Catalyst-Free Multicomponent Synthesis of Novel Chromene Carbonitriles from Pyrazole Aldehydes using Ethanol

Introduction  

MDR varieties of many pathogens threaten health as well as economy. Ugi- Multicomponent Reaction has played a vital part in pharmaceutical chemistry. Traditional Ugi-MCRs provide one-step synthesis of molecules with peptide core. Ugi-MCRs with a number of modifications were made available, which enabled medicinal chemists to design diverse molecular scaffolds and have enlarged its application in modern drug evolution tremendously. The multicomponent reaction’s applications in drug design like molecules were notable^1-3. MCRs also play a vital role in agrochemical industries. Several studies have revealed the importance of innovative synthetic organic methods via one-pot multi-component reactions (MCRs)⁴. Simple protocols, environmentally friendly principles, usage of readily available low-cost reactants and greater product yields were the advantages of one-pot synthesis compared to conventional multistep synthesis⁵. These reactions enable the production of variety of heterocyclic compounds without the necessity for isolation of intermedeiates⁶. Reduced reaction time, simple workup method, greater selectivity, high atom economy and the ability to employ green solvents are all the added advantages of MCRs⁷.

The vast majority of marketed pharmaceuticals contain heterocycles as common fragments and hence heterocycles play essential role in modern drug synthesis. They played a crucial influence in the contemporary organic synthesis development. Heterocycles were largest diverse class of synthesized compounds with notable biomedical, commercial and chemical uses. Large number of natural products, diverse drugs and biologically active substances contain heterocycles in their structures. Considering the importance of heterocycles, substantial attentions were paid to strategize various eminent methods for their synthesis. Heterocyclic chemistry has its origin in organic synthesis and medicinal chemistry⁸.

Chromenes were a group of heterocycles containing oxygen atom, bicyclic, formed by fusion of a pyran ring with that of a benzene ring. They were most common types of naturally occurring heterocyclic compounds with diverse spectrum of biological activities. They were found in plants, bacteria, fungi and animals. Chromenes were important cores in medicinal chemistry, since they exhibit a myriad of biological activities like β-secretase inhibition, anti-dyslipidemic and anti-neoplastic behaviour.  Chemotherapeutic chromenes such as EPC2407, LY290181 and LY290191 are well known for their anticancer activities⁹.

4-Aryl-4H-Chromene possessed ER-antagonists activity against MCF-7 cell line¹⁰ and phenyl benzo[h]chromene have shown inhibitory activation against tumour cell lines¹¹.  Bis chromene derivatives were prepared and their anti-influenza virus activities were studied¹². 2-aryl-4H-chromene was prepared and its prominent α-glucosidase inhibitory activities were studied¹³. 2‑Amino‑4H‑Chromenes possess a broad range of medicinal activities¹⁴. Vinyl-2H-chromene-3‑carbonitriles, prepared by Knoevenagal condensation were found to have enhanced optical properties and could be used as dyes¹⁵. Optically active nitro-2H-chromenes containing best antibacterial properties were reported¹⁶.  4H-chromene-3-carboxylates were synthesized and their   potential elastase inhibitory action was found to be predominent¹⁷.

Various catalysts were utilized in the synthesis of chromenes over the past few decades and are as follows, Fe₃O₄ nanoparticles¹⁸, L-Proline¹⁹, DABCO²⁰, Bi-functional organocatalysts 1-[(3,5-bis(tri-fluoromethyl)phenyl)]thiourea²¹, squaramide organocatalysts by Tandem-Michael cyclization²², tandem Michael-asymmetric reaction using Chiral squaramide catalyst²³, morpholine²⁴, TMEDA²⁵, L-Cysteine functionalized magnetic nanoparticles (LCMNP)²⁶, meglumine²⁷, Catalyst-free synthesis under ultrasound irradiation²⁸, NaO^tBu²⁹, CuFe₂O₄ nanocatalyst³⁰, Na₂CO₃³¹_,  piperidine³², chitosan catalysed microwave assisted³³, eco-friendly synthesis under ultrasonication³⁴, Polystyrene-supported p-toluene sulfonic acid³⁵and  K₂CO₃³⁶.

The lack of literatures with synthesis of chromene cores imbibing pyrazole aldehydes have been the driving force for the synthesis of these compounds. In our aim to build a novel library of biologically active targets, we discuss the catalyst-free, one-step, three-component synthesis of functionalized chromene carbonitriles process in RT.

Figure 1: Biologically Active 4H-Chromenes. Click here to View figure

Experimenital

Material and methods

Chemicals and reagents

The chemicals involved in the reaction were bought from Sigma-Aldrich (U.S.A) .

pre-coated aluminium sheets of silica gel [CCM Gel de silica 60 F254-0.2mm thickness (Merck, Germany)] was utilized to perform analytical T.L Chromatography. Silica gel of 230-400 mesh size ( Merck, India ) was used for performing column chromatography.

Analytical Equipment

FT-IR spectra were recorded with a Lambda spectrophotometer. Using DMSO_, NMR spectra (¹H and ¹³C) of the compounds were acquired at 400MHz and 100MHz respectively with spectrometer of BRUKER Company with TMS as standard. QTRAP system (4000) [LC/MS/MS (UPLC)-hybrid triple quadruple/Linear Ion trap] was used for recording the mass spectra.

General Procedure – Synthesis of 4-(2-amino-3-cyano-7, 7-dimethyl-5-oxo-5, 6, 7, 8-

tetrahydro-4H-chrome-4yl)-1-phenyl-1H-pyrazole-3-carboxylates 4a-4l:

At room temperature, reaction mixture containing 5,5-dimethylcyclohexane-1,3-dione (0.25g), malononitrile (0.11g) and  pyrazole aldehyde  (0.2g) was stirred in ethanol(10ml) for 2 hrs. Thin layer chromatographic technique was used to confirm the reaction progress. Formed precipitate was filtered, purified by column chromatography [20% E.A: 80% P.E mixture] and pure product was obtained. ¹H, ¹³CNMR, FT–IR and L.C-M.S spectroscopic techniques were utilized to characterize the prepared compounds and results were tabulated 2.

Scheme 1: Synthesis of Chromenes. Click here to View scheme

Results and their Discussion

Table 1: Solvent-Screening

Derivatives	Reaction Time (hrs.)	Product Yield (%)a
		Water	Methanol	Ethanol
4a	2.0	45	65	94
4b	2.5	38	60	93
4c	2.0	41	61	95
4d	2.2	45	71	96
4e	2.5	33	55	91
4f	3.5	30	54	89
4g	2.0	32	59	92
4h	2.5	33	55	92
4i	3.0	43	62	94
4j	2.2	34	54	88
4k	2.1	41	60	91
4l	2.2	45	61	92

^a Isolated yield

Using water, methanol and ethanol, solvent screening was carried out. It was found that, poor yield was obtained in water; better results were obtained while using methanol and excellent yield were seen with ethanol. The obtained results were given in table 1.

Table 2: Preparation of Chromenes (4a-4l). Click here to View figure

Figure 2: structural diagrams of compound 4e Click here to View figure

The proton NMR spectrum of product-4e shows a 6 protons singlet in 1.36ppm must be due to the presence of two methyl(-CH₃) group. 2 protons singlet at 2.94ppm was due protons at C-8 position and two protons singlet at 3.40ppm was assigned to C-6 position. 1 proton singlet in 5.11ppm was attributed for chromene [pyran]ring proton C-4 position. The ten protons multiplet at 7.47 – 7.94ppm was attributed to aromatic protons. The singlet 8.21ppm was assigned to proton of pyrazole ring. Two protons singlet in 9.22ppm assigned to presence of amine (-NH₂).

In the ¹³C NMR spectra, the peaks ranges between 114.3 – 138.8ppm were because of aromatic ring carbons. Peak in 24.5ppm was attributed for 2 methyl carbon. Peak at 32.5, 34.5, 42.4, 54.7 and 79.1ppm was assigned to C-7, C-4, C-8, C-6 and C-3. Carbon at position 3’, 4’ and 5’ of pyrazole ring are appeared at 153.0, 115.0 and 120.3ppm respectively. The peak at 114.8ppm showed to Carbon of nitrile group. Peak at 155.3ppm was assigned for C-2. Peak at 196.5ppm was due to carbonyl (-C=O) carbon. [M+H]⁺ of LC-MS spectrum revealed molecular ion peak at m/z 437.

Figure 3: 1H-NMR spectrum of product 4e Click here to View figure

Figure 4: 13C-NMR spectrum of product-4e Click here to View figure

Figure 5: L.C-M.S spectrum of product-4e. Click here to View figure

Figure 6: IR spectrum of product-4e Click here to View figure

Characterisation Of Products 4a-4l

Table 3: Molecular mass and Physical properties of synthesized compounds 4a-4l.

Compound	Molecular Mass	m/z  (M+H)+	Colour and  Appearance	Nature	Retention Factor (20%E.A:P.E)
4a	432.89	433	Pale yellow	solid	0.40
4b	522.78	523	Yellow	solid	0.43
4c	418.89	419	Pale yellow	solid	0.38
4d	508.85	509	Dark yellow	solid	0.36
4e	436.89	437	Light yellow	solid	0.41
4f	469.79	471	White	solid	0.39
4g	514.88	515	Pale Orange	solid	0.48
4h	466.96	467	Whitish Orange	solid	0.52
4i	480.86	481	Brownish yellow	solid	0.58
4j	560.77	561	Light Orange	solid	0.42
4k	604.86	605	Pale yellow	solid	0.46
4l	556.95	557	Reddish yellow	solid	0.47

Table 4  : Elemental analysis data for compounds 4a-4l.

Compound	Molecular Formula		Elemental Analysis
			% of C	%of H	% of N	% of O	% of Br	% of Cl
4a	C24H24N4O4	Calculated	66.65	5.59	12.96	14.80
		Found	66.62	5.56	12.94	14.74
4b	C24H22N6O8	Calculated	55.17	4.24	16.09	24.50
		Found	55.13	4.20	16.06	24.44
4c	C23H22N4O4	Calculated	66.02	5.30	13.39	15.29
		Found	66.00	5.28	13.36	15.27
4d	C23H20N6O8	Calculated	54.33	3.96	16.53	25.17
		Found	54.29	3.93	16.48	25.14
4e	C27H24N4O2	Calculated	74.29	5.54	12.84	7.33
		Found	74.22	5.52	12.80	7.28
4f	C27H23ClN4O2	Calculated	68.86	4.92	11.90	6.79		7.53
		Found	68.82	4.87	11.86	6.74		7.49
4g	C27H23BrN4O2	Calculated	62.92	4.50	10.87	6.21	15.50
		Found	62.90	4.46	10.83	6.17	15.38
4h	C28H26N4O3	Calculated	72.09	5.62	12.01	10.29
		Found	72.10	5.59	12.04	10.18
4i	C29H28N4O3	Calculated	72.48	5.87	11.66	9.99
		Found	72.42	5.82	11.58	9.92
4j	C27H21ClN6O2	Calculated	57.81	3.77	14.98	17.11		6.32
		Found	57.41	3.72	14.93	17.18		6.46
4k	C27H21BrN6O6	Calculated	53.57	3.50	13.88	15.86	13.20
		Found	53.52	3.48	13.85	15.84	13.19
4l	C28H24N6O7	Calculated	60.43	4.35	15.10	20.12
		Found	60.41	4.32	15.08	20.10

 

Table 5: Spectral data for newly prepared compounds 4a-4l.

Product	1H NMR: 400MHz, DMSO, ⸹ppm	13C NMR: 100MHz, DMSO, ⸹ppm	FT-IR [ KBr, cm-1 ]
4a	1.03(s, 3H ), 1.10 (s, 3 H ), 1.41(t, 3 H, J = 7.2 Hz), 2.19 (s, 2 H), 2.44 (s, 2 H ), 4.36 (q, 2H, J  = 7.1 Hz), 4.64 ( s, 2 H ), 4.88 ( s, 1H), 7.26-7.71( m, 5 H ), 7.88 (s, 1 H );	14.4, 26.2, 27.5, 28.9, 32.0, 40.6, 50.7, 58.0, 61.1, 61.5, 111.9, 118.9, 120.1, 127.6, 127.9, 128.8, 129.4, 129.9, 139.4, 141.7, 158.2, 162.2, 162.3, 196.1.	3758.07, 3142.77, 2184.51, 1710.95, 1640.22, 1409.86, 1289.99, 1157.03, 1068.48, 932.03, 751.63, 692.48, 619.27, 555.36
4b	1.13 ( s, 3H), 1.20 ( s, 3H), 1.43( t, 3H, J = 7.3 Hz ), 2.20( s, 2H ), 2.46 ( s, 2H ), 4.34( q, 2H, 7.2 Hz ), 4.66 ( s, 2H ), 4.89 ( s, 1H), 7.90 ( s, 1 H ),  8.23 ( d, 1 H, J = 8.4 Hz ),  8.80 (d, 1H, J = 8.4 Hz), 8.93 ( s,1 H )	14.2, 26.4, 27.8, 28.8, 32.0, 40.4, 50.4, 58.3, 61.4, 61.9, 112.6, 117.6, 121.1, 127.3, 127.7, 128.9, 129.3, 129.9, 137.4, 141.5, 158.6, 161.2, 162.1, 197.3	3757.17, 3146.87, 2183.50, 1711.93, 1641.12, 1288.89, 1156.33, 1067.45, 931.13, 752.53, 691.47, 618.17, 554.16
4c	1.09  (s, 3 H ), 1.15 ( s, 3 H ), 2.15 ( s,  2 H ), 2.39 ( s, 2 H), 3.91 (s, 3 H,), 4.61( s, 2 H ), 4.79 ( s, 1 H), 7.35-7.80 ( m, 5 H ), 7.91 (s, 1 H )	26.8, 27.9, 30.1, 32.4, 40.3, 50.1, 52.4, 58.7, , 61.9, 112.0, 118.2, 120.7, 126.3, 127.4, 128.0, 129.0, 130.2, 139.1, 142.2, 157.6, 162.7, 163.1, 198.6	3756.08, 3143.67, 2184.11, 1713.90, 1642.32, 1407.85, 1287.79, 1067.38, 931.13, 752.64, 691.88, 618.25, 556.26
4d	1.12 ( s, 3 H ), 1.28 ( s, 3 H ), 2.23 (s,  2 H ), 2.41 ( s, 2 H ), 3.89 ( s, 3 H ), 4.64 ( s, 2 H ), 4.80 ( s, 1 H ), 7.94 ( s, 1 H ),  8.28 ( d, 1 H, J = 8.2 Hz ),  8.86 ( d, 1H, J = 8.2Hz ), 8.90 ( s,1 H )	25.4, 27.8, 28.2, 32.3, 41.3, 50.0, 51.7, 58.0, 61.2, 111.3, 116.2, 120.6, 126.4, 127.3, 128.7, 129.1, 130.1, 136.4, 142.4, 157.8, 160.7, 162.4, 198.4	3756.17, 3142.47, 2183.52, 1711.56, 1641.25, 1408.53, 1154.13, 1067.58, 933.13, 755.73, 691.58, 617.37, 551.56
4e	1.12 ( s, 3 H ), 1.19 ( s, 3 H), 2.23 ( s, 2 H ), 2.41 ( s, 2 H ), 4.80 ( s, 1 H), 4.98 (s, 2 H ), 6.98-7.12 ( m, 5 H ), 7.56-7.88 ( m, 5 H ), 8.01 ( s, 1 H )	27.1, 32.6, 38.2, 51.9, 58.6, 113.2, 117.6, 119.3, 123.4, 126.8, 127.8, 129.0, 133.5, 139.4, 150.2, 154.5, 159.8, 198.1	3759.27, 3140.67, 2174.51, 1715.95, 1629.22, 1401.66, 1285.89, 1048.43, 931.23, 750.51, 692.08, 611.27, 552.36
4f	1.10 ( s, 3 H ), 1.20 ( s, 3 H ), 2.25 ( s, 2H ), 2.38 ( s, 2 H ), 4.79 ( s, 1 H ), 4.99 ( s, 2 H ), 6.79-7.20  ( m, 5 H ), 7.63(d, 2H, J = 7.4Hz), 7.97(d, 2H, J = 7.5Hz) , 8.01( s, 1 H )	26.9, 31.8, 37.6, 52.3, 58.0, 112.6, 116.4, 120.0, 123.2, 126.4, 127.6, 131.8, 132.6, 139.7, 151.4, 156.6, 159.0, 200.4.	3754.00, 3138.57, 2183.41, 1711.85, 1400.76, 1279.79, 1147.13, 1065.48, 931.03, 751.63, 692.48, 610.27, 555.36
4g	1.11 ( s, 3 H ), 1.23 ( s, 3 H), 2.25 ( s, 2H ), 2.37 ( s, 2 H ), 4.79 ( s, 1 H ), 4.93 ( s, 2 H ), 6.76-7.18 ( m, 5 H ), 7.62 ( d, 2  H, J = 7.3 Hz ), 7.89 ( d, 2 H, J = 7.1 Hz ), 8.34 ( s, 1 H )	26.6, 31.7, 36.9, 53.3, 59.3, 112.4, 117.3, 121.0, 123.5, 126.1, 128.3, 131.0, 132.4, 139.4, 151.0, 155.6, 158.3, 199.4	3753.11, 3141.57, 1715.85, 1630.12, 1412.16, 1285.79, 1150.13, 1061.38, 931.13, 750.83, 691.38, 618.37, 554.16
4h	1.15 ( s, 3 H ), 1.20 ( s, 3 H ), 2.23 ( s, 2 H ), 2.41 ( s, 2 H ), 3.78 ( s, 3 H ), 4.81 ( s, 1 H ), 4.97 ( s, 2 H ), 6.75-7.14 ( m, 5 H ), 7.64 (d, 2 H, J = 7.1 Hz ), 7.86 ( d, 2 H, J = 7.2 Hz ), 8.41 ( s,  1 H )	24.3, 32.6, 34.4, 52.8, 56.2, 60.1, 110.8, 116.1, 120.0, 122.3, 124.5, 126.4, 130.2, 133.4, 140.6, 152.7, 154.2, 160.1, 200.4	3751.57, 3143.47, 2183.41, 1700.94, 1630.11, 1405.16, 1275.59, 1155.13, 1063.38, 744.53, 691.38, 613.17, 553.26
4i	1.11 ( s, 3 H ), 1.19 ( s, 3 H ), 2.18 ( s, 2 H ), 2.45 ( s, 2 H ), 4.84 ( s, 1 H ), 4.88 ( s, 2 H ), 6.81-7.26 ( m, 5 H ), 7.72 ( d , 2 H, J = 7.5 Hz ), 7.92 ( d, 2 H, J = 7.6 Hz ), 8.96 ( s, 1 H )	14.6, 23.3, 32.8, 34.6, 51.6,  61.0, 65.8, 111.5, 118.0, 120.5, 121.8, 124.2, 126.8, 131.2, 135.1, 142.4, 152.4, 156.7, 165.2, 202.0	3748.27, 3140.71, 2182.41, 1622.11, 1409.86, 1289.99, 1157.03, 1068.48, 932.03, 751.63, 692.48, 619.27, 555.36
4j	1.11 ( s, 3 H ), 1.22 ( s, 3 H ), 2.31 ( s, 2 H ), 2.35 ( s, 2 H ), 4.82 ( s, 1 H ), 4.97 ( s, 2 H ), 7.86 ( s, 1 H ),  8.36 ( d, 1 H, J = 8.2 Hz ),  8.94 ( d, 1 H, J = 8.2 Hz ),7.61 ( d, 2 H,J = 7.6 Hz ), 7.92 ( d, 2 H, J = 7.6 Hz ), 8.22 ( s, 1 H )	25.6, 31.6, 38.4, 52.8, 58.4, 113.1, 116.2, 121.1, 123.5, 125.1, 127.1, 131.3, 132.8, 138.4, 152.2, 157.8, 158.4, 203.0	3751.27, 3143.57, 2180.21, 1704.05, 1635.32, 1408.68, 1287.59, 1038.58, 930.13, 751.65, 695.36, 610.37, 555.26
4k	1.12 ( s, 3 H ), 1.24 ( s, 3 H ), 2.30 ( s, 2 H ), 2.34 ( s, 2 H ), 4.80 ( s, 1 H), 4.95 ( s, 2 H ), 7.89 ( s, 1 H),  8.38 ( d, 1 H,  J = 8.2 Hz ),  8.96 ( d, 1 H, J = 8.2 Hz ),7.62 ( d, 2 H, J = 7.6 Hz ), 7.91 ( d,  2H,  J = 7.6 Hz ), 8.27 ( s, 1H )	25.4, 31.3, 38.6, 51.7, 57.5, 113.3, 117.0, 120.9, 122.7, 125.3, 127.0, 132.0, 134.1, 138.1, 151.6, 157.2, 159.1, 202.6.	3746.97, 3143.67, 2186.61, 1705.55, 1625.20, 1277.89, 1167.23, 1056.44, 930.13, 750.33, 690.28, 618.17, 545.16
4l	1.16 ( s, 3 H ), 1.28 ( s, 3 H), 2.36 ( s, 2 H), 2.39 ( s, 2 H), 3.78 ( s, 3 H), 4.86 ( s, 1 H ), 5.01 ( s, 2 H), 7.85 (s, 1 H ),  8.36 ( d, 1 H, J = 8.2 Hz ),  8.91 ( d, 1 H, J = 8.2 Hz ),7.68 ( d, 2 H, J = 7.6 Hz ), 7.94 ( d, 2 H, J = 7.6 Hz ), 8.28 ( s, 1 H )	25.1, 31.5, 38.1, 51.3, 55.1 57.8, 112.3, 116.8, 121.2, 122.2, 124.9, 126.8, 132.2, 134.5, 137.0, 152.5, 157.7, 160.1, 201.8	3742.32, 3140.57, 2183.21, 1702.91, 1401.42, 1285.69, 1150.02, 1056.47, 931.83, 756.66, 694.58, 617.37, 554.86

 

Conclusion

In summary, we have presented an unique, Catalyst-Free three component reaction which provides a simple methodology for synthesising chromene derivatives using pyrazole aldehydes, malononitrile and dimedone using various solvents. Regarding solvents, ethanol was found to be the most suitable solvent. The current method is advantageous for it’s milder cum quicker reaction procedure, high desired compounds yield, eco-friendly, simple experimental and purification procedures, making it an efficient synthetic scenario to the 4H-chromene-3-carbonitriles. Our future perspective is to carry out single-crystal XRD and evaluate various pharmaceutical activities for   4H-chromene-3-carbonitrile derivatives.

Acknowledgement

S. J. thanks the DST-FIST for FT-IR, A.Veeriya Vandayar Memorial Sri Pushpam College, Poondi, Thanjavur. Our thanks to Gandhigram Rural University, Dindugal.

Conflict of Interest

No conflict of interest

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