Flexible synthesis of pyrimidines with chiral monofluorinated and difluoromethyl side chains

Article abstract of DOI:10.1021/jo900674u

(Chemical Equation Presented) Chiral pyrimidines with a fluorine atom in the benzylic position are easily accessible in high enantiomeric excesses from optically active propargylic intermediates by two complementary routes. Both the use of optically activ

Full text of DOI:10.1021/jo900674u

SCHEME 1. Retrosynthetic Analysis for the Preparation of
Type A and D Pyrimidines
Flexible Synthesis of Pyrimidines with Chiral
Monofluorinated and Difluoromethyl Side Chains
Pierre Bannwarth,† Alain Valleix,‡ Danielle Gre´e,† and
Rene´ Gre´e*,†
Laboratoire de Chimie et Photonique Mole´culaires,
UniVersite´ de Rennes 1, CNRS UMR 6510, AVenue du
Ge´ne´ral Leclerc, 35042 Rennes Cedex, France, and
Eurisotope, Centre d’Etudes Nucle´aires de Saclay,
91191 Gif sur YVette, France
rene.gree@uniV-rennes1.fr
ReceiVed March 31, 2009
particularly attractive target molecules. Several years ago, we
started a research program on new strategies for the synthesis
of fluorinated molecules, based on the use of easily accessible
propargylic fluorides.3 In particular, we have demonstrated that
these derivatives are highly versatile intermediates for the
synthesis of linear compounds,4 as well as carbo-5 and hetero-
cycles.6 Now we have become interested in the preparation of
novel pyrimidines with fluorine atoms in the benzylic position,
and more specifically in this paper, we will develop two aspects:
(i) In the first part, we will describe a versatile synthesis of
type A optically active pyrimidines monofluorinated on the side
chain, taking advantage of the easy access to type B propargylic
fluorides. Furthermore, two different routes to highly enantio-
enriched pyrimidines A will be reported and compared.
(ii) In the second part, we will extend our propargylic strategy
to difluoromethyl compounds and we will report the synthesis
of type D pyrimidines. In this part, we will take advantage of
the new versatile, albeit labile, E and F propargylic derivatives.
All of these pyrimidines have two to three points of molecular
diversity, and therefore this strategy could be of interest in the
preparation of chemical libraries.
As a model for studying the preparation of pyrimidines from
propargylic ketones, we have selected fluoride 3 because it is
easily prepared in good yield from butyn-3-ol (1), in both
racemic and highly enantio-enriched forms. Furthermore, the
p-bromo substituent can be used for the preparation of chemical
libraries.6 Upon reaction with the appropriate amidines and
guanidines in the presence of Na2CO3, this ketone (()-3 afforded
in fair to excellent yields the target racemic pyrimidines (()-
4a-4d (Scheme 2). All of these derivatives have been fully
characterized by their spectral and analytical data.
Chiral pyrimidines with a fluorine atom in the benzylic
position are easily accessible in high enantiomeric excesses
from optically active propargylic intermediates by two
complementary routes. Both the use of optically active
propargylic fluorides and the fluorination of the chiral
pyrimidine in the final stage give excellent results in terms
of enantiocontrol. On the other hand, original pyrimidines
with a difluoromethyl side chain are also obtained in a few
steps from new propargylic ketones bearing a CHF2 sub-
stituent on the triple bond.
Pyrimidines are widely recognized as important heterocycles
in bioorganic and medicinal chemistry.1 On the other hand, it
is well-known that the introduction of fluorine in organic
molecules strongly modifies their physical, chemical, and
biological activities, and this has also been of much use in
fluorobiorganic chemistry.2 Therefore, pyrimidines bearing one
or several fluorine atom(s) on the side chains appear to be
The next step was the preparation of the corresponding
pyrimidines, in optically active form. Toward this goal, the
derivative (-)-4a was selected as a model and the synthesis
† Universite´ de Rennes 1.
(3) Prakesch, M.; Gre´e, D.; Gre´e, R. Acc. Chem. Res. 2002, 35, 175–181.
For a recent review on the chemistry of propargylic and allylic fluorides, see:
(a) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. ReV. 2008, 108, 1943–
1981, and references cited therein.
(4) (a) Manthati, V.; Gre´e, D.; Gre´e, R. Eur. J. Org. Chem. 2005, 3825–
3829. (b) Manthati, V. L.; Murthy, A. S. K.; Caijo, F.; Drouin, D.; Lesot, P.;
Gre´e, D.; Gre´e, R. Tetrahedron: Asymm. 2006, 17, 2306–2310, and references
cited therein.
(5) (a) Gre´e, D.; Gre´e, R. Tetrahedron Lett. 2007, 48, 5435–5438. (b) Pujari,
S. A.; Kaliappan, K. P.; Valleix, A.; Gre´e, D.; Gre´e, R. Synlett 2008, 2503–
2507.
(6) Blayo, A.-L.; Le Meur, S.; Gre´e, D.; Gre´e, R. AdV. Synth. Catal. 2008,
350, 471–476.
‡ Eurisotope, Centre d’Etudes Nucle´aires de Saclay.
(1) For a recent review on the synthesis of pyrimidines, see: (a) Hill, M. D.;
Movassaghi, M. Chem.sEur. J. 2008, 14, 6836–6844, and references cited
therein.
(2) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical Frontiers in
Fluorine Chemistry; ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996. (b) Welch, J. T.; Eswarakrishnan, S. Fluorine in
Bioorganic Chemistry; Wiley Interscience: New York, 1991. (c) Welch, J. T.
Tetrahedron 1987, 43, 3123–3197. (d) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 127, 303–319. (e) Be´gue´, J.-P.; Bonnet-Delpon, D. J. Fluorine
Chem. 2006, 127, 992–1012. (f) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–
1029, and references cited therein.
4646 J. Org. Chem. 2009, 74, 4646–4649
10.1021/jo900674u CCC: $40.75 2009 American Chemical Society
Published on Web 05/19/2009

SCHEME 2. Synthesis of Monofluorinated Pyrimidines
(()-4a-4d
SCHEME 4. Synthesis of Pyrimidines 11a-11d
SCHEME 3. Enantioselective Synthesis of Fluorinated
Pyrimidine (-)-4a
tion of (-)-5 is likely related to the fact that the pyrimidine
nucleus is known as a “π-deficient” heteroaromatic system.8
Therefore, it is not stabilizing a potential carbenium ion during
the DAST-mediated fluorination, and it allows excellent ste-
reocontrol by the SN2 process. In conclusion, for this type of
heterocycle, both routes are possible to access the desired
optically active target molecule (-)-4a in similar overall yields
and ee’s.
Several examples of heteroaromatic derivatives with a CHF2
chain have already been reported, and they demonstrated some
interesting biological properties.9 Furthermore, pyrimidines with
such a chain, and designed to treat CNS disorders, have been
reported in a recent patent.10 Therefore, we decided to extend
our propargylic fluoride synthetic strategy to the preparation of
pyrimidines with a difluoromethyl side chain. It was checked
first with the same p-bromophenyl substituent, and the key
intermediates were the propargylic derivatives 9 and 10 (Scheme
4). The ketone 8 was prepared from acetal 6 in two steps and
in excellent overall yield (91%). Removal of the acetal group
was performed using pure formic acid11 under controlled
reaction conditions to afford labile electrophilic alkyne 9, which
was characterized only by NMR. To the best of our knowledge,
very few compounds of this type have been described up to
now, and some have been proposed as intermediates in the
synthesis of (E)-3-acylprop-2-enoic acids.12 The crude aldehyde
9 was submitted directly to a DAST-mediated reaction to yield
the fluorinated propargylic ketone 10, which is also a highly
reactive and labile intermediate. Therefore, it has been charac-
terized by NMR and used directly for the preparation of target
pyrimidines 11a-11d under the same reaction conditions as
those described previously. These heterocycles, obtained in
24-45% overall yield from 8, have been fully characterized
by their spectral and analytical data.
was studied following two different routes (Scheme 3). In the
first pathway, the optically active fluoride (-)-3 was prepared
from (S)-butynol, as previously described,6 and used for the
synthesis of pyrimidine (-)-4a by condensation with acetami-
dine. In the second route, the pyrimidine (-)-5, with an alcohol
on the side chain, was first prepared from acetylenic intermediate
(-)-2. Then, (diethylamino)sulfur trifluoride (DAST)-mediated
fluorination was performed on (-)-5 to access (-)-4a. This
allows for the first time a full comparison between the two
reaction pathways. The analysis of the enantiomeric excess (ee)
could be performed by chiral high-performance liquid chroma-
tography on pyrimidines (-)-5 and (-)-4a, and the results are
the following:
(a) The pyrimidine (-)-5, with an alcohol side chain, had an
ee ) 99%, thus establishing clearly that propargylic precursor
(-)-2 had an ee g 99%.
(b) The ee of pyrimidine (-)-4a, obtained from (-)-3 through
the propargylic fluoride route, was 97.2%. This result is fully
consistent with our previous results in the synthesis of pyridines,
where excellent stereocontrol was also observed during the
heterocyclization process.6
Then we extended our synthesis to the preparation of
pyrimidines 16a-16d bearing a C5 alkyl chain. The route
(c) The pyrimidine (-)-4a, obtained by direct fluorination
(8) (a) Katritzky, A. R. Handbook of Heterocyclic Chemistry, 1st ed.;
Pergamon: New York, 1985. (b) Eicher, T.; Hauptmann, S.; Speicher, A. The
Chemistry of Heterocycles, 2nd ed.; Wiley-VCH: New York, 2003; Chapter 6
and references cited therein.
of alcohol (-)-5, had an ee ) 96.4%.
These data demonstrate that, for this heterocycle, there is very
little erosion of stereochemistry during the DAST-mediated
fluorination reaction. This result is interesting because it had
been clearly established earlier that fluorination in the benzylic
position is strongly dependent upon the nature of the substituents
on the aromatic system: the electron-withdrawing groups, which
destabilize benzylic carbonium ions, favor stereocontrol by the
SN2 process, while the electron-donating substituents favor
racemization.7 The very high stereocontrol during the fluorina-
(9) For triazoles with antitubercular activity, see: (a) Costa, M. S.; Boechat,
N.; Rangel, E. A.; Da Silva, F. de C.; De Souza, A. M. T.; Rodrigues, C. R.;
Castro, H. C.; Junior, I. N.; Lourenc¸o, M. C. S.; Wardwell, S. M. S. V.; Ferreira,
V. F. Biorg. Med. Chem. 2006, 14, 8644–8653. For examples of difluorometh-
ylimidazoles as antileishmanial agents, see: (b) Ferreira, S. B.; Costa, M. S.;
Boechat, N.; Bezerra, R. J. S.; Genestra, M. S.; Canto-Cavalheiro, M. M.; Kover,
W. B.; Ferreira, V. F. Eur. J. Med. Chem. 2007, 42, 1388–1395. However, it
has to be mentioned also that difluoromethylimidazoles are unstable under basic
conditions. (c) Tuan, E.; Kirk, K. L. J. Fluorine Chem. 2006, 127, 980–982.
(10) For a recent patent on pyrimidines with a CHF2 side chain, designed
for treating CNS disorders, see: (a) Gatti McArthur, S.; Wichmann, J.; Woltering,
T. PCT WO2007110337, 2007.
(7) (a) Fritz-Langhals, E. Tetrahedron Lett. 1994, 35, 1581–1854. (b) Fritz-
Langhals, E. Tetrahedron: Asymm. 1994, 5, 981–986.
(11) Gorgues, A. Bull. Soc. Chim. Fr. 1974, 529–530.
(12) Obrecht, D.; Weiss, B. HelV. Chim. Acta 1989, 72, 117–122.
J. Org. Chem. Vol. 74, No. 12, 2009 4647

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

was filtered, and the layers were separated. The organic layer was
washed, dried over MgSO4, and concentrated under vacuum to give
a yellow oil. After purification on a silica gel column (1:1 pentane/
ether), compound 8 was obtained as a yellow oil (1.15 g, 96%
yield); Rf ) 0.49 (9/1 pentane/AcOEt). 1H NMR (CDCl3, 300 MHz):
δ 8.01-7.92 (m, 2H); 7.66-7.57 (m, 2H); 5.49 (s, 1H); 3.87-3.59
(m, 4H); 1.25 (t, J ) 7.3 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ
176.2; 135.0; 132.1; 131.0; 130.0; 91.2; 88.2; 81.1; 61.7; 15.1.
HRMS (EI). Calcd for C12H10O279Br [M - C2H5O]+: m/z 264.9864.
Found: m/z 264.9853.
Synthesis of 4-(4-Bromophenyl)-4-oxobut-2-ynal (9): To a
solution of 8 (1.15 g, 3.7 mmol) in CH2Cl2 (25 mL) was added
formic acid (25 mL), and it was stirred under reflux for exactly
1 h. Then the excess of formic acid and the ethyl formate formed
were removed under vacuum, without water wash, to give 9 as a
brown oil, which could not be further purified. It was characterized
by NMR and used immediately for the next step. 1H NMR (CDCl3,
300 MHz): δ 9.67 (s, 1H); 8.00-7.91 (m, 2H); 7.73-7.62 (m, 2H).
13C NMR (CDCl3, 75 MHz): δ 175.2; 164.5; 134.2; 132.5; 131.0;
129.0; 86.1; 85.9.
crude product was purified on a silica gel column with pentane/
AcOEt as the eluent.
Synthesis of 4-(4-Bromophenyl)-6-(difluoromethyl)-2-meth-
ylpyrimidine (11a): Pyrimidine 11a was obtained as a pale-yellow
solid (96.0 mg, 35% yield over three steps); Rf ) 0.12 (98/2 pentane/
Et2O). Mp: 98 °C. 1H NMR (CDCl3, 300 MHz): δ 8.03-7.92 (m,
2H); 7.73 (s, 1H); 7.67-7.57 (m, 2H); 6.54 (t, JHF ) 55.0 Hz,
1H); 2.81 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.0 (t, JCF
)
1.0 Hz); 164.7; 161.0 (t, JCF ) 26.0 Hz); 135.1, 132.3, 128.8, 126.3,
112.7 (t, JCF ) 242.0 Hz); 109.0 (t, JCF ) 3.3 Hz); 26.0. 19F NMR
(CDCl3, 282 MHz): δ -119.55 (d, J ) 55.0 Hz). HRMS (EI). Calcd
for C12H9N2F279Br [M+]: m/z 297.9917. Found: m/z 297.9915.
General Procedure for the Synthesis of the Difluoropyrim-
idines 16a-16d: To a solution of the previous 14 (crude in CHCl3,
0.88 mmol expected) in CH3CN (15 mL) were added Na2CO3 (2.11
mmol, 2.4 equiv) and amidine/guanidine derivatives (1.06 mmol,
1.2 equiv). The solution was stirred under reflux overnight. After
cooling, the mixture was filtered and concentrated under vacuum.
The product was purified on a silica gel column with pentane/AcOEt
as the eluent.
Synthesis of 4-(Difluoromethyl)-2-methyl-6-pentylpyrimidine
Synthesis of 1-(4-Bromophenyl)-4,4-difluorobut-2-yn-1-one
(10): A solution of the previous 9 (crude, 3.7 mmol expected) in
CHCl3 (stabilized with amylene, 66 mL) was stirred under argon
at 35 °C. Then DAST (0.97 mL, 7.4 mmol, 2 equiv) was added
dropwise, and the mixture was stirred at 35 °C for 1.5 h. It was
washed with water until neutral pH and dried over MgSO4. The
intermediate 10 was highly volatile, and therefore the reaction
mixture was not concentrated and was used immediately for the
next step. In order to obtain the NMR data of 10, the reaction was
reproduced on a small scale in CDCl3. 1H NMR (CDCl3, 300 MHz):
δ 8.03-7.92 (m, 2H); 7.74-7.62 (m, 2H); 6.43 (t, JHF ) 53.5 Hz,
1H). 13C NMR (CDCl3, 125 MHz): δ 174.9 (t, JCF ) 2.2 Hz); 134.3,
132.1, 131.1, 129.2, 103.2 (t, JCF ) 235.7 Hz); 82.51 (t, JCF ) 6.9
Hz); 80.92 (t, JCF ) 35.1 Hz). 19F NMR (CDCl3, 282 MHz): δ
-109.3 (d, J ) 54.0 Hz).
(16a): Pyrimidine 16a was obtained as a pale-yellow oil (36.2 mg,
19% yield over three steps); Rf ) 0.2 (95/5 pentane/AcOEt). H
1
NMR (CDCl3, 300 MHz): δ 7.24 (s, 1H); 6.47 (t, JHF ) 55.0 Hz,
1H); 2.77 (t, J ) 7.7 Hz, 2H); 2.73 (s, 3H); 1.79-1.63 (m, 2H);
1.40-1.29 (m, 4H); 0.89 (t, J ) 6.8 Hz, 3H). 13C NMR (CDCl3,
75 MHz): δ 173.2; 168.3; 159.9 (t, JCF ) 26.0 Hz); 112.8 (t, JCF
)
242.0 Hz); 112.4 (t, JCF ) 3.0 Hz); 60.4, 38.2, 31.5, 28.7, 25.9,
22.4, 21.0, 14.2, 13.9. 19F NMR (CDCl3, 282 MHz): δ -119.58
(d, J ) 55.0 Hz). HRMS (EI). Calcd for C9H11N2F2 [M - C2H5]+:
m/z 185.0890. Found: m/z 185.0892.
Acknowledgment. We thank CNRS and MESR for financial
support and for a research fellowship (to P.B.). We thank Prof.
F. Mongin for fruitful discussions.
General Procedure for the Synthesis of the Difluoropyrim-
idines 11a-11d: To a solution of the previous 10 (crude in CHCl3,
0.92 mmol expected) in CH3CN (15 mL) were added Na2CO3 (2.36
mmol, 2.4 equiv) and amidine/guanidine derivatives (1.06 mmol,
1.2 equiv). The solution was stirred overnight under reflux. After
cooling, the mixture was filtered and concentrated in vacuo. The
Supporting Information Available: Complementary ex-
1
perimental procedures, analytical data, and H, 13C, and 19F
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900674U
J. Org. Chem. Vol. 74, No. 12, 2009 4649