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New Methods for the Synthesisof Imidazoline-N-OxidesNecdet Coskun a & Dogan Sümengen aa Department of Chemistry, Uludag University, Bursa,Turkey

Version of record first published: 23 Sep 2006

To cite this article: Necdet Coskun & Dogan Sümengen (1993): New Methods forthe Synthesis of Imidazoline-N-Oxides, Synthetic Communications: An InternationalJournal for Rapid Communication of Synthetic Organic Chemistry, 23:12, 1699-1706

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SYNTHETIC COMMUNICATIONS, 23(12), 1699-1706 (1993)

NEW METHODS FOR THE SYNTHESIS OF IMIDAZOLINE-N-OXIDES

Necdet Coskun and Dogan Shengen Department of Chemistry, Uludag University, Bursa, Turkey

ABSTRACT: A3-lrnidazoline-3-oxides were prepared by the reaction of corresponding aromatic Schiff bases with syn-2- bromoacetophenone oxime. 5,6-Dihydro-4H-l,2,5-oxadiazines were isolated as byproduct in some instances.

Many imidazole derivatives have powerful pharmacological

properties. Some are valuable medicaments, which are distinguished in

particular by their vasodilating, vasoconstricting, and antihistaminic

1 action.

Busch and Kammerer have shown that syn-2-

phenylaminoacetophenone oximes react with excess of benzaldehyde in

ethanol to give 5,6-dihydro-4H- 1,2,5-0xadiazines. In the same work it

was shown, that pseudo form of the tolylaminoacetophenone oxime

* To whom correspondence should be addressed

1699

Copyright 0 1993 by Marcel Dekkcr, Inc.

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1700 COSKUN AND SUMENGEN

RiaN R 2&

1

Et 3N

2 Ph

R 2 ( g 0 - N

4 3

1-4 R' R2 1-4 R' R2

a H H f H 3-OMe;4-OH

b H 3,4-(OMe), g 4-Me 3-OMe;4-OH

C H 2,3-(OMe), h 4 0 M e H

d 4-Me H i 4-Br H

e H 3,4-(OC$O)

2 reacted with benzaldehyde to form N-hydroxyimidazoline. On the other

hand, 5,6-dihydro-l,2$-0xadiazines have been obtained from the reaction

of syn-2-aminoacetophenone oximes with acetaldehyde. A -1rnidazoline-

N-oxides were also detected . Furthermore, it has been reported that 6- oxo-1,2,5-oxadiazines were formed from syn-2-aminoacetophenone

4 oximes and phosgene .

3

3

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IMIDAZOLINE-N-OXIDES 1701

Table 1 Yields and spectroscopic data for compounds 3

Yield (%) m.p.(’C) IR Molecular MS (70 eV)

Method Method (solvent) (cm’ ’) Formula M+, miz

A B EtOH C=N

3 a 22 20

3b 24 23

3 c 29 27

3 d 25 25

3 e 31 26

3 f 30 29

3g 29 2 7

3 h 23 24

3 i 28 25

197-199 1595

149-150 1595

147-148 1600

196-197 1620

204-206 1595

177-180 1600

164-167 1620

187-188 1620

189-190 1590

%! 1 H1 gN2*

%! 3H2 2N2%

%!3b2&%

c;! 2H2 ON20

%2H1 8N2%

C22H2ON2S

% 3H22b%

G2 2H2 O N 2 0 2

% 1 H1 7N20Br

31 4

374

374

328

358

360

374

344

393

3 A method for the synthesis of A -imidazoline-N-oxides using anti-

2-aminooximes and aldehydes was reported5.

In this work the reaction of syn-2-bromoacetophenone o ~ i m e ~ ’ ~

with Schiff bases were investigated (method A). A3-Imidazoline-N-oxides

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1702 COSKUN AND SUMENGEN

Table 2 'H NMR data for compounds 3

Product

3 a

3b

3 c

3 d

3 e

4.95(1 H,dd,J=l5,3),5.31(1 H,dd,J=l5,5),6.36(1 H,dd,

J=5,3), 6.65-6.77(3H,m), 7.1 5-7.23(2H,m),7.40-

7.44(3H,m), 7.49-7.64(5H,m), 8.40(2H,dd,J=7.5,3.7).

3.75(3H,~), 3.76(3H,~), 4.90(1 H,dd,J=l5,3), 5.29( 1 H,

dd,J=l5,5),6.25(1 H ,dd,J=5,2), 6.66-6.77(3H,m), 6.94

-6.98( 1 H ,m), 7.O9-7.23(4HI m), 7.50-7.55(3H Jm),

8.39(2H,dd,J=7,4).

3.84(3H,s), 3.88(3H.s), 4.89(1 H,dd,J=i 5.02,2.53),

5.20(1H,dd,J=15.01,5.36),6.62-6.74(4H,m), 7.06(3H,

t,J=6.35),7.18(2H,t,J=7.61), 7.50-7.55(3H,m), 8.41

(2H,dd,J=7.48,2.22).

2.1 6(3H,~),4.88( 1 H,dd,J=l5,2.5),5.29( 1 H ,dd,J=15,5)

6.31 (1 H,dd,J=5,2.3), 6.57(2H,d,J=8), 6.99(2H,d,J=8),

7.37-7.42(3H,m) ,7.467.62(5H,m),8.39(2H,dd,J=7,3)

4.88( 1 H,dd,J=l5.13,2.37), 5.28(1 H,dd,J=l5.08,5.26),

6.02(2H,s) ,6.25( 1 H,dd,J=5.03,2.37),6.66-6.77(3H,m)

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IMIDAZOLINE-N-OXIDES 1703

Table 2 'H NMR data for compounds 3 (continued)

~ ~~

6.91-6.95(1 H,d,J=7.8), 7.1 1-7.24(4H,m),7.50-7.54

(3H,m), 8.38(2H,dd.J=6.06,2.23).

3 f 3.76(3H,s), 4.89( 1 H,dd,J=l5,3), 5.27( 1 H,dd,J=l5,5),

6.19(1 H,dd,J=5,3), 6.66-6.80(4H,m), 6.97(1 H,dd,J=

8,2), 7.15-7.23(3H,rn), 7.49-7.54(3H,m),8.37-8.44

(2H,m), 9.1 1(1H,bs).

39 2.1 7(3H,S), 3.76(3HIs), 4.84( 1 H,dd,J=15,2),5.24(1 H,

dd,J=15,5), 6.14(1H,dd,J=4,2), 6.59(2H,d,J=9), 6.77

(1 H,d,J=8), 6.94-7.02(3H,m), 7.1 2(1 H,d,J=2),7.50-

7.53(3H,rn), 8.36-8.41 (2H,m), 9.10( 1 H,bs,)

3h 3.65(3HIs), 4.84(1 H,dd,J=15.03,2.83),5.28( 1 H,dd,J=

15.01,5.26), 6.27( 1 H,dd,J=5.19,2.79),6.60-6.64(2H,

m), 6.77-6.83(2H,m), 7.37-7.43(3H,m), 7.48-7.62

5H ,m), 8.37(2H,dd,J=7.56,2.28).

3 i 4.93(1 H,dd,J=l5.16,2.25), 5.28(1 H,dd,J=l5.2,5.18),

6.35(1 H,dd,J=5,2.12), 6.56-6.65(2H,m), 7.23-7.55

(6H,m). 7.57-7.66(5H,m), 8.35-8.41(2H,rn).

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1704 COSKUN AND SUMENGEN

were isolated. We have also obtained same products when aromatic

aldehydes and mines were used as starting compounds (method B). In

both of these methods, intermediates 2 were formed and in some

instances these intermediate salts were isolated. The salts were easily

soluble in water, and were hydrolyzed to give the 2-

pheny laminoacetophenone oximes and corresponding benzaldehydes.

The intermediates (compounds 2) did not react when refluxed in

dichloroethane for 5 h. However, when equimolar amount of

triethylamine was added compounds 3 and small amounts of compounds

4 were isolated . Their identity was confirmed by comparing the physical

and spectroscopic data with those reported in the literature. Furthermore,

the isolated imidazoline-N-oxides were subjected to acidic hydrolysis in

ethanol and the resulting products were identified as the corresponding

aromatic aldehydes and 2-phenylaminoacetophenone oximes. In addition

2-phenylaminoacetophenone oxime reacted with benzaldehyde and the

product was identical with compound 3a obtained by either method A or

B.

8

Analytical and spectroscopic data of compounds 3 were given in Table

1 and Table 2.

EXPERIMENTAL

Method A. Compound 1 ( I .8g, Ommoi) and syn-2-bromoacetor ienone

oxime (2.14g, lommol) were refluxed in dichloroethane (2OmL) for 30

min on a water bath. The addition of triethylamine (lg, l0mmol)

solidified the reaction mixture. Dichloroethane (10mL) was added and the

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IMID AZOLINE-N-OXIDES 1705

mixture was refluxed for 4 h, then the solvent was removed by vacuum

distilation. The residual solid was extracted with warm benzene

(3X2OmL), and the extract was concentrated and filtered. To the filtered

solution, Et20 was added and the resulting precipitate was kept overnight in an ice-box. The white and amorphous solid was recrystallized from

ethanol and dried at 80 OC to give compound 3a, (20%); m.p. 197-

199 OC.

Method B. In a flask equiped with a Dean-Stark trap, veratrum

aldehyde (1.66g, lOmmol) and aniline (0.93g, l0mmol) were refluxed in

benzene (30ml) for 3h. The solvent was removed by evaporation under

vacuum, and the solution of syn-2-bromoacetophenone oxime

(2.14g,lOmmol) in dichloroethane (2OmL) was added. The mixture was

refluxed on a water bath for 30 min, then hiethylamine (lg,lOmmol) was

added and refluxed for 4h. The product was isolated and purified as

described in method A to give compound 3b, (23%); m.p. 149-15O0C.

REFERENCES

1. Acheson, R. M., in "An Introduction to the Chemistry of

Heterocyclic Compounds", John Wiley and Sons, New York,

1976, p.362.

Bush, M., and'Kammerer, R., Ber., 1930, 63, 649.

Gnichtel, H., Chem. Ber., 1970,103, 3442.

Gnichtel, H., Thiele, S., Chem. Ber., 1971,104, 1507.

2.

3.

4.

5. Gnichtel, H., Chem. Ber., 1970,103, 2411.

6. P.Blurnberg, C. Thanawalla, A. Ash, J. Org. Chem..,1971,3

2023

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1706 COSKUN AND SUMENGEN

7. J . Smith, J. Heidema, E. Kaiser, J . Am. Chem. S0c.J. Am.

Chem.Soc. 1972,27.9274

2 8. Compound 4a has a m.p. 121OC; (lit . m.p. 121OC) IR (KBr)

1590 0 - l (C=N); 'H NMR (DMSOW 6 4.04,4.54

(2H,ABsystern,J~~18.85),6.81(1 H,s),6.94 (1 H,t,J=7.02),

7.1 6-7.54 (12H,m),7.61-7.69 (2H,m).

(Received in UK 18 January 1993)

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