Catalytic Asymmetric Pauson-Khand eaction U. Khand; G.. Knox; P. L. Pauson; W. E. Watts J. Chem. Soc. Chem. Commun. 1971, 36 Won-jin Chung 02/25/2003
The General Pattern of the Pauson-Khand eaction Co 2 (C) 8 D 1 2 1 = C C 2 Co 2 (C) 6 (C) 3 Co Co(C) 3 Formal [2+2+1] cycloaddition Stoichiometric amount of the metal Long reaction time Schore, N. E.; Croudace, M. C. J. rg. Chem. 1981, 46, 5436
Improved eaction Conditions Promoters Tertiary amine N-oxides - oom temperature - Generate free coordination sites at cobalt by oxidative removal of C ligands Shambayati, S.; Crowe, W. E.; Schrieber, S. L. TL 1990, 31, 5289 Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S..; Yoo, S.-E. Synlett 1991, 204 Primary amines as solvent - Few minutes Sugihara, T. et al. ACIEE 1997, 36, 2801
Improved eaction Conditions Sulfides - Mild condition p-ts N Co 2 (C) 6 N 2 83 o C, 30 min, 15% p-ts N p-ts N Co 2 (C) 6 n-bu S C 3 ClC 2 C 2 Cl p-ts N 83 o C, 30 min, 79% Co 2 (C) 6 + Ph n-bu S C 3 ClC 2 C 2 Cl Ph 83 o C, 30 min, 79% Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett 1991, 204
Catalytic Pauson-Khand eactions Cobalt Catalyzed ethylene/c (310-360 bar) Co 2 (C) 8 (0.22 mol%) C 5 11 C 5 11 150 o C, 16h, 48% igh C pressure, high temperature autenstrauch, V.; Megard, P.; Conesa, J.; Kuster, W. ACIEE 1990, 29, 1413 Co 2 (C) 8 (3 mol%) Et 2 C Et 2 C P(Ph) 3 (10 mol%) C (1 atm), DME 120 o C, 82% Et 2 C Et 2 C The ligands stabilize the active cobalt intermediates. Jeong, N.; wang, S..; Lee, Y.; Chung, Y. K. JACS 1994, 116, 3159
Catalytic Pauson-Khand eactions Cobalt Catalyzed Et 2 C Et 2 C (ind)co(cd) (2 mol%) C (15 atm) DME, 100 o C, 64% Et 2 C Et 2 C Lee, B. Y.; Chung, Y. K.; Jeong, N.; Lee, Y.; wang, S.. JACS 1994, 116, 8793 Co 2 (C) 8 (5 mol%) Et 2 C Et 2 C C (1 atm) DME, 50-55 o C hv = 95% D = 83% Et 2 C Et 2 C Photochemical 8% starting enyne remaining after 14h Thermal 15 % starting enyne remaining after 14h Pagenkopf, B. L.; Livinghouse, T. JACS 1996, 118, 2285 Belanger, D. B.; Mahony, D. J..; Livinghouse, T. TL 1998, 39, 7637
Catalytic Pauson-Khand eactions Cobalt Catalyzed Et 2 C Et 2 C Co 2 (C) 8 (2.5 mol%) C (30 atm), C 2 (112 atm) 90 o C, 82% Et 2 C Et 2 C Super critical fluids promote the reaction. Jeong, N.; wang, S..; Lee, Y. W.; Lim, J. S. JACS 1997, 119, 10549 Me 2 C Me 2 C Co 2 (C) 8 (1 mol%) additive C (7 atm), toluene 120 o C Me 2 C Me 2 C additive yield DME (4 mol%) 94% 2 (4 ml) 97% ard Lewis Bases Sugihara, T.; Yamaguchi, M. Synlett 1998, 1384
Catalytic Pauson-Khand eactions Cobalt Catalyzed Co(acac) 2 (5 mol%) Et 2 C Et 2 C NaB 4 (10 mol%) C (30-40 atm), C 2 Cl 2 Et 2 C Et 2 C 100 o C, 66% Lee, N. Y.; Chung, Y. K. TL 1996, 37, 3145 Et 2 C Et 2 C Co 4 (C) 12 (1 mol%) C (10 atm), C 2 Cl 2 Et 2 C Et 2 C 150 o C, 92% Kim, J. W.; Chung, Y. K. Synthesis 1998, 142
Catalytic Pauson-Khand eactions Cobalt Catalyzed Me 2 C Me 2 C Co 3 (C) 9 (m 3 -C) (1 mol%) C (7 atm), toluene Me 2 C Me 2 C 120 o C, 98% Sugihara, T.; Yamaguchi, M. JACS 1998, 120, 10782 CoBr 2 (0.4 eq) + Zn (0.43 eq) C (1 atm), 110 o C toluene/t-bu In situ generation of the alkyne-co 2 (C) 6 complex ajesh, T.; Periasamy, M. TL 1999, 40, 817
Catalytic Pauson-Khand eactions Titanium Catalyzed Titanocene TMS 3 + N Ph Me 3 SiCN benzene, 45 o C Ph Ph catalyst mol% yield Cp 2 Ti(PMe 3 ) 2 10 80% Cp 2 TiCl 2 / n-buli 10 82% Ni(CD) 2 / Ligand 5 60% Berk, S. C.; Grossman,. B.; Buchwald, S. L. JACS 1993, 115, 4912 Berk, S. C.; Grossman,. B.; Buchwald, S. L. JACS 1994, 116, 8593 Ph catalyst (5 mol%) C (18 psig) toluene, 90 o C Ph catalyst yield ee Cp 2 Ti(C) 2 92% - C Ti C 85% 96% icks, F. A.; Buchwald, S. L. JACS 1996, 118, 11688 icks, F. A.; Buchwald, S. L. JACS 1999, 121, 7026
Catalytic Pauson-Khand eactions uthenium Catalyzed Et 2 C Et 2 C u 3 (C) 12 (2 mol%) C (10-15 atm) Et 2 C Et 2 C solvent, 140-150 o C 11 solvent yield Murai dioxane 86% Mitsudo DMAc 78% Morimoto, T.; Chatani, N.; Fukumoto, Y.; Murai, S. JC 1997, 62, 3762 Kondo, T.; Suzuki, N.; kada, T.; Mitsudo, T. JACS 1997, 119, 6187
Catalytic Pauson-Khand eactions hodium Catalyzed Et 2 C Et 2 C Ph [hcl(c) 2 ] 2 (1 mol%) C (1 atm), dibutyl ether 130 o C, 94% Et 2 C Et 2 C Ph Koga, Y.; Kobayashi, T.; Narasaka, K. CL 1998, 249 Et 2 C Et 2 C Ph trans-[hcl(c)(dppp)] 2 (2.5 mol%) C (1 atm), toluene 110 o C, 99% Et 2 C Et 2 C Ph Jeong, N.; Lee, S.; Sung, B. K. rganometallics 1998, 17, 3642
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach S C Co C C C Co C C -C (D), N 2 +C (C) S Co C C C C Co C The sulfur ligated complex can be isolated. The equilibrium can be controlled. Maximum concentration of complex A - 40% de Maximum concentration of complex B - 92% de - Could not be used with less reactive olefins
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach 1. Co 2 (C) 6 2. NM S rt, 44h * dr 9:1 (+)-15-nor-pentalenene Tormo, J.; Moyano, A.; Pericas, M. A.; iera, A. JC 1997, 62, 4851
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach S 1. Co 2 (C) 8 2. 65 o C, 42h hexanes *S * 1.4 : 1 C C C Co S C Co C C NM (6 eq) C 2 Cl 2, -20 o C 28h *S * * 4.6 : 1 In the absence of the chelating sulfur moiety : low diastereoselectivity Pericas, M. A.; iera, A. et al. Tetrahedron 1997, 53, 8651
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach C C C Co C Co C C N 2 S toluene 25-45 o C or NM 2 (6 eq) Xc C 2 Cl 2 Thermal conditions - dr 523:1 xidative conditions - dr 800:1 Pericas, M. A.; iera, A. et al. JACS 1997, 119, 10225
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach S C C Co C Co C C C + S * * + S * * Close proximity Low reactivity Low selectivity The dicobalthexacarbonyl alkynyl sulfoxide complex is configurationally unstable. Pericas, M. A.; iera, A. et al. TA 1999, 10, 457
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach Co 2 (C) 8 S S C 3 CN, 80 o C 44% Zn, N 4 Cl TF, rt 96% ee The chiral sulfoxide moiety was attached to the olefin. cis and trans vinyl sulfoxides afforded only one isomer upon cyclization. Adrio, J.; Carretero, J. C. JACS 1999, 121, 7411
Asymmetric Pauson-Khand eactions Chiral Complex Approach X E X X P P X C Co Co C C C Ph + 5 eq toluene 80 o C Ph E=NMe : 3-5 days, 90-98% yield E=(-)-a- methyl-benzylamine : 16% ee Greene, A. E. et al.jc 1999, 64, 3492
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach Co Mo C C C C C toluene 61% 100% de Chiral mixed metal complex Thermally stable utherford, D. T.; Christie, S. D.. TL 1998, 39, 9805 10-15 mol% (S,S)-(EBTI)TiMe 2 N N 14 psig C, toluene, 12-45 h, 95 o C Sturla, S. J.; Buchwald, S. L. JC 1999, 64, 5547
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach Jeong, N.; Sung, B. K.; Choi, Y. K. JACS 2000, 122, 6771
Asymmetric Pauson-Khand eactions Chiral Auxiliary Approach Shibata, T.; Takagi, K. JACS 2000, 122, 9852
Asymmetric Pauson-Khand eactions Chiral Promoter Approach C C Co Co C C C C Chiral promoter should be able to differentiate between the enantiotopic ligands. Chiral N-oxides were used. Maximum ee 33% Kerr, W. J.; Kirk, G. G.; Middlemiss, D. Synlett 1995, 1085 Derdau, V.; Laschat, S.; Jones, P. G. eterocycles 1998, 48, 1445
Asymmetric Pauson-Khand eactions Chiral Precursor Approach TMS Me Cr(C) 3 Li 1. 2. Br 3. Ts TMS TMS 1. Co 2 (C) 8 2. NM (10 eq) 88% TMS TMS Quattropani, A. et al. JACS 1997, 119, 4773
Asymmetric Pauson-Khand eactions Chiral Precursor Approach Me Me 1 1. Co 2 (C) 8 1 1 2 or 1 2 2. D or TMAN or NM 1 1 2 Depending on groups, yields ranged from 0 to 96%. The product ratio ranged from 1:1 to 100:0. Mukai, C.; anaoka, M. et al. JCS PT1 1998, 2903 Mukai, C.; anaoka, M. et al. TL 1998, 39, 7909
Asymmetric Pauson-Khand eactions Chiral Precursor Approach Et TMS 1. Co 2 (C) 8 2. Et 2 AlCl, -78 o C 82% 2 steps C C Co C C Co C C C 3 CN, air reflux, 15 min 85% (5:1) or NM, C 2 Cl 2 70% (11:1) or ultrasound C 3 CN, 40 o C (+)-epoxydictymene 45% (3:1) Schreiber, S. L. et al. JACS 1994, 116, 5505 Schreiber, S. L. et al. JACS 1997, 119, 4353
Pauson-Khand reaction - Mechanistic Studies C C Co C C Co C C ' '' C C C C Co Co C C '' ' C CC C C Co Co '' C ' ' '' -Co 2 (C) 5 C C Co C C Co C ' '' C CC C Co Co C ' '' The currently accepted mechanistic pathway Magnus, P.; Principe, L. M. TL 1985, 26, 4851 Beyond the fact that a hexacarbonyldicobalt-alkyne complex is involved, little is actually known about the mechanism. No group has observed any of the proposed intermediates.
Pauson-Khand reaction - Mechanistic Studies C Co C C Co C C C -C C Co C Co C C C C Co C Co C C C 2 C C L Co Co C C L C Co C Co C L C The reaction was interrupted by exposing the reaction mixture to an oxygen containing atmosphere. Krafft, M. E. et al. JACS 1996, 118, 6080
Pauson-Khand reaction - Summary The P-K reaction allows for a rapid increase in molecular complexity from relatively simple starting materials. Several promoters can make the reaction efficient. Many kinds of metal complexes can be used as catalysts. igh levels of enantioselectivity can be achieved. The reaction mechanism is not clear.