Synthesis of first representatives of 3,3′-bi(6,8-dialkyl-2,4-dioxa- 6,8-diazabicyclo[3.3.0]octan-7-ones)

Article abstract of DOI:10.1002/jhet.5570430523

The first representatives of 3,3′-bi(2,4-dioxa-6,8-diazabicyclo[3.3. 0]octan-7-ones) have been synthesized by a reaction of glyoxal as form of 2,2′-bi(4,5-dihydroxy-1,3-dioxalane) with N,N′-dialkylureas. Their structures have been supported by X-ray analy

Full text of DOI:10.1002/jhet.5570430523

Sep-Oct 2006
1295
Synthesis of First Representatives of
3,3'-Bi(6,8-dialkyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones)
Andrey S. Sigachev,* Angelina N. Kravchenko, Galina A. Gazieva, Pavel A. Belyakov,
Natal'ya G. Kolotyrkina, Oleg V. Lebedev, Nina N. Makhova
N. D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences,
47 Leninsky pr, 119991 Moscow, RUSSIA,
Fax: (internal) +7 (495) 135 5328
E-mail: sias@server.ioc.ac.ru
and Konstantin A. Lyssenko
A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences,
28 Vavilova str., 119991, Moscow, RUSSIA,
Fax: (internal) +7 (495) 135 5085
E-mail: kostya@xrlab.ineos.ac.ru
Received December 30, 2005
R1
HO
HO
OH
OH
NH
O
O
O
O
O
O
NH
R2
R1
N
R1
R1
N
O
O
O
N
O
O
N
O
O
N
N
R2
R2
R2
The first representatives of 3,3'-bi(2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones) have been synthesized
by a reaction of glyoxal as form of 2,2ꢀ-bi(4,5-dihydroxy-1,3-dioxalane) with N,N'-dialkylureas. Their
structures have been supported by X-ray analysis. 1,3-Dialkylimidazolidine-2,4-diones (hydantoins) have
been isolated as by-products and their formation mechanism has been experimentally confirmed.
J. Heterocyclic Chem., 43, 1295 (2006).
Introduction.
fragments connected by the C(3)-C(3') bond was
proved by spectroscopic methods and the structure of
2g by X-ray analysis.
For several years we have been interested in
chemistry and stereochemistry of 2,4,6,8-tetraaza-
bicyclo[3.3.0]octan-3,7-diones (glycolurils) [1-9],
possessing a wide range of biological activity [9-12].
R1
N
R
N
R
N
R1
N
S
N
R2
O
O
O
O
O
O
O
O
In particular, they represent
a
novel class of
S
O2S
SO2
neurotropic compounds [2,3,9,10]. The synthesis of
glycolurils is based on the reaction of glyoxal or 4,5-
dihydroxyimidazolidin-2-ones with N-nucleophiles
containing urea fragments in the water or water-
methanol at pH 1 [4-7,13,14]. Recently [15], looking
for new biologically active compounds, we have tried
to synthesize derivatives of 3,7-dithia-2,4,6,8-tetraaza-
N
R2
N
R
N
R
2
1
R1 = R2 = Me (a); R1 = R2 = Et (b); R1 = Me, R2 = Et (c);
R1 = R2 = n-Pr (d); R1 = R2 = i-Pr (e);
R1 = R2 = n-Bu (f); R1 = R2 = s-Bu (g).
In the same paper [15] we suggested that formation of 2
could be explained by reaction of sulfamides with glyoxal
in one of its hydrated forms — 2,2'-bi(4,5-dihydroxy-1,3-
dioxolane) or trimer dihydrate 5. It is known [16-20], that
in water solutions glyoxal exists in different hydrated
forms: bisgem-diol 3, dimer dihydrate 4 with a dioxolane
cycle, trimer dihydrate 5 with bisdioxolane fragment, and
in the form of the dioxane structure 6 and other oligomers
7 & 8, including both dioxolane and dioxane cycles
(Scheme 1). Structure of these hydrates and their contents
bicyclo[3.3.0]octan-3,3,7,7-tetraoxide 1
– sulfoana-
logues of glycolurils. But instead of the expected
bicyclic compounds 1, reaction of 40% water solution
of glyoxal with 1,3-dialkylsulphamides at pH 1 gave
derivatives of a new heterocyclic system — 1,3-
dioxolano[4,5-c]-1,2,5-thiadiazolidine
— 3,3'-bi(6,8-
dialkyl-2,4-dioxa-7-thia-6,8-diazabicyclo[3.3.0]octan-7,7-
dioxides) 2 (5-11% yield). The structure of bisbicycles
2 with two 1,3-dioxolano[4,5-c]-1,2,5-thiadiazolidine

1296
A. S. Sigachev, A. N. Kravchenko, G. A. Gazieva, P. A. Belyakov,
N. G. Kolotyrkina, O. V. Lebedev, N. N. Makhova and K. A. Lyssenko
Vol 43
1
in solutions were established by ꢀ and 13ꢁ NMR in D2ꢂ
Results and Discussion.
and DMSO-d6.
Analysis of the available literature showed that there is
only one paper [21] describing compound with structure
distinguishes from glycolurils. It was obtained in a low yield
by the reaction of 40% glyoxal with 1,3-dimethylurea 10a
or 1,3-dimethyl-4,5-dihydroxyimidazolidin-one 11a at RT
and pH 2 (3-19 days). Authors of paper [21] ascribed to this
Scheme 1
HO
HO
OH
OH
3
HO
HO
O
O
OH
OH
compound the structure of
9 with four annelated
HO
HO
O
O
OH
OH
heterocycles only on the basis of the elemental analysis, IR-
1
and H NMR spectroscopy. These data, however, do not
6
4
prove that the reported compound 9 is not an isomeric
bisbicyclic system 12a with the central dioxolane fragment.
HO
OH
HO
O
O
O
O
OH
Me
N
Me
N
Me
N
O
O
O
O
Me
N
O
O
O
O
O
O
O
O
HO
OH
n
O
O
O
O
HO
OH
N
N
N
N
5
7
Me
Me
Me
Me
12a
9
O
O
OH
OH
O
O
O
O
O
HO
HO
The first step of this investigation included an attempt to
obtain structures 12 under conditions used for synthesis of
bisbicycles 2 and to repeat the published synthesis of 9 in
order to re-investigate its structure with modern methods.
The reaction of 1,3-dimethyl- or 1,3-diethylurea 10a,b
with glyoxal in the form of 2,2'-bi(4,5-dihydroxy-1,3-
dioxolane) 5 in conc. HCl (20 ºꢁ, 1 h.) led to gum-like
products of the unknown structure. The investigation of
precipitates obtained after 7 days from a solution of ureas
10a,b and glyoxal, under conditions described in the
O
m
n
8
Assuming that the trimer dihydrate 5 played a key role
in the formation of 2, we used solid glyoxal for their
synthesis. That resulted in an increased in their respective
yields to 54-85%.
Electron Impact Ionization Mass Spectrometry (EIMS)
shows that all compounds 2 produce a fragment equal to a
half of the molecular ion. It means that such electron-
affected fragmentation involves the C(3)-C(3') bond
breakage. Moreover, we discovered that EIM spectrum of
solid glyoxal also contained a fragmentary ion equal to a
half of the molecular ion corresponding to the structure 5.
This factor may be decisive for the determination of the
structure of similar compounds.
1
literature for formation of 9, showed characteristic H
NMR spectra of 3,3'-bi(2,4-dioxa-6,8-diazabicylo[3.3.0]-
octan-7-ones) 12 (Scheme 2). Singlets at 4.78-4.79 ppm,
can be attributed to the ꢁ(3)ꢀ-ꢁ(3')ꢀ groups connecting
two identical 6,8-dialkyl-2,4-dioxa-6,8-diazabicyclo-
[3.3.0]octan-7-one fragments. The ratio of integral
intensities of these signals, N-Me (N-Et) groups, and
bridging ꢁ(1)ꢀ-ꢁ(5)ꢀ & ꢁ(1')H-C(5') fragments did not
contradict the structure of the desired bisbicycles 12a,b.
The value of the chemical shift of ꢁ(3)H-C(3')H group
also does not contradict the structures 12a,b as chemical
shifts of the bridging CH-CH protons in bisdioxane
We intend to continue this research to explore reactions
of glyoxal in the form of 2,2'-bi(4,5-dihydroxy-1,3-
dioxolane) 5 with other N-bisnucleophiles (e.g. 1,3-
dialkylureas) as a route to a novel heterocyclic system
3,3ꢀ-bi(2,4-dioxa-6,8-diazabicylo[3.3.0]octan-7-one)
Scheme 2
R1
N
R1
R1
N
R1
N
O
HO
HO
OH
OH
O
O
O
O
NH
O
O
O
O
i, ii
O
O
O
O
N
R2
N
R2
N
R2
NH
R2
10a-d
5
12a-d
13a-d
R1 = R2 = Me (a), R1 = R2 = Et (b), R1 = Me, R2 = t-Bu (c), R1 = Me, R2 = c-C6H11 (d).
Reagents and conditions. (i) H2O or H2O:MeOH (1:5), 20 °C, pH 5, 60 days (49-56%); (ii) H2O or H2O:MeOH (1:5), 60 °C, pH 6, 2 h (41-45%).

Sep-Oct 2006
Synthesis of First Representatives of
3,3'-Bi(6,8-dialkyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones)
1297
fragment of the 1,4,5,8-tetraoxadecaline derivatives are
equal to 4.4-4.6 ppm. [22]. High resolution mass (HRM)
spectra show the expected molecular ions. EIM spectra
contain typical for 12 fragmentary ions with mass equal to
a half of the molecular ions, corresponding to a break of
the central ꢀ(3)-ꢀ(3') bond.
Finally, the structure of heterocyclic systems 12a,b (on
the example of 12b) was established by the X-ray
diffraction study. It showed unambiguously that the
obtained products were not triply annelated tetracycles 9.
In fact, they contained two identical bicyclic parts — 6,8-
dialkyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones
linked by a carbon-carbon bond (Figure 1).
According to XRD of the 12b crystallize with two
independent molecules both of which are located in the
center of symmetry and thus correspond to meso-form.
The imidazolidine cycles are almost planar (the r.m.s
deviation is not more than 0.01Å) and dioxane ones are
characterized by the envelope conformation with the
deviation of C(3) atom by 0.46 and 0.51Å.
Thin-layer chromatography of the reaction masses has
shown that in all cases at pH 2 and 20 ºꢀ two months
were needed to achieve full conversion of initial ureas.
Moreover, targeted bisbicycles 12a-d were produced in
the yields as low as 14-16%. The same reactions
conducted at pH 5 and at 20 °ꢀ during 2 months led to an
increase in the yields of compounds 12ꢀ-d up to 49-56%.
In order to reduce the reaction duration an interaction of
ureas 10a,c with glyoxal 5 was studied at pH 5 or 6 and at
60 °ꢀ during 1-7 h. It was established that at pH equal to
5 urea 10a is fully exhausted to the end of the fourth hour,
and urea 10c — to the end of the second hour, and at pH 6
ureas 10a,c are in fact not visible at the end of the second
hour. Probably, in these conditions the concentration of
glyoxal in the form 5 in the reaction mass is more than
twice higher that at pH 5 and at the same temperature.
The yields of bisbicyles 12b,d, obtained by the reaction of
trimer dihydrate glyoxal 5 with the ureas 10b,d under the
same conditions have the same order and comprise 41 and
45% respectively. Although the conducting of the
reactions at pH 5, 20 °ꢀ during two months occurs with
the slightly bigger yields of compounds 12a-d (49-56%),
these conditions are not preparative enough. Thus, the
optimal conditions for the synthesis of 3,3'-bi(6,8-dialkyl-
2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones) 12 are pH
6 of the fresh water glyoxal solution in the form 5, 60 °ꢀ
and duration of the reaction 2 hours.
1H NMR Spectra of bisbicycles 12c,d represent a more
complicated case than the ones for the compounds 12a,b.
The appearance of the signals of protons at ꢀ(1, 1') and C(5,
5') in the form of systems ꢁꢂ (dd) in the in the area of 5.53-
5.82 ppm testifies to their inequivalence what is connected
with the peculiarities of the stereochemistry of these
compounds. Thus, compounds 12a,b (with the same
substituents at the nitrogen atoms) contain 4 asymmetric
carbon atoms — 1, 5, 1', 5', and compounds 10ꢁ,d (with
different substituents by the nitrogen atoms) — 6 asymmetric
carbon atoms: 1, 3, 5, 1', 3', 5'. In the compounds 12a,b
carbon atoms 3 and 3' are pseudoasymmetric.
Figure 1. General view of one of the independent molecules of 12b.
Selected bond lengths (Å): C(1)-N(8) 1.422(2), C(1)-O(2) 1.428(2),
C(1)-C(5) 1.543(3), O(1)-C(7) 1.214(2), O(2)-C(3) 1.407(2), C(3)-O(4)
1.410(2), O(4)-C(5) 1.424(2), C(5)-N(6) 1.424(2), N(6)-C(7) 1.363(2),
N(6)-C(9) 1.457(2), N(8)-C(11) 1.453(2).
The yields of compounds 12a,b obtained by the published
procedure are pretty low (14-16%). In order to optimize the
yields, the influence of different parameters on the reaction
of 1,3-dialkylureas 10a-d with glyoxal in the form of 2,2'-
bi(4,5-dihydroxy-1,3-dioxolane) 5 was studied (Scheme 2).
Since the content of 5 in water solution depends its
concentration, pH and temperature, we hoped to find
conditions providing preferential formation of the desired
bisbicycles 12. In order to achieve this, we varied pH of the
water solution of glyoxal (2, 5 or 6), temperature (20 or 60
°ꢀ), duration of the reaction (1-7 h at 60 °ꢀ or 2 months at
20 °ꢀ), and the ratio of reagents. Trimer dihydrate of glyoxal
5 was dissolved in a minimal volume of water (solution with
pH 5). After adjustment of pH with concentrated HCl or 20%
NaHCO3 when necessary, it was combined with a solution of
ureas 10a,b in a 5-fold amount of water or a 5-fold amount
of MeOH for low soluble ureas 10c,d.
R1
N
R1
N
H
H
H
2
O
2`
O
3
1
1`
O
H
H
5`
O
5
3`
N
O
4
O
4`
N
H
R2
R2
12a-d
R1 = R2 = Me (a), R1 = R2 = Et (b),
R1 = Me, R2 = t-Bu (c), R1 = Me, R2 = c-C6H11 (d).
Moreover, the configuration of the ꢀ(1) – (S), C(5) –
(R), C(1') – (R) and C(5') — (S) atoms is strictly set and
does not depend on the priority or configuration of the
substituents at the nitrogen atoms as it is fully determined
by the sequence of atoms O, N, C in each 6,8-dialkyl-2,4-

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A. S. Sigachev, A. N. Kravchenko, G. A. Gazieva, P. A. Belyakov,
N. G. Kolotyrkina, O. V. Lebedev, N. N. Makhova and K. A. Lyssenko
Vol 43
dioxa-6,8-diazabicyclo[3.3.0]octan-7-one fragment of
bisbicycle 12. The hydrogen atoms in the bridging
fragmentes ꢀ(1)ꢁ-ꢀ(5)ꢁ and C(1')H-C(5')H are cis-
oriented. Besides, for the pseudoasymmetric atoms ꢀ(3)
and ꢀ(3') three combinations of their configurations are
possible: s,r ( = r,s); r,r and s,s. In case of equal non-
chiral substituents by the nitrogen atom (R = Me, Et),
molecules of compounds 12a,b have a plane of symmetry
and appear to be meso-forms, what was confirmed by the
X-ray diffraction data for bisbicycle 12b. If the
substituents at the nitrogen atoms are structurally
different, like in the case of 12c,d, then for them
theoretically one can suppose the formation of the mixture
of diastereomeric meso-forms and racemates: 2 meso-
forms and 4 racemates.
Saturation of t-Bu signal results in decreasing of CH2
signal intensity. On the other hand, saturation of Me
signal does not affect signals of any other groups.
Comparing 13c and 14c NOE experiments point to 13c,
since in 14c one can expect decreasing in of CH2 signal
intensity after saturation of Me signal.
1
Indeed the H NMR spectra of crude compounds 12c,d
fix the protons signals in the field 4.78-4.79 ppm a mixture
of the diastereoisomers with the prevalence of one of them.
The prevailing stereoisomers were obtained in the individual
state after their crystallization from methanol and fully
determined spectrally. However, the obtained data don't
allow relating them to any concrete stereoisomer.
Figure 2. Difference mode NOE experiments of 13c in DMSO-d6
Since the yields of 12 were not quantitative, we looked
into structure of by-products. Oily residues from the
1
mother solutions were studied by H NMR. Their spectra
contained signals similar to those of the reported NMR
spectra of unsubstituted hydantoin [23,24] and 1,3-
dimethylhydantoin [25], suggesting presence of
hydantoins 13ꢀ,b or structural isomers (ratio 9:1) 13ꢁ,d
and 14ꢁ,d. A general feature of these spectra is the
presence of CH2 singlets at 3.89-4.05 ppm.
Figure 3. General view of 13c. Selected bond lengths (Å): O(1)-C(2)
1.2231(19), N(1)-C(2) 1.355(2)N(1)-C(5) 1.462(2), N(1)-C(6) 1.488(2),
O(2)-C(4) 1.212(2), C(2)-N(3) 1.410(2), N(3)-C(4) 1.371(2), N(3)-C(10)
1.453(2), C(4)-C(5) 1.511(2); bond angles(º): C(2)-N(1)-C(5) 110.6(1),
C(2)-N(1)-C(6) 124.8(1), C(5)-N(1)-C(6) 123.2(1), O(1)-C(2)-N(1)
129.1(15), O(1)-C(2)-N(3) 123.1(14), N(1)-C(2)-N(3) 107.8(13), C(4)-
N(3)-C(2) 111.9(1), C(4)-N(3)-C(10) 124.7(1), C(2)-N(3)-C(10)
123.6(1), O(2)-C(4)-N(3) 126.2(2), O(2)-C(4)-C(5) 127.7(1), N(3)-C(4)-
C(5) 106.1(1), N(1)-C(5)-C(4) 103.3(1).
Me
N
Me
N
O
O
O
N
N
O
Alk
Alk
13c,d
14c,d
Alk = t-Bu (c), R = c-C6H11 (d).
In addition, the structure of the obtained hydantoins was
established by the X-ray diffraction study. According to
XRD the hydantoin cycle is characterized by the envelope
conformation with the deviation of methylene atom C(5)
by 0.099(3)Å from the plane of N(1), C(2), N(3) and
C(4). The bonds lengths in the N(1)-C(2)- N(3)-C(4)
fragment alternate with the maximum value observed for
C(2)-N(3) one 1.410(2)Å (Figure 3). The pronounced
acidity of the hydrogen atoms at C(5) atom leads to the
formation in crystal of the relatively strong C-H…O
contacts with H…O distances equal to 2.26-2.35Å.
The formation of hydantoins 13 and 14 during the
synthesis of bisbicycles 12 can be explained by a
pinacolin-like rearrangement of the corresponding 4,5-
dihydroxyimidazolidin-2-ones 11a-d. The latter could
form as a result of the transformation of 5 under reaction
Compounds 13a,b were obtained form the oily remains by
extraction with ether. The solid mixtures of hydantoins 13c,d
and 14c,d are precipitated from methanol. After the
crystallization of the latter from the methanol only the
dominating isomers were obtained. The yields of hydantoins
13a-d are equal to 18-20%. The physical-chemical
1
characteristics and the H NMR spectrum of compound 13a
are consistent with the literature data for the 1,3-dimethylgid-
antoin [25]. Hydantoins 13b-d are described in the literature
[26-28] but were characterized only by the element analysis
and melting points (13b — boiling point). So, we have
characterized compounds 13b-d by 1H NMR spectroscopy.
To prove the structure of compound 13c, difference
mode NOE experiments [29] were applied (Figure 2).

Sep-Oct 2006
Synthesis of First Representatives of
3,3'-Bi(6,8-dialkyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones)
1299
conditions to other forms of glyoxal (e.g. bisgem-diol 3,
Scheme 1) followed by reaction with ureas 10. Usually,
4,5-dihydroxyimidazolidin-2-ones are not used as
precursors for the synthesis of hydantoins 13 and 14.
Other methods are preferred for this purpose [27,28,30].
At the same time, the formation of hydantoins as by-
products of glycolurils synthesis from ureas and 40%
solution of glyoxal or 4,5-dihydroxyimidazolidin-2-ones
at pH 1 has been observed by us earlier [5].
are different or equivalent. The carbon atoms in
compounds 11ꢀ with the cis-disposition of the hydroxyl
groups have an opposite configuration. In the case of the
same substituents at the nitrogen atoms these compounds
have a symmetry plane and represent meso-form. If the
substituents at the nitrogen atoms in the cis-isomers are
different then these compounds are chiral. Earlier [33] cis-
and trans-isomers have been obtained for the compound
11a.
To confirm the fact of the formation of hydantoins 13a-
d and 14c,d in the optimal conditions for obtaining
bisbicycles 12 we synthesized 1,3-dialkyl-4,5-
dihydroxyimidazolydin-2-ones 11a-d by the condensation
of ureas 10a-d with 40% glyoxal water solution under
standard conditions [5]. Compounds 11a,b have been
reported earlier [14,31,32], and 11c,d have been obtained
and characterized for the first time.
R1
N
R1
N
OH
OH
OH
OH
O
O
N
R2
N
R2
11a-d
11'a-d
R1 = R2 = Me (a), R1 = R2 = Et (b), R1 = Me, R2 = t-Bu (c),
R1 = Me, R2 = c-C6H11 (d).
Then, the synthesized compounds 11 were treated with
water (11a,b) or with the water-methanol mixture (11c,d)
at pH 6 and 60 °ꢀ for 2 h, which resulted in hydantoins 13
and 14 in 75-80% yield (Scheme 3).
Besides, it is known [34,35] that 4,5-
dihydroxyimidazolydin-2-ones 11 belong to that
class of compounds which is capable of crystallizing
Scheme 3
R1
N
R1
N
R1
N
R1
OH
OH
HO
HO
OH
OH
O
NH
i
ii
O
O
O
O
N
R2
N
R2
N
R2
NH
R2
O
10a-d
11a-d
13a-d
14c,d
3
R1 = R2 = Me (a), R1 = R2 = Et (b), R1 = Me, R2 = t-Bu (c), R1 = Me, R2 = c-C6H11 (d).
Reagents and conditions. (i) H2O or H2O:MeOH (1:5), 45-50 °C, pH 4-5, 2 h (35-52%); (ii) pH 6, 2 h, 60 °C (75-80%).
The physical-chemical characteristics of the obtained
hydantoins 13a,b and mixture of hydantoins 13c,d and
14c,d (also in the ratio 9:1) corresponded to the above-
described. In the latter case after the crystallization from
methanol the dominating isomers 13c,d were obtained.
The presence of the isomers 14c,d was established only
spectrally. This result shows that dehydratation of 1-alkyl-
3-methyl-4,5-dihydroxyimidazolydin-2-ones 11c,d is a
regioselective process that leads the predominating
formation of 13c,d.
1,3-Dialkyl-4,5-dihydroxyimidazolydin-2-ones 11a-d
as well as bisbicyclic systems 12 are of interest from the
point of view of stereochemistry. Compounds 11 contain
two asymmetric carbon atoms C(4), C(5) with OH in
trans- and cis-positions. In the trans-isomers these atoms
have the same configuration and such compounds are
racemates, which can be theoretically resolved into
enantiomers, regardless of the fact that the N-substitutents
as conglomerates (a mixture of gomochiral crystals).
In order to find the conglomerates among the
synthesized compounds 11 the crystallization of the
earlier unknown 1-alkyl-3methyl-4,5-dihydroxy-
imidazolydin-2-ones 11c,d was investigated. We
have managed to obtain a suitable for the X-ray
diffraction study single crystal of only compound
11c. The X-ray diffraction study of 11c has revealed
that it crystallized as a racemate (sp. group Pbca).
The hydroxyl groups are characterized by the trans-
disposition with the torsion angle O(3)C(5)C(4)O(2)
equal to 143.6º. The five-membred cycle is
characterized by twist conformation with the
deviation of C(4) and C(5) atoms by –0.18 and
0.25Å, respectively. In crystal molecules are
assembled in zig-zag layers parallel to crystal-
lographic plane ab by the O-H…O bonds (O…O
2.669(2) and 2.809(2)Å).

1300
A. S. Sigachev, A. N. Kravchenko, G. A. Gazieva, P. A. Belyakov,
N. G. Kolotyrkina, O. V. Lebedev, N. N. Makhova and K. A. Lyssenko
Vol 43
Thus, for the first time the interaction of 1,3-
dialkylureas 10 with glyoxal in the hydrate form of 2,2'-
bi(4,5-dihydroxy-1,3-dioxolan) 5 was studied in details
and the first representatives of the previously unknown
bisbicylcic systems of 3,3'-bi(6,8-dialkyl-2,4-dioxalan-
6,8-diazabicyclo[3.3.0]octan-7-one 12a-d were prepared.
Their structure was confirmed by the combination of the
data for the element analysis, NMR-spectroscopy, MSEI,
HMRS and X-ray analysis. Besides, it was established
that the corresponding hydantoins are formed as the by-
products. The suggested scheme of their formation was
confirmed experimentally.
Figure 4. General view of 11ꢀ. Selected bond lengths(Å): N(1)-C(2)
1.368(3), N(1)-C(5) 1.452(3), O(1)-C(2) 1.228(3), O(2)-C(4) 1.409(3),
O(3)-C(5) 1.409(3), C(2)-N(3) 1.358(3), N(3)-C(4) 1.433(3); bond
EXPERIMENTAL
angles(º): C(2)-N(1)-C(5) 109.7(2), C(2)-N(1)-C(7)
123.7(2), C(5)-
The 1H and 13C NMR spectra were recorded on a Bruker AM-
300 instrument in a DMSO-d6 at 300.13 MHz and 75.47 MHz
respectively. The chemical shifts value (ꢀ) were expressed
N(1)-C(7) 124.4(2), O(1)-C(2)-N(3) 125.1(2), O(1)-C(2)-N(1) 126.4(2),
N(3)-C(2)-N(1) 108.4(2), C(2)-N(3)-C(4) 111.2(2), C(2)-N(3)-C(11)
123.2(2), C(4)-N(3)-C(11) 124.4(2).
Table 1
Crystal data and structure refinement parameters for 11c, 12b and 13c.
Compound
11c
12b
13c
Empirical formula
Formula weight
Diffractometer
Wavelength
C8H16N2O3
188.23
C16H26N4O6
370.41
C8H14N2O2
170.21
Siemens P3
Mo-Kꢁ
Siemens P3
Mo-Kꢁ
Colorless prism
298(2)
Syntex P21
Mo-Kꢁ
Crystal colour, habit
Temperature (K)
Crystal system
Space group
a (Å)
colorless prism
298(2)
colorless prism
173(2)
Orthorhombic
Pbca
Triclinic
P-1
Monoclinic
P21/n
10.834(2)
8.501(2)
22.128(4)
6.0438(12)
11.825(2)
13.825(3)
101.55(3)
97.35(3)
93.19(3)
956.7(4)
2(1)
6.3028(13)
16.862(3)
8.8358(18)
b (Å)
c (Å)
ꢀ(º)
ꢁ (°)
104.13(3)
ꢂ (º)
V (Å3)
Z(Z')
2038.0(7)
8(1)
816
910.7(3)
4(1)
368
F(000)
396
1.286
Dcalc (g cmꢀ1)
Linear absorption, μ (cmꢀ1)
Scan type
1.227
0.94
1.242
0.90
0.99
ꢃ/2ꢃ
ꢃ/2ꢃ
64
ꢃ/2ꢃ
56
2ꢃmax (°)
56
99.7
Completeness of dataset (%)
Reflections measured
Independent reflections
Observed reflections [I > 2ꢂ(I)]
Parameters
99.8
3551
98.7
2355
5041
3551 [0.000]
1679
130
4606 [0.0261]
3195
239
2172 [0.0630]
1665
121
Final R(Fhkl) : R1
WR2
GOF
0.042
0.1312
1.052
0.0532
0.0880
0.0545
0.1421
0.962
1.037
0.203,-0.162
ꢃꢄmax, ꢃꢄmin (e Åꢀ3)
0.201, -0.168
0.397, ꢀ0.214

Sep-Oct 2006
Synthesis of First Representatives of
3,3'-Bi(6,8-dialkyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones)
1301
relative to chemical shifts for the deuterated solvent (2.50 ppm
and 39.51 ppm for the proton and carbon NMR, respectively).
Mass spectra were measured on an MS 30 spectrometer.
3,3'-Bi(6-cyclohexyl-8-methyl-2,4-dioxa-6,8-diazabicyclo-
[3.3.0]octan-7-one (12d)
1
Mp 314-316 ºC. Rf = 0.75 (MeOH:CH3Cl=1:5, v/v); H nmr
The crystal structures 11c, 12b and 13c were solved by a
direct method and refined by the full-matrix least-squares
against F2 in anisotropic approximation for nonhydrogen atoms.
All hydrogen atoms were located from the Fourier density
synthesis and refined in isotropic approximation. Crystal data
and structure refinement parameters for 11c, 12b and 13c are
given in Table 1. All calculations were performed using the
SHELXTL software. The crystallographic data have been
deposited with the Cambridge Crystallographic Data Center,
CCDC293638 for 11ꢀ, CCDC293639 for 12b and CCDC293640
for 13c. Copies of this information may be obtained free of
charge from: The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (Fax: +44-1223-336033; e-mail: deposit@ccdc.
cam.ac.uk or http://www.ccdc.cam.ac.uk).
(DMSO-d6): ꢀ 0.98-1.37(br.m, 8, 4ꢁꢄ2), 1.42-1.90 (br.m, 12,
6ꢁꢄ2), 2.75(s, 6, 2N-CH3), 3.49(m, 2, 2N-CH-(CH2)2), 4.82(s, 2,
2ꢁꢄ), 5.53(d, 2, 2N-CH-O, J = 4.9 Hz), 5.71(d, 2, 2N-CH-O, J
= 4.9 Hz). 13C nmr ([2H6]DMSO), ꢀ: 25 (CH2), 28 (CH2), 30
(CH3), 32 (ꢁꢄ2), 52 (ꢁꢄ), 85 (C5,C5') 87 (ꢁ1,C1'), 99 (C3,C3'),
157 (ꢁ ). ms: m/z: 225 (M+/2), 153, 115, 98, 82, 68.
Anal. Calcd. for C22H34N4O6 (450,53): C, 58.65; H, 7.61; N,
12.44. Found: C, 58.79; H, 7.80; N, 12.57
General Procedure for the Synthesis of 1,3-dialkyl-4,5-
dihydroxyimidazolidin-2-ones 11a-d.
A small amount of the concentrated HCl was added drop wise
to pH 4-4.5 to the solution of 0.04 mol glyoxal (the 40% water
solution) and the corresponding urea 10 (0.04 mol). The reaction
mass was held at 45-50 °C during 2 hours. The reaction masses
for the synthesis of 11a,b were evaporated in vacuo to give oily
residues and were crystallized from ꢂꢃ ꢄ to give 11a and 11b
in 32 and 25% yields, respectively. The reaction masses for the
synthesis of 11c,d were evaporated in vacuo to half of their
volume. By the cooling a crystalline precipitates were obtained.
The residues 11c,d were collected by filtration and were
crystallized from ꢂꢃ ꢄ to give 11c and 11d in 35 and 52%
yields, respectively.
The Optimal Procedure for the Synthesis of 3,3'-Bi(6,8-dialkyl-
2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-ones) 12a-d
The trimer dihydrate of glyoxal 5 (0.01 mol) was dissolved at
50 °C in the minimal volume of water (4 ml).The 20% water
solution of NaHꢁ 3 was added to the solution up to pH value 6.
The corresponding dialkylurea (0.02 mol) 10 was dissolved in
H2O (for 10a,b) or MeOH (for 10c,d) in the 5-fold amount to the
glyoxal solution in water. The obtained solutions were combined
and held during 2 hours at 60 ºꢁ. The reaction masses were left
at room temperature overnight. The residues 12a-d were collected
by filtration and were crystallized from ꢂꢃ ꢄ to give 12a, 12b,
12c and 12d in 42, 41, 43 and 45% yields, respectively.
1-tert-Butyl-3-methyl-4,5-dihydroxyimidazolidin-2-one (11c).
Mp 156-158 ºC; 1H nmr (DMSO-d6): ꢀ 1.31 (s, 9, 3ꢁ-ꢁꢄ3),
2.63 (s, 3, N-CH3), 4.40 (br.m, 1, ꢁꢄ), 4.65 (br.m, 1, ꢁꢄ), 5.83
(br.m, 1, ꢄ), 6.00 (br.m, 1, ꢄ).
Anal. Calcd. for C8H16N2O3 (188,22): C, 51.05; H, 8.57; N,
14.88. Found: C, 50.94; H, 8.69; N, 14.99
3,3'-Bi(6,8-dimethyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-
one (12a).
Mp 237-238 °C. Rf = 0.68 (MeOH:CH3Cl=1:5, v/v); 1H nmr
(DMSO-d6): ꢀ 2.76(s, 12, 4ꢁꢄ3), 4.79 (s, 2, 2ꢁꢄ), 5.61 (s, 4,
4N-CH-O). 13C nmr ([2H6]DMSO), ꢀ: 28 (ꢁꢄ3), 87 (ꢁꢄ), 99
(ꢁꢄ), 157 (ꢁ )
1-Cyclohexyl-3-methyl-4,5-dihydroxyimidazolidin-2-one (11d).
1
Mp 164-166 ºC; H nmr (DMSO-d6): ꢀ 0.8-1.76(br.m, 10,
5ꢁꢄ2), 2.60 (s, 3, N-CH3), 4.37 (br.m, 1, ꢁꢄ), 4.66 (br.m, 1,
ꢁꢄ), 5,90 (br.m, 1, ꢄ), 6.05 (br.m, 1, ꢄ)
Anal. Calcd. for C12H18N4O6 (314.29): C, 45.86; H, 5.77; N,
17.83. Found: C, 45.59; H, 5.97; N, 17.91.
Anal. Calcd. for C10H18N2O3 (214,26): C, 56.06; H, 8.47; N,
13.07. Found: C, 55.90; H, 8.25; N, 12.95
3,3'-Bi(6,8-diethyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]octan-7-one
(12b).
General Procedure for the Synthesis of 3-alkyl-1-methylimida-
zolidin-2,4-diones 13a-d.
Mp 225-227 ºC. Rf = 0.73 (MeOH:CH3Cl=1:5, v/v);1H nmr
(DMSO-d6): ꢀ 1.11 (m, 12, 4ꢁꢄ3), 3.24 (m, 8, 4ꢁꢄ2), 4.78 (s, 2,
2ꢁꢄ), 5.72 (s, 4, 4ꢁꢄ). 13C nmr ([2H6]DMSO), ꢀ: 13 (ꢁꢄ3), 36
(ꢁꢄ2), 86 (ꢁꢄ), 99 (ꢁꢄ), 157 (ꢁ ). ms: m/z: 185 (M+/2), 157
(M+/2-CH2O), 141, 140, 112, 86, 58, 56.
1,3-Dialkyl-4,5-dihydroxyimidazolidin-2-ones 11a-d (0.02
mol) were dissolved at RT in the minimal amount of H2O (for
11a,b) or H2O-MeOH mixture (1:5) (for 11c,d). A 20% water
Anal. Calcd. for C16H26N4O6 (370,40): C, 51.88; H, 7.08; N,
15.13. Found: C, 52.02; H, 7.20; N, 14.96.
solution of NaHꢁ was added to the solution up to pH 6. The
3
reaction masses were held at 60 °ꢁ during 2 h. The reaction
masses for the synthesis of 13a,b were evaporated in vacuo to
give oily residues, which were extracted with the ether. The
obtained solutions evaporated in vacuo to give a crystalline
precipitates, which were crystallized from MeOH to give 13a,b
in 77 and 75% yields, respectively. The reaction masses for the
synthesis of 13c,d were placed in the refridgerator. The residues
13c,d were collected by filtration and were crystallized from
ꢂꢃ ꢄ to give 13c and 13d in 78 and 80% yields, respectively.
3,3'-Bi(6-tert-butyl-8-methyl-2,4-dioxa-6,8-diazabicyclo[3.3.0]-
octan-7-one (12c).
1
Mp 247-249 ºC. Rf = 0.82 (MeOH:CH3Cl=1:5, v/v); H nmr
(DMSO-d6): ꢀ 1.34 (s, 18, 6ꢁ-ꢁꢄ3), 2.69 (s, 6, 2N-CH3), 4.74 (s,
2, 2ꢁꢄ), 5.54 (d, 2, 2N-CH-O, J = 5.0 Hz), 5.82 (d, 2, 2N-CH-O, J
= 5.0 Hz). 13C nmr ([2H6]DMSO), ꢀ: 27 (C-CH3), 28 (N-ꢁꢄ3), 53
(ꢁꢄ2), 85 (C(5),C(5')) 86 (ꢁ(1),C(1')), 98 (C(3),C(3')), 157 (ꢁ ).
ms: m/z: 199 (M+/2), 155, 154, 143, 115, 98, 84, 72, 70. HMRS,
Found (M+ H)+, 399.2237. C18H30N4O6 requires M, 398.2165.
Anal. Calcd. for C18H30N4O6 (398,45): C, 54.26; H, 7.59; N,
14.06. Found: C, 54.11; H, 7.71; N, 13.95.
1,3-Diethylimidazolidin-2,4-dione (13b).
Bp 260-261 °C; 1H nmr (DMSO-d6): ꢀ 1.04 (t, 6, CH3, J = 6.0
Hz), 3.32 (m, 4, N-CH2), 3.85 (s, 2, CH2).

1302
A. S. Sigachev, A. N. Kravchenko, G. A. Gazieva, P. A. Belyakov,
N. G. Kolotyrkina, O. V. Lebedev, N. N. Makhova and K. A. Lyssenko
Vol 43
[12] A. A. Bakibaev, R. R. Akmedzhanov, A. Yu. Yagovkin, T. P.
Novozheeva, V. D. Filiminov, A. S. Saratnikov, Khim. Pharm. Zhurn.,
27, 29 (1993) (in Russian) [Pharm. Chem. J. (Engl. Transl.), 27, 401
(1993)].
Anal. Calcd. for C7H12N2O2 (156,18): C, 53.83; H, 7.74; N,
17.94. Found: C, 53.76; H, 7.82; N, 18.01.
1-tert-Butyl-3-methylimidazolidin-2,4-dione (13c).
[13] J. Nematollahi and R. Ketchan. J. Org. Chem., 28, 2378
(1963).
[14] H. Petersen. Synthesis., 5, 273 (1973).
[15] G. A. Gazieva, A. N. Kravchenko, O. V. Lebedev, K. A.
Lyssenko, M. O. Dekaprilevich, V. M. Men'shov, Yu. A. Strelenko, N.
N. Makhova. Mend. Commun., 138 (2001).
[16] I. Ya. Slonim, B. M. Arshava and V. N. Klyuchnikov. in Sb.
«Sovremennie aspekti YaMR spectroskopii polimerov» (Modern aspects
of NMR spectroscopy of polymers), St. Petersburg – Nizhnekamsk, 53
(1994) (in Russian).
[17] J. P. Guette, G. Mattioda, B. Metivier, Actualite Chimique, 5,
23 (1982).
1
Mp 104-106 ºC; H nmr (DMSO-d6): ꢀ 1.46(s, 9, 3ꢀ-ꢀꢁ3),
2.80(s, 3, N-CH3), 4.05(s, 2, ꢀꢁ2)
Anal. Calcd. for C8H14N2O2 (170,21): C, 56.45; H, 8.29; N,
16.46. Found: C, 56.57; H, 8.45; N, 16.28.
1-Cyclohexyl-3-methylimidazolidin-2,4-dione (13d).
1
Mp 112-114 ºC; H nmr (DMSO-d6): ꢀ 0.9-1.75(br.m, 10,
5ꢀꢁ2), 2.79(s, 3, Cꢁ3), 3,69(m, 1, N-CH), 3.89(s, 2, ꢀꢁ2)
Anal. Calcd. for C10H16N2O2 (196,25): C, 61.20; H, 8.22; N,
14.27. Found: C, 61.01; H, 8.35; N, 14.39
[18] E. B. Whipple, J. Amer. Chem. Soc., 92, 7183 (1970).
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and oxides, John Wiley & Sons, New York, NY, 1963, pp 167-168.
[21] R. H. Barker, S. L. Vail, G. B. Barcelo, J. Heterocycl. Chem.,
3, 354 (1996).
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