Epoxidation of 2-Styrylchromone derivatives

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XXI. EUROPEAN COLLOQUIUM

ON

HETEROCYCLIC CHEMISTRY

OOKOF

BSTRACTS

)(.

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'J.

.

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Soprol1

HUNC~l\RY 2004 Stpl 12. -I)th

SEPTEMBER

12-15™, 2004

LISZT

FERENC CONGRESS AND CULTURE CENTER

SOPRON,HUNGARY

;

•

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TP-41

EPOXIDATION OF 2-STYRYLCHROMONE DERIVATIVES

Clementina M. M. Santos,a

,

b

Artur M. S. Silva

,

b

Jose A. S. Cavaleiro,b Tamas Patonay,

c

and Albert Levai,c

a

Department of Agro-lndustries, Escola Superior Agraria de Bragan9a,

5301-855 Bragan9a, Portugal

bOepartment

of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

c

oepartment of Organic Chemistry, University of Debrecen, H-4010

Debrecen, Hungary

2-Styrylchromones constitute a small group of natural heterocyclic compounds with

significant biological properties. Certain natural and synthetic hydroxyl derivatives

have shown important pharmacological and mainly antioxidant activities [1 ,2].

We are interested in the design of new 2-styrylchromones analogues containing

hydroxyl groups at C-3 and in the Ca=C~ systems because they could increase the

antioxidation activity of these type of compounds [2]. Our first approach is the

preparation of epoxy systems and then we will try to open the epoxy ring to give the

desired hydroxyl derivatives. We studied the epoxidation of 2-styryl-chromones

1

with hydrogen peroxide and iodosylbenzene using [salen Mn(lll)] as catalyst, and

the epoxy products

2

were obtained in moderate yields. Since the best results were

obtained with iodosylbenzene, we applied oxidant to compounds

3

in order to prepare

4. In this communication, we will report the synthetic details and the structural

characterisation of the epoxides 3 and 4.

Salen Mn(lll) 1,3 R 1 = H; 2 H₂0 ₂or PhiO R = H, Cl, Me, N02 1 R 1 0 R 1 0 2,4 R

=

OH 1,2 3,4 R2

=

H, Cl, Me, N0₂

Acknowledgements: Thanks are due to the University of Aveiro, FCT and FEDER

for funding the Qrganic Chemistry Research Unit and the project POCTI/QUI/38394/

2001. One of us (C.M.M. Santos) is also grateful to PRODEP 5.3 for financial

support.

1. (a) Doria G, Romeo C, Forgione A, Sberze P, Tibolla N, Corno ML, Cruzzola

G, Cadelli

G,

Eur.

J.

Med. Chem. - Chim. Ther.

1979,

14, 347. (b) Gerwick

WH, Lopez A, Van Duyne GD, Clardy J, Ortiz W, Baez A, Tetrahedron Left.,

1986,

27, 1979; (c) Gerwick WH , J. Nat. Prod.

1989,

52, 252; (d) Desideri

N

,

Conti C, Mastromarino P, Mastropaolo F, Antiviral Chem. Chemother. 2000,

11, 373.

2.

e.g. (a) Fernandes E, Carvalho F, Silva AMS, Santos CMM, Pinto DCGA,

Cavaleiro JAS, Bastes ML, J. Enz. lnhib. , 2002, 17, 45; (b) Fernandes E,

Carvalho M, Carvalho F, Silva AMS, Santos CMM, Pinto DCGA, Cavaleiro

JAS, Bastes ML, Arch. Toxicol., 2003, 77, 500.

- - - - 172

---XXI

sr

EuROPEAN CoLLOQUIUM oN HETERocvcuc CHEMISTRY

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ETE

SOPRON, SEPTEMBER

12-l5

T

H'

2004

WE HAVE THE

PLEASURE

TO CONFIRM

THE ATTENDANCE OF

ANT OS,

._...LEMENT

PORTUGALIA

DR. GYORGY HAJOS

DR. PETER MATYUS

CO-CHAIRMAN

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • _• • • • • • • _• • • • _• • • • • • • • • • _• • • • ' • • 0 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • _• • • • • • • • • •••••••••••••••••••••••• ••~•••••••••• •••••••••••••••••• • ••••••••••••••• •• •• •• •• • ••••••••• o •e•••• • •••••••••••• e• •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• •• • •• ••••••• • I '

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Epoxidation of 2-styryl

Clementina M. M. Santos,

a,b

Artur M.

Tamás Patonay

c

a

_{Department of Agro-Industries, Escola}

b

_{Department of Chemistry, University of}

c

_{Department of Organic Chemistry, University}

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chromones derivatives

S. Silva,

b

José A. S. Cavaleiro,

b

and Albert Levaí

c

Superior Agrária de Bragança,

Aveiro, 3810-193 Aveiro, Portugal

Debrecen, H-4010 Debrecen, Hungary

Portugal

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Introduction

 2-Styrylchromones constitute a small group of natural

heterocyclic compounds with significant biological properties such as pharmacological and antioxidant activities [1,2].

 We are interested in the design of new 2-styrylchromone

analogues containing hydroxy groups because they could increase the antioxidation activity of this type of compounds [2].

 Our first approach is the preparation of epoxy systems and then we will try to open the epoxy ring to give the desired hydroxy derivatives.

 In this communication, we will report the synthetic details and the structural characterisation of the epoxides 3 and 4.

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 In order to prepare epoxides 3 and 4, we started our study with the epoxidation of 2-styrylchromone 1a (R=H) with different experimental conditions.

 We have used hydrogen peroxide (method A) and

iodosylbenzene (method B) as oxidants and [salen Mn(III)] as catalyst.

Epoxidation studies of 2-styrylchromones

O O R1 R2 O O R1 R2 O Salen Mn(III) H₂O₂ or PhIO 1,2 3,4 1,3 R1 = H 2,4 R1 = OH a)R2 = H, b) R2 = Cl, c) R2 = CH₃, d) R2 = NO₂

Reaccional scheme

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Yields obtained in the epoxidation of 2-styrylchromone 1a in different experimental conditions:

Exp. Catal. (equiv) Ligand (equiv) Oxidant (equiv)

Solvent Conditions  Efec.

 1 A 0.05 1-MeIm 0.7 H₂O₂aq 30% 30 CH₂Cl₂/CH₃OH 3.0 ml 40 C ; N₂ 19h No reac. 0.0 2 A 0.05 1-MeIm 0.7 H₂O₂aq 30% 60 CH₂Cl₂/CH₃OH 4.0 ml 40 C ; N₂ 2 days 26.7 62.4 70.9 3 A 0.05 1-MeIm 0.7 H₂O₂aq 30% 60 CH₃CN 4.0 ml 60 C ; N₂ 20h 3a 5.1 63.4 13.9 4 A 0.05 PyNO 0.7 H₂O₂aq 30% 60 CH₂Cl₂/CH₃OH 4.0 ml 40 C ; N₂ 15h No reac. 0.0 5 A 0.05 NH₄OAc 0.4 H₂O₂aq 30% 60 CH₂Cl₂/CH₃OH 4.0 ml r.t. ; N₂ 8h No reac. 0.0 6 A 0.05 1-MeIm 0.3 H₂O₂aq 30% 60 CH₂Cl₂/CH₃OH 4.0 ml 40 C ; N₂ 2 days No reac. 0.0 7 A 0.05 (4x) 1-MeIm 0.7 (4x) H₂O₂aq 30% 60 (4x) CH₂Cl₂/CH₃OH 4.0 ml (4x) 40 C ; N₂ 2 days 6.0 41.9 10.3 Method A

Salen: N,N’-bis(3,5- -tert-butylsalicylidine)

-1,2-cyclohexanediaminomanganese (III) chloride 1-MeIm: 1-methylimidazol

4OAc: ammonium acetate

r.t.: room temperature Legend:

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Exp. Catalis. (equiv.) Ligand (equiv.) Oxidant (equiv.)

Solvent Conditions  Efec.

 1 B 0.05 PyNO 0.5 PhIO 2 CH₃CN 4.0 ml r.t. ; N₂ 4 days 15.6 40.1 36.2 2 B 0.05 PyNO 0.5 PhIO 2 CH₃CN 4.0 ml 60 C ; N₂ 16h 21.2 1a 46.3 39.5 3 B 0.05 PyNO 0.5 PhIO 2 CH₃CN 4.0 ml 0 80 C ; N₂ 2 days 11.6 1a 44.0 15.3 4 B 0.1 --- PhIO 1+1 CH₂Cl₂ 5.0 ml r.t.reflux ; N₂ 3 days 3.8 80.2 19.4 5 B 0.05 (4x) PyNO 0.5 (4x) PhIO 1 (4x) CH₃CN 4.0 ml 60 C ; N₂ 3 days 9.8 25.7 13.2 6 B 0.05 PyNO 0.5 PhIO 2 Py 4.0 ml r.t.reflux ; N₂ 2 days No reac. 0.0 7 B 0.05 PyNO 0.5 PhIO 2 CH₃CN 4.0 ml r.t. ; N₂ 4 h 14.6 47.9 29.8 8 B 0.05 PyNO 0.5 PhIO ; 2 (4x0.5 eq.) CH₃CN 4.0 ml r.t. ; N₂ 4 h 22.9 25.1 30.6 Method B

PyNO: pyridine N-oxide _{PhIO: iodosylbenzene} Legend:

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Products H2O2 aq. 30% / 1-MeIm PhIO / PyNO

Yield (%) Efec. Yield (%) Yield (%) Efec. Yield (%)

3 a) R2 _{= H} _26.7 _70.9 _21.2 _39.5 b) R2 _{= Cl} _4.0 _32.3 _9.7 _36.2 c) R2 _{= CH} 3 7.6 34.7 15.3 27.0 d) R2_{= NO} 2 2.7 37.2 4.4 13.1 4 a) R2 _{= H} _2.9 _13.5 _22.2 _39.3 b) R2 _{= Cl} _3.4 _38.0 _11.8 _21.8 c) R2 _{= CH} 3 3.3 26.6 3.8 16.2 d) R2 _{= NO} 2 2.6 4.3 7.3 20.1

Taking into consideration the best yields obtained, we applied the conditions to the other 2-styrylchromones and the epoxy products 3 and 4 were obtained in moderate yields.



The best conditions obtained in the two methods are

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Structural elucidation

8 7 6 5 4 3 2 1 0 -0 . 0 0 1 1 . 0 6 3 1 . 1 0 2 1 . 1 2 1 1 . 1 3 5 1 . 1 9 3 1 . 2 1 2 1 . 2 4 5 1 . 2 5 3 1 . 2 7 0 2 . 1 7 6 3 . 7 9 5 3 . 8 0 0 3 . 8 4 8 4 . 3 7 8 6 . 4 8 8 7 . 2 6 5 7 . 4 2 4 7 . 4 4 9 7 . 4 6 3 7 . 4 7 4 7 . 4 9 2 7 . 5 5 0 7 . 5 7 9 7 . 6 8 6 7 . 6 9 1 7 . 7 1 4 7 . 7 3 8 7 . 7 4 2 8 . 2 0 0 1 . 0 4 6 1 . 0 1 0 1 . 0 2 1 2 . 1 4 7 2 . 1 4 2 1 . 1 5 0 1 . 0 6 9 2 . 1 0 4 .3 O O NO₂ O 3d (R1 = H ; R2 = NO₂) 5 6 7 8 9 10 1' 2' 3' 5' 4' 6' 2 3 4   , -epoxy-4’-nitro-2-styrylchromone H-H-3 H-3’,5’ _H-2’,6’ H-5 H-7 H-8H-6 CHCl₃ 1

H NMR

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180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 125 130 135 140 145 150 155 160 ppm C-C-3 C-8 C-4 C-2 C-9 _C-4’ C-1’ C-7 C-2’,6’ _C-3’,5’ C-6 C-5 C -10 CDCl₃

C NMR

, -epoxy-4’-nitro-2-styrylchromone

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ppm 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 ppm 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 H-H-3 H-3’,5’ H-2’,6’ H-5 H-7 H-8H-6 C-C-3 C-8 C-7 C-3’,5’ C-2’,6’ C-6 C-5

HSQC

, -epoxy-4’-nitro-2-styrylchromone

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18 13 12 11 10 9 8 7 6 5 4 3 2 1 0 1 . 0 6 1 1 . 0 5 4 1 . 0 0 0 1 . 1 2 4 1 . 1 4 4 3 . 4 8 8 2 . 2 1 5 1 . 0 2 4 3.7 3.8 3.9 4.0 4.1 4.2 4.3 4.4 6.5 6.6 6.7 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 ppm 1 . 0 0 0 1 . 1 2 4 1 . 1 4 4 3 . 4 8 8 2 . 2 1 5 O O NO₂ O 4d (R1 = OH ; R2 = NO₂) 5 6 7 8 9 10 1' 2' 3' 5' 4' 6' 2 3 4   OH , -epoxy-5-hydroxy-4’-nitro-2-styrylchromone H-5-OH H-3’,5’ H-2’,6’ H-7 CHCl₃ H-8 H-6 H-3 1

_{H NMR}

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190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm 110 115 120 125 130 135 140 145 150 155 160 ppm C-C-3 C-8 C-4 C-2 C-9 _C-4’ C-1’ C-7 C-2’,6’ C-3’,5’ C-6 C-5 CDCl₃

C NMR

, -epoxy-5-hydroxy-4’-nitro-2-styrylchromone

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ppm 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 ppm 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 H-H-3’,5’ _H-2’,6’ H-7 _{H-8 H-6} H-3 C-C-3C-8 C-7 C-2’,6’ C-3’,5’ C-6

HSQC

, -epoxy-5-hydroxy-4’-nitro-2-styrylchromone

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Conclusion

 The most appropriated ligant for the epoxidation with hydrogen

peroxide is 1-methylimidazol while with iodosylbenzene is pyridine

N-oxide.

 With hydrogen peroxide we used a biphasic system as solvent

while with iodosylbenzene we used an organic system.

 In general, the best yields for the epoxidation of

2-styrylchromones are obtained using iodosylbenzene as oxidant but the more effective in the conversion of the substracts are the method using hydrogen peroxide.

Acknowledgements

Thanks are due to the University of Aveiro, FCT and FEDER for funding the Organic Chemistry Research Unit and the project POCTI/QUI/38394/2001. One of us (C.M.M. Santos) is also grateful to PRODEP 5.3 for finantial support.

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1. (a) Doria G., Romeo C., Forgione A., Sberze P., Tibolla N., Corno M.L.,

Cruzzola G., Cadelli G., Eur. J. Med. Chem. - Chim. Ther. 1979, 14,

347. (b) Gerwick W.H., Lopez A., Van Duyne G.D., Clardy J., Ortiz

W., Baez A., Tetrahedron Lett., , 27, 1979; (c) Gerwick W.H., J.

Nat. Prod. 1989, 52, 252; (d) Desideri N., Conti C., Mastromarino P.,

Mastropaolo F., Antiviral Chem. Chemother. , 11, 373.

2. (a) Fernandes E., Carvalho F., Silva A.M.S., Santos C.M.M., Pinto

D.C.G.A., Cavaleiro J.A.S., Bastos M.L., J. Enz. Inhib., 2002, 17, 45; (b)

Fernandes E., Carvalho M., Carvalho F., Silva A.M.S., Santos C.M.M.,

Pinto D.C.G.A., Cavaleiro J.A.S., Bastos M.L., Arch. Toxicol., 2003, 77,

500; c) Filipe P., Silva A.M.S., Morliére P., Brito C.M., Patterson, L.K., Hug G.L., Silva J.N., Cavaleiro J.A.S., Maziére, J-C, Freitas J.P., Santus

R., Biochem. Pharmacol., , 67, 2207.