SCHEME 5. Synthesis of Pyrimidines 16a-16d
routes, through the propargylic fluoride or by fluorination of
formylpyrimidine, can be used with success.
In conclusion, this study confirms the versatility of propargylic
fluorides in the synthesis of useful building blocks for further
applications in organic and medicinal chemistry. The chiral
propargylic fluorides are easily accessible in high enantiomeric
purity and afford by condensation with amidines or guanidines
interesting pyrimidines with several points of molecular diver-
sity. On the other hand, it has been established that direct
fluorination of the alcohol on the side chain also affords the
target fluorinated pyrimidine in high ee and, therefore, both
routes are possible for this π-electron-deficient heterocycle.
Furthermore, new electrophilic alkynes, including derivatives
bearing a CHF2 substituent on the triple bond, have been
prepared and used in the synthesis of the corresponding
pyrimidines. Even if they are sensitive molecules, intermediates
such as 9, 10, 13, and 14 could be of much use in the synthesis.
The development of this chemistry, as well as the preparation
of other heterocycles starting from propargylic fluorides, is under
active study in our group and will be reported in due course.
SCHEME 6. Alternative Synthesis of Pyrimidine 16a
Experimental Section
followed was the same as that for 11 and involved as key
intermediates the new propargylic derivatives 13 and 14
(Scheme 5). The propargylic ketone 12 was prepared from acetal
6 in two steps, following previously described reactions.13
Removal of the acetal group was performed using pure formic
acid11 to afford labile electrophilic alkyne 13, which was
submitted directly to fluorination to yield 14. This DAST-
mediated reaction had to be performed under carefully controlled
reaction conditions (dilution and temperature); otherwise, the
corresponding tetrafluoropropargylic derivative 15 was obtained.
This second fluorination has not been observed in the case of
10. This indicates a higher reactivity, in fluorination, of the
propargylic ketone with the alkyl chain as compared to the aryl-
type derivative. Both 13 and 14 were also very reactive and
labile compounds characterized only by NMR and used directly
for the next steps. Condensation of 14 with the required amidines
or guanidines afforded the target pyrimidines 16a-16d in
5.5-19% overall yields from 12. The lower yields obtained in
the case of this C5 alkyl chain are probably due, at least in part,
to the well-known volatility of small fluorinated molecules such
as 14, which makes isolation difficult. On the other hand, ynones
such as 13 and 14 are highly reactive and probably much more
prone to decomposition than derivatives with the p-bromo
substituent.
As discussed previously, an alternative strategy could be to
first prepare the pyrimidine nucleus bearing the aldehyde group14
and then perform the fluorination reaction (Scheme 6). There-
fore, the pyrimidine 17 was prepared in good yield from
intermediate 12. However, all attempts to remove the acetal
group using pure formic acid were unsuccessful, affording
mostly degradation products. On the other hand, hydrolysis using
sulfuric acid14 in THF afforded the desired aldehyde 18, albeit
in moderate yield. Then, a reaction with 2 equiv of DAST at
35 °C afforded the desired pyrimidine 16a. Therefore, for these
series of pyrimidines with the difluoromethyl side chain, both
General Procedure for the Monofluorinated Pyrimidines: To
a solution of 3 (0.39 mmol) in acetonitrile (6 mL) were added
sodium carbonate (0.94 mmol, 2.4 equiv) and amidine/guanidine
derivatives (0.47 mmol, 1.2 equiv). The solution was stirred under
reflux for 3 h. After cooling, the mixture was filtered and
concentrated in vacuo. The product was purified on a silica gel
column with a mixture of pentane/AcOEt as the eluent.
Synthesis of 4-(4-Bromophenyl)-6-(1-fluoroethyl)-2-methylpy-
rimidine [(()-4a]: Pyrimidine 4a was obtained as a pale-yellow
solid (89.6 mg, 78% yield); Rf ) 0.29 (9/1 pentane/AcOEt). Mp:
1
45 °C. H NMR (CDCl3, 300 MHz): δ 8.03-7.97 (m, 2H); 7.66
(bs, 1H); 7.65-7.60 (m, 2H); 5.63 (dq, JHF ) 48.1 Hz, J ) 6.6
Hz, 1H); 2.78 (s, 3H); 1.71 (dd, JHF ) 24.5 Hz, J ) 6.6 Hz, 3H).
13C NMR (CDCl3, 75 MHz): δ 170.1 (d, JCF ) 24.7 Hz); 168.0 (d,
JCF ) 3.0 Hz); 163.9 (d, JCF ) 1.5 Hz); 135.9, 132.2, 128.8, 125.6,
108.2 (d, JCF ) 8.3 Hz); 90.5 (d, JCF ) 172.1 Hz); 26.1, 21.4 (d,
JCF ) 26.4 Hz). 19F NMR (CDCl3, 282 MHz): δ -183.61 (dq, J1
) 48.0 Hz, J2 ) 24.0 Hz). HRMS (EI). Calcd for C13H12N2F79Br
[M+]: m/z 294.0168. Found: m/z 294.0172.
Synthesis of 1-(4-Bromophenyl)-4,4-diethoxybut-2-yn-1-ol (7):
To a solution of 6 (1.12 mL, 7.54 mmol) in anhydrous THF (10
mL) under argon at -78 °C was added dropwise n-BuLi (a 1.6 M
solution in hexane, 5.2 mL, 8.32 mmol, 1.1 equiv). The reaction
mixture was stirred for 1 h at this temperature, and p-bromoben-
zaldehyde (1.7 g, 9.1 mmol, 1.2 equiv) was added. The reaction
mixture was stirred for 3 h with the temperature rising slowly to
room temperature before the addition of a saturated NH4Cl solution.
Then water (50 mL) was added, and the aqueous phase was
extracted with diethyl ether (3 × 50 mL). The organic layers were
washed, dried over MgSO4, and concentrated in vacuo to give a
yellow oil. After purification on a silica gel column, compound 7
was obtained as a yellow oil (2.25 g, 95% yield); Rf ) 0.27 (75/25
1
pentane/AcOEt). H NMR (CDCl3, 300 MHz): δ 7.49-7.32 (m,
4H); 5.43 (bd, J ) 5.7 Hz, 1H); 5.3 (d, J ) 1.3 Hz, 1H); 3.77-3.46
(m, 4H); 1.20 (t, J ) 7.3 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ
139.1; 131.6; 128.3; 122.3; 91.22; 84.8; 81.8; 63.5; 61.1; 61.0; 15.0.
HRMS (EI). Calcd for C14H17O379Br [M+]: m/z 312.0361. Found:
m/z 312.0355.
Synthesis of 1-(4-Bromophenyl)-4,4-diethoxybut-2-yn-1-one
(8): 2-Iodoxybenzoic acid (IBX; 3.2 g, 11.5 mmol, 3 equiv) was
dissolved in DMSO (20 mL) at 60 °C. A solution of 7 (1.2 g, 3.83
mmol) in CH2Cl2 (28 mL) was added, and the mixture was stirred
under reflux for 3 h. Ice-cold water was added to quench the
reaction, and a white suspension appeared. The reaction mixture
(13) Kerouredan, E.; Prakesch, M.; Gre´e, D.; Gre´e, R. Lett. Org. Chem. 2004,
1, 78–80.
(14) For two recent examples of synthesis and the use of formylpyrimidines,
see: (a) Verron, J.; Malherbe, P.; Prinssen, E.; Thomas, A. W.; Nock, N.;
Masciadri, R. Tetrahedron Lett. 2007, 48, 377–380. (b) Choung, W.; Lorsbach,
B. A.; Sparks, T. C.; Ruiz, J. M.; Kurth, M. J. Synlett 2008, 3036–3040.
4648 J. Org. Chem. Vol. 74, No. 12, 2009