Studies on the Syntheses of Heterocycles from 3-Arylsydnone-4- carbohydroximic Acid Chlorides with N-Arylmaleimides, [1,4]Naphthoquinone and Aromatic Amines

 Mei-Hsiu Shih*( 施美秀 )

Department of Chemical Engineering, Southern Taiwan University of Technology, Tainan, Taiwan, 710,  

3-Arylsydnone-4-carbohydroximic acid chlorides (1) could react with N-arylmale- imides (3a-3b) or 2-methyl-N-phenylmaleimide (3c) to give 3-(3-aryl-sydnon-4-yl)-5- aryl-3a,6a-dihydro-pyrrolo[3,4-d]isoxazole-4,6-diones (4a-4h) or 6a-methyl-3-(3-aryl sydnon-4-yl)-5-phenyl-3a,6a-dihydro-pyrrolo[3,4-d]isoxazole-4,6-diones (4i-4l) res- pectively. However, 3-(arylsydnon-4-yl)-naphtho[2,3-d]isoxazole-4,9-diones (6a-6d) were obtained in good yield by the reaction of carbohydroximic acid chlorides 1 with [1,4] naphthoquinone. Furthermore, 2-(3-arylsydnon-4-yl)benzoxazoles (9a-9d) and 2-(3-arylsydnon-4-yl)benzothiazoles (9e-9h) were obtained via the reaction of carbohydroximic acid chlorides 1 with o

rtho substituted aromatic amines 7a-7b.

• Results and discussion• 3-Arylsydnone-4-carbohydroximic acid chlorides (1) are versatile precusors for the synt

heses of corresponding nitrile oxides 2 which can undergo various dipolar 1,3-cycloaddi

tion and 1,3-addition reactions, leading to cyclic and open chain products, respectively.

• In this report, the reaction of carbohydroximic acid chlorides 1 with some dipolaro- phile

s such as N-arylmaleimides and [1,4]naphthoquinone was studied. Thus, treat- ment of 1

with N-aryl-maleimides (3a-3b) or 2-methyl-N-phenylmaleimide (3c) in the presence of

triethylamine produced 3-(3-arylsydnon-4-yl)-5-aryl-3a,6a-dihydro- pyrrolo [3,4-d]isoxa

zole-4,6-diones (4a-4h) or 6a-methyl-3-(3-arylsydnon-4-yl)-5-phenyl-3a,6a- dihydro-py

rrolo[3,4-d] isoxazole-4,6-diones (4i-4l) in high yields (Scheme 1). Among these new pr

oducts, the yellow crystal 4l obtained was analy- tically pure and suitable for X-ray struc

ture determination. Figure 1 shows the molecular structure of 6a-methyl -3-[3-(4'-ethoxy

phenyl)sydnon-4-yl]-5-phenyl-3a,6a-dihydro-pyrrolo[3,4-d] isoxazole- 4,6-dione (4l).

• The experimental results indicated that the reaction of nitrile oxides 2 with various N-ary

lmaleimides (3a-3c) is a typical 1,3-dipolar cycloaddition. Furthermore, the X-ray struct

ure of 4l has a cis isoxazolinyl group, implying the concerted mechanism of 1,3-dipolar

cycloaddition. However, acid chlorides 1 reacted with [1,4]naphthaqui- none (3d) to giv

e 3-(3-arylsydnon-4-yl)-naphtho[2,3-d]isoxazole-4,9-diones (6a-6d) directly, but not 1,

3-dipolar cycloaddition adducts 3-(3-arylsydnon-4-yl)-naphtho[2,3-d] isoxazole-4,9-diol

s (5), as shown in Scheme 1. Although the compounds 5 were not found and isolated in t

he reaction, one might speculate that compounds 5 contain hydroquinone moiety, which

is readily undergoing air oxidation to form the more stable compounds 6. However, the i

soxazolinyl compounds 4a-4h are relatively stable and could not converted into the corr

esponding isoxazoles by oxidation with N-bromosuc-cinimide (NBS). The structures of c

ompounds 6a and 6c were also verified by X-ray diffraction and are displayed in Figs. 2,

3.

• C-2 substituted benzoxazole and benzothiazole derivatives exhibit interesting antiviral, a

ntibacterial and herbicidal activities and can be widely applied in medicine. In this study,

a useful and general methodology for new and efficient reactions of hydroxamoyl chlori

des with aromatic amines had been established. Treatment of compounds 1a-1d with two

equivalents of o-aminophenol (7a) in dichloromethane-ethanol gave 2-(3-arylsydnon -4-

yl)benzoxazoles (9a-9d) in good yields (Scheme 2).

•

An excess of o-aminophenol was used to trap the hydrogene chloride released during the

reaction. Compound 1 was added slowly to the solution of o-aminophenol at 0℃ to mini

mize the dimerization of nitrile oxides 2. The nucleophilic substitution of o-aminophenol

with compound 1 was very rapid. The starting materials 1a-1d reacted completely to giv

e intermediates 8 within 1 h by T.L.C. survey. Then the reaction mixture was stirred or le

ft standing at room temperature over 3-4 days for further cyclization. Experimental tests

showed that adding 2-3 drops of sulfuric acid to the reaction solution at this stage would

accelerate the cyclisation to give the desired products. The crystals of benzoxazoles 9a-9

d would automatically precipitate out in the solution and the isolation and purification of

9a-9d then become very easy. The benzoxazoles 9a-9d could be proved to be produced

by the corresponding interme- diates 8 after elimination of hydroxylamine moiety (Sche

me 2). The reaction of 1 with o-aminophenol should be conducted in much more solvent

to prevent the inter- mediate 8 from precipitating out and to ensure a cyclisation reaction

step proceed successfully. Dissolved in CH2Cl2/EtOH and kept standing for several days,

the isolated compounds 8 would cyclize automatically to the desired products 9. Similar

treatment of 3-arylsydnone-4-carbohydroximic acid chlorides (1) with two equiva- lents

of o-aminothiophenol (7b) produced the corresponding benzothiazoles 9e-9h, as describ

ed in Scheme 2. The structure of compounds 9e and 9g were also verified by X-ray diffr

action and are displayed in Fig. 4, 5.

• Conclusion• In summary, the compounds 1 reacted with [1,4]naphthoquinone in the presence of trieth

ylamine to give fused ring heterocycles 6a-6d directly, but not 1,3-dipolar cyclo- additio

n adducts 5 which were not found and isolated in the reaction. One might speculate that

compounds 5 contain hydroquinone moiety and are readily undergoing air oxidation to f

orm the more stable compounds 6. However the acid chlorides 1 reacted with N-arylmal

eimides (3a-3b) or 2-methyl-N-phenylmaleimide (3c) to give the 1,3-dipolar cycloadditi

on products 4a-4h or 4i-4l respectively. Based on the frontier molecular orbitals concept

and X-ray structure of 4l with a cis isoxazolinyl group, the reaction mechanism of the 1,

3-dipolar cycloaddition should be proved to be concerted again. Furthermore, the isoxaz

olinyl compounds 4a-4h are very stable and could not converted into the corresponding i

soxazoles by oxidation with NBS. Besides that, C-2 substituted benzoxazole 9a-9d and b

enzothiazole derivatives 9e-9h were obtained in good yields via the reaction of carbohyd

roximic acid chlorides 1 with ortho substituted aromatic amines 7a-7b. The fused ring he

terocycles 9 were produced by the corresponding intermediates 8 after elimination of hy

droxylamine moiety.

Scheme 1

•1a : Ar = C6H5 1b : Ar = p-CH3C6H4 1c : Ar = p-CH3OC6H4 1d : Ar = p-C2H5OC6H4 3a : Ar' = C6H5 3b : Ar' = p-BrC6H4

•  

Figure 1. Crystal structure of compound 4l Figure 2. Crystal structure of compound 6a  Figure 3. Crystal structure of compound 6c  •  

Scheme 2•

• 1a: Ar = C6H5 1b: Ar = p-CH3C6H4 1c: Ar = p-CH3OC6H4 1d: Ar = p- C2H5OC6H4 7a: ZH=OH 7b: ZH=SH

•  •

Figure 5. Crystal structure of compound 9g Figure 4. Crystal structure of compound 9e •  •  

N

NO

Ar

O

N

OHCl

HCl

Base

1 2

N

NO

Ar N

O

O

DMFNBS

N OO

Ar'

N

NO

Ar

O

NO

NO

N

NO

Ar

O

N OO

Ar'

3c

N

O

O

ph

H3C

N

O

O

Ar'

N OO

ph

CH3

N

NO

Ar

O

NO

Et3NN

NO

Ar

O

N

OHCl

N

NO

Ar

O

ON

OO OO

3d

O

O ONN

NO

Ar

O

5

1a-1d

3a-3b

4a-4h

6a-6d

4i-4l

N

NO

Ar

O

ZN

N

NO

Ar

O

N

OHCl

N

NO

Ar

O

C N OH

HN

+H2N

HZ

2

ZHNH2OH_

8 9a-9h7a-7b1a-1d