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Synlett 2004(4): 623-626  
DOI: 10.1055/s-2004-817776
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Palladium-Catalyzed Allylic Alkylations via anti/syn-π-Allyl ­Intermediates

Uli Kazmaier*, Matthias Pohlman
Institut für Organische Chemie, Universität des Saarlandes, Postfach 151150, 66041 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
Further Information

Publication History

Received 20 November 2003
Publication Date:
10 February 2004 (online)

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Abstract

Highly reactive chelated enolates are versatile nucleophiles for palladium-catalyzed allylic alkylations, which react already at -78 °C. Therefore, typical side reactions such π-σ-π-isomerizations can be suppressed. Suitably substituted (Z)-allylic substrates give rise to anti/syn-π-allyl complexes, which react ­regioselectively with these nucleophiles at the anti-position.

Key words

allylic alkylation - amino acids - chelated enolates - palladium - π-σ-π-isomerization

    References

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6

The syn/anti terminology is used to describe the orientation of the substituents on the allyl moiety relative to the H-atom at the central carbon atom.

14

Obtained from the corresponding alkynes via Lindlar hydrogenation. rac-6: 1H NMR (300 MHz): δ = 0.90 (t, J 7,6 = 7.3 Hz, 3 H, 7-H), 1.33 (m, 2 H, 6-H), 1.49 (m, 1 H, 5-H), 1.69 (m, 1 H, 5-H), 1.72 (dd, J 1,2 = 7.1 Hz, J 1,3 = 1.7 Hz, 3 H, 1-H), 3.74 (s, 3 H, 9-H), 5.29-5.42 (m, 2 H, 3-H, 4-H), 5.65 (dq, J 2,3 = 10.2 Hz, J 2,1 = 6.9 Hz, 1 H, 2H). 13C NMR (75 MHz): δ = 13.4, 13.8 (2 q, C-1, C-7), 18.2 (t, C-6), 36.6 (t, C-5), 54.5 (q, C-9), 74.2 (d, C-4), 128.6, 128.7 (2 d, C-2, C-3), 155.2 (s, C-8). Elemental analysis: calcd for C9H16O3 (172.22): C, 62.77; H, 9.36. Found: C, 62.79; H, 9.46.
rac-7: 1H NMR (300 MHz): δ = 0.89 (t, J 1,2 = 7.4 Hz, 3 H, 1-H), 1.31 (d, J 7,6 = 6.3 Hz, 3 H, 7-H), 1.39 (m, 2 H, 2-H), 2.10 (m, 2 H, 3-H), 3.73 (s, 3 H, 9-H), 5.34 (dd, J 5,4 = J 5,6 = 9.7 Hz, 1 H, 5-H), 5.44-5.55 (m, 2 H, 4-H, 6-H). 13C NMR (75 MHz): δ = 13.6 (q, C-1), 20.9 (q, C-7), 22.6 (t, C-2), 29.7 (t, C-3), 54.4 (q, C-9), 71.2 (d, C-6), 128.8, 133.4 (2 d, C-4, C-5), 155.1 (s, C-8). Elemental analysis: calcd for C9H16O3 (172.22): C, 62.77; H, 9.36. Found: C, 62.72; H, 9.45.

15

Typical Procedure for Palladium-Catalyzed Allylic Alkylations of Chelated Glycine Ester Enolate: At -20 °C a solution of LHMDS, obtained from HMDS (111 mg, 0.69 mmol) and 1.6 M BuLi (0.39 mL, 0.625 mmol) in THF (1 mL) was prepared. This solution was cooled to
-78 °C before it was added to a solution of the protected amino acid ester (0.25 mmol) in THF (1 mL). After 20 min at -78 °C a solution of ZnCl2 (38 mg, 0.275 mmol) in THF (1 mL) was added under vigorous stirring. After additional 30 min a solution of [allylPdCl]2 (1 mg, 2.5 µmol, 1 mol%), PPh3 [3 mg (11.3 µmol, 4.5 mol%)] and the corresponding allylic ester (0.5 mmol) in THF (3 mL) was added. The solution was stirred and warmed up to r.t. in the cooling bath overnight. Subsequently, the solution was diluted with Et2O and hydrolyzed with 1 N KHSO4 solution. The aqueous phase was extracted twice with Et2O, and the combined organic phases were dried over anhyd Na2SO4. After evaporation of the solvent the crude product was purified by silica gel column chromatography (eluent: hexanes/EtOAc).
rac-8: 1H NMR (300 MHz): δ = 0.86 (t, J 1,2 = 7.4 Hz, 3 H, 1-H), 1.04 (d, J 7,6 = 7.0 Hz, 3 H, 7-H), 1.34 (qt, J 2,1 = J 2,3 = 7.4 Hz, 2 H, 2-H), 1.45 (s, 9 H, 11-H), 1.96 (td, J 3,2 = J 3,4 = 6.9 Hz, 2 H, 3-H), 2.76 (m, 1 H, 6-H), 4.41 (dd, J 8,N-H = 8.6 Hz, J 8,6 = 4.4 Hz, 1 H, 8-H), 5.22 (dd, J 5,4 = 15.4 Hz, J 5,6 = 7.7 Hz, 1 H, 5-H), 5.52 (dt, J 4,5 = 15.4 Hz, J 4,3 = 6.6 Hz, 1 H,
4-H), 6.64 (d, J N-H,8 = 7.7 Hz, 1 H, N-H). 13C NMR (75 MHz): δ = 13.5, (q, C-1), 16.8 (q, C-7), 22.4 (t, C-2), 27.8 (q, C-11), 34.6 (t, C-3), 39.5 (d, C-6), 57.2 (d, C-8), 83.0 (s, C-10), 115.8 (q, J 13,F = 288.2 Hz, C-13), 128.4, 133.7 (2 d, C-4, C-5), 157.0 (q, J 12,F = 37.5 Hz, C-12), 169.1 (s, C-9). Elemental analysis: calcd for C15H24F3NO3 (323.36): C, 55.72; H, 7.48; N, 4.33. Found: C, 55.96; H, 7.46; N, 4.37.
rac-9: 1H NMR (500 MHz): δ = 0.85 (t, J 7,6 = 7.3 Hz, 3 H, 7-H), 1.23 (m, 2 H, 6-H), 1.34 (m, 2 H, 5-H), 1.44 (s, 9 H, 11-H), 1.64 (dd, J 1,2 = 5.8 Hz, J 1,3 = 1.3 Hz, 3 H, 1-H), 2.54 (m, 1 H, 4-H), 4.48 (dd, J 8,N-H = 8.9 Hz, J 8,4 = 4.4 Hz, 1 H, 8-H), 5.11 (ddq, J 3,2 = 15.0 Hz, J 3,4 = 8.9 Hz, J 3,1 = 1.3 Hz, 1 H, 3-H), 5.52 (dq, J 2,3 = 15.1 Hz, J 2,1 = 6.3 Hz, 1 H, 2-H), 6.64 (d, J N-H,8 = 7.5 Hz, 1 H, N-H). 13C NMR (75 MHz): δ = 13.8 (q, C-7), 17.9 (q, C-1), 20.2 (t, C-6), 28.0 (q, C-11), 33.1 (t, C-5), 45.3 (d, C-4), 56.3 (d, C-8), 83.0 (s, C-10), 115.8 (q, J 13,F = 286.3 Hz, C-13), 128.2, 129.7 (2 d, C-2, C-3), 156.9 (q, J 12,F = 37.3 Hz, C-12), 169.2 (s, C-9). Selected signals of the minor syn-diastereomer: 1H NMR (300 MHz): δ = 1.45 (s, 9 H, 11-H), 2.37 (m, 1 H, 4-H), 4.41 (dd, J 8,N-H = 8.5 Hz, J 8,4 = 5.2 Hz, 1 H, 8-H), 6.78 (s, 1 H, N-H). 13C NMR (75 MHz): δ = 20.2 (t, C-6), 33.4 (t, C-5), 45.8 (d, C-4), 56.1 (d, C-8), 83.1 (s, C-10), 128.8, 129.6 (2 d, C-2, C-3), 168.8 (s, C-9).

17

Substrate rac-10 was obtained from ethyl-3-iodo-(Z)-propenoate via DIBALH reduction, addition of methyl magnesiumbromide, protection and subsequent Negishi coupling with propynylzinc chloride.
rac-10: 1H NMR (300 MHz): δ = 1.36 (d, J 7,6 = 6.6 Hz, 3 H, 7-H), 1.96 (d, J 1,4 = 2.2 Hz, 3 H, 1-H), 3.74 (s, 3 H, 9-H), 5.52 (dq, J 4,5 = 10.7 Hz, J 4,1 = 2.4 Hz, 1 H, 4-H), 5.63 (m, 1 H, 6-H), 5.77 (dd, J 5,4 = 10.5 Hz, J 5,6 = 8.3 Hz, 1 H, 5-H). 13C NMR (75 MHz): δ = 4.4 (q, C-1), 20.0 (q, C-7), 54.5 (q, C-9), 73.3 (d, C-6), 74.9 (s, C-2), 92.8 (s, C-3), 111.6 (d, C-4), 139.6 (d, C-5), 155.0 (s, C-8). HRMS (CI): calcd for C9H12O3: 168.0786. Found: 168.0782.

18

Crystal data of rac-11: C15H20F3NO3, M r = 319.32, monoclinic, space group C2/c, a = 19.051(4) Å, b = 9.122(2) Å, c = 20.374 (4) Å, α = 90°, β = 91.17(3)°, γ = 90°, V = 3539.9 (13) Å3, Z = 8, ρcalc. = 1.198 Mg/m3, F(000) = 1344, λ = 0.71073 Å, T = 293 K, µ(MoKa) = 0.103 mm-1. Of the 10775 measured reflections 2751 were independent [R (int) = 0.0510]. The final refinement converged at R1 = 0.0973 for I > 2σ(I), wR2 = 0.1856 for all data. The data for structure 11 were collected on a Stoe IPDS diffractometer, the structure was solved by direct methods (SHELXS-97) and refined with all data by full matrix least squares on F2. CCDC 221039 contains the supplemetary crystallographic data of 11. The data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax: +44(1223)336033 or deposit@ccdc.cam. ac.uk).

19

rac-12: 1H NMR (300 MHz): δ = 1.35 (d, J 7,6 = 6.6 Hz, 3 H, 7-H), 1.92 (d, J 1,4 = 2.2 Hz, 3 H, 1-H), 3.75 (s, 3 H, 9-H), 5.17 (dq, J 6,5 = J 6,7 = 6.6 Hz, 1 H, 6-H), 5.70 (dq, J 4,5 = 17.2 Hz, J 4,1 = 2.2 Hz, 1 H, 4-H), 5.97 (dd, J 5,4 = 16.4 Hz, J 5,6 = 6.6 Hz, 1 H, 5-H). 13C NMR (75 MHz): δ = 4.0 (q, C-1), 19.8 (q, C-7), 54.4 (q, C-9), 74.1 (d, C-6), 87.6 (s, C-2/C-3), 112.6 (d, C-4), 139.4 (d, C-5), 154.7 (s, C-8). Elemental analysis: calcd for C9H12O3 (168.19): C, 64.27; H, 7.19. Found: C, 63.94; H, 7.13. HRMS (EI): calcd for C9H12O3: 168.0786. Found: 168.0773. rac-13: 1H NMR (500 MHz): δ = 1.72 (d, J 7,6 = 6.6 Hz, 3 H, 7-H), 1.85 (d, J 1,4 = 2.2 Hz, 3 H, 1-H), 3.76 (s, 3 H, 9-H), 5.56 (ddq, J 5,6 = 14.8 Hz, J 5,4 = 6.9 Hz, J 5,7 = 1.6 Hz, 1 H, 5-H), 5.61 (d, J 4,5 = 6.9 Hz, 1 H, 4-H), 5.98 (dq, J 6,5 = 14.8 Hz, J 6,7 = 6.6 Hz, 1 H, 6-H). 13C NMR (125 MHz): δ = 3.7 (q, C-1), 17.5 (q, C-7), 54.8 (q, C-9), 68.8 (d, C-4), 74.8, 84.1 (2 s, C-2, C-3), 126.3, 131.8 (2 d, C-5, C-6), 154.9 (s, C-8). Elemental analysis: calcd for C9H12O3 (168.19): C, 64.27; H, 7.19. Found: C, 64.28; H, 7.31.

21

The diastereoselectivity could only be determined exactly for the major diastereomer. GC (Chirasil-l-Val, temp(isothermic). 105 °C, injector: 250 °C, detector: 275 °C): tR( anti -11 ) = 52.39′, tR( anti -11 ) = 54.32′, tR( syn -11 ) = 58.44′, tR( syn -11 ) = 59.87′, tR( anti -14 ) = 111.83′, tR( syn -14 ) = 120.19′, tR( anti -14 ) = 125.10′, tR( syn -14 ) = 134.83′.
rac-11: 1H NMR (300 MHz): δ = 1.45 (s, 9 H, 11-H), 1.70 (ddd, J 1,2 = 6.6 Hz, J 1,3 = J 1,4 = 1.5 Hz, 3 H, 1-H), 1.79 (d, J 7,4 = 2.2 Hz, 3 H, 7-H), 3.57 (m, 1 H, 4-H), 4.57 (dd,
J 8,N-H = 8.5 Hz, J 8,4 = 4.4 Hz, 1 H, 8-H), 5.34 (ddq, J 3,2 = 15.1 Hz, J 3,4 = 6.3 Hz, J 3,1 = 1.5 Hz, 1 H, 3-H), 5.83 (dqd, J 2,3 = 15.1 Hz, J 2,1 = 6.3 Hz, J 2,4 = 1.5 Hz, 1 H, 2-H), 6.83 (d, J N-H,8 = 8.1 Hz, 1 H, N-H). 13C NMR (75 MHz): δ = 3.2 (q, C-7), 17.6 (q, C-1), 28.0 (q, C-11), 38.0 (d, C-4), 56.0 (d, C-8), 74.5, 81.8 (2 s, C-5, C-6), 83.4 (s, C-10), 115.7 (q, J 13,F = 287.8 Hz, C-13), 125.4, 130.0 (2 d, C-2, C-3), 156.7 (q, J 12,F = 37.9 Hz, C-12), 167.5 (s, C-9). Selected signals of the minor syn-diastereomer: 1H NMR (500 MHz): δ = 1.66 (ddd, J 1,2 = 6.6 Hz, J 1,3 = J 1,4 = 1.4 Hz, 3 H, 1-H), 1.81 (d, J 7,4 = 1.8 Hz, 3 H, 7-H), 5.31 (ddq, J 3,2 = 15.1 Hz, J 3,4 = 5.7 Hz, J 3,1 = 1.7 Hz, 1 H, 3-H).
rac-14: 1H NMR (300 MHz): δ = 1.05 (d, J 7,6 = 6.6 Hz, 3 H, 7-H), 1.47 (s, 9 H, 11-H), 1.91 (d, J 1,4 = 2.2 Hz, 3 H, 1-H), 2.87 (m, 1 H, 6-H), 4.50 (dd, J 8,N-H = 8.4 Hz, J 8,6 = 4.4 Hz, 1 H, 8-H), 5.50 (d, J 4,5 = 15.9 Hz, 1 H, 4-H), 5.84 (dd, J 5,4 = 15.9 Hz, J 5,6 = 7.5 Hz, 1 H, 5-H), 6.71 (d, J N-H,8 = 7.5 Hz, 1 H, N-H). 13C NMR (75 MHz): δ = 3.9 (q, C-1), 15.6 (q, C-7), 27.8 (q, C-11), 39.6 (d, C-6), 56.6 (d, C-8), 83.5, (s, C-10), 86.3 (s, C-2/C-3), 112.6 (d, C-4), 115.5 (q, J 13,F = 286.0 Hz, C-13), 139.8 (d, C-5), 156.8 (q, J 12,F = 37.4 Hz, C-12), 168.3 (s, C-9). Selected signals of the minor syn-diastereomer: 1H NMR (300 MHz): δ = 1.10 (d, J 7,6 = 7.1 Hz, 3 H, 7-H), 1.47 (s, 9 H, 11-H), 2.71 (m, 1 H, 6-H), 4.44 (dd, J 8,N-H = 8.4 Hz, J 8,6 = 4.9 Hz, 1 H, 8-H), 6.80 (d, J N-H,8 = 8.9 Hz, 1 H, N-H). 13C NMR (75 MHz): δ = 15.9 (q, C-7), 40.2 (d, C-6), 56.5 (d, C-8), 83.4 (s, C-10), 86.1 (s, C-2/C-3), 112.4 (d, C-4), 140.3 (d, C-5), 167.2 (s, C-9). HRMS (CI): calcd for C10H13NF3O5: 319.1395. Found: 319.1394.