Chiral N-Heterocyclic Carbene Ligands Bearing a Pyridine Moiety for the Copper-Catalyzed Alkylation of N-Sulfonylimines with Dialkylzinc Reagents

Article abstract of DOI:10.1002/chem.201404241

Amino acid-derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N-heterocyclic carbene ligands. The copper-catalyzed asymmetric alkylation of various N-sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee). The addition of HMPA to the reaction mixture as a co-solvent is critical in terms of chemical yield and enantioselectivity. A wide range of N-sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction. Amino acid-derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N-heterocyclic carbene ligands. The copper-catalyzed asymmetric alkylation of various N-sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee; see scheme). A wide range of N-sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction.

Full text of DOI:10.1002/chem.201404241

DOI: 10.1002/chem.201404241
Full Paper
&
Asymmetric Alkylation
Chiral N-Heterocyclic Carbene Ligands Bearing a Pyridine Moiety
for the Copper-Catalyzed Alkylation of N-Sulfonylimines with
Dialkylzinc Reagents
Takahiro Soeta,* Tomohiro Ishizaka, Yuta Tabatake, and Yutaka Ukaji*[a]
Abstract: Amino acid-derived chiral imidazolium salts, each
bearing a pyridine ring, were developed as N-heterocyclic
carbene ligands. The copper-catalyzed asymmetric alkylation
of various N-sulfonylimines with dialkylzinc reagents in the
presence of these chiral imidazolium salts afforded the corre-
sponding alkylated products with high enantioselectivity (up
to 99% ee). The addition of HMPA to the reaction mixture as
a co-solvent is critical in terms of chemical yield and enantio-
selectivity. A wide range of N-sulfonylimines and dialkylzinc
reagents were found to be applicable to this reaction.
Introduction
NHC precursor derived from axial-symmetric aminohydroxy-
naphthalene and was able to obtain high enantioselectivity in
copper-catalyzed reactions.[9] As a result of these various break-
throughs, chiral multidentate NHC chemistry has attracted sig-
nificant attention.[10] For example, Katsuki,[11] Sakaguchi,[12] Wil-
liams,[13] Hayashi,[14] and Tomioka[15] all independently devel-
oped chiral multidentate NHC precursors for copper-catalyzed
asymmetric reactions and were each successful in achieving
high enantioselectivity.
The application of N-heterocyclic carbenes (NHCs) in organic
synthesis has dramatically increased since Bertrand, Arduengo
and their co-workers reported the first stable nucleophilic car-
bene around 1990.[1] NHCs have become extremely popular li-
gands in organometallic chemistry[2] and many complexes in-
corporating NHCs have been used in synthetic methods, in-
cluding cross coupling and metathesis reactions. In addition,
applications of chiral NHCs to catalytic asymmetric reactions
have been reported, with good to excellent stereoselectivity. In
2001, Woodward reported the first copper-catalyzed conjugate
addition of diethylzinc,[3] and Alexakis expanded this method
to allow asymmetric synthesis using chiral NHC precursors de-
rived from C2-symmetric diamines.[4] Okamoto also reported
a copper-catalyzed asymmetric allylic alkylation reaction using
the same catalyst as Alexakis.[5] In 2004, Arnold reported the
isolation of the first-ever chiral chelating copper(II) alkoxy-NHC
complex and obtained moderate enantioselectivity from the
copper-catalyzed conjugate addition of diethylzinc to cyclo-
hexenone.[6] Mauduit also introduced an alcohol moiety to the
NHC ligand to achieve higher enantioselectivity during catalyt-
ic asymmetric conjugate addition.[7] The efficient conjugate ad-
dition of Grignard reagents to b-substituted cyclic enones has
Herein, we report the synthesis of a series of chiral imidazoli-
um salts, derived from commercially available l-amino acids
and each bearing a pyridine moiety. In addition, we describe
the application of these chiral imidazolium salts to the copper-
catalyzed asymmetric alkylation of N-sulfonylimines with di-
alkylzinc reagents.[16] We have recently developed a family of
chiral triazolium salts bearing a pyridine moiety, which have
been shown to catalyze both the benzoin condensation reac-
tion and the intramolecular Stetter reaction to give products
with up to 99% ee.[17] However, to the best of our knowledge,
the compounds described herein represent the first chiral imi-
dazolium salts incorporating a pyridine ring to be reported in
the literature.
also been developed through the utilization of Mauduit’s Results and Discussion
ligand.[8] Furthermore, dramatic improvements have been re-
Synthesis of chiral imidazolium salts
ported by Hoveyda, who developed a chiral bidendate alkoxy-
We initially designed and synthesized a range of chiral imida-
zolium salts, all bearing a pyridine ring (Figure 1), each of
which was readily prepared from commercially available l-
amino acids (Scheme 1). During the synthesis of these com-
pounds, the aminoalkyl bromide hydrogenbromides 14a–d
were prepared by the reduction of l-amino acids with LiAlH4
followed by neutralization and subsequent bromination of the
alcohol group by treatment with PBr3.[18] The pyridinoimidazole
compounds 15a–c were prepared from the reaction of imida-
zole and the corresponding aryl bromide derivatives in the
[a] Dr. T. Soeta, T. Ishizaka, Y. Tabatake, Prof. Dr. Y. Ukaji
Division of Material Chemistry
Graduate School of Natural Science and Technology
Kanazawa University
Kakuma, Kanazawa, Ishikawa, 920-1192 (Japan)
Fax: (+81)76-264-5742
E-mail: soeta@se.kanazawa-u.ac.jp
ukaji@staff.kanazawa-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404241.
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NHC–copper-catalyzed asymmetric alkylation of N-sulfonyl-
imines with dialkylzinc reagents
We began our studies with the reaction of N-sulfonylimine 1a
with diethylzinc (2E) in the presence of 5.0 mol% of copper(II)
triflate and 6.5 mol% of the chiral imidazolium salt in toluene
at 08C. Although 1a was consumed after 12 h and the desired
ethylated product 3aE was obtained in 90% yield, no enantio-
selectivity was achieved (Table 1, entry 1). As a small amount of
insoluble material was observed in the post-reaction solution,
we examined the use of varying amounts of hexamethylphos-
phoramide (HMPA) as a co-solvent, with the aim of obtaining
a clear solution. The addition of 10 mol% HMPA to the solvent
mixture had no effect on the insoluble material, and gave the
same level of enantioselectivity as was observed without
HMPA (entry 2). However, the addition of 10 equivalents of
HMPA resulted in an almost clear solution with no insoluble
material, as well as a dramatic improvement in the
enantioselectivity, such that the product (R)-3aE was
obtained with 99% ee (entry 3).[20] As it was evident
that both the solvent and the copper source influ-
enced the efficiency of the reaction, we subsequently
examined the ethylation of N-sulfonylimine with di-
ethylzinc by using different solvents and copper salts.
When employing dichloromethane as the solvent,
the reaction proceeded slowly to afford the product
3aE in 54% yield with 8% ee (entry 4). Interestingly,
coordinative solvents such as diethyl ether, THF, and
MeCN were found to be applicable to this reaction,
giving 3aE in high enantioselectivities, and the addi-
tion of HMPA to the reaction mixture as a co-solvent
is critical in terms of chemical yield and enantioselec-
tivity (entries 5–10).
Figure 1. Amino acid-derived chiral imidazolium salts bearing a pyridine
ring.
Other copper salts were also investigated in the
asymmetric ethylation of N-sulfonylimine; copper(II)
salts such as copper(II) triflate and CuCl2·2H2O exhib-
ited the highest efficiency, generating the desired
product 3aE with ee values of 99% and 98%, respec-
tively (entries 3 and 11). In addition, copper(I) salts
were also effective in this reaction, affording the
product with excellent enantioselectivities in high
yields, with the exception of CuCl (entries 12–17). In
all cases, none of the product generated by the
direct reduction of diethylzinc was observed, even in
trials in which lower catalytic performance was found, such as
entry 16. Even at lower catalyst loadings (1.0 mol% of Cu(OTf)2
and 1.3 mol% of 4a), the reaction proceeded cleanly to afford
the product 3aE in good yield and with consistently high
enantioselectivity (entry 18). Based on previous reports,[21] the
oxidation state of the active copper catalyst in the addition re-
action of dialkylzinc reagents might be copper(I). That is, in
situ reduction of copper(II) takes place prior to the formation
of the NHC–copper complex. Subsequent alkyl transfer from
zinc to copper gives NHC–CuI–R and R–Zn–X species, which
react with N-sulfonylimine.
Scheme 1. General synthesis of the chiral imidazolium salts.
presence of copper salt.[19] The hydrobromide salts of the ami-
noalkyl bromides were coupled to 15a–c in MeCN under reflux
conditions to give the series of ammoniumalkyl imidazolium
salt derivatives, 16. Finally, modification of the amino group
was accomplished by reaction with the corresponding acyl
chloride in the presence of potassium carbonate followed by
treatment with ammonium salt solutions to give the desired
imidazolium salts. In the case of 12, the ammonium alkyl imi-
dazolium salt was treated with phthalic anhydride and potassi-
um carbonate in toluene under reflux conditions. In the syn-
thesis of the imidazolium salt 6, the pivalamide 14a’, which
was derived from the reaction of 14a with pivaloyl chloride,
was coupled with 3-pyridinoimidazole 15c.
We next turned our attention to the structures of the chiral
imidazolium salts 4–12. We determined that ClÀ (as in 4a) was
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lium salt, we conducted the asymmetric alkylation of N-sulfo-
nylimine 1a with the imidazolium salt 5, which contained
a phenyl ring rather than the 2-pyridine ring. The reaction pro-
ceeded smoothly, giving the product 3aE in 86% yield but
with only 63% ee (entry 5). This result clearly indicates that the
pyridinyl group played an important role in achieving the high
stereoselectivity observed in the prior reactions. The position
of the nitrogen atom on the pyridine moiety was also critical
to obtaining the ethylated product 3aE with high enantiose-
lectivity. Thus, the introduction of a nitrogen atom at the C3-
position of the aromatic ring (as in 6) lowered the enantiose-
lectivity still further (entry 6). The use of the chiral imidazolium
salts derived from l-alanine, 7, l-phenylalanine, 8, and l-pro-
line, 9, also resulted in relatively low enantioselectivities (en-
tries 7–9). The effect of the amidocarbonyl moiety was also in-
vestigated. Imidazolium salt 4a, which contained the bulkier
pivaloyl group, was found to function as the best ligand for
the copper-catalyzed reaction, and gave 3aE with 99% ee,
whereas NHC precursors bearing isobutylamide or benzamide
groups showed lower enantioselectivity (entries 10 and 11). Fi-
nally, we determined that the hydrogen atom of the amidocar-
bonyl group may be a vital factor in terms of achieving high
stereoselectivity. Thus, when a phthalimide group was intro-
duced to form imidazolium salt 12 and this compound was
used in the catalytic ethylation of 1a, the enantioselectivity
was reduced significantly to 35% ee (entry 12).
Table 1. Copper-catalyzed asymmetric ethylation of N-sulfonylimine with
diethylzinc.[a]
Entry
Solvent
Cu salt
Yield [%]
ee [%]
1[b]
2[c]
3
toluene
toluene
toluene
CH2Cl2
Et2O
Et2O
THF
THF
MeCN
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl2·2H2O
CuTC[d]
(CuOTf)2–PhH
Cu(MeCN)4BF4
CuCN
CuCl
CuI
90
67
85
54
85
16
88
32
91
50
98
95
97
99
99
39
90
92
0
8
99
8
4
5
93
26
89
58
82
0
98
96
93
95
89
95
96
91
6[b]
7
8[b]
9
10[b]
11
12
13
14
15
16
17
18[e]
Cu(OTf)2
[a] Using 2.0 equiv of 2E and 10 equiv of HMPA unless otherwise noted.
[b] In the absence of HMPA. [c] Using 10 mol% of HMPA. [d] CuTC=cop-
per(I) thiophene-2-carboxylate. [e] Using 1.0 mol% of Cu(OTf)2 and
1.3 mol% of 4a.
Applying the optimized reaction conditions, the scope of
the catalytic asymmetric alkylation was subsequently demon-
strated by experimenting with various N-sulfonylimines and di-
alkylzinc compounds (Table 3). It was gratifying to observe that
suitable for use as the counter anion to the imidazolium salt in
this reaction, whereas the reactions employing chiral imidazoli-
À
À
um salts bearing BrÀ (4b), BF4 (4c) and PF6 (4d) all resulted
in lower enantioselectivities (Table 2, entries 1–4). The role of
counter anions of the imidazolium salts on the enantioselectiv-
ity was not clear; however, the counter anion might effect to
the solubility and/or stability of the NHC–copper complex. To
examine the effect of the pyridine ring portion of the imidazo-
Table 3. Catalytic asymmetric alkylation of N-tosylimines with various di-
alkylzinc compounds.[a]
Entry
R1
R2
Yield [%]
ee [%][e]
Table 2. Effects of various chiral imidazolium salts on the copper-cata-
lyzed asymmetric ethylation of N-tosylimines.[a]
1
2
3
4
5
6
7
8
C6H5 (1a)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
Et (2E)
iPr (2I)
Me (2M)
Me (2M)
Me (2M)
85 (3aE)
94 (3bE)
91 (3cE)
88 (3dE)
95 (3eE)
97 (3 fE)
88 (3gE)
93 (3hE)
93 (3iE)
99 (3jE)
76 (3kE)
86 (3aI)
41 (3aM)
63 (3aM)
84 (3aM)
99
89
91
90
94
96
93
90
93
91
75
84
87
84
85
1-naphthyl (1b)
2-naphthyl (1c)
2-MeC6H4 (1d)
3-MeC6H4 (1e)
4-MeC6H4 (1 f)
4-MeOC6H4 (1g)
4-CF3C6H4 (1h)
4-BrC6H4 (1i)
2-furyl (1j)
c-C6H11 (1k)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
Entry
Imidazolium salt
Yield[%]
ee [%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
5
6
7
8
9
85
88
89
94
86
80
87
92
77
90
90
86
99
82
90
64
63
15
30
43
4
9
10
11
12
13[b]
14[c]
15[d]
[a] Using 2.0 equiv of 2 and 10 equiv of HMPA unless otherwise noted.
[b] The reaction was quenched after 72 h. [c] The reaction was carried out
at room temperature for 48 h. [d] Using 10 equiv of 2M at room temper-
ature for 24 h. [e] The absolute configurations of 3, except for 3aE, 3aI,
and 3aM, were assigned based on the analogous reactions in Scheme 1.
Also see refs. [20] and [21].
9
10
11
12
10
11
12
87
86
35
[a] Using 2.0 equiv of 2E and 10 equiv of HMPA.
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m=multiplet), coupling constant (J) and integration. 13C NMR spec-
tra were recorded on JEOL ECS 400 (100 MHz) NMR spectrometer.
The chemical shifts were determined in the d-scale relative to
CDCl3 (d=77.0 ppm). The IR spectra were measured on JASCO FT/
IR-230 spectrometers. The MS spectrum was recorded with a JEOL
SX-102 A mass spectrometer, JMS-T100TD, and Bruker microtof II.
All of the melting points were measured with YANAGIMOTO micro
melting point apparatus. Dehydrated solvents were purchased for
the reactions and used without further desiccation. Flash column
chromatography was performed by using Cica silica gel 60N,
spherical neutral (37563–84).
our catalytic system was applicable to a wide range of N-tosyli-
mines when the reactions were performed with 5 mol%
Cu(OTf)2 and 6.5 mol% imidazolium salt 4a in toluene at 08C.
The N-tosylimines 1b and 1c, derived from 1-naphthaldehyde
and 2-naphthaldehyde, respectively, were found to act as good
substrates, generating the corresponding products 3bE and
3cE with 89% ee and 91% ee (entries 2 and 3). The reactions
of 1d, 1e, and 1 f, having 2-, 3- and 4-methylphenyl groups,
gave 3dE, 3eE and 3 fE with 90% ee, 94% ee, and 96% ee, re-
spectively (entries 4–6). Even the relatively deactivated N-tosyl-
imine 1g, derived from 4-methoxybenzaldehyde, was applica-
ble to this reaction, giving the product 3gE in 88% yield with
93% ee (entry 7). We also investigated substituted N-tosyl-
imines bearing an electron-withdrawing group at the para-po-
sition of the phenyl group; the reactions of N-tosylimines 1h
and 1i, derived from 4-(trifluoromethyl)benzaldehyde and 4-
bromobenzaldehyde, with diethylzinc (2E) gave the corre-
sponding ethylated products 3hE and 3iE with 90% ee and
93% ee (entries 8 and 9). The reaction of 1j, having a heterocy-
clic 2-furyl group, gave 3jE in 99% yield with 91% ee
(entry 10). It is noteworthy that the enolizable imine 1k was ef-
ficiently ethylated without undergoing enolization, giving the
corresponding product 3kE in reasonable yield and enantiose-
lectivity (entry 11). An isopropyl group was also introduced
into 1a by using the diisopropylzinc (2I), to afford (R)-3aI[21]
with 84% ee in 86% yield (entry 12).
General procedure for the alkylation of N-sulfonylimines
with dialkylzinc reagentes catalyzed by NHC–copper com-
plexes
Under Ar atmosphere, the solution of imidazolium salt 4 (11.4 mg,
0.033 mmol) in 0.8 mL of HMPA and 2.0 mL of toluene was added
to Cu(OTf)2 (9.07 mg, 0.025 mmol). The mixture was diluted with
toluene (10.1 mL) and the whole was cooled to 08C. After 15 min,
a hexane solution of dialkylzinc (1.0 mL, 1.0 mmol) was added
dropwise over 3 min at 08C and stirred for 30 min. A solution of
imine 1a (130 mg, 0.5 mmol) in 3.0 mL of toluene was added drop-
wise over 6 min at 08C. After 24 h, the reaction was quenched
with 10% HCl and stirred at room temperature for another 30 min.
The organic layer was separated and the water layer was extracted
with ethyl acetate. The combined organic layers were washed with
sat. NaHCO3 and brine, and then dried over Na2SO4. The sample
was concentrated and purified by silica gel column chromatogra-
phy.
In contrast, the methylation of 1a with dimethylzinc (2M)
was very slow at 08C and generated (R)-3aM[22] with 87% ee in
41% yield after 72 h (entry 13). The conversion was improved
when this reaction was conducted at room temperature, af-
fording 3aM with 84% ee in 63% yield (entry 14). Finally, we
were able to obtain 3aM in 84% yield without any loss of
enantioselectivity when the reaction was carried out at room
temperature using 10 equivalents of 2M (entry 15).
In the case of the asymmetric methylation, dimethylzinc (1.0m in
toluene) was used.
(R)-4-Methyl-N-(1-phenylpropyl)benzenesulfonamide (3aE): Silica
gel column chromatography (hexane/acetone=10:1 to 5:1) gave
3aE (123 mg, 85% yield) as a white solid. The ee was determined
to be 99% by HPLC (Daicel Chiralcel OD-H, hexane/iPrOH=15:1,
0.6 mLminÀ1, 254 nm, major 19.0 min and minor 25.3 min). M.p.=
102.0–102.68C; [a]2D5 =47.5 (c=0.53 in EtOH); 1H NMR (400 MHz,
CDCl3): d=0.71 (t, J=7.2 Hz, 3H), 1.64 (m, 1H), 1.75 (m, 1H), 2.29
(s, 3H), 4.18 (m, 1H), 4.62 (d, J=7.2 Hz, 1H), 6.92 (m, 2H), 7.04–
7.10 (m, 5H), 7.46 ppm (d, J=6.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=10.4, 21.3, 30.5, 59.8, 126.5, 126.9, 127.0, 128.1, 129.1,
137.6, 140.8, 142.7 ppm; IR (KBr): n=3270, 2960, 1600, 1500, 1460,
1320, 1160, 1000 cmÀ1; HRMS (DART): (m/z) calcd for C16H20NO2S:
290.1215 [M+H]+; found: 290.1223.
Conclusion
We have successfully synthesized a series of amino acid-de-
rived chiral imidazolium salts, each bearing a pyridine ring, and
applied these compounds to the copper-catalyzed asymmetric
alkylation of N-tosylimines, achieving satisfactory yields and
enantioselectivities. Furthermore, the addition of HMPA to the
reaction mixture as a co-solvent is critical in terms of chemical
yield and enantioselectivity. A wide range of N-tosylimines and
dialkylzinc reagents were found to be applicable to this reac-
tion. As the tosyl group of the substrate is easily removed
without any loss of enantioselectivity,[23] this method would
also be applicable to the synthesis of chiral amines.
General procedure for the synthesis of ammoniumalkyl imi-
dazolium salt (16)
Aminoalkyl bromide hydrogenbromide (1.0 equiv) and pyridinoimi-
dazole (1.0 equiv) in MeCN (1.0m) were heated at reflux for 3 days.
After removing the solvent under reduced pressure, the resulting
solid was recrystallized from EtOH to afford the desired products.
((S)-1-(2-Ammonio-3-methylbutyl)-3-(pyridin-2-yl)-1H-imidazol-3-
ium) dibromide (16aa): Recrystallization from EtOH gave 16aa
(790 mg, 59%, 3.7 mmol scale) as a white solid. M.p.=237.9–
238.88C; [a]2D5 =14.8 (c=1.09 in MeOH); 1H NMR (400 MHz,
[D4]MeOH): d=1.20 (d, J=6.8 Hz, 6H), 2.21 (m, 1H), 3.93 (m, 1H),
4.73 (m, 1H), 4.77 (m, 1H), 7.65 (m, 1H), 8.02–8.07 (m, 2H), 8.18 (m,
1H), 8.54 (m, 1H), 8.66 (m, 1H), 10.2 ppm (brs, 1H) NH2 proton
was not observed cleanly; 13C NMR (100 MHz, [D4]MeOH): d=18.3,
18.4, 30.8, 50.7, 57.8, 115.6, 121.5, 125.5, 126.8, 137.3, 141.8, 148.0,
150.6 ppm; IR (KBr): n=3430, 2880, 2000, 1740, 1600, 1550, 1510,
Experimental Section
General
1H NMR was recorded on a JEOL ECS 400 (400 MHz) NMR spec-
trometer. Chemical shifts d are reported in ppm using TMS as an
internal standard. Data are reported as follows: Chemical shift, mul-
tiplicity (s=singlet, d=doublet, t=triplet, q=quartet, sept=septet,
Chem. Eur. J. 2014, 20, 16773 – 16778
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1480, 1440, 1340, 1250, 1220, 1080, 1070 cmÀ1; HRMS (ESI): (m/z)
calcd for C13H19N4: 231.1604 [MÀ(HBr+BrÀ)]+; found: 231.1605.
kis, Tetrahedron: Asymmetry 2001, 12, 2083–2086; c) J. Pytkowicz, S.
Roland, P. Mangeney, Tetrahedron: Asymmetry 2001, 12, 2087–2089.
[5] S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto, Tetrahedron Lett. 2004,
45, 5585–5588.
General procedure for the synthesis of chiral imidazolium
salt (4–12)
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Wilson, Chem. Commun. 2004, 1612–1613; b) P. L. Arnold, A. C. Scaris-
brick, A. J. Blake, C. Wilson, Chem. Commun. 2001, 2340–2341.
[7] a) M. Magrez, Y. L. Guen, O. Baslꢃ, C. Crꢃvisy, M. Mauduit, Chem. Eur. J.
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Acyl chloride (1.5 equiv) was added slowly to a suspension of 16
and K2CO3 (3.0 equiv) in MeCN (0.76m) at 08C. The whole was
warmed to room temperature and stirred for 24 h. The reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure. The resulting material was dissolved in
CHCl3 and the solution was washed ten times with sat. NH4Cl (for
4a), sat. NH4Br (for 4b), sat. NH4BF4 (for 4c), or sat. NH4PF6 (for 4d).
The solvent was removed under reduced pressure and the residue
was purified by silica-gel column chromatography.
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(S)-1-(3-Methyl-2-pivalamidobutyl)-3-(pyridin-2-yl)-1H-imidazol-
3-ium chloride (4a): Silica-gel column chromatography (CHCl3/
MeOH=10:1 to 3:1) gave 4a (191 mg, 36% yield, 1.5 mmol scale)
as an amorphous. [a]D25 =À131.3 (c=0.50 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.04 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz,
3H), 1.07 (s, 9H), 2.05 (sept, J=6.8 Hz, 1H), 4.26 (m, 1H), 4.35 (m,
1H), 5.23 (dd, J=12.4, 6.2 Hz, 1H), 7.38 (brs, 1H), 7.45 (m, 1H),
7.70 (d, J=9.6 Hz, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.14 (m, 1H),
8.53 (m, 1H), 11.9 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=
18.7, 19.5, 27.4, 31.2, 38.7, 51.2, 53.8, 113.7, 117.9, 123.5, 124.9,
136.0, 140.2, 145.7, 149.1, 179.5 ppm; IR (KBr): n=3440, 2960, 1650,
1600, 1540, 1480, 1450, 1370, 1210, 1080, 1000 cmÀ1; HRMS (ESI):
(m/z) calcd for C18H27N4O: 315.2179 [MÀCl]+; found: 315.2187.
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This work was partially supported by a Grant-in-Aid for Young
Scientists (B) (24750037) and a Grant-in-Aid for Scientific Re-
search (B) (24350022) from the Japan Society for the Promo-
tion of Science.
Keywords: asymmetric alkylation
·
copper catalysis
·
enantioselectivity · N-heterocyclic carbenes · N-sulfonylimines
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