Synthesis of 1,2,3-triazolium ionic liquid-supported chiral imidazolidinones and their application in asymmetric alkylation reaction

Article abstract of DOI:10.3390/molecules24183349

New 1,2,3-triazolium ionic liquid-supported chiral imidazolidinones were developed. The feasibility of the ionic liquid-supported imidazolidinones as chiral auxiliaries was demonstrated in sequential propionylation-alkylation-cleavage reactions, which provided the chiral product with good to excellent chemical yields (up to 90%) and high selectivities (up to 94% ee). The progress of the reactions could be monitored by TLC and NMR, and the ionic liquid-supported chiral auxiliaries could be recovered by simple extraction.

Full text of DOI:10.3390/molecules24183349

molecules
Article
Synthesis of 1,2,3-Triazolium Ionic Liquid-Supported
Chiral Imidazolidinones and Their Application in
Asymmetric Alkylation Reaction
Yunkyung Jeong, Yunjeong Park and Jae-Sang Ryu *
College of Pharmacy & Graduate School of Pharmaceutical Sciences, Ewha Womans University,
52 Ewhayeodae-gil, Seodaemun-Gu, Seoul 03760, Korea; echo4001@naver.com (Y.J.);
amethyst-21@hanmail.net (Y.P.)
* Correspondence: ryuj@ewha.ac.kr; Tel.: +82-2-3277-3008; Fax: +82-2-3277-2851
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Wim Dehaen
Received: 19 August 2019; Accepted: 13 September 2019; Published: 14 September 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: New 1,2,3-triazolium ionic liquid-supported chiral imidazolidinones were developed. The
feasibility of the ionic liquid-supported imidazolidinones as chiral auxiliaries was demonstrated in
sequential propionylation-alkylation-cleavage reactions, which provided the chiral product with
good to excellent chemical yields (up to 90%) and high selectivities (up to 94% ee). The progress of
the reactions could be monitored by TLC and NMR, and the ionic liquid-supported chiral auxiliaries
could be recovered by simple extraction.
Keywords: ionic liquid; 1,2,3-triazolium; chiral imidazolidinone; asymmetric alkylation;
chiral auxiliaries
1. Introduction
Since the Evans’ group first developed enantioselective alkylation reactions using chiral
oxazolidinone enolates in 1980 [
widely applied to many asymmetric reactions, such as aldol [
conjugated addition [ ], and other reactions. As shown over the course of several decades, the
1], oxazolidinone auxiliaries have been extensively studied and
2,
3
], alkylation [ ], Diels-alder [ ],
4
,
5
6
7
use of chiral oxazolidinones offers several benefits in asymmetric reactions: Easy preparation, easy
installation, easy removal, high selectivity, and recyclability. However, Evans’ chiral auxiliaries are
expensive and recovering them is tedious work. Due to these issues, continued efforts have been made
over the past decades to develop polymer-supported forms [8] of Evans’ chiral auxiliaries as convenient
and practical tools for producing chiral compound libraries. The major advantages of this method are
rapid isolation of the desired chiral product and facile recovery of the polymer-supported auxiliary by
simple filtration. Nevertheless, their use in asymmetric reactions has been problematic [9–12]. Indeed,
a relatively narrow range of reaction conditions and substrates have been covered, and inconsistent
yields and stereoselectivity levels have been observed compared to the analogous solution-phase
reactions [
in the reaction media [13
9
–
12]. These problems can be ascribed to the presence of polymer supports that are insoluble
14]. In general, the heterogeneous reaction conditions of solid-phase synthesis
,
cause several issues, including site–site interactions [15], nonlinear kinetic behavior, diffusion-limited
reactivity, unequal distribution of reagents, reduced reactivity, extended reaction times, and reagent
leaching. Owing to these drawbacks, soluble matrices such as poly(ethylene glycol) [16–18], linear
polystyrenes [19], and polyethylenes [20] have drawn increasing attention as alternative supports in
combinatorial synthesis [21]. However, soluble polymer-supported synthesis can be wasteful because a
large amount of solvents is required to precipitate the polymer support at the end of the reaction. While
many attempts to develop efficient matrices for chiral auxiliaries have been made, the results have been
Molecules 2019, 24, 3349; doi:10.3390/molecules24183349
www.mdpi.com/journal/molecules

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unsatisfactory. Currently, it is highly desirable and necessary to develop new soluble matrix-supported
reusable chiral auxiliaries.
In contrast to insoluble polymers, ionic liquid-supported compounds are soluble in certain organic
solvents, and are compatible with most common reagents [22]. In particular, the recovery of ionic
liquid-supported material is easily accomplished by simple extraction after a reaction is complete [23].
In this context, ionic liquids have been considered as alternative soluble supports for Evans’ chiral
auxiliaries. Among several potential ionic liquids, 1,2,3-triazolium ionic liquid was selected as the best
ionic liquid support. Previously, we reported the use of 1,3-dialkyl-1,2,3-triazolium ionic liquids as
stable and recyclable solvents [24]. The applicability of these ionic liquids as new reaction media was
also shown for the Baylis-Hillman reaction, where 1,3-dialkyl-1,2,3-triazolium ionic liquids exhibited
properties comparable to those of imidazolium ionic liquids in terms of thermal stability and miscibility.
Compared with imidazolium ionic liquids, 1,2,3-triazolium ionic liquids are chemically inert under
acidic [25] or basic [24] conditions, which make them more suitable media or supports for acid- or
base-mediated reactions. Therefore, 1,2,3-triazolium ionic liquids are considered to be the best supports
for Evans’ chiral auxiliaries. Herein, we first reports ionic liquid-supported Evans’ chiral auxiliaries
(Figure 1). Compared to solid-supported chiral auxiliaries, 1,2,3-triazolium ionic liquid-supported
chiral auxiliaries possess several advantages: i) The reaction can be conducted under homogeneous
conditions; ii) it is easy to monitor progress of the reaction using TLC; iii) it is not necessary to
translate solution-phase reactions to solid-phase reactions because there is no insoluble polymer
support that can have a significant effect on both reactivity and selectivity; iv) ionic liquid-supported
intermediates/products can be monitored by NMR after removal of the solvents; v) the product can
easily be isolated and ionic liquid-supported chiral auxiliaries can be recycled by simple extraction.
Figure 1. 1,2,3-Triazolium ionic liquid-supported chiral imidazolidinone auxiliaries 1a–c and 2a–c.
2. Results and Discussion
2.1. Synthesis of Ionic Liquid-supported Imidazolidinone 1a–c
1,2,3-Triazolium-tethered imidazolidinone 1a–c and 2a–c were easily produced by Cu-catalyzed
Huisgen 1,3-dipolar cycloaddition [26] using n-butyl azide and alkyne (Scheme 1), which proved
useful for the synthesis of substituted 1,2,3-triazolium ionic liquids. Synthesis commenced with the
azidation of commercially available n-butyl bromide (
captured by N-(5-hexynyl)phthalimide via a Cu-catalyzed click reaction, which gave 1,4-disubstituted
1,2,3-triazole at an 89% yield in two steps. The phthalimide moiety was then ruptured by aminolysis
using hydrazine-hydrate to afford a primary amine at a yield of 98%, which was readily condensed
with Boc-protected amino acids in the presence of EDCI HCl and HOBt. In this step, three amino acids
carrying benzyl, t-butyl, and i-propyl substituents were coupled to to synthesize benzyl-, t-butyl-,
and i-propyl-substituted imidazolidinones. The subsequent treatment of the Boc-protected amines
7a with TFA led to the production of the primary amines 8a in almost quantitative yields. The
3). In situ generated n-butyl azide (4) was
5
6
·
6
–
c
–c

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amide moieties of 8a
–c
were reduced with LiAlH4 to yield the diamines 9a
–c
, which were converted
into the imidazolidinones 10a–c using CDI and Et3N.
Scheme 1. Synthesis of (S)-4-alkyl-1-(4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)imidazolidin-2-ones 10a–c.
At this stage, we needed to confirm that no epimerization occurred throughout the synthesis
route shown in Scheme 1. Therefore, the enantiopurity of the synthesized 1,2,3-triazole-tethered
(S)-4-benzyl-2-imidazolidinone 10a was examined by Mosher’s method [27,28]. For this purpose,
1,2,3-triazole-tethered (R)-4-benzyl-2-imidazolidinone 10a0 was also prepared by the same synthetic
route using Boc-d-Phe-OH instead of Boc-l-Phe-OH (Scheme S1, Supplementary Materials). With
both 1,2,3-triazole-tethered (S)-4-benzyl-2-imidazolidinone 10a and (R)-4-benzyl-2-imidazolidinone
10a’ in hand, the enantiopurity was determined by NMR. Synthesized 1,2,3-triazole-tethered
(S)-4-benzyl-2-imidazolidinone 10a and (R)-4-benzyl-2-imidazolidinone 10a0 were separately treated
with (R)-Mosher’s acid chloride to obtain crude Mosher’s imide 11a and 11a0, respectively, as shown
in Scheme 2. After analyzing the NMR spectra of the crude mixtures, it was confirmed that both 10a
and 10a0 were enantiomerically pure, and no epimerization occurred during synthesis.

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O
Ph
F3C OMe
n-BuLi, THF
Cl
N
N
N
N
O
O
O
N
N
Ph
N
N
NH
N
F3C OMe
–78 °C
rt
Ph
Ph
10a
11a
O
Ph
N
N
N
N
O
O
O
Cl
N
N
F3C OMe
Ph
N
N
NH
N
n-BuLi, THF
F3C OMe
–78 °C
rt
Ph
Ph
10a'
11a'
Scheme 2. Synthesis of (S)-4-benzyl-1-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)-3-((S)-2-methoxy-2-
trifluoromethylphenylacetyl)imidazolidin-2-one (11a) and (R)-4-benzyl-1-[4-(1-butyl-1H-1,2,3-triazol-4-
yl)butyl]-3-((S)-2-methoxy-2-trifluoromethylphenylacetyl)imidazolidin-2-one (11a0).
The 1-butyl-3-methyl-1,2,3-triazolium ionic liquid-supported imidazolidinones 1a
synthesized according to Scheme 3. The 1-butyl-1,2,3-triazole-tethered imidazolidinones 10a
–
–
c
c
were
were
methylated with methyl iodide under neat conditions, which afforded 1-butyl-3-methyl-1,2,3-triazolium
iodide salts 12a in the form of sticky oils. Then, the 1-butyl-3-methyl-1,2,3-triazolium iodide salts
12a–c were treated with LiNTf2 in deionized water to produce 1,2,3-triazolium NTf2 salts 1a–c.
–
c
Scheme 3.
Synthesis of the 1-butyl-3-methyl-1,2,3-triazolium ionic liquid-supported
imidazolidinones 1a–c.
All synthesized 1-butyl-3-methyl-1,2,3-triazolium ionic liquid-supported imidazolidinones 12a–c
and 1a–c were liquids at room temperature and considered room temperature ionic liquids (RTILs) [29].
Especially, the 1,2,3-triazolium NTf2 salts 1a
–
c
were liquids even at
78 ◦C. The 1,2,3-triazolium NTf2
−
◦
salts 1a◦
–
c
dissolved well in THF at
−
78 C. Even though n-BuLi was added in the THF solution
at
−
78 C, it remained as a clear solution. Thus, the NTf2 salts 1a
–
c
were considered useful for
low-temperature asymmetric reactions.
2.2. Application to Asymmetric Reactions
To assess the feasibility of asymmetric alkylation reactions using the ionic liquid-supported
chiral auxiliaries 1a , sequential propionylation-alkylation-cleavage reactions beginning with 1a–c
–c
(Scheme 4) began to be investigated. Propionylation of 1a
–
c
was performed using propionyl chlori◦de
◦
and n-BuLi as a base at
−
78 C, and yielded 13a
–
c
. All reagents were soluble in THF at
−
78 C
and the reaction mixture remained homogeneous throughout the reaction. The progress of the
reactions was monitored by TLC and the formation of 13a
was successfully verified by 1H-NMR
of the crude mixture after completion of the reaction. Although 13a could be purified by column
–
c
–
c
chromatography, this study demonstrated the feasibility of the ionic liquids as liquid supports for
Evans’ auxiliaries without column chromatography. Therefore, after the propionylation reaction,
asymmetric alkylation reactions of 13a
propionylation immediately after the separation of the crude products 13a–c from excess reagents by
simple extraction. Then, the resulting crude alkylated products 14a were treated with aqueous 2
–c using 3-chlorobenzyl bromide and NaHMDS followed the
–
c

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N NaOH solution in 1,4-dioxane at room temperature to cleave chiral products, which gave chiral
)-3-(3-chlorophenyl)-2-methylpropionic acid (15) and regenerated the crude 1,2,3-triazolium NTf2
salts 1a . Upon completion of the reaction, the product was separated by simple extraction with
(−
–
c
EtOAc after acidification with 10% HCl. The isolated 15 was purified by column chromatography and
the enantiomeric excess (ee) was determined by chiral HPLC after modification to the corresponding
N-phenylpropanamide.
Scheme 4. Asymmetric synthesis of (R)-( )-3-(3-chlorophenyl)-2-methylpropionic acid (15) using 1a–c.
−
Table 1 shows the yields and ee’s of the sequential three-step reactions using the
1-butyl-3-methyl-1,2,3-triazolium ionic liquid-supported imidazolidinones 1a , which functioned
as efficient chiral auxiliaries in terms of selectivity. In the sequential reactions using 1a , the
–
c
–
c
ee values were as high as 91–93%, but moderate yields were observed. Therefore, each step
of the sequential reactions was scrutinized. Interestingly, an N-methylated byproduct 13c’ was
isolated in the propionylation reaction using 1c after column chromatography (Scheme 5), the
structure of which was unambiguously identified as an N-methylated imidazolidinone-ionic liquid
13c0 by 2D NMR experiments (NOESY, COSY, and HMBC, Supplementary Materials). Possibly,
◦
when propionylation of 1a
–
c
was performed using n-BuLi solution as a base at
−
78 C, the anion
generated in situ by deprotonation of imidazolidinone abstracted the methyl group from the
1-butyl-3-methyl-1,2,3-triazolium cation intermolecularly. It was found that the methyl group of
1-butyl-3-methyl-1,2,3-triazolium could act as a methylating agent. Therefore, the ionic liquids were
modified to improve stability.
Table 1. Yield and enantiomeric excess (ee) of (−)-15 in ionic liquid (1a–c)-supported reactions.a.
ee b
Entry
IL-Supported Imidazolidinone
Yield (%) a
1
2
3
1a
1b
1c
66
49
59
91
93
93
a
b
Isolated yields in three steps. Determined by HPLC analysis of the corresponding N-phenylpropanamide on a
chiral stationary phase.
Scheme 5. The formation of N-methylated byproduct 13c’ in the propionylation reaction using 1c.

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2.3. Synthesis of Ionic Liquid-Supported Imidazolidinone 2a–c
As the methyl group of 1-butyl-3-methyl-1,2,3-triazolium-supported isopropyl imidazolidinone
1c was turned out labile under the propionylation reaction conditions, it was decided to incorporate
a more sterically hindered n-butyl group into the 1,2,3-triazolium core instead of the methyl group
in order to develop more versatile supports and to avoid undesirable side reactions. Based on
this revised design, the 1,3-dibutyl-1,2,3-triazolium NTf2 salts 2a
disubstituted triazoles 10a were butylated using n-butyl iodide under neat conditions, which afforded
1,3-dibutyl-1,2,3-triazolium iodide salts 16a in 77–92% yields. Then, the iodide salts 16a were
treated with LiNTf2 in deionized water for anion metathesis, which produced the 1,2,3-triazolium
NTf2 salts 2a . All synthesized 1,3-dibutyl-1,2,3-triazolium-supported imidazolidinones 16a and
2a were liquids at room temperature and were considered room temperature ionic liquids (RTILs).
–c were prepared (Scheme 6). The
–c
–
c
–c
–c
–c
–
c
The 1,2,3-triazolium NTf2 salts 2a
asymmetric reactions.
–
c
were liquid even at
78 ◦C and were suitable for low-temperature
−
Scheme 6. Synthesis of the 1,3-dibutyl-1,2,3-triazolium ionic liquid-supported imidazolidinones 2a–c.
2.4. Application to Asymmetric Reactions
With the more sterically hindered 1,3-dibutyl-1,2,3-triazolium-supported imidazolidinones 2a–c
in hand, the same feasibility tests as those done for ionic liquid-supported chiral auxiliaries were
performed (Scheme 7). Sequential propionylation- alkylation-cleavage reactions were carried out as
described above, and (
in Table 2, high yields and ee’s were observed for all reactions using the 1,3-dibutyl-1,2,3-triazolium
NTf2 salts 2a . The crude product ( )-15 obtained after cleavage was very pure, as shown in Figure 2.
−
)-3-(3-chlorophenyl)-2-methylpropionic acid (15) was obtained. As shown
–
c
−
Notably, no disruption of either the imidazolidinone ring or the 1,2,3-triazolium was observed for all
recovered 2a–c after cleavage with 2 N NaOH [30,31]. In particular, the corresponding N-methylated
byproducts were not observed and most of the recovered ionic liquid-supported chiral auxiliaries
remained intact. As the reactions were conducted under homogeneous conditions, it was not necessary
to translate solution-phase reactions to solid-phase reactions. Thus, the progress of the reactions could
be monitored by TLC and NMR, which revealed consistent yield and selectivity. The inconsistent yield
and selectivity problems that originated from heterogeneous solid-phase reactions were resolved by
the use of ionic liquid-supported imidazolidinones.
Scheme 7. Asymmetric synthesis of (R)-( )-3-(3-chlorophenyl)-2-methylpropionic acid (15) using 2a–c.
−

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Table 2. Yields and enantiomeric excess (ee) of (−)-15 in ionic liquid (2a–c)-supported reactions.a
ee b
Entry
IL-Supported Imidazolidinone
Yield (%) a for 3 Steps
1
2
3
2a
2b
2c
90
81
80
90
90
94
a
b
Isolated yields in three steps. Determined by HPLC analysis of the corresponding N-phenylpropanamide on a
chiral stationary phase.
Figure 2. The NMR spectrum of crude (
using 2a.
−
)-15 obtained after cleavage in the sequential reactions
It is particularly interesting whether the presence of the ionic liquid-tether lowers the ee or not.
Thus, the enantiomeric excesses of the reactions using 2a with those using Evans’ auxiliary (Scheme 8)
were directly compared. The reactions were conducted under the standard conditions used in the
Scheme 7, and observed 91% ee for ( )-15. As expected, the obtained ee’s for both reactions were
−
comparable (91% ee for Scheme 8 versus 90% ee for Table 2, entry 1), and no decrease of the ee’s was
observed. The 1,2,3-triazolium ionic liquid-tether did not affect the stereoselectivity.
Scheme 8. Asymmetric synthesis of (R)-( )-3-(3-chlorophenyl)-2-methylpropionic acid (15) using
−
Evans’ auxiliary.
3. Materials and Methods
3.1. General Methods
All reactions were performed in oven-dried glassware fitted with a glass stopper under positive
pressure of Ar with magnetic stirring, unless otherwise noted. The air- and moisture-sensitive liquids
and solutions were transferred via syringe or stainless-steel cannula. TLC was performed on 0.25 mm
E. Merck silica gel 60 F254 plates (Merck, Kenilworth, IL, USA) and visualized under UV light (254 nm)
or by staining with cerium ammonium molybdenate (CAM), potassium permanganate (KMnO4) or
p-anisaldehyde. Flash chromatography was performed on E. Merck 230–400 mesh silica gel 60 (Merck).
The reagents were purchased from commercial suppliers, and used without further purification unless

Molecules 2019, 24, 3349
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otherwise noted. The solvents were distilled from proper drying agents (CaH2 or Na wire) under Ar
atmosphere at 760 mm Hg. All moisture- and/or oxygen-sensitive solids were handled and stored in a
glove box under N2. The NMR spectra were recorded on at 24 ◦C. The chemical shifts were expressed
in ppm relative to TMS (1H, 0 ppm), CDCl3 (1H, 7.26 ppm; 13C, 77.2 ppm), DMSO-d6 (1H, 2.50 ppm;
13C, 39.5 ppm), acetone-d6 (1H, 2.05 ppm; 13C, 206.3, 29.9 ppm), CD3OD (1H, 3.31 ppm; 13C, 49.1 ppm)
or C6H5F (19F,
113.15 ppm); coupling constants were expressed in Hz. The high resolution mass
−
spectra (HRMS) were obtained by ESI (TOF analyzer) or FAB (magnetic sector analyzer). The optical
rotations were determined in acetone, CHCl3 or MeOH. Chiral HPLC analysis for the determination
of the enantomeric excess (ee) was performed on a chiral Lux 5u Cellulose-1 column (5 µm, 1000 Å,
250 × 4.6 mm). The solvents were eluted at a flow rate of 0.8 mL/min at room temperature using
a binary solvent system (solvent A: hexane, solvent B: isopropanol, 90% A over 30 min) with UV
detection at 254 nm.
3.2. Synthesis
N-[4-(1-Butyl-1H-1,2,3-triazol-4-yl)butyl]phthalimide (
) (800 L, 7.29 mmol) and sodium azide (949 mg, 14.6 mmol) in anhydrous DMF (11 mL) was stirred
at 120 ◦C for 14 h. After the mixture was cooled to rt, N-(5-hexynyl)phthalimide (1.66 g, 7.29 mmol) and
CuI (139 mg, 730
mol) were added, and the solution was stirred at 80 ◦C for 19 h. Upon completion
5). In a screw-cap vial, a mixture of 1-bromobutane
(3
µ
µ
of the reaction, the reaction mixture was cooled to rt and concentrated in vacuo. The purification by
column chromatography on silica gel (3:1 hexanes/EtOAc) afforded a desired triazole 5 (2.13 g, 89%) as
a light-yellow solid. TLC: Rf 0.21 (3:1 hexanes/EtOAc). mp: 73.4–74.8 ◦C. 1H NMR (400 MHz, CDCl3):
δ
7.84 (dd, J = 5.6, 2.8 Hz, 2H), 7.71 (dd, J = 5.6, 2.8 Hz, 2H), 7.28 (s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.72 (t,
J = 6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.77–1.71 (m, 4H), 1.35 (sextet,
J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 168.6, 147.6, 134.1, 132.3, 123.3,
120.7, 50.0, 37.8, 32.5, 28.3, 26.9, 25.3, 19.9, 13.6. LRMS (ESI) m/z (rel int): (pos) 327 ([M + H]+, 100), 282
([M – C3H8]+, 100). HRMS (ESI) m/z calcd for C18H23N4O2+ ([M + H]+) 327.1816, found 327.1822.
4-(1-Butyl-1H-1,2,3-triazol-4-yl)butylamine (6). In a 100 mL roundbottom flask, phthalimide 5 (1.10 g,
3.38 mmol) was dissolved in anhydrous THF (5 mL) at rt. Hydrazine hydrate (1.41 mL, 28.9 mmol)
was added and the mixture was stirred at 40 ◦C for 6 h. Upon completion of the reaction, the reaction
mixture was diluted with Et2O (70 mL) and insoluble solid was filtered off. The filtrate was washed
with aqueous 10% NaOH (3 mL) (pH 12), and dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo to yield analytically pure amine 6 as a colorless liquid (648 mg, 98%). TLC: Rf 0.02 (1:1
1
hexanes/EtOAc). H NMR (400 MHz, CDCl3):
δ 7.26 (s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.6 Hz,
2H), 2.72 (t, J = 7.2 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.6 Hz, 2H), 1.52 (m, 2H),
1.35 (sextet, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 147.9, 120.4, 49.8,
41.9, 33.3, 32.3, 26.7, 25.5, 19.7, 13.4. LRMS (ESI) m/z (rel int): (pos) 219 ([M + Na]+, 100), 180 ([M
NH2]+, 100). HRMS (ESI) m/z calcd for C10H20N4Na+ ([M + Na]+) 219.1580, found 219.1578.
−
(S)-tert-Butyl [1-((4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl]carbamate (7a).
In a 50 mL roundbottom flask, amine 6 (261 mg, 1.33 mmol), Boc-l-Phe-OH (353 mg, 1.33 mmol),
EDCI
·
HCl (286 mg, 1.46 mmol), and HOBt hydrate (198 mg, 1.46 mmol) were dissolved in anhydrous
·
CH2Cl2 (5.8 mL) at rt. The mixture was stirred at rt for 5 h. Upon completion of the reaction, 10% wt
citric acid (11 mL) was added and the two layers were separated. The aqueous layer was extracted with
CH2Cl2 (2
×
30 mL) and combined organic extracts were washed with saturated aqueous NaHCO3
(15 mL) and brine (15 mL) sequentially. It was then dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The purification by column chromatography on silica gel (20:1 CH2Cl2/MeOH)
afforded a desired amide 7a as a white foam (566 mg, 96%). TLC: Rf 0.19 (1:2 hexanes/EtOAc). mp:
1
98.8–100.8 ◦C. [α]D21.4 = +4.2 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ 7.30–7.19 (m, 6H), 5.82 (br s,
1H), 5.05 (br s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 4.27 (q, J = 7.6 Hz, 1H), 3.19 (q, J = 6.4 Hz, 2H), 3.07 (dd,
J = 13.6, 6.4 Hz, 1H), 3.02 (dd, J = 13.6, 7.6 Hz, 1H), 2.67 (t, J = 7.6 Hz, 2H), 1.88 (quintet, J = 7.6 Hz, 2H),

Molecules 2019, 24, 3349
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1.58 (quintet, J = 7.2 Hz, 2H), 1.45 (m, 2H), 1.40 (s, 9H), 1.36 (sextet, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3):
δ 171.3, 155.6, 147.7, 137.0, 129.5, 128.8, 127.1, 120.7, 80.3, 56.2, 50.1,
39.3, 39.0, 32.5, 28.9, 28.4, 26.7, 25.2, 19.9, 13.7. LRMS (ESI) m/z (rel int): (pos) 444 ([M + H]+, 100), 388
([M − C4H7]+, 75). HRMS (ESI) m/z calcd for C24H38N5O3+ ([M + H]+) 444.2969, found 444.2977.
(R)-tert-Butyl [1-((4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl]carbamate (7a0).
7a0 was synthesized according to the procedure described for the synthesis of 7a. Amine 6 (719 mg,
3.66 mmol), Boc-d-Phe-OH (991 mg, 3.66 mmol), EDCI
(544 mg, 4.03 mmol) were used. Reaction time: 6 h. Yield: 1.60 g, 98%. White solid. TLC: Rf 0.19 (1:2
·
HCl (772 mg, 4.03 mmol), and HOBt hydrate
·
hexanes/EtOAc). mp: 107.1–109.1 ◦C. [α]D22.5
=
−
5.7 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ
1
7.30–7.19 (m, 6H), 5.89 (br s, 1H), 5.08 (br s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 4.28 (q, J = 7.6 Hz, 1H), 3.19 (q,
J = 6.8 Hz, 2H), 3.07 (dd, J = 13.6, 6.4 Hz, 1H), 3.02 (dd, J = 13.6, 7.6 Hz, 1H), 2.67 (t, J = 7.2 Hz, 2H), 1.87
(quintet, J = 7.2 Hz, 2H), 1.59 (quintet, J = 7.6 Hz, 2H), 1.44 (m, 2H), 1.40 (s, 9H), 1.36 (sextet, J = 7.2 Hz,
2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 171.0, 155.4, 147.5, 136.9, 129.3, 128.6, 126.9,
120.5, 80.1, 56.1, 49.9, 39.1, 38.8, 32.3, 28.8, 28.3, 26.5, 25.1, 19.7, 13.5. LRMS (ESI) m/z (rel int): (pos) 444
([M + H]+, 100), 388 ([M
found 444.2969.
−
C4H7]+, 23). HRMS (ESI) m/z calcd for C24H38N5O3+ ([M + H]+) 444.2969,
(S)-tert-Butyl [1-((4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)amino)-3,3-dimethyl-1-oxobutan-2-yl]carbamate (7b).
7b was synthesized according to the procedure described for the synthesis of 7a. Amine 6 (813 mg,
4.14 mmol), Boc-tert-Leu-OH (931 mg, 3.95 mmol), EDCI
·
HCl (832 mg, 4.34 mmol), and HOBt hydrate
·
(587 mg, 4.34 mmol) were used. Reaction time: 14 h. Yield: 1.52 g, 94%. Colorless oil. TLC: Rf 0.43
(10:1 CH2Cl2/MeOH). [α]2D2.7 = +1.3 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ 7.27 (s, 1H), 5.78 (br
1
s, 1H), 5.25 (br d, J = 8.8 Hz, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.75 (br d, J = 9.2 Hz, 1H), 3.29 (m, 2H), 2.73 (t,
J = 7.2 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.2 Hz, 2H), 1.59 (m, 2H), 1.43 (s, 9H),
1.35 (sextet, J = 7.2 Hz, 2H), 0.98 (s, 9H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 170.9,
155.8, 147.5, 120.6, 79.6, 62.5, 49.9, 39.1, 34.5, 32.3, 28.9, 28.3, 26.7, 26.6, 25.1, 19.7, 13.5. LRMS (ESI) m/z
(rel int): (pos) 410 ([M + H]+, 100), 354 ([M – C4H7]+, 22). HRMS (ESI) m/z calcd for C21H40N5O3+
([M + H]+) 410.3126, found 410.3129.
(S)-tert-Butyl [1-((4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl)amino)-3-methyl-1-oxobutan-2-yl]carbamate (7c).
7c was synthesized according to the procedure described for the synthesis of 7a. Amine 6 (690 mg,
3.51 mmol), Boc-l-Val-OH (727 mg, 3.35 mmol), EDCI
(498 mg, 3.68 mmol) were used. The crude mixture was purified by column chromatography on silica
·
HCl (706 mg, 3.68 mmol), and HOBt hydrate
·
gel (30:1 CH2Cl2/MeOH). Reaction time: 8 h. Yield: 1.26 g, 95%. White solid. TLC: Rf 0.52 (10:1
CH2Cl2/MeOH). mp: 81.5–83.5 ◦C. [α]D21.6
= δ 7.27 (s,
15.4 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3):
−
1H), 6.03 (br s, 1H), 5.02 (br s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.84 (dd, J = 8.8, 6.0 Hz, 1H), 3.29 (q, J = 6.8 Hz,
2H), 2.73 (t, J = 7.6 Hz, 2H), 2.14 (m, 1H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.6 Hz, 2H),
1.59 (m, 2H), 1.44 (s, 9H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H),
0.90 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
171.6, 155.9, 147.6, 120.6, 79.8, 60.1, 49.9, 39.1,
32.3, 30.9, 28.9, 28.3, 26.7, 25.1, 19.7, 19.3, 17.8, 13.5. LRMS (ESI) m/z (rel int): (pos) 396 ([M + H]+, 100),
340 ([M
C4H7]+, 45). HRMS (ESI) m/z calcd for C20H38N5O3+ ([M + H]+) 396.2969, found 396.2961.
−
(S)-2-Amino-N-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]-3-phenylpropanamide (8a). In a 250 mL roundbottom
flask, Boc protected amine 7a (1.87 g, 4.21 mmol) was dissolved in CH2Cl2 (33 mL) at rt under air. A
solution of TFA in CH2Cl2 (20% v/v, 48 mL) was added dropwise for 2 h. Upon completion of the
reaction, the reaction mixture was diluted with CH2Cl2 (30 mL), cooled to 0 ◦C, and basified with
saturated aqueous NaHCO3 (800 mL). The aqueous layer was extracted with CH2Cl2 (3
The combined organic extracts were then dried over anhydrous Na2SO4, filtered, and concentrated in
×
100 mL).
vacuo to yield analytically pure amine 8a as a white solid (1.52 g, quantitative yield). TLC: Rf 0.65
(5:1 CH2Cl2/MeOH). mp: 57.2–59.2 ◦C. [α]D21.6
=
−
44.3 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ
1
7.33–7.21 (m, 6H), 4.31 (t, J = 7.2 Hz, 2H), 3.62 (dd, J = 9.2, 4.0 Hz, 1H), 3.31–3.25 (m, 3H), 2.73 (t, J = 7.2

Molecules 2019, 24, 3349
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Hz, 2H), 2.71 (dd, J = 13.2, 9.2 Hz, 1H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.70 (quintet, J = 7.2 Hz, 2H),
1.57 (m, 2H), 1.36 (sextet, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
174.3,
147.8, 138.1, 129.4, 128.8, 126.9, 120.7, 56.6, 50.0, 41.2, 38.9, 32.4, 29.2, 26.9, 25.3, 19.9, 13.6. LRMS (ESI)
m/z (rel int): (pos) 344 ([M + H]+, 100), 180 ([M Bn]+, 33). HRMS (ESI) m/z calcd for
n-Bu NH2
C19H30N5O+ ([M + H]+) 344.2445, found 344.2442.
δ
−
−
−
(R)-2-Amino-N-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]-3-phenylpropanamide (8a0). 8a0 was synthesized
according to the procedure described for the synthesis of 8a. Amine 7a0 (818 mg, 1.84 mmol) and a
solution of TFA in anhydrous CH2Cl2 (20% v/v, 16 mL) were used. Reaction time: 1 h. Yield: 615 mg,
97%. White solid. TLC: Rf 0.65 (5:1 CH2Cl2/MeOH). mp: 62.5–64.5 ◦C. [α]D20.6
= 16.9 (c 1.0, MeOH).
−
1H NMR (400 MHz, CDCl3): δ 7.33–7.21 (m, 6H), 4.32 (t, J = 7.2 Hz, 2H), 3.59 (dd, J = 9.2, 4.0 Hz, 1H),
3.29 (t, J = 7.2 Hz, 2H), 3.27 (dd, J = 13.6, 4.0 Hz, 1H), 2.73 (t, J = 7.2 Hz, 2H), 2.68 (dd, J = 13.6, 9.2 Hz,
1H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.70 (quintet, J = 7.2 Hz, 2H), 1.56 (m, 2H), 1.36 (sextet, J = 7.2 Hz,
2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
174.2, 147.7, 138.0, 129.3, 128.7, 126.8, 120.6,
56.6, 49.9, 41.1, 38.8, 32.3, 29.1, 26.8, 25.2, 19.7, 13.5. LRMS (ESI) m/z (rel int): (pos) 344 ([M + H]+, 100),
180 ([M C4H9 NH2
Bn]+, 37). HRMS (ESI) m/z calcd for C19H30N5O+ ([M + H]+) 344.2445,
found 344.2445.
−
−
−
(S)-2-Amino-N-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]-3,3-dimethylbutanamide (8b). 8b was synthesized
according to the procedure described for the synthesis of 8a. Amine b (1.16 g, 2.84 mmol) and a
7
solution of TFA in anhydrous CH2Cl2 (20% v/v, 30 mL) were used. Reaction time: 1.5 h. Yield: 871 mg,
99%. White solid. TLC: Rf 0.17 (10:1 CH2Cl2/MeOH). mp: 45.0–47.0 ◦C. [α]D21.8 = +27.8 (c 1.0, MeOH).
1H NMR (400 MHz, CDCl3):
δ
7.27 (s, 1H), 6.81 (br s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.29 (m, 2H), 3.09 (s,
1H), 2.74 (t, J = 7.2 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.73 (quintet, J = 7.2 Hz, 2H), 1.58 (m, 2H),
1.35 (sextet, J = 7.2 Hz, 2H), 0.99 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
173.5,
147.6, 120.6, 64.4, 49.9, 38.7, 34.0, 32.3, 29.1, 26.8, 26.7, 25.2, 19.7, 13.5. LRMS (ESI) m/z (rel int): (pos) 310
([M + H]+, 100), 180 ([M t-Bu]+, 37). HRMS (ESI) m/z calcd for C16H32N5O+ ([M +
n-Bu NH2
H]+) 310.2601, found 310.2605.
δ
−
−
−
(S)-2-Amino-N-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]-3-methylbutanamide (8c). 8c was synthesized
according to the procedure described for the synthesis of 8a. Amine c (933 mg, 2.36 mmol) and a
7
solution of TFA in anhydrous CH2Cl2 (20% v/v, 20 mL) were used. Reaction time: 2.5 h. Yield: 687 mg,
99%. Ivory solid. TLC: Rf 0.33 (10:1 CH2Cl2/MeOH). mp: 58.9–60.9 ◦C. [α]D21.9 = +5.9 (c 1.0, MeOH).
1H NMR (400 MHz, CDCl3):
δ 7.36 (br s, 1H), 7.27 (s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.31 (m, 2H), 3.23
(d, J = 3.6 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 2.30 (m, 1H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.73 (quintet,
J = 7.6 Hz, 2H), 1.58 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.98 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H),
0.81 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
174.2, 147.7, 120.6, 60.2, 49.9, 38.7, 32.3, 30.8,
n-Bu
29.2, 26.8, 25.2, 19.8, 19.7, 16.1, 13.5. LRMS (ESI) m/z (rel int): (pos) 296 ([M + H]+, 100), 180 ([M
−
− NH2 − i-Pr]+, 53). HRMS (ESI) m/z calcd for C15H30N5O+ ([M + H]+) 296.2445, found 296.2450.
(S)-N1-[4-(1-Butyl-1H-1,2,3-triazol-4-yl)butyl]-3-phenylpropane-1,2-diamine (9a). In a 100 mL roundbottom
flask, amide 8a (1.40 g, 4.09 mmol) was dissolved in anhydrous THF (16 mL) at rt. The reaction mixture
was cooled to 0 ◦C and LiAlH4 (931 mg, 24.5 mmol) was added. It was then stirred at 0 ◦C for 30 min and
heated under reflux for 7 h. Upon completion of the reaction, the resulting grey suspension was cooled
to 0 ◦C, quenched with saturated aqueous Na2SO4, and diluted with EtOAc (70 mL). The precipitate
was filtered off, and the filtrate was concentrated by rotary evaporation. The residue was diluted with
CH2Cl2 (100 mL), dried over anhydrous K2CO3, filtered, and concentrated in vacuo. The purification
by column chromatography on silica gel (15:1 CH2Cl2/MeOH
a desired diamine 9a as a pale yellow solid (1.17 g, 87%). TLC: Rf 0.04 (MeOH). mp: 38.1–40.1 ◦C.
[α]D21.0 = +6.3 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3):
7.32 7.18 (m, 6H), 4.31 (t, J = 7.2 Hz, 2H),
→10:1 CH2Cl2/MeOH→MeOH) afforded
δ
−
3.09 (ddd, J = 13.6, 8.8, 4.8 Hz, 1H), 2.78 (dd, J = 13.6, 4.8 Hz, 1H), 2.73 (t, J = 7.2 Hz, 2H), 2.70 (dd,
J = 11.6, 4.8 Hz, 1H), 2.64 (q, J = 7.2 Hz, 2H), 2.49 (dd, J = 13.6, 8.8 Hz, 1H), 2.45 (dd, J = 11.6, 8.8 Hz,

Molecules 2019, 24, 3349
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1H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.2 Hz, 2H), 1.55 (m, 2H), 1.35 (sextet, J = 7.2 Hz,
2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CD3OD):
149.0, 140.2, 130.4, 129.6, 127.5, 123.1, 56.3,
δ
53.3, 51.0, 50.5, 43.2, 33.4, 30.0, 28.3, 26.1, 20.7, 13.8. LRMS (ESI) m/z (rel int): (pos) 330 ([M + H]+,
100), 282 ([C15H32N5]+, 11), 180 ([M
([M + H]+) 330.2652, found 330.2659.
−
C2H6N2
−
Bn]+, 23). HRMS (ESI) m/z calcd for C19H32N5+
(R)-N1-[4-(1-Butyl-1H-1,2,3-triazol-4-yl)butyl]-3-phenylpropane-1,2-diamine (9a0). 9a0 was synthesized
according to the procedure described for the synthesis of 9a. Amide
a0 (425 mg, 1.24 mmol) and
LiAlH4 (299 mg, 7.88 mmol) were used. Reaction time: 6 h. Yield: 361 mg, 88%. White solid. TLC: Rf
0.04 (MeOH). mp: 47.2–49.2 ◦C. [α]D21.1 7.6 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3):
7.32–7.18
8
=
−
δ
(m, 6H), 4.31 (t, J = 7.2 Hz, 2H), 3.09 (br s, 1H), 2.78 (dd, J = 13.2, 4.8 Hz, 1H), 2.73 (t, J = 7.6 Hz, 2H),
2.68 (m, 1H), 2.64 (q, J = 7.2 Hz, 2H), 2.50 (dd, J = 13.2, 8.8 Hz, 1H), 2.45 (dd, J = 11.2, 8.8 Hz, 1H), 1.87
(quintet, J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.6 Hz, 2H), 1.55 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.95
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CD3OD):
δ 149.0, 140.2, 130.4, 129.6, 127.5, 123.2, 56.4, 53.3,
51.0, 50.5, 43.2, 33.4, 30.0, 28.3, 26.1, 20.7, 13.8. LRMS (ESI) m/z (rel int): (pos) 330 ([M + H]+, 100), 282
([C15H32N5]+, 48), 180 ([M
330.2652, found 330.2658.
−
C2H6N2
−
Bn]+, 22). HRMS (ESI) m/z calcd for C19H32N5+ ([M + H]+)
(S)-N1-[4-(1-Butyl-1H-1,2,3-triazol-4-yl)butyl]-3,3-dimethylbutane-1,2-diamine (9b). 9b was synthesized
according to the procedure described for the synthesis of 9a. Amide 8b (2.30 g, 7.42 mmol) and LiAlH4
(1.69 g, 44.5 mmol) were used. Reaction time: 24 h. Yield: 1.47 g, 67% (brsm: 83%). Colorless oil.
TLC: Rf 0.07 (MeOH). [α]2D1.7 = +23.8 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3):
δ 7.25 (s, 1H), 4.31 (t,
J = 7.2 Hz, 2H), 2.77 (dd, J = 11.2, 2.4 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 2.67 (dt, J = 11.2, 7.2 Hz, 1H), 2.59
(dt, J = 11.2, 7.2 Hz, 1H), 2.46 (dd, J = 11.2, 2.4 Hz, 1H), 2.21 (t, J = 11.2 Hz, 1H), 1.87 (quintet, J = 7.2 Hz,
2H), 1.73 (quintet, J = 7.6 Hz, 2H), 1.57 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H), 0.88
(s, 9H). 13C NMR (100 MHz, DMSO-d6):
δ 146.8, 121.5, 59.1, 51.3, 49.2, 48.8, 33.3, 31.7, 29.3, 26.9, 26.3,
25.0, 19.1, 13.3. LRMS (ESI) m/z (rel int): (pos) 296 ([M + H]+, 100), 282 ([C15H32N5]+, 21). HRMS (ESI)
m/z calcd for C16H34N5+ ([M + H]+) 296.2809, found 296.2814.
(S)-N1-[4-(1-Butyl-1H-1,2,3-triazol-4-yl)butyl]-3-methylbutane-1,2-diamine (9c). 9c was synthesized
according to the procedure described for the synthesis of 9a. Amide 8c (900 mg, 3.05 mmol) and
LiAlH4 (482 mg, 18.3 mmol) were used. Reaction time: 24 h. Yield: 694 mg, 81% (brsm: 89%). Milky
oil. TLC: Rf 0.05 (MeOH). [α]D21.8 = +16.3 (c 1.0, MeOH). 1H NMR (400 MHz, CDCl3):
δ 7.25 (s, 1H), 4.31
(t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.69–2.56 (m, 4H), 2.34 (dd, J = 11.6, 9.6 Hz, 1H), 1.87 (quintet,
J = 7.2 Hz, 2H), 1.72 (quintet, J = 7.6 Hz, 2H), 1.60–1.52 (m, 3H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.95 (t,
J = 7.2 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
148.1,
120.4, 56.6, 54.2, 49.9 (2C), 32.5, 32.3, 29.8, 27.3, 25.6, 19.8, 19.4, 17.8, 13.5. LRMS (ESI) m/z (rel int): (pos)
282 ([M + H]+, 82), 141 ([M NH2]+, 100). HRMS (ESI) m/z calcd for C15H32N5+
nBu C2HN3
([M + H]+) 282.2652, found 282.2662.
−
−
−
(S)-4-Benzyl-1-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]imidazolidin-2-one (10a). In a 100 mL roundbottom
flask, diamine 9a (440 mg, 1.34 mmol) was dissolved in anhydrous DMF (1.3 mL) at rt. Et3N (470 L,
µ
3.34 mmol) and CDI (335 mg, 2.00 mmol) were added. The resulting reaction mixture was stirred at
120 ◦C for 13 h. Upon completion of the reaction, the reaction mixture was cooled to rt, and concentrated
in vacuo. The purification by column chromatography on silica gel (15:1 CH2Cl2/MeOH) afforded a
desired imidazolidinone 10a as a colorless liquid (470 mg, 99%). TLC: Rf 0.49 (10:1 CH2Cl2/MeOH).
[α]2D2.3
= δ 7.34–7.30 (m, 2H), 7.28–7.23 (m, 2H),
27.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
−
7.19–7.17 (m, 2H), 4.31 (t, J = 7.2 Hz, 2H), 4.30 (br s, 1H), 3.86 (m, 1H), 3.50 (t, J = 8.8 Hz, 1H), 3.20 (m,
2H), 3.13 (dd, J = 8.8, 6.0 Hz, 1H), 2.83 (dd, J = 13.2, 6.0 Hz, 1H), 2.77 (dd, J = 13.2, 8.8 Hz, 1H), 2.75 (t,
J = 7.6 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.69 (m, 2H), 1.57 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H),
0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.7, 147.8, 137.2, 129.2, 128.9, 127.0, 120.7, 51.4,

Molecules 2019, 24, 3349
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50.3, 50.0, 43.0, 42.1, 32.4, 27.2, 26.7, 25.3, 19.8, 13.6. LRMS (ESI) m/z (rel int): (pos) 356 ([M + H]+, 16),
282 ([C15H32N5]+, 100). HRMS (ESI) m/z calcd for C20H30N5O+ ([M + H]+) 356.2445, found 356.2440.
(R)-4-Benzyl-1-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]imidazolidin-2-one (10a0). 10a0 was synthesized
according to the procedure described for the synthesis of 10a. Diamine 9a0 (179 mg, 542
µmol), Et3N
(190 µL, 1.36 mmol) and CDI (132 mg, 814 µmol) were used. Reaction time: 13 h. Yield: 175 mg, 91%.
Colorless liquid. TLC: Rf 0.49 (10:1 CH2Cl2/MeOH). [α]2D2.8 = +26.4 (c 1.0, CHCl3). H NMR (400 MHz,
1
CDCl3):
δ 7.34–7.30 (m, 2H), 7.27–7.22 (m, 2H), 7.19–7.17 (m, 2H), 4.31 (t, J = 7.2 Hz, 2H), 4.29 (br s, 1H),
3.86 (m, 1H), 3.49 (t, J = 8.4 Hz, 1H), 3.23 (dq, J = 14.0, 7.2 Hz, 2H), 3.20 (m, 2H), 3.13 (dd, J = 8.8, 6.0 Hz,
1H), 2.82 (m, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.69 (m, 2H), 1.56 (m, 2H), 1.35
(sextet, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.7, 147.8, 137.3, 129.2,
129.0, 127.1, 120.7, 51.5, 50.4, 50.1, 43.1, 42.2, 32.5, 27.2, 26.8, 25.4, 19.9, 13.7. LRMS (ESI) m/z (rel int):
(pos) 356 ([M + H]+, 100), 282 ([C15H32N5]+, 95). HRMS (ESI) m/z calcd for C20H30N5O+ ([M + H]+)
356.2445, found 356.2452.
(S)-4-(tert-Butyl)-1-[4-(1-butyl-1H-1,2,3-triazol-4-yl)butyl]imidazolidin-2-one (10b). 10b was synthesized
according to the procedure described for the synthesis of 10a. Diamine 9b (1.35 g, 4.55 mmol), Et3N
(1.60 mL, 11.4 mmol) and CDI (1.11 g, 6.83 mmol) were used. Reaction time: 15 h. Yield: 1.46 g,
◦
quantitative yield. Colorless crystal. TLC: Rf 0.29 (30:1 CH2Cl2/MeOH (
×
2)). mp: 80.3–82.3 C.
[α]2D2.6
=
−
6.9 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ
7.27 (s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 4.30 (s,
1H), 3.41–3.34 (m, 2H), 3.25 (dt, J = 13.6, 7.2 Hz, 1H), 3.15 (dd, J = 13.6, 7.2 Hz, 1H), 3.13 (m, 1H), 2.75 (t,
J = 7.6 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.68 (m, 2H), 1.58 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H),
δ 161.9, 147.8, 120.6, 58.8, 49.9, 46.4,
42.9, 33.2, 32.3, 27.0, 26.6, 25.2, 25.0, 19.7, 13.5. LRMS (ESI) m/z (rel int): (pos) 322 ([M + H]+, 100), 282
([C15H32N5]+, 42). HRMS (ESI) m/z calcd for C17H32N5O+ ([M + H]+) 322.2601, found 322.2603.
1
0.95 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H). 13C NMR (100 MHz, CDCl3):
(S)-4-Isopropyl-1-[4-(1-butyl-1,2,3-triazol-4-yl)butyl]imidazolidin-2-one (10c).
10c was synthesized
according to the procedure described for the synthesis of 10a. Diamine 9c (2.05 g, 7.30 mmol),
Et3N (2.60 mL, 18.2 mmol) and CDI (1.77 g, 10.9 mmol) were used. Reaction time: 14.5 h. Yield: 1.78 g,
79%. White solid. TLC: Rf 0.29 (30:1 CH2Cl2/MeOH (
×
2)). mp: 109.7–111.7 ◦C. [α]D21.7
= 9.0 (c 1.0,
−
MeOH). 1H NMR (400 MHz, CDCl3):
δ
7.27 (s, 1H), 4.32 (s, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.46 (t, J = 8.4
Hz, 1H), 3.36 (ddd, J = 16.0, 7.2, 1.6 Hz, 1H), 3.26 (dt, J = 13.6, 7.2 Hz, 1H), 3.14 (dt, J = 13.6, 7.2 Hz, 1H),
3.06 (dd, J = 8.4, 7.2 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.73–1.63 (m, 3H),
1.60 (m, 2H), 1.35 (sextet, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 162.0, 147.8, 120.6, 55.8, 49.9, 48.8, 43.0, 33.1, 32.3 27.1, 26.6,
25.3, 19.7, 18.4, 17.9, 13.5. LRMS (ESI) m/z (rel int): (pos) 308 ([M + H]+, 100), 282 ([C15H32N5]+, 25).
HRMS (ESI) m/z calcd for C16H30N5O+ ([M + H]+) 308.2445, found 308.2450.
(S)-4-[4-(4-Benzyl-2-oxoimidazolidin-1-yl)butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium iodide (12a). In a
screw-cap vial, a mixture of 10a (161 mg, 454 µmol) and MeI (28.3 µL, 454 µ
mol) was stirred at 80 ◦C.
After 24 h, the reaction mixture was cooled to rt. The purification by column chromatography on silica
gel (15:1 CH2Cl2/MeOH) afforded a desired compound 12a (183 mg, 81%) as a light-yellow sticky gum.
TLC: Rf 0.15 (10:1 CH2Cl2/MeOH). [α]D22.3
=
−
16.0 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ
9.33 (s,
1
1H), 7.31 (m, 2H), 7.25–7.19 (m, 3H), 4.68 (t, J = 7.6 Hz, 2H), 4.36 (s, 1H), 4.28 (s, 3H), 3.97 (m, 1H), 3.62
(t, J = 8.8 Hz, 1H), 3.32 (dt, J = 14.4, 7.2 Hz, 1H), 3.18 (dd, J = 8.8, 6.4 Hz, 1H), 3.16 (m, 1H), 3.04 (m, 2H),
2.87 (dd, J = 13.6, 5.6 Hz, 1H), 2.81 (dd, J = 13.6, 7.6 Hz, 1H), 2.03 (quintet, J = 7.6 Hz, 2H), 1.84 (m, 2H),
1.70 (m, 2H), 1.44 (sextet, J = 7.6 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 162.1,
144.5, 137.1, 129.6, 129.3, 128.8, 126.8, 54.0, 51.3, 50.2, 42.0, 41.8, 38.9, 31.3, 26.6, 24.0, 23.2, 19.5, 13.5.
LRMS (FAB) m/z (rel int): (pos) 370 ([C21H32N5O]+, 100), 278 ([C21H32N5O
m/z calcd for C21H32N5O+ 370.2601, found 370.2603.
−
Bn]+, 15). HRMS (FAB)
(S)-4-[4-[4-(tert-Butyl)-2-oxoimidazolidin-1-yl])butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium iodide (12b). 12b
was synthesized according to the procedure described for the synthesis of 12a 10b (1.46 g, 4.54 mmol)
.

Molecules 2019, 24, 3349
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and MeI (290
µ
L, 4.54 mmol) were used. Reaction time: 24 h. Yield: 1.80 g, 86%. Yellow gum. TLC: Rf
0.47 (10:1 CH2Cl2/MeOH). [α]D22.8
=
−
8.1 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ
9.41 (s, 1H),
1
4.70 (t, J = 7.6 Hz, 2H), 4.53 (br s, 1H), 4.26 (s, 3H), 3.51–3.45 (m, 2H), 3.36 (dt, J = 14.4, 6.8 Hz, 1H),
3.22–3.14 (m, 2H), 3.04 (td, J = 8.0, 2.8 Hz, 2H), 2.04 (quintet, J = 7.6 Hz, 2H), 1.86 (quintet, J = 7.6 Hz,
2H), 1.73 (sextet, J = 7.6 Hz, 2H), 1.44 (sextet, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H), 0.88 (s, 9H). 13
C
NMR (100 MHz, CDCl3):
δ 162.2, 144.5, 129.7, 58.8, 54.0, 46.5, 41.7, 38.5, 33.3, 31.3, 26.4, 25.1, 24.0, 22.9,
19.5, 13.4. LRMS (FAB) m/z (rel int): (pos) 336 ([C18H34N5O]+, 100), 278 ([C18H34N5O
HRMS (FAB) m/z calcd for C18H34N5O+ 336.2758, found 336.2758.
−
t-Bu]+, 15).
(S)-4-[4-(4-Isopropyl-2-oxoimidazolidin-1-yl)butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium iodide (12c). 12c
was synthesized according to the procedure described for the synthesis of 12a 10c (1.78 g, 5.78 mmol)
and MeI (360 L, 5.78 mmol) were used. Reaction time: 24 h. Yield: 2.39 g, 92%. Colorless oil. TLC: Rf
0.26 (10:1 CH2Cl2/MeOH). [α]D21.8 6.0 (c 0.50, MeOH). 1H NMR (400 MHz, CDCl3):
9.39 (s, 1H),
.
µ
=
−
δ
4.69 (t, J = 7.6 Hz, 2H), 4.52 (br s, 1H), 4.27 (s, 3H), 3.56 (t, J = 8.8 Hz, 1H), 3.46 (qm, J = 8.8 Hz, 1H), 3.36
(dt, J = 14.4, 7.2 Hz, 1H), 3.19 (dt, J = 14.4, 6.0 Hz, 1H), 3.11 (dd, J = 8.8, 7.6 Hz, 1H), 3.04 (m, 2H), 2.04
(quintet, J = 7.6 Hz, 2H), 1.86 (m, 2H), 1.73 (m, 1H), 1.68 (sextet, J = 7.6 Hz, 2H), 1.44 (sextet, J = 7.6 Hz,
2H), 0.99 (t, J = 7.6 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3):
δ 162.5, 144.6, 129.8, 55.9, 54.0, 48.9, 41.8, 38.6, 33.1, 31.3, 26.4, 24.0, 23.1, 19.5, 18.5, 17.9, 13.4.
LRMS (FAB) m/z (rel int): (pos) 322 ([C18H34N5O]+, 100), 278 ([C18H34N5O
m/z calcd for C18H34N5O+ 322.2601, found 322.2603.
−
i-Pr]+, 10). HRMS (FAB)
(S)-4-[4-(4-Benzyl-2-oxoimidazolidin-1-yl)butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (1a). In a 25 mL roundbottom flask, 12a (463 mg, 930
µmol)
and LiNTf2 (267 mg, 930
was stirred at 40 ◦C for 24 h. Upon completion of the reaction, the reaction mixture was cooled to rt,
and extracted with CH2Cl2 (5 9 mL). The combined organic extracts were dried over anhydrous
µmol) were dissolved in deionized water (1.6 mL). The reaction mixture
×
Na2SO4, and filtered. The concentration by rotary evaporation afforded a desired 1a (577 mg, 95%)
as a light yellow liquid. TLC: Rf 0.10 (10:1 CH2Cl2/MeOH). [α]D22.4
(400 MHz, CDCl3):
=
−
6.5 (c 1.0, CHCl3). H NMR
1
δ 8.40 (s, 1H), 7.31 (m, 2H), 7.26–7.17 (m, 3H), 4.53 (t, J = 7.6 Hz, 2H), 4.34 (br s, 1H),
4.21 (s, 3H), 3.94 (m, 1H), 3.57 (t, J = 8.8 Hz, 1H), 3.34 (dt, J = 14.4, 6.4 Hz, 1H), 3.18 (dt, J = 14.4, 6.0
Hz, 1H), 3.17 (dd, J = 8.8, 6.4 Hz, 1H), 2.93 (m, 2H), 2.87 (dd, J = 13.6, 5.6 Hz, 1H), 2.77 (dd, J = 13.6,
8.0 Hz, 1H), 1.99 (quintet, J = 7.6 Hz, 2H), 1.77 (m, 2H), 1.69 (m, 2H), 1.41 (sextet, J = 7.6 Hz, 2H), 0.99 (t,
J = 7.6 Hz, 3H). 13C NMR (100 MHz, acetone-d6):
δ 162.4, 145.9, 138.6, 130.2, 129.4, 129.1, 127.4, 121.1 (q,
JC-F = 319.6 Hz), 54.4, 51.9, 50.4, 42.6, 42.5, 38.1, 32.0, 27.2, 24.7, 23.1, 20.0, 13.6. 19F NMR (376 MHz,
CDCl3): δ −79.3. LRMS (FAB) m/z (rel int): (pos) 370 ([C21H32N5O]+, 100), 278 ([C21H32N5O
−
Bn]+,
25). HRMS (FAB) m/z calcd for C21H32N5O+ 370.2601, found 370.2602.
(S)-4-[4-[4-(tert-Butyl)-2-oxoimidazolidin-1-yl]butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (1b). 1b was synthesized according to the procedure described for the
synthesis of 1a 12b (331 mg, 714 mmol) and LiNTf2 (205 mg, 714 mmol) were used. Reaction time: 24
h. Yield: 417 mg, 95%. Colorless oil. TLC: Rf 0.56 (10:1 CH2Cl2/MeOH). [α]D22.9
5.7 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3):
8.45 (s, 1H), 4.54 (t, J = 7.6 Hz, 2H), 4.34 (s, 1H), 4.22 (s, 3H), 3.45–3.41
.
=
−
δ
(m, 2H), 3.34 (dt, J = 14.4, 6.4 Hz, 1H), 3.20 (t, J = 6.0 Hz, 1H), 3.16 (m, 1H), 2.96 (m, 2H), 1.99 (quintet,
J = 7.6 Hz, 2H), 1.79 (quintet, J = 7.6 Hz, 2H), 1.71 (m, 2H), 1.42 (sextet, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6
Hz, 3H), 0.87 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 162.2, 144.8, 128.3, 119.8 (q, JC-F = 319.7 Hz), 58.8,
53.9, 46.3, 41.6, 37.4, 33.2, 31.0, 26.3, 24.9, 23.7, 22.3, 19.4, 13.2. 19F NMR (376 MHz, CDCl3): δ −79.2.
LRMS (FAB) m/z (rel int): (pos) 336 ([C18H34N5O]+, 100), 278 ([C18H34N5O
m/z calcd for C18H34N5O+ 336.2758, found 336.2760.
−
t-Bu]+, 13). HRMS (FAB)
(S)-4-[4-(4-Isopropyl-2-oxoimidazolidin-1-yl)butyl]-1-butyl-3-methyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (1c). 1c was synthesized according to the procedure described for the
synthesis of 1a. 12c (1.92 g, 4.27 mmol) and LiNTf2 (1.23 g, 4.27 mmol) were used. Reaction time:

Molecules 2019, 24, 3349
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24 h. Yield: 2.46 g, 96%. Colorless oil. TLC: Rf 0.39 (10:1 CH2Cl2/MeOH). [α]D21.7
=
−
3.9 (c 1.0, MeOH).
1H NMR (400 MHz, CDCl3):
δ 8.34 (s, 1H), 4.52 (t, J = 7.6 Hz, 2H), 4.46 (s, 1H), 4.21 (s, 3H), 3.52 (t,
J = 8.8 Hz, 1H), 3.41 (qd, J = 8.8, 1.6 Hz, 1H), 3.33 (dt, J = 14.4, 6.4 Hz, 1H), 3.17 (dt, J = 14.4, 6.4 Hz, 1H),
3.09 (dd, J = 8.8, 7.6 Hz, 1H), 2.94 (m, 2H), 1.98 (quintet, J = 7.6 Hz, 2H), 1.77 (quintet, J = 7.6 Hz, 2H),
1.73–1.64 (m, 3H), 1.41 (sextet, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 162.4, 144.8, 128.2, 119.8 (q, JC-F = 319.7 Hz), 55.9, 53.9,
48.7, 41.7, 37.4, 33.0, 31.0, 26.3, 23.6, 22.4, 19.4, 18.2, 17.7, 13.2. 19F NMR (376 MHz, CDCl3): δ −79.3.
LRMS (FAB) m/z (rel int): (pos) 322 ([C17H32N5O]+, 100), 278 ([C1H34N5O
62). HRMS (FAB) m/z calcd for C18H34N5O+ 322.2601, found 322.2607.
−
i-Pr]+, 11), 57 ([C4H9]+,
(S)-4-[4-(4-Benzyl-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium iodide (16a). In a screw-cap
vial, a mixture of 10a (354 mg, 995 µmol) and n-BuI (115 µL, 995 µmol) in DMF (100 µL) was stirred at
100 ◦C. After 24 h, the reaction mixture was cooled to rt. The purification by column chromatography
on silica gel (30:1 CH2Cl2/MeOH) afforded a desired triazolium iodide 16a (467 mg, 92%) as a yellow
oil. TLC: Rf 0.36 (20:1 CH2Cl2/MeOH). [α]D20.0
=
−
37.2 (c 1.2, CHCl3). H NMR (400 MHz, CDCl3):
δ
1
9.60 (s, 1H), 7.33–7.30 (m, 2H), 7.26–7.19 (m, 3H), 4.73 (t, J = 7.2 Hz, 2H), 4.48 (t, J = 7.2 Hz, 2H), 4.31 (br
s, 1H), 3.97 (m, 1H), 3.64 (t, J = 8.8 Hz, 1H), 3.35 (dt, J = 14.4, 6.8 Hz, 1H), 3.22–3.14 (m, 2H), 2.98 (m,
2H), 2.90 (dd, J = 13.2, 5.2 Hz, 1H), 2.77 (dd, J = 13.2, 8.4 Hz, 1H), 2.04 (quintet, J = 7.6 Hz, 2H), 1.95 (m,
2H), 1.86 (quintet, J = 7.2 Hz, 2H), 1.74 (m, 2H), 1.42 (sextet, J = 7.2 Hz, 4H), 1.01 (t, J = 7.2 Hz, 3H), 0.99
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.8, 143.9, 137.1, 130.1, 129.1, 128.8, 126.9, 54.1,
51.4, 51.2, 50.4, 42.0, 41.6, 31.4, 31.0, 26.4, 24.2, 22.7, 19.6, 19.5, 13.4, 13.3. LRMS (ESI) m/z (rel int): (pos)
412 ([C24H38N5O]+, 100), 394 ([C24H38N5O
412.3071, found 412.3071.
−
H2O]+, 3). HRMS (ESI) m/z calcd for C24H38N5O+
(S)-4-[4-(4-(tert-Butyl)-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium iodide (16b). 16b was
synthesized according to the procedure described for the synthesis of 16a 10b (161 mg, 500 mol) and
.
µ
n-BuI (58.0
µ
L, 500
µ
mol) in DMF (50
µ
L) were used. Reaction time: 38 h. Yield: 229 mg, 91%. Yellow
oil. TLC: Rf 0.16 (20:1 CH2Cl2/MeOH). [α]D20.0
=
−
38.4 (c 0.82, CHCl3). H NMR (400 MHz, CDCl3):
1
δ
9.63 (s, 1H), 4.74 (t, J = 7.2 Hz, 2H), 4.48 (t, J = 7.2 Hz, 2H), 4.34 (br s, 1H), 3.51–3.45 (m, 2H), 3.36
(m, 1H), 3.21–3.14 (m, 2H), 3.00 (td, J = 8.0, 5.2 Hz, 2H), 2.04 (quintet, J = 7.2 Hz, 2H), 1.95 (quintet,
J = 7.2 Hz, 2H), 1.87 (quintet, J = 7.2 Hz, 2H), 1.74 (sextet, J = 7.6 Hz, 2H), 1.43 (sextet, J = 7.2 Hz, 2H),
1.42 (sextet, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H), 0.88 (s, 9H). 13C NMR (100
MHz, CDCl3):
δ 162.1, 143.9, 130.1, 58.8, 54.1, 51.1, 46.5, 41.5, 33.3, 31.4, 31.0, 26.3, 25.1, 24.2, 22.6, 19.6,
19.5, 13.4, 13.3. LRMS (ESI) m/z (rel int): (pos) 378 ([C21H40N5O]+, 100), 361 ([C21H39N5O
2). HRMS (ESI) m/z calcd for C21H40N5O+ 378.3227, found 378.3227.
−
H2O]+,
(S)-4-[4-(4-Isopropyl-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium iodide (16c). 16c was
synthesized according to the procedure described for the synthesis of 16a 10c (154 mg, 500 mol) and
.
µ
n-BuI (58
µ
L, 500
µ
mol) in DMF (50
µ
L) were used. Reaction time: 34 h. Yield: 190 mg, 77%. Yellow oil.
TLC: Rf 0.2 (10:1 CH2Cl2/MeOH). [α]D20.0
=
−
39.8 (c 0.54, CHCl3). H NMR (400 MHz, CDCl3):
δ
9.64 (s,
1
1H), 4.74 (t, J = 7.2 Hz, 2H), 4.48 (t, J = 7.2 Hz, 2H), 4.35 (br s, 1H), 3.58 (t, J = 8.8 Hz, 1H), 3.45 (qm,
J = 7.2 Hz, 1H), 3.35 (dt, J = 14.4, 2.8 Hz, 1H), 3.18 (dt, J = 14.4, 6.4 Hz, 1H), 3.11 (dd, J = 8.8, 7.6 Hz, 1H),
2.99 (m, 2H), 2.04 (quintet, J = 7.6 Hz, 2H), 1.95 (quintet, J = 7.2 Hz, 2H), 1.87 (m, 2H), 1.78–1.65 (m,
3H), 1.42 (sextet, J = 7.6 Hz, 4H), 1.01 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.8 Hz,
3H), 0.90 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 162.4, 144.1, 130.2, 56.0, 54.2, 51.3, 49.1,
41.7, 33.2, 31.5, 31.1, 26.5, 24.4, 22.8, 19.7, 19.6, 18.5, 18.1, 13.6, 13.5. LRMS (ESI) m/z (rel int): (pos) 364
([C20H38N5O]+, 100), 387 ([C20H38N5O + Na]+, 1). HRMS (ESI) m/z calcd for C20H38N5O+ 364.3071,
found 364.3062.
(S)-4-[4-(4-Benzyl-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (2a). In a screw-cap vial, 16a (164 mg, 321
µmol) and LiNTf2 (92.2 mg,
321
µ
mol) were dissolved in deionized water (0.54 mL). The reaction mixture was stirred at 40 ◦C

Molecules 2019, 24, 3349
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for 24 h. Upon completion of the reaction, the reaction mixture was cooled to rt, and extracted with
CH2Cl2 (3 3 mL). The combined organic extracts were dried over anhydrous MgSO4, and filtered.
×
The concentration by rotary evaporation afforded the desired NTf2 salt 2a (192 mg, 86%) as a yellow oil.
TLC: Rf 0.53 (15:1 CH2Cl2/MeOH). [α]D20.0
=
−
42.1 (c 1.1, CHCl3). H NMR (400 MHz, CDCl3):
δ
8.43 (s,
1
1H), 7.33
−
7.30 (m, 2H), 7.26
−
7.17 (m, 3H), 4.54 (t, J = 7.6 Hz, 2H), 4.45 (t, J = 7.6 Hz, 2H), 3.96 (m, 1H),
3.14 (m, 2H), 2.92 (m, 2H), 2.87 (dd, J = 13.6,
5.2 Hz, 1H), 2.77 (dd, J = 13.6, 8.4 Hz, 1H), 1.99 (quintet, J = 7.6 Hz, 2H), 1.95 (quintet, J = 7.6 Hz, 2H),
1.78 (m, 2H), 1.69 (m, 2H), 1.42 (sextet, J = 7.6 Hz, 2H), 1.40 (sextet, J = 7.6 Hz, 2H), 1.00 (t, J = 7.6 Hz,
3.58 (t, J = 8.8 Hz, 1H), 3.34 (dt, J = 14.4, 6.8 Hz, 1H), 3.22
−
3H), 0.99 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 161.9, 144.3, 137.0, 129.1, 128.8, 128.6, 126.9,
119.8 (q, JC-F = 319.7 Hz), 54.0, 51.4, 50.9, 50.2, 41.9, 41.6, 31.1, 30.8, 26.3, 23.9, 22.3, 19.5, 19.4, 13.3, 13.2.
19F NMR (376 MHz, CDCl3): δ −79.2. LRMS (ESI) m/z (rel int): (pos) 412 ([C24H38N5O]+, 100), 394
([C24H38N5O − H2O]+, 10). HRMS (ESI) m/z calcd for C24H38N5O+ 412.3071, found 412.3069.
(S)-4-[4-(4-(tert-Butyl)-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (2b). 2b was synthesized according to the procedure described for the
synthesis of 2a. 16b (199 mg, 393 µmol) and LiNTf2 (113 mg, 393 µmol) were used. Reaction time: 24 h.
Yield: 204 mg, 79%. Light yellow oil. TLC: Rf 0.69 (10:1 CH2Cl2/MeOH (
×
2)). [α]2D0.0
= 68.0 (c 0.40,
−
1
CHCl3). H NMR (400 MHz, CDCl3):
δ 8.43 (s, 1H), 4.54 (t, J = 7.6 Hz, 2H), 4.46 (t, J = 7.6 Hz, 2H),
3.52–3.46 (m, 2H), 3.37 (m, 1H), 3.22–3.14 (m, 2H), 2.92 (td, J = 8.0, 4.8 Hz, 2H), 1.99 (quintet, J = 7.6 Hz,
2H), 1.95 (quintet, J = 7.6 Hz, 2H), 1.79 (sextet, J = 7.6 Hz, 2H), 1.71 (m, 2H), 1.43 (sextet, J = 7.6 Hz, 2H),
1.40 (sextet, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.88 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 162.5, 144.5, 128.8, 120.2 (q, JC-F = 318.9 Hz), 59.4, 54.2, 51.1, 46.7, 42.0, 33.4, 31.3,
31.0, 26.5, 25.1, 24.1, 22.6, 19.7, 19.6, 13.5, 13.4. 19F NMR (376 MHz, CDCl3): δ −79.2. LRMS (ESI) m/z
(rel int): (pos) 378 ([C21H40N5O]+, 100), 383 ([C21H40N5O + Na
for C21H40N5O+ 378.3227, found 378.3237.
−
H2O]+, 1). HRMS (ESI) m/z calcd
(S)-4-[4-(4-Isopropyl-2-oxoimidazolidin-1-yl)butyl]-1,3-dibutyl-1H-1,2,3-triazolium
bis(trifluoromethanesulfonyl)imide (2c). 2c was synthesized according to the procedure described for the
synthesis of 2a
h. Yield: 197 mg, 89%. Colorless oil. TLC: Rf 0.26 (10:1 CH2Cl2/MeOH). [α]D20.0
1H NMR (400 MHz, CDCl3):
8.44 (s, 1H), 4.55 (t, J = 7.2 Hz, 2H), 4.45 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 8.8
.
16c (169 mg, 343
µmol) and LiNTf2 (98.6 mg, 343
µmol) were used. Reaction time: 24
=
−
29.7 (c 1.0, CHCl3).
δ
Hz, 1H), 3.46 (dt, J = 8.8, 7.2 Hz, 1H), 3.37 (dt, J = 14.4, 7.2 Hz, 1H), 3.18 (dt, J = 14.4, 6.4 Hz, 1H),
3.12 (dd, J = 8.8, 7.6 Hz, 1H), 2.92 (m, 2H), 1.99 (quintet, J = 7.2 Hz, 2H), 1.95 (quintet, J = 7.2 Hz,
2H), 1.80 (m, 2H), 1.73–1.65 (m, 3H), 1.43 (sextet, J = 7.2 Hz, 2H), 1.40 (sextet, J = 7.2 Hz, 2H), 1.01 (t,
J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). 13C NMR (100
MHz, CDCl3):
δ 162.3, 144.3, 128.5, 119.8 (q, JC-F = 319.6 Hz), 56.0, 53.9, 50.9, 48.8, 41.7, 33.0, 31.1, 30.8,
26.3, 24.0, 22.3, 19.5, 19.4, 18.2, 17.7, 13.3, 13.2. 19F NMR (376 MHz, CDCl3): δ −79.2. LRMS (ESI) m/z
(rel int): (pos) 378 ([C20H38N5O]+, 100), 346 ([C20H38N5O
C20H38N5O+ 364.3071, found 364.3066.
−
H2O]+, 1). HRMS (ESI) m/z calcd for
3.3. Representative Procedure for Ionic Liquid-Supported Asymmetric Benzylation
In a 1 mL roundbottom flask, benzylimidazolidinone ionic liquid 2a (69.3 mg, 100
µ
mol) was
mol, 2.5 M
78 ◦C. The reaction mixture was then stirred for 20 min and propionyl
mol) was added dropwise. After stirring at
78 ◦C for 6 h, the reaction mixture
dissolved in anhydrous THF (0.37 mL) at rt, and n-butyllithium solution (44
in hexanes) was added at
chloride (11 L, 120
µL, 110 µ
−
µ
µ
−
was warmed to rt, quenched with saturated aqueous NH4Cl (1 mL), and diluted with CH2Cl2 (5 mL).
The mixture was basified with 10% aqueous NaOH (3 mL). The aqueous layer was separated, and
extracted with CH2Cl2 (2
×
8 mL). The combined organic layers were washed with brine (8 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo at 60 ◦C for 14 h. The colorless liquid
17a was used directly in the next step without further purification. In a 1 mL roundbottom flask,
imidazolidinone 17a was dissolved in anhydrous THF (0.32 mL) at rt. The reaction mixture was cooled

Molecules 2019, 24, 3349
16 of 18
to
−
78 ◦C and NaHMDS solution (180
µ
L, 180
µ
mol, 1 M in THF) was added. The mixture was then
stirred for 1 h, and a solution of 3-chlorobenzyl bromide (26.2 µL, 199 µmol) in THF (0.08 mL) was
added dropwise, warmed to 0 ◦C, and stirred for 7 h. Upon completion of the reaction, the reaction
mixture was quenched with saturated aqueous NH4Cl (10 mL), warmed to rt, and extracted with
EtOAc (3
anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The colorless liquid 18a was used
directly in the next step without further purification. In a screw cap vial, benzylated 8a was dissolved
×
20 mL). The combined organic layers were washed with brine (30 mL) and dried over
1
in a mixture of anhydrous 1,4-dioxane (0.30 mL) and 2 N NaOH (0.30 mL) at rt and the reaction mixture
was stirred at 80 ◦C for 3.5 h. Upon completion of the reaction, the reaction mixture was cooled to 0 ◦C
and extracted with CH2Cl2 (3
pH 2 and extracted with EtOAc (3
Na2SO4, filtered, and concentrated in vacuo to give crude chiral IL 2a. The combined EtOAc layers
×
4 mL). The aqueous layer was acidified with 10% HCl (5 drops) to
4 mL). The combined CH2Cl2 layers were dried over anhydrous
×
were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield analytically pure acid
( )-15 as a colorless liquid (18.0 mg, 91%). The recovered ionic liquid 2a (66.7 mg) was dried in vacuo
−
and reuse for the next cycle. (
1H NMR (400 MHz, CDCl3):
−
)-
1
5: TLC: Rf 0.20 (30:1 CH2Cl2/MeOH). [α]D20.0
= 28.5 (c 1.0, acetone).
−
δ
7.24–7.18 (m, 3H), 7.07 (dt, J = 14.4, 1.6 Hz, 1H), 3.05 (dd, J = 13.6, 6.8
Hz, 1H), 2.78 (sextet, J = 7.2 Hz, 1H), 2.67 (dd, J = 13.6, 7.6 Hz, 2H), 1.20 (d, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3):
δ 181.9, 141.1, 134.2, 129.7, 129.1, 127.2, 126.7, 41.0, 38.9, 16.5. HRMS (ESI) m/z calcd
for C10H10ClO2− ([M − H]−) 197.0375, found 197.0383.
3.4. Synthesis of N-Phenyl (R)-3-(3-chlorophenyl)-2-methylpropionamide ((R)-S3) for HPLC Analysis
In a 1 mL roundbottom flask, acid (R)-(
DMAP (0.7 mg, 5.6 mol) were dissolved in anhydrous THF (0.13 mL) at rt. After aniline (8.2
mol) was added, the mixture was stirred for 2 h at rt. Upon completion of the reaction, the reaction
−
)-15 (16.0 mg, 80.5
µmol), DCC (18.3 mg, 88.6
µ
mol), and
µ
µL, 88.6
µ
mixture was filtered through a plug of Celite. The filtrate was diluted with Et2O (5 mL) and washed
with 1 N HCl (2 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The purification by column chromatography on silica gel (9:1 hexanes/EtOAc) afforded a
1
desired (R)-S3 (9.5 mg, 43%, 94% ee) as a white solid. TLC: Rf 0.16 (9:1 hexanes/EtOAc). H NMR (400
MHz, CDCl3):
δ
7.38 (d, J = 8.0 Hz, 2H), 7.30 (m, 2H), 7.22 7.19 (m, 3H), 7.10 (m, 2H), 6.85 (br s, 1H),
−
3.05 (dd, J = 13.6, 8.4 Hz, 1H), 2.73 (dd, J = 13.6, 7.2 Hz, 1H), 2.56 (sextet, J = 6.8 Hz, 1H), 1.29 (d, J = 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 173.4, 141.7, 137.5, 134.3, 129.8, 129.0, 128.9, 127.3, 126.7, 124.4,
120.1, 44.7, 40.1, 17.9. HRMS (ESI) m/z calcd for C16H17ClNO+ ([M + H]+) 274.0993, found 274.1002.
4. Conclusions
The ionic liquid-supported imidazolidinone chiral auxiliaries were developed. The ionic
liquid-supported chiral imidazolidinone auxiliaries 1a
synthesized in 9 steps from commercially available bromobutane. Asymmetric alkylation–cleavage
reactions were performed that produced ( )-3-(3-chlorophenyl)-2-methylpropionic acid (15) with
–c and 2a–c were rationally designed and
−
high yield and high enantioselectivity. In this study, the problems associated with heterogeneous
reactions, such as the difficulty with reaction monitoring, moderate stereoselectivity, nonlinear kinetic
behavior, diffusion-limited reactivity, unequal distribution of reagents, low reactivity, extended reaction
times, and reagent leaching could be resolved. It is believed that the ionic liquid-supported chiral
imidazolidinone auxiliaries could also be widely used for other asymmetric reactions.
Supplementary Materials: The following are available online: Scheme S1 and copies of 1H and 13C spectra of all
new compounds synthesized in this work.
Author Contributions: Y.J. synthesized IL-supported imidazolidinones and conducted the application reactions;
Y.P. performed comparison experiments using Evans’ oxazolidinone; Y.J. and J.-S.R. wrote the manuscript.
Y.P. and J.-S.R. revised the manuscript; Conceptualization, J.-S.R.; methodology, Y.J.; validation, Y.J. and Y.P.;
investigation, Y.J. and Y.P.; resources, J.-S.R.; data curation, Y.J. and Y.P.; writing—original draft preparation, Y.J.

Molecules 2019, 24, 3349
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and J.-S.R.; writing—review and editing, Y.J. and J.-S.R.; supervision, J.-S.R.; project administration, J.-S.R.; funding
acquisition, J.-S.R.
Funding: This research was supported by National Research Foundation (NRF) funded by the Korean government
(MSIT), the Bio & Medical Technology Development Program (NRF-2017M3A9F5029066) and MRC Program
(2018R1A5A2025286).
Conflicts of Interest: The authors declare no conflicts of interest.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).