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Preparation and Cyclization of
4-chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene
- 2,2-dioxide1
Li Tian *                                                                                Lunzu Liu
Department of Chemistry and Life Chemistry      State Key Laboratory of Elemento-Organic              Tianjin Normal University                    Institute of Elemento-Organic Chemistry Tianjin, P. R. China 300074                                      Nankai University
tian_lili@eyou Tianjin, P. R. China 300074
lunzuliu@hotmail
Abstract
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 formamidine, o-amino-phenol, phthalamine, amino-pyrazole and
amino-tetrazole to give the corresponding heterocyclic compounds.
Keywords: Vilsmeier reagent, chloroformylation, β-chlorovinylaldehyde,
heterocyclic compounds.
1 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 β-phosphoryliminium chloride (A) rather than the β-chloroiminium phosphate (B) [2] (Figure 1).
We recently reported that the Vilsmeier’s reaction applied on acetylphosphonate led stereospecifically t
o (Z)-β-phosphonyl-β-chlorovinylaldehyde[3]. We investigated this syhthesis more deeply and widened it to 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide 4. Chloroformylation of 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide 4 with Vilsmeier reagent (DMF/POCl3) afforded successfully to cyclic β-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 heterocyclic compounds.
1 Support by Specialezed Research Fund for the Doctoral Program of Higher Educatiom (No. 2002005006)
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N C
H OP(P)Cl 2
R 1R
2
Cl
N C
H R 1R
2
PO 2Cl 2
(A)                                          (B)
Figure 1  The two forms of Vilsmeier reagent
2 Results and Discussion
The action of DMF/POCl 3 on 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide (4) at 30℃ led to the sole product—4-chloro-5,5-dimethyl-3-formyl-1,2-oxathiole 2,2-dioxide (5) with excellent yield (64.5%) (Scheme 1). The reaction of 5 with formamidine, amino-pyrazole, amino-tetrazole, o-amino-phenol, phthalamine, 5-phenyl-4-amino-3-mercapto-(4H)-1,2,4-triazoles, gave the corresponding heterocyclic compounds (6-10) in the presence of K 2CO 3 (Scheme 2). These heterocyclic compounds were all characterized by their 1H, 13C NMR and elemental analysis.
Scheme 1
2
1
4  4                                                      5
O
S
O
O Cl
CHO CH 3CH 3
DMF/POCl 3O S O
CH 3CH 3
O
Scheme 2
7(a-b)
7a : X=H, Y=H 7b : X=CN, Y=MeS
8
9a : X=O 9b : X=NH
10
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Of all the new compounds, compound 9a , 9b and 10 has a seven-membered ring, which is commonly considered unstable because the high strain in seven-membered ring. X-ray diffraction of single crystal of 10 further established the structure [4]. As depicted in Figure 2, there undoubtedly exists a seven-membered ring C11-C10-C9-S1-C8-N3-N4.
Figure 2  X-ray structure of compound 10
When 4-chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide 5 reacted with phthalamine and amino-pyrazole in presence of K 2CO 3 to give the expected compounds 7a  and 9b respectively, we also obtained a little amount of the imines 11 and 12 which resulted by the reaction of the carbaldehyde group of 5 with the amino group of amino-pyrazole or phthalamine  (Scheme 3).
According to the compounds we obtained 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 amino-pyrazole or phthalamine to the carbaldehyde group of 5 gives imines 11 and 12; in the second step, intramolecular nucleophilic substitution of the nitrogen atom in 11 or 12 with chlorine atom on C 4 in them forms the final compounds 7a  and 9b .
Scheme 3
-HCl
9b
1    11
23
N
N NH 2
O S O
O
Cl
CH CH 3CH 3
N
N
N
H
O N NH
O
S
O O
3a 44a O S O
O
Cl
CH CH 3
CH 3
N H 2N 9
10    11a                                                                    12
1414
The reaction of 4-chloro-5,5-dimethyl-3-formyl-1,2-oxathiolene 2,2-dioxide 5 with hydrazine, hydroxylamine in the presence of K 2CO 3 can only give the intermediates hydrazones 13 and oxime 14
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(Scheme 4), which can’t cyclize further to give the corresponding pyrazoles or isoxazole in the presence of NaH, K 2CO 3 or DMAP.
Scheme 4
13b : R=Ph
13a : R= CH 314
13(a-b)
5
O
S O O
Cl
CH=N OH
O
S O
O Cl
CH=N NHR
HCl
NH 2OH R-NH-NH 222
/H 2O K 2CO 3+
O S O
O
Cl
CHO
3 Experimental
Mps were determined with a Thomas-Hoover melting-points apparatus. 1H NMR spetra were determined with a Bruker AC-P30 in CDCl 3 (CD 3)2CO or  DMSO solution. Chemical shifts were reported in ppm (δ) downfield from Me4Si. Elemental Analyses were performed on Yanaco Chn Cor D
er MF-3 apparatus.
3.1 S y nt h e sis  o f  Com p ou n d 4 (S ch e me  5)
To a solution of acetone cyanohydrin  1 (4.0 mL, 43.8 mmol) in dry CH 2Cl 2 (25mL) and Et 3N (12 mL, 87.5 mmol)) was added dropwise the methane sulfonyl chloride (4.8 mL, 62.1 mmol) whilst maintaining the temperature between 0 and 5℃. The reaction was allowed to reach room temperature and was stirred for 2 hours. The mixture was filtered over Celite to remove triethylamine hydrochloride and the filtrate was evaporated. Silica gel (2:1, petroleum ether: AcOEt) of the residue yielded compound 2 (5.30 g, 74%) as a colourless oil.
Compound 2 (0.43g, 2.65 mmol) in dry THF (12 mL) was stirred with 60% NaH dispersion in oil (0.13g, 3.18 mmol, 1.2 equiv) for 3 hours at rt. Water was added slowly to destroy the excess NaH and the mixture was extracted with AcOEt (3×30 mL). The dried organic layer (MgSO 4) was evaporated to yield a white solid 3 which was recrystallized from CH 2Cl 2:acetone =2:1 as colourless plates (0.305 g, 71%): mp 175-176℃(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 evaporated t
o leave a solid residue that upon recrystallization from hexane: toluene (2:1) gave 4 (0.21 g, 66%) as colourless plates: mp 58-59℃(lit [4] mp 59℃).
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Scheme 5
4
3
1
3
3
S O
O
CH 3
CH 3
O NaH
OSO 2CH 3
CH 3
CH 3
322CH 3SO 2Cl
CN
OH CH 3CH 3
3.2  Th e p rep a rat ion  of  4-ch l oro-5,5-d ime t h yl-3-f orm yl-1,2-oxat h io len e
2,2-d iox id e (5) To a solution of POCl 3 (0.12 mol) in CH 2Cl 2 (15 mL) was added dropwise a solution of DMF (0.12 mol) in CH 2Cl 2 (5 mL) at 0℃ under N 2 atmosphere. The 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℃.The reaction mixture was stirred for 30 h at room temperature. 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 CH 2Cl 2 (3×30 mL). The combined organic layers were washed with 50 mL brine, dried over Na 2SO 4, filtered and concentrated in vacuo. The crude yellow products was purified by recrystallization from AcOEt : petroleum ether (1:2) to give 5 as white crystals (2.73 g, 64.5%), mp: 175-176℃.
1
H NMR(300 MHz,CDCl 3): δ = 9.88(s,1H,-CHO), 1.75[s,6H, (CH 3)2].
13
C NMR(300 MHz, CDCl 3): δ=178.22(-CHO), 159.64(C 5), 121.55(C 4), 90.12[(CH 3)2-C-O], 26.78 (CH 3-).
Anal. Calcd for C 6H 7SO 4Cl: C,34.21; H,3.35. Found: C,34.15; H,3.53.
3.3 Ge nera l pro cedur e f or  t h e cyc liza ti on of  c ompound 5
To a solution of compounds 5 (1 mmol) in CH 2Cl 2 (5 mL), was added dropwise a solution of formamidine, amino-pyrazole [6-7], amino-tetrazole [8], o-amino-phenol, phthalamine or 5-phenyl-4-amino-3-mercapto-(4H)-1,2,4-triazoles [9], methyl-hydrazine [10], phenylhydrazine and hydroxylamine hydrochloride (1 mmol) in CH 2Cl 2 or water at 10 ℃, then K 2CO 3 (1 mmol) in water (2 mL) was added dropwise. The reaction mixture was kept at 30℃ for 2-3 h. The aqueous layer was extracted with CH 2Cl 2 (3×10 mL). The combined organic layers were washed with 20 mL saturated brine, dried over Na 2SO 4, filtered and concentrated. The residue was seperated 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.
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3.3.1 3,3-Dim et h yl-2-o xa-1-t h ia-4,6-d i aza-in d an1,1-d iox id e (6)
White crystals, yield: 46.36%, mp: 128-129℃
1H NMR(300 MHz, CDCl
3
): δ = 9.45(s, 1H, H7), 9.29(s, 1H, H5),1.85[s, 6H, (CH3)2].
13C NMR(300 MHz, CDCl
3): 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.
3.3.2 3,3-Dim et h yl-8H-2-o xa-1-t h ia-3b,4,8-t riaza-in d ac en e 1,1-d iox id e (7a) Yellow crystals, yield: 50.2%; mp: 213-215℃.
1H NMR(300 MHz, CDCl
3reaction between pvp and amino
): δ =9.21(s, 1H, H9), 8.41(s, 1H, H5), 6.86(s, 1H, H6), 1.94 [s, 6H, (CH3)2].
13C NMR(300 MHz, CDCl
3): 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.
3.3.3 6-C yan o-3,3-d im e th yl-5-me t h yls ul f an yl-1,3-d ih y dr o-2-oxo-1-t h ia-3b,4,8-
t r iaza-in d acen e 1,1-d ioxid e (7b)
White crystals, yield: 61.29%, mp: 237-239℃.
1H NMR(300 MHz, CDCl
3
): δ =7.05(s,1H,H9 ), 2.75(s, 3H, -SCH3),1.86[s, 6H, (CH3)2].
13C NMR(300 MHz, DMSO): δ=164.06(C
3a ), 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.
3.3.4 3,3-Dim et h yl-8H-2-o xa-1-t h ia-3b,4,5,6,8-p en t aaza-in d ace n e 1,1-d ioxid e
(8)
White crystals, yield: 60.50%, mp: 160-162℃.
1H NMR(300 MHz, CDCl
3
): δ =8.91(s,1H, H9), 1.82[s, 6H, (CH3)2].
13C NMR(300 MHz, CDCl
3):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.
3.3.5 3,3-Dim et h yl-3H-2,4-d ioxa-1-t h ia-10-aza-b e n zo-azu len e1,1-d io xid e (9a) White crystal, yield: 45.36%, mp: 171-172℃.
1H NMR(300 MHz, CDCl
3
) (ppm): δ =7.23-6.98(m, 4H, Ph), 5.54(s, 1H, H11), 1.76 [s, 6H, (CH3)2].
13C NMR[300 MHz, (CD
3)2CO] (ppm): δ=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-)

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