Efficient synthesis of useful heterocycles via transition metal-catalyzed cascade processes

Article abstract of DOI:10.1007/s11164-014-1593-x

This paper reports our recent results from synthesis of some useful heterocycles, for example oxazolidinones, indoles, and quinoxalinones, by transition metal-catalyzed cascade processes. The scope and limitations of these procedures and the reaction mech

Full text of DOI:10.1007/s11164-014-1593-x

Res Chem Intermed
DOI 10.1007/s11164-014-1593-x
Efficient synthesis of useful heterocycles via transition
metal-catalyzed cascade processes
•
Shinji Tanimori Ushio Inaba Yoshihiro Kato
•
•
•
Haruna Ura Hiroaki Kashiwagi
•
•
Takeshi Nishimura Mitsunori Kirihata
Received: 31 December 2013 / Accepted: 24 January 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract This paper reports our recent results from synthesis of some useful
heterocycles, for example oxazolidinones, indoles, and quinoxalinones, by transition
metal-catalyzed cascade processes. The scope and limitations of these procedures
and the reaction mechanism for formation of the heterocycles are also discussed.
Keywords Palladium catalyst Á Oxazolidone Á Indoles Á Copper catalyst Á
One-pot synthesis Á Quinoxalinones
Introduction
Nitrogen-containing heterocyclic compounds are useful building blocks for
development of pharmaceuticals, agrochemicals, functional materials, and dyes
[1]. A huge number of methods have been reported for construction of heterocyclic
structures [2]. Transition metal-catalyzed cascade processes are attractive methods
for preparation of heterocycles [3]. Because of the mild reaction conditions, broad
functional group tolerance, simple reaction manipulations, short reaction steps, and
cost effectiveness, the methods are practical and green processes for efficient
synthesis of heterocyclic compounds [4]. In this paper we describe the facile
synthesis of oxazolidinones [5], indoles [6], and quinoxalinones [7] by palladium
and copper-catalyzed cascade processes.
S. Tanimori (&) Á U. Inaba Á Y. Kato Á H. Ura Á H. Kashiwagi Á T. Nishimura Á M. Kirihata
Department of Bioscience and Informatics, Graduate School of Life and Environmental Sciences,
Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan
e-mail: tanimori@bioinfo.osakafu-u.ac.jp
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Palladium-catalyzed synthesis of oxazolidinones
Oxazolidinone 1 (Fig. 1) is a five-membered heterocycle containing nitrogen and
oxygen atoms. Oxazolidinone derivatives have a wide variety of biological activity.
For example, antifungal drug linezolid 2 has been used for treatment of vancomycin-
resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus
(MRSA).
Initially, we expected that reaction of amines with a symmetrical dicarbonate 3,
with two leaving groups, as starting materials, under palladium-catalyzed condi-
tions, would furnish oxazolidinones 4 via, first, intermolecular allylic amination,
followed by intramolecular nucleophilic attack (Fig. 2).
To test the hypothesis, we investigated reaction of dicarbonate 3 with benzylamine
as model substrates in the presence of [Pd(g3–C3H5)Cl]2 (0.062 mol%) and 1,1-
bis(diphenylphosphino)ferrocene (dppf) (1.6 mol%) in dichloromethane at room
temperature. This gave oxazolidone 4a in moderate yield (58 %) (Fig. 3) [5].
We next investigated the generality, scope, and limitations of this oxazolidinone-
forming reaction. A wide range of amines with benzyl, cyclic, unsaturated, free
Fig. 1 Structures of oxazolidinone (1) and linezolid (2)
Fig. 2 Reaction pathway proposed for formation of oxazolidinone
Fig. 3 Reaction of dicarbonate 3 with benzylamine
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Efficient synthesis of useful heterocycles
Table 1 Synthesis of oxazolidinone derivatives
hydroxyl, and amino groups afforded corresponding oxazolidinones with moderate
to excellent yields except for aniline derivatives (Table 1).
Copper-catalyzed synthesis of 2,3-disubstituted indoles
The indole skeleton is well known as a structure frequently found in natural
products and drugs (Fig. 4). Traditional methods for synthesis of indoles, for
example the Fischer indole synthesis, have problems with regioselectivity at the
cyclization positions when unsymmetrical substrates are used. Accordingly,
development of a selective method for synthesis of substituted indoles is still an
important task in organic synthesis.
We expected that reaction of 2-haloanilines and b-keto esters would afford
2-alkyl or aryl-3-indole carboxylic acid esters via two possible routes (Fig. 5). Path
A includes, first, enamine formation, followed by intramolecular Heck-type
coupling. Path B consists of, first, C–C bond formation, then subsequent C–N
bond-forming cyclization to afford the indole.
Results from optimization of indole synthesis by reaction of 2-iodoaniline 5 with
methyl acetoacetate 6 as model substrates are listed in Table 2. In the presence of
copper iodide the desired indole 7 was formed in 35 % yield [6]. Several additives,
bases, and solvents were tried, as shown in entries 2–7. It was found the best
conditions were use of BINOL as additive in the presence of cesium carbonate as
base in DMSO at 50 °C for 4 h (Table 2, entry 7).
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Fig. 4 Biologically active indoles
Fig. 5 Plausible pathways for formation of the indole structure
Table 2 Results from studies conducted to optimize indole formation
Entry
Additive
Base
Solvent
Yield (%)a
1
2
3
4
5
6
7
a
None
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
DMSO
DMSO
DMSO
DMF
35
26
36
26
61
48
79
L-Proline
Ethylenediamine
MeNHCH2CO2H
BINOL
DMSO
DMSO
DMSO
BINOL
BINOL
Isolated yield after silica get chromatography
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Efficient synthesis of useful heterocycles
Table 3 Synthesis of substituted indoles
Under the optimized conditions, a series of b-keto esters, 1,3-diketones, and a b-
keto amide was used in this transformation. As shown in Table 3, bulky,
unsaturated, aromatic, and heteroaromatic b-keto esters produced the corresponding
indoles in moderate to excellent yields. 1,3-Diketones (Table 3 entries 9 and 10) and
a b-keto amide also afforded indoles in good yields.
General and practical access to chiral quinoxalinones, with low copper-catalyst
loading
Quinoxaline and quinoxalinone are also important substructures for development of
pharmaceuticals, agrochemicals, and functional materials. Some known bioactive
quinoxalinones have a chiral center at the C3 position (Fig. 6). We therefore wished
to develop a general and practical method for synthesis of chiral quinoxalinones.
It was expected that, as shown in Fig. 7, reaction of 2-haloanilines with amino
acids in the presence of copper catalyst would directly enable one-pot synthesis of
chiral quinoxalinones by sequential Buchwald–Hartwig type C–N bond formation
and amide bond formation.
To our delight, reaction of 2-bromoaniline 8 with phenylalanine 9 in the presence
of 1 mol% cuprous chloride provided the desired chiral quinoxalinones 10 in
excellent yield (Table 4, entry 1) [7]. The effect of additives was next investigated.
As shown by entries 2 and 3, EDA and TMEDA were less effective in the
transformations. Slightly better conversion was realized by use of DMEDA (entry 4)
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Fig. 6 Biologically active quinoxalinones
Fig. 7 Working hypothesis for formation of chiral quinoxalinone
Table 4 Optimization of the reaction conditions
Entry
CuCl (mol%)
Temp. (°CC)
Time (h)
Additive
Yield (%)a
1
2
3
4
5
6
a
1
120
120
120
120
110
120
12
12
12
12
24
48
None
91
86
81
93
99
71
1
EDA
1
TMEDA
DMEDA
DMEDA
DMEDA
1
1
0.5
Isolated yield
and, finally, entry 5 at lower temperature was selected as the optimum conditions.
Reduction of the amount of catalyst to 0.5 mol% resulted in poor conversion, even
the reaction time was increased (entry 6).
Under these optimized conditions, a variety of amino acids, including branched,
bulky, disubstituted, free hydroxyl, cyclic, tryptophan, those with electron-donating
and withdrawing groups on aromatic ring, pyridine, and N-substituted aniline,
tolerated the reaction, providing a series of chiral quinoxalinones in good yield
without the need for protection of amino and carboxyl groups (Table 5)
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Table 5 Synthesis of quinoxalinones
Fig. 8 Synthesis of GW420867X (11)
To demonstrate the utility of the transformation, the anti-HIV agent GW420867X
(11) was synthesized from commercially available reagents in two steps in high
yield (Fig. 8).
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Conclusions
In this paper we report our efforts to synthesize useful heterocyclic structures by
means of transition metal-catalyzed cascade processes. As series of oxazolidinones,
indoles, and quinoxalinones with diverse structures was synthesized efficiently by
use of simple experimental procedures under relatively mild conditions. These
methods could therefore serve as powerful tools enabling facile access to
heterocyclic building blocks for discovery of new drugs and functional materials.
Acknowledgments We thank Professors Masakazu Anpo (OPU) and San-LangWong (TKU) for giving
us the opportunity to submit this paper.
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