HETEROCYCLES, Vol. 51. No.
1,1999
131
RING CONTRACTION O F 3-CARBOXAMIDE OR 3-CARBOXYLATE O F
4-EYDROXY-2-METEYL -2H-1,2-BENZOTHIAZINE -1,l-DIOXIDE AND ANALOGOUS l(2H)-ISOQUINOLINONE-3-CARBOXYLATE
Ali Kbalaj* and Neda Adibpour
College ofPhamcy, Tehran Medical Sciences University, [Link]-6451, Tehran, Iran
Abstract-A novel ring transformation of 3-carhoxylate or 3-carhoxamide of 4-
hydroxy-2-methyl-2H-1,2-benzothia~e-l,l-dioxide analogous I(2H)-isoand
quinolinone-3-carboxylate to the 5-membered rings upon the reaction with carhonyl
compounds in the presence of primary or secondary amines is described.
During the course of our investigations for the synthesis ofprodrugs ofthe popular antiinflammatory agent piroxicam (la)' through the reaction with ethyl methyl ketone in the presence of pyrrolid'me in benzene, the only product isolated was shown by spectroscopic and analytical data to be 2-methyl- 1,2-benzoisothiazol3(2H)-one 1,l-dioxide (2a)' which is a known metabolite of l a . ~ o m p o u n d was also obtained when (Za) we carried out the same reaction with isopropyl 4-hydroxy-Z-methyl-2H-1,2-benzothiazine-3-ca1boxylate 1,l-dioxide (lb) instead of l a . These findings led us to investigate the utility of this reaction for the ring transformation of 1,2-dihydro-4-hydro~-methyl-l-oxo-3-isoquinolinecarboxylic methyl ester (lc)' acid under similar conditions and the structure of the product of this reaction was established as 2-methyl-1Hisoindole-1,3(2H)-dione (2b)' (Scheme 1).
Ethyl methyl ketone
Pyrrolidine
w : N - M e
Scheme 1
132
HETEROCYCLES. Vol. 51, No. 1,1999
Further experiments showed that the ring contraction of la-cwas also successfit1 for the reaction with other carbonyl compounds in the presence ofprimary or secondaly amines (Tahlel), but failed with tertialy amines.
Tablel. Ring contraction of la-c to 2a-b upon the reaction with carbonyl compounds in the presence of primaly or secondaly amines
acetone
I
butylamine pyrrolidine
I
39 52 32 43
beddehyde ethyl methyl ketone methyl isopropyl ketone
pyrrolidine morpholine
I
I
ethyl methyl ketone
I
propionaldehyde aniline 28
While we are not certain about the fate ofthe extruded ring carbon (C-3) with the attached substituents as weU as that of the amine and aldehyde or ketone reactants, following important parameters for transformation of la-c to 2a,b have been investigated. No reaction occurs in the absence of either amines or carbouyl compounds, conliming the requirement for participation of both reactants in the ring contraction. No reaction occurs between la-c and preformed N-(2-buten-2-yl)pyrrotidine'even in the presence of pyrrolidine, eliminating the possibility that ring contraction might proceed through the reaction of la-cwith
in srtu generated enamines from the carbonyl compounds and amines.
From these results it seems that the mechanism of the reaction may involves the nucleophilic addition of the enolate ions of the amine salts (3) resulting fiom the reaction of la-c with amines to the carhonyl group to give the intermediate (4). Inductive iduences ofthe C-3 bearing two electron withdrawing groups as well as the carbonyl group increase the positive character of C-3 and make it susceptible to the nucleophilic substitution. The steric interference between the substituents at C-3 and the methyl group at N-2 assisted by the nucleophilic addition ofthe amine nitrogen to C-3 would force the amide nitrogen ofthe intermediate (4) out of the plane and result in the formation ofthe ring-opened intermediate (5). The final step ofthe reaction may involve nucleophilic attack of the sulfonamide nitrogen of the intermediate (5) to the carbonyl group to give products (2a,b) with concurrent elimination of C-3 and attached substituents. (Scheme 2)
HETEROCYCLES, Vol. 51, No. 1.1999
133
qCoR+ ..-KN'Me COR
0
II
'a,
R ' jN+. H '" '
Scheme 2
The lack of reactivity of tertiary amines compared with primary and secondary amines for conversion of la-c to 2a,b may be attributed to the greater steric hindrance and lower nncleophilicity to induce conversion of the intermediate (4) to 2a,h. Consistent with this mechanism ring transformation failed with N-demethyl analogue ( 1 ~ in which nitrogen atom is less nucleophilic in comparison with that of lc and it )~ lacks the steric hindrance ofthe methyl group. Further support for the mechanism was given by the experiment in which preformed crystalline (3) prepared 6om the reaction of l a with morpholine in E~OH'was treated with ethyl methyl ketone to give 2a. In summary,although ring expansion ofN-substituted derivatives (2a)' and (2b)' is a general synthetic
i route for the preparation of the s x membered rings (la-c), the findings described in this paper is the fist
example for the reverse ring contraction.
EXPERIMENTAL Melting points were determined with a Reichelt hot plate melting point apparatus and are uncorrected. TLC analyses were performed on 250-Eastman 13181 silicagel sheets; spots were visualized under ordinary fluorescent light or 254 nm W light. MS spectra were recorded with a F i g a n TSQ-70 instrument .'H
NMR spectra were measured in deuterochloroformwith a Bruker AC-80 (80 iWh)spectrometer relative to
TMS as internal standard. IR spectra were recorded on a Perkin-Elmer 781 spectrophotometer. Elemental analyses were performed by the microanalytical laboratory, Iran National Oil Company. Piroxicam (la) was
134
HETEROCYCLES, Vol. 51. No. 1.1999
supplied by the Alhavi Pharmaceutical Company in Iran. The known isoquinoline (lc) used in the present study was prepared according to the reported method in the l i t e r a t ~ e . ~
1,l-dioxide (lb). HsopropyP Chydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate To a stirred solution of0.8 g (0.2 mol) of sodium hydroxide in water (50 mL) and EtOH (65 mL) at it was l,l-dioxoide6 and the added 6 g (0.2 mol) of isopropyl4-hydroxy-2H-l,2-benzothiazine-3-carboxylate mixture was heated at reflux for 20 min. To the resulting solution after cooling to rt was added 6.3 mL (0.1 mol) of methyl iodide and stirring was continued for 8 h. The obtained precipitate was collected by filteration, washed with water (20 mL) and the crude product was reclystallized fiom MeOH to give 5 g (86%) of l b : mp 105C ;lR(KEh): 1600, 1340, and 1190 cm"; 'H NMR ( CDCG): S 12.22 (s, l y OH), 7.99-7.76 (m, 4 Y aromatic), 5.32 (m,J = 6.3 Hz, IH, -CH-), 2.95 (s, 3H, N-CH& and 1.35 (d, J = 6.3 Hz, 2H, CH3)ppm; MS: m/l297(M+). Anal. Calcd for CI~H~SNOSS: C, 52.54; H,5.04; N,4.71. Found: C, 52.23; H, 4.95; N, 4.43.
General procedure for the ring transformation of la-c to 2a,b is as foUows : The appropriate primary or secondary amine (9 mmol) was added to a stirred mixture of 1(6 mmol) in anhydrous benzene (10 mL)at it and the resulting clear yellow solution after heating at reflux for 10 min gave a suspension which upon addition of the carbonyl compound (6 mmol) was changed to a solution. The solution was then allowed to stir at reflux for 4 h and the progress ofthe formation ofthe product was checked by TLC analyses (benzene/chlorofom= 614). After cooling to rt unreacted 1was filtered and the organic solution was washed successively with 5% HCI (2 mL), 5% sodium hydroxide solution (2 mL), and water (2 t x2) and dried over anhydrous MgSO.,. The residue after evaporation ofthe solution under d reduced pressure was crystallized from EtOH to give 2. 2a: mp 131-132T (lit.: 130 T ) ; IR(KBr): 1720,1375,1330, and 1160 cm-'; 'HNMR(CDCL): 6 8.057.82 (m, 4H, aromatic), and 3.27 (s, 3 Y N-CH3) ;MS mlz: 197 . 2b:mp 130C(lit.: 126 -128'C); lR(KBr): 1725, 1610, and 1450 cm-' ; 'HNMR(cDCL): 6 8.12-7.76 (m, 4H, aromatic),and 3.47 (s, 3 Y N-CH3); MS miz: 161.
REFERENCES
1. R.N. Brogden, R.C. Heel, T.M. Speight, and G.S. Avery, Drugs, 1984,28, 292 2. Y. Inoue, M. Taguchi, and H. Hashimoto, Synthesis ,1986, 332. 3. J. G. Lombardio, J. Med. Chem., 1981, 24, 39. 4. J. G. Lomhardino,J. Heterocycl. Chem., 1970,7, 1057.
HETEROCYCLES, Val. 51, No. 1,1999
135
5. R Jacquier, C. Petms, and F. Petrus, Bull. Chem. Soc. Fr., 1966,2845.
6. C. B. Schapira, I. [Link], and S. Lamdan, J. Heterocycl. Chem., 1980, 17, 1281. 7. R G. W. Spickett, J. Moragues Mauri, A Vega Noverola and J. M. Prieto Soto, Span. ES.507,666, 1982 (Chem. Abstr., l982,98,179396g).
8. L. R CasweU and R D. Campbell , J. Org. Chem., 1961,26,4175.
Received, 1 4 t h November, 1997
