Synthesis of Disubstituted Ynamides from β,β-Dichloroenamides and Electrophiles

Abstract

Treatment of β,β-dichloroenamides with n-butyllithium, followed by addition of an electrophile, provides disubstituted yn­amides in far greater yield than direct functionalization of terminal ynamides.

alkynes - dihaloenamides - disubstituted ynamides

References and Notes

For recent reviews of ynamides, see:

<A NAME="RG10107ST-1A">1a</A> Katritzky AR. Jiang R. Singh SK. Heterocycles  2004,  63:  1455 

<A NAME="RG10107ST-1B">1b</A> Zhang Y. Hsung RP. Chemtracts  2004,  17:  442 

<A NAME="RG10107ST-1C">1c</A> Zificsak CA. Mulder JA. Hsung RP. Rameshkumar C. Wei L.-L. Tetrahedron  2001,  57:  7575 

See also:

<A NAME="RG10107ST-1D">1d</A> Mulder JA. Kurtz KCM. Hsung RP. Synlett  2003,  1379 

<A NAME="RG10107ST-1E">1e</A> Viehe HG. Chemistry of Acetylenes   Marcel Dekker; New York: 1969.  Chap. 12. p.861-912  

<A NAME="RG10107ST-1F">1f</A> Viehe HG. Angew. Chem., Int. Ed. Engl.  1967,  6:  767 

<A NAME="RG10107ST-1G">1g</A> Himbert G. In Methoden der Organischen Chemie (Houben-Weyl)   Kropf H. Schaumann E. Georg Thieme Verlag; Stuttgart: 1993.  p.3267-3443  

<A NAME="RG10107ST-2A">2a</A> Zhang X. Zhang Y. Huang J. Hsung RP. Kurtz KCM. Oppenheimer J. Petersen ME. Sagamanova IK. Shen L. Tracey MR. J. Org. Chem.  2006,  71:  4170 

<A NAME="RG10107ST-2B">2b</A> Hirano S. Fukudome Y. Tanaka R. Sato F. Urabe H. Tetrahedron  2006,  62:  3896 

<A NAME="RG10107ST-2C">2c</A> Villeneuve K. Riddell N. Tam W. Tetrahedron  2006,  62:  3823 

<A NAME="RG10107ST-2D">2d</A> Dunetz JR. Danheiser RL. Org. Lett.  2003,  5:  4011 

<A NAME="RG10107ST-3A">3a</A> Stang PJ. J. Org. Chem.  2003,  68:  2997 

<A NAME="RG10107ST-3B">3b</A> Brückner D. Synlett  2000,  1402 

<A NAME="RG10107ST-3C">3c</A> Brückner D. Tetrahedron  2006,  62:  3809 

<A NAME="RG10107ST-3D">3d</A> Witulski B. Stengel T. Angew. Chem. Int. Ed.  1998,  37:  489 

<A NAME="RG10107ST-4A">4a</A>

For a special issue devoted to the chemistry of ynamides, see: Tetrahedron 2006, 62, issue 16. For recent references, see:

<A NAME="RG10107ST-4B">4b</A> Zhang X. Li H. You L. Tang Y. Hsung RP. Adv. Synth. Catal.  2006,  348:  2437 

<A NAME="RG10107ST-4C">4c</A> Tracey MR. Oppenheimer J. Hsung RP. J. Org. Chem.  2006,  71:  8629 

<A NAME="RG10107ST-4D">4d</A> Couty S. Meyer C. Cossy J. Angew. Chem. Int. Ed.  2006,  45:  6726 

<A NAME="RG10107ST-4E">4e</A> Couty S. Meyer C. Cossy J. Tetrahedron Lett.  2006,  47:  767 

<A NAME="RG10107ST-4F">4f</A> Tanaka K. Takeishi K. Noguchi K. J. Am. Chem. Soc.  2006,  128:  4586 

<A NAME="RG10107ST-4G">4g</A> Buissonneaud D. Cintrat J.-C. Tetrahedron Lett.  2006,  47:  3139 

<A NAME="RG10107ST-4H">4h</A> Dunetz JR. Danheiser RL. J. Am. Chem. Soc.  2005,  127:  5776 

<A NAME="RG10107ST-4I">4i</A> Tanaka R. Yuza A. Watai Y. Suzuki D. Takayama Y. Sato F. Urabe H. J. Am. Chem. Soc.  2005,  127:  7774 

<A NAME="RG10107ST-4J">4j</A> Couty S. Barbazanges M. Meyer C. Cossy J. Synlett  2005,  905 

<A NAME="RG10107ST-4K">4k</A> Riddell N. Villeneuve K. Tam W. Org. Lett.  2005,  7:  3681 

<A NAME="RG10107ST-4L">4l</A> Zhang Y. Tetrahedron Lett.  2005,  46:  6483 

<A NAME="RG10107ST-5A">5a</A> Rodríguez D. Castedo L. Saá C. Synlett  2004,  783 

For our contributions, see:

<A NAME="RG10107ST-5B">5b</A> Martínez-Esperón MF. Rodríguez D. Castedo L. Saá C. Tetrahedron  2006,  62:  3843 

<A NAME="RG10107ST-5C">5c</A> Martínez-Esperón MF. Rodríguez D. Castedo L. Saá C. Org. Lett.  2005,  7:  2213 

<A NAME="RG10107ST-5D">5d</A> Rodríguez D. Castedo L. Saá C. Synlett  2004,  377 

<A NAME="RG10107ST-6">6</A> Tracey MR. Zhang Y. Frederick MO. Mulder JA. Hsung RP. Org. Lett.  2004,  6:  2209 

In most of these articles, the authors have reported the preparation of a single compound using this procedure. See:

<A NAME="RG10107ST-7A">7a</A> Marion F. Coulomb J. Servais A. Courillon C. Fensterbank L. Malacria M. Tetrahedron  2006,  62:  3856 

<A NAME="RG10107ST-7B">7b</A> See ref. 4i

<A NAME="RG10107ST-7C">7c</A> Witulski B. Alayrac C. Tevzadze-Saeftel L. Angew. Chem. Int. Ed.  2003,  42:  4257 

<A NAME="RG10107ST-7D">7d</A> Witulski B. Lumtscher J. Bergsträßer U. Synlett  2003,  708 

<A NAME="RG10107ST-7E">7e</A> Frederick MO. Mulder JA. Tracey MR. Hsung RP. Huang J. Kurtz KCM. Shen L. Douglas CJ. J. Am. Chem. Soc.  2003,  125:  2368 

<A NAME="RG10107ST-7F">7f</A>

Two push-pull ynamides have been reported using the same procedure and ClCO₂Et as electrophile, with very different efficiency: Ref. 7a, 90% yield.

<A NAME="RG10107ST-7G">7g</A>

Ref. 2c, 11% yield.

<A NAME="RG10107ST-8">8</A>

Deuteration studies of 4 using EtMgBr and LDA as bases and MeOD as deuterium source showed 50% and 66% deuterium incorporation, respectively (by ¹H NMR integration). These results showed the incomplete efficiency of metalation of terminal ynamides.

This strategy has been widely used for the synthesis of substituted ynamines, see:

<A NAME="RG10107ST-9A">9a</A> Löffler A. Himbert G. Synthesis  1994,  383 ; and references therein

<A NAME="RG10107ST-9B">9b</A> For a recent report on the synthesis of N-(ethynyl)benzotriazoles, see: Katritzky AR. Singh SK. Jiang R. Tetrahedron  2006,  62:  3794 

<A NAME="RG10107ST-9C">9c</A> During our research, the same methodology has been reported for the synthesis of a single push-pull ynamide, see: Mori M. Wakamatsu H. Saito N. Sato Y. Narita R. Sato Y. Fujita R. Tetrahedron  2006,  62:  3872 

<A NAME="RG10107ST-10">10</A>

Disubstituted ynamides have previously been synthesized from dichloroenamides by a Suzuki-Miyaura cross-coupling reaction followed by HCl elimination. See ref. 4j.

<A NAME="RG10107ST-11">11</A>

Other electrophiles such as MeI and EtI also work but with lower yields (30-35%), ynamide 4 was also obtained as secondary product.

<A NAME="RG10107ST-12">12</A>

Typical Procedure for N -(3-Oxobut-1-ynyl)- N -phenyl Tosylamide ( 5d)
n-Butyllithium (0.64 mL, 1.6 M in hexane) was slowly added to a solution of 6 (0.16 g, 0.47 mmol) in dry THF (7 mL) at -78 °C. After 5 min, Ac₂O (57 µL, 0.61 mmol) was added and the mixture was allowed to reach r.t. (TLC showed clean conversion). The volatiles were removed and the residue was dissolved in EtOAc (20 mL) and washed with brine (2 × 30 mL). The organic layer was dried over anhyd Na₂SO₄ and evaporated to dryness. The crude residue was purified by column chromatography on silica gel using 5:1 hexane-EtOAc as eluent, yielding 5d (0.13 g, 90%) as colorless prisms; mp 110-112 °C. ¹H NMR (250 MHz, CDCl₃): δ = 7.61 (d, J = 8.4 Hz, 2 H), 7.38-7.28 (m, 5 H), 7.21-7.15 (m, 2 H), 2.44 (s, 3 H), 2.32 (s, 3 H). ¹³C NMR + DEPT (62.83 MHz, CDCl₃): δ = 183.0 (CO), 145.9 (C), 137.1 (C), 132.7 (C), 129.9 (2 × CH), 129.4 (2 × CH), 129.2 (CH), 128.1 (2 × CH), 126.4 (2 × CH), 88.3 (C), 75.7 (C), 31.8 (CH₃), 21.7 (CH₃). HRMS: m/z calcd for C₁₇H₁₅NO₃S: 313.0772; found: 313.0770.

<A NAME="RG10107ST-13">13</A>

Prepared as described in ref. 3b.

<A NAME="RG10107ST-14">14</A>

Methylation of 7a-d was also accomplished in satisfactory yields following the same procedure as for 5c.

<A NAME="RG10107ST-15">15</A>

Bisynamide 9: white solid. ¹H NMR (250 MHz, CDCl₃): δ = 7.57 (d, J = 8.3 Hz, 4 H), 7.32-7.22 (m, 14 H), 2.41 (s, 6 H), 0.33 (s, 6 H). ¹³C NMR + DEPT (62.83 MHz, CDCl₃): δ = 145.1 (2 × C), 138.2 (2 × C), 132.5 (2 × C), 129.4 (4 × CH), 129.1 (4 × CH), 128.3 (2 × CH), 128.3 (4 × CH), 126.1 (4 × CH), 96.0 (2 × C), 70.3 (2 × C), 21.7 (2 × CH₃), 0.5 (2 × CH₃). HRMS: m/z calcd for C₃₂H₃₀N₂O₄S₂Si: 598,1416; found: 598.1414.

<A NAME="RG10107ST-16">16</A>

Other members of the silyl bisynamide series exemplified by 9 have also been prepared. Optimization of this procedure for the synthesis of nonsymmetrical derivatives is in progress.

<A NAME="RG10107ST-17">17</A> Mulder JA. Kurtz KCM. Hsung RP. Coverdale H. Frederick MO. Shen L. Zificsak CA. Org. Lett.  2003,  5:  1547