Enamine-Based Domino Strategy for C-Acylation/Deacetylation of Acetoacetamides: A Practical Synthesis of β-Keto Amides

Abstract

A practical three-step route for C-acylation/deacetylation of acetoacetamides is described. Initial enamination of the acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which are acylated at the α-carbon with excellent selectivity. The C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole.

β-keto amide - enaminone - C-acylation - domino reaction - 1,3-dicarbonyl

References and Notes

<A NAME="RG06610ST-1A">1a</A> Zhou C.-Y. Che C.-M. J. Am. Chem. Soc.  2007,  129:  5828 

<A NAME="RG06610ST-1B">1b</A> Kumar K. Sai S. Gilbert TM. Klumpp DA. J. Org. Chem.  2007,  72:  9761 

<A NAME="RG06610ST-1C">1c</A> Bagley MC. Chapaneri K. Dale JW. Xiong X. Bower J. J. Org. Chem.  2005,  70:  1389 

<A NAME="RG06610ST-1D">1d</A> Lieby-Muller F. Constantieux T. Rodriguez J. J. Am. Chem. Soc.  2005,  127:  17176 

<A NAME="RG06610ST-1E">1e</A> Szczepankiewicz BG. Heathcock CH. J. Org. Chem.  1994,  59:  3512 

<A NAME="RG06610ST-1F">1f</A> Messeri T. Pentassuglia G. Di Fabio R. Tetrahedron Lett.  2001,  42:  3227 

<A NAME="RG06610ST-1G">1g</A> Cerreti A. D’Annibale A. Trogolo C. Umani F. Tetrahedron Lett.  2000,  41:  3261 

<A NAME="RG06610ST-2A">2a</A> Moya P. Castillo M. Primo-Yufera E. Couillaud F. Martinez-Manez R. Garcera M.-D. Miranda MA. Primo J. Martinez-Pardo R. J. Org. Chem.  1997,  62:  8544 

<A NAME="RG06610ST-2B">2b</A> Cantin A. Moya P. Castillo M. Primo J. Miranda MA. Primo-Yufera E. Eur. J. Org. Chem.  1999,  221 

<A NAME="RG06610ST-2C">2c</A> Moya P. Cantin A. Castillo M.-A. Primo J. Miranda MA. Primo-Yufera E. J. Org. Chem.  1998,  63:  8530 

<A NAME="RG06610ST-2D">2d</A> Muzaffar A. Brossi A. J. Nat. Prod.  1990,  53:  1021 

<A NAME="RG06610ST-3">3</A> Yip K.-T. Li J.-H. Lee O.-Y. Yang D. Org. Lett.  2005,  7:  5717 

<A NAME="RG06610ST-4A">4a</A> Kuzma PC. Brown LE. Harris TM. J. Org. Chem.  1984,  49:  2015 

<A NAME="RG06610ST-4B">4b</A> Chen Y. Sieburth SMcN. Synthesis  2002,  2191 

<A NAME="RG06610ST-4C">4c</A> Gotor V. Liz R. Testera AM. Tetrahedron  2004,  60:  607 

<A NAME="RG06610ST-5A">5a</A> Evans DA. Ennis MD. Le T. J. Am. Chem. Soc.  1984,  106:  1154 

<A NAME="RG06610ST-5B">5b</A> Kashima C. Fukuchi I. Takahashi K. Hosomi A. Tetrahedron  1996,  52:  10335 

<A NAME="RG06610ST-6A">6a</A> Hendi SB. Hendi MS. Wolfe JF. Synth. Commun.  1987,  17:  13 

<A NAME="RG06610ST-6B">6b</A> Groß AG. Deppe H. Schober A. Tetrahedron Lett.  2003,  44:  3939 

<A NAME="RG06610ST-7">7</A> Neo AG. Delgado J. Polo C. Marcaccini S. Marcos CF. Tetrahedron Lett.  2005,  46:  23 

<A NAME="RG06610ST-8">8</A> Dekhane M. Douglas KT. Gilbert P. Tetrahedron Lett.  1996,  37:  1883 

<A NAME="RG06610ST-9A">9a</A> Witzeman JS. Nottingham WD. J. Org. Chem.  1991,  56:  1713 

<A NAME="RG06610ST-9B">9b</A> Kibler CJ. Weissberger A. Org. Synth., Coll. Vol. III   Wiley; New York: 1955.  p.108 

<A NAME="RG06610ST-9C">9c</A> Hoffman RV. Huizenga DJ. J. Org. Chem.  1991,  56:  6435 

<A NAME="RG06610ST-9D">9d</A> Cossy J. Thellend A. Synthesis  1989,  753 

<A NAME="RG06610ST-10">10</A> Kim H.-O. Olsen RK. Choi O.-S. J. Org. Chem.  1987,  52:  4531 

<A NAME="RG06610ST-11A">11a</A> Stefane B. Polanc S. Synlett  2004,  698 

<A NAME="RG06610ST-11B">11b</A> Stefane B. Polanc S. Tetrahedron  2007,  63:  10902 

<A NAME="RG06610ST-12A">12a</A> Sung K. Wu S.-Y. Synth. Commun.  2001,  31:  3069 

<A NAME="RG06610ST-12B">12b</A> Williams JW. Krynitsky JA. Org. Synth., Coll. Vol. III   Wiley; New York: 1955.  p.10 

<A NAME="RG06610ST-13A">13a</A> Sato M. Ogasawara H. Komatsu S. Kato T. Chem. Pharm. Bull.  1984,  32:  3848 

<A NAME="RG06610ST-13B">13b</A> Clemens RJ. Hyatt JA. J. Org. Chem.  1985,  50:  2431 

<A NAME="RG06610ST-13C">13c</A> Ramana CV. Mondal MA. Puranik VG. Gurjar MK. Tetrahedron Lett.  2006,  47:  4061 

<A NAME="RG06610ST-14">14</A> Xu F. Armstrong JD. Zhou JX. Simmons B. Hughes D. Ge Z. Grabowski EJJ. J. Am. Chem. Soc.  2004,  126:  13002 

<A NAME="RG06610ST-15A">15a</A> Straley JM. Adams AC. Org. Synth., Coll. Vol. IV   Wiley; New York: 415. 

<A NAME="RG06610ST-15B">15b</A> Hao W. Zhang Y. Ying T. Lu P. Synth. Commun.  1996,  26:  2421 

<A NAME="RG06610ST-15C">15c</A> Gukhman EV. Reutov VA. Russ. J. Gen. Chem.  1999,  69:  1608 

<A NAME="RG06610ST-15D">15d</A> Renault O. Guillon J. Dallemagne P. Rault S. Tetrahedron Lett.  2000,  41:  681 

<A NAME="RG06610ST-15E">15e</A> Katritzky AR. Wang Z. Wang M. Wilkerson CR. Hall CD. Akhmedov NG. J. Org. Chem.  2004,  69:  6617 

<A NAME="RG06610ST-15F">15f</A> Zou X. Jia X. Wang X. Xie G. Synth. Commun.  2007,  37:  1617 

<A NAME="RG06610ST-16">16</A> Venkov AP. Angelov PA. Synthesis  2003,  2221 

<A NAME="RG06610ST-17">17</A> Venkov AP. Angelov PA. Synth. Commun.  2003,  33:  3025 

<A NAME="RG06610ST-18">18</A> Kofoed T. Hansen HF. Ørum H. Koch T. J. Peptide Sci.  2001,  7:  402 

<A NAME="RG06610ST-19">19</A>

Preparation of β-Enamino Amides 2: The corresponding acetoacetamide 1 (5 mmol) was added to a solution of Boc-monoprotected ethylenediamine (5 mmol) in CH₂Cl₂ (20 mL) or MeOH (20 mL) for acetoacetamide 1h (1, R^¹ = H) and the reaction mixture was stirred over anhyd Na₂SO₄ for 24 h at r.t. After that, the sulfate was filtered off and the solvent was removed by distillation. The residue was triturated with small amount of Et₂O to give practically clean β-enamino amide in nearly quantitative yield (93-98%). Compound 2a (2, R^¹ = Ph) has moderate solubility in CH₂Cl₂ and crystallizes out of the reaction mixture, so special care must be taken to wash it thoroughly off the drying agent. The β-enamino amides 2 are air-stable and can be stored safely at r.t., but they easily decompose on silica gel.

<A NAME="RG06610ST-20">20</A>

Preparation of α-Acyl-β-enamino Amides 3; General Procedure: The corresponding acid chloride (1 mmol) was slowly added to a magnetically stirred solution of enamino amide 2 (1 mmol), DMAP (0.2 mmol, 25 mg) and Et₃N (1 mmol, 0.14 mL) in CH₂Cl₂ (20 mL). The reaction mixture was stirred for 1 h at r.t. and after that was transferred to a separating funnel with additional 20 mL of CH₂Cl₂, where it was washed with 5% aq solution of AcOH (15 mL) and then with sat. aq NaHCO₃ (15 mL). The organic phase was dried over Na₂SO₄ and the solvent was distilled off. The residue crystallized upon trituration with Et₂O or Et₂O-PE (1:1) to give the corresponding product 3 in 50-90% yield. Additional 10-30% were isolated from the ethereal washings after column chromatography on silica gel with Et₂O as the eluent [increasing polarity to Et₂O-MeOH (10:1) for products 3 with R^¹ = H].

<A NAME="RG06610ST-21">21</A>

Preparation of β-Keto Amides 6; General Procedure: The corresponding intermediate 3 (200 mg) was dissolved in TFA (2 mL), the solution was stirred for 40 min at r.t. and the reaction was quenched with aq solution of MeCOONa (3 mol/L, 20 mL). The resulting mixture was stirred for 20 min at r.t. and then extracted with CH₂Cl₂ [3 × 20 mL (5 × 20 mL for 6h and 10 × 20 mL for 6c and 6i)]. In the case of 6i the aqueous phase was saturated with NaCl prior to extraction. The combined organic layers were washed with sat. aq NaHCO₃ (15 mL) and dried over Na₂SO₄. The solvent was distilled off to afford practically clean β-keto amides. In some cases enol tautomer was registered immediately after isolation, but it gradually converted to the keto form.

<A NAME="RG06610ST-22">22</A>

All reactions were carried out in untreated CH₂Cl₂ and open to air.