Phase transfer agent assisted biphasic CuAAC reaction

Article abstract of DOI:10.1039/c4ra03356f

A phase transfer agent assisted biphasic Cu(i) catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction system was developed. A biphasic reaction medium consisting of water and an organic solvent ensures the dissolution of reagents and substrates

Full text of DOI:10.1039/c4ra03356f

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Phase transfer agent assisted biphasic CuAAC
reaction†
Cite this: RSC Adv., 2014, 4, 26516
*
Jae Hyun Kim and Sanghee Kim
A phase transfer agent assisted biphasic Cu(I) catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC)
reaction system was developed. A biphasic reaction medium consisting of water and an organic solvent
ensures the dissolution of reagents and substrates. Tris(triazolylmethyl)amine ligands with an appropriate
hydrophilic–lipophilic balance are able to extract copper from the aqueous phase to the organic phase,
accelerating the CuAAC reaction rate. The present system is widely applicable to substrates with various
functionalities, including a free amino group and especially to lipophilic substrates.
Received 14th April 2014
Accepted 9th June 2014
DOI: 10.1039/c4ra03356f
www.rsc.org/advances
problem, the use of organic-soluble Cu(I) complexes has been
suggested such as (PPh3)3$CuBr, (EtO)3P$CuI,11a bis-tri-
azolylidene dicopper(I) complexes11b and C3H7COOCu(PPh3)2.11c
Introduction
While the traditional thermal azide–alkyne 1,3-dipolar cyclo-
addition reaction requires prolonged heating at elevated
temperatures and results in mixtures of both 1,4- and 1,5-
substituted triazole regioisomers,1 the Cu(I) catalyzed version
(CuAAC) provides only the 1,4-regioisomer under relatively mild
conditions.2 Since its discovery, CuAAC has emerged as the
archetypical example of “click chemistry”,3 and has found
widespread application in many areas such as drug discovery,
material science, and bioconjugation.4 This broad application
was made possible in part by the advent of new reaction
conditions that are more efficient and adaptable than the
original CuAAC conditions.5
The original CuAAC conditions suggested by Sharpless use
an in situ generated Cu(I) catalyst derived from the reaction of
CuSO4$5H2O and sodium ascorbate, and a mixture of water and
t-BuOH.2a The general issues in the development of new CuAAC
conditions are generating the effective Cu(I) catalyst and
maintaining high levels of the catalytically active Cu(I) during
the reaction. As a consequence, a wide range of Cu(I) sources
have been introduced, and various Cu ligands were developed to
prevent the formation of unreactive polynuclear Cu(I) acetylides
and increase the thermodynamic stability of Cu(I).5b,6,7 Alterna-
tively, a variety of immobilized copper catalysts have been
devised for heterogeneous or soluble polymer catalyst systems.8
Another important issue has been the different solubility
preferences of the Cu(I) catalyst and substrates.9 As one may
notice, most of the copper salts have limited solubility in
organic solvents10 while the substrates of interest in organic
synthesis generally have a high organic solubility. To solve this
Although these ligand chelated Cu(I) reagents exhibited better
organic solubility and high reactivity, they possess some draw-
backs. For example, phosphine based Cu(I) complexes have the
intrinsic risk of the Staudinger reduction of azide.5c In some
cases, these catalysts require harsh reaction conditions, such as
elevated temperatures. In addition, the lengthy and complex
procedures for catalysts preparation reduce the wide applica-
tion of such catalysts.
Another way of solving the problem derived from the
different solubility preferences is the careful choice of solvent
systems.5a Most commonly, the reaction is performed in a
mixture of water and water-miscible organic solvent, which
facilitates solvation of hydrophobic substrates while still
retaining the advantages of water. Organic solvents of inter-
mediate polarity, such as THF, acetone, pyridine, CH3CN, and
DMSO, are oen employed when partially organic soluble CuI
or organic-soluble Cu complexes are used as a source of Cu(I).
The two-phase solvent system composed of water and organic
solvent was also reported to be effective to produce the triazole
products with or without a ligand.12 Although many solvent
systems are available, nding the optimum solvent is still a
case-to-case basis because there is no obvious correlation
between which solvent is used and performance of the reaction.
Given our interest in developing reliable, general reaction
conditions for CuAAC in organic synthesis, we sought to explore
the possibility of applying the concept of phase transfer catal-
ysis (PTC) as a solution for the different solubility preferences.
PTC is an efficient and widely used method for promoting
reactions between reaction partners that are present in two
immiscible phases.13 However, the concept of PTC has rarely
been applied to CuAAC reactions,14 and its potential use has not
been sufficiently explored. One of the few investigations
employing this concept is the utilization of b-cyclodextrin in
College of Pharmacy, Seoul National University, Seoul 151-742, Korea. E-mail:
pennkim@snu.ac.kr; Fax: +82-2-888-0649; Tel: +82-2-880-2487
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for all of the nal products and azide 7. See DOI: 10.1039/c4ra03356f
26516 | RSC Adv., 2014, 4, 26516–26523
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water medium.14a Although this reaction system quickly
To identify phase transfer agents that fulll the above
provides the product by making a host–guest complex within conditions, we surveyed several types of ligands which have
the hydrophobic cyclodextrin cavity, there are some substrate been devised to promote the Cu(I) catalyzed triazole formation.
limitations due to the capacity allowances of cyclodextrins.15 This effort resulted in the selection of tris(triazolylmethyl)
Polyethylene glycol 400 (PEG-400) has been employed as a phase amine ligands that are easily available and consist of several
transferring agent in a one-pot multi-component CuAAC reac- variants with different physicochemical properties.7a,18 Four
tion in water medium.14b,c In this case, a large excess of PEG-400 typical tris(triazolylmethyl)amine ligands (1a–d, Fig. 2) with
was used as like a co-solvent.
different functional groups and log P values were chosen for the
Unlike the previous phase transfer CuAAC reactions in which rst step of the development. Benzyl azide (2a) and phenyl
substrates are delivered to the water medium, we employed an acetylene (3a) were chosen as a CuAAC reaction partners, and
aqueous/organic two-phase solvent system and planned to water soluble CuSO4$5H2O (0.5 mol%) and sodium ascorbate
transfer copper from the aqueous phase to the organic phase (1.5 mol%) were used to generate the Cu(I) in situ. A mixture of
where the reaction occurs. We envisioned that the aqueous CH2Cl2–H2O (1 : 1) was employed as a biphasic solvent system
biphasic reaction system would be advantageous for a broad (Table 1).
range of substrates and would be highly generalizable if the
When the reaction was performed without a ligand for
biphasic CuAAC reactions could be facilitated by a phase 240 min (entry 1), most of the starting materials remained intact
transfer agent. Herein, we report our studies on this subject and and the desired product was obtained in poor yield (20%).
describe new CuAAC reaction conditions which are highly effi- However, in the presence of TTTA (1a), the reaction was
cient, especially when a lipophilic substrate is involved.
completed within 20 min with the formation of product in
nearly quantitative yield (entry 2). TBTA (1b) increased the
reaction rate such that the reaction was completed within 40
min (entry 3).19 BTTAA (1c) was far less effective in accelerating
the reaction (entry 4). The most hydrophilic ligand THPTA (1d)
signicantly retarded the reaction, resulting in only 3% product
yield even aer 240 min (entry 5).
Results and discussion
Our working hypothesis for the phase transfer agent assisted
CuAAC reaction is shown in Fig. 1. The in situ generated Cu(I)
catalyst produced by the reaction of Cu(II) and sodium ascorbate
in aqueous phase would be ferried into the organic phase by a
phase transfer agent as a complex form.16 Similarly to other
organic-soluble Cu(I) complexes, the relocated Cu(I) species
would promote the CuAAC reactions in the organic phase.
During the reaction process, Cu(I) can be inadvertently oxidized
to Cu(II). In aqueous phase in which sodium ascorbate is dis-
solved, these oxidized Cu(II) species can revert back to the
catalytically active Cu(I) species,17 which are able to reenter the
cycle with the help of the phase transfer agent.
In this phase transfer system, the phase transfer agents
should be able to encapsulate Cu(I) in the aqueous phase or at
the interface to deliver it to the organic phase. In addition, it is
advantageous if they are able to be coordinated with Cu(I)
during the reaction to enhance the rate of reaction and to
protect the Cu(I) from oxidation.
To verify whether the observed reaction rates were related to
the phase transfer activity of tris(triazolylmethyl)amine ligands,
we used ICP-MS analysis to measure the copper content in the
organic layer of the substrate-blank biphasic reaction system. As
shown in Table 2, the copper content in the organic layer was
very low (78 ppb) without any ligand (entry 1). In the presence of
TTTA (1a, C log P ¼ 1.1), the copper content was increased
approximately 900 times (entry 2). TBTA (1b, C log P ¼ 2.7) also
resulted in an increase of copper content by approximately
500 times (entry 3). The more hydrophilic ligands 1c and 1d did
not cause a signicant increase in the copper content (entries
4 and 5). This result indicated that the tris(triazolylmethyl)-
amine ligands with appropriate hydrophilic–lipophilic balances
are able to extract copper from the aqueous phase to the organic
phase, thereby accelerating the rate of the CuAAC reaction.
To understand the mechanism of copper transfer, we
measured the partition ratio of TTTA (1a) between CH2Cl2 and
1
H2O by H NMR analysis. To our surprise, although the calcu-
lated log P value for 1a is 1.1, only a negligible amount of 1a was
resided in the aqueous layer while the overwhelming majority of
Fig. 1 Schematic representation of phase transfer agent assisted
CuAAC reaction.
Fig. 2 Structures of tris(triazolylmethyl)amine ligands (1a–d).
RSC Adv., 2014, 4, 26516–26523 | 26517
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Table 1 Effects of tris(triazolylmethyl)amine ligands on the CuAAC Table 3 Effects of solvent systems on the CuAAC reactiona
reactiona
Entry
Solvent
Time (min)
Yieldb (%)
Entry
Ligand
Time (min)
Yieldb (%)
1
2
3
4
5
6
CHCl3–H2O (1 : 1)
Toluene–H2O (1 : 1)
CH2Cl2–H2O (1 : 1)
t-BuOH–H2O (2 : 1)
H2O
25
50
15
360
360
360
100
97
100
99
78
<1
1
2
3
4
5
None
1a
1b
1c
1d
240
20
40
240
240
20
100
100
47
3
CH2Cl2
a
a
Reaction conditions: 2a (0.50 mmol), 3a (0.55 mmol), CuSO4$5H2O
Reaction conditions: 2b (0.50 mmol), 3a (0.55 mmol), CuSO4$5H2O
(0.5 mol%), Na ascorbate (1.5 mol%), and ligand (0.5 mol%) in
(0.5 mol%), Na ascorbate (1.5 mol%), and 1a (0.5 mol%) in solvent (1
mL) at rt.
tetrachloroethane as an internal standard.
CH2Cl2–H2O (1 : 1) (1 mL) at rt. Determined by 1H NMR analysis
b
Determined by 1H NMR analysis using 1,1,2,2-
b
using 1,1,2,2-tetrachloroethane as an internal standard.
Table
2 Effects of tris(triazolylmethyl)amine ligands on the Cu
The scope of applicability of the phase transfer agent assis-
ted CuAAC reaction was explored with 0.5 mol% of TTTA (1a) in
a biphasic CH2Cl2–H2O medium containing CuSO4$5H2O and
ascorbate (0.5 and 1.5 mol%, respectively; conditions (A)). First,
we applied various types of azides to the reaction system. As
shown in Table 4, the azide structure has no signicant effect on
the reaction rates. All of the reactions proceeded efficiently and
were completed in less than 15 min, with excellent isolated
yields (entries 1–5). However, the effects of alkyne structures on
the reaction rates were signicant. Alkynes with an ester group
or a phenyl group proceeded efficiently, resulting in the corre-
sponding triazole products within 20 min in excellent yields
(entries 6 and 7). The N-Boc group at the propargylic position of
the alkyne substrate did not affect the reaction rates (entry 8).
Propargyl alcohols were also suitable for this reaction system,
yielding product in less than 50 min (entries 9 and 10). The
reaction of the t-butyl substituted alkyne was completed in 50
min (entry 11). However, the reaction of the n-hexyl or cyclo-
hexyl substituted alkynes was not completed within the same
time. These substrates required an increase in copper and
sodium ascorbate loading (1.5 and 4.5 mol%, respectively;
conditions (B)) for completion within 50 min (entries 12 and
13). The cycloadditions of propynoic acid also proceeded effi-
ciently under these higher copper loading conditions (entry 14).
Noteworthy was the result obtained in the biphasic CuAAC
reaction of propargyl amine (entry 15) because the CuAAC
reaction generally fails or gives low yield in the presence of free
amino groups as a consequence of the coordination between
the Cu(I) ion and the amino group.7a,21 Under higher reagent
loading conditions, the triazole product 4q was successfully
obtained in 97% yield. In addition, the reactions between free
amine containing azides 2h–j and the phenyl acetylene (3a)
proceeded efficiently in this reaction system (entries 16–18).
We demonstrated the utility and efficiency of the phase
transfer agent assisted biphasic CuAAC reaction by applying it to
the synthesis of an immunostimulant a-GalCer analog 5
(Scheme 1).22 Because this synthesis required a highly lipophilic
content in the CH2Cl2 layera
Entry
Ligand
C log Pb
Cu contentc (ppb)
1
2
3
4
5
None
1a
1b
1c
1d
—
1.1
2.7
78
70 330
39 475
125
ꢀ0.37
ꢀ3.7
128
a
Conditions: CuSO4$5H2O (0.0025 mmol), Na ascorbate (0.0075 mmol),
and ligand (0.0025 mmol) in CH2Cl2–H2O (1 : 1) (1 mL) at rt for 30 min.
b
C log P values were calculated using ChemBioDraw Ultra 13.0.
Determined by ICP-MS analysis.
c
1a was detected in the CH2Cl2 layer. This result suggested that
the complexation between 1a and Cu(I) might occur mostly at or
near the interface between CH2Cl2 and H2O, and then this
complex would move to the organic phase to promote the
CuAAC reactions.13c,20
Toluene and CHCl3 can also be used as the organic phase of
the biphasic system (Table 3). The CuAAC reaction between the
highly lipophilic alkyl azide 2b and phenyl acetylene (3a) in
biphasic CHCl3–H2O medium was completed in 25 min in the
presence of 1a (entry 1), and the reaction in toluene–H2O was
completed in 50 min (entry 2). Although the reaction in these
solvent systems was slower than reactions performed in the
CH2Cl2–H2O solvent system (entry 3), the necessary reaction
time was still short and the yield was very high. The corre-
sponding reaction in the monophasic t-BuOH–H2O solvent
system was much less efficient and reached full conversion in
360 min (entry 4). When water was used as the only solvent, full
conversion was not reached even aer 360 min primarily
because of the limited solubility of substrates (entry 5). The
reaction in only CH2Cl2 solvent provided a trace amount of the
product in 360 min because of the limited solubility of
CuSO4$5H2O and sodium ascorbate (entry 6).
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Table 4 CuAAC reaction with various alkynes and azides using phase transfer agenta
Entry
R1
R2
Conditionsb
Time (min)
4
Yieldc (%)
1
2
3
4
5
6
7
8
Cyclohexyl (2c)
C2H5OCOCH2 (2d)
p-NO2C6H4CH2 (2e)
p-BrC6H4CH2 (2f)
p-CH3OC6H4CH2 (2g)
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
15
5
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
97
98
96
96
99
98
100
95
99
95
98
98
100
91
97
98
93
96
10
15
10
15
20
30
50
40
50
40
50
20
180
20
120
50
Ph (3a)
CO2C2H5 (3b)
p-CH3OC6H4 (3c)
CH2NHBoc (3d)
CH2OH (3e)
Cyclohexane-1-ol (3f)
t-Bu (3g)
n-Hex (3h)
Cyclohexyl (3i)
CO2H (3j)
CH2NH2 (3k)
Ph (3a)
9
10
11
12
13
14
15
16
17
18
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
PhCH2 (2a)
NH2C2H4 (2h)
NH2C6H12 (2i)
CH3NHC6H12 (2j)
Ph (3a)
Ph (3a)
4s
4t
a
Reaction conditions: 2 (0.50 mmol), 3 (0.55 mmol), 1a (0.5 mol%), with conditions A or B in CH2Cl2–H2O (1 : 1) (1 mL) at rt. b (A) CuSO4$5H2O (0.5
c
mol%), Na ascorbate (1.5 mol%). (B) CuSO4$5H2O (1.5 mol%), Na ascorbate (4.5 mol%). Isolated yield.
consisting of water and an organic solvent ensures a complete
dissolution of reagents and substrates, thus broadening the
scope of possible substrates. Among the tested tris(triazolyl-
methyl)amine Cu ligands, TTTA (1a) and TBTA (1b) afforded the
expected phase transfer activity. The developed biphasic reac-
tion system is highly efficient, especially when a lipophilic
substrate is involved. The present system is widely applicable to
substrates with various functionalities including a free amino
group, making the CuAAC reaction more reliable.
Experimental
General considerations
Scheme 1 Efficient synthesis of a-GalCer analog 5 using the phase
transfer agent assisted CuAAC reaction.
All chemicals were reagent grade and used as purchased. The
reactions were monitored with TLC analysis using silica gel
60 F-254 thin layer plates. Compounds on the TLC plates were
sprayed with either potassium permanganate or phosphomo-
lybdic acid and visualized under UV light. Flash column chro-
matography was conducted on silica gel 60 (230–400 mesh).
Optical rotations were measured using a sodium lamp (D line
589.3 nm). Melting points were measured using an electro-
thermal capillary melting point apparatus and are uncorrected.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded in d units relative to the deuterated solvent. IR spectra
were measured on a Fourier transform infrared spectrometer.
High-resolution mass spectra (HRMS) were recorded using FAB.
alkyne 6, the CuAAC reaction of azide 7 with 6 under the
conventional reaction system was not met with great success.
For example, when the reaction was performed in monophasic
t-BuOH–H2O solvent system, the triazole product 5 was obtained
in only 20% aer 24 h even in the presence of TTTA (1a).
However, under the presented biphasic system, we successfully
obtained 5 in 92% yield in a short reaction time (2 h).
Conclusions
In summary, we have developed a phase transfer agent assisted Inductively coupled plasma mass spectrometry (ICP-MS) anal-
biphasic CuAAC reaction system. A biphasic reaction media ysis was performed for copper quantitation.
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Preparation of the starting materials
1-Octyl-4-phenyl-1H-1,2,3-triazole (4b)
Azides 2a–g were synthesized according to procedures provided White solid (128.6 mg, 100%); m.p. 78–80 ꢂC; 1H NMR
by Alvarez et al.23 Azides 2h,24 2i and 2j,25 and alkyne 3d26 was (400 MHz, CDCl3) d 7.80–7.78 (m, 2H), 7.72 (s, 1H), 7.38–7.34
also prepared according to the procedures in the literature. The (m, 2H), 7.29–7.25 (m, 1H), 4.31 (t, J ¼ 7.2 Hz, 2H), 1.91–1.84 (m,
NMR data were in agreement with those published for benzyl 2H), 1.28–1.21 (m, 10H), 0.83 (t, J ¼ 6.7 Hz, 3H); 13C NMR
azide (2a),23 1-azidooctane (2b),23 azidocyclohexane (2c),23 (100 MHz, CDCl3) d 147.5, 130.6, 128.6 (2C), 127.9, 125.5 (2C),
ethyl 2-azidoacetate (2d),27 1-(azidomethyl)-4-nitrobenzene 119.4, 50.2, 31.5, 30.2, 28.9, 28.8, 26.3, 22.4, 13.9; IR (neat, cmꢀ1
)
(2e),28 1-(azidomethyl)-4-bromobenzene (2f),29 1-(azidomethyl)- nmax 3120, 3092, 3064, 2954, 2917, 2849, 1484, 1463, 1356, 1215,
4-methoxybenzene (2g),28 2-azidoethan-1-amine (2h),24 6-azido- 1190, 1078, 1051, 976, 839, 760, 693; HRMS (FAB): calcd for
hexan-1-amine (2i),25 6-azido-N-methylhexan-1-amine (2j)25 and
tert-butyl prop-2-ynylcarbamate (3d).26
C
16H24N3 [M + H]+ 258.1970, found 258.1976.
1-Cyclohexyl-4-phenyl-1H-1,2,3-triazole (4c)
White solid (110.2 mg, 97%); m.p. 107–108 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.80–7.78 (m, 2H), 7.75 (s, 1H), 7.37–7.33
(m, 2H), 7.27–7.23 (m, 1H), 4.39 (tt, J ¼ 11.8, 3.7 Hz, 1H), 2.17–
2.14 (m, 2H), 1.87–1.67 (m, 5H), 1.44–1.19 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 147.0, 130.7, 128.6 (2C), 127.7, 125.4 (2C),
117.3, 59.9, 33.3 (2C), 24.94 (2C), 24.89; IR (neat, cmꢀ1) nmax
3126, 2936, 2854, 1480, 1452, 1374, 1223, 1054, 1000, 894, 826,
761, 691; HRMS (FAB): calcd for C14H18N3 [M + H]+ 228.1501,
found 228.1503.
Measurement of partition ratio of TTTA (1a) between CH2Cl2
and H2O
In a vial tted with a screw cap, TTTA (1a, 85.6 mg, 0.2 mmol)
was dissolved in CH2Cl2–H2O (1 : 1, 2 mL) and stirred at rt
for 1 or 12 h. Aer phase separation, 0.5 mL of each layer
was carefully sampled and the solvents were evaporated.
The 1a in each residue was measured by 1H NMR in CDCl3
using 1,1,2,2-tetrachloroethane as an internal standard. In
the sample taken from the H2O layer, no peak of 1a was
identied.
Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (4d)
White solid (113.3 mg, 98%); m.p. 93–94 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.89 (s, 1H), 7.80–7.78 (m, 2H), 7.38–7.35 (m, 2H), 7.30–
7.26 (m, 1H), 5.13 (s, 2H), 4.19 (q, J ¼ 7.2 Hz, 2H), 1.23 (t, J ¼ 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.1, 147.7, 130.2, 128.6
General procedure for CuAAC reactions
In a vial tted with a screw cap, freshly prepared stock solutions
of CuSO4$5H2O (50 mL, 50 mM stock solution in DDW, 0.5
mol%), TTTA (1a, 50 mL, 50 mM stock solution in CH2Cl2,
0.5 mol%), and sodium ascorbate (50 mL, 150 mM stock solution
in DDW, 1.5 mol%) were added to a mixture of azide 2
(0.5 mmol, 1.0 equiv.) and acetylene 3 (0.55 mmol, 1.1 equiv.) in
DDW (0.40 mL) and CH2Cl2 (0.45 mL). The reaction was allowed
to proceed at rt and monitored by TLC. Aer total consumption
of the starting azide, the reaction mixture was poured into
saturated NH4Cl aqueous solution (10 mL). The aqueous layer
was extracted with CH2Cl2 (2 ꢁ 10 mL).
(2C), 127.9, 125.5 (2C), 121.1, 62.1, 50.6, 13.7; IR (neat, cmꢀ1
)
nmax 3135, 2948, 1752, 1465, 1442, 1346, 1214, 1197, 1074, 1014,
763, 692; HRMS (FAB): calcd for C12H14N3O2 [M + H]+ 232.1086,
found 232.1087.
1-(4-Nitrobenzyl)-4-phenyl-1H-1,2,3-triazole (4e)
1
White solid (134.4 mg, 96%); m.p. 157–159 ꢂC; H NMR (400
MHz, CDCl3) d 8.20–8.18 (m, 2H), 7.79–7.74 (m, 3H), 7.42–7.29
(m, 5H), 5.66 (s, 2H); 13C NMR (100 MHz, CDCl3) d 148.6, 148.0,
141.7, 130.1, 128.9 (2C), 128.5 (2C), 128.4, 125.7 (2C), 124.3 (2C),
119.7, 53.1; IR (neat, cmꢀ1) nmax 3127, 3083, 1606, 1517, 1347,
1222, 1077, 1045, 861, 803, 761, 729, 690; HRMS (FAB): calcd for
For the carboxylic acid containing compound 4p, the mixture
was acidied to pH 1 with 1 N HCl aqueous solution and
extracted with CH2Cl2 (5 ꢁ 10 mL).
15H13N4O2 [M + H]+ 281.1039, found 281.1034.
For the free amine containing compounds 4q and 4r, the
reaction mixture was poured into 25% NH4OH aqueous solu-
tion (10 mL) and extracted with CH2Cl2 (3 ꢁ 10 mL).
C
1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (4f)
The combined organic layers were dried over MgSO4, and
concentrated in vacuo. When required, the product was puried
by ash column chromatography on silica gel.
White solid (150.4 mg, 96%); m.p. 150–152 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.78–7.76 (m, 2H), 7.66 (s, 1H), 7.48–7.45
(m, 2H), 7.39–7.37 (m, 2H), 7.31–7.27 (m, 1H), 7.14–7.12 (m,
2H), 5.47 (s, 2H); 13C NMR (100 MHz, CDCl3) d 148.3, 133.7,
132.2 (2C), 130.3, 129.6 (2C), 128.8 (2C), 128.2, 125.6 (2C), 122.8,
119.5, 53.4; IR (neat, cmꢀ1) nmax 3107, 3083, 1483, 1461, 1431,
1350, 1219, 1073, 1047, 1010, 799, 961, 687; HRMS (FAB): calcd
for C15H13BrN3 [M + H]+ 314.0293, found 314.0292.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (4a)
White solid (117.3 mg, 100%); m.p. 130–132 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.79–7.77 (m, 2H), 7.66 (s, 1H), 7.28–7.26
(m, 8H), 5.51 (s, 2H); 13C NMR (100 MHz, CDCl3) d 148.0, 134.6,
130.4, 129.0 (2C), 128.7 (2C), 128.6, 128.0, 127.9 (2C), 125.5 (2C),
119.5, 54.0; IR (neat, cmꢀ1) nmax 3141, 3027, 2976, 1468, 1449,
1-(4-Methoxybenzyl)-4-phenyl-1H-1,2,3-triazole (4g)
1361, 1222, 1140, 1073, 1044, 766, 727, 693; HRMS (FAB): calcd White solid (131.1 mg, 99%); m.p. 139–140 ꢂC; 1H NMR
for C15H14N3 [M + H]+ 236.1188, found 236.1189.
(400 MHz, CDCl3) d 7.77–7.75 (m, 2H), 7.62 (s, 1H), 7.35
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(t, J ¼ 7.7 Hz, 2H), 7.28–7.21 (m, 3H), 6.86 (d, J ¼ 8.6 Hz, 2H),
5.44 (s, 2H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.8,
147.9, 130.5, 129.5 (2C), 128.6 (2C), 128.0, 126.6, 125.5 (2C),
119.3, 114.4 (2C), 55.2, 53.6; IR (neat, cmꢀ1) nmax 3107, 3083,
1483, 1461, 1219, 1073, 1010, 816, 799, 761, 687; HRMS (FAB):
calcd for C16H16N3O [M + H]+ 266.1293, found 266.1291.
1-Benzyl-4-(tert-butyl)-1H-1,2,3-triazole (4m)
White solid (105.1 mg, 98%); m.p. 84–86 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.29–7.24 (m, 3H), 7.19–7.17 (m, 2H), 7.15 (s, 1H), 5.39
(s, 2H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) d 157.8, 134.9,
128.7 (2C), 128.2, 127.7 (2C), 118.3, 53.6, 30.5, 30.1 (3C); IR
(neat, cmꢀ1) nmax 3119, 2961, 2865, 1531, 1495, 1457, 1361,
1341, 1231, 1202, 1051, 821, 713, 673; HRMS (FAB): calcd for
C
13H18N3 [M + H]+ 216.1501, found 216.1498.
Ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate (4h)
White solid (113.3 mg, 98%); m.p. 84–86 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.98 (s, 1H), 7.25–7.17 (m, 5H), 5.48 (s, 2H), 4.25 (q, J ¼
7.2 Hz, 2H), 1.24 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
160.3, 140.1, 133.7, 128.9 (2C), 128.6, 127.9 (2C), 127.2, 60.8,
54.0, 13.9; IR (neat, cmꢀ1) nmax 3126, 2983, 1715, 1539, 1368,
1226, 1044, 1022, 776, 716, 693; HRMS (FAB): calcd for
1-Benzyl-4-hexyl-1H-1,2,3-triazole (4n)
White solid (119.0 mg, 98%); m.p. 52–54 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.35–7.29 (m, 3H), 7.23–7.21 (m, 2H), 7.15 (s, 1H), 5.45
(s, 2H), 2.65 (t, J ¼ 7.8 Hz, 2H), 1.64–1.56 (m, 2H), 1.34–1.25 (m,
6H), 0.83 (t, J ¼ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 148.6,
134.9, 128.8 (2C), 128.3, 127.7 (2C), 120.4, 53.6, 31.3, 29.1, 28.7,
25.5, 22.3, 13.8; IR (neat, cmꢀ1) nmax 3112, 3065, 2957, 2919,
2853, 1553, 1493, 1456, 1433, 1325, 1212, 1130, 1051, 1029, 856,
703, 691; HRMS (FAB): calcd for C15H22N3 [M + H]+ 244.1814,
found 244.1816.
C
12H14N3O2 [M + H]+ 232.1086, found 232.1088.
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (4i)
White solid (132.3 mg, 100%); m.p. 142–144 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.71–7.69 (m, 2H), 7.56 (s, 1H), 7.37–7.27
(m, 5H), 6.92–6.89 (m, 2H), 5.52 (s, 2H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 159.5, 147.9, 134.7, 129.0 (2C), 128.6, 127.9
(2C), 126.9 (2C), 123.2, 118.7, 114.1 (2C), 55.2, 54.0; IR (neat,
cmꢀ1) nmax 3138, 3040, 2949, 2838, 2098, 1614, 1557, 1495, 1454,
1436, 1349, 1249, 1170, 1070, 1027, 973, 832, 794, 717; HRMS
(FAB): calcd for C16H16N3O [M + H]+ 266.1293, found 266.1286.
1-Benzyl-4-cyclohexyl-1H-1,2,3-triazole (4o)
White solid (120.4 mg, 100%); m.p. 109–111 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.37–7.31 (m, 3H), 7.24–7.22 (m, 2H), 7.12
(s, 1H), 5.46 (s, 2H), 2.72–2.71 (m, 1H), 2.01–1.99 (m, 2H), 1.77–
1.66 (m, 3H), 1.37–1.29 (m, 4H), 1.22–1.18 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 153.9, 134.9, 128.8 (2C), 128.3, 127.8 (2C),
119.1, 53.7, 35.1, 32.8 (2C), 25.9 (2C), 25.8; IR (neat, cmꢀ1) nmax
3121, 2925, 2851, 1540, 1495, 1450, 1264, 1208, 1128, 1049, 821,
754, 721, 699; HRMS (FAB): calcd for C15H20N3 [M + H]+
242.1657, found 242.1660.
tert-Butyl((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)carbamate
(4j)
Light yellow solid (137.0 mg, 95%); m.p. 91–93 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.40 (s, 1H), 7.37–7.23 (m, 5H), 5.48 (s, 2H),
5.04 (brs, 1H, NH), 4.34 (d, J ¼ 5.9 Hz, 2H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 155.7, 145.7, 134.5, 128.9 (2C), 128.5, 127.8
(2C), 121.7, 79.3, 53.9, 35.9, 28.2 (3C); IR (neat, cmꢀ1) nmax 3405,
3111, 3063, 2978, 2954, 1688, 1515, 1454, 1268, 1169, 1123,
1054, 796, 717, 695; HRMS (FAB): calcd for C15H21N4O2 [M + H]+
289.1665, found 289.1666.
1-Benzyl-1H-1,2,3-triazole-4-carboxylic acid (4p)
White solid (92.1 mg, 91%); m.p. 184–185 ꢂC; 1H NMR
(400 MHz, (CD3)2SO) d 12.92 (brs, 1H, CO2H) 8.75 (s, 1H), 7.40–
7.33 (m, 5H), 5.64 (s, 2H); 13C NMR (100 MHz, (CD3)2SO) d 161.6,
140.1, 135.6, 128.9, 128.8 (2C), 128.2, 128.0 (2C), 53.0; IR (neat,
cmꢀ1) nmax 3115, 2556, 1681, 1540, 1495, 1425, 1232, 1049, 944,
895, 783, 714, 687; HRMS (FAB): calcd for C10H10N3O2 [M + H]+
204.0773, found 204.0767.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanol (4k)
White solid (93.4 mg, 99%); m.p. 77–79 ꢂC; 1H NMR (400 MHz,
CDCl3) d 7.43 (s, 1H), 7.31–7.28 (m, 3H), 7.21–7.19 (m, 2H), 5.42
(s, 2H), 4.67 (s, 2H), 3.71 (brs, 1H, OH); 13C NMR (100 MHz,
CDCl3) d 148.2, 134.4, 129.0 (2C), 128.6, 128.0 (2C), 121.8, 55.9,
54.0; IR (neat, cmꢀ1) nmax 3252, 3140, 2934, 1457, 1222, 1129,
1036, 1012, 837, 788, 717, 691; HRMS (FAB): calcd for
(1-Benzyl-1H-1,2,3-triazol-4-yl)methanamine (4q)
White solid (91.2 mg, 97%); m.p. 106–109 ꢂC; 1H NMR
(400 MHz, (CD3)2SO) d 7.92 (s, 1H), 7.39–7.30 (m, 5H), 5.56 (s,
2H), 3.75 (s, 2H), 2.31 (brs, 2H, NH2); 13C NMR (100 MHz,
(CD3)2SO) d 150.1, 136.2, 128.7 (2C), 128.0, 127.9 (2C), 121.8,
52.7, 37.2; IR (neat, cmꢀ1) nmax 3345, 3137, 2917, 1604, 1494,
1454, 1328, 1212, 1124, 1050, 898, 802, 726, 693, 668; HRMS
(FAB): calcd for C10H13N4 [M + H]+ 189.1140, found 189.1135.
C
10H12N3O [M + H]+ 190.0980, found 190.0980.
1-(1-Benzyl-1H-1,2,3-triazol-4-yl)cyclohexan-1-ol (4l)
White solid (122.1 mg, 95%); m.p. 125–126 ꢂC; 1H NMR
(400 MHz, CDCl3) d 7.35 (s, 1H), 7.31–7.25 (3H), 7.19–7.17 (m,
2H), 5.40 (s, 2H), 3.05 (brs, 1H, OH), 1.91–1.25 (m, 10H); 13C
NMR (100 MHz, CDCl3) d 156.0, 134.6, 128.8 (2C), 128.4, 127.9
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)ethan-1-amine (4r)
White solid (92.0 mg, 98%); m.p. 75–77 ꢂC; 1H NMR (400 MHz,
(2C), 119.5, 69.3, 53.8, 37.9 (2C), 25.2, 21.7 (2C); IR (neat, cmꢀ1
)
nmax 3293, 2933, 2856, 1497, 1454, 1334, 1250, 1217, 1158, 1055, (CD3)2SO) d 8.54 (s, 1H), 7.84 (d, J ¼ 7.3 Hz, 2H), 7.44 (t, J ¼ 7.5
979, 795, 727; HRMS (FAB): calcd for C15H20N3O [M + H]+ Hz, 2H), 7.32 (t, J ¼ 7.3 Hz, 1H), 4.36 (t, J ¼ 6.2 Hz, 2H), 3.02 (m,
258.1606, found 258.1599.
2H); 13C NMR (100 MHz, (CD3)2SO) d 146.1, 130.9, 128.8 (2C),
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127.7, 125.1 (2C), 121.6, 52.7, 41.7; IR (neat, cmꢀ1) nmax 3338, (m, 25H), 0.65 (t, J ¼ 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3–
3125, 2952, 1461, 1217, 1075, 1039, 828, 760, 693; HRMS (FAB): CD3OD, 2 : 1) d 99.2, 73.5, 71.6, 70.5, 69.8, 69.5, 68.4, 67.3, 61.4,
calcd for C10H13N4 [M + H]+ 189.1140, found 189.1135.
61.3, 31.8, 31.5, 29.33, 29.26, 29.21, 28.9, 25.4, 22.2, 13.5; IR
(neat, cmꢀ1) nmax 3325, 2917, 2851, 2100, 1569, 1469, 1262,
1137, 1065, 1023, 696, 763, 717; HRMS (FAB): calcd for
6-(4-Phenyl-1H-1,2,3-triazol-1-yl)hexan-1-amine (4s)
C
24H48N3O8 [M + H]+ 506.3441, found 506.3438.
White solid (113.7 mg, 93%); m.p. 68–71 ꢂC; 1H NMR (400 MHz,
C5D5N) d 8.41 (s, 1H), 8.17 (d, J ¼ 7.4 Hz, 2H), 7.46 (t, J ¼ 7.6 Hz,
2H), 7.33 (t, J ¼ 7.4 Hz, 1H), 4.36 (t, J ¼ 7.1 Hz, 2H), 2.65 (t, J ¼
6.8 Hz, 2H), 1.85–1.78 (m, 2H), 1.37–1.21 (m, 6H); 13C NMR
(100 MHz, C5D5N) d 147.7, 132.0, 129.3 (2C), 128.2, 126.0 (2C),
121.0, 50.2, 42.1, 33.3, 30.4, 26.4 (2C); IR (neat, cmꢀ1) nmax 3286,
3118, 3008, 2924, 2849, 1578, 1483, 1462, 1215, 1077, 838, 758,
692; HRMS (FAB): calcd for C14H21N4 [M + H]+ 245.1766, found
245.1768.
a-GalCer analog 5
In a vial tted with a screw cap, freshly prepared stock solutions
of CuSO4$5H2O (30 mL, 50 mM stock solution in DDW, 1.5
mol%), TTTA (1a, 10 mL, 50 mM stock solution in CH2Cl2,
0.5 mol%), and sodium ascorbate (30 mL, 150 mM stock solution
in DDW, 4.5 mol%) were added to a mixture of 7 (50.5 mg,
0.1 mmol) and 6 (40 mg, 0.11 mmol) in DDW (0.44 mL) and
CH2Cl2 (0.49 mL). The reaction was allowed to proceed at rt for 2
h. The crude reaction mixture was ltered and rinsed with Et2O
(10 mL) and DDW (10 mL). The resulting solid was dried in
vacuo to afford 5 (78.6 mg, 92%) as a white solid. m.p. 166–
168 ꢂC; [a]D25 +45.9 (c 0.3, pyridine); 1H NMR (400 MHz, C5D5N) d
8.28 (s, 1H), 7.07 (d, J ¼ 6.6 Hz, 1H, NH), 6.70 (m, 1H, OH), 6.56
(m, 1H, OH), 6.51 (m, 1H, OH), 6.43 (d, J ¼ 6.3 Hz, 1H, OH), 6.32
(m, 1H, OH), 5.97 (m, 1H, OH), 4.97 (dd, J ¼ 11.5, 4.2 Hz, 1H),
4.69 (dd, J ¼ 11.3, 6.8 Hz, 1H), 4.61 (m, 1H), 4.51–4.34 (m, 6H),
4.14 (m, 1H), 2.77 (t, J ¼ 7.7 Hz, 2H), 2.16 (m, 1H), 1.81–1.58 (m,
6H), 1.31–1.25 (m, 63H), 0.86 (t, J ¼ 6.9 Hz, 6H); 13C NMR
(100 MHz, C5D5N) d 147.8, 122.1, 101.7, 76.7, 73.2, 72.2, 71.5,
71.0, 70.2, 67.4, 62.8, 62.7, 34.3, 32.1, 30.2, 30.00, 29.96, 29.89,
29.73, 29.62, 29.58, 26.3, 26.2, 22.9, 14.2; IR (neat, cmꢀ1) nmax
3360, 2916, 2848, 1729, 1464, 1149, 1069, 1029, 794, 719; HRMS
(FAB): calcd for C50H98N3O8 [M + H]+ 868.7354, found 868.7348.
N-Methyl-6-(4-phenyl-1H-1,2,3-triazol-1-yl)hexan-1-amine (4t)
White solid (124.1 mg, 96%); m.p. 58–60 ꢂC; 1H NMR (400 MHz,
(CD3)2SO) d 8.57 (s, 1H), 7.84 (d, J ¼ 7.5 Hz, 2H), 7.44 (t, J ¼ 7.6
Hz, 2H), 7.32 (t, J ¼ 7.2 Hz, 1H), 4.38 (t, J ¼ 7.0 Hz, 2H), 2.39–2.38
(m, 2H), 2.23 (s, 3H), 1.89–1.82 (m, 2H), 1.38–1.26 (m, 6H); 13
C
NMR (100 MHz, (CD3)2SO) d 146.2, 130.9, 128.8 (2C), 127.7,
125.0 (2C), 121.1, 51.4, 49.4, 36.1, 29.6, 29.0, 26.2, 25.8; IR (neat,
cmꢀ1) nmax 3297, 3118, 3091, 2925, 2850, 2787, 1462, 1439, 1357,
1215, 1077, 1051, 838, 759, 692; HRMS (FAB): calcd for C15H23N4
[M + H]+ 259.1923, found 259.1917.
Azide 7
Prepared according to the previously described procedure in
which a glycosylation donor was changed to a galactosyl deriv-
ative.30 TMSI (858 mL, 6.03 mmol) was added to a solution of
1,2,3,4,6-penta-O-trimethylsilyl-a-D-galactose31 (3.26 g, 6.03
mmol) in CH2Cl2 (60 mL) at 0 ꢂC. The reaction mixture was
stirred under N2 atmosphere for 15 min before benzene (60 mL)
was added. The solvent was removed under reduced pressure
and the glycosyl iodide intermediate obtained was dissolved in
CH2Cl2 (60 mL) and kept under N2 atmosphere. In a separate
Acknowledgements
This work was supported by the Bio & Medical Technology
Development Program (NRF-2013M3A9B8031389) of the
National Research Foundation of Korea (NRF) grant funded by
the Korea government (MSIP). This work was also supported by
the project of Global Ph. D. Fellowship of the NRF conducts
from 2012.
˚
ask, a mixture of activated 4 A molecular sieves (1.50 g), n-
Bu4NI (4.47 g, 12.1 mmol), i-Pr2NEt (1.58 mL, 9.05 mmol) and
(2S,3S,4R)-2-azido-3,4-O-isopropylidene-1,3,4-octadecanetriol32
(770 mg, 2.01 mmol) in CH2Cl2 (60 mL) was prepared and
stirred under an argon atmosphere at rt for 15 min. The solu-
tion of glycosyl iodide in CH2Cl2 was then added drop-wise over
5 min and the resulting mixture was stirred overnight. Aer
removal of the solvent under reduced pressure, Et2O (60 mL)
and H2O (60 mL) were added and the phases were separated.
The organic phase was concentrated under reduced pressure.
MeOH (60 mL) and PTSA$H2O (39.9 mg, 0.21 mmol) were added
to the crude mixture and stirred at rt for 5 h. The reaction was
quenched by the addition of NaHCO3 (300 mg, 3.57 mmol),
ltered, and then concentrated under reduced pressure. The
crude mixture was puried by ash column chromatography
(CHCl3–MeOH, 6 : 1) to afford azide 7 (650 mg, 64%, a-anomer
only) as a white solid. m.p. 195 ꢂC (dec.); [a]D25 +103.9 (c 0.3,
CHCl3–MeOH, 1 : 1); 1H NMR (400 MHz, CDCl3–CD3OD, 2 : 1) d
4.69 (d, J ¼ 3.5 Hz, 1H), 3.90 (dd, J ¼ 10.8 Hz, 3.2 Hz, 1H), 3.75–
3.46 (m, 8H), 3.40–3.36 (m, 2H), 1.42–1.33 (m, 2H), 1.21–1.04
Notes and references
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3 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
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4 For reviews, see: (a) J. E. Moses and A. D. Moorhouse, Chem.
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Drug Discovery Today, 2003, 8, 1128; (c) G. C. Tron, T. Pirali,
R. A. Billington, P. L. Canonico, G. Sorba and
26522 | RSC Adv., 2014, 4, 26516–26523
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6 For review see: S. Dıez-Gonzalez, Curr. Org. Chem., 2011, 15, 18 (a) J. E. Hein, J. C. Tripp, L. B. Krasnova, K. B. Sharpless and
´
´
2830.
V. V. Fokin, Angew. Chem., Int. Ed., 2009, 48, 8018; (b)
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´
S. Dıez-Gonzalez and S. P. Nolan, Angew. Chem., Int. Ed.,
´
`
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A. K. Diallo, J. R. Aranzaes, D. Astruc and J.-M. Vincent, 19 The use of TBTA (1b) for performing the CuAAC reaction
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with the same Cu(I) sources in the same biphasic system
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20 H.-M. Yang and H.-S. Wu, Catal. Rev.: Sci. Eng., 2003, 45, 463.
¨
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