N-Amino-N-methylmorpholinium Salts: Highly Active Aziridination Reagents for Chalcones

Abstract

A highly effective aziridination reagent, based on N-­methylmorpholine, is reported which effects rapid conversion of chalcones to N-unfunctionalised aziridines at room temperature.

aziridine - hydrazinium salts - chalcone - aminimine

References and Notes

<A NAME="RD15006ST-1">1</A>

Current address: Department of Chemistry, University of Bath, Bath BA2 7AY, UK.

<A NAME="RD15006ST-2">2</A> Sweeney JB. Chem. Soc. Rev.  2002,  31:  247 

<A NAME="RD15006ST-3">3</A> For a review of aziridine opening, see: Hu XE. Tetrahedron  2004,  60:  2701 

<A NAME="RD15006ST-4">4</A> McCoull W. Davis FA. Synthesis  2000,  1347 

For reviews on aziridine synthesis, see:

<A NAME="RD15006ST-5A">5a</A> Halfen JA. Curr. Org. Chem.  2005,  9:  657 

<A NAME="RD15006ST-5B">5b</A> Muller P. Fruit C. Chem. Rev.  2003,  103:  2905 

<A NAME="RD15006ST-5C">5c</A> Osborn HMI. Sweeney J. Tetrahedron: Asymmetry  1997,  8:  1693 

<A NAME="RD15006ST-6">6</A> For a two-step asymmetric aziridination of chalcones using chiral rare-earth-metal-catalysed Michael addition of hydroxylamines, see: Jin XL. Sugihara H. Daikai K. Tateishi H. Jin YZ. Furuno H. Inanaga J. Tetrahedron  2002,  58:  8321 

<A NAME="RD15006ST-7">7</A> Sugihara H. Daikai K. Jin XL. Furuno H. Inanaga J. Tetrahedron Lett.  2002,  43:  2735 

Recent examples of asymmetric chalcone aziridination:

<A NAME="RD15006ST-8A">8a</A> Ma LG. Jiao P. Zhang QH. Xu JX. Tetrahedron: Asymmetry  2005,  16:  3718 

<A NAME="RD15006ST-8B">8b</A> Ma LG. Du DM. Xu JX. J. Org. Chem.  2005,  70:  10155 

<A NAME="RD15006ST-8C">8c</A> Xu JX. Ma LG. Jiao P. Chem. Commun.  2004,  1616 

<A NAME="RD15006ST-9">9</A> Xu J. Jiao P. J. Chem. Soc., Perkin Trans. 1  2002,  1491 

<A NAME="RD15006ST-10">10</A> Ikeda I. Machii Y. Okahara M. Synthesis  1980,  650 

<A NAME="RD15006ST-11">11</A> Appel R. Heinen H. Schollhorn R. Chem. Ber.  1966,  99:  3118 

<A NAME="RD15006ST-12">12</A> Donskaya OV. Elokhina VN. Nakhmanovich AS. Vakul’skaya TI. Larina LI. Vokin AI. Albanov AI. Lopyrev VA. Tetrahedron Lett.  2002,  43:  6613 

<A NAME="RD15006ST-13">13</A>

Compound 2a: Ba(NO₃)₂ (10.3 g, 40 mmol), Ba(OH)₂ (12.5 g, 40 mmol) and N-methyl morpholine (4.4 mL, 40 mmol) were added to H₂O (60 mL) to give a turbid white mixture. This was added in 2-mL portions to a solution of hydroxylamine-O-sulfonic acid (5.6 g, 50 mmol) in H₂O (50 mL) to give a white precipitate immediately. The mixture was then heated at reflux for 18 h. The white precipitate was filtered off and the filtrate was concentrated under reduced pressure leaving a white crystalline solid. This solid was then recrystallised (H₂O) to give the hydrazinium nitrate salt 2a (7.13 g, 99%) as a white solid. ¹H NMR (400 MHz, DMSO): δ = 5.96 (2 H, br, NH₂), 3.99-3.93 (2 H, m, OCH₂), 3.87-3.82 (2 H, m, OCH₂), 3.59-3.53 (2 H, m, NCH₂), 3.44-3.52 (2 H, m, NCH₂), 3.33 (3 H, s, NCH₃). ¹³C NMR (100 MHz, DMSO): δ = 62.2 (CH₂), 60.4 (CH₂), 56.6 (CH₃).
Compound 2b: To a solution of N-aminomorpholine (8.9 mL, 92 mmol, 1.0 equiv) in THF (60 mL) at 0 °C was added neat MeI (6.0 mL, 96 mmol, 1.05 equiv) dropwise over 5 min. During this time, a white precipitate was observed to form and after completion of the addition of MeI, the reaction mixture was warmed to r.t. for 30 min. Et₂O (100 mL) was added and the white solid was isolated by filtration and subsequently washed with Et₂O (4 ×). The morpholinium iodide salt 2b (17.18 g, 77%) was isolated as a white powder which was recrystallised from hot EtOH-MeOH (3:1) to give clear plates. ¹H NMR (400 MHz, DMSO): δ = 5.97 (2 H, s, NH₂), 3.96 (2 H, ddd, J = 13.2, 9.2, 3.9 Hz, CH₂), 3.86 (2 H, dt, J = 12.8, 3.2 Hz, CH₂), 3.60 (2 H, ddd, J = 12.8, 9.2, 3.2 Hz, CH₂), 3.48 (2 H, br d, J = 12.4 Hz, CH₂), 3.41 (3 H, s, CH₃). ¹³C NMR (100 MHz, DMSO): δ = 62.4, 60.1, 56.4.
Aziridination of E -Chalcones; General ProcedureMethod A: Chalcone (0.20 g, 0.96 mmol) and morpholinium iodide 2b (0.24 g, 1.05 mmol, 1.1 equiv) were dissolved in DMSO (10 mL) at r.t. To this solution was added solid t-BuOK (0.12 g, 1.07 mmol, 1.1 equiv) in 10 portions over 1 min. During this addition a bright red colour forms. After 5 min, H₂O (50 mL) and Et₂O (50 mL) were added. The reaction was extracted with Et₂O (100 mL) and washed with H₂O (2 × 100 mL) and brine (50 mL). The organic layer was dried over MgSO₄, filtered and the solvent removed in vacuo. The crude product was further purified on silica gel (PE-Et₂O, 4:1) to give the aziridine (0.13 g, 61%) as a fine white solid; mp 100-101 °C. IR (KBr): 3268 (NH), 1668 (C=O) cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.00-7.20 (10 H, m, Ar), 3.52 (1 H, dd, J = 7.9, 2.4 Hz), 3.18 (1 H, dd, J = 9.2, 2.4 Hz), 2.68 (1 H, t, J = 8.5, NH). MS (CI): m/z (%) = 224 (M + H, 100).
Method B: N-Methyl-N-aminomorpholinium nitrate (2a, 0.17 g, 0.96 mmol) and NaOH (0.04 g, 0.96 mmol) were added to MeCN (4 mL) and the resulting solution was stirred at r.t. for 30 min. Chalcone (0.10 g, 0.48 mmol) was then added and the mixture was stirred for a further 3 h. The reaction was then quenched with a sat. solution of NH₄Cl (20 mL) and extracted with toluene (3 × 20 mL). The organic layers were then washed with a sat. solution of NH₄Cl (20 mL), dried over Na₂SO₄ and the solvent was removed in vacuo. The crude product was further purified on silica gel (PE-Et₂O, 4:1) to give the aziridine (0.10 g, 95%); data as above.
NMR data for aziridine products in Table entries 1, 2, 4-9,⁹ 10, 11,⁶ and 14-17⁹ corresponded to those in the literature. Other aziridines also gave satisfactory spectroscopic data in accord with their assigned structures.
Caution. While no problems were encountered during our work, hydrazinium salts should be considered as potentially hazardous and should be handled with appropriate pre-cautions. Differential scanning calorimetry studies indicated an exotherm for iodide salt 2b at ca. 170 °C; no exotherm was noted for nitrate 2a at temperatures up to 300 °C.