A new synthetic route to polyalkoxypyrimidines based on the reaction of esters and methyl thiocyanate

Article abstract of DOI:10.1002/ejoc.200600222

The reaction of aliphatic esters with methyl thiocyanate and triflic anhydride affords substituted 4-alkoxy-2,6-bis(methylthio)pyrimidines with minor amounts of substituted S-methyl N-alkanoylthiocarbamates. The structure of the starting ester appears to

Full text of DOI:10.1002/ejoc.200600222

FULL PAPER
DOI: 10.1002/ejoc.200600222
A New Synthetic Route to Polyalkoxypyrimidines Based on the Reaction of
Esters and Methyl Thiocyanate
Antonio Herrera,[a] Roberto Martínez-Alvarez,*[a] Pedro Ramiro,[a] John Almy,[b]
Dolores Molero,[c] and Angel Sánchez[c]
Keywords: Heterocycles / Alkoxypyrimidines / Methyl thiocarbamates / Aromatic nucleophilic substitution / Cyclization /
Oxidation
The reaction of aliphatic esters with methyl thiocyanate and
triflic anhydride affords substituted 4-alkoxy-2,6-bis(methyl-
thio)pyrimidines with minor amounts of substituted S-methyl
N-alkanoylthiocarbamates. The structure of the starting ester
appears to determine the ratio of final products. Methylthio
groups on the pyrimidine ring can be easily converted into
methylsulfonyl groups by oxidation. Controlled substitution
of one or both methylsulfonyl groups leads to the formation
of aminodialkoxy- and trialkoxypyrimidines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
We describe herein the facile synthesis of a variety of substi-
tuted mono-, di- and trialkoxypyrimidines.
Introduction
Alkoxypyrimidines derivatives are an important class of
heterocyclic compounds with applications in several dif-
ferent areas. Thus, 4-alkoxypyrimidines are used as the ba-
sis for the design of compounds as potential inhibitors cy-
clin-dependent kinases 1 and 2,[1] while dimethoxypyrim-
idines are important intermediates for the preparation of an-
tihypertensive and antithrombotic drugs.[2] Dimethoxypyr-
imidines are also employed as herbicides agents to control
plant growth[3,4] or fungicides.[5] Trialkoxypyrimidine deriv-
atives are versatile building blocks for the agrochemical in-
dustry. In particular, dialkoxypyrimidinyloxy salicylic acids
derivatives represent a new class of substances exhibiting
potent herbicide activity.[6,7]
The synthesis of polyalkoxypyrimidines derivatives often
involves tedious multi-step procedures using expensive or
toxic reagents and affording low yields.[8,9] Alternative
methods generally employ the displacement of chlorine
atoms from chloroazines derivatives.[1,10–12] Recently, 2,4-di-
methoxypyrimidine derivatives have been prepared from
uracils by Wittig olefination.[13]
Results and Discussion
The cocyclization of nitriles and ketones in the presence
of triflic anhydride was reported as an useful method to
prepare alkyl- and arylpyrimidines.[14] The extension of this
synthetic procedure to other carbonylic compounds leads
to variously substituted pyrimidines and other nitrogen-
containing rings.[15–21] The application of this methodology
to the reaction of aliphatic esters 1 with nitriles affords
the substituted 4-alkoxypyrimidines 2 in good yields
(Scheme 1).[18] Access to the polyalkoxypyrimidines 3 via
4-alkoxypyrimidines involves several steps, some requiring
harsh conditions. The importance of the di- and trialkoxy-
pyrimidines prompted us to explore a different path to these
target compounds.
In spite of their importance, there is no synthetic method
to prepare polyalkoxypyrimidines from readily available
starting materials with high yields in a few reaction steps.
[a] Departamento de Química Orgánica, Facultad de Ciencias
Químicas, Universidad Complutense,
28040 Madrid, Spain
Fax: +34-913944103
E-mail: rma@quim.ucm.es
[b] Department of Chemistry, California State University,
Stanislaus, Turlock, CA 95382, USA
Scheme 1.
[c] CAI de RMN, Universidad Complutense,
28040 Madrid, Spain
The reaction of the aliphatic esters 1 with two equiv. of
methyl thiocyanate in the presence of triflic anhydride
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Polyalkoxypyrimidines by the Reaction of Esters and Methyl Thiocyanate
FULL PAPER
(Tf2O) forms mainly 4-alkoxy-2,6-bis(methylthio)pyrim-
idines (4) with variable amounts of S-methyl alkanoylthio-
carbamates (5) (Scheme 2 and Table 1). When alkyl acetates
were used, S-methyl N-acetylthiocarbamate (5a) was the ex-
clusive product.
Scheme 2.
Table 1. 4-Alkoxy-2,6-bis(methylthio)pyrimidines 4 and S-methyl
N-alkanoylthiocarbamates 5.
R1
R2
Yield[a]
Yield[a]
H
H
Me
Bu
CH3(CH2)7
Ph
Me
Et
Pr
Et
Et
Et
Et
Pr
5a (58%)
5a (51%)
4b (78%)
4c (42%)
4d (45%)
4e (71%)
4f (69%)
5c (43%)
5d (42%)
6 (19%)
[a] Isolated product.
Scheme 3.
Formation of the pyrimidines and carbamates can be ex-
plained with a mechanism outlined in Scheme 3. Electro-
philic attack by Tf2O at one of the two oxygen atoms of the instability of the olefinic intermediate 9 compared with its
ester group leads to the alternative triflyloxycarbenium ion counterparts when R1 is an alkyl or phenyl group. Similar
7 or the triflyloxyoxonium ion 10. Theoretical calculations results were found in the study of the regioselectivity of the
using molecular mechanics (PM3 and AM1) within Hyper- reaction of aliphatic ketones and nitriles.[22]
chem v7.51 program show that 7 is more stable than inter-
On the other hand, the differences found in the product
mediate 10 (see Table 1 of Supporting Information). Inter- distributions when nitriles or thiocyanates are used are
mediate 7 is trapped by the thiocyanate forming a nitrilium likely to be controlled by the relative rates of reaction of
ion 8, which reacts with a second molecule of thiocyanate. these reagents with the intermediates 7 and 10. Hence, a
Elimination of TfOH and a subsequent cyclization affords less nucleophilic reagent leads to both pyrimidines and car-
the olefinic intermediate 9 which finally gives the pyrim- bamates.
idine 4.
It is interesting to note that the reaction of ethyl phenyl-
In the alternate path, intermediate 10 undergoes nucleo- acetate (1e) with methyl thiocyanate affords an isoquinoline
philic displacement of an alkyltriflate molecule (R2OTf) by derivative 6 as well as the corresponding alkoxypyrimidine
methyl thiocyanate to form the intermediate 11. In this case, 4e (Scheme 4). Isoquinolines are the main products of the
the absence of the TfO leaving group precludes the forma- reaction of alkyl phenylacetates with nitriles.[23] In this case,
tion of a double bond (as in 9); as a consequence, the in- the ethoxy isoquinoline formed from ring closure of the in-
volvement of a second molecule of nitrile is not needed. termediate 11 undergoes Tf2O-catalyzed transesterification
Basic hydrolysis during the work-up of the reaction leads with a second molecule of 1e, affording 6.
to the formation of the thiocarbamate 5. The elimination
The alkoxypyrimidines (4) and S-methylthio carbamates
of R2OTf was demonstrated by the finding that either ethyl (5) were easily separated by column chromatography. This
acetate or propyl acetate affords the same thiocarbamate 5a reaction can be used as a versatil tool to prepare two dif-
(Table 1). Apparently the nature of the R2 group does not ferent classes of substances. The thiomethyl group attached
play any role in this process.
to a pyrimidine ring can be only removed under harsh con-
The exclusive formation of the carbamates 5 when R1 = ditions.[24] However, the thiomethyl group can be easily oxi-
H (alkyl acetates) can be explained assuming the relative dized to methylsulfonyl, which is a better leaving group.
Eur. J. Org. Chem. 2006, 3332–3337
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3333

A. Herrera, R. Martínez-Alvarez, P. Ramiro, J. Almy, D. Molero, A. Sánchez
FULL PAPER
Scheme 6.
The reaction of 12 with an equimolecular amount of
sodium methoxide produces the corresponding methoxy de-
rivative 15, which can be converted into the dimethoxy de-
rivative 16 by reaction with an additional equivalent of so-
dium methoxide. The direct conversion of 12 into the 2,6-
dimethoxyderivative 15 is easily carried out using directly
two equivalents of the reagent (Scheme 7).
Scheme 4.
Oxidation of the alkoxypyrimidines (4) with mCPBA af-
fords the corresponding 4-alkoxy-2,6-bis(methylsulfonyl)-
pyrimidines (12) (Scheme 5 and Table 2).
Scheme 5.
Scheme 7.
In summary, we report a new synthetic route for the
Table 2. 4-Alkoxy-2,6-bis(methylsulfonyl)pyrimidines 12.
preparation of a variety of substituted aminoalkoxy-, di-
and trialkoxypyrimidines based on the reaction of esters
and methyl thiocyanate. This reaction also permits the
preparation of thiocarbamates from acetates.
Compound
Yield (%)[a]
12b
12c
12d
12e
12f
91
96
86
95
85
Experimental Section
[a] Yield of isolated product.
All reagents were commercial grade and were used as received un-
less otherwise indicated. Triflic anhydride was prepared from TfOH
and redistilled twice prior to use.[26,27] Solvents were distilled from
an appropriate drying agent before use. Reactions were monitored
by thin-layer chromatography. Column chromatography was per-
Methylsulfonyl pyrimidines are excellent synthetic inter-
mediates because they can undergo nucleophilic substitu-
tion with a variety of reagents under mild conditions.[25]
The displacement of one or both methylsulfonyl groups can formed using silica gel 60. Melting points were determined in a
Gallenkamp apparatus in open capillary tubes and are uncorrected.
The IR spectra were measured with a Shimadzu FTIR 8300 instru-
ment. NMR spectra were recorded with a Bruker DPX 300 and
be controlled either by the reaction conditions or by the
amount of the corresponding reagent. The methylsulfonyl
group at the C6 position can be first removed while the
substitution at the C2 position requires more rigorous con-
ditions. Thus, the reaction of 12 with ammonia affords the
corresponding aminopyrimidines 13. The remaining meth-
ylsulfonyl group cannot be removed with ammonia, but it
can be easily displaced with sodium methoxide leading to
the formation of 4-amino-2-methoxypyrimidines 14
(Scheme 6).
1
Bruker Avance AV 500 at 300 MHz for H and 75.47 MHz for 13C
and 500 MHz for 1H and 125.72 MHz for 13C, respectively. Chemi-
cal shifts are given in δ units (ppm) to residual CHCl3 (7.26 and
77.0 ppm, respectively) and DMSO (2.50 and 39.5 ppm, respec-
tively). J values are given in Hz. NMR assignments were ac-
complished with help of DEPT and 2D spectra. Mass spectra (EI)
were recorded with a HP 5989A quadrupole instrument at 70 eV
with a source temperature of 200 °C. Mass spectra (ESI) were car-
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Polyalkoxypyrimidines by the Reaction of Esters and Methyl Thiocyanate
FULL PAPER
ried out with a Bruker Esquire ion-trap spectrometer. Elemental
analyses were performed with a Perkin–Elmer 2400 CHN appara-
tus.
Ar-H). 13C NMR (CDCl3): δ = 13.4 (CH3S), 14.1 (CH3S), 14.3
(CH3CH2), 62.6 (CH2O), 113.7 (C5), 128.0 (arom.), 128.3 (arom.),
130.2 (arom.), 132.5 (arom.), 164.4 (C6), 168.0 (C4), 168.8 (C2).
IR (KBr): ν = 1541, 1514, 1342, 1042 cm–1.
˜
General Procedure for the Preparation of 4-Alkoxy-2,6-bis(methyl-
thio)pyrimidines 4: To a solution containing methyl thiocyanate
(2.19 g, 30.0 mmol) and the corresponding ester (10.0 mmol) in
20 mL of dichloromethane at –78 °C was added dropwise a solu-
tion of triflic anhydride (4.23 g, 15.0 mmol) in 20 mL of dichloro-
methane. The reaction mixture was stirred at this temperature for
1 h and allowed to stand at 0 °C for 4 d. The reaction mixture was
hydrolyzed by careful addition of saturated aqueous solution of
sodium hydrogen carbonate until was basic. The organic layer was
washed with brine and dried with magnesium sulfate. The solvent
was removed in vacuo and the residue was purified by flash
chromatography using hexane/ethyl acetate, 8:2 as eluent. The
crude product was recrystallized.
4-Butoxy-5-methyl-2,6-bis(methylthio)pyrimidine (4f): Following the
general procedure, the reaction with the butyl propanoate 1f gave
1.80 g of a yellow undistillable oil, 69% yield. C11H18N2OS2
(258.4): calcd. C 51.13, H 7.02, N 10.84, S 24.82; found C 50.99,
H 6.90, N 10.77, S 24.69. ESI-MS: m/z (%) = 259 [M+H]+. 1H
NMR (CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.44 (sext,
2 H, J = 7.4 Hz, 2 H, CH3CH2CH2), 1.73 (quint, J = 6.5 Hz, 2 H,
CH2CH2CH2), 2.01 (s, 3 H, CH3), 2.54 (s, 3 H, CH3S), 2.55 (s, 3
H, CH3S), 4.33 (t, J = 6.5 Hz, 2 H, CH2O). 13C NMR (CDCl3): δ
= 9.6 (CH3), 12.7 (CH3CH2), 13.6 (CH3S), 13.8 (CH3S), 19.0
(CH2), 31.0 (CH2), 66.1 (CH2O), 108.0 (C5), 165.0 (C6), 166.6
(C4), 166.8 (C2). IR (film): ν = 2961, 1553, 1533, 1344 cm–1.
˜
4-Ethoxy-5-methyl-2,6-bis(methylthio)pyrimidine (4b): Following
the general procedure, the reaction with the ethyl propanoate 1b
gave 1.80 g of a white solid, 78% yield; m.p. 51–52 °C (MeOH).
C9H14N2OS2 (230.3): calcd. C 46.93, H 6.13, N 12.16, S 27.84;
found C 46.85, H 6.03, N 12.09, S 27.71. ESI-MS: m/z = 231
[M+H]+, 253 [M+Na]+. 1H NMR (CDCl3): δ = 1.37 (t, J =
7.2 Hz, 3 H, CH3CH2), 2.02 (s, 3 H, CH3), 2.54 (s, 3 H, CH3S),
S-Methyl N-Acetylthiocarbamate (5a): Following the general pro-
cedure, the reaction with ethyl acetate gave 0.77 g of a pale yellow
solid 58% yield (from propyl acetate 51% yield); m.p. 146–147 °C
(CHCl3/hexane).From propyl acetate, 51% yield. C4H7NO2S
(133.1): calcd. C 36.08, H 5.30, N 10.52, S 24.08; found C 35.93,
H 5.23, N 10.44, S 23.92. EI-MS: m/z (%) = 133 [M+·, not ob-
served], 90 (10) [M – CH3CO], 45 (14) [CH3S+], 43 (100)
1
2.57 (s, 3 H, CH3S), 4.39 (q, J = 7.2 Hz, 2 H, CH3CH2). 13C NMR [CH3CO+]. H NMR ([D6]DMSO): δ = 2.31 (s, 3 H, CH3S), 2.37
(CDCl3): δ = 9.9 (CH3), 13.0 (CH3S), 14.1 (CH3S), 14.5 (CH3CH2), (s, 3 H, CH3), 8.53 (br. s, 1 H, NH). 13C NMR ([D6]DMSO): δ =
62.5 (CH2), 109.0 (C5), 165.8 (C6), 166.8 (C4), 167.1 (C2). IR 11.8 (CH S), 23.7 (CH ), 169.4 (CO), 170.0 (COS) IR (KBr): ν =
˜
3
3
(KBr): ν = 2980, 1554, 1340, 1053 cm–1.
3142, 1651, 1257, 1184 cm–1.
˜
5-Butyl-4-ethoxy-2,6-bis(methylthio)pyrimidine (4c): Following the
general procedure, the reaction with ethyl hexanoate 1c gave 1.14 g
S-Methyl N-Hexanoylthiocarbamate (5d): Following the general
procedure, the reaction with ethyl hexanoate 1c gave 0.81 g of a
of a white solid, 42% yield; m.p. 47–48 °C (MeOH). C12H20N2OS2 white solid 43% yield; m.p. 80–81 °C (MeOH). C8H15NO2S
(272.4): calcd. C 52.90, H 7.40, N 10.28, S 23.54; found C 52.79, (189.2): calcd. C 50.76, H 7.99, N 7.40, S 16.94; found C 50.66, H
H 7.33, N 10.13, S 23.45. EI-MS: m/z (%) = 272 (57) [M+], 257 7.86, N 7.29, S 16.77. ESI-MS: m/z (%) = 212 [M+Na]+. 1H NMR
(43) [M – CH3], 243 (41) [M – C2H5], 229 (100) [M – C3H7]. ESI-
(CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H, CH3CH2), 1.28–1.36 (m, 4
H, 2CH2), 1.67 (q, J = 7.4 Hz, 2 H, CH2CH2CH2), 2.34 (s, 3 H,
MS: m/z = 273 [M+H]+. 1H NMR (CDCl3): δ = 0.93 (t, J = 7.1 Hz,
3 H, CH3CH2), 1.25–1.27 (m, 4 H, CH2), 1.35 (t, J = 7.1 Hz, 3 H, CH3S), 2.48 (t, J = 7.4 Hz, 2 H, CH2CO) 8.17 (br. s, 1 H, NH).
CH3CH2O), 2.50 (t, J = 7.1 Hz, 2 H, CH2CH2) 2.54 (s, 6 H, CH3S), 13C NMR (CDCl3): δ = 12.5 (CH3S), 13.8 (CH3), 22.3 (CH2), 24.1
4.39 (q, J = 7.2 Hz, 2 H, CH2O). 13C NMR (CDCl3): δ = 12.9 (CH2), 31.2 (CH2), 37.0 (CH2), 170.5 (COS), 172.6 (CO) IR (KBr):
(CH3S), 13.8 (CH3CH2), 14.0 (CH3S), 14.4 (CH3CH2O), 22.6 ν = 3192, 1717, 1649, 1257, 1223 cm–1.
˜
(CH2), 24.6 (CH2), 62.3 (CH2O), 113.0 (C5), 165.3 (C6), 166.8
S-Methyl N-Decanoylthiocarbamate (5d): Following the general
(C4), 166.9 (C2). IR (KBr): ν = 2955, 2924, 1551, 1340 cm–1.
˜
procedure, the reaction with ethyl decanoate gave 1d 1.03 g of a
4-Ethoxy-2,6-bis(methylthio)-5-octylpyrimidine (4d): Following the pale yellow solid 42% yield; m.p. 88–89 °C (MeOH). C12H23NO2S
general procedure, the reaction with ethyl decanoate 1d gave 1.48 g (245.3): calcd. C 58.74, H 9.45, N 5.71, S 13.07; found C 58.64, H
of a white solid, 45% yield; m.p. 29–30 °C (MeOH). C16H28N2OS2 9.33, N 5.64, S 12.98. ESI-MS: m/z (%) = 246 [M+H]+, 268
(328.5): calcd. C 58.49, H 8.59, N 8.53, S 19.52; found C 58.32, H
[M+Na]+. 1H NMR (CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H,
CH3CH2), 1.26–1.36 (m, 12 H, 6CH2), 1.66 (q, J = 7.3 Hz, 2 H,
8.43, N 8.39, S 19.40. EI-MS: m/z (%) = 328 (42) [M+·], 313 (61)
[M – CH3], 281 (70) [M – CH3S], 243 (32) [M – C6H13], 229 (100) CH2CH2CH2), 2.34 (s, 3 H, CH3S), 2.48 (t, J = 7.3 Hz, 2 H,
[M – C7H15]. 1H NMR (CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H, CH2CO) 8.76 (br. s, 1 H, NH). 13C NMR (CDCl3): δ = 12.5
CH3CH2), 1.28–1.48 (m, 15 H, 1 CH3, 6 CH2), 2.49 (t, J = 7.3 Hz,
(CH3S), 14.0 (CH3), 22.6 (CH2), 24.4 (CH2), 29.0 (CH2), 29.2
2 H, CH2CH2) 2.54 (s, 3 H, CH3S), 2.56 (s, 3 H, CH3S), 4.40 (q, J (CH2), 29.3 (CH2), 31.8 (CH2), 36.9 (CH2), 171.4 (COS), 173.1
= 7.2 Hz, 2 H, CH2O). 13C NMR (CDCl3): δ = 13.1 (CH3S), 14.0
(CH3S), 14.1 (CH3CH2), 14.5 (CH3CH2O), 22.6 (CH2), 25.0 (CH2),
27.5 (CH2), 29.2 (CH2), 29.3 (CH2), 29.5 (CH2), 31.9 (CH2), 62.4
(CH2O), 113.2 (C5), 165.3 (C6), 166.7 (C4), 166.9 (C2). IR (KBr):
(CO). IR (KBr): ν = 3258, 1728, 1163, 1149 cm–1.
˜
1-(Methylthio)isoquinolin-3-yl Phenylacetate (6): Following the ge-
neral procedure, the reaction with ethyl phenylacetate 1e gave
0.30 g of a yellow solid 19% yield; m.p. 79–80 °C (EtOH).
C18H15NO2S (309.3): calcd. C 69.88, H 4.89, N 4.53, S 10.36; found
C 69.70, H 4.70, N 4.47, S 10.25. EI-MS: m/z (%) = 309 (6) [M+·],
191 (100), 91 (40) [C7H7+]. 1H NMR (CDCl3): δ = 2.69 (s, 3 H,
CH3S), 4.00 (s, 2 H, CH2), 7.08 (s, 1 H, H4), 7.36 (t, J = 7.4 Hz, 1
H, H4Ј), 7.42 (t, J = 7.4 Hz, 2 H, H3Ј, H5Ј), 7.48 (d, J = 7.4 Hz,
2 H, H2Ј, H6Ј), 7.53 (t, J = 7.7 Hz, 1 H, H6), 7.66 (t, J = 7.7 Hz,
ν = 2925, 1551, 1529, 1340, 1049 cm–1.
˜
4-Ethoxy-5-phenyl-2,6-bis(methylthio)pyrimidine (4e): Following the
general procedure, the reaction with ethyl phenylacetate 1e gave
2.07 g of a white solid, 71% yield; m.p. 83–84 °C (MeOH).
C14H16N2OS2 (202.4): calcd. C 57.50, H 5.52, N 9.58, S 21.93;
found C 57.42, H 5.39, N 9.45, S 21.79. EI-MS: m/z (%) = 292
1
(100) [M+·], 263 (15) [M – C2H5], 231 (26). H NMR (CDCl3): δ = 1 H, H7), 7.74 (d, J = 7.7 Hz, 1 H, H5), 8.19 (d, J = 7.7 Hz, 1 H,
1.26 (t, J = 7.1 Hz, 3 H, CH3CH2), 2.48 (s, 3 H, CH3S), 2.60 (s, 3 H8). 13C NMR (CDCl3): δ = 13.0 (CH3S), 41.4 (CH2), 106.2 (C4),
H, CH3S), 4.39 (q, J = 7.1 Hz, 2 H, CH2O), 7.28–7.44 (m, 5 H,
124.5 (C8), 125.9 (C4a), 126.5 (C6), 127.1 (C5), 127.3 (C4Ј), 128.7
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A. Herrera, R. Martínez-Alvarez, P. Ramiro, J. Almy, D. Molero, A. Sánchez
FULL PAPER
(C3Ј, C5Ј), 129.4 (C2Ј), 130.7 (C7), 133.4 (C1Ј), 137.7 (C8a), 152.9 CH3SO2), 4.60 (q, J = 7.1 Hz, 2 H, CH2O), 7.37–7.51 (m, 5 H, Ar-
(C3), 160.8 (C1), 169.9 (CO). IR (KBr): ν = 1749, 1551, 1227, H). 13C NMR (CDCl3): δ = 13.8 (CH3CH2), 39.1 (CH3SO2), 40.5
˜
1142 cm–1.
(CH3SO2), 66.2 (CH2O), 123.5 (C5), 127.5 (arom.), 128.1 (arom.),
129.7 (arom.), 129.8 (arom.), 162.9 (C6), 170.2 (C4, C2). IR (KBr):
˜
General Procedure for the Preparation of 4-Alkoxy-2,6-bis(methyl-
sulfonyl)pyrimidines 12: To a stirred solution of the corresponding
4-alkoxy-2,6-bis(methylthio)pyrimidine 4 (4.0 mmol) in 15 mL of
dichloromethane was added slowly a solution containing mCPBA
(3.12 g, 18 mmol) in 20 mL of dichloromethane. The mixture was
stirred at room temperature for 4 h. An aqueous solution of sodium
thiosulfate (5%) was then added, shaked and the layers separated.
The aqueous layer was extracted with dichloromethane and the
combined organic layers washed with sodium hydrogen carbonate,
brine and dried with magnesium sulfate. The solvent was removed
in vacuo and the residue was purified by recrystallization.
ν = 1437, 1342, 1317, 1144 cm–1.
4-Butoxy-5-methyl-2,6-bis(methylsulfonyl)pyrimidine (12f): Follow-
ing the general procedure, the reaction with 4f gave 1.04 g of a
white solid, 81% yield; m.p. 89–90 °C (MeOH). C11H18N2O5S2
(322.4): calcd. C 40.98, H 5.63, N 8.69, S 19.89; found C 40.80, H
1
5.55, N 8.59, S 19.87. ESI-MS: m/z (%) = 323 [M+H]+. H NMR
(CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.49 (sext, 2
H, J = 7.3 Hz, 2 H, CH3CH2CH2), 1.84 (quint, J = 7.3 Hz, 2 H,
CH2CH2CH2), 2.58 (s, 3 H, CH3), 3.32 (s, 3 H, CH3SO2), 3.41 (s,
3 H, CH3SO2), 4.56 (t, J = 6.6 Hz, 2 H, CH2O). 13C NMR
(CDCl3): δ = 10.0 (CH3), 13.5 (CH3CH2), 19.0 (CH2), 30.2 (CH2),
38.9 (CH3SO2), 39.9 (CH3SO2), 69.5 (CH2O), 120.3 (C5), 161.5
4-Ethoxy-5-methyl-2,6-bis(methylsulfonyl)pyrimidine (12b): Follow-
ing the general procedure, the reaction with 4b gave 1.07 g of a
white solid, 91% yield; m.p. 130–131 °C (MeOH). C9H14N2O5S2
(294.3): calcd. C 36.72, H 4.79, N 9.52, S 21.79; found C 36.59, H
4.69, N 9.39, S 21.66. EI-MS: m/z (%) = 294 (21) [M+·], 266 (41)
(C6), 162.4 (C2), 170.7 (C4). IR (KBr): ν = 2953, 1566, 1304,
˜
1144 cm–1.
General Procedure for the Preparation of 4-Aminopyrimidines 13: A
continuous stream of ammonia was bubbled through a solution of
the corresponding bis(methylsulfonyl)pyrimidine 12 (1.5 mmol) in
25 mL of dichloromethane at room temperature. After 16 h, the
solvent was distilled off, the residue washed with water and purified
by recrystallization.
1
[M – C2H4], 250 (100) [M – C2H4O], 215 (15) [M – CH3SO2]. H
NMR (CDCl3): δ = 1.50 (t, J = 7.1 Hz, 3 H, CH3CH2), 2.59 (s, 3
H, CH3), 3.32 (s, 3 H, CH3SO2), 3.41 (s, 3 H, CH3SO2), 4.64 (q, J
= 7.2 Hz, 2 H, CH3CH2). 13C NMR (CDCl3): δ = 10.2 (CH3), 14.0
(CH2) 39.0 (CH3SO2), 40.0 (CH3SO2), 65.9 (CH2), 120.5 (C6),
161.6 (C5), 162.6 (C2), 170.7 (C4). IR (KBr): ν = 1560, 1431, 1346,
˜
6-Ethoxy-5-methyl-2-(methylsulfonyl)pyrimidin-4-amine (13b): Fol-
lowing the general procedure, the reaction with 11b gave 0.31 g of
a white solid, yield 89%; m.p. 135–136 °C (MeOH). C8H13N3O3S
(231.2): calcd. C 41.55, H 5.76, N 18.17, S 13.86; found C 41.40,
H 5.66, N 18.11, S 13.70. EI-MS: m/z (%) = 231 (16) [M+·], 216 (6)
1313, 1136 cm–1.
5-Butyl-4-ethoxy-2,6-bis(methylsulfonyl)pyrimidine (12c): Following
the general procedure, the reaction with 4c gave 1.29 g of a white
solid, 96% yield; m.p. 108–109 °C (MeOH). C12H20N2O5S2 (336.4):
calcd. C 42.84, H 5.99, N 8.33, S 19.06; found C 42.70, H 5.81, N
8.22, S 18.95. EI-MS: m/z (%) = 336 (18) [M+·], 321 (15) [M – CH3],
307 (100) [M – C2H5], 279(46) [M – C4H9], 257 (50) [M – CH3SO2].
1H NMR (CDCl3): δ = 0.94 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.38–
1.62 (m, 4 H, CH2), 1.46 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.02 (t,
J = 7.1 Hz, 2 H, CH2CH2) 3.30 (s, 3 H, CH3SO2), 3.37 (s, 3 H,
CH3SO2), 4.61 (q, J = 7.2 Hz, 2 H, CH2O). 13C NMR (CDCl3): δ
= 13.54 (CH3CH2CH2), 13.91 (CH3CH2O), 22.8 (CH2), 24.2
(CH2), 30.5 (CH2), 39.0 (CH3SO2), 40.2 (CH3SO2), 65.7 (CH2O),
1
[M – CH3], 187 (100) [M – C2H4O]. H NMR (CDCl3): δ = 1.38
(t, J = 7.1 Hz, 3 H, CH3CH2), 2.32 (s, 3 H, CH3), 3.23 (s, 3 H,
CH3SO2), 4.37 (q, J = 7.1 Hz, 2 H, CH2O), 5.00 (br. s, 2 H, NH2).
13C NMR (CDCl3): δ = 8.4 (CH3), 14.1 (CH3CH2), 39.6 (CH3SO2),
62.5 (CH2O), 101.3 (C5), 160.4 (C4), 162.6 (C2), 169.3 (C6). IR
(KBr): ν = 3516, 3194, 1425, 1344, 1311, 1240 cm–1.
˜
6-Ethoxy-2-(methylsulfonyl)-5-phenylpyrimidin-4-amine (13e): Fol-
lowing the general procedure, the reaction with 12e gave 0.42 g of
a white solid, 96% yield; m.p. 150–151 °C (MeOH). C13H15N3O3S
(293.3): calcd. C 53.23, H 5.15, N 14.32, S 10.93; found C 53.15,
H 4.99, N 14.22, S 10.84. EI-MS: m/z (%) = 293 (100) [M+·], 278
125.2 (C5), 161.6 (C6), 164.5 (C2), 170.7 (C4). IR (KBr): ν = 2961,
˜
1558, 1344, 1317, 1140 cm–1.
4-Ethoxy-2,6-bis(methylsulfonyl)-5-octylpyrimidine (12d): Following
the general procedure, the reaction with 4d gave 1.35 g of a white
solid, 86% yield; m.p. 101–102 °C (MeOH). C16H28N2O5S2 (392.5):
calcd. C 48.96, H 7.19, N 7.14, S 16.34; found C 48.82, H 7.09, N
7.06, S 14.40. EI-MS: m/z (%) = 392 (5) [M+·], 377 (7) [M – CH3],
313 (100) [M – CH3SO2]. 1H NMR (CDCl3): δ = 0.88 (t, J =
7.6 Hz, 3 H, CH3CH2), 1.27–1.36 (m, 10 H, 5CH2), 1.48 (t, J =
7.1 Hz, 3 H, CH3CH2O) 1.60 (m, 2 H, CH2CH2CH2), 3.03 (t, J =
7.6 Hz, 2 H, CH2CH2), 3.32 (s, 3 H, CH3SO2), 3.39 (s, 3 H,
CH3SO2), 4.64 (q, J = 7.1 Hz, 2 H, CH2O). 13C NMR (CDCl3): δ
= 14.0 (CH3CH2O), 14.1 (CH3CH2), 22.6 (CH2), 24.6 (CH2), 28.5
(CH2), 29.0 (CH2), 29.1 (CH2), 29.7 (CH2), 31.8 (CH2), 39.1
(CH3SO2), 40.3 (CH3SO2), 65.8 (CH2O), 125.4 (C5), 161.7 (C6),
1
(4) [M – CH3], 265 (11) [M – C2H4]. H NMR (CDCl3): δ = 1.25
(t, J = 7.1 Hz, 3 H, CH3CH2), 3.06 (s, 3 H, CH3SO2), 4.34 (q, J =
7.1 Hz, 2 H, CH2O), 5.24 (br. s, 2 H, NH2), 7.30–7.42 (m, 5 H, Ar-
H). 13C NMR ([D6]DMSO): δ = 14.0 (CH3CH2), 40.3 (CH3SO2),
62.6 (CH2O), 107.3 (C5), 127.3 (arom.), 130.9 (arom.), 131.0
(arom.), 161.2 (C4), 162.8(C2), 168.5 (C6). IR (KBr): ν = 3161,
˜
1583, 1302, 1238, 1207, 1059 cm–1.
General Procedure for the Preparation of Methoxypyrimidines 14,
15 and 16: solution containing 1.5 mmol of the corresponding
mono or bis(methylsulfonyl)pyrimidines and 1.5 mmol of sodium
methoxide (4.0 mmol for the double substitution) in 20 mL of dry
methanol was refluxed for 15 h. After addition of water and extrac-
tion with dichloromethane, the organic layers were washed with
brine. Elimination of solvent affords a residue, which was purified
by recrystallization.
162.7 (C2), 171.0 (C4). IR (KBr): ν = 1556, 1431, 1344, 1310,
˜
1140 cm–1.
4-Ethoxy-2,6-bis(methylsulfonyl)-5-phenylpyrimidine (12e): Follow-
ing the general procedure, the reaction with 4e gave 1.35 g of a
white solid, 95% yield; m.p. 137–138 °C (MeOH). C14H16N2O5S2
(356.4): calcd. C 47.18, H 4.52, N 7.86, S 17.99; found C 47.11, H
6-Ethoxy-2-methoxy-5-phenylpyrimidin-4-amine (14e): Following
the general procedure, the reaction of 12e gave 0.36 g of a white
solid, 97% yield; m.p. 110–111 °C (MeOH). C13H15N3O2 (245.2):
calcd. C 63.66, H 6.16, N 17.13; found C 63.53, H 6.08, N 17.10.
4.40, N 7.78, S 17.79. EI-MS: m/z (%) = 356 (100) [M+·], 328 (44)
[M – C2H4], 277 (28) [M – SO2CH3]. H NMR (CDCl3): δ = 1.35 EI-MS: m/z (%) = 245 (100) [M+·], 230 (17) [M – CH3], 228 (18)
(t, J = 7.1 Hz, 3 H, CH3CH2), 3.29 (s, 3 H, CH3SO2), 3.39 (s, 3 H, [M – NH3]. 1H NMR (CDCl3): δ = 1.29 (t, J = 7.1 Hz, 3 H,
1
3336
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3332–3337

Polyalkoxypyrimidines by the Reaction of Esters and Methyl Thiocyanate
FULL PAPER
Golding, R. G. Griffin, P. Jewsbury, L. N. Johnson, D. R. New-
ell, M. E. M. Noble, L. Z. Wang, I. R. Hardcastle, Bioorg.
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CH3CH2), 3.90 (s, 3 H, CH3O), 4.39 (q, J = 7.1 Hz, CH2O), 5.47
(br. s, 2 H, NH2), 7.30–7.37 (m, 5 H, Ar-H). 13C NMR (CDCl3):
δ = 14.5 (CH3), 54.1 (CH3O), 62.7 (CH2O), 96.2 (C5), 126.6
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(arom.), 127.6 (arom.), 130.8 (arom.), 131.7 (arom.), 159.9 (C4),
167.5 (C2), 168.1 (C6). IR (KBr): ν = 3481, 3337, 1560, 1553,
˜
1373 cm–1.
4-Ethoxy-5-methyl-2-(methylsulfonyl)-6-methoxypyrimidine (15b):
Following the general procedure, the reaction of 11b gave 0.33 g of
a white solid, 90% yield; m.p. 107–108 °C (MeOH). C9H14N2O4S
(246.2): calcd. C 43.98, H 5.73, N 11.37, S 13.02; found C 43.88,
H 5.60, N 11.20, S 12.90. EI-MS: m/z (%) = 246 (22) [M+·], 218
1
(13) [M – C2H4], 202 (100) [M – C2H4O]. H NMR (CDCl3): δ =
1.42 (t, J = 7.1 Hz, CH3CH2), 2.40 (s, 3 H, CH3), 3.32 (s, 3 H,
CH3SO2), 3.97 (s, 3 H, CH3O), 4.48 (q, J = 7.1 Hz, 2 H, CH2O).
13C NMR (CDCl3): δ = 9.0 (CH3), 14.2 (CH3CH2), 39.9 (CH3SO2),
55.1 (CH3O), 64.1 (CH2O), 109.5 (C5), 162.3, 162.8, 171.4 (C4).
[7] C. Luthy, H. Zoulder, T. Rapold, G. Seifert, B. Urwyler, T.
Heinis, H. C. Steinrucken, J. Allen, Pest. Manage. Sci. 2001,
57, 205–224.
[8] H. Eilingsfeld, H. Schenermann, Chem. Ber. 1968, 101, 2426–
IR (KBr): ν = 1589, 1556, 1391, 1371, 1308, 1132 cm–1.
2434.
˜
[9] T. Sakasai, T. Sakamoto, H. Yamanaka, Heterocycles 1995, 41,
1275–1290.
4-Ethoxy-2,6-dimethoxy-5-methylpyrimidine (16b): Following the
general procedure, the reaction of 11b or 14b gave 0.28 g of a pale
yellow solid, 95% yield; m.p. 39–40 °C (MeOH). C9H14N2O3
(198.2): calcd. C 54.53, H 7.12, N 14.13; found C 54.44, H 7.10, N
14.09. ESI-MS: m/z (%) = 199 [M+H]+. 1H NMR (CDCl3): δ =
1.34 (t, J = 7.1 Hz, CH3CH2), 1.88 (s, 3 H, CH3), 3.89 (s, 3 H,
CH3O), 3.91 (s, 3 H, CH3O), 4.36 (q, J = 7.1 Hz, 2 H, CH2O). 13C
NMR (CDCl3): δ = 6.6 (CH3), 14.4 (CH3CH2), 53.7 (CH3O), 54.0
(CH3O), 62.3 (CH2O), 92.5 (C5), 162.0 (C2), 169.0 (C6), 169.4
[10] I. Gómez, E. Alonso, D. J. Ramón, M. Yus, Tetrahedron 2000,
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[11]
[12]
[13]
Y. Bessard, R. Crettaz, Tetrahedron 1999, 55, 405–412.
Y. Bessard, R. Crettaz, Tetrahedron 2000, 56, 4739–4745.
E. Coutouli-Argyropoulou, C. Zachariadou, J. Heterocycl.
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A. García Martínez, A. Herrera Fernández, F. Mor-
eno Jímenez, A. García Fraile, L. R. Subramanian, M. Han-
ack, J. Org. Chem. 1992, 57, 1627–1630.
[14]
(C4). IR (KBr): ν = 2990, 1611, 1583, 1381, 1155 cm–1.
˜
[15] A. Herrera Fernández, R. Martínez-Alvarez, R. Chioua, M.
Chioua, Tetrahedron Lett. 2003, 44, 2149–2151.
[16] A. Herrera Fernández, R. Martínez-Alvarez, R. Chioua, F. Be-
nabdelouahab, M. Chioua, Tetrahedron 2004, 60, 5475–5479.
[17] A. García Martínez, A. Herrera Fernández, D. Molero Vilchez,
M. Hanack, L. R. Subramanian, Synthesis 1992, 1053–1054.
[18] A. García Martínez, A. Herrera Fernández, R. Martínez-Alva-
rez, D. Molero Vilchez, M. L. Laorden, L. R. Subramanian,
Tetrahedron 1999, 55, 4825–4830.
[19] A. Herrera Fernández, R. Martínez-Alvarez, P. Ramiro, Tetra-
hedron 2003, 59, 7331–7336.
[20] A. Herrera Fernández, R. Martínez-Alvarez, P. Ramiro, A.
Sánchez, R. Torres, J. Org. Chem. 2004, 69, 4545–4547.
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Chatt, R. Chioua, A. Sánchez, J. Almy, Tetrahedron 2006, 62,
2799–2811.
4-Ethoxy-2,6-dimethoxy-5-octylpyrimidine (16d): Following the ge-
neral procedure, the reaction of 11d gave 0.42 g of a pale yellow
undistillable oil 94% yield. C16H28N2O3 (296.4): calcd. C 64.83, H
9.52, N 9.45; found C 64.70, H 9.40, N 9.34. EI-MS: m/z (%) =
296 (14) [M+·], 265 (7) [M – CH3], 251 (17) [M – C2H5O], 197
(100) [M – C8H17]. 1H NMR (CDCl3): δ = 0.85 (t, J = 7.6 Hz,
CH3CH2CH2), 1.24 (m, 12 H, 6CH2), 1.33 (t, J = 7.1 Hz,
CH3CH2O), 2.38 (t, J = 7.6 Hz, 2 H, CH2), 3.89 (s, 3 H, CH3O),
3.90 (s, 3 H, CH3O), 4.36 (q, J = 7.1 Hz, 2 H, CH2O). 13C NMR
(CDCl3): δ = 14.0 (CH3), 14.6 (CH3), 21.5 (CH2), 22.6 (CH2), 28.5
(CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 31.9 (CH2), 53.8
(CH3O), 54.2 (CH3O) 62.2 (CH2O), 97.8 (C5), 162.1 (C2), 169.15,
169.5. IR (film): ν = 2926, 1582, 1462, 1381, 1142 (cm–1).
˜
Supporting Information (see also the footnote on the first page of
this article): 1H NMR, 13C NMR and DEPT spectra of compounds
4b-f, 5a, 5c, 5d, 6, 11b-f, 12b, 12e, 13e, 14b, 15b and 15d.
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Chioua, A. Sánchez, Tetrahedron 2002, 58, 10053–10058.
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M. L. Laorden Gutierrez, L. R. Subramanian, Synlett 1993,
229–230.
Acknowledgments
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Chemistry (Eds.: A. R. Katritzky, C. W. Rees), Pergamon Press,
Oxford, 1984, vol 3, p. 89–93.
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85–126.
We gratefully acknowledge the DGESIC (Spain, grant BQU2002-
00406) for financial support. We also thank the CAIs of the UCM
for recording MS and NMR spectra and determining the elemental
analyses.
[1] V. Mesguiche, R. J. Parsons, C. E. Arris, J. Bentley, F. T. Boyle,
N. J. Curtin, T. G. Davies, J. A. Endicott, A. E. Gibson, B. T.
Received: March 13, 2006
Published Online: May 29, 2006
Eur. J. Org. Chem. 2006, 3332–3337
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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