Mild and Catalyst-Free Microwave-Assisted Synthesis of 4,6-Disubstituted 2-Methylthiopyrimidines - Exploiting Tetrazole as an Efficient Leaving Group

Article abstract of DOI:10.1055/s-0035-1560577

Typically, 4,6-disubstituted 2-thiomethylpyrimidines are synthesized starting from 4,6-dichloro-2-thiomethylpyrimidine or an amino-substituted precursor. However, these reactions take several hours up to days and require multiple steps. Herein, we report a novel, easy, and quick-to-prepare synthetic intermediate, namely 2-(methylthio)-4,6-di(1H-tetrazol-1-yl)pyrimidine, for the synthesis of these interesting target compounds. The intermediate can be transformed within minutes into desired substituted pyrimidines under mild conditions with moderate to excellent yields. The reaction can be conducted in an automated microwave system, at room temperature or by conventional heating. Furthermore, we demonstrate the robustness of the method in a one-pot procedure.

Full text of DOI:10.1055/s-0035-1560577

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2606–2610
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Letter
Synlett
Mild and Catalyst-Free Microwave-Assisted Synthesis of 4,6-
Disubstituted 2-Methylthiopyrimidines – Exploiting Tetrazole as
an Efficient Leaving Group
Andreas Thomanna
Jens Eberharda
Giuseppe Allegrettaa
Martin Emptinga
Rolf W. Hartmann*a,b
a Helmholtz-Institute for Pharmaceutical Research Saarland,
Saarland University, Campus E8.1, 66123 Saarbrücken,
Germany
rolf.hartmann@helmholtz-hzi.de
b Department of Pharmacy, Pharmaceutical and Medicinal
Chemistry, Saarland University, Campus C2.3,
66123 Saarbrücken, Germany
Received: 15.06.2015
Accepted after revision: 03.09.2015
Published online: 21.10.2015
several hours and days to couple different nucleophiles to
the 4- and 6-position of pyrimidine.8,10,11,15–17 Interestingly,
to directly decorate the pyrimidine core with a tetrazole
substituent a novel method can be employed, which has re-
cently been published by us.18 Unfortunately, the developed
protocol using different conditions failed to introduce a
tetrazole moiety into the 6-chloro-N,N-dimethyl-2-(meth-
ylthio)pyrimidin-4-amine scaffold (see Table 1 in Support-
ing Information). We hypothesized that the electron-donat-
ing properties of the dimethylamine substituent in the 6-
position drastically reduced the leaving-group properties of
the chloro substituent at the 4-position. Consequently, we
tried to synthesize 4-chloro-2-(methylthio)-6-(1H-tetrazol-
1-yl)pyrimidine, but to our surprise the major product was
compound 1, substituted with two tetrazoles. NMR analysis
revealed both tetrazoles to be attached in the same regiose-
lectivity to the 2-thiomethylpyrimidine core. However, an
unambiguous clarification of the structure was achieved by
X-ray crystallography. The structure coordinates of com-
pound 1 revealed that the tetrazole substituents were
linked via N1 of the tetrazole scaffold (viz. N3 and N7 in Fig-
ure 1) to the 4- and 6-position of 2-thiomethylpyrimidine
(C4 and C2 in Figure 1).
Moreover, when applying four equivalents of tetrazole
instead of one, the reaction can be completed with almost
quantitative yield (97%) within 10 minutes at 60 °C under
microwave irradiation.19 With regard to product yield, we
could not determine any differences between thermal heat-
ing and microwave conditions (Table 1).
As microwave irradiation ensures a homogeneous and
fast energy input, we consider this procedure the method-
of-choice for facile and rapid generation of intermediate 1
(Scheme 1).
DOI: 10.1055/s-0035-1560577; Art ID: st-2015-b0444-l
Abstract Typically, 4,6-disubstituted 2-thiomethylpyrimidines are syn-
thesized starting from 4,6-dichloro-2-thiomethylpyrimidine or an ami-
no-substituted precursor. However, these reactions take several hours
up to days and require multiple steps. Herein, we report a novel, easy,
and quick-to-prepare synthetic intermediate, namely 2-(methylthio)-
4,6-di(1H-tetrazol-1-yl)pyrimidine, for the synthesis of these interesting
target compounds. The intermediate can be transformed within min-
utes into desired substituted pyrimidines under mild conditions with
moderate to excellent yields. The reaction can be conducted in an auto-
mated microwave system, at room temperature or by conventional
heating. Furthermore, we demonstrate the robustness of the method in
a one-pot procedure.
Keywords tetrazole, pyrimidine, combinatorial chemistry, medicinal
chemistry, nucleophilic aromatic substitution
Tetrazole moieties have drawn increasing attention by
medicinal chemists as they can be exploited for the genera-
tion of bioactive small molecules.1 In addition to their de-
sirable physicochemical properties, these azoles display
reasonable metabolic stability and can serve as bioisosteric
replacements of carboxylic acids.2 The family of 4,6-disub-
stituted pyrimidines and tetrazolyl-substituted pyrimidines
is a prominent class of chemical scaffolds for the design of
kynurenine-3-monooxygenase inhibitors,3,4 c-Kit modula-
tors,5 herbicides,6 Bmi-1 inhibitors,7 kinase inhibitors,8–10
cell protective agents,11 antibacterials,12–14 inhibitors of
NFκB DNA binding,15 and corticotropin releasing hormone
type 1 antagonists.16 One well-reported step for the synthe-
sis of these interesting target compounds proceeds via SNAr
reaction conditions employing 4,6-dichloro-2-methylthio-
pyrimidine as a commercially available starting material.
These conditions generally require reaction times between
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venient leaving group. Thus, this method may be easily im-
plemented in automated combinatorial chemistry ap-
proaches.
To test the scope of the reaction, we used different ni-
trogen-, oxygen-, and sulfur-containing nucleophiles
(Scheme 2). For instance, alkyl (2, 3), saturated and unsatu-
rated heterocyclic amines (6–9), benzylamine (5), and un-
substituted amine (4) were successfully attached to the py-
rimidine core yielding the substituted pyrimidines in mod-
erate to excellent yields (Table 2) within minutes.
Preliminary tests with aromatic amines, such as aniline,
showed no conversion and are not suitable to be used in
this reaction.
Figure 1 X-ray crystal structure of 1 revealing the regiochemistry of
attached tetrazol-1-yl substituents; blue = nitrogen, grey = carbon,
yellow = sulfur, white = hydrogen
N
N
N
N
N
N
N
N
N
N
S
N
S
nucleophile
base, solvent
10 min, MW or r.t.
N
N
Table 1 Conditions Used To Obtain 2-(Methylthio)-4,6-di(1H-tetrazol-
1-yl)pyrimidine (1)a
R
N
N
N
Method
Conditions
Yield (%)
1
2–20
Scheme 2 Generic reaction scheme for the generation of 6-substitut-
ed 4-(1H-tetrazol-1-yl)-2-thiomethylpyrimidines
Heating
DMF, 60 °C, Et3N, 1H-tetrazole, 10 min
DMF, 60 °C, Et3N, 1H-tetrazole, 10 min
95
97
Microwave
a Conditions: 1 equiv of 4,6-dichloro-2-methylthiopyrimidine and 4 equiv
of 1H-tetrazole were employed.
The subset of oxygen-containing nucleophiles consisted
of methanol, sodium hydroxide, sodium ethoxide, and phe-
nol. With no exception, all hydroxyderivatives readily react-
ed with 1 to achieve the corresponding 6-substituted 4-
(1H-tetrazol-1-yl)-2-thiomethylpyrimidines (10–13, Table
2). Notably, the methoxy group can be conveniently at-
tached at room temperature under treatment with potassi-
um carbonate in a methanol–THF mixture. 4-Hydroxypy-
rimidine is known to be a very weak acid (pKa = 8.59).21
Thus, we were curious whether 10 also shows acidic char-
acter and conducted titration experiments to determine its
pKa. Indeed, 10 showed a pKa of 3.17 ± 0.05 which is about
five orders of magnitude lower than the unsubstituted 4-
hydroxypyrimidine. A plausible explanation for the in-
crease in acidity could be the electron-withdrawing proper-
ties of the tetrazole and thiomethyl substituent with re-
spective Hammett constants of σmetatetrazole = 0.52 and
σmetathiomethyl = 0.15.22
N
N
N
N
N
N
S
Cl
N
S
N
DMF, 1H-tetrazole
60 °C, 10 min, MW
N
N
Cl
N
N
97%
1
Scheme 1 Reaction conditions to obtain compound 1
Moreover, to investigate the applicability of our novel
synthetic route for automated combinatorial synthesis we
performed all reactions in an automated microwave system
(Tables 2 and 3).
Inspired by a previously observed side reaction, we test-
ed whether compound 1 could be an appropriate precursor
for the synthesis of further 4,6-disubstituted target com-
pounds. Indeed, di-tetrazolyl intermediate 1 could be suc-
cessfully transformed into compound 2 under microwave
irradiation by usage of one equivalent dimethylamine. In
addition to the clean conversion, the reaction only needs 10
minutes for completion and, hence, is much faster than tra-
ditional approaches.8,10,11,15–17 Moreover, due to its acidity,20
the cleaved tetrazole can be directly removed from the re-
action mixture by simple aqueous workup, making it a con-
To study the reactivity of 1 towards thiols, we used al-
kylmercaptans, benzylmercaptan, and thiophenols as reac-
tants. All sulfur-containing nucleophiles were successfully
introduced into the 2-thiomethylpyrimidine core in good to
excellent yields (13–19, Table 2).
Notably, these results show that 1 is also able to react
with sterically hindered (15, 20), electron-poor (18), and
electron-rich (19) nucleophiles demonstrating that the pro-
cedure can be used in automated robotic systems for one-
pot combinatorial approaches. Furthermore, this protocol is
a convenient approach for the synthesis of 6-substituted
4-(1H-tetrazol-1-yl)-2-thiomethylpyrimidines which we
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Table 2 Microwave-Assisted Synthesis of 6-Substituted 4-(1H-tetrazol-1-yl)-2-thiomethylpyrimidines 2–20a
Nucleophile
Product
R
Method
Yield (%)
dimethylamine
methylamine
ammoniab
2
NMe2
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
DMF, Et3N, 60 °C
THF, H2O, 60 °C
THF, K2CO3, r.t.
EtOH, r.t.
66
53
60
80
88
95
94
63
70
85
88
68
83
82
79
96
99
84
85
3
NHMe
4
NH2
benzylamine
5
NHBn
pyrrolidine
6
pyrrolidin-1-yl
morpholin-1-yl
piperidin-1-yl
imidazol-1-yl
OH
morpholine
7
piperidine
8
imidazole
9
sodium hydroxide
methanol (excess)
sodium ethoxide
phenol
10
11
12
13
14
15
16
17
18
19
20
OMe
OEt
OPh
DMF, Et3N, 60 °C
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
DMF, K2CO3, r.t.
ethylmercaptan
tert-butylmercaptan
benzylthiol
SEt
St-Bu
SBn
thiophenol
SPh
4-chlorothiophenol
4-methoxythiophenol
2-methylthiophenol
S(4-ClC6H4)
S(4-MeOC6H4)
S(2-MeC6H4)
a Except noted otherwise, a 1:1 stoichiometry of reactant and compound 1 was used. Reactions were carried out under microwave irradiation for 10 min.
b As a 7 N solution in MeOH.
could not obtain using a substituted chloro-substituted pre-
cursor (compare Table 1 and Table 1 in Supporting Informa-
tion).
To investigate whether both tetrazole substituents can
also be replaced in one pot, we used thiophenol, imidazole,
and sodium methanolate as representative reactants
(Scheme 3,Table 3).
In all three cases, the corresponding 4,6-homo-disubsti-
tuted 2-thiomethylpyrimidine compounds (21–23) were
obtained within 10–20 minutes in near quantitative yields
(except 24, vide supra) which underlines the good leaving-
N
N
N
N
R1
N
S
N
N
S
2–4 equiv nucleophile
base, solvent,
10–20 min, MW or r.t.
N
N
R2
N
N
N
1
17, 21–24
Scheme 3 Reaction conditions of the one-pot procedure to replace
both tetrazole substituents in 1 to obtain 4,6-homo- or 4,6-hetero-
disubstituted 2-thiomethylpyrimidines
Table 3 Microwave-Assisted One-Pot Synthesis of 4,6-Disubstituted 2-Thiomethylpyrimidines 17 and 21–24a
Nucleophile (equiv)
Product
R1
1H-tetrazol-1-yl
R2
SPh
Method
Yield (%)
thiophenol (1)
17b
21
22
23
24
DMF, Et3N, 20 min, 60 °C to r.t., ‘one-pot’
MeOH, 60 °C
83
96
95
99
31
methanolate (3)
MeO
MeO
thiophenol (2)
SPh
SPh
DMF, K2CO3, 10 min, r.t.
imidazole (4)
imidazol-1-yl
NBn
imidazol-1-yl
SPh
DMF, Et3N, 20 min, 80–100 °C
DMF, Et3N, K2CO3, 20 min, 60–120 °C
benzylamine (1) + thiophenol (1)
a Compound 1 was used as a starting material unless otherwise noted. In all reactions 1 equiv of starting material was treated with the equivalents of nucleophile
indicated in brackets.
b For compound 17, 4,6-dichloro-2-thiomethylpyrimidine was employed as starting material.
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group properties of the tetrazolyl group (Scheme 3 and Ta-
ble 3).
Acknowledgment
We thank Michael Hoffmann for recording HRMS spectra and Volker
Huch for the determination of the X-ray crystal structure of com-
pound 1. Many thanks go to Nadja Klippel for synthetic support.
To study the robustness and broaden its applicability for
combinatorial chemistry and with regard to the good over-
all yields we investigated if the reaction could also be used
as a one-pot sequence to introduce two different substitu-
ents using intermediate 1 as starting material. Consequent-
ly, we used one equivalent of benzylamine and after 10
minutes of reaction time, we added one equivalent of thio-
phenol to replace the remaining tetrazole substituent from
in situ prepared 5. The hetero-4,6-disubstituted product 24
was successfully obtained in this one-pot, two-step reac-
tion (Scheme 3 and Table 3).
To demonstrate the applicability for library synthesis
and with respect to the excellent yield of 1, we speculated
whether the method could be also exploited for another
one-pot procedure which directly starts from the commer-
cially available chlorinated starting material. The idea was
to charge the reaction with a nucleophile after 1 was
formed in situ and apply 10 additional minutes of micro-
wave irradiation to yield the final product. For this reaction,
we chose thiophenol as a model reactant, and as expected,
the two-step one-pot sequence showed complete conver-
sion within 20 minutes, and 17 was isolated in high yield
(Table 3). These model reactions clearly demonstrate the
good leaving-group characteristics of the tetrazole group
(fast to replace by nucleophiles and easy to remove from the
reaction mixture) for SNAr reactions at 2-thiomethylpyrimi-
dine cores. By this means, homo- and hetero-disubstituted
compounds were easily prepared.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560577.
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References and Notes
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(19) Experimental Procedure for the Synthesis of 2-(Methylthio)-
4,6-di(1H-tetrazol-1-yl)pyrimidine (1)
data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
4,6-Dichloro-2-methylthiopyrimidine (195 mg, 1 equiv, 1.0
mmol) and 1H-tetrazole (280 mg, 4 equiv, 4.0 mmol) was dis-
solved in anhydrous DMF (3 mL). To the orange solution Et3N
(580 μL,4 equiv, 4.0 mmol) was given, and the mixture was
stirred in a capped vial for 10 min in a CEM Discover SP micro-
wave at 60 °C and 50 W power. The reaction mixture was
poured into H2O, filtered, and washed with H2O to yield an off-
white solid (yield: 255 mg, 0.97 mmol, 97%); mp 193 ± 3 °C
(decomp.). UV-Vis (MeOH): 221, 236, 269, 320 nm. FT-IR: 3168,
3138, 3098, 2161, 1704, 1597, 1563, 1539, 1466, 1446, 1432,
1416, 1403, 1330, 1316, 1307, 1284, 1248, 1189, 1170, 1101,
1092, 1073, 1004, 990, 951, 937, 881, 846, 824, 791, 758, 710,
681, 659 cm–1. 1H NMR (300 MHz, DMSO-d6): δ = 10.51 (s, 2 H),
8.24 (s, 1 H), 2.77 (s, 3 H) ppm. 13C NMR (75 MHz, DMSO-d6):
δ = 174.1, 154.9, 142.5, 142.4, 95.8, 14.2 ppm. ESI-MS: m/z =
235.1 [M + H – N2]+, 207.1 [M + H – 2N2]+. HRMS: m/z calcd:
263.05704; found: 263.05688 [M + H]+. CCDC 1052351 contains
the supplementary crystallographic data for this paper. These
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unstable. Although we experienced no difficulties in handling
these compounds, all experiments were performed on a small
scale (0.4–1.0 mmol) and with best safety precautions (e.g.,
gloves, protective eyewear, shield).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2606–2610