Direct Synthesis of α-Amino Amides from N-Alkyl Amines by the Copper-Catalyzed Oxidative Ugi-Type Reaction

Abstract

α-Amino amides can be accessed directly form N-alkyl amines by the isocyanide-compatible oxidative copper-peroxide conditions even in the presence of water. Various functional groups are tolerated in the reaction, leading to the synthesis of various α-amino amides in moderate yield. A plausible mechanism is proposed in which an oxidative Ugi-type three-component pathway is supposed to be involved.

α-amino amide - isocyanide - Ugi reaction - copper catalysis - multicomponent reaction

References and Notes

<A NAME="RW57711ST-1A">1a</A> Dolle RE. Mol. Diversity  1998,  3:  199 

<A NAME="RW57711ST-1B">1b</A> Weber L. Curr. Med. Chem.  2002,  9:  2085 

<A NAME="RW57711ST-1C">1c</A> Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 

<A NAME="RW57711ST-1D">1d</A> Sexton KE. Lee HT. Massa M. Padia J. Patt WC. Liao P. Pontrello JK. Roth BD. Spahr MA. Ramharack R. Bioorg. Med. Chem.  2003,  11:  4827 

<A NAME="RW57711ST-1E">1e</A> Beguin C. LeTiran A. Stables JP. Voyksnerc RD. Kohn H. Bioorg. Med. Chem.  2004,  12:  3079 

<A NAME="RW57711ST-2A">2a</A> Iden HS. Lubell WD. J. Comb. Chem.  2008,  10:  691 

<A NAME="RW57711ST-2B">2b</A> Cuny G. Bois-Choussy M. Zhu JP. J. Am. Chem. Soc.  2004,  126:  14475 

<A NAME="RW57711ST-2C">2c</A> Erb W. Neuville L. Zhu JP. J. Org. Chem.  2009,  74:  3109 

<A NAME="RW57711ST-3A">3a</A> Porter JR. Wirschun WG. Kuntz KW. Snapper ML. Hoveyda AH. J. Am. Chem. Soc.  2000,  122:  2657 

<A NAME="RW57711ST-3B">3b</A> Takamura M. Hamashima Y. Usuda H. Kanai M. Shibasaki M. Angew. Chem. Int. Ed.  2000,  39:  1650 

<A NAME="RW57711ST-3C">3c</A> Lin YS. Alper H. Angew. Chem. Int. Ed.  2001,  40:  779 

<A NAME="RW57711ST-3D">3d</A> Wang MX. Lin SJ. J. Org. Chem.  2002,  67:  6542 

<A NAME="RW57711ST-3E">3e</A> Alcaide B. Almendros P. Aragoncillo C. Chem. Eur. J.  2002,  8:  3646 

<A NAME="RW57711ST-3F">3f</A> Ntaganda R. Milovic T. Tiburcioz J. Thadani AN. Chem. Commun.  2008,  4052 

<A NAME="RW57711ST-3G">3g</A> Loser R. Frizler M. Schilling K. Gutschow M. Angew. Chem. Int. Ed.  2008,  47:  4331 

<A NAME="RW57711ST-3H">3h</A> Noorduin WL. Izumi T. Millemaggi A. Leeman M. Meekers H. Van Enckevort WJP. Kellogg RM. Kaptein B. Vlieg E. Blackmond DG. J. Am. Chem. Soc.  2008,  130:  1158 

<A NAME="RW57711ST-3I">3i</A> Hirner S. Somfai P. J. Org. Chem.  2009,  74:  7798 

<A NAME="RW57711ST-4A">4a</A> Domling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

<A NAME="RW57711ST-4B">4b</A> Dömling A. Chem. Rev.  2006,  106:  17 

<A NAME="RW57711ST-4C">4c</A> El Kaim L. Grimaud L. Tetrahedron  2009,  65:  2153 

<A NAME="RW57711ST-4D">4d</A> Lygin AV. Meijere A. Angew. Chem. Int. Ed.  2010,  49:  9094 

<A NAME="RW57711ST-5A">5a</A> Henriques A. Kan C. Chiaroni A. Riche C. Husson HP. J. Org. Chem.  1982,  47:  803 

<A NAME="RW57711ST-5B">5b</A> Han-ya Y. Tokuyama H. Fukuyama T. Angew. Chem. Int. Ed.  2011,  50:  4884 

<A NAME="RW57711ST-6">6</A> Tanaka Y. Hasui T. Suginome M. Org. Lett.  2007,  9:  4407 

<A NAME="RW57711ST-7A">7a</A> Li CJ. Acc. Chem. Res.  2009,  42:  335 

<A NAME="RW57711ST-7B">7b</A> Murahashi S.-I. Komiya N. Terai H. Angew. Chem. Int. Ed.  2005,  44:  6931 

<A NAME="RW57711ST-7C">7c</A> Rajendra PD. Subbarayappa A. Adv. Synth. Catal.  2011,  353:  1695 

<A NAME="RW57711ST-7D">7d</A> Nicolaou KC. Mathison CJN. Montagnon T. Angew. Chem. Int. Ed.  2003,  42:  4077 

<A NAME="RW57711ST-7E">7e</A> Nicolaou KC. Mathison CJN. Montagnon T. J. Am. Chem. Soc.  2004,  126:  5192 

<A NAME="RW57711ST-8A">8a</A> Ngouansavanh T. Zhu JP. Angew. Chem. Int. Ed.  2007,  46:  5775 

<A NAME="RW57711ST-8B">8b</A> Jiang GX. Chen J. Huang JS. Che CM. Org. Lett.  2009,  11:  4568 

<A NAME="RW57711ST-9A">9a</A> Brioche J. Masson G. Zhu JP. Org. Lett.  2010,  12:  1432 

<A NAME="RW57711ST-9B">9b</A> Feuer H. Rubinstein H. Nielsen AT. J. Org. Chem.  1958,  23:  1107 

<A NAME="RW57711ST-9C">9c</A> Saegusa T. Kobayashi S. Ito Y. Bull. Chem. Soc. Jpn.  1970,  43:  275 

<A NAME="RW57711ST-10A">10a</A> Saegusa T. Ito Y. Kobayashi S. Hirota K. Takeda N. Can. J. Chem.  1969,  47:  1217 

<A NAME="RW57711ST-10B">10b</A> Saegusa T. Ito Y. Kobayashi S. Takeda N. Hirota K. Tetrahedron Lett.  1967,  8:  521 

<A NAME="RW57711ST-10C">10c</A> Saegusa T. Ito Y. Kobayashi S. Takeda N. Hirota K. Tetrahedron Lett.  1967,  8:  1273 

<A NAME="RW57711ST-11">11</A> Ye X. Xie CS. Pan YY. Han LH. Xie T. Org. Lett.  2010,  12:  4240 

<A NAME="RW57711ST-12A">12a</A> Ley SV. Thomas AW. Angew. Chem. Int. Ed.  2003,  42:  5400 

<A NAME="RW57711ST-12B">12b</A> Evano G. Blanchard N. Toumi M. Chem. Rev.  2008,  108:  3054 

<A NAME="RW57711ST-13A">13a</A> Boess E. Sureshkumar D. Sud A. Wirtz C. Fares C. Klussmann M. J. Am. Chem. Soc.  2011,  133:  8106 

<A NAME="RW57711ST-13B">13b</A> Li Z. Bohle S. Li C.-J. Proc. Natl. Acad. Sci. U.S.A.  2006,  103:  8928 

<A NAME="RW57711ST-13C">13c</A> Ghobrial M. Schnurch M. Mihovilovic MD. J. Org. Chem.  2011,  76:  8781 

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Representative Procedure for the Three-Component Reaction
Into an oven-dried flask, N,N-dimethylaniline (1a, 242 mg, 2.0 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (2a, 195 mg, 1.0 mmol), CuCl (10 mg, 0.1 mmol), Ph₃P (26 mg, 0.1 mmol), and TBHP (70% aq, 2.4 mmol) were added at r.t.. Under the protection of N₂, MeCN (5 mL) was added, and the reaction mixture was allowed to react at 80 ˚C for 6 h. After the end of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated until the solvent was completely removed. The residue was then separated on a silica gel column, and the final product was obtained as a yellow powder (190 mg, 57%). ^¹H NMR (400 MHz, CDCl₃, TMS): δ = 7.72 (d, J = 8.8 Hz, 2 H), 7.29-7.35 (m, 3 H), 7.27 (m, 1 H), 6.89 (t, J = 7.4 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 2 H), 4.69 (d, J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 2.99 (s, 3 H), 2.46 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.4, 149.0, 145.6, 133.7, 130.0, 129.5, 128.9, 119.3, 113.4, 59.8, 58.6, 40.1, 21.8. HRMS (EI): m/z calcd for C₁₇H₂₀N₂O₃S [M]⁺: 332.1195; found: 332.1186.