Synthesis of 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles

Article abstract of DOI:10.1016/j.mencom.2013.07.012

Reaction between 4-bromo-5-nitrophthalonitrile and Biginelli pyrimidinethiones affords 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles.

Full text of DOI:10.1016/j.mencom.2013.07.012

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 215–216
Synthesis of 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles
Zhanna V. Chirkova,a Rinat Sh. Tukhvatshin,a Sergei I. Filimonov,*a Sergey A. Ivanovskii,a
Igor G. Abramov,a Sergey I. Firgang,b Galina A. Stashinab and Kyrill Yu. Suponitskyc
a Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 4852 44 0729;
e-mail: filimonovsi@ystu.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: galina_stashina@chemical-block.com
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 9202; e-mail: kirshik@yahoo.com
DOI: 10.1016/j.mencom.2013.07.012
Reaction between 4-bromo-5-nitrophthalonitrile and Biginelli pyrimidinethiones affords 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles.
Biginelli compounds1–3 are currently subject to intense studies
H
NC
NC
Br
R1
S
N
due to their wide-ranging bioactivity. On the other hand, sulfanyl
derivatives of phthalonitriles behave as powerful inhibitors of
monoamine oxidase B (MAO-B) and can be used for the treat-
ment of neurodegenerative disorders, such as Parkinson disease.4
In view of this, the reaction of 4-bromo-5-nitrophthalonitrile
(BNPN) 1 with 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylic acid esters 2a–e to give tricyclic compounds of the benzo-
thiazole series is of particular interest. For example, a method
was proposed for synthesizing pyrimido[2,1-b][1,3]benzothiazoles
by modified Biginelli three-component condensation where amino-
benzothiazole was used instead of thiourea, which was carried
out by prolonged heating above 100°C.5,6 A synthesis of similar
compounds at 90–95°C by nucleophilic substitution using sub-
stituted chlorodinitrobenzenes as the substrates and aqueous
potassium hydroxide as the deprotonating agent was reported.7
Previously, we described the preparation of benzofuran-5,6-di-
carbonitriles having a 2-oxo(thioxo)-1,2,3,4-tetrahydropyrimidine
moiety at 2-position using a three-component modified Biginelli
reaction.8 No data on the synthesis of substituted 7,8-dicyano-
pyrimido[2,1-b][1,3]benzothiazoles is available in the literature.
The aim of this work was to study the reaction of 4-bromo-
5-nitrophthalonitrile 19 with substituted 1,2,3,4-tetrahydropyri-
midine-2-thiones obtained by the classical three-component
Biginelli reaction.1
+
EtO
NH
NO2
1
O
R2
BNPN
2a–e
TEA
R2
R1
N
S
CN
CN
N
S
CN
CN
O
O
NH
O2N
NH
O2N
OEt R2
OEt R1
3a–e
3'a–e
R1
O
N
R2
N
S
S
EtO
EtO
N
N
CN
CN
R2
O
R1
CN
CN
4a–e
4'a–e
a R1 = Me, R2 = Ph
d R1 = Me, R2 = 2-thienyl
e R1 = Ph, R2 = 4-MeOC6H4
b R1 = Me, R2 = 4-MeC6H4
c R1 = Me, R2 = 4-MeOC6H4
Scheme 1
The reaction of BNPN 1 with compounds 2a–e was carried
out in DMF solution at room temperature for 12–20 h (until
the BNPN TLC spot disappeared) using TEA as the deproton-
ating agent. The reaction gave substituted 7,8-dicyanopyrimido-
[2,1-b][1,3]benzothiazole-3-carboxylates 4a–e in 55–78% yields
(Scheme 1). A similar product was obtained in refluxing iso-
propyl alcohol (reaction was completed in 4–8 h). According to
1H NMR data, each pyrimido[2,1-b][1,3]benzothiazole-3-carb-
oxylate is formed as one isomer. On the other hand, bearing in
mind the assumed reaction scheme, two isomeric products 4
and 4' with different structures can be formed. However, even if
reactant 2e with both aromatic substituents R1 and R2 was used,
nothing of isomeric product 4'e was detected.†
NOESY spectroscopy was used to determine the structure
of benzothiazoles 4a–e. The cross peaks of coupling of the H-6
proton in the phthalonitrile moiety with aromatic protons of the
adjacent substituent and with H-4 of the heterocycle (the most
intense signal) are the key signals for identification. This experi-
ment showed that the H-6 and H-4 hydrogen atoms are located
nearly in the same plane and at the minimum spatial distance,
whereas the substituent at the H-4 atom is in the axial position.
This arrangement of the substituents in the pyrimido[2,1-b][1,3]-
benzothiazoles remains the same as in the original Biginelli
†
IR spectra were measured on a Perkin-Elmer RX-1 spectrometer in the
range of 700–4000 cm–1 using suspensions of substances in Nujol. Mass
spectra were obtained using a FINNIGAN MAT INCOS 50 mass spec-
trometer; the ionization energy was 70 eV. NMR spectra were recorded
on a Bruker DRX-500 instrument at 30°C for solutions in DMSO-d6.
Signals of residual protons of the solvent in 1H NMR spectra (dH 2.50 ppm)
or the signal of DMSO-d6 in 13C NMR spectra (dC 39.5 ppm) were used
as references for chemical shift measurements.
Two-dimensional spectra were recorded using standard Bruker tech-
niques. The mixing time in NOESY spectra was 0.3 s.
BNPN 1 was synthesized according to a published procedure.20 Pyri-
midinethiones 2a–e were synthesized using a reported technique.21
General procedure for the synthesis of compounds 4a–e. Method A.
Pyrimidinethione 2a–e (0.01 mol) and BNPN 1 (0.01 mol) were dissolved
in DMF (10 ml). TEA (0.022 mol) was added to the solution and the
mixture was stirred for 12–20 h at room temperature. The reaction mixture
was poured into water. The resulting resinous precipitate was separated
and crystallized from ethanol.
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 215–216
compounds whose configuration was determined by XRD.10,11
In turn, this specifies the regioselectivity in the formation of
target products 4a–e.
However, the possible intermediates were never detected. One
should take into account that alkylation of Biginelli compounds
with dibromoethane18 or haloacetic acids19 under mild conditions
initially gives a product of substitution at the sulfur atom, which
then undergoes intramolecular cyclization at the N(1) atom.18
Therefore, in our case it can be assumed that initially the reac-
tion in the presence of TEA affords intermediate 3 with the most
energeticallypreferablesystemofconjugatedbonds[C(4)=N(3)],
whose stabilization is favoured by the carboxy moiety, which
leads to individual isomers 4a–e.
The data derived from NMR studies were ultimately confirmed
by XRD data for compound 4c.‡ The general view of compound
4c is shown in Figure 1. The benzothiazole moiety is planar, while
the dihydropyrimidine ring annelated with it deviates from a
planar structure towards a boat conformation [the N(1) and C(4)
atoms deviate from the plane]. In agreement with the prediction
based on NMR data, the methoxyphenyl substituent occupies an
axial position. It is rotated almost perpendicularly relative to the
plane of the tricyclic moiety [the interplanar angle is 82.46(2)°],
whereas the pseudo-torsional angle H(4)C(4)C(6)H(6) is 47°,
which corresponds to the closest approach of the hydrogen atoms.
The most interesting feature in the process we studied is that
the rare for thioamides sequential intramolecular SNAr reac-
tions12,13 readily occur. This can be explained by the Smiles
rearrangement.14–16 In reactions between BNPN and mono- or
bifunctional O-, N-, S-nucleophiles, the reactive bromine atom
was replaced first, usually to stall on monosubstitution products.17
In order to study the regularities of the reaction of substrate 1
with bifunctional pyrimidine S,N-nucleophiles 2a–e in detail,
monitoring of the process was attempted by NMR spectroscopy.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.07.012.
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Method B. Pyrimidinethione 2a–e (0.01 mol), BNPN 1 (0.01 mol) and
TEA (0.022 mol) were mixed in isopropyl alcohol (20 ml). The mixture
was refluxed for 4–8 h, then cooled. The precipitate that formed was
filtered off and recrystallized from ethanol. The yield is somewhat higher
in this method and the product is well purified by recrystallization, so the
yields are given for method B.
Ethyl 7,8-dicyano-2-methyl-4-phenyl-4H-pyrimido[2,1-b][1,3]benzo-
thiazole-3-carboxylate 4a: yield 67%, mp 218–220°C (decomp.). IR
(n/cm–1): 2232 (CºN), 1684 (C=O), 1605 (C=C), 1588 (Ar), 1243 (C–O–C).
1H NMR, d: 1.21 (t, 3H, Me, J 7.1 Hz), 2.34 (s, 3H, Me), 4.08 (dq, 2H,
CH2, J 7.1 Hz), 6.58 (s, 1H, 4-H), 7.25 (t, 1H, 4'-H, J 7.5 Hz), 7.33 (t, 2H,
3'-H, 5'-H, J 7.5 Hz), 7.51 (d, 2H, 2'-H, 6'-H, J 7.5 Hz), 8.28 (s, 1H, 9-H),
8.47 (s, 1H, 6-H). MS, m/z (%): 400 [M+] (24), 371 [M+ – Et] (27), 327
(72), 323 (100), 295 (42), 249 (29), 225 (44), 184 (24), 128 (19), 115 (15),
77 (18). Found (%): C, 65.85; H, 3.96; N, 13.93. Calc. for C22H16N4O2S
(%): C, 65.99; H, 4.03; N, 13.99.
Ethyl 7,8-dicyano-2-methyl-4-(2-thienyl)-4H-pyrimido[2,1-b][1,3]benzo-
thiazole-3-carboxylate 4d: yield 78%, mp 246–248°C (decomp.). IR
(n/cm–1): 2233 (CºN), 1670 (C=O), 1602 (C=C), 1245 (C–O–C). 1H NMR,
d: 1.23 (t, 3H, Me, J 7.1 Hz), 2.35 (s, 3H, Me), 4.13 (dq, 2H, CH2,
J 7.1 Hz), 6.93 (dd, 1H, 4'-H, J 3.5 Hz, J 5.0 Hz), 6.95 (s, 1H, 4-H), 7.25
(d, 1H, 3'-H, J 3.5 Hz), 7.42 (d, 1H, 5'-H, J 5.0 Hz), 8.50 (s, 1H, 9-H),
8.57 (s, 1H, 6-H). MS, m/z (%): 406 [M+] (38), 377 [M+ – Et] (21), 361
[M+ – OEt] (18), 333 [M+ – COOEt] (72), 250 (15), 225 (18), 184 (30),
101 (28), 58 (100), 42 (51). Found (%): C, 58.98; H, 3.56; N, 13.72. Calc.
for C20H14N4O2S2 (%): C, 59.10; H, 3.47; N, 13.78.
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Received: 11th March 2013; Com. 13/4084
‡
Crystal data for 4c. Crystals of C23H18N4O3S are monoclinic, space
group P21/n: a = 13.1107(3), b = 10.8298(3) and c = 14.6076(4) Å, b =
= 104.2200(10)°, V = 2010.53(9)Å3, Z = 4, M = 430.47, dcalc = 1.422 g cm–3,
m = 0.196 mm–1. 27642 reflections were collected by a SMART APEX II
CCD diffractometer [l(MoKa) = 0.71073 Å, graphite monochromator,
w-scans, 2q < 62°] at 100 K. The structure was solved by the direct
methods and refined by the full-matrix least-squares procedure in aniso-
tropic approximation. 6399 independent reflections (Rint = 0.0332) were
used in the refinement procedure that converged to wR2 = 0.0937 calcu-
lated on Fh2kl [GOF = 1.020, R1 = 0.0354 calculated on Fhkl using 5308
reflections with I > 2s(I)].
CCDC 923901 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2013.
For characteristics of compounds 4b,c,e, see Online Supplementary
Materials.
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