Synthesis of amino acid derived imidazolidinium salts as new NHC precatalysts

Article abstract of DOI:10.1016/j.tetasy.2011.11.015

The preparation of new chiral symmetrically and unsymmetrically N,N′-disubstituted imidazolium based NHC salts Ib, IIb, IIIa-c and IVc-h from the amino acids l-proline and l-phenylalanine, is reported. Some preliminary tests have been carried out, demonstrating that the chiral NHCs give chiral induction in organometallic catalysis and can be used as organocatalysts.

Full text of DOI:10.1016/j.tetasy.2011.11.015

Tetrahedron: Asymmetry 22 (2011) 1994–2006
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of amino acid derived imidazolidinium salts as new NHC precatalysts
⇑
Ragnhild B. Strand, Trygve Helgerud, Tina Solvang, Christian A. Sperger, Anne Fiksdahl
Department of Norwegian, University of Science and Technology, NTNU, NO-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
The preparation of new chiral symmetrically and unsymmetrically N,N0-disubstituted imidazolium based
NHC salts Ib, IIb, IIIa–c and IVc–h from the amino acids L-proline and L-phenylalanine, is reported. Some
preliminary tests have been carried out, demonstrating that the chiral NHCs give chiral induction in orga-
nometallic catalysis and can be used as organocatalysts.
Article history:
Received 6 October 2011
Accepted 24 November 2011
Available online 7 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
We are working on the preparation, modification and applica-
tion of new chiral NHCs, our aim herein was to synthesize new chi-
N-Heterocyclic carbenes (NHCs) represent a versatile class of
compound due to their favourable role in transition metal
catalysed reactions.1 Over the last decade they have been devel-
oped as a powerful supplement to traditional amine or phosphine
ligands.2 In contrast to asymmetric transformations using chiral
phosphine metal complexes, reactions with chiral NHC ligands
are rare, typically represented by allylic Pd-catalysed alkylations
ral NHC salts I–III, with a stereogenic centre derived from the
amino acid -proline, located in a side chain of one or both of the
aromatic N-substituents on the imidazolium ring (Scheme 1).
Additionally, a series of new closely related NHC salts IV with
the stereogenic centre directly connected to the nitrogen of the
L
imidazolium backbone was prepared from
L-phenylalanine based
on a literature procedure11 (Scheme 1).
and
a
-arylations, Cu- and Rh-catalysed Michael additions, catalytic
A few preliminary results on the chiral induction of the new
NHCs as ligands in asymmetric organometallic catalysis and as
organocatalysts in stereoselective reactions are reported. A future
aim of this project is to systematically investigate the utility of
the chiral NHC compounds in asymmetric synthesis.
hydrogenations in the presence of Ir or Rh, desymmetrisation by
Ru-based ring closing metathesis (RCM) or hydrosilylation reac-
tions with Rh- or Ru-catalysts.3–5
Recent investigations have also demonstrated the advantages of
using NHCs as organocatalysts. Their highly nucleophilic proper-
ties are useful in aldehyde activation in so-called umpolung
reactions.6,7 NHC organocatalytic reactions have been further
extended. Thus, novel aspects of NHCs also include asymmetric
organocatalytic transformations performed with chiral NHCs, such
as stereoselective cross-annulation lactone synthesis, in which the
crucial step is the formation of an activated homoenolate interme-
2. Results and discussion
2.1. Chiral NHC salts based on
L-proline
2.1.1. Chiral building blocks
diate, obtained from a chiral NHC and an
a,b-unsaturated aldehyde
The symmetrically and unsymmetrically substituted NHC salts
Ib, IIb and IIIa–c were prepared from -prolinol aniline building
blocks 4a–c (Scheme 2). The N-nitrophenylprolinol was
synthesized in a two step procedure in a 94% overall yield via an
ipso-substitution of 2-fluoronitrobenzene with -proline methyles-
by an umpolung reaction.8
L
In order to allow a greater variety of enantioselective metal cat-
alysed transformations as well as to broaden the application of
NHCs as chiral organocatalysts, there is a large potential for new
chiral NHCs in novel areas of stereoselective synthesis.
Several approaches have been made to introduce chiral ele-
ments when designing chiral NHC frameworks. In most examples
the chirality has been incorporated as a stereogenic centre in the
N-alkyl side chain or in the imidazole backbone, often based on
amino acid building blocks.9 In addition, several chiral NHCs have
a planar chiral element or an axial chiral unit.10
2
L
ter to afford N-arylproline ester 1, which was subsequently reduced
with LiBH4 to provide the alcohol key intermediate 2 without
affecting the nitro group.12–14 Attempts to selectively reduce the es-
ter functionality within 1 with NaBH4 or LiAlH4 were unsuccessful,
giving a mixture of unidentified products, including reduction of
the nitro group to give the respective aniline derivative. The exclu-
sive reduction of ester 1 allows further selective transformations of
the alcohol moiety (e.g., alkylation, silylation), due to the absence of
a nucleophilic aniline nitrogen. An initial selective reduction of the
nitro group of intermediate 1 to obtain the respective aniline
⇑
Corresponding author. Tel.: +47 735 940 94.
E-mail address: anne.fiksdahl@chem.ntnu.no (A. Fiksdahl).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.11.015

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
1995
OR
RO
OR
N
N
N
N+
N+
PF6
N
N
N
N
Ph
OR
-
-
-
PF6
PF6
R'
II: R´ = 3,5-Me
IV
I
III: R´ = 2,4,6-Me
Scheme 1. General structures of the target NHC salts.
MeO2C
NO2
F
HO
HO
N
N
N
LiBH4
SnCl2
CO2Me
N
Cl-
EtOH, reflux
78%
NEt3, CH3CN
reflux
THF, rt
94%
NO2
NO2
NH2
H
H
> 98%
2
1
4a
Imidazole
TBDMSCl
THF, rt
NaH, MeI
THF, rt
75%
97%
OTBDMS
OTBDMS
MeO
MeO
N
N
N
SnCl2
Pd-C/H2
N
EtOAc, rt
84%
EtOH, reflux
83%
NO2
NH2
NO2
NH2
3c
4b
3b
4c
Scheme 2. Preparation of chiral building blocks from L-proline.
derivative was ruled out, as this would allow an intramolecular
cyclization, providing an unwanted quinoxalinone product.15
Amino alcohol 4a was obtained in a 78% yield by treating the
nitrobenzene derivative 2 with SnCl2 in refluxing EtOH. The nitro
alcohol 2 was also protected as a methyl ether, to afford the
O-methyl derivative 3b (75%) which was further converted to the
aniline derivative 4b (83%) by SnCl2 reduction. The TBDMS-
protected building block 4c was prepared from alcohol 2 by
introduction of the silyl group with TBDMSCl in the presence of
imidazole (97%) and subsequent catalytic hydrogenation of the
remaining nitro group in intermediate 3c, affording the O-TBDMS
aniline derivative 4c in an 84% yield.
2.1.3. NHC salt Ib
Due to these observations, the methylated NHC derivative Ib
was synthesized. Bisamine 6b was prepared from O-methyl-
protected aniline 4b in two steps (70%) via bisamide 5b, as
described for 6a (Scheme 3). However, in some cases the reduction
of bisamide 5b gave a partial cleavage of the two methyl ether
moieties and bisamine diol 6a was also unexpectedly isolated
(70%). A plausible mechanism for the observed hydride ether cleav-
age, otherwise regarded to be stable towards such reduction, is
discussed below (Scheme 4). The hydrochloric salt of bisamine
6b was prepared by treatment with a hydrochloric methanol solu-
tion, generated from acetyl chloride in anhydrous methanol.
Subsequent cyclization of the hydrochloride salt of 6b to form
the imidazolium NHC backbone was performed by heating in
trimethyl orthoformate.16 The crude cyclization product was dis-
solved in DCM with an excess of KPF6 in order to allow counterion
exchange.11 The hexafluorophosphate counterion afforded better
solubility and a higher Rf-value of the NHC salt Ib compared to
the respective chloride counterion (this being an advantage in
the final chromatographic purification step) providing the desired
NHC salt Ib in a 75% yield.
2.1.2. NHC salt Ia
The formation of bisamide 5a was achieved by coupling two
aniline molecules 4a with one unit of oxalyl chloride in a 28% yield
(Scheme 3). The low yield was caused by the presence of two
nucleophilic moieties in the amino alcohol 4a, affording a mixture
of different products, in addition to the desired bisamide 5a. Sub-
sequent reduction of the two amide functionalities in 5a with
LiAlH4 provided bisamine 6a in a 96% yield. However, the final
cyclization step of bisamine 6a in the presence of trimethyl ortho-
formate at 120 °C to give imidazolium salt Ia was unsuccessful.16
1H NMR studies of the crude reaction mixture revealed that a com-
plex mixture of different products were formed, even when the
reaction temperature was lowered to 80 °C. Final treatment of
the crude reaction mixture with KPF6 followed by subsequent flash
chromatography provided, according to 1H NMR spectroscopy,
only trace amounts of the desired NHC salt Ia, still containing
unidentified byproducts. Experiments on similar compounds
(10a, 15) are discussed later (Schemes 5 and 6), showing that a
reaction of the free hydroxy groups with excess orthoformate
had taken place in addition to the desired cyclization.
2.1.4. NHC salt IIa
The direct preparation of NHC salt IIa from alcohol 4a was
unsuccessful, which was in line with the observations made for
the attempts to transform 4a into NHC salt Ia (Scheme 3). The
two nucleophilic functions of aminoalcohol 4a gave rise to product
mixtures and a low yield (25%) of the bisamide coupling product
9a. Only trace amounts of NHC compound IIa were obtained by
orthoformate cyclization of bisamine alcohol 10a, due to additional
unidentified reactions of the free alcohol with the orthoformate,
acting both as a solvent and a reagent.

1996
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
RO
RO
N
N
RO
NH
NH
N
N
RO
N
OR
(COCl)2
THF, rt
O
LiAlH4
1. HCl/MeOH
N+
PF6
N
O
THF, reflux
2. CH(OMe)3, 80°C
NH2
-
3.
KPF6, DCM
HN
OR
HN
OR
4a: R = H
Ia: R = H (traces)
Ib: R = Me (75%)
N
4b: R = Me
N
6a: R = H (96%)
6b: R = Me (87%)
5a: R = H (28%)
5b: R = Me (81%)
Scheme 3. Preparation of symmetrically substituted chiral NHC salts, based on
L-proline.
N
N
N
LiAlH4
- R´H
HN
N
R
N
O
O
LiO
R
AlH2
R
H2Al
R´
R´
H
Li
Scheme 4. Proposed mechanism for LiAlH4 ether cleavage.20
2.1.5. NHC salt IIb
methyl protected ether 10b was obtained in a 74% yield by
subsequent treatment of alcohol 10a with methyl iodide in the
presence of potassium tert-butylate.19 Depending on the reaction
conditions, lower yields, ranging from 25% to 56%, were obtained
by using a stronger base, such as sodium hydride (pKa ꢀ35), which
may give additional partial aniline deprotonation, not observed by
the more selective tBuOK (pKa ꢀ17).21 The final orthoformate
cyclization of bisamine 10b followed by immediate counterion
exchange readily afforded the NHC hexafluorophosphate salt IIb
in a 68% yield.
In contrast to the preparation of the symmetrically substituted
NHC salt Ib, the synthesis of IIb with two different N-substituents
was performed by stepwise introduction of the two substituents
(Scheme 5). The achiral monoamide 8a was prepared in two steps
from 3,5-dimethylaniline 7a and ethyl chlorooxoacetate in a 94%
overall yield, according to a literature procedure.11,17 The monoa-
mide 8a and the chiral O-TBDMS protected aniline derivative 4c
were reacted to give the corresponding bisamide 9c in a 46% yield
by the DCC/HOBt coupling method, known from peptide synthe-
sis.17,18 The reduction of bisamide 9c with LiAlH4 provided the
bisamine alcohol 10a in an 88% yield, rather than the desired
O-TBDMS protected bisamine. The additional silyl ether cleavage
was unexpected, since TBDMS ethers, in general, are considered
to be stable to these reaction conditions.19 However, a mechanism
for the LiAlH4 cleavage of similar TBDMS-ethers being in close
proximity to a heteroatom (e.g., nitrogen), has been proposed
(Scheme 4).20
An initial hydride deprotonation of a secondary amine in the
substrate would form an N-Al adduct. The proximate O-silyl group
undergoes a cleavage of the silicon–oxygen bond, caused by hy-
dride attack, releasing the lithium alkoxide, which is hydrolysed
during the aqueous workup. It was shown that the position of
the amine relative to the O-silyl moiety is crucial for the stability
and reactivity of the TBDMS-ether. Due to the assisting amide
groups in appropriate positions, relative to the ether groups, the
proposed mechanism may explain the observed LiAlH4 cleavage
of the TBDMS-ether of bisamide 9c, as well as the partial methyl
ether cleavage of 5b (Scheme 3).
2.1.6. NHC salts IIIa–c
The 3,5-dimethylphenyl substituent of IIb was replaced by the
mesityl moiety (2,4,6-trimethylphenyl) in the unsymmetrically
substituted NHC derivatives IIIa–c, prepared by a similar synthetic
pathway as described for product IIb (Scheme 5). The DCC/HOBt
coupling between the chiral building block 4c and monoamide
8b, prepared from 2,4,6-trimethylaniline 7b in a 91% yield, affor-
ded the bisamide 11 in a 72% yield. Subsequent hydride reduction
and purification of the crude product by Kugelrohr distillation gave
bisamine alcohol 12a in a 91% yield, due to additional reductive
silyl ether cleavage (see 5b and 9b–c above). In order to avoid
unwanted side-reactions in the final cyclization step, the alcohol
moiety was protected as the TBDMS-ether 12c (74%). However,
the final orthoformate cyclization of 12c only afforded small
amounts of two NHC salts, the expected O-TBDMS product IIIc
(8%), and the orthoformate derivative IIIb (11%), formed in situ
after TBDMS-ether cleavage of IIIc during the reaction. Products
IIIb and IIIc were separated and isolated by flash chromatography
after counterion exchange. In order to synthesize NHC salt IIIa,
bearing a free alcohol functionality in the side chain, a method to
remove the orthoformate group by treatment of derivative IIIb
with a deuterated methanolic DCl solution (0.1 M), was developed.
The experiment was monitored by 1H NMR spectroscopy and
The bisamide methyl ether 9b was likewise prepared from
methyl ether 4b and monoamide 8a (50%). Subsequent LiAlH4
bisamide reduction afforded the bisamine alcohol 10a in an 80%
yield, due to the additional hydride cleavage of the ether group,
as discussed above for the methyl and silyl ethers 5b and 9c. The

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
1997
R´
R´
R'
NH
NH
R'
1. ClCOCO2Et
2. NaOH
4a, 4b or 4c
LiAlH4
DCC/HOBt
O
O
NH
THF, rt
THF, reflux
O
HN
OR
NH2
HN
CO2H
N
N
8a (94%)
8b (91%)
7a-b
OR
from 9b (80%)
from 9c (88%)
9a: R = H (25%)
9b: R = Me (50%)
9c: R = TBDMS (46%)
7a, 8a, 9c, 10a,b, IIa,b: R´ = 3,5-Me
7b, 8b, 11, 12a,c, IIIa-c: R´ = 2,4,6-Me
10a: R = H
i)
10b: R = Me (74%)
11: R = TBDMS (72%)
12a: R = H, from 11 (91%)
12c: R = TBDMS (74%)
ii)
i) tBuOK, MeI, THF, rt
ii) Imidazole, TBDMSCl, THF, rt
N
OR
N+
PF6
N
1. HCl/MeOH
10a, 10b or 12c
2. CH(OMe)3, 80°C
3. KPF6, DCM
-
´R
IIa: R = H, from 10a (traces)
IIb: R = Me, from 10b (68%)
IIIa: R = H (quant.)
HCl, MeOH
IIIb: R = CH(OMe)2, from 12c (11%)
IIIc: R = TBDMS, from 12c (8%)
Scheme 5. Preparation of unsymmetrically substituted chiral NHC salts, based on
L-proline.
Ph
OH
H2N
H
N
O
O
NH2
LiAlH4
ClCOCO2Et
H
N
13
Ph
N
THF, reflux
91%
DCM reflux
85%
H
pyridine, DCM
98%
CO2Et
O
OH
7c
8c
14
1. HCl/MeOH
2. HC(OCH3)3
N
N
N
N
H
Ph
Ph
OR
RCl, NEt3
DCM, rt
N
Ph
X
N
H
PF6
toluene, 90°C
87%
OH
OH
15
IVa: X = Cl
IVb: X = PF6 (98%)
IVc: R = Ms (71%)
IVd: R = Ac (64%)
KPF6, H2O
IVe: R = Pivaloyl (65%)
IVf: R = Bz (78%)
IVg: R = TMS (75%)
IVh: R = TBDMS (93%)
Scheme 6. Preparation of unsymmetrically substituted chiral NHC salts, based on L-phenylalanine.
revealed that full deprotection took place within 40 min at room
temperature. These results were also confirmed in a parallel pre-
parative experiment with a methanolic HCl solution, providing a
quantitative yield of NHC salt IIIa after purification.

1998
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
2.2. Chiral NHC salts based on
2.2.1. NHC salts IVc–h
L
-phenylalanine
formed, which was converted quantitatively into the desired
NHC salt IVa by HCl/MeOH treatment of the product mixture. A fi-
nal counterion exchange with KPF6 provided the desired hexa-
The OH-containing NHC precursor IVa (Scheme 6) has previously
been prepared in a 35% yield from aniline derivative 7c.22 We found
that the reported method was inconvenient, due to complex prod-
uct mixtures, inefficient work-up procedures and, thus, low yields.
In order to study the role of the free and the modified hydroxyl
group in the final NHC salts and their respective properties in catal-
ysis, we wanted to prepare a number of derivatives by masking the
hydroxyl-group. A series of new derivatives of NHC salt IVa were
fluorophosphate salt IVb in a 98% yield. A number of
derivatizations of the free alcohol group were carried out by stir-
ring a solution of IVb in DCM and NEt3 in the presence of the
respective electrophiles to provide the corresponding derivatives
IVc (OMs), IVd (OAc), IVe (OPiv), IVf (OBz), IVg (OTMS) and IVh
(OTBDMS) in moderate to good yields (Scheme 6).
2.3. Chiral induction, preliminary results
synthesized from L-phenylalanine (Scheme 6), based on a conve-
nient procedure to incorporate a stereogenic centre with amino acid
origin directly onto one of the N-substituents of the imidazole
framework of the NHC salts.11 The preparation- of new mesylate
A few preliminary tests, which were conducted without any
efforts to optimize the reaction conditions, were carried out in
order to indicate the potential of the new chiral NHCs to induce
chiral induction in; (i) Cu-NHC catalysed conjugated addition
(Table 1);11,23 (ii) NHC-organocatalysed cross-annulation
(Table 2);8,24,25 and (iii) gold(I)-NHC catalysed cyclopropanation
(Table 3).26 The three different NHC based systems afforded high
catalytic activity in all reactions (i–iii), with high to quantitative
conversions into products 17, 20 and 23, respectively. The diastere-
oselectivity of the reactions (ii) and (iii), represented by the
obtained trans/cis ratios of the products 20 and 23 (Tables 2 and
3), were approximately the same as reported.24–26
(i) The enantioselective copper-catalysed conjugate addition of
diethylzinc to cyclohexen-2-one 16, affording ethyl adduct 17,
has been used as a test reaction for many chiral catalytic systems,
including Cu-NHCs.11,23,24 All of our tested NHC-ligands afforded
chiral induction in this reaction (Table 1). NHC-ligand Ib displayed
moderate, but promising enantioselectivity (57% ee). Lower enanti-
oselectivity was obtained for NHCs IIb and IVb–e (8.5–23% ee),
relative to the 27% ee achieved by using commercial 1,3-bis((S)-
1-phenylethyl)-1H-imidazol-3-ium tetrafluoroborate X.24 Optimi-
zation of the reaction conditions is expected to increase the
enantiomeric purity, since 39–54% ee previously is reported for
NHC X in this reaction.24
(ii) The organocatalytic properties of the previously known NHC
salt IVa22 with a free OH group, and some of our new OH-masked
NHC compounds IVb,e,h were tested in the cross-annulation
reaction of enal 11 and ketone 12 (Table 2). The target trans- and
cis- g-lactones 20 are formed by this organocatalysed conjugate
umpolung reaction. The enantioselectivities (16–27% ee) obtained
by our OH-masked new NHCs IVb,e,h were comparable to previ-
ously reported values (<25%).25a Moreover, these O-derivatives
afforded nearly twofold chiral induction (in average >20% ee) com-
pared to the unmasked compound IVa (11–14% ee). Poor to high
enantioselectivity (19–94% ee) was later obtained by chiral cyclo-
phane-type NHCs.6
IVc, ester IVd–e and silyl ether IVg–h NHC derivatives from L-phen-
ylalanine as the chiral source is hereby presented (Scheme 6).
Ester 8c, prepared from 2,6-diisopropylaniline and ethyl chloro-
oxoacetate (98% yield), was converted into the corresponding
chiral bisamide 14 with (S)-phenylalaninol 13 in an 85% yield.11
Hydride reduction (91%) followed by orthoformate cyclization of
bisamine 15 in toluene afforded the NHC salt IVa in an 87% yield.
Thus, using this four-step method afforded IVa in a 66% overall
yield from the aniline derivative 7c, nearly twice as high relative
to the previously used method.22 As indicated by 1H NMR spectros-
copy, only small amounts of the orthoformate by-product was
Table 1
Cu-NHC catalysed conjugate addition11,23
O
O
NHC (3 mol%)
Cu(OTf)2 (2 mol%)
nBuLi (8 mol%)
ZnEt2 (1.5 equiv)
Et2O, rt
Et
17
16
NHC-salt
Conv.a
%
%ee (S)b
Ib
>99
>99
>99
76
>99
80
57
11
8.5
23
14
IIb
IVb
IVc
IVd
IVe
Xc
13
>99
27 (39–54)d24
a
b
c
Determined by GLC.
Determined by chiral GLC (Lipodex E).
Commercial 1,3-bis((S)-1-phenylethyl)-1H-imidazol-3-ium tetrafluoroborate.
The corresponding NHCAgCl complex used; optimized reactions at ꢁ20 to
d
ꢁ78 °C.24
Table 2
NHC-organocatalysed cross-annulation8,25
O
O
O
O
chiral NHC 20 mol%
O
O
H
Ph
CF3
Ph
trans-20
DBU
THF, rt, 18 h
F3C
Ph
19
Ph
Ph
Ph
CF3
18
cis-20
NHC-salt
Conv.a
%
Ratiob (trans:cis)
%eec trans
%eec cis
IVa
IVb
IVe
IVh
92
72
>99
>99
69:31
72:28
62:38
64:36
11
24
24
22
14
16
27
25
a
b
c
Determined by GLC.
Determined by 1H NMR spectroscopy.
Determined by chiral GLC (Varian CP-Chirasil-Dex CB).

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
1999
Table 3
Au-NHC catalysed olefin cyclopropanation26a
OAc
OAc
OAc
5% Au-NHC-Cl, 5% AgNTf2
DCM, rt, 1 h
OAc
22
21
OAc
OAc
cis-23
trans-23
NHC salt
Conv.a
>99
%
Ratiob (trans:cis)
%eec trans
%eec cis
d
IVa0
38:62
10
9
a
b
c
Determined by GLC.
Determined by 1H NMR spectroscopy.
Determined by chiral GLC (Lipodex E).
d
NHC salt IVa0 is the Clꢁ counterion analogue of IVa (PF6ꢁ). The Au(I)NHC–Cl complex was prepared from the corresponding NHC–Cl precursor via the silver carbene
complex (NHCAgCl) with (i) Ag2O and (ii) AuCl(Me2S).26b,c
(iii) We have recently investigated gold(I)-catalysed olefin cyclo-
propanation from specific propargylic substrates.26a Based on this
experience, we replaced the original gold(I)phosphine-catalyst with
the chiral gold(I)-NHC-IVa0 catalytic system (Table 3).26b Even if the
chiral induction in the reaction was poor (9–10% ee), this un-opti-
mized reaction represents the first chiral gold(I)-catalysed olefin
cyclopropanation and may indicate a potential for such chiral
Au(I)-NHC catalytic systems in asymmetric cyclopropanations.
General and systematic studies of the catalytic properties of
new chiral NHCs are currently in progress in our laboratories.
4. Experimental
4.1. General
Dry THF, Et2O and DCM were collected from an MB SPS-800 sol-
vent purification system. Unless otherwise stated, all reactions
were performed under a nitrogen atmosphere in pre-dried glass-
ware. Flash chromatography was performed with Merck silica gel
(SDS, 60 Å, 40–63 m) or with a Supelco Versa Flash system with
commercially prepacked Versa Flash cartridges. 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX 400 MHz spectrom-
eter. Chemical shifts (d) are reported in parts per million (ppm) rel-
ative to TMS as an internal standard or by calibration on the
solvent resonance peak. Coupling constants (J) are reported in
Hertz (Hz). The attributions of the chemical shifts were determined
by means of COSY, HSQC, HMQS, HMBC and NOESY experiments.
High resolution mass spectra (HRMS) were determined with an
Agilent 6520 QTOF MS (ESI) or with a Finnigan MAT 95 XL MS
(EI). Optical rotations were measured on a Perkin–Elmer Model
341 Polarimeter. IR spectra were obtained with a Nicolet 20SXF
FT-IR spectrometer, recorded on a Smart Endurance reflexion cell.
Melting points were recorded on a Stuart SMP3 apparatus.
3. Conclusion
New chiral symmetrically and unsymmetrically N,N0-disubsti-
tuted imidazolium based NHC salts, Ib, IIb and IIIa–c derived from
L-proline and IVb–h from L-phenylalanine, have been prepared.
Key steps in the syntheses were the coupling of oxalyl chloride
with the appropriate chiral aminoalcohol derivative or stepwise
coupling of chlorooxoacetate with the proper aniline and aminoal-
cohol derivatives. Subsequent diamide hydride reduction, final
orthoformate cyclization of the bisamine intermediates and a
counterion exchange readily afforded the desired chiral NHC
hexafluorophosphate salts. The NHC salts Ib, IIb and IVb–h were
prepared in 4–7 steps, affording 68% to quantitative yield in each
step after purification to allow proper characterisation of the
new intermediates. For the direct preparation of these NHC salt,
chromatographic purification of the intermediates would,
however, not be required.
4.2. Chiral NHC-salts based on L-proline
4.2.1. (S)-Methyl-1-(2-nitrophenyl)pyrrolidine-2-carboxylate
127,28
Methyl (S)-pyrrolidine-2-carboxylate was prepared29 from (S)-
proline (10.2 g, 88.6 mmol) and SOCl2 (11.6 g, 7.10 mL, 97.5 mmol)
in refluxing MeOH (60 mL) for 2 h. Subsequent removal of the
excess solvent and SOCl2 yielded the proline ester (15.9 g, quant.)
as a grey oil.30 The title compound 1 was prepared according to
the literature15 from 2-fluoro-1-nitro benzene (6.92 g, 5.18 mL,
49.0 mmol) and methyl (S)-pyrrolidine-2-carboxylate (7.55 g,
45.6 mmol) as bright yellow crystals (12.0 g, quant.) and was used
without further purification. Mp 71–73 °C; Rf (25% EtOA/n-pen-
Some unexpected observations, in particular those affecting the
preparation of NHC salts IIIa–c, were made:
(i) The diamide hydride reduction proceeded with additional
partial or full cleavage of the methyl or silyl ethers present.
(ii) The two nucleophilic functionalities of aminoalcohol 4a gave
rise to product mixtures and low yields of the bisamide
coupling products.
(iii) Depending on the reaction conditions of the final orthofor-
mate cyclization of bisamine precursors bearing free alcohol
groups, orthoformate derivative products may be formed. A
quantitative cleavage method to remove the orthoformate
group was developed successfully.
tane) 0.51; ½a 2D0
ꢂ
¼ ꢁ849 (c 0.21, MeOH); mmax (neat) 3000 (br),
3050 (br), 2869, 1744, 1511, 1379, 1208, 846 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 7.69 (1H, dd, J 8.2, 1.6 Hz, Harom.), 7.35 (1H,
ddd, J 8.7, 7.1, 1.6 Hz, Harom.), 6.81 (1H, dd, J 8.6, 1.1 Hz, Harom.),
6.77 (1H, ddd, J 7.1, 1.1 Hz, Harom.), 4.43–4.39 (1H, m, NCH), 3.68
(3H, s, OCH3), 3.52–3.49 (1H, m, NCHaHbCH2), 3.18–3.13 (1H, m,
NCHaHbCH2), 2.50–2.40 (1H, m, CHCHaHbCH2), 2.12–2.06 (2H, m,
CHCHaHbCH2, CH2CHaHbCH2), 1.89–1.98 (1H, m, CH2CHaHbCH2);
13C NMR (100 MHz, CDCl3) d 173.2 (CO), 141.3 (Carom.), 138.3
(Carom.), 133.0 (CHarom.), 126.6 (CHarom.), 117.2 (CHarom.), 116.6
(CHarom.), 61.8 (CH), 52.4 (OCH3), 51.2 (NCH2CH2), 30.9 (NCHCH2),
24.6 (NCH2CH2); HRMS (ESI): MH+, found 251.1030. C12H15N2O4
requires 251.1026.
A few preliminary results on the application of some of the new
NHCs in asymmetric reactions are also reported. All of the
un-optimized reactions afforded chiral induction, but mostly low
enantioselectivity was observed. We are currently investigating
the ability of the new chiral NHC compounds as ligands in different
asymmetric organometallic catalysis reactions and as organocata-
lysts in stereoselective reactions.

2000
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
4.2.2. (S)-(1-(2-Nitrophenyl)pyrrolidin-2-yl)methanol 212,28
The nitro derivative 1 (2.51 g, 10.0 mmol) was dissolved in dry
THF (50 mL) and cooled to 0 °C. LiBH4 (333 mg, 15.3 mmol) dis-
solved in THF (30 mL) was added slowly. After stirring overnight
at room temperature, ethanol (50 mL) was added carefully, and
the reaction mixture was stirred for an additional 6 h before a half
saturated solution of NH4Cl (120 mL) was added. The aqueous layer
was extracted with EtOAc (3 ꢃ 60 mL) and the combined organic
layers were dried over Na2SO4. The solvent was removed under
reduced pressure. Purification by flash chromatography (25%
EtOAc/n-pentane) provided product 2 (2.10 g, 94%) as bright red
m, CHCHaHbCH2), 2.01–1.85 (2H, m, CHCHaHbCH2 + CH2CHaHbCH2),
1.81–1.71 (m, 1H, CH2CHaHbCH2), 0.83 (9H, s, C(CH3)3), ꢁ0.06 (3H,
s, Si(CH3)2), ꢁ0.10 (3H, s, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d
142.5 (Carom.), 138.2 (Carom.), 132.7 (CHarom.), 126.7 (CHarom.),
117.2 (CHarom.), 116.2 (CHarom.), 63.7 (CH2OSi), 59.9 (CH), 52.7
(NCH2CH2), 29.1 (CHCH2CH2), 25.8 (C(CH3)3), 24.7 (CH2CH2CH2),
18.1 (C(CH3)3), ꢁ5.7 (Si(CH3)2), ꢁ5.8 (Si(CH3)2); HRMS (ESI): MH+,
found 337.1939. C17H29N2O3Si requires 337.1942.
4.2.5. (S)-(1-(2-Aminophenyl)pyrrolidin-2-yl)methanol 4a
The nitro derivative 2 (502 mg, 2.26 mmol) and SnCl2 (2.35 g,
12.4 mmol) were dissolved in dry EtOH (20 mL) and heated at reflux.
After 3 h a solution of NaOH (50 mL, 5 M) was added. The aqueous
layer was extracted with DCM (3 ꢃ 100 mL), and the combined or-
ganic layers were washed with brine (200 mL) and dried (Na2SO4).
Removal of the solvents in vacuo and purification by flash chroma-
tography (50% EtOAc/n-pentane) provided 4a (337 mg, 78%) as a
colourless oil that turned black when stored at rt. Rf (25% EtOAc/n-
crystals. Mp 74–78 °C; Rf (25% EtOAc/n-pentane) 0.09; ½a D20
¼
ꢂ
ꢁ1950 (c 0.41, MeOH); mmax (neat) 3528 (br), 2869, 1601,
1495 cmꢁ1
H
H
;
1H NMR (400 MHz, CDCl3) d 7.76 (1H, dd, J 8.2, 1.6 Hz,
arom.), 7.38 (1H, ddd, J 8.6, 7.1, 1.6 Hz, Harom.), 7.11 (1H, d, J 8.4,
arom.), 6.81 (1H, ddd, J 8.2, 7.1, 1.1 Hz, Harom.), 4.16–4.09 (1H, m,
CH), 3.81 (1H, dd, J 11.5, 4.1 Hz, CHaHbOH), 3.56 (1H, dd, J 11.5,
2.2 Hz, CHaHbOH), 3.49 (1H, dt, J 10.3, 5.9 Hz, NCHaHbCH2), 2.72
(1H, m, NCHaHbCH2), 2.21–2.13 (1H, m, CHCHaHbCH2), 2.12–2.05
(1H, m, CHCHaHbCH2), 2.05–1.9 (1H, m, CH2CHaHbCH2), 1.88–1.83
(1H, m, OH), 1.82–1.72 (1H, m, CH2CHaHbCH2); 13C NMR
(100 MHz, CDCl3) d 142.2 (Carom.), 139.4 (Carom.), 133.1 (CHarom.),
126.7 (CHarom.), 117.5 (CHarom.), 117.2 (CHarom.), 61.7 (CH2OH),
59.7 (CH), 53.3 (NCH2CH2), 27.9 (CHCH2CH2), 25.2 (CH2CH2CH2);
HRMS (ESI): MH+, found 223.1083. C11H15N2O3 requires 223.1077.
pentane) 0.10; ½a D20
¼ þ6:4 (c 0.54, MeOH); mmax (neat) 3340 (br),
ꢂ
2947–2871 (br), 1607, 1497, 1279 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.13–7.08 (1H, m, Harom.), 6.98–6.92 (1H, m, Harom.), 6.80–6.71 (2H,
m, Harom.), 3.61 (2H, s, NH2), 3.51–3.36 (4H, m, CH + CH2OH + NCHa-
Hb), 2.90–2.80 (1H, m, NCHaHbCH2), 2.11–2.04 (1H, m,
CHCHaHbCH2), 1.96–1.79 (3H, m, CHCHaHbCH2 + CH2CH2CH2); 13C
NMR (100 MHz, CDCl3) d 143.3 (Carom.), 136.7 (Carom.), 125.2
(CHarom.), 122.3 (CHarom.), 119.2 (CHarom.), 115.7 (CHarom.), 64.2
(CH2OH), 63.5 (CH), 54.4 (NCH2CH2), 27.7 (CHCH2CH2), 24.0
(CH2CH2CH2); HRMS (ESI): MH+, found 193.1333. C11H17N2O,
requires 193.1335.
4.2.3. (S)-2-(Methoxymethyl)-1-(2-nitrophenyl)-pyrrolidine 3b
The nitro derivative 2 (1.00 g, 4.50 mmol) in THF (100 mL) was
added to NaH (130 mg, 5.42 mmol) suspended in THF (60 mL) at
0 °C and stirred for 20 min. Next, MeI (764 mg, 335 lL, 5.40 mmol)
was added and the solution was allowed to warm to rt over 4 h.
After the addition of a saturated NH4Cl solution (100 mL) the aque-
ous layer was extracted with EtOAc (3 ꢃ 150 mL). The combined
organic layers were washed with brine (200 mL), dried (Na2SO4)
and evaporated to dryness. The crude product was purified by flash
chromatography (25% EtOAc/n-pentane) yielding product 3b
(802 mg, 75%) as a yellow oil. Rf (25% EtOAc/n-pentane) 0.43;
4.2.6. (S)-2-(2-(Methoxymethyl)pyrrolidin-1-yl)aniline 4b
The title compound 4b was prepared from 3b (780 mg,
3.30 mmol) and SnCl2 (3.30 g, 17.4 mmol) in dry EtOH (30 mL) as
described above for 4a. Purification by flash chromatography
(20% EtOAc/n-pentane) yielded 4b (570 mg, 83%) as a grey solid.
Mp 29–30 °C; Rf (25% EtOAc/n-pentane) 0.35; ½a D20
¼ þ0:2 (c 0.91,
ꢂ
MeOH); mmax (neat) 3371, 3274 (br), 2872, 2805, 1611, 1497,
½
a 2D0
ꢂ
¼ ꢁ1790 (c 1.0, MeOH); mmax (neat) 2873 (br), 1602, 1507,
;
1101, 749 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.12–7.08 (1H, m,
1170, 1093 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.76 (1H, dd, J 8.2,
;
Harom.), 6.95–6.89 (1H, m, Harom.), 6.75–6.69 (2H, m, Harom.), 4.05
1.7 Hz, Harom.), 7.37 (1H, ddd, J 8.6, 7.0, 1.7 Hz, Harom.), 7.09 (1H,
dd, J 8.7, 1.0, Harom.), 6.75 (1H, ddd, J 8.2, 7.1, 1.2 Hz, Harom.), 4.06
(1H, ddd, J 14.6, 7.2, 3.8 Hz, CH), 3.57 (1H, dd, J 9.7, 3.8 Hz, CHa-
HbOCH3), 3.48 (1H, dt, J 10.1, 6.0 Hz, NCHaHbCH2), 3.31 (3H, s,
OCH3), 3.27 (1H, dd, J 9.7, 6.9 Hz, CHaHbOCH3), 2.77–2.71 (1H, m,
NCHaHbCH2), 2.33–2.26 (1H, m, CHCHaHbCH2), 2.02–1.93 (1H, m,
CH2CHaHbCH2), 1.91–1.80 (1H, m, CHCHaHbCH2), 1.79–1.69 (1H,
m, CH2CHaHbCH2); 13C NMR (100 MHz, CDCl3) d 142.4 (Carom.),
138.4 (Carom.), 132.8 (CHarom), 126.6 (CHarom.), 116.8 (CHarom.),
116.4 (CHarom.), 74.0 (CH2OCH3), 59.2 (OCH3), 58.2 (CH), 52.5
(NCH2CH2), 29.9 (CHCH2CH2), 24.8 (CH2CH2CH2); HRMS (ESI):
MH+, found 237.1226. C12H17N2O3 requires 237.1234.
(2H, s, NH2), 3.55 (1H, ddd, J 14.0, 7.1, 4.0 Hz, CH), 3.41 (1H, ddd,
J 9.4, 6.8, 5.0 Hz, NCHaHbCH2), 3.31 (1H, dd, J 9.3, 4.0 Hz, CHa-
HbOCH3), 3.27 (3H, s, OCH3), 3.14 (1H, dd, J 9.2, 7.1 Hz, CHa-
HbOCH3), 2.76 (1H, dt, J 9.4, 7.5 Hz, NCHaHbCH2), 2.20–2.09 (1H,
m, CHCHaHbCH2), 1.95–1.86 (2H, m, CH2CH2CH2), 1.85–1.75 (1H,
m, CHCHaHbCH2); 13C NMR (100 MHz, CDCl3) d 143.7 (Carom.),
136.7 (Carom.), 124.7 (CHarom.), 121.7 (CHarom.), 118.4 (CHarom.),
115.2 (CHarom.), 75.1 (CH2OCH3), 61.3 (CH), 59.0 (OCH3), 53.6
(NCH2CH2), 28.8 (CHCH2CH2), 23.9 (CH2CH2CH2); HRMS (ESI):
MH+, found 207.1491. C12H19N2O requires 207.1492.
4.2.7. (S)-2-(2-((tert-Butyldimethylsilyloxy)methyl)pyrrolidin-
1-yl)aniline 4c
4.2.4. (S)-2-((tert-Butyldimethylsilyloxy)methyl)-1-(2-
nitrophenyl) pyrrolidine 3c
The nitro derivative 3c (156 mg, 0.464 mmol) was dissolved in
EtOAc (10 mL) and Pd/C (50 mg 10%w/w Pd, 0.05 mmol, 10 mol %)
was added. The reaction mixture was placed under an H2 atmo-
sphere (5 atm) for 4 h. The catalyst was removed by filtration, and
the solvent was removed in vacuo. Purification by flash chromatog-
raphy (25% EtOAc/n-pentane) yielded the title compound 4c
(120 mg, 84%) as a slightly purple oil. Rf (25% EtOAc/n-pentane)
The nitro alcohol 2 (106 mg, 0.477 mmol), imidazole (68 mg,
1.00 mmol) and TBDMSCl (81 mg, 0.54 mmol) were dissolved in
THF (1 mL). After stirring for 2 h at room temperature, n-pentane
(2 mL) was added and the solution was purified by flash chroma-
tography (1% EtOAc/n-pentane) yielding 3c (156 mg, 97%) as a yel-
low oil. Rf (25% EtOAc/n-pentane) 0.82; ½a D20
ꢂ
¼ ꢁ1272 (c 1.1,
0.91; ½a 2D0
ꢂ
¼ þ1:2 (c 1.0, MeOH); mmax (neat) 2953, 2855, 1608,
MeOH); mmax (neat) 2927 (br), 2856 (br), 1603, 1511, 1109,
1251, 1088, 834 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.12–7.09 (1H,
;
1093 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.76 (1H, J 8.2, 1.6 Hz,
arom.), 7.35 (1H, ddd, J 8.7, 7.0, 1.7 Hz, Harom.), 7.11–7.06 (1H, m,
arom.), 6.73 (1H, J 8.2, 7.1, 1.1 Hz, Harom.), 4.04–3.97 (1H, m, CH),
m, Harom.), 6.92–6.90 (1H, m, Harom.), 6.75–6.72 (2H, m, Harom.), 4.03
(2H, s, NH2), 3.54–3.49 (2H, m, CH, CHaHbOSi,), 3.48–3.42 (1H, m,
NCHaHbCH2), 3.38–3.32 (1H, m, CHaHbOSi), 2.78 (1H, dt, J 9.3,
7.3 Hz, NCHaHbCH2), 2.18–2.05 (1H, m, CHCHaHbCH2), 1.96–1.77
(3H, m, CHCHaHbCH2 + CH2CH2CH2), 0.88 (9H, s, C(CH3)3), ꢁ0.01
H
H
3.66 (1H, dd, J 10.4, 3.6 Hz, CHaHbOSi), 3.53–3.45 (2H, m, CHaHb-
OSi + NCHaHbCH2), 2.86–2.79 (1H, m, NCHaHbCH2), 2.27–2.19 (1H,

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
2001
(3H, s, Si(CH3)2), ꢁ0.02 (3H, s, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d
143.4 (Carom.), 136.8 (Carom.), 124.4 (CHarom.), 121.7 (CHarom.), 118.4
(CHarom.), 115.1 (CHarom.), 65.2 (CH2OSi), 62.9 (CH), 53.7 (NCH2CH2),
28.4 (CHCH2CH2), 25.9 (C(CH3)3), 23.9 (CH2CH2CH2), 18.2 (C(CH3)3),
ꢁ5.4 (Si(CH3)2), ꢁ5.5 (Si(CH3)2); HRMS (ESI): MH+, found 308.2207.
NCH2CH2N + CH2OH + CH + NCHaHbCH2)
2.84–2.77
(2H,
m,
NCHaHbCH2), 2.04–1.94 (2H, m, CHCHaHbCH), 1.90–1.79 (6H,
m, CH2CH2CH2 + CHCHaHbCH2); 13C NMR (100 MHz, CDCl3)
145.1 (2 ꢃ Carom.), 136.8 (2 ꢃ Carom.), 125.5 (2 ꢃ CHarom.), 121.9
d
(2 ꢃ CHarom.), 117.6 (2
x
CHarom.), 110.7 (2 ꢃ CHarom.),
C
17H31N2OSi requires 308.2200.
64.4 (2 ꢃ CH), 62.9 (2 ꢃ CH2OH), 54.5 (2 ꢃ NCH2CH2), 43.6
(2 ꢃ NCH2CH2N), 26.8 (2 ꢃ CHCH2CH2), 23.9 (2 ꢃ CH2CH2CH2);
HRMS (ESI): MH+, found 411.2754. C24H35N4O4 requires 411.2755.
4.2.8. N1,N2-Bis(2-((S)-2-(methanol) pyrrolidin-1-yl)phenyl)
oxalamide 5a
Oxalyl chloride (31.5
dropwise to an ice cold suspension of compound 4a (141 mg,
0.734 mmol) and NEt3 (105 L 0.757 mmol) in THF (1.5 mL). The
l
L, 46.6 mg, 0.367 mmol) was added
4.2.11. N1,N2-Bis(2-(S)-2-(methoxymethyl) pyrrolidin-1-yl)
ethane-1,2-diamine 6b
The title compound 6b was prepared from bisamide 5b
(183 mg, 0.392 mmol), LiAlH4 (100 mg, 2.64 mmol) in THF
(15 mL) as described above for bisamine 6a, yielding 6b (149 mg,
l
reaction mixture was allowed to warm to room temperature over-
night before a satd Na2CO3-solution (30 mL) was added and the
aqueous layer was extracted with DCM (4 ꢃ 30 mL). The combined
organic layers were washed with brine (80 mL), dried (Na2SO4) and
evaporated to dryness. Purification by flash chromatography (2%
iPrOH/toluene) afforded 5a (45 mg, 28%) as pale green crystals.
87%) as
¼ þ21 (c 0.64, MeOH); mmax (neat) 2871 (br), 1595, 1505,
1263, 1109 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.15–7.11 (2H, m,
arom.), 7.07–7.01 (2H, m, Harom.), 6.72– 6.66 (4H, m, Harom.), 5.15
a light orange oil. Rf (25% EtOAc/n-pentane) 0.68;
½ ꢂ
a 2D0
;
H
Mp 103–104 °C; Rf (2% iPrOH/toluene) 0.17; ½a D20
ꢂ
¼ þ51 (c 0.38,
(2H, s, NH), 3.56–3.48 (2H, m, CH), 3.45 (4H, s, NCH2CH2N), 3.45–
3.38 (2H, m, NCHaHbCH2), 3.30–3.26 (2H, m, CHaHbOCH3), 3.25
(6H, s, OCH3), 3.11–3.05 (2H, m, CHaHbOCH3), 2.80–2.71 (2H, m,
NCHaHbCH2), 2.20–2.10 (2H, m, CHCHaHbCH2), 1.94–1.85 (4H, m,
CH2CH2CH2), 1.84–1.75 (2H, m, CHCHaHbCH2); 13C NMR
(100 MHz, CDCl3) d 145.4 (2 ꢃ Carom.), 136.3 (2 ꢃ Carom.), 125.2
(2 ꢃ CHarom.), 121.5 (2 ꢃ CHarom.), 116.6 (2 ꢃ CHarom.), 109.9
(2 ꢃ CHarom.), 75.0 (2 ꢃ CH2OCH3), 61.6 (2 ꢃ CH), 59.0 (2 ꢃ OCH3),
53.8 (2 ꢃ NCH2CH2), 43.5 (NCH2CH2N), 28.7 (2 ꢃ CHCH2CH2), 23.8
(2 ꢃ CH2CH2CH2); HRMS (ESI): MNa+, found 461.2896.
MeOH); mmax (neat) 3526, 3393, 2868, 1669, 1584, 1510, 1445,
761 cmꢁ1 1H NMR (400 MHz, CDCl3) d 10.50 (2H, s, NH), 8.15–
;
8.11 (2H, m, Harom.), 7.21–7.16 (2H, m, Harom.), 7.10–7.00 (4H, m,
Harom.), 3.54–3.45 (4H, m, CH + CHaHbOH), 3.44–3.37 (2H, m, CHa-
HbOH), 3.34–3.27 (2H, m, NCHaHbCH2), 2.85–2.75 (2H, m,
NCHaHbCH2), 2.44 (2H, s, OH), 2.11–1.80 (8H, m, CHCH2CH2); 13C
NMR (100 MHz, CDCl3) d 157.5 (2 ꢃ CO), 141.1 (2 ꢃ Carom.), 132.8
(2 ꢃ Carom.), 125.8 (2 ꢃ CHarom.), 124.8 (2 ꢃ CHarom.), 122.2
(2 ꢃ CHarom.), 120.3 (2 ꢃ CHarom.), 64.4 (2 ꢃ CH), 63.3 (2 ꢃ CH2OH),
55.9 (2 ꢃ NCH2CH2), 27.7 (2 ꢃ CHCH2CH2), 24.7 (2 ꢃ CH2CH2CH2);
HRMS (ESI): MH+, found 439.2358. C24H31N4O4 requires 439.2340.
C26H38N4NaO2 requires 461.2887.
4.2.12. 2-(3,5-Dimethylphenylamino)-2-oxoacetic acid 8a
The ester was prepared11 from ethyl chlorooxoacetate (2.22 g,
1.82 mL, 16.3 mmol), 3,5-dimethyl aniline (1.64 g, 1.69 mL,
13.5 mmol) and pyridine (1.29 g, 1.31 mL, 16.3 mmol). The reac-
tion mixture was allowed to warm to room temperature over
1.5 h and an aqueous work up afforded the ester in quantitative
yield. The ester (1.04 g, 4.70 mmol) was used in the next step with-
out purification. Hydrolysis of the ester was performed in accor-
dance with the literature.17 Stirring the ester in THF (25 mL) and
NaOH (30 mL, 1 M) and subsequent acidic work up yielded the acid
8a (855 mg, 94%) as a white solid. Mp 170 °C (dec.); Rf (25% EtOAc/
4.2.9. N1,N2-Bis(2-((S)-2-(methoxymethyl)pyrrolidin-1-
yl)phenyl)oxalamide 5b
The title compound 5b was prepared from 4b (1.00 g,
4.85 mmol), K2CO3 (1.67 g, 12.08 mmol, 2.5 equiv), and oxalyl chlo-
ride (310 mg, 210 lL, 2.45 mmol) in THF (12 mL) as described
above for 5a. Purification by flash chromatography (25% EtOAc/n-
pentane) yielded 5b (913 mg, 81%) as pale green crystals. Mp
109–110 °C; Rf (25% EtOAc/n-pentane) 0.51; ½a D20
¼ þ63 (c 1.0,
ꢂ
MeOH); mmax (neat) 3277, 2872, 1669, 1587, 1440, 1119,
761 cmꢁ1 1H NMR (400 MHz, CDCl3) d 10.60 (2H, s, NH), 8.45–
;
n-pentane) 0.01; mmax (neat) 3311, 3197, 1754, 1683, 1360 cmꢁ1
;
8.40 (2H, m, Harom.), 7.33–7.28 (2H, m, Harom.), 7.20–7.12 (4H, m,
Harom.), 3.62–3.55 (2H, m, CH), 3.44–3.38 (2H, m, NCHaHbCH2),
3.35–3.29 (2H, m, CHaHbOCH3), 3.25–3.20 (8H m, CHaHbO-
CH3 + OCH3), 2.88–2.81 (2H, m, NCHaHbCH2), 2.26–2.17 (2H, m,
CHCHaHbCH2), 2.11–2.03 (2H, m, CH2CHaHbCH2), 1.99–1.86 (4H,
m, CH2CHaHbCH2 + CHCHaHbCH2); 13C NMR (100 MHz, CDCl3) d
157.7 (2 ꢃ CO), 140.7 (2 ꢃ Carom.), 133.9 (2 ꢃ Carom.), 125.3
(2 ꢃ CHarom.), 125.1 (2 ꢃ CHarom.), 122.6 (2 ꢃ CHarom.), 119.5
(2 ꢃ CHarom.), 75.4 (2 ꢃ CH2OCH3), 62.4 (2 ꢃ CH), 59.0 (2 ꢃ OCH3),
55.6 (2 ꢃ NCH2CH2), 29.2 (2 ꢃ CHCH2CH2), 24.3 (2 ꢃ CH2CH2CH2);
HRMS (ESI): MH+, found 467.2666. C26H35N4O4 requires 467.2653.
1H NMR (400 MHz, DMSO-d6) d 14.01 (1H, s, COOH), 10.49 (1H, s,
NH), 7.38 (2H, s, Harom.), 6.78 (1H, s, Harom.), 2.24 (6H, s, ArCH3);
13C NMR (100 MHz, DMSO-d6) d 162.7 (COOH), 157.2 (CO), 138.1
(2 ꢃ Carom.), 137.9 (Carom.), 126.5 (CHarom.), 118.5 (2 ꢃ CHarom.),
21.5 (2 ꢃ ArCH3); HRMS (ESI): (MꢁH)ꢁ, found 192.0669.
C10H10NO3 requires 192.0666.
4.2.13. 2-(2,4,6-Trimethylphenylamino)-2-oxoacetic acid 8b17,31
The title compound 8b was prepared in two steps as described
above for 8a. The ester was prepared from ethyl chlorooxoacetate
(1.22 g, 1.00 mL, 8.95 mmol), 2,4,6-trimethylaniline (963 mg,
1.00 mL, 7.12 mmol) and pyridine (707 mg, 0.72 mL, 8.94 mmol).
The reaction mixture was allowed to warm to room temperature
over 2 h and an aqueous work up afforded the ester in quantita-
tive yield. The ester (1.76 mg, 7.46 mmol) was used in the next
hydrolysis step without any purification yielding the acid 8b
(1.41 g, 91%) as a white solid. 1H NMR (400 MHz, CDCl3) d 8.45
(1H, s, NH), 6.94 (2H, s, Harom.), 2.30 (3H, s, p-ArCH3), 2.20 (6H,
s, o-ArCH3).
4.2.10. N1,N2-Bis(2-(S)-2-(hydroxymethyl) pyrrolidin-1-yl)
ethane-1,2-diamine 6a
At first, LiAlH4 (62 mg, 1.63 mmol) suspended in THF (1.5 mL)
was added carefully to an ice cold solution of bisamide 5a
(130 mg, 0.296 mmol) dissolved in THF (4 mL) and the reaction
mixture was refluxed overnight. The remaining LiAlH4 was
quenched by the addition of a NaOH solution (20 mL, 5 M) and
the aqueous layers extracted with DCM (3 ꢃ 40 mL). The combined
organic layers were dried (Na2SO4), and the solvent was removed
under reduced pressure yielding the bisamine 6a (117 mg, 96%)
4.2.14. Ethyl (2,6-diisopropylanilin)-2-oxoacetate 8c17
The title compound 8c was prepared from 2,6-diisopropylani-
line (10.3 g, 11.0 mL, 52.4 mmol, 90%) and ethyl chlorooxoacetate
7c (8.67 g, 7.10 mL, 63.5 mmol) according to the literature.11 The
as a colourless oil. ½a D20
ꢂ
¼ þ9 (c 0.17, MeOH); mmax (neat) 3345
(br), 1594, 1503 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.11–7.02
(4H, m, Harom.), 6.75–6.70 (4H, m, Harom.), 3.50–3.30 (12H, m,

2002
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
crude product was purified by Versa flash chromatography (11%
EtOAc/n-pentane) to provide 8c (14.2 g, 98%) as a white solid. Rf
(11% EtOAc/n-pentane) 0.18. 1H NMR (400 MHz, CDCl3) d 8.36
(1H, s, NH), 7.37–7.31 (1H, m, Harom.), 7.22–7.19 (2H m, Harom.),
4.45 (2H, q, J 7.1 Hz, OCH2CH3), 3.01 (2H, J 6.8 Hz, 2 ꢃ CH(CH3)2),
1.46 (3H, J 7.1 Hz, OCH2CH3), 1.21 (12H, J 6.8, 2 ꢃ CH(CH3)2).
with DCM (3 ꢃ 20 mL). After drying (Na2SO4) the solvent was re-
moved in vacuo and the crude product was purified by flash chro-
matography (20% EtOAc/n-pentane) affording 10b (72 mg, 74%) as
a pale orange oil. Rf (25% EtOAc/n-pentane) 0.6; ½a D20
¼ þ20 (c 0.64,
ꢂ
MeOH); mmax (neat) 3372 (br), 2871 (br), 1596, 1506, 1263 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.10–7.07 (1H, m, Harom.), 7.02–6.98
(1H, m, Harom.), 6.68–6.63 (2H, m, Harom.), 6.36 (1H, s, Harom.),
6.26 (2H, s, Harom.), 3.50–3.44 (1H, m, CH), 3.38–3.28 (5H, m,
HNCH2CH2NH + NCHaHbCH2), 3.24 (1H, dd, J 9.4, 4.6 Hz, CHaH-
bOCH3), 3.22 (3H, s, OCH3) 3.10 (1H, dd, J 9.3, 6.5 Hz, CHaHbOCH3),
2.76 (1H, dt, J 9.5, 7.6 Hz, NCHaHbCH2), 2.22 (6H, s, ArCH3), 2.14–
2.04 (1H, m, CHCHaHbCH2), 1.91–1.83 (2H, m, CH2CH2CH2) 1.78–
1.70 (1H, m, CHCHaHbCH2); 13C NMR (100 MHz, CDCl3) d 148.2
(Carom.), 145.2 (Carom.), 138.7 (2 ꢃ Carom.), 136.6 (Carom.), 125.2
(CHarom.), 121.7 (CHarom.), 119.3 (CHarom.), 116.8 (CHarom.), 110.8
(2 ꢃ CHarom.), 110.2 (CHarom.), 74.9 (CH2OCH3), 62.0 (CH), 58.8
(OCH3), 53.8 (NCH2CH2), 43.1 (NCH2CH2N), 43.0 (NCH2CH2N),
28.4 (CHCH2CH2), 23.8 (CH2CH2CH2), 21.6 (ArCH3); HRMS (ESI):
MH+, found 354.2550. C22H32N3O (M+H+) requires 354.2540.
4.2.15. (S)-N1-(2-(2-((tert-Butyldimethylsilyloxy)methyl)
pyrrolidin-1-yl)phenyl)-N2-(3,5-dimethylphenyl)oxalamide 9c
At first, DCC (130 mg, 0.630 mmol) dissolved in DCM (1 mL) was
added on ice cooling to a suspension of 8a (100 mg, 0.517 mmol) and
HOBt (160 mg, 1.18 mmol) in THF (2 mL) containing molecular
sieves (4 Å). After stirring for 1 h at 0 °C, the chiral aniline derivative
4c (154 mg, 0.502 mmol) was added and the reaction mixture was
allowed to warm to room temperature overnight. The solvent was
removed under reduced pressure, and the solid residue was sus-
pended in EtOAc and filtered. The filtrate was washed with an aque-
ous citric acid solution (25 mL, 10% w/w), NaHCO3 (25 mL, 5% w/w)
and brine (25 mL). The organic layers were dried (Na2SO4), and evap-
orated to dryness. Purification by flash chromatography (0.5% Et2O/
toluene) yielded bisamide 9c (111 mg, 46%) as pale green crystals.
4.2.18. (S)-N1-(2-(2-((tert-Butyldimethylsilyloxy)methyl)
pyrrolidin-1-yl)phenyl)-N2-mesityloxalamide 11
Mp 192 °C; Rf (10% Et2O/n-pentane) 0.41; ½a D20
¼ þ53 (c 0.59,
ꢂ
MeOH); mmax (neat) 3358, 2927, 2854, 1684, 1519, 1456,
1081 cmꢁ1 1H NMR (400 MHz, CDCl3) d 10.45 (1H, s, NH), 9.29
;
The title compound 11 was prepared from DCC (438 mg,
2.12 mmol), 8b (359 mg, 1.73 mmol), HOBt (539 mg, 3.99 mmol)
and 4c (587 mg, 1.92 mmol) as described above for 9c. Purification
by flash chromatography (0.5% Et2O/toluene) yielded the bisamide
11 (622 mg, 72%) as pale green crystals. Mp 99–101 °C;
(1H, s, NH), 8.37–8.32 (1H, m, Harom.), 7.33–7.25 (3H, m, Harom.),
7.17–7.12 (2H, m, Harom.), 6.84 (1H, s, Harom.), 3.63–3.57 (1H, m,
CH), 3.55–3.50 (1H, m, CHaHbOSi), 3.48–3.41 (2H, m, CHaHbO-
Si + NCHaHbCH2), 2.85–2.79 (1H, m, NCHaHbCH2), 2.34 (6H, s,
ArCH3), 2.23–2.14 (1H, m, CHCHaHbCH2), 2.10–1.99 (1H, m,
CH2CHaHbCH2), 1.98–1.80 (2H, m, CH2CHaHbCH2 + CHCHaHbCH2),
0.79 (9H, s, C(CH3)3), ꢁ0.09 (3H, s, Si(CH3)2), ꢁ0.10 (3H, s, Si(CH3)2);
13C NMR (100 MHz, CDCl3) d 157.7 (CO), 157.4 (CO), 141.0 (Carom.),
139.0 (2 ꢃ Carom.), 136.3 (Carom.), 133.0 (Carom.), 127.1
(CHarom.), 125.3 (CHarom.), 124.5 (CHarom.), 122.0 (CHarom.), 119.5
(CHarom.), 117.5 (2 ꢃ CHarom.), 65.9 (CH2OSi), 63.9 (CH), 55.7
(NCH2CH2), 28.8 (CHCH2CH2), 25.8 (C(CH3)3), 24.1 (CH2CH2CH2),
21,3 (ArCH3), 18.1 (C(CH3)3), ꢁ5.5 (Si(CH3)2), ꢁ5.6 (Si(CH3)2); HRMS
(ESI): MH+, found 482.2844. C27H40N3O3Si requires 482.2833.
½
a 2D0
ꢂ
¼ þ54:7 (c 1.0, MeOH); mmax (neat) 3298, 3226, 2940, 2850
(br), 1659, 1510, 1451, 1102, 835,747 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 10.52 (1H, s, NH), 8.85 (1H, s, NH), 8.39–8.34 (1H, m, Har-
om.), 7.30–7.27 (1H, m, Harom.), 7.18–7.12 (2H, m, Harom.), 6.93 (2H,
s, Harom.), 3.60–3.52 (1H, m, CH), 3.50 (1H, dd, J 9.8, 4.9 Hz, CHaH-
bOSi), 3.42 (1H, dd, J 9.8, 6.3 Hz, CHaHbOSi), 3.43–3.38 (1H, m,
NCHaHb), 2.81 (1H, dd, J 9.0, 7.3 Hz, NCHaHb), 2.28 (3H, s, p-ArCH3),
2.22 (6H, s, o-ArCH3), 2.19–2.09 (1H, m, CHCHaHbCH2), 2.02–1.94
(1H, m, NCH2CHaHb), 1.94–1.84 (1H, m, NCH2CHaHb), 1.84–1.74
(m, 1H, CHCHaHbCH2), 0.76 (9H, s, C(CH3)3), ꢁ0.11 (s, 6H, Si(CH3)2),
-0.12 (6H, s, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d 158.7 (CO),
157.2 (CO), 140.9 (Carom.), 137.5 (Carom.), 134.7 (2 ꢃ Carom.), 133.3
(Carom.), 129,9 (Carom.), 129,1 (2 ꢃ CHarom.), 125.3 (CHarom.), 124.7
(CHarom.), 122.3 (CHarom.), 119.3 (CHarom.), 66.0 (CH2OSi), 63.7
(CH), 55.7 (NCH2), 28.7 (CHCH2CH2), 25.8 (C(CH3)3), 24.1
(NCH2CH2), 20.9 (p-ArCH3), 18.4 (o-ArCH3), 18.1 (C(CH3)3), -5.5
(Si(CH3)2), -5.6 (Si(CH3)2); HRMS (EI): M+, found 495.2914.
C28H41N3O3Si requires 495.2912.
4.2.16. (S)-(1-(2-(2-(3,5-Dimethylphenylamino) ethylamino)
phenyl)pyrrolidin-2-yl) methanol 10a
The title compound 10a was prepared from bisamide 9c (150 mg,
0.311 mmol) and LiAlH4 (82 mg, 2.2 mmol) in THF (6 mL) as described
above for 6b. Purification by flash chromatography (2% iPrOH/toluene)
yielded 10a (93 mg, 88%) as a slightly orange oil. Rf (2% iPrOH/toluene)
0.16; ½a 2D0
ꢂ
¼ þ10 (c 1.2, MeOH);
mmax (neat) 3353 (br), 2917 (br), 1597,
1506, 1264 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.20–7.15 (1H, m,
H
arom.), 7.14–7.09 (1H, m, Harom.), 6.81–6.73 (2H, m, Harom.), 6.46
4.2.19. (S)-(1-(2-(2-(Mesitylamino)ethylamino)phenyl)
pyrrolidin-2-yl)methanol 12a
(1H, s, Harom.), 6.37 (2H, s, Harom.), 3.50–3.39 (7H, m, CH + NCH2
CH2N + CH2OH), 3.39–3.32 (1H, m, NCHaHbCH2), 2.91–2.83 (1H, m,
NCHaHbCH2), 2.31 (6H, s, ArCH3), 2.14–2.04 (1H, m, CHCHaHbCH2),
1.99–1.82 (3H, m, CH2CH2CH2 + CHCHaHbCH2); 13C NMR (100 MHz,
CDCl3) d 148.1 (Carom.), 145.0 (Carom.), 138.8 (2 ꢃ Carom.), 136.5 (Carom.),
125.6 (CHarom.), 122.3 (CHarom.), 119.6 (CHarom.), 117.4 (CHarom.), 110.9
(2 ꢃ CHarom.), 110.6 (CHarom.), 64.6 (CH2OH), 63.3 (CH), 54.6
(NCH2CH2), 43.1 (NCH2CH2N) 42.9 (NCH2CH2N), 27.3 (CHCH2CH2),
23.9 (CH2CH2CH2), 21.4 (ArCH3); HRMS (ESI): MH+, found 340.2375.
C21H30N3O requires 340.2383.
The title compound 12a was prepared from bisamide 11
(591 mg, 1.19 mmol) and LiAlH4 (337 mg, 8.89 mmol) in THF
(16 mL) as described above for 6a. No purification was required
to provide the desired diamine 12a (386 mg, 91%) as an orange
oil. ½a 2D0
ꢂ
¼ þ19:2 (c 1.0, MeOH); mmax (neat) 3354 (br), 2950–
2800 (br), 1506, 1037, 740 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d
7.13 (1H, dd, J 7.8, 1.4 Hz, Harom.), 7.05 (1H, dt, J 7.5, 1.5 Hz, Harom.),
6.82 (2H, s, Harom.), 6.71 (1H, dt, J 7.6. 1.4 Hz, Harom.), 6.68 (1H, dd, J
8.0, 1.4 Hz,
Harom.), 5.37 (1H, br, NH), 3.47–3.27 (6H, m,
4.2.17. (S)-N1-(3,5-Dimethylphenyl)-N2-(2-(2-(methoxymethyl)
pyrrolidin-1-yl)phenyl)ethane-1,2-diamine 10b
Diamine alcohol 10a (93 mg, 0.27 mmol) dissolved in THF
(1 mL) was added to a solution of tBuOK (42 mg, 0.37 mmol) in
CH + CH2OH + NCHaHb + ArNHCH2), 3.22–3.16 (2H, m, MesNHCH2),
2.82 (1H, dt, J 9.3, 7.6 Hz, NCHaHbCH2), 2.26 (6H, s, o-ArCH3), 2.22
(3H, s, p-ArCH3), 2.10–1.98 (1H, m, CHCHaHbCH2), 1.94–1.84 (3H,
m, CHCHaHbCH2 + NCH2CH2); 13C NMR (100 MHz, CDCl3) d 145.6
(Carom.), 142.9 (Carom.), 136.4 (Carom.), 132.1 (Carom.), 130.4
(2 ꢃ Carom.), 129.5 (2 ꢃ CHarom.), 125.8 (CHarom.), 122.2 (CHarom.),
117.6 (CHarom.), 110.8 (CHarom.), 64.5 (CH), 63.3 (CH2OH), 54.8
(NCH2CH2), 47.8 (MesNHCH2), 44.7 (ArNHCH2), 27.1 (CHCH2CH2),
THF (1 mL) at 0 °C and stirred for 1 h. Next, MeI (46 mg, 20 lL,
0.32 mmol) was added and the reaction mixture was allowed to
warm to room temperature overnight. The reaction mixture was
poured into water (20 mL) and the aqueous layer was extracted

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
2003
24.0 (CH2CH2CH2), 20.6 (o-ArCH3), 18.1 (p-ArCH3). HRMS (EI): M+,
found 353.2469. C22H31N3O requires 353.2462.
NMR (400 MHz, CDCl3) d 9.82 (1H, s, NCHN), 7.40–7.36 (1H, m,
arom.), 7.33–7.28 (2H, m, Harom.), 7.24–7.19 (1H, m, Harom.),
6.99–6.94 (3H, m, arom.), 4.92 (1H, dt, 11.5, 8.3 Hz,
NCHaHbCH2N), 4.70 (1H, dt, J 11.7, 8.9 Hz, NCH2CHaHbN), 4.54
(1H, dt, 11.2, 8.6 Hz, NCH2CHaHbN), 4.38–4.29 (1H, m,
NCHaHbCH2N), 3.76–3.70 (1H, m, CH), 3.48 (1H, dd, 10.3,
H
H
J
4.2.20. (S)-N1-(2-(2-((tert-Butyldimethylsilyloxy)methyl)pyrroli
din-1-yl)phenyl)-N2-mesitylethane-1,2-diamine 12c
The title compound 12c was prepared from 12a (303 mg,
0.857 mmol), imidazole (133 mg, 1.95 mmol) and TBDMSCl
(145 mg, 0.962 mmol) as described above for 3c. Purification by
flash chromatography (3% EtOAc/n-pentane) yielded 12c (296 mg,
J
J
2.8 Hz, CHaHbOCH3), 3.33 (1H,dd, J 10.2, 2.6 Hz, CHaHbOCH3)
3.27–3.22 (4H, m, OCH3 + NCHaHbCH2), 2.83–2.78 (1H, m,
NCHaHbCH2), 2.36 (6H, s, ArCH3), 2.14–1.83 (4H, m, CHCH2CH2),
74%) as
¼ þ4:7 (c 1.0, MeOH); mmax (neat) 3300 (br), 2950–2820,
1507, 1251, 1090, 834, 738 cmꢁ1 1H NMR (400 MHz, CDCl3) d
a
brownish oil. Rf (25% EtOAc/n-pentane) 0,85;
13C NMR (100 MHz, CDCl3)
d 154.7 (NCHN), 141.7 (Carom.),
½
a 2D0
ꢂ
140.3 (2 ꢃ Carom.), 135.6 (Carom.), 131.9 (Carom.), 129.5
(CHarom.), 129.3 (CHarom.), 125.5 (CHarom.), 123.2 (CHarom.), 122.7
(CHarom.), 115.8 (2 ꢃ CHarom.), 71.5 (CH2OCH3), 60.0 (CH), 58.7
(OCH3), 55.0 (NCH2CH2), 50.0 (NCH2CH2N), 48.2 (NCH2CH2N),
27.2 (CHCH2CH2), 24.1 (NCH2CH2), 21.3 (2 ꢃ ArCH3); HRMS
(ESI): M+, found 364.2405. C23H30N3O requires 364.2383.
;
7.11 (1H, dd, J 7.8, 1.4, Harom.), 6.97 (1H, m, Harom.), 6.82 (2H, s,
Harom.), 6.67 (1H, dt, J 7.6, 1.4 Hz, Harom.), 6.64 (1H, dd, J 8.0,
1.3 Hz, Harom.), 5.10 (1H, br, NH), 3.56–3.32 (4H, m, CHaHbOSi +
CH + NCHaHb + ArNHCHaHb), 3.30–3.20 (2H, m, ArNHCHaHb +
CHaHbOSi), 3.19–3.11 (2H, m, MesNHCH2), 2.68 (1H, J 9.1, 7.4 Hz,
NCHaHb), 2.25 (6H, s, o-ArCH3), 2.23 (3H, s, p-ArCH3), 2.16–2.05
(1H, m, CHCHaHbCH2), 1.91–1.72 (3H, m, CHCHaHbCH2 + NCH2CH2),
0.83 (9H, s, C(CH3)3), ꢁ0.06 (3H, s, Si(CH3)2), ꢁ0.07 (3H, s,
Si(CH3)2); 13C NMR (100 MHz, CDCl3) d 145.3 (Carom.), 143.2
(Carom.), 136.6 (Carom.), 131.6 (2 ꢃ Carom.), 130.1 (Carom.), 129.4
(2 ꢃ CHarom.), 124.9 (CHarom.), 121.4 (CHarom.), 116.9 (CHarom.),
110.1 (CHarom.), 65.5 (CH2OSi), 62.9 (CH), 54.1 (NCH2), 48.1 (Mes-
NHCH2), 44.6 (ArNHCH2), 28.7 (CHCH2CH2), 25.9 (C(CH3)3), 23.8
(NCH2CH2), 20.6 (p-ArCH3), 18.3 (C(CH3)3), 18.2 (o-ArCH3), -5.4
(Si(CH3)2), -5.5 (Si(CH3)2); HRMS (EI): M+, found 467.3318.
4.2.23. (S)-1-(2-(2-((Dimethoxymethoxy)methyl)pyrrolidin-1-yl)
phenyl)-3-mesityl-4,5-dihydro-1H-imidazol-3-ium hexa fluoro
phosphate IIIb and (S)-1-(2-(2-((tert-butyldimethylsilyl oxy)meth
yl)pyrrolidin-1-yl)phenyl)-3-mesityl-4,5-dihydro-1H-imidazol-3-
ium hexafluorophosphate IIIc
The ring closing procedure was performed with diamine 12c
(106 mg, 0.230 mmol) as described above for Ib. Purification by
flash chromatography (0.5% acetone/DCM) afforded two pure
NHC precatalysts IIIb (16 mg, 11%) as
a pink oil and IIIc
(12 mg, 8%) as pink crystals. IIIb: Rf (10% acetone/DCM) 0.20;
1H NMR (400 MHz, CD3OD) d 9.10 (1H, s, NCHN), 7.47–7.43
(1H, m, Harom.), 7.43–7.35 (2H, m, Harom.), 7.20–7.12 (1H, m,
C28H45N3OSi requires 467.3326.
4.2.21. (S)-3-(3,5-Dimethylphenyl)-1-(2-(2-(methoxymethyl)
pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate Ib
Harom.), 7.09 (2H, s, Harom.), 5.01–4.90 (1H, m, NCHaHbCH2N),
4.77 (1H, s, CH(OCH3)2), 4.51–4.27 (3H, m, NCHaHbCH2N), 3.97–
3.91 (1H, m, CHaHbO), 3.59–3.52 (1H, m, NCHaHbCH2CH2),
3.50–3.43 (2H, m, CHCHaHbO + NCHaHbCH2CH2), 2.99 (3H, s,
OCH3), 2.94 (3H, s, OCH3), 2.52–2.43 (6H, m, o-ArCH3), 2.42
(3H, s, p-ArCH3), 2.33–2.23 (1H, m, CHCHaHbCH2), 2.02–1.82
(3H, m, CHCHaHbCH2).
The bisamine 6b (61 mg, 0.14 mmol) was dissolved in DCM
(2 mL) and a methanolic HCl solution (280 mL, 1 M) was added.
After 20 min, the solvents were removed in vacuo and HC(OCH3)3
(0.9 mL) was added. The reaction was heated to 110 °C for 5 h be-
fore the solvent was removed under reduced pressure. KPF6
(26 mg, 0.14 mmol) was added to the crude product dissolved in
DCM and stirred for another 20 min. The reaction mixture was
purified by flash chromatography (1% MeOH/DCM) yielding the
NHC precatalyst Ib (63 mg, 75%) as light brown crystals. Mp
IIIc: mp 174–175 °C; Rf (10% acetone/DCM) 0.22; ½a D20
¼ þ43 (c
ꢂ
0.65, MeOH); m ;
max (neat) 3000–2850, 1624, 1256, 1088, 834 cmꢁ1
1H NMR (400 MHz, CDCl3) d 8.84 (1H, s, NCHN), 7.44 (1H, dd, J 8.0,
1.6, Harom.), 7.35–7.30 (1H, m, Harom.), 7.27–7.23 (1H, m, Harom.),
7.21–7.16 (1H, m, Harom.), 6.97 (2H, s, Harom.), 5.05–4.97 (1H, m,
NCHaHbCH2N), 4.46–4.37 (3H, m, NCHaHbCH2N), 3.70–3.64 (1H,
m, NCHCH2), 3.55 (1H, dd, J 11.1, 3.1 Hz, CHaHbOSi), 3.47–3.41
(2H, m, CHaHbOSi + NCHaHbCH2), 2.88–2.81 (1H, m, NCHaHbCH2),
2.38–2.27 (9H, m, ArCH3), 2.09–1.99 (1H, m, CHCHaHbCH2), 1.98–
1.86 (2H, m, CH2CH2CH2), 1.84–1.73 (1H, m, CHCHaHbCH2), 0.60
(9H, s, C(CH3)3), ꢁ0.27 (3H, s, Si(CH3)2), ꢁ0.32 (3H, s, Si(CH3)2);
13C NMR (100 MHz, CDCl3) d 158.6 (NCHN), 143.9 (Carom.), 140.8
(2 ꢃ Carom.), 131.1 (Carom.), 130.4 (Carom.), 130.1 (2 ꢃ CHarom.),
130.0 (Carom.), 129.8 (CHarom.), 125.1 (CHarom.), 123.9 (CHarom.),
122.8 (CHarom.), 63.9 (CH2OSi), 62.1 (NCHCH2), 55.6 (NCH2CH2),
51.0 (NCH2CH2N), 50.7 (NCH2CH2N), 27.2 (NCH2CH2), 25.6
(C(CH3)3), 23.9 (CH2CH2CH2), 21.0 (p-ArCH3), 18.2 (C(CH3)3), 17.4
(o-ArCH3), -5.8 (Si(CH3)2), ꢁ6.1 (Si(CH3)2); HRMS (ESI): M+, found
478.3254. C29H44N3OSi requires 478.3248.
135–138 °C; Rf (1% MeOH/DCM) 0.48; ½a D20
ꢂ
¼ þ177 (c 0.24, MeOH);
mmax (neat) 2926 (br), 1289, 1260, 831 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) d 9.38 (1H, s, NCHN), 7.41–7.30 (4H, m, Harom), 7.26–7.22
(2H, m, Harom.), 7.15–7.09 (2H, m, Harom.), 4.97–4.83 (2H, m,
NCH2CH2N), 4.28–4.15 (2H, m, NCH2CH2N), 3.80–3.72 (2H, m,
CH), 3.40–3.25 (6H, m, CH2OCH3 + NCHaHbCH2), 3.16 (6H, s,
OCH3), 2.93–2.84 (2H, m, NCHaHbCH2), 2.18–2.09 (2H, m,
CHCHaHbCH2), 1.99–1.88 (6H, m, CH2CH2CH2 + CHCHaHbCH2);
13C NMR (100 MHz, CDCl3) d 158.3 (NCHN), 143.3 (2 ꢃ Carom.),
130.6 (2 ꢃ Carom.), 129.8 (2 ꢃ CHarom.), 125.1 (2 ꢃ CHarom.), 124.0
(2 ꢃ CHarom.), 121.6 (2 ꢃ CHarom.), 73.1 (2 ꢃ CH2OCH3), 60.1
(2 ꢃ CH), 58.9 (2 ꢃ OCH3), 49.9 (NCH2CH2N), 28.2 (2 ꢃ CHCH2CH2),
24.2 (2 ꢃ CH2CH2CH2); HRMS (ESI): M+, found 449.2910.
C27H37N4O2 requires 449.2911.
4.2.22. (S)-3-(3,5-Dimethylphenyl)-1-(2-(2-(methoxymethyl)
pyrrolidin-1-yl)phenyl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate IIb
4.2.24. (S)-1-(2-(2-(Hydroxymethyl)pyrrolidin-1-yl)phenyl)-3-
mesityl-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate
IIIa
The NHC precatalyst IIb was prepared from 10b (76 mg,
0.22 mmol) and HC(OMe)3 (2 mL) and subsequent counterion ex-
changed using KPF6 (40 mg, 0.22 mmol) as described above for
Ib. Purification by flash chromatography (10% MeOH/DCM) affor-
ded the title compound IIb (75 mg, 68%) as pale green crystals.
The NHC precatalyst IIIb (16 mg, 0.027 mmol) was dissolved in
CD3OD (1 mL) and DCl (0.26 mL, 0.1 M) was added. After stirring
for 40 min the solvents were evaporated in vacuo and the crude
was dissolved in DCM and filtered through a pad of silica (14% ace-
tone/DCM) yielding the title compound IIIa (14 mg, quant.) as pink
Mp 139.5–141.0 °C; Rf (10% MeOH/DCM) 0.2; ½a D20
ꢂ
¼ þ2 (c 0,
crystals. Mp 174–175 °C; Rf (10% acetone/DCM) 0.49; ½a D20
¼ þ30 (c
ꢂ
19, MeOH); mmax (neat) 2920 (br), 1298, 1294, 827 cmꢁ1
;
1H

2004
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
0.30, MeOH); mmax (neat) 3594 (br), 3000–2800, 1625, 1258,
833 cmꢁ1 1H NMR (400 MHz, acetone-d6) d 9.39 (1H, s, NCHN),
NMR (400 MHz, CDCl3) d 7.33–7.26 (2H, m, Harom.), 7.25–7.18 (3H,
m, Harom.), 7.11–7.02 (2H, m, Harom.), 3.65 (1H, dd, J 10.8, 4.0 Hz
CH2OH), 3.38 (1H, dd, J 10.8, 5.6 Hz CH2OH), 3.25 (2H, sept, J 6.8,
CH(CH3)2), 3.01–2.72 (7H, m, NHCHCH2 + NHCH2CH2NH + CH2Ph),
1.23 (12H, d, J 6.8, CH(CH3)2); 13C NMR (100 MHz, CDCl3) d 143.1
(Carom.), 142.4 (2 ꢃ Carom.), 138.5 (Carom.), 129.2 (2 ꢃ CHarom.), 128.6
(2 ꢃ CHarom.), 126.4 (CHarom.), 123.8 (CHarom.), 123.5 (2 ꢃ CHarom.),
63.0 (CH2OH), 60.4 (NHCHCH2), 51.9 (CH2NH), 47.4 (CH2NH), 38.2
(CH2Ph), 27.6 (CH(CH3)2), 24.3 (CH(CH3)2), 24.2 (CH(CH3)2); HRMS
(EI): M+, found 354.2667. C23H34N2O requires 354.2666.
;
7.53 (1H, dd, J 7.9, 1.4 Hz, Harom.), 7.46–7.38 (2H, m, Harom.),
7.21–7.15 (1H, m, Harom.), 7.10 (2H, s, Harom.), 5.18–5.07 (1H, m,
NCHaHbCH2N), 4.70–4.52 (3H, m, NCHaHbCH2N), 3.92 (1H, br s,
OH), 3.87–3.81 (1H, m, CHaHbOH), 3.68–3.61 (1H, m,
NCHaHbCH2CH2), 3.60–3.49 (2H, m, CHCHaHbOH), 3.04–2.97 (1H,
m, NCHaHbCH2CH2), 2.52–2.36 (6H, m, o-ArCH3), 2.32 (3H, s, p-
ArCH3), 2.17–2.11 (1H, m, CHCHaHbCH2), 2.00–1.89 (3H, m,
CHCHaHbCH2); 13C NMR (100 MHz, CDCl3) d 160.8 (NCHN), 145.4
(Carom.), 141.4 (Carom.), 136.5 (2 ꢃ Carom.), 132.1 (Carom.), 131.6
(Carom.), 130.7 (2 ꢃ CHarom.), 130.5 (CHarom.), 125.7 (CHarom.), 124.3
(CHarom.), 123.1 (CHarom.), 62.7 (CHCH2OH), 55.5 (NCH2CH2CH2),
52.0 (NCH2CH2N), 51.5 (NCH2CH2N), 28.5 (CHCH2CH2), 24.8
(CH2CH2CH2), 21.0 (p-ArCH3), 17.8 (o-ArCH3); HRMS (ESI): M+,
found 364.2386. C23H30N3O requires 364.2383.
4.3.4. (S)-3-(2,6-Diisopropylphenyl)-1-(1-hydroxy-3-phenylpro-
pan-2-yl)-4,5-dihydro-1H-imidazol-3-ium chloride IVa22
The title compound IVa was prepared from diamine 15 (1.52 g,
4.29 mmol), anhydrous HCl/methanol⁄ solution (2.02 M, 2.15 mL,
4.34 mmol), toluene (12.4 mL) and trimethyl orthoformate
(2.30 mL, 21.0 mmol) in accordance with the literature.11 The reac-
tion mixture was heated to 90 °C for 20 h. Removal of the solvent
by filtration and a subsequent ether wash gave the title compound
IVa (1.50 g, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) d 8.53
(1H, s, NCHN), 7.40–7.34 (3H, m, Harom.), 7.32–7.28 (3H, m, Harom.),
7.21 (1H, dd, J 7.8, 1.3 Hz, Harom.), 7.14 (1H, dd, J 7.8, 1.3 Hz, Harom.),
6.03 (1H, s, OH), 5.04–4.93 (1H, m, NCHCH2OH), 4.57–4.48 (1H, m,
CH2CHaHb N), 4.31–4.24 (1H, m, CHaHbCH2N), 4.14–4.06 (1H, m,
CH2CHaHb N), 4.00–3.88 (1H, m, CHaHbCH2N), 3.99 (1H, dd, J 12.3,
3.6 Hz, CHaHbOH), 3.83–3.75 (1H, m, CHaHbOH), 3.11 (1H, sept, J
6.8 Hz, CH(CH3)2), 3.03 (1H, dd, J 14.6, 4.3 Hz, CHaHbPh), 2.81 (1H,
dd, J 14.6, 11.2 Hz, CHaHbPh), 2.28 (1H, sept., J 6.8 Hz, CH(CH3)2),
1.26 (3H, d, J 6.8 Hz, CH(CH3)2), 1.25 (3H, d, J 6.8 Hz, CH(CH3)2),
4.3. Chiral NHC-salts based on L-phenylalanine
4.3.1. (S)-Phenylalaninol (13)32
The title compound 13 was prepared from (S)-phenylalanine
(10.0 g, 60.5 mmol) and LiAlH4 (4.59 g, 121 mmol) according to
the literature.33 The work-up was carried out by adding water
(50 mL) and NaOH (1 M, 30 mL), the precipitate was washed with
ether (80 mL) and the water phase was extracted with additional
ether (3 ꢃ 80 mL). The combined organic layers were dried
(MgSO4) and the solvents evaporated in vacuo to provide 13
(7.67 g, 84%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) d
7.34–7.29 (2H, m, Harom.), 7.28–7.18 (3H, m, Harom.), 3.64 (1H,
dd, J 10.6, 3.9 Hz, CHaCHbOH), 3.38 (1H, dd, J 10.6, 7.2 Hz,
CHaCHbOH), 3.17–3.09 (1H, m, CH), 2.80 (1H, dd, J 13.5, 5.2 Hz,
CHaCHbPh), 2.53 (1H, dd, J 13.5, 8.5 Hz, CHaCHbPh), 1.96–1.70
(3H, m, OH + NH2).
1.13 (3H, d, J 6.8 Hz, CH(CH3)2), 1.01 (3H, d, J 6.8 Hz, CH(CH3)2); 13
C
NMR (100 MHz, CDCl3) d 159.4 (NCHN), 147.2 (Carom.), 146.1
(Carom.), 136.0 (Carom.), 131.0 (CHarom.), 129.6 (Carom.), 129.0
(2 ꢃ CHarom.), 128.6 (2 ꢃ CHarom.), 127.2 (CHarom.), 125.0 (CHarom.),
124.5 (CHarom.), 61.9 (NCHCH2), 60.5 (CH2OH), 52.9 (NCH2CH2N),
44.6 (NCH2CH2N), 34.2 (CH2Ph), 28.5 (CH(CH3)2), 28.4 (CH(CH3)2),
25.0 (CH(CH3)2), 24.7 (CH(CH3)2), 24.1 (CH(CH3)2), 23.9 (CH(CH3)2).
4.3.2. (S)-N1-(2,6-Diisopropylphenyl)-N2-(1-hydroxy-3-phenyl
propan-2-yl)oxalamide 14
⁄Anhydrous
HCl/methanol:
acetyl
chloride
(1.45 mL,
20.3 mmol) was added slowly to MeOH (8.60 mL) at 0 °C and the
solution was stirred for 15 min before use.
The title compound 14 was prepared from 8c (8.46 g,
30.5 mmol) and 13 (5.56 g, 36.8 mmol) in accordance with the
literature.11 Purification of the crude product by Versa flash
chromatography (25% EtOAc/n-pentane) provided the oxalamide
14 (9.94 g, 85%) as a white solid. Mp 186 °C; Rf (25% EtOAc/n-
4.3.5. (S)-3-(2,6-Diisopropylphenyl)-1-(1-hydroxy-3-phenylp
ropan-2-yl)-4,5-dihydro-1H-imidazol-3-ium hexafluoro
phosphate IVb
pentane) 0.19; ½a D20
ꢂ
¼ ꢁ64:0 (c 1.00, acetone); mmax (neat) 3270
At first, KPF6 (2.31 g, 12.6 mmol) was added in one portion to
IVa (2.45 g, 6.11 mmol) dissolved in H2O (50 mL). After stirring
for 3 h at room temperature DCM (100 mL) was added. The aque-
ous layer was extracted with additional DCM (2 ꢃ 50 mL). The
combined organic layers were washed with brine, dried (MgSO4)
and evaporated to dryness giving the title compound IVb (3.07 g,
98%) as a pale yellow crystalline solid. Mp 107 °C; Rf (10% DCM/
(br), 1658, 1499 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 8.65 (1H, s,
NH), 7.78 (1H, d, J 9.2 Hz, NH), 7.36–7.15 (9H, m, Harom.), 4.28–
4.18 (1H, m, NHCH), 3.82–3.76 (1H, m, CH2OH), 3.74–3.67 (1H,
m, CH2OH), 3.04–2.89 (4H, m, CH2Ph + CH(CH3)2), 2.05 (1H, t, J
5.4 Hz, OH), 1.19 (6H, d, J 6.9 Hz, CH(CH3)2), 1.18 (6H, d, J
6.9 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3) d 159.7 (CO),
159.2 (CO), 145.8 (2 ꢃ Carom.), 137.2 (Carom.), 129.5 (Carom),
129.3 (2 ꢃ CHarom.), 128.9 (CHarom.), 128.6 (2 ꢃ CHarom.), 126.7
(CHarom.), 123.6 (2 ꢃ CHarom.), 63.1 (CH2OH), 53.7 (NCHCH2),
38.0 (CH2Ph), 28.8 (2 ꢃ CH(CH3)2), 23.6 (CH(CH3)2), 23.5
(CH(CH3)2); HRMS (EI): M+, found 382.2258. C23H30N2O3 requires
382.2251.
acetone) 0.13; ½a D20
ꢂ
¼ ꢁ60:6 (c 1.03, acetone); mmax (neat) 3590
(w, br), 2965, 1636, 835 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.67
(1H, s, NCHN), 7.41–7.31 (3H, m, Harom.), 7.31–7.24 (3H, m, Harom.),
7.18 (1H, dd, J 7.8, 1.3 Hz, Harom.), 7.14 (1H, dd, J 7.8, 1.3 Hz, Harom.),
4.44–4.35 (1H, m, NCHCH2), 4.31–4.06 (3H, m, CH2CH2N), 4.04–
3.88 (2H, m, CH2CH2N + CH2OH), 3.81–3.71 (1H, m, CH2OH),
3.43–3.36 (1H, m, OH), 3.00 (1H, dd, J 14.5, 5.4 Hz, CH2Ph), 2.91
(1H, dd, J 14.5, 10.6 Hz, CH2Ph), 2.85 (1H, sept., J 6.8 Hz, CH(CH3)2),
2.27 (1H, sept., J 6.8 Hz, CH(CH3)2), 1.22 (3H, d, J 6.8 Hz, CH(CH3)2),
1.14 (3H, d, J 6.8 Hz, CH(CH3)2), 1.12 (3H, d, J 6.8 Hz, CH(CH3)2),
0.98 (3H, d, J 6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, CDCl3) d
158.0 (NCHN), 146.8 (Carom.), 146.4 (Carom.), 135.7 (Carom.), 131.1
(CHarom.), 129.4 (Carom.), 129.1 (2 ꢃ CHarom.), 128.7 (2 ꢃ CHarom.),
127.3 (CHarom.), 124.8 (CHarom.), 124.7 (CHarom.), 62.1 (NCHCH2),
60.7 (CH2OH), 52.9 (NCH2CH2N), 45.2 (NCH2CH2N), 34.2 (CH2Ph),
28.5 (CH(CH3)2), 28.3 (CH(CH3)2), 24.6 (2 ꢃ CH(CH3)2), 24.0
4.3.3. (S)-2-(2-(2,6-Diisopropylphenylamino)ethylamino)-3-
phenylpropan-1-ol 15
The title compound 15 was prepared from oxalamide 14 (9.72 g,
25.4 mmol) and LiAlH4 (3.84 g, 101 mmol) according to a literature
procedure.11 The aqueous layer was extracted with EtOAc
(4 ꢃ 200 mL) using brine to separate the two phases. Drying over
MgSO4 and removal of the solvents in vacuo gave the desired
diamine 15 (8.2 g, 91%) as a light yellow oil. ½a D20
ꢂ
¼ ꢁ10:1 (c 1.00,
acetone); mmax (neat) 3351 (w, br), 2963 (w), 1456, 1436 cmꢁ1
;
1H

R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
2005
(CH(CH3)2), 23.8 (CH(CH3)2); HRMS (EI): M+, found 365.2581.
24H33N2O requires 365.2587.
(4 mL) gave the title compound IVe (148 mg, 65%) as a white solid.
C
Mp 233 °C; ½a 2D0
ꢂ
¼ ꢁ46:7 (c 1.04, acetone);
mmax (neat) 2967 (w, br),
1732, 1633, 1267, 1142, 844, 825 cmꢁ1
;
1H NMR (400 MHz, ace-
4.3.6. (S)-3-(2,6-Diisopropylphenyl)-1-(1-(methylsulfonyloxy)-
3-phenylpropan-2-yl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate IVc
tone-d6) 8.72 (1H, s, NCHN), 7.53–7.29 (8H, m, Harom.), 4.81–4.73
(1H, m, NCHCH2OPiv), 4.71–4.29 (6H, m, NCH2CH2N + CH2OPiv),
3.35 (1H, dd, J 14.4, 4.9 Hz, CH2Ph), 3.25 (1H, dd, J 14.5, 10.6 Hz,
CH2Ph), 3.02 (1H, sept., J 6.8 Hz, CH(CH3)2), 2.41 (1H, sept., J
6.8 Hz, CH(CH3)2), 1.26 (9 H, s, C(CH3)3), 1.26 (3H, d, J 6.8 Hz,
CH(CH3)2), 1.19 (3H, d, J 6.8 Hz, CH(CH3)2), 1.18 (3H, d, J 6.8 Hz,
CH(CH3)2), 0.98 (3H, d, J 6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, ace-
tone-d6) d 176.9 (CO), 158.4 (NCHN), 146.4 (Carom.), 146.3 (Carom.),
135.9 (Carom.), 131.0 (CHarom.), 129.8 (Carom.), 129.0 (2 ꢃ CHarom.),
128.9 (2 ꢃ CHarom.), 127.4 (CHarom.), 124.8 (CHarom.), 124.7
(CHarom.), 62.4 (CH2OPiv), 60.0 (NCHCH2), 53.4 (NCH2CH2N), 45.6
(NCH2CH2N), 38.4 (C(CH3)3), 33.9 (CH2Ph), 28.2 (CH(CH3)2), 28.0
(CH(CH3)2), 26.4 (C(CH3)3), 24.0 (CH(CH3)2), 23.9 (CH(CH3)2), 23.6
(CH(CH3)2), 23.5 (CH(CH3)2); HRMS (EI): M+, found 449.3172.
At first, MeSO2Cl (23.2
ll, 0.296 mmol) was added on ice cooling
to a solution of IVb (100 mg, 0.196 mmol) and NEt3 (42.0
l
l,
0.303 mmol) in DCM (1.1 mL). After 2.5 h at rt, the reaction mixture
wasdilutedwithEtOAc(5 mL)andwashedwithcitricacid(10%w/w,
3 ꢃ 1.5 mL) and brine (3 ꢃ 3 mL). The organic layer was dried
(MgSO4) and the solvents removed in vacuo giving the title com-
pound IVc (82 mg, 71%) as a white solid. Mp 194 °C. ½a D20
¼ ꢁ51:1
ꢂ
(c 1.02, acetone); mmax (neat) 2963 (w, br), 1640, 1336, 1176,
833 cmꢁ1 1H NMR (400 MHz, acetone-d6) 8.18 (1H, s, NCHN),
;
7.53–7.28 (8H, m, Harom.), 4.86–4.69 (3H, m, NCHCH2OH), 4.62–
4.28 (4H, m, NCH2CH2N), 3.34 (1H, dd, J 14.5, 5.2 Hz, CH2Ph), 3.30–
3.22 (4H, m, CH2Ph + SO2CH3), 3.02 (1H, sept., J 6.8 Hz, CH(CH3)2),
2.55 (1H, sept., J 6.8 Hz, CH(CH3)2), 1.25 (3H, d, J 6.8 Hz, CH(CH3)2),
1.19 (3H, d, J 6.8 Hz, CH(CH3)2), 1.18 (3H, d, J 6.8 Hz, CH(CH3)2)
1.02 (3H, d, J 6.8 Hz, CH(CH3)2); 13C NMR (100 MHz, acetone-d6)
159.0 (NCHN), 146.6 (Carom.), 146.4 (Carom.), 135.6 (Carom.), 130.9
(CHarom.), 129.9 (Carom.), 128.9 (2 ꢃ CHarom.), 128.8 (2 ꢃ CHarom.),
127.3 (CHarom.), 124.7 (CHarom.), 124.6 (CHarom.), 67.1 (CH2OMs),
59.8 (NCHCH2), 53.2 (NCH2CH2N), 45.8 (NCH2CH2N), 36.6 (SO2CH3),
33.2(CH2Ph), 28.1(CH(CH3)2), 28.0(CH(CH3)2), 24.1(CH(CH3)2), 24.0
(CH(CH3)2), 23.2 (CH(CH3)2), 23.1 (CH(CH3)2); HRMS (EI): M+, found
443.2364. C25H35N2O3S requires 443.2363.
C29H41N2O2 requires 449.3163.
4.3.9. (S)-1-(1-(Benzoyloxy)-3-phenylpropan-2-yl)-3-(2,6-diiso
propylphenyl)-4,5-dihydro-1H-imidazol-3-ium hexafluoro
phosphate IVf
Benzoyl chloride (250
ll, 2.16 mmol) was added to an ice cold
solution of IVb (508 mg, 0.995 mmol) and NEt3 (280
ll, 2.02 mmol)
in DCM (20 mL). After 6 h at room temperature, EtOAc (50 mL) was
added. The organic layer was washed with water (20 mL) and brine
(25 mL), dried (MgSO4) and evaporated to dryness. Purification of
the crude product by Versa flash chromatography (50% EtOAc/n-
pentane) gave IVf (477 mg, 78%) as a white solid. Mp 189 °C; Rf
4.3.7. (S)-1-(1-Acetoxy-3-phenylpropan-2-yl)-3-(2,6-
diisopropylphenyl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate IVd
(50% EtOAc/n-pentane) 0.14; ½a D20
ꢂ
¼ ꢁ33:3 (c 1.01, acetone); mmax
(neat) 2964 (w, br), 1718, 1632, 1267, 1118, 831 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 8.11 (2H, d, J 7.8 Hz, Harom.), 7.77 (1H, s, NCHN),
7.62–7.58 (1H, m, Harom.), 7.51–7.44 (2H, m, Harom.), 7.42–7.28 (6H,
m, Harom.), 7.12–7.05 (2H, m, Harom.), 4.93–4.81 (2H, m, NCHCH2OBz),
4.52–4.41 (2H, m, CH2OBz + NCH2CH2N), 4.32–4.21 (1H, m,
NCH2CH2N), 4.15–3.90 (2H, m, NCH2CH2N), 3.21–3.14 (1H, m,
CH2Ph), 3.08–2.99 (1H, m, CH2Ph), 2.42 (1H, sept., J 6.8 Hz,
CH(CH3)2), 2.06 (1H, sept., J 6.8 Hz, CH(CH3)2), 1.06 (3H, d, J
6.8 Hz, CH(CH3)2), 1.03 (3H, d, J 6.8 Hz, CH(CH3)2), 0.90 (3H, d, J
6.7 Hz, CH(CH3)2), 0.98 (3H, d, J 6.7 Hz, CH(CH3)2); 13C NMR
(100 MHz, CDCl3) d 166.5 (CO), 157.8 (NCHN), 146.2 (Carom.), 146.1
(Carom.), 134.7 (Carom.), 133.8 (CHarom.), 131.2 (CHarom.), 129.9
(2 ꢃ CHarom.), 129.3 (CHarom.), 129.0 (Carom.), 128.9 (2 ꢃ CHarom.),
128.8 (2 ꢃ CHarom.), 128.7 (Carom.), 127.6 (CHarom.), 124.8 (CHarom.),
124.7 (CHarom.), 62.5 (CH2OBz), 59.6 (NCHCH2), 53.3 (NCH2CH2N),
45.1 (NCH2CH2N), 34.2 (CH2Ph), 28.6 (CH(CH3)2), 28.3 (CH(CH3)2),
24.5 (CH(CH3)2), 24.2 (CH(CH3)2), 24.0 (CH(CH3)2), 23.9 (CH(CH3)2);
HRMS (EI): M+, found 469.2857. C31H37N2O2 requires 469.2850.
Acetyl chloride (21.0
ll, 0.294 mmol) was added on ice cooling
to a solution of IVb (100 mg, 0.196 mmol) and NEt3 (41.0
l
l,
0.296 mmol) in DCM (1.0 mL). After 2.5 h at room temperature,
the reaction mixture was diluted with EtOAc (5 mL) and washed
with citric acid (10% w/w, 3 ꢃ 1.5 mL) and brine (3 ꢃ 3 mL). The or-
ganic layer was dried (MgSO4) and the solvents evaporated in va-
cuo providing IVd (69 mg, 64%) as a white solid. Mp 204 °C;
½
a 2D0
ꢂ
¼ ꢁ46:6 (c 1.02, acetone); mmax (neat) 2969 (w, br), 1742,
1635, 833 cmꢁ1 1H NMR (400 MHz, acetone-d6) d 8.75 (1H, s,
;
NCHN), 7.51–7.30 (8H, m, Harom.), 4.73–4.64 (1H, m, NCHCH2OH),
4.62–4.27 (6H, m, NCH2CH2N + CH2OAc), 3.31 (1H, dd, J 14.5,
5.5 Hz, CH2Ph), 3.25 (1H, dd, J 14.4, 10.1 Hz, CH2Ph), 3.02 (1H, sept.,
J 6.8 Hz, CH(CH3)2), 2.53 (1H, sept., J 6.8 Hz, CH(CH3)2), 2.11 (3H, s,
COCH3), 1.28 (3H, d, J 6.8 Hz, CH(CH3)2), 1.20 (3H, d, J 6.8 Hz,
CH(CH3)2), 1.19 (3H, d, J 6.8 Hz, CH(CH3)2) 1.02 (3H, d, J 6.8 Hz,
CH(CH3)2); 13C NMR (100 MHz, acetone-d6) 169.6 (CO), 158.4
(NCHN), 146.3 (Carom.), 146.2 (Carom.), 135.9 (Carom.), 130.8 (CHarom.),
129.8 (Carom.), 128.8 (2 ꢃ CHarom.), 128.7 (2 ꢃ CHarom.), 127.1
(CHarom.), 124.6 (CHarom.), 124.5 (CHarom.), 61.8 (CH2OAc), 59.7
(NCHCH2), 53.1 (NCH2CH2N), 45.8 (NCH2CH2N), 33.6 (CH2Ph),
28.1 (CH(CH3)2), 27.9 (CH(CH3)2), 23.9 (CH(CH3)2), 23.8 (CH(CH3)2),
23.1 (CH(CH3)2), 22.9 (CH(CH3)2), 19.5 (COCH3); HRMS (EI): M+,
found 407.2694. C26H35N2O2 requires 407.2693.
4.3.10. (S)-3-(2,6-Diisopropylphenyl)-1-(1-(trimethylsilyl)-3-
phenylpropan-2-yl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate IVg
At first, TMSCl (38.0
solution of IVb (100 mg, 0.196 mmol), DMAP (1.6 mg, 0.013 mmol)
and NEt3 (42.0 l, 0.303 mmol) in DCM (2 mL). After 6 h at room
ll, 0.300 mmol) was added to an ice cold
l
temperature, the reaction mixture was diluted with more DCM
(4 mL) and saturated NaHCO3 (4 mL) was added. The organic layer
was washed with water (4 mL) and brine (4 mL), dried (MgSO4)
and evaporated to dryness. Filtration through a short pad of silica
with acetone gave the title compound IVg (86 mg, 75%) as a light
4.3.8. (S)-3-(2,6-Diisopropylphenyl)-1-(1-phenyl-3-(pivaloyloxy)
propan-2-yl)-4,5-dihydro-1H-imidazol-3-ium hexafluoro
phosphate(V) IVe
Pivaloyl chloride (96.0
ll, 0.780 mmol) was added on ice cool-
ing to a solution of IVb (195 mg, 0.382 mmol) and NEt3 (109
l
l,
yellow solid. Mp 187 °C; ½a D20
ꢂ
¼ ꢁ47:1 (c 1.03, acetone);
mmax (neat)
0.786 mmol) in DCM (2.0 mL). After 7 h at room temperature
EtOAc (25 mL) was added. The organic layer was washed with
water (2 ꢃ 8 mL), dried (MgSO4) and evaporated to dryness. The
crude product was filtered through a short pad of silica with ace-
tone to remove residues of NEt3. Recrystallisation from EtOAc
2964 (w, br), 1634, 1253, 827 cmꢁ1 1H NMR (400 MHz, acetone-
;
d6) 8.67 (1H, s, NCHN), 7.52–7.31 (8H, m, Harom.), 4.61–4.55 (1H,
m, NCH2CH2N), 4.47–4.28 (4H, m, NCH2CH2N + NCHCH2OSi), 4.10
(1H, dd, J 11.2, 3.8 Hz, CH2OSi), 4.00 (1H, dd, J 11.2, 7.9 Hz, CH2OSi),
3.22 (1H, dd, J 14.3, 5.1 Hz, CH2Ph), 3.15 (1H, dd, J 14.4, 10.3 Hz,

2006
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
CH2Ph), 2.99 (1H, sept., J 6.9 Hz, CH(CH3)2), 2.56 (1H, sept., J 6.8 Hz,
CH(CH3)2), 1.27 (3H, d, 6.8 Hz, CH(CH3)2), 1.20 (3H, d,
References
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J
1. (a) Hermann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290; (b) Wurtz, S.; Glorius,
F. Acc. Chem. Res. 2008, 41, 1523.
6.8 Hz, CH(CH3)2), 1.19 (3H, d, J 6.8 Hz, CH(CH3)2), 1.02 (3H, d, J
6.8 Hz, CH(CH3)2), 0.19 (9H, s, Si(CH3)3); 13C NMR (100 MHz,
acetone-d6) 158.6 (NCHN), 146.6 (Carom.), 146.4 (Carom.), 136.6
(Carom.), 130.8 (CHarom.), 130.1 (Carom.), 128.8 (2 ꢃ CHarom.), 128.7
(2 ꢃ CHarom.), 127.0 (CHarom.), 124.7 (CHarom.), 124.6 (CHarom.),
62.6 (NCHCH2), 60.7 (CH2OTMS), 53.0 (NCH2CH2N), 45.9
(NCH2CH2N), 33.7 (CH2Ph), 28.2 (CH(CH3)2), 28.0 (CH(CH3)2), 24.0
(SiC(CH3)3), 24.0 (2 ꢃ CH(CH3)2), 23.2 (CH(CH3)2), 23.0 (CH(CH3)2),
-1.7 (Si(CH3)3); HRMS (EI): M+, found 437.2986. C27H41N2OSi
requires 437.2983.
2. (a) Zinn, F. K.; Vciu, M. S.; Nolan, S. P. Annu. Rep. Prog. Chem. Sect. B 2004, 100,
231; (b) Strassner, T. Top. Organomet. Chem. 2007, 22, 125; (c) Someya, H.;
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4.3.11. (S)-3-(2,6-Diisopropylphenyl)-1-(1-(t-butyldimethyl
silyl)-3-phenylpropan-2-yl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate IVh
At first, TBDMSCl (119 mg, 0.790 mmol) dissolved in DCM
(0.8 mL) was added to an ice cold solution of IVb (280 mg,
0.548 mmol) and imidazole (97 mg, 1.42 mmol in DCM (1.2 mL).
After stirring for 5 h at room temperature, the reaction was
quenched with saturated NaHCO3 (2 mL). The water phase was ex-
tracted with EtOAc (4 ꢃ 5 mL) and the combined organic layers
were washed with brine and dried (MgSO4). Removal of the sol-
vents in vacuo gave the title compound IVh (317 mg, 93%) as a
white solid. Mp 215 °C; ½a D20
ꢂ
¼ ꢁ43:7 (c 1.00, acetone);
mmax (neat)
2964 (w, br), 1633, 1249, 1160, 827 cmꢁ1; 1H NMR (400 MHz, ace-
tone-d6) 8.64 (1H, s, NCHN), 7.51–7.26 (8H, m, Harom.), 4.67–4.55
(1H, m, NCH2CH2N), 4.54–4.25 (4H, m, NCH2CH2N + NCHCH2OSi),
4.17 (1H, dd, J 11.2, 3.8 Hz, CH2OSi), 4.07 (1H, dd, J 11.2, 8.3 Hz,
CH2OSi), 3.23 (1H, dd, J 14.4, 4.4 Hz, CH2Ph), 3.13 (1H, dd, J 14.4,
10.7 Hz, CH2Ph), 2.99 (1H, sept., J 6.7 Hz, CH(CH3)2), 2.46 (1H, sept.,
J 6.8 Hz, CH(CH3)2), 1.26 (3H, d, J 6.8 Hz, CH(CH3)2), 1.19 (6H, d, J
6.8 Hz, CH(CH3)2), 0.99 (3H, d, J 6.8 Hz, CH(CH3)2), 0.97 (9H, s,
C(CH3)3), 0.19 (3H, s, Si(CH3)2), 0.17 (3H, s, Si(CH3)2); 13C NMR
(100 MHz, acetone-d6) 158.4 (NCHN), 146.4 (Carom.), 146.3 (Carom.),
136.4 (Carom.), 130.8 (CHarom.), 129.9 (Carom.), 128.9 (2 ꢃ CHarom.),
128.8 (2 ꢃ CHarom.), 127.1 (CHarom.), 124.7 (CHarom.), 124.6
(CHarom.), 62.7 (NCHCH2), 61.8 (CH2OSi), 53.1 (NCH2CH2N), 45.6
(NCH2CH2N), 33.6 (CH2Ph), 28.2 (CH(CH3)2), 28.0 (CH(CH3)2), 25.2
(Si(CH3)2C(CH3)3), 24.0 (CH(CH3)2), 23.9 (CH(CH3)2), 23.4
(CH(CH3)2), 23.3 (CH(CH3)2), 17.8 (SiC(CH3)3), ꢁ6.40 (Si(CH3)2),
ꢁ6.50 (Si(CH3)2); HRMS (EI): M+, found 479.3444. C30H47N2OSi re-
quires 479.3452.
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Acknowledgment
The Research Council of Norway is acknowledged for the finan-
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