An Efficient Multicomponent Approach For Solvent Free Synthesis Biology Essay

The chromene mediety is an of import structural constituent in both biologically active and natural compounds. The basic structural model of chromenes is a common characteristic of many tannic acids and polyphenols [ 1 ] found in tea, fruits, veggies and ruddy vino. These compounds are of particular of import, due to their biological effects. Fused chromenes are biologically active compounds with assorted activities such as antimicrobic, [ 2 ] mutagenicitical, [ 3 ] antiviral, [ 4, 5 ] antiproliferative, [ 6 ] antitumoral, [ 7 ] and cardinal nervous system activities [ 8 ] . These medieties are besides present in natural alkaloids, flavonoids, vitamin Es, and anthocyanins. [ 9 ] Functionalized chromenes have late played an ever-increasing function in the man-made attacks to assuring compounds in the field of medicative chemical science. [ 10 ] Among the different types of chromene systems, 2-amino-4H-chromenes ( or 2-amino-4H-benzo [ B ] pyrans ) are of peculiar public-service corporation as they belong to favor medicative scaffolds functioning for the coevals of small-molecule ligands with extremely pronounced spasmolytic, diuretic, anticoagulant, and antianaphylactic activities. [ 11 ]

Multicomponent reactions ( MCRs ) , in which three or more reactants are combined together in a individual reaction flask to bring forth a merchandise integrating most of the atoms contained in the starting stuffs [ 12 ] is a promising attack for the readying of compound libraries in the field of modern medicative and combinative chemical science. [ 13 ] The rapid assembly of molecular diverseness using MCRs has received a great trade of attending. For illustration, the Hantzsch, [ 14a ] Ugi, [ 14b, degree Celsius ] and Biginelli [ 14d ] multicomponent reactions are the methods of pick to fix functionalized 1,4-dihydropyridine, benzodiazepinedione, and dihydropyrimidine privileged scaffolds, severally. Combinations of solvent-free and MCR one-pot multicomponent condensations represent really powerful green chemical engineering processs from both the economical and man-made point of position and stand for a possible instrument to execute a close ideal synthesis because they enhance the rate of many organic reactions and afford quantitative outputs.

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2-Amino-4H-chromenes are by and large prepared by refluxing active methylene compounds ( largely malononitrile ) , with an aldehyde and an activated phenol in the presence of risky organic bases like piperidine in organic dissolvers such as ethyl alcohol and acetonitrile for several hours [ 15 ] . Recently, comparatively benign accelerators such as cetyltrimethylammonium chloride ( CTACl ) , [ 16 ] cetyltrimethylammonium bromide, [ 17 ] KSF clay, [ 18 ] KF/Al2O3, [ 19 ] TiCl4, [ 20 ] triethylamine, [ 21 ] basic aluminum oxide, [ 22 ] MgO, [ 23 ] heteropolyacids, [ 24 ] basic ionic liquids, [ 25 ] iodine/K2CO3, [ 26 ] and DABCO [ 27 ] have been used in this reaction. However, some of these accelerators such as MgO and basic aluminum oxide can merely catalyse the condensation reaction of aromatic aldehydes and malononitrile with active ?-naphthol, and are non suited for less active ?-naphthols, whereas other accelerators require longer reaction times, arduous workup processs and afford merely moderate outputs. For these grounds the development of an environmentally benign and simple process for synthesis of 2-amino-4H-chromenes has therefore become peculiarly absorbing and remains a great challenge.

In continuance of our involvements on developing environmentally benign protocols for solvent-free multi-component reactions [ 28 ] , we report herein our consequences for synthesis of 2-amino-4H-chromenes with Na carbonate that expeditiously catalyzed three-component condensation of an aldehyde, malononitrile and an activated phenol with first-class outputs under solvent-free status. This method has many advantages, such as no demand to toxic organic dissolvers and toxic accelerators, its lower cost, high outputs, and simpleness in processing which are good to the industry and to the environment. Other benefits are no demand for isolation of any intermediate, therefore cut downing overall reaction clip, salvaging money, energy and natural stuffs.

Consequences and Discussion

The theoretical account reaction was carried out merely by blending of p-chlorobenzaldehyde ( 1 ) , malononitrile ( 2 ) and ?-naphthol ( 3b ) ( 1.0 mmol each ) and assorted basic or acidic accelerators ( 0.1 mmol ) in a howitzer and stamp ( Scheme 1 ) . The resulting mixture was heated in a drying oven at the temperature and for the given clip in Table 1.

Scheme 1.

In the absence of any accelerator no reaction was observed at room temperature and all starting stuffs remained unchanged, whereas after raising the temperature to 125 & A ; deg ; C aldehyde and malononitrile were disappeared. Below this temperature the output of 4 ( Ar=p-ClC6H4 ) is negligible and hence there is no singular output of 6, even in the presence of Na2CO3 accelerator.

The procedure represents a typical condensation in which the benzylidenemalononitrile 4 ( Scheme 2 ) , incorporating the electron-poor C-C dual bond is fast and quantitatively produced by Knoevenagel condensation of malononitrile and the aromatic aldehyde and subsequent H2O riddance. As we have antecedently reported [ 28b ] , this measure of the reaction easy occurs under solvent-free status and without adding any accelerator, but is uncomplete at lower temperatures. The formation of this intermediate was secured by military policeman and NMR of the merchandise 4 after 4 hours. By increasing the temperature to 150 & A ; deg ; C the merchandise 6b was formed with sensible output. As it is shown in Table 1, among the assorted basic or acidic accelerators, Na carbonate was found to be the best 1 for this synthesis affording quantitative outputs of 6b under solvent-free status in one hr. This is of particular involvement, because Na2CO3 is a really inexpensive, environmentally friendly and available accelerator.

The 2nd measure represents a typical cascade reaction [ 29 ] and presumptively involves ortho C-alkylation of ?- or ?-naphthol giving the intermediate 5. Nucleophilic add-on of the phenolic OH group to the CN mediety bring forthing the concluding 2-amino-4H-chromenes 6 requires the intercession of the accelerator, as the uncatalyzed reaction afforded no singular merchandise at 125 & A ; deg ; C.

Scheme 2.

Table 1. Consequence of assorted accelerators on readying of 6b

Catalysta

Time ( H )

Temperature ( & A ; deg ; C )

Output ( % ) of 6

4

rt

4

125

4

150

78

Na2CO3

1

rt

Na2CO3

1

125

100

NaHCO3

1

125

89

SiO2

4

125

60

Al2O3

3.5

125

55

Na2SO4

3.5

125

67

a 0.1 mmol each for 1.0 mmol of 1.

The range and the generalization of the present method were so farther demonstrated by the reaction of assorted aromatic aldehydes with malononitrile and ?- or ?-naphthol. In all instances up to quantitative outputs in sensible reaction times were obtained. Both a- and b-naphthol are plenty active to give the corresponding merchandises in high output. Contrary to that has been reported antecedently [ 27 ] , no singular lessening in the outputs was observed for the ortho-substituted benzaldehyde derived functions.

The reactions of p-hydroxybenzaldehyde with 2 and 4-chloro-1-naphthol, and 1 and 2 with 4-hydroxycumarine proceed besides swimmingly to give 6q and 6s severally, nevertheless with moderate outputs, perchance due to their lower activity against a- and b-naphthols.

The constructions of all merchandises were determined on the footing of their analytical and/or spectral informations. The 1H NMR spectra of the merchandises show a characteristic individual extremum at 4.90-5.90 ppm for H-4 and the 13C NMR spectra exhibit a specific extremum in the part of 54-60 ppm that is related to C-4.

Table 2. Synthesis of 2-amino-4H-chromenes under solvent-free status catalyzed by Na carbonate a

Entry

Argon

Naphthol

Merchandise

Time

( min )

Output

( % )

M P ( & A ; deg ; C )

1

p-ClC6H4

a-naphthol

6a

30

99

232 ( 231-232 ) 25

2

p-ClC6H4

b-naphthol

6b

60

100

203-205 ( 206-208 ) 25

3

p-NO2C6H4

a-naphthol

6c

60

91

210-212 ( 188-189 ) 23

4

p-NO2C6H4

b-naphthol

6d

120

90

185-186 ( 188 ) 25

5

p-OMeC6H4

a-naphthol

6e

40

91

179-181 ( 176-179 ) 24

6

p-OMeC6H4

b-naphthol

6f

120

88

188-189 ( 182-183 ) 25

7

o-ClC6H4

a-naphthol

6g

30

96

235-237 ( 236-237 ) 16

8

o-ClC6H4

b-naphthol

6h

40

94

259-261 ( 259-261 ) 16

10

m-NO2C6H4

a-naphthol

6i

15

98

210-213 ( 208-211 ) 24

11

m-NO2C6H4

b-naphthol

6j

30

92

232-235 ( 239-241 ) 22

12

p-OHC6H4

a-naphthol

6k

45

100

227-228 ( 187-188 ) 16

13

p-CNC6H4

a-naphthol

6l

30

98

258-261 ( 258-260 ) 22

14

p-CNC6H4

b-naphthol

6m

50

95

275-277 ( 285-287 ) 22

15

p-BrC6H4

a-naphthol

6n

30

99

241-243 ( 241-243 ) 22

16

o-NO2C6H4

a-naphthol

6o

15

100

237-239 ( 241-242 ) 22

17

C6H5

b-naphthol

6p

40

100

273-275 ( 280 ) 25

18

p-OHC6H4

60

76

242-243 ( 241-242 ) 30

19

p-ClC6H4

150

67

263-266 ( 263-265 ) 31

a mmol ratio of aldehyde/malononitrile/naphthol/Na2CO3 is 1.0/1.0/1.0/0.1.

In drumhead, we have reported a new and effectual methodological analysis for the eco-compatible readying of 2-amino-4H-chromenes via one-pot three component reaction of aromatic aldehydes, malononitrile and active naphthols utilizing a catalytic sum of Na2CO3 under solvent-free conditions. The usage of commercially available and cheap accelerator, avoiding usage of risky organic bases and organic dissolvers, easy workup, short reaction times, and mild reaction conditions make this method really attractive and practical.

Material and methods

All of the chemical stuffs used in this work were purchased from Merck or Fluka and used without farther purification. Melting points were determined with an Electrothermal thaw point setup and are uncorrected. Infrared ( IR ) spectra were recorded with a Shimadzu 8400s FT-IR spectrometer utilizing potassium bromide pellets. 500MHz 1HNMR spectra were recorded on a DRX-500 Advance Bruker spectrometer. The chemical displacements are reported in ppm ( ?-scale ) relative to internal TMS and matching invariables are reported in DMSO-d6. Merchandises are all known compounds and were identified by comparing of their physical and spectra informations with those reported in the literature.

General process for readying of 2-Amino-4H-Chromenes

In a typical experiment, a stoichiometric mixture of an aldehyde ( 1 ) , malononitrile ( 2 ) , naphthol ( 1.0 mmol each ) and sodium carbonate ( 0.1 mmol ) mixed together utilizing a howitzer and stamp. The consequence mixture was heated in a drying oven at 125 & A ; deg ; C. After chilling, the mixture was washed with hot H2O and purified by recrystallization from hot ethyl alcohol, if necessary. The consequences are summarized in Table 2.

Selected word picture informations:

Compound 6a: 4H-Naphtho [ 1,2-b ] pyran-3-carbonitrile,2-amino-4- ( 4-chlorophenyl )

IR ( KBr ) , ? ( cm-1 ) : 3408, 3326, 2190, 1649, 1590 ; 1H NMR ( DMSO-d6, 500 MHz ) , ? ( ppm ) : 5.36 ( s, 1H, CH ) , 7.0 ( s, 2H, NH2 ) , 7.20 ( vitamin D, 2H, J=8.2 Hz, ArH ) , 7.33-7.38 ( m, 3H, ArH ) , 7.41-7. 47 ( m, 2H, ArH ) , 7.81 ( vitamin D, 1H, J=8.02 Hz, ArH ) , 7.91-7.96 ( m, 2H, ArH ) .

Compound 6b: 1H-Naphtho [ 2,1-b ] pyran-2-carbonitrile,3-amino-1- ( 4-chlorophenyl )

IR ( KBr ) , ? ( cm-1 ) : 3452, 3334, 2190, 1666, 1590, 1409 ; 1H NMR ( DMSO-d6, 500 MHz ) , ? ( ppm ) : 4.95 ( s, 1H, CH ) , 7.09 ( vitamin D, 1H, J=8.53 Hz ArH ) , 7.19 ( s, 2H, NH2 ) , 7.27 ( vitamin D, 2H, J=8.37 Hz, ArH ) , 7.36 ( vitamin D, 2H, J=8.35 Hz, ArH ) , 7.57-7.66 ( m, 3H, ArH ) , 7.89 ( vitamin D, 1H, J=8.02 Hz, ArH ) , 8.24 ( vitamin D, 1H, J=8.31 Hz, ArH ) .

Compound 6j: 1H-Naphtho [ 2,1-b ] pyran-2-carbonitrile,3-amino-1- ( 3-nitrophenyl )

IR ( KBr ) , ? ( cm-1 ) : 3462, 3356, 2190, 1654, 1589 ; 1H NMR ( DMSO-d6, 500 MHz ) , ? ( ppm ) : 5.63 ( s, 1H, CH ) , 7.17 ( s, 2H, NH2 ) , 7.38 ( vitamin D, 1H, J=8.9 Hz, ArH ) , 7.42-7.48 ( m, 2H, ArH ) , 7. 57 ( T, 1H, J=7.8 Hz, ArH ) , 7.67 ( vitamin D, 1H, J=7.7 Hz, ArH ) , 7.86 ( vitamin D, 1H, J=8. 2 Hz, ArH ) , 7.93 ( vitamin D, 1H, J=7.6 Hz, ArH ) , 7.98 ( vitamin D, 1H, J=8.9 Hz, ArH ) , 8.03 ( vitamin D, 1H, J=8.07 Hz, ArH ) , 8.08 ( s, 1H, ArH ) , 13C NMR ( DMSO-d6, 125 MHz ) , 57.82, 115.47, 117.74, 121.04, 122.18,122.72, 124.36, 126.03, 128.28, 129.48, 130.78, 130.95, 131.33, 131.73, 134.59, 147.84, 148.75, 148.86, 160.84.

Compound 6o: 4H-Naphtho [ 1,2-b ] pyran-3-carbonitrile,2-amino-4- ( 2-nitrophenyl )

IR ( KBr ) , ? ( cm-1 ) : 3419, 3326, 2192, 1651, 1590 ; 1H NMR ( DMSO-d6, 500 MHz ) , ? ( ppm ) : 4.94 ( s, 1H, CH ) , 7.09 ( vitamin D, 1H, J=7.9 Hz, ArH ) , 7.19 ( s, 2H, NH2 ) , 7.21-7.23 ( vitamin D, 2H, J=7.6 Hz, ArH ) , 7.51 ( vitamin D, 2H, J=7.33 Hz, ArH ) , 7.59-7.65 ( m, 3H, ArH ) , 7.89 ( vitamin D, 1H, J=7.7 Hz, ArH ) , 8.23 ( vitamin D, 1H, J=7.9 Hz, ArH ) . 13C NMR ( DMSO-d6, 125 MHz ) , 56.62, 118.19, 120.95, 121.24, 121.58, 123.59, 124.89, 126.94, 127.62,1 27.75, 128.57, 130.82, 132.48, 133.62, 143.61, 145.95, 161.02.

Recognition

We acknowledge Iran University of Science and Technology ( IUST ) for partial fiscal support of this work.