INTRODUCTION:

Multi component reactions (MCRs) allow the creation of several bonds in a single operation and are attracting increasing attention as one of the most powerful emerging synthetic tools for the creation of molecular diversity and complexity^1-3. These reactions provide instantaneous access to large compound libraries with diverse functionality. Moreover, MCRs are both atom and step economic as they avoid time consuming costly purification processes in addition to the protection and deprotection steps^4,5.

Compounds containing 4H-pyran skeletons are of important classes of organic compounds on account of their interesting pharmacological and biological properties. Many of these compounds are known to have potential applications in pharmaceutical field. They are widely used as anticancer⁶, antimicrobial⁷, antioxidant⁸, and antiproliferative properties⁹.

4H-Pyran derivatives are also potential calcium channel antagonists, which are structurally similar to biologically active 1,4-dihydropyridines¹⁰. They are often used in cosmetics and pigments, and utilized as potentially biodegradable agrochemicals¹¹. Therefore, the synthesis of such compounds has attracted strong interest.

Considering the broad spectrum of biological activities of 4H-pyrans, synthetic chemists have developed numerous protocols for their syntheses including two-step as well as one-pot three component synthesis, catalyzed by ammonium acetate¹², thiourea dioxide¹³, MgO Nano powders¹⁴, MgO nanoplates¹⁵, ZnO nanoparticles¹⁶ and CuO nano-structures¹⁷. Each of these reported methods has its own merits, with at least one of the limitation of drastic condition, long reaction times, low yields, and effluent pollution. This has clearly indicated that there is still scope to develop an efficient and eco-sustainable method for the synthesis of 4H-pyrans. The 4H-pyrans were obtained by the three component condensation of ethyl acetoacetate, aldehydes with malononitrile using cafeine as catalyst in aqueous ethanol.

In recent years, use of natural materials as promising catalysts in organic reactions has received a considerable amount of attention due to their green credentials. Caffeine (trimethylxanthine (Fig. 1) is a plant alkaloid, found in numerous plant species, where it acts as a natural pesticide that paralyzes and kills certain insects feeding upon them. It is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The most commonly used caffeine-containing plants are coffee, tea, and to some extent cocoa¹⁸.

Figure 1 Structure of Caffeine

Caffeine has emerged as natural, green, cheap and efficient catalyst in various organic transformations. A one-pot, four-component procedure has been used for the green synthesis of benzo[a][1,3]oxazino[6,5-c]phenazine derivatives using Caffeine as catalyst¹⁹. Caffeine was applied as a homogeneous catalyst for the one-pot synthesis of benzo[a]pyrano[2,3-c]phenazine²⁰ and tetrahydrobenzo[b]pyran derivatives²¹. Organic compounds are very good pharamacophores performing wide range of biological activities^22-27.

In line with of our studies towards the development of new routes to the environmentally benign synthesis of biologically active molecules^28-32, in this manuscript, we wish to report the applicability of caffeine on the three-component reaction of aryl aldehydes, ethyl acetoacetate, and malononitrile for the synthesis of novel 2-amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate derivatives in aqueous ethanol media at reflux condition (Scheme 1). This is a one-pot reaction, which is not only operationally simple but also consistently gives the corresponding products in good to excellent yields.

Scheme – 1 Synthesis of various 2-amino-3-cyano-6-methyl-4-aryl-4H-pyran-5-ethylcarboxylate derivatives

2. Experimental:

2.1 Apparatus and analysis:

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. All yields refer to isolated products unless otherwise stated. ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) spectra were obtained using Bruker DRX- 500 Advance at ambient temperature, using TMS as internal standard. FT-IR spectra were obtained as KBr discs on Shimadzu spectrometer. Mass spectra were determined on a Varion - Saturn 2000GC/MS instrument. Elemental analysis were measured by means of Perkin Elmer 2400 CHN elemental analyzer flowchart.

2.2 General procedure to synthesis of 2-amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate derivatives using Caffeine as catalyst:

A mixture of ethyl acetoacetate (1 mmol), aldehydes (1 mmol), malononitrile (1 mmol) and catalyst Caffeine, in 5ml of EtOH-H₂O (1:1) were refluxed for appropriated time. After the TLC indicates the disappearance of starting materials, the reaction was cooled to room temperature, CH₂Cl₂ (20 ml) was added and the insoluble material was filtered to separate the catalyst. The filtrate was concentrated under vacuum and the crude residue was purified by recrystallization.2-Amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate was obtained as crystals. The recovered catalyst can be washed consequently with diluted acid solution, water and then acetone. After drying, it can be reused without noticeable loss of reactivity. The products were identified by IR, ¹H NMR, ¹³C NMR, mass, elemental analysis and melting points.

2.3 Spectral data for the synthesized compounds

(4a-j)

2-Amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate (4a)

IR (KBr, cm^-1): 3427, 3349, 3199, 2216, 1679, 1634, 1483, 1214, 788. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.09 (t, J = 7.2 Hz, 3H, CH₃CH₂), 2.19 (s, 3H, CH₃), 4.16 (q, J = 7.0 Hz, 2H, CH₃CH₂), 4.91 (s, 1H, CH), 5.07 (s, 2H, NH₂), 7.22-7.39 (m, 5H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.3, 18.8, 40.4, 59.9, 106.3, 118.7, 125.7, 127.3, 129.5, 131.3, 144.2, 147.0, 159.2, 167.2 ppm; MS (ESI): m/z 285 (M+H)⁺. Anal. Calcd. for C₁₆H₁₆N₂O₃ (%): C, 67.60; H, 5.60; N, 9.86. Found: C, 67.53; H, 5.55; N, 9.86.

2-Amino-3-cyano-6-methyl-4-(4-fluorophenyl)-4H-pyran-5-ethylcarboxylate (4b):

IR (KBr, cm^-1): 3413, 3343, 3215, 2216, 1661, 1636, 1481, 1204, 780. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.2 Hz, 3H, CH₃CH₂), 2.17 (s, 3H, CH₃), 4.05 (q, J = 7.2 Hz, 2H, CH₃CH₂), 4.90 (s, 1H, CH), 5.22 (s, 2H, NH₂), 7.21 (d, J=7.2 Hz, 2H, Ar-H), 7.39 (d, J=7.2 Hz, 2H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.0, 19.1, 39.7, 59.7, 105.7, 120.2, 125.0, 127.5, 129.0, 131.0, 144.7, 147.0, 159.3, 166.4 ppm; MS (ESI): m/z 303 (M+H)⁺. Anal. Calcd. for C₁₆H₁₅FN₂O₃ (%): C, 63.57; H, 4.96; N, 9.27. Found: C, 63.54; H, 4.91; N, 9.21.

2-Amino-3-cyano-6-methyl-4-(3-hydroxyphenyl)-4H-pyran-5-ethylcarboxylate (4c):

IR (KBr, cm^-1): 3435, 3342, 3214, 2204, 1674, 1646, 1496, 1206, 776. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.30 (s, 3H, CH₃), 4.13 (q, J = 7.3 Hz, 2H, CH₃CH₂), 4.93 (s, 1H, CH), 5.07 (s, 2H, NH₂), 7.10 (d, J=7.4 Hz, 2H, Ar-H), 7.42 (d, J = 7.4 Hz, 2H, Ar-H), 9.57 (s, 1H, OH) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.2, 20.2, 39.3, 59.7, 105.7, 119.3, 125.1, 127.4, 129.0, 131.0, 144.1, 147.4, 158.4, 167.0 ppm; MS (ESI): m/z 301 (M+H)⁺. Anal. Calcd. for C₁₆H₁₆N₂O₄ (%): C, 64.00; H, 5.33; N, 9.33. Found: C, 63.94; H, 5.32; N, 9.28.

2-Amino-3-cyano-6-methyl-4-(3-nitrophenyl)-4H-pyran-5-ethylcarboxylate (4d):

IR (KBr, cm^-1): 3402, 3336, 3204, 2215, 1683, 1639, 1481, 1223, 789. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.24 (t, J = 7.2 Hz, 3H, CH₃CH₂), 2.25 (s, 3H, CH₃), 4.12 (q, J = 7.1 Hz, 2H, CH₃CH₂), 4.88 (s, 1H, CH), 5.26 (s, 2H, NH₂), 7.14 (d, J=7.2 Hz, 2H, Ar-H), 7.41 (d, J=7.2 Hz, 2H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.1, 19.5, 39.8, 59.7, 105.9, 119.5, 125.1, 127.5, 129.0, 131.0, 144.3, 146.6, 158.9, 166.6 ppm; MS (ESI): m/z 330 (M+H)⁺. Anal. Calcd. for C₁₆H₁₅N₃O₅ (%): C, 58.35; H, 4.56; N, 12.76. Found: C, 58.32; H, 4.54; N, 12.71.

2-Amino-3-cyano-6-methyl-4-(4-chlorophenyl)-4H-pyran-5-ethylcarboxylate (4e):

IR (KBr, cm^-1): 3437, 3337, 3213, 2213, 1673, 1645, 1475, 1207, 789. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.15 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.27 (s, 3H, CH₃), 4.07 (q, J = 7.2 Hz, 2H, CH₃CH₂), 4.89 (s, 1H, CH), 5.24 (s, 2H, NH₂), 7.07 (d, J=7.6 Hz, 2H, Ar-H), 7.31 (d, J=7.6 Hz, 2H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 14.2, 19.6, 40.2, 59.8, 105.8, 119.4, 126.3, 127.6, 129.0, 131.0, 144.0, 146.2, 159.2, 167.5 ppm; MS (ESI): m/z 319 (M+H)⁺. Anal. Calcd. for C₁₆H₁₅ClN₂O₃ (%): C, 60.29; H, 4.71; N, 8.79. Found: C, 60.25; H, 4.66; N, 8.74.

2-Amino-3-cyano-6-methyl-4-(4-nitrophenyl)-4H-pyran-5-ethylcarboxylate (4f):

IR (KBr, cm^-1): 3424, 3336, 3216, 2224, 1675, 1640, 1481, 1211, 783. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.18 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.28 (s, 3H, CH₃), 4.18 (q, J = 7.2 Hz, 2H, CH₃CH₂), 4.84 (s, 1H, CH), 5.14 (s, 2H, NH₂), 7.04 (d, J=7.2 Hz, 2H, Ar-H), 7.38 (d, J=7.2 Hz, 2H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 14.7, 19.6, 40.4, 60.4, 106.1, 119.7, 126.2, 127.2, 129.0, 131.0, 144.6, 147.1, 159.2, 167.4 ppm; MS (ESI): m/z 330 (M+H)⁺. Anal. Calcd. for C₁₆H₁₅N₃O₅ (%): C, 58.35; H, 4.56; N, 12.76. Found: C, 58.33; H, 4.55; N, 12.73.

2-Amino-3-cyano-6-methyl-4-(3-methylphenyl)-4H-pyran-5-ethylcarboxylate (4g):

IR (KBr, cm^-1): 3455, 3329, 3198, 2210, 1688, 1644, 1466, 1222, 780. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.13 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.22 (s, 3H, CH₃), 2.2 (s, 3H, CH₃), 4.22(q, J = 7.1 Hz, 2H, CH₃CH₂), 4.88 (s, 1H, CH), 5.27 (s, 2H, NH₂), 7.17 (d, J = 7.4 Hz, 2H, Ar-H), 7.28 (d, J = 7.4 Hz, 2H Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.3, 18.3, 19.9, 39.2, 59.6, 105.3, 120.0, 126.0, 127.6, 128.3, 129.0, 131.0, 144.9, 147.5, 159.1, 166.2 ppm; MS (ESI): m/z 299 (M+H)⁺. Anal. Calcd. for C₁₇H₁₈N₂O₃ (%): C, 68.44; H, 6.08; N, 9.39. Found: C, 68.46; H, 6.03; N, 9.34.

2-Amino-3-cyano-6-methyl-4-(4-bromophenyl)-4H-pyran-5-ethylcarboxylate (4h):

IR (KBr, cm^-1): 3424, 3324, 3204, 2217, 1667, 1637, 1482, 1212, 791. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.17 (t, J = 7.0 Hz, 3H, CH₃CH₂), 2.21 (s, 3H, CH₃), 4.09 (q, J = 7.0 Hz, 2H, CH₃CH₂), 4.92 (s, 1H, CH), 5.16 (s, 2H, NH₂), 7.11 (d, J=7.4 Hz, 2H, Ar-H), 7.37 (d, J=7.4 Hz, 2H, Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 14.6, 19.7, 39.5, 60.5, 105.4, 120.4, 125.4, 127.5, 128.2, 129.0, 131.0, 144.8, 146.9, 158.2, 167.6 ppm; MS (ESI): m/z 363.9 (M+H)⁺. Anal. Calcd. for C₁₆H₁₅BrN₂O₃ (%): C, 52.90; H, 4.13; N, 7.71. Found: C, 52.87; H, 4.08; N, 7.70.

2-Amino-3-cyano-6-methyl-4-(4-methylphenyl)-4H-pyran-5-ethylcarboxylate (4i):

IR (KBr, cm^-1): 3441, 3322, 3204, 2213, 1676, 1639, 1484, 1217, 783. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.16 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.21 (s, 3H, CH₃), 2.34 (s, 3H, CH₃), 4.19 (q, J = 7.1 Hz, 2H, CH₃CH₂), 4.97 (s, 1H, CH), 5.27 (s, 2H, NH₂), 7.11 (d, J = 7.4 Hz, 2H, Ar-H), 7.36 (d, J = 7.4 Hz, 2H Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.3, 18.3, 19.9, 39.2, 59.6, 105.3, 120.0, 126.0, 127.6, 128.3, 129.0, 131.0, 144.9, 147.5, 159.1, 166.2 ppm; MS (ESI): m/z 299 (M+H)⁺. Anal. Calcd. for C₁₇H₁₈N₂O₃ (%): C, 68.44; H, 6.08; N, 9.39. Found: C, 68.40; H, 6.05; N, 9.34.

2-Amino-3-cyano-6-methyl-4-(4-methoxyphenyl)-4H-pyran-5-ethylcarboxylate (4j):

IR (KBr, cm^-1): 3439, 3324, 3203, 2215, 1675, 1634, 1489, 1221, 779. ¹H NMR (500 MHz, DMSO-d₆) δ: 1.22 (t, J = 7.4 Hz, 3H, CH₃CH₂), 2.30 (s, 3H, CH₃), 3.58 (s, 3H, OCH₃), 4.15 (q, J = 7.1 Hz, 2H, CH₃CH₂), 4.91 (s, 1H, CH), 5.21 (s, 2H, NH₂), 7.16 (d, J = 7.4 Hz, 2H, Ar-H), 7.31 (d, J = 7.4 Hz, 2H Ar-H) ppm; ¹³C NMR (125 MHz, DMSO-d₆) δ: 15.3, 19.9, 39.2, 54.2, 59.6, 105.3, 120.0, 125.9, 127.1, 129.0, 131.0, 144.9, 147.5, 158.9, 166.2 ppm; MS (ESI): m/z 315 (M+H)⁺. Anal. Calcd. for C₁₇H₁₈N₂O₄ (%): C, 64.97; H, 5.73; N, 8.92. Found: C, 64.93; H, 5.70; N, 8.89.

3. Results and discussion:

In order to optimize the conditions, we studied the reaction of ethyl acetoacetate, 4-fluoro benzaldehyde with malonitrile and Caffeine (5mol %) as a simple model substrate in various conditions. The reaction was performed in various solvents, temperatures, amount of catalyst and also with different catalysts as shown in Table – 1. The results presented in Table – 1 indicates that the use of 5mol % of Caffeine maintaining the yield at 95%, so this amount is sufficient to promote the reaction in EtOH-H₂O (1:1) under reflux condition (Table - 1, Entry 7).

Table 1: Optimization of reaction conditions for the synthesis of 2-amino-3-cyano-6-methyl-4-(4-fluorophenyl)-4H-pyran-5-ethylcarboxylate (4b)^a

Entry	Catalyst	Amount (mol%)	Solvent	Temperature (^oC)	Time (min)	Yield (%)^b
1	Caffeine	5	CH₃CN	Reflux	60	50
2	Caffeine	5	H₂O	Reflux	60	72
3	Caffeine	5	MeOH	Reflux	50	76
4	Caffeine	5	EtOH	Reflux	50	73
5	Caffeine	5	CHCl₃	Reflux	60	48
6	Caffeine	5	Solvent-free	Reflux	40	29
7	Caffeine	5	EtOH-H₂O (1:1)	Reflux	25	95
8	Caffeine	5	EtOH-H₂O (1:1)	Rt	60	39
9	Caffeine	5	EtOH-H₂O (1:1)	40	50	58
10	Caffeine	5	EtOH-H₂O (1:1)	50	40	74
11	Caffeine	5	EtOH-H₂O (1:1)	60	30	88
12	Caffeine	0	EtOH-H₂O (1:1)	Reflux	60	0
13	Caffeine	3	EtOH-H₂O (1:1)	Reflux	40	51
14	Caffeine	10	EtOH-H₂O (1:1)	Reflux	30	95

^aReaction conditions: 4-fluorobenzaldehyde (1 mmol), malononitrile (1 mmol), and ethyl acetoacetate (1 mmol), solvent 5 mL.

^bIsolated yields

Table 2: Preparation of various 2-Amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylatederivatives^a

Entry	R1	Product	Time (min)	Yield (%)^b	Mp (^oC)
1	H	4a	35	93	194 – 195
2	4-F	4b	25	95	187 – 188
3	3-OH	4c	35	90	160 – 162
4	3-NO₂	4d	35	90	181 – 183
5	4-Cl	4e	25	92	170 – 172
6	4- NO₂	4f	25	91	183 – 185
7	3-CH₃	4g	45	87	171– 172
8	4-Br	4h	25	93	173 – 175
9	4-CH₃	4i	45	88	178 – 179
10	4-OCH₃	4j	45	88	141 – 143

^aReaction conditions: ethyl acetoacetate (1 mmol), aldehyde (1mmol) and malononitrile (1mmol) in the presence of Caffeine (5mol %) in EtOH-H₂O (1:1) at reflux.

^bIsolated yield.

Encouraged by this successful three-component reaction, synthesis of diverse 2-amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate derivatives 4a-j was undertaken. The aromatic aldehydes bearing electron-withdrawing and electron donating groups were found to be equally effective to produce 2-amino-4H-pyrans 4a-j in very good yields (Table – 2).

Recyclability of catalysts is an important aspect of a reaction from an economical and environmental point of view, and has attracted much attention in recent years. Thus the recovery and reusability of Caffeine was investigated. After completion of the reaction, the reaction mixture was cooled to ambient temperature, CH₂Cl₂ was added, and the Caffeine was filtered off. The recycled catalyst has been examined in the next run. The Caffeine catalyst could be reused four times without any loss of its activity and yields ranged from 95 to 90 %.

4. Conclusion:

In conclusion, a simple, efficient and green protocol was demonstrated for the synthesis of 2-amino-3-cyano-6-methyl-4-phenyl-4H-pyran-5-ethylcarboxylate derivatives via one-pot multicomponent reactions in EtOH-H₂O (1:1) at reflux condition. General applicability, operational simplicity, mild reaction conditions, non-toxic and inexpensive catalyst were the advantages of the present procedure.

5. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

6. ACKNOWLEDGEMENTS:

All the authors are grateful to C. Abdul Hakeem College Management for the facilities and support.

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Received on 26.07.2023 Modified on 22.09.2023

Asian J. Research Chem. 2023; 16(6):438-442.

DOI: 10.52711/0974-4150.2023.00072