Preparation and cyclization of 4-chloro-5,5-dimethyl-3-formyl-1,2- oxathiolene 2,2-dioxide

Article abstract of DOI:10.1002/hc.20094

Chloroformylation of 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide 4 with Vilsmeier reagent (DMF/POCl₃) led to the formation of cyclic β-chlorovinylaldehyde (4-chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide 5). Compound 5 reacted with

Full text of DOI:10.1002/hc.20094

Heteroatom Chemistry
Volume 16, Number 3, 2005
Preparation and Cyclization of 4-Chloro-5,5-
dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide
Li Tian1 and Lun-Zu Liu2
1College of Chemistry and Life, Tianjin Normal University, Tianjin, 300074, People’s Republic of
China
2State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin, 300074, People’s Republic of China
Received 2 November 2004; revised 29 December 2004
of 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide 4
ABSTRACT: Chloroformylation of 5,5-dimethyl-1,2-
with Vilsmeier reagent (DMF/POCl3) afforded suc-
cessfully cyclic ꢀ-chlorovinylaldehyde 5 (4-chloro-
5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide).
5 is a very useful intermediate for the synthesis of
oxathiolan-4-one 2,2-dioxide 4 with Vilsmeier reagent
(DMF/POCl3) led to the formation of cyclic β-chloro-
vinylaldehyde
(4-chloro-5,5-dimethyl-3-formyl-1,2-
oxathiolene 2,2-dioxide 5). Compound 5 reacted with
formamidine, o-aminophenol, 1,2-phenylenediamine,
aminopyrazole, and aminotetrazole to give the corres-
heterocyclic compounds.
ꢀ
C
ponding heterocyclic compounds. 2005 Wiley Period-
RESULTS AND DISCUSSION
icals, Inc. Heteroatom Chem 16:200–204, 2005; Published
online in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/hc.20094
The action of DMF/POCl3on 5,5-dimethyl-1,2-oxa-
thiolan-4-one 2,2-dioxide 4 at 30◦C led to the sole
product 4-chloro-5,5-dimethyl-3-formyl-1,2-oxathio-
lene 2,2-dioxide 5 in 64.5% yield (Scheme 1). The
reaction of 5 with formamidine, aminopyrazole,
aminotetrazole, o-aminophenol, 1,2-phenylenedia-
mine, and 5-phenyl-4-amino-3-mercapto-(4H)-1,2,4-
triazoles gave the corresponding heterocyclic com-
pounds 6–10 in the presence of K2CO3 (Scheme 2).
These heterocyclic compounds were all character-
ized by their 1H, 13C NMR, and elemental analysis.
Of all the new compounds, compounds 9a, 9b,
and 10 have a seven-membered ring, which is com-
monly considered unfavorable because of the high
strain in seven-membered ring. X-ray diffraction
analysis of a single crystal of 10 further established
the structure [4]. As depicted in Fig. 2, there un-
doubtedly exists a seven-membered ring C11-C10-C9-
S1-C8-N3-N4. Selective bond distances and angles are
listed under Fig. 2.
INTRODUCTION
The Vilsmeier reagent, HCONR1R2/POCl3, has found
extensive application in the synthesis of aldehyde
derivatives and formamidines [1]. The reagent is an
equilibrium mixture of two iminium salts, the more
reactive being the ꢀ-phosphoryliminium chloride (A)
rather than the ꢀ-chloroiminium phosphate (B) [2]
(Fig. 1).
We recently reported that application of the
Vilsmeier’s reaction to acetylphosphonate led stereo-
specific formation of (Z)-ꢀ-phosphonyl-ꢀ-chloro-
vinylaldehyde [3]. We investigated this synthesis
more deeply and widened it to 5,5-dimethyl-1,2-
oxathiolan-4-one 2,2-dioxide 4. Chloroformylation
On treatment of 4-chloro-5,5-dimethyl-3-formyl-
1,2-oxathiolene 2,2-dioxide 5 with 1,2-phenylenedia-
mine and aminopyrazole in the presence of K2CO3,
Correspondence to: Li Tian; e-mail: lilytianli@hotmail.com.
Contract grant sponsor: Ministry of Education of China.
2005 Wiley Periodicals, Inc.
c
ꢀ
200

Preparation and Cyclization of 4-Chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide 201
FIGURE 1 The two forms of Vilsmeier reagent.
which gave the expected compounds 7a and 9b, re-
spectively, we also obtained small amounts of the
imines 11 and 12 that resulted by the reaction of the
formyl group of 5 with the amino group of aminopy-
razole or 1,2-phenylenediamine (Scheme 3).
As shown in Scheme 3, a plausible pathway for
this reaction would consist of two steps: in the first
step, 1,2-addition of the amino groups of aminopy-
razole or 1,2-phenylenediamine to the formyl group
of 5 gives imines 11 and 12; in the second step, in-
tramolecular nucleophilic substitution of the nitro-
gen atom in 11 or 12 with chlorine atom on C4 in
them forms the final compounds 7a and 9b.
SCHEME 2
The reaction of 4-chloro-5,5-dimethyl-3-formyl-
1,2-oxathiolene 2,2-dioxide 5 with hydrazine, hy-
droxylamine in the presence of K2CO3 can only
give the intermediates hydrazones 13 and oxime 14
(Scheme 4), which cannot cyclize further to give the
corresponding pyrazoles or isoxazole in the presence
of NaH, K2CO3, or DMAP.
were determined with a Bruker AC-P30 in CDCl3
(CD3)2CO or DMSO solution. Chemical shifts were
reported in ppm (δ) downfield from Me4Si. Ele-
mental analyses were performed on a Yanaco CHN
Corder MT-3 apparatus.
Synthesis of Compound 4
To a mixture of acetone cyanohydrin 1 (4.0 mL,
43.8 mmol) in dry CH2Cl2 (25 mL) and Et3N (12 mL,
87.5 mmol)) was added dropwise methane sulfonyl
chloride (4.8 mL, 62.1 mmol) whilst maintaining the
temperature between 0 and 5◦C. The reaction was
allowed to reach room temperature and was stirred
CONCLUSIONS
In conclusion, chloroformylation of 5,5-dimethyl-
1,2-oxathiole-4-one 2,2-dioxide 4 with Vilsmeier
reagent (DMF/POCl3) led to 3-carbaldehyde-4-
chloro-5,5-dimethyl-1,2-oxa-thiolene 2,2-dioxide 5.
Compound 5 is a very useful intermediate in
organic synthesis. It reacted with formamidine,
o-aminophenol, 1,2-phenylenediamine, aminopyra-
zole, and aminotetrazole to give the corresponding
heterocyclic compounds in high yields.
EXPERIMENTAL
Melting points were determined with a Thomas–
1
Hoover melting points apparatus. H NMR spectra
FIGURE 2 X-ray structure of compound 10. The hydro-
gen atoms are omit◦ted for clarity. Selective bond dis-
˚
tance (A) and angles ( ): S(1) C(8) = 1.723(4), S(1) C(9) =
1.748(3), C(9) C(10) = 1.338(4), C(10) C(11) = 1.448(3),
C(11) N(4) = 1.275(4), N(4) N(3) = 1.389(4). C(10) C(11)
N(4) = 131.5(3), C(11) N(4) N(3) = 118.2(3), C(8) S(1)
C(9) = 98.58, S(1) C(9) C(10) = 123.9(3).
SCHEME 1

202 Tian and Liu
SCHEME 3
SCHEME 5
for 2 h. The mixture was filtered over Celite to re-
move triethylamine hydrochloride, and the filtrate
was evaporated. Column chromatography (2:1 mix-
ture of petroleum ether and AcOEt as the eluent) of
the residue yielded compound 2 (5.30 g, 74%) as a
colorless oil.
mixture was stirred at room temperature for 0.5 h.
Then 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide
4 (3.28 g, 0.02 mol) was added dropwise at 0◦C. The
reaction mixture was stirred for 30 h at room tem-
perature. The mixture was poured slowly through a
condenser to a bottle which contained 150 g crushed
ice, and stirred for 3 h more. The aqueous layer
was then extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with 50 mL
brine, dried over Na2SO4, filtered and concentrated
in vacuo. The crude yellow product was purified by
recrystallization from AcOEt : petroleum ether (1:2)
to give 5 as white crystals (2.73 g, 64.5%), mp 175–
Compound 2 (0.43 g, 2.65 mmol) in dry THF
(12 mL) was stirred with 60% NaH dispersion in oil
(0.13 g, 3.18 mmol, 1.2 equiv) for 3 h at r.t. Water
was added slowly to destroy the excess NaH, and
the mixture was extracted with AcOEt (3 × 30 mL).
The dried organic layer (MgSO4) was evaporated to
yield a white solid 3 that was recrystallized from
CH2Cl2:acetone = 2:1 as colorless plates (0.305 g,
71%): mp 175–176◦C (lit [5] mp 175–176◦).
To a solution of 3 (0.305 g, 1.87 mmol) in EtOH
(10 mL) was added concentrated HCl (1 mL) and
then the mixture was stirred for 5 min. The mixture
was filtered over Celite, and the filtrate was evapo-
rated to leave a solid residue that, upon recrystalliza-
tion from hexane: toluene (2:1), gave 4 (0.21 g, 66%)
as colorless plates: mp 58–59◦C (lit [4] mp 59◦C) (see
Scheme 5).
1
176◦C; H NMR (CDCl3, 300 MHz): δ 9.88 (s, 1H,
CHO), 1.75 [s, 6H, (CH3)2]; 13C NMR (300 MHz,
CDCl3): δ = 178.22 ( CHO), 159.64 (C5), 121.55 (C4),
90.12 [(CH3)2 C O], 26.78 (CH3 ); Anal. Calcd for
C6H7SO4Cl: C, 34.21; H, 3.35 Found: C, 34.15; H,
3.53.
General Procedure for the Cyclization
of Compound 5
The Preparation of 4-Chloro-5,5-dimethyl-3-
formyl-1,2-oxathiolene 2,2-dioxide (5)
To a mixture of compounds 5 (1 mmol) in CH2Cl2 (5
mL) was added dropwise a solution of formamidine,
aminopyrazole [6,7], aminotetrazole [8], o-amino-
phenol, 1,2-phenylenediamine, or 5-phenyl-4-amino-
3-mercapto-(4H)-1,2,4-triazole [9], methylhydrazine
[10,11], phenylhydrazine, and hydroxylamine hy-
drochloride (1 mmol) in CH2Cl2 or water at 10◦C,
then K2CO3 (1 mmol) in water (2 mL) was added
dropwise. The reaction mixture was kept at 30◦C
for 2–3 h. The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with 20 mL saturated brine, dried over
Na2SO4, filtered, and concentrated. The residue was
separated by silica gel using AcOEt : petroleum ether
(3:1) as developing solvent to afford corresponding
heterocyclic compounds 6–14, which can be purified
by recrystallizing from suitable solvents.
To a mixture of POCl3 (0.12 mol) in CH2Cl2 (15 mL)
was added dropwise a solution of DMF (0.12 mol)
in CH2Cl2 (5 mL) at 0◦C under N2 atmosphere. The
SCHEME 4

Preparation and Cyclization of 4-Chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide 203
3,3-Dimethyl-2-oxa-1-thia-4,6-diaza-indan 1,1-
[(CD3)2CO]: δ 171.94 (C3a), 154.12 (C11), 133.34,
130.03, 129.23, 124.92, 123.19, 121.19 (Ph), 117.95
(C11a), 90.90 [(CH3)2 C O], 25.68 (CH3 ) Anal.
Calcd for C12H12N2SO3: C, 54.49; H, 4.57; N, 10.60.
Found: C, 54.26; H, 4.62; N, 10.79.
dioxide (6). White crystals, yield 46.36%, mp
1
128–129◦C; H NMR (CDCl3, 300 MHz,): δ 9.45 (s,
1H, H7), 9.29 (s, 1H, H5),1.85 [s, 6H, (CH3)2]; 13C
NMR (CDCl3): δ 170.31 (C3a), 162.25 (C5), 151.93
(C7), 125.45 (C7a), 93.09 (C3), 26.21 (CH3 ); Anal.
Calcd for C7H8N2SO3: C, 41.99; H, 4.03; N, 13.99.
Found: C, 41.95; H, 4.08; N, 13.93.
3,3-Dimethyl-7-phenyl-3H-2-oxa-1,4-dithia-
5,6,8,9-tatraaza-cyclopenta-azulene 1,1-dioxide (10).
Yellow crystals, yield 72.5%; mp 215–217◦C (de-
1
3,3-Dimethyl-8H-2-oxa-1-thia-3b,4,8-triaza-inda-
compose); H NMR (CDCl3, 300 MHz) δ 7.86–7.92
cene 1,1-dioxide (7a). Yellow crystals, yield 50.2%;
(m, 3H, Ph), 7.51–7.57 (m, 3H, Ph, and CH N)
1.83 [s, 6H, (CH3)2]; 13C NMR (CDCl3): δ 161.19
(C10), 157.15 (C3a), 142.59 (C8), 139.99 (C5), 131.24,
129.51, 128.65, 126.92 (Ph), 124.74 (C10a), 90.47
[(CH3)2 C O], 25.93 ( 2CH3); Anal. Calcd for
C14H12N4S2O3: C, 48.26; H, 3.47; N, 16.08. Found: C,
48.14; H, 3.50; N, 16.12.
1
mp 213–215◦C; H NMR (CDCl3, 300 MHz,): δ 9.21
(s, 1H, H9), 8.41 (s, 1H, H5), 6.86 (s, 1H, H6), 1.94
[s, 6H, (CH3)2]; 13C NMR (CDCl3): δ 160.35 (C3a),
149.68 (C9), 149.3 (C7), 132.57 (C5), 114.54 (C9a),
98.19 (C6), 93.44 (C3), 26.63 (CH3 ); Anal. Calcd for
C9H9N3SO3: C, 39.21; H, 3.66; N, 15.24. Found: C,
39.19; H, 3.76; N, 15.37.
(4-Chloro-5,5-dimethyl-2,2-dioxo-2,5-dihydro-
[1,2]oxathiol-3-ylmethylene)-(2H-pyrazol-3-yl)-amine
(11). White crystals, yield 15.8%; mp 217–219◦C; 1H
NMR (CDCl3, 300 MHz) δ 9.21 (s, 1H, NH N CH),
8.40 (s, 1H, CH N), 6.86 (s, 1H, C CH), 1.94 [s,
6H, (CH3)2]; Anal. Calcd for C9H10N3SO3: C, 45.18;
H, 3.79; N, 17.56. Found: C, 45.22; H, 3.86; N, 17.33.
6-Cyano-3,3-dimethyl-5-methylsulfanyl-1,3-dihy-
dro-2-oxo-1-thia-3b,4,8-triaza-indacene 1,1-dioxide
(7b). White crystals, yield 61.29%, mp 237–239◦C;
1H NMR (CDCl3, 300 MHz,): δ 7.05 (s, 1H, H9),
2.75 (s, 3H, SCH3), 1.86 [s, 6H, (CH3)2]; 13C NMR
(DMSO): δ 164.06 (C3a), 162.09 (C9), 152.72 (C7),
136.01 (C5), 122.36 (C9a), 115.46 ( C N), 111.79
(C6), 92.59 (C3), 25.95 ( 2CH3), 13.18 (CH3S );
Anal. Calcd for C11H10N4S2O3: C, 42.57; H, 3.25; N,
18.05. Found: C, 42.40; H, 3.39; N, 17.98.
N-(4-Chloro-5,5-dimethyl-2,2-dioxo-2,5-dihydro-
[1,2]oxathiol-3-ylmethylene)-benzene-1,2-diamine
(12). Yellow crystals, yield 26.67%, mp 138–139◦C;
1H NMR (CDCl3, 300 MHz) δ 8.35 (s, 1H, H C N),
7.08–7.13 (m, 2H, Ph), 6.62–6.71(d, J = 7.68 Hz,
1H, Ph), 6.62–6.67 (d, J = 7.68 Hz, 1H, Ph), 2.93
(s, NH2), 1.73 [s, 6H, (CH3)2]; Anal. Calcd for
C12H13N2SO3Cl: C, 47.74; H, 4.48; N, 9.42. Found: C,
47.92; H, 4.36; N, 9.31.
3,3-Dimethyl-8H-2-oxa-1-thia-3b,4,5,6,8-penta-
aza-indacene 1,1-dioxide (8). White crystals, yield
60.50%, mp 160–162◦C; 1H NMR (CDCl3, 300 MHz):
δ 8.91 (s, 1H, H9), 1.82 [s, 6H, (CH3)2]; 13C NMR
(300 MHz, CDCl3): δ 173.75 (C3a), 166.30 (C7),
154.33 (C9), 121.16 (C9a), 92.40 [(CH3)2 C O], 26.11
( 2CH3); Anal. Calcd for C7H7N5SO3: C, 34.85; H,
2.93; N, 29.03. Found: C, 34.77; H, 2.88; N, 28.93.
N-(4-Chloro-5,5-dimethyl-2,2-dioxo-2,5-dihydro-
[1,2]oxathiol-3-ylmethyl-ene)-Nꢁ-methyl-hydrazine
(13a). White crystals, yield 56.8%, mp 130–131◦C;
1H NMR (CDCl3, 300 MHz,): δ 6.94 (s, 1H, CH N),
2.97 (s, CH3N ) 1.67 [s, 6H, (CH3)2]; 13C NMR
(CDCl3): δ 154.7 (CH NNHCH3), 138.85 (C4), 116.14
(C3), 89.07 (C5), 32.65 (NH CH3), 25.74 (2CH3);
Anal. Calcd for C7H11N2SO3Cl: C, 35.22; H, 4.66; N,
11.73. Found: C, 34.87; H, 4.98; N, 11.73.
3,3-Dimethyl-3H-2,4-dioxa-1-thia-10-aza-benzo-
azulene 1,1-dioxide (9a). White crystals, yield
45.36%, mp 171–172◦C; 1H NMR (CDCl3, 300 MHz):
δ 7.23–6.98 (m, 4H, Ph), 5.54 (s, 1H, H11), 1.76 [s, 6H,
(CH3)2]; 13C NMR [(CD3)2CO]: 157.07 (C3a), 149.64
(C11), 128.03, 127.26, 124.65, 120.70, 117.04 (Ph),
115.57 (C10a), 88.25 [(CH3)2 C O], 26.12 (CH3 );
Anal. Calcd for C12H11SO4: C, 54.33; H, 4.18; N, 5.28.
Found: C, 54.47; H, 4.18; N, 5.14.
N-(4-Chloro-5,5-dimethyl-2,2-dioxo-2,5-dihydro-
[1,2]oxathiol-3-ylmethylene)-Nꢁ-phenyl-hydrazine
(13b). Yellow crystals, yield 67.5%, mp 161–162◦C;
1H NMR (CDCl3, 300 MHz): δ 8.21 (s, 1H, NH),
7.36 (s, CH N), 7.30–6.90 (m, 5H, Ph), 1.69 [s, 6H,
(CH3)2]; 13C NMR (CDCl3): δ 142.48 (CH NNH),
138.91 (C4), 121.29 (C3), 129.62, 129.39, 122.14,
113.64 (Ph), 89.30 (C5), 25.70 (2CH3); Anal. Calcd
3,3-Dimethyl-3,4-dihydro-2-oxa-1-thia-4,10-dia-
za-benzo-azulene 1,1-dioxide (9b). Purple crystals,
yield 56.82%; mp 172–173◦C; 1H NMR (CDCl3,
300 MHz): δ 6.71–6.78 (m, 2H, Ph), 6.54–6.58 (d,
J = 6.58 Hz, 1H, H8), 6.37 (s, 1H, H11), 5.98–6.02 (d,
J = 6.58 Hz, 1H, H5), 1.59 [s, 6H, (CH3)2]; 13C NMR

204 Tian and Liu
[3] Qian, D. Q.; Liu, Y. X.; Cao, R. Zh.; Liu, L. Z. Phos-
phorus, Sulfur, and Silicon 2000, 158, 179.
[4] Crystallographic data for the structure reported in
this article have been deposited with Cambridge
Crystallographic Data Centre as supplementary
publication No. CCDC 253013.
for C12H13N2SO3Cl: C, 31.94; H, 3.57; N, 6.21. Found:
C, 32.01; H, 3.66; N, 6.17.
4-Chloro-5,5-dimethyl-2,2-dioxo-2,5-dihydro-
[1,2]oxathiole-3-carbaldehyde oxime (14). White
crystals, yield 68.9%, mp 154–155◦C; 1H NMR
(CDCl3, 300 MHz,): δ 8.64 (s, 1H, OH), 7.94 (s,
CH N), 1.71 [s, 6H, (CH3)2]; 13C NMR (CDCl3): δ
146.87 (CH NOH), 137.76 (C4), 127.14 (C3), 90.32
(C5), 25.51 (2CH3). Anal. Calcd for C6H8NSO4Cl: C,
47.92; H, 4.36; N, 9.31. Found: C, 48.08; H, 4.46; N,
9.86.
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