(η6-arene)ruthenium(N-heterocyclic carbene) complexes for the chelation-assisted arylation and deuteration of arylpyridines: Catalytic studies and mechanistic insights

Article abstract of DOI:10.1002/adsc.201000049

A series of (η⁶-arene)ruthenium complexes have been tested in the arylation of arylpyridines. One (η⁶-p-cymene)ruthenium(N- heterocyclic carbene) complex (labelled as 1 in the text) was found to be the most effective, being capable of arylating a wide set of substantially different arylpyridines. Complex 1 is also able to promote the regioselective deuteration of a series of arylated N-heterocycles, via a nitrogen-directed mechanism. Two of the deuterated amines were used to measure the kinetic isotope effect (KIE) in the arylation process. The detection of an inverse KIE, together with the observation that the C-H activation process does not require the addition of a base, suggest that the rate-limiting step in the arylation process may be different to that of previously reported studies.

Full text of DOI:10.1002/adsc.201000049

FULL PAPERS
DOI: 10.1002/adsc.201000049
ACHTUNGTRENNUNG
Amparo Prades,a Macarena Poyatos,a and Eduardo Perisa,*
a
Dpto. de Quꢀmica Inorgꢁnica y Orgꢁnica, Universitat Jaume I, Avda. Sos Baynat, 12071 Castellꢂn, Spain
Fax : (+34)-96-472-8214; phone: (+34)-96-472-9165; e-mail: eperis@qio.uji.es
Received: January 20, 2010; Published online: April 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000049.
Abstract: A series of (h6-arene)ruthenium complexes tope effect (KIE) in the arylation process. The detec-
have been tested in the arylation of arylpyridines. tion of an inverse KIE, together with the observation
One (h6-p-cymene)ruthenium(N-heterocyclic car- that the C H activation process does not require the
À
bene) complex (labelled as 1 in the text) was found addition of a base, suggest that the rate-limiting step
to be the most effective, being capable of arylating a in the arylation process may be different to that of
wide set of substantially different arylpyridines. previously reported studies.
Complex 1 is also able to promote the regioselective
deuteration of a series of arylated N-heterocycles,
via a nitrogen-directed mechanism. Two of the deu- Keywords: arylation of pyridines; chelation-assisted
terated amines were used to measure the kinetic iso- catalysis; deuteration; isotope effect; ruthenium
Introduction
À
Ruthenium-catalyzed C C bond formation processes
through C H activation have emerged as valuable al-
À
ternatives to traditional cross-coupling reactions using
organometallic reagents and highly reactive electro-
philes.[1] Among the Ru catalysts used, those contain-
ing h6-arene[2] and N-heterocyclic carbene (NHC)[3] li-
gands, have shown an extraordinary catalytic versatili-
ty that has been used in a wide set of non-metatheti-
cal transformations applied to the production of ad-
Scheme 1. Ruthenium catalysts employed in this paper.
vanced materials.[4] Because biaryl compounds are
important motifs in organic synthesis and medicinal
chemistry,[5] following the pioneering works of Oi and
co-workers,[6] many efforts are currently being made different h6-arene ligands (hexamethylbenzene, p-
to generate efficient ruthenium catalysts for the direct cymene and methyl benzoate), and different NHC
arylation of arenes.[6–11]
(and one phosphine) ligands seemed a good choice
We recently described
a
series of ꢃ(h6-p- for the tuning of the electronic and steric properties
cymene)RuACHTUNGTRENNUNG(NHC)ꢄ complexes that were applied to of the metal centre. From this study, we have ob-
several hydrogen-borrowing catalytic reactions.[12] tained a highly active catalyst for the effective aryla-
Being aware of the extraordinary ability of these com- tion of a wide set of pyridines. Remarkably, the same
À
plexes to promote C H activation processes, we now catalyst is able to regioselectively deuterate the 2-po-
have decided to extend their use to the arylation of sitions of the aryl groups bound to a series of N-het-
pyridines with aryl halides. The easy access toꢃ
arene)Ru(NHC)ꢄ complexes allowed us to prepare an excellent possibility to study the kinetic isotope
compounds 1–6 shown in Scheme 1. The use of three effect in the arylation of arylpyridines, and compare
(h6- erocycles. The deuteration of these positions affords
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Adv. Synth. Catal. 2010, 352, 1155 – 1162
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1155

Amparo Prades et al.
FULL PAPERS
Table 1. Catalyst screening in the arylation of 2-phenylpyri-
the results with previously reported mechanistic pro-
posals for this reaction.[6,7,13]
dine.[a]
Results and Discussion
Compounds 1,[14] 4[15] and 7[16] were synthesized ac-
cording to literature methods. Compounds 2, 3 and 6
were prepared following the transmetallation from a
pre-formed Ag(I)-NHC complex. The preparation of
compound 5 was better achieved by deprotonating
the imidazolium salt with Cs2CO3 (Scheme 2). All the
Entry cat.
Conditions
t [h] 10a [%][b] 10b [%][b]
1
1
NaOAc/Na2CO3 20
15
–
–
25
–
1
–
–
5
2
none NaOAc/Na2CO3 20
3
4
5
6
2
1
1
1
1
1
2
3
4
5
6
6
7
8
9
NaOAc/Na2CO3 20
NaOAc/K2CO3
NaOAc/K2CO3 18
5
>95 (91)
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
KOAc/K2CO3
5
3
7
5
5
5
5
5
3
5
5
5
20
–
>95 (92)
7
25
60
4
25
10
–
70
22
1
40
89
–
>95
60
10
10
42
–
8[c]
9
10
11
12
13
14
15
16
17
18
–
25
68
20
9
none KOAc/K2CO3
–
[a]
Reaction conditions: NaOAc or KOAc (0.05 mmol), cata-
lyst (0.025 mmol), 2 mL of NMP as solvent, room tem-
perature for 1 h, then 2-phenylpyridine (0.5 mmol), PhCl
(1.25 mmol), Na2CO3 or K2CO3 (1.5 mmol), 1208C.
Scheme 2. Synthesis of compounds 2, 3, 5 and 6.
[b]
[c]
details concerning the characterization of these new
complexes are described in the Experimental Section.
We first studied the different activities of com-
plexes 1–9 in the arylation of 2-phenylpyridine with
chlorobenzene (Table 1). For the study of this stan-
dard reaction we used the previously described reac-
Yields and ratios determined by GC (internal standard:
1
anisole) and by H NMR. Isolated yields in parenthesis.
Using 2 mL of toluene as solvent instead of NMP.
tion conditions (1208C in NMP)[6–9] and a catalyst cymene ligand providing the best results. This obser-
loading of 5 mol%. The optimization of the amount vation is difficult to justify if we consider that the re-
and type of bases added was carried out with catalyst lease of the coordinated arene ligand is necessary for
1, for which the best catalytic performances were the catalytic activity of these species, because this
found when using a mixture of KOAc and K2CO3. would imply that the methyl benzoate ligand (more
Under these reaction conditions, the arylation of 2- weakly bound to the metal) should have provided the
phenylpyridine was studied for all compounds. As can best outcomes. The change of the nature of the N-
be seen from the data shown in Table 1 (entries 6–17), alkyl group at the NHC ligand also provides changes
the best performances were provided by 1, which ach- in the catalytic activity of the complexes under study.
À
ieved full conversion to the bisarylated product 10b in Complex 4 (N Me), provides good activity although
5 h. In fact, we previously showed that the NHCs with the formation of the bisarylated product is rather
À
n-Bu wingtips provided excellent activities in C H ac- poor compared to the monoarylated one (entry 11),
tivation processes promoted by ꢃCp*Ir
A
À
although we still do not have a satisfactory explana- completed after 5 h. In addition, complex 6 (N n-
tion for this observation.[17]
Oct) shows similar activity to 1 after 5 h (entry 13),
In general, it is observed that the introduction of but the outcome after 3 h is significantly lower
the NHC ligands provides better performances than (entry 14).
those provided by the metal precursors without this
Once we confirmed that catalyst 1 was the most
ligand (entries 16 and 17) or with a phosphine active one in the arylation of 2-phenylpyridine, we de-
(entry 15). The arene ligand has also a clear influence cided to extend its use to other substrates. Table 2
in the catalytic outcome of the system, with the p- shows the catalytic results when compound 1 was
1156
asc.wiley-vch.de
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1155 – 1162

ACHTUNGTRENNUNG
(h6-Arene)ruthenium(N-heterocyclic carbene) Complexes for the Chelation-Assisted Arylation
Table 2. Arylation of pyridines using catalyst 1.[a]
Pyridine Ar-X
t [h]
4
a [%][b] Monoarylated
b [%][b] Bisarylated
>95 (92) (10b)
90 (10b)
1
2
–
4
1 (10a)
–
3
4
>95 (90)
60 (12b)
ACHTUNGTNER(NUNG 11b)
4
5
25 (12a)
–
5
5
>95 (91) (13b)
6 (14b)
6
24
24
24
24
24
80 (14a)
4 (14a)
45 (15a)
15 (15a)
15 (15a)
7
90 (14b)
2 (15b)
8
9
<5 (15b)
5 (15b)
10
11
12
13
5
94 (89) (16a)
50 (16a)
12
6
5
92 (17a)
14
–
95 (81) (18b)
[a]
Reaction conditions: KOAc (0.05 mmol), catalyst 1 (0.025 mmol), 2 mL of NMP as solvent, room temperature for 1 h,
then substrate (0.5 mmol), Ar-X (1.25 mmol or 0.75 mmol), K2CO3 (1.5 mmol), 1208C.
Yields and ratios determined by GC (internal standard: anisole) and by H NMR. Isolated yields in parenthesis.
[b]
1
used in the arylation of 2-phenylpyridine, benzo[h]-
Hydrogen/deuterium exchange processes are pow-
quinoline and N-phenylpyrazole with different arylat- erful methods to evaluate the potential of a catalyst
[19]
À
ing agents. Interestingly, the catalyst is capable of pro- for the cleavage and formation of C H bonds.
viding good results for all three substrates, a feature Since the mechanism of the arylation of arylpyridines
that illustrates its wide applicability. For the reactions implies the regioselective C H activation at the 2-po-
with 2-phenylpyridine, 1 provides higher activity than sition of the aromatic rings of 2-substituted pyridines,
À
previously reported ruthenium catalysts that generally we thought that it may be possible to use catalyst 1
À
need longer reaction times (>10 h) to achieve lower for the N-directed regioselective deuteration of C H
product yields[6–8] and compares well with the most ef- bonds of different pyridines. The process seemed
ficient catalytic systems reported for this process.[13,18] even more plausible after the recent description of
In general, it seems that the use of chloroarenes pro- the selective deuteration of benzo[h]quinoline at the
vides higher conversions than iodo- and bromoarenes, C-10 position using a dirhodium(II) complex, al-
a trend that is also observed in the arylation of ben- though in this case the reaction needed a stoichiomet-
zo[h]quinoline (compare entries 11 and 12).
ric amount of the dimetallic species (the reaction is
Adv. Synth. Catal. 2010, 352, 1155 – 1162
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1157

Amparo Prades et al.
FULL PAPERS
not catalytic) and base.[20] Table 3 shows the selective
In general, the search of catalysts able to selectively
deuteration of five different pyridines in the presence deuterate organic molecules is a matter of continuous
of MeOH-d4 at 1208C with 5 mol% of catalyst. It is interest because deuterium labelled compounds can
important to point out that this reaction can be easily be used in a wide range of applications such as the
1
monitored by H NMR, for which a growth of the res- study of biologically active systems, solvents for NMR
onance of the CH3OH proton is concomitant with the spectroscopy, and the study of reaction mechanisms.[21]
deuteration of the pyridine. This observation suggests In our case, the possibility to selectively deuterate
À
À
a C D rather than O D activation in the functioning pyridines provides an excellent opportunity for the
of the deuterium source in the catalytic cycle, a fact experimental study of the reaction mechanism of the
that is confirmed by the absence of reaction when arylation of these substrates. In this sense, the time-
CH3OD is used instead of MeOH-d4. As an example course monitoring of the arylation of 2-phenylpyri-
of the monitoring of the process, Figure 1 shows two dine-d2 and 2-phenylpyridine, allowed us to determine
1H NMR spectra of the deuteration of N-phenylpyra- a kinetic isotope effect (KIE) of kH/kD =0.46 (based
zole at t=0 h and t=10 h, that clearly illustrates that on the determination of t1/2 values at 1208C). For the
the signals due to the protons at the 2-position of the reaction carried out with benzo[h]quinoline-d, a simi-
phenyl ring disappear after 10 h of reaction.
lar substantial inverse KIE of kH/kD =0.43 was deter-
As can be seen from the results shown above, the mined. This inverse KIE is different from the normal
selective deuteration proceeds in an almost quantita- (positive) KIEs found for other related hydrogen ab-
tive manner, without the need of addition of any addi- straction processes,[20,22] implying that a different
tive such as a base, except for the imine and 8-methyl- mechanism should be at play or, at least that a differ-
quinoline, for which KOAc is needed (entries 5 and ent transition state is determining the kinetics of the
6). Remarkably, the deuteration of the sp3 C H process. Those processes implying the metal-mediated
À
À
bonds at the methyl group of 8-methylquinoline is activation of C H bonds are believed to occur via
À
also almost quantitative. To the best of our knowl- transient s-C H (agostic) complexes. On the basis of
edge, this is the first time that this selective deutera- computational calculations applied to the ruthenium-
tion of arylpyridines has been described.
catalyzed arylation of 2-phenylpyridine, Maseras and
Dixneuf found that this agostic intermediate pre-
Table 3. Deuteration of pyridines in MeOH-d4 using 1.[a]
Entry
Substrate
Product
t [h]
Conversion [%][b]
92 (89)
1
2-phenylpyridine
7
2
3
benzo[h]quinoline
5
90(82)
1,2-bis(2-pyridyl)ethylene
10
>95
4
5
N-phenylpyrazole
10
>95
methylbenzylimine
8-methylquinoline
10[c]
10[c]
>95
6
80
[a]
Reaction conditions: catalyst 1 (0.025 mmol), substrate (0.5 mmol), 4 mL of MeOH-d4, 1208C.
Conversion determined by H NMR. Isolated yields in parenthesis.
Using KOAc (0.05 mmol).
[b]
[c]
1
1158
asc.wiley-vch.de
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1155 – 1162

ACHTUNGTRENNUNG
(h6-Arene)ruthenium(N-heterocyclic carbene) Complexes for the Chelation-Assisted Arylation
Conclusions
In conclusion, we have obtained a series of highly ef-
fective catalysts for the chelation-assisted direct aryla-
tion of a wide series of pyridines, which clearly illus-
trates the wide applicability of the catalysts used.
Remarkably, catalyst 1 also resulted an efficient
catalyst for the N-directed regioselective deuteration
2
3
À
of sp and sp C H bonds, a process that is unprece-
dented in the literature. Most substrates undergo this
C H activation process in the absence of a base, al-
though methylbenzylimine and 8-methylquinoline re-
quired catalytic amounts of KOAc in order to accom-
plish their deuteration.
À
The easy access to selective deuterated arylpyri-
dines allowed the determination of the kinetic isotope
effect in the direct arylation of arylpyridines, which
being inverse suggests that the reaction mechanism
proceeds via a different mechanism than those pro-
posed for other related hydrogen abstraction process-
es.[20,22] Our results suggest that, contrary to what has
been proposed for other catalysts, the rate-limiting
step for this ruthenium-catalyzed process does not
À
imply the C H proton abstraction. Calculations in
order to determine the rate-limiting transition state of
this catalytic process may be an interesting task to de-
velop in the next future.
Experimental Section
Figure 1. 1H NMR spectra of the Ru-mediated deuteration
of N-phenylpyrazole after 0 h and 10 h of reaction.
General Remarks
The metal complexes [RuCl2(h6-p-cymene)]2,[16] [RuCl (h6-
2ACHTUNGTRENNUNG
CMe)6]2,[25] [RuCl2(h6-methyl benzoate)]2,[26] 1,[14] 4[15] and
7[16] and the ligand precursors 1,3-di-n-butylimidazolium
iodide and 1,3-dimethylimidazolium iodide[27] were prepared
according to literature procedures. All other reagents were
used as received from commercial suppliers and used with-
out further purification. NMR spectra were recorded on a
Varian Innova 300 MHz and 500 MHz, using CDCl3 and
DMSO-d6 as solvents. Electrospray mass spectra (ESI-MS)
were recorded on a Micromass Quatro LC instrument; ni-
trogen was employed as drying and nebulizing gas. Elemen-
tal analyses were carried out on a EuroEA3000 Eurovector
Analyser.
À
ferred the C H cleavage through proton abstraction
over a C H oxidative addition generating an Ru(IV)
À
with a hydride ligand.[7] However, this group did not
report calculations in order to determine the transi-
tion state responsible for the rate-limiting step of the
overall reaction. While a single-step reaction is almost
invariably characterized by a normal primary KIE,
À
the observation of an inverse KIE in a C H activa-
tion process is commonly taken to imply an inter-
mediate in a multistep reaction prior to the determin-
ing step.[23] In our case, the inverse KIE may imply
Synthesis of the Metal Complexes
À
1,2-Di-n-octylimidazolium iodide: To a round-bottom flask
were added imidazole (480 mg, 7 mmol), NaOH (420 mg,
10.5 mmol), TBABr (50 mg, 0.15 mmol), and a few drops of
water. The mixture was stirred at room temperature for 1 h,
and then iodooctane (1.3 mL, 7 mmol) was added. After
48 h at room temperature, the reaction mixture was extract-
ed with CH2Cl2/H2O and the organic extracts were collected
and dried over Na2SO4. Evaporation of the solvent under
vacuum gave an oil which was further reacted with iodooc-
tane (1.3 mL, 7 mmol). The mixture was refluxed overnight
to give the desired product; yield: 2.6 g (90%). 1H NMR
that the C H abstraction is not the rate-limiting step
in the catalytic cycle,[23,24] probably indicating that the
À
À
agostic intermediate has an intact, strong C H or C
D bond.[23] It is important to recall that, for our Ru-
catalyzed deuteration reactions, the results indicate
À
that the C H activation is a metal-mediated process
that takes place in the absence of a base, which also
supports the idea that the rate-limiting step of the cat-
alytic reaction does not imply the proton abstraction
from the phenyl ring of the arylpyridine compound.
Adv. Synth. Catal. 2010, 352, 1155 – 1162
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1159

Amparo Prades et al.
FULL PAPERS
(300 MHz, CDCl3): d=10.22 (s, 1H, NCHN), 7.41 (s, 2H,
Compound 5 was obtained as a yellow solid by precipitation
with diethyl ether; yield: 215 mg (50%). H NMR (CDCl3,
3
1
CHimidazole), 4.34 (t, JH,H =7.35 Hz, 4H, NCH2 n-Oct), 1.92 (m,
3
300 MHz): d=6.88 (s, 2H, CHimidazole), 3.64 (s, 6H, NCH3),
2.10 [s, 18H, (CH3)6]; 13C{1H} NMR (75 MHz, CDCl3): d=
181.9 (Ccarbene-Ru), 123.4 (CHimidazole), 92.8 [(CCH3)6], 37.2
(NCH3), 15.7 [(CCH3)6]; electrospray MS (15 V): m/z (frag-
ment)=395.4 [MÀCl]+; anal. calcd. for C17H26Cl2N2Ru (mol.
wt. 430.38): C 47.44, H 6.09, N 6.51; found: C 47.56, H 6.05,
N 6.42.
4H, CH2 n-Oct), 1.31 (m, 20H, CH2 n-Oct), 0.85 (t, JH,H
=
6.00 Hz, 6H, CH3 n-Oct); 13C{1H} NMR (75 MHz, CDCl3): d=
136.7 (NCHN), 122.7 (CHimidazole), 50.4 (NCH2 n-Oct), 31.8
(CH2 n-Oct), 30.4 (CH2 n-Oct), 29.1 (CH2 n-Oct), 29.0 (CH2 n-Oct),
26.3 (CH2 n-Oct), 22.7 (CH2 n-Oct), 14.1 (CH3 n-Oct); electrospray
MS (15 V): m/z (fragment)=293.3 [MÀI]+; anal. calcd. for
C19N2H37I (mol. wt. 420.41): C 54.28, H 8.87, N 6.66; found:
C 54.56, H 8.78, N 6.59.
Synthesis of 6: Silver oxide (76 mg, 0.33 mmol) was added
to a solution of 1,3-di-n-octylimidazolium iodide (138 mg,
0.33 mmol) in CH2Cl2. The solution was stirred at room tem-
perature for 1 h, and [RuCl2(h6-p-cymene)]2 (100 mg,
0.16 mmol) was then added. The mixture was refluxed for
3 h under the exclusion of light, the suspension was filtered
through Celite and the solvent was evaporated under reduce
pressure. The crude solid was purified by column chroma-
tography. Elution with a mixture of CH2Cl2/acetone (9:1) af-
forded the separation of an orange band that contained
compound 6. Compound 6 was obtained as an orange solid
by precipitation with ether; yield: 105 g (53%). 1H NMR
(300 MHz, CDCl3): d=7.05 (s, 2H, CHimidazole), 5.37 (d,
3JH,H =6.00 Hz, 2H, CHp-cym), 5.06 (d, 3JH,H =5.70 Hz, 2H,
CHp-cym), 4.56 (br, 2H, NCH2 n-Oct), 3.97 (br, 2H, NCH2 n-Oct),
2.91 (sept, 3JH,H =6.90 Hz, 1H, CHisop p-cym), 2.03 (s, 3H,
CH3p-cym), 1.97 (br, 2H, CH2 n-Oct), 1.67 (br, 2H, CH2 n-Oct),
Synthesis of 2: Silver oxide (58 mg, 0.25 mmol) was added
to a solution of 1,3-di-n-butylimidazolium iodide (154 mg,
0.50 mmol) in CH2Cl2. The suspension was stirred at room
temperature for 1 h, and [RuCl2ACTHNUTRGNEUNG
(h6-CMe)6]2 (167 mg,
0.25 mmol) was then added. The mixture was refluxed for
2 h under the exclusion of light. The suspension was filtered
through Celite and the solvent was evaporated under re-
duced pressure. The crude solid was purified by column
chromatography. Elution with a mixture of CH2Cl2/acetone
(4:1) afforded the separation of an orange band containing
compound 2. Compound 2 was obtained as an orange solid
by precipitation with diethyl ether; yield: 160 mg (62%).
1H NMR (500 MHz, CDCl3): d=7.04 (s, 2H, CHimidazole),
4.55 (td, 3JH,H =11.87 Hz, 2JH,H =4.83 Hz, 2H, NCH2 n-Bu),
3.66 (td, 3JH,H =11.75 Hz, 2JH,H =4.83 Hz, 2H, NCH2 n-Bu),
1.99 [s, 18H, (CH3)6], 1.63 (m, 2H, CH2 n-Bu), 1.51 (m, 2H,
3
3
1.30 (br, 20H, CH2 n-Oct), 1.25 (d, JH,H =7.20 Hz, 6H, CH3isop
CH2 n-Bu), 1.38 (m, 4H, CH2 n-Bu), 0.98 (t, JH,H =7.25 Hz, 6H,
3
p-cym), 0.87 (t, JH,H =6.60 Hz, 6H, CH3 n-Oct); 13C{1H} NMR
CH3 n-Bu); 13C{1H} NMR (75 MHz, CDCl3): d=176.1 (Ccarbene
-
(75 MHz, CDCl3): d=173.4 (Ccarbene-Ru) 121.7 (CHimidazole),
108.0 (CHisop p-cym), 99.3 (Cqp-cym), 85.3 (CHp-cym), 83.0
(CHp-cym), 51.7 (NCH2), 32.0 (CH2 n-Oct), 30.9 (CHisop p-cym),
29.6 (CH2 n-Oct), 29.3 (CH2 n-Oct), 27.1 (CH3isop p-cym), 22.8 (CH2
n-Oct), 22.7 (CH2 n-Oct), 18.8 (CH3isop p-cym), 14.2 (CH3 n-Oct);
electrospray MS (15 V): m/z (fragment)=563.3 [MÀCl]+;
anal. calcd. for RuCl2C29H50N2 (mol. wt. 598.70): C 58.18, H
8.42, N 4.68; found: C 57.96, H 8.47, N 4.67.
Ru) 121.8 (CHimidazole), 93.6 [(CCH3)6], 51.2 4 (NCH2 n-Bu),
34.0 (CH2 n-Bu), 20.4 (CH2 n-Bu), 15.6 [(CCH3)6], 14.1 (CH3
n-Bu); electrospray MS (15 V): m/z (fragment)=479.2
[MÀCl]+; anal. calcd. for C23H38Cl2N2Ru (mol. wt. 514.54):
C 53.69, H 7.44, N 5.44; found: C 53.75, H 7.47, N 5.41.
Synthesis of 3: Silver oxide (37.5 mg, 0.162 mmol) was
added to a solution of 1,3-di-n-butylimidazolium iodide
(100 mg, 0.324 mmol) in CH2Cl2. The suspension was stirred
at room temperature for 1 h, and [RuCl2(h6-methyl ben-
zoate)]2 (100 mg, 0.162 mmol) was then added. The mixture
was refluxed overnight under the exclusion of light. The
crude mixture was filtered through Celite and the solvent
removed under reduced pressure. Complex 3 was obtained
as a moderately unstable red solid by precipitation from
CH2Cl2/diethyl ether; yield: 99 mg (62%). 1H NMR
(300 MHz, CDCl3): d=7.06 (s, 2H, CHimidazole), 6.27 (d,
3JH,H =6.00 Hz, 2H, CHortho-benzoate), 5.84 (t, 3JH,H =5.50 Hz,
Catalytic Experiments
Arylation of 2-phenylpyridine: The ruthenium complex (1–
9) (0.025 mmol) and KOAc (0.05 mmol) were stirred in
NMP (2 mL) at room temperature in a thick-walled glass
tube for 1 h. Then 2-phenylpyridine (0.5 mmol), Ar-X
(1.25 mmol) and K2CO3 (1.50 mmol) were added. The re-
sulting mixture was stirred at 1208C. H2O and EtOAc were
added to the cold reaction mixture. The organic phase was
dried with Na2SO4 and concentrated under vacuum. The re-
maining residue was purified by column chromatography on
silica gel (hexanes/EtOAc mixture) to yield the correspond-
ing ortho-arylated products. Yields and ratios were deter-
3
1H, CHpara-benzoate), 5.71 (t, JH,H =5.80 Hz, 2H, CHmeta-benzoate),
4.40 (br, 2H, N-CH2 n-Bu), 3.98 (br, 2H, N-CH2 n-Bu), 3.89 (s,
3H, -COOCH3), 1.89 (br, 2H, CH2 n-Bu), 1.65 (br, 2H, CH2
3
n-Bu), 1.41 (m, 4H, CH2 n-Bu), 0.97 (t, JH,H =7.20 Hz, 6H, CH3
n-Bu); 13C{1H} NMR (75 MHz, CDCl3): d0168.4 (Ccarbene-Ru),
166.4 (COOCH3), 122.1 (CHimidazole), 90.9 (Cq benzoate), 88.3,
(CHbenzoate), 86.7 (CHbenzoate), 82.5 (Cq benzoate), 53.4
(COOCH3), 51.4 (NCH2 n-Bu), 34.0 (CH2 n-Bu), 20.3 (CH2 n-Bu),
14.1 (CH3 n-Bu); electrospray MS (15 V): m/z (fragment)=
1
mined by H NMR spectroscopy and by GC analyses using
anisole (0.5 mmol) as internal standard. According to previ-
ously reported spectroscopic data, products were identified
as 10a,[6] 10b,[6] 11b,[6] 12a,[28] 12b[28] 14a,[11] 14b,[11]15a[6] and
15b.[6]
453.5 [MÀCl]+; FT-IR (KBr): n=1723 cmÀ1 (n(C O)).
=
Synthesis of 5: A mixture of [RuCl2ACTHNUTRGNEUNG
(h6-CMe)6]2 (200 mg,
2-(4,4’’-Dibutyl-1,1’:3’,1’’-terphenyl-2’yl)pyridine (13b)
1
0.30 mmol), 1,3-di-n-methylimidazolium iodide (150 mg,
0.67 mmol), and Cs2CO3 (1.5 g, 4.70 mmol) in CH3CN was
refluxed for 6 h. The mixture was filtered, the solvent was
evaporated and the crude solid was purified by column chro-
matography. Elution with CH2Cl2/acetone (9:1) afforded the
separation of a yellow band that contained compound 5.
(Table 2, entry 5): H NMR (300 MHz, CDCl3): d=8.31 (d,
3JH,H =4.50 Hz, 1H), 7.44 (m, 3H), 7.29 (m, 1H), 6.97 (m,
8H), 6.88 (m, 2H), 2.53 (t, 3JH,H =7.65 Hz, 4H), 1.55 (m,
4H), 1.31 (m, 4H), 0.91 (t, 3JH,H =7.35 Hz, 6H); 13C{1H}
NMR (75 MHz, CDCl3): d=148.6 (CH), 142.1 (Cq), 141.0
(Cq), 139.1 (CH), 134.5(CH), 129.7 (CH), 129.5 (CH), 128.3
1160
asc.wiley-vch.de
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1155 – 1162

ACHTUNGTRENNUNG
(h6-Arene)ruthenium(N-heterocyclic carbene) Complexes for the Chelation-Assisted Arylation
(Cq), 127.9 (CH), 127.1 (Cq), 120.9 (Cq), 35.4 (CH2), 33.6
(CH2), 22.5 (CH2), 14.1 (CH3).
[5] D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893–930.
Arylation of benzo[h]quinoline: KOAc (0.05 mmol) and
catalyst 1 (0.025 mmol) were stirred in NMP (2 mL) at room
temperature in a thick-walled glass tube for 1 h. Then ben-
zo[h]quinoline (0.5 mmol), Ar-X (0.75 mmol) and K2CO3
(1 mmol) were added. The resulting mixture was stirred at
1208C. H2O and EtOAc were added to the cold reaction
mixture. The organic phase was dried with Na2SO4 and con-
centrated under vacuum. The remaining residue was puri-
fied by column chromatography on silica gel (hexanes/
EtOAc mixture) to yield the monoarylated product. Yields
[6] S. Oi, S. Fukita, N. Hirata, N. Watanuki, S. Miyano, Y.
Inoue, Org. Lett. 2001, 3, 2579–2581.
[7] I. Ozdemir, S. Demir, B. Cetinkaya, C. Gourlaouen, F.
Maseras, C. Bruneau, P. H. Dixneuf, J. Am. Chem. Soc.
2008, 130, 1156–1157.
[8] I. Ozdemir, S. Demir, N. Gurbuz, B. Cetinkaya, L.
Toupet, C. Bruneau, P. H. Dixneuf, Eur. J. Inorg. Chem.
2009, 1942–1949; S. Demir, I. Ozdemir, B. Cetinkaya,
J. Organomet. Chem. 2009, 694, 4025–4031.
[9] L. Ackermann, P. Novak, R. Vicente, N. Hofmann,
Angew. Chem. 2009, 121, 6161–6164; Angew. Chem.
Int. Ed. 2009, 48, 6045–6048; F. Pozgan, P. H. Dixneuf,
Adv. Synth. Catal. 2009, 351, 1737–1743; L. Acker-
mann, P. Novak, Org. Lett. 2009, 11, 4966–4969.
[10] S. Oi, Y. Ogino, S. Fukita, Y. Inoue, Org. Lett. 2002, 4,
1783–1785; S. Oi, H. Sato, S. Sugawara, Y. Inoue, Org.
Lett. 2008, 10, 1823–1826; S. Oi, E. Aizawa, Y. Ogino,
Y. Inoue, J. Org. Chem. 2005, 70, 3113–3119; S. Oi, K.
Sakai, Y. Inoue, Org. Lett. 2005, 7, 4009–4011.
[11] S. Oi, R. Funayama, T. Hattori, Y. Inoue, Tetrahedron
2008, 64, 6051–6059.
1
and ratios were determined by H NMR spectroscopy and
by GC analyses using anisole (0.5 mmol) as internal stan-
dard. According to previously reported spectroscopic data,
products were identified as 16a[6] and 17a.[6]
Arylation of N-phenylpyrazole: KOAc (0.05 mmol) and
catalyst 1 (0.025 mmol) were stirred in NMP (2 mL) at room
temperature in thick-walled glass tube for 1 h. Then N-phe-
nylpyrazole (0.5 mmol), chlorobenzene (1.25 mmol) and
K2CO3 (1.50 mmol) were added. The resulting mixture was
stirred at 1208C. The purification of the arylated product
was carried out as explained above. Conversions were deter-
1
mined by H NMR spectroscopy and by GC analyses using
[12] A. Prades, M. Viciano, M. Sanau, E. Peris, Organome-
anisole (0.5 mmol) as internal standard. According to previ-
ously reported spectroscopic data, product was identified as
18b.[20]
Deuteration of pyridines in MeOH-d4: A mixture of the
substrate (0.5 mmol) and catalyst 1 (0.025 mmol) in MeOH-
d4, was heated at 1208C in a thick-walled glass tube fitted
with a Teflon cap. At the desired reaction times, aliquots
were extracted from the reaction vessel and added to an
NMR tube with 0.5 mL of CDCl3.
tallics 2008, 27, 4254–4259.
[13] N. Luo, Z. Yu, Chem. Eur. J. 2010, 16, 787.
[14] L. Mercs, A. Neels, M. Albrecht, Dalton Trans. 2008,
5570–5576.
[15] W. A. Herrmann, M. Elison, J. Fischer, C. Kocher,
G. R. J. Artus, Chem. Eur. J. 1996, 2, 772–780.
[16] M. A. Bennett, A. K. Smith, J. Chem. Soc. Dalton
Trans. 1974, 233–241.
[17] R. Corberan, M. Sanau, E. Peris, J. Am. Chem. Soc.
2006, 128, 3974–3979; A. Prades, R. Corberan, M.
Poyatos, E. Peris, Chem. Eur. J. 2009, 15, 4610–4613;
A. Prades, R. Corberan, M. Poyatos, E. Peris, Chem.
Eur. J. 2008, 14, 11474–11479.
[18] P. Arockiam, V. Poirier, C. Fischmeister, C. Bruneau,
P. H. Dixneuf, Green Chem. 2009, 11, 1871–1875.
[19] B. Chaudret, R. Poilblanc, Organometallics 1985, 4,
1722–1726; P. G. Jessop, R. H. Morris, Coord. Chem.
Rev. 1992, 121, 155–284; S. Sabo-Etienne, B. Chaudret,
Coord. Chem. Rev. 1998, 178, 381–407; F. Kakiuchi, S.
Murai, Acc. Chem. Res. 2002, 35, 826–834; M. H. G.
Prechtl, M. Holscher, Y. Ben-David, N. Theyssen, R.
Loschen, D. Milstein, W. Leitner, Angew. Chem. 2007,
119, 2319–2322; Angew. Chem. Int. Ed. 2007, 46, 2269–
2272.
Acknowledgements
We gratefully acknowledge financial support from MEC of
Spain (CTQ2008-04460) and Bancaixa (P1.1B2007-04;
P1.1A2008-02). We also like to thank the Ramon y Cajal pro-
gram (M.P.). A.P. thanks the Ministerio de Ciencia e Innova-
ciꢀn for a fellowship. The authors are grateful to the Serveis
Centrals d’Instrumentaciꢀ Cientꢁfica (SCIC) of the Universi-
tat Jaume I for providing us with spectroscopic facilities. We
also wish to thank Prof. Feliu Maseras from the ICIQ for his
useful comments on the mechanism of the reactions under
study.
[20] M. Kim, J. Kwak, S. Chang, Angew. Chem. 2009, 121,
9097–9101; Angew. Chem. Int. Ed. 2009, 48, 8935–
8939.
References
[1] W. J. Sommer, M. Weck, Coord. Chem. Rev. 2007, 251,
860–873; M. Pagliaro, S. Campestrini, R. Ciriminna,
Chem. Soc. Rev. 2005, 34, 837–845; B. M. Trost, F. D.
Toste, A. B. Pinkerton, Chem. Rev. 2001, 101, 2067–
2096.
[2] B. Therrien, Coord. Chem. Rev. 2009, 253, 493–519.
[3] V. Dragutan, I. Dragutan, L. Delaude, A. Demonceau,
Coord. Chem. Rev. 2007, 251, 765–794.
[21] A. F. Thomas, Deuterium Labeling in Organic Chemis-
try, Meridith Corporation, New York, 1971; T. H.
Lowry, K. S. Richardson, Mechanism and Theory in Or-
ganic Chemistry, Harper and Row, New York, 1987; U.
Pleiss, R. Voges, Synthesis and Applications of Isotopi-
cally Labeled Compounds, Vol. 7, John Wiley, New
York, 2001; T. Junk, W. J. Catallo, Chem. Soc. Rev.
1997, 26, 401–406.
[4] A. Mukherjee, Synlett 2006, 1128–1129; B. Schmidt,
Eur. J. Org. Chem. 2004, 1865–1880; B. Alcaide, P. Al-
mendros, Chem. Eur. J. 2003, 9, 1259–1262.
[22] M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J.
Am. Chem. Soc. 2006, 128, 8754–8756; D. Garcia-Cua-
Adv. Synth. Catal. 2010, 352, 1155 – 1162
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1161

Amparo Prades et al.
FULL PAPERS
drado, A. A. C. Braga, F. Maseras, A. M. Echavarren, J.
Am. Chem. Soc. 2006, 128, 1066–1067.
[25] M. A. Bennett, T. N. Huang, T. W. Matheson, A. K.
Smith, Inorg. Synth. 1982, 21, 74–78.
[26] M. Melchart, A. Habtemariam, O. Novakova, S. A.
Moggach, F. P. A. Fabbiani, S. Parsons, V. Brabec, P. J.
Sadler, Inorg. Chem. 2007, 46, 8950–8962.
[27] A. Sala, F. Ferrario, E. Rizzi, S. Catinella, P. Traldi,
Rapid Commun. Mass Spectrom. 1992, 6, 388–393.
[28] L. Ackermann, Org. Lett. 2005, 7, 3123–3125.
[23] W. D. Jones, Acc. Chem. Res. 2003, 36, 140–146.
[24] K. E. Janak, D. G. Churchill, G. Parkin, Chem.
Commun. 2003, 22–23; D. G. Churchill, K. E. Janak,
J. S. Wittenberg, G. Parkin, J. Am. Chem. Soc. 2003,
125, 1403–1420.
1162
asc.wiley-vch.de
ꢅ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1155 – 1162