One-pot preparation of 2,6-disubstituted 4-(trifluoromethyl)pyrimidines via the tandem cyclization, dehydration, and oxidation reaction of α,β- unsaturated trifluoromethyl ketones using POCl3-pyridine-silica gel and MnO2 systems

Article abstract of DOI:10.1055/s-1999-2741

The treatment of α,β-unsaturated trifluoromethyl ketones with amidines in acetonitrile gave the corresponding 4-hydroxy-4(trifluoromethyl)-3,5,6- trihydropyrimidines, followed by successive dehydration with phosphorus oxychloride-pyridine-silica gel and oxidation with manganese(IV) oxide, producing 2,6-disubstituted 4-(trifluoromethyl)pyrimidines in good to excellent yields.

Full text of DOI:10.1055/s-1999-2741

756
LETTER
One-pot Preparation of 2,6-Disubstituted 4-(Trifluoromethyl)pyrimidines via
the Tandem Cyclization, Dehydration, and Oxidation Reaction of a,b-
Unsaturated Trifluoromethyl Ketones Using POCl3-Pyridine-Silica Gel and
MnO2 Systems
Kazumasa Funabiki,* Hiroko Nakamura, Masaki Matsui, Katsuyoshi Shibata*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu, 501-1193, Japan
Fax +81-58-230-1893; E-mail: kfunabik@apchem.gifu-u.ac.jp
Received 25 March 1999
ketones 3 with amidines, including the tandem efficient
Abstract: The treatment of a,b-unsaturated trifluoromethyl ketones
dehydration–oxidation reaction from the adducts 4 using
this system (Scheme 2).
with amidines in acetonitrile gave the corresponding 4-hydroxy-4-
(trifluoromethyl)-3,5,6-trihydropyrimidines, followed by succes-
sive dehydration with phosphorus oxychloride-pyridine-silica gel
and oxidation with manganese(IV) oxide, producing 2,6-disubsti-
tuted 4-(trifluoromethyl)pyrimidines in good to excellent yields.
R2
Key words: 4-(trifluoromethyl)pyrimidine, POCl3-pyridine, silica
HN
NH2·HCl
gel, dehydration, oxidation
r.t.
NaOH
Trifluoromethylated nitrogen-containing heterocycles,
such as pyridines, pyrimidines, pyrazoles, pyrroles, and
related compounds, have gained much attention due to
their versatile utility in agricultural and medicinal chem-
istries. In close connection with these circumstances, re-
markable progress has been made in the development of a
facile access to the trifluoromethylated aza-heterocycles
using trifluoromethylated building blocks. However, few
successful examples are known of the efficient dehydra-
tion from the a-trifluoromethylated a-hydroxy intermedi-
ate 1 under neutral or weakly basic conditions, which has
formed by the reaction of a-trifluoromethylated ketones
with various reagents, because of the potent electron with-
R2
R2
HN
NH2
O
N
NH
OH
R1
CF3
MeCN, reflux
R1
CF3
3
4
R2
1) POCl3-pyridine-silica gel
2) MnO2
N
N
MeCN, reflux
R1
CF3
5
drawing properties of the trifluoromethyl group Scheme 2
(Scheme 1).
The following procedure is representative of the one-pot
condensation of trifluoromethyl ketone 3 with amidines.
A suspension of benzamidine hydrochloride (1.0 mmol)
and sodium hydroxide (NaOH) (1.1 mmol) in acetonitrile
(MeCN) (3 ml) was stirred at room temperature for 1 h,
then, to the mixture was slowly added ketone 3a (1 mmol)
at that temperature. After the mixture was refluxed for
3 h, POCl (4.0 mmol), pyridine (8.0 mmol), and SiO(Mer-
ck Art. 7734) (1.2 g) were sequentially introduced into the
mixture at room temperature, then the resulting suspen-
sion was stirred at reflux temperature for 24 h. Manga-
nese(IV) oxide (MnO) (1.4 g) was added to the
suspension, and the mixture was refluxed for an additional
2.5 h. The entire mixture was concentrated under vacuum
to give the residue, which was chromatographed on silica
gel using hexane:benzene (1:2), producing the 2,6-
diphenyl-4-(trifluoromethyl)pyrimidine (5a) (0.258 g) in
86% yield.
dehydrating reagent
NH
N
OH
X
CF3
X
CF3
2
1
Scheme 1
During the course of our current studies on the synthesis
of trifluoromethylated nitrogen-containing heterocycles,
we have recently reported a facile route to the 2-(trifluo-
romethyl)-1,4-dihydro-, 2-(difluoromethyl)-, and 6-(tri-
fluoromethyl)-pyridines via effective dehydration from 1
using phosphorus oxychloride (POCl)-pyridine-silica gel
(SiO).
This communication discloses the one-pot preparation of
2,6-disubstituted 4-(trifluoromethyl)pyrimidines 5 by the
reaction of b-substituted a,b-unsaturated trifluoromethyl
Synlett 1999, No. 6, 756–758 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
One-pot Preparation of 2,6-Disubstituted 4-(Trifluoromethyl)pyrimidines
757
The results for the one-pot synthesis of 2,6-disubsti-
tuted 4-(trifluoromethyl)pyrimidines are summarized in
Table 1.
References and Notes
(1) For a recent report, see: Cocco, M. T.; Congiu, C.; Onnis, V.
J. Heterocycl. Chem. 1997, 34, 1283.
(2) For recent reports, see:
Sullivan, R. W.; Bigam, C. G.; Erdman, P. E.; Palanki, M. S.
S.; Anderson, D. W.; Goldman, M. E.; Ransone, L. J.; Suto,
M. J. J. Med. Chem. 1998, 41, 413.
Zanatta, N.; Fagundes, M. B.; Ellensohn, R.; Marques, M.;
Bonacorso, H. G.; Martins, M. A. J. Heterocycl. Chem. 1998,
35, 451.
Okada, E.; Kinomura, T.; Higashiyama, Y. Heterocycles
1998, 48, 2347.
Luo, B.-H.; Guan, H.-P.; Hu, C.-M. Synlett 1997, 1261.
Okada, E.; Kinomura, T.; Takeuchi, H.; Hojo, M.
Heterocycles 1997, 44, 349.
Table 1. One-pot preparation of 4-trifluoromethylated pyrimidines 5
R2
Pyrimidine 5
Entry
R1
Yielda(%) of 5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
1
2
3
4
5
6
7
8
9
Ph
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-CF3C6H4
4-NO2C6H4
2-Thienyl
2-Furyl
c-Hex
86
75
63
71
79
40 (70)b
67
69
75
Zanatta, N.; Cortelini, M. D. F. M.; Carpes, M. J. S.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem.
1997, 34, 509.
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-CF3C6H4
Me
5j
5k
5l
5m
5n
10
11
12
13
14
a
Ph
Ph
Ph
Ph
63
65
50
61
9c
(3) For recent reports, see:
Kawase, M.; Koiwai, H.; Yamano, A.; Miyamae, H.
Tetrahedron Lett. 1998, 39, 663.
Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha,
J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S.
A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40,
1347.
Yu, H.-B.; Huang, W.-Y. Synlett 1997, 679. Strekowski, L.;
Lin, S. –Y. J. Hetrocycl. Chem. 1997, 34, 1625. Guan, H. P.;
Tang, X. Q.; Luo, B. H.; Hu, C. M. Synthesis 1997, 1489.
Takahashi, M.; Muta, S.; Nakazato, H. J. Heterocycl. Chem.
1997, 34, 1395.
Ph
b
Isolated yields. Carried out at room temparture only in
c
the preparation of 4. Determined by 19F NMR.
Various aromatic (Entries 1-5 and 10-13), heteroaromatic
(Entries 7 and 8), and aliphatic (Entry 9) ketones 3 react
well with benzamidine hydrochloride to give the corre-
sponding 5 in moderate to good yields. Unexpectedly, the
reaction of 3f did not proceed readily to give fair yields of
5f under the usual conditions, being accompanied by un-
identified products, which could be improved by lowering
the reaction temperature in the preparation of 4 from 3
(Entry 6). Other aromatic amidines smoothly underwent
the condensation reaction affording good yields of 5 (En-
tries 10-13). The reaction of acetamidine hydrochloride,
unfortunately, provided an unsatisfactory result, probably
due to its high basicity or low stability, and the yield was
not increased at all in spite of the reaction conditions be-
ing varied (Entry 14).
(4) For recent reports, see:
Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.;
Miyashiro, J. M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie,
J. L.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1619.
Bartnik, R.; Bensadat, A.; Cal, D.; Faure, R.; Khatime, N.;
Laurent, A.; Laurent, E.; Rizzon, C. Bull. Soc. Chim. Fr. 1997,
134, 725.
(5) For recent reviews, see:
Differding, E.; Frick, W.; Lang, R. W.; Martin, P.; Schmit, C.;
Veenstra, S.; Greuter, H. Bull. Soc. Chim. Belg. 1990, 99, 647.
Silvester, M. J. Adv. in Heterocycl. Chem. 1994, 59, 1.
(6) Except for the ring-aromatization-promoted dehydration, an
excess amount of conc. H2SO4 or trifluoroacetic acid is
usually required, see:
In summary, we demonstrated an effective dehydration of
the 4-hydroxy-4-(trifluoromethyl)-3,5,6-trihydropyrim-
idines, which were formed by the reaction of a,b-unsatur-
ated trifluoromethyl ketones with amidines, by the POCl-
pyridine-SiO system, and the successive oxidation of the
formed dehydrated products in the presence of MnO lead-
ing to the corresponding 2,6-disubstituted 4-(trifluoro-
methyl)pyrimidines in good yields. The present one-pot
reaction can serve as a convenient and alternative method
for the synthesis of 2,6-disubstituted 4-(trifluorometh-
yl)pyrimidines.
(a) Singh, S. P.; Kapoor, J. K.; Kumar, D.; Threadgill, M. D.
J. Fluorine Chem. 1997, 83, 73.
(b) Mclnally, T.; Tinker, A. C. J. Chem. Soc., Perkin Trans. 1
1988, 1837.
(c) Okada, E.; Tsukushi, N.; Kunihiro, N.; Tomo, Y.
Heterocycles 1998, 49, 297.
(d) Okada, E.; Okumura, H.; Nishida, Y.; Kitahora, T.
Heterocycles 1999, 50, 377. For reports on effective
dehydration using POCl3 or SOCl2-pyridine, see:
(e) Kim, D. H. J. Heterocycl. Chem. 1986, 23, 1523.
(f) Lee, L. F.; Stikes, G. L.; Molyneaux, J. M.; Sing, Y. L.;
Chupp, J. P.; Woodard, S. S. J. Org. Chem. 1990, 55, 2872,
and Ref. 6d.
Acknowledgement
(7) (a) Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu H.;
Shibata, K. Tetrahedron Lett. 1996, 37, 4177.
(b) Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu, H.;
Shibata, K. Synlett 1997, 591.
We are grateful to Dr. H. Muramatsu for his valuable discussion.
(c) Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.;
Matsui, M.; Muramatsu H.; Shibata, K. Synthesis 1997, 1321.
Synlett 1999, No. 6, 756–758 ISSN 0936-5214 © Thieme Stuttgart · New York

758
K. Funabiki et al.
LETTER
Macquarrie, D. J. Tetrahedron Lett. 1998, 39, 4125.
Kotsuki, H.; Shimanouchi, T.; Ohshima, R.; Fujiwara, S.
Tetrahedron 1998, 54, 2709.
(d) Katsuyama, I.; Ogawa, S.; Nakamura, H.; Yamaguchi, Y.;
Funabiki, K.; Matsui, M; Muramatsu H.; Shibata, K.
Heterocycles 1998, 48, 779.
(e) Yamaguchi, Y.; Katsuyama, I.; Funabiki, K.; Matsui, M.;
Muramatsu, H.; Shibata, K. J. Heterocycl. Chem. 1998, 35,
805.
Li, T.; Wang, J. –X.; Zheng, X. –J. J. Chem. Soc., Perkin
Trans. 1 1998, 3975. Ranu, B. C.; Sakar, A.; Majee, A. J. Org.
Chem. 1997, 62, 1841.
(f) Funabiki, K.; Noma, N.; Kuzuya, G.; Matsui, M.; Shibata,
K. J. Chem. Res. in press.
Kotsuki, H.; Arimura, K. Tetrahedron Lett. 1997, 38, 7583.
Varma, R. S.; Dahiya, R.; Saini, R. K. Tetrahedron Lett. 1997,
38, 8819.
(8) For the preparation of 4-hydroxy-2,6-diphenyl-4-(trifluoro-
methyl)-3,5,6-trihydropyrimidines 4a from the a,b-un-
saturated trifluoromethyl ketone 3a, potassium t-butoxide
(t-BuOK), Na2CO3, and triethylamine were not suitable, and
the yield of 4a became low (4-18%).
(9) After quenching, extraction, drying, concentration, column
chromatography (hexane:EtOAc=1:1), and recrystallization,
the major isomer of 4-hydroxy-2,6-diphenyl-4-(trifluoro-
methyl)-3,5,6-trihydropyrimidine (4a) was obtained in 86%
yield. The data for the major isomer of 4a are as follows:
Mp 204-206 °C; IR (KBr) 3392 (NH), 3062 (OH) cm-1; 1H
NMR (400 MHz, CDCl3, TMS) d 1.84 (dd, J = 13.0, 12.7 Hz,
1H), 2.30 (dd, J = 13.0, 3.9 Hz, 1H), 3.76 (br s, 1H), 4.57 (dd,
J = 12.7, 3.9 Hz, 1H), 5.59 (br s, 1H), 7.35-7.52 (m, 8H), 7.74-
7.76 (m, 2H); 19F NMR (376 MHz, CDCl3, ext. CF3COOH) d
-7.68 (s, 3F); MS (EI) m/z (rel intensity) 320 (M+; 12), 251
(58), 121 (17), 104 (100).
(10) In the absence of SiO2, the reaction did not cleanly proceed to
give the product 3a in less than 70% yield, together with some
unidentified products in the TLC monitoring. At present,
although the exact role of SiO2 is not clear, the absorption of
reagents onto the surface of SiO2 may be crucial for the
efficiency of the reaction. Further studies on the mechanistic
aspects for the part of SiO2 are now in progress. For recent
reviews of organic reactions in the presence of SiO2, see:
Nishiguchi, T. J. Synth. Org. Chem. Jpn. 1993, 51, 308, and
references cited therein. For recent reports, see: Ogawa, H.;
Amano, M.; Chihara, T. Chem. Commun. 1998, 495.
Chisem. I. C.; Rafelt, J.; Shieh, M. T.; Chisem, J.; Clark, J. H.;
Jachuck, R.; Macqarrie, D.; Ramshaw, C.; Scott, K. Chem.
Commun. 1998, 1949.
(11) MnO2 was purchased from Nacarai Tesque, Inc. N-
Bromosuccinimide (NBS) (1 equiv.) was also effective for the
oxidation.
(12) All compounds gave satisfactorily analytical data. Selected
data for 5: 2,6-Diphenyl-4-(trifluoromethyl)pyrimidine
(5a): Mp 83-84 °C; 1H NMR (400 MHz, CDCl3, TMS) d 7.52-
7.60 (m, 6H), 7.90 (s, 1H), 8.26-8.29 (m, 2H), 8.63-8.65 (m,
2H); 19F NMR (376 MHz, CDCl3, ext. CF3COOH) d 7.76 (s,
3F); MS (EI) m/z (rel intensity) 300 (M+; 100), 128 (79), 103
(48).
6-(4-Methoxyphenyl)-2-phenyl-4-(trifluoromethyl)-
pyrimidine (5b): Mp 120-121 °C; 1H NMR (400 MHz,
CDCl3, TMS) d 3.91 (s, 3H), 7.07 and 8.26 (AB quartet, J =
9.0 Hz, 4H), 7.52-7.55 (m, 3H), 7.82 (s, 1H), 8.61-8.63 (m,
2H); 19F NMR (376 MHz, CDCl3, ext. CF3COOH) d 7.62 (s,
3F); MS (EI) m/z (rel intensity) 330 (M+; 100), 128 (24), 102
(18), 90 (15).
2-(4-Methoxyphenyl)-6-phenyl-4-(trifluoromethyl)-
pyrimidine (5j): Mp 85-86 °C; 1H NMR (400 MHz, CDCl3,
TMS) d 3.91 (s, 3H), 7.04 and 8.60 (AB quartet, J = 8.8 Hz,
4H), 7.55-7.58 (m, 3H), 7.82 (s, 1H), 8.24-8.27 (m, 2H); 19
F
NMR (376 MHz, CDCl3, ext. CF3COOH) d 7.68 (s, 3F); MS
(EI) m/z (rel intensity) 330 (M+; 100), 128 (36), 103 (29).
(13) Benzamidine hydrochloride was commercially available from
Tokyo Kasei Co., Ltd. Other aromatic amidine hydrochlorides
were prepared according to the previous literature, see: Moss,
R. A.; Ma, W.; Merrer, D. C.; Xue, S. Tetrahedron Lett. 1995,
36, 8761.
Braga, A. L.; Rodrigues, O. E. D.; Avila, E. D.; Silveira, C. C.
Tetrahedron Lett. 1998, 39, 3395. Chandrasekhar, S.;
Ramachander, T.; Takhi, M. Tetrahedron Lett. 1998, 39,
3263.
Article Identifier:
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