Palladium-Catalyzed Suzuki-Miyaura Coupling Reactions Involving β,β-Dihaloenamides: Application to the Synthesis of Disubstituted Ynamides

Abstract

β,β-Dihaloenamides can be successfully involved in ­palladium-catalyzed Suzuki-Miyaura coupling reactions. Whereas the resulting trisubstituted (Z)-β-bromoenamides could participate in a second cross-coupling leading to β,β-disubstituted enamides, the (Z)-β-chloroenamides have been converted to disubstituted ­ynamides by an E₂ elimination.

Key words

cross-coupling - palladium - enamides - eliminations - ynamides

References

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• 14e

  The Pd-catalyzed hydrogenolysis of the gem-dibromo-enamide 13 with n-Bu₃SnH led to the (Z)-b-bromoenamide 26 (55%), whose configuration was readily assigned by ¹H NMR, and to the fully reduced enamide 27 (15%) as a by-product. However, no trace of the (E) geometrical isomer of compound 26 could be detected. A similar hydrogenolysis of the gem-dichloroenamides could not be achieved (Scheme [4] ).

  

  Scheme 4

  This result confirms that in b,b-dihaloenamides of type A, the oxidative addition of Pd(0) complexes occurs at the less-hindered carbon-halogen bond, as in the non-hetero-substituted series. For the Pd-catalyzed hydrogenolysis of 1,1-dibromoalkenes, see:

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• 16 Some chiral disubstituted ynamides have been synthesized from enamides by bromination (Br₂ or NBS) leading to stereomeric mixtures of β-bromoenamides, in which the (Z) isomer was selectively converted to the desired disubstituted ynamide by treatment with a base (t-BuOK, THF) whereas the (E) isomer did not react; see: Wei L.-L. Mulder JA. Xiong H. Zificsak CA. Douglas CJ. Hsung RP. Tetrahedron  2001,  57:  459 
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10

Tosylation of but-3-enylamine hydrochloride, benzylamine and p-anisidine (TsCl, Et₃N, CH₂Cl₂, 0 °C to r.t.) afforded the corresponding sulfonamides 1a (58%), 1b (77%) and 1c (84%), respectively. Benzoylation of aminoacetaldehyde dimethylacetal (BzCl, Et₃N, cat. DMAP, CH₂Cl₂, 0 °C) provided the benzamide 1d (87%).

12

Representative Procedure: N -Benzyl- N -[( Z )-2-chloro-2-phenylvinyl]-4-methylbenzenesulfonamide (7).
To a solution of the gem-dichloroenamide 3b (178 mg, 0.500 mmol) in THF (10 mL) were successively added benzeneboronic acid (98 mg, 0.80 mmol, 1.6 equiv), a 1 M aq solution of NaOH (1.50 mL, 1.50 mmol, 3 equiv) and Pd(PPh₃)₄ (29 mg, 0.025 mmol, 0.05 equiv). After 3 h at reflux, the reaction mixture was cooled to r.t., filtered through a pad of Celite (EtOAc) and the filtrate was evaporated under reduced pressure. The crude material was purified by flash chomatography (petroleum ether-EtOAc, 90:10) to afford 195 mg (98%) of 7 as a white solid; mp 124 °C. IR: 1595, 1490, 1445, 1345, 1160, 1090, 1030, 915, 815, 780, 760, 740 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.76 (d, J = 8.3 Hz, 2 H), 7.37-7.24 (m, 12 H), 6.53 (s, 1 H), 4.81 (s, 2 H), 2.43 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 143.8 (s), 136.7 (s), 136.05 (s), 136.0 (s), 132.9 (s), 129.7 (d, 2 C), 129.4 (d), 128.49 (d, 3 C or 2 C), 128.47 (d, 2 C or 3 C), 128.4 (d), 127.8 (d), 127.3 (d, 2 C), 126.9 (d, 2 C), 122.9 (d), 52.2 (t), 21.6 (q). MS (EI, 70 eV): m/z (%) = 400 (1) [M(³⁷Cl) + H⁺], 399 (3) [M(³⁷Cl)⁺], 398 (2) [M(³⁵Cl) + H⁺], 397 (9) [M(³⁵Cl)⁺], 362 (1) [M - Cl⁺], 242 (4) [M - Ts⁺], 206 (5), 178 (2), 155 (2), 92 (8), 91 (100), 89 (4), 65 (7). Anal. Calcd for C₂₂H₂₀ClNO₂S: C, 66.40; H, 5.07; N, 3.52. Found: C, 66.47; H, 4.99; N, 3.48.

13

In all the cross-couplings investigated, GC-MS and NMR analyses of the crude β-haloenamides indicate a stereoisomeric ratio > 95:5.

15

The (Z)-olefinic configuration of the β-chloroenamides of type B was further confirmed by their ability to undergo dehydrochlorination (E₂ anti-elimination) by treatment with a base, whereas the (E) geometrical isomers would not react under these conditions, see ref. 16.

22

Representative Procedure: N -Benzyl- N -(2-phenylethynyl)-4-methylbenzenesulfonamide ( 21).
To a solution of β-chloroenamide 7 (100 mg, 0.251 mmol) in toluene (10 mL) were successively added 50% aq NaOH (10 mL) and tetrabutylammonium hydrogensulfate (17 mg, 0.050 mmol, 0.2 equiv) and the resulting mixture was vigorously stirred at r.t. After 7 h, the reaction mixture was cooled to 5 °C, and diluted with H₂O and Et₂O. The layers were separated and the aqueous phase was extracted with Et₂O. The combined extracts were washed with a sat. aq solution of NH₄Cl, brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether-EtOAc, 95:5) to afford 74 mg (81%) of 21 as a pale yellow waxy solid. IR: 3060, 3030, 2235, 1595, 1490, 1445, 1420, 1355, 1160, 1050, 1030, 940, 815, 765, 690, 655 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.77 (d, J = 8.3 Hz, 2 H), 7.30-7.14 (m, 12 H), 4.55 (s, 2 H), 2.40 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.7 (s), 134.7 (s), 134.5 (s), 131.1 (d, 2 C), 129.8 (d, 2 C), 128.9 (d, 2 C or 3 C), 128.6 (d, 2 C), 128.2 (d, 3 C), 127.7 (d, 3 C or 2 C), 122.8 (s), 82.7 (s), 71.4 (s), 55.7 (t), 21.7 (q). MS (EI, 70 eV): m/z (%) = 361 (21) [M⁺], 207 (9), 206 (45) [M - Ts⁺], 205 (6), 179 (26), 178 (11), 165 (3), 155 (3), 105 (6), 92 (8), 91 (100), 65 (13).