SYNTHESIS OF CHROMENE DERIVATIVES USING MICROWAVE-ASSISTED METHOD Nguyen Thi Thanh Mai", Le Thi Hong Nhung

VIETNAM JOURNAL OF CHEMISTRY

DOI: IO15625/0866-7144.20I6-O0268 54(2) 233-237

AFRIL2016

SYNTHESIS OF CHROMENE DERIVATIVES USING MICROWAVE-ASSISTED METHOD

Nguyen Thi Thanh Mai", Le Thi Hong Nhung Faculty of Chemistry, Hanoi University of Industry Received 7 March 2016; Accepted for publication 26 April 2016 Abstract

affem several advanag'ls: ^ . r^tt^Z^fS^i^ZT^:^:^:^^"-"'' '^f''"™- ^"^ « "

stmcmres were confirmed by IR, 'H-and "C-NMR soeon^ 2 yields. The preducts were equally available and dieir h a v e b e e n t . . e d ™ e r e s u l , s s h o w e d d . t t o e y r s : = i r r S r ; t r i r a g l ; ^ r ^ S ^ ^ ^ ^ ^ ^

Keywords. Chromene; solvem-fiee; microwave-assisted mediod 1. INTRODUCTION

The microwave-assisted organic syndiesis method IS becomtog an increasingly popular method which replaces die classical ones because it proves to be a clean, cheap, and convenient mediod This mediod often affords higher yields to short reaction times and has been extended to almost all areas of chemistty [1]. Numerous organic reactions assisted by microwave have been performed and reviewed to die articles or books. These reactions involved different ones, such as die acylation and alkylation aromatic nucleophilic substittrtion, condensation' cycloaddittons, heterocyclization, reairangeraents' reactton of organometallic compounds, oxidation and reduction [2,4]. On die odier hand, chromene derivatives are nowadays an important group of organic compounds diat are used as additives to food and cosmetics, optical brightening agentsand uispersed fluorescent and laser dyes [3 4]

Cliromenes can be syndiesized by mediods such as Llaisen reanangement, Perkto and Pechmann reaction as well as Knoevenagel condensation. This paper describes die condensation reaction of some mmes widi 6-butoxy-2-oxo-2/f-chromene.4- carbaldehydc 4 or 3-acetyl-6-substittited-i//- chromene-2-one 7 under microwave irradiation Fudiermore, die syndiesized chromenes were screened for antimicrobial and antiftngal activities.

2. EXPERIMENTAL

Melting point was measured by ustog Thiele's

apparaftis to capillary and uncoirected. The FTIR- spectta were recorded on Magna 760 FT-IR Specttometer (NICOLET, USA) in fonn of mixing widl KBr and using reflex-measure medlod. ' H - NMR (500 MHz), "C-NMR (125 MHz) spectta were recorded on an AVANCE AMX 500 FT-NMR Specttometer (BRUKER, Gennan) at 500 13 MHz, usmg DMSO-* as solvem and TMS as an internal reference, 5 to ppm. Bioassays were cairied out to Hospital 19-8, Hanoi, Vietiiam.

Geneml procedure for the synthesis of nine chromenes [5-7]

Procedure A (under refluxing condilionf A mixtiire of 6-butoxy-2-oxo-2ff-chromene-4- carbaldehyde4 or 3-acetyl-6-substihited-27/- chromen-2-one 7 (2.5 mmol), amines (5 mmol) and five drops of acetic acid to 5 ml 96% edianol was retluxed for 20 mmutes to home MW oven at 750W concenttated and cooled. The separated product wai filtered and reciystiillized from an appropriate solvent to give chromenes 5a-e and 8a-f.

Procedure B (under microwave-assisted and solvent-ft-ee conditions) [1,7,8] A mixtiire of 6- butoxy-2-oxo-2/f-chromene-4-carbaldehyde 4 or 3- acetyl-«-substitiited-2ffchromene-2-one 7 (2.5mmol), and five drops of acetic acid, stirred for 30 mmutes at 60-70 "C and dien mixed carefiilly widl amines (5 mmol) to an MW mbe and irradiated

^ iMing die MW program as follows. Power: 120 w; hold time.-3-5 minutes; temperattire: 100 °C

VJC, 54(2) 2016

After completion of the reaction, the mixture was tteated with water (10 ml), and the precipitate was washed with water (50 ml) several times; washed and crystallized from ethanol (30 ml) and dried to give pure chromenes 5a-e and 8a-f Results of the above synthesis were represented in table 1.

2.1. Compound 5a

'HNMR (DMSO-*, 5, ppm): 8.65 (s, IH, H-a);

8.41-8.43 (d, \H,J= 8.4 Hz, H-7); 7.37 (s, IH, H- 5); 7.27 - 7.25 (d, l H , y - 7 . 2 Hz, H-8); 6.79(s, IH, H-3); 4.03-4.00 (t, 2H, H-l"); 3.37-3.48 (m, 2H, H- 2"); 1.71-1.65 (m, 5H, Hl'-HS'); 1.56 (m, 2H, H- 3"); 0.97-0.94 (t, 3H, H-4"). "C NMR (DMSO-*, 6, ppm): 160.3 (C=0); 164.1 (C-N); 161.5 (C-6);

110.1-143.2 (aromatic carbons); 19.3 - 68.2 (CHj);

14.8 (CHj).

2.2. Compound 5b

'HNMR (DMSO-*, 5, ppm): 8.96 (s, IH, H-a);

8.44-8.45 (d, J- 8.2 Hz, IH, H-8); 7.45 (m, 2H, H- 2'& H-4'); 7.50 (IH, H-7); 7.44 (IH, H3'), 7.39 (s, IH, H-5); 7.29 (2H, HI' & H5') 7.03 (s, IH, H-3);

4.07-4.05 (t, 2H, H-l»); 1.75-1.71 (m, 2H, H-2");

1.48-1.44 (ra, 2H, H-3"); 0.95-0.92 (t, 3H, H-4"). " c NMR (DMSO-*, 6, ppm): 159.5 (C=0); 164.7 (C=N); 162.0 (C-6); 110.5-154.0 (aromatic carbons);

67.5 (C-1"); 32.6 (C2»), 18.6 (C-3"); 14.7{CH,).

23. Compound 5c

'HNMR (DMSO-rf,, 8, ppm): 9.06 (s, IH, H-a);

8.67; (d, IH, d, y - 8.0 Hz, H-7'); 8.34 (IH, H-4')- 8.03 (IH, H-l'); 7.96 (IH, H-8); 7.65 (IH, H-3');

7.64 (IH, H-6'); 7.63 (2H, H2'& H5'); 7.48, (IH H- 7); 7.34 (IH, H-5); 7.17 (s, IH, H-3); 4.12 (2H, H- 1"); 1.77 ( 2 a H-2"); 1,47 (2H, H-3"); 0.93 (3H, H- 4"). "C NMR (DMSO-*, 5, ppm): 155.1 (CO)- 184.7 (C=N); 159.1 (C-6); 110.5 - 154.7 (aromatic carbons); 67-95 (CHj); 13,6 (CH3).

2.4. Compound Sd

'HNMR (DMSO-4, S, ppm): 8.44 (s, l a H-a)- 7,30 (d, y - 7.3 Hz, H-7); 8.64 (s, IH H-5'); 7.10 (s IH, H-5) 8.15-8.22 (d, 7 = 7.2 Hz, IH H-8); 6.99 (s, IH, H-3); 3.32-5.62 (t, 2H, H-l"); 2.49-2.51 (m, 2H, H-2"); 1.26 (2H, H-3"); 0.98 (3H, H^"); 7.98 (4H, H- 2'", H-6'"& H-2'"', H-6""); 7.56 (4H, H-3'", H-5"'&

H-3'"', H-5'"'); 7.29 ( 2 ^ H-4"'& H-4'"'). " c NMR (DMSO-*, 5, ppm): 159.7 (C-O); 163.5 (C=N)-

Synthesis of chromene derivtdives... i 162.5; (CS); 164.2 (C-4'& C6'); 110.1 - 153i ^ (aromaticcarbons); 19.3-68.4 (CHO; I't.l (CHj).

2.5. Compound 5e

'HNMR (DMSO-*, 6, ppm): 8.22 (s, IH, H-a);

7.21 (d, y = 7.2 Hz, IH, H-7); 8.55 (s, IH, H-5');

6.99 (s, IH, H-5) 8.15-8.22 (d,y= 7.2 Hz, 1H,H- 8); 6.33 (s, IH, H-3); 4.21,4.88 (t, 2H, H-l"); 1.49 - 2.17 (m, 4H, H-2", H-3"); 0.96 (m, 3H, H-4"); 3.38 (3H, OCH3); 7.95 (m, 2H, H-2"'& H-6"'); 7.55 (2H H-3"' & H-5"'); 7.49 (IH, H4"') 7.89 (2H, H-2»"& * H-6""); 7.12 (H-3"" & H-5'"'). "C NMR (DMSa

* , 6, ppm): 159.4 (C=0); 163.7 (C=N); 161.2 (C- 6); 165.2 (C-4'& C6'); 110.0-150.4 (aromatic carbons); 19.0-68.4 (CH;); 13.9 (CH,); 55.7 (OCHj).

2.6. Compound 8a

'HNMR (DMSO-* 8, ppm): 8.21 (s, IH, H-4)' 7.89 (d, J= 8.4 Hz, IH, H-7'); 7.72 (d, J - 7.5 Hz, IH, H-l'); 7.70 (IH, IH, H-4'); 7.67 (IH, H-3');

7.65 (m, IH, H-5), 7.50 (m, IH, H-6'); 7.49 (m, IH, H-7); 7.48 (m, IH, H-2'); 7.45 (d, y = 7.8 Hz, IH, H-8); 7.46 (m, IH, H-6); 2.54 (3H, H-b). "C NMR (DMSO-*, 8, ppm): 158.4 (C-O); 195.0 (C-N); I 154.5 (C-O); 146 (C-N); 116-134 (aromatic i

carbons); 29.9 (CHj). j I

2.7. Compound 8b

'HNMR (DMSO-*, 8, ppm): 8.15 (s, IH, H-4);

8.02 (d, J - 8.4 Hz, IH, H-5); 7.38 (m, H-6); 7.98 (m, H-7); 7.50 (d, y = 7.9 Hz, 1H, H-8); 6.98 (H-r& , H5'); 7.34 (H-2'& H4'); 7.02 (m, H-3'); 2.09 (3H, . H-b). "C NMR (DMSO-*, S, ppm): 159.1 (C=0); i 175.6 (C=N); 153.5 (C-O); 136.1 (C-N); 116.1- t, ni.l (aromatic carbons); 19.5 (CH3).

2.8. Compound 8c

'HNMR (DMSO-*, 8, ppm): 8.01 (s, IH, H-5);

7.69 (d, y - 7.7 Hz, l a H-7'); 7.72 (H-l'& H-5');

7.34 (m, H-2' & H-4'); 7.07 (m, 2.5, H-3'); 7,55 (d, f J - 7.9 Hz, H-4); 7.89 (m, IH, H-7); 7.45 (m, H-8); f 2.44 (m, 3H, H-b). "C NMR (DMSO-*, 5, ppm):

159.3 (C-O); 182.1 (C=N); 151.5 (C-O); 136.2 (C- N); 113.4-132.9 (aromatic carbons); 19.5 (CHj).

2.9. Compound 8d

'HNMR (DMSO-*, 6, ppm): 7.56 (s, IH, H4);

8.29 (d, y - 7.3 Hz, IH, H-7'); 8.06 (H-l'& H5);

VJC, 54(2)2016

^fmW^' " ' <*•'= 8-2 Hz, l a H-3'); 7.62 Vi-,^ ^ ^' '-^^ ( ' ^ ' " ' "-2"): " 5 ( l a H-8);

" r x S o ; , ' - ^ " ^ ' " ' "-'>: 2-<M K 3 a H-b).

r r - ^ . ' ° " ^ ° ^ " ^ ' PP"")^ '59.9 (C=0); 194.7 n l ? , ^ -^ (C-O); 147.7 (C-N); 132.3 (C-Cl);

110-1J4 (aromatic carbons); 19.3 (CHj).

2.10. Compoand 8e

•7 J ^ ! ^ (DMSO-rf., 8, ppm): 8.08 (s, l a H-5)-

•tilt^ iVv "^ ' " ' "'"'• '-'2 (H-l'& H-5' 7.34 (m, H-2' & H-4'); 7.07 (m, l a H-3'); 7 55 (d, /-7.44Hz, m , H-4); 7.89(d, J^l.2 ^ . H ^ . (DMSO-*, 6, ppm): 159.5 (C=0); 179 1 fO=Nl- ' " • ' (C-O);''*-" ' ^ ^ ' "^-^ - 134.3-(ar™2- carhons);19.7(CH3).

2.11. Compound 8f

RoiTf-!iTJ°-''"^- I""")^ '•« fe IH, H-4);

8.27 (d, y = 7.2 Hz, l a H7'); 8.02 (d, y - 7 53 Hz.

IH, H-l'); 8.15 ( l a M, H-4'); 779 (IH H - 3 ^ 7.63 (m, m, H-6'); 7.57 (m, IH, H-2')- 7 35 (d J=

12 Hz. l a H-8); 7.54(ia H-7); 7.55 (m 1H,H- 6); 2.04 {3aH-b)."CNMR (i>MSO-rf.

6, ppm): 159.6 (C-O); 189.5 (C=N)- 152 5 (C OV HW (C-N); 115.1-139.4 (aromatic'cartasf i S (LHiJ.

3. RESULTS AND DISCUSSION

The derivatives of chromenes could be easily synd,es,zed by nucleophilic addition of corresponding amine compounds to 6-butoxy-2-oxo- 2*chromene-4-carbaldehyde 4 or (3-acelyl-6- subsntt,ted-2/f-chromene-2-one7. The proposed

Nguyen Thi Thanh Mai, et al.

mechanism for die firmftion of products was shown mfigm-e 1. We perfonned diis reaction ustog two different microwave-assisted mediods- bv refluxmg m edianol and by executing under solvent- free condition to several mmutes. We have fomid diat die solvent-free conditions under microwave madiation offers several advantages because solvents are often expensive, toxic, difficult to remove in case of aprotic dipolar solvents widi high tolmg point, and are environmentally polluting agentti. Moreover, liquid-liquid extiaction is avoided m die isolation of reaction products, and die absence of solvem preventt, die risk of hazardous explosions when die reaction takes place to a microwave oven Hie reactions were usually completed widito 3-5 minutes and gave improved yield (55-84 %) over conventional mettiods to a shorter time. Moreover die work-up procedure is simply reduced to die"

reco^hzation of product ftom an appropriate solvem, wh,le die refluxing method of foZtion of these chromenes involves longer reaction times (20 minutes) and lower yield (63-70 %). The syndieUe processes could be represented ta figure 2.

The IR spectta of compounds (5a-e and 8a-f), contiitoed absoiption at 1697-1765 cm' fC-O pyione), 1523-1675 cm"' (C-N), and 1023-1275 cm"

(C-O-C, aiyl edier). The 'H-NMR spectta of compomids 8a-f showed singlet signals at S - 8 21- 8.65 ppm (H-4) and 8.10-8.96 ppm (HO to 5a-e, Signals of aromatic protons appeared at S = 7 44- 7.96 ppm, while mediyl signals at 8 - 2 40-2 40 ppm. The C-NMR spectta showed signals of the carbonyl C=0 shifted downfleld at 8 195.0 ppm to addition, diere were resonance peaks in upfield region at 6 - 29.92-39.99 ppm dial indicated die presence of mediyl groups and 8 = 146.93-158 34 ppra belonged to C=C.

Fig I: The proposed mechanism for die fonnation of compound 5

VJC, 54(2) 2016 Synthesis cf chromene tierivatives...

R': Cl, Br, H.

5a: R' - CdH„, Sb: R' - CsHj, Sc: R'- C,rfl,, 5d: R' - C„H„Na, 5e: R' - C„HuN;0 8a: R' - Ciifl,, R'- a 8b: R'- C^,, R^- H, Sc: R' - CjHj, R ' - 6-CI, Sd: R' - C„H,, R' - 6-CI, Se: R' - CsHj, R' - 6-Br, Sf: R' - C,i,H,, R» - 5-Br

Fig. 2: Synthesis of chromene derivatives

Compounds Sa Sb 5c Sd 8a 8b 8c 8d 8e Sf

Ta bie 1: Physical parameters of compounds Sa-e Melting point (°C)

A 80-82 71-72 92-93 130-132 230-232 218-219 220-221 225-226 224-225 233-234

B 80-82 71-72 92-93 130-132 231-232 218-219 220-221 225-226 224-225 233-234

Yield (%) A 76 72 75 69 66 68 70 65 66 63

U 80 80 84 84 58 55 70 55 56 67

IR and 8a-l spectrum (cm"') A

Vc<

1720 1707 1724 1697 1751 1740 1742 1742 1751 1734

Vc-N

1556 1523 1561 1533 1656 1596 1675 1645 1663 1674

1121 1023 1205 1256 1203 1103 1201 1169 1159 1159

B 1720 1707 1724 1697 1750 1740 1741 1743 1752 1734

1556 1523 1561 1533 1656 1596 1675 1645 1663 1675

vcoc 1121 1022 1203 1256 1275 1203 1103 1201 1169 1159 1158 A: under solvent-free microwave method by microwave refluxing method; B: under solvent-free microwave method.

Table 2: Response of various micro-organisms to substituted chromenes 5a-e and 8a-e

Compounds 5a Sb Sc Sd Se 8a 8b 8c 8d 8e

Diameter of zone inhibition

£. coli 100 pg/ml

(-)

₁₈

(-) (-)

13

(-) (-) (-) (-) (-)

150 pg/ml

(-) (-) (-) (-)

₁₅

17 15 16 16 16

(mm) 5. aureus 100 pg/ml

(-) (-) (-) (-)

22 15 17 13

(-) (-)

150 pg/ml

(-) (-) (-) (-)

26 18 19 15

(-)

₁₄

100 pg/ml 25 25 30 30 22 35 23 27 22 22

C. albicans 150 pg/ml

28 30 30 30 32 40 32 32 27 30

V-IC, 54(2) 2016

Compounds 5a-e and 8«-e were screened for meir antibacterial and antifimgal activities agamst Escherichia coli. Staphylococcus aureus and i!^"^-. '^'''"°" ^^ * ° ""'^ diffusion mediod (table 2). All tested compounds have antifimgal activities, among diem compound 8 todicated a remarkable biological activity to concenttation of 150 pg/ml. Compound 8a showed highest antibacterial and antifimgal activity.

Chromenes 8 a - c h a v e had significant biological activities agamst S.aureus to concentiation 100 pg/ml. Compound 8d exhibited no antifimgal activity agatost Staphylococcus aureus All chromenes Sa-e had no biological activities against Escherichia coli Staphvl ococcus aureus, Candida albicans to 100 ua/ml concenttation. Compounds Sa-e were less antibacterial active.

4. CONCLUSION

Eleven new compounds of chromene derivatives Sa-e and 8a-f have been syndiesized ftom coirespondmg 6-butoxy-2-oxo-M-chromene^- orbaldehyde 4 or 3-acetyl-6-substittited-2//- chromene-2-one 7 and amines using microwave- Bsisted mediods. Their stiuctiires were identified by die combination of IR, 'H- and "C-NMR specttal data. Tins mediod afl-ords die chromene derivatives m moderate to good yields. The tested results showed diat diey possess remarkable antimicrobial activities agamst Caiulida albicans.

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Corresponding aulhor: Nguyen Thi Thanh Mai Faculty of Chemical Technology Hanoi Universily of todusOy, HaUI Tu Liem, Hanoi Vietiiam

E-mail: mainguyen65hb@gmail.com; Telephone: 0948839469.