Unexpected formation of 2′-deoxy-N3-(3,3,3-trifluoro-1-propenyl)uridine via a Michael-type addition to 3,3,3-trifluoropropyne

Article abstract of DOI:10.1016/S0040-4039(03)01702-7

Reaction of 3,3,3-trifluoropropyne with 2′-deoxy-5-iodouridine under conditions that have previously been used to prepare 5-alkynyl-2′-deoxyuridine derivatives gave 2′-deoxy-N3-(3,3,3-trifluoro-1-propenyl)uridine. This unexpected alkylation is a result of a Michael-type addition of N3 on the pyrimidine base to the electron deficient trifluoropropyne.

Full text of DOI:10.1016/S0040-4039(03)01702-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6899–6901
Unexpected formation of
2%-deoxy-N3-(3,3,3-trifluoro-1-propenyl)uridine via a
Michael-type addition to 3,3,3-trifluoropropyne
Panadda Chirakul and Snorri Th. Sigurdsson*
Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA
Received 24 June 2003; revised 3 July 2003; accepted 8 July 2003
Abstract—Reaction of 3,3,3-trifluoropropyne with 2%-deoxy-5-iodouridine under conditions that have previously been used to
prepare 5-alkynyl-2%-deoxyuridine derivatives gave 2%-deoxy-N3-(3,3,3-trifluoro-1-propenyl)uridine. This unexpected alkylation is a
result of a Michael-type addition of N3 on the pyrimidine base to the electron deficient trifluoropropyne.
© 2003 Elsevier Ltd. All rights reserved.
The selective introduction of a fluorine atom or a
fluorinated moiety into a biologically active molecule is
emerging as an effective tool for modifying its physico-
chemical properties and physiological behavior.1,2 In
addition, the study of conformational changes in bio-
polymers as a function of conditions, mutations or
interactions with other macromolecules or drugs can be
facilitated by spectroscopic methods that utilize fluorine
atoms. For example, 19F solution NMR has been used
to study conformational changes in the hammerhead
ribozyme.3 Large-scale conformational changes in bio-
polymers have also been determined by 19F–31P rota-
tional–echo double resonance (REDOR) solid state
NMR for observing ligand binding and the coupled
conformational change of 5-enolpyruvylshikimate-3-
phosphate synthase.4 This strategy has also been
extended to nucleic acids to measure distances between
a phosphodiester and a fluorine atom placed on either
a sugar or a base moiety.5,6
idine base with concomitant elimination of a fluorine
atom. Although this problem could be circumvented for
DNA by using more labile protecting groups and
milder deprotection conditions, this approach cannot
be extended to RNA synthesis due to the lack of
commercially available reagents. Therefore, we decided
to
prepare
2%-deoxy-5-(3,3,3-trifluoro-1-propy-
nyl)uridine 1, in which a similar elimination of fluorine
would not be as facile due to formation of a cumulene
intermediate, and would thus be more stable under
standard deprotection conditions.
Reaction of commercially available 2%-deoxy-5-
iodouridine with 3,3,3-trifluoropropyne in dimethylform-
amide in the presence of tetrakis(triphenylphos-
phine)palladium(0) and copper iodide8 (Scheme 1)
resulted in a new major product in 80% yield.9 How-
To increase the range of distance measurements past 20
,
A in nucleic acids by solid state NMR, we are inter-
ested in incorporation of a trifluoromethyl group in
place of a fluorine atom. Recently, we reported that the
trifluoromethyl group at position 5 of 2%-deoxyuridine
was converted to a cyano group by aqueous ammonia
under standard deprotection conditions during DNA
synthesis.7 This transformation takes place through an
addition–elimination mechanism initiated by nucleo-
philic addition of ammonia to position 6 of the pyrim-
* Corresponding author.
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01702-7

6900
P. Chirakul, S. T. Sigurdsson / Tetrahedron Letters 44 (2003) 6899–6901
(Scheme 2). This result also shows that the car-
bonꢀiodine bond in the nucleoside is readily reduced
under these reaction conditions. In a separate experi-
ment, the Pd/Cu catalyst was shown not to be necessary
for the N3 alkylation of 5-iodo-2%-deoxyuridine with
3,3,3-trifluoropropyne. Moreover, the reaction of 3,3,3-
trifloropropyne with 2%-deoxyuridine gave nucleoside 2,
demonstrating that the iodine is not required for incor-
poration of the trifluoropropenyl group. Based on our
experiments, we postulate that the mechanism of N-
alkylation in formation of 2 is analogous to the
Michael reaction,15 where the pyrimidine N3 adds as a
nucleophile to the terminal carbon of the alkyne, which
is electrophilic due to the presence of the strongly
electron withdrawing CF3 group.
In
conclusion,
2%-deoxy-N3-(3,3,3-trifluoro-1-pro-
penyl)uridine (2) was synthesized in high yield from
commercially available materials. The 3,3,3-trifluoro-
propenyl group (CF3CHꢁCH-) has been used to
improve the properties of candidate compounds for
medicines or agricultural chemicals.16,17 In particular,
trifluoromethyl enamine is an intermediate in the syn-
thesis of apolipoprotein B inhibitors.18 Although a vari-
ety of methods have been developed for synthesizing
3,3,3-trifluoropropenyl compounds, they exhibit several
disadvantages and require multistep reactions. The
direct alkylation of pyrimidines with trifluoropropyne
reported here suggests a general approach for the syn-
theses N3-trifluoropropenylated nucleosides.
Scheme 2.
ever, the spectroscopic data10 were not consistent with
the desired compound (1). The molecular weight (m/z
345.0673 (M+Na)+, ESI-TOF) was two units higher
than expected and in combination with 13C and 1H
NMR provided direct evidence for incorporation of
-CHꢁCH-CF3 instead of -CꢂC-CF3. Specifically, the 13
C
NMR spectrum of compound 2 in DMSO-d6 showed
three new quartets at 129.88 (J=5.81 Hz), 121.55 (J=
1
285.27 Hz), and 118.30 (J=35.26 Hz) ppm and the H
NMR spectrum exhibited two olefinic protons at 6.65
(d) and 6.37 (dq) ppm. Furthermore, a 135DEPT experi-
ment showing a proton at the 5 position and J-coupling
observed between the protons in the 5 and 6 positions
in a 2D-COSY spectrum ruled out the connectivity of
the trifluoromethyl-containing side chain at the 5 posi-
tion. The NMR spectroscopic data10 for compound 2
showed clearly that the trifluoropropenyl group was
attached on the base of nucleoside, rather than the
sugar. The connectivity of the trifluoropropenyl group
to the base was further supported by MS–MS analysis,
which showed a loss of deoxyribose. However, the
spectroscopic data could not be used to determine
where the trifluoropropenyl group was linked to the
base.
Acknowledgements
This work was supported by the National Institutes of
Heath (GM 58914). The authors thank V. Pons for
technical assistance (Schlenk line) and helpful discus-
sions, and Dr. M. Sadilek for assistance with LC/MS
analyses.
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was added copper iodide (20 mg, 0.1 mmol) and tetra-

P. Chirakul, S. T. Sigurdsson / Tetrahedron Letters 44 (2003) 6899–6901
6901
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NMR (DMSO-d6, 500 MHz): 7.99 (1H, d, J=8.15 Hz,
H6), 6.65 (1H, d, J=9.30 Hz, NCHꢁ), 6.37 (1H, dq,
J=17.25, 8.5 Hz, CF3CHꢁ), 6.16 (1H, t, J=6.45 Hz,
H1%), 5.83 (1H, d, J=8.10 Hz, H5), 5.28 (1H, d, J=3.70
Hz, 3%OH), 5.01 (1H, m, 5%OH), 4.25 (1H, m, H3%), 3.81
(1H, m, H4%), 3.61 (2H, m, H5% and H5¦), 2.10 (2H, m,
H2% and H2¦). 13C NMR (DMSO-d6, 199 MHz): 160.46
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121.55 (CF3, J=285.27 Hz), 118.30 (ꢁC2, J=35.26 Hz),
100.42 (C5), 87.34 (C4%), 84.44 (C1%), 69.84 (C3%), 60.76
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1
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