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Topic: N-Heterocyclic carbene catalysis
N-heterocyclic carbenes (NHC’s) are neutral species that possesses a divalent carbon atom with an electron
sextet. They were recognized and isolated as stable molecules at the end of 1980’s and beginning of 1990’s
but the first evidence of their existence as reactive intermediates was presented almost hundred years
earlier. NHC’s have broad field of application in organometallic chemistry (ligands for metathesis,
hydrogenation not covered here) and in organocatalysis as nucleophilic catalysts.
1
NHC catalysis
NHC’s can be generated from the parent imidazolium, triazolium or thiazolium salts by treatment with a base
and can be represented both as ylides or carbenes.
Y
X
N R
Y
X
N R
Base
Y
ylide
carbene
S
N R'
thiazolylidene
R N
X
N R
H
N R'
imidazolylidene
R N
N
N R'
triazolylidene
General Structures of nucleophilic carbenes
Nolan ACIE 2007, 46, 2988
- pKa values of precatalysts and 13C shifts NHC’s
Glorius ACIE 2010, 49, 6940
- NHC nucleophilicity:
The observed reactivity of NHC originates from their high Lewis basicity, not nucleophilicty.
The attack of NHCs to the carbonyl group of aldehydes occurs under kinetic control and has a lower degree
of reversibility.
Mayr ACIE 2011, 50, 6915
- The effect of the N-substitution is also of important consequence in both the properties of the NHC and in
the catalytic pathway.
1
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Bode Chem. Sci. 2012, 3, 192
See also Rovis Chem. Lett. 2008, 37, 2
NHC intermediates:
- While the initial NHC-aldehyde adducts have been isolated and reported by many groups, the enaminol
Breslow intermediate (see Thiamine catalyzed Benzoin reaction mechanism) remains elusive.
2
Cyanide ion catalyzed benzoin condensation
O
O
O
KCN
Ph
H
Ph
The benzoin condensation was the
first organic reaction with its
mechanism fully elucidated.
O
OH
H
Ph
Ph
CN
CN
Ph
HO
Ph
Ph CN
OH
O
H
OH
O
Ph
Ph CN
Ph
Liebig Annalen der Pharmacie, 1833, 3, 249
For mechanism: Lapworth, J. Chem. Soc., Trans. 1903, 83, 995 & 1904, 85, 1206
In the benzoin reaction (and many other NHC-catalyzed reactions), the aldehyde carbon undergoes a
reversed polarity from an electrophilic center to being a nucleophilic center. This concept is termed
“umpolung.”
Corey JOC 1975, 40, 231 & Seebach ACIE 1979, 18, 239
3
Thiamine catalyzed benzoin reaction
Thiamine or vitamin B1 is the first water soluble vitamin described and an important coenzyme in a number
of biochemical reactions.
In the beginning of 1940’s Ugai found that thiamine in the presence of a base catalyzed the benzoin reaction.
Recognizing the similarities in reactivity of the cyanide anion and thiamine, Breslow proposed that a
stabilized carbene is responsible for the reactivity of thiamine. This work of Breslow in 1950’s constitute first
mechanistic description of NHC’s.
2
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Ugai J. Pharm. Soc. Jpn. 1943, 63, 296 & Breslow JACS 1958, 80, 3719
The mechanism of the benzoin reaction is complicated, see
Breslow Tet. Lett., 1994, 35, 699 & Leeper, JOC, 2001, 66, 5124.
4
Acyl anion
As mentioned above upon NHC addition to a carbonyl, the latter undergoes a reversed polarity and this
newly generated acyl anion has been used in many transformations.
For a review of catalyzed reactions of acyl anion equivalents, see Johnson ACIE 2004, 43, 1326
4.1
Enantioselective 1,2 additions – Benzoin reaction
Sheehan JACS 1966, 88, 3666 & Enders ACIE 2002, 41, 1743
For computation investigation, see Houk PNAS 2004, 101, 5770
3
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- A catalytic enantioselective intramolecular benzoin reaction:
Suzuki ACIE 2006, 45, 3492 & ACIE 2011, 50, 2297
- A cross-benzoin between aldehydes and ketone has also been achieved using very electron poor ketone
substrate.
Enders Chem. Commun. 2010, 46, 6282
- A more challenging problem is the chemoselective cross-benzoin reaction between two aldehydes, due to
the self condensation
Ryu and Yang Org. Lett. 2011, 3, 880
See also: Zeitler and Connon JOC, 2011, 76, 347 & Synthesis 2011, 2, 190
- Aza-benzoin variant - Aldehyde-imine coupling via acyl anion chemistry
O
R1
H +
R4
N
O
I
N
O
R2
O
S
O
R
H
N
N
H
H
N
Et
R5
(15 mol %)
base
R
R4
R5
O
up to 90%
up to 87% ee
Miller JACS 2005, 127, 1654
4
Update to 2013
4.2
Bode Research Group
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1,4 additions – Stetter reaction
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- Mechanism and early example
Enders Helv. Chim. Acta. 1996, 79, 1899
- The research program of Prof. Tom Rovis (Colorado State University) has established the current state of
the art for enantioselective Stetter reactions.
Rovis JACS 2002, 124, 10298
- Stetter reaction is not as well studied mechanistically as benzoin reaction:
Rovis OL 2011, 13, 1742
4.2.1
Intermolecular variants
Many aldehydes can be used in Stetter reaction unfortunately formaldehyde undergoes benzoin
condensation too fast and can not be used as a C1 source. However recently group of prof. Chi reported use
of biomass-based carbohydrates as formal formaldehyde (C1) source for intermolecular Stetter reaction:
5
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Chi JACS, 2013, 135, 8113
- Enantioselective variants
Enders Chem Commun 2008, 3989
- The effect of the catalyst conformation in an intermolecular Stetter reaction
Rovis JACS 2009, 131, 10872 & Rovis and Houk JACS 2011, 133, 11249
- A bifunctional additive (catechol) was found to accelerate the reaction’s rate
6
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Rovis JACS 2011, 133, 10402
5
Summary: reactive intermediates generated from -functionalized aldehyde
R2
O
N
N
N R
3
R2
N
Base
R2
N
ylide
carbene
R1
N
N R
3
N
N R azolium
3
H
H
OH
R1
OH
R2
N
R1
N N
OH
R2
N
R1
N N
R3
N N
R3
Breslow intermediate
O
R1
H
H+
transfer
R3
acyl anion
oxidation
R2
N
H
acyl azolium R1
R2
N
N N
R3
homoenolate
R2
N a,b unsaturated
acyl azolium
N N
O
R1
enolate
O
R2
N
protonation
H
N N
R3
R3
Recently group of Prof. Chi reported generation and reactions of the homoenolates from saturated esters.
Chi Nat. Chem. 2013, 5, 835
For a full mechanism of cyclopentene formation see 6.4 or the reference above
6
6.1
Homoenolate reactions
-lactone synthesis
For a review of NHC-homoenolate chemistry, see Nair Chem. Soc. Rev. 2011, 40, 5336
7
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O
R1
O
H
H
R1
Mes
N
OH
N
Mes
N
Mes
R1
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O
R1
H
+
R2
N
N
Cl
N Mes
(8 mol %)
DBU (7 mol %)
THF/t-BuOH
rt, 3-15 h
O
H
Mes N
O
R1
R2
Mes
Mes
Breslow intermediate
O
O
O
R2
Mes
N
R1
OH
R2
O
O
Mes
N
R1
N
Mes
R1
R2
O
OH
R1
N
Mes
Mes
N
homoenolate
O
N
activated carboxylate
Mes
Mes
N
H
R2
Bode JACS 2004, 126, 8126 and Glorius ACIE 2004, 43, 6205
- Rendering -lactone formation enantioselective however remains challenging
You Adv. Synth. Catal. 2008, 350, 1885
6.2
-lactam synthesis
Bode OL 2005, 7, 3131 & Bode JACS 2008, 130, 17266
Bode ACIE, 2012, 51, 9433
- A Lewis acid can also be used for preorganization; however, an uncommon protecting group was needed.
8
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Scheidt Nature Chem. 2010, 2, 766
- A Bronsted acid was found to improve the selectivity of a -lactam formation reaction
Rovis JACS 2011, 133, 12466
6.3
Other electrophilic acceptors
O
Ph
O
O
+
R1
N
H
R2
R3
N
N BF4
N Me
O
O
O
N
Ph (20 mol %)
Et3N (20 mol %)
R1
H
MeOH MeO
OH
N 3
R
R1
R3
R2
R2
62-80%
81-93% ee
Scheidt JACS 2008, 130, 2416
Ar N
N
O
+
R
Cl
N Ar
O
MeO
Ar = 2,6-(iPr)2C6H3
O
N
(10 mol %)
O
KOtBu (10 mol %)
H
H +,
CH3OH
NH O
R
R
OMe
Zhang and Ying OL 2008, 10, 953
6.4
Cyclopentene synthesis
O
Mes N
O
H
Ar'
Ar
(6 mol %)
DBU (12 mol %)
+
R1
Cl
N Mes
Ar
R1
Ar'
55-88%
O
O
OH
Mes
N
Ar
N
Ph
Ph
Ph
Ph
O
Mes
N
Ar
Mes
homoenolate equivalent
N
O
Mes
N
O
Ph
N
MesAr
Ph
O
Ar
O
Ph
Ph
Mes
Nair JACS 2006, 128, 8736
- Alternatively the mechanism of cyclopentene formation reaction maybe considered as Benzoin oxy−Cope
rearrangement, rather than homoenolate chemistry.
9
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Bode JACS 2007, 129, 3520
- Recently Scheidt has revisited cyclopentene formation and applied the use of a Lewis acid
Scheidt JACS 2010, 132, 5345
For a review on NHC-Lewis acid cooperativity, see Scheidt Chem. Sci. 2012,3, 53
6.5
Cyclopentane synthesis
The nature of the precatalyst used controls the stereochemical outcome that results in two complex
pathways with absolute control of product selectivity
Bode OL 2009, 11, 677
7
Enolate
7.1
Catalytic generation of NHC-bound enolate
R2
O
R1
R2=H
R2
O–
Cl
R1
R2
OH
SO3Na R2=H
R1
Cl
7.2
R2
R2=H
H
R
N
R
N
Y
H
R2
enolate
Hetero Diels-Alder reaction from aldehydes and related compounds
10
O
R1
C
R1
O
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Ph
O
R1 +
H
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Cl
O
Mes
N
N
N
O
R1
R2
Ph
Me
Ph
Ph
Ph c-Hex
n-C9H19 Me
OTBS Ph
R1
0.5 mol% cat
1.5 equiv NEt3
0.2 M EtOAc, rt
CO2Me
Diels-Alder
H
R2
N
N
Mes
Mes
N
N
N
(Z)-enolate
Me
nuc. addition
O
Ph
O–
Ph
N
99
99
86
99
97
88
98
76
71
80
Me
Me
O
MeO2C
O
MeO2C
O
MeO2C
d.r. % yield % ee
>20:1
15:1
>20:1
>20:1
3:1
Ph
Me
MeO2C
O
O
R2
Mes N N
N
O
O
Cl
Elimination
Me
O–
H
Cl
Me
N
Ph
N
N
Cl
Bode JACS 2006, 128, 15008
7.2.1 Hetero Diels-Alder reaction, a bisulfite salt variant
- The issue of handing and storage of chloroaldehyde was addressed by its in situ generation via a masked
bisulfite salt adduct.
OH
R1
1 mol% cat
1.0 M aq K2CO3
(3.2 equiv)
O
SO3Na +
O
O
O
R3
n-Pr EtO2C
80% yield, >99% ee
O
Ph
O
CO2Et EtO2C
84% yield, 90% ee
R2
O
O
Ph
R1
O
R3 0.16 M Toluene, rt
R2
Cl
O
n-Pr
78% yield, >99 %ee
Ph
O
Me
CO2Et
65% yield, 99% ee
Bode OL 2008, 10, 3817
- Recently our group has demonstrated the use of enal in hetero Diels-Alder reactions
O
10 mol% cat
15 mol% base
O
+
H
R1
R2
O
Ph
EtO2C
R3
0.1 M CH2Cl2
40 oC, 6-16 h
O
Me
O
Me
NHCbz
Me
98% yield, >20:1 d.r., 99% ee
EtO2C
O
R1
O
R3
R2
O
O
Me
n-C3H7
OH
Me
89% yield, >20:1 d.r., 99% ee
MeO2C
O
p-MeOC6H4
60% yield, >20:1 d.r., 99% ee
Bode PNAS 2010, 107, 20661
- A generation of enolate via formylcyclopropanes
Chi OL 2011, 13, 5366
- An aza-Diels-Alder reaction has also been achieved
11
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Bode JACS 2006, 128, 8418
- A Mannich reaction has also been reported for the synthesis of -amino acid derivatives
O
Me
O
ArO
N
+
H
Ar = 4-NO2C6H4
R
Ts
N
1) Me
Ph
H
N BF4
N Mes
Ts
(10 mol %)
4-NO2-C6H4ONa (2 euqiv)
2) BnNH2
NH O
R
NHBn
56-75%
88-95% ee
Scheidt JACS 2009, 131, 18028
7.3
Generation of NHC-bound enolate via ketene
- Many formal [2+2] and [3+2] cycloadditions have been reported for the synthesis of  -lactones and lactams
Ye ACIE 2010, 49, 8412
- Ye has demonstrated this strategy also in many [4+2] cycloaddition reactions
12
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Ye JOC 2010, 75, 6973, ACIE 2009, 121, 198, & Chem. Commun. 2011, 2381
7.4
Generation of NHC-bound enolate for enantioselective protonation
- Rovis has demonstrated the proof of this principle
Rovis JACS 2005, 127, 16406 & JACS 2010, 132, 2860
- Ketenes have also been used. Impressive results can be obtained with some substrates. This works best
when the two substituents on the ketene differ greatly in size.
Ye OBC 2009, 7, 346 & Smith Adv. Synth. Catal. 2009, 351, 3001
8
Acyl azoliums
“Acyl azoliums are fascinating reactive intermediates with chemistry
quite distinct from that of other activated carboxylic acid derivates….
These species have long been studied for their unusual reactivity and role in
biochemical pathways. Unlike other acylating agents, acyl azoliums display a
high preference for ester formation or hydrolysis rather than amide formation.
This is attributed to the rapid formation of kinetically important hydrates or
hemiacetals that undergo general base catalyzed C-C bond cleavage in the
acid or ester forming step.”
Bode JACS 2010, 132, 8810
13
Update to 2013
8.1
Internal redox esterification
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Epoxy aldehyde
Bode JACS, 2004, 126, 8126
- Mechanism:
- Redox esterification from -bromoaldehyde was concurrently reported:
N
O
R1
R2
H
R3OH
N BF4
N Ph
(20 mol %)
O
R1
OR3
Et3N (1 eq)
R2
Br
55-91%
Rovis, JACS, 2004, 126, 9518
- Other redox reaction of other -functionalized aldehydes
14
Update to 2013
- Protonation of homoenolate
Bode Research Group
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N BF4
N Mes
(5 mol %)
N
O
+
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R1
OH
R1
R2
N
R2OH
OH
N N
R3
Breslow intermediate
DIPEA (10 mol %)
THF, 60 °C
H
R1
O
R1
R2
N
N N
H
H+
transfer
R3
OR2
63–97%
O
R2
N
R1
H
H+
R1
N N
R3
homoenolate
enolate
O
R2
N
H
N N
R3
acyl azolium
Bode OL 2005, 7, 3873
8.2
Catalytic amidation reactions
- Amidation reactions are difficult to achieve due to acyl azolium’s reluctance to acylate amines. This
property has been utilized in chemoselective amidation by intramolecular O to N transfer.
Movassaghi OL 2005, 7, 2453 & TL 2008, 49, 4316
- The use of cocatalyst (i.e. HOAt or imidazole) solves the chemoselectivity issue
(A) Rovis JACS 2007, 129, 13796 & (B) Bode JACS 2007, 129, 13798
8.3
Oxidative esterification
- Although the reaction outcomes are the same (net oxidation of aldehyde), the mechanism for each oxidant
may differ (i.e. electron transfer, hydride transfer, or benzoin type addition).
15
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(A) Studer JACS, 2010, 132, 1190 & (B) Chi ACIE 2013, 132 8750 and related work, Chi Nature Chem.
2013, 5, 835 &
(C) Zhao ACIE, 2013, 52, 1731 & for other KR, see Maruoka OL 2005, 7, 1347; Suzuki Tetrahedron 2006,
62, 302; Studer Synthesis 2011, 12, 1974 & Yashima CEJ 2011, 17, 8009
9
-Hydroxyenone as aldehyde surrogate
Bode and co-workers have previously acknowledged the relative difficulty of preparing cinnamaldehyde
derivatives and introduced -hydroxyenones as easily prepared (one step from commercial materials via
aldol condensation) and stored surrogates.
N
Surrogate concept: retro-benzoin reaction
N
O
OH
R1
R1
Me Me
Me Me
N
H
N
R1
retro-benzoin
N
N Mes
O
O
R1
N
N Mes
O
OH
Me Me
O
Me
H
R1
Mes
N Mes
OH
O
N
N N
16
Me
OH
N
R1
Mes
N N
Breslow
intermediate
Update to 2013
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Ar
O
O O
S
N
O O
S
N
O
DBU (50 mol %)
R2
DBU (15 mol %)
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HN
R4
58%
3:1 dr
O
R1
Ph
(5-20 mol %)
DBU (50 mol %)
SO2Ar
N
Ph
DBU (50 mol %)
N Cl
N Mes
N
Br
p-BrC6H4
Ph
+
H
O
R1
N
Me Me
O
CO2Me
35-76%
2:1-10:1 dr
OH
R1
43-99%
2:1-12:1 dr
O
R1
O
R2
R1
Ar
MeO2C
SO2Ar
Ph
77%
3.5:1 dr
R3
O
R1
DIPEA (20 mol %)
1,2,4-triazole (10 mol %)
21-99%
N
R4
R3
Bode JACS 2009, 131, 8714 & Chem. Commun. 2009, 4566
10
NHC promoted sigma-tropic rearrangement
- Bicyclo--lactam formation
Bode JACS 2008, 130, 418
- Claisen rearrangement via α,β-unsaturated acyl azolium. A competing plausible conjugate addition between
the enol and the unsaturated acyl azolium was ruled out by a detailed kinetics analysis.
H
OH
O
H
O 1
10 mol % 1
PhCH3, 40 °C
no added base
R1
+
R2
R3
Mes
N вАУ
Cl
N
N
O
O
R1
R3
R2
tautomerization
and lactonization
azolium catalyzed
internal redox reaction
OH
O
R1
N
R3 Mes
R2
N
N
N
O Mes
HO
N N
I a,b-unsaturated acyl azolium
activated carboxylate
R3
R1
N
HO
N
N
O Mes
R1
R3
R2 II
R2 III
Claisen rearrangement
For Examples:
O
O
O
O
O
O
HO
HO
O
O
Ph
DH‡ = +15.30 kcal/mol
DS‡ = – 25.50 cal/K.mol
kobs = – 3.41x10-4 s-1
rate = -kobs [cat]1[ald]0.5[Nu]-0.5
Ph
CO2Me
MeO
74% yield
99% ee
Me
CO2Et
73% yield
88% ee
MeO2C
79% yield
68% ee
O
p-ClC6H4 OTBS
90% yield
96% ee
O
MeO2C
Bu
OTBS
78% yield
99% ee
Bode JACS 2010,132, 8810
- An aza-Claisen variant of the above reaction has also been achieved. Here, the key α,β-unsaturated acyl
azolium was catalytically generated via an oxidation of the Breslow intermediate instead of an internal redox
reaction. -hydroxyenones can also be used as aldehyde surrogate in this reaction.
17
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Bode Org. Lett. 2011, 13, 5378
11
,-Unsaturated acyl azolium
- Redox esterification
Mes
N
Cl
5 mol%
O
Mes
R
N
O
R1OH
3 equiv
Toluene, 60 oC, 2 h
H
O
E/Z ratio in all cases >95:5
OR1
R
O
O
OMe
O
Me
Me
OEt
48% yield
63% yield
OEt
OEt
Me
H
66% yield
90% yield
O
Zeitler OL 2006, 8, 637
- ,-unsaturated acyl azolium: observation and mechanistic investigation
Cl- Me
Me
O
N
H
Ar
O
N
N
10 mol%
MeOH
O
Me
Ar
OH
R
N
N
RN
Ar
MeO
N
RN
MeOH
18
O
RDS
R
N
Ar
OMe
DH‡ = + 23.60 kcal/mol
DS‡ = – 2.93 cal/K.mol
kobs = – 5.41x10-5 s-1
rate = -kobs [cat]0.5[ynal]1[MeOH]-0.5
Hammett r = -0.69
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m
o
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acyl azolium 1
! max = 355 nm
O
N
O
C1
Hc
C2
Hd
N N
Mes
n
Cl
Chemical Formula: C30H27ClN3O2+
m/z: 496.1793 (found by LC-HRMS)
m/z: 496.1792 (calculated)
react rapidly with MeOH, H2O
but not piperidine
2D NMR correlations
Bode ACIE 2011, 50, 1673
- Rearrangement reaction in conjunction with electrocyclic ring opening reaction
Lupton Chem. Sci. 2012, 3, 380
- Alternative approaches to dihydropyranone synthesis
(A) redox approach: Xiao Adv. Synth. Catal. 2010, 352, 2455 & Chem. Commun. 2011, 47, 8670,
(B) oxidative approach: Studer ACIE, 2010, 49, 9266 & You OL, 2011, 13, 4080
- A [4+2] cycloadditions via ,-unsaturated acyl azolium
Lupton JACS, 2011, 133, 4694
12 NHC catalyzed hydroacylation reactions
- Recently the group of Glorius (Uni. Munster) has contributed to many advances in this area of research.
For reviews see: Glorius Chem. Lett. 2011, 40, 786 & Acc. Chem. Res. 2011, 44, 1182
19
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Glorius ACIE, 2011, 50, 4983 & ACIE, 2013, 52, 2585
- Other variations
Glorius ACIE, 2010, 49, 9761 & OL, 2011, 13, 98 & ACIE, 2011, 52, 12626
13 Dual catalysis using NHC
- Iminium-NHC catalysis
Rovis JACS, 2009, 131, 13628
20
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- Photoredox-NHC catalysis
Rovis JACS 2012, 134, 8094
14 Chiral triazolium and imidazolium catalysts synthesis
14.1 Chiral thiazolium salts
(R)
HO
Cl
S
N
O
O
Me
Me
O H O
O
OTBS
Me
O H OH
Me
1) HCl, MeOH, H2O
S
KOtBu
N
2) TBSCl, Et3N, DMAP
O
Tf2O, pyr
S
S
N
TfO
N
OTBS
Leeper, TL, 1997, 38, 3611
14.2 Imidazolium salts
O
H
O
H
R NH2
(2 equiv)
nPrOH
R N
H
N R
H
ClCH2OEt
THF
R N
N R
Cl
Arduengo Tetrahedron 1999, 55, 14523
14.3 chiral aminoindanol-derived imidazolium salts
21
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O
H
NH2
Br
OH
NH2
CH3
NH
CH3
HCO2Et
O
NaH, THF
CH3
O
AcOH
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Oxone
acetone
NaHCO3
O
CH3
O
ClO4
OAc
N
Ac2O
HClO4
OHO
O O
H
CH3 (COCl)
2
N
CH3
H
N
DMSO
Et3N
O
O
H
NaH
NH
O
CH3
O
O
RNH2
R
N
ClO4
CH3
OAc
N
R
N
ClO4
Ac2O
cat. HClO4
CH3
N
O
O
Bode Tetrahedron 2008, 64, 6961
14.4 Chiral pyrrolidinone-derived triazolium salts
O
Meldrum's acid R
R
DMAP
OH
DCC
NH
NH
O
Boc
CH2Cl2
Boc
O
N
R
N BF4
N Ar
O
O
O
Me
O
Me
NaBH4
AcOH
CH2Cl2
Ar
N
H
NH BF 4
R
Boc
O
NH
Me
O
O
Me
O
NH
R
OMe
N
HC(OEt) 3
PhCl
toluene
110 oC;
TFA
CH2Cl2
Ar-NHNH2
CH2Cl2
R
N
Me3O+BF4CH2Cl2
R
Rovis JOC, 2005, 70, 5725
14.5 Chiral aminoindanol-derived triazolium salt
Bode Org. Synth. 2010, 87, 362
14.6 Chiral triazolium and imidazolium precatalyst reactivity comparison
22
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23
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Bode OL 2008, 10, 957