Synlett 2007(12): 1963-1965  
DOI: 10.1055/s-2007-984529
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

David Rodríguez, M. Fernanda Martínez-Esperón, Luis Castedo, Carlos Saá*
Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Fax: +34(98)1595012; e-Mail: qocsaa@usc.es;
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Publikationsverlauf

Received 27 April 2007
Publikationsdatum:
25. Juni 2007 (online)

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.

8

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.

10

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

11

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

12

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.

13

Prepared as described in ref. 3b.

14

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

15

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.

16

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.