rachel a. byerly current literature june 20, 2009ccc.chem.pitt.edu/wipf/current...

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Rachel A. Byerly Current Literature June 20, 2009

Rachel Byerly @ Wipf Group of 16 7/7/2009

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• Cascade Cyclization Reactions

• “The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to syntheticstrategies.”

K. C. Nicolaou

Five Classifications of Cascade Cyclization Reactions:1. Nucleophilic Cascades2. Electrophilic Cascades3. Radical Cascades4. Pericyclic Cascades5. Transition-Metal-Catalyzed Cascades

• generates molecular complexity enantioselectively• catalytic• bond construction unparalleled by nature• Pd—blossomed into powerful tool over the past 25 years• Heck is most popular Pd-catalyzed cascade reaction

Nicolaou, K.C.; Edmonds, D.J.; Bulger, P.G. Angew. Chem. Int. Ed. 2006, 45, 7134-7186.


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• Pericyclic Diels-Alder/Schmidt cascade to stenine:

Nicolaou, K.C.; Edmonds, D.J.;Bulger, P.G. Angew. Chem. Int. Ed.2006, 45, 7134-7186.

Y. Zeng, S. Reddy, E. Hirt, J. Aubé,Org. Lett. 2004, 6, 4993-4995.

Et

N3

TMSO

O

+

SnCl4, CH2Cl2,

-78oC to -55oC

OEt

OTMS

N3

O

Cl4Sn

Cl4Sn Et

OTMS

NNN

H

exo-Diels-Alder reaction

N

Et

OTMS

HOCl4Sn

NN

intramolecular Schmidt reaction + silyl ether hydrolysis

70%

3:1 a:b

N NO O

O O

Et EtH

H

H H

HH

+

a b

a onlyN

EtH

H

HO

O Me

H

stenine

!!

!!


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• Sample of Heck cyclization cascades and their weaknesses:

Barluenga, J.; Fernández, M.A.; Aznar,F.; Valdés, C.Chem. Eur. J. 2005, 11, 2276-2283.

Hitce, J.; Baudoin, O. Adv. Synth. Catal. 2007, 349, 2054-2060.

• needs activation

• only forms2 new bonds

Yip, K.; Zhu, N.; Yang, D. J. Am.Chem. Soc. 2006, 128, 3130-3131.

• only forms2 new bonds

Ph Br H2N

Br

+

Pd, ligand

base

HN

Ph70%

Br

HNPh

Br

NPh

alkenylamination Heck

reaction

X

Br

CN

C(sp3)-H

activation

Pd, ligand

base

X = BrX = Cl

X

Br

CN

X = BrX = Cl

NC

CN

77%

71%

Heckcyclization

NH

X

O

Pd(OAc)2 (10 mol%)

pyridine (40 mol%)

toluene, O2 (1 atm), 50oC

N

X

O

70-95%


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• Heck-type cascade cyclization popularity

…not without drawbacks

1. preactivation of precursors leads to stoichiometric amounts of hydrohalic or triflic acids2. palladium complexes usually contain air-sensitive phosphine ligands3. reaction scope limited to carbon-carbon bond formation

Goal:

to refine methodology toward cascade cyclization reactions that are more atom-economicaland applicable to carbon-heteroatom bond formation

Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.


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• Previous work…..

• used Pd(OAc)2/pyridine and Pd(TFA)2/(-)-sparteine as the catalyst systems• obtain racemic and enantioenriched indoline derivatives• free of any undesired monocyclization products even in the absence of tandem relays

Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.Yip, K.; Zhu, N.; Yang, D. J. Am. Chem. Soc. 2006, 128,3130-3131.


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• Synthesis of starting material (1a)

• Title Paper: Palladium Catalyzed Highly Diastereoselective Oxidative Cascade Cyclization Reactions

• isoquinoline and quinoline as ligands instead of pyridine and (-)-sparteine• Pd(OAc)2/isoquinoline or quinoline as the catalyst system• unsaturated anilides cyclize under an oxygen atmosphere (1 atm)• furnish structurally versatile indoline derivatives• good yields (~80%)• make 1 C-N bond and 2 C-C bonds in a single step (one of which is a quaternary center)• excellent diastereoselectivity (dr > 24:1)


J. Chem. Res., Synopses. 1988, 10, 346-347.

aniline: $45.10 for 500 gallyl chloride: $25.60 for 500 mL(Aldrich)

Cl+

1. (Boc)2O, THF

2. NaH3. HCl, H2O 90%

HN

BF3 OEt

toluene reflux

NH2NH2

Cl

O

pyridine

CH2Cl20oC to rt

NH

O

82%


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• Ligand screening

5.6:17689isoquinoline7

4.2:17086quinoline6

1.5:15673pyridine5

1:1.43952quinoxaline4

1:3.226428-methylquinoline3

1:6.32465acridine2

1:8.339436-methoxyquinoline1

product ratio (2a:3a)yield (%) 2a+3aconversion (%)ligandentry


NH

O Pd(OAc)2 (10 mol%)

ligand (40 mol%)


N N

O O

H H

+

1a 2a3a


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• Basicity correlation with reaction conversion and product ratio

• hypothesized that the basicities played a major role in suppressing olefin isomerization



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• Solvent effect and oxidant screening



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• Ligand to Pd (II) ratio and effect of Pd source



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• Scope of the cascade cyclization using quinoline and isoquinoline as ligands

55:534:29OMe

70:355:7F

81:360:9H

isoquinoline (2a:3a % yield)quinoline (2a:3a %yield)X

NH


ligand (40 mol%)


N N

O O

H H

+

1a 2a3a

X X X

25endo

4559exo

isoquinoline (% yield)quinoline (% yield)


NH


ligand (40 mol%)


N

O

H

+

1d 2d3d

N

O

H


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• Scope of the cascade cyclization using quinoline and isoquinoline as ligands, continued

NH


ligand (40 mol%)


1e

N/A553

77N/A2

N/A331

isoquinoline (% yield)quinoline (% yield)n

key scope points: • quinoline and isoquinoline have similar rxn times • Pd/(OAc)2/isoquinoline resulted in better yields• cyclization not correlate with substrate’s electronic properties• endo-olefinic products form by secondary addition of palladium hydride to the exo moiety


NH

O

Pd(OAc)2 (10 mol%)

ligand (40 mol%)


Ph

n

n = 1

n = 2

n = 3

N

O

H

Ph

n


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• Transition State Model



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• Key nOe interactions



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• Conclusions:

• new palladium-catalyzed oxidative cyclization reactions• highly diastereoselective• construct three new bonds and two chiral centers in a single step (one of which is a quaternary center)• Pd(OAc)2/isoquinoline and Pd(OAc)2/quinoline systems are an extension of the well documented Pd(OAc)2/pyridine system • pushes past the previous reaction scope to include formation of a carbon-nitrogen bond• overall more atom-economical and applicable in pursuit of green chemistry



rachel a. byerly current literature june 20, 2009ccc.chem.pitt.edu/wipf/current...

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