An efficient synthesis of thioisomunchnones derived from uracils and uridine: Novel type of mesoionic nucleosides

Article abstract of DOI:10.1021/ol990385u

equation presented Synthetic approaches to a variety of thioisomUnchnones derived from uracils and uridine are described, as well as their properties and cycloaddition tendencies. The anhydro-3-hydrocy-2-phenyl-6-(2′,3′,5′-tri-O-benzoyl-β-D- ribofuranosyl)thiazolo[3,2-c]pyrimidine-5(6H)-on-4-ium hydroxide represents a novel class of mesoionic nucleosides.

Full text of DOI:10.1021/ol990385u

ORGANIC
LETTERS
2000
Vol. 2, No. 5
581-584
An Efficient Synthesis of
Thioisomu1nchnones Derived from
Uracils and Uridine: Novel Type of
Mesoionic Nucleosides1
,†
Heinrich Wamhoff,* Christof Ho1hmann,† and Pa´l Soha´r‡
Kekule´-Institut fu¨r Organische Chemie und Biochemie, UniVersita¨t Bonn,
Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany, and Institute of Inorganic and
General Chemistry, Eo¨tVo¨s-Lora´nd UniVersity, Pa´zma´ny se´tany 2,
H-1117 Budapest, Hungary
wamhoff@uni-bonn.de
Received December 6, 1999
ABSTRACT
Synthetic approaches to a variety of thioisomu1nchnones derived from uracils and uridine are described, as well as their properties and
cycloaddition tendencies. The anhydro-3-hydrocy-2-phenyl-6-(2′,3′,5′-tri-O-benzoyl-â-D-ribofuranosyl)thiazolo[3,2-c]pyrimidine-5(6H)-on-4-ium
hydroxide represents a novel class of mesoionic nucleosides.
In 1951 Duffin and Kendall2 postulated for the first time a
mesoionic thioisomu¨nchnone structure for the product formed
from S-(2-pyridyl)thioglycolic acid and acetanhydride.3
Recently, several derivatives of thiosiomu¨nchnone, or an-
hydro-4-hydroxy-1,3-thiazolium hydroxide, structure 1 (Fig-
ure 1), have been prepared.4
R represents an aryl residue which is needed for
stabilization.
As thioisomu¨nchnones based upon uracils5 are unknown
in the literature hitherto, we report here a short and efficient
synthesis of this novel class of compounds. In the first step,
the uracil derivatives were smoothly transformed with the
aid of Lawesson’s reagent into the 4-thioxo derivatives 4.6
Upon treatment with DL-R-bromoarylacetyl chloride 5 under
mild conditions, these thiouracils are converted to afford the
(1) Reactions of Uracils, 25. For part 24, see: Wamhoff, H.; Sattler, C.;
Soha´r, P.; Rohonczy, J. Synth. Commun. 1999, 29, 3919-3937.
(2) Duffin, G. F.; Kendall, J. D. J. Chem. Soc. 1951, 734-739.
(3) Koenigs, E.; Geisler, H. Ber. Dtsch. Chem. Ges. 1924, 57, 2076-
2079. Tschitschibabin, A. E.; Woroshtzov, N. N. Ber. Dtsch. Chem. Ges.
1933, 66, 364-372. Earl, J. C.; Mackney, A. W. J. Chem. Soc. 1935, 899-
900.
Figure 1. Some thioisomu¨nchnones.
(4) Padwa, A.; Harring, S. R.; Hertzog, D. L.; Nadler, W. R. Synthesis
1994, 993-1004. Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis
1994, 123-141.
Thiazolo[3,2-a]- (2) and thiazolo[3,2-c]pyrimidines (3)
represent condensed mesoionic systems.5 In most cases,
(5) Review: Wamhoff, H.; Dzenis, J.; Hirota, K. AdV. Heterocycl. Chem.
1992, 55, 129-259.
† Universita¨t Bonn.
(6) Kaneko, K.; Katayama, H.; Wakabayashi, T.; Kumonaka, T. Synthesis
1988, 152-154.
‡ Eo¨tvo¨s-Lora´nd University.
10.1021/ol990385u CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/11/2000

anhydro-2-aryl-3-hydroxythiazolo[3,2-c]pyrimidin-5(6H)-on-
4-ium hydroxides 6 in moderate to good yields (21-83%)
(Scheme 1).7 Suprisingly, this synthesis was not transferable
to the isomeric 2-thiouracils.
Although in the literature the term “mesoionic nucleosides”
has been used for several years,10 compounds 10 and 11
shown in Scheme 3 represent zwitterionic or betainic
nucleosides according to the definition of Ollis and Rams-
den,11 where the term “mesoionic” is reserved for five-
membered heterocycles and anhydro-5-(dimethylamino)-3-
mercapto-4-methyl-1-â-D-ribofuranosyl-1,2,4-triazolium
hydroxide 12 described by Yokoyama et al.12 is the only
real mesoionic nucleoside known hitherto (Figure 2).
Scheme 1
This transformation could be easily transferred to uridine,
after protection of the sugar moiety 7 and thionation with
P4S10 in pyridine8 in 91-98% yield (Scheme 2). 9 represents
Figure 2.
While uracils are known to possess a weak solubility in
common solvents generally (therefore 1,3-dialkylated deriva-
tives serve as model compounds),5 the thioisomu¨nchnones
derived from uracils show a similar behavior; the solubility
can be effectively improved by substitution of the remaining
lactamic NH by a methyl substituent or by a sugar moiety
(Figure 3).
Scheme 2
Figure 3. Substituent dependency of the solubility.
the first nucleosidic thioisomu¨nchnones, derived from uri-
dine, a novel class of mesoionic nucleosides that have been
characterized by spectroscopic methods, especially FAB-MS
and MALDI-TOF.9
The thioisomu¨nchnones 6 and 9 obtained form intense
colored solids and exhibit typical and characteristic negative
solvatochromism.13 As shown in Table 1, the N-methylated
mesoionic thiazolo[3,2-c]pyrimidine 6b exhibits in its UV-
vis spectrum the highest UV shift, ∆ λmax ) 92 nm, for the
(7) Representative Procedure. anhydro-3-Hydroxy-8-methyl-2-phe-
nylthiazolo[3,2-c]pyrimidine-5(6H)-on-4-ium hydroxide 6 (R1 ) H, R2 )
Me, R3 ) H). To a suspension of 4-thiothymine (4 mmol, 510 mg) in
absolute CHCl3 (10 mL) is added dropwise a solution of acid chloride 5
(930 mg, 4 mmol) in absolute CHCl3 (4 mmol). The mixture is stirred for
15 min; then absolute NEt3 (1.12 mL, 8 mmol) is slowly added. The color
of the suspension changes significantly from yellow-orange to deep violet
in a slightly exothermic reaction. After the solution is stirred for an additional
3-4 h at ambient temperature, the precipitate is filtered off, washed with
CHCl3, dissolved in TFA, and precipitated again with H2O. The product is
stirred for 10 min in boiling H2O and filterd hot, and the thioisomu¨nchnone
is washed with EtOH and ether and dried finally at 50 °C in vacuo. Yield:
650 mg (63%) of a ruby-red amorphous solid, mp 246-249 °C; FTIR (KBr)
3046, 2875, 1765, 1622, 1577, 1368, 1230, 1169 cm-1; UV (MeCN) λ
(log ꢀ) ) 503 (3.21), 404 (3.42), 301 (3.37); 1H NMR (250.13 MHz, TFA-
d) δ 2.46 (s, 3H), 7.54-7.57 (m, 3H), 7.76-7.80 (m, 3H); 13C NMR (100.62
MHz, TFA-d) δ 13.99, 112.49, 114.65, 127.63, 128.78, 131.37, 132.27,
137.23, 148.26, 150.59, 161.40; MS (EI, 70 eV) m/z (rel intensity) 258.0
(M+, 54%); HR-MS calcd for C13H10N2O2S 258.0463, found 258.0468.
Anal. Calcd for C13H10N2O2S: C, 60.45; H, 3.90; N, 10.85; S, 12.41.
Found: C, 60.06; H, 3.88; N, 10.86; S, 12.38.
(8) Fox, J. J.; Van Praag, D.; Wempen, I.; Doerr, I. L.; Cheong, L.; Knoll,
J. E.; Eidinoff, M. L.; Bendick, A.; Brown, G. B. J. Am. Chem. Soc. 1959,
81, 178-187.
(9) Representative Procedure. anhydro-3-Hydroxy-2-phenyl-6-(2′,3′,5′-
tri-O-benzoyl-â-D-ribofuranosyl)thiazolo[3,2-c]pyrimidine-5(6H)-on-4-
ium hydroxide 9 (R ) H). To a solution of 1-(2′,3′,5′-tri-O-benzoyl-â-D-
ribofuranosyl)-4-thiouracil (2.29 g, 4 mmol) in absolute CHCl3 (10 mL) is
added dropwise a solution of freshly distilled acid chloride 5 (930 mg, 4
582
Org. Lett., Vol. 2, No. 5, 2000

soluble methylated (6b) or glycosylated (9) thioisomu¨nch-
nones with acetylenedicarboxylates (DMAD), after 1,3-
dipolar cycloaddition, the intermediary adducts underwent
a sulfur extrusion reaction to form 1,8-dioxo-2H,8H-pyrido-
[1,2-c]pyrimidinedicarboxylates 14a,b.
Table 1. Dependency of the λmax from the Polarity of the
Solvent
Scheme 3
CT band; these measurements parallel the earlier findings
of Ishchenko14 for a related pyrimidine derivative.
As mesoionic heterocycles of the type A15 contain masked
or latent 1,3-dipole moieties,11 thioisomu¨nchnones may be
considered as latent thiocarbonylylides; Potts et al.16 have
systematically investigated the cycloaddition tendency of
dipolarophiles toward thioisomu¨nchnones and found that
reactive acetylene derivatives can lead in a cycloaddition-
extrusion sequence either to pyrimidones (S-extrusion) or
thiophenes (isocyanate extrusion), directed more by steric
than electronic effects.16 We have found that in reacting
6b had to be heated for 18 h while nucloside 9 was
converted after 70 h of standing at room temperature;
however, the product 14b formed could only be purified with
difficulty.17
Then, we reacted thioisomu¨nchnone 6b with 4-(3′-chloro-
phenyl)-1,2,4-triazoline-3,5-dione 1518 for the first time at
temperatures lower than and up to room temperature (ac-
companied by intense color changes). The colorless com-
pound precipitating from the solution was not the expected
reaction product; MS revealed that subsequent fragmentations
took place.19
mmol) within 10 min, which causes a color change from orange to red.
Then absolute NEt3 (1.12 mL, 8 mmol) is slowly added, while the solution
changes from red to deep violet in a slightly exothermic reaction. The
suspension formed is stirred for 3-4 h at ambient temperature, and the
ammonium salts formed are removed by treatment with a saturated NaHCO3
solution and 2-fold extraction with H2O. After drying (Na2SO4) the solvent
is evaporated and the residue is dried at 50 °C in vacuo: yield 2.70 g (98%)
of a deep violet amorphous solid of mp 106-110 °C; FTIR (KBr) ν 3067,
2967, 1726, 1624, 1593, 1266, 1094 cm-1; UV (MeCN) λ (log ꢀ) ) 529
(4.11), 281 (4.14), 227 (4.86); 1H NMR (400, 13 MHz, DMSO-d6) δ 4.78
(m, 2H), 4.92 (dt, 1H, J ) 7.25, 3.94 Hz), 6.05 (pt, 1H, J ) 6.65 Hz), 6.15
(dd, 1H, J ) 6.15, 3.20 Hz), 6.41 (d, 1H, 2.96 Hz), 7.11 (t, 1H, J ) 7.38
Hz), 7.20(d, 1H, J ) 7.63 Hz), 7.38 (dd, 2 Hz, J ) 8.37, 7.38 Hz), 7.47
(dd, 2H, J ) 8.13, 7.51 Hz), 7.56 (m, 4H), 7.66-7.76 (m, 4H), 7.89 (m,
3H), 7.97 (d, 1H, J ) 7.38 Hz), 8.01 (dd, 2H, J ) 8.36, 1.23 Hz), 8.09 (dd,
2H, J ) 8.36 Hz); 13C NMR (100.62 MHz, CDCl3) δ 63.85, 71.74, 74.28,
80.73, 90.28, 94.31, 101.19, 124.27-133.82, 145.01, 146.75, 156.66,
165.25-166.09; MS (FAB) m/z (rel intensity) 689.1 (M+, 6.5%); MALDI-
TOF Da/e (rel intensity) (688.8 (M+, 100%) 689.8 (M + H+, 41%), 44.59
(M+ - aglycone).
Scheme 4. Suggested Cycloaddition Extrusion Mechanism
(10) Glennon, R. A.; Schubert, E.; Bass, R. G. Tetrahedron Lett. 1981,
22, 2753-2756. Bambury, R. E.; Feeley, D. T.; Lawton, G. C.; Weaver, J.
M.; Wemple, J. J. Chem. Soc., Chem. Commun. 1984, 422-423. Schubert,
E. M.; Schram, K. H.; Glennon, R. A. J. Heterocycl. Chem. 1985, 22, 889-
905.
(11) Ollis, W. D.; Ramsden, C. A. AdV. Heterocycl. Chem. 1976, 19,
1-22. Cf. also: Coburn, R. A. J. Heterocycl. Chem. 1971, 8, 881-887.
Coburn, R. A.; Capellotti, R. A.; Glennon, R. A. J. Heterocycl. Chem. 1973,
10, 479-485. Coburn, R. A.; Glennon, R. A. J. Heterocycl. Chem. 1973,
10, 487-494.
(12) Yokoyama, M.; Ikuma, T.; Obara, N.; H. Togo, H. J. Chem. Soc.,
Perkin Trans. 1 1990, 3243-3247.
(13) Review: Reichardt, C. Chem. Ber. 1994, 94, 2319-2358; Nachr.
Chem. Techn. Lab. 1997, 45, 759-763. Solvatochromism: Hantzsch, A.
Ber. Dtsch. Chem. Ges. 1922, 55, 953-979. Kosover, E. M. J. Am. Chem.
Soc. 1958, 80, 3253-3270. Cf. also some own measurements on pseudocross-
conjugated mesomeric betaines: Wamhoff, H.; Schmidt, A. J. Org. Chem.
1993, 58, 6976-6984.
(14) Ishchenko, A. A.; Kachkovskii, A. D.; Romanov, N. N.; Fedotov,
K. V. Ukr. Khim. Zh. 1985, 51, 987-993 [Chem. Abstr. 1986, 104, 98492a].
(15) Cf. Ramsden, C. A. In ComprehensiVe Organic Chemistry, Vol. 4;
Barton D. H. R., Sammes, P. G., Eds.; Pergamon Press: Oxford, 1979; pp
1171-1228.
(16) Potts, K. T.; Houghton, E.; Singh, K. P. J. Org. Chem. 1974, 39,
3627-3631. Potts, K. T.; Bordeaux, K. G.; Kuehnling, W. R.; Salsbury,
R. L. J. Org. Chem. 1985, 50, 1666-1676.
The molecular formula of 19 derived from the HMQC
(CH-COSY) and HMBC (CH-COLOC) experiments leads
(17) 14b was enriched after 2-fold column chromatography (silica gel;
1
EE/PE 3:2 and 1:1); the H NMR displays all relevant signals, especially
the protons of the sugar moiety, and both the methyl ester groups; MS-
(FAB) m/z 799.1 (M+), 663.3 (M+ - CO), 445.1 (M+ - aglycon). A
complete purification could not be achieved, as each chromatography leads
to a partial decomposition of the product.
Org. Lett., Vol. 2, No. 5, 2000
583

to the unambiguous identification of the methine C and the
Me group as well as single atoms of the pyrimidine and
aromate moieties; further information follows from the
fragmentation pattern in MS and HR-MS.
On the basis of thess data, we suggest the following
cycloaddition-extrusion mechanism: After cycloaddition to
intermediate 16, sulfur is extruded by ring cleavage of the
central triazinone ring to 17 which by moisture loses
“phenylglyoxal” 18 to form the final urazolylpyrimidine 19.
However, a radical attack of the triazolyl radical (via
disproportion reaction always concomitant with the triazo-
linediones)18 could be discussed as well leading to an
alternative fragmentation of the thioisomu¨nchnone ring
(Scheme 4).
(18) Wamhoff, H.; Wald, K.Org. Prep. Proced. Int. 1975, 7, 251-253;
Chem. Ber. 1977, 110, 1699-1715.
(19) Preparation of 19: A suspension of 6b (129 mg, 0.5 mmol) in CH2-
Cl2 (10 mL) is cooled to -30 °C and a solution of 15 (105 mg, 0.5 mmol)
in CH2Cl2 (5 mL) is slowly added, and intense and reversible color changes
are observed. After addition, the reaction mixture is stirred for additional 2
h at -30 °C and for the same time after warming to ambient temperature.
After standing for 2 d in the dark for completion of the reaction, the colorless
precipitated product is filtered off, washed with CH2Cl2, and dried at 50
°C in vacuo to give 73 mg (46%) of 19 as colorless amorphous solid: mp
254 °C (dec); IR (KBr) ν ) 3436, 3134, 3087, 2967, 1779, 1735, 1697,
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie, the BASF Aktiengesellschaft, and
the BAYER AG. We thank the International Bu¨ro of the
DLR for supporting the German-Hungarian Research Project
(BMBF/OMFB Agreement UNGX-234).
OL990385U
1
1651, 1627 cm-1; UV (DMSO) λmax (log ꢀ) ) 350 (4.01), 327 (3.93); H
NMR (500.13 MHz, DMSO-d6) δ ) 3.43 (s, 3H), 7.13 (d, 1H, J ) 7.24
Hz), 7.51 (dpt, 1H, J ) 7.46, 1.80 Hz), 7.54 (dpt, 1H, J ) 8.16, 1.84 Hz),
7.57 (ptd, 1H, J ) 7.52, 0.49 Hz), 7.64 (ptd, 1H, J ) 1.94, 0.51 Hz), 8.20
(d, 1H, J ) 7.58 Hz); 13C NMR (125.76 MHz, DMSO-d6) δ ) 38.50, 93.36,
126.47, 127.60, 129.32, 131.47, 133.19, 133.80, 148.62, 150.29, 152.08,
155.88, 156.59; MS (EI, 70 eV) m/z (rel intensity) 319.1 (M+, 0.9%), 211.0
(M+ - C5H4N2O, 0.2%), 166.1 (M+ - C7H4ClNO, 100%), 125.0 (M+
-
C7H6N4O3, 47%); HR-MS (FAB) calcd for C13H10ClN5O3 319.0472, found
319.0481; calcd for C8H6ClN3O2 211.048, found 211, 0147; calcd for
C6H6N4O2 166.0491, found 166.0493; calcd for C6H4ClN 125.0033, found
125.0035.
584
Org. Lett., Vol. 2, No. 5, 2000