Design and synthesis of urea-linked aromatic oligomers-a route towards convoluted foldamers

Article abstract of DOI:10.1002/chem.200901094

Herein we report the design and synthesis of crescent-shaped and helical urea-based foldamers, the curvature of which is controlled by varying the constituent building blocks and their connectivity. These oligomers are comprised of two, three or five alternating aromatic heterocycles (pyridazine, pyrimidine or pyrazine) and methyl-substituted aromatic carbocycles (tolyl, o-xylyl or m-xylyl) connected together through urea linkages. A crescent-shaped conformational preference is encoded within these π-conjugated urea-linked oligomers based on intramolecular hydrogen bonding and steric interactions; the degree of curvature is tuned by the urea connectivity to the heterocycles and the aryl groups. NMR characterization of these foldamers confirms the intramolecular hydrogen-bonded conformation expected (Z,E configuration of the urea bond) in both the pyridazyl and pyrimidyl foldamers in solution. An X-ray crystal structure of the N³,N⁶-diisobutylpyridazine-4,6- diamine-o-tolyl urea-linked foldamer (4) confirms the presence of N-H...N hydrogen bonds between the heterocyclic nitrogen atom and the free hydrogen of the urea linkage. Additionally, the tolyl methyl group interacts unfavourably with the urea carbonyl oxygen, thus destabilising the alternate planar conformation.

Full text of DOI:10.1002/chem.200901094

DOI: 10.1002/chem.200901094
Design and Synthesis of Urea-Linked Aromatic Oligomers—A Route
Towards Convoluted Foldamers
James J. Mousseau,[a, b] Liyan Xing,[a, b] Nathalie Tang,[a] and Louis A. Cuccia*[a]
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FULL PAPER
Abstract: Herein we report the design
and synthesis of crescent-shaped and
helical urea-based foldamers, the cur-
vature of which is controlled by varying
the constituent building blocks and
their connectivity. These oligomers are
comprised of two, three or five alter-
nating aromatic heterocycles (pyrida-
zine, pyrimidine or pyrazine) and
methyl-substituted aromatic carbocy-
cles (tolyl, o-xylyl or m-xylyl) connect-
ed together through urea linkages. A
crescent-shaped conformational prefer-
ence is encoded within these p-conju-
gated urea-linked oligomers based on
intramolecular hydrogen bonding and
steric interactions; the degree of curva-
ture is tuned by the urea connectivity
to the heterocycles and the aryl groups.
NMR characterization of these foldam-
ers confirms the intramolecular hydro-
gen-bonded conformation expected
(Z,E configuration of the urea bond) in
both the pyridazyl and pyrimidyl fold-
AHCTUNGTRENNUNG
foldamer (4) confirms the presence of
À
N H···N hydrogen bonds between the
heterocyclic nitrogen atom and the free
hydrogen of the urea linkage. Addi-
tionally, the tolyl methyl group inter-
acts unfavourably with the urea car-
bonyl oxygen, thus destabilising the al-
ternate planar conformation.
Keywords: helical structures · het-
erocycles · hydrogen bonds · supra-
molecular chemistry · ureas
Introduction
have the potential to exist as an unfolded b-sheet (intermo-
lecular hydrogen bonding) or a folded helical structure (in-
tramolecular hydrogen bonding)[17] and 5) benzoylurea olig-
omers that mimic extended a-helices.[18]
Complex, well-defined structures found throughout nature
are continuously intriguing and inspiring biologists, bio-
chemists and chemists. A recurring theme in most biological
macromolecules is the presence of controlled and well-de-
fined intramolecular folding. Consequently, there has been
much effort in recent years to prepare synthetic analogues
of natural folding molecules to better understand the mech-
anism of natural folding, which is of vital importance to
most protein, polysaccharide and nucleic acid structure–
function relationships.[1,2] The term foldamer[3,4] was recently
redefined by Gellman as “unnatural oligomers that display
conformational propensities akin to those of proteins and
nucleic acids”.[5]
The research described herein deals with backbone rigidi-
fied crescent-shaped foldamers in which local conformation-
al preferences stabilise folded structures and reduce the
number of non-folded states to promote well-defined molec-
ular conformations. Specifically, the rotation about all single
bonds within the structures is restricted in such a fashion as
to greatly favour one conformation over all others. In es-
sence, the goal is to understand and control intramolecular
non-covalent interactions in relation to the unfavourable en-
tropy associated with self-organisation. This work describes
the synthesis and characterisation of molecular building
blocks from which foldamers with varying degrees of curva-
ture can be obtained. They are based on the relative orien-
tation between consecutive heterogeneous backbone units
as defined by precisely designed non-covalent interactions.
For example, directly linked heteroaromatic foldamers com-
prised of alternating pyridine–pyrazine (meta–ortho connec-
tivity),[11] pyridine–pyrimidine (meta–meta connectivity)[12] or
pyridine–pyridazine (meta–para connectivity)[13] rings form
helical structures with four, six or twelve heterocycles per
helical turn, respectively, due to the preferred transoid con-
formation of inter-heterocyclic bonds. Precise shape control
has also been demonstrated in amide-linked carbocyclic aro-
matic[6] or heteroaromatic[19] foldamers in which the ortho,
meta and/or para connectivity in combination with the re-
stricted rotation associated with hydrogen bonding ultimate-
ly control the conformation of the building blocks thus the
degree of curvature in the final folded structure. Not surpris-
ingly, one can take advantage of crescent-shaped building
blocks with varying degrees of curvature to access a wide
range of shape-persistent macrocyclic compounds in one or
more synthetic steps.[20–24] Clearly, a high degree of preorga-
nisation during synthesis can have a self-templating effect to
promote intramolecular macrocyclisation under non-high di-
lution conditions.
Several families of aromatic crescent or helical foldamers
with predictable structures have been studied extensively
and include carbocyclic aromatic and heteroaromatic oligo-
ACHTUNGTRENNUNGamACHTUNGTRENNUNG
ides,[6–8] aromatic oligohydrazines,[9] aromatic oligohydra-
zides[10] and directly linked aromatic heterocycles.[11–13] Of
À
specific importance to this research is the aryl NHCO link-
age that encompasses the urea foldamers described herein.
Examples of urea-linked foldamers particularly pertinent to
this account include: 1) enforced folding and cyclisation of
backbone-rigidified aromatic oligoureas of meta-linked ben-
zene rings,[14] 2) poly(ureido-para-phthalimidyl) foldamers in
[15]
À
which the urea N H groups adopt a cisoid conformation,
3) aromatic antibacterial urea oligomers with NH···S interac-
tions on every ring,[16] 4) naphthyridinylurea oligomers that
[a] J. J. Mousseau, L. Xing, N. Tang, Prof. L. A. Cuccia
Department of Chemistry & Biochemistry
Concordia University, 7141 Sherbrooke Street West
Montreal, Quebec, H4B 1R6 (Canada)
Fax : (+1)514-848-2868
E-mail: cuccial@alcor.concordia.ca
[b] J. J. Mousseau, L. Xing
These two authors contributed equally to this article.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901094.
Chem. Eur. J. 2009, 15, 10030 – 10038
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L. A. Cuccia et al.
Results and Discussion
We recently described the synthesis of macrocycles bearing
urea linkages between alternating pyridazyl and tolyl moiet-
ies (e.g., MC6; Figure 1).[24] The ease of macrocyclisation
Figure 1. Macrocycle (MC6) and foldamer (6) bearing urea linkages be-
tween alternating pyridazyl and tolyl moieties. Foldamer 6 is shown in its
optimal helical conformation with hydrogen bonds represented as hash
lines.
was attributed to the high degree of pre-organisation pres-
ent in the growing molecule and it was envisioned that these
same building blocks and interactions could provide access
to helical foldamers (e.g. 6; Figure 1). There are three main
interactions working in concert to influence the conforma-
Figure 2. Structure of the heterocyclic core units N3,N6-diisobutylpyrida-
zine-4,6-diamine (1), N4,N6-diisobutylpyrimidine-4,6-diamine (2) and
N2,N3-diisobutylpyrazine-2,3-diamine (3). Variations in the heteroaromat-
ic (1a, 2a and 3a) or carbocyclic aromatic (1a, 1b and 1c) group of the
basic building blocks yield different angles of curvature, between the
broken bonds, for the heteroaromatic/urea/carbocyclic aromatic unit. Hy-
drogen bonds are represented as hash lines.
À
tion and folding in this design: 1) N H···N hydrogen bonds
between the heterocyclic nitrogen atom and the free hydro-
À
gen of the urea linkage, 2) C H···O hydrogen bonding inter-
actions between the carbonyl oxygen of the urea linkage
and the ortho hydrogen atom on the neighbouring non-het-
erocyclic ring and 3) steric repulsion between the non-aro-
matic methyl group and the urea carbonyl group. Finally, a
favourable slipped stack p–p interaction between overlap-
ping aromatic groups is also possible once one turn of the
helix is obtained. These interactions are expected to act in a
cooperative fashion to restrict rotation about all single
bonds of the urea linkage.
in 76% yield. The isobutyl group was chosen to increase sol-
ubility of the foldamers and to promote the formation of
crystalline products. Compound 4 was prepared in 74%
yield by reacting diamine 1 with excess o-tolylene isocya-
nate. Products, such as 4, containing tolyl groups at the ter-
mini were designated as being capped as the chain can no
longer be extended. Foldamer 6 was prepared in 39% yield
from the reaction of the half-capped compound 5 with toly-
lene-2,6-diisocyanate (TDI) in chloroform for 16 h at 408C.
Products containing the o-xylyl moiety (oxyl foldamers)
were prepared using a different route. Since the correspond-
ing diisocyanate was not commercially available, the urea
linkages were formed using the corresponding biscarbamate.
Compound 7 was synthesised from the bisisopropenyl carba-
mate of 2,3-dimethylbenzene-1,4-diamine.[25,26] Compound 7
was subsequently capped with excess o-tolylene isocyanate
to give compound 8 in 54% yield. Pyridazyl oligomers con-
taining the m-xylyl monomer (mexyl foldamers) were pre-
pared similarly to the oxyl foldamers. Compound 9 was pre-
pared in one pot using the bis-p-nitrophenyl carbamate of
1,5-dimethyl-2,4-phenylenediamine; which was reacted in
situ with diamine 1.[25,27] This was readily converted to com-
pound 10 by capping with o-tolylene isocyanate.
With the foldamer design in place, the next step was to
explore possibilities for tuning the curvature of these mole-
cules. It was envisaged that by varying the diazine moeity
(pyridazines 1, pyrimidines 2 and pyrazines 3; Figure 2) one
could influence the degree of curvature by virtue of the sub-
stitution pattern of the heterocycle (1a, 2a and 3a, respec-
tively; Figure 2). Furthermore, varying the non-heterocyclic
moiety from tolyl to o-xylyl or m-xylyl also provides a
means of altering the curvature of the repeating motif (1a,
1b and 1c, respectively; Figure 2). A useful way of looking
at this flexible design principle with regards to curvature is
to calculate the number of aromatic units needed to form a
macrocycle using each motif. For example, motifs 1a, 1b
and 1c would form macrocycles with four, twleve and six ar-
omatic units, respectively.
Pyrimidyl foldamers were synthesised according to
Scheme 2. N4,N6-Diisobutylpyrimidine-4,6-diamine (2) was
prepared similarly to N3,N6-diisobutylpyridazine-3,6-diamine
(1), starting from 4,6-dichloropyrimidine and isobutyl amine.
Products 11 and 12 were prepared from diamine 2 and o-tol-
ylene isocyanate. However, due to the lower reactivity of di-
Pyridazyl foldamers were synthesised following the se-
quence of reactions shown in Scheme 1. N3,N6-Diisobutyl-
pyridazine-3,6-diamine (1) was prepared as previously de-
scribed by reacting 3,6-dichloropyridazine with isobutyl
amine in a Parr reactor at 1558C to give the desired product
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Convoluted Foldamers
FULL PAPER
Scheme 1. a) o-Tolylene isocyanate (3 equiv), CHCl3, 508C, 5 h, 74%; b) o-tolylene isocyanate (1.2 equiv), CHCl3, 508C, 5 h, 68%; c) TDI (0.5 equiv),
CHCl3, 24 h, 39%; d) NaOH (3.5 equiv), 22 (1 equiv), H2O, EtOAc, isopropenyl chloroformate (2.8 equiv), 3 h, then 8 (1.1 equiv), N-methyl pyrolidine
(20 mol%), 558C, 48 h, 16% (over 2 steps); e) o-tolylene isocyanate (6.4 equiv), CHCl3, 558C, 24 h, 54%; f) 4-nitrophenyl chloroformate (2.5 equiv),
CH2Cl2, 23 (1 equiv), DIEA (2 equiv), 1 h, then 8 (1.1 equiv) 20 h, RT, 13% (over 2 steps); g) o-tolylene isocyanate (6.4 equiv), CHCl3, 558C, 24 h, 51%.
pared in 21% yield from the reaction of 3 with TDI
(Scheme 3). The rational for the poor yield is the high
degree of steric strain in the system as a result of the ortho
substitution of the pyrazine heterocycle.
Scheme 3. a) TDI (0.5 equiv), toluene, 908C, 24 h, 21%.
Scheme 2. a) o-Tolylene isocyanate (1 equiv), toluene, 908C, 24 h, 73%;
b) o-tolylene isocyanate (3 equiv), toluene, 908C, 48 h, 75%; c) TDI
(0.45 equiv), toluene, 908C, 24 h, 44%.
Folding in pyridazyl foldamers: The designed pre-organisa-
tion was observed with the crescent-shaped, capped folda-
mer 4. This was determined through proton NMR spectros-
amine 2 in comparison to diamine 1, presumably due to the
relative electron deficiency of the pyrimidine heterocycle,
the reaction required elevated temperatures to obtain good
conversions.[28] Compound 13 was obtained in 44% yield
from the reaction of diamine 2 with TDI. Again, elevated
temperatures were required for the reaction to proceed. At-
tempts to prepare longer pyrimidyl oligomers were unsuc-
cessful. Interestingly, when compound 13 was treated with
o-tolylene isocyanate, formation of compound 12 was ob-
served. Compound 13 likely degrades to the corresponding
TDI and N4,N6-diisobutylpyrimidine-4,6-diamine, which
then reacts with the excess o-tolylene isocyanate present in
solution. Attempts to circumvent this reversibility were un-
successful. The reactions of compound 2 with the same oxyl
and mexyl biscarbamates used to prepare compounds 7 and
9 were unsuccessful, again likely due to the decreased nucle-
ophilicity of diamine 2 versus diamine 1.
copy as the chemical shift of the urea proton was observed
at d=11.57 ppm in comparison to non-hydrogen bonded
heterocyclic urea protons at dꢀ10.6 ppm.[24] This degree of
deshielding is also characteristic of hydrogen-bonded amide-
based foldamers.[7] Additionally, the proton at the 6-position
of the tolyl group was shifted to d=7.97 ppm, compared to
d=7.13 ppm in o-tolylene isocyanate, suggesting that hydro-
gen bonding with the urea carbonyl oxygen is also present
(Figure 3). NOESY analysis detected an NOE cross peak
between the urea proton and the tolyl methyl group, a con-
sequence of hydrogen-bond restricted rotation about the
linking urea bonds and the unfavourable steric interaction
between the tolyl methyl group and the urea carbonyl group
(Figure 1).[29] This preferred Z,E configuration of the urea
bond was confirmed from the X-ray structure of foldamer 4
(Figure 4).[30] The N H···N distance was measured at a rea-
À
sonable hydrogen-bond distance of 1.91 ꢁ. There is also evi-
dence for molecular helicity as the two terminal tolyl groups
display a slight twisting out of plane due to weak van der
Waals repulsion between the two tolyl methyl groups.
N2,N3-Diisobutylpyrazine-2,3-diamine (3) was obtained
from the reaction of isobutyl amine with 2,3-dichloropyra-
zine. This diamino heterocycle was the least reactive of the
three diazines. The reaction of diamine 3 with o-tolylene iso-
cyanate was unsuccessful; however, compound 14 was pre-
À
Evidence for similar N H···N hydrogen bonding interac-
tions was observed in compound 6, in which the urea pro-
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L. A. Cuccia et al.
Figure 4. X-ray crystal structure of foldamer 4—front and side view (left
and right); stick and space-filling representation (upper and lower). For
clarity only the M-helix is shown.
groups.[29] The oxyl C H···O protons at the 5- and 6-posi-
À
Figure 3. 1H NMR spectra of compounds 4 and 6 from d=6.9 to 8.1 ppm.
The chemical shifts due to p–p stacking in H-3, H-4 and H-5 are high-
lighted with arrows.
tions in compound 7 exhibited a chemical shift at d=
7.48 ppm while the mexyl proton at the 6-position in com-
pound 9 was at d=8.15 ppm. Protons H-5 and H-6 of the
oxyl group each hydrogen bond to one carbonyl oxygen on
either side of the ring, while both carbonyl oxygen atoms
can hydrogen bond with a single proton at the 6-position in
the mexyl group. Encouraged by the consistency of the fold-
tons were present at d=11.58 and 11.44 ppm (Figure 5).
Compound 6 is expected to give a full helical turn with the
terminal tolyl groups in a slipped p-stacking arrangement.
This stacking was confirmed by
1H NMR spectroscopy
for
which the terminal tolyl pro-
tons are more shielded than
those of compound 4 due to
ring anisotropy in the helical
conformation (Figure 3).
As expected, both com-
pounds 7 and 9 displayed simi-
lar NMR signatures as those
observed for compound 4. The
urea proton signals occurred at
d=10.25 and 10.15 ppm for 7
and 9, respectively, indicative
À
of the expected N H···N hy-
drogen bonding. Additionally,
2D NOESY analysis of com-
pounds 7 and 9 showed the
same NOE effect between the
urea proton and the xylyl
methyl groups, suggesting that
the same urea Z,E configura-
tion was present, again due to
restricted rotation about the
urea bonds and steric interac-
tions between the carbonyl
oxygen and the tolyl methyl
1
À
Figure 5. H NMR spectra of compounds 6, 8 and 10 from d=7 to 12 ppm. The N H···N hydrogen bonded
protons are highlighted with black and white squares.
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Convoluted Foldamers
FULL PAPER
ing properties observed thus
far, longer oxyl and mexyl
foldACHTUNGTRENNUNGamers were synthesised. A
comparison of the 1H NMR
spectra of foldamers 6, 8 and
10 shows that similar folding
patterns are present in all
three
Though the xylyl pentamers do
not complete full helical
systems
(Figure 5).
a
turn, the same hydrogen bond-
induced chemical shifts and
NOESY analysis confirm their
folding.[29] Most importantly,
due to the difference in the
linking of the tolyl, oxyl and
mexyl oligomers, three unique
curvatures were obtained al-
lowing for fine control of the
overall shape in the final
foldamers.
Figure 6. 1H NMR spectrum of the tolyl proton region of compound 12 in [D]chloroform (upper) and
[D4]methanol (lower). The chemical shift of H6 is highlighted with an arrow.
Folding in pyrimidyl foldamers: Similar to pyridazyl com-
pound 5, pyrimidyl compound 11 also displayed a level of
preorganisation due to hydrogen bonding as indicated by
the relatively downfield location of the urea proton. This
was also observed in the capped compound 12 and the un-
capped compound 13, for which the chemical shifts of the
urea protons were observed at d=12.55 and 12.80 ppm, re-
spectively. As with the pyridazyl foldamers, NOESY analysis
of compound 12 displayed an NOE cross peak between the
urea protons and the tolyl methyl group, again demonstrat-
ing the transoid relationship between the carbonyl oxygen
and the tolyl methyl group.[29] However, unlike the pyridazyl
foldamers, the presence of a proton at the 2-position of the
pyrimidine ring should yield a NOE cross peak with the
tolyl methyl group as the distance was estimated to be ap-
proximately 2.6 ꢁ. Indeed, a cross peak was observed, con-
firming the expected folding motif of compound 12. As ob-
served for the pyridazyl foldamers, this folding was assisted
drogen bonding the oligomer no longer adopts its designed
folded conformation.
Folding in pyrazyl foldamers: The pyrazyl oligomer 14 ex-
hibited markedly different conformational properties as
compared to the corresponding pyridazyl and pyrimidyl
compounds (9 and 13, respectively). Whereas in the last two
cases, the urea proton chemical shifts were greater than d=
10 ppm, the pyrazine urea proton signal of compound 14
was observed only at 6.93 ppm, suggesting that hydrogen
bonding does not occur, and thus the oligomer is not folding
as designed. This was further confirmed through NOESY
experiments in which the expected cross peak between H-6
of the pyrazyl group and the methyl protons of the tolyl
group was not observed.[29] A possible explanation for this is
due again to steric strain of the system. The unfavourable
steric interaction between the isobutyl chains attached at
the ortho-position of the heterocycle with the carbonyl
À
by the presence of C H···O hydrogen bonds as protons at
À
the 6-position of the tolyl group were detected at d=8.05
and 8.28 ppm for compounds 12 and 13, respectively. In
order to confirm the importance of hydrogen bonding for
group of the urea linkage likely induces a rotation of the C
N urea bonds, increasing the distance between the urea
proton and the heterocyclic nitrogen atom. This increased
distance can thereby prevent hydrogen bonding, thus allow-
ing for alternate conformations for the oligomer.
1
folding a H NMR spectrum of compound 12 was obtained
in neat [D4]methanol. As expected, the urea proton under-
went complete deuterium exchange. Additionally, H-6 of
the tolyl ring was shifted upfield from d=8.05 to 7.75 ppm.
This is believed to be the result of a solvent induced disrup-
tion of intramolecular hydrogen bonding, since the remain-
ing tolyl chemical shifts were unchanged (Figure 6). Perhaps
the most poignant example of this conformational disruption
was observed through the NOESY spectra of compounds 12
and 13, in which the NOE cross peak between H-2 of the
pyrimidine ring and the tolyl methyl protons disappeared,
suggesting that these groups are now too far apart to ob-
serve the NOE effect.[29] Under conditions that disrupt hy-
Conclusion
The synthesis and characterisation of alternating aromatic
heterocycles and methyl-substituted aromatic carbocycles
connected together through urea linkages was described.
Particularly attractive in this system is the ability to control
molecular curvature by varying the constituent building
blocks and their connectivity. In the case of the pyridazyl
and pyrimidyl urea-linked foldamers, the intended folding
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L. A. Cuccia et al.
1.91–1.70 (m, 2H; CH), 0.99 ppm (d, 3J=6.7 Hz, 12H; CH3); 13C NMR
(75 MHz, CDCl3, 258C): d=163.2, 157.9, 79.3, 49.5, 28.4, 20.5 ppm; IR
(KBr): n˜ =3431, 2962, 2875, 1603, 1528, 1471, 1248 cmÀ1; MALDI-TOF:
m/z calcd: 223.18; found: 223.09 [M+H]+; elemental analysis calcd (%)
for C12H22N4: C 64.83, H 9.97, N 25.20; found: C 64.84, H 9.65, N 25.08.
patterns were supported by NMR and X-ray crystallograph-
ic data. However, the desired hydrogen bonding was not ob-
served in the case of the pyrazyl molecule, likely as a result
of steric strain. The main limitations encountered in the
work described herein was the often poor reactivity of het-
N2,N3-Diisobutylpyrazine-2,3-diamine (3): 2,3-Dichloropyrazine (2.5 g,
16.8 mmol) and isobutyl amine (7 mL, 70.4 mmol) were placed in a Parr
reactor. The solution was stirred at 1708C for 16 h after which a precipi-
tate formed. The crude product was dissolved in chloroform and washed
with saturated NaHCO3 (2ꢂ50 mL) and water (2ꢂ50 mL). The solvent
was concentrated to 5 mL and the mixture was then purified by column
chromatography (chloroform/acetone, 9:1) to yield a brown solid in 79%
yield (2.95 g). Rf =0.56 (chloroform/acetone, 9:1); m.p.=88–908C;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.46 (s, 2H; CH), 3.96 (brs,
2H; NH), 3.29–3.23 (m, 4H; CH2), 2.05–1.90 (m, 2H; CH), 1.01 ppm (d,
3J=6.7 Hz, 12H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=144.9,
129.7, 49.2, 28.0, 20.5 ppm; IR (KBr): n˜ =3426, 3020, 2962, 2872, 1600,
1550, 1504, 1223 cmÀ1; MALDI-TOF: m/z calcd: 222.18; found: 222.79
[M]+; elemental analysis calcd (%) for C12H22N4: C 64.83, H 9.97, N
25.20; found: C 64.55, H 9.72, N 24.9.
ACHTUNGTRENNUNGeroACHTUNGTRENNUNGcyclic amines in the formation of urea linkages and/or
steric factors which are detrimental in the formation of
longer foldamers.[31] Overall, this system represents an im-
plementation of a basic structural design principle for en-
forcing controlled and flexible folding in macromolecular
systems. Clearly, foldamers continue to be valuable model
systems for understanding how natural systems such as pro-
teins, nucleic acids and oligosaccharides undergo their com-
plex folding.
Experimental Section
N3,N6-Diisobutylpyridazine-4,6-diamine–o-tolyl urea-linked “trimer” (4):
o-Tolylene isocyanate (0.39 g, 2.9 mmol) was added through a syringe to
General: All reagents were obtained from Aldrich and were used with-
out further purification unless specified otherwise. All solvents used were
HPLC grade. Dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and
chloroform used in reactions were obtained anhydrous in SureSeal bot-
tles and used under nitrogen flow. [D]Chloroform (CDCl3, 99.8%) and
[D6]DMSO (99.8%) were purchased from Cambridge Isotopes. Melting
points (m.p.) were recorded with a capillary melting point apparatus
(Thomas Hoover) and are uncorrected. The recorded Rf values were de-
termined by a standard thin-layer chromatography (TLC) procedure:
0.25 mm silica gel plates (Aldrich, Z122785-25EA) eluted with the speci-
fied solvents. FTIR spectra were recorded with a Magna-IR spectrometer
550 (Nicolet) in KBr pellets. 300 MHz 1H NMR spectra and 75 MHz
13C NMR spectra were recorded on a Varian 300 spectrometer. MALDI-
TOF mass spectra were obtained using a Micromass BAA037 (Micro-
mass, UK) time-of-flight mass spectrometer. A nitrogen laser (337 nm
wavelength) was used to desorb the sample ions. The matrices used were
dihydroxybenzoic acid (DHB), dithranol (DIT), or trans-indoacrylic acid
(IAA) and the spectra were recorded in the positive reflectron mode.
FAB mass spectra (8 KV, Xe) were recorded on a KRATOS MS25RFA
with mNBA (meta-nitrobenzyl alcohol) as matrix. ESI spectra were re-
corded on a FINNIGAN LCQ DUO mass spectrometer using an ESI
probe by infusion (10 mLminÀ1) with an integrated syringe pump. X-ray
diffraction data was collected on a Bruker D8 X-ray diffractometer with
a
solution of N3,N6-Diisobutylpyridazine-4,6-diamine
1
(0.22 g,
0.97 mmol) in anhydrous chloroform (4 mL). The resulting light brown
solution was stirred at 508C under nitrogen for 5 h. When the reaction
was complete by TLC, methanol (5 mL) was added and product mixture
was stirred overnight at room temperature to react with the excess of o-
tolylene isocyanate. Solvent was removed under vacuum and the crude
product was redissolved in chloroform (10 mL) and filtered. The filtrate
was concentrated to half the volume and then separated by silica gel
column chromatography (chloroform/acetone, 9:1) to yield the product
as a white wax in 74% yield (0.36 g). Single crystals suitable for X-ray
diffraction were obtained by slow evaporation of an ethanol solution.
Rf =0.63 (chloroform/ethyl acetate, 9:1); m.p.=130–1318C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=11.57 (s, 2H; NH), 8.05–7.97 (m, 2H;
CH) 7.47 (s, 2H; CH), 7.20–7.26 (m, 4H, CH), 7.10–7.04 (m, 2H; CH),
3
3.98 (d, J=6.9 Hz, 4H; CH2), 2.39 (s, 6H; CH3), 2.02–1.80 (m, 2H, CH),
1.01 ppm (d, 3J=6.6 Hz, 12H; CH3); 13C NMR (300 MHz, CDCl3, 258C):
d=154.5, 153.5, 137.3, 130.4, 128.7, 126.7, 124.1, 122.3, 121.9, 51.5, 27.7,
20.1, 18.8 ppm; IR (KBr): n˜ =2960, 2864, 1676, 1591, 1550, 1460, 1446,
1213 cmÀ1
;
ESI: m/z calcd: 489.29; found: 489.2 [M+H]+, 511.1
[M+Na]+ 998.9 [2M+Na]+.
N3,N6-Diisobutylpyridazine-4,6-diamine–o-tolyl urea-linked “dimer” (5):
Compound 1 (0.50 g, 2.25 mmol) was placed in a round bottom flask and
dissolved in anhydrous chloroform (10 mL). The flask was fitted with a
nitrogen filled balloon and heated to 508C. O-Tolyl isocyanate (0.28 mL,
2.25 mmol) was added dropwise through a syringe and the solution was
left to stir for 16 h. Methanol (5 mL) was added to quench any unreacted
isocyanate and the chloroform was evaporated under vacuum. The solid
was redissolved in chloroform and insoluble material was filtered. The fil-
trate was concentrated to half its volume and the product was purified by
silica gel column chromatography (chloroform/acetone, 9:1) to give a
pale yellow solid in 56% yield (0.47 g). Rf =0.6 (chloroform, acetone
9:1); m.p.=89–908C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=10.60
(s, 1H; NH), 7.82 (d, 3J=7.5 Hz, 1H; CH), 7.10–7.13 (m, 2H; CH), 7.07
(d, 3J=9.3 Hz, 1H; CH), 6.95 (t, 3J=7.5 Hz, 1H; CH), 6.73 (d, 3J=
a
graphite-monochromatised MoKa radiation (0.71073 ꢁ),
q scans at
100(2) K.
N3,N6-Diisobutylpyridazine-4,6-diamine (1): 3,6-Dichloropyrazine (10 g,
67.1 mmol) and isobutyl amine (30 mL, 302 mmol) were placed in a Parr
reactor. The solution was stirred at 1558C for five days. The dark brown
solid obtained was dissolved in chloroform and washed with NaHCO3
(2ꢂ25 mL) and distilled water (2ꢂ25 mL). The mixture was then concen-
trated and purified by column chromatography (chloroform/methanol/
acetone, 8.5:1.0:0.5) to give the desired product in 76% yield (10.78 g).
Rf =0.48 (chloroform/methanol/acetone, 8.5:1.0:0.5); m.p.=141.4–
142.58C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=6.66 (s, 2H; CH),
4.50 (brs, 2H; NH), 3.16–3.14 (m, 4H; CH2), 1.80–1.95 (m, 2H; CH),
0.96 ppm (d, 3J=6.3 Hz, 12H; CH3); 13C NMR (75 MHz, CDCl3, 258C):
d=134.5, 118.0, 50.4, 28.3, 20.4 ppm; IR (KBr): n˜ =3437, 3021, 2916,
1566, 1501, 1485, 1215 cmÀ1; MALDI-TOF: m/z calcd: 223.18; found:
223.25 [M+H]+.
3
9.3 Hz, 1H; CH), 5.30–5.23 (m, 1H; NH), 3.79 (d, J=6.9 Hz, 2H; CH2),
3.28–3.17 (m, 2H; CH2), 2.27 (s, 3H; CH3), 2.00–1.87 (m, 2H, CH), 0.95
(d, 3J=6.3 Hz, 6H; CH3), 0.91 ppm (d, 3J=6.3 Hz, 6H; CH3); 13C NMR
(75 MHz, CDCl3, 258C): d=156.8, 154.3, 151.7, 137.4, 130.2, 129.3, 126.4,
123.7, 122.5, 122.4, 117.4, 52.1, 49.6, 28.2, 27.7, 20.3, 19.9, 18.4 ppm; ESI:
m/z calcd: 356.24; found: 356.3 [M+H]+, 378.2 [M+Na]+, 733.1
[2M+Na]+.
N3,N6-Diisobutylpyridazine-4,6-diamine–o-tolyl urea-linked “pentamer”
(6): Tolylene-2,6-diisocyanate (0.13 g, 0.72 mmol) was added dropwise
through a syringe over a period of 4 h under nitrogen to a solution of
N4,N6-Diisobutylpyrimidine-4,6-diamine
(2):
4,6-Dichloropyrimidine
(6.48 g, 43.4 mmol) and isobutyl amine (25.9 mL, 260 mmol) were place
in a tube that subsequently sealed. The solution was heated at 1608C for
three days after which a precipitate formed. The crude reaction mixture
was recrystallised from 99% ethanol to obtain a white crystalline solid in
64% yield (5.67 g). Rf =0.95 (chloroform/acetone, 8:2); m.p.=188–
1898C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.05 (s, 1H; CH),
5.21 (s, 1H; CH), 4.83 (brs, 2H; NH), 3.02 (t, 3J=6.7 Hz, 4H; CH2),
monocapped dimer
5 (0.51 g, 1.45 mmol) in anhydrous chloroform
(2 mL) at 408C, . The reaction was allowed to stir for another 20 h. Then
10036
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10030 – 10038

Convoluted Foldamers
FULL PAPER
methanol (2 mL) was added and the product mixture was stirred at room
temperature for 4 h to remove DIT and its isocyanate derivatives formed
during the reaction. The solvent was removed under vacuum and the
solid residue was redissolved in chloroform (10 mL) and filtered. The fil-
trate was concentrated to half the volume and purified by silica gel
column chromatography (chloroform/acetone, 8:2) to yield a light yellow
product in 39% yield (0.25 g). Rf =0.7 (chloroform/acetone, 8:2); m.p.=
120–1228C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=11.58 (s, 2H;
NH), 11.44 (s, 2H; NH), 7.98 (d, 3J=7.8 Hz, 2H; CH), 7.56 (d, J=
8.1 Hz, 2H; CH), 7.47 (brs, 4H; CH), 7.23 (t, 3J=8.1 Hz, 1H; CH), 7.18
gen filled balloon and anhydrous methylene chloride (4 mL) was added
to give
a suspension. 1,5-Dimethyl-2,4-phenylenediamine (0.153 g,
1.1 mmol) and DIEA (0.40 mL, 2.2 mmol) in anhydrous methylene chlo-
ride (4 mL) was added dropwise yielding an orange solution. The solu-
tion was left to stir at room temperature for 1 h. A solution of compound
1 (0.43 g, 1.9 mmol) with triethyl amine (0.30 mL) dissolved in methylene
chloride (1 mL) was added dropwise. The solution was left to stir for 20 h
and the reaction was monitored using TLC. The solution was left to stir
for an additional 4 d with no apparent change shown on TLC. The sol-
vent was evaporated and the yellow solid was dissolved in chloroform
and filtered to remove insoluble material. The filtrate was washed with
distilled water concentrated and purified by column chromatography
3
(t, J=7.8 Hz, 2H; CH), 7.12–7.00 (m, 2H; CH), 6.98 (t, 3J=7.5 Hz, 2H;
CH), 4.03–3.97 (m, 8H; CH2), 2.35 (s, 3H; CH3), 2.34 (s, 6H; CH3), 2.05–
1.90 (m, 4H; CH), 1.00 (d, 3J=2.4 Hz, 12H; CH3), 0.99 ppm (d, 3J=
6.6 Hz, 12H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=154.5, 153.9,
153.4, 137.4, 137.3, 130.3, 128.5, 126.7, 126.4, 124.1, 123.9, 122.0, 121.9,
120.8, 51.6, 51.5, 27.7, 20.1, 18.8, 13.6 ppm; ESI: m/z calcd: 885.52; found:
885.5 [M+H]+, 907.4 [M+Na]+, 923.4 [M+K]+.
(chloroform/acetone, 0.77:0.23) to give
a white solid in 13% yield
(0.080 g). Rf =0.5 (chloroform/acetone, 0.77:0.20); m.p.=187–1908C;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=10.15 (s, 2H; NH), 8.15 (s,
1H; CH), 7.11 (d, 3J=9.8 Hz, 2H, CH), 6.91 (s, 1H, CH), 6.76 (d, 3J=
9.8 Hz, 2H; CH), 5.03 (brt, 3J=5.5 Hz, 2H; NH), 3.78 (d, 3J=7.3 Hz,
3
N3,N6-Diisobutylpyridazine-4,6-diamine–o-xylyl urea-linked “trimer” (7):
NaOH (0.12 g, 3.00 mmol) was dissolved in water (1 mL) in a round-bot-
tomed flask and cooled on ice. 2,3-Dimethylbenzene-1,4-diamine (0.12 g,
0.87 mmol) was dissolved in ethyl acetate (2 mL) and added to the
NaOH solution. The mixture was stirred for 10 min on ice after which
isopropenyl chloroformate (0.270 mL, 2.40 mmol) was added dropwise.
After stirring for 45 min at 08C, the flask was removed from the ice and
stirred at room temperature for 3 h. The mixture was then diluted in
ethyl acetate (20 mL) and washed with saturated NaCl solution (2ꢂ
50 mL) then distilled water (2ꢂ50 mL). The ethyl acetate was evaporated
and the beige biscarbamate was triturated with cold heptane. The o-xylyl
bisisopropenyl carbamate was next added to a round-bottomed flask with
compound 1 (0.22 g, 1.00 mmol) and the flask was purged with nitrogen
and fitted with a nitrogen filled balloon. Anhydrous THF (1 mL) was
added, the resulting solution was heated to 558C and N-methyl pyroli-
dine (0.020 mL, 0.2 mmol) was added dropwise. The mixture was stirred
at 558C for 48 h. The product was then purified by silica gel column chro-
matography, first with silica (chloroform/acetone, 8:2), then with alumina
(methylelene chloride/ethyl acetate, 9:1) to yield a cream-coloured solid
in 16% yield (0.088 g). Rf =0.3 (chloroform/acetone, 8:2); m.p.=140–
1428C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=10.25 (s, 2H; NH),
7.48 (s, 2H; CH), 7.14 (d, 3J=9.6 Hz, 2H; CH), 6.62 (d, 3J=9.6 Hz, 2H;
CH), 4.99 (brt, 3J=4.2 Hz, 2H; CH2), 3.81 (d, 3J=7.49 Hz, 4H; CH2),
3.21 (t, 3J=6.7, 4H; CH2), 2.13 (s, 6H; CH3), 1.83–1.99 (m, 4H; CH),
1.00 (d, 3J=6.7 Hz, 12H; CH3), 0.92 ppm (d, 3J=6.6 Hz, 12H; CH3);
13C NMR (75 MHz, CDCl3, 258C): d=156.6, 154.6, 152.0, 133.6, 130.2,
122.8, 121.9, 116.8, 52.2, 49.7, 28.2, 27.7, 20.3, 19.9, 14.9 ppm; IR (KBr):
n˜ =3443, 3020, 2963, 1666, 1494, 1464, 1260 cmÀ1; MALDI-TOF: m/z
calcd: 633.43; found: 633.50 [M+H]+.
4H; CH2), 3.18 (t, J=6.4 Hz, 4H; CH2), 2.19 (s, 6H; CH3), 2.05–1.89 (m,
4H; CH), 0.99 (d, 3J=6.7 Hz, 12H; CH3), 0.89 ppm (d, 3J=6.7 Hz, 12H;
CH3); 13C NMR (75 MHz, CDCl3, 258C): d=156.7, 154.1, 152.1, 135.1,
131.6, 125.6, 123.0, 117.7, 116.3, 52.3, 49.8, 28.2, 27.7, 20.3, 20.0, 17.7 ppm;
IR (KBr): n˜ =3444, 3019, 2970, 1675, 1593, 1523, 1426, 1210 cmÀ1
;
MALDI-TOF: m/z calcd: 633.43; found: 633.52 [M+H]+; elemental anal-
ysis calcd (%) for C34H52N10O2: C 64.53, H 8.28, N 22.13; found: C 63.40,
H 7.04, N 20.94.
N3,N6-Diisobutylpyridazine-4,6-diamine–m-xylyl urea-linked “pentamer”
(10): Crude compound
9 (0.13 g; 0.074 g, 0.12 mmol determined by
1H NMR spectroscopy) was dissolved in anhydrous chloroform (3 mL)
under a nitrogen atmosphere. o-Tolyl isocyanate (0.080 mL, 0.7 mmol)
was added dropwise and the reaction mixture was stirred at 558C for
24 h. After cooling, methanol (5 mL) was added and the mixture was
stirred for 4 h. The solvent was concentrated to 2 mL and purified by
column chromatography (chloroform/acetone, 9:1) to give a white solid
in 51% yield (0.055 g). Rf =0.7 (chloroform/acetone, 9:1); m.p.=122–
1238C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=11.64 (s, 2H; NH),
11.28 (s, 2H; NH), 8.35 (s, 1H; CH), 7.97 (d, J=6.6 Hz, 2H, CH), 7.44–
7.46 (m, 4H; CH), 7.16–7.26 (m, 4H; CH), 6.99–7.06 (m, 3H; CH), 3.96
3
(d, J=7.4 Hz, 8H; CH2), 2.37 (s, 6H; CH3), 2.29 (s, 6H; CH3), 1.89–2.05
(m, 4H; CH), 0.96–1.00 ppm (m, 24H; CH3); 13C NMR (75 MHz, CDCl3,
258C): d=154.6, 154.5, 153.7, 153.6, 137.4, 135.3, 132.0, 130.5, 128.9,
126.8, 125.8, 124.2, 122.4, 122.2, 121.8, 117.9, 51.6, 51.6, 27.8, 20.2, 18.9,
18.2 ppm; IR (KBr): n˜ =3007, 2965, 1679, 1541, 1459, 1210 cmÀ1
MALDI-TOF: m/z calcd: 899.53; found: 899.49 [M+H]+.
;
N4,N6-Diisobutylpyrimidine-4,6-diamine–tolyl urea-linked “dimer” (11):
Compound 2 (0.50 g, 2.25 mmol) was placed in a flame-dried flask along
with a stir bar. The flask was purged with nitrogen and fitted with a nitro-
gen filled balloon, after which anhydrous toluene (10 mL) was added. o-
Tolyl isocyanate (0.28 mL, 2.25 mmol) was added dropwise and the solu-
tion was stirred at 908C for 24 h. The solution was allowed to cool and
methanol (5 mL) was added to quench any remaining isocyanate. The
solvent was evaporated and chloroform (10 mL) was added to the result-
ing white solid. The mixture was filtered to remove insoluble material,
and the filtrate was purified by column chromatography (methylelene
N3,N6-Diisobutylpyridazine-4,6-diamine–o-xylyl urea-linked “pentamer”
(8): Crude compound
7 (0.13 g; 0.068 g, 0.11 mmol calculated from
1H NMR spectroscopy) was dissolved in anhydrous chloroform (3 mL)
under a nitrogen atmosphere. o-Tolyl isocyanate (0.080 mL, 0.70 mmol)
was added dropwise and the reaction mixture was stirred at 558C for
24 h. After cooling to room temperature, methanol (5 mL) was added
and the mixture was stirred for 4 h. The solvent was concentrated to
2 mL and purified by column chromatography (chloroform/acetone, 9:1)
to give a cream-coloured solid in 54% yield (0.053 g). Rf =0.7 (chloro-
form/acetone, 9:1); m.p.=117–1188C; 1H NMR (300 MHz, CDCl3, 258C,
chloride/ethyl acetate, 9.5:0.5) to yield
a white solid in 73% yield
(0.583 g). Rf =0.33 (methylelene chloride/ethyl acetate, 9.5:0.5); m.p.:
110–1118C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=12.93 (s, 1H;
NH), 8.23 (s, 1H; CH), 8.06 (d, 3J=7.7 Hz, 1H; CH), 7.15–7.25 (m, 2H;
3
TMS): d=11.71 (s, 2H; NH), 11.37 (s, 2H; NH), 8.02 (d, J=8.1 Hz, 2H;
3
CH), 7.59 (s, 1H; CH), 7.47 (s, 4H; CH), 7.17–7.26 (m, 4H; CH), 7.03 (t,
CH), 7.00 (t, J=8.4 Hz, 1H; CH), 5.82 (s, 1H; CH), 5.40 (brs, 1H; NH),
J=7.0 Hz, 2H; CH), 3.98 (d, 3J=7.5 Hz, 8H; CH2), 2.38 (s, 6H; CH3),
3.88 (d, 3J=7.1 Hz, 2H; CH2), 3.30–3.12 (brm, 2H; CH2), 2.38 (s, 3H;
CH3), 2.10–2.00 (m, 1H; CH), 2.00–1.92 (m, 1H; CH), 1.05–0.95 ppm (m,
12H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=163.6, 160.1, 155.5,
153.8, 137.8, 130.1, 128.2, 126.5, 123.3, 121.5, 86.8, 50.1, 49.2, 28.2, 26.7,
20.2, 20.1, 18.8 ppm; IR (KBr): n˜ =3430, 3034, 2964, 2872, 1687, 1599,
1550, 1460, 1152 cmÀ1; MALDI-TOF: m/z calcd: 356.23; found: 356.25
[M+H]+.
3
2.31 (s, 6H; CH3), 1.92–2.09 (m, 4H; CH), 1.00 ppm (d, J=6.6 Hz, 24H;
CH3); 13C NMR (75 MHz, CDCl3, 258C): d=154.6, 154.5, 154.1, 153.5,
137.5, 133.8, 130.5, 130.0, 128.6, 126.9, 124.1, 122.3, 122.1, 121.9, 121.8,
51.7, 51.5, 27.8, 20.2, 19.0, 15.5 ppm; IR (KBr): n˜ =3027, 2964, 1679, 1541,
1449, 1210 cmÀ1
; MALDI-TOF: m/z calcd: 899.53; found: 899.62
[M+H]+.
N3,N6-diisobutylpyridazine-4,6-diamine–m-xylyl urea-linked “trimer” (9):
4-Nitrophenyl chloroformate (0.57 g, 2.8 mmol) was added to a round
bottom flask and purged with nitrogen. The flask was fitted with a nitro-
Capped
N4,N6-diisobutylpyrimidine-4,6-diamine–tolyl
urea-linked
“trimer” (12): Compound 2 (0.11 g, 0.5 mmol) was placed in a flame-
dried flask along with a stir bar. The flask was purged with nitrogen and
Chem. Eur. J. 2009, 15, 10030 – 10038
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10037

L. A. Cuccia et al.
fitted with a nitrogen filled balloon, after which anhydrous toluene
(2 mL) was added. o-Tolyl isocyanate (0.2 g, 1.5 mmol) was added drop-
wise and the solution was stirred at 908C for 48 h. The mixture was al-
lowed to cool to room temperature and methanol (5 mL) was added to
quench any remaining isocyanate. The solvent was evaporated and
chloroform (10 mL) was added to the resulting white solid. The mixture
was filtered to remove insoluble material, and the filtrate was purified by
column chromatography (methylelene chloride/ethyl acetate, 9.5:0.5) to
yield a cream-coloured solid in 75% yield (0.183 g). Rf =0.67 (methyle-
lene chloride/ethyl acetate, 9.5:0.5); m.p.=143–1458C; 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=12.55 (s, 2H; NH), 8.58 (s, 1H; CH),
8.05 (d, 3J=8.2 Hz, 2H; CH), 7.20–7.260 (m, 4H; CH), 7.06 (t, 3J=
Carrie, Aurelie Mazille, and Angela Saverimuthu. We also thank Prof.
Anne Petitjean, Prof. Bruce Lennox and Dr. Rolf Schmidt for useful dis-
cussions and advice. NSERC (Canada), FQRNT (Quꢃbec), CFI
(Canada), and Concordia University are thanked for financial support.
We also acknowledge our membership in the FQRNT-supported, multi-
university Centre for Self-Assembled Chemical Structures (CSACS).
[1] I. Huc, L. Cuccia in Foldamers: tructure, Properties, and Applications
(Eds.: S. Hecht, I. Huc), Wiley-VCH, Weinheim, 2007, p. 3.
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Lett. 2007, 9, 1797.
[11] F. Heirtzler, M. Neuburger, k. Kulike, J. Chem. Soc. Perkin Trans. 1
2002, 809.
[12] G. S. Hanan, J.-M. Lehn, N. Kyritsakas, J. Fischer, J. Chem. Soc.
Chem. Commun. 1995, 765.
[13] L. A. Cuccia, J.-M. Lehn, H. J.-C. M. Schmutz, Angew. Chem. 2000,
112, 239; Angew. Chem. Int. Ed. 2000, 39, 233.
[14] A. Zhang, Y. Han, K. Yamato, X. C. Zeng, B. Gong, Org. Lett. 2006,
8, 803.
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J. A. J. M. Vekemans, E. W. Meijer, Org. Lett. 2006, 8, 383.
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Murray, J. Am. Chem. Soc. 2001, 123, 10475.
3
8.2 Hz, 2H; CH), 6.43 (s, 1H; CH), 3.99 (brd, J=7.3 Hz, 4H; CH2), 2.42
(s, 6H; CH3), 2.20–2.00 (m, 2H; CH), 1.05 ppm (d, 3J=6.7 Hz, 12H;
CH3); 13C NMR (75 MHz, CDCl3, 258C): d=161.4, 153.7, 153.4, 137.6,
130.6, 128.7, 127.0, 124.3, 122.2, 92.8, 50.8, 27.1, 20.4, 19.1 ppm; IR (KBr):
n˜ =3028, 2965, 1694 1582, 1539, 1458, 1201, 1148 cmÀ1; MALDI-TOF:
m/z calcd: 489.29; found: 489.34 [M+H]+
Uncapped
N4,N6-diisobutylpyrimidine-4,6-diamine–tolyl
urea-linked
“trimer” (13): Compound 2 (1 g, 4.5 mmol) was placed in a flame-dried
flask along with a stir bar. The flask was purged with nitrogen and fitted
with a nitrogen filled balloon, after which anhydrous toluene (16 mL)
was added. Tolylene-2,6-diisocyanate (0.3 mL, 2.1 mmol) was added
dropwise and the solution was heated at 908C for 24 h. The solvent was
evaporated to give a white solid, which was then re-dissolved in chloro-
form (10 mL). Insoluble material was removed by vacuum filtration. The
filtrate was concentrated to half its volume and purified by column chro-
matography (chloroform/acetone, 8:2) to give a white solid in 44% yield
(0.560 g). Rf =0.68 (chloroform/acetone, 8:2); m.p.=174–1758C;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=12.80 (s, 2H; NH), 8.28 (s,
2H; CH), 7.65 (d, 3J=7.9 Hz, 2H; CH), 7.20 (t, 3J=8.2 Hz, 1H; CH),
5.80 (s, 2H; CH), 5.35 (brs, 1H; NH), 3.88 (brd, 3J=7.3 Hz, 4H; CH2),
3.20–3.12 (brm, 4H; CH2), 2.35 (s, 3H; CH3), 2.10–2.00 (m, 2H; CH),
2.00–1.92 (m, 2H; CH), 1.10–0.95 ppm (m, 24H; CH3); 13C NMR
(75 MHz, CDCl3, 258C): d=163.5, 160.2, 155.5, 154.1, 137.7, 126.2, 122.4,
119.5, 50.2, 49.2, 28.2, 26.7, 20.2, 20.1, 13.5 ppm; IR (KBr): n˜ =3431, 3027,
2964, 2973, 1686, 1596, 1551, 1470, 1216, 1153 cmÀ1; MALDI-TOF: m/z
calcd: 619.41; found: 619.64 [M+H]+.
[18] J. M. Rodriguez, A. D. Hamilton, Angew. Chem. 2007, 119, 8768;
Angew. Chem. Int. Ed. 2007, 46, 8614.
N2,N3-Diisobutylpyrazine-2,3-diamine uncapped urea-linked “trimer”
(14): Compound 3 (0.50 g, 2.25 mmol) was placed in a flame-dried flask
along with a stir bar. The flask was purged with nitrogen and fitted with
a nitrogen filled balloon, after which anhydrous toluene (10 mL) was
added. Tolylene-2,6-diisocyanate (0.16 mL, 1.12 mmol) was added drop-
wise and the solution was stirred at 908C for 24 h, after which additional
tolylene-2,6-diisocyanate was added (0.050 mL, 0.35 mmol) and the solu-
tion was allowed to stir for an additional 24 h at 908C. The solvent was
evaporated to give a brown gum, which was purified by column chroma-
tography (chloroform/acetone, 8.5:1.5) to give a cream-coloured solid in
21% yield (0.130 g). Rf =0.49 (chloroform/acetone, 8.5:1.5); m.p.=198–
2008C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.04 (d, 3J=2.4 Hz,
2H; CH), 7.72 (d, 3J=2.4 Hz, 2H; CH), 7.35 (d, 3J=7.8 Hz, 2H; CH),
7.11 (t, 3J=7.8 Hz, 1H; CH), 6.93 (s, 2H; NH), 4.99 (t, 3J=5.9 Hz, 2H;
NH), 3.55 (brs, 4H; CH2), 3.29 (d, 3J=5.9 Hz, 4H; CH2), 2.01–1.85 (m,
7H; CH, CH3), 0.96 (d, 3J=6.8 Hz, 12H; CH3), 0.91 ppm (d, 3J=6.8 Hz,
12H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=154.5, 151.1, 141.9,
137.1, 136.8, 129.9, 126.4, 122.8, 119.9, 53.0, 48.6, 28.4, 28.2, 20.3, 20.2,
[19] C. Bao, B. Kauffmann, Q. Gan, K. Srinivas, H. Jiang, I. Huc, Angew.
Chem. 2008, 120, 4221; Angew. Chem. Int. Ed. 2008, 47, 4153.
[20] L. Yuan, W. Feng, K. Yamato, A. R. Sanford, D. Xu, H. Guo, B.
Gong, J. Am. Chem. Soc. 2004, 126, 11120.
[21] H. Jiang, J.-M. Leger, P. Guionneau, I. Huc, Org. Lett. 2004, 6, 2985.
[22] E. Berni, C. Dolain, B. Kauffmann, J.-M. Leger, C. Zhan, I. Huc, J.
Org. Chem. 2008, 73, 2687.
[23] W. Feng, K. Yamato, L. Yang, J. S. Ferguson, L. Zhong, S. Zou, L.
Yuan, X. C. Zeng, B. Gong, J. Am. Chem. Soc. 2009, 131, 2629.
[24] L. Xing, U. Ziener, T. C. Sutherland, L. A. Cuccia, Chem. Commun.
2005, 5751.
[25] The synthesis of 2,3-dimethylbenzene-1,4-diamine and 1,5-dimethyl-
2,4-phenylenediamine is described in the Supporting Information.
[26] I. Gallou, M. Eriksson, X. Zeng, C. Senanayake, V. Farina, J. Org.
Chem. 2005, 70, 6960.
[27] A. Wiszniewska, D. Kunce, N. N. Chung, P. W. Schiller, J. Izdebski,
Lett. Pept. Sci. 2003, 10, 33.
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Chem. Int. Ed. 2006, 45, 7781.
[29] NOESY spectra for compounds 4, 6, 7, 8, 9, 10, 12, 13 and 14 are
available in the Supporting Information.
12.1 ppm; IR (KBr): n˜ =3443, 3020, 2962, 1682, 1505, 1472, 1213 cmÀ1
MALDI-TOF: m/z calcd: 619.41; found: 619.50 [M+H]+.
;
[30] Detailed crystallographic information is available in the Supporting
Information.
Acknowledgements
[31] A. Zhang, J. S. Ferguson, K. Yamato, C. Zheng, B. Gong, Org. Lett.
2006, 8, 5117.
Much of this work would not have been possible without the initial ef-
forts of Carolin Madwar, Johnston Hoang, Neenah Navasero, Jessie
Received: April 24, 2009
Published online: September 11, 2009
10038
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Chem. Eur. J. 2009, 15, 10030 – 10038