Triorganoindium reagents in Rh-catalyzed C–H activation/C–C cross-coupling reactions of 2-arylpyridines

Article abstract of DOI:10.3390/molecules23071582

The activation of C–H bonds through catalytic reactions using transition metals is an important challenge in organic chemistry in which the intermediates are related to those produced in the classical cross-coupling reactions. As part of our research program devoted to the development of metal-catalyzed reactions using indium organometallics, a protocol for the C–H activation and C–C coupling of 2-arylpyridines with triorganoindium reagents under Rh(I) catalysis is reported. Under the optimized conditions, we found that Me₃In and Ar₃In reagents reacted with 2-arylpyridines and related compounds in the presence of Rh(PPh₃)₃Cl, in PhCl/THF (9:1), at 120^?C for 48 h, to afford the ortho-coupling products in moderate to good yields. The nitrogen atom in the pyridine ring acts as a directing group to assist the functionalization at the ortho position of the aryl group forming a new C–C bond at this position.

Full text of DOI:10.3390/molecules23071582

molecules
Article
Triorganoindium Reagents in Rh-Catalyzed C–H
Activation/C–C Cross-Coupling Reactions
of 2-Arylpyridines
ID
ID
Ricardo Riveiros ID , Rubén Tato, José Pérez Sestelo * and Luis A. Sarandeses *
Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química, Universidade da
Coruña, E-15071 A Coruña, Spain; rriveiros@udc.es (R.R.); rubentatorodriguez@hotmail.com (R.T.)
* Correspondence: sestelo@udc.es (J.P.S.); luis.sarandeses@udc.es (L.A.S.);
Tel.: +34-881-012-041 (J.P.S.); +34-881-012-174 (L.A.S.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 24 May 2018; Accepted: 26 June 2018; Published: 29 June 2018
Abstract: The activation of C–H bonds through catalytic reactions using transition metals is an
important challenge in organic chemistry in which the intermediates are related to those produced in
the classical cross-coupling reactions. As part of our research program devoted to the development of
metal-catalyzed reactions using indium organometallics, a protocol for the C–H activation and C–C
coupling of 2-arylpyridines with triorganoindium reagents under Rh(I) catalysis is reported. Under
the optimized conditions, we found that Me3In and Ar3In reagents reacted with 2-arylpyridines and
related compounds in the presence of Rh(PPh3)3Cl, in PhCl/THF (9:1), at 120 ◦C for 48 h, to afford
the ortho-coupling products in moderate to good yields. The nitrogen atom in the pyridine ring acts
as a directing group to assist the functionalization at the ortho position of the aryl group forming a
new C–C bond at this position.
Keywords: C–H activation; cross-coupling reactions; rhodium-catalyzed; indium organometallics
1. Introduction
Since our discovery [
organometallics has been established as a useful tool in organic synthesis [
triorganoindium reagents (R3In) can efficiently couple with a variety of organic electrophiles under
palladium catalysis with high atom economy [ ]. The process can be extended to other organoindium
1
,2], the palladium catalyzed cross-coupling reaction of indium(III)
3,4]. In this reaction,
5–8
reagents [9–13] and transition metals in catalysis [14–17].
The formation of C–C bonds by C–H activation and cross-coupling with organometallics and
related nucleophiles under transition metal catalysis constitutes a methodology of great interest due to
the atom economy of the process and the challenge that represent the selective functionalization of
one C–H bond [18
coordination with the metal center to form a metallacycle that reacts with the organometallic to
afford the coupling product (Scheme 1) [20 21]. In this field, Oi et al. reported the Rh(I)-catalyzed
,19]. Usually, a heteroatom acts as directing group for the C–H activation through
,
ortho-arylation of 2-phenylpyridines with organotin compounds [22], a catalytic system also used
in related reactions using boronic acids [23]. In 2003, Murai et al. reported the Ru(II)-catalyzed
ortho-arylation of aryl ketones with boronates [24]. After these pioneering contributions, some coupling
reactions of organometallic species with C–H bonds under different transition metal catalysis (Pd, Rh,
Ru, Fe, Ir) have been reported [25
with organometallic reagents and related nucleophiles constitutes an interesting topic, developed
under palladium [31 32] and iron catalysis [33]. Despite the novelty of this methodology, and to the
best of our knowledge, organoindium compounds have not been applied as carbon nucleophiles
–30]. Among them, the C–H activation of 2-phenylpyridines
,
Molecules 2018, 23, 1582; doi:10.3390/molecules23071582
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1582
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in transition metal catalyzed C–H functionalization. Herein, we report the first examples of C–H
activation/cross-coupling reaction of R3In with 2-arylpyridines and related compounds under
Rh catalysis.
DG
H
DG
R
M’cat
+
R M
DG = directing group
M = B, Sn, Mg
M’cat = Pd, Rh, Ru, Fe, Ir
Scheme 1. C–H activation/C–C cross coupling reactions.
2. Results and Discussion
Our research started by testing the reaction of triorganoindium reagents with 2-(p-tolyl)pyridine
(1
) under Rh(I) catalysis as a model. In this reaction, the nitrogen atom should serve as a directing
group to activate a C–H bond forming a metallacycle, which, by a transmetallation and reductive
elimination process, should afford the C–H activation/C–C cross-coupling product. At the outset,
we found that the reaction of Me3In (100 mol %) with 1 in the presence of Rh(PPh3)3Cl (10 mol %) at
120 ◦C in THF gave methylated compound 2a in a low 16% yield after 48 h and most of the starting
2-(p-tolyl)pyridine recovered (Table 1, entry 1). Analogously, the reaction using Ph3In (100 mol %) gave
2b in 17% yield along with important amounts of 1,10-biphenyl, formed by reductive dimerization of
the organoindium in the reaction media (entry 2). Using other Rh(I) complexes such as Rh(cod)(acac),
Rh(nbd)(acac) or [Rh(cod)Cl]2 combined with phosphines did not improve the yields (entries 3–6).
The influence of the solvent was also studied and, considering that R3In are prepared as THF solutions,
various solvent mixtures were used. Using toluene/THF (9:1) the reaction with Ph3In (100 mol %) and
Rh(PPh3)3Cl (10 mol %) at 120 ◦C for 48 h gave 2b in a similar 18% yield (entry 7). Considering that
polar non-protic chlorinated solvents have been successfully used in Rh(I)-catalyzed C–H activation
reactions [22,34,35] 1,1,2,2-tetrachloroethane/THF (9:1) was tested as solvent, obtaining a 27% yield
of 2b and a 4% of the o,o0-disubstituted product 2bb (entry 8). Considering that some of the starting
0
2-(p-tolyl)pyridine is recovered and part of the Ph3In is consumed with the formation of 1,1 -biphenyl,
we decided to carry out the reaction using 150 mol % of Ph3In. Under these conditions, the yield of 2b
increased up to 42% (along with a 16% of 2bb; entry 9). Analogously, the reaction using 150 mol % of
Me3In also gave a satisfactory 60% yield of 2a (entry 10). Finally, we found that using chlorobenzene
as cosolvent the reaction results in a good 80% yield of 2a using Me3In, and in 47% yield of 2b in
the reaction with Ph3In (entries 11 and 12). Recently, Li et al. reported the arylation of arylpyridines
under rhodium catalysis using chlorobenzene as solvent [35]. Interestingly, we observed that the use
0
of chlorobenzene diminishes the formation of the o,o -disubstituted product and that the conversion of
the starting material is not complete under the reaction conditions.

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Table 1. Reaction of indium organometallics with 2-(p-tolyl)pyridine under rhodium catalysis 1.
R
Rh(I) cat. (10%)
N
N
N
R3In
+
+
solvent
Me
R
Me
R
Me
120 ºC, 48 h
1
2a, R = Me
2b, R = Ph
2aa, R = Me
2bb, R = Ph
Entry
R (mol % of R3In)
Catalyst
Solvent
Yield (%) 2
1
2
3
Me (100)
Ph (100)
Me (100)
Me (100)
Me (100)
Me (100)
Ph (100)
Ph (100)
Ph (150)
Me (150)
Me (150)
Ph (150)
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(cod)(acac)
THF
THF
THF
THF
THF
THF
16
17
14
15
14
15
18
27 (4)
42 (16)
60 (34)
80 (12)
47 (6)
4
Rh(nbd)(acac)
[Rh(cod)Cl]2, Ph3P
[Rh(cod)Cl]2, Cy3P
Rh(PPh3)3Cl
5 3
6 3
7
Toluene/THF (9:1)
Cl2CHCHCl2/THF (9:1)
Cl2CHCHCl2/THF (9:1)
Cl2CHCHCl2/THF (9:1)
PhCl/THF (9:1)
8
9
10
11
12
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
PhCl/THF (9:1)
2
1 Reactions performed in a Schlenk tube using 10 mol % of the rhodium complex at 120 ◦C for 48 h. In parentheses
,
3
yield of the o,o0-dicoupling product (2aa
,
2bb) obtained.
5 mol % of rhodium complex and 20 mol % of
phosphine used.
With the optimized conditions in hand, we explored the versatility of the reaction using various
2-arylpyridines. The reaction of Me3In with 2-phenylpyridine ( ) yielded the methylated compound
7a in a good 84% yield (and a 7% of the o,o0-dicoupled product 7aa, Table 2, entry 3). Alternatively,
3
the reaction of Ph3In with 2-phenylpyridine (3) afforded 7b in 53% yield (6% of the disubstituted
compound 7bb, entry 4).
Table 2. Reaction of R3In with 2-arylpyridines under rhodium catalysis 1.
RhCl(PPh3)3 (10%)
N
N
R3In
+
R'
R'
PhCl/THF (9:1)
120 ºC, 48 h
R
1, 3–6
2-Arylpyridine
2, 7–10
Entry
R
Product
Yield (%) 2
N
N
1
Me
80 (12)
47 (6)
Me
Me
Me
2a
1
N
2
Ph
Me
Ph
2b

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Table 2. Cont.
Entry
2-Arylpyridine
R
Product
Yield (%) 2
N
N
3
Me
Ph
84 (7)
Me
3
7a
N
4
5
53 (6)
Ph
7b
N
N
Me
Ph
60
Me
8a
4
N
6
57
Ph
8b
N
N
N
N
7
Me
Ph
62
Me
5
9a
9b
N
N
8
57 (7)
Ph
N
N
9
Me
Ph
93
Me
6
10a
10b
N
10
72
Ph
N
25 3
11
CH2=CH
10c

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Table 2. Cont.
Entry
2-Arylpyridine
R
Product
N
Yield (%) 2
20 3
12
4-CF3C6H4
10d
CF3
N
45 3
13
4-FC6H4
10e
F
N
30 3
14
3-FC6H4
F
10f
1
2
Reactions performed in a Schlenk tube using 10 mol % of the rhodium complex at 120 ◦C for 48 h. In parentheses,
yield of the o,o0-dicoupling product obtained. Cl2CHCHCl2/THF (9:1) was used as solvent.
3
The reaction was also tested with 2-(2-naphthyl)pyridine (4), a compound with two
nonsymmetrical o-positions of the aryl group. Under the optimized conditions, the reaction of
4
with Me3In and Ph3In allowed the synthesis of 8a and 8b in 60% and 57% yields, respectively (entries 5
and 6) without isolation of the double coupling products. The selectivity for the first C–H activation in
a substrate where the two ortho positions are different in terms of electron density and steric hindrance
is remarkable.
Additionally, we also tested the reactivity of 2-phenylpyrimidine (5), a substrate possessing two
nitrogen atoms. The reaction with Me3In under the optimized conditions, afforded 9a in 62% yield as
the only product (entry 7). Using Ph3In, the monoarylated compound 9b was obtained in 57% yield,
accompanied by the formation of a 7% yield of the disubstituted product 9bb (entry 8).
To improve the selectivity of the process, we used a rigid substrate such as benzo[h]quinoline (
as starting material. In this case, the reaction of with Me3In afforded 10a as the only reaction product
in an excellent 93% yield (entry 9). Furthermore, the reaction of with Ph3In afforded compound 10b
6)
6
6
in a 72% yield (entry 10). In these set of experiments, we demonstrated the efficiency of organoindium
reagents in the transfer of methyl and phenyl groups in C–H coupling reactions with 2-arylpyridines.
At this point we also decided to test the versatility of the process using other triorganoindium
reagents under the same reaction condition and using 1,1,2,2-tetrachloroethane as solvent. The reaction of
trivinylindium with
other triarylindium species such as tris[4-(trifluoromethyl)phenyl]indium, tris(4-fluorophenyl)indium and
tris(3-fluorophenyl)indium, under the usual conditions, led to the compounds 10d in moderated yields
6 afforded 10c in a modest 25% yield (entry 11). Alternatively, the reaction of 6 with
–f
(20–45%; entries 12–14). Although the isolated yields of these last reactions might not be optimal, overall,
these results represent the first examples of application of triorganoindium reagents in the Rh-catalyzed
C–H activation and C–C cross-coupling with 2-arylpyridines and analogs and constitute a new entry in
the reactivity of these compounds.
Although the mechanism of these reactions was not studied, based on previous reports [22,23,34],
we believe the reaction proceeds via C–H activation of the ortho position of the 2-arylpyridine by an
organorhodium(I) intermediate, which is generated by transmetallation of Rh(I)Cl species with the
triorganoindium reagent. The resulting organoaryl(hydrido)rhodium species then undergoes reductive

Molecules 2018, 23, 1582
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elimination to give the coupling product and a Rh(I)H species. Finally, the chlorinated solvent could
participate in the regeneration of the active catalytic Rh(I) species by hydrogen/chloride exchange or
HCl elimination. As for the proposal of Oi et al. [22], trichloroethylene was detected by 1H NMR of the
reaction crude when 1,1,2,2-tetrachloroethane was used as solvent.
3. Materials and Methods
3.1. Materials and Reagents
All reactions were carried out in flamed dried glassware, under argon atmosphere, using standard
gastight syringes, cannulas, and septa. Reaction temperatures refer to external bath temperatures.
Anhydrous THF was obtained by distillation from the sodium ketyl of benzophenone. Chlorobenzene
and 1,1,2,2-tetrachloroethane were dried and stored over microwave-activated 4 Å molecular sieves.
All other commercially available reagents were used as received. Organolithium reagents (phenyllithium
and methyllithium) were titrated prior to use. Organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated by using a rotary evaporator at aspirator pressure. Reactions were monitored by TLC
using pre-coated silica gel plates (Alugram Xtra SIL G/UV254, 0.20 mm thick), UV light as the visualizing
agent and ethanolic phosphomolybdic acid as the developing agent. Flash column chromatography was
performed on silica gel (230–400 mesh). 1H and 13C NMR were recorded in CDCl3 at 300 MHz for 1H
and 75 MHz for 13C, at 300 K, and calibrated to the solvent peak. DEPT data were used to assign carbon
types (see Supplementary Materials). Mass spectra were obtained with EI ionization at 70 eV. IR spectra
were recorded on a FT-IR spectrometer with an ATR (Attenuated Total Reflectance) accessory.
3.2. Preparation of Triorganoindium Reagents
Triorganoindium compounds were prepared according to previously published methods [36] by
treatment of the corresponding organolithium reagent (3 equiv, ~0.5 M in THF) with a solution of InCl3
◦
(1 equiv, 0.45 M in THF) at
−
78 C and warming to room temperature. Organolithium reagents derived
from 1-bromo-4-(trifluoromethyl)benzene, 1-bromo-4-fluorobenzene, 1-bromo-3-fluorobenzene and
vinyl bromide were prepared by metal-halogen exchange reaction with t-BuLi (2 equiv) at −78 ◦C.
3.3. Preparation of Compounds 4 and 5
2-(2-Naphthyl)pyridine (4) [37]. To a solution of 2-bromopyridine (0.96 mL, 10.0 mmol) and Pd(dppf)Cl2
(408 mg, 0.5 mmol) in THF (50 mL), tri(2-naphthyl)indium (10.0 mmol, ~0.3 M in THF) was added.
The mixture was stirred at 80 ◦C during 20 h, and the reaction was quenched by addition of drops of
MeOH. The solvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed
with HCl (5%, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated.
The crude was purified by flash chromatography (10% EtOAc/hexane), affording, after concentration
and drying,
(CDCl3, 300 MHz
7.87–7.97 (m, 4 H), 8.16 (dd, J = 8.6, 1.8 Hz, 1 H), 8.50 (d, J = 1.5 Hz, 1 H), 8.77 (ddd, J = 4.9, 1.5,
1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
120.8 (CH), 122.1 (CH), 124.5 (CH), 126.3 (CH), 126.3
9
(1.05 g, 5.12 mmol, 51%) as a yellow solid. M.p. 69–70 ◦C (lit. [37], 77–78 ◦C); 1H NMR
7.27 (ddd, J = 7.2, 4.9, 1.0 Hz, 1 H), 7.50–7.55 (m, 2 H), 7.80 (td, J = 7.7, 1.8 Hz, 1 H),
)
δ
δ
(CH), 126.5 (CH), 127.6 (CH), 128.4 (CH), 128.7 (CH), 133.5 (C), 133.6 (C), 136.6 (C), 136.8 (CH), 149.7
(CH), 157.3 (C) ppm; IR (ATR) 3053, 3010, 2919, 2849 cm−1; MS (EI) m/z (%) 205 (M+, 100), 204
([M − H]+, 75); HRMS (EI) m/z calcd for C15H11N 205.0886, found 205.0881.
2-Phenylpyrimidine (5) [38]. To a solution of 2-chloropyrimidine (1.21 g, 10.0 mmol) and Pd(dppf)Cl2
(408 mg, 0.5 mmol) in THF (50 mL), triphenylindium (4.0 mmol, ~0.3 M en THF) was added. The
mixture was stirred at 80 ◦C for 4 h and the reaction quenched by addition of drops of MeOH. The
solvent was evaporated and EtOAc (25 mL) was added. The organic phase was washed with HCl
(5%, 15 mL), satd. NH4Cl (15 mL) and brine (15 mL), dried, filtered, and concentrated. The crude
was purified by flash chromatography (20% EtOAc/hexane) affording, after concentration and drying,
◦
◦
1
12 (1.42 g, 9.09 mmol, 91%) as a white solid. M.p. 36–38 C (lit. [38], 36–38 C). H NMR (CDCl3,

Molecules 2018, 23, 1582
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300 MHz
) δ 6.95 (t, J = 4.9 Hz, 1 H), 7.42–7.49 (m, 3 H), 8.47–8.50 (m, 2 H), 8.66 (d, J = 4.9 Hz, 2 H) ppm;
13C NMR (CDCl3, 75 MHz)
δ
119.0 (CH), 128.2 (2
×
CH), 128.6 (2
×
CH), 130.8 (CH), 137.5 (C), 157.1
(
2 × CH), 164.5 (C) ppm; IR (ATR) 3087, 3066, 3039 cm−1; MS (EI) m/z (%) 156 (M+, 92), 103 (100);
HRMS (EI) m/z calcd for C10H8N2 156.0682, found 156.0683.
3.4. General Procedure C–H Activation/C–C Cross-Coupling with Indium(III) Organometallics under Rhodium
Catalysis
In a Schlenk tube, a solution of R3In (0.375 mmol, ~0.3 M en THF) and the arylpyridine (0.25 mmol
)
were successively added to a solution of Rh(PPh3)3Cl (24 mg, 0.025 mmol) in chlorobenzene (20 mL).
◦
The mixture was stirred at 120 C during 48 h, and the reaction quenched by addition of drops
of MeOH. The solvent was evaporated and CHCl3 (25 mL) was added. The organic phase was
washed with aq. NH3 (5%, 15 mL), dried, filtered, and concentrated. The crude was purified by flash
chromatography (Et2O/hexane) affording, after concentration and drying, the cross-coupling products.
2-(2,4-Dimethylphenyl)pyridine (2a) [39]. Colorless oil (37 mg, 0.200 mmol, 80%). 1H NMR (CDCl3,
300 MHz
(d, J = 7.5 Hz, 1 H), 7.39 (dt, J = 7.9, 1.0 Hz, 1 H), 7.73 (td, J = 7.7, 1.8 Hz, 1 H), 8.69 (ddd, J = 4.9, 1.8,
1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
20.2 (CH3), 21.1 (CH3), 121.3 (CH), 124.0 (CH), 126.5
) δ 2.35 (s, 3 H), 2.38 (s, 3 H), 7.10 (d, J = 7.7 Hz, 2 H), 7.23 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.31
δ
(CH), 129.6 (CH), 131.4 (CH), 135.5 (C), 135.9 (CH), 137.6 (C), 137.9 (C), 149.1 (CH), 160.1 (C) ppm;
IR (ATR) 2954, 2922, 2853, 2360 cm−1; MS (EI) m/z (%) 183 (M+, 44), 182 ([M
m/z calcd for C13H13N 183.1043, found 183.1027.
−
H]+, 100); HRMS (EI)
2-(2,4,6-trimethylphenyl)pyridine (2aa) [40]. Colorless oil (6 mg, 0.030 mmol, 12%) 1H NMR (CDCl3,
300 MHz 2.03 (s, 6 H), 2.33 (s, 3 H), 6.94 (s, 2 H), 7.24–7.30 (m, 2 H), 7.18 (td, J = 7.7, 1.6 Hz, 1 H),
8.72–8.74 (m, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
20.0 (2 CH3), 21.0 (CH3), 121.6 (CH), 124.8
)
δ
δ
×
(CH), 128.3 (2
×
CH), 135.2 (C), 135.6 (2
×
C), 136.5 (CH), 137.5 (C), 149.2 (CH), 159.7 (C) ppm; IR (ATR)
2952, 2921, 2855, 2358 cm−1; MS (EI) m/z (%) 197 (M+, 34), 196 ([M
−
H]+, 100); HRMS (EI) m/z calcd
for C14H15N 197.1199, found 197.1181.
2-(5-Methyl[1,10-biphenyl]-2-yl)pyridine (2b) [41]. White solid (29 mg, 0.118 mmol, 47%). 1H NMR
(CDCl3, 300 MHz) 2.46 (s, 3 H), 6.86 (dt, J = 7.9, 1.0 Hz, 1 H), 7.08 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H),
7.14–7.19 (m, 2 H), 7.21–7.31 (m, 5 H), 7.36 (td, J = 7.7, 1.8 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 8.63 (ddd,
J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
21.2 (CH3), 121.0 (CH), 125.3 (CH), 126.6
(CH), 128.0 (2 CH), 128.3 (CH), 129.6 (2 CH), 130.4 (CH), 131.2 (CH), 135.0 (CH), 136.7 (C), 138.3
δ
δ
×
×
(C), 140.4 (C), 141.5 (C), 149.3 (CH), 159.2 (C) ppm; IR (ATR) 3025, 2921, 2852 cm−1; MS (EI) m/z (%) 245
(M+, 32), 244 ([M
−
H]+, 100); HRMS (ESI) m/z calcd for C18H16N ([M + H]+) 246.1277, found 246.1275.
2-(50-Methyl[1,10:30,10’-terphenyl]-20-yl)pyridine (2bb) [42]. White solid. (5 mg, 0.015 mmol, 6%) H
1
NMR (CDCl3, 300 MHz)
8.31 (ddd, J = 4.9, 1.6, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
2 × CH), 126.8 (CH), 127.5 (4 CH), 129.6 (4 CH), 130.1 (2 CH), 134.7 (CH), 135.8 (C), 137.7 (C),
δ
2.49 (s, 3 H), 6.85–6.92 (m, 2 H), 7.09–7.18 (m, 10 H), 7.26–7.32 (m, 3 H),
δ
21.2 (CH3), 120.6 (CH), 126.1
(
×
×
×
141.7 (2 × C), 141.7 (2
×
C), 148.4 (CH), 159.0 (C) ppm; IR (ATR) 3054, 3026, 2955, 2922, 2852 cm−1; MS
(EI) m/z (%) 321 (M+, 52), 320 ([M
−
H]+, 100); HRMS (ESI) m/z calcd for C24H20N ([M + H]+) 322.1590,
found 322.1589.
1
2-(2-Methylphenyl)pyridine (7a) [43]. Colorless oil (36 mg, 0.210 mmol, 84%). H NMR (CDCl3, 300 MHz
)
δ
2.38 (s, 3 H), 7.23–7.32 (m, 4 H), 7.39–7.43 (m, 2 H), 7.75 (td, J = 7.7, 1.9 Hz, 1 H), 8.71 (ddd, J = 4.9, 1.9,
1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
δ
20.2 (CH3), 121.5 (CH), 124.0 (CH), 125.8 (CH), 128.2
(CH), 129.6 (CH), 130.7 (CH), 135.7 (C), 136.0 (CH), 140.4 (C), 149.2 (CH), 160.0 (C) ppm; IR (ATR) 3059,
2924, 2359 cm−1; MS (EI) m/z (%) 169 (M+, 34), 168 ([M
([M − H]+) 168.0808, found 168.0814.
−
H]++, 100); HRMS (EI) m/z calcd for C12H10N
1
2-(2,6-dimethylphenyl)pyridine (7aa) [39]. Colorless oil (3 mg, 0.016 mmol, 7%) H NMR (CDCl3,
300 MHz) δ 2.05 (s, 6 H), 7.10–7.12 (m, 2 H), 7.18–7.29 (m, 3 H), 7.77 (td, J = 7.7, 1.9 Hz, 1 H), 8.73 (ddd,

Molecules 2018, 23, 1582
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J = 4.9, 1.9, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
δ
20.1 (2
×
CH3), 121.6 (CH), 124.4 (CH),
127.5 (2
×
CH), 127.8 (CH), 135.7 (2
×
C), 136.2 (CH), 140.4 (C), 149.7 (CH), 159.9 (C) ppm; IR (ATR)
2924, 2854, 2360, 2214 cm−1; MS (EI) m/z (%) 183 (M+, 35), 182 ([M
for C13H12N ([M − H]+) 182.0964, found 182.0963.
−
H]+, 100); HRMS (EI) m/z calcd
2-[1,10-Biphenyl]-2-yl-pyridine (7b) [44]. White solid (31 mg, 0.132 mmol, 53%). M.p. 86–87 ◦C (lit. [44],
86.5–87.5 C); 1H NMR (CDCl3, 300 MHz)
1 H), 7.15–7.19 (m, 2 H), 7.22–7.25 (m, 3 H), 7.39 (td, J = 7.7, 1.8 Hz, 1 H), 7.41–7.51 (m, 3 H), 7.69–7.74
(m, 1 H), 8.64 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
121.3 (CH), 125.3
(CH), 126.6 (CH), 127.6 (CH), 128.0 (2 CH), 128.5 (CH), 129.7 (2 CH), 130.4 (2
δ 6.89 (dt, J = 7.9, 1.0 Hz, 1 H), 7.10 (ddd, J = 7.5, 4.9, 1.0 Hz,
◦
δ
×
×
×
CH), 135.1 (CH),
−1
139.4 (C), 140.6 (C), 141.3 (C), 149.4 (CH), 159.2 (C) ppm; IR (ATR) 3052, 3018, 2919, 2850 cm
m/z (%) 231 (M+, 26), 230 ([M
; MS (EI)
−
H]+, 100); HRMS (ESI) m/z calcd for C17H14N ([M + H]+) 232.1120,
found 232.1123.
2-[1,10:30,10’-terphenyl]-20-yl-pyridine (7bb) [44]. White solid (4 mg, 0.013 mmol, 6%) M.p. 123–124 ◦C
◦
(lit. [44], 118–119.5 C); 1H NMR (CDCl3, 300 MHz)
td, J = 7.7, 1.8 Hz, 1 H), 7.45–7.48 (m, 2 H), 7.52–7.57 (m, 1 H), 8.33 (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H) ppm;
13C NMR (CDCl3, 75 MHz)
120.8 (CH), 126.2 (2 CH), 126.7 (CH), 127.6 (4 CH), 128.1 (CH), 129.4
C), 141.8 (2 C), 148.5 (CH), 158.9 (C);
δ 6.88–6.94 (m, 2 H), 7.10–7.18 (m, 10 H), 7.30
(
δ
×
×
(2
×
CH), 129.6 (4
×
CH), 134.8 (CH), 138.5 (C), 141.6 (2
×
×
IR (ATR) 3056, 2923 cm−1; MS (EI) m/z (%) 307 (M+, 51), 306 ([M
−
H]+, 100); HRMS (ESI) m/z calcd for
C23H18N ([M + H]+) 308.1433, found 308.1429.
◦
2-(3-Methyl-2-naphthyl)pyridine (8a) [39]. White solid (33 mg, 0.150 mmol, 60%). M.p. 79–80 C;
1H NMR (CDCl3, 300 MHz)
δ 2.53 (s, 3 H), 7.29 (ddd, J = 8.2, 5.2, 1.5 Hz, 1 H), 7.42–7.53 (m, 3 H),
7.75–7.87 (m, 4 H), 7.89 (s, 1 H), 8.76 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
δ 20.8 (CH3), 121.7 (CH), 124.2 (CH), 125.4 (CH), 126.3 (CH), 126.9 (CH), 127.9 (CH), 128.7 (CH), 128.8
(CH), 131.9 (C), 133.4 (C), 133.8 (C), 136.2 (CH), 139.4 (C), 149.2 (CH), 160.0 (C) ppm; IR (ATR) 3052,
3007, 2958, 2920, 2849 cm−1; MS (EI) m/z (%) 219 (M+, 57), 218 ([M
−
H]+, 100); HRMS (EI) m/z calcd
for C16H13N 219.1043, found 219.1035.
◦
2-(3-Phenyl-2-naphthyl)pyridine (8b) [44]. Brown solid (40 mg, 0.142 mmol, 57%). M.p. 107–108 C
(lit. [44], 103.5–106 ◦C); 1H NMR (CDCl3, 300 MHz)
4.9, 1.0 Hz, 1 H), 7.28 (s, 5 H), 7.43 (td, J = 7.7, 1.8 Hz, 1 H), 7.52–7.55 (m, 2 H), 7.89–7.97 (m, 3 H), 8.22
(s, 1 H), 8.68 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
121.4 (CH), 125.5 (CH),
126.3 (CH), 126.7 (CH), 126.7 (CH), 127.7 (CH), 128.0 (2 CH), 128.2 (CH), 129.5 (CH), 129.8 (2 CH),
δ 6.98 (dt, J = 7.9, 1.0 Hz, 1 H), 7.14 (ddd, J = 7.5,
δ
×
×
130.1 (CH), 132.6 (C), 133.2 (C), 135.1 (CH), 137.8 (C), 138.5 (C), 141.3 (C), 149.4 (CH), 159.1 (C) ppm;
IR (ATR) 3054, 2923, 2853 cm−1; MS (EI) m/z (%) 281 (M+, 47), 280 ([M
calcd for C21H14N ([M − H]+) 280.1121, found 280.1126.
−
H]+, 100); HRMS (EI) m/z
1
2-(2-Methylphenyl)pyrimidine (9a) [45]. Pale yellow oil (26 mg, 0.155 mmol, 62%). H NMR (CDCl3,
300 MHz) δ 2.56 (s, 3 H), 7.22 (t, J = 4.9 Hz, 1 H), 7.27–7.36 (m, 3 H), 7.80–7.83 (m, 1 H), 8.85 (d, J = 4.9 Hz,
2 H) ppm; 13C NMR (CDCl3, 75 MHz)
131.2 (CH), 137.1 (C), 138.1 (C), 156.8 (2
δ
20.9 (CH3), 118.4 (CH), 125.8 (CH), 129.4 (CH), 130.3 (CH),
×
CH), 167.7 (C) ppm; IR (ATR) 3034, 2924, 2853 cm−1; MS (EI)
m/z (%) 170 (M+, 73), 169 ([M
−
H]+, 100); HRMS (EI) m/z calcd for C11H10N2 170.0838, found 170.0830.
2-[1,10-Biphenyl]-2-yl-pyrimidine (9b) [46]. White solid (33 mg, 0.142 mmol, 57%). M.p. 100–102 C
◦
◦
(lit. [46], 102–103 C); 1H NMR (CDCl3, 300 MHz)
(m, 3 H), 7.46–7.56 (m, 3 H), 7.80–7.83 (m, 1 H), 8.64 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3,
75 MHz 118.4 (CH), 126.4 (CH), 127.3 (CH), 127.9 (2 CH), 129.1 (2 CH), 129.3 (CH), 130.4 (CH),
CH), 168.1 (C) ppm; IR (ATR) 3057, 3024, 2922,
H]+, 100); HRMS (EI) m/z calcd for C16H11N2
δ 7.10 (t, J = 4.9 Hz, 1 H), 7.14–7.18 (m, 2 H), 7.21–7.27
)
δ
×
×
130.7 (CH), 138.2 (C), 141.4 (C), 141.6 (C), 156.7 (2
×
2852, 2326 cm−1; MS (EI) m/z (%) 232 (M+, 25), 231 ([M
([M − H]+) 231.0917, found 231.0915.
−

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0
0
0
0
2-[1,1 :3 ,1 ’-terphenyl]-2 -yl-pyrimidine (9bb) [46]. White solid (5 mg, 0.016 mmol, 7%) M.p. 145–146 ◦C
(lit. [46], 146–148 ◦C); 1H NMR (CDCl3, 300 MHz)
6.92 (t, J = 4.9 Hz, 1 H), 7.12–7.20 (m, 10 H), 7.48
(dd, J = 7.5, 1.0 Hz, 2 H), 7.57 (dd, J = 8.7, 6.4 Hz, 1 H), 8.46 (d, J = 4.9 Hz, 2 H) ppm; 13C NMR (CDCl3,
75 MHz) 118.0 (CH), 126.4 (2 CH), 127.8 (4 CH), 128.6 (CH), 129.1 (4
CH), 129.2 (2 × CH), 137.6
(C), 141.3 (2 C), 155.9 (2
δ
δ
×
×
×
×
C), 141.4 (2
×
×
CH), 168.1 (C) ppm; IR (ATR) 3058, 2918, 2850, 2324 cm−1
;
MS (EI) m/z (%) 308 (M+, 76), 307 ([M
307.1230, found 307.1231.
−
H]+, 100); HRMS (EI) m/z calcd for C22H15N2 ([M − H]+)
10-Methylbenzo[h]quinoline (10a) [38]. White solid (45 mg, 0.232 mmol, 93%). M.p. 70–71 ◦C; 1H NMR
(CDCl3, 300 MHz) 3.40 (s, 3 H), 7.49 (dd, J = 8.0, 4.3 Hz, 1 H), 7.57–7.60 (m, 2 H), 7.66 (d, J = 8.8 Hz,
1 H), 7.80–7.83 (m, 2 H), 8.16 (dd, J = 8.0, 1.9 Hz, 1 H), 9.06 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR
(CDCl3, 75 MHz) 27.2 (CH3), 120.5 (CH), 125.4 (CH), 126.7 (CH), 127.2 (CH), 127.4 (C), 128.8 (CH),
δ
δ
129.9 (C), 131.1 (CH), 135.1 (C), 135.2 (CH), 138.7 (C), 147.1 (CH), 149.0 (C) ppm; IR (ATR) 3046, 2960,
2922, 2851, 2740 cm−1; MS (EI) m/z (%) 193 (M+, 100), 192 ([M
−
H]+, 66); HRMS (ESI) m/z calcd for
C14H12N ([M + H]+) 194.0964, found 194.0961.
1
10-Phenylbenzo[h]quinoline (10b) [44]. Yellow oil (46 mg, 0.180 mmol, 72%). H NMR (CDCl3, 300 MHz)
δ
7.33 (dd, J = 8.0, 4.3 Hz, 1 H), 7.36–7.42 (m, 5 H), 7.56 (dd, J = 7.3, 1.4 Hz, 1 H), 7.67–7.72 (m, 2 H), 7.87
(d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 8.0, 1.4 Hz, 1 H), 8.09 (dd, J = 8.0, 1.9 Hz, 1 H), 8.44 (dd, J = 4.3, 1.9 Hz,
1 H) ppm; 13C NMR (CDCl3, 75 MHz)
121.0 (CH), 125.6 (CH), 125.9 (CH), 127.0 (CH), 127.2 (C), 127.3
(2 CH), 127.9 (CH), 128.2 (CH), 128.7 (2 CH), 129.0 (C), 131.4 (CH), 134.9 (C), 135.1 (CH), 141.7 (C),
δ
×
×
146.4 (C), 146.8 (C), 146.8 (CH) ppm; IR (ATR) 3049, 3028, 2923 cm−1; MS (EI) m/z (%) 255 (M+, 27), 254
([M − H]+, 100); HRMS (ESI) m/z calcd for C19H14N ([M + H]+) 256.1120, found 256.1113.
10-Ethenylbenzo[h]quinoline (10c) [47]. Yellow oil (13 mg, 0.0625 mmol, 25%). 1H NMR (CDCl3,
300 MHz
7.65–7.70 (m, 2 H), 7.80–7.84 (m, 2 H), 7.89 (dd, J = 8.0, 1.3 Hz, 1 H), 8.18 (dd, J = 8.0, 1.9 Hz, 1 H), 8.61
(dd, J = 17.3, 10.8 Hz, 1 H), 9.06 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz
112.5
(CH2), 120.9 (CH), 125.6 (CH), 127.6 (CH), 128.3 (CH), 128.54 (CH), 128.55 (CH), 134.7 (2 × C), 135.6
) δ 5.41 (dd, J = 10.8, 1.9 Hz, 1 H), 5.63 (dd, J = 17.3, 1.9 Hz, 1 H), 7.51 (dd, J = 8.0, 4.3 Hz, 1 H),
)
δ
(CH), 139.2 (2
×
C), 142.4 (CH), 147.6 (CH), 148.1 (C) ppm; IR (ATR) 3047, 2923, 2852, 2359 cm−1; MS
(EI) m/z (%) 205 (M+, 27), 204 ([M
−
H]+, 100); HRMS (EI) m/z calcd for C15H10N ([M
−
H]+) 204.0808,
found 204.0807.
10-[4-(Trifluoromethyl)phenyl]benzo[h]quinoline (10d) [48]. Yellow oil (16 mg, 0.0495 mmol, 20%).
1H NMR (CDCl3, 300 MHz)
7.35 (dd, J = 8.0, 4.3 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.51 (dd, J = 7.3
1.1 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.71 (t, J = 7.3 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 8.8 Hz,
1 H), 7.98 (dd, J = 8.0, 1.4 Hz, 1 H), 8.11 (dd, J = 8.0, 1.8 Hz, 1 H), 8.40 (dd, J = 4.3, 1.8 Hz, 1 H) ppm; 13
NMR (CDCl3, 75 MHz)
121.3 (CH), 124.3 (q, 3JCF = 3.8 Hz, 2 CH), 124.7 (q, 1JCF = 271.7 Hz, CF3),
126.1 (CH), 127.1 (CH), 127.3 (C), 127.7 (q, 2JCF = 31.7 Hz, C), 128.2 (CH), 128.5 (CH), 128.8 (C), 128.9
δ
,
C
δ
×
(
2 × CH), 131.1 (CH), 134.9 (C), 135.3 (CH), 140.2 (C), 146.4 (C), 146.9 (CH), 150.2 (C) ppm; IR (ATR)
2928 cm−1; MS (EI) m/z (%) 323 (M+, 30), 322 ([M
−
H]+, 100); HRMS (ESI) m/z calcd for C20H13NF3
([M + H]+) 324.0994, found 324.0993.
1
10-[4-(Fluorophenyl)benzo[h]quinoline (10e) [48]. Yellow oil (31 mg, 0.113 mmol, 45%). H NMR (CDCl3,
300 MHz)
7.71 (d, J = 9.1 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.94 (dd, J = 8.0, 1.4 Hz, 1 H), 8.10 (dd, J = 8.0, 1.9 Hz,
1 H), 8.46 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz) 114.1 (d, 2JCF = 21.3 Hz, 2
CH),
121.1 (CH), 126.0 (CH), 127.0 (CH), 127.2 (C), 128.1 (CH), 128.3 (CH), 129.0 (C), 130.1 (d, 3JCF = 7.8 Hz,
δ 7.07–7.13 (m, 2 H), 7.27–7.37 (m, 3 H), 7.53 (dd, J = 7.3, 1.4 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H),
δ
×
2
×
CH), 131.5 (CH), 135.0 (C), 135.3 (CH), 140.6 (C), 142.2 (d, 4JCF = 3.5 Hz, C), 146.7 (C), 146.8 (CH),
161.5 (d, 1JCF = 243.1 Hz, CF) ppm; IR (ATR) 3049, 2926, 2870 cm−1; MS (EI) m/z (%) 273 (M+, 28), 272
([M − H]+, 100); HRMS (ESI) m/z calcd for C19H13NF ([M + H]+) 274.1026, found 274.1022.
10-[3-(Fluorophenyl)benzo[h]quinoline (10f). Yellow oil (21 mg, 0.075 mmol, 30%). 1H NMR (CDCl3,
300 MHz) δ 7.03–7.08 (m, 2 H), 7.12–7.15 (m, 1 H), 7.32–7.38 (m, 2 H), 7.54 (dd, J = 7.3, 1.4 Hz, 1 H),

Molecules 2018, 23, 1582
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7.70 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.96 (dd, J = 8.0, 1.4 Hz, 1 H),
8.11 (dd, J = 8.0, 1.9 Hz, 1 H), 8.46 (dd, J = 4.3, 1.9 Hz, 1 H) ppm; 13C NMR (CDCl3, 75 MHz)
112.4
d, 2JCF = 21.1 Hz, CH), 115.8 (d, 2JCF = 21.5 Hz, CH), 121.2 (CH), 124.4 (d, 4JCF = 2.7 Hz, CH), 126.1
δ
(
(CH), 127.0 (CH), 127.2 (C), 128.2 (CH), 128.3 (CH), 128.7 (d, 3JCF = 8.5 Hz, CH), 128.9 (C), 131.1 (CH),
134.9 (C), 135.2 (CH), 140.3 (d, 4JCF = 2.0 Hz, C), 146.5 (C), 147.0 (CH), 148.6 (d, 3JCF = 8.3 Hz, C), 162.4
(d, 1JCF = 243.3 Hz, CF) ppm; IR (ATR) 3048, 2955, 2924, 2854 cm−1; MS (EI) m/z (%) 273 (M+, 30), 272
([M − H]+, 100); HRMS (ESI) m/z calcd for C19H13NF ([M + H]+) 274.1026, found 274.1023.
4. Conclusions
In summary, we report a novel protocol for the C–H activation and C–C coupling of
2-arylpyridines with triorganoindium reagents under rhodium catalysis. Reactions proceeded
regioselectively to the ortho position of the aryl group with methyl- and phenylindium reagents
in moderate to good yields. The use of chlorobenzene as solvent is useful to minimize the
o,o0-disubstituted products. This contribution represents a new entry about the reactivity of
organoindium reagents and could help to develop further studies on C–H activation reactions.
Additionally, the reactions reported represent a new example for the transmetallation of organic
groups from indium to rhodium.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/23/7/1582/
s1: Copies of 1H NMR and 13C NMR spectra of the compounds 2, 4, 5 and 7–10.
Author Contributions: L.A.S., J.P.S. and R.R. conceived and designed the experiments; R.T. performed the
experiments and analyzed the data; L.A.S., J.P.S. and R.R. wrote the paper.
Funding: We gratefully acknowledge the Spanish Ministerio de Economía y Competitividad (CTQ2015-68369-P),
Xunta de Galicia (GRC2014/042) and EDRF funds for financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2a, 2b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b are available from
the authors.
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