The Biginelli Reaction: Development and...
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The Biginelli Reaction: Development and Applications
Eric WoerlyCHEM 535 SeminarNovember 24, 2008
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Activity of Monastrol:
Mayer, T. U. and coworkers Science 1999, 286, 971.
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The Biginelli Reaction:Original Report:
Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.Hu, E. H.; Sidler, D. R.; Dolling, U.‐H. J. Org. Chem. 1998, 63, 3454.
Holden, M.S.; Crouch, D. S. J. Chem. Educ. 2001, 78, 1104.
• Variable reaction yields• Limited substrate scope
• Reaction times• Experimentally simple
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Biginelli Reaction Citations
SciFinder Scholar; Research topic search: “Biginelli reaction,” 10/23/2008.
Asymmetric variation,
Applications
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Expanded Substrate Scope
• Mechanistic studies• Reaction conditions
• Library synthesis• Enantioenriched material
• Applications
Kappe, C. O. Tetrahedron 1993, 49, 6937.
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Folkers’ Mechanism
Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55, 3784.
O H
Me O
EtO2C
H2N O
NH2 H2N O
NHNH
H2N
O
Me O
EtO2C
O H
Me
EtO2C
NH
O
NH2
H2N O
NH2
Me O
EtO2C
Me
EtO2C
NH
O
NHX
X = -OH, -NHCONH2
Me
EtO2C
NH
O
NH
Low product yield.Likely not reaction
pathway.
High product yield.Fragmentation to
urea andbenzaldehydenot ruled out.
Hydrolysis of-carbamidocrotonate
suspected.
High product yield.
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Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 8741.Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
Fissekis’ Mechanism
• Evidence for: • Enone to product
• Evidence against:•Reaction with thiourea
O H
Me O
EtO2C
HN O
NH2-H2O
Me O
EtO2C
NH
O
H2NMe
Me O
EtO2CNH
ONHMe
H+
Me O
EtO2C+H+
-H+
Me
EtO2C
N NH
S
observed
Me
EtO2C
N S
NH
MeMe
EtO2C
N O
NH
Me
NH
S
H2NMe
-H2O
not observed
Me
Me
O H
Me O
EtO2C
HN S
NH2
Me
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Kappe, C. O. J. Org. Chem. 1997, 62, 7201.Hu, E. H.; Sidler, D. R.; Dolling, U.‐H. J. Org. Chem. 1998, 63, 3454.
Kappe’s Mechanism
EtO2C
NH
O
NH
HOF3C
EtO2C
O
NH
ONH2
MeMe Me
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Modified Reaction Conditions
Hu, E. H.; Sidler, D. R.; Dolling, U.‐H. J. Org. Chem. 1998, 63, 3454.Kappe, C. O.; Falsone, S. F. Synlett 1998, 7, 718.
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Modified Reaction Conditions:Substrate Scope
Hu, E. H.; Sidler, D. R.; Dolling, U.‐H. J. Org. Chem. 1998, 63, 3454.Kappe, C. O.; Falsone, S. F. Synlett 1998, 7, 718.
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Microwave Assisted Synthesis
Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624.
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Solid‐Phase Synthesis
Wipf, P.; Cunningham, A. Tet. Lett. 1995, 36, 7819.
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Solid‐Phase Synthesis
Valverde, M. G.; Dallinger, D.; Kappe, C. O. Synlett 2001, 6,
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Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49.
Solid‐Phase Synthesis
HN S
NH2 HCl
NH
N
SR3
R2O2CR1
NH
NH
SR3
R2O2CR1
AcOHH2O
NH
NH
OR3
R2O2CR1
NH
NH
NHR3
R2O2CR1
TFAEtSH
NH4OAcMeCN
O H
R1
R3 O
R2O2C
NMPCs2CO390 oC16 hr
NH
NH
OMe
EtO2C
71%
NH
NH
SMe
EtO2C
66%
NH
NH
NHMe
EtO2C
62%
NH
NH
OMe
EtO2C
61%
NH
NH
SMe
EtO2C
59%
CF3 CF3
NH
NH
OMe
EtO2C
68%
NH
NH
SMe
EtO2C
62%
NO2 NO2
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Solid‐Phase Synthesis
Perez, R.; Beryozkina, T.; Zbruyev, O. I.; Haas, W.; Kappe, C. O. J. Comb. Chem. 2002, 4, 501.
• Premature cleavage from the resin
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Fluorous‐Phase Synthesis
Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917.
SubstrateF reaction ProductF
SubstrateF
extraction
+ byproducts
ProductFdetachment
Product
F+ extraction
Product
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Fluorous‐Phase Synthesis
Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917.
N
NH
OMe
EtO2C
O
OFluorous: 71%Original: 74%
N
NH
OMe
EtO2C
O
OFluorous: 55%Original: 62%
N
NH
OMe
EtO2C
O
OFluorous: 69%Original: 78%
OMe
N
NH
OEt
EtO2C
O
OFluorous: 47%Original: 73%
N
NH
OMe
BnO2C
O
OFluorous: mixture
Original: 56%
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Summary of ManifoldsO H
R1
R3 O
R2O2C
HN X
NH2+N
NH
XR3
R2O2CR1
H+
R4R4
O H
R1
R3 O
R2O2C
N
NH
OR3
R2O2CR1
O
OH
HN
NH2
O
O
O
O
O
O
OR1
O H
R2
H2N X
NH2
NH
NH
XR1
R2
HO
O
Solution-phaseMicrowave assisted
Solid-phase
O H
R1
R3 O
R2O2C
HN
NH2
O
O
O
Si(Rfh)3 N
NH
OR3
R2O2CR1
O
O
Fluorous-phase
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Importance of Enantiopure Material
Atwal, K. S. and coworkers J. Med. Chem. 1991, 34, 806.Debonis, S. and coworkers Biochemistry 2003, 42, 338.
Atwal, K. S. and coworkers J. Med. Chem. 1990, 30, 2629.
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Resolution
Atwal, K. S. and coworkers J. Med. Chem. 1991, 34, 806.
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Asymmetric Induction
Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W. Tetrahedron 1992, 48,
• Location of chiral auxiliary
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Asymmetric Synthesis
Munoz‐Muniz, O.; Juaristi, E. Arkivoc 2003, xi, 16.
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Chiral Ytterbium Catalyst
Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386.
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Chiral Ytterbium Catalyst
Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386.
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Chiral Bronsted Acid Approach
Chen, X.‐H.; Xu, X.‐Y.; Liu, H.; Cun, L.‐F.; Gong, L.‐Z. J. Am. Chem. Soc. 2006, 128, 14802.
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Chiral Bronsted Acid Approach
Chen, X.‐H.; Xu, X.‐Y.; Liu, H.; Cun, L.‐F.; Gong, L.‐Z. J. Am. Chem. Soc. 2006, 128, 14802.
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Xin, J.; Chang, L.; Hou, Z.; Shang, D.; Liu, X.; Feng, X. Chem. Eur. J. 2008, 14, 3177.
Chiral Proline Derivative Approach
5 mol % tBuNH2 TFA5 mol %
2-chloro-4-nitrobenzoic acidDioxane:THF (1:4)
rt2.5 d
NH
HO HN
OO H
Me O
R2O2C
H2N O
NH2+
NH
NH
XMe
R2O2CR1
R1
5 mol %
NH
NH
OMe
EtO2C
60%90:10 e.r.
NH
NH
OMe
EtO2C
46%88.5:11.5 e.r.
NH
NH
OMe
EtO2C
60%98.5:1.5 e.r.
Cl
NH
NH
OMe
MeO2C
50%98.5:1.5 e.r.
NH
NH
OMe
iPrO2C
57%87.5:12.5 e.r.
OMeBr
(R)34% - 73%
85:15 e.r. - 99:1 e.r.
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Xin, J.; Chang, L.; Hou, Z.; Shang, D.; Liu, X.; Feng, X. Chem. Eur. J. 2008, 14, 3177.
Chiral Proline Derivative Approach
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Monastrol Synthesis
Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386.
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SNAP‐7941 Synthesis
Goss, J. M.; Schaus, S. E. J. Org. Chem. 2008, 73, 7651.
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Ptilomycalin A Synthesis
Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 1995, 117, 2657.
NH
N
O
O
O
14O
O
TBSO
Me
H OH
H2N
N
O
OHHOO
O
14O
O
TBSO
Me
O
+
EtOHAcOH
morpholineNa2SO4
61%88:12 d.r.
HN N
HNO
O
H
H
Me
Me
OO
NO
H2N
NH2
Ptilomycalin A
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Conclusions
• Mechanistic studies
• Reaction conditions
• Library synthesis
• Enantioenriched material
• Applications
N O
NH2
BF3
F3B
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Future Directions
• Further mechanistic studies
• Asymmetric methods
• Asymmetric solid‐phase synthesis
• Exploration of biological activity
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Acknowledgments
Professor DenmarkCHEM 535 ClassMarty BurkeBurke Group