Catalytic Carbonylation of 3-Bromomethyl-5,6-dihydro-4H-1,2-oxazines: General Approach to the Synthesis of 3-Methoxycarbonylmethyl-5,6-dihydro-4H-1,2-oxazines from Available Precursors

Abstract

A general approach to the stereoselective synthesis of previously unknown 5,6-dihydro-4H-1,2-oxazine-3-yl acetates by catalytic carbonylation of available 3-bromomethyl-5,6-dihydro-4H-1,2-oxazines is elaborated.

1,2-oxazines - carbonylations - palladium

References and Notes

1 Klenov MS. Lesiv AV. Khomutova YA. Nesterov ID. Ioffe SL. Synthesis  2004,  1159 

2 Cotel G. Denmark SE. Nitronates In The Chemistry of Heterocyclic Compounds   Vol. 59:  Pawda A. Pearson WH. J. Wiley & Sons Inc.; New York: 2002.  p.83-167  

3 Lapidus AL. Eliseev OL. Bondarenko TN. Sizan OE. Ostapenko AG. Beletskaya IP. Synthesis  2002,  317 

4

Compounds 2; General Procedure
Bromide 1 (1.0 mmol), Et₃N (1.5 mmol), Pd(PPh₃)₂Cl₂ (0.01 mmol), and MeOH (10 mL) were placed in a stainless steel reactor equipped with a Hastelloy^® liner and magnetic stirrer. The reactor was flushed with CO, pressurized (15 bar), and heated to 100 °C with stirring for 3 h. The resulting mixture was evaporated under reduced pressure, treated with an aq solution of NaHSO₄ (2 mmol) and extracted with Et₂O (3 × 15 mL). The combined extracts were washed with brine (10 mL), dried (Na₂SO₄), and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (Table [1] ).
Methyl [4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihydro-4 H -1,2-oxazin-3-yl]acetate (2a)
Oil; R _f 0.56 (silica gel; hexane-EtOAc, 1:1, UV). ¹H NMR (300.13 MHz, CDCl₃): δ = 1.36 (s, 6 H, 2 Me), 1.89 (dd, J = 11.8, 13.8 Hz, 1 H, CH₂), 2.06 (dd, J = 7.9, 13.8 Hz, 1 H, CH₂), 2.95 (d, J = 17.1 Hz, 1 H, CH ₂CO₂Me), 3.19 (d, J = 17.1 Hz, 1 H, CH ₂ CO₂Me), 3.64 (s, 3 H, CO₂Me), 3.66 (dd, J = 7.9, 11.8 Hz, 1 H, CH), 3.80 (s, 3 H, OMe), 6.87 (d, J = 8.5 Hz, 2 H, Ph), 7.06 (d, J = 8.5 Hz, 2 H, Ph). ¹³C NMR (CDCl₃): δ = 22.6 and 28.4 (2 × Me), 38.5 and 38.7 (2 × CH₂), 40.5 (CH), 52.0 (CO₂ CH₃), 55.3 (OMe), 75.0 (CON), 114.6 (Ph-CH), 129.4 (Ph-CH), 131. 8 (Ph-C), 153.9 (C=NO), 158.9 (COMe), 170.6 (CO₂Me). Anal. Calcd for C₁₆H₂₁NO₄: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.20; H, 7.35; N, 4.75.

5 Hesse M. Meier H. Zeeh B. Spektroskopische Methoden in der Organischen Chemie   Thieme; Stuttgart: 1995.  p.108 

6 Lambert JB. Takeuchi Y. Cyclic Organonitrogen Stereodynamics   VCH; New York: 1992.  p.170 

7 Juaristi E. Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1996. 

A few successful attempts to prepare α-amino acids from 3-methoxycarbonyl-5,6-dihydro-4H-1,2-oxazines and β-amino acids from 4-methoxycarbonyl-5,6-dihydro-4H-1,2-oxazines were reported previously, see:

8a Chrystal EJT. Gilchrist TL. Stretch W. J. Chem. Res., Synop.  1987,  180 

8b Henning R. Lerch U. Urbach H. Synthesis  1989,  265 

8c Tishkov AA. Reissig H.-U. Ioffe SL. Synlett  2002,  863