Glycoluril derivatives form hydrogen bonded tapes rather than cucurbit[n]uril congeners

Article abstract of DOI:10.1016/S0040-4020(02)01307-8

The synthesis and X-ray crystallographic characterization of diphenylglycoluril derivatives (1-4) that possess one or two alkyl groups on their N- or O-atoms is reported. Compounds 1-4 preferentially form linear hydrogen bonded tapes in the crystal by het

Full text of DOI:10.1016/S0040-4020(02)01307-8

Tetrahedron 58 (2002) 9769–9777
Glycoluril derivatives form hydrogen bonded tapes rather than
cucurbit[n]uril congeners
Anxin Wu,a,b James C. Fettingera and Lyle Isaacsa
,
*
aDepartment of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
bNational Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
Received 30 August 2002; revised 9 October 2002; accepted 15 October 2002
Abstract—The synthesis and X-ray crystallographic characterization of diphenylglycoluril derivatives (1–4) that possess one or two alkyl
groups on their N- or O-atoms is reported. Compounds 1–4 preferentially form linear hydrogen bonded tapes in the crystal by heterochiral
recognition processes. We do not observe cyclic hydrogen bonded cucurbit[n]uril congeners that would result from homochiral recognition
processes. The high propensity of alkylated derivatives of diphenylglycoluril to form hydrogen bonded tapes stands in stark contrast to the
reported X-ray crystal structures of other known alkylated derivatives of glycoluril. We attribute this high propensity to form tapes to the
phenyl and alkyl substituents that impart good solubility in non-polar aprotic solvents which do not compete for H-bonds. These results
suggest that suitably functionalized glycoluril derivatives have untapped potential in studies of crystal engineering. q 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
notation to describe the hydrogen bond motifs in this
paper.9,10 One of the most important motifs for studies of
crystal engineering involves the formation of hydrogen
bonded tapes. Tapes comprise linear aggregates of
molecules where each molecule is hydrogen bonded to
exactly two other molecules by the formation of eight-
membered rings typically forming R22(8) H-bonding motifs.
Hydrogen bonded tapes have been observed for several
classes of molecules including cyanuric acid and mela-
mine,11 bicyclic bis-lactams,12 diketopiperazines,13,14
thioureas,15 and benzimidazolene-2-thiones,16 and has
been the subject of excellent reviews.17,18 To date, known
X-ray crystal structures of compounds containing a single
glycoluril ring include the parent glycoluril,19,20 its 3a,6a
derivatives,8,21,22 nitrated derivatives,23 molecular clips,24
components for molecular encapsulation,25 hexacyclic
compounds,26 acylated derivatives,27–29 cyclic ethers,30,31
and alkylated derivatives.32–37 To the best of our knowl-
edge, however, no glycoluril derivatives have been reported
to form H-bonded tapes in the crystal.38 This deficiency is
particularly surprising since: (1) the well developed nature
of the synthetic chemistry of glycoluril allows the
preparation of a wide range of derivatives, (2) the rigid
glycoluril skeleton results in derivatives with well defined
geometries, (3) it is one of a small number of non-planar
building blocks, and (4) many of the derivatives of
glycoluril are inherently chiral due to substitution pattern
alone which can lead to interesting stereochemical proper-
ties. In this paper we report that alkylated glycoluril
derivatives (^)-1, (^)-2, 3, and (^)-4 form hydrogen
bonded tapes in the crystal by heterochiral recognition
processes.
Glycoluril (5) is an important building block for both
molecular and supramolecular chemistry. For example,
glycoluril derivatives have been used in a variety of
applications including polymer cross-linking, psychotropic
agents, explosives, in the stabilization of organic com-
pounds against photodegradation, textile waste stream
purification, and combinatorial chemistry.1 In the area of
supramolecular chemistry, glycoluril derivatives have been
used as the basis for molecular capsules,2 molecular clips,3
models of polyketide biosynthesis,4 self-complementary
facial amphiphiles,5 xerogels,6 and the cucurbit[n]uril
(CB[n]) family.7
One area of glycoluril supramolecular chemistry that has
been less well explored is its utilization as a platform for
studies of crystal engineering.8 We use Etter’s graph set
Keywords: glycoluril; hydrogen bonding; tapes; cucurbituril; crystal
engineering.
*
Corresponding author. Tel.: þ1-301-405-1884; fax: þ1-301-314-9121;
e-mail: li8@umail.umd.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01307-8

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A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
Figure 1. Schematic representation of the connectivity observed in the crystal structures of 5a and 5b. The blue and red highlighted regions depict two possible
linear tape motifs that can be excised from the crystal lattice. The green region highlights a hypothetical tape motif formed by the side-by-side interactions of
glycoluril molecules.
2. Results and discussion
These substituents are intended to enforce the formation of
tapes by preventing H-bonding interactions perpendicular to
the tapes. We designed dibenzyl diphenyl glycoluril
derivatives 3 and (^)-4 to with this consideration in mind
(Scheme 1). In particular, we chose to use phenyl and benzyl
substituents on these molecules to improve their solubility
characteristics in non-polar aprotic organic solvents. The
use of polar protic solvents for the crystallization of related
dialkyl glycoluril derivatives lead to non-tape struc-
tures.32 – 34,36 A third linear tape shown in green is
conceptually accessible by the transposition of two
H-bond donating NH groups with the H-bond acceptor
CvO groups. The enol forms of the ureidyl groups present
just such a transposition. To express the H-bonding
information present in the enol form, we targeted di-O-
alkylated glycoluril derivatives. For this purpose, we
prepared (^)-1, and as a side product obtained mono-
alkylated (^)-2 (Scheme 1).
2.1. Design of the molecular components for H-bonded
self-assembly
Fig. 1 shows a schematic representation of the connectivity
observed in the crystal structures of 5a and 5b. All four
H-bond donating NH groups and both H-bond accepting
ureidyl CvO groups become fully H-bonded through the
formation of R22(8) motifs comprising N–H· · ·O H-bonds.
This leads to a molecular sheet in which each molecule is
H-bonded to four neighboring molecules. Following the
conceptual framework developed by Whitesides for crystal
engineering the cyanuric acid·melamine lattice,11,14,16 we
decided to examine the crystal structure of 5a for the
presence of repetitive H-bonding tape motifs. The regions
highlighted in blue and red represent two infinite tapes that
might be accessible by appending substituents to the 1,6-
and 1,4-positions of the glycoluril skeleton, respectively.
Through our work on the chemistry and recognition
properties of methylene bridged glycoluril dimers, we
have become interested in the chemistry of cucurbit[n]uril,
its derivatives, and its congeners.39 As a secondary
motivation for the synthesis and X-ray crystallographic
characterization of 1 and 3, we considered the influence of
relative stereochemistry on the formation of H-bonded
tapes. Tapes formed from 1 or 3, for example, display their
phenyl groups on alternate sides of the tape which leads to
linear tapes. The alternative mode of aggregation, that
displays the all of the phenyl groups on the same side of the
tape would lead to cyclic tape-like structures 1n and 3n,
respectively. Compounds 1n and 3n can be considered H-
bonded cucurbit[n]uril congeners. Such aggregates could be
expected to retain some of the interesting molecular
recognition properties that have been demonstrated for
cucurbit[n]uril and molecular capsules.2,40,41
Scheme 1. Synthesis of 1–4. Conditions: (a) Et3OBF4, ClCH2CH2Cl; (b)
EtOH, HCl, reflux.

A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
9771
Figure 2. ORTEP plot of the molecular structures of: (a) (^)-1 and (b) (^)-
2 in the crystal. Only one enantiomer is shown. Thermal ellipsoids are
drawn at the 50% probability level.
Figure 3. ORTEP plot of the molecular structures of (a) 3 and (b) (^)-4 in
the crystal. Only one enantiomer is shown. Thermal ellipsoids are drawn at
the 50% probability level.
5c was ethylated with Et3OBF4 in ClCH2CH2Cl to deliver
(^)-1 (5%) and (^)-2 (22%) in modest yield.42 Conden-
sation of benzylurea (6) and benzil (7) in refluxing EtOH
saturated with HCl yielded 3 (20%) and (^)-4 (20%).
Compound (^)-1 is C2 symmetric and contains two NH
groups and two H-bond accepting CvN groups whereas
(^)-2 is C1 symmetric containing three NH groups and two
H-bond acceptors (CvO and CvN). Compounds 3 and
(^)-4 contain two benzyl substituents on the same, and
opposite sides of the glycoluril rings, respectively. These
two benzyl substituents reduce the number of hydrogen
bonding ureidyl NH groups to two and while retaining both
carbonyl groups as potential H-bond acceptors. Compounds
1, 2, and 4 are chiral; in this study we obtained and used the
corresponding racemic mixtures.
2.3. Molecular structure of 1–4 as determined by X-ray
crystallography
We were able to obtain single crystals of 1–4 by
recrystallization from non-polar solvents (1: CHCl3, 2:
CH2Cl2/CH3CN and CHCl3/MeOH, 3: CHCl3/CH3CN and
CH2Cl2/CH3CN, 4: C6H6, ClCH2CH2Cl, and PhCH3). Fig. 2
shows ORTEP plots of the molecular structures of (^)-1
and (^)-2 in the crystal. The structures of (^)-1 and (^)-2
2.2. Synthesis of molecular components for H-bonded
self-assembly
Scheme 1 shows the synthesis of 1–4. Diphenyl glycoluril

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A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
are similar to those reported previously for other glycoluril
derivatives. Both compounds contain cis-fused five-mem-
bered rings bearing two phenyl groups which imparts
curvature to the molecule. The mean planes through the two
five-membered rings intersect with angles of 109.78 (1) and
109.68 (2). These values are somewhat smaller than those
observed for dimethylated derivatives of 5a (121.48)36 and
5b (117.98)34 and correlates with the increase in steric bulk
of the substituents on the convex face of glycoluril. The
glycoluril skeletons are significantly twisted which is
manifested in the dihedral angles between the ipso
C-atoms of the phenyl rings and the bridgehead C-atoms
(1: 138) and (2: 228). This twisting is commonly observed in
glycoluril derivatives and has ranged from 0834,36 to 30.58,29
with values up to 248 being observed for derivatives of 5c.43
The intramolecular distance between the O-atoms amount to
˚
˚
5.46 A (2) and 5.53 A (3) which are in the range commonly
observed for diphenyl glycoluril derivatives.22e,i,j,39 This
distance defines the potential cavity depth of the hypo-
thetical cyclic oligomer 3n formed by its self-association.
This cavity depth is slightly smaller than that of CB[6]
7b
˚
(5.98–6.04 A).
Fig. 3 shows the X-ray crystal structures 3 and (^)-4. The
molecular structures of 3 and (^)-4 are similar to those
obtained for related glycoluril derivatives previously.
Again, the cis-fused five-membered rings bearing phenyl
groups enforces their cup shaped geometry. The angle
between the mean planes defined by the five-membered
rings amounts to 111.58 (3) and 110.88 (4). The distance
between the carbonyl O-atoms amounts to 5.76 A (3) and
˚
5.58 A (4). The dihedral angle between the ipso carbons of
the phenyl rings amounts to 28.78 (3) and 14.48 (4).
Compound 3 is among the most twisted glycoluril
derivatives reported to date.29,38
Figure 5. Schematic representations of the connectivity observed in H-
bonded tapes of: (a) 3 and (b) (^)-4.
2.4. Hydrogen bond mediated self-association in the solid
state
˚
Figs. 4 and 5 show schematic representations of H-bonded
tapes that are observed in the solid state structures of 1–4.
The geometrical parameters of the hydrogen bonds in these
tapes are unremarkable (Table 1).44
Compound 1 possesses two NH groups and two CvN
H-bond acceptor groups. The spatial arrangement of these
groups dictates the formation of R22(8) H-bonding motifs by
the formation of two N–H· · ·N H-bonds (Fig. 4(a)). The
relative orientation of the phenyl groups on the convex face
of the molecule between the two H-bonded molecules is
determined by the chirality of the monomer. For example,
the homochiral aggregation of two molecules of (R,R)-1 or
two molecules of (S,S)-1 by H-bonding produces a dimer
where all four phenyl rings are displayed on the same face of
the aggregate. In theory, this process of enantiomeric self-
recognition would terminate in the cyclization to form
H-bonded cucurbit[n]uril analogs 1n.45 In the crystal,
however, we observe the formation of H-bonded tapes
formed exclusively by heterochiral recognition processes.
The chirality of the monomers in the H-bonded tapes
alternates (e.g. (R,R)-1·(S,S)-1) as shown in Fig. 4(a). This
alternation of chirality results in two phenyl rings being
Table 1. Geometrical parameters of the H-bonds found in tapes of 1–4
˚
N· · ·N (A)
˚
N· · ·O (A)
Compound
N–H· · ·N (8)
N–H· · ·O (8)
1
2.899(2)
2.905(2)
2.9327(14)
172(2)
172(2)
165.1(14)
2
3
2.8282(13)
2.895(3)
2.857(3)
175.1(15)
164(3)
164(2)
Figure 4. Schematic representations of the connectivity observed in H-
bonded tapes of: (a) (^)-1 and (b) (^)-2. The double headed arrow
identifies a close contact between the unsatisfied H-bond donor N–H group
and the adjacent phenyl ring indicative of an NH· · ·p H-bond.
4
2.8165(19)
175(2)

A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
9773
Figure 6. Cross-eyed stereoviews of the X-ray crystal structures of: (a) (^)-1 viewed along the a-axis, and (b) (^)-2·(C6H6)0.5 viewed along the c-axis. C: grey;
H: orange; N: dark blue; O: red; H-bonds: striped. Hydrogen atoms not involved in hydrogen bonds have been omitted for clarity. The arrows highlight
important aspects of the three-dimensional packing.
displayed on one face of the dimer and two on the other.
Repetition of this process leads to a linear aggregate in the
form of a hydrogen-bonded tape.
face of the dimer, the other has two on one face and two on
the other as depicted (Fig. 5(a)). In each case, the
dimerization occurs by the formation of two N–H· · ·O
H-bonds to yield the R22(8) H-bonding motif commonly
observed in the crystal structures of amides. Further
oligomerization by alternation of the phenyl rings leads to
the observed H-bonded tape. The alternative mode of
aggregation in which all phenyl groups are displayed on one
side of the molecule would lead to the cyclic structure 3n.
We do not observe these types of structures for 3 either in
solid state or in solution likely due to the efficient packing of
the tapes in the solid state and an insufficient number of
hydrogen bonds to overcome the unfavourable entropy
associated with the formation of 3n in solution.46,47 We note,
however, that this pattern of H-bonds can be enforced by
covalent connection of the glycoluril rings as has been
beautifully demonstrated by Rebek in the formation of
H-bonded capsules.2,40
Compound (^)-2 also crystallizes in the form of H-bonded
tapes (Fig. 4(b)). The situation is far more complicated in
this case, however, due to chirality, the presence of two
distinct H-bonding faces, and the imbalance in the number
of H-bond donors and acceptors.12 In practice, heterochiral
aggregation is observed exclusively. For example, the
H-bonded tape shown in Fig. 4(b) can be built up by
the heterochiral self-association of (R,R)-2 and (S,S)-2 by
the formation of two N–H· · ·N hydrogen bonds to yield the
achiral meso building block (R,R)-2·(S,S)-2. Despite its
achiral nature, the two ureidyl groups of (R,R)-2·(S,S)-2 are
enantiotopic. This dimeric building block then undergoes a
second level of heterochiral oligomerization by formation of
two N–H· · ·OvC H-bonds between ureidyl groups of
alternating topicity to form standard amide type dimeric
eight-membered rings. The result of this heterochiral
recognition process is the creation of the H-bonded tape
shown in Fig. 4(b) in which the phenyl rings are displayed
on alternating faces of the tape by the formation of two
different R22(8) motifs.
Fig. 5(b) shows a schematic representation of the R22(8)
H-bonded motif formed by (^)-4 in the solid state. Similar
to (^)-1, the aggregation of (^)-4 can occur by either a
homochiral ((R,R)-4n and (S,S)-4n) or a heterochiral
recognition process. In practice, we observe the formation
of H-bonded tapes by the heterochiral recognition process in
which molecules of (R,R)-4 H-bond exclusively with
molecules of (S,S)-4 and vice versa through the formation
of eight-membered H-bonded rings. This alternation of
chirality places the phenyl substituents on opposing sides of
the H-bonded tape. The hypothetical homochiral recog-
nition process would generate a H-bonded helix.48
Fig. 5 shows schematic representations of H-bonded tapes
formed by 3 and (^)-4 based on their X-ray crystal
structures. Despite the fact that 3 is achiral, its ureidyl
groups are enantiotopic. Therefore, the self-association of 3
can theoretically produce two dimeric aggregates that are
diastereomers—one with all four phenyl substituents on one

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A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
Figure 7. Cross-eyed stereoviews of the X-ray crystal structures of: (a) 3·CHCl3 viewed along the b-axis, and (b) (^)-4 viewed along the c-axis. C: grey; H:
orange; Cl: light green; N: dark blue; O: red; H-bonds: striped. Hydrogen atoms not involved in hydrogen bonds have been omitted for clarity. The arrows
highlight important aspects of the three-dimensional packing.
2.5. Packing of the hydrogen bonded tapes in the crystal
H-bonded tapes. The growth of the H-bonded tapes occurs
alternately along the ab-axis and along the ab-diagonal as
one moves along the c-axis. Order along the c-axis is
promoted by the presence of sheets of solvating PhH rings.
An examination of the geometry of the interacting aromatic
rings reveals that each PhH ring interacts with phenyl rings
of two molecules of 2 with a T-shaped geometry.
Compounds 1–4 form tapes by the formation of H-bonded
eight-membered rings. Conceptually, a three-dimensional
solid can then be built up by the packing of these tapes in a
variety of manners. Fig. 6 shows stereoscopic represen-
tations of the crystal structures of (^)-1 and (^)-2. As
described above, (^)-1 forms H-bonded tapes in the crystal;
Fig. 6(a) shows a view down the a-axis of the crystal which
corresponds to the long axis of the tape. As can be readily
seen from Fig. 6(a), the tapes of (^)-1 pack in the crystal
with their long axes parallel to one another. This three-
dimensional packing is facilitated along the b-axis by the
interdigitation of the OCH2CH3 groups. Along the c-axis,
the predominant mode of interaction involves the phenyl
rings forming favorable p–p interactions.49 An examin-
ation of the geometry of these interactions reveals the
predominant formation of T-shaped edge-to-face type
interactions.50 The three-dimensional packing of (^)-2 is
more complex. The tape grows along the ab-diagonal by the
formation of H-bonded eight-membered rings between
molecules of 2 of alternating chirality as shown (Fig.
6(b)). Similar to the packing of 1, tapes of 2 pack with their
long axes parallel to one another. In the case of 2, however,
the formation of NH· · ·p interactions51 appears to promote
the alignment of the tapes along the ab-axis. As shown
schematically (Fig. 4(b)), the unsatisfied H-bond donating
NH group adjacent to the OEt group forms a close contact
with one of the C-atoms on the phenyl ring of the adjacent
tape. In return, the unsatisfied NH group on this adjacent
molecule forms an identical close contact with the phenyl
ring of the original molecule. Layers of solvating PhH
delineate the boundaries of the sheets comprising the
Fig. 7 shows stereoviews of the packing of the tapes formed
by 3 and (^)-4 in three dimensions. Similar to 1, the tapes of
3 align with their long axes parallel to one another along the
b-axis (Fig. 7(a)). Ordering along the c-axis is promoted by
p–p interactions between the tapes. Examination of the
geometry of the interacting phenyl rings reveals both offset
face-to-face p-stacking and T-shaped edge-to-face type
interactions. This ordering along the c-axis results in slabs
of H-bonded tapes. These slabs of H-bonded tapes do not
interact with one another in a direct fashion along the a-axis.
Rather, layers of solvating CHCl3 molecules interact with
the phenyl rings on the sides of the slabs through C–H· · ·p
interactions.52 Just like 3, the tapes formed by (^)-4 align
with their long axes parallel to one another, in this case
along the c-axis. The three-dimensional ordering of these
tapes along the a- and b-axes is, once again promoted by p–
p interactions. In this case, both phenyl substituents on the
convex face of the glycoluril interact in an edge-to-face type
manner with the benzyl groups on the opposing molecules.
3. Conclusion
In summary, we have presented the synthesis and X-ray
crystal structures of alkylated glycoluril derivatives (^)-1,

A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
9775
(^)-2, 3, and (^)-4. In contrast to the known crystal
structures of glycoluril derivatives, all four compounds form
H-bonded tapes in the crystal by the formation of R22(8)
hydrogen bonding motifs. This tape forming process is the
result of exclusive heterochiral recognition processes within
the tapes. The alternative homochiral recognition processes
that would lead to cyclic tapes—congeners of cucurbit-
[n]uril—are not observed. We attribute the high propensity
of 1–4 to form tapes to the use of phenyl and benzyl
substituents which impart good solubility characteristics in
non-polar aprotic solvents. These non-polar aprotic solvents
do not compete for H-bonds with the ureidyl groups and that
results in the predictable formation of H-bonded tapes.
Collectively, the results presented in this paper suggest that
glycoluril derivatives have significant potential as a building
block in studies of crystal engineering.
d6): 166.4, 142.1, 127.7, 127.6, 127.2, 95.9, 64.8, 15.5. MS
(EI): m/z 350 (100, Mþ). HR-MS (EI): m/z 350.1735 (Mþ,
C20H22N4O2, calcd 350.1743).
Compound 2. Mp 250–2518C. TLC (CHCl3/MeOH 25:1) Rf
0.13. IR (KBr, cm21): 3425m, 3176s, 2988w, 1720s, 1606s,
1
1518m, 1449m, 1374m, 1332s, 1227m, 1024m. H NMR
(400 MHz, DMSO-d6): 7.64 (s, 1H), 7.53 (s, 1H), 7.47 (s,
1H), 7.05–6.85 (m, 10H), 4.40–4.25 (m, 2H), 1.33 (t,
J¼7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): 164.6,
161.3, 140.4, 139.2, 127.2, 127.1, 126.8, 91.6, 85.6, 64.1, 14.5
(14 resonances expected, 11 found). MS (FAB, Magic Bullet):
m/z 323 (100, [MþH]þ). HR-MS (FAB, Magic Bullet): m/z
323.1508 ([MþH]þ, C18H19N4O2, calcd 323.1518).
4.2.2. Compounds 3 and 4. A mixture of 6 (31.5 g,
0.21 mol) and 7 (22.0 g, 0.105 mol) was dissolved in EtOH
(210 mL) with heating. The homogenous solution was
saturated with HCl gas and heated at reflux for 20 h. The
reaction mixture was cooled to room temperature, filtered,
and the solid was washed with EtOH. The crude solid
(22.0 g) was chromatographed (SiO2, CHCl3/MeOH 50:1 to
9:1) in 4 g portions yielding cis-1 (10.0 g, 20%) and trans-1
(10.0 g, 20%) as white solids.
4. Experimental
4.1. General
Starting materials were purchased from Alfa-Aesar, Acros,
and Aldrich and were used without further purification.
Compound 5c was prepared according to the literature
procedure.53 TLC analysis was performed using pre-coated
glass plates from Analtech or E. Merck. Column chroma-
tography was performed using silica gel (230–400 mesh,
0.040–0.063 mm) from E. Merck using eluents in the
indicated v:v ratio. Melting points were measured on a
Meltemp apparatus in open capillary tubes and are
uncorrected. IR spectra were recorded on a Nicolet Magna
spectrophotometer as KBr pellets or thin films on NaCl
plates and are reported in cm21. NMR spectra were
measured on Bruker AM-400 and DRX-400 instruments
Compound 3. Mp 289–2908C. TLC (CHCl3/MeOH 50:1) Rf
0.11. IR (KBr, cm21): 3395w, 3216m, 3090w, 3063w,
1
2925w, 1716s, 1688s, 1467m, 1448s. H NMR (400 MHz,
DMSO-d6): 8.40 (s, 2H), 7.30–7.00 (m, 16H), 6.93 (t,
J¼7.8 Hz, 2H), 6.65 (d, J¼7.8 Hz, 2H), 4.36 (d, J¼16.8 Hz,
2H), 3.84 (d, J¼16.8 Hz, 2H). 13C NMR (100 MHz,
DMSO-d6): d 160.2, 139.0, 137.1, 132.9, 128.7, 128.2,
128.2, 128.0, 127.9, 127.6, 127.1, 126.6, 126.5, 90.3, 79.6,
44.7. MS (FAB, glycerolþTFA): m/z 475 (4, [MþH]þ), 91
(100, C7Hþ7 ). HR-MS (FAB, glycerolþTFA): m/z 475.2087
([MþH]þ, C30H27N4O2, calcd 475.2134).
1
operating at 400 MHz for H and 100 MHz for 13C. Mass
spectrometry was performed using a VG 7070E magnetic
sector instrument by electron impact (EI) or by fast atom
bombardment (FAB) using the indicated matrix. The matrix
‘magic bullet’ is a 5:1 (w:w) mixture of dithiothreitol/
dithioerythritol. Elemental analyses were performed by
Midwest MicroLab (Indianapolis, IN).
Compound (^)-4. Mp 332–3348C. TLC (CHCl3/MeOH
50:1) Rf 0.33. IR (KBr, cm21): 3418m, 3193m, 3084m,
1
3066m, 2922w, 2863w, 1716s, 1692s, 1474s, 1450s. H
NMR (400 MHz, DMSO-d6): d 8.43 (s, 2H). 7.30–6.95 (m,
20H), 4.49 (d, J¼16.2 Hz, 2H), 3.86 (d, J¼16.2 Hz, 2H).
13C NMR (100 MHz, DMSO-d6): d 159.0, 139.0, 135.1,
128.4, 127.9, 127.8, 127.2, 127.1, 126.5, 84.7, 43.9. MS (FAB,
glycerolþTFA): m/z 475 (23, [MþH]þ), 91 (100, C7H7þ). HR-
MS (FAB, glycerolþTFA): m/z 475.2117 ([MþH]þ,
C30H27N4O2, calcd 475.2134). Anal. calcd for C30H26N4O2
(474.55): C 75.93, H 5.52. Found: C 76.01, H 5.53.
4.2. Synthesis and characterization of 1–4
4.2.1. Compounds 1 and 2. A mixture of 5c (2.94 g,
10.0 mmol) and Et3OBF4 (3.80 g, 20.0 mmol) in ClCH2-
CH2Cl (10 mL) was heated at reflux under N2 for 2 days
while being stirred vigorously. The reaction mixture was
quenched with aq. K2CO3 (50% sat., 50 mL), extracted with
CHCl3 (2£250 mL), dried over anhydrous K2CO3 and
concentrated. The residue was washed with EtOAc (2 mL),
centrifuged, and the supernatant decanted leaving a crude
white solid. Flash chromatography (SiO2, CHCl3/MeOH
50:1) gave 1 (186 mg, 5%) and 2 (715 mg, 22%) as white
solids.
4.3. X-Ray crystallographic analyses
Crystallographic data for the structures reported in this
paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no.
CCDC-192264 (1), CCDC-192265 (2), CCDC-192266 (3),
and CCDC-192267 (4). Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44-1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
Compound 1.42 Mp 241–2428C. TLC (CHCl3/MeOH 25:1)
Rf 0.37. IR (KBr, cm21): 3381w, 3064s, 2902m, 2828m,
1626s, 1582m, 1498s, 1471m, 1378m, 1332s, 1229m,
1
4.3.1. Crystal data for 1. C20H22N4O2, M¼350.42,
T¼193(2) K, crystal system orthorhombic, space group
1081m, 1038s. H NMR (400 MHz, DMSO-d6): 7.32 (br
s, 2H), 7.05–7.00 (m, 4H), 7.00–6.85 (m, 6H), 4.31 (br s,
˚
˚
˚
4H), 1.33 (t, J¼7.0 Hz, 6H). 13C NMR (100 MHz, DMSO-
Fdd2, a¼9.8463(3) A, b¼17.6634(5) A, c¼44.8679(13) A,

9776
A. Wu et al. / Tetrahedron 58 (2002) 9769–9777
3
˚
708, 1978. (c) Wang, A.; Bassett, D. US Patent 4,310,450,
1982. (d) Yinon, J.; Bulusu, S.; Axenrod, T.; Yazdekhasti, H.
Org. Mass Spectrom. 1994, 29, 625–631. (e) Boileau, J.;
Carail, M.; Wimmer, E.; Gallo, R.; Pierrot, M. Propellants,
Explos., Pyrotech. 1985, 10, 118–120. (f) Krause, A.;
Aumueller, A.; Korona, E.; Trauth, H. US Patent 5,670,613,
1997. (g) Karcher, S.; Kornmuller, A.; Jekel, M. Water Sci.
Technol. 1999, 40, 425–433. (h) Pryor, K. E.; Rebek, Jr. J.
Org. Lett. 1999, 1, 39–42.
a¼908, b¼908, g¼908, V¼7803.4(4) A , Z¼16, rcalcd
¼
1.193 g cm23
,
m¼0.079 mm21
,
F(000)¼2976, crystal
dimensions 0.562£0.280£0.102 mm3, u-range 1.82–
27.508, index ranges 212#h#12, 222#k#22,
258#l#58, Ntot¼30067, Nindep¼4491 (Rint¼0.0310),
data/restraints/parameters¼4491/1/325, GOF on F 2¼
1.072, final R indices [I.2s(I)]: R1¼0.0.0410, wR2¼
0.1071, R indices (all data): R1¼0.0532, wR2¼0.1150,
23
˚
largest diff. peak and hole 0.218 and 20.185 e A
.
2. Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, Jr. J. Angew. Chem.
Int. Ed. 2002, 41, 1488–1508.
4.3.2. Crystal data for 2. C21H21N4O2, M¼361.42,
T¼193(2) K, crystal system monoclinic, space group C2/c,
3. Rowan, A. E.; Elemans, J. A. A. W.; Nolte, R. J. M. Acc.
Chem. Res. 1999, 32, 995–1006.
˚
˚
˚
a¼12.6833(7) A, b¼14.6934(8) A, c¼20.0209(11) A,
3
˚
4. (a) Sun, S.; Harrison, P. Tetrahedron Lett. 1992, 33,
7715–7718. (b) Sun, S.; Harrison, P. J. Chem. Soc., Chem.
Commun. 1994, 2235–2236.
a¼908, b¼95.5590(10)8, g¼908, V¼3713.6(4) A , Z¼8,
rcalcd¼1.293 g cm23
,
m¼0.086 mm21
,
F(000)¼1528,
crystal dimensions 0.491£0.291£0.245 mm3, u-range
2.04–27.498, index ranges 216#h#16, 219#k#19,
225#l#25, Ntot¼28955, Nindep¼4274 (Rint¼0.0274),
data/restraints/parameters¼4274/0/329, GOF on F 2¼
1.086, final R indices [I.2s(I)]: R1¼0.0400, wR2¼
0.0990, R indices (all data): R1¼0.0530, wR2¼0.1068,
5. (a) Isaacs, L.; Witt, D.; Lagona, J. Org. Lett. 2001, 3,
3221–3224. (b) Isaacs, L.; Witt, D. Angew. Chem. Int. Ed.
2002, 41, 1905–1907.
¨
6. Kolbel, M.; Menger, F. M. Chem. Commun. 2001, 275–276.
7. (a) Kim, J.; Jung, I.-S.; Kim, S.-Y.; Lee, E.; Kang, J.-K.;
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Arnold, A. P.; Blanch, R. J.; Snushall, B. J. Org. Chem. 2001,
66, 8094–8100.
23
˚
largest diff. peak and hole 0.254 and 20.206 e A
.
4.3.3. Crystal data for 3. C31H27Cl3N4O2, M¼593.92,
T¼153(2) K, crystal system monoclinic, space group
˚
˚
P2(1)/c,
a¼15.6468(11) A,
b¼10.8710(9) A,
c¼
˚
17.0339(9) A, a¼908, b¼95.532(5)8, g¼908, V¼
8. Kurth, D. G.; Fromm, K. M.; Lehn, J.-M. Eur. J. Inorg. Chem.
2001, 1523–1526.
2883.9(3) A , Z¼4, rcalcd¼1.368 g cm23, m¼0.354 mm21
,
3
˚
F(000)¼1232,
crystal
u-range
dimensions
2.23–24.988,
0.500£0.375£
9. Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126.
10. Etter, M. C. J. Phys. Chem. 1991, 95, 4601–4610.
11. Zerkowski, J. A.; MacDonald, J. C.; Seto, C. T.; Wierda, D. A.;
Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 2382–2391.
12. Brienne, M.-J.; Gabard, J.; Leclercq, M.; Lehn, J.-M.; Cesario,
0.050 mm3,
index ranges
218#h#18, 212#k#12, 220#l#20, Ntot¼10511,
Nindep¼5064 (Rint¼0.0650), data/restraints/parameters¼
5064/1/503, GOF on F 2¼0.978, final R indices [I.2s(I)]:
R1¼0.0487, wR2¼0.0955, R indices (all data): R1¼0.1053,
wR2¼0.1124, largest diff. peak and hole 0.245 and
´
M.; Pascard, C.; Cheve, M.; Dutruc-Rosset, G. Tetrahedron
Lett. 1994, 35, 8157–8160.
23
˚
20.274 e A
.
13. Palmore, G. T. R.; Luo, T.-J. M.; McBride-Wieser, M. T.;
Picciotto, E. A.; Reynoso-Paz, C. M. Chem. Mater. 1999, 11,
3315–3328.
4.3.4. Crystal data for 4. C30H26N4O2, M¼474.55,
T¼193(2) K, crystal system monoclinic, space group C2/c,
14. Palacin, S.; Chin, D. N.; Simanek, E. E.; MacDonald, J. C.;
Whitesides, G. M.; McBride, M. T.; Palmore, G. T. R. J. Am.
Chem. Soc. 1997, 119, 11807–11816.
˚
˚
˚
a¼16.241(3) A, b¼12.987(2) A, c¼11.8330(19) A, a¼908,
3
˚
b¼98.872(3)8, g¼908, V¼2466.0(7) A , Z¼4, rcalcd¼1.278
g cm23, m¼0.082 mm21, F(000)¼1000, crystal dimensions
0.686£0.245£0.220 mm3, u-range 2.02–27.508, index
ranges 221#h#21, 216#k#16, 214#l#15, Ntot¼2795,
Nindep¼2795 (Rint¼0.0000), data/restraints/parameters¼
2795/0/221, GOF on F 2¼1.124, final R indices [I.2s(I)]:
R1¼0.0465, wR2¼0.1470, R indices (all data): R1¼0.0570,
wR2¼0.1576, largest diff. peak and hole 0.279 and
15. McBride, M. T.; Luo, T.-J. M.; Palmore, G. T. R. Cryst.
Growth Des. 2001, 1, 39–46.
16. Simanek, E. E.; Tsoi, A.; Wang, C. C. C.; Whitesides, G. M.;
McBride, M. T.; Palmore, G. T. R. Chem. Mater. 1997, 9,
1954–1961.
17. MacDonald, J. C.; Whitesides, G. M. Chem. Rev. 1994, 94,
2383–2420.
´
18. Melendez, R. E.; Hamilton, A. D. Top. Curr. Chem. 1998, 198,
97–129.
23
˚
20.189 e A
.
19. Li, N.; Maluendes, S.; Blessing, R. H.; Dupuis, M.; Moss,
G. R.; DeTitta, G. T. J. Am. Chem. Soc. 1994, 116,
6494–6507.
Acknowledgements
20. Xu, S.; Gantzel, P. K.; Clark, L. B. Acta Crystallogr., Sect. C
1994, C50, 1988–1989.
We thank the National Institutes of Health (GM61854) for
generous financial support. L. I. is a Cottrell Scholar of
Research Corporation.
21. Modric, N.; Poje, M.; Vickovic, I. Acta Crystallogr., Sect. C
1995, 51, 2594–2595.
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