Microwave-Promoted ortho-C?H Bond (Hetero)arylation of Arylpyrimidines in Water Catalyzed by Ruthenium(II)?Carboxylate

Article abstract of DOI:10.1002/cctc.201800250

Efficient diarylation of ortho-C?H bonds of 2-arylpyrimidines was achieved by Ru(II)?carboxylate-catalyzed reaction with aryl bromides in water, whereas meta-substituted phenylpyrimidines selectively led to monoarylation. The reaction is strongly accelerated under microwave irradiation, and is compatible with various functional groups on both coupling partners. As established from Hammett plots, electron-withdrawing groups on the pyrimidine substrates facilitate the arylation, while both, electron-withdrawing and electron-donating groups on the aryl bromides lead to a faster reaction. The C?H functionalization of 2-arylpyrimidines with heteroaryl halides provides potential multidentate ligands.

Full text of DOI:10.1002/cctc.201800250

Accepted Article
Title: Microwave-promoted ortho-C-H Bond (Hetero)arylation of
Arylpyrimidines in Water Catalyzed by Ruthenium(II)-Carboxylate
Authors: Miha Drev, Uroš Grošelj, Bine Ledinek, Franc Perdih, Jurij
Svete, Bogdan Štefane, and Franc Požgan
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10.1002/cctc.201800250
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Microwave-promoted ortho-C–H Bond (Hetero)arylation of
Arylpyrimidines in Water Catalyzed by Ruthenium(II)–Carboxylate
Miha Drev,[a] Uroš Grošelj,[a] Bine Ledinek,[a]‡ Franc Perdih,[a] Jurij Svete,[a] Bogdan Štefane[a] and
Franc Požgan*[a]
[9]
Abstract: Efficient diarylation of ortho-C–H bonds of 2-
arylpyrimidines was achieved by Ru(II)–carboxylate-catalyzed
reaction with aryl bromides in water, whereas meta-substituted
phenylpyrimidines selectively led to monoarylation. The reaction is
strongly accelerated under microwave irradiation, and is compatible
with various functional groups on both coupling partners. As
established from Hammett plots, electron-withdrawing groups on the
pyrimidine substrates facilitate the arylation, while both, electron-
withdrawing and electron-donating groups on the aryl bromides lead
to a faster reaction. The C–H functionalization of 2-arylpyrimidines
with heteroaryl halides provides potential multidentate ligands.
disubstituted benzamide (96%) in the presence of [Rh(cod)Cl]2
and naphthylation (48% mono, 30% di) via Rh(III)-catalyzed C–
H activation[10] have been reported. RuCl3 was used as a
catalyst for diphenylation of 2-phenylpyrimidine either with
phenyltosylate (85%)[11] or with phenyl iodide (83%) but in the
presence of peroxide in NMP.[12] Nakamura and co-workers
demonstrated
an
iron-catalyzed
phenylation
of
2-
phenylpyrimidine (81% mono, 9% di) with the corresponding
Grignard reagent using 1,2-dichloro-2-methylpropane as an
oxidant.[13] The catalytic system arising from [Cp*RhCl2]2, AgF,
and Cu(OAc)2 was used in arylation of N-(2-pyrimidyl)indoles
with organosilicon reagents in THF/H2O solvent.[14] Cp*Rh(III)- or
Cp*Ir(III)-catalyzed
direct
ortho-C–H
arylation
of
2-
arylpyrimidines with quinone diazides furnished pyrimidyl-
containing phenols.[15] Oxidative C–H arylation of 2-
phenylpyrimidine with phenylboronic acid was achieved with
Co(II) catalyst (28%) in the presence of Mn(OAc)2 as oxidant.[16]
Very recently an efficient Rh(III)-catalyzed ortho-alkylation of
phenoxy substrates with diazo compounds was performed using
Introduction
Catalytic C–H bond activation and subsequent formation of new
C–C bonds, or C–heteroatom bonds, which avoids the use of
pre-functionalized coupling partners, has remarkably contributed
to the development of efficient processes for the construction of
complex molecular architectures from simple precursors.[1] By
reducing synthetic steps and improving atom economy, catalytic
C–H bond functionalization becomes more attractive in
comparison with classical catalytic cross-couplings. Although Pd
and Rh catalysts are very efficient in enabling the
functionalization of various C–H bonds,[2,3] the use of cheaper,
easy-to-prepare, air stable, often stable in water and functional
groups tolerant ruthenium(II) catalysts[4] have attracted much
interest in further development of catalytic systems for the C–H
bond activation. A wide variety of functional groups have been
evaluated as directing groups by chelation assistance,[5] of which
a great number are based on nitrogen as coordinating atom.[6]
A pyrimidine core can be found in many biologically active
natural or synthetic compounds and pharmaceutical agents, as
well as in ligands and functional materials, and consequently the
development of efficient methods for the synthesis of
functionalized, especially arylated or π-conjugated pyrimidines is
still highly desirable.[7] This can now elegantly be achieved via
pyrimidine-directed C–H bond activation/functionalization.[8]
However, mostly individual examples of catalytic ortho-C–H
bond arylation of 2-phenylpyrimidine emerged. One recent
example of diphenylation of 2-phenylpyrimidine with N,N-
pyrimidine as the directing group via
a
six-membered
rhodacyclic intermediate.[17] Even though the above mentioned
methodologies are capable of efficiently producing functionalized
pyrimidines, they usually require either the use of stoichometric
amounts of oxidant, high boiling point organic solvents,
extended reactions times, expensive Rh catalysts, or reactive
arylating reagents such as Grignard compounds.
As part of our ongoing interest in metal-catalyzed
functionalization of (hetero)arenes,[18] the direct ortho-C–H
diarylation of 4-phenylpyrimidine in 1,4-dioxane at temperature
of 150 °C has been reported[8] with a priviliged bulky carboxylate
partner. In the present study, we have investigated ways to
selectively arylate arylpyrimidines under greener conditions
under microwave activation. Although activation of sp2 C–H
bonds with ruthenium catalysts has been achieved in water,[19]
the examples of combining it with microwave heating are very
scarce. Adrio et al. have shown that direct arylation of 2-
phenylpyridine in the presence of RuCl3∙nH2O-Zn-NaOAc
catalytic system in water can be significantly accelerated by the
use of microwave irradiation.[20] There are several reports on Pd-
catalyzed C–H functionalization under microwave conditions
which require DMF or DMAc as solvents.[21] We describe herein
the first Ru(II)-catalyzed ortho-C–H (hetero)arylation of
pyrimidine substrates in water promoted by microwave under
milder environmentally benign conditions.
[a]
M. Drev, Prof. Dr. U. Grošelj, B. Ledinek, Prof. Dr. F. Perdih, Prof.
Dr. J. Svete, Prof. Dr. B. Štefane, and Prof. Dr. F. Požgan
Faculty of Chemistry and Chemical Technology, University of
Ljubljana, Večna pot 113, SI-1000 Ljubljana (Slovenia)
E-mail: franc.pozgan@fkkt.uni-lj.si
‡
Present address: Fakultät für Chemie und Mineralogie, Universität
Leipzig, Johannisallee 29, D-04103 Leipzig (Germany)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Screening of reaction conditions.[a]
Entry
1
Additive (mol%)
Solvent
H2O
T (°C)
Time (min)
30
Conv.[b] (%)
92
2a/3a/4a[b]
–
180
30/67/3
2
KOPiv (20)
H2O
180
180
180
180
130
150
150
150
150
30
30
30
30
60
60
60
60
60
84
34/60/6
2a (18%),[c] 3a (43%)[c]
3
PCCA (20)
H2O
99
4/85/10
4
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
PCCA (20)/PPh3 (10)
H2O
100
100
99
0/90/10
3a (86%),[c] 4a (3%)[c]
5[d]
H2O
0/98/2
3a (92%)[c]
6
H2O
32/60/8
0/94/6
7
H2O
100
99
8
NMP
toluene
1,4-dioxane
38/62/0
75/20/5
45/45/10
9
38
10
7
[a]Reagents and conditions: 1a (0.25 mmol), 4-bromotoluene (0.625 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Na2CO3 (0.75 mmol), solvent (1 mL), argon.
[b]Conversion and ratio determined by 1H NMR analysis. [c]Isolated yield by radial chromatography. [d]1 mmol 1a used. MW = microwave heating
selectivity (Table 1, entry 3). The activity of the ruthenium
catalyst system was further improved by employing of
combination of PCCA/PPh3 as additives to give quantitative
conversion of 1a furnishing 3a and 4a in a 9:1 ratio (Table 1,
Results and Discussion
entry 4). Interestingly, performing the reaction of 1a with 4-
bromotoluene at a larger scale (1 mmol of 1a) resulted in higher
isolated yield of 3a with negligible formation of by-product 4a
(Table 1, entry 5 vs. 4). Conversion and diarylation selectivity
were not affected by the base used; Na2CO3, Li2CO3, Cs2CO3,
K3PO4, KOAc: 100% conv., 3a/4a ~90/10. We have also tried
other carboxylic acids, such as 2-mesitylenecarboxylic acid
(2a/3a/4a, 6/84/10), 1-adamantanecarboxylic acid (2a/3a/4a,
2/90/8), and N-acylglycine (2a/3a/4a, 3/89/8), but bulky PCCA
was most efficient (2a/3a/4a, 0/98/2). Notably, when the reaction
of 1a with 4-bromotoluene was performed under optimized
We initiated our investigation with the coupling reaction of 2-
phenylpyrimidine (1a) and 4-bromotoluene with Ru(II) catalyst
employing microwave heating (MW) in water. Pleasingly, 92%
conversion was achieved in the presence of 5 mol% [RuCl2(p-
°
cymene)]2 as the catalyst in only 0.5 h at 180 C without the
addition of any sufactant (Table 1, entry 1). The analysis of the
crude reaction mixture revealed the formation of the expected
mono- and diarylated products 2a and 3a, and a small amount
(3%) of compound 4a as a formal homocoupling product of 2a.
The addition of catalytic amount of KOPiv had a slightly negative
effect on the conversion degree (Table 1, entry 2). Interestingly,
the use of sterically demanding carboxylate ligand formed in situ
from bulky 1-phenylcyclopentane-1-carboxylic acid (PCCA) and
Na2CO3 significantly improved both, conversion and diarylation
°
conditions though with conventional heating (180 C) without
microwaves for 0.5 h, a 59% conversion (2a/3a/4a, 80/16/4) was
observed,
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. Table 2. Scope of ortho-C–H functionalization of pyrimidines 1 with aryl bromides.[a]
[a]Reagents and conditions: 1 (0.25 mmol), aryl bromide (0.625 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Na2CO3 (0.75 mmol), PCCA (0.05 mmol), PPh3 (0.025
mmol), H2O (1 mL), argon. [b]5–10 % of 4 detected in the crude reaction mixture. [c]2.5 equiv. of aryl chloride instead of aryl bromide used. [d]Ratio determined by
1H NMR analysis. Isolated yields are given.
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thus clearly demonstrating the profit of microwaves on the rate
of the reaction. Our Ru(II)/PCCA/PPh3 catalytic system is also
operative at temperatures lower than 180 C, but in order to
With optimized conditions in hand we investigated the scope and
generality of the direct ortho-arylation. The results shown in
Table 2 reveal that our methodology is compatible with a wide
range of substituents in the pyrimidine substrates and aryl
bromides. The reactions of 1a with 4-bromoanisole, 4-
°
reach high conversions and diarylation selectivity reaction times
had to be doubled (Table 1, entries 6 and 7). For comparison,
we performed the arylation reaction of 1a in different organic
bromoacetophenone,
bromofluorobenzene,
4-bromo-N,N-dimethylaniline,
4-
°
solvents with optimized catalytic system at 150 C for 1 h, but
4-bromo(trifluoromethyl)benzene,
water appeared to be by far the best solvent providing the
highest diarylation selectivity (Table 1, entry 7 vs. 8–10). The
best diarylation selectivity was obtained under conditions of
entry 5 offering 92% of isolated product 3a.
bromobenzene as well as with 1-bromo-4-tert-butylbenzene
proceeded smoothly to selectively give diarylated products 3b–
h in moderate-to-excellent yields (41–92%) within only 0.5 h.
With all the tested aryl bromides, complete consumption of 1a
was observed. It is worth mentioning that with the exception of
4-bromoanisole and 4-bromo(trifluoromethyl)benzene, the by-
products 4 were detected in all the crude reaction mixtures (see
ESI). It is important to note that the catalytic system comprising
Ru(II)/PCCA/PPh3 is not restricted only to aryl bromides. Indeed,
direct C–H arylation proceeded also with the less reactive aryl
chloride, as in the reactions of 1a with p-chloroanisole and p-
chlorotoluene nearly quantitative conversions (˃97%) though
moderate diarylation selectivities were observed in only 0.5 h,
and led to derivatives 2a,b and 3a,b.
We studied phenylpyrimidines 1b–f bearing meta-
substituents on the benzene ring in direct arylation with 4-
bromotoluene. With methyl- and trifluoromethyl-substituted
phenylpyrimidines 1b and 1c the reactions were completed in 1
h providing 59% and 51% isolated yields of monoarylated
products 2i and 2j, respectively. With methoxypyrimidine 1d a
100% conversion was obtained in 1 h leading to 58% and 25%
isolated yields of both, mono- and diarylated products 2k and 3k.
Interestingly, fluoro-substituted pyrimidine 1e gave exclusively
sterically more congested diarylated product 2l (69% yield)
already in 0.5 h, while a chloro-analogue 1f yielded an
aproximately 1:1 mixture of mono- and diarylated products 2m
(45% yield) and 3m (40% yield) within the same reaction time.
Finally, 2-(m-methylphenyl)pyrimidine (1b) was reacted for 0.5–1
Figure 1. Time profile of the arylation of 1a with 4-bromotoluene. Relative
amounts determined by 1H NMR of the crude reaction mixtures.
A time profile of the reaction of 1a with 4-bromotoluene at 180 °C
in water catalyzed by Ru(II)/PCCA/PPh3 system revealed that
the reaction is very fast under microvawe heating. An 87%
conversion with the formation of 2a/3a/4a in a ratio of 60/32/8
was obtained instantly after reaching the temperature 180 °C (~3
min) (Fig. 1, also see ESI). Ten-minute heating at 180 °C
resulted already in nearly complete conversion with 4/90/6 ratio
of 2a/3a/4a, and after additional 20 min the monoarylated
product 2a was not detected. However, the relative amount
(~10%) of the homocoupling product 4a formed at the begining,
remained constant during the course of the reaction.
h
with 4-bromoanisole, 4-bromo-N,N-dimethylaniline, 4-
bromofluorobenzene, bromobenzene, and 4-
bromo(trifluoromethyl)benzene to give high isolated yields (70–
83%) of monoarylated products 2n–s, while 4-
bromoacetophenone gave a 53% yield of diarylated product 3t
together with 30% of monoarylated product 2t.
Scheme 1. Successive arylation of 1b. Reagents and conditions: 1b (0.25 mmol), aryl bromide (0.3125 or 0.5 mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Na2CO3
(0.75 mmol), PCCA (0.05 mmol), PPh3 (0.025 mmol), H2O (1 mL), argon.
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6[d]
85
45
5/95
not isolated
Since arylation of meta-substituted pyrimidines preferentially
furnished monoarylated products due to steric hindrance (see
Table 2), the remaining ortho C–H bond could be utilized for
further functionalization. Indeed, the monoarylated derivative 2o
was first obtained (NMR evidence: 98% conversion; mono/di,
95/5) from the monoarylation of pyrimidine 1b with
bromobenzene in the presence of Ru(II)/PCCA/PPh3 at the less
hindered site (Scheme 1). Then 4-bromoacetophenone together
with an additional amount of Ru(II)/PCCA/PPh3 were added to
the crude product in order to execute the second ortho-arylation.
Consequently, the mixed diarylated pyrimidine product 3u was
isolated in 65% overall yield.
7
90/10
8
9
30
21
100/0
100/0
not isolated
After successful arylations of arylpyrimidines 1 with aryl
bromides we turned our attention to ortho-C–H functionalization
of 1a with heteroaromatic halides for their potential to access
bidentate ligands. The reactions were systematically stopped
after 0.5 h. It turned out that heteroaryl halides were in general
less reactive than para-substituted aryl bromides. With 2-
bromopyridine or 2-chloropyridine 90% conversion was obtained
leading to dominant formation of the monoarylated product 5a
(Table 3, entries 1 and 2). The reactions with 6-methyl-2-
bromopyridine and 2-bromoquinoline attained quantitative
conversions and provided almost exclusively diarylated products
6b and 6c in moderate yields (Table 3, entries 3 and 4).
10
11
60
75/25
5/95
100
Table 3.[a] Scope of ortho-C–H functionalization of 1a with heteroaryl halides.
12
13
99
98
5/95
Entry
1
Het-X
Conv.
(%)[b]
5/6[b]
Yield (%)[c]
0/100
90
64/36
14
90
23/77
2
3
85
58/42
5/95
not isolated
100
[a]Reagents and conditions: 1a (0.25 mmol), heteroaryl halide (0.75 mmol),
[RuCl2(p-cymene)]2 (0.0125 mmol), Na2CO3 (0.75 mmol), PCCA (0.05
mmol), PPh3 (0.025 mmol), H2O (1 mL), argon. [b]Conversion and ratio
4
5
97
0/100
0/100
°
determined by 1H NMR analysis. [c]Isolated yield. [d]performed at 150 C for
1 h.
On the other hand, the diarylated product 6d was obtained
by the reaction of 1a with 2-bromo-3-methylpyridine with high
isolated yield (Table 3, entry 5). Performing the reaction of 1a
100
°
and 2-bromo-3-methylpyridine at lower temperature (150 C) for
extended time of 1 h resulted in decrease of conversion but with
comparable diarylation selectivity (Table 3, entry 6 vs. 5).
Pyrimidyl halides and 2-chloropyrazine were less suitable
arylating agents than pyridine derivatives and predominantly
yielded monoarylated products 5e–g (Table 3, entries 7–10).
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Five-membered heteroaromatics also participated in the present
arylation reaction of C–H bonds as coupling partners. Pyrimidine
1a reacted with bromothiophenes nearly quantitatively to give
diarylated products 6h–j in moderate isolated yields together
with isolable small quantities of dimers 7h–j, while monoarylated
products were not detected (Table 3, entries 11–13). With 2-
bromofuran, both, mono- and diarylated products 5k and 6k
were isolated (Table 3, entry 14).
[a]Reagents and conditions: 1b (0.25 mmol), [RuCl2(p-cymene)]2 (0.0125
mmol), Na2CO3 (0.75 mmol), PCCA (0.05 mmol), PPh3 (0.025 mmol), D2O (1
mL), argon. [b]Labelling assigned by 1H NMR.
We were also able to isolate metallacycle 10 from the reaction of
1a with 2 equiv. of [(p-cymene)RuCl2]2 by using the method
reported by Dixneuf et al. for the synthesis of five-membered
ruthenacycles from arene with some N-containing functionalities
(Scheme 3).[22] Ruthenacycle 10 successfully catalyzed the
arylation of 1a with 4-bromotoluene and provided identical
reaction outcome as the pre-catalyst [RuCl2(p-cymene)]2
(Scheme 3 vs. Table 1, entry 4: 3a (90%), 4a (10%) at 180 °C).
Scheme 2. Diarylation of 2-arylpyrimidine 8 with substitution on the pyrimidine
ring. Reagents and conditions: 8 (0.25 mmol), aryl bromide (0.625 mmol),
[RuCl2(p-cymene)]2 (0.0125 mmol), Na2CO3 (0.75 mmol), PCCA (0.05 mmol),
PPh3 (0.025 mmol), H2O (1 mL), argon.
Scheme 3. Synthesis of and catalysis with cyclometallated complex 10.
Finally, we performed the C–H arylation of 2-arylpyrimidine
substrate 8 containing substituents on the pyrimidine and
benzene rings. The reactions of 8 with 4-bromoacetophenone,
4-bromoanisole, and 2-bromo-3-methylpyridine proceeded
smoothly in 0.5 h to give selectively diarylated products 9a–c in
good yields (Scheme 2).
To demonstrate the applicability of the synthesized heteroaryl-
pyrimidines as potential ligands, the compound 6d was
evaluated for its coordination to a ruthenium(II) center. The
reaction of pyrimidine
6d with [RuCl2(p-cymene)]2 in the
The reaction of methyl-containing pyrimidine 1b with
Ru(II)/PCCA/PPh3 catalytic system in deuteriated water under
presence of NaPF6 in methanol at room temperature for only 0.5
h resulted in the formation of a cationic complex 11 in an
excellent 86% isolated yield (Scheme 4). The structure of 11
was unambiguously confirmed by X-ray analysis, which revealed
that the ligand 6d is coordinated to the ruthenium ion in a
bidentate manner through the formation of a seven-membered
chelate ring (see ESI).
°
microwave irradiation at 130 C for 5 min resulted in a more
pronounced H/D exchange at C-6' than at C-2' (Table 4). This
indicates that C–H activation is reversible by nature, and occurs
more easily at the less hindered site. However, at elevated
temperature (180 °C), a 95% H/D exchange at both ortho
positions was observed. More interestingly, we noticed that H-
4,6 and H-5 protons of the pyrimidine ring also exchanged with
deuterium, though to a lesser extent (see ESI). Noteworthy, H/D
exchange did not occur in the absence of catalyst. These
experiments demonstrate, that our Ru(II)/PCCA/PPh3 catalytic
system can also be utilized in hydrogen isotope exchange
labelling under microwave irradiation in water.
Table 4. Deuterium exchange experiments.[a]
Scheme 4. Coordination of ruthenium to bis(pyridine)-pyrimidine ligand.
To get the insight into the mechanism of the arylation in water
under microwave heating conditions, competitive experiments
were carried out. First, equimolar amounts of 1a and meta-
substituted 2-phenylpyrimidine 1b–f were reacted with excess of
4-bromotoluene (2.5 equiv.). A Hammet plot resulted in a linear
fit with positive slope of ρ = 0.25 indicating that electron-
withdrawing groups facilitate the arylation (Fig. 2).
% incorporation of deuterium in the given position[b]
H-4
0
H-5
0
H-6
0
H-2’
16
H-6’
83
130 °C, 5 min
180 °C, 30 min
75
43
75
95
95
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dimethylaniline. However, the arylation selectivity was more
pronounced with substrate 1c having electron-withdrawing F3C
group and approaches close to 1:1 in the case of 1b bearing
weakly electron-donating Me group. These results suggest that
arylation is more sensitive to the electronic nature of the
pyrimidine substrate than to that of substituents on the aryl
bromide. If electronic properties of substituents on the aryl
bromide were important, one would expect electron-poor 4-
bromoacetophenone to react faster with pyrimidine 1b having
electron-donating group.
Figure 2. Hammett plot of 2-(m-R-C6H4)pyrimidines 1b–f with 4-bromotoluene.
Next, we carried out intermolecular competition experiments by
reacting equimolar amounts of phenyl bromide and electronically
different para-substituted aryl bromides with sterically hindered
methyl-containing pyrimidine 1b (Fig. 3). The data plotted in Fig.
3 represent a V-shaped Hammett plot, which clearly indicates a
change in reaction mechanism at the transition from electron-
donating to electron-withdrawing aryl bromide substitution.[23]
Although resulting ρ values (ρ(EDG) = –1.0, ρ(EWG) = +1.1) are
relatively small and must be interpreted with caution, the change
in sign is indicative for minor, yet mechanistically significant,
adjustments to the redistribution of electron charge density
during traversal of the rate determining transition state(s).[24]
In addition, competition experiments reacting 4-
bromoacetophenone and 4-bromo-N,N-dimethylaniline with
differently meta-substituted phenylpyrimidines were carried out
(Scheme 5, also see ESI). Both phenylpyrimidines 1b (R = Me)
and 1c (R = F3C) bearing either electron-donating or electron-
withdrawing group, reacted preferentially with 4-bromo-N,N-
Figure 3. Hammett plot of methyl-pyrimidine 1b with p-R-C6H4Br.
Scheme 5. Intermolecular competition experiments of arylation.
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diarylated arene. Five-membered oxa- and tiaheterocycles
provided satisfactory yields of di-heteroarylated products. As
demonstrated with successful diarylations of 4-methyl-2-(4-
(trifluoromethyl)phenyl)pyrimidine, the presence of a methyl
group next to the pyrimidine nitrogen atom does not influence
the C–H activation process. This green methodology provides a
series of polyconjugated pyrimidines with high site-selectivity
On the basis of our experimental studies we proposed a
mechanism of C–H arylation reaction of 2-arylpyrimidines in
water as shown in Scheme 6. Coordination of pyrimidine 12 to
the Ru(II) center is followed by reversible cyclometallation,
assisted by carboxylate to give the complex 13 via concerted-
metallation-deprotonation (CMD) mechanism.[25] The oxidative
addition of aryl bromide followed by reductive elimination gives
the arylation product 16 with regeneration of Ru(II) catalyst. The
Hammett plot in Fig. 2 and the region on the left in Fig. 3
suggest that the reductive elimination is the rate-limiting step.
The arylation most probably proceeds through transition state 15,
where a developing negative charge can be stabilized by
electron-withdrawing meta-substituent (e.g. R = F3C) on the
pyrimidine substrate. Our observations are consistent with
through
synthesized bis(pyridyl)-pyrimidyl-substituted benzene acted as
bidentate-chelator, and coordinated to ruthenium via
a five-membered ruthenacyclic intermediate. The
a
pyrimidine and pyridine nitrogens. The insight into the
mechanism of the arylation reaction with aryl
†Electronic supplementary information (ESI) available. CCDC
1588516 (11). For ESI and crystallographic data in CIF or other
electronic format see DOI: …
results
of
direct
Ru(II)-catalyzed
arylation
of
N-
quinolinylbenzamides in toluene as reported by Chatani et al.[26]
Acknowledgements
Financial support from the Slovenian Research Agency through
grants P1-0230-0179 and P1-0230-0175 is gratefully
acknowledged. We thank EN-FIST Centre of Excellence,
Dunajska 156, 1000 Ljubljana, Slovenia, for using Bruker Alpha
FTIR spectrophotometer and Supernova diffractometer. We
thank Prof. Pierre H. Dixneuf (Institut des Sciences Chimiques,
Université de Rennes) for discussions and evaluation of this
manuscript.
Keywords: ruthenium • water • monoarylation • pyrimidines •
microwave
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Microwave-promoted ortho-C–H Bond
(Hetero)arylation of Arylpyrimidines
in Water Catalyzed by Ruthenium(II)–
Carboxylate
Ru(II)-catalyzed C–H bond cleavage of 2-arlylpyrimidines is achieved
by microwave irradiation in water as a green solvent.
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