Regioselective synthesis of 2,8-disubstituted 1,5-diphenylglycolurils

Full text of DOI:10.1016/j.mencom.2014.04.017

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 173–175
Regioselective synthesis of 2,8-disubstituted 1,5-diphenylglycolurils
Vladimir V. Baranov,a Maria M. Antonova,a Yulia V. Nelyubina,b Natal’ya G. Kolotyrkina,a
Igor E. Zanin,c Angelina N. Kravchenko*a and Nina N. Makhovaa
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: kani@server.ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
c Voronezh State University, 394000 Voronezh, Russian Federation. Fax: +7 473 220 8755; e-mail: iezan@mail.ru
DOI: 10.1016/j.mencom.2014.04.017
A new synthetic approach to 2,8-disubstituted 1,5-diphenylglycolurils is based on condensation of 1-(hydroxyalkyl)ureas (ureido
alcohols) with tetrahydroimidazooxazolone and tetrahydroimidazooxazinone derivatives which were unexpectedly obtained by acid-
catalyzed reaction of ureido alcohols with benzil. An X-ray diffraction study of the supramolecular organization of the obtained
compounds revealed the chirality of the crystals of achiral glycoluril molecules.
Glycolurils are used as psychotropic agents,1–3 anion-binding
receptors4 and molecular capsules.5 In recent years, 2,8-disub-
stituted glycolurils attract attention as molecular templates for
intramolecular Claisen-type condensations6 and promising sub-
strates in combinatorial7 and supramolecular8 chemistry. The
fact of chirality generation from achiral glycoluril molecules was
revealed in the study of supramolecular organization in the solid
state of three representatives of 2,8-disubstituted 1,5-diarylglycol-
urils.9 Self-organization of molecules is of great importance for
the understanding of biological processes.10
Ph
Ph
H
N
H
N
H
N
OMe
Ph
*
O
O
O
i
N
*
+
N
N
O
Ph
*
ii
1a
n
n
n
for 3a
R
OH
HO
1a n = 0
1b n = 1
4 n = 0
Ph
O
O
NH2
NH
5 n = 1, R = H
6 n = 1, R = OH
O
+
Ph
Condensation of monosubstituted ureas with benzil is the
principal access to 2,8-disubstituted 1,5-diphenylglycolurils,11–13
however, only 1-methyl- and 1-benzylureas11,13 and N-carbamoyl-
glycine benzyl ester12 were previously used. These reactions occur
regioselectively giving along with the major 2,8-disubstituted
glycolurils 1 minor 2,6-disubstituted glycolurils. Here N-hydroxy-
alkylureas (ureido alcohols) have not been tested. It seems reasonable
to attach hydroxyalkyl groups at the glycoluril nitrogen atoms since
this may facilitate intermolecular hydrogen bonding and thus affect
ordering of the molecules in the crystal.
Ph
H
2
Ph
Ph
N
N
R
OH
n
*
ii
O
O
Ph
iii
for
3b,c
N
N
*
*
OH
3a n = 0
3b n = 1, R = H
3c n = 1, R = OH
O
O
*
*
R
R
7b R = H
7c R = OH
8b R = H
8c R = OH
Scheme 1 Reagents and conditions: i, MeOH, HCl, reflux, 2 h; ii, PriOH,
To prepare 2,8-di(hydroxyalkyl)-1,5-diphenylglycolurils, we
performed the reaction between benzil 2 and ureido alcohols
3a–c. First, the previously known11–13 conditions were tested,
but reaction did not occur upon refluxing for 12 h in benzene
with trifluoroacetic acid.
Carrying out the process in alcohols led to unexpected results.
Condensation of compounds 3a–c with benzil in MeOH proceeded
selectively to predominantly give hitherto unknown methyl ethers of
tetrahydroimidazooxazolone 4 and tetrahydroimidazooxazinones
5,6 in 38, 66 and 61% yields, respectively (Scheme 1).† The
expected glycolurils 1a,b were obtained in low yields (14 and
5%, respectively).
HCl, reflux, 2 h; iii, DMSO, heating to a boil, 5 min.
1H and 13C NMR spectra of each structure 4–6 exhibit only one
set of signals which means that the reaction is highly diastereo-
selective. According to X-ray diffraction (XRD) data, the phenyl
groups in compounds 4–6 are trans-oriented to the imidazolidine
ring, while the asymmetric carbon atoms have 7R*,7aR* or
8R*,8aR*-configuration in bicyclic compounds 4,5, or 3R*,8R*,
8aR*-configuration in compound 6. The homogeneity of com-
pounds 4, 5 was confirmed by powder XRD.
The condensation of ureido alcohol 3a with benzil in PriOH
under the same conditions proceeded regioselectivly to afford
glycoluril 1a in 68% yield, whereas the reaction of compounds
3b,c gave only hitherto unreported tetrahydroimidazooxazinones
7b,c in 63 and 65% yields, respectively. 1H and 13C NMR study
showed that compound 7b is formed as a single diastereomer
similar to methyl ether 5. XRD studies of crystals 7b confirm
that the phenyl groups have trans orientation with respect to the
imidazoline ring. The 1H and 13C NMR spectra of compound 7c
with three chiral centers contain doubled signals of NH protons
(two singlets at d 8.19 and 8.26 ppm) and broadened singlets of
OH protons (d 5.72 and 6.62 ppm), indicating that this compound
is formed as two diastereomers.
The synthesis of compounds 4–6 by one-step procedure seems
to be a new easy method totally different from published data.14–17
†
Ureido alcohols 3a–c were obtained by N-carbamoylation of amino
alcohols as described;20,21 compound 3c was previously unknown.
For synthetic procedures and characteristics of compounds 1a–c, 3a–c,
4–6, 7a–c, 8b,c, 9 and 10 as well as crystal data for compounds 1a,b, 4–6,
7b, see Online Supplementary Materials.
CCDC 967848–967853 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk. For details,
see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2014.
© 2014 Mendeleev Communications. All rights reserved.
– 173 –

Mendeleev Commun., 2014, 24, 173–175
Ph
H
Ph
O
O
Ph
H
N
NH2
NH
Ph
Ph
Ph
N
N
N
N
N
OH
Ph
OMe
Ph
O
*
O
O
O
O
Ph
Ph
2
N
– H2O
N
*
O
O
O
...
R
OH
n
*
R
n
n
n
n
R
R
7a–c
R
4–6
OH
10a–c
OH
8a–c
+ H+
– H2O
3a–c
+ H+
MeOH
H
H
N
O
N
Ph
Ph
Ph
Ph
Ph
H
N
H
N
H
N
O
3a,b
– H+
NH
Ph
m
N
n = 0, 1
m = 0, 1
O
O
O
O
OH
N
N
N
O
n
R
n
m
n
HO
OH
1a–c
intermediate B
Scheme 2
intermediate A
When compounds 7b,c are heated to the boiling point of
DMSO-d6 in NMR tubes, the signals of OH protons at C(7) at
d 5.89–5.97 ppm (7b) or at C(8) at d 5.72–6.48 ppm (7c) and
the signals of NH in 7b (s, d 8.05 ppm) and 7c (2s from the
diastereomers at d 8.19 and 8.26 ppm) disappear and signals of
dihydroimidazooxazinones 8b,c (Scheme 1) appear. We failed to
isolate compounds 8b,c since they revert to the original 7b,c at
Along with glycoluril 1c, bicyclic product 7b was unexpectedly
isolated. Glycolurils 1b (69% yield) and 1c (90% yield) were also
obtained in the condensation of compound 7b with ureido alcohols
3b and 3a, respectively, by refluxing of suspensions of the reactants
in methanol in the presence of hydrochloric acid (Scheme 4).
The chemistry herein performed is a new approach to pre-
viously inaccessible 2,8-di(hydroxyalkyl)glycoluril derivatives.
Note that the reaction is fully regioselective giving no isomeric
2,6-derivatives.
The supramolecular organization in the solid state of glycol-
urils 1a,b is of intense interest. According to XRD, glycolurils
1a,b are severely twisted about the bridgehead dihedral angle,
which is 18.9(1)° and 25.0(1)°, so the resulting crystal structure
1
room temperature. Compounds 8b,c were characterized by H
and 13C NMR spectra (see Online Supplementary Materials).
The results obtained suggest the following key stages of the
processes (Scheme 2). Evidently, benzil 2 and ureido alcohols 3
give first intermediates 10, which cyclize into bicyclic systems
7 being in equilibrium with their dehydration products 8. One
can expect that in acid medium, intermediates 7 and 8 would
generate carbonium ions which can then react both with methanol
to give compounds 4–6 and with ureido alcohols to provide the
desired glycolurils 1.
may be described as consisting of two chiral enantiomers (space
–
groups P21/n and P1; Figure 1). Other geometric parameters are
also similar, expect for those related to (CH2)nOH groups. They
both are characterized by a cisoid arrangement of phenyl substi-
tuents [the angle C(5)C(1)C(3)C(11) equals to 18.9(1)–25.3(1)°],
an envelope conformation of imidazole moieties [with the atom
C(3) deviated by 0.31(1)–0.39(1) Å and the angle between the
mean planes being 107.8(1)–112.4(1)°], and a cisoid disposi-
tion of hydroxyalkyl groups [the respective pseudo-torsion angle
CNNC is 7.9(1)–15.2(1)°]. However, the latter groups have
significantly different conformations: they are both anti in 1a
but gauche-anti and gauche-gauche in 1b. The gauche-gauche
conformation of the second hydroxypropyl chain in 1b is stabilized
by an intramolecular H-bond with one of the C=O groups [O···O
2.6912(12) Å, ÐOHO 170(1)°].
Oxazolone 7a was synthesized from compound 9 under the
action of HNO3. Oxazoline 9 was prepared by condensation of
ureido alcohol 3a with benzoin 11.18 Depending on the amount
of HNO3 used, compound 9 can transform into either product 10
(2 equiv. HNO3) or 7a (diastereomeric mixture, 4 equiv. HNO3)
(Scheme 3,† cf. ref. 19).
To accomplish synthesis of 2,8-di(hydroxyalkyl)-1,5-diphenyl-
glycolurils, we performed reactions between compounds 7a–c and
3a,b by refluxing in alcohols (PriOH for 7a, MeOH for 7b, or
both in PriOH and MeOH for 7c). Symmetric glycoluril 1a was
obtained in the highest yield (93%) by refluxing the mixture of
compounds 3a and 7a for 20 min. Nonsymmetric glycoluryl 1c
was prepared from compounds 3b and 7a in 8 h (41% yield).
Ph
H
N
OH
Ph
*
Ph
N
i,iii
ii,iv
O
N
*
O
O
Ph
N
ii
OH
n
H
7a n = 0
7b n = 1
Ph
Ph
Ph
O
OH
Ph
NH2
NH
N
Ph
Ph
Ph
H
N
H
N
H
N
H
N
i
HO
O
+
O
*
10
+ 7b
O
N
O
O
O
*
N
N
N
N
iii
Ph
Ph
H
N
n
n
HO
3a
HO
OH
Ph
OH
O
HO
OH
HO
11
9
1c
N
1a n = 0
1b n = 1
O
7a
Scheme 4 Reagents and conditions: i (for 7a), 3a, PriOH, HCl, reflux,
20 min; ii (for 7a), 3b, PriOH, HCl, reflux, 8 h; iii (for 7b), 3b, MeOH, HCl,
reflux, 8 h; iv (for 7b), 3a, MeOH, HCl, reflux, 8 h.
Scheme 3 Reagents and conditions: i, (CH2OH)2, 160°C, 1 h; ii, MeCN,
2 equiv. HNO3, 5 min; iii, MeCN, 4 equiv. HNO3, 5 min.
– 174 –

Mendeleev Commun., 2014, 24, 173–175
form double chains through O–H···O bonds [O···O 2.719(2) and
C(8)
2.725(2) Å, ÐNHO 167(1) and 171(1)°]. The overall centrosym-
metric packing of 6 results from weak intermolecular interactions.
The latter include, among others, C–H···O, C–H···p and S···p
contacts. In the case of the bicycles 4 and 5 geometrical criteria
allow distinguishing C–H···O, C–H···p and H···H contacts and
additional contacts C–H···N with acetonitrile molecules in 6.
In conclusion, the condensation of ureido alcohols 3a–c with
benzil 2 affords new tetrahydroimidazooxazolone 7a and tetra-
hydroimidazooxazinones 7b,c, whose reaction with ureido alcohols
result in 2,8-bis(hydroxyalkyl)glycolurils. It has been found that
chirality is generated in the crystals of non-chiral compounds 1a,b.
C(7)
C(6)
C(8)
C(14)
C(13)
C(9)
C(10)
C(9)
C(7)
C(15)
C(16)
C(14)
C(10)
C(13)
C(12)
C(5)
C(15)
C(16)
C(6)
C(5)
C(1)
C(1)
C(3)
C(11)
N(1)
C(2)
O(1)
C(12)
C(11)
C(3)
N(4)
N(2)
C(17)
C(18)
N(3)
C(22)
C(20)
N(1)
C(21)
C(4)
N(3)
C(20)
O(4)
N(4)
C(2)
O(1)
O(4)
N(2)
C(4)
C(19)
O(2)
O(2)
C(17)
C(18)
O(3)
C(19)
O(3)
This work was supported by Presidium of the Russian Academy
of Sciences (Program P-8) and the Russian Foundation for Basic
Research (project no. 14-03-31676).
1a
1b
Figure 1 Molecular structures of compounds 1a,b in representation of
atoms via thermal ellipsoids at 50% probability level.
Online Supplementary Materials
As a result of these differences, the molecules of 1a and 1b pack
differently in crystals. In 1a, intermolecular N–H···O(hydroxyl)
bonds [N···O 2.851(2) and 2.877(2)Å, ÐNHO 168(1)° and 175(1)°]
assemble the glycoluril species into chiral tapes, which are held
together by O–H···O=C bonds [O···O 2.659(2) and 2.771(2) Å,
ÐOHO 159(1)° and 166(1)°] in such a manner as to form centro-
symmetric dimers of neighboring molecules from different tapes.
In 1b, however, intermolecular N–H···O(hydroxyl) bonds [N···O
2.8359(14) and 2.9260(13) Å, ÐNHO 169(1)° and 165(1)°] results
in double chains of centrosymmetrically bonded glycoluril species;
these are assembled by O–H···O=C bond [O···O 2.7012(13) Å,
ÐOHO 167(1)°] into corrugated layers. In both cases, the 3D
framework is completed through numerous weaker interactions,
which include, among others, C–H···O, C–H···p and H···H contacts.
The homogeneity of compounds 1a,b was confirmed by
powder XRD (see Table S1, Figures S1,S2, Online Supple-
mentary Materials).
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.04.017.
References
1 M. D. Mashkovskii, Lekarstvennye sredstva (Drugs), Novaya Volna,
Moscow, 2013, vol. 1, p. 83 (in Russian).
2 I. S. Ryzhkina, Yu. V. Kiseleva, O. A. Mishina, A. P. Timosheva, S. Yu.
Sergeeva, A. N. Kravchenko and A. I. Konovalov, Mendeleev Commun.,
2013, 23, 262.
3 A. N. Kravchenko and Yu. A. Strelenko, Mendeleev Commun., 2013,
23, 104.
4 (a) S. In and J. Kang, Tetrahedron Lett., 2005, 46, 7165; (b) S. In, J. Kang
and S. J. Cho, Supramol. Chem., 2007, 19, 243.
5 (a) F. Hof, S. L. Craig, C. Nuckolls and J. Rebek, Jr., Angew. Chem.
Int. Ed., 2002, 41, 1488; (b)V. Havel, J. Svec, M. Wimmerova, M. Dusek,
M. Pojarova and V. Sindelar, Org. Lett., 2011, 13, 400; (c) P. Toman,
E. Makrlík and P. Vanüra, Chem. Phys. Lett., 2012, 547, 63.
6 (a) S. Sun, L. Edwards and P. Harrison, J. Chem. Soc., Perkin Trans. 1,
1998, 437; (b) M. Rahimizadeh, K. Kam, S. I. Jenkins, R. S. McDonald
and P. H. M. Harrison, Can. J. Chem., 2002, 80, 517.
The other four bicycles X-rayed (4–6 and 7b) have molecular
geometry with the expected differences governed by the nature
of a substituent R and the value of n (see Scheme 1); the dif-
ferences in their crystal packing mainly results from co-crystal-
lization of 6 and 7b with solvate molecules of acetonitrile and
DMSO, respectively (Figure S5, Table S2). Note that in the crystal
of 6 there are two symmetry independent species of the product
having opposite configurations – R,R,R and S,S,S. Compounds 4,
5 and 7b also crystallize as all-S,S and all–-R,R isomers, both present
in the centrosymmetric space groups P1, P21/c and C2/c.
All having a diphenylimidazole fragment in common, they
are characterized by a transoid arrangement of phenyl substi-
tuents [the angle C(6)C(4)C(5)C(12) is 89.4(1)–96.0(1)°] and
an envelope conformation of imidazole moieties [with the atom
C(4) deviated by 0.34(1)–0.47(1) Å]. The conformations of the
oxazole rings with n = 0 (4) and n = 1 (5, 6 and 7b) are envelope
[with the atom C(4) deviated by 0.54(1) Å] and chair [with the
atoms C(18) and N(3) deviated by 0.66(1)–0.68(1) and 0.55(1)–
0.56(1) Å], respectively.
7 K. E. Pryor and J. Rebek, Jr., Org. Lett., 1999, 1, 39.
8 (a) D. Ma, Z. Gargulakova, P.Y. Zavalij, V. Sindelar and L. Isaacs, J. Org.
Chem., 2010, 75, 2934; (b) M. Stancl, Z. Gargulakova and V. Sindelar,
J. Org. Chem., 2012, 77, 10945; (c) L.-P. Cao, X.-G. Meng, J.-Y. Ding,
H.-L. Xi and A.-X. Wu, J. Chem. Crystallogr., 2011, 41, 425; (d) J. Wang,
J. Xiang, A.-X. Wu and X.-G. Meng, Cryst. Eng. Comm., 2013, 15, 10079.
9 (a) D. W. Johnson, L. C. Palmer, F. Hof, P. M. Iovine and J. Rebek, Jr.,
Chem. Commun., 2002, 2228; (b) D. W. Johnson, F. Hof, L. C. Palmer,
T. Martin, U. Obst and J. Rebek, Jr., Chem. Commun., 2003, 1638.
10 J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, 1995, p. 223.
11 A. R. Butler and E. Leitch, J. Chem. Soc., Perkin Trans. 2, 1980, 103.
12 A.-X. Wu, J. C. Fettinger and L. Isaacs, Tetrahedron, 2002, 58, 9769.
13 K. E. Pryor and J. Rebek, Jr., Org. Lett., 1999, 1, 39.
14 C. Agami, F. Amiot, F. Couty and L. Dechoux, Tetrahedron Lett., 1998,
39, 5373.
15 Z.-K. Liao and H. Kohn, J. Org. Chem., 1984, 49, 3812.
16 G. Bobowski, J. Heterocycl. Chem., 1981, 18, 1179.
17 C. Metzger and J. Kurz, Chem. Ber., 1975, 108, 372.
18 Y. B. Kim, C. S. Kim and C. K. Lee, J. Heterocycl. Chem., 1994, 31, 1653.
19 H. Biltz, Ber. Deutsch. Chem. Ges., 1908, 41, 167.
20 A. N. Kravchenko, E. Yu. Maksareva, P. A. Belyakov, A. S. Sigachev,
K. Yu. Chegaev, K. A. Lyssenko, O. V. Lebedev and N. N. Makhova,
Russ. Chem. Bull., Int. Ed., 2003, 52, 192 (Izv. Akad. Nauk, Ser. Khim.,
2003, 180).
21 E. E. Smissman, J. W. Ayres, P. J. Wirth and D. R. Abernethy, J. Org.
Chem., 1972, 37, 3486.
The major supramolecular motif in the crystals of these four
bicycles is a centrosymmetric dimer formed by N–H···O bonds
that is observed [N···O 2.8538(11)–2.903(2) Å, ÐNHO 173(1)°–
177(1)°] in 4, 5 and 7b. In the latter cases, these dimers are also
supplemented by two solvate DMSO molecules through O–H···O
bonds [O···O 2.6848(18) Å, ÐNHO 172(1)°]. In the crystal 6,
containing two symmetry independent bicycle species and a
solvate acetonitrile molecule, the H-bonded associates are chiral
chains formed by each independent bicycle molecule separately
through N–H···O bonding [N···O 2.862(3) and 2.902(3) Å, ÐNHO
161(1)° and 174(1)°], which are then combined together to
Received: 11th December 2013; Com. 13/4268
– 175 –