Laser synthesis: A solvent-free approach for the preparation of phenylthiazolo[5,4-: B] pyridine derivatives

Article abstract of DOI:10.1039/d0ra10094c

We describe here a rapid and straightforward solvent-free method to access phenylthiazolo[5,4-b]pyridines using a Nd-YAG laser NANO-NY81-10 (λ = 355 nm, 10 Hz pulse frequency; 8 ns pulse duration). This newly presented method successfully brings several improvements to the laser assisted synthesis of N,S-heterocycles. We are able to provide a solvent-, metal- and base-free method with good yield and a substantial reduction in reaction time. This journal is

Full text of DOI:10.1039/d0ra10094c

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Laser synthesis: a solvent-free approach for the
preparation of phenylthiazolo[5,4-b]pyridine
derivatives†
Cite this: RSC Adv., 2021, 11, 5003
Rihab Jemili,ab Joana F. Campos, a Nicolas Dumuis,b Herve Rabat,b Nadjib Semmarb
´
a
*
and Sabine Berteina-Raboin
We describe here a rapid and straightforward solvent-free method to access phenylthiazolo[5,4-b]pyridines
using a Nd-YAG laser NANO-NY81-10 (l ¼ 355 nm, 10 Hz pulse frequency; 8 ns pulse duration). This newly
presented method successfully brings several improvements to the laser assisted synthesis of N,S-
heterocycles. We are able to provide a solvent-, metal- and base-free method with good yield and
a substantial reduction in reaction time.
Received 30th November 2020
Accepted 21st January 2021
DOI: 10.1039/d0ra10094c
rsc.li/rsc-advances
media in conventional heating and could also lead to different
compounds depending on the type of reaction envisaged. For
Introduction
this reason, in this work, our team reports an innovative and
unexplored approach to the synthesis of S,N-heterocycles. It
involves making use of a laser beam to obtain phenylthiazolo
[5,4-b]pyridine derivatives in order to develop the initial
parameters since laser energy has seldom been studied in
organic synthesis. Indeed, to the best of our knowledge, the
construction of 9-azauorene from 2-azidobiphenyl using LED,9
laser10 (Table 1) or visible light11 is the only reported preparation
of nitrogen containing heterocycles in the literature.
The thiazole heterocycle occupies a signicant place in medic-
inal chemistry. This skeleton is present in various products with
essential medicinal properties such as vitamin B1 (thiamine).
This ring is also present in various products synthesized in the
laboratory.
The preparation of thiazoles has soared in recent years,
notably benzothiazole, which has proven its potential in
successful biological applications (Fig. 1). Scott and Njardarson,
from their analysis of sulfur-containing US FDA-approved
drugs, pointed out that 23 of the approved drugs contain at
least one thiazole and that 3 drugs contain a benzothiazole.
Earlier, in 2014, Njardarson's team demonstrated that 4 of the
10 most commonly used nitrogen heterocycles also contain
a sulfur atom and that thiazole is one of them. Additionally,
they reported a remarkable fact: 67% of all thiazole-containing
pharmaceuticals belong to the large class of b-lactam antibi-
otics.1–3 Photoreaction in organic synthesis is a domain that has
been growing in recent years. Due to an increasing exploration
and expansion effort, several teams have been involved in the
construction of heterocycles in order to perform pharmaco-
modulation through another synthesis strategy, while obtaining
derivatives with potential biological activity.4–8 We surmised
that the use of laser energy could signicantly improve the
energy consumption of reactions compared to the activation of
a
´
´
Institut de Chimie Organique et Analytique (ICOA), Universite d'Orleans, UMR, CNRS
´
7311, BP 6759, rue de Chartres, 45067 Orleans cedex 2, France. E-mail: sabine.
berteina-raboin@univ-orleans.fr
b
´
´
GREMI (Groupe de Recherches sur l'Energetique des Milieux Ionises), UMR CNRS
´
´
´
7344, Universite d'Orleans, 14 rue d'Issoudun, BP 6744, 45067 Orleans Cedex 2,
France
Fig. 1 Structure of some FDA approved drugs with skeletons similar to
† Electronic supplementary information (ESI) available. See DOI:
those reported in this article.
10.1039/d0ra10094c
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Table 1 Comparison of equipment used in the study
Results and discussion
Apparatus
Pulse frequency
Pulse duration
Ref.
10
To determine which laser was the most suitable for our purpose,
and before starting the reaction optimization process, a UV
This work spectrum of compound 1 was recorded.
Nd-YAG laser
8 kHz
1–10 Hz
26 ns
10 ns
The UV spectrum showed that 3-amino-2-chloropyridine has
a maximum absorption at 311 nm in EtOH, thus guiding us
towards the most efficient reactant sensitization. From this
information we determined the optic GAP of our starting
material: 3.98 eV at 311 nm. Although the maximum absorption
of 3-amino-2-chloropyridine in ethanol was at 311 nm, it was
decided to pursue this study at 355 nm as this starting
compound presents very acceptable absorbance results at this
wavelength; moreover, the laser available in our laboratory is at
355 nm and is not adjustable.
Photocyclisation optimization using an Nd-YAG laser NANO-
NY81-10 (l ¼ 355 nm, 10 Hz pulse frequency; pulse duration 8
ns) (Fig. 2 and 3) was carried out in two distinct parts. The
inuence of the solvent was studied rst, then the amount of
energy needed for the synthesis process was assessed.
Considering the above, it seemed important to explore this
synthesis approach in order to improve general knowledge in
the eld of new and greener synthetic strategies for the
construction of O,S,N-heterocycles.12–21 To prepare the benzo-
thiazole skeleton, and aer reviewing the literature, we found
that Ramakrishnan's team had successfully used the potential
of photochemical synthesis. The photocyclization of haloge-
nated thioacetanilides gave a high yield of halogenated 2-
methylbenzothiazoles (Scheme 1a).22
The 2-(indol-1-yl)benzothiazoles were obtained in moderate
to good yield from the irradiation of N-phenyl-1H-indole-1-
carbothioamides at 254 nm for 8–55 h (Scheme 1b);23 2-ben-
zoylaminonaphtho[2,1-d]thiazole was obtained from N-benzoyl-
N0-(1-chloro-2-naphthyl)thiourea using MeOH as solvent for
12 h in 65% yield (Scheme 1c).24
Practically, we reacted 3-amino-2-chloropyridine (1 equiv.)
with phenyl isothiocyanate (1 equiv.) and varied the amount of
solvent or starting material (Fig. 4).
A literature review to identify the best conditions for this
cyclization from aminochloropyridines showed that the most
commonly used conditions made use of EtOH and MeOH as
solvent; the reaction time ranged from 16 h to 18 h using
classical heating25–27 and 8 h to 55 h using photochemical
irradiation.22–24
The use of laser energy allows a shorter reaction time,
probably due to the energy being efficiently conducted by the
beam which limits the energy loss that can occur either in
conventional thermal heating or through the use of LED lamps
for example.
The purpose of this series of experiments was to demon-
strate the inuence of concentration on performance. In Fig. 4,
two methods were tested (2 h, 355 nm, 60 mJ): the rst series
consisted in keeping the amount of solvent constant (1 mL) and
varying the amount of starting reactants to obtain the desired
concentration (curve A). It can be seen that the yield improved
with the reactant concentration. The second method (curve B)
consisted in keeping the quantities of the starting products
Fig. 2 Experimental setup with Nd-YAG laser NANO-NY81-10.
Fig. 3 Top view of photoreactor with reaction tube (left) and reaction
Scheme 1 Reported literature.
tube (right).
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Fig. 4 Influence of the solvent on reaction yield.
constant and varying the quantity of solvent (2 mL, 1.5 mL, 1.25
mL, 1 mL, 0.5 mL, 0.25 mL). In this case, the solvent amount,
hence the concentration of reactants, was limited due to the size
of the reactor. The reactions were performed with peak power
between 1.3 and 7.5 MW. As expected, the concentration
allowed an increase in yield over the reaction time set at the
start. In order to ensure an impact zone of the laser beam in
relation to the reactor content, the quantities on which we
worked were deliberately limited, although the reactors can
contain a greater volume.
Fig. 5 Synthesis of phenylthiazolo[5,4-b]pyridines.
By observation, it was found that the absence of solvent was
benecial in this process and from these data, we moved on to
phase 2 of the optimization, the energy study (Table 2).
The desired compound was obtained with an interesting
yield range. Each time the energy input was decreased, the yield
perceptibly worsened and the reaction time increased (Table 2,
entry 1–6). This process proved to be a good alternative to the
most commonly used synthetic routes. Based on our results, the
scope and limitations of the optimized conditions for the
preparation of phenylthiazolo[5,4-b]pyridines were assessed
using several isothiocyanates (Fig. 5). Concerning compounds 2
and 6, which could not be obtained, it is possible that the
reactivity of the 3-pyridylisothiocyanate was not great enough
The phenylthiazolo[5,4-b]pyridines 1–9 were synthesized in
moderate to excellent yields, demonstrating the generalizability
of this method (Fig. 5). The methodology presented successfully
brings several improvements to the synthesis of N,S-heterocy-
cles. Using laser synthesis, we are able to provide a solvent-,
metal- and base-free methodology with good yield and
a substantial reduction in reaction time.
Experimental
Materials and methods: laser
An Nd:YAG laser source was employed in this study. This laser
source works at a wavelength of 1064 nm in the fundamental
state. Thanks to the second and third harmonic generators, the
532 and 355 nm wavelengths are also available. The laser
frequency (repetition rate) is also tunable from 1 to 10 Hz, with
a mean pulse time of 10 ns. In the present experiments and due
to the absorption coefficient of the glass employed (reaction
tube), the maximum photon energy that could be used was
355 nm. For this wavelength, the maximum output energy is 100
and that there was
biphenylisothiocyanate.
a
p
stacking problem with
Table 2 Influence of the energy input on reaction yield
Yielda (%)
t
(h)
Entry
Energyb (mJ)
Solvent free
1
2
3
4
5
6
60 ꢀ 0.5
50 ꢀ 0.5
40 ꢀ 0.5
30 ꢀ 0.5
20 ꢀ 0.5
11 ꢀ 0.5
2
3
4
4
4
4
90
80
72
55
15
8
a
Isolated yield aer purication via column chromatography. b Photon
energy: 3.49 eV.
Fig. 6 Laser frequency.
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Fig. 9 (A) represents schematic view of the incident beam interaction
with the glass tube; (B) represents TracePro® simulation of the mul-
tireflection inside the reactor.
Fig. 7 Pulse duration of an Nd-YAG NANO-NY81-10 laser.
Conclusions
mJ per pulse. An optical polarizer device was also used to
monitor the irradiation energy in the range 10 to 100 mJ. A
Gentec® Joulemeter/Powermeter was employed for the directed
measurement of the incident beam energy. The working
conditions were 10 Hz for the repetition rate, with a pulse
duration close to 10 ns, measured thanks to a Hamamatsu®
high rise time photodiode (<500 ps) as shown in Fig. 6 and 7.
The tube holder/reactor is a cylindrical chamber that
contains a metallic reector on the wall position. The reactor
was designed in CAD (Fig. 8) and the entire product construc-
tion was then carried out by 3D printing (stereo-lithography). Its
internal diameter is 87 mm and its height 80 mm. The reecting
wall is made of 0.5 mm thick polished stainless steel. All the
other elements were produced using traditional machining.
As demonstrated using TracePro® soware (Fig. 9: (A)
schematic view of the incident beam interaction with the glass
tube; (B) TracePro® simulation of the multireection inside the
reactor), this reector helps to ensure that all reected parts of
the incident laser beam are nally focused into the tube center.
Thanks to an X, Y, Z micro-positioning stage, the irradiated zone
on the tube is also fully controlled.
The use of a new, simple and efficient solvent-free procedure
enabled the preparation of phenylthiazolo[5,4-b]pyridine
derivatives. This laser synthesis protocol proved to be a good
alternative to the most commonly used synthetic routes. In this
study, in addition to eliminating the need for solvent, two
reaction parameters were improved: time and yield. These rst
encouraging results will be the basis of our future studies on the
use of laser energy applied to the synthesis of interesting
organic compounds and on the study of reaction mechanisms.
Author contributions
J. F. C. and S.$B. R. conceived and designed the synthetic
pathway. R. J. and N. S. were involved in planning the laser
synthesis. N. D. built the reactor. H. R. was responsible for the
maintenance of the laser. R. J. performed the experiments. J. F.
C. collected the data and draed the initial version of the
manuscript. S. B. R. and N. S. reviewed and edited the
manuscript.
Conflicts of interest
Synthetic procedures
There are no conicts to declare.
General procedure. In
a sealed tube, the 3-amino-2-
chloropyridine (200 mg, 1.55 mmol) was mixed with the iso-
thiocyanate (1 eq.). The tube was irradiated with an Nd-YAG
nanosecond laser (l ¼ 355 nm). The product thus formed was
Acknowledgements
This work is part of the project entitled “APR-IR SPLACh” fun-
ded by the Region Centre-Val-de-Loire.
puried with
a chromatography column, CH2Cl2/MeOH
(90 : 10).
References
1 K. A. Scott and J. T. Njardarson, Analysis of US FDA-Approved
Drugs Containing Sulfur Atoms, Top. Curr. Chem., 2018, 376,
5, DOI: 10.1007/s41061-018-0184-5.
2 M. T. Chhabria, S. Patel, P. Modi and P. S. Brahmkshatriya,
Thiazole:
Therapeutic Importance of its Derivatives, Curr. Top. Med.
Chem., 2016, 16, 2841–2862, DOI: 10.2174/
1568026616666160506130731.
A
Review on Chemistry, Synthesis and
3 E. Vitaku, D. T. Smith and J. T. Njardarson, Analysis of the
structural diversity, substitution patterns, and frequency of
nitrogen heterocycles among U.S. FDA approved
Fig. 8 3D representation of the reactor.
5006 | RSC Adv., 2021, 11, 5003–5007
© 2021 The Author(s). Published by the Royal Society of Chemistry

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pharmaceuticals, J. Med. Chem., 2014, 57, 10257–10274, DOI: 16 J. F. Campos and S. Berteina-Raboin, Eucalyptol as bio-based
10.1021/jm501100b.
4 N. Kaur, P. Bhardwaj, M. Devi, Y. Verma and P. Grewal,
Photochemical reactions in ve and six-membered
solvent for Migita–Kosugi–Stille coupling reaction on O,S,N-
heterocycle, Catal. Today, 2020, 358, 138–142, DOI: 10.1016/
j.cattod.2019.11.004.
polyheterocycles synthesis, Synth. Commun., 2019, 49, 17 N. Fresneau, M.-A. Hiebel, L. A. Agrofoglio and S. Berteina-
2281–2318, DOI: 10.1080/00397911.2019.1622732.
5 N. Kaur, Photochemical reactions as key steps in ve-
membered N-heterocycle synthesis, Synth. Commun., 2018,
48, 1259–1284, DOI: 10.1080/00397911.2018.1443218.
Raboin, Efficient Synthesis of Unprotected C-5-Aryl/
Heteroaryl-2'-deoxyuridine via a Suzuki–Miyaura Reaction
in Aqueous Media, Molecules, 2012, 17, 14409–14417, DOI:
10.3390/molecules171214409.
6 N. Kaur, Synthesis of seven and higher membered nitrogen 18 N. Fresneau, M.-A. Hiebel, L. A. Agrofoglio and S. Berteina-
containing heterocycles using photochemical irradiation,
Synth. Commun., 2018, 48, 2815–2849, DOI: 10.1080/
00397911.2018.1501488.
Raboin, One-pot Sonogashira-cyclization protocol to obtain
substituted furopyrimidine nucleosides in aqueous
conditions, Tetrahedron Lett., 2012, 53, 1760–1763, DOI:
10.1016/j.tetlet.2012.01.106.
7 N. Kaur, Photochemical Reactions: Synthesis of Six-
membered N-heterocycles, Curr. Org. Chem., 2017, 14, 972– 19 M.-A. Hiebel, Y. Fall, M.-C. Scherrmann and S. Berteina-
998, DOI: 10.2174/1570179414666170201150701.
8 K. Mizuno, Y. Nishiyama, T. Ogaki, K. Terao, H. Ikeda and
K. Kakiuchi, Utilization of microow reactors to carry out
synthetically useful organic photochemical reactions, J.
Photochem. Photobiol., C, 2016, 29, 107–147, DOI: 10.1016/
j.jphotochemrev.2016.10.002.
Raboin,
Straightforward
Synthesis
of
Various
2,3-Diarylimidazo[1,2-a]pyridines in PEG400 Medium
through One-Pot Condensation and C–H Arylation, Eur. J.
Org. Chem., 2014, 21, 4643–4650, DOI: 10.1002/
ejoc.201402079.
20 M.-A. Hiebel and S. Berteina-Raboin, Iodine-catalyzed
regioselective sulfenylation of imidazoheterocycles in
PEG400, Green Chem., 2015, 17, 937–944, DOI: 10.1039/
c4gc01462f.
21 G. Dumonteil, M.-A. Hiebel, M.-C. Scherrmann and
S. Berteina-Raboin, Iodine-catalyzed formation of
´
9 S. Parisien-Colette, C. Cruche, X. Abel-Snape and
S. K. Collins, Photochemical intramolecular amination for
the synthesis of heterocycles, Green Chem., 2017, 19, 4798–
4803, DOI: 10.1039/c7gc02261a.
¨
´
´
10 E. Bremus-Kobberling, A. Gillner, F. Avemaria, C. Rethore
¨
and S. Brase, Photochemistry with laser radiation in
substituted 2-aminobenzothiazole derivatives in PEG400,
condensed phase using miniaturized photoreactors,
RSC Adv., 2016, 6, 73517–73521, DOI: 10.1039/c6ra15971k.
Beilstein J. Org. Chem., 2012, 8, 1213–1218, DOI: 10.3762/ 22 R. Paramasivam, R. Palaniappan and V. T. Ramakrishnan,
bjoc.8.135.
Photochemical synthesis of 2-methylbenzothiazoles, J.
Chem. Soc., Chem. Commun., 1979, 260–261, DOI: 10.1039/
c39790000260.
11 L. Yang, Y. Zhang, X. Zou, H. Lu and G. Li, Visible-light-
promoted intramolecular C–H amination in aqueous
solution: synthesis of carbazoles, Green Chem., 2018, 20, 23 S. Muthusamy, R. Paramasivam and V. T. Ramakrishnan,
1362–1366, DOI: 10.1039/c7gc03392c.
12 J. F. Campos, A. Pacheco-Benichou, C. Fruit, T. Besson and
S. Berteina-Raboin, Synthesis of Benzo-Fused 11H-Pyrido
Photochemical synthesis of 2-substituted benzothiazoles, J.
Heterocycl. Chem., 1991, 28, 759–763, DOI: 10.1002/
jhet.5570280335.
[2,1-b]quinazolin-11-ones
Coupling/Pyridine Dearomatization
Eucalyptol, Synthesis, 2020, 52(20), 3071–3076, DOI:
10.1055/s-0040-1707158.
by
a
Buchwald–Hartwig 24 G. Jayanthi, S. Muthusamy and V. T. Ramakrishnan,
Sequence
in
Photoreaction of N-arylcarbonyl-N0-arylthiourea derivatives,
J. Photochem. Photobiol., C, 1998, 116, 103–108, DOI:
10.1016/s1010-6030(98)00294-9.
13 J. F. Campos, M. Loubidi, M.-C. Scherrmann and S. Berteina- 25 H. G. Choi, J. Zhang, E. Weisberg, J. D. Griffin, T. Sim and
Raboin, A Greener and Efficient Method for Nucleophilic
Aromatic Substitution of Nitrogen-Containing Fused
Heterocycles, Molecules, 2018, 23, 684, DOI: 10.3390/
molecules23030684.
N. S. Gray, Development of ‘DFG-out’ inhibitors of
gatekeeper mutant kinases, Bioorg. Med. Chem. Lett., 2012,
22, 5297–5302, DOI: 10.1016/j.bmcl.2012.06.036.
26 H. W. Aitland and G. A. Molander, A facile synthesis of
14 J. F. Campos, M.-C. Scherrmann and S. Berteina-Raboin,
Eucalyptol: a new solvent for the synthesis of heterocycles
containing oxygen, sulfur and nitrogen, Green Chem., 2019,
21, 1531–1539, DOI: 10.1039/c8gc04016h.
15 J. F. Campos and S. Berteina-Raboin, Eucalyptol as a Bio-
Based Solvent for Buchwald-Hartwig Reaction on O,S,N-
Heterocycles, Catalysts, 2019, 9, 840–850, DOI: 10.3390/
catal9100840.
2-aminothiazolo[5,4-b]-
pyridines, J. Heterocycl. Chem., 1977, 14, 129–134, DOI:
10.1002/jhet.5570140125.
and
2-aminothiazolo[4,5-c]
27 H. W. Altlang, The Smiles rearrangement of 2-tetrazolylthio-
3-aminopyridines, J. Org. Chem., 1976, 41, 3395–3399, DOI:
10.1021/jo00883a013.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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