Conformation and stereodynamics of 2,2′-disubstituted N,N′-diaryl ureas

Article abstract of DOI:10.1039/b802673d

Except in the most hindered of cases, N,N′-diaryl N,N′-dimethyl ureas adopt a conformation with the two aryl rings disposed cis to one another. Variable temperature NMR studies reveal the rate at which the Ar-N bonds rotate as well as the conformational preference of ortho disubstituted ureas in which more than one cis orientation is possible. In general, a conformation in which the aryl rings lie close in space but with their most bulky 2-substituents aligned anti is preferred, but with particularly bulky 2-substituents, conformations in which one of the aryl rings points away from the other may also be populated. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802673d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Conformation and stereodynamics of 2,2ꢀ-disubstituted N,Nꢀ-diaryl ureas†
Jonathan Clayden,*a Lo¨ıc Lemie`gre,‡a Mark Pickwortha and Lyn Jonesb
Received 18th February 2008, Accepted 13th May 2008
First published as an Advance Article on the web 16th June 2008
DOI: 10.1039/b802673d
Except in the most hindered of cases, N,Nꢀ-diaryl N,Nꢀ-dimethyl ureas adopt a conformation with the
two aryl rings disposed cis to one another. Variable temperature NMR studies reveal the rate at which
the Ar–N bonds rotate as well as the conformational preference of ortho disubstituted ureas in which
more than one cis orientation is possible. In general, a conformation in which the aryl rings lie close in
space but with their most bulky 2-substituents aligned anti is preferred, but with particularly bulky
2-substituents, conformations in which one of the aryl rings points away from the other may also be
populated.
stacking.10,14–16 It has been suggested that a preference for p-
Introduction
stacking may be overcome, at least in the solid state, by electron-
deficiency in the two aromatic rings.15 In this paper we describe
our kinetic and thermodynamic investigation of the conformation
and stereodynamics of some simple ureas.17
Foldamers – oligomers which adopt a well-defined conformation
over nanometre scales1,2 – are a field of interest because of
the potential use in materials or biological chemistry of such
molecules. Many foldamers have been shown to adopt helical
conformations, and in some cases those conformations have
been controlled using side chain or terminal stereochemistry.3,4
Foldamers made from polyamides or polyureas can be considered
structurally analogous to helical peptides, and most foldamers
of this type maintain their conformation through a network of
hydrogen bonds.2,4,5
We are particularly interested in the potential of foldamers for
transmission of stereochemical influences, and for that reason have
sought to work with oligomers whose structure is compatible with
a variety of potentially stereoselective reactions and which there-
fore do not contain acidic NH protons.6 Governing conformation
in such molecules is a challenge, but we have found that dipole
interactions can be used to orientate a series of tertiary amide
groups along a polyaromatic chain.7 p-Stacking interactions8 can
also give rise to global conformational control: for example,
extended stacked structures built from ureas of diamines have
been reported to adopt helical conformations.9
Results and discussion
Synthesis of the ureas
Simple symmetrical ureas 3 (R1 = R2, R3 = H, except 3k which
was made by the method used for unsymmetrical ureas described
below) were made by condensing 2-substituted anilines 1 with
diphosgene 4 or triphosgene 518 and double methylation of the
products 2 (Scheme 1; Table 1, entries 1–4 and 6). Condensation
of N-methylanilines was slower, but avoided the methylation step
and gave acceptable yields of products (entry 2).
N-Methylation of aromatic amides and ureas has been proposed
as a general strategy for control of conformation about the C–N
bonds of such compounds, since it leads to structures in which
close Ar–Ar contacts are prevalent.10–13 However, little detailed
work has been reported on the conformational preferences of
simple mono-ureas, despite the fact that the helicity of an oligo-
urea is dependent on the adoption by each individual urea linkage
of a well-defined local conformation.
N,Nꢀ-Dimethyl-N,Nꢀ-diaryl ureas generally adopt a confor-
mation about the two N–CO bonds that allows the aryl rings
to lie cis to one another, presumably because of favourable p-
aSchool of Chemistry, University of Manchester, Oxford Road, Manchester,
M13 9PL, U.K. E-mail: clayden@man.ac.uk
bPfizer Central Research Ltd, Sandwich, Kent, CT13 9NJ, UK
† Electronic supplementary information (ESI) available: Additional exper-
imental information. See DOI: 10.1039/b802673d
‡ Current address: Ecole Nationale Supe´rieure de Chimie de Rennes,
CNRS UMR6226 “Sciences Chimiques de Rennes”, Av. G. Leclerc, 35700
Rennes, France.
Scheme 1 Synthesis of ureas.
2908 | Org. Biomol. Chem., 2008, 6, 2908–2913
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Table 1 Symmetric and unsymmetrical ureas
Entry Reagent R1
R2
R3
Yield 2 Product Yield 3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4
F
Cl
Br
Me
Et
F
Cl
Br
Me
Et
H
H
H
H
H
H
H
H
H
H
H
90
70
65
94
96
95
97
98
97
—
98
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
95
4
5
70a; 65b
95
4
Fig. 1 Conformation and Ar–N rotation in 3l–u.
4
93
81
88
96
7a
4
Et
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
conformation (in the solid state) is N,Nꢀ-dimethyl-N,Nꢀ-bis(2,4-
dinitrophenyl)urea.15
i-Pr
Me
Et
i-Pr
t-Bu
F
Cl
Br
I
Me
Et
i-Pr
t-Bu
OMe
OCF3 Me
t-Bu
6a
6a
4
95
79c
95
The diastereotopicity of the 2,6-dimethyl groups furthermore
indicates that both Ar–N bonds rotate slowly on the NMR
timescale. Raising the temperature at which the 1H NMR spectrum
was acquired led to coalescence of the methyl signals. Rotation
about either Ar–N bond interconverts these diastereotopic signals
MeA and MeB (Fig. 1), and dynamic NMR techniques (modelling
line broadening at increasing temperature in toluene using com-
mercial software gNMR to quantify exchange rates) and Eyring
analysis of the exchange rates obtained21 allowed us to extract
the associated free energies of activation DG‡. These values can
be interpreted as rates for Ar–N bond rotation about the less
hindered of the two Ar–B bonds (though an alternative mechanism
of interconversion, in which Ar–N rotation is not rate determining,
is discussed below), and their values at temperatures close to
the coalescence point are reported in Table 2. For purposes of
comparison, estimates of the half life for interconversion of the
conformers extrapolated to 298 K are also given in Table 2. No
coalescence was observed in the case of 3s – this compound is
discussed further below.
Half-lives for conformational interconversion are consistent
with those published for related compounds,19 and increase
slightly with increasing steric hindrance, though the steric effect
is relatively small (except when R1 = t-Bu), presumably either
because the R1 substituent moves away from the other ring during
conformer interconversion about the Ar–N bond or because Ar–N
rotation is not in fact rate determining in most cases (see below).
Electron-withdrawing substituents have a lowering effect on the
barrier height, perhaps by weakening the urea conjugation and
allowing greater N–CO flexibility or by stabilizing the coplanar
arrangement the ring, and the urea must pass through at the
transition state for rotation. Only 3s has a barrier high enough to
suggest resolvability into atropisomers22 – the estimated minimum
barrier to enantiomerisation in this compound suggests a room
3j
3k
3l
6a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6c
Me 80
Me 93
Me 78
Me 86
Me 86
Me 97
Me 98
Me 98
Me 96
Me 33
97
96
98
77
95
97
94
90
3m
3n
3o
3p
3q
3r
3s
3t
66
3u
3v
95
H
H
90d
70d
a From 2 using dimethyl sulfate; b From 5 using N-methyl-2-bromoaniline;
c Yield from 1. d See references.19,20
Unsymmetrical ureas were made by one of two methods. When
an appropriate isocyanate 6 was available, an aniline 1 was added
to an isocyanate 6 and the product was methylated (Table 1, entries
8–21). With some relatively unhindered isocyanates, however, sig-
nificant amounts of symmetrical ureas derived from the isocyanate
component of the mixture were also formed, presumably by in situ
hydrolysis of the isocyanate to an aniline. Replacing the isocyanate
with an O-phenyl or O-p-nitrophenyl carbamate 7 (formed by
addition of the aniline to phenyl or p-nitrophenyl chloroformate)
solved this problem (entry 6). The “homocoupling” problem was
much less significant when the isocyanate 6 was 2,6-disubstituted.
Activated carbamates were also convenient alternatives when the
appropriate isocyanates were not readily available commercially.
Yields of the additions and methylations were good except in the
cases with deactivated anilines (entry 21).
Conformation and stereodynamics
Many of the ureas 3 displayed exchange-broadened 1H NMR
spectra at room temperature. In most cases, however, the ex-
changing peaks decoalesced and were sharp at temperatures
below −50 ◦C in toluene. At such temperatures, ureas 3l–u show
only one set of peaks, which includes (in most cases) a pair of
diastereotopic methyl groups. Results described below show that
urea N–CO bonds rotate slowly on the NMR timescale below
−50 ◦C, so the simplicity of these spectra suggests that only
a single N–CO–N conformer is populated in solution. Previous
reports of conformational preference in N,Nꢀ-diaryl-N,Nꢀ-dialkyl
ureas have concluded that the conformation in which both aryl
rings lie close to one another (the cis,cis or endo conformation
shown in Fig. 1) is generally preferred.10,14–16 Exo conformers
(see Fig. 3) of N,Nꢀ-diaryl-N,Nꢀ-dimethyl ureas are generally not
observed: the only known example of such a urea favouring the exo
Table 2 Activation parameters associated with bond rotation in 3l–u
Entry
Urea
R1
DG‡/kJ mol−1
T/Ka
t
1/2/ms (298 K)b
1
2
3
4
5
6
7
8
9
3l
F
Cl
Br
I
Me
Et
i-Pr
t-Bu
OMe
OCF3
38.0 1.0
50.9 1.5
56.3 1.5
62.6 1.5
52.9 1.0
56.8 1.5
61.7 1.5
>84c
193
233
263
288
253
273
298
383
233
183
0.02
2.4
5.0
15.6
2.6
5.2
7.5
>5800
2.2
3m
3n
3o
3p
3q
3r
3s
3t
48.9 1.5
39.4 1.0
10
3u
0.59
a Temperature for which DG‡ is reported. b Estimated by extrapolation of
the Eyring plot to 298 K. c Estimated minimum value: no coalescence at
110 ◦C.
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Table 3 Activation parameters and ratios associated with conformer interconversion in 3
Entry Urea R1
R4
Ratio of conformers anti-3:syn-3a (T/◦C)b
t
1/2/ms (298 K) DG‡min–maj/kJ mol−1 (298 K) DG‡maj–min/kJ mol−1 (298 K)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
F
F
Broad (all)
—
0.15
5.0
0.11
3.4
4.0
—
—
Cl
Br
Me
Et
Et
Cl
Br
Me
Et
57 : 43 (−90)
70 : 30 (−75)
50 : 50 (−70)
50 : 50 (−80)
51.9 1.8
60.2 1.5
51.4 3.2
59.8 1.2
59.8 1.5
62.5 1.5
58.2 1.3d
60.5 1.0e
59.6 1.0d
60.9 1.0e
—
52.4 1.8
61.5 1.5
51.4 3.2
59.8 1.2
60.6 1.5
64.2 1.5
58.2 1.3d
62.1 1.0e
59.6 1.0d
62.5 1.0e
—
i-Pr 60 : 40 (−50)
3g
3h
i-Pr i-Pr 70 : 30 (−30)
13.3
Me
Et
t-Bu 35 : 35 : 15 : 15 (−90)
1.8d
5.9e
3.1d
7.0e
6.1d
70 : 30 (−20)
t-Bu 35 : 35 : 15 : 15 (−90)
70 : 30 (−50)
9
3i
10
11
12
3j
i-Pr t-Bu Mixture (−90)
73 : 27 (−50)
26e
64.1 1.5e
—
—
65.9 1.5e
—
—
3k
3v
t-Bu t-Bu Mixture (−90)
31d
—
60 : 40 (+100)
t-Bu
H
60 : 40 (−90)c
2.6
58.9 0.9
59.5 0.9
a Arbitrary assignment of anti stereochemistry to major conformer. b In d8-toluene unless otherwise stated. c In CD3OD. d Faster of two rotational
processes. e Slower of two rotational processes.
temperature half-life of racemisation of at least minutes. The
corresponding half-life for the other compounds is of the order
of milliseconds.
−10 and +20 ◦C, according to peak separation. A related study of
an N,Nꢀ-dimethyl-bis(1-naphthyl)urea reported observation of an
“uninformative” mixture of conformers.16
In contrast with ureas 3l–u, ureas 3a–g showed two sets of
peaks in their 1H NMR spectra, corresponding to two conformers,
at the slow exchange limit. As shown in Table 3, ratios of the
conformers varied from 1 : 1 to 4 : 1, depending on the sizes
of R1 or R2, and we assign them the structures syn-3 and anti-3
illustrated in Fig. 3. The paired signals coalesce on raising the
Given the known preference of similar ureas for cis,cis (endo)
conformations, we assume the conformational interconversion
observed by NMR is that between anti- and syn-3a–g, as illustrated
in Fig. 3. We assume that the major conformer has the less ster-
ically hindered anti stereochemistry.23 We discount an alternative
possibility, that one of the conformers results from isomerisation
about the N–CO bond (the exo conformers in Fig. 3), since
such conformers would then likewise have been observed in 3l–
1
temperature. Fig. 2 shows an example of the typical set of H
NMR spectra obtained for 3g, illustrating paired signals at low
temperature and the coalescences as the temperature rises. In this
case, signals assigned to the two conformers coalesce between
1
u. Moreover, both conformers display H NMR signals in the
region d 7.0–6.0, suggestive of a close Ar–Ar interaction.10,12
Fig. 3 Interconverting conformers of ureas 3a–k.
Using the same dynamic NMR techniques as for 3l–u21 gave
exchange rates associated with the interconversion of these
conformers. As in Table 2, we associate these values with the rate of
Ar–N bond rotation, though a possible alternative interpretation
is that interconversion takes place via exo conformers with rate-
determining N–CO rotation. Fig. 4 illustrates the lineshapes
modelled at a series of temperatures around Tc, the coales-
cence temperature, for the ortho protons of 3e. The ratios of
the two conformers observed at the slow exchange limit are
Fig. 2 VT NMR study of monourea 3g. Signals labelled a correspond to
anti-3g; signals labelled s correspond to syn-3g.
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dinitrophenyl)ureas15) is provided by 3v.20 The symmetry of one
of the rings precludes the existence of syn and anti isomers, but
this compound nonetheless exhibits two clean sets of peaks in its
1H NMR spectrum in a 60 : 40 ratio at −90 ◦C which coalesce
at around −20 ◦C. One (the less abundant) of these sets of peaks
clearly lacks the shielded aromatic 1H NMR signals characteristic
of the p-stacked ureas,16 as expected for an exo conformer. We
speculate that once the combined steric bulk carried by the two
rings reaches a certain point, steric repulsion begins to counteract
p-stacking interactions: a t-butyl group on either ring is sufficient
to provide such a degree of repulsion.
On warming to around −50 to −20 ◦C, the signals in 3h–k
coalesce in pairs to give two sets of peaks in the ratios shown in
Table 3. At higher temperatures, coalescence of the resulting pairs
of signals takes place for 3h–j, as observed for 3b–g. Table 3 shows
that the barriers to both bond rotations are similar in magnitude.
The complexity of the signals arising from the interconverting
mixture of four conformers at low temperature makes further
detailed analysis impossible. The second coalescence does not take
1
place for 3k, whose H NMR spectrum displays two conformers
(in a ratio of about 60 : 40) at least up to 100 ◦C.
The conformational mixtures observed in ureas 3a–k suggest
that further extension of these compounds into oligoureas should
serve only to compound the complexity of the conformational
mixtures. This is clearly at odds with the reported well-defined
helical conformations of more extended oligoureas.9 Further work
aimed at understanding the origin of the conformation of helical
oligoureas is under way.
Experimental
Fig. 4 Modelling lineshape in 3e (ortho protons).
Full experimental data is given in the supporting information.
Typical procedures are listed below. Details of instrumentation
etc. have been reported before.13
presented in Table 3, along with half-lives for interconversion
of the conformers obtained by extrapolating (for purposes of
comparison) the Eyring plots to 298 K. The rates are consistent
with those previously determined for simpler analogues of 3,16,19
and (like the conformational ratios) are only weakly dependent
on steric hindrance, presumably either because R1 or R4 moves
away from the other ring during the rotation or because the
interconversion does indeed proceed through rate-determining
N–CO rotation. Conformational exchange in 3a was too fast at
accessible temperatures to determine kinetic parameters by VT
NMR.
t-Butyl substituted ureas 3h–k display different conformational
behaviour. At low temperature (−90 ◦C in toluene or MeOH), four
sets of peaks become apparent, presumably a result of appreciable
population of conformers represented in Fig. 3 as exo-anti-3 and
exo-syn-3. Two of the conformers are similar to those seen in 3d–g
in that they display aromatic signals in the d 6.6–6.0 ppm region,
and we assume that these are endo conformers. The other two
conformers have aromatic signals lying around d 7.0 ppm, and
we assume these are exo conformers, populated because of the
greater steric hindrance experienced in these heavily substituted
ureas. Although difficult to quantify precisely because of exchange
broadening, the population of the exo conformers increases with
increasing steric hindrance, and in 3k the upfield endo signals
form only perhaps 10% of the total aromatic signals. Evidence
that the additional pairing of signals arises from the presence of
exo conformers (which are reported to be favoured in bis(2,4-
1,3-Bis(2-isopropylphenyl)urea, 2g
2-Isopropylaniline (1.35 g, 1.42 cm3, 10 mmol), was dissolved
◦
in CH2Cl2 (20 cm3) at 0 C and triethylamine (2.2 g, 3.1 cm3,
22 mmol) added in one portion. Diphosgene (0.99 g, 0.60 cm3,
5.0 mmol) was added dropwise and the reaction mixture allowed
to warm to room temperature over 18 h. The white precipitate
was isolated and recrystallised from EtOAc–pentane to give 1,3-
bis(2-isopropylphenyl)urea 2g (2.87 g, 97%), as white plates, m.p.
188–190 ◦C (from EtOAc–pentane); Rf (EtOAc–pentane, 3 : 7)
0.50; tmax (film)/cm−1 3318 and 3302 (N–H) and 1647 (C O); dH
=
(400 MHz; d6-DMSO) 8.63 [2 H, s, (NH) × 2], 7.57 (2 H, dd, J 8.0
and 2.0, CH-d), 7.24 (2 H, dd, J 8.0 and 2.0, CH-a), 7.10 (2 H, td,
J 8.0 and 2.0, CH-c), 7.03 (2 H, td, J 8.0 and 2.0, CH-b), 3.31 [2
H, hept, J 7.0, (CH) × 2] and 1.20 [12 H, d, J 7.0 (CH3) × 4]; dC
=
(100 MHz; d6-DMSO) 154.9 (C O), 140.6 (C), 136.7 (C), 126.2
(CH), 125.8 (CH), 124.8 (CH), 124.4 (CH), 27.5 (CH) and 23.9
(CH3); m/z (CI) 297 (100%, M + H+); (Found: M + H+, 297.1959,
C19H24N2O requires M + H, 297.1962).
1-(2-Isopropylphenyl)-3-(2,6-dimethylphenyl)urea, 2r
2-Isopropylaniline (0.68 g, 0.71 cm3, 5.0 mmol), was dissolved
in CH2Cl2 (10 cm3) at room temperature. 2,6-Dimethylphenyl
isocyanate (0.74 g, 0.70 cm3, 5.0 mmol) added dropwise and
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stirred for 20 h. The solvent was removed under reduced pressure
and the residue recrystallised from EtOAc–petrol to give 1-(2-
isopropylphenyl)-3-(2,6-dimethylphenyl)urea 2r (1.5 g, 98%), as
white cubes, m.p. 255–257 ◦C (from EtOAc–pentane); Rf (EtOAc–
[3 H, s, (CH3)A], 1.63 [3 H, s, (CH3)B] and 1.11 [6 H, s, 2 × (CH3)];
=
dC (100 MHz; CDCl3) 164.4 (C O), 146.6 (C), 143.0 (C), 142.3
(C), 136.8 (C), 136.4 (C), 128.8 (CH), 128.7 (CH), 128.6 (CH),
127.2 (CH), 126.8 (CH), 126.6 (CH), 126.2 (CH), 40.4 (NCH3)A,
37.4 (NCH3)B, 27.4 (CH), 25.6 (CH3)A, 23.4 (CH3)B, 18.0 (CH3)C
and 17.9 (CH3)D; m/z (ESI+) 311 (100%, M + H+); (Found: M +
H+, 311.2098, C20H26N2O requires M + H, 311.2118). Purity was
established by LC–MS analysis.
pentane, 1 : 4) 0.29; tmax (film)/cm−1 1631 (C O); dH (400 MHz;
=
d6-DMSO) 7.92 [1 H, s, (NH)A], 7.89 [1 H, br., (NH)B], 7.58 (1 H,
dd, J 8.0 and 2.0, CH-d), 7.24 (1 H, dd, J 8.0 and 2.0, CH-a), 7.10
(1 H, td, J 8.0 and 2.0, CH-c), 7.07–6.98 (4 H, m, CH-b, CH-e
and CH-f), 3.18 [1 H, hept, J 7.0, (CH)], 2.21 [6 H, s, (CH3) ×
2] 1.20 [3 H, s, (CH3)A] and 1.18 [3 H, s, (CH3)B]; dC (100 MHz;
Acknowledgements
=
d6-DMSO) 154.2 (C O), 140.2 (C), 136.8 (C), 136.3 (C), 136.2
We are grateful to the EPSRC and to Pfizer Ltd for support of this
work.
(C), 128.4 (CH), 126.5 (CH), 126.4 (CH), 125.8 (CH), 124.5 (CH),
124.4 (CH), 125.4 (CH), 27.6 (CH), 23.7 (CH3) and 18.9 (CH3);
m/z (ESI+) 283 (100%, M + H+); (Found: M + H+, 283.1804,
C18H22N2O requires M + H, 283.1810).
References and notes
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pentane, 3 : 7) 0.61; tmax (film)/cm−1 1646 (C O); dH (400 MHz;
=
CDCl3) 7.05 (2 H, d, J 7.0, CH-d), 6.91 (2 H, t, J 7.0, CH-c), 6.55
(2 H, br., CH-a), 6.07 (2 H, br., CH-b), 2.97 [6 H, s, (NCH3) ×
2], 2.86 [2 H, br., (CH) × 2] and 1.05 (12 H, br., (CH3) × 4];
=
dC (100 MHz; CDCl3) 162.9 (C O), 146.0 (C), 142.9 (C), 128.3
(CH), 126.9 (CH), 126.6 (CH), 126.3 (CH), 40.2 (NCH3), 27.3
(CH), 25.9 (CH3) and 23.5 (CH3); m/z (ESI+) 325 (100%, M + H+);
(Found: M + H+, 325.2274. C21H29N2O requires M + H, 325.2270).
Elem. Anal. for C21H28N2O: calcd: C, 77.74%; H, 8.70%; N, 8.63%;
found: C, 77.68%; H, 8.79%; N, 8.63%.
8 S. L. Cockroft, C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urch,
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1-(2-Isopropylphenyl)-1,3-dimethyl-3-(2,6-dimethylphenyl)urea, 3r
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17 N,Nꢀ-Diaryl ureas exhibit a rich lithiation chemistry in which confor-
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18 More recent work has indicated that carbonyl diimidazole may also be
a successful reagent for these couplings.
1-(2-Isopropylphenyl)-3-(2,6-dimethylphenyl)urea 2r (1.20 g,
4.2 mmol) was dissolved in THF (30 cm3) and cooled to
0 ◦C. Sodium hydride (0.42 g, 11.5 mmol) was added portionwise
and stirred at room temperature for 1 h. Methyl iodide (0.86 cm3,
12.6 mmol) was added and stirred at room temperature for
18 h. Water (40 cm3) was added and extracted with EtOAc (3 ×
30 cm3). The combined organic fractions were dried (MgSO4),
filtered and concentrated under reduced pressure. The residue
was purified by flash column chromatography (SiO2; 10% EtOAc
in pentane) to give 1-(2-isopropylphenyl)-1,3-dimethyl-3-(2,6-
dimethylphenyl)urea 3r (1.24 g, 94%), as off-white blocks, m.p.
90–92 ◦C (from EtOAc–pentane); Rf (EtOAc–pentane, 1 : 4) 0.73;
tmax (film)/cm−1 1632 (C O); dH (400 MHz; CDCl3) 7.12 (1 H, d,
=
J 7.0, CH-d), 7.05 (1 H, d, J 7.0, CH-a), 6.90 (2 H, br., CH-b and
CH-c), 6.71 (2 H, br., CH-e1 and CH-e2), 6.19 (1 H, br., CH-f), 3.07
[3 H, s, (NCH3)A], 3.02–2.90 [4 H, br., (CH) and (NCH3)B], 2.08
2912 | Org. Biomol. Chem., 2008, 6, 2908–2913
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19 T. Adler, J. Bonjoch, J. Clayden, M. Font-Bard´ıa, M. Pickworth, X.
Solans, D. Sole´ and L. Vallverdu´, Org. Biomol. Chem., 2005, 3, 3173.
20 J. Clayden, H. Turner, M. Pickworth and T. Adler, Org. Lett., 2005, 7,
3147.
22 M. Oki, Top. Stereochem., 1983, 14, 1.
23 The assignment of anti stereochemistry to the major conformer
remains tentative, though related di-ortho-substituted ureas (J. Clayden,
and M. Pickworth, unpublished results) display endo,anti conforma-
tions in the solid state, as do all extended di-meta-substituted polyureas
(ref. 9).
21 J. Sandstro¨m, Dynamic NMR Spectroscopy, Academic Press, New
York, 1982.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2908–2913 | 2913
©