Facile Synthesis of ortho-Halo-Substituted 4-Aryl-2-Aminobutyric Acids

Abstract

Herein we describe an efficient and practical route for the regioselective synthesis of 4-(5-bromo/chloropyrazol-1-yl)-2-aminobutyric acids. The compounds have been prepared by regioselective C-5 halogenation of 1-(3,3-dimethoxypropyl)-1H-pyrazole followed by a Strecker synthesis. In addition, Boc-protected 2-amino-4-(2-chlorophenyl)butyric acid and 2-amino-4-(3-chloropyridin-2-yl)butyric acid have been synthesized.

amino acids - 1-alkyl-5-halopyrazole - Strecker synthesis - Heck reaction - Grignard reaction

References

<A NAME="RM07707SS-1A">1a</A> Evans DA. Britton TC. Ellman JA. Dorow RL. J. Am. Chem. Soc.  1990,  112:  4011 

<A NAME="RM07707SS-1B">1b</A> Adlington RM. Baldwin JE. Catterick D. Pritchard GJ. J. Chem. Soc., Chem. Commun.  1997,  1757 

<A NAME="RM07707SS-1C">1c</A> Adlington RM. Baldwin JE. Catterick D. Pritchard GJ. J. Chem. Soc., Perkin Trans. 1  2001,  668 

<A NAME="RM07707SS-1D">1d</A> Anastasia L. Anastasia M. Allevi P. J. Chem. Soc., Perkin Trans. 1  2001,  2404 

<A NAME="RM07707SS-1E">1e</A> Taggi AE. Hafez AM. Lectka T. Acc. Chem. Res.  2003,  36:  10 

<A NAME="RM07707SS-1F">1f</A> Krebs A. Ludwig V. Pfizer J. Dürner G. Göbel MW. Chem. Eur. J.  2004,  10:  544 

<A NAME="RM07707SS-1G">1g</A> Duthaler RO. Tetrahedron  1994,  50:  1539 

<A NAME="RM07707SS-1H">1h</A> Sardina FJ. Rapoport H. Chem. Rev.  1996,  96:  1825 

<A NAME="RM07707SS-2A">2a</A> Behr LC. Fusco R. Jarboe CH. In Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings   Interscience; New York: 1967.  p.6-8 and 13-16  

<A NAME="RM07707SS-2B">2b</A> Jacobs TL. In Heterocyclic Compounds   Vol. 5:  Elderfield RC. Wiley; New York: 1957.  p.55 

<A NAME="RM07707SS-2C">2c</A> Habraken CL. Moore JA. J. Org. Chem.  1965,  30:  1892 

<A NAME="RM07707SS-3">3</A> Eskildsen J. Vedsø P. Begtrup M. Synthesis  2001,  1053 

<A NAME="RM07707SS-4A">4a</A> Effenberger F. Krebs A. J. Org. Chem.  1984,  49:  4687 

<A NAME="RM07707SS-4B">4b</A> Butler DE. Alexander SM. J. Org. Chem.  1972,  37:  215 

<A NAME="RM07707SS-5">5</A> For acetal cleavage with HClO₄, see: Heath RR. Doolittle RE. Sonnet PE. Tumlinson JH. J. Org. Chem.  1980,  45:  2910 

<A NAME="RM07707SS-6">6</A> For synthesis of α-aminonotriles, see: Mai K. Patil G. Tetrahedron Lett.  1984,  25:  4583 

<A NAME="RM07707SS-7">7</A> A synthesis of 17 with Br instead of Cl has been reported using a Pd-catalyzed coupling of an amino-functionalized organozinc reagent with 2-bromoiodobenzene: Deboves HJC. Hunter C. Jackson RFW. J. Chem. Soc., Perkin Trans. 1  2002,  733 

<A NAME="RM07707SS-8">8</A> Jeffrey T. J. Chem. Soc., Chem. Commun.  1984,  1287 

<A NAME="RM07707SS-9">9</A> Bell TW. Hu L.-Y. Patel SV. J. Org. Chem.  1987,  52:  3847