Advanced Guareschi–Thorpe synthesis of pyridines in green buffer, and pH-controlled aqueous medium with ammonium carbonate

Abstract

Hydroxy-cyanopyridines are easily synthesized via an advanced version of the Guareschi–Thorpe reaction by either three-component condensation of alkyl cyanoacetate or cyanoacetamide with 1,3-dicarbonyls and ammonium carbonate in an aqueous medium. Reactions proceed productively to give the desired products in high yields. Simple mechanistic monitoring showed the role of (NH₄)₂CO₃ as both a nitrogen source for the pyridine ring and the reaction promoter. This new multicomponent approach for pyridine synthesis is inexpensive, user-friendly, and eco-friendly, while green buffer conditions, versatility, precipitation of products in the reaction medium, and simple work-up are extra advantages.

Hydroxy-cyanopyridines are easily synthesized via an advanced version of the Guareschi–Thorpe reaction by three-component condensation of alkyl cyanoacetate or cyanoacetamide with 1,3-dicarbonyls and ammonium carbonate in aqueous medium.

1. Introduction

Pyridine derivatives, which are extensively used as the solvent, catalyst, and base,^1–3 constitute the skeletal part of the critical bio-organic medicals and are synthon precursors for vitamins, pharmaceuticals, food flavors, paints, dyes, adhesives, herbicides, insecticides, and rubbers.^4,5 Despite the development of various methods for the synthesis of pyridines,^6,7 the Guareschi–Thorpe (GT) method that gives hydroxy pyridines or their pyridone tautomer has rarely been investigated.^8–11 The importance of this reaction is due to the bioactivity of the pyridone/hydroxypyridine tautomer pairs,^12–14 in which their pyrimidine aza-analogs have an important roles in the structure of DNA nucleotides and related biomolecules. Besides, these tautomer pairs are critical intermediates for the synthesis of pharmaceuticals¹⁵ and clinically used medicines,¹⁶ including pirfenidone,¹⁷ ciclopirox,¹⁸ and huperazine.¹⁹ The original GT reaction⁸ is a usual method for the Hantzsch synthesis of pyridines²⁰ and a [3 + 2 + 1] synthetic strategy to provide the hydroxy pyridines via the three-component reaction of a β-diester with ammonium acetate and ethylcyanoacetate.²¹ Classical GT reaction is a multi-component reaction (MCR) run by refluxing the excess of cyanoethylacetate, diethylmalonate, and ammonium acetate in an azeotropic mixture of acetic acid, benzene, and water for 45 hours.²² A two-component [3 + 3] variant of the GT reaction for condensation of β-dicarbonyl compounds and cyanoacetamide, in not so high yields, has also been reported in organic solvents.²³ To avoid the negative impacts of the volatile organic solvents (VOSs) and corrosive catalysts, the development of more green water-based versions of GT reaction is highly anticipated.

Generally, the synthetic reactions need solvent, while most of organic solvents are volatile, toxic, flammable, and their reusing needs energy consumption. Green chemistry aims to minimize the VOS hazards in chemical processes by replacing them with more sustainable alternatives.²⁴ Water is the greenest alternative for the VOSs.²⁵ Thus, carrying out the organic reactions in water has been extensively developed.²⁶ Water-based organic reactions are highly desirable due to the advantages of the zero E-factor of water, polarity, hydrogen-bonding network, and hydrophobic interactions with organic materials to decrease the activation volume-change (ΔV)^# and enhance the reaction rate.²⁷ Additionally, a series of water-based organic reactions accelerated by microwave^28–30 or ultrasound irradiation³¹ occurred within minute scale times instead of days. Combination of the water-based organic synthesis³² with the multi-component reactions^33,34 provided water-based MCRs³⁵ as a highlight division of green chemistry to produce the complex bioorganic molecules. Typically, water-based MCRs have developed as recent post-methods for the synthesis of various heterocyclic compounds.^36,37 We have also developed Michael, Mannich, Biginelli, Hantzch, and other MCRs for the synthesis of heterocycles in water.^38–43 Catalyst-free MCRs in aqueous media are advanced promising examples of an ideal reaction for the synthesis of organic compounds, especially when the final product precipitates in water. Due to the importance of the hydroxy pyridine/pyridone derivatives and water-based organic reactions, we reported herein a new green version of GT reaction in water. In this method, ammonium carbonate is either a non-toxic nitrogen source or a pH-controlled agent for water-based synthesis of hydroxy pyridines under thermally or ultrasound conditions (Scheme 1).

Scheme 1. Guareschi–Thorpe reaction in water using ammonium carbonate.

2. Results and discussion

In our preliminary experiment, the three-component GT reaction of ethyl acetoacetate, ethyl cyanoacetate, and ammonium acetate performed in refluxed azeotropic mixture of H₂O : HOAc for 24 h. Upon cooling to room temperature, no precipitated product, and reaction analysis indicated the formation of a mixture of products together with the remaining starting materials. Based on our previous experiences on the selection of nitrogen source for heterocycles^39–44 and to reach a better yield, we compared the GT synthesis of 2,6-dihydroxy-3-cyano-4-methyl pyridine (1a) by three-component reaction of ethyl acetoacetate, ethyl cyanoacetate, and various ammonium salts in an aqueous media (Table 1).

Optimization of nitrogen source in GT model reaction^a.

Entry	Nitrogen source (mmol)	Solvent (mL)	Time (h)	Yield (%)
1	NH4Cl (1)	H2O	8	32
2	NH3 (1)	H2O	45	40
3	NH4OAc (1)	H2O	24	68
4	NH4NO3 (1)	H2O	10	38
5	NH4Cl/Na2CO3 (1)	H2O	6	70
7	(NH4)2CO3 (1)	H2O	5	75
8	(NH4)2CO3 (0.5)	H2O	10	72
9	(NH4)2CO3 (1.5)	H2O	5	90
10	(NH4)2CO3 (2)	H2O	5	93
11	(NH4)2CO3 (2)	H2O : EtOH (1 : 1, v/v)	4	96
12	(NH4)2CO3 (2)	EtOH	5	85
13	(NH4)2CO3 (2)	H2O : HOAc (1 : 1)	24	53
14	(NH4)2CO3 (2)	HOAc	24	50
15b	(NH4)2CO3 (2)	H2O : EtOH (1 : 1, v/v)	4	95

^aReaction conditions: ethyl cyanoacetate (1 mmol), ethyl acetoacetate (1 mmol), solvent (2 mL), nitrogen source, 80 °C.

^bReaction in 20 mmol scale.

As results show, the maximum yield of hydroxy pyridine 1a is due to the reactions run with (NH₄)₂CO₃ (entries 7–12), although only 68% yield of 1a was isolated after 24 h by the same set-upped reaction with ammonium acetate at 80 °C (entry 3). However, the best yield of product 1a was obtained from the reaction run with 2 mmol ammonium carbonate and 1 : 1 volume ratio of H₂O : EtOH as solvent (entry 11), which in one mmol of (NH₄)₂CO₃ is nitrogen source and the other mol acts as the reaction promoter. The lower yield of reaction in EtOH is due to the sublimation of (NH₄)₂CO₃ (entry 12). A 20 mmol scale-up of this one-pot three-component GT reaction was also successful to give the high yield of product 1a under the optimized conditions (entry 15).

Mechanistically, we assumed the reaction of (NH₄)₂CO₃ with ethyl cyanoacetate in an aqueous medium of reaction for the in situ production of cyanoacetamide as an intermediate. To clarify the details, we designed two individual reactions between (NH₄)₂CO₃ and the other starting materials in water, so ethyl acetoacetate was left unchanged and alkyl cyanoacetate reacted with the released ammonia from (NH₄)₂CO₃ to give the cyanoacetamide. Comparative condensation of various alkyl cyanoacetates with ammonium carbonate showed the reactivity order of methyl cyanoacetate > ethyl cyanoacetate >> tert-butyl cyanoacetate, in agreement with the steric factor of alkyl groups (Scheme 2).

Scheme 2. Experimental investigation on the possible mechanism.

Following the above reaction of alkyl cyanoacetates with ammonium carbonate by subsequent addition of ethyl acetoacetate led to product 1a again, although with a 5% higher yield for methyl cyanoacetate at a shorter reaction time. From a mechanistic standpoint, ammonium carbonate releases ammonia and also gives carbonic acid, which both can possibly promote the reaction. Bubbling of CO₂ at beginning the reaction confirmed decomposition of possibly formed carbonic acid at reaction temperature (80 °C). Thus synthetic process initiates by aminolysis of cyanoacetic ester to cyanoacetamide, which undergoes an aldol condensation with the β-ketoester to give a 1,5-dicarbonyl intermediate that finally cyclizes to afford the corresponding pyridine in high yield and purity (Scheme 3).

Scheme 3. Proposed mechanism for the roles of (NH₄)₂CO₃ in GT reaction.

The generality of the (NH₄)₂CO₃-catalyzed GT reaction was demonstrated by the synthesis of cyano hydroxypyridines (1a–1i) via the GT reaction of ethyl cyanoacetate, (NH₄)₂CO₃, and various β-ketoesters or 1,3-diketones under the optimized conditions in 1 : 1 volume ratio of H₂O : EtOH (Table 2).

GT reaction of ethyl cyanoacetate, (NH₄)₂CO₃, and 1,3-dicarbonyls^a.

Entry	R	R1	Product	Time (h)	Isolated yield (%)
1	CH3	OEt		4	96
2	CH3	OMe		3.5	98
3	CH3	O-tBu		8	85
4	Ph	OEt		7	93
5	CF3	OEt		2.5	95
6	CH2Cl	OEt		9	90
7	n-Propyl	OEt		7	85
8	Me	Me		5	90
9	Me	Ph		4	87
10	CF3			4	84
11	CF3	Me		3	90

^aReaction conditions: ethyl cyanoacetate (1 mmol), 1,3-dicarbonyl (1 mmol), (NH₄)₂CO₃ (2 mmol), H₂O : EtOH (1 : 1), 80 °C.

According to the results, all reactions moved along outstandingly by green conversion of starting materials to high yielding products with no noticeable side product observed by using (NH₄)₂CO₃ as dual ring nitrogen source and reaction promoter. For 2,6-dihydroxy-4-propylpyridine-3-carbonitrile (1e), the FT-IR and ¹H NMR were satisfactory, but some duplicated peaks in ¹³C NMR spectrum (125 MHz, DMSO-d₆) may be due to the increase in pyridone tautomer in pyridone/hydroxypyridine tautomer pairs of this 4-aliphatic substituted product (see the ESI†). However, this protocol was suitable for the substituted β-ketoesters (entries 1–7), and 1,3-diketones (8–11). Reducing of reaction times for 1,3-diketones versus β-ketoesters can be attributed to the higher electrophilic property and reactivity of the ketone carbonyl group than carbonyl of ester, whereas the electron-withdrawing group of CF₃ dramatically accelerated the rate of both reaction types (entries 5, 10, and 11) (see also the ESI† for details).

Aqueous solutions of (NH₄)₂CO₃ are well-known powerful buffer solutions with pH = 6.5–7.5. Thus, ammonium carbonate serves two functions in this GT reaction. It behaves either as a mild basic buffer to catalyze the condensation of β-ketoester with ethylcyanoacetate or as a nitrogen source for the resultant pyridine ring, especially when cyanoacetate derivatives were used as starting materials.

To clear the role of (NH₄)₂CO₃ and to support the formation of cyanoacetamide as the reaction intermediate, two parallel reactions of ethyl cyanoacetamide and ethyl acetoacetate in the presence and the absence of ammonium carbonate in water/EtOH solution (1 : 1 volume ratio) were attempted. These reactions gave a 96% and 40% of a significant solitude product after 3 h and 10 h, respectively. Isolation of the product by filtration and NMR analysis showed the formation of product 1a, in both reactions, to reveal the critical role of cyanacetamide as a reaction intermediate. The extension of time from 3 h to 10 h and lowering yield for the reaction run without ammonium carbonate offers the role of (NH₄)₂CO₃ for reaction promotion besides to its role for providing the nitrogen atom of the pyridine ring (Scheme 4).

Scheme 4. The role of (NH₄)₂CO₃ in GT synthesis of 1a from cyanoacetamide.

As often found with MCRs, the simple reaction conditions are compatible with the atmosphere and amenable to up-scaling. Therefore, a 20-fold scale GT reaction of ethyl cyanoacetamide, ethyl acetoacetate, and (NH₄)₂CO₃ was carried out to give the corresponding pyridine product 1a in 95% yield, although reaching the final pH of the reaction media to ∼7 was affected intensively on the reaction yield.

By supporting the formation of cyanoacetamide intermediate in GT reaction, the generality of the advanced GT reaction was tested by condensation of cyanoacetamide and various β-ketoesters or 1,3-diketones at the optimized reaction conditions with (NH₄)₂CO₃ (Table 3).

(NH₄)₂CO₃-promoted GT reaction of cyanoacetamide with 1,3-dicarbonyls^a.

Entry	R	R1	Product	Time (h)	Isolated yield (%)
1	CH3	OEt		3	97
2	CH3	OMe		2.5	96
3	CH3	O-tBu		5	91
4	Ph	OEt		3	95
5	CF3	OEt		1.5	94
6	CH2Cl	OEt		6	78
7	n-Propyl	OEt		3	80
8	Me	Me		1.5	95
9	Me	Ph		1	95
10	CF3			1.5	93
11	CF3	Me		1	97

^aReaction conditions: cyano-acetamide (1 mmol), 1,3-dicarbonyl (1 mmol), (NH₄)₂CO₃ (1 mmol), H₂O : EtOH (1 : 1, v/v), 80 °C.

Having easy access to such cyano hydroxypyridines, we investigated the three-component condensation of ethyl acetoacetate with malononitrile and ammonium carbonate in the same fashion, which gave the desired 2-amino-3-cyanopyridine product in excellent yields after the simple addition of water. By running a similar experiment with benzoylacetone, the reaction proceeded smoothly to give the corresponding product in high yield (Scheme 5) (see also the ESI† for details).

Scheme 5. Condensation of malononitrile and ethyl acetoacetate or benzoylacetone with (NH₄)₂CO₃.

3. Conclusion

In conclusion, we have developed an advanced version of the Guareschi–Thorpe reaction in an aqueous medium of ammonium carbonate as either a solid ammonia source or buffered catalyst for the high yielding synthesis of a variety of known and new hydroxy cyanopyridines from either alkyl cyanoesters or cyanoacetamide and 1,3-dicarbonyls. The efficiency of this protocol is based on the accessibility of starting materials, high yields and purities of products, simple work-up without the use of organic solvents, and eco-environmentally friendly green conditions.

4. Experimental

4.1. General

All chemicals were purchased from Sigma-Aldrich and Merck (Germany) in analytical grade and used without further purification. Reactions followed by thin layer chromatography on silica gel 60 F₂₅₄ (Merck). Fourier transform infrared (FT-IR) spectra were recorded on a Bruker Equinox 55 FT-IR spectrometer in the range of 4000–400 cm⁻¹ using KBr discs. Melting points were determined with a Buchi B-540 apparatus and are uncorrected. NMR spectra of products were recorded as a DMSO-d₆ solution in a Bruker 500 MHz spectrophotometer instrument, chemical shifts and J-values are in ppm and Hz, respectively.

4.2. General procedure for the three-component GT synthesis of hydroxyl-cyano-pyridines

A mixture of a 1,3-dicarbonyl compound (1 mmol), alkyl cyanoacetate (1 mmol), and ammonium carbonate (2 mmol) in EtOH (1 mL) : H₂O (1 mL) mixture was stirred at 80 °C for the given time. Solidification of the final products took place during this period. After the reaction completion (TLC monitoring), cold water was added, the precipitated solid product was filtered, washed with water, dried, and characterized with no further purification by melting point, FT-IR, or NMR spectra (see ESI S₃–S₂₆†).

4.3. General procedure for the two-component synthesis of hydroxyl-cyano-pyridines

A mixture of a 1,3-dicarbonyl compound (1 mmol), cyanoacetamide (1 mmol), and ammonium carbonate (1 mmol) in EtOH (1 mL) : H₂O (1 mL) mixture was stirred at 80 °C for the given time. And the solid product was isolated and characterized as above.

Conflicts of interest

The authors declare no competing interest.