Steric Promotion of the Intramolecular Pauson-Khand Reaction of Aryl Enynes

Abstract

The intramolecular Pauson-Khand reaction of 1,8-enynes derived from salicylaldehyde derivatives has been investigated. Substrates derived from salicylaldehyde itself reacted poorly in this reaction, but related substrates containing ortho-tert-butyl substituents participated quite effectively and in many cases the ­cyclizations proceeded with high levels of diastereoselectivity.

organometallic - substituent effects - cyclization - stereoselectivity - cobalt-alkyne complexes

References and Notes

<A NAME="RS03207ST-1A">1a</A> Schore NE. Chem. Rev.  1988,  88:  1081 

<A NAME="RS03207ST-1B">1b</A> Schore NE. Org. React. (N. Y.)  1991,  40:  1 

<A NAME="RS03207ST-1C">1c</A> Schore NE. In Comprehensive Organometallic Chemistry II, Transition Metal Alkyne Complexes: Pauson-Khand Reaction   Vol. 12:  Hegedus LS. Pergamon; Oxford: 1995.  p.703 

<A NAME="RS03207ST-1D">1d</A> Geis O. Schmalz H.-G. Angew. Chem. Int. Ed.  1998,  37:  911 

<A NAME="RS03207ST-1E">1e</A> Ingate ST. Marco-Contelles J. Org. Prep. Proced. Int.  1998,  30:  123 

<A NAME="RS03207ST-1F">1f</A> Chung YK. Coord. Chem. Rev.  1999,  188:  297 

<A NAME="RS03207ST-1G">1g</A> Brummond KM. Kent JL. Tetrahedron  2000,  56:  3263 

<A NAME="RS03207ST-1H">1h</A> Gibson SE. Stevanazzi A. Angew. Chem. Int. Ed.  2003,  42:  1800 

<A NAME="RS03207ST-1I">1i</A> Blanco-Urgoiti J. Anorbe L. Perez-Serrano L. Dominguez G. Perez-Castells J. Chem. Soc. Rev.  2004,  33:  32 

<A NAME="RS03207ST-1J">1j</A> Gibson SE. Mainolfi N. Angew. Chem. Int. Ed.  2005,  44:  3022 

<A NAME="RS03207ST-1K">1k</A> Struebing D. Beller M. Top. Organomet. Chem.  2006,  18:  165 

<A NAME="RS03207ST-2">2</A> For an excellent discussion of abnormal cyclization pathways and products, see: Bonaga LVR. Krafft ME. Tetrahedron  2004,  60:  9795 

For related work with allenynes, see:

<A NAME="RS03207ST-3A">3a</A> Ahmar M. Chabanis O. Gauthier J. Cazes B. Tetrahedron Lett.  1997,  38:  5277 

<A NAME="RS03207ST-3B">3b</A> Mukai C. Nomura I. Yamanishi K. Hanaoka M. Org. Lett.  2002,  4:  1755 

<A NAME="RS03207ST-3C">3c</A> Brummond KM. Chen HF. Fisher KD. Kerekes AD. Rickards B. Sill PC. Geib SJ. Org. Lett.  2002,  4:  1931 

<A NAME="RS03207ST-3D">3d</A> Mukai C. Nomura I. Kitagaki S. J. Org. Chem.  2003,  68:  1376 

<A NAME="RS03207ST-3E">3e</A> Mukai C. Inagaki F. Yoshida T. Yoshitani K. Hara Y. Kitagaki S. J. Org. Chem.  2005,  70:  7159 

<A NAME="RS03207ST-3F">3f</A> Mukai C. Hirose T. Teramoto S. Kitagaki S. Tetrahedron  2006,  61:  10983 

<A NAME="RS03207ST-4">4</A> Krafft ME. Fu Z. Bonaga VR. Tetrahedron Lett.  2001,  42:  1427 

<A NAME="RS03207ST-5A">5a</A> Blanco-Urgoiti J. Casarrubios L. Pérez-Castells J. Tetrahedron Lett.  1999,  40:  2817 

<A NAME="RS03207ST-5B">5b</A> Pérez-Serrano L. Blanco-Urgoiti J. Casarrubios L. Domínguez G. Pérez-Castells J. J. Org. Chem.  2000,  65:  3513 

<A NAME="RS03207ST-5C">5c</A> Perez-Serrano L. Gonzalez-Perez P. Casarrubios L. Dominguez G. Perez-Castells J. Synlett  2000,  1303 

<A NAME="RS03207ST-5D">5d</A> Blanco-Urgoiti J. Casarrubios L. Dominguez G. Perez-Castells J. Tetrahedron Lett.  2001,  42:  3315 

<A NAME="RS03207ST-5E">5e</A> Perez-Serrano L. Casarrubios L. Dominguez G. Perez-Castells J. Chem. Commun.  2001,  2602 

<A NAME="RS03207ST-5F">5f</A> Perez-Serrano L. Dominguez G. Perez-Castells J. J. Org. Chem.  2004,  69:  5413 

<A NAME="RS03207ST-6A">6a</A> Lovely CJ. Seshadri H. Synth. Commun.  2001,  31:  2479 

<A NAME="RS03207ST-6B">6b</A> Lovely CJ. Seshadri H. Wayland BR. Cordes AW. Org. Lett.  2001,  3:  2607 

<A NAME="RS03207ST-6C">6c</A> Madu CE. Seshadri H. Lovely CJ. Tetrahedron  2007,  63:  5019 

<A NAME="RS03207ST-7">7</A>

Congested systems arising from the cyclization of internal alkynes and 2,2-disubstituted olefins were generally poor substrates in this reaction. See ref. 6c for further discussion of this issue.

<A NAME="RS03207ST-8A">8a</A> For a review of this area, see: Sammes PG. Weller DJ. Synthesis  1995,  1205 

<A NAME="RS03207ST-8B">8b</A> Also see: Jung ME. Piizzi G. Chem. Rev.  2005,  105:  1735 

<A NAME="RS03207ST-9">9</A> For another example of this abnormal regiochemistry, see: Comer E. Rohan E. Deng L. Porco JA. Org. Lett.  2007,  9:  2123 

<A NAME="RS03207ST-10A">10a</A> Shambayati S. Crowe WE. Schreiber SL. Tetrahedron Lett.  1990,  31:  5289 

<A NAME="RS03207ST-10B">10b</A> Jeong N. Chung YK. Lee BY. Lee SH. Yoo S.-E. Synlett  1991,  204 

<A NAME="RS03207ST-11">11</A> Belanger DB. O’Mahony DJR. Livinghouse T. Tetrahedron Lett.  1998,  39:  7637 

<A NAME="RS03207ST-12">12</A>

Our initial explanation of this change was that bulky silyl ether led to an increase in the reactive conformer population, resulting in enhanced cyclization yields. In other words, the silyl ether was serving as a type of steric buttressing element. However, our subsequent experience with related substrates suggests that this may be only one aspect that contributes to the increased yield. We subsequently observed that substrates containing a free propargylic hydroxyl group were prone to several types of side reactions, and its protection may lead to a reduction of these types of reactions.

<A NAME="RS03207ST-13">13</A> For a complementary approach to this type of ring system through the Pauson-Khand reaction, see: Mohamed AB. Green JR. Masuda J. Synlett  2005,  1543 

<A NAME="RS03207ST-14">14</A>

Control experiments suggest the diastereomer ratios are kinetically controlled, as the epimeric ketones do not appear to interconvert upon heating in toluene, or on treatment with Et₃N, although at this point, we cannot rule out the possibility of a Co-catalyzed epimerization.

<A NAME="RS03207ST-15A">15a</A> Nicholas KM. Acc. Chem. Res.  1987,  20:  207 

<A NAME="RS03207ST-15B">15b</A> Green JR. Curr. Org. Chem.  2001,  5:  809 

<A NAME="RS03207ST-15C">15c</A> Teobald BJ. Tetrahedron  2002,  58:  4133 

<A NAME="RS03207ST-16">16</A>

It is also conceivable that the ionization and reduction take place prior to cyclization, and experiments to address this possibility are currently underway.

<A NAME="RS03207ST-17">17</A>

It is quite likely that the active complexes (number and type of ligands) are not the same under oxidative and thermal conditions, and thus the differences observed under these two reaction conditions may not only be a result of the temperature differences, but of the precise identity of the active complex.

<A NAME="RS03207ST-18A">18a</A> Thermodynamic study: Connor RE. Nicholas KM. J. Organomet. Chem.  1977,  125:  C45 

<A NAME="RS03207ST-18B">18b</A> Kinetic study: Kuhn O. Rau D. Mayr H. J. Am. Chem. Soc.  1998,  120:  900 

<A NAME="RS03207ST-19A">19a</A> Magnus P. Principe LM. Tetrahedron Lett.  1985,  26:  4851 

<A NAME="RS03207ST-19B">19b</A> Magnus P. Principe LM. Slater MJ. J. Org. Chem.  1987,  52:  1483 

<A NAME="RS03207ST-20">20</A>

The stereochemistry of the major cycloadducts was determined either through NOE experiments, or in the case of 39, by desilylation and comparison to exo-23, to which it was identical.

<A NAME="RS03207ST-21">21</A>

Selected experimental procedures and selected characterization data. 4,6-Di- tert -butyl-2-(-3-phenyl-2-propynyl)-2-propenyloxybenzene ( 19): Triethylsilane (1.24 g, 10.7 mmol) was added at r.t. to a solution of 16 (2.0 g, 5.3 mmol) in CH₂Cl₂ (10 mL) under a N₂ atmosphere. Then trifluoroacetic acid (2.43 g, 21.3 mmol) was added and stirred for 20 min. The reaction mixture was quenched with aq NaHCO₃ and extracted with CH₂Cl₂ (2 × 10 mL) to give a yellow liquid. The crude product was purified by flash chromatography (hexane-EtOAc, 95:5) to give 19 as a light yellow liquid (1.87 g, 98%). ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (d, J = 2.5 Hz, 1 H), 7.44 (m, 2 H), 7.30 (d, J = 2.5 Hz, 1 H), 7.29 (d, J = 3.0 Hz, 3 H), 6.11 (ddt, J = 4.6, 11.0, 17.0 Hz, 1 H), 5.55 (dq, J = 1.8, 17.4 Hz, 1 H), 5.32 (dq, J = 1.8, 10.5 Hz, 1 H), 4.46 (dt, J = 1.8, 4.6 Hz, 2 H), 3.83 (d, J = 5.0 Hz, 2 H), 1.46 (s, 9 H), 1.38 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.6, 146.1, 142.0, 134.0, 131.7, 129.9, 128.3, 127.8, 125.5, 124.0, 123.2, 116.5, 88.7, 82.1, 74.1, 35.5, 34.7, 31.6, 31.3, 20.9. IR (neat): 2959, 2870, 1451, 1225, 991, 755 cm^-1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₃₃O: 361.2526; found: 361.2538.
General Procedure for the Oxidative PK Reaction (Procedure A): Co₂(CO)₈ (1.1 equiv) was added to a stirred solution of enyne in CH₂Cl₂ and under N₂ at r.t. The reaction mixture was stirred for 5 h at r.t. The reaction mixture was cooled to 0 °C before NMO (12 equiv) was added in three portions at 30 min intervals and then left to stir for 2 h. The reaction mixture was then filtered through a pad of Celite and SiO₂ (ca 1:1) and washed with EtOAc. After rotary evaporation, the crude product was purified by flash chromatography (hexane-EtOAc mixtures).
General Procedure for the Thermal PK Reaction (Procedure B): Co₂(CO)₈ (1.1 equiv) was added to a stirred solution of enyne in toluene and under N₂ and stirred for 5 h at r.t. The reaction mixture was then heated at 70 °C under N₂ for overnight. Workup and purification was identical to Procedure A.
6,8-Di- tert -butyl-1-phenyl-4,4a-dihydro-3 H ,10 H -5-oxabenzo[ f ]azulen-2-one ( 22): The PK cyclization was carried out according to the general Procedures A and B. The enyne 19 (130 mg, 0.36 mmol) was dissolved in the appropriate solvent (10 mL). Co₂(CO)₈ (136 mg, 0.40 mmol) and NMO (460 mg, 3.93 mmol) were added according to the general procedure. The crude product was purified by flash chromatography (hexane-EtOAc, 9:1) to afford 22 (60 mg, 43% using Procedure A and 64 mg, 46% using Procedure B) as a yellow solid; mp 160-162 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (t, J = 7.8 Hz, 2 H), 7.40 (d, J = 2.8 Hz, 1 H), 7.34 (d, J = 2.8 Hz, 2 H), 7.30 (s, 1 H), 7.14 (s, 1 H), 4.67 (dd, J = 5.5, 11.5 Hz, 1 H), 3.91 (d, J = 12.8 Hz, 1 H), 3.76 (d, J = 12.8 Hz, 1 H), 3.54 (m, 1 H), 3.35 (t, J = 11.5 Hz, 1 H), 2.75 (dd, J = 7.1, 18.9 Hz, 1 H), 2.03 (dd, J = 2.8, 18.8 Hz, 1 H), 1.41 (s, 9 H), 1.35 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 205.5, 172.0, 156.8, 146.7, 141.9, 139.7, 131.3, 129.7, 129.6, 128.3, 128.2, 125.3, 123.0, 76.2, 44.1, 36.9, 36.7, 35.2, 34.7, 31.6, 30.7. IR (neat): 2958, 1705, 1474, 758 cm^-1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₃₂O₂Na: 411.2295; found: 411.2266.


6,8-Di- tert -butyl-10-hydroxy-1-phenyl-4,4a-dihydro-3 H ,10 H -5-oxabenzo[ f ]azulen-2-one ( 25): The PK cyclization of the enyne 16 (250 mg, 0.67 mmol) in the appropriate solvent (10 mL), was carried out following the general Procedures A and B. Co₂(CO)₈ (250 mg, 0.73 mmol) and NMO (1.22 g, 10.4 mmol) were added according to the general procedures. The crude product was purified by flash chromatography (silica gel, hexane-EtOAc, 90:10) to afford the reduced PK product 22 (142 mg, 55%) and the expected PK product 25 (70 mg, 26%) as a 1:1 mixture of epimers using Procedure A. Procedure B afforded only exo-25 (255 mg, 94%) as a light yellow solid; mp 171-173 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (m, 3 H), 7.35 (d, J = 2.8 Hz, 1 H), 7.23 (m, 2 H), 7.14 (d, J = 2.8 Hz, 1 H), 5.49 (d, J = 9.2 Hz, 1 H), 4.61 (dd, J = 5.7, 11.5 Hz, 1 H), 4.09 (m, 1 H), 3.51 (t, J = 11.9 Hz, 1 H), 3.15 (d, J = 8.7 Hz, 1 H), 2.76 (dd, J = 6.9, 19.3 Hz, 1 H), 2.03 (dd, J = 2.8, 18.8 Hz, 1 H), 1.40 (s, 9 H), 1.32 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 205.3, 172.3, 156.3, 147.3, 142.8, 139.6, 133.0, 130.7, 129.6, 128.5, 128.3, 125.1, 125.0, 77.9, 73.7, 38.8, 36.7, 35.3, 34.7, 31.5, 30.7. IR (neat): 3435, 2959, 1702, 1598, 756 cm^-1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₃₃O₃: 405.2424; found: 405.2425.

<A NAME="RS03207ST-22">22</A>

Some initial experiments with olefins with terminal substitution have been successful, but internal substitution is apparently not tolerated.