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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 ortho substituted aromatic amines 7a-7b.
Results and discussion
Cl
OH
Ar
3-Arylsydnone-4-carbohydroximic acid chlorides (1) are versatile precusors for the
N
syntheses of corresponding nitrile oxides 2 which can undergo various dipolar 1,3cycloaddition and 1,3-addition reactions, leading to cyclic and open chain products,
N
respectively.
philes such as N-arylmaleimides and [1,4]naphthoquinone was studied. Thus, treat- ment
N
N
HCl
O
O
1
In this report, the reaction of carbohydroximic acid chlorides 1 with some dipolaro-
O
Ar'
O
presence of triethylamine produced 3-(3-arylsydnon-4-yl)-5-aryl-3a,6a-dihydro- pyrrolo
N
N
N
isoxazole-
arylmaleimides (3a-3c) is a typical 1,3-dipolar cycloaddition. Furthermore, the X-ray
Cl
structure of 4l has a cis isoxazolinyl group, implying the concerted mechanism of 1,3-
H3C
OH
Ar
O
CH3
O
N
N
N
O
1a-1d
to give 3-(3-arylsydnon-4-yl)-naphtho[2,3-d]isoxazole-4,9-diones (6a-6d) directly, but
O
O
Ar
3c
Et3N
N
N
O
ph
N
dipolar cycloaddition. However, acid chlorides 1 reacted with [1,4]naphthaqui- none (3d)
N
N
N
N
O
N
NBS DMF
ph
O
The experimental results indicated that the reaction of nitrile oxides 2 with various N-
O
O
Ar
O
O
4a-4h
4,6-dione (4l).
N
O
O
Ar
for X-ray structure determination. Figure 1 shows the molecular structure of 6a-methyl 3-[3-(4'-ethoxyphenyl)sydnon-4-yl]-5-phenyl-3a,6a-dihydro-pyrrolo[3,4-d]
O
Ar'
O
3a-3b
these new products, the yellow crystal 4l obtained was analy- tically pure and suitable
Ar'
N
O
N
[3,4-d]isoxazole-4,6-diones (4a-4h) or 6a-methyl-3-(3-arylsydnon-4-yl)-5-phenyl-3a,6a-
O
2
Scheme 1
of 1 with N-aryl-maleimides (3a-3b) or 2-methyl-N-phenylmaleimide (3c) in the
dihydro-pyrrolo[3,4-d] isoxazole-4,6-diones (4i-4l) in high yields (Scheme 1). Among
N O
Ar
Base
N
O
O
4i-4l
O
O
not 1,3-dipolar cycloaddition adducts 3-(3-arylsydnon-4-yl)-naphtho[2,3-d] isoxazole4,9-diols (5), as shown in Scheme 1. Although the compounds 5 were not found and
O
isolated in the reaction, one might speculate that compounds 5 contain hydroquinone
O
3d
moiety, which is readily undergoing air oxidation to form the more stable compounds 6.
N
N
N
O
O
5
converted into the corresponding isoxazoles by oxidation with N-bromosuc-cinimide
Ar
O
N
N
However, the isoxazolinyl compounds 4a-4h are relatively stable and could not
O
O
Ar
O
6a-6d
O
N
O
O
(NBS). The structures of compounds 6a and 6c were also verified by X-ray diffraction
•
1a : Ar = C6H5 1b : Ar = p-CH3C6H4 1c : Ar = p-CH3OC6H4 1d : Ar = p-C2H5OC6H4 3a : Ar' = C6H5 3b : Ar' = p-BrC6H4
and are displayed in Figs. 2, 3.
C-2 substituted benzoxazole and benzothiazole derivatives exhibit interesting antiviral,
antibacterial 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
chlorides with aromatic amines had been established. Treatment of compounds 1a-1d
with two equivalents of o-aminophenol (7a) in dichloromethane-ethanol gave 2-(3arylsydnon -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
minimize the dimerization of nitrile oxides 2. The nucleophilic substitution of oaminophenol with compound 1 was very rapid. The starting materials 1a-1d reacted
completely to give intermediates 8 within 1 h by T.L.C. survey. Then the reaction
Figure 1. Crystal structure of compound 4l
•
Figure 2. Crystal structure of compound 6a
mixture was stirred or left standing at room temperature over 3-4 days for further •
cyclization. Experimental tests showed that adding 2-3 drops of sulfuric acid to the
Figure 3. Crystal structure of compound 6c
Scheme 2
•
reaction solution at this stage would accelerate the cyclisation to give the desired
products. The crystals of benzoxazoles 9a-9d 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 intermediates 8 after elimination of hydroxylamine moiety (Scheme 2). The reaction of 1 with
o-aminophenol should be conducted in much more solvent to prevent the inter- mediate
Cl
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
N
would cyclize automatically to the desired products 9. Similar treatment of 3arylsydnone-4-carbohydroximic acid chlorides (1) with two equiva- lents of oaminothiophenol (7b) produced the corresponding benzothiazoles 9e-9h, as described in
N
O
1a-1d
and are displayed in Fig. 4, 5.
•
+
ZH
HN
H2N
C N OH
Ar
2
N
_ NH OH
2
O
7a-7b
O
addition 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 form the more stable compounds 6. However the acid chlorides 1 reacted
with N-arylmaleimides (3a-3b) or 2-methyl-N-phenylmaleimide (3c) to give the 1,3dipolar cycloaddition 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
•
converted into the corresponding isoxazoles by oxidation with NBS. Besides that, C-2 •
good yields via the reaction of carbohydroximic acid chlorides 1 with ortho substituted •
aromatic amines 7a-7b. The fused ring heterocycles 9 were produced by the •
corresponding intermediates 8 after elimination of hydroxylamine moiety.
O
1a: Ar = C6H5 1b: Ar = p-CH3C6H4 1c: Ar = p-CH3OC6H4 1d: Ar = p- C2H5OC6H4 7a: ZH=OH 7b: ZH=SH
triethylamine to give fused ring heterocycles 6a-6d directly, but not 1,3-dipolar cyclo-
substituted benzoxazole 9a-9d and benzothiazole derivatives 9e-9h were obtained in
O
9a-9h
8
In summary, the compounds 1 reacted with [1,4]naphthoquinone in the presence of
again. Furthermore, the isoxazolinyl compounds 4a-4h are very stable and could not
N
N
N
O
Z
Ar
N
HZ
N
Scheme 2. The structure of compounds 9e and 9g were also verified by X-ray diffraction
Conclusion
OH
Ar
Figure 5. Crystal structure of compound 9g
Figure 4. Crystal structure of compound 9e