A new route to 4-ethynyl-N-hydroxy-2-imidazolidinones via oxime addition

Article abstract of DOI:10.1016/S0040-4020(00)00306-9

A rapid route was developed to afford ethynyl-substituted imidazole derivatives which served as key compounds for arylalkynyl-coupling reactions. Addition of mono-silylated acetylene to O-protected oximes was carried out in the absence of Lewis acids, directly affording the title compounds 3a-c in a one-pot reaction. Limitations and dependence of the feasibility on N¹- substituents are discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00306-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3697±3701
A New Route to 4-Ethynyl-N-hydroxy-2-imidazolidinones via
Oxime Addition
*
Thomas Ullrich, Peter Sulek, Dieter Binder and Michael Pyerin
Institute of Organic Chemistry, Vienna University of Technology, Getreidemarkt 9/154/4, A-1060 Vienna, Austria
Received 3 February 2000; revised 31 March 2000; accepted 12 April 2000
AbstractÐA rapid route was developed to afford ethynyl-substituted imidazole derivatives which served as key compounds for aryl±
alkynyl-coupling reactions. Addition of mono-silylated acetylene to O-protected oximes was carried out in the absence of Lewis acids,
directly affording the title compounds 3a±c in a one-pot reaction. Limitations and dependence of the feasibility on N1-substituents are
discussed. q 2000 Elsevier Science Ltd. All rights reserved.
In the course of our studies on novel NSAIDs (non-steroidal
anti-in¯ammatory drugs), we developed a synthetic route to
ethynyl-substituted cyclic N-hydroxyureas 3a±c in few
steps, starting from cheap commercial materials and provid-
ing unlimited variety of N1-substituents (alkyl and aryl).
The key reaction represents a nucleophilic addition of
TMS-protected lithium acetylide to an isomeric mixture of
the appropriate oxime ethers 1a±c which were obtained
through routine chemistry in three steps and high yields,
followed by double deprotection of compounds 2a±c
(Schemes 1 and 2). Acetals 4a±c were synthesized accord-
ing to the literature,1 acylated and hydrolyzed to aldehydes
5a±c, and reacted with O-methoxymethyl(MOM)-protected
hydroxylamine derived from phthalimide 62 with methyl-
hydrazine.
Often, poor conversions have been observed for this reac-
tion type. Uno et al. reported formation of hydroxylamines
in moderate to good yields by adding various nucleophiles
across C±N double bonds of (Z)-oximes in toluene and in
the presence of BF3 as precomplexating agent and anion
scavenger in this solvent.4 We found that addition of our
nucleophilic agent, (trimethylsilyl)ethynyl lithium salt,5 in
the absence of any Lewis acid, led to immediate cyclization
when treated with the isomeric mixture of oxime ethers
1a±c, probably via formation of a reactive, negative-
charged hydroxylamino species I that underwent intra-
molecular reaction with the carbon atom of the carbamic
ester group (Scheme 3). The (E)-isomer remained inert to
the chosen conditions.
This step was optimized by variation of solvent and
temperature. Diethyl ether was preferable to other solvents
such as toluene or THF, as the formed lithium salt (LiOMe;
LiOPh) precipitated from the solution. Low temperatures
promoted the selectivity of the reaction but also reduced
solubility of the reactants. Best results were achieved at
158C and afforded 49±72% referred to the (Z)-oxime
NMR spectroscopic analysis of 1a±c revealed E/Z isomers
ranging from 60:40 to 40:60, thus affecting yields of the
following addition reaction, as the (Z)-isomers of similar,
a-hydrogen containing oxime ethers are known to react
preferentially in addition reactions with organometallic
compounds.3
Scheme 1.
Keywords: cyclization; addition; oximes; cyclic hydroxyurea; imidazole; protective groups.
* Corresponding author. E-mail: mpyerin@mail.zserv.tuwien.ac.at
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00306-9

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T. Ullrich et al. / Tetrahedron 56 (2000) 3697±3701
Scheme 2. Reagents: (i) K2CO3, DMF, 608C; (ii) (a) Cl-COOR0, NaHCO3(aq.), THF, rt; (b) 2N HCl, 558C; (iii) CH3NHNH2, Et2O, 08C.
Scheme 3. Reagents: (i) THF, 158C.
(Table 1). No improvement could be accomplished by
varying other conditions such as molar ratios of reactants.
Modest yields of this reaction were mainly contributed to a
competing elimination process (structures I and III) which
resulted in the corresponding carbamate IV and methyl-
oxime V as side products (30±40%), as deduced from H
NMR analysis (Scheme 4). The by-products and unchanged
(E)-oxime could be removed by ¯ash chromatography.
R0 did not affect yields. Table 1 summarizes yields obtained
for each of the substituents.
Cleavage of the MOM group in compounds 2a±c was
performed with 4N methanolic HCl6 and subsequent treat-
ment with K2CO3 for alkaline cleavage of TMS7 (Scheme
5). The obtained title compounds 3a±c could be easily
puri®ed by recrystallization.
1
The choice of the carbamic ester residue R0 played an
important role, as deterioration of the conversion was
observed for increasing 1I effects exhibited by the
N-substituent R. For the cyclization of the methyl derivative
2a it was essential to use R0ˆPh due to its better leaving
group properties. R0ˆMe gave no considerable conversion
in this case. For both aryl compounds 2b and 2c change of
The presence of the unprotected N-hydroxyurea group did
not adversely affect the desired aryl±alkynyl Stille-type
coupling reaction, using 5-[(4-¯uorophenyl)methyl)]-2-
iodothiophene 7 as a well-known lipid binding template8
that we employed in our studies. This reaction was carried
out in dry THF and excess diisopropylamine, with
Pd(PPh3)4 and copper(I)iodide as catalysts9 (Scheme 6).
Products 8a±c were purely obtained in 50±60% yield
after work-up and recrystallization.
Table 1. Yields of one-pot addition/cyclization in dependence of substitu-
ents
Product
R
R0
Yield (%)
Conclusions
2a
2b
2c
Me
Ph
4-MeOPh
Ph
Me
Me
49
72
63
Although the one-pot addition/cyclization was over-
shadowed by lack of selectivity, the method described

T. Ullrich et al. / Tetrahedron 56 (2000) 3697±3701
3699
Scheme 4.
represents a new synthetic route which is quick, cheap
and easy to handle. The obtained alkynyl-substituted
N-hydroxy-imidazolidinones served as substrates for aryl±
alkynyl coupling, thus proving their usefulness as synthons.
Due to the facile synthesis of the precursor compounds, a
reasonable overall yield could be achieved.
assignments are pointed out (p). The following abbrevia-
tions are used to indicate spin multiplicities: s (singlet), bs
(broad singlet), d (doublet), dd (doublet of doublets), t
(triplet) or m (multiplet). Elemental analyses (C, H, and
N) were performed by the Microanalytical Laboratory,
Institute of Physical Chemistry at Vienna University,
Austria.
Experimental
General procedure for the formation of aldehydes 5a±c
Unless otherwise indicated, all reagents were purchased
from commercial suppliers and used without further puri®-
cation. TLC analyses were carried out on precoated silica
gel plates (Merck 60 F254), and spots were visualized with
UV light. Chromatography refers to ¯ash chromatography
using Fluka silica gel 60, 220±240 mesh. Melting points
To a stirred, saturated solution of NaHCO3 (1100 ml) was
added dropwise a solution of the appropriate acetal 4a±c
(0.619 mol) in THF (1100 ml), followed by addition of
methyl chloroformiate (1.36 mol) at room temperature.
After stirring for 15 h, the organic layer was separated and
evaporated, and the aqueous phase was extracted with
ether. The combined organic layers were dried (Na2SO4),
evaporated and short-path distilled in vacuo for puri®cation.
The distillate was taken up in excess 6N hydrochloric acid
and vigorously stirred at 558C for 30 min. After cooling
down to room temperature, the organic layer was separated,
and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4), evaporated
and short-path distilled to yield 5b and 5c in 84 and 91%
yield, respectively. 5a was obtained by reaction with phenyl
chloroformiate and passed on to the subsequent step imme-
diately after hydrolysis without work-up.
1
were measured on a Ko¯er bank and are uncorrected. H
NMR spectra were recorded on a Bruker 200FS FT-NMR-
spectrometer and are reported as ppm down®eld from Me4Si
with multiplicity, number of protons, and coupling
constant(s) in Hertz indicated parenthetically. Ambiguous
(2-Oxoethyl)phenylcarbamic acid methyl ester (5b). This
compound was obtained as a bright yellow liquid, bp 1058C
(0.5 mbar); Rf (PE/EtOAc 2:1) 0.3; H NMR (CDCl3): d
1
3.72 (s, 3H, O±CH3), 4.39 (s, 2H, CH2); 7.19±7.30 (m,
3H, phenyl), 7.31±7.41 (m, 2H, phenyl), 9.69 (s, 1H,
Scheme 5. Reagents: (i) 4N methanolic HCl, 408C; (ii) K2CO3, 258C.
Scheme 6. Reagents: (i) Pd(PPh3)4, CuI, (iPr)2NH, THF, 258C.

3700
T. Ullrich et al. / Tetrahedron 56 (2000) 3697±3701
CHO). Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N,
7.25. Found: C, 62.00; H, 5.73; N, 7.28.
Jˆ6 Hz), 7.56 (t, 1H, CH, Jˆ5 Hz). Anal. Calcd for
C13H18N2O5: C, 55.31; H, 6.43; N, 9.92. Found: C, 55.19;
H, 6.26; N, 10.08.
(2-Oxoethyl)(4-methoxyphenyl)carbamic acid methyl
ester (5c). This compound was obtained as a brownish
General procedure for the one-pot addition/cyclization
1
oil, bp 958C (0.1 mbar); Rf (PE/EtOAc 3:1) 0.2; H NMR
(CDCl3): d 3.72 (s, 3H, O±CH3), 3.80 (s, 3H, OCH3), 4.37
(s, 2H, CH2); 6.88 (d, 2H, phenyl, Jˆ8 Hz), 7.18 (d, 2H,
phenyl, Jˆ8 Hz), 9.70 (s, 1H, CHO). Anal. Calcd for
C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.49;
H, 6.06; N, 6.06.
A solution of freshly prepared (trimethylsilyl)acetylene
lithium salt (178 mmol) in dry ether (200 ml) was added
to a solution of the appropriate oxime ether 1a±c
(60.6 mmol) under a nitrogen atmosphere at 158C. After
stirring for 25 min at room temperature, the mixture was
quenched with aqueous NaHCO3, and the organic layer
was separated. The aqueous layer was extracted with
ether, and the combined organic phases were washed with
brine, dried (Na2SO4) and evaporated to an oily residue.
General procedure for the formation of oxime ethers
1a±c
2-[(Methoxy)methoxy]-2H-isoindol-1(3H),3-dione 6 (23.0 g,
111 mmol) was suspended in dry ether (250 ml) under a
nitrogen atmosphere. To the vigorously stirred mixture
was added dropwise methylhydrazine (4.97 g, 108 mmol)
at 08C, followed by warming to room temperature and
stirring for 4 h. The precipitate was ®ltered off, and the
®ltrate containing free O-(methoxymethyl)hydroxylamine
(103 mmol) was dropped to a solution of the appropriate
aldehyde 5a±c (82 mmol) in dry ether. After stirring for
1 h under nitrogen, the mixture was washed with 2N HCl,
and the aqueous layer re-extracted three times with ether.
The combined organic layers were dried (Na2SO4) and
evaporated. The oily residue was puri®ed by ¯ash chromato-
graphy (silica gelÐtoluene/EtOAc 3:1) to give 1a±c in 98,
85 and 95% yield, respectively.
3-[(Methoxy)methoxy]-1-methyl-4-[2-(trimethylsilyl)-
ethynyl]-2-imidazolidinone (2a). The crude product was
puri®ed by ¯ash chromatography (silica gelÐPE/EtOAc
5:2) to give a yellow oil (49%); Rf (PE/EtOAc 2:1) 0.4;
1H NMR (CDCl3): d 0.18 (s, 9H, Si±CH3), 2.82 (s, 3H,
N±CH3), 3.25 (dd, 1H, CH2a, Jˆ8 Hz, 8), 3.48 (dd, 1H,
CH2b, Jˆ8, 8 Hz), 3.58 (s, 3H, O±CH3), 4.28 (dd, 1H,
CH, Jˆ8, 8 Hz), 4.94 (d, 1H, O±CH2a, Jˆ7 Hz), 5.03 (d,
1H, O±CH2b, Jˆ7 Hz). Anal. Calcd for C11H20N2O3Si: C,
51.53; H, 7.86; N, 10.93. Found: C, 52.01; H, 7.68; N, 10.47.
3-[(Methoxy)methoxy]-1-phenyl-4-[2-(trimethylsilyl)-
ethynyl]-2-imidazolidinone (2b). The crude product was
recrystallized from n-hexane to give colorless crystals
(72%); mp 75±768C;) Rf (PE/ether 2:1 0.3; 1H NMR
(CDCl3): d 0.18 (s, 9H, Si±CH3), 3.63 (s, 3H, O±CH3),
3.76 (dd, 1H, CH2a, Jˆ8, 8 Hz), 3.92 (dd, 1H, CH2b, Jˆ8,
8 Hz), 4.46 (dd, 1H, CH, Jˆ8, 8 Hz), 5.01 (d, 1H, O±CH2a,
Jˆ7 Hz), 5.11 (d, 1H, O±CH2b, Jˆ7 Hz), 7.12 (t, 1H,
phenyl, Jˆ8 Hz), 7.35 (t, 2H, phenyl, Jˆ8 Hz), 7.52 (d,
2H, phenyl, Jˆ8 Hz). Anal. Calcd for C16H22N2O3Si: C,
60.35; H, 6.96; N, 8.80. Found: C, 60.62; H, 6.85; N, 8.85.
[[(Methoxy)methoxyimino]ethyl]methylcarbamic acid
phenyl ester (1a). This compound was obtained as a
1
yellowish oil; Rf (PE/ether 1:1) 0.1; H NMR (CDCl3): d
2.99±3.17 (m, 3H, N±CH3), 3.44 (s, 3H, O±CH3), 4.18 (d,
2H, N±CH2, Jˆ6 Hz), 4.32 (d, 2H, N±CHp2, Jˆ4 Hz), 5.09
(s, 2H, O±CH2), 5.13 (s, 2H, O±CHp2), 6.90 (t, 1H, CHp,
Jˆ4 Hz), 7.09±7.28 (m, 3H, phenyl), 7.29±7.41 (m, 2H,
phenyl), 7.54 (t, 1H, CH, Jˆ6 Hz). Anal. Calcd for
C12H16N2O4: C, 57.13; H, 6.39; N, 11.10. Found: C,
57.38; H, 6.66; N, 11.09.
3-[(Methoxy)methoxy]-1-(4-methoxyphenyl)-4-[2-(tri-
methylsilyl)ethynyl]-2-imidazolidinone (2c). The crude
product was puri®ed by ¯ash chromatography (silica
gelÐPE/EtOAc 4:1) and obtained as colorless crystals
[[(Methoxy)methoxyimino]ethyl]phenylcarbamic acid
methyl ester (1b). This compound was obtained as a color-
1
(63%), mp 107±1088C; Rf (PE/EtOAc 3:1) 0.7; H NMR
1
less oil; Rf (toluene/EtOAc 3:1) 0.5; H NMR (CDCl3): d
(CDCl3): d 0.15 (s, 9H, Si±CH3), 3.63 (s, 3H, O±CH3), 3.74
(s, 3H, O±CH3), 3.88 (dd, 1H, CH2a, Jˆ8, 8 Hz), 4.12 (dd,
1H, CH2b, Jˆ8, 8 Hz), 4.46 (dd, 1H, CH, Jˆ8, 8 Hz), 5.01
(d, 1H, O±CH2a, Jˆ7 Hz), 5.09 (d, 1H, O±CH2b, Jˆ7 Hz),
6.87 (d, 2H, phenyl, Jˆ8 Hz), 7.41 (d, 2H, phenyl, Jˆ8 Hz).
Anal. Calcd for C17H24N2O4Si: C, 58.59; H, 6.94; N, 8.04.
Found: C, 58.88; H, 7.05; N, 8.13.
3.37 (s, 3H, O±CH3), 3.38 (s, 3H, O±CHp3), 3.71 (s, 3H,
O±CH3), 3.73 (s, 3H, O±CHp3), 4.40 (d, 2H, N±CH2,
Jˆ5 Hz), 4.61 (d, 2H, N±CH2p, Jˆ3 Hz), 5.03 (s, 2H,
O±CH2), 5.09 (s, 2H, O±CHp2), 6.95 (t, 1H, CHp,
Jˆ3 Hz), 7.13±7.42 (m, 5H, phenyl), 7.59 (t, 1H, CH,
Jˆ5 Hz). Anal. Calcd for C12H16N2O4: C, 57.13; H, 6.39;
N, 11.10. Found: C, 57.35; H, 6.21; N, 10.98.
[[(Methoxy)methoxyimino]ethyl]-(4-methoxyphenyl)car-
bamic acid methyl ester (1c). This compound was obtained
as a yellowish oil; Rf (PE/EtOAc 3:1) 0.4; 1H NMR
(CDCl3): d 3.37 (s, 3H, O±CH3), 3.38 (s, 3H, O±CHp3),
3.69 (s, 3H, O±CH3), 3.71 (s, 3H, O±CHp3), 3.78 (s, 3H,
O±CH3), 3.80 (s, 3H, O±CHp3), 4.37 (d, 2H, N±CH2,
Jˆ5 Hz), 4.63 (d, 2H, N±CHp2, Jˆ3 Hz), 5.02 (s, 2H,
O±CH2), 5.07 (s, 2H, O±CHp2), 6.83 (d, 2H, phenyl,
Jˆ6 Hz), 6.89 (d, 2H, phenylp, Jˆ6 Hz), 7.09 (t, 1H, CHp,
Jˆ3 Hz), 7.10 (d, 2H, phenyl, Jˆ6 Hz), 7.14 (d, 2H, phenyl,
General procedure for deprotection
The protected imidazolidinone 2a±c (2.92 mmol) was
dissolved in a 4 N solution of HCl in dry MeOH(40 ml)
and stirred at 408C for 3 h. Water (50 ml) was added, and
the solution was extracted with EtOAc. The combined
organic layers were dried (Na2SO4) and evaporated. The
residue was dissolved in dry MeOH (30 ml), and anhydrous
K2CO3 (560 mg, 4.05 mmol) was added. After stirring for
4 h at room temperature, the suspension was taken up in

T. Ullrich et al. / Tetrahedron 56 (2000) 3697±3701
3701
water (30 ml) and extracted with EtOAc. The combined
organic layers were dried (Na2SO4) and evaporated.
phenyl), 9.38 (br s, 1H, OH). Anal. Calcd for
C17H15FN2O2S: C, 61.80; H, 4.58; N, 8.48. Found: C,
61.94; H, 4.78, N, 8.39.
4-Ethynyl-3-hydroxy-1-methyl-2-imidazolidinone (3a).
The crude product was digested with ether to give colorless
4-[[5-(4-Fluorophenyl)methyl]-2-thienyl]ethynyl]-3-hy-
droxy-1-phenyl-2-imidazolidinone (8b). The product was
recrystallized from toluene to give colorless crystals (60%);
mp 119±1208C; Rf (toluene/EtOAc 3:1) 0.4; 1H NMR
(CDCl3): d 3.77 (dd, 1H, CH2a, Jˆ8, 8 Hz), 4.10 (dd, 1H,
CH2b, Jˆ8, 8 Hz), 4.15 (s, 2H, thienyl-CH2), 4.71 (dd, 1H,
CH, Jˆ8, 8 Hz), 6.85 (d, 1H, thienyl, Jˆ4 Hz), 7.12 (dd,
2H, phenyl, Jˆ9, 1 Hz), 7.20 (d, 1H, thienyl, Jˆ4 Hz),
7.31±7.25 (m, 3H, ¯uorophenyl, phenyl), 7.36 (dd, 2H,
phenyl, Jˆ9, 1 Hz), 7.67 (dd, 2H, ¯uorophenyl, Jˆ8,
1 Hz), 9.63 (br s, 1H, OH). Anal. Calcd for
C22H17FN2O2S: C, 67.33; H, 4.37; N, 7.14. Found: C,
67.40; H, 4.51, N, 7.07.
1
crystals (80%), mp 149±1518C; Rf (PE/EtOAc 1:1) 0.5; H
NMR (dmso-d6): d 2.69 (s, 3H, N±CH3), 3.12 (dd, 1H,
CH2a, Jˆ8, 8 Hz), 3.41 (d, 1H, ethyne-H, Jˆ2 Hz), 3.52
(dd, 1H, CH2b, Jˆ8, 8 Hz), 4.14 (dd, 1H, CH, Jˆ8, 8 Hz),
9.32 (br s, 1H, OH). Anal. Calcd for C6H8N2O2: C, 51.42; H,
5.75; N, 19.99. Found: C, 51.46; H, 5.73, N, 19.74.
4-Ethynyl-3-hydroxy-1-phenyl-2-imidazolidinone (3b).
The crude product was recrystallized from toluene to give
colorless crystals (85%), mp 157±1608C. Rf (PE/ether 1:2)
0.5; 1H NMR (dmso-d6): d 3.49 (d, 1H, ethyne-H, Jˆ2 Hz),
3.62 (dd, 1H, CH2a, Jˆ8, 8 Hz), 4.03 (dd, 1H, CH2b, Jˆ8,
8 Hz), 4.43 (dd, 1H, CH, Jˆ8, 8 Hz), 7.12 (t, 1H, phenyl,
Jˆ8 Hz), 7.36 (t, 2H, phenyl, Jˆ8 Hz), 7.55 (d, 2H, phenyl,
Jˆ8 Hz), 9.69 (s, 1H, OH). Anal. Calcd for C11H10N2O2: C,
65.34; H, 4.98; N, 13.85. Found: C, 65.46; H, 5.11, N, 13.73.
4-[[5-[(4-Fluorophenyl)methyl]-2-thienyl]ethynyl]-3-hy-
droxy-1-(4-methoxyphenyl)-2-imidazolidinone (8c). The
product was triturated with methyl t-butyl ether to give
colorless crystals (56%), mp 134±1358C; Rf (toluene/
EtOAc 3:1) 0.35; 1H NMR (CDCl3): d 3.75 (dd, 1H,
CH2a, Jˆ8, 8 Hz), 3.78 (s, 3H, O±CH3), 3.94 (dd, 1H,
CH2b, Jˆ8, 8 Hz), 4.08 (s, 2H, thienyl-CH2), 4.62 (dd, 1H,
CH, Jˆ8, 8 Hz), 6.63 (d, 1H, thienyl, Jˆ4 Hz), 6.87 (d, 2H,
phenyl, Jˆ8 Hz), 7.00±7.18 (m, 2H, ¯uorophenyl), 7.19 (d,
1H, thienyl, Jˆ4 Hz), 7.20 (dd, 2H, ¯uorophenyl, Jˆ8,
8 Hz), 7.42 (d, 2H, phenyl, Jˆ8 Hz), 9.71 (br s, 1H, OH).
Anal. Calcd for C23H19FN2O3S: C, 65.39; H, 4.55; N, 6.63.
Found: C, 65.65; H, 4.85, N, 6.61.
4-Ethynyl-3-hydroxy-1-(4-methoxyphenyl)-2-imidazoli-
dinone (3c). The crude product was digested with acetone to
give colorless crystals (81%), mp 143±1458C (decomp.); Rf
1
(PE/EtOAc 1:1) 0.4; H NMR (dmso-d6): d 3.50 (d, 1H,
ethyne-H, Jˆ2 Hz), 3.63 (dd, 1H, CH2a, Jˆ8, 8 Hz), 3.72
(s, 3H, O±CH3), 4.01 (dd, 1H, CH2b, Jˆ8, 8 Hz), 4.42 (dd,
1H, CH, Jˆ8, 8 Hz), 6.95 (d, 2H, phenyl, Jˆ8 Hz), 7.48 (d,
2H, phenyl, 6, Jˆ8 Hz), 9.63 (br s, 1H, OH). Anal. Calcd for
C15H20N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C, 61.88;
H, 5.43, N, 11.96.
General procedure for aryl±alkynyl coupling
Acknowledgements
The deprotected imidazolidinone 3a±c (2.47 mmol), pal-
ladium tetrakis(triphenylphosphine) (64 mg, 0.060 mmol)
and copper(I)iodide (23 mg, 0.120 mmol) were suspended
in dry THF (30 ml) and stirred for 5 min at room tempera-
ture. 5-[(4-¯uorophenyl)methyl]-2-iodothiophene 7 (788 mg,
2.47 mmol) was added to the mixture, followed by another
5 min of stirring and addition of diisopropylamine (3.5 ml,
34.6 mmol). After 2 h of stirring, the mixture was quenched
with 2 N HCl (100 ml), and the organic layer was separated.
The aqueous phase was extracted with ether, and the
combined organic layers were washed with a NaHCO3 solu-
tion, dried (Na2SO4) and evaporated to give a solid, which
was triturated with cold diisopropyl ether and puri®ed by
¯ash chromatography (silica gelÐtoluene/EtOAc 3:1).
We wish to thank Mrs Ines Elhofer and Mr Otto Schweizer
for their help in synthesizing the starting materials.
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droxy-1-methyl-2-imidazolidinone (8a). The product was
triturated with cold acetone to give colorless crystals (52%),
mp 143±1448C; Rf (PE/EtOAc 2:5) 0.4; 1H NMR (CDCl3):
d 2.69 (s, 3H, N±CH3), 3.18 (dd, 1H, CH2a, Jˆ8, 8 Hz), 3.58
(dd, 1H, CH2b, Jˆ8, 8 Hz), 4.13 (s, 2H, thienyl-CH2), 4.42
(dd, 1H, CH, Jˆ8, 8 Hz), 6.85 (d, 1H, thienyl, Jˆ4 Hz),
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