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.

cross-coupling - palladium - enamides - eliminations - ynamides

References

Pd- and Ni-catalyzed cross-coupling reactions with Grignard reagents:

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2 Iron-catalyzed coupling reactions between 1,1-dichloro-1-alkenes and Grignard reagents have been recently reported, see: Dos Santos M. Franck X. Hocquemiller R. Figadère B. Peyrat J.-F. Provot O. Brion J.-D. Alami M. Synlett  2004,  2697 

Cross-coupling reactions with organozinc reagents:

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1,1-Dibromoalkenes bearing a suitably located carbon-carbon triple bond in the side chain undergo oxidative addition of Pd(0) complexes at the cis carbon-bromine leading to the alkyne carbopalladation followed by cross-coupling:

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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%).

11 Brückner D. Synlett  2000,  1402 

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.

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:

14a Uenishi J. Kawahama R. Yonemitsu O. Tsuji J. J. Org. Chem.  1996,  61:  5716 

14b Uenishi J. Kawahama R. Shiga Y. Yonemitsu O. Tsuji J. Tetrahedron Lett.  1996,  37:  6759 

14c Uenishi J. Kawahama R. Yonemitsu O. Tsuji J. J. Org. Chem.  1998,  63:  8965 

14d Uenishi J. Kawahama R. Izaki Y. Yonemitsu O. Tetrahedron  2000,  56:  3493 

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.

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 

17 Zificsak CA. Mulder JA. Hsung RP. Rameshkumar C. Wei L.-L. Tetrahedron  2001,  57:  7575 ; and references therein

18 Witulski B. Gößmann M. Synlett  2000,  1793 

19 Mulder JA. Kurtz KCM. Hsung RP. Synlett  2003,  1379 ; and references therein

20a Frederick MO. Mulder JA. Tracey MR. Hsung RP. Huang J. Kurtz KCM. Shen L. Douglas CJ. J. Am. Chem. Soc.  2003,  125:  2368 

20b Dunetz JR. Danheiser RL. Org. Lett.  2003,  5:  4011 

20c Zhang Y. Hsung RP. Tracey MR. Kurtz KCM. Vera EL. Org. Lett.  2004,  6:  1151 

21a Rodríguez D. Castedo L. Saá C. Synlett  2004,  377 

21b Rodríguez D. Castedo L. Saá C. Synlett  2004,  783 

21c Tracey MR. Zhang Y. Frederick MO. Mulder JA. Hsung RP. Org. Lett.  2004,  6:  2209 

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).