliccia,b Ubaldina Galli,a
Ettore Novellino,b Fiorella Meneghetti,c Mariateresa Giustiniano*b and Gian Cesare Tron*a
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a Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale “A. Avogadro”, Largo
Donegani 2, 28100 Novara, Italy.
b Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II”, via D. Montesano 49,
80131 Napoli, Italy.
c Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25,
20133 Milano, Italy.
Corresponding Authors:
Mariateresa Giustiniano mariateresa.giustiniano@unina.it
Gian Cesare Tron giancesare.tron@uniupo.it
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TABLE OF CONTENTS
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R
NC
O
O
S
N3
N
N
t-BuOK
O
S
+
O
R
DMF, 0 °C to rt
30 minutes
Me
O
Me
S
Me
NC
O
26 examples (90-25%)
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ABSTRACT
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Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a
novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two
molecules of TosMIC participate in the reaction mechanism in two different ways, with the second
molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the
final product.
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Serendipitously obtained in low yield (14%) by irradiating tosyldiazomethane in liquid hydrogen
cyanide by the Dutch Professor Jan Strating and his former student Albert Van Leusen in 1967,1
toluenesulfonylmethyl isocyanide (TosMIC) rapidly turned from a chemical curiosity to the most
important and versatile functionalized isocyanides ever synthesized.2
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Indeed, in 1972 the same authors presented a safer and scalable synthetic route for TosMIC3 and in
the same year Albert Van Leusen started his independent career on TosMIC chemistry
demonstrating the versatility of this non-smelling, shelf stable isocyanide as a valuable reagent in
organic synthesis. Preparations of substituted oxazoles and thiazoles by reacting TosMIC and
carbonyl compounds4 or carboxymethyl dithioates,5 respectively, were published. Over the course
of the years, Professor Van Leusen and his group were able to expand the chemical boundaries of
TosMIC, recognizing that the consecutive presence of an isocyanide, an acidic CH, and a leaving
group allowed for unprecedent transformations with different reactants. Imidazoles, 1,2,4-triazoles,
and pyrroles could be easily obtained by reacting TosMIC with different electrophiles such as
imines,6 aryldiazonium salts,7 and Michael acceptors.8 Furthermore, TosMIC could also be used as
a reagent for converting a ketone to a nitrile in aprotic solvents,9 or as masked formaldehyde
reagent to form symmetrical and unsymmetrical ketones10 or benzyl derivatives.11 The versatility of
TosMIC was then recognized by other chemists who, with their imagination and intuition, pushed
further the boundaries of its chemistry. Excellent reviews on TosMic appeared in the literature
covering the period from 1972 to 2018.12
The most rationale use of TosMIC is to exploit its α-acidity (pKa= 12-14)13 in order to favor the
nucleophilic attack of the TosMIC anion to an electrophile, and finally use the isocyano group as a
carbenoid to form a five-membered rings in a 5-endo trig ring closure.14 Following this strategy,
successful examples have been reported with the following electrophiles: carbonyls, imines, carbon
disulfide, nitriles, isothiocyanates, Michael adducts, pyridine N-oxides, isoquinolines, acyl
chlorides, diazonium salts and ketimines. On the basis of the electrophile strength, better results
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were obtained using strong bases for less electrophilic partners. Recently, the use of transition
metals has amplified and modified the chemical reactivity of TosMIC, opening a new chapter in its
already rich history. For example, the metal assisted syntheses of E-vinyl sulfones,15 α-sulfonated
ketones,16 and sulfonyl benzofurans17 have been reported.
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Reflecting on the electrophiles reported in the literature able to react with the TosMIC anion, we
became aware that no reports on the reaction between TosMIC and aryl azides were available.
Although azides are almost always considered as 1,3-dipolar species or nitrenes precursors of via
thermal or photochemical degradation, the terminal nitrogen atom can be intercepted by
nucleophiles and azides can also be considered electrophilic reagents. Example of reactions where
azides behave like electrophiles are the Dimroth triazole synthesis and the Staudiger reaction.18 For
this reason, we decided to evaluate the reaction of TosMIC with aryl azides. As a model reaction,
we chose TosMIC (1) and phenyl azide (2). When the reaction was carried out in THF at room
temperature in the absence of a base, no reaction occurred. But when under the same reaction
conditions, t-BuOK was added, the reaction proceeded very fast, and we noticed a rapid evolution
of gas. The main product was isolated, and its structure unequivocally determined by single crystal
X-ray diffraction to be the 4-tosyl-1-phenylimidazole (3) obtained in 12% yield (Scheme 1).
NC
N
N
O S O
N3
t-BuOK
O
S
O
+
THF, rt
Me
1
2
3
Me
Scheme 1. Reaction between TosMIC and phenyl azide affords 4-tosyl-1-phenylimidazole and
ORTEP19 view of 3 and the relative arbitrary atom numbering scheme (thermal ellipsoids at 40%
probability).
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A literature search showed that 4-tosyl-1-arylimidazoles were already reported via different
synthetic strategies. For example, they could be prepared by reacting arylazasulfones 5 with
TosMIC20 or via oxidation of dilithiated 1-phenyl-4-tosyl-1H-imidazole-5-thiol 6 with alkaline
potassium ferricyanide21 or, finally via reaction between aryl formamidate 7 or aryl formamidines
and TosMIC in the presence of sodium hydride (Figure 1).22
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O
N N S
Me
5
O
TosMIC
t-BuOK
Li
N
S
DMSO
rt
N
OEt
N
TosMIC
O
N
N
K3Fe(CN)6
SLi
S
O
Me
DME,NaH
rt
O
O
N
NaOH
water
rt
X
X= C, N
6
4
7
Me
Figure 1. Reported methods for the synthesis of 4-tosyl-1-arylimidazoles.
While these methods can give access to 4-tosyl-1-arylimidazoles, there are evident limitations
associated with them such as the use of strong base, problems of selectivity, reaction time, required
synthesis of intermediates, and use of external oxidants which can restrict the versatility of these
transformations.
As the preparation of aryl azides is an easy task which does not suffer limitations, thus allowing for
the preparations of any aromatic azide, this novel transformation could give access to an increased
number of functionalized 4-tosyl-1-arylimidazoles not attainable with the other reported methods.
For this reason, we considered this novel transformation worthy of further studies and
improvements. At first, reasoning on the possible reaction mechanism, it was clear that two
equivalents of TosMIC participated actively in this transformation. A possible scenario for this
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multicomponent reaction is represented in Scheme 2. To initiate the process, the TosMIC anion
attacks N-3 of the azide to form intermediate A. Subsequently, N-1 intercepts the isocyanide in a 6
endo-trig cyclization to form anion B, which is quenched by a proton source (e.g. tert-butanol) to
form C. Due to its instability, C undergoes a [4+2] cycloreversion to form D with loss of nitrogen.
The imine of D then undergoes attack by a second molecules of TosMIC anion, followed by ring
closure to form E. At this point, after protonation, intermediate F regains aromaticity through a base
assisted mechanism with the expulsion of the most acidic proton and loss of hydrogen cyanide and
sulfinate. Under strong basic conditions, excess of t-BuOK deprotonates the newly formed
hydrogen cyanide, avoiding the release of toxic HCN. It is worth to note that the two molecules of
TosMIC participate in the reaction mechanism in two different ways, with the second molecule in
the scheme undergoing a fragmentation resulting in the incorporation of a C-H into the final
molecule. To the best of our knowledge, this mechanistic feature has never been reported for the
TosMIC reagent. HRMS infusion of the reaction mixture revealed the presence both intermediates
A or B and p-toluensulfinic acid, while intermediate D was not detectable probably due to its
instability (see supporting information).
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O
S
N
N
O
S
N
N
N N N
N
N
Me
N
N
Me
O
O
O
B
NC
S
A
O
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t-BuOH
Me
O
N
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N
S
Me
retro [4+2]
N
H
O
S
N
O
O
N
D
O
N
N
N
S
Me
S
O
N
N2
N
O
O
Me
O
C
S
O
Me
E
Me
t-BuOH
H
N
N
N
H
O
S
O
O
N
S
O
S
HCN
+
+
O
N
O
Me
tBuOK
O
S
O
F
Me
Me
3
CN
Me
Scheme 2. Plausible reaction pathway.
Relying on this mechanistic scenario, several reaction parameters were varied (solvent, base,
temperature, reagent equivalents) in order to increase the yield and control the exothermicity of the
reaction. The results are shown in the supporting information. As expected, increasing the number
of TosMIC and base equivalents boosted the yield with t-BuOK still being the best base, since it has
the possibility to exchange protons with intermediates B and E. Cooling the reaction to 0 °C before
adding the base had the beneficial effect of increasing the yield. Interestingly, when a polar protic
solvent (MeOH) was used, no reaction was observed after 30 minutes; aprotic solvents (DMSO,
DMF) were the best choice to carry out the reaction. Best reaction conditions (DMF, 2.5 equiv. of
TosMIC, 0 °C then rt, 30 minutes) increased the yield of 3 to 58%. With these optimal conditions in
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hand, the substrate scope of the reaction using different aryl azides (A-U) and TosMIC analogues
(V-X) (Figure 2) was evaluated, resulting in 23 additional successful examples (8-30) as shown in
Figure 3.
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Aryl azides
N3
N3
N3
N3
N3
N3
N3
O
O
MeO
OMe
N
O
F
OMe
Me
A
C
D
F
G
E
L
B
N3
N3
N3
O
N3
N3
N
N3
N3
N
O
Br
Cl
F
H
I
K
M
N
J
N3
N3
N3
N3
N3
N3
N3
I
OMe
Cl
NO2
Cl
Cl
MeO
OMe
NO2
OMe
Br
P
R
T
U
O
Q
S
TosMIC analogues
NC
NC
NC
O S O
O S O
O S O
Br
OMe
V
W
X
Figure 2. Building blocks used.
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O
F
OMe
Ph
O
Ph
MeO
MeO
N
N
N
N
N
N
N
N
N
N
N
7
8
SO2
SO2
SO2
SO2
SO2
9
Me
Me
Me
Me
Br
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Me
8
9
10
11
12
(71%)
(65%)
(35%)
N
(58%)
(40%
Me
Cl
N
N
N
N
N
N
N
N
N
O
Ph
N
SO2
SO2
SO2
SO2
SO2
Me
Me
Me
Me
Me
13
14
15
16
17
(71%)
(68%)
(36%)
(67%)
(56%)
F
O2N
O
N
O
N
N
N
N
N
N
N
N
N
N
Ph
SO2
SO2
SO2
SO2
SO2
Me
19
Me
Me
Me
Me
22
18
20
21
(61%)
(25%)
(37%)
(45%)
(69%)
OMe
MeO
MeO
Br
Cl
Cl
N
N
MeO
N
N
N
Cl
N
N
N
SO2
SO2
SO2
SO2
Me
Me
Me
Me
23 (57%)
24 (67%)
25 (90%)
26 (50%)
I
Cl
O2N
O2N
N
N
N
N
N
N
N
N
SO2
SO2
SO2
Cl
SO2
MeO
Me
30 (32%)
27 (37%)
28 (59%)
29 (61%)
O
Cl
N
N
N
N
SO2
SO2
O
Cl
Br
Br
31 (27%)
32 (82%)
Figure 3. 4-arylsulfonyl-1-(hetero)arylimidazoles synthesized
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When electron withdrawing groups (EWGs) were present on the aryl azides, the reaction afforded
higher yields. This is in line with the same observation for the Dimroth reaction, as the presence of
EWGs increase the electrophilic nature of the azide group.23 However, the reaction was also
successful with aryl azides containing electron donating groups, with only a slight reduction in
yields, and even with sterically demanding substrates. Finally, the use of heteroaryl azides were
well tolerated, together with the use of TosMIC analogues. When two different TosMIC analogues
were used, the reaction led to both the two possible products in a 1:1 ratio. Moreover, a TosMIC
analogue substituted at the alpha position with a phenyl ring was also tested, but unfortunately, no
definite products were obtained. Notably, the reaction was very fast, with full conversion of starting
materials in less than 30 minutes. Simple column chromatography and methanol recrystallization
afforded the desired products.
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The presented reaction does not work with aliphatic azides, vinyl azides, boronic azides, and
toluene sulphonyl azide, as we detected an inseparable reaction mixture. When acyl azides were
employed, we isolated 5-aryl-4-tosyloxazoles in high yield. This is exemplified by the reaction in
Scheme 3. In this case, acyl azide 33 behaves like an acyl choride4 towards the TosMIC anion and,
after acylation of the α-carbon of TosMIC, enolization and ring closure of the isocyanide, the
corresponding 4,5-disubstituted oxazole 34 is formed.
O
CN
O S O
N
N3
O
O S O
t-BuOK, DMF
+
0 °C to rt
80%
Me
Me
33
1
34
Scheme 3. With acylazides, 5-aryl-4-tosyloxazoles are formed.
In conclusion, following the idea that aryl azides have never been considered as potential
electrophilic partner in the Van Leusen reaction with the anion of TosMIC, we demonstrated the
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feasibility of this strategy, enabling the formation of 4-arylsulfonyl-1-(hetero)arylimidazoles in
good yields. In this novel multicomponent reaction, two molecules of TosMIC participate in the
reaction mechanism displaying two distinct chemical behaviors, and sulfinic acid anion and
hydrogen cyanide fragmentation of TosMIC was reported for the first time. The versatility of this
reaction associated with the ready availability of aryl azides, operational simplicity, and reduced
reaction times renders this methodology much more attractive with respect to previously reported
routes.
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EXPERIMENTAL SECTION
Solvents and Reagents. Commercially available reagents and solvents were used without further
purification. When necessary the reactions were performed in oven-dried glassware under a positive
pressure of dry nitrogen.
Chromatography. Column chromatography was performed on silica gel (70–230 mesh ASTM)
using the reported eluents. Thin layer chromatography (TLC) was carried out on 5 x 20 cm plates
with a layer thickness of 0.25 mm (Silica gel 60 F254). When necessary they were developed with
KMnO4.
Spectra. Infrared spectra were recorded on a FT-IR Thermo-Nicolet Avatar spectrometer with
1
13
absorption maxima (νmax) recorded in wavenumbers (cm-1). H and C APT NMR were recorded
on at 400 MHz. High-resolution ESI-MS spectra were performed on a Thermo LTQ Orbitrap XL
mass spectrometer. The spectra were recorded by infusion into the ESI source using MeOH as the
solvent. Chemical shifts (δ) are reported in part per million (ppm) relative to residual solvent peak.
Melting points were determined using a Stuart Scientific SMP3 apparatus and remain uncorrected.
General preparation of phenyl azides (A-U). The aryl azides were readily synthesized in two
steps starting from the corresponding anilines.
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Preparation of aryl azides. The corresponding aniline (5 mmol) was suspended in water (1 M, 5
mL); hydrochloric acid (2M, 2.5 mL) was added dropwise and a solution of sodium nitrite (1.1
equiv., 5.5 mmol, 379 mg) in water (3M, 1.8 mL) was added at 0°C. The reaction was stirred at 0°C
for 10 minutes. A solution of sodium azide (1.1 equiv., 5.5 mmol, 358 mg) in water (6M, 0.9 mL)
was added at 0°C and the reaction mixture was stirred for additional 10 minutes.
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The aryl azide was extracted with dichloromethane (x3), the organic phase was washed with brine,
evaporated under reduced pressure, and used without further purification in the multicomponent
reaction. Phenyl azides A-U matched the NMR data as reported in literature (see supporting
information for references)24-42, while the aryl azide S was newly synthesized.
4-azido-1-bromo-2-chlorobenzene (S). The crude material was purified by column
chromatography (n-hexane/ EtOAc 199:1) to give the product as yellowish solid (767 mg, 66%
yield). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 1H), 7.12 (d, Jm = 2.4 Hz, 1H), 6.80 (dd,
13
J1 = 8.8 Hz, J2 = 2.8 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 140.5, 135.6, 134.5, 120.8,
118.6, 117.8. Mp 46-47 °C.
Preparation of benzoyl azide (33). Benzoyl chloride (5 mmol) was dissolved in acetone (1.5 M,
3.3 mL) at 0°C; a 3M solution of sodium azide (1.5 equiv., 7.5 mmol, 0.49 g) in water was added
dropwise at 0°C and the reaction mixture was stirred at room temperature until the complete
formation of the product as judged by TLC (typically 10 minutes).
The benzoyl azide was extracted with ethyl acetate (x3), the organic phase was washed with brine,
evaporated under reduced pressure, and the crude was purified by chromatographic column.
Benzoyl azide 31 matched the NMR data as reported in literature.43
General preparation of 1-phenyl-4-(phenylsulfonyl)-1H-imidazoles (3, 8-32). The isocyanide
(0.62 mmol, 2.5 equiv.) was dissolved in DMF (0.25 M), potassium tert-butoxide (0.62 mmol, 2.5
equiv., 70 mg) was added at 0 °C. After 2 minutes the aryl azide (0.25 mmol, 1 equiv.), was added
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and the reaction mixture was stirred at 0 °C for 10 minutes and at room temperature for 20 minutes.
The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted 3
times with ethyl acetate, and the collected organic phases were then washed one more time with
brine. After evaporation of the solvent, the crude material was purified by column chromatography.
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1-phenyl-4-tosyl-1H-imidazole (3). The crude material was purified by column chromatography
(PE/EtOAc 8:2 and PE/EtOAc 6:4) to give the product as yellowish solid (43 mg, 58% yield). The
model reaction was then carried out at 1 mmol scale, referred to aryl azide, without noticing any
1
reduction in yield. H NMR (400 MHz, CDCl3) δ 7.98-7.94 (m, 3H), 7.81 (s, 1H), 7.52-7.42 (m,
13
3H), 7.37-7.31 (m, 4H), 2.40 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 144.3, 143.6, 137.7,
135.9, 130.2, 129.8, 128.9, 128.0, 122.2, 121.9, 21.6. IR (KBr) 3146, 3126, 2923, 1595, 1514, 1316,
1179, 1144, 1086, 763 νmax/cm-1; Mp 144-146 °C; MS (ESI) m/z (M+H)+ Calcd for C16H15N2O2S+:
299.0849; Found: 299.0844 [M+H]+.
1-(3-fluorophenyl)-4-tosyl-1H-imidazole (8). The crude material was purified by column
chromatography (PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as a light brown solid (56
mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.97-7.94 (m, 3H), 7.82 (s, 1H), 7.52-7.47 (m, 1H),
7.32 (d, J= 8.0 Hz, 2H), 7.20-7.10 (m, 3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1
(d, Jipso= 248.7 Hz), 144.4, 144.0, 137.5, 137.1 (d, Jm= 9.8 Hz), 131.8 (d, Jm= 9.0 Hz), 129.8, 128.1,
122.0, 117.5 (d, Jp= 3.3 Hz), 115.9 (d, Jo= 20.9 Hz), 109.6 (d, Jo= 25.1 Hz), 21.6. IR (KBr) 3138,
3083, 2924, 1613, 1602, 1521, 1326, 1304, 1142, 857, 694 νmax/cm-1; Mp 157-159 °C; MS (ESI)
m/z (M+H)+ Calcd for C16H14FN2O2S+: 317.0755; Found: 317.0750 [M+H]+.
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1-([1,1'-biphenyl]-4-yl)-4-tosyl-1H-imidazole (9). The crude material was purified by column
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chromatography (PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as an amorphous black
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solid (61 mg, 65% yield). H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 3H), 7.87 (s, 1H), 7.69 (d,
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J= 8.4 Hz, 2H), 7.57 (d, J= 7.6 Hz, 2H), 7.47-7.36 (m, 5H), 7.31 (d, J= 8.0 Hz, 2H), 2.39 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 144.3, 143.5, 141.9, 139.2, 137.7, 134.9, 129.8, 129.0, 128.7,
128.1, 128.0, 127.0, 122.2, 21.6. IR (KBr) 3120, 3057, 2918, 1595, 1525, 1488, 1319, 1183, 1145,
1086, 693, 602 νmax/cm-1; MS (ESI) m/z (M+H)+ Calcd for C22H19N2O2S+: 375.1162; Found:
375.1158 [M+H]+.
1-(4-phenoxyphenyl)-4-tosyl-1H-imidazole (10). The crude material was purified by column
chromatography (PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as an amorphous brown
solid (51 mg, 52% yield). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J= 8.0 Hz, 2H), 7.89 (s, 1H), 7.76
(s, 1H), 7.40-7.29 (m, 6H), 7.20-7.16 (m, 1H), 7.10-7.03 (m, 4H), 2.41 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 158.1, 156.0, 144.3, 143.4, 137.6, 130.8 (2C), 130.0, 129.7, 128.0, 124.3, 123.7,
122.5, 119.5, 119.4, 21.6. IR (KBr) 3155, 3134, 3121, 3054, 2922, 1588, 1519, 1489, 1312, 1243,
1144, 1085, 694 νmax/cm-1; MS (ESI) m/z (M+H)+ Calcd for C22H19N2O3S+: 391.1111; Found:
391.1105 [M+H]+.
4-tosyl-1-(3,4,5-trimethoxyphenyl)-1H-imidazole (11). The crude material was purified by
column chromatography (PE/EtOAc 7:3 and PE/EtOAc 6:4) to give the product as an amorphous
black solid (59 mg, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.96-7.91 (m, 3H), 7.76 (s, 1H), 7.32
(d, J= 8.0 Hz, 2H), 6.54 (s, 2H), 3.87 (s, 6H), 3.85 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 154.1, 144.3, 143.3, 138.4, 137.6, 131.7, 129.8, 128.0, 122.7, 100.1, 61.0, 56.4, 21.6. IR
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(KBr) 3125, 2963, 2849, 1600, 1514, 1465, 1262, 1095, 1028, 801 νmax/cm-1; MS (ESI) m/z
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(M+Na)+ Calcd for C19H20N2NaO5S: 411.0991; Found: 411.0967 [M+Na]+.
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4-(4-(4-tosyl-1H-imidazol-1-yl)phenyl)morpholine (12). The crude material was purified by
column chromatography (PE/EtOAc 6:4 and PE/EtOAc 5:5) to give the product as a pink solid (38
mg, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J= 7.2 Hz, 2H), 7.85 (s, 1H), 7.71 (s, 1H),
7.32 (d, J= 7.6 Hz, 2H), 7.25-7.22 (m, 2H), 6.95 (d, J= 8.0 Hz, 2H), 3.87-3.85 (m, 4H), 3.20-3.18
(m, 4H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.4, 144.2, 143.1, 137.8, 129.7, 128.0,
127.9, 123.2, 116.0, 66.6, 48.7, 21.6. IR (KBr) 3148, 3128, 2954, 2813, 1528, 1450, 1303, 1237,
1137, 1116, 926, 830 νmax/cm-1; Mp 198-200 °C; MS (ESI) m/z (M+H)+ Calcd for C20H22N3O3S+:
384.1377; Found: 384.1371 [M+H]+.
1-(p-tolyl)-4-tosyl-1H-imidazole (13). The crude material was purified by column chromatography
(PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as an amorphous reddish solid (53 mg, 68%
yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 8.0 Hz, 2H), 7.90 (s, 1H), 7.77 (s, 1H), 7.31-7.22
(m, 6H), 2.38 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.2, 143.3, 139.0, 137.8, 137.4, 133.5,
130.7, 129.7, 128.0, 122.3, 121.8, 21.6, 21.0. IR (KBr) 3151, 3107, 3063, 2962, 2919, 1521, 1312,
1302, 1139, 1086, 816, 662 νmax/cm-1; MS (ESI) m/z (M+H)+ Calcd for C17H17N2O2S+: 313.1006;
Found: 313.1000 [M+H]+.
1-(2-phenoxyphenyl)-4-tosyl-1H-imidazole (14). The crude material was purified by column
chromatography (PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as an amorphous brown
solid (35 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J= 8.0 Hz, 2H), 7.91 (s, 1H), 7.77
13
(s, 1H), 7.38-7.28 (m, 6H), 7.07-7.01 (m, 4H), 2.37 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
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158.0, 156.0, 144.3, 143.3, 137.7, 130.8, 130.1, 129.8, 128.0, 124.3, 123.7, 119.5, 21.6. IR (KBr)
3152, 3121, 3071, 1588, 1522, 1488, 1318, 1236, 1141, 1086, 693 νmax/cm-1; MS (ESI) m/z (M+H)+
Calcd for C22H19N2O3S+: 391.1111; Found: 391.1106 [M+H]+.
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1-(4-chlorophenyl)-4-tosyl-1H-imidazole (15). The crude material was purified by column
chromatography (PE/EtOAc 9:1 and PE/EtOAc 7:3) to give the product as a light brown solid (56
mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 7.97-7.92 (m, 3H), 7.79 (s, 1H), 7.48 (d, J= 8.8 Hz,
13
2H), 7.34-7.31 (m, 4H), 2.41 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 144.4, 143.9, 137.5,
134.8, 134.4, 130.4, 129.8, 128.0, 123.2, 122.1, 21.6. IR (KBr) 3125, 3078, 2922, 1597, 1519, 1321,
1140, 1083, 706, 605 νmax/cm-1; Mp 173-175 °C; MS (ESI) m/z (M+H)+ Calcd for C16H14ClN2O2S+:
333.0460; Found: 333.0448 [M+H]+.
1-(3-bromophenyl)-4-tosyl-1H-imidazole (16). The crude material was purified by column
chromatography (PE/EtOAc 8:2 and PE/EtOAc 6:4) to give the product as an orange-pink solid (53
mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 7.97-7.93 (m, 3H), 7.81 (s, 1H), 7.58-7.54 (m, 2H),
13
7.41-7.26 (m, 4H), 2.41 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 144.4, 144.0, 137.5, 137.0,
132.0, 131.5, 129.8, 128.1, 125.1, 123.7, 120.6, 21.6. IR (KBr) 3153, 3113, 3063, 2922, 1594, 1516,
1490, 1315, 1303, 1142, 1087, 673, 601νmax/cm-1; Mp 190-192 °C; MS (ESI) m/z (M+Na)+ Calcd
for C16H13BrN2NaO2S: 400.9758 (97.3%); Found: 400.9745 [M+Na]+.
3-(4-tosyl-1H-imidazol-1-yl)quinoline (17). The crude material was purified by column
chromatography (PE/EtOAc 6:4 and PE/EtOAc 5:5) to give the product as a light brown solid (67
mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.95 (d, Jm= 2.4 Hz, 1H), 8.21-8.10 (m, 3H), 7.96-
13
7.89 (m, 4H), 7.80-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.31-7.29 (m, 2H), 2.38 (s, 3H); C{1H}
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NMR (100 MHz, CDCl3) δ 147.6, 144.6, 144.2, 144.0, 137.3, 130.9, 129.8, 129.5, 129.3, 128.6,
128.3, 128.0 (2C), 127.2, 122.5, 21.6. IR (KBr) 3140, 3112, 3062, 2918, 1610, 1515, 1317, 1189,
1147, 1084, 693, 607 νmax/cm-1; Mp 189-191 °C; MS (ESI) m/z (M+Na)+ Calcd for C19H15N3NaO2S:
372.0783; Found: 372.0763 [M+Na]+.
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1-(4-fluorophenyl)-4-tosyl-1H-imidazole (18). The crude material was purified by column
chromatography (PE/EtOAc 8:2 and PE/EtOAc 7:3) to give the product as an orange solid (48 mg,
61% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 8.4 Hz, 2H), 7.90 (s, 1H), 7.77 (s, 1H), 7.38-
13
7.30 (m, 4H), 7.21-7.17 (m, 2H), 2.40 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 163.6, 161.1,
144.4, 143.7, 137.6, 132.1 (d, Jo=3.2 Hz), 129.8, 128.0, 124.1 (d, Jm= 8.6 Hz), 122.5, 117.2 (d, Jo=
23.1 Hz), 21.6. IR (KBr) 3138, 3089, 3066, 2962, 2922, 1525, 1326, 1261, 1142, 1088, 1020, 807,
694 νmax/cm-1; Mp 163-165 °C dec; MS (ESI) m/z (M+H)+ Calcd for C16H14FN2O2S+: 317.0755;
Found: 317.0750 [M+H]+.
1-([1,1'-biphenyl]-2-yl)-4-tosyl-1H-imidazole (19). The crude material was purified by column
chromatography (PE/EtOAc 9:1 and PE/EtOAc 7:3) to give the product as an orange solid (23 mg,
25% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J= 8.0 Hz, 2H), 7.57-7.47 (m, 3H), 7.43 (d, J=
13
5.6 Hz, 2H), 7.36-7.21 (m, 6H), 7.01 (d, J= 7.6 Hz, 2H), 2.42 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 144.0, 142.4, 137.9, 137.8, 136.9, 133.6, 131.5, 129.8, 129.6, 128.9, 128.8, 128.1, 127.9,
126.0, 124.7, 21.6. IR (KBr) 3146, 3117, 3055, 3029, 2917, 1595, 1514, 1482, 1315, 1177, 1141,
694, 660 νmax/cm-1; Mp 165-167 °C; MS (ESI) m/z (M+H)+ Calcd for C22H19N2O2S+: 375.1162;
Found: 375.1149 [M+H]+.
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1-(benzo[d][1,3]dioxol-5-yl)-4-tosyl-1H-imidazole (20). The crude material was purified by
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column chromatography (PE/EtOAc 7:3 and PE/EtOAc 6:4) to give the product as an amorphous
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black solid (31 mg, 36% yield). H NMR (400 MHz, CDCl3) δ 7.96 (d, J= 8.4 Hz, 2H), 7.83 (s,
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1H), 7.70 (s, 1H), 7.32 (d, J= 8.0 Hz, 2H), 6.88-6.79 (m, 3H), 6.06 (s, 2H), 2.40 (s, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 148.9, 148.2, 144.3, 143.2, 137.7, 130.1, 129.8, 128.0, 122.7, 115.9,
108.8, 103.9, 102.3, 21.6. IR (KBr) 3142, 2915, 1517, 1317, 1306, 1246, 1149, 1037, 691, 604
νmax/cm-1; MS (ESI) m/z (M+Na)+ Calcd for C17H14N2NaO4S: 365.0572; Found: 365.0556 [M+Na]+.
4-(4-tosyl-1H-imidazol-1-yl)pyridine (21). The crude material was purified by column
chromatography (PE/EtOAc 6:4 and PE/EtOAc 3:7) to give the product as a yellow solid (34 mg,
1
45% yield). H NMR (400 MHz, DMSO-d6) δ 8.76-8.75 (m, 2H), 8.06 (s, 1H), 7.98-7.94 (m, 3H),
7.35-7.33 (m, 4H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 155.4, 150.8, 144.7, 143.5,
143.3, 138.0, 130.4, 127.9, 115.4, 22.3. IR (KBr) 3137, 2963, 2921, 1591, 1519, 1323, 1143, 1085,
819, 806 νmax/cm-1; Mp 195-197 °C; MS (ESI) m/z (M+H)+ Calcd for C15H14N3O2S+: 300.0802;
Found: 300.0794 [M+H]+.
1-(4-nitrophenyl)-4-tosyl-1H-imidazole (22). The crude material was purified by column
chromatography (n-hexane/ EtOAc 6:4) to give the product as a yellowish solid (59 mg, 69% yield).
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J= 9.2 Hz, 2H), 8.02 (d, Jm= 1.6 Hz, 1H), 7.98 (d, J= 8.4 Hz,
2H), 7.92 (d, Jm= 1.2 Hz, 1H), 7.59 (d, J= 9.2 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 2.43 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 145.1, 144.7, 140.5, 137.1, 129.9, 128.2, 126.0, 122.0, 110.0,
21.6. IR (KBr) 3132, 2922, 2853, 1594, 1518, 1311, 1287, 1140, 1077, 853, 603, 534 νmax/cm-1; Mp
228-229 °C; MS (ESI) m/z (M+H)+ Calcd for C16H14N3O4S+: 344.0700; Found: 344.0693 [M+H]+.
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1-(3,5-dichlorophenyl)-4-tosyl-1H-imidazole (23). The crude material was purified by column
chromatography (n-hexane/ EtOAc 8:2) to give the product as a yellowish solid (52 mg, 57% yield).
1H NMR (400 MHz, CDCl3) δ 8.34-8.32 (m, 1H), 8.28 (s, 1H), 8.01-7.98 (m, 2H), 7.90 (s, 1H),
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7.76-7.75 (m, 2H), 7.35 (d, J= 8.4 Hz, 2H), 2.43 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
144.6, 144.5, 137.4, 137.3, 136.7, 129.8, 129.0, 128.1, 121.8, 120.5, 21.6. IR (KBr) 3070, 2920,
2851, 1589, 1573, 1432, 1303, 1141, 1084, 799, 665, 599, 532 νmax/cm-1; Mp 209-210 °C; MS (ESI)
m/z (M+H)+ Calcd for C16H13Cl2N2O2S+: 367.0070; Found: 367.0064 [M+H]+.
1-(3,4-dimethoxyphenyl)-4-tosyl-1H-imidazole (24). The crude material was purified by column
chromatography (n-hexane/ EtOAc 8:2) to give the product as a brownish solid (60 mg, 67% yield).
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J= 8.0 Hz, 2H), 7.88 (d, Jm= 1.2 Hz, 1H), 7.74 (d, Jm= 1.2
Hz, 1H), 7.32 (d, J= 8.0 Hz, 2H), 6.94-6.89 (m, 2H), 6.82 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.40 (s,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 150.0, 149.5, 144.2, 143.1, 137.8, 129.7, 129.2, 128.0,
122.8, 114.5, 111.6, 106.2, 56.2, 21.6. IR (KBr) 3160, 2921, 2852, 1600, 1517, 1442, 1236, 1136,
1082, 1025, 662, 599, 536 νmax/cm-1; Mp 130-131 °C; MS (ESI) m/z (M+H)+ Calcd for
C18H19N2O4S+: 359.1061; Found: 359.1057 [M+H]+.
1-(4-bromo-3-chlorophenyl)-4-tosyl-1H-imidazole (25). The crude material was purified by
column chromatography (n-hexane/ EtOAc 8:2) to give the product as a brown to red solid (93mg,
90% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.48 (s, 1H), 8.16 (d, Jm= 2.4 Hz, 1H),
7.92 (d, J= 8.8 Hz, 1H), 7.81 (d, J= 8.0 Hz, 2H), 7.70 (dd, Ja= 8.4 Hz, Jb= 2.4 Hz, 1H), 7.41 (d, J=
13
7.6 Hz, 2H), 2.36 (s, 3H); C{1H} NMR (100 MHz, DMSO-d6) δ 144.6, 142.6, 138.7, 138.3,
136.5, 135.2, 134.8, 130.3, 127.8, 123.5, 121.8, 121.1, 21.5. IR (KBr) 3111, 2922, 2852, 1592,
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1513, 1463, 1313, 1138, 1084, 810, 634, 585, 532 νmax/cm-1; Mp 183-184 °C; MS (ESI) m/z (M+H)+
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Calcd for C16H13BrClN2O2S+: (97%) 412.9544; Found: 412.9536 [M+H]+.
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1-(3,5-dimethoxyphenyl)-4-tosyl-1H-imidazole (26). The crude material was purified by column
chromatography (n-hexane/ EtOAc 8:2) to give the product as brownish oil (45 mg, 50% yield). 1H
NMR (400 MHz, CDCl3) δ 7.95 (d, J= 7.6 Hz, 2H), 7.88 (s, 1H), 7.73 (s, 1H), 7.31 (d, J= 7.6 Hz,
13
2H), 6.91-6.83 (m, 3H), 3.90 (s, 6H), 2.39 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 150.0,
149.5, 144.2, 143.1, 137.7, 129.7, 129.2, 128.0, 122.8, 114.5, 111.6, 106.2, 56.2, 21.6. IR (KBr)
3124, 2924, 2838, 1599, 1517, 1315, 1235, 1136, 1084, 1020, 660, 597, 534 νmax/cm-1; MS (ESI)
m/z (M+H)+ Calcd for C18H19N2O4S+: 359.1061; Found: 359.1053 [M+H]+.
1-(2-iodophenyl)-4-tosyl-1H-imidazole (27). The crude material was purified by column
chromatography (n-hexane/ EtOAc 8:2) to give the product as a yellow solid (39 mg, 37% yield).
1H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 3H), 7.77 (d, Jm= 1.2 Hz, 1H), 7.61 (d, Jm= 1.2 Hz,
13
1H), 7.50-7.46 (m, 1H), 7.35-7.21 (m, 4H), 2.42 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ
144.2, 142.9, 140.4, 139.1, 138.7, 137.7, 131.4, 129.7, 129.6, 128.0, 127.6, 124.4, 95.1, 21.6. IR
(KBr) 3159, 3106, 2921, 2851, 1511, 1312, 1139, 1084, 766, 688, 660, 602, 533 νmax/cm-1; Mp 180-
181 °C; MS (ESI) m/z (M+H)+ Calcd for C16H14IN2O2S+: 424.9816; Found: 424.9806 [M+H]+.
1-(3,5-dichlorophenyl)-4-(naphthalen-2-ylsulfonyl)-1H-imidazole (28). The crude material was
purified by column chromatography (n-hexane/ EtOAc 8:2) to give the product as a yellowish solid
(59 mg, 58.5% yield). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.03-7.81 (m, 6H), 7.64-7.58 (m,
13
2H), 7.43 (s, 1H), 7.31 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 144.2, 137.4, 137.1, 136.7,
135.2, 132.2, 129.7, 129.5 (2C), 129.2, 129.1, 127.9, 127.5, 122.9, 122.1, 120.6. IR (KBr) 3127,
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2922, 1583, 1518, 1311, 1144, 1124, 1072, 852, 751, 682, 665, 588 νmax/cm-1; Mp 212-213 °C; MS
(ESI) m/z (M+H)+ Calcd for C19H13Cl2N2O2S+: 403.0070; Found: 403.0062 [M+H]+.
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4-(naphthalen-2-ylsulfonyl)-1-(3-nitrophenyl)-1H-imidazole (29). The crude material was
purified by column chromatography (n-hexane/ EtOAc 8:2) to give the product as a brownish solid
1
(58 mg, 61% yield). H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.65-8.60 (m, 3H), 8.20-8.10
13
(m, 4H), 8.01-7.63 (m, 5H); C{1H} NMR (100 MHz, DMSO-d6) δ 148.9, 142.4, 139.1, 138.1,
137.0, 135.0, 132.1, 131.7, 130.0, 129.9, 129.7, 129.0, 128.3, 128.2, 128.1, 124.1, 123.1, 116.8. IR
(KBr) 3152, 3121, 1535, 1518, 1346, 1318, 1143, 1125, 1070, 737, 662, 537 νmax/cm-1; Mp 163-
164°C; MS (ESI) m/z (M+Na)+ Calcd for C19H13N3NaO4S: 402.0524; Found: 402.0516 [M+Na]+.
4-((4-methoxyphenyl)sulfonyl)-1-(3-nitrophenyl)-1H-imidazole (30). The crude material was
purified by column chromatography (n-hexane/ EtOAc 6:4) to give the product as a yellow to
orange solid (29 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.62 (s, 1H), 8.56
(s, 1H), 8.24-8.19 (m, 2H), 7.88-7.78 (m, 3H), 7.13-7.11 (m, 2H), 3.81 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.7, 149.1, 145.1, 136.9, 131.6, 131.5, 130.4, 127.4, 123.4, 121.4, 117.0, 114.5,
55.7. IR (KBr) 3110, 2921, 2851, 1591, 1525, 1348, 1298, 1256, 1135, 737, 673, 600, 545 νmax/cm-
1; Mp 180-181 °C; MS (ESI) m/z (M+Na)+ Calcd for C16H13N3NaO5S: 382.0474; Found: 382.0459
[M+Na]+.
4-((4-bromophenyl)sulfonyl)-1-(3,5-dimethoxyphenyl)-1H-imidazole (31). The crude material
was purified by column chromatography (n-hexane/ EtOAc 6:4) to give the product as a yellowish
1
amorphous solid (29 mg, 27% yield). H NMR (400 MHz, CDCl3) δ 7.98 (d, J= 8.8 Hz, 2H), 7.92
(d, Jm= 1.2 Hz, 1H), 7.78 (d, Jm= 1.6 Hz, 1H), 7.70 (d, J= 8.8 Hz, 2H), 6.95-6.94 (m, 2H), 6.85 (d,
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Jm= 2.0 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 150.0, 149.7,
142.4, 139.8, 138.0, 132.4, 129.6, 129.1, 128.6, 123.3, 114.6, 111.6, 106.3, 56.3, 56.2. IR (KBr)
3087, 2925, 2022, 1516, 1236, 1064, 1008, 856 νmax/cm-1; MS (ESI) m/z (M+H)+ Calcd for
C17H16BrN2O4S+: 423.0009; Found: 423.0010 [M+H]+.
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4-((4-bromophenyl)sulfonyl)-1-(3,5-dichlorophenyl)-1H-imidazole (32). The crude material was
purified by column chromatography (n-hexane/ EtOAc 9:1) to give the product as a yellowish
1
amorphous solid (89 mg, 82% yield). H NMR (400 MHz, CDCl3) δ 7.98-7.95 (m, 3H), 7.85 (s,
1H), 7.71 (d, J= 8.4 Hz, 2H), 7.49 (s, 1H), 7.34-7.37 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ
143.8, 139.3, 137.3, 137.2, 136.8, 132.5, 129.6, 129.2, 128.9, 123.0, 122.3, 120.6. IR (KBr) 3135,
2922, 2230, 1571, 1432, 1313, 1140, 1064, 742, 628 νmax/cm-1; MS (ESI) m/z (M+H)+ Calcd for
C15H10BrCl2N2O2S+: 430.9018; Found: 430.9026 [M+H]+.
5-phenyl-4-tosyloxazole (34). The crude material was purified by column chromatography
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(PE/EtOAc 9.5:0.5 and PE/EtOAc 8:2) to give the product as a pink solid (61 mg, 75% yield). H
NMR (400 MHz, CDCl3) δ 7.98-7.85 (m, 5H), 7.51-7.50 (m, 3H), 7.31 (d, J=8.4 Hz, 2H), 2.41 (s,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 152.7, 149.2, 145.0, 137.1, 135.6, 130.9, 129.8, 129.0,
128.6, 128.2, 125.5, 21.7. IR (KBr) 3143, 2963, 2922, 1595, 1512, 1313, 1263, 1144, 1112, 1032,
812, 671 νmax/cm-1; Mp 133-135 °C dec.; MS (ESI) m/z (M+H)+ Calcd for C16H14NO3S+: 300.0689;
Found: 300.0688 [M+H]+.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
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Table with the optimization reaction conditions, Spectroscopic data, HRMS spectra of reaction
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mixture, Crystallographic description of 3, Copies of 1H and 13C spectra, (PDF)
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Cif file of 3 (CCDC number: 1884065) (PDF)
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AUTHOR INFORMATION
Corresponding Authors
* E-mail: mariateresa.giustiniano@unina.it;
giancesare.tron@uniupo.it
ACKNOWLEDGMENTS
Financial support from Università del Piemonte Orientale, Novara and Università degli Studi
“Federico II” Napoli, Italy is acknowledged.
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the problem due to the partial negative charge on the isocyanide carbon atom. Anyway, although
considered unfavorable in the first Baldwin rules, examples of successful 5-endo dig have been
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15) Phanindrudu, M.; Tiwari, D. K.; Sridhar, B.; Likhar, P. R.; Tiwari, D. K. Magnetically
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22) Intermediate C and D are unstable, and we were not able to isolate them or to identify them
using HPLC-DAD and UHPLC-HRMS for a real-time monitoring of the reaction, while it was
easily detected the presence of p-toluensulfinic acid.
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31) Bertrand, H. C.; Schaap, M.; Baird, L.; Georgakopoulos, N. D.; Fowkes, A.; Thiollier, C.;
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