Short synthesis of chiral 4-substituted (S)-imidazolinium salts bearing sulfonates and their use in γ-selective reactions of allylic halides with grignard reagents

Article abstract of DOI:10.1002/ejoc.201101336

A one-pot reaction of Boc-protected amino alcohols and 2-sulfobenzoic anhydride followed by the addition of a wide variety of primary amines has allowed rapid access to diverse libraries of amidosulfonates 1,2-C ₆H₄(SO₃

Full text of DOI:10.1002/ejoc.201101336

FULL PAPER
DOI: 10.1002/ejoc.201101336
Short Synthesis of Chiral 4-Substituted (S)-Imidazolinium Salts Bearing
Sulfonates and Their Use in γ-Selective Reactions of Allylic Halides with
Grignard Reagents
Christopher M. Latham,[a] Alexander J. Blake,[a] William Lewis,[a] Matthew Lawrence,[a]
and Simon Woodward*[a]
Keywords: Synthetic methods / Asymmetric catalysis / C–C coupling / Amino alcohols / Carbene ligands
A one-pot reaction of Boc-protected amino alcohols and 2-
sulfobenzoic anhydride followed by the addition of a wide
variety of primary amines has allowed rapid access to diverse
libraries of amidosulfonates 1,2-C6H4(SO3–)(COCHR1-
process, which involved reduction with BH3·SMe2 and cycli-
sation with HC(OEt)3. Two examples (R1 = Bn, R2 = 2,6-
iPrC6H3 and R1 = iPr, R2 = 3,5-Me2C6H3) have been crystallo-
graphically characterised, the latter as a PF6 salt. The imid-
CH2NH2+R2) (R1 = Bn, iPr, Ph; R2 = aryl, CHMePh, 1-ada- azolinium sulfonate zwitterions (1 mol-%) catalysed ad-
mantyl), of which two examples have been characterised by ditions of RMgBr (R = alkyl) to (E)-ArC(R)=CHCH2Br (R = H,
X-ray crystallography. These reactions proceed by SN2 open- Me). Additions to cinnamyl bromides showed high γ (SN2Ј)
ing of unisolated oxazoline intermediates. The amidosulf-
onates have been converted to imidazolinium sulfonate zwit-
terions (N-heterocyclic carbene precursors) in a two-step
selectivity (up to 18.4:1) and provided significantly enantio-
merically enriched products (up to 82% ee).
5b, seven are to prepare the precursor diamine from 2,4,6-
Me3C6H2NH2.[8] Very few publications deal with the for-
mation of imidazolium NHC precursors by SN2 substitu-
tion reactions using simple amines.[9] We conceived that
Introduction
N-Heterocyclic carbene ligands (NHCs) are of high util-
ity in contemporary catalytic chemistry.[1] These strongly re-
tained spectator ligands can provide metal catalysts of ex-
ceptional activity and selectivity for a wide range of trans-
formations, which include metathesis,[2] highly efficient pal-
ladium-catalysed C–C cross-coupling[3] and conjugate ad-
dition.[4] Free NHCs are themselves also active organocata-
lysts due to their powerful σ donor characteristics.[5] The
majority of such NHCs are accessed by deprotonation of
imidazolium-based precursor salts and in some cases both
these and their metal complexes are commercially available.
Chiral 4,5-substituted imidazoliniums 1 (Scheme 1) have
proved very useful ligand motifs in modern asymmetric ca-
talysis, especially those species that contain additional teth-
ering donor groups.[6] Thus, Buchwald–Hartwig coupling
has allowed the relatively efficient construction of 2–5a[7]
from commercial (R,R)-1,2-diphenylethylenediamine. How-
ever, in generalising such ligand families, quite significant
synthetic effort can be involved in the preparation of parent
chiral diamines that are not comercially available. For ex-
ample, of the eight steps required to access highly useful
[a] School of Chemistry, The University of Nottingham, University
Park,
Nottingham NG7 2RD, UK
Fax: +44-115-9513564
E-mail: simon.woodward@nottingham.ac.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101336 or from
the author.
Scheme 1. Recent examples of NHC ligand precursors related to
this work.
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S. Woodward et al.
FULL PAPER
homologues of 5b, i.e. 6, might be rapidly prepared from the SN2 reaction cleanly were 2,4,6-tri-tert-butylaniline
commercial chiral, enantiopure 1,2-amino alcohol deriva- (which underwent subsequent acid-promoted stepwise de-
tives by such a route to provide an attractive addition to tert-butylation to give mixtures, from which the only iso-
the ligand family shown in Scheme 1 and allow comparison lable compound was the 4-tert-butylaniline derivative 8ag)
of their efficacy in asymmetric catalysis.
and tritylamine, which was the only amine tried that gave
no reaction. Compounds 8 were often crystalline, but re-
quired primary isolation by chromatography (CH2Cl2/
MeOH, 19:1) to remove minor polar byproducts. Amides 8
eluted in a well defined manner and were often strongly
fluorescent; the slightly visible bands simplified their chro-
matographic isolation. Typically 8 were obtained as colour-
less foams or crystals, both of which commonly contained
occluded solvents. The connectivity in 8 was confirmed by
X-ray crystallography, which also revealed the zwitterionic
nature of these compounds. An extensive array of intra- and
intermolecular hydrogen bonding was observed in two of
the derivatives (Figures 1 and 2), which led to monomers or
dimers in the solid state.
Results and Discussion
Amido Sulfonic Acid Synthesis
We have previously demonstrated the multistep prepara-
tion of the amido sulfonic acids 8 from commercial Boc-
protected amino alcohols 7 by isolation of oxazolines 9 and
their subsequent reaction with two highly nucleophilic
amines R2NH2 (R2 = Bn, 2-C10H7CH2) (Scheme 2).[10] We
reasoned that 8 would be an efficient precursor to sulf-
onated chiral diamines for the synthesis of 6 if: (i) 9 did not
have to be isolated, (ii) the opening of 9 showed very high
generality for any primary amine and (iii) 8 could be re-
duced chemoselectively. Although it was anticipated that
less nucleophilic amines would participate in such acid-in-
duced oxazoline opening reactions, highly hindered anilines
(which are likely to be the most suited to subsequent cata-
lytic ligand applications) might be poor candidates for such
SN2 reactions. However, we were gratified to find that the
opening of 9 is very general indeed. Even rather hindered
anilines react smoothly with in situ-generated 9 to lead
cleanly to 8 in moderate to very good yields (40–89%) un-
der simple Dean–Stark conditions. A selection of these are
shown in Scheme 2. For the most hindered systems, pro-
longed heating was required (up to 7 d but with acceptable
yields) and amines with lower boiling points were avoided
to prevent them from azeotroping out of the reaction mix-
ture.
Figure 1. Molecular structure of 8ba·1/3EtOH. Selected intramolec-
ular hydrogen bonding interactions [Å]: N(1)···O(2) 3.1047(19),
N(2)···O(1) 2.8384(19).
Scheme 2. Synthesis of amido sulfonic acids. (i) 2-Sulfobenzoic an-
hydride, PhCl, 170 °C, 2–3 h. (ii), R2NH2, PhCl, 170 °C, 17 h–7 d.
Figure 2. Molecular structure of the hydrogen bonded dimer
(8bd·MeOH)2. Selected hydrogen bonding interactions [Å]: N(8C)···
O(4D) 2.756(5), N(11C)···O(1C) 2.832(5), N(11C)···O(2D)
2.823(5),N(11D)···O(2C)2.909(5),N(11D)···O(1D)2.838(5),O(2S)···
The chemistry in Scheme 2 was extended to other hin-
dered, nonaromatic amines including 1-adamantylamine
(8ad, 8bd). The only amines studied that did not undergo O(3C) 2.796(5), O(4S)···O(3D) 2.726(8).
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Synthesis of Sulfonated Chiral Carbene Precursors
The new one-pot approach allowed rapid access to a di- ple of 10 to confirm this. As we do not know which of the
verse range of compounds and H bonding motifs as 8 was amines is protonated in the solid state, the parent structure
effectively prepared in a single step from commercially 10 is given in Scheme 3 for simplicity. These compounds
available reagents. This is a very powerful procedure for were isolated as oils, from which occluded solvent was re-
generating compound libraries. Recently, members of this moved under prolonged exposure to high vacuum. In solu-
library have been found to have activity against UDP-Galp tion, rapid exchange of the NH and SO3H protons with the
mutase.[11] This is a promising target enzyme in the myco- solvent was apparent in their 1H NMR spectra in [D4]-
bacterium that causes tuberculosis. Due to the evolution of MeOH.
resistant bacteria in this class there is a pressing need to
attain new therapeutic agents in this field, and the simple
synthesis of a diverse range of 8 provided by the one-pot
procedure described here will prove vital in further screen-
ing.
Preparation of Diamino Sulfonic Acids
Reduction of 8 to the diamino sulfonic acids 10 was
achieved by BH3·SMe2 (Scheme 3).
Imidazolinium Sulfonate Synthesis
Cyclisation of 10 to the imidazolinium sulfonates 6 pro-
ceeded cleanly under mild heating with HC(OEt)3, and 6
were isolated as zwitterions by polar chromatography in
good yields (Scheme 4). Generally, these sulfonates also oc-
cluded solvents, which were removed under high vacuum.
Scheme 3. Reduction of 8 to 10. (i) BH3·SMe2, tetrahydrofuran,
60–90 °C, 3 d. (ii) MeOH, 90 °C, 2 h. Equivalent zwitterionic struc-
tures where either of the amines in 10 is protonated are equally
valid.
Borane is the preferred reducing agent for the prepara-
tion of 10 as other reducing agents, such as LiAlH4, re-
quired an aqueous work up, which led to the loss of the
Scheme 4. Synthesis of 6. (i) (EtO)3CH, EtOH, 100 °C, 17 h. Com-
pounds 6bc (39%) and 6ca (55%) were synthesised without purifi-
cation of their precursor 10, see text.
highly water soluble 10. We speculate that borane reduction
of 8 leads to the intermediate 11, which is expected to be
broken down under methanolysis. Subsequent distillation
of the B(OMe)3 coproduct and excess methanol could be
It was anticipated that reduction and cyclisation could
achieved under vacuum, and the resultant solid 10 was puri- be carried out without the need to purify 10 by chromatog-
fied by chromatography (CH2Cl2/MeOH, 19:1). This pro- raphy. However, trace levels of borane produced byprod-
cedure is complicated by the near coelution of 8 and 10 ucts, which limited the utility of this approach. For exam-
under high polarity eluent conditions. Complete conversion ple, 6bc (R1 = iPr, R2 = 3,5-Me2C6H3) was only isolated in
had to be ensured in order to simplify the isolation of 10. a low yield (39%, over two steps) from the reaction mixture
This can be achieved with excess borane and a long reaction as its crystalline hexafluorophosphate salt. The situation
time; 72 hours was found to be sufficient for the completion was improved for more hindered systems; 6ca (R1 = Ph, R2
of all reactions. The best substrates for the reduction were = mesityl) was attained in 55% yield from 8ca after
those that have more hindered units in the R2 group, e.g. chromatography without isolation of 10bc. The major prob-
10ab and 10bb. Less hindered aryls and benzylic substitu- lem in these direct preparations of 6 from 8 was the forma-
ents led to more significant byproduct formation. It is pre- tion of imidazolinidines by reduction by residual borane.
sumed that 10 exist in equilibria with zwitterionic states Overall, intermediate isolation of 10 was the preferred ap-
where protonation of either of the amines is equally proach. Crystallisation of 6, in most cases, did not provide
favoured. However, we were unable to crystallise an exam- anything other than powdery solids. However, the most hin-
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701

S. Woodward et al.
FULL PAPER
dered salt (6ab) crystallised as fine needles from EtOAc that with R1. There are, however, no clear factors that affect the
contained traces of EtOH and water (Figure 3) and con- positioning of the benzylic sulfonate ligand. The N–CH2
firmed that the desired motif had been obtained.
torsion angle in 6ab is marginally larger than that in H-6bc,
but this is largely compensated by a reversed trend in the
contiguous CH2–Cipso torsion angle. Thus, the positioning
of this substituent, based on the X-ray data available, de-
pends on the subtle interplay of both the R1 and R2 substit-
uents. Hoveyda’s more selective ligand, 5b,[8] has a closer
SO2O···Cim contact (2.82 Å) than that seen in 6.
Asymmetric Catalysis
In view of the recent interest in using ligand 4 in “cop-
per-free” NHC-catalysed additions of Grignard reagents to
allylic halides,[12] we screened the ligand precursor 6ab as
a catalyst in the SN2Ј addition of commercial solutions of
EtMgBr to various (E)-cinnamyl electrophiles (Table 1).
–
The presence of the –CH2C6H4SO3 donor was expected to
lead to systems that showed significant enantioselectivity.
Initial trials revealed Et2O to be the best solvent and –15 °C
to be an optimal temperature. To allow initial identification
of the best leaving groups, reactions of (E)-
PhCH=CHCH2X (12) and EtMgBr were run under iden-
tical conditions (Table 1). Although cinnamyl bromide was
clearly the best substrate, we initially found a slight varia-
tion of the ee values for the γ-product 13 based on both the
age and quantity of the EtMgBr source used.[13] This effect
was mirrored in the 13:14 regioselectivity (older bottles of
EtMgBr, which contained more than trace amounts of
EtOMgBr, as determined by Gilman titration, gave signifi-
cantly inferior γ selectivities). Two solutions were found to
overcome the detrimental effects of ROMgBr contami-
nation: the use of 3 equiv. of freshly prepared Grignard rea-
gents (see Entry 2) or alternatively to conduct the reaction
in the presence of an excess of flame-dried MgSO4
(0.5 equiv.). The latter is believed to coordinate the alkoxide
and sequester it from the homogeneous reaction to the
MgSO4 slurry. Of the two techniques, the former was the
most useful in the majority of cases.
Figure 3. Molecular structure of 6ab·H2O. Selected torsion angles
[°] and nonbonded distances [Å]: C(10)–N(2)–C(18)–C(19) 91.8,
C(10)–N(1)–C(7)–C(6) 136.9, N(1)–C(7)–C(6)–C(1) 60.9; C(10)···
O(1) 2.92.
We could not obtain crystals suitable for XRD of a less
hindered example of 6 but we crystallised the related hexa-
fluorophosphate adduct [H-6bc]PF6 (Figure 4) by slow
evaporation of a methanolic solution of 6bc and NH4PF6.
This salt adduct was formed by direct addition of NH4PF6
to the reaction mixture during the cyclisation reaction. In
view of the very distinct difference in the asymmetric cata-
lytic behaviour of 6ab and 6bc (see Table 2 later) it is in-
structive to compare their crystal structures. The most sig-
nificant difference is in the placement of R2 in 6ab (2,6-
iPr2C6H3), which is essentially perpendicular to the plane
of the imidazolinium, whereas it is almost coplanar in [H-
6bc]PF6 (3,5-Me2C6H3). In both compounds the –CH2C6-
–
H4SO3 group is deflected to the bottom face of the imid-
Table 1. Leaving group optimisation. (i) EtMgBr (1.1 equiv.), di-
ethyl ether, 6ab (1 mol-%), –15 °C, 17 h.
azolimium core in order to minimise 1,2-steric interactions
Entry
X
Conversion [%] γ/α
ee [%]
1
2
3
4
Cl
Br
74
74
46
36
9.4:1
6–18.4:1
4.0:1
44
70–76
54
OP(O)Ph2
OP(O)(OEt)2
6.9:1
63
Using the optimal conditions, the ligand library 6 was
tested for the addition of EtMgBr to (E)-cinnamyl bromide.
This showed that 6ab (R1 = Bn, R2 = 2,6-diisoprop-
ylphenyl) was the optimal promoter (Table 2). Further at-
Figure 4. Molecular structure of [H-6bc]PF6. Selected torsion
angles [°] and nonbonded distances [Å]: C(8)–N(2)–C(14)–C(15)
154.3, C(8)–N(1)–C(7)–C(2) 133.0, N(1)–C(7)–C(2)–C(1) 58.6;
C(8)···O(1) 3.07.
702
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Synthesis of Sulfonated Chiral Carbene Precursors
tempted optimisation by either increasing the loading of Table 3. Scope and limitation of Grignard additions to allyl brom-
ides. (i) R5MgBr (3.0 equiv.), diethyl ether, 6ba (1 mol-%), –15 °C,
17 h.
6ab to 3 mol-% or lowering the reaction temperature gave
no benefit.
Table 2. Screening of 6aa–ca. (i) EtMgBr (1.1 equiv.), diethyl ether,
6 (1 mol-%), –15 °C, 17 h.
Conversion
6
R1
R2
[%]
ee [%] γ/α
aa
ab
ae
af
ba
bb
bc
bd
ca
Bn
Bn
Bn
Bn
iPr
iPr
iPr
iPr
Ph
2,4,6-Me3C6H2
2,6-iPr2C6H3
CHPh2
(S)-CHMePh
2,4,6-Me3C6H2
2,6-iPr2C6H3
3,5-Me2C6H3
1-adamantyl
2,4,6-Me3C6H2
100
100
82
71
76
65
33
70
58
9
5.6:1
18.4:1
1.7:1
1:2.7
2.8:1
11.6:1
1:2
Conversion
[%]
Entry R3
R4
R5MgBr
γ/α
ee [%]
41
100
100
97
44
100
1
2
H
H
Me Me
Me Et
81
33
99
99
99
98
99
99
98
99
99
99
99
93
1.0:6.8
1.1:1
1.5:1
18.4:1
5.8:1
3.2:1
8.3:1
1.0:1.5
3.3:1
4.1:1
2.3:1
–
58
73
76
71
66
78
57
71
82
73
38
74
32
3
4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
nPr
iPr
nBu
iBu
Me
Et
nPr
iPr
28
36
1:6.9
1:1.6
5
6
H
H
In view of the crystal structures of 6ab and [H-6bc]PF6
7
8
H
H
we speculate that a perpendicularly-placed large aryl frag-
ment in the R2 sector plays a pivotal role to determine both
the regio- and enantioselectivity (compare 6ab and 6bc,
Table 2). Further increasing the size of R2 reverses the regi-
ochemistry (compare 6ab and 6bd, Table 2) and depresses
the enantioselectivity, which suggests that the phenyl group
of 12b (X = Br; R3, R4 = H) is close to this quadrant in the
selective transition state. However, appropriate placement
9
CF3
CF3
CF3
CF3
CF3
CF3
10
11
12
13
14
1.0:1.0
2.8:1
1.1:1.0
nBu
iBu
posal is supported by the fact that the presence of an elec-
tron-withdrawing CF3 substituent in 12 typically has a
somewhat positive effect on the enantioselectivity of the
product. The behaviour of the methylcinnamyl bromide
here is at odds with its normal behaviour observed by
Alexakis[12] where the same substrate using 4 provided the
highest level of γ selectivity.
–
of the CH2C6H4SO3 group for magnesium coordination is
also critical, as branching in R1 severely reduces the
enantioselectivity (6aa, 6ba and 6ca, Table 2).
Optical rotation studies confirmed that 6ab engenders
the formation of (R)-13. Using the optimal ligand and con-
ditions, a range of different Grignard reagents and sub-
strates were tested (Table 3). These additions are also as-
signed to Re selectivity based on polarimetry results of the
reaction mixtures. Racemic comparison mixtures that con-
tained α-14 and (Ϯ)-γ-13 were prepared by equivalent reac-
tions of R5MgBr and 12 catalysed by achiral SIMes. These
reactions provide high γ selectivities (of racemic materials).
Interestingly, the mesityl groups of SIMes were also de-
ployed perpendicular to the plane of the heterocycle (C–
Nave torsion angle 66.6°) in a similar manner to 6ab.[14]
Conclusions
We have demonstrated a step-efficient method for the
preparation of a new class of NHC-ligand precursors,
which provides highly active catalysts (turnover number
about 100) for γ selective additions to cinnamyl electro-
philes (up to 18.4:1) without the use of transition metals.
Such systems are of interest both because of the different
method of activation they demonstrate (by Mg–NHC com-
plexes rather than traditional transmetallation to transition
metal complexes) and also because of their relevance to sus-
tainable chemistry through the use of widely available
“light” elements.
A number of conclusions can be drawn from Table 3.
Firstly, the cavity presented by the NHC ligand derived
from 6ab is not able to easily accommodate methylcinnamyl
derivatives (R4 = Me, compare Entries 1 and 2 with the rest
of Table 3). Two possibilites are consistent with this obser-
vation: either the transition state is simply too cluttered to
accept this substrate easily, or the enantioselectivity arises
from a face–edge π stacking interaction between the ligand
R2 group and the aryl unit in 12, which is perterbed by
the presence of the γ-methyl group. The first possibility is
supported by the fact that branching in the Grignard rea-
Experimental Section
General: The general experimental set up has been described pre-
viously.[10] Full descriptions of the preparative and catalytic pro-
cedures are given in the Supporting Information.
Formation of Amino Amido Sulfonic Acids (8): To a solution of 2-
sulfobenzoic acid anhydride (1.1–1.3 equiv.) in chlorobenzene
(50 mL per ca. 5 mmol) was added Boc-protected amino alcohol
(1.0 equiv.) and the flask fitted with a Dean–Stark apparatus. The
gent is not well tolerated (Entries 10–14), and the latter pro- reaction mixture was heated to reflux (2–3 h, bath temperature
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703

S. Woodward et al.
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170 °C), allowed to cool (20–50 °C) and the required amine or anil-
ine added (1.3–1.5 equiv.). The reaction mixture was heated to re-
flux for 17 h–7 d (bath temperature 170 °C). The mixture was al-
lowed to cool and the solvent removed under vacuum. The result-
ant solid was typically purified by column chromatography using
2–5% methanol in dichloromethane as the eluent (8aa, 8ab, 8ag,
8ba and 8bb are slightly visible on SiO2 due to natural fluorescence,
which aided their separation. The Rf values in 5% methanol in
dichloromethane are typically ≈ 0.35–0.45). The compounds readily
occlude solvents, which were removed by prolonged drying under
vacuum. The formation of 8ba and 8bd are representative.
Formation of Diamino Sulfonic Acids (10): In dried glassware under
an argon atmosphere 8 (1 equiv.) was dissolved in dry tetra-
hydrofuran (10 mL per gram of 8) and excess borane dimethylsul-
fide complex (6 mL per gram of 8) was added. The reaction mixture
was then heated to reflux (bath temperature ≈ 70 °C, ≈ 90 °C for
adamantyl derivatives) for 3 d under an inert atmosphere, allowed
to cool to ambient temperature and quenched with methanol at
0 °C. The solvent was removed under vacuum, and the resultant
gummy solid redissolved in methanol (5 mL per expected mmol of
product 10) and heated to reflux for 2 h to hydrolyse the borates.
The solvent was removed under vacuum to give oils or glassy
foams. Purification was achieved by flash chromatography; typi-
cally a column of 6–9 cm high by 3.5 cm in diameter was needed
to separate about 1.0 g of crude 10. An eluent of 2–5% methanol
in dichloromethane was used to obtain the products. The location
of the diamino sulfonic acid was ascertained by TLC using 5%
methanol in dichloromethane. Staining, first with ninhydrin (red/
brown-green spots) then bleaching with potassium permanganate
visualised the products. The Rf values in 5% methanol in dichloro-
methane are typically ≈ 0.3–0.45. Once the product 10 was isolated
the column was flushed with methanol 40% in dichloromethane to
ensure complete recovery. For the synthesis of 6, chromatographic
purification of 10 is preferred but not essential. Noncrystalline 10
typically occluded small amounts of dichloromethane (which did
not affect their subsequent reactivity). Data for 10bc are represen-
tative.
(S)-2-[{1-(Mesitylamino)-3-methylbutan-2-yl}carbamoyl]benzene-
sulfonic Acid (8ba): Boc-(L)-valinol (1.92 g, 9.50 mmol), 2-sulfo-
benzonic acid anhydride (1.81 g, 9.83 mmol), and 2,4,6-trimeth-
ylaniline (1.47 g, 10.92 mmol) were heated to reflux for 2 d and
provided 8ba as a white powder (2.54 g, 66%), which crystallised
as glistening colourless needles from EtOH/hexane; m.p. 196–
198 °C. [α]D = –43.6 (c = 1.08, EtOH). 1H NMR (400 MHz,
CDCl3): δ = 1.00 (d, J = 6.8 Hz, 3 H, CHMeα), 1.01 (d, J = 6.8 Hz,
3 H, CHMeβ), 2.02 (oct, J = 6.8 Hz, 1 H, CHCMe2), 2.29 (s, 3 H,
ArMe), 2.52 (s, 6 H, 2ϫ ArMe), 3.29 (dd, J = 12.5, 3.6 Hz, 1 H,
CHCH2α), 4.12 (app t, J = 12.5 Hz, 1 H, CHCH2β), 4.37–4.47 (m,
1 H, CHNHCO), 6.93 (s, 2 H, Ar), 7.46–7.52 (m, 2 H, Ar), 7.63–
7.68 (m, 1 H, Ar), 8.05–8.11 (m, 1 H Ar), 8.81 (d, J = 8.8 Hz, 1
H, NHamine), 9.10 (br., 1 H, NHamide), 10.80 (br., 1 H, SO3H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 17.8 (2ϫ ArCH3), 18.9
(CHCH3α), 19.3 (CHCH3β), 20.8 (ArCH3), 30.2 [CH(CH3)2], 53.8
(NCH), 55.5 (NCH2), 127.7 (Ar-CH), 129.0 (Ar-CH), 130.3 (Ar-
CH), 130.4 (Ar-CH), 130.8 (ipso-C, Ar), 130.9 (2ϫ Ar-CH, ArMe),
131.3 (2ϫ ipso-C, Ar), 133.0 (ipso-C, Ar), 139.8 (ipso-C, Ar), 142.0
(S)-2-[{(1-{(3,5-Dimethylphenyl)amino}-3-methylbutan-2-yl)amino}-
methyl]benzenesulfonic Acid (10bc): Using 8bc (0.45 g, 1.15 mmol)
provided 10bc as a white powder (0.36 g, 83%); m.p. 180–182 °C.
1
[α]D = +57.1 (c = 0.40, CHCl3). H NMR (400 MHz, CDCl3): δ =
(ipso-C, Ar), 171.4 (C=O) ppm. IR (CHCl ): ν = 3775, 3683, 3620,
˜
3
0.97 (d, J = 6.8 Hz, 3 H, CHMeα), 1.11 (d, J = 7.2 Hz, 3 H,
CHMeβ), 1.62 (br., s, 1 H, NH), 2.00–2.11 (m, 1 H, CHMe2), 2.30
(s, 6 H, 2ϫ ArMe), 3.23–3.33 (m, 1 H, NCHCH2α), 3.53–3.71 (m,
1 H, NCHCH2β) overlapped by (m, 1 H, NCHCH2), 4.30 (d, J =
13.0 Hz, 1 H, ArCH2α), 4.39 (d, J = 13.0 Hz, 1 H, ArCH2β), 5.17
(br., s, 1 H, NH), 6.34 (s, 2 H, Ar), 6.47 (s, 1 H, Ar), 6.91 (app d,
J = 7.6 Hz, 1 H, Ar), 7.33 (td, J = 7.6, 1.2 Hz, 1 H, Ar), 7.40 (td,
J = 7.6, 1.2 Hz, 1 H, Ar), 8.04 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 8.62
(br., s, 1 H, SO3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.6
(CHCH3α), 18.3 (CHCH3β), 21.6 (2ϫ ArCH3), 28.6 (CHMe2), 42.9
(NCH2CHN), 50.6 (ArCH2), 61.4 (NCHCH2), 110.7 (2ϫ Ar-CH),
120.3 (Ar-CH), 127.0 (2ϫ ipso-C, Ar), 128.5 (Ar-CH), 130.2 (Ar-
CH), 130.9 (Ar-CH), 133.1 (Ar-CH), 139.3 (ipso-C, Ar), 144.4
3456, 3009, 2976, 2895, 2412, 2248, 1885, 1642, 1602, 1522, 1476,
1423, 1334, 1239, 1046, 928, 877, 849, 660, 626 cm–1. HRMS (ESI):
calcd. for C21H27N2O4S [M – H]+ 403.1697; found 403.1699. Crys-
tallises from EtOH as 8ba·1/3EtOH; C21.7H30N2O4.3S (419.75):
calcd. C 61.97, H 7.20, N 6.67; found C 61.96, H 7.33, N 6.71.
(S)-2-[{1-(Adamantan-1-ylamino)-3-methylbutan-2-yl}carbamoyl]-
benzenesulfonic Acid (8bd): Boc-(L)-valinol (1.49 g, 7.33 mmol), 2-
sulfobenzonic acid anhydride (1.36 g, 7.38 mmol), and adamantyl-
amine (1.30 g, 8.61 mmol) were heated to reflux for 6 d and pro-
vided 8bd as a white powder (1.24 g, 40%), which crystallised as
small colourless needles from methanol; m.p. Ͼ 300 °C. [α]D
=
1
–51.3 (c = 1.06, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.90–
0.97 (m, 6 H, CHMe2 ), 1.54 (dA B, JA B = 12.6 Hz, 3 H,
CHCH2αCH), 1.62 (dAB, JAB = 12.6 Hz, 3 H, CHCH2βCH), 1.94
(app s, 6 H, CH2), overlapped by 1.84–1.96 (m, 1 H, CHMe2), 2.09
(s, 3 H, CH2CHCH2), 3.08–3.20 (br., m, 2 H, NCH2), 4.35–4.55
(br., m, 1 H, NCH), 7.45–7.52 (m, 2 H, Ar), 7.60–7.65 (m, 1 H,
Ar), 7.91 (br., s, 1 H, NHamine), 8.13–8.15 (m, 1 H, Ar) overlapped
by 8.17 (br., d, J = 9.2 Hz, 1 H, NHamide), 8.54 (br., s, 1 H, SO3
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 18.0 [CH(Me)CH3],
(ipso-C, Ar), 146.7 (ipso-C, Ar) ppm. IR (CHCl ): ν = 3691, 3606,
˜
3
3385, 3011, 2972, 2922, 2860, 1602, 1522, 1476, 1446, 1399, 1379,
1338, 1304, 1252, 1193, 1161, 1085, 1045, 1014, 964, 905, 826, 621,
606 cm–1. HRMS (ESI): Calcd. for C20H27N2O3S [M – H]+
375.1748; found 375.1753. 10bc·0.1CH2Cl2: calcd. C 62.71, H 7.38,
N 7.28; found C 62.45, H 7.52, N 7.06.
Formation of Imidazolinium Sulfonate Zwitterions (6): Distilled tri-
19.3 [CH(Me)CH3], 29.0 (CH2CHCH2), 31.2 (CHMe2), 35.4 ethyl orthoformate (3 mL per 1 mmol of 10) was added to a solu-
(CHCH2CH), 38.0 (CHCH2CH), 41.2 (NCH2CH), 52.4 (NCH), tion of 10 (1 equiv.) in ethanol (3 mL per 1 mmol of 10). The reac-
58.6 [adamantyl-C, (CH)3CNH], 127.8 (Ar-CH), 129.6 (Ar-CH), tion mixture was heated to reflux (17 h, bath temperature 80 °C).
130.3 (Ar-CH), 130.4 (Ar-CH), 133.5 [ipso-C, ArC(=O)N], 141.9
The ethanol was removed under vacuum, and residual orthofor-
(ipso-C, ArSO ), 169.8 (C=O) ppm. IR (CHCl ): ν = 3692, 3606, mate was decanted to give oily residues, which gave a foam-like
˜
3
3
3271, 3011, 2969, 2922, 2859, 2683, 2602, 2454, 2337, 1947, 1843,
1642, 1596, 1564, 1483, 1466, 1454, 1392, 1363, 1326, 1310, 1294,
1251, 1164, 1141, 1080, 1041, 1016, 980, 962, 939, 901, 872, 853,
660, 616 cm–1. HRMS (ESI): calcd. for C22H31N2O4S [M – H]+
419.2010; found 419.2000. Crystallises from MeOH as 8bd·MeOH;
C23H36N2O5S (452.61): calcd. C 61.03, H 8.02, N 6.19; found C
60.75, H 7.76, N 6.44.
solids under high vaccuum. Purification of 6 was achieved by col-
umn chromatography using 2–5% methanol in dichloromethane as
the eluent (the Rf values in 5% methanol in dichloromethane are
typically about 0.4–0.5) to provide colourless foams. Crystallisation
was achieved in many cases by the slow evaporation of methanol, a
mixture of chloroform or dichloromethane and ethyl acetate, which
typically provided hydrated materials.
704
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 699–707

Synthesis of Sulfonated Chiral Carbene Precursors
(S)-2-[(4-Benzyl-1-mesityl-4,5-dihydro-1H-imidazol-3-ium-3-yl)-
methyl]benzenesulfonate (6aa): Using 10aa (0.62 g, 1.42 mmol) pro-
vided 6aa as a white powder (0.49 g, 77%); m.p. 279–280 °C. [α]D
= +107.5 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.02
(br., s, 3 H, ArMeα), 2.21 (br., s, 3 H, ArMeβ), 2.276 (s, 3 H, ArMe,
para), 3.03 (dd, J = 14.0, 8.4 Hz, 1 H, PhCH2α), 3.32 (dd, J = 14.0,
4.4 Hz, 1 H, PhCH2β), 3.59 (dd, J = 11.6, 7.7 Hz, 1 H, NCHCH2α),
4.14 (t, J = 11.6 Hz, 1 H, NCHCH2β), 4.59 (dtd, J = 8.4, 7.7,
J = 14.0 Hz, ArCH2αN), 5.66 [s, 1 H, NCH(Ph)2], 5.71 (d, J =
14.0 Hz, ArCH2βN), 6.98–7.06 (m, 2 H, Ar), 7.09–7.18 (m, 3 H,
Ar), 7.28–7.39 (m, 12 H, Ar), 7.43–7.48 (m, 1 H, Ar), 7.92 (s, 1
H, NCHN), 8.31 (dd, J = 8.0, 1.2 Hz, 1 H, Ar) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 37.3 (PhCH2), 50.3 (ArCH2), 53.0
(NCH2CHN), 59.7 (NCHCH2), 67.0 [NCH(Ph2)], 127.7 (Ar-CH),
127.9 (ipso-C, Ar), 128.3 (2ϫ Ar-CH), 128.5 (2ϫ Ar-CH), 129.0
(Ar-CH), 129.0 (Ar-CH), 129.2 (2ϫ Ar-CH), 129.3 (4ϫ Ar-CH),
4.4 Hz, 1 H, NCHCH2), 4.82 (d, J = 14.2 Hz, 1 H, ArCH2αN), 129.4 (2ϫ Ar-CH), 129.6 (Ar-CH), 129.7 (Ar-CH), 129.9 (Ar-CH),
4.84 (d, J = 14.2 Hz, 1 H, ArCH2βN), 6.84 (s, 2 H, Ar), 7.11–7.13
(m, 2 H, Ar), 7.24–7.39 (m, 5 H, Ar), 7.46 (td, J = 7.6, 1.2 Hz, 1
H, Ar), 8.27 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 8.33 (s, 1 H, NCHN)
131.3 (Ar-CH), 134.2 (ipso-C, Ar), 135.4 (ipso-C, Ar), 135.6 (ipso-
C, Ar), 146.2 (ipso-C, Ar), 159.1 (NCHN) ppm. IR (CHCl ): ν =
˜
3
3693, 3672, 3606, 3442, 3109, 3090, 3066, 3011, 2935, 2887, 2857,
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 17.7 (br., 2ϫ ArCH3, 2467, 2254, 1955, 1900, 1814, 1702, 1641, 1604, 1586, 1497, 1474,
ortho) 21.0 (ArCH3, para), 37.5 (PhCH2), 49.9 (ArCH2), 54.8
1454, 1372, 1349, 1331, 1302, 1274, 1192, 1143, 1087, 1021, 1004,
(NCHCH2), 60.2 (NCHCH2), 127.8 (Ar-CH), 128.2 (ipso-C, Ar), 945, 909, 882, 867, 831, 660, 619 cm–1. HRMS (ESI): calcd. for
129.2–129.6 (br., 2ϫ Ar-CH) overlapped by [129.3 (2ϫ Ar-CH),
129.3 (Ar-CH), 129.5 (2ϫ Ar-CH)], 129.7 (Ar-CH), 129.8 (Ar-
C30H27N2O3S [M – H]+ 495.1748; found 495.1770. Recrystalli-
sation by slow evaporation of CHCl3/EtOAc solutions gave micro-
CH), 130.5 (ipso-C, Ar), 131.5 (Ar-CH), 134.1 (ipso-C, Ar), 140.0 crystals of a hydrate 6ae·1½H2O; C29H35N2O3.5S (499.67): calcd.
(ipso-C, Ar), 146.5 (ipso-C, Ar), 148.0–156.0 (v. br, 2 ϫ ipso-C,
C 69.71, H 7.38, N 5.61; found C 69.56, H 7.16, N 5.59.
ArMe), 159.4 (NCHN) ppm. IR (CHCl ): ν = 3691, 3606, 3440,
˜
3
2-[({S}-4-Benzyl-1-{(S)-1-phenylethyl}-4,5-dihydro-1H-imidazol-3-
ium-3-yl)methyl]benzenesulfonate (6af): Using 10af (0.15 g,
0.35 mmol) provided 6af as a white powder (0.11 g, 72%); m.p.
250 °C (dec). [α]D = +50.7 (c = 0.30, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.72 (d, J = 6.8 Hz, 3 H, CHMe), 2.77 (dd, J = 13.6,
8.8 Hz, 1 H, PhCH2α), 3.14–3.21 (m, 1 H, PhCH2β) overlapped by
(m, 1 H, NCH2αCH), 3.64 (t, J = 11.6 Hz, 1 H, NCH2βCH), 4.20
(dtd, J = 11.6, 8.8, 4.4 Hz, 1 H, NCHCH2), 4.52 (d, J = 14.4 Hz,
1 H, ArCH2αN), 4.79 [q, J = 6.8 Hz, 1 H, ArCH(Me)N], 5.97 (d,
J = 14.4 Hz, 1 H, ArCH2βN), 6.93–6.98 (m, 2 H, Ar), 7.12 (dd, J
= 7.6, 0.8 Hz, 1 H, Ar), 7.24–7.39 (m, 9 H, Ar), 7.48 (td, J = 6.4,
1.6 Hz, 1 H, Ar), 8.32 (dd, J = 8.0, 1.2 Hz, 1 H, Ar), 8.88 (s, 1 H,
NCHN) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 19.4 (CHCH3),
37.7 (PhCH2), 49.7 (ArCH2), 51.1 (NCH2CH), 58.2 [PhCH(CH3)-
3064, 3010, 2928, 2465, 1637, 1604, 1496, 1480, 1455, 1372, 1300,
1267, 1192, 1142, 1088, 1021, 958, 855, 660, 619 cm–1. HRMS
(ESI): calcd. for C26H27N2O3S [M – H]+ 447.1748; found 447.1747.
Recrystallisation by slow evaporation of CHCl3/EtOAc solutions
gave a microcrystalline 10aa·¾H2O; C26H29.5N2O3.75S (462.09):
calcd. C 67.58, H 6.43, N 6.06; found C 67.47, H 6.36, N 6.05.
(S)-2-[{4-Benzyl-1-(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol-
3-ium-3-yl}methyl]benzenesulfonate (6ab): Using 10ab (0.19 g,
0.40 mmol) provided 6ab as a white powder (0.14 g, 72%); m.p.
200–205 °C. [α]D = +45.0 (c = 0.50, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 1.15–1.21 (m, 12 H, 4ϫ CHMe), 2.44 (quint, J =
6.8 Hz, 1 H, ArCHαMe), 3.06 (dd, J = 14.0, 8.2 Hz, 1 H, PhCH2α),
3.34 (dd, J = 14.0, 4.4 Hz, 1 H, PhCH2β), 3.43 (quint, J = 6.8 Hz,
1 H, ArCHβMe), 3.69 (dd, J = 11.4, 7.6 Hz, 1 H, NCH2α), 4.18 (t, N], 29.3 (NCHCH2), 127.0 (2 ϫ Ar-CH), 127.6 (Ar-CH), 128.6
J = 11.4 Hz, 1 H, NCH2β), 4.73 (dtd, J = 12.0, 7.6, 8.2, 4.4 Hz, 1 (ipso-C, Ar), 128.7 (Ar-CH), 129.1 (2ϫ Ar-CH), 129.2 (2ϫ Ar-
H, NCHCH2), 4.84 (d, J = 14.0 Hz, 1 H, ArCH2αN), 5.92 (d, J =
CH), 129.2 (2ϫ Ar-CH), 129.6 (Ar-CH), 129.7 (2ϫ Ar-CH), 131.4
14.0 Hz, 1 H, ArCH2βN), 7.07–7.13 (m, 2 H, Ar), 7.17 (dd, J = (Ar-CH), 134.4 (ipso-C, Ar), 137.6 (ipso-C, Ar), 146.3 (ipso-C, Ar),
8.0, 1.6 Hz, 1 H, Ar), 7.22 (dd, J = 8.0, 1.2 Hz, 1 H, Ar), 7.26–7.32
(m, 1 H, Ar), 7.33–7.45 (m, 5 H, Ar), 7.53 (td, J = 8.0, 1.6 Hz, 1
H, Ar), 8.12 (s, 1 H, NCHN), 8.34 (dd, J = 8.0, 1.2 Hz, 1 H, Ar)
158.3 (NCHN) ppm. IR (CHCl ): ν = 3691, 3606, 3450, 3089, 3066,
˜
3
3011, 2932, 2858, 2466, 2338, 1953, 1886, 1811, 1642, 1603, 1511,
1497, 1456, 1444, 1386, 1375, 1355, 1304, 1285, 1268, 1192, 1143,
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 24.2 (CHCH3αα), 24.3 1117, 1087, 1047, 1021, 959, 909, 831, 660, 619 cm–1. HRMS (ESI):
(CHCH3αβ), 24.9 (CHCH3βα), 25.0 (CHCH3ββ), 27.8 (CHMe2α), calcd. for C25H25N2O3S [M – H]+ 433.1591; found 433.1600.
28.5 (CHMe2β), 37.6 (PhCH2), 50.3 (ArCH2), 57.2 (NCH2CH),
Recrystallisation by slow evaporation of CHCl3/EtOAc solutions
60.5 (NCH), 124.3 (Ar-CH), 125.4 (Ar-CH), 127.6 (ipso-C, Ar), gave microcrystals of a monohydrate 6af·H2O; C25H28N2O4S
128.0 (Ar-CH), 129.4 (2ϫ Ar-CH), 129.4 (2ϫ Ar-CH), 129.6 (Ar- (452.57): calcd. C 66.35, H 6.24, N 6.19; found C 66.22, H 6.07, N
CH), 129.7 (Ar-CH), 129.8 (ipso-C, Ar), 130.2 (Ar-CH), 131.0 (Ar-
CH), 131.2 (Ar-CH), 133.8 (ipso-C, Ar), 145.9 (ipso-C, Ar), 146.7
(ipso-C, Ar), 148.4 (ipso-C, Ar), 159.0 (NCHN) ppm. IR (CHCl3):
6.14.
(S)-2-[(4-Isopropyl-1-mesityl-4,5-dihydro-1H-imidazol-3-ium-3-yl)-
methyl]benzenesulfonate (6ba): Using 10ba (0.23 g, 0.58 mmol) pro-
vided 6ba (0.21 g, 90%) as a olourless light foam-like solid; m.p.
243–245 °C. [α]D = +28.3 (c = 1.04 in methanol). 1H NMR
(400 MHz, CDCl3): δ = 0.89 (d, J = 7.0 Hz, 3 H, CHMeα), 1.11
(d, J = 7.0 Hz, 3 H, CHMeβ), 2.24 (s, 6 H, 2ϫ ArMe, ortho), 2.28
(s, 3 H, ArMe, para) 2.45–2.49 (m, 1 H, CHMe2), 3.68 (dd, J =
12.5, 3.4 Hz, 1 H, NCH2αCH), 4.13 (dd, J = 12.5, 11.8 Hz, 1 H,
NCH2βCH), 4.35 (ddd, J = 12.5, 11.8, 3.4 Hz, 1 H, NCH), 4.59 (d,
J = 14.0 Hz, 1 H, ArCH2β), 5.79 (d, J = 14.0 Hz, 1 H, ArCH2α),
6.91 (br., s, 2 H, Ar), 7.25 (dd, J = 7.4, 1.4 Hz, 1 H, Ar), 7.32 (td,
J = 7.4, 1.4 Hz, 1 H, Ar), 7.39 (td, J = 7.4, 1.4 Hz, 1 H, Ar), 8.19
(dd, J = 7.4, 1.4 Hz, 1 H, Ar), 8.32 (s, 1 H, NCHN) ppm. 13C
ν = 3668, 3065, 3010, 2971, 2929, 2889, 2871, 2468, 1949, 1880,
˜
1808, 1634, 1590, 1497, 1457, 1387, 1367, 1344, 1264, 1187, 1171,
1143, 1088, 1056, 1044, 1021, 990, 960, 935, 899, 866, 841, 660, 619
cm–1. HRMS (ESI): calcd. for C29H33N2O3S [M – H]+ 489.2217;
found 489.2223. Recrystallisation by slow evaporation of CHCl3/
EtOAc solutions gave needles of monohydrate that was readily
dried to the hemihydrate 6aa·½H2O; C29H35N2O3.5S (499.67):
calcd. C 69.71, H 7.38, N 5.61; found C 69.56, H 7.16, N 5.59.
(S)-2-[(1-Benzhydryl-4-benzyl-4,5-dihydro-1H-imidazol-3-ium-3-
yl)methyl]benzenesulfonate (6ae): Using 10ae (0.20 g, 0.41 mmol)
provided 6ae as a white powder (0.17 g, 99%); m.p. 223–224 °C.
1
[α]D = +45.0 (c = 0.60, CHCl3). H NMR (400 MHz, CDCl3): δ = NMR (100.6 MHz, CDCl3): δ = 14.6 (CHCH3α), 18.1 (CHCH3β),
2.92 (dd, J = 14.0, 7.2 Hz, 1 H, PhCH2α), 3.05 (dd, J = 14.0, 4.4 Hz, 18.2 (2ϫ ArCH3, ortho), 21.0 (2ϫ ArCH3, para), 26.6 (CHMe2),
1 H, PhCH2β), 3.39 (dd, J = 11.4, 6.4 Hz, 1 H, NCH2α), 3.83 (t, J
49.6 (ArCH2), 50.5 (NCH2CH), 64.2 (NCHCH2), 128.2 (ipso-C,
= 11.4 Hz, 1 H, NCH2β), 4.27–4.35 (m, 1 H, NCHCH2), 4.51 (d, Ar), 129.2 (Ar-CH), 129.6 (Ar-CH), 129.7 (Ar-CH), 130.1 (br., 2ϫ
Eur. J. Org. Chem. 2012, 699–707
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
705

S. Woodward et al.
FULL PAPER
Ar-CH), 130.8 (ipso-C, Ar), 131.5 (Ar-CH), 134.8 (br., ipso-C, Ar),
CHCl3/EtOAc solutions gave microcrystals of a monohydrate
136.9 (br., ipso-C, Ar), 139.9 (ipso-C, Ar), 146.4 (ipso-C, Ar), 159.7 6bc·H2O; C21H28N2O4S (404.52): calcd. C 62.35, H 6.98, N 6.93;
(NCHN) ppm. IR (CHCl ): ν = 3434, 3060, 3008, 2932, 2877, 1718,
found C 62.60, H 6.92, N 6.61. The compound could only be crys-
tallised by partial conversion to its hexafluorophosphate salt, H-
6bc·PF6.
˜
3
1639, 1508, 1466, 1445, 1395, 1373, 1335, 1268, 1193, 1142, 1087,
1021, 986, 956, 855, 833, 660, 619 cm–1. HRMS (ESI): calcd. for
C22H27N2O3S [M – 2H]+ 399.1748; found 399.1753. Recrystalli-
sation by slow evaporation of CHCl3/EtOAc solutions gave micro-
crystals of a monohydrate 6ba·H2O; C25H28N2O4S (452.57): calcd.
C 63.13, H 7.22, N 6.69; found C 63.02, H 7.18, N 6.51.
(S)-2-[{1-(Adamantan-1-yl)-4-isopropyl-4,5-dihydro-1H-imidazol-3-
ium-3-yl}methyl]benzenesulfonate (6bd): Using 10bd (0.20 g,
0.50 mmol) provided 6bd (0.127 g, 76%) as a colourless solid; m.p.
277 °C. [α]D = –13.2 (c = 0.79, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 0.88 (d, J = 6.8 Hz, 3 H, CHMeα), 0.92 (d, J = 6.0 Hz,
3 H, CHMeβ), 1.68 [d, J = 12.6 Hz, 3 H, (CH)CH2αα(CH)], 1.73
[d, J = 12.6 Hz, 3 H, (CH)CH2αβ(CH)], 1.93 [d, J = 11.4 Hz, 3 H,
(CH)CH2βα(CH)], 1.99 [d, J = 11.4 Hz, 3 H, (CH)CH2ββ(CH)], 2.20
[s, 3 H, (CH)CH2(CH)], 2.23–2.32 (m, 1 H, CHMe2), 3.52 (dd, J =
10.4, 6.6 Hz, 1 H, NCH2α), 3.85 (dd, J = 12.2, 10.4 Hz, 1 H,
NCHCH2β) overlapped by 3.94 (ddd, J = 12.2, 6.6, 3.2 Hz, 1 H,
CHCH2), 4.34 (d, J = 14.2 Hz, 1 H, ArCH2αN), 5.82 (d, J =
14.2 Hz, 1 H, ArCH2βN), 7.17 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 7.34
(td, J = 7.6, 1.2 Hz, 1 H, Ar), 7.44 (td, J = 7.6, 1.2 Hz, 1 H, Ar),
8.28 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 8.44 (s, 1 H, NCHN) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 14.1 (CHCαH3), 17.9 (CHCβH3),
27.0 (CHMe2 ), 29.0 [3 ϫ (CH2 )3 CH(CH2 )3 ], 35.6 (3 ϫ
CHCαH2CH), 40.5 (3 ϫ CHCβH2CH), 43.9 (NCHCH2), 49.4
(ArCH2), 56.8 [adamantyl-C, (CH2)3CN], 62.3 (NCHCH2), 128.5
(ipso-C, Ar), 129.6 (2ϫ Ar-CH), 129.6 (Ar-CH), 131.2 (Ar-CH),
(S)-2-[{1-(2,6-Diisopropylphenyl)-4-isopropyl-4,5-dihydro-1H-imid-
azol-3-ium-3-yl}methyl]benzenesulfonate (6bb): Using 10bb (1.12 g,
2.60 mmol) provided 6bb (1.07 g, 92%) as a white foam-like solid;
1
m.p. 155–157 °C. [α]D = +53.5 (c = 0.11 in chloroform). H NMR
(400 MHz, CDCl3): δ = 0.92 (d, J = 6.8 Hz, 3 H, CHCHMeα),
1.15 (d, J = 6.8 Hz, 3 H, CHCHMeβ), 1.24 (d, J = 6.8 Hz, 3 H,
ArCHMeαα), 1.27 (d, J = 6.8 Hz, 3 H, ArCHMeαβ), 1.29 (d, J =
6.8 Hz, 3 H, ArCHMeβα), 1.31 (d, J = 6.8 Hz, 3 H, ArCHMeββ),
2.43–2.53 (m, 1 H, CHCHMe2), 2.80 (septet, J = 6.8 Hz, 1 H,
ArCHMe2α), 3.53 (septet, J = 6.8 Hz, 1 H, ArCHMe2β), 3.72 (dd,
J = 11.8, 9.6 Hz, 1 H, NCHCH2α), 4.17 (t, J = 11.8 Hz, 1 H,
NCHCH2β), 4.46–4.53 (m, 1 H, NCHCH2), 4.60 (d, J = 14.0 Hz,
ArCH2α), 4.81 (d, J = 14.0 Hz, ArCH2β), 7.21–7.26 (m, 2 H, Ar),
7.24–7.30 (m, 1 H, Ar), 7.36–7.42 (m, 1 H, Ar), 7.43–7.47 (m, 1 H,
Ar), 7.48–7.52 (m, 1 H, Ar), 8.11 (s, 1 H, NCHN), 8.31–8.34 (m,
1 H, Ar) ppm. 1 3 C NMR (100.6 MHz, CDCl3 ): δ = 14.4
(CHCHCH3α), 18.2 (CHCHCH3β), 24.1 (ArCHCH3αα), 24.5
(ArCHCH3αβ), 24.6 (ArCHCH3βα), 25.0 (ArCHCH3ββ), 26.5
(CHCHMe2), 27.8 (ArCαHMe2), 28.6 (ArCβHMe2), 49.5 (PhCH2),
53.2 (NCHCH2), 64.5 (NCHCH2), 124.3 (Ar-CH), 125.3 (Ar-CH),
128.0 (ipso-C, Ar), 129.2 (Ar-CH), 129.7 (Ar-CH), 129.7 (Ar-CH),
130.2 (ipso-C, Ar), 130.9 (Ar-CH), 131.4 (Ar-CH), 145.9 (ipso-C,
Ar), 146.5 (ipso-C, Ar), 148.2 (ipso-C, Ar), 159.5 (NCHN) ppm.
146.3 (ipso-C, Ar), 156.2 (NCHN) ppm. IR (CHCl ): ν = 3668,
˜
3
3408, 3125, 3063, 3011, 2973, 2921, 2878, 2858, 2686, 2462, 2361,
2339, 1940, 1834, 1639, 1576, 1505, 1472, 1453, 1395, 1365, 1347,
1308, 1287, 1265, 1192, 1142, 1117, 1097, 1086, 1047, 1020, 984,
958, 909, 881, 831, 660, 645, 619 cm–1. HRMS (ESI): calcd. for
C23H31N2O3S [M – H]+ 415.2061; found 415.2080. The compound
was crystallised (microneedles, CHCl3/EtOAc) as its NaOH adduct
6ba·NaOH; C23H33N2NaO4S (456.57): calcd. C 60.50, H 7.29, N
6.14; found C 60.82, H 7.47, N 6.12.
IR (CHCl ): ν = 3689, 3010, 2969, 2931, 2873, 2361, 2338, 1639,
˜
3
1506, 1465, 1444, 1388, 1372, 1337, 1194, 1142, 1103, 1087, 1056,
1021, 928, 834, 662, 619 cm– 1 . HRMS (ESI): calcd. for
C25H33N2O3S [M – H]+ 411.2217; found 411.2200. Recrystalli-
sation by slow evaporation of CHCl3/EtOAc solutions gave micro-
crystals of a monohydrate 6bb·H2O; C25H36N2O4S (460.63): calcd.
C 65.19, H 7.88, N 6.08; found C 65.03, H 7.82, N 5.76.
(S)-2-[(1-Mesityl-4-phenyl-4,5-dihydro-1H-imidazol-3-ium-3-yl)-
methyl]benzenesulfonate (6ca): Using using 8ca (1.44 g, 3.29 mmol),
without purification of intermediate 10ca, provided 6ca (0.79 g,
55%) as a white solid; m.p. 263–270 °C. [α]D = +7.2 (c = 1.15,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.26 (br., s, 3 H, ArMeα,
ortho) overlapped by 2.30 (s, 3 H, ArMe, para) and overlapped by
2.38 (br., s, 3 H, ArMeβ, ortho), 3.78 (dd, J = 11.6, 9.4 Hz, 1 H,
NCH2α), 4.35 (d, J = 14.0 Hz, 1 H, ArCH2αN), 4.56 (t, J = 11.6 Hz,
1 H, NCH2β), 5.29 (dd, J = 9.4, 2.8 Hz, 1 H, NCHCH2), 5.81 (d,
J = 14.0 Hz, 1 H, ArCH2βN), 6.62 (dd, J = 7.2, 0.8 Hz, 1 H, Ar),
6.90 (br., s, 2 H, Ar), 7.20 (td, J = 7.6, 1.2 Hz, 1 H, Ar), 7.33–7.35
(m, 2 H, Ar), 7.42 (td, J = 7.6, 1.2 Hz, 1 H, Ar), 7.50–7.55 (m, 3
H, Ar), 8.267 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 8.70 (s, 1 H, NCHN)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 18.0 (br., 2ϫ ArCH3,
ortho), 21.0 (ArCH3, para), 49.8 (ArCH2), 59.0 (NCHCH2), 63.3
(NCHCH2), 127.4 (2ϫ Ar-CH), 127.8 (ipso-C, Ar), 129.0 (Ar-CH),
129.4 (Ar-CH), 129.6 (Ar-CH), 129.8 (2ϫ Ar-CH), 129.8 (3ϫ Ar-
CH), 130.5 (ipso-C, Ar), 132.1 (Ar-CH), 135.1 (ipso-C, Ar), 135.9
(ipso-C, Ar), 137.1 (ipso-C, Ar), 140.0 (ipso-C, Ar), 146.2 (ipso-C,
(S)-2-[{1-(3,5-Dimethylphenyl)-4-isopropyl-4,5-dihydro-1H-imid-
azol-3-ium-3-yl}methyl]benzenesulfonate (6bc): Using 8bc (1.34 g,
3.45 mmol), without purification of intermediate 10bc, provided
6bc (0.52 g, 39%) as a white foam-like solid; m.p. 231 °C. [α]D
=
1
–125.8 (c = 1.25, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.91
(d, J = 7.2 Hz, 3 H, CHMeα), 0.97 (d, J = 6.8 Hz, 3 H, CHMeβ),
2.25 (s, 6 H, 2ϫ ArMe) overlapped by 2.24–2.36 (m, 1 H, CHMe2),
3.88 (dd, J = 10.4, 6.8 Hz, 1 H, NCH2α), 4.13–4.18 (m, 1 H,
NCHCH2N), 4.25–4.30 (m, 1 H, NCH2β), 4.52 (d, J = 14.2 Hz, 1
H, ArCH2αN), 5.95 (d, J = 14.2 Hz, 1 H, ArCH2βN), 6.78 (s, 1 H,
Ar), 6.91 (s, 2 H, Ar), 7.22 (dd, J = 7.2, 1.2 Hz, 1 H, Ar), 7.35 (td,
J = 7.2, 1.2 Hz, 1 H, Ar), 7.43 (td, J = 7.6, 1.2 Hz, 1 H, Ar),
8.25 (dd, J = 7.6, 1.2 Hz, 1 H, Ar), 9.33 (NCHN) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 14.2 (CHCH3), 17.9 (CHCH3), 21.2 (2ϫ
ArCH3), 26.9 (CHMe2), 48.7 (NCHCH2N), 50.0 (ArCH2), 63.5
(NCHCH2N), 115.6 (2ϫ Ar-CH), 128.1 (ipso-C, Ar), 128.6 (Ar-
CH), 129.4 (Ar-CH), 129.7 (Ar-CH), 129.8 (Ar-CH), 131.5 (Ar-
CH), 135.7 (ipso-C, Ar), 139.4 (ipso-C, Ar), 139.9 (ipso-C, Ar),
Ar), 160.2 (NCHN) ppm. IR (CHCl ): ν = 3691, 3606, 3416, 3093,
˜
3
3064, 3011, 2467, 1957, 1636, 1496, 1480, 1457, 1445, 1372, 1329,
1265, 1192, 1142, 1088, 1021, 957, 909, 868, 855, 833, 660, 619
cm–1. HRMS (ESI): calcd. for C25H26N2NaO3S [M + Na]+
457.1556; found 457.1558. Recrystallisation by slow evaporation of
CH2Cl2/EtOAc solutions gave microcrystals of 6ca·¾CH2Cl2;
C25.7H27.5Cl1.5N2O3S (497.65): calcd. C 62.07, H 5.56, N 5.62;
found C 62.28, H 5.76, N 5.38.
146.0 (ipso-C, Ar), 156.0 (NCHN) ppm. IR (CHCl ): ν = 3691,
˜
3
3607, 3411, 3010, 2973, 2934, 2878, 2739, 2465, 2337, 1943, 1834,
1637, 1616, 1599, 1517, 1472, 1445, 1396, 1375, 1344, 1330, 1271,
1192, 1143, 1114, 1087, 1067, 1021, 958, 917, 881, 837, 660, 620,
605 cm–1. HRMS (ESI): calcd. for C21H26N2NaO3S [M + Na]+
409.1556; found 409.1556. Recrystallisation by slow evaporation of
Allylic Substitution Reaction of Cinnamyl Derivatives Using Grig-
nard Reagents: In flame-dried glassware (typically carousel reactor
706
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 699–707

Synthesis of Sulfonated Chiral Carbene Precursors
recent developments, see: S. Kehrli, D. Martin, D. Rix, M.
Mauduit, A. Alexakis, Chem. Eur. J. 2010, 16, 9890–9904; c)
K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 4455–
4462.
tubes) under argon, 6 (5.3 μmol) and any additive (if required) were
suspended in dry diethyl ether (1.0 mL), to which was added a solu-
tion of the appropriate cinnamyl derivative (0.53 mmol) in Et2O
(1.0 mL). The reaction mixture was stirred (10–15 min) at room
temperature before being cooled to –15 °C and stirred for a further
10 min. The alkylmagnesium bromide (3.0 equiv.) was added drop-
wise (over 2–4 min). The colourless reaction mixture was then
stirred (200 rpm, 17 h) at –15 °C, quenched by addition of satu-
rated, acidified NH4Cl solution and stirred (30–60 min) whilst be-
ing warmed to room temperature. The organic layer was extracted
into Et2O, dried (Na2SO4) and filtered though a plug of silica be-
fore the solvent was removed in vacuo. Purification by column
chromatography (pentane as eluent) gave a mixture of α and γ
products. Yields and conversions (Table 3) were determined by iso-
lation, NMR spectroscopy or GC, against an internal standard, as
appropriate, ee values were determined by chiral GC using a Chira-
cil-Dex-CB column. Details of the known products are given in the
Supporting Information.
[5]
For recent reviews in this area, see: a) A. T. Biju, N. Kuhl, F.
Glorius, Acc. Chem. Res. 2011, DOI: 10.1021/ar2000716; b) N.
Marion, S. Díez-González, S. P. Nolan, Angew. Chem. 2007,
119, 3046; Angew. Chem. Int. Ed. 2007, 46, 2988–3000; c) D.
Enders, K Breuer, in: Comprehensive Asymmetric Catalysis, vol.
3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, Germany, 1999, p. 1093; d) D. Enders, T. Balensiefer, O.
Niemeier, M. Christmann, in: Enantioselective Organocatalysis:
Reactions and Experimental Procedures (Ed.: P. I. Dalko),
Wiely-VCH, Weinheim, Germany, 2007, p. 331; e) D. Enders,
O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; f) V.
Nair, S. Vellalath, B. P. Babu, Chem. Soc. Rev. 2008, 37, 2691.
For an overview, see: a) S. T. Liddle, I. S. Edworthy, P. L. Ar-
nold, Chem. Soc. Rev. 2007, 36, 1732–1744; b) for use in allylic
Cu catalysis, see: T. Jennequin, J. Wencel-Delord, D. Rix, J.
Daubignard, C. Crevisy, M. Mauduit, Synlett 2010, 1661–1665.
For use in conjugate addition Cu catalysis, see: M. Tissot, A.
Pérez Hernández, D. Müller, M. Mauduit, A. Alexakis, Org.
Lett. 2011, 13, 1524–1527.
For an overview of NHC precursor routes, see: a) L.
Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz, V.
César, Chem. Rev. 2011, 111, 2705–2733; b) for synthesis of 2,
see: J. J. Van Veldhuizen, J. E. Campbell, R. E. Giudici, A. H.
Hoveyda, J. Am. Chem. Soc. 2005, 127, 6877–6882; c) for syn-
thesis of 3, see: T. Uchida, T. Katsuki, Tetrahedron Lett. 2009,
50, 4741–4743; d) for synthesis of 4, see: O. Jackowski, A.
Alexakis, Angew. Chem. 2010, 122, 3418; Angew. Chem. Int.
Ed. 2010, 49, 3346–3350; e) for synthesis of 5a, see: M. K.
Brown, T. L. May, C. A. Baxter, A. H. Hoveyda, Angew. Chem.
2007, 119, 1115; Angew. Chem. Int. Ed. 2007, 46, 1097–1100.
[6]
[7]
CCDC-843838 (for 6ab), -843839 (for [H-6bc]PF6), -843836 (for
8ba) and -843837 (for 8bd) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and spectroscopic data for all
compounds.
Acknowledgments
We are grateful to Prof. Alexandre Alexakis for helpful preliminary
discussions and for hosting a short visit (C. M. L.). We thank the
Engineering and Physical Research Council (EPSRC) for a partial
funding contribution to the COST (European Cooperation in Sci-
ence and Technology) D40 Action, which facilitated this pro-
gramme. We thank Mr Raju Ghosh for preparing an additional
sample of 10bb.
[8]
[9]
For synthesis of 5b, see: Y. Lee, K. Akiyama, D. G. Gillingham,
M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130,
446–447.
For a rare example, see: a) B. A. Bhanu Prasad, S. R. Gil-
bertson, Org. Lett. 2009, 11, 3710–3713. For a related system
see: b) A. Fürstner, M. Alcarazo, V. César, C. W. Lehmann,
Chem. Commun. 2006, 2176–2178.
[10] a) R. I. Robinson, J. C. Stephens, S. M. Worden, A. J. Blake,
C. Wilson, S. Woodward, Eur. J. Org. Chem. 2004, 4596–4605.
For Lewis-acid-promoted opening of oxazolines, see: b) M. J.
Fazio, J. Org. Chem. 1984, 49, 4889–4893.
[11] S. Karunan Partha, A. Sadeghi-Khomami, S. Cren, R. I. Rob-
inson, S. Woodward, K. Slowski, L. Berast, B. Zheng, N. R.
Thomas, D. A. R. Sanders, Molecular Informatics 2011, DOI:
10.1002/minf.201100085 further screening of an enlarged li-
brary is underway.
[12] a) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 15604–
15605; b) O. Jackowski, A. Alexakis, Angew. Chem. 2010, 122,
3418; Angew. Chem. Int. Ed. 2010, 49, 3346–3350; c) Y. Lee, B.
Li, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 11625–11633.
[13] A similar effect has been noticed in organoaluminium chemis-
try, see: P. K. Fraser, S. Woodward, Chem. Eur. J. 2003, 9, 776–
783.
[1] For general overviews, see: a) N-Heterocyclic Carbenes in Tran-
sition Metal Catalysis, Topics in Organometallic Chemistry (Ed.:
F. Glorius), vol. 21, Springer-Verlag, Berlin/Heidelberg, 2007;
b) N-Heterocyclic Carbenes in Synthesis (Ed.: S. P. Nolan),
Wiley-VCH, Weinheim, Germany, 2006; c) N-Heterocyclic
Carbenes (Ed.: S. Díez-González), RSC Publishing, Cam-
bridge, UK, 2010. For steric factors, see: d) T. Dröge, F. Glor-
ius, Angew. Chem. Int. Ed. 2010, 49, 6940–6952. For electronic
factors, see: e) H. Jacobsen, A. Correa, A. Poater, C. Costabile,
L. Cavallo, Coord. Chem. Rev. 2009, 253, 687–703.
[2] For a comprehensive review, see: a) . G. C. Vougioukalakis,
R. H. Grubbs, Chem. Rev. 2010, 110, 1746–1787. For recent
developments in chiral Ru complexes see: S. Tiede, A. Berger,
D. Schlesiger, D. Rost, A. Lühl, S. Blechert, Angew. Chem. Int.
Ed. 2010, 49, 3972–3975.
[3] For a review of commercial PEPPSI catalysts: a) E. A. B.
Kantchev, C. J. O’Brien, M. G. Organ, Aldrichim. Acta 2006,
39, 97–111. For alternatives and recent developments, see: b)
C. Lohre, T. Dröge, C. Wang, F. Glorius, Chem. Eur. J. 2011,
17, 6052–6055; c) F. Godoy, C. Segarra, M. Poyatos, E. Peris,
Organometallics 2011, 30, 684–688; d) Z. Xi, B. Liu, W. Chen,
J. Org. Chem. 2008, 73, 3954–3957.
[14] a) Data taken from the X-ray structure “RUYTUB”, see: B. F.
Straub, M. Wrede, K. Schmid, F. Rominger, Eur. J. Inorg.
Chem. 2010, 1907–1911 and http://webcsd.ccdc.cam.ac.uk/; b)
for a recent example of chiral symmetrical NHC analogues in
this chemistry, see: J.-N. Levy, C. Latham, L. Roisin, N. Kand-
ziora, P. Di Fruscia, A. J. P. White, S. Woodward, M. J.
Fuchter, Org. Biomol. Chem. 2011, DOI: 10.1039/C1OB06780J.
Received: September 13, 2011
[4] For an overview see: a) J. Wencel, M. Mauduit, H. Hénon, S.
Kehrli, A. Alexakis, Aldrichim. Acta 2009, 42, 43–50; b) For
Published Online: December 1, 2011
Eur. J. Org. Chem. 2012, 699–707
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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