Synthesis and reactivity of spiro[1,3,4-thiadiazoline-2,4′- thioflavans] and analogues

Article abstract of DOI:10.1002/jhet.25

(Chemical Equation Presented) Racemic thioflavanone (thio)acylhydrazones undergo transformation into racemic 3-acetylspiro[1,3,4-oxa(thia)-diazoline-2, 4′-thioflavans] with trans O(1) or S(1) and Ph(2′eq) under acetylating conditions. Conjugation between the ethylenic bond and sp ² C(4) in thioflavones encumber both the formation of (thio)acylhydrazones and their subsequent spirocyclization. On the other hand, subsequent dehydrogenation of the thiopyran moiety of spiro compounds results in formation of sp² C(4) and simultaneous degradation of the spirodiazoline ring.

Full text of DOI:10.1002/jhet.25

May 2009
Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-
thioflavans] and Analogues
399
´ ´
Laszlo Somogyi*
Department of Organic Chemistry, University of Debrecen, Debrecen H-4010, Hungary
*E-mail: somoladeszerv@freemail.hu
Received May 29, 2008
DOI 10.1002/jhet.25
Published online 7 May 2009 in Wiley InterScience (www.interscience.wiley.com).
Racemic thioflavanone (thio)acylhydrazones undergo transformation into racemic 3-acetylspiro[1,3,4-
oxa(thia)-diazoline-2,40-thioflavans] with trans O(1) or S(1) and Ph(20eq) under acetylating conditions.
Conjugation between the ethylenic bond and sp2 C(4) in thioflavones encumber both the formation of
(thio)acylhydrazones and their subsequent spirocyclization. On the other hand, subsequent dehydrogena-
tion of the thiopyran moiety of spiro compounds results in formation of sp2 C(4) and simultaneous
degradation of the spirodiazoline ring.
J. Heterocyclic Chem., 46, 399 (2009).
INTRODUCTION
examinations for the synthesis of 2-phenyltetrahydro-
quinoline (5j) [16] and flavanone-spiro-oxa(thia)diazol-
ines (5k, l) [17a], respectively, we aimed at the synthe-
sis of their bioisosteric spiro-thioflavonoid analogs [l7b].
A great variety of natural benzopyrans, e.g., chrom
(an)ones, flav(an)ones, exhibit biological activity and
have beneficial effects as free radical scavengers, antiox-
idants, CNS active agents, aldose reductase inhibitors
[1], aromatase inhibitors [2], etc. Some synthetic (halo-
genated, nitro) derivatives have significant anxiolytic
properties [3]. Carbonyl condensation products, e.g.,
oximes [4], imines [5], acyl hydrazones, thiosemicarba-
zones [6] have been reported to display antimicrobial
and estrogen receptor activities, respectively. Also
flavone-related, naturally occurring 2-arylquinolines [7]
and antimitotic 2-phenylquinolones [8] are known.
RESULTS AND DISCUSSION
As potential substrates for cyclization into oxa(thia)-
diazolines 5a–i under acetylating conditions, hydrazone
derivatives 3 and 4 of thioflav(an)ones 1 and 2 were
prepared from the corresponding carbonyl parent com-
pounds 1 and 2, respectively, by known methods (see
Table 3 and Experimental section).
Recently, also the chemistry and the biological proper-
ties of the bioisosteric thioflavonoid compounds [9],
including (spiro)heterocyclic derivatives [10], excite
increasing interest. Thiochrom(an)ones and thioflav
(an)ones as well as their 1-oxides and 1,1-dioxides have
been reported to have antimicrobial [11], antiviral [12],
and antitumor [8,9c,13] properties. The synthesis and her-
bicidal properties of benzothiopyran-4-one hydrazones
[14a] and related cyclic O-O-acetals spiro[benzothio-
pyran-4,20-dioxolanes] [14b] have been described, as well.
Formerly, we have observed that under physiological
conditions the potentially biological active cyclic
N,O- and N,S-acetals 3-acetyl-1,3,4-oxa(thia)diazolines
undergo deacetylation and transform into (thio)acylhy-
drazones [15]. Therefore, in consideration of the afore-
mentioned literature findings, as an extension of our
In comparison with aryl aralkyl ketones due to elec-
tronic (e.g., conjugative) effects aryl vinyl ketones exhibit
a diminished reactivity toward carbonyl condensation
agents. This is markedly valid for the cyclic analogs
(thio)flavones [18], capable of resonance between contrib-
uting (thio)benzopyrylium dipole structures. Moreover
C
V
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400
L. Somogyi
Vol 46
also the oxidation state of sulfur in these unsaturated com-
pounds (e.g., 2a–c) affects reactivity [19]. Nevertheless,
analogously to the synthesis of flavone (acyl)hydrazones
[18a,b] thioflavone hydrazone (4a) has been successfully
produced [19b,c] by condensing hydrazine with thio-
flaven-4-thione [20] or its derivative 4-methylthio-
flavylium iodide [19b], instead of thioflavone (2a).
Spirocyclization of racemic thioflavanone (thio)acyl-
hydrazones 3 into spiro(thia)oxadiazolines 5a–e was
accomplished (see Table 4) in good yields by using
acetylating agents Ac2O/py or Ac2O/ZnCl2 previously
successfully applied [16,17,21] for (spiro)cyclization of
various ketone (thio)acylhydrazones. As a result of the
heterocyclization, C(4) of the thiopyran ring became sp3
hybridized and asymmetric, thus theoretically enabling
the formation of racemic 2,4-diastereomers. Newly
As to the conjugation between the sp2 C(4) and the
C¼¼C bond of the thioflaven ring, similarly to that previ-
ously found [17a] for the flavone analogs, this encumbered
not only the formation of (thio)acylhydrazones but also
their subsequent cyclization into spiro(thia)oxadiazolines.
On the other hand, devoid of a chance for conjugation,
dehydrogenation of the thiopyran ring of the spirohetero-
cycles 5 became difficult in comparison with that of the thi-
oflavanone parent compound (1a) [21], nevertheless when
eventually performed, it led to the cleavage of the diazo-
line rings with transformation of the spiro-C into the sp2
hybrid state (C(4)¼¼O,N). Therefore, the mutual action of
the hybrid electron orbital states of C(4) and C(2), C(3)
carbons was studied experimentally in detail with the
(trans)formation of spirocompounds 5 and their precursors
(acyl)hydrazones 3, 4, and related compounds as well.
spirothiadiazolines 5c,d,e with trans S(1) and Ph(20eq
)
structures were stated to form HPLC separable isomers
in solution due to a hindered rotation of the endocyclic
N(3)Ac group [17b] (Scheme 1). Recently, the stereo-
structure of 3-acetylspiro[1,3,4-oxadiazoline-2,40-thiofla-
van] (5a) and 3-acetylspiro[1,3,4-thiadiazoline-2,40-thio-
flavans] (5c,d,e), prepared likewise under acetylating
conditions, has been stated by 1H- and 13C NMR, as
well as X-ray analytical methods and MOPAC QM cal-
culations to have trans O(1) or S(1) and Ph(20eq) [17b].
1
The ‘‘anomalous’’ H NMR spectra (remarkable down-
field shift of signals H(30ax), attributed to the anisotropy
Scheme 1
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Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-thioflavans] and Analogues
401
Table 1
1
200 MHz H NMR(CDCl3) data of thioflavans 3a-c.a
d (ppm)
J (Hz)
2ax,3eq
Compound
H(2ax
)
H(3ax
)
H(3eq
)
2ax,3ax
3ax,3eq
d other
3a
3b
3c
4.35
4.40
4.47
2.88
3.02
2.92
3.27
3.31
3.08
12.4
12.5
11.5
3.5
3.5
3.5
16.8
17.0
15.5
5.39 (2H,NH2)
9.08 (NH), 2.38 (Ac)
2.34 (2Ac)
a For data of 1a-c see ref. [22a].
effect of the near N(3)Ac C¼¼O group) are observed
also in the present work (Tables 1 and 2) confirming the
analogous stereostructure of spiro products 5a,b,f–i.
Treatment of semicarbazone 3d with Ac2O/ZnCl2 at
room temperature for 3d afforded oxadiazoline 5a
(Scheme 2) but with Ac2O/py at 100ꢀC for 3 h 5a and
diacetylhydrazone 3c. Similarly, on treatment with
Ac2O/py at 145ꢀC (bath) for 45 min phenylthiosemicar-
bazone 3f underwent transformation to give thiadiazo-
line 5e (mp 192–194ꢀC, from EtOAc) and oxadiazoline
5a (mp 210.5–212ꢀC, from CHCl3/EtOAc), after purifi-
cation by column chromatography, in 60 and 6% yields,
respectively [17b]. The degradation of semicarbazones
[23] and thiosemicarbazones [17a,23a,c] under acylating
conditions is well documented. By treatment with Ac2O/
ZnCl2 at room temperature, thioflavanone acetylhydra-
zone (3b) was transformed into spiro-oxadiazoline 5a
(see Scheme 2 and Table 4). Under similar conditions,
however, semicarbazone 1,1-dioxide 3h resisted cycliza-
tion and also degradation to the corresponding acetyl-
hydrazone, instead acetylsemicarbazone 3i was formed
(Scheme 3), 200 MHz 1H NMR(DMSO-d6, d, ppm):
11.53 and 10.75, 2 brs, 2H, 2NH; 2.14, s, 3H, Ac.
Attempted syntheses of 5h and 5j by treating 3h and 3g,
respectively, with Ac2O/pyridine at 100ꢀC for 3 h
resulted in the formation of multicomponent mixtures.
Thus, the tendency for spiro-cyclization seems to be
diminished or even ceased by the presence of strong
electron-withdrawing components at position 1. There-
fore, the synthesis of spiro-oxadiazoline 10-oxides and
10,10-dioxides was attempted by oxidation of the corre-
sponding spirothioflavans. Hot NaIO4/aq. 2-PrOH (sub-
strate/oxidant ratio, 1:4) has been reported [24] to trans-
form thioflavanone (1a) into thioflavone 1,1-dioxide
(2c). Presumably due to the absence of a sp2 hybridiza-
tion at position 4, under similar conditions (mole ratio
1:8) spiro-oxadiazoline 5a was transformed, without
dehydrogenation, into a mixture of the corresponding 10-
oxide 5f and 10,10-dioxide 5h. The selective syntheses of
sulfoxides 5a!5f and 5b!5g were accomplished by
treatment with NaIO4/aq. 2-PrOH or with dimethyldiox-
irane generated in situ by potassium peroxymonosulfate
(2 KHSO5 ꢁ KHSO4 ꢁ K2SO4) in aq. Me2CO. Potassium
permanganate oxidation of spiro-oxadiazoline 5a,b
afforded the corresponding sulfones 5h,i in very good
yields (see Scheme 4 and Experimental section).
The effect of a C(2)¼¼C(3) unsaturation and also that
of the oxidation state of sulfur in the benzo heterocycle
Table 2
200 MHz H NMR(CDCl3) data of 5-substituted 3-acetylspiro[1,3,4-oxadiazoline-2,40-thioflavans] as well as 10- and 10,10-oxides 5a,b,f–i.
1
d (ppm)a
J (Hz)
20ax,30eq
Compound
H(20ax
)
H(30ax
)
H(30eq
)
20ax,30ax
30ax,30eq
d CH3
b
c
d
e
f
5a
5b
5f
5g
5h
5i
4.70
4.83
4.40
4.55
4.90
5.03
3.59
3.65
3.66
3.74
4.33
4.40
2.50
2.62
2.57
2.70
2.63
2.75
13.3
13.5
7.4
13.5
13.5
13.6
2.1
2.0
0.8
1.5
1.3
1.7
13.8
14.0
8.5
15.5
14.7
14.7
g
a The H(30ax) signals of spiro compounds are downfield shifted in comparison with those of hydrazones 3 (cf. Table 1). This can be attributed to
the carbonyl neighbouring anisotropy effect of Ac(3) [17b].
b 2.28, Ac(3); 2.07, Me(5).
c 2.40, Ac(3); 2.08, Me(5).
e 2.39, Ac(3).
f 2.31, Ac(3); 2.07, Me(5).
g 2.44, Ac(3).
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402
L. Somogyi
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Scheme 2
Scheme 4
could be well demonstrated. Thus, though treatment
with Ac2O/py at 100ꢀC has been reported [17a] to trans-
form flavone thiosemicarbazone into the corresponding
diacetylhydrazone, a similar treatment of thioflavone thi-
osemicarbazone (4d) afforded (see Experimental sec-
tion) spirothiadiazoline 6 and diacetylhydrazone 4c in
56 and 18% yields, respectively. However, on treatment
with Ac2O/py even under milder conditions (see Experi-
mental section), thioflavone 1,1-dioxide thiosemicarba-
zone (4e) was degraded to acetylhydrazone 4f in 69%
yield and no 3-acetyl-5-acetylaminospiro[1,3,4-thiadia-
zoline-2,40-thioflaven] 10,10-dioxide could be isolated
(Scheme 5).
Moreover, reaction of spiro-oxadiazoline 5b with hot
DDQ/dioxane/TsOH led to the formation of a mixture
comprising substrate 5b and degradation product thiofla-
vone 2a.
For dehydrogenation of the benzoheterocycle, in com-
parison with flavanones, as an additional reaction rout is
known the transformation of thiochromanone 1-oxides
(e.g. 1b) into thiochromones (e.g. 2a) in alkaline solu-
tion [28,19b] or under Pummerer-type reaction condi-
tions [29,19b,25b]. Thus, treatments with Ac2O/TsOH
or Ac2O/dimethylaminopyridine (DMAP) have been
reported [22b] to transform 1b into 2a, but with the
Ac2O/Et3N couple via cleavage of the thiopyran ring,
into disulfide 7 (Scheme 6).
On the basis of these findings, the dehydrogenation of
spirocompounds 5 (X ¼ S) to the corresponding spiro-
thioflavens via transformation of the spirothioflavan 1-
oxides (X ¼ SO) under acetylating conditions in the
presence of acid or base (nucleophilic) catalysts, hence
under circumstances successfully applied just for the
As an alternative rout for preparing spiro[oxa(thia)-
diazoline-2,40-thioflavens] the dehydrogenation of the
corresponding thioflavan analogs 5 was investigated.
The powerful one-electron acceptor oxidant CAN is
known [24,25] to dehydrogenate thioflavanone (1a) to
thioflavone (2a) readily at room temperature. However,
for transforming spirothioflavans 5 into the correspond-
ing thioflaven analogs, CAN turned out to be unsuitable
as this agent transformed 5b into thioflavone (2a) with
simultaneous degradation of the spiro-oxadiazoline moi-
ety (see Scheme 6 and Experimental section). This early
experience prompted us to investigate the dehydrogena-
tion of thiopyran [21,24,22] and that of the N,S-acetal
1,3,4-thiadiazoline [26] or N,O-acetal 1,3,4-oxadiazoline
[27] systems separately, by using various types of oxi-
dants and dehydrogenating agents of diverse mecha-
nisms of action. Also the attempts for dehydrogenating
the thiopyran ring of spirocompound 5 by iodobenzene
1,1-diacetate (IBDA, (diacetoxyiodo)-benzene) or 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) produced
unsatisfactory results. After treating spiro-oxadiazoline
5a with IBDA for preserving the diazoline moiety at
room temperature in AcOH for 7 d or in MeOH for 14
d the substrate could be recovered in ca. 60% yield.
Scheme 5
Scheme 3
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Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-thioflavans] and Analogues
403
Scheme 6
section) and benzoylhydrazone 4g, respectively, in very
good yields, but it converted thiosemicarbazone 3e in
dioxane solution to give a multicomponent mixture. Reac-
tion with DDQ transformed hydrazone 3a into the corre-
sponding azine 8 as well as its partially and fully dehydro-
genated derivatives 9 and 10, respectively. Azine 8 was
obtained also by treating hydrazone 3a with I2/DMSO or
by condensing hydrazone 3a with thioflavanone (1a).
DDQ dehydrogenation of azine 8 afforded azine 10 in
80% yield (see Scheme 8 and Experimental section).
Attempts for dehydrogenating azine 8–10 by treatment
with hot NaIO4/aq. dioxane or hot IBDA/MeOH (or diox-
ane) were unsuccessful as in these cases very complex
mixtures of products were formed. Hypervalent iodine ox-
idation of hydrazine [30] to the reductive, instable diimide
and that of aromatic hydrazones to azines [31] have been
reported already.
spirocyclization, seemed to be feasible. However, pre-
sumably due to the lack of a sp2 C(4) moiety similar
treatments of sulfoxide 5f with Ac2O/Et3N at room tem-
perature for 48 h and that of 5g with the Ac2O/DMAP
couple at room temperature for 72 h or with Ac2O/py at
100ꢀC for 22 h were found to be ineffective and the
unchanged substrates could be recovered in 78, 90, and
67% yields, respectively. Treatment with Ac2O/(TsOH)
transformed spirothioflavan 10-oxides, both 5f and 5g,
into thioflavone diacetylhydrazone (4c) with cleavage of
the oxadiazoline ring and a subsequent transacetylation,
respectively (see Experimental section); thus, 2,3-dehy-
drogenation of the benzothiopyran ring was accompa-
nied by a sp3!sp2 change at C(4) (Scheme 7).
The synthesis of thioflavanone hydrazones [19b] (e.g.,
by boiling thioflavanone 1a with N2H4ꢁH2O/EtOH to
give the corresponding hydrazone 3a) is a clear-cut
reaction. Because of a reversible flavanone (1d) ꢀ 20-
hydroxychalcone (2-cinnamoyl-phenol, 2-hydroxyphenyl
stiryl ketone) transformation, on treatment with hydra-
zine flavanone undergoes reaction, depending on the
reaction conditions, to give the corresponding hydrazone
and 3-(2-hydroxyphenyl)-5-phenyl-4,5-dihydropyrazole,
respectively [32a,b,18e]. An analogous treatment of fla-
vone (2d) with hydrazine or the thermal rearrangement
of flavone hydrazone has been reported to afford the
Owing to the unsatisfactory results with the dehydro-
genation of spirocompounds 5, also similar transforma-
tion of their nitrogen-containing precursors thioflavanone
(acyl)hydrazones (3) with sp2 C(4) was investigated.
Treatment with DDQ dehydrogenated acylhydrazones
3b,j to acetylhydrazone 4b (prepared also by partial
deacetylation of diacetylhydrazone 4c, see Experimental
Scheme 8
Scheme 7
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404
L. Somogyi
Vol 46
spirocyclization. Additional 20,30-dehydrogenation of the
spirocompounds with various dehydrogenating agents
had no result or was accompanied by degradation of the
spirodiazoline ring with a simultaneous sp3!sp2 change
at C(4).
Scheme 9
EXPERIMENTAL
Melting points (uncorrected): Kofler block. Solutions were
concentrated under reduced pressure in a rotary evaporator
(<50ꢀC, bath), TLC: Kieselgel 60 F254 (Merck, Alurolle). IR
(KBr disks): Perkin-Elmer 16 PC-FT spectrometer. 200 MHz
1H- and 50 MHz 13C NMR: Bruker WP 200 SY, 360 MHz
1H- and 90 MHz 13C NMR: Bruker AM 360 spectrometer; for
recording the 13C spectra, J-echo techniques were used.
General operations of processing the reaction mixtures
(see Tables 3 and 4). (A) The product was collected by filtra-
tion in the cold. (B) The cold mixture was poured into ice-
water. (C) A solution of the product in CHCl3 was treated
with fuller’s earth and charcoal and then concentrated. (D) For
decomposing the excess of BzCl, drop-by-drop water (1.25
mL) was added with cooling and stirring and the mixture was
kept at room temperature for 1 h. (E) The mixture was con-
centrated. (F) The residue was triturated with MeOH in the
cold. (G) The residue was triturated with water in the cold.
Dehydrogenation of thioflavanone (1a) by PhI(OAc)2 to
2a. A solution of 1a (0.120 g, 0.5 mmol) and PhI(OAc)2
(0.247 g, 0.75 mmol) in MeOH (5 mL) was kept at room tem-
perature for 12 d and then concentrated (finally at ca. 1 Torr).
A solution of the residue in MeOH (0.5 mL) deposited on
seeding TLC homogeneous and with an authentic compound
identical thioflavone (2a, 0.082 g, 68.6%; when reacted at boil-
ing for 2 d, in a sixfold scale, a 86.2% yield has been observed
[21]), mp 125.5ꢀC.
corresponding pyrazole derivative 11b [32b,18e]. As a
result of the special electron shell structure the more
pronounced nucleophilicity and the conjugative interac-
tion of sulfur [19] within the heterocycle may appear in
some characteristic properties of the molecule, thus
extending our synthetic works with (thio)flavonoids
[16,17a,21,24,22a] we (re)examined the reaction
between thioflavone and hydrazine. Recently we have
found [33] that the treatment of thioflavone (2a) with
N2H4ꢁH2O in hot 2-PrOH leads to the formation of 3-(2-
mercaptophenyl)-5-phenylpyrazole (11a) which by a
subsequent spontaneous oxidation in a CHCl3 solution
affords disulfide 12a. (It is well known that the oxida-
tion of alkyl- and arylthiols by molecular oxygen to
disulfides may be catalyzed by aliphatic amines or alkali
hydroxides [34].) As due to the possibility for a proto-
tropic change, the structure of pyrazoles [35] with aro-
matic substituents cannot be unequivocally elucidated
by IR and NMR spectrometry, this has been carried out
[33] eventually by a MALDI-TOF mass spectrometric
study of the acetyl derivative 12b.
In connection with our previous findings [22b] that
heterolysis of disulfide 7 leads to the formation of thio-
flavanone (1a) and 2-benzylidenebenzo[b]thiophen-
3(2H)-one (thioaurone) we attempted the transformation
of disulfide 7 with N2H4ꢁH2O/2-PrOH to obtain the 4,5-
dihydro analogs of 11a or 12a. However, this reaction
afforded thioflavanone hydrazone (3a) and pyrazole 11a
which was isolated as disulfide 12a (see Scheme 9 and
Experimental section).
Thioflavone acetylhydrazone (4b). (a) A mixture of thiofla-
vanone acetylhydrazone (3b, 0.371 g, 1.25 mmol), DDQ
(0.307 g, 1.32 mmol, 98%), anhydrous dioxane (12 mL), and a
catalytic amount of p-toluenesulphonic acid (TsOH) was
boiled with stirring for 24 h, then cooled to give a solid (0.597
g, a mixture of 4b and DDQH2), which when stirred with aq.
NaHCO3 in excess, in the presence of some 2-PrOH as a
humidifier, afforded undissolved title acetyl-hydrazone 4b
(0.250 g, 68%), mp 256–257ꢀC.
(b) A mixture of diacetylhydrazone 4c (0.168 g, 0.5 mmol),
MeOH (10 mL) and pyridine (2 drops) was boiled with stirring
for 6 h to give, on cooling, acetylhydrazone 4b (0.131 g,
89%), mp 257.5ꢀC.
A similar partial deacetylation was
observed during purification of 4c by CC [Kieselge1 60,
Merck; CHCl3/EtOAc (95:5)], when 4b, mp 258ꢀC was iso-
lated. IR(KBr, m, cmꢂ1): 1666 (s, Amide-I). 1H NMR(200
MHz, DMSO-d6, d, ppm): 11.17 (s, 0.7 H, NH) and 10.79 (s,
0.3 H, NH) presumably due to an E/Z isomerism, 8.33–8.25
(m, 1 H, H(5)), 7.90–7.78 (m, 2 H, HAAr), 7.61 (s, 1 H,
H(3)), 7.58–7.43 (m, 6 H, HAAr), 2,29 (s, 2.1 H, 0.7 Ac) and
2.07 (s, 0.9 H, 0.3 Ac). Anal. Calcd. for C17H14N2OS C, 69,4;
H, 4.8; N, 9.5; S, 10.9. Found: C, 69.3; H, 4.8; N, 9.6; S, 11.0.
Thioflavone thiosemicarbazone (4d). A mixture of thiofla-
vone (2a, 10.008 g, 42 mmol), powdered thiosemicarbazide
(6.000 g, 65.8 mmol), MeOH (100 mL), and conc. HCl (1 mL,
11.7 mmol) was boiled with stirring for 65 h and then cooled.
CONCLUSION
Thioflavanone (thio)acylhydrazones transform into 3-
acetylspiro[1,3,4-(thia)oxadiazoline-2,40-thioflavans] with
trans S(l) or O(l) and Ph(20eq) under acetylating condi-
tions. The presence of 2,3-unsaturation or oxidation of
sulfur of thioflav(an)one render more difficult both the
synthesis of (thio)acylhydrazones and the subsequent
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Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-thioflavans] and Analogues
405
Table 3
Preparation and properties of thioflavanone hydrazones 3 (see also ref. [17b]).
Reaction
components (mmol)
Solvent
(mL)
Reaction temp. (ꢀC)b
(time (h))
% Yield
cruded (pure)
Mp (ꢀC)
(solvent)
Formulaa
(mol. mass)
Product
Workupc
B
3b
3a
(10)
3a
(20)
3hk
(5)
Ac2Oe
(40)
Ac2O(530)
ZnCl2(37)f
Ac2O(185)
ZnCl2(13)f
BzCl
pyf
(10)
15
(3.5)
23
(20)i
100g,h
243
(CHCL3/hexane)
137
C17H16N2OS
(296.4)
C19H18N2O2S
(338.4)
3c
3i
3j
B
Cj
B
(6.7)
99.5
(69)
99m
(PhH/hexane)
241
(EtOH)
23
(62)
<10 (0.2)l
23 (7)
C18H17N3O4S
(371.4)
3a
(10)
pyf
(15)
D
B
237–238
(CHCl3/2-PrOH)
C22H18N2OS
(358.4)
(11)
(85)n
a The C, H, N, and S analyses date for the products are agreeing with the theoretical values within ꢃ 0.3–0.4% limit.
b Bath if not bp.
c For general operations of processing the reaction mixtures see Experimental.
d Without workup of the mother liquors if not stated otherwise.
e To a solution of 3a in pyridine was added Ac2O dropwise with cooling and stirring during 10 min.
f Anhydrous.
g TLC homogeneous.
h Mp 242ꢀC.
i The mixture was stirred at least until the dissolution was complete.
j To give spiro compound isomer 5a see also Table 4. The CHCl3 mother liquor was concentrated and the residue stirred with PhH at room temper-
ature to extract 3c, IR (KBr, v, cmꢂ1); 1725 (s), 1689 (ꢀs), 1652 (m), 1610 (s).ꢀ
k
´
TLC (CHCl3/MeOH(9:1)) homogeneous; mp 253–254 C, ref. [19b] 245–247 C (EtOH); the sample was a generous gift of J Balint Ph.D and pre-
pared [19b] by boiling a mixture of thioflavanone 1,1-dioxide (1c), semicarbazide hydrochloride (in 10% excess), and EtOH containing a catalytic
amount of concd. HCl for ca. 4 h.
l Dropwise addition of BzCl to a solution of 3a in anhydrous pyridine with ice cooling and stirring.
m TLC almost homogeneous, 234–236ꢀC.
n IR (KBr, v, cmꢂ1): 1642 (s).
The solid was collected by filtration and washed several times
with water and then with hexane to give crude product 4d
(10.877 g, 83%), mp 208–210ꢀC (ref. [19b] 204–207ꢀC (from
EtOH)). The mother liquor was concentrated and the residue
triturated with water to give a second crop (1.624 g, 12%) of
4d. C16H13N3S2.
Thioflavone thiosemicarbazone 1,1-dioxide(4e). A mixture
of powdered sulfone 2c (0.270 g,
1
mmol), powdered
Table 4
Preparation and properties of 3-acetylspiro[1,3,4-thiadiazoline-2,40-thioflavans] 5a,b.a
Reaction
components (mmol)
Reaction temp. (ꢀC)b
(time (h))
% Yield
crude (pure)d
Mp(ꢀC)
(solvent)
Formulae
(mol.mass)
Product
Workupc
5a
3b
(2)
3a
(2)
3a
(10)
3j
(4)
Ac2O(64)
ZnCl2(4.4)f
Ac2O(53)
ZnCl2(3.7)f
Ac2O(159)
py(124)l
25
(20)g
23
Bh
C
99i,j
(95)
95
(85)k
99.5
(60)
99
210–211
(CHCl3/EtOAc)
210–211
C19H18N2O2S
(338.4)
Bh
C
(20)g
135
(2)
(CHCl3/EtOAc)
210
(CHCl3/EtOAc)
206
(EtOAc)
Bh
C
5b
Ac2O(106)
py(74)l
100
(4)
E,F
C
C24H20N2O2S
(400.5)
(88)
a For preparation of analogous spiro 1,3,4-thiadiazolines (5c,d,e) see ref. [17b].
b Bath, if not bp.
c For general operations of processing the reaction mixtures see Experimental.
d Without workup of mother liquors if not stated otherwise.
e The C,H,N, and S analyses data for the products are agreeing with the theoretical values within ꢃ 0.3-0.4% limit.
f To a solution of anhydrous ZnCl2 in Ac2O was added the substrate.
g The reaction mixture was stirred at least until the dissolution was complete.
h To give a crude product.
i TLC homogeneous product.
j Mp 206-208 ꢀC.
k From the mother liquor TLC homogeneous diacetythydrazone 3c,(6.7%), mp 137ꢀC (from PhH/hexane) could be isolated, cf. Table 3.
l Pyridine, anhydrous.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

406
L. Somogyi
Vol 46
thiosemicarbazide (0.100 g, 1.1 mmol), MeOH (4.7 mL), and
MeOH/HCl (0.3 mL ca. 0.35 mmol HCl; prepared by mixing
4.5 mL MeOH and 0.5 mL conc. HCl) was boiled with stirring
for 9 h to give crude thiosemicarbazone 4e (0.318 g, 92.5), mp
234–236ꢀC, identical with an authentic [19b] compound (found
mp 233–236ꢀC, reported [19b] 192ꢀC (from EtOH)).
C16H13N3O2S2. The crude product was pure enough for subse-
quent transformations.
ponent residue by CC (Silica Woelm 100–200 lm, CHCl3/
Et2O (95:5)] afforded thioflavone (2a, 0.096 g, 40%), mp
124ꢀC [ref. [25] 124.5–125.5ꢀC (from anhydrous EtOH), ref.
[36] 122–123ꢀC (from MeOH)]. 1H NMR(200 MHz, CDCl3,
d, ppm): 8.58–8.53 (m, 1 H, H(5)), 7.73–7.50 (m, 8 H,
HAAr), 7.25 [s, 1 H, H(3) (for CHCl3 was d 7.26); ref. [37]
7.27 (s, 1 H, H(3) (CDCl3); Bruker 300 spectrometer), ref.
[36] 7.35 (CDCl3; Varian T-60 and/or EM-390 instruments)].
The product was identical in all respects [inclusive also TLC
and IR(KBr)] with an authentic compound.
Attempted dehydrogenation of spirothioflavan 5b by
DDQ. A mixture of 5b (0.200 g, 0.5 mmol), DDQ (0.243 g,
0.525 mmol, 98%), anhydrous dioxane (6 mL), and anhydrous
4-toluenesulfonic acid (a catalytic amount) was stirred at room
temperature for 5 h and at 93ꢀC (bath) for 17 h, then concen-
trated. For the removal of TsOH and DDQH2, the doughy resi-
due was partitioned between aq. NaHCO3 and CHCl3. The
organic layer washed with water and dried (MgSO4) contained
[TLC, CHCl3/EtOAc (95:5)] ca. equal amounts of unchanged
5b and thioflavone (2a) as the major components besides
traces of four minor ones.
Degradation of thioflavone thiosemicarbazone 1,1-dioxide
(4e) to acetylhydrazone 4f. A mixture of thiosemicarbazone
4e (1.030 g, 3 mmol), Ac2O (4.5 mL, 48 mmol) and anhydrous
pyridine (3 mL, 37 mmol) was stirred at 51ꢀC bath for 5 h and
kept at room temperature for 16 h. The crystalline solid was
collected by filtration, washed with Ac2O and hexane, dried
over KOH and silica gel in vacuum desiccator to give TLC
[CHCl3/EtOAc (8:2), CHCl3/Et2O (8:2), or CHCl3/MeOH
(95:5)] homogeneous crude product (0.678 g, 69.2%), mp 275–
276ꢀC (the hot melt resolidified and melted finally at 281–
282ꢀC) or when recrystallized from CHCl3/EtOH, mp 275ꢀC.
The Ac2O/py mother liquor was concentrated, the solid residue
was triturated with anhydrous EtOH (1 mL) in the cold to give
a second crop of 4f (0.079 g, 8.1%), mp 278ꢀC and then 284ꢀC.
3-Acetyl-5-methylspiro[1,3,4-oxadiazoline-2,40-thioflavan]
10-oxide (5f). (a) To a solution of NaIO4 (0.428 g, 2 mmol) in
water (10 mL) were added 5a (0.169 g, 0.5 mmol) and 2-
PrOH (10 mL). The mixture was boiled with stirring for 5 h,
cooled and then concentrated. The residue was diluted with
water up to ca. 30 mL to give 5f (0.103 g, 85%), mp 209–
212ꢀC.
1
IR(KBr, m, cmꢂ1): 1678 (s), 1638 (m), 1562 (m). H NMR(200
MHz, DMSO-d6, d, ppm); 8.36–8.31 and 8.08–8.03 (both m
and 1 H, 2 H-Ar), 7.97 (s, 1 H, H(3)) 7.90–7.86 and 7.84–7.72
(both m and 2 H, 4 HAAr), 7.63–7.58 (m, 3 H, HAAr), 2.34 (s,
3 H, Ac). Anal. Calcd. for C17H14N2O3S C, 62.6; H, 4.3; N,
8.6; S 9.8. Found C, 63.0; H, 4.4; N, 8.4; S, 10.0.
Thioflavone benzoylhydrazone (4g). A mixture of thioflava-
none benzoylhydrazone (3j, 0.166 g, 0.462 mmol), DDQ
(0.112 g, 0.485 mmol, 98%), anhydrous dioxane (4 mL), and a
catalytic amount of TsOH was boiled with stirring tor 14 h,
then cooled and concentrated. For the removal of DDQH2, the
residue was stirred with aq. NaHCO3 in the presence of some
drops of 2-PrOH as a humidifier to leave undissolved crude
product 4g (0.152 g, 92%). A solution of the crude product in
CHCl3 was treated with charcoal and concentrated. Crystalliza-
tion of the residue from 2-PrOH (7 mL) afforded pure 4g
(0.121 g, 73%), mp 240ꢀC. 1H NMR(360 MHz, DMSO-d6,d,
ppm): 11.28 (bs, 1 H, NH), 8.47 (bs shaped m, 1 H, H(5)),
7.90–7.83 (m, 4 H, H(6,7,8) and H(3)), 7.61–7.51 (m, 10 H, 2
Ph). Anal. Calcd. for C22H16N2OS C, 74.1; H, 4.5; N, 7.9.
Found C, 74.3; H, 4.6; N, 7.9.
(b) To a suspension of powdered 5a (3.384 g, 10 mmol) in
Me2CO (300 mL) were added, both in small portions, pow-
dered OXONE (2 KHSO5ꢁKHSO4ꢁK2SO4, 3.60 g, 5.85 mmol)
and water (35 mL) with stirring at 4–8ꢀC (bath temperature)
during 6 h. The mixture was stirred with cooling for 4 h and
at room temperature for 14 h, and then filtered. The filtrate
was concentrated and the residue crystallized from EtOAc to
give crude 5f (3.395 g, 96%), mp 200–202ꢀC, contaminated
(TLC) with a small amount of 5a. Purification of the crude
product by CC [silica gel 60; CHCl3/EtOAc (9:1)] and subse-
quent crystallization from EtOAc afforded TLC homogeneous
5f (2.381 g, 67%), mp 208–209ꢀC. IR(KBr, m, cmꢂ1): 1046 (s,
S¼¼O); 13C NMR(50 MHz, CDCl3, d, ppm): 166.19 (C¼¼O),
153.89 (C(5)), 143.39, 134.50 and 132.88 (3 quat. aromatic C),
131.18, 130.92, 129.07, 128.99 (2 C), 128.48 (2 C), 127.22,
and 126.29 (9 aromatic ¼¼CH), 97.65 (spiro C(2,40)), 62.99
(C(20)), 34.08 (C(30)), 22.02 (CH3ACO), 11.36 (CH3(5)). Anal.
Calcd. for C19H18N2O3S C, 64.4; H, 5.1; N 7.9; S, 9.05.
Found: C, 64.1; H, 5.1; N, 7.8; S, 9.1.
3-Acetyl-5-phenylspiro[1,3,4-oxadiazoline-2,40-thioflavan]
10-oxide (5g). (a) To a solution of 5b (3.604 g, 9 mmol) in hot
2-PrOH (290 mL) was added a solution of NaIO4 (3.850 g, 18
mmol) in warm water (100 mL). The mixture was boiled for 2
h and then diluted with water up to ca. 600 mL to give crude
5g (2.917 g, 78%) contaminated with a small amount of sul-
fone 5i. Purification by CC [Silica Woelm 100–200 lm,
CHCl3/EtOAc (95:5)] afforded TLC homogeneous product 5g
(1.929 g, 51.5%) mp 216–218ꢀC (from CHCl3/EtOAc).
IR(KBr, m, cmꢂ1): 1044 (s, S¼¼O). Anal. Calcd. for
C24H20N2O3S C, 69.2; H, 4.8; N 6.7; S 7.7. Found: C 69.4; H
4.9; N, 6.6; S, 7.6.
Attempted dehydrogenation of spirothioflavan 5a by
PhI(OAc)2. A mixture of finely powdered 5a (0.169 g, 0.5
mmol), PhI(OAc)2 (0.247 g, 0.75 mmol) and MeOH (5 mL)
was stirred at room temperature for 14 d. The solid was col-
lected by filtration to give TLC homogeneous starting 5a
(0.104 g, 62%), mp 215–216ꢀC.
For a transformation of thioflavanone (1a) to 2a, under simi-
lar conditions, see Experimental section.
CAN degradation of spiro-oxadiazoline 5b to thioflavone
(2a). According to the literature method [25] for the CAN
dehydrogenation of thioflavanone (1a), to a solution of finely
powdered spirocompound 5b (0.401 g, 1 mmol) in MeCN (30
mL), placed in a separatory funnel, was added a solution of
CAN (3.838 g, 7 mmol) in water (10 mL). The mixture was
shaken carefully and when the effervescence ceased, diluted
with water (50 mL) and extracted with Et2O (6 ꢄ 12 mL).
The Et2O solution was washed with aq. NaHCO3 and water,
dried (MgSO4), and concentrated. Separation of the multicom-
(b) To a suspension of powdered 5b (4.005 g, 10 mmol) in
Me2CO (300 mL) were added, both in small portions,
Journal of Heterocyclic Chemistry
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May 2009
Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-thioflavans] and Analogues
407
powdered OXONE (potassium peroxymonosulfate, 3.70 g, 6
mmol) and water (35 mL) with stirring at 4–8ꢀC (bath temper-
ature) during 4 h. The mixture was stirred on with cooling for
7 h and at room temperature for 12 h and then filtered; the
solid was washed with water to leave undissolved crude 5g
(2.071 g, 50%). The aq. Me2CO mother liquor was concen-
trated, the residue triturated with water to give a second crop
of 5g (1.967 g 47%). A solution of the crude products in
CHCl3 was treated with charcoal and concentrated. The resi-
due was crystallized from EtOAc to give pure title compound
5g (3.666 g 88%), mp 208–210ꢀC, TLC identical with the
product described in (a).
temperature during 20 min. The mixture was stirred further for
2 h, and then for dissolving the oxidant, water (12 mL) was
added in portions during 1.5 h. After an additional stirring for
1 h the precipitated solid was collected by filtration, washed
with water to give TLC homogeneous crude 5i (0.389 g,
90%), mp 227–228ꢀC. A solution of the crude product in
CHCl3 was treated with charcoal and concentrated. The resi-
due was boiled in 2-PrOH (3 mL) to give analytically pure 5i
(0.378 g, 87%), mp 228ꢀC. IR(KBr, m, cmꢂ1): 1312 (s), 1156
(s) and 1136 (s) (SO2). Anal. Calcd. for C24H20N2O4S C, 66.6;
H, 4.7; N, 6.5; S, 7.4. Found: C, 66.5; H, 4.7; N, 6.4; S, 7.4.
5-Acetamido-3-acetylspiro[1,3,4-thiadiazoline-2,40-thioflaven]
Transformation of spiro[oxadiazoline-2,40-thioflavan] 10-
oxides 5f and 5g into thioflavone diacetylhydrazone (4c). (a)
A mixture of 5-methyl spirocompound 5f (3.544 g, 10 mmol),
Ac2O (50 mL, 530 mmol) and TsOH (like a pea) was heated
at 98ꢀC (bath) with stirring for 16 h, then cooled and concen-
trated. The cold residue was triturated with ice/water for 1 h,
and then extracted with CHCl3. The CHCl3 solution was
washed with aq. NaHCO3 and water, dried (MgSO4), and con-
centrated. Recrystallization of the residue two times from
EtOAc afforded pale yellow crystals of 4c (1,534 g, 46%), mp
175ꢀC. IR(KBr, m, cmꢂ1): 1720(s), 1706(s), 1690(s), 1682(s),
´
(6). A mixture of thıosemicarbazone 4d (1.869 g, 6 mmol),
Ac2O (15 mL, 159 mmol) and pyridine (3 mL, 37 mmol) was
kept at 100ꢀC for 3 h and then at 4ꢀC for 18 h to give yellow
crystals of crude diacetylhydrazone 4c (0.367 g, 18%), mp
170–171ꢀC, TLC [CHCl3/MeOH (9:1)] identical with an
authentic compound. The mother liquor was concentrated and
the residue triturated with anhydrous EtOH under cooling, and
for increasing the separation of crystals, gradually hexane (16
mL) was added then kept at room temperature for ca. 16 h to
give a crystalline second crop of product (1.090 g). The
mother liquor of the second crop was concentrated and the res-
idue triturated with water to give a solid (0.874 g). The second
and third crops of crude products contained the same com-
pound as the major component [TLC, CHCl3/MeOH (9:1)].
Purification of the third crop by CC [silica gel 60; CHCl3/Et2O
(8:2)] and when combined with the second crop, subsequent
crystallization from Et2O with addition of hexane afforded
pure 6 (1.328 g, 56%), mp 248–249ꢀC. IR(KBr, m, cmꢂ1):
1674 (s), 1646 (s), 1614 (s). 1H NMR(200 MHz,CDCl3, d,
ppm): 9.20 (s, 1 H, NHAc), 7.59–7.54 (m, 2 H, HAAr), 7.39–
7.22 (m, 7 H, HAAr), 6.50 (s, 1 H, H(30)), 2.43 (s, 3 H, Ac),
1.91(s, 3 H, Ac). 13C NMR(50 MHz, CDCl3, d, ppm): 169.74
and 169.47 (2 C¼¼O), 145.02 (C(5)), 136.74, 133.42, 132.96,
and 129.70 (3 quat. aromatic C, and C(20)), 129.27, 128.72 (2
C), 128.01, 127.48, 126.75 (2 C), 126.33, and 125.16 (9 aro-
matic ¼¼CH), 120.08 (C(30)), 79.92 (spiro C(2,40)), 23.69 and
22.30 (2 CH3AC¼¼O). Anal. Calcd. for C20H17N3O2S2 C, 60.7;
H, 4.3; N, 10.6; S, 16.2. Found C, 60.8; H, 4.4; N, 10.6; S,
16.3.
Thioflavanone azine (8). (a) To a solution of hydrazone 3a
(0.509 g, 2 mmol) in DMSO (3 mL) at ca. 60ꢀC was added
0.1M I2/DMSO (3 mL, 0.3 mmol). The mixture was kept at
100ꢀC for 45 min and then gradually water (ca. 25 mL) was
added to give crude 8 (0.471 g, 99%, mp 267ꢀC) containing
some unchanged 3a. Heating the crude product in MeOH (5
mL) left undissolved pure 8 (0.358 g, 75%), mp 270–271ꢀC
(ref. [19b] 270ꢀC (PhH), prepared by condensing thioflavanone
1a with hydrazine hydrate).
(b) A mixture of thioflavanone (1a, 1.502 g, 6.25 mmol),
hydrazone 3a (1.272 g, 5 mmol), 2-PrOH (25 mL), and a cata-
lytic amount of TsOH was boiled with stirring for 10 h to give
crude (1.697 g, 71%; mp 269–270ꢀC) or recrystallized 8
(1.495 g, 63%), mp 270ꢀC (from Diglyme or PhH), TLC iden-
tical with the product described in (a). C30H24N2S2.
1
1648(w), 1592(s). H NMR(360 MHz, CDCl3, d, ppm): 8.77–
8.75 (m, 1 H, H(5)), 7,58–7.43 (m, 8 H, HAAr), 6.80 (s, 1 H,
H(3), 2.47 (s, 6 H, 2 Ac). 13C NMR(90 MHz, CDCl3, d, ppm):
170.28 (2 C, 2 C¼¼O), 162.56, 148.81, 136.98, and 134.45
(quat. aromatic C), 130.62 (2 C), 129.15 (2 C), 127.82, 127.02
(3 C), and 126.34 (aromatic CH), 111.99 (C(3)), 25.90 (2 C,
CH3AC¼¼O). Anal. Calcd. for C19H16N2O2S C, 67.8; H, 4.8;
N, 8.3; S, 9.5. Found: C, 67.8; H, 4.8; N, 8.4; S, 9.6.
(b) A mixture of 5-pheny1 spirocompound 5g (0.833 g, 2
mmol), Ac2O (10 mL, 106 mmol) and TsOH (like a pepper)
was heated at 100ꢀC (bath) with stirring for 18 h, then cooled
and concentrated. The cold residue was triturated with MeOH
(2 mL) for 2.5 h and then water (ca. 7 mL) was added in por-
tions to give a solid (0.707 g). A solution of the product in
CHCl3 was treated with charcoal and concentrated. The resi-
due was crystallized from EtOAc to give 4c (0.292 g, 43%),
mp 174.5–175ꢀC, identical (TLC, IR) with the product
obtained from the 5-methyl spirocompound 5f aforementioned
in (a).
3-Acetyl-5-methylspiro[1,3,4-oxadiazoline-2,40-thioflavan]
10,10-dioxide (5h). To a suspension of powdered spirothiofla-
van 5a (1.692 g, 5 mmol) in 96% AcOH (50 mL) were
added, both in small portions, powdered KMnO4 (1.613 g,
10.2 mmol) and water (10 mL) at room temperature with
cooling and stirring during 45 min. The mixture was stirred
further for 1.5 h and then under cooling 30% H2O2 (ca. 1.2
mL) was added drop-by-drop until discoloration. The mixture
was diluted with water up to ca. 200 mL, kept at 4ꢀC for 1.5
h to give crystalline crude 10,10-dioxide 5h (1.449 g, 78%),
mp 224–225ꢀC. Recrystallization from PhMe afforded pure
5h (1.313 g 71%), mp 227ꢀC. IR(KBr, m, cmꢂ1): 1314 (s),
1154 (s), 1138 (s) (SO2). Anal. Calcd. for C19H18N2O4S C,
61.6; H, 4.9; N, 7.6; S, 8.7. Found: C, 61.8; H, 4.9; N, 7.5;
S, 8.6.
Dehydrogenation of thioflavanone azine (8) to azine
10. A mixture of azine 8 (0.119 g, 0.25 mmol), DDQ (0.122
g, 0.525 mmol, 98%), anhydrous dioxane (10 mL), and a cata-
lytic amount of TsOH was boiled with stirring for 18 h then
concentrated. The residue was washed with CHCl3 and the
3-Acetyl-5-phenylspiro[1,3,4-oxadiazoline-2,40-thioflavan]
10,10-dioxide (5i). To a solution of spirothioflavan 5b (0.401 g,
1 mmol) in 96% AcOH (16 mL) was added powdered KMnO4
(0.395 g, 2.5 mmol) in small portions with stirring at room
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

408
L. Somogyi
Vol 46
REFERENCES AND NOTES
solid stirred with aq. NaHCO3 in the presence of some drops
of 2-PrOH as a humidifier to give 10 (0.095 g, 80%), purplish
crystals of a metallic lustre, mp 283–286ꢀC (ref. [19b] 280–
285ꢀC (from EtOH), prepared by treatment of 4-methylthio-
thioflavylium iodide or thioflaven-4-thione with N2H4ꢁH2O).
C30H20N2S2.
[1] (a) Rastelli, G.; Antolini, L.; Benvenuti, S.; Constantino, L.
Bioorg Med Chem 2000, 8, 1151; (b) Rastelli, G.; Constantino, L.;
Gamberini, M, C.; Del Corso, A.; Mura, U.; Petrash, J. M.; Ferrari, A,
M.; Pacchioni, S. Bioorg Med Chem 2002, 10, 1427.
[2] Pouget, C.; Fagnere, C.; Basly, J.-P.; Habrioux, G.; Chulia,
A.-J. Bioorg Med Chem Lett 2002, 12, 1059.
Reaction of thioflavanone hydrazone (3a) with DDQ, for-
mation of azines 8 and 9. A mixture of hydrazone 3a (1.017
g 4 mmol), DDQ (0.973 g, 4.2 mmol, 98%) and anhydrous
dioxane (20 mL) was stirred at room temperature for some
minutes, whilst the deep green color of the solution, produced
by a transiently formed charge-transfer complex, became
brownish-red and under significant effervescence the mixture
thickened. Hereupon, the mixture was boiled for 4 h with stir-
ring, and then concentrated. For removing DDQH2 the residue
was stirred with aq. NaHCO3 at room temperature to leave
undissolved a brownish solid (0.967 g, mp 213–220ꢀC) con-
sisting of two major components (TLC, CHCl3). Purification
by CC (silica gel 60, CHCl3) afforded azine 8 (0.387 g, 41%,
mp 270ꢀC (from PhMe) and orange-red crystals of 9 (0.104 g,
11%), mp 255–256ꢀC (from CHCl3/EtOAc). 1H NMR(200
MHz, CDCl3, d, ppm): 8.59–8.56 (m, 1 H, H(5)), 8.48–8.45
(m, 1 H H(5)), 7.81 (s, 1 H, ¼¼CH(3)), 7.71–7.66 (m, 2 H,
HAAr), 7.50–7.16 (m, 14 H, HAAr), 4.48 (dd, 1 H, J2,3e ¼ 3
[3] (a) Medina, J. H.; Viola, H.; Wolfman, C.; Marder, M.;
Wasowski, C.; Calvo, D.; Paladini, A. C. Neurochem Res 1997, 22,
419; (b) Medina, J. H.; Viola, H.; Wolfman, C.; Marder, M.; Wasow-
ski, C.; Calvo, D.; Paladini, A. C. Chem Abstr 1997, 126, 338223p;
(c) Paladini, A. C.; Medina, J. H. (Univ. of Strathclyde), PCT Int.
Appl. WO 9714414, 1997; (d) Paladini, A. C.; Medina, J. H. Chem
Abstr 1997, 126, 343430h; (e) Paladini, A. C.; Marder, M.; Viola, H.;
Wolfman, C.; Wasowski, C.; Medina, J. H. J Pharm Pharmacol 1999,
51, 519; (f) Griebel, G.; Perrault, G.; Tan, S.; Schoemaker, H.; Sanger,
D. J. Neuropharmacology 1999, 38, 965; (g) Griebel, G.; Perrault, G.;
Tan, S.; Schoemaker, H.; Sanger, D. J. Chem Abstr 1999, 131,
194094a.
[4] (a) Metodiewa, D.; Koceva-Chyla, A.; Kochman, A.; Przy-
tulska, H. Curr Top Biophys 1998, 22 (Suppl. B) 143; (b) Metodiewa,
D.; Koceva-Chyla, A.; Kochman, A.; Przytulska, H. Chem Abstr 2000,
132, 329419d.
[5] (a) Raut, A. W.; Doshi, A. G.; Raghuwanshi, P. B. Orient J
Chem 1998, 14, 337; (b) Raut, A. W.; Doshi, A. G.; Raghuwanshi, P.
B. Chem Abstr 1999, 130, 75900e.
Hz, J2,3a ¼ 13 Hz, H(2)), 4.19 (q, 1 H, J2,3e ¼ 3 Hz, J3e3a
¼
17.5 Hz, He(3)), 3.13 (q, 1 H, J2,3a ¼ 13 Hz, J3e,3a ¼ 17.5 Hz,
Ha(3)). Anal. Calcd. for C30H22N2S2 C, 75.9; H, 4.7; N, 5.9.
Found: C, 75.8; H, 4,6; N, 5,9.
[6] (a) Hussain, S.; Kothari, S.; Vyas, R.; Verma, B. L. Orient
J Chem 1999, 15, 495; (b) Hussain, S.; Kothari, S.; Vyas, R.; Verma,
B. L. Chem Abstr 2000, 132, 251047j; (c) Xiong, X.; Mei, Q.; Zou,
Y.; Gan, H.; Zhao, M.; Zhao, D. Zhongguo Yaowu Huaxue Zazhi
2000, 10, 258; (d) Xiong, X.; Mei, Q.; Zou, Y.; Gan, H.; Zhao, M.;
Zhao, D. Chem Abstr 2001, 135, 76752y.
Transformation of 2-cinnamoylphenyl disulfide (7) into
thioflavanone hydrazone (3a) and pyrazole 11a. A mixture
of 98% N2H4ꢁH2O (9 mL, ꢅ180 mmol), 2-PrOH (25 mL) and
7 [22b] (4.307 g, 9 mmol, 18 mmol of chalcone moiety)
was stirred at room temperature for 5 h and then the clear so-
lution formed was kept at 100ꢀC for 16 h. The solution was
cooled and deep freezed at ca. ꢂ20ꢀC for 2.5 d to give crude
(2.093 g, 91.4%, yield calculated for 9 mmol, mp 116–117ꢀC)
or recrystallized 3a, mp 120–121ꢀC (from MeOH), identical
[mp, TLC: CHCl3/EtOAc (95:5), IR] with an authentic com-
pound prepared from 1a (see ref. [17b]). The mother liquor of
the crude product was concentrated, the residue dissolved in
Me2CO (3 mL) and for transforming 11a into the more
easily isolable disulfide 12a, kept at 4ꢀC for 4 d. The depos-
ited crystals were collected by filtration and washed with
Me2CO/hexane (1:1) to give crude (0.190 g, 4.2%, mp 226–
227ꢀC) or recrystallized 12a, mp 230ꢀC (from 2-methoxyethyl
ether with addition of water). The product is identical [mp,
TLC: CHCl3/MeOH (9:1), IR] with that obtained by treating
thioflavone with hydrazine hydrate [33]. Anal. Calcd. for
C30H22N4S2 C, 71.7; H, 4.4; N, 11.1. Found: C, 71.8; H, 4.5;
N, 11.1.
[7] Varma, R. S.; Kumar, D. Tetrahedron Lett 1998, 39, 9113.
[8] Wang, H.-K.; Bastow, K. F.; Cosentino, L. M.; Lee, K.-H.
J Med Chem 1996, 39, 1975.
[9] (a) Schneller, S. W. Adv Heterocycl Chem 1975, 18, 59;
(b) Konieczny, M. T.; Horowska, B.; Kunikowski, A.; Konopa, J.;
Wierzba, K.; Yamada, Y.; Asao, T. J Org Chem 1999, 64, 359; (c)
Kumar, P.; Bodas, M. S. Tetrahedron 2001, 57, 9755; references cited
therein.
¨
[10] (a) Schonberg, A.; Singer, E. Chem Ber 1963, 96, 1256; (b)
Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M. Tetrahedron 1994, 50,
´ ´ ´
7865; (c) Jedlovska, E.; Levai, A.; Toth, G.; Balazs, B.; Fisera, L.
´
J Heterocycl Chem 1999, 36, 1087; (d) Levai, A. Khim Geterotsikl
Soedin 1997, 747; references cited therein.
[11] (a) Nakazumi, H.; Ueyama, T.; Kitao, T. J Heterocycl
Chem 1984, 21, 193; (b) Nakazumi, H.; Ueyama, T.; Kitao, T. J Het-
erocycl Chem 1985, 22, 1593; (c) Fang, L.; Guo, C.; Zhang, W. She-
nyang Yaoke Daxue Xuebao 1998, 15, 8; (d) Fang, L.; Guo, C.;
Zhang, W. Chem Abstr 1998, 129, 2603l8p; (e) Yu, X.; Liu, J.; Li, X.;
Zhang, G.; Fang, L. Huaxi Yaoxue Zazhi, 1998, 13, 73; (f) Yu, X.;
Liu, J.; Li, X.; Zhang, G.; Fang, L. Chem Abstr 1998, 129, 330629s;
(g) Fang, L.; Dai, Z.; Zhang, G. Shenyang Yaoke Daxue Xuebao
1998, 15, 116; (h) Fang, L.; Dai, Z.; Zhang, G. Chem Abstr 1998,
129, 316113n; (i) Macritchie, J. A.; O’Mahony, M. J.; Lindell, S. D.
(Hoechst A.-G.; Agrevo UK Ltd.) PCT Int. Appl. WO 98 27,080,
1998; (j) Macritchie, J. A.; O’Mahony, M. J.; Lindell, S. D. Chem
Abstr 1998, 129, 81666d.
´ ´
Acknowledgments. The author thanks Mrs. Katalin Trefas for
´
the microanalyses and for recording the IR spectra, Mme Sara
´
1
´
Balla and Mrs. Eva Jozsa for recording the 200 and 360 MHz H-
as well as 50 and 90 MHz 13C NMR spectra. Thanks are due, with
´
´
particular deference, to the late Janos Balint, Ph.D. (BIOGAL
Pharmaceutical Works, Debrecen, Hungary) for the generous gift
of authentic samples of 3a,d,h and 4a,d,e for identification. Fi-
nancial support from the Hungarian Scientific Research Fund
(OTKA Grant numbers: T025016 and T037201) for this work is
gratefully acknowledged.
[12] Dhanak, D.; Keenan, R. M.; Burton, G.; Kaura, A.; Darcy,
M. G.; Shah, D. H.; Ridgers, L. H.; Breen, A.; Lavery, P.; Tew, D. G.;
West, A. Bioorg Med Chem 1998, 8, 3677.
[13] (a) Konopa, I. K.; Konieczny, M. T.; Horowska, B.; Kuni-
kowski, A.; Asao, T.; Nishino, H.; Yamada, Y. (Taiho Pharmaceutical
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
Synthesis and Reactivity of Spiro[1,3,4-thiadiazoline-2,40-thioflavans] and Analogues
409
´
Co. Ltd. Japan), Jpn. Kokai Tokkyo Koho JP 09 25,278[97 25,278],
1997; (b) Konopa, I. K.; Konieczny, M. T.; Horowska, B.; Kunikow-
ski, A.; Asao, T.; Nishino, H.; Yamada, Y. Chem Abstr 1997, 126,
185986n; (c) Watanabe, K.; Saito, T.; Niimura, K. (Kureha Chemical
Industry Co., Ltd., Japan) Eur. Pat. Appl. EP 758,649, 1997; (d) Wata-
nabe, K.; Saito, T.; Niimura, K. Chem Abstr 1997, 126, 199456b; (e)
Nussbaumer, P.; Lehr, P.; Billich, A. J Med Chem 2002, 45, 4310.
[14] (a) Tseng, C.-P. (E. I. Du Pont De Nemours and Company,
USA) PCT Int. Appl. WO 98 35,954, 1998; (b) Tseng, C.-P. Chem
Abstr 1998, 129, 175555u; (c) Tseng, C.-P. (E. I. Du Pont De Nem-
ours and Company, USA), PCT Int. Appl. WO 98 49,159, 1998; (d)
Tseng, C.-P. Chem Abstr 1998, 129, 316221w.
[22] (a) Benyei, A. C.; Somogyi, L. Phosphorus Sulfur Silicon,
1998, 143, 191; (b) Somogyi, L. Can J Chem 2001, 79, 1159.
[23] (a) Somogyi, L. Liebigs Ann Chem 1991, 1267; (b) Somo-
gyi, L. Bull Chem Soc Jpn 2001, 74, 873, 2465; references cited
therein; (c) Martins Alho, M. A.; D’Accorso, N. B. Carbohydr Res
2000, 328, 481.
[24] Somogyi, L. Liebigs Ann Chem 1994, 959.
´
´ ´
[25] Bognar, R.; Balint, J.; Rakosi, M. Liebigs Ann Chem 1977,
1529.
[26] (a) Somogyi, L. Heterocycles 2004, 63, 2243; (b) Somogyi,
L. J Heterocycl Chem 2006, 43, 1141.
[27] Somogyi, L. J Heterocycl Chem 2007, 44, 1235.
¨
[28] Arndt, F.; Flemming, W.; Scholz, E.; Lowensohn, V.;
[15] Lenkey, B.; Somogyi, L. Acta Microbiol Immunol Hung
1996, 43, 263.
¨
Kallner, G.; Eiestert, B. Ber Dtsch Chem Ges 1925, 58, 1612.
[29] Morin, R. B.; Spry, D. O.; Mueller, R. A. Tetrahedron Lett
1969, 849.
´
[16] Somogyi, L.; Batta, Gy.; To†kes, A. L. Liebigs Ann Chem
1992, 1209.
[17] (a) Somogyi, L. Tetrahedron 1991, 47, 9305; (b) Somogyi,
´
L.; Batta, Gy.; Gunda, T. E.; Benyei, A. Cs. J Heterocycl Chem 2008,
[30] Moriarty, R. M.; Vaid, R. K.; Duncan, M. P. Synth Com-
mun 1987, 17, 703.
45, 489; references cited therein.
[31] Ramsden, C. A.; Rose, H. L. Synlett 1997, 27.
´ ´
[32] (a) Kallay, F.; Janzso, G.; Koczor, I. Tetrahedron 1965, 21,
[18] (a) Diesbach, H.; Kramer, H. Helv Chim Acta 1945, 28,
1399; (b) Baker, W.; Harborne, J. B.; Ollis, W. D. J Chem Soc 1952,
´ ´
1303; (c) Janzso, G.; Kallay, F.; Koczor, I. Tetrahedron 1966, 22,
´ ´
19; (b) Kallay, F.; Janzso, G.; Koczor, I. Tetrahedron 1965, 21, 3037.
´ ´
[33] Keki, S.; Nagy, L.; Deak, Gy.; Zsuga, M.; Somogyi, L.;
´ ´
2909; (d) Kallay, F.; Janzso, G.; Koczor, I. Tetrahedron Lett 1968,
´ ´
3853; (e) Kallay, F.; Janzso, G.; Koczor, I. Acta Chim Acad Sci Hung
´
Levai, A. J Am Soc Mass Spectrom 2004, 15, 879.
[34] Capozzi, G.; Modena, G. In The Chemistry of the Thiol
Group; Patai, S., Ed.; Wiley: London, 1974; Part 2, pp 785–839.
[35] (a) Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. In
Advance Heterocycles Chemistry; Academic Press: London, 1976; (b)
Elguero, J. Pyrazoles and their Benzo Derivatives, in Comprehensive
Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Perga-
mon Press: Oxford, 1984; Vol. 5 (Potts, K. T., Ed.), pp 167–303; (c)
Bensaude, O.; Chevrier, M.; Dubois, J.-E. Tetrahedron 1978, 34, 2259;
(d) Tarrago, G.; Ramdani, A.; Elguero, J.; Espada, M. J Heterocycl
Chem 1980, 17, 137.
1968, 58, 97.
[19] (a) Janssen, M. J. Bonding in and Properties of Unsaturated
Sulphones, in Organic Sulphur Chemistry, Structure, Mechanism and
Synthesis; Stirling, C. J. M., Ed., Butterworths: London, 1975, pp 19–
´
42; (b) Balint, J. Synthesis of Thioflavonoids: Oxidative and Reductive
Transformations, Reactions with Oxo Reagents (in Hungarian).
Ph.D. Dissertation, Kossuth Lajos University, Debrecen (Hungary),
´
1978; (c) David, E. R.; Balint, J.; Rakosi, M. Acta Chim Hung 1985,
´
´
´
118, 297.
[20] Arndt, F.; Nachtwey, P.; Pusch, J. Ber Dtsch Chem Ges
[36] Wadsworth, D. H.; Detty, M. R. J Org Chem 1980, 45,
4611.
1925, 58, 1644.
[21] Somogyi, L. Synth Commun 1999, 29, 1857; references
cited therein.
[37] Wang, H.-K.; Bastow, K. F.; Cosentino, L. M.; Lee, K.-H.
J Med Chem 1996, 39, 1975.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet