Synthesis and characterization of novel cycloalkanespiro-5-hydantoin phosphonic acids

Article abstract of DOI:10.1080/10426501003751254

A series of new cycloalkanespiro-5-hydantoin phosphonic acids have been synthesized and characterized. The mixture of [(2,4-dioxo-1,3-diazaspiro-alkane- 3-yl)-methyl]phosphonic acids and [(2,4-dioxo-1,3-diazaspiro-alkane-1,3-diyl) dimethyl]diphospho-nic acids was obtained from cycloalkanespiro-5-hydantoins, formaldehyde, and phosphorus trichloride in a molar ratio of 1:2:2, by a procedure modified by us. Their structures were proved by means of IR, 1H, 13C{1H} and 31P NMR spectroscopy. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003751254

This article was downloaded by: [Pennsylvania State University]
On: 19 May 2013, At: 01:05
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis and Characterization of
Novel Cycloalkanespiro-5-Hydantoin
Phosphonic Acids
a
a
b
Emilia D. Naydenova , Petar T. Todorov & Kolio D. Troev
a
University of Chemical Technology and Metallurgy, Department of
Organic Chemistry, Sofia, Bulgaria
b
Institute of Polymers, Bulgarian Academy of Sciences, Sofia,
Bulgaria
Published online: 02 Jul 2010.
To cite this article: Emilia D. Naydenova , Petar T. Todorov & Kolio D. Troev (2010): Synthesis and
Characterization of Novel Cycloalkanespiro-5-Hydantoin Phosphonic Acids, Phosphorus, Sulfur, and
Silicon and the Related Elements, 185:7, 1315-1320
To link to this article: http://dx.doi.org/10.1080/10426501003751254
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 185:1315–1320, 2010
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003751254
SYNTHESIS AND CHARACTERIZATION OF NOVEL
CYCLOALKANESPIRO-5-HYDANTOIN PHOSPHONIC
ACIDS
1
1
2
Emilia D. Naydenova, Petar T. Todorov, and Kolio D. Troev
1
University of Chemical Technology and Metallurgy, Department of Organic
Chemistry, Sofia, Bulgaria
2
Institute of Polymers, Bulgarian Academy of Sciences, Sofia, Bulgaria
A series of new cycloalkanespiro-5-hydantoin phosphonic acids have been synthesized and
characterized. The mixture of [(2,4-dioxo-1,3-diazaspiro-alkane-3-yl)-methyl]phosphonic
acids and [(2,4-dioxo-1,3-diazaspiro-alkane-1,3-diyl)dimethyl]diphospho-nic acids was ob-
tained from cycloalkanespiro-5-hydantoins, formaldehyde, and phosphorus trichloride in a
molar ratio of 1:2:2, by a procedure modified by us. Their structures were proved by means
1
13
1
31
of IR, H, C{ H} and P NMR spectroscopy.
Keywords α-Aminophosphonic acids; cycloalkanespiro-5-hydantoins; phosphorus trichloride
INTRODUCTION
α-Aminophosphonic acids are structurally analogous to aminocarboxylic acids. The
structures of aminophosphonic acids are of interest because of the biological role of
their derivatives. These compounds possess a variety of biological activities, including
anticancer, antiviral, antibacterial, antifungal, and other activities. The established an-
tiproliferative effects, together with the low mammalian toxicity of these agents, has
conditioned tremendous interest towards designing novel antineoplastic agents.1 Syn-
thesis of aminophosphonic acids is an active area of research, and many methods are
now available.7 Novel α-aminophosphonic acids with moderate clastogenic effect were
synthesized reacting 1,3-oxazolidin-2-one derivatives with formaldehyde and phosphorus
–6
–12
1
3, 14
trichloride.
Cyclic or heterocyclic rings, introduced into the molecular skeleton, in-
crease its rigidity and modify the electronic effects. Thus in recent years, many cyclic
15
α-aminophosphonic acids or aminophosphonates have been prepared. A series of α,α-
disubstituted cyclic derivatives of N-(phosphonomethyl)glycine were obtained from cy-
cloalkaneaminocarboxylic acids, and their biological activity was studied.16
Hydantoin derivatives are synthetically valuable, e.g., as precursors to α-amino acid
and pyruvic acid derivatives.1
7–19
Hydantoins, substituted at C-5, are important medicinal
Received 14 July 2008; accepted 5 March 2010.
We gratefully acknowledge the financial support by the University of Chemical Technology and
Metallurgy–contract No. 10507.
Address correspondence to Prof. Dr. Kolio D. Troev, Institute of Polymers, Bulgarian Academy of Sciences,
Sofia 1113, Bulgaria. E-mail: ktroev@polymer.bas.bg
1
315

1
316
E. D. NAYDENOVA ET AL.
compounds. Numerous applications have been found for hydantoin derivatives due to their
2
0
21
22
antidepressant and antiviral activities, the inhibition of binding of HIV to lymphocytes,
23
as well as their anticonvulsant and cardiac antiarrhythmic effects. Taking into account
this fact, we describe in this article the synthesis of novel α-aminophosphonic acids with
potential biological activity by reacting phosphorus trichloride with formaldehyde and
cycloalkanespiro-5-hydantoins.
RESULTS AND DISCUSSION
In our present studies, we used the modified procedure described by Engelmann and
24
Pikl, according to which phosphorus trichloride, formaldehyde, and oxazolidinone deriva-
tives are used as the starting compounds for the preparation of the aminophosphonic acids.
The new α-aminophosphonic acids were obtained from cycloalkanespiro-5-hydantoins,
formaldehyde, and phosphorus trichloride as shown in Scheme 1. Cycloalkanespiro-5-
O
O
OH
OH
N
CH
2
P
2
(CH )n
HN
O
2
O
NH
O
(
66 %)
KCN + (NH
4
)
2
CO
3
3
1. HCHO + CH COOH
(
CH
2
)n
O
2
(CH )n
+
NH OH + C
4
2
H
5
OH
HN
2. PCI
. H
3
O
P
3
2
0
a n = 0
b n = 1
c n = 2
O
OH
OH
N
CH2
1
2
(CH )n
d n = 3
N
O
OH
OH
CH
2
P
O
3
(
33 %)
Scheme 1
hydantoins 1a–1d, phosphorus trichloride, and formaldehyde were used as starting com-
pounds in a molar ratio of 1:2:2. The compounds 1a–1d were prepared by the Bucherer–Lieb
25
reaction. The rate of hydroxymethylation of the two nitrogen atoms is different. Hydrox-
ymethylation at the N-3 atom proceeds faster because of the higher acidity of the NH-bond
compared to that of the N-1 atom.26 In the P NMR spectrum of the reaction product, two
31
2
signals are observed at 20.6 ppm (triplet with JPH = 13.5 Hz) and at 18.1 ppm (triplet with
2
JPH = 11.0 Hz). The signal at 20.6 ppm can be assigned to the phosphorus atom of the
fragment connected to N-3, and that at 18.1 ppm to the phosphorus atom of the fragment
connected to N-1. The intensity ratio of 2:1 confirms the difference in the reactivity of the
two NH-groups in the cycloalkanespiro-5-hydantoins (see Table I).
Unfortunately, the new synthesized compounds could not be separated. The formation
of [(2,4-dioxo-1,3-diazaspiro-alkane-3-yl)methyl]phosphonic acids 2a–2d and [(2,4-dioxo-
1
1
,3-diazaspiro-alkane-1,3-diyl)dimethyl]diphosphonic acids 3a–3d was confirmed by H,
C{ H}, P NMR, and IR spectroscopy.
1
3
1
31

CYCLOALKANESPIRO-5-HYDANTOIN PHOSPHONIC ACIDS
1317
Table I 31P NMR data of the new cycloalkanespiro-5-hydantoin phosphonic acids 2 and 3
31
2
δ
P (ppm) / JPH (Hz)
2
3
2
3
2
3
2
3
a
a
b
b
c
c
d
d
20.6 (t) / 13.5
18.1 (t) / 11.0
19.4 (t) / 15.0
15.5 (t) / 12.0
20.0 (t) / 11.6
17.0 (t) / 12.2
21.1 (t) / 14.5
17.6 (t) / 12.0
1
2
In the H NMR spectra of all compounds 3a–3d, doublets with a characteristic JPH
coupling constant of 11–15 Hz are observed for the P CH2 protons. Direct evidence
for the formation of the P–C bond in the P–CH2 fragment is the doublets that appear in
13
1
1
the C{ H} NMR spectra of all compounds 3a–3d with a characteristic JPC coupling
31
constant of 154–156 Hz (see the Experimental section). In the P NMR spectrum of the
reaction mixture, an additional signal appears at 22 to 23 ppm, which is characteristic of a
phosphonic structure. Further studies to elucidate the structure of these products and their
formation are in progress.
CONCLUSION
In this article, the synthesis and characterization of new [(2,4-dioxo-1,3-
diazaspiro-alkane-3-yl)methyl]phosphonic acids and [(2,4-dioxo-1,3-diazaspiro-alkane-
1,3-diyl)dimethyl] diphosphonic acids, prepared by reacting cycloalkanespiro-5-hydantoins
with formaldehyde and phosphorus trichloride, is described.
EXPERIMENTAL
Instruments and Reagents
Cycloalkanones, phosphorus trichloride, paraformaldehyde, and the solvents were
purchased from Fluka and Merck, and were used without further purification.
The infrared (IR) spectra were recorded in KBr pellets with a Perkin-Elmer Model
1600 Series FT-IR instrument. Melting points (mp) were determined on a Koffler micro-
scope and were uncorrected. The purity of the products was checked by TLC on precoated
plates of silica gel 60 F254 (Merck) using as the mobile phase a 3:1:1 mixture of n-BuOH,
AcOH, and H2O. Spots on TLS chromatograms were detected by chlorine/o-tolidine reac-
1
13
31
tion. The H, C, and P NMR spectra were obtained with a Bruker DRX 400 spectrometer
13
1
at 400.13, 100.61, and 161.97 MHz, respectively. C NMR spectra were fully H decou-
pled. Chemical shifts are reported in δ values (ppm), and J values are reported in hertz
(Hz).
The compounds 1a–1d were prepared by the Bucherer–Lieb reaction.25,27
Preparation of Cycloalkanespiro-5-hydantoins (1a–1d)
by Bucherer–Lieb Synthesis
To a solution of the cycloalkanone (0.0594 mol) in ethanol (55 mL) and water
(50 mL), sodium cyanide (6.63 g, 0.1 mol) and ammonium carbonate (34.6 g, 0.36 mol) were

1
318
E. D. NAYDENOVA ET AL.
added. The mixture was refluxed for 6 h with stirring. After dilution with water, the cooled
mixture was acidified with concentrated hydrochloric acid. The crude cycloalkanespiro-5-
◦
hydantoin precipitated overnight upon cooling at 5 C. The pure compound was crystallized
from water as colorless crystals.
1
,3-Diazaspiro[4.4]nonane-2,4-dione (1a). Yield 96.0% (8.79 g), Rf = 0.74,
◦
−1
3 1 2
mp = 204–205 C; IR (KBr, cm ): 3215 ( N H), 3074 ( N H), 1788 ( C O), 1737
4
1
6
(
C O). H NMR (d -DMSO): δ = 1.8–2.1 (m, 8H, CH2), 7.3 (s, 1H, NH), 10.4 (s, 1H,
13 1 6
NH). C{ H} NMR (d -DMSO): δ = 23.8 (C-3,4), 35.8 (C-2,5), 69.9 ( C ), 157.4
-C O, 168.9 4-C O.
,3-Diazaspiro[4.5]decane-2,4-dione (1b). Yield 88.2% (8.81 g), Rf = 0.87,
2
1
◦
4
−1
3
1
mp = 219–220 C; IR (KBr, cm ): 3198 ( N H), 3070 ( N H), 2951–2858 (C H), 1775
2
1
6
(
C O), 1727 ( C O). H NMR (d -DMSO): δ = 1.6–1.9 (m, 10H, CH2), 8.2 (s, 1H, NH),
1 6
1
6
0.3 (s, 1H, NH). 13C{ H} NMR (d -DMSO): δ = 23.1 (C-3,5), 25.4 (C-4), 36.0 (C-2,6),
8.7 ( C ), 157.0 2-C O, 167.7 4-C O.
1
,3-Diazaspiro[4.6]undecane-2,4-dione (1c). Yield 76.2% (8.23 g), Rf = 0.87,
◦
−1
3 1
mp = 213–215 C; IR (KBr, cm ): 3282 ( N H), 3055 ( N H), 2941–2852 (C H), 2347
2
4
1
6
(
(
3
NH), 1770 ( C O), 1709 ( C O). H NMR (d -DMSO): δ = 1.5–1.8 (m, 12H, CH2), 8.2
s, 1H, NH), 10.4 (s, 1H, NH). 13C{ H} NMR (d -DMSO): δ = 21.9 (C-3,6), 26.8 (C-4,5),
1 6
5.9 (C-2,7), 66.7 ( C ), 157.3 2-C O, 172.7 4-C O.
1
,3-Diazaspiro[4.7]dodecane-2,4-dione (1d). Yield 91.0% (10.59 g), Rf =
◦
−1
3 1 2
0
1
(
(
.79, mp = 240–241 C; IR (KBr, cm ): 3250 ( N H), 3183 ( N H), 1765 ( C O),
4 1 6
713 ( C O). H NMR (d -DMSO): δ = 1.5–2.1 (m, 14H, CH2), 8.2 (s, 1H, NH),10.4
13
1
6
s, 1H, NH). C{ H} NMR (d -DMSO): δ = 20.0 (C-3,7), 24.2 (C-5), 26.8 (C-4,6), 38.1
C-2,8), 68.0 ( C ), 158.1 2-C O, 176.0 4-C O.
Preparation of [(2,4-Dioxo-1,3-diazaspiro-alkane-3-yl)methyl]-
phosphonic Acids (2a–2d), [(2,4-Dioxo-1,3-diazaspiro-alkane-1,3-diyl)
dimethyl]diphosphonic Acids (3a–3d) in Ratio of 2:1: General Procedure
The respective cycloalkanespiro-5-hydantoins (0.0059 mol) and paraformaldehyde
(0.36 g, 0.0119 mol) were placed under argon in a four-necked round-bottomed flask
equipped with a magnetic stirrer, reflux condenser, thermometer, dropping funnel, and
argon inert. Under vigorous stirring glacial acetic acid (5.95 mL) was added dropwise. A
◦
white suspension formed. The reaction mixture was refluxed (∼115 C) for 12.5 h, after
◦
which it became a clear solution. Then the temperature was lowered to 20 C and 1.04 mL
(
1.63 g, 0.0119 mol) of phosphorus trichloride was added dropwise. During and after the
◦
addition hydrogen chloride evolved. The reaction mixture was refluxed (∼118 C) for 6 h.
Subsequently 6.80 mL of distilled water was added. After 4 h further refluxing, the reaction
mixture was concentrated under reduced pressure.
The solvent was evaporated, and the product left was dissolved in a large excess of
methanol. After filtration, the filtrate was evaporated to give a residue, which was purified
by precipitation in methanol/ethyl acetate and collected by filtration. The purification step
was repeated several times to give compounds (2a–2d and 3a–3d).
[(2,4-Dioxo-1,3-diazaspiro[4.4]nonane-3-yl)methyl]phosphonic Acid (2a),
[
(
(
(
(2,4-Dioxo-1,3-diazaspiro[4.4]nonane-1,3-diyl)dimethyl]diphosphonic Acid
−1
3a). Yellow oil, yield 45.0% (0.66 g), Rf = 0.45; IR (KBr, cm ): 3424 (OH), 2942–2854
2
4
1
C H), 1730 ( C O), 1708 ( C O), 1156 (P O), 1114, 1012 (P O H). H NMR
2
400.13 MHz, CD3OD): δ = 1.1—1.9 (m, 8H, CH2), 3.2 (d, JPH = 11.5 Hz, 2H, P CH2),

CYCLOALKANESPIRO-5-HYDANTOIN PHOSPHONIC ACIDS
1319
2
3
.3 (d, JPH = 10.0 Hz, 2H, P CH2), 5.6 (br.s., 2H, P OH), 8.2 (br.s., 2H, P OH).
1
3
1
C{ H} NMR (100.61 MHz, CD3OD): δ = 21.5 (CH2), 24.2 (CH2), 25.2 (CH2), 34.5
1
1
(
(
2
d, JPC = 149.6 Hz, P CH2), 59.0 (d, JPC = 154.1 Hz, P CH2), 63.4 (–C ), 156.4
31 2
2-C O), 177.7 (4-C O). P NMR (161.97 MHz, CD3OD): = 18.1 (t, JPH = 11.0 Hz),
2
0.6 (t, JPH = 13.5 Hz) intensity integral ratio of 2:1.
[
(2,4-Dioxo-1,3-diazaspiro[4.5]decane -3-yl)methyl]phosphonic Acid (2b),
[
(
(
(2,4-Dioxo-1,3-diazaspiro[4.5]decane-1,3-diyl)dimethyl]diphosphonic Acid
−1
3b). Yellow oil, yield 48.0% (0.74 g), Rf = 0.41; IR (KBr, cm ): 3397 (OH), 2942–2854
2
4
1
C H), 1740 ( C O), 1713 ( C O), 1150 (P O), 1036, 914 (P O H). H NMR (400.13
2
MHz, CD3OD): δ = 1.5—2.1 (m, 10H, CH2), 3.5 (d, JPH = 11.0 Hz, 2H, P CH2), 3.8
2
13
1
(
d, JPH = 9.0 Hz, 2H, P CH2), 5.7 (br.s., 2H, P OH), 8.1 (br.s., 2H, P OH). C{ H}
1
NMR (100.61 MHz, CD3OD): δ = 21.0 (C-4), 22.0 (C-3,5), 26.0 (C-2,6), 38.5 (d, JPC
1
=
150.5 Hz, P CH2), 60.0 (d, JPC = 156.6 Hz, P CH2), 68.0 (–C ), 156.7 (2-C O),
76.7 (4-C O). 31P NMR (161.97 MHz, CD3OD): δ = 15.5 (t, JPH = 12.0 Hz), 19.4 (t,
2
1
2
JPH = 15.0 Hz) intensity integral ratio of 2:1.
[(2,4-Dioxo-1,3-diazaspiro[4.6]undecane-3-yl)methyl]phosphonic Acid
(
2c), [(2,4-Dioxo-1,3-diazaspiro[4.6]undecane-1,3-diyl)dimethyl]diphosphonic
−1
Acid (3c). Yellow oil, yield 42.0% (0.68 g), Rf = 0.43; IR (KBr, cm ): 3348 (OH),
2
4
1
2
955–2859 (C H), 1745 ( C O), 1710 ( C O), 1171 (P O), 1013, 965 (P O H). H
2
NMR (400.13 MHz, CD3OD): δ = 1.2—1.9 (m, 12H, CH2), 3.3 (d, JPH = 12.0 Hz, 2H,
2
P CH2), 3.5 (d, JPH = 11.0 Hz, 2H, P CH2), 5.2 (br.s., 2H, P OH), 8.4 (br.s., 2H,
13
1
P OH). C{ H} NMR (100.61 MHz, CD3OD): δ = 20.0 (CH2), 24.9 (CH2), 26.0 (CH2),
1
1
3
4.0 (CH2), 37.0 (d, JPC = 156.6 Hz, P CH2), 57.6 (d, JPC = 152.1 Hz, P CH2), 61.0
31
(
–C ), 159.7 (2-C O), 176.0 (4-C O). P NMR (161.97 MHz, CD3OD): δ = 17.0 (t,
2
2
JPH = 12.2 Hz), 20.0 (t, JPH = 11.6 Hz) intensity integral ratio of 2:1.
[
(2,4-Dioxo-1,3-diazaspiro[4.7]dodecane-3-yl)methyl]phosphonic Acid
(
2d), [(2,4-Dioxo-1,3-diazaspiro[4.7]dodecane-1,3-diyl)dimethyl]diphosphonic
−1
Acid (3d). Yellow oil, yield 45.8% (0.79 g), Rf = 0.47; IR (KBr, cm ): 3261 (OH),
2
4
1
2
925–2855 (C H), 1765 ( C O), 1710 ( C O), 1180 (P O), 1012, 969 (P O H). H
2
NMR (400.13 MHz, CD3OD): δ = 1.1—1.9 (m, 8H, CH2), 3.2 (d, JPH = 11.5 Hz, 2H,
2
P CH2), 3.3 (d, JPH = 10.0 Hz, 2H, P CH2), 5.8 (br.s., 2H, P OH), 8.0 (br.s., 2H,
13
1
P OH). C{ H} NMR (100.61 MHz, CD3OD): δ = 21.8 (C-5), 24.4 (C-4,6), 27.7 (C-
1
1
3
6
(
,7), 33.0 (C-2,8), 38.5 (d, JPC = 153.2 Hz, P CH2), 58.7 (d, JPC = 155.5 Hz, P CH2),
4.6 (–C ), 155.9 (2-C O), 178.9 (4-C O). P NMR (161.97 MHz, CD3OD): δ = 17.6
31
2
2
t, JPH = 12.0 Hz), 21.1 (t, JPH = 14.5 Hz) intensity integral ratio of 2:1.
REFERENCES
1
. (a) K. D. Troev, Chemistry and Application of H-Phosphonates (Elsevier, Amsterdam 2006);
b) P. Kafarski and B. Lejczak, Aminophosphonic and Aminophosphinic Acids: Chemistry and
(
Biological Activity (Wiley, New York, 2000), p. 407.
2
. E. W. Logusch, D. M. Walker, J. F. McDonald, J. E. Franz, J. J. Villafranca, C. L. Dilanni, J. A.
Colanduoni, B. Li, and J. B. Shineller, Biochemistry, 29, 366 (1990).
3
4
5
6
. T. D. Meek and J. J. Villiafranca, Biochemistry, 19, 5513 (1980).
. J. Oleksyszyn, B. Boduszek, Ch. M. Kam, and J. C. Powers, J. Med. Chem., 37, 226 (1994).
. W. W. Smith and P. A. Bartlett, J. Am. Chem. Soc., 120, 4622 (1998) and references cited therein.
. J. W. Goding, Monoclonal Antibodies: Principles and Practice (Academic Press, New York,
1
986).

1
320
E. D. NAYDENOVA ET AL.
7
8
9
. M. Kabachnik and T. Medved, Dokl. Acad. Nauk SSSR, 83, 689 (1952).
. E. K. Fields, J. Am. Chem. Soc., 74, 1528 (1952).
. I. A. Natchev, Liebigs. Ann. Chem., 9, 861 (1988).
1
0. (a) K. Troev, Phosphorus, Sulfur, and Silicon, 127, 167 (1997) (b) K. Troev, Sh. Cremer, and G.
Haegele, Heteroatom Chem., 10, 627 (1999) (c) E. Naydenova, K. Troev, M. Topashka-Ancheva,
G. Haegele, I. Ivanov, and A. Kril, Amino Acids, 33, 695 (2007).
1
1
1
1. P. P. Giannousis and P. A. Bartlett, J. Med. Chem., 30, 1603 (1987).
2. J. Huang and R. Chen, Heteroatom Chem., 11, 480 (2000).
3. E. Naydenova, M. Topashka-Ancheva, P. Todorov, Ts. Yordanova, and K. Troev, Bioorg. Med.
Chem., 14, 2190 (2006).
1
1
1
1
4. P. Todorov, E. Naydenova, R. Petrova, B. Shivachev, and K. Troev, Acta Crystallogr. Sect. C,
62, o661 (2006).
5. (a) N. Rabasso, N. Louaisil, and A. Fadel, Tetrahedron, 62, 7445 (2006) (b) N. Louaisil, N.
Rabasso, and A. Fadel, Synthesis, 289 (2007).
6. E. Naydenova, P. Todorov, M. Topashka-Ancheva, G. Momekov, Ts. Yordanova, S. Konstantinov,
and K. Troev, Eur. J. Med. Chem., 43, 1199 (2008).
7. N. A. Meanwell, H. R. Roth, E. C. R. Smith, D. L. Wedding, and J. J. K. Wright, J. Org. Chem.,
56, 6897 (1991).
18. R. Sarges and P. J. Oates, Prog. Drug. Res., 40, 99 (1993).
1
9. P. Barraclough, M. L. Bolofo, H. Giles, J. Gillam, C. J. Harris, M. G. Kelly, P. Leff, A. McNeill,
A. D. Robertson, R. J. Stepney, and B. J. R. Whittle, Bioorg. Med. Chem., 4, 81 (1996).
0. F. L. Wessels, T. J. Schawn, and S. F. Pong, J. Pharm. Sci., 69, 1102 (1980).
1. A. A. El-Barbarly, A. I. Khodair, E. B. Pedersen, and C. Nielsen, J. Med. Chem., 37, 73 (1994).
2. W. M. Cloyd, S. W. Lynn, K. Ramsey, and S. Baron, Virology, 173, 581 (1989).
3. M. L. Brown, G. B. Brown, and W. J. Brouillette, J. Med. Chem., 40, 602 (1997).
4. (a) M. Engelmann and J. Pikl, U.S. Pat. 2,304,156 (1942); (b) J. Pikl, U.S. Pat. 2,328,358 (1943).
5. H. Bucherer and V. Lieb, J. Prakt. Chem., 141, 5 (1934).
2
2
2
2
2
2
2
6. (a) J. Rubido, C. Pedregal, M. Espada, and J. Elguero, Synthesis, 3, 307 (1985) (b) E. Ware,
Chem. Reviews, 46, 403 (1950).
27. E. Naydenova, N. Pencheva, J. Popova, N. Stoyanov, M. Lazarova, and B. Aleksiev, Il Farmaco,
57, 189 (2002).