Direct access to pyrazolo(benzo)thienoquinolines. Highly effective palladium catalysts for the intramolecular C-H heteroarylation of arenes

Article abstract of DOI:10.1039/c2cc37905h

A short and atom-efficient strategy to obtain a series of pyrazolo(benzo)thienoquinolines is developed. Alternative catalytic systems for the key intramolecular direct heteroarylation of arenes are presented and include the first example of C-H (hetero)arylation of (hetero)arenes catalyzed by very low catalyst loadings of a palladium source.

Full text of DOI:10.1039/c2cc37905h

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Direct access to pyrazolo(benzo)thienoquinolines.
Highly effective palladium catalysts for the
intramolecular C–H heteroarylation of arenes†
Cite this: Chem. Commun., 2013,
49, 1413
Received 29th August 2012,
Accepted 2nd January 2013
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´
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Fatima Churruca, Susana Hernandez, Marıa Perea, Raul SanMartin* and
Esther Dom´ınguez*
DOI: 10.1039/c2cc37905h
www.rsc.org/chemcomm
A short and atom-efficient strategy to obtain a series of pyrazolo-
Transition-metal catalyzed C–H bond functionalization has emer-
(benzo)thienoquinolines is developed. Alternative catalytic systems for ged as an important alternative to conventional cross-coupling reac-
the key intramolecular direct heteroarylation of arenes are presented tions of metalated aromatic reagents because of its advantages in
and include the first example of C–H (hetero)arylation of (hetero)arenes terms of atom- and step economy as well as synthetic efficiency.6 While
catalyzed by very low catalyst loadings of a palladium source.
palladium catalyzed C–H arylation of heterocycles has been extensively
studied, examples of intramolecular heteroarylation of arenes are
Much of the success of the drug discovery process relies on scarce in the literature,7 and only the pioneering work of Ames and
selective and rational design of novel therapeutic agents.1 In co-workers7a,b had been reported at the time we started our research.
this context, privileged structures have proven to be valuable
In view of these scattered precedents, we considered to explore
scaffolds in medicinal chemistry.2 As shown in Fig. 1, pyrazole the intramolecular heteroarylation of arenes as a novel and versatile
and benzothiophene are two examples of privileged structures method in organic synthesis as well as in material sciences. Thus,
present in small molecule modulators of diverse targets.3 herein we present a straightforward, atom-efficient and general
Considering our experience in the design of general strategies synthetic strategy to obtain a series of pyrazolo(benzo)thieno-
that provide access to fused polyheteroaromatic scaffolds,4 we quinolines 1 that involves intramolecular C–H heteroarylation
envisioned the application of this concept to the construction of of arenes as the key step.
a novel core skeleton 1, synthesized through the combination of
1-Aryl-5-(benzo)thienylpyrazoles 2 were readily prepared in a two-
benzothiophene and pyrazole moieties. In addition to its potential step sequence8 consisting of aminomethylenation of commercially
pharmacological properties, such a polyheterocyclic framework is available 2-acetyl-3-bromo(benzo)thienes with N,N-dimethylform-
of interest because of its promising applications in the develop- amide dimethyl acetal (DMFDMA), followed by a tandem amine
ment of novel functional organic materials.5
exchange–intramolecular heterocyclization with a number of aryl
hydrazines (for detailed information see ESI†). Then, we started to
explore the feasibility of performing the desired intramolecular
heterocyclization. In this context, we had two main features to
consider: (1) the lack of a directing group which coordinates to
the metal centre usually required for the selective and efficient
activation of the ubiquitously available C–H bond;6 and (2) the
possible poisoning and deactivation of the palladium catalyst by
sulfur due to its strong complexation ability to the metal.9 Thus, a
series of preliminary assays using common palladium sources as
catalysts were carried out on pyrazole 2a and we found out that
the use of ligandless Pd(OAc)2 with K2CO3, LiCl and nBu4NBr in
DMF afforded satisfactorily quinoline 1a.10
With the establishment of a viable reaction system, the generality
and scope of our protocol were further extended to a series of
benzothienylaryl- as well as thienylarylpyrazoles 2 with different
arene substitution patterns. As shown in Scheme 1, the optimized
reaction conditions proved to be remarkably general: the moderate
to good yields obtained in most of the range of models assayed
feature a minor dependence on the electronic nature of the
Fig. 1 Pyrazole and benzothiophene core containing bioactive molecules.
Department of Organic Chemistry II, Faculty of Science and Technology, University
of the Basque Country, 48940 Leioa, Spain. E-mail: raul.sanmartin@ehu.es;
Fax: +34 946012748; Tel: +34 946015435
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C spectra of all new compounds.
See DOI: 10.1039/c2cc37905h
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Chem. Commun., 2013, 49, 1413--1415 1413

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Table 1 Selected assays for the direct arylation of benzothienylphenylpyrazole
2a using pincer catalysts
Entry Cat (mol%) Base (equiv.) Solvent T (1C) Time (h) Aa (%) Ba (%)
1b
2
1
1
1
1
K2CO3 (5)
DMF
130 15
140 22
140 22
140 20
32
27
62
71
Na2CO3 (2.5) DMF
K2CO3 (1.5) DMA
KOAc (2.5) PEG-
400
38
86
41
3c
4
d
d
5
6
7
8
9
1
1
1
0.5
0.2
KOAc (1.5) Toluene 140 16
—
83
86
85
81
—
76
92
61
55
KOAc (2.5) DMF
KOAc (1.5) DMA
KOAc (1.5) DMA
KOAc (1.5) DMA
140 16
130 16
130 18
130 48
Scheme 1 Synthesis of pyrazolo(benzo)thienylquinolines 1.
substituents in the arene. In addition, comparison of the results for
both heterocycles (thiophene vs. benzothiophene) suggests that
slightly better yields were obtained for the benzothienyl derivatives,
probably due to the presence of the additional aromatic ring. Hence,
a
Isolated yield. Reaction conditions: 2a (0.2 mmol), solvent (2 mL),
sealed tube under Ar. b nBu4NBr and LiCl were used as additives.
c
d
Pivalic acid was used as an additive. Recovery of starting material.
an attractive, general three-step synthetic route to novel pyrazolo- activity of both pincer complexes in promoting the desired C–H
(benzo)thienoquinolines 1 was developed. The key intramolecular heteroarylation in the presence of KOAc and various polar solvents
C–H arene heteroarylation reaction, which proceeds smoothly under (Table 1). The best results were obtained using DMA as solvent: with
a readily available catalytic system, ligandless Pd(OAc)2, constitutes a only 1 mol% of a palladium complex and using a slight excess of
suitable, atom-economical method which employs commercially base target product 1a was isolated in very good yields (entry 7).
available starting materials such as N-arylhydrazines, whose deriva-
It is also worth mentioning the significant 71% yield obtained
tives are otherwise tedious to prepare.
with catalyst 3a in PEG-400 (entry 4), which constitutes an alter-
In the last few years we11 and others12 have prepared palladium native environmentally friendly reaction medium.14
pincer-type complexes and applied them as efficient catalysts in a
The presence of the 2-bromo substituent was necessary for the
variety of chemical transformations. Their exceptional catalytic per- reaction to occur, since non-brominated 1-phenyl-5-(thiophen-2-yl)-
formance, derived mainly from their unique balance of stability vs. 1H-pyrazole failed to couple oxidatively.10d The catalyst loading
reactivity, makes them an appealing and important tool in organic required to effect the reaction was next evaluated. Although pincer
synthesis. To our surprise, and despite the high number of studies of 3b resulted to be less active in lower amounts, it was possible to
pincer catalysts in the Heck reaction, the C–H (hetero)arylation of further decrease the loading of complex 3a down to 0.2 mol% while
(hetero)arenes mediated by palladium pincer complexes remains still maintaining a good yield of the coupled product (entry 9). It
unknown, as well as any other C–H functionalization, except for the should be pointed out that this value represents the lowest catalyst
´
publications of Selander and Szabo on the selective borylation of loading achieved so far for such intramolecular coupling of (hetero)-
alkenes and allylation of imines.12b Moreover, the reports dealing with aryl halide with a nonfunctionalized ortho-aromatic position, a
pincer catalysts involve either method development or mechanistic reaction that usually requires 5–10 mol% of a catalyst.5a
investigations. To date, there is only one synthetic application for the
An optimal loading of 1 mol% was established as the most
preparation of relatively complex molecules and/or natural products.13 effective for further studies on the scope of the reaction. The
Encouraged by the excellent results of our investigations on the application of the optimized conditions to a series of (benzo)-
application of PCP and PCN type palladium complexes as novel and thienylarylpyrazoles 2 led to the corresponding quinolines 1 in good
alternative catalytic systems in various cross-coupling reactions,11a,b to excellent yields (Scheme 1). The reaction seems to be again
we considered to explore their potential as synthetic tools in our marginally affected by the substituents on the aromatic ring and
approach for the construction of the pyrazolo(benzo)thienyl- safe for the slight dependence of complex 3a on the nature of
quinoline framework. Thus, we next proceeded to evaluate the the heterocycle, this new simple protocol proved to be exceptional
catalytic performance of catalysts 3a–b in the direct intramolecular in providing access to pyrazolo(benzo)thienoquinolines 1. The pre-
heteroarylation of arenes, which, to the best of our knowledge, sence of palladium nanoparticles (average size 8 nm) was confirmed
would constitute the first example of a pincer catalyzed direct arene by TEM analysis. A relatively long induction time and a meaningful
arylation or heteroarylation. When we subjected pyrazole 2a to the sigmoidal kinetic curve were observed in a preliminary kinetic study.
above optimized conditions using complex 3a instead of Pd(OAc)2 as These facts, along with the mercury drop test and a moderate
the catalyst, quinoline 1a was isolated in 32% yield. Encouraged by recycling of the organic layer containing the active species, suggested
this first attempt, further optimization assays by varying the the participation of Pd(0) species.10a–c Although more mechanistic
base–solvent system were carried out and revealed the excellent studies should be carried out, we tentatively propose that a
c
1414 Chem. Commun., 2013, 49, 1413--1415
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the University of the Basque Country for a predoctoral scholar-
ship. Finally, technical and human support provided by SGIker
(UPV/EHU, MICINN, GV/EJ, ESF) is gratefully acknowledged.
Notes and references
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4 For selected references see: (a) R. Olivera, R. SanMartin, F. Churruca
Scheme 2 Mechanistic proposal for the formation of derivatives 1 mediated by
palladacycles 3.
´
and E. Domınguez, J. Org. Chem., 2002, 67, 7215; (b) M. Carril,
´
R. Sanmartin, E. Domınguez and I. Tellitu, Tetrahedron, 2007, 63, 690.
5 For selected reports on the application of fused polyheterocyclic com-
pounds in material sciences see: (a) A. Chaskar, H.-F. Chen and K.-T.
Wong, Adv. Mater., 2011, 23, 3876; (b) P. Dutta, W. Yang, S. H. Eom,
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Li, D. Liu, F. Shen, D. Ma, Z. Wang, T. Feng, Y. Xu, B. Yang and Y. Ma,
Scheme 3 Intermolecular direct arylation of thiophenes 4.
steady release of Pd nanoparticles by pincers 3 under reaction
conditions is the key to the reaction outcome (Scheme 2).
Given the excellent catalytic or pre-catalytic activity featured
by palladacycles 3 to perform this arene C–H heteroarylation,
and considering that the heteroaromatic sp2 direct arylation
catalyzed by palladium pincer complexes still remains unex-
plored, we were intrigued to carry out related pioneering
studies on the direct arylation of thiophene derivatives.
As shown in Scheme 3, the coupling of 2-substituted thiophenes
with bromobenzene provided the corresponding 5-phenylthio-
phenes regioselectively with a catalyst loading as low as 0.2 mol%.
It should be remarked that comparable low amounts of catalyst
in such reactions have been previously achieved by Doucet and
co-workers,15 but whereas significant excess of a thiophene
coupling partner was required in their procedures, our protocol
features equimolar coupling reagents, a slight excess of base
and proceeds without any additional additive.
´
Adv. Funct. Mater., 2012, 22, 2797; (d) R. D. Costa, E. Ortı, H. J. Bolink, F.
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8 This tandem has been successfully applied by our group to the
synthesis of different heterocycles. For a recent example see:
´
´
S. Hernandez, I. Moreno, R. SanMartin, M. T. Herrero and
E. Domınguez, Org. Biomol. Chem., 2011, 9, 2251.
´
´
´
In summary, we have successfully developed a short and atom-
efficient strategy to novel pyrazolo(benzo)thienoquinolines 1. Three
complementary methodologies of general applicability for the key
intramolecular C–H heteroarylation of arenes are presented and
include the use of readily available palladium sources, such as
Pd(OAc)2 as well as phosphine-based palladium pincer complexes.
The latter procedure constitutes the first example of heteroarylation
of arene C–H bonds mediated by such a low amount of a palladium
precatalyst. Additionally, preliminary results demonstrate that
palladacycles 3 also act efficiently in the direct arylation of aromatic
heterocycles. The multiple advantages associated with the use of
relatively low loadings of palladium cannot be ignored, above all in
the field of medicinal chemistry. Further studies on this reaction
focusing on the optimization of catalyst loadings are ongoing and
will be reported in due course.
9 Z. Vıt, H. Kmentova, L. Kaluˇza, D. Gulkova and M. Boaro, Appl.
Catal., B, 2011, 108–109, 152.
10 (a) For a comparison between several reactions conditions, TEM images of
the DMA–H2O layer after extraction with ethyl acetate, kinetic curves for
the reaction leading to 1a and recycling assays, see ESI;† For the use of
palladium nanoparticles in direct arylation reactions, see: (b) D. Saha,
L. Adak and B. C. Ranu, Tetrahedron Lett., 2010, 51, 5624; (c) Y. Huang,
Z. Lin and R. Cao, Chem.–Eur. J., 2011, 17, 12706; (d) In addition, a number
of oxidants (FeCl3, VOF3, PIFA, Ag2O, TiCl4, Cu(OTf)2, MoCl5, Pd(OAc)2-
Cu(OAc)2, inter alia) also failed to promote this oxidative coupling.
´
11 (a) F. Churruca, R. SanMartin, I. Tellitu and E. Domınguez, Tetra-
´
hedron Lett., 2006, 47, 3233; (b) B. Ines, R. SanMartin, F. Churruca,
E. Dominguez, M. K. Urtiaga and M. I. Arriortua, Organometallics,
2008, 27, 2833; (c) G. Urgoitia, R. SanMartin, M. T. Herrero and
´
E. Domınguez, Green Chem., 2011, 13, 2161.
12 (a) D. Morales-Morales and C. M. Jensen, The Chemistry of Pincer
Compounds, Elsevier, Amsterdam, 2007; (b) N. Selander and
K. Szabo, Chem. Rev., 2011, 111, 2048 and references therein.
13 Z. Li, Y. Gao, Y. Tang, M. Dai, G. Wang, Z. Wang and Z. Yang, Org.
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´
This research was supported by the University of the Basque 14 J. Chen, S. K. Speat, J. G. Huddleston and R. D. Rogers, Green Chem.,
2005, 7, 64.
Country/Basque Government (Projects GIC10/52/IT-370-10,
S-PC10UN10 and UFI QOSYC 11/22) and the Spanish Ministry
15 (a) A. Battace, M. Lemhadri, T. Zair, H. Doucet and M. Santelli, Adv.
Synth. Catal., 2007, 349, 2507; (b) J. Roger, F. Poˇzgan and H. Doucet,
of Science and Innovation (CTQ2010-20703). S.H. thanks
Green Chem., 2009, 11, 425.
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This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1413--1415 1415