Self-condensation of 3-cyanothiochromone upon the action of benzyl- and phenethylamine

Article abstract of DOI:10.1007/s11172-010-0373-z

Reflux of 3-cyanothiochromone with benzylamine in toluene afforded 17-benzyl-6,7,14,15-tetrahydro-7,15-epiminobis(8H,16H-dithiochromeno)[2,3-b: 2′,3′-f][1,5]diazocine-6,14-dione, the self-condensation product of 2-amino-3-(benzyliminomethyl)thiochromone. Similar reaction with phenethylamine leads to 2-(thiochromon-3-yl)-5H-thiochromeno[2,3-d]-pyrimidin-5-one. Mechanism of formation of the dimeric products was considered.

Full text of DOI:10.1007/s11172-010-0373-z

Russian Chemical Bulletin, International Edition, Vol. 59, No. 11, pp. 2155—2158, November, 2010
2155
Selfꢀcondensation of 3ꢀcyanothiochromone
upon the action of benzylꢀ and phenethylamine
V. Ya. Sosnovskikh,a D. V. Sevenard,b V. S. Moshkin,a and O. S. El´tsovc
aA. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: vyacheslav.sosnovskikh@usu.ru
bHansa Fine Chemicals GmbH, BITZ,
1 Fahrenheitstrasse, 28359 Bremen, Germany
cB. N. Eltsyn Ural Federal Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation
Reflux of 3ꢀcyanothiochromone with benzylamine in toluene afforded 17ꢀbenzylꢀ6,7,14,15ꢀ
tetrahydroꢀ7,15ꢀepiminobis(8H,16Hꢀdithiochromeno)[2,3ꢀb:2´,3´ꢀf][1,5]diazocineꢀ6,14ꢀdiꢀ
one, the selfꢀcondensation product of 2ꢀaminoꢀ3ꢀ(benzyliminomethyl)thiochromone. Similar
reaction with phenethylamine leads to 2ꢀ(thiochromonꢀ3ꢀyl)ꢀ5Hꢀthiochromeno[2,3ꢀd]ꢀ
pyrimidinꢀ5ꢀone. Mechanism of formation of the dimeric products was considered.
Key words: 3ꢀcyanothiochromone, benzylamine, phenethylamines, selfꢀcondensation,
17ꢀbenzylꢀ6,7,14,15ꢀtetrahydroꢀ7,15ꢀepiminobis(8H,16Hꢀdithiochromeno)[2,3ꢀb:2´,3´ꢀf]ꢀ
[1,5]diazocineꢀ6,14ꢀdione, 2ꢀ(4ꢀoxoꢀ4Hꢀthiochromenꢀ3ꢀyl)ꢀ5Hꢀthiochromeno[2,3ꢀd]pyrꢀ
imidinꢀ5ꢀone.
It is known that treatment of 3ꢀformylchromone (1a)
and 3ꢀformylthiochromone (1b) with hydroxylamine easily
leads to the formation of 3ꢀcyanochromone (2a)1,2 and
3ꢀcyanothiochromone (2b).3 Chemical properties of
3ꢀcyanochromone (2a) were studied in detail.4 One of its
most important reactions is the reaction with water, which
yields 2ꢀaminoꢀ3ꢀformylchromone (3a)5,6 capable of selfꢀ
condensation to 2ꢀ(4ꢀoxoꢀ4Hꢀchromenꢀ3ꢀyl)ꢀ5Hꢀchromꢀ
eno[2,3ꢀd]pyrimidinꢀ5ꢀone (4a)7,8 (Scheme 1). Unlike for
2a, data on the reactivity of 3ꢀcyanothiochromone (2b)
are absent in the literature.
conditions used earlier5,6 for the preparation of amino alꢀ
dehyde 3a, that is apparently due to higher aromaticity of
the thiopyrone ring and lower electrophilicity of the C(2)
atom, which hinders addition of the water molecule at this
atom and cleavage of the S—C(2) bond. Nevertheless,
reflux of nitrile 2b with benzylamine in the presence of
Et3N in toluene for 1 h led to 72% isolated yield of imine
of the target chromone 3b, viz., 2ꢀaminoꢀ3ꢀ(benzylꢀ
iminomethyl)thiochromone (5). Further treatment of 5
with benzylamine (toluene, Et3N, reflux, 12 h) revealed
a new direction of the reaction, which is uncharacteristic
of the chromone system. It turned out that under these
conditions, imine 5 dimerizes to 2,6,9ꢀtriazabicycloꢀ
[3.3.1]nonane 6 in 28% yield, which increases to 37% if
the reaction is carried out directly from 2b without isoꢀ
lation of the intermediate imine 5. As far as we know,
Results and Discussion
While studying9 chemical properties of thiochromones
1b and 2b, we failed in the transformation 2b → 3b under
Scheme 1
X = O (a), S (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2101—2103, November, 2010.
1066ꢀ5285/10/5911ꢀ2155 © 2010 Springer Science+Business Media, Inc.

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Sosnovskikh et al.
Scheme 2
4´
Reaction conditions: i. PhCH3, Et3N, reflux 1 h; ii. PhCH3, Et3N, reflux 10—12 h.
derivatives obtained earlier10 by the reaction of 5ꢀaminoꢀ
3,4ꢀdiphenylthieno[2,3ꢀc]pyridazineꢀ6ꢀcarbaldehyde with
aliphatic primary amines were the only example of 1,5ꢀdiꢀ
azocines fused with a heterocyclic system. Note that simꢀ
ilar reaction of 3ꢀcyanothiochromone (2b) with phenꢀ
ethylamine gave the earlier unknown dimer 4b, which is
a thioanalog of chromenopyrimidine 4a (Scheme 2).
It is important to note that the keeping a sample of 6 in
DMSOꢀd6 leads to the appearance of signals for the secꢀ
ond compound, which turned to be identical to 2ꢀ(4ꢀoxoꢀ
4Hꢀthiochromenꢀ3ꢀyl)ꢀ5Hꢀthiochromeno[2,3ꢀd]pyrimidinꢀ
5ꢀone (4b). A prolonged keeping at room temperature for
12 days, heating at 70—90 °C for 2 h, as well as addition of
CF3CO2D, lead only to a somewhat (from 15 to 20%)
increase in the content of dimer 4b. A plausible mechaꢀ
nism of transformation 5 → 6 → 4b is given in Scheme 3
and includes in the initial step (addition involving the
amino group of one molecule at the benzylimino funcꢀ
tional group of other molecule) formation of intermediate
A, whose further intramolecular cyclization due to the
elimination of one molecule of benzylamine as a result of
1,2ꢀAN and SN reactions gives 1,5ꢀdiazocine 6. This comꢀ
pound, being a diaminal, is capable of further partial
recyclization to thermodynamically more stable thioꢀ
Scheme 3
R = CH2Ph, CH2CH2Ph

Selfꢀcondensation of 3ꢀcyanothiochromone
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 11, November, 2010 2157
2ꢀAminoꢀ3ꢀ(benzyliminomethyl)thiochromone (5). A solution
of thiochromone 2b (150 mg, 0.8 mmol), benzylamine (85 mg,
0.8 mmol), and triethylamine (2 drops) in toluene (3 mL) was
refluxed for 1 h. After the reaction mixture was cooled, a precipꢀ
itate formed was filtered off, sequentially washed with toluene
and diethyl ether, and dried. The yield was 170 mg (73%),
a yellowish powder, m.p. 218—219 °C. IR, ν/cm–1: 3236, 3210,
1615, 1590, 1576, 1527, 1509. Found (%): C, 68.94; H, 4.52;
N, 9.22. C17H14N2OS. Calculated (%): C, 69.36; H, 4.79; N, 9.52.
1H NMR, δ: 4.73 (s, 2 H, CH2); 7.24—7.38 (m, 5 H, Ph);
7.45—7.50 (m, 1 H, H(6)); 7.58—7.62 (m, 2 H, H(7), H(8));
8.28 (d, 1 H, H(5), J = 7.7 Hz); 9.03 (s, 1 H, HC=N); 9.08 (br.s,
1 H, NH); 11.81 (br.s, 1 H, NH).
17ꢀBenzylꢀ6,7,14,15ꢀtetrahydroꢀ7,15ꢀepiminobis(8H,16Hꢀ
dithiochromeno)[2,3ꢀb:2´,3´ꢀf][1,5]diazocineꢀ6,14ꢀdione (6). A.
A solution of thiochromone 2b (150 mg, 0.8 mmol), benzylamine
(135 mg, 1.26 mmol), and triethylamine (4 drops) in toluene
(3 mL) was refluxed for 14 h. After the reaction mixture was
cooled, a precipitate formed was filtered off, sequentially washed
with toluene and diethyl ether, and dried. The yield of the product
was 72 mg (37%).
chromenopyrimidine 4b through the intermediates B, C,
D, and E. We assume that this process consists in the
8ꢀmembered ring opening to the intermediate B and
1,4ꢀANꢀaddition of the amino group at the enone fragꢀ
ment with the formation of spiro intermediate C, which
further through pyrimidines D and E recyclizes to thioꢀ
chromeno[2,3ꢀd]pyrimidinꢀ5ꢀone 4b with the loss of the
second molecule of benzylamine (Scheme 3).
In the case of 2b and phenethylamine, the initially
formed chromone 5 with the phenethyl group at the imine
nitrogen atom undergoes selfꢀcondensation to the interꢀ
mediate A, which, omitting the step of formation of comꢀ
pound 6 (1,2ꢀAN), directly gives B. Further, intermediate
B by the 1,4ꢀAN mechanism cyclizes to the intermediate
C, which through D and E is transformed to dimer 4b.
In the 1H NMR spectrum of 1,5ꢀdiazocine 6 in
DMSOꢀd6, in addition to the signals of aromatic protons
there are present signals for the NCH2 group of ABꢀsysꢀ
2
tem (δ 3.64, JAB = 13.2 Hz), that reflects a chiral nature
B. A solution of thiochromone 5 (150 mg, 0.51 mmol),
benzylamine (55 mg, 0.51 mmol), and triethylamine (2 drops) in
toluene (3 mL) was refluxed for 12 h. The treatment described in
procedure A yielded compound 6 (35 mg, 28%). Colorless powꢀ
der, m.p. 240—242 °C. IR (DTIR), ν/cm–1: 3243, 3211, 1595,
1574, 1561, 1504. Found (%): C, 66.95; H, 3.63; N, 8.62.
C27H19N3O2S2. Calculated (%): C, 67.34; H, 3.98; N, 8.73.
1H NMR, δ: 3.64 (ABꢀsystem, 2 H, CH2, J = 13.2 Hz); 5.34 (d, 2 H,
2 CH, J = 3.3 Hz); 7.27—7.38 (m, 5 H, Ph); 7.46 (ddd, 2 H,
2 H(6), J = 8.0 Hz, J = 7.3 Hz, J = 1.2 Hz); 7.56 (td, 2 H, 2 H(7),
J = 7.5 Hz, J = 1.5 Hz); 7.62 (dd, 2 H, 2 H(8), J = 8.0 Hz,
J = 1.0 Hz); 8.24 (dd, 2 H, 2 H(5), J = 8.0 Hz, J = 1.5 Hz); 9.52
(d, 2 H, 2 NH, J = 3.3 Hz). 13C NMR, δ: 53.1, 61.0, 106.2, 126.0,
126.8, 127.5, 128.4, 129.1, 129.4, 131.0, 132.2, 137.2, 153.4, 174.6.
2ꢀ(4ꢀOxoꢀ4Hꢀthiochromenꢀ3ꢀyl)ꢀ5Hꢀthiochromeno[2,3ꢀd]ꢀ
pyrimidinꢀ5ꢀone (4b). A solution of thiochromone 2b (150 mg,
0.8 mmol), phenethylamine (145 mg, 1.2 mmol), and triethylꢀ
amine (4 drops) in toluene (3 mL) was refluxed for 10 h. After
the reaction mixture was cooled, a precipitate formed was filꢀ
tered off, washed with toluene, recrystallized from acetic acid,
and dried. The yield was 37 mg (25%), yellow needleꢀlike crysꢀ
tals, m.p. 248—250 °C. IR (DTIR), ν/cm–1: 1633, 1587, 1547,
1510. Found (%): C, 63.83; H, 2.65; N, 7.46. C20H10N2O2S2.
Calculated (%): C, 64.15; H, 2.69; N, 7.48. 1H NMR, δ: 7.69 (t, 1 H,
H(6´), J = 7.5 Hz); 7.71 (t, 1 H, H(7), J = 7.5 Hz); 7.81 (td, 1 H,
H(7´), J = 7.5 Hz, J = 1.2 Hz); 7.87 (td, 1 H, H(8), J = 7.5 Hz,
J = 1.2 Hz); 7.94 (dd, 1 H, H(8´), J = 8.5 Hz); 7.96 (d, 1 H, H(9),
J = 8.5 Hz); 8.46 (dd, 1 H, H(5´), J = 8.0 Hz, J = 1.5 Hz); 8.48
(dd, 1 H, H(6), J = 8.0 Hz, J = 1.5 Hz); 9.07 (s, 1 H, H(2´)); 9.59
(s, 1 H, H(4)). 13C NMR, δ: 121.5 (C(4a)), 127.8 (C(8´)), 127.9
(C(9)), 128.4 (C(6´)), 128.8 (C(7)), 129.1 (C(5´)), 129.5 (C(6)),
129.9 (C(5a)), 132.6 (C(7´)), 132.9 (C(3´)), 133.1 (C(4a´)), 134.5
(C(8)), 135.8 (C(9a)), 136.5 (C(8a´)), 145.0 (C(2´)), 158.9 (C(4)),
164.8 (C(2)), 167.5 (C(10a)), 176.7 (C(4´)), 179.2 (C(5)).
of compound 6, and two twoꢀproton doublets for the CH
and NH groups at δ 5.34 and 9.52 (3JCH,NH = 3.3 Hz),
respectively. The structure of dimer 4b was confirmed by
the 1H and 13C NMR spectroscopic data, full assignment
of all the signals was made based on analysis of the results
of 1H—13C HSQC and HMBC 2Dꢀexperiments. The most
informative are the following crossꢀpeaks in the 2D HMBC
spectrum in DMSOꢀd6: H(2´)/C(3´), H(2´)/C(8a´),
H(2´)/C(2), H(2´)/C(4´), H(4)/C(4a), H(4)/C(2),
H(4)/C(10a), H(4)/C(5). The 1H NMR spectrum of comꢀ
pound 4b is characterized by a double set of signals for the
aromatic protons, which are very close in chemical shifts
and partially overlap, as a result, the doublets of doublets
for the protons H(6) and H(5´) are found at δ 8.47 as
a triplet of doublets with J = 8.0, 1.5 Hz. The signals for
the protons H(2´) and H(4) are the most downfield and
are observed at δ 9.07 and 9.59, respectively.
In conclusion, selfꢀcondensation of 3ꢀcyanothioꢀ
chromone upon the action of benzylamine or phenethyꢀ
lamine in boiling toluene leads to different products. In
the first case, to the product of dimerization, 17ꢀbenzylꢀ
6,7,14,15ꢀtetrahydroꢀ7,15ꢀepiminobis(8H,16Hꢀdithioꢀ
chromeno)[2,3ꢀb:2´,3´ꢀf][1,5]diazocineꢀ6,14ꢀdione, while
in the second, to 2ꢀ(thiochromonꢀ3ꢀyl)ꢀ5Hꢀthiochromꢀ
eno[2,3ꢀd]pyrimidinꢀ5ꢀone.
Experimental
IR spectra were recorded on a Perkin—Elmer Spectrum BXꢀII
spectrometer in KBr pellets and Bruker Alpha FTIR spectromeꢀ
ter with the appliance of disturbed total internal reflection
(DTIR) (ZnSe crystal). 1H and 13C NMR spectra were recorded
on a Bruker DRXꢀ400 and Bruker Avance II spectrometer in
DMSOꢀd6 (400 and 100 MHz, respectively) using Me4Si as an
internal standard. 3ꢀCyanothiochromone 2b was obtained acꢀ
cording to the known procedure.3
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Received July 8, 2010