Chemistry and dynamics of interaction of nucleosides with pentafluoropyridine

Article abstract of DOI:10.1080/15257770500230772

Interaction of pentafluoropyridine with hydroxyl groups of thymidine, uridine, adenosine, and deoxyadenosine at room temperature leads to the formation of aryl ethers of nucleosides with a high yield. Under severe conditions, one more tetrafluoropyridine residue is attached to pyrimidine fragments of T and U, while purine heterocycle in A remains intact. Nucleoside derivatives are formed with a quantitative yield and can be used in situ as intermediates for, as an example, molecular design of arene analogs of nucleic acids. The reaction with thymidine is a successive-parallel process, the limited stage being arylation of the secondary hydroxyl group. The presence of the vicinal hydroxyl group in pentose results in the opposite rate ratio of the formation of primary and secondary tetrafluoropyridyl ethers of adenine and uridine. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/15257770500230772

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Chemistry and Dynamics of Interaction of Nucleosides
with Pentafluoropyridine
V. V. Litvak a , I. Ya. Mainagashev a & O. G. Bukhanets a
a Institute of Chemical Biology and Fundamental Medicine , Siberian Division of Russian
Academy of Sciences , pr. akademika Lavrent'eva 8, Novosibirsk, Russia
Published online: 31 Aug 2006.
To cite this article: V. V. Litvak , I. Ya. Mainagashev & O. G. Bukhanets (2005) Chemistry and Dynamics of Interaction
of Nucleosides with Pentafluoropyridine, Nucleosides, Nucleotides and Nucleic Acids, 24:9, 1373-1385, DOI:
10.1080/15257770500230772
To link to this article: http://dx.doi.org/10.1080/15257770500230772
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (9):1373–1385, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1080/15257770500230772
CHEMISTRY AND DYNAMICS OF INTERACTION OF NUCLEOSIDES
WITH PENTAFLUOROPYRIDINE
5
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
Institute of Chemical
Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences,
Novosibirsk, Russia
5
Interaction of pentafluoropyridine with hydroxyl groups of thymidine, uridine, adenosine, and
deoxyadenosine at room temperature leads to the formation of aryl ethers of nucleosides with a high
yield. Under severe conditions, one more tetrafluoropyridine residue is attached to pyrimidine fragments
of T and U, while purine heterocycle in A remains intact. Nucleoside derivatives are formed with a
quantitative yield and can be used in situ as intermediates for, as an example, molecular design of arene
analogs of nucleic acids. The reaction with thymidine is a successive-parallel process, the limited stage
being arylation of the secondary hydroxyl group. The presence of the vicinal hydroxyl group in pentose
results in the opposite rate ratio of the formation of primary and secondary tetrafluoropyridyl ethers of
adenine and uridine.
Keywords Nucleosides, Arylation, SNAr, Pentafluoropyridine
INTRODUCTION
Elaboration of new methods of functionalization of key biopolymer fragments
is of great interest for fundamental and applied bioorganic chemistry, molecular
biology, biotechnology, etc.[1–5]
SNAr reactions used, for example, for introduction of aryl groups into
nucleosides[6] can be employed for this purpose. We believe that for the successful
modification of nucleophilic centers of nucleosides these reagents can be involved
in reactions with pentafluoropyridine bearing several selectively substituting
halogen atoms. This approach allows further multiple transformations of the
introduced pentafluoropyridine fragments. Revelation of chemical characteristics of
nucleosides as polynucleophilic targets in SNAr reactions is also of interest.
Accepted 12 May 2005.
Address correspondence to V. V. Litvak, Institute of Chemical Biology and Fundamental Medicine, Siberian
Division of Russian Academy of Sciences, pr. akademika Lavrent’eva 8, Novosibirsk 630090, Russia.
1373
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1374
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
SCHEME 1
RESULTS AND DISCUSSION
We have studied the interaction of thymidine, T (II), uridine, U (XII),
adenosine, A (XI), and deoxyadenosine, dA (III) with pentafluoropyridine (I)
bearing at least three fluoroatoms capable of successive nucleophilic substitution
(Schemes 1, 2, and 3). Noncatalytic synthesis of ethers is known to occur via the
interaction of activated arenes with previously prepared alcoholates of alkali metals
in the media of corresponding alcohols. This variant of Williamson synthesis is
hardly applicable to arylation of nucleosides for several reasons. They are, for
example, the high activity of atomic hydrogen forming upon preparation of
SCHEME 2

Interaction with Pentafluoropyridine
1375
SCHEME 3
alcoholates, the low solubility of polyalcoholates in solvents usually used in SNAr
reactions, and complication of preparation of nucleoside alcoholates. Therefore, the
synthesis of arene derivatives VI, VII, XIII–XVI and the study of some ethers
formation were carried out in situ when nucleophiles were generated via reactions
of their precursors with bases—triethylamine (Schemes 1 and 2) and K2CO3
(Scheme 3). Although the reaction rate is higher in the presence of K2CO3, a part of
pentafluoropyridine in this case is wasted for the formation of g-hydroxyl-a,b,a’,b’-
tetrafluoropyridine. The most efficient media for such reactions, DMF, appears to
be the most acceptable solvent in our case, too. The reaction conditions were
chosen so that only one—the most mobile—fluorine atom in g-position of
pentafluoropyridine[7] was substituted in the reaction with nucleosides. As a result,
arylation products VI, VII, XIII, and XIV were prepared as individual compounds
with high yields. Products preserving several mobile halogen atoms sustain more
severe conditions (57°C, 54 h); this stipulates a possibility of using them in situ as
intermediates for the consecutive modification of SNAr type.
To assign signals of polyfluorinated fragments attached to the primary or
secondary hydroxyl groups in arylation products IV–VII, 19F NMR spectra of
ethers IX and X formed in reactions of pentafluoropyridine with ethanole and
iso-propanole were initially registered (Scheme 1, Figure 1). Multiplet assigned to
b,b’-2F (c) of ethyl ether IX is shifted to the higher field (3.84 ppm; here and then
chemical shifts correspond to the centers of symmetric multiplets) compared to that
for iso-propyl derivative X (4.86 ppm) (Figure 1d). Signals of fluorine atoms in 2, 6
positions of pyridine rings of primary ether IX are also disposed in higher field
compared to secondary ether X (see Experimental). These data indicate that

1376
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
FIGURE 1 Fragments of 19F NMR spectra of the reaction mixtures (Scheme 1) that correspond to [b],[b]’-
fluorine atoms of pyridyl rings A, C, A’, and C’ of (III), (IV), and (V). The spectra are registered after 0.75 (a), 3 (b),
and 16 (c, final) h after the beginning of the reaction; (d), fragments of 19F NMR spectra of the reaction mixtures
containing [b],[b]’-fluorine atoms of pyridyl rings of ethers (VII) and (VIII).

Interaction with Pentafluoropyridine
1377
multiplets in lower fields corresponding to products V–VII belong to fluorine
atoms in b,b’-positions of rings C and C’ of ethers at the secondary carbon atoms,
while multiplets in higher fields correspond to analogous halogen atoms of rings A
and A’ of the primary ethers. The other reason for such assignment can be
significantly higher rate of the formation of ethers IV and IX in comparison with
that of ethers V and X, respectively.
In general, arylation of nucleoside hydroxyl groups with pentafluoropyridine is
carried out with comparable rates (Figures 1a, b; 2;3b, d). Maximum accumulation
of monoethers IV and V, for example, amounts to 18 and 7% in 3 h, respectively
(Figure 2); by this time, 13% of the final product VI is already formed.
Like diethers VI and VII, the quantitative formation of triethers XIII and XIV is
observed (Scheme 2). Signals of fluorine atoms at b,b’ positions of the isolated
products consist also of two multiplets (Figure 3a, c). Analogously, multiplets in the
higher field can be assigned to fragments at the 5’ oxygen atoms (A rings), and
combined multiplets in the lower field can be attributed to corresponding
fragments of the secondary ethers (C and D) with twice the intensity.
The nitrogen atoms of the pyrimidine cycle can be brought into the reaction at
higher temperatures using the excess of pentafluoropyridine and K2CO3 as a
condensing agent. As a result, the formation of tri- and tetrafluoropyridyl derivatives
FIGURE 2 Kinetic curves of arylation of thymidine with pentafluoropyridine. The relative content of
components of the reaction mixture is considered as (Ii/I0) 100%, where Ii and I0 are the integral intensities of
fluorine resonances of the reaction components and the initial pentafluoropyridine, respectively: 1, substrate (I); 2,
intermediate (III); 3, intermediate (IV); 4, diether (V); 5, the overall content of ethers (III)–(V) and triethylamine
hydrofluoride (VI).

1378
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
FIGURE 3 Fragments of 19F NMR spectra of the reaction mixtures containing a,b-fluorine atoms of pyridyl rings
of ethers (XIII), (XIV), and (XV). Presented spectra: (a), isolated ether (XIV); (b), ether (XIV) on the initial portion
of the kinetic curve; (c), isolated ether (XIII); (d), ether (XIII) on the initial portion of the kinetic curve; (f), isolated
ether (XV).

Interaction with Pentafluoropyridine
1379
of T (XVI) and U (XV) is observed (Scheme 3). 19F NMR spectra are presented on
Figure 3f. Signals of all fluorine atoms of pyridyl fragments attached to the nitrogen
atom are observed in lower field. Multiplets of fluorine atoms in a, a’ positions (73
ppm) have a more complicated structure and more components as compared to
hydroxyl derivatives. Signals of b,b’ fluorine atoms in XV appear as two
approximate multiplets (center at 21 ppm) of equal intensity, multiplets of XVI
being overlapped. These signals are broadened, which is stipulated by the
additional interaction of fluorine atoms with pyrimidine nitrogen. The individual
products have no absorption bands of protons at nitrogens in IR and PMR spectra.
The data confirm the attachment of the forth substrate molecule to nitrogen, but not
to the other nucleophilic centers of pyrimidine. Purine base in XIII is not modified
under the conditions of arylation of pyrimidine fragment.
It should be noted that the signals of b,b’ fluorine atoms appear to be rather
sensitive to the nature of g-arene substituents. It can be used for both the
interpretation of the interaction of polyfluorinated substrates with polynucleophilic
molecules and various physicochemical investigations.
Kinetics of the process shown on Scheme 1 was followed by 19F NMR spectra
(Figures 1 and 2). Accumulation of ethers VI and V was determined by measuring
integral intensities of signals of fluorine atoms of C’ and C rings, respectively. The
content of ether IV, whose multiplet overlaps the signals of fragment A’ (Figure 1a,
b), was calculated by dividing the integral intensity of signals of fluorine atoms in
ring C’ (diether VI). The data in Figures 1 and 2 confirm the reactions drawn on
Scheme 1. The substitution of g-fluorine of pentafluoropyridine results in the
exponential increase of signal intensity at 29.5 ppm (Figure 2, curve 1). At any time,
decreasing the substrate in the reaction mixture is in accordance with the
accumulation of the reaction products. Concentrations of monoethers IV and V
increase from zero, achieve maximum, and decrease again to zero. The kinetic
curve of diether VI formation goes through maximum in the region of the highest
summary concentrations of monoethers IV and V; the tangent of the angle of slope
values are equal to 0.6, 1.2, 1.4, 2.8, 1.8, and 1.5 in 1.5, 2.15, 2.65, 3.1, 3.6, and 4.05
h of the reaction, respectively. S-Like dependence 4 (Figure 2) also confirms its
formation in the successive processes from its precursors (ethers IV and V), the rate
of the former formation being three times higher (curves 2 and 3, respectively).
To reveal specific properties of polynucleophilic reagents, we compare the
rates of arylation of primary and secondary hydroxyl groups in thymidine and in
mononucleophiles—ethanol and iso-propanol (Scheme 1). The rate ratios of the
formation of ethers IX and X as well as of primary and secondary thymidine
ethers IV and V measured on the initial regions of kinetic curves give the follow-
ing values:
IV=V ¼ 3:1f1g; IX=X ¼ 4:3f2g; IV=IX ¼ 2:2f3g; V=X ¼ 2:5f4g
The values {1} and {2} can be caused by higher ionization of the primary
hydroxyl group in the presence of triethylamine and by lower steric hindrances as

1380
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
compared to the secondary hydroxyl group. The ratios {3} and {4}, however,
contradict the ratios {1} and {2} and the known data,[8] that an amplification of
methylene groups in alcoholates leads to decreasing the reactivity of a nucleophile
as it is in the ratios {1} and {2}, but not to an increase of that as in ratios {3} and
{4}. Thus, thymidine hydroxyl groups attached to the relatively large pentose
molecule appear to be more reactive than analogous nucleophilic centers in simpler
molecules. The possible explanation of the revealed specificity of polynucleophilic
molecules can be participation of the hydrogen atom of one of the hydroxyl groups
in intermolecular solvataion, which causes an increase of concentration of the
intermediate Meisenheimer s-complex. Formation of the intermediate in the
analyzing process is the limited stage, as it is for the reactions of activated arenes
with anion reagents. The other distinguishing factor of polynucleophilic compounds
making them more active reagents can be participation of the 5’- and 3’-hydroxyl
groups in spiro-complex formation, the more stable intermediate than the classic
Meisenheimer s-complex. Therefore, one can assume that in the presence of
vicinal hydroxyl groups in pentose, the role of the spiro-cyclic intermediate in
changing ratios of arylation rates will be especially noticeable. Compounds of this
type (for example, adducts of nucleosides with polynitroarenes) are well
known.[9–12] Indeed, the kinetic investigation of the ethers XIII and XIV formation
showed more rapid accumulation of the primary ethers than of the secondary ethers
during all the process. The most characteristic example of the initial reaction stages
is presented in Figure 3. Signals of individual ethers XIII, XIV, and their precursors
are shown in Figure 3a, b and 3c, d, respectively. In the beginning of the reaction, a
half of the integral multiplet intensity in low field (centers at ꢀ 5.75 and 6.45 ppm)
assigned to b,b’-fluorine atoms of the secondary esters exceeds by half the multiplet
intensity of the primary ethers (4.45 and 5.15 ppm) (Figure 3b, d). Despite seven
arylation products exist in the reaction mixture, multiplets at 4.4 ppm are
symmetric and their chemical shift is not changed during all the process. Thus,
there is no significant cross-impact of the substituents in 2’, 3’, and 5’-positions. The
complicated signals at ꢀ 5.75 and 6.45 ppm (Figure 3b, d) consist of three general,
partly overlapping multiplets of the close intensity. These signals belong,
apparently, to the mixture three secondary ethers in about equal proportion.
Thus, the formation of secondary ethers for ribonucleosides having three
hydroxyl groups is carried out faster than in the case of deoxyribonucleosides
containing only two hydroxyl groups (Scheme 1). One of the reasons of the
conversion of reactivity of two nucleophilic centers (5’>3’ for dioxy- and 3’>5’ for
trioxy-derivatives) can be intensification of substitution at vicinal hydroxyl groups
because of intermolecular nucleophilic substitution (Smiles rearrangement) carrying
out via intermediate spiro-cyclic Meisenheimer s-complex.[9–13] Formation of such
an intermediate with participation of the 5’ and 3’ hydroxyls is also possible; the
rate of its accumulation and its stability, however, must be significantly lower. It
should be noted that the potentiality of anion s-complexes in organic synthesis[13] is
not expanded yet into nucleoside chemistry.

Interaction with Pentafluoropyridine
1381
It should be noted that an increase of congenerous nucleophilic groups on the
same molecule results in appreciable difference of their reactivity that can be
utilized for the selective modification of biopolymers.
EXPERIMENTAL
1H and 19F NMR spectra were registered on Bruker WP 200 SY spectrometer
(Germany) at 295 K and working frequencies of 200.13 and 188.28 MHz,
respectively. The values of chemical shifts (d, ppm) were measured relative to
1
internal standards SiMe4 for H and C6F6 for 19F NMR. The coupling constants
J are given in Hz. Melting points were determined using Koefler S 30 A/G table
(Germany).
The following chemicals were used: thymidine (Yamasa Shoyu Co., Ltd.,
Japan), adenosine and deoxyadenosine (Reanal, Hungary), and uridine (NPO
Biokhimreaktiv, Russia). Pentafluoropyridine had no admixtures according to 19F
NMR spectrum. Silica gel (40–100 mm) was used for column chromatography.
Solvents were purified according to known procedures[10] and stored over
˚
molecular sieves 4 A.
The completeness of reactions and homogeneity of the resulting products were
monitored by TLC and HPLC. TLC was carried out on Kieselgel 60F254 (Merck,
Germany) in 10:1 (A), 20:1 (B), 5:1 (C) CHCl3–MeOH mixtures and 10:1 (D)
benzol–dioxane mixtures. Analytical HPLC was carried out on the microcolumn
liquid chromatograph Milikchrom-1 (Nauchpribor, Russia) using a CHROM
system for collection and analysis of chromatographic data,[11] a Nucleosil 100-5 C-
18, 5-mm column (Macherey-Nagel, Germany) and elution during 20 min in a
gradient of CH3CN (70–90%) in 0.1% TFA at a flow rate of 100 mL/min.
Interaction of thymidine with pentafluoropyridine using the
19F NMR. Pentafluropyridine (147 mg, 0.87 mmol) and triethylamine (96 mg,
0.95 mmol) were added to a solution of thymidine (100 mg, 0.41 mmol) in DMF
(0.4 mL), and the reaction mixture was kept at room temperature, while registering
19F NMR spectra in 0.5, 0.75, 1.0, 1.5, 3.0, 6.0, and 12 h after the beginning of the
reaction. Relative contents of the products were determined according to integral
intensities of resonances in the range of 1–6 ppm (Figures 1, 2).
Interaction of ethanol and isopropanol with pentafluoropyr-
idine using the 19F NMR. Triethylamine (97 mg, 0.95 mmol) and ethanol
(44 mg, 0.95 mmol) or isopropanol (57 mg, 0.95 mmol) were added to a solution of
pentafluropyridine (154 mg, 0.91 mmol) in DMF (0.4 mL), and the reaction
mixtures were kept at room temperature, while registering 19F NMR spectra in 10,
20, 30, and 40 h after the beginning of the reactions. Relative contents of the
products IX and X were determined according to integral intensities of resonances
in the range of 1–6 ppm.

1382
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
3’,5’-O-bis(a,b,b’,a’-tetrafluoropyrid-g-yl)thymidine (VI). Pen-
tafluropyridine (166 mg, 0.98 mmol) and triethylamine (111 mg, 1.10 mmol) were
added to a solution of thymidine (116 mg, 0.48 mmol) in DMF (0.5 mL), and the
reaction mixture was kept for 16 h at 56–58°C. The completion of the reaction was
registered by 19F NMR by the absence of pentafluropyridine. The reaction mixture
was poured into ice and water and neutralized with concentrated HCl. The
resulting precipitate was filtered, washed with distilled water, and dried in air and
then in vacuum over NaOH to give the product with a yield of 250 mg (96% to
thymidine) with the purity of 91% (here and hereinafter, according to HPLC). The
product with Rf 0.5 (A) was purified by column chromatography on silica gel
(elution with CHCl3). A portion of the product (100 mg) isolated by
chromatography was recrystallized from 20% isopropanol in hexane to give (VI)
1
˜
(36 mg) with a purity exceeding 99%; mp 88–90°C; H NMR (NDCl3): 6 (3 H, s,
CH3), 2.48–2.79 (2 H, m, H2’), 4.60 (1 H, br. s, H4’), 4.80 (2 H, br. s, H5’), 5.52 (1 H,
br. s, H3’), 6.30 (1 H, d., H1’), 7.17 (1 H, s, H6), and 9.59 (1 H, br. s, 3-NH); 19F
NMR (DMF): 4.58 [2 F, m, 5’-([b],[b]’-difluoropyrid-4-yl)], 5.55 [2 F, m, 3’-([b],[b]’-
difluoropyrid-4-yl)], 70.69 [2 F, m, 5’-([a],[a]’-difluoropyrid-4-yl)], and 71.16 [2 F, m,
3’-([a],[a]’-difluoropyrid-4-yl)]. Found, %: C 44.12 and 45.31; H 2.29 and 2.42; N
10.43 and 10.25; F 28.36 and 28.59. C20H12F8N4O5. Calc., %: C 44.46, H 2.24, N
10.37, F 28.13.
3’,5’-O-bis(a,b,b’,a’-tetrafluoropyrid-g-yl)adenosine (VII). Pen-
tafluropyridine (371.9 mg, 2.2 mmol) and triethylamine (253 mg, 2.5 mmol) were
added to a solution of adenosine (251.3 mg, 1 mmol) in DMF (2 mL), and the
reaction mixture was kept for 7 days at room temperature. The reaction was
monitored and the product (VII) was isolated as described above for (VI) with a
yield of 459 mg (83.6% to adenosine). A portion of the product was recrystallized
1
˜
from isopropanol; mp 120–123°N. H NMR (acetone ꢁ d6): 3.26 (2 H, m, H2’);
4.85 (1 H, br. s, H4’); 5.04 (2 H, br. s, H5’); 5.98 (1 H, br. s, H4’); 6.64 (4 H, br. s,
H2’, NH2); 8.18 (2 I, d, H2, H8); 19F NMR (DMF): 4.70 [2 F, m, 5’-([b],[b]’-
`
difluoropyrid-4-yl)]; 5.71 [2 F, m, 3’-([b],[b]’-difluoropyrid-4-yl)]; 70.54 [2 F, m, 5’-
([a],[a]’-difluoropyrid-4-yl)], and 71.06 [2 F, m, 3’-([a],[a]’-difluoropyrid-4-yl)].
Found, %: C 43.72 and 44.06; H 2.18 and 2.21; N 17.88 and 16.98; F 27.76 and
˜
27.45. C20H11F8N7O3. Calc., %: N 43.73, H 2.02, N 17.85, F 27.66.
3’,5’-O-tris(a,b,b’,a’-tetrafluoropyrid-g-yl)adenosine (XIII).
Pentafluoropyridine (506 mg, 2.99 mmol) and triethylamine (331 mg, 3.28 mmol)
were added to a solution of adenosine (250 mg, 0.94 mmol) in DMF (2 mL), and the
reaction mixture was kept for 8 days at room temperature. The reaction was
monitored and the product (XI) was isolated as described above for (V) with a
guantitative yield (810 mg) and 97% purity. After recrystallization from propanol the
1
˜
purity of (XI) exceeded 99%; mp 81–83°C; H NMR (NDCl3): 4.78–5.00 (3 H, m,
H5’, H4’), 5.92 (2 H, br. s, 6-NH), 6.12 (1 H, d., H3’), 6.34–6.40 (2 H, m, H1’ and

Interaction with Pentafluoropyridine
1383
H2’), 7.91 (1 H, s, H8), and 8.18 (1 H, s, H2). 19F NMR (DMF): 4.78 [2 F, m, 5’-
([b],[b]’-difluoropyrid-4-yl)], 6.72 [2 F, m, 3’-([b],[b]’-difluoropyrid-4-yl)], 70.57 [2 F,
m, 5’-([a],[a]’-difluoropyrid-4-yl)], and 71.51 [2 F, m, 3’-([a],[a]’-difluoropyrid-4-yl)].
Found, %: C 42.51 and 42.23; H 1.96 and 1.73; N 15.41; F 32.26 and 32.56.
C25H10F12N8O4. Calc., %: C 42.03, H 1.41, N 15.69, F 31.91.
2’,3’,5’-O-tris(a,b,b’,a’-tetrafluoropyrid-g-yl)uridine (XIV).
Pentafluropyridine (554 mg, 3.28 mmol) and triethylamine (363 mg, 3.58 mmol)
were added to a solution of uridine (250 mg, 1.02 mmol) in DMF (2 mL), and
the reaction mixture was kept for 6 days at room temperature. The product was
isolated with a yield of 86% (709 mg, 86% purity) as described above. Purification
by column chromatography on silica gel (elution with 49:1 CHCl3-MeOH)
yielded the product with Rf 0.5 (B), which was recrystallized from 7:3 propanol-
1
˜
water to give (XII) (315 mg, 99% purity ); mp 78–80°C. H NMR (NDCl3):
4.76–5.00 (3 H, m, H5’ and H4’), 5.61 (2 H, br. s, H2’ and H3’), 5.77 (1 H, d.,
H5), 5.96 (1 H, s, H1’), 7.42 (1 H, d., H6), 9.52 (1 H, br. s, 3-NH). 19F NMR
(DMF): 4.82 [2 F, m, 5’-([b],[b]’-difluoropyrid-4-yl)], 6.18 [2 F, m, 3’-([b],[b]’-
difluoropyrid-4-yl)], 70.64 [2 F, m, 5’-([a],[a]’-difluoropyrid-4-yl)], 71.52 [2 F, m, 3’-
([a],[a]’-difluoropyrid-4-yl)]. Found, %: C 41.79 and 42.08; H 1.59 and 1.71, N
10.01, F 32.56 and 32.84. C24H9F12N5O6. Calc., %: C 41.70, H 1.31, N 10.13,
F 32.97.
2’,3’,5’-O-3-N-tris(a,b,b’,a’-tetrafluoropyrid-g-yl)thymidine
(XVI). Pentafluropyridine (760.7 mg, 4.5 mmol) and K2CO3 (691 mg, 5 mmol)
were added to a solution of thymidine (242.2 mg, 1 mmol) in DMF (3 mL), and the
reaction mixture was kept for 5 days at 60°C. The completion of reaction was
monitored by 19F NMR. The reaction mixture was poured into ice water and
neutralized with concentrated HCl. The resulting precipitate was filtered, washed
with distilled water, and dried in air and then in vacuum over NaOH to give the
product with a yield of 829 mg (78.8% to thymidine). Purification by column
chromatography on silica gel (elution with CHCl3) yielded the product with Rf 0.8
(C), which was recrystallized from propanol to give (XVI) 543 mg; mp 36–38°C.
1
˜
H NMR (NDCl3): 1.96 (3 H, s., CH3); 2.62 (2 H, m., H2’); 4.57 (1 H, d, H3’); 4.75 (2
H, br. s, H5’); 5.44 (1 H, br. s, H4’); 6.30 (1 H, m., H1’); 7.18 (1 H, br. s, H6). 19F
NMR (DMF): 6.99 [2 F, m, 5’-([b],[b]’-difluoropyrid-4-yl)]; 7.35 [2 F, m, 3’-([b],[b]’-
difluoropyrid-4-yl)]; 22.35 [2 F, m, N3-([b],[b]’-difluoropyrid-4-yl)]; 72.25 [2 F, m, 5’-
([a],[a]’-difluoropyrid-4-yl)]; 73.33 [2 F, m, 3’-([a],[a]’-difluoropyrid-4-yl)]; 75.82 [2 F,
m, N3-([a],[a]’-difluoropyrid-4-yl)]. Found, %: N 43.31; H 1.56; N 9.77; F 33.10.
C29H8F16N6O6. Calc., %: N 43.56, N 10.16; H 1.61; F 33.07.
˜
˜
2’,3’,5’-O-3-N-Tetra(a,b,b’,a’-tetrafluoropyrid-g-yl)uridine
(XV). Pentafluropyridine (1014.3 mg, 6 mmol) and K2CO3 (967.4 mg, 7 mmol)
were added to a solution of uridine (242.2 mg, 1 mmol) in DMF (3 mL), and the

1384
V. V. Litvak, I. Ya. Mainagashev, and O. G. Bukhanets
reaction mixture was kept for 6 days at 50°C. The product was isolated with a yield
of 660 mg (78.57 to uridine) as described above. Purification by column
chromatography on silica gel (elution with benzene) yielded the product with Rf
0.6 (D), which was recrystallized from ether-hexane to give (XV) (300 mg); mp 41–
1
˜
42°C. H NMR (NDCl3): 4.91 (2 H, br. s, H5’); 5.55 (2 H, br. s, H2’, H3’); 6.00 (1 H,
d., H5); 6.15 (1 H, s., H4’); 7.27 (1 H, s., H1’); 7.63 (1 H, d., H6). 19F NMR (DMF):
4.80 [2 F, m, 5’-([b],[b]’-difluoropyrid-4-yl)]; 5.84 [2 F, m, 3’-([b],[b]’-difluoropyrid-4-
yl)]; 6.17 [2 F, m, 2’-([b],[b]’-difluoropyrid-4-yl)]; 20.37 [2 F, m, N3-([b],[b]’-
difluoropyrid-4-yl)]; 70.46 [2 F, m, 5’-([a],[a]’-difluoropyrid-4-yl)]; 71.38 [2 F, m,
3’,N3-([a],[a]’-difluoropyrid-4-yl)]; 73.3 [2 F, m, 2’-([a],[a]’-difluoropyrid-4-yl)].
˜
˜
Found, %: N 41.64; H 0.91; N 9.89; F 36.27. C29H8F16N6O6. Calc., %: N 41.45, N
10.00; H 0.96; F 36.17.
g-Ethoxy-a,b,b’,a’-tetrafluoropyridine (IX). 19F NMR: 3.86 (2 F,
m, F3, and F5), 70.41 (2 F, m, F2, and F6). The contents of (IX) at the above-
mentioned time points were 66, 82, 87, and 91%, respectively.
g-Isopropyloxy-a,b,b’,a’-tetrafluoropyridine (X). 19F NMR: 4.89
(2 F, m, F3, and F5), 70.67 (2 F, m, F2, and F6). The contents of (X) at the above-
mentioned time points were 13, 24, 35, and 43%, respectively.
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