Treatment of polyfluoro-1,1-dihydroalkyl sulfones with sodium cyanate and triethylamine: A new method for the synthesis of 6-(polyfluoroalkyl)uracils

Article abstract of DOI:10.1002/1099-0690(200205)2002:10<1619::AID-EJOC1619>3.0.CO;2-8

Polyfluoro-1,1-dihydroalkyl benzyl sulfones 1 reacted with sodium cyanate in the presence of Et₃N to give triethylammonium salts of uracil derivatives 2. The structure of 2b was established by X-ray determination. Acidification of compounds 2 with aqueous HCl gave 5-(benzylsulfonyl)-6-(polyfluoroalkyl)pyrimidine-2,4(1H,3H)-diones 3. Alkylation of compounds 3 with CH₃I afforded products methylated at N-2, confirmed by X-ray diffraction. Treatment of 3 with PCl₅ gave dichloropyrimidines 7. The chlorine atoms in compounds 7 with polyfluoroalkyl substituents of different lengths showed differing reactivities in reactions with ammonia and methanol. The sites of substitution of chlorine atoms in 7 were elucidated by X-ray studies. Direct amination of 3 occurred together with desulfonylation on heating in HMPA, with formation of 6-(polyfluoroalkyl)-substituted 2,4-bis(dimethylamino)pyrimidines 13. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200205)2002:10<1619::AID-EJOC1619>3.0.CO;2-8

FULL PAPER
Treatment of Polyfluoro-1,1-dihydroalkyl Sulfones with Sodium Cyanate and
Triethylamine: A New Method for the Synthesis of 6-(Polyfluoroalkyl)uracils
Vadim M. Timoshenko,[a] Yarema V. Nikolin,[a] Alexander N. Chernega,[a] and
Yuriy G. Shermolovich*[a]
Keywords: Cyanate / Cyclizations / Desulfonylation / Fluorine / Nitrogen heterocycles
Polyfluoro-1,1-dihydroalkyl benzyl sulfones 1 reacted with
pounds 7 with polyfluoroalkyl substituents of different
sodium cyanate in the presence of Et3N to give triethylam- lengths showed differing reactivities in reactions with ammo-
monium salts of uracil derivatives 2. The structure of 2b was nia and methanol. The sites of substitution of chlorine atoms
established by X-ray determination. Acidification of com-
in 7 were elucidated by X-ray studies. Direct amination of 3
pounds 2 with aqueous HCl gave 5-(benzylsulfonyl)-6-(poly-
occurred together with desulfonylation on heating in HMPA,
fluoroalkyl)pyrimidine-2,4(1H,3H)-diones 3. Alkylation of with formation of 6-(polyfluoroalkyl)-substituted 2,4-bis(di-
compounds 3 with CH3I afforded products methylated at N-
2, confirmed by X-ray diffraction. Treatment of 3 with PCl5
gave dichloropyrimidines 7. The chlorine atoms in com-
methylamino)pyrimidines 13.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
trialkylammonium salts of triazoles.[14] In this paper we re-
port on the treatment of sulfones 1 with sodium cyanate to
afford 6-polyfluoroalkyl-substituted uracils, and some
chemical properties of the compounds obtained.
The pyrimidine framework is widespread in nature; there
are many biologically and physiologically active compounds
that incorporate its nucleus. Pyrimidine derivatives have
therefore been extensively studied and great attention paid
to the development of methods for their synthesis,[1] espe-
cially of uracils Ϫ universal synthetic intermediates for the
obtainment of various heterocycles with pyrimidine rings.[2]
One goal of these investigations focused on the synthesis of
pyrimidine compounds with polyfluoroalkyl substitu-
ents.[3,4]
The general methods for the synthesis of fluorinated de-
rivatives of pyrimidines consist either of direct polyfluorin-
ation of uracils[5Ϫ7] or of the use of acyclic fluorine-con-
taining building blocks. The most used building blocks are
trifluoromethacrylonitrile,[8] ethyl trifluoroacetate,[9] and
fluorinated derivatives of aminocrotonic acid[10] or its struc-
tural analogues.[11]
Results and Discussion
We have found that treatment of polyfluoro-1,1-dihy-
droalkyl sulfones with sodium cyanate in the presence of
triethylamine affords triethylammonium salts of uracils 2,
which are easily converted into uracils 3 by treatment with
hydrochloric acid (Scheme 1). Compounds 3 can also be
obtained without isolation of salts 2, by immediate acid-
ification of the reaction mixture with hydrochloric acid. The
optimal molar ratio of reagents for production of uracils 3
in high yields was established to be sulfone 1/Et3N/Na-
OCN ϭ 1:1:2.
In previous works we have reported on the preparation
and properties of polyfluoro-1,1-dihydroalkyl sulfones 1 Ϫ
new reagents for the synthesis of fluorine-containing com-
pounds. We have described the application of sulfones 1 for
the preparation of enamines, imines, and ketones,[12] and of
hydrazones, osazones and pyrazoles.[13] In the presence of
tertiary amines, sulfones 1 react with sodium azide to give
[a]
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine,
Murmanskaya Str. 5, Kiev 02094, Ukraine
Fax: (internat.) ϩ 38-44/573-2643
E-mail: sherm@ukrpack.net
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Scheme 1. Synthesis of compounds 3a and 3b
Eur. J. Org. Chem. 2002, 1619Ϫ1627  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0510Ϫ1619 $ 20.00ϩ.50/0
1619

V. M. Timoshenko, Y. V. Nikolin, A. N. Chernega, Y. G. Shermolovich
FULL PAPER
˚
The structure of compound 2b was established by single-
crystal X-ray diffraction (Figure 1, Table 1). It was found
that, in the solid state, the compound comprises a pyrimidi-
nium anion and an HNEt3 cation, connected by the rela-
tively strong[15] N(4)ϪH(4)···O(2) hydrogen bond. In turn,
two anions are bound in the centrosymmetric dimer by the
pair of N(3)ϪH(3)···O(1Ј) intermolecular hydrogen bonds.
The N(1)C(2)N(3)C(4)C(5)C(6) heterocycle is planar within
Table 1. Comparison of selected bond lengths [A] and angles [°] in
2b, 5a, 8a, and 9b
2b
5a
8a
9b[a]
1.426(8)
S(1)ϪO(3)
S(1)ϪO(4)
S(1)ϪC(5)
S(1)ϪC(7)
N(1)ϪC(2)
C(2)ϪN(3)
N(3)ϪC(4)
C(4)ϪC(5)
C(5)ϪC(6)
C(6)ϪN(1)
C(2)ϪO(1)
C(4)ϪO(2)
1.429(2)
1.431(2)
1.749(2)
1.781(2)
1.364(3)
1.365(3)
1.372(3)
1.435(3)
1.392(3)
1.323(3)
1.235(3)
1.237(2)
1.441(2)
1.439(2)
1.745(2)
1.790(3)
1.356(4)
1.384(3)
1.398(3)
1.433(4)
1.392(3)
1.323(3)
1.234(3)
1.228(3)
1.435(2)
1.441(2)
1.770(2)
1.788(3)
1.316(3)
1.308(3)
1.354(3)
1.426(3)
1.389(3)
1.340(3)
1.728(2)[b]
1.336(3)[c]
1.424(8)
1.795(11)
1.803(13)
1.299(15)
1.314(16)
1.321(14)
1.374(14)
1.380(15)
1.342(14)
1.347(16)
1.714(12)[d]
˚
0.078 A, the benzene ring being twisted out of this plane
by 21.7°.
C(6)N(1)C(2) 117.8(2)
N(1)C(2)N(3) 118.4(2)
C(2)N(3)C(4) 125.6(2)
N(3)C(4)C(5) 114.5(2)
C(4)C(5)C(6) 116.5(2)
C(5)C(6)N(1) 125.6(2)
119.5(2)
119.0(2)
123.5(2)
114.8(2)
118.2(2)
123.9(2)
114.6(2)
129.6(2)
116.53(2)
119.6(2)
116.6(2)
122.9(2)
117.9(11)
125.2(12)
116.4(10)
124.0(10)
114.2(10)
121.7(11)
[a]
[b]
Average values for two independent molecules.
C(2)ϪCl(1)
[c]
[d]
distance. C(4)ϪN(4) distance. C(4)ϪCl(1) distance.
Figure 1. Crystal structure of the salt 2b; selected interatomic dis-
˚
tances [A] and angles [°]: N(4)···O(2) 2.791(2), H(4)···O(2) 1.93(3)
˚
A, N(4)H(4)O(2) 173(2)°; N(3)···O(1Ј) 2.776(2), H(3)···O(1Ј) 1.95(3)
˚
A, N(3)H(3)O(1Ј) 174(2)° (primed atoms are generated from the
asymmetric unit by the inversion center)
To explain the formation of 2 it should be taken into
account that sulfones 1 are dehydrofluorinated with triethy-
lamine to yield vinyl fluorides I, which is the first step for
Scheme 2. Proposed reaction sequence for the formation of salts
2a and 2b
all reactions of sulfones
1 that we have studied
previously.[12Ϫ14] This reaction step is reversible, and re- pure state do not react with sodium cyanate under the con-
moval of either triethylammonium hydrofluoride or vinyl ditions applied for production of salts 2 (CH3CN, 70 °C,
fluoride I from the region of the reaction pushes the equi- 6 h). The reaction of triethylammonium cyanate with vinyl
librium to the right (Scheme 2).
isocyanate II results in the formation of salt 2.
It should be noted that treatment of sulfones 1 with so-
Monitoring of the reactions by 19F NMR spectroscopy
showed that only signals of vinyl fluoride I,[16] starting sul- dium thiocyanate and Et3N under similar conditions af-
fone 1 (disappearing in the course of the reaction), and final forded vinyl isothiocyanates 4. No cyclization to the desired
salt 2 were observed in the reaction mixture, no other inter- corresponding thiouracil derivatives was observed
mediate products being detected. Further steps of the reac- (Scheme 3). The formation of 4 was confirmed by 1H NMR
tion should therefore be reasonably rapid. The reaction and IR spectroscopy, the latter revealing intense absorption
probably proceeds by nucleophilic substitution of the vi- bands, attributable to the isothiocyanato group, in the
nylic fluorine atom in I by the isocyanate group, with inter- 2050Ϫ2100 cmϪ1 region.
mediate formation of vinyl isocyanate II. Only triethylam-
The alkylation of the ammonium salts of substituted ur-
monium cyanate III, formed by reaction between sodium acils is well documented.[17] In contrast, triethylammonium
cyanate and triethylamine hydrofluoride, can be the source salts 2 do not react with alkyl halides or tosylates in boiling
of the isocyanate ion, since isolated vinyl fluorides I in the acetonitrile. Potassium salts, which can easily be prepared
1620
Eur. J. Org. Chem. 2002, 1619Ϫ1627

A New Method for the Synthesis of 6-(Polyfluoroalkyl)uracils
FULL PAPER
Scheme 3. Reaction between 1 and sodium thiocyanate
with equimolar amounts of KOH and 3, have low solubilit-
ies in most conventional solvents (in particular in the
CH3CN/CH3OH mixture used to study the reaction), which
makes their use difficult. However, application of 2 equiv. of
KOH affords the highly soluble dipotassium salts IV, which
easily react with methyl iodide at room temperature to pro-
vide K salts of monomethylated uracils 5. No further
methylation at the other possible site of 5 was observed
even on prolonged boiling of the reaction mixture. After
acidification of salts 5 with hydrochloric acid, N-methylur-
acils 6 were obtained (Scheme 4).
Figure 2. Crystal structure of the salt 5a; selected interatomic dis-
˚
tances [A] and angles [°]: K(1)···O(2) 2.624(2), K(1)···O(4) 2.885(2),
˚
K(1)···O(1Ј) 2.763(2), K(1)···O(3ЈЈ) 2.799(2) A, O(2)K(1)O(4)
61.4(2)° [primed and double primed atoms are connected with the
corresponding atoms in the asymmetric unit by the (Ϫx ϩ 2, Ϫy,
Ϫz ϩ 2) and (x Ϫ 3/2, Ϫy Ϫ 1/2, z Ϫ 1/2) operations]; hydrogen
atoms are omitted for clarity
Scheme 5. Synthesis of dichlorides 7a and 7b and their reactions
with ammonia
Scheme 4. Alkylation of compounds 3a, 3b with CH3I
An X-ray diffraction study of 5a was used to confirm the
formation of the K salt and to establish the site of al- group.[20] To examine this we studied reactions between
kylation. The crystal structure of 5a is shown in Figure 2, dichloropyrimidine 7 and ammonia and methanol.
selected bond lengths and angles are listed in Table 1. The
Treatment of 7a with 2 equiv. of gaseous ammonia (and
N(1)C(2)N(3)C(4)C(5)C(6) heterocycle is planar within also in excess) in diethyl ether afforded as the main reaction
˚
0.061 A, the benzene ring being twisted out of this plane product the derivative 4-amino-2-chloropyrimidine (8a),
by 41.2°. The main bond lengths and angles in anion 5a which, due to its low solubility, precipitated from the reac-
are quite similar to the corresponding values in 2b. Some tion mixture. An X-ray diffraction study confirmed the
shortening of the S(1)ϪC(5) bond in 2b and 5a in compar- formation of the 4-amino-substituted pyrimidine (Figure 3,
ison with 8a and 9b (see below) and with the standard for Table 1).
The
central
6-membered
ring
IV
2
[18,19]
˚
S ϪC(sp ) bond range 1.76Ϫ1.78 A
is apparently N(1)C(2)N(3)C(4)C(5)C(6) is almost planar: deviations
˚
connected with the delocalization of the negative charge not from least-square plane do not exceed 0.026 A. The N(4)H2
only over the pyrimidine heterocycle, but also towards the amino group is approximately coplanar to this plane (the
SO2Bzl group.
corresponding dihedral angle being only 8.2°), whereas the
One path for synthetic application of uracils is their C(8)ϪC(13) benzene ring is twisted out of this plane by
transformation into reactive dichloropyrimidines. Uracils 3 37.1°. The N(4) atom has a trigonal-planar bond configura-
react with PCl5 to give dichloropyrimidines 7 (Scheme 5).
The chlorine atoms in 7 are not equally reactive in nucleo- jugation, the exocyclic N(4)ϪC(4) bond is at 1.336(3) A sig-
tion [sum of the bond angles 360.0(6)°]. Because of n-π con-
˚
philic substitution reactions. A chlorine atom should be nificantly shorter than the standard value for the
2
2
[21]
˚
more active in the position in the heterocycle para to the N(sp )ϪC(sp ) single bond of 1.45 A.
As an interesting
nitrogen atom and ortho to the electronegative sulfonyl peculiarity of the molecular structure 9a, one should note
Eur. J. Org. Chem. 2002, 1619Ϫ1627
1621

V. M. Timoshenko, Y. V. Nikolin, A. N. Chernega, Y. G. Shermolovich
FULL PAPER
the strong[15] intramolecular H bond N(4)ϪH(41)···O(4) tains two independent molecules (A and B). The
‘‘assisted by resonance’’.[22]
N(1)C(2)N(3)C(4)C(5)C(6) cyclic systems in these molec-
ules are planar within 0.056 and 0.036 A, respectively, the
˚
benzene rings being almost coplanar with these planes (the
corresponding dihedral angles being only 2.5° in molecule
A and 14.8° in molecule B). All the bond lengths and angles
in 9b are unexceptional.[18,19]
Figure 3. A perspective view and labelling scheme for the molecule
8a; the main geometrical parameters of the intramolecular H bond:
˚
N(4)···O(4) 2.722(3), O(4)···H(41) 2.02(3) A, N(4)H(41)O(4)
135.2(2)°
In the case of compound 7b, with the more lipophilic
hexafluoropropyl substituent, treatment with ammonia pro-
ceeded in solution to give at least three products even with
Figure 4. A perspective view and labelling scheme for the independ-
only 2 equiv. of ammonia (1 equiv. as reagent and 1 equiv. ent molecule A of the compound 9b; hydrogen atoms are omitted
as base), as deduced from 19F NMR observations. Never-
for clarity
theless, an excess of ammonia afforded diaminopyrimidine
8b in high yield.
Comparison of the main geometric parameters of the
N(1)C(2)N(3)C(4)C(5)C(6) ring in anions 2b and 5a on one
In contrast, treatment of 7b with methanol in diethyl
hand, and in neutral molecules 8a and 9b on the other
ether in the absence of HCl acceptor afforded the product
(Table 1), shows that the N(1)ϪC(2), C(2)ϪN(3), and
N(3)ϪC(4) bonds are noticeably longer in the former struc-
tures, whereas the C(6)ϪN(1) bond is slightly shorter. In
9b, monomethoxy-substituted at C-2, in high yield
(Scheme 6).
this regard, one could suppose somewhat different types of
electron density delocalization in these two types of hetero-
cyclic systems.
Dichloride 7a reacted with an equimolar amount of
methanol under analogous conditions to give a mixture of
monosubstituted products V in a 1:1 ratio, as revealed by
1H NMR spectroscopy. Further substitution of other chlor-
ine atoms proceeded under more forcing conditions, at re-
flux with methanol in toluene in the presence of pyridine.
In the reactions between dichloride 7 and stronger nucle-
ophiles and bases Ϫ secondary alkylamines Ϫ the rates of
nucleophilic substitution of the chlorine atoms were equal-
ized and both chlorine atoms were easily substituted to fur-
nish 2,4-bis(dialkylamino)pyrimidines (11, 12) (Scheme 7).
2,4-Bis(dialkylamino)pyrimidines can be obtained by the
direct amination of uracils with amides of phosphorous or
phosphoric acids.[23] It has also been reported[24] that uracil
Scheme 6. Reactions of dichlorides 7a and 7b with methanol
derivatives with substituents R at the 5-position (specifically
The substitution at C-2 was confirmed by a single-crystal R ϭ Cl, Br, CH2OH) underwent a reductive elimination of
X-ray diffraction study of the compound 9b (Figure 4, R during these amination reactions. Studying the chemical
Table 1). It was found that the asymmetric unit of 9b con- properties of uracils 3, we found that heating of these com-
1622
Eur. J. Org. Chem. 2002, 1619Ϫ1627

A New Method for the Synthesis of 6-(Polyfluoroalkyl)uracils
FULL PAPER
tions with ammonia and methanol. Uracils 3 underwent
amination with simultaneous reductive desulfonylation on
treatment with hexamethylphosphoramide.
Experimental Section
Scheme 7. Reactions of dichlorides 7a and 7b with secondary
General Remarks: All solvents were purified by standard proced-
ures. Melting points were determined with a Boetius heating table
and values are uncorrected. NMR spectra were recorded with
Varian VXR 300 (299.9 MHz for 1H and 75.4 MHz for 13C) and
Varian Gemini 200 (188.1 MHz for 19F) machines. Chemical shifts
are given in ppm referenced to residual nondeuterated solvent sig-
nals in chloroform (δ ϭ 7.26 for 1H NMR and 77.16 for 13C NMR)
amines
pounds with an excess of hexamethylphosphoramide
(HMPA) at 215Ϫ220 °C resulted in the formation of 2,4-
bis(dimethylamino)-6-(polyfluoroalkyl)pyrimidines
(13)
that did not contain benzylsulfonyl groups. N,N-Dimethyl-
benzylsulfonamide was isolated from a reaction mixture
(Scheme 8). Thus, the replacement of the benzylsulfonyl
group by a hydrogen atom had taken place along with am-
ination. It is difficult to offer an acceptable mechanism for
this reaction; it is possible only to assume that the sources
of protons for the formation of the reduced pyrimidine
must be some acid impurity present in HMPA (or their pro-
duction during high-temperature reactions), because desul-
fonylation reactions with freshly distilled HMPA were no-
ticeably slowed down.
1
and dimethyl sulfoxide (δ ϭ 2.50 for H NMR and 39.52 for 13C
NMR). For 19F NMR spectra chemical shifts are reported in ppm
relative to an internal standard hexafluorobenzene (δ ϭ Ϫ162.9).
The degree of substitution at the C atoms was determined by APT
experiments. The progress of all reactions was monitored by 19F
NMR spectroscopy. Elemental analysis was performed in the Ana-
lytical Laboratory of the Institute of Organic Chemistry, NAS of
Ukraine.
General Procedure for the Preparation of Triethylammonium Salts
2a and 2b and 5-(Benzylsulfonyl)-6-(polyfluoroalkyl)pyrimidine-
2,4(1H,3H)-diones (3a and 3b): Et3N (1.1 mL, 7.8 mmol) was added
to a solution of sulfone 1 (7.4 mmol) in 15 mL of acetonitrile, the
mixture was stirred for 5 min and powdered NaOCN (1.0 g,
15.4 mmol) was added. The suspension was stirred at 70 °C for
4Ϫ6 h (monitoring by 19F NMR), and the hot mixture was filtered
through a layer of Celite. After cooling, a quantity of triethylam-
monium salt 2 precipitated, and was taken for analysis. The warm
solution of salt 2 in acetonitrile was acidified with conc. HCl (5
mL) and, after this had stood for 12 h, precipitated crystals were
filtered off, washed with water, dried, and recrystallized from eth-
anol.
1
Salt 2a: M.p. 230Ϫ232 °C (decomp.). H NMR ([D6]DMSO): δ ϭ
10.43 (broad s, 1 H, NH), 7.30 (m, 3 H, ArH), 7.20 (m, 2 H, ArH),
2
6.70 (t, JH,F ϭ 55.2 Hz, 1 H, CHF2), 4.56 (s, 2 H, CH2SO2), 3.39
(broad, NH ϩ H2O), 3.07 (q, 6 H, NCH2), 1.16 (t, 9 H, CH3). 19
F
2
NMR (CH3CN): δ ϭ Ϫ120.10 (d, JH,F ϭ 55.2 Hz, 2 F, CF2H).
Scheme 8. Desulfonylation of compounds 3, 11, and 12
2
13C NMR ([D6]DMSO): δ ϭ 163.19 (s, C4), 161.29 (t, JC,F
ϭ
21.1 Hz, C6), 158.77 (s, C2), 130.50 (s, ArC-ortho), 129.97 (s, ArC-
para), 128.07 (s, ArC-meta), 127.97 (s, ArC-ipso), 108.31 (t, 1JC,F ϭ
240.0 Hz, CF2H), 103.07 (s, C5), 59.55 (s, CH2SO2), 45.75 (s,
CH2N), 8.55 (s, CH3). C18H25F2N3O4S (417.464): calcd. C 51.79,
H 6.04, N 10.07, S 7.68; found C 51.62, H 6.00, N 10.14, S 7.34.
We have found that HMPA also acts as a desulfonylation
agent for dialkylamino-substituted pyrimidines 11 and 12,
which allowed us to obtain amino-6-(polyfluoroalkyl) de-
rivatives of pyrimidines 13 and 14 not substituted at the 5-
positions. Such desulfonylation reactions in the presence of
HMPA have not been described previously.
1
Salt 2b: M.p. 228Ϫ230 °C (decomp.). H NMR ([D6]DMSO): δ ϭ
10.64 (s, 1 H, NH), 7.29 (m, 3 H, ArH), 7.24 (m, 2 H, ArH), 7.06
2
3
(tt, JH,F ϭ 54.6, JH,F ϭ 6.0 Hz, 1 H, CHF2), 4.59 (s, 2 H,
CH2SO2), 3.37 (broad, NH ϩ H2O), 3.04 (q, 6 H, NCH2), 1.15 (t,
9 H, CH3). 19F NMR (CH3CN): δ ϭ Ϫ104.64 (m, 2 F, CF2),
Conclusion
Ϫ128.65 (m, 2 F, CF2), Ϫ135.87 (dm, 2JH,F ϭ 54.6 Hz, 2 F, CF2H).
In summary, we have found a new method for the syn-
thesis of 6-(polyfluoroalkyl)uracils, consisting of a ring-
closure reaction of fluorovinyl sulfones with 2 equiv. of tri-
ethylammonium cyanate, generated by treatment of 1,1-dihy-
dropolyfluoroalkyl sulfones 1 with sodium cyanate and trie-
thylamine. The chlorine atoms in dichloropyrimidines 7
formed from uracils 3, bearing polyfluoroalkyl substituents
2
13C NMR ([D6]DMSO): δ ϭ 163.72 (s, C4), 158.00 (t, JC,F
ϭ
29.8 Hz, C6), 156.86 (t, 4JC,F ϭ 2.8 Hz, C2), 130.80 (s, ArC-ortho),
129.96 (s, ArC-para), 128.02 (s, ArC-meta), 127.89 (s, ArC-ipso),
114.15 (tt, JC,F ϭ 265.8, JC,F ϭ 25.6 Hz, CF2CF2CF2H), 111.98
2
1
1
(tm, JC,F ϭ 265.8 Hz, CF2CF2CF2H), 108.48 (tt, JC,F ϭ 252.0,
2JC,F ϭ 27.6 Hz, CF2H), 103.94 (s, C5), 60.14 (s, CH2SO2), 45.83 (s,
CH2N), 8.69 (s, CH3). C20H25F6N3O4S (517.484): calcd. C 46.42, H
of different lengths, displayed differing reactivities in reac- 4.87, N 8.12, S 6.20; found C 45.87, H 4.85, N 8.15, S 6.58.
Eur. J. Org. Chem. 2002, 1619Ϫ1627
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V. M. Timoshenko, Y. V. Nikolin, A. N. Chernega, Y. G. Shermolovich
FULL PAPER
5-(Benzylsulfonyl)-6-(difluoromethyl)pyrimidine-2,4(1H,3H)-dione ([D6]DMSO): δ ϭ 7.29 (m, 3 H, ArH), 7.19 (m, 2 H, ArH), 6.69
2
(3a): Yield 81%, m.p. 257Ϫ260 °C. 1H NMR ([D6]DMSO): δ ϭ
12.15 (s, 1 H, NH), 12.4 (s, 1 H, NH), 7.37 (m, 3 H, ArH), 7.30
(m, 2 H, ArH), 7.17 (t, 2JH,F ϭ 52.5 Hz, 1 H, CHF2), 4.76 (s, 2 H,
(t, JH,F ϭ 55.3 Hz, 1 H, CHF2), 4.58 (s, 2 H, CH2), 3.13 (s, 3 H,
NCH3). 19F NMR (CH3CN): δ ϭ Ϫ120.27 (d, JH,F ϭ 55.3 Hz, 2
2
F, CF2H). 13C NMR ([D6]DMSO): δ ϭ 162.36 (s, C4), 158.91 (t,
CH2), 3.35 (broad, NH ϩ H2O). 19F NMR (CH3CN): δ ϭ Ϫ120.09 2JC,F ϭ 21.3 Hz, C6), 157.92 (s, C2), 130.35 (s, ArC-ortho), 129.52
2
(d, JH,F ϭ 52.5 Hz, 2 F, CF2H). 13C NMR ([D6]DMSO): δ ϭ
(s, ArC-para), 127.97 (s, ArC-meta), 127.92 (s, ArC-ipso), 108.21 (t,
160.15 (s, C4), 150.62 (t, JC,F ϭ 24.5 Hz, C6), 149.52 (s, C2), 1JC,F ϭ 241.0 Hz, CF2H), 102.23 (t, JC,F ϭ 2.7 Hz, C5), 59.37 (s,
2
3
131.04 (s, ArC-ortho), 128.83 (s, ArC-para), 128.65 (s, ArC-meta),
CH2), 26.76 (s, NCH3). The solution was concentrated, the solid
3
127.92 (s, ArC-ipso), 110.76 (t, JC,F ϭ 4.1 Hz, C5), 106.65 (t, residue was dissolved in 15 mL of warm water, and 5 mL of conc.
1JC,F ϭ 245.3 Hz, CF2), 60.20 (s, CH2). C12H10F2N2O4S (316.284): HCl was added to precipitate 6a. Yield 86%, m.p. 211Ϫ213 °C
calcd. C 45.57, H 3.19, N 8.86, S 10.14; found C 45.23, H 3.30, N
9.06, S 10.13.
(CH3CN/H2O, 2:1). 1H NMR ([D6]DMSO): δ ϭ 7.37 (m, 3 H,
2
ArH), 7.32 (m, 2 H, ArH), 7.13 (t, JH,F ϭ 52.3 Hz, 1 H, CHF2),
4.77 (s, 2 H, CH2), 3.36 (broad, NH ϩ H2O), 3.21 (s, 3 H, NCH3).
19F NMR (CH3CN): δ ϭ Ϫ120.07 (d, 2JH,F ϭ 52.3 Hz, 2 F, CF2H).
13C NMR ([D6]DMSO): δ ϭ 159.17 (s, C4), 149.52 (s, C2), 148.66
5-(Benzylsulfonyl)-6-(2,2,3,3,4,4-hexafluoropropyl)pyrimidine-
2,4(1H,3H)-dione (3b): Yield 90%, m.p. 253Ϫ255 °C. 1H NMR
([D6]DMSO): δ ϭ 11.84 (s, 1 H, NH), 7.34 (m, 3 H, ArH), 7.27
(m, 2 H, ArH), 6.87 (tt, 2JH,F ϭ 51.9, 3JH,F ϭ 5.9 Hz, 1 H, CHF2),
5.31 (broad, NH ϩ H2O), 4.74 (s, 2 H, CH2). 19F NMR (CH3CN):
δ ϭ Ϫ101.73 (m, 2 F, CF2), Ϫ122.00 (m, 2 F, CF2), Ϫ138.06 (dm,
2JH,F ϭ 51.4 Hz, 2 F, CF2H). 13C NMR ([D6]DMSO): δ ϭ 160.94
2
(t, JC,F ϭ 24.7 Hz, C6), 130.98 (s, ArC-ortho), 128.67 (s, ArC-
para), 128.47 (s, ArC-meta), 127.75 (s, ArC-ipso), 110.23 (t, 3JC,F ϭ
1
4.6 Hz, C5), 106.55 (t, JC,F ϭ 244.7 Hz, CF2H), 60.08 (s, CH2),
27.31 (s, NCH3). C13H12F2N2O4S (330.314): calcd. C 47.27, H 3.66,
N 8.48, S 9.71; found C 47.18, H 3.58, N 8.47, S 9.54.
2
(s, C4), 150.91 (s, C2), 148.86 (t, JC,F ϭ 28.6 Hz, C6,), 131.03 (s,
ArC-ortho), 128.41 (s, ArC-para), 128.26 (s, ArC-meta), 128.10 (s, 5-(Benzylsulfonyl)-6-(1,1,2,2,3,3-hexafluoropropyl)-3-methylpyr-
ArC-ipso), 113.32 (tm, 1JC,F ϭ 265.1 Hz, CF2CF2CF2H), 112.90 (s, imidine-2,4(1H,3H)-dione (6b): Compound 6b was obtained from
1
2
C5), 111.82 (tt, JC,F ϭ 264.6, JC,F ϭ 32.4 Hz, CF2CF2CF2H),
3b (1.0 g, 2.4 mmol), in the same manner as 6a. Yield 89%, m.p.
108.48 (tt, JC,F ϭ 250.8, JC,F ϭ 29.6 Hz, CF2H), 60.96 (s, CH2). 214Ϫ216 °C (CH3CN/H2O, 2:1). 1H NMR ([D6]DMSO): δ ϭ 7.32
C14H10F6N2O4S (416.304): calcd. C 40.39, H 2.42, N 6.73, S 7.70;
found C 40.44, H 2.50, N 6.65, S 7.92.
1
2
(m, 3 H, ArH), 7.25 (m, 2 H, ArH), 6.96 (tt, 2JH,F ϭ 52.5, 3JH,F ϭ
5.8 Hz, 1 H, CHF2), 4.69 (s, 2 H, CH2), 4.20 (broad, NH ϩ H2O),
3.18 (m, 3 H, NCH3). 19F NMR (CH3CN): δ ϭ Ϫ102.00 (m, 2 F,
1-(Benzylsulfonyl)-3,3-difluoro-2-isothiocyanatoprop-1-ene
(4a):
2
CF2), Ϫ122.35 (m, 2 F, CF2), Ϫ137.78 (dm, JH,F ϭ 52.5 Hz, 2 F,
Dried NaSCN (0.61 g, 7.5 mmol) was added to a solution of sul-
fone 1a (1.0 g, 3.7 mmol) and Et3N (0.52 mL, 3.7 mmol) in 10 mL
of acetonitrile. The solution was heated at 70 °C for 4 h and, after
cooling, was poured into water. The mixture was then extracted
with chloroform (2 ϫ 30 mL), the organic phase was dried with
Na2SO4, and the solvent was evaporated at reduced pressure. The
residue was extracted several times with boiling hexane. Compound
4a crystallized on cooling of the hexane solution. Yield 70%, m.p.
CF2H). 13C NMR ([D6]DMSO): δ ϭ 160.63 (s, C4), 151.90 (s, C2),
2
148.73 (t, JC,F ϭ 28.5 Hz, C6), 131.03 (s, ArC-ortho), 128.39 (s,
ArC-ipso), 128.28 (s, ArC-para), 128.19 (s, ArC-meta), 113.36 (tt,
1JC,F ϭ 264.9, 2JC,F ϭ 31.7 Hz, CF2CF2CF2H), 110.86 (tm, 1JC,F ϭ
264.9 Hz, CF2CF2CF2H), 110.46 (s, C5), 108.79 (tt, 1JC,F ϭ 251.8,
2JC,F ϭ 29.8 Hz, CF2H), 60.72 (s, CH2), 27.32 (s, NCH3).
C15H12F6N2O4S (430.334): calcd. C 41.87, H 2.81, N 6.51, S 7.45;
found C 41.83, H 2.80, N 6.58, S 7.57.
76Ϫ78 °C. IR (film): ν˜ ϭ 2050 cmϪ1 (NCS). 1H NMR (CDCl3):
2
δ ϭ 7.39 (m, 5 H, ArH), 6.29 (s, 1 H, CHϭ), 6.01 (t, JH,F
ϭ
5-(Benzylsulfonyl)-2,4-dichloro-6-(polyfluoroalkyl)pyrimidines
7.
54.3 Hz, 1 H, CHF2), 4.39 (s, 2 H, CH2). 19F NMR (CDCl3): δ ϭ General Procedure: PCl5 (6 mmol) was added to a suspension of
Ϫ120.91 (d, JH,F ϭ 54.3 Hz, 2 F, CF2H). NMR 13C (CDCl3): δ ϭ pyrimidinedione 3 (2 mmol) in 15 mL of benzene and the mixture
2
2
144.75 (s, CϭS), 136.05 (t, JC,F ϭ 25.8 Hz, HCF2C), 131.06 (s,
was heated under reflux for 12 h. After cooling, the solution was
ArC-ortho), 129.69 (s, ArC-para), 129.20 (s, ArC-meta), 126.74 (s, decanted and the solvents were evaporated under vacuum. The res-
3
1
ArC-ipso), 122.20 (t, JC,F ϭ 5.4 Hz, CHϭ), 109.80 (t, JC,F
ϭ
idue was triturated with cool hexane, and solid was filtered off and
249.5 Hz, CF2H), 62.27 (s, CH2). C11H9F2NO2S2 (289.304): calcd. crystallized from hexane.
C 45.67, H 3.14, N 4.84, S 22.16; found C 45.68, H 3.11, N 4.81,
Dichloride 7a: Yield 82%, m.p. 128Ϫ130 °C. 1H NMR (CDCl3):
S 21.78.
2
δ ϭ 7.36 (m, 3 H, ArH), 7.23 (m, 2 H, ArH), 6.89 (t, JH,F
ϭ
1-(Benzylsulfonyl)-1,1,2,2,3,3-hexafluoro-2-isothiocyanatopent-1-ene
(4b): By the procedure described above for 4a, compound 4b was
obtained as a red, viscous oil, which contained about 10% of im-
53.1 Hz, 1 H, CHF2), 4.72 (s, 2 H, CH2). 19F NMR (C6H6): δ ϭ
2
Ϫ118.36 (d, JH,F ϭ 53.1 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ
2
164.14 (t, JC,F ϭ 24.1 Hz, C6), 163.82 (s, C4), 163.31 (s, C2),
purities according to the NMR spectra. No special attempts were
130.96 (s, ArC-ortho), 130.39 (s, ArC-para), 129.63 (s, ArC-meta),
1
3
made to purify this product. IR (film): ν˜ ϭ 2100 cmϪ1 (NCS). H 129.44 (t, JC,F ϭ 3.2 Hz, C5), 125.46 (s, ArC-ipso), 107.26 (t,
NMR (CDCl3): δ ϭ 7.41 (m, 5 H, ArH), 6.45 (s, 1 H, CHϭ), 5.99 1JC,F
ϭ
246.2 Hz, CF2), 62.19 (s, CH2). C12H8Cl2F2N2O2S
2
3
(tt, JH,F ϭ 51.9, JH,F ϭ 5.0 Hz, 1 H, CHF2), 4.41 (s, 2 H, CH2).
(353.178): calcd. Cl 20.08, N 7.93, S 9.08; found Cl 20.01, N 7.95,
19F NMR (CDCl3): δ ϭ Ϫ116.34 (m, 2 F, CF2), Ϫ129.86 (m, 2 F, S 9.20.
CF2), Ϫ137.69 (dm, JH,F ϭ 51.9 Hz, 2 F, CF2H).
2
Dichloride 7b: Yield 94%, m.p. 108Ϫ110 °C. 1H NMR (CDCl3):
2
3
5-(Benzylsulfonyl)-6-(difluoromethyl)-3-methylpyrimidine-
2,4(1H,3H)-dione (6a): A solution of 3a (0.76 g, 2.4 mmol) in 5 mL
of CH3CN was added to a solution of KOH (0.25 g, 4.46 mmol) in
3 mL of methanol, followed by CH3I (0.14 mL, 2.25 mmol). The
δ ϭ 7.46Ϫ7.31 (m, 5 H, ArH), 6.47 (tt, JH,F ϭ 52.6, JH,F ϭ
5.5 Hz, 1 H, CHF2), 4.75 (s, 2 H, CH2). 19F NMR (C6H6): δ ϭ
Ϫ102.20 (m, 2 F, CF2), Ϫ125.89 (m, 2 F, CF2), Ϫ136.32 (dm,
2JH,F ϭ 52.6 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ 165.49 (s,
2
solution was allowed to stand at room temperature for 24 h. A C4), 161.79 (s, C2), 160.67 (t, JC,F ϭ 30.0 Hz, C6), 132.94 (s, C5),
quantity of K salt 5a precipitated as colorless crystals, which were
131.55 (s, ArC-ortho), 130.09 (s, ArC-para), 129.35 (s, ArC-meta),
124.68 (s, ArC-ipso), 113.62 (tt, JC,F ϭ 263.3, JC,F ϭ 30.8 Hz,
2
collected and used for X-ray and NMR analyses. 1H NMR
1624
Eur. J. Org. Chem. 2002, 1619Ϫ1627

A New Method for the Synthesis of 6-(Polyfluoroalkyl)uracils
FULL PAPER
1
CF2CF2CF2H), 111.24 (tm, JC,F ϭ 266.4 Hz, CF2CF2CF2H), and the mixture was heated under reflux for 4 h. The solvent was
1
2
108.75 (tt, JC,F ϭ 254.1, JC,F ϭ 30.8 Hz, CF2H), 62.78 (s, CH2). evaporated, and the residue was treated with CH3OH/H2O (10:1),
C14H8Cl2F6N2O2S (453.198): calcd. Cl 15.65, N 6.18, S 7.08; found
Cl 15.39, N 6.16, S 7.09.
filtered off, and recrystallized from methanol. Yield 72%, m.p.
134Ϫ136 °C. 1H NMR (CDCl3): δ ϭ 7.35Ϫ7.28 (m, 3 H, ArH),
2
7.20Ϫ7.16 (m, 2 H, ArH), 7.04 (t, JH,F ϭ 53.6 Hz, 1 H, CHF2),
5-(Benzylsulfonyl)-2-chloro-6-(difluoromethyl)pyrimidine-4-amine
(8a): Ammonia gas was passed at 5Ϫ10 °C for 1 h through a solu-
tion of dichloride 7a (0.71 g, 2 mmol) in 40 mL of diethyl ether,
and the solvent was evaporated. The remained solid was washed
with water and recrystallized. Yield 75%, m.p. 208Ϫ210 °C
4.55 (s, 2 H, CH2), 4.20 (s, 3 H, OCH3), 4.09 (s, 3 H, OCH3). 19F
NMR (toluene): δ ϭ Ϫ119.63 (d, 2JH,F ϭ 53.6 Hz, 2 F, CF2H). 13
C
NMR (CDCl3): δ ϭ 169.45 (s, C4), 166.67 (s, C2), 163.36 (t,
2JC,F ϭ 23.5 Hz, C6), 130.71 (s, ArC-ortho), 129.48 (s, ArC-para),
3
129.06 (s, ArC-meta), 127.33 (s, ArC-ipso), 112.55 (s, JC,F
ϭ
(CH3CN). 1H NMR ([D6]DMSO): δ ϭ 9.05 (broad, 1 H, NH),
1
3.8 Hz, C5), 107.41 (t, JC,F ϭ 243.1 Hz, CF2H), 62.19 (s, CH2),
56.24 (s, OCH3), 56.15 (s, OCH3). C14H14F2N2O4S (344.334): calcd.
C 48.83, H 4.10, N 8.14, S 9.31; found C 48.78, H 4.12, N 8.16,
S 9.34.
2
7.69 (broad, 1 H, NH), 7.42Ϫ7.31 (m, 5 H, ArH), 6.82 (t, JH,F
ϭ
53.1 Hz, 1 H, CHF2), 4.85 (s, 2 H, CH2). 19F NMR ([D6]DMSO):
δ ϭ Ϫ118.82 (d, JH,F ϭ 53.1 Hz, 2 F, CF2H). 13C NMR
2
2
([D6]DMSO): δ ϭ 162.52 (s, C4), 161.97 (s, C2), 160.80 (t, JC,F
ϭ
5-(Benzylsulfonyl)-2,4-bis(dialkylamino)-6-(polyfluoroalkyl)-
pyrimidines 11, 12. General Procedure: A solution of morpholine
(0.39 mL, 4.5 mmol) in 5 mL of benzene was added dropwise to
a solution of dichloropyrimidine 7 (1 mmol) (for dimethylamino
derivatives: dimethylamine was passed through a solution of
dichloride) in 15 mL of benzene and mixture was stirred for 0.5 h.
The solvent was evaporated, and the residue was carefully washed
with water, dried, and recrystallized.
22.9 Hz, C6), 131.37 (s, ArC-ortho), 129.12 (s, ArC-para), 128.71
3
(s, ArC-meta), 126.82 (s, ArC-ipso), 110.53 (t, JC,F ϭ 4.0 Hz, C5),
1
107.41 (t, JC,F
ϭ
242.1 Hz, CF2H), 60.78 (s, CH2).
C12H10ClF2N3O2S (333.737): calcd. Cl 10.62, N 12.59, S 9.61;
found Cl 10.59, N 12.51, S 9.81.
5-(Benzylsulfonyl)-6-(1,1,2,2,3,3-hexafluoropropyl)pyrimidine-2,4-
diamine (8b): Ammonia gas was passed at 5Ϫ10 °C for 0.5 h
through a solution of dichloride 7b (0.91 g, 2 mmol) in 40 mL of
diethyl ether, and the solvent was evaporated. The remained solid
was washed with water and recrystallized. Yield 94%, m.p.
198Ϫ200 °C (benzene). 1H NMR ([D6]DMSO): δ ϭ 7.70Ϫ6.90
(overlapped, 10 H, 5 ArH ϩ CHF2 ϩ 2 NH2), 4.55 (s, 2 H, CH2).
19F NMR (Et2O): δ ϭ Ϫ104.41 (m, 2 F, CF2), Ϫ129.07 (m, 2 F,
Compound 11a: Yield 82%, m.p. 121Ϫ122 °C (hexane/benzene, 4:1).
1H NMR (CDCl3): δ ϭ 7.33Ϫ7.14 (m, 5 H, ArH), 6.97 (t, 2JH,F ϭ
54.3 Hz, 1 H, CHF2), 4.42 (s, 2 H, CH2), 3.24 (m, 3 H, NCH3),
3.09 (m, 9 H, 3 NCH3). 19F NMR (CDCl3): δ ϭ Ϫ120.22 (d,
2JH,F ϭ 54.3 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ 163.59 (s,
C4), 163.10 (t, 2JC,F ϭ 21.8 Hz, C6), 159.97 (s, C2), 130.87 (s, ArC-
ortho), 128.78 (s, ArC-para), 128.62 (s, ArC-meta), 128.43 (s, ArC-
2
CF2), Ϫ136.65 (dm, JH,F ϭ 51.4 Hz, 2 F, CF2H). 13C NMR
2
([D6]DMSO): δ ϭ 162.65 (s, C4), 161.14 (s, C2), 156.81 (t, JC,F
ϭ
1
ipso), 109.72 (t, JC,F ϭ 241.5 Hz, CF2H), 102.59 (s, C5), 64.62 (s,
29.5 Hz, C6), 131.16 (s, ArC-ortho), 128.57 (s, ArC-para), 128.36 (s,
1
2
CH2), 42.34 (s, NCH3), 37.01 (s, NCH3). C16H20F2N4O2S
(370.414): calcd. C 51.88, H 5.44, N 15.13, S 8.66; found C 51.30,
H 5.68, N 15.12, S 8.26.
ArC-meta), 127.82 (s, ArC-ipso), 114.33 (tt, JC,F ϭ 264.0, JC,F
ϭ
1
26.2 Hz, CF2CF2CF2H), 111.97 (tm, JC,F
ϭ
260.3 Hz,
CF2CF2CF2H), 110.26 (tt, 1JC,F ϭ 251.9, 2JC,F ϭ 29.5 Hz, CF2H),
101.37 (s, C5), 62.04 (s, CH2). C14H12F6N4O2S (414.334): calcd. C
40.58, H 2.92, N 13.52, S 7.74; found C 40.75, H 3.02, N 13.53,
S 7.69.
Compound 11b: Yield 95%, m.p. 144Ϫ146 °C (hexane/benzene, 9:1).
1H NMR (CDCl3): δ ϭ 7.34 (m, 5 H, ArH), 6.56 (tt, 2JH,F ϭ 53.4,
3JH,F ϭ 6.2 Hz, 1 H, CHF2), 4.61 (s, 2 H, CH2), 3.19 (s, 6 H, CH3),
3.14 (broad d, 6 H, CH3). 19F NMR (C6H6): δ ϭ Ϫ106.73 (m, 2
5-(Benzylsulfonyl)-4-chloro-6-(1,1,2,2,3,3-hexafluoropropyl)-2-
methoxypyrimidine (9b): Methanol (1 mL) was added to a solution
of dichloropyrimidine 7b (0.91 g, 2 mmol) in 40 mL of diethyl ether,
and the solution was allowed to stand for 24 h. The solvent was
evaporated, and the residue was recrystallized from ethanol/H2O
(4:1). Yield 79%, m.p. 121Ϫ123 °C. 1H NMR (CDCl3): δ ϭ 7.37
(m, 5 H, ArH), 6.50 (tt, 2JH,F ϭ 52.8, 3JH,F ϭ 5.3 Hz, 1 H, CHF2),
4.70 (s, 2 H, CH2), 4.16 (s, 3 H, OCH3). 19F NMR (Et2O): δ ϭ
Ϫ102.25 (m, 2 F, CF2), Ϫ126.07 (m, 2 F, CF2), Ϫ136.41 (dm,
2JH,F ϭ 52.8 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ 165.95 (s,
C4), 163.96 (s, C2), 161.49 (t, 2JC,F ϭ 29.6 Hz, C6), 131.55 (s, ArC-
ortho), 129.75 (s, ArC-para), 129.18 (s, ArC-meta), 127.03 (s, C5),
2
F, CF2), Ϫ129.02 (m, 2 F, CF2), Ϫ136.30 (dm, JH,F ϭ 53.4 Hz, 2
F, CF2H). 13C NMR (CDCl3): δ ϭ 163.09 (s, C4), 159.19 (t, 2JC,F ϭ
27.8 Hz, C6), 158.59 (s, C2), 131.36 (s, ArC-ortho), 128.73 (s, ArC-
para), 128.63 (s, ArC-meta), 128.41 (s, ArC-ipso), 113.74 (tt,
1JC,F ϭ 261.0, 2JC,F ϭ 29.2 Hz, CF2CF2CF2H), 111.43 (tm, 1JC,F ϭ
1
2
265.1 Hz, CF2CF2CF2H,), 108.94 (tt, JC,F ϭ 252.6, JC,F
ϭ
29.2 Hz, CF2H), 104.46 (s, C5), 63.84 (t, J ϭ 5.1 Hz CH2), 41.65
(s, NCH3), 37.10 (s, NCH3). C18H20F6N4O2S (470.434): calcd. C
45.96, H 4.29, N 11.91, S 6.82; found C 45.97, H 4.24, N 11.89,
S 7.09.
Compound 12a: Yield 78%, m.p. 155Ϫ156 °C (hexane/benzene, 3:2).
1H NMR (CDCl3): δ ϭ 7.32Ϫ7.18 (m, 3 H, ArH), 7.23 (t, 2JH,F ϭ
54.4 Hz, 1 H, CHF2), 7.10 (m, 2 H, ArH), 4.38 (s, 2 H, CH2SO2),
1
2
125.62 (s, ArC-ipso), 113.75 (tt, JC,F ϭ 263.1, JC,F ϭ 29.0 Hz,
1
CF2CF2CF2H), 111.37 (tm, JC,F ϭ 265.9 Hz, CF2CF2CF2H),
1
2
108.85 (tt, JC,F ϭ 253.5, JC,F ϭ 29.7 Hz, CF2H), 62.74 (s, CH2),
57.32 (s, OCH3). C15H11ClF6N2O3S (448.777): calcd. Cl 7.90, N
6.24; found Cl 7.72, N 6.26.
3.90 (m, 2 H, NCH2CH2O), 3.75 (m, 10 H, NCH2CH2O), 3.41 (m,
2
4 H, NCH2CH2O). 19F NMR (C6H6): δ ϭ Ϫ119.13 (d, JH,F
ϭ
54.5 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ 165.35 (s, C4), 163.26
(t, JC,F ϭ 22.0 Hz, C6), 159.58 (s, C2), 130.53 (s, ArC-ortho),
2
5-(Benzylsulfonyl)-6-(difluoromethyl)-2,4-dimethoxypyrimidine
(10a): Methanol (1 mL) was added to a solution of dichloropyrimi-
dine 7a (0.71 g, 2 mmol) in 40 mL of diethyl ether. The solution
was allowed to stand for 24 h and the solvent was evaporated. The
residue, as indicated by NMR spectroscopic data (two sets of sig-
nals in a 1:1 ratio), was found to be a mixture of monomethoxy-
substituted chloropyrimidines V. This mixture was dissolved in 30
mL of toluene, methanol (1 mL) and pyridine (0.5 mL) were added,
128.76 (s, ArC-para), 128.49 (s, ArC-meta), 128.29 (s, ArC-ipso),
109.00 (t, JC,F ϭ 242.7 Hz, CF2H), 104.91 (s, C5), 66.66 (s,
CH2SO2), 66.65 (s broad, OCH2), 64.29 (s, OCH2), 51.82 (s,
NCH2), 44.33 (broad s, NCH2). C20H24F2N4O4S (454.484): calcd.
N 12.33, S 7.05; found N 12.26, S 7.28.
1
Compound 12b: Yield 80%, m.p. 187Ϫ189 °C (hexane/benzene, 5:1).
1H NMR (CDCl3): δ ϭ 7.33Ϫ7.21 (m, 5 H, ArH), 6.37 (tt, 2JH,F ϭ
Eur. J. Org. Chem. 2002, 1619Ϫ1627
1625

V. M. Timoshenko, Y. V. Nikolin, A. N. Chernega, Y. G. Shermolovich
FULL PAPER
52.8, 3JH,F ϭ 5.8 Hz, 1 H, CHF2), 4.56 (s, 2 H, CH2SO2), 3.73 (m, Compound 13a: This compound was prepared by the general pro-
10 H, NCH2CH2O), 3.63 (m, 6 H, NCH2CH2O). 19F NMR (C6H6): cedure described above, starting either from compound 3a (time of
δ ϭ Ϫ105.70 (m, 2 F, CF2), Ϫ127.68 (m, 2 F, CF2), Ϫ136.64 (dm,
reaction 1 h) or from compound 11a (time of reaction 3.5 h), and
2JH,F ϭ 52.8 Hz, 2 F, CF2H). 13C NMR (CDCl3): δ ϭ 163.61 (s, purified by distillation followed by low-temperature crystallization
2
2C4), 159.49 (t, JC,F ϭ 27.7 Hz, C6), 158.01 (s, C2), 131.09 (s, from pentane. Yield 71% (starting from 3a), 52% (starting from
ArC-ortho), 128.93 (s, ArC-para), 128.73 (s, ArC-meta), 128.32 (s,
11a), b.p. 60Ϫ66 °C (0.05 Torr), m.p. 36Ϫ38 °CϪ 1H NMR
1
2
2
ArC-ipso), 114.20 (tt, JC,F
ϭ
258.9, JC,F
ϭ
29.4 Hz (CDCl3): δ ϭ 6.26 (t, JH,F ϭ 55.8 Hz, 1 H, CHF2), 6.03 (s, 1 H,
CF2CF2CF2H), 110.08 (tm, JC,F ϭ 261.2 Hz, CF2CF2CF2H), C5-H), 3.14 (s, 6 H, CH3), 3.08 (s, 6 H, CH3). 19F NMR (CDCl3):
1
1
2
109.22 (tt, JC,F ϭ 253.8, JC,F ϭ 29.1 Hz, CF2H), 105.47 (s, C5),
δ ϭ Ϫ120.05 (d, 2JH,F ϭ 55.8 Hz, 2 F, CF2H). 13C NMR (CDCl3):
66.70 (s, OCH2), 66.56 (s broad, OCH2), 64.25 (t,25 J ϭ 4.1 Hz,
δ ϭ 163.56 (s, C4), 162.21 (s, C2), 159.72 (t, JC,F ϭ 24.7 Hz, C6),
2
1
3
CH2SO2), 50.71 (s, NCH2), 44.46 (broad s, NCH2). 113.95 (t, JC,F ϭ 241.0 Hz, HCF2), 87.03 (t, JC,F ϭ 4.1 Hz, C5),
C22H24F6N4O4S (554.504): calcd. N 10.10, S 5.78; found N 10.02,
S 5.85.
37.03 (s, CH3), 36.85 (s, CH3). C9H14F2N4 (216.230): calcd. C
49.99, H 6.53, N 25.91; found C 49.92, H 6.67, N 25.87.
2,4-Bis(dialkylamino)-6-(polyfluoroalkyl)pyrimidines 13, 14. General
Procedure: A mixture of compound 3/11/12 (2 mmol) and HMPTA
(3 mL) was heated at 215Ϫ220 °C for 1Ϫ4 h, the reaction being
monitored by 19F NMR spectroscopy. When the reaction was com-
plete, water (50 mL) was added and the mixture was extracted with
Compound 13b: This compound was prepared by the general pro-
cedure described above, starting either from compound 3b (time of
reaction 1 h) or from compound 11b (time of reaction 4 h), and
purified by crystallization from hexane/diethyl ether (4:1). Yield
78% (starting from 3b), 57% (starting from 11b), m.p. 70Ϫ72 °C.
2
3
CHCl3 (3ϫ20 mL). After drying with Na2SO4 and evaporation of 1H NMR (CDCl3): δ ϭ 6.65 (tt, JH,F ϭ 53.2, JH,F ϭ 6.2 Hz, 1
solvent, diethyl ether (10Ϫ15 mL) was added to the obtained res-
idue, and a large quantity of undissolved N-(dimethylamino)ben-
H, CHF2), 6.14 (s, 1 H, C5-H), 3.12 (s, 6 H, CH3), 3.10 (broad s,
6 H, CH3). 19F NMR (CDCl3): δ ϭ Ϫ118.91 (m, 2 F, CF2),
zylsulfonamide was filtered off [m.p. 98Ϫ100 °C, ref.[25] m.p. 101 Ϫ134.37 (m, 2 F, CF2), Ϫ138.81 (dm, 2JH,F ϭ 53.2 Hz, 2 F, CF2H).
°C. 1H NMR (CDCl3): δ ϭ 7.39 (m, 5 H, ArH), 4.24 (s, 2 H, CH2), 13C NMR (CDCl3): δ ϭ 163.39 (s, C4), 161.83 (s, C2), 155.82 (t,
2.72 (s, 6 H, NCH3)]. The mother liquor was concentrated and the
crude product was purified by crystallization as detailed below.
1
2
2JC,F ϭ 26.0 Hz, C6), 113.16 (tt, JC,F ϭ 255.2, JC,F ϭ 28.5 Hz,
1
CF2CF2CF2H), 111.02 (tm, JC,F ϭ 261.6 Hz, CF2CF2CF2H),
Table 2. Crystal data and structure refinement parameters for compounds 2b, 5a, 8a, and 9b
2b
5a
8a
9b
Empirical formula
Cell parameters
C20H25F6N3O4S
C13H11F2KN2O4S
C12H10ClF2N3O2S
C15H11ClF6N2O3S
˚
a [A]
10.956(2)
22.053(3)
11.049(2)
117.84(1)
2360.4(7)
4
9.206(2)
15.509(2)
10.594(3)
93.00(2)
1510.5(8)
4
7.986(2)
5.508(1)
30.956(7)
93.99(3)
1358.2(5)
4
18.757(3)
10.054(2)
19.649(7)
90
3705.3(1.6)
8 (two independent
molecules)
1.61
˚
b [A]
˚
c [A]
β [°]
3
˚
V [A ]
Z
Dcalcd. [g·cmϪ3
]
1.46
1.62
1.63
Crystal system
Space group
monoclinic
P21/a
19.18
517.49
1077
monoclinic
P21/n
48.13
368.40
757
monoclinic
P21/c
42.60
333.74
685
orthorhombic
Pca21
36.39
448.77
1812
µ [cmϪ1
M
]
F(000)
Crystal size [mm]
Index ranges
0.56 ϫ 0.56 ϫ 0.56
0 Ͻ h Ͻ 12
0 Ͻ k Ͻ 25
Ϫ12 Ͻ l Ͻ 12
70
0.31 ϫ 0.59 ϫ 0.65 0.12 ϫ 0.19 ϫ 0.37
0.12 ϫ 0.50 ϫ 0.63
Ϫ1 Ͻ h Ͻ 22
Ϫ1 Ͻ k Ͻ 11
Ϫ1 Ͻ l Ͻ 22
65
0 Ͻ h Ͻ 11
0 Ͻ k Ͻ 18
Ϫ12 Ͻ l Ͻ 12
70
0 Ͻ h Ͻ 9
0 Ͻ k Ͻ 6
Ϫ36 Ͻ l Ͻ 36
65
θmax [°]
No. of reflections:
collected
4363
3072
2709
4039
independent
in refinement
R(int)
No. of refined parameters
Obsd./var.
4009
3530 [I Ͼ 3σ(I)]
0.011
315
11.2
2773
2410 [I Ͼ 3σ(I)]
0.021
208
11.6
2251
1875 [I Ͼ 3σ(I)]
0.034
199
9.4
3165
1984 [I Ͼ 2σ(I)]
0
395
5.0
Final R indices
R
Rw
0.043
0.045
1.097
0.055
0.065
1.115
0.036
0.040
1.127
0.063
0.063
1.193
GOF
Weighting coefficients
2.10, Ϫ0.60, 0.93, Ϫ0.67 4.13, 2.61, 2.88
0.32/Ϫ0.32 0.46/Ϫ0.73
1.13, 0.05, 0.68, Ϫ0.16, 0.11 1.42, 0.78, 0.79, 0.16, 0.41
Largest peak/hole [e·cmϪ3
]
0.22/Ϫ0.34
0.27/Ϫ0.24
1626
Eur. J. Org. Chem. 2002, 1619Ϫ1627

A New Method for the Synthesis of 6-(Polyfluoroalkyl)uracils
FULL PAPER
108.71 (tt, 1JC,F ϭ 253.7, 2JC,F ϭ 29.0 Hz, HCF2), 88.98 (t, 3JC,F ϭ
5.7 Hz, C5), 37.04 (s, CH3), 36.80 (s, CH3). C11H14F6N4 (316.250):
calcd. C 41.78, H 4.46, N 17.72; found C 41.70, H 4.60, N 17.78.
(The pyrimidines), suppl. 2, John Wiley & Sons, New York,
1985.
H. Wamhoff, J. Dzenis, K. Hirota, Adv. Heterocycl. Chem.
1992, 55, 129Ϫ159.
M. J. Silvester, in: Advances in Heterocyclic Chemistry (Ed.: A.
R. Katritzky), Academic Press, New York, London, 1994, p.
1Ϫ40.
D. V. Sevenard, O. G. Khomutov, O. V. Koryakova, V. V. Satta-
rova, M. I. Kodess, J. Stelten, I. Loop, E. Lork, K. I. Pashkev-
ich, G.-V. Röschenthaler, Synthesis 2000, 1738Ϫ1748.
H. Uno, T. Terakawa, H. Suzuki, Synthesis 1989, 381Ϫ382.
O. D. Gupta, B. Twamley, R. L. Kirshmeier, M. Schreeve, J.
Fluorine Chem. 2000, 106, 199Ϫ204.
[2]
[3]
Compound 14a: This compound was prepared by the general pro-
cedure described above, starting from compound 12a (time of reac-
tion 4 h), and purified by crystallization from hexane/diethyl ether
[4]
1
(4:1). Yield 47%, m.p. 117Ϫ119 °C. H NMR (CDCl3): δ ϭ 6.26
2
(t, JH,F ϭ 56.0 Hz, 1 H, CHF2), 6.14 (s, 1 H, C5-H), 3.75 (m, 12
H, NCH2CH2O), 3.61 (m, 4 H, NCH2CH2O). 19F NMR (CDCl3):
[5]
[6]
δ ϭ Ϫ119.99 (d, 2JH,F ϭ 56.0 Hz, 2 F, CF2H). 13C NMR (CDCl3):
2
δ ϭ 163.46 (s, C4), 161.55 (s, C2), 160.42 (t, JC,F ϭ 24.6 Hz, C6),
[7]
[8]
´
´
1
3
M. Medebielle, M. A. Oturan, S. Pinson, J.-M. Saveant, J. Org.
Chem. 1996, 61, 1331Ϫ1340.
113.50 (t, JC,F ϭ 242.1 Hz, HCF2), 88.29 (t, JC,F ϭ 3.7 Hz, C5),
66.92 (s, CH2O), 65.58 (s, CH2O), 44.30 (s, CH2N).
2
C. Heidelberger, D. Parsons, D. C. Remy, J. Am. Chem. Soc.
1962, 84, 3597Ϫ3598.
H. Gershon, A. T. Grefig, A. A. Scala, J. Heterocycl. Chem.
1983, 20, 219Ϫ223.
A. W. Lutz, S. H. Trotto, J. Heterocycl. Chem. 1972, 9,
513Ϫ522.
H.-B. Yu, W.-Y. Huang, J. Fluorine Chem. 1997, 84, 65Ϫ67.
Yu. G. Shermolovich, V. M. Timoshenko, V. V. Listvan, L. N.
Markovskii, Russ. J. Org. Chem. 1998, 34, 1112Ϫ1116.
V. M. Timoshenko, Ya. V. Nikolin, N. P. Kolesnik, Yu. G. Sher-
molovich, Zh. Org. Khim. (Russ.) 2001, 37, 666Ϫ673
V. M. Timoshenko, Ya. V. Nikolin, E. B. Rusanov, A. N. Cher-
nega, Yu. G. Shermolovich, Chem. Heterocycl. Compd. 2001,
4, 518Ϫ524.
C13H18F2N4O2 (300.300): calcd. C 51.99, H 6.04, N 18.66; found
C 51.83, H 6.09, N 18.57.
[9]
[10]
Compound 14b: This compound was prepared by the general pro-
cedure described above, starting from compound 12b (time of reac-
tion 4 h), and was crystallized from hexane/diethyl ether (7:1) after
standing at Ϫ20 °C overnight. Yield 64%, m.p. 131Ϫ133 °C. 1H
[11]
[12]
2
3
NMR (CDCl3): δ ϭ 6.39 (tt, JH,F ϭ 52.8, JH,F ϭ 6.1 Hz, 1 H,
CHF2), 6.23 (s, 1 H, C5-H), 3.73 (m, 12 H, NCH2CH2O), 3.62 (m,
4 H, NCH2CH2O). 19F NMR (CDCl3): δ ϭ Ϫ119.10 (m, 2 F, CF2),
Ϫ133.73 (m, 2 F, CF2), Ϫ138.58 (dm, 2JH,F ϭ 52.8 Hz, 2 F, CF2H).
13C NMR (CDCl3): δ ϭ 163.38 (s, C4), 161.44 (s, C2), 156.63 (t,
[13]
[14]
1
2
2JC,F ϭ 25.7 Hz, C6), 112.94 (tt, JC,F ϭ 256.0, JC,F ϭ 29.4 Hz,
[15]
[16]
L. N. Kuleshova, P. M. Zorkii, Acta Crystallogr., Sect. B 1981,
37, 1363Ϫ1366.
1
CF2CF2CF2H), 110.75 (tm, JC,F ϭ 262.3 Hz, CF2CF2CF2H),
108.37 (tt, 1JC,F ϭ 253.7, 2JC,F ϭ 29.2 Hz, HCF2), 90.42 (t, 3JC,F ϭ
5.3 Hz, C5), 66.88 (s, CH2O), 66.59 (s, CH2O), 44.49 (s, CH2N),
44.39 (s, CH2N). C15H18F6N4O2 (400.320): calcd. C 45.01, H 4.53,
N 14.00; found C 45.11, H 4.54, N 14.05.
A mixture of cis and trans isomers in a 1:5 ratio was observed
for 4a, and only a trans isomer [JH,F(trans) ϭ 30 Hz] for 4b.
J. Suwinski, K. Walczak, Synthesis 2001, 225Ϫ228.
F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G.
Orpen, R. Taylor, J. Chem. Soc., Perkin Trans. 2 1987, S1ϪS19.
V. A. Naumov, O. N. Kataeva, Molecular structure of organic
compounds of oxygen and sulfur, Nauka, Moscow, 1990, p.
113Ϫ128 (Russ.), Chem. Abstr. 1991, 114, 121381f.
D. J. Brown, in: Comprehensive Heterocyclic Chemistry (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon Press, New York, 1984,
vol. 3, p. 57Ϫ155.
M. Burke-Laing, M. Laing, Acta Crystallogr., Sect. B 1976,
32, 3216Ϫ3224.
V. Bertolasi, P. Gilli, V. Ferretti, G. Gilli, Acta Crystallogr.,
Sect. B 1995, 51, 1004Ϫ1015.
E. A. Arutyunyan, V. I. Gunar, S. I. Zav’yalov, Izv. Akad. Nauk
Ser. Khim. (Russ.) 1970, 4, 904Ϫ909.
E. A. Arutyunyan, V. I. Gunar, E. P. Gracheva, S. I. Zav’yalov,
Izv. Akad. Nauk Ser. Khim. (Russ.) 1969, 3, 655Ϫ662.
We cannot unambiguously explain the multiplicity of these sig-
nals; it may be a C-F coupling constant with fluorine nuclei
for one of CF2 groups. This is a feature of (dialkylamino)pyri-
midines 11b and 12b with long polyfluoroalkyl substituents, the
corresponding derivatives with shorter polyfluoroalkyl sub-
stituent 11a and 12a show singlets for CH2SO2 group carbon
nuclei.
C. K. Ingold, I. H. Ingold, F. R. Show, J. Chem. Soc. 1927, 818.
A. C. T. North, D. C. Phillips, F. S. Mathews, Acta Crystallogr.,
Sect. C 1968, 24, 351Ϫ359.
J. R. Carruthers, D. J. Watkin, Acta Crystallogr., Sect. C 1979,
35, 698Ϫ699.
[17]
[18]
[19]
[20]
X-ray Crystallographic Study: Crystal data, data collection and pro-
cessing parameters are given in Table 2. All crystallographic meas-
urements were performed at 20 °C with a CAD-4 EnrafϪNonius
diffractometer (Cu-Kα radiation) using ω-2θ scan mode (the ratio
of the scanning rates ω/2θ ϭ 1.2). All data were corrected for Lor-
entz and polarization effects and an empirical absorption correc-
tion based on azimuthal scan data[26] was applied. The structures
were solved by direct methods. Non-hydrogen atoms were refined
by full-matrix, least-squares techniques in the anisotropic (iso-
tropic/anisotropic for 9b) approximation. The Chebushev weighting
scheme[27] was used. All hydrogen atoms in 2b, 5a, and 8a were
located in the difference Fourier maps, in 9b they were placed in
calculated positions. All H atoms were included in the final refine-
ment with the fixed positional and thermal parameters. Only the
atoms H(3) and H(4) in 2b and H(41) and H(42) in 9b were refined
isotropically. The Flack test[28] was applied for the absolute config-
uration determinations of 9b [the enantiopole parameter was re-
fined to 0.11(8) using 2044 reflections with the nonaveraged Friedel
equivalents]. All structural calculations were carried out with the
CRYSTALS program package.[29] CCDC-166789 (2b), -166790
(5a), -166787 (8a), and -166788 (9b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
H. D. Flack, Acta Crystallogr., Sect. A 1983, 39, 876Ϫ879.
D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge,
CRYSTALS, Chemical Crystallography Laboratory, University
of Oxford, UK, 1996, issue 10.
Received November 5, 2001
[1]
D. J. Brown, The Chemistry of Heterocyclic Compounds, vol. 16
[O01535]
Eur. J. Org. Chem. 2002, 1619Ϫ1627
1627