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Rachel A. Byerly Current Literature June 20, 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)
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
NH
O Pd(OAc)2 (10 mol%)
ligand (40 mol%)
toluene, O2 (1 atm), 70oC
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
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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• Solvent effect and oxidant screening
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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• Ligand to Pd (II) ratio and effect of Pd source
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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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
O Pd(OAc)2 (10 mol%)
ligand (40 mol%)
toluene, O2 (1 atm), 70oC
N N
O O
H H
+
1a 2a3a
X X X
25endo
4559exo
isoquinoline (% yield)quinoline (% yield)
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
NH
O Pd(OAc)2 (10 mol%)
ligand (40 mol%)
toluene, O2 (1 atm), 70oC
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
O Pd(OAc)2 (10 mol%)
ligand (40 mol%)
toluene, O2 (1 atm), 70oC
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
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
NH
O
Pd(OAc)2 (10 mol%)
ligand (40 mol%)
toluene, O2 (1 atm), 70oC
Ph
n
n = 1
n = 2
n = 3
N
O
H
Ph
n
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• Transition State Model
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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• Key nOe interactions
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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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
Yip, K.; Zhu, N.; Yang, D. Org. Lett. 2009, 11, 1911-1914.
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