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

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.

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

References

1 Hegedus LS. Transition Metals in the Synthesis of Complex Organic Molecules   University Science Book; Herndon: 1999. 

2 For a detailed survey of palladium-catalyzed reactions, see: Malleron JC. Fiaud JC. Legros JY. Handbook of Palladium-Catalyzed Organic Reactions   Academic Press; San Diego: 1997. 

Reviews:

3a Godleski SA. Comprehensive Organic Synthesis   Vol 4:  Trost BM. Fleming I. Semmelhack MF. Pergamon; Oxford: 1991.  p.585-661  

3b Lübbers T. Metz P. Houben Weyl: Methoden der organischen Chemie - Stereoselective Synthesis   Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart/New York: 1996.  p.2371-2473  

3c Trost BM. Van Vranken DL. Chem. Rev.  1996,  96:  395 

3d Williams JMJ. Synlett  1996,  705 ; and references cited therein

4a Kazmaier U. Curr. Org. Chem.  2003,  317 

4b Kazmaier U. Pohlman M. In Metal Catalyzed C-C and C-N Coupling Reactions   de Meijere A. Diederich F. Wiley-VCH; Weinheim: . , in press; and references cited therein

5 Consiglio G. Waymouth RM. Chem. Rev.  1989,  89:  257 

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.

7 Corradini P. Maglio G. Musco A. Paiaro G. J. Chem. Soc., Chem. Commun.  1966,  618 

8 An early example for an allylation of ketone enolates with retention of configuration was described by: Lui F.-T. Negishi E.-I. J. Org. Chem.  1985,  50:  4762 

For iridium catalyzed reactions with retention of olefin geometry see:

9a Takeuchi R. Kashio M. J. Am. Chem. Soc.  1998,  120:  8647 

9b Takeuchi R. Shiga N. Org. Lett.  1999,  265 

9c Takeuchi R. Tanabe K. Angew. Chem. Int. Ed.  2000,  39:  1975 ; Angew. Chem. 2000, 112, 2051

10 For reduction of p-allyl palldium complexes at low temperature with retention of olefin geometry see: Hutzinger MW. Oehlschlager AC. J. Org. Chem.  1991,  56:  2918 

Reviews:

11a Kazmaier U. Amino Acids  1996,  11:  283 

11b Kazmaier U. Liebigs Ann. Recl.  1997,  285 

11c Kazmaier U. Recent Res. Devel. Org. Chem.  1998,  2:  351 

12a Kazmaier U. Zumpe FL. Angew. Chem. Int. Ed.  1999,  38:  1468 ; Angew. Chem. 1999, 111, 1572

12b Weiß TD. Helmchen G. Kazmaier U. Chem. Commun.  2002,  1270 

13a Kazmaier U. Zumpe FL. Angew. Chem. Int. Ed.  2000,  39:  802 ; Angew. Chem. 2000, 112, 805

13b Kazmaier U. Zumpe FL. Eur. J. Org. Chem.  2001,  4067 

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).

16 The regio- and diastereoselectivity were determined by GC using the chiral column Chirasil-L-Val. Programm: [T0 (3 min) = 100 °C, 2 °C/min to T = 180 °C, injector: 250 °C, detector: 275 °C]: t_R(anti-9) = 19.62¢, t_R (syn-9) = 19.81¢, t_R(anti-9) = 20.29¢, t_R(syn-9) = 20.49¢ t_R(anti-8) = 22.22¢, t_R(syn-8) = 22.42¢, t_R(anti-8) = 22.68¢, t_R(syn-8) = 22.93¢. The syn-configured reference samples required were obtained by chelate-Claisen-rearrangement according to: Kazmaier U. Angew. Chem., Int. Ed. Engl.  1994,  33:  998 ; Angew. Chem. 1994, 106, 1046

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) ų, Z = 8, ρ_calc. = 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: [phone] or [e-mail]. 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.

For discussions concerning the memory effect see:

20a Trost BM. Bunt RC. J. Am. Chem. Soc.  1996,  118:  235 

20b Hayashi T. Kawatsura M. Kozumi Y. J. Am. Chem. Soc.  1998,  120:  1681 

20c Lloyd-Jones GC. Stephen SC. Chem.-Eur. J.  1998,  4:  2539 

20d Acemoglu L. Williams JM. J. Adv. Synth. Catal.  2001,  343:  75 

20e Fairlamb IJS. Lloyd-Jones GC. Stephan V. Kocovsky P. Chem.-Eur. J.  2002,  8:  4443 

20f Gais HJ. Jagusch T. Spalthoff N. Gerhards F. Frank M. Raabe G. Chem.-Eur. J.  2003,  9:  4202 

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): t_{R( anti -11 )} = 52.39′, t_{R( anti -11 )} = 54.32′, t_{R( syn -11 )} = 58.44′, t_{R( syn -11 )} = 59.87′, t_{R( anti -14 )} = 111.83′, t_{R( syn -14 )} = 120.19′, t_{R( anti -14 )} = 125.10′, t_{R( 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.