Synthesis and stacked conformations of symmetrical and unsymmetrical oligo-ureas of metaphenylenediamine

Article abstract of DOI:10.1021/jo061989w

The addition of substituted anilines to nitro-substituted isocyanates followed by reduction generates new aniline-substituted ureas, which can be further extended in a one- or two-directional iterative manner to form oligomeric ureas based on a m-phenylen

Full text of DOI:10.1021/jo061989w

Synthesis and Stacked Conformations of Symmetrical and
Unsymmetrical Oligo-ureas of Metaphenylenediamine
Jonathan Clayden,* Lo¨ıc Lemie`gre,† and Madeleine Helliwell
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
clayden@man.ac.uk
ReceiVed September 27, 2006
The addition of substituted anilines to nitro-substituted isocyanates followed by reduction generates new
aniline-substituted ureas, which can be further extended in a one- or two-directional iterative manner to
form oligomeric ureas based on a m-phenylenediamine monomer. Oligo-ureas with up to eight urea linkages
are reported. Fully N-substituted oligo-ureas are crystalline, and the X-ray crystal structures display ring-
1
stacked conformations. H NMR studies indicate that the stacked conformation persists in solution.
Introduction
solution.4,5 As part of a program of research6 into methods for
rational control of conformation, and potential applications for
such control, we were interested in developing versatile routes
to a series of foldamers based upon oligo-ureas, and in this
paper, we describe our synthetic approach.
Oligomers or polymers that adopt a defined secondary
structure have been termed foldamers,1 and considerable
progress has been made toward using synthetic foldamers to
mimic the conformations of biological oligomers.2 N,N′-
Dimethyl-N,N′-diaryl ureas generally adopt a conformation
about the two N-CO bonds that allows the aryl rings to lie cis
to one another, presumably because of favorable π-stacking.3
On the basis of NMR and X-ray crystallographic evidence, it
also appears that oligo-ureas of N,N-dimethylmetaphenylene-
diamine also exhibit this ring stacking, extended over a longer
range, generating a helical conformation in both solid state and
Results and Discussion
Synthesis of Unsymmetrical Oligo-ureas. Symmetrical
oligo-ureas (i.e., at least two urea linkages) have been synthe-
sized7 by multiple condensation reactions,4 but for our studies,
a more flexible route to unsymmetrical oligo-ureas of various
chain lengths was required. We chose to use an iterative method
beginning with a terminal aniline 1. Condensation with the
(4) Tanatani, A.; Kagechika, H.; Azumaya, I.; Fukutomi, R.; Ito, Y.;
Yamaguchi, K.; Shudo, K. Tetrahedron Lett. 1997, 38, 4425.
(5) Lewis, F. D.; Kurth, T. L.; Hattan, C. M.; Reiter, R. C.; Stevenson,
C. D. Org. Lett. 2004, 6, 1605.
* Corresponding author. Tel.: 44-161-275-4612. Fax: 44-161-275-4939.
† Current address: EÄ cole Nationale Supe´rieure de Chimie de Rennes, CNRS
UMR6226 “Sciences Chimiques de Rennes”, Av. G. Leclerc, 35700 Rennes,
France.
(1) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893.
(2) (a) Nakano, T.; Okamoto, Y. Chem. ReV. 2001, 101, 4013. (b) Huc,
I. Eur. J. Org. Chem. 2004, 17. (c) Licini, G.; Prins, L. J.; Scrimin, P. Eur.
J. Org. Chem. 2005, 969. (d) Reggelin, M.; Doerr, S.; Klussmann, M.;
Schultz, M.; Holbach, M. Proc. Natl. Acad. Sci. 2004, 101, 5461.
(3) (a) Lepore, G.; Migdal, S.; Blagdon, D. E.; Goodman, M. J. Org.
Chem. 1973, 38, 2590. (b) Lepore, U.; Castronuovo Lepore, G.; Ganis, P.;
Germain, G.; Goodman, M. J. Org. Chem. 1976, 41, 2134. (c) Yamaguchi,
K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.; Shudo,
K. J. Am. Chem. Soc. 1991, 113, 5474. (d) Kurth, T. L.; Lewis, F. D. J.
Am. Chem. Soc. 2003, 125, 13760.
(6) (a) Clayden, J. Chem. Commun. 2004, 127. (b) Clayden, J.; Lund,
A.; Vallverdu´, L.; Helliwell, M. Nature (London) 2004, 431, 966. (c)
Clayden, J.; Vassiliou, N. Org. Biomol. Chem. 2006, 4, 2667. (d) Clayden,
J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002, 124, 5266. (e)
Betson, M. S.; Clayden, J.; Lam, H. K.; Helliwell, M. Angew. Chem., Int.
Ed. 2005, 44, 1241. (f) Betson, M. S.; Clayden, J.; Helliwell, M.; Mitjans,
D. Org. Biomol. Chem. 2005, 3, 3898. (g) Betson, M. S.; Clayden, J.;
Helliwell, M.; Johnson, P.; Lai, L. W.; Pink, J. H.; Stimson, C. C.; Vassiliou,
N.; Westlund, N.; Yasin, S. A.; Youssef, L. H. Org. Biomol. Chem. 2006,
4, 424. (h) Clayden, J.; Vallverdu´, L.; Helliwell, M. Org. Biomol. Chem.
2006, 4, 2106.
(7) Full experimental data remain unreported.
10.1021/jo061989w CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/08/2007
2302
J. Org. Chem. 2007, 72, 2302-2308

Synthesis of Oligo-ureas of Metaphenylenediamine
SCHEME 1. Synthesis of Oligo-ureas
SCHEME 2. Direct Formation of a Methylated Urea
SCHEME 3. Symmetrical Di-ureas
TABLE 2. Synthesis of Symmetrical Di-ureas
entry
compound
R1
R2
R3
yield (%)
TABLE 1. Synthesis of Unsymmetrical Oligo-ureas
1
2
3
4
5
6
7
17a
17b
17c
17d
17e
17f
H
H
H
H
H
Et
H
H
H
H
H
H
H
i-Pr
Et
73a
85b
83b
46b,c
75b
77b
76
entry
compound
R1
R2
R3
R4
stepsa
yieldb (%)
i-Pr
Et
Br
Et
H
1
2
3
4
7
9a
9b
9c
s-Bu
Et
H
H
s-Bu
Et
H
Et
H
H
H
Et
H
H
H
Et
H
H
H
H
Et
i-Pr
H
H
i-Pr
H
H
H
H
4
4
4
4
6
6
6
8
8
8
8
8
57
53
43
67
47
42
41
48
35
17
17
30
Br
Br
Br
H
Br
Br
H
i-Pr
Br
Br
Br
9d
17g
H
10a
10b
10c
11a
11b
11c
11d
11e
8
9
a From 18. b From 2e. c NaOH instead of NaH was used in the methy-
lation; NaH gave mainly decomposition products.
H
11
12
13
14
15
s-Bu
s-Bu
Et
i-Pr
H
In view of the difficulty of handling the intermediate NH
oligo-ureas, we attempted N-methylation of the nitroaryl ureas
3 and 5 formed as the chain grows. However, these reactions
gave mainly decomposition products. We also tried to form
methylated ureas directly from N-methyl-O-phenylcarbamates,8
but these failed to react with N-methyl anilines. The reaction
of the N-methyl aniline 12 with an NH carbamate 13 proceeded
only in the presence of trimethylaluminum9 to give low yields
of the mono-N-methylated urea 14 (Scheme 2).
Synthesis of Symmetrical Oligo-ureas. Symmetrical di-ureas
16 and 17 were made by condensation of an appropriate aniline
(either secondary anilines such as 15 or primary anilines 1) with
the available meta-phenylene diisocyanate 2e (Scheme 3 and
Table 2). Alternatively, meta-phenylenediamine 18 was con-
densed with an isocyanate 2.
H
i-Pr
a Number of synthetic steps from 1 to product. b Overall yield of
N-methylated oligo-urea. Intermediates were not isolated.
available meta-nitrophenyl isocyanate 2a generated the rather
intractable ureas 3, which turned out to be only sparingly
soluble, precluding reduction of the nitro group using tin
chloride. However, hydrogenation over palladium in a solvent
mixture of THF and methanol returned the anilines 4 in good
yield, ready for further iterative cycles of condensation and
reduction. Up to three cycles were achieved, forming the amino-
di-urea 6 via nitrourea 5 and amino-tri-urea 8 via nitrodiurea 7
(Scheme 1).
The aminourea oligomers 4, 6, and 8 were generally capped
by condensation with an available isocyanate 2. The N-
unprotected oligo-ureas formed by these methods were all more
or less completely insoluble in chlorinated solvents, but global
methylation with an excess of methyl iodide and sodium hydride
in THF gave tractable, and in some cases beautifully crystalline,
permethylated oligo-ureas 9, 10, and 11 (Table 1).
The synthesis of longer symmetrical oligo-ureas (triurea 23,
tetraurea 24, heptaurea 25, and octaurea 26) was carried out by
linking together anilines 4 or 8 using carbonyl diimidazole
(8) Thavonekhan, B. Synthesis 1997, 1189.
(9) Lee, S. H.; Matsushita, H.; Clapham, B.; Janda, K. D. Tetrahedron
2004, 60, 3439.
J. Org. Chem, Vol. 72, No. 7, 2007 2303

Clayden et al.
SCHEME 4. Symmetrical Oligo-ureas
(for oligomers containing odd numbers of urea linkages) or
meta-phenylene diisocyanate 2e (for oligomers containing even
numbers of urea linkages) (Scheme 4). The products 23-26
were isolated after methylation of the NH oligo-ureas 19-22.
Conformation. Stacked structures were exhibited in the solid
state by the crystalline di-ureas 17a,b,e-g, whose X-ray crystal
structures are shown in Figure 1. All of the oligo-ureas
furthermore exhibit in their 1H NMR spectra in CDCl3 an upfield
shift of the 2 proton of the phenylenediamine rings to around
6.0 ppm due to the shielding effect characteristic of rings
participating in a π-stacked structure.4 Viewing the ring stack
end-on (as shown in the second of each pair of structures in
Figure 1) clearly shows how the H-2′ proton (shaded) is
sandwiched between the two aromatic rings. The upfield shift
is even more pronounced at low temperature (the other aromatic
signals remain largely unshifted) possibly indicating annealing
of the stacked conformation as the temperature drops.
Rotation about the Ar-N bonds of 17b,c generates in
principle three diastereoisomeric conformers -(syn,syn, syn,-
anti, and anti,anti) by the terminology of Figure 2.10 Similar
sets of conformers are in principle possible for 17f,g as well.
In the crystalline state, ortho-substituted 17b adopts the syn,-
syn conformation, while the meta-substituted ureas 17f,g adopt
an anti,anti conformation. However, for 17f,g, the Ar-N bonds
bear no ortho substituents, and the three conformers interconvert
too fast to be distinguishable by NMR even at low temperature.
In 17b,c, the two Ar-N bonds at the middle ring rotate too
fast on the NMR time scale for conformers to be evident,11
leaving only the two relative orientations of the terminal rings
(Et or i-Pr groups syn or anti) as detectable conformers. At low
temperature (below -30 °C in CDCl3), the 1H NMR spectra of
17b,c do indeed exhibit two sets of peaks in a ratio of 55:45
for 17b and 50:50 for 17c. Raising the temperature of the NMR
probe resulted in coalescence, from which we deduce barriers
of 59.6 ( 2.5 (17b) and 61.3 ( 1.8 (17c) kJ mol-1, respectively,
for interconversion of the conformers.
Diurea 9a is chiral by virtue of its terminal sec-butyl group.
The Ar-N bond adjacent to the sec-butyl group can therefore
adopt two diastereoisomeric conformations relative to the sec-
butyl stereogenic center. In the 1H NMR spectrum of this
compound, the two conformers were evident in a 50:50 ratio.
In the X-ray crystal structure of 9a (Figure 3a), each unit cell
contains one molecule of the di-urea in each of the two
conformations. The di-urea is a rudimentary helix, and this result
may have important implications for future applications of the
chirality of helical oligo-ureas.
Of the more extended oligo-ureas, only 10a was crystalline.
Figure 3b shows its solid-state conformation, containing four
stacked aryl rings. Like 9a, its NMR spectrum showed a 1:1
(10) More detailed studies of the conformational preferences and
stereodynamics of simple ureas will be reported shortly: Clayden, J.;
Pickworth, M.; Jones, L., manuscript in preparation.
(11) Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bard´ıa, M.; Pickworth,
M.; Solans, X.; Sole´, D.; Vallverdu´, L. Org. Biomol. Chem. 2005, 3, 3173.
2304 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Oligo-ureas of Metaphenylenediamine
FIGURE 1. (a) Stacked conformation of 17a. ΝΜR [δ(H2′) ) 6.08 (23 °C)] and X-ray crystal structure. (b) Stacked conformation of 17b. ΝMR
[δ(H2′) ) 5.88 (23 °C)] and X-ray crystal structure. (c) Stacked conformation of 17c. NMR [δ(H2′) ) 5.81 (23 °C)] (d) Stacked conformation of
17e. ΝΜR [δ(H2′) ) 5.65 (23 °C)] and X-ray crystal structure. (e) Stacked conformation of 17f. ΝΜR [δ(H2′) ) 5.99 (23 °C) and 5.80 (-50 °C);
δ(H2,2′′) ) 6.52 (23 °C) and 6.36 (-50 °C)] and X-ray crystal structure. (f) Stacked conformation of 17g. NMR [δ(H2′) ) 6.01 (23 °C) and 5.81
(-60 °C); δ(H2,2′′) ) 6.49 (23 °C) and 6.35 (-60 °C)] and X-ray crystal structure.
J. Org. Chem, Vol. 72, No. 7, 2007 2305

Clayden et al.
was added. The reaction mixture was stirred at room temperature
(r.t.) for 3 h and evaporated under reduced pressure. CH2Cl2/
petroleum ether was added, and the was solid collected by filtration.
The white powder was dried under vacuum and dissolved in MeOH
(20 mL). Pd/C 10% (50 mg) was added, and the reaction mixture
was stirred overnight, at r.t., under a hydrogen atmosphere. After
removal of the Pd/C by filtration through celite, the solvent was
evaporated under reduced pressure, and the product was precipitated
in CH2Cl2/petroleum ether and collected by filtration. The white
powder was dried under vacuum and dissolved in dry THF
(20 mL), and phenyl isocyanate (663 µL, 6.10 mmol, 2 equiv) was
added. The reaction mixture was stirred at r.t. for 3 h and evaporated
under reduced pressure. CH2Cl2 was added, and the solid was
collected by filtration. The white powder was dried under vacuum
and partially dissolved in THF (20 mL). NaH 60% in mineral oil
(610 mg, 15.2 mmol, 5 equiv) and methyl iodide (950 µL,
15.2 mmol, 5 equiv) were added successively, and the reaction
mixture was stirred overnight before adding H2O (2 mL). The
aqueous phase was extracted with CH2Cl2, and the combined
organic phases were dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography on silica gel (AcOEt/petroleum
ether: 50:50) afforded 802 mg (57%) of urea 9a as a white powder.
mp: 113 °C. IR νmax cm-1: 3057, 2963, 1659, 1650, 1597, 1431,
FIGURE 2. Conformers about a urea linkage.
mixture of two conformers due to the stereogenic center within
the sec-butyl group. The tetra- and octa-ureas 11b,d, 24, and
26 showed upfield shifts in their aromatic signals (Figure 4)
characteristic of stacked conformations. As the stack of π-sys-
tems lengthens, in principle a helix forms, and our ongoing work
seeks to determine the stability of, and to find ways to control,
such helical conformations.
Experimental Section
N,N′,N′′,N′′′-Tetramethyl-1-(2-sec-butylphenylureyl)-3-phe-
nylureylbenzene 9a. Under a nitrogen atmosphere, 3-nitrophenyl-
isocyanate (500 mg, 3.05 mmol, 1 equiv) was dissolved in dry THF
(10 mL), and 2-sec-butylaniline (550 µL, 3.66 mmol, 1.2 equiv)
FIGURE 3. (a) Stacked conformation of 9a. NMR [δ(H2′) ) 5.96 (23 °C)] and X-ray crystal structure (b) Stacked conformation of 10a. X-ray
crystal structure.
1
FIGURE 4. Stacked conformations in tetra- and octa-ureas. H NMR shifts at 23 °C.
2306 J. Org. Chem., Vol. 72, No. 7, 2007

Synthesis of Oligo-ureas of Metaphenylenediamine
1
878. H NMR (300 MHz, CDCl3) δ (ppm): 0.73 (3H, bs), 1.13
at r.t., under a hydrogen atmosphere. After removal of the Pd/C by
filtration through celite, the solvent was evaporated under reduced
pressure, and the product was precipitated in CH2Cl2/petroleum
ether and collected by filtration. The sequence of events from
addition of 3-nitrophenylisocyanate (2 equiv in THF, 50 mL) to
hydrogenation (in MeOH/DMF: 80:20, 50 mL) was repeated twice
in a similar manner. After precipitation in CH2Cl2, the white powder
(1.3 g) was dried under vacuum and dissolved in dry THF/DMF:
40:5 (45 mL). Phenylisocyanate (522 µL, 4.80 mmol, 2.0 equiv)
was added. The reaction mixture was stirred at r.t. for 3 h and
evaporated under reduced pressure. CH2Cl2 was added, and the solid
was collected by filtration. The white powder was dried under
vacuum and partially dissolved in THF (50 mL). 60% NaH in
mineral oil (960 mg, 24.0 mmol, 10 equiv) and methyl iodide
(1.50 mL, 24.0 mmol, 10 equiv) were added successively, and the
reaction mixture was stirred overnight. H2O (5 mL) was added,
and the aqueous phase was extracted with CH2Cl2. The combined
organic phases were dried (MgSO4) and concentrated under reduced
pressure. Purified by recrystallization from Et2O/petroleum ether
gave the urea 11a (1.33 mg, 48%) as a white powder. mp: 86 °C.
IR νmax cm-1: 3004, 2965, 1659, 1597, 1428. 1H NMR (300 MHz,
CDCl3) δ (ppm): 0.71-1.72 (8H, m), 2.50 (1H, m), 2.80 (3H, s),
2.88 (3H, s), 2.90 (3H, s), 2.91 (6H, s), 2.93 (3H, s), 3.07 (3H, s),
3.12 (3H, s), 5.92 (1H, t, J ) 1.7 Hz), 6.04 (2H, t, J ) 1.8 Hz),
6.21 (1H, d, J ) 8.0 Hz), 6.35 (6H, m), 6.61 (1H, t, J ) 7.3 Hz),
6.70 (5H, m), 6.96 (5H, m). 13C NMR (75 MHz, CDCl3) δ (ppm):
12.5, 29.6, 34.4, 39.05, 39.09 (2C), 39.13, 39.2, 39.3, 39.8, 40.0,
122.0 (2C), 122.1, 122.2, 122.5, 122.6, 123.0 (2C), 123.2, 125.0,
125.6 (2C), 125.7, 126.4, 126.7, 128.3, 128.4, 128.57 (2C), 128.62,
145.3, 145.6, 145.7 (3C), 145.8 (3C), 146.7, 160.3 (2C), 160.7,
161.6. MS (APCI+): 783 (MH+). HRMS for C46H55N8O4 (MH+):
calcd: 783.4341; found: 783.4332. Elem. Anal. for C46H54N8O4:
calcd: C, 70.56%; H, 6.95%; N, 14.31%; found: C, 70.12%; H,
6.82%; N, 14.00%.
(3H, bs), 1.48 (2H, m), 2.52 (1H, sept, J ) 7.0 Hz), 2.84 (3H, s),
2.97 (3H, s), 3.07 (3H, s), 3.13 (3H, s), 5.96 (1H, t, J ) 2.0 Hz),
6.23 (1H, d, J ) 7.8 Hz), 6.36 (1H, d, J ) 7.7 Hz), 6.51 (1H, d,
J ) 8.0 Hz), 6.62 (1H, t, J ) 7.7 Hz), 6.70 (2H, d, J ) 7.2 Hz),
6.77 (1H, t, J ) 8.0 Hz), 6.84-7.06 (5H, m). 13C NMR (75 MHz,
CDCl3) δ (ppm): 12.5, 21.0 (bs), 31.9 (bs), 34.4, 39.1, 39.3, 39.7,
40.0, 122.4, 122.6, 123.2, 124.9, 125.6, 125.7, 126.3, 126.7, 128.5,
128.6 (2C), 142.4 (bs), 144.8 (bs), 145.3, 146.0, 146.5, 160.7, 161.7.
MS (APCI+): 459.5 (MH+). HRMS for C28H35N4O2 (MH+):
calcd: 459.2755; found: 459.2753. Elem. Anal. for C28H34N4O2:
calcd: C, 73.33%; H, 7.47%; N, 12.22%; found: C, 73.45%; H,
7.65%; N, 12.18%.
N,N′,N′′,N′′′,N′′′′,N′′′′′-Hexamethyl-1-[3-(2-sec-butylphenyl-
ureyl)phenyl]-3-[( 3-phenylureyl)phenyl]urea 10a. Under a ni-
trogen atmosphere, 3-nitrophenylisocyanate (300 mg, 1.83 mmol,
1 equiv) was dissolved in dry THF (7 mL), and 2-sec-butylaniline
(340 µL, 2.19 mmol, 1.2 equiv) was added. The reaction mixture
was stirred at r.t. for 3 h and evaporated under reduced pressure.
CH2Cl2/petroleum ether was added, and the solid was collected by
filtration. The white powder was dried under vacuum and dissolved
in THF/MeOH: 70:30 (50 mL). Pd/C 10% (30 mg) was added,
and the reaction mixture was stirred overnight, at r.t., under
hydrogen atmosphere. After removal of the Pd/C by filtration
through celite, the solvent was evaporated under reduced pressure,
and the product was precipitated in CH2Cl2/petroleum ether and
collected by filtration. The sequence of events starting from the
addition of 3-nitrophenylisocyanate (1.5 equiv in THF, 30 mL) to
hydrogenation (in MeOH/DMF: 80:20, 30 mL) was repeated. After
precipitation in CH2Cl2, the white powder (516 mg) was dried under
vacuum and dissolved in dry THF (40 mL). Phenylisocyanate
(270 µL, 2.48 mmol, 2.0 equiv) was added. The reaction mixture
was stirred at r.t. for 3 h and evaporated under reduced pressure.
CH2Cl2 was added, and the solid was collected by filtration. The
white powder was dried under vacuum and partially dissolved in
THF (20 mL). 60% NaH in mineral oil (397 mg, 9.92 mmol,
8 equiv) and methyl iodide (620 µL, 9.92 mmol, 8 equiv) were
added successively. The reaction mixture was stirred overnight, and
H2O (2 mL) was added. The aqueous phase was extracted with
CH2Cl2, and the combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography on
silica gel (CH2Cl2/MeOH: 90:10) afforded 536 mg (47%) of urea
10a as a white powder. mp: 106 °C. IR νmax cm-1: 3002, 2963,
2930, 1659, 1650, 1597, 1430, 1357. 1H NMR (500 MHz, CDCl3)
δ(ppm): 0.68-1.48 (8H, bm), 2.51 (1H, sext, J ) 7.0 Hz), 2.82
(3H, s), 2.91 (3H, s), 2.92 (3H, s), 2.94 (3H, s), 3.07 (3H, s), 3.12
(3H, s), 5.93 (1H, t, J ) 1.8 Hz), 6.05 (1H, t, J ) 1.9 Hz), 6.21
(1H, d, J ) 7.4 Hz), 6.33 (1H, d, J ) 8.0 Hz), 6.36 (1H, m), 6.42
(2H, m), 6.61 (1H, t, J ) 6.9 Hz), 6.70 (3H, m), 6.76 (1H, t, J )
7.8 Hz), 6.88 (1H, t, J ) 7.4 Hz), 6.93 (1H, t, J ) 7.4 Hz), 6.99
(2H, t, J ) 7.5 Hz), 7.04 (1H, dd, J ) 1.3, 7.8 Hz). 13C NMR
(125 MHz, CDCl3) δ(ppm): 12.6 (bs), 21.0 (bs), 31.9 (bs), 34.4,
39.1, 39.1, 39.2, 39.3, 39.7, 40.0, 122.1, 122.2, 122.5, 122.6, 123.1,
123.2, 125.0, 125.6 (2C), 125.7, 126.3, 126.7, 128.4, 128.5 (3C),
128.6, 142.5, 145.3, 145.6, 145.8, 145.9 (2C), 146.6, 160.4, 160.7,
161.7. MS (APCI+): 622 (MH+). HRMS for C37H45N6O3 (MH+):
calcd: 622.3548; found: 622.3552. Elem. Anal. for C37H44N6O3:
calcd: C, 71.59%; H, 7.14%; N, 13.54%; found: C, 71.75%; H,
7.12%; N, 13.36%.
N,N′,N′′,N′′′-Tetramethyl-1,3-diphenyldiureylbenzene 17a.
Under nitrogen atmosphere, 1,3-phenylenediamine (100 mg,
0.925 mmol, 1 equiv) was dissolved in dry THF (7 mL) and
phenylisocyanate (440 µL, 1.85 mmol, 2.2 equiv) was added. The
mixture was stirred at r.t. for 3 h and evaporated under reduced
pressure. CH2Cl2 was added, and the solid was collected by
filtration. The white powder was dried under vacuum and suspended
in THF (15 mL). 60% NaH in mineral oil (185 mg, 4.63 mmol, 5
equiv) and methyl iodide (290 µL, 4.63 mmol, 5 equiv) were added
successively, and the reaction mixture was stirred overnight before
adding H2O (2 mL). The aqueous phase was extracted with CH2-
Cl2 and the combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography on
silica gel (AcOEt/PE: 30:70) afforded 270 mg (73%) of urea 17a
as a white powder. mp: 168 °C. IR νmax cm-1: 3061, 1659, 1593,
1
1494, 1425, 1357. H NMR (300 MHz, CDCl3) δ (ppm): 2.96
(6H, s), 3.12 (6H, s), 6.06 (1H, t, J ) 2.1 Hz), 6.43 (2H, dd,
J ) 2.1, 8.0 Hz), 6.70 (5H, m), 6.88 (2H, m), 6.99 (4H, dt, J ) 1.2
,8.0 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm): 39.1, 39.3, 122.2,
123.2, 124.9, 125.7, 128.4, 128.5, 145.3, 145.7, 160.8. MS (CI/
NH3): 403 (MH+, 100). MS (EI, 70 ev): 402 (M+, 3), 134 (100),
106 (85). HRMS for C24H27N4O2 (MH+): calcd: 403.2129;
found: 403.2128. Elem. Anal. for C24H26N4O2: calcd: C, 71.62%;
H, 6.51%; N, 13.92%; found: C, 71.85%; H, 6.61%; N, 13.99%.
N,N′,N′′,N′′′,N′′′′,N′′′′′-Hexamethyl-1,3-bis[3-(2-isopropylphe-
nylureyl)phenyl]urea 23. Under nitrogen atmosphere, 3-nitrophe-
nylisocyanate (700 mg, 4.27 mmol, 1 equiv) was dissolved in dry
THF (10 mL), and 2-isopropylaniline (725 µL, 5.12 mmol, 1.2
equiv) was added. The reaction mixture was stirred at r.t. for 3 h
and evaporated under reduced pressure. CH2Cl2/petroleum ether
was added, and the solid was collected by filtration. The white
powder was dried under vacuum and dissolved in MeOH (30 mL).
Pd/C 10% (100 mg) was added, and the reaction mixture was stirred
overnight, at r.t., under a hydrogen atmosphere. After removal of
the Pd/C by filtration through celite, the solvent was evaporated
N,N′,N′′,N′′′,N′′′′,N′′′′′,N′′′′′′,N′′′′′′′-Octamethyl-1-[3-(2-sec-bu-
tylphenylureyl)phenylureyl]-3-[3-(phenylureyl)phenylureyl]ben-
zene 11a. Under a nitrogen atmosphere, 3-nitrophenylisocyanate
(600 mg, 3.66 mmol, 1 equiv) was dissolved in dry THF (20 mL)
and 2-sec-butylaniline (680 µL, 4.38 mmol, 1.2 equiv) was added.
The reaction mixture was stirred at r.t. for 3 h and evaporated under
reduced pressure. CH2Cl2/petroleum ether was added, and the solid
was collected by filtration. The white powder was dried under
vacuum and dissolved in THF/MeOH: 70:30 (100 mL). Pd/C 10%
(50 mg) was added, and the reaction mixture was stirred overnight,
J. Org. Chem, Vol. 72, No. 7, 2007 2307

Clayden et al.
under reduced pressure, and precipitation from CH2Cl2/petroleum
ether and filtration gave a white powder (1.09 g). The white powder
was dried under vacuum and dissolved in dry THF (30 mL).
Carbonyl diimidazole (CDI) (330 mg, 2.02 mmol, 0.5 equiv) was
added. The reaction mixture was stirred at 70 °C for 18 h and
evaporated under reduced pressure. CH2Cl2 was added, and the solid
was collected by filtration. The white powder was dried under
vacuum and suspended in THF (30 mL). 60% NaH in mineral oil
(646 mg, 16.2 mmol, 8 equiv) and methyl iodide (1.01 mL,
16.2 mmol, 8 equiv) were added successively, and the mixture was
stirred overnight before adding H2O (2 mL). The aqueous phase
was extracted with CH2Cl2, and the combined organic phases were
dried (MgSO4) and concentrated under reduced pressure. Flash
chromatography on silica gel (CH2Cl2/MeOH: 95:5) afforded
766 mg (55%) of urea 23 as a white powder. mp: 164 °C. IR νmax
146.5, 160.2, 161.6. MS (APCI+): 811 (MH+). HRMS for
C48H59N8O4 (MH+): calcd: 811.4667; found: 811.4654. Elem.
Anal. for C48H58N8O4: calcd: C, 71.08%; H, 7.21%; N, 13.82%;
found: C, 71.02%; H, 7.14%; N, 13.79%.
N,N′,N′′,N′′′,N′′′′,N′′′′′,N′′′′′′,N′′′′′′′,N′′′′′′′′,N′′′′′′′′′,N′′′′′′′′′′,N′′′′′′′′′′′,N′′′′′′′′′′′,
N′′′′′′′′′′′′′-Tetradecamethyl-1,3-bis[3-(3-(3-(2-isopropylphenyl-
ureyl)phenylureyl)phenylureyl)phenyl]urea 25. By the method
used for compound 10a, 3-nitrophenylisocyanate (1.05 g, 6.41
mmol, 1 equiv) and 2-isopropylaniline (1.09 mL, 7.69 mmol, 1.2
equiv) gave an intermediate aniline. Carbonyldiimidazole (151 mg,
0.930 mmol, 0.5 equiv) was used instead of phenylisocyanate,
heating the mixture for 5 h in THF at 70 °C. Methylation in THF
(30 mL) with NaH 60% in mineral oil (744 g, 18.6 mmol, 20 equiv)
and methyl iodide (1.16 mL, 18.6 mmol, 10 equiv) gave crude
material that was purified by flash chromatography on silica gel
(CH2Cl2/MeOH: 90:10) to yield urea 25 (640 mg, 15%) as a white
powder. mp: 192 °C. IR νmax cm-1: 3003, 2968, 1659, 1650, 1597,
1431, 1356, 874. 1H NMR (300 MHz, CDCl3) δ (ppm): 1.08 (12H,
d, J ) 6.9 Hz), 2.77 (2H, m), 2.78 (6H, s), 2.84 (6H, s), 2.85
(6H, s), 2.86 (12H, s), 2.89 (6H, s), 3.04 (6H, s), 5.90 (2H, t, J )
1.8 Hz), 6.00 (4H, m), 6.25-6.38 (14H, m), 6.65 (6H, m), 6.71
(2H, t, J ) 8.0 Hz), 6.93 (2H, t, J ) 7.5 Hz), 7.06 (2H, d, J )
7.8 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm): 22.7, 25.2, 27.2,
39.1 (10C), 39.7, 39.9, 122.0, 122.5, 122.8, 123.1, 125.8, 126.3,
126.7, 128.3, 128.4, 128.6, 141.8, 145.4, 145.5, 145.60, 145.61,
145.7, 145.8, 146.5, 160.1, 160.2, 161.6. MS (APCI+): 1298
(MH+). Elem. Anal. for C75H88N14O7: calcd: C, 69.42%; H, 6.84%;
N, 15.11%; found: C, 69.30%; H, 6.82%; N, 15.13%.
1
cm-1: 2995, 2965, 1659, 1651, 1597, 1428, 1355, 872. H NMR
(300 MHz, CDCl3) δ(ppm): 1.10 (12H, d, J ) 6.8 Hz), 2.77
(2H, m), 2.82 (6H, s), 2.92 (6H, s), 3.07 (6H, s), 5.94 (2H, t, J )
1.9 Hz), 6.27 (2H, dd, J ) 1.3, 7.9 Hz), 6.35 (2H, dd, J ) 1.0, 7.9
Hz), 6.42 (2H, dd, J ) 1.1, 8.0 Hz), 6.65 (2H, dt, J ) 1.5, 7.5 Hz),
6.75 (2H, t, J ) 8.0 Hz), 6.95 (2H, t, J ) 7.3 Hz), 7.08 (2H, dd,
J ) 1.5, 7.8 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm): 22.7, 25.2,
27.2, 39.1, 39.7, 40.0, 122.6, 122.7, 123.3, 125.8, 126.3, 126.8,
128.5, 128.6, 141.9, 145.8, 145.9, 146.5, 160.4, 161.7. MS
(APCI+): 649 (MH+). HRMS for C39H49N6O3 (MH+): calcd:
649.3861; found: 649.3871. Elem. Anal. for C39H48N6O3: calcd:
C, 72.19%; H, 7.46%; N, 12.95%; found: C, 71.96%; H, 7.40%;
N, 12.78%.
N,N′,N′′,N′′′,N′′′′,N′′′′,N′′′′′′,N′′′′′′′′-Octamethyl-1,3-bis[3-(2-iso-
propylphenylureyl)phenylureyl]benzene 24. Under nitrogen at-
mosphere, 3-nitrophenylisocyanate (700 mg, 4.27 mmol, 1 equiv)
was dissolved in dry THF (10 mL), and 2-isopropylaniline
(725 µL, 5.12 mmol, 1.2 equiv) was added. The mixture was stirred
at r.t. for 3 h and evaporated under reduced pressure. CH2Cl2/
petroleum was added, and the solid was collected by filtration. The
white powder was dried under vacuum and dissolved in MeOH
(30 mL). Pd/C 10% (100 mg) was added, and the reaction mixture
was stirred overnight, at r.t., under hydrogen atmosphere. After
removal of the Pd/C by filtration on celite, the solvent was
evaporated under reduced pressure, and the product was precipitated
in CH2Cl2/petroleum ether and collected by filtration (1.09 g). The
white powder was dried under vacuum and dissolved in dry THF
(30 mL). 1,3-Phenylene diisocyanate (326 mg, 2.02 mmol,
0.5 equiv) was added. The mixture was stirred at r.t. for 3.5 h and
evaporated under reduced pressure. CH2Cl2 was added, and the solid
was collected by filtration. The white powder was dried under
vacuum and suspended in THF (20 mL). 60% NaH in mineral oil
(808 mg, 20.2 mmol, 10 equiv) and methyl iodide (1.26 mL,
20.2 mmol, 10 equiv) were added successively, and the reaction
mixture was stirred overnight before adding H2O (2 mL). The
aqueous phase was extracted with CH2Cl2, and the combined
organic phases were dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography on silica gel (CH2Cl2/MeOH: 95:
5) afforded 785 mg (45%) of urea 24 as a white powder. mp:
152 °C. IR νmax cm-1: 3005, 2968, 1659, 1650, 1597, 1431, 1357.
1H NMR (300 MHz, CDCl3) δ (ppm): 1.08 (12H, d, J ) 6.8 Hz),
2.78 (2H, m), 2.80 (6H, s), 2.88 (6H, s), 3.05 (6H, s), 5.91 (2H, t,
J ) 2.0 Hz), 6.02 (1H, t, J ) 2.0 Hz), 6.26 (2H, dd, J ) 1.2,
7.9 Hz), 6.30 (2H, dd, J ) 2.1, 8.0 Hz), 6.33 (2H, d, J ) 7.9 Hz),
6.38 (2H, d, J ) 8.0 Hz), 6.63 (3H, m), 6.68 (1H, d, J ) 8.0 Hz),
6.74 (1H, d, J ) 8.0 Hz), 6.93 (2H, dt, J ) 1.2, 7.5 Hz), 7.07 (2H,
dd, J ) 1.4, 7.9 Hz). 13C NMR (75 MHz, CDCl3) δ (ppm): 22.7,
25.2, 27.2, 39.0, 39.1, 39.7, 40.0, 122.0, 122.4, 122.5, 122.9, 123.2,
125.8, 126.3, 126.8, 128.3, 128.4, 128.6, 141.8, 145.6, 145.7, 145.8,
N,N′,N′′,N′′′,N′′′′,N′′′′′,N′′′′′′,N′′′′′′′,N′′′′′′′′,N′′′′′′′′′,N′′′′′′′′′′,N′′′′′′′′′′′,N′′′′′′′′′′′′,
N′′′′′′′′′′′′,N′′′′′′′′′′′′′′,N′′′′′′′′′′′′′′′-Hexadecamethyl-1,3-bis[3-(3-(3-
(2-isopropylphenylureyl)phenylureyl)phenylureyl)phenylureyl]-
benzene 26. By the method used for compound 10a, 3-nitrophe-
nylisocyanate (525 mg, 3.20 mmol, 1 equiv) and 2-isopropylaniline
(545 µL, 3.85 mmol, 1.2 equiv) gave an intermediate aniline. 1,3-
Phenyldiisocyanate (74.5 mg, 0.465 mmol, 0.5 equiv) was used
instead of phenyl isocyanate. After methylation in THF (20 mL)
with NaH 60% in mineral oil (372 g, 9.3 mmol, 20 equiv) and
methyl iodide (580 µL, 9.3 mmol, 10 equiv), a crude product was
obtained that was purified by flash chromatography on silica gel
(CH2Cl2/MeOH: 90:10) to yield octa-urea 26 (415 mg, 18%) was
isolated by as a white powder. mp: 196 °C. IR νmax cm-1: 3005,
2968, 2932, 1659, 1650, 1597, 1431, 1356, 875. 1H NMR
(500 MHz, CDCl3) δ (ppm): 1.08 (12H, d, J ) 6.5 Hz), 2.77
(2H, m), 2.79 (6H, s), 2.85 (18H, s), 2.86 (12H, s), 2.89 (6H, s),
3.05 (6H, s), 5.91 (2H, t, J ) 2.0 Hz), 6.00 (5H, m), 6.25-6.31
(12H, m), 6.33 (2H, d, J ) 8.0 Hz), 6.37 (2H, d, J ) 6.0 Hz),
6.61-6.67 (7H, m), 6.72 (2H, t, J ) 8.0 Hz), 6.93 (2H, t, J )
7.5 Hz), 7.07 (2H, dd, J ) 1.2, 7.8 Hz). 13C NMR (75 MHz, CDCl3)
δ (ppm): 22.7, 25.3, 27.2, 39.1 (12C), 39.7, 40.0, 122.0, 122.5,
122.8, 122.9, 123.2, 125.8, 126.3, 126.8, 128.4, 128.5, 128.6, 141.8,
145.50 (4C), 145.55, 145.58, 145.63, 145.7, 145.8, 146.5, 160.0,
160.1, 160.2, 161.6. MS (APCI+): 1461 (MH+). Elem. Anal. for
C84H98N16O8: calcd: C, 69.11%; H, 6.77%; N, 15.35%; found:
C, 68.84%; H, 6.81%; N, 15.11%.
Acknowledgment. We are grateful to the Leverhulme Trust
and the EPSRC for support of this work.
Supporting Information Available: Experimental procedures
and data for 9b-d, 10b,c, 11b,e, 16, and 17b-g. X-ray crystal-
lographic data (CIF) for 9a, 10a, 17a, 17b, 17e, 17f, and 17g. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO061989W
2308 J. Org. Chem., Vol. 72, No. 7, 2007