# Hantzsch Reaction Starting Directly from Alcohols through a Tandem Oxidation Process

Authors: Xiaobing Liu; Bin Liu
Journal: Journal of Chemistry
 (2017)

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## Abstract

A Brønsted acidic ionic liquid, 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO4]), has been successfully applied to catalyze sequential oxidation of aromatic alcohols with NaNO3 followed by their condensation with dicarbonyl compound and ammonium acetate. The corresponding pyridine analogues of Hantzsch 1,4-dihydropyridines could be obtained as a major product with high yields by the multicomponent reaction. The present work utilizing alcohols instead of aldehyde in Hantzsch reaction is a valid and green alternative to the classical synthesis of the corresponding pyridine analogues of Hantzsch 1,4-dihydropyridines.


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## Body

## 1. Introduction

1,4-Dihydropyridines and their derivatives are an important class of heterocycles in biologically active and naturally occurring molecules [1–3]. Many methods for the preparation of 1,4-dihydropyridines have been reported and most of them are mainly confined to the modification and optimization of the Hantzsch multicomponent synthesis between an aldehyde, a 1,3-dicarbonyl compound, and a source of ammonia [4–6]. At the same time, the oxidative aromatization of 1,4-dihydropyridines has also been extensively studied and numerous oxidizing reagents, namely, CuBr2 [7], SiO2/P2O5-SeO2 [8], H2O2/Co(OAc)2 [9], and Na2S2O4/TBHP [10], have been used for the aromatization of 1,4-dihydropyridines. Some reports have observed that the direct oxidative procedure was very efficient for the preparation of Hantzsch pyridines under microwave-assisted condition or solvent-free condition [11–13]. However, the search for the new readily available and green methods is still being actively pursued.The aldehydes in Hantzsch reaction are more volatile, toxic, or unstable than their corresponding alcohols. Recently, tandem oxidative processes (TOP) [14–16] in which the alcohol is oxidized to the aldehyde in situ have developed into an innovative addition to synthetic organic chemistry. Garima et al. [17] reported an efficient oxidative access to 3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic alcohols. In the literature, a Brønsted acidic ionic liquid has been successfully applied to catalyze sequential oxidation of aromatic alcohols with NaNO3 followed by their condensation with urea and dicarbonyl compounds.Ionic liquids have attracted extensive interest and played a dual solvent-catalyst role in organic synthesis due to their favourable properties [18]. Brønsted acidic ionic liquids combining the advantageous characteristics of solid acids and mineral acids are designed to replace traditional mineral liquid acids in catalytic action [19]. In continuation of our interest in exploring green catalysis of ionic liquids [20, 21], we herein report a Brønsted acidic ionic liquid 3-(N,N-dimethyldodecylammonium) propanesulfonic acid hydrogen sulphate ([DDPA][HSO4]) catalyzed sequential oxidation of aromatic alcohols with NaNO3 followed by their condensation with dicarbonyl compound and ammonium acetate. We have found that the corresponding pyridine analogues of 1,4-dihydropyridines could be obtained as a major product by the multicomponent reaction, whereas only trace amounts of 1,4-dihydropyridines were detected (Scheme 1).Scheme 1
Synthesis of the corresponding pyridine analogues of 1,4-dihydropyridines directly from aromatic alcohols.


## 2. Materials and Methods

### 2.1. General Reagents and Instrumentation

All starting chemicals (AR grade) were purchased from commercial suppliers and used without further purification. Melting points were determined on a Thomas-Hoover capillary apparatus and were uncorrected. The IR spectra were recorded with a Bomem Michelson model 102 FTIR.1H NMR spectra were recorded on Bruker DRX (500 MHz) spectrometer. Gas chromatography (GC) was recorded on a HP 6890 Plus GC instrument. Elemental analyses were performed on a Yanagimoto MT3CHN recorder. The ionic liquid [DDPA][HSO4] was synthesized according to the literature procedures [22].


### 2.2. Experimental Procedures

A mixture of an aromatic alcohol (3 mmol), sodium nitrate (6 mmol), and [DDPA][HSO4] (1.2 mmol) was heated with stirring at 80°C for 5–30 min in a round-bottomed flask. After oxidation of the aromatic alcohol (monitored by TLC), dicarbonyl compound (3 mmol) and ammonium acetate (3 mmol) were added. The mixture was heated with stirring at 80°C for 1–3 h. The reaction was monitored by TLC after an interval of 15 min. After completion, the reaction mixture was cooled to rt and extracted with ethyl acetate. The organic layer was separated and washed with brine solution and then dried over anhydrous Na2SO4. Solvent was removed in vacuo and the crude product was purified by chromatography over silica gel. The aqueous layer (containing the ionic liquid) could be reused directly in the next run without further purification.


## 2.1. General Reagents and Instrumentation

All starting chemicals (AR grade) were purchased from commercial suppliers and used without further purification. Melting points were determined on a Thomas-Hoover capillary apparatus and were uncorrected. The IR spectra were recorded with a Bomem Michelson model 102 FTIR.1H NMR spectra were recorded on Bruker DRX (500 MHz) spectrometer. Gas chromatography (GC) was recorded on a HP 6890 Plus GC instrument. Elemental analyses were performed on a Yanagimoto MT3CHN recorder. The ionic liquid [DDPA][HSO4] was synthesized according to the literature procedures [22].


## 2.2. Experimental Procedures

A mixture of an aromatic alcohol (3 mmol), sodium nitrate (6 mmol), and [DDPA][HSO4] (1.2 mmol) was heated with stirring at 80°C for 5–30 min in a round-bottomed flask. After oxidation of the aromatic alcohol (monitored by TLC), dicarbonyl compound (3 mmol) and ammonium acetate (3 mmol) were added. The mixture was heated with stirring at 80°C for 1–3 h. The reaction was monitored by TLC after an interval of 15 min. After completion, the reaction mixture was cooled to rt and extracted with ethyl acetate. The organic layer was separated and washed with brine solution and then dried over anhydrous Na2SO4. Solvent was removed in vacuo and the crude product was purified by chromatography over silica gel. The aqueous layer (containing the ionic liquid) could be reused directly in the next run without further purification.


## 3. Results and Discussion

In the initial experiments, the multicomponent reaction of benzyl alcohol, ethyl acetoacetate, and ammonium acetate was selected as a model reaction (Scheme2). We studied the tandem oxidative cyclocondensation of benzyl alcohol, ethyl acetoacetate, and ammonium acetate in the presence of [DDPA][HSO4] with NaNO3 at 80°C, but no reaction took place even after stirring the reaction mixture for 12 h. However, we observed the formation of 1,4-dihydropyridine and its corresponding pyridine when ethyl acetoacetate and ammonium acetate were added to the reaction after the oxidation of the alcohol to the aldehyde was complete.Scheme 2
Model Hantzsch reaction directly from benzyl alcohol in [DDPA][HSO4].Subsequently, different ionic liquids were screened for the same model reaction. The results are summarized in Table1. It was shown that the reaction was unsuccessful in [Hmim]NO3 and [bmin]BF4 because an acidic hydrogen is absent in the two ionic liquids. The reaction could proceed effectively in [DDPA][HSO4] but relatively low yields of product in [Hmim][H2PO4]. This is probably due to the lower Brønsted acidity associated with [H2PO4]. Thus, [DDPA][HSO4] plays a dual role as an acid catalyst and as a solvent for both the oxidation of alcohol and the subsequent condensation. The product 4a could be converted to product 3a in the exposure of air and the NaNO3-[DDPA][HSO4] system could speed up the process.Table 1
Model of Hantzsch reaction directly from benzyl alcohol in different ionic liquidsa.
Entry
Ionic liquid
Ratiob
Yield (%)c
1
[DDPA][HSO4]
3a : 4a = 93 : 7
91
2
[Hmim][H2PO4]
3a : 4a = 86 : 14
37
3
[Hmim]NO3
—
—
4
[bmin]BF4
—
—
aBenzyl alcohol (3 mmol), ethyl acetoacetate (3 mmol), ammonium acetate (3 mmol), ionic liquid (1.2 mmol), and NaNO3 (6 mmol), 1 h. bYields and ratios were based on GC analysis. cYields referred to the desired product 3a.To explore the stability of the ionic liquid after reaction, the recycling performance of [DDPA][HSO4] in the same model reaction was investigated. After the reaction, the products were separated from the catalytic system by extraction with ethyl acetate. The aqueous layer (containing the catalyst) was reused in the next run without further purification. As shown in Figure 1, the catalyst could be reused at least five times without significant decrease in catalytic activity.Figure 1
Reusability of the ionic liquid [DDPA][HSO4].With these results in hand, we decided to explore the scope of this method. A variety of substituted aromatic alcohols was extended in the procedure in the presence of [DDPA][HSO4] and the obtained results are summarized in Table 2. It can be seen that the tandem oxidation of aromatic alcohols followed by their condensation with dicarbonyl compound and ammonium acetate in the presence of [DDPA][HSO4] proceeded smoothly to give the corresponding products in good yields. Aromatic alcohols with a strong electron-withdrawing group required a longer time for the reaction (Table 2, entries 8 and 9), whereas aromatic alcohols with electron-donating substitutes gave excellent yields (Table 1, entries 2, 4, 5, and 6) in a shorter reaction time. An important feature of the present protocol is the ability to tolerate variation in all components simultaneously.Table 2
Hantzsch reaction of different substrates catalyzed by [DDPA][HSO4]a.
Entry
R1
R2
Time (h)
Yield (%)b
Mp °C (lit. Mp °C)c
1
C6H5
CH3
1
91
118 (118) [7]
2
4-MeO-C6H4
CH3
1
93
91 (92) [7]
3
4-Cl-C6H4
CH3
2
85
118 (120) [7]
4
C6H5
CH3CH2
1
90
60-61 (63-64) [23]
5
2-MeO-C6H4
CH3CH2
1
93
58 (55–57) [24]
6
4-MeO-C6H4
CH3CH2
1
91
52 (51-52) [7]
7
4-Cl-C6H4
CH3CH2
2
83
66 (65–67) [23]
8
3-NO2-C6H4
CH3CH2
3
76
60 (60) [7]
9
4-NO2-C6H4
CH3CH2
3
72
115 (114-115) [23]
aBenzyl alcohol (3 mmol), ethyl acetoacetate (3 mmol), ammonium acetate (3 mmol), ionic liquid (1.2 mmol), and NaNO3 (6 mmol). bYields were based on GC analysis and referred to the desired product 3. cMp of product 3.A plausible mechanism for the sequential oxidation of aromatic alcohols with NaNO3 followed by their condensation with dicarbonyl compound and ammonium acetate is depicted in Scheme 3. In acidic ionic liquid [DDPA][HSO4], aromatic alcohols were oxidized to aromatic aldehydes with NaNO3. After the oxidation completion, a multicomponent reaction of the aromatic aldehydes, dicarbonyl compound, and ammonium acetate was conducted in [DDPA][HSO4] and then the Hantzsch 1,4-dihydropyridines were formed. Subsequently, the Hantzsch 1,4-dihydropyridines could be further oxidized to the desired corresponding pyridine analogues with NaNO3-[DDPA][HSO4] in air.Scheme 3
Plausible mechanism for Hantzsch reaction directly from alcohol in [DDPA][HSO4].


## 4. Conclusions

In conclusion, we have described an efficient protocol for Hantzsch reaction starting from alcohols using NaNO3-[DDPA][HSO4] system. The protocol involves [DDPA][HSO4] catalyzed sequential oxidation of aromatic alcohols with NaNO3 followed by their condensation with dicarbonyl compound and ammonium acetate. The corresponding pyridine analogues of Hantzsch 1,4-dihydropyridines could be obtained as a major product with high yields by the multicomponent reaction. The present work utilizing alcohols instead of aldehyde in Hantzsch reaction is a valid and green alternative to the classical synthesis of the corresponding pyridine analogues of Hantzsch 1,4-dihydropyridines.



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*Source: 5646908-2017-07-16.xml*