Efficient Synthesis of α-Chloro Ketones via Reaction of Organometallic Reagents with N-Methoxy-N-Methylchloroacetamide

Synlett

Volumn 1996, Issue 3, 1996, Pages 225-226

  Tillyer, R ^a   Frey, L F ^a   Tschaen, D M ^a   Dolling, U H ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

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Indexed keywords

EID: 0001798464     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1996-5388     Document Type: Article

References (14)

1. 3-chloroacetyl chloride is not (<40% yield, 3:1 para:ortho). The situation was not improved by variation of Lewis acid, solvent, or by the use of other chloroacetic acid derivatives.
2. 2.
3. For a review of this reaction see O'Neill, B. T., in 'Comprehensive Organic Synthesis', ed. Trost, B. M., Pergamon Press, 1991, Volume 1, 397.
4. The best reported procedures for acylation of chloroacetyl chloride involve a) organomanganese reagents. Friour G.; Cahiez G.; Normant J. F. Synthesis 37 1984; b) organovanadium reagents. Hirao T.; Misu D.; Yao K.; Agawa T. Tetrahedron Lett. 929, 1986.
5. The best reported procedures for acylation of chloroacetyl chloride involve a) organomanganese reagents. Friour G.; Cahiez G.; Normant J. F. Synthesis 37 1984; b) organovanadium reagents. Hirao T.; Misu D.; Yao K.; Agawa T. Tetrahedron Lett. 929, 1986.
6. Nahm S.; Weinreb S. M. Tetrahedron Lett., 22, 3815, 1981.
7. Sibi M. K. Org. Prep. Proc. Int., 25, 15, 1993.
8. 2) of N,O-dimethylhydroxylamine hydrochloride with chloroacetyl chloride. See Nuzillard J.-M.; Boumendjel G.; Massiot G. Tetrahedron Lett., 30, 3779, 1989. This paper describes the conversion of amide 3 into the corresponding Homer-Emmons reagent for use in the synthesis of α,β-unsaturated aldehydes. For use of 3 in the synthesis of α,β-unsaturated ketones see Evans D. A.; Kaldor S. W.; Jones T. K.; Clardy J.; Stout T. J. J. Am. Chem. Soc., 112, 7001, 1990.
9. 2) of N,O-dimethylhydroxylamine hydrochloride with chloroacetyl chloride. See Nuzillard J.-M.; Boumendjel G.; Massiot G. Tetrahedron Lett., 30, 3779, 1989. This paper describes the conversion of amide 3 into the corresponding Homer-Emmons reagent for use in the synthesis of α,β-unsaturated aldehydes. For use of 3 in the synthesis of α,β-unsaturated ketones see Evans D. A.; Kaldor S. W.; Jones T. K.; Clardy J.; Stout T. J. J. Am. Chem. Soc., 112, 7001, 1990.
10. 2O (250 mL) was added, successively, N,O-dimethylhydroxylamine hydrochloride (20 g, 205 mmol) and organic solvent (250 mL, toluene or MTBE). The mixture was cooled to -5°C and chloroacetyl chloride (19.6 ml, 246 mmol) was added over 5 min (temperature maintained <0°C). The vigorously stirred mixture was allowed to warm to 25°C over 30 min, the layers were separated, and the aqueous layer was extracted with organic solvent (3×100 mL, toluene or MTBE). The combined organic extracts were concentrated (MTBE used as solvent) to give the amide 3b (26.8 g, 95%) as a white solid. Alternatively, the combined organic extracts (toluene used as solvent) were concentrated to 250 mL to effect azeotropic drying (water content 100 μg/mL) and the solution of 3b was used directly in reactions with organometallic reagents.
11. Yield determined by quantitative HPLC analysis of the organic layer after workup, compared to a standard solution of chromatographed ketone 1.
12. Low level (<2%) by-products from formation of the Grignard reagent included the corresponding phenol (oxidation) and biaryl (homocoupling). The former was significantly reduced by degassing the reaction solvent and the HCl used for quench.
13. 3, 75 MHz) δ 14.7, 45.8, 125.1, 129.0, 130.4, 147.5, 190.2.
14. In most cases the crude products were sufficiently pure to be used for subsequent reactions without further purification.