The Sonogashira Cross-Coupling Reaction of Alkenyl Chlorides with Aliphatic Acetylenes

Abstract

The Sonogashira cross-coupling reaction between amino acid based alkenyl chlorides and aliphatic acetylenes is reported. The present approach can be used in natural product synthesis and as an alternative to usually more expensive and unstable vinyl-­iodides.

Key words

acetylenes - alkenyl halides - Sonogashira cross-­coupling - amino acids - enediynes

References and Notes

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11

Boc-(prop-2-yne-1-yl)-Gly-OH (5) was prepared according to the procedure described in ref. 8. Yield 74%; yellow oil; R _f  = 0.44 (toluene-EtOAc-AcOH, 10:2:0.5). ^¹H NMR (300 MHz, CDCl₃, trans and cis): δ = 1.45, 1.49 (s, 9 H, CH₃ Boc), 2.28 (br t, 1 H, H3 propargyl), 4.17 (m, 4 H, H11′ propargyl, α Gly). ^¹³C NMR (75 MHz, CDCl₃, trans and cis): δ = 28.2 (CH₃ Boc), 36.6, 37.3 (C1 propargyl), 47.1 (α Gly), 72.7, 73.0 (C3 propargyl), 78.5 (C Boc), 81.4, 81.6 (C2 propargyl), 154.6, 154.8 (CO Boc), 175.3 (CO Gly). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₁₀H₁₅NNaO₄: 236.0893; found: 236.0887.

12

Synthesis of Boc-[penta-5-chloro-4-( Z )-ene-2-yne-1-yl]-Gly-OH (6)
A mixture of Pd(Ph₃P)₄ (12 mg, 0.035 mmol), CuI (12 mg, 0.053 mmol), cis-DCE (65 µL, 0.7 mmol), and piperidine (136 µL, 1.40 mmol) dissolved in dry THF (1 mL) was stirred for 30 min under argon. A solution of Boc-(prop-2-yne-1-yl)-Gly-OH (5, 75 mg, 0.35 mmol) and piperidine (68 µL, 0.70 mmol) in THF (2 mL) was added dropwise by the syringe, and the reaction was stirred at r.t. overnight. Solvent was evaporated, and the residue purified by flash chroma-tography. Yield 59% (56 mg); yellow oil; R _f  = 0.54 (toluene-EtOAc-AcOH, 10:2:0.5). ^¹H NMR (300 MHz, DMSO-d ₆, trans and cis): δ = 1.36, 1.41 (s, 9 H, CH₃ Boc), 2.69 (s, 1 H, H3 chloroenyne), 3.91, 3.93 (br s, 2 H, α Gly), 4.26, 4.28 (H11′ chloroenyne), 6.19 (br td, 1 H, H4 chloro-enyne), 6.79 (d, ^³ J _4,5 = 7.3 Hz, 1 H, H5 chloroenyne). ^¹³C NMR (75 MHz, DMSO-d ₆, trans and cis): δ = 27.8, 27.9 (CH₃ Boc), 37.3, 38.03 (C1 chloroenyne), 47.4, 47.7 (α Gly), 77.6, 77.9 (C Boc), 79.9, 80.0 (C2 chloroenyne), 93.4, 93.5 (C3 chloroenyne), 112.0 (C4 chloroenyne), 129.1 (C5 chloroenyne), 154.6, 154.2 (CO Boc), 170.7 (CO Gly). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₁₂H₁₆ClNNaO₄: 296.0660; found: 296.0652.

13

Synthesis of Boc-[octa-8-hydroxy-2,6-diyne-4-( Z )-ene-1-yl]-Gly-OH (7)
A mixture of Pd(Ph₃P)₄ (13 mg, 0.011mmol), CuI (10 mg, 0.041 mmol), Boc-[penta-5-chloro-4-(Z)-ene-2-yne-1-yl]-Gly-OH (6, 45 mg, 0.164 mmol), and piperidine (38 µL, 0.41 mmol) dissolved in dry THF (1 mL) was stirred for 30 min under argon. A solution of propargyl alcohol (20 µL, 0.328 mmol) in THF (1 mL) was added dropwise by the syringe, and the reaction was stirred at r.t. overnight. Solvent was evaporated and the residue purified by flash chromatog-raphy. Yield 67% (32 mg); yellow oil; R _f  = 0.60 (EtOAc-toluene-AcOH, 10:5:0.5). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 1.37 (s, 9 H, CH₃ Boc), 3.94 (br s, 2 H, α Gly), 4.27 (br d, 4 H, H11′, H88′ enediyne), 6.00 (br td, 1 H, H4 enediyne), 6.04 (br td, 1 H, H5 enediyne). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 27.8 (CH₃ Boc), 37.2 (C1 enediyne), 47.4 (α Gly), 49.4 (C8 enediyne), 79.5 (C Boc), 79.8 (C2 enediyne), 81.3 (C7 enediyne), 92.4 (C3 enediyne), 97.5 (C6 enediyne), 119.0 (C4 enediyne), 120.1 (C5 enediyne), 154.2 (CO Boc), 170.8 (CO Gly). HRMS (MALDI): m/z [M + H]⁺ calcd for C₁₅H₁₉NO₅: 294.1336; found: 294.1322.

15

General Procedure for the Synthesis of 8 (PhCN)₂PdCl₂, (0.02 mmol), CuI (0.02 mmol), 2 (0.2 mmol), and piperidine (0.40 mmol) were dissolved in dry THF (1 mL), and the reaction was stirred for 30 min under argon. A solution of 5 (0.40 mmol) and piperidine (0.80 mmol) in 2 mL of dry THF was added dropwise by the syringe, and the reaction was stirred at r.t. until all acetylene was consumed. Solvent was evaporated and the residue purified by flash column chromatography.
Boc ₂ -Tyr- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl](Boc)-Gly-OH (8a) Yield 51%; yellow oil; R _f  = 0.64 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 11.54 min. ^¹H NMR (300 MHz, CD₃OD): δ = 1.37, 1.44, 1.48, 1.52 (s, 27 H, CH₃ Boc), 2.87, 3.08 (dd, ^³ J _{α , β} = 8.4 Hz, ^³ J _{α , β ′} = 5.9 Hz, ^² J _{β , β ′} = 13.5 Hz, 2 H, ββ′ Tyr), 4.12 (m, 5 H, α Tyr, α Gly, H88′ enediyne), 7.04 (d, ^³ J _{δ , ε} = 8.4 Hz, 2 H, ε Tyr), 4.35 (br d, 2 H, H11′ enediyne), 5.89 (s, 2 H, H4,5 enediyne), 7.26 (d, ^³ J _{δ , ε} = 8.4 Hz, 2 H, δ Tyr). ^¹³C NMR (75 MHz, CD₃OD, trans and cis): δ = 28.0, 28.6, 28.7, 28.8 (CH₃ NHBoc, OBoc), 30.5 (C1 enediyne), 38.6 (β Tyr), 38.9, 39.3 (C8 enediyne), 48.1 (α Gly), 57.4 (α Tyr), 80.9, 81.0, 84.4 (C Boc), 82.4, 82.5, 82.9, 83.00 (C2, C7 enediyne), 92.6, 92.7, 93.8, 93.9 (C3, C6 enediyne), 120.4, 120.5 (C4 enediyne), 120.9, 121.1 (C5 enediyne), 122.3 (ε Tyr), 131.6 (δ Tyr), 136.2 (γ Tyr), 151.6, 153.6 (CO Boc), 156.8, 157.7 (ζ Tyr), 173.2, 173.3 (CO Gly), 173.9 (CO Tyr). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₃₄H₄₅N₃NaO₁₀: 678.2997; found: 678.2980.
Boc-Phe- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl](Boc)-Gly-OH (8b)
Yield 58%; yellow oil; R _f  = 60 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 10.59 min. ^¹H NMR (300 MHz, CD₃OD): δ = 1.36, 1.44, 1.47 (s, 18 H, CH₃ Boc), 2.85, 3.08 (dd, ^³ J _{α , β} = 8.7 Hz, ^³ J _{α , β ′} = 5.7 Hz, ^² J _{β , β ′} = 13.5 Hz, 2 H, ββ Phe), 4.10 (m, 4 H, H88′ enediyne, α Gly), 4.27 (m, 1 H, α Phe), 4.35 (br d, 2 H, H11′ enediyne), 5.88 (s, 2 H, H4,5 enediyne), 7.22 (m, 5 H, arom. Phe). ^¹³C NMR (75 MHz, CD₃OD, trans and cis): δ = 28.6, 28.7, 28.8 (CH₃ Boc), 30.5 (C1 enediyne), 38.6, 39.2 (C8 enediyne), 39.5 (β Phe), 48.2 (α Gly), 57.4 (α Phe), 80.8, 81.0 (C Boc), 82.4, 82.5, 82.9, 83.0 (C2, C7 enediyne), 92.6, 92.7, 93.8, 93.9 (C3, C6 enediyne), 120.3, 120.4 (C4 enediyne), 120.9, 121.0 (C5 enediyne), 127.8 (ζ Phe), 129.5 (ε Phe), 130.6 (δ Phe), 138.5 (γ Phe), 156.8, 157.6 (CO Boc), 173.2 (CO Gly), 174.1 (CO Phe). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₉H₃₇N₃NaO₇: 562.2523; found: 562.2509.
Boc-Val- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl](Boc)-Gly-OH (8c) Yield 64%; yellow oil; R _f  = 0.57 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 10.22 min. ^¹H NMR (300 MHz, CD₃OD): δ = 0.94 (br t, 6H, γ Val), 1.44 (br s, 18 H, CH₃ Boc), 2.01 (s, 1 H, β Val), 3.85 (d, ^³ J _{α , β} = 6.9 Hz, 1 H, α Val), 4.14 (m, 4 H, H88′ enediyne, α Gly), 4.36 (br d, 2 H, H11′ enediyne), 5. 87 (s, 2 H, H4,5 enediyne). ^¹³C NMR (75 MHz, CD₃OD, trans and cis): δ = 18.7, 19.8 (γ Val), 28.6, 28.7, 28.8 (CH₃ Boc), 30.4 (C1 enediyne), 32.4 (β Val), 38.6, 39.2 (C8 enediyne), 48.1 (α Gly), 61.6 (α Val), 80.7, 80.9 (C, Boc), 82.4, 82.5, 82.8, 83.0, (C2, C6 enediyne), 92.5, 92.6, 93.9, 94.0 (C3, C7 enediyne), 120.3, 120.4 (C4 enediyne), 120.8, 120.9 (C5 enediyne), 156.8 (CO Boc), 173.3 (CO Gly), 174.4 (CO Val). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₅H₃₇N₃NaO₇: 514.2524; found: 514.2537.


Boc-Gly- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl](Boc)-Gly-OH (8d) Yield 37%; yellow oil; R _f  = 0.27 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 9.14 min. ^¹H NMR (600 MHz, CD₃OD): δ = 1.45 (s, 18 H, CH₃ Boc), 3.72 (br s, 2 H, α Gly^¹), 4.09, 4.12 (br s, 2 H, H88′ enediyne), 4.20 (br s, 2 H, α Gly^²), 4.34, 4.36 (br s, 2 H, H11′ enediyne), 5.87 (s, 2 H, H4,5 enediyne). ^¹³C NMR (150 MHz, CD₃OD, trans and cis): δ = 28.6, 28.7, 28.8 (CH₃ Boc), 30.5 (C1 enediyne), 38.6, 39.3 (C8 enediyne), 44.7 (α Gly^¹) 48.2 (α Gly^²), 80.9 (C Boc), 82.4, 82.5, 82.9 (C2, C7 enediyne), 92.6, 92.7, 94.0 (C3, C6 enediyne), 120.3, 120.4 (C4 enediyne), 120.8, 121.0 (C5 enediyne), 156.8, 157.7 (CO Boc), 172.4 (CO Gly^¹), 173.4 (CO Gly^²). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₂H₃₁N₃NaO₇: 472.2054; found: 472.2066.
Boc-Ala- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl](Boc)-Gly-OH (8e) Yield 77%; yellow oil; R _f  = 0.40 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 9.40 min. ^¹H NMR (600 MHz, CD₃OD): δ = 1.30 (d, ^³ J _{α , β} = 7.2 Hz, 3 H, β Ala), 1.44 (s, 18 H, CH₃ Boc), 4.11 (m, 3 H, α Ala, α Gly), 4.18 (br d, 2 H, H88′ enediyne), 4.34 (br d, 2 H, H11′ enediyne), 5.88 (s, 2 H, H4,5 enediyne). ^¹³C NMR (150 MHz, CD₃OD, trans and cis): δ = 18.5 (δ Ala), 28.6, 28.7, 28.8 (CH₃ Boc), 30.6 (C1 enediyne), 38.6, 39.3 (C8 enediyne), 48.1 (α Gly), 51.7 (α Ala), 80.8, 80.9, 81.0 (C Boc), 82.4, 82.5, 83.0 (C2, C7 enediyne), 92.5, 94.0 (C3, C6 enediyne), 120.3, 120.4 (C4 enediyne), 120.9, 121.0 (C5 enediyne), 156.8, 157.7 (CO Boc), 173.3 (CO Gly), 175.7, 175.7 (CO, Ala). HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₃H₃N₃NaO₇: 486.2211; found: 486.2233.
Boc-Lys(Boc)- N -[octa-2,6-diyne-4-( Z )-ene-1,8-diyl]- (Boc)-Gly-OH (8f) Yield 69%; yellow oil; R _f  = 0.24 (toluene-EtOAc-AcOH, 5:5:0.5); t _R = 10.07 min. ^¹H NMR (300 MHz, CD₃OD): δ = 1.43, 1.44 (br d, 31 H, CH₃ Boc, γγ′, δδ′ Lys), 1.75 (m, 2 H, ββ′ Lys), 3.03 (t, ^³ J _{δ , ε} = 6.6 Hz, 2 H, εε′ Lys), 3.99 (br d, 1 H, α Lys), 4.15 (m, 4 H, H88′ enediyne, α Gly), 4.35 (br d, 2 H, H11′ enediyne), 5.88 (s, 2 H, H4,5 enediyne). ^¹³C NMR (75 MHz, CD₃OD, trans and cis): δ = 24.3 (γ Lys), 28.6, 28.7, 28.9, 29.0 (CH₃ Boc), 30.6 (C1 enediyne), 30.7
(δ Lys), 33.2 (β Lys), 38.6, 39.3 (C8 enediyne), 41.2 (ε Lys), 48.1 (α Gly), 56.1 (α Lys), 80.0, 80.8, 81.0 (C Boc), 82.4, 82.5, 82.9, 83.0 (C2, C7 enediyne), 92.6, 92.7, 94.0 (C3, C6 enediyne), 120.4, 120.5 (C4 enediyne), 120.9, 121.0 (C5 enediyne), 156.7, 156.8, 158.0, 158.7 (CO Boc), 173.2, 173.3 (CO Gly), 175.1 (CO Lys). HRMS (MALDI): m/z
[M + Na]⁺ calcd for C₃₁H₄₈N₄NaO₉: 643.3314; found: 643.3296.