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The Mannich Reaction: New Light On An Old Story Literature meeting Julie Côté November 27, 2007. The Mannich Reaction. Applications: Polymer chemistry ( hardeners , cross- linkers and reaction accelerators ) Plant protections Pharmaceutical area. Cribrochalina.

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The Mannich Reaction: New Light On An Old Story Literature meeting Julie Côté November 27, 2007

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The Mannich Reaction:

New Light On An Old Story

Literature meeting

Julie Côté

November 27, 2007


The MannichReaction

  • Applications:

  • Polymerchemistry(hardeners, cross-linkers and reactionaccelerators)

  • Plant protections

  • Pharmaceutical area

Cribrochalina

Potent cytotoxic agent

Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S.J. J. Am. Chem. Soc. 2005, 127,4596-4598.


Dr. Ulrich Franz Carl Mannich

Mechanism was discover in 1912

Organic chemists in this area argue that this reaction has become the most important C-C bond-forming reaction!

Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.


Limitation of the MannichReaction

This type was first used in early 20th century but neaded drastic reaction and long reaction time

The first methods developed were non-catalytic and employed preformed enolates and enamine with chiral auxiliary control

Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Enders, D.; Ward, D.; Adam, J.; Raabe, G. Angew. Chem. Int. Ed. Engl. 1996, 35, 981.


Presentation

  • Organocatalytic Mannich reaction

  • Proline catalyst

  • Cinchona alkaloids catalyst

  • Thiourea catalyst

  • Bronsted acid catalyst

  • Avancement in direct asymmetric mannich reaction

  • Aldimine MR

  • Anti-selective MR

  • Quaternary carbon center MR

  • Nitro MR

  • One pot three component MR

Indirect MR with Bronsted acid catalyst

Vinylogous MR


Aldimine in Direct AsymmetricMannichReaction : UnmodifiedKetones

  • Very low yields and ee’s

  • High amount of catalyst

  • long reaction time

Notz, W. Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, III, C.F. Tetrahedron Lett. 2001, 42, 199-201.


Aldimine in direct asymmetricMannichReaction : UnmodifiedAldehyde

  • Proceed smoothly with excellent enantioselectivity

  • Higher diastereoselectivities were achived with increased bulkiness of the substituents on the aldehyde

Cordova, A.; Watanabe. S. I.; Tanaka, F.; Notz, W.; Barbas, III, C. F. . J. Am. Chem. Soc. 2002, 124, 1866-1867.


Aldimine in Direct AsymmetricMannichReaction : IonicLiquids

  • Solvent and catalyst are readily recycled

  • Faster reaction in ionic liquids: result from ionic based activation of the imine electrophile.

  • Can be performed on a multi-gram scale

  • - non volatile

  • Tunable polarity

  • High thermal stability

  • Great abily to dissolve catalyst

  • « Green » solvent

Chowdari, N.S.; Ramachary, D.B.; Barbas, III, C. F. Synlett, 2003, 12, 1906-1909.


Aldimine in Direct AsymmetricMannichReaction : Protecting Group

Initially homogenous reaction mixture

After consumption of the starting material : precipitation

B

A

  • Easy clivage of Boc

  • Provides stable crystalline

  • compounds without purification

  • Drastic oxidative condition

  • Harmful reagents: (NH4)Ce(NO3)6,

  • (CAN)

Yang, J. W.; Stadler, M. List, B. Angew. Chem. Int. Ed. 2007, 46, 609-611.


Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

(E)-Enamine predominate

Lacking the stereodirecting carboxylate of proline, the topicity is altered

Facial selection is controlled by proton transfer

Si-face of imine is now attacked by re-face of the enamine

  • Moderate yields and ee

Si-face of imine is attacked by enamine si-face

Cordova, A.; Barbas, III, C.F. Tetrahedron Lett. 2002, 43, 7749-7752.


Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

Structural features at the 5-position were installed to fix the enamine conformation

To avoid steric interaction between the substituents at the 5 the imine, substituents 3- and 5- are in trans -configuration

Acid position to affect control of enamine and imine facial selection

Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.


Aldimine in direct asymmetricMannichReaction :Anti-Selective

Ineffective in MR with ketones . Hypothesis: origined from the relatively slow formation of the enamine intermediates due to steric interaction with Me group of the catalyst

Zhang, H.; Mifsud, M. Tanaka, F.; Barbas, III, C. F. J. Am. Chem. Soc. 2006, 128, 9630-9631.


Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

  • Furnish three contiguous stereocenters in one step in good %

  • The asymmetric reductive MTR proceed via a catalytic

  • asymmetric domino reaction and furnish amino acid

Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.


Aldimine in Direct AsymmetricMannichReaction :Anti-Selective

Zhao, G. L.; Cordova, A.; Tetrahedron Lett. 2006, 47, 7417-7421.


Aldimine in Direct AsymmetricMannichReaction :Anti-Selective


1,3-Dicarbonyls and AcylAldimineswithCinchonaAlkaloidsCatalyst

Brandon, M. Lou, S.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256-11257.


Malonates and AcylAldimineswithBifunctionalCinchonaAlkaloidsCatalyst

  • Cinchona alkaloid derivatives bearing a thiourea functionnality might act as efficient bifunctional catalysts for malonates with simple imines

Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048-6049.


AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters

R1 and R2 need to be very diffirent to access good syn/anti ratio

Chowdari, N. S.; Suri, J. F.; Barbas, III, C. F. Org. Lett. 2004, 6, 2507-2510.


AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters

(DHQD)2PYR

Interesting solvent effect was demonstrated which gave drastic changes in stereoselectivity

Toluene

CH2Cl2

Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M. Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 2896-2899.


AsymmetricMannichReactionAdductswithQuaternaryCarbonCenters

Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006, 8, 2003-2006.


AsymmetricNitro-MannichReaction

Limitations: proceeded smoothly with imine which contains an electron-withdrawing substituent and need prolonged reaction time with electron-donating group.

Aza-Henry Reaction

Metal-free of the nitro-Mannich reaction have recently evolved

Yamada, K. I.; Harwood, S. J.; Gröger, H.; Shibasaki, M. Angew. Chem. Int. Ed. 1999, 38, 3504-3506.


AsymmetricNitro-MannichReaction

Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org Lett. 2004, 6, 625-627. Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.


AsymmetricNitro-MannichReaction

  • Future work includes the expansion of the methodology to different substrates and investigation of the synthetic utility of the addition products.

The Thiourea moiety play a role in activation of N-Boc imine in the nucleophilic addition step and in nitroalkane deprotonation

Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, T. Chem. Eur. J. 2006, 12, 466-476.


Three-Component Mannich Reaction

List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337.


Three-Component Mannich Reaction

JACS, 2002, 124 827

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.


Mechanism of the Proline catalizedMannichReaction

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.


Mechanism of the Proline catalizedMannichReaction

List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.


Three-Component Mannich Reaction Optimization

Accelerates the reaction but also suppresses side reactions

Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208-11209.


Three-Component Mannich Reaction Optimization

Reducing the time of reaction

Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-2891.


Access to Chiral 1,2- and 1,4 Diamines

Protecting group dependent regioselectivity

Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas, III, C. F. Org Lett. 2006, 8, 2839-2842.


Green Three-Component Mannich Reaction

The reaction might take place at the interface of organic materiels with water in heterogeneous system.

  • Low loading of catalyst

  • Good yields

  • Clean reaction

  • Need vigourous stirring

  • Environmentally benign

Azizi, N.; Torkiyan, L.; Saidi, M.R. Org. Lett. 2006, 8, 2079-2082.


Synthesis of interesting 1,3-Diaryl-5-spirohexahydropyrimidines

Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.


Mechanism

Wei, H. L.; Yan, Z. Y.; Niu, Y. N.; Li, Q. G.; Liang, M. Y. J. Org. Chem. 2007, 72, 8600.


Mechanism


Application in Synthesis

Antibiotic that inhibits the biosynthesis of chitin in cell wall by competitively inhibiting chitin synthase

Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61, 11393-11404.


Bifunctional Bronsted Acid Activation of the MannichReaction

Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 21, 6756-6761.


Bifunctional Bronsted Acid Activation of the MannichReaction

Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523.


Bifunctional Bronsted Acid Activation of the MannichReaction

Possible intramolecularhydrogenbonding

Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.


Bifunctional Bronsted Acid Activation of the MannichReaction

The addition of a stoichiometric achiral proton source isrequired to accomplish a catalytic cycle of chiral bronstedacidcatalyts

Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 15, 3175-3178.


VinylogousMannichReaction

  • The VMR is rapidly emerging as an important process for the construction of derivatives of –aminocarbonyl compounds

  • Because the iminium and dienol components employed in this addition may be either acyclic or cyclic, a wide variety of adducts may be converted into a broad array of alkaloids and nitrogen heterocyclicles.

Martin, S. F. Acc. Chem. Res. 2002, 35, 895-904.


VinylogousMannichReaction

Access to lactam

  • Addition to the si-face of the imine

Battistini, L.; Rassu, G.; Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron Asymmetry, 1999, 10, 765-773.


VinylogousMannichReaction

Lactam

Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.


VinylogousMannichReaction

1-Bidentate chelation with aldimine

3- Intramolecular desilylation by the lewis basic amide

2-The catalyst-bond imine may react with the siloxyfuran by an endo type addition

4-Product release is facilited by iPrOH

Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2006, 45, 7230-7233.


VinylogousMannichReaction

  • Vinyloxirane is a valuable and highly reactive species

  • Ring-opening and/or rearrangement processes are promoted by Lewis acids or transition-metal catalysts.

Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.


VinylogousMannichReaction

Lautens, M.; Tayama, E.; Nguyen, D. Org. Lett. 2004, 6, 345-347.


VinylogousMannichReaction: Application in Synthesis

  • The indole alkaloids of Ergot family have attracted the attention of synthetic chemists for decades

  • The mostwell-knownrepresentative of this class islysergicacid and rugulovasines A and B representnovel types withinthisfamily

Liu, T. Y.; Cui, H. L.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S. Chen, Y. C. J. Am. Chem. Soc. 2007, 129, 1878-1879.


Summary

  • Significant advancements have been reported in the direct asymmetric MR.

  • High yields, dr and ee are possible using organocatalysis with relatively mild reaction conditions.

  • Highly functionallized products are possible (ie. Nitro-Mannichs, quaternary carbon centers, 3 contiguous chiral centers).

  • Usage in total synthesis still relatively rare.

  • The use of the PMP protecting group remains widespread, although some work has been done to develop relatively <PMP-free protocols>.


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