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Decarboxylative C(sp3)‐N and C(sp3)‐O Cross Coupling
Runze Mao, Johnathan Balon, Adrian Frey and Xile Hu*
Laboratory of Inorganic Synthesis and Catalysis, EPFL, 1015 Lausanne, Switzerland
C(sp3)-heteroatom (N, O) bond are ubiquitous in medicinal, material and agro chemistry. Catalytic C(sp3)-heteroatom cross coupling of alkyl electrophiles with heteroatom
nucleophiles is an underdeveloped disconnection strategy to forge C(sp3)-heteroatom bonds, with the potential to overcome major limitations of existing methods. Here we
employ tandem photoredox and copper catalysis to achieve decarboxylative C(sp3)-heteroatom coupling of alkyl N-hydroxyphthalimide (NHPI) esters with heteroatom
nucleophiles under mild conditions. This method can be used to synthesize a diverse set of valuable products using readily available alkyl carboxylic acids, including many
natural products and drugs. Complementarity in scope and functional group tolerance to existing methods, and proposed mechanism were demonstrated.
Introduction
Acknowledgments
References:
ConclusionsDecarboxylative C(sp3)-heteroatom coupling of alkyl NHPI esters has beenachieved using tandem photoredox and copper catalysis. This coupling methodallows for rapid transformation of readily available alkyl carboxylic acids into alkylaryl amines, primary amines or alkyl aryl ethers, which are important compounds inmedicinal chemistry. This method provides a new disconnection strategy andexhibits complementary scope and functional group tolerance compared totraditional C(sp2)-heteroatom cross coupling and SN2 reactions.
[1] R. Mao, A. Frey, J. Balon, X. Hu, Nat. Catal. 2018, 1, 120. [2] R. Mao, J. Balon, X. Hu, Angew. Chem., Int. Ed. 2018, 57, 9501. [3] R. Mao, J. Balon, X. Hu, Angew. Chem., Int. Ed. 2018, just accepted
Challenge Hypothetical Pathway
This work is supported by the NoNoMeCat Marie Skłodowska-Curietraining network funded by the European Union under the Horizon 2020Program (675020-MSCA-ITN-2015-ETN). We also thank SCNAT andSCS for a financial support through a «Chemistry Travel Award»
5 0 0 6 0 0 7 0 0 8 0 0
0
5
1 0
1 5
W a v e le n g th (n m )
Inte
ns
ity
(A
.U.)
Ir
I r+ G u a ia c o l
I r+ E t3N
Ir+ C u
Ir+ N H P I e s te r
Ir+ C u + N H P I e s te r
Ir+ C u + G u a ia o l
5 5 0 6 0 0 6 5 0 7 0 0
0
5
1 0
1 5
W a v e le n g th (n m )
Inte
nts
ity
(A
.U.)
I r
0 .2 5 m M C uI+ E t3 N
0 .5 m M C uI+ E t3 N
0 .7 5 m M C uI+ E t3 N
0 21 0- 4
41 0- 4
61 0- 4
81 0- 4
0 .0
0 .5
1 .0
1 .5
2 .0
2 .5
[Q u e n c h e r ] (M )
I 0/I
Y = 1 1 7 3 X + 1
R2
= 0 .9 6 8 2
S te rn -V o lm e r p lo t
C uI+ E t3 N (1 :1 ) a s th e q u e n c h e r
Mechanistic Studies and Applications
Late-Stage Modification of Natural Products and Drugs
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