Iridium-Catalyzed Borylation of Primary C(sp3)-H Bonds
2020.12.11
Reporter:Yu Yibo
Supervisor:Prof. Ma Shengming
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
2
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
3
Background
Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2.
Well developed:
Less developed:
C-H bonds are stronger and less electron rich
4
RR
H
R
R R
R R
R
H
HH
H
RR
FG
R
R R
R R
R
FG
FGH
FG
benzylic C-H
allylic C-H
secondary C-H
tertiary C-H
R H
HH C-H Functionalization
R FG
HH
primary C-H
Background
Brown, H. C. et al., Pure & Appl. Chem. 1987, 59, 879.Aggarwal, V. K. et al., Chem. Eur. J. 2011, 17, 13124.Sigman, M. S. et al., Chem. Rev. 2011, 111, 1417.Morken, J. P. et al., Synlett 2018, 29, 1749.
H2O2, NaOH
or NaBO3R OH Oxidation
MeONH 2,
t-BuO
K
R NH2
CsF
or TBAF, H2 O
R H Protodeboronation
Amination
[Pd]BaseR'X
R R'Suzuki-Miyaura coupling
[Pd]R'X
Base
operational simplicityenvironmentally benign nature
thermal stability of the transmetalation agents
Application of Alkylboron Reagents:
5
R +O
HBO
[RhCl(PPh3)] RBO
O
R +O
HBO
[IrCl(cod)]2/dppe
HBcat
OBO
HBpin
R + HBBr2•SMe2-78 oC
Et2OR
BBr2•SMe2
R''OHB(OR'')2R
R''OH = H2O, alcohol or diol
R
Background
Tranditional Synthesis of Alkylboron Reagents:
(1) From Grignard and Lithium Reagents
(2) via Hydroboration
Cons: Multistep synthetic sequencesFunctionalized precursor
Limited functional group compatibility
Sigman, M. S. et al., Chem. Rev. 2011, 111, 1417. 6
Background
Hartwig, J. F. et al., Science 1997, 277, 211.
Hartwig, J. F. et al., Angew. Chem., Int. Ed. 1999, 38, 3391.
Hartwig, J. F. et al., Science 2000, 287, 1995.
7
Background
8
Bergman, R. G. et al., J. Am. Chem. Soc. 1982, 104, 352.
Graham, W. A. G. et al., J. Am. Chem. Soc. 1982, 104, 3723.Graham, W. A. G. et al., J. Am. Chem. Soc. 1983, 105, 7190.
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
9
Borylation of activated substrates--Benzylic C-H
Ir
BpinN
N SiMe2Bpin
H
Hartwig, J. F. et al., Chem. Sci. 2014, 5, 694.10
R
Bpin
Bpin
A
ArBr (1 eq.)Pd[P(t-Bu)3]2 (5.0 mol%)
NaOH (3 eq.)THF/H2O, 70 oC, 16 h
ArI (1 eq.)Pd[P(t-Bu)3]2 (5.0 mol%)
CsF (2 eq.)THF, 70 oC, 16 h
B
(1.5 eq.)
R
Bpin
Ar RAr
TMSCl (1.2 eq.)KI (1.2 eq.)
H2O (1.2 eq.)CH3CN, 25 oC
SiMe2HR
Bpin
Bpin
Hartwig, J. F. et al., Chem. Sci. 2014, 5, 694.11
Borylation of activated substrates--Benzylic C-H
Hartwig, J. F. et al., J. Am. Chem. Soc. 2015, 137, 8633.12
Borylation of activated substrates--Benzylic C-H
Hartwig, J. F. et al., J. Am. Chem. Soc. 2015, 137, 8633.
IrNN Bpin
Bpin
SiEt3
I
TS-I
II
TSb-II
TSa-II
III
TSb-III
IV
0.0
24.1
17.3
24.9
28.0
11.3
15.6
4.5
+ PhCH3
IrNN Bpin
Bpin
SiEt3
Ph
H
IrNN Bpin
Bpin
SiEt3
Ph
H
IrNN Bpin
Bpin
SiEt3
Ph
H IrNN Bpin
SiEt3
HOR Ir
NN H
SiEt3
Bpin
+ PhCH2Bpin
IrNN H
Bpin
SiEt3
Ph
Bpin
IrNN Bpin
Bpin
SiEt3
Ph
H
IrNN Bpin
Bpin
SiEt3
Ph
H
Gsolkcal/mol
M06, LANL2TZ, 6-31++G**
13
Borylation of activated substrates--Benzylic C-H
IrNN Bpin
Bpin
SiEt3
IrNN Bpin
Bpin
SiEt3
Ar
H
IrNN Bpin
Bpin
SiEt3
Ar
H
IrNN Bpin
SiEt3
H
Ar Bpin
ArCH3
Turnover-Limiting Step
Et3SiBpin
Et3SiHI
II
III
IV
Hartwig, J. F. et al., J. Am. Chem. Soc. 2015, 137, 8633.14
Borylation of activated substrates--Benzylic C-H
Suginome, M. et al., J. Am. Chem. Soc. 2012, 134, 17416. 15
R1Si
CH3
R2Cl
(4 eq.)1.2 mmol
B2pin2 (1 eq.)[Ir(OMe)(COD)]2 (2.5 mol%)
Me4phen (5 mol%)
cyclohexane80 oC, 12 h
i-PrOHEt3N
cyclohexane N NMe
Me Me
Me
Me4phen
55 (93)%a, 78%b 58 (77)%a
H3CSi
H3C Oi-PrBpin H3C
Sii-PrO Oi-Pr
BpinSi
H3C Oi-PrBpinSi
H3C
CH3i-PrO
81%
OSi
H3C Oi-PrBpinSii-PrO
H3C
H3C67%
a 1H NMR yield before isolated in the parentheses. b 120mmol scale.
selected examples:
82%
n-BuSi
H3C Oi-PrBpin
R1SiR2
ClBpin
R1SiR2
Oi-PrBpin
Borylation of activated substrates--Silanes
Himo, F. et al., Chem. Sci. 2015, 6, 1735.
M06, LANL2TZ(f), 6-311+G(2d,2p)
X
16
Borylation of activated substrates--Silanes
“α-silyl effect”α-carbanion stabilizing effect of silicon
Suginome, M. et al., Organometallics 2013, 32, 617017
Borylation of activated substrates--Silanes
Reactivity: Ar-H > Ar-CH3 > Si-CH3 > alkyl-CH3
18
Control experiments:
Suginome, M. et al., Organometallics 2013, 32, 6170
Borylation of activated substrates--Silanes
Hyland, S.N. et al., Tetrahedron Letters 2019, 60, 1096
R1
O
NMe
BpinBCl3, CH2Cl2, -78 oC
then MeOH, H2O R1
O
NMe
BOH
OH
R1 = Me 91%t-Bu 74%
N
NO
NH O
HN B
OH
OH
Me
Me
Ph
Bortezomib (Velcade )
O
NH O
HN B
OH
OH
Me
Me
lxazomib (Ninlaro )
Cl
Cl
OBOH
CO2H
HNO
S
RPX7009 (Vaborbactam )
20
Borylation of activated substrates
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
21
NMe
+ B2pin2[Ir(COD)Cl]2 (5 mol%)
n-octane, refluxN Bpin(3.5 eq.)
BpinBpin
N Bpin
BpinBpin
OMe
95 (81)%a
N Bpin
BpinBpin
<1%
MeO
N Bpin
BpinBpin
77 (52)%a
N Bpin
BpinBpin
NO2
1%
N Bpin
BpinBpin
57 (44)%aN Bpin
BpinBpin
2%
selected examples:
a isolated yield in the parentheses.
Sato, Y. et al., Chem. Commun. 2013, 49, 560123
Borylation of unactivated substrates
Hartwig, J. F. et al., J. Am. Chem. Soc. 2014, 136, 8755.
β-selectivity
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RX CH3
n RX
n Bpin
X = NR, O
B2pin2 (1 eq.)Ir( 6-mes)(Bpin)3
Me4phenKHF2
RX
n BF3-K+
RX
n Ar
[Pd]ArXN N
Me
Me Me
Me
Me4phen(9 eq.)
NEt
Me Bpin
84%
NEt
Et Bpin
103%
GC yield
NEt
n-Pr Bpin
108%Et:n-Pr = 83:17
NEt
n-Bu Bpin
129%Et:n-Bu = 86:14
NMe
n-Pr
69%n-Pr:Me = 96:4
Bpin On-Pr Bpin
146%Et:n-Pr = 85:15
On-Bu Bpin
130%Et:n-Bu = 87:13
Ot-Bu Bpin
112%
selected examples:
Borylation of unactivated substrates
Hartwig, J. F. et al., J. Am. Chem. Soc. 2014, 136, 8755.26
β-selectivity
Borylation of unactivated substrates
Hartwig, J. F. et al., J. Am. Chem. Soc. 2014, 136, 8755.
2. C-HꞏꞏꞏO interaction1. Weak Lewis acid-base interaction
27
Borylation of unactivated substrates
Hartwig, J. F. et al., J. Am. Chem. Soc. 2014, 136, 8755.
1. Repulsive steric interactions
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3. C-HꞏꞏꞏO interactions
2. Weak Lewis acid-base interactions
β-selectivity
Borylation of unactivated substrates
Schley, N. D. et al., J. Am. Chem. Soc. 2020, 142, 6488
IrNN
X
X
postulated3-binding mode
MXX
5-Cp*
R
B2pin2 (1 eq.)[Ir(OMe)(COD)]2 (5 mol%)
Ligand (10 mol%)
neat, 120 oCBpin
N NMe
Me Me
Me
Me4phen82%
N N
L14%
N N
L220%
N N
L37%
F
N N
L4180%
F
N N
L548%
F
N N
L622%
F F
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Borylation of unactivated substrates
R H
B2pin2 (2-3 eq.)[Ir(OMe)(COD)]2 (2.5 mol%)
2-mphen (5 mol%)
cyclooctane, 100 oCO: open vial under N2
R BpinN
N
2-mphenMe
MeBpin
8
O: 79 (65)%a
mono:di = 6:1
Bpin8
BpinOH
Bpin
O: (49)%a
+R
Bpin6
OO
R = H O: 60 (47)%a
Me O: 81 (54)%a
Br Bpin
Bpin
O: 58 (36)%a
N Bpin4
O: 73 (63)%a
a isolated yield in the parentheses.
selected examples:
limitimg reagent
Hartwig, J. F. et al., Science 2020, 368, 736.32
Borylation of unactivated substrates
Hartwig, J. F. et al., Science 2020, 368, 736.
O+ B2pin2
(0.47 M)
(MesH)Ir(Bpin)3 (5 mol%)Ligand (5 mol%)
neat, 100 oC O
Bpin
N NMeD
D
DD D
D
D
2-mphen-d7
NN CD3
2-mphen-d3
NN Me
2-mphen
33
Borylation of unactivated substrates
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
34
Borylation of methane
Poor selectivityOverfunctionalization
Mindiola, D. J. et al., Science 2016, 351, 1424.Sanford, M. S. et al., Science 2016, 351, 1421.
Challenge!35
Borylation of methane
Mindiola, D. J. et al., Science 2016, 351, 1424.
+ B2pin2
2068 kPaCH4
[Ir(OMe)(COD)]2 (1.25 mol%)L3 (2.5 mol%)
cyclohexane, 120 oC, 16 h-MeOBpin
N NMe
Me Me
Me
L3
H3C Bpin CH2(Bpin)2 HBpin O(Bpin)21 2 3 4
+ + +
N NL1
N NBpin
L2
Bpin
2.0%1:2 = 3.9:1
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Borylation of methane
Mindiola, D. J. et al., Science 2016, 351, 1424.
IrXX
Ir1/2 +N
N+ 2 R2B BR2
-XBR2
-X = OMe, ClR2 = pinacolate
IrNN
BR2BR2
BR2
IrNN
BR2BR2
BR2
CH3H
IrNN
BR2BR2
BR2
H2C H
IrNN
BR2BR2
BR2
a
b
b-TS
HCH3
IrNN
HBR2
BR2
BR2
CH3
cc-iso
IrNN
HBR2
BR2
BR2H3C
c-iso-TS
IrNN
HBR2
BR2 dH3C BR2
R2B BR2
H BR2
=
N N
N
N
37
Background01
022.1 Borylation of activated substrates
2.2 Borylation of unactivated substrates
2.3 Borylation of methane
03Summary and outlook
CONTENT >>
38
Summary and outlook
Summary
40
Unactivated substrates :
R H
HH
Methane:
H3C H
IrNN
BR2BR2
BR2
HCH3
IrNN
HBR2
BR2
BR2
CH3
c c-iso
P P MeMe
MeMe
dmpe
Mindiola, D. J.
Summary and outlook
Outlook
1. The utilization of HBpin
2. The utilization of phosphine ligands
3. The borylation of tertiary C-H bonds
4. Metal-free
41