Efficient C2 functionalisation of 2H-2-imidazolines

Article abstract of DOI:10.1039/b713065a

Alkylation and oxidation of 2H-2-imidazolines, followed by regioselective deprotection, thionation and microwave-assisted Liebeskind-Srogl reaction, efficiently led to 2-aryl-2-imidazolines as new analogues of p53-hdm2 interaction inhibitors (Nutlins). Th

Full text of DOI:10.1039/b713065a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient C2 functionalisation of 2H-2-imidazolines
Robin S. Bon,a Nanda E. Sprenkels,a Manoe M. Koningstein,a Rob F. Schmitz,a Frans J. J. de Kanter,a
Alexander Do¨mling,b Marinus B. Groena and Romano V. A. Orru*a
Received 24th August 2007, Accepted 22nd October 2007
First published as an Advance Article on the web 8th November 2007
DOI: 10.1039/b713065a
Alkylation and oxidation of 2H-2-imidazolines, followed by regioselective deprotection, thionation and
microwave-assisted Liebeskind–Srogl reaction, efficiently led to 2-aryl-2-imidazolines as new analogues
of p53-hdm2 interaction inhibitors (Nutlins).
Consequently, our method could be exploited to synthesise
Introduction
new, Nutlin-type, p53-hdm2 interaction inhibitors. The approach
The 2-imidazoline scaffold is found in many biologically active
renders analogues containing an additional carboxylate that may
small molecules that target numerous pharmaceutically relevant
binding sites and receptors.1 Although substitution patterns are
serve to enhance water solubility. However, the 2H-2-imidazolines
that result from our MCR should be arylated at C2. Here, we
diverse, most biologically active 2-imidazolines are substituted at
present an efficient synthetic strategy to achieve this.
C2. For example, the Nutlins, which are highly functionalised
2-imidazolines that shown both in vitro and in vivo antitumor
activity, all contain a C2 aryl moiety that is believed to be
essential.2 The Nutlins are strong inhibitors of hdm2, a protein
Results and discussion
Four relevant 2H-imidazolines (Scheme 1, 4–7) were selected as
that negatively modulates the transcriptional activity and stability
of the p53 tumor suppressor protein.3 C2-Substituted imidazolines
can be prepared by the condensation of a diamine with an
imidate, but variation of the substituents is not straightforward.4
Alternatively, a trimethylsilyl chloride mediated multicomponent
reaction (MCR) between oxazolones, aldehydes and amines can
be employed.5 However, this leads to the formation of C2-
functionalised 2-imidazolines with trans-oriented C4/C5 phenyl
groups. Although some reports exist of methods that give cis-
oriented C4/C5 phenyl groups,5 these seem less efficient for the
synthesis of Nutlin analogues, which require cis-oriented C4/C5
phenyl groups.
Recently, we reported a versatile MCR involving amines,
aldehydes and isocyanoacetates to access 2H-2-imidazolines.6 All
substituents can be varied easily by the choice of readily available
reagents. Furthermore, the reaction generally favours formation of
the diastereomer with cis-oriented aryl functionalities at C4/C5.
starting materials for our synthetic study. The two cis-oriented
p-chlorophenyl (PCP) groups in the backbone of analogues 4
and 5 are also found in Nutlins, where they seem crucial for
the interaction with the Trp23 and Leu26 pockets of hdm2.2
The imidazolines 6 and 7, containing a 5-indolyl substituent, are
also highly relevant, since, according to NMR studies of Nutlins
bound to hdm2,4 these may improve binding to the Trp23 domain
of hdm2. Thus, application of the MCR using isocyanoacetate
17 in combination with two different aldehydes (2) and amines
(3) provides the corresponding 2H-2-imidazolines 4–7 in high
yields.
Direct C2 functionalisation of 4–7 proved not to be straight-
forward, and a procedure for selective C2 arylation had to be
developed. Recently, Liebeskind and Srogl reported the Pd(0)-
catalyzed, Cu(I)-mediated coupling of thioether-type species with
boronic acids under neutral conditions.8 The high thiophilicity
of the soft Cu(I) carboxylate cofactor facilitates selective C–C
coupling with isothioureas even in the presence of a Suzuki-active
bromide.9 This elegant procedure has been used to directly arylate
dihydropyrimidine-2-thiones under microwave irradiation.10 We
envisioned the mild and easy sulfoxidation of 2H-2-imidazolinium
salts through the reaction of in situ-generated N-heterocyclic
carbenes with elemental sulfur as an appropriate method to
aDepartment of Chemistry, Vrije Universiteit Amsterdam, De Boelelaan
1083, 1081, HV, Amsterdam, The Netherlands. E-mail: orru@few.vu.nl;
Fax: +31 20 5987488; Tel: +31 20 5987447
bPharmaceutical Sciences & Chemistry, University of Pittsburgh, BST3
10019, Pittsburgh, PA, 15261, USA
Scheme 1 2H-2-Imidazolines 4–7 obtained from a 3-component reaction (3-CR).
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Table 1 Liebeskind–Srogl arylation of 12 and 16
Scheme 2 Possible route for C2 functionalisation of 2H-2-imidazolines.
synthesise precursors for Liebeskind–Srogl reactions (Scheme 2).11
Strategic choice of R1 and R3 groups should allow selective
deprotection of N1 or N3, leading to Nutlin analogues.
Methylation and sulfoxidation of imidazoline 4 affords the
cyclic thiourea 9 in good yield (Scheme 3). Chromatographic
separation of the diastereomers was achieved but cleavage of the p-
methoxybenzyl (PMB) group could not be realised. Both oxidative
and acidic conditions cause decomposition, probably because
of the sensitive thiocarbonyl group. Therefore, an alternative
route was considered. Imidazolidin-2-thiones can be prepared by
the thionation of imidazolidin-2-ones using Lawesson’s reagent.12
For this, oxidation of 2H-2-imidazolines was required. Although
(low-yielding) oxidations of benzimidazoles with mCPBA are
known,13 this procedure proved unsuitable for the direct oxidation
of imidazolines. In contrast, mCPBA-mediated oxidation of
imidazolinium salt 8 affords cyclic urea 10 as a mixture of
diastereomers, in a combined yield of 82% (Scheme 3). For a
clean reaction it proved important to add the mCPBA to a cooled
solution of 8. The diastereomers of 10 are conveniently separated
by chromatography.
Product
T/◦C
Isolated yield (%)
17
17
18
18
19
19
20
20
100
130
100
130
100
130
100
130
14
51
24
41
34
65
6
55
Scheme 5 Synthesis of Liebeskind–Srogl precursor 16.
conditions reported by Kappe et al. (PhB(OH)2, Pd(PPh3)4, Cu(I)
Scheme 3 Oxidation and thionation of C2.
◦
thiophene-2-carboxylate, THF, microwave, 100 C, 30 min).10
These conditions, however, gave only traces of C2-arylated
products. Conditions were further refined with respect to the
solvent, and the reactions proceeded much better in DMF instead
of THF. Also, the reaction temperature appears crucial and is
important for achieving good conversions to the desired cross-
coupling products. Although not fully optimized yet, running the
Treatment of trans-10 with TFA (to cleave off the PMB-group)
and subsequent thionation provides the Liebeskind–Srogl precur-
sor 12 with a C5 ester function in very high yields (Scheme 4).14
◦
reaction at 130 C for 1 h ultimately led to efficient Liebeskind–
Srogl cross-coupling of 12 and 16 with two different boronic acids,
and the corresponding 2-aryl-2-imidazolines 17–20 were isolated
in good yields.
Scheme 4 Synthesis of Liebeskind–Srogl precursor 12.
With the above-described methodology available, we now
turned to the synthesis of Liebeskind–Srogl precursors containing
the ester functionality at C4. Clean formation of imidazolinium
salt 13 from 5 can be achieved using PMBBr and NaI under
Finkelstein conditions (Scheme 5). Oxidation then gives cyclic urea
14 in reasonable yield, and the diastereomers could be separated
chromatographically. Deprotection and subsequent thionation of
trans-14 both went smoothly, affording efficiently the desired
Liebeskind–Srogl precursor 16.14
With 12 and 16 in hand, we could now perform the Liebeskind–
Srogl reactions (Table 1). Reactions were run in sealed vessels with
controlled single-mode microwave heating. Initially, coupling re-
actions between boronic acids and 12 or 16 were performed under
Conclusion
In conclusion, a versatile route toward C2-functionalized 2-
imidazolines containing Nutlin-like backbones has been de-
veloped. Besides the 3-component reaction to access 2H-2-
imidazolines, key steps involve the oxidation at C2 and the
Liebeskind–Srogl coupling of cyclic thioureas with boronic acids.
The analogues 17–20 have been prepared in good overall yields
(23% to 35%) starting from commercially available aldehydes
and amines. The high overall yields and the flexibility make this
procedure amenable to library synthesis of potential p53-hdm2
interaction inhibitors.
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CDCl3) d (ppm) 7.36 (s, 4H), 4.67 (s, 1H), 3.73 (s, 3H), 2.60 (br s,
2H).
Experimental
General
Methyl 2-(4-chlorophenyl)-2-formamidoacetate. Methyl 2-
amino-2-(4-chlorophenyl)acetate (2.79 g, 14.0 mmol) was dis-
solved in ethyl formate (80 mL), and a small crystal of pTSA
was added. The reaction mixture was refluxed overnight, cooled
to rt and the solvent was evaporated. The product was dissolved in
DCM, washed with water, dried with Na2SO4, and concentrated
in vacuo to afford the title compound as a yellow solid (3.15 g,
All reactions were carried out under atmospheric conditions,
unless stated otherwise. Standard syringe techniques were applied
for transfer of air-sensitive reagents and dry solvents. Melting
points were measured using a Stuart Scientific SMP3 melting
point apparatus and are uncorrected. Infrared (IR) spectra
were obtained from CHCl3 films on NaCl tablets (unless noted
otherwise), using a Matteson Instuments 6030 Galaxy Series
FT-IR spectrophotometer, and wavelengths (m) are reported
1
99%) H NMR (200 MHz, CDCl3) d (ppm) 8.22 (s, 1H), 7.31 (s,
4H), 6.86 (br s, 1H), 5.62 (d, J = 7.2 Hz, 1H), 3.72 (s, 3H); 13C
NMR (63 MHz, CDCl3) d (ppm) 176.6 (C), 170.6 (C), 160.5 (CH),
134.6 (C), 129.2 (2 × CH), 129.0 (2 × CH), 54.4 (CH3), 53.2 (CH);
HRMS (EI, 70 eV) calculated for C10H10ClNO3 (M+) 227.0349,
found 227.0346.
1
in cm−1. H and 13C nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker Avance 400 (400.13 MHz and
100.61 MHz respectively) or a Bruker Avance 250 (250.13 MHz
and 62.90 MHz respectively) with chemical shifts (d) reported in
ppm downfield from tetramethylsilane. MS and HRMS spectral
data were recorded on a Finnigan Mat 900 spectrometer or in the
Laboratory of Organic Chemistry of the Wageningen University
(NL) on a Finnigan MAT95 spectrometer. Chromatographic
purification refers to flash chromatography using the indicated
Methyl 2-(4-chlorophenyl)-2-isocyanoacetate 1. This reaction
was carried out under an inert atmosphere of dry nitrogen. Methyl
2-(4-chlorophenyl)-2-formamidoacetate (910 mg, 4.0 mmol) was
dissolved in DCM (10 mL) and cooled to −30 ◦C. Triphos-
gene (504 mg, 1.7 mmol) and N-methylmorpholine (1.57 mL,
14.3 mmol) were added slowly. The solution turned darker orange,
and after 30 minutes at −30 ◦C the temperature was raised to −5 ◦C
and kept at this temperature for an additional 3 hours, during
which time the solution slowly turned darker. The reaction mixture
was quenched in 20 mL of ice-water. The layers were separated,
and the aqueous layer was extracted with Et2O. The organic
layers were combined, washed with brine and dried with Na2SO4.
Concentration in vacuo followed by flash column chromatography
(cyclohexane–ethyl acetate = 4 : 1), afforded 1 as an orange oil
˚
solvent (mixture) and Baker 7024-02 silica gel (40 l, 60 A).
Thin layer chromatography was performed using silica plates
from Merck (Kieselgel 60 F254 on aluminium with fluorescence
indicator. Compounds on TLC were visualised by UV-detection
unless stated otherwise. THF was dried and distilled from sodium
benzophenone ketyl prior to use. DCM was dried and distilled
from CaH2 prior to use. Toluene was distilled from sodium prior
to use. DMF was dried and distilled from phenylzinc iodide
prior to use. Other commercially available reagents were used as
purchased.
1
(640 mg, 77%). H NMR (250 MHz, CDCl3) d (ppm) 7.42 (br s,
4H), 5.35 (s, 1H), 3.80 (s, 3H); 13C NMR (63 MHz, CDCl3) d
(ppm) 165.6 (C), 162.2 (C), 135.8 (C), 130.2 (C), 129.4 (2 × CH),
128.0 (2 × CH), 59.6 (C), 53.9 (CH3); IR (neat) 2954 (m), 2148
(s), 1753 (s), 1493 (s), 1435 (m), 1250 (m), 1211 (m), 1092 (s), 1014
(s); HRMS (EI, 70 eV) calculated for C10H8ClNO2 (M+) 209.0244,
found 209.0248.
Microwave experiments
Microwave-assisted reactions were performed in a Discover (CEM
Corporation) single-mode microwave instrument producing con-
trolled irradiation at 2450 MHz, using standard sealed microwave
glass vials. Reaction temperatures were monitored with an IR
sensor on the outside wall of the reaction vials. Reaction times
refer to hold times at the indicated temperatures, not to total
irradiation times.
General Procedure I for the synthesis of 2-imidazolines
Reactions were carried out under an inert atmosphere of dry
nitrogen at a concentration of 1 M of aldehyde 2, 1 M of amine
3, and 0.5 M of isocyanide 1 in dry DCM or MeOH. Na2SO4 and
the aldehyde were added, at rt, to a stirred solution of the amine.
After the mixture was stirred for 2 h, the isocyanide was added and
the reaction mixture was stirred at rt for an additional 18 h. The
reaction mixture was filtered and concentrated in vacuo. The crude
product was purified by flash column chromatography (c-hexane–
EtOAc–Et3N = 2 : 1 : 0.01, gradient, unless stated otherwise).
1-(4-Chlorophenyl)-2-methoxy-2-oxoethanaminium chloride.
p-Chlorophenylglycine (8.62 g, 46.5 mmol) was dissolved in
MeOH (110 mL). The solution was cooled to 0 ◦C and thionyl
chloride (6.8 mL, 93 mmol) was added dropwise. The reaction
mixture was heated under reflux for 3 h. Cooling to rt followed
by concentration in vacuo afforded the title compound as a white
solid (10.98 g, quant.) 1H NMR (250 MHz, D2O) d (ppm) 7.54 (d,
J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 5.30 (s, 1H), 3.82 (s,
3H).
Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-4,5-dihydro-
1H-imidazole-4-carboxylate 4. According to General Procedure
I, reaction between p-methoxybenzylamine (2.74 g, 20 mmol), p-
chlorobenzaldehyde (2.80 g, 20.0 mmol) and isocyanoacetate 1
(2.07 g, 9.9 mmol) in DCM, followed by column chromatography
(EtOAc–Et3N = 1 : 0.01), afforded 4 (3.96 g, 85%) as a 71 : 29
mixture of diastereomers as a yellow solid. 1H NMR (250 MHz,
CDCl3) d (ppm) 7.47 (d, J = 43.0 Hz, 1H), 7.36–7.21 (m, 3H +
4H), 7.10–6.98 (m, 4H + 4H), 6.89–6.76 (m, 5H + 5H), 5.28 (s,
1H), 4.64 (s, 1H), 4.36–4.31 (m, 1H + 1H), 3.82 (s, 3H), 3.74 (s,
Methyl 2-amino-2-(4-chlorophenyl)acetate.1-(4-Chlorophenyl)-
2-methoxy-2-oxoethanaminium chloride (3.33 g, 14.1 mmol) was
suspended in EtOAc (100 mL). Saturated NaHCO3 (aq.) (80 mL)
was added and the suspension was stirred until the organic layer
was clear and slightly orange. The layers were separated and
the aqueous layer was extracted twice with EtOAc. The organic
layers were combined, washed with brine and dried with Na2SO4.
Filtration and concentration in vacuo afforded the title compound
as a yellow–orange solid (2.79 g, 99%) 1H NMR (250 MHz,
132 | Org. Biomol. Chem., 2008, 6, 130–137
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3H), 3.83–3.74 (m, 4H + 1H), 3.28 (s, 3H); 13C NMR (63 MHz,
CDCl3) d (ppm) 173.5 (C), 170.6 (C), 159.4 (C), 156.7 (CH), 155.9
(CH), 141.6 (C), 135.9 (C), 134.9 (C), 134.4 (C), 133.7 (2 × C),
133.6 (2 × C), 133.2 (C), 120.0 (2 × CH), 129.4 (2 × CH), 129.3
(2 × CH), 129.0 (2 × CH), 128.8 (2 × CH), 128.3 (2 × CH), 128.2
(2 × CH), 128.08 (2 × CH), 128.06 (2 × CH), 127.8 (2 × CH),
127.1 (C), 126.9 (C), 114.1 (2 × CH), 114.2 (2 × CH), 84.7 (C),
83.8 (C), 72.4 (CH3), 68.5 (CH3), 55.1 (CH3 + CH3), 53.1 (CH),
52.1 (CH), 48.6 (CH2), 48.1 (CH2); IR (neat) 1730 (s), 1602 (s);
HRMS (EI, 70 eV) calculated for C25H22Cl2N2O3 (M+) 468.1007,
found 468.1002.
1599 (s), 1512 (s), 1452 (s), 1370 (s), 1248 (s), 1153 (s), 1089 (s);
HRMS (EI, 70 eV) calculated for C32H32ClN3O5 (M+) 573.2030,
found 573.2036.
tert-Butyl 3-(1-butyl-4-(4-chlorophenyl)-4-(methoxycarbonyl)-
4,5-dihydro-1H-imidazol-5-yl)-1H-indole-1-carboxylate 7. Ac-
cording to General Procedure I, reaction between n-butylamine
(1.10 g, 15.0 mmol), N-Boc-indolecarboxaldehyde (3.68 g,
15.0 mmol) and isocyanoacetate 1 (2.89 g, 13.8 mmol) in MeOH,
followed by column chromatography, afforded 7 (5.9 g, 84%) as a
76 : 24 mixture of diastereomers as a pale yellow solid. 1H NMR
(400 MHz, CDCl3, 328 K) d (ppm) 8.14 (d, J = 8.4 Hz, 1H), 7.95
(d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.57
(d, J = 7.9 Hz, 1H), 7.35–6.99 (m, 6H + 5H), 6.88 (d, J = 8.3 Hz,
2H + 2H), 5.83 (s, 1H), 5.04 (s, 1H), 3.74 (s, 3H), 3.16 (s, 3H),
3.13–3.04 (m, 1H + 1H), 2.90–2.84 (m, 1H + 1H), 1.69 (s, 9H),
1.63 (s, 9H), 1.52–1.45 (m, 2H), 1.37–1.12 (m, 2H + 4H), 0.85 (t,
J = 7.3 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) d (ppm) 174.0 (C), 156.4 (CH), 156.1 (CH), 149.4 (C),
149.3 (C), 136.9 (2 × C), 133.6 (C), 128.1 (3 × CH + 5 × CH),
127.3 (2 × CH), 125.5 (CH), 124.1 (CH + CH), 122.7 (CH + CH),
120.1 (CH), 115.6 (C), 115.3 (CH), 114.9 (CH), 84.3 (C), 83.9 (C),
67.9 (CH), 62.6 (CH), 53.2 (CH3), 52.1 (CH3), 44.8 (CH2), 44.3
(CH2), 30.3 (CH2), 30.2 (CH2), 28.2 (3 × CH3), 28.1 (3 × CH3),
19.8 (CH2), 19.7 (CH2), 13.6 (CH3), 13.5 (CH3); the aliphatic
CH signals could only be found with gs-HSQC measurements at
328 K; the quaternary carbons of the minor diastereomer of 7
could not be detected; IR (KBr) 2957 (s), 1734 (s), 1599 (s), 1570
(m), 1452 (s), 1370 (s), 1257 (s), 1155 (s), 1089 (s); HRMS (EI, 70
eV) calculated for C28H32ClN3O4 (M+) 509.2081, found 509.2082.
Methyl 1-butyl-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imida-
zole-4-carboxylate 5. According to General Procedure I, reac-
tion between n-butylamine (730 mg, 10.0 mmol), p-chlorobenz-
aldehyde (1.40 g, 10.0 mmol) and isocyanoacetate 1 (990 mg,
4.74 mmol) in DCM, followed by column chromatography
(EtOAc–Et3N = 1 : 0.01), afforded 5 (1.61 g, 84%) as a 74 : 26
mixture of diastereomers as a pale yellow oil. 1H NMR (250 MHz,
CDCl3) d (ppm) 7.69 (d, J = 8.7 Hz, 2H), 7.39–7.34 (m, 4H), 7.30–
7.26 (m, 3H + 1H), 7.05–7.01 (m, 2H + 2H), 6.90–6.86 (m, 2H +
2H), 5.51 (s, 1H), 4.81 (s, 1H), 3.77 (s, 3H), 3.28 (s, 3H), 3.20–3.08
(m, 1H + 1H), 2.89–2.78 (m, 1H + 1H), 1.54–1.13 (m, 4H + 4H),
0.92–0.79 (m, 3H + 3H); 13C NMR (100.6 MHz, CDCl3) d (ppm)
173.8 (C), 170.6 (C), 156.8 (CH), 156.1 (CH), 141.9 (C), 136.1 (C),
135.2 (C), 134.4 (C), 134.0 (C), 133.6 (C), 133.5 (C), 133.1 (C),
129.8 (2 × CH), 129.2 (2 × CH), 128.8 (2 × CH), 128.4 (2 × CH),
128.17 (2 × CH), 128.15 (2 × CH), 128.08 (2 × CH), 127.8 (2 ×
CH), 84.65 (C), 83.9 (C), 73.5 (CH3), 68.7 (CH3), 53.1 (CH), 52.1
(CH), 44.8 (CH2), 44.5 (CH2), 30.2 (CH2), 30.0 (CH2), 19.8 (CH2),
19.7 (CH2), 13.6 (CH3), 13.5 (CH3); IR (neat) 1729 (s), 1599 (s);
HRMS (EI, 70 eV) calculated for C21H22Cl2N2O2 (M+) 404.1058,
found 404.1046.
4,5-Bis(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(methoxycarbo-
nyl)-3-methyl-4,5-dihydro-1H-imidazolium iodide 8. Methyl
iodide (447 mg, 3.15 mmol) was added to a solution of
imidazoline 4 (1.408 g, 3 mmol) in DCM (20 mL). The reaction
mixture was stirred at rt for 18 h and concentrated in vacuo to
afford 8 (1.83 g, quant.) as a 68 : 32 mixture of diastereomers as a
pale yellow solid. 1H NMR (250 MHz, CDCl3) d (ppm) 10.65 (s,
1H), 10.52 (s, 1H), 7.48–7.29 (m, 4H + 2H), 7.20–7.17 (m, 4H +
6H), 7.01–6.91 (m, 2H + 2H), 6.91–6.83 (m, 2H + 2H), 5.73 (s,
1H), 5.45 (d, J = 14.1 Hz, 1H), 5.31 (d, J = 14.4 Hz, 1H), 5.14 (s,
1H), 4.23–4.13 (m, 1H + 1H), 3.96 (s, 3H), 3.80 (s, 3H + 3H), 3.56
(s, 3H), 3.34 (s, 3H), 3.26 (s, 3H); 13C NMR (63 MHz, CDCl3) d
(ppm) 168.9 (C), 165.8 (C), 160.5 (C), 160.2 (C), 160.1 (CH), 158.4
(CH), 136.9 (2 × C), 135.8 (C), 135.6 (C), 132.9 (C), 131.3 (2 ×
CH), 131.0 (4 × CH), 130.5 (2 × CH), 130.0 (2 × CH), 129.9 (C),
129.8 (2 × CH), 129.3 (2 × CH), 129.1 (2 × CH), 128.9 (2 × CH),
128.88 (2 × CH), 128.84 (C), 123.4 (2 × C), 123.1 (C), 114.7 (2 ×
CH), 114.6 (2 × CH), 80.6 (C), 80.2 (C), 74.1 (CH3), 70.2 (CH3),
55.4 (2 × CH3), 54.6 (CH), 53.2 (CH), 50.5 (CH2), 50.4 (CH2),
34.9 (CH3), 33.3 (CH3); IR (neat) 1745 (s), 1642 (s), 1611 (s).
tert-Butyl 3-(4-(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(methoxy-
carbonyl)-4,5-dihydro-1H-imidazol-5-yl)-1H-indole-1-carboxylate
6. According to General Procedure I, reaction between p-meth-
oxybenzylamine (384 mg, 2.8 mmol), N-Boc-indolecarbox-
aldehyde (690 mg, 2.8 mmol) and isocyanoacetate 1 (419 mg,
2.0 mmol) in DCM, followed by column chromatography,
afforded 6 (364 mg, 76%) as a 58 : 42 mixture of diastereomers as
an orange–pink solid. 1H NMR (400 MHz, DMSO-d6, 360 K): d
(ppm) 8.09 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.63 (s,
1H), 7.61–7.56 (m, 3H + 3H), 7.54 (s, 1H), 7.48 (d, J = 7.8 Hz,
1H), 7.38–7.32 (m, 2H + 2H), 7.25–7.20 (m, 1H + 1H), 7.09–7.01
(m, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.97 (br s, 1H + 1H), 6.91 (d,
J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.7 Hz,
2H), 5.58 (s, 1H), 4.99 (s, 1H), 4.46 (d, J = 15.1 Hz, 1H), 4.39 (d,
J = 14.9 Hz, 1H), 3.86–3.82 (m, 1H + 1H), 3.75 (s, 3H), 3.70 (s,
3H), 3.64 (s, 3H), 3.07 (s, 3H), 1.67 (s, 9H), 1.59 (s, 9H); 13C NMR
(100.6 MHz, DMSO-d6, 360 K) d (ppm) 172.5 (C), 170.2 (C),
158.4 (C), 158.3 (C), 156.8 (CH), 156.1 (CH), 148.5 (C), 148.2
(C), 142.2 (C + C), 137.3 (C + C), 134.8 (C + C), 131.7 (C), 131.2
(C), 128.72 (4 × CH), 128.67 (4 × CH), 128.3 (CH), 128.1 (C +
C), 128.1 (2 × CH), 127.4 (2 × CH), 126.4 (CH), 125.4 (CH),
124.0 (CH), 123.6 (CH), 122.0 (CH), 121.8 (CH), 119.6 (CH),
119.4 (C), 115.8 (C), 114.3 (CH), 114.0 (CH), 113.54 (2 × CH),
113.46 (2 × CH), 83.8 (C + C), 83.4 (C + C), 65.1 (CH), 61.4
(CH), 54.8 (CH3), 54.7 (CH3), 52.0 (CH3), 50.8 (CH3), 47.5 (CH2),
47.3 (CH2), 27.4 (3 × CH3), 27.3 (3 × CH3); IR (KBr) 1733 (s),
Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-
2-thioxoimidazolidine-4-carboxylate 9. This reaction was carried
out under an inert atmosphere of dry argon. A Schlenk tube was
charged with imidazolinium iodide 8 (608 mg, 1.0 mmol), KOtBu
(118 mg, 1.05 mmol) and S8 (256 mg, 1.0 mmol). THF (30 mL)
was added and the reaction mixture was stirred at rt for 2 h.
Then, water was added and the mixture was extracted with EtOAc
(3×). The organic layers were dried with Na2SO4 and concentrated
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in vacuo. Purification using flash column chromatography (toluene
visualisation on TLC with UV and with iodine) afforded 9a
(229 mg, 45%) and 9b (92 mg, 18%) as white solids.
concentrated in vacuo. Purification was performed using flash
column chromatography (c-hexane–EtOAc = 1 : 1, gradient).
trans-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-oxoimidazol-
idine-4-carboxylate 11. According to General Procedure II,
deprotection of imidazolidinone trans-10 (455 mg, 0.88 mmol),
followed by column chromatography, afforded 11 (304 mg, 91%)
as a white solid. Mp 214–216 ◦C; 1H NMR (250 MHz, CDCl3) d
(ppm) 7.29–7.06 (m, 4H), 6.93 (d, J = 8.3 Hz, 2H), 6.72 (d, J =
8.4 Hz, 2H), 5.56 (s, 1H), 5.50 (br s, 1H), 3.92 (s, 3H), 2.89 (s,
3H); 13C NMR (63 MHz, CDCl3) d (ppm) 171.4 (C), 161.1 (C),
135.8 (C), 135.2 (C), 134.4 (C), 134.0 (C), 129.0 (2 × CH), 128.4
(4 × CH), 128.2 (2 × CH), 75.7 (C), 61.5 (CH3), 53.1 (CH), 29.1
(CH3); IR (KBr) 1734 (s), 1716 (s); HRMS (EI, 70 eV) calculated
for C18H16Cl2N2O3 (M+) 378.0538, found 378.0526.
1
9a (most polar isomer): H NMR (250 MHz, CDCl3) d (ppm)
7.12–7.03 (m, 6H), 6.82 (d, J = 8.6 Hz, 2H), 6.85–6.66 (m, 4H),
5.74 (d, J = 14.7 Hz, 1H), 5.29 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H),
3.76 (d, J = 14.7 Hz, 1H), 3.26 (s, 3H); 13C NMR (63 MHz, CDCl3)
d (ppm) 170.5 (C), 159.2 (2 × C), 134.6 (C), 134.5 (C), 132.0 (C),
131.3 (C), 129.8 (4 × CH), 128.6 (2 × CH), 128.51 (2 × CH),
128.45 (2 × CH), 127.5 (C), 113.9 (2 × CH), 77.8 (C), 68.1 (CH3),
55.2 (CH3), 53.3 (CH), 49.1 (CH2), 34.2 (CH3); IR (neat) 1751 (s),
1610 (m); HRMS (EI, 70 eV) calculated for C26H24Cl2N2O3S (M+)
514.0885, found 514.0902.
9b (least polar isomer): Mp 120–121 ◦C; 1H NMR (250 MHz,
CDCl3) d (ppm) 7.36 (d, J = 8.5 Hz, 2H), 2.50 (d, J = 8.7 Hz, 2H),
7.11–7.04 (m, 6H), 6.81 (d, J = 8.6 Hz, 2H), 5.79 (d, J = 14.6 Hz,
1H), 4.73 (s, 1H), 3.80 (s, 3H), 3.62 (d, J = 14.6 Hz, 1H), 3.28
(s, 3H), 3.08 (s, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 183.0
(C), 168.1 (C), 159.5 (C), 136.3 (C), 135.4 (C), 135.0 (C), 133.3
(C), 130.2 (4 × CH), 129.1 (2 × CH), 128.1 (4 × CH), 127.2 (C),
114.0 (2 × CH), 77.5 (C), 70.8 (CH3), 55.3 (CH3), 52.2 (CH), 48.7
(CH2), 33.1 (CH3); IR (neat) 1737 (s), 1612 (m); HRMS (EI, 70 eV)
calculated for C26H24Cl2N2O3S (M+) 514.0885, found 514.0899.
cis-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-oxoimidazolidine-
4-carboxylate. According to General Procedure II, deprotection
of imidazolidinone cis-10 (516 mg, 1.0 mmol), followed by column
chromatography, afforded the title compound (396 mg, 99%) as
a white solid. 1H NMR (250 MHz, CDCl3) d (ppm) 7.45 (d, J =
8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H),
7.12 (d, J = 8.5 Hz, 2H), 5.19 (s, 1H), 4.86 (s, 1H), 3.33 (s, 3H),
2.63 (s, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 168.6 (C), 160.8
(C), 136.1 (C), 135.8 (C), 135.1 (C), 135.0 (C), 129.1 (2 × CH),
128.8 (2 × CH), 128.75 (2 × CH), 128.72 (2 × CH), 76.0 (C), 65.1
(CH), 52.1 (CH3), 28.2 (CH3); IR (KBr) 1747 (s), 1720 (s), 1494
(m), 1435 (m); HRMS (EI, 70 eV) calculated for C18H16Cl2N2O3
(M+) 378.0538, found 378.0531.
Methyl 4,5-bis(4-chlorophenyl)-1-(4-methoxybenzyl)-3-methyl-
2-oxoimidazolidine-4-carboxylate 10. To a cooled (0 ◦C) solution
of imidazolinium iodide 8 (611 mg, 1.0 mmol) in DCM (20 mL),
85% mCPBA (610 mg, 3.0 mmol) was added. The yellow solution
abruptly turned red. The reaction mixture was stirred at rt for
18 h, washed twice with saturated Na2CO3 (aq.), dried with
Na2SO4 and concentrated in vacuo. Purification using flash column
chromatography (c-hexane–EtOAc = 4 : 1) afforded trans-10
(289 mg, 58%) and cis-10 (120 mg, 24%) as white solids.
General Procedure III for the thionation of imidazolidinones
Reactions were performed under an inert atmosphere of dry
nitrogen at a concentration of 0.020 M of imidazolidinone in
dry toluene. A reaction vessel was charged with imidazolidinone
(1 equiv.) and Lawesson’s reagent (1 equiv.). Toluene was added
and the suspension was heated to reflux temperature. The resulting
solution was refluxed for 18 h, cooled to room temperature and
concentrated in vacuo. The crude product was loaded on to a pre-
packed silica column. Impurities were eluted with toluene and
then the product was eluted with toluene–EtOAc = 4 : 1, gradient.
Visualisation on TLC was performed with UV and with iodine.
trans-10 (most polar isomer): Mp 88–90 ◦C; 1H NMR
(250 MHz, CDCl3) d (ppm) 7.09–6.95 (m, 6H), 6.81–6.68 (m,
6H), 5.03 (s, 1H), 4.96 (d, J = 14.8 Hz, 1H), 3.79 (s, 3H), 3.79 (s,
3H), 3.52 (d, J = 14.8 Hz, 1H), 2.94 (s, 3H); 13C NMR (63 MHz,
CDCl3) d (ppm) 171.2 (C), 160.2 (C), 159.2 (C), 134.3 (C), 134.1
(C), 132.7 (C), 132.1 (C), 130.0 (4 × CH), 128.6 (2 × CH), 128.4
(2 × CH), 128.3 (2 × CH), 128.0 (C), 113.9 (2 × CH), 73.8 (C),
64.3 (CH3), 55.3 (CH3), 53.0 (CH), 45.5 (CH2), 29.6 (CH3); IR
(neat) 1738 (s), 1710 (s), 1611 (m); HRMS (EI, 70 eV) calculated
for C26H24Cl2N2O4 (M+) 498.1113, found 498.1096.
trans-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-thioxoimida-
zolidine-4-carboxylate 12. According to General Procedure III,
thionation of imidazolidinone 11 (1.00 g, 2.64 mmol), followed
by column chromatography, afforded 12 (2.46 g, 93%) as a white
cis-10 (least polar isomer): Mp 143–145 ◦C; 1H NMR (200 MHz,
CDCl3) d (ppm) 7.29–6.90 (m, 10H), 6.73 (d, J = 8.7 Hz, 2H),
4.95 (d, J = 14.6 Hz, 1H), 4.39 (s, 1H), 3.72 (s, 3H), 3.40 (d,
J = 14.6 Hz, 1H), 3.26 (s, 3H), 2.66 (s, 3H); 13C NMR (63 MHz,
CDCl3) d (ppm) 168.9 (C), 159.5 (C), 159.3 (C), 136.4 (C), 135.0
(C), 134.6 (C), 133.7 (C), 130.1 (2 × CH), 129.6 (2 × CH), 128.8
(4 × CH), 128.4 (2 × CH), 127.7 (C), 114.0 (2 × CH), 73.7 (C),
67.2 (CH3), 55.3 (CH3), 52.0 (CH), 45.2 (CH2), 28.6 (CH3); IR
(neat) 1741 (s), 1711 (s), 1611 (m); HRMS (EI, 70 eV) calculated
for C26H24Cl2N2O4 (M+) 498.1113, found 498.1107.
1
solid. H NMR (250 MHz, CDCl3) d (ppm) 7.06–6.99 (m, 4H),
6.84 (d, J = 8.3 Hz, 2H), 6.60–6.55 (m, 3H), 5.63 (s, 1H), 3.86
(s, 3H), 3.10 (s, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 184.4
(C), 170.3 (C), 134.9 (C), 134.5 (C), 133.9 (C), 130.7 (C), 128.8
(2 × CH), 128.6 (2 × CH), 128.4 (4 × CH), 80.0 (C), 65.0 (CH),
53.5 (CH3), 33.5 (CH3); IR (KBr) 3174 (br), 1737 (s), 1596 (w),
1491 (s), 1393 (m), 1256 (s); HRMS (EI, 70 eV) calculated for
C18H16Cl2N2O2S (M+) 394.0310, found 394.0303.
General Procedure II for the Cleavage of PMB groups
cis-Methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-thioxoimidazol-
idine-4-carboxylate. According to General Procedure III,
thionation of cis-methyl 4,5-bis(4-chlorophenyl)-3-methyl-2-
oxoimidazolidine-4-carboxylate (374 mg, 0.98 mmol), followed
by column chromatography, afforded the title compound (336 mg,
A 0.25–0.30 M solution of imidazolidinone was refluxed for
1 h. After cooling to rt followed by evaporation of TFA, the
crude product was dissolved in EtOAc, washed with saturated
NaHCO3 (aq.) solution and brine, dried with Na2SO4 and
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87%) as a white solid. 1H NMR (250 MHz, CDCl3) d (ppm) 7.40
(d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.3 Hz,
2H), 7.09 (d, J = 8.3 Hz, 2H), 8.95 (s, 1H), 5.04 (s, 1H), 3.28
(s, 3H), 2.92 (s, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 183.9
(C), 167.4 (C), 135.7 (C), 135.32 (C), 135.28 (C), 134.8 (C), 129.3
(2 × CH), 128.80 (2 × CH), 128.75 (2 × CH), 128.5 (2 × CH),
80.1 (C), 68.8 (CH), 52.4 (CH3), 32.3 (CH3); IR (KBr) 3162 (br),
1737 (s), 1596 (w), 1491 (s), 1393 (m), 1256 (s); HRMS (EI, 70 eV)
calculated for C18H16Cl2N2O2S (M+) 394.0310, found 394.0299.
128.7 (4 × CH + 4 × CH), 128.2 (2 × CH), 128.2 (2 × CH), 127.9
(2 × CH + 2 × CH), 113.7 (2 × CH), 113.4 (2 × CH), 74.0 (C),
73.8 (C), 69.1 (CH), 64.7 (CH), 55.24 (CH3), 55.20 55.2 (CH3), 52.7
55.2 (CH3), 51.8 55.2 (CH3), 46.8 (CH2), 46.0 (CH2), 42.0 (CH2),
41.8 (CH2), 29.0 (CH2), 28.8 (CH2), 20.0 (CH2), 19.9 (CH2), 13.74
(CH3), 13.67 (CH3); IR (KBr) 1707 (s), 1513 (s), 1244 (s); HRMS
(EI, 70 eV) calculated for C29H30Cl2N2O4 (M+) 540.1583, found
540.1587.
cis-14 (least polar isomer): 1H NMR (250 MHz, CDCl3) d (ppm)
7.42–7.27 (m, 8H), 7.17–7.06 (m, 8H), 6.88–6.62 (m, 2H + 4H),
6.60 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H), 4.96 (d, J = 15.9 Hz, 1H),
4.81 (s, 1H), 4.35 (d, J = 15.1 Hz, 1H), 4.18–4.11 (m, 1H + 1H),
3.81 (s, 3H), 3.79 (s, 3H), 3.73–3.60 (m, 1H + 1H), 3.38 (s, 3H),
3.23 (s, 3H), 2.75–2.64 (m, 1H + 1H), 1.54–1.22 (m, 4H + 4H),
0.99–0.85 (m, 3H + 3H); 13C NMR (63 MHz, CDCl3) d (ppm)
170.5 (C), 168.9 (C), 160.7 (C), 160.3 (C), 158.5 (2 × C), 137.3 (C),
134.9 (C), 134.6 (C), 134.3 (C), 134.1 (C), 133.8 (C), 132.7 (C),
132.6 (C), 130.9 (C), 130.3 (C), 129.7 (2 × CH), 128.9 (2 × CH),
128.7 (4 × CH + 4 × CH), 128.2 (2 × CH), 128.2 (2 × CH), 127.9
(2 × CH + 2 × CH), 113.7 (2 × CH), 113.4 (2 × CH), 74.0 (C),
73.8 (C), 69.1 (CH), 64.7 (CH), 55.24 (CH3), 55.20 55.2 (CH3), 52.7
55.2 (CH3), 51.8 55.2 (CH3), 46.8 (CH2), 46.0 (CH2), 42.0 (CH2),
41.8 (CH2), 29.0 (CH2), 28.8 (CH2), 20.0 (CH2), 19.9 (CH2), 13.74
(CH3), 13.67 (CH3); IR (KBr) 1707 (s), 1513 (s), 1244 (s); HRMS
(EI, 70 eV) calculated for C29H30Cl2N2O4 (M+) 540.1583, found
540.1587.
1-Butyl-4,5-bis(4-chlorophenyl)-3-(4-methoxybenzyl)-4-(meth-
oxycarbonyl)-4,5-dihydro-1H-imidazolium iodide 13. p-Methoxy-
benzyl bromide (1.46 g, 7.28 mmol) was added to a solution of
imidazoline 5 (2.95 g, 7.28 mmol) and NaI (1.09 g, 7.28 mmol) in
acetone (90 mL). The reaction mixture was stirred at rt for 18 h,
filtered and concentrated in vacuo to afford 13 (4.75 g, quant.)
1
as a 74 : 26 mixture of diastereomers as a white solid. H NMR
(400 MHz, CDCl3) d (ppm) 9.40 (s, 1H), 9.27 (s, 1H), 7.68 (d, J =
8.6 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.47–7.42 (m, 2H + 2H), 7.22
(d, J = 8.6 Hz, 2H), 7.16–7.07 (m, 6H + 2H), 6.96 (d, J = 8.5 Hz,
2H), 6.91–6.86 (m, 4H), 6.16 (s, 1H), 5.59 (s, 1H), 5.21 (d, J =
14.5 Hz, 1H), 4.66 (d, J = 14.5 Hz, 1H), 4.52 (d, J = 13.6 Hz, 1H),
4.35 (d, J = 13.7 Hz, 1H), 3.89 (s, 3H), 3.89–3.82 (m, 1H), 3.84
(s, 3H), 3.82 (s, 3H), 3.79–2.65 (m, 1H), 3.38–3.35 (m, 1H), 3.36
(s, 3H), 3.26–3.19 (m, 1H), 1.71–1.57 (m, 2H + 2H), 1.32–1.21 (m,
2H + 2H), 0.90–0.84 (m, 3H + 3H); 13C NMR (101 MHz, CDCl3)
d (ppm) 169.0 (C), 166.0 (C), 160.1 (C), 158.6 (2 × CH), 156.2
(C), 136.9 (C), 136.8 (C), 135.9 (C), 135.8 (C), 133.2 (C), 132.2
(C), 131.7 (2 × CH), 130.3 (2 × CH), 130.1 (2 × CH), 129.93 (C),
129.89 (2 × CH), 129.7 (2 × CH), 129.5 (2 × CH), 129.4 (2 ×
CH), 129.20 (2 × CH), 129.17 (2 × CH), 129.1 (2 × CH), 128.6
(C), 125.7 (C), 124.0 (C), 114.8 (2 × CH), 114.6 (2 × CH), 80.7
(C), 80.6 (C), 76.9 (CH), 71.4 (CH), 55.4 (CH3), 55.3 (CH3), 54.4
(CH3), 53.0 (CH3), 50.6 (CH2), 50.3 (CH2), 47.6 (CH2), 47.3 (CH2),
29.3 (CH2), 29.0 (CH2), 19.6 (CH2), 19.5 (CH2), 13.5 (CH3), 13.4
(CH3); IR (KBr) 1641 (s), 1513 (m), 1250 (s).
Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-oxoimidazolidine-4-
carboxylate 15. According to General Procedure II, deprotection
of imidazolidinone trans-14 (2.15 g, 3.97 mmol), followed by
column chromatography, afforded 15 (1.57 g, 94%) as a white
solid. 1H NMR (250 MHz, CDCl3) d (ppm) 7.66 (d, J = 8.8 Hz,
2H), 7.43–7.38 (m, 4H), 7.29 (d, J = 8.5 Hz, 2H), 7.13–7.09 (m,
6H), 6.91 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 5.50 (s, 1H), 5.47 (s,
1H), 4.77 (s, 1H), 3.82 (s, 3H), 3.65–3.51 (m, 1H + 1H), 3.35 (s,
3H), 2.60–2.48 (m, 1H + 1H), 1.47–1.35 (m, 2H), 1.33–1.13 (m,
2H + 2H), 1.10–1.07 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H), 0.77 (t,
J = 7.1 Hz, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 172.5 (C),
169.3 (C), 160.0 (C), 159.4 (C), 139.3 (C), 135.0 (C), 134.7 (C),
134.5 (C), 134.3 (C), 134.2 (C), 133.5 (C), 133.1 (C), 128.9 (2 ×
CH), 128.9 (2 × CH), 128.49 (2 × CH), 128.46 (2 × CH), 127.3
(4 × CH), 127.2 (4 × CH), 70.3 (CH), 69.4 (C), 68.9 (C), 65.7
(CH), 53.5 (CH3), 52.6 (CH3), 41.0 (CH2), 40.6 (CH2), 29.4 (CH2),
29.3 (CH2), 19.7 (CH2), 19.6 (CH2), 13.6 (CH3), 13.5 (CH3); IR
(KBr) 3233 (br), 2956 (m), 1701 (s), 1492 (s), 1231 (s), 1092 (s);
HRMS (EI, 70 eV) calculated for C21H22Cl2N2O3 (M+) 420.1007,
found 420.0989.
Methyl 1-butyl-4,5-bis(4-chlorophenyl)-3-(4-metho◦xybenzyl)-2-
oxoimidazolidine-4-carboxylate 14. To a cooled (0 C) solution
of imidazolinium iodide 13 (265 mg, 0.41 mmol) in DCM (8 mL),
85% mCPBA (247 mg, 1.22 mmol) was added. The yellow
solution abruptly turned dark orange. The reaction mixture was
stirred at rt for 18 h, while a colour change from dark orange
to light pink to dark red was observed. Then, the reaction
mixture was washed twice with saturated Na2CO3 (aq.), dried with
Na2SO4 and concentrated in vacuo. Purification using flash column
chromatography (pentane–EtOAc = 7 : 1, visualisation on TLC
with CerMOP [(NH4)6Mo7O24·4H2O (1.1 g L−1), Ce(SO4)2·4H2O
(4 g L−1) in H2SO4 (10%)]) afforded trans-14 (109 mg, 49%) and
cis-14 (36 mg, 16%) as white solids.
Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-thioxoimidazolidine-4-
carboxylate 16. According to General Procedure III, thionation
of imidazolidinone 15 (250 mg, 0.59 mmol), followed by column
1
trans-14 (most polar isomer): H NMR (250 MHz, CDCl3) d
1
(ppm) 7.42–7.27 (m, 8H), 7.17–7.06 (m, 8H), 6.88–6.62 (m, 2H +
4H), 6.60 (d, J = 8.7 Hz, 2H), 5.58 (s, 1H), 4.96 (d, J = 15.9 Hz,
1H), 4.81 (s, 1H), 4.35 (d, J = 15.1 Hz, 1H), 4.18–4.11 (m, 1H +
1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73–3.60 (m, 1H + 1H), 3.38 (s,
3H), 3.23 (s, 3H), 2.75–2.64 (m, 1H + 1H), 1.54–1.22 (m, 4H +
4H), 0.99–0.85 (m, 3H + 3H); 13C NMR (63 MHz, CDCl3) d (ppm)
170.5 (C), 168.9 (C), 160.7 (C), 160.3 (C), 158.5 (2 × C), 137.3 (C),
134.9 (C), 134.6 (C), 134.3 (C), 134.1 (C), 133.8 (C), 132.7 (C),
132.6 (C), 130.9 (C), 130.3 (C), 129.7 (2 × CH), 128.9 (2 × CH),
chromatography, afforded 16 as a white solid (245 mg, 94%). H
NMR (400 MHz, CDCl3) d (ppm) 7.63 (d, J = 8.7 Hz, 2H), 7.43
(d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.28–7.20 (m, 2H),
7.15–7.10 (m, 6H), 7.04 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 6.84
(s, 1H), 5.70 (s, 1H), 4.92 (s, 1H), 4.22–4.14 (m, 1H), 4.09–4.05
(m, 1H), 3.83 (s, 3H), 3.38 (s, 3H), 2.79–2.72 (m, 1H), 2.67–2.63
(m, 1H), 1.57–1.49 (m, 2H), 1.35–1.26 (m, 2H + 2H), 1.09–1.03
(m, 2H), 0.92 (t, J = 7.3 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C
NMR (101 MHz, CDCl3) d (ppm) 182.9 (C), 181.8 (C), 171.4 (C),
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167.9 (C), 136.2 (C), 135.5 (C), 135.2 (C), 134.7 (2 × C), 133.4 (C),
132.6 (C), 131.9 (C), 129.2 (2 × CH), 128.7 (4 × CH), 128.7 (4 ×
CH), 127.2 (4 × CH), 126.8 (2 × CH), 74.4 (CH), 72.4 (C), 72.2
(C), 69.7 (CH), 53.8 (CH3), 52.8 (CH3), 45.0 (CH2), 44.3 (CH2),
29.1 (CH2), 28.9 (CH2), 19.7 (CH2), 19.4 (CH2), 13.7 (CH3), 13.5
(CH3); IR (KBr) 3162 (br), 2952 (s), 1729 (s), 1593 (m), 1491 (s),
1231 (s); HRMS (EI, 70 eV) calculated for C21H22Cl2N2O2S (M+)
436.0779, found 436.0777.
7.09–6.92 (m, 8H + 4H), 5.73 (s, 1H), 4.95 (s, 1H), 3.78 (s, 3H),
3.31–3.21 (m, 1H + 1H), 3.25 (s, 3H), 2.85–2.79 (m, 1H + 1H),
1.37–1.06 (m, 4H + 4H), 0.71 (t, J = 7.2 Hz, 3H), 0.59 (t, J =
7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) d (ppm) 174.5 (C), 171.4
(C), 167.7 (C), 167.1 (C), 143.1 (2 × C), 135.9 (C), 134.5 (C), 133.3
(C), 132.6 (C), 132.4 (C), 131.9 (C), 130.0 (2 × C), 131.0 (CH),
130.8 (C), 130.2 (2 × CH), 129.6 (2 × CH), 129.1 (2 × CH), 128.99
(2 × CH), 128.97 (2 × CH + 2 × CH), 128.9 (2 × CH), 128.8 (2 ×
CH + 2 × CH), 128.7 (2 × CH), 128.6 (2 × CH), 128.2 (2 × CH),
82.8 (C), 82.6 (C), 75.4 (CH), 70.3 (CH), 53.5 (CH3), 52.6 (CH3),
45.9 (CH2), 45.8 (CH2), 30.6 (CH2), 30.1 (CH2), 19.8 (CH2), 19.4
(CH2), 13.9 (CH3), 13.7 (CH3); IR (KBr) 2928 (s), 1726 (s), 1490
(s), 1241 (s); HRMS (EI, 70 eV) calculated for C25H23Cl2N2 (M+ −
CO2Me) 421.1238, found 421.1223; the molecular ion could not
be detected.
General Procedure IV for the microwave-assisted
Liebeskind–Srogl reactions
A dry microwave vessel was charged with imidazolidine-2-thione
(0.25 mmol), aryl boronic acid (0.38 mmol), Cu(I) thiophene-
2-carboxylate (144.7 mg, 0.75 mmol) and Pd(PPh3)4 (8.9 mg,
7.5 lmol). The vessel was flushed with Ar and sealed. Dry
DMF was added through the septum and the reaction mixture
was irradiated in the microwave at 130 ◦C for 1 h, unless
stated otherwise. After cooling, DMF was removed in vacuo at
50 ◦C. The crude mixture was diluted with saturated NaHCO3
(aq.) and extracted with DCM. The organic layer was washed
twice with saturated NaHCO3 (aq.), dried with Na2SO4 and
concentrated in vacuo. Purification was performed with flash
column chromatography (c-hexane–EtOAc–Et3N = 5 : 1 : 0.01,
gradient).
Methyl 1-butyl-4,5-bis(4-chlorophenyl)-2-(4-methoxyphenyl)-
4,5-dihydro-1H-imidazole-4-carboxylate
20. According
to
General Procedure IV, arylation of imidazolidin-2-thione 16
(109 mg, 0.25 mmol) with p-methoxyphenyl boronic acid (58 mg,
0.38 mmol) followed by column chromatography afforded 20
(71 mg, 55%) as a yellow solid, together with starting material
1
16 (14 mg, 13%). H NMR (250 MHz, CDCl3) d (ppm) 7.81 (d,
J = 8.5 Hz, 2H), 7.68–7.60 (m, 2H + 2H), 7.39–7.36 (m, 2H),
7.08–6.90 (m, 10H + 6H), 5.70 (s, 1H), 4.90 (s, 1H), 3.87 (s, 3H +
3H), 3.77 (s, 3H), 3.33–3.23 (m, 1H + 1H), 3.23 (s, 3H), 2.88–2.80
(m, 1H + 1H), 1.33–1.01 (m, 4H + 4H), 0.85 (t, J = 6.0 Hz, 3H),
0.72 (t, J = 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) d (ppm)
174.6 (C), 171.6 (C), 167.5 (C), 166.9 (C), 161.8 (C), 161.7 (C),
143.3 (2 × C), 137.5 (C), 136.2 (C), 134.6 (C), 134.0 (C), 133.7
(C), 133.3 (C), 130.7 (2 × CH), 130.5 (2 × CH), 130.2 (2 × CH +
2 × CH), 129.6 (2 × CH), 129.1 (2 × CH), 128.8 (2 × CH), 128.7
(2 × CH), 128.6 (2 × CH), 128.1 (2 × CH), 123.1 (C), 123.0 (C),
114.6 (2 × CH), 114.3 (2 × CH), 82.8 (C), 82.5 (C), 75.5 (CH),
70.3 (CH), 55.8 (CH3 + CH3), 53.5 (CH3), 52.5 (CH3), 46.3 (CH2),
46.2 (CH2), 30.2 (CH2), 30.1 (CH2), 20.1 (CH2), 19.8 (CH2), 14.0
(CH3), 13.8 (CH3); IR (KBr) 2924 (s), 1734 (s), 1611 (s), 1490 (s),
trans-Methyl
4,5-bis(4-chlorophenyl)-1-methyl-2-phenyl-4,5-
dihydro-1H-imidazole-5-carboxylate 17. According to General
Procedure IV, arylation of imidazolidin-2-thione 12 (100 mg,
0.25 mmol) with phenyl boronic acid (46 mg, 0.38 mmol) followed
by column chromatography afforded 17 (56 mg, 51%) as a yellow
1
solid together with starting material 12 (2 mg, 2%). H NMR
(250 MHz, CDCl3) d (ppm) 7.79–7.68 (m, 2H), 7.57–7.45 (m,
3H), 7.06 (d, J = 8.6 Hz, 2H), 7.03 (s, 4H), 6.79 (d, J = 8.5 Hz,
2H), 5.96 (s, 1H), 3.97 (s, 3H), 2.87 (s, 3H); 13C NMR (63 MHz,
CDCl3) d (ppm) 173.2 (C), 165.5 (C), 137.4 (C), 133.6 (C), 133.0
(C), 132.5 (C), 130.8 (C), 130.8 (CH), 129.5 (2 × CH), 128.7 (2 ×
CH), 128.5 (2 × CH), 128.4 (2 × CH), 128.1 (2 × CH), 127.6 (2 ×
CH), 81.1 (C), 76.0 (CH), 52.9 (CH3), 33.0 (CH3); IR (KBr) 1726
(s), 1589 (m), 1487 (m), 1379 (m), 1231 (m); HRMS (EI, 70 eV)
calculated for C24H20Cl2N2O2 (M+) 438.0902, found 438.0883.
1251 (s); HRMS (EI, 70 eV) calculated for C26H25Cl2N2 (M+
CO2Me) 451.1344, found 451.1336; the molecular ion could not
be detected.
−
trans-Methyl 4,5-bis(4-chlorophenyl)-2-(4-methoxyphenyl)-1-
methyl-4,5-dihydro-1H-imidazole-5-carboxylate 18. According
to General Procedure IV, arylation of imidazolidin-2-thione 12
(100 mg, 0.25 mmol) with p-methoxyphenyl boronic acid (58 mg,
0.38 mmol) followed by column chromatography afforded 18
(48 mg, 41%) as a yellow solid, together with starting material 12
Acknowledgements
Part of this work was performed with financial support from
the Dutch Science Foundation (NWO-VICI). Dr M. T. Smoluch
(VUA) is kindly acknowledged for the (HR)MS measurements.
1
(5 mg, 5%). H NMR (250 MHz, CDCl3) d (ppm) 7.69 (d, J =
8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.01 (br s, 6H), 6.77 (d,
J = 8.5 Hz, 2H), 5.92 (br s, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 2.89 (s,
3H); IR (KBr); HRMS (EI, 70 eV) calculated for C25H22Cl2N2O3
(M+) 468.1007, found 468.1002.
References and notes
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1
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