Pyrroloisoxazoles as a Building Block for 3-Enoyltetramic Acids

Abstract

3-Methylpyrrolo[3,4-c]isoxazoles prepared by nitrile ­oxide cycloaddition, are deprotonated and condensed with aromatic aldehydes; N-O bond cleavage with Mo(CO)₆ affords 3-enoyltetramic acids whilst with H₂-catalyst further reduction to 3-acyltetramic acids is observed.

acyltetramic acid - isoxazole - cycloaddition - condensation - heterocycle

References

For a review and leading references, see:

1a Royles BJL. Chem. Rev.  1995,  95:  1981 

1b Jones RCF. Bhalay G. Carter PA. Duller KAM. Dunn SH. J. Chem. Soc., Perkin Trans. 1  1999,  765 

2 Jones RCF. Bhalay G. Carter PA. Duller KAM. Vulto SIE. J. Chem. Soc., Perkin Trans. 1  1994,  2513 

3 Jones RCF. Dawson CE. O’Mahony MJ. Synlett  1999,  873 

4 Dixon DJ. Ley SV. Longbottom DA. Org. Lett.  2000,  3:  3611 ; and references cited therein

5 The enamine geometry was undetermined and is drawn as E for convenience.

6 Stork G. McMurry JE. J. Am. Chem. Soc.  1967,  89:  5461 

7

Similar treatment of 4b afforded the N-methyl derivative.

8

Under these conditions aliphatic ketones MeCO(CH₂)_2-6Me as electrophiles also gave low yields (12-28%) but of the hydroxy adducts.

9

6-Methyl-3-[2-(4-nitrophenyl)ethenyl]-5,6-dihydro-4 H -pyrrolo[3,4- c ]isoxazol-4-one ( 10b): To 3,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]isoxazol-4-one (4a, 0.050 g, 0.329 mmol) under nitrogen at 20 °C was added dry MeOH (5 mL) followed by 4-nitrobenzaldehyde (0.109 g, 0.723 mmol, 2.2 mol equiv), and sodium methoxide (0.021 g, 0.395 mmol, 1.2 mol equiv) in dry MeOH (4 mL). The reaction mixture was stirred for 1 min at 20 °C then heated under reflux for 2 h and immediately cooled in an ice bath. The resulting yellow crystals were filtered off and dried in vacuo (0.062 g, 66%); (Anal. Calcd for C₁₄H₁₁N₃O₄: C, 58.95; H, 3.89; N, 14.73%; [M⁺] 285.0750. Found: C, 59.09; H, 3.80; N, 14.60%; [M⁺] 285.0747.). ¹H NMR (250 MHz, CDCl₃): δ = 1.59 (3 H, d, J = 7 Hz, CH ₃CH), 4.88 (1 H, q, J = 7 Hz, CHCH₃), 6.03 (1 H, br s, NH), 7.26 (1 H, d, J = 16 Hz, CH=CH), 7.76 (2 H, d, J = 9 Hz, ArH), 8.06 (1 H, d, J = 16 Hz, CH=CH), 8.28 (2 H, d, J = 9 Hz, ArH). ¹³C NMR (400 MHz, CDCl₃): δ = 20.4 (CH₃), 48.9 (CHCH₃), 112.1 (C), 115.2 (CH=CH), 124.6 and 129.9 (ArCH), 134.8 (ArC), 141.5 (CH=CH), 148.8, 161.8 and 162.8 (C), 173.4 (C=O). MS: m/z = 285 [M⁺], 270, 176, 164, 147, 102, 90, 55, 43.

10

Crystal data for 10d and 10g are deposited at the Cambridge Crystallographic Centre Database.

11

Condensation products 10 in general displayed no optical rotation. It is assumed loss of optical integrity occurred under the basic conditions used, cf. ref. 3.

12

The acyltetramic acids are drawn as the exo-enol tautomer that forms the major tautomer in CDCl₃ solution, and the tautomer observed in the solid state, see ref. 1.

13 Nitta M. Kobayashi T. J. Chem. Soc., Chem. Commun.  1982,  877 

14 See: Jones RCF. Bhalay G. Carter PA. J. Chem. Soc., Perkin Trans. 1  1993,  1715