Formation of 5,6-cyclopentano-uracil by cyclization of the bisamide of adipic acid induced by oxalyl chloride

Article abstract of DOI:10.1016/j.tet.2010.04.032

Cyclization of the bisamide of adipic acid induced by oxalyl chloride will eventually yield a product of the composition C₉H₈N₂O₅, which upon hydrolysis gave 5,6-cyclo-pentanouracil. The structures of both compounds were established by X-ray crystallography.

Full text of DOI:10.1016/j.tet.2010.04.032

Tetrahedron 66 (2010) 4601e4603
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Formation of 5,6-cyclopentano-uracil by cyclization of the bisamide of adipic acid
induced by oxalyl chloride
,
b
Jan Bergman a , Per H. Svensson
*
a Department of Biosciences and Nutrition, Karolinska Institute, SE 141 57 Huddinge, Sweden
b AstraZeneca R&D, Solid State Analysis, SE 151 85 Södertälje, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclization of the bisamide of adipic acid induced by oxalyl chloride will eventually yield a product of the
composition C9H8N2O5, which upon hydrolysis gave 5,6-cyclo-pentanouracil. The structures of both
compounds were established by X-ray crystallography.
Received 28 January 2010
Received in revised form 16 March 2010
Accepted 6 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 10 April 2010
Keywords:
Acyl isocyanates
Uracils
Cyclizations
1. Introduction
suggested intermediate 5 will subsequently undergo cyclization to
yield finally 7 (after reaction with water and elimination of CO2
The 7-azaindole derivative 1 has been considered to be the
active principle in the defencive secretion of the millipede
Rhinocricus padbergi.1,2 The purported identification (MS and
retention times) relies on its identify with a compound obtained by
treating the bisamide of adipic acid with oxalyl chloride to give
a product with the composition C9H8N2O5 and assigned (in 1968)
structure 2. In a final step this molecule was reacted with hydrazine
hydrate (or aniline), which removed the elements of COþCO2 to
give the final product with the composition C7H8N2O2, which was
considered to be the 7-azaindole derivative 1.3
and HCl).
In other words the real structure of the previously reported
compound 2 should be that of 7 and likewise the purported
azaindole derivative consequently must be quite another
1
heterocycle, namely 5,6-cyclopentano-uracil 6, a molecule known
and synthesized since 1947.7e11 The structure of 6 obtained as
described in Scheme 2 was fully confirmed by an independent
synthesis starting by condensation of 2-carbethoxycyclopentanone
with thiourea. This compound (a thio derivative of 6) was in a final
step converted to the fused uracil derivative 6 under acidic condi-
tions. Compound 7 featured a diagnostic CH signal at 48.2 ppm in
the 13C NMR spectrum, which is incompatible with the originally
assigned structure. Formation of oxazolidine-4,5-diones when
various amide type molecules are treated with oxalyl chloride has
previously been observed on several occasions. Thus acetanilide
yields 2-methylene-1-phenyloxazolidine-4,5-dione 8 and gluta-
rimide will give oxazolidine-4,5-dione 9.12,13 The assigned struc-
tures of 6 and 7 were fully confirmed by analysis by X-ray
crystallography.
If correct this extraordinary condensation at an unactivated
methylene group during the transformation of 2 to 1 would be truly
remarkable (Scheme 1).
Reactions of carboxylic acid amides with oxalyl chloride have
been studied in detail already during the early 1960s4e6 and the
predominant products are acyl isocyanates. The acyl isocyanate
derived from adipic acid amide was indeed formed and reported
in the paper from 1968.3 With this in mind we considered that
adipoyl isocyanate 3 might undergo intramolecular cyclizations as
outlined in Scheme 2. Such a cyclization will draw on the high
electrophilicity of the acyl carbonyl group in combination with
that enolization will now be possible via the carbonyl group on
the other side. It is quite conceivable that this process is initiated
by O-acylation of 3 or its enol 4 with oxalyl chloride. The
* Corresponding author. Fax: þ468 608 1501; e-mail address: jan.bergman@ki.se
(J. Bergman).
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doi:10.1016/j.tet.2010.04.032

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J. Bergman, P.H. Svensson / Tetrahedron 66 (2010) 4601e4603
O
O
N
N2H4 H2O
(ClCO-)2
(H2C)4
O
H2NOC-(CH2)4-CONH2
1,2-dichloroethane
reflux, 18 h
O
N
N
H
O
N
O
O
1
2
Scheme 1. (From Ref. 3).
(ClCO)2
1,2-dichloroethane
reflux, 18 h
H2NOC(CH2)4CONH2
OH
O=C=N-CO(CH2)4CO-N=C=O
3
O
O
N
H
H
N=C=O
N
C
O
O
NH
(ClCO)2
Cl
N
N=C=O
O
O
O
O
O
O
O
O
O
[4]
[5]
7
NH
N2H4 H O
•
2
7
N
H
O
6
Scheme 2.
Finally, from the data available in the literature and those pre-
sented here we consider it likely that the active principle in the
defence secretion of the millipede R. padbergi is 5,6-cyclopentano-
uracil 6. Interestingly another defence compound isolated from the
millipede Glomeris marginata,14,15 glomerin 10, has a somewhat
related structure, i.e., both are fused pyrimidine derivatives.
The crystal structures of 6 and 7 were determined by X-ray
crystallographic analysis, the details of which are given in the
Experimental section. The molecular structure and the unit cell of 6
are shown in Figure 1. The molecules are linked together via both
monomeric and dimeric NeH/O]C hydrogen bonds to form an
infinite two-dimensional network. The packing coefficient (percent
Figure 1. The molecular (a) and crystal structure (b) of 6.

J. Bergman, P.H. Svensson / Tetrahedron 66 (2010) 4601e4603
4603
filled van der Waals space in the unit-cell) is 71.9%, indicating an
efficient molecular framework in the solid-state. The molecular
packing is also facilitated by stacking and vdW interactions. The
distance between the planes of two adjacent aromatic moieties is
3.1.1. 5,6-Cyclopentano-uracil. Compound 7 (1.12 g, 10 mmol) and
hydrazine hydrate (3 mL) in ethanol (40 mL) were heated at reflux
for 15 min and filtered, solid formed upon concentration and
cooling was collected, 530 mg (67%), mp: 280 ꢀC dec. The 13C and
1H NMR data were in agreement with those in the literature.11
ꢀ
approximately 3.3 A.
The molecular and crystal structure of 7 is shown in Figure 2.
The molecules are linked together via NeH/O]C hydrogen bonds
as well as several strong vdW interactions. The traditional hydro-
gen bonds form infinite chains along the a-axis. The packing
coefficient is 73.2%, indicating a very efficient molecular packing in
the solid-state. Some unusually short intermolecular contacts are
present in the crystal structure, which is probably a result of the
efficient molecular packing.
3.2. Single-crystal X-ray analysis
X-ray structures were recorded at 200 K on a BrukerApexII
diffractometer with graphite-monochromated Mo K(a) radiation.
Lattice parameters were obtained by least-squares fits to the scat-
tering angles of reflections observed in several pre-scans. The
intensity data collection was performed by
u and 4 scans; all raw
Figure 2. The molecular (a) and crystal structure (b) of 7.
2. Conclusions
data were corrected for Lorentz and polarization effects. The
structures were solved by direct methods and refined by full matrix
least-squares analyses with anisotropic temperature factors for all
atoms except protons. Proton positions were calculated using
known molecular geometries, refined in riding mode with fixed
isotropic temperature factors.
It has been demonstrated that a simple aliphatic starting
material (hexane 1,6-diamide) can be converted to fused pyrimi-
dine derivatives. This type of cyclizations should be extendible to,
e.g., pentane 1,5-diamide and suitable monoamides.
3. Experimental
3.1. General
References and notes
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M. G.; Cabrera, A. C. Entomotropica 2003, 18, 79e82.
Melting points were uncorrected and determined using a Büchi
B-545 apparatus. Melting points >300 ꢀC are not listed. NMR
spectra were obtained in DMSO-d6 on a Bruker 300 MHz. Infrared
spectra were recorded with an Avatar 330 FT-IR apparatus (Thermo
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Compound 7. To a suspension of a hexane 1,6-diamide (adipa-
mide) (7.2 g, 50 mmol) in dichloromethane (250 mL) oxalyl chlo-
ride (12 mL) was added and the mixture was heated at reflux
temperature for 18 h. After that period the brown solid formed was
collected and recrystallized (with addition of active carbon) from
acetone, 3.6 g (33%), mp: 312e314 ꢀC. The sample used for X-ray
analysis was repeatedly recrystallized from acetone. IR 3200, 3118,
2973, 1824, 1810, 1730, 1704, 1378, 1349, 1299, 1209, 1122, 1009,
748 cmꢁ1; 1H NMR 1.75 (t, 2H), 2.06e2.16 (m, 4H), 3.22 (d, 1H), 11.5
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(s, 1H); 13C NMR
(d), 98.2 (s), 144.6 (s), 151.1 (s), 156.1 (s), 170.3 (s).
d (DMSO-d6, 75 MHz) 19.6 (t), 24.4 (t), 35.5 (t), 48.2