(β-D-ribofuranosyl)formamidine in the design and synthesis of 2-(β-D-ribofuranosyl)pyrimidines, including RF-containing derivatives

Article abstract of DOI:10.1002/ejoc.201300107

A wide range of novel 2-(β-D-ribofuranosyl)pyrimidines, including R^F-containing derivatives, have been synthesized by the reaction of (β-D-ribofuranosyl)formamidine with various dielectrophilic substrates such as 3-alkoxy- and 3-chloro-1-(polyf

Full text of DOI:10.1002/ejoc.201300107

FULL PAPER
DOI: 10.1002/ejoc.201300107
(β-
D
-Ribofuranosyl)formamidine in the Design and Synthesis of
2-(β-
D
-Ribofuranosyl)pyrimidines, Including RF-Containing Derivatives
Viktor O. Iaroshenko,*[a,b] Sergii Dudkin,[a] Vyacheslav Ya. Sosnovskikh,[c]
Alexander Villinger,[a] and Peter Langer*[a,d]
Keywords: Nucleosides / Drug design / Drug discovery / Fluorine / Ribonucleosides / Alkynes
A wide range of novel 2-(β-
D
-ribofuranosyl)pyrimidines, in-
dielectrophilic substrates such as 3-alkoxy- and 3-chloro-1-
(polyfluoroalkyl)propen-1-ones, 3-nitro- and 3-(phenyl-
ethynyl)chromones and heteroaryl acetylenic ketones.
cluding RF-containing derivatives, have been synthesized by
the reaction of (β-D-ribofuranosyl)formamidine with various
compounds that, over the last three decades, have found
extensive applications in biological chemistry, life-science,
and medicine. To date there are a large number of marketed
drugs, so called fluorinated purine and pyrimidine anti-
metabolites, that are broadly used for the treatment of nu-
merous cancers and viral infections (Figure 1).[1c,1d]
Inspired by the relevance of fluorinated purine and pyr-
imidine nucleosides and taking into account our experi-
ence[3] in the design and synthesis of fluorinated purines,
their nucleosides and isosteres as potential drug-like scaf-
folds, our laboratory has undertaken this study to develop
a new class of pyrimidine C-ribosides with polyfluoroalkyl
substituents in the 4-position by the annulation of the pyr-
imidine core onto 1-(β-d-ribofuranosyl)formamidine 3. At
the same time, the inclusion of this prospective building-
block in the design of diverse C-riboside libraries by the
reaction of 3 with the a set of common nonfluorinated 1,3-
CCC-bielectrophiles was our second target.
The most fruitful approach described for the synthesis of
C-nucleosides (the linkage originates from the C-1Ј position
of the ribose sugar moiety and joins the carbon of the het-
erocyclic base) involves the preparation of the desired het-
erocycle from a C-glycosyl derivative functionalized at the
C-1Ј substituent. One type of C-glycosyl derivative that has
received much attention is represented by the 3-(ribofur-
anosyl)propiolates 1, some of which have been utilized to
prepare triazole and pyrazole C-nucleosides through 1,3-
dipolar cycloaddition reactions to the triple bond.[4] Their
reactions with guanidine readily affords 6-(β-d-ribofuran-
osyl)pyrimidines,[5] whereas 2-(d-ribofuranosyl)-2-formyl-
acetates 2 give 5-(β-d-ribofuranosyl)isocytosine.[6]
Another useful C-ribosyl derivative is 1-(β-d-ribofuran-
osyl)formamidine hydrochloride 3 (2,5-anhydro-d-allon-
amidine hydrochloride, Figure 2), which reacted with ap-
propriate dielectrophilic substrates, such as dimethyl cyano-
iminodithiocarbonate, ethyl acetoacetate, sodium diethyl
oxaloacetate, and ethyl 4-(dimethylamino)-2-oxo-3-buteno-
Introduction
Substituting hydrogen by fluorine in organic compounds
is one of the most powerful synthetic tools available to in-
fluence a variety of molecular properties. The strategy has
been widely applied in medicinal chemistry and drug design
as a way of tuning metabolic stability, modifying chemical
reactivity, and improving transportation and absorption
characteristics of pharmaceuticals.[1] The presence of fluor-
ine in drug candidates and marketed drugs is now common-
place. The impact made by fluorine on molecular properties
has been well-studied and described in the literature.[1,2] To
date there are more than 200 pharmaceuticals known with
at least one fluorine atom. Literature analysis highlights the
presence of fluorine in 10–15% of launched drugs world-
wide over the past 50 years, with a noticeable increase in
the past five years.[1b] One can find fluorine in pharmaceuti-
cals and drug candidates in a variety of structural presenta-
tions, for instance, molecules containing between 1 and 21
fluorine atoms are applicable in all therapeutic areas.
Pivotal positions among all classes of fluorinated phar-
macologically active compounds have been occupied by nu-
cleosides with fluorine functionality either in the sugar or
in the heterocyclic part. Fluorinated nucleosides and their
analogues represent a class of organic fluorine-containing
[a] Institut für Chemie, Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax: +49-381-49864112
E-mail: viktor.iaroshenko@uni-rostock.de
iva108@google-mail.com
peter.langer@uni-rostock.de
Homepage: http://www.langer.chemie.uni-rostock.de
[b] National Taras Shevchenko University,
62 Volodymyrska Str., 01033 Kyiv, Ukraine
[c] Department of Chemistry, Ural Federal University,
51 Lenina Ave., 620000 Ekaterinburg, Russia
[d] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300107
3166
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3166–3173

2-(β-d-Ribofuranosyl)pyrimidines
activity and reactivity of the derived fluorinated com-
pounds.[1c,1d] In this context, of special interest is the syn-
thesis of the hitherto unknown RF-containing 2-(β-d-ribo-
furanosyl)pyrimidines, which may be viewed as partially
fluorinated analogues of C-nucleosides that exhibit impor-
tant biological activities.[9] When the presence of a per-
fluorinated residue is required in a bioactive target mole-
cule, either the fluoroalkylation reaction[10] of a convenient
intermediate or the synthesis from perfluoroalkyl-substi-
tuted precursors may be employed.[11,12] When the latter ap-
proach is used, 3-alkoxy-1-(polyfluoroalkyl)propen-1-ones
are often employed as the electrophilic species for the syn-
thesis of RF-containing compounds.[13] We now report that
a perfluoroalkyl chain can be introduced at C-4 of 2-(β-d-
ribofuranosyl)pyrimidines by reaction of 3-ethoxy-1-(per-
fluoroalkyl)propen-1-ones and 3,3-dimethoxy-1-(poly-
fluoroalkyl)propen-1-ones with 1-(β-d-ribofuranosyl)form-
amidine hydrochloride 3 (Scheme 1).
Figure 1. Fluorinated purine and pyrimidine antimetabolites clini-
cally used for the treatment of numerous cancers and viral infec-
tions.
ate, to give 2-(β-d-ribofuranosyl)-1,3,5-triazines[7] and 2-(β-
d-ribofuranosyl)pyrimidines.[8] However, pyrimidine C-nu-
cleosides with the glycosyl moiety at C-2 have not received
much attention despite the fact that some of them are useful
in treating a wide variety of diseases, including infections,
infestations, neoplasms, and autoimmune diseases.[9]
Scheme 1. Synthesis of 2-(β-d-ribofuranosyl)-4-(polyfluoroalkyl)-
pyrimidines 4 and 5. Reagents and conditions: (i) SnCl4, TMSCN,
CH2Cl2, 24 h (room temp.) then 6 h (reflux);[14] (ii) MeONa,
MeOH, 72 h;[15] (iii) NH3 in MeOH, NH4Cl, 72 h;[8] (iv) MeONa,
DBU, DMF, 80 °C, 3 h (for 4a); (v) K2CO3, molecular sieves (4 Å),
DMF, 60 °C, 4–5.5 h, under argon (for 4b, 5a, and 5b).
The key synthetic intermediate 3, which had previously
been synthesized, was prepared by the reported pro-
cedures[8,14,15] from 2,3,5-tri-O-acetyl-β-d-ribofuranosyl
acetate through the O-acetylated cyanide and reaction with
catalytic amounts of MeONa in MeOH to give the de-
blocked methyl β-d-ribofuranosyl-1-carboximidate, which
afforded 1-(β-d-ribofuranosyl)formamidine 3 on treatment
with methanolic ammonia. Amidine 3 has advantages over
functionalized C-glycosides previously used for the synthe-
sis of pyrimidine C-nucleosides. Protecting groups were not
required for the synthesis of amidine 3 nor were protecting
Figure 2. Types of C-1Ј glycosyl derivatives.
Results and Discussion
It is well-known that the inclusion of a CF3 group can groups required for its direct use in ring-closure procedures
have profound and often unexpected results on biological (Scheme 1).[8]
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3167

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FULL PAPER
Previously, 4-ethoxy-1,1,1-trifluorobut-3-en-2-one was molecule. This is therefore a novel and general synthesis of
condensed with acetamidine and benzamidine to give a 6-R-4-RF-2-(β-d-ribofuranosyl)pyrimidines 7 with poten-
mixture of the corresponding tetrahydropyrimidines and tial biological activity.
pyrimidines.[16] After some optimization, we found that
treatment of 3 with 4-ethoxy-1,1,1-trifluorobut-3-en-2-one
in N,N-dimethylformamide (DMF) at 80 °C in the presence
of MeONa and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
resulted in the formation of 2-(β-d-ribofuranosyl)-4-(tri-
fluoromethyl)pyrimidine (4a), which is unsubstituted at C-
5 and C-6. Perfluoroethylated analogue 4b was prepared in
59% isolated yield in DMF in the presence of K2CO3 and
Scheme 2. Synthesis of 2-(β-d-ribofuranosyl)-4-(polyfluoroalkyl)-
molecular sieves (4 Å) at 60 °C.[17] Reaction of 3 with 3,3-
dimethoxy-1-(polyfluoroalkyl)propen-1-ones (RF = CF3,
CHF2) under the latter conditions gave 2-(β-d-ribofurano-
syl)-6-methoxy-4-RF-pyrimidines 5a and 5b in 72–75%
yields (Scheme 1). The preparation of compounds 4 and 5
is the first reported synthesis of a pyrimidine ring C-nu-
cleoside containing a polyfluoroalkyl group.[1c,1d,18] The
structure of 4a was confirmed by X-ray single crystal analy-
sis (Figure 3).[19]
pyrimidines 7a–i from 1-RF-1,3-diketones. Reagents and conditions:
(i) SOCl2, CHCl3, reflux, 3 h (Method A);[20] (ii) oxalyl chloride,
DMF, CH2Cl2, –78 °C to room temp. (Method B);[21] (iii) K2CO3,
molecular sieves (4 Å), DMF, 0 °C, 2 h.
Table 1. Yield of compounds 6a–i and 7a–i.
6, 7
RF
R
Yield of 6
Yield of 7
[%][a][b]
[%][a]
a
b
c
d
e
f
g
h
i
CF3
CF3
CF3
CF3
CF3
CF3
CF3
n-C3F7
n-C3F7
Ph
92 (A)
81 (A)
99 (A)
57 (A)
52 (B)
63 (B)
88 (B)
93 (A)
74 (A)
71
73
42
38
57
55
67
55
49
2-thienyl
4-EtC6H4
2-naphthyl
Me
iPr
2-furyl
Ph
4-FC6H4
[a] Yield of pure isolated product. [b] Method A (with SOCl2) or B
[with (COCl)2] used to prepare 6 are given in parentheses.
To establish the generality of this cyclization, compound
3 was subjected to analogous reactions with chloroketo
esters 6j and 6k, prepared from methyl benzoylpyruvate,
Figure 3. Molecular structure of 4a.
methyl
(2-thenoyl)pyruvate,
and
oxalyl
chloride
We decided to include 1-RF-1,3-diketones in this study
to obtain the corresponding 6-substituted 2-(β-d-ribofur-
anosyl)-4-RF-pyrimidines, however, to our great disappoint-
ment, this chosen strategy has never been successful in our
hands. To overcome this problem, we considered other
chemical equivalents of a 1,3-CCC-RF synthon, namely, a
series of α,β-unsaturated chloro ketones 6, which were ob-
tained starting from easily accessible 1-RF-1,3-diketones by
usual chlorination procedures with thionyl chloride
(CHCl3, reflux, 3 h, Method A)[20] or oxalyl chloride
(DMF, CH2Cl2, –78 °C to room temp., Method B).[21] The
products were distilled under high vacuum to afford a yel-
low or green liquid consisting of a mixture of Z- and E-
regioisomers 6, which were not separated (Scheme 2). It was
found that treatment of chloro ketones 6 with amidine 3 in
DMF in the presence of K2CO3 and molecular sieves at
0 °C resulted in the formation of 2-(β-d-ribofuranosyl)pyr-
imidine 7a–i in good yields (38–73%). In most cases, the
reaction was complete after 2 h and the products could be
isolated by column chromatography. The results are sum-
marized in Table 1 (application of Method A was possible
only in the case of perfluoro-substituted diketones and only
if they are not sensitive to acids). As can be seen from
Table 1, the reaction has virtually no limitations with re-
(Method B), and pyrimidines 7j and 7k were obtained un-
der the same conditions in 33 and 42% yields, respectively
(Scheme 3). These results clearly show that the present reac-
tion could be applicable to various types of chloro ketones
Scheme 3. Synthesis of 4-(methoxycarbonyl)-2-(β-d-ribofuranosyl)-
pyrimidines 7j and 7k and their derivatives 8a and 8b. Reagents and
conditions: (i) oxalyl chloride, DMF, CH2Cl2, –78 °C to room temp.
spect to the nature of the substituents in the chloro ketone (Method B); (ii) K2CO3, molecular sieves (4 Å), DMF, 0 °C, 2 h.
3168 Eur. J. Org. Chem. 2013, 3166–3173
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2-(β-d-Ribofuranosyl)pyrimidines
6, providing a simple and rapid synthetic route to a wide 5H-chromeno[4,3-d]pyrimidines, the configuration of which
range of 4,6-disubstituted pyrimidine nucleosides 7. The was unambiguously established as the Z form from X-ray
1
structures of products 7 were characterized by IR, H, 19F, diffraction analysis. Following this precedent for the use of
and 13C NMR spectroscopic data as well as by MS and 3-alkynylchromones in pyrimidine synthesis, 3-(phenyleth-
HRMS analysis. It should be noted that no α-anomers were ynyl)chromone was treated with C-glycosyl amidine 3 in the
observed. All our attempts to synthesize the corresponding presence of K2CO3 and molecular sieves in DMF to pro-
ribofuranosylpyrimidines from 4,4,4-trifluoro-1-phenyl- duce benzopyrano[4,3-d]pyrimidine 11, with a glycosyl moi-
butane-1,3-dione,
phenylbutane-1,3-dione, and ethyl 4,4,4-trifluoro-3-oxobut- by assuming the initial formation of intermediate 11Ј ac-
anoate failed. companied by intramolecular nucleophilic addition of the
2-(ethoxymethylene)-4,4,4-trifluoro-1- ety attached at C-2. This transformation can be rationalized
Nucleoside 7k was employed for the synthesis of other hydroxyl group at the triple bond (Scheme 4). We also
nonfluorinated nucleoside derivatives. When this compound hoped to increase the scope of this reaction to include 3-
was dissolved in methanolic ammonia and stirred at room (trifluoroacetyl)chromone[25] and 4-chloro-3-(trifluoroacet-
temperature overnight, carbamoylpyrimidine 8a, possessing yl)coumarin,[26] however, these attempts were unsuccessful.
a ribosyl moiety at the 2-position, was obtained in quantita-
Previously, alkynyl ketones have been condensed with
tive yield. Treatment of 7k with hydrazine hydrate in meth- amidines to give pyrimidines.[27] To demonstrate the ability
anol at room temperature resulted in the formation of hy- of amidine 3 to add to acetylenic ketones, it was allowed to
drazide 8b in 83% yield (Scheme 3).
react with ketones 12 and 13. It is significant that amidine
It is known that 3-nitro- and 2-methyl-3-nitrochrom- 3 smoothly reacted with these electrophilic substrates under
ones[22] react with amidines and guanidine to give the corre- our reaction conditions (K2CO3, molecular sieves, DMF)
sponding 5-nitropyrimidines.[23] These reactions proceed by to produce the expected products 14 and 15 in good yields
nucleophilic 1,4-addition followed by pyrone ring opening (52–68%; Scheme 5).
and intramolecular condensation at the carbonyl group. We
In conclusion, we have developed a simple and conve-
found that, in the case of amidine 3 and 3-nitrochromone, nient method for the synthesis of 2-(β-d-ribofuranosyl)pyr-
analogous cyclization took place in the presence of MeONa imidines, including RF-containing derivatives, by using (β-
and NEt3 in MeOH, yielding 5-nitropyrimidine 9a in 36% d-ribofuranosyl)formamidine and various dielectrophilic
yield (Scheme 4). A similar result was obtained with 2- substrates. These compounds constitute an important struc-
methyl-3-nitro- and 2-butyl-3-nitrochromones in DMF, tural subunit of a variety of biologically active compounds,
which gave compounds 9b and 9c in 35 and 48% yields, and their biological evaluation is being studied in our labo-
respectively. The reduction of the nitro group of these com- ratory. On the other hand, the combinatorial aspect of the
pounds by hydrogenation in the presence of Pd/C (10 mol- synthetic strategies developed here can be used in biology-
%) afforded the expected 5-aminopyridines 10a–c in quanti- oriented syntheses of mechanism-based enzyme inhibitors
tative yield.[22]
and pitfalls, and UV-active labels for nucleic acids and pro-
Li, Duan and Hu[24] condensed 3-iodochromone with teins. Both these aspects are also under intense study in our
phenylacetylene and amidines to give (5Z)-5-benzylidene- laboratory.
Scheme 4. Synthesis of C-nucleosides 9–11 from 3-nitro- and 3-(phenylethynyl)chromones. Reagents and conditions: (i) MeONa, NEt3,
MeOH, 80 °C, 1.5 h (for 9a); (ii) MeONa, NEt3, DMF, 50 °C, 5 h, under argon (for 9b and 9c); (iii) H2, Pd (10% on charcoal), MeOH,
2 d; (iv) K2CO3, molecular sieves (4 Å), DMF, 60 °C, 6 h, under argon.
Eur. J. Org. Chem. 2013, 3166–3173
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V. O. Iaroshenko, P. Langer et al.
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2-one (0.190 g, 1.03 mmol, 1.1 equiv.), K2CO3 (0.26 g, 1.88 mmol,
2 equiv.), molecular sieves (0.3 g, 4 Å), and DMF (4 mL), and the
reaction mixture was stirred at 60 °C for 5.5 h under argon. After
cooling to room temperature, the inorganic precipitate was filtered
off and the filtrate was evaporated under reduced pressure. The
crude residue was purified by short-path column chromatography
[silica gel (10 g); CHCl3 (400 mL), then EtOAc (Rf = 0.19–0.29)].
The EtOAc fraction was evaporated to give the desired product,
yield 0.209 g (72%); white solid; m.p. 129 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 3.52–3.63 (m, 1 H, 5Ј-Ha), 3.63–3.72 (m, 1 H, 5Ј-
Hb), 3.92–4.00 (m, 1 H, 4Ј-H), 4.06 (s, 3 H, MeO), 4.06–4.14 (m,
1 H, 3Ј-H), 4.20–4.27 (m, 1 H, 2Ј-H), 4.65 (dd, J = 6.8, 4.7 Hz, 1
H, 5Ј-OH), 4.80 (d, J = 4.0 Hz, 1 H, 1Ј-H), 5.00 (d, J = 6.0 Hz, 1
H, 3Ј-OH), 5.28 (d, J = 5.7 Hz, 1 H, 2Ј-OH), 7.45 (s, 1 H, 5-
H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ = 55.7 (MeO), 63.0
(CH2OH), 72.4 (C-3Ј), 76.6 (CH-2Ј), 85.7 (CH-4Ј), 86.6 (CH-1Ј),
Scheme 5. Synthesis of C-nucleosides 14 and 15 from acetylenic
ketones. Reagents and conditions: (i) K2CO3, molecular sieves (4 Å),
DMF, 70 °C, 4 h, under argon.
1
105.3 (CH-5), 121.5 (q, JC,F = 274.6 Hz, CF3), 155.3 (q, JC,F
=
35.0 Hz), 171.0, 171.7 ppm. 19F NMR (282 MHz, [D6]DMSO): δ
= –68.7 (s, CF3) ppm. MS (EI, 70 eV): m/z (%) = 311 (1.74) [M +
H]+, 310 (1.25) [M]+, 233 (12), 222 (16), 221 (100), 219 (27), 208
(16), 207 (90), 205 (19), 68 (11). HRMS (ESI): calcd. for
C11H14F3N2O5 [M + H]+ 311.08493; found 311.08440. IR (ATR):
Experimental Section
General: All solvents were purified and dried by standard methods.
NMR spectra were recorded with Bruker AV 300 and Bruker AV
400 spectrometers. IR spectra were recorded with a Perkin–Elmer
FT IR 1600 spectrometer (ATR). Mass spectra were obtained with
a Hewlett–Packard GC/MS 5890/5972 instrument (EI, 70 eV) with
GC inlet or with an MX-1321 instrument (EI, 70 eV) with direct
inlet. Column chromatography was performed on silica gel (63–
200 mesh, Merck). Silica gel Merck 60F254 plates were used for
TLC. Chemical yields refer to pure isolated substances.
ν = 3346 (m), 3159 (m), 3118 (w), 2966 (w), 2937 (w), 2908 (w),
˜
2889 (w), 1606 (m), 1585 (w), 1558 (m), 1504 (w), 1479 (s), 1456
(w), 1435 (m), 1383 (s), 1348 (m), 1331 (m), 1304 (m), 1267 (m),
1225 (m), 1201 (s), 1186 (m), 1176 (m), 1151 (s), 1140 (s), 1099 (s),
1057 (s), 1034 (s), 1026 (s), 986 (s), 957 (s), 899 (m), 879 (s), 870
(s), 839 (m), 800 (m), 768 (s), 756 (s), 723 (m), 687 (s), 631 (s), 586
(m), 561 (m) cm–1.
4-Phenyl-2-(β-D-ribofuranosyl)-6-(trifluoromethyl)pyrimidine (7a):
2-(β-
D
-Ribofuranosyl)-4-(trifluoromethyl)pyrimidine (4a): In
a
3
Initial diketone was previously activated by conversion into the cor-
responding α,β-unsaturated β-chloro ketone. To a solution of 4,4,4-
trifluoro-1-phenylbutane-1,3-dione (2.0 g, 9.25 mmol, 1 equiv.) in
chloroform (6 mL), was added SOCl2 (2.258 g, 27.8 mmol,
3 equiv.), followed by addition of DMF (0.034 g, 0.46 mmol,
0.05 equiv.). The mixture was heated to reflux for 3 h, then the
solvent (containing an excess of SOCl2) was evaporated, and the
residue was distilled under high vacuum to afford a green liquid
consisting of a mixture of isomers 6a (1.994 g, 92%).
25 mL flask were placed 1-(β-d-ribofuranosyl)formamidine
(0.3 g, 1.41 mmol, 1 equiv.), MeONa (0.069 g, 1.27 mmol,
0.9 equiv.), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.043 g,
0.282 mmol, 0.2 equiv.), and DMF (3 mL), then 4-ethoxy-1,1,1-tri-
fluoro-3-buten-2-one (0.474 g, 2.82 mmol, 2 equiv.) was added and
the reaction mixture was stirred at 80 °C for 3 h under argon. After
cooling to room temperature, the inorganic precipitate was filtered
off and the filtrate was evaporated under reduced pressure. The
crude product was purified by column chromatography [silica gel
(120 g); EtOAc (Rf = 0.08–0.14)], yield 0.130 g (33%); white solid;
m.p. 93–95 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 3.50–3.60
(m, 1 H, 5Ј-Ha), 3.61–3.71 (m, 1 H, 5Ј-Hb), 3.93–4.01 (m, 1 H, 4Ј-
H), 4.02–4.11 (m, 1 H, 3Ј-H), 4.22–4.30 (m, 1 H, 2Ј-H), 4.70 (dd,
J = 6.6, 4.7 Hz, 1 H, 5Ј-OH), 4.92 (d, J = 4.7 Hz, 1 H, 1Ј-H), 5.04
(d, J = 5.9 Hz, 1 H, 3Ј-OH), 5.28 (d, J = 5.7 Hz, 1 H, 2Ј-OH), 8.02
(d, J = 5.1 Hz, 1 H, 5-H), 9.25 (d, J = 5.1 Hz, 1 H, 6-H) ppm. 13C
NMR (63 MHz, [D6]DMSO): δ = 63.0 (CH2OH), 72.3 (CH-3Ј),
76.8 (CH-2Ј), 86.1 (CH-4Ј), 86.5 (CH-1Ј), 117.3 (CH-5), 121.5 [q,
1JC,F = 275.2 Hz, CF3], 154.9 (q, 2JC,F = 35.6 Hz, C-4), 162.1 (CH-
6), 170.3 (C-2) ppm. 19F NMR (282 MHz, [D6]DMSO): δ = –68.6
(s, CF3) ppm. MS (GC, 70 eV): m/z (%) = 280 (0.36) [M]+], 203
(11) [M – CF3]+, 191 (100), 189 (18), 178 (17), 177 (33). HRMS
(ESI): calcd. for C10H12F3N2O4 [M + H]+ 281.07437; found
In a 25 mL flask were placed 1-(β-d-ribofuranosyl)formamidine 3
(0.15 g, 0.71 mmol, 1 equiv.), K2CO3 (0.39 g, 2.82 mmol, 4 equiv.),
and DMF (3 mL), then the previously prepared α,β-unsaturated β-
chloro ketone 6a (0.182 g, 0.78 mmol, 1.1 equiv.) was added at 0 °C
and the reaction was stirred at this temperature in the presence of
molecular sieves (4 Å) for 1.5 h. The mixture was allowed to stand
at room temperature overnight (18 h), then the inorganic precipi-
tate was filtered off and the filtrate was evaporated under reduced
pressure. The crude product was purified by column chromatog-
raphy [silica gel (40 g), EtOAc (Rf = 0.30–0.39)], yield 0.178 g
(71%); light-green solid; m.p. 77–78 °C. 1H NMR (300 MHz,
CDCl3): δ = 4.73 (dd, 2J = 12.3, 3J = 1.3 Hz, 1 H, 5Ј-Ha), 3.93 (br.
2
3
s, 3 H, OH), 4.04 (dd, J = 12.3, J = 2.5 Hz, 1 H, 5Ј-Hb), 4.28 (s,
3
1 H, 4Ј-H), 4.41–4.50 (m, 2 H, 2Ј-H, 3Ј-H), 5.27 (d, J = 2.7 Hz, 1
H, 1Ј-H), 7.45–7.60 (m, 3 H, Ph), 7.84 (s 1 H, 5-H), 7.99–8.08 (m
2 H, Ph) ppm. 13C NMR (63 MHz, CDCl3): δ = 62.2 (CH2OH),
71.6 (CH-3Ј), 78.0 (CH-2Ј), 85.2 (CH-4Ј), 85.9 (CH-1Ј), 111.9 (CH-
281.07441. IR (ATR): ν = 3390 (m), 3153 (m), 2979 (w), 2929 (w),
˜
2817 (w), 1588 (w), 1576 (m), 1462 (w), 1449 (w), 1418 (m), 1337
(s), 1320 (w), 1307 (m), 1295 (w), 1250 (w), 1225 (w), 1202 (m),
1171 (s), 1150 (s), 1119 (s), 1100 (m), 1079 (s), 1042 (m), 1002 (w),
975 (w), 909 (m), 887 (m), 851 (m), 800 (w), 761 (m), 719 (m), 703
(m), 677 (s), 649 (s), 586 (w), 542 (m), 528 (m) cm–1.
1
5), 120.7 (q, JC,F = 275.6 Hz, CF3), 127.9 (CHAr), 129.6 (CHAr),
2
132.7 (CHAr), 135.2, 156.5 (q, JC,F = 36.0 Hz, C-6), 167.8,
170.6 ppm. 19F NMR (282 MHz, CDCl3): δ = –69.8 (s, CF3) ppm.
MS (GC, 70 eV): m/z (%) = 356 (1.8) [M]+, 268 (15), 267 (100), 253
(32). HRMS (ESI): calcd. for C16H16F3N2O4 [M + H]+ 357.10567;
4-Methoxy-2-(β-D-ribofuranosyl)-6-(trifluoromethyl)pyrimidine (5a):
In a 25 mL flask were placed 1-(β-d-ribofuranosyl)formamidine 3
found 357.10634. IR (ATR): ν = 3354 (s), 3078 (w), 2925 (m), 2854
˜
(0.2 g, 0.94 mmol, 1 equiv.), 1,1,1-trifluoro-4,4-dimethoxy-3-buten-
(w), 1595 (s), 1548 (s), 1501 (w), 1479 (w), 1454 (w), 1427 (w), 1388
3170
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3166–3173

2-(β-d-Ribofuranosyl)pyrimidines
(s), 1333 (w), 1282 (w), 1261 (s), 1207 (m), 1179 (s), 1136 (s), 1100
(s), 807 (w), 756 (s), 706 (m), 687 (m), 665 (m), 624 (s), 579 (m),
(s), 1078 (s), 1051 (s), 1025 (s), 1001 (m), 990 (m), 943 (m), 929 542 (s) cm–1.
(m), 880 (m), 833 (m), 802 (w), 770 (s), 750 (m), 711 (m), 687 (s),
5-Amino-4-(2-hydroxyphenyl)-2-(β-D-ribofuranosyl)pyrimidine (10a):
666 (m), 633 (s), 596 (m), 573 (m), 548 (s) cm–1.
In a 25 mL flask were placed 4-(2-hydroxyphenyl)-5-nitro-2-(β-d-
ribofuranosyl)pyrimidine (9a; 0.118 g, 0.34 mmol), Pd/C (0.012 g,
10 wt.-%) and MeOH (3.5 mL). The system was washed three times
with argon and then three times with hydrogen. The reaction mix-
ture was stirred for 2 d at room temperature under atmospheric
pressure. When the reduction was complete (reaction monitored by
TLC), the mixture was filtered through a Celite pad (2–3 cm),
which was washed three times with MeOH. The filtrate was evapo-
rated under reduced pressure and the residue was thoroughly dried
under high vacuum to give the pure product, yield 0.108 g (100%);
pale-yellow amorphous solid form. 1H NMR (300 MHz, [D6]-
DMSO): δ = 3.50 (dd, J = 11.7, 3.8 Hz, 1 H, 5Ј-Ha), 3.65 (dd, J =
11.7, 3.7 Hz, 1 H, 5Ј-Hb), 3.88–3.97 (m, 1 H, 4Ј-H), 4.05–4.13 (m,
1 H, 3Ј-H), 4.18–4.27 (m, 1 H, 2Ј-H), 4.76 (d, J = 4.5 Hz, 1 H, 1Ј-
H), 4.78–5.86 (br. m, 5 H, OH, NH2), 6.94–7.06 (m, 2 H, 3ЈЈ-H,
5ЈЈ-H), 7.31–7.79 (m, 1 H, 4ЈЈ-H), 7.45 (dd, J = 7.7, 1.5 Hz, 1 H,
6ЈЈ-H), 8.29 (s, 1 H, 6-H), 10.44 (br. s, 1 H, 2ЈЈ-OH) ppm. 13C NMR
(63 MHz, [D6]DMSO): δ = 62.9 (CH2OH), 72.2 (CH-3Ј), 76.6 (CH-
2Ј), 85.4 (CH-4Ј), 86.4 (CH-1Ј), 117.3 (CHAr), 120.3 (CHAr), 124.3,
131.4 (CHAr), 131.6 (CHAr), 140.1, 144.7 (CHAr), 149.2, 156.0,
157.2 ppm. MS (EI, 70 eV): m/z (%) = 319 (54) [M]+, 230 (100),
217 (12), 216 (83), 214 (14), 201 (10). HRMS (EI): calcd. for
2-(β-D-Ribofuranosyl)-6-(2-thienyl)pyrimidine-4-carboxamide (8a):
Methyl 2-(β-d-ribofuranosyl)-6-(2-thienyl)pyrimidine-4-carboxyl-
ate (7k; 0.1 g, 0.28 mmol, 1 equiv.) was dissolved in 7 m ammonia
solution in methanol (0.81 mL, 5.7 mmol, 20 equiv.) and stirred at
room temperature overnight (18 h), then the solvent was evapo-
rated under reduced pressure and the residue was thoroughly dried
under high vacuum to give the pure product, yield 0.096 g (100%);
1
white amorphous solid form. H NMR (300 MHz, [D6]DMSO): δ
= 3.57–3.67 (m, 1 H, 5Ј-Ha), 3.67–3.77 (m, 1 H, 5Ј-Hb), 3.94–4.01
(m, 1 H, 4Ј-H), 4.15–4.23 (m, 1 H, 3Ј-H), 4.32–4.39 (m, 1 H, 2Ј-
H), 4.74 (dd, J = 6.2, 5.3 Hz, 1 H, 5Ј-OH), 4.90 (d, J = 4.5 Hz, 1
H, 1Ј-H), 4.98 (d, J = 5.9 Hz, 1 H, 3Ј-OH), 5.24 (d, J = 5.5 Hz, 1
H, 2Ј-OH), 7.31 (dd, J = 4.9, 3.8 Hz, 1 H, 4ЈЈ-H), 7.94 (dd, J =
4.9, 1.1 Hz, 1 H, 3ЈЈ-H), 8.06 (br. s, 1 H, NH-a), 8.26 (br. s, 1 H,
NH-b), 8.28 (dd, J = 3.8, 1.1 Hz, 1 H, 5ЈЈ-H), 8.33 (s, 1 H, 5-
H) ppm. 13C NMR (76 MHz, [D6]DMSO): δ = 63.3 (CH2OH), 72.7
(CH-3Ј), 76.4 (CH-2Ј), 85.9 (CH-4Ј), 86.7 (CH-1Ј), 111.7 (CH-5),
130.2 (CHAr), 131.0 (CHAr), 133.1 (CHAr), 142.2, 159.1, 161.6,
165.7, 169.2 ppm. MS (EI, 70 eV): m/z (%) = 337 (1) [M]+, 301
(16), 292 (10), 249 (12), 248 (100), 234 (27), 161 (11), 134 (52), 108
(11). HRMS (ESI): calcd. for C14H16N3O5S [M + H]+ 338.08052;
C H N O [M]+ 319.11627; found 319.11684. IR (ATR): ν = 3324
˜
15 17
3
5
found 338.08071. IR (ATR): ν = 3306 (s), 3093 (m), 2928 (m), 2874
˜
(s), 3207 (s), 2928 (m), 2873 (m), 1633 (w), 1608 (w), 1568 (m),
1558 (m), 1549 (w), 1504 (w), 1495 (w), 1488 (w), 1447 (s), 1418
(m), 1398 (m), 1327 (m), 1295 (m), 1249 (m), 1206 (m), 1158 (w),
1097 (s), 1082 (s), 1047 (s), 985 (m), 911 (m), 889 (m), 857 (m), 831
(m), 799 (m), 756 (s), 700 (s), 667 (s), 633 (s), 596 (s), 534 (s) cm–1.
(m), 1682 (s), 1574 (s), 1525 (s), 1429 (s), 1394 (s), 1344 (s), 1317
(s), 1228 (m), 1200 (m), 1095 (s), 1078 (s), 1034 (s), 991 (s), 947
(m), 889 (s), 858 (s), 812 (m), 779 (m), 714 (s), 665 (s), 617 (s), 534
(s) cm–1.
4-(2-Hydroxyphenyl)-5-nitro-2-(β-D-ribofuranosyl)pyrimidine (9a):
(5Z)-5-Benzylidene-2-(β-D-ribofuranosyl)-5H-chromeno[4,3-d]-
A sealed ACE pressure tube was charged with 1-(β-d-ribofuranos-
yl)formamidine 3 (0.3 g, 1.41 mmol, 1 equiv.), MeONa (0.080 g,
1.48 mmol, 1.05 equiv.), AcOH (0.008 g, 0.14 mmol, 0.1 equiv.),
NEt3 (0.143 g, 1.41 mmol, 1 equiv.) and MeOH (4.5 mL). After 3-
nitrochromone (0.493 g, 1.41 mmol, 1 equiv.) was added, the reac-
tion mixture was stirred at 80 °C for 1.5 h under argon. After cool-
ing to room temperature the inorganic precipitate was filtered off
and the filtrate was evaporated under reduced pressure. The crude
product was purified by column chromatography [silica gel (110 g);
EtOAc (Rf = 0.11–0.19)], yield 0.176 g (36%); yellow amorphous
pyrimidine (11): In a 25 mL flask were placed 1-(β-d-ribofuranos-
yl)formamidine 3 (0.15 g, 0.71 mmol, 1 equiv.), 3-(phenylethynyl)-
chromone (0.174 g, 0.71 mmol, 1 equiv.), K2CO3 (0.293 g,
2.1 mmol, 3 equiv.), molecular sieves (0.225 g, 4 Å), and DMF
(3 mL), and the reaction mixture was stirred at 60 °C for 6 h under
argon. After cooling to room temperature, the inorganic precipitate
was filtered off and the filtrate was evaporated under reduced pres-
sure. The crude product was recrystallized from MeOH to afford
the pure product, yield 0.237 g (83%); yellow solid; m.p. 204–
1
206 °C. H NMR (300 MHz, [D6]DMSO): δ = 3.56–3.69 (m, 1 H,
solid. 1H NMR (300 MHz, [D6]DMSO): δ = 3.52–3.62 (m, 1 H, 5Ј- 5Ј-Ha), 3.70–3.81 (m, 1 H, 5Ј-Hb), 3.97–4.06 (m, 1 H, 4Ј-H), 4.12–
Ha), 3.62–3.72 (m, 1 H, 5Ј-Hb), 3.95–4.04 (m, 1 H, 4Ј-H), 4.07–
4.22 (m, 1 H, 3Ј-H), 4.28–4.37 (m, 1 H, 2Ј-H), 4.84–4.95 (m, 2 H,
4.16 (m, 1 H, 3Ј-H), 4.28–4.37 (m, 1 H, 2Ј-H), 4.71 (dd, J = 6.4, 1Ј-H, 5Ј-OH), 5.03 (d, J = 6.1 Hz, 1 H, 3Ј-OH), 5.29 (d, J = 5.7 Hz,
4.9 Hz, 1 H, 5Ј-OH), 4.97 (d, J = 4.7 Hz, 1 H, 1Ј-H), 5.05 (d, J =
5.9 Hz, 1 H, 3Ј-OH), 5.34 (d, J = 5.7 Hz, 1 H, 2Ј-OH), 6.94 (dd,
1 H, 2Ј-OH), 6.77 (s, 1 H, =CH-Ph), 7.23–7.38 (m, 3 H, Ar), 7.41–
7.51 (m, 2 H, Ar), 7.56–7.65 (m, 1 H, Ar), 7.89 (d, J = 7.6 Hz, 1
J1 = 8.1, 1.0 Hz, 1 H, 3ЈЈ-H), 7.07 (td, J = 7.7, 1.0 Hz, 1 H, 5ЈЈ- H, Ar), 8.20–8.27 (m, 1 H, Ar), 9.34 (s, 1 H, 6-H) ppm. 13C NMR
H), 7.45 (ddd, J = 8.1, 7.4, 1.7 Hz, 1 H, 4ЈЈ-H), 7.71 (dd, J = 7.7,
1.7 Hz, 1 H, 6ЈЈ-H), 9.37 (s, 1 H, 6-H), 10.52 (s, 1 H, 2ЈЈ-OH) ppm.
(63 MHz, [D6]DMSO): δ = 63.1 (CH2OH), 72.4 (CH-3Ј), 76.8 (CH-
2Ј), 85.7 (CH-4Ј), 86.9 (CH-1Ј), 106.5 (CH), 117.5 (CH), 118.9,
13C NMR (63 MHz, [D6]DMSO): δ = 63.0 (CH2OH), 72.5 (CH- 120.3, 124.6 (CHAr), 125.2 (CHAr), 127.9 (CHAr), 129.5 (CHAr),
3Ј), 76.9 (CH-2Ј), 86.1 (CH-4Ј), 86.5 (CH-1Ј), 116.4 (CHAr), 120.7 129.8 (CHAr), 135.1 (CHAr), 135.4, 144.2, 152.4, 154.3 (CHAr),
(CHAr), 122.7, 131.5 (CHAr), 133.8 (CHAr), 144.4, 154.2 (CHAr),
156.4, 158.2, 171.7 ppm. MS (EI, 70 eV): m/z (%) = 349 (59) [M]+,
313 (16), 303 (39), 267 (10), 260 (100), 258 (12), 249 (14), 246 (66),
230 (13), 217 (11), 216 (10), 214 (17), 213 (46), 201 (13), 200 (30),
199 (25), 197 (13), 186 (26), 185 (14), 173 (12), 172 (19), 171 (42),
170 (31), 169 (20), 144 (13), 116 (11), 115 (13), 102 (11), 91 (12),
89 (24), 63 (11), 43 (15). HRMS (EI): calcd. for C15H15N3O7 [M]+
155.5, 169.2 ppm. MS (EI, 70 eV): m/z (%) = 405 (64) [M + H]+,
404 (100) [M]+, 368 (20), 316 (56), 315 (99), 314 (51), 313 (30), 302
(50), 301 (88), 300 (15), 299 (12), 286 (23), 285 (32), 273 (13), 272
(11), 271 (32), 256 (11), 247 (16), 246 (78), 206 (15), 189 (12), 128
(12), 73 (11), 44 (16), 43 (14). HRMS (ESI): calcd. for C23H21N2O5
[M + H]+ 405.14450; found 405.14481. IR (ATR): ν = 3273 (s),
˜
3064 (m), 2916 (m), 2871 (w), 1658 (w), 1644 (w), 1607 (m), 1595
(m), 1573 (m), 1543 (m), 1494 (w), 1461 (m), 1447 (m), 1424 (m),
1415 (m), 1392 (w), 1331 (m), 1316 (m), 1281 (m), 1242 (m), 1210
(w), 1189 (w), 1161 (w), 1098 (s), 1052 (s), 1043 (s), 1019 (m), 985
(m), 942 (w), 908 (m), 865 (m), 837 (w), 825 (w), 813 (w), 792 (w),
349.09045; found 349.09066. IR (ATR): ν = 3242 (s), 2932 (w),
˜
2879 (w), 1606 (w), 1581 (s), 1545 (s), 1524 (m), 1504 (w), 1453
(m), 1427 (m), 1355 (s), 1303 (m), 1265 (m), 1210 (w), 1159 (w),
1070 (s), 1080 (s), 1047 (s), 984 (w), 943 (w), 910 (w), 888 (w), 850
Eur. J. Org. Chem. 2013, 3166–3173
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3171

V. O. Iaroshenko, P. Langer et al.
FULL PAPER
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759 (s), 746 (s), 731 (m), 716 (m), 687 (s), 675 (m), 665 (m), 639
(s), 627 (s), 606 (m), 551 (m) cm–1.
4-Phenyl-6-(pyridin-3-yl)-2-(β-D-ribofuranosyl)pyrimidine (14): In a
25 mL flask were placed 1-(β-d-ribofuranosyl)formamidine
3
(0.2 g, 0.94 mmol, 1 equiv.), 3-phenyl-1-(pyridin-3-yl)propyn-1-one
(0.195 g, 0.94 mmol, 1 equiv.), K2CO3 (0.26 g, 1.88 mmol, 2 equiv.),
molecular sieves (0.3 g, 4 Å), and DMF (4 mL), and the reaction
mixture was stirred at 70 °C for 4 h under argon. After cooling to
room temperature, the inorganic precipitate was filtered off and the
filtrate was evaporated under reduced pressure. The crude residue
was purified by short-path column chromatography [silica gel
(12 g), CHCl3 (1 L), then EtOAc (1.5 L; Rf = 0.03–0.09)]. The
EtOAc fraction was evaporated to give the desired product, yield
0.156 g (68%); yellow amorphous solid. 1H NMR (300 MHz,
[D6]DMSO): δ = 3.60–3.71 (m, 1 H, 5Ј-Ha), 3.72–3.81 (m, 1 H, 5Ј-
Hb), 4.01–4.08 (m, 1 H, 4Ј-H), 4.21–4.29 (m, 1 H, 3Ј-H), 4.39–4.47
(m, 1 H, 2Ј-H), 4.86 (dd, J = 6.2, 4.9 Hz, 1 H, 5Ј-OH), 5.02 (d, J
= 4.2 Hz, 1 H, 1Ј-H), 5.03 (d, J = 5.9 Hz, 1 H, 3Ј-OH), 5.28 (d, J
= 5.5 Hz, 1 H, 2Ј-OH), 7.60–7.71 (m, 4 H, Ph), 8.37–8.45 (m, 2 H,
Ar), 8.65 (s, 1 H, 5-H), 8.69–8.75 (m, 1 H, Ar), 8.78–8.85 (m, 1 H,
Ar), 9.55 (s, 1 H, Ar) ppm. 13C NMR (63 MHz, [D6]DMSO): δ =
63.2 (CH2OH), 72.7 (CH-3Ј), 76.8 (CH-2Ј), 85.7 (CH-4Ј), 87.4
(CH-1Ј), 112.8 (CH-5), 124.9 (CHAr), 128.4 (CHAr), 129.9 (CHAr),
132.3 (CHAr), 132.9, 135.8 (CHAr), 137.1, 149.6 (CHAr), 152.7
(CHAr), 163.3, 165.4, 169.9 ppm. MS (EI, 70 eV): m/z (%) = 365
(9.1) [M]+, 277 (29), 276 (100), 274 (14), 263 (20), 262 (75), 248
(10), 247 (16), 234 (14), 233 (13), 105 (12), 104 (12). HRMS (ESI):
calcd. for C20H20N3O4 [M + H]+ 366.14483; found 366.14506. IR
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˜
(s), 1556 (m), 1531 (s), 1504 (m), 1485 (m), 1471 (m), 1452 (m),
1427 (m), 1417 (m), 1410 (m), 1365 (s), 1331 (m), 1294 (m), 1244
(m), 1192 (m), 1101 (s), 1078 (s), 1043 (s), 1026 (s), 1001 (s), 991
(s), 941 (m), 876 (m), 827 (m), 818 (m), 768 (s), 743 (s), 690 (s), 665
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Supporting Information (see footnote on the first page of this arti-
1
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publication CCDC-923959 and can be obtained free of
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Received: January 19, 2013
Published Online: April 4, 2013
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