A Novel Protocol for Selective Construction of Morpholin-2-one and Morpholin-3-one Heterocycles from Aminoethanol with Divinyl Fumarate

Abstract

A simple and efficient method for selective construction of morphlin-2-one and morphlin-3-one heterocyclic derivatives has been developed from N-substituted aminoethanols and divinyl fumarate. The selectivity of this catalyst-free reaction was easily controlled by different solvents.

Key words

aminoethanol - divinyl fumarate - catalyst-free - selectivity - morpholinone

References and Notes

• 1a Nilsson JW. Kvarnström I. Musil D. Nilsson I. Samulesson B. J. Med. Chem.  2003,  46:  3985 
• 1b Wijtmans R. Vink MKS. Schoemaker HE. van Deilt FL. Blaauw RH. Synthesis  2004,  641 
• 1c Couladours EA. Moutsos VI. Pitsinos EN. Tetrahedron Lett.  2004,  45:  7779 
• 2 Drew MGB. Harwood LM. Park G. Price DW. Tyler SNG. Park CR. Cho SGL. Tetrahedron  2001,  57:  5641 
• 3 Shikre BA. Deshmukh ARAS. Tetrahedron: Asymmetry  2004,  15:  1081 
• 4a Nakamura M. Miyashita H. Yamaguchi M. Shirasaki Y. Nakamura Y. Inoue J. Bioorg. Med. Chem.  2003,  11:  5449 
• 4b Dahlgren A. Johansson P. Kvarnstrom I. Musil D. Nilsson I. Samuelsson B. Bioorg. Med. Chem.  2002,  10:  1829 
• 5a Brener E. Baldwin RM. Tamagnan G. Org. Lett.  2005,  7:  937 
• 5b Tan W. Zhao BX. Shi M. Aha L. Miao JY. Shiin DS. Chin. J. Chem.  2006,  24:  396 
• 6 Zhao MM. McNamara JM. Ho GJ. Emerson KM. Song ZG. Tschaen DM. Brands KMJ. Dolling UH. Grabowski EJ. Reider PJ. J. Org. Chem.  2002,  67:  6743 
• 7 Dahlgren A. Johansson PO. Kvarnstrom I. Musil D. Nilsson I. Samuelsson B. Bioorg. Med. Chem.  2002,  10:  1829 
• 8a Yang T. Aampbell L. Dixon D. J. Am. Chem. Soc.  2007,  129:  12070 
• 8b Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 
• 8c Tietze LF. Chem. Rev.  1996,  96:  115 
• 8d Lu X. Zhang C. Xu Z. Acc. Chem. Res.  2001,  34:  535 
• 8e Methot JL. Roush WR. Adv. Synth. Catal.  2004,  346:  1035 
• 8f Lu XY. Du YS. Lu C. Pure Appl. Chem.  2005,  77:  1985 
• 8g Valentine DH. Hillhouse JH. Synthesis  2003,  317 
• 9a Layer RW. Chem. Rev.  1963,  63:  489 
• 9b Haury VE. US 2,421,937;  Chem. Abstr. 1947,  41, 5892 
• 9c Anderson JC. Chapman HA. Org. Biomol. Chem.  2007,  5:  2413 
• 9d Christoph G. Stratmann C. Coldham I. Hoppe D. Org. Lett.  2006,  20:  4469 

10

Supplementary information can be obtained from the corresponding author upon request.

11

Typical Procedure for the Synthesis of Morpholin-3-one
Benzylethanolamine (0.75 g, 0.05 mol) was dissolved in MTBE and the divinyl fumarate (1.68 g, 0.1 mol) was added. The reaction mixture stirred at 50 °C and monitored by TLC. Upon completion of the reaction, the combined solvents were removed under reduced pressure to give a yellow oil which was purified by column chromatography (hexane-EtOAc = 3:1) to give the product. ¹H NMR (500 MHz, CDCl₃): δ = 7.26-7.36 (m, 6 H), 4.89 (dd, 1 H, J = 1.50, 12.40 Hz), 4.76 (d, 1 H, J = 14.65 Hz), 4.56 (m, overlapped, 2 H), 4.50 (d, 1 H, J = 14.65 Hz), 3.99 (m, 1 H), 3.79 (m, overlapped, 1 H), 3.52 (d, 1 H, J = 4.25 Hz), 3.12 (m, 2 H), 3.02 (m, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 168.05, 168.02, 141.34, 136.31, 129.03, 128.51, 128.02, 98.30, 74.38, 63.42, 50.20, 46.08, 37.35 ppm. IR (neat): 1751 (C=O), 1647 (C=C) cm^-1. ESI-MS: m/z = 275.8 [M + H]⁺. HRMS: m/z calculated for C₁₅H₁₇NO₄: 275.1158; found: 275.1154.