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Synlett 2007(13): 2011-2016  
DOI: 10.1055/s-2007-984880
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Christian E. Madu, Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas, Arlington, TX 76019, USA
Fax: +1(817)2723808; e-Mail: lovely@uta.edu;
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Publikationsverlauf

Received 11 May 2007
Publikationsdatum:
12. Juli 2007 (online)

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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.

Key words

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

7

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.

12

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.

14

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.

16

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

17

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.

20

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.

21

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.

22

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