Synthesis of 2,4-diarylsubstituted-pyridines through a Ru-catalyzed four component reaction

Article abstract of DOI:10.1039/c5ob00162e

A ruthenium-catalyzed one-pot synthesis of 2,4-diarylsubstituted pyridines from acetophenones, ammonium acetate and DMF under an oxygen atmosphere is described. The carbon atom situated at C6 of the pyridine ring comes from the methyl group of DMF and the nitrogen atom comes from ammonium acetate.

Full text of DOI:10.1039/c5ob00162e

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Synthesis of 2,4-diarylsubstituted-pyridines
through a Ru-catalyzed four component reaction†
Cite this: DOI: 10.1039/c5ob00162e
Yang Bai,a Lichang Tang,a Huawen Huanga and Guo-Jun Deng*a,b
Received 28th January 2015,
Accepted 3rd March 2015
DOI: 10.1039/c5ob00162e
www.rsc.org/obc
A ruthenium-catalyzed one-pot synthesis of 2,4-diarylsubstituted
pyridines from acetophenones, ammonium acetate and DMF under
an oxygen atmosphere is described. The carbon atom situated at
C6 of the pyridine ring comes from the methyl group of DMF and
the nitrogen atom comes from ammonium acetate.
Pyridines represent an important class of heterocycles which
are prevalent in many natural products, functional materials,
agrochemicals and pharmaceutical drugs.1 In addition, pyri-
dines have also been well-known as important ligands (such as
bipyridine and terpyridine), organic bases and catalysts.2 As a
consequence, it is not surprising that the research interest
toward the synthesis and functionalization of pyridine and its
derivatives remains highly active and extensive despite the
long history of pyridine chemistry.3
Classic methods for the synthesis of pyridine rings are
mainly based on condensation reactions of activated carbonyl
compounds with amines, such as the Hantzsch pyridine syn-
thesis (Scheme 1a),4 the Chichibabin reaction (Scheme 1b),5
the Vilsmeier–Haack reaction6 and the Bohlmann–Rahtz pyri-
dine synthesis.7 These methods or their modified procedures
are proved to be powerful and general for the synthesis of sym-
metrical pyridines. In recent years, unsymmetrical pyridine
synthesis has attracted considerable attention. The transition-
metal-catalyzed reactions have emerged as efficient methods to
synthesize unsymmetrical substituted pyridines.8 The ruthe-
nium-catalyzed cycloisomerization of 3-azadienynes,9 the Cu-
or Pd-catalyzed reaction of oxime carboxylates,10 the metal-
catalyzed cycloaddition11 and Rh-catalyzed ring expansion12 all
showed great potential for the facile preparation of substituted
pyridines. The transition-metal catalyzed cross-coupling reac-
tion of activated pyridines was a very useful procedure for the
Scheme 1 Various procedures for pyridine synthesis.
preparation of unsymmetrical aryl-substituted pyridines.13
Recently, the direct arylation,14 alkylation15 and alkenylation16
of simple pyridines via C–H functionalization have emerged as
efficient approaches for the unsymmetrically substituted pyri-
dine preparation.
In the past few years, exploring new carbon sources to con-
struct a pyridine moiety has attracted considerable interest.
N,N-Dimethylformamide (DMF) is a commonly used polar
solvent. In addition, DMF can participate in many reactions by
serving as useful building blocks, such as CO, O, NMe2, Me
and CHO.17 Recently, the Guan group developed an efficient
ruthenium-catalyzed method for symmetrical pyridine syn-
aKey Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: (+86)0731-5829-2251; Tel: (+86)0731-5829-8601
bKey Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00162e
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thesis from ketoximes and DMF (Scheme 1c).18 In this process, Increasing the ammonium acetate loading to 0.6 mmol
DMF was used as the source of C4. Wan and co-workers found increased the reaction yield to 86% (entry 16, 80% isolated
that enaminone also could be used as the C4 source for con- yield).
struction of various substituted pyridines in the presence of a
With the optimized conditions established, a number of
copper catalyst.19 Compared to the extensively investigated substituted acetophenones were investigated (Table 2). Aceto-
routes for symmetrical pyridines, efficient and general phenones with an electron-donating group reacted smoothly
methods for unsymmetrical pyridine preparation using DMF to give the corresponding heterocyclic products in moderate to
as the carbon source under mild conditions are less explored. good yields (2b–2f). The substituents at the para or meta posi-
Herein, we report a new approach for the synthesis of 2,4-dia- tion of acetophenones had little steric effect on the reaction
rylsubstituted pyridines via four-component condensation and yields. For example, the desired products 2e and 2f were
cyclization reactions using acetophenones, ammonium acetate obtained in 65% and 68% yields when 4′-methoxyacetophe-
and DMF.20 The methyl group of DMF acted as the source of none and 3′-methoxyacetophenone were employed respectively.
C6, providing unsymmetrical diaryl-substituted pyridines in Electron-withdrawing substituents on acetophenones signifi-
good yields with high regio-selectivity (Scheme 1d).
cantly decreased the reaction yields (2i–2k). For instance, when
In the initial experiment we examined the reaction with 4-acetylbenzonitrile was used, the desired product 2j was
acetophenone (1a) in DMF using molecular oxygen as the observed in only 45% yield. When halogen substituents pre-
oxidant and ammonium acetate as the nitrogen source. As sented at the para and meta position of acetophenones, the
shown in Table 1, five different ruthenium salts were screened. corresponding products were obtained in fairly good yields
Among the catalysts investigated, RuCl3·3H2O showed the best (2l–2o). For example, 2m and 2o were obtained in 64% and
efficiency (entries 1–5). Then several solvents were screened in 67% yields when 4′-bromoacetophenone and 3′-bromoaceto-
the presence of 5 mol% RuCl3·3H2O (entries 5–9), and among phenone were used respectively. However, the reaction yields
them DMF showed the best efficiency to give 2a in 64% yield decreased significantly when the substituents were located at
(entry 5). Moderate yield was observed when DMSO was used
as the solvent (entry 6). However, reactions in other solvents
such as toluene, acetonitrile and NMP were much less efficient
(entries 7–9). These results indicated that the solvent was prob-
Table 2 Ru-catalyzed cyclization of acetophenones with NH4OAc and
DMFa
ably involved in the reaction. Various nitrogen sources were
investigated and ammonium acetate showed the best activity
(entries 5, 10–13). The yield of 2a decreased dramatically when
air or argon was used instead of oxygen (entries 14 and 15).
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst
“N”
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Ru(PPh3)3Cl2
Ru(acac)3
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4Cl
HCO2NH4
CO(NH2)2
NH3·H2O
NH4OAc
NH4OAc
NH4OAc
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
MeCN
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
50
36
52
24
64
43
0
0
Ru(COD)Cl2
Ru(Bpy)3Cl2·6H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
RuCl3·3H2O
9
5
10
11
12
13
14c
15d
16e
Trace
Trace
Trace
26
16
9
86 (80f)
a Conditions: 1a (0.4 mmol), catalyst (5 mol%), NH4OAc (0.4 mmol),
solvent (0.5 mL), 24 h under oxygen unless otherwise noted. b GC yield a Reaction conditions: unless otherwise noted, the reaction was carried
based on 1/2 1a. c Under air. d Under Ar. e 0.6 mmol NH4OAc was used. out with 0.4 mmol of ketone, 5 mol% RuCl3·3H2O, 0.6 mmol NH4OAc
f Isolated yield.
in DMF (0.5 mL) at 120 °C for 24 h under O2. b 48 h.
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the ortho position (2p and 2q), probably because of the high
steric hindrance.
A similar result was obtained when
1-(naphthalen-1-yl)ethanone was used, and the desired
product 2h was obtained in only 35% yield. To our delight, the
desired product 2r was obtained in 70% yield when 3′,4′-
dichloroacetophenone was used.
To gather more information about the reaction mechanism,
a series of control experiments were carried out under
different conditions (Scheme 2). A deuterated pyridine product
(2s) was obtained when d7-DMF was used as the solvent
(Scheme 2a). This result demonstrates that DMF participates
in the reaction. The starting material could be smoothly con-
verted into the desired product 2a using DMA as a solvent,
demonstrating that the C6 in the product is not provided by
the carbon of the formyl group in the DMF (Scheme 2b). To
further confirm the C6 source in the product, DEF was used as
the solvent and 6-methyl substituted pyridine (2t) was
obtained (Scheme 2c). This means the C6 in the pyridine ring
should come from the N-methyl group of DMF. In addition,
15N-containing product 2u was observed in 75% yield when
15NH4OAc (in situ generated from 15NH4Cl and AgOAc) was
used (Scheme 2d). This reaction shows that the nitrogen atom
of the pyridine ring comes from NH4OAc.
Based on these control experiments and related litera-
ture,18,21 a possible mechanism to illustrate this reaction is
presented in Scheme 3. Homo-condensation of 1a yields a
methyl ketene intermediate A (detected by GC-MS) which can
be further converted into imine intermediate B in the presence
of NH4OAc. Tautomerization of B generates an intermediate C.
Meanwhile, oxidation of DMF by [Ru]/O2 gives an iminium
species D. Subsequent addition of D to C provides intermedi-
Scheme 3 Proposed mechanism.
ate E and then intermediate E is oxidized into F by the [Ru]/O2
catalytic system. Finally, the resulting intermediate F under-
goes 6π electron cyclization and methylamide elimination to
give the final pyridine product 2a.
In conclusion, we have developed a novel approach for the
synthesis of pyridine using RuCl3·3H2O as the catalyst. The
methyl group of DMF performed as the one carbon source in
the transformation. An ammonium salt NH4OAc was utilized
as the cheap nitrogen resource. Readily available aceto-
phenones were used as the starting materials and 2,4-diaryl-
substituted pyridines were obtained as the sole products in all
cases. This strategy afforded an efficient approach for the syn-
thesis of biologically active aryl-substituted unsymmetrical pyr-
idines from readily available starting materials. The generality
and synthetic applications of this methodology are under
investigation.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the Hunan Provin-
cial Natural Science Foundation of China (11JJ1003, 12JJ7002),
the New Century Excellent Talents in University from Ministry
of Education of China (NCET-11-0974), and the Hunan Provin-
cial Innovative Foundation for Postgraduate (CX2014B264).
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