Ring-Closing Olefin Metathesis and Radical Cyclization as Competing Pathways Bernd Schmidt,*,† Michael Pohler,† and Burkhard Costisella‡ FB Chemie-Organische Chemie and FB Chemie-Gemeinsame Einrichtungen-NMR-Spektroskopie, Universita¨ t Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
[email protected] Received September 24, 2003
Abstract: First and second generation Grubbs’ catalyst mediate under otherwise identical conditions two different cyclization modes with high selectivity: a ring-closing metathesis and an atom-transfer radical addition (ATRA) pathway.
Olefin metathesis has become one of the most important tools in organic synthesis over the past 10 years1 due to the discovery of stable and defined precatalysts based on molybdenum2 and ruthenium.3 Two classes of ruthenium-based “Grubbs”-type catalysts are widely used today: the first generation catalyst A4 and the second generation catalysts B5a and C5b (Figure 1). The imidazolylidene-substituted precatalysts B and C are generally considered to be more reactive in olefin metathesis reactions, e.g. in the conversion of electronpoor6a or electron-rich C-C double bonds,6b which react only slowly or not at all in the presence of the first generation catalyst A. Only few examples have been reported where first and second generation catalyst give qualitatively different results. For example, the E/Z selectivity in macro-RCM reactions may depend on the choice of catalyst.7 An example where the ring size in an ene-diene macro-RCM reaction depends on the catalyst has been published by Wagner et al.8 In both cases, the †
FB Chemie-Organische Chemie. FB Chemie-Gemeinsame Einrichtungen. (1) Reviews: (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2055. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388. (c) Fu¨rstner, A. Angew. Chem., Ind. Ed. 2000, 39, 3013-3043. (2) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886. (3) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9856-9857. (4) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (5) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. (b) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674-2678. (6) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207. (b) van Otterlo, W. A. L.; Ngidi, E. L.; de Koning, C. B. Tetrahedron Lett. 2003, 44, 64836486. (7) (a) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem. 2000, 65, 7990-7995. (b) Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069. (c) Murga, J.; Falomir, E.; Garcia-Fortanet, J.; Carda, M.; Marco, J. A. Org. Lett. 2002, 4, 3447-3449. (8) Wagner, J.; Martin-Cabrejas, L. M.; Grossmith, C. E.; Papageorgiou, C.; Senia, F.; Wagner, D.; France, J.; Nolan, S. P. J. Org. Chem. 2000, 65, 9255-9260. ‡
FIGURE 1. First (A) and second (B, C) ruthenium-based metathesis catalysts.
more active catalysts B or C lead to the formation of the thermodynamically preferred products, whereas the less active catalyst A gives the kinetically preferred product. Recently, it was noted that ruthenium carbene complexes catalyze a variety of nonmetathesis transformations.9 An example where precatalyst A mediates an enyne metathesis reaction and precatalyst B, at least to a certain extent, an oxidative cyclization has been published by Mori et al.10 The first nonmetathesis reactivity pattern described for ruthenium carbene complexes was the atom transfer radical addition reaction, often referred to as the Kharash reaction.11 Snapper et al.12a and Demonceau et al.12b described that olefins react with CHCl3 and CCl4, respectively, in the presence of precatalyst A to form addition products rather than the expected cross-metathesis products.13 It was recently described by ourselves14 and by others15 that diallyl carbinols, derived from double addition of allylmagnesium bromide to esters, show comparatively low reactivity in ruthenium-catalyzed ring-closing metathesis if carbene complex A is used. In contrast, smooth conversion to the expected cyclopentenols is observed with the second generation catalyst B.14b This observation prompted us to investigate if the lower metathesis activity of A can be exploited to selectively promote a 5-exo-trig cyclization via a radical pathway.16 5-Exo-trig cyclization reactions by metal-catalyzed atom radical transfer addition (ATRA) reactions have been described in the literature;17 however, ruthenium-based metathesis catalysts have, to the best of our knowledge, never been used in this reaction. (9) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259-1262. (10) Mori, M.; Saito, N.; Tanaka, D.; Takimoto, M.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 5606-5607. (11) Kharash, M. S.; Jensen, E. V.; Urry, W. H. J. Am. Chem. Soc. 1947, 69, 1100-1105. (12) (a) Tallarico, J. A.; Malnick, L. M.; Snapper, M. L. J. Org. Chem. 1999, 64, 344-345. (b) Simal, F.; Demonceau, A.; Noels, A. F. Tetrahedron Lett. 1999, 40, 5689-5693. (13) For a review on Ru-catalyzed nonmetathesis C-C bond-forming reactions, see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067-2096. For other examples of atom radical transfer addition mediated by Ru-carbene complexes, see: (b) De Clercq, B.; Verpoort, F. Tetrahedron Lett. 2001, 42, 8959-8963. (c) De Clercq, B.; Verpoort, F. J. Organomet. Chem. 2003, 672, 11-16. (14) (a) Schmidt, B.; Wildemann, H. J. Chem. Soc., Perkin Trans. 1 2002, 1050-1060. (b) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003, 1, 2512-2517. (15) Clive, D. L. J.; Cheng, H. Chem. Commun. 2001, 605-606. (16) (a) Brace, N. O. J. Org. Chem. 1967, 32, 2711-2718. (b) Brace, N. O. J. Org. Chem. 1969, 34, 2441-2445.
10.1021/jo0353942 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/17/2004
J. Org. Chem. 2004, 69, 1421-1424
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SCHEME 1. Radical Cyclization and Ring-Closing Metathesis Pathway
TABLE 1. Yields and Diastereoselectivities of Radical and Metathesis Cyclization of starting entry material 1 2 3 4 a
1a 1b 1c 1d
R -C(CH3)3 -CH2Cl -(CH2)3OBn -(CH2)3OAc
Diallylcarbinolsa
radical cyclization RCM product product (yield; dr) (yield) 2a (76%; >95:5) 2b (55%; 5:1) 2c (72%; 4:1) 2d (71%; 5:1)
SCHEME 2.
Characteristic NOE Interactions
SCHEME 3. Mechanistic Intermediates and Transition State Geometries in the Cyclization 1f2
3a (83%) 3b (68%) 3c (71%) 3d (71%)
For reagents and conditions, see Scheme 1.
We started our investigation with metathesis precursor 1a, derived from ethyl pivaloate. Treatment of 1a with a catalytic amount (5 mol %) of first generation catalyst A in tetrachloromethane led to no noticeable conversion at ambient temperature. Heating the mixture to reflux, however, induced clean conversion to a single diastereoisomer of a 1:1 addition product, which was identified as the desired cyclization product 2a by elemental analysis and by spectroscopic means. We could neither detect any linear products resulting from single- or double-Kharash reaction of the diene precursor 1a nor any cyclopentene 3a resulting from ring-closing metathesis. Next, we checked whether the metathesis activity of second generation catalyst B is sufficiently enhanced to compete with the initiation of the radical cyclization pathway. To this end, 1a was treated with B under conditions identical with those described above for the radical-initiated cyclization of 1a catalyzed by first generation catalyst A. Indeed, clean ring-closing metathesis to 3a was observed. We were unable to detect 2a in the 1H NMR spectrum of the crude reaction mixture. The same experiments were conducted with other diallyl carbinols 1b-d, and similar results were obtained in every case, as illustrated in Scheme 1 and Table 1. The formation of 2a is highly diastereoselective, with the level of diastereoselectivity exceeding 95:5. For 2b-d bearing sterically less demanding substituents R than 2a, the ratio of diastereoisomers is somewhat lower (approximately 4:1 to 5:1). Surprisingly, a relative configuration is strongly preferred where all substituents are located on the same face of the cyclopentane ring. The relative configuration was elucidated by one-dimensional, (17) (a) Grigg, R.; Devlin, J.; Ramasubbu, A.; Scott, R. M.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1987, 1515-1520. (b) Huther, N.; McGrail, P. T.; Parsons, A. F. Tetrahedron Lett. 2002, 43, 2535-2538. (c) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1992, 57, 5144-5149. (d) Huang, W.-Y.; Zhao, G.; Ding, Y. J. Chem. Soc., Perkin Trans. 1 1995, 1729-1730. (e) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A. F.; Whittaker, D. T. E. J. Chem. Soc., Perkin Trans. 1 2001, 1187-1194. (f) Tsai, J. Y.; Bouhadir, K. H.; Zhou, J. L.; Webb, T. R.; Sun, Y. H.; Shevlin, P. B. J. Org. Chem. 2003, 68, 1235-1241.
1422 J. Org. Chem., Vol. 69, No. 4, 2004
gradient-selected NOE experiments; characteristic NOE interactions are depicted in Scheme 2. Thus, upon irradiation at the tert-butyl resonance in 2a, NOE effects were observed for the -CH2CCl3 moiety (NOE 1) as well as for the -CH2Cl moiety (NOE 2). No enhancement of the signals resulting from the methine protons was observed. For 2b, upon irradiation at the resonance for the H5 signal, enhancement of signals was observed for both protons of the -CH2Cl moiety (NOE 1), for one proton of the other -CH2Cl moiety (NOE 3), and for both protons of the -CH2CCl3 moiety (NOE 2). Again, no NOE interaction with the two methine protons was observed. The all-cis configuration observed for our cyclization products is in accord with results reported by Grigg et al.17a and by Tsai et al.17f and appears to be the result of kinetic control. Addition of a CCl3 radical to one terminal double bond of diallylcarbinol 1 results in the formation of a secondary radical 4, which adopts a transition state geometry where the substituent R is located in an equatorial orientation and the hydroxy group in an axial orientation. 5-Exo-trig cyclization gives the radical 5, which subsequently abstracts a chlorine from CCl4 (Scheme 3).18 In an attempt to extend the concept outlined above to other substrates, we investigated the reactivity of diallylsilanes 6. The application of first generation ruthenium catalysts to the synthesis of silacycloalkenes has recently been described by Undheim et al.19 Although ring-closing metathesis products are obtained in good yields, rather high catalyst loadings and elevated temperatures are required to achieve complete conversion. We had previously observed that RCM of diallyldiphenylsilane 6a using 5 mol % of Ru-based catalyst A proceeds only with poor conversion, even in refluxing toluene.20 In contrast, (18) For a review on stereoselective radical reactions, see: Bar, G.; Parsons, A. F. Chem. Soc. Rev. 2003, 32, 251-263. (19) Ahmad, I.; Falck-Pedersen, M. L.; Undheim, K. J. Organomet. Chem. 2001, 625, 160-172. (20) Schmidt, B. Unpublished results.
SCHEME 4. Radical Addition Pathway and RCM of Diallylsilanes
with the terminal alkenes for the vacant coordination site at the ruthenium. The observation that for second generation catalysts, which have a much lower tendency toward coordination of Lewis bases,23 ring-closing metathesis reactivity is strongly preferred with these substrates is in line with this assumption. To provide further evidence for this theory, we subjected the methyl ether of 1a to the protocol developed for radical cyclization of diallylcarbinols (1 f 2, Scheme 1). Under these conditions, ether 9 is cleanly converted to the RCM product 10. No products resulting from radical reactions could be detected (eq 2).
with second generation catalyst B a 70% yield of silacyclopentene 7a is obtained under otherwise identical conditions (eq 1). This is, to the best of our knowledge, the first metathesis-based synthesis of 7a that has been widely used as a synthetic building block.21
This situation appears well-suited to apply the conditions used for the transformation 1 f 2 (Scheme 1). However, substrate 6a does not cyclize but undergoes a double addition of CCl4 to yield a linear product 8a. We assume that the larger silicon atom in combination with the two sterically demanding phenyl substituents leads to a transition state geometry that is unfavorable for cyclization reactions, due to a larger distance between the reacting centers. The same result was observed for the dimethyl analogue 6b, indicating that the effect is mainly due to the silicon, rather than the phenyl substituents. Gratifyingly, application of the protocol used for the transformation 1 f 3 (Scheme 1) to 6a gives silacyclopentene 7a in good yield without noticeable formation of any radical addition product (Scheme 4). While the reduced RCM activity of first generation catalyst A toward diallylsilanes can be understood if the larger atomic radius of silicon is taken into account, the low activity toward diallylcarbinols is somewhat surprising. Numerous five-membered carba-, oxa-, or azacycles with similar steric demand have been prepared by using the first generation catalyst; diallylmalonate, for instance, is a commonly used test substrate in ring-closing metathesis reactions and was found to cyclize comparatively facile in the presence of first generation catalysts.22 Thus, it appears likely that the free hydroxy function in diallylcarbinols 1 is responsible for the reduced metathesis activity of first generation catalysts toward these substrates. We propose that the OH moiety competes (21) (a) Mignani, S.; Damour, D.; Bastart, J.-P.; Manuel, G. Synth. Commun. 1995, 25, 3855-3861. (b) Mignani, S.; Barreau, M.; Damour, D.; Renaudon, A.; Dejean, V.; Manuel, G. Synth. Commun. 1998, 28, 1163-1173. For reviews on silicon-carbon heterocycles, see: (c) Hermanns, J.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1 1998, 22092230. (d) Hermanns, J.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1 1999, 81-102. (22) (a) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887-3897. (b) Bentz, D.; Laschat, S. Synthesis 2000, 17661773.
In conclusion, we describe that for RCM substrates that are difficult to cyclize a cyclization mode involving atom radical transfer addition can efficiently compete with the metathesis pathway. Radical cyclization occurs with high diastereoselectivity, and the diastereoselectivity observed is obviously the result of kinetic control. Furthermore, we present examples where first and second generation ruthenium catalysts give qualitatively different results, with the less active metathesis catalyst selectively promoting a nonmetathesis reactivity pattern. Experimental Section General. General information concerning experimental techniques and product characterization14b and details for NOEspectroscopic measurements have been published previously.24 J values are given in Hz and δ values are given in ppm. The number in parentheses following the δC value indicates the number of coupled protons. Whenever complete signal assignment is given, this is based on H,H- or H,C-correlation spectroscopy. General Procedure for the Synthesis of Cyclization Products 2. To a solution of the corresponding precursor 1 (1.6 mmol) in tetrachloromethane (3.0 mL) was added catalyst A (60 mg, 5 mol %) under an atmosphere of argon. The mixture was heated to reflux for 16 h; the solvent was evaporated and the residue was purified by chromatography on silica with cyclohexane-MTBE mixtures as eluent. 3-Chloromethyl-1-tert-butyl-4-(2,2,2-trichloroethyl)cyclopentanol (2a). 2a was obtained from 1a (100 mg, 0.6 mmol) as a colorless liquid. Yield: 146 mg (76%). Chromatography: cyclohexane/MTBE 10:1 (v/v). 1H NMR (400 MHz, CDCl3): δ 3.64 (dd, 1 H, J ) 11.0, 4.5, HCHCl), 3.49 (dd, 1 H, J ) 11.0, 7.3, HCHCl), 3.01 (dd, 1 H, J ) 14.3, 4.9, HCHCCl3), 2.96 (m, 1 H, CHCH2CCl3), 2.79 (m, 1 H, CHCH2Cl), 2.74 (dd, 1 H, J ) 14.3, 6.3, HCHCCl3), 1.98 (dd, 1 H, J ) 14.3, 6.3, H5), 1.83 (ddd, 1 H, J ) 13.0, 6.5, 1.5, H2), 1.80 (dm, 1 H, J ) 13.0, H2′), 1.73 (ddd, 1 H, J ) 14.3, 8.4, 2.0, H5′), 1.39 (s, 1 H, OH), 0.96 (s, 9 H, tBu). 13C NMR (100 MHz, CDCl ): δ 99.8 (0, CCl ), 85.6 (0, COH), 3 3 54.9 (2, CH2CCl3), 47.2 (2, CH2Cl), 41.5 (2, C5), 41.2 (1, CHCH2Cl), 38.6 (2, C2), 38.0 (1, CHCH2CCl3), 36.5 (0, CMe3), 25.6 (3, CH3). IR (neat, NaCl): 3480 (br w), 2964 (m), 1477 (w), 1370 (m), 1069 (w), 780 (m), 705 (m) cm-1. MS (EI, 70 eV): m/z 305 (M+ - OH,
