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Cite this: Org. Biomol. Chem., 2014, 12, 4243

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Synthesis of 1,4-dihydroquinoline derivatives under transition-metal-free conditions and their diverse applications† Xue-Qiang Chu, You Zi, Hua Meng, Xiao-Ping Xu* and Shun-Jun Ji* A transition-metal-free process for the synthesis of 1,4-dihydroquinoline derivatives starting from simple

Received 3rd March 2014, Accepted 21st April 2014

enaminones with aldehydes via intermolecular cascade cyclization in a one-pot protocol is developed.

DOI: 10.1039/c4ob00475b

This methodology affords a variety of products in moderate to good yields. Particularly, the use of the enaminone fragment in 1,4-dihydroquinoline derivatives 3 as a leaving group for further diverse appli-

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cations with C-nucleophiles is proved to be feasible.

The transition-metal (TM)-catalyzed cross-coupling reactions are direct and powerful strategies for the construction of new C–N bonds, which are featured in the synthesis of various pharmaceuticals and biologically active molecules.1 Although some success has been achieved with Pd (Buchwald–Hartwig amination),2 Cu (Ullmann or Goldberg-type reaction),3 Fe,4 or Ni5 catalysts for this transformation in the past few decades, they still suffer from a number of drawbacks: (i) use of expensive catalysts, ligands or additives; (ii) need harsh conditions (e.g., under inert gas protection); (iii) limited starting materials (organometallic reagents for Caryl–N coupling);6 (iv) trace-metal contamination (especially in production of APIs).7 Hence, developing a cheaper, less toxic, and eco-friendly methodology is highly desirable, and in this context, TM-free processes aroused extensive attention.8–15 For instance, Tu,10 Bolm,11 and others12,14 described the base-promoted amination of aryl halides with N-nucleophiles. Considerable efforts have been directed towards the formation of heterocycles,13 especially through intra or intermolecular N-arylation.11c–f,14 Quinoline, as a privileged skeleton, is a core element of many pharmaceutically relevant compounds and natural products.15 Quinoline derivatives have been widely used in the manufacture of dyes and the discovery of experimental drug candidates.16 Among them, 1,4-dihydroquinolines have attracted special research interest,17 because of their potential utilities as calcium channel modulators (1,4-DHPs),17a–c brain delivery carriers,17d antiurease compounds,17e HIV-1 inhibi-

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, People’s Republic of China. E-mail: [email protected], [email protected]; Fax: (+)86-512-65880307; Tel: +86-512-65880307 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob00475b

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Scheme 1 Acid or transition-metal catalyzed synthesis of quinoline derivatives.

tors,17f the M1 muscarinic receptor modulators,17g and organic optoelectronic materials.17h Traditional strategies for the assembly of the quinoline ring system involve an initial intermolecular reaction of an aniline with a carbonyl compound or its precursor, which suffered from a lack of readily available starting materials (o-aminobenzaldehydes) and harsh reaction conditions (e.g. Scheme 1, A).18 Recently, transition-metalcatalyzed syntheses of quinoline derivatives have also been developed. Palladium, rhodium, ruthenium, and iron salts or complexes are used as catalysts in combination with strong bases.19 Our goal is to seek for an efficient method for the synthesis of quinoline derivatives by transition-metal-free intermolecular cyclization from simple and readily accessible substrates. Considering our previous findings (Scheme 1, B),19a,g we designed A as a building block, which could be generated via the Baylis–Hillman reaction20 from β-enaminone and benzaldehyde, and then under basic conditions, the ortho-substituent of the aldehyde serving as a leaving group leads to the final ring-closed product, the 1,4-dihydroquinoline derivative (Scheme 2).11c–f To carry out our trials, β-enaminone 2a (easily prepared from the corresponding amine with diketone) and o-bromobenzaldehyde were selected as model substrates. To our delight, the desired product 1,4-dihydroquinoline 3aa could be obtained in 33% LC-yield without the involvement of any

Org. Biomol. Chem., 2014, 12, 4243–4251 | 4243

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Organic & Biomolecular Chemistry Table 2

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Scheme 2

TM-free synthesis of 1,4-dihydroquinoline derivatives.

Table 1

Optimization of the reaction conditionsa

Entry

L

Base

Solvent (2 ml)

Temp. (°C)

Time (h)

LC yieldb (%)

1 2 3 4 5 6 7 8 9 10 11e 12e 13e 14e 15e

Br Cl NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2

Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 t-BuOK NaOAc — KOH DABCOd K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4

Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene MeCN EtOH DMF DMSO

110 110 110 110 110 110 110 110 110 110 120 Reflux Reflux 120 120

12 12 12 24 12 24 24 12 24 12 12 12 12 12 12

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Synthesis of 1,4-dihydroquinoline derivatives under transition-metal-free conditions and their diverse applications.

A transition-metal-free process for the synthesis of 1,4-dihydroquinoline derivatives starting from simple enaminones with aldehydes via intermolecula...
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