Unexpected synthesis of (trifluoroethyl)pyrimidines from the heterocyclisation of α-trifluoroacetylpropanenitriles

Article abstract of DOI:10.1016/S0040-4039(02)02245-1

Some 4-trifluoromethyl-2-aminopyrimidines analogous to trimethoprim and 5-trifluoroethyl-2,4-diaminopyrimidines analogous to pyrimethamine were prepared from enamino(trifluoromethyl)ketones and α-trifluoroacetylpropanenitriles, respectively. A novel heter

Full text of DOI:10.1016/S0040-4039(02)02245-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9233–9235
Unexpected synthesis of (trifluoroethyl)pyrimidines from the
heterocyclisation of a-trifluoroacetylpropanenitriles
Hatice Berber,a Mustapha Soufyane,b Maud Santillana-Hayatc and Catherine Miranda,*
aIFR 53, UMR/CNRS 6013, Universite´ de Reims Champagne Ardenne, Faculte´ de Pharmacie, 51 rue Cognacq-Jay,
51096 Reims Cedex, France
bDe´partement de Chimie, Faculte´ des Sciences, BP 20, 24000 El Jadida, Morocco
cLaboratoire de Parasitologie-Mycologie, Faculte´ de Me´decine-Hoˆpital Saint-Louis, 15 rue de l’Ecole de Me´decine,
75006 Paris, France
Received 5 June 2002; revised 30 September 2002; accepted 1 October 2002
Abstract—Some 4-trifluoromethyl-2-aminopyrimidines analogous to trimethoprim and 5-trifluoroethyl-2,4-diaminopyrimidines
analogous to pyrimethamine were prepared from enamino(trifluoromethyl)ketones and a-trifluoroacetylpropanenitriles, respec-
tively. A novel heterocyclisation between a trifluoromethylated b-ketonitrile and guanidine was described. © 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
However these drugs are only effective in combination
with sulfonamides and frequently induce severe side
effects.5–7 Therefore development of more potent
derivatives remains an important goal.
Heterocyclic compounds containing a CF3 group con-
tinue to receive much attention from pharmaceutical
communities.1 Most of the syntheses of such com-
pounds involve heterocyclisation using trifluoromethyl-
ated building blocks.2 Along this route, trifluoromethyl-
ated b-enaminoketones are efficient and versatile syn-
thons for the preparation of various nitrogen
heterocycles.3 In the pyrimidine series, we recently
reported the preparation of some 4-trifluoro-
methylpyrimidines and of their derived nucleoside ana-
logues.4
2. Results and discussion
2.1. 2-Aminopyrimidines (Scheme 1)
Enaminoketones 1 and 2 were prepared by procedures
described previously,4 and then were reacted with
guanidine hydrochloride to give pyrimidines 3 (65%)8
and 4 (88%), respectively.
The present work was undertaken to apply the metho-
dology to the synthesis of fluorinated aminopyrimidines
analogous to trimethoprim (TMP).
The bisaromatic ketone 3 was easily reduced to alcohol
5 (95%).
Aminopyrimidines
trimethoprim
(TMP)5
and
pyrimethamine (PYR)6 have become the reference
drugs for prophylaxis and treatment of opportunistic
infections due to Pneumocystis carinii and Toxoplasma
gondii.
* Corresponding author. Tel.: +33-326-913587; fax: +33-326-918029;
e-mail: catherine.mirand@univ-reims.fr
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02245-1

9234
H. Berber et al. / Tetrahedron Letters 43 (2002) 9233–9235
Anti-Toxoplasma activities of derivatives 3, 4 and 5
were assessed in vitro using a tissue culture model
combined with an immunoenzymatic assay for quantifi-
cation of Toxoplasma growth; TMP was tested in paral-
lel as a reference drug.9 Ten concentrations were tested
for each compound. Estimated IC50 for 3, 4 and 5 were
28.9, 32.9, 44.2 mg/ml, respectively, versus 4.3 mg/ml for
TMP. The inhibitory concentrations were close to those
that were found to be cytopathic for tissue culture.
of b-ketonitriles with guanidine. In this context, Russell
achieved the synthesis of PYR10 in 1951 and other
workers described later the preparation of some tri-
fluoromethyl derivatives11–13 (Scheme 2, entry 1). Simi-
larly Stenbuck’s industrial process for the preparation
of TMP14 involved an a-aryl-b-acrylonitrile which
could be in tautomeric equilibrium with its enolic form
(entry 2).
So, we envisaged to prepare compounds 9a,b from the
enol ethers 8a,b. Claisen condensation of phenylpropio-
nitriles 6a,b (Scheme 3) with ethyl trifluoroacetate using
LDA afforded b-ketonitriles15 in their more stable
hydrated forms 7a,b as shown on the 13C NMR spectra
(l ꢀ93 ppm instead of 180 ppm) (75 and 63% yields,
respectively).
2.2. 2,4-Diaminopyrimidines
Further experiments were conducted in order to pre-
pare compounds closely related to TMP. Therefore we
turned to 5-benzyl-6-trifluoromethyl-2,4-diaminopyri-
midines, for which, synthesis required other fluorinated
intermediates.
Attempt at catalysed acid condensation of 7a and
guanidine hydrochloride, modeled on the methods
sometimes used in nonfluorinated series16 was unsuc-
cessful (reaction mixture unchanged). As in the above
mentioned examples, it was necessary to activate 7a,b
as enol ethers. Treatment of 7a and 7b by triethyl
orthoformate12 easily gave the compounds 8a (78%)
and 8b (88%), which were isolated as Z,E isomeric
mixtures, and characterized on the basis of NMR and
mass spectra.
A general method employed for the synthesis of 2,4-
diaminopyrimidines consists of condensing enol ethers
Finally when 8a was reacted with guanidine as free
base,17 a pyrimidine was obtained, whose structure was
10a (78%) instead of the TMP analogue 9a. Similarly
8b was transformed to 10b (56%). These compounds
were fully characterized.
Scheme 2.
Scheme 3.

H. Berber et al. / Tetrahedron Letters 43 (2002) 9233–9235
9235
A complementary experience shed light on the mecha-
Stevens, M. F. G. J. Med. Chem. 2001, 44, 2555–2564.
nism of this unexpected reaction. Treating 8a with
guanidine hydrochloride in the presence of potassium
carbonate at reflux did not allow heterocyclisation.
Nevertheless, equilibration of the enol ether 10a to the
enenitrile 11a occurred (ratio 50:50). The tautomer 11a
was isolated and characterized by its spectroscopic data
(NMR and MS).
8. 2-Amino-5-trifluoroacetyl-4-(3%,4%,5%-trimethoxy)phenyl-
pyrimidine was isolated as a by product (20%).
9. Derouin, F.; Chastang, Cl. Antimicrob. Agents
Chemother. 1989, 33, 1753–1759.
10. Russell, P. B.; Hitchings, G. H. J. Am. Chem. Soc. 1951,
73, 3763–3770.
11. Baker, B. R.; Jordaan, J. H. J. Heterocyclic Chem. 1965,
2, 162–170.
This result suggested that the phenylpyrimidines 10a
and 10b presumably originate from a 1,4 Michael addi-
tion of guanidine on the tautomeric form 11, followed
by EtOH elimination, then cyclisation on the nitrile
carbon as shown in Scheme 3.
12. Roth, B.; Strelitz, J. Z. J. Org. Chem. 1969, 34, 821–836.
13. Barlin, G. B.; Kotecka, B.; Rieckmann, K. H. Aust. J.
Chem. 1996, 49, 647–650.
14. (a) Stenbuck, P.; Hood, H. M. US Patent 3 049 544,
1962; (b) Stenbuck, P.; Baltzly, R.; Hood, H. M. J. Org.
Chem. 1963, 28, 1983–1988.
Unfortunately, compounds 10a and 10b, which can be
considered as ‘inverted’ PYR derivatives did not show
any significant activity against Toxoplasma gondii. This
novel type of heterocyclisation is currently under
investigation.
15. General procedure for the preparation of 7a,b. A solution
of 6a,b in anhydrous THF was added to a solution of
LDA (1.2 equiv. generated in situ) under a nitrogen
atmosphere at −78°C. The mixture was stirred for 20 min,
and CF3CO2Et (1.5 equiv.) was added at −78°C. After
stirring for 3 h at −78°C, the reaction mixture was
neutralized by aqueous solution of NH4Cl. The aqueous
layer was extracted with CH2Cl2 (3×) and the combined
organic layers were dried over MgSO4, filtered and the
solvent was removed in vacuo. The residue was then
purified by flash chromatography to give 7a,b.
Acknowledgements
We thank the ‘Ministe`re de l’Education Nationale, de
la Recherche et de la Technologie’ for financial support
and for a doctorate’s fellowship (H.B.), P. Sigaut (MS),
C. Petermann (NMR) for spectroscopic recordings,
Professor J. Le´vy, Professor J. M. Pinon, Professor F.
Derouin and Dr. D. Aubert for fruitful advice.
16. Butler, D. E.; Alexander, S. M. J. Heterocyclic Chem.
1982, 19, 1173–1177.
17. Typical experimental procedure. Preparation of 10a,b. A
solution of guanidine hydrochloride (6 equiv.) in anhy-
drous methanol (0.3 mL/mmol of guanidine hydrochlo-
ride) was added to a stirred solution of sodium methoxide
(6 equiv.) prepared in situ in anhydrous methanol (0.3
mL/mmol of sodium methoxide) under an atmosphere of
nitrogen at rt. The mixture was stirred for 5 min, filtered,
and added to 8a,b (1 equiv.). The reaction mixture was
heated to reflux for 4 h, cooled at rt, concentrated in
vacuo, and purified by flash chromatography to yield the
title compounds. They were fully characterized with rele-
vant spectroscopic data. Selected data: 10a: EIMS m/z
268 (M+, 100), 267 (91), 199 (M+−CF3, 92); HRMS calcd
for C12H11F3N4: 268.0940. Found: 268.0936. lH (DMSO-
References
1. (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioor-
ganic Chemistry; Wiley: New York, 1991; (b) Filler, R.;
Kobayashi, Y.; Yagupolskii, L. M. Organofluorine Com-
pounds in Medicinal Chemistry and Biomedical Applica-
tion; Elsevier: Amsterdam, 1993.
2. Andrew, R. J.; Mellor, J. M. Tetrahedron 2000, 56,
7267–7272 and cited references.
3. (a) Soufyane, M.; Mirand, C.; Le´vy, J. Tetrahedron Lett.
1993, 34, 7737–7740; (b) Kawase, M.; Hirabayashi, M.;
Saito, S.; Yamamoto, K. Tetrahedron Lett. 1999, 40,
2541–2544.
4. (a) Soufyane, M.; Van den Broek, S.; Khamliche, L.;
Mirand, C. Heterocycles 1999, 51, 2445–2451; (b) Berber,
H.; Soufyane, M.; Mirand, C.; Schmidt, S.; Aubertin, A.
M. Tetrahedron 2001, 54, 7375–7639.
5. Fischl, M. A.; Dickinson, G. M.; La Voie, L. J. Am.
Med. Assoc. 1988, 259, 1185–1189 and cited references.
6. Leport, C.; Raffi, F.; Matheron, S.; Katlama, C.; Reg-
nier, B.; Saimot, A. G.; Marche, C.; Vedrenne, C.; Vilde,
J. L. Am. J. Med. 1988, 84, 94–100 and cited references.
7. (a) Gangjee, A.; Devraj, R.; Queener, S. F. J. Med.
Chem. 1997, 40, 470–478; (b) Rosowsky, A.; Papoulis, A.
T.; Queener, S. F. J. Med. Chem. 1998, 41, 913–918; (c)
Chan, D. C. M.; Laughton, C. A.; Queener, S. F.;
3
d6) 3.40 (q, JH,F=10.5 Hz, 2H, CH2), 6.09 (s, 2H, NH2),
6.56 (s, 2H, NH2), 7.23–7.49 (m, 5H, Ph-H); lC (DMSO-
2
d6) 29.8 (q, JC,F=29.1 Hz, C
6
H2-CF3), 92.5 (C-5), 126.9
(q, 1JC,F=279.1 Hz, CF3), 128.3 (CH-ar), 139.9 (C-ar),
162.0 (C-2), 164.3 (C-4), 167.5 (C-6); lF (CD3OD) −62.3
(t, 3JF,H=10.5 Hz, 3F, CF3-CH2). 10b: EIMS m/z 358
(M+, 100), 357 (56), 137 (91); HRMS calcd for
C15H17F3N4O3: 358.1255. Found: 358.1253. lH (DMSO-
d6) 3.44 (q, 3JH,F=10.9 Hz, 2H, CH2), 3.71 (s, 3H,
CH3O), 3.78 (s, 6H, 2×CH3O), 6.01 (s, 2H, NH2), 6.51
(br s, 2H, NH2), 6.59 (s, 2H, 2×Ho); lC (DMSO-d6) 30.0
(q, 2JC,F=29.0 Hz, C
(CH3O), 92.5 (C-5), 105.7 (2×CHo), 126.9 (q, JC,F
6 H2-CF3), 56.1 (2×CH3O), 60.3
1
=
279.2 Hz, CF3), 135.5 (C-ar), 137.2 (C-ar), 152.6 (2×C-
ar), 162.0 (C-2), 164.1 (C-4), 167.5 (C-6); lF (DMSO-d6)
3
−58.7 (t, JF,H=10.9 Hz, 3F, CF3-CH2).