Toward a Greener Barluenga-Valdés Cross-Coupling: Microwave-Promoted C-C Bond Formation with a Pd/PEG/H2O Recyclable Catalytic System

Article abstract of DOI:10.1021/acs.orglett.9b03310

A green Barluenga-Valdés cross-coupling reaction for the synthesis of 1,1-diarylethylenes using palladium catalysis has been developed. The new catalytic system based on Pd/Xphos-SO₃Na or Pd/MeDavephos-CF₃SO₃ in PEG/H₂O under microwave irradiation was found to be the best conditions for this transformation. The recyclability of the palladium catalyst system was also studied, and it was found to be active over nine runs without significant loss in its activity.

Full text of DOI:10.1021/acs.orglett.9b03310

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
́
Toward a Greener Barluenga−Valdes Cross-Coupling: Microwave-
Promoted C−C Bond Formation with a Pd/PEG/H2O Recyclable
Catalytic System
Diana Lamaa,† Estelle Messe,† Vincent Gandon,‡ Mouad Alami,*,† and Abdallah Hamze*,†
†
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BioCIS UMR 8076, Universite Paris-Sud, CNRS, Universite Paris-Saclay, Equipe Labellisee Ligue Contre Le Cancer, Laboratoire
́
́
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de Chimie Therapeutique, Faculte de Pharmacie, rue J.-B. Clement, F−92296 Chatenay-Malabry, France
‡
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Institut de Chimie Moleculaire et des Materiaux d’Orsay (ICMMO), CNRS UMR 8182, Universite Paris-Sud, Universite
Paris-Saclay, Batiment 420, 91405 Orsay Cedex, France
S
* Supporting Information
́
ABSTRACT: A green Barluenga−Valdes cross-coupling reaction for the synthesis of 1,1-diarylethylenes using palladium
catalysis has been developed. The new catalytic system based on Pd/Xphos−SO3Na or Pd/MeDavephos−CF3SO3 in PEG/
H2O under microwave irradiation was found to be the best conditions for this transformation. The recyclability of the palladium
catalyst system was also studied, and it was found to be active over nine runs without significant loss in its activity.
he formation of C=C double bonds from carbonyl
decomposition via the Bamford−Stevens reaction, (2) in
Tcompounds is among the most important issues in comparison to classical couplings (Heck, Kumada, Suzuki
coupling), this method does not require the use of
stoichiometric organometallic reagents, (3) and the starting
building block (NTH) is obtained easily from carbonyl
derivatives.
organic synthesis. Alkene units are important constituents in a
variety of bioactive compounds.1 Among them, 1,1-diaryl-
ethylene compounds are identified as an important scaffold in a
variety of bioactive molecules such as the antineoplastic agent
bexarotene (Targretin)2 or the antivascular compound isoCA-
4.3 Among the well-known methods used in the double bond
construction, the Wittig,4 the Peterson,5 the Tebbe−Petasis,6
and the Julia7 reactions constitute major milestones in this
chemistry. The main drawbacks of these methods can be
summarized as follows: (1) the use of stoichiometric quantities
of metal, (2) low reactivity of sterically hindered ketones
leading to slow reactions and poor yields, (3) and poor
chemoselectivity and functional group tolerance due to the use
of strong metal bases. In parallel to these methods, metal-
catalyzed processes represent general and mild routes for
́
However, since the pioneering work of Barluenga−Valdes
for the formation of Csp2−Csp2 bonds, to our knowledge,
there is no green protocol available for this efficient coupling.
The main drawback of this cross-coupling is related to the use
of a toxic solvent (such as dioxane,10 toluene, or 1,2-
dichloroethane11). Moreover, palladium belongs to the list of
precious and endangered elements that find a major use as a
catalyst in many C−C bond constructions.12 It is therefore
important to focus on its recovery and recycling. In this work,
we sought to develop a green version of this interesting
reaction by using more environmentally benign solvents and
recycling the catalytic system (Scheme 1). This approach
would enable cross-coupling process in a sustainable manner
and can find application in numerous pharmaceutical
processes.
obtaining alkene derivatives.1a,8 In 2007, Barluenga and Valdes’
́
groups developed an interesting Pd-catalyzed Csp2−Csp2
bond-forming reaction that employs N-tosylhydrazones
(NTH) derived from ketones as a nucleophilic partner and
organic halides.9 This methodology benefits from many
advantages including (1) N-tosylhydrazones constitute a
reliable in situ source of diazo compounds without the typical
Received: September 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03310
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hydrosilylation of terminal alkynes,16 and C−H bond
activation.17
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Scheme 1. Traditional Barluenga−Valdes Cross-Coupling
Conditions vs. Green Conditions
We started with several mixtures of PEG-400, PEG-600, or
glycerol with water at different ratios (entries 1−3), and the
best yield of 51% was obtained with the PEG-400:H2O (2:1)
combination (entry 1). The use of glycerol instead of PEG led
to a decrease of the yield (entry 3). We then changed the
palladium source, Pd(0) vs Pd(II) (Table S1), and no
improvement of the yield of the reaction was observed. Next,
we turned our attention to the base parameter. Excitingly, the
use of K2CO3 as a base proved to be a good choice, and the
yield was significantly increased to 72% after conventional
heating at 120 °C for 3 h (entry 4). At this stage, we tried
microwave (MW) irradiation instead of conventional heating
(entries 5−8). We were pleased to observe that the MW-
promoted cross-coupling is advantageous in this trans-
formation when compared to the conventional heating; the
reaction proved much faster (20 min vs 3 h) with slightly
higher yields (entries 4 and 5). Following these results, fine-
tuning of the temperature parameter (entry 6) led us to find
the optimal conditions and provide the desired 1,1-diaryl-
ethylene 3a in a 86% yield (entry 6). To prove the importance
of MW irradiation in this coupling, we performed the reaction
under similar conditions to entry 6 but by using conventional
heating. In this case, compound 3a was formed in a moderate
yield of 50%, emphasizing the importance of MW irradiation.
The use of a 1:1 Pd:ligand ratio led to a decrease of the yield
from 86 to 62%. Performing the reaction only in PEG-400, or
only in water, led to a significant decrease of the yield (entries
7 and 8). Finally, we examined the effect of the ligand source
on this transformation. As one could expect, the use of
nonionic ligands such as Xphos or Sphos led to a dramatic
decrease of the yield (Table S1). However, the use of the
home-prepared salt form of the DavePhos ligand (MeDave-
Phos·CF3SO3),18 allowed the desired product 3a to be
obtained with a good yield (entry 9). For comparison, the
use of nonmodified Davephos led to a significant drop of the
yield (Table S1).
To initiate this study, 4-bromoanisole 1a and NTH 2a were
chosen as model substrates to explore the cross-coupling
reaction conditions (Table 1 and Table S1 in the Supporting
a
Table 1. Optimization of the Reaction Conditions
With the optimized conditions in hand, we investigated the
substrate scope of this cross-coupling reaction using a series of
aryl halides 1 and different NTHs 2. As presented in Scheme 2,
the reaction worked efficiently, affording the coupling products
in good to high yields (compounds 3a−x). Both electron-
donating and electron-withdrawing groups on the aryl halides
underwent the reaction to afford the desired products in good
to high yields (compounds 3a−c, 3f−i). Also, the reaction
proceeded successfully with different substituents at various
positions on the aryl halides, including a methoxy group at the
ortho position (3c). In addition, the reaction tolerated the use
of a functional group on the electrophilic partner such as
ketone, nitrile, and nitro groups (compounds 3f−i). It should
be noted that the coupling tolerates the use of heterocyclic
electrophilic partners, and the corresponding products were
obtained in good yields (compounds 3k−m). Next, we
evaluated the nature of the electrophilic partner (X = Cl,
OTf). No reaction was observed when aryl chlorides were used
under our standard conditions.
a
Reaction conditions: substrate 1a (0.25 mmol), NTH 2a (0.3
mmol), [Pd] catalyst (2 mol %), ligand (4 mol %), and base (0.55
mmol) in 2 mL of solvent were used in a sealed tube. MW heating
was applied. Performing the reaction in conditions similar to entry
10, in a sealed tube but without MW irradiation led to compound 3a,
in only 50% yield. Performing the reaction with a 1:1 ratio of
Pd:ligand led to 3a in 62% yield.
b
c
d
However, a good yield was obtained by using aryl triflate as
an electrophilic coupling partner, and compounds 3c, 3e, 3g,
and 3j were obtained in good yields. It is noteworthy that this
coupling is highly chemoselective and tolerates the presence of
Information). With respect to the choice of solvent, we
examined the use of polyethylene glycol (PEG), which was
employed in several organic reactions as a green alternative to
toxic organic solvents.13 Indeed, PEGs have been successfully
utilized as reaction media for metal-catalyzed coupling
reactions, such as a Sonogashira14 and Heck couplings,15
a chlorine atom on the aromatic ring, which is not the case for
19
́
the classical Barluenga−Valdes protocol (compound 3j).
B
DOI: 10.1021/acs.orglett.9b03310
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Letter
Scheme 2. Substrate Scope of the Green Cross-Coupling
between Electrophilic Partner 1 and NTH 2
Scheme 3. Utility in Synthesis: Applications of the Cross-
Coupling in PEG400/H2O to the Synthesis of Bioactive
Compounds
a
a
Reaction Conditions: substrate 1 (0.25 mmol), NTH 2 (0.3 mmol),
Pd2dba3·CHCl3 (2 mol %), XPhos−SO3Na (4 mol %), and K2CO3
(0.55 mmol) in 2 mL of solvent in a sealed tube, MW 100 °C, 20 min.
Circumventing this low reactivity of aryl chlorides would allow
for sequential couplings in fragment-based drug discovery or
late-stage coupling (vide infra) and therefore open the door for
more chemical space. Encouraged by these results, we further
examined the substrate scope with respect to the second
partner of the cross-coupling. The protocol was effective for a
variety of NTHs having electron-donating (3n) or electron-
withdrawing (3q−t) groups, and the desired products were
obtained in good to high yields. Notably, the reaction tolerates
the use of heterocyclic NTH (compounds 3u and 3v).
Importantly, cyclic and trisubstituted olefins (compounds 3w
and 3x) were obtained in satisfactory yields by using the
corresponding NTH derivatives. Further, we were interested to
demonstrate the synthetic utility of this methodology. As
shown in Scheme 3, the gram-scale synthesis (4.5 mmol, 1 g)
of compound 3a was realized with a satisfactory yield (73%).
IsoCombretastatin A-4 (isoCA-4)20 and isoAminocombre-
tastatin A-4 (isoNH2CA-4)3,21 are two stable isomers of natural
combretastatin A-4 with highly cytotoxic and antivascular
activity. With the optimized conditions in hand, the reactions
proceeded successfully in a one-step fashion, and the two
compounds isoCA-4 (3y) and isoNH2CA-4 (3z) were obtained
in good yields (Scheme 3b,c). Notably, and in comparison to
previous methods, we demonstrated in this application that our
new conditions tolerate the presence of free phenol or the
aniline group as a cross-coupling partner, without the need for
additional steps of protection/deprotection. Next, the
synthetic potential of this green catalytic cross-coupling was
well-illustrated by the formal synthesis of bexarotene (3aa,
Targretin), an approved drug for use as an RXR agonist, a drug
currently used in the treatment of cutaneous T-cell
lymphoma.22 This method is also suitable for the rapid
generation of bexarotene analogues in a one-step manner
(Scheme 3d), starting from commercial 6-bromo-1,1,4,4,7-
pentamethyl-1,2,3,4-tetrahydronaphthalene (1q). It is impor-
C
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tant to note that the reported formal synthesis of bexarotene
starting from an alkyne derivative requires the use of toxic
alkenylstannane intermediate, and the overall yield based on
alkyne is 39% after three steps.23
In comparison, our one-step procedure provides the desired
product in 60% yield. Finally, as we demonstrated above that
this protocol tolerates the presence of the chlorine atom on the
electrophilic partner (Scheme 2, compound 3j), we took
advantage of this observation to carry out the synthesis of a key
intermediate (3ac) of sertraline (Zoloft), which is an
antidepressant known as a selective serotonin reuptake
inhibitor (Scheme 3). The coupling was completely chemo-
selective, and the desired compound was obtained in a good
yield, which constitutes an alternative synthesis to already
described methods.24
Figure 1. Procedure of the catalytic system recycling at the top.
Efficiency of the recycled catalytic system at the bottom.
To illustrate the usefulness and the large applications of the
cross-coupling method, we tried to further extend the scope of
the reaction to 2-phenyl-3-(1-phenylvinyl)-benzo[b]thiophene
derivatives 4 (Scheme 4). Performing the coupling between 3-
To our delight, the first reusability trial and six successive
experiments were consistent in their yields (Figure 1). Only
after the eighth cycle, a slight decrease in yield was observed.
In conclusion, this work reports a Pd-catalyzed cross-
coupling reaction for the synthesis of 1,1-diarylethylene with a
large chemical diversity. The developed methodology employs
an ecocompatible and a green reaction, as it uses a
biodegradable solvent. This MW-promoted transformation
uses a homogeneous recyclable catalytic system Pd/PEG-400/
H2O, which worked efficiently for the synthesis of 1,1-
diaryethylene products.
Scheme 4. Substrate Scope of the Cross-Coupling between
3-Bromo-2-Phenylbenzo[b]thiophene 1 and NTH 2
Moreover, a variety of bioactive and approved compounds
could be successfully synthesized using this green methodology
with good to excellent yields. Finally, this catalytic system
could be reused up to seven cycles with no significant loss of
catalytic activity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03310.
Experimental procedures, compound characterizations,
1
and H and 13C NMR spectra (PDF)
bromo-2-(4-methoxyphenyl)benzo[b]thiophene 1 and NTH 2
derived from 3′,4′,5′-trimethoxyacetophenone under the
standard conditions led to the formation of the desired
product 4a in a low 35% yield. However, changing the Xphos·
SO3Na ligand for MeDavephos·CF3SO3, without any other
experimental change, led to a significant improvement of the
yield to 65%. To demonstrate the scope of this ligand, several
NTH and benzo[b]thiophene derivatives having electron-
donating or electron-withdrawing groups were coupled
successfully in good yield (compounds 4a−f).
Finally, we decided to examine the reusability of the solvent
and the catalytic system (Figures 1 and S1). The cross-
coupling reaction of bromoanisole 1a (1.0 mmol) and N-
tosylhydrazone 2a (1.2 mmol) was evaluated under our
standard conditions. After completion of the reaction, the
yellow reaction mixture was extracted five times with 2 mL of
pentane. The combined pentane extracts containing the
product mixture were then subjected to purification. The
PEG/H2O layer was then evaporated with a rotavapor for 10
min to remove traces of pentane and was used for a second
reaction by charging with the same substrates (bromoanisole,
N-tosylhydrazone, and K2CO3) without any addition of the
catalytic system (Pd2dba3 and Xphos·SO3Na).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: abdallah.hamze@u-psud.fr. (A.H.)
*E-mail: mouad.alami@u-psud.fr. (M.A.)
ORCID
Vincent Gandon: 0000-0003-1108-9410
Abdallah Hamze: 0000-0001-8425-1971
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors gratefully acknowledge the support of this project by
CNRS, Univ. Paris-Sud, and by La Ligue Nationale Contre le
■
́
Cancer through an Equipe Labellisee 2014 grant. The BioCIS
UMR 8076 laboratory is a member of the Laboratory of
Excellence LERMIT supported by a grant from Agence
Nationale de la Recherche (ANR-10-LABX-33). D.L. thanks
̀
́
the Ministere de l’Enseignement Superieur, de la Recherche et
de l’Innovation (MESRI) for her Ph.D. grant.
D
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REFERENCES
■
(1) (a) Naret, T.; Provot, O.; Alami, M.; Hamze, A. Asian J. Org.
Chem. 2017, 6, 1509−1518. (b) Prunet, J. Angew. Chem., Int. Ed.
2003, 42, 2826−2830. (c) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.;
Henry, S. S.; Jagdmann, G. E.; Coleman, D. S.; Johnson, M. P.; Andis,
S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett. 2004, 14, 3099−3102.
(2) Wagner, C. E.; Jurutka, P. W.; Marshall, P. A.; Groy, T. L.; van
der Vaart, A.; Ziller, J. W.; Furmick, J. K.; Graeber, M. E.; Matro, E.;
Miguel, B. V.; Tran, I. T.; Kwon, J.; Tedeschi, J. N.; Moosavi, S.;
Danishyar, A.; Philp, J. S.; Khamees, R. O.; Jackson, J. N.; Grupe, D.
K.; Badshah, S. L.; Hart, J. W. J. Med. Chem. 2009, 52, 5950−5966.
(3) Hamze, A.; Giraud, A.; Messaoudi, S.; Provot, O.; Peyrat, J.-F.;
Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. ChemMedChem 2009, 4, 1912−1924.
(4) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44−57.
(5) Peterson, D. J. J. Org. Chem. 1968, 33, 780−784.
(6) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611−3613.
(7) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833−4836.
(8) (a) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320−328.
́
(b) Lebel, H.; Davi, M.; Díez-Gonzalez, S.; Nolan, S. P. J. Org. Chem.
2007, 72, 144−149.
́
(9) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.
2007, 119, 5683−5686. (b) For review see, Barluenga, J.; Valdes, C.
́
Angew. Chem., Int. Ed. 2011, 50, 7486−7500. (c) Qiu, D.; Mo, F.;
Zhang, Y.; Wang, J. Adv. Organomet. Chem. 2017, 67, 151−219. (d)
For recent reviews, see: Xia, Y.; Wang, J. Chem. Soc. Rev. 2017, 46,
2306−2362.
(10) According to the CHEM21 selection guide of classical solvents,
dioxane was classified as a hazardous solvent, while toluene represents
a problematic solvent, see Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.;
McElroy, C. R.; Abou-Shehada, S.; Dunn, P. Green Chem. 2016, 18,
288−296.
(11) DCE is on the REACh authorization list and should not be
used anymore at the industrial scale in Europe, without authorization.
(12) Piontek, A.; Bisz, E.; Szostak, M. Angew. Chem., Int. Ed. 2018,
57, 11116−11128.
(13) PEG-400 is an inexpensive, biodegradable, nonhalogenated,
and nontoxic solvent, with an acute oral toxicity (LD50) of 26 800
mg/kg in rabbits.
(14) Zhao, H.; Cheng, M.; Zhang, J.; Cai, M. Green Chem. 2014, 16,
2515−2522.
(15) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S.; Reddy, N. R.
Org. Lett. 2002, 4, 4399−4401.
(16) Xu, C.; Huang, B.; Yan, T.; Cai, M. Green Chem. 2018, 20,
391−397.
(17) Yedage, S. L.; Bhanage, B. M. Green Chem. 2016, 18, 5635−
5642.
(18) For the prepartion of the MeDavePhos·CF3SO3 ligand, please,
see the experimental part in the supporting information.
(19) Roche, M.; Hamze, A.; Provot, O.; Brion, J. D.; Alami, M. J.
Org. Chem. 2013, 78, 445−454.
(20) Messaoudi, S.; Treguier, B.; Hamze, A.; Provot, O.; Peyrat, J.
F.; De Losada, J. R.; Liu, J. M.; Bignon, J.; Wdzieczak-Bakala, J.;
Thoret, S.; Dubois, J.; Brion, J. D.; Alami, M. J. Med. Chem. 2009, 52,
4538−4542.
(21) Aziz, J.; Brachet, E.; Hamze, A.; Peyrat, J.-F.; Bernadat, G.;
Morvan, E.; Bignon, J.; Wdzieczak-Bakala, J.; Desravines, D.; Dubois,
J.; Tueni, M.; Yassine, A.; Brion, J.-D.; Alami, M. Org. Biomol. Chem.
2013, 11, 430−442.
(22) Shen, D.; Yu, X.; Wu, Y.; Chen, Y.; Li, G.; Cheng, F.; Xia, L.
Expert Rev. Anticancer Ther. 2018, 18, 487−499.
(23) Yoshida, H.; Shinke, A.; Kawano, Y.; Takaki, K. Chem.
Commun. 2015, 51, 10616−10619.
́
(24) Thalen, L. K.; Zhao, D.; Sortais, J.-B.; Paetzold, J.; Hoben, C.;
̈
Backvall, J.-E. Chem. - Eur. J. 2009, 15, 3403−3410.
E
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