Ionic-liquid tagged prolines as recyclable organocatalysts for enantioselective α-aminoxylations of carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2011.01.031

With the aim of improving catalytic performance and recyclability various ionic-liquid-tagged organocatalysts (ILTOCs) based on (S)-proline as organocatalysts and triazolium or guanidinium salts as ionic liquid tags were applied in the asymmetric α-aminox

Full text of DOI:10.1016/j.tet.2011.01.031

Tetrahedron 67 (2011) 1812e1820
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Ionic-liquid tagged prolines as recyclable organocatalysts for enantioselective
a-aminoxylations of carbonyl compounds
*
€
Sadaf Sadiq Khan, Jabbar Shah, Jurgen Liebscher
Institute of Chemistry, Humboldt-University Berlin, Brook-Taylor-Street 1-2, 12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
With the aim of improving catalytic performance and recyclability various ionic-liquid-tagged organo-
Received 16 November 2010
Received in revised form 5 January 2011
Accepted 12 January 2011
Available online 15 January 2011
catalysts (ILTOCs) based on (S)-proline as organocatalysts and triazolium or guanidinium salts as ionic
liquid tags were applied in the asymmetric
a-aminoxylation of ketones and aldehydes with nitro-
sobenzene in IL as solvents. Amongst such ILTOC’s compounds were found which performed better (ee
>99%, yield 97%) than (S)-proline in reported cases. Recycling and reusage of ILTOCs were easily possible
and yields higher than 80% and ees higher than 90% were obtained until the fifth cycle. Important in-
formation about the crucial role of water in recycling of proline-derived organocatalysts in reactions with
carbonyl compounds via enamine activation was found to prevent blockade of the organocatalyst by
oxazolidinone formation.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
result in regioisomeric a-oxamination products, a problem which
was solved by applying proper organocatalysts (in fact proline am-
ides derived from 2-aminoalcohols gave preferably the corre-
Opticallyactive a-hydroxycarbonyl compounds have gained wide
interest as important intermediates in organic synthesis and as
building blocks for natural products and bioactive compounds.
Among the various synthetic routes to this important class of com-
sponding a
-hydroxylamino carbonyl compounds)17 and conditions.
Unlike the aldol reaction, the aminoxylation results in an amine,
which itself can also act as an organocatalyst and thus can cause
autocatalysis and non-linear asymmetric induction when 6 acts in
a similar way as proline 1.18
pounds organocatalyzed a-aminoxylation of carbonyl compounds
has become very popular in recent years also from the point of view
of Green Chemistry.1e11 This strategy uses nitrosoarenes as reagents
(recently also TEMPO was also successfully employed)12 and either
chiral amines or less often13 chiral Brønsted acids as organocatalysts
O
O
R2
R1
(for the mechanism of the proline catalyzed
Scheme 1). It results in -aminoxycarbonyl compounds, which can
easily be transformed into -hydroxy analogues by NeO bond
a-aminoxylation see
N
OH
2
a
R1
CO2H
a
- H2O
cleavage either by excess of the nitrosoarene10 or by copper sulfate.3
Eventually, the carbonyl group was reduced in a final step when
sodium borohydride was added1,3,5,7,14 giving rise to optically active
2-aminoxyalcohols or 1,2-diols as other important classes of building
N
H
R2
1
3
Ph
NH
O
O
R1
Ph
+ H2O
blocks in organic synthesis.
a-Aminoxylation can also be involved in
R2
other subsequent or tandem reactions, such as formation of oxa-
6
zines,8,9,11,15 carbon-chain extended
a
-hydroxyketones14,16 or vicinal
O
O
diols14 thus providing additional synthetic applications. As com-
pared with the organocatalyzed aldol reaction (in fact the amino-
xylation of carbonyl compounds is often termed as nitroso aldol
O
O
Ph
N
N
O
N
H
NH
O
reaction) the a-aminoxylation has some peculiarities. Thus it can
R1
R1
R2
4
5
R2
* Corresponding author. Tel.: þ49 30 20937550; fax: þ49 30 20937552; e-mail
Scheme 1. Mechanism of (S)-proline catalyzed a-aminoxylation of carbonyl com-
address: liebscher@chemie.hu-berlin.de (J. Liebscher).
pounds with nitrosobenzene.19
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.031

S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
1813
Although (S)-proline is most abundant as catalyst in organo-
catalyzed -aminoxylation also other chiral secondary amines, such
a
as substituted prolines,9 binaphthyl-derived amines,5,20 (S)-pyrroli-
din-2-yl-tetrazoles,7,8,10,11,14,15 2-aminomethylpyrrolidine sulfon-
amides,4,11 thioproline,6 and others10 were applied with great
success. After optimisation, most of these methods provided high
yields and excellent stereoselectivities. The catalysts are easily
available and environmentally benign in most cases. Recently water
could be used as solvent for
a general issue in catalysis recycling of the catalyst is an important
aspect of Green Chemistry. This aspect was addressed in -amino-
a
-aminoxylation with success.6 As
a
xylation by fixation of the catalyst on polymer supports, where 4-
hydroxyproline was linked to Merrifield resin by Cu(I)-catalyzed
cycloaddition of alkynes to azides (click chemistry).21 However,
performance of this catalyst in recycling was only demonstrated
until the second recycling, where high ees (99%) were maintained
while the yield dropped from 81 to 75%. As an alternative for catalyst
recycling aminoxylations with (S)-proline were carried out in ionic
liquids as solvents. Here, the catalyst was retained by the IL during
extraction of the products by organic solvents (e.g., diethyl ether)
leaving behind a so-called working solution (IL with catalyst), which
can be used in the next batch. Although this methodology was
reported to work excellently with mere (S)-proline,22 these results
are questionable as shown by Guo et al. demonstrating a consider-
able decrease of yields in each recycling step going down to 50% ee
after the fifth recycling.23 As a recent methodology to improve the
solubility in ionic liquids and decreasing solubility in less polar or-
ganic solvents so-called ionic-liquid-tagged organocatalysts (ILTOC)
were developed wherein an IL-unit is covalently linked to the
organocatalytic moiety.24,25 The aim of this strategy is to reduce
leaching during the extraction of products and thus to improve
recycling. Sometimes a synergistic catalytic effect is observed when
the organocatalyst and the IL are covalently linked. Very recently and
parallel to our investigations, this methodology was also applied in
a
-aminoxylation by using an ILTOC consisting of an imidazolium
salts linked to position 4 of (S)-proline.26 Here, high yields (79%) and
enantioselectivities (>99%) were maintained in the -aminoxylation
a
of cyclohexanone with nitrosobenzene until the seventh run.
We have been using 1,2,3-triazolium25,27,28 and guanidinium
salts as IL-tags for organocatalysts in several reactions. Both tags
can be easily synthesized and allow a wide structural variation. The
1,2,3-triazolium rings are easily available by Cu-catalyzed 1,3-di-
polar cycloaddition of alkynes to azides followed by N-methylation
and eventual salt metathesis. Guanidinium salts are easily obtained
by alkylation of pentasubstituted guanidines. So far, these types of
ILTOCs were applied to aldol reactions, nitro-Michael reactions and
Mannich reactions and showed synergistic effects as well as good
recyclability in a number of cases.
2. Results and discussion
2.1. Asymmetric
a-aminoxylation
Here, we report the
a-aminoxylations of carbonyl compounds
with nitrosobenzene using (S)-prolines or a lysine derivative tagged
withtriazoliumsalts 7aec, 8aef or guanidinium salts 9a,b (Scheme 2,
see also chapter 2.2.). This collection of ILTOCs (Scheme 2) allowed
studying the effect of substituents, anions, linkers, hydrophilicity, and
lipophilicity on the catalytic performance. All ILTOCs were first
Scheme 2. Application of ILTOCs 7e9 in
[BF4].
a-aminoxylation of cyclohexanone in [bmim]
screened in the
a-aminoxylation of cyclohexanone with nitro-
sobenzene using [bmim][BF4] as IL solvent at room temperature (see
Scheme 2). It turned out that the 1,2,3-triazolium tagged proline
tetrafluoroborate 7a gave superior ee (>99%) and yield (91%). These
results are better than reported in cases wherein simple (S)-proline
was used.11 Exchanging the anion with triflate (ILTOC 7b) resulted in
a somewhat lower ee (92%). Unexpectedly, the triazolium-tagged
proline 7c lacking a substituent in position 4 of the 1,2,3-triazole ring
and thus is less lipophilic performed worse resulting in 78% ee and
82% yield after prolonged reaction time. We expected the proline 7d
with three IL-tags to be very promising for recycling because of its
highlyionic character. Unfortunately, itprovided only 50% eeand thus
was not worth to submit to recycling experiments. In the other

1814
S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
triazolium-tagged prolines 8 the triazolium unit was tethered to the
proline as ether or ester and the configuration at position 4 of the
proline moiety was opposite. The lipophilic dodecyl derivative 8c
gave a high ee (96%), while the short chain carboxylate 8b (8% ee) or
carboxylic acid 8a (10% ee) behaved unsatisfactorily. Placing a second
we also detected the hemiacetal 12 (Scheme 4) by HPLCeMS in the
working solution (ILTOC and IL) after the product 6a was extracted
from the reaction mixture. Such oxazolidinones are generally found
in proline catalyzed reaction of carbonyl compounds29 and were
sometimes applied as soluble ‘proline catalysts’. According to re-
cent NMR-investigations they were proposed as intermediates in
the catalytic cycle of aldol reactions where they form enamines (in
our case 13), which then are attacked by the nitrosobenzene
(Scheme 1). The equilibrium between the oxazolidinone and the
enamine (e.g., 12 and 13) is reported to be dependent on the water
content of the medium and the amount of (S)-proline. When in our
cases starting materials, that is, the carbonyl compound and
nitrosobenzene are added to the working solution after recycling
from a previous batch, part of the proline catalyst 7 remains cap-
tured as 12 or 13 and cannot be liberated by hydrolysis because of
the absence of water. Thus the amount of catalyst is reduced.
Therefore, we tried to improve the recycling procedure by the ad-
dition of a small amount of water after each recycling. Indeed, some
improvement could be achieved (Table 1, values in parenthesis,
entries 1e5). The improving effect of the addition of water was
even more obvious when after the sixth run water was added to the
working solution for the first time and the resulting working so-
lution was then used in the seventh run (see entries 6 and 7). As
a result, the ee increased from 24% in the sixth run to 54% in the
seventh run. Advantageous effect of water in proline catalyzed aldol
reactions is known,30 but it has not been looked at in cases of
recycling of proline catalysts, wherein it seems to play an even
more important role.
a-amino acid moiety in the side chain of the 1,2,3-triazolium salt (8d)
had a disadvantageous effect resulting in only 52% ee. Unexpectedly,
the triazoliumILTOC8fwheretheprolinemoietyisreplacedbyanon-
cyclic a-amino acid unit failed to give any enantioselectivity. In this
context it is worth mentioning that this ILTOC 8f gave very good re-
sults inaldol reactions, which were better thancorrespondingproline
derivatives.27 Guanidinium-tagged prolines 9a,b performed better
than the analogous 1,2,3-triazolium tagged proline 8e but could not
compete with the best ILTOCs 7a,b and 8c in the triazolium series.
In order to test scope and limitation of our favorite ILTOC 7a we
also investigated
sobenzene in [bmim][BF4]. Since the expected
a
-aminoxylation of aldehydes with nitro-
-phenylaminoxy-
a
aldehydes are known to be unstable they were reduced to the
corresponding 3-arylaminoxyalcohols by sodium borohydride after
isolation (Scheme 3).
O
1. 10 mol% 7a
[bmim][ BF4] rt, 15 min
OH
+
PhHNO
Ph-N=O
2. NaBH4, EtOH
rt, 10 min
R
R
10
11a (R = i Pr, 83% yield, 96% ee)
11b (R = Bn, 89% yield, 98% ee)
Scheme 3.
a-Aminoxylation/reduction of aldehydes with nitrosobenzene catalyzed
by 7a.
N
n-Bu
N
n-Bu
N
N
Isobutyraldehyde as well as 3-phenylpropionaldehyde gave the
-phenylaminoxyalcohols 11a and 11b, respectively, in high yields
N
N
a
and very good enantioselectivities thus proving that our method-
ology is also suitable to the -aminoxylation of aldehydes.
Since the ILTOC 7a turned out to be the best ILTOC in the test
a
N
N
O
O
a
-
O
HO
aminoxylation its recyclability was investigated using [bmim][BF4]
or [emim] [BF4] as solvents and diethyl ether or cyclohexane for
extraction of the products from the reaction mixture (see Table 1).
It turned out that in general the enantioselectivities and yields
decreased with each recycling. Reaction time had to increase to get
complete conversion of the starting material. Extraction with cy-
clohexane turned out to be advantageous over diethyl ether.
[emim] [BF4] did not work as well as [bmim][BF4] demonstrating
that small differences in the type of IL can have an effect on the
recyclability of the ILTOC. The decrease of the performance upon
recycling is likely to be caused by leaching. This assumption is in
line with the advantage found with cyclohexane as extracting sol-
vent (Table 1), which is less polar than diethyl ether and thus
leaches less of the polar ILTOC from the reaction mixture. However,
13
12
Scheme 4. ILTOC 7a trapped as oxazolidinone 12.
2.2. Synthesis of ionic-liquid-tagged organocatalysts
ILTOCS 7a,25 8a,27 8b,27 8c,25 8d,27 8e,25 8f,27 9a,31 and 9b31 were
published by us before. The other members are new. They were
synthesized adopting procedures used for the preparation of the
other 1,2,3-triazolium-based ILTOCs ,that is, Cu-catalyzed [3þ2]
cycloaddition of alkynes to azides followed by N-methylation of the
Table 1
Recycling of ILTOC 7a in
a
-aminoxylation of cyclohexanone to 6a using different IL and different solvents in extraction of the reaction mixture (see also Scheme 2)
[bmim][BF4] extr. Et2O [bmim][BF4] extr. C6H12 [emim] [BF4] extr. C6H12
eea Yielda eea Yielda
Cycle
%
%
minb
%
%
minb
ee %
Yield %
minb
1
2
3
4
5
6
7
>99 (99)
99 (99)
90 (92)
78 (86)
62 (78)
24
91 (91)
83 (87)
77 (83)
71 (72)
67 (61)
n.d.
15
20
30
40
60
99 (>99)
99 (99)
96 (97)
92 (95)
90 (92)
95 (97)
91 (95)
90 (92)
82 (89)
76 (83)
15
20
30
40
60
98
96
92
88
82
94
92
88
85
79
15
25
30
50
85
54c
n.d.
a
Values in brackets were obtained if 18
Reaction time.
ml H2O was added after each cycle.
b
c
H2O (18 ml) was added for the first time after sixth cycle before running this seventh cycle, that is, the performance of working solution improved after sixth cycle by
addition of water.

S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
1815
Scheme 5. Synthesis of ILTOC 7b.
resulting 1,2,3-triazoles and final salt metathesis (Schemes 5e7).
All cycloadditions as well as the N-alkylations and salt metatheses
provided high yields.
work this strategy was recently used by Ryu and Jeong in order to
synthesize 1,3-dialkyl-1,2,3-triazolium salts as ionic liquids useful
for BayliseHillman reactions.32
In order to obtain the C-unsubstituted 1,2,3-triazolium salt 7c
(Scheme 6) TMSeethyne was used as alkyne component in the
reaction with the 4-azidoproline derivative 16 and the resulting
TMSetriazole 17 was desilylated by fluoride. Independently of our
The ILTOC 7d containing three IL-tags was synthesized via
twofold click reaction at the propargyl ether 21, introducing a fur-
ther propargyl group (formation of 24) and another click reaction
with the azido-substituted organocatalytic moiety 16.
N
N
Me3Si
N
N3
OBn
OBn
SiMe3
+
CuSO4, Na ascorbate
N
O
N
O
t-BuOH/H2O(1:1), 1 d
Cbz
Cbz
16
96%
17
TBAF, THF
6 h, rt
N
N
N
I
N
N
N
OBn
OBn
CH3I, CH3CN
reflux
N
O
94%
N
O
Cbz
Cbz
97%
18
19
1. AgBF4, MeOH
2. Pd/C, H2, MeOH
BF4
N
N
N
OH
95%
O
N
H
7c
Scheme 6. Synthesis of ILTOC 7c.

1816
S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
OTBS
OTBS
OTBS
NaH, THF, 0 oC-rt
propargyl bromide
HO
O
O
N
N
n-BuN3
N
HO
O
O
N
CuSO4, Na ascorbate
59%
n-Bu
n-Bu
MeOH
80%
20
21
N
N
22
OH
NaH, THF, 0 oC - rt
O
N
O
TBAF, THF
propargyl bromide
N
N
O
O
N
N
O
n-Bu
n-Bu
N
51%
24
N
n-Bu
n-Bu
99%
N
N
N
N
23
N
N3
N
N
O
CO2Bn
N
N
N
O
N
95%
Cbz
16
CH3I, CH3CN
reflux
N
O
N
CO2Bn
N
25
n-Bu
n-Bu
CuSO4, Na ascorbate
MeOH
Cbz
N
N
BF4
N
BF4
N
O
I
N
N
N
O
N
1. AgBF4, MeOH
2. Pd/C, H2, MeOH
N
O
O
I
N
N
CO2H
O
N
N
H
94%
n-Bu
N
O
N
n-Bu
N
CO2Bn
90%
N
N
N
n-Bu
n-Bu
Cbz
7d
BF4
26
N
N
I
N
Scheme 7. Synthesis of ILTOC 7d.
3. Conclusion
4. Experimental
4.1. General
In summary, (S)-proline derivatives (ILTOCs) with covalently
linked 1,2,3-triazolium or guanidinium salts as IL-tags were in-
vestigated in order to develop new organocatalysts for asym-
1H NMR and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively, with a Bruker AC300 in CDCl3 or CD3OD with TMS as an
internal standard. MS analyses were carried out on Varian MAT 711
and Thermo Finnigan LTQ-FT-ICR-MS. Silica gel (0.04e0.063 mm,
Merck) was used for preparative column chromatography. Starting
materials 14,2516,33 and 2034 were obtained by reported procedures.
All the other chemicals were purchased from commercial suppliers.
metric
a-aminoxylations, which can be recycled and reused.
Although the IL-tag and the corresponding linkers are not directly
involved in the reaction but their structure influences the per-
formance of these organocatalyst largely and thus has to be cho-
sen carefully. The most efficient ILTOC 7a could be used in five
subsequent reaction cycles maintaining an ee of 90% and 76%
yield. The role of traces of water was addressed in recycling ex-
periments in organocatalyzed reactions of carbonyl compounds
via enamine intermediates for the first time where part of the
organocatalyst was trapped by undesirable oxazolidinone for-
mation and addition of water improved the performance of the
working solution.
4.2. General procedure for asymmetric a-aminoxylation of
ketones in [bmim][BF4] catalyzed by ILTOC 7a
To a 10 mL round-bottom flask equipped with a magnetic stir-
ring bar and charged with [bmim][BF4] (1.5 mL) catalyst 7a (34 mg,

S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
1817
10 mol %) and cyclohexanone (294 mg, 3 mmol) were added. The
mixture was stirred for 2 min, followed by the addition of nitro-
sobenzene (107 mg, 1 mmol). The resulting solution was stirred at
room temperature until the color of the mixture turned yellow
from green and the aminoxylation reaction was determined to be
complete by TLC. The reaction mixture was then extracted with
diethyl ether (6ꢀ5 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and concentrated in vacuum. Puri-
fication of the crude product was done by column chromatography
(silica gel, ethyl acetate/petroleum ether as eluant) to give (2R)-2-
aminoxy ketone 6a.
6.97e7.02 (m, 3H), 7.25e7.31 (m, 2H); HPLC (Chiracel AD-H,
i-propanol/hexane¼5:95, flow rate 0.5 mL/min,
l¼244 nm):
tminor¼25.5 min, tmajor¼29.5 min, ee 96%.
4.6. Synthesis of ILTOCs
4.6.1. 3-((3S,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yl)-5-butyl-
1-methyl-3H-1,2,3-triazol-1-ium trifluoromethanesulfonate (15). To
a solution of triazole 14 (0.584 g, 1.26 mmol) in dry CH2Cl2 (2 mL)
MeOTf (0.14 mL, 1.26 mmol) was added and the mixture was stirred
at room temperature for 1 h under an argon atmosphere. Evapora-
tion of the solvent in vacuo gave oil that was washed with Et2O
(2ꢀ15 mL) and finally kept under vacuum for several hours to afford
the pure product. Light yellow oil, yield 98%. 1H NMR (300 MHz,
4.3. General experimental procedure for asymmetric
a
-aminoxylation/reduction of aldehydes 10 to
a-
phenylaminoxyalcohols 11
CDCl3):
d
(ppm)¼8.47 (s, 1H, CHtriazole), 7.28e7.36 (m, 10H, CHarom),
5.48 (m,1H, NeCHeCH2eN), 4.98e5.16 (m, 4H, 2ꢀCH2ePh), 4.57 (m,
1H, NeCHeCO2), 4.16e4.18 (m, 2H, NeCH2eCHeN), 4.13 (m, 1H,
NeCHeCH2eCH), 3.99 (s, 3H, CH3eN), 3.05(m,1H, NeCHeCH2eCH),
2.67e2.75 (m, 2H, CeCH2eCH2), 1.60e1.67 (m, 2H, CH3eCH2eCH2),
1.35e1.47 (m, 2H, CH3eCH2), 0.95 (t, 3H, CH3eCH2). 13C NMR
To a 10 mL round-bottom flask equipped with a magnetic stirring
bar and charged with [bmim][BF4] (1.5 mL) catalyst 7a (34 mg,
10 mol %) and 3-phenylpropanal 10b (402 mg, 3 mmol) or iso-
valeraldehyde 10a (258 mg, 3 mmol) were added. The mixture was
stirred for 2 min, followed by the addition of nitrosobenzene
(107 mg, 1 mmol). The resulting solution was stirred at room tem-
perature until the color of the mixture turned yellow from green and
the aminoxylation reaction was determined to be complete by TLC.
The reaction mixture was then extracted with ethyl ether (6ꢀ5 mL).
To the combined ether layers ethanol (10 mL) and sodium borohy-
dride (171 mg, 4.5 mmol) were added. The reaction mixture was
stirred for 10 min at room temperature. The reaction was quenched
with saturated solution of sodium bicarbonate (10 mL) and the
resulting mixture was extracted with ethyl acetate (3ꢀ5 mL). The
combined organic extracts were dried over anhydrous sodium sul-
fate and concentrated in vacuum. Purification of the crude product
was done by column chromatography (silica gel, ethyl acetate/pe-
troleum ether as eluant) to give (2R)-2-aminoxyalcohol 11a and 11b.
(75 MHz, CDCl3):
d
(ppm)¼170.9 (O]CeO), 154.0 (O]CeN), 145.1
(Ctriazole), 135.7 (Carom), 135.0 (Carom), 129.4 (CHarom), 128.6 (CHarom),
128.6 (CHarom), 128.5 (CHarom), 128.2 (CHarom), 128.0 (CHarom), 127.8
(CHtriazole), 67.7 (CH2ePh), 67.2 (CH2ePh), 61.4 (NeCHeCO2), 57.3
(NeCHeCH2eN), 51.2 (NeCH2eCHeN), 37.4 (CH3eN), 35.2
(NeCHeCH2eCH), 28.6 (CH3eCH2eCH2), 22.9 (CeCH2eCH2), 22.0
(CH3eCH2), 13.4 (CH3eCH2). HRMS: m/z [MþH]þ calcd for
C27H34N4Oþ4 : 478.257; found: 478.255.
4.6.2. 5-Butyl-3-((3S,5S)-5-carboxypyrrolidin-3-yl)-1-methyl-3H-
1,2,3-triazol-1-ium trifluoromethanesulfonate (7b). To a solution of
the protected triazolium triflate 15 (0.78 g, 1.24 mmol) in anhydrous
MeOH (10 mL), Pd/C (180 mg) was added and the mixture was pres-
surized under H2 at 5 bar. After stirring overnight, the Pd/C was filtered
off and the filtrate was concentrated under vacuum to give the desired
product 7b. Light yellow oil, yield 98%. 1H NMR (CD3OD, 300 MHz):
4.4. Procedure for recycling and reuse of ILTOC 7a in
a
-aminoxylation of cyclohexanone in [bmim][BF4]
d
(ppm)¼8.69 (s,1H, CHtriazole), 5.71e5.72 (m,1H, NeCHeCH2eN), 4.57
(m, 1H, NeCHeCO2), 4.24 (s, 3H, CH3eN), 4.00e4.04 (m, 2H,
NeCH2eCHeN), 3.32e3.36 (m, 1H, NeCHeCH2eCH), 3.19 (m, 1H,
NeCHeCH2eCH), 2.86e2.91 (m, 2H, CeCH2eCH2), 1.72e1.82 (m, 2H,
CH3eCH2eCH2), 1.47e1.57 (m, 2H, CH3eCH2), 1.02 (t, 3H, CH3eCH2).
To a 10 mL round-bottom flask equipped with a magnetic stir-
ring bar and charged with [bmim][BF4] (1.5 mL) catalyst 7a (34 mg,
10 mol %) and cyclohexanone (294 mg, 3 mmol) were added. The
mixture was stirred for 2 min, followed by the addition of nitro-
sobenzene (107 mg, 1 mmol) and the resulting solution was stirred
at room temperature for 15 min. The reaction mixture was
extracted with diethyl ether (6ꢀ5 mL). The residue after was dried
under vacuum at 60 ꢁC and reused for the next run of reaction. This
procedure was repeated until seventh run as shown in the Table 1.
13C NMR (CD3OD, 75 MHz):
d
(ppm)¼145.5 (Ctriazole), 127.9 (CHtriazole),
62.1 (NeCHeCO2), 59.4 (NeCHeCH2-N), 49.7 (NeCH2eCHeN), 36.9
(CH3eN), 33.8 (NeCHeCH2eCH), 28.3 (CH3eCH2eCH2), 22.4
(CeCH2eCH2), 21.7 (CH3eCH2), 12.5 (CH3eCH2). HRMS: m/z [MþH]þ
calcd for C12H22N4Oþ2 : 254.173; found: 254.171.
4.6.3. (2S,4S)-Dibenzyl
4-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)
4.5.
a
-Aminoxylation products
pyrrolidine-1,2-dicarboxylate (17). Azide 16 (1 g, 2.63 mmol), tri-
methylsilylacetylene (0.31 g, 3.16 mmol), CuSO4 (0.082 g, 20 mol %),
and sodium ascorbate (0.21 g, 40 mol %) were suspended in a mixed
solution of tert-butanol/water (4 mL,1/1) at room temperature. After
the mixture was stirred for 24 h, water (10 mL) was added and the
mixture was extracted with ethyl acetate (3ꢀ10 mL). The combined
organic layers were washed with brine (10 mL) and then dried over
Na2SO4. Evaporation of the solvent in vacuo gave yellow oil that was
used in the next step without further purification. Yellow oil, yield
4.5.1. (2R)-2-Anilinoxycyclohexanone (6a). 1H NMR (300 MHz,
CDCl3):
d
(ppm)¼1.68e1.85 (m, 3H), 1.99e2.09 (m, 2H), 2.35e2.55
(m, 3H), 4.37e4.43(m, 1H), 6.92e6.98 (m, 3H), 7.23e7.31 (m, 2H);
HPLC (Chiracel AD-H, i-propanol/hexane¼10:90, flow rate 0.5 mL/
min,
l¼244 nm): tminor¼4.9 min, tmajor¼29.5 min, ee 99%.
4.5.2. (2R)-3-Phenyl-2-anilinoxypropanol (11a). 1H NMR (300 MHz,
CDCl3):
(dd, 1H), 3.86 (dd, 1H), 4.16e4.18 (m, 1H), 6.85e6.88 (m, 2H),
6.94e6.99 (m, 1H), 7.20e7.34 (m, 7H); HPLC (Chiracel AD-H,
d
(ppm)¼2.84 (1H, dd), 3.07 (1H, dd),1.40e1.47 (m, 1H), 3.73
96%. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼7.87 (s, 1H,
CHeCHeNeCH), 7.21e7.32 (m, 10H, 10ꢀCHarom), 5.01e5.27 (m, 4H,
2ꢀCH2ePh), 4.57e4.60 (m, 1H, CHeC]O), 4.27e4.31 (m, 1H,
CHeNtriazole), 3.94e4.02 (m, 1H, CH2eCHeC]O), 2.96e2.98 (m, 1H,
CH2eCHeC]O), 2.67e2.77 (m,1H, CH2eNeC]O), 2.42e2.48(m,1H,
CH2eNeC]O), 0.29 (s, 9H, 3ꢀCH3eSi). 13C NMR (CDCl3, 75 MHz):
i-propanol/hexane¼10:90, flow rate 0.5 mL/min,
l¼244 nm):
tminor¼24.7 min, tmajor¼32.1 min, ee 98%.
4.5.3. (R)-3-Methyl-2-(phenylaminoxy)butan-1-ol (11b). 1H NMR
(300 MHz, CDCl3):
(ppm)¼0.99 (d, J¼6 Hz, 3H), 1.05 (d, J¼6 Hz,
3H), 2.01e2.07 (m, 1H), 3.73e3.76 (m, 1H), 3.88e3.92 (m, 2H),
d
(ppm)¼171.1 (CHeC]O),154.7 (NHeC]O),151.4 (CHeCeSi),136.0
d
(Carom), 129.9 (CHeCHeNeCH), 128.6 (CHarom), 128.5 (CHarom), 128.4
(CHarom), 128.3 (CHarom), 128.1 (CHarom), 128.0 (CHarom), 67.8

1818
S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
(CH2ePh), 67.7 (CH2ePh), 65.4 (CHeC]O), 57.9 (CHeNtriazole), 52.1
(CH2eNeC]O), 30.0 (CH2eCHeC]O), 0.67 (CH3eSi). HRMS (ESI):
m/z [MþH]þ calcd for C25H30N4O4Si: 479.2115; found: 479.2066.
130.4 (CHeNeCH3), 62.5 (CHeC]O), 59.7 (CHeNtriazole), 49.6
(CH2eNH), 39.4 (CH3eN), 34.2 (CH2eCHeC]O). HRMS (ESI): m/z
[M]þ calcd for C8H13N4O2þ: 197.1039; found: 197.1007.
4.6.4. (2S,4S)-Dibenzyl 4-(1H-1,2,3-triazol-1-yl)pyrrolidine-1,2-di-
carboxylate (18). To a solution of triazole 17 (1.20 g, 2.51 mmol) in
anhydrous THF (10 mL) TBAF (1 M in THF, 1.02 mL, 2.51 mmol) was
added dropwise. The reaction was monitored for the disappearance
of starting materials by TLC. After 6 h at room temperature, the
reaction mixture was concentrated in vacuo. The remaining 17 was
purified by column chromatography (silica gel, 2:1 chloroform/ac-
etone, Rf¼0.68). Light yellow oil, yield 94%. 1H NMR (CDCl3,
4.6.7. (2,3-Bis(prop-2-ynyloxy)propoxy)(tert-butyl)dimethylsilane
(21). To a solution of 3-(tert-butyldimethylsilyloxy)propane-1,2-diol
20 (0.8 g, 3.9 mmol) in anhydrous THF (37 mL), sodium hydride
(0.28 g,11.7 mmol) was added. The suspension was stirred for 30 min
andcooled withan icebath. With vigorousstirring propargyl bromide
(0.9 mL, 9.75 mmol)wasaddedover1 h, andthereactionmixturewas
stirred for 3 days at room temperature. MeOH was added carefully
until gas formation ceased (destruction of excess sodium hydride).
Thesolventwasremovedundervacuoandtheresiduewastakenupin
CH2Cl2 (25 mL) and water (15 mL). After phase separation the organic
phase was carefully washed with water and dried with magnesium
sulfate. The solvent was removed and the raw product waspurified by
column chromatography (silica gel, 9:1 hexane/EtOAc, Rf¼0.53). Light
300 MHz):
d
(ppm)¼7.83 (s,1H, CHeCHeNeCH), 7.20e7.37 (m,11H,
CHeCHeNeCHþ10ꢀCHarom), 5.01e5.24 (m, 4H, 2ꢀCH2ePh),
4.54e4.58 (m, 1H, CHeC]O), 4.21e4.25 (m, 1H, CHeNtriazole),
3.94e4.01 (m, 1H, CH2eCHeC]O), 2.94e2.96 (m, 1H, CH2eCHeC]
O), 2.62e2.75 (m, 1H, CH2eNeC]O), 2.43e2.46 (m, 1H,
CH2eNeC]O). 13C NMR (CDCl3, 75 MHz):
d
(ppm)¼171.0 (CHeC]
yellow liquid, yield 59%. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼
O), 154.4 (NHeC]O), 141.1 (CHeCHeNeCH), 135.9 (Carom), 128.6
(CHarom), 128.5 (CHarom), 128.5 (CHarom), 128.3 (CHarom), 128.0
(CHarom), 127.5 (CHarom), 126.9 (CHeCHeNeCH), 67.7 (CH2ePh),
67.4 (CH2ePh), 65.1 (CHeC]O), 57.9 (CHeNtriazole), 51.5
(CH2eNeC]O), 29.7 (CH2eCHeC]O). HRMS (ESI): m/z [MþH]þ
calcd for C22H22N4O4: 407.1719; found: 407.1682.
4.28e4.31 (m, 2H, CeCH2eOeCH), 4.14e4.17 (m, 2H,
CeCH2eOeCH2), 3.56e3.76 (m, 5H, CH2eCHeCH2), 2.39 (m, 2H,
2ꢀCH^C), 0.87 (s, 9H, 3ꢀCH3eCeSi), 0.049 (s, 6H, 2ꢀCH3eSi). 13C
NMR (CDCl3, 75 MHz):
d
(ppm)¼80.2 (CH^C), 79.6 (CH^C), 78.1
(CH2eCHeCH2), 74.6 (CH^C), 74.2 (CH^C), 69.6 (CH2eOeCH2), 62.8
(CH2eOeSi), 58.6 (CeCH2eOeCH), 57.7 (CeCH2eOeCH2), 25.9
(CH3eCeSi), 18.3 (CH3eCeSi), ꢂ5.3 (CH3eSi). HRMS (ESI): m/z
[MþH]þ calcd for C15H26O3Si: 283.1721; found: 283.1672.
4.6.5. 3-((3S,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-yl)-1-
methyl-3H-1,2,3-triazol-1-ium iodide (19). To a solution of the tri-
azole 18 (1 g, 2.46 mmol) in MeCN (50 mL), MeI (0.76 mL,12.3 mmol,
5 equiv) was added. The reaction mixture was refluxed under an
argon atmosphere overnight. After completion of the reaction, the
solvent was removed to obtain the product, which was purified by
washing with diethyl ether (3ꢀ20 mL). Brown-yellow oil, yield 97%.
4.6.8. 4,40-(3-(tert-Butyldimethylsilyloxy)propane-1,2-diyl)bis(oxy)
bis(methylene)bis(1-butyl-1H-1,2,3-triazole) (22). To a solution of n-
butyl azide 0.3 g (2.84 mmol, 2 equiv) in MeOH (10 mL) sodium
ascorbate (0.11 g, 40 mol %), CuSO4 (0.07 g, 30 mol %), and the al-
kyne 21 (0.4 g, 1.42 mmol, 1 equiv) were added. The solution was
stirred at room temperture for 2e3 days (TLC check). After com-
pletion of the reaction, water (20 mL) was added and the mixture
was extracted with ethyl acetate (3ꢀ20 mL). The combined organic
layers were washed with brine (20 mL) and then dried over Na2SO4.
Evaporation of the solvent in vacuo gave a colorless liquid that was
used in the next step without further purification. Colorless liquid,
1H NMR (CDCl3, 300 MHz):
d
(ppm)¼9.18 (s,1H, CHeNeCH3), 9.03 (s,
1H, CHeCHeNeCH3), 7.21e7.31 (m, 10H, 10ꢀCHarom), 4.97e5.14 (m,
4H, 2ꢀCH2ePh), 4.57e4.66 (m, 1H, CHeC]O), 4.21e4.26 (m, 4H,
CH3eNþCHeNtriazole), 3.92e4.00 (m, 1H, CH2eCHeC]O), 3.14e3.19
(m,1H, CH2eCHeC]O), 2.77e2.81 (m,1H, CH2eNeC]O), 2.27e2.28
(m, 1H, CH2eNeC]O). 13C NMR (CDCl3, 75 MHz):
d
(ppm)¼170.9
(CHeC]O), 153.8 (NHeC]O), 135.8 (Carom), 132.2 (CHeNeCH3),
129.5 (CHarom), 128.7 (CHarom), 128.6 (CHarom), 128.2 (CHarom), 128.0
(CHarom),127.7 (CHarom),127.0 (CHeCHeNeCH3), 67.6 (CH2ePh), 67.3
(CH2ePh), 61.9 (CHeC]O), 57.3 (CHeNtriazole), 51.4 (CH2eNeC]O),
41.4 (CH3eN), 35.8 (CH2eCHeC]O). HRMS (ESI): m/z [M]þ calcd for
C23H25N4Oþ4 : 421.1876; found: 421.1886.
yield 80%. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼7.58 (s, 2H,
2ꢀCHtriazole), 4.61e4.76 (m, 4H, 2ꢀCH2eCtriazole), 4.30e4.32 (m, 4H,
CH2eNtriazole), 3.54e3.66 (m, 5H, CH2eCHeCH2), 1.84e1.85 (m, 4H,
2ꢀCH2eCH2eCH3), 1.30e1.33 (m, 4H, 2ꢀCH2eCH3), 0.89e0.93 (m,
6H, 2ꢀCH3eCH2), 0.84e0.86 (s, 9H, 3ꢀCH3eCeSi), 0.01 (s, 6H,
2ꢀCH3eSi). 13C NMR (CDCl3, 75 MHz):
d
(ppm)¼122.2 (CHtriazole),
79.0 (CH2eCHeCH2), 70.4 (CH2eCHeCH2eOeSi), 64.0 (CH2eOeSi),
63.9 (CH2eCtriazole), 62.7 (CH2eCtriazole), 50.0 (CH2eNtriazole), 32.1
(CH2eCH2eCH3), 25.8 (CH3eCeSi), 19.6 (CH2eCH3), 18.2
(CH3eCeSi), 13.4 (CH3eCH2), ꢂ5.4 (CH3eSi). HRMS (ESI): m/z
[MþH]þ calcd for C23H44N6O3Si: 481.3211; found: 481.3164.
4.6.6. 3-((3S,5S)-5-Carboxypyrrolidin-3-yl)-1-methyl-3H-1,2,3-tri-
azol-1-ium tetrafluoroborate (7c). In a 50 mL round-bottom flask
the triazolium iodide 19 (1.09 g, 1.98 mmol) was dissolved in an-
hydrous MeOH (20 mL). In a second flask (which was either brown
colored or wrapped in aluminum foil to exclude light), AgBF4
(0.39 g, 1.98 mmol) was dissolved in anhydrous MeOH (20 mL). The
AgBF4 solution was added dropwise to the solution of the tri-
azolium iodide 19 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
the protected triazolium tetrafluoroborate as yellow oil. To a solu-
tion of this tetrafluoroborate (1.00 g, 1.97 mmol) in anhydrous
MeOH (20 mL), Pd/C (180 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
the final product 7c. Light yellow oil, yield 95%. 1H NMR (CD3OD,
4.6.9. 2,3-Bis((1-butyl-1H-1,2,3-triazol-4-yl)methoxy)propan-1-ol
(23). To a solution of the triazole 22 (0.473 g, 1 mmol) in anhydrous
THF (15 mL) TBAF (1 M in THF, 0.5 mL,1 mmol) was dropwise added.
The reaction was monitored for the disappearance of starting ma-
terials by TLC. After 6 h at room temperature, the reaction mixture
was concentrated in vacuo. Column chromatography on silica gel
(2:1 hexane/EtOAc, Rf¼0.11) afforded the unprotected alcohol 23
(0.36 g, 99%) as a colorless liquid. Colorless liquid, yield 99%. 1H NMR
(CDCl3, 300 MHz):
d
(ppm)¼7.58 (s, 1H, CHtriazole), 7.54 (s, 1H,
CHtriazole), 4.69 (m, 2H, CH2eCtriazole), 4.58 (m, 2H, CH2eCtriazole),
4.26e4.28 (m, 4H, 2ꢀCH2eNtriazole), 3.61e3.69 (m, 5H,
CH2eCHeCH2), 1.79e1.82 (m, 4H, 2ꢀCH2eCH2eCH3), 1.24e1.31 (m,
4H, 2ꢀCH2eCH3), 0.85e0.89 (m, 6H, 2ꢀCH3eCH2). 13C NMR (CDCl3,
300 MHz):
d
(ppm)¼8.73 (s, 1H, CHeNeCH3), 7.95 (s, 1H,
CHeCHeNeCH3), 4.41e4.48 (m, 1H, CHeC]O), 4.32e4.36 (m, 1H,
CHeNtriazole), 4.14 (s, 3H, CH3eN), 3.95e4.08 (m, 2H, CH2eNH),
3.12e3.23 (m, 1H, CH2eCHeC]O), 2.87e2.96 (m, 1H, CH2eCHeC]
75 MHz):
d
(ppm)¼145.2 (Ctriazole), 144.7 (Ctriazole), 122.4 (CHtriazole),
78.9 (CH2eCHeCH2), 70.3 (CH2eCHeCH2eOH), 64.7 (CH2eOH),
62.0 (CH2eCtriazole), 58.8 (CH2eCtriazole), 50.0 (CH2eNtriazole), 32.1
O). 13C NMR (CD3OD, 75 MHz):
d
(ppm)¼131.8 (CHeCHeNeCH3),

S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
1819
(CH2eCH2eCH3), 19.6 (CH2eCH3), 13.4 (CH3eCH2). HRMS (ESI): m/z
[MþH]þ calcd for C17H30N6O3: 367.2405; found: 367.2356.
ium) iodide (26). To a solution of the triazole 25 (0.35 g, 0.44 mmol)
in MeCN (10 mL), MeI (0.55 mL, 8.8 mmol, 20 equiv) was added.
The reaction mixture was refluxed under an argon atmosphere
overnight. After completion of the reaction, the solvent was re-
moved to obtain the product 26, which was purified by washing
with diethyl ether (3ꢀ10 mL). Brown-yellow oil, yield 90%. 1H NMR
4.6.10. 4,40-(3-(Prop-2-ynyloxy)propane-1,2-diyl)bis(oxy)bis(methy-
lene)bis(1-butyl-1H-1,2,3-triazole) (24). To a solution of 2,3-bis((1-
butyl-1H-1,2,3-triazol-4-yl)methoxy)propan-1-ol 23 (0.4 g, 1.1 mmol)
in anhydrous THF (10 mL) sodium hydride (0.042 g, 1.76 mmol) was
added. The suspension was stirred for 30 min and cooled with an ice
bath. With vigorous stirring propargyl bromide (0.16 mL, 1.76 mmol)
was added over 1 h, and the reaction mixture was stirred for 3 days at
room temperature. MeOH was added carefully until gas formation
ceased (destruction of excess sodium hydride). The solvent was re-
moved in vacuo and the residue was taken up in CH2Cl2 (5 mL) and
water (5 mL). After phase separation the organic phase was carefully
washed with water and dried with magnesium sulfate. The solvent was
removed and the raw product 24 was purified by column chroma-
tography (silica gel, 1:1 hexane/EtOAc and then only EtOAc, Rf¼0.10).
(CDCl3, 300 MHz):
d
(ppm)¼9.40 (s, 1H, CHtriazole), 9.32e9.33 (s, 2H,
CHtriazole), 7.24e7.30 (m, 10H, 2ꢀCHarom), 5.20e5.32 (m, 4H,
2ꢀCH2ePh), 5.04e5.11 (m, 4H, CHeC]OþCHeNtriazoleþCH2e
NeC]O), 4.97e5.02 (m, 2H, CH2eCtriazole), 4.58e4.63 (m, 4H,
2ꢀCH2eCtriazole), 4.38 (s, 3H, CH3eN), 4.35 (s, 3H, CH3eN), 4.23 (s,
3H, CH3eN), 4.14e4.19 (m, 4H, 2ꢀCH2eNtriazole), 3.93e4.08 (m, 5H,
OeCH2eCHeCH2eO), 3.09e3.14 (m, 1H, CH2eCHeC]O), 2.83e2.84
(m, 1H, CH2eCHeC]O), 1.92e1.98 (m, 4H, 2ꢀCH2eCH2eCH3),
1.30e1.42 (m, 4H, 2ꢀCH2eCH3), 0.89e0.94 (m, 6H, 2ꢀCH3eCH2).
13C NMR (CDCl3, 75 MHz):
d
(ppm)¼170.9 (CHeC]O), 153.6
(NeC]O), 141.3 (Ctriazole), 140.9 (Ctriazole), 138.3 (Carom), 128.6
(CHarom), 128.5 (CHarom), 128.4 (CHarom), 128.2 (CHarom), 128.1
(CHarom), 128.0 (CHarom), 78.2 (OeCH2eCHeCH2eO), 70.9
(OeCH2eCHeCH2eO), 67.6 (CH2ePh), 67.2 (CH2ePh), 62.0
(CH2eCtriazole), 61.2 (CH2eCtriazole), 57.6 (CHeC]O), 54.0
(CHeNtriazole), 51.3 (CH2eNtriazole), 51.2 (CH2eNeC]O), 40.3
(CH3eN), 40.2 (CH3eN), 40.1 (CH3eN), 35.5 (CH2eCHeC]O), 31.2
(CH2eCH2eCH3), 19.3 (CH2eCH3), 13.3 (CH3eCH2). HRMS (ESI): m/z
[M]3þ calcd for C43H61N10O37þ: 276.4901; found: 276.4854.
Colorless liquid, yield 51%.1H NMR (CDCl3, 300 MHz):
d
(ppm)¼7.59 (s,
1H, CHtriazole), 7.55 (s, 1H, CHtriazole), 4.77 (s, 2H, CH2eCtriazole), 4.63 (s,
2H, CH2eCtriazole), 4.27e4.34 (m, 4H, 2ꢀCH2eNtriazole), 4.12e4.13 (m,
2H, CH2eC^CH), 3.79 (m, 1H, CH2eCHeCH2), 3.60e3.63 (m, 4H,
CH2eCHeCH2), 2.39e2.41 (m, 1H, CH2eC^CH), 1.81e1.85 (m, 4H,
2ꢀCH2eCH2eCH3),1.28e1.36 (m, 4H, 2ꢀCH2eCH3), 0.89e0.94 (m, 6H,
2ꢀCH3eCH2). 13C NMR (CDCl3, 75 MHz):
d
(ppm)¼145.3 (Ctriazole),
144.9 (Ctriazole),122.5 (CHtriazole),122.3 (CHtriazole), 79.5 (CH2eCHeCH2),
74.6
(CH2eCHeCH2eOeCH2eC^CH),
70.2
(C^CH),
69.6
(CH2eOeCH2eC^CH), 64.9 (CH2eCtriazole), 63.8 (CH2eCtriazole), 58.5
(CH2eC^CH), 50.0 (CH2eNtriazole), 32.2 (CH2eCH2eCH3), 19.6
(CH2eCH3), 13.4 (CH3eCH2). HRMS (ESI): m/z [MþH]þ calcd for
C20H32N6O3: 405.2501; found: 405.2459.
4.6.13. 5,50-(3-((1-((3S,5S)-5-Carboxypyrrolidin-3-yl)-3-methyl-1H-
1,2,3-triazol-3-ium-4-yl)methoxy)propane-1,2-diyl)-bis-(oxy)-bis-
(methylene)-bis-(3-butyl-1-methyl-3H-1,2,3-triazol-1-ium)
tetra-
fluoroborate (7d). In a 50 mL dry, round-bottom flask triazolium
iodide 26 (0.4 g, 0.33 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 (0.32 g,
1.65 mmol, 5 equiv) was dissolved in anhydrous MeOH (20 mL). The
AgBF4 solutionwas added dropwise to the solution of iodide 26 until
no more precipitate (AgI) was formed. After the precipitate had
settled down, the clear supernatant solution was separated, dried,
andevaporated giving a quantitativeyield of the tetrafluoroborate as
yellow oil. To a solution of this tetrafluoroborate (0.35 g, 0.32 mmol)
in anhydrous MeOH (5 mL), Pd/C (40 mg) was added and the mix-
ture was pressurized under H2 at 5 bar. After stirring overnight, the
Pd/C was filtered off and the filtratewas concentrated under vacuum
to give desire product 7d.
4.6.11. (2S,4S)-Dibenzyl 4-(4-((2,3-bis((1-butyl-1H-1,2,3-triazol-4-
yl)methoxy)propoxy)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1,2-
dicarboxylate (25). To a solution of azide 16 (0.19 g, 0.5 mmol) in
MeOH (5 mL) sodium ascorbate (0.02 g, 20 mol %), CuSO4 (0.012 g,
15 mol %), and alkyne 24 (0.2 g, 0.5 mmol) were added. The solution
was stirred at room temperature for 2e3 days (TLC check). After
completion of the reaction, water (10 mL) was added and the mix-
ture was extracted with ethyl acetate (3ꢀ10 mL). The combined or-
ganic layers were washed with brine (10 mL) and then dried over
Na2SO4. Evaporation of the solvent in vacuo gave 25 as colorless
liquid that was used in the next step without further purification.
Light yellow oil, yield 95%. 1H NMR (CDCl3, 300 MHz):
d
(ppm)¼7.76
(s, 1H, CHtriazole), 7.64 (s, 1H, CHtriazole), 7.59 (s, 1H, CHtriazole),
7.30e7.35 (m, 10H, 2ꢀCHarom), 5.08e5.26 (m, 4H, 2ꢀCH2ePh),
4.95e5.06 (m, 2H, CHeC]OþCHeNtriazole), 4.78 (s, 2H, CH2eCtria-
zole), 4.60e4.63 (m, 4H, 2ꢀCH2eCtriazole), 4.29e4.36 (m, 4H,
2ꢀCH2eNtriazole), 3.94e3.97 (m, 1H, OeCH2eCHeCH2eO),
3.76e3.82 (m, 2H, CH2eNeC]O), 3.60e3.64 (m, 4H,
OeCH2eCHeCH2eO), 2.91e2.96 (m,1H, CH2eCHeC]O), 2.64e2.78
(m, 1H, CH2eCHeC]O), 1.81e1.93 (m, 4H, 2ꢀCH2eCH2eCH3),
Colorless oil, yield 94%. 1H NMR (CD3OD, 300 MHz):
8.70 (s, 1H, CHtriazole), 8.59 (s, 1H, CHtriazole), 8.58 (s, 1H, CHtriazole),
4.88e4.90 (m, 8H,
d
(ppm)¼
CHeC]OþCHeNtriazoleþCH2eNeC]
Oþ2ꢀCH2eCtriazole), 4.86 (s, 2H, CH2eCtriazole), 4.28 (s, 3H, CH3eN),
4.27 (s, 3H, CH3eN), 4.26 (s, 3H, CH3eN), 4.58e4.62 (m, 4H,
2ꢀCH2eNtriazole), 4.01e4.05 (m, 2H, OeCH2eCHeCH2eO), 3.80 (m,
3H, OeCH2eCHeCH2eO), 3.31e3.36 (m, 2H, CH2eCHeC]O),
1.97e2.02 (m, 4H, 2ꢀCH2eCH2eCH3), 1.38e1.44 (m, 4H,
2ꢀCH2eCH3), 0.97e1.02 (m, 6H, 2ꢀCH3eCH2). 13C NMR (CD3OD,
1.30e1.40 (m, 4H, 2ꢀCH2eCH3), 0.91e0.97 (m, 6H, 2ꢀCH3eCH2). 13
C
NMR (CDCl3, 75 MHz):
d
(ppm)¼171.1 (CHeC]O), 154.4 (NeC]O),
75 MHz):
d
(ppm)¼141.3 (Ctriazole), 141.0 (Ctriazole), 140.6 (Ctriazole),
145.5 (Ctriazole), 136.0 (Carom), 128.6 (CHarom), 128.6 (CHarom), 128.2
(CHarom), 128.1 (CHarom), 128.0 (CHarom), 127.9 (CHarom), 121.9
(CHtriazole),
(OeCH2eCHeCH2eO), 70.2 (OeCH2eCHeCH2eO), 67.5 (CH2ePh),
67.3 (CH2ePh), 64.7 (CH2eCtriazole), 63.8 (CH2eCtriazole), 60.4
(CH2eCtriazole), 57.9 (CHeC]O), 57.6 (CHeNtriazole), 50.1 (CH2eNtria-
129.6 (CHtriazole), 129.0 (CHtriazole), 128.9 (CHtriazole), 78.1
(OeCH2eCHeCH2eO), 70.5 (OeCH2eCHeCH2eO), 70.4 (OeCH2e
CHeCH2eO), 61.8 (CH2eCtriazole), 60.5 (CH2eCtriazole), 59.7
(CH2eCtriazole), 58.7 (CHeC]O), 53.2 (CHeNtriazole), 50.0
(CH2eNtriazole), 47.2 (CH2eNeC]O), 37.8 (CH3eN), 37.4 (CH3eN),
37.3 (CH3eN), 33.3 (CH2eCHeC]O), 30.7 (CH2eCH2eCH3), 18.9
(CH2eCH3), 12.2 (CH3eCH2). HRMS (ESI): m/z [M]3þ calcd for
C28H49N10O35þ: 201.7966; found: 201.7917.
121.9
(CHtriazole),
121.8
(CHtriazole),
77.2
zole),
50.0
(CH2eNeC]O),
35.1
(CH2eCHeC]O),
32.2
(CH2eCH2eCH3), 19.7 (CH2eCH3), 13.5 (CH3eCH2). HRMS (ESI): m/z
[MþH]þ calcd for C40H52N10O7: 785.4001; found: 785.3981.
Acknowledgements
4.6.12. 5,50-(3-((1-((3S,5S)-1,5-Bis(benzyloxycarbonyl)pyrrolidin-3-
yl)-3-methyl-1H-1,2,3-triazol-3-ium-4-yl)methoxy)propane-1,2-diyl)
bis(oxy)bis(methylene)-bis-(3-butyl-1-methyl-3H-1,2,3-triazol-1-
We gratefully acknowledge financial support by Deutsche For-
schungsgemeinschaft (DFG). Priority Programme Organocatalysis

1820
S.S. Khan et al. / Tetrahedron 67 (2011) 1812e1820
127, 1080e1081; Lu, M.; Lu, Y.; Zhu, D.; Zeng, X.; Zhong, G. Angew. Chem., Int. Ed.
2010, 49, 1e5.
14. Jiao, P.; Kawasaki, M.; Yamamoto, H. Angew. Chem., Int. Ed. 2009, 48,
(SPP 1179). We thank Prof. Dr. Willi Kantlehner, Fachhochschule
Aalen for providing pentasubstituted guanidines. We further ac-
knowledge donation of chemicals from Saltigo GmbH, Bayer Ser-
vices GmbH & Co. OHG, BASF AG, and Sasol GmbH.
3333e3336.
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Supplementary data
17. Guo, H. M.; Cheng, L.; Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Chem. Commun.
Supplementary data includes NMR spectra of the products
obtained. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2011.01.031.
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