Slow interconversion of enantiomeric conformers or atropisomers of anilide and urea derivatives of 2-substituted anilines

Article abstract of DOI:10.1039/b507202f

N-Acylated 2-substituted anilines undergo slow Ar-N bond rotation, allowing in some cases isolation of enantiomeric or diastereoisomeric atropisomers and in others the determination of the rate of Ar-N bond rotation by NMR. 2-Iodoanilides bearing a branch

Full text of DOI:10.1039/b507202f

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A R T I C L E
Slow interconversion of enantiomeric conformers or atropisomers of
anilide and urea derivatives of 2-substituted anilines
Thomas Adler,a Josep Bonjoch,b Jonathan Clayden,*a Merce` Font-Bard´ıa,c Mark Pickworth,a
Xavier Solans,c Daniel Sole´b and Llu´ıs Vallverdu´a,b
a School of Chemistry, University of Manchester, Oxford Road, Manchester, UK M13 9PL
b Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, Universitat de Barcelona, Av. Joan
XXIII s/n, 08028 Barcelona, Spain
c Department de Cristal·lografia, Mineralogia i Dipo`sits Minerals, Universitat de Barcelona,
Mart´ı i Franque`s s/n, 08028 Barcelona, Spain
Received 23rd May 2005, Accepted 29th June 2005
First published as an Advance Article on the web 26th July 2005
N-Acylated 2-substituted anilines undergo slow Ar–N bond rotation, allowing in some cases isolation of
enantiomeric or diastereoisomeric atropisomers and in others the determination of the rate of Ar–N bond rotation
by NMR. 2-Iodoanilides bearing a branched N-substituent demonstrate sufficient enantiomeric stability to be
resolvable, either by HPLC or by formation of diastereoisomeric lactanilide derivatives. For the first time, the rates of
Ar–N rotation in 2-substituted N,Nꢀ-diarylureas have been established: they mainly fall in the region of
50–70 kJ mol−1 with a relatively weak dependence on substituent size.
may be detected by NMR.26–28 † The only known exceptions
Introduction
to date are derivatives of 2-tert-butyl anilines, whose anilide
A growing interest, over the last decade, in the potential
derivatives are sufficiently hindered to exist as atropisomers
of non-biaryl atropisomers in synthesis1,2 and in medicinal
even without a 6-substituent.20 Mindful of the requirement
chemistry3 has prompted investigations into the stereoselec-
for 2,6-disubstitution, recent work by Curran has employed
tivity of their reactions,4–8 their enantioselective synthesis,8–14
a “dummy” 6-trimethylsilyl substituent to allow the retention
and their use as chiral auxiliaries11,15,16 and chiral ligands.9,17
of axial stereochemistry in reactions of anilides which would
Many of these studies have involved compounds such as
otherwise racemise rapidly.25 Conformational interconversion
benzamides 1,2,7,14,18 or maleimides, succinimides and anilides
is also possible around the N–CO bond of 3, but when the
carbonyl substituent is small (Me for example, as in acetanilides)
2 and 3.5,6,8,11–13,16,19–21 These amide-type functional groups have
featured highly because the rigidity of the amide raises the
barrier to conformational interconversion and increases the
likelihood that conformers may exist as separable atropisomers.
=
only the N–CO conformer shown (which has Ar and the C O
group trans) is detectable by NMR.20 The alternative N–CO
bond rotation has been studied in some depth in a range of
In this paper we report our exploration of the rates of confor-
ureas,23,24 and is consistently significantly faster than that in the
mational interconversions in some subclasses of 3: anilides 4
corresponding amides.
bearing a single 2-iodo substituent, 2-substituted N-alkyl-N,Nꢀ-
diarylureas 5 and N,Nꢀ-dialkyl-N,Nꢀ-diarylureas 6. We reveal
Results and discussion
that iodoanilides 4 carrying a branched N-alkyl substituent turn
In connection with studies on the palladium-catalysed cycli-
sation reactions of iodoarylaminoketones,30,31 we had made
some 2-iodoanilides. Some of these compounds showed slow
rotation in their NMR spectra. Both 4a and 4b, for example,
out to have a remarkably high barrier to rotation, giving rise to
atropisomerism without the need for further heavy substitution.
While the conformational preferences of 5 and 6 have been
studied22 their rates of racemisation have until now remained
unexplored.23,24
ꢀ
ꢀ
exhibited diastereotopic protons Ha and Hb (and Ha and Hb
for 4a), indicating transient chirality which we ascribe to slow
rotation (on the NMR timescale) about the ArC–N bond
(Scheme 1). While anilide 4a existed as a single conformer
about its N–CO bond, simplifying its analysis by NMR,20
4b was a mixture of N–CO geometrical conformers. Variable
temperature NMR spectroscopy of 4b allowed us to estimate,
using the lineshape modelling program gNMR,‡ a value of
Scheme 1 Anilides exhibiting slow Ar–N rotation.
In general, atropisomerism is a feature of anilides 3 only
when X and Y = H: in other words, only derivatives of 2,6-
disubstituted anilines are usually atropisomeric,20,25 though the
interconverting conformers of mono-orthosubstituted anilides
† Benzamides similarly are atropisomeric generally only when they are
2,6-disubstituted,29a with the exception of certain peri-substituted 1-
naphthamides.29b
‡ Cherwell Scientific.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
3 1 7 3
©

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Fig. 1 HPLC trace of 4a [chiral stationary phase: Chiralcel OT(+)].
Scheme 2 Mono-orthosubstituted anilides.
DG‡ = 80.5
0.5 kJ mol−1 over the range 80–120 ◦C for the
alkylation (for 11a) or reductive amination from 2-iodoaniline
barrier to C–N rotation, corresponding to an estimated§ half-
life for enantiomerisation at 25 ◦C of 14 s and therefore a
half-life for racemisation at this temperature of just 7 s.
This figure is similar to that obtained with related mono-
orthosubstituted anilides bearing unbranched N-substituents.26
With 4a however, we were unable to attain coalescence at
high temperatures but we found that the enantiomers were
sufficiently stable to be separated by HPLC on a chiral stationary
phase [Chiralcel OT(+)] (Fig. 1). Each resolved enantiomer was
10d,34 but unfortunately both 9 and 11a were resistant to
acetylation, preventing the formation of 4c and 4d. However,
acetylation of 11b–d gave the anilides 4e–4g and reaction of
11d with phenyl isocyanate gave the urea 4h. None of the three
compounds could be resolved by HPLC, though 4e did show
two overlapping peaks in its HPLC trace. Variable temperature
NMR spectroscopy of 4g up to a temperature of 120 ◦C
(DMSO) showed that coalescence of the diastereotopic methyl
doublets occurred at a temperature higher than this and allowed
us to estimate a minimum barrier to rotation about C–N◦of
>97 kJ mol−1, or an estimated half-life for racemisation at 25 C
of at least a few hours. Variable temperature NMR investigations
of 4h (modelling coalescence of the diastereotopic methyl
doublets) in contrast gave a barrier to rotation of 65.7 kJ mol−1
at 25 ◦C, corresponding to a half-life for racemisation of about
3 × 10−2 seconds, indicating that N-phenyl ureas have signi-
ficantly lower barriers to Ar–N rotation than the corresponding
anilides.
◦
incubated at 40 C and kinetic analysis of its first-order decay
to a racemic mixture showed a half-life for racemisation of 9.2 h
at this temperature, corresponding to DG‡ = 104.9 kJ mol−1.
Assuming constancy of DG‡ with temperature, the estimated
half-life for racemisation of 4a at 25 ◦C was 36 hours.
Iodoanilide 4a is the first anilide 3 bearing a single ortho
substituent (other than t-Bu20) to have been shown to exhibit
atropisomerism32 at room temperature. The principal feature
distinguishing it from the less stable enantiomers of 4b and
from other known achiral anilides20,26,27 is the bulky, branched
cyclohexyl substituent at N. We therefore decided to make a
further series of anilide derivatives of 2-iodoanilines 11 bearing
branched N-alkyl groups (Scheme 2).
With an additional stereogenic centre in the molecule the
presumed stable pairs of enantiomers of 4e–g would become
pairs of diastereoisomers, allowing their more straightforward
separation. Treatment of 11d with (S)-O-acetyl lactoyl chloride
gave the two atropisomeric diastereoisomers of 4i in, initially,
approximately a 1 : 1 ratio. The diastereoisomers were separated
by flash chromatography. On incubating either enantiomer at
50 ◦C in 5 : 1 hexane–isopropanol, slow conversion (in a
matter of hours) was observed, leading eventually to a ratio of
atropisomeric diastereoisomers of 4i of 5.25 : 1 M : P. Analysis
of the epimerisation by the method of Siddall and Stewart28 gave
a half-life for the equilibration of 32.5 min at 50 ◦C. From this,
We were able to synthesise the anilines 9 (by the method of
Paul and Haberfield33 from bromobenzene 7), and 11a–d by
§ From the more or less constant value obtained for DG‡ we assume that,
in common with many other bond rotation processes, DS‡ is small. The
half-life for enantiomerisation at 25 ◦C in this instance was established
by assuming DG‡ is constant with temperature. The rate of racemisation
is double the rate of enantiomerisation.
3 1 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3

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and the equilibrium constant, we derived barriers to rotation
from (M)-4i to (P)-4i of 99.0 0.5 kJ mol−1 at 50 ◦C and from
(P)-4i to (M)-4i of 103.5 0.5 kJ mol−1 at 50 ◦C.
Just as 3 is conformationally uniform about the N–CO bond
provided R2 is small, N,Nꢀ-dialkyl-N,Nꢀ-diarylureas 6 are known
to adopt a well defined conformation about the two N–CO
bonds placing the two Ar rings cis.22 We hoped that this would
both facilitate studies of their rate of racemisation and also
allow us to investigate a potential new class of atropisomeric
molecules.
When the mixture of diastereoisomers was stored at room
temperature for several days, however, the enrichment of the
major diastereoisomer (P)-4i increased to 100% in a process
driven by the crystallisation. An X-ray crystal structure (Fig. 2)
confirmed the stereochemistry of this more stable and more
crystalline diastereoisomer.¶ Lactic acid derivatives of anilides
have previously been used in a similar way as a means of
resolution of related atropisomers.6,11,13,21,35
We therefore made a series of ureas bearing a range of
sterically and electronically contrasting 2-substituents by con-
densation of the available anilines 10a–h with phenylisocyanate
(Scheme 3). Alkylation of the disubstituted ureas 12a–h with
benzyl bromide yielded the N,N,Nꢀ-trisubstituted ureas 5a–
h.36 Interestingly, this first alkylation took place at the more
hindered N atom, possibly because conjugation between this
nitrogen anion and the ring is lessened by the impossibility of
coplanarity between the urea and the ring.36 A second alkylation
with methyl iodide gave the parallel series of fully alkylated ureas
6a–h. Barriers to Ar–CO rotation were determined by variable
temperature NMR in DMSO, modelling lineshapes close to
coalescence using gNMR, and the results are shown in Table 1.
The overall message from these results is that, with one or two
exceptions, the size of the substituent ortho to the C–N bond in a
monosubstituted 2-phenyl urea is of relatively small importance.
Most of the “doubly alkylated” anilides 6 had barriers between
around 50 and 60 kJ mol−1 at room temperature, corresponding
to half-lives for racemisation of between 10−5 and 10−3 s while
most of the “singly alkylated” anilides 5 had barriers between
about 60 and 70 kJ mol−1, corresponding to half-lives for
racemisation approaching 0.5 s at room temperature. Alkylation
of the second nitrogen of the urea leads to a decrease in rotational
barrier of about 10 kJ mol−1, an effect possibly attributable to
a decrease in ground-state strain.23 Two substituents provide
exceptions to this general rule: fluoro, in which the barrier is so
low that it could not be measured (no diastereotopic protons
were seen in 5a, even at −50 ◦C in CDCl3) and t-Bu, which
in 6h gave a barrier (determinable with only poor accuracy) of
Fig. 2 X-Ray crystal structure of (P)-4i.
These studies were not pursued further, but indicated that N-
sec-alkyl anilides bearing a 2-substituent form a new class of
non-biaryl atropisomeric molecules with potential application
in asymmetric synthesis or catalysis.1
◦
around 80 kJ mol−1, or a half-life for racemisation at 25 C of
¶ CCDC reference number 273163. See http://dx.doi.org/10.1039/
b507202f for crystallographic data in CIF or other electronic format.
somewhere between 1 and 100 s.
Scheme 3 ortho-Substituted N,Nꢀ-diarylureas.
Table 1 Barriers to enantiomerisation of 5 and 6
Entry
X =
Cpd., yield (%)
DG‡ (25 ◦C)/kJ mol−1
Cpd., yield (%)
DG‡ (25 ◦C)/kJ mol−1
1
2
3
4
5
6
7
8
F
Cl
Br
I
Me
Et
5a 56
5b 42
5c 39
5d 42
5e 44
5f 33
5g 60
5h 58
—
6a 98
6b 71
6c 71
6d 90
6e 47
6f 38
6g 82
6h 87
—
58.8 3.0
61.8 3.0
67.7 1.5
64.5 2.7
69.3 4.0
70.0 4.0
69.8 7.0
50.6 3.0
53.5 2.3
56.9 2.4
56.7 2.3
60.6 1.5
60.0 20
i-Pr
t-Bu
80.0
6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
3 1 7 5

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Table 2 Varying N-alkyl groups
Minor rotamer: 53.2 (CH2), 117.2 (CH2), 128.6 (CH), 130.1
(CH), 139.5 (CH).
Anal. Calcd for C14H18INO2: C, 46.81; H, 5.05; N, 3.90.
Found: C, 46.66; H, 5.05; N, 3.88.
Entry
R =
Cpd.
DG‡ (25 ◦C)/kJ mol−1
1
2
3
4
5
Me
Et
Bn
(Bn)
(I)
6i
6j
6k
6l
5l
58.7
64.8
61.6
59.2
65.7
N-Cyclohexyl-N-(2-iodophenyl)acetamide 4e. A solution of
N-cyclohexyl-2-iodoaniline34 (95 mg, 0.31 mmol) in Ac2O
(5 mL) was stirred for 48 h at 85 ◦C. Water was added and
the mixture was stirred at room temperature until only one
layer was observed. The mixture was alkalinized with Na2CO3 (s)
and CH2Cl2 was added. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were dried, filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (CH2Cl2) to yield
4e (88 mg, 81%). 1H-NMR (CDCl3, 300 MHz) d 0.76 (dd, J =
3.9 and 12.3 Hz, 1H), 0.97 (tt, J = 3.9 and 12.3 Hz, 1H), 1.20–
1.48 (m, 3H), 1.55–1.74 (m, 3H), 1.75 (s, 3H, CH3CO), 1.96 (d,
J = 12 Hz, 1H), 2.13 (d, J = 12 Hz, 1H), 4.43 (tt, J = 3.6 and
12 Hz, 1H, CHN), 7.06 (td, J = 8.1 and 1.5 Hz, 1H, H-4), 7.21
(dd, J = 8.1 and 1.5 Hz, 1H, H-6), 7.40 (td, J = 8.1 and 1.5 Hz,
1H, H-5), 7.94 (dd, J = 8.1 and 1.5 Hz, 1H, H-3). 13C-NMR
(CDCl3, 75.5 MHz) d 23.9 (CH3CO), 25.5, 25.7 and 25.8 (C-3ꢀ,
C-4ꢀ and C-5ꢀ), 30.1 and 32.2 (C-2ꢀ and C-6ꢀ), 56.1 (C-1ꢀ), 103.7
(C-2), 129.2, 129.5 and 130.3 (C-4, C-5 and C-6), 140.2 (C-3),
143.3 (C-1), 169.7 (CO).
For convenience of analysis, because of the AB system which
results, we studied N-benzyl derivatives of urea 12, but we were
also eager to establish the role of the size of this N-substituent
on the barrier to rotation, given the evident importance of the
branched substituent in 4. We therefore made the small family
of derivatives 6i–6l and determined the barrier to Ar–N rotation
for each by following the coalescence of the pair of i-Pr doublets
by VT NMR. Table 2 shows the results, which indicate broadly
that moving from Me to Et to Bn has little effect on the barrier to
rotation at ambient temperature. A comparison between the two
compounds 5d and 5l, both 2-iodophenylureas, but one bearing
N-Bn and one N-i-Pr, confirms this view, that the N-substituent
has little role to play in the size of the barrier in ureas.
Although the barriers to rotations in these ureas are lower
than in the corresponding anilides, the Ar–N bonds seem to
rotate much more slowly than the corresponding N–CO bonds
of similar N,N,Nꢀ,Nꢀ-tetrasubstituted ureas, whose reported
barriers to rotation are less than 35 kJ mol−1.23
This kinetic study will lay the foundation for future synthetic
and stereochemical investigations with N,Nꢀ-diaryl ureas which
will be published in due course.36
N-(2-Ethylpropyl)-N-(2-iodophenyl)acetamide 4f. A solu-
tion of 11c (89 mg, 0.31 mmol) in Ac2O (5 mL) was stirred
for 48 h at 85 ◦C. Water was added and the mixture was stirred
at room temperature until only one layer was observed. The
mixture was alkalinized with Na2CO3 (s) and CH2Cl2 was added.
The aqueous layer was extracted with CH2Cl2 and the combined
organic layers were dried, filtered and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2) to yield 4f (100 mg, 98%). 1H-NMR
Experimental
ꢀ
(CDCl3, 300 MHz) d 0.93–1.04 (m, 2H, CH2 and CH2 ), 0.99 (t,
General
ꢀ
J = 7 Hz, 3H, CH3), 1.00 (t, J = 7 Hz, 3H, CH3 ), 1.50 (h, J =
1H and 13C NMR spectra were recorded on a Varian XL
300 MHz Fourier Transform instrument. VT NMR studies were
recorded on an Inova 300 MHz Fourier Transform instrument.
NMR data are presented as follows: chemical shift d (in ppm
relative to dTMS = 0), multiplicity, coupling constant J (quoted
in hertz, Hz), integration, and assignment. IR spectra were
recorded on an ATi Matson Genesis Series Fourier Transform
spectrometer. Wavelengths of maximum absorbance are quoted
in wavenumbers (cm−1). Low resolution mass spectra (EI and
CI) were recorded on a Fisons VG Trio 2000 quadrupole
mass spectrometer. High resolution mass spectra were recorded
on a Kratos Concept-IS mass spectrometer. Analytical TLC
was carried out on Machery-Nagel pre-coated 0.2 mm silica
plates with fluorescent indicator on aluminium. The drying
agent used prior to purification was magnesium sulfate. Flash
chromatography37 was carried out using Fluorochem Davisil
40–63 lm 60 A silica under a positive pressure of air.
ꢀ
7 Hz, 1H, CH2), 1.73–1.87 (m, 1H, CH2 ), 1.80 (s, 3H, CH3CO),
4.49 (h, J = 5.1 Hz, 1H, CH), 7.04 (td, J = 7.8 and 1.5 Hz,
1H, H-4), 7.19 (dd, J = 7.8 and 1.5 Hz, 1H, H-6), 7.39 (td, J =
7.8 and 1.5 Hz, 1H, H-5), 7.94 (dd, J = 7.8 and 1.5 Hz, 1H,
H-3). 13C-NMR (CDCl3, 75.5 MHz) d 11.1 and 11.7 (CH3), 23.9
(CH3CO), 24.6 and 25.9 (CH2), 103.7 (C-2), 129.3, 129.7 and
129.9 (C-4, C-5 and C-6), 140.5 (C-3), 143.4 (C-1), 170.5 (CO).
N-(2-Iodophenyl)-N-isopropylacetamide 4g. To a solution of
N-isopropyl-2-iodoaniline34 (98 mg, 0.37 mmol) and pyridine
(0.1 mL, 1.16 mmol) in dry CH2Cl2 (1 mL) at 0 ◦C was
added acetyl chloride (40 lL, 0.56 mmol). The mixture was
stirred for 3 h at room temperature and then water and CH2Cl2
were added. The aqueous phase was separated and the organic
phase was washed with HCl 1N and sat. aq. NaHCO3. The
solution was dried, filtered and the solvent was evaporated
under reduced pressure. The crude product was purified by flash
chromatography (CH2Cl2) to yield 4g (107 mg, 95%). 1H-NMR
(CDCl3, 300 MHz) d 0.98 (d, J = 6.9 Hz, 3H, CH3), 1.27 (d, J =
6.9 Hz, 3H, CH3), 1.76 (s, 3H, CH3CO), 4.77 (h, J = 6.9 Hz,
1H, -CH-), 7.07 (td, J = 8.1 and 1.5 Hz, 1H, H-4), 7.22 (dd,
J = 7.8 and 1.5 Hz, 1H, H-6), 7.41 (td, J = 7.8 and 1.2 Hz,
1H, H-5), 7.95 (dd, J = 8.1 and 1.2 Hz, 1H, H-3). 13C-NMR
(CDCl3, 75.5 MHz) d 19.6 and 22.1 (CH3), 23.9 (CH3CO), 48.1
(CH), 103.6 (C-2), 129.3, 129.6 and 130.1 (C-4, C-5 and C-6),
140.3 (C-3), 142.9 (C-1), 169.8 (CON). IR (film) 1659 cm−1.
The following compounds have been published previously:
4-[N-acetyl-N-(2-iodophenyl)amino]cyclohexanone 4a;31 N-
tert-butylaniline 8;33 N-tert-butyl-2,4-diiodoaniline 9;38 N-
cyclohexyl-2-iodoaniline 11b;34 N-isopropyl-2-iodoaniline
11d.39
N-Allyl-N-(tert-butoxycarbonyl)-2-iodoaniline. 4b was made
by the method of Boger and McKie.40 1H-NMR (CDCl3,
200 MHz) d 1.36 and 1.54 (2 s, 9H, (CH3)3, major and minor
Boc rotamer respectively), 3.77 (dd, J = 15 and 6.8 Hz, 1H,
CH2), 4.50 (dd, J = 15 and 5.6 Hz, 1H, CH2), 5.03–5.11 (m, 2H,
N-Benzhydryl-2-iodoaniline 11a. To
a solution of 2-
iodoaniline (1 g, 4.56 mmol) in CH3CN (55 mL) was added
LiI (cat.), K2CO3 (2.5 g, 18.1 mmol) and benzhydryl bromide
(1.2 g, 4.85 mmol). The mixture was stirred at reflux temperature
overnight. The solvent was evaporated under reduced pressure,
and the residue was combined with CH2Cl2 and H2O. The
aqueous layer was extracted with CH2Cl2, and the combined
organic layers were dried, filtered and the solvent was removed
=
=
CH2), 5.85–6.05 (m, 1H, CH ), 6.98 (ddd, J = 7.8, 7.4 and
1.6 Hz, 1H, H-4), 7.12 (dd, J = 7.4 and 1.6 Hz, 1H, H-6), 7.32 (t,
J = 7.4 Hz, 1H, H-5), 7.86 (d, J = 7.8 Hz, 1H, H-3). 13C-NMR
(CDCl3, 50 MHz) d Major rotamer: 28.3 (CH3), 52.0 (CH2),
80.3 (C(CH3)3), 100.5 (C), 117.8 (CH2), 128.5 (CH), 128.9 (CH),
129.8 (CH), 133.5 (CH), 139.2 (CH), 144.1 (C), 153.7 (CO).
3 1 7 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3

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under reduced pressure. The crude product was purified by flash
chromatography (petrol to petrol–AcOEt 95 : 5) to yield 11a
(1.7 g, 97%). 1H-NMR (CDCl3, 300 MHz) d 4.84 (bs, 1H, NH),
5.57 (s, 1H, CH), 6.43 (t, J = 7.8 Hz, 1H, H-4), 6.45 (d, J =
7.8 Hz, 1H, H-6), 7.07 (t, J = 7.8 Hz, 1H, H-5), 7.28–7.37
(m, 10H), 7.70 (d, J = 7.8 Hz, 1H, H-3). 13C-NMR (CDCl3,
75.5 MHz) d 63.5 (CHPh2), 86.2 (C-2), 112.6 (C-6), 119.5 (C-4),
127.7 (C-2ꢀ), 127.9 (C-4ꢀ), 129.3 (C-3ꢀ), 129.7 (C-5), 139.24 (C-3),
142.7 (C-1ꢀ), 146.7 (C-1). IR (film) 3387 cm−1. HRMS Calcd for
C19H16NI: 385.0327. Found 385.0343.
1.2 Hz, 1H, H-5), 7.47 (dd, J = 7.8 and 1.8 Hz, 1H, H-6), 7.96
(dd, J = 7.8 and 1.2, 1H, H-3). 13C-NMR (CDCl3, 75.5 MHz) d
16.9 (CH3CHCO), 19.2, 20.7 and 21.5 (CH3), 50.7 (CHN), 68.8
(CH3CHCO), 102.7 (C-2), 129.1, 130.0 and 131.4 (C4-, C-5 and
C-6), 140.4 (C-3), 141.9 (C-1), 169.8 and 170.0 (CO). IR (film)
1724, 1654 cm−1. Anal. Calcd for C14H18INO3: C, 44.82; H, 4.84;
N, 3.73. Found: C, 44.72; H, 4.90; N, 3.68. [a25D] = + 35.3 (c =
0.7, MeOH).
1
(M)-4i: H-NMR (CDCl3, 300 MHz) d 1.02 (d, J = 6.6 Hz,
3H, CH3), 1.23 (d, J = 6.6 Hz, 3H, CH3), 1.32 (d, J = 6.6 Hz,
3H, CH3), 2.08 (s, 3H, CH3CO), 4.73 (qn, J = 6.6 Hz, 1H,
CH(CH3)2), 4.94 (q, J = 6.6 Hz, 1H, C*HCO), 7.11 (t, J =
7.8 Hz, 1H, H-4), 7.21 (dd, J = 7.8 and 1.5 Hz, 1H, H-6),
7.43 (t, J = 7.8 Hz, 1H, H-5), 7.98 (d, J = 7.8, 1H, H-3). 13C-
NMR (CDCl3, 75.5 MHz) d 17.6 (CH3CHCO), 19.2, 21.4 and
21.9 (CH3), 49.3 (CHN), 68.3 (CH3CHCO), 103.3 (C-2), 129.0,
130.0 and 131.2 (C4-, C-5 and C-6), 140.6 (C-3), 141.0 (C-1),
169.2 and 169.7 (CO).
N-(2-Ethylpropyl)-2-iodoaniline 11c. To a solution of 2-
iodoaniline (202 mg, 0.92 mmol) and 2-pentanone (0.1 mL,
0.92 mmol) in dry MeOH (10 mL) was added decaborane (33 mg,
0.27 mmol). The solution was stirred at room temperature for
17 h. The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography (petrol
1
to petrol–AcOEt 95 : 5) to yield 11c (197 mg, 75%). H-NMR
(CDCl3, 300 MHz) d 1.01 (t, J = 7.5 Hz, 6H, CH3), 150–176
(m, 4H), 3.35 (q, J = 6 Hz, 1H, CH), 4.08 (bs, 1H, NH), 6.44
(ddd, J = 7.8, 7.2 and 1.5 Hz, 1H, H-4), 6.60 (d, J = 8.1 Hz,
1H, H-6), 7.23 (ddd, J = 8.1, 7.2 and 1.5 Hz, 1H, H-5), 7.71 (dd,
J = 7.8 and 1.5 Hz, 1H, H-3). 13C-NMR (CDCl3, 75.5 MHz) d
10.1 (CH3), 26.5 (CH2), 55.9 (CH), 85.7 (C-2), 110.9 (C-6), 117.7
(C-4), 129.2 (C-5), 139.1 (C-3), 146.9 (C-1). IR (film) 2962 cm−1.
HRMS Calcd for C11H16NI: 289.0327. Found 289.0322.
1-(2-Fluorophenyl)-3-phenylurea 12a. Phenyl isocyanate
(5.36 g, 4.92 ml, 45.0 mmol) was dissolved in DCM (100 ml) at
room temperature and 2-fluoroaniline 10a (5.00 g, 4.34 ml, 1 eq)
was added. After 1 h a white solid began to settle out. After
stirring for 1 d, the white precipitate was filtered and washed with
cold CH2Cl2 (250 ml). Drying under high vacuum gave 8.59 g
(37.3 mmol, 82.9%) of the desired product, mp 176–177 ◦C. 1H
NMR (300 MHz, DMSO) d 9.09 (s, 1H, N–HF), 8.57 (s, 1H,
N–H), 8.19 (dt, 3J = 8.3 Hz, 4J = 1.6 Hz, 1H, H5), 7.48 (d, 3J =
1-(2-Iodophenyl)-1-isopropyl-3-phenylurea
4h. 2-Iodo-N-
3
isopropylaniline 11d (1.90 g, 7.3 mmol) was dissolved in toluene
(20 cm3) and phenyl isocyanate (0.80 cm3, 8.0 mmol) was added
dropwise. The mixture was heated to reflux and maintained
at this temperature for 18 h. The solvent was evaporated
under reduced pressure and the residue purified by flash silica
chromatography (SiO2; 5% to 50% EtOAc in petrol) to give
1-(2-iodophenyl)-1-isopropyl-3-phenylurea 4h (1.37 g, 49% +
20% RSM) as white blocks, mp 82–84 ◦C; Rf (EtOAc–petrol,
7.5 Hz, 2H, H11, H15), 7.32 (t, J = 7.6 Hz, 2H, H12, H14), 7.24
3
(mc, 1H, H4), 7.16 (t, J = 7.7 Hz, 1H, H13), 7.02 (mc, 2H, H3,
H5). 13C NMR (75 MHz, DMSO) d 115.7 (d, 19.0 Hz), 118.81
(C11, C15), 121.20, 122.78, 123.1 (d, 7.5 Hz), 125.21, 125.26, 128.3
=
(d, 10.3 Hz), 129.6 (C12, C14), (N–Ar), (N–ArF), (C–F), (C O):
140.16, 152.90, 154.28, 151.09. IR (film) 3279, 1644 cm−1.
1-(2-Chlorophenyl)-3-phenylurea 12b. Phenyl isocyanate
(3.20 g, 2.94 ml, 26.9 mmol) was dissolved in DCM (100 ml)
at room temperature and 2-chloroaniline 10b (3.43 g, 2.83 ml,
1 eq) was added in one portion. After 3 h a white solid settled
out. The precipitate was filtered and washed with cold CH2Cl2
(200 ml). Drying under high vacuum afforded 4.70 g (19.0 mmol,
70.9%), mp180–182 ◦C. 1H NMR (300 MHz, DMSO) d 7.03 (mc,
2H, Ar–H), 7.32 (mc, 3H, Ar–H), 7.49 (mc, 3H, Ar–H), 8.20 (dd,
3 : 10) 0.42; mmax (film)/cm−1 3428 and 3339 (NH), 2979 and
1
=
2936 (CH3), 2881 (CH) and 1670 (C O); H-NMR (CDCl3,
300 MHz) d 8.04 (1 H, dd, J 8.0 and 1.5, CH-f), 7.50 (1 H,
td, J 8.0 and 1.5, CH-d), 7.39 (1 H, dd, J 8.0 and 1.5, CH-c),
7.33–7.21 (4 H, m, CH-g and CH-h), 7.17 (1 H, td, J 8.0 and
1.5, CH-e), 7.03 (1 H, tt, J 7.0 and 1.2, CH-i), 5.79 (1 H, br. s,
NH), 4.83 (1 H, sept, J 6.3, CH-a), 1.39 [3 H, d, J 6.3, (CH-b)A]
and 1.08 [3 H, d, J 6.3, (CH-b)B]; 13C-NMR (CDCl3, 75 MHz)
4
3J = 8.3 Hz, J = 1.6 Hz, 1H, H6), 8.34 (s, 1H, N–H), 9.44 (s,
1H, N–HCl). 13C NMR (75 MHz, DMSO) d 118.91 (C11, C15),
=
d 153.6 (C O), 141.3 (C), 141.2 (CH), 139.0 (C), 131.5 (CH),
121.99 (C6), 122.60 (Cl–Ar), 122.84 (C13), 123.96 (C4), 128.29
130.6 (CH), 130.3 (CH), 129.0 (CH), 123.5 (CH), 120.5 (CH),
104.6 (C), 49.1 (CH), 23.3 (CH3) and 20.4 (CH3); m/z (CI) 381
(40%, M + H+) and 253 (40, M + H+–I); (Found: M + H+,
381.0459, C16H18N2OI requires M + H, 381.0458).
(C5), 129.62 (C12, C14), 129.92 (C3), 136.72 (N–ArCl), 140.18
−1
=
(N–Ar), 152.85 (C O). IR (film) 3279, 1644 cm .
1-(2-Bromophenyl)-3-phenylurea 12c. Phenyl isocyanate
(2.08 g, 1.91 ml, 17.4 mmol) was dissolved in DCM (100 ml)
at room temperature and 2-bromoaniline 10c (3.00 g, 1 eq) was
added in one portion. After stirring for 4 days the reaction
mixture was filtered and a white solid isolated. Washing with
cold CH2Cl2 (200 ml) and drying under high vacuum afforded
3.56 g (12.2 mmol, 70.3%), mp 189–190 ◦C. 1H NMR (300 MHz,
DMSO) d 7.00 (mc, 2H, H3, H13), 7.34 (mc, 3H, H5, H12, H14),
7.50 (mc, 2H, H11, H15), 7.63 (dd, 3J = 8.0 Hz, 4J = 1.5 Hz, 1H,
H3), 8.10 (dd, 3J = 8.3 Hz, 4J = 1.6 Hz, 1H, H6), 8.16 (s, 1H, N–
H), 9.48 (s, 1H, N–HBr). 13C NMR (75 MHz, DMSO) d 113.72
(C–Br), 118.92 (C11, C15), 122.83 (C6), 122.92 (C13), 124.75 (C4),
(S)-N-(2-Acetoxypropanoyl)-N-isopropyl-2-iodoaniline (M)-
4i and (P)-4i. A stirred solution of N-isopropyl-2-iodoaniline
11d (198, 0.76 mol), and pyridine (150 lL, 1.74 mol)
in dry CH2Cl2 was cooled at
0
◦C, and (S)-(−)-2-
acetoxypropionylchloride (150 lL, 1.15 mmol) was added under
an atmosphere of N2. The mixture was stirred for 4 h at
room temperature. Water was added and the organic phase was
separated, washed with HCl 1N, NaHCO3 and brine, dried,
and the solvent was evaporated under reduced pressure. The
crude product was purified by flash chromatography (CH2Cl2 to
CH2Cl2–MeOH 2%) to yield (P)-4i (51 mg, 18%), a mixture of
(P)-4i and (M)-4i (1 : 1) (107 mg) and (M)-4i (94◦mg, 33%). A
solution of each diastereomer was warmed at 85 C and these
were converted to the thermodynamic mixture (5.25 : 1). This
thermodynamic mixture was stored at room temperature for
several days and it was transformed totally to (P)-4i (89% total
128.79 (C5), 129.61 (C12, C14), 133.20 (C3), 137.81 (N–Ar), 140.21
−1
=
(N–ArBr), 152.89 (C O). IR (film) 3279, 1645 cm .
1-(2-Iodophenyl)-3-phenylurea 12d. 2-Iodoaniline 10d (1.63 g,
1.50 ml, 13.7 mmol) was added in one portion to a solution of
phenyl isocyanate in CH2Cl2 (100 ml). After 72 h a brownish
precipitate had been formed. The settlings were filtered and
washed with cold CH2Cl2 (200 ml). Drying under high vacuum
afforded 3.76g (11.1 mmol, 81.2%) of the desired product as
◦
1
yield). (P)-4i: mp 149–150 C; H-NMR (CDCl3, 300 MHz) d
1.09 (d, J = 6.6 Hz, 3H, CH3), 1.37 (d, J = 6.6 Hz, 3H, CH3),
1.40 (d, J = 6.6 Hz, 3H, CH3), 1.99 (s, 3H, CH3CO), 4.5 (qn,
J = 6.6 Hz, 1H, CH(CH3)2), 4.67 (q, J = 6.6 Hz, 1H, C*HCO),
7.09 (td, J = 7.8 and 1.8 Hz, 1H, H-4), 7.41 (td, J = 7.8 and
◦
1
a white brownish solid, mp 200–201 C. H NMR (300 MHz,
DMSO) d 6.86 (t, 3J = 7.4 Hz, 1H, H4), 7.00 (t, 3J = 7.3 Hz, 1H,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
3 1 7 7

View Online
H13), 7.34 (mc, 3H, H5, H12, H14); H3, H6, (H11, H15): 7.50 (d, 3J =
7.9 Hz, 2H), 7.86 (d, 3J = 8.0 Hz, 2H); 7.91 (s, 1H, N–H), 9.45 (s,
1 H, N–HI). 13C NMR (75 MHz, DMSO) d 92.08 (C–I), 118.90
(C11, C15), (C6), (C13): 122.73, 123.80, 125.77 (C4), 129.30 (C5),
129.59 (C12, C14), 139.66 (C3), (Ar–N), (Ar–NI): 140.34, 140.57;
153.10 (C = O). IR (film) 3279, 1646 cm−1.
(55.6 mg, 1.39 mmol, 1.2 eq) was dissolved in THF (5 ml, dry)
and was stirring for 0.5 h before addition of benzyl bromide
(198 mg, 0.14 ml, 1.16 mmol, 1.0 eq). After stirring for 42 h, first
Et2O (5 ml) and then distilled H2O (1 ml) were added. The aque-
ous phase was washed with Et2O (3 × 10 ml) and the combined
organic phases were dried over Na2SO4. Evaporation and drying
under high vacuum gave 320 mg (crude yield) of a highly viscous
oil. The crude product was purified by column chromatography
using a mixture of petrol–ethyl acetate (10 : 1). The desired
product was obtained as a white solid (209 mg, 56.3%), mp
108–109 ◦C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.30. 1H NMR
(300 MHz, CDCl3) d 4.97 (s, 2H, Ph–CHAH, Ph–CHHB), 6.19 (s,
1H, N–H), 7.06 (mc, 1H, Ar–H), 7.16 (mc, 2H, Ar–H), 7.32 (mc,
11H, Ar–H). 13C NMR (75 MHz, CDCl3) d 52.65 (Ph–CH2),
117.77 (d, J = 19.8), 117.77 (C3), 120.04 (C11, C15), 123.58 (C6),
125.56 (d, J = 4.0 Hz), 125.57 (C5), 127.73 (C13), 128.66 (C18,
C22), 128.93 (C19, C21), 129.12 (C12, C14), 130.57 (d, J = 7.8 Hz),
1-(2-Methylphenyl)-3-phenylurea 12e. Phenyl isocyanate
(3.20 g, 2.94 ml, 26.9 mmol) was dissolved in DCM (100 ml) at
room temperature and o-toluidine 10e (2.88 g, 2.91 ml, 1 eq) was
added in one portion. After 5 min, a white solid began to settle
out. After stirring for 12 h, the white precipitate was filtered and
washed with cold CH2Cl2 (250 ml). Drying under high vacuum
afforded 5.81 g (25.7 mmol, 95.5%) of the desired product as
a white solid, mp 201–202 ◦C. 1H NMR (300 MHz, DMSO) d
2.27 (s, 3H, CH3); (H4), (H13), (H3, H5): 6.97 (mc, 2H), 7.17 (mc,
2H); 7.31 (mc, 2H, H12, H14), 7.50 (d, 3J = 7.5 Hz, 2H, H11, H15),
3
7.88 (d, J = 8.1 Hz, 1H, H6); (N–HMe), (N–H): 7.94 (s, 1 H),
=
130.58 (C4), 131.50 (C20); (C17), (Ar–NF), (C O), (N–Ar), (C–F):
9.04 (s, 1 H). 13C NMR (75 MHz, DMSO) d 18.63 (CH3), 118.71
137.87, 138.80, 154.47, 157.26, 160.61. m/z (CI) 321 (100%, M +
(C11, C15), 121.72 (C6), (C13) (C4): 122.41, 123.36; 126.88 (C5),
H+), 202 (40%, (C6H5F)NH2 (C7H7)), 91 (57%, C7H7 ); m/z (EI)
+
+
128.17 (C–Me), 129.55 (C12, C14), 130.90 (C3); (C–N), (C–NMe):
+
+
201 (10%, (C6H5F)NH2 (C7H7)), 91 (100%, C7H7 ). (Found:
MH+, 321.1395. C20H18O1 N2F1 requires MH, 321.1398). IR
(film): m/cm−1 = 3300 (m) (N–H), 3058 (w) (Ar–H), 1659 (s)
−1
=
138.14, 140.62; 153.38 (C O). IR (film) 3276, 1636 cm .
1-(2-Ethylphenyl)-3-phenylurea 12f. Phenyl isocyanate (3.20 g,
2.94 ml, 26.9 mmol) was dissolved in DCM (100 ml) at room
temperature and 2-ethylaniline 10f (3.26 g, 3.33 ml, 1 eq) was
added in one portion. After stirring for 18 h, the white precipitate
was filtered and washed with cold CH2Cl2 (250 ml). Drying
under high vacuum afforded 6.09 g (25.5 mmol, 94.3%) of the
desired product as a white solid. 1H NMR (300 MHz, DMSO)
=
(C O), 1597 (m), 1531 (s), 1500 (s), 1455 (w), 1442 (s).
1-Benzyl-1-(2-chlorophenyl)-3-phenylurea 5b. A mixture of
the urea 12b (250 mg, 1.01 mmol) and sodium hydroxide
(48.7 mg, 1.22 mmol, 1.2 eq) was dissolved in THF (7 ml, dry)
and was stirring for 0.5 h before addition of benzyl bromide
(174 mg, 0.12 ml, 1.01 mmol, 1.0 eq). After stirring for 21 h,
first Et2O (5 ml) and then distilled H2O (1 ml) were added.
The aqueous phase was washed with Et2O (3 × 10 ml) and
the combined organic phases were dried over Na2SO4. After
evaporation of Et2O and drying under high vacuum the crude
product was purified by column chromatography using a mixture
of petrol ether–ethyl acetate (10 : 1). The desired product was
obtained as white crystals (143 mg, 0.43 mmol, 42%), mp 115–
116 ◦C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.38. 1H NMR
(300 MHz, CDCl3) d 4.34 (s, 1H, PhCHAH), 5.56 (s, 1H,
PhCHHB), 6.03 (s, 1H, N–H), 7.07 (dd, 3J = 7.7 Hz, 4J = 0.9 Hz,
2H, H18, H22), 7.25–7.45 (m, 12H, Ar–H), 7.61 (mc, 1H, H6).
13C NMR (75 MHz, CDCl3) d 52.18 (CH2–Ph), 120.34 (C11,
C15), 123.71 (C6), 127.80 (C13), 128.56 (C4), 128.68 (C18, C22),
129.12 (C19, C21), 129.31 (C12, C14), 130.37 (C20), 131.57 (C5),
132.14 (C3), 134.47 (Ar–Cl), 137.83 (N–Ar), 138.03 (C–CH2),
3
3
d 1.20 (t, J = 7.5 Hz, 3H, CH3), 2.63 (q, J = 7.5 Hz, 2H,
CH2); (H13), (H4),(H3, H5): 7.0 (mc, 2H), 7.18 (mc, 2H); 7.30 (mc,
3
2H, H12, H14), 7.49 (mc, 2H, H11, H15), 7.82 (dd, J = 7.9 Hz,
4J = 1.2 Hz, 1H, H6), (N–H), (N–HEt): 7.92 (s, 1H), 9.03 (s,
1H). 13C NMR (75 MHz, DMSO) d 15.02 (-CH3), 24.52 (CH2),
118.68 (C11, C15), 122.39 (C6), 122.77 (C4 or C13), 123.88 (C13 or
C4), 126.77 (C5), 129.13 (C3), 129.55 (C12, C14), 134.45 (C–Et);
=
(C–N), (C–NEt): 137.25, 140.65; 153.58 (C O).
1-(2-Isopropylphenyl)-3-phenylurea 12g. Phenyl isocyanate
(2.50 g, 2.29 ml, 21.0 mmol) was dissolved in DCM (100 ml) at
room temperature and 2-isopropyl aniline 10g (2.84 g, 2.97 ml,
1 eq) was added in one portion. After stirring for 18 h, the white
precipitate was filtered and washed with cold CH2Cl2 (200 ml).
Drying under high vacuum afforded 3.48 g (13.7 mmol, 65.2%)
of the desired product as a white solid, mp 166–168 ◦C. 1H NMR
(300 MHz, DMSO) d 1.22 (d, 3J = 6.8 Hz, 6H, 2 × CH3), 3.18
=
138.78 (N–ArCl), 154.48 (C O). m/z (CI) 337 (100%, M +
3
H+), 247 (25%, M + H+-benzyl), 182 (21%, (C6H5)CH2–NH+–
(sept, J = 6.8 Hz, 1H, Hiso), 6.98 (mc, 1H, H4), 7.13 (mc, 2H,
+
(C6H4)), 91 (18%,C7H7 ); m/z (EI) 336 (9%, M+), 301 (19%, M+–
H13, H5), 7.30 (mc, 3H, H12, H14, H3), 7.49 (mc, 2H, H11, H15),
7.70 (dd, 3J = 7.9 Hz, 4J = 1.4 Hz, 1H, H6). 13C NMR (75 MHz,
DMSO) d 23.86 (2 × isoCH3), 27.53 (CHiso), 118.66 (C11, C15),
122.33 (C6), (C4) (C13): 124.27, 125.96; 126.45 (C5), 129.53 (C12,
Cl), 91 (100%, C7H7 ). (Found: MH+, 337.1103. C20H18O1N2Cl1
+
requires MH, 337.1102). IR (film): m/cm−1 = (N–H): 3425 (w),
3335 (w); (Ar–H): 3062 (w), 3031 (w); (alkyl C–H): 2925 (w),
=
2854 (w); (C O) 1679 (s); 1523, 1441, 1313 (m), 1240 (m), 752
C14), 136.23 (C3); (Ar–N), (Ar–Nisoprop): 140.11, 140.73; 153.86
−1
(m), 731 (m), 699 (m).
=
(C O). IR (film) 3272, 1640 cm .
1-Benzyl-1-(2-bromophenyl)-3-phenylurea 5c. A mixture of
the urea 12c (350 mg, 1.21 mmol) and sodium hydroxide
(57.9 mg, 1.45 mmol, 1.2 eq) was dissolved in THF (7 ml, dry)
and was stirring for 0.5 h before addition of benzyl bromide
(207 mg, 0.14 ml, 1.21 mmol, 1.0 eq). After stirring for 15 h,
first Et2O (5 ml) and then distilled H2O (1 ml) were added.
The aqueous phase was washed with Et2O (3 × 10 ml) and
the combined organic phases were dried over Na2SO4. After
evaporation of Et2O and drying under high vacuum the crude
product was purified by column chromatography using a mixture
of petrol ether–ethyl acetate (10 : 1). The desired product was
obtained as white crystals (179 mg, 0.47 mmol, 39%), mp 116–
118 ◦C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.30. 1H NMR
(300 MHz, CDCl3) d 4.26 (d, 15.0 Hz, 1H, Ph–CHAH), 5.60 (d,
15.0 Hz, 1H, Ph–CHHB), 5.95 (s, 1H, NH), 7.0–7.1 (m, 3H, Ar–
H), 7.2–7.4 (m, 10H, Ar–H), 7.78–7.81 (m, 1H, H6). 13C NMR
(75 MHz, CDCl3) d 52.13 (Ph–CH2), 120.24 (C11, C15), 123.61
1-(2-tert-Butylphenyl)-3-phenylurea 12h. Phenyl isocyanate
(2.38 g, 2.18 ml, 20.0 mmol) was dissolved in DCM (100 ml) at
room temperature and 2-tert-butyl-aniline 10h (2.98 g, 3.12 ml,
1 eq) was added in one portion. After stirring for 18 h, the white
precipitate was filtered and washed with cold CH2Cl2 (200 ml).
Drying under high vacuum afforded 4.82 g (17.9 mmol, 89.9%)
◦
1
of the desired product as a white solid, mp = 214–215 C. H
NMR (300 MHz, DMSO) d 6.96 (mc, 1H, H4), 7.12–7.34 (m,
5H, H3, H5, H12, H13, H14), 7.39 (dd, 3J = 7.7 Hz, 4J = 1.8 Hz,
1H, H6), 7.49 (mc, 2H, H11, H15). 13C NMR (75 MHz, DMSO) d
31.23 (3 × CH3), 35.25 (CtBu), 118.57 (C11, C15), 122.19 (C6); (C4)
(C13): 126.16, 126.83; 126.90 (C3), 129.50 (C12, C14), 130.86 (C5),
136.67 (Ar–tBu), 140.97 (C–N), 144.96 (C–NtBu), 152.24 (C O).
=
IR (film) 3280, 1640 cm−1.
1-Benzyl-1-(2-fluorophenyl)-3-phenylurea 5a. A mixture of
the urea 12a (266 mg, 1.16 mmol) and sodium hydroxide
3 1 7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3

View Online
(C–Br), 128.67 (C18, C22), 129.09 (C19, C21), 129.19 (C20), 129.42
(C12, C14); (C13), (C6), (C4), (C5), (C3): 127.78, 129.49, 130.55,
132.35, 134.79; (C17), (N–Ar), (N–ArBr): 137.86, 138.84, 139.53;
(5 ml) and then distilled H2O (1 ml) were added. The aqueous
phase was washed with Et2O (3 × 10 ml) and the combined
organic phases were dried over Na2SO4. Evaporation and drying
under high vacuum gave 0.64 g (crude yield) of a highly viscous
oil. The crude product was purified by column chromatography
using a mixture of petrol ether–ethyl acetate (10 : 1). The desired
product was obtai◦ned as a white solid (224 mg, 0.68 mmol,
32.6%), mp 58–60 C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.27.
1H NMR (300 MHz, CDCl3) d 1.15 (t, 3J = 7.6 Hz, 3H, CH3Et),
154.21 (C O). m/z (CI) 383 (63%, 81Br, M + H+), 381 (54%,
=
+
79Br, M + H+), 301 (45%,M+–Br), 91 (100%, C7H7 ); m/z (EI)
301 (17%, M+–Br), 91 (100%, C7H7 ). (Found: MH+, 381.0597.
+
C20H18O1 N2Br1 requires MH, 381.0597). IR (film): m/cm−1
=
(N–H): 3424 (w), 3332 (w); (Ar–H): 3061 (w), 3029 (w); (C–H
=
alkyl): 2959 (w), 2928 (w); 1678 (s) (C O), 1595 (m), 1523 (s),
1499 (m), 1473 (m), 1441 (s).
2
2.56 (mc, 2H, CH2Et), 4.44 (d, J = 14.4 Hz, Ph–CHAH), 5.33
2
(d, J = 14.4 Hz, Ph–CHHB), 6.04 (s, 1H, N–H), 7.01 (mc,
1-Benzyl-1-(2-iodophenyl)-3-phenylurea 5d. A mixture of the
urea 12d (300 mg, 0.89 mmol) and sodium hydroxide (43.4 mg,
1.07 mmol, 1.2 eq) was dissolved in THF (7 ml, dry) and was
stirring for 0.5 h before addition of benzyl bromide (152 mg,
0.11 ml, 0.89 mmol, 1.0 eq). After stirring for 18 h, first Et2O
(5 ml) and then distilled H2O (1 ml) were added. The aqueous
phase was washed with Et2O (3 × 10 ml) and the combined
organic phases were dried over Na2SO4. Evaporation and drying
under high vacuum gave a highly viscous yellowish oil. The
crude product was purified by column chromatography using a
mixture of toluene–ethyl acetate (20 : 1). The desired product
was obta◦ined as a white solid (158 mg, 0.37 mmol, 41.5%), mp
120–122 C, Rf (10 : 1 petrol (40/60)–EtOAc) = 0.66). 1H NMR
(300 MHz, CDCl3) d 4.18 (d, 2J = 14.7 Hz, 1H, PhCHAH), 5.63
(d, 2J = 14.7 Hz, 1H, PhCHHB), 5.90 (s, 1H, N–H), 6.96 (dd, 3J =
7.8 Hz, 4J = 1.7 Hz, 1H, H6), 7.15 (mc, 2H, Ar–H, 7.25 (mc, 9H,
Ar–H), 8.05 (dd, 3J = 7.9 Hz, 4J = 1.5 Hz, 1H, H3). 13C NMR
(75 MHz, CDCl3) d 52.25 (Ph–CH2), 101.46 (I–Ar); (C6), (C13),
(C4), (C20), (C5): 123.61, 127.8, 130.10, 130.65, 131.79; 120.30
(C11, C15); (C18, C22), (C19, C21), (C12, C14): 128.69, 129.09, 129.58;
2H, H4?, H13?), 7.26 (mc, 10H, Ar–H), 7.35 (mc, 2H, Ar–H).
13C NMR (75 MHz, CDCl3) d 14.64 (CH3Et), 23.56 (CH2Et),
53.00 (Ph–CH2), 119.70 (C11, C15); (C4), (C6), (C13), (C5), (C20),
(C3): 123.24, 127.69, 127.73, 129.42, 130.22, 130.34; (C18, C22),
(C19, C21), (C12, C14): 128.62, 129.09, 129.49; (C2), (N–ArEt),
=
(N–Ar), (C17): 138.21, 138.71, 139.06, 143.32; 154.83 (C O).
m/z (CI) 331 (100%, M + H+), 241 (23%, M + H+–(C7H7 ) +
+
H+), 91 (60%, (C7H7 )); m/z (EI) 91 (100%, (C7H7 )). (Found:
MH+, 331.1807.C22H23O1 N2 requires MH, 331.1805). IR (film):
m/cm−1 = 3419 (w) (N–H); (Ar–H): 3061 (w), 3030 (w); (alkyl
+
+
=
C–H); 2970 (w), 2932 (w), 2875 (w); 1677 (s) (C O), 1594 (m),
1521 (s), 1501 (m), 1440(s).
1-Benzyl-1-(2-isopropylphenyl)-3-phenylurea 5g. A mixture
of the urea 12g (500 mg, 1.97 mmol) and sodium hydroxide
(94.5 mg, 2.36 mmol, 1.2 eq) was dissolved in THF (8 ml, dry)
and was stirring for 0.5 h before addition of benzyl bromide
(404 mg, 0.28 ml, 1.16 mmol, 1.0 eq). After stirring for 18.5 h,
first Et2O (5 ml) and then distilled H2O (1 ml) were added.
The aqueous phase was washed with Et2O (3 × 10 ml) and the
combined organic phases were dried over Na2SO4. Evaporation
and drying under high vacuum gave 669 mg (crude yield) of a
highly viscous oil. The crude product was purified by column
chromatography using a mixture of petrol ether–diethyl ether
(10 : 1). The desired product was obtained as a white solid
(407 mg, 1.18 mmol, 60.0%), mp 92–94 ◦C, Rf (4 : 1 petrol
(C17), (N–Ar), (C3), (N–ArI): 137.88, 138.89, 141.15, 142.83;
+
=
153.95 (C O). m/z (CI) 429 (10%, M + H ), 303 (100%, M +
H+–I). m/z (EI) 91 (100%, C7H7 ). (Found: MH+, 429.0456.
+
C20H18O1N2I1 requires MH, 429.0458). IR (film): m/cm−1 = (N–
H): 3422 (m), 3321 (m); (Ar–H): 3059 (m), 3029 (m); 2927 (w)
=
(C–H alkyl), 1676 (C O), 1595 (s), 1523 (s), 1494 (s), 1441 (s).
1
(40/60)–Et2O) = 0.30. H NMR (300 MHz, CDCl3) d 1.02 (d,
3
3J = 6.9 Hz, CH3isoA) 1.20 (d, J = Hz, CH3isoB), 3.13 (sept,
1-Benzyl-1-(2-methylphenyl)-3-phenylurea 5e. A mixture of
the urea 12e (500 mg, 2.21 mmol) and sodium hydroxide (106 mg,
2.65 mmol, 1.2 eq) was dissolved in THF (8 ml, dry) and was
stirring for 0.5 h before addition of benzyl bromide (378 mg,
0.26 ml, 2.21 mmol, 1.0 eq). After stirring for 60 h, first Et2O
(5 ml) and then distilled H2O (1 ml) were added. The aqueous
phase was washed with Et2O (3 × 10 ml) and the combined
organic phases were dried over Na2SO4. Evaporation and drying
under high vacuum gave 698 mg (crude yield) of a highly viscous
oil. The crude product was purified by column chromatography
using a mixture of petrol ether–ethyl acetate (10 : 1). The desired
product was obtained as awhitesolid (307 mg, 1.0mmol, 44.0%),
mp 72–74 ◦C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.37. 1H NMR
(300 MHz, CDCl3) d 2.18 (s, 3H, Ar–CH3), 4.53 (d, 2J = 14.5 Hz,
2
3J = 6.8 Hz, 1H, CHiso), 4.54 (d, J = 14.3 Hz, Ph–CHAH),
5.28 (d, 2J = 14.3 Hz, Ph–CHHB), 6.04 (s, 1H, N–H), 7.02 (mc,
2H, H4, H13), 7.27 (mc, 10H, Ar–H), 7.43 (mc, 2H, Ar–H). 13C
NMR (75 MHz, CDCl3) d 24.04 (CH3isoA), 24.51 (CH3isoB), 53.41
(Ph–CH2), 119.62 (C11, C15); (C6), (C4), (C13), (C5), (C3), (C20):
123.24, 127.60, 127.74, 128.15, 129.72, 130.06; (C18, C22), (C19,
C21), (C12, C14): 128.66, 129.12, 129.58; (C–Nisoprop), (C–N), (C2),
=
(C17): 137.71, 138.18, 139.04, 148.33; 155.01 (C O). m/z (CI)
+
345 (100%, M + H+), 91 (8%, (C7H7 )). m/z (EI) 91 (100%,
(C7H7 )). (Found: MH+, 345.1967. C23H25O1 N2 requires MH,
+
345.1961). IR (film): m/cm−1 = 3420 (w) (N–H), (Ar–H): 3061
(w), 3029 (w); (C–H alkyl): 2963 (w), 2926 (w), 2867 (w); 1677
=
(s) (C O); 1594 (m), 1522 (s), 1500 (m), 1488 (m), 1440 (s).
2
1H, Ph–CHAH), 5.27 (d, J = 14.3 Hz, 1H, Ph–CHHB), 6.07
1-Benzyl-1-(2-tert-butylphenyl)-3-phenylurea 5h. A mixture
of the urea 12h (500 mg, 1.87 mmol) and sodium hydroxide
(89.5 mg, 2.24 mmol, 1.2 eq) was dissolved in THF (8 ml, dry)
and the solution was stirring for 0.5 h before addition of benzyl
bromide (319 mg, 0.22 ml, 1.87 mmol, 1.0 eq). After stirring for
18 h, first Et2O (5 ml) and then distilled H2O (1 ml) were added.
The aqueous phase was washed with Et2O (5 × 10 ml) and the
combined organic phases were dried over Na2SO4. Evaporation
and drying under high vacuum gave 584 mg (crude yield) of
a highly viscous oil and a waxy solid. The crude product was
purified by column chromatography using a mixture of petrol
ether–ethyl acetate (10 : 1). The desired product was obtained as
a white solid (388 mg, 1.1 mmol, 58.0%), mp 120–122 ◦C, Rf (4 :
1 petrol (40/60)–EtOAc) = 0.45. 1H NMR (300 MHz, CDCl3)
d 1.51 (s, 9H, 3 × CH3), 3.89 (d, 2J = 14.4 Hz, 1H, Ph–CHAH),
(d, 2J = 14.4 Hz, 1H, Ph–CHHB), 6.01 (s, 1H, N–H), 6.65 (dd,
3J = 7.9 Hz, 4J = 1.5 Hz, 1H, H3), 7.04 (mc, 1H), 7.13 (dt, 3J =
3
(s, 1H, N–H), 7.03 (d, J = 7.4 Hz, 1H, H3), 7.3 (mc, 13H,
Ar–H). 13C NMR (75 MHz, CDCl3) d 17.76 (Ar–CH3), 52.58
(Ph–CH2), 119.75 (C11, C15); (C6), (C4), (C13), (C5), (C20), (C3):
123.27, 127.72, 127.97, 129.19, 130.13, 132.23; (C18, C22), (C19,
C21), (C12, C14): 128.63,129.10, 129.49, (C–Me), (N–ArMe), (N–
=
Ar), (C–CH2): 137.66, 138.22, 139.15, 139.39; 154.60 (C O).
m/z (CI) 317 (100%, M + H+), 91 (18%, (C7H7 )); m/z (EI)
+
316 (5%, M+), 91 (100%, (C7H7 )). (Found: MH+, 317.1651.
+
C21H21O1 N2 requires MH, 317.1648). IR (film): m/cm−1 = (N–
H): 3419 (m), 3328 (m); (Ar–H): 3061 (m), 3029 (m); (alkyl–H):
=
2924 (m); (C O) 1677 (s); 1594 (s), 1522 (s), 1441 (s), 1357 (s),
1311 (s), 1243 (s), 1212 (s), 753 (s), 728 (s), 700 (s).
1-Benzyl-1-(2-ethylphenyl)-3-phenylurea 5f. A mixture of the
urea 12f (500 mg, 2.08 mmol) and sodium hydroxide (100 mg,
2.50 mmol, 1.2 eq) was dissolved in THF (8 ml, dry) and was
stirring for 0.5 h before addition of benzyl bromide (356 mg,
0.25 ml, 2.08 mmol, 1.0 eq). After stirring for 7 h, first Et2O
4
7.5 Hz, J = 1.6 Hz, 1H, H4 or H5 or H13 or H20), 7.34 (mc,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
3 1 7 9

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3
4
9H, Ar–H), 7.68 (dd, J = 8.2 Hz, J = 1.5 Hz, 1H, H6?). 13C
NMR (75 MHz, CDCl3) d 32.36 (3 × CH3), 36.59 (Ctert), 54.32
(Ph–CH2), 119.70 (C11, C15); (C6), (C4), (C13), (C3), (C5), (C20):
123.26, 127.60, 127.78, 129.54, 130.58, 133.00; (C18, C22), (C19,
C21), (C12, C14): 128.63, 129.10, 130.02; (N–ArtBu), (C2), (N–
1-Benzyl-1-(2-bromophenyl)-3-methyl-3-phenylurea 6c.
A
mixture of the urea 5c (149.5 mg, 0.39 mmol) and sodium
hydroxide (18.8 mg, 0.47 mmol, 1.2 eq) was dissolved in THF
(6 ml, dry) and the solution was stirring for 0.5 h before
addition of iodomethane (83.6 mg, 0.04 ml, 0.59 mmol, 1.5 eq).
After stirring for 18 h, first Et2O (5 ml) and then distilled H2O
(1 ml) were added. The aqueous phase was washed with Et2O
(3 × 10 ml) and the combined organic phases were dried over
Na2SO4. Evaporation and drying under high vacuum gave
140 mg (crude yield) of a highly viscous oil and a waxy solid.
The crude product was purified by column chromatography
using a mixture of petrol ether–ethyl acetate (10 : 1). The desired
product was obtained as a white solid (147 mg, 0.28 mmol,
70.8%), mp 101–102 ◦C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.45.
1H NMR (300 MHz, CDCl3) d 3.26 (s, 3H, N–CH3), 4.82 (s,
=
Ar), (C17): 138.16, 138.34, 138.98, 148.65; 155.16 (C O). m/z
(CI) 360 (100%, M + H+), 301 (57%, (M–tBu)+); m/z (EI) 301
(21%, (M–tBu)+), 182 (47%, (C7H7)–NH+–(C6H5)), 91 (100%,
(C7H7)+). (Found: MH+, 359.2118. C24H27O1 N2 requires MH,
359.2118). IR (film): m/cm−1 = 3421 (w) (N–H), (Ar–H): 3061
=
=
(w), 3030 (w); 2962 (w) (C–H alkyl), 1678 (C O), (C C): 1594
(m), 1521 (s), 1500 (m), 1486 (m), 1440 (s).
1-Benzyl-1-(2-fluorophenyl)-3-methyl-3-phenylurea
6a. A
mixture of the urea 5a (dry) (99.5 mg, 0.31 mmol) and sodium
hydride (62.2 mg, 1.55 mmol, 5 eq) was dissolved in DMF
(5 ml, dry). Iodomethane (221 mg, 0.10 ml, 1.55 mmol, 5 eq)
was added and after stirring for 18 h the excess of NaH and
MeI was quenched with H2O (3 ml). After washing the aqueous
phase with Et2O (5 × 10 ml), the combined Et2O phases were
dried over Na2SO4 and evaporated under high vacuum. The
crude product was purified by column chromatography using
a mixture of petrol ether–ethyl acetate (10 : 1). The desired
product was obt◦ained as a white solid (102 mg, 0.305 mmol,
98%), mp 80–82 C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.34. 1H
NMR (300 MHz, CDCl3) d 3.26 (s, 3H, N–Me), 4.80 (s, 2H,
Ph–CHAHB), 6.60 (dt, 3J = 7.6 Hz, 4J = 1.9 Hz, 1H, H4 or H5
or H13 or H20), 6.73 (mc, 2H, Ar–H), 6.82 (mc, 2H, Ar–H), 6.94
(mc, 2H, Ar–H), 7.07 (mc, 2H, Ar–H), 7.30 (mc, 5H, Ar–H).
13C NMR (75 MHz, CDCl3) d 39.96 (N–Me), 54.37 (Ph–CH2);
(C2), (C3), (C6), (C13), (C5), (C4), (C20), 116.0 (d, J = 20.4 Hz),
124.07 (d, J = 3.8 Hz), 125.38, 127.50 (d, J = 3.0 Hz), 127.62,
129.88 (d, J = 1.4 Hz); 125.93 (C11, C15); (C18, C22), (C19, C21),
(C12, C14): 128.42, 128.96, 129.18; (N–Ar), (C17), (C–NArF),
3
4
2H, PhCHAH, PhCHHB), 6.32 (dd, J = 7.7 Hz, J = 1.8 Hz,
1H, H3), 6.78 (mc, 3H, Ar–H), 7.02 (mc, 3H, Ar–H), 7.32 (mc,
7H, Ar–H). 13C NMR (75 MHz, CDCl3) d 40.37 (N–CH3),
54.35 (Ph–CH2), 123.60 (C–Br); (C6), (C13), (C4), (C20), (C5),
(C3): 125.65, 126.36, 127.45, 127.54, 127.55, 133.28; (C18, C22),
(C19, C21), (C14, C12): 128.43, 129.08, 129.51; (Ar–N), (C–CH2),
=
(N–ArBr): 138.11, 142.33, 145.57; 160.56 (C O). m/z (CI) 395
(100%, M + H+, 79Br), 397 (97%, M + H+, 81Br), 315 (50%,
+
(M–79Br)+), 91 (72%, C7H7 ); m/z (EI) (10%, (M–79Br)+), 91
(100%, C7H7 ), 77 (36%, C6H5 ). (Found: MH+, 395.0754.
+
+
C21H20O1 N2Br1 requires MH, 395.0754). IR (film): m/cm−1
=
(Ar–H): 3061 (w), 3029 (w); 2928 (w) (C–H alkyl), 1659 (s)
=
(C O), 1595 (m), 1584 (m), 1522 (m), 1494 (m), 1474 (m), 1454
(m), 1440 (m).
1-Benzyl-1-(2-iodophenyl)-3-methyl-3-phenylurea 6d. A mix-
ture of the urea 5d (dry) (128 mg, 0.30 mmol) and sodium hydride
(35.9 mg, 1.5 mmol, 5 eq) was dissolved in DMF (5 ml, dry).
Iodomethane (212 mg, 0.09 ml, 1.5 mmol, 5 eq) was added and
after stirring for 19 h the excess of NaH and MeI was quenched
with H2O (3 ml). After washing the aqueous phase with Et2O
(5 × 10 ml), the combined Et2O phases were dried over Na2SO4
and evaporated under high vacuum. The crude product was
purified by column chromatography using a mixture of petrol
ether–ethyl acetate (10 : 1). The desired product was obtained as
white crystals (119 mg, 0.27 mmol, 90%), mp 89–90 ◦C, Rf (4 :
1 petrol (40/60)–EtOAc) = 0.13. 1H NMR (300 MHz, CDCl3)
d 3.25 (s, 3H, N–CH3), 5.23 (s, 2H, Ph–CHAHB), 6.21 (dd, 3J =
7.8 Hz, 4J = 1.6 Hz, 1H, H6), 6.65 (dt, 3J = 7.7 Hz, 4J = 1.8 Hz,
1H, H4), 6.75 (mc, 2H, Ar–H), 7.00 (mc, 4H, Ar–H), 7.30 (mc,
=
(C O), (C–F): 138.20, 145.48, 156.32, 159.63, 160.92. m/z (CI)
335 (100%, M + H+), 91 (30%, (C7H7)+); m/z (EI) 91 (100%,
(C7H7)+). (Found: MH+,335.1556. C21H20O1 N2F1 requires MH,
335.1554). IR (film): m/cm−1 = (Ar–H): 3063 (w), 3031 (w);
=
2935 (w) (C–H alkyl), 1660 (s) (C O), 1596 (s), 1585 (m), 1499
(s), 1456 (m), 1436 (m), 1421 (m).
1-Benzyl-1-(2-chlorophenyl)-3-methyl-3-phenylurea 6b.
A
mixture of the urea 5b (138 mg, 0.41 mmol) and sodium
hydroxide (19.7 mg, 0.49 mmol, 1.2 eq) was dissolved in THF
(5 ml, dry) and the solution was stirring for 0.5 h before
addition of iodomethane (87.5 mg, 0.04 ml, 0.62 mmol, 1.5 eq).
After stirring for 18 h, first Et2O (5 ml) and then distilled H2O
(1 ml) were added. The aqueous phase was washed with Et2O
(3 × 10 ml) and the combined organic phases were dried over
Na2SO4. Evaporation and drying under high vacuum gave
140 mg (crude yield) of a highly viscous oil and a waxy solid.
The crude product was purified by column chromatography
using a mixture of petrol ether–ethyl acetate (10 : 1). The desired
product was obtai◦ned as a white solid (102 mg, 0.29 mmol,
70.8%), mp 94–96 C, Rf (4 : 1 petrol (40/60)–EtOAc) = 0.44.
1H NMR (300 MHz, CDCl3) d 3.25 (s, 3H, N–CH3), 4.82 (s,
2H, Ph–CHAHB), 6.39 (dd, 3J = 8.0 Hz, 4J = 1.6 Hz, 1H, H3),
3
4
5H, Ar–H), 7.65 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H, H3). 13C
NMR (75 MHz, CDCl3) d 40.72 (N–CH3), 54.63 (Ph–CH2),
99.64 (Ar–I); (C6), (C13), (C4), (C20), (C5), (C3): 125.74, 127.50,
127.58, 128.35, 131.22, 139.81; 126.56 (C11, C15); (C18, C22), (C19,
C21), (C12, C14): 128.47, 129.15, 129.62; (C17), (N–Ar), (N–ArI);
=
138.02, 145.50, 145.69; 160.18 (C O). m/z (CI) 443 (15%, M +
H+), 315 (49%, M + H+–I), 108 (100%, MeNH2 –(C6H5)), 91
+
(37%, C7H7 ); m/z (EI) 442 (5%, M+), 315 (28%, M + H+–I), 91
+
(100%, C7H7 ). (Found: MH+, 443.0616. C21H20O1 N2I1 requires
+
MH, 443.0615). IR (film): m/cm−1 = (Ar–H); 3061 (m), 3029
=
(m); (alkyl–H): 2963 (w), 2929 (m); (C O) 1656 (s); 1596 (s),
1495 (s), 1377 (s), 1019 (m), 750 (s), 722 (s), 697 (s).
3
4
6.76 (mc, 2H, Ar–H), 6.89 (dt, J = 7.7 Hz, J = 1.6 Hz, 1H,
1-Benzyl-1-(2-methylphenyl)-3-methyl-3-phenylurea 6e. A
3
4
H4), 7.02 (mc, 3H, Ar–H), 7.13 (dd, J = 8.1 Hz, J = 1.5 Hz,
1H, H6), 7.3 (mc, 6H, Ar–H). 13C NMR (75 MHz, CDCl3) d
40.20 (N–Me), 54.18 (Ph–CH2), 126.22 (C11, C15); (C6), (C13),
(C4), (C20), (C5), (C3), (Ar–Cl): 120.10, 125.58, 126.96, 127.25,
127.51, 129.99, 130.98; (C18, C22), (C19, C21), (C12, C14): 128.40,
mixture of the urea 5e (204 mg, 0.65 mmol) and sodium
hydroxide (31.0 mg, 0.77 mmol, 1.2 eq) was dissolved in THF
(5 ml, dry) and the solution was stirring for 0.5 h before addition
of iodomethane (137 mg, 0.06 ml, 0.97 mmol, 1.5 eq). After
stirring for 20 h, the same quantity of iodomethane (137 mg,
0.06 ml, 0.97 mmol, 1.5 eq) was added again and the reaction
mixture was stirred for the following 20 h. Then Et2O (5 ml)
and distilled H2O (1 ml) were added. The aqueous phase was
washed with Et2O (3 × 10 ml) and the combined organic phases
were dried over Na2SO4. Evaporation and drying under high
vacuum gave 220 mg (crude yield) of a highly viscous yellowish
oil. The crude product was purified by column chromatography
129.02, 129.44; (Ph–C), (N–ArCl), (N–Ar), 138.14, 140.88,
+
=
145.49; 160.75 (C O). m/z (CI) 351 (100%, M + H ), 91 (18%,
(C7H7)+); m/z (EI) 350 (4%, M+), 91 (100%, (C7H7)+). (Found:
MH+, 351.1254. C24H17O1N2Cl1 requires MH, 351.1254). IR
(film): m/cm−1 = (Ar–H): 3061 (w), 3029 (w); 2928 (w) (C–H
=
alkyl), 1657 (C O), 1595 (m), 1523 (m), 1494 (s), 1479 (s) 1454
(w), 1439 (m).
3 1 8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3

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+
using a mixture of petrol–diethyl ether (10 : 1). The desired
product was obtained as a white solid (100 mg, 0.30 mmol,
47%), mp 86–87 ◦C, Rf (4 : 1 petrol (40/60)–Et2O) = 0.15.
1H NMR (300 MHz, CDCl3) d 1.94 (s, 3H, Ar–CH3), 3.20 (s,
3H, N–CH3), 6.35 (d, 2J = 7.7 Hz, 1H, H3), 6.59 (mc, 1H,
Ar–H), 6.72 (mc, 2H, Ar–H), 6.96 (mc, 5H, Ar–H), 7.28 (mc,
5H, Ar–H). 13C NMR (75 MHz, CDCl3) d 17.96 (Ar–CH3),
40.42 (N–CH3), 55.02 (Ph–CH2); (C6), (C4), (C13), (C5), (C20),
(C3): 125.64, 126.27, 126.32, 127.46, 129.33, 130.63; 126.41
(C11, C15); (C18, C22), (C19, C21), (C12, C14): 128.38, 128.93,
(C6H5)), 91 (100%, C7H7 ); m/z (EI) 358 (3%, M+), 107 (77%,
MeNH+–(C6H5)), 91 (100%, C7H7 ). (Found: MH+, 359.2118.
+
C24H27O1 N2 requires MH+, 359.2118). IR (film): m/cm−1 = (Ar–
H): 3061 (w), 3034 (w); (alkyl–H): 2982 (m), 2962 (s), 2926 (m),
=
2913 (m), 2868 (m); (C O) 1645 (s); 1595 (s), 1493 (s), 1448 (s),
1420 (s), 1381 (s), 757 (s), 741 (s), 701 (s).
1-Benzyl-1-(2-tert-butylphenyl)-3-methyl-3-phenylurea
6h.
A mixture of the urea 5h (dry) (102 mg, 0.285 mmol) and sodium
hydride (34.2 mg, 1.43 mmol, 5 eq) was dissolved in DMF
(5 ml, dry). Iodomethane (202 mg, 0.09 ml, 1.43 mmol, 5 eq)
was added and after stirring for 16 h the excess of NaH and
MeI was quenched with H2O (3 ml). After washing the aqueous
phase with Et2O (5 × 10 ml), the combined Et2O phases
were dried over Na2SO4 and evaporated under high vacuum.
The crude product was purified by column chromatography
using a mixture of petrol ether–ethyl acetate (10 : 1). The
desired product was obtained as a waxy white mass (92 mg,
129.52; (C2), (N–ArMe), (N–Ar), (C17): 135.95, 138.32, 142.39,
+
=
146.01; 161.52 (C O). m/z (CI) 331 (100%, M + H ), 108
+
+
(44%, MeNH2 –(C6H5)), 91 (71%, C7H7 ); m/z (EI) 91 (100%,
C7H7 ). (Found: MH+, 331.1800. C22H23O1 N2 requires MH,
+
331.1805). IR (film): m/cm−1 = (Ar–H): 3062 (m), 3029 (m);
=
(alkyl–H) 2927 (m); (C O) 1655 (s); 1596 (s), 1495 (s), 1378 (s),
1328 (s), 753 (s), 723 (s), 700 (s).
1
1-Benzyl-1-(2-ethylphenyl)-3-methyl-3-phenylurea
6f. A
0.25 mmol, 87%), Rf (4 : 1 petrol (40/60)–EtOAc) = 0.34. H
mixture of the urea 5f (131 mg, 0.40 mmol) and sodium
hydroxide (19.1 mg, 0.48 mmol, 1.2 eq) was dissolved in THF
(5 ml, dry) and the solution was stirring for 0.5 h before
addition of iodomethane (84.3 mg, 0.04 ml, 0.60 mmol, 1.5 eq).
After stirring for 60 h, first Et2O (5 ml) and then distilled H2O
(1 ml) were added. The aqueous phase was washed with Et2O
(3 × 10 ml) and the combined organic phases were dried over
Na2SO4. Evaporation and drying under high vacuum gave
137 mg (crude yield) of a highly viscous oil. The crude product
was purified by column chromatography using a mixture of
toluene–ethyl acetate (20 : 1). The desired product was obtained
as a white solid (52 mg, 0.15 mmol, 37.8%), Rf (4 : 1 petrol
(40/60)–Et2O) = 0.15. 1H NMR (300 MHz, CDCl3) d 1.05
NMR (300 MHz, CDCl3) d 1.48 (s, 9H, 3 × CH3), 3.10 (s, 3H,
2
2
N–CH3), 3.82 (d, J = 14.5 Hz, 1H, Ph–CHAH), 5.71 (d, J =
3
4
14.5 Hz, 1H, Ph–CHHB), 5.81 (dd, J = 8.0 Hz, J = 1.3 Hz,
3
4
1H, H3), 6.36 (dt, J = 8.0 Hz, J = 1.5 Hz, H4), 6.57 (mc,
2H, Ar–H), 6.94 (mc, 6H, Ar–H), 7.39 (mc, 4H, Ar–H). 13C
NMR (75 MHz, CDCl3) d 32.49 (3 × CH3), 36.35 (CtertBu), 41.44
(N–CH3), 56.82 (Ph–CH2); (C6), (C4), (C13), (C3), (C5), (C20):
125.54, 125.80, 126.72, 127.63, 129.17, 133.08; 126.98 (C11,
C15); (C18, C22), (C19, C21), (C12, C14): 128.63, 129.13, 129.50;
(Ar–CtBu), (C17), (N–ArtBu), (N–Ar): 139.15, 141.17, 146.32,
146.80; 161.55 (C = O). m/z (CI) 373 (100%, M + H+), 315
+
(18%, M + H+–tBu), 108 (72%, MeNH2 –(C6H5)), 91 (63%,
C7H7 ); m/z (EI) 315 (27%, M + H+–tBu), 91 (100%, C7H7 ).
+
+
3
3
(Found: MH+, 373.2284. C25H29O1 N2 requires MH, 373.2274).
(s, J = 7.6 Hz, 3H, CH3), 2.29 (q, J = 7.6 Hz, 2H, CH2),
IR (film): m/cm−1 = 2960 (alkyl–H) (m); 1649 (C O) (s); 1595
3.17 (s, 3H, N–CH3), 4.55 (bs, 1H, Ph–CHAH), 4.92 (bs, 1H,
=
3
4
Ph–CHHB), 6.29 (dd, J = Hz, J = Hz, 1H, H3), 6.78 (mc,
3H, Ar–H), 7.00 (mc, 5H, Ar–H), 7.29 (mc, 5H, Ar–H). 13C
NMR (75 MHz, CDCl3) d 13.98 (CH3Et), 23.10 (CH2Et), 40.52
(N–CH3), 55.39 (Ph–CH2); (C6), (C4), (C13), (C5), (C20), (C3):
125.57, 125.99, 126.46, 127.44, 128.26, 129.43; 126.53 (C11,
C15); (C22, C18), (C19, C21), (C12, C14); 128.39, 128.94, 129.51;
(m), 1494 (m), 1380 (m), 756 (m), 696 (m).
1-(2-Isopropylphenyl)-1,3-dimethyl-3-phenylurea 6i. Sodium
hydroxide (1.40 g, 35 mmol), potassium carbonate (1.00 g,
7.0 mmol), tetrabutylammonium hydrogen sulfate (0.05 g,
1.4 mmol) and 1-(2-isopropylphenyl)-3-phenylurea 10g (1.80 g,
7.0 mmol) were suspended in toluene (50 cm3) and the mixture
heated to reflux for 1 h. Dimethyl sulfate (2.00 g, 15 mmol) was
added dropwise and reflux continued for 18 h. After cooling
to room temperature, the mixture was filtered, the filtrate
washed with 1 N hydrochloric acid (3 × 50 cm3) and water
(2 × 150 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (SiO2; EtOAc–petrol, 15 : 85) to give 1-(2-
isopropylphenyl)-1,3-dimethyl-3-phenylurea 6i (1.80 g, 91%),
(C2), (N–Ar), (C17), (N–ArtBu): 138.32, 141.40, 141.78, 146.08;
+
=
161.79 (C O). m/z (CI) 345 (100%, M + H ), 108 (11%,
+
+
+
MeNH2 –(C6H5)), 91 (10%, C7H7 ); m/z (EI) 91 (81%, C7H7 ).
IR (film): m/cm−1 = (Ar–H): 3061 (w), 3029 (w); (C–H alkyl):
=
2966 (w), 2932 (w), 2875 (w); 1652 (C O), 1596 (s), 1584 (m),
1494 (s), 1452 (m), 1433 (m), 1421 (m). (Found: MH+, 345.1966.
C23H25O1 N2 requires MH, 345.1961).
1-Benzyl-1-(2-isopropylphenyl)-3-methyl-3-phenylurea 6g.
A
as colourless cubes, mp 82–84 ◦C (from EtOAc–petrol); Rf
mixture of the urea 5g (dry) (200 mg, 0.581 mmol) and sodium
hydride (69.8 mg, 2.91 mmol, 5 eq) was dissolved in DMF (5 ml,
dry). Iodomethane (413 mg, 0.18 ml, 2.91 mmol, 5 eq) was
added and after stirring for 21 h the excess of NaH and MeI was
quenched with H2O (3 ml). After washing the aqueous phase
with Et2O (5 × 10 ml), the combined Et2O phases were dried
over Na2SO4 and evaporated under high vacuum. The crude
product was purified by column chromatography using a mixture
of petrol ether–ethyl acetate (10 : 1). The desired product was
obtained as white crystals (171 mg, 0.48 mmol, 82%), mp 112–
114 ◦C. 1H NMR (300 MHz, CDCl3) d 0.78 (bs, 3H, MeA), 1.25
(bs, 3H, MeB), 2.84 (sept, 3J = 6.8 Hz, 1H, iso-H), 3.15 (s, 3H,
1
(EtOAc–petrol, 1 : 4) 0.25; mmax (film)/cm−1 1710 (C O); H
=
NMR (300 MHz, CDCl3) d 7.52–7.20 (m, 2H, CH-a) 7.17 (dd,
1H, J = 8.0 and 2.0, CH-d), 7.11–6.78 (m, 3H, CH-c, CH-e and
CH-f), 6.76–6.69 (m, 2H, CH-b), 6.4 (dd, 1H, J = 8.0 and 1.0,
CH-g), 3.18 [s, 3H, (NCH3)A], 3.13 [s, 3H, (NCH3)B], 2.95 (sept,
1H, J = 7.0, CH-h), 1.22 [m, 6H, (CH3)A and (CH3)B]. 13C NMR
=
(75 MHz, CDCl3) d 162.4 (C O), 146.5 (C), 146.1 (C), 142.4 (C),
129.1 (CH), 129.0 (CH), 128.9 (CH), 126.8 (CH), 126.4 (CH),
126.2 (CH), 125.6 (CH), 40.6 (NCH3)A, 40.1 (NCH3)B, 27.9 (CH)
and 24.5 (CH3); m/z (CI) 283 (100%, M + H+); (Found: M +
H+, 283.1803, C18H23N2O requires M + H, 283.1805).
1,3-Diethyl-1-(2-isopropylphenyl)-3-phenylurea 6j. Sodium
hydroxide (1.60 g, 40 mmol), potassium carbonate (1.12 g,
7.9 mmol), tetrabutylammonium hydrogen sulfate (0.06 g,
0.16 mmol) and 1-(2-isopropylphenyl)-3-phenylurea 10g (2.0 g,
7.9 mmol) were suspended in toluene (50 cm3) and the mixture
heated to reflux for 1 h. Ethyl iodide (0.63 cm3, 17 mmol) was
added dropwise and reflux continued for 18 h. After cooling
to room temperature, the mixture was filtered, the filtrate was
washed with 1 N hydrochloric acid (3 × 30 cm3) and water
2
2
N–CH3), 4.61 (d, J = 13.5 Hz, 1H, Ph–CHAH), 4.94 (d, J =
13.8 Hz, 1H, Ph–CHHB), 6.11 (dd, 3J = 8.1 Hz, 4J = 1.3 Hz, 1H,
H3), 6.56 (dt, 3J = 7.6, 4J = 1.6 Hz, 1H, H4), 6.68 (m, 2H, Ar–H),
6.94–7.14 (m, 5H, Ar–H), 7.22–7.36 (m, 5H, Ar–H). 13C NMR
(75 MHz, CDCl3) d 23.18 (iso-MeA), 24.94 (iso-MeB), 27.63 (iso-
CH), 40.67 (N–Me), 55.81 (Ph–CH2), (C6), (C4), (C13), (C5), (C3),
(C20): 125.61, 125.71, 126.48, 126.68, 127.54, 129.34; 126.51 (C11,
C15); (C18, C22), (C19, C21), (C12, C14): 128.52, 129.08, 129.67; (C17),
(C2), (N–Arisoprop), (N–Ar): 138.40, 140.71, 146.53, 146.56; 162.32
+
+
=
(C O). m/z (CI) 359 (77%, M + H ), 108 (82%, MeNH2 –
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
3 1 8 1

View Online
(20 cm3) and the mixture heated at reflux for 1 h. Benzyl bromide
(2 × 25 cm3), dried (MgSO4), filtered and concentrated under
reduced pressure to give a mixture of products as analysed by
NMR. The residue (1.45 g) was dissolved in THF (50 cm3)
and sodium hydride (0.28 g, 7.0 mmol in mineral oil) was
added before being stirred at room temperature for 2 h. Ethyl
iodide (0.56 cm3, 11 mmol) was added and the mixture stirred
at room temperature for 18 h. Water (30 cm3) was added
and extracted with EtOAc (3 × 30 cm3) and the combined
organic fractions were dried (MgSO4), filtered and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (SiO2; EtOAc–petrol, 1 : 9) to give 1,3-
diethyl-1-(2-isopropylphenyl)-3-phenylurea 6j (1.35 g, 55%), as
(0.54 cm3, 4.2 mmol) was added dropwise and reflux continued
for 18 h. After cooling to room temperature, the mixture was
filtered, the filtrate washed with 1 N hydrochloric acid (3 ×
30 cm3) and water (2 × 25 cm3), dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (SiO2; EtOAc–petrol, 1 : 9)
to give 1,3-dibenzyl-1-(2-bromo-4-methylphenyl)-3-phenylurea
6l (0.66 g, 73%), as white needles, mp 111–113 ◦C (from
EtOAc–petrol); Rf (EtOAc–petrol, 1 : 4) 0.43; mmax (film)/cm−1
1
=
1711 (C O) and 734 (C–Br); H NMR (300 MHz, CDCl3) d
7.35–7.20 [m, 10H, (NCH2Ar)A and (NCH2Ar)B], 7.16 (d, 1H,
J = 1.0, CH-f), 6.99–6.92 (m, 3H, CH-a and CH-c), 6.67–6.59
(m, 2H, CH-b), 6.51 (ddq, 1H, J = 8.1, 2.0, 1.0, CH-e), 6.13
(d, 1H, J = 8.1, CH-d), 5.45–4.30 [m, 4H, (NCH2Ar)A and
(NCH2Ar)B], 2.18 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) d
a colourless oil, Rf (EtOAc–petrol, 1 : 4) 0.50; mmax (film)/cm−1
1
=
2958 and 2912 (CH3), 2880 (CH) and 1710 (C O); H NMR
(300 MHz, CDCl3) d 7.16 (dd, 1H, J = 8.0 and 2.0, CH-d),
7.10–6.96 (m, 4H, CH-a and CH-b), 6.71–6.60 (m, 3H, CH-c,
CH-e and CH-f), 6.28 (dd, 1H, J = 8.1 and 1.0, CH-g), 3.75 [br.,
2H, (NCH2CH3)A], 3.40 [br., 2H, (NCH2CH3)B], 3.00 (sept, 1H,
J = 7.0, CH-h), 1.22 [br. m, 6H, (CH3)A and (CH3)B], 1.18 [t,
=
160.6 (C O), 143.5 (C), 139.4 (C), 138.4 (C), 138.2 (C), 137.7
(C), 133.5 (CH), 131.2 (CH), 129.6 (CH), 129.5 (CH), 128.7
(CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 127.7 (CH), 127.5
(CH), 127.3 (CH), 125.8 (CH), 123.2 (C), 56.1 (NCH2Ar)A, 54.4
(NCH2Ar)B and 20.8 (CH3); m/z (CI) 485 (25%, M + H+), 281
(30, M + H+–Br) and 318 (65, M + H+–Br–C7H7); (Found: M+,
484.1134, C28H25N2OBr requires M, 484.1145).
3H, J = 7.0, (NCH2CH3)A], 1.10 [t, 3H, J = 7.0, (NCH2CH3)B].
13
=
C NMR (75 MHz, CDCl3) d 161.8 (C O), 146.4 (C), 144.2
(C), 141.1 (C), 129.4 (CH), 128.8 (CH), 127.7 (CH), 126.5
(CH), 126.4 (CH), 125.8 (CH), 125.5 (CH), 47.1 (NCH2CH3)A,
46.7 (NCH2CH3)B, 27.4 (CH), 24.4 (CH3)A, 22.4 (CH3)B, 14.0
(NCH2CH3)A and 13.3 (NCH2CH3)A; m/z (CI) 311 (100%, M +
H+); (Found: M + H+, 311.2116, C20H27N2O requires M + H,
311.2118).
Acknowledgements
We are grateful to the EPSRC, the EU (Erasmus/Socrates),
Pfizer, the Leverhulme Trust, the MEC (Spain, CTQ2004-04701)
and DURSI-Catalonia (grant 2001SGR-00083) for funding.
1,3-Dibenzyl-1-(2-isopropylphenyl)-3-phenylurea 6k. Sodium
hydroxide (1.60 g, 40 mmol), potassium carbonate (1.12 g,
7.9 mmol), tetrabutylammonium hydrogen sulfate (0.06 g,
0.16 mmol) and 1-(2-isopropylphenyl)-3-phenylurea 10g (2.0 g,
7.9 mmol) were suspended in toluene (50 cm3) and the mixture
heated to reflux for 1 h. Benzyl bromide (0.93 cm3, 17 mmol) was
added dropwise and reflux continued for 18 h. After cooling to
room temperature, the mixture was filtered, the filtrate washed
with 1 N hydrochloric acid (3 × 30 cm3) and water (2 ×
25 cm3), dried (MgSO4), filtered and concentrated under reduced
pressure to give a mixture of products as analysed by NMR. The
residue (1.26 g) was dissolved in THF (50 cm3), sodium hydride
(0.14 g, 4.0 mmol in mineral oil) was added and stirred at room
temperature for 2 h. Benzyl bromide (0.35 cm3, 6 mmol) was
added dropwise and the mixture stirred at room temperature for
18 h before water (30 cm3) and EtOAc (30 cm3) were added. The
aqueous layer was extracted with EtOAc (3 × 30 cm3) and the
combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure. The residue was purified
by flash silica chromatography (SiO2; EtOAc–petrol, 1 : 9) to
give 1,3-dibenzyl-1-(2-isopropylphenyl)-3-phenylurea 95 (1.30 g,
40%), as colourless cubes, mp 112–114 ◦C (from EtOAc–petrol);
References
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=
(CH3), 2884 (CH) and 1710 (C O); H NMR (300 MHz, CDCl3)
d 7.45–7.20 [m, 10H, (NCH2Ar)A and (NCH2Ar)B], 7.16 (dd, 1H,
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=
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(C), 144.0 (C), 140.8 (C), 138.5 (C), 138.1 (C), 129.8 (CH),
129.6 (CH), 128.6 (CH), 128.7 (CH), 128.5 (CH), 128.3 (CH),
128.1 (CH), 127.9 (CH), 127.5 (CH), 127.4 (CH), 126.7 (CH),
126.4 (CH), 125.7 (CH), 56.2 (NCH2Ar)A, 56.0 (NCH2Ar)B, 27.6
(CH), 25.2 (CH3)A and 23.3 (CH3)B; m/z (CI) 435 (25%, M +
H+); (Found: M + H+, 435.2447, C30H31N2O requires M + H,
435.2431).
1,3-Dibenzyl-1-(2-bromo-4-methylphenyl)-3-phenylurea
6l.
Sodium hydroxide (0.39 g, 10 mmol), potassium carbonate
(0.28 g, 1.9 mmol), tetrabutylammonium hydrogen sulfate
(0.01 g, 0.04 mmol) and 1-(2-bromo-4-methylphenyl)-
3-phenylurea (0.60 g, 1.9 mmol) were suspended in toluene
3 1 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3

View Online
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 7 3 – 3 1 8 3
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