Catalytic three-component one-pot reaction of hydrazones, dihaloarenes, and amines

Article abstract of DOI:10.1021/ol303194s

A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and various primary and secondary amines was devised, producing nitrogen-containing 1,1'-diarylethylenes in good yields. The two C-C and C-N bonds formed through this

Full text of DOI:10.1021/ol303194s

ORGANIC
LETTERS
2013
Vol. 15, No. 1
148–151
Catalytic Three-Component One-Pot
Reaction of Hydrazones, Dihaloarenes,
and Amines
Maxime Roche, Abdallah Hamze,* Jean-Daniel Brion, and Mouad Alami*
Univ Paris-Sud, CNRS, BioCIS UMR 8076, LabEx LERMIT, Laboratoire de Chimie
ꢀ
Therapeutique, Faculte de Pharmacie, 5 Rue J. B. Clement, Chatenay-Malabry,
F-92296, France
ꢀ
ꢀ
^
abdallah.hamze@u-psud.fr; mouad.alami@u-psud.fr
Received November 20, 2012
ABSTRACT
A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and various primary and secondary amines was
devised, producing nitrogen-containing 1,10-diarylethylenes in good yields. The two CꢀC and CꢀN bonds formed through this coupling have
been catalyzed by a single Pd-catalyst in a one-pot fashion.
The search for practically simple and highly efficient
methods to access complex structures is an ongoing chal-
lenge for the organic chemist. In this context, transition-
metal-catalyzed multicomponent reactions (MCRs), most
notablyusingpalladium, allowthe efficientconstruction of
elaborate molecules from simple precursors, in a single
step without isolation of any intermediate.1 In these
types of reactions, various bonds can be successively
created in one operation, and it is of great interest when
a single catalyst is able to initiate two or more mecha-
nistically distinct reactions in a multicomponent trans-
formation (autotandem catalysis).2 Such a process is
particularly attractive in view of ecological and eco-
nomical concerns (e.g., catalyst and solvent economy,
operational simplicity, etc.).
valuable and readily available reagents in CꢀC4 and
Cꢀheteroatom5 bond-forming reactions through metal-
catalyzed processes. Because there are many different
reactions that can be catalyzed by the same catalyst, great
potential exists to link these reactions in a sequence.
Recently, N-tosylhydrazones containing an amino group
have been coupled with o-dihalobenzenes6 through an
efficient sequential CdC bond formation and intramole-
cular CꢀN cross-coupling to produce phenanthridine and
acridine derivatives.
Although significant progress has been achieved on
sequential transformations of N-tosylhydrazones through
autotandem catalysis,7 to our knowledge, only one study
(4) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel,
P.; Amar, F.; Valdes, C. Chem.;Eur. J. 2008, 14, 4792. (c) Barluenga, J.;
In recent years, N-tosylhydrazones have attracted ex-
tensive attention because of their various useful ap-
plications in organic synthesis.3 In particular, they are
ꢀ
Escribano, M.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2010, 49,
6856. (d) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011,
133, 3296.
(5) (a) Feng, X.-W.; Wang, J.; Zhang, J.; Yang, J.; Wang, N.; Yu,
X.-Q. Org. Lett. 2010, 12, 4408. (b) Hamze, A.; Treguier, B.; Brion, J.-D.;
€
(1) (a) Domling, A. Chem. Rev. 2006, 106, 17. (b) Balme, G.;
Bossharth, E.; Monteiro, N. In Metal-catalyzed Multicomponent Reac-
ꢀ
Alami, M. Org. Biomol. Chem. 2011, 9, 6200. (c) Barluenga, J.; Tomas-
ꢀ
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Gamasa, M.; Aznar, F.; Valdes, C. Eur. J. Org. Chem. 2011, 2011, 1520.
tions. In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; John
Wiley & Sons: Weinheim, Germany, 2006; pp 224ꢀ271. (c) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234.
(2) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.;Eur. J. 2009, 15,
12168.
~
ꢀ
(6) (a) Barluenga, J.; Quinones, N.; Cabal, M.-P.; Aznar, F.; Valdes,
C. Angew. Chem., Int. Ed. 2011, 50, 2350. (b) Huang, Z.; Yang, Y.; Xiao,
Q.; Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2012, 6586–6593.
(7) (a) Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.; Zhang, Y.; Wang,
J. Org. Lett. 2011, 13, 968. (b) Ye, F.; Shi, Y.; Zhou, L.; Xiao, Q.; Zhang,
Y.; Wang, J. Org. Lett. 2011, 13, 5020. (c) Zhou, L.; Xiao, T.; Dong, X.
Org. Biomol. Chem. 201210.1039/C2OB26867A.
ꢀ
(3) (a) For reviews, see: Barluenga, J.; Valdes, C. Angew. Chem., Int.
Ed. 2011, 50, 7486. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41,
560.
r
10.1021/ol303194s
Published on Web 12/18/2012
2012 American Chemical Society

compound 5a, together with symmetrically disubstituted
byproduct 6a (entry 1). Products derived from undesired
side reactions, such as mono- or diamination of 2a, were
not observed,13 clearly suggesting that the CdC bond
formation occurred faster than C;N cross-coupling. Ex-
amination of reaction parameters revealed that increasing
the amount of base to 3.5 equiv slightly raised the yield of
4a (entry 2). We were delighted to find that the use of a 1/1
ratio of p-anisidine 3a and hydrazone 1a leads to improve-
ment in performance of this MCR, and 4a was isolated in a
72% yield (entry 3). Finally, fine-tuning of the temperature
and the reaction time led to 4a in an excellent isolated yield
of 92% (entry 5), showing that this MCR is viable and
indeed highly selective.
Scheme 1. MCRs of Tosylhydrazones with Dihaloarenes and
Amines through Palladium-Catalyzed Carbene Migratory
Insertion and CꢀN Cross-Coupling
has explored MCRs of N-tosylhydrazones with an aryl
halide and a terminal alkyne.8
As a continuation of our interest in the 1,1-diarylethyl-
ene unit synthesis,9 as a promising cytotoxic agent,10
combined with the development of MCRs,11 we report
here a novel Pd-catalyzed three-component coupling be-
tween N-tosylhydrazones 1, dihaloarenes 2, and amines 3
leading to a faster CdC bond formation and an efficient
intermolecular C;N cross-coupling (Scheme 1). The val-
ue of this MCR is in its brevity and ease of synthesis of the
desired substrates 4, as well as in the palladium-based
catalytic system preventing both the formation of symme-
trical disubstituted byproducts from dihaloarenes 2 and
reaction of amines 3 with N-tosylhydrazones 1.5b In addi-
tion, the availability of amines and dihaloarenesmakes this
approach sufficiently diversity-oriented, thus fulfilling the
recent demand for the generation of large combinatorial
chemical libraries.
We began the exploration of this MCR process with a
model reaction between N-tosylhydrazone 1a (1.2 equiv),
4-chloroiodobenzene 2a (1 equiv), and p-anisidine 3a
(1 equiv) using our previously optimized protocol:12 PdCl2-
(MeCN)2 (2 mol %), Xphos (4 mol %), and NaOtBu
(3 equiv) in fluorobenzene (Table 1). Under these condi-
tions, the desired product 4a, formed through two consecu-
tive processes, CꢀC cross-coupling and intermolecular
CꢀN bond forming reactions, was isolated in a moderate
47% yield after 14 h at 110 °C. Careful analysis by NMR
showed a significant amount of C;C monocoupling
Table 1. Optimization of the One-Pot Reaction Conditionsa
ratiob
aniline
(equiv)
time (h)/
yield of
4a (%)c
entry
temp °C
4a
5a
6a
1
2
3
4
5
1.0
1.0
1.2
1.2
1.2
14/110
14/110
14/110
6/110
62
33
17
0
5
47
72
11
8
55d
72d
75d
92d,f
92
94
0
6
0e
6/120
100
0
a The reactions were carried out in a sealed tube with hydrazone 1a
(1.2 mmol), 2a (1 mmol), 3a (x equiv), PdCl2(MeCN)2 (2 mol %), Xphos
(4 mol %), and NaOtBu (3 equiv) at mentioned temperature in PhF (4.0
mL). b Ratio was determined by 1H NMR in the crude mixture; see
Supporting Information. c Yield of isolated product 4a. d 3.5 equiv of
1
NaOtBu were used. e Not detected by H NMR in the crude reaction.
f Using Pd2(dba)3, Pd(OAc)2, or Pd(acac)2 in place of PdCl2(MeCN)2
furnished 4a in 51%, 78%, and 69% yield, respectively.
Next, the substrate diversity and the efficiency of the
PdCl2(MeCN)2/Xphos catalytic system on this three-
component coupling were examined with various hydra-
zone, dihaloarene, and amine components (Table 2). In-
itially, the scope of the reaction was examined with respect
to the dihalogenated aromatic system and the nature of
amine, including primary and secondary anilines as well as
aliphatic amines. Reactions with para-, meta-, and ortho-
anisidines 3aꢀc proceeded efficiently to form the expected
products 4aꢀc in good yields (entries 1ꢀ3). The electronic
nature of the substituents on the anilines did not have
a significant effect on the reaction. Electron-donating
or -withdrawing substrates all reacted to give the
(8) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010,
132, 13590.
(9) (a) Treguier, B.; Hamze, A.; Provot, O.; Brion, J. D.; Alami, M.
Tetrahedron Lett. 2009, 50, 6549. (b) Hamze, A.; Veau, D.; Provot, O.;
Brion, J. D.; Alami, M. J. Org. Chem. 2009, 74, 1337. (c) Brachet, E.;
Hamze, A.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12,
4042. (d) Hamze, A.; Brion, J.-D.; Alami, M. Org. Lett. 2012, 14, 2782.
(10) (a) 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. (b) Hamze, A.; Rasolofonjatovo, E.; Provot, O.; Mousset, C.;
Veau, D.; Rodrigo, J.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.;
Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. ChemMedChem 2011, 6,
2179.
(11) (a) Russo, O.; Messaoudi, S.; Hamze, A.; Olivi, N.; Peyrat, J. F.;
Brion, J. D.; Sicsic, S.; Berque-Bestel, I.; Alami, M. Tetrahedron 2007,
63, 10671. (b) Audisio, D.; Messaoudi, S.; Brion, J. D.; Alami, M. Eur. J.
Org. Chem. 2010, 1046.
(12) Roche, M.; Hamze, A.; Provot, O.; Brion, J. D.; Alami, M.
J. Org. Chem. 2012jo-2012-023268.
(13) For recent review on Pd-catlayzed amination, see: Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2011, 2, 27.
Org. Lett., Vol. 15, No. 1, 2013
149

Table 2. Scope of One-Pot, Three-Component Reaction of N-Tosylhydrazones with Dihalogenated Arenes and Aminesa
a The reactions were carried out in a sealed tube with hydrazones 1 (1.2 mmol), aryl halides 2 (1 mmol), amines 3 (1.2 mmol), PdCl2(MeCN)2 (2 mol %),
Xphos (4 mol %), and NaOtBu (3.5 equiv) at 120 °C in PhF (4.0 mL). b Isolated yield of product 4. c Aniline 3a was added after 1 h of coupling between 1a and
2d. d 4r was obtained by acidic hydrolysis of N-aryl imine adduct in a THF/HCl solution; see Supporting Information.
corresponding products 4aꢀg in good yields (entries 1ꢀ7).
In the same manner, switching the halide group from the
para-position tothemeta- or ortho-positiononthearylring
of 2 does not significantly influence the overall yield of the
reaction, demonstrating that steric factors have little influ-
ence on the rate of CdC and C;N bond formation
(compare entries 1 and 4, 5). Interestingly, this three-
component coupling was found also to proceed success-
fully with heterocyclic amines, such as 5-aminoquinoline
3f, furnishing 4h in a 65% yield (entry 8). To illustrate
the usefulness of this MCR, we prepared from hydra-
zone 1a and dihalogenated aromatic compound 2g the
150
Org. Lett., Vol. 15, No. 1, 2013

1,1-diarylethylene 4i in one step, which could be
regarded as an analogue of antivascular isoNH2-
combretastatin-A414 (entry 9).
intermediates 1. After some experimentation, we were
pleased to successfully achieve a one-pot MCR protocol.
In this process, carbonyl compounds 7a,b and sulfonyl
hydrazide were stirred in PhF for 2 h at 90 °C, and then all
the reagents were added to the reaction mixture. Following
this procedure, yields similar to those from hydrazones 1
were obtained (Scheme 2).
Next we examined the efficiency of this MCR
with secondary anilines. Thus, reactions with diphenyl-
amine 3g, N-methylaniline 3h, indoline 3i, and 1,2,3,4-
tetrahydroquinoline 3j all reacted to give the corresponding
coupling products with yields ranging from 55 to 85%
(entries 10ꢀ14). It is intersting to note that this reaction
can be applied successfully to a trihalogenated aromatic
system. A good yield of 4o was obtained when using 1,3-
dichloro-5-iodobenzene 2e as a coupling partner. Accord-
ingly, one CdC bond and two C;N bonds were formed
efficiently, representing an average 90% yield for each of
the three steps of this MCR (entry 15). In addition, we
found also that our coupling conditions proved also to be
successful with dihalogenated heteroaromatic partner 2f;
in this case, compound 4p was obtained in a satisfactory
51% yield (entry 16).
Scheme 2. One-Pot MCR from Carbonyl Compounds 7a,b
Furthermore, we investigated whether it might be pos-
sible to carry out this MCR with aliphatic amines. To our
delight, satisfactory to good yields were obtained with
primary and secondary amines, such as n-octylamine 3k,
dibutylamine 3l, and 1-methylpiperazine 3m (entries
17ꢀ19). Extending this MCR to include benzophenone
imine 3n as an ammonia surrogate allows the formation of
the corresponding N-aryl imine adduct, which was then
hydrolyzed to furnish the desired aniline 4t with an overall
acceptable yield of 45% (entry 20).
To broaden the substrate scope, we further investigated
this MCR with respect to hydrazones 1. Gratifyingly, as
depicted in Table 2 (entries 21ꢀ28), the entire coupling
proceeded cleanly and selectively in good to excellent yields.
Functionalized N-tosylhydrazones containing electron-
donating or -withdrawing groups proved to be suitable
substrates in this MCR. It is noteworthy that the chloro
substituent on the phenyl ring of hydrazone 1c and 1d was
tolerated, enabling further metal-catalyzed functionaliza-
tion processes (entries 22ꢀ23).
In conclusion, we have succeeded in developing a novel
three-component reaction of N-tosylhydrazones, polyha-
loarenes, and amines, allowing efficient sequential CdC
bond formation and intermolecular C;N cross-coupling.
Our optimized conditions allowed us to prepare 1,1-
diarylethylene derivatives 4 of biological interest that
accommodated a wider combination of nitrogen substitu-
ents at the aromatic ring. Good to excellent yields were
obtained using a wide range of amine partners, including
primary and secondary anilines as well as aliphatic amines.
The process is very general with regard to other coupling
partners, the tosylhydrazone and the dihalogenated aro-
matic system. Moreover, it is not necessary to isolate the
tosylhydrazone partner, and the reaction can be conducted
in a one-pot manner directly from the carbonyl compound.
All of these features make this simple and general MCR of
broad utility for the synthesis and development of new
medicinal agents. Further studies on the scope and syn-
thetic applications are in progress.
The effectiveness of our protocol was also demonstrated
with N-tosylhydrazones 1g,h containing a secondary car-
bon atom R to the hydrazone function to provide tetra-
substituted olefins 4z and 4aa having a cycloalkylidene
unit in good yields (entries 26 and 27). Finally, cyclic
N-tosylhydrazone1i, whichis derivedfrom cyclooctanone,
also undergoes smooth MCR to afford 4ab in 68% yield
(entry 28).
As sulfonyl hydrazones could be simply prepared by
mixing relative sulfonyl hydrazides and the carbonyl com-
pounds, we investigated whether the reaction could be
carried out in a one-pot fashion directly from carbonyl
compounds 7, avoiding the isolation of the tosylhydrazone
Acknowledgment. The authors gratefully acknowledge
support of this project by CNRS. Our laboratory (BioCIS
UMR 8076) is a member of the laboratory of excellence
LERMIT supported by a grant from ANR (ANR-10-
LABX-33).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) 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.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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