A novel synthesis of spiro 1,3-dithiin and spiro 1,3-thiazine derivatives under Phase Transfer Catalysis (PTC) conditions

Article abstract of DOI:10.1080/10426500490468065

Ketene S,S-acetals 1a,b or ketene N,S-acetals 2a,b reacts in situ with a variety of ylidenemalononitriles to afford the desired spiro [1,3]dithiin heterocycles 3a,b-11a,b or spiro[1,3/thiazine heterocycles 12a,b-20a,b. Treatment of 2-(1-acetyl-2-oxopropyl

Full text of DOI:10.1080/10426500490468065

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Phosphorus, Sulfur, and Silicon and the Related
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A NOVEL SYNTHESIS OF SPIRO 1,3-DITHIIN AND SPIRO
1,3-THIAZINE DERIVATIVES UNDER PHASE TRANSFER
CATALYSIS (PTC) CONDITIONS
Ahmed M. M. El-Saghier a
a South Valley University, Sohag, Egypt
Version of record first published: 16 Aug 2010.
To cite this article: Ahmed M. M. El-Saghier (2004): A NOVEL SYNTHESIS OF SPIRO 1,3-DITHIIN AND SPIRO 1,3-THIAZINE
DERIVATIVES UNDER PHASE TRANSFER CATALYSIS (PTC) CONDITIONS, Phosphorus, Sulfur, and Silicon and the Related Elements,
179:7, 1237-1250
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Phosphorus, Sulfur, and Silicon, 179:1237–1250, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490468065
A NOVEL SYNTHESIS OF SPIRO 1,3-DITHIIN
AND SPIRO 1,3-THIAZINE DERIVATIVES UNDER
PHASE TRANSFER CATALYSIS (PTC) CONDITIONS
Ahmed M. M. El-Saghier
South Valley University, Sohag, Egypt
(Received April 21, 2003; accepted November 7, 2003)
Ketene S,S-acetals 1a,b or ketene N,S-acetals 2a,b reacts in situ with a
variety of ylidenemalononitriles to afford the desired spiro [1,3]dithiin
heterocycles 3a,b–11a,b or spiro[1,3]thiazine heterocycles 12a,b–
20a,b. Treatment of 2-(1-acetyl-2-oxopropylidene)spiro[1,3]thiazine
derivatives 13b, 17d, and 18d with malononitrile afforded the corre-
sponding dispiro heterocycles 21, 22, and 23.
Keywords: Dispiro heterocycles; ketene acetals; spiro-1,3-dithiin;
spiro-1,3-thiazine
Dithioacetals can be prepared by condensation of carbonyl compounds
with thiols or dithiols in the presence of protic acids, Lewis acids, and
some silicon reagents.1−9
Recently, transdithioacetalization of acetals has gained favor as al-
ternative method for the preparation of dithioacetals in which catalysts
such as BF3, OEt2,10 Bui2AlS(CH2)2SAlBui ,11 and CoCl2, Me3SiCl12
have been employed. Also, the recent wo2rks on dithioacetalization
of carbonyl compounds and transdithiacetalization reactions8,9,13 in-
troduce compounds that potentially carry a positive halonium ion
and can be used as efficient catalysts for both dithioactalization and
transdithioacetalization reactions. The compounds used for that pur-
pose include: 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TABCO),14−17
N-bromosuccinimide (NBS), and molecular bromine (Br2). Cyclic
The author wishes to thank Dr. Jerzy Suwinski and Mr. Mounir Abbas, Institute of Or-
ganic Chemistry and Technology, Silesian Technical University, 44-100 Gliwice, Poland,
for the empirical calculation.
Address correspondence to Ahmed M. M. El-Saghier, South Valley University, Faculty
of Science, Department of Chemistry, Sohag, Egypt. E-mail: el saghier@yahoo.com
1237

1238
A. M. M. El-Saghier
S,S-acetals for example, 1,3-dithianes and 1,3-dithiolanes, also have
found wide synthetic uses as precursors of acyl anion equivalents and
as masked methylene group in organic synthesis.1−3,18
DISCUSSION
Our recent work on the synthesis of ketene-acetals uses simple phase-
transfer catalysis conditions in one-pot reaction, the acetals formed
being used in heterocyclic synthesis. In an extension of our previous
work on the application of phase transfer catalysis in heterocyclic syn-
thesis via ketene S,S- or N,S-acetals,19−26 we report here the synthe-
sis of ketene S,S-acetals 1a,b or ketene N,S-acetals 2a,b by reaction
of either malononitrile or acetylacetone along with carbon disulfide or
phenyl isothiocyanate in 1:1 molar ratio using solid-liquid phase trans-
fer catalysis conditions [dioxane/K2CO3/tetrabutyl ammonium bromide
(TBAB)].
Cyanoketene S,S-acetal 1a or ketoketene S,S-acetal 1b was then al-
lowed to react in situ with cycloalkylidenemalononitriles using PTC
conditions in one-pot reaction to give the desired spiro cycloalkyli-
dene[1,3]dithiin heterocycles 3(n = 1), 4(n = 2) in an excellent yield.
Spectral evidence strongly supported the structures, in particular, the
1
signals in the H NMR spectrum for the NH2 groups at δ 6.20 for 3a
(Y CN), δ 6.00 for 3b (Y COCH3), δ 6.30 for 4a (Y CN) and δ 6.10 for
4b (Y COCH3).
The reaction mechanism was assumed to proceed via two steps where
a preliminary nucleophilic addition of one of the two SH groups formed
to the ethylenic bond followed by cyclization via another nucleophilic
attack of the other SH group to the cyano group.

Spiro 1,3-Dithiin and Spiro 1,3-Thiazine Derivatives
1239
Also, ketene S,S-acetal 1a or 1b was allowed to react with a
variety of ylidenemalononitrile including: 2-oxazolylidene-, 2-(2,3-
dihydrobenzo-[d]oxazolylidene)-,2-thiazolylidene-, 2-(2,3-dihydrobenzo-
[d]thiazolylidene-, 2-perhydro-2-imidazolylidene-, 2-(2,3-dihydro-1H-
benzo[d]-imidazolyliden)-, and 2-(2-oxo-2,3-dihydro-1H-3-indolyliden)-
malononitrile in situ using the same PTC conditions to afford the
corresponding spiro[1,3]dithiin heterocycles 5a,b–11a,b (cf. Scheme 1).
SCHEME 1
The IR spectra of these compounds showed the appearance of the
characteristic bands corresponding to NH2 group, C O of the acetyl
1
groups in 5b–11b and NH2 groups, CN groups in 5a–11a. H NMR
TABLE I Spiro 1,3-Dithiin and Spiro 1,3-Thiazine Derivatives
Comp. no.
Y
X
Comp. no.
Y
X
3a, 4a, 11a, 12a, 13a, 20a
3b, 4b, 11b, 12b, 13b, 20b
5a, 8a, 14a, 17a
CN
COCH3
CN
—
—
O
6a, 9a, 15a, 18a
6b, 9b, 15b, 18b
7a, 10a, 16a, 19a
CN
COCH3
CN
S
S
NH
NH
5b, 8b, 14b, 17b
COCH3
O
7b, 10b, 16b, 19b COCH3

1240
A. M. M. El-Saghier
showed the appearance of NH2 signals for all spiro[1,3]dithiin deriva-
tives 5a,b–11a,b and the appearance of a new signal for –CH3 referring
to acetyl groups in 5b–11b (cf. Tables I and II).
In connection with this basic idea, cyanoketene N,S-acetal 2a
and ketoketene N,S-acetal 2b were allowed to react with cyclo-
alkylidenemalononitriles to give the corresponding cycloalkylidene
spiro[1,3]thiazine derivatives 12a,b, 13a,b.
In the same line for the synthesis of spiro derivatives, the previous
ylidenemalononitriles were allowed to react with intermediate 2a or 2b
to afford the spiro[1,3]thiazine heterocycles 14a,b–20a,b (cf. Scheme 2).
SCHEME 2

1241

1242

1243

1244

1245

1246
A. M. M. El-Saghier
The reaction mechanism was assumed to go through cycloaddition
reaction where a nucleophilic attack of the SH group of compound
1 or 2 to the ethylenic bond followed by a nucleophilic attack of the
XH group to the cyano group and cyclization. Here we have a chi-
ral center formed through the addition of the thioc or dithioc acid to
the double bond of ketene acetals. The overall yield as an insepara-
ble mixture of the possible regioisomeric adducts is generally good.
The 1H-NMR spectrum of these adducts shown only one set of sig-
nals. Also, the semi-empirical calculation made by Suwinski group to
compare between the energy barriers for the six derivatives of keten-
acetals containing heteroatoms (oxazole, thiazole, and pyrazole nu-
cleis) by MOPAC2000 calculation, they found that the reactivity of
the three types of nuclei is on the follwing order thiazole > oxazole >
pyrazole.
Treatment of 2-(1-acetyl-2-oxopropylidene)spiro[1,3]thiazine deriva-
tives 13a, 17d, and 18d with malononitrile in refluxing ethanol contain-
ing piperidine for about 2 h, where dispiro heterocycles 21–23, were pre-
cipitated. The reaction pathway was assumed to follow a preliminary
hydrolysis of one of the two acetyl groups followed by a nucleophilic ad-
dition malononitrile at the ethylenic bond with subsequent cyclization
(cf. Scheme 3).
The IR and 1H NMR data of all dispiro derivatives 21–23 are in accor-
dance with its structure, where showed the following absorption bands
in its ir spectrum, 3450, 3350, 3210 cm−1 for 2 NH2, 2220, 2210 cm−1
for 2CN groups and absence of the characteristic bands of C O from
the starting materials 13b, 17b, and 18b referring to the deacyla-
1
tion and cyclization. The H NMR displays four signals appeared as
broad bands between δ 6.50–6.30 (2H, NH2), δ 6.00–5.80 (2H, NH2),
singlets at δ 5.20(1H, CH) for the ethylenic hydrogen of γ -pyrane ring

Spiro 1,3-Dithiin and Spiro 1,3-Thiazine Derivatives
1247
SCHEME 3
and singlets at δ 2.10 (3H,CH3) for methyl groups. The olefinic sig-
nal was located at δ 5.20(1H, CH), its high-field position points to
E-configuration around the chiral atom bearing the pyrane ring27 (cf.
Tables I and II).
The deacylation of one of the acetyl groups for ketene-acetals using
methanol and a catalytic amount of sodium methoxide were reported
by Huang et al.28 Also, we reported in a previous work23 the synthe-
sis of spiro compounds using ketoketene-acetals and active methylene
in one-pot reaction and we provide the reaction experimentally in two
step reactions where, hydrolysis of one of the two acetyl group using
ethanol/piperidine or methanol/MeONa which was separated and al-
lowed to react with the active methylene in the second step to give the
same products.
EXPERIMENTAL
All melting points were determined on a Gallenkamp apparatus
and were uncorrected. IR spectra were recorded on a Nicolet 710
FT-IR spectrophotometer using the KBr disc technique. 1H NMR
spectra were measured on a Varian EM 360L, 60 MHz NMR

1248
A. M. M. El-Saghier
spectrometer in a suitable deuterated solvent, using TMS as internal
standard. Elemental analyses were performed on a Perkin-Elmer 240 C
microanalyzer.
Synthesis of Spiro(4-amino-5-cyano-2-ylidene[1,3]dithiin
6:1’ Cycloalkanes) 3a,b, 4a,b, Spiro(4-amino-5-cyano-2-
ylidene[1,3]dithiin 6:2’ Azolidines) 5a,b–7a,b, Spiro(4-
amino-5-cyano-2-ylidene[1,3]dithiin 6:2’ Bezazoles)
8a,b–10a,b and Spiro(4-amino-5-cyano-2-ylidene[1,3]-
dithiin 6:3’ Imidazoline-2’-ones) 11a,b
General Procedure
An equimolar mixture (0.05 mmol) of malononitrile or acetylace-
tone and carbon disulfide, tetrabutyl ammonium bromide (TBAB)
(0.5 mmol) in 70 ml dioxane was treated with anhydrous K2CO3
(7.0 g). The reaction mixture was stirred for 2 h at room temper-
ature. The formed dianionic ambident compounds 1a,b were then
treated with one of the following ylidenemalononitriles (0.05 mol), e.g.,
cyclopentylidene-, cyclohexylidene-, 2-oxazolylidene-, 2-(2,3-dihydro-
benzo[d]oxazolylidene-, 2-thiazolylidene-, 2-(2,3-dihydrobenzo-[d]-
thiazolylidene-, 2-perhydro-2-imidazolylidene-, 2-(2,3-dihydro-1H-
benzo[d]imidazolylidene- and 2-(2-oxo-2,3-dihydro-1H-3-indolylidene-
malononitrile. The reaction mixture was stirred at 70◦C for 4 h,
filtered, and the solid potassium carbonate layer was dissolved in
water and filtered. The filtrate was acidified with acetic acid and the
separated solid was crystallized from the appropriate solvent to give
compounds 5a,b–11a,b. The organic layer was evaporated in vacuo
and the residue was treated with water, filtered and crystallized from
the appropriate solvent to give compounds 3a,b and 4a,b.
Synthesis of Spiro(4-amino-5-cyano-2-ylidene[1,3]-
thiazine 6:1’ Cycloalkanes) 3a,b, 4a,b, Spiro(4-amino-
5-cyano-2-ylidene[1,3]thiazine 6:2’ Azolidines) 5a,b–7a,b,
Spiro(4-amino-5-cyano-2-ylidene[1,3]thiazine 6:2’ Bez-
azoles) 8a,b–10a,b and Spiro(4-amino-5-cyano-2-ylidene-
[1,3]thiazine 6:3’ Imidazoline-2’-ones) 11a,b
General Procedure
An equimolar mixture (0.05 mmol) of malononitrile or acetylace-
tone and phenyl isothicyanate PhNCS, tetrabutylammonium bromide
(TBAB) (0.5 mmol) in 70 ml dioxane was treated with anhydrous
K2CO3 (7.0 g). The reaction mixture was stirred for 2 h at room tem-
perature. The formed dianionic ambident compounds 2a,b were then

Spiro 1,3-Dithiin and Spiro 1,3-Thiazine Derivatives
1249
treated with one of the following ylidenemalononitriles (0.05 mmol),
e.g., cyclopentylidene-, cyclohexylidene-, 2-oxazolylidene-, 2-(2,3-
dihydrobenzo[d]oxazolylidene-, 2-thiazolylidene-, 2-(2,3-dihydrobenzo-
[d]thiazolylidene-, 2-perhydro-2-imidazolylidene-, 2-(2,3-dihydro-1H-
benzo[d]imidazolylidene- and 2-(2-oxo-2,3-dihydro-1H-3-indolylidene-
malononitrile. The reaction mixture was stirred at 70◦C for 4 h, filtered,
and the solid potassium carbonate layer was dissolved in water and fil-
tered. The filtrate was acidified with acetic acid and the separated solid
was crystallized from the appropriate solvent to give compounds 14a,b–
20a,b. The organic layer was evaporated in vacuo and the residue was
treated with water, filtered and crystallized from the appropriate sol-
vent to give compounds 12a,b and 13a,b.
Synthesis of Dispiro(4,2’-diamino-5,3’-dicyano-6’-
methyl-5-phenylpyrane 4’:2 [1,3]thiazine 6:1’’
Cyclohexane) 21, Dispiro (4,2’-Diamino-5,3’-dicyano-6’-
methyl-5-phenylpyrane 4’:2 [1,3]thiazine 6:2’’
benzoxazole) 22 and Dispiro(4,2’-diamino-5,3’-dicyano-
6’-methyl-5-phenylpyrane 4’:2 [1,3]thiazine 6:2’’
benzthiazole) 23
General Procedure
Malononitrile (0.01 mmol, 0.66 g) and piperidine (1 ml) were
added to a stirred suspension of the appropriate spiro[4-amino-
2-(1-acetyl-2-oxopropylidene)-5-cyano-3-phenyl[1,3]thiazine 6:1ꢁ cyclo-
hexane] 13b or spiro[4-amino-2-(1-acetyl-2-oxopropylidene)-5-cyano-
3-phenyl[1,3]thiazine 6:2ꢁ benzoxazole] 17b or spiro[4-amino-2-(1-
acetyl-2-oxopropy-lidene)-5-cyano-3-phenyl[1,3]thiazine 6:2ꢁ benzthia-
zole] 18b (0.01 mmol) in (40 ml). The reaction mixture was heated at
reflux for 2 h and left to cool. The resulting solid was collected by filtra-
tion and recrystallized from the appropriate solvent to give compounds
21 or 22 or 23 respectively.
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