Nucleophilic, Heterocyclic, Carbene-Catalyzed, Solvent-Free, One-Pot Synthesis of Polyhydroquinolines via Multicomponent Hantzsch Reaction: An Efficient and Ecofriendly Approach

Abstract A simple, efficient, and ecofriendly one-pot method has been reported for the synthesis of polyhydroquinolines in excellent yield using nucleophilic heterocyclic carbene as catalyst. The generalized approach is the Hantzsch four-component reaction of aromatic aldehyde, ethyl acetoacetate, cyclic 1,3-diketone, and ammonium acetate. GRAPHICAL ABSTRACT


POLYHYDROQUINOLINES VIA HANTZSCH REACTION
It is well known that thiamine hydrochloride (vitamin B 1 ) is an inexpensive and nontoxic reagent containing a pyrimidine ring and a thiazole ring. Hydrogen on the carbon between S and N (i.e., at position 2) is acidic enough to be removed by the base, thereby providing required functionality to carry out several reactions in our body (and other living organisms), which include decarbonylation of pyruvic acid to acetaldehyde and conversion of pyruvic acid to acetoin. Vitamin B 1 (VB 1 ) analogs have been used as powerful catalysts for many carbon-carbon and carbon-heteroatom bond-formation reactions. Because most of the Hantzsch reactions are reported using Lewis acids or protic catalysts, only some nucleophiles such as triphenylphosphine, a Lewis base, are used as catalysts in the Hantzsch reaction. With the elucidation of active compound of VB 1 as a nucleophilic carbene=zwitterions, we had the opportunity to explore for the first time a thiazolium-based nucleophilic heterocyclic carbene as a green catalyst for the synthesis of polyhydroquinolines (PHQs) using Hantzsch condensation reaction.

RESULTS AND DISCUSSION
We found thiazolium ion (NHC), a basic, soft, and reusable ecofriendly species, can be used for the preparation of large number of PHQs in considerably short time with good yields. To compare its efficiency with various catalytic systems, we have used a range of catalysts. The results are summarized in Table 1. As evident from Table 1, thiazolium NHC shows comparatively better yield in considerably less time. The amount of catalyst is also comparatively very low, almost less than one-tenth in comparison to most of the other catalysts. We have used these catalysts for the synthesis of PHQs, but the best results were obtained when NHC was used as a catalyst under solvent-free condition. See Scheme 2.
To estimate the influence of NHC concentration on reaction time and percentage yield, the amount of catalyst was varied from 0 to 10 mol%. As shown in Table 1 (entries 8-13), elevated amounts of catalyst improved the product yield and shortened the reaction time. When catalyst concentration was 1 mol%, the yield was found to be 74% in 45 min, but when the catalyst concentration was increased to 5 mol%, the yield was found to be 92% in 20 min. Further increase in concentration of catalyst (10 mol%) did not show any significant improvement in the yield. Therefore, the one-pot condensation was carried out taking 5 mol% as catalyst concentration.
To examine the extent of the catalyst's application in condensation reaction (Scheme 3), we have applied the optimized catalyst concentration (i.e., 5 mol% thiazolium ion) to a large number of aromatic aldehydes having both electronwithdrawing and electron-donating substituents, at 60 C. It was found that almost all studied aldehydes react efficiently to give excellent yields in shorter reaction time (as shown in Table 2). We have also used aliphatic aldehydes for the Hantzsch condensation using NHC as promoter of the reaction and found that these aliphatic  Araldehydes þ ethylacetoacetate þ dimedone þ ammonium acetate þ NHC (5 mol%).

POLYHYDROQUINOLINES VIA HANTZSCH REACTION
aldehydes also react smoothly to produce corresponding dihydropyridines in excellent yields with just 5 mol% of NHC. The plausible mechanistic pathway for the synthesis of product 4 is shown in Scheme 3. Identity of the products was confirmed by comparison of the physical and spectral data (IR and 1 H NMR) with those of the reported compounds [19][20][21][22][23][24][25][26][27][28][29][30] (see the supporting information).

CONCLUSION
In summary, we have reported that thiazolium ion (nucleophilic heterocyclic carbene) is a highly efficient and green catalyst for the synthesis of PHQs by means of four-component condensation of an aldehyde, b-dicarbonyl compounds, and ammonium acetate in one pot. This method is applicable to a wide range of substrates including aromatic and aliphatic, providing the corresponding PHQs in excellent yields. The present methodology offers many advantages such as reduced reaction time and economic viability of the catalyst compared with other conventional catalysts. Most importantly, the proposed method seems to be one of the best examples of green methodology.

EXPERIMENTAL Preparation of Catalyst (NHC)
Thiamine hydrochloride (0.5 g) was dissolved in 1.6 ml of water and 6 ml of 95% ethanol was added. The solution was cooled in an ice bath and then 1 ml of 3M NaOH was added dropwise with stirring in a manner such that the temperature remained below 20 C. Intense yellow-colored solution changed to pale yellow solution, resulting in the formation of thiazolium ion (N-heterocyclic carbene).

Synthesis of PHQs (4a-l) Using NHC as Catalyst
Aldehyde (5 mmol), ethylacetoacetate (5 mmol), dimedone (5 mmol), and ammonium acetate (5.2 mmol) were added to 5 mol% of NHC, and the resulting mixture was heated to 60 C for an appropriate time (monitored by thin-layer chromatography, TLC). The reaction mixture, after being cooled to room temperature, was poured into cold water and extracted with ethylacetate. The organic layer was washed with brine and dried over Na 2 SO 4 under reduced pressure (formation of crude yellow products). The products were purified by recrystallization from ethanol to afford PHQs in 90-96% yield.