Synthesis of 5-fluorovinyl derivatives of pyrimidines via Suzuki-Miyaura coupling and their 1,3-dipolar cycloaddition reactions with nitrones

Article abstract of DOI:10.1016/j.jfluchem.2011.11.005

A simple two-step synthesis of a new class of fluorinated isoxazolidinyl derivatives of pyrimidine is described. The reactions proceed via the Suzuki-Miyaura coupling followed by highly regioselective 1,3-dipolar cycloaddition with nitrones. Removal of th

Full text of DOI:10.1016/j.jfluchem.2011.11.005

Journal of Fluorine Chemistry 135 (2012) 225–230
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of 5-fluorovinyl derivatives of pyrimidines via Suzuki–Miyaura
coupling and their 1,3-dipolar cycloaddition reactions with nitrones
*
´
Hanna Wojtowicz-Rajchel , Henryk Koroniak
Adam Mickiewicz University, Department of Chemistry, Grunwaldzka 6, 60-780 Poznan´, Poland
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple two-step synthesis of a new class of fluorinated isoxazolidinyl derivatives of pyrimidine is
described. The reactions proceed via the Suzuki–Miyaura coupling followed by highly regioselective 1,3-
dipolar cycloaddition with nitrones. Removal of the pyrimidine protecting groups leads to a fluorinated
isoxazolidine analogue of pseudouridine.
Received 4 October 2011
Received in revised form 14 November 2011
Accepted 14 November 2011
Available online 23 November 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Fluorinated nucleobases
Isoxazolidines
Cross-coupling
Cycloaddition
Pseudouridine
1. Introduction
groups to molecules, only a few reports have been published on the
reactions of fluoroalkenes with nitrones [7].
1,3-Dipolar cycloadditions of nitrones to alkenes leading to
isoxazolidines are especially important in organic chemistry [1].
Numerous uses of isoxazolidines have been reported in total
synthesis, often based on their ability to be transformed into
polyfunctional amines including aminoalcohols, aminoketones
and esters [2]. In recent years much attention has been paid to
heterocyclic nucleosides having an isoxazolidine moiety instead of
a ribofuranose ring. The synthesis of modified isoxazolidine
nucleosides using nitrones and N-vinyl nucleobases as dipolar-
ophiles is the most convenient and simplest method [3]. Some of
these nucleosides have been found to show high cytostatic activity
[4]. To the best of our knowledge only a few papers have reported
on the synthesis of isoxazolidine and isoxazole analogues of C-
nucleosides. These compounds were obtained from the 1,3-dipolar
cycloadditions of nitrones based on a pyrimidine ring with the
appropriate dipolarophiles [5].
2. Results and discussion
In the course of our work on fluorovinyl derivatives of nucleic
acid bases [8], in this paper we wouldlike to report our results on the
palladium-catalysed Suzuki–Miyaura cross-coupling of fluoroalk-
enes with pyrimidine derivatives and on the use of the products as
dipolarophiles in 1,3-dipolar cycloadditions with nitrones. A new
class of fluorinated isoxazolidine derivatives was synthesised and
furthermore, as a result of non-standard hydrolysis of protecting
groups, a fluorinated isoxazolidine derivative of pseudouridine was
obtained. The classical route to fluorovinylpyrimidines involves
palladium-catalysed cross-coupling reactions of perfluoroalkenyl-
zinc reagents with halogenopyrimidines in Negishi reactions [9].
Pentafluoropropenylpyrimidines can also be alternatively obtained
by lithiation of bromopyrimidines at positions C-5 or C-6 followed
by Michael type addition–elimination reactions with hexafluor-
opropene (HFP) [8a,10]. Unfortunately, the organozinc method is
characterised by unsatisfactory yields, while the lithiated pyrimi-
dines only react with HFP, which is strongly activated electrophile
due to the electron withdrawing CF3 group.
Fluorinated analogues of biologically important compounds
have aroused much interest because of their unique properties
which are important for medicinal chemistry and biochemistry [6].
Although there is a growing interest in the development of new
methods for the introduction of a fluorine atom or fluorinated
Coupling reactions of the previously described 5-(dihydrox-
yboryl)-2,4-bis(alkoxy)-pyrimidines 4–6 [11] with the appropriate
olefins in the presence of Pd(PPh3)4 and KOH took place smoothly
in THF at 65–70 8C to give compounds 7–9 but in unsatisfactory
yields. The use of AsPh3 as an external ligand has considerably
* Corresponding author. Tel.: +48 61829 1304; fax: +48 61829 1507.
E-mail address: wojto@amu.edu.pl (H. Wo´jtowicz-Rajchel).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.11.005

226
H. Wo´jtowicz-Rajchel, H. Koroniak / Journal of Fluorine Chemistry 135 (2012) 225–230
product was the corresponding homocoupled C-5–C-50 bipyrimi-
dinyl (entry 8).
Table 1
5-Fluorovinyl derivatives of pyrimidines via Suzuki–Miyaura coupling reactions.
Entry
Product
R
R1
R2
R3
Yield (%)a
The direct 1,3-dipolar cycloaddition of 5-fluorovinyl pyrimi-
dines 8a–c as dipolarophiles and N-methyl- and N-benzyl-
methylenenitrones was performed according to Scheme 2, and
the results are presented in Table 2. The reaction procedure is
simple and straightforward. The nitrones were generated in situ by
reaction of paraformaldehyde with the hydrochloride of the
appropriate substituted hydroxylamine in the presence of
triethylamine, or had been prepared earlier according to known
procedures [12]. Cycloadditions of the nitrones were carried out in
a glass pressure tube in toluene at 80 8C for 48–72 h.
1
2
3
4
5
6
7
8
7a
7b
8a
8b
8c
9a
9b
10
C2H5
t-Bu
F
F
F
65 (49)
45
F
F
F
C2H5
t-Bu
F
CF3
CF3
CF3
H
F
68 (34)
40
F
F
CH2Ph
C2H5
t-Bu
F
F
71 (47)
61 (17)
40
CF3
CF3
CF3
H
H
F
H
C2H5
F
0
a
Isolated yields of the reaction using the catalytic system Pd(PPh3)4/AsPh3.
Yields in parentheses are those from the reaction without AsPh3.
Each time two diastereoisomers of the product were obtained
with significant dominance of one of them. As followed by 19F NMR
spectroscopy, the ratio of the two diastereoisomers differs from
3.9:1 to 4.9:1. The cycloaddition reactions were completely
regiospecific. Moreover, only the isomer E was actively involved
in the 1,3-dipolar cycloaddition, while the Z isomer remained
unchanged (or almost unchanged) in the reaction mixture. Also, in a
simple model system, the reaction of perfluoroprop-1-enyl benzene
(E/Z ratio = 4.8:1) with N-methyl-methylenenitrone results in 1,3-
dipolar cycloaddition giving 4,5-difluoro-2-methyl-5-phenyl-4-
(trifluoromethyl)isoxazolidine 18 with diastereoisomeric ratio
improved the yield of this reaction, so the catalytic system
Pd(PPh3)4/AsPh3 was assumed particularly beneficial and was used
in transformations of this type (Table 1). The exceptions were
compounds 7b, 8b and 9b as under the reaction conditions the t-
butoxy groups underwent hydrolysis reactions which significantly
decreased the yields of these compounds (Scheme 1). The coupling
reactions with 2-bromo-1,1,3,3,3-pentafluoropropene failed total-
ly. Monitoring of the reactions by 1F NMR did not allow the
detection of the formation of any fluorinated product, and the only
Scheme 1. Suzuki–Miyaura coupling reactions between fluoroalkenes and 5-(dihydroxyboryl)-2,4-bis(alkoxy)-pyrimidines 4–6.
Scheme 2. The synthesis of fluoroisoxazolidines 11–15.

H. Wo´jtowicz-Rajchel, H. Koroniak / Journal of Fluorine Chemistry 135 (2012) 225–230
227
Table 2
E and displayed the trans configuration between two fluorine
atoms, was confirmed from the single crystal X-ray data (Fig. 1)
[14]. Unfortunately, detailed analysis of the 19F and 1H NMR
spectra, using the J values was impossible because the signals were
unusually broad and without detectable couplings between H, F
and H, H atoms.
Dipolar cycloadditions of nitrones to 5-fluorovinyl pyrimidine derivatives.
Entry
Starting
Product (ratio of
diastereoisomers)
R
R1
R2
Yield
(%)
material
(E/Z ratio)
1
2
3
4
5
8a (2.1: 1)
8a (2.1: 1)
8b (2.3: 1)
8c (2.5: 1)
7a
11 (3.9:1)
12 (4.1:1)
13 (4.7:1)
14 (4.9:1)
15
C2H5
C2H5
t-Bu
CF3
CF3
CF3
CF3
F
CH2Ph
CH3
45a
58a
53a
55a
38
Standard attempts at removal of the protective ethyl and benzyl
groups from pyrimidines 12 and 14 failed and did not produce the
expected pseudouridine analogue. The use of trimethylchlorosi-
lane in the presence of NaI as well as heating in acetic acid in the
presence of NaI led to cleavage of the N–O bond of the isoxazolidine
ring and gave compound 16 (multiplets assigned to the two clearly
distinguishable protons of a CH2 group in the 1H NMR spectrum
and a multiplet assigned to CF in the 19F NMR spectrum). Attempts
at removal of the benzyl groups by catalytic hydrogenolysis on
palladium led also to reductive cleavage of the isoxazolidine ring.
In all the above reactions, the highly electronegative F-10 atom was
abstracted from the C-10 which is particularly susceptible to
nucleophilic attack. The mechanism of the reaction of compound
15 in the CH3COOH/NaI was different and the cleavage of the N–O
bond led to a pyrimidine derivative with a linear substituent
C(O)CF2CH2NHCH3 at C-5 (a triplet assigned to a CH2 group with
equivalent protons in the 1H NMR spectrum, J = 14 Hz and a triplet
assigned to a CF2 group in the 19F NMR spectrum, J = 14 Hz).
The isoxazolidine analogue of pseudouridine 17 was obtained
in a yield of 77% as a result of non-standard hydrolysis of
compound 13 in anhydrous THF at room temperature using on
almost equimolar amount of HCl (Scheme 4).
CH3
CH2Ph
C2H5
CH3
CH3
a
Isolated yield based on the mixture of E and Z stereoisomers.
1.7:1 (Scheme 3). This observation can be seen when the
dipolarophile configuration undergoes the partial inversion. To
understand this phenomenon one can assume (i) kinetic control of
the cycloaddition (E vs Z different reaction rate for reaction with
nitrone) or (ii) possible not clear concerted reaction mechanism. In
the case of electron-deficient dipolarophiles the two step pathway
with a zwitterionic intermediate may compete with the concerted
mechanism[13]. However, the isomerization can also occur through
the displacement of fluoride anion at C-10 under formation of a well
stabilized oxocarbenium anion and then the re-addition of fluoride.
The cycloaddition of 7a and the formation of compound 15 follow
the plausible mechanism of isomerization at the stage of products,
with water as a nucleophile.
The structures of compounds 11–15 were determined on the
basis of 1H, 19F and 13C NMR spectra and MS spectrometry.
Moreover, the structure of compound 13, arised from stereoisomer
Scheme 3. The synthesis of 4,5-difluoro-2-methyl-5-phenyl-4-(trifluoromethyl)isoxazolidine.
Fig. 1. ORTEP drawing of the X-ray crystallographic structure of compound 13 [15]. The thermal ellipsoids are drawn at the 50% probability level.

228
H. Wo´jtowicz-Rajchel, H. Koroniak / Journal of Fluorine Chemistry 135 (2012) 225–230
Scheme 4. Conditions: (a) Me3SiCl, NaI, CH3CN, RT, 24 h; (b) CH3COOH, NaI, 90 8C, 1–2 h; (c) 2–3 eq. HCl, anhydrous THF, RT, 24 h.
3. Conclusion
ene or 1-bromo-1,2,3,3,3-pentafluoroprop-1-ene, 6 mmol, 2.0 M
excess), as a solution in THF, was added to the reaction mixture
In summary, a simple synthesis of a new class of isoxazolidine
derivatives of pyrimidine based on the reaction of nitrones and 5-
fluorovinyl pyrimidines obtained by Suzuki–Miyaura coupling is
presented. The fluorinated isoxazolidines were obtained as two
diastereoisomers with complete regioselectivity and with a good
degree of diastereoselectivity. The mild hydrolysis conditions led
to removal of the pyrimidine protecting groups without breaking
the N–O bond of the isoxazolidine ring and hence to a fluorinated
analogue of pseudouridine. Further investigation of this trans-
formsations is ongoing and the results will be reported in due
course.
using a syringe. The reaction mixture was then heated under
stirring at 65–70 8C for 6–12 h. The progress of the reaction was
monitored by TLC checking of the loss of starting 5-(dihydrox-
yboryl)-2,4-bis(alkoxy)-pyrimidine. After cooling the organic layer
was separated and the aqueous residue was extracted with CH2Cl2
(2 ꢀ 10 mL). The combined organic layers were washed with water
and dried over Na2SO4. Solvents were removed under reduced
pressure and the crude product was purified by column
chromatography (silica gel, hexane, a gradient of hexane/CH2Cl2
from 3:1 to 1:2, v/v and CH2Cl2) affording the corresponding
compounds 7–9.
4. Experimental
4.2.1. 2,4-Diethoxy-5-(1,2,2-trifluorovinyl)pyrimidine (7a)
Colorless oil; yield 484 mg, 65%; 1H NMR (CDCl3, 300 MHz):
d
4.1. Synthesis
1.34 and 1.37 (t, J = 7 Hz, 6H, CH2–CH3), 4.37 and 4.42 (q, J = 7 Hz,
4H, CH2–CH3), 8,17 (d, J = 2 Hz, 1H, H-6); 19F NMR (CDCl3,
5-(Dihydroxyboryl)-2,4-bis(alkoxy)-pyrimidines 4–6 were pre-
pared according to Refs. [11]. All other starting materials and
reagents were obtained from Fluka or Sigma–Aldrich. Iodotri-
282 MHz):
d
ꢁ100.16 (dd, J = 30 Hz and J = 70 Hz, 1F, CF55CFF),
ꢁ116.6 (dd, J = 70 Hz and J = 117 Hz, 1F, CF55CFF), ꢁ167.68 (dd,
J = 30 Hz and J = 117 Hz, 1F, CF55CF2); MS (EI) 70 eV, m/z (rel. int):
248 [M]+ (64), 192 (51), 121 (83), 59 (100); Anal. Calcd. for
fluoroethylene,
2-bromo-3,3,3-trifluoropropene,
1-bromo-
1,2,3,3,3-pentafluoropropene and 2-bromo-1,1,3,3,3-pentafluoro-
propene were purchased from SynQuest Labs Inc. Toluene was
distilled from NaH and was stored over molecular sieves (0.4 nm).
All reactions were monitored by TLC or 19F NMR. Thin layer
chromatography was performed with 60 F254 TLC plates (Merck).
Column chromatography was performed with silica gel (Merck,
particle size 0.063–0.200 mm, 70–230 mesh). The coupling and
cycloaddition reactions were carried out under an argon atmo-
sphere.
C10H11N2O2F3: C, 48.39; H, 4.47; N, 11.28. Found: C, 48.01; H, 4.19;
N, 11.02.
4.2.2. 2,4-Di-tert-butoxy-5-(1,2,2-trifluorovinyl)pyrimidine (7b)
Colorless oil; yield 410 mg, 45%; 1H NMR (CDCl3, 300 MHz):
d
1.60–1.62 (m, 18H, t-Bu), 8.25 (d, J = 2 Hz, 1H, H-6); 19F NMR
(CDCl3, 282 MHz):
d
ꢁ101.2 (dd, J = 30 Hz and J = 71 Hz, CF55CFF),
ꢁ115.9 (dd, J = 71 Hz and J = 116 Hz, CF55CFF), ꢁ167.4 (dd,
J = 30 Hz and J = 116 Hz, CF55CF2); MS (EI) 70 eV, m/z (rel. int):
304 [M]+ (3), 192 (71), 57 (100); Anal. Calcd. for C14H19N2O2F3: C,
55.26; H, 6.29; N, 9.20. Found: C, 55.01; H, 6.37; N, 9.01.
1H, 13C and 19F NMR spectra were recorded with a Varian
Gemini 300 MHz spectrometer (300.069 MHz for 1H, 101.25 MHz
for 13C and 282.318 MHz for 19F) in CD3OD, CDCl3, TFA-d and
DMSO-d6 as solvents. TMS was the internal standard in 1H NMR,
4.2.3. 2,4-Diethoxy-5-(perfluoroprop-1-enyl)pyrimidine (8a)
CFCl3 was used as a reference for 19F NMR. Chemical shifts for 1
H
Colorless oil; yield 608 mg, 68%; 1H NMR (CDCl3, 300 MHz):
d
NMR are reported in ppm downfield from TMS and for 19F NMR
upfield from CFCl3. The mass spectra were recorded on a AMD 402
spectrometer, ionisation was achieved through electron impact
(EI). The elemental analyses were made on PerkinElmer apparatus.
Melting points were determined on a Boetius apparatus and are
reported uncorrected.
1.37–1.50 (m, 6H, CH2–CH3), 4.40–4.55 (m, 4H, CH2–CH3), 8.17 (d,
J = 2 Hz, 1H, Z isomer, H-6) and 8.27 (d, J = 1 Hz, 1H, E isomer, H-6);
19F NMR (CDCl3, 282 MHz):
d
E isomer: ꢁ67.99 (dd, J = 11 Hz and
J = 22 Hz, 3F, CF3), ꢁ136.32 (dq, J = 141 Hz and J = 22 Hz, 1F,
CF55CFCF3), ꢁ165.87 (dq, J = 141 Hz and J = 11 Hz, 1F, CF55CFCF3), Z
isomer: ꢁ67.81 (dd, J = 8 Hz and J = 14 Hz, 3F, CF3), ꢁ112.13 (m, 1F,
CF55CFCF3), ꢁ151.23 (m, 1F, CF55CFCF3); MS (EI) 70 eV, m/z (rel.
int): 298 [M]+ (64), 254 (99), 226 (100); HRMS: calculated for
4.2. General synthetic procedure and analytical data of compounds 7–
9
C11H11N2O2F5 298.07403. Found 298.07508.
In a glass pressure tube equipped with a magnetic stirrer, 5-
(dihydroxyboryl)-2,4-bis(alkoxy)-pyrimidine 4–6 (3 mmol) was
dissolved in THF (20–30 mL). Then Pd(PPh3)4 (105 mg, 0.09 mmol),
AsPh3 (150 mg, 0.5 mmol) and 5 mL of 2 M KOH were added to the
tube. The reactants were kept under argon or nitrogen atmosphere.
The fluorovinyl halide, (1,1,2-trifluoro-2-iodoethene, 2-bromo-
3,3,3-trifluoroprop-1-ene, 2-bromo-1,1,3,3,3-pentafluoroprop-1-
4.2.4. 2,4-Di-tert-butoxy-5-(perfluoroprop-1-enyl)pyrimidine (8b)
Colorless oil; yield 425 mg, 40%; 1H NMR (CDCl3, 300 MHz):
d
1.60–1.65 (m, 18H, t-Bu), 8.18 (s, 1H, Z isomer, H-6) and 8.29 (s, 1H,
E isomer, H-6); 19F NMR (CDCl3, 282 MHz):
d
E isomer: ꢁ66.4 (dd,
J = 12 Hz and J = 22 Hz, 3F, CF3), ꢁ134.9 (dq, J = 140 Hz and
J = 22 Hz, 1F, CF55CFCF3), ꢁ164.1 (dq, J = 140 Hz and J = 12 Hz,
1F, CF55CFCF3), Z isomer: ꢁ66.3 (dd, J = 8 Hz and J = 14 Hz, 3F, CF3),

H. Wo´jtowicz-Rajchel, H. Koroniak / Journal of Fluorine Chemistry 135 (2012) 225–230
229
ꢁ109.7 (m, 1F, CF55CFCF3), ꢁ151.2 (m, 1F, CF55CFCF3); MS (EI)
70 eV, m/z (rel. int): 354 [M]+ (1), 242 (39), 57 (100); HRMS:
calculated for [M-(C8H18 + H2)]+: C7H3N2O2F5 242.01147. Found
242.00928.
J = 30 Hz, C-10), 121.2 (dq, J = 283 Hz and J = 32 Hz, CF3)), 127.5,
128.1, 128.6 and 128.9 (s, Ph), 158.8 (brs, C-6), 166.0 (s, C-2), 168.2
(d, J = 2.8 Hz, C-4); MS (EI) 70 eV, m/z (rel. int): 433 [M]+ (14), 91
(100); Anal. Calcd. for C19H20N3O3F5: C, 52.66; H, 4.65; N, 9.70.
Found: C, 52.47; H, 4.81; N, 9.49.
4.2.5. 2,4-Bis(benzyloxy)-5-(perfluoroprop-1-enyl)pyrimidine (8c)
Colorless solid; m.p. 46–51 8C; yield 899 mg, 71%; 1H NMR
4.3.2. 5-(2,4-Diethoxypyrimidin-5-yl)-4,5-difluoro-2-methyl-4-
(trifluoromethyl)isoxazolidine (12)
(CDCl3, 300 MHz):
Ph), 8.28 (s, 1H, Z isomer, H-6) and 8.40 (s, 1H, E isomer, H-6); 19
NMR (CDCl3, 282 MHz):
d 5.46–5.52 (m, 4H, CH2), 7.34–7.48 (m, 10H,
F
Solidified oil; yield 207 mg, 58%; diastereoisomeric ratio 4.1:1;
d
E isomer: ꢁ66.6 (dd, J = 11 Hz and
1H NMR (CDCl3, 300 MHz):
d 1.41 (t, J = 7 Hz, 3H, CH2–CH3), 1.43 (t,
J = 22 Hz, 3F, CF3), ꢁ135.1 (dq, J = 141 Hz and J = 22 Hz, 1F,
CF55CFCF3), ꢁ164.0 (dq, J = 141 Hz and J = 11 Hz, 1F, CF55CFCF3),
Z isomer: ꢁ66.1 (dd, J = 8 Hz and J = 14 Hz, 3F, CF3), ꢁ110.6 (m, 1F,
CF55CFCF3), ꢁ148.9 (m, 1F, CF55CFCF3); MS (EI) 70 eV, m/z (rel. int):
422 [M]+ (6), 331 (12), 91 (100); HRMS: calculated for C21H15N2O2
F5 422.10538. Found 422.10845.
J = 7 Hz, 3H, CH2–CH3), 3.01(s, 3H, CH3), 3.20 (brs, 1H, H-3a0), 4.03
(brs, 1H, H-3b0), 4.44 (q, J = 7 Hz, 2H, CH2–CH3), 4.48 (q, J = 7 Hz, 2H,
CH2–CH3), 8.43 (s, 1H, H-6); 19F NMR (CDCl3, 282 MHz):
d
ꢁ74.98
and ꢁ77.06 major (brs, 3F, CF3), ꢁ99.17 and ꢁ112.72 major (brs, 1F,
F-10), ꢁ165.82 major and ꢁ166.72 (brs, 1F, F-20); 13C NMR (CDCl3,
101 MHz):
d 14.0 (s, CH2–CH3), 14.3 (s, CH2–CH3), 45.9 (brs, CH3),
62.4 (brs, C-30), 63.1 (s, CH2–CH3), 63.8 (s, CH2–CH3), 102.4 (dm,
J = 202 Hz, C-20), 104.9 (d, J = 29 Hz, C-5), 114.5 (dd, J = 240 Hz and
J = 31 Hz, C-10)), 121.3 (dq, J = 285 Hz and J = 31 Hz, CF3)), 158.4 (brs,
C-6,), 166.1 (s, C-2), 168.3 (d, J = 3.1 Hz, C-4)); MS (EI) 70 eV, m/z (rel.
int): 357 [M]+ (100), 298 (34), 254 (86); Anal. Calcd. for
4.2.6. 2,4-Di-ethoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)pyrimidine
(9a)
Colorless oil; yield 480 mg, 61%; 1H NMR (CDCl3, 300 MHz):
d
1.31 and 1.36 (t, J = 7 Hz, 6H, CH2–CH3), 4.35 and 4.39 (q, J = 7 Hz,
4H, CH2–CH3), 5.71 (q, J = 1 Hz, 1H, CF3C55CHH), 6.04 (q, J = 1 Hz,
C13H16N3O3F5: C, 43.70; H, 4.52; N, 11.76. Found: C, 43.59; H,
1H, CF3C55CHH), 8.08 (s, 1H, H-6); 19F NMR (CDCl3, 282 MHz):
d
4.29; N, 11.49.
ꢁ66.00 (s, 3F, CF3); MS (EI) 70 eV, m/z (rel. int): 262 [M]+ (69), 218
(100), 191 (86); Anal. Calcd. for C11H13N2O2F3: C, 50.38; H, 5.00; N,
10.68. Found: C, 49.99; H, 4.79; N, 10.45.
4.3.3. 5-(2,4-Di-tert-butoxypyrimidin-5-yl)-4,5-difluoro-2-methyl-
4-(trifluoromethyl) isoxazolidine (13)
White crystal; m.p. = 111–113 8C; yield 219 mg, 53%; for X-ray
analysis the compound was crystallized from hexane. Diastereo-
d 1.62 major and
1.66 (s, 9H, t-Bu), 1.64 major and 1.67 (s, 9H, t-Bu), 3.00 (brs, 3H,
CH3), 3.15 (brs, 1H, H-3a0), 4.01 (brs, 1H, H-3b0), 8.37 major and
4.2.7. 2,4-Di-tert-butoxy-5-(3,3,3-trifluoroprop-1-en-2-
yl)pyrimidine (9b)
isomeric ratio 4.7:1; 1H NMR (CDCl3, 300 MHz):
White crystal; m.p. 38–42 8C; Yield 382 mg, 40%; 1H NMR (CDCl3,
300 MHz):
d
1.63 (s, 18H, t-Bu), 5.67 (q, J = 1 Hz, 1H, CF3C55CHH),
6.01 (q, J = 1 Hz, 1H, CF3C55CHH), 8.16 (s, 1H, H-6); 19F NMR (CDCl3,
8.44 (brs, 1H, H-6); 19F NMR (CDCl3, 282 MHz):
d
ꢁ75.06 and
282 MHz):
d
ꢁ65.18 (s, 3F, CF3). MS (EI) 70 eV, m/z (rel. int): 318 [M]+
ꢁ77.26 major (brs, 3F, CF3), ꢁ99.52 and ꢁ113.63 major (brs, 1F, F-
(2), 206 (100), 57 (79); Anal. Calcd. for C15H21N2O2F3: C, 56.60; H,
6.65; N, 8.80. Found: C, 56.31; H, 6.79; N, 8.57.
10), ꢁ165.15 major and ꢁ168.57 (brs, 1F, F-20); 13C NMR (CDCl3,
101 MHz): d 28.3 (s, C–CH3), 28.4 (s, C–CH3), 45.7 (s, CH3), 63.4 (brs,
C-30), 81.1 (s, C–CH3), 83.0 (s, C–CH3), 102.5 (m, C-20), 105.2 (d,
J = 29 Hz, C-5), 114.6 (dd, J = 238 Hz and J = 30 Hz, C-10), 121.0 (dq,
J = 285 Hz and J = 31 Hz, CF3), 158.4 (brs, C-6), 165.0 (s, C-2), 167.7
(d, J = 3 Hz, C-4); MS (EI) 70 eV, m/z (rel. int): 413 [M]+ (13), 357
(20), 301 (55), 139 (100), 57 (56); Anal. Calcd. for C17H24N3O3F5: C,
49.39; H, 5.85; N, 10.16. Found: C, 49.44; H, 6.34; N, 10.01.
4.3. General synthetic procrdure and analitical data of compounds
11–15 and 18
A mixture of paraformaldehyde (36 mg, 1.2 mmol), triethyla-
mine (152 mg, 1.5 mmol) and N-methylhydroxylamine hydrochlo-
ride or N-benzylhydroxylamine hydrochloride (1.2 mmol) in
anhydrous toluene (10 mL) was placed in a glass pressure tube
equipped with a magnetic stirrer and stirred at 70 8C for 1 h. The
solution was cooled to room temperature, the corresponding 2,4-
dialkoxypyrimidine 7a, 8a–c (1 mmol) was then added and the
solution was heated at 80 8C for 48–72 h. The solvent was
evaporated and the residue was washed a few times with CHCl3.
The organic layers were dried with Na2SO4 and evaporated under
reduced pressure to afford a crude mixture which was purified by
column chromatography (silica gel, hexane, a gradient of hexane/
CH2Cl2 and a gradient of CH2Cl2/CH3OH). The same procedure was
applied for compound 18.
4.3.4. 5-(2,4-Di-benzyloxypyrimidin-5-yl)-4,5-difluoro-2-methyl-4-
(trifluoromethyl) isoxazolidine (14)
Solidified yellow oil; yield 265 mg, 55%; diastereoisomeric ratio
4.9:1; 1H NMR (CDCl3, 300 MHz):
1H, H-3a0), 3.85 (br s, 1H, H-3b0), 5.39 (s, 2H, CH2), 5.45 (s, 2H, CH2),
7.25–7.50 (m, 10H, Ph), 8.48 (s, 1H, H-6); 19F NMR (CDCl3,
d 2.71 (brs, 3H, CH3), 2.92 (brs,
282 MHz):
d
ꢁ74.90 and ꢁ77.27 major (brs, 3F, CF3), ꢁ99.24 and
ꢁ113.68 major (brs, 1F, F-10), ꢁ165.75 major and ꢁ168.44 (br s, 1F,
F-20); 13C NMR (CDCl3, 101 MHz):
d 45.4 (s, CH3), 62.3 (d, J = 18 Hz,
C-30), 69.3 (s, CH2), 69.6 (s, CH2), 102.6 (dm, J = 200 Hz, C-20), 105.4
(d, J = 30 Hz, C-5), 114.5 (ddm, J = 238 Hz and J = 30 Hz, C-10), 121.2
(dqm, J = 285 Hz and J = 33 Hz, CF3), 128.0–135.9 (s, Ph), 158,2 (brs,
C-6), 165.7 (s, C-2), 168.1 (d, J = 4 Hz, C-4); MS (EI) 70 eV, m/z (rel.
int): 481 [M]+ (14), 390 (3), 91 (100); Anal. Calcd. for
4.3.1. 2-Benzyl-5-(2,4-diethoxypyrimidin-5-yl)-4,5-difluoro-4-
(trifluoromethyl)isoxazolidine (11)
Solidified yellow oil; yield 195 mg, 45%; diastereoisomeric ratio
C23H20N3O3F5: C, 57.38; H, 4.19; N, 8.73. Found: C, 57.12; H,
4.40; N, 8.51.
3.9:1; 1H NMR (CDCl3, 300 MHz):
d
1.40 (t, J = 7 Hz, 3H, CH2–CH3),
1.42 (t, J = 7 Hz, 3H, CH2–CH3), 3.41 (brs, 1H, H-3a0), 3.86 (brs, 1H,
H-3b0), 4.15–4.52 (m, 6H, CH2 and CH2–CH3), 7.26–7.42 (m, 5H,
4.3.5. 5-(2,4-Diethoxypyrimidin-5-yl)-4,4-difluoro-2-
methylisoxazolidin-5-ol (15)
Ph), 8.41 (s, 1H, H-6); 19F NMR (CDCl3, 282 MHz):
d
ꢁ75.25 and
ꢁ76.71 major (brs, 3F, CF3), ꢁ100.13 and ꢁ112.19 major (brs, 1F, F-
Solidified oil; yield 116 mg, 38%; ratio 3.5:1; 1H NMR (CDCl3,
10), ꢁ166.04 major and ꢁ167.74 (brs, 1F, F-20); 13C NMR (CDCl3,
300 MHz): d 1.35 (t, J = 7 Hz, 6H, CH2–CH3), 2.84 (brs, 3H, CH3), 2.95
101 MHz):
d
14.0 (s, CH2–CH3), 14.3 (s, CH2–CH3), 56.6 (s, CH2),
(brs, 1H, H-3a0), 3.66 (brs, 1H, H-3b0), 4.33 (q, J = 7 Hz, 2H CH2–
CH3), 4.44 (q, J = 7 Hz, 2H, CH2–CH3), 8.37 (s, 1H); 19F NMR (CDCl3,
59.1 (brs, C-30), 63.1 (s, CH2–CH3), 63.8 (s, CH2–CH3), 101.7 (dm,
J = 203 Hz, C-20), 104.6 (d, J = 28 Hz, C-5)), 114.4 (dd, J = 238 Hz and
282 MHz):
d
ꢁ105.27 major (br d, J = 230 Hz, 1F, F-2a0), ꢁ107.18

230
H. Wo´jtowicz-Rajchel, H. Koroniak / Journal of Fluorine Chemistry 135 (2012) 225–230
major (br d, J = 230 Hz, 1F, F-2b0), ꢁ107.20 (br d, J = 226 Hz, 1F, F-
2a0), ꢁ115.01 (br d, J = 226 Hz, 1F, F-2b0); 13C NMR (CDCl3,
White crystal; m.p. = 195–198 8C; yield 55 mg, 77%; diastereo-
isomeric ratio after crystalissation 9.4:1; 1H NMR (DMSO-d6,
101 MHz):
d
14.1 (s, CH2–CH3), 14.3 (s, CH2–CH3), 45.1 (s, CH3),
300 MHz):
3b0), 7.63 (brs, 1H, H-6), 11.37 (brs, 2H, NH), (TFA-d, 300 MHz):
3.75 (m, 3H, CH3), 4.44 (m, 1H, H-3a0), 5.07 (m, 1H, H-3b0), 8.18 (m,
1H, H-6); 19F NMR (DMSO-d6, 282 MHz):
d
2.87 (s, 3H, CH3), 3.34 (brs, 1H, H-3a0), 4.14 (brs, 1H, H-
63.1(s, CH2–CH3), 63.6 (s, CH2–CH3), 64.4 (t, J = 27 Hz, C-30), 100.1
(dd, J = 30 Hz and J = 25 Hz, C-10), 108.9 (s, C-5), 127.6 (t, J = 262 Hz,
C-20), 157.3 (s, C-6), 165.2 (s, C-2), 168.0 (s, C-4); MS (FAB): m/
z = 306 [M + 1]+; Anal. Calcd. for C12H17N3O4F2: C, 47.21; H, 5.61; N,
13.76. Found: C, 46.91; H, 5.83; N, 13.50.
d
d
ꢁ69.16 (brs, 3F, CF3)
and ꢁ71.40 major (m, 3F, CF3), ꢁ94.75 (brs, 1F, F-10) and ꢁ106.88
major (m, 1F, F-10), ꢁ163.33 major (dqm, J = 16 Hz and J = 8 Hz, 1F,
F-20) and ꢁ163.34 (brs, 1F, F-20); 13C NMR (TFA-d, 101 MHz):
d 47.4
4.3.6. 4,5-Difluoro-2-methyl-5-phenyl-4-
and 45.8 (s, CH3), 60.9 and 61.4 (d, J = 25 Hz, C-30), 99.1 (dm,
J = 210 Hz, C-20), 107.8 (d, J = 25 Hz, C-5), 114.0 (m, C-10), 122.7 (dq,
J = 280 Hz and J = 29 Hz, CF3), 147.4 and 147.6 (s, C-2), 152.0 (s, C-
6), 165.9 and 166.3 (s, C-4); MS (EI) 70 eV, m/z (rel. int): 302
[M + 1]+ (2), 240 (43), 139 (100); Anal. Calcd. for C8H8N3O3F5: C,
35.89; H, 2.68; N, 13.95. Found: C, 35.55; H, 2.93; N, 13.62.
(trifluoromethyl)isoxazolidine (18)
Obtained from perfluoroprop-1-enyl benzene (208 mg,
1 mmol) under typical procedure; oil; yield 131 mg, 49%;
diastereoisomeric ratio 1.7:1; 1H NMR (CDCl3, 300 MHz):
d
= 2.98 (s, 3H, CH3), 3.07 (brs, 1H, H-3a0), 4.03 (brs, 1H, H-3b0),
7.32–7.51 (m, 5H, Ph); 19F NMR (CDCl3, 282 MHz):
d
ꢁ74.46 and
ꢁ76.20 major (brs, 3F, CF3), ꢁ101.32 and ꢁ111.75 major (brs, 1F, F-
Acknowledgements
10), ꢁ160.69 major and ꢁ169.03 (brs, 1F, F-20); 13C NMR (CDCl3,
101 MHz):
d 46.4 major and 49.5 (brs, CH3), 59.6 and 61.8 major
We thank Prof. Andrzej Katrusiak (Adam Mickiewicz University,
(brs, C-30), 102.8 (m, C-10), 115.5 (dm, J = 230 Hz, C-20), 120.9 (qm,
J = 283 Hz, CF3), 127.3, 127.9, 128.1 and 130.5 (s, Ph); GC–MS, m/z:
267 [M]+; Anal. Calcd. for C11H10N1O1F5: C, 49.45; H, 3.77; N, 5.24.
Found: C, 49.21; H, 3.92; N, 5.07.
´
Poznan, Poland) for the X-ray analysis. Support from the State
Committee for Scientific Research (grant no. N N 204 017935) is
acknowledged.
References
4.4. Hydrolysis of protective groups and analytical data of compounds
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16 and 17
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d]pyrimidine-2,5(3H,6H)-dione (16)
Sodium iodide (168 mg, 1.12 mmol) was added to a solution of
compound 12 (100 mg, 0.28 mmol) in glacial acetic acid (3 mL) and
the mixture was heated at 90 8C for 3 h. The solvent was removed
by evaporation under reduced pressure and water (4 mL) was
added to the dark residue. The solution was partially decolorized
by the addition of a small amount of Na2S2O3 and then extracted
with ethyl acetate (4 ꢀ 4 mL). The combined organic layers were
washed with water and dried over Na2SO4. Solvents were removed
under reduced pressure and the crude product was purified by
column chromatography (silica gel, CH2Cl2, a gradient of CH2Cl2/
CH3OH from 50:1 to 10:1, v/v) affording the compound 16.
White crystal; m.p. = 252–255 8C; yield 51 mg, 68%; 1H NMR
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Elsevier, Amsterdam, 1982;
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Chemical Society, Washington DC, 1996.
(CD3OD, 300 MHz):
1H, H-3b0), 8.43 (s, 1H, H-6), (DMSO-d6, 300 MHz):
CH3), 4.02–4.20 (m. 2H, H-3a0 and H-3b0), 8.47 (s, 1H, H-6), 12.15
d
3.27 (s, 3H, CH3), 4.09 (m, 1H, H-3a0), 4.14 (m,
3.13 (s, 3H,
d
[7] (a) M.A. Bigdeli, A.E. Tipping, J. Fluorine Chem. 58 (1992) 101–110;
(b) A. Loupy, A. Petit, D. Bonnet-Delpon, J. Fluorine Chem. 75 (1995) 215–216;
(c) J. Jakowiecki, R. Loska, M. Ma˛kosza, J. Org. Chem. 73 (2008) 5436–5441;
(d) T.B. Nguyen, A. Martel, R. Dhal, G. Dujardin, Synlett (2009) 2492–2496;
(e) S. Bigotti, L. Malpezzi, M. Molteni, A. Mele, W. Panzeri, M. Zanda, Tetrahedron
Lett. 50 (2009) 2540–2542.
(bs, 1H, NH); 19F NMR (DMSO-d6, 282 MHz):
d
ꢁ78.01 (d, J = 9 Hz,
3F, CF3), ꢁ178.60 (m, 1F, F-20); 13C NMR (DMSO-d6, 101 MHz):
d
35.3 (s, CH3), 49.2 (d, J = 26 Hz, C-30), 87.1 (dq, J = 195 Hz and
J = 30 Hz, C-20), 100.2 (s, C-5), 124.4 (dq, J = 286 Hz and J = 30 Hz,
CF3), 150.4, 153.9 and 161.4 (s, C-2, C-4 and C-6), 177.9 (d,
J = 19 Hz, C-10); MS (EI) 70 eV, m/z (rel. int): 265 [M]+ (100), 196,
(12), 123 (25); Anal. Calcd. for C9H7N3O2F4: C, 40.77; H, 2.66; N,
15.85. Found: C, 41.09; H, 2.36; N, 15.71.
[8] (a) H. Wo
´jtowicz-Rajchel, M. Migas, H. Koroniak, J. Org. Chem. 71 (2006) 8842–
8846;
´
(b) H. Wojtowicz-Rajchel, H. Koroniak, A. Katrusiak, Eur. J. Org. Chem. (2008)
368–376;
´
(c) H. Wojtowicz-Rajchel, M. Pasikowska, A. Olejniczak, A. Kartusiak, H. Koroniak,
New J. Chem. 34 (2010) 894–902.
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Chem. 71 (1995) 135–137;
(b) H. Wo´jtowicz-Rajchel, I. Bednarczyk, A. Katrusiak, H. Koroniak, Mendeleev
Commun. 14 (2004) 63–65.
[10] P.L. Coe, M.R. Harnden, A.S. Jones, S.A. Noble, R.T. Walker, J. Med. Chem. 25 (1982)
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[13] R. Huisgen, G. Mloston, E. Langhals, J. Am. Chem. Soc. 108 (1986) 6401–6402.
[14] Crystal data for 13: C17H24F5N3O3, colorless, formula weight 413.39, monoclinic,
4.4.2. 5-(4,5-Difluoro-2-methyl-4-(trifluoromethyl)isoxazolidin-5-
yl)pyrimidine-2,4(1H,3H)-dione (17)
To a stirred solution of acetyl chloride (57 mg, 0.72 mmol) and
methanol (32 mg, 1 mmol) in anhydrous THF (1 mL) at 0 8C was
added dropwise a solution of compound 13 (100 mg, 0.24 mmol) in
anhydrous THF (1 mL) The reaction was kept at the above
temperature for an additional 1 h and then was stirred overnight
at room temperature. The solvents were removed by evaporation
under reduced pressure and the white residue was washed with a
mixture of hexane and CH2Cl2 1:1 (v/v). The remaining crude
product was crystallized from a small amount of ethanol affording
the compound 17. Any attempts of purification or analyses of
compound 17 on a silica gel lead to decomposition of it.
˚
˚
space group P21/n, unit cell dimensions: a = 12.7994(3) A, b = 10.0435(2) A,
3
˚
˚
c = 16.0070(4) A, b = 100.738(2)8, volume = 2021.69(8) A , Z = 4, calculated den-
sity = 1.358 g/cm3, T = 293(2) K, F(0 0 0) = 864, 8130 reflections collected, 3944
unique with Rint = 0.0113, final R1 = 0.0484, wR2 = 0.1347 (I > 2.sI).
[15] Crystallographic data for compound 13 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDC 821873,
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223 336033 or deposit@ccdc.
cam.ac.uk.