A modular synthesis of chiral aminoindanol-derived imidazolium salts

Article abstract of DOI:10.1016/j.tet.2008.03.072

A modular synthesis of N-substituted chiral imidazolium salts derived from (1R,2S)-(+)-1-amino-2-indanol is described. A wide range of amines are amenable to late stage introduction of the N-substituent to provide N-aryl, N-alkyl, and N-amino imidazolium salts, which serve as precursors to chiral N-heterocyclic carbenes (NHCs). A multi-gram synthesis of the N-mesityl derivative provides an important imidazolium salt for ongoing studies aimed at the development and understanding of NHC-catalyzed annulations. Critical to the success of this synthetic strategy is a chemoselective alkylation, 6-exo-tet ring closure of a formamide onto an epoxide, and a heterocyclic interconversion strategy.

Full text of DOI:10.1016/j.tet.2008.03.072

Tetrahedron 64 (2008) 6961–6972
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A modular synthesis of chiral aminoindanol-derived imidazolium salts
*
Justin R. Struble, Jeffrey W. Bode
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6354, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A modular synthesis of N-substituted chiral imidazolium salts derived from (1R,2S)-(þ)-1-amino-2-in-
danol is described. A wide range of amines are amenable to late stage introduction of the N-substituent
to provide N-aryl, N-alkyl, and N-amino imidazolium salts, which serve as precursors to chiral N-het-
erocyclic carbenes (NHCs). A multi-gram synthesis of the N-mesityl derivative provides an important
imidazolium salt for ongoing studies aimed at the development and understanding of NHC-catalyzed
annulations. Critical to the success of this synthetic strategy is a chemoselective alkylation, 6-exo-tet ring
closure of a formamide onto an epoxide, and a heterocyclic interconversion strategy.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 19 January 2008
Received in revised form 18 March 2008
Accepted 19 March 2008
Available online 22 March 2008
Dedicated to Professor John Hartwig
in honor of his 2007 Tetrahedron Young
Investigator Award
1. Introduction
The use of a simple organic molecule as a catalyst raises the
promises of developing enantioselective variants of these annula-
Over the past two decades, N-heterocyclic carbenes (NHCs) have
received increasing attention due to their storied role as ligands for
transition metal complexes1 and, more recently, their remarkable
properties as catalysts in their own right.2,3 As an increasing
number of processes catalyzed by either NHCs or their transition
metal complexes are reported, interest in developing highly
enantioselective variants through the design and synthesis of chiral
NHCs continues to grow.4 To this end, important advances have
been made by Grubbs,5 Hoveyda,6 Burgess,7 Glorius,4a Mont-
gomery,8 and many others in the preparation and application of
novel, chiral imidazolium-derived NHCs for catalytic applications
(Fig. 1).
In our own studies, we have pioneered the development of
novel NHC-catalyzed redox processes of a-functionalized alde-
hydes, resulting in conceptually novel approaches to ester9,10 and
amide11,12 formation and the development of a new generation of
highly selective annulation reactions from simple starting mate-
rials.13,14 Interestingly, these novel NHC-catalyzed reactions appear
to fall into two discrete categories:15 those catalyzed by imidazo-
lium-derived NHCs13 and those promoted by triazolium-derived
NHCs.14 For example, our group13 and that of Glorius16 have in-
dependently documented the imidazolium-derived NHC-catalyzed
generation of homoenolate equivalents from enals.17,18 These
species undergo nucleophilic additions to aldehydes, activated
ketones, imines, and enones to give stereochemically rich annula-
tion products under exceptionally mild and simple reaction con-
ditions (Fig. 2).
tions through the design and synthesis of chiral NHC catalysts.
Indeed, chiral triazolium-derived NHCs have been employed as
highly selective catalysts for benzoin and intramolecular Stetter
reactions.19,20 Our group has also reported a number of novel
annulation processes that employ chiral N-mesityl substituted
aminoindanol-derived triazolium precatalyst 1 for highly enantio-
selective annulations for inverse electron demand hetero-
Diels–Alder reactions and benzoin-oxy-Cope reactions (Fig. 3).14 In
almost all cases, the NHC catalyst 1 affords the expected products in
good yields and outstanding enantioselectivities.
In contrast, the use of 1 or other triazolium-derived NHCs
uniformly fails to provide products arising from NHC-catalyzed
generation of homoenolates. The lack of reactivity of the triazolium
salts coupled with the relative difficulty in preparing chiral imid-
azolium salts that promote homoenolate-based annulations of
enals has stymied the development of enantioselective variants of
these promising annulation reactions.
In seeking to address this, we have recently developed a prac-
tical synthesis of chiral imidazolium-derived NHC precatalysts
built onto the chiral aminoindanol backbone that has proved so
successful for enantioselective NHC-catalyzed reactions. In this
account, we document these studies in detail, including the
application of this synthetic route to diverse chiral N-substituted
imidazolium salts and their preparation on a multi-gram scale.
2. Results and discussion
2.1. Retrosynthetic analysis
The intense interest in the development and understanding of
N-heterocyclic carbenes and their complexes has led to a number of
* Corresponding author. Tel.: þ1 215 573 1953.
E-mail address: bode@sas.upenn.edu (J.W. Bode).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.072

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J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
Ph
Ph
O
O
Cy
Me
N
Me
Me
N
N
N
N
N
Me
Mes
HO
Cy
–
BF4
Me
Cl–
OTf
Cy
Me
Cy
Figure 1. Selected chiral imidazolium salts as NHC precursors.
imidazolium salts from N-formyl amino ketones or aldehydes. We
reasoned that chiral aminoindanol-derived imidazolium salts such
as 2 could be similarly accessed from intermediates 3 and 4, a ret-
rosynthetic analysis that considerably simplifies access to this
highly desired class of NHC precursors. We further postulated that
the diastereomeric formyl ketones 3 and 4 could be derived from
epoxides 5 and 6 by intramolecular cyclization and oxidation. In
turn, 5 and 6 would be obtained from readily available chiral
aminoindanol 7 by N-formylation, alkylation, and epoxidation
(Scheme 1).
OH
Mes
N
N
Mes
N
O
Y
Mes
R1
+
R1
H
R2
H
10 mol %
N
Mes
Y = O
NSO2Ar
catalytically generated
CHCXR3
homoenolate equivalent
R1
R1
R2
R1
R2
or
or
R2
O
SO2Ar
O
R3
N
O
2.2. Alkylation strategy
Figure 2. NHC-promoted annulations of catalytically generated homoenolates with
various electrophiles.
We began our studies with a literature procedure for the
N-formylation of (1R,2S)-(þ)-1-amino-2-indanol 7.25 We initially
surmised that the N-formylated amide 8 would be reluctant to
undergo alkylation, making possible selective O-alkylation in the
subsequent step. This O-alkylation, however, proved to be difficult
and yields greater than 40% were never consistently achieved even
after several attempts to optimize the reaction parameters. In many
cases, competing N-alkylation of the formamide reduced the iso-
lated yields of the desired product. In contrast, excellent overall
yields of the desired N-formyl O-crotylated product 10 were ach-
ieved simply by switching the order of the steps and performing the
O-alkylation directly on unprotected aminoindanol (Scheme 2).
Me
O
N
N
Cl–
N
Me
Me
1
Figure 3. N-Mesityl substituted aminoindanol-derived triazolium precatalyst.
notable advances in their preparation.21–23 Unfortunately, in our
hands, we were generally unable to extend these routes to the
preparation of our desired chiral bicyclic imidazolium salts. During
the course of these efforts, Fu¨rstner reported a new synthetic entry
into unsymmetrically N,N0-disubstituted imidazolium salts based
on a heterocyclic interconversion strategy.24 This elegant procedure
hinges on a three-step, one-pot protocol to prepare diverse
2.3. Epoxidation and cyclization
With 10 in hand, we were pleased to find that epoxidation
occurred readily under a variety of straightforward conditions.
Treatment of the alkene with excess m-CPBA (w3 equiv) in CH2Cl2
Me
O
O
O
CH3
Me
Me
CH3
CH3
O
NH2
OH
H
H
N
NH
N
ClO4
N
O
O
O
3, 4
5, 6
2
7
Scheme 1. Retrosynthetic analysis featuring N-formyl ketones 3 and 4.
O
Br
Me
H
HCO2Et
AcOH
NH
O
NaH, THF
H
OH
0 °C→70°
37 % yield
62 °C, 16 h
92 % yield
CH3
NH
8
O
7
Br
Me
10
HCO2Et
AcOH
CH3
NH2
NaH, THF
0 °C→70°
64 % yield
O
62 °C, 16 h
87 % yield
9
Scheme 2. Chemoselective alkylation and formylation of 1,2-aminoindanol.

J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6963
were cognizant of the fact that the two diastereomeric epoxides 5
and 6 would likely undergo ring formation at vastly different rates,
potentially leading to complications or byproducts.
O
O
mCPBA,
rt, 16 h
91 % yield or
H
H
CH3
O
CH3
NH
NH
When the other formyl olefin, ent-10, derived from the opposite
enantiomer of aminoindanol was used as the starting material, the
epoxidation also proceeded cleanly to afford ent-6 as a 5:1 mixture
of diastereomers. A single diastereomer could be obtained after one
recrystallization from hexanes/EtOAc. This diastereomer also
cyclized cleanly in the presence of sodium hydride to afford 14 in
76% yield. Although yields of the morpholine products were con-
sistently higher when pure diastereomers were employed in the
ring-closing step, there does not appear to be a significant rate
difference in the cyclization of the two diastereomeric epoxides.
Despite the different stereochemistry, both diastereomers proved
amenable to the subsequent steps and gave the identical imid-
azolium salts as the final product. These observations coupled with
other findings on the conversion of 3 and 4 to the final product led
to our decision to stay with the lower yielding, but with opera-
tionally simpler achiral epoxidation and ring closure shown in
Scheme 3 for further studies.
Acetone, Oxone,
NaHCO3, rt, 2 h
81 % yield
O
O
10
5, 6
HO
O
HO
O
10 equiv NaH
DMF, 0 °C, 90 min
52 % yield
CH3
CH3
H
H
N
N
+
O
O
11
12
Scheme 3. Epoxidation and intramolecular epoxide opening (m-CPBA¼3-chloroper-
oxybenzoic acid).
overnight provided 5 and 6 in nearly quantitative yield, as a 1:1
mixture of diastereomers. The only drawback to this method was
purification of the epoxide, which required the removal of excess
peracid and the acid byproduct, and led to the formation of colored
impurities that proved difficult to remove upon scale-up. We
therefore turned to epoxidation via in situ generation of dime-
thyldioxirane (DMDO).26 This epoxidation was clean and scalable,
but afforded slightly lower conversions than m-CPBA. Nevertheless,
this approach proved to be the method of choice for preparative
scale synthesis of the diastereomeric mixture of epoxides 5 and 6
(Scheme 3).
2.4. Oxidation
An early route to the chiral imidazolium salts began with ally-
lation rather than crotylation of aminoindanol 7. While epoxidation
and cyclization proceeded cleanly, we encountered serious diffi-
culties in obtaining the N-formyl aldehyde via oxidation of cycli-
zation product 16. Oxidation of the primary alcohol using standard
protocols (TEMPO, TPAP, IBX, SO3$pyridine, DMP) yielded little or
none of the desired aldehyde but rather numerous byproducts and
returned starting material, with the major side product identified
as over-oxidized morpholinone 17 (Scheme 5).
Early attempts to induce a 6-exo-tet ring closure onto the ep-
oxide under basic conditions (NaH or KHMDS) were stymied by low
yields and decomposition. A single precedent for this ring closure
employed 10 equiv of NaH in DMF.27 Indeed, ring closure ensued
under these conditions, but yields were only moderate (w50%), and
purification and characterization of 11 and 12 proved difficult due
to the resultant mixture of diastereomers and amide rotamers.
We sought to improve the overall yield of the cyclization
through the stereoselective synthesis of a single epoxide dia-
HO
O
O
O
H
H
N
N
[O]
7
other
products
stereomer via Shi epoxidation (Scheme 4).28 Since the
D-fructose
+
O
O
derived Shi catalyst was more readily prepared than its enantiomer,
we explored this hypothesis by using the two enantiomers of
aminoindanol, 7 and ent-7, and a single enantiomer of the Shi
catalyst. When formyl olefin 10, derived from (1R,2S)-(þ)-cis-
1-amino-2-indanol, 7, was employed, the epoxidation was quite
efficient (w90% yield) but the diastereoselectivity was only mod-
erate (5:1). However, a single diastereomer of the epoxide, 5, was
obtained after one recrystallization from hexanes/EtOAc. In evalu-
ating the modest yield and product mixture of the cyclization, we
16
17
Scheme 5. Unexpected oxidative cleavage of N-formyl amino alcohol 18.
To circumvent this unexpected difficulty, we elected to in-
troduce the crotyl group during alkylation, which would sub-
sequently lead to a secondary alcohol poised for oxidation to the
ketone. We were pleased to find that Dess–Martin periodinane
(DMP) gave smooth conversion to the ketone in high yield. Further
O
Me
Me
O
O
Me
Me
O
O
O
15
HO
O
O
H
CH3
H
H
H
H
60 mol % 15, Oxone
O
O
Me
Me
NH
N
nBu4N+HSO4−, Na2(EDTA)
NaH, DMF
0 °C, 90 min
74% yield
10
O
O
2:1 CH3CN:DMM
pH 10.5, 0 °C, 5 h
91 % yield
O
5
13
HO
H
O
O
CH3
NH
N
60 mol % 15, Oxone
nBu4N+HSO4−, Na2(EDTA)
NaH, DMF
0 °C, 90 min
76% yield
O
ent-10
2:1 CH3CN:DMM
pH 10.5, 0 °C, 5 h
80 % yield
ent-6
14
Scheme 4. Stereoselective synthesis of morpholines 13 and 14 by Shi epoxidation (DMM¼dimethoxymethane).

6964
J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
studies, particularly for larger scale preparation of ketones 3 and 4,
also identified Swern oxidation conditions that also afforded the
ketone in good yield on a 10-g scale. Under the Swern conditions,
we found the N-formyl ketones to be sensitive toward epimeriza-
tion affording 3 as the major diastereomer (Scheme 6).
O
O
O
O
DMP, CH2Cl2,
Me
Me
H
H
rt, 3 h
or
11 and 12
(as mixture of
diastereomers)
N
N
+
(COCl)2,
DMSO, NEt3
CH2Cl2
O
O
4
3
−60 °C, 2.5 h
(major product
from Swern oxidation)
Scheme 6. Oxidation of secondary alcohols 11 and 12 (DMP¼1,1,1-triacetoxy-1,1-
dihydro-1,2-benziodoxol-3(1H)-one).
O
O
CH3
OAc
O
CH3
H
N
ClO4
N
Ac2O, HClO4
0 °C→rt, 2 h
O
O
3 or 4
18
MesNH2
CH2Cl2/PhMe
rt, 12 h
Figure 4. ORTEP plot of N-mesityl substituted imidazolium salt 2.
Mes
N
Mes
N
CH3
OH
CH3
carbonyls. Initial attempts to form the oxazolinium salt 18 by treat-
ment of the N-formyl ketones with Ac2O and aqueous or anhydrous
acids HCl and HBF4 proved unsuccessful. Reactions performed at
low temperature returned only starting material; upon heating
deprotection of the N-formyl group was observed. When HClO4 was
employed, a trace amount of product was observed by mass spec-
trometric analysis of the crude reaction mixture. From this initial
hint, we quickly discerned that the oxazolinium adduct was heat
sensitive. Thus, treatment of the formyl ketone with HClO4 in Ac2O
was carried out at 0 ꢀC to prevent deformylation. Furthermore, the
oxazolinium salt could not be handled or stored for an extended
period of time. Once triturated from the reaction mixture, residual
solvent was removed in vacuo at rt since even a gentle warming of
the solution upon rotary evaporation bath caused decomposition.
We further found that cleaner, at least analytically, reactions oc-
curred when diastereomers 3 and 4 were taken on separately
through the modified Fu¨rstner protocol, although the identical final
product and similar yields were obtained in each case. These
ClO4
ClO4
N
N
Ac2O, cat. HClO4
CH2Cl2,70 °C
O
O
2
19
Scheme 7. Heterocyclic interconversion and elimination for the synthesis of imid-
azolium salts (Mes¼2,4,6-trimethylphenyl).
2.5. Oxazolinium formation and conversion to N-substituted
imidazolium salts
Ketone intermediates 3 and 4 are the key precursors to Fu¨rst-
ner’s heterocyclic interconversion strategy for the synthesis of
imidazolium salts from an oxazolinium intermediate. Although
Fu¨rstner had demonstrated a remarkably diverse range of com-
pounds prepared with this strategy, he reported no examples of the
use of sterically hindered anilines with ketone-derived amino
O
O
CH3
CH3
CH3
O
Oxone,
acetone,
NaHCO3
EtOAc/H2O
rt, 2h
81% yield
H
H
NH2
OH
crotyl bromide
NaH, DMF
0→70 °C, 2 h
64% yield
HCO2Et
AcOH, THF
62 °C, 16 h
87% yield
NH2
NH
NH
O
O
O
NaH, DMF
0 °C, 2 h
52% yield
7
9
10
5, 6
Me
Me
Me
Me
OH
Me
Me
CH3
OH
O
OAc
CH3
O
O
N
O
N
CH3
CH3
ClO4
H
(COCl)2,
DMSO, NEt3
CH2Cl2
H
CH3
ClO4
N
ClO4
Ac2O, HClO4
ClCH2CH2Cl
70 °C, 6 h
51 % yield
MesNH2
Toluene
CH2Cl2
rt, 12 h
Ac2O
HClO4
0 °C→rt
2 h
N
N
N
N
O
O
O
O
O
−60 °C, 2.5 h
87 % yield
over 3 steps
19
3
11, 12
2
18
Scheme 8. Preparative scale synthesis of N-mesityl substituted imidazolium salt 2 (crotyl¼3-methyl-(E)-but-2-enyl and Mes¼2,4,6-trimethylphenyl).

J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6965
important modifications led to a robust and reliable procedure for
the preparation of 18, which served as the key starting material for
a modular synthesis of diverse N-substituted NHCs (Scheme 7).
Acetal 18 was allowed to react with a variety of amines giving
rise to the aminal intermediate (e.g., with 2,4,6-trimethylanilne, 19)
as a set of diastereomers. Although in several cases the aminal
could be isolated, purification was difficult and most of the aminal
intermediates were used directly for the elimination step without
purification. Furthermore, the diastereomers could not be sepa-
rated, but this was without consequence as the offending stereo-
genic center is destroyed upon acid elimination to give the
imidazolium salt. We also improved upon Fu¨rstner’s heterogeneous
protocol, which used toluene as the solvent, for a homogeneous one
with CH2Cl2/toluene that often allowed a cleaner rearrangement to
the aminal intermediate.
The acid-catalyzed acylation/elimination strategy originally
outlined by Fu¨rstner typically led to decomposition and only trace
amounts of the desired imidazolium salt were in our hands. We
found that by dramatically reducing the equivalents of Ac2O
a cleaner reaction occurred, a finding mirrored by Fu¨rstner in a re-
cent application of this methodology.29 Still, in several cases, pu-
rification of the imidazolium salt was hindered by an intractable oil
formed in the reaction. During the optimization of the reaction for
large-scale production of 2, we discovered that changing from
a heterogeneous protocol (toluene) to a homogeneous one (1,2-
dichloroethane) provided cleaner elimination allowing for easier
purification of the imidazolium salt. Furthermore, under these
conditions the reaction could be readily monitored by 1H NMR of an
aliquot from the reaction.
These conditions30 proved (vide infra) reliable for a broad range
of amines, allowing access to a diverse set of N-substituted imid-
azolium salts that can be used as precursors to N-heterocyclic
carbene ligands and catalysts.
2.6. Preparative scale production of N-mesityl imidazolium
catalyst 2
Given our success of utilizing the N-mesityl substituted, ami-
noindanol-derived triazolium salt 1 for highly enantioselective
annulation reactions, we were particularly interested in un-
dertaking a systematic survey of the differences between the imi-
dazolium and triazolium salts of otherwise identical structure.31 In
anticipation of these studies, we applied our optimized route to the
synthesis of the aminoindanol-derived NHC precursors to a pre-
parative scale synthesis of 2. Beginning with (1R,2S)-(þ)-cis-1-
amino-2-indanol, each step up to the oxazolinium intermediate can
Table 1
N-Substituted chiral aminoindanol-derived imidazolium salts prepared from common acetal intermediate 18
R
N
R
N
CH3
OAc
O
CH3
OH
RNH2, PhMe
or
RNH2,PhMe/CH2Cl2
CH3
Ac2O, cat. HClO4
PhMe or ClCH2CH2Cl
ClO4
ClO4
ClO4
N
N
N
O
70–80 °C, 0.25–20 h
rt, 3–16 h
O
O
18
2, 20–32
Me
N
Br
OMe
N
HO
Me
Me
Me
Me
Me
Me
CH3
N
N
CH3
CH3
N
CH3
CH3
ClO4
ClO4
N
N
ClO4
ClO4
ClO4
N
N
N
O
O
O
O
O
2, 78% yield
i-Pr
20, 51% yield
21, 70% yield
t-Bu
22,33 61% yield
23,33 35% yield
O
t-Bu
F3C
CF3
CH3
CH3
N
i-Pr
N
N
CH3
N
CH3
N
N
CH3
CH3
ClO4
N
ClO4
ClO4
N
ClO4
N
ClO4
N
N
O
O
O
O
O
24, 48% yield
25,33 35% yield
26, 75% yield
27, 63% yield
28,33 53% yield
H
N
i-Pr
t-Bu
Me
Br
N
N
N
O
N
CH3
CH3
CH3
CH3
ClO4
N
ClO4
ClO4
N
ClO4
N
N
O
O
O
O
29,33 50% yield
30,33 20% yield
31,33 22% yield
32,33 69% yield

6966
J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
be performed on >8 g scale. The final three-step sequence was
performed on a 5-g scale to produce w4.5 g of 2 in 51% yield from
the formyl ketone intermediate 3 (Scheme 8). The structure of this
compound was confirmed by single crystal X-ray diffraction
(Fig. 4).32
Silica Gel 60 (230–400 Mesh) using a forced flow of 0.1–0.5 bar. 1H
and 13C NMR were measured on a Varian Unity 400 spectrometer at
400 and 100 MHz or on Bruker Avance II at 500 and 125 MHz, re-
spectively. Chemical shifts are expressed in parts per million (ppm)
downfield from residual solvent peaks and coupling constants are
reported in hertz (Hz). Splitting patterns are indicated as follows:
br, broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.
Minor diastereomers, amide rotamers, and atropisomers are
2.7. Synthesis of other N-substituted chiral imidazolium salts
An important consideration in any catalyst or ligand design
strategy is the ability to rapidly access structural derivatives that
may enhance reactivity or selectivity in a catalytic reaction. A major
attraction of the Fu¨rstner method, and our implementation of it to
prepare chiral amino alcohol-derived imidazolium salts, is the
ability to introduce a wide range of N-substituents at the final stage
of the synthesis simply by choice of the appropriate amine.
In preliminary studies, we have confirmed that this modular
approach to chiral imidazolium salts is indeed viable and provides
access to diverse N-substituents (Table 1). Indeed both hindered
and unhindered anilines work well in the reaction, making possible
the preparation of 2, 20–26, and 29–32. Unprotected functional
groups including phenols and amides do not significantly suppress
the heterocyclic interconversion. Alkyl amines are also excellent
reaction partners, allowing, for example, the synthesis of N-Me
substituted imidazolium 28. Even hydrazines are viable, providing
access to N-morpholino imidazolium 27.
marked by an asterisks ( ). Infrared (IR) spectra were recorded on
*
a JASCO FT/IR-430 spectrophotometer and are reported as wave-
numbers (cmꢁ1). Optical rotations were acquired using a JASCO
DIP-370 polarimeter operating at the sodium D line with a 100 mm
path length cell and are reported as follows: [a]T (concentration
(g/mLꢂ100), solvent).
4.1.1. (1R,2S)-2-((E)-But-2-enyloxy)-2,3-dihydro-1H-inden-
1-amine (9)
A flame dried 500 mL round bottom flask equipped with
a magnetic stir bar was charged with NaH (60% oil dispersion,
960 mg, 24 mmol, 1.2 equiv). NaH was washed with anhydrous
pentane (1ꢂ50 mL) and the pentane removed via syringe. The flask
was charged with THF (200 mL) and cooled to 0 ꢀC. (1R,2S)-(þ)-1-
Amino-2-indanol (3.0 g, 20 mmol, 1.0 equiv) was added in two
portions 10 min apart. The suspension was stirred until H2(g)
evolution had ceased. The flask was equipped with a water jacketed
condenser and heated to 70 ꢀC under N2(g). A solution (66 v/v% in
THF) of trans-crotyl bromide (85% purity, 2.7 mL, 22 mmol,
1.1 equiv) was added dropwise over 90 min. The resulting bluish-
purple solution was stirred for an additional 40 min at which time it
had turned light tan in color. The mixture was cooled to 0 ꢀC and
quenched with satd NH4Cl(aq) dropwise. The suspension was
poured into a separatory funnel and 250 mL of brine added. The
organic phase was separated and the aqueous phase extracted with
EtOAc (2ꢂ150 mL). The organic phases were combined and dried
over Na2SO4, filtered, and concentrated in vacuo. The resulting oil
was dissolved in Et2O (200 mL) and treated with 4 M HCl in dioxane
(5.0 mL) at 0 ꢀC. The white precipitate was collected by vacuum
filtration and washed with excess Et2O to afford the HCl salt of
compound 9, which was freebased with 1 N NaOH and extracted
with Et2O. Concentration of the ethereal phase yielded compound 9
as a colorless oil (2.6 g, 64%). 1H NMR (500 MHz, CDCl3) d 7.38–7.36
(m, 1H), 7.22–7.19 (m, 3H), 5.76–5.71 (m, 1H), 5.64–5.59 (m, 1H),
4.27 (d, 1H, J¼5.4 Hz), 4.13 (dd, 1H, J¼10.8, 5.4 Hz), 4.08–4.0 (m,
2H), 3.02–2.98 (m, 1H), 1.72 (dd, 3H, J¼6.4, 1.4 Hz), 1.59 (br s, 2H);
13C NMR (125 MHz, CDCl3) d 144.9, 140.0, 129.6, 127.8, 127.0, 125.2,
124.5, 81.3, 70.6, 65.2, 58.4, 36.0, 17.9; IR (thin film) n 3378, 3022,
2914, 2857, 1587, 1458, 1342, 1105, 966 cmꢁ1; HRESIþ/TOF-MS calcd
for C13H18NO2 [M]þ 203.1310, found 204.1403 (MþH).
3. Conclusion
In summary, we have documented a modular, scalable route to
the preparation of chiral aminoindanol-derived imidazolium salts,
which will find use as precursors to N-heterocyclic carbene
catalysts and ligands. Our eight-step route takes advantage of
a chemoselective alkylation, intramolecular epoxide opening, and
a modification of the Fu¨rstner imidazolium synthesis to achieve a
robust, scalable methodology for the preparation of N-aryl, N-alkyl,
and N-amino imidazolium salts. We have recently established that
precatalysts such as 2 can serve as catalysts for enantioselective
NHC-catalyzed homoenolate additions of enals to aldehydes, im-
ines, and enones. We anticipate that the facile access to diverse and
complex imidazolium salts will facilitate our own ongoing studies
aimed at improving the reactivity and selectivity of these novel
annulation reactions. Furthermore, our studies provide one of the
first practical routes to chiral bicyclic imidazolium salts that may
find use as novel ligands for transition metal mediated reactions
and NHC-catalyzed transformations.
4. Experimental
4.1. General methods
4.1.2. N-((1R,2S)-2-((E)-But-2-enyloxy)-2,3-dihydro-1H-inden-1-
yl)formamide (10)
All reactions utilizing air- or moisture-sensitive reagents were
performed in dried glassware under an atmosphere of dry nitrogen.
Dichloromethane and 1,2-dichloroethane were distilled over CaH2.
Toluene, THF, DMF, DMSO, and EtOAc were dried by passage over
activated alumina under Ar atmosphere. Acetic anhydride was
shaken over P2O5, separated, shaken over K2CO3, filtered, and then
fractionally distilled. All commercially available anilines were
fractionally distilled prior to use. Perchloric acid was purchased
from Fisher Scientific as 60 or 70 wt % solutions in water. Other
reagents were used without further purification. Thin-layer chro-
matography (TLC) was performed on Merck precoated plates (silica
gel 60 F254, Art 5715, 0.25 mm) and were visualized by fluorescence
quenching under UV light or by staining with phosphomolybdic
acid. Silica-gel preparative thin-layer chromatography (PTLC) was
performed using plates prepared from Merck Kieselgel 60 PF254
(Art 7747). Column chromatography was performed on E. Merck
A 0.50 M solution of (1R,2S)-2-((E)-but-2-enyloxy)-2,3-dihydro-
1H-inden-1-amine (5.2 g, 26 mmol, 1.00 equiv) in THF (50 mL) was
treated with ethyl formate (16 mL, 200 mmol, 7.90 equiv) and cata-
lytic glacial acetic acid (0.070 mL, 1.3 mmol, 0.05 equiv). The flask
was equipped with a water jacketed condenser and refluxed under
N2(g) in an oil bath for 15 h. The solution was concentrated in vacuo
and the resulting crude solid recrystallized from a 70:30 mixture of
hexanes/EtOAc and collected by vacuum filtration in two crops to
afford 10 as a white solid (5.2 g, 87%). 1H NMR (500 MHz, CDCl3)
d 8.38 (s, 1H), 7.33–7.20 (m, 4H), 6.38 (br s, 1H), 5.73–5.58 (m, 1H),
5.57–5.51 (m, 2H), 4.32–4.30 (m, 1H), 4.05–4.01 (m, 1H), 3.96–3.92
(m, 1H), 3.08–3.0 (m, 2H), 1.70 (d, 2H, J¼6.3 Hz); 13C NMR
(125 MHz, CDCl3) d 161.3, 141.3, 139.8, 130.3, 128.4, 127.3, 127.3,
125.2, 124.8, 79.4, 70.6, 54.5, 36.7,18.0; IR (thin film) n 3071, 3025,
2919, 2856, 1652, 1448, 1400 cmꢁ1; mp 69–72 ꢀC; HRESIþ/TOF-MS

J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6967
calcd for C14H17NO2 [M]þ 231.1259, found 232.1434 (MþH),
254.1153 (MþNa).
mixture of diastereomers (2.24 g, 91%). Recrystallization (heaxanes/
EtOAc, 1:1) afforded diastereomerically pure 5. Epoxide ent-6 was
prepared in an analogous manner from formamide ent-10 (80%).
Compound 5: 1H NMR (500 MHz, methanol-d4) d 8.25 (s, 1H), 7.25–
7.19 (m, 4H), 5.47 (d, 1H, J¼5.4 Hz), 4.32 (dd, 1H, J¼9.9, 4.4 Hz), 3.81
(dd, 1H, J¼11.6, 2.8 Hz), 3.47 (dd, 1H, J¼11.6, 5.8 Hz), 3.07 (d, 2H,
J¼4.4 Hz), 2.92–2.88 (m, 2H), 1.27 (d, 3H, J¼5.2 Hz); 13C NMR
(500 MHz, methanol-d4) d 163.8, 142.1, 141.4, 129.2, 128.0, 126.0,
125.2, 82.4, 71.2, 59.3, 55.7, 53.3, 37.5, 17.4; IR (thin film) n 3266,
4.1.3. Representative epoxidation procedure using m-CPBA:
N-((1R,2S)-2-((3-methyloxiran-2-yl)methoxy)-2,3-dihydro-
1H-inden-1-yl)formamides (5 and 6)
To a 0.088 M solution of N-((1R,2S)-2-((E)-but-2-enyloxy)-2,3-
dihydro-1H-inden-1-yl)formamide (5.2 g, 22 mmol, 1.0 equiv) in
CH2Cl2 (250 mL) was added m-CPBA (70–75% purity, 28 g, 80 mmol,
4.0 equiv). The solution was stirred at ambient temperature until
the starting material was consumed as visualized by TLC (ca. 12 h).
The solution was diluted with CH2Cl2 (500 mL), washed with water
(1ꢂ1 L), 1 N NaOH(aq) (1ꢂ1 L), and then again with water (1ꢂ1 L).
The organic phase was dried over Na2SO4, filtered, and concen-
trated in vacuo to a yellow oil, which was purified by flash column
chromatography (gradient, hexanes/EtOAc, 1:1/1:1.5) to yield
compounds 5 and 6 as a white solid as a 1:1 mixture of dia-
stereomers (5.1 g, 91%). 1H NMR (400 MHz, CDCl3) d 8.34 (s, 1H),
7.30–7.19 (m, 4H), 6.56 (d,1H), 5.61–5.56 (m,1H), 4.34–4.27 (m,1H),
3.81–3.78 (m, 1H), 3.58 (dd, 2H, J¼5.2, 11.6 Hz), 3.11–3.02 (m, 2H),
2.93–2.83 (m, 2H), 1.31–1.27 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 161.5, 141.0, 139.7, 128.3, 127.3, 125.2, 124.6, 81.4, 69.9, 58.1, 54.7,
52.2, 37.1, 17.4; IR (thin film) n 3307, 3030, 2990, 2924, 2859, 1684,
1497, 1384, 1119, 1084 cmꢁ1; mp 77–79 ꢀC; HRESIþ/TOF-MS calcd
for C14H17NO3 [M]þ 247.1208, found 248.1370 (MþH), 270.1107
(MþNa).
3059, 2997, 2919, 2868, 1653, 1544, 1382, 1082, 864, 727 cmꢁ1
;
HRESIþ/TOF-MS calcd for C14H17NO3 [M]þ 247.1208, found
248.1282 (MþH), 270.1097 (MþNa). Compound ent-6: 1H NMR
(500 MHz, methanol-d4) d 8.25 (s, 1H), 7.25–7.20 (m, 4H), 5.48 (d,
1H, J¼5.4 Hz), 4.33 (dd, 1H, J¼9.8, 4.4 Hz), 3.80 (dd, 1H, J¼11.5,
3.1 Hz), 3.45 (dd, 1H, J¼11.5, 6.0 Hz), 3.06 (d, 2H, J¼4.3 Hz), 2.94–
2.87 (m, 2H), 1.28 (d, 3H, J¼5.2 Hz); 13C NMR (500 MHz, methanol-
d4) d 163.8, 142.1, 141.4, 129.2, 128.0, 126.0, 125.2, 82.2, 71.1, 59.2,
55.7, 53.3, 37.4, 17.4; IR (thin film) n 3260, 3048, 2919, 2868, 1650,
1544, 1382, 1082, 858, 727 cmꢁ1
C
;
HRESIþ/TOF-MS calcd for
14H17NO3 [M]þ 247.1208, found 248.1247 (MþH), 270.1104 (MþNa).
4.1.6. (4aR,9aS)-3-(1-Hydroxyethyl)-2,3,9,9a-tetrahydroindeno-
[2,1-b][1,4]oxazine-4(4aH)-carbaldehydes (11 and 12)
A flame dried 1 L round bottom flask equipped with a magnetic
stir bar was charged with NaH (60% oil dispersion, 15.2 g,
380 mmol, 10.0 equiv). NaH was washed with anhydrous pentane
(120 mL) and the pentane removed via syringe. The flask was
charged with DMF (500 mL) and cooled to 0 ꢀC. A 1.0 M solution
of N-((1R,2S)-2-((3-methyloxiran-2-yl)methoxy)-2,3-dihydro-1H-
inden-1-yl)formamide (9.90 g, 40.0 mmol, 1.00 equiv) in DMF
(40 mL) was added dropwise over 80 min and stirred for an addi-
tional 30 min during which time it had turned blue in color. The
mixture was slowly quenched with ice-cold satd aq NH4Cl. The
majority of DMF was removed in vacuo and the resultant oil diluted
with EtOAc (400 mL) and water (300 mL). The organic phase was
separated and the aqueous phase extracted with EtOAc
(2ꢂ300 mL). The combined organic phases were washed with brine
(2ꢂ500 mL), dried over Na2SO4, filtered, and concentrated in vacuo
to a red oil, which was purified by flash column chromatography
(gradient, CH2Cl2/acetone, 6:1/4:1/2:1) to yield compounds 11
and 12 as an inseparable complex mixture of diastereomers and
amide rotamers as an orange solid (5.0 g, 52%). IR (thin film) n 3408,
4.1.4. Representative epoxidation procedure using in situ DMDO
To a vigorously stirred mixture of NaHCO3 (14.5 g, 171 mmol,
5.00 equiv), water (260 mL), EtOAc (170 mL), N-((1R,2S)-2-((E)-but-
2-enyloxy)-2,3-dihydro-1H-inden-1-yl)formamide (8.0 g, 34.5 mmol,
1.00 equiv), and acetone (25.5 mL, 345 mmol, 10.0 equiv) in a 1 L
round bottom flask was added dropwise a 0.235 M solution of
OxoneÒ (42.5 g, 69.0 mmol, 2.00 equiv) in water (250 mL) over 1 h.
The biphasic mixture was then stirred for an additional 1 h at
ambient temperature. The organic phase was separated and the
aqueous phase extracted with EtOAc (500 mL). The combined
organic phases were washed with brine (500 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (gradient, hexanes/EtOAc,
50:50 /40:60/30:70/20:80) to yield 5 and 6 as a white solid
and as a 1:1 mixture of diastereomers (6.45 g, 81%).
3071, 3046, 3024, 2975, 2911, 1651, 1410, 1273, 1106, 1077 cmꢁ1
;
4.1.5. Representative procedure for Shi epoxidation: N-((1R,2S)-
2-(((2R,3R)-3-methyloxiran-2-yl)methoxy)-2,3-dihydro-1H-inden-
1-yl)formamide (5)
HRESIþ/TOF-MS calcd for C14H17NO3 [M]þ 247.1208, found
248.1208 (MþH).
A 500 mL round bottom flask was charged with magnetic stir
bar, N-((1R,2S)-2-((E)-but-2-enyloxy)-2,3-dihydro-1H-inden-1-yl)-
formamide (2.31 g, 10.0 mmol, 1.0 eqiuv), the Shi catalyst derived
4.1.7. (3S,4aR,9aS)-3-((R)-1-Hydroxyethyl)-2,3,9,9a-tetrahydro-
indeno[2,1-b][1,4]oxazine-4(4aH)-carbaldehyde (13)
A flame dried 50 mL round bottom flask equipped with a mag-
netic stir bar was charged with NaH (60% oil dispersion, 1.23 g,
30.8 mmol, 10.0 equiv). NaH was washed with anhydrous pentane
(7.0 mL). The flask was charged with 38.0 mL of DMF and cooled
to 0 ꢀC. A 0.16 M solution of N-((1R,2S)-2-(((2R,3R)-3-methyloxir-
an-2-yl)methoxy)-2,3-dihydro-1H-inden-1-yl)formamide (762 mg,
3.08 mmol, 1.00 equiv) in DMF (28 mL) was added dropwise over
75 min. The mixture was stirred for an additional 25 min. The
mixture was slowly poured over ice-cold satd aq NH4Cl (250 mL).
The solution was extracted with EtOAc (5ꢂ100 mL). The combined
organic phases were washed with brine (2ꢂ1 L), dried over MgSO4,
filtered, and concentrated in vacuo to a yellow oil, which was pu-
rified by flash column chromatography (gradient, CH2Cl2/acetone,
8:1/4:1/2:1) to yield 13 as a white solid as a w3:1 mixture
of rotamers (564 mg, 74%). Alcohol 14 was prepared as w1.5:1
mixture of rotamers in an analogous manner from epoxide ent-6
from
D-fructose (0.775 g, 3.00 mmol, 0.300 equiv), tetrabutyl-
ammonium hydrogen sulfate (0.153 g, 0.450 mmol, 0.450 equiv),
pH 10.5 buffer (100 mL) comprising 0.050 M aqueous solution of
Na2B4O7 in a 0.40 mM aqueous solution of Na2(EDTA), and a mix-
ture of CH3CN/dimethoxymethane (1:2, 150 mL) and cooled to 0 ꢀC.
A solution of OxoneÒ (10.1 g, 16.5 mmol, 1.65 equiv) in 0.40 mM
Na2(EDTA) (70 mL) was added via syringe pump over 2.5 h; si-
multaneously, a 1.0 M solution of K2CO3 (70 mL) was added in small
portions. After half of the addition was complete, another portion of
Shi catalyst (0.775 g, 3.00 mmol, 0.300 equiv) was added. Once the
addition was complete, the biphasic mixture was allowed to stir at
0 ꢀC for an additional 2.5 h. Water was added (500 mL) and the
mixture was extracted with CH2Cl2 (4ꢂ150 mL). The combined
organic phases were washed with water (1ꢂ150 mL), dried over
MgSO4, filtered, and concentrated in vacuo to a colorless oil. Puri-
fication by flash column chromatography (gradient, hexanes/ace-
tone, 3:1/2:1/1:1) afforded 5 and 6 as a white solid and as a 5:1
(76%). Compound 13: 1H NMR (500 MHz, CDCl3) d 8.84
8.21 (s, 1H), 7.34–7.20 (m, 4H), 7.34–7.10 (m, 4H), 5.87
*
(s, 1H),
(d, 1H,
*
*

6968
J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
J¼3.9 Hz), 4.92 (d, 1H, J¼4.5 Hz), 4.53–4.47 (m, 2H), 4.53–4.47
2H), 4.46
(dd, 1H, J¼4.6, 1.5 Hz), 4.21 (d, 1H, J¼5.7 Hz), 3.89 (dd,
1H, J¼12.0, 3.3 Hz), 3.85 (d, 1H, J¼2.5 Hz), 3.74 (dd, 1H, J¼12.0,
9.0 Hz), 3.63
(dd, 1H, J¼11.5, 10.9 Hz), 3.57–3.54 (m, 1H), 3.25–
3.22 (m, 1H), 3.07–3.04 (m, 2H), 2.95 (d,
(d, 1H, J¼2.6 Hz), 2.51
1H, 3.9 Hz), 1.78 (s, 1H), 1.31
(d, 3H, J¼6.5 Hz), 1.23 (d, 3H,
*
(m,
a 1.50 M solution of DMSO (13.6 mL, 192 mmol, 5.00 equiv) in
CH2Cl2 (128 mL). Next, a 1.00 M solution of (4aR,9aS)-3-(1-hydro-
xyethyl)-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]oxazine-4(4aH)-carb-
aldehyde (9.50 g, 38.4 mmol, 1.00 equiv) in CH2Cl2 (38.4 mL) was
added portionwise over 30 min. The solution was allowed to warm
to ꢁ20 ꢀC and stirred for 1 h. The solution was cooled to ꢁ60 ꢀC,
NEt3 (53.2 mL, 384, mmol, 10.0 equiv) was added dropwise over
30 min, and stirring continued for 30 min before allowing the so-
lution to warm to rt. A white precipitate was filtered and the filtrate
washed with water (2ꢂ500 mL). The combined aqueous phases
were extracted with CH2Cl2 (2ꢂ500 mL); the combined organic
phases were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography (gradi-
ent, CH2Cl2/acetone, 20:1/10:1/5:1/2:1) to yield 3 and 4 as
white solids (8.20 g, 87%).
*
*
*
*
*
*
*
*
J¼6.8 Hz); 13C NMR (500 MHz, CDCl3) d 163.4, 162.0, 141.1, 141.0,
138.8, 137.2, 129.2, 128.0, 127.5, 127.1, 126.1, 125.6, 124.2, 123.4, 78.0,
77.7, 65.5, 65.2, 64.4, 64.3, 61.9, 58.9, 57.4, 56.4, 38.5, 37.1, 21.2,
19.5; IR (thin film) n 3422, 2975, 2908, 1639, 1273, 1105, 1074, 1032,
738 cmꢁ1; HRESIþ/TOF-MS calcd for C14H17NO3 [M]þ 247.1208,
found 248.1325 (MþH). Compound 14: 1H NMR (500 MHz, CDCl3)
d 8.40
5.56 (d, 1H, J¼4.5 Hz), 4.82
J¼4.3 Hz), 4.33–4.29 (m, 1H), 4.33–4.29 (m, 1H), 4.25 (d, 1H,
J¼12.0 Hz), 4.02 (dd, 1H, J¼9.2, 2.8 Hz), 3.53 (dd, 1H, J¼12.0,
2.9 Hz), 3.48–3.40 (m, 2H), 3.48–3.40 (m, 2H), 3.15–3.09 (m, 2H),
*
(s, 1H), 8.33 (s, 1H), 7.31–7.15
*
(m, 4H), 7.31–7.15 (m, 4H),
*
(d, 1H, J¼4.3 Hz), 4.37
*
(t, 1H,
*
*
*
*
4.1.10. Conversion of N-formyl ketones 3 or 4 to acetal 18
3.15–3.09 (m, 2H), 3.06–2.99 (m, 1H), 2.13 (d, 1H, J¼4.9 Hz), 1.82
*
To an oven dried 25 mL round bottom flask equipped with a
magnetic stir bar and charged with either 3 or 4 (245 mg,
1.00 mmol,1.00 equiv) was added Ac2O (1.5 mL,16 mmol,16 equiv).
The mixture was cooled to 0 ꢀC and HClO4 (70%, 0.10 mL, 1.2 mmol,
1.2 equiv; or 60%, 0.12 mL, 1.2 mmol, 1.2 equiv) was added dropwise
over 20 min. The brown solution was allowed to warm to rt and
then stirred for 2–3 h. The solution was twice triturated with Et2O
and the supernatant decanted each time. Residual solvent was
removed from the resulting white solid in vacuo at ambient tem-
perature to afford the crude oxazolinium salt 18 either as a white
solid or as a brown oil (388 mg, quant.), which was immediately
used in the subsequent conversion to the imidazolium salts.
(d, 1H, J¼5.5 Hz), 1.19
*
(d, 3H, J¼6.0 Hz), 1.17 (d, 3H, J¼6.2 Hz); 13C
NMR (500 MHz, CDCl3) d 163.8, 163.6, 140.1, 140.1, 139.9, 128.7,
128.1, 127.2, 127.0, 125.7, 125.3, 124.4, 123.6, 78.0, 77.8, 65.6, 64.9,
64.6, 64.4, 60.4, 59.3, 55.7, 53.7, 38.4, 38.2, 20.9, 20.4; IR (thin film)
n 3417, 2980, 2913, 1659, 1412, 1269, 1110, 1077, 1032, 912,
727 cmꢁ1; HRESIþ/TOF-MS calcd for C14H17NO3 [M]þ 247.1208,
found 248.1316 (MþH).
4.1.8. (4aR,9aS)-3-Acetyl-2,3,9,9a-tetrahydroindeno[2,1-b][1,4]-
oxazine-4(4aH)-carbaldehydes (3 and 4)
A 0.50 M solution of (4aR,9aS)-3-(1-hydroxyethyl)-2,3,9,9a-
tetrahydroindeno[2,1-b][1,4]oxazine-4(4aH)-carbaldehyde (3.73 g,
15.1 mmol, 1.00 equiv) in CH2Cl2 (30.0 mL) was added to a suspen-
sion of Dess–Martin periodinane (8.4 g, 22.5 mmol, 1.50 equiv) in
CH2Cl2 (115 mL). The solution was stirred at rt until all the starting
material was consumed as indicated by TLC (ca. 3 h). The solution
was diluted with CH2Cl2, and washed with 1 N NaOH (1ꢂ150 mL),
water (2ꢂ225 mL), and brine (150 mL). The solution was filtered
through Celite, dried over Na2SO4, and concentrated in vacuo to
afford a crude solid, which was purified by flash column chroma-
tography (hexanes/acetone, 3:2) to give the ketones as a set of
diastereomer 3 and its amide rotamer and diastereomer 4 as tan
and white solid (3.25 g, 88%). The diastereomers could be sepa-
rated by flash column chromatography. Compound 3: 1H NMR
4.1.11. Procedure for multi-gram synthesis of N-mesityl substituted
imidazolium salt 215
To an oven dried 100 mL Schlenk flask equipped with a mag-
netic stir bar and charged with ketone 3 (5.0 g, 20 mmol, 1.0 equiv)
was added Ac2O (30 mL, 326 mmol, 16 equiv). The mixture was
cooled to 0 ꢀC and HClO4 (60%, 2.6 mL, 25 mmol, 1.2 equiv) was
added dropwise over 20 min. The brown solution was allowed to
warm to rt and then stirred for 2 h. The solution was twice trit-
urated with Et2O and the supernatant decanted each time. The
resulting white solid was dried in vacuo and dissolved in a mini-
mal amount of CH2Cl2 before 1 vol equiv of toluene was added.
Next, 2,4,6-trimethyl aniline (32 mL, 31 mmol, 1.5 equiv) was
added and the solution stirred overnight. The brown solution was
concentrated in vacuo to an oil. The oil was dissolved in a minimal
amount of CH2Cl2 and triturated with Et2O in a sonicating bath.
The white precipitate was collected by vacuum filtration and
washed with excess Et2O to give the aminal intermediate as
a white solid and as a mixture of diastereomers (5.9 g, 63%). This
white solid (5.9 g, 13 mmol, 1.0 equiv) was transferred to an oven
dried 200 mL round bottom flask equipped with a magnetic stir
bar and dissolved in 85 mL of 1,2-dichloroethane (0.15 M). Next,
Ac2O (2.4 mL, 25 mmol, 2.0 equiv) and HClO4 (60%, 0.26 mL,
2.5 mmol, 0.20 equiv) were added and the solution heated to
70 ꢀC. The reaction was monitored by 1H NMR analysis of aliquots
from the reaction. After 4 h, another 0.26 mL of HClO4 was added
in order to drive the reaction to completion. The reaction was
complete as indicated from NMR after an additional 2 h of stirring.
The solution was cooled to rt and concentrated in vacuo. The
resulting oil was dissolved in a minimal amount of CH2Cl2 and
triturated with Et2O in a sonicating bath. The precipitate was
collected by vacuum filtration to afford 2 as a white crystalline
solid (4.6 g, 81%, 51% over three steps).
(500 MHz, CDCl3) d 8.57 (s, 1H), 8.39
7.32–7.18 (m, 4H), 5.58
(d, 1H, J¼4.1 Hz), 4.96 (d, 1H, J¼4.2 Hz),
4.71 (d, 1H, J¼3.3 Hz), 4.44 (d, 1H, J¼3.4 Hz), 4.42–4.40 (m, 2H),
4.32 (m, 2H), 3.61 (dd, 1H, J¼12.2,
(t, 1H, J¼4.5 Hz), 3.83–3.78
4.0 Hz), 3.13–3.12
(m, 1H), 3.10–3.09 (m, 1H), 3.02 (d, 1H, J¼
16.9 Hz), 2.98 (3H); IR (thin
(d, 1H, J¼16.9 Hz), 2.08 (s, 3H), 2.00
film) n 2906, 1724, 1673, 1460, 1402, 1357, 1105, 1044 cmꢁ1 13C
*
(s, 1H), 7.34–7.18 (m, 4H),
*
*
*
*
*
*
*
*
;
NMR (500 MHz, CDCl3) d 204.8, 203.1, 164.7, 163.7, 140.1, 140.0,
138.3, 138.1, 128.5, 128.1, 126.9, 126.8, 126.6, 126.5, 125.5, 125.0,
124.9, 78.2, 78.1, 65.3, 64.2, 65.3, 64.2, 60.2, 56.6, 56.2, 38.3, 38.1,
27.3, 27.3; HRESIþ/TOF-MS calcd for C14H15NO3 [M]þ 245.1052,
found 246.1113 (MþH), 268.0951 (MþNa).Compound 4: 1H NMR
(400 MHz, CDCl3) d 8.37 (s, 1H), 7.30–7.20 (m, 4H), 5.05 (d, 1H,
J¼4.6 Hz), 4.58 (q, 1H, J¼4.5 Hz), 4.30 (dd, 1H, J¼4.3, 7.4 Hz), 3.90
(dd, 1H, J¼4.3, 12.0 Hz), 3.78 (dd, 1H, J¼7.4, 12.0 Hz), 3.12 (d, 2H,
J¼4.0 Hz), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3) d 203.0, 163.5,
140.7, 138.6, 129.3, 127.6, 126.1, 124.1, 77.8, 64.4, 59.0, 58.0, 36.9,
28.4; IR (thin film) n 3074, 3018, þ2908, 2864, 1721, 1675, 1400,
1218 cmꢁ1; mp 174–176 ꢀC; HRESI /TOF-MS calcd for C14H15NO3
[M]þ 245.1052, found 246.1096 (MþH), 268.0970 (MþNa).
4.1.9. Procedure for Swern oxidation
4.1.12. Preparation of N-mesityl substituted imidazolium salt 2
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (700 mg, 1.8 mmol, 1.0 equiv) were added
To a 0.256 M solution of oxalyl chloride (6.70 mL, 76.8 mmol,
2.50 equiv) in CH2Cl2 (300 mL) cooled to ꢁ60 ꢀC was slowly added

J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6969
toluene (10 mL) and 2,4,6-trimethyl aniline (0.38 mL, 2.7 mmol,
1.5 equiv). The heterogeneous mixture was stirred at ambient
temperature for 3 h. The solvent was decanted and the precipitate
washed with Et2O (2ꢂ10 mL). Residual solvent was removed in
vacuo to afford the aminal intermediate as a light white solid and as
a mixture of diastereomers (835 mg, quant.). A mixture of the
aminal intermediate (98 mg, 0.21 mmol, 1.0 equiv) in toluene
(1.0 mL) was treated with Ac2O (0.40 mL, 0.42 mmol, 2.0 equiv) and
HClO4 (70%, 7.0 mL, 0.082 mmol, 0.20 equiv) and heated at 80 ꢀC for
2.5 h. The solution was allowed to cool to rt and concentrated in
vacuo. The crude solid was suspended in Et2O and placed in
a sonicating bath. Once the precipitate had become white, it was
collected by vacuum filtration and washed with EtOAc to yield 2
(73 mg, 78% over three steps). 1H NMR (500 MHz, acetone-d6)
d 9.71 (s, 1H), 7.64 (d, 1H, J¼7.6 Hz), 7.44 (d, 2H, J¼7.4 Hz), 7.40 (t,
1H, J¼7.4 Hz), 7.22 (s, 2H), 6.10 (d, 1H, J¼4.0 Hz), 5.11 (d, 1H,
J¼15.0 Hz), 5.06 (t, 1H, J¼4.5 Hz), 4.98 (d, 1H, J¼15.0 Hz), 3.49 (dd,
1H, J¼4.8, 17.0 Hz), 3.23 (d, 1H, J¼17.0 Hz), 2.40 (s, 3H), 2.14 (s, 3H),
2.08 (s, 3H), 2.06 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 141.9,
141.5, 137.8, 136.0, 135.9, 135.2, 130.3, 130.2, 129.8, 129.6, 127.8,
126.2, 125.8, 125.2, 124.0, 78.0, 61.4, 60.0, 38.0, 20.8, 17.1, 7.6; IR
afford 135 mg of 21 as a brown solid. The filtrate was then purified
by flash column chromatography (gradient, CH2Cl2/acetone, 19:1/
9:1) to afford another 145 mg of 21 as an off-white powder
(230 mg, 70% over three steps). 1H NMR (500 MHz, acetone-d6)
d 9.77 (s, 1H), 7.79–7.72 (m, 5H), 7.67 (d, 1H, J¼7.6 Hz), 7.41 (d, 1H,
J¼7.4 Hz), 7.38 (t, 1H, J¼7.4 Hz), 7.30 (t, 1H, J¼7.4 Hz), 5.99 (d, 1H, J¼
4.1 Hz), 5.08 (d, 1H, J¼15.1 Hz), 4.99 (t, 1H, J¼4.5 Hz), 4.95 (d, 1H,
J¼15.0 Hz), 3.47 (dd,1H, J¼16.9, 4.8 Hz), 3.21 (d,1H, J¼16.9 Hz), 2.23
(s, 3H); 13C NMR (125 MHz, acetone-d6) d 141.7, 137.8, 135.6, 134.5,
131.7, 131.0, 130.0, 127.9, 127.4, 126.3, 126.1, 125.0, 124.7, 78.3, 61.5,
60.2, 38.2, 8.6; IR (thin film) n 3121, 3059, 2928, 1545, 1460, 1217,
1094, 774 cmꢁ1
;
HRESIþ/TOF-MS calcd 303.1492 [M]þ, found
303.1502; [a]2D0 ꢁ177.4 (c 0.19, CH2Cl2).
4.1.15. Preparation of N-2-methyl-4-methoxyphenyl substituted
imidazolium salt 22
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) was added
toluene (5 mL) and 4-methoxy-2-methylaniline (0.20 mL,
1.50 mmol, 1.50 equiv). The heterogeneous mixture was stirred at
ambient temperature for 12 h. The supernatant was decanted, the
crude oil washed with Et2O (2ꢂ10 mL), and residual solvent re-
moved in vacuo to afford the crude aminal intermediate as a light
purple solid and as mixture of diastereomers (430 mg, 92% yield). A
suspension of the crude aminal intermediate (430 mg, 0.92 mmol,
1.0 equiv) in toluene (4.0 mL) was treated with Ac2O (0.18 mL,
1.8 mmol, 2.0 equiv) and HClO4 (70%, 16 mL, 0.18 mmol, 0.20 equiv).
The mixture was stirred at 80 ꢀC for 1 h. After allowing the reaction
to cool to rt, the reaction was concentrated in vacuo to a brown
solid. This solid was suspended in Et2O, at which time had turned
into an oil, in a sonicating bath while methanol was dropwise
added as needed until the oil began to precipitate as a light purple
powder. This precipitate was collected by vacuum filtration and the
purification process repeated on the filtrate to afford a second crop
of 22 as a light purple solid and as a 1:1 mixture of atropisomers
(370 mg, 66%, 61% over three steps). 1H NMR (500 MHz, acetone-d6)
d 9.71 (d, 1H, J¼10 Hz), 7.63 (d, 1H, J¼7.6 Hz), 7.56 (d, 1H, J¼8.4 Hz),
7.44–7.38 (m, 2H), 7.32 (s, 1H), 7.12 (d, 1H, J¼2.4 Hz), 7.05 (dd, 1H,
J¼8.6, 2.4 Hz), 6.04 (s, 1H), 5.09 (d, 1H, J¼14.9 Hz), 5.03 (s, 1H), 4.95
(d, 1H, J¼4.6 Hz), 3.91 (s, 3H), 3.48 (d, 1H, J¼16.9 Hz), 3.23 (d, 1H,
J¼17.0 Hz), 2.20 (d, 3H, J¼12.0 Hz), 2.12 (s, 3H); 13C NMR (125 MHz,
acetone-d6) d 162.4, 141.8, 137.9, 136.0, 130.0, 129.9, 128.0, 126.7,
126.4, 125.9, 125.0, 124.8, 124.4, 117.3, 113.6, 78.3, 61.5, 60.2, 56.1,
38.3, 17.5, 8.2; IR (thin film) n 3126, 3053, 2930, 1544, 1502, 1463,
1217, 1094, 734 cmꢁ1; HRESIþ/TOF-MS calcd 347.1754 [M]þ, found
347.1768; [a]2D0 ꢁ147.5 (c 0.28, CH2Cl2).
(thin film) n 3122, 3047, 2925, 2860, 1539, 1461, 1214, 1097 cmꢁ1
;
HRESIþ/TOF-MS calcd for C23H25N2Oþ [M]þ 345.1961, found
345.1931; [a]2D0 ꢁ134.0 (c 0.55, CH2Cl2).
4.1.13. Preparation of N-2,6-dimethyl-4-bromophenyl substituted
imidazolium salt 20
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 4-bromo-2,6-dimethyl aniline (300 mg,
1.50 mmol, 1.50 equiv). The heterogeneous mixture was stirred at
ambient temperature for 13 h. The precipitate was collected by
vacuum filtration and washed with Et2O to afford the aminal in-
termediate as a white powder and as a mixture of diastereomers
(300 mg, 57%). A 0.25 M solution of the aminal intermediate
(200 mg, 0.38 mmol, 1.0 equiv) in 1,2-dichloroethane (1.5 mL) was
treated with Ac2O (0.070 mL, 0.76 mmol, 2.0 equiv) and HClO4 (70%,
6.0 mL, 0.080 mmol, 0.20 equiv) and heated at 70 ꢀC for 3 h. The
solution was allowed to cool to rt, and a precipitate collected by
vacuum filtration and washed with 1,2-dichloroethane to afford 20
as a yellow solid (170 mg, 89%, 51% over three steps). 1H NMR
(400 MHz, acetone-d6) d 9.78 (s, 1H), 7.65–7.63 (m, 3H), 7.44 (d,
1H, J¼7.4 Hz), 7.40 (t,1H, J¼7.3 Hz), 7.33 (t,1H, J¼7.4 Hz), 6.10 (d,1H,
J¼3.7 Hz), 5.13 (d, 1H, J¼15.0 Hz), 5.06 (t, 1H, J¼4.3 Hz), 4.98 (d, 1H,
J¼15.0 Hz), 3.49 (dd, 1H, J¼16.9, 4.8 Hz), 3.23 (d, 1H, J¼17.0 Hz),
2.21 (s, 3H), 2.13 (s, 6H); 13C NMR (100 MHz, acetone-d6) d 141.8,
139.4,138.1,132.8,132.6,131.9,130.1,128.2,126.5,125.9,125.8,125.4,
124.3, 78.3, 61.8, 60.3, 38.3, 17.4, 7.9; IR (KBr pellet) n 3115, 3042,
2913, 2852, 1533, 1460, 1203, 1099, 858, 747 cmꢁ1; HRESIþ/TOF-MS
calcd 409.0910 [M]þ, found 409.0914; [a]D20 ꢁ109.8 (c 0.25, CH2Cl2).
4.1.16. Preparation of N-2-hydroxy-6-methylphenyl substituted
imidazolium salt 23
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (5 mL) and 2-hydroxy-6-methylaniline (185 mg,
1.50 mmol, 1.50 equiv). The heterogeneous mixture was stirred at
ambient temperature for 14 h. The solution was triturated with
Et2O, the supernatant was decanted, and residual solvent removed
in vacuo to afford a mixture of the crude aminal intermediate and
parent aniline as a brown solid (482 mg, quant. crude yield). A
suspension of the crude aminal intermediate (450 mg, 1.0 mmol,
1.0 equiv) in toluene (4.0 mL) was treated with Ac2O (0.12 mL,
1.2 mmol, 1.2 equiv) and HClO4 (70%, 17 mL, 0.20 mmol, 0.20 equiv).
The mixture was stirred at 80 ꢀC for 1 h. After allowing the reaction
to cool to rt, the supernatant was decanted, residual solvent re-
moved in vacuo, and the product precipitated from CH2Cl2. The
precipitate was collected by vacuum filtration to afford 23 as a light
gray powder and as a 4:1 mixture of atropisomers (150 mg, 35%
4.1.14. Preparation of N-phenyl substituted imidazolium salt 21
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (5 mL) and aniline (0.13 mL, 1.50 mmol, 1.50 equiv). The
heterogeneous mixture was stirred at ambient temperature for
16 h. The solution was decanted, the remaining oil washed with
Et2O (2ꢂ10 mL), and excess solvent removed in vacuo to afford the
aminal intermediate as a brown foam and as a mixture of dia-
stereomers (420 mg, quant. crude yield). A suspension of the
aminal intermediate (420 mg, 1.0 mmol, 1.0 equiv) in toluene
(4.0 mL) was treated with Ac2O (0.19 mL, 2.0 mmol, 2.0 equiv) and
HClO4 (70%, 17 mL, 0.20 mmol, 0.20 equiv). The mixture was stirred
at 80 ꢀC for 45 min. After allowing the reaction to cool to rt, the
supernatant was decanted, excess solvent removed in vacuo, and
the resulting residue triturated with Et2O in a sonicating bath to
over three steps). 1H NMR (500 MHz, acetone-d6) d 9.74
(s, 1H),
*

6970
J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
9.72 (s, 1H), 9.48 (br s, 1H, OH), 9.43
*
(br s, 1H, OH), 7.64
*
(d, 1H,
(m,
(d, 1H, J¼8.6 Hz), 7.08 (d, 1H,
J¼8.2 Hz), 7.03 (d, 1H, J¼7.6 Hz), 6.11 (d, 1H, J¼4.1 Hz), 6.08 (d,
1H, J¼4.1 Hz), 5.12 (d, 1H, J¼15.0 Hz), 5.12–5.09 (m, 2H), 5.06 (t,1H,
J¼4.5 Hz), 4.97 (d, 1H, J¼15.0 Hz), 4.96 (d, 1H, J¼14.9 Hz), 3.53–
3.50 (d, 1H, J¼16.9 Hz),
(m, 1H), 3.49 (dd, 1H, J¼16.9, 4.9 Hz), 3.24
(s, 3H), 2.11 (s, 3H), 2.10
J¼4.3 Hz), 4.95 (d, 1H, J¼15.1 Hz), 3.50 (dd, 1H, J¼17.0, 4.8 Hz), 3.23
(d, 1H, J¼17.0 Hz), 2.34 (s, 3H); 13C NMR (125 MHz, acetone-d6) d
141.8,137.6,136.7,136.3,134.0,133.7,130.2,129.3,127.9,126.7,126.4,
125.0, 125.0, 78.4, 61.7, 60.2, 38.3, 8.6; IR (thin film) n 3148, 3058,
2937, 1543, 1368, 1280, 1105, 1076, 905, 604 cmꢁ1; HRESIþ/TOF-MS
calcd 439.1240 [M]þ, found 439.1246; [a]D20 ꢁ141.9 (c 0.15, CH2Cl2).
J¼7.5 Hz), 7.58 (d, 1H, J¼7.6 Hz), 7.45–7.41 (m, 3H), 7.41–7.34
*
3H), 7.30 (t, 1H, J¼7.4 Hz), 7.09
*
*
*
*
*
*
3.22 (d, 1H, J¼16.9 Hz), 2.21 (s, 3H), 2.15
*
*
4.1.19. Preparation of N-3,5-di-tert-butylphenyl substituted
imidazolium salt 26
(s, 3H); 13C NMR (125 MHz, acetone-d6) d 153.9, 153.8, 141.8, 138.0,
137.8, 136.4, 133.0, 132.9, 132.8, 130.1, 130.0, 128.2, 128.0, 126.6,
126.5, 126.4, 124.8, 124.5, 124.3, 122.9, 120.8, 115.3, 115.2, 78.3, 61.6,
60.2, 38.3, 17.3, 7.9; IR (KBr pellet) n 3350, 3132, 3053, 2924, 1592,
1544, 1477, 1298, 1105, 951, 738, 624 cmꢁ1; HRESIþ/TOF-MS calcd
333.1598 [M]þ, found 333.1607; [a]2D0 ꢁ129.6 (c 0.22, MeOH).
To a solution of oxazolinium salt 18 (388 mg, 1.00 mmol,
1.00 equiv) in CH2Cl2 (3 mL) were added toluene (10 mL) and 3,5-
di-tert-butylaniline (0.23 mL, 1.50 mmol, 1.50 equiv). The solution
was stirred at ambient temperature for 16 h during which a white
solid had precipitated. The precipitate was collected by vacuum
filtration and washed with Et2O to afford the aminal intermediate
as a white powder and as a mixture of diastereomers (420 mg, 79%
yield). A 0.25 M solution of the aminal intermediate (420 mg,
0.79 mmol, 1.0 equiv) in 1,2-dichloroethane (3.1 mL) was treated
with Ac2O (0.15 mL, 1.6 mmol, 2.0 equiv) and HClO4 (70%, 14 mL,
0.16 mmol, 0.20 equiv) and stirred at 70 ꢀC for 30 min. After
allowing the solution to cool to rt, the solvent was removed in
vacuo and the residue purified by flash column chromatography
(CH2Cl2/MeOH, 30:1) to afford 26 as a light yellow foam (385 mg,
95%, 75% over three steps). 1H NMR (500 MHz, acetone-d6) d 9.75
(s, 1H), 7.80 (t, 1H, J¼1.7 Hz), 7.65–7.63 (m, 3H), 7.41 (d, 1H, J¼
7.4 Hz), 7.35 (t, 1H, J¼7.3 Hz), 7.29 (t, 1H, J¼7.4 Hz), 5.97 (s, 1H,
J¼4.2 Hz), 5.06 (d, 1H, J¼15.0 Hz), 4.96 (t, 1H, J¼4.4 Hz), 4.90 (d, 1H,
J¼15.0 Hz), 3.46 (dd, 1H, J¼16.9, 4.9 Hz), 3.20 (d, 1H, J¼16.9 Hz),
2.23 (s, 3H), 1.41 (s, 18H); 13C NMR (125 MHz, acetone-d6) d 154.0,
141.6, 137.8, 135.5, 134.2, 129.9, 127.8, 126.2, 126.0, 125.3, 124.9,
124.5,121.6, 78.2, 61.3, 60.1, 38.1, 35.8, 31.4, 8.7; IR (thin film) n 3126,
3053, 2952, 2868, 1608, 1597, 1538, 1477, 1365, 1248, 1096, 733,
624 cmꢁ1; HRESIþ/TOF-MS calcd 415.2744 [M]þ, found 415.2742;
[a]2D0 ꢁ133.7 (c 0.25, CH2Cl2).
4.1.17. Preparation of N-2,6-diisopropylphenyl substituted
imidazolium salt 24
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 2,6-diisopropyl aniline (0.28 mL, 1.50 mmol,
1.50 equiv). The heterogeneous mixture was stirred at ambient
temperature for 12 h. Et2O was added, the supernatant decanted,
and the resultant oil concentrated in vacuo to afford the aminal
intermediate as a light yellow foam and as a mixture of di-
astereomers (360 mg, 71%). A mixture of the aminal intermediate
(360 mg, 0.71 mmol, 1.0 equiv) in toluene (3.0 mL) was treated with
Ac2O (0.13 mL, 1.4 mmol, 2.0 equiv) and HClO4 (70%, 12 mL,
0.14 mmol, 0.20 equiv) and heated at 80 ꢀC for 15 min. The solution
was allowed to cool to rt, concentrated in vacuo, and the residue
purified by flash column chromatography (gradient, CH2Cl2/MeOH,
98:2/95:5) to give 24 as a yellow foam (235 mg, 68%, 48% over
three steps). 1H NMR (500 MHz, acetone-d6) d 9.93 (s, 1H), 7.72–7.69
(t, 1H, J¼7.8 Hz), 7.57–7.52 (m, 3H), 7.46 (d, 1H, J¼7.4 Hz), 7.40 (t, 1H,
J¼7.4 Hz), 7.33 (t, 1H, J¼7.4 Hz), 6.10 (d, 1H, J¼4.0 Hz), 5.11 (d, 1H,
J¼15.0 Hz), 5.07 (t, 1H, J¼4.4 Hz), 4.98 (d, 1H, J¼15.0 Hz), 3.49 (dd,
1H, J¼16.9, 4.8 Hz), 3.23 (d, 1H, J¼16.9 Hz), 2.80 (d, 1H, J¼16.9 Hz),
2.64 (septet, 1H, J¼6.8 Hz), 2.26 (septet, 1H, J¼6.8 Hz), 2.10 (s, 3H),
1.26 (dd, 6H, J¼10.0, 6.8 Hz), 1.21 (dd, 6H, J¼6.8, 2.5 Hz); 13C NMR
(125 MHz, acetone-d6) d 147.1, 146.9, 142.0, 138.2, 135.8, 133.0, 130.2,
129.1, 128.0, 126.9, 126.6, 126.0, 125.8, 125.8, 124.1, 123.7, 78.3, 61.8,
60.3, 38.4, 25.3, 25.2, 23.4, 23.2, 8.3; IR (thin film) n 3116, 3045, 2965,
2929, 2871, 1538, 1462, 1202, 1099, 733, 624 cmꢁ1; HRESIþ/TOF-MS
calcd 387.2431 [M]þ, found 387.2446; [a]D20 ꢁ94.5 (c 0.22, CH2Cl2).
4.1.20. Preparation of N-morpholino substituted imidazolium salt 27
To a solution of oxazolinium salt 18 (388 mg, 1.00 mmol,
1.00 equiv) in CH2Cl2 (5 mL) were added toluene (5 mL) and 4-
aminomorpholine (0.15 mL, 1.50 mmol, 1.50 equiv). The heteroge-
neous mixture was stirred at ambient temperature for 18 h. Et2O
was added to the mixture causing an oil to form. The supernatant
was decanted. The oil was dissolved in a minimal amount of CH2Cl2
(w5 mL) and triturated with Et2O, the supernatant decanted, and
residual solvent removed in vacuo to afford the aminal in-
termediate as a light yellow solid and as a mixture of diastereomers
(360 mg, 84%). A 0.25 M solution of the aminal intermediate
(360 mg, 0.84 mmol, 1.0 equiv) in 1,2-dichloroethane (3.4 mL) was
treated with Ac2O (0.15 mL, 1.6 mmol, 2.0 equiv) and HClO4 (70%,
7.0 mL, 0.080 mmol, 0.10 equiv) and stirred at 70 ꢀC for 20 h. After
allowing the solution to cool to rt, the solvent was removed in
vacuo and the residue purified by flash column chromatography
(gradient, CH2Cl2/MeOH, 95:5/90:10) to afford 27 as a yellow
solid (260 mg, 75%, 63% over three steps). 1H NMR (500 MHz, ace-
tone-d6) d 10.09 (s, 1H), 7.58 (d, 1H, J¼7.7 Hz), 7.41–7.35 (m, 2H),
7.30 (t, 1H, 7.3 Hz), 5.90 (d, 1H, J¼4.1 Hz), 5.00 (d, 1H, J¼15.0 Hz),
4.95 (t, 1H, J¼4.4 Hz), 4.82 (d, 1H, J¼15.1 Hz), 3.92 (t, 4H, J¼4.5 Hz),
3.47 (t, 4H, J¼4.5 Hz), 3.43–3.40 (m, 1H), 3.17 (d, 1H, J¼16.9 Hz),
2.35 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 141.7, 137.7, 132.9,
130.0, 127.9, 126.4, 125.8, 124.8, 122.7, 78.3, 67.3, 61.4, 60.0, 57.2,
38.2, 7.4; IR (thin film) n 3115, 2969, 2863, 1460, 1270, 1102, 1080,
4.1.18. Preparation of N-3,5-bis(trifluoromethyl)phenyl substituted
imidazolium salt 24
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 3,5-bis(trifluoromethyl)aniline (0.23 mL,
1.50 mmol, 1.50 equiv). The heterogeneous mixture was stirred at
ambient temperature for 16 h. The supernatant was decanted, the
crude oil washed with Et2O (1ꢂ10 mL), and residual solvent re-
moved in vacuo to afford the crude aminal intermediate as a yellow
solid and a mixture of diastereomers (560 mg, quant. crude yield). A
suspension of the crude aminal intermediate (560 mg, 1.0 mmol,
1.0 equiv) in toluene (4.0 mL) was treated with Ac2O (0.19 mL,
2.0 mmol, 2.0 equiv) and HClO4 (70%, 17 mL, 0.20 mmol, 0.20 equiv).
The mixture was stirred at 80 ꢀC for 15 min. After allowing the
reaction to cool to rt, the supernatant was decanted, the residual
solvent removed in vacuo, and the resulting residue suspended in
a mixture of Et2O/EtOAc (2:1, 7 mL) and sonicated until pre-
cipitation had occurred; then 25 was collected by vacuum filtration
as a white solid (190 mg, 35% over three steps). 1H NMR (500 MHz,
acetone-d6) d 10.00 (s, 1H), 8.60 (s, 2H), 8.47 (s, 1H), 7.63 (d, 1H,
J¼7.7 Hz), 7.43 (d, 1H, J¼7.5 Hz), 7.39 (t, 1H, J¼7.4 Hz), 7.29 (t, 1H, J¼
7.4 Hz), 6.04 (d, 1H, J¼4.1 Hz), 5.13 (d, 1H, J¼15.1 Hz), 5.02 (t, 1H,
923, 741 cmꢁ1
;
HRESIþ/TOF-MS calcd 312.1707 [M]þ, found
312.1720; [a]2D0 ꢁ174.5 (c 0.20, CH2Cl2).
4.1.21. Preparation of N-methyl substituted imidazolium salt 28
To a solution of oxazolinium salt 18 (388 mg, 1.00 mmol,
1.00 equiv) in CH2Cl2 (5 mL) were added toluene (5 mL) and a 2.0 M

J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6971
solution (THF) of N-methyl amine (0.75 mL, 1.50 mmol, 1.50 equiv).
The heterogeneous mixture was stirred at ambient temperature for
12 h. The precipitate was collected by vacuum filtration and washed
with Et2O to afford the aminal intermediate as a white powder and
as a mixture of diastereomers (310 mg, 86% yield). A 0.25 M solu-
tion of the aminal intermediate (300 mg, 0.83 mmol, 1.0 equiv) in
1,2-dichloroethane (3.3 mL) was treated with Ac2O (0.16 mL,
1.7 mmol, 2.0 equiv) and HClO4 (70%, 7.0 mL, 0.080 mmol,
0.10 equiv) and stirred at 70 ꢀC for 10 min. After allowing the
solution to cool to rt, the solvent was removed in vacuo and the
resultant residue dissolved in a minimal amount of CH2Cl2 and
triturated with toluene. The precipitate was collected by vacuum
filtration to afford 28 as a white powder (180 mg, 64%, 53% over
three steps). 1H NMR (400 MHz, acetone-d6) d 9.56 (s, 1H), 5.53 (d,
1H, J¼7.6 Hz), 7.41–7.30 (m, 2H), 7.28 (t, 1H, J¼7.3 Hz), 5.91 (s, 1H),
5.02 (d, 1H, J¼15.2 Hz), 4.95 (t, 1H, J¼4.5 Hz), 4.83 (d, 1H, J¼
15.0 Hz), 4.06 (s, 3H), 3.43 (dd, 1H, J¼16.9, 4.9 Hz), 3.18 (d, 1H,
J¼17.0 Hz), 2.36 (s, 3H); 13C NMR (100 MHz, acetone-d6) d 141.6,
138.1, 135.7, 129.9, 127.9, 126.2, 126.0, 124.7, 124.0, 78.2, 61.1, 60.0,
38.1, 34.2, 7.8; IR (thin film) n 3137, 3076, 2930, 1636, 1558, 1446,
1253, 1096, 760, 738, 624 cmꢁ1; HRESIþ/TOF-MS calcd 241.1335
[M]þ, found 241.1338; [a]D20 ꢁ163.7 (c 0.33, CH2Cl2).
Ac2O (0.16 mL, 1.7 mmol, 2.0 equiv) and HClO4 (70%, 16 mL,
0.17 mmol, 0.20 equiv) and heated at 80 ꢀC for 45 min. The solution
was decanted and the oil concentrated in vacuo to a brown foam,
which was dissolved in a minimal amount of EtOAc, placed in
a sonicating bath, and triturated with Et2O. Isolation by vacuum
filtration afforded 30 in three crops as a yellow solid and w10:1
mixture of atropisomers (90 mg, 23%, 20% over three steps). 1H
NMR (500 MHz, acetone-d6) d 9.97 (s,1H), 9.94 (s,1H), 7.89 (dd,1H,
*
J¼8.2, 1.4 Hz), 7.71–7.68 (m, 1H), 7.68
*
(d, 1H, J¼1.5 Hz), 7.60–7.57
(m, 1H), 7.54–7.49 (m, 1H), 7.49–7.47
*
(m 1H), 7.46–7.41 (m, 4H),
7.40 (d, 1H, J¼7.4 Hz), 7.30–7.16
6.01 (d, 1H, J¼4.2 Hz), 5.13 (d, 1H, J¼15 Hz), 5.10–5.08
(t, 1H, J¼4.4 Hz), 4.93 (dd, 1H, J¼15.0, 1.0 Hz), 3.50 (dd, 1H, J¼16.9,
5.0 Hz), 3.31
(dd, 1H, J¼16.8, 4.1 Hz), 3.24 (d, 1H, J¼16.9 Hz), 3.15
*
(m, 7H), 6.18
*
(d, 1H, J¼5.0 Hz),
*
(m, 2H), 5.02
*
*
(d,1H, J¼16.7 Hz), 2.16
*
(s, 3H), 2.14 (s, 3H),1.32 (s, 9H),1.29 (s, 9H);
*
13C NMR (125 MHz, acetone-d6) d 147.5, 142.0, 138.1, 137.0, 132.6,
131.7, 131.5, 131.3, 130.8, 130.2, 129.0, 128.8, 128.7, 128.1, 128.0, 127.9,
126.6, 125.0, 124.3, 78.3, 61.6, 60.1, 38.3, 36.9, 32.1, 8.92; IR (thin
film) n 3123, 3056, 2967, 1540, 1482, 1213, 1099, 733, 624 cmꢁ1
;
HRESIþ/TOF-MS calcd 359.2118 [M]þ, found 359.2112; [a]2D0 ꢁ202.7
(c 0.073, CH2Cl2).
4.1.24. Preparation of N-2-bromophenyl substituted imidazolium
salt 31
4.1.22. Preparation of N-2-isopropylphenyl substituted imidazolium
salt 29
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 2-bromoaniline (0.140 mL, 1.50 mmol,
1.50 equiv). The heterogeneous mixture was stirred at ambient
temperature for 12 h. The solution was concentrated in vacuo to
a brown foam, which was suspended in Et2O (10 mL) and EtOAc
(4 mL), placed in a sonicating bath, and methanol (<1 mL) added
until a solid precipitate formed. The precipitate was collected by
vacuum filtration to afford two crops of the aminal intermediate as
a white solid and as a mixture of diastereomers (130 mg, 26%). A
mixture of the aminal intermediate (125 mg, 0.25 mmol, 1.0 equiv)
in toluene (1.0 mL) was treated with Ac2O (47 mL, 0.50 mmol,
2.0 equiv) and HClO4 (70%, 4.0 mL, 0.050 mmol, 0.20 equiv) and
stirred at 80 ꢀC for 30 min. The solution was concentrated in vacuo
and the residue purified by flash column chromatography (gradi-
ent, CH2Cl2/MeOH, 98:2/95:5/92:8/90:10) to afford 31 as
a yellow solid as a 2:1 mixture of atropisomers (100 mg, 83% yield,
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 2-isopropyl aniline (0.21 mL, 1.50 mmol,
1.50 equiv). The heterogeneous mixture was stirred at ambient
temperature for 12 h. The precipitate was suspended in EtOAc,
collected by vacuum filtration, and washed with EtOAc to afford the
aminal intermediate as a white powder and as a mixture of di-
astereomers (325 mg, 71%). A mixture of the aminal intermediate
(325 mg, 0.70 mmol,1.0 equiv) in toluene (2.8 mL) was treated with
Ac2O (0.13 mL, 1.4 mmol, 2.0 equiv) and HClO4 (70%, 13 mL,
0.14 mmol, 0.20 equiv) and heated at 80 ꢀC for 1 h. The solution was
decanted and the oil concentrated in vacuo to a brown foam, which
was dissolved in a minimal amount of EtOAc, placed in a sonicating
bath, and triturated with Et2O. Isolation of the precipitate by
vacuum filtration provided two crops of 29, 100 and 120 mg, re-
spectively, as a white powder (220 mg, 71%, 50% over three steps)
and as a 50:50 mixture of atropisomers. 1H NMR (500 MHz, ace-
tone-d6) d 9.85 (d, 1H, J¼1.6 Hz), 7.75–7.73 (m, 2H), 7.65–7.51 (m,
3H), 7.47–7.39 (m, 2H), 7.35–7.30 (m, 1H), 6.06 (dd, 1H, J¼28.6,
4.2 Hz), 5.13–5.08 (m, 1H), 5.05–5.02 (m, 1H), 4.99–4.91 (m, 1H),
22% over three steps). 1H NMR (500 MHz, acetone-d6) d 9.90
1H), 9.82 (s, 1H), 8.01 (d, 1H, J¼8.0 Hz), 7.97 (d, 1H, J¼7.3 Hz), 7.79–
7.70 (m, 3H), 7.66
(d, 1H, J¼7.6 Hz), 7.61 (d, 1H, J¼7.6 Hz), 7.44 (d,
1H, J¼7.4 Hz), 7.39 (t, 1H, J¼7.3 Hz), 7.32 (t, 1H, J¼7.3 Hz), 6.14 (d,
1H, J¼3.6 Hz) 6.02 (d, 1H, J¼3.8 Hz), 5.13 (d, 1H, J¼15.1 Hz), 5.12
(d, 1H, J¼15.0 Hz), 5.01 (t, 1H, J¼4.4 Hz), 5.01 (t, 1H, J¼4.4 Hz), 4.92
(d, 1H, J¼15.0 Hz), 3.50 (dd, 1H, J¼16.9, 4.7 Hz), 3.50 (dd, 1H,
J¼16.9, 4.7 Hz), 3.24 (d, 1H, J¼16.9 Hz), 3.22 (d, 1H, J¼16.9 Hz),
2.17
(s, 3H), 2.14 (s, 3H); 13C NMR (125 MHz, acetone-d6) d 141.8,
*
(s,
*
*
*
3.49–3.46 (m, 1H), 3.23 (dd, 1H, J¼16.9, 2.7 Hz), 2.77
*
(septet, 1H,
*
J¼6.9 Hz), 2.59 (septet, 1H, J¼6.9 Hz), 2.12 (d, 3H, J¼2.6 Hz), 1.30–
1.24 (m, 6H); 13C NMR (125 MHz, acetone-d6) d 146.8, 146.6, 142.0,
141.8, 138.1, 137.8, 136.0, 135.8, 132.9, 132.9, 131.7, 130.2, 130.1, 129.0,
128.7, 128.5, 128.5, 128.4, 128.3, 128.1, 128.0, 127.0, 126.8, 126.6,
126.4, 125.0, 124.9, 124.1, 78.3, 61.7, 61.6, 60.3, 60.2, 38.4, 38.3, 28.9,
28.6, 24.8, 24.8, 23.4, 23.0, 8.4, 8.3; IR (thin film) n 3120, 3057, 2967,
2930, 2871, 1540, 1461, 1268, 1224, 1099, 733, 623 cmꢁ1; HRESIþ/
TOF-MS calcd 345.1916 [M]þ, found 345.1955; [a]2D0 ꢁ113.3 (c 0.12,
CH2Cl2).
*
*
*
*
138.0, 136.4, 136.1, 134.9, 134.8, 134.2, 133.5, 131.1, 130.8, 130.5,
130.4, 130.1, 128.1, 128.0, 126.6, 126.5, 126.3, 125.0, 124.7, 124.3,
121.9, 78.3, 61.7, 60.2, 38.4, 38.2, 8.4, 8.3; IR (thin film) n 3124, 3058,
2926, 1544, 1482, 1267, 1219, 1092, 736, 622 cmꢁ1; HRESIþ/TOF-MS
calcd 381.0597 [M]þ, found 381.0607; [a]D20 ꢁ84.9 (c 011, CH2Cl2).
4.1.23. Preparation of N-2-tert-butylphenyl substituted
imidazolium salt 30
4.1.25. Preparation of N-2-(N-methylbenzamido) substituted
imidazolium salt 32
To a round bottom flask charged with a magnetic stir bar and
oxazolinium salt 18 (388 mg, 1.00 mmol, 1.00 equiv) were added
toluene (10 mL) and 2-tert-butyl aniline (0.24 mL, 1.50 mmol,
1.50 equiv). The heterogeneous mixture was stirred at ambient
temperature for 15 h. The aminal intermediate was collected by
vacuum filtration as a tan powder and as a mixture of dia-
stereomers (410 mg, 86%). A mixture of the aminal intermediate
(410 mg, 0.86 mmol, 1.0 equiv) in toluene (3.5 mL) was treated with
To a 1.0 M solution of oxazolinium salt 18 (388 mg, 1.00 mmol,
1.00 equiv) in CH2Cl2 in a round bottom flask charged with a mag-
netic stir bar was added a 1 M solution of 2-amino-N-methyl-
benzamide34 (1.5 mL, 1.5 mmol, 1.5 equiv) in CH2Cl2 followed by
toluene (3 mL). The cloudy solution was stirred at ambient tem-
perature for 16 h. The solution was triturated with Et2O, the
supernatant decanted, and residual solvent removed in vacuo to
afford the aminal intermediate as a light tan foam and as a mixture

6972
J.R. Struble, J.W. Bode / Tetrahedron 64 (2008) 6961–6972
6. Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860–3864.
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8. Chaulagain, M. R.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129,
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of diastereomers (475 mg, 99%). A 0.25 M solution of the aminal
intermediate (475 mg, 0.99 mmol, 1.0 equiv) in 1,2-dichloroethane
(4.0 mL) was treated with Ac2O (0.19 mL, 2.0 mmol, 2.0 equiv) and
HClO4 (70%, 17 mL, 0.20 mmol, 0.20 equiv). The solution was stirred
at 70 ꢀC for 30 min, concentrated in vacuo, and the residue purified
by flash column chromatography (CH2Cl2/MeOH, 95:5) to afford 32
as a white solid (320 mg, 70%, 69% over three steps). 1H NMR
(500 MHz, acetone-d6) d 9.67 (s, 1H), 7.9 (br s, 1H, NH), 7.89–7.77
(m, 4H), 7.62 (d, 1H, J¼7.6 Hz), 7.41 (d, 1H, J¼7.4 Hz), 7.38 (t, 1H,
J¼7.4 Hz), 7.32 (t, 1H, J¼7.4 Hz), 5.97 (s, 1H), 5.04 (d, 1H, J¼15.0 Hz),
4.99 (br s, 1H), 4.89 (d, 1H, J¼15.0 Hz), 3.47 (dd, 1H, J¼16.9, 4.8 Hz),
3.20 (d, 1H, J¼16.9 Hz), 2.81 (d, 3H, J¼4.7 Hz), 2.10 (s, 3H); 13C NMR
(125 MHz, acetone-d6) d 166.4,141.6,138.1,136.6,135.4,132.5,132.4,
131.9, 129.9, 129.8, 129.6, 127.9, 127.2, 126.2, 124.8, 123.6, 78.3, 61.5,
60.1, 38.3, 26.8, 8.4; IR (thin film) n 3362, 3128, 3061, 2931, 1662,
1604, 1545, 1217, 1099, 734, 623 cmꢁ1; HRESIþ/TOF-MS calcd
360.1707 [M]þ, found 360.1711; [a]D20 ꢁ124.9 (c 0.19, CH2Cl2).
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J. Org. Chem. 2004, 9, 2025–2035; (f) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
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Acknowledgements
Partial support for this work was provided by the National
Science Foundation (CHE-0449587). Unrestricted support from
Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb,
and Eli Lilly is gratefully acknowledged. We thank Donald Gauthier
of Merck & Co. for a generous gift of aminoindanol. We thank
Michael Rommel for his studies on the stereoselective epoxidation
and ring closure of 5. We thank Patrick J. Carroll for the X-ray
crystallographic structure. J.W.B is
a fellow of the Packard
Foundation, the Beckman Foundation, the Sloan Foundation, and a
Cottrell Scholar.
Supplementary data
23. Nyce, G. W.; Csihony, S.; Waymouth, R. M.; Hedrick, J. L. Chem.dEur. J. 2004, 10,
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29. Fu¨rstner, A.; Alcarazo, M.; Ce´sar, V.; Krause, H. Org. Synth. 2008, 85, 35–44.
30. Our optimized protocol was subsequently used on substrates 22, 28–30, and 34
and scale-up of 2.
31. The experimental details for this optimized route to N-mesityl substituted
imidazolium salt 2 were reported in Supplementary data of our work cited in
Ref. 15.
Copies of 1H NMR and 13C NMR spectra as well as crystallo-
graphic data can be found in the online version. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2008.03.072.
References and notes
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´
´
32. Crystallographic data (excluding structural factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 674712. Copies of the data can be ob-
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1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
33. These examples were prepared only once. The diminished yields of several of
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formed in the reaction.
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