Transcript J. Am. Chem. Soc. 2012

by
William Schulz Bechara
Charette/Collins Literature Meeting
November 13th, 2012
The History of C–H Amination
¨In 1878, the structure of piperidine was still unknown, and A. W. Hofmann made
attempts to add hydrogen chloride or bromine to it in the belief that the compound
possessed unsaturation.¨
R
N
H
Br
Br2
Br
Derivatization
X
X
Wolff M. E. Chem. Rev. 1963, 63, 55.
1
The History of C–H Amination
¨In 1878, the structure of piperidine was still unknown, and A. W. Hofmann made
attempts to add hydrogen chloride or bromine to it in the belief that the compound
possessed unsaturation.¨
1. Br2
2. H2SO4, 140 ˚C
N
H
X
3. OH
N
¨Hofmann made the surprising discovery that […] a tertiary amine was obtained,
and this product was later shown to be octahydroindolizine.¨
(a) Wolff M. E. Chem. Rev. 1963, 63, 55. (b) Hofmann, A. W. Chem. Ber. 1879, 12, 984.
2
The History of C–H Amination
¨In 1878, the structure of piperidine was still unknown, and A. W. Hofmann made
attempts to add hydrogen chloride or bromine to it in the belief that the compound
possessed unsaturation.¨
1. Br2
2. H2SO4, 140 ˚C
N
H
3. OH
N
¨Hofmann made the surprising discovery that […] a tertiary amine was obtained,
and this product was later shown to be octahydroindolizine.¨
(a) Wolff M. E. Chem. Rev. 1963, 63, 55. (b) Hofmann, A. W. Chem. Ber. 1879, 12, 984.
2
Isolation of Intermediates
1. Br2
2. H2SO4, 140 ˚C
N
H
N
3. OH
Br2
OH
H2SO4
N
Br
Wolff M. E. Chem. Rev. 1963, 63, 55.
heat
N
H
H
Br
3
Isolation of Intermediates
1. Br2
2. H2SO4, 140 ˚C
N
H
N
3. OH
Br2
OH
H2SO4
N
Br
Wolff M. E. Chem. Rev. 1963, 63, 55.
heat
N
H
H
Br
3
Hofmann–Löffler–Freytag Reaction
¨In 1909, K. Löffler and C. Freytag extended the scope of this transformation and
demonstrated the synthetic utility of the process as exemplified by their elegant
synthesis of nicotine.¨
R1
n
N
X
R2
n
1. H+, heat
R1
N
R2
2. Base
n = 1,2
x = Cl, Br, I
R1 = alkyl, aryl, H
R2 = alkyl, aryl, H
1. H+, heat
N
Br
N
H
2. Base
N
N
Nicotine
rac
(a) Wolff M. E. Chem. Rev. 1963, 63, 55. (b) Löffler, K.; Freytag, C. Chem. Ber. 1909, 42, 3427.
4
Mechanistic Studies
In 1950s and 60s…
H2SO4
N
N Cl
D
N
Cl
heat
or
hn, Cl2
or
H2O2
H
H2SO4
90 ˚C
D
+
N
N
rac
kH/kD = 3.54
Indication that C−H bond cleavage : rate-limiting step of the reaction
(a) Wolff M. E. Chem. Rev. 1963, 63, 55. (b) Wawzonek, S.; Thelan, P. J. J. Am. Chem. Soc. 1950, 72, 2118.
(c) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1960, 78, 1657.
5
Mechanism
-Acidic Conditions :
-Initiation :
R1
N
X
R1
H
R2
R2
H
X
-Propagation :
R1
N
X
N
N
H
heat
or
hn
R1
H
R2
R1
H
N
H
N
R2
R1
H
R1
N
H
R2
H
N
H
X
Wolff M. E. Chem. Rev. 1963, 63, 55.
0, 1
R2
H
N
H
R2
R1
R1
X
R2
H
R1
-Basic Conditions :
H
N
or
radical initiator
H
-Termination :
R2
OH
R1
R2
H
N
X
H
R2
H
n
R1
N
R2
n = 1, 2
6
Rise of Nitrene Chemistry
MsHN
MsN3
150 ˚C
MsN
+
+ N2
+
NHMs
TsNCl2
Zn dust
reflux
NHMs
NHTs
TsN
+ ZnCl2
(a) Breslow, D. S.; Sloan, M. F. Tetrahedron Lett. 1968, 9, 5349.
(b) Breslow, D. S.; Edwards, E. I.; Linsay, E. C.; Omura, H. J. Am. Chem. Soc. 1976, 98, 4268.
7
Rise of C-H Insertion/ and C-H Activation/Amination
C-H Insertion
C-H Activation
H
H
X N
X
X = PhI, N2,
HOTs,...
R2
EWG
LnMet
N
EWG
MetLn
R2
H
R1
R1
or R2
+ Oxidant
+ Base
H MetLn
R2
H
N
R2
DG
DG = directing group
DG
R1
Y
H N
EWG
EWG
Y = H, OR3
(a) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061. (b) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926.
8
Selectfluor Mediated Oxidation of Alcohols and Aldehydes
Selectfluor
(F-TEDA-BF4)
Cl
BF4
N
Selectfluor (2.20 equiv.)
N F
F4 B
MeCN, reflux, 48 h
87%
OH
O
Selectfluor (1.05 equiv.)
Selectfluor (1.20 equiv.)
MeCN, reflux, 18 h
43%
MeCN, reflux, 31 h
46%
O
OH
O
via
F
H
Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. Synlett, 1994, 831.
O
via
F
9
Unexpected Selectfluor Mediated C-H Functionalization
Selectfluor
(F-TEDA-BF4)
Selectfluor
OH
O
MeCN, reflux, 16 h
Cl
BF4
N
N F
F4 B
BF4
Selectfluor
OH
aq. NaOH
O
MeCN, reflux, 16 h
DCM, 16 h
N
H
Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629.
OH
NHAc
10
Unexpected Selectfluor Mediated C-H Functionalization
Selectfluor
(F-TEDA-BF4)
Selectfluor
OH
O
MeCN, reflux, 16 h
Cl
BF4
N
N F
F4 B
BF4
Selectfluor
OH
aq. NaOH
O
MeCN, reflux, 16 h
DCM, 16 h
N
H
Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629.
OH
NHAc
10
Selectfluor Mediated C-H Functionalization
R3
H
R1
R1
H
BF4
N
OH
R2
Selectfluor (2.2 equiv.)
H
R3CN (0.1 M)
reflux, 16 h
R1
O
O
49%
R1
Et
BF4
HN
50%
N
HN
BF4
O
Cl
30%
Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629.
N F
F4 B
Pr
HN
BF4
N
R2
BF4
O
Selectfluor
(F-TEDA-BF4)
BF4
O
21%
11
Proposed Mechanism - Ritter-Type C−H Amination
Cl
BF4
N
H
OH
R1
R1
F4B
O
R1
R1
F
heat
R2
MeCN
H
R1
R1
R3
R3
R2
R2
O
OH
Selectfluor
R1
R1
R2
O
R1
R1
R1
OH
R1
R1
H
R2
BF4
N
N F
R2
H
R1
N
BF4
OH
H
BF4
N
O
R2
Banks, R. E.; Lawrence, N. J.; Besheesh, M. K.; Popplewell, A. L.; Pritchard, R. G. Chem. Commun. 1996, 1629.
12
Ritter Reaction
i. H2SO4
ii. RCN
iii. Work-up
O
R
N
H
Work-up
H2SO4
RCN
N
R
13
Baran…
Modified Bank's conditions
OH
OH
H
OH
Selectfluor (2.2 equiv.)
OH
t-Bu
N
O
MeCN (0.1 M)
reflux, 16 h
t-Bu
7%
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
14
Optimization
H
i F-TEDA-PF6
CuBr2
Zn(OTf)2
OH
t-Bu
MeCN (0.1 M)
rt, 1 h
ii. NaOH work-up
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
F-TEDA-PF6
N
O
Cl
t-Bu
PF6
N
N F
F6 P
15
Optimization
H
i F-TEDA-PF6
CuBr2
Zn(OTf)2
OH
t-Bu
F-TEDA-PF6
N
Cl
O
PF6
N
MeCN (0.1 M)
rt, 1 h
ii. NaOH work-up
t-Bu
N F
F6 P
R3
N
R1
R1
1:1 MeCN:aq NaOH (1 M)
O
R2
80 °C, 2 h
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
AcHN
R1
R1
R3
R2
15
C-H Amination with Inexpensive Source of Nitrogen
R3
R2
R1
OH
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, rt, 1-2 h
R3
R2
R1
H
2. 1:1 MeCN:aq NaOH (1 M)
80 °C, 2 h
NHAc
OH
NHAc
OH
NHAc
NHAc
t-Bu
84%
53%
OH
42%
(dr 2:1)
O
NHAc
NHAc
OH
91%
81% garm-scale
AcHN
O
NHAc
NHAc
65%
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
61%
23%
16
C-H Amination with Inexpensive Source of Nitrogen
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, 50 ˚C, 4 h
R2
R2
H
R1
NHAc
39%
NHAc
R1
2. aq NaOH (1 M)
work-up
NHAc
51%
NHAc
41%
NHAc
H
62%
NHAc
H
NHAc
+
NHAc
H
90%
NHAc
25%
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
H
36%
(mixture of three unassigned of regioand stereoisomers at C1 and C2)
17
Isomerization of cis-Decalin
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, 50 ˚C, 4 h
H
H
NHAc
H
+
2. aq NaOH (1 M)
work-up
H
+
H
H
NHAc
NHAc
H
16%
NHAc
H
H
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
H
5%
18
Hydrolysis
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, rt, 1-2 h
OH
2. aq NaOH (1 M)
work-up
93%
1. HCl (3 M), 110 ˚C, 24 h
O
OH
78%
NH2
N
2. HCl (3 M)
110 ˚C, 16 h
93% (2 steps)
1. NaOH (1 equiv)
80 ˚C, 2 h
OH
NHAc
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
19
Mechanistic Studies
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
TEMPO (5 equiv)
MeCN, 50 ˚C, 4 h
H
2. aq NaOH (1 M)
work-up
H
D
D
+
D
D
D D
D D
D
D
D
D
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, rt, 1-2 h
2. aq NaOH (1 M)
work-up
O
HN
X
NHAc
D
D
+
D
D
D NHAc
D
D
D
D
D D
KH/KD = 3.5
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547.
20
Mechanistic Hypothesis - SET
CuBr2
+
Pre-mixing also works
Cl
PF6
N
N F
Cun+1
F6 P
O
H
MeCN
50 ˚C
N
work-up
HN
OH
PF6
n = 1 or 2
Cl
N
F6 P
Isolated
(X-ray)
Cun
N CuBr2
Kochi :
+
HF
Cl
N
R
PF6
N H
F 6P
+
Cu(III)Br2F
CuCl2
or CuBr2
or CuBr
CuCl
R
H
?
1. CuBr2 (0.25 equiv)
Zn(OTf)2 (0.5 equiv)
F-TEDA-PF6 (2 equiv)
MeCN, 50 ˚C, 4 h
O
?
HN
2. aq NaOH (1 M)
work-up
(a) Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 2547. (b) Kochi, J. K. Science 1967, 155, 415.
21
F+ Mediated Oxidation of Metal; PdII / PdIV – AuI / AuIII
NHTf
Pd(OAc)2 (10 mol%)
+
N
OTf
F
(2.0 equiv.)
H
F
Pd(OAc)2 (10 mol%)
+
N
N
BF4
F
(2.5 equiv.)
H
Ph
DMF (1.25 equiv)
120 ˚C, 72 h
NHCbz
+
Ph
PhO2S
SO2Ph
N
F
(2.0 equiv.)
Cl
YH
N
+
BF4
N F
F4B
(2.0 equiv.)
N
Tf
F
N
5:1 CF3C6H5/MeCN
MW, 150 ˚C, 1.5 h
Pd(O2CCF3)2 (10 mol%)
F
NCbz
BHT (1 equiv)
PhMe, 3 A M.S., rt
AuPPh3Cl (5 mol%)
Y
Ph
PhB(OH)2 (2.0 equiv)
MeCN, 60 ˚C, 2 h
(a) Nyffeler, P. T.; Durón, S. G.; Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192 . (b) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am.
Chem. Soc. 2009, 131, 10806. (c) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134. (d) Rosewall, C. F.; Sibbald, P. A.; Liskin, D.
22
V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488. (e) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474.