Aldehydes as alkyl carbanion equivalents for additions to carbonyl
compounds.!
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Haining Wang, Xi-Jie Dai and Chao-Jun Li, Nat Chem. DOI:10.1038/nchem.2677!
!
Steph McCabe!
Wipf Group Current Literature 03/04/2017!
!
Steph McCabe @ Wipf Group
Page 1 of 15
1 3/4/2017
Strategies to Access 2° and 3° Alcohols by
Carbonyl Addition !
stoichiometric
[M]
X
R1
R2
[M]
R1
R1, R2, R3, R4 = alkyl, aryl or H
X = Cl, Br, I, Sn etc
[M] = Mg, Li, Cu, Al, Zn, Ti etc
R2
metallation
O
R4
R3
O
R3
R2
R1
cat. L*[M]-H
H
R1
R2
R1
R4
R3 OH
O
R4
R3
R2
R4
THIS
WORK
N
R1
[M]L*
NH2
R2
N2H4
O
R1
R2
hydrazone
fromation
metal-hydride
addition
R1, R2, R3, R4 = alkyl, aryl or H
[M] = Ru
R1, R2, R3, R4 = alkyl, aryl or H
[M] = Ir, Rh, Ru, Cu, Ni, etc.
2 Steph McCabe @ Wipf Group
Page 2 of 15
3/4/2017
Strategies to Access 2° and 3° Alcohols by
Carbonyl Addition !
stoichiometric
[M]
X
R1
R2
O
[M]
R1
R2
R3
R4
R1
R3 OH
R4
R2
metallation
R1, R2, R3, R4 = alkyl, aryl or H
X = Cl, Br, I, Sn etc
[M] = Mg, Li, Cu, Al, Zn, Ti etc
Limitations: !
!
•  Stoichiometric, pre-formed organometallic reagents!
!
•  Air & moisture sensitive!
!
•  Copious metal waste!
!
•  Pre-synthesis of organohalide substrates!
!
•  high nucleophilicity and basicity (= poor selectivity)!
3 Steph McCabe @ Wipf Group
Page 3 of 15
3/4/2017
Strategies to Access 2° and 3° Alcohols by
Carbonyl Addition !
O
R2
cat. L*[M]-R
R
R2
R1
R1
R3
R2
R4
R1
[M]L*
R4
R3 OH
copper-catalysed borylative enantioselective additions
S
PPh2
(5 mol%)
PPh2
O
Me
Ph
CuCl (5 mol%)
+
O
Ph
Me
Ph
20 mol% NaOt-Bu, 1.1 equiv. B2(pin)2
THF, 22 °C, 8 h;
then NaBO3•4H2O, THF/H2O (1:1), 22 °C, 4 h
HO
OH
HO
HO
Ph
76%, 98:2 dr
95:5 er
O
Et
O
O
OH
tylonolide
JACS, 2014, 136, 11304 (Hoyveda)
4 Steph McCabe @ Wipf Group
Page 4 of 15
3/4/2017
Strategies to Access 2° and 3° Alcohols by
Carbonyl Addition !
O
metal-hydride
addition
R2
H
cat. L*[M]-H
R1
R1
R2
R2
R4
R3
R1
[M]L*
R4
R3 OH
Ru-catalyzed reductive coupling
Ph
+
HClRu(CO)(PCy3)2 (cat 6 mol%)
AgOTf (9 mol%)
100 °C, 2-PrOH (300 mol%)
O
OH
Ph
Ar
Ar
Me
ACIE, 2016, 55, 16119 (Krische)
diastereoselective ketone 1,2-addition addition of enantioenriched cuprates
R2
R3
+
R1
1.5 equiv.
O
R4
1.0 equiv.
Cu(OAc)2 (5 mol%)
(S,S)-Ph-BPE (6 mol%)
Ph
Ph
P
P
Ph
Ph
(MeO)2MeSiH, t-BuOH
cyclohexane
r.t., 12 h
R2
R3
R1
4
HO R
>30 examples
90-99% ee
Science, 2016, 353, 144 (Buchwald)
5 Steph McCabe @ Wipf Group
Page 5 of 15
3/4/2017
This Work!
O
N 2H 4
O
R1
N
R2
R1
H2O
O
R3
R4
R1
NH2
R1
R2
R3
OH
R4
R2
hydrazone
formation
R1, R2 = alkyl, aryl or H
L
P
Cl
Ru P
Cl
R2
N
H 2N
R1
R3 R4
cat. [M]L*
N2
R3, R4 = alkyl, aryl or H
Cl
R3 H L
Ru
P
N
N
P
O
R4
R2
R1
H Cl L
R3
N
N Ru P
P
O
4
R
R2
- N2
R1
R3
OH
R4
R2
Zimmerman-Traxler TS
6 Steph McCabe @ Wipf Group
Page 6 of 15
3/4/2017
Optimization!
O
O
H
H 2N
N2H4•H2O
(1.3 equiv.)
Ph
H
THF, r.t. 30 min
Ph (1 equiv.)
[Ru(p-cymene)Cl2]2 (0.75 mol%)
ligand (1.5 mol%)
N
Ph
Base (25 mol%), additive (50 mol%)
THF, 45 °C, 3 h, under N2
(1.2 equiv.)
Entry!
Ligand!
Base!
Additive!
OH
Ph
Ph
H
Yield (%)!
1!
-!
K3PO4!
CsF!
13!
2!
dppe!
K3PO4!
CsF!
78!
3!
dppp!
K3PO4!
CsF!
92!
4!
dppf!
K3PO4!
CsF!
58!
5!
dmpe!
-!
CsF!
3!
6!
dmpe!
K2CO3!
CsF!
57!
7!
dmpe!
Cs2CO3!
CsF!
51!
8!
dmpe!
KOtBu!
CsF!
82!
9!
dmpe!
K3PO4!
CsF!
95!
10!
dmpe!
K3PO4!
-!
85!
Ph
P
dppe = Ph P
Ph
dppp = Ph P
Ph
Ph
P
Ph
Ph
Ph
P
dppf =
Fe
Ph
Ph
P
Ph
dmpe =
Me
P
Me
Me
P
Me
7 Steph McCabe @ Wipf Group
Page 7 of 15
3/4/2017
Substrate Scope: Hydrazone Precursor Carbonyl!
O
Me
R1
N2H4•H2O
(1.3 equiv.)
O
H
R1
THF, r.t. 30 min
Ph (1 equiv.)
[Ru(p-cymene)Cl2]2 (0.75 mol%)
dmpe (1.5 mol%)
NH2
N
Me
R1
K3PO4 (25 mol%), CsF (50 mol%)
THF, 45 °C, 3 h, under N2
H
(1.2 equiv.)
OH
Ph
H
Aromatic aldehydes
MeO
Me
O
Me
OH
Ph
OH
Cl
F3C
Me
OH
Ph
H
86%
OH
H
94%
Me
Me
Ph
65%
OH
OH
Cl
H
Ph
97%
Me
Ph
H
85%
Me
O
NC
Me
OH
O
H
98%
Ph
H
Ph
H
58%
Cl
Me
OH
Ph
H
94%
Me
Me
OH
OH
Ph
H
43%
Me
N
Me
Ph
OH
Ph
H
95%
H
67%
8 Steph McCabe @ Wipf Group
Page 8 of 15
3/4/2017
Substrate Scope: Hydrazone Precursor Carbonyl!
O
Me
R1
O
R2
N2H4•H2O
(1.3 equiv.)
NH2
N
R1
THF, r.t. 30 min
R2
(1.2 equiv.)
Me
ketones
Ph (1 equiv.)
[Ru(p-cymene)Cl2]2 (0.75 mol%)
dmpe (1.5 mol%)
K3PO4 (25 mol%), CsF (50 mol%)
THF, 45 °C, 3 h, under N2
Me
OH
30% (*80 °C, 20 h, K-OtBu)
Me
N
Ph
75%
Me
OH
Ph
H
H
aliphatic aldehyde
OH
23% (*80 °C, 20 h, , K-OtBu)
OH
O
Ph
R2
Me
Me
Me
OH
Ph
Ph
heterocyclic aldehydes
Me
R1
53%
OH
Ph
H
20%
9 Steph McCabe @ Wipf Group
Page 9 of 15
3/4/2017
Substrate Scope: Electrophilic Carbonyl!
R4
N2H4•H2O
(1.3 equiv.)
O
Ph
Ph
THF, r.t. 30 min
NH2
N
H
(1.2 equiv.)
O
R3
(1 equiv.)
R1
[Ru(p-cymene)Cl2]2 (0.75 mol%)
dmpe (1.5 mol%), K3PO4 (25 mol%)
CsF (50 mol%), THF, 45 °C, 3 h
R4 OH
R3
H
aromatic ketones
F3C
Ph
OH
OH
Ph
Ph
Et
OH
Ph
Me
OH
OMe
89%
Ph
Me
OH
Ph
Me
OH
93%
93%
65%
Ph
Me
OH
Ph
HO
Ph
OH
Br
I
F
p-Br, 86%
o-Br 71%
79%
84%
76%
70%
heterocyclic ketones
Ph
Me
OH
O
80%
10 Steph McCabe @ Wipf Group
Page 10 of 15
3/4/2017
Substrate Scope: Electrophilic Carbonyl!
O
R4
Ph
O
N2H4•H2O
(1.3 equiv.)
Ph
THF, r.t. 30 min
R3
NH2
N
H
(1.2 equiv.)
(1 equiv.)
R1
[Ru(p-cymene)Cl2]2 (0.75 mol%)
dmpe (1.5 mol%), K3PO4 (25 mol%)
CsF (50 mol%), THF, 45 °C, 3 h
R4 OH
R3
H
aliphatic ketones
Ph
HO
Ph
Me
OH
88%
Ph
Me
OH
OMe
55%
Ph
Me
HO
Ph
85%
71%
Ph
OH
Ph
Me
56%
OH
Me
82%
Et
OH
Et
50%
Ph
Me
OH
n-C5H11
75%
11 Steph McCabe @ Wipf Group
Page 11 of 15
3/4/2017
Substrate Scope: Electrophilic Carbonyl!
R4
N2H4•H2O
(1.3 equiv.)
O
Ph
Ph
THF, r.t. 30 min
O
R3
NH2
N
(1 equiv.)
R1
[Ru(p-cymene)Cl2]2 (0.75 mol%)
dmpe (1.5 mol%), K3PO4 (25 mol%)
CsF (50 mol%), THF, 45 °C, 3 h
H
(1.2 equiv.)
R4 OH
R3
H
labile functionality tolerated
Ph
Me
OH
OMe
N
Me
O
77%
Ph
Me
OH
OMe
88%
O
Ph
Ph
O
OH
N
H
85%
Ph
Me
OH
OH
Ph
50%
complex natural product
H
H
Ph
OH
H
H
68%
12 Steph McCabe @ Wipf Group
Page 12 of 15
3/4/2017
Substrate Scope: Electrophilic Carbonyl!
O
Ph
O
Ph
N2H4 in THF (1.0 M)
r.t. 30 min
R3
NH2
N
H
(1 equiv.)
R1
[Ru(p-cymene)Cl2]2 (1.5 mol%)
dmpe (12 mol%), K3PO4 (25 mol%)
CsF (50 mol%), DMSO, t-BuOH, 120 °C, 6 h
H
OH
R3
H
aromatic/aliphatic aldehydes
OH
OH
Ph
Ph
48%
OH
Et
Ph
61%
Et
Ph
n-C7H15
50%
13 Steph McCabe @ Wipf Group
Page 13 of 15
3/4/2017
Asymmetric Variant!
O
Ph
(1 equiv.)
Ph
O
N2H4•H2O
THF, r.t., 30 min
Ph
NH2
N
[Ru(COD)Cl2]n (1.5 mol%)
L1(1.5 mol%), L2 (1.5 mol%)
Ph
K3PO4 (25 mol%),THF, 50 °C, 4 h
OH
Ph
52% yield
76:25 er
Ph
Ph
P
Me
P
Ph
Ph
(S,S)-Ph-BPE
L1
H 2N
NH2
Ph
Ph
(S,S)-DPEN
L2
14 Steph McCabe @ Wipf Group
Page 14 of 15
3/4/2017
Conclusions!
O
N 2H 4
O
R1
N
R2
R1
H2O
R1, R2 = alkyl, aryl or H
R3 R4
cat. [M]L*
NH2
R1
R2
R3
OH
R4
R2
hydrazone
formation
N2
R3, R4 = alkyl, aryl or H
•  Hydrazones act as carbanion equivalents for Ru-­‐catalyzed carbonyl 1,2-­‐addiBons to aldehydes and ketones to yield 2° and 3° alcohols •  Green alternaBve to classic methods that uBlize stoichiometric organometallic reagents •  Hydrazones can be derived from naturally-­‐occurring aldehydes and ketones •  Excellent chemoselecBvity •  Broad funcBonal group tolerance •  ReacBon scope largely features at least one aromaBc carbonyl partner •  ReacBon moderately enanBoselecBve 15 Steph McCabe @ Wipf Group
Page 15 of 15
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