Diversity-Oriented Synthesis of a Library of Star-Shaped 2H-Imidazolines

Article abstract of DOI:10.1021/acscombsci.5b00107

A library of star-shaped 2H-imidazolines has been synthesized via Debus-Radziszewski condensation from 1,2-diketones and ketone starting materials. Selective reduction of one imine group of the 2H-imidazole intermediate with LiAlH₄ or catalytic flow hydrogenation furnished 2H-imidazolines, which could be conveniently diversified by reacting the amine N with electrophiles, resulting in a set of 21 amide-, carbamate-, urea-, and allylamine-containing products. In total, five points of diversification could be used, which allow the production of a set of functionally diverse compounds. The synthesis of acylated 2H-imidazolidines resulted in intrinsically labile compounds, which spontaneously degraded to acyclic derivatives, as shown for the reaction of 2H-imidazolidine with hexylisocyanate.

Full text of DOI:10.1021/acscombsci.5b00107

Research Article
pubs.acs.org/acscombsci
Diversity-Oriented Synthesis of a Library of Star-Shaped
2H‑Imidazolines
Xuepu Yu,† Nikolaus Guttenberger,† Elisabeth Fuchs, Martin Peters, Hansjorg Weber,
̈
and Rolf Breinbauer*
Institute of Organic Chemistry, Graz University of Technology, A-8010 Graz, Austria
S
* Supporting Information
ABSTRACT: A library of star-shaped 2H-imidazolines has been synthesized
via Debus−Radziszewski condensation from 1,2-diketones and ketone starting
materials. Selective reduction of one imine group of the 2H-imidazole
intermediate with LiAlH4 or catalytic flow hydrogenation furnished 2H-
imidazolines, which could be conveniently diversified by reacting the amine N
with electrophiles, resulting in a set of 21 amide-, carbamate-, urea-, and
allylamine-containing products. In total, five points of diversification could be
used, which allow the production of a set of functionally diverse compounds.
The synthesis of acylated 2H-imidazolidines resulted in intrinsically labile compounds, which spontaneously degraded to acyclic
derivatives, as shown for the reaction of 2H-imidazolidine with hexylisocyanate.
KEYWORDS: aminal, Birch reduction, 1,2-diketones, diversity elements, heterocycles, imidazolines, imine reduction,
protein−protein interaction
attractive features: (1) With its pronounced sp3 character, it
INTRODUCTION
■
should overcome the “flatland” limitation of many heterocycles
and exhibit an attractive 3D shape.13 (2) Due to the
conformational plasticity of five-membered rings, several
conformations might be adaptable, which might be useful in
addressing surface structures. (3) All carbon atoms are
amenable for substitution and together with the amine N
present up to five attachment points for diversity elements. (4)
The two ring nitrogens should improve aqueous solubility and
allow potential hydrogen bonding and polar interactions.
Surprisingly, the literature contains only a few reports
describing the synthesis of 2H-imidazolines starting from α-
halogenoketones14 or α-aminoketones,15 by photochemical
degradation of 4,5-diphenyl-2,2,6,6-tetramethyl-l,3-
diazabicyclo[3.1.0]hex-3-ene,16 by reduction of quaternary
salts of 2H-imidazoles,17 by cycloaddition of 2-azaallyllithium
compounds with arylnitriles,18 or by electrochemical oxidation
of ketones in ammoniacal methanol.19 To the best of our
knowledge, no systematic effort has been reported to exploit
this scaffold for library synthesis.
Over the last two decades, it has been recognized that many
cellular processes are controlled by protein−protein (PPI) and
peptide−protein interactions. The inhibition of such inter-
actions has been identified as a new opportunity and paradigm
in drug discovery.1 However, high-throughput screening
campaigns against PPIs with conventional libraries typically
result in low hit rates, which have two obvious reasons: (1) the
inhibition of PPIs is intrinsically more difficult than inhibition
of an enzyme or a small-molecule binding G-protein-coupled
receptor (GPCR) because PPI sites are distinguished by the
cooperativity of several intermolecular interactions (“hot
spots”)2 over a large surface area,3 which (2) are poorly
addressed by historical compound collections that have been
optimized to hit enzymes and GPCRs with their defined and
cave-like binding sites. It is generally believed that the emerging
drug targets4 of PPIs and peptide−protein interactions very
likely need new types of molecules mimicking peptide segments
with a larger area and multiple interaction points.5 Among such
new scaffolds, α-helix mimetics,6 β-turn mimetics,7 and
macrocyclic structures8 have been identified as promising
synthetic goals. More recently, star-shaped molecular struc-
tures, especially 1H-imidazolines, have emerged as a new
privileged scaffold for addressing protein−protein interactions,
such as the p53-MDM2 inhibitor Nutlin-3 (A),9 NF-kB
inhibitor (B),10 and the neuropeptide Y Y5 receptor antagonist
(C) (Figure 1).11 An efficient multicomponent reaction has
been reported as an efficient access for this compound class,
which allows the introduction of up to five substituents.12
Inspired by these intriguing examples, we envisioned
establishing 2H-imidazolines as a new scaffold for library
generation, which in our reasoning should have the following
For the synthesis of our 2H-imidazoline library, we
considered a route starting from very accessible 1,2-diketone,
which in a Debus−Radziszewski reaction is transformed into
2H-imidazole (Figure 2). Imine reduction results in 2H-
imidazolines, which could be diversified further by reaction of
the resulting amine nucleophile with various electrophiles. This
article reports our successful implementation of this flexible
Received: July 6, 2015
Revised: September 19, 2015
© XXXX American Chemical Society
A
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Figure 1. Structures of known 1H-imidazoline-based inhibitors.
Figure 2. Access to 2H-imidazolines starting from 1,2-diketones.
Scheme 1. Overview of the Multistep Synthesis of a 2H-Imidazoline Library
synthetic strategy, offering many opportunities for diversifica-
Scheme 3. Oxidation of Alkynes 2 toward 1,2-Diketones 3
tion.
RESULTS AND DISCUSSION
Our synthetic strategy starts with 1,2-diketones for the
formation of imidazoles, which we envisioned to access through
■
Scheme 2. Sonogashira Coupling Reactions of Aryl Halides
with Phenylacetylene 1
Table 1. PdCl2/PPh3-Catalyzed Sonogashira Coupling
Reaction of Aryl Halides with Phenylacetylene 1
oxidation of the appropriate alkyne precursors (Scheme 1).
First, we used a Sonogashira coupling to functionalize the
terminal alkynes 1, furnishing disubstituted alkynes 2.
Oxidation of 2 resulted in the formation of 1,2-diketones 3.
The final step to obtain the required imidazole products 4
required a three-component reaction with a ketone and
ammonia. Selective reduction of one CN bond of 4 resulted
in 2H-imidazolines 5, which could then be further derivatized
to target structures 6.
entry
R1
R2
product
yield (%)
1
2
3
4
5
6
7
8
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
2a
2b
2c
2d
2e
2f
92
85
75
87
97
83
94
83
3-Me-Ph−
4-MeO-Ph−
4-NC-Ph−
4-O2N-Ph
2-pyridyl−
4-pyridyl−
5-pyrimidyl−
2g
2h
For the synthesis of alkynes, a Sonogashira coupling
suggested a straightforward way to connect terminal alkynes
B
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Table 2. 1,2-Diketone Products 3 Obtained via Oxidation of
Disubstituted Alkynes
Scheme 5. Formation of 2H-Imidazoles 4 via the Debus−
Radziszewski Three-Component Reaction
entry
R1
R2
product
method
yield (%)
1
2
3
4
5
6
7
8
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
Ph−
3a
3b
3b
3c
3c
3d
3e
3f
B
A
B
A
B
B
B
B
76
45
82
44
89
86
64
30
3-Me-Ph−
3-Me-Ph−
4-O2N-Ph−
4-O2N-Ph−
4-OMe-Ph
4-pyridyl−
2-pyridyl−
containing basic pyridine groups, which would be protonated
upon addition of 2 M H2SO4 and therefore hardly extractable
by EtOAc at that stage. When using normal workup conditions,
we could only isolate 8% of product 3e. In contrast, if we did
not add NaNO2 and 2 M H2SO4, the yield was 30%.
Consequently, for 3e,f, we skipped quenching the excess
KMnO4 and directly extracted the products from the reaction
mixture. In summary, Method B using KMnO4 resulted in
substrate yields better than those with Ru-catalyzed oxidation
Method A.
with sp2 carbons, thereby directly leading to the appropriate
starting materials for the formation of aryl-substituted 1,2-
diketones. When testing several conditions for the Sonogashira
reaction, we found that for our purposes the Cu-free method by
Guan et al. using aqueous conditions was ideally suited20
because it gave less homocoupling product of the terminal
alkyne than all Cu-based Sonogashira conditions we tried. We
synthesized eight alkynes 2a−2h in yields between 75 and 97%
with this convenient method (Scheme 2 and Table 1).
While this method turned out to be very effective for the
oxidation of any type of aryl/hetaryl-substituted alkynes, it
showed its limitations when alkyl-substituted alkynes were
subjected to this oxidation reaction, for which we found an
alternative access via Au(I)-catalyzed migration of 1,4-
bispropargyl acetates developed by Nevado.23 With this
strategy, we synthesized 2,6-dimethylheptane-3,4-dione (3g)
(Scheme 4). By n-BuLi-mediated deprotonation of the terminal
alkyne and electrophilic quench with isobutyraldehyde, 2,6-
dimethylhept-3-yne-2,5-diol (7) could be isolated in 91% yield
(Scheme 4). Acetylation of 7 with Ac2O produced diacetate 8,
which was isomerized using 0.02 equiv of [(IPr)Au(NTf2)] in
the presence of anhydrous DCM followed by ester cleavage
with 2.0 equiv of K2CO3 and MeOH, producing 2,6-
dimethylheptane-3,4-dione (3g) in 78% yield (64% overall
yield). While the individual reaction steps progressed smoothly,
the isolation of the quite volatile 3g imposed an experimental
challenge that required the careful removal of the solvent.
Interestingly, after the removal of the solvents, the resulting oily
residue separated into two phases, whereby the lower phase
solidified. The oily supernatant was taken off with a pipet and
identified as the desired product 3g. The solid residue was
identified as the reaction catalyst, which was washed with small
amounts of n-pentane and could be recovered in a yield of 50%
and reused as catalyst in subsequent isomerization experiments.
With a set of 1,2-diketones 3a−g in hand, we could pursue
the synthesis of 2H-imidazoles using a Debus−Radziszewski
The 1,2-disubstituted alkynes obtained in the previous step
served as excellent starting materials for the oxidative
conversion into 1,2-diketones. For phenyl-substituted sub-
strates, an established Ru-catalyzed method21 using 1.0 equiv of
aryl alkyne, 3.0 equiv of NaIO4, 0.25 equiv of MgSO4, 0.08
equiv of NaHCO3, and 0.01 equiv of RuCl3 in the presence of
acetonitrile, CCl4, and water resulted in complete conversion
after 17−20 h at rt (Scheme 3 and Table 2, Method A). While
this method proved satisfactory for the oxidation of phenyl-
substituted alkynes, it completely failed for heteroaryl-
substituted alkynes such as 2f, for which no conversion could
be observed even after 3 days. Fortunately, an alternative
method described by Lee22 using KMnO4 as a stoichiometric
oxidant in the presence of acetone proved to be a more
universal approach for the oxidation of disubstituted alkynes to
the corresponding 1,2-diketones (Scheme 3 and Table 2,
Method B). Here the strict monitoring of the reaction progress
turned out to be essential because longer reaction times led to
the overoxidation of the 1,2-diketones into carboxylic acid
cleavage products. The typical workup involves the reduction of
unreacted KMnO4 to Mn2+ ions by adding NaNO2 and 2 M
H2SO4 in small portions. After being stirred for 30 min, the
products were extracted with ethyl acetate and subsequently
purified. This workup was modified for products 3e,f
Scheme 4. Au(I)-Catalyzed Rearrangement Leading to the Unsymmetrical Alkyl-Substituted 1,2-Diketone 3g
C
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Table 3. 2H-Imidazoles Derived from 1,2-Diketones via the
Debus−Radziszewski Three-Component Reaction
Scheme 6. Reduction of 4a with Different Hydride-Reducing
Reagents under Various Conditions
Table 4. Reaction Conditions for the Reduction of 2H-
Imidazole
entry
conditions
Et3SiH, TFA, rt
yield of 5a (%)
1
2
3
4
5
6
7
8
0
0
DIBAL-H, toluene, reflux
LiBEt3H, THF, 0−50 °C
NaBH4, MeOH, 0−50 °C
HSiCl3, DMF, DCM, 0 °C to rt
NaBH4, BH3, THF, 0 °C to rt
phthalic acid, BH3, THF, −12 °C to rt
LiAlH4, THF, 0 °C to rt, 2.5 h
0
40
30
86
84
81
Scheme 7. Heterogeneous Reduction of 4a to 5a Using an H-
Cube Device
to the transformation. Two of the three components in the
imidazole-forming reaction, the 1,2-diketones and the ketone
compound, provide the opportunity to introduce a high degree
of variation into the synthesis. For the 1,2-diketones, we had
phenyl groups containing methoxy, nitro, bromo, and chloro
substituents or featuring pyridine as hetaryl substituents to
form the corresponding 2H-imidazole derivatives (entries 2−7,
Table 3). For the second diversity-creating building block in the
imidazole formation, we used different ketones, such as
cyclohexanone, 3-pentanone, 4-heptanone, and 4-phenyl-2-
butanone (entries 8, 9, and 13, Table 3). We also introduced
basic residues derived from N-methyl-4-piperidone and 1-
ethoxycarbonyl-4-piperidone to potentially improve the water
solubility of the imidazole (entries 10 and 11, Table 3).
Additionally, we decorated one of the heterocyclic product with
a (−)-menthone-derived moiety to potentially discover an
impact of stereochemical factors on the biological activity
(entry 12, Table 3).
After the five-membered ring structure was assembled, the
reduction of the CN moiety in the 2H-imidazoles was the
next important step to further increase the diversity of the
heterocyclic library (Scheme 6). A wide range of hydride-
reducing agents have been described in the literature for
reducing imidazoles to their corresponding dihydro and
tetrahydro counterparts. Inspired by these reports, we have
applied different reducing agents under various conditions to
reduce the CN bonds, as shown in Scheme 6. As listed in
Table 4, we observed that for our substrate reducing agents
such as lithium triethylborohydride (LiBEt3H),25 diisobutyla-
luminum hydride (DIBAL-H),26 and Et3SiH27 were not strong
three-component reaction comprising the synthesized 1,2-
diketones, a ketone, and ammonium acetate (Scheme 5).24
In total, we have synthesized 13 compounds based on this
method in yields of 47−98%. To obtain a diverse compound
library, we subjected substrates with different functional groups
28
enough to mediate the desired transformation. HSiCl3
produced 5a in 30% yield. Interestingly, NaBH4 delivered 5a
D
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Table 5. Optimization of the Flow-Through Hydrogenation of Imidazole 4a Using the H-Cube Device
a
entry
catalyst
concentration (M)
flow rate (mL/min)
temperature (°C)
pressure (bar)
conversion (%)
1
2
Raney-Ni
Raney-Ni
Raney-Ni
5% Pt/C
0.15
0.15
0.15
0.1
0.7
0.7
0.7
1.0
0.7
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
35
50
60
60
80
80
25
40
40
60
60
60
80
80
80
1
10
20
60
60
80
1
3
10
70
83
75
1
4
5
5% Pt/C
0.15
0.1
6
5% Pt/C
7
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
0.1
8
0.05
0.1
20
40
60
60
80
60
80
80
9
9
11
51
57
55
77
80
81
10
11
12
13
14
15
0.1
0.05
0.1
0.1
0.1
0.05
a
Estimated by GC-MS analysis via integration of the TIC signals.
Table 6. Synthesis of Various 2H-Imidazolines
Scheme 8. N-Acylation and N-Allylation of Imidazolines 5
that over time reoxidation to the starting material 4a occurred.
After a few days of exposure to air, the product was completely
reoxidized to the starting material. This indicates that
compound 5a is not stable under these conditions and provides
another explanation why full conversions in the reduction step
were generally not achieved.
As an alternative to the hydride-reducing agents, we
investigated the catalytic hydrogenation with heterogeneous
catalysts using an H-Cube flow reactor to reduce 4a to 5a as a
test example (Scheme 7).32 To find the optimal reaction
conditions, we used different catalysts under various conditions,
as shown in Table 5. The best yield was obtained when using
5% Pt/C at 0.15 M concentration of 4a in THF, a flow rate of
0.7 mL/min at 80 °C, and 60 bar hydrogen pressure was used
(83% yield).
a
Isolated as an 85:15 mixture of product/2H-imidazole.
in 40% yield, which could be further improved by adding BH3
as a reducing agent using Opatz’ conditions developed for the
reduction of acyclic 1,2-diimines.29 BH3/phthalic acid showed
equal efficiency, but ultimately, we settled on LiAlH4 as a
reducing agent,30 as it gave by far the fastest reduction and
decent yields. Importantly, any attempt to reduce also the
second imino group by using excess reducing reagents or
elevated temperatures failed, indicating that this second
transformation is much more difficult to achieve, as has been
observed before.17,31 In the isolation process of 5a, we noticed
E
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Table 7. Diversification of 2H-Imidazolines by Reaction with Various Electrophiles
a
All transformations were performed in dry DCM.
Using the described methods for the 2H-imidazole reduction,
in total, five different 2H-imidazolines were synthesized, which
are listed in Table 6. Imidazole 4i was readily reduced to the
2H-imidazoline 5c via a flow-through hydrogenation using the
H-Cube device in good yield (90%). It is interesting to note
that for 4f we had to reduce the H2 pressure from 80 to 40 bar
and the temperature from 80 to 50 °C in order to not obtain
the fully reduced imidazolidine (as detected via crude NMR).
In contrast, compound 5d readily reoxidized back to the
corresponding 2H-imidazole upon workup, which explains the
low yield of 24%.
2H-Imidazole 4a was readily reduced to 5a in good yield
(86%), with LiAlH4 as the reducing agent. Starting from 4j,
compound 5b was achieved in an acceptable 55% yield, using
the same reducing agent. For the reduction of 4h, we used the
method of Opatz with NaBH4/BH3 as the reducing agent.29
2H-Imidazoline 5e was achieved in a good 84% yield.
F
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The carbamate formation of 5b to 6p was achieved in an
acceptable yield of 66% using 19.7 equiv of pyridine and 4.9
equiv of methylchloroformiate (−78 °C to rt, overnight).
In order to gain access to the hexyl-, cyclohexyl-, and
phenylurea derivatives, we used a modified protocol by
Hecht.33 Using 3.0 equiv of the appropriate isocyanate in dry
DCM (0 °C to rt), six different urea derivatives (6f−h, 6q,r,
6u) were obtained with 72−86% yields. Urea substrates 6s and
6t were obtained in acceptable yields of 51 and 66%,
respectively. These yields are being attributed to difficulties in
product isolation (semipreparative HPLC had to be performed
following the flash column chromatography). In order to switch
the polarity of the compounds, the free carboxylic acid
derivative 6i was synthesized by adding a solution of pyridine,
and 6.3 equiv of succinic anhydride was added to 5a in dry
DCM at 0 °C. Full conversion to the free carboxylic acid was
detected after 16 h, furnishing 6i in 80% isolated yield.
Having successfully synthesized various acylated imidazoline
derivatives, we investigated various allylation methods to
introduce the corresponding functional groups. While allyl
bromide with NaH in DMF did not produce any product,
switching to K2CO3 as base delivered the product 6j in 57%
yield. The yield of 6j could be further improved by using 3.0
equiv of allyl bromide and 2.0 equiv of potassium carbonate in
the presence of 0.1 equiv of TBAI in dry DMF at 60 °C
overnight, producing 86% of 6j (Table 7).34
Scheme 9. Birch Reduction of Imidazole 4 to 2H-
Imidazolidines 9
To further increase the diversity of the compound library via
the introduction of additional functional groups, we used
amide-, allyl-, carbamate-, and urea-forming reactions (Scheme
8 and Table 7). Our first attempts at the acylation of the free
amines with acid chlorides centered on a protocol by Kanemasa
(Scheme 8).32 This method (2.0 equiv of Et3N, 1.2 equiv of the
appropriate acyl chloride, dry DCM, −78 °C) was applied for
the two reactions, where acryloyl chloride was used as the
electrophile. For 6a and 6k, yields of 86% were achieved. A
slight modification (warming to rt overnight) was used for the
2-thienylacylation of 5a to 6c (95% yield) and for the
trifluoroacetylation reactions using TFAA as the electrophile.
Compound 6d was isolated in 68% yield, and compound 6m
was isolated in 69% yield.
Having established synthetic access to 2H-imidazolines, we
explored the possibility of the second imine group being
reduced, leading to 2H-imidazolidines featuring an aminal
moiety, which we planned to stabilize via electron-withdrawing
substituents. In order to obtain the desired 2H-imidazolidines,
we had to seek alternatives to the application of metal hydrides.
Inspired by the work of Corey, we used their Birch conditions
(Li in liquid NH3) for the full conversion to the 2H-imidazoline
rac-9a (Scheme 9).24a The mechanism of this transformation is
believed to proceed over a dianion intermediate which explains
the strict selectivity for the thermodynamically more stable
trans-product.35 The Birch protocol delivered also piperidone
derived product 9b in equally excellent yield.
Acetylation of 5b was performed under adapted conditions
(2.2 equiv of pyridine, 1.6 equiv of acetyl chloride, −78 °C to
rt, overnight), as ketene formation is possible for acid chlorides
exhibiting an α-CH when using Et3N as a base. A large excess of
base and acetyl chloride had to be added after the reaction was
stirred overnight because no conversion was detected via TLC.
6l was isolated in a yield of 82%. The isobutyrylamide 6d was
synthesized accordingly to 6k, but instead of −78 °C, the
reaction was performed at 0 °C because isobutyryl acid chloride
was expected to be a less potent electrophile. After 3.5 h,
additional acid chloride had to be added and full conversion
was detected overnight, resulting in 68% isolated yield for 6d.
In an attempt to enhance reaction rates, pyridine was tested
as a base; the equivalents were increased, and the reaction was
run at 0 °C and warmed to rt, resulting in decent yield for 6e
(79% yield), 6n (65%, yield), and 6o (42% yield).
With the 2H-imidazolidines in hand, our initial attempts
centered on additional functionalizations. To this end, we
subjected rac-9a to various acyl chlorides and anhydrides under
Scheme 10. Proposed Mechanism for the Fragmentation of the Imidazolidine Ring
G
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Notes
standard conditions. With the exception of the successful
reaction with acryloyl chloride, which had been reported before
by Kanemasa,32 we were not able to functionalize rac-9a with
other acylating agents such as Ac2O, AcCl, or TFAA and ended
up with varying amounts of uncharacterized side products and
starting material. When we reacted rac-9a with an isocyanate
electrophile in order to produce the correspondent urea
derivative, we were finally able to isolate and characterize a
distinct reaction product. Treatment of 2H-imidazolidine rac-
9a with hexylisocyanate gave acyclic diurea 10 in a yield of 64%
(Scheme 10). This unforeseen reactivity might be attributed to
increased conformational stress, which renders the mono- or
disubstituted derivative unstable and triggers the fragmentation
of the aminal moiety. Based on our observations, we speculate
that the formation of 10 could occur according to the reaction
pathway suggested in Scheme 10: upon treatment of rac-9a
with hexylisocyanate, the urea derivative 11 is formed. The
conformational strain of 11 is released upon fragmentation to
12, additionally driven by the good leaving group tendency of
the ureido moiety. While 12 could not be observed directly, we
could follow the generation of intermediate 13 via HPLC-ESI-
MS, which after prolonged reaction time was consumed by
reaction with hexylisocyanate to furnish 10, which could be
isolated in 64% yield and fully characterized.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by grants of the PLACEBO (Platform for
Chemical Biology) project as part of the Austrian Genome
Project GEN-AU funded by the Forschungsforderungsgesell-
schaft (FFG) and Bundesministerium fur Wissenschaft and
Forschung (BMWF), NAWI Graz, and BioTechMed Graz is
gratefully acknowledged. We thank Thomas Schlatzer, Harald
Podversnik, Sebastian Tassoti, and Jakob Mottweiler for skillful
experimental support.
̈
̈
ABBREVIATIONS
■
DCM, dichloromethane; DMF, N,N-dimethylformamide;
HPLC, high-pressure liquid chromatography; IPr, 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene; rt, room temperature;
TBAI, tetrabutylammonium iodide; TFA, trifluoroacetic acid;
TFAA, trifluoracetic anhydride; THF, tetrahydrofuran; TIC,
total ion count; TLC, thin-layer chromatography
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We believe that a similar combination of conformational
stress and an improved leaving group tendency of amido and
ureido groups is also responsible for the intrinsic lability of
other acylated 2H-imidazolidine derivatives, making this
compound class elusive for library synthesis and screening.
CONCLUSION
■
In summary, we have presented an efficient synthetic access to
2H-imidazolines starting from 1,2-disubstituted alkynes and a
ketone as starting materials, which were converted to 2H-
imidazoles in a three-step synthesis. Reduction of these
intermediates with LiAlH4 or by catalytic hydrogenation with
Pd/C as catalyst led to the selective reduction of only one
imino group, resulting in 2H-imidazolines, which could be
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isocyanates or chloroformiates, leading to a diverse set of
compounds. Our attempts toward the fully reduced 2H-
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.5b00107.
Experimental procedures and copies of 1H NMR and 13
NMR spectra of all compounds (PDF)
C
AUTHOR INFORMATION
Corresponding Author
*E-mail: breinbauer@tugraz.at.
■
Author Contributions
†X.Y. and N.G. contributed equally to this publication.
H
DOI: 10.1021/acscombsci.5b00107
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DOI: 10.1021/acscombsci.5b00107
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