A New Route to 1,3-bis-Exocyclic Dienes Using a Palladium-mediated
Cyclization/Coupling Reaction of Conjugated Enynes with Organic Halides and Triflates

Abstract

The palladium catalyzed tandem cyclization/coupling reaction of conjugated enynes having a stabilizing carbon nucleophile with unsaturated halides or triflate afforded stereodefined functionalized 1,3-bis-exocyclic dienes. Moderate yields were obtained with substrates of type 1. However, higher homologs of type 2 led to the formation of functionalized 1,3-bis-exocyclic dienes and hexatrienes in good yields. An initial study on the sequential cyclization/coupling reaction/electrocyclization in a one-pot procedure leading to cyclohexadienes is also presented.

Key words

palladium - cyclizations - enynes - dienes - electrocyclization

References

• 1a Tsuji J. Palladium Reagents and Catalysts, Innovations in Organic Chemistry   Wiley; Chichester: 1995. 
• 1b

  Tetrahedron Symposium-in-Print, 1996, 52, 35

• 1c Metal-catalysed Cross-coupling Reactions   Diederich F. Stang PJ. Wiley-VCH; Weinheim: 1998.  p.99 
• 1d Takacs JM. Weidner JJ. Newsome PW. Takacs BE. Chidambaram R. Shoemaker R. J. Org. Chem.  1995,  60:  5261 ; and references cited therein
• 2a Balme G. Bouyssi D. Tetrahedron  1994,  50:  403 
• 2b Coudanne I. Balme G. Synlett  1998,  998 
• 2c Bruyère D. Gaignard G. Bouyssi D. Balme G. Lancelin JM. Tetrahedron Lett.  1997,  38:  827 
• 2d Garçon S. Vassiliou S. Cavicchioli M. Hartmann B. Monteiro N. Balme G. J. Org. Chem.  2001,  66:  4069 ; and references cited therein
• 2e Balme G. Bouyssi D. Monteiro N. In Handbook of Organopalladium Chemistry for Organic Synthesis   Negishi E.-i. Wiley Interscience; New York: 2002.  p.2245 
• For some examples using organometallic compounds see:
• 3a Nugent WA. Thorn DL. Harlow RL. J. Am. Chem. Soc.  1987,  109:  2788 
• 3b Bailey WF. Wachter-Jurcsak NM. Pineau MR. Ovaska TV. Warren RR. Lewis CE. J. Org. Chem.  1996,  61:  8216 
• 3c Trost BM. Shi Y. J. Am. Chem. Soc.  1993,  115:  12491 
• 3d Trost BM. Romero DL. Rise F. J. Am. Chem. Soc.  1994,  116:  4268 
• 3e Grigg R. Stevenson P. Worakun T. Tetrahedron  1988,  44:  2033 
• 3f Le Paih J. Rodríguez DC. Dérien S. Dixneuf PH. Synlett  2000,  95 
• 4a Cousseau J. Synthesis  1980,  805 
• 4b Barton TJ. Lin J. Ijadi-Maghsoodi S. Power MD. Zhang X. Ma Z. Shimizu H. Gordon MS. J. Am. Chem. Soc.  1995,  117:  11695 
• The palladium(0) catalyst generated in situ by reduction of PdCl₂(PPh₃)₂ with n-BuLi has been found particularly effective in related carbopalladation reactions:
• 6a

  See ref. [2d]

• 6b Bottex M. Cavicchioli M. Hartmann B. Monteiro N. Balme G. J. Org. Chem.  2001,  175 
• 8 Bouyssi D. Balme G. Fournet G. Monteiro N. Goré J. Tetrahedron Lett.  1991,  32:  1641 
• 9a Fournet G. Balme G. Goré J. Tetrahedron  1991,  47:  6293 
• 9b Coudanne I. PhD Dissertation   Université Claude Bernard; Lyon: 1997. 
• 10 Klusener PAA. Kulik W. Brandsma L. J. Org. Chem.  1987,  52:  5261 
• For related examples of palladium catalyzed reaction combined with 6-π electrocyclization processes see:
• 13a

  See ref. [2c]

• 13b Gilchrist TL. Summersell RJ. Tetrahedron Lett.  1987,  28:  1469 
• 13c Gilchrist TL. Healy MAM. J. Chem. Soc., Perkin Trans. 1  1992,  749 
• 13d Trost BM. Pfrengle W. Urabe H. Dumas J. J. Am. Chem. Soc.  1992,  114:  1923 
• 13e Grigg R. Savic V. Tetrahedron Lett.  1996,  36:  6565 
• 13f von Zezschwitz P. Petry F. de Meijere A. Chem.-Eur. J.  2001,  7:  4035 
• Similar results were recently reported for palladium catalyzed tandem cyclization/coupling reactions involving commercial β-bromostyrene:
• 14a

  See ref. [6]

• 14b Arcadi A. Cacchi S. Cassetta A. Fabrizi G. Parisi LM. Synlett  2001,  1605 

5

The palladium-diphenylphosphinoethane was preformed by heating Pd(OAc)₂ (5 mol%) and dppe (5 mol%) in the presence of 1-heptene (10 mol%, THF, 50 °C) until a homogeneous dark red solution was obtained.

7

The demethoxycarbonylation of malonate ester using Krapcho’s conditions generally needs prolonged heating in polar solvent. The strain generated by the two contiguous exocyclic double bonds and the malonate could explain this rather mild conditions.

11

Only traces of the corresponding coupling product were observed which were easily removed by flash chromatography.

12

Experimental Procedure for the Synthesis of 6a:
Potassium hydride (35% in mineral oil) was washed with anhyd THF, dried and stored under nitrogen prior to use.
To a suspension of KH (48 mg, 1.2 mmol) in 3 mL of anhyd THF was added 18-C-6 (53 mg, 0.2 mmol), enyne 2a (191 mg, 1 mmol) in 4 mL of THF, and iodobenzene (170 µL, 1.5 mmol). This mixture was stirred at r.t. for 15 min. In a separate flask, n-BuLi (2 M in hexanes) was added dropwise at r.t. to a suspension of PdCl₂(PPh₃)₂ (35 mg, 0.05 mmol) in 3 mL of THF until the mixture becomes dark green. After heating at reflux for 5 min and cooling, the mixture turned to a dark red homogeneous solution and was added at r.t. via a cannula to the cyanoester anion prepared above. The resulting mixture was then stirred at 30 °C for 3 h (monitored by TLC until completion). The solution was then filtered through a short pad of silica gel (eluting with diethyl ether) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography with petroleum ether/Et₂O 80/20 to afford 6a as a pale yellow solid (206 mg, 77%). ¹H NMR (CDCl₃, 300 MHz, ppm): δ = 1.94 (2 H, m), 2.17 (1 H, dt, J = 14.0, 6.5 Hz), 2.43 (2 H, t, J = 6.5 Hz), 2.60 (1 H, dt, J = 14.0, 5.5 Hz), 3.85 (3 H, s), 4.81 (1 H, d, J = 1.1 Hz), 5.02 (1 H, d, J = 1.5 Hz), 6.63 (1 H, s), 7.18-7.30 (3 H, m), 7.34 (2 H, m). ¹³C NMR (CDCl₃, 50 MHz, ppm): δ = 23.46, 35.36, 35.44, 53.19, 53.66, 117.35, 117.94, 127.44, 128.04, 128.07, 128.95, 135.73, 135.76, 141.05, 167.13. Anal. Calcd for C₁₇H₁₇NO₂: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.43; H, 6.50; N, 5.19.
The E-configuration of this isomer was deduced from differential NOE experiments in the ¹H NMR.