Syntheses of novel 4-polyfluoroalkyl-substituted 5,6-oligomethylene pyrimidines

Article abstract of DOI:10.1055/s-2000-8200

2-Acylcycloalkanones having polyfluoroalkyl groups react with guanidine, urea, thiourea, methylisothiourea, benzamidine, guanylthiourea, dicyanodiamide, and trifluoroacetylurea by Lewis-acid catalysis to form the corresponding 5,6-oligomethylene pyrimidines. A decrease in the yields along with increase of polyflyoroalkyl substituent length in the molecule of the starting 1,3-diketone was observed in the case of reagents with lower nucleophilicity (urea, thiourea, dicyanodiamide). The pyrimidines obtained from aromatic aldehydes showed E-configuration with respect to the arylidene double bond. Tautomeric structures as a function of the substituent in 2 position in the pyrimidine ring both in liquid and solid state were investigated by X-ray diffraction, IR and NMR spectroscopy.

Full text of DOI:10.1055/s-2000-8200

1738
PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene
Pyrimidines
Dmitrii V. Sevenard,a Oleg G. Khomutov,b Olga V. Koryakova,b Valeriya V. Sattarova,b Mikhail I. Kodess,b Johannes
Stelten,a Ildiko Loop,a Enno Lork,a Kazimir I. Pashkevich,*b Gerd-Volker Röschenthaler*a
a Institute of Inorganic and Physical Chemistry, University of Bremen, Leobener Strasse, D-28334 Bremen, Germany
Fax +49(421)2184267; E-mail: gvr@chemie.uni-bremen.de
b Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, 20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Feder-
ation
Received 26 May 2000; revised 17 July 2000
of the carbocyclic system to generate 5,6-polymethylene
Abstract: 2-Acylcycloalkanones having polyfluoroalkyl groups re-
substituted pyrimidine. Furthermore, the structure of the
new compounds was investigated especially with respect
to the possible tautomeric equilibria.
act with guanidine, urea, thiourea, methylisothiourea, benzamidine,
guanylthiourea, dicyanodiamide, and trifluoroacetylurea by Lewis-
acid catalysis to form the corresponding 5,6-oligomethylene pyrim-
idines. A decrease in the yields along with increase of polyflyoro-
alkyl substituent length in the molecule of the starting 1,3-diketone
was observed in the case of reagents with lower nucleophilicity
(urea, thiourea, dicyanodiamide). The pyrimidines obtained from
aromatic aldehydes showed E-configuration with respect to the
arylidene double bond. Tautomeric structures as a function of the
substituent in 2 position in the pyrimidine ring both in liquid and
solid state were investigated by X-ray diffraction, IR and NMR
spectroscopy.
Results and Discussion
In contrast to the synthesis of 2-aminopyrimidines8 by
condensation of similar alicyclic 1,3-diketones (e.g. 2-tri-
fluoroacetylhomoadamantanone), with an excess of
guanidine carbonate, where heating up to 300 °C without
a solvent for three hours seemed to be necessary, we ob-
tained polyfluoroalkyl substituted pyrimidines in accept-
able yields under mild conditions. Refluxing the 1,3-
diketones 1c, 1g and guanidine 2c in propan-2-ol in the
presence of BF3 OEt2 gave the pyrimidines 3a, 3b as
colorless solids in 92 and 57% yield, respectively. Simi-
larly, other 5,6-oligomethylene substituted 4-polyfluor-
alkyl pyrimidines were synthesized. The reaction of
2-polyfluoroacyl cycloalkanones 1a i with urea (2a),
thiourea (2b), benzamidine (2d), methylisothiourea (2e)
and guanylthiourea 2f gave the compounds 3c t
(Scheme 1, Table 1). Attempts to prepare an N-acyl sub-
stituted pyrimidine by reacting 1,3-diketone 1c with tri-
fluoroacetyl urea (4) failed but yielded 3c (43%), proba-
bly via alcoholysis of the amide function (Scheme 1).
Key words: 2-polyfluoroacyl cycloalkanones, urea, guanidines,
benzamidine, pyrimidines, tautomerism, Lewis acids, cyclizations,
heterocycles
Introduction
Polyfluoralkyl substituted derivatives of pyrimidine are of
great interest because of their herbicidal,1,2 fungicidal,1,3
antibiotic,3–5 antiviral6 or antineoplastic7 properties. The
condensation of N C N binucleophiles (urea and its
derivates, guanidines and amidines) with polyfluoro-
alkyl-containing 1,3-bielectrophiles (1,3-diketones,3-9a,10
1,3-keto esters,1,9a 1,3-keto amides,9 , -enones and their
derivatives11,12) is considered the main procedure for the
syntheses, a variant of the classical Traube method. How-
ever, not in every case such a reaction takes a clear-cut
course and produces a heterocyclic system; e.g. 2-phe-
nylpyrimidine could not be prepared by condensing 5-tri-
In the reactions of 2-polyfluoroacyl cycloalkanones 1 the
yields turned out to be significantly dependent on the
chain length of the polyfluoroalkyl substituent; in the case
of urea the products 3c (RF = CF3) 64%, 3d
(RF = CF2CF2H) 40%, 3e (R = C3F7) 16% and in the case
of thiourea the productsF 3g (RF = CF3) 34%, 3h
(RF = CF2CF2H) 17%, 3i (RF = C3F7) 2% were obtained in
yields noted respectively. When compound 1 with
RF = C8F17 was used, the formation of the respective pyri-
midine could not be observed. If compound 3l was synthe-
sized according to Ref. 3 (without catalyst in ethanol,
Method B) the yield was found to be 49%, considerably
lower than in the presence of BF3 OEt2 (81%). The 1,3-
diketones 1c, 1f reacted with dicyanodiamide 5 in two
steps, similar to other 1,3-diketones;7,13 pyrimidines 6
formed in the first instance hydrolyze to give the 2-ure-
idopyrimidines 7a (63%) and 7b (4%) (Scheme 2). Using
methanol as a solvent not a trace of 7a was found.
fluoroacetylhomoadamantanone
with
benzamidine
hydrochloride.8 Simultaneously, the reaction of 2-trifluo-
roacetylcyclopentanone with benzamidine9a yielded not
only the corresponding pyrimidine, but also an aminovi-
nyl ketone, the product of the condensation of only one
carbonyl group of the substrate. The majority of the liter-
ature about the syntheses of fluorine-containing pyrim-
idines refers to trifluoromethyl derivatives. The influence
of polyfluoro alkyl substituents on the reaction pathway
remains to be studied.
Herein we discuss the reaction of 2-polyfluoracylcycloal-
kanones with several 1,3-N,N‘-binucleophiles, the influ-
ence of the polyfluoroalkyl chain length and the ring size
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PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines
1739
Scheme 1
In order to study the nucleophilicity of the amino function ethylaminobenzylidene)-6-trifluoroacetylcyclohexanone
in the polyfluoroalkylated 2-aminopyrimidines, com- (10)14 with guanidine (Method E, Scheme 3), however
pound 3a was reacted with benzaldehyde. In this case sur- with 17% yield only (using Method D, 67% yield was
prisingly, the E-benzylidene derivative 9a was formed, achieved) (Table 1). Heating a mixture of equimolar
the product of the condensation at the methylene group in amounts of endione 10 and urea the expected compound
position 6 of the pyrimidine ring. Other pyrimidines 3 de- 9c was not observed; probably because of the lower nu-
scribed above reacted analogously to afford compounds 9 cleophilicity of urea compared to guanidine.
with yields in the range of 50 100% (Method D, Scheme
3), which are not affected by the carbocyclic ring size, by
the length of the polyfluoroalkyl chain, by the substituent
X in the pyrimidine 3 and by the properties of the sub-
stituted benzaldehydes 8. Quinazoline derivative 9b
could be synthesized also by condensation of 2-(E)-(p-di-
1
The H NMR data for compounds 9a k account for the
E-configuration of arylidene C=C double bond (Table 2).
The resonance of the arylidene proton of compound 9e
was observed at = 7.95 and its E-configuration con-
firmed by X-ray diffraction (Figure). In the same shift
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

1740
D. V. Sevenard et al.
PAPER
range ( = 7.7 8.2, see Table 2) the respective signals for
9a d,f k were found. Structure similar to 4-(E)-
arylidene-1,3-diketones show resonances at = 7.5 7.914
( = 6.6 6.8 for Z-isomeres).
The pyrimidine derivatives 3, 7, 9 having a proton at the
heteroatom can form three different tautomers, C-E. The
"mercaptopyrimidine-thiolactam" (Z = S), "aminopyrimi-
dine-amidine" (Z = NH) and "hydroxypyrimidine-lac-
tam" (Z = O) equilibria were investigated via IR (solid
state and in solution) and NMR spectroscopy (see struc-
tures 3a,c,g,h,l and 9b,e and f, where all pyrimidine deri-
vates are given in the aromatic form).
In the S-methylated mercaptopyrimidine 3l, the pyrimi-
dine structure C only is possible. Therefore its solid state
1
IR absorptions at = 1415, 1460, 1545, 1565 cm , attrib-
uted to the pyrimidine ring, could be used as a reference.
For compounds 3h and 3g features similar to 3l [and ad-
1
sorption (SH) 2580 cm ] were observed in CHCl3 so-
Scheme 2
lution, indicating the main presence of the
Scheme 3
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines
1741
Table 1 Preparation and Properties of Compounds 3, 7 and 9
Starting
Materials
Producta
Reaction Meth- Yield (%)
od
Reaction Time Mp (oC) (solvent)
(h)
1c and 2c
1g and 2c
1c and 2a
1c and 4
3a
3b
3c
3c
3d
3e
3f
3g
3h
3i
A
A
A
C
92
57
64
43
40
16
16
34
17
2
9
7
145 146 (hexane)
97 98 (heptane)
206 207 (toluene)
21
20
20
21
13
14
14
14
19
11
1d and 2a
1f and 2a
1a and 2b
1c and 2b
1d and 2b
1f and 2b
1d and 2d
1c and 2e
1d and 2e
1e and 2e
1g and 2e
1a and 2f
1b and 2f
1c and 2f
1d and 2f
1h and 2f
1i and 2f
1c and 5
A
A
A
A
A
A
A
A
A, B
A
A
A
A
A
A
A
A
A
A
D
D
E
D
D
D
D
D
D
D
D
D
196 197 (butan-1-ol/hexane, 2:1)
161 162 (heptane)
130 131 (petroleum ether)
123b (heptane)
130b (hexane/toluene, 5:1)
104 105 (heptane)
3j
3k
3l
59
46
91 92 (perfluoro-1,1-dimethylcyclohexane)
58 59 (perfluoro-1,1-dimethylcyclohexane)
41(perfluoro-1,1-dimethylcyclohexane)
33 34 (chromatography)
Oil
>270 (dec.) (butan-1-ol)
222 223 (toluene)
270 271 (butan-1-ol)
211 212 (butan-1-ol)
189 191 (toluene)
174 175 (toluene)
192 193 (toluene)
81 (A); 49 (B) 18 (A); 18 (B)
3m
3n
3o
3p
3q
3r
3s
3t
7a
7b
9a
9b
9b
9c
9d
9e
9f
72
85
46
16
82
78
41
62
63
4
41
67
17
57
100
91
85
83
97
62
50
83
10
10
4
6
4
6
10
6
20
20
10
10
26
8
1f and 5
175 176 (hexane/toluene, 1:1)
169 170 (heptane)
174 175 (hexane/toluene, 1:1)
3a and 8d
3a and 8a
10 and 2c
3c and 8a
3c and 8b
3c and 8c
3c and 8d
3c and 8e
3c and 8f
3e and 8c
3f and 8a
3g and 8d
268 270 (toluene/MeOH, 4:1)
>290b (butan-1-ol)
261 262 (toluene)
8
20
20
12
15
20
5
222 223 (toluene)
9g
9h
9i
9j
9k
248 250b (EtOH)
236 237 (hexane/toluene, 1:1)
228 229 (butan-1-ol)
>160 (DMF/H2O, 4:1)
105 106 (butan-1-ol)
20
a Satisfactory microanalyses or HRMS values (3s, 9g, 9j: ±0.0009) obtained: C ±0.44, H ±0.31, F ±0.49, N ±0.44. Exceptions: 9k, C 0.62; 3n,
H
0.50; 3k F 0.48, 3l 0.5, 9k +0.5; 3n N 1.13.
b Sublimation point.
mercaptopyrimidine form C. The thiolactam tautomer D present as the aminopyrimidine form
C
with
1
1
or E as the dominating species were established for 3h and
(NH2) = 3405, 3510 cm and (NH2) = 1585 cm (for
3g in the solid state spectra. The IR absorptions around IR absorptions, see Table 3). The compounds 3c, 9e,f ex-
= 3076 and 3168 cm 1 correspond to valence vibrations ist in the solid state (see the X-ray diffraction results of 9e)
of NH with strong hydrogen bonding.15 Around 1570 cm
and in CHCl3 solution in the lactam tautomeric form (see
1
the vibration for the C=N C=C fragment is observed, also Ref. 17), (C=O) were observed in the 1636 1664
the absorption at 900 cm 1 is due to (C=S).16 In the case cm 1 and the broad absorption in the 2500 3140 cm re-
1
of the solid state IR spectrum of 3a both the aminopyrim- gion corresponds to NH with strong hydrogen bonding.
idine C and the amidine isomer D or E were present indi-
The 1H, 13C and 19F NMR spectra of the new compounds
1
cated by (NH2) = 3184, 3312 cm (C), (NH2) = 1642
recorded in CDCl3 and DMSO-d6 solution (Tables 2,
cm-1 (C) and ( =NH) = 3472 cm 1 (D, E); in solution the
aminopyrimidine form C with the characteristic absorp-
4 7) show typically one set of signals, indicating that
only one form (C, D or E) is present in solution besides
tions for the pyrimidine ring system, (NH2) = 3420, 3532
the products of the reaction of trifluoracetyl cycloal-
1
and (NH2) = 1608 cm were found. For compound 9b
kanones with thiourea, namely the compounds 3f, g,
features similar to 3a were observed. In the solid state IR
where in DMSO-d6 two sets of signals were obtained due
spectrum compound 9b showed absorptions due to the
to two coexisting tautomers (for 3g in 1H NMR spectrum
aminopyrimidine derivative C, e.g. (NH2) = 3190, 3310
an 80:20 ratio was found), however, in the less polar
cm 1 and (NH2) = 1610 cm 1 and less intense bands for
CDCl3 only one isomer was present. To assign the signals
tautomer D or E; in CHCl3 solution compound 9b was
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

1742
D. V. Sevenard et al.
PAPER
Table 2 1H NMR Data of Compounds 9
Product
(CH2)n+1
1H NMR, , J (Hz)
Ar
X
=CH
9aa
1.74 1.86 (m, 2 H),
2.77 2.92 (m, 4 H)
5.2 (br s)
7.25 7.45 (m)
8.1 (br s)
9ba
1.77 1.89 (m, 2 H),
2.79 2.95 (m, 4 H)
5.1 (br s)
1.22 (t, 6 H, 3JH-H = 7.1), 3.43 (q, 4 H, 3JH-H
7.1), 6.70 (d, 2 H, 3JH-H = 8.9), 7.42 (d, 2 H,
3JH-H = 8.9)
=
=
8.05 (t, 4JH-H = 2.0)
9ca
9db
9eb
9fa
1.59 2.01 (m, 2 H),
2.57 2.94 (m, 4 H)
11.8 (br s)
12.1 (br s)
12.2 (br s)
12.3 (br s)
12.25 (s)
1.21 (t, 6 H, 3JH-H = 7.1), 3.42 (q, 4 H, 3JH-H
7.1), 6.62 7.51 (m, 4 H)
7.7 (br s)
7.9 (br s)
7.95 (s)
7.93 (s)
8.01 (s)
8.07 (s)
1.7 (br s, 2 H), 2.8 (br s,
4 H)
3.32 (s, 6 H), 6.7, 7.4 (both br s, both 2 H)
1.61 1.81 (m, 2 H),
2.65 2.85 (m, 4 H)
3.76 (s, 3 H), 6.96 (d, 2 H, 3JH-H = 8.0), 7.42 (d,
2 H, 3JH-H = 8.0)
1.68 1.93 (m, 2 H),
2.72 2.85 (m, 4 H)
7.25 7.48 (m)
7.31 7.46 (m)
7.31 7.53 (m)
9fb
9gb
1.63 1.75 (m, 2 H),
2.67 2.80 (m, 4 H)
1.62 1.78 (m, 2 H),
2.63, 2.76 (both
12.35 (s)
unres. t, both 2 H)
9hb
9ib
9jb
1.83 1.92 (m, 2 H),
2.46 2.91 (m, 4 H)
12.5 (br s)
7.36 7.89 (m)
8.2 (br s)
8.0 (br s)
7.91 (s)
c
1.71 1.77 (m, 2 H), 2.8
(br s, 4 H)
3.79 (s, 3 H), 6.95 7.51 (m, 4 H)
2.96 (s, 4 H)
13.8 (br s)
1.09 (t, 6 H, 3JH-H = 7.0), 3.39 (q, 4 H, 3JH-H
7.0), 6.73 (d, 2 H, 3JH-H = 8.9), 7.36 (d, 2 H,
3JH-H = 8.9)
=
c
9ka
1.74 1.87 (m, 2 H),
2.80 2.86 (m, 4 H)
7.25 7.39 (m)
8.0 (br s)
a In CDCl3.
b In DMSO-d6.
c Signal not found.
to the respective two isomers 13C NMR a gradient selected compound 3g in CDCl3 solution, similar to the findings in
2D HMBC18 spectra were recorded. In the case of C-6 the respective solution IR spectrum.
coupling with the protons of the alicycle was detected, but
1
In the H NMR spectra of the 2-amino substituted com-
not for C-2. The chemical shift difference
(C-2) for the
pounds 3a,b, 9a,b the singlet in the 5.1 5.8 ppm region is
due to the NH2 group (CDCl3 solution). This fact, the sim-
ilarity with 13C NMR data of 3a,s, 9b (Tables 6, 7) and
the respective data for non-fluorinated derivatives of
2-aminopyrimidines7,13 led to the assumption, that
products of 2-polyfluoracyl cycloalkanones and guani-
dine derivatives preferred the 2-aminopyrimidine C form
in solution, independent of the solvent nature, the chain
length of the polyfluoroalkyl substituent and the presence
of an arylidene substituent.
two forms were found to be 12.8 (3f) and 14.3 ppm (3g)
(Table 6) and was regarded as indicative to assign the
structure of the tautomers in DMSO-d6 solution. The dif-
ference is too large for the presence of isomers D and E,
where the C-2 nuclei have a very similar electronic envi-
ronment. Consequently one of the thiolactams D or E and
the mercaptopyrimidine form C are present. Analogous to
the IR investigation 2-methylthiopyrimidine 3k with a
fixed pyrimidine structure was used as a reference com-
pound assigning the sets of signals. The comparison
showed that the C values for the respective carbon nuclei
of 3k and those for the less abundant tautomers of 3f,g
were similar (Table 6) indicating a mercaptopyrimidine
structure C. The same applies for the only tautomer of
The structures of the compounds 3c, 9d g in DMSO-d6
have been investigated through DPFGSE NOE experi-
ments.19 In 3c the NOE effect has been found for the
"acidic" proton ( = 12.43) and the "aliphatic" CH2 group
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PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines
1743
Conclusion
In conclusion, new pyrimidine derivatives have been ob-
tained by reacting 2-polyfluoroacyl cycloalkanones with
N C N binucleophiles. The product yield decreases with
increasing length of the RF substitutent. From 2-polyfluo-
roacyl cycloalkanones and thiourea new compounds were
obtained, which prefer in the solid state the thiolactam and
in CDCl3 solution the mercaptopyrimidine form. In
DMSO-d6 solutions the thiolactam (major) and the mer-
capto pyrimidine isomer (minor) were present. 4-Polyflu-
oroalkylated pyrimidines having the nitrogen containing
substituent in 2-position are found as aminopyrimidines in
CDCl3 or DMSO-d6 solutions, however, in the solid state
pyrimidine and amidine form coexist. In the pyrimidine
derivatives synthesized from urea only one isomer, lactam
E, is present in solution and in the solid state.
Mass-spectra (EI, 70 eV) were carried out on a MAT 8200 spec-
trometer. NMR spectra were recorded in CDCl3 solutions on a Tesla
BS-587A instrument operating at 80 MHz (1H, TMS internal stan-
dard), 20.1 MHz (13C, TMS internal standard), 75.3 MHz (19F,
CFCl3 internal standard) and Bruker DPX-200 spectrometer operat-
ing at 200.1 MHz (1H), 50.3 MHz (13C) and 188.3 MHz (19F). For
Figure Molecular Structure of 9e (with two independent molecu-
les A and B, thermal elipsoids with 50% probability). Selected bond
distances [pm] and bond angles [°] for A: C(1) C(2) 152.8(3), C(2)
N(1) 131.4(3), C(2) C(9) 140.4(3), N(1) C(3) 137.3(3), C(3) O(1)
123.4(2), C(3) N(2) 137.9(3), N(2) C(4) 136.3(2), C(4) C(9)
138.9(3), C(4) C(5) 147.6(3), C(5) C(10) 134.8(3), C(6) C(7)
151.7(3), C(7) C(8) 151.8(3); N(1) C(2) C(9) 127.41(19), N(1)
C(2) C(1) 112.98(18), C(2) N(1) C(3) 117.05(17), N(1) C(3)
N(2) 117.72(17), C(3) N(2) C(4) 125.07(17), N(2) C(4) C(9)
117.19(18), C(5) C(4) C(9) 122.42(17), C(4) C(5) C(10)
120.17(17), C(5) C(6) C(7) 113.47(17), C(6) C(7) C(8)
109.86(19), C(7) C(8) C(9) 110.22(19), C(4) C(9) C(8)
120.29(18), C(5) C(10) C(11) 130.82(17)
2D HMBC:
(1H) = 14.1 s,
(13C) = 6.7 s, evolution period
90
90
n
for JC-H (long-range) 60 s. For DPFGSE NOE experiment:
90
(1H) = 14 s, mixing time 0.8 s. The IR spectra of the quinazolines
3 and 9 were recorded on a Specord-75 IR and Specord M-80 in the
area of 400 4000 cm 1 either in CHCl3 (1% solution) or as suspen-
sions in nujol or in fluorinated oils. Chromatography was performed
on a silica gel column (normal phase, MATREX, Grace GmbH).
2-Polyfluoroacylcycloalkanones 1a,c,21 d,h,22 e,23 f, i,24 b,g were
prepared by a Claisen-type condensation of cyclopentanone or cy-
clohexanone and the respective alkyl polyfloroacylates in the pres-
ence of LiH in anhyd. benzene.22 2-(E)-(p-diethylamino-
benzylidene)-6-trifluoroacetylcyclohexanone (10) was prepared ac-
cording to Ref. 14.
2-(2,2,3,3-Tetrafluoropropanoyl)cyclopentanone (1b)
Colorless liquid; yield: 65%; bp 95 96 °C/15 Torr.
1H NMR (major enol-tautomer): = 1.90 2.05 (m, 2 H, CH2), 2.48
(t, 2 H, CH2, 3JH-H = 8.0 Hz), 2.74 2.84 (m, 2 H, CH2), 6.05 (tt, 1 H,
CF2H, 2JH-F = 53.0 Hz, 3JH-F = 4.6 Hz), 13.40 (s, 1 H, OH).
upon reciprocal excitation. For compounds 9d g the
NOE effect for the "acidic" proton and the ortho protons
in the benzene ring were observed with excitation of pro-
ton at C-8. Models for the different pyrimidine tautomers
of 3c, 9d g show clearly, that only in the lactam E the
"acidic" NH protons and aliphatic CH2 (arylidene) in po-
sition 6 are close enough to show the NOE effect. These
findings are in agreement with the IR investigations and
data for non-fluorinated analogues.20 No NOE effect for
the protons at the heteroatom upon excitation of the CH2
protons in position 6 of heterocycle 3g and upon excita-
tion of the benzylidene proton in compound 9j was found,
thus indirectly supporting the assumptions made above.
Anal. calcd C, 45.29; H, 3.80; F, 35.82. Found: C, 45.18; H, 4.14;
F, 34.96.
2-(2,2,3,3,4,4,5,5-Octafluoropenthanoyl)cyclohexanone (1g)
Colorless liquid; yield: 51%; bp 109 110 °C/9 Torr.
1H NMR (major enol-tautomer): = 1.65 1.87 (m, 4 H, 2 CH2),
2.22 2.52 (m, 4 H, 2 CH2), 6.16 (tt, 1 H, CF2H, 2JH-F = 52.0 Hz, 3JH-
F = 5.5 Hz), 15.1 (br s, 1 H, OH).
Anal. calcd: C, 40.51; H, 3.09; F, 46.59. Found: C, 40.25; H, 2.76;
F, 46.84.
Compounds 3 and 7; General Procedure
Method A: To a mixture of 1 (5 mmol) and 2 or 5 (5 mmol) in propa-
2-nol (15 mL) (2c e were generated in situ from hydrochlorides
2c,d and hydrogen sulfate 2e by treatment with 7 mmol Et3N) were
added BF3 OEt2 (3 drops). The mixture was refluxed (see Table 1),
then cooled and diluted with H2O (100 mL).
Workup Procedures:
a) 3b,c,e,f,i,j,l, 7a,b: The mixture was extracted with CHCl3 (3 × 10
mL), the combined extracts were dried (MgSO4) and evaporated to
Scheme 4
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

1744
D. V. Sevenard et al.
PAPER
Scheme 5
give a solid residue which was recrystallized (Table 1) to afford
crystals 3b,c,j,l, 7a,b (colorless), 3e (pale yellow), 3f,i (yellow).
b) 3a,d,g,k,o t: The precipitate was dried and recrystallized to af-
ford crystals 3a (pale yellow), 3d,k,o,q t (colorless), 3g (yellow),
3p (pink).
Table 3 Selected IR Data of Compounds 3 and 9
Product
IR, (cm−1)
Pyrimidine
N H
C=N C=C =NH
C=Z
–
CZ H
NH2
3la
1415, 1460, 1545, 1565
–
–
–
–
–
3ha
3hb
3ga
3gb
3aa
3ab
9ba
9bb
3ca
3cb
9ea
9fa
–
3076, 3168
1570
–
–
900
–
–
–
1415, 1445, 1545, 1575
–
–
2585
–
–
3060, 3160
1580
–
–
902
–
–
–
1420, 1462, 1558, 1580
–
–
2570
–
1420, 1456, 1552, 1582
1486, 3030, 3110
–
3472
–
–
–
–
–
–
–
–
–
–
1642, 3184, 3312
1424, 1456, 1556, 1582
–
–
–
–
1608, 3420, 3532
1425, 1500, 1540, 1586
1500
1505
–
3465
–
1610, 3190, 3310
1432, 1495, 1540, 1585
–
–
–
–
–
–
–
–
1585, 3405, 3510
–
–
–
–
–
1560, 2500–3050
1560, 2500–3050
1536, 3056, 3140
1544, 3056, 3140
1544
1620
1620
1600
1620 sh
1620 sh
1658
1664
1636
1646
1656
–
–
–
–
–
9fb
a Nujol or fluorinated oil.
b In CHCl3.
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines
1745
Table 4 1H NMR Data of Compounds 3 and 7
Prod-
1H NMR , J (Hz)
uct
(CH2)n+2
X
RF
3aa
3ab
3ba
3ca
3cb
3db
3ea
3fb
1.75 1.88 (m, 4 H), 2.69 2.76 (m, 4 H)
1.64 1.78 (m, 4 H), 2.56 2.68 (m, 4 H)
1.76 1.88 (m, 4 H), 2.8 (br s, 4 H)
5.8 (br s, 2 H)
6.86 (s, 2 H)
5.6 (br s, 2 H)
13.7 (br s, 1 H)
12.43 (s, 1 H)
12.4 (br s, 1 H)
13.9 (br s, 1 H)
14.5 (br s, 1 H)
6.23 (tt, 1 H, 2JH-F = 57.9, 3JH-F = 5.7)
1.79 1.93 (m, 4 H), 2.66 2.86 (m, 4 H)
1.66 (m, 4 H), 2.45 2.49 (m, 2 H), 2.62 (s, 2 H)
1.46 1.91 (m, 4 H), 3.11 3.53 (m, 4 H)
1.78 1.84 (m, 4 H), 2.72 2.89 (m, 4 H)
6.92 (tt, 1 H, 2JH-F = 51.8, 3JH-F = 5.9)
1.96 2.11 (m, 2 H), 2.80 (t, 2 H, 3JH-H = 6.6), 2.89
(t, 2 H, 3JH-H = 7.8)
3ga
1.76 1.92 (m, 4 H), 2.8 (br s, 2 H), 2.90 (t, 2 H,
9.5 (br s 1 H)
3JH-H = 5.7)
3gb,c
1. 1.57 1.71 (m, 4 H), 2.45 2.51 (m, 2 H), 2.63 2.75
(m, 2 H) 2. 1.71 1.81 (m, 4 H), 2.45 2.51
(m, 2 H), 2.76 2.85 (m, 2 H)
1. 14.2 (br s, 1 H)
2.d
3ha
3ia
1.77 1.90 (m, 4 H), 2.82 2.88 (m, 4 H)
1.76 2.90 (m, 8 H)
8.1 (br s, 1 H)
5.5 (br s, 1 H)
6.53 (tt, 1 H, 2JH-F = 52.8, 3JH-F = 5.6)
6.75 (tt, 1 H, 2JH-F = 52.8, 3JH-F = 5.7)
3ja
1.87 1.99 (m, 4 H), 3.04 3.16 (m, 4 H)
7.43 7.56 (m, 3 H),
8.31 8.43 (m, 2 H)
3kb
3la
1.81 (m, 4 H), 2.83 (m, 4 H)
2.52 (s, 3 H)
2.52 (s, 3 H)
2.52 (s, 3 H)
2.53 (s, 3 H)
1.81 1.93 (m, 4 H), 2.75 3.00 (m, 4 H)
1.75 1.98 (m, 4 H), 2.78 3.05 (m, 4 H)
1.76 1.92 (m, 4 H), 2.86 2.92 (m, 4 H)
1.92 2.30 (m, 2 H), 3.10 3.61 (m, 4 H)
6.54 (tt, 1 H, 2JH-F = 53.0, 3JH-F = 5.7)
6.24 (tt, 1 H, 2JH-F = 52.2, 3JH-F = 5.7)
3ma
3na
3ob
9.2, 9.9, 10.8 (3 br s,
all 1 H)
3pb
3qb
3rb
3sa
3tb
2.00 2.29 (m, 2 H), 2.89 3.21 (m, 4 H)
1.77 1.84 (m, 4 H), 2.47 2.88 (m, 4H)
1.79 1.82 (m, 4 H), 2.87 3.04 (m, 4 H)
1.81 1.98 (m, 4 H), 2.88 2.99 (m, 4 H)
1.75 1.79 (m, 4 H), 2.46 2.87 (m, 4 H)
1.78 1.82 (m, 4 H), 2.76 2.84 (m, 4 H)
1.77 1.81 (m, 4 H), 2.80 2.87 (m, 4 H)
9.2, 9.8, 11.0 (3 br s,
all 1 H)
6.88 (tt, 1 H, 2JH-F = 52.2, 3JH-F = 5.1)
9.1, 9. 1, 10.5 (3 br s,
all 1 H)
9.2, 9.8, 10.6 (3 br s,
all 1 H)
6.96 (tt, 1 H, 2JH-F = 52.0, 3JH-F = 5.5)
7.1, 8.7, 10.1 (3 br s,
all 1 H)
9.0, 9.7, 10.4 (3 br s,
all 1 H)
7ab
7bb
7.2, 8.1, 9.8 (3 br s,
all 1 H)
7.2, 8.0, 9.8 (3 br s,
all 1 H)
a In CDCl3.
b In DMSO-d6.
c Ratio 80:20.
d Signal not found.
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

1746
D. V. Sevenard et al.
PAPER
Table 5 19F NMR Data of Compounds 3 and 9
c) 3h,m,n: The mixture was extracted with CHCl3 (3 × 10 mL). The
combined extracts were dried (MgSO4) and evaporated to give a
residue which was purified by column chromatography (eluent:
CHCl3) and recrystallized to afford crystals 3h (yellow), 3m (color-
less) and 3n as a yellow oil (Table 1).
Product
3aa
19F NMR , J (Hz)
67.01 (s)
3ca
68.71 (s)
Method B: A mixture of 1c (1.30 g, 5.7 mmol) and hydrogen sulfate
2e (0.76 g, 4.4 mmol) in EtOH (20 mL) was refluxed (see Table 1),
then cooled and diluted with H2O (100 mL), extracted with CHCl3
(3 × 10 mL). The combined extracts were dried (MgSO4) and evap-
orated give a solid residue which was recrystallized (Table 1).
3cb
69.83 (t, 5JF-H = 1.1)
69.74 (unsymm.s)
68.35 (t, 5JF-H = 1.4)
68.44 (s), 68.41 (s)c
3fa
3gb
Method C: To a mixture of 1c (0.62 g, 3.2 mmol) and 0.50 g
(3.2 mmol) 4 in propan-2-ol (10 mL) were added BF3 OEt2 (3
drops). The mixture was refluxed (see Table 1), then cooled, diluted
with H2O (100 mL), extracted with CHCl3 (3 × 10 mL) and the com-
bined extracts were dried (MgSO4). Removal of the solvent gave a
solid residue which was recrystallized (Table 1).
3ga
3sb
126.71(m, 2 F), 123.11 (m, 2 F), 112.05 (t,
2 F, 4JF-F = 12.1), 82.01 (t, 3 F, 4JF-F = 10.3)
9bb
9da
9ea
9fb
67.75 (s)
Compounds 9; General Procedure
66.76 (s)
Method D: To a mixture of 3 (5 mmol) and 8 (5 mmol) in propan-2-
ol (15 mL) were added BF3 OEt2 (3 drops). The mixture was re-
fluxed (see Table 1), then cooled and diluted with H2O (100 mL).
66.86 (s)
69.07 (t, 5JF-H = 1.1)
66.93 (s)
Workup Procedures:
9ga
a) 9a,b,h: he mixture was extracted with CHCl3 (3 × 10 mL), the
combined extracts were dried (MgSO4) and evaporated to gave a
residue which was recrystallized to afford crystals 9a (colorless), 9b
(yellow), 9h (pale yellow);
a In DMSO-d6.
b In CDCl3.
c Ratio 80:20.
Table 6 13C NMR Data of Compounds 3
Prod-
13C NMR , J (Hz)
uct
(CH2)n+2
C-2
C-4
C-5
C-6
RF
3aa
22.18, 33.05 (both s), 22.70 (q,
161.78(q, 4JC-F
= 1.0)
152.79 (q,2JC-F
= 32.2)
115.34 (s)
171.0 (s)
122.58(q, 1JC-F
= 277.3)
5JC-F = 0.8), 23.35 (q, 4JC-F
=
2.4)
3cb
3ca
20.12, 21.55, 27.48 (3 s), 21.63
157.7 (q, 4JC-F
= 1.2)
161.64 (q,2JC-F
= 34.2)
111.21 (s)
161.15 (s)
120.02(q, 1JC-F
= 279.1)
(q, 4JC-F = 2.9)
20.85, 22.07, 28.5(3 s), 22.26
156.5 (br s)
159.37 (q, 2JC-F
= 31.9)
110.1 (br s)
163.6 (br s)
121.38(q, 1JC-F
= 278.9)
(q, 4JC-F = 2.5)
3fa,c
1. 22.69, 31.98 (both s), 28.33
(q, 4JC-F = 1.3) 2. 22.69, 34.45
(both s), 28.5 (br s)
1. 180.01 (s)
2. 167.20 (s)
1. 152.68 (q,
2JC-F = 35.2)
2. 149.49 (q,
2JC-F = 36.2)
121.08 (s)
130.99 (q,
3JC-F = 0.9)
1. 172.41 (s)
2. 182.63 (s)
1. 122.13 (q,
1JC-F = 277.3)
2. 121.65 (q,
1JC-F = 275.6)
3gb
21.19, 21.65, 31.60 (3 s), 23.07
171.41 (s)
153.15 (q, 2JC-F
= 32.0)
122.62 (s)
168.8 (br s)
120.88(q, 1JC-F
= 277.5)
(q, 4JC-F = 2.4)
3ga,d
1. 20.42, 21.50, 27.77 (3 s),
1. 179.41 (s)
2. 165.11 (s)
1. 154.86 (q,
2JC-F = 33.0)
2. 152.70 (q,
2JC-F = 33.8)
1. 116.23 (s)
2. 126.52 (s)
1. 163.07 (s)
2. 172.80 (s)
1. 121.28 (q,
1JC-F = 278.7)
2. 121.83 (q,
1JC-F = 277.2)
22.49 (q, 4JC-F = 2.4) 2. 21.74,
33.19 (both s), 23.81 (q, 4JC-F
2.0)
=
3ka,e
3sa,f
20.67, 32.12 (both s), 20.9 (br
167.9 (br s)
151.16 (q, 2JC-F
= 33.2)
122.85 (s)
124.89 (s)
170.45 (s)
173.25 (s)
121.08(q, 1JC-F
= 277.3)
s), 22.62 (q, 4JC-F = 2.4)
21.48, 33.57 (both s), 22.1 (br
155.17 (t, 4JC-F
= 1.1)
151.15 (t,
108.01
126.16 (ms)
s), 24.17 (t, 4JC-F = 5.0)
2JC-F = 24.3)
a In DMSO-d6.
b In CDCl3.
c Ratio 2:1.
d
Ratio 4:1.
e 13.25 (s, CH3).
f
181.69 (s, CS).
Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Syntheses of Novel 4-Polyfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines
1747
Table 7 13C NMR Data of Compounds 9
Prod-
uct
13C NMR , J(Hz)
(CH2)n+1
C-2
C-4
C-5
C-6
C-7
C-8
Ar + other signals
RF
9ba
22.48, 28.09
160.65
(s)
153.80 (q,
117.30
165.39
(s)
129.11
(s)
132.92
(s)
13.09 (s, CH3),
44.81 (s, CH2),
111.38, 124.04,
132.61, 147.87
(all s, C6H4)
122.13 (q,
(both s), 24.09
2JC-F = 32.8) (s)
1JC-F = 276.5)
(q, 4JC-F = 2.3)
9eb
22.12, 27.37
(both s), 23.7
(br s)
161.92
(s)
155.57 (q,
117.8
164.2
(br s)
130.85
(s)
132.61
(s)
56.09 (s, CH3),
114.93, 129.10,
132.52, 160.22
(all s, C6H4)
122.09 (q,
2JC-F = 31.0) (br s)
1JC-F = 276.7)
9fb
21.18, 26.30
161.14
(s)
154.79 (q,
117.32
163.05
(s)
127.97
(s)
131.53
(s)
128.28, 129.69,
132.19, 135.73
(all s)
121.44 (q,
(both s), 22.75
2JC-F = 33.0) (s)
1JC-F = 292.0)
(q, 4JC-F = 2.4)
9gb
22.18, 27.08
(both s), 23.8
(br s)
162.8
(br s)
155.81 (q,
119.3
164.2
(br s)
135.6
(br s)
127.88,
130.70,
131.87
128.86, 130.39,
134.36, 134.91,
(all s, C6H4, C–8)
122.04 (q,
2JC-F = 34.5) (br s)
1JC-F = 277.4)
9jb
26.52, 29.28
(both s)
180.27
(br s)
150.93 (q,
123.43
165.38
(s)
126.91
(s)
134.93
(s)
13.35 (s, CH3),
44.75 (s, CH2),
112.38, 123.02,
133.71, 149.55
(all s, C6H4)
121.40 (q,
2JC-F = 33.5) (s)
1JC-F = 277.1)
a In CDCl3.
b In DMSO-d6.
b) 9c g,i,j: The precipitate was dried and recrystallized to afford
crystals 9f,g (pale yellow), 9c,d,j (red), 9e,i (yellow);
tropically and the position of the hydrogen atoms were calculated as
a riding model. An absorbtion correction was not applied. The
1
weighting scheme was w
=
2(Fo)2 + (0.0618P)2 + 1.1150P with
c) 9k: The mixture was extracted with CHCl3 (3 × 10 mL) and the
combined extracts were dried (MgSO4). Evaporation of the solvent
gave a residue which was purified by column chromatography (elu-
ent: CHCl3) and recrystallized to afford pale yellow crystals (Table
1).
P = 1/3(Fo2 + 2Fc2). Goodness of fit at F2 1.020; final R values
[I>2 (I)], R1 = 0.0512, wR2 = 0.1129; R value (all reflections)
R1 = 0.1044, wR2 = 0.1955.
Method E: To a mixture of guanidine hydrochloride (0.15 g,
1.6 mmol) and Et3N (0.18 g, 1.8 mmol) in propan-2-ol (15 mL) was
added 10 (0.55 g, 1.6 mmol) and BF3 OEt2 (3 drops). The mixture
was refluxed, then cooled, diluted with H2O (100 mL) and extracted
with CHCl3 (3 × 10 mL). The combined extracts were dried
(MgSO4) and evaporated to give a residue which was crystallized
from hexane, washed with warm hexane (5 mL) and recrystallized
(Table 1)
Acknowledgement
We gratefully acknowledge the financial support of the Deutsche
Forschungsgemeinschaft (Grant 436 RUS 113/445/0) and generous
gifts of chemicals from Dr. K.-H. Hellberg, Solvay Fluor und Deri-
vate GmbH, Hannover, Germany. Inge Erxleben and Dr. Peter
Schulze are thanked for recording mass spectra. We also thank Dr.
Lyudmila N. Bazhenova and coworkers, Institute for Organic Syn-
thesis, Ural Branch, Russian Academy of Sciences, Ekaterinburg
(Russian Federation) for carrying out elemental analyses.
X-Ray Crysatal Data of 9e
The X-ray structural analysis of 9e (single crystal crystallized from
a DMF, yellow prisms, C17H15F3N2O2 (336.31); 0.8 × 0.7 × 0.6
mm3, triclinic P 1 with a = 1066.40(10), b = 1190.50(10),
References
c = 1210.10(10)
pm,
= 103.930(10)o,
= 91.430(10)°,
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Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis 2000, No. 12, 1738–1748 ISSN 0039-7881 © Thieme Stuttgart · New York