One-pot direct C-H arylation of arenes in water catalysed by RuCl 3·nH2O-NaOAc in the presence of Zn

Article abstract of DOI:10.1039/c3cc43452d

The inexpensive and commercially available catalytic system RuCl ₃·nH₂O-NaOAc-Zn is active in water for the direct C-H arylation of arenes with aryl/heteroaryl chlorides. The reaction can be accelerated by the use of microwave irradiation and can also be scaled up to a multi-gram scale with excellent isolated yields.

Full text of DOI:10.1039/c3cc43452d

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One-pot direct C–H arylation of arenes in water
catalysed by RuCl3ꢀnH2O–NaOAc in the
presence of Zn†
Cite this: Chem. Commun., 2013,
49, 8320
Received 9th May 2013,
Accepted 5th June 2013
a
a
b
´
Luis A. Adrio,z Jose Gimeno* and Cristian Vicent
DOI: 10.1039/c3cc43452d
www.rsc.org/chemcomm
The inexpensive and commercially available catalytic system oxide ligands in the presence of M2CO3, have been widely used.3,4 It
RuCl3ꢀnH2O–NaOAc–Zn is active in water for the direct C–H arylation is presently well known that the cooperative action of the carbonate
of arenes with aryl/heteroaryl chlorides. The reaction can be accelerated and carboxylates or phosphine oxides as C–H bond activation
by the use of microwave irradiation and can also be scaled up to a partners of ruthenium(II) catalysts favours the formation of key
multi-gram scale with excellent isolated yields.
intermediate cyclometallated species.5
The catalytic direct arylation procedure itself constitutes an
Transition metal catalyzed direct arylation via direct activation– important contribution to the processes in the context of green
functionalization of C–H bonds has emerged as an efficient chemistry. However, the ruthenium catalysed processes proceed at
methodology for C(sp2)–C(sp2) bond forming reactions using high temperature and, hence, require the use of organic solvents with
organic halides as electrophiles and heterocyclic arenes as high boiling point, typically toluene or NMP (N-methyl-2-pyrrolidone).
pronucleophilic substrates (Scheme 1). This synthetic route In the search for more benign solvents and reaction conditions,
provides an appealing alternative to traditional cross-coupling Dixneuf, Bruneau and co-workers, have recently reported that the
processes using stoichiometric amounts of usual organometal- [RuCl2(Z6-p-cymene)]2–4KO2CR system in the presence of K2CO3
lic reagents (Li, Mg, Zn, B, and Sn), avoiding the generation of catalyses the reaction of heteroarylbenzene derivatives with aryl and
less toxic wastes since the acid HX is the unique by-product.
heteroaryl halides (2-phenylpyridine and phenylchloride) using water
Although regioselective functionalization of arenes via C–H as the reaction medium.6 Remarkably, it was found that the catalytic
activation (mainly by rhodium and palladium catalysts) is well- activity in water7 is higher than in organic solvents (NMP) allowing
documented,1 ruthenium based versions have also shown excellent the transformation to be performed even at room temperature.6
catalytic activity both in terms of efficiency and regioselectivity.2 When the ruthenium(II) complex [RuCl2(PPh3)(p-cymene)] is used as
In this regard, catalytic systems generated from the ruthenium(II) a catalyst, ortho-monoarylation derivatives are formed selectively.7b
dimers [RuCl2(Z6-arene)]2 (arene = p-cymene, benzene) associated Following on from seminal contributions on the use of the commer-
with N-heterocyclic carbene, carboxylate, phosphine or phosphine cially available RuCl3ꢀnH2O as a catalyst for the direct arylation of
arenes,8 herein we report the catalytic activity of the RuCl3ꢀnH2O–Zn–
NaOAc system in the direct arylation of 2-phenylpyridine with aryl
chlorides in water via C–H bond functionalization (Scheme 2). The
following features of this catalytic system are remarkable: (i) this is
the first example of a RuCl3ꢀnH2O based catalytic system active with
aryl chloride substrates in water,9 (ii) a high regioselectivity is achieved
giving rise to mono-/diarylated ratios up to 90/10%, (iii) it represents
an easy, efficient and one-pot catalytic procedure using inexpensive
Scheme 1 Direct arylation reactions.
aryl chlorides and a commercially available catalytic system.
Kinetic and mechanistic studies on autocatalytic C–H bond
activation of 2-phenylpyridine via deprotonation with the acetate
ligand, using [Ru(OAc)2(Z6-arene)] as a catalyst precursor, establish
the crucial role of coordinatively unsaturated Ru(II)-acetate species
which allows the C–H deprotonation to generate a metallacycle
intermediate.5b Since the Ru(III) to Ru(II) reduction is readily achieved
in water,10 we envisaged that the Ru(II)-acetate-aqua species might be
a
´
´
´
Laboratorio de Quımica Organometalica y Catalisis (Unidad Asociada al CSIC),
´
´
´
´
Departamento de Quımica Organica e Inorganica, Instituto Universitario de Quımica
´
Organometalica ‘‘Enrique Moles’’ Universidad de Oviedo, E-33071 Oviedo, Spain.
E-mail: jgh@uniovi.es; Fax: +34 985103446; Tel: +34 985103461
b
´
´
Serveis Centrals d’Instrumentacio Cientıfica, Universitat Jaume I,
´
Avenida Sos Baynat s/n, 12071 Castello, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc43452d
´
´
´
‡ Present address: Departamento Quımica Inorganica, Facultad de Quımica,
Universidad de Santiago de Compostela, 15752, Santiago de Compostela, Spain. formed directly from a mixture of RuCl3ꢀnH2O and NaOAc with an
c
8320 Chem. Commun., 2013, 49, 8320--8322
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Table 2 Additive and solvent effects in the reaction of 2-phenylpyridine with
chlorobenzene
Entry
Additive (eq.)
Solvent
Conversion (m/d)b
1
2
3a
4
5
6
7
8
PTA (0.1)
TPPMS (0.1)
AcOH (1)
Cs2CO3 (1.1)
—
—
—
—
Water
Water
Water
Water
THF
29 (80/20)
0 (–/–)
31 (90/10)
0 (–/–)
70 (85/15)
74 (81/19)
17 (100/0)
0 (90/10)
Scheme 2
Glycerola
EtOH
Toluene
appropriate reductant. In our initial studies, we investigated the
phenylation of 2-phenyl pyridine with a slight excess of chloro-
benzene (1.2 mmol) in order to reach the monoarylation, using
5 mol% of RuCl3ꢀnH2O paired with a series of suitable reductants
such as Zn, H3PO2, NaH2PO2, hydrazine or NaBH4 in the presence of
several deprotonating reagents i.e. NaOAc, Na(acac), NaOH, Na2CO3
or Cs2CO3 in water at 110 1C (see Table S1 in ESI†).11 Good catalytic
conversions (65–99%) are found when either Zn or H3PO2 is used
as a reductant in the presence of Na(acac) or NaOAc (Table 1,
entries 2–5). The reactions exclusively gave the mono- and diarylated
derivatives without formation of side-products. In the presence of the
Brønsted bases, NaOH or carbonate salts, the reaction did not occur
(Table 1; entries 6–9). It is also worth noting that the use of Cs2CO3
inhibits the reaction even in the presence of the otherwise active
NaOAc (Table 1; entry 4 vs. entry 9). This catalytic behaviour strongly
contrasts with that shown for a wide series of Ru(II) catalysts reported
to date, for which the presence of an excess of K2CO3 is required for
the reaction to occur.6,7b Among the suitable reductants tested
(Zn and H3PO2), the latter is very sensitive to the stoichiometry when
used in the presence of Na(acac) (see entries 5 and 6 in Table S1,
ESI†) whereas Zn showed similar conversions and selectivities
independent of the stoichiometric amount and the base used (see
entries 3 and 7–9 in Table S1, ESI†). In order to stabilize the putative
Ru(II) intermediate, water-soluble phosphines (PTA and TPPMS) were
added to the resulting aqueous medium (Table 2; entries 1 and 2).
However, lower conversions were found in the former case while the
latter precludes the reaction. Apparently, these phosphines are prone
to coordinate the ruthenium available sites vs. the binding ability of
the substrates. Significantly, the C–H activation in water appears to
be more efficient than in organic solvents such as toluene and THF,
glycerol and ethanol (Table 1; entry 4 vs. Table 2 entries 5–8).
One of the optimised conditions (Table 1; entry 4) was used for
the monoarylation of 2-phenylpyridine with a wide range of function-
alized aryl chlorides. The results are summarized in Table 3. The
catalytic system showed its reliability over a wide array of substrates
Reaction conditions: RuCl3ꢀnH2O (0.05 mmol, 5 mol%), 2-phenylpyridine
(1 mmol), chlorobenzene (1.2 mmol), NaOAc (3 mmol), Zn (0.15 mmol),
110 1C for 16–20 h in 2 mL of solvent. a 200 1C. Conversion and product
b
ratio determined by NMR.
producing similar results independent of the electronic properties of
the aryl halide. The lower conversion observed for substrates 4 and 5
is probably due to their poor solubility in water compared to the
other substrates. On the other hand, the modest results observed
with aryl halides 7 and 8 are the consequence of the steric hindrance
produced by the presence of substituents ortho to the reactive
chloride. From entries 9–13 (Table 3) we could observe that this
catalytic system also shows good activity when heteroaryl halides are
used, the only exception is substrate 13 where the presence of a
methoxy substituent in the meta position erodes the yield observed
(a decrease in selectivity is observed in this series of heterocyclic
halides). This is due to the fact that when the first arylation takes
place, the newly bonded heteroaryl group can itself act as a directing
group thus competing with the incoming substrate for the formation
of the diarylated product. To our delight, the effect of increasing the
reaction temperature (140 1C) under microwave conditions12 notably
decreases reaction times almost reaching a quantitative conversion
(Table 3; method 2) after just 1 h, although also slightly increasing
the formation of the diarylated product (d), apparently at the expense
of the monoarylated (m) one (Table 3; method 2 vs. method 1). The
use of microwave heating also allowed the use of the reductant
NaH2PO2, otherwise inactive in the thermal version (see ESI† for
details). Due to the high selectivity and straightforward workup/
purification of the reaction, mild reaction conditions and low catalyst
loading, the method is highly amenable to scaling-up. The prepara-
tion of 1-(4-methoxyphenyl)-2-phenylbenzene (3m) in multi-gram
quantities is a representative example (see ESI†). Insights into the
nature of the Ru-containing species13 in the catalytic RuCl3–Zn
(or H3PO2)–NaOAc system in aqueous media were obtained from
electrospray ionization mass spectrometry (ESI-MS).14 Either in the
absence or in the presence of substrates, putative monomeric
Ru(II) species were not observed by ESI-MS, being the dimeric
[Ru2(m-OAc)4]+ cation being the only detectable Ru-containing
species, which suggest that formally Ru(II)–Ru(III) [Ru2]5+ species
are initially formed (see Fig. S1 and S3, ESI†).15 Further evidence
for the presence of dimeric [Ru2(m-OAc)4]+ species as potential active
catalysts has been assessed by performing the direct arylation of
2-phenylpyridine with chlorobenzene (1.2 mmol) using isolated
[Ru2(m-Cl)(m-OAc)4]x (2.5 mol%) as a catalyst precursor in the
presence of either AgSbF6 or AgNO3 in water at 110 1C. Although
low conversions are achieved after 3 h (18% and 23%, respectively)
the reactions are totally selective towards the monoarylated product
(m/d: 100/0). The Ru(II)–Ru(III) catalyst is also active in THF showing
Table 1 Screening conditions for the reaction of 2-phenylpyridine with chlorobenzene
Entry Base (eq.)
Reductant (eq.) Conversion (m/d)a
1
2
3
4
5
6
7
8
9
NaOAc (3)
—
0 (–/–)
86 (89/11)
87 (83/17)
82 (88/12)
65 (93/7)
0 (–/–)
0 (–/–)
0 (–/–)
0 (–/–)
Na(acac) (3)
Na(acac) (3)
NaOAc (3)
Zn (0.25)
H3PO2 (0.1)
Zn (0.15)
H3PO2 (0.1)
Zn (0.25)
Zn (0.25)
Zn (0.25)
NaOAc (3)
NaOH (1.1)
Cs2CO3 (1.1)
Na2CO3 (1.1)
NaOAc(3) + Cs2CO3 (1.1) Zn (0.15)
Reaction conditions: RuCl3ꢀnH2O (0.05 mmol, 5 mol%), 2-phenylpyr-
idine (1 mmol), chlorobenzene (1.2 mmol), base, 110 1C for 16–20 h in
2 mL of water. Conversion and product ratio determined by NMR.
a
c
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Table 3 Functionalization of 2-phenylpyridine with aryl chlorides and heteroaryl
We are indebted to the MICIIN of Spain (Projects CTQ2010-
14796/BQU) and Consolider Ingenio 2010 (CSD2007-00006) for
financial support.
chlorides
Notes and references
1 For representative reviews, see: (a) B.-J. Li, S.-D. Yang and Z.-J. Shi,
Synlett, 2008, 949; (b) L. Ackermann, R. Vicente and A. R. Kapdi,
Angew. Chem., Int. Ed., 2009, 48, 9792; (c) D. A. Colby, R. G. Bergman
and J. A. Ellman, Chem. Rev., 2009, 110, 624; (d) L. Ackermann, Chem.
Rev., 2011, 111, 1315; (e) C. Fischmeister and H. Doucet, Green Chem.,
2011, 13, 741. For a recent review on C–H bond activation in water,
see: ( f ) B. Li and P. H. Dixneuf, Chem. Soc. Rev., 2013, 42, 5744.
2 (a) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112
5879; (b) L. Ackermann and R. Vicente, Top. Curr. Chem., 2010, 292, 211.
3 For leading reports, see: (a) L. Ackermann, Org. Lett., 2005, 7, 3123;
(b) L. Ackermann, A. Althammer and R. Born, Angew. Chem., Int. Ed.,
2006, 45, 2619; (c) L. Ackermann, R. Vicente and A. Althammer, Org. Lett.,
2008, 10, 2299; (d) S. Oi, R. Funayama, T. Hattori and Y. Inoue, Tetrahedron,
2008, 64, 6051 and references therein; (e) L. Ackermann, R. Born and
R. Vicente, ChemSusChem, 2009, 2, 546; ( f) F. Pozgan and P. H. Dixneuf,
Adv. Synth. Catal., 2009, 351, 1737; (g) P. Arockiam, V. Poirier,
C. Fischmeister, C. Bruneau and P. H. Dixneuf, Green Chem., 2009,
Entry ArCl or Het-X
Method Conv. (m/d)a
1
2
1
2
1
2
1
2
1
1
2
1
1
2
82 (88/12)
87 (78/22)
93 (88/12)b
96 (71/29)
79 (92/8)
92 (78/22)
31 (66/34)c
25 (52/48) f
84 (79/21)
29 (only m)
45 (85/15) f
40 (84/16) f
89 (71/29)
88 (71/29)
1
2
3
R = H
(1)
(2)
(3)
R = p-CH3
R = p-OCH3
4
5
6
R = p-CN
R = p-OH
R = m-N(CH3)2 (6)
R = o-NH2
(4)
(5)
7
8
9
(7)
(8)
(9)
R = o-Cl
´
11, 1871; (h) L. Ackermann, P. Novak, R. Vicente, V. Pirovano and H. K.
1
2
78 (55/45)
74 (59/41)
Potukuchi, Synthesis, 2010, 2245; (i) Y. Aihara and N. Chatani, Chem. Sci.,
2013, 4, 664; ( j) J. Kim, J. Kim and S. Chang, Chem.–Eur. J., 2013, 23, 7328;
(k) A. Prades, M. Poyatos and E. Peris, Adv. Synth. Catal., 2010, 352, 1155.
4 Other ruthenium complexes have also been used as catalysts in
direct arylations, (a) [RuCl2(COD)]n: M. Seki, ACS Catal., 2011, 1, 607;
(b) [RuH(codyl)]2[BF4]: W. Li, P. B. Arockiam, C. Fischmeister,
C. Bruneau and P. H. Dixneuf, Green Chem., 2011, 13, 2315;
(c) [RuCl2(PPh3)3]: see ref. 9.
5 (a) I. Ozdemir, S. Demir, B. Cetinkaya, C. Gourlaouen, F. Maseras,
C. Bruneau and P. H. Dixneuf, J. Am. Chem. Soc., 2008, 130, 1156;
(b) E. Ferrer Flegeau, C. Bruneau, P. H. Dixneuf and A. Jutand, J. Am.
Chem. Soc., 2011, 133, 10161; (c) L. Ackermann, R. Vicente,
H. K. Potukuchi and V. Pirovano, Org. Lett., 2010, 12, 5032.
6 P. B. Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf,
Angew. Chem., Int. Ed., 2010, 49, 6629.
7 For further examples of ruthenium(II) catalysts active in water, see:
(a) B. Li, K. Devaraj, C. Darcel and P. H. Dixneuf, Tetrahedron, 2012,
68, 5179; (b) P. B. Arockiam, C. Fischmeister, C. Bruneau and
P. H. Dixneuf, Green Chem., 2013, 15, 67; (c) K. S. Singh and
P. H. Dixneuf, ChemCatChem, 2013, 5, 1313; (d) L. Ackermann,
N. Hofmann and R. Vicente, Org. Lett., 2011, 13, 1875.
10
11
(10)
(11)
1
2
79 (51/49)
67 (66/34)
1
2
68 (76/24)d
47 (16/84)
12
13
(12)
(13)
5
1
2
24 (88/12)
19 (74/26)e
Method 1: RuCl3ꢀnH2O (0.05 mmol,
mol%), 2-phenylpyridine
(1 mmol), aryl/heteroaryl halide (1.2 mmol), NaOAc (3 mmol), Zn
(0.15 mmol), 110 1C for 20 h in 2 mL of water. Method 2: RuCl3ꢀnH2O
(0.05 mmol, 5 mol%), 2-phenylpyridine (1 mmol), aryl/heteroaryl halide
(1.2 mmol), NaOAc (3 mmol), Zn (0.15 mmol), 140 1C under MW
a
irradiation for 1 h in 2 mL of water. Conversion and product ratio
b
c
determined by NMR. 0.25 eq. Zn, 1 eq. NaOAc, 1.5 eq. Ar–Cl. 0.25 eq.
d
e
f
Zn, 1 eq. NaOAc, 42 h a 110 1C. 1.5 eq. Ar–Cl. 180 1C, 1 h. Homo-
coupling of 2-phenylpyridine instead of the diarylated product.
higher conversions and lower selectivity depending on the silver salts
used (conversion; m/d values of 94; 67/33 and 68; 82/18% for AgSbF6
and AgNO3, respectively). Remarkably, ESI(+)-MS analysis of the
RuCl3–Zn (or H3PO2)–NaOAc catalytic system in THF solutions also
revealed the presence of the dimeric [Ru2(m-OAc)4]+ cation (see ESI†).
In summary, in this work, we have shown that the RuCl3ꢀnH2O–
Zn–NaOAc catalytic system is active for the selective ortho mono-
arylation of 2-phenylpyridine and functionalized aryl chlorides in
water.16 Since it is formed from commercially available components,
inexpensive aryl chloride substrates, and no further addition of
K2CO3isneeded,itcanbeusedpreferablytotheruthenium(II)catalysts
[Ru(O2CR)2(Z6-p-cymene)] and [RuCl2(PPh3)(Z6-p-cymene)].6,7b Since
the reaction is also amenable on a multi-gram scale, the practical
application of this methodology provides an attractive synthetic
tool to conventional direct arylation methodologies via C–H bond
activation–functionalization of arenes by N-containing heterocyclic
directing groups. This is a further example of the ruthenium based
catalyticsystemactiveinwater whichnotonlyavoidstheuseoforganic
8 For examples active in NMP, see: (a) L. Ackermann, A. Althammer
and R. Born, Synlett, 2007, 2833; (b) K. Cheng, Y. Zhang, J. Zhao and
C. Xie, Synlett, 2008, 1325; (c) L. L. Ackermann, A. A. Althammer and
R. R. Born, Tetrahedron, 2008, 64, 6115.
9 It has also been described that RuCl3ꢀnH2O is active for aryl chlorides
in NMP at 140 1C but the addition of PPh3 and M2CO3 (M = Na, K) as a
base, is required: (a) N. Luo and Z. Yu, Chem.–Eur. J., 2010, 16, 787. For
a similar reaction carried out in polyethylene glycol (PEG), see:
(b) L. Ackermann and R. Vicente, Org. Lett., 2009, 11, 4922.
10 (a) The Chemistry of Ruthenium, ed. E. A. Seddon and K. R. Seddon,
Elsevier Science, 1984; (b) Advanced Inorganic Chemistry, ed.
F. A. Cotton, G. Wilkinson, C. A. Murillo and M. Bochmann, John
Wiley & Sons, 6th edn, 1999.
11 Attempts to use the isolated complexes [Ru(acac)2L2] (L = Me2SO, PPh3)
under similar reaction conditions were unsuccessful (see ESI† for details).
12 For a review on microwave assisted C–C bond forming reactions, see:
V. P. Mehta and E. V. Van der Eycken, Chem. Soc. Rev., 2011, 40, 4925.
13 Catalysis by ruthenium nanoparticles was ruled out as both TEM
images and Hg poisoning tests were negative.
14 Examples on mechanistic studies based on ESI-MS can be found in
¨
(a) M. N. Eberlin, Eur. J. Mass Spectrom., 2007, 13, 19; (b) D. Schroder,
Acc. Chem. Res., 2012, 45, 1521.
15 (a) F. A. Cotton, M. Matusz and B. Zhong, Inorg. Chem., 1988, 27, 4368;
(b) N. Komiya, T. Nakae, H. Sato and T. Naota, Chem. Commun., 2006, 4829.
solvents but also reaches an enhanced catalytic activity.17 Further 16 The reactions proceed under biphasic ‘‘on water’’ conditions.
17 (a) Ruthenium Catalysts and Fine Chemistry, ed. C. Bruneau and
synthetic applications of this catalytic methodology in aqueous media
andmechanisticstudiestogaininsightintotheactiveintermediateare
P. H. Dixneuf, Springer, Berlin, 2004; (b) Metal-Catalyzed Reactions in
Water, ed. P. H. Dixneuf and V. Cadierno, Wiley-VCH, 2013; (c) Water in
presently under way.
Organic Synthesis, ed. Shu Kobayashi, Thieme, Stuttgart, Germany, 2012.
c
8322 Chem. Commun., 2013, 49, 8320--8322
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