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Vitamin B12, A Natural and Green Catalyst for the One-pot Three-Component Synthesis of 4H-Pyran Annulated Systems

Mohammad Dodangeh, Malek-Taher Maghsoodlou*, Mehrnoosh Kangani, Farideh Paymozd and Nourallah Hazeri

Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran

*Corresponding Author:
Malek-Taher Maghsoodlou
Department of Chemistry
Faculty of Science
University of Sistan and Baluchestan
P. O. Box: 98135-674, Zahedan
Iran
Tel: +985412416586
Fax: +985412416586
E-mail: [email protected]

Received date: April 25, 2016; Accepted date: July 27, 2016; Published date: July 29, 2016

Citation: Dodangeh M, Maghsoodlou MT, Kangani M et al. Vitamin B12, A Natural and Green Catalyst for the One-pot Three-Component Synthesis of 4H-Pyran Annulated Systems. Curr Trends Nutraceuticals. 2016, 1:2.

 

 
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Abstract

Vitamin B12 was found as a natural and efficient catalyst for the one-pot three-component synthesis of 4H-pyran annulated systems from the condensation between aryl aldehydes, malononitril and 1,3 dicarbonil compounds in aqueous media at ambient and thermal condition. Vitamin B12 is an organometallic compound that can play the catalytic role in the organic reactions. It has many active sites that make this catalyst affect significantly in spite of its very low amount (0.00017 g). This methodology has number of advantages such as: use of very small amount of catalyst, easy access, short reaction times, high yields, easy work up and use of non-toxic and hazardous catalyst and solvents. Although, all products were obtained just with a simple filtration and no need to column chromatography.

Keywords

Vitamin B12; 4H-pyrane annulated systems; High yields; Non-toxic; Hazardous catalyst; Solvents

Introduction

The word “Vitamin B12” is generally used for cyanocobalamin that is a water-soluble substance. Vitamin B12 is the first organometallic compound that naturally occurs. In addition, it is a crucial nutrient for human growth and cell development [1]. Vitamin B12 (molecular weight 1355.4) is stable in aqueous solution between pH 4 and 7 can be heated at 120˚C without significant loss [2]. The B12 not only has biological function in nervous system, but also diminishes the risk of heart diseases. This vitamin plays an essential role in human biological system, include DNA synthesis and regulation, enzymatic reaction, red blood cell formation and etc. [3]. Moreover, It has a complex organometallic cofactor with a central cobalt (III) atom to coordinate with coring ring consisting of six donor ligands [3,4] (Figure 1). The performed studies about the vitamin B12’s structure and biochemistry in the areas of chemistry, psychology and medicine have awarded four Noble [4]. Vitamin B12 has been already used for many organic reactions such as: methyltransferases [5], the asymmetric catalyst for the enantioselective cyclopropanation of alkenes [6], catalyzed carbon-carbon bond forming reaction [7] and catalyzed dehydrogenation reaction [8].

nutraceuticals-Vitamin-B12;

Figure 1: The structure of Vitamin B12.

Tetrahydrobenzopyran, and their derivatives are of considerable interest as they includes a wide range of biological properties [9], such as spasmolytic, diuretic, anticoagulant, anticancer, and anti-anaphylactic activity [10]. In addition, they can be used as cognitive enhancers for the treatment of neurodegenerative diseases, containing amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, AIDS-associated dementia, Alzheimer’s disease, and Down’s syndrome, as well as for the treatment of schizophrenia and myoclonus [11]. In addition, a number of 2- amino-4H-pyrans are useful as photoactive materials [12]. These molecules are biologically active and find application in pharmacological properties such as anticoagulant, spasmolytic, diuretic, anti-anaphylactic, and anticancer agents [10]. Some of the 2-aminobenzochromene derivatives are useful cosmetics and pigments [13] and are utilized as potential biodegradable agrochemicals [14]. Some methods have been reported for the preparing of tetrahydrobenzopyran, and pyrano [2,3-d] pyrimidine derivatives [15-29]. However, some of these methods have drawbacks, such as long reaction times, use of expensive reagents, low yields, harsh reaction conditions, effluent pollution, and tedious work-up procedures. In continue of our research on multi-component reactions [30-37], herein we report easy and green synthesis of 4H-pyran annulated systems from the reaction between aromatic aldehydes, malononitrile and dimedone/barbituric acid and thiobarbituric acid in the presence of vitamin B12 as catalyst in aqueous media at ambient and thermal conditions (Scheme 1).

nutraceuticals-catalyst-aqueous

Scheme 1: The structure of Vitamin B12.

Methodology

Melting points and IR spectra were measured with an Electro-thermal 9100 apparatus and a JASCO FT-IR-460 plus spectrometer, respectively. The 1H NMR spectra were obtained on Bruker DRX-400 & 300 Advance instruments with DMSO as a solvent. All reagents and solvents are obtained from Fluka and Merck and used without further purification. The Vitamin B12 was purchased from the Sigma-Aldrich company. TLC was performed on Silica–gel Polygram SILG/UV 254 plates.

General procedure for the synthesis of 2- amino-7,7-dimethyl-5-oxo-5,6,7,8- tetrahydro-4H-chromenes

Vitamin B12 (0.00017 g) dissolved in H2O: Et-OH (3:1 mL), then a mixture of aromatic aldehyde (1 mmol), malononitrile (1 mmol), and 1,3-dicarbonyl compounds (1 mmol) was added to above solution and stirred at 60°C for products (4a-4h) and ambient temperature for other products (5a-5g, 6a-6d). After completion of the reaction, as indicated by thin-layer chromatography (TLC), the reaction mixture was filtered and residue was washed with ethanol (3 × 5 mL) to separate catalyst. The crude product was recrystallized from ethanol to afford the pure product. The desired pure products were characterized by comparison of their physical data (melting points, IR and 1H NMR) with those of known compounds in the literature.

Spectral data for selected products

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro- 4H-chromene-3-carbonitrile (4b).

IR (KBr, cm-): 3329, 3394,3215, 2204, 1681; 1H NMR (400 MHz, DMSO-d6): δ (ppm): 1.02 (s, 3H),1.14 (s,3H), 2.13 (d, J = 16.1 Hz, 1H), 2.28 (d, J = 16.2 Hz, 1H),2.56 (s, 2H),4.30 (s, 1H), 6.25 (s, 2H, br), 7.17–7.32 (5H, Ar).

2-Amino-5,6,7,8-tetrahydro-4-(4-methyl)-7,7-dimethyl-5- oxo-4H-chromene-3- carbonitrile (4f)

IR (KBr, cm-): 3466, 3322, 2954, 2191, 1675, 1248; 1H NMR (400 MHz, DMSO-d6): δ (ppm): 1.09 (s, 3H), 1.12 (s, 3H), 2.22 (dd, J = 16.4 Hz, 2H), 2.31 (s, 3H), 2.46 (dd, J = 17.6, 2H), 4.53(s, 2H), 4.71(s, 1H), 6.713–6.808 (m, 2H), 6.971 (t, 1H).

2-Amino-5,6,7,8-tetrahydro-4-(4-hydroxyphenyl)-7,7- dimethyl-5-oxo-4Hchromene-3-carbonitrile (4h)

IR (KBr, cm-): 3,287, 3,165, 2,962, 2,184, 1,672, 1,208; 1H NMR (400 MHz, DMSO-d6): δ (ppm): 1.051(s, 3H), 1.11 (s, 3H), 2.26 (dd, J = 16.4 Hz, 2H), 2.465 (s, 2H), 4.34 (s, 1H), 4.51(s, 2H), 5.24 (s, 1H), 6.725–7.104 (dd, J = 8.4, 4H).

IR (KBr, cm-): 3,287, 3,165, 2,962, 2,184, 1,672, 1,208; 1H NMR (400 MHz, DMSO-d6): δ (ppm): 1.051(s, 3H), 1.11 (s, 3H), 2.26 (dd, J = 16.4 Hz, 2H), 2.465 (s, 2H), 4.34 (s, 1H), 4.51(s, 2H), 5.24 (s, 1H), 6.725–7.104 (dd, J = 8.4, 4H).

3-carbonitrile (4j)

IR (KBr, cm-1): 3,304, 3,205, 2,947, 2,172, 1,674, 1,213; 1H NMR (400 MHz, DMSO-d6): δ (ppm): 1.07 (s, 3H), 1.13 (s, 3H), 2.24 (dd, J = 16 Hz, 2H), 2.44 (dd, J = 17.6, 2H), 3.83 (s, 3H), 3.94 (s, 3H), 4.52(s, 2H), 4.77(s, 1H), 6.712–6.807 (dd, J = 8, 2H), 6.973 (t, J = 8, 1H).

7-amino-5-(4-nitrophenyl)-2,3,4,5-tetrahydro-2,4-dioxo-1Hpyrano[ 2,3-d]pyrimidine-6-carbonitrile (5a)

1H NMR (300 MHz, DMSO-d6): δ (ppm): 4.43 (s, 1H, CH), 7.30-8.45 (m, 6H, Ar & NH2), 11.15 (s, 1H, NH), 12.20 (s, 1H, NH).

7-amino-5-(4-bromophenyl)-2,3,4,5-tetrahydro-2,4- dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (5b)

1H NMR (300 MHz, DMSO-d6): δ (ppm): 4.24 (s, 1H, CH), 7.18-7.85 (m, 6H, Ar & NH2), 11.14 (s, 1H, NH), 12.12 (s, 1H, NH).

7-amino-5-(4-chlorophenyl)-2,3,4,5-tetrahydro-2,4- dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (5d)

1H NMR (300 MHz, DMSO-d6): δ (ppm): 4.25 (s, 1H, CH), 7.18 (s, 2H, NH2), 7.24-7.34 (m, 4H, Ar), 11.11 (s, 1H, NH), 12.11 (s, 1H, NH).

7-amino-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-2,4- dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (5e)

1H NMR (300 MHz, DMSO-d6): δ (ppm): 4.25 (s, 1H, CH), 7.08-7.16 (m, 6H, Ar & NH2), 11.01 (s, 1H, NH), 12.10 (s, 1H, NH).

7-amino-5-(3-chlorophenyl)-2,3,4,5-tetrahydro-2,4-dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (5g)

1H NMR (300 MHz, DMSO-d6): δ (ppm): 4.27 (s, 1H, CH), 7.18-7.34 (m, 6H, Ar & NH2), 11.10 (s, 1H, NH), 12.30 (s, 1H, NH).

7-amino-5-(4-bromophenyl)-2,3,4,5-tetrahydro-4-oxo-2- thioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (6b)

1H NMR (300 MHz, DMSO-d6): δ(ppm): 4.93 (s, 1H, CH), 5.91 (s, 2H, NH2), 6.94-7.37 (m, 4H, Ar), 11.66 (s, 1H, NH), 12.26 (s, 1H, NH).

Results and Discussions

In order to be able to synthesis of 2-amino-4H-pyran derivatives in a more efficient way, minimizing the time and amount of catalyst, the reaction of 4-nitrobenzaldehyde, malononitrile and dimedone/barbituric acid/thiobarbituric acid was selected as a model system. The reaction was carried out in different solvents, and temperatures. The best results were obtain in H2O: Et-OH (3:1 mL) at ambient temperature for the 5a and 6a and 60°C for the 4a (Table 1). As can be seen in Table 2, 12.54 μmol %) of vitamin B12 (0.00017 g) was the most effective amount to catalyze the reactions.

Entry product Solvent Catalyst Temperature Isolated yield %
1 4a H2O Vitamin B12 60 70
2 4a H2O:EtOH (2:1) Vitamin B12 60 71
3 4a H2O:EtOH (3:1) Vitamin B12 60 86
4 4a H2O:EtOH (4:1) Vitamin B12 60 65
5 4a H2O:EtOH (3:1) Vitamin B12 r.t -
6 4a H2O:EtOH (3:1) Vitamin B12 40 45
7 4a H2O:EtOH (3:1) Vitamin B12 50 70
8 5a H2O:EtOH (3:1) Vitamin B12 r.t 94
9 5a H2O:EtOH (3:1) Vitamin B12 50 60
10 5a H2O:EtOH (1:1) Vitamin B12 r.t 65
11 6a H2O:EtOH (3:1) Vitamin B12 r.t 80
12 6a H2O:EtOH (3:1) Vitamin B12 50 66
13 6a H2O:EtOH (1:1) Vitamin B12 r.t 70

Table 1: Optimization of solvent and temperature in synthesis of compound 4a, 5a and 6a.

Entry product Catalyst µ (mol %) Time (min) Yield(%)
1 4a 2.21 80 60
2 4a 3.7 35 71
3 4a 8.12 29 82
4 4a 12.54 15 86
5 4a 15.5 20 86
6 4a 70.38 20 86
7 5a 2.21 15 70
8 5a 3.7 13 76
9 5a 8.12 10 80
10 5a 12.54 4 94
11 5a 15.5 5 94
12 5a 70.38 5 94
13 6a 2.21 15 68
14 6a 3.7 10 70
15 6a 8.12 8 75
16 6a 12.54 5 80
17 6a 15.5 5 80
18 6a 70.38 5 80

Table 2: Optimization catalyst in synthesis of compound 4a, 5a and 6a.

Using these optimized reaction, the scope and efficiency of the reaction were explored for the synthesis of a wide variety of 4H-pyrans annulated systems using aromatic aldehydes, malononitriles and 1,3-dicarbonyl compounds. The results are summarized in Table 3 [38-50].

Entry Ar 1,3-dicarbonil compounds Product Time (min) Yeild% MP(Obs) (°C) MP(Lit) (°C) [ref]
1 4-NO2 C6H4 3a 4a 15 86 180-181 183-185 [38]
2 C6H5 3a 4b 20 85 229-230 233-235 [38]
3 4-Cl C6H4 3a 4c 26 79 219-220 218 [38]
4 4-F C6H4 3a 4d 39 80 205-206 208-210 [39]
5 4-Br C6H4 3a 4e 18 75 207-208 207-209 [40]
6 4-Me C6H4 3a 4f 20 85 214-215 215-218 [41]
7 2-NO2 C6H4 3a 4g 19 85 221-222 223-225 [42]
8 4-OH C6H4 3a 4h 30 85 212-213 214-215 [43]
9 3-NO2 C6H4 3a 4i 120 88 208-209 208-211 [44]
10 2,3-(OMe)2 C6H4 3a 4j 42 88 217-218 214-216 [45]
11 3-Cl C6H4 3a 4k 53 82 221-222 226-227 [36]
12 4-NO2 C6H4 3b 5a 4 94 245-246 245 [46]
13 4-Br C6H4 3b 5b 3 91 240-241 235–236 [47]
14 C6H5 3b 5c 5 89 220-222 223 [48]
15 4-Cl C6H4 3b 5d 3 89 244-245 242-244 [46]
16 4-F C6H4 3b 5e 3 96 232-233 225-226 [46]
17 4-Me C6H4 3b 5f 2 90 226-227 225 [48]
18 3-Cl C6H4 3b 5g 3 85 237-238 240-241 [47]
19 4-NO2 C6H4 3c 6a 5 80 232-233 233–235 [49]
20 4-Br C6H4 3c 6b 5 90 236-237 236 [49]
21 3-Cl C6H4 3c 6d 22 85 237-238 237-238 [49]
22 3-NO2 C6H4 3c 6e 20 93 238-239 235-236 [50]

Table 3: Preparation of 4H-pyran substitutes.

Interestingly, a variety of aryl aldehydes including electron withdrawing or releasing substituents (ortho-, meta-, and para-substituted) participated well in this reaction and gave the product in good to excellent yield.

A mechanism was proposed for this reaction. As can be seen in scheme 2, First, Knoevenagal condensation between 1 and 2 produced 2-benzylidenemalononitrile B, Michael addition of B with C (1,3-dicarbonyl compound), and followed cyclization and tautomerization afforded the corresponding product F. There are many reactive sites in the vitamin B12 molecule that can active carbonyl group (Figure 1).

nutraceuticals-one-pot-three-component

Scheme 2: The structure of Vitamin B12.

In order to assess the efficiency and generality of this methodology, the obtained result from the reaction of 4- nitrobenzaldehyde and malononitrile with substrate 3a, 3b and 3c by this method has been compared with those of the previously reported methods (Table 4). It was found that the present method is convincingly superior to the reported methods with respect to reaction time, yield of the product and amount of the catalyst.

Entry product Catalyst/Condition Time Yield (%) Reference
1 4a Melt/130°C 1 h 100 [38]
2 4a Urea (10 mol%)/ EtOH:H2O/ r.t 5 h 92 [39]
3 4a (NH4)2.HPO4/ H2O/r.t 2 h 78 [40]
4 4a Phenylboronic acid/ EtOH.H2O/reflux 30 min 88 [41]
5 4a Vitamin B12/ H20:EtOH, 60°C 15 min 86 Present work
6 5a Zn|(L) prline|2/ EtOH/reflux 30min 90 [48]
7 5a L-proline/EtOH/r.t 45 min 73 [49]
8 5a Triethanolamine/Choline chloride Zncl2/ 75°C/EtOH 92 sec 67 [50]
9 5a Vitamin B12/H2O:EtOH/r.t 4 min 94 Present work
10 6a L-proline/EtOH/r.t 90 min 76 [49]
11 6a Triethanolamine/Choline chloride Zncl2/ 75°C/EtOH 240 sec 42 [50]
12 6a Vitamin B12/H2O:EtOH/r.t 5 min 80 Present work

Table 4: Comparison of the efficiency of vitamin B12 with other reported catalysts in literature.

Conclusion

In conclusion, Vitamin B12 can be used as a promising ecofriendly catalyst for the synthesis of 4H-pyrans annulated system. Moreover, this method has several other advantages such as, high yields, operational simplicity, clean and neutral reaction conditions, which makes it a useful and attractive process for the synthesis of a wide variety of biologically active compounds.

Acknowledgment

We gratefully acknowledge financial support from the Research Council of the University of Sistan and Baluchestan.

References

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