1,2,3-triazolium-tagged prolines and their application in asymmetric aldol and Michael reactions

Article abstract of DOI:10.1055/s-0029-1217039

Novel 1,2,3-triazolium-tagged proline derivatives were synthesized by copper-catalyzed click-reaction of alkynes with azides and N-alkylation of the resulting 1,2,3-triazoles. They were applied as recyclable organocatalysts in direct asymmetric aldol and

Full text of DOI:10.1055/s-0029-1217039

PAPER
3975
1,2,3-Triazolium-Tagged Prolines and Their Application in Asymmetric Aldol
and Michael Reactions
1
, 2,3-Tria
a
zolium-Tag
b
ged Prolines
b
in Asymme
t
a
ric
A
ldol
a
r
nd Michae
l
Re
S
a
ctions hah, Sadaf S. Khan, Haiko Blumenthal, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
Received 3 April 2009; revised 20 July 2009
years.11,12 In such cases, imidazolium and pyridinium salts
were used as IL-tags, which were covalently linked to
amines, proline, sulfonic acids or alcohols as organocata-
lytic units.13,14 In addition to an easier recycling of these
Abstract: Novel 1,2,3-triazolium-tagged proline derivatives were
synthesized by copper-catalyzed click-reaction of alkynes with
azides and N-alkylation of the resulting 1,2,3-triazoles. They were
applied as recyclable organocatalysts in direct asymmetric aldol and
Michael reactions with high enantioselectivity and diastereoselec- conjugates, better catalytic performance was observed in
tivity. These catalysts performed better than (S)-proline itself; that
a few cases as compared with non-tagged organocatalysts;
is to say, a synergistic effect of the triazolium and the proline moiety
that is to say that synergistic effects can occur by combin-
exists. The reactions could be carried out either in conventional sol-
ing IL-tags with organocatalysts.15,16
vents or in ionic liquids. The catalysts were easily recycled and re-
1,2,3-Triazolium salts were recently developed by us as a
new class of ILs.17 They can be synthesized in a straight-
forward and versatile way by a copper-catalyzed cycload-
dition of azides with alkynes (Huisgen–Meldal–Sharpless
click reaction), followed by N-alkylation of the resulting
1,2,3-triazoles. This methodology has already been used
to attach triazolium tags to a chiral amines derived from
(S)-prolinol.18 These IL-tagged amines catalyzed Michael
additions to b-nitrostyrenes in excellent yields and enan-
tioselectivities and could be easily recycled and reused.
used several times.
Key words: aldol reaction, Michael reaction, asymmetric synthe-
sis, organocatalysis, ionic liquids, click reaction
The rapidly developing field of organocatalysis is in the
focus of contemporary research, in particular, in asym-
metric organic synthesis.1,2 It finds wide application in
academia and also in industries. Various classes of orga-
nocatalysts, such as amino acids, thioureas, chiral diols
(BINOL, TADDOL, etc.) are useful in this field. Amongst
them, (S)-proline has found manifold applications, e. g. in
aldol, Mannich and Michael reactions, and its use has re-
sulted in high yields and often good stereoselectivities.3
From the point of view of green chemistry, recycling of
catalysts and solvents is an important issue. In this field,
the application of ionic liquids (ILs) became a novel
method with which to meet this challenge.4–6 ILs possess
very high boiling points and are essentially non-volatile.
Thus, they can be applied as reaction medium, wherein
volatile products can be removed by distillation and the
remaining IL can be directly reused. As an alternative,
products formed in polar IL as reaction medium can be
separated by solvent extraction, whilst retaining the IL for
reuse. Recently, a number of organocatalyzed reactions
were implemented in ILs.7–10 In general, it is convenient
to retain the catalyst in the IL as a so-called working solu-
tion in such procedures. This goal can be achieved by
equipping the organocatalyst with an IL-tag. Such IL-
tagged organocatalysts can either be used in the IL as re-
action medium as outlined above or can be used in tradi-
tional organic solvents where recycling is possible by
extracting the products from the reaction mixture and re-
using the remaining IL-tagged organocatalyst. Several ex-
amples have been developed in this field over the last few
We herein report attempts to apply the triazolium-based
IL-tagging to (S)-prolines in order to obtain novel IL-
tagged organocatalysts. Furthermore, their catalytic per-
formance in aldol reactions and Michael additions is dis-
closed.
The syntheses of all new triazolium-tagged prolines start-
ed with trans-4-hydroxy-(S)-proline. Position 4 was cho-
sen as the tethering point for the triazolium unit while the
amino and carboxyl functions were protected by Cbz and
benzyl, respectively (formation of 1)19 by known proce-
dures. Three different synthetic strategies were used. In a
first strategy (Scheme 1) the 4-hydroxy group of 1 was
transformed into the azido group to give the functional-
ized proline 2 via the tosylate by inversion of configura-
tion according to a known procedure.20 Click reaction of 2
with 1-hexyne was catalyzed by copper sulfate, in the
presence of sodium ascorbate, affording high yields of the
1,2,3-triazole 3. Methylation with methyl iodide to the
1,2,3-triazolium iodide 4 and salt metathesis with silver
tetrafluoroborate (AgBF4) gave 5 in excellent yields.
Deprotection by Pd/C-catalyzed hydrogenation resulted
in the triazolium-tagged proline 6.
In a second approach, the proline part was used as the
alkyne reactant in the click reaction. We maintained the 4-
hydroxy function of the diprotected proline 1 and intro-
duced a propargyl unit by adopting a reported Williamson
ether synthesis for N-boc-protected t-butyl 4-hydroxypro-
linate.21 Click reaction of the resulting propargyl ether 7
with dodecyl azide gave 71% of the triazole 8 after chro-
SYNTHESIS 2009, No. 23, pp 3975–3982
Advanced online publication: 12.10.2009
DOI: 10.1055/s-0029-1217039; Art ID: T07009SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

3976
J. Shah et al.
PAPER
matographic separation (Scheme 2). Its transformation We applied 20 mol% of the corresponding triazolium-
into the triazolium salt tagged proline 11 was implement- tagged (S)-proline 6, 11 or 16 in the direct aldol reactions
ed again by methylation to 9, salt metathesis to 10 and fi- of aromatic aldehydes 18 with acetone, cyclohexanone, or
nal hydrogenative deprotection. All steps proceeded in cyclopentanone as CH-acidic components, using an ex-
excellent yields.
cess of the ketone 17 as solvent (Scheme 4). All three cat-
alysts performed similarly well, although catalyst 11 was
slightly inferior (Table 1).
As a third target, we chose proline 16, wherein the triazo-
lium unit is connected to the 4-hydroxy function by a
longer tether (Scheme 3) and applied the proline moiety Excellent diastereoselectivities and ee values above 90%
as alkylating reagent for the 1,2,3-triazole unit. Thus, the were obtained with cyclohexanone in most cases. Cyclo-
diprotected proline 1 was esterified with 5-bromovaleric pentanone gave lower diastereoselectivities and enantio-
acid giving the known ester 12,22 which was further used selectivities as compared with cyclohexanone (see 19a
as alkylating reagent for 1,4-di(n-butyl)-1,2,3-triazole and 19g in Table 1). 81% ee could be achieved in the aldol
(13). Salt metathesis of the resulting triazolium bromide reaction of acetone with 4-nitrobenzaldehyde, in the pres-
14 (76% yield) with AgBF4 and hydrogenative deprotec- ence of catalyst 16, giving 19h. At this point it can be con-
tion led to the triazolium-tagged proline 16.
cluded that triazolium-tagged prolines 6, 11, and 16 are
useful organocatalysts for aldol reactions. Obviously the
type of tethering of the triazolium unit to the 4-position of
the proline does not affect the catalytic performance sig-
nificantly.
With the three new triazolium-tagged prolines 6, 11 and
16 in hand we approached their application in organocat-
alyzed reactions. The asymmetric aldol reaction was one
of the first examples wherein (S)-proline and its deriva-
tives were used as organocatalysts, giving high yields and We further investigated the behavior of the triazolium-
good enantioselectivities. Since the pioneering work of tagged proline 6 in recycling experiments for the aldol re-
List and Barbas in 2000/2001,23–25 numerous applications action of cyclohexanone with 4-bromobenzaldehyde
have been published, amongst them, aldol reactions in (Scheme 5, Table 2). At first, we chose the same reaction
ionic liquids26,27 as well as the use of imidazolium- or conditions as before, i. e. an excess of cyclohexanone as
ammonium-tagged prolines in organic solvents or ionic solvent and 20 mol% of the catalyst (Method A). The re-
liquids.15,16
HO
O
HO
N3
CO2Bn
N
ref. 21
CO2Bn
N
Cbz
ref. 19
CO2Bn
Cbz
N
CO2Bn
N
cbz
1
7
1
cbz
2
Me(CH2)11N3
hex-1-yne, Na ascorbate,
CuSO4 (cat.),
MeOH, 48 h, r.t.
90%
CuSO4(cat), Na ascorbate,
MeOH, 48 h
71%
n-Bu
N
n-Bu
I
I
N
N
MeI, MeCN
C12H25
N
N
Me
N
reflux, 12 h
Me
N
O
N
C12H25
N
N
N
N
O
MeI, MeCN,
argon, reflux, 12 h
quantitative yield
CO2Bn
CO2Bn
N
CO2Bn
N
quantitative
yield
N
CO2Bn
Cbz
N
cbz
cbz
9
Cbz
8
4
3
quantitative
yield
AgBF4,
MeOH,
r.t.
AgBF4, MeOH, r.t.
quantitative
yield
BF4
Me
n-Bu
N
Me
N
N
Me
N
BF4
n-Bu
N
N
BF4
C12H25
BF4
C12H25
N
O
O
Me
H2 (5 bar),
Pd/C, 12 h, r.t.
N
N
N
N
N
H2 (5 bar), Pd/C,
MeOH, 12 h
CO2H
83%
N
CO2Bn
N
Cbz
H
CO2Bn
OH
N
N
H
Cbz
O
88%
5
6
10
11
Scheme 1
Scheme 2
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

PAPER
1,2,3-Triazolium-Tagged Prolines in Asymmetric Aldol and Michael Reactions
3977
O
triazolium tag
HO
O
Br
OH
N
H
O
OH
R3
O
O
CO2Bn
N
O
ref. 22
CO2Bn
N
6, 11, 16
Cbz
H
R3
Cbz
+
R1
R2
R1
R2
1
12
17
18
19
N
N
N
n-Bu
O
Br
13
n-Bu
n-Bu
O
OH
O
OH
O
OH
n-Bu
O
N
90 °C, 10 min
76%
N
N
CO2Bn
N
Br
Cl
NO2
19a
Cbz
19b
19c
14
O
OH
O
OH
O
OH
O
BF4
n-Bu
O
N
N
AgBF4, MeOH, r.t.
quantitative yield
OMe
F
19d
19e
19f
N
CO2Bn
N
n-Bu
O
OH
OH
O
Cbz
15
O
BF4
NO2
n-Bu
NO2
O
N
H2 (5 bar), Pd/C, MeOH
91%
19g
19h
N
N
Scheme 4
CO2H
N
H
n-Bu
16
diethyl ether occurred (Table 2, footnote a). Indeed, ex-
traction with less polar cyclohexane gave better results in
recycling experiments (Table 2, footnote b). Under these
conditions, 88% yield with 68% ee and a diastereomeric
ratio of 97:3 could be achieved in the 5th cycle. However,
as reported in other recycling efforts in organocatalysis,
there was still a drop in yields and enantioselectivities.
Leaching of the organocatalyst can lower the reaction
rates thus leading to lower yields in the same reaction
time. However, enantioselectivities should not be affected
by this loss unless a relative increase of a non-enantiose-
lective background reaction occurs. On the other hand, a
Scheme 3
action mixture was worked up by extraction with diethyl
ether or cyclohexane. The triazolium-tagged organocata-
lyst 6 remained as an oil, which was concentrated under
vacuum and combined with fresh reactants to run the next
cycle. High yields above 80% were achieved until the 5th
cycle and the diastereoselectivity remained excellent.
However, the enantioselectivity diminished after each re-
cycling, finally reaching 44% ee. We supposed that leach-
ing of the organocatalyst during the extraction with
Table 1 Aldol Reactions Catalyzed by Ionic Liquid Tagged Prolines 6, 11 and 16
Catalyst 6
Catalyst 11
Catalyst 16
Product
19a
Time (h) Yield (%) anti/ syn
eea (%) Time (h) Yield (%) anti/ syn eea (%) Time (h) Yield (%) anti/ syn eea (%)
24
22
31
40
18
27
48
37
98
99
96
91
95
92
89
84
99:1
98:2
99:1
97:3
96:4
88:12
67:33
–
98
92
90
99
90
81
89
76
27
22
34
41
13
25
42
39
94
96
99
92
90
87
91
79
99:1
98:2
99:1
97:3
96:4
88:12
67:33
–
96
74
82
91
62
77
86
69
26
21
34
48
20
29
51
39
99
97
95
92
90
79
83
79
99:1
98:2
99:1
97:3
96:4
88:12
67:33
–
94
84
94
95
72
83
90
81
19b
19c
19d
19e
19f
19g
19h
a Of major diastereomer.
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

3978
J. Shah et al.
PAPER
O
was applied in the addition of propionaldehyde to b-ni-
trostyrene affording unsatisfactory yield (44%) and enan-
tioselectivity (28%).29 However, an improvement in the
ee was achieved by introducing a TBDMSO group in the
4-position of proline.29 High yields (94–95%) and low ee
values (23%) were obtained in the (S)-proline catalyzed
Michael addition of cylohexanone to b-nitrostyrene.30,31
Chiral pyrrolidines derived from (S)-proline via reduction
or Grignard reaction allowed such Michael additions to be
run in a satisfactory manner.32 Amongst them, triazolium
salt and imidazolium salt tagged chiral pyrrolidines were
also successfully employed.18,33
6 (20 mol%), r.t., 22 h
+
19b
O
Method A:
in cyclohexanone
(90–94% yield,
anti/syn 99:1, ee 92%)
H
Br
Method B:
in
n-Hex
I
N
Et2N
N(n-Pr)2
We applied the triazolium-tagged proline 6 in the Michael
addition of cyclohexanone, cyclopentanone and acetone
to b-nitrostyrene (Scheme 6, Table 3). High yields were
obtained and the ee values were higher (48–54% for cy-
clohexanone adducts) than in known cases, in which (S)-
proline was used.33,34 Thus, a synergistic effect apparently
occurs, caused by the combination of (S)-proline with the
triazolium tag within the catalyst 6. The reason for this is
not clear but it is possible that the IL-tag could act as a
Lewis acid to activate the nitrostyrene in the cyclic transi-
tion-state proposed in such reactions.35 Cyclopentanone
reacted with lower diastereoselectivity and enantioselec-
tivity (entry 5). The outcome of the Michael addition of
acetone to b-nitrostyrene was totally unsatisfactory from
the point of view of stereoselectivity (6% ee, entry 6).
(99% yield,
anti/syn 99:1, ee 94%)
Method C:
in [bmim] BF4
(98% yield,
anti/syn 98:2, ee 92%)
Scheme 5
partial epimerization at the 2-position of the proline moi-
ety could occur, as observed in the application of (S)-pro-
line and 4-hydroxy-(S)-proline in coupling reactions, due
to intermediate enolization.28 We are presently develop-
ing an IL-tagged hydroxyproline derivative with a quater-
nary C-atom at the 2-position which cannot epimerize and
will investigate its performance in recycling experiments.
The next recycling experiments were performed in ionic
liquids, namely N,N-diethyl-N¢-hexyl-N¢-methyl-N¢¢,N¢¢-
dipropylguanidinium iodide (Method B) and 1-butyl-3-
Table 3 Products 21 of the Michael Addition to Nitrostyrenes Cat-
alyzed by 6
ee (%)a
50
–
Entry
Product
21a
Yield (%)
anti/syn
95:5
methylimidazolium tetrafluoroborate (bmim BF4 , Meth-
od C) as solvents (Table 2). Equimolar ratios of cyclohex-
anone and 4-bromobenzaldehyde were used and the
reaction mixture was extracted with diethyl ether. Work-
ing in the guanidinium salt (Method B) gave somewhat
better results than the neat reaction (Method Aa). The
1
2
3
4
5
6
98
94
99
93
82
79
21b
21c
90:10
88:12
96:14
67:33
–
54
48
–
21d
21e
52
commercially available bmim BF4 , however, led to a
more rapid decrease in enantioselectivity after recycling
(Table 2, Method C, cycles 4 and 5).
27
21f
6
We further envisaged applying triazolium-tagged prolines
to Michael reactions with b-nitrostyrene. Proline itself
a Of major diastereomer.
Table 2 Recycling Experiments in Aldol Reaction to Aldol 19b Catalyzed by 6
Cycle Yield (%)/Time (h)
Method
anti/syn
Method
Aa
ee (%)c
Method
Aa
Aa
Ab
B
C
Ab
B
C
Ab
92
84
74
72
68
B
C
1
2
3
4
5
90/22
90/25
88/29
85/38
84/41
94/22
92/23
91/32
91/38
88/43
99/22
96/25
90/29
89/38
88/41
99/22
97/25
95/29
90/38
89/41
99:1
98:2
98:2
99:1
97:3
99:1
98:2
98:2
97:3
97:3
99:1
98:2
98:2
96:4
96:4
98:2
98:2
97:3
97:3
95:5
92
86
74
64
44
94
78
76
74
66
92
75
64
49
36
a Extraction with Et2O.
b Extraction with cyclohexane.
c Of major diastereomer.
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

PAPER
1,2,3-Triazolium-Tagged Prolines in Asymmetric Aldol and Michael Reactions
3979
Thermo Finnigan LTQ-FT-ICR-MS spectrometers. Silica gel
(0.04–0.063 mm, Merck) was used for preparative column chroma-
tography. Compounds 1,19 2,20 7,21 and 1222 were synthesized ac-
cording to literature procedures. All the other materials were
purchased from commercial suppliers. Configurations of major
products were elucidated by comparing optical rotation with litera-
ture data.30,36
O
6 (10 mol%), TFA (cat.),
r.t., 24 h
O
R3
+
NO2
NO2
R3
78–99%,
R1
R2
17
anti/syn 67:33–96:4
ee 6–54%
R1
R2
20
21
(2S,4S)-Dibenzyl-4-(4-butyl-1H-1,2,3-triazol-1-yl)pyrrolidine-
1,2-dicarboxylate (3)
OMe
To a solution of 2 (0.3 g, 0.79 mmol) in MeOH (10 mL), 1-hexyne
(0.1 ml, 0.79 mmol), sodium ascorbate (0.313 g, 1.58 mmol, 20
mol%) and CuSO4 (0.188 g, 1.8 mmol, 15 mol%) were added. The
reaction mixture was stirred for 48 h (reaction monitored by TLC)
then quenched by adding H2O (30 mL). The mixture was extracted
with EtOAc (3 × 30 mL) and the organic layer was washed with
brine (3 × 30 mL) and then dried and evaporated. The product 3 was
purified by column chromatography (Rf = 0.37; CHCl3–acetone,
2:1).
O
O
NO2
NO2
NO2
O
NO2
21a
21b
21c
Yield: 328 mg (90%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.34–7.33 (m, 10 H, Ar), 7.22 (br
s, 1 H, N-CH=C), 5.24–5.06 (m, 4 H, 2 × CH2-Ar), 5.02 (m, 1 H, N-
CH-CH2-N), 4.57 (m, 1 H, N-CH-CO2), 4.22 (m, 1 H, N-CH2-CH-
N), 3.92 (m, 1 H, N-CH2-CH-N), 2.94 (m, 1 H, N-CH-CH2-CH),
2.68 (t, J = 7.2 Hz, 2 H, C-CH2-CH2), 2.58 (m, 1 H, N-CH-CH2-
CH), 1.62 (m, 2 H, CH3-CH2-CH2), 1.37 (m, 2 H, CH3-CH2), 0.94
(t, J = 7.3 Hz, 3 H, CH3).
O
O
O
NO2
NO2
NO2
21d
21e
21f
13C NMR (75 MHz, CDCl3): d = 171.1 (O=CO), 154.0 (O=C-N),
148.9 (C-triazole), 135.9 (C-Ar), 135.2 (C-Ar), 128.6–127.9 (Ar-
CH), 119.3 (N-CH=C), 67.6 (CH2-Ar), 67.3 (CH2-Ar), 57.9 (N-CH-
Scheme 6
Since the performance of the triazolium-tagged proline 6 CO2), 57.0 (N-CH-CH2-N), 51.8 (N-CH2-CH-N), 35.2 (N-CH-CH2-
CH), 31.5 (CH3-CH2-CH2), 25.3 (C-CH2-CH2), 22.3 (CH3-CH2),
13.8 (CH3-CH2).
HRMS: m/z [M + H]+ calcd for C26H31N4O4: 463.234; found:
463.234.
as organocatalyst in Michael additions could not compete
with known chiral pyrrolidine derivatives, we refrained
from investigating the recyclability of 6 as well as from
testing the other triazolium-tagged prolines 11 and 16 in
these Michael reactions.
3-[(3S,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yl]-5-butyl-
In summary, we have developed three triazolium-tagged
(S)-prolines 6, 11 and 16 as organocatalysts, and thus
demonstrated their ability to establish ionic liquid tags by
the combination of copper-catalyzed Huisgen–Meldal–
Sharpless cycloaddition reaction of alkynes with azides
and alkylation of the resulting 1,2,3-triazoles. The tagged
prolines were applied in direct aldol reactions of ketones
either without an additional solvent or in ionic liquids, af-
fording high yields and stereoselectivities. The triazoli-
um-tagged proline 6 could be recycled and reused several
times, maintaining good performance until the fourth cy-
cle. After this, the enantioselectivity decreased below
70% ee. Improved catalytic performance of 6, as com-
pared with proline, was also observed in Michael addition
to b-nitrostyrene. However, the outcome of this reaction
was not good enough to compete with other known orga-
nocatalysts. At present we are investigating ways to im-
prove the recyclablity of our IL-tagged organocatalysts by
variation of the anions, by special filtration techniques
and by using proline derivatives which are devoid of pos-
sible racemization through epimerization.
1-methyl-3H-1,2,3-triazol-1-ium Iodide (4)
To a solution of the triazole 3 (0.6 g, 1.5 mmol) in MeCN (50 mL),
MeI (0.48 mL, 1.1 g, 8 mmol) was added. The reaction mixture was
refluxed under an argon atmosphere overnight. After completion of
the reaction, the solvent was removed to obtain 4.
Yield: 1.2 g (100%); brown oil.
1H NMR (300 MHz, CDCl3): d = 9.0 (s, 1 H, N-CH=C), 7.30–7.20
(m, 10 H, Ar), 5.89 (m, 1 H, N-CH-CH2-N), 5.14–4.98 (m, 4 H, 2 ×
CH2-Ar), 4.57 (m, 1 H, N-CH-CO2), 4.21 (m, 2 H, N-CH2-CH-N),
4.07, 4.02 (s, 3 H, CH3-N)*, 3.15 (m, 1 H, N-CH-CH2-CH), 2.78 (t,
J = 7.2 Hz, 2 H, C-CH2-CH2), 2.68 (m, 1 H, N-CH-CH2-CH), 1.69
(m, 2 H, CH3-CH2-CH2), 1.44 (m, 2 H, CH3-CH2), 0.94 (t, J = 7.2
Hz, 3 H, CH3). * Partially doubled sets of peaks due to rotamers.
13C NMR (75 MHz, CDCl3): d = 170.9 (O=C-O), 153.6 (O=C-N),
144.7 (C-triazole), 135.6 (C-Ar), 134.9 (C-Ar), 128.5–127.6 (Ar-
CH), 127.6 (N-CH=C), 67.4 (CH2-Ar), 67.0 (CH2-Ar), 61.8 (N-CH-
CO2), 57.1 (N-CH-CH2-N), 51.0 (N-CH2-CH-N), 38.3 (CH3-N),
35.6 (N-CH-CH2-CH), 28.6 (CH3-CH2-CH2), 23.4 (C-CH2-CH2),
21.9 (CH3-CH2), 13.4 (CH3-CH2).
HRMS: m/z [M + H]+ calcd for C27H34N4O4 : 478.257; found:
478.255.
+
3-[(3S,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yl]-5-butyl-
1-methyl-3H-1,2,3-triazol-1-ium Tetrafluoroborate (5)
In a 50 mL dry, round-bottom flask, 4 (0.5 g, 0.82 mmol) was dis-
solved in anhydrous MeOH (15 mL). In a second flask (which was
either brown colored or wrapped in aluminum foil to exclude light),
1H NMR and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively, with a Bruker AC 300, in CDCl3 with TMS as internal
standard. MS analyses were carried out on Varian MAT 711 and
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

3980
J. Shah et al.
PAPER
AgBF4 (0.159 g, 0.82 mmol) was dissolved in anhydrous MOH (15
mL). The AgBF4 solution was added dropwise to the solution of 4
until no more precipitate (AgI) was formed. After the precipitate
had settled down, the clear supernatant solution was separated,
dried and evaporated giving a quantitative yield of 5 as yellow oil.
NMR spectra were identical to 4.
1H NMR (300 MHz, CDCl3): d = 9.26, 9.30 (2 × s, 1 H, N-CH=C)*,
7.40–7.21 (m, 10 H, Ar), 5.20–5.02 (m, 4 H, 2 × CH2-Ar), 5.04 (m,
2 H, C-CH2-O), 4.62 (m, 2 H, N-CH2-CH2), 4.50 (m, 1 H, CH-O-
CH2), 4.47 (m, 1 H, CH-COOBn), 4.25 (s, 3 H, CH3), 3.65 (m, 2 H,
CH2-N), 2.53 (m, 1 H, CH2-CH-O), 2.19 (m, 1 H, CH2-CH-O), 1.82
(m, 2 H, N-CH2-CH2), 1.33–1.25 (m, 18 H, 9 × CH2), 0.90 (t,
J = 6.0 Hz, 3 H, CH3). * Doubled sets of peaks due to rotamers.
5-Butyl-3-[(3S,5S)-5-carboxypyrrolidin-3-yl]-1-methyl-3H-
1,2,3-triazol-1-ium Tetrafluoroborate (6)
To a solution of 5 (1 g, 1.77 mmol) in anhydrous MeOH (15 mL),
Pd/C (80 mg) was added and the mixture was pressurized under H2
at 5 bar. After stirring overnight, the Pd/C was filtered off and the
filtrate was concentrated under vacuum to give 6.
13C NMR (75 MHz, CDCl3): d = 171.8 (CH-COOBn), 154.4 (N-
COO-CH2), 140.2 (N-C-CH2), 128.5 (10 CH, Ar), 67.2 (O-CH2-
Ar), 59.3 (CH2-O-CH), 57.7 (CH-COOBn), 54.4 (CH2-N), 50.3
(CH2-CH2-N), 39.5 (N-CH3), 36.5 (CH2-CH-O), 31.8 (CH3-CH2-
CH2), 29.6 (7 × CH2), 26.1 (CH2-CH2-N), 22.6 (CH3-CH2), 14.1
(CH3, CH2-CH-O).
Yield: 0.5 g (83%); yellow oil.
+
HRMS: m/z [M + H]+ calcd for C36H52N4O5 : 620.393; found:
1H NMR (300 MHz, CDCl3): d = 8.67 (s, 1 H, N-CH=C), 5.66 (m,
1 H, N-CH-CH2-N), 4.37 (m, 1 H, N-CH-CO2), 4.24 (s, 3 H, CH3-
N), 4.07 (m, 2 H, N-CH2-CH-N), 3.12 (m, 2 H, N-CH-CH2-CH),
2.88 (t, J = 7.2 Hz, 2 H, C-CH2-CH2), 2.7 (m, 2 H, N-CH-CH2-CH),
1.77 (m, 2 H, CH3-CH2-CH2), 1.52 (m, 2 H, CH3-CH2), 1.02 (t,
J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 145.4 (C-triazole), 127.6 (N-
CH=C), 62.4 (N-CH-CO2), 60.1 (N-CH-CH2-N), 49.4 (N-CH2-CH-
N), 36.7 (CH3-N), 34.3 (N-CH-CH2-CH), 28.3 (CH3-CH2-CH2),
22.4 (C-CH2-CH2), 21.7 (CH3-CH2), 12.5 (CH3-CH2).
620.390.
5-{[(3R,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yl-
oxy]methyl}-3-dodecyl-1-methyl-3H-1,2,3-triazol-1-ium Tetra-
fluoroborate (10)
In a 50 mL dry, round-bottom flask, the iodide salt 9 (0.5 g, 0.66
mmol) was dissolved in anhydrous MeOH (15 mL). In a second
flask (which was either brown-colored or wrapped in aluminum foil
to exclude light), AgBF4 (0.128 g, 0.66 mmol) was dissolved in an-
hydrous MeOH (15 mL) and the AgBF4 solution was added drop-
wise to the solution of 9 until no more precipitate (AgI) was formed.
After the precipitate had settled down, the clear supernatant solution
was separated, dried and evaporated giving a quantitative yield of
10 as a yellow oil. NMR spectra were identical to 9.
HRMS: m/z [M + H]+ calcd for C12H22N4O2 : 254.173; found:
+
254.171.
Dibenzyl (2S,4R)-4-[(1-Dodecyl-1H-1,2,3-triazol-4-yl)meth-
oxy]pyrrolidine-1,2-dicarboxylate (8)
5-{[(3R,5S)-5-Carboxypyrrolidin-3-yloxy]methyl}-3-dodecyl-1-
methyl-3H-1,2,3-triazol-1-ium Tetrafluoroborate (11)
To a solution of 10 (0.6 g, 1.41 mmol) in anhydrous MeOH (15
mL), Pd/C (80 mg) was added and the mixture was pressurized un-
der H2 at 5 bar. After stirring overnight, the Pd/C was filtered off
and the filtrate was concentrated under vacuum to give 11.
To a solution of 7 (0.9 g, 2 mmol) and 1-azidododecane (0.5g, 2
mmol) in MeOH (50 mL), sodium ascorbate (0.1 g, 0.5 mmol, 20
mol%) and CuSO4 (0.1 g, 0.4 mmol, 15 mol%) were added. The re-
action mixture was stirred for 48 h (monitored by TLC) and
quenched by adding H2O (30 mL). After extraction with EtOAc
(3 × 30 mL), the combined organic layer was washed with brine
(3 × 30 mL), dried and concentrated under vacuum. The remainder
was purified by column chromatography (Rf = 0.32; CHCl3–ace-
tone, 6:1) to give product 8.
Yield: 0.825 g (88%); yellow oil.
1H NMR (300 MHz, DMSO-d6): d = 8.89 (s, 1 H, N-CH=C), 4.82
(m, 2 H, C-CH2-O), 4.58 (m, 2 H, N-CH2-CH2), 4.36 (m, 1 H, CH-
O-CH2), 4.02 (m, 1 H, CH-CO2H), 4.23 (s, 3 H, CH3-N), 3.34 (m,
2 H, CH2-N), 2.50 (m, 2 H, CH2-CH-O), 2.08 (m, 2 H, CH2-CH-O),
1.89 (m, 2 H, N-CH2-CH2), 1.37–1.27 (m, 18 H, 9 × CH2), 0.84 (t,
J = 6.4 Hz, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (COOH), 140.5 (N-C-
CH2), 129.9 (N-CH=C), 78.7 (CH2-O-CH), 59.5 (CH-COOH), 53.5
(CH2- N), 50.3 (CH2-CH2-N), 38.5 (N-CH3), 35.0 (CH2-CH-O),
31.7 (CH3-CH2-CH2), 29.6 (7 × CH2), 25.8 (CH2-CH2-N), 22.5
(CH3-CH2), 14.3 (CH3, CH2-CH-O).
Yield: 1.0 g (71%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.49, 7.51, (2 × s, 1 H, N-CH=C)*,
7.36–7.23 (m, 10 H, Ar), 5.23–5.01 (m, 4 H, 2 × CH2-Ar), 4.63 (m,
2 H, C-CH2-O), 4.50 (m, 1 H, CH-O-CH2), 4.34 (m, 2 H, N-CH2-
CH2), 4.31 (m, 1 H, CH-COOBn), 3.69 (m, 2 H, CH2-N), 2.42 (m,
1 H, CH2-CH-O), 2.11 (m, 1 H, CH2-CH-O), 1.73 (m, 2 H, N-CH2-
CH2), 1.33–1.27 (m, 18 H, 9 × CH2), 0.90 (t, J = 6.0 Hz, 3 H, CH3).
* Doubled sets of peaks due to rotamers.
13C NMR (75 MHz, CDCl3): d = 172.4 (CH-COOBn), 154.9 (N-
COO-CH2), 136.3 (N-C-CH2), 128.5 (10 × CH, Ar), 122.3 (N-
CH=C), 67.1 (O-CH2-Ar), 62.7 (CH2-O-CH), 57.8 (CH-COOBn),
52.1 (CH2-N), 50.4 (CH2-CH2-N), 35.4 (CH2-CH-O), 31.9 (CH3-
CH2-CH2), 29.6 (7 × CH2), 26.5 (CH2-CH2-N), 22.6 (CH3-CH2),
14.1 (CH3 and CH2-CH-O).
HRMS: m/z [M + H]+ calcd for C21H40N4O3 : 396.309; found:
396.307.
+
1,4-Dibutyl-1H-1,2,3-triazole (13)
To a solution of butyl azide (2.5 g, 25.2 mmol, 1 equiv) in MeOH
(75 mL), sodium ascorbate (1 g, 5 mmol, 20 mol%), CuSO4 (0.61g,
3.8 mmol, 15 mol%) and 1-hexyne (25.2 mmol, 2.9 mL) were add-
ed. The mixture was stirred until the reaction went to completion
(reaction monitored by TLC; typically 2–3 d), then H2O (250 mL)
was added and the mixture was extracted with EtOAc (3 × 100 mL).
The combined organic layers were washed with brine (3 × 100 mL)
and dried over NaSO4. Evaporation of the solvent under vacuum
gave a yellow oily residue which was purified by column chroma-
tography (Rf = 0.65; CHCl3–acetone, 9:1).
HRMS: m/z [M + H]+ calcd for C35H49N4O5: 605.370; found:
605.369.
5-{[(3R,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidine-3-
yloxy]methyl}-3-dodecyl-1-methyl 3H-1,2,3-Triazol-1-ium Io-
dide (9)
The triazole 8 (0.6 g, 1.5 mmol) was dissolved in MeCN (50 mL),
MeI (0.48 mL, 1.1 g, 8 mmol) was added and the reaction mixture
was refluxed under an argon atmosphere overnight. After comple-
tion of the reaction, the solvent was removed to obtain 9.
Yield: 82%.
1H NMR (300 MHz, CDCl3): d = 7.23 (s, 1 H, CH), 4.22 (t, J = 7.2
Hz, 2 H, CH3CH2CH2CH2N), 2.62 (t,
Yield: 1.2 g (100%); yellow oil.
J = 7.7 Hz, 2 H,
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

PAPER
1,2,3-Triazolium-Tagged Prolines in Asymmetric Aldol and Michael Reactions
3981
CH3CH2CH2CH2C), 1.77 (m, 2 H, CH3CH2CH2CH2N), 1.56 (m,
2 H, CH3CH2CH2CH2C), 1.27 (m, 4 H, CH2CH3), 0.83 (m, 6 H,
CH3CH2).
13C NMR (75 MHz, CDCl3): d = 148.2 (C-triazole), 120.4 (CH-tri-
azole), 49.7 (CH3CH2CH2CH2N), 32.2 (CH3CH2CH2CH2C), 31.5
CH-O), 2.90 [t, J = 7.0 Hz, 2 H, CH3-(CH2)2-CH2-C], 2.50 (m, 2 H,
CH2-CH-CO2), 2.17 (m, 2 H, CH2-CH2-CO2), 2.0 (m, 2 H, N+-CH2-
CH2), 1.88 (m, 2 H, CH2-CH2-CO2), 1.76 (m, 2 H, CH2-CH2-CH2-
CO2), 1.65 (m, 2 H, N-CH2-CH2), 1.37 (m, 6 H, CH3-CH2-CH2),
0.98 (m, 6 H, CH3-CH2).
(CH3CH2CH2CH2C),
(CH3CH2CH2CH2C),
(CH3CH2CH2CH2N), 13.3 (CH3CH2CH2CH2C).
HRMS (ESI): m/z [M]+ calcd for C10H19N3: 182.1657; found:
182.1673.
25.2
19.6
(CH3CH2CH2CH2N),
(CH3CH2CH2CH2N),
22.2
13.7
13C NMR (75 MHz, CD3OD): d = 172.3 (CO-O-C), 144.6 (N-C-
CH2), 121.8 (C-CH-N), 72.7 (O-CH-CH2), 53.2 (N+-CH2), 50.9 (N-
CH-CH2), 50.2 (N-CH2-CH), 49.6 (N-CH2), 31.9 (CH-CH2-CH),
31.3 (CH2-CO2), 30.7 (N-N-CH2-CH2), 28.7 (C-CH2-CH2), 27.4 (C-
CH2), 24.5 (N+-CH2-CH2), 21.8, 21.7 (CH2-CH2-COO), 19.2, 19.0
(CH3-CH2), 12.7, 12.4 (CH3).
+
1-{5-[(3R,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yloxy]-
5-oxopentyl}-3,5-dibutyl-3H-1,2,3-triazol-1-ium Bromide (14)
A mixture of compound 12 (1.10 g, 2.12 mmol) and 1,4-dibutyl-1H-
1,2,3-triazole (13; 0.46 g, 2.54 mmol) was heated at 90 °C for 10
min, then cooled to 20 °C and washed with Et2O (6 × 15 mL). The
residue was dissolved in MeOH (3 mL), and Et2O (15 mL) was
gradually added to the stirred solution. The separated oil was placed
under vacuum (0.5 Torr) for 2 h to afford compound 14.
HRMS: m/z [M + H]+ calcd for C20H36N4O4 : 396.273; found:
396.273.
Asymmetric Direct Aldol Reaction to 19; Typical Procedure
A catalytic amount of catalyst 6 (34 mg, 20 mol%) was added to a
flask containing 4-nitrobenzaldehyde (76 mg, 0.5 mmol) and cyclo-
hexanone (0.26 mL, 2.5 mmol) in a closed system. The reaction
mixture was stirred at r.t. for 28 h and subsequently extracted with
Et2O (5 × 10 mL). The combined organic extracts were dried with
anhydrous MgSO4 and the solvent was removed under reduced
pressure. The crude aldol product 19a was purified by silica gel col-
umn chromatography (n-hexane–EtOAc, 4:1) to afford the aldol
product as a white solid36 (107 mg, 86% yield).
The diastereomeric anti/syn ratio was determined by 1H NMR anal-
ysis of the reaction mixture [d = 5.48 (d, J = 1.8 Hz, 1 H, syn, mi-
nor), 4.89 (d, J = 8.8 Hz, 1 H, anti, major)]. Enantiomeric excess
was determined by HPLC with a Chiralcel AD column (n-hexane–
i-PrOH, 90:10; 1.0 mL/min; l = 254 nm; 25 °C): tR = 26.3 min (mi-
nor) and 34.9 min (major).
Yield: 1.12 g (76%); yellow, viscous oil; Rf = 0.36 (CHCl3–acetone,
4:1).
1H NMR (300 MHz, CDCl3): d = 9.52 (s, 1 H, N-CH=C), 7.32–7.20
(m, 10 H, Ar), 5.26 (m, 1 H, CH-CO2-CH2), 5.25–4.98 (m, 4 H,
CH2-Ar), 4.77 (m, 1 H, N-CH-CO2), 4.53 (m, 2 H, N+-CH2), 4.29 [t,
J = 7.2 Hz, 2 H, CH3-(CH2)2-CH2-N], 3.74 (m, 2 H, N-CH2-CH-O),
2.89 [t, J = 7.2 Hz, 2 H, CH3-(CH2)2-CH2-C], 2.37 (m, 1 H, CO2-
CH-CH2), 2.21 (m, 2 H, CH2-CH2-CO2), 2.01 (m, 2 H, N+-CH2-
CH2), 1.99 (m, 1 H, CH2-CH-CO2), 1.76 (m, 2 H, CO2-CH2-CH2-
CH2), 1.64 (m, 2 H, N-CH2-CH2), 1.37 (m, 6 H, CH3-CH2-CH2),
0.95 (m, 6 H, CH3-CH2).
13C NMR (75 MHz, CDCl3): d = 171.9, 171.6 (CO-O-C), 154.6
(CO-O-CH2), 144.1 (CO-O-CH2), 136.0 (N-C-CH2), 135.3, 135.0
(C-Ph), 129.8–127.8 (CH-Ar), 120.4 (C-CH-N), 72.7 (O-CH-CH2),
67.3 (CH2-Ph), 57.9 (N+-CH2), 53.9 (N-CH-CH2), 52.6 (N-CH2-
CH), 50.9 (N-CH2), 36.4 (CH-CH2-CH), 32.9 (CH2-CO2), 31.4 (N-
N-CH2-CH2), 29.4 (C-CH2-CH2), 28.0 (C-CH2), 23.3 (N+-CH2-
CH2), 22.2, 21.2 (CH2-CH2-COO), 19.4 (CH3-CH2), 13.4, 13.4
(CH3).
1H NMR (300 MHz, CDCl3): d = 8.20 (d, J = 8.6 Hz, 2 H), 7.50 (d,
J = 8.7 Hz, 2 H), 4.89 (d, J = 8.4 Hz, 1 H), 4.07 (s, 1 H), 2.57–2.63
(m, 1 H), 2.32–2.49 (m, 2 H), 1.31–2.12 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 214.8, 148.4, 147.6, 127.9, 123.5,
74.0, 57.2, 42.7, 30.8, 27.7, 24.7.
Recycling the Catalyst; Typical Experimental
The reaction mixture was extracted with either Et2O or cyclohexane
(3 × 15 mL). The combined organic layers were concentrated under
vacuum and, after column chromatography, the pure aldol product
was obtained. The residual catalyst (Method A) or catalyst with ion-
ic liquid (Method B, C) was concentrated under vacuum to remove
residual solvent and then reused for the next run.
+
HRMS: m/z [M + H]+ calcd for C35H47N4O6 : 619.349; found:
619.348.
1-{5-[(3R,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yloxy]-
5-oxopentyl}-3,5-dibutyl-3H-1,2,3-triazol-1-ium Tetrafluoro-
borate (15)
Aldol Reaction in Ionic Liquid and Recycling; Typical Proce-
dure
In 50 mL dry, round-bottom flask, the iodide salt 14 (0.5 g, 0.71
mmol) was dissolved in anhydrous MeOH (15 mL). In a second
flask (which was either brown-colored or wrapped in aluminum foil
to exclude light), AgBF4 (0.14 g, 0.71 mmol) was dissolved in an-
hydrous MeOH (15 mL) and the solution was added dropwise to the
solution of 14 until no more precipitate (AgI) was formed. After the
precipitate had settled down, the clear supernatant solution was sep-
arated, dried and evaporated giving a quantitative yield of 15 as a
yellow oil. NMR spectra were identical to 14.
A catalytic amount of catalyst 6 (34 mg, 20 mol%) was added to 4-
nitrobenzaldehyde (76 mg, 0.5 mmol), cyclohexanone (0.26 mL,
2.5 mmol) and ionic liquid (0.5 mL). The flask was closed and the
reaction mixture was stirred at r.t. for 28 h and subsequently extract-
ed with Et2O (5 × 10 mL). The combined organic extracts were
dried with anhydrous MgSO4 and the solvent was removed under
reduced pressure. The crude aldol product was purified by silica gel
column chromatography (n-hexane–EtOAc, 4:1) to afford aldol
product. The residual ionic liquid containing catalyst was concen-
trated under vacuum to remove solvent and then reused in the next
run.
3,5-Dibutyl-1-{5-[(3R,5S)-5-carboxypyrrolidin-3-yloxy]-5-oxo-
pentyl}-3H-1,2,3-triazol-1-ium Tetrafluoroborate (16)
To the solution of 15 (1 g, 1.42 mmol) in anhydrous MeOH (15
mL), Pd/C (80 mg) was added and the mixture was pressurized un-
der H2 at 5 bar. After stirring overnight, the Pd/C was filtered off
and the filtrate was concentrated under vacuum to give 16.
Michael Addition of Cyclohexanone to Nitrostyrene; Typical
Procedure
Nitrostyrene (37 mg, 0.25 mmol) and catalyst 6 (17 mg, 10 mol%)
were mixed with cyclohexanone (0.5 mL, 5 mmol) in the presence
of TFA (0.00625 mmol, 0.2 mL) at r.t. [the bulk solution of TFA in
cyclohexanone was freshly prepared from TFA (5 mL) and cyclo-
hexanone (12.5 mL)]. After stirring for 24 h, the homogeneous re-
Yield: 0.62 g (91%); yellow oil.
1H NMR (300 MHz, CD3OD): d = 8.55 (s, 1 H, N-CH=C), 5.45 (m,
1 H, CO2-CH), 4.92 (m, 1 H, N-CH-CO2H), 4.60 (m, 2 H, N+-CH2),
4.37 [t, J = 7.0 Hz, 2 H, CH3-(CH2)2-CH2-N], 3.66 (m, 2 H, N-CH2-
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York

3982
J. Shah et al.
PAPER
action mixture was diluted with Et2O (15 mL) to precipitate the
catalyst. The organic layer was separated, concentrated and loaded
onto a silica gel column to afford the Michael product 21a.30,37
(12) Sebesta, R.; Kmentova, I.; Toma, S. Green Chem. 2008, 10,
484.
(13) Yang, S.-D.; Shi, Y.; Sun, Z.-H.; Zhao, Y.-B.; Liang, Y.-M.
Tetrahedron: Asymmetry 2006, 17, 1895.
(14) Zhou, L.; Wang, L. Chem. Lett. 2007, 36, 628.
(15) Miao, W.; Chan, T. H. Adv. Synth. Catal. 2006, 348, 1711.
(16) Lombardo, M.; Pasi, F.; Easwar, S.; Trombini, C. Adv.
Synth. Catal. 2007, 349, 2061.
(17) Hanelt, S.; Liebscher, J. Synlett 2008, 1058.
(18) Yacob, Z.; Shah, J.; Leistner, J.; Liebscher, J. Synlett 2008,
2342.
Yield: 60 mg (98%); white solid; syn/anti 99:1, 99% ee [HPLC on
a Chiralpak AD column, l = 215 nm; i-PrOH–n-hexane, 10:90;
flow rate = 0.8 mL/min; tR = 10.90 (minor), 15.53 min (major)].
1H NMR (300 MHz, CDCl3): d = 7.35–7.23 (m, 3 H), 7.20–7.14 (m,
2 H), 4.94 (dd, J = 12.4, 4.4 Hz, 1 H), 4.43 (dd, J = 12.4, 10.0 Hz,
1 H), 3.76 (m, 1 H), 2.74–2.64 (m, 1 H), 2.52–2.34 (m, 2 H), 2.13–
2.03 (m, 1 H), 1.83–1.50 (m, 4 H), 1.30–1.18 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 212.0, 137.7, 128.9, 127.7, 78.9,
52.5, 43.9, 42.7, 33.2, 28.5, 25.0.
(19) Ganorkar, R.; Natarajan, A.; Mamai, A.; Madalengoitia, J. S.
J. Org. Chem. 2006, 71, 5004.
(20) Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66,
1038.
Acknowledgment
(21) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653.
(22) Siyutkin, D. E.; Kucherenko, A. S.; Struchkova, M. I.;
Zlotin, S. G. Tetrahedron Lett. 2008, 49, 1212.
(23) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(24) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F. III J. Am.
Chem. Soc. 2001, 123, 5260.
We thank Claudia Köthe for experimental assistance and Prof. Dr.
Willi Kantlehner, Fachhochschule Aalen for providing substituted
guanidines as precursors for ionic liquids. We acknowledge donati-
on of chemicals from Saltigo GmbH, Bayer Services GmbH & Co.
OHG, BASF AG and Sasol GmbH.
(25) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc.
2000, 122, 2395.
(26) Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova,
E. Chem. Commun. 2002, 2510.
References
(27) Loh, T.-P.; Feng, L.-C.; Yang, H.-Y.; Yang, J.-Y.
Tetrahedron Lett. 2002, 43, 8741.
(28) Remuzon, P.; Bouzard, D.; Guiol, C.; Jacquet, J. P. J. Med.
Chem. 1992, 35, 2898.
(29) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem. Int. Ed. 2005, 44, 4212.
(30) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F. III J. Am. Chem. Soc. 2006, 128, 4966.
(31) Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.; Cheng, J.-P.
J. Org. Chem. 2006, 71, 9244.
(32) Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron Lett. 2008,
49, 1249.
(1) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis:
From Biomimetic Concepts to Application in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005.
(2) Dalko, P. I. In Enantioselective Organocatalysis; Dalko, P.
I., Ed.; Wiley-VCH: Weinheim, 2007, 1.
(3) Mukherjee, S.; Yang Jung, W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
(4) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, Vol.
1; Wiley-VCH: Weinheim, 2008.
(5) Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis, Vol.
2; Wiley-VCH: Weinheim, 2008.
(6) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72,
(33) Wu, L.-Y.; Yan, Z.-Y.; Xie, Y.-X.; Niu, Y.-N.; Liang, Y.-M.
1391.
Tetrahedron: Asymmetry 2007, 18, 2086.
(34) Xu, D.; Luo, S.; Yue, H.; Wang, L.; Liu, Y.; Xu, Z. Synlett
2006, 2569.
(35) Yan, Z.-Y.; Niu, Y.-N.; Wei, H.-L.; Wu, L.-Y.; Zhao, Y.-B.;
Liang, Y.-M. Tetrahedron: Asymmetry 2007, 17, 3288.
(36) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem. Int. Ed. 2006, 45,
958.
(7) Kotrusz, P.; Alemayehu, S.; Toma, S.; Schmalz, H.-G.;
Adler, A. Eur. J. Org. Chem. 2005, 4904.
(8) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F. III Synlett
2003, 1906.
(9) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J.
Org. Chem. 2004, 1577.
(10) Hagiwara, H.; Okabe, T.; Hoshi, T.; Suzuki, T. J. Mol. Catal.
A: Chem. 2004, 214, 167.
(37) Ni, B.; Zhang, Q.; Headley, A. D. Tetrahedron: Asymmetry
2007, 18, 1443.
(11) Bica, K.; Gaertner, P. Eur. J. Org. Chem. 2008, 3235.
Synthesis 2009, No. 23, 3975–3982 © Thieme Stuttgart · New York