One-pot synthesis of N2-aminoprotected 6-substituted and cycloalka[d] 4-trifluoromethyl-2-acetylaminopyrimidines

Article abstract of DOI:10.1002/jhet.5570450228

(Chemical Equation Presented) The one-pot synthesis of a novel series of amino-protected 6-alkyl-, 6-aryl-, 6-heteroaryl- and 5,6-fused-cycloalkane 4-trifluoromethyl-2-acetylaminopyrimidines, where alkyl = Me; aryl = Ph, 4-CH₃Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OCH₃Ph, 4-NO ₂Ph, 4,4′-biphenyl, 1-naphthyl; heteroaryl = 2-thienyl, 2-furyl and cycloalkyl = c-C₆H₄, c-C₇H₅ from the reaction of substituted 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 1-acetylguanidine in acetonitrile or propan-2-ol as solvent, is reported. The acetylamino group of 2-acetylaminopyrimidines was hydrolyzed under three different conditions to afford the corresponding free 2-aminopyrimidines.

Full text of DOI:10.1002/jhet.5570450228

One-pot Synthesis of N2-Aminoprotected 6-Substituted and
Cycloalka[d] 4-Trifluoromethyl-2-acetylaminopyrimidines
Mar-Apr 2008
483
Helio G. Bonacorso,* Adriana Ferla, Cleber A. Cechinel, Nilo Zanatta and
Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa
Maria, 97105-900, Santa Maria, RS, Brasil. (E-mail: heliogb@base.ufsm.br)
Received June 25, 2007
CF3
CF3
R1
R1
R
O
OCH3
R
N
O
i
ii
N
31 - 85 %
58 - 90 %
F3C
R
N
N
H
CH3
N
NH2
R1
R = Alkyl, Aryl, Heteroaryl; R1 = H; R-R1 = Cycloalkyl
(i) = Acetylguanidine; (ii) = Hydrolysis (3 methods).
The one-pot synthesis of a novel series of amino-protected 6-alkyl-, 6-aryl-, 6-heteroaryl- and 5,6-fused-
cycloalkane 4-trifluoromethyl-2-acetylaminopyrimidines, where alkyl = Me; aryl = Ph, 4-CH3Ph, 4-FPh, 4-
ClPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 4,4'-biphenyl, 1-naphthyl; heteroaryl = 2-thienyl, 2-furyl and
cycloalkyl = c-C6H4, c-C7H5 from the reaction of substituted 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones
with 1-acetylguanidine in acetonitrile or propan-2-ol as solvent, is reported. The acetylamino group of 2-
acetylaminopyrimidines was hydrolyzed under three different conditions to afford the corresponding free
2-aminopyrimidines.
J. Heterocyclic Chem., 45, 483 (2008).
substituents into a heterocycle frequently results in
compounds, which display more potent activity than the
parent, a fact which is probably due to the lipophilicity of
the perfluoroalkyl substituents [5,6]. One of the better
methods to introduce a trifluoromethyl group into
heterocycles is based on the trifluoromethylated building
block approach. This approach relies on the trifluoro-
acetylation of enolethers or acetals to give, in an one-step
and good yield, 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones
(β-alkoxyvinyl trifluoromethyl ketones) which proved to
be useful building blocks for the regiospecific synthesis of
numerous heterocyclic compounds. Extensive studies
have been devoted to the synthesis of pyrimidines and
pyrimidinones from β-alkoxyvinyl trichloro(fluoro)-
methyl ketones and their cyclocondensation reactions
involving a variety of nitrogenated 1,3-dinucleophiles,
since 1991. Studies about the regiochemistry of the
reactions of these ketones with urea [7-9], N-methylurea
[10], 2-methyl-2-thiopseudourea sulfate [11], guanidine
hydrochloride [12], acetamidine and benzamidine
hydrochloride [13] and N-methyl thiourea [14] have been
developed in our research group. Recently, β-ethoxyvinyl
trifluoromethyl ketone and their cycloalkane analogues, as
building blocks to construct fluorine containing
heterocycles, have been also widely studied and reviewed
[15].
INTRODUCTION
Over the past 50 years numerous pyrimidines have been
prepared and their pharmacology evaluated. Various 2-
amino-4-substituted-5-alkylpyrimidines were reported to
have diuretic activity and, in addition, numerous 2-amino-
pyrimidines have exhibited bacteriostatic, fungicidal and
antiviral activity [1].
The two problems in attempting to synthesize N-
substituted pyrimidines are the regioselective introduction
of the desired N-substituent and the unequivocal
determination of the position of the substituent. The
solution to these problems has been well explored by
protection amines and has been documented successfully
by many groups [2].
Although, the N-acetylation reaction of amino-
pyrimidines is the most studied and widely used method
[3], the pivaloyl group, an amine protecting group, has
often been used during the synthesis of 2-amino-4(3H)-
pyrimidinones and fused analogues such as 2-amino-
4(3H)-quinazolinone or 2-amino-3H-pteridine derivatives.
According to Bavetsias et al. [4] the pivaloyl group brings
an additional benefit over other groups, such as acetyl, in
that these amino protected compounds are more soluble in
organic solvent and, therefore, easier to handle.
Moreover, since 2004, a simple methodology for
pivalamide (trimethylacetamide) hydrolysis using
Fe(NO3)3.9H2O in methanol at room temperature can be
efficiently employed [4].
Striving for future biological evaluations, and as an
extension of these findings we are now investigating the
possibility of obtaining a novel series of 6-alkyl-, 6-aryl-,
6-heteroaryl- and 5,6-fused-cycloalkyl-substituted
4-trifluoromethyl-2-acetylaminopyrimidine 3 (N2-amino-
Of particular relevance to fluorine chemistry, a review
of the literature has shown that the introduction of a
trifluoromethyl group and higher homologue CnF2n+1

484
H. G. Bonacorso, A. Ferla, C. A. Cechinel, N. Zanatta, and M. A. P. Martins
Vol 45
acetylaminopyrimidines 3 from 2-aminopyrimidines 4, as
described in our work. Specifically for the N-acetylation
reaction of 4b, the respective 2-acetylamino derivative 3b
was obtained only in a yield of 30 %. On the other hand,
our results demonstrated that 2-acetylamino-4(3H)-
pyrimidine 3b can be obtained in a yield of 80 %, in a
single reaction step from the cyclocondensation reaction
of 1-acetylguanidine and 4-methoxy-4-phenyl-1,1,1-
trifluorobut-3-en-2-one (1b).
protected pyrimidines), in a one-pot reaction using the
trifluoromethylated ketones 1 and 1-acetylguanidine (2) in
a building block approach.
Scheme I
CF3
i
R1
R
O
N
N
N
H
CH3
O
OCH
NH
O
3
3 a-n
Scheme II
CF
R
N
NH2
CH3
3
R1
1a-p
CF3
CF3
H
CF3
2
R1
N
N
O
O
i or ii or iii
ii
N
58- 90 %
R
N
NH2
R
N
N
H
CH3
N
CH3
N
R
3a, 3b, 3e, 3g
4a, 4b, 4e, g
H
3 o-p
3,4
R
a
b
e
g
1-4
a
b
c
d
e
f
g
Me Ph 4-ClPh 4-OMePh
R
R1
Me
H
Ph
H
4-MePh
H
4-FPh 4-ClPh 4-BrPh 4-OMePh
H
H
H
H
(i): Fe(NO3)3 . 9H2O, MeOH, 40 ˚C, 24 h (58 - 90 %); (ii): NaOH 1M, EtOH, reflux,
20 h (70 - 85 %); (iii): HCl conc., EtOH, reflux, 20 h (66 - 80 %).
1-4
R
R1
h
4-NO2Ph
H
i
j
k
l
4-ClPh
Me
4-OMePh 4-Biphenyl 1-Naphthyl
Me
H
H
Since it is known that numerous 2-aminopyrimidines
exhibit bacteriostatic, fungicidal, antiviral and diuretic
activities [1], we attempted to perform the hydrolysis of
the acetamide group of some compounds 3 using a
procedure similar to that described by Bavetsias et al. [4].
We found that upon treatment with Fe(NO3)3•9H2O in
methanol for 24 h at 40 ºC, 2-acetylaminopyrimidines
derivatives, 3a, 3b, 3e and 3g, gave the corresponding 2-
aminopyrimidines, 4a, 4b, 4e and 4g, in satisfactory
yields (58 – 90 %). Subsequently, to obtain the above
cited compounds 4, alkaline conditions [20] [aqueous sol.
of sodium hydroxide 1 M in ethanol (7:3) at 100 ºC for 20
hours] or acidic conditions [21] [concentrated HCl in
ethanol, heating at reflux for 20 hours] were also
successfully utilized for the acetamide hydrolysis,
furnishing yields of 70 – 85 % and 66 – 80%,
respectively. However, the hydrolysis conditions using
Fe(NO3)3•9H2O are milder and the work-up of these
reactions was also simple and efficient (Scheme II).
1-4
R
m
2-Thienyl 2-Furyl
n
o
p
-(CH ) - -(CH )
2 4 2 5
-
R1
H
H
(i) = CH3CN, 80-85 ˚C, 24 h, (31-85%); (ii) = BF3.OEt2, i-PrOH, 80-85 ˚C, 20 h, (42-62%).
RESULTS AND DISCUSSION
The 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1a-h)
were synthesized from the trifluoroacetylation reaction of
the respective enolethers (1a, 1o-p) or acetals (1b-n) with
trifluoroacetic anhydride according to previous
publications [16,17]. The best reaction conditions,
selected physical and spectral data for compounds 3 and 4
are presented in the experimental part.
The cyclocondensation reactions of compounds 1 with
1-acetylguanidine were carried out in acetonitrile (for 3a-
n) or in propan-2-ol in the presence of a catalytic amount
of boron trifluoride diethyl etherate (for 3o-p) by a
procedure described in the literature [18] for similar
molecules (Scheme I). The reactions were monitored by
TLC and the optimal reaction time and temperature is 24
hours at 80 - 85 °C for the synthesis of 3a-n and 20 hours
at 80 – 85 ºC for 3o-p.
An investigation of the literature demonstrated that the
attainment of some acetylaminopyrimidines has been
carried out in the presence of acetic anhydride under
reflux conditions for approximately 2 hours. Baker et al.
[19] carried out the N-acetylation reaction of
2-methylmercapto-4-amino-6-dimethylaminopyrimidine
utilizing the above described reaction condition, isolating
2-methylmercapto-4-acetylamino-6-dimethylaminopyrim-
idine in yields of 90 %. The methodology described by
Baker et al. [19] was used in an attempt to obtain 2-
NMR Spectroscopy. The unambiguous 1H and 13C
NMR chemical shift assignments of pyrimidines 3 and
pyrimidinones 4, in DMSO-d6 as solvent, were made with
the help of homo- and heteronuclear 2D NMR
experiments and by comparison with NMR data of other
2-pyrazolines formerly synthesized in our laboratory.
The trifluoromethylated heterocycles 3a-p present the
1
typical H chemical shifts of pyrimidine ring protons at δ
7.56 – 8.33 (H-5). The protons of the acetylamino group
1
showed H chemical shifts at δ 10.89 – 11.13 (NH) and
the methyl group at δ 2.21– 2.31 ppm.
The typical 13C chemical shifts for the trifluoro-
methylated heterocycles 3a-p present of pyrimidine ring
carbons at δ 154.8 – 158.3 ppm (C-2), 154.3 – 155.9

Mar-Apr 2008
One-pot Synthesis of N2-Aminoprotected 6-Substituted and Cycloalka[d]
485
4-Trifluoromethyl-2-acetylaminopyrimidines
(C-4, 2JC-F = 35), 105.7 – 120.3 (C-5), 158.5 - 169.2 (C-
C, 55.52; H, 3.58; N, 14.94%. Found: C, 55.56; H, 3.61; N,
15.09%.
1
6) and 119.8 – 127.5 (CF3, JC-F = 275). The carbonyl
carbon of the acetylamino group showed 13C chemical
shifts at δ 169.0 – 170.3 ppm and the methyl group at δ
20.9 – 24.8 ppm.
4-Trifluoromethyl-6-(4-methylphenyl)-2-acetylaminopyr-
imidine (3c): This compound was obtained as white solid; yield
72%; mp. 159 – 161 °C. 1H NMR (DMSO-d6): δ = 11.01 (s, 1H,
NH), 8.25 (d, 2H, ArH, J = 8.2), 8.14 (s, 1H, H-5); 7,39 (d, 2H,
ArH, J = 8.2), 2.41 (s, 3H, CH3), 2.28 (s, 3H, CH3). 13C NMR
(DMSO-d6): δ = 169.2 (C=O), 167.0 (C-6), 158.1 (C-2), 155.7
We consider the one-pot reaction presented to be a
useful and convenient alternative to obtain N2-protected 4-
trifluoromethylpyrimidines. In summary, the use of this
methodology allowed for the isolation of a new series of
trifluoromethylated 2-acetylaminopyrimidines which have
been prepared in an analytically pure form and in good
yields. Moreover, examples of 2-aminopyrimidine
derivatives have been easily isolated by three similar
methods, in good yields, for future chemical and
biological studies.
2
(q, JCF = 35, C-4), 142.3, 132.1, 129.4, 127.5, (6C, ArC), 120.5
1
(q, JCF = 275, CF3), 106.6 (C-5), 24.7 (CH3), 20.9 (CH3). MS
[m/z (%)] for C14H12F3N3O (295.09): 295 (M+, 48), 253 (100),
238 (14).Anal. Calcd. for C14H12F3N3O (295.09): C, 56.95; H,
4.10; N, 14.23%. Found: C, 56.72; H, 3.84; N,14.24%.
4-Trifluoromethyl-6-(4-fluorophenyl)-2-acetylaminopyr-
imidine (3d). This compound was obtained as white solid; yield
55%; mp. 154 – 156 °C. 1H NMR (DMSO-d6): δ = 10.99 (s, 1H,
NH), 8.39-8.43 (m, 2H, ArH), 8.17 (s, 1H, H-5), 7.39-7.44 (m,
2H, ArH), 2.29 (s, 3H, CH3). 13C NMR (DMSO-d6): δ = 169.1
(C=O), 166.0 (1C, ArC), 163.2 (C-6), 158.04 (C-2), 155.9 (q,
2JCF = 35, C-4), 131.4, 130.3, 130.2, 116.4, 115.8, (5C, ArC),
127.5 (q, 1JCF= 275, CF3), 106.9 (C-5), 24.7 (CH3). MS [m/z (%)]
for C13H9F4N3O (299.07): 299 (M+,43), 257 (100), 146 (19).
Anal. Calcd. for C13H9F4N3O (299.07): C, 52.18; H, 3.03; N,
14.04%. Found: C, 51.95; H, 2.85; N, 13.76%.
EXPERIMENTAL
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined on a Reichert
Thermovar and on an Electrothermal Mel-Temp 3.0 apparatus and
4-Trifluoromethyl-6-(4-chlorophenyl)-2-acetylaminopyr-
imidine (3e). This compound was obtained as white solid; yield
80%; mp. 161 – 163 °C. 1H NMR (DMSO-d6): δ = 11.07 (s, 1H,
NH), 8.37 (d, 2H, ArH, J = 8.3), 8.21 (s, 1H, H-5), 7.65 (d, 2H,
ArH, J = 7.5), 2.28 (s, 3H, CH3). 13C NMR (DMSO-d6): δ =
1
are uncorrected. H and 13C NMR spectra were acquired on a
Bruker DPX 400 spectrometer (1H at 400.13 MHz and 13C at
100.62 MHz) 5 mm sample tubes, 298 K, digital resolution ±0.01
ppm, in DMSO-d6 and using TMS as internal reference. Mass
spectra were registered in a HP 6890 GC connected to a HP 5973
MSD and interfaced by a Pentium PC. The GC was equipped with
a split-splitless injector, autosampler, cross-linked HP-5 capillary
column (30m, 0.32mm of internal diameter), and helium was used
as the carrier gas. The CHN elemental analyses were performed
on a Perkin Elmer 2400 CHN elemental analyser (São Paulo
University - USP / Brazil).
2
169.1 (C=O), 165.9 (C-6), 158.1 (C-2), 155.9 (q, JCF=35, C-4),
137.0, 133.7, 129.3, 128.9 (6C, ArC), 119.8 (q, 1JCF = 275, CF3),
107.0 (C-5), 24.7 (CH3). MS [m/z (%)] for C13H9ClF3N3O
(315.04): 315 (M+,38), 273 (100), 162 (14). Anal. Calcd. for
C13H9ClF3N3O (315.04): C, 49.46; H, 2.87; N, 13.31%. Found:
C, 49.36; H, 2.88; N,13.11%.
4-Trifluoromethyl-6-(4-bromophenyl)-2-acetylaminopyr-
imidine (3f). This compound was obtained as white solid; yield
85%; mp. 168 – 170 °C. 1H NMR (DMSO-d6): δ = 11.08 (s, 1H,
NH), 8.30 (d, 2H, ArH, J = 8.8), 8.2 (s, 1H, H-5), 7.80 (d, 2H,
ArH, J = 8.8), 2.27 (s, 3H, CH3). 13C NMR (DMSO-d6): δ =
169.0 (C=O), 166.0 (C-6), 158.1 (C-2), 155.9 (q, 2JCF = 35, C-4),
General Procedure for the Preparation of 6-Substituted 4-
Trifluoromethyl-2-acetylaminopyrimidines (3a-n). To
a
stirred solution of 1-acetylguanidine (0.202g, 2 mmol) in
acetonitrile (5 mL) kept at room temperature (20 - 25ºC), was
added pure ketone 1 (2 mmol). The mixture was stirred for 24 h
at 80 - 85 ºC. After cooling (< 10°C), the crystalline solids were
filtered off and recrystallized from ethyl acetate.
4-Trifluoromethyl-6-methyl-2-acetylaminopyrimidine (3a).
This compound was obtained as white solid, yield 67%, mp. 117
– 119 °C. 1H NMR (DMSO-d6): δ = 10.89 (s, 1H, NH), 7.56 (s,
1H, H-5), 2.55 (s, 3H, CH3), 2.21 (s, 3H, CH3). 13C NMR
(DMSO-d6): δ = 172.3 (C=O), 169.1 (C-6), 157.8 (C-2), 154.3
(q, 2JCF = 35.0, C-4), 120.5 (q, 1JCF = 275, CF3), 111.3 (C-5), 24.6
(CH3), 23.9 (CH3). MS [m/z (%)] for C8H8F3N3O (219.06): 219
(M+, 29), 177 (100), 150 (17). Anal. Calcd. for C8H8F3N3O
(219.06): C, 43.80; H, 3.68; N, 19.17%. Found: C, 43.41; H,
3.59; N, 19.07%.
1
134.0, 131.9, 129.5, 126.0, (6C, ArC), 120.4 (q, JCF = 275.5,
CF3), 107.0 (C-5), 24.7 (CH3). MS [m/z (%)] for C13H9BrF3N3O
(359.49): 359 (M+, 48), 317 (100). Anal. Calcd. for
C13H9BrF3N3O (359.49): C, 43.36; H, 2.52; N, 15.83. Found: C,
43.06; H, 2.40; N, 15.49%.
4-Trifluoromethyl-6-(4-methoxyphenyl)-2-acetylamino-
pyrimidine (3g). This compound was obtained as white solid;
1
yield 85%; mp. 133 – 135 °C. H NMR (DMSO-d6): δ = 10.94
(s, 1H, NH), 8.33 (d, 2H, ArH, J = 8.8), 8.10 (s, 1H, H-5), 7.12
(d, 2H, ArH, J = 9.0), 3.87 (s, 3H, OCH3), 2.28 (s, 3H, CH3). 13
C
NMR (DMSO-d6): δ = 169.4 (C=O), 166.7 (1C, ArC), 162.6 (C-
2
6), 158.1 (C-2), 155.6 (q, JCF = 35, C-4), 129.5, 128.9, 114.3,
(5C, ArC), 120.7 (q, 1JCF = 275, CF3), 106.2 (C-5), 55.4 (OCH3),
24.9 (CH3). MS [m/z (%)] for C14H12F3N3O2 (311.09): 311 (M+,
57), 269 (100), 254 (14). Anal. Calcd. for C14H12F3N3O2
(311.09): C, 54.02; H, 3.89; N, 13.50%. Found: C, 54.10; H,
3.61; N, 13.25%.
4-Trifluoromethyl-6-(4-nitrophenyl)-2-acetylaminopyr-
imidine (3h). This compound was obtained as white solid; yield
53%; mp. 184 – 186 °C. 1H NMR (DMSO-d6): δ = 11.16 (s, 1H,
NH), 8.57 (d, 2H, ArH, J = 8.8), 8.57 (d, 2H, ArH, J = 8.8), 8.42
4-Trifluoromethyl-6-phenyl-2-acetylaminopyrimidine (3b).
This compound was obtained as white solid, yield 80%, mp. 134
– 136 °C. H NMR (DMSO-d6): δ = 11.05 (s, 1H, NH), 8.33 –
1
8.37 (m, 2H, ArH), 8.19 (s, 1H, H-5), 7.59 - 7.62 (m, 3H, ArH),
2.30 (s, 3H, CH3). 13C NMR (DMSO-d6): δ = 169.2 (C=O),
167.2 (C-6), 158.2 (C-2), 155.8 (q, 2JCF = 35, C-4), 134.9, 132.0,
1
128.8, 127.6, (6C, ArC) 120.5 (q, JCF = 275, CF3), 107.0 (C-5),
24.8 (CH3). MS [m/z (%)] for C13H10F3N3O (281.08): 281 (M+,
62), 239 (100), 69 (5). Anal. Calcd. for C13H10F3N3O (281.08):

486
H. G. Bonacorso, A. Ferla, C. A. Cechinel, N. Zanatta, and M. A. P. Martins
Vol 45
(s, 1H, H-5), 2.28 (s, 3H, CH3). 13C NMR (DMSO-d6): δ = 169.0
(C=O), 164.8 (C-6), 158.1 (C-2), 156.4 (q, JCF = 35, C-4),
149.2, 140.5, 128.8, 123.7, (6C, ArC), 120.3 (q, 1JCF = 275, CF3),
108.0 (C-5), 24.7 (CH3). MS [m/z (%)] for C13H9F3N4O3
(326.06): 326 (M+,24), 284 (100), 238 (19). Anal. Calcd. for
C13H9F3N4O3 (326.06): C, 47.86; H, 2.78; N, 17.17%. Found: C,
47.76; H, 2.46; N, 17.02%.
CF3), 105.7 (C-5), 24.9 (CH3). MS [m/z (%)] for C11H8SF3N3O
(287.03): 287 (M+,67), 245 (100), 69 (5). Anal. Calcd. for
C11H8SF3N3O (287.03): C, 45.99; H, 2.81; N, 14.63%. Found: C,
45.90; H, 2.53; N, 14.60%.
2
4-Trifluoromethyl-6-(2-furyl)-2-acetylaminopyrimidine (3n).
This compound was obtained as white solid; yield 52%; mp. 126
1
– 128 °C. H NMR (DMSO-d6): δ = 8.07 (s, 1H, ArH), 7.79 (s,
1H, H-5), 7.60 (d, 1H, ArH, J = 2.5), 6.82 (t, 1H, ArH, J =1.8),
2.28 (s, 3H, CH3). 13C NMR (DMSO-d6): δ = 170.0 (C=O),
158.5 (C-6), 158.3 (C-6), 155.5 (q, 2JCF = 35, C-4), 150.2, 147.7,
115.7, 113.5 (4C, Furyl), 120.5 (q, 1JCF = 275, CF3), 105.3 (C-5),
25.0 (CH3). MS [m/z (%)] for C11H8F3N3O2 (271.08): 271
(M+,71), 229 (100). Anal. Calcd. for C11H8F3N3O2 (271.08): C,
48.72; H, 2.97; N, 15.49%. Found: C, 48.96; H, 3.01; N,
15.66%.
General Procedure for the Preparation of Fused-
cycloalkane 4-Trifluoromethyl-2-acetylaminopyrimidines
(3o-p). To a stirred solution of 1-acetylguanidine (0.707g, 7
mmol) in propan-2-ol (10 mL) kept at room temperature (20 -
25ºC), was added pure ketone 1 (5 mmol) and boron trifluoride
diethyl etherate (sol. 45% in MeOH) (10 drops). The mixture
was stirred for 20 h at 80 - 85 ºC. After cooling (< 10°C), the
crystalline solids were filtered off, washed with propan-2-ol to
remove the residual 1-acetylguanidine and recrystallized from
ethyl acetate.
4-Trifluoromethyl-5,6,7,8-tetrahydro-2-acetylaminoquin-
azoline (3o). This compound was obtained as white solid; yield
42%; mp. 152 – 154 °C. 1H NMR (DMSO-d6): δ = 10.74 (s, 1H,
NH), 2.82 (m, 4H, 2CH2), 2.18 (s, 3H, CH3), 1.81 (s, 4H, 2CH2).
13C NMR (DMSO-d6): δ = 171.3 (C=O), 169.2 (C-8a), 154.8 (C-
2), 151.8 (q, 2JCF = 33, C-4), 121.4 (q, 1JCF = 277, CF3), 127.6 (C-
4a), 31.0 (CH2), 26.5 (CH2), 26.3 (CH2), 25.4 (CH2), 25.1 (CH2),
24.9 (CH3). MS [m/z (%)] for C11H12F3N3O (259.23): 259
(M+,24), 216 (100), 189 (43). Anal. Calcd. for C11H12F3N3O
(259.23): C, 50.97; H, 4.67; N, 16.21%. Found: C, 51.07; H,
4.71; N, 16.30%.
4-Trifluoromethyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]-2-
acetylaminopyrimidine (3p). This compound was obtained as
white solid; yield 62%; mp. 167 – 169 °C. 1H NMR (DMSO-d6):
δ = 10.75 (s, 1H, NH), 3.05 (m, 2H, CH2), 2.84 (m, 2H, CH2),
2.19 (s, 3H, CH3), 1.82 (m, 2H, CH2), 1.64 (m, 2H, CH2), 1.61
(m, 2H, CH2). 13C NMR (DMSO-d6): δ = 177.0 (C=O), 169.2
(C-9a), 154.8 (C-2), 150.2 (q, 2JCF=35, C-4), 121.5 (q, 1JCF =275,
CF3,), 127.6 (C-4a), 31.0 (CH2), 26.5 (CH2), 26.3 (CH2), 25.4
(CH2), 25.1 (CH2), 24.9 (CH3). MS [m/z (%)] for C12H14F3N3O
(273.25): 273 (M+, 29), 231 (100), 203 (29). Anal. Calcd. for
C12H14F3N3O (273.25): C, 52.75; H, 5.16; N, 15.38%. Found: C,
52.69; H, 5.12; N, 15.62%.
4-Trifluoromethyl-5-methyl-6-(4-chlorophenyl)-2-acetyl-
aminopyrimidine (3i). This compound was obtained as white
solid; yield 39%; mp. 158 – 160 °C. 1H NMR (DMSO-d6): δ =
10.95 (s, 1H, NH), 7.70 (d, 2H, ArH, J = 8.8), 7.62 (d, 2H, ArH,
J = 8.8), 2.33 (s, 3H, CH3), 2.21 (s, 3H, CH3). 13C NMR
(DMSO-d6): δ = 169.2 (C=O), 169.0 (C-6), 155.0 (C-2), 153.4
2
(q, JCF = 33.1, C-4), 135.6, 134.8, 131.1, 128.4, (6C, ArC),
1
123.1 (q, JCF = 277, CF3), 118.3 (C-5), 24.6 (CH3), 13.8 (CH3).
MS [m/z (%)] for C14H11F3N3O2 (329.11): 329 (M+,24), 286
(100). Anal. Calcd. for C14H11F3N3O2 (329.11): C, 51.00; H,
3.36; N, 12.74%. Found: C, 50.88; H, 2.99; N, 12.69%.
4-Trifluoromethyl-5-methyl-6-(4-methoxyphenyl)-2-acetyl-
aminopyrimidine (3j). This compound was obtained as white
1
solid; yield 36%; Mp. 145 – 147 °C. H NMR (DMSO-d6): δ =
10.84 (s, 1H, NH), 7.66 (d, 2H, ArH, J = 8.8), 7.09 (d, 2H, ArH,
J = 8.8), 3.85 (s, 3H, OCH3), 2.36 (s, 3H, CH3), 2.23 (s, 3H,
CH3). 13C NMR (DMSO-d6): δ = 169.5 (C=O), 169.2 (C-6),
160.0 (ArC), 155.0 (C-2), 153.2 (q, 2JCF = 34, C-4), 131.0, 128.9,
1
113.6, 113.1 (5C, ArC), 121.4 (q, JCF = 277, CF3), 119.8 (C-5),
55.2 (OCH3), 24.5 (CH3), 13.9 (CH3). MS [m/z (%)] for
C15H14F3N3O2 (325.29): 325 (M+,71), 283 (100). Anal. Calcd.
for C15H14F3N3O2 (325.29): C, 55.39; H, 4.34; N, 12.92%.
Found: C, 55.23; H, 4.33; N, 12.90%.
4-Trifluoromethyl-6-biphenyl-2-acetylaminopyrimidine (3k).
This compound was obtained as white solid; yield 70%; mp. 186
1
– 188 °C. H NMR (DMSO-d6): δ = 11.06 (s, 1H, NH), 8.43-
8.47 (d, 2H, ArH, J = 8.5), 8.25 (s, 1H, H-5), 7.88-7.92 (d, 2H,
ArH, J = 8.5), 7.78-7.83 (m, 2H, ArH), 7.74-7.57 (m, 3H, ArH),
2.30 (s, 3H, CH3). 13C NMR (DMSO-d6): δ = 169.2 (C=O),
166.7 (C-6), 158.1 (C-2). 155.0 (q, 2JCF = 35, C-4), 143.6, 138.8,
133.8, 128.9, 128.2, 128.1, 127.0, 126.7 (12C, ArC), 120.7 (q,
1JCF = 275, CF3), 107.0 (C-5), 24.8 (CH3). MS [m/z (%)] for
C19H14F3N3O (357.11): 357 (M+,62), 315 (100). Anal. Calcd. for
C19H14F3N3O (357.11): C, 63.86; H, 3.95; N, 11.76%. Found: C,
63.53; H, 3.97; N, 11.70%.
4-Trifluoromethyl-6-naphthyl-2-acetylaminopyrimidine (3l).
This compound was obtained as white solid; yield 35%; mp. 127
1
– 128 °C. H NMR (DMSO-d6): δ = 11.13 (s, 1H, NH), 8.50-
8.52 (m, 1H, ArH), 8.12 - 8.14 (d, 1H, ArH, J = 8.3), 8.03 - 8.05
(m, 1H, ArH), 7.89 (s, 1H, H-5), 7.86-7.88 (d, 2H, ArH, J = 8.0),
7.65-7.67 (d, 1H, ArH, J = 7.6), 7.59-7.67 (m, 2H, ArH), 2.31 (s,
3H, CH3). 13C NMR (DMSO-d6): δ = 170.1 (C=O), 169.2 (C-6),
General Procedures for the Preparation of 6-Substituted 4-
Trifluoromethyl-2-aminopyrimidines (4a, 4b, 4e, 4g).
2
157.8 (C-2), 155.4 (q, JCF = 35, C-4), 134.0, 133.4, 131.0,
129.8, 128.9, 128.4, 127.2, 126.9, 125.8, 125.2 (10C, ArC),
1
120.3 (q, JCF = 275, CF3), 111.9 (C-5), 24.7 (CH3). MS [m/z
Method A [4]. To a stirred solution of acetylaminopyrim-
idines 3 (2 mmol) in methanol (20 mL) kept at room temperature
(20 - 25ºC), was added in one portion Fe(NO3)3•9H2O (0.2
mmol, 0.08g). The mixture was stirred for 24 h at 40 ºC. After
cooling (< 5°C), the crystalline solids were collected by
filtration and recrystallized from ethanol (58 – 90 % yields).
(%)] for C17H12F3N3O (331.29): 331 (M+, 62), 288 (100), 220
(52). Anal. Calcd. for C17H12F3N3O (331.29): C, 61.63; H, 3.65;
N, 12.68%. Found: C, 61.87; H, 3.68; N, 12.87%.
4-Trifluoromethyl-6-(2-thienyl)-2-acetylaminopyrimidine
(3m). This compound was obtained as white solid; yield 48%;
mp. 143 – 145 °C. 1H NMR (DMSO-d6): δ = 8.34 (d, 1H, ArH, J
=3.9), 8.13 (s, 1H, H-5), 7.95 (d, 1H, ArH, J = 4.9), 7.30 (t, 1H,
ArH, J = 4.4), 2.29 (s, 3H, CH3). 13C NMR (DMSO-d6): δ =
169.5 (C=O), 162.2 (C-6), 158.1 (C-2), 155.5 (q, 2JCF = 35, C-4),
Method
B [20]. To a stirred solution of acetylamino-
pyrimidines 3 (2 mmol) in ethanol (15 mL) kept at room
temperature (20 - 25ºC), was added, in one portion, concentrated
HCl (15 mL). The mixture was refluxed for 20 h. After cooling (<
5°C), the reaction was neutralized with an aqueous solution of
1
128.9, 130.9, 132.9, 140.7, (4C, Thienyl), 120.5 (q, JCF = 275,

Mar-Apr 2008
One-pot Synthesis of N2-Aminoprotected 6-Substituted and Cycloalka[d]
487
4-Trifluoromethyl-2-acetylaminopyrimidines
REFERENCES
NaOH (50% w/v). The solids were collected by filtration, washed
with ice-water (20 mL), dried under reduced pressure in a P2O5
dessicator and recrystallized from ethanol (66 – 80 % yields).
Method C [21]. To a stirred solution of acetyl-amino-
pyrimidines 3 (2 mmol) in a mixture of ethanol:water (7:3) (10
mL) kept at room temperature (20 - 25ºC), was added in one
portion NaOH (1 M, 10 mL). The mixture was refluxed for 20 h.
After cooling (< 5°C), the reaction was neutralized with 37%
HCl. The solids were collected by filtration, washed with ice-
water (20 mL), dried under reduced pressure in a P2O5 dessicator
and recrystallized from ethanol (70 – 85 % yields).
*
Author to whom correspondence should be addressed (E-mail:
heliogb@base.ufsm.br).
[1] Skulnick, H. I.; Ludens, J. H.; Wendling, M. G.; Glenn, E.
M.; Rohloff, N. A.; Smith, R. J.; Wierenga, W. J. Med. Chem. 1986, 29,
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[4] Bavetsias, V.; Henderson, E. A.; McDonald, E. Tetrahedron
Lett. 2004, 45, 5643.
4-Trifluoromethyl-6-methyl-2-aminopyrimidine (4a). This
compound was obtained as white solid, yield 58 % (A), 66 %
(B), 70 % (C), mp. 127 – 129 ºC (mp. 129 ºC, lit. [22]). 1H
NMR (DMSO-d6): δ = 7.21 (s, 2H, NH2), 6.88 (s, 1H, H5), 2.36
(s, 3H, CH3). 13C NMR (DMSO-d6): δ = 171.9 (C-6), 163.6 (C-
2), 154.7 (q, 2JCF =34, C-4), 120.9 (q, 1JCF =275, CF3,), 105.2 (C-
5), 24.7 (CH3). MS [m/z (%)] for C6H6N3F3 (177.05) = 177(M+,
100), 158 (27), 108 (40), 69 (60).
[5] Filler, R. Organofluorine Chemicals and Their Industrial
Applications, R.E Banks Ed., Ellis Harwood, London, 1979.
[6] Inouye, Y.; Tezuka, K.; Takeda, W.; Sugai, S. J. Fluorine
Chem. 1987, 35, 275.
[7] Zanatta, N.; Pachoski, I. L.; Martins, M. A. P.; Blanco, I. J.
Braz. Chem. Soc. 1991, 2, 118.
[8] Zanatta, N.; Madruga, C. C.; Marisco, P. C.; Flores, A. F. C.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem. 2000, 37, 1213.
[9] Bonacorso, H. G.; Lopes, I. S.; Wastowski, A. D.; Zanatta, N.;
Martins, M. A. P. J. Fluorine Chem., 2003, 120, 29.
[10] Blanco, I.; Pacholski, I. L.; Zanatta, N.; Martins, M. A. P.
Quím. Nova 1993, 16, 15.
4-Trifluoromethyl-6-phenyl-2-aminopyrimidine (4b). This
compound was obtained as white solid, yield 90 % (A), 80 %
(B), 76 % (C), mp. 130 – 132 °C (mp. 133 – 133.5 ºC, lit. [22]).
1H NMR (DMSO-d6): δ = 8.16 – 8.21 (m, 2H, ArH), 7.56 – 7.57
(m, 3H, ArH), 7.52 (s, 1H, H5), 7.40 (s, 2H, NH2). 13C NMR
[11] Zanatta, N.; Madruga, C. C.; Clerici, E.; Martins, M. A. P. J.
Heterocycl. Chem. 1995, 32, 735.
2
[12] Zanatta, N.; Corteline, M. F. M.; Carpes, M. J. S.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem. 1997, 34, 509.
[13] Zanatta, N.; Fagundes, M. B.; Ellensohn, R.; Marques, M.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem. 1998, 35, 451.
[14] Bonacorso, H. G.; Martins, M. A. P.; Bittencourt, S. R. T.;
Lourega, R. V.; Zanatta, N.; Flores, A. F. C. J. Fluorine Chem. 1999, 99,
177.
(DMSO-d6): δ = 166.9 (C-6), 163.9 (C-2), 156.1 (q, JCF = 34,
C-4), 135.9, 131.3, 129.1, 128.7 (6C, ArC), 120.1 (q, 1JCF =275,
CF3), 100.8 (C-5). MS [m/z (%)] for C11H8N3F3 (239.07) = 239
(M+, 100), 218 (14), 128 (27), 77 (17).
4-Trifluoromethyl-6-(4-chlorophenyl)-2-aminopyrimidine
(4e). This compound was obtained as white solid, yield 86 %
(A), 77 % (B), 83 % (C), mp. 181 – 183 °C. 1H NMR (DMSO-
d6): δ = 8.20 – 8.24 (d, 2H, ArH), 7.57 – 7.59 (d, 2H, ArH), 7.63
(s, 1H, H5), 7.43 (s, 2H, NH2). 13C NMR (DMSO-d6): δ = 165.7
(C-6), 163.9 (C-2), 156.3 (q, 2JCF = 34, C-4), 136.3, 134.6, 128.9,
[15] Zhu, S. Z.; Wang,;Y. L.; Peng,W. M.; Song, L. P.; Jin, G. F.
Curr. Org. Chem. 2002, 6, 1057.
[16a] Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P.
Synthesis 1991, 483; (b) Martins, M. A. P.; Siqueira, G. M.; Flores, A. F.
C.; Clar, G.; Zanatta, N. Quím. Nova 1994, 17, 24; [b] Martins, M. A. P.;
Siqueira, G. M.; Flores, A. F. C.; Clar, G.; Zanatta, N. Chem. Abstr. 1995,
122, 187063a; [c] Bonacorso, H. G.; Bittencourt, S. R. T.; Martins, M. A.
P.; Lourega, R. V.; Zanatta, N.; Flores, A. F. C. J. Fluorine Chem. 1999,
99, 177; [d] Bonacorso, H. G.; Costa, M. B.; Moura, S.; Pizzuti, L.;
Martins, M. A. P.; Zanatta, N.; Flores, A. F. C. J. Fluorine Chem. 2005,
126, 1396; [e] Bonacorso, H. G.; Cechinel, C. A.; Oliveira, M. R.; Costa,
M. B.; Martins, M. A. P.; Zanatta, N.; Flores, A. F. C. J. Heterocycl.
Chem. 2005, 42, 1055.
1
128.8 (6C, ArC), 120.1 (q, JCF =275.4, CF3), 100.7 (C-5). MS
[m/z (%)] for C11H7N3F3Cl (273.03) = 273 (M+, 100), 252 (12),
162 (20), 75 (15). Anal. Calcd. for C11H7ClF3N3 (273.03): C,
48.28; H, 2.58; N, 15.36%. Found: C, 48.40; H, 2.64; N,
15.51%.
4-Trifluoromethyl-6-(4-methoxyphenyl)-2-aminopyrimid-
ine (4g). This compound was obtained as white solid, yield 81 %
1
(A), 76 % (B), 85 % (C), mp. 192 – 193 °C. H NMR (DMSO-
[17a] Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S.
Chem. Lett. 1976, 499; [b] Kamitori, Y.; Hojo, M.; Masuda, R.; Fujitani,
T.; Kobuchi, T.; Nishigaki, T. Synthesis 1986, 340; [c] Hojo, M.; Masuda,
R.; Okada, E. Tetrahedron Lett. 1986, 1013.
[18] Bonacorso, H. G.; Costa, M. B.; Lopes, I. S.; Oliveira, M. R.;
Drekener, R. L.; Martins, M. A. P.; Lourega, R. V.; Zanatta, N.; Flores,
A. F. C. Synth. Comm. 2005, 35, 3055.
d6): δ = 8.16 - 8.20 (d, 2H, ArH), 7.48 (s, 1H, H5), 7.29 (s, 2H,
NH2), 7.06 - 7.10 (d, 2H, ArH), 3.85 (OCH3). 13C NMR (DMSO-
2
d6): δ = 166.4 (C-6), 163.8 (C-2), 162.0 (ArC), 155.8 (q, JCF
=
1
34, C-4), 128.9, 128.1, 114.1 (5C, ArC), 120.8 (q, JCF = 275,
CF3), 100.0 (C-5), 55.3 (OCH3). MS [m/z (%)] for C12H10N3F3O
(269.23) = 269 (M+, 100), 254 (7), 206 (12), 92 (6). Anal. Calcd.
for C12H10F3N3O (269.23): C, 53.54; H, 3.74; N, 15.61%. Found:
C, 53.72; H, 3.80; N, 15.79%.
[19] Baker, B. R.; Schaub, R. E.; Joseph, J. P. J. Org. Chem. 1953,
19, 638.
[20] Jones, T. R.; Calvert, A. H.; Jackman, A. L.; Eakin, M. A.;
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A.; Harland, S. J.; Davies, L. C.; Harrap, K. R. J. Med. Chem. 1985, 28,
1468.
[21] Akama, T.; Shida, Y.; Sugaya, T.; Ishida, H.; Gomi, K.; Kasai,
M. J. Med. Chem. 1996, 39, 3461.
[22] Nishiwaki, T. Bull. Chem. Soc. Jpn. 1969, 42, 3024.
Acknowledgments. The authors are thankful to Conselho
Nacional de Desenvolvimento Científico e Tecnológico – CNPq
(Process No. 303636/2002-5) for financial support. Fellowships
from Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior - CAPES (to A. Ferla and C. A. Cechinel) are also
acknowledged.