Microwave-enhanced efficient regioselective synthesis of 1,3,4-trisubstituted 2-mercaptoimidazoles on a soluble support

Article abstract of DOI:10.1002/adsc.201100640

A novel efficient synthetic method for regioselective synthesis of optically active 2-mercapto-imidazoles with three points of structural diversity was investigated on a polyethylene glycol (PEG) support. The key synthetic steps involve (i) synthesis of t

Full text of DOI:10.1002/adsc.201100640

FULL PAPERS
DOI: 10.1002/adsc.201100640
Microwave-Enhanced Efficient Regioselective Synthesis of 1,3,4-
Trisubstituted 2-Mercaptoimidazoles on a Soluble Support
Gorakh S. Yellol,a Cheng-Ting Chou,a Wang-Jin Chang,a Barnali Maiti,a
and Chung-Ming Suna,*
a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan
E-mail: cmsun@mail.nctu.edu.tw
Received: August 9, 2011; Revised: September 28, 2011; Published online: January 13, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100640.
Abstract: A novel efficient synthetic method for re- by NOE studies. In addition to three sets of structur-
gioselective synthesis of optically active 2-mercapto- al diversity, supplementary chirality at the a-position
ACHTUNGTRENNUNGimidazoles with three points of structural diversity of the 2-mercaptoimidazole skeleton is the key fea-
was investigated on a polyethylene glycol (PEG) ture of this synthesis. A representative set of 2-mer-
support. The key synthetic steps involve (i) synthesis captoimidazoles was efficiently assembled on soluble
of thiourea derivatives of polymer-supported amino support utilizing various l-amino acids, isothiocya-
acids with isothiocyanates and (ii) one-pot regiose- nates and a-bromoaryl ketones with good yields.
lective condensation of PEG-linked thiourea with a-
bromo ketones to furnish the 2-mercaptoimidazole
skeleton under microwave conditions. An excellent Keywords: mercaptoimidazoles; microwave chemis-
regioselectivity was observed during this one-pot try; nitrogen heterocycles; polyethylene glycol; solu-
condensation reaction which was further supported ble supported synthesis
Introduction
design of potent pharmaceutical agents. Methimazole
is an antithyroid drug[3] (Figure 1, A) and 4-substitut-
Chemical genomics is a prevailing approach to ex- ed-2-mercaptoimidazoles exhibit promising anti-in-
plore biological profiles in the early discovery phase flammatory activity.[4] The 1,4-diaryl-2-mercaptoimi-
of new drugs. The principle of chemical genomics is dazoles (KRM-III) are known for the inhibition of T-
based on the fact that small molecules may be used to cell antigen receptors (Figure 1, B).[5] Highly substi-
agitate the functions of specific biological targets, thus tuted 2-mercaptoimidazoles are used as potent CCR2
aiding the understanding of molecular details of com- antagonists (Figure 1, C) as well as antioxidants
plex biological mechanisms.[1] Design and synthesis of (Figure 1, D).[6] Pharmaceutical industries have great
small organic molecule libraries which span large interest in heterocyclic compounds a encompassing
areas of biologically relevant chemical space is the natural amino acid units as they occupy a special posi-
key chemical challenge in drug discovery. High-
throughput synthesis and diversity-oriented synthesis
have evolved as advanced tools to persue the increas-
ing demand for small organic molecules in initial drug
discovery. The diversity of chemical libraries may
derive from the high substitutional, stereochemical
and skeletal diversity of its members as used to ex-
plore the additional biological profile with known bio-
logical functions.[2]
In the annals of nitrogen-heterocyclic compounds,
the 2-marcaptoimidazole system has its own identity
as a key structural component of several bioactive
molecules and has been widely employed in the zoles
Figure 1. Pharmacologically important 2-mercaptoimida-
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Scheme 1. Designed strategy towards trisubstituted 2-merchaptoimidazoles.
tion in biological activity profiles.[7] Hence further de- Result and Discussion
velopment of an advanced synthetic route for the syn-
thesis of the mercaptoimidazole motif containing a Polyethylene glycol (PEG 6000) was used as a soluble
chiral amino acid unit featuring substitutional and ste- polymer support to the synthesis of 2-merchaptoimi-
reochemical diversity is warranted.
dazole. The solubility of PEG in most of polar organic
Apart from the regular [3+2] approach using the solvents favour its use as soluble support as well as fa-
a-amino carbonyl compounds,[8] substituted imidazo- cilitating the reaction progress monitoring by conven-
line-2-thiones have been synthesized by the ring ex- tional spectroscopic methods. The insolubility of PEG
pansion of azirines,[9] direct metallation reactions[10] in less polar solvents facilitates the purification of all
and by the reaction of trimethylsilyl cyanide with PEG-supported compounds by simple precipitation.
methyl isothiocyanate.[11] Previous studies to investi- The PEG support is not only stable under harsh mi-
gate the ambident nucleophilicity of 2-mercaptoimi- crowave conditions but also provides a suitable polar
dazole revealed the preference for S-alkylation under medium for efficient microwave absorption. At the
alkaline conditions.[12] The janus-like orientation came outset of our study, the commercially available, Fmoc-
to light during the conformational study of 4,5-isopro- protected l-amino acids were loaded onto PEG
pyl-1,3-benzylimidazoline-2-thione by NMR and mo- through esterification. The N-Fmoc-l-amino acids
lecular mechanics calculations and the results show were treated with dicyclohexylcarbodiimide (DCC)
that 1,3-disubstituted imidazoline-2-thiones prefer the and 4-dimethylaminopyridine (DMAP) in dichloro-
crowded syn conformation in which the two groups methane at room temperature for 12 h to obtain the
on the nitrogens are oriented away from the ring.[13] polymer-linked N-Fmoc-l-amino esters 2 (Scheme 2).
With this fact in mind, we have designed a new strat- The time required for the esterification reaction was
egy towards the synthesis of thioureas-derived natural brought down to 12 min under focused microwave ir-
amino acids and their final cyclization with a-halo ke- radiation at 808C. The resultant polymer-linked
tones between the two nitrogens of thiourea amino esters 2 were precipitated in ether solution.
(Scheme 1). The N-alkylation is preferred over S-al- The precipitate was filtered and the residue washed
kylation following the cyclization to generate product successively to remove the side products and unreact-
II regioselectively.
ed reagents. The separated polymer-linked amino
In recent times, chemists are increasingly looking esters 2 were used for next step without further purifi-
for the application of advanced reaction techniques cation. The removal of the Fmoc group from polymer
such as microwave heating in conjunction with soluble conjugates 2 was carried out with 10% piperidine in
polymer supports to develop multidisciplinary syner- dichloromethane at room temperature for 1 h to
getic approaches that make compound synthesis obtain polymer-bound amino esters 3. However,
easier, faster and more useful with an emphasis on under microwave irradiation the desired Fmoc depro-
quality and high-throughput purification tech- tection was achieved in 1 min at 758C. It is worthy of
niques.[14] In continuation to our recent research mention that the polymer ester linkage remains intact
aimed at the synthesis of biologically interesting het- under harsh microwave conditions. The same precipi-
erocyclic molecules for new drug discovery,[15] here tation work-up protocol has been followed to purify
we report a novel and efficient synthetic protocol for the polymer-bound amino esters 3. The removal of
the rapid synthesis of optically active 2-mercaptoimi- Fmoc group was cleanly observed by its 1H NMR
dazoles under microwave irradiation with three sets spectrum.
of diversity.
Towards the synthesis of 2-merchaptoimidazoles,
we next focused our attention to synthesize thiourea
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Microwave-Enhanced Efficient Regioselective Synthesis of 1,3,4-Trisubstituted 2-Mercaptoimidazoles
Scheme 2. Synthesis of soluble polymer-supported thiourea derivatives.
derivatives of polymer-bound amino esters 3. Through irradiation furnishing the desired polymer-immobi-
the terminal amine functionality of compound 3, it lized thiourea 5 in 8 min at 1208C (Scheme 2). The
was envisaged that treatment of compounds 3 with polymer thiourea conjugates 5 were purified by the
1
isothiocyanate could deliver the expected thiourea in precipitation-filtration protocol. The H NMR analy-
one step with the introduction of second diversity in sis of compound 5 depicts the characteristic set of
the skeleton. The polymer-bound amino esters 3 was peak at 4.1 ppm corresponding to PEG in addition to
first treated with isothiocyanate for 24 h in dichloro- introduction of isothiocyanate group peaks. The two
methane which did not provide any expected result. NH peaks absorbing at 7.3 ppm and 11.8 ppm indicate
The further refluxing of this reaction gave a trace the thiourea structure 5. These results suggest that the
amount of desired thiourea product, hence polymer- microwave irradiation not only reduced the reaction
bound aminoester 3 was recovered from these reac- time but significantly enhanced the reaction efficiency
tions. Alternatively, the base-catalyzed nucleophilic and outcome. On using various alkyl, aryl and hetero-
attack of a primary amine to the isothiocyanate to aryl isothiocyanates in this reaction proceeded
generate the polymer-bound monothiourea deriva- smoothly to produce respective thiourea with intro-
tives was also attempted. However, when using tri- duction of additional set of diversity that highlights
ACHTUNGTRENNUNG
produce the thiohydantoin skeleton 4 in a traceless we then turned our attention to the cyclization of the
fashion.[16] The intramolecular cyclization was attrib- l-amino acid-derived thiourea derivatives 5 with a-
uted to activation of the nitrogen in presence of a bromo ketones. The various a-bromo aryl ketones
base. Hence it was decided to run the reaction with- were reacted with polymer-bound thiourea derivatives
out base. Gratifyingly, polymer-bound amino ester 3 5 in refluxing dichloromethane (Scheme 3). The reac-
reacts with isothiocyanate under focused microwave tion involves the regioselective nucleophilic substitu-
Scheme 3. Soluble supported synthesis of 2-mercaptoimidazoles.
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Table 1. Soluble supported synthesis of 2-mercaptoimidazoles 7.
[a]
[b]
Yields were determined on the weight of purified samples (%).
HPLC analysis (UV detection at 254 nm) of the crude samples (%).
tion of the a-bromo atom by thiourea and subsequent ring. The desired polymer-bound 2-mercaptoimida-
in situ intramolecular cyclization with the carbonyl zoles 6 were obtained after 8 h in refluxing dichloro-
moiety leading to the cyclized 2-mercaptoimidazole methane. However, upon exposure of the same reac-
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Microwave-Enhanced Efficient Regioselective Synthesis of 1,3,4-Trisubstituted 2-Mercaptoimidazoles
tion to microwave irradiation it furnished polymer- ing the Hb proton enhances the Hc proton signals by
bound 2-mercaptoimidazoles 6 in 8 min at 1208C. The 1.82%. There is no interaction observed between the
desired polymer-linked 2-mercaptoimidazoles 6 were Ha protons and the Hb protons showing their remote-
purified by the same precipitation procedure and ob- ness. Additionally, irradiating the Hd proton enhances
tained in quantitative yields with three sets of struc- the Hc proton signals by 1.002%. This suggests that
tural diversity in the skeleton. The structure of com- the phenyl group bearing the Hc protons is in be-
1
pound 6 was characterized by H NMR spectroscopy tween the Ha proton and the benzyl group. Moreover
where a characteristic imidazole ring proton resonates the COSY and HMBC studies also support the struc-
at 5.78 ppm. Moreover, excellent regioselectivity was ture 7j (data in the Supporting Information). These
observed during this one-pot condensation reaction combined observations clearly confirm the structure
which was later confirmed by NOE analysis and an of compound 7j and demonstrate the regioselectivity
HMBC study after removal of the polymer support.
of the condensation reaction.
Finally, the removal of polymer support from 6 by
The plausible steps involved in the one-pot regiose-
cleaving the polymer ester linkage was achieved using lective condensation of polymer-bound thiourea 5
sodium methoxide solution in methanol at ambient with a-halo ketones to provide polymer-bound 2-mer-
temperature for 12 h to furnish 2-mercaptoimidazoles captoimidazoles 6 are described in Scheme 4. Based
7. However, with the utilization of microwave irradia- on the observed outcome of the reaction, we pro-
tion, the desired cleavage of the polymer support was
achieved in 10 min at 908C. The released polymeric
support was precipitated by cold ether and removed
by filtration. The crude compound was then subjected
to HPLC analysis which indicated moderate to good
(66–97%) purity. Further chromatography purification
afforded the 2-mercaptoimidazoles derivatives 7 in
good overall yields (70–92%) as shown in Table 1.
The removal of the PEG support was confirmed by
the absence of the characteristic set of peaks of poly-
ethylene glycol absorbing at 4.1 ppm. Through execu-
tion of the described reaction sequence, various 2-
mercaptoimidazole derivatives 7 were synthesized
with three diverse substitutions from amino acids, iso-
thiocyanate and a-bromo aryl ketones as shown in
Table 1. This developed strategy shows a significantly
widened scope with various a-bromo ketones and iso-
thiocyanates including aromatic isothiocyanates. With
the utilization of chiral amino acids, we are able to in-
troduce chirality at the a-position of the 2-mercaptoi-
midazole skeleton.
To confirm the results obtained along with the re-
gioselectivity of the condensation reaction, we carried
the 1D NOE analysis of compound 7j. The character-
istic NOE interaction pattern is shown in Figure 2. Ir-
radiation of the Ha proton enhances the Hc proton
signal by 0.34%. Irradiation of the Hc proton leads to
the enhancement of the Ha proton signal by 1.01%
which also enhanced the Hb and Hd proton signals
by 0.56% and 1.81%, respectively. Similarly, irradiat-
Scheme 4. Plausible mechanism for the regioselective con-
densation of 5 with a-bromo ketones.
Figure 2. Key NOE interaction in compound 7j.
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posed that the reaction proceeded via a sequence of of thiourea 5 with the a-halo ketone by the mechanis-
regioselective nucleophilic bromo substitution and in- tic path A to deliver 2-mercaptoimidazoles 6.
tramolecular cyclization followed by dehydration. Ini-
With the designed sequence of reaction, we success-
tially, the bromo group was selectively substituted by fully synthesized the 2-merchaptoimidazole featuring
the secondary nitrogen of thiourea 5. The regioselec- chirality at the a-position. The preservation of chiral
tivity between the nucleophilic substitution and attack integrity of the conjugates 7 throughout the four-step
on carbonyl carbon is due to the character of secon- reaction sequence on the polymer support under
dary nitrogens as a soft nucleophile which preferen- harsh microwave conditions was evaluated by chiral
tially reacts with a soft halide electrophile. A point of HPLC studies. For exact evaluation of chirality, we
interest is the regiochemistry in the reaction of thiour- have synthesized the enantiomer of compound 7a fol-
ea 5 with a-bromo ketones, in view of the similar nu- lowing the same reaction sequence and analyzed the
cleophilicities of the two thioamido nitrogens. Both chiral HPLC of both 7a and its enantiomer 7s. The
possibilities were considered mechanistically to find comparative chiral HPLC (diacel chiralcel OD) anal-
out a workable route for comparison with the results ysis of 7a and its enantiomer 7s is depicted in
obtained. Here it was contemplated that the attack Figure 3. This analysis showed practically a very insig-
through the N1 nitrogen atom of thiourea follow nificant loss of chirality (about 5% racemization, 90%
mechanistic path A while N2-nitrogen attack to ee). High enantiomeric excesses of 2-mercaptoimida-
bromo group could follow path B as shown in zoles were observed in the majority of the cases,
Scheme 4, both leading to the N-alkylated adduct A1 during the multistep reaction sequence on the soluble
and B1, respectively. Further liberation of protons polymer support under microwave conditions.
from adducts A1 could afford intermediate A2. Sub-
sequently, intramolecular cyclization through conden-
sation of the N2-nitrogen with the carbonyl functional- Conclusions
ity of the ketone afforded adducts A3. Liberation of a
water molecule from A3 can furnish 2-mercaptoimi- In conclusion, we have developed an efficient and
dazoles 6 which exactly matched with the results ob- soluble polymer-supported regioselective synthesis of
tained. Thus, the mechanistic pathway B was discard- optically active 2-mercaptoimidazoles with three
ed as its final outcome 6’ was mismatched with the re- points of structural diversity under the focused micro-
sults obtained. This evidently proves the condensation wave irradiation. The key step in this synthesis in-
Figure 3. Comparative chiral HPLC analysis of 7a and its enantiomer 7s.
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Microwave-Enhanced Efficient Regioselective Synthesis of 1,3,4-Trisubstituted 2-Mercaptoimidazoles
and dried well to afford PEG-bound thio-urea 5; yield: 1.0 g
(87%).
cludes the one-pot regioselective nucleophilic substi-
tution reaction of PEG-bound l-amino acid-derived
thiourea with a-bromo ketones followed by intramo-
lecular cyclization to furnish the 2-mercaptoimidazole
skeleton. Different combinations of l-amino acids,
isothiocyanates and a-bromo aryl ketones were used
to create the substitutional diversity as well as chirali-
ty in the 2-mercpatoimidazole skeleton. A representa-
tive small library was rapidly synthesized through ac-
celeration of the rates of all the reactions with micro-
wave irradiation as well as separation and purification
of each polymer-bound intermediate by simple pre-
cipitation. Thus, this synthetic strategy represents a
well-defined tool for the rapid generation of a library
of biologically important 2-mercaptoimidazoles from
readily available building blocks.
General Procedure for the Preparation of PEG-
Bound 2-Mercaptoimidazole (6)
Aryl a-bromo ketone (0.48 mmol) was added to a stirred so-
lution of PEG bound-thiourea derivative
5
(1.0 g,
0.16 mmol) in dry CH2Cl2 (10 mL) in a dry, nitrogen-purged
microwave vial at room temperature. Then reaction mixture
was irradiated by microwave at 1208C for 8 min. After com-
pletion, the reaction mixture was precipitated with cold
ether (50 mL). The precipitate was filtered through a fritted
funnel, washed with cold ether (50 mLꢁ2) and dried well to
afford the PEG-bound 2-mercaptoimidazoles 6 in good
yields.
General Procedure for the Synthesis of 2-
Mercaptoimidazole (7)
Experimental Section
NaOMe (0.10 g, 0.04 mmol) was added to a solution of
PEG-bound 2-mercaptoimidazole 6 (1.2 g, 0.20 mmol) in
methanol (20 mL) in a 20 mL microwave vial. The reaction
mixture was stirred under microwave irradiation at 908C for
10 min. After completion of the reaction, methanol was re-
moved under reduced pressure. A small quantity of di-
chloromethane was added and mixture was filtered to
remove undissolved material. Then filtrate was again pre-
cipitated with cold ether (100 mL). The precipitated PEG
was removed by filtration. The filtrate was concentrated
under reduced pressure, dried well and subjected to HPLC
analysis with UV detection at l=254 nm [column: Sphere-
clone 5m Si (250ꢁ4.6 mm); gradient: 35% ethyl acetate in
hexane; flow rate: 1 mLminÀ1]. The residue was further pu-
rified by column chromatography (ethyl acetate/hexane, 2:3)
to afford the 2-mercaptoimidazoles 7 in good yields.
General Procedure for the Synthesis of PEG-bound
Fmoc-l-amino Acid (2)
Fmoc-l-amino acid 1 (0.29 g, 0.96 mmol), PEG-6000 (1.00 g,
0.16 mmol) and N,N’-dimethylaminopyridine (DMAP)
(0.005 g) were placed in a dry, nitrogen-purged 20-mL mi-
crowave vial in dry CH2Cl2 (7 mL). A solution of N,N’-dicy-
clohexylcarbodiimide (DCC) (0.19 g, 0.96 mmol) in CH2Cl2
(5 mL) was added drop wise to the reaction mixture for a
period of 5 min at room temperature which was then irradi-
ated by microwave at 808C (1 bar) for 12 min. The reaction
mixture was cooled and filtered to remove insoluble DCU.
The solvent was evaporated and the residue was precipitat-
ed with cold ether. The product was filtered through a frit-
ted funnel and washed (50 mLꢁ2) to remove any unreacted
reagents and then dried under vacuum to give PEG-bound
Fmoc-l-amino acid 2 as a white solid; yield: 1.18 g (95%).
Methyl
(2S)-2-(3-benzyl-4-phenyl-2-thioxo-2,3-dihydro-
1H-imidazol-1-yl)-3-phenylpropanoate
(7a):
1H NMR
(300 MHz, CDCl3): d=7.39–7.28 (m, 3H), 7.24 (s, 5H),
7.21–7.14 (m, 5H), 6.92–6.90 (m, 2H), 5.74 (s, 1H), 5.17 (d,
J=15.6 Hz, 1H), 4.84 (d, J=15.6 Hz, 1H), 4.00 (dd, J=7.9,
5.7 Hz, 1H), 3.72 (s, 3H), 3.30 (dd, J=13.2, 5.4 Hz, 1H),
3.13 (dd, J=13.5, 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=173.2, 161.9, 140.8, 138.5, 137.7, 131.7, 129.6, 129.1, 128.9,
128.5, 128.2, 127.9, 127.4, 126.9, 126.3, 95.6, 68.9, 51.9, 48.4,
40.3; MS (EI): m/z=428; HR-MS (EI): m/z=428.1560,
calcd. for C26H24N2O2S: 428.1558; [a]2D5: À19.2 (c 1.0,
CH2Cl2); IR (KBr): n=3028, 1714, 1614, 1494, 1453 cmÀ1.
Methyl (2S)-2-[3-butyl-4-(naphthalen-2-yl)-2-thioxo-2,3-
General Procedure for the Synthesis of PEG-Bound
l-Amino Acid (3)
The PEG-bound Fmoc-l-amino acid 2 (1.2 g, 0.18 mmol)
was placed in a dry, nitrogen-purged 20-mL microwave vial.
Piperidine (10%) in dry CH2Cl2 (10 mL) was added to this
vial. The vial was irradiated at 758C for 1 min. After com-
pletion, the reaction mixture was precipitated with cold
ether. The precipitate was filtered through a fritted funnel
and washed (50 mLꢁ2) and dried to afford PEG-bound l-
amino acid 3; yield: 0.92 g (98%).
dihydro-1H-imidazol-1-yl]-3-phenylpropanoate
(7b):
1H NMR (300 MHz, CDCl3): d=7.89–7.82 (m, 4H), 7.57–
7.52 (m, 2H), 7.42–7.38 (m, 1H), 7.33–7.18 (m, 5H), 5.78 (s,
1H), 3.96–3.87 (m, 2H), 3.73 (s, 3H), 3.70–3.65 (m, 1H),
3.31 (dd, J=13.2, 5.7 Hz, 1H), 3.15 (dd, J=13.5, 8.1 Hz,
1H), 1.45–1.33 (m, 2H), 1.09–1.01 (m, 2H), 0.69 (t, J=
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.2, 140.9,
138.5, 133.2, 133.0, 129.6, 128.4, 128.2, 128.2, 127.8, 126.9,
126.8, 126.3, 125.9, 95.9, 68.7, 52.0, 45.3, 29.8, 29.8, 19.7, 13.7;
MS (EI): m/z=444; HR-MS (EI): m/z=444.1871, calcd. for
C27H28N2O2S 444.1871; [a]2D5: À43.8 (c 1.0, CH2Cl2); IR
(KBr): n=2954, 1742, 1614, 1434 cmÀ1.
General Procedure for the Preparation PEG-Bound
Thiourea (5)
The PEG-bound l-amino acid 3 (0.92 g, 0.15 mmol) was dis-
solved in CH2Cl2 (10 mL) in a dry, nitrogen-purged 20-mL
microwave vial. Isothiocyanate (0.051 g, 0.45 mmol) was
added to the reaction mixture at room temperature. The re-
action mixture was irradiated by microwave at 1208C
(2 bar) for 8 min. After completion, reaction mixture was
precipitated with cold ether. The precipitate was filtered
through a fritted funnel, washed with cold ether (50 mLꢁ2)
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Methyl (2S)-2-(3-butyl-4-phenyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-yl)-3-phenylpropanoate (7c): H NMR (300 MHz,
(300 MHz, CDCl3): d=7.44–7.38 (m, 3H), 7.33–7.31 (m,
2H), 5.70 (s, 1H), 3.94–3.76 (m, 1H), 3.70 (s, 3H), 3.69–3.59
(m, 2H), 1.85–1.69 (m, 3H), 1.54–1.36 (m, 2H), 1.13–1.01
(m, 2H); 0.96–0.86 (m, 6H); 0.70 (t, J=7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=174.4, 161.2, 140.8, 132.2,
128.9, 128.8, 128.6, 95.0, 65.7, 51.8, 44.7, 43.1, 29.9, 24.9, 23.3,
21.9, 19.6, 13.7; MS (EI): m/z=360; HR-MS (EI): m/z=
360.1871, calcd. for C20H28N2O2S: 360.1871; [a]2D5: À31.4 (c
1.0, CH2Cl2); IR (KBr): n=2954, 1745, 1613, 1444 cmÀ1.
Methyl (2S)-2-[3-benzyl-4-(naphthalen-2-yl)-2-thioxo-2,3-
1
CDCl3): d=7.42–7.40 (m, 3H), 7.34–7.29 (m, 5H), 7.24–7.17
(m, 2H), 5.69 (s, 1H), 3.92–3.81 (m, 2H), 3.71 (s, 3H), 3.65–
3.58 (m, 1H), 3.29 (dd, J=13.4, 5.4 Hz, 1H), 3.15–3.12 (m,
1H), 1.42–1.29 (m, 2H), 1.11–1.02 (m, 2H), 0.71 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.3, 161.7,
140.9, 138.5, 131.9, 129.6, 129.0, 128.8, 128.6, 128.1, 126.3,
95.2, 68.8, 52.0, 44.9, 40.2, 29.8, 19.6, 13.7; MS (EI): m/z=
394; HR-MS (EI): m/z=394.1714, calcd. for C23H26N2O2S:
394.1715; [a]2D5: À21.9 (c 1.0, CH2Cl2); IR (KBr): n=3027,
2954, 2859, 2359, 1742, 1612 cmÀ1.
dihydro-1H-imidazol-1-yl]-4-methylpentanoate
(7i):
1H NMR (300 MHz, CDCl3): d=7.85–7.71 (m, 3H), 7.69 (s,
1H), 7.54–7.47 (m, 2H), 7.30–7.27 (m, 1H), 7.24–7.19 (m,
3H), 7.07–7.05 (m, 2H), 5.88 (s, 1H), 5.16–4.97 (m, 2H),
3.84–3.80 (m, 1H), 3.76 (s, 3H), 1.93–1.84 (m, 1H), 1.79–
1.71 (m, 1H), 1.69–1.56 (m, 1H), 0.92 (dd, J=8.2, 6.9 Hz,
6H); 13C NMR (75 MHz, CDCl3): d=174.2, 161.4, 140.9,
138.0, 133.2, 132.9, 129.1, 128.5, 128.3, 128.2, 127.8, 127.3,
126.9, 126.9, 126.7, 126.1, 95.9, 65.6, 51.9, 48.7, 43.1, 24.7,
23.4, 21.8; MS (EI): m/z=444; HR-MS (EI): m/z=444.1871,
calcd. for C27H28N2O2S: 444.1871; [a]2D5: À32.7 (c 1.0,
CH2Cl2); IR (KBr): n=2952, 1741, 1615, 1433 cmÀ1.
Methyl (2S)-2-(3-butyl-4-phenyl-2-thioxo-2,3-dihydro-1H-
1
imidazol-1-yl)-3-methylbutanoate (7d): H NMR (300 MHz,
CDCl3): d=7.41–7.36 (m, 3H), 7.35–7.31 (m, 2H), 5.68 (s,
1H), 3.95–3.84 (m, 1H), 3.71 (s, 3H), 3.66–3.57 (m, 1H),
3.39 (d, J=6.3 Hz, 1H), 2.33–2.22 (m, 1H), 1.59–1.37 (m,
2H), 1.16–1.04 (m, 2H), 0.98 (t, J=5.7 Hz, 6H), 0.73 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.6, 161.1,
140.8, 132.2, 128.9, 128.8, 128.6, 94.9, 73.6, 51.6, 44.8, 32.8,
29.9, 19.7, 18.5, 13.7; MS (EI): m/z=346; HR-MS (EI): m/
z=346.1710, calcd. for C19H26N2O2S: 346.1715; [a]2D5: À41.8
(c 1.0, CH2Cl2); IR (KBr): n=2957, 1742, 1615, 1444 cmÀ1.
Methyl (2S)-2-[3-butyl-4-(4-methylphenyl)-2-thioxo-2,3-di-
hydro-1H-imidazol-1-yl]-3-methylbutanoate (7e): 1H NMR
(300 MHz, CDCl3): d=7.18 (s, 4H), 5.16 (s, 1H), 3.90–3.81
(m, 1H), 3.67 (s, 3H), 3.65–3.55 (m, 1H), 3.37 (d, J=6.3 Hz,
1H), 2.35 (s, 3H), 2.29–2.20 (m, 1H), 1.59–1.37 (m, 2H),
1.17–1.03 (m, 2H), 0.97 (t, J=6.6 Hz, 6H), 0.72 (t, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=173.5, 161.1,
140.8, 138.8, 129.3, 129.3, 128.6, 94.5, 73.5, 51.5, 44.8, 32.8,
29.9, 21.3, 19.7, 18.3, 13.7; MS (EI): m/z=360; HR-MS (EI):
m/z=360.1875, calcd. for C20H28N2O2S: 360.1871; [a]2D5:
À40.2 (c 1.0, CH2Cl2); IR (KBr): n=2957, 1743, 1610, 1509,
1433 cmÀ1.
Methyl
(2S)-2-(3-benzyl-4-phenyl-2-thioxo-2,3-dihydro-
1H-imidazol-1-yl) propanoate (7j): 1H NMR (300 MHz,
CDCl3): d=7.38–7.28 (m, 3H), 7.16–7.14 (m, 5H), 7.02–6.99
(m, 2H), 5.76 (s, 1H), 4.99 (s, 2H), 3.85 (dd, J=13.6, 6.6 Hz,
1H), 3.71 (s, 3H), 1.49 (d, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=174.2, 161.3, 140.8, 137.7, 131.8, 129.1,
128.9, 128.5, 128.2, 127.5, 127.0, 95.5, 62.3, 51.9, 48.3, 19.1;
MS (EI): m/z=352; HR-MS (EI): m/z=352.1246, calcd. for
C20H20N2O2S: 352.1245; [a]2D5: À47.5 (c 1.0, CH2Cl2); IR
(KBr): n=2948, 1741, 1615, 1444 cmÀ1.
Methyl (2S)-2-[3-benzyl-4-(naphthalen-2-yl)-2-thioxo-2,3-
dihydro-1H-imidazol-1-yl]propanoate
(7k):
1H NMR
(300 MHz, CDCl3): d=7.86–7.71 (m, 3H), 7.66 (s, 1H),
7.55–7.48 (m, 2H), 7.28–7.26 (m, 1H), 7.21–7.19 (m, 3H),
7.08–7.06 (m, 2H), 5.88 (s, 1H), 5.07 (s, 2H), 3.92 (dd, J=
13.4, 6.9 Hz, 1H), 3.76 (s, 3H), 1.55 (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=174.2, 161.4, 140.9, 137.8,
133.3, 132.9, 129.1, 128.5, 128.3, 128.2, 127.8, 127.6, 127.1,
126.9, 126.8, 126.2, 95.9, 62.4, 52.0, 48.7, 19.1; MS (EI):
m/z=402; HR-MS (EI): m/z=402.1398, calcd. for
C24H22N2O2S: 402.1402; [a]2D5: À29.4 (c 1.0, CH2Cl2); IR
(KBr): n=2957, 1741, 1615, 1453 cmÀ1.
Methyl (2S)-2-[3-benzyl-4-(4-methylphenyl)-2-thioxo-2,3-
1
dihydro-1H-imidazol-1-yl]-3-methylbutanoate (7f): H NMR
(300 MHz, CDCl3): d=7.37–7.29 (m, 3H), 7.23–7.16 (m,
5H), 7.04–7.02 (m, 2H), 5.77 (s, 1H), 5.11 (d, J=15.6 Hz,
1H), 4.90 (d, J=15.6 Hz, 1H), 3.72 (s, 3H), 3.45 (d, J=
6.3 Hz, 1H), 2.30–2.20 (m, 1H), 0.90 (dd, J=6.7, 3.0 Hz,
6H); 13C NMR (75 MHz, CDCl3): d=173.3, 161.1, 140.7,
137.8, 131.7, 128.9, 128.8, 128.4, 128.0, 127.1, 126.7, 95.2,
73.4, 51.5, 48.3, 32.6, 19.5, 18.2; MS (EI): m/z=380; HR-MS
(EI): m/z=380.1558, calcd. for C22H24N2O2S: 380.1558; [a]25:
À24.3 (c 1.0, CH2Cl2); IR (KBr): n=2957, 1740, 161D7,
1444 cmÀ1.
Methyl (2S)-2-[3-benzyl-4-(biphenyl-4-yl)-2-thioxo-2,3-di-
hydro-1H-imidazol-1-yl]propanoate
(7l):
1H NMR
(300 MHz, CDCl3): d=7.63–7.56 (m, 4H), 7.48 (t, J=
7.2 Hz, 2H), 7.42–7.37 (m, 1H), 7.28–7.23 (m, 5H), 7.13–
7.11 (m, 2H), 5.84 (s, 1H), 5.09 (s, 2H), 3.93 (dd, J=13.5,
6.6 Hz, 1H), 3.76 (s, 3H), 1.56 (d, J=6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=174.2, 161.3, 141.8, 140.6, 140.1, 137.8,
130.7, 129.3, 129.0, 128.3, 127.9, 127.5, 127.2, 127.1, 95.7,
62.4, 52.0, 48.5, 19.2; MS (EI): m/z=428; HR-MS (EI):
m/z=428.1557, calcd. for C26H24N2O2S: 428.1558; [a]2D5:
À29.4 (c 1.0, CH2Cl2); IR (KBr): n=2948, 1740, 1608,
1453 cmÀ1.
Methyl (2S)-2-[3-benzyl-4-(naphthalen-2-yl)-2-thioxo-2,3-
1
dihydro-1H-imidazol-1-yl]-3-methylbutanoate (7g): H NMR
(300 MHz, CDCl3): d=7.85–7.71 (m, 3H), 7.69 (s, 1H),
7.54–7.48 (m, 2H), 7.31–7.28 (m, 1H), 7.25–7.20 (m, 3H),
7.10–7.08 (m, 2H), 5.87 (s, 1H), 5.17 (d, J=15.6 Hz, 1H),
4.98 (d, J=15.6 Hz, 1H), 3.92 (dd, J=13.4, 6.9 Hz, 1H),
3.76 (s, 3H), 2.38–2.27 (m, 1H), 0.98–0.95 (m 6H);
13C NMR (75 MHz, CDCl3): d=173.5, 161.4, 140.9, 138.1,
133.2, 132.9, 129.2, 128.5, 128.2, 127.8, 127.4, 126.9, 126.9,
126.7, 126.1, 95.8, 73.6, 51.7, 48.8, 32.8, 19.7, 18.5; MS (EI):
m/z=430; HR-MS (EI): m/z=430.1714, calcd. for
C26H26N2O2S: 430.1715; [a]2D5: À20.3 (c 1.0, CH2Cl2); IR
(KBr): n=2957, 1739, 1617, 1453 cmÀ1.
Methyl (2S)-2-(3-butyl-4-phenyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-yl)propanoate
(7m):
1H NMR
(300 MHz,
CDCl3): d=7.41–7.37 (m, 3H), 7.35–7.30 (m, 2H), 5.71 (s,
1H), 3.80–3.67 (m, 3H), 3.72 (s, 3H), 1.49–1.40 (m, 5H),
1.14–1.02 (m, 2H), 0.71 (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=174.4, 161.0, 140.9, 132.2, 128.9, 128.7,
Methyl (2S)-2-(3-butyl-4-phenyl-2-thioxo-2,3-dihydro-1H-
imidazol-1-yl)-4-methylpentanoate
(7h):
1H NMR
194
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Adv. Synth. Catal. 2012, 354, 187 – 196

Microwave-Enhanced Efficient Regioselective Synthesis of 1,3,4-Trisubstituted 2-Mercaptoimidazoles
128.6, 95.0, 62.4, 51.9, 44.7, 29.9, 19.6, 19.0, 13.7; MS (EI):
m/z=318; HR-MS (EI): m/z=318.1404, calcd. for
C17H22N2O2S: 318.1402; [a]2D5: À27.8 (c 1.0, CH2Cl2); IR
(KBr): n=2955, 1743, 1614, 1445 cmÀ1.
7.15–7.10 (m, 5H), 6.87–6.85 (m, 2H), 5.72 (s, 1H), 5.12 (d,
J=15.6 Hz, 1H), 4.80 (d, J=15.6 Hz, 1H), 3.94 (dd, J=7.9,
5.7 Hz, 1H), 3.69 (s, 3H), 3.25 (dd, J=13.2, 5.4 Hz, 1H),
3.07 (dd, J=13.5, 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=173.1, 161.9, 140.7, 138.4, 137.7, 131.7, 129.6, 129.3, 129.0,
128.9, 128.3, 128.1, 127.3, 126.8, 126.1, 95.5, 68.8, 51.9, 48.3,
40.2; [a]2D5: À0.37 (c 1.0, CH2Cl2).
Methyl (2S)-2-[3-butyl-4-(naphthalen-2-yl)-2-thioxo-2,3-
dihydro-1H-imidazol-1-yl]propanoate
(7n):
1H NMR
(300 MHz, CDCl3): d=7.89–7.84 (m, 4H), 7.56–7.52 (m,
2H), 7.41 (dd, J=8.4, 1.5 Hz, 1H), 5.82 (s, 1H), 3.86–3.77
(m, 3H), 3.75 (s, 3H), 1.59–1.47 (m, 5H), 1.15–1.03 (m, 2H),
0.70 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
174.4, 161.1, 140.9, 133.2, 133.1, 129.5, 128.3, 128.2, 128.1,
127.8, 126.9, 126.8, 125.9, 95.6, 62.5, 52.0, 45.0, 29.9, 19.6,
19.1, 13.7; MS (EI): m/z=368; HR-MS (EI): m/z=368.1560,
calcd. for C21H24N2O2S: 368.1558; [a]2D5: À29.4 (c 1.0,
CH2Cl2); IR (KBr): n=2954, 1742, 1614, 1434 cmÀ1.
Supporting Information
1
The H NMR, 13C NMR, IR and HR-MS for compounds 7.
These data are available as Supporting Information.
Acknowledgements
Methyl (2S)-2-[3-butyl-4-(4-methylphenyl)-2-thioxo-2,3-di-
hydro-1H-imidazol-1-yl]propanoate
(7o):
1H NMR
The authors thank the National Science Council of Taiwan
for the financial assistance and the authorities of the National
Chiao Tung University for providing the laboratory facilities.
This paper is particularly supported by “Aim for the Top
University Plan” of the National Chiao Tung University and
Ministry of Education,Taiwan.
(300 MHz, CDCl3): d=7.19 (m, 4H), 5.66 (s, 1H), 3.81–3.65
(m, 3H), 3.70 (s, 3H), 2.36 (s, 3H), 1.50–1.40 (m, 5H), 1.14–
1.02 (m, 2H), 0.71 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=174.4, 161.0, 140.9, 138.9, 129.3, 129.2, 128.6,
94.6, 62.4, 51.9, 44.7, 29.9, 21.3, 19.6, 19.0, 13.7; MS (EI):
m/z=332; HR-MS (EI): m/z=332.1559, calcd for
C18H24N2O2S 332.1558; [a]2D5: À48.1 (c 1.0, CH2Cl2); IR
(KBr): n=2955, 2871, 1743, 1608, 1434 cmÀ1.
References
Methyl 2-(3,4-diphenyl-2-thioxo-2,3-dihydro-1H-imidazol-
1
1-yl)-3-phenylpropanoate (7p): H NMR (300 MHz, CDCl3):
[1] a) S. L. Schreiber, Nature 2009, 457, 153–154; b) K. Ki-
kuchi, Chem. Soc. Rev. 2010, 39, 2048–2053; c) S. V.
Frye, Nat. Chem. Biol. 2010, 6, 159–161.
[2] a) W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring,
Nat. Commun. 2010, 80, 1–13; b) R. J. Spandl, A. Bend-
erb, D. R. Spring, Org. Biomol. Chem. 2008, 6, 1149–
1158.
d=7.34 (d, J=7.2 Hz, 2H), 7.30 (t, J=7.2 Hz, 1H), 7.22–
7.12 (m, 6H), 7.10 (d, J=7.2 Hz, 2H), 7.04 (t, J=7.2 Hz,
1H), 6.90 (d, J=7.2 Hz, 2H), 6.69 (m, 1H), 5.49 (s, 1H),
4.52 (dd, J=10.8, 3.6 Hz, 1H), 3.94 (dd, J=13.8, 10.8 Hz,
1H), 3.82 (s, 3H), 3.22 (dd, J=13.8, 3.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=170.3, 156.4, 150.4, 140.1, 137.5, 130.8,
129.8, 129.3, 129.2, 128.9, 128.3, 128.2, 126.5, 122.9, 121.2,
95.0, 60.0, 52.5, 32.8; MS (ESI): m/z=415 [M+1]; [a]2D5:
+122.5 (c 0.025, CH2Cl2); IR (KBr): n=3025, 1745, 1616,
1488 cmÀ1.
Methyl 2-[3-(4-fluorophenyl)-4-phenyl-2-thioxo-2,3-dihy-
dro-1H-imidazol-1-yl]-3-phenylpropanoate (7q): 1H NMR
(300 MHz, CDCl3): d=7.35 (t, J=8.1 Hz, 1H), 7.26–7.14
(m, 8H), 7.12–7.08 (m, 2H), 6.92–6.86 (m, 2H), 6.69 (m,
1H), 5.52 (s, 1H), 4.48 (dd, J=10.8, 3.6 Hz, 1H), 3.94 (dd,
J=13.8, 10.8 Hz, 1H), 3.83 (s, 3H), 3.20 (dd, J=13.8,
3.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=170.4, 160.0,
158.1, 157.0, 146.8, 140.3, 137.5, 130.8, 129.4, 129.1, 128.5,
126.6, 122.5, 115.9, 115.8, 95.0, 60.1, 52.6, 32.9; MS (ESI):
m/z=433 [M+1]; [a]2D5: À230.5 (c 0.025, CH2Cl2); IR (KBr):
n=2948, 1745, 1616, 1500 cmÀ1.
Methyl 2-[3-(4-methoxyphenyl)-4-phenyl-2-thioxo-2,3-di-
hydro-1H-imidazol-1-yl]-3-phenylpropanoate (7r): 1H NMR
(300 MHz, CDCl3): d=7.32 (t, J=7.8 Hz, 1H), 7.24–7.08
(m, 5H), 7.06 (d, J=7.8 Hz, 2H), 6.98–6.87 (m, 5H), 6.69
(m, 1H), 5.49 (s, 1H), 4.51 (dd, J=10.8, 3.6 Hz, 1H), 3.95
(dd, J=13.8, 10.8 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.22
(dd, J=13.8, 3.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
170.5, 156.1, 155.5, 144.0, 140.2, 137.7, 131.0, 129.4, 129.0,
128.9, 128.4, 128.3, 126.5, 122.1, 114.6, 94.9, 60.0, 55.5, 52.6,
32.9; MS (ESI): m/z=445 [M+1]; [a]2D5: À67.4 (c 0.025,
CH2Cl2); IR (KBr): n=2948, 1745, 1616, 1504 cmÀ1.
[3] A. Taurog, M. L. Dorris, F. S. Guziec, Endocrinology
1989, 124, 30–39.
[4] a) A. Beliaev, D. A. Learmonth, P. Soares-da-Silva, J.
Med. Chem. 2006, 49, 1191–1197; b) F. Isaia, M. C. Ara-
goni, A. Massimiliano, F. Demartin, F. A. Devillanova,
G. Floris, A. Garau, M. B. Hursthouse, V. Lippolis, R.
Medda, F. Oppo, M. Pira, G. Verani, J. Med. Chem.
2008, 51, 4050–4053.
[5] E. J. Jung, M. Hur, Y. L. Kim, G. H. Lee, J. Kim, I.
Kim, M. Lee, H. K. Han, M. S. Kim, S. Hwang, S. Kim,
A. M. Woo, Y. Yoon, H. J. Park, J. Won, J. Pharmacol.
Exp. Ther. 2009, 331, 1005–1013.
[6] a) G. V. Lommen, J. Doyon, E. Coesemans, S. Boeckx,
M. Cools, M. Buntinx, B. Hermans, J. VanWauwe,
Bioorg. Med. Chem. Lett. 2005, 15, 497–500; b) K. P.
Bhabak, G. Mugesh, Inorg. Chim. Acta 2010, 363,
2812–2818.
[7] a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem.
Rev. 2003, 103, 893–930; b) W. R. J. D. Galloway, A.
Bender, M. Welchc, D. R. Spring, Chem. Commun.
2009, 2446–2462.
[8] H. Schubert, W. D. Rudorf, Z. Chem. 1971, 11, 175–
180.
[9] I. Handke, E. Schaumann, J. Org. Chem. 1988, 53,
5298–5300.
[10] B. T. Phillips, D. A. Claremon, S. L. Varga, Synthesis
1990, 761–762.
[11] S. Inaba, I. Ojima, J. Organomet. Chem. 1979, 169, 171–
184.
Methyl
1H-imidazol-1-yl)-3-phenylpropanoate
(400 MHz, CDCl3): d=7.34–7.25 (m, 3H), 7.20 (s, 5H),
(2S)-2-(3-benzyl-4-phenyl-2-thioxo-2,3-dihydro-
(7s):
1H NMR
Adv. Synth. Catal. 2012, 354, 187 – 196
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
195

Gorakh S. Yellol et al.
FULL PAPERS
[12] Q. F. Soper, C. W. Whitehead, O. K. Behrens, J. J.
Corse, R. G. Jones, J. Am. Chem. Soc. 1948, 70, 2849–
2851.
[13] a) U. Berg, I. Petterson, J. Org. Chem. 1987, 52, 5177–
5184; b) U. Berg, C. Roussell, J. Am. Chem. Soc. 1980,
102, 7848–7853.
Yellol, W. J. Chang, M. L. Sun, C. M. Sun, Tetrahedron
2011, 67, 2110–2117.
[15] a) K. Chanda, B. Maiti, G. S. Yellol, M. H. Chien, M. L.
Kuo, C. M. Sun, Org. Biomol. Chem. 2011, 9, 1917–
1926; b) G. S. Yellol, W. C. Tsai, C. M. Sun, Chem.
Commun. 2010, 46, 9170–9172; c) B. Maiti, K. Chanda,
C. M. Sun, Org. Lett. 2009, 11, 4826–4829.
[14] a) Y. S. Hsiao, G. S. Yellol, L. H. Chen, C. M. Sun, J.
Comb. Chem. 2010, 12, 723–732; b) C. T. Chou, G. S.
[16] a) W. B. Yeh, M. J. Lin, M. J. Lee, C. M. Sun, Mol. Di-
versity 2003, 7, 185–198.
196
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 187 – 196