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Transi'on-‐Metal-‐Free Oxyaryla'on of Alkenes with Aryl Diazonium Salts and TEMPONa
Joshua Sacher Wipf Group Current Literature
October 6, 2012
Marcel Hartmann, Yi Li, and Armido Studer J. Am. Chem. Soc. ASAP DOI: 10.1021/ja307638u
RN2BF4
R
O NTEMPO-Na
+
Josh Sacher @ Wipf Group Page 1 of 14 10/6/2012
PharmaceuMcals and Natural Products
OHMe2N
MeO
Effexor
OMe
OMeOMe
OHMeO OH
Combrestatin
O
O
NMe2
Darvon
N
OHHO
O
OH
O
Rohitukine
OHOH
NH
OO O
OH
HO
Coumabiocin F
de Souza, N. J. In Human Medicinal Agents from Plants. ACS, 1993, 331 Cheenpracha, S.; Vidor, N. B.; Yoshida, W. Y.; Davies, J.; Chang, L. C. J. Nat. Prod. 2010, 73, 880.
Josh Sacher @ Wipf Group Page 2 of 14 10/6/2012
Alkene ArylaMon • Heck ReacMon
• TM Catalyzed CarboetherificaMon/aminaMon
XR
RM, ligand, base+
R
[M]
R
Z
X = halogen, OTf
Z = OR, NR2
ZH ZAr
Ar XM, ligand, base
Wolfe, J. P. Synle?, 2008, 2913. Schultz, D. M.; Wolfe, J. P. Synthesis, 2012, 44, 351
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β-‐Aryl-‐α-‐Heteroalkanes • Au-‐Catalyzed oxyarylaMons
– Russell:
– Toste:
Ball, L. T.; Green, M.; Lloyd-‐Jones, G. C.; Russell, C. A. Org. Le?. 2010, 12, 4724 Melhado, A. D.; Brezovich, W. E., Jr.; Lackner, A. D.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 8885
SiMe3R
RPh3PAuCl (5%)
SelectfluorR-OH (10% v/v)
MeCN, 70 °C, 15 h
OR+
B(OH)2R
Rdppm(AuBr)2 (5%)
SelectfluorR-OH (10% v/v)
MeCN, 50 °C, 14 h
OR+
Alkene: N(Phth)
R-OHMeOHEtOHt-BuOHAcOH
Ph-B(OH)279%85%33%62%
Ph-SiMe371%69%[27%]79%
1234
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Diazonium Salts as Aryl Radical Precursors
• Sandmeyer ReacMon
• Meerwein ArylaMon
NN
XCu(I)XSET
– Cu(II)X2
NN
– N2
Cu(II)X2
– Cu(I)X
X
NN
XCu(I)XSET
– Cu(II)X2
EWG PhEWG
Cu(II)X2
– Cu(I)X
PhEWG Ph
EWG
XX –Ph
EWG
+
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Normal ReacMons with TEMPO
N O
TEMPO
N O N OH
R1 R2
OH
H R1 R2
O
[O] [O]
N O Na+
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TEMPO-‐Na
Li, Y.; Studer, A. Angew. Chem. Int. Ed., 2012, 51, 8221
N ONa0
N O Na+
TEMPO TEMPO-Na
TEMPO-NaCF3I
OCF3
O
I
ONaO
cat. napthTHF
R1TEMPO R1F3C
TEMPOR2
R3
R2R3
+ +
N O Na+
TEMPO-NaREDUCING AGENT
N O
TEMPOOXIDIZING AGENT
Josh Sacher @ Wipf Group Page 7 of 14 10/6/2012
TEMPO-‐Na OxyarylaMon Mechanism
RN2BF4
R
O NTEMPO-Na
+
N2+X-
R R
R
OTEMP
N O Na+
N O
SET
N2+X-
+ TEMPO Ph N N OTEMP Ph + N2 + TEMPO
Josh Sacher @ Wipf Group Page 8 of 14 10/6/2012
Scope of the ReacMon: Aryl Diazoniums
R
N2BF4TEMPO-Na
PhCF3, rt, 3 h OTEMP+
RH
4-Ph4-MeO4-CO2Me
4-I4-Br3-Br2-Br
2,4-Me2
Yield89%75%81%83%63%82%84%81%80%
123456789
R
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Scope of the ReacMon: Alkenes N2BF4
R1 TEMPO-Na
PhCF3, rt, 3 h+
R3
R2
R1R3
OTEMPR2
OTEMP
R
R4-Me
4-OMe4-Cl4-CN4-CF34-Br3-F3-Br
3-OMe3-CF32-Br
2-OMe2-F
Yield74%80%70%72%84%82%65%83%76%77%81%79%75%
12345678910111213
OTEMP OTEMPBr
OTEMP
O
OTEMP
OTEMP OTEMP
OTEMP OTEMP
52% 55%
52% 66%
60% 67%
53%, 88:12 dr 49% >98:2 dr
Josh Sacher @ Wipf Group Page 10 of 14 10/6/2012
…So Now What?
OTEMP
ZnAcOH/H2O, rt
99% OH
H
O
mCPBA
CH2Cl2, rt86%
PhSHt-BuPh, 120 °C
99%
Josh Sacher @ Wipf Group Page 11 of 14 10/6/2012
Summary
• New method for oxyarylaMon of alkenes • PotenMally useful alternaMve to TM cat reacMons • Mild condiMons, fast reacMons • Good funcMonal group compaMbility • Unaffected by sterics/electronics • Easy to do further transformaMons
• Drawbacks • Low yields for aliphaMc alkenes • Excess alkene needed • TEMPO-‐Na freshly prepared • More substrates? SelecMvity with dienes?
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Josh Sacher @ Wipf Group Page 13 of 14 10/6/2012
Au-‐catalyzed Mechanism
Melhado, A. D.; Brezovich, W. E., Jr.; Lackner, A. D.; Toste, F. D. J. Am. Chem. Soc. 2010, 132, 8885 Tkatchouk, E.; Mankad, N. P.; Benitez, D.; Goddard, W. A., III; Toste, F. D. J. Am. Chem. Soc. 2011, 133, 14293
X Au L
N NCl
F
HN NCl
Au LF
X
R
R
AuX
FL
R' OH
AuX
FL
OR'R
AuX
FL
OR'R
BPh
HO OH
R
OR'Ph
Ph B(OH)2
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