Synthesis of trifluoromethylated analogues of 4,5-dihydroorotic acid

Article abstract of DOI:10.1002/ejoc.201403495

4-(Trifluoromethyl)pyrimidin-2(1H)-ones react with trimethylsilyl cyanide in the presence of a tertiary amine catalyst to give Michael-like 1,4-conjugate hydrocyanation adducts exclusively at the 3,6-positions. The resulting 2-oxo-6-(trifluoromethyl)- 1,2,3,4-tetrahydropyrimidine-4-carbonitriles have been used to synthesize new trifluoromethylated 4,5-dihydroorotic acid analogues and their esters in racemic as well as enantiopure forms by a chiral auxiliary approach. The orthogonal intramolecular C-F...C=O interaction between the fluorine atom of the CF₃ group and the carbon atom of the ester group observed in the crystal state may stabilize the sterically unfavourable conformation of the methyl 2-oxo-6-(trifluoromethyl) hexahydropyrimidine-4-carboxylate molecule with axially oriented substituents.

Full text of DOI:10.1002/ejoc.201403495

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
FULL PAPER
DOI: 10.1002/ejoc.201403495
Synthesis of Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
Volodymyr A. Sukach,*[a] Anastasia A. Resetnic,[b] Viktor M. Tkachuk,[a] Zhengguo Lin,[b]
Ulrich Kortz,[b] Mykhailo V. Vovk,[a] and Gerd-Volker Röschenthaler[b]
Keywords: Nitrogen heterocycles / Fluorine / Cyanides / Noncovalent interactions
4-(Trifluoromethyl)pyrimidin-2(1H)-ones react with trimethyl- as enantiopure forms by a chiral auxiliary approach. The or-
silyl cyanide in the presence of a tertiary amine catalyst to thogonal intramolecular C–F···C=O interaction between the
give Michael-like 1,4-conjugate hydrocyanation adducts ex- fluorine atom of the CF3 group and the carbon atom of the
clusively at the 3,6-positions. The resulting 2-oxo-6-(trifluoro- ester group observed in the crystal state may stabilize the ste-
methyl)-1,2,3,4-tetrahydropyrimidine-4-carbonitriles
have rically unfavourable conformation of the methyl 2-oxo-6-(tri-
been used to synthesize new trifluoromethylated 4,5-dihy- fluoromethyl)hexahydropyrimidine-4-carboxylate molecule
droorotic acid analogues and their esters in racemic as well with axially oriented substituents.
idinium side-chain of Arg.[4,5] Additionally, coordination to
Introduction
the metal ion Zn2+ is sometimes observed.[6] Such electro-
Organofluorine compounds are of paramount impor-
positive regions are strongly attractive to hydrogen-bond ac-
tance in the modern chemical industry, and they have also
cepting C=O, OH, thiol, and carboxylate groups. The ques-
found widespread application in crop protection, medicine,
tion of how efficiently they can be replaced by fluorine-con-
and materials science.[1] There is an ever-growing variety of
taining moieties as bioisosteres is being actively re-
searched.[7] Therefore, the synthesis of new fluorinated ana-
logues of biologically active small molecules is of great inter-
est in organofluorine and medicinal chemistry.
synthetic fluorinated molecules, including approved and in-
vestigational drug substances containing one or more single
fluorine atoms or fluorinated functional groups (CHF2,
CF3, OCF3, and SCF3 are common).[2] The persistent inter-
est in such compounds may be attributed to the advan-
tageous chemical, physicochemical, and biological proper-
ties imparted by fluorine incorporation.
Fluorination has become a powerful tool for the modula-
tion of crucial parameters of drug-candidate molecules. This
approach is often used to influence metabolic stability and
cell permeability, and to control the conformation of biolo-
gically active molecules.[3] There are numerous examples
showing that fluorine atoms can significantly contribute to
ligand binding affinity and selectivity through different
types of positive nonbonding interactions within the active
site of the corresponding protein target.[4] Fluoro-
philic environments in proteins include the peptide bonds,
which can be involved in C–F···H–N, C–F···C=O, and
C–F···H–Cα interactions, as well as the side-chain amide res-
idues of Asn and Glu, and the positively charged guan-
Trifluoromethyl ketimines are an important class of fluo-
rinated compounds that have generated considerable recent
research interest.[8] The electron-accepting properties of the
trifluoromethyl group make the typically deactivated ket-
imine C=N double bond readily susceptible to the addition
of various C-nucleophiles. As a result, plenty of synthetic
methods for the preparation of trifluoromethylated
amines,[9] α- and β-amino ketones,[10] β-aminonitroalk-
anes,[11] and α-aminonitriles,[12] as well as α- and β-amino
acids[13,14] have been developed over the past few decades.
Much research has focussed on the chemistry of trifluoro-
methyl ketimines containing a reactive endo heterocyclic
C=N bond.[15] Compounds of this type have found wide-
spread application as starting materials in the synthesis of
new fluorinated cyclic amine derivatives[15c,16] and 3,4-di-
hydroquinazolin-2-ones (including asymmetric versions).[17]
4-(Trifluoromethyl)pyrimidin-2(1H)-ones
1
(Scheme 1),
which also belong to the class of cyclic ketimines, stand out
due to their ambident electrophilic nature.[18] They have
been much less studied until now, despite their synthetic
availability[15d–15f] and the fact that they are original fluori-
nated derivatives of pyrimidin-2-one, a key heterocyclic
component of nucleic acids. A first insight into the reactiv-
ity of compounds 1 with nucleophiles was recently provided
by our group.[19] We demonstrated that compounds 1 re-
versibly react with acetone at the endocyclic C=N or C=C
[a] Department of Organic Reactions Mechanisms, Institute of
Organic Chemistry, National Academy of Sciences of Ukraine,
Murmans’ka 5, Kyiv 02660, Ukraine
E-mail: vsukach@gmail.com
http://www.ioch.kiev.ua
[b] School of Engineering and Science, Jacobs University Bremen,
Campus Ring 1, 28759 Bremen, Germany
E-mail: g.roeschenthaler@jacobs-university.de
http://www.jacobs-university.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403495.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
bond, depending on the catalyst used, and also on whether through interactions of carboxylate, carbonyl, and thiol
thermodynamic or kinetic control is operative (Scheme 1). groups or fluorine atom(s) with the Zn2+ cofactor and
In the reaction catalysed by secondary amines, the forma- hydrogen-bond donating regions.[21] The synthesis of new
tion of Michael-like adduct 2 is preferred under kinetically fluorinated analogues of DHO is a promising research field
controlled conditions. Mannich-like adducts 3 are thermo- from both theoretical and practical points of view, taking
dynamically stable, and are formed after a prolonged reac- into account, on the one hand, a call to clarify the fluorine
tion time. Unfortunately, because of the pronounced revers- effect on molecular binding to the protein active sites,[22]
ibility of these conversions, both products were isolated in and, on the other hand, the urgent need for new medi-
racemic form. Another drawback was the very limited scope cations in the relevant therapeutic areas.[23]
of ketone nucleophiles (only acetone was suitable).
In this paper, we report the first catalytic hydrocyanation
reaction of 4-(trifluoromethyl)pyrimidin-2(1H)-ones 1. This
conversion has opened up a synthetic route to several race-
mic and enantiopure trifluoromethylated DHO analogues
that could mimic the transition state of the DHOase enzy-
matic reaction.
Results and Discussion
The 4-(trifluoromethyl)pyrimidin-2(1H)-ones (i.e., 1)
used in this study were prepared by the procedure of Gerus
and Zanatta starting from 4-ethoxy-1,1,1-trifluoro-3-buten-
2-one and ureas.[15f,15g] Simple N1-methyl-substituted com-
pound 1a was used to screen cyanide sources and solvents
for the hydrocyanation reaction (Table 1). As cyanide
sources, we tested TMSCN (TMS = trimethylsilyl; in com-
bination with iPrOH as the trimethylsilyl group acceptor),
acetone cyanohydrin, and HCN.
Scheme 1. Summary of previous and present studies.
An initial experiment was carried out using TMSCN in
To further illustrate the reactivity and synthetic potential toluene. We found that a catalytic amount of organic base
of pyrimidones 1, we have used hydrogen cyanide as a dif- (triethylamine) was necessary for the reaction to take place.
ferent type of C-nucleophile. In this case, the formation of After as little as 3–5 min of stirring the reaction mixture at
the analogous kinetic product (i.e., 4) provides easy access room temperature, the sparingly soluble starting pyrimid-
to compounds 5, new trifluoromethylated derivatives of one (i.e., 1a) had completely dissolved, and this was
dihydroorotic acid (DHO, Scheme 1). DHO is a crucial followed by the rapid precipitation of 3-methyl-2-oxo-6-(tri-
component of pyrimidine nucleotide biosynthesis. It is fluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carbonitrile
formed in the cyclization of N-carbamoyl-l-aspartic acid (4a) as a white bulky solid. The isolated yield after filtration
catalysed by the zinc metalloenzyme dihydroorotase and washing with hexane was 72% (Table 1, entry 1). We
(DHOase; Scheme 2).[20]
also found that a toluene/hexane mixture (2:1) gave a higher
DHOase has long been known as a target for antimalar- yield (93%) of 4a (Table 1, entry 2). The material obtained
1
ial and anticancer drug development. Its most potent inhib- was Ͼ95% pure according to H NMR spectroscopy. The
itors (structures I–IV, Scheme 2) exert their action through formation of the 3,6-adduct was initially confirmed by 19F
mimicry of the transition state of the enzymatic reaction and 13C NMR spectroscopy. The chemical shift of the
Scheme 2. Enzymatic reaction catalysed by dihydroorotase (DHOase) and structures of its inhibitors.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
Table 1. Screening of the cyanide source, solvent, and time for the 6.33 ppm) as a result of the reverse reaction. Interestingly,
hydrocyanation reaction of 1-methyl-4-(trifluoromethyl)pyrimidin-
compound 4a, which is stable for weeks in CDCl3 solution,
decomposes upon addition of a catalytic amount of triethyl-
2(1H)-one (1a).[a]
amine to form a mixture of 1a, 4a, and 6. This suggests that
the exclusive formation of 4a under conditions of kinetic
control is due to displacement of the equilibrium through
product precipitation. The choice of reaction solvent is
therefore crucial, as demonstrated by the unsatisfactory re-
sults with CH2Cl2, iPrOH, and MTBE (methyl tert-butyl
ether; Table 1, entries 7–10). The complex degradation pro-
Entry[a] Cyanide source
Solvent
Time Yield of 4a
[h]
cesses observed after a prolonged reaction time (Table 1,
entries 6, 9, and 10) are presumably due to the increased
acidity of the C-4 proton in the 4a molecule; the resulting
carbanion species can lead to unidentified side-reactions.
Using the optimized conditions for the hydrocyanation
of 1a (Table 1, entry 2), we went on to study the scope of
the reaction using various N1-substituted 4-(trifluoro-
methyl)pyrimidin-2(1H)-ones (i.e., 1b–1i). As expected, sim-
ple primary alkyl substituents were well tolerated (com-
pounds 4b–4g, Scheme 3). To explore secondary N1-alkyl
derivatives, we synthesized previously unknown compound
1h in both racemic and enantiopure form [using (1S)-1-
phenylethanamine as a chiral pool starting material]. The
yield of the corresponding racemic nitrile (i.e., 4h) was al-
most quantitative. A diastereomeric ratio of 5:1, determined
[%][b]
1
2
3
4
5
6
7
8
9
10
TMSCN
toluene
toluene/hexane, 2:1
toluene
1
1
1
1
1
24
24
1
24
24
72
93
TMSCN
Me2C(OH)CN[c]
–
–
–
[d]
HCN[c]
toluene
[d]
[e]
TMSCN, 1.2 equiv. toluene/hexane, 2:1
[f]
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
toluene
MTBE
CH2Cl2
CH2Cl2
iPrOH
–
[d]
–
[g]
–
–
[f]
[f]
–
[a] Reaction conditions: compound 1a (1.5 mmol), cyanide source
(3 mmol), iPrOH (3 mmol), Et3N (0.3 mmol), solvent (5 mL),
20 °C. [b] Yields of pure isolated product. [c] Without iPrOH.
[d] No reaction. [e] 1.8 mmol of TMSCN and iPrOH were used, a
4a/1a mixture (5:1) was isolated. [f] Not isolated, decomposition.
[g] Conversion 71%, formation of a 4a/6 mixture (4:1).
1
by H and 19F NMR spectroscopy, represented a high dia-
stereoselectivity. The racemic major isomer was purified af-
fluorine nuclei was observed at δ = –71.00 ppm. The signal ter the next step (Scheme 3, see below for detailed descrip-
of the C-6 carbon was detected at δ = 131.58 ppm (quartet, tion). Unfortunately, optically pure (S)-1h gave no crystal-
2JC,F = 37.4 Hz). All these measurements were recorded in line product 4h with any of the solvents and temperatures
CDCl3. These data rule out structure 6 in which the fluor- tested. Finally, the reaction was carried out in toluene at
ine and corresponding C-4 carbon atoms would be more 0–5 °C, and quenched after 1 h with acetic acid (0.5 equiv.).
shielded, and so have smaller chemical shifts of δ ≈ –82 and After washing the clear toluene solution with water, a mix-
60 ppm, respectively.[19]
ture of enantiopure diastereomers 4h (5:1 ratio, total 73%),
The use of acetone cyanohydrin and HCN instead of starting pyrimidone (7%), and regioisomeric product 6h
TMSCN in toluene did not result in any noticeable forma- (20%) was isolated, and was used in the next step in an
tion of 4a (Table 1, entries 3 and 4). The efficiency of hydro- attempt to separate a more stable enantiopure compound
cyanation with TMSCN could be explained by a mecha- (4R,1ЈS)-4h derivative by preparative chromatography (see
nism involving initial trimethylsilylation of the oxygen atom below for details). As N1-tert-alkyl and N1-aryl pyrimidones
and activation of the electrophilic centres for attack by the 1 are not available by any known methods, we could not
cyanide anion. The O-silylated intermediate is then cleaved study the effect of these substituents on the course of the
by 2-propanol to give the final product (i.e., 4a). The use reaction. N1-Unsubstituted pyrimidone 1i reacted dif-
of 1.2 equiv. of TMSCN led to incomplete conversion of 1a ferently to give mainly the O-silylated derivative under a
(Table 1, entry 5). iPrOH can be replaced by methanol.
variety of tested conditions.
Prolongation of the reaction time to 24 h resulted in the
Compounds 4a–4h are white solids with a faint almond
gradual dissolution of the initially formed precipitate, a smell, and they can be crystallized from nonpolar solvents
darkening of the reaction mixture, and, finally, tar forma- (CHCl3, toluene) and stored for a few months without no-
tion on the flask walls (Table 1, entry 6). 19F NMR analysis ticeable decomposition. On heating to the melting point,
of the reaction mixture always indicated the presence of the they rapidly release HCN, which causes the sample to solid-
starting material (up to 20%), along with regioisomeric ify (a “double melting point” effect). Derivative 4g pro-
product 6 having a chemical shift of δ = –81.90 ppm (in duced fine single crystals from CDCl3 solution that were
toluene). A large number of unidentified signals were ob- analysed by X-ray crystallography in order to unambigu-
served after the reaction was run for 24 h. This behaviour ously prove the 3,6-adduct structure of compounds 4 (Fig-
points to the reversibility of the hydrogen cyanide addition. ure 1, see Supporting Information for details).
Clear evidence for an equilibrium between 4a, 1a, and HCN
To prepare trifluoromethylated dihydroorotic acid ana-
1
was provided by H NMR spectra of supposedly pure 4a logues from nitriles 4a–4h, we first developed a prepara-
recorded in [D6]DMSO, which, however, showed the signals tively convenient method for cyano group methanolysis.
of the three components (including the HCN proton at δ = This used HCl (4 m solution in dioxane), and the reaction
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
Scheme 3. Synthesis of 3-alkyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carbonitriles 4a–4h and their derivatives, viz.,
methyl 3-alkyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carboxylates 7a–7i and 3-alkyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-
tetrahydropyrimidine-4-carboxylic acids 5a–5i. Reaction conditions: i) Compound 1a–1h (1.5 mmol), TMSCN (3 mmol), iPrOH (3 mmol),
Et3N (0.3 mmol), toluene/hexane (2:1; 5 mL), 20 °C, 1 h; ii) Compound 4a–4h (1.5 mmol), MeOH (6 mmol), HCl (4 m in anhydrous
dioxane; 6 mL), 0–5 °C, 6 h; iii) H2O (10 mL), 20 °C, 1 h; iv) Compound 7a–7h (1 mmol), LiOH (0.95 mmol), THF/H2O (1:1; 5 mL),
20 °C, 16 h; v) HCl (conc.), pH 2; vi) Compound 5f, 5h, 7f, or 7h (1 mmol), CF3CO2H (5 mL), reflux, 30 min, yields of pure isolated
products.
we concluded that the corresponding enantiopure ester 7h
prepared from (S)-1h has an R configuration at its newly
formed endocyclic chiral centre.
Figure 1. X-ray crystal structure of compound 4g.
proceeded through the formation of the corresponding
imino ester hydrochlorides. Taking into account the intrin-
sic instability of the starting nitriles (i.e., 4), it was quite
inappropriate to directly hydrolyse them to carboxylic acids
by hydrogen bonds.
under the commonly used harsh alkaline or acidic condi-
Figure 2. X-ray crystal structure of racemic compound
(1ЈSR,4RS)-7h. Molecules are assembled into heterochiral dimers
tions.
Subsequent hydrolysis of the ester group with a sub
The proposed method gave methyl 3-alkyl-2-oxo-6-(tri- stoichiometric amount of LiOH in THF/H2O (1:1) pro-
fluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carboxylates vided the corresponding target acids (i.e., 5a–5h) in excel-
7a–7h in high yields without chromatographic purification lent yields. Unfortunately, acid 5h was obtained as a 2:1
(Scheme 3). The major diastereomer of racemic 7h was eas- inseparable mixture of two isomers owing to isomerization
ily isolated by a single crystallization from MeOH/H2O at the C-4 atom of 5h during the hydrolysis of the ester
1
(3:1) in 47% overall yield (starting from racemic 4h as a group. Moreover, H NMR analysis of the isolated sample
mixture of two diastereomers). The relative configuration of unreacted ester 7h clearly indicated that the starting ma-
of its stereogenic centres was determined by X-ray crystal- terial had also isomerized under the conditions used. This
lography to be (4RS,1ЈSR). In the crystalline state, the mol- process is likely to be induced by the increased acidity of the
ecules of this compound are assembled into heterochiral di- H-4 proton due to the effect of the trifluoromethyl group.
mers by hydrogen bonds (Figure 2, see Supporting Infor-
mation for details). From the X-ray crystallographic data logues of dihydroorotic acid was prepared by the reactions
A series of N3-alkyl-substituted trifluoromethylated ana-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
described above. The N3-unsubstituted racemic compounds
5i and 7i, which are not accessible through direct hydro-
cyanation of 1i, were readily obtained by removal of the 4-
methoxybenzyl or 1-(1-phenylethyl) substituents after a
short time at reflux in trifluoroacetic acid (TFA; Scheme 3).
Likewise, the developed approach provides easy access to
an enantiopure (R) form of 7i, which is configurationally
stable under the relatively drastic conditions of refluxing
TFA, but which rapidly decomposes in basic media, such
as a dilute LiOH solution. The enantiomeric composition
was confirmed by its transformation into optically pure
derivative (4R,6S)-10d (see below). Carboxylic acid 5i is
a
dihydroorotic acid analogue, with the endocyclic
–CH2(C=O)– moiety replaced by the structurally similar
–CH=C(CF3)– moiety. This compound is of potential inter-
est in medicinal chemistry as a new fluorinated building
block and as a mimic of dihydroorotase inhibitor I (see
Scheme 2).
Figure 3. X-ray crystal structure of compound 8. The CF3 and
COOH groups were found in equatorial positions.
The use of excess LiOH in the hydrolysis led to the simul-
taneous hydration of the endocyclic double bond to form a
cyclic hydroxyaminal (at a much slower rate than the nor- It has been demonstrated that an efficient and highly re-
mal hydrolytic process). Compound 5e or 7e, when treated gioselective hydrogenation leading to methyl 2-oxo-6-(tri-
with 4 equiv. of LiOH at room temperature for 16 h, was fluoromethyl)hexahydropyrimidine-4-carboxylates 10 and
converted into a mixture of diastereomeric salts of 3- the corresponding acids (i.e., 11) is readily achievable under
benzyl-6-hydroxy-2-oxo-6-(trifluoromethyl)hexahydropyrim- mild conditions with hydrogen gas (1 atm) in the presence
idine-4-carboxylic acids 8 and 9 in a ratio of 1.9:1, as shown of a Pd/C catalyst at room temperature (Scheme 5).
by the 19F NMR spectra of the reaction mixture. Acidifica-
tion to pH 2 resulted in the precipitation of the nearly pure
major diastereomer (i.e., 8), and this was followed by
crystallization from aqueous MeOH to give a 45% yield of
the isolated material (Scheme 4).
Scheme 5. Diastereoselective hydrogenation of acids 5a, 5f, 5i and
their methyl esters 7a, 7f, 7h, 7i. Reaction conditions (1 mmol of
the corresponding substrate was used): MeOH (5 mL), H2 (1 atm),
Pd/C (cat.), 1 h, 20 °C, yields of pure isolated products.
Scheme 4. Cyclic hydroxyaminal formation from compounds 5e
and 7e. Reaction conditions: i) Compound 5e or 7e (1 mmol),
LiOH (4 mmol), THF/H2O (1:1; 6 mL), 20 °C, 16 h; ii) HCl (aq.),
pH 2, yields of pure isolated products.
The relative configuration of the two endocyclic stereo-
genic centres in the molecules of the obtained single dia-
stereomers was assigned as (4RS,6SR), i.e., cis, based on
The structure of 8 was determined by X-ray crystallo- the X-ray crystallographic data for compound 10a (Fig-
graphic analysis, and it was shown to be the (4RS,6RS) iso- ure 4, see Supporting Information for details). Thus, the
mer with the CF3 and COOH groups in equatorial orienta- enantiopure 10d that was obtained from (R)-7i has an
tions (Figure 3, see Supporting Information for details). In (4R,6S) configuration. The enantiomeric composition of
contrast to the crystal structures of compounds 4g and 7h, enantiopure (4R,6S,1ЈS)-10c was confirmed by 19F NMR
the molecules of 8 are assembled into homochiral associa- spectroscopy using quinine as a chiral solvating agent (see
tions by hydrogen bonds between the OH, COOH, and Supporting Information for details). The structure of acid
endocyclic CONH groups. The minor diastereomer (i.e., 9) 11a was confirmed by its esterification with methanol to
was isolated in a pure state in 17% yield from the mother give 10a. These results allowed us to conclude that the dia-
liquor remaining after the filtration of 8.
stereoselective hydrogenation gave cis products for all the
As previously reported, the C=C double bond of N-acyl- described examples.
ated α-trifluoromethyl-substituted enamines can be reduced
A particular feature of the crystal structure of 10a is the
by treatment with sodium borohydride in THF/H2O.[24] sterically unfavourable axial orientation of both the CF3
Compounds 5 and 7, which have a similar structural motif, and COOMe groups. Even though crystal packing forces
proved almost completely unreactive under such conditions. may be a key structural determinant in the solid state,[25]
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
Figure 4. X-ray crystal structure of compound 10a. The molecule
has a conformation with axially oriented CF3 and COOMe groups.
The dashed line shows the short orthogonal intramolecular
C–F···C=O contact. The label indicates the distance between the
corresponding fluorine and carbon atoms.
Scheme 6. Synthesis of N3-unsubstituted compounds 10d and 11d
by acidic cleavage of 4-methoxybenzyl and 1-(1-phenylethyl) sub-
stituents and hydrolysis of esters 10b and 10c with the formation
of diastereomeric acids 11b/12a and 11c/12b mixtures. Reaction
conditions (1 mmol of the corresponding substrate was used):
i) CF3CO2H (5 mL), reflux, 30 min; ii) LiOH (0.95 mmol), THF/
H2O (1:1, 6 mL), 20 °C, 16 h, then aq. HCl, pH 2, yields of pure
isolated products.
the observed conformational preference can also be ex-
plained by the attractive intramolecular orthogonal
multipolar C–F···C=O interaction.[5a,26] A short contact be-
tween one of the fluorine atoms and the carbon atom of the
ester group (2.714 Å distance) with an apparent orthogonal
geometry supports this hypothesis (Figure 4). Similar inter-
molecular interactions are typical of protein–ligand com-
plexes, and they affect the binding mode and biological
Conclusions
We have shown that the reaction of N1-alkyl-4-(trifluoro-
properties of many fluorine-containing drugs.[1,4] We believe methyl)pyrimidin-2(1H)-ones 1 with TMSCN in the pres-
that the described fluorine effect can control the conforma- ence of a tertiary amine catalyst and an alcohol results in
tion of other trifluoromethylated hetero- and carbocyclic the selective and highly efficient 1,4-conjugate addition of
small molecules, and that it therefore has potential as a new HCN to the endocyclic C=C bond of the pyrimidine ring.
conformational tool in the rational design of organocata- Using a chiral auxiliary approach, an asymmetric version
lysts and biologically active compounds.[27]
of this transformation was also accomplished. The resulting
Surprisingly, the 4-methoxybenzyl and 1-(1-phenylethyl) nitriles (i.e., 4a–4h) appear to be versatile starting com-
N3-substituents tolerated mild hydrogenation conditions pounds for the synthesis of racemic trifluoromethylated di-
without undergoing reductive cleavage. It was possible to hydroorotic acid analogues 5a–5i as well as their methyl es-
subsequently remove them by heating the corresponding re- ters 7a–7i. Esters 7h and 7i were prepared in enantiopure
duced products (i.e., 10b, 10c, and 11b) in refluxing TFA forms. A highly diastereoselective reduction of the 2-oxo-
without isomerization at the endocyclic chiral centre at 1,2,3,4-tetrahydropyrimidine ring of compounds 5 and 7
C-4 (Scheme 6).
into the 2-oxohexahydropyrimidine moiety of compounds
This approach has provided an alternative route to race- 10 and 11 was easily achieved by straightforward hydrogen-
mic and enantiopure (4R,6S) ester 10d and racemic acid ation with hydrogen gas in the presence of a Pd/C catalyst
11d, which are interesting as a new low-molecular weight under mild conditions. The developed method allowed the
fluorinated heterocyclic building block and a trifluoro- preparation of racemic 2-oxo-6-(trifluoromethyl)hexahy-
methyl-containing mimic of dihydroorotase inhibitor III dropyrimidine-4-carboxylic acids 11 and their methyl esters
(see Scheme 2). However, the aforementioned isomerization 10. Enantiopure forms of esters 10c and 10d were isolated.
did occur during the hydrolysis of the ester group in com- The X-ray crystallographic study of compound 10a revealed
pounds 10b and 10c (even though substoichiometric a hitherto unknown example of an intramolecular orthogo-
amounts of LiOH were used). Unexpectedly, isomers 12a nal C–F···C=O interaction that may stabilize the molecule
and 12b were the major components in the resulting insepa- in a sterically unfavourable conformation. The compounds
rable mixture of diastereomeric acids (Scheme 6). Therefore, prepared in this study show promise as new fluorinated
such a route could not be used for the preparation of dia- building blocks and mimics of dihydroorotase enzyme in-
stereomerically pure 11d by subsequent acidic cleavage of hibitors that could be of particular interest in medicinal
the N3-substituent.
chemistry.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
58.58, H 4.89, N 17.00; found C 58.65, H 4.90, N 16.91. LCMS:
[M + H]+ 248, [M – CN]+ 221.
Experimental Section
General Details: All chemicals were obtained from commercial sup-
pliers (Sigma–Aldrich, Enamine Ltd.), and were used without fur-
ther purification. Solvents were purified by standard methods. H
2-Oxo-3-(prop-2-en-1-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carbonitrile (4c): Yield 0.29 g (85%), m.p. 125–127 °C. 1H
NMR (CDCl3): δ = 3.58 (dd, J = 15.07, 8.35 Hz, 1 H), 4.72 (d, J
= 15.51 Hz, 1 H), 5.03 (s, 1 H), 5.37–5.40 (m, 3 H), 5.71 (s, 1 H),
9.11 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 45.3, 47.4, 93.1 (q,
1
(399.78 or 299.94 MHz), 13C (100.53 or 125.71 MHz), and 19F
(188.14 or 376.17 MHz) NMR spectra were recorded with Jeol
ECX 400, Varian VXR-300, and Varian Mercury 400 instruments
using tetramethylsilane or CCl3F as an internal standard. 1H NMR
spectroscopic data are reported as chemical shifts (ppm) followed
by relative integrals, multiplicities (“s” singlet, “d” doublet, “t”
triplet, “q” quartet, “dd” doublet of doublets, “dt” doublet of trip-
lets, “dq” doublet of quartets, “sext” sextet, “m” multiplet, “br.”
broad), and coupling constants (Hz). LCMS spectra were recorded
with an Agilent 1100 Series high-performance liquid chromato-
graph equipped with a diode matrix with an Agilent LCMSD SL
mass-selective detector. Crystal data for all compounds were col-
lected with a Bruker APEX-II CCD detector. Optical rotations
were measured with an Anton Paar MCP 300 polarimeter (sample-
cell path length 100 mm, wavelength 589 nm). Preparative
chromatography was carried out using a low-pressure (up to 3 atm)
CombiFlash Companion apparatus equipped with a UV detector
(eluent hexane/methyl tert-butyl ether). Microanalyses were per-
formed in the Microanalytical Laboratory of the Institute of Or-
ganic Chemistry, National Academy of Sciences of Ukraine. Com-
pounds 1a–1i were prepared according to literature procedures (see
Supporting Information for the general procedure and characteri-
zation data for new compounds).
1
3JC,F = 4.99 Hz), 114.3, 118.4 (q, JC,F = 273.76 Hz), 120.7, 129.8,
2
131.1 (q, JC,F = 36.90 Hz), 151.3 ppm. 19F NMR (CDCl3): δ =
–71.5 ppm. C9H8F3N3O (231.17): calcd. C 46.76, H 3.49, N 18.18;
found C 46.80, H 3.41, N 18.15. LCMS: [M + H]+ 232, [M – CN]
+
205.
3-Butyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carbonitrile (4d): Yield 0.32 g (86%), m.p. 102–104 °C. 1H NMR
(CDCl3): δ = 0.95 (t, J = 7.68 Hz, 3 H), 1.35 (sext, J = 7.68 Hz, 2
H), 1.58–1.62 (m, 2 H), 3.17–3.21 (m, 1 H), 3.80–3.85 (m, 1 H),
5.05 (s, 1 H), 5.36 (s, 1 H), 9.15 (s, 1 H) ppm. 13C NMR (CDCl3):
1
δ = 13.1, 19.3, 28.1, 45.7, 46.6, 92.8, 114.8, 118.5 (q, JC,F
=
273.76 Hz), 131.3 (q, JC,F = 36.90 Hz), 151.6 ppm. 19F NMR
(CDCl3): δ = –71.6 ppm. C10H12F3N3O (247.22): calcd. C 48.58, H
4.89, N 17.00; found C 48.44, H 3.80, N 17.09. LCMS: [M + H]+
248, [M – CN]+ 221.
2
3-Benzyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carbonitrile (4e): Yield 0.38 g (91%), m.p. 131–133 °C. 1H NMR
(CDCl3): δ = 4.02 (d, J = 14.88 Hz, 1 H), 4.83–4.86 (m, 1 H), 5.31–
5.35 (m, 1 H), 5.50 (d, J = 14.90 Hz, 1 H), 7.30–7.45 (m, 5 H), 8.45
3
(br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 45.7, 48.6, 93.5 (q, JC,F
1
General Procedure for the Synthesis of 2-Oxo-6-(trifluoromethyl)-
1,2,3,4-tetrahydropyrimidine-4-carbonitriles 4a–4g: Compound 1a–
1g (1.5 mmol), 2-propanol (0.18 g, 3 mmol), and triethylamine
(0.03 g, 0.3 mmol) were mixed in a toluene/hexane mixture (2:1;
5 mL), and then TMSCN (0.75 mL, 3 mmol) was added at 20 °C.
The mixture was stirred for 1 h. The resulting white precipitate was
collected by filtration, washed with hexane (10 mL), and dried in
air. The resulting products were Ͼ95% pure, and were used in the
next stage without further purification.
= 4.82 Hz), 114.5, 118.9 (q, JC,F = 273.59 Hz), 128.8, 129.3, 131.4
2
(q, JC,F = 36.61 Hz), 133.8, 152.1 ppm. 19F NMR (CDCl3): δ =
–70.8 ppm. C13H10F3N3O (281.23): calcd. C 55.52, H 3.58, N
14.94; found C 50.55, H 3.54, N 14.95. LCMS: [M + H]+ 282, [M –
CN]+ 255.
3-(4-Methoxybenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydro-
pyrimidine-4-carbonitrile (4f): Yield 0.45 g (96%), m.p. 135–137 °C.
1H NMR (CDCl3): δ = 3.81 (s, 3 H), 3.96 (d, J = 14.88 Hz, 1 H),
4.83 (d, J = 5.04 Hz, 1 H), 5.30 (d, J = 5.02 Hz, 1 H), 5.42 (d, J =
14.86 Hz, 1 H), 6.90 (dd, J = 8.47, 1.83 Hz, 2 H), 7.26 (dd, J =
8.46, 1.84 Hz, 2 H), 8.58 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ =
In the case of enantiopure compound S-1h, the reaction mixture
was kept for 30 min at 5 °C. The clear solution was quenched with
acetic acid (0.036 g, 0.9 mmol), the mixture was washed with dis-
tilled water (2ϫ 10 mL), the organic phase was dried with sodium
sulfate, and the solvent was evaporated. The residue, which con-
tained (1ЈS,4R)-4h (61%) and (1ЈS,4S)-4h (12%) along with re-
gioisomer 6h (20%) and starting material S-1h (7%), was used in
the next step without further purification.
3
45.4, 48.1, 55.4, 93.6 (q, JC,F = 4.79 Hz), 114.5, 114.6, 119.0 (q,
1JC,F = 273.65 Hz), 125.5, 130.3, 131.3 (q, 2JC,F = 36.90 Hz), 151.6,
160.1 ppm. 19F NMR (CDCl3): δ = –70.8 ppm. C14H12F3N3O2
(311.26): calcd. C 54.02, H 3.89, N 13.50; found C 54.15, H 3.90,
N 13.44. LCMS: [M + H]+ 312, [M – CN]+ 285.
3-(4-Fluorobenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carbonitrile (4g): Yield 0.40 g (90%), m.p. 148–150 °C. 1H
NMR (CDCl3): δ = 4.06 (d, J = 15.11 Hz, 1 H), 4.84 (d, J =
5.04 Hz, 1 H), 5.33 (d, J = 5.04 Hz, 1 H), 5.39 (d, J = 15.12 Hz, 1
H), 7.08–7.13 (m, 2 H), 7.33–7.40 (m, 2 H), 8.99 (br. s, 1 H) ppm.
13C NMR (CDCl3): δ = 45.8, 48.1, 93.5 (q, 3JC,F = 4.82 Hz), 114.4,
3-Methyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carbonitrile (4a): Yield 0.29 g (93%), m.p. 120–122 °C. 1H NMR
(CDCl3): δ = 3.09 (s, 3 H), 5.02–5.06 (m, 1 H), 5.37–5.41 (m, 1 H),
8.50 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 33.5, 49.4, 93.1 (q,
3JC,F = 4.79 Hz), 114.5, 119.0 (q, 1JC,F = 273.17 Hz), 131.5 (q, 2JC,F
= 37.38 Hz), 151.8 ppm. 19F NMR (CDCl3): δ = –71.0 ppm.
C7H6F3N3O (205.14): calcd. C 40.98, H 2.95, N 20.48; found C
40.92, H 2.90, N 20.50. LCMS: [M + H]+ 206, [M – CN]+ 179.
2
1
116.3 (d, JC,F = 22.16 Hz), 118.9 (q, JC,F = 273.59 Hz), 129.6 (d,
4JC,F = 2.89 Hz), 130.6 (d, JC,F = 7.71 Hz), 131.4 (q, JC,F
=
3
2
36.61 Hz), 151.9, 161.5 (d, JC,F = 248.54 Hz) ppm. 19F NMR
(CDCl3): δ = –112.5 (s, 1 F), –70.8 (s, 3 F) ppm. C13H9F4N3O
(299.22): calcd. C 52.18, H 3.03, N 14.04; found C 52.19, H 2.97,
N 14.10. LCMS: [M + H]+ 300, [M – CN]+ 273.
1
3-(2-Methylpropyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carbonitrile (4b): Yield 0.30 g (81%), m.p. 134–136 °C. 1H
NMR (CDCl3): δ = 0.89 (d, J = 6.65 Hz, 3 H), 0.96 (d, J = 6.66 Hz,
3 H), 1.98–2.01 (m, 1 H), 2.90 (dd, J = 13.74, 9.29 Hz, 1 H), 3.73
(dd, J = 14.18, 9.30 Hz, 1 H), 4.98 (d, J = 3.99 Hz, 1 H), 5.36 (d,
2-Oxo-3-(1-phenylethyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carbonitrile (4h): Mixture of racemic diastereomers (5:1,
J = 4.02 Hz, 1 H), 9.02 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 1ЈSR,6RS:1ЈSR,6SR), yield 0.39 g (88 %), m.p. 121–123 °C. 1H
3
19.2, 19.4, 25.7, 46.9, 52.8, 92.8 (q, JC,F = 4.99 Hz), 114.6, 118.5
NMR (CDCl3): δ = 1.62 (d, J = 7.10 Hz, 0.6 H), 1.81 (d, J =
7.10 Hz, 3 H), 4.50 (d, J = 6.18 Hz, 1 H), 4.86 (d, J = 6.18 Hz, 0.2
H), 5.27 (d, J = 5.95 Hz, 1 H), 5.45 (d, J = 5.95 Hz, 0.2 H), 5.83
1
2
(q, JC,F = 273.26 Hz), 131.5 (q, JC,F = 36.40 Hz), 151.9 ppm. 19F
NMR (CDCl3): δ = –71.4 ppm. C10H12F3N3O (247.22): calcd. C
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
(q, J = 7.10 Hz, 1 H), 5.89 (q, J = 7.10 Hz, 0.2 H), 7.35–7.49 (m, Methyl 3-Benzyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrim-
6 H), 8.44 (br. s, 1 H), 8.53 (br. s, 0.2 H) ppm. 13C NMR (CDCl3): idine-4-carboxylate (7e): Yield 0.38 g (81%), m.p. 155–157 °C (tolu-
3
1
δ = 15.74, 15.78, 40.9, 41.7, 52.8, 53.5, 94.6 (q, JC,F = 4.82 Hz), ene). H NMR (CDCl3): δ = 3.71 (s, 3 H), 3.95 (d, J = 15.11 Hz,
116.7, 119.0 (q, 1JC,F = 273.59 Hz), 127.9, 128.8, 129.1, 129.3, 131.8 1 H), 4.51–4.55 (m, 1 H), 5.29 (d, J = 15.11 Hz, 1 H), 5.32–5.36
(q, 2JC,F = 36.61 Hz), 137.4, 152.4, 152.5 ppm. 19F NMR (CDCl3): (m, 1 H), 7.23–7.37 (m, 5 H), 8.26 (s, 1 H) ppm. 13C NMR ([D6]-
3
δ = –70.5 (s, 1 F), –70.4 (s, 0.2 F) ppm. C14H12F3N3O (295.26): DMSO): δ = 49.2, 53.1, 57.7, 98.2 (q, JC,F = 4.79 Hz), 120.0 (q,
calcd. C 56.95, H 4.10, N 14.23; found C 57.13, H 4.17, N 14.15.
1JC,F = 272.69 Hz), 127.9, 128.3, 129.0, 129.4 (q, 2JC,F = 34.98 Hz),
137.2, 152.6, 170.0 ppm. 19F NMR ([D6]DMSO): δ = –69.1 ppm.
C14H13F3N2O3 (314.26): calcd. C 53.51, H 4.17, N 8.91; found C
53.55, H 4.09, N 10.56. LCMS: [M + H]+ 315.
LCMS: [M + H]+ 296, [M – CN]+ 269.
General Procedure for the Synthesis of Methyl 2-Oxo-6-(trifluoro-
methyl)-1,2,3,4-tetrahydropyrimidine-4-carboxylates (7a–7h): Com-
pound 4a–4h (1.5 mmol) was added to a mixture of anhydrous
methanol (0.192 g, 6 mmol) and HCl (4 m in anhydrous dioxane;
6 mL) at 5 °C. The reaction mixture was stirred at this temperature
for 6 h. Then water (10 mL) was added, and the mixture was stirred
for 1 h at 22 °C. The resulting precipitate formed was collected by
filtration, washed with water (10 mL), and dried in air. For the
preparation of enantiopure (4R,1ЈS)-7h, the mixture obtained after
stirring in water was extracted with dichloromethane (20 mL), the
organic layer was washed with water (20 mL), and dried with so-
dium sulfate, and the solvent was evaporated. The residue was sub-
jected to preparative chromatography.
Methyl 3-(4-Methoxybenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-
tetrahydropyrimidine-4-carboxylate (7f): Yield 0.41 g (79%), m.p.
123–125 °C (toluene). 1H NMR ([D6]DMSO): δ = 3.58 (s, 3 H),
3.69 (s, 3 H), 3.90 (d, J = 14.88 Hz, 1 H), 4.60–4.65 (m, 1 H), 4.85
(d, J = 14.88 Hz, 1 H), 5.53–5.57 (m, 1 H), 6.86 (d, J = 8.70 Hz, 2
H), 7.16 (d, J = 8.70 Hz, 2 H), 9.77 (s, 1 H) ppm. 13C NMR ([D6]
DMSO): δ = 48.5, 53.1, 55.5, 57.3, 98.1 (q, 3JC,F = 4.79 Hz), 114.4,
1
2
120.0 (q, JC,F = 272.69 Hz), 128.9, 129.4 (q, JC,F = 34.99 Hz),
130.0, 152.6, 159.2, 170.1 ppm. 19F NMR ([D6]DMSO): δ =
–69.1 ppm. C15H15F3N2O4 (344.29): calcd. C 52.33, H 4.39, N 8.14;
found C 53.21, H 4.40, N 8.13. LCMS: [M + H]+ 345.
Methyl 3-(4-Fluorobenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetra-
hydropyrimidine-4-carboxylate (7g): Yield 0.42 g (84%), m.p. 132–
134 °C (toluene). 1H NMR ([D6]DMSO): δ = 3.58 (s, 3 H), 4.03
(d, J = 15.11 Hz, 1 H), 4.71–4.74 (m, 1 H), 4.83 (d, J = 15.11 Hz,
1 H), 5.55–5.59 (m, 1 H), 7.09–7.16 (m, 2 H), 7.25–7.31 (m, 1 H),
9.81 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 48.5, 53.1, 57.7,
Methyl 3-Methyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrim-
idine-4-carboxylate (7a): Yield 0.26 g (74%), m.p. 128–130 °C (tolu-
1
ene). H NMR ([D6]DMSO): δ = 2.76 (s, 3 H), 3.67 (s, 3 H), 4.87
(d, J = 5.04 Hz, 1 H), 5.52 (d, J = 5.04 Hz, 1 H), 9.66 (s, 1 H)
ppm. 13C NMR ([D6]DMSO): δ = 33.8, 53.1, 59.7, 97.7 (q, 3JC,F
=
4.79 Hz), 119.9 (q, 1JC,F = 272.69 Hz), 129.4 (q, 2JC,F = 34.98 Hz),
152.6, 169.9 ppm. 19F NMR ([D6]DMSO): δ = –69.0 ppm.
C8H9F3N2O3 (238.16): calcd. C 40.34, H 3.81, N 11.76; found C
40.30, H 3.83, N 11.71. LCMS: [M + H]+ 239.
3
2
98.2 (q, JC,F = 4.82 Hz), 115.7 (d, JC,F = 21.19 Hz), 119.9 (q,
2
3
1JC,F = 272.62 Hz), 129.4 (q, JC,F = 34.68 Hz), 130.5 (d, JC,F
=
=
4
1
8.67 Hz), 133.5 (d, JC,F = 2.89 Hz), 152.6, 162.0 (d, JC,F
242.76 Hz), 170.1 ppm. 19F NMR ([D6]DMSO): δ = –68.3 (s, 3 F),
–114.6 (s, 1 F) ppm. C14H12F4N2O3 (332.25): calcd. C 50.61, H
3.64, N 8.43; found C 50.67, H 3.58, N 8.44. LCMS: [M + H]+
333.
Methyl 3-(2-Methylpropyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetra-
hydropyrimidine-4-carboxylate (7b): Yield 0.32 g (77%), m.p. 140–
1
142 °C (toluene). H NMR ([D6]DMSO): δ = 0.77 (d, J = 6.57 Hz,
3 H), 0.84 (d, J = 6.57 Hz, 3 H), 1.76–1.90 (m, 1 H), 3.55–3.72 (m,
4 H), 4.84 (d, J = 5.69 Hz, 1 H), 5.58 (d, J = 5.69 Hz, 1 H), 9.65
(s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 19.7, 26.0, 52.6, 52.9,
Methyl (4RS)-2-Oxo-3-[(1SR)-1-phenylethyl]-6-(trifluoromethyl)-
1,2,3,4-tetrahydropyrimidine-4-carboxylate (7h): Yield 0.23 g (47%),
m.p. 150–152 °C (MeOH/H2O, 2:1). 1H NMR ([D6]DMSO): δ =
1.34 (d, J = 7.10 Hz, 6 H), 3.66 (s, 3 H), 4.39–4.44 (m, 1 H), 5.56
(d, J = 6.41 Hz, 1 H), 5.59 (d, J = 7.10 Hz, 1 H), 7.22–7.37 (m, 5
H), 9.81 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 17.1, 52.3, 53.3,
3
1
57.7, 97.6 (q, JC,F = 3.99 Hz), 119.5 (q, JC,F = 272.26 Hz), 129.1
(q, 2JC,F = 34.90 Hz), 152.4, 169.9 ppm. 19F NMR ([D6]DMSO): δ
= –69.0 ppm. C11H15F3N2O3 (280.24): calcd. C 47.14, H 5.39, N
10.00; found C 47.21, H 5.41, N 10.12. LCMS: [M + H]+ 281.
1
53.5, 98.5 (q, 3JC,F = 4.82 Hz), 120.0 (q, JC,F = 272.62 Hz), 127.2,
Methyl 2-Oxo-3-(prop-2-en-1-yl)-6-(trifluoromethyl)-1,2,3,4-tetra-
2
128.0, 129.1, 129.9 (q, JC,F = 35.16 Hz), 141.1, 152.8, 171.3 ppm.
hydropyrimidine-4-carboxylate (7c): Yield 0.29 g (73%), m.p. 102–
19F NMR ([D6]DMSO): δ = –68.6 ppm. C15H15F3N2O3 (328.29):
calcd. C 54.88, H 4.61, N 8.53; found C 54.70, H 4.69, N 8.50.
LCMS: [M + H]+ 329.
1
104 °C (toluene). H NMR ([D6]DMSO): δ = 3.50 (dd, J = 15.15,
8.10 Hz, 1 H), 3.68 (s, 3 H), 4.29 (dd, J = 15.15, 4.24 Hz, 1 H),
4.76 (d, J = 5.60 Hz, 1 H), 5.12 (s, 1 H), 5.17 (d, J = 8.70 Hz, 1
H), 5.58 (d, J = 5.60 Hz, 1 H), 5.69–7.75 (m, 1 H), 9.76 (s, 1 H)
Methyl (4R)-2-Oxo-3-[(1S)-1-phenylethyl]-6-(trifluoromethyl)-
1,2,3,4-tetrahydropyrimidine-4-carboxylate (7h): Yield 0.1 g (22%),
oily colourless substance. [α]2D0 = +273.6 (c = 0.75, MeOH).
3
ppm. 13C NMR ([D6]DMSO): δ = 47.8, 52.6, 56.8, 97.6 (q, JC,F
1
2
= 5.49 Hz), 117.7. 119.5 (q, JC,F = 272.76 Hz), 129.0 (q, JC,F
=
34.91 Hz), 132.9, 151.8, 169.7 ppm. 19F NMR ([D6]DMSO): δ =
–69.0 ppm. C10H11F3N2O3 (264.20): calcd. C 45.46, H 4.20, N
10.60; found C 45.37, H 4.13, N 10.62. LCMS: [M + H]+ 265.
General Procedure for the Synthesis of 2-Oxo-6-(trifluoromethyl)-
1,2,3,4-tetrahydropyrimidine-4-carboxylic Acids (5a–5h): Com-
pound 7a–7h (1 mmol) was dissolved in tetrahydrofuran (3 mL),
and a solution of LiOH (0.0228 g, 0.95 mmol) in water (3 mL) was
added at 20 °C. The reaction mixture was stirred at this tempera-
ture for 16 h. The solvent was evaporated, and water (10 mL) was
added. The mixture was washed with dichloromethane (2 ϫ
10 mL). The aqueous layer was stirred under vacuum for 20 min
to completely remove the organic solvent, and then it was acidified
with concentrated hydrochloric acid to pH 2. The white precipitate
formed was collected by filtration, washed with water (2ϫ 5 mL),
and dried in air.
Methyl 3-Butyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimid-
ine-4-carboxylate (7d): Yield 0.31 g (74%), m.p. 108–110 °C (tolu-
1
ene). H NMR ([D6]DMSO): δ = 0.86 (t, J = 7.14 Hz, 3 H), 1.22
(sext, J = 7.14 Hz, 2 H), 1.35–1.50 (m, 2 H), 2.72–2.80 (m, 1 H),
3.65–3.73 (m, 4 H), 4.89 (d, J = 4.39 Hz, 1 H), 5.55 (d, J = 4.39 Hz,
1 H), 9.64 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 13.7, 19.4,
3
1
28.9, 45.5, 52.6, 57.3, 97.5 (q, JC,F = 4.49 Hz), 119.5 (q, JC,F
=
272.26 Hz), 129.0 (q, JC,F = 35.40 Hz), 152.0, 170.0 ppm. 19F
NMR ([D6]DMSO): δ = –69.1 ppm. C11H15F3N2O3 (280.24): calcd.
C 47.14, H 5.39, N 10.00; found C 47.10, H 5.33, N 10.03. LCMS:
[M + H]+ 281.
2
3-Methyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carboxylic Acid (5a): Yield 0.17 g (77%), m.p. 197–199 °C (ethanol/
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
water, 1:2). 1H NMR ([D6]DMSO): δ = 4.69 (dq, J = 5.72, 1.60 Hz,
3-(4-Fluorobenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
1 H), 5.50–5.54 (m, 1 H), 9.55 (d, J = 1.37 Hz, 1 H) ppm. 13C imidine-4-carboxylic Acid (5g): Yield 0.28 g (88%), m.p. 185–187 °C
NMR ([D6]DMSO): δ = 33.8, 59.8, 98.3 (q, 3JC,F = 4.80 Hz), 120.0
(ethanol/water, 2:1). 1H NMR ([D6]DMSO): δ = 3.89 (d, J =
15.34 Hz, 1 H), 4.56 (d, J = 4.58 Hz, 1 H), 4.96 (d, J = 15.34 Hz,
1 H), 5.55 (d, J = 4.58 Hz, 1 H), 7.08–7.16 (m, 2 H), 7.25–7.31 (m,
2 H), 9.72 (s, 1 H), 12.50 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO):
δ = 48.5, 57.7, 98.9 (q, 3JC,F = 4.79 Hz), 115.7 (d, 2JC,F = 35.16 Hz),
1
2
(q, JC,F = 272.62 Hz), 131.8 (q, JC,F = 35.16 Hz), 152.7,
170.8 ppm. 19F NMR ([D6]DMSO): δ = –68.6 ppm. C7H7F3N2O3
(224.14): calcd. C 37.51, H 3.15, N 12.50; found C 37.55, H 3.14,
N 12.40. LCMS: [M + H]+ 225.
1
2
120.1 (q, JC,F = 272.62 Hz), 128.9 (q, JC,F = 35.64 Hz), 130.4 (d,
3-(2-Methylpropyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carboxylic Acid (5b): Yield 0.2 g (75%), m.p. 210–212 °C
(ethanol/water, 1:2). 1H NMR ([D6]DMSO): δ = 0.77 (d, J =
6.57 Hz, 3 H), 0.84 (d, J = 6.57 Hz, 3 H), 1.78–1.90 (m, 1 H), 2.42–
2.53 (m, 1 H), 3.63 (dd, J = 14.05, 7.88 Hz, 1 H), 4.67 (d, J =
3JC,F = 8.67 Hz), 133.7 (d, JC,F = 2.89 Hz), 152.8, 162.0 (q, JC,F
= 242.76 Hz), 170.8 ppm. 19F NMR ([D6]DMSO): δ = –68.6 ppm.
C13H10F4N2O3 (318.22): calcd. C 49.07, H 3.17, N 8.80; found C
59.20, H 3.11, N 8.88. LCMS: [M + H]+ 319.
4
1
5.26 Hz, 1 H), 5.57 (d, J = 5.26 Hz, 1 H), 9.53 (s, 1 H) ppm. 13C
2-Oxo-3-(1-phenylethyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
3
NMR ([D6]DMSO): δ = 19.8, 26.0, 53.0, 57.9, 98.3 (q, JC,F
=
imidine-4-carboxylic Acid (5h): Mixture of two diastereomers (2:1),
4.99 Hz), 119.6 (q, 1JC,F = 272.26 Hz), 128.7 (q, 2JC,F = 35.40 Hz),
152.5, 170.7 ppm. 19F NMR ([D6]DMSO): δ = –68.6 ppm.
C10H13F3N2O3 (266.22): calcd. C 45.12, H 4.92, N 10.52; found C
45.14, H 4.80, N 10.44. LCMS: [M + H]+ 267.
1
yield 0.26 g (83%), m.p. 158–160 °C (ethanol/water, 2:1). H NMR
([D6]DMSO): δ = 1.37 (d, J = 7.10 Hz, 3 H), 1.49 (d, J = 7.10 Hz,
1.5 H), 4.25–4.30 (m, 1 H), 4.65–4.69 (m, 0.5 H), 5.41 (q, J =
7.10 Hz, 0.5 H), 5.50–5.64 (m, 2.5 H), 7.17–7.37 (m, 7.5 H), 9.54
(d, J = 2.06 Hz, 0.5 H), 9.70 (d, J = 2.06 Hz, 1 H), 12.52 (br. s, 0.5
H), 13.16 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 17.2, 17.5,
2-Oxo-3-(prop-2-en-1-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyr-
imidine-4-carboxylic Acid (5c): Yield 0.19 g (76%), m.p. 201–202 °C
(ethanol/water, 1:2). 1H NMR ([D6]DMSO): δ = 3.41 (dd, J =
15.39, 6.59 Hz, 1 H), 4.38 (dd, J = 15.39, 4.39 Hz, 1 H), 4.60 (d, J
= 4.94 Hz, 1 H), 5.11–5.20 (m, 2 H), 5.59 (d, J = 5.49 Hz, 1 H),
5.69–5.79 (m, 1 H), 9.65 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ
3
3
52.1, 53.5, 53.6, 54.8, 99.2 (q, JC,F = 4.79 Hz), 99.5 (q, JC,F
=
4.79 Hz), 120.1 (q, JC,F = 272.21 Hz), 127.1, 127.9, 128.7 (q, 2JC,F
= 35.40 Hz), 129.1, 139.8, 141.4, 152.7, 153.0, 170.9, 172.2 ppm.
19F NMR ([D6]DMSO): δ = –68.60 (s, 1 F), –68.69 (s, 2 F) ppm.
C14H13F3N2O3 (314.26): calcd. C 53.51, H 4.17, N 8.91; found C
53.57, H 4.15, N 8.82. LCMS: [M + H]+ 315.
1
3
1
= 47.8, 56.8, 98.3 (q, JC,F = 4.49 Hz), 117.7, 119.6 (q, JC,F
=
2
272.26 Hz), 128.6 (q, JC,F = 34.91 Hz), 133.1, 151.9, 170.5 ppm.
19F NMR ([D6]DMSO): δ = –68.6 ppm. C9H9F3N2O3 (250.17):
calcd. C 43.21, H 3.63, N 11.20; found C 43.32, H 3.60, N 11.25.
LCMS: [M + H]+ 251.
General Procedure for the Synthesis of Compounds (5i) and (7i):
Compound 5f, 5h, 7f, or 7h (1 mmol) was dissolved in CF3CO2H
(5 mL) and heated at reflux for 30 min. The solvent was evapo-
rated, and the residue was treated with diethyl ether (20 mL). The
solid was collected by filtration and then recrystallized.
3-Butyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carboxylic Acid (5d): Yield 0.2 g (75%), m.p. 216–218 °C (ethanol/
1
water, 2:1). H NMR ([D6]DMSO): δ = 0.86 (t, J = 7.14 Hz, 3 H),
Methyl 2-Oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carboxylate (7i): Starting from 7f, yield 0.15 g (69%); starting from
(4RS,1ЈSR)-7h, yield 0.17 g (78 %), m.p. 163–165 °C (racemic,
1.22 (sext, J = 7.14 Hz, 2 H), 1.35–1.50 (m, 2 H), 2.70–2.75 (m, 1
H), 3.66–3.73 (m, 1 H), 4.72 (d, J = 4.39 Hz, 1 H), 4.72 (d, J =
4.39 Hz, 1 H), 5.54 (d, J = 4.39 Hz, 1 H), 9.52 (s, 1 H) ppm. 13C
1
acetonitrile). H NMR ([D6]DMSO): δ = 3.65 (s, 3 H), 4.70 (s, 1
3
NMR ([D6]DMSO): δ = 13.7, 19.5, 28.9, 45.6, 57.4, 98.2 (q, JC,F
H), 5.44 (d, J = 3.90 Hz, 1 H), 7.29 (s, 1 H), 9.46 (s, 1 H) ppm.
1
2
= 4.49 Hz), 119.6 (q, JC,F = 272.26 Hz), 128.6 (q, JC,F
=
3
13C NMR ([D6]DMSO): δ = 53.0, 53.4, 97.9 (q, JC,F = 3.85 Hz),
35.40 Hz), 152.1, 170.8 ppm. 19F NMR ([D6]DMSO): δ =
–68.5 ppm. C10H13F3N2O3 (266.22): calcd. C 45.12, H 4.92, N
10.52; found C 45.13, H 4.99, N 10.55. LCMS: [M + H]+ 267.
1
2
120.1 (q, JC,F = 272.62 Hz), 129.3 (q, JC,F = 34.68 Hz), 152.5,
171.3 ppm. 19F NMR ([D6]DMSO): δ = –69.0 ppm. C7H7F3N2O3
(224.14): calcd. C 37.51, H 3.15, N 12.50; found C 37.42, H 3.10,
N 12.48. LCMS: [M + H]+ 225.
3-Benzyl-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-
carboxylic Acid (5e): Yield 0.25 g (83%), m.p. 165–167 °C (ethanol/
water, 2:1). 1H NMR ([D6]DMSO): δ = 3.82 (d, J = 15.34 Hz, 1
H), 4.51 (d, J = 4.58 Hz, 1 H), 5.07 (d, J = 15.34 Hz, 1 H), 5.55
(d, J = 15.34 Hz, 1 H), 7.18–7.36 (m, 5 H), 9.72 (d, J = 1.60 Hz, 1
H), 13.05 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 49.1, 57.6,
98.8 (q, 3JC,F = 4.79 Hz), 120.1 (q, 1JC,F = 272.69 Hz), 127.9, 128.2,
Methyl (4R)-2-Oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimid-
ine-4-carboxylate (7i): Starting from (4R,1ЈS)-7h, yield 0.17 g
(77%), m.p. 168–170 °C (chloroform/hexane, 9:1). [α]2D0 = +54.0 (c
= 0.5, MeOH).
2-Oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-4-carboxylic
Acid (5i): Starting from 5f, yield 0.14 g (65%); starting from 5h (as
a mixture of diastereomers), yield 0.15 g (71%), m.p. 205–207 °C
(2-propanol). 1H NMR ([D6]DMSO): δ = 4.54–4.58 (m, 1 H), 5.43
(d, J = 3.90 Hz, 1 H), 7.18 (s, 1 H), 9.36 (s, 1 H), 12.5 (br. s, 1 H)
2
129.0 (q, JC,F = 34.99 Hz), 129.1, 137.3, 152.8, 170.8 ppm. 19F
NMR ([D6]DMSO): δ = –68.7 ppm. C13H11F3N2O3 (300.23): calcd.
C 52.01, H 3.69, N 9.33; found C 51.91, H 3.65, N 9.37. LCMS:
[M + H]+ 301.
3
ppm. 13C NMR ([D6]DMSO): δ = 53.5, 98.5 (q, JC,F = 4.82 Hz),
3-(4-Methoxybenzyl)-2-oxo-6-(trifluoromethyl)-1,2,3,4-tetrahydro-
1
2
120.2 (q, JC,F = 272.62 Hz), 128.8 (q, JC,F = 34.68 Hz), 152.6,
172.1 ppm. 19F NMR ([D6]DMSO): δ = –68.7 ppm. C6H5F3N2O3
(210.11): calcd. C 34.30, H 2.40, N 13.33; found C 34.37, H 2.38,
N 13.33. LCMS: [M + H]+ 211.
pyrimidine-4-carboxylic Acid (5f): Yield 0.28 g (85%), m.p. 181–
1
183 °C (ethanol/water, 2:1). H NMR ([D6]DMSO): δ = 3.69 (s, 3
H), 3.76 (d, J = 15.11 Hz, 1 H), 4.46 (d, J = 5.04 Hz, 1 H), 4.99
(d, J = 15.11 Hz, 1 H), 5.52 (d, J = 5.04 Hz, 1 H), 6.86 (d, J =
8.47 Hz, 2 H), 7.15 (d, J = 8.47 Hz, 2 H), 9.69 (s, 1 H) ppm. 13C
(4RS,6RS)-3-Benzyl-6-hydroxy-2-oxo-6-(trifluoromethyl)hexahydro-
3
NMR ([D6]DMSO): δ = 48.4, 55.5, 57.2, 98.7 (q, JC,F = 4.79 Hz), pyrimidine-4-carboxylic Acid (8): Compound 5e or 7e (1 mmol) was
1
2
114.4, 120.0 (q, JC,F = 272.14 Hz), 129.0, 129.0 (q, JC,F
=
dissolved in tetrahydrofuran (3 mL), and a solution of LiOH
35.16 Hz), 129.9, 152.7, 159.2, 170.8 ppm. 19F NMR ([D6]DMSO): (4 mmol) in water (3 mL) was added. The reaction mixture was
δ = –68.7 ppm. C14H13F3N2O4 (330.26): calcd. C 50.91, H 3.97, N
stirred at 20 °C for 16 h. The solvent was evaporated, and water
(10 mL) was added. The resulting solution was acidified with con-
8.48; found C 50.93, H 4.01, N 8.45. LCMS: [M + H]+ 331.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
centrated hydrochloric acid to pH 2. The resulting white precipitate
was collected by filtration, washed with water (2ϫ 5 mL), dried in
air, and recrystallized from MeOH/H2O (1:1), yield 0.14 g (45%),
8.67 Hz) ppm. C15H17F3N2O4 (346.30): calcd. C 52.02, H 4.95, N
8.09; found C 51.99, H 4.97, N 8.20. LCMS: [M + H]+ 347.
Methyl (4RS,6SR)-2-Oxo-3-[(1SR)-1-phenylethyl]-6-(trifluoro-
methyl)hexahydropyrimidine-4-carboxylate (10c): Yield 0.29 g
(89%), m.p. 162–164 °C (toluene). 1H NMR ([D6]DMSO): δ = 1.33
(d, J = 7.33 Hz, 3 H), 2.01–2.10 (m, 1 H), 2.26 (d, J = 15.57 Hz, 1
H), 3.59 (s, 3 H), 4.02 (dd, J = 7.10, 2.06 Hz, 1 H), 4.04–4.12 (m,
1 H), 5.55 (q, J = 7.10 Hz, 1 H), 7.08 (d, J = 4.12 Hz, 1 H), 7.20–
7.33 (m, 5 H) ppm. 13C NMR ([D6]DMSO): δ = 17.1, 23.5, 49.9
(q, 2JC,F = 31.63 Hz), 51.0, 52.4, 52.6, 125.5 (q, 1JC,F = 281.80 Hz),
127.2, 127.6, 128.9, 142.5, 154.9, 171.9 ppm. 19F NMR ([D6]-
DMSO): δ = –75.7 (d, J = 8.67 Hz) ppm. C15H17F3N2O3 (330.30):
calcd. C 54.54, H 5.19, N 8.48; found C 54.59, H 5.09, N 8.50.
LCMS: [M + H]+ 331.
1
m.p. 180–182 °C. H NMR ([D6]DMSO): δ = 2.22 (dd, J = 14.51,
5.95 Hz, 1 H), 2.33 (dd, J = 14.51, 7.56 Hz, 1 H), 3.83 (d, J =
16.03 Hz, 1 H), 3.95 (t, J = 6.87 Hz, 1 H), 5.17 (d, J = 15.80 Hz,
1 H), 7.17–7.32 (m, 6 H), 7.61 (s, 1 H), 12.76 (br. s, 1 H) ppm. 13C
NMR ([D6]DMSO): δ = 31.8, 48.5, 54.0, 79.6 (q, 2JC,F = 31.79 Hz),
1
123.9 (q, JC,F = 286.11 Hz), 127.5, 127.9, 128.9, 138.0, 154.6,
172.1 ppm. 19F NMR ([D6]DMSO): δ = –83.1 ppm. C13H13F3N2O4
(318.25): calcd. C 49.06, H 4.12, N 8.80; found C 49.09, H 4.07, N
8.83. LCMS: [M + H]+ 319.
(4RS,6SR)-3-Benzyl-6-hydroxy-2-oxo-6-(trifluoromethyl)hexahydro-
pyrimidine-4-carboxylic Acid (9): The remaining acidic filtrate from
the synthesis of compound 8 described above was evaporated to
dryness, and the residue was treated with methanol. The insoluble
material was removed by filtration, and the solvent was evaporated
from the filtrate. The resulting residue was recrystallized from
Methyl (4R,6S)-2-Oxo-3-[(1S)-1-phenylethyl]-6-(trifluoromethyl)-
hexahydropyrimidine-4-carboxylate (10c): Yield 0.30 g (90%), m.p.
158–160 °C (toluene). [α]2D0 = +36.7 (c = 0.72, MeOH).
Methyl (4RS,6SR)-2-Oxo-6-(trifluoromethyl)hexahydropyrimidine-
4-carboxylate (10d): Starting from 5i, yield 0.20 g (89%); starting
from 10b, yield 0.17 g (75%), m.p. 178–180 °C (chloroform). 1H
NMR ([D6]DMSO): δ = 2.04 (dt, J = 13.97, 5.84 Hz, 1 H), 2.27
(dt, J = 13.97, 5.84 Hz, 1 H), 4.04–4.17 (m, 2 H), 6.73 (s, 1 H),
1
acetonitrile, yield 0.054 g (17%), m.p. 171–173 °C. H NMR ([D6]-
DMSO): δ = 2.05 (dd, J = 13.57, 6.53 Hz, 1 H), 2.33 (d, J =
13.34 Hz, 1 H), 3.80 (d, J = 15.68 Hz, 1 H), 3.93 (dd, J = 6.18,
2.18 Hz, 1 H), 5.12 (d, J = 15.68 Hz, 1 H), 7.04 (br. s, 1 H), 7.17–
7.30 (m, 5 H), 7.42 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 30.3,
2
7.06 (s, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 21.9, 49.9 (q, JC,F
2
49.6, 53.6, 79.9 (q, JC,F = 31.79 Hz), 124.0 (q, 1JC,F = 287.07 Hz),
1
= 30.92 Hz), 49.9, 125.0 (q, JC,F = 280.74 Hz), 154.1, 171.4 ppm.
127.5, 127.8, 128.9, 138.5, 153.9, 172.0 ppm. 19F NMR ([D6]-
DMSO): δ = –83.4 ppm. C13H13F3N2O4 (318.25): calcd. C 49.06,
H 4.12, N 8.80; found C 49.15, H 4.13, N 8.72. LCMS: [M + H]+
319.
19F NMR ([D6]DMSO): δ = –75.7 (d, J = 7.22 Hz) ppm.
C7H9F3N2O3 (226.15): calcd. C 37.18, H 4.01, N 12.39; found C
37.17, H 4.07, N 12.30. LCMS: [M + H]+ 227.
Methyl (4R,6S)-2-Oxo-6-(trifluoromethyl)hexahydropyrimidine-4-
carboxylate (10d): Starting from (4R,6S)-7i, yield 0.2 g (88%);
starting from (4R,6S,1ЈS)-10c, yield 0.16 g (71%), m.p. 170–172 °C
(2-propanol/hexane, 1:9). [α]2D0 = +3.92 (c = 1.2, MeOH).
General Procedure for the Synthesis of Methyl (4RS,6SR)-2-Oxo-
6-(trifluoromethyl)hexahydropyrimidine-4-carboxylates 10a–10d and
(4RS,6SR)-2-Oxo-6-(trifluoromethyl)hexahydropyrimidine-4-carb-
oxylic Acids (11a, 11b, and 11d): Compound 5a, 5f, 5i, 7a, 7f, 7h,
or 7i (1 mmol) was dissolved in MeOH (5 mL), and Pd/C catalyst
(10%; 100 mg) was added. Hydrogen gas was bubbled into the re-
sulting suspension while stirring. The reaction was monitored by
TLC or 19F NMR spectroscopy. After the starting material had
completely disappeared (about 1 h), the mixture was filtered, and
the solvent was evaporated. The resulting white solid residue was
recrystallized.
(4RS,6SR)-3-Methyl-2-oxo-6-(trifluoromethyl)hexahydropyrimidine-
4-carboxylic Acid (11a): Yield 0.20 g (88 %), m.p. 220–222 °C
(acetonitrile). 1H NMR ([D6]DMSO): δ = 2.25 (dt, J = 14.68,
3.21 Hz, 1 H), 2.31–2.38 (m, 1 H), 2.78 (s, 3 H), 3.97–4.06 (m, 1
H), 4.08 (dd, J = 7.12, 3.43 Hz, 1 H), 7.02 (d, J = 3.89 Hz, 1 H)
2
ppm. 13C NMR ([D6]DMSO): δ = 22.1, 35.0, 50.3 (q, JC,F
=
F
30.67 Hz), 56.9, 125.5 (q, 1JC,F = 281.80 Hz), 154.5, 172.4 ppm. 19
NMR ([D6]DMSO): δ = –75.2 (d, J = 8.67 Hz) ppm. C7H9F3N2O3
(226.15): calcd. C 37.18, H 4.01, N 12.39; found C 37.20, H 3.90,
N 12.32. LCMS: [M + H]+ 227.
Compounds 10d and 11d were also obtained according to the gene-
ral procedure for the synthesis of compounds 5i and 7i, starting
from compounds 10b, 10c, or 11b as appropriate.
(4RS,6SR)-3-(4-Methoxybenzyl)-2-oxo-6-(trifluoromethyl)hexa-
hydropyrimidine-4-carboxylic Acid (11b): Yield 0.30 g (90%), m.p.
215–217 °C (acetonitrile). 1H NMR ([D6]DMSO): δ = 2.17–2.27
(m, 1 H), 2.30–2.34 (m, 1 H), 3.65–3.74 (m, 4 H), 4.02–4.08 (m, 1
H), 6.84 (d, J = 8.70 Hz, 2 H), 7.13 (d, J = 8.24 Hz, 2 H), 7.19 (d,
J = 3.89 Hz, 1 H), 12.98 (br. s, 1 H) ppm. 13C NMR ([D6]DMSO):
Methyl (4RS,6SR)-3-Methyl-2-oxo-6-(trifluoromethyl)hexahy-
dropyrimidine-4-carboxylate (10a): Yield 0.22 g (92%), m.p. 157–
159 °C (toluene). H NMR ([D6]DMSO): δ = 2.25–2.31 (m, 1 H),
1
2.40 (dt, J = 15.11, 7.33 Hz, 1 H), 2.79 (s, 3 H), 3.61 (s, 3 H), 3.99–
4.10 (m, 1 H), 4.28 (dd, J = 7.33, 2.75 Hz, 1 H), 7.11 (d, J =
3.89 Hz, 1 H) ppm. 13C NMR ([D6]DMSO): δ = 22.0, 35.1, 50.2 (q,
2
δ = 22.2, 48.7, 50.2 (q, JC,F = 30.67 Hz), 53.8, 55.5, 114.3, 125.5
1
2JC,F = 30.67 Hz), 52.6, 56.7, 125.6 (q, JC,F = 282.76 Hz), 154.3,
1
(q, JC,F = 282.76 Hz), 129.4, 130.3, 154.5, 158.9, 172.1 ppm. 19F
171.3 ppm. 19F NMR ([D6]DMSO): δ = –75.7 (d, J = 8.67 Hz)
ppm. C8H11F3N2O3 (240.18): calcd. C 40.01, H 4.62, N 11.66;
found C 40.04, H 4.53, N 11.62. LCMS: [M + H]+ 241.
N M R ( [ D 6 ] D M S O ) : δ = – 7 7 . 2 ( d , J = 8 . 6 7 H z ) p p m .
C14H15F3N2O4 (332.27): calcd. C 50.61, H 4.55, N 8.43; found C
50.65, H 4.61, N 8.35. LCMS: [M + H]+ 333.
Methyl (4RS,6SR)-3-(4-Methoxybenzyl)-2-oxo-6-(trifluoromethyl)- (4RS,6SR)-2-Oxo-6-(trifluoromethyl)hexahydropyrimidine-4-carb-
hexahydropyrimidine-4-carboxylates (10b): Yield 0.31 g (90%), m.p.
167–169 °C (toluene). H NMR ([D6]DMSO): δ = 2.20–2.36 (m, 2
H), 3.60 (s, 3 H), 3.69 (s, 3 H), 3.75 (d, J = 15.34 Hz, 1 H), 4.02–
4.14 (m, 2 H), 5.06 (d, J = 15.34 Hz, 1 H), 6.84 (d, J = 8.70 Hz, 2
oxylic Acid (11d): Starting from 5i, yield 0.19 g (90%); starting
from 11b, yield 0.14 g (66%), m.p. 248–250 °C (acetonitrile). 1H
NMR ([D6]DMSO): δ = 1.93 (dt, J = 13.74, 7.10 Hz, 1 H), 2.26
(dt, J = 13.74, 5.72 Hz, 1 H), 3.98–4.02 (m, 1 H), 4.07–4.16 (m, 1
1
H), 7.13 (d, J = 8.70 Hz, 2 H), 7.25 (d, J = 4.12 Hz, 1 H) ppm. 13
C
H), 6.46 (s, 1 H), 7.02 (s, 1 H), 12.00 (br. s, 1 H) ppm. 13C NMR
NMR ([D6]DMSO): δ = 22.4, 48.9, 50.2 (q, 2JC,F = 31.63 Hz), 52.6, ([D6]DMSO): δ = 22.9, 50.5, 50.6 (q, JC,F = 30.67 Hz), 125.5 (q,
2
1
54.1, 55.5, 114.3, 125.5 (q, JC,F = 282.76 Hz), 129.5, 130.2, 154.3,
1JC,F = 280.84 Hz), 154.8, 172.7 ppm. 19F NMR ([D6]DMSO): δ =
–75.7 (d, J = 7.22 Hz) ppm. C6H7F3N2O3 (212.3): calcd. C 33.97,
158.9, 171.1 ppm. 19F NMR ([D6]DMSO): δ = –75.6 (d, J =
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
4961; c) N. M. Golovach, V. N. Tkachuk, V. A. Sukach, M. V.
Vovk, Russ. J. Org. Chem. 2012, 48, 1187–1190.
F. Zhang, Z.-J. Liu, J.-T. Liu, Org. Biomol. Chem. 2011, 9,
3625–3628.
a) Y.-L. Liu, X.-P. Zeng, J. Zhou, Chem. Asian J. 2012, 7, 1759–
1763; b) X.-M. Yuan, J. Xu, Z.-J. Liu, X.-J. Yang, L.-M. Wang,
Y. Zhang, X.-Y. Yang, X.-P. He, J.-T. Liu, J. Fluorine Chem.
2012, 144, 102–107; c) F. Palacios, A. M. Ochoa de Retana, S.
Pascual, G. F. De Troconiz, Tetrahedron 2011, 67, 1575–1579;
d) Y.-L. Liu, T.-D. Shi, F. Zhou, X.-L. Zhao, X. Wang, J. Zhou,
Org. Lett. 2011, 13, 3826–3829.
H 3.33, N 13.21; found C 34.11, H 3.30, N 13.21. LCMS: [M +
H]+ 213.
[11]
[12]
CCDC-1008782 (for 4g), -1008783 (for 7h), 1008785 (for 8), and
1008784 (for 10a) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
1
cle): experimental data for compounds 1c, 1d, 1f–1h, copies of H
and 13C spectra of all new compounds, 19F NMR spectra with
quinine additive as a chiral solvating agent, detailed X-ray structure
analysis of 4g, 7h, 8 and 10a.
[13]
a) S. Fustero, P. Bello, J. Miró, M. Sánchez-Roselló, M. A.
Maestro, J. González, C. del Pozo, Chem. Commun. 2013, 49,
1336–1338; b) K. Morisaki, M. Sawa, J.-Y. Nomaguchi, H.
Morimoto, Y. Takeuchi, K. Mashima, T. Ohshima, Chem. Eur.
J. 2013, 19, 8417–8420; c) D. Enders, K. Gottfried, G. Raabe,
Adv. Synth. Catal. 2010, 352, 3147–3152; d) R. Husmann, E.
Sugiono, S. Mersmann, G. Raabe, M. Rueping, G. Bolm, Org.
Lett. 2011, 13, 1044–1047; e) J. Yang, Q.-Q. Min, Y. He, X.
Zhang, Tetrahedron Lett. 2011, 52, 4675–4677; f) S. Fustero,
M. Sánchez-Roselló, C. Báez, C. del Pozo, J. L. García Ruano,
J. Alemán, L. Marzo, A. Parra, Amino Acids 2011, 41, 559–
573; g) G. T. Shchetnikov, M. A. Zotova, C. Bruneau, P. H.
Dixneuf, S. N. Osipov, Eur. J. Org. Chem. 2010, 1587–1592.
a) F. Grellepois, J. Org. Chem. 2013, 78, 1127–1137; b) F.
Acknowledgments
V. A. S. is grateful to the Deutsche Forschungsgemeinschaft (DFG)
for financial support (grant number RO 362/56-1), and thanks Dr.
Maxim Ponomarenko for helpful discussions, and Dr. Andriy Pota-
man for valuable assistance in the chromatographic purification of
enantiopure compounds.
[14]
[15]
Palacios,
A. M. Ochoa de Retana,
S. Pascual,
G.
[1] a) P. Kirsch, Modern Fluoroorganic Chemistry – Synthesis Re-
activity, Applications, 2nd ed., Wiley-VCH, Weinheim, Ger-
many, 2013; b) V. Gouverneur, K. Müller (Eds.), Molecular
Medicine and Medicinal Chemistry, vol. 6: Fluorine in Pharma-
ceutical and Medicinal Chemistry – From Biophysical Aspects
to Clinical Applications, Imperial College Press, London, 2012.
[2] J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev.
2014, 114, 2432–2506.
[3] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem.
Soc. Rev. 2008, 37, 320–330; b) V. A. Soloshonok, K. Mikami,
T. Yamazaki, J. T. Welch, J. F. Honek (Eds.), Current Fluoroor-
ganic Chemistry – New Synthetic Directions, Technologies, Ma-
terials, and Biological Applications, vol. 949, American Chemi-
cal Society, Washington, 2007; c) K. L. Kirk, J. Fluorine Chem.
2006, 127, 1013–1039; d) R. Filler, R. Saha, Future Med. Chem.
2009, 1, 777–791; e) D. O’Hagan, Chem. Soc. Rev. 2008, 37,
308–319.
Fernández de Trocóniz, J. M. Ezpeleta, Eur. J. Org. Chem.
2010, 6618–6626.
a) A. V. Gulevich, N. E. Shevchenko, E. S. Balenkova, G.-V.
Röschenthaler, V. G. Nenajdenko, Synlett 2009, 403–406; b)
N. E. Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G.
Nenajdenko, Synthesis 2010, 120–126; c) O. I. Shmatova, N. E.
Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G.
Nenajdenko, Mendeleev Commun. 2013, 23, 92–93; d) V. A. Su-
kach, V. M. Tkachuk, E. B. Rusanov, G.-V. Roeschenthaler,
M. V. Vovk, Tetrahedron 2012, 68, 8408–8415; e) H. Berber, M.
Soufyane, C. Mirand, S. Schmidt, A.-M. Aubertin, Tetrahedron
2001, 57, 7369–7375; f) N. Zanatta, D. Faoro, L. da. S. Fer-
nandes, P. B. Brondani, D. C. Flores, A. F. C. Flores, H. G.
Bonacorso, M. A. P. Martins, Eur. J. Org. Chem. 2008, 5832–
5838; g) I. I. Gerus, S. I. Vdovenko, M. G. Gorbunova, V. P.
Kukhar’, Chem. Heterocycl. Compd. 1991, 27, 398–406; h) J. W.
Corbett, S. S. Ko, J. D. Rodgers, L. A. Gearhart, N. A.
Magnus, L. T. Bacheler, S. Diamond, S. Jeffrey, R. M. Klabe,
B. C. Cordova, S. Garber, K. Logue, G. L. Trainor, P. S. An-
derson, S. K. Erickson-Viitanen, J. Med. Chem. 2000, 43,
2019–2030; i) N. A. Magnus, P. N. Confalone, L. Storace, M.
Patel, C. C. Wood, W. P. Davis, R. L. Parsons Jr., J. Org. Chem.
2003, 68, 754–761.
a) O. I. Shmatova, N. E. Shevchenko, E. S. Balenkova, G.-V.
Röschenthaler, V. G. Nenajdenko, Eur. J. Org. Chem. 2013,
3049–3058; b) I. L. Odinets, O. I. Artyushin, K. A. Lyssenko,
N. E. Shevchenko, V. G. Nenajdenko, G.-V. Röschenthaler, J.
Fluorine Chem. 2009, 130, 662–666; c) A. V. Gulevich, N. E.
Shevchenko, E. S. Balenkova, G.-V. Röschenthaler, V. G.
Nenajdenko, Synlett 2009, 403–406; d) O. I. Shmatova, V. G.
Nenajdenko, Eur. J. Org. Chem. 2013, 6397–6403.
a) B. Jiang, J. J. Dong, Y. G. Si, X. L. Zhao, Z. G. Huang, M.
Xu, Adv. Synth. Catal. 2008, 350, 1360–1366; b) H. Xie, Y.
Zhang, S. Zhang, X. Chen, W. Wang, Angew. Chem. Int. Ed.
2011, 50, 11773–11776; Angew. Chem. 2011, 123, 11977–11980;
c) H.-N. Yuan, S. Wang, J. Nie, W. Meng, Q. Yao, J.-A. Ma,
Angew. Chem. Int. Ed. 2013, 52, 3869–3873; Angew. Chem.
2013, 125, 3961–3965; d) F.-G. Zhang, X.-Y. Zhu, S. Li, J. Nie,
J.-A. Ma, Chem. Commun. 2012, 48, 11552–11554; e) H.-N.
Yuan, S. Li, J. Nie, Y. Zheng, J.-A. Ma, Chem. Eur. J. 2013, 19,
15856–15860.
[4] a) C. Bissantz, B. Kuhn, M. Stahl, J. Med. Chem. 2010, 53,
5061–5084; b) K. Müller, C. Faeh, F. Diederich, Science 2007,
317, 1881–1886.
[5] a) F. Hof, D. M. Scofield, W. B. Schweizer, F. Diederich, An-
gew. Chem. Int. Ed. 2004, 43, 5056–5059; Angew. Chem. 2004,
116, 5166–5169; b) G.-F. Hao, F. Wang, H. Li, X.-L. Zhu, W.-
C. Yang, L.-S. Huang, J.-W. Wu, E. A. Berry, G.-F. Yang, J.
Am. Chem. Soc. 2012, 134, 11168–11176; c) C. Dalvit, A. Vulp-
etti, ChemMedChem 2011, 6, 104–114; d) H.-J. Schneider,
Chem. Sci. 2012, 3, 1381–1394; e) C. Dalvit, A. Vulpetti, Chem-
MedChem 2012, 7, 262–272.
[6] a) L. R. Scolnick, A. M. Clements, J. Liao, L. Crenshaw, M.
Hellberg, J. May, T. R. Dean, D. W. Christianson, J. Am. Chem.
Soc. 1997, 119, 850–851; b) M. Lee, C. W. Chan, S. C. Graham,
R. I. Christopherson, J. M. Guss, M. J. Maher, J. Mol. Biol.
2007, 370, 812–825.
[7] N. A. Meanwell, J. Med. Chem. 2011, 54, 2529–2591.
[8] J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011, 111,
455–529.
[9] a) T. Guo, R. Song, B.-H. Yuan, X.-Y. Chen, X.-W. Sun, G.-
Q. Lin, Chem. Commun. 2013, 49, 5402–5404; b) G. Huang, Z.
Yin, X. Zhang, Chem. Eur. J. 2013, 19, 11992–11998; c) H.
Xiao, Y. Huang, F.-L. Qing, Tetrahedron: Asymmetry 2010, 21,
2949–2955.
[16]
[17]
[18]
[10] a) L.-H. Sun, Z.-Q. Liang, W.-Q. Jia, S. Ye, Angew. Chem. Int.
Ed. 2013, 52, 5803–5806; Angew. Chem. 2013, 125, 5915–5918;
b) Y. Liu, Y. Huang, F.-L. Qing, Tetrahedron 2012, 68, 4955–
a) F. Rise, D. Grace, K. Undheim, J. Organomet. Chem. 1988,
338, 341–346; b) J. J. Fox, T.-L. Su, L. M. Stempel, K. A. Wat-
anabe, J. Org. Chem. 1982, 47, 1081–1084; c) A. Katoh, Y. Om-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
V. A. Sukach at al.
FULL PAPER
ote, C. Kashima, J. Heterocycl. Chem. 1984, 21, 53–55; d) F. [24]
Rise, K. Undheim, J. Organomet. Chem. 1985, 291, 139–144;
e) C. Kashima, A. Katoh, Y. Yokota, Y. Omote, J. Chem. Soc.
a) A. Arnone, P. Bravo, S. Capelli, G. Fronza, S. V. Meille, M.
Zanda, J. Org. Chem. 1996, 61, 3375–3387; b) P. Bravo, Tetra-
hedron Lett. 1995, 36, 3043–3046.
Perkin Trans. 1 1981, 489–492; f) F. Rise, C. Romming, K.
Undheim, Acta Chem. Scand., Ser. B 1985, 39, 459–468.
[19] V. A. Sukach, V. M. Tkachuk, V. M. Shoba, V. V. Pirozhenko,
E. B. Rusanov, A. A. Chekotilo, G.-V. Röschenthaler, M. V.
Vovk, Eur. J. Org. Chem. 2014, 1452–1460.
[20] I. Lieberman, A. Kornberg, J. Biol. Chem. 1954, 207, 911–924.
[21] Y. Li, F. M. Raushel, Bioorg. Chem. 2005, 33, 470–483.
[22] D. B. Berkowitz, K. R. Karukurichi, R. de la Salud-Bea, D. L.
Nelson, C. D. McCune, J. Fluorine Chem. 2008, 129, 731–742.
[23] a) J. L. Adams, T. D. Meek, S.-M. Mong, R. K. Johnson, B. W.
Metcalf, J. Med. Chem. 1988, 31, 1355–1359; b) F. W. Muregi,
S. Kanoc, H. Kinoa, A. Ishih, Exp. Parasitol. 2009, 121, 376–
380.
[25]
H. P. G. Thompson, G. M. Day, Chem. Sci. 2014, DOI:
10.1039/C4SC01132E.
[26] a) R. Paulini, K. Müller, F. Diederich, Angew. Chem. Int. Ed.
2005, 44, 1788–1805; Angew. Chem. 2005, 117, 1820–1839; b)
K. Nishide, Y. Hagimoto, H. Hasegawa, M. Shiro, M. Node,
Chem. Commun. 2001, 2394–2395.
[27] a) L. E. Zimmer, C. Sparr, R. Gilmour, Angew. Chem. Int. Ed.
2011, 50, 11860–11871; Angew. Chem. 2011, 123, 12062–12075;
b) L. Hunter, Beilstein J. Org. Chem. 2010, 6, 38–52.
Received: November 19, 2014
Published Online: ᭿
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43495
/KAP1
Date: 12-01-15 18:03:23
Pages: 13
Trifluoromethylated Analogues of 4,5-Dihydroorotic Acid
Fluorinated Compounds
V. A. Sukach,* A. A. Resetnic,
V. M. Tkachuk, Z. Lin, U. Kortz,
M. V. Vovk, G.-V. Röschenthaler ..... 1–13
Synthesis of Trifluoromethylated Ana-
logues of 4,5-Dihydroorotic Acid
A preparatively convenient route to tri-
fluoromethylated analogues of 4,5-dihydro-
orotic acid and their esters featuring intra-
molecular orthogonal dipolar C–F···C=O
interactions in the crystal state is presented.
Keywords: Nitrogen heterocycles / Fluor-
ine / Cyanides / Noncovalent interactions
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
13