ecent Advancements In The [2+2+2] Cycloaddition Brandon Dutcher January 17, 2007 ichigan tate University
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity Enantioselectivity Conclusions Acknowledgments
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity Enantioselectivity Conclusions Acknowledgments
General Information [2+2+2] cycloaddition first reported by Bertholet in 1866 First transition metal catalyzed [2+2+2] cycloaddition by eppe et. al. in 1948. A multitude of metals have been employed on the catalysis of the [2+2+2] i, Co, Pd, Cr, h, Zr, b, Ir, Ta, and Ti The [2+2+2] cycloaddition has been found to have a wide range in synthesis
Important [2+2+2] Cycloadditions Bertholet First [2+2+2] cycloaddition Thermally induced reaction eppe Used the ickel complex i(p 3 ) 2 (C) 2 Between 25 C and 80 C 3 H 2 (P 3 ) 2 i(c) 2 benzene 65% H C 2 (P 3 ) 2 i(c) 2 benzene H H H H C 2 H =Bu Kotha,.; Brachmachary, E.; Lahiri, K. Eur. J. rg. Chem. 2005, 4741-4767 eppe, V.W.; chweckendeik, W.J. Justus Leibigs Ann. Chem. 1948, 560, 104-116
General [2+2+2] Cycloaddition Tolerant of many functional groups or catalyst Applicable to many π-bond containing systems Excellent for building aromatic systems benzene and pyridine moieties ymmetry favored exothermic ( H= -594 kj/mol) High temperature or catalyst required due to entropic factors Kotha,.; Brachmachary, E.; Lahiri, K. Eur. J. rg. Chem. 2005, 4741-4767
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity Enantioselectivity Conclusions Acknowledgments
π-bond ystem Approach To The tal Three possibilities for alignment Two possibilities give the 1,2,4 trisubstituted ring ne gives 1,3,5 trisubstituted ring tatistically slightly greater than a 2 to 1 mixture of 1,2,4- to 1,3,5-trisubstituted rings Kotha,.; Brachmachary, E.; Lahiri, K. Eur. J. rg. Chem. 2005, 4741-4767
tal-carbon Insertion chanism - - - Kotha,.; Brachmachary, E.; Lahiri, K. Eur. J. rg. Chem. 2005, 4741-4767
Diels-Alder Type chanism - - Kotha,.; Brachmachary, E.; Lahiri, K. Eur. J. rg. Chem. 2005, 4741-4767
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity ubstrate control eagent control Chemoselectivity Enantioselectivity Conclusions Acknowledgments
tatistical egioselectivity of [2+2+2] cycloaddition tatistically a slightly greater than a 2 to 1 1,2,4- to 1,3,5-trisubstitution ratio 1,2,4 tri-substituted only 1,2,4 tri-substituted only ixture of Both
Tethered Alkynes 1 2 =,, C(C 2 ) 2 etc. 1 3 3 3 3 2 Force regiochemistry of alkyne reaction peed up reaction intramolecular reaction Increase yield
acrocycles by [2+2+2] Cycloaddition ptol 15 mol% CpCo(C) 2 o-xylene 140 o C, 100 h ptol ptol meta para α,ω-diynes Yield % ta:para 42 1:1 57 1:1 55 1:7 Et 2 C Et2 C (CH 2 ) 7 (CH 2 ) 6 49 3:4 aryanoff, B.E.; et. al. J. Am. Chem. oc. 2006, 128, 3473-3485
acrocycle egioselectivity Tol- p-tol p-tol p-tol p-tol
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity ubstrate control eagent control Chemoselectivity Enantioselectivity Conclusions Acknowledgments
rtho/meta electivity f Tethered Alkynes 2 mol% [Ir(cod)Cl] 2 4 mole % ligand argon Entry 1 n-bu Ligand DPPE Conditions Benzene r.t 0.5 h Yield% 92 atio / 20/80 2 P P 2 DPPE 2 n-ct DPPE Benzene r.t 1 h 80 19/81 2 P 3 4 5 6 (CH 2 ) 3 H n-bu n-ct (CH 2 ) 3 H DPPE DPPF DPPF DPPF Benzene r.t 12 h Benzene reflux 1 h Benzene reflux 1 h Benzene reflux 2 h 75 84 83 68 18/82 88/12 86/14 84/16 Fe DPPF P 2 Takeuchi,.; et. al. J. rg. Chem. 2006, 71, 543-552
egioselective Pathways ta Pathway Ir Cl P P Ir P P rtho Pathway Ir Cl P A P B Ir Cl P B P A P B Ir Cl P A Takeuchi,.; et. al. J. rg. Chem. 2006, 71, 543-552
ubstrate Directed egioselectivity CpCo B C 2 H 2 (1atm) THF -40 o C to rt, 4 h (Pin)B CoCp B(Pin) A (Pin)B CoCp B(Pin) B Entry A/B (yield%) 1 2 tbu ipr - 2A/2B 1:0 (18) (Pin)B CoCp 3 4 5 C 6 H 13 CH 2 3A/3B 1.5:1 (93) 4A/4B 1:9 (84) 5A/5B 1:20 (92) B(Pin) =tbu 59% Aubert, C.; Vollhardt, K.P.C.; alacria,.; et. al. Angew. Chem. Int. Ed. 2005, 44, 7114-7118
1,2,4 Trisubstitution Using Titanium- Calixarene Complexes Catalyst a, toluene A B Entry 1 2 3 4 T p-tol, -dimethylamine A(Yield%) 2 3 <3 -- B(Yield%) 98 97 >97 100 Cl Cl Ti i Lapido, F.T.; zerov,.v.; Patrick, B.. J. Am. Chem. oc. 1999, 121, 7941-7942
1,3,5 Trisubstitution Using Titanium- Calixarene Complexes Cl Ti Cl Cl Ti Cl Catalyst a, toluene r.t., 20 h A Cl Cl Ti B 1: 65% yield ratio A:B 77:23 Cl Ti Cl 2: 95% yield ratio A:B 85:15 orohashi,.;yokomakura, K., Hattori, T, iyanao,. Tet. Lett. 2006, 47, 1157-1161
1,3,5 Trisubstitution Using Titanium- Calixarene Complexes (continued) Pr i i Pr i Pr i i H Pr i H Catalyst a, toluene r.t., 20 h A H B H 3: =: 93% yield ratio A:B 83:17 4: =CH 2 : 94% yield ratio A:B 1:99 5: =: 95% yield ratio A:B 32:68 6: =CH 2 : 85% yield ratio A:B 33:67 orohashi,.;yokomakura, K., Hattori, T, iyanao,. Tet. Lett. 2006, 47, 1157-1161
1,3,5 Trisubstitution Using Titanium- Calixarene Complexes (continued) 2.5 mol% 2 a, toluene A B Entry 1 2 3 4 5 4-Tol 4-CF 3 C 6 H 4 Pr ct T Temp ( o C) 23 23 23 23 50 Time (h) 3.5 3.5 15 15 15 Yield% 95 30 73 71 14 atio A:B 95:5 ~100:0 75:25 95:5 100:0 Cl Cl Ti Ti Cl Cl 2 orohashi,.;yokomakura, K., Hattori, T, iyanao,. Tet. Lett. 2006, 47, 1157-1161
Lapido catalyst vs. orohashi catalyst Cl Cl Ti Cl Cl Ti Ti Cl Cl i
Lapido catalyst vs. orohashi catalyst Cl Cl Ti Cl Cl Ti Cl Ti Cl i
1,2,4 regioselectivity Cl Cl Ti i Ti i Ti i orohashi,.;yokomakura, K., Hattori, T, iyanao,. Tet. Lett. 2006, 47, 1157-1161
1,2,4 regioselectivity (continued) Ti i Ti i
1,3,5 egioselectivity Ti Ti Ti Ti
1,3,5 egioselectivity (continued) Ti Ti Ti Ti
Explanation of egioselectivity Ti Ti
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity itriles, olefins and alkynes Isocyanates, isothiocyanates and carbondisulfide Enantioselectivity Conclusions Acknowledgments
lefin vs. itrile C 2 mol % Wilkinson's catalyst tbuh 82 o C, 6 h C 59% Grigg,.; cott,.; tevenson, P. J. Chem. oc. Perkin Trans I, 1988, 1365-1369 C 3 mol% [h(cod) 2 ]BF 4 / BIAP CH 2 Cl 2, rt-40 o C P 2 P 2 =C(C 2 ) 2 59% BIAP Tanaka, K.; uzuki,.; ishida, G. Eur. J. rg. Chem., 2006, 3917-3922
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity itriles, olefins and alkynes Isocyanates, isothiocyanates and carbondisulfide Enantioselectivity Conclusions Acknowledgments
Alkenyl Isocyanates and Alkynes [h(ethylene) 2 Cl] 2 (5 mol%) C P(4--C 6 H 4 ) 3 10 mol% toluene, 110 o C 1 2 3 4 Entry Yield% 3 Yield% 4 1 p-tol -- 63 2 p-c 6 H 4 -- 72 3 2-thiophenyl 34 38 4 3-furanyl 31 36 5 n-pr 60 trace 6 n-bu 70 12 7 (CH 2 ) 2 TB 56 Trace ovis, T.; Yu,.T. J. Am. Chem. oc. 2006, 128, 2782-2783
chanistic Pathways C Pathway B h h h h 1 2 1 h Pathway A h h h h 3 4 ovis, T.; Yu,.T. J. Am. Chem. oc. 2006, 128, 2782-2783
(+)-Lasubine II H H
(+)-Lasubine II H H 2 1 C [h(ethylene) 2 Cl] 2 (5 mol%) P(4--C 6 H 4 ) 3 10 mol% toluene, 110 o C 2 1 1 2 1 = H 2= ovis, T.; Yu,.T. J. Am. Chem. oc. 2006, 128, 2782-2783
Total ynthesis of (+)-Lasubine II H C H L= 5 mol% h(c 2 H 2 ) 2 Cl] 2 10 mol% L Toluene, 110 o C P 1) P 3, DEAD p-nitrobenzoic acid 2) K 2 C 3, H 64% yield Pd/C, H 2 H ovis, T.; Yu,.T. J. Am. Chem. oc. 2006, 128, 12370-12371 H H 62% yield 98% ee H 80% yield d.r.>20:1
Isocyanate electivity C 5 mol% Cp*uCl(cod) DCE, 90 o C Argon Entry Yield% 1 C(C 2 ) 2 87 2 C(C 2 ) 2 1-napthyl 79 3 C(C 2 ) 2 2-furyl 87 4 C(C 2 ) 2 Bn 93 5 C(C 2 ) 2 Pr 89 6 C(C 2 ) 2 Cy 85 7 58 8 60 Yamamoto, Y.; Takagishi, H. J. Am. Chem. oc. 2005, 127, 605-613
Isothiocyanate And Carbon Disulfide electivity 2 C 2 C C 10 mol% Cp*uCl(cod) dichloroethane, 90 o C Argon 2 C 2 C Entry 1 2 3 4 5 Cy C 2 Et C Yield% 88 50 71 76 54 Yamamoto, Y.; Takagishi, H. J. Am. Chem. oc. 2005, 127, 605-613
Isothiocyanate And Carbon Disulfide electivity (continued) Y C [h(cod)cl] 2 /2BIAP (5 mol% h) dichloroethane 80 o C, 12-20 h Y entry Y Yield% 1 C(C 2 ) 2 88 2 C(C 2 ) 2 (4-ClC 6 H 4 ) 89 3 C(C 2 ) 2 85 4 C(C=) 2 81 5 C(C=) 2 74 6 C(CH 2 ) 2 87 7 C(CH 2 ) 2 75 Tanaka, K.; Wada, A.; oguchi, K. rg. Lett. 2006, 8, 907-909
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity Enantioselectivity Conclusions Acknowledgments
Total Chirality Transfer H >95%ee () P 2 >95%ee () CpCo(C) 2 CpCo THF, hν H P quant. >95%ee alacria,.; Aubert, C.; Buisine,. ynthesis, 2000, 7, 985-989
Chirality Transfer chanism approach syn to H Cp Co P H Cp Co P approach anti to P = P H P H Co P CpCo Cp alacria,.; Aubert, C.; Buisine,. ynthesis, 2000, 7, 985-989
rtho-diarylbenzenes Ar 10 mol% [IrCl(cod)] 2 + 2(,)-DUPH Ar Ar P Ar xylene P Entry Ar Temp. ( C) Time (hours) Yield% %ee dl:meso A (,)-DUPH 1 2 A B 60 r.t. 0.5 18 82 68 90 87 5:1 >20:1 B D 3 4 5 C D E 60 60 60 0.3 0.3 0.5 86 >99 95 90 95 90 14:1 2:1 12:1 C E 2 Cl hibata, T.;Tsuchikama, K.; tsuka, Tetrahedron: Asym, 2006, 17, 614-619
dl rtho-dinaphthylbenzene tructure: ChemDraw 3D
Chiral Intermediate Ir P P Ir P P
Enantioselective Isothiocyanate Addition 2 C [h(cod)cl] 2 /2()-BIAP (10 mol% h) C dichloroethane 2 C 60 o C, 12 h 1 2 ()-(+)-3 98%, 61% ee 2 C 1 h 2 2 A 2 C B h h High %ee Low %ee 3 C 2 Tanaka, K.; Wada, A.; oguchi, K. rg. Lett. 2006, 8, 907-909
Chiral Anilides 3 10% 2 3 2 [h(cod) 2 ]BF 4 / 1 ()-xyl-biap 1 i 3 CH 2 Cl 2, rt 1 15-42 h 1 i 3 entry 1 2 3 Yield% %ee 1 C(C 2 ) 2 Bn 29 97 2 C(C 2 ) 2 79 97 3 2 (4-BrC 6 H 4 ) Bn 69 98 4 Et 62 96 Tanaka, K.; Takeishi, K.; oguchi, K. J. Am. Chem. oc. 2006, 128, 4586-4587
Chiral Anilide - electivity Ar 3 i Ar 3 10% 2 3 2 [h(cod) 2 ]BF 4 / 1 ()-xyl-biap 1 i 3 CH 2 Cl 2, rt 1 15-42 h 1 i 3 P P Ar h 1 3 1 Ar 2 1 1 Ar 3 i Ar h P P Ar 3 Ar 2 Tanaka, K.; Takeishi, K.; oguchi, K. J. Am. Chem. oc. 2006, 128, 4586-4587
Enantioselective 1,4-Diene-Ynes to Bridged Cyclohexenes [h(cod) 2 ]BF 4 / 1 tolbiap 10 mol% DCE, 60 o C * 1 2 * 1 2 2 Entry 1 Time (h) Yield% %ee 1 2 Ts Ts Bu H 48 6 46 83 >99 93 P(p-Tol) 2 P(p-Tol) 2 3 C(C 2 Bn) 2 H 48 76 93 4 24 40 92 tolbiap hibata, T.; Tahara, Y. J. Am. Chem. oc. 2006, 128, 11766-11767
Enantioselective 1,4-Diene-Ynes to Cyclohexadienes 1 [h(cod) 2 ]BF 4 / tolbiap 10 mol% DCE, 60 o C * 1 3 Entry 1 Time (h) Yield% %ee 1 2 Ts C(C 2 Bn) 2 H 12 6 91 80 99 90 P(p-Tol) 2 P(p-Tol) 2 3 48 55 94 tolbiap hibata, T.; Tahara, Y. J. Am. Chem. oc. 2006, 128, 11766-11767
1,4-diene-yne cyclization mechanism 1 1 olefin insertion 1 2 * * - 2 = H * 1 2 * 2 2 2 1 1 2 * 3 H H hibata, T.; Tahara, Y. J. Am. Chem. oc. 2006, 128, 11766-11767
Chiral pyrocycles From Diynes and Exo-thylene Compounds Entry =C(C 2 Bn) 2 Exo-methylene [h(cod){()-xylyl-binap}]bf 4 (5 mol%) dichloroethane, 80 o C, 30 min Yield% %ee Y n 1 94 99 2 93 98 P(3,5-ylyl) 2 P(3,5-ylyl) 2 3 88 97 ()-xylyl-binap 4 62 81 hibata, T.; Kuwata, Y.; Tsuchikama, K. J. Am. Chem. oc. 2006, 128, 13686-13687
Chiral Intermediate 3,5-xylyl 3,5-xylyl P h PH 3,5-xylyl 3,5-xylyl lylyx-5,3 lylyx-5,3 h 3,5-xylyl P P 3,5-xylyl =C(C 2 Bn) 2
utline verview of [2+2+2] cycloaddition chanism of the [2+2+2] cycloaddition Issues with selectivity egioselectivity Chemoselectivity Enantioselectivity Conclusions Acknowledgments
Conclusions [2+2+2] cycloaddition is a useful synthetic tool Wide scope of reaction highly functional group tolerant Excellent multi-component reaction Enantioselective and regioselective advancements increase synthetic value of [2+2+2] cycloaddition