The reactivity of related 6-amino- and 5,6-diaminouracils derived from 2-amino-5-(phenoxymethyl)-2-oxazoline: Efficient access to bicyclic pyrimidine derivatives

Article abstract of DOI:10.1055/s-2007-983748

8-(Dimethylamino)-3-(2-hydroxy-3-phenoxypropyl)-xanthine has been obtained from 6-amino-1-(2-hydroxy-3-phenoxypropyl)uracil by an azodicarboxylate Michael-type addition involving a reactive diene. 6-Amino-1-(2-hydroxy-3- phenoxypropyl)uracil was easily pr

Full text of DOI:10.1055/s-2007-983748

PAPER
2193
The Reactivity of Related 6-Amino- and 5,6-Diaminouracils Derived from
2-Amino-5-(phenoxymethyl)-2-oxazoline: Efficient Access to Bicyclic
Pyrimidine Derivatives
R
elated 6-A
m
t
é
5,6-Diam
p
inouracils:
E
f
ficient
A
cce
a
ss to Bicyc
n
lic Pyrimidin
e
e
D
erivatives Massip,a Jean Guillon,*a Pascal Sonnet,b Jean-Michel Léger,a Jean-Jacques Bosc,a Christa E. Müller,c
Christian Jarrya
a
EA 4138 – Pharmacochimie, UFR des Sciences Pharmaceutiques, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat,
33076 Bordeaux Cedex, France
Fax +33(5)57571352; E-mail: Jean.Guillon@chimphys.u-bordeaux2.fr
EA 3901 – DMAG, Faculté de Pharmacie, Université de Picardie Jules Verne, 1 rue des Louvels, 80037 Amiens Cedex 1, France
b
c
Universität Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Poppelsdorf, Kreuzbergweg 26, 53115 Bonn, Germany
Received 21 March 2007; revised 3 May 2007
Me
Abstract: 8-(Dimethylamino)-3-(2-hydroxy-3-phenoxypropyl)-
N
8
Me
xanthine has been obtained from 6-amino-1-(2-hydroxy-3-phen-
oxypropyl)uracil by an azodicarboxylate Michael-type addition in-
9
4
N
4
3
N
2
7
N
H
5
volving
a reactive diene. 6-Amino-1-(2-hydroxy-3-phenoxy-
N
O
5
6
O
1
O
3
propyl)uracil was easily prepared from racemic 2-amino-5-(phen-
oxymethyl)-2-oxazoline. Moreover, these chemical investigations
also led to the identification of a racemic 7-aminooxazolo[5,4-d]py-
rimidin-5(6H)-one, obtained by the condensation reaction of the
phosgeniminium chloride, Viehe’s salt, with 5,6-diamino-1-(2-hy-
droxy-3-phenoxypropyl)uracil.
NH2
OH
2
N
H
O
O
1
1
2
Figure 1 Structure of 8-(dimethylamino)-3-(2-hydroxy-3-phenoxy-
propyl)xanthine (2) and its precursor, 2-amino-2-oxazoline 1
Key words: bicyclic compounds, ene reactions, uracils, fused-ring
systems, Michael additions
The first attempt to synthesize xanthine 2 was based on
the reaction of 5,6-diaminouracil 31 with N,N-dimethyl-
formamide dimethyl acetal (DMFDMA) (Scheme 1).
This only led to the formation of the 8-unsubstituted xan-
thine 4,1 probably through nucleophilic attack of the sec-
ond amino function on the amidine carbon atom of the
intermediate, followed by deamination.
In a previous paper, we reported the synthesis of new xan-
thines derived from racemic 2-amino-2-oxazoline 1 and
evaluated as A1 and A2A adenosine receptor antagonists.1
Preliminary structure–activity relationship (SAR) results
were drawn on the basis of affinity data in relation to the
nature and position of certain substituents on the xanthine
moiety. For example, it was shown that the N-7 atom in
the xanthine ring should be unsubstituted in order to es-
tablish a hydrogen bond with the A1 adenosine receptor
required to increase the affinity and to modulate the selec-
tivity. Conversely, large and functionalized substituents at
N-3 in the xanthine moiety are well accepted by both A1
and A2A receptor subtypes.
Then, we reacted 3 with phosgeniminium chloride
(Viehe’s salt)4 in dichloromethane at room temperature
and at reflux. All experiments led to the stable racemic 7-
aminooxazolo[5,4-d]pyrimidin-5(6H)-one 5 in 58% yield
(Scheme 2) through two hypothetical mechanisms.
The first mechanism (Hypothesis A) involves the power-
ful electrophilic phosgeniminium chloride reacting with
the amino group at the 5-position of 3 to form intermedi-
ate I after hydrogen chloride elimination (Figure 2). Then,
the reactivity of the carbon–oxygen bond in the a-posi-
tion, through its enolic form, allows the formation of the
oxazolo[5,4-d]pyrimidin-5(6H)-one system. Alternative-
ly (Hypothesis B), intermediate I could be rearranged to
ammonium salt II after departure of a second hydrogen
chloride molecule (Figure 2), followed by nucleophilic
addition of the oxygen atom at C-4 of the uracil ring to the
carbodiimide carbon atom. Hence, a 4,5-cyclization
would occur via a positively charged oxygen atom, based
on the near coplanarity of the nitrogen atoms.5 Finally, the
loss of a third hydrogen chloride molecule would lead to
the oxazolo[5,4-d]pyrimidin-5(6H)-one 5.5
In this paper, we report additional modulation around the
xanthine moiety to fulfill the adenosine receptor antago-
nists pharmacophoric requirements. The introduction of
an amino function in position 8 was selected for receptor-
binding purpose, and we chose to promote the classical
amino(phenoxy)propanol pharmacophore, associated
with b-adrenergic receptor blockade, as the N-3 substitu-
ent on the xanthine ring. These considerations led us to
design the racemic 8-(dimethylamino)-3-(2-hydroxy-3-
phenoxypropyl)xanthine (2) as
a lead compound
(Figure 1).2,3
Structural elucidation of 5 was achieved by H and 13C
NMR spectroscopy on the basis of previous results for
compounds from the oxazolo[5,4-d]pyrimidinone or -di-
one series.5,6 As 5 could be isolated as a single monocrys-
1
SYNTHESIS 2007, No. 14, pp 2193–2197
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983748; Art ID: T05707SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

2194
S. Massip et al.
PAPER
Me
Me
H
N
N
N
N
O
OH
N
O
O
H
2
NH2
NH2
O
DMFDMA
O
N
1
OH
NH2
Me
N
3
O
N
H
N
O
O
N
Me
OH
O
N
H
N
H
N
N
O
OH
4
N
H
O
O
72%
Scheme 1
tal, we performed an X-ray crystallography study
(Figure 3). The oxazolo[5,4-d]pyrimidin-5(6H)-one moi-
ety is almost planar with the maximum deviation from
planarity being found for N12 lying 0.013(2) Å from the
plane defined by the bicyclic system. The N14–C15 and
N22–C21 bonds were determined to be 1.31(7) and
1.29(8) Å, respectively, as typically observed for nitro-
gen–carbon double bonds,7,8 while O20–C21, O20–C15,
N22–C16, and N23–C21 were found to be identical in
length to the comparable conjugated carbon–oxygen and
carbon–nitrogen single bonds in the molecule, i.e. 1.37–
1.38 and 1.34–1.39 Å, respectively. The dimethylamino
nitrogen, N23, was determined to be sp3 hybridized. All
these X-ray data also confirmed the enamine tautomeric
form of 5 in the solid state. Moreover, 5 was found to be
a racemic (R/S) mixture as highlighted by the determined
spatial group (P21/c).
Me
Me
Cl
Cl
2
+
N
Cl–
3
NH2
Me
Me
N
N
O
N
OH
O
N
5
O
58%
NH2
OH
O
N
N
O
N
N
H
7-amino-2-(2-furyl)-5-[(4-hydoxyphenyl)ethylamino]oxazolo[5,4-d]pyrimidine
Next, our attention turned to performing the synthesis of
the target compound 2 via aminouracil 6, which is easily
prepared from the corresponding 2-amino-2-oxazoline 1.1
Access to the 8-(dimethylamino)xanthine moiety
Scheme 2
Me
NH2
Me
H
N
N+
R
N
–Cl
Cl
OH
O
N
H
O
I
Me
NH2
N
C
+
Me
–Cl
N
R
N
OH
O
N
H
O
II
Figure 3 The ORTEP drawing of 5 with thermal ellipsoids at 30%
Figure 2 Structures of the hypothetical intermediates I and II
level
Synthesis 2007, No. 14, 2193–2197 © Thieme Stuttgart · New York

PAPER
Related 6-Amino- and 5,6-Diaminouracils: Efficient Access to Bicyclic Pyrimidine Derivatives
2195
NH2
1) NaOEt
N
2) HCl, H2O
O
1
O
N
O
8
Me
N
Me
N
NH2
O
N
DMFDMA
6
63%
OH
O
N
O
N
H
O
9
71%
OH
O
N
H
O
Me
N
Me
N
COOEt
DEAD
N
COOEt
∆
O
N
N
2
31%
H
OH
7
O
N
H
O
84%
Scheme 3
(Scheme 3) was based on the Walsh and Wamhoff tomography (PET).14 This prompted us to develop new
procedure9,10 consisting of a cyclization reaction of substituted oxazolo[5,4-d]pyrimidin-5(6H)-ones such as
Michael adduct 7 leading to the 3-substituted 8-(dimethyl- 5, easily designed from the 2-amino-2-oxazoline scaffold
amino)xanthine 2.
1, obtained through one heterocyclization using a Viehe’s
salt. Finally, pharmacological evaluation of compounds 2
and 5 as potential A1 and A2A adenosine receptor antag-
onists will be investigated.
6-Aminouracil 6 was directly formed by the hydrolysis of
bicyclic compound 81 in an alkaline medium that resulted
in the opening of the oxazoline ring. Heating a toluene so-
lution of 6 with DMFDMA11 led to an efficient reactive
heterocyclic diazadiene 9. Compound 9 was then treated
with diethyl azodicarboxylate (DEAD) in toluene (110
°C, 8 h) to give 5-hydrazinouracil 7. As a Michael adduct
model, 7 could be considered as a key intermediate in the
formation of new 8-(dimethylamino)theophylline deriva-
tives by thermal cyclization reactions.9,10,12,13 Hence, the
target 8-(dimethylamino)xanthine 2 was obtained by heat-
Melting points were determined with an SM-LUX-POL Leitz hot-
stage microscope and are uncorrected. The IR spectra were record-
ed on a Bruker IFS-25 spectrophotometer; NMR spectra (1H, 13C,
and 1H COSY) were recorded at 300 MHz or 75 MHz with TMS as
an internal standard using a Bruker AVANCE 300 spectrometer.
Analytical TLC was carried out on 0.25-mm precoated silica gel
plates (POLYGRAM SIL G/UV254) with visualization by irradia-
tion with a UV lamp. Silica gel 60 (70–230 mesh) was used for col-
ing 7 in nitrobenzene at 190–200 °C (Scheme 3). The umn chromatography. Analyses indicated by the symbols of the
elements were within 0.3% of the theoretical values.
structure of 2 was assigned on the basis of elemental and
spectral analyses. The 1H NMR spectrum of 2 showed two
3-(2-hydroxy-3-phenoxypropyl)xanthine (4)1
singlets at 11.40 and 10.70 ppm, highly characteristic for
A stirring mixture of 5,6-diaminouracil 3 (0.7 g, 2.4 mmol), DMF-
NH protons in positions 7 and 1 of the xanthine moiety.
DMA (0.33 g, 2.73 mmol), and AcOH (0.2 mL) in EtOH (14 mL)
Such a shielded signal observed at 11.40 ppm for the pro-
ton on the N-7 atom of the xanthine skeleton has been al-
ready described in the literature data (d = ~11.30 ppm).9,10
was refluxed for 4 h. The mixture was then evaporated under re-
duced pressure and the crude residue was triturated in Et2O, filtered,
and dried to give 4 as colorless crystals. Yield: 0.47 g (65%).
In conclusion, this paper highlights the reactivity of 6-
aminouracil 6 and 5,6-diaminouracil 3, both derived from
2-amino-2-oxazoline 1, leading to racemic 8-(dimethyl-
7-Amino-2-(dimethylamino)-6-(2-hydroxy-3-phenoxypro-
pyl)oxazolo[5,4-d]pyrimidin-5(6H)-one (5)
A stirring mixture of 5,6-diaminouracil 3 (1.46 g, 5 mmol), Viehe’s
amino)-3-(2-hydroxy-3-phenoxypropyl)xanthine (2) and salt (1.95 g, 12 mmol), and anhyd CH2Cl2 (50 mL), protected from
atmospheric moisture, was allowed to stand at r.t. for 5 h and then
was refluxed until the evolution of HCl had ceased (5 h). After cool-
ing at r.t., the solvent of the heterogeneous mixture was removed in
vacuo and the residue was mixed with H2O (30 mL) and then with
oxazolo[5,4-d]pyrimidin-5(6H)-one 5, respectively. From
3, by using various dimethylformamide dialkyl acetals, it
should now be possible to introduce new substituents in
position 8 of the xanthine moiety, thereby increasing mo-
KHCO3, added slowly until the evolution of CO2 had ceased. The
lecular diversity and allowing the synthesis of new
polysubstituted xanthines. In addition, 7-amino-2-(2-fur-
yl)-5-[(4-hydroxyphenyl)ethylamino]oxazolo[5,4-d]pyri-
midine (Scheme 2) was recently identified as a potential
A2A adenosine receptor antagonist for positron emission
resultant oxazolopyrimidinone 5 was isolated as colorless crystals
by suction using a glass filter, washed with H2O then EtOH, and
dried. Yield: 1.00 g (58%); mp 330 °C.
IR (KBr): 3410, 3320, 3200, 1660, 1630 cm–1.
Synthesis 2007, No. 14, 2193–2197 © Thieme Stuttgart · New York

2196
S. Massip et al.
PAPER
6{[(Dimethylamino)methylene]amino}-1-(2-hydroxy-3-phen-
oxypropyl)-5-[1,2-bis(ethoxycarbonyl)hydrazino]uracil (7)
A stirring mixture of uracil 9 (1.0 g, 3.03 mmol) and DEAD (0.53
g, 3.15 mmol) was refluxed in toluene (20 mL) for 8 h. The toluene
was removed in vacuo to give a dark red oil. A small amount of
EtOAc was added to the residue, the suspension was cooled, and the
separated product was collected by filtration. The Michael adduct
was washed with EtOAc and dried in vacuo to give the product as
orange crystals. Yield: 1.29 g (84%); mp 70 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.58 (s, 2 H, NH2), 7.27 (t, J =
7.6 Hz, 2 H, H-3¢, H-5¢), 6.92 (t, J = 7.6 Hz, 1 H, H-4¢), 6.89 (d, J =
7.6 Hz, 2 H, H-2¢, H-6¢), 5.48 (d, J = 4.1 Hz, 1 H, OH), 4.13–4.09
(m, 2 H, CH, CH2), 4.00–3.94 (m, 3 H, CH2), 3.00 [s, 6 H, N(CH3)2].
13C NMR (75 MHz, DMSO-d6): d = 165.3, 158.5, 156.9, 154.4,
148.9, 129.5, 120.6, 114.5, 103.8, 70.3, 66.9, 46.4, 37.4.
Anal. Calcd for C16H19N5O4: C, 55.64; H, 5.54; N, 20.28. Found: C,
55.73; H, 5.46; N, 20.16.
IR (KBr): 3400, 3210, 1720, 1655 cm–1.
The structure of compound 5 was established by X-ray crystallog-
raphy (Figure 2). Colorless single crystals of 5 were obtained by
slow evaporation from MeOH–CHCl3 (20:80) soln. The unit cell di-
mensions were determined using the least-squares fit from 25 re-
flections (25° < q < 35°). Intensities were collected with an Enraf-
Nonius CAD-4 diffractometer using the CuKa radiation and a
graphite monochromator up to q = 45°. The data were collected to
relatively low resolution, i.e. no reflections were observed for q
>45° with lCu. The data were corrected for Lorentz and polarization
effects and for empirical absorption correction.15 Structure 5 was
determined by direct methods SHELX 8616 and refined using
SHELX 9717 suite of programs. Crystallographic data for structure
8 in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC-
612139.18
1H NMR (300 MHz, DMSO-d6): d = 11.03 (br s, 1 H, NH-3), 8.99
(s, 1 H, N–NH), 7.76 (s, 1 H, N=CH), 7.25 (t, J = 7.7 Hz, 2 H, H-3¢,
H-5¢), 6.90 (t, J = 7.7 Hz, 1 H, H-4¢), 6.83 (d, J = 7.7 Hz, 2 H, H-2¢,
H-6¢), 5.23 (br s, 1 H, OH), 4.20–3.84 (m, 9 H, CH2CHCH2, OCH2),
3.02 (s, 3 H, NCH3), 2.94 (s, 3 H, NCH3), 1.19 (t, J = 7.4 Hz, 3 H,
CH3), 1.09 (t, J = 7.4 Hz, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.1, 160.4, 158.4, 157.0,
153.3, 151.7, 150.2, 129.5, 120.3, 114.3, 101.5, 69.5, 66.2, 63.3,
61.5, 44.1, 40.2, 34.3, 14.5.
Anal. Calcd for C22H30N6O8: C, 52.17; H, 5.97; N, 16.59. Found: C,
52.26; H, 5.83; N, 16.48.
8-(Dimethylamino)-3-(2-hydroxy-3-phenoxypropyl)xanthine
(2)
6-Amino-1-(2-hydroxy-3-phenoxypropyl)uracil (6)
Michael adduct 7 (1.30 g, 2.58 mmol) was heated in nitrobenzene
(7 mL) between 190–200 °C for 1.5 h. The solution was then cooled
to 10 °C. A small amount of Et2O was added, and the resulting solid
was filtered and washed with Et2O. The crude product was then
crystallized (EtOH) and obtained as beige crystals. Yield: 0.28 g
(31%); mp 184 °C.
To a solution of Na (1.29 g, 56 mmol) in anhyd EtOH (100 mL) was
added 8 (3.62 g, 14 mmol). The resulting solution was refluxed for
8 h and the solvent was then removed in vacuo. The solid residue
was dissolved in H2O and the obtained solution was acidified to pH
5–6 with aq HCl. The precipitate was collected by filtration, washed
with EtOH and then petroleum ether, and dried to give the product
as pale yellow crystals. Yield: 2.44 g (63%); mp 182 °C.
IR (KBr): 3425, 3170, 1700, 1630 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.40 (br s, 1 H, NH-7), 10.70
(br s, 1 H, NH-1), 7.24 (t, J = 7.4 Hz, 2 H, H-3¢ and H-5¢), 6.88–6.80
(m, 3 H, H-2¢, H-4¢, H-6¢), 5.31 (br s, 1 H, OH), 4.39–4.31 (m, 1 H,
CH), 4.02–3.91 (m, 4 H, CH2), 2.93 [s, 6 H, N(CH3)2].
13C NMR (75 MHz, DMSO-d6): d = 158.8, 156.1, 152.3, 151.8,
150.2, 129.8, 121.1, 114.8, 106.9, 70.7, 66.5, 46.3, 40.5, 40.2.
IR (KBr): 3380, 3310, 3180, 1730, 1695 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.05 (br s, 1 H, NH), 7.28 (t,
J = 7.6 Hz, 2 H, H-3¢, H-5¢), 6.92 (t, J = 7.6 Hz, 1 H, H-4¢), 6.89 (d,
J = 7.6 Hz, 2 H, H-2¢, H-6¢), 6.62 (s, 2 H, NH2), 5.71 (br s, 1 H, OH),
4.60 (s, 1 H, H-5), 4.07–3.76 (m, 5 H, CH2CHCH2).
13C NMR (75 MHz, DMSO-d6): d = 162.5, 158.5, 156.8, 151.6,
129.5, 120.7, 114.5, 76.3, 70.1, 67.0, 44.8.
Anal. Calcd for C16H19N5O4: C, 55.64; H, 5.54; N, 20.28. Found: C,
55.56; H, 5.62; N, 20.35.
Anal. Calcd for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15. Found: C,
56.54; H, 5.38; N, 15.22.
References
6-{[(Dimethylamino)methylene]amino}-1-(2-hydroxy-3-phen-
oxypropyl)uracil (9)
(1) Massip, S.; Guillon, J.; Bertarelli, D.; Bosc, J.-J.; Léger, J.-
M.; Lacher, S.; Bontemps, C.; Dupont, T.; Müller, C. E.;
Jarry, C. Bioorg. Med. Chem. 2006, 14, 2697.
(2) Stinson, S. C. Chem. Eng. News 1998, 76, 83.
(3) Hoffman, B. B.; Lefkowitz, R. J. Adrenergic receptor
antagonists, In Goodman and Gilman’s The
A stirring mixture of 6-aminouracil 6 (4.26 g, 15.4 mmol), DMFD-
MA (1.93 g, 16.2 mmol), and anhyd toluene (40 mL) was refluxed
for 6 h. The mixture was cooled and filtered to remove small
amounts of the starting amine. After evaporation of the toluene so-
lution, the crude product was purified by column chromatography
(CH2Cl2–MeOH, 4:1) to give yellow crystals. Yield: 3.63 g (71%);
mp 134 °C.
Pharmacological Basis of Therapeutics, 8th ed.; Gilman, A.
G.; Rall, T. W.; Nies, A. S.; Taylor, P., Eds.; McGraw-Hill:
New York, 1990, 221–383.
IR (KBr): 3360, 3350, 1720, 1675 cm–1.
(4) Kokel, B. J. Heterocycl. Chem. 1994, 31, 1185.
(5) Sayed Ahmed, A. F. J. Chem. Res., Synop. 1998, 697.
(6) Kokel, B. Tetrahedron Lett. 1996, 37, 3849.
(7) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.;
Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2
1987, S1.
(8) Cousson, A. Acta Crystallogr., Sect. C 1992, 48, 74.
(9) Walsh, E. B.; Wamhoff, H. Chem. Ber. 1989, 1673.
(10) Walsh, E. B.; Nai-Jue, Z.; Fang, G.; Wamhoff, H.
Tetrahedron Lett. 1988, 29, 1673.
1H NMR (300 MHz, DMSO-d6): d = 10.62 (br s, 1 H, NH), 7.93 (s,
1 H, N=CH), 7.23 (t, J = 7.5 Hz, 2 H, H-3¢, H-5¢), 6.89 (t, J = 7.5
Hz, 1 H, H-4¢), 6.82 (d, J = 7.5 Hz, 2 H, H-2¢, H-6¢), 5.20 (br s, 1 H,
OH), 4.97 (s, 1 H, H-5), 4.14–4.08 (m, 1 H, CH), 4.05–4.01 (m, 2
H, CH2), 3.87–3.81 (m, 2 H, CH2), 3.02 (s, 3 H, NCH3), 2.93 (s, 3
H, NCH3).
13C NMR (75 MHz, DMSO-d6): d = 163.2, 158.5, 157.1, 156.4,
152.0, 129.4, 120.4, 114.3, 76.8, 70.2, 66.7, 47.3, 40.7, 34.4.
Anal. Calcd for C16H20N4O4: C, 57.82; H, 6.06; N, 16.86. Found: C,
57.69; H, 5.98; N, 16.92.
(11) Parsch, U.; Engels, J. W. Chem. Eur. J. 2000, 6, 1409.
(12) Yoneda, F.; Nagamatsu, T. J. Am. Chem. Soc. 1974, 96,
5607.
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Related 6-Amino- and 5,6-Diaminouracils: Efficient Access to Bicyclic Pyrimidine Derivatives
2197
(13) Yoneda, F.; Higuchi, M.; Matsumoto, S. J. Chem. Soc.,
Perkin Trans. 1 1977, 1754.
(14) Holschbach, M. H.; Bier, D.; Stüsgen, S.; Wutz, W.; Sihver,
W.; Coenen, H. H.; Olsson, R. A. Eur. J. Med. Chem. 2006,
41, 7.
(15) North, A. C. T.; Phillips, D. C.; Mathews, F. S. Acta
Crystallogr., Sect. A 1968, 24, 351.
(17) Sheldrick, G. M. SHELX 97 Program for the refinement of
crystal structures; University of Göttingen, Germany, 1997.
(18) The supplementary X-ray crystallographic data of
compound 5 (CCDC-612139) can be obtained from
Cambridge Crystallographic Data Centre, University
Chemical Lab, 12 Union Road, Cambridge CB2 1EZ, UK;
e-mail: deposit@ccdc.cam.ac.uk.
(16) Sheldrick, G. M.; Kröger, C.; Goddard, R. SHELX 86 in
Crystallographic Computing 3; Oxford University Press:
New York, 1985, 175–189.
Synthesis 2007, No. 14, 2193–2197 © Thieme Stuttgart · New York