Iodine mediated an efficient and greener thiocyanation of aminopyrimidines by a modification of the Kaufmann's reaction

Article abstract of DOI:10.1016/j.tetlet.2011.03.058

A new, safe, and efficient methodology for the thiocyanation of some aminopyrimidine derivatives has been implemented. The thiocyanation reactions proceeded at room temperature with high yields and selectivity. This route is a less toxic alternative to other common thiocyanation techniques because it uses molecular iodine as a halogen source, which is less reactive and easier to handle than chlorine or bromine.

Full text of DOI:10.1016/j.tetlet.2011.03.058

Tetrahedron Letters 52 (2011) 2652–2654
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Tetrahedron Letters
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Iodine mediated an efficient and greener thiocyanation of aminopyrimidines
by a modification of the Kaufmann’s reaction
Ricaurte Rodríguez a, , Patricia Camargo a, César A. Sierra a, Carlos Y. Soto a, Justo Cobo b, , Manuel Nogueras b
⇑
⇑
a Departamento de Química, Universidad Nacional de Colombia, Bogotá AA 14490, Colombia
b Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, safe, and efficient methodology for the thiocyanation of some aminopyrimidine derivatives has
been implemented. The thiocyanation reactions proceeded at room temperature with high yields and
selectivity. This route is a less toxic alternative to other common thiocyanation techniques because it
uses molecular iodine as a halogen source, which is less reactive and easier to handle than chlorine or
bromine.
Received 6 February 2011
Revised 10 March 2011
Accepted 11 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Thiocyanation
Aminopyrimidines
Molecular iodine
Kaufmann’s reaction
2-Aminothiazolo[4,5-d]pyrimidines
From the synthetic point of view thiocyanation of aliphatic and
aromatic organic compounds is a gateway to new kinds of organic
molecules, which are very attractive for medicinal and organic syn-
thetic chemists, as they can be transformed into a new class of
compounds with a sulfur atom in their structures.
There is very little detailed experimental information about the
synthesis of several thiocyanates of aminopyrimidine derivatives.
The most common procedure, known as the Kaufmann methodol-
ogy,1 has several drawbacks. These issues include the employment
of acetic acid or pyridine as a solvent, low temperature, excess of
reagent, and the use of molecular chlorine or bromine, which are
highly toxic and difficult to handle. Furthermore, in most of the
cases, the reported yields under these reaction conditions are low
as a result of complex reaction mixtures.2
C) can undergo an intramolecular nucleophilic attack to yield
compounds type D and/or E (Scheme 1).
The controversial findings on the thiocyanation of some
aminopyrimidine derivatives and the fact that there is not enough
information available in the literature5 about the structural charac-
terization of the final products encourage us to find an optional
synthetic methodology. So, in our continuing research program
on the reactivity and transformation of aminopyrimidine
derivatives into new compounds with attractive pharmacological
activity,6 we envisioned that molecular iodine, owing to its unique
properties as nontoxic and easy to handle mild catalyst, can be
used as a halogen source in the Kaufmann reaction.
On the other hand, there is a significant discrepancy regarding
the results from the thiocyanation of some aminopyrimidines at
the C-5 position. Baker and Chatfield reported the synthesis of
compounds type A; while Maggiolo and Hitchings have claimed
the synthesis of 2-aminothiazolo[4,5-d]pyrimidine derivatives
(type B) occurring via an intermediate type A, under similar exper-
imental conditions. At the same time, Maggiolo and Hitchings have
reported that under heating thiocyanopyrimidine compounds
(type A) can be transformed into isothiocyanopyrimidine deriva-
tives type C.2–4 Subsequently, it is possible that compounds (type
R
2
R
2
R
1
S
N
R
NCS
NH
N
1
N
NH
2
R
Δ
N
B
R
N
C
2 Δ
R
2
3
5
6
R
SCN
1
N
Δ
R
N
NH
2
2
R
R
2
A
2
H
N
H
N
R
R
1
1
N
N
SH
S
N
N
H
R
N
D
R
N
⇑
Corresponding authors. Tel.: +57 1 3165000; fax: +57 1 3165220 (R.R.).
E-mail addresses: rrodrigueza@unal.edu.co (R. Rodríguez), jcobo@ujaen.es (J.
E
Cobo).
Scheme 1. Possible transformations of thiocyanate derivative A.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.058

R. Rodríguez et al. / Tetrahedron Letters 52 (2011) 2652–2654
2653
could be rationalized on the basis of the different transformations
that compounds type A can undergo (Scheme 1).3,11
R
R
1
1
SCN
N
N
N
We want to comment on two facts in these reactions. The first is
that when 2-amino-4,6-dichloropyrimidine was subjected to react
under the described conditions, no product was formed. This fact is
presumably due to the presence of electron-withdrawing chlorine
atoms, which deactivate the pyrimidine ring toward the electro-
philic species. The second point concerns 2,4,6-triaminopyrimidine
(7), which is highly activated, as opposed to 2-amino-4,6-dichloro-
pyrimidine. The reaction takes place in 5 min at 0 °C, and gives a
complex mixture of compounds. On the bases of IR and NMR spec-
tra we speculated that that mixture is constituted basically by the
thiocyanate derivative 9 (2044 cmÀ1 in the IR spectrum and
111.95 ppm in the 13C NMR) and the corresponding 2-aminothiaz-
olo[4,5-d]pyrimidine derivative since in the 1H NMR spectrum
there is no signal from 4.0 to 6.0 ppm for the proton at the C-5 po-
sition of the starting 2,4,6-triaminopyrimidine.10
R
N
R
R
R
R
N
R
2
2
1a-f
2a-f
O
O
R
1
R
1
SCN
NH4SCN
I2 / MeOH
r.t.
N
R
N
R
N
R
2
2
3a-f
4a-f
O
O
R
1
R
1
SCN
N
N
O
N
O
N
R
6a-b
R
2
2
R
1
1
5a-b
Scheme 2. Thiocyanation of some aminopyrimidine derivatives.
Surprisingly, in the latter case, our findings are in contradiction
with those of Baker and Chatfield who claimed the synthesis of
compound 9 in refluxing ethanol (Scheme 3).3
During the preparation of this manuscript, an article was pub-
lished that confirms our findings on the reactivity of some triami-
nopyrimidines toward thiocyanation, and the important role of the
5-thiocyanatopyrimidines that we are reporting here as intermedi-
ates in the synthesis of other interesting compounds.11
We report here a green, practical, and efficient methodology for
the thiocyanation of some aminopyrimidine derivatives without
any ambiguity, using molecular iodine to promote the reaction
and methanol as a solvent at room temperature.7 To the best of
our knowledge, this is the first time that iodine is used in a
Kaufmann type reaction with aminopyrimidines derivatives
(Scheme 2).
Each compound was fully characterized on the basis of its ana-
lytical and spectroscopic properties as IR, 1H and 13C NMR (includ-
ing DEPT-135) or MS.
A possible mechanism for the electrophilic thiocyanation of the
aminopyrimidine derivatives is depicted in Scheme 4.
Preliminary biological screenings have demonstrated that some
of these thiocyanate derivatives exhibit interesting inhibitory ac-
tion on Escherichia coli and Mycobacterium smegmatatis cultures.
In conclusion, we have established a new, greener, practical,
and efficient methodology which uses molecular iodine for obtain-
As shown in Table 1, this methodology affords the expected
products in good to excellent yields.
In all 1H NMR spectra, it is possible to observe the disappear-
ance of the signal between 4.1 and 6.0 ppm due to the proton at
the C-5 position from the starting aminopyrimidine. This informa-
tion together with the appearance of a signal for a quaternary car-
bon between 111.1 and 113.0 ppm in the 13C NMR spectra, clearly
show the thiocyanation of the aminopyrimidine derivatives (signal
for isothiocyanates appears at around 130 ppm).9 These findings
are corroborated by FT-IR spectra, which show a signal between
2141 and 2160 cmÀ1 assignable to the thiocyanate group.
On the other hand, the fact that some of the synthesized com-
pounds decompose during melting point measurement (Table 1)
NH2
NH2
NH2
Br
SCN
NH2
KSCN
Br2
N
N
N
EtOH
Δ
H2N
N
7
NH2
H2N
N
8
NH2
H2N
N
9
30min
Scheme 3. Reported synthesis of thiocyanate derivative 9.
Table 1
Products from thiocyanation of aminopyrimidine derivatives: 1a–f, 3a–f and 5a,b
Compounda
R
R1
R2
tb (min)
Yieldc (%)
Mpd (°C)
IRe
(m
cmÀ1
)
13C NMRf
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
SMe
NH2
SMe
OMe
NH2
NH2
NH2
OMe
SMe
SMe
Me
NH2
OMe
OMe
OMe
OMe
Cl
H
H
Me
H
H
NH2
OMe
NH2
NH2
Me
15
20
60
87g
70
75
92
50
0
90
95
87
85i
86
95
73g
86
197–200
192–194
161–164
155–158
190–192
____
239–241
207–210
178–181
208–210
197–199
189–193
232–234
156–158
2156
2155
2156
2152
2155
____
2152
2155
2156
2156
2141
2156
2160
2160
111.2
112.0
111.1
111.4
111.6
____
113.0
112.3
111.8
111.2
111.9
112.2
112.6
112.4
45
120
____h
25
20
20
30
30
35
70
Cl
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
OMe
—
—
Me
H
Me
6a
6b
20
a
b
c
d
e
f
As shown in Scheme 2.
TLC controlled.
Yields of isolated products.
Most of them are actually decomposition rather than melting points.
Absorption band for the thiocyanate group.
Chemical shift for the thiocyano carbon.
Ref. 3.
After 24 h at room temperature.
Ref. 8.
g
h
i

2654
R. Rodríguez et al. / Tetrahedron Letters 52 (2011) 2652–2654
-I-
References and notes
+SCN
R1
NH4SCN +
NCS I
I
I
-NH4I
R1
1. (a) Kaufman, H. P.; Weber, E. Arch. Pharm. 1929, 267, 201; (b) Kaufmann, H. P.
Ber. 1929, 62, 390; (c) Kaufmann, H. P.; Kuchler, K. Ber. 1934, 67, 944; (d)
Kaufmann, H. P.; Schulz, P. Arch. Pharm. 1935, 31, 273.
R1
+SCN
NH2
H
SCN
SCN
2. Maggiolo, A.; Hitchings, G. H. J. Am. Chem. Soc. 1951, 73, 4226.
3. Baker, J. A.; Chatfield, P. V. J. Chem. Soc. (C) 1970, 2478.
4. Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzukib, Y.; Kodomari, M.
Tetrahedron 2006, 62, 3201.
N
N
N
N
-H+
N
R
R
NH2
N
R
NH2
5.
A ) showed some thiocyanates of
recent search on the web (SciFinderÒ
Scheme 4. Proposed mechanism for the thiocyanation.
aminopyrimidine derivatives unfortunately in most of the cases there were
not bibliographic information available.
6. (a) Insuasty, B.; García, A.; Quiroga, J.; Abonia, R.; Nogueras, M.; Cobo, J. Eur. J.
Med. Chem. 2010, 45, 2841; (b) Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2010, 51, 1107; (c)
Rodríguez, R.; Nogueras, M.; Cobo, J.; Glidewell, C. Acta Crystallogr. 2009, C65,
o111; (d) Rodríguez, R.; Nogueras, M.; Cobo, J.; Glidewell, C. Acta Crystallogr.
2009, C65, o441; (e) Quiroga, J.; Trilleras, J.; Gálvez, J.; Insuasty, B.; Abonía, R.;
Nogueras, M.; Cobo, J. Tetrahedron Lett. 2009, 50, 6404; (f) Cobo, J.; Nogueras,
M.; Low, J. N.; Rodríguez, R. Tetrahedron Lett. 2008, 49, 7272; (g) Rodríguez, R.;
Cobo, J.; Nogueras, M.; Low, J. N.; Glidewell, C. Acta Crystallogr. 2008, C64, o376;
(h) Rodríguez, R.; Cobo, J.; Nogueras, M.; Low, J. N.; Glidewell, C. Acta
Crystallogr. 2008, C64, o392; (i) Insuasty, B.; Orozco, F.; Lizarazo, C.; Quiroga,
J.; Abonia, R.; Hursthouse, M.; Nogueras, M.; Cobo, J. Bioorg. Med. Chem. 2008,
16, 8492; (j) Quiroga, J.; Trilleras, J.; Gálvez, J.; Insuasty, B.; Abonía, R.;
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7. General procedure for thiocyanation of aminopyrimidine derivatives: Ammonium
thiocyanate (3 mmol) and iodine (1.0 mmol) are added at room temperature to
a stirred solution of the corresponding aminopyrimidine derivative (1.0 mmol)
in methanol (10 mL). After completion of the reaction (TLC control), a sodium
thiosulfate solution [20% (w/v)] is added to destroy the remaining iodine. The
solid formed is filtered off, washed with water, and recrystallized from a
methanol/water solution. For more details see Table 1 and Supplementary data.
8. Okafor, C. O. J. Heterocycl. Chem. 1980, 17, 1587.
ing several thiocyanates of aminopyrimidine derivatives, which
have been fully characterized, and show promising bioactivities.
In addition, these compounds constitute a valuable precursor to
potential bioactive fused pyrimidine derivatives bearing a sulfur
atom in the heterocyclic nucleus.
Acknowledgments
R.R. thanks Fundación Banco de la República (project reference
2575) for the financial support to this investigation. J.C. and M.N.
thank the Consejería de Economía, Innovación y Ciencia (Junta de
Andalucía, Spain), the Universidad de Jaén and Ministerio de Cien-
cia e Innovación (project reference SAF2008-04685-C02-02) for
financial support. Authors thank Christopher Thompson for
reviewing the present manuscript.
Supplementary data
9. At the same time the typical signal for a tertiary carbon at C-5 position
disappears in DEPT-135 spectra.
10. For details see Supplementary data.
11. Jang, M. Y.; Jonghe, S.; Segers, K.; Anné, J.; Herdewijn, P. Bioorg. Med. Chem.
2011, 19, 702.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.058.