Tandem Reactions in Organic
Synthesis
Townsend Group Meeting
Dorothy Ackerman
February 24, 2015
Common Terms used to Describe
Tandem Reactions
• Tandem: “one after another”
• Sequential: “one pot”
• Domino: “two or more tranformations forming bonds,
taking place under the same reaction conditions”
• Cascade: “describes how reactions happen-each
subsequent change happens under structural change
provided by the previous step”
L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, WileyVCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006
Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992.
Characteristics of Tandem Reactions
•
•
•
•
•
Occur in succession
locally, one after another
Can have independent reaction sites
Composed of ordinary reactions
Sometimes in situ generation of reactive
species
L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, WileyVCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006
Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992.
Benefits of Tandem Reactions
• Minimizes steps to build complex molecules
• Cost factor: less waste reduces materials used
• Often reduces natural resources used
L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, WileyVCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006
Ho, Tse-Lok. Tandem Organic Reactions, Wiley, New York, 1992.
D. A. Barrera-Adame, J. M. Alvarez-Caballero, E. D. Coy-Barrera. Revista Facultad de
Ciencias Basicas. 2012, 2, 292-309.
Categories of Tandem Reactions
• Nature of the first step:
1. Cationic
2. Anionic
3. Radical
4. Pericyclic
5. Photochemical
6. Transition Metal-Catalyzed
7. Oxidation or Reduction Initiated
8. Enzyme Assisted
Cationic Reactions
Kumausallene via Prins/Pinacol: Overman, 1991
Triterpene Sophoradiol: Fish and Johnson, 1994
T.A. Grese, K.D. Hutchinson, L.E. Overman, J. Org. Chem. 1993, 53, 2468-2477.
Fish, P. V.; Johnson, W. S. J. Org. Chem. 1994, 59, 2324
Cationic Reactions
Benzil Domino Cyclization: Dyker, 1999
G. Dyker, W. Stirner, G. Henkel, M. Kockerling, Tetrahedron Lett. 1999, 40, 7457-7458
Cationic Reactions
Double Reactivity of THF-inactivated AlEt3: Tu, 2003
X. Li, B. Wu, X. Z. Zhao, T. X. Jia, T. Q. Tu, D. R. Li, Synlett 2003, 623-626
Anionic Reactions
• Several well-known tandem reactions that
proceed via an anionic process:
– Robinson annulation
– Michael reaction
– Pictet-Spengler cylcization
– Reductive amination
Anionic Reactions
Robinson Annulation leads to Weiland-Miescher Ketone: 1950
Cortisone: Barkley, 1956
P. Wieland. K. Miescher, Helv. Chim. Acta 1950, 33, 2215
L. B. Barkley, W. S. Knowles, H. Raffelson, Q. E. Tompson, J. Am. Chem. Soc. 1956, 78, 4111
Anionic Reactions
Michael-Aldol: Oshima, 2001
Zimmerman-Traxler Model:
E-enolates lead trans product
Z-enolates lead syn product
Z. Han, S. Uehira, H. Shinokubo, K. Oshima, J. Org. Chem. 2001, 66, 7854-7857
Anionic Reactions
SN2 and Wittig Olefination: Huang, 2003
Knoevenagel and hetero Diels-Alder: Gallos, 2003
Y. L. Lin, H. S. Kuo, Y. W. Wang, S. T. Huang, Tetrahedron, 2003, 59, 1277-1281
J. K. Gallos, A. E. Koumbis, Arkivoc, 2003, 6, 135-144
Radical Reactions
• Ideal for sequencing
• Useful for building ring systems
• Able to add to inactivated double or triple bonds
L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in Organic Synthesis, WileyVCH Verlag GmbH & Co. KGaA, Weinheim, Germany. 2006
Radical Reactions
Azadirachtin: Nicolaou, 2003
K. C. Nicolaou, A. J. Roecker, H. Monenschein, P. Guntupalli, M. Follmann, Ange. Chem. Int. Ed. 2003, 42, 3637-3642
Radical Reactions
Sevenfold 6-endo-trig Cyclization: Pattenden, 1999
S. Handa, G. Pattenden, J. Chem. Soc. Perkin Trans. 1 1999, 843-845
Pericyclic Reactions
Pagodane: Prinzbach, 1987
W. D. Fessner, G. Sedelmeier, P R. Spurr, G. Rihs, H. Prinzbach. J. Am. Chem. Soc. 1987, 109, 4626-4642
Pericyclic Reactions
Steroid Skeleton from D-Galactose: Sherburn, 2003
Cyclopentenones: Jung, 2001
C. I. Turner, R. M. Williamson, P. Turner, M. S. Sherburn, Chem. Comm. 2003, 1610-1611
M. E. Jung, P. Davidov, Org. Lett. 2001, 3, 3025-3027
Photochemically Induced Reactions
1,2-disubstitued Cyclopentanes: Tietze, 1992
Tetra-substituted Furans: Agosta, 1996
L. F. Tietze, J. R. Wunsch, M. Noltemeyer, Tetrahedron, 1992, 48, 2081-2099
A. K. Mukherjee, P. Margaretha, W. C. Agosta, J. Org Chem. 1996, 61, 3388-3391
Photochemically Induced Reactions
Cyclic γ-Keto Esters: Komatsu, 2002
I. Ryu, S. Kreimerman, R. Araki, S. Nishitani, Y. Oderaotoshi, S. Minakata, M. Komatsu, J. Am. Chem. Soc. 2002, 124, 3812-3813
Transition Metal-Catalyzed Reactions
Estradiol: Tietze, 1996
Enetetraynes Cyclization: Negishi, 1994
L. F. Tietze, T. Nobel, M. Spescha, Angew. Chem. Int. Ed. Engl. 1996, 35, 2259-2261
L. F. Tietze, T. Nobel, M. Spescha, J. Am. Chem. Soc. 1998, 35, 8971-8977
T. Sugihara, C. Coperet, Z. Owczwarczyk, L. S. Harring, E. Negishi, J. Am. Chem. Soc. 1994, 116, 6923-7924
Transition Metal-Catalyzed Reactions
Equilenin: Nemoto, 1999
H. Nemeto, M. Yoshida, K. Fukumoto, M. Ihara, Tetrahedrom Lett. 1999, 40, 907-910
M. Yoshida, Yakugaku Zasshi, 2004, 124, 425-435
Transition Metal-Catalyzed Reactions
Tropane nucleus: Davies, 1997
Spiro and Dioxa-Triquinane: Nandurdikar, 2004
H. M. L. Davies, J. J. Matasi, L. M. Hodges, N. J. S. Huby, C. Thornley, N. Kong, J. H. Houser, J. Org Chem. 1997, 62, 1095-1105
H. M. L. Davies, Curr. Org. Chem. 1998, 2, 463-488.
K. P. Kaliappan, R. S. Nandurdikar, Chem. Comm. 2004, 2506-2507.
Transition Metal-Catalyzed Reactions
Pauson-Khand and Diels-Alder lead to tetracycles: Chung, 2000
Hydrozirconation lead to biscyclopronanes: Wipf, 2003
S. U. Son, Y. K. Chung, S. G. Lee, J. Org. Chem. 2000, 65, 6142-6144
P. Wipf, C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc. 2003, 125, 761-768.
Oxidation/Reduction Initiated
Reactions
Chiral Cyclobutanones: Katzenellenbogen, 1997
G. M. Anstead, K. E. Carlson, J. A. Katzenellenbogen, Steroids 1997, 62, 268-303
Oxidation/Reduction Initiated
Reactions
Substituted alcohols: Williams, 2005
Bridged-ring systems: Arsenivadis, 2003
P. J. Black, M. C. Edwards, J. M. J. Williams, Tetrahedron, 2005, 61, 1363-1374.
L. Finet, J. I. Candela Lena, T. Kaoudi, N. Birlirakis, S. Arseniyadis, Chem. Sur. J. 2003, 9, 3813-3820.
Oxidation/Reduction Initiated
Reactions
Maoecrystal : Reisman, 2011
J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J. Am. Chem. Soc., 2011, 133, 4964–14967
Use of Enzymes
Rerrangement of Paclitaxel precursor: Vyas, 1995
Epoxide Opening: Williams, 1987
Taxane Anticancer Agents: Basic Science and Current Status (Eds.: G. I. Gerog, T. T. Chem, I. Ojima, D. M. Vyas), American
Chemical Society, Washington, DC, 1995, ACS Symposium Series 538
S. T. Russel, J. A. Robinson, D. J. Williams, J. Chem. Soc. Chem. Commun. 1987, 351-352.
Multicomponent Reactions
• Type I: all reactions are reversible
– Amines, carbonyl compounds, and weak acids
• Type II: majority of reactions are reversible
– Final irreversible step pushed equilibrium forward
• Type III: practically all reactions are
irreversible
– Majority of biochemical compounds fromed this
way
Multicomponent Reactions
Acylcarboxamide: Passerini, 1921
Peptide-like structures: Ugi, 1960
M. Passerini, Gazz. Chim. Ital. 1921 51, 126; M. Passerini, Gazz. Chim. Ital. 1921 51, 181.
I. Ugi, R. Meyr, U. Fetzer, C. Steinbrukner, Angew. Chem. 1959, 71, 386
I. Ugi, C. Steinbruckner, Angew. Chem. 1960, 72, 267-268.
Multicomponent Reactions
Thiazolines: Assinger, 1956
Tropinone: Robinson, 1917
F. Assinger, Angew. Chem. 1956, 68, 413.
R. Robinson, J. Chem. Soc. 1917, 111, 762-768