Chinese Chemical Letters  2014, Vol.25 Issue (01):159-162   PDF    
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Zinatossadat Hossaini.Solvent-free synthesis of substituted five membered heterocycles：One-pot reaction of primary amine and alkyl propiolate or isothiocyanate in the presence of oxalyl chloride[J]. Chin. Chem. Lett., 2014,25(01): 159-162   
Solvent-free synthesis of substituted five membered heterocycles：One-pot reaction of primary amine and alkyl propiolate or isothiocyanate in the presence of oxalyl chloride
Zinatossadat Hossaini     
* Corresponding authors at:Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
Received:2013-7-8, Revised:2013-9-4, online:2013-11-5.
E-mail addresses:zshossaini@yahoo.com
Abstract: A novel, convenient and efficient approach to the synthesis of pyrrole and imidazole derivatives via the reaction between primary amines, alkyl propiolates or isothiocyanate and oxalyl chloride is described. The method offers several advantages including high yields of products and performing reaction under solvent-free conditions.
Key words: Solvent-free condition     Primary amines     Pyrroles     Imidazole     Isothiocyanate     Alkyl propiolate     Oxalyl chloride    
1. Introduction

Five membered heterocycles with a nitrogen atom, such as pyrroles and imidazoles, are important building blocks in a wide number of biologically active compounds [1, 2, 3, 4, 5, 6]. Among them, pyrroles are heterocycles of great importance because of their frequent presence in natural products similar to heme, chlorophyll, vitamin B12, and various cytochrome enzymes [7]. Some recently isolated pyrrole-containing marine natural products have been found to display significant cytotoxicity and function as multidrug resistance (MDR) reversal agents [8]. Many of these biologically active compounds function as chemotherapeutic agents. Also, polysubstituted pyrroles are molecular structures with immense importance in material science [9]. They have also been employed as antioxidative [10], antibacterial [11, 12], ionotropic [13, 14], antitumor [15], anti-inflammatory [16, 17] and antifungal agents [18]. Also, the imidazole system can be found in numerous medically relevant compounds, such as the fungicide Ketoconazole [19] and its family members, the benzodiazepine antagonist Flumazenil [20], the antineoplastic drug Dacarbazine [21], the antibiotic Metronidazole [22], the antiulcerative agent Cimetidine [23], the antihyperthyroid drug Methimazole [24], the prohormone Thyroliberin [25], the muscarinic receptor agonist Pilocarpine [26] and the hypnotic agent Etomidate [27].Our research group reported the synthesis of a series of pyrroles and imidazoles using the reaction of primary amines with either alkyl propiolates or isothiocyanates in the presence of oxalyl chloride 3 under solvent-free conditions in good yields.

2. Experimental

All chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. IR spectra were measured on a Shimadzu IR-460 spectrometer. 1HNMR and 13CNMR spectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively, and were obtained for solutions in CDCl3 using TMS as the internal standard or 85% H3PO4 as the external standard.

2.1. General procedure for preparation of compounds 4a-e

To a mixture of primary amine 1 (2 mmol) and alkyl propiolate 2 (2 mmol) was added oxalyl chloride 3 (2.5 mmol) at 50 ℃. The reaction mixture was then stirred for 3 h. After completion of the reaction [TLC (AcOEt/hexane, 1:6, v/v) monitoring], the reaction mixture was purified by flash column chromatography on silica gel (Merck 230-400 mesh) using n-hexane-EtOAc as eluent to afforded pure compounds 4 (Scheme 1).

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Scheme 1.Synthesis of compound 4 using primary amine, alkyl propiolate and oxalyl chloride.
2.2. General procedure for preparation of compounds 9a-e

To a mixture of primary amine 1 (2 mmol) and arylisothiocyanate 8 (2 mmol) was added oxalyl chloride 3 (2.5 mmol) at 70 ℃. The reaction mixture was then stirred for 5 h. After completion of the reaction [TLC (AcOEt/hexane, 1:4, v/v) monitoring], the reaction mixture was purified by flash column chromatography on silica gel (Merck 230-400 mesh) using nhexane- EtOAc as eluent to afforded pure compounds 9 (Scheme 2).

3. Results and discussion

3.1. Pyrrole derivatives

Synthesis of pyrrole derivatives 4 using the reaction of primary amines 1 and alkyl propiolate 2 in the presence of oxalyl chloride 3 under solvent-free conditions at 50 ℃ in good yields was investigated.

The starting point for our experiments was to optimize the reaction conditions such as solvent and reactions time for the production of 1H-pyrrole and 1H-imidazol derivatives (Table 1). Solvent free condition and 50 ℃ is suitable for synthesis of compound 4a and solvent free condition and 70 ℃ is suitable for synthesis of compound 9a.

Table 1
Optimization of reaction conditions of compounds 4a and 9a.
Structures of compounds 4a-e were determined on the basis of their IR, 1H NMR and 13C NMR spectra, and these data were showed in Supporting information. The mass spectra of these compounds display molecular ion peaks at the appropriate m/z values. For example, the 1H NMR spectrum of 4a exhibits two singlets at δ 3.75 and δ 8.65 for methoxy and methine protons, respectively. Two doublets occur at δ 4.84 (d, 2J = 11.7 Hz) and δ 5.15 (d, 2J = 11.7 Hz) for CH2 protons along with signals for an aromatic moiety. Although the mechanism of this reaction has not been established, a plausible rationalization can be advanced to explain product formation (Scheme 3). On the basis of the well established chemistry of amine nucleophiles, it is reasonable to assume that pyrrole derivatives 4 result from the initial addition of primary amines to the alkyl propiolate and subsequent attack of the intermediate 5 on compound 3 to produce intermediate 6. Intramolecular nucleophilic attack of the nitrogen to carbonyl group in compound 6 generates compound 7, followed by elimination of HCl to produce 4.

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Scheme 2.Synthesis of compound 9 using primary amine, isothiocyanate and oxalyl chloride.

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Scheme 3.Proposed mechanism for the synthesis of compound 4.

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Scheme 4.Proposed mechanism for the synthesis of compound 9.
3.2. Imidazole derivatives

Under similar conditions, three component reactions between primary amine 1, arylisothiocyanate 8 and oxalyl chloride 3 at 70 ℃ under solvent-free conditions produce 1H-imidazole derivatives 9 in excellent yields (Scheme 2).

The structures of compounds 9 were assigned by IR, 1H NMR, 13C NMR and mass spectral data, and these data were showed in Supporting information. For example, the 1H NMR spectrum of 9a exhibited one singlet for methyl protons at (δ 2.35) and one singlet for NCH2 protons at (δ 5.14) along with signals for an aromatic moiety. Three resonances at 154.3 (C=O), 156.7 (C=O), and 183.6 (C=S) ppm were observed in the 13C NMR spectrum of 9a, which is attributed to the carbonyl and thionyl groups, further confirming the proposed structure. Although we have not established the mechanism of the reaction between the amines and arylisothiocyanate in the presence of oxalyl chloride in an experimental manner, a possible explanation is proposed in Scheme 4. Compound 9 result from the initial addition of the amine to isothiocyanate and subsequent attack of the resulting reactive compound 10 on the oxalyl chloride to yield intermediate 11. Cyclization of the intermediate 11 by elimination of HCl leads to compound 9.

4. Conclusion

In conclusion, we reported a novel method involving primary amines and alkyl propiolates or isothiocyanate in the presence of oxalyl chloride for the synthesis of 1H-pyrrole or 1H-imidazole derivatives. The advantages of our work are that the reaction is performed under solvent-free conditions without using a catalyst.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2013.09.015.

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