Switching the Reaction Mode of 4-Methoxycarbonyl-4-chloro-5-spirocyclopropaneisoxazolidines by N-Aryl Substitution

Abstract

4-Methoxycarbonyl-4-chloro-5-spirocyclopropaneisoxazolidines, easily obtained by in situ cycloadditions of nitrones to methyl 2-chlorocyclopropylideneacetate and 2-chlorospiropentyl-ideneacetate, in contrast to their known thermal rearrangements leading to δ-lactams, undergo rearrangement to their respective tetrahydropyridones, when the nitrone nitrogen is substituted by an aryl moiety.

1,3-dipolar cycloadditions - chlorocyclopropylidene-acetate - N-aryl nitrones - thermal rearrangement - tetrahydropyridones

References and Notes

<A NAME="RG15210ST-1">1</A> Brandi A. Cicchi S. Cordero FM. Goti A. Chem. Rev.  2003,  103:  1213 

<A NAME="RG15210ST-2A">2a</A> Cordero FM. Brandi A. Querci C. Goti A. De Sarlo F. Guarna A. J. Org. Chem.  1990,  55:  1762 

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<A NAME="RG15210ST-2C">2c</A> Machetti F. Cordero FM. De Sarlo F. Guarna A. Brandi A. Tetrahedron Lett.  1996,  37:  4205 

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<A NAME="RG15210ST-4">4</A> Ochoa E. Mann M. Sperling D. Fabian J. Eur. J. Org. Chem.  2001,  4223 

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<A NAME="RG15210ST-7">7</A> Revuelta J. Cicchi S. Faggi C. Kozhushkov SI. de Meijere A. Brandi A. J. Org. Chem.  2006,  71:  2417 

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<A NAME="RG15210ST-9B">9b</A> de Meijere A. Kozhushkov SI. Yufit DS. Boese R. Haumann T. Pole DL. Sharma PK. Warkentin J. Liebigs Ann.  1996,  601 

<A NAME="RG15210ST-10">10</A>

A solution of 3d (37.0 mg, 0.252 mmol, 1 equiv) and 11a (100 mg, 0.505 mmol, 2 equiv) in CHCl₃ (1 mL) was left at r.t. for 5 d. After concentration in vacuo, the crude material was purified by flash column chromatography (silica gel, eluent Et₂O-PE = 1:5) to afford compound 13a (35 mg, 0.102 mmol, 40%) as a yellow oil (R _f  = 0.13).
Methyl 3-Chloro-1-phenyl-4-oxo-2-phenyl-piperidine-3-carboxylate (13a)
^¹H NMR (200 MHz, CDCl₃): δ = 2.81-3.00 (m, 1 H, CH₂), 3.02-3.23 (m, 2 H, CH₂), 3.31-3.43 (m, 1 H, CH₂), 3.94 (s, 3 H, CO₂CH₃), 5.94 (s, 1 H, CH), 6.80-6.89 (m, 2 H, PhH), 6.92-7.05 (m, 4 H, PhH), 7.05-7.36 (m, 4 H, PhH). ^¹³C NMR (50 MHz, CDCl₃): δ = 39.9 (t), 41.5 (t), 54.0 (q, OCH₃), 72.1 (d, CHN), 73.1 (s, CCl), 119.0 (d, 2 C, Ph), 121.8 (d, Ph), 127.8 (d, 2 C, Ph), 128.0 (d, Ph), 128.4 (d, 2 C, Ph), 128.9 (d, 2 C, Ph), 131.3 (s, Ph), 149.0 (s, NPh), 167.4 (s, CO₂Me), 197.7 (s, C=O). Anal. Calcd for C₁₉H₁₈ClNO₃: N, 4.07; C, 66.38; H, 5.28. Found: N, 4.32; C, 66.20; H, 5.66.

<A NAME="RG15210ST-11">11</A>

Representative Procedure
A solution of 3e (44.0 mg, 0.254 mmol, 1 equiv) and 11a (100 mg, 0.507 mmol, 2 equiv) in DCE (1 mL) was heated at 80 ˚C for 3.5 h. After concentration in vacuo, the crude material was purified by flash column chromatography (silica gel, eluent Et₂O-PE = 1:5) to afford 14a (28 mg, 0.076 mmol, 30%) as a brown oil (R _f  = 0.29) and 15a (30 mg, 0.090 mmol, 36%) brown oil (R _f  = 0.18).
Methyl 7-Chloro-6-phenyl-8-oxo-5-phenyl-5-azaspiro[2.5]octane-7-carboxylate (14a): mixture of two diastereomers.
Diastereomer 14ax: ^¹H NMR (400 MHz, CDCl₃): δ = 0.89-0.95 (m, 1 H, c-PrH), 1.15-1.22 (m, 1 H, c-PrH), 1.70-1.73 (m, 2 H, c-PrH), 3.40 (d, ^² J = 12.0 Hz, 1 H, CH₂), 3.50 (s, 3 H, OCH₃), 3.89 (d, ^² J = 12.0 Hz, 1 H, CH₂), 5.40 (s, 1 H, CH), 6.76-7.43 (m, 10 H, Ph).
Diastereomer 14ay: ^¹H NMR (400 MHz, CDCl₃): δ = 0.89-0.95 (m, 1 H, c-PrH), 1.15-1.22 (m, 1 H, c-PrH), 1.47-1.51 (m, 1 H, c-PrH), 1.90-1.95 (m, 1 H, c-PrH), 3.10 (dd, ^² J = 12.0 Hz, ⁴ J = 0.8 Hz, 1 H, CH₂), 3.33 (dd, ^² J = 12.0 Hz, ⁴ J = 0.8 Hz, 1 H, CH₂), 3.88 (s, 3 H, OCH₃), 5.91 (d, J = 0.8 Hz, 1 H, CH), 7.60-7.43 (m, 10 H, PhH).
Diastereomers 14ax,ay: ^¹³C NMR (100 MHz, CDCl₃): δ = 16.8, 20.7, 22.1, 24.9, 26.9, 28.5, 49.9, 51.0, 52.9, 53.8, 71.5, 72.8, 115.1, 116.7, 119.4, 120.6, 122.4, 124.7, 127.7, 127.9, 128.1, 128.2, 128.3, 128.8, 128.9, 129.2, 132.5, 136.2, 148.7, 162.9, 167.2, 198.4. Anal. Calcd for C₂₁H₂₀ClNO₃: N, 3.79; C, 68.20; H, 5.45. Found: N, 4.20; C, 68.13; H, 5.77.


Methyl 6-Phenyl-4-oxo-5-phenyl-5-azaspiro[2.5]oct-6-ene-7-carboxylate (15a) ^¹H NMR (400 MHz, CDCl₃): δ = 0.42-0.59 (m, 2 H, CH₂), 0.93-1.09 (m, 2 H, CH₂), 1.21-1.30 (m, 2 H, CH₂), 3.79 (s, 3 H, OCH₃), 7.08-7.50 (m, 10 H, Ph). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.1 (t), 20.8 (t, 2 C, c-Pr), 21.4 (s, c-Pr), 52.7 (q, OCH₃), 76.9 (s, CCO₂Me), 126.5 (d, Ph), 127.2 (d, Ph), 127.7 (d, Ph), 128.5 (d, Ph), 129.2 (d, Ph), 129.5 (d, Ph), 134.7 (s, Ph), 140.9 (s, NPh), 146.4 (s, CPh), 163.2 (s, CO₂Me), 175.7 (s, C=O). Anal. Calcd for C₂₁H₁₉NO₃: N, 4.20; C, 75.66; H, 5.74. Found: N, 4.38; C, 75.26; H, 6.01.

<A NAME="RG15210ST-12A">12a</A> de Meijere A. Weitemeyer C. Schallner O. Spielmann W. Chem. Ber.  1979,  112:  908 

<A NAME="RG15210ST-12B">12b</A> de Meijere A. Angew. Chem., Int. Ed. Engl.  1979,  18:  809 ; and references cited therein