Five-membered Rings containing Three Oxygen or Sulfur Atoms

(49)

The thermolysis products obtained from l,3,2-dioxathiolan-4-one 2-oxides (50) (cyclic sulfites of a-hydroxy carboxylic acids) depend on the substitution pattern. In the case R1 = R2 = CH2C1 (65JCS791) or R1 = Ph, R2 = H <70JCS(B)1049), a carbonyl compound, sulfur dioxide and carbon monoxide are formed (path A). If R1 and R2 represent rc-alkyl groups <65JCS79l, 66HC(2l-l)l, 74MI43302), predominantly polymers of type (51) are obtained (path B). The rate-determining process of path B is the primary ring scission with elimination of sulfur dioxide and concurrent ring contraction to form an a-lactone intermediate which then rapidly polymerizes (71JCS(B)1384). Pyrolytic splitting of sulfur trioxide from the 1,4,2dioxathiolane 2,2-dioxide derivative (52) yields the sodium salt (53) of (±)-(cw-l,2epoxypropyl)phosphonic acid, whose esters have antibiotic properties (70GEP1924138).

R'R2CO + SO, + CO

A

R1 O I II

R

path A

-o-c-c I2 (50)

"

R (51)

+ so 3 (53)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

869

4.33.3.1.3 Photolysis UV irradiation of simple 3,5-dialkyl-l,2,4-trioxolanes such as (54) leads mainly to the same fission products, though in different amounts, as the thermal decomposition {cf. Section 4.33.3.1.2), namely hydrocarbons, aldehydes, acids, carbon monoxide and carbon dioxide. A homolytic cleavage of the O—O bond (step a) followed by double /3-scission (step b) has been suggested as a possible mechanism (68TL3291, 68TL5397) and this interpretation is supported by the photochemical formation of cyclopropane from cyclopentene ozonide (55) (68TL3291), and of 1,2,3,4-tetramethylcyclobutene from hexamethylbicyclohexene ozonide (56) (68C392). Pr1 \J

£, -^> MeCH2Me + Pr'—Pr'+Pr'CHO + Pr'CO(54) Me ,O C>\

-HCO2H -CO

(55)

On UV irradiation on silica gel, the 1,2,4-trithiolane derivative (57) undergoes a reversible conversion into the 1,3-dithietane derivative (58) (79MI43300). Aryl-substituted 1,3,2dioxathiolane 2-oxides, e.g. (40), undergo [5 -> 1 + 2 + 2] photocycloeliminations to give arylcarbenes which can be utilized synthetically (72JOC2589).

c

s

v5

(Pr i O 2 C) 2 C< s >C,CO 2 P r i ,

^

(57)

(58)

Ph

Ph-A-O

h >3

I12V-* + i SO, *-'2 + Ph,CO 2 -^» Ph,C:

Ph ° (40)

4.33.3.1.4

Polymerization

Besides monomeric ozonides (29) and/or dimeric carbonyl oxides (30) {cf. Section 4.33.3.1.1), ozonolysis of alkenes frequently yields, depending on reaction conditions and substitution pattern, more or less large amounts of oligomers or polymers of ozonides, based on their elemental composition (B-31MI43300, 40CRV(27)437, 58CRV925). Since 1,2,4trioxolanes, once formed, do not tend to polymerize, these polymers most likely arise from the highly reactive primary ozonides and/or their fragmentation products. One possible reaction which could initiate polymerization is the attack of a Criegee zwitterion (28) on the unreacted primary ozonide (26), affording an intermediate of type (59) (67JOC3369). However, to obtain detailed data on structure and mode of formation of polymeric ozonides, further investigations are necessary. O

.

I

i

i

'

'

'

~r X - ^ + c-o-o-c-o-o-o-c

)£o f*V O" (28)

(26)

(59)

The few known monocyclic 1,2,3-trithiolanes have proved to be rather unstable compounds with a marked tendency towards polymerization. Thus simple alkyl-substituted

870

Five-membered Rings containing Three Oxygen or Sulfur Atoms

derivatives such as (60) polymerize at room temperature within some hours to form rubbery, soluble materials having molecular weights up to over 300 000 (77MI43302). Catalyzed by trimethyl phosphite or other mild bases such as acetonitrile, ethanol or acetone, tetrafluoro1,2,3-trithiolane (35) polymerizes at - 8 0 to - 4 0 °C to a white solid of relatively low molecular weight. Polymerization of (35) also takes place at room temperature without catalysts, but in this case the molecular weight of the polymer is reduced (62JOC3995). Et

F F^-s

„

f—\ /

room temp

\c/b

c

* ( C 4 H 8 S 3*,,

/ F-7

s> (60)

\ 'MeO)3P, ~80°C c * (C 2 F 4 S 3 ) n

X^

pa (35) O

°\

^t± --O-S-CH2CH

C ^° (16)

Depending on the method of preparation (cf. Section 4.33.4.2.1), 1,3,2-dioxathiolane 2-oxide (16) or its derivatives are obtained at first in the form of low molecular weight polymers which at elevated temperatures depolymerize to the corresponding monomers (57USP2798877, 61ZOB1332). The polymerization of such cyclic sulfites is catalyzed by bases (e.g. dialkylanilines or pyridines). The formation of polymers on thermolysis of 1,3,2dioxathiolan-4-one 2-oxides has been described in Section 4.33.3.1.2.

4.33.3.2 Reactions with Electrophiles 4.33.3.2.1 Reactions involving protons or Lewis acids Similar to the thermal fragmentation in solvents (cf. Section 4.33.3.1.2) and the basecatalyzed cleavage (cf. Section 4.33.3.3.1), the acid-catalyzed decomposition of ozonides (61) usually gives aldehydes and carboxylic acids. The reaction rate depends on the proton-donating strength of the catalyst, e.g. HClO 4 sH 2 SO 4 »HCl (59ACS342) or on its concentration, respectively (75ZOR7). Regarding the point of initial protonation, both the ether oxygen (path A) and a peroxidic oxygen of the 1,2,4-trioxolane ring (path B) have been considered. In the latter case the reaction is believed to proceed via a protonated carbonyl oxide (62), whose rearrangement and deprotonation give rise to the carboxylic acid. As evidence for this mechanism it was cited (75ZOR7) that if acetic acid were used as solvent, acetyloxyalkyl hydroperoxide (63) was obtained as by-product. By analogy to (62) a complex-stabilized zwitterion (65) was suggested to be the crucial intermediate in the reaction of certain 1,2,4-trioxolanes with antimony pentachloride (80JA288); thus from (61; R = C 5 Hn) the corresponding 1,2,4,5-tetroxane (66) was obtained in good yield, probably by reaction of (65) with excess (61) rather than by simple dimerization, cf. (8UA1789).

(64)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

871

Ph

n

Ph

Ph ^ " ° (67)

Depending on the substituents in (61) and on the concentration of the catalyst, however, other products may also subsequently be formed. In some cases, SbQ 5 -complexed primary intermediates of type (65) could even be isolated and characterized by NMR spectroscopy as well as by well-defined chemical reactions (8UA1789). Treatment of tetraphenyl-1,2,4trioxolane (67) with antimony pentachloride or liquid sulfur dioxide, a mild Lewis acid, gave benzophenone and phenyl benzoate in a molar ratio of 1:1 (80JA288). The formation of the ester corresponds to that of the carboxylic acid from (61) via path A or path B. On treatment with anhydrous hydrogen chloride in chloroform the cyclic enediol sulfite (25) did not yield the substituted desyl chloride (69), as one would expect, but was recovered unchanged. This was explained by steric shielding of the enediol double bond towards nucleophilic attack of chloride ion and by additional stabilization due to the formation of the pseudoaromatic system (68) (63JOC1075). Photochemical reaction of 1,3,2-dioxathiolane 2-oxide (16) (ethylene sulfite) with metal carbonyl derivatives such as MnC 5 H 5 (CO) 3 and Cr(CO) 6 led to complexes of type (70) and (71), respectively, in which the sulfur functions as electron donor (65CB2248). Boron trichloride converted 1,3,2-dioxathiolane 2-oxides into the corresponding 3-chloro-l,3,2-dioxaborolane derivatives (62JCS1505). On heating with aqueous acid, tetramethyl-l,3,2-dioxathiolane 2,2-dioxide (72) underwent, after protonation and ring opening, a rapid pinacol-type rearrangement to afford pinacolone in good yield (74JOC3415). Mes Mes

^

o

K O

Mes

x s ^. X)

"

Mes

^Jr^.

Q

\«/S^.+ ° OH

y

MesCVVS O OH

ci"

/ X

M e s

, '

Mes-C-Cl |

cr

(25)

-C=o

H (69)

(68) O ^Mn(C 5 H 5 )(CO) 2 Mn(c5H5)(CO)3

(70) Me Me—/—O ^

"

Me" (72)

"

"""

'

^O

"

^

M e 3 CCOMe

+ H 2 SO 4

^ " ^

Acid-catalyzed reactions of the systems under discussion with nucleophilic reactants will be.dealt with in Section 4.33.3.3. 4.33.3.2.2 Electrophilic addition at double bonds Examples of this reaction type are the addition of O,0-diethyl dithiophosphate at the endocyclic double bond of 1,3,2-dioxathiole 2-oxide (73) (62USP3053852) and the addition of bromine or sulfur trioxide at the vinyl group of the cyclic sulfate (31) (79IZV118). S EtON S

Jl ,P—SH +

EtO^

o ( >^ O

v-o

EtO — •

Iv

S

^o

(73)

F

F

F F/

' \

F2C-CF Br Br

i

c'^O y\

^O

F-

Br

2

F \ F

7—o[ ^.O / ' o

\

(31)

F

X

O

so 3

F

F

o TT s

F-j-o-s=o ( II

o

Five-membered Rings containing Three Oxygen or Sulfur Atoms

872

4.33.3.2.3 Oxidation without ring cleavage Oxidation reactions which take place with retention of the ring skeleton are known only in the 1,2,4-trithiolane and 1,3,2-dioxathiolane 2-oxide series. Oxidation of 1,2,4trithiolane (4) with sodium periodate in aqueous acetone at 0-5 °C gave a mixture of 1-oxide (74) and 4-oxide (37) in a ratio of 1:1 (76JOC2465), while oxidation with hydrogen peroxide in Bu'OH/THF at -30 °C in the presence of a catalytic quantity of V2O5 gave (37) in pure form (77CC287). The transformation of five-membered cyclic sulfites into the corresponding sulfates has been effected mainly with calcium permanganate as oxidant (63CRV557). Q

°\X \

(37)

,S

\

. NalO4,0-5 °C

O (74)

,S

\

H 2 O 2 ,-3Q°C,

,S

\

S

s

(4)

(37)

4.33.3.2.4 Oxidative ring cleavage The oxidative decomposition of ozonides of type (61) leads to carboxylic acids and is of considerable synthetic importance (cf. Section 4.33.5.1). Amongst the oxidizing agents used are oxygen (usually catalyzed by ozone or metal salts), hydrogen peroxide (especially in alkaline solution), peracids (e.g. performic or peracetic acid), chromic acid, potassium permanganate, or silver oxide suspended in sodium hydroxide solution (40CRV(27)437, 58CRV925). Ph to].

Ph

2RCO,H

Ph (61)

12H,O

S' (75) Cl

O

O

o (16)

2Ph 2 CCl 2 + 3H 2 SO 4 +18HC1

™

V o

1,2,4-Trithiolanes of type (75) proved to be stable against oxidation with hydrogen peroxide in acid medium at room temperature. However, on treatment with chlorine and water in glacial acetic acid, the trithiolane (75) was cleaved to 2 moles of benzophenone dichloride and 3 moles of sulfuric acid per mole of cyclic trisulfide (47JOC807). Cyclic sulfites of 1,2-diols likewise undergo an oxidative ring-opening on treating with chlorine, and from 1,3,2-dioxathiolane 2-oxide (16) 2-chloroethyl chlorosulfate was obtained (67JCS(C)314). UV irradiation had no effect on either the rate or the nature of the product, indicating that the chlorination does not proceed by a radical mechanism. 4.33.3.3 Reactions with Nucleophiles 4.33.3.3.1 O-Nucleophiles If the ozonolysis of an alkene is performed in the presence of an alcohol, then the intermediate Criegee zwitterion (28) formed by cycloreversion of the primary ozonide (26) {cf. Section 4.33.3.1.1) reacts with the alcohol to give an a-alkoxyalkyl hydroperoxide (76) (75AG765). This ozonolysis technique is of preparative importance because here the unwelcome formation of dimeric peroxides of type (30) as well as of oligomeric ozonides {cf. Section 4.33.3.1.4) is avoided. In certain cases the hydroperoxides (76) can be dehydrated thermally to carboxylic acid esters (62CJC1189). Addition of acetic acid or hydrogen peroxide to the zwitterion (28) has also been observed, giving a,a-bishydroperoxides (77) (75AG765). In an analogous fashion, ozonolysis of alkenes in water leads to a-hydroxyalkyl hydro-

Five-membered Rings containing Three Oxygen or Sulfur Atoms

873

peroxides (79) which are, however, unstable and decompose to carboxylic acids and water, or to carbonyl compounds (aldehydes or ketones) and hydrogen peroxide (B-72MI43303). The same end products can be formed by acid hydrolysis of 1,2,4-trioxolanes (29) which proceeds likewise via the hydroperoxide (79). Here the first step consists in the hydrolytic cleavage of an acetal C—O bond, resulting in a,a '-dihydroxydialkyl peroxides (78) which could be isolated in some cases (58CRV925). OOH OOH

H,O

C=O + H,O, Another role is ascribed to the water in the ozonolysis of a,/3-unsaturated carbonyl compounds. The 'abnormal' course of this reaction (cleavage of the alkenic double bond as well as the C—C bond adjacent to the carbonyl group) is rationalized in terms of a fragmentation of the intermediate 1,2,4-trioxolanes (80) initiated by hydration of the carbonyl group (67AHC(8)165). The base-catalyzed decomposition of 1,2,4-trioxolanes of type (33) apparently involves nucleophilic attack at the ring hydrogen atom to afford a carbonyl compound and the salt of a carboxylic acid (67AHC(8)165), this reaction being closely related to the decomposition of ozonides by solvents (cf. Section 4.33.3.1.2). Instead of hydroxyl ions, of course, other basic nucleophiles such as amines may be used (71CC1094).

R'CO,H + HCO2H + R2R3CO

R'R 2 CO + R3CO2

Tetraalkyl-substituted 1,2,4-trithiolanes (81) are remarkably stable towards aqueous acids and bases, even at elevated temperatures. On treating with methanolic potassium hydroxide, however, they are cleaved into ketones and potassium sulfide (66HC(2l-i)i). Under similar conditions the 1,2,4-trithiolane derivative (82) undergoes a ring contraction accompanied by saponification of the ester groups. This reaction probably involves the reductive cleavage of the disulfide linkage by the alcoholic base followed by recyclization with elimination of sulfide ion (71CJC1477). Analogous ring transformations of 3,5-bismethylene-l,2,4trithiolanes can be effected photochemically (cf. Section 4.33.3.1.3) or by desulfurization with triethyl phosphite or triphenylphosphine (cf. Section 4.33.3.3.6). KOH, MeOH

• R'R2CO + K2S

(81) CO2Et i, NaOH, EtOH

HO,C

MX

HO2C

EtO2C (82)

S

CO,H CO2H

874

Five-membered Rings containing Three Oxygen or Sulfur Atoms

As a rule the acid- and base-catalyzed hydrolysis of 1,3,2-dioxathiolane 2-oxide (16) and its monocyclic derivatives (63CRV557,76CRV747) occurs with S—O bond fission and retention of configuration at carbon. The rate-determining step of the perchloric acid catalyzed hydrolysis is formulated as the addition of water to the conjugate acid (83) to afford a tetracoordinate intermediate which, in turn, undergoes a fast ring cleavage. For the hydrolysis catalyzed by mineral acids such as hydrochloric or hydrobromic acid, another mechanism (nucleophilic catalysis, cf. Section 4.33.3.3.5) is tenable. The rate-determining step of the alkaline hydrolysis consists of the attack by hydroxyl ion on sulfur to yield anion (84); the subsequent step then proceeds at least 100 times faster. The hydrolysis of catechol sulfite (48) was faster than that of (16) by a factor of 104 in neutral solution and 105 in the presence of hydroxide ion. Both (16) and (48) reacted with alkali 103 times faster than their open-chain analogs, dimethyl sulfite and diphenyl sulfite. Because of the close similarity in the heats of hydrolysis of cyclic and open-chain sulfites in both the aliphatic and aromatic series, the kinetic acceleration in the cyclic esters cannot arise from some kind of ring strain but has been attributed to entropy strain (76CRV747). H+

O

H2O slow

(83) OH"

fast I H 2 O , -H 4 ", - H 2 S O 3

OH S

: N

, O OH~, -Si

2-

.~

-» I

fasT

CH2OH

(84)

o

l> + MeOSO,

s'

•o'S>

(16)

(85) ArCT

ArOCH2CH2OSO2 (86)

" o > ArOCH2CH2OH (87)

C-X-C-O-CH 2 CH 2 -O

II

(88)

Reaction of (16) with sodium methoxide gave, besides other products, ethylene oxide and sodium methyl sulfite. The surprising absence of 1,2-ethanediol mono- or di-methyl ether among the products suggests that initial alkoxide ion attack occurred exclusively at sulfur, possibly via anion (85) or a zwitterion of type +CH2CH2O~. The conjugate acid of (85), HOCH2CH2OSO2Me, could be detected by XH NMR spectroscopy as an intermediate in the transesterification of (16) with methanol or of dimethyl sulfite with glycol (76CRV747). In contrast to the attack of the methoxide ion at sulfur, phenolates react with (16) predominantly at carbon to yield aryloxyethyl sulfites (86) which are easily converted into the corresponding aryl 2-hydroxyethyl ethers (87) (63CRV557). In these reactions, which involve C—O bond fission, the cyclic sulfite acts as an alkylating agent. A similar reaction path underlies the formation of 2-hydroxyethyl acetate from (16) and acetic acid <66HC(21-l)l), and of polyesters (88) from (16) and dicarboxylic acids X(CO2H)2 in which X is, for example, (CH2)4 (57BRP781169) orp-C6H4 (59USP2870127). On reacting 4-chloromethyl1,3,2-dioxathiolane 2-oxide (89) with phenolates, besides the five-membered cyclic sulfites (90) the six-membered 5-aryloxy-l,3,2-dioxathiane 2-oxides (92) were obtained. This interesting ring expansion probably proceeds via an intermediate of type (91) (66HC(2l-l)l). l,3,2-Dioxathiolan-4-one 2-oxides (50) decompose rapidly in the presence of water and mineral acids to form a-hydroxy carboxylic acids, the detailed mechanism of hydrolysis being unknown. Nucleophilic attack on (50) by alcohols occurs at the acyl carbon atom and, with elimination of sulfur dioxide, gives a-hydroxy carboxylic acid esters (76CRV747). In a similar fashion to (50), l,2,3-oxadithiolan-5-one 2-oxides react rapidly with water to yield the parent a-mercaptocarboxylic acids (77MI43301).

Five-membered Rings containing Three Oxygen or Sulfur Atoms

875

C1CH, ArOCH

-c -

ArO "O' (92)

R'R 2 C-CO 2 R 3 OH

OH

In contrast to 1,3,2-dioxathiolane 2-oxide (16), the corresponding 2,2-dioxide (18) and their saturated monocyclic derivatives are hydrolyzed, predominantly with C—O bond cleavage, in either acid, neutral or alkaline solution. As shown by experiments with 18 O-labeled solvent, it is only under strongly alkaline conditions that (18) undergoes S—O bond fission (14%). On the other hand, catechol sulfate is cleaved by alkali exclusively with S—O bond fission. This difference is readily understandable since nucleophilic attack at the aromatic carbon atoms should be extremely improbable. Like five-membered cyclic sulfites, the corresponding cyclic sulfates are in part considerably more reactive than their open-chain analogs, catechol sulfate reacting with alkali 2xlO 7 times faster than does diphenyl sulfate (B-77MI43300). As expected, cyclic sulfates of aliphatic 1,2-diols are powerful alkylating agents towards a series of O-nucleophiles. Thus from (18) and phenolates, amine oxides or carboxylates the corresponding alkylation products (93), (94) and (95), respectively, are formed in high yields (72JHC891). Halogen atoms or alkoxy groups attached to the ring carbon atoms may be involved in the nucleophilic displacement. The methanolysis of the perfluorinated cyclic sulfate (96) leading to the carboxylic acid ester (97) (73IZV2725) and the acid-catalyzed cleavage of the 4,5-dimethoxy derivative (98) yielding hexafluorobisacetyl (77JA1214) provide two examples of reactions of this type. >H 86%

> ArOCH2CH2OSO3 (93)

O

o

14%

O

QN-O"

(18)

/

=

N-OCH 2 CH 2 OS0 3 " (94) RCO1

O

> RCO2CH2CH2OSO3~ (95) OMe

OMe -O

MeOH, 60 °C

O

F3C-C-CO2Me

(96)

F3CCOCOCF3 F3C

OH (97)

" (98)

V O

Being the cyclic anhydride of ethane-1,2-disulfinic acid, 1,2,5-oxadithiolane 2,5-dioxide (99) hydrolyzed to the parent acid in an almost quantitative fashion on boiling for 1 minute in water (76CRV747). In an analogous manner, 1,2,5-oxadithiolane 2,2,5,5-tetroxide (100) and its benzo-, naphtho- and thieno-fused derivatives were hydrolyzed by water or, more rapidly, by hot alkali to the corresponding 1,2-disulfonic acids or their salts, respectively <66HC(21-l)l). H2O

CH2-CH2 HO2S

SO2H

H,O

CH,—CH2 HO,S

SO3H

876

Five-memberxd Rings containing Three Oxygen or Sulfur Atoms

4.33.3.3.2 S-Nucleophiles Reactions of trioxolanes and trithiolanes with S-nucleophiles have received little attention. With thiophenolates, ethylene sulfite (16) and ethylene sulfate (18) react in the same manner as they do with phenolates (cf. Section 4.33.3.3.1). However, unlike (93), the reaction products of ethylene sulfate with phenolates which are relatively stable in aqueous solution, the corresponding thio derivative (101) readily hydrolyzed to (8-thiophenoxyethyl alcohol (103) (72JHC891). This may be rationalized in terms of the well-known neighboring effect in ethyl sulfides having a good leaving group in the /3-position. In the present case a cyclic sulfonium ion (102) may be formed which would react rapidly with water to give (103).

PhS"

\

n

-%

u

-o" %

o

" s °4

^

H

PhS

OH

o

(18)

(101)

(102)

(103)

4.33.3.3.3 N-Nucleophiles The ozonolysis of alkenes in liquid ammonia or in aqueous ammonia solutions leads via the primary ozonides (26) and carbonyl oxides (28) to a-aminoalkyl hydroperoxides (104). These products, however, under the reaction conditions readily undergo subsequent reactions, e.g. condensation with the carbonyl product (27) of the ozonolysis to give imines of type (105). In the case of suitable cycloalkenes, especially five-membered alkenes, this condensation step corresponds to a ring expanding recyclization, affording nitrogen heterocycles which in part may be stabilized by aromatization. Thus the 'amozonolysis' of cyclopentadiene leads, via (106) and (107), to pyridine in 18% yield, and indene can be transformed into isoquinoline in 62% yield (64JOC2240). In certain cases a-aminoalkyl hydroperoxides of type (104), or those formed from (28) and primary amines, undergo cyclodehydration to give oxaziridines (66CB3233). N-Nucleophiles such as hydroxylamine, phenylhydrazine or pyridine, on the other hand, may function as reductants if present during ozonolysis (cf. Section 4.33.3.3.6).

O

O 3 ,NH 3

(106)

(107)

Primary, secondary and tertiary amines behave towards 1,2,4-trioxolanes bearing at least one ring hydrogen atom first of all like a proton acceptor, initiating the base-catalyzed fragmentation already discussed in Section 4.33.3.3.1. Treatment of tetraalkyl-l,2,4-trithiolanes (81) with primary amines at low temperatures (s=0°C) gave the Schiff's bases (110). This reaction represents the reversal of the Asinger trithiolane synthesis (cf. Section 4.33.4.2.3). At elevated temperatures, besides (110), disulfides of type (111) were formed, possibly by reaction of the primary intermediate (108) with hydrogen sulfide liberated in the step (109)-• (110) <59LA(627)195>. In the case of unsubstituted 1,2,4-trithiolane (81; R1 = R =H), the primary intermediate (108) decomposed thermally to give thioformamides (112); secondary amines reacted in a similar fashion (67CPB988). The reaction of substituted 3,5-bismethylene-l,2,4-trithiolanes (113) with aliphatic (73GEP2151228) or aromatic primary amines (74EGP104784) gave a-mercaptoenamines (114) or the tautomeric thioamides (115). Bifunctional N-nucleophiles such as arylhydrazines, o-aminophenol or o-phenylenediamine transformed (113) into five- and seven-membered N-heterocycles (116) (73EGP102382) and (117; X = O , NH), respectively (74EGP106041). In these ring interconversions, in which the cyano group is involved, the system (113) functions as a C3 synthon.

Five-membered Rings containing Three Oxygen or Sulfur Atoms R3 R2 HN. SH

3

R NH,

R R2

S

/ R2

-H 2 S -CH,S

\

2

R

(108)

60-70 °C

SH (109)

3 60 °C H 2 S R NH

0°cT|-H2S

R2

HS

\

CH-S-S-CH

NHR3

R

(112)

(111)

/

c=c \

NC

R

°2C

\

CN R'NHNH, -H,S

NC

RO,C

S

NC

NHR'

NHR (115)

(114)

RO,C

2

(110)

SH

RO2C

RNH,

RO2C

NHR3

1

a

2

(81)

H-C;

R2

R NH,

877

SH

(113) NH2 XH

CO2R

-H,S

X-NH, (117)

1,3,2-Dioxathiolane 2-oxide (16) reacted with primary and secondary amines to give /3-aminoethyl sulfites (118) or, by subsequent hydrolysis, the corresponding /3-aminoethanols (120) <66HC(2i-i)i). Treatment of (16) with tertiary amines resulted in sulfitobetaines (119) (71BRP1257851), whose thermal decomposition yielded acetaldehyde among other products (60JOC651). O

(118) H*

R3N —»

3NCH2CH2OSO2"

(119)

(16)

-SO,

R1R2NCH2CH2OH (120)

R3N + CH3CHO + SO2

H+, H2O - H 2 S O 4

_

(121)

R'R^NH

R3NCH2CH2OSO3 O (18)

O

1,3,2-Dioxathiolane 2,2-dioxide (18) alkylated ammonia as well as primary and secondary amines to give /3-aminoethyl sulfates (121) (72JHC891) which can also be hydrolyzed to form (120) (73USP3743653). Reaction of (18) with tertiary amines afforded sulfatobetaines (122) (75JPR943). l,3,2-Dioxathiolan-4-one 2-oxides (50) were converted by aniline into a-hydroxycarboxylic acid anilides (123) and sulfur dioxide, while phenylhydrazine liberated the parent acids (124) without release of sulfur dioxide (66HC(2i-l)l). Analogous to the methanolysis of the perfluorinated cyclic sulfate (96) (cf. Section 4.33.3.3.1), the aminolysis of this compound gave the anilide (125) (73IZV2725).

878

Five-membered Rings containing Three Oxygen or Sulfur Atoms OH I

PhNH,2

R

R'R2C-CONHPh < "' -so 2

,°V-r> /

V. 2 A

(123)

\

o

/

PhNHNH,

sa

^

+

o

OH

I + PhNHN=SO R'R2C—CO2H

(50)

(124) OH

NHPh (96)

(125)

4.33.3.3.4 C-Nucleophiles 1,2,3-Trioxolanes and 1,2,4-trioxolanes react with C-nucleophiles such as Grignard reagents or organolithium compounds, resulting, as with various other reductants, in reductive ring cleavage (see Section 4.33.3.3.6). 3,5-Dimethyl-l,2,4-trithiolane (126) reacted with methyllithium at -60 °C to give intermediate (127) which was transformed into 4,6-dimethyl-2,3,5,7-tetrathiaoctane (128) in the presence of excess dimethyl disulfide (78HCA2809). Compound (128) is a constituent of roasted pork'meat (cf. Section 4.33.5.2). Me S—(

Me /

/

,S

/N* 6

MeLi, -60°C

\ _ I

S

(126)

Me S—( MeS-SMe

/

Li

\ i

Me

Me

(127)

(128)

The reaction of phenylmagnesium bromide with 1,3,2-dioxathiolane 2-oxide (16) gave 3.4-23% ethylene bromohydrin (131) and 42-60% diphenyl sulfoxide (132), depending on the conditions of the reaction. The bromohydrin (131) arises from a nucleophilic displacement at carbon by bromide ion, presumably via (129) and (130), while the sulfoxide (132) is formed by repeated attack of the Grignard reagent at sulfur (56JA454).

c

\

PhMgBrOEU

,S\ ^O

~*

<\

,S-

O

Ph

O

PhMg+Br

/_ — ^ • Mg, | / ~"'OEt2 -Mg-OEt 2

x

Mr

(16)

/

Di

O +xo

a

Mg/ "••OEt2

H2O

x

MgPh

CH2OH

-^-» I CH 2 Br

(130) PhMgBr

(131)

Ph Ph ph \+ I _ H2O \ * S—O—Ma ---OEt, > S=O

BrMgOCH2CH2OMgBr X

^ S v O o

Br

(129) O Ph \ / S

~\

Br-^

/ Ph

|

6

2

/

Br

Ph (132)

Starting from 1,3,2-dioxathiolane 2,2-dioxide (18) and organometallic compounds, /?substituted ethyl sulfates of type (133; R=CH(CO2Me), Ph, PhC=C) may be synthesized (72JHC891). Reaction of glyoxal sulfate (134) with cyclopentadienylsodium followed by treatment with triethylamine led to the fulvene (135) (72AG297); the lithium salt of phenalene reacts in a similar fashion <80Ml4330l). = NaCH(CO2Me)2, LiPh, LiC=CPh)

(135)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

879

4.33.3.3.5 Halide ions On reaction with sodium iodide in glacial acetic acid, 1,2,4-trioxolanes undergo a reductive ring cleavage which will be discussed in Section 4.33.3.3.6. In the presence of potassium fluoride, 5,5-difluoro-l,2,4-trioxolan-3-one (136) isomerized at low temperatures to give bis(fluoroformyl) peroxide (137). Since the reaction is reversible (cf. Section 4.33.4.2.5), isomerization occurred with an equilibrium being established (72IC2531).

O

°" F" F / ° ^ ~ F

O «=^ FX

F

° F 7 ^F -F- °

O<=±

FNL

ft

O <=± F C - O - O - C F

(136)

(137)

With hydrohalic acids as catalysts, the hydrolysis of 1,3,2-dioxathiolane 2-oxide (16) is considered to occur (partly or entirely) via a halosulfite intermediate, e.g. (138; X = C1). The marked acceleration of the aqueous hydrolysis of catechol cyclic sulfite by small amounts of fluoride ion is likewise attributed to a nucleophilic catalysis (76CRV747). The nucleophilic attack of (16) at carbon by halide ion on reaction with phenylmagnesium bromide has already been discussed in Section 4.33.3.3.4. O

(16)

(138)

On treating with cesium fluoride in diglyme or acetonitrile, the perfluorinated cyclic sulfate (96) underwent an exothermic fragmentation to trifluoro-2-oxopropionyl fluoride (139) and sulfuryl fluoride, presumably via initial attack at sulfur by fluoride ion (73IZV2725). O o -C-CF + SO2F2 (139)

4.33.3.3.6 Reductive ring cleavage Low-temperature reduction of primary ozonides with isopropylmagnesium halides leads to 1,2-glycols. This reaction provided the chemical evidence that in primary ozonides, based on their 1,2,3-trioxolane structure (26), the C—C linkage of the starting alkene was retained. If the ozonolysis is performed in the presence of a reductant which itself is stable to ozone, then one obtains directly carbonyl compounds (aldehydes and/or ketones) without any additional treatment of the ozonolysis mixture. Tetracyanoethylene, for example, may function as such a reducing agent, being oxidized by (26) to the epoxide (140). Reaction (26) —• (140) represents a convenient detection method for primary ozonides. It also allows for the isolation of the carbonyl compounds in those cases in which rearrangements would otherwise give rise to abnormal ozonolysis products (75AG765). Similarly, depending on the nature of the reducing agent, 1,2,4-trioxolanes (29) are cleaved to yield either alcohols or carbonyl compounds (cf. Scheme 8) (40CRV(27)437, NC

XN

:=o + o=c

+ NC

—C—OH (140) i i i y~^\ ii \ / —C—OH + HO—C— <— v7 V. —> c = O + O=C / X I I /^O" (29) i, LiAlH4> NaBH4, BH 3 THF, RMgX or MeLi; ii, Zn, Sn, Mg, Raney Ni, Pd/H2, Fe 2+ , Sn2+, I", SO2, HSO3" H 2 PO 2 , HOP(OR)2> HCHO, pyridine, Ph3P, NH2OH, PhNHNH2 or polarographic reduction Scheme 8 Reductive cleavage of 1,2,3-trioxolanes and 1,2,4-trioxolanes

880

Five-membered Rings containing Three Oxygen or Sulfur Atoms

58CRV925, B-78MI43300). The well-defined, reductive decomposition of ozonides is of considerable importance not only in its preparative aspects but also for mechanistic studies. Thus triphenylphosphine reduction, which occurs by exclusive attack at the peroxidic oxygen atoms of (29), may be used as a chemical method for determining the location of the 18O label in ozonides (76JOC892,76JA4526) (physical methods relating to this aspect are discussed in Sections 4.33.2.2.2 and 4.33.2.2.7). On reduction with lithium aluminum hydride, tetraalkyl-substituted 1,2,4-trithiolanes (81) undergo ring cleavage to give thiols. However, they are stable against trialkyl phosphites or triphenylphosphine. The last reagent, moreover, easily converts 3,5-bismethylene derivatives (141), in which X and/or Y are electron-attracting groups, into the corresponding 1,3-dithietane derivatives (142) (66T3001, 66CC577, 71CJC1477). Ring contractions of this type may also be achieved photochemically {cf. Section 4.33.3.1.3) or by treating with alcoholic alkali {cf. Section 4.33.3.3.1). Reductive cleavage of (141) with zinc and acetic acid leads to, among other products, thioethers (143) and/or sulfur-free compounds (144) (71CJC1477, 71TL1781). Reduction of (81; R x =R 2 = Ph) with Raney nickel likewise proceeds with desulfurization to give diphenylmethane (47JOC807). X

,S.

Y

Y

S (142)

X

R2

R2

S

(81)

X CHCH 2 -S-CH 2 CH (143)

(144)

ds-4,5-Dimethyl-l,3,2-dioxathiolane-2-thione (145) was reduced by Raney nickel to meso-2,3-butanediol as the sole product. The corresponding trans isomer, however, yielded sterically pure (±)-2,3-butanediol under the same conditions (65JOC2696). Me

Me /

\

Raney Ni H

o'^S

C—OH

" H-C-OH Me

(145)

4.33.3.4 Reactions with Carbonyl Compounds Ozonolysis of an alkene in the presence of a carbonyl compound which is more reactive, or which is present in higher concentration than that formed by cycloreversion of the primary ozonide (146), results in the zwitterionic carbonyl oxide reacting preferably with the added carbonyl compound to give ozonide (147) (58CRV925). In accordance with the Criegee mechanism {cf. Section 4.33.3.1.1) the oxygen of the added carbonyl component is incorporated into (147) as an ether oxygen rather than as a peroxidic oxygen atom R

R'

M R2 ° (146)

' - x c=o R

2/

R2

\

C0

R2

R4 ° (147)

,

Five-membered Rings containing Three Oxygen or Sulfur Atoms

881

(75AG765, B-78MI43300). The outlined method is of preparative importance since it permits the synthesis of 1,2,4-trioxolanes which cannot be obtained by other procedures (cf. Section 4.33.4.2.3). The acid-catalyzed reaction of 1,3,2-dioxathiolane 2-oxide (16) with carbonyl compounds leads to 1,3-dioxolanes (149), i.e. cyclic acetals of glycol (66HC(21-l)l). The ring transformation occurs exclusively with S—O bond fission and a mechanism involving a seven-membered intermediate (148) has been postulated. However, in the presence of traces of water the intermediate formation of glycol and its reaction with the carbonyl compound cannot entirely be ruled out (66BCJ1785). R2 +

o=c

O

C-R>

'A

V

O- ^OH

o

,-TR1

~^* K A

(16)

(148)

o

H2O

-so,

CH2OH

R,

O

R2

O (149)

4.33.3.5 Reactions with Radicals Reactions of trioxolanes and trithiolanes with radical species have received little attention. The action of hydroxyl radicals on 1,3,2-dioxathiolane 2-oxide (16) gave rise to the radicals (150), (151) and (152), which were detected by ESR spectroscopy after trapping with the nitromethane aci anion <76JCS(P2)i040). The /-butoxyl radical likewise attacked (16) at sulfur to yield radical (153) <77JMR(27)509>. s.

S

*C

°\ /OH

S

oA

O

o

(16)

(150)

Bu'O

O

o •o'

H

X

OH%

•* C H 2 = C H 2 O H + SO 3 T

Q

o

(153)

(152)

(151)

_O -2HC1

(18)

O

O (154)

Contrary to the oxidative ring cleavage of (16) on treatment with chlorine, a reaction which does not proceed by a radical mechanism (cf. Section 4.33.3.2.4), the photochemical chlorination of 1,3,2-dioxathiolane 2,2-dioxide (18) to give the 4,5-dichloro derivative (154), occurs unambiguously by a radical process. Subsequent dechlorination on (154) with magnesium in refluxing THF gave 1,3,2-dioxathiole 2,2-dioxide (19) (vinylidene sulfate) (68JA2970).

882

Five-membered Rings containing Three Oxygen or Sulfur Atoms

4.33.4 SYNTHESIS 4.33.4.1 General Survey of Ring Syntheses 4.33.4.1.1 Syntheses from non-heterocyclic compounds The syntheses of monocyclic five-membered heterocycles containing three oxygen or sulfur atoms can be classified into three groups, according to the number of building blocks required to form the ring in a one-step process: (/) One-component syntheses, in which a suitable starting molecule is cyclized by linkage of two heteroatoms or of a heteroatom and a carbon atom. Rings with three identical adjacent heteroatoms cannot be prepared in this way. (ii) Two-component syntheses, in which the five-membered ring can be built up either by a [2 + 3] process or by a [4 +1] process. The most usual variations of the [2 + 3] method are C2 + X3, C2 + X2 Y and CX+CX2, while the [4 + 1] approach accommodates combinations such as C2X2 + X, C2X2 + Y and C2XY+Y. Ring closure reactions proceeding with C—C bond linkage are unknown in these heterocyclic systems. (Hi) Multi-component syntheses, in which the ring is formed via non-isolated intermediates from more than two (identical or different) building blocks, e.g. by the combination CX + X2 + C, 2CX + X or 2C + 3X. Only systems with a 1,2,4-arrangement of identical heteroatoms have been prepared by these procedures. The various possibilities for these three types of syntheses are listed schematically in Table 10. Several of these reactions are of special preparative importance and they will be discussed in more detail in the subsection indicated in the last column in Table 10. In all other cases literature references are given. 4.33.4.1.2 Syntheses by ring transformations Characteristic types of ring transformations leading from three-, four-, five- or sixmembered heterocycles to five-membered systems with three oxygen or sulfur atoms are summarized in Table 11. In general, such reactions, because of their limited applicability, are of minor preparative interest when compared with syntheses from non-heterocyclic starting compounds. Exceptions are the ring enlargement of epoxides by sulfur dioxide and the very important rearrangement of primary ozonides (1,2,3-trioxolanes) into ozonides (1,2,4-trioxolanes).

4.33.4.2 Syntheses of Various Types of Derivatives 4.33.4.2.1 Parent systems (including S-oxides and S,S-dioxides) In this and the following subsections the basic structures will be discussed in the order in which they are arranged in Scheme 1 (cf. Section 4.33.1). In the case of the hypothetical parent systems 1,3,2-dioxathiolane (7), 1,4,2-dioxathiolane (8), 1,2,3-oxadithiolane (9) and 1,2,5-oxadithiolane (11), the corresponding 5-oxides and 5,S-dioxides will be regarded as the individual basic structures. The sole possibility of preparing the two parent compounds of the trioxolane series consists in the action of ozone on ethylene. When this ozonation was performed under suitable conditions, e.g. in a condensed phase at temperatures below -175 °C, the formation of 1,2,3-trioxolane (1) was observed (72JA4856, 8UA2578) (cf. Section 4.33.2.2.4). However, because of its thermal instability, this primary ozonide cannot be isolated but rearranged at temperatures above -100 °C to 1,2,4-trioxolane (2), ethylene ozonide, a colorless, explosive liquid extremely sensitive to impact <42LA(583)187). The mechanism of the ring transformation (1) -> (2) has been discussed in Section 4.33.3.1.2. In the trithiolane series only the parent compound (4) with a 1,2,4-arrangement of heteroatoms is known. It was obtained besides some 1,2,4,6-tetrathiepane as a distillable, pale yellow liquid on vigorous stirring of an aqueous solution of Na2S2.5 (prepared from Na2S-9H2O and the corresponding amount of sulfur) with excess methylene chloride according to a multi-component synthesis: 2CH2C12 + 2Na2Sx -> (4) + 4NaCl (cf. Table 10)

Table 10 Ring Syntheses of Monocyclic Five-membered Heterocycles Containing Three Oxygen or Sulfur Atoms from Non-heterocyclic Compounds

Type of synthesis One-component syntheses (formation of one bond)

Arrangement of heteroatoms in the starting systems

r

Starting components utilized HO—C-C—O—SO2—OH HO-SOn-C—C—SOn—OH S=C-S-C=S

HO—C—O-O-C—OH HS-C—S-S-C—SH S=C—S—S-C=S

Heterocyclic ring skeleton obtained" -H,O

-• 1,3,2-[C2O2S]

-H 2 O (n = 1 or 2) 1,2,5-[C 2 OS 2 ]

h -2r

-H 2 O -H 2 S ,2

-21". -[S]

R2S—C-C—O—SO2

Section or reference in which the reaction is cited 4.33.4.2.1

TO

a. So

4.33.4.2.1

1,2,4-[C2S3]

4.33.4.2.4

l,2,4-tC 2 O 3 ]

32CB1274

1,2,4-[C2S3]

74AC(R)305

1,2,4-[C2S3]

4.33.4.2.4

1,3,2-[C2O2S]

66GEP1223397

S'

1 s

Two-component syntheses (formation of two bonds)

X \

\

/

c=c+sx \

Br—C—C-Br + Na 2 S 4

-[s]

-> 1,2,3-[C2O3]

4.33.4.2.1 4.33.4.2.3

-• 1,2,3-[C2S3]

4.33.4.2.6

1,2,3-[C2S3]

4.33.4.2.3

00 00

00 00 p

Table 10 (Continued)

Type of synthesis

Arrangement of heteroatoms in the starting systems

1y X

Starting components utilized

c=c+so n

Heterocyclic ring skeleton obtained" + l,3,2-tC2O2S]

(n = 2 or 3)

-C-CO-+SO3 A c O - C - C - O A c + (MeO)2SO2 Br—C—C—Br + Ag2SO4 N a S - C = C - S N a + SOC12 HS—C—C—SH + S(NR2)2

n

74JOC3415

• 1,3,2-[C2O2S]

4.33.4.2.1

> 1,3,2-[C2O2S]

4.33.4.2.1

1,2,3-[C2S3]

4.33.4.2.3

-» 1,2,3-[C2S3]

4.33.4.2.3

-2NaCI

HO—C=C—OH + SOC12 H O - C - C - O H + SOnCl2 HO—C—C-OH + S2C12

H O - C - C - O H + SO2

r

H O - C - C - S H + SOC12 Y

1,3,2-[C2O2S]

4.33.4.2.1

1,3,2-[C2O2S]

60CB1129

1,3,2-[C2O2S]

HO—C-C—OH + F2S=NCF2CF3 HO-C—C—OH + (MeO)2SO

1,3,2-[C2O2S]

63JOC1075 4.33.4.2.1 4.33.4.2.3 4.33.4.2.1 4.33.4.2.3 4.33.4.2.4

1,3,2-[C2O2S] U i)3)2-[C2O2S]

-2MeOH CH2N2 -MeOH, - N 2 -2HC1

> 1,2,3-[C2OS2]

sr

4.33.4.2.1 4.33.4.2.3 4.33.4.2.6

1,3,2-[C2O2S] -2AcOMe -2AgBr

Section or reference in which the reaction is cited

4.33.4.2.1

8

s. O

? 1

Cl—C-S—S—C—C1 + Na2S

-c"

,

/

S"

=•C or

\

C

/

-2NaCl

1,2,4-[C2S3]

4.33.4.2.3

-> l,2,4-tC 2 S 3 ]

4.33.4.2.3

SH [O]

-[S]

\

\

Multi-component syntheses (formation of more than two bonds)

-

-[s]

> 1,2,4-[C2S3]

4.33.4.2.3

-» 1,2,4-[C 2 O 3 ]

73JA3343

4

re

So

I X *

X

i

2Cl-C-S-Cl + 2Na2S

X

•

•

-4NaCl -> 1,2,4-[C2S3] -[S] [O]

N

I

4.33.4.2.3

•> 1,2,4-[C2S3]

4.33.4.2.3

2 C=O + 2H2S + S

[Amine] •> 1,2,4-[C2S3] -2H 2 O

4.33.4.2.3

2 CF2 + 4NaSH

-4NaF -• 1,2,4-[C2S3] -[S]

4.33.4.2.3

-4NaCI

4.33.4.2.1

3 C=S

x

2

I'

-)c=o

X

1

3

[ C-SRJ

cs2

31

Sx

> 1,2,4-[C2S3]

I 3

"3=

[C2O3] trioxolane, [C2S3] trithiolane, [C2O2S] dioxathiolane, [C2OS2] oxadithiolane; cf. Scheme 1.

00 00

886

Five-membered Rings containing Three Oxygen or Sulfur Atoms

Table 11 Formation of Monocyclic Five-membered Heterocycles containing three Oxygen or Sulfur Atoms by Ring Interconversion

Type of ring transformation Insertion of an —SO2—moiety

Insertion of a sulfur atom

Starting systems

Heterocyclic ring skeleton obtained" (n=2or3)

S(OR) 2

S

ho.S

Rearrangement

* 1,3,2-[C2O2S]

4.33.3.1.2

-> 1,2,4-[C2S3]

1,2,4-[C2O3]

SOC1,

-zci.

-> 1,3,2-[C2O2S]

80ABC2169

4.33.3.1.1 4.33.4.2.1 4.33.4.2.3 75JOM(101)57

O

,o

MeONa

1,2,4-[C2S3]

68HCA1421, 75LA1513

Photofragmentation and recyclization of the intermediates

-> 1,2,4-[C2S3]

80ABC2169, 75TL555

Desulfurization

-> 1,2,4-[C2S3]

66T3001

Ring cleavage, partial desulfurization, and recombination of the intermediates

1

4.33.4.2.1 4.33.4.2.6

O

Insertion of sulfur

Displacement of a ring heteroatom (Z = GeR2 or AsR)

-> 1,3,2-[C2O2S]

O

Q

Section or reference in which the reaction is cited

See footnote a in Table 10.

(67CPB988) (the conversion of (4) into its 1-oxide (74) and 4-oxide (37) has been described in Section 4.33.3.2.3). The 4,5-unsubstituted 1,3,2-dioxathiolane system (7) exists only in the form of its 2-oxide and 2,2-dioxide or their derivatives. 1,3,2-Dioxathiolane 2-oxide (16) represents the parent compound of saturated five-membered cyclic sulfites. It is a colorless, distillable liquid which can be prepared according to the methods shown in Scheme 9. The most convenient laboratory technique is the reaction of ethylene glycol with thionyl chloride <66HC(2l-l)l). Another possibility is the transesterification of dimethyl sulfite with ethylene glycol (76CRV747). The reaction of ethylene oxide with sulfur dioxide, frequently described in the patent literature (66HC(2i-i)i), depends on the reaction conditions. It leads either directly HOCH2CH2OH + SOC12

-2HC1

' ^ HOCH2CH2OH + (MeO)2SO " ^ O "

(16)

0-10°cj[R3N] -FCH2CH2-O-S-O4-

L

O L

Scheme 9 Methods for preparing 1,3,2-dioxathiolane 2-oxide (ethylene sulfite)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

887

to (16) or first to a polymer which depolymerizes on heating to give ethylene sulfite in nearly quantitative yield (cf. Section 4.33.3.1.4). l,3,2-Dioxathiolane-2-thione, the thiono analog of (16), was obtained from ethylene glycol and S2C12 in the presence of triethylamine (65JOC2696).

1,3,2-Dioxathiolane 2,2-dioxide (18), the parent compound of saturated five-membered cyclic sulfates, has been prepared from 1,2-ethylene dibromide and silver sulfate in 25% yield as well as from glycol diacetate and dimethyl sulfate in 66% yield (66HC(2l-l)l) (cf. Scheme 10). Unlike the ready formation of ethylene sulfite (16) from ethylene glycol and thionyl chloride or from ethylene oxide and sulfur dioxide, the corresponding reactions with sulfuryl chloride (68JHC289) or sulfur trioxide (66HC(2l-l)l) gave only low yields of ethylene sulfate. In contrast, satisfactory results have been obtained by permanganate oxidation of (16) in acetone (63JA602) (cf. Section 4.33.3.2.3) or by transesterification of (16) with sulfuric acid to give 2-hydroxyethylsulfuric acid followed by treatment with thionyl chloride (66HC(2l-l)i) (cf. Scheme 10). The synthesis of 1,3,2-dioxathiole 2,2-dioxide (19), the 4,5-unsaturated derivative of (18), from (18) via chlorination and dechlorination has been described in Section 4.33.3.5. BrCH2CH2Br + Ag2SO4

~so^

AcOCH2CH2OAc + (MeO)2SO2 Scheme 10

HOCH 2 CH 2 OSO,H

Methods for preparing 1,3,2-dioxathiolane 2,2-dioxide (ethylene sulfate)

The 2-oxide of 1,2,3-oxadithiolane (9) has been prepared via a two-component synthesis from 2-hydroxyethanethiol and thionyl chloride in diethyl ether using triethylamine as hydrogen chloride acceptor (75ACS(A)414). The 2,5-dioxide (99) of 1,2,5-oxadithiolane (11) represents the cyclic anhydride of 1,2-ethanedisulfinic acid. It was obtained by controlled hydrolysis of 1,2ethanebis(disulfinyl) chloride (76CRV747). 1,2,5-Oxadithiolane 2,2,5,5-tetroxide (100), i.e. 1,2-ethanedisulfonic anhydride, has been prepared by heating the acid with thionyl chloride <66HC(21-1)1>.

The parent system 1,3,4-oxadithiolane (12) was claimed to be formed on reacting a,a '-dichlorodimethyl ether with sodium tetrasulfide in the presence of a base and subsequent steam distillation of the polymer obtained. However, since neither a structural proof nor any properties were described, the existence of this ring system should be considered in doubt <66HC(2l-l)l>. 4.33.4.2.2 Benzo derivatives Most compounds of this type are cyclic sulfite and sulfate esters of aromatic 1,2-diols as well as anhydrides of aromatic 1,2-disulfonic acids. The simplest representatives with unsubstituted benzene rings are 1,3,2-benzodioxathiole 2-oxide (48) (catechol sulfite), the corresponding 2,2-dioxide (156) (catechol sulfate) and 2,1,3-benzoxadithiole 1,1,3,3tetroxide (158) (1,2-benzenedisulfonic anhydride). Compound (48) was synthesized by refluxing catechol with thionyl chloride in the presence of pyridine. In a similar fashion, from 2-mercaptophenol 1,2,3-benzoxadithiole 2-oxide was prepared (81AG603). The dioxide (156) was obtained in two steps by reaction of catechol monosodium salt with sulfuryl chloride in benzene at 0-10 °C and subsequent reflux of the intermediate (155) in the presence of pyridine.

o

s?~*~~ ^ O H

i, conversion to

^ ^ \ ^

s=o (48)

(155)

(156)

The tetroxide (158) was formed on heating the dipotassium salt (157) with chlorosulfonic acid. 1,2-Benzenedisulfonic acid, in turn, has been prepared by diazotization of o-aminobenzenesulfonic acid, conversion into the mercaptobenzenesulfonic acid, and final oxidation.

Five-membered Rings containing Three Oxygen or Sulfur Atoms

888

(158)

Besides the benzo derivatives just described, a series of compounds with a substituted benzene ring as well as those condensed with other aromatic or heteroaromatic systems is known. They all are accessible by the same or similar methods (66HC(2l-l)l). 4.33.4.2.3 C-Linked substituents Like the parent compound (1), alkyl- and/or aryl-substituted 1,2,3-trioxolanes can be prepared only through ozonation of the corresponding alkenes. Primary ozonides derived from aliphatic cis alkenes are much more unstable and decompose at lower temperature than those formed from the corresponding trans alkenes. Under suitable conditions, some of these compounds can be obtained at low temperatures in the form of colorless explosive precipitates (75AG765, B-78MI43300). The most 'stable' monocyclic 4,5-dialkyl derivative and, at the same time, the very first primary ozonide actually isolated in crystalline form, is fra«s-4,5-f-butyl-l,2,3-trioxolane. On warming up to -60 °C it rearranged exothermically to give the corresponding 1,2,4-trioxolane derivative (60CB689). The primary ozonide of styrene proved to be likewise relatively 'stable' showing no decay until about -55 °C (79JA2524). A discussion has appeared of more recent quantum chemical investigations on the formation of some alkyl-substituted primary ozonides and their interconversion into final ozonides (81JA3619, 81JA3627). The synthesis of monocyclic alkyl- and/or aryl-substituted 1,2,4-trioxolanes by ozonolysis of alkenes is only possible when the alkene possesses at least one hydrogen atom at the C—C double bond, otherwise 1,2,4,5-tetroxanes (30) (cf. Section 4.33.3.1.1), oligomeric ozonides (cf. Section 4.33.3.1.4) and/or other subsequent products are formed. Exceptions are tetrasubstituted ethylenes having electron-attracting substituents such as haloalkyl or ester groups at the alkenic double bond. Thus trans-l,4-dibromo-2,3-dimethyl-2-butene (159) and 2,3-dimethyl crotonic acid methyl ester (161) were converted into the corresponding 1,2,4-trioxolanes (160) and (162), respectively (75AG765, B-78MI43300). CH,Br Me

3

Me ° „ Me

CO2Me

Me

O O

Me

BrCH (160)

(159)

Me

Me

(162)

(161)

The transformation of tetrasubstituted ethylenes into 1,2,4-trioxolanes may also be achieved if the ozonolysis is carried out in the presence of a 'foreign' carbonyl compound as described in Section 4.33.3.4. With formaldehyde as added carbonyl compound, 3,3disubstituted derivatives are obtained, whereas in the presence of excess ketone (e.g. by using the latter as solvent), the ozonolysis gives rise to tetrasubstituted 1,2,4-trioxolanes which are difficult to prepare by other methods. Reactions (163) -> (164) and (165) —• (166) provide two examples of this versatile 1,2,4-trioxolane synthesis. Unlike the parent system (2), alkyl- and/or aryl-substituted 1,2,4-trioxolanes generally are stable, non-explosive compounds. Mixtures of 'crossed' ozonides (cf. Section 4.33.3.1.1) or of cis and trans isomers can be separated by thin layer, column or gas chromatography. The cis isomers of symmetrical 3,5-disubstituted 1,2,4-trioxolanes are meso forms, whereas the corresponding trans isomers represent racemates which in some cases have been resolved into their optical antipodes (75AG765, B-78MI43300). Me

Me Me

Me

Me (163)

°3.HCHO -Me,CO

Me

O

Ph

Ph

O

O' (164)

Me

Ph

Ph (165)

O3,Me2CO -Ph,CO '

Ph

O

Ph (166)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

889

The principles underlying alternative formation of 1,2,4-trioxolanes by cyclodehydration of a,a'-dihydroxydialkyl peroxides (Rieche's 'ozonide synthesis without ozone'), or by photooxidation of diazo compounds in the presence of aldehydes, are outlined in Table 10. In the 1,2,3-trithiolane series only a few representatives containing C-linked substituents are known. The 4-ethyl derivative (60) was obtained as an unstable, distillable, yellow liquid on treating 1,2-dimercaptobutane (167) with diphthalimido sulfide (77UP43300) (for the marked tendency of (60) to polymerize, cf. Section 4.33.3.1.4). The reaction of the vicinal dibromides (168; R = SO3Na, O(CH2)2SO3Na and S(CH2)2SO3Na) with sodium tetrasulfide resulted in the corresponding 3-alkyl-substituted 1,2,3-trithiolanes (169). These are soluble in water and can be characterized by their benzylisothiuronium salts (67UKZ596). EtCHSH

r-^

S(NR2)2

CH2SH "

2HNR

RCH2CHBr

>' V s / S

C H

^

'

"

( l H 2 B r TlNaBT^

R = phthalimido (167) (60)

(168)

(169)

The synthesis of 4,5-dicyano-l,2,3-trithiole 2-oxide (172) starts from sodium cyanide and carbon disulfide which via (170) gave the disodium salt of 2,3-mercaptomaleonitrile (171; M = Na). Treatment of the corresponding silver salt (171; M = Ag) with thionyl chloride yielded (172) (66HC(21-l)l). Phenylsulfine (174), prepared in situ by dehydrohalogenation of phenylmethanesulfinyl chloride (173), slowly decomposed in ether solution at room temperature to give cis- and franx-stilbenes, frans-4,5-diphenyl-l,2,3trithiolane 1,1-dioxide (36) and a 5,6-diphenyl-l,2,3,4-tetrathiane dioxide (68JCS(C)1612). The mechanisms of formation of these heterocycles are obscure. NC

NC SM

NaCN + CS 2 —> NC-C* "SNa

2HC1

SM (171)

(170)

s

SOCI 2

(172) Ph

PhCH 2 SOCl —

=t3HCl

PhCHSO

roon emp

"

V-s

> PhCH=CHPh Ph'

(173)

(174)


P

(36)

V<

Symmetrical 3,5-dialkyl-l,2,4-trithiolanes (178) can be synthesized in reasonable yield by chlorination of dialkyl disulfides (175) to a-chloroalkyl sulfenyl chlorides (176), which are then reacted with potassium iodide to give di-a-chloroalkyl disulfides (177). Subsequent cyclization with sodium sulfide gave (178) (72T3489). When (176) was treated with one molar equivalent of sodium sulfide, the reductive dimerization and cyclization was effected in one step (78HCA1404). Treatment of perfluoropropene with sodium hydrogen sulfide in THF resulted in the formation of 3,5-bis(2,2,2-trifluoroethyl)-l,2,4-trithiolane (179) (72IZV2517). C\ RCH2-S-S-CH2R

^

Cl

> 2RCH-SC1 _ 2 K ^ ' _,> R C H - S - S - C H R

(175)

(176)

'

2

(177) Na 2 S -2NaCl

2CF 3 CF=CF 2 _

(179)

(178)

Usual methods for preparing substituted 1,2,4-trithiolanes of type (81) are shown in Scheme 11.-According to Asinger et al. (59LA(627)195), the common action of hydrogen sulfide and sulfur on ketones at 0 °C in the presence of a primary aliphatic amine leads to

Five-membered Rings containing Three Oxygen or Sulfur Atoms

890

3,3,5,5-tetraalkyl-substituted derivatives. The mechanism of this multi-component synthesis has been discussed in connection with the reverse reaction, the cleavage of (81) by primary amines {cf. Section 4.33.3.3.3). The reaction also proceeds with some aldehydes, but fails with formaldehyde, acetophenone and benzophenone. Under acid conditions, however, benzophenone readily reacts with hydrogen sulfide in ethanol to give (81; R1 = R2 = Ph) (66HC(2l-l)l). Another way to tetrasubstituted derivatives is the action of aerial oxygen (66HC(2l-l)l), sulfur <66JPR(306)ll6>, tetrachloro-o-quinone (65TL3361) or chloramine-T (71CC179) on thioketones. Geminal dithiols can also be oxidized to 1,2,4-trithiolanes of type (81) (62JOC488, 72USP3694498). ' \

\ C = O +H,S + S R2

R

C=O+H2S

2

(81)

c=s R2

Scheme 11 Methods for preparing 3,3,5,5-tetrasubstituted 1,2,4-trithiolanes

3,5-Bismethylene-l,2,4-trithiolanes (141), in which X and/or Y as a rule represent electron-attracting groups such as COR, CO2R, CONH2, CN, CF3, etc., are obtained from dithio acids, their anions (180) or dianions (181) by oxidation with bromine (62CB2861, 70BCJ2938), iodine (62CB2861, 65LA(684)37, 72JOC3226, 76JCS(P1)17O6, 77JCS(P1)1273), peroxydisulfate <62CB286l, 71CJC1477) or sulfuric acid <73BSF58l). T h e dithio anions (180) and (181)

can be readily prepared by reaction of the corresponding active methylene compound with carbon disulfide in basic medium. Other methods for synthesizing 1,2,4-trithiolanes of type (141) are the treatment of sulfonium ylides (182) with carbon disulfide (71TL1781) or the reaction of thioketenes (183) with sulfur at elevated temperatures (70JOC3470). The syntheses of 1,2,4-trithiolanes by the ring transformations listed in Table 11 also lead without exception to 3,5-bismethylene derivatives. \

CH, + CS,

\

CH—C C (180)

V

C=C (181)

[O]

X

(182)

X A

C=SMe + CS2 (141)

\

c=c=s + s (183)

1,3,2-Dioxathiolane 2-oxides containing C-linked substituents can be synthesized, in principle, according to the same methods shown in Scheme 9 for preparing the parent compound, ethylene sulfite (16). Here also the reaction of the corresponding 1,2-diols (including 1,2-enediols) with thionyl chloride is the most important laboratory method. In the case of polyhydroxy compounds the remaining hydroxy groups frequently are displaced by the chloro substituent (66HC(2l-i)i). Treatment of simple aliphatic 1,2-diols such as propylene glycol or meso- and (±)-2,3-butanediol with sulfur monochloride (S2C12) results in the formation of the corresponding l,3,2-dioxathiolane-2-thiones (65JOC2696). Another route to alkyl-substituted cyclic suljites consists of the photosulfoxidation of alkenes, i.e. their photoreaction with sulfur dioxide and oxygen (74T2053). Alkyl-substituted 1,3,2-dioxathiolane 2,2-dioxides can be prepared in a similar manner to the parent compound, ethylene sulfate (18) <66HC(2i-i)i) {cf. Scheme 10, Section 4.33.4.2.1). The method of choice is the permanganate oxidation of the corresponding cyclic sulfites {cf. Section 4.33.3.2.3) since the direct reaction of 1,2-diols with sulfuryl chloride often proceeds less smoothly than does the reaction with thionyl chloride. 4,5Diaryl-l,3,2-dioxathiole 2,2-dioxides of type (186) are obtained by treatment of 9,10-

Five-membered Rings containing Three Oxygen or Sulfur Atoms

891

dihydroanthracene derivatives (184; R = Ph, PhC=C) with sulfuric acid, half-esters of structure (185) being suggested as intermediates in this reaction (66HC(2l-l)l).

(184)

(185)

(186)

4.33.4.2.4 N-Linked substituents Trioxolanes containing iV-linked substituents appear to be unknown but 1,2,4-trithiolanes of this type are readily accessible. 3,5-Bis(N,A^dialkyliminium) salts (188) can be prepared according to a one-step synthesis by oxidation either of ./V,iV,iV',N'-tetraalkylthiuram disulfide complexes such as (187) (76MI43300) or of JV,iV,JV',JV'-tetraalkylthiuram monosulfides (189) with halogens (75MI43300). 3,5-Bis(arylhydrazones) (191) of 1,2,4trithiolane-3,5-dione are formed on oxidation of aryldithiocarbazic acids (190) (7UCS(B)415) or by desulfurization of l,2,4,5-tetrathiane-3,6-dione bis(arylhydrazones) (192) which can likewise be obtained by oxidation of (190) (69G780).

R,N

s s // \\ s—s

NR,

7NR2

S—-f / \

NR,

VS

(187)

CI2,Br2orI2 X2" *

R,N' (189)

(188) N-NHAr

ArNHNHCS,H

y

H2O,

ArNH(191)

(190)

(192)

Pentafluoroethyleneiminosulfur difluoride (193) reacted with ethylene glycol in the presence of anhydrous sodium fluoride to give the imine derivative (194) of 1,3,2-dioxathiolane (79IC213). a-Hydroxy ketones in fuming sulfuric acid undergo reaction with difluoramine to form substituted 4-difluoroamino-l,3,2-dioxathiolane 2,2-dioxides (195) and, under similar conditions, a,j8-diketones give substituted 4,5-bis(difluoramino)-l,3,2-dioxathiolane 2,2-dioxides (196). Difluoramine is conveniently generated in situ by the interaction of A^A^-difluorourea with sulfuric acid (69JOC917).

ICF 2 CF 3 (194)

R—C — O

HX-OH

HNF 2 , H 2 SO 4

fr v

\

(195)

o

R-C=O I R'-C=O

NF2 R-/—O

2HNF 2 , H 2 SO 4 -2H2O

*

F,N O

O

(196)

4.33.4.2.5 O-Linked substituents (including oxo derivatives) The sole representative of this type in the trioxolane series is 5,5-difluoro-l,2,4-trioxolan3-one (136), the ozonide of the unknown difluoroketene F 2 C=C=O. It has been prepared by the reversible isomerization of bis(fluoroformyl) peroxide (137) at low temperatures with activated potassium fluoride (72IC2531) as described in Section 4.33.3.3.5. CHC VOL 6-CC*

892

Five-membered Rings containing Three Oxygen or Sulfur Atoms

l,3,2-Dioxathiolan-4-one 2-oxides (50) {cf. Section 4.33.3.1.2), the so-called anhydrosulfites of a-hydroxy carboxylic acids, are synthesized by reacting the latter with thionyl chloride (66HC(2l-l)l). a-Thiocarboxylic acids react analogously, yielding 1,2,3oxadithiolan-4-one 2-oxides (77MI43301). The bicyclic orthosulfite (46) {cf. Scheme 7, Section 4.33.3.1.2) was obtained by treatment of perfluoropinacol with excess sulfur dichloride and pyridine in ether (76JA2895). Monocyclic orthosulfites of type (47) resulting from 3,3-dialkyl-l,2-dioxetanes and dialkyl sulfoxylates were detected only in solution at low temperatures (75JA3850), since they polymerized at room temperature or decomposed as shown in Scheme 7. The synthesis of the 4,5-dimethoxy-l,3,2-dioxathiolane 2,2-dioxide (98) from perfluoro2-butene involved reaction with sodium methoxide, resulting in a mixture of cis and trans isomers of the vinyl diether (197). Subsequent action of sulfur trioxide on (197) gave, probably via the 1,2-oxathietane 2,2-dioxide (198), the cyclic sulfate (98) <77JA1214>, a convenient precursor to hexafluorobiacetyl {cf. Section 4.33.3.3.1). OMe F3C CF 3 CF=CFCF 3

OMe

p3C

OMe

F,C

2NaF

(197)

4.33.4.2.6 Halogens attached to the ring The ozonolysis of chloro- and bromo-substituted alkenes has not resulted in stable, halogenated 1,2,4-trioxolanes but has resulted in a variety of other products derived mostly from subsequent reactions of the acyl halide and halogenated carbonyl oxide expected from a Criegee cleavage of the alkene {cf. Section 4.33.3.1.2). Reaction by non-Criegee pathways may also produce products such as epoxides or haloalkanes (72CB3638,76JA2877). In contrast, ozonolysis of vinyl fluoride (79JOC3181), 1,1-difluoroethylene (79JPC1545, 80JA7572), cis- and trans- 1,2-difluoroethylene (77JA7239) and trifluoroethylene (80JA7572) gave the corresponding fluorinated 1,2,4-trioxolanes (199), (200), (201) (as a mixture of cis and trans isomers) and (202), respectively, among other volatile products {e.g. acyl fluorides, carbonyl fluoride and epoxides). The yields decreased in the above order and in the case of perfluoroethylene only traces of tetrafluoro-l,2,4-trioxolane (203) were detected (68MI43301). A quantum chemical investigation of the ozonolysis of fluoroalkenes has been published (8UA3633). A fluorinated l,2,4-trioxolan-3-one (136), obtained in a different way, was described in Section 4.33.4.2.5. The direct introduction of halogen atoms such as fluorine, chlorine or bromine into 1,2,4-trioxolanes fails due to the ready cleavage of the ring under these reaction conditions and products such as aldehydes and carboxylic acids are formed (54USP2665280).

(199)

(200)

(201)

(202)

(203)

The sole representative in the trithiolane series containing halogen substituents in the ring is tetrafluoro-l,2,3-trithiolane (35). It is found in 10% yield associated with the major product tetrafluoro-l,2,3,4-tetrathiane (204) by reaction of tetrafluoroethylene with the vapors of boiling sulfur at atmospheric pressure (62JOC3995). The compound is rather unstable and rapidly polymerized as described in Section 4.33.3.1.4. F

F

F-4—S

'

(35)

c

^

(204)

4,4,5-Trifluoro-5-trifluoromethyl-l,3,2-dioxathiolane 2,2-dioxide (96) was obtained among other products by reaction of perfluoropropene oxide with sulfur trioxide at 150°C (73IZV2725). Perfluorobutadiene reacted with sulfur trioxide to give the cyclic sulfate (31)

Five-membered Rings containing Three Oxygen or Sulfur Atoms

893

(79IZV118) and the formation of (31) is analogous to the reaction (197)-+(98) via a four-membered 1,2-oxathietane 2,2-dioxide intermediate. Subsequent products derived from (31) by electrophilic addition reactions at the alkenic double bond have been described in Section 4.33.3.2.2 and the synthesis of 4,5-dichloro-l,3,2-dioxathiolane 2,2-dioxide (154) by chlorination of ethylene sulfate (18) is discussed in Section 4.33.3.5. Cyclic sulfites, on the other hand, cannot be halogenated without ring opening (cf. Section 4.33.3.2.4). F 2

so 3

F

F

/°\^.O

ri7

nr

r c

r F

F

2so3

3

/

7

°x O

\

F

F (31)

(96)

4.33.5 APPLICATIONS 4.33.5.1 Applications in Research and Industry The easy formation and cleavage of 1,2,4-trioxolanes in the ozonolysis of alkenes is of both analytical and synthetic significance. No example of a double bond shift during ozonolysis is known and the kinds of ozonolysis product permit conclusions regarding the position of the double bond in the original alkene to be made. This is also true for compounds containing several C—C double bonds. The classical example of such a structural elucidation is that of natural rubber by Harries who obtained, after reductive work up, laevulinic aldehyde as the sole ozonolysis product. Consequently, natural rubber possesses a polyisoprene structure with 1,5-oriented double bonds (cf. Scheme 12). Similarly, the structure of synthetic rubbers and other polymers and copolymers may be investigated and evidence obtained concerning the extent to which a given diene polymerizes by 1,4- or by 1,2-addition, the extent to which head-to-head or head-to-tail polymerization occurs, whether a systematic or completely random distribution of monomers is produced in the polymer during copolymerization, and which of the multiple bonds of a given polyfunctional monomer is involved in the polymerization (58CRV925). - - -CH 2 -c4=CH-CH 2 -CH 2 -c4=CH-CH 2 -CH 2 -cicH- - Me

Me

Me

ii, reduction

- - - C H 2 - C H 2 - C = O + O = C H - C H 2 - C H 2 - C = O + O = C H - C H 2 - C H 2 - C = O + O=CH - - Me

Me

Me

Scheme 12 Structure elucidation of natural rubber by ozonolysis

In laboratory practice, ozonolysis has wide applications as an important synthetic method for the conversion of alkenes into aldehydes or carboxylic acids which are otherwise difficultly accessible (40CRV(27)437, 58CRV925). The ozonolysis of oleic acid-followed by oxidative work-up is an industrial preparation of azelaic and pelargonic acids (58CRV925). A more recent patent describes the production of perfluorocarboxylic acids CF3(CF2)nCO2H (n = 5, 7, 9) by ozonolysis of alkenes of the type CF 3 (CF 2 ) n CH=CHR (R = H, Me) and subsequent oxidative decomposition of the 1,2,4-trioxolanes formed (77BRP1473807). Ozonolysis also plays an important role in the destruction of unsaturated organic wastes in industrial waters (B-72MI43303, B-78MI43301). Some derivatives of 1,2,3-trithiolane are of interest as potential starting compounds for sulfur-containing polymers (63USP3088935, 77MI43302) and 1,2,4-trithiolanes have been patented as vulcanization accelerators (60EGP19H9), as materials for preparing plastic sulfur compositions (70GEP2004305), and as additives of lubricants for high pressure applications (74GEP2352586). The possibility of forming 1,3,2-dioxathiolane 2-oxides (cyclic sulfites) from 1,2-diols and thionyl chloride may be used to obtain information on the steric arrangement of the hydroxyl groups (63CRV557). Since the S = O group is a chromophore (cf. Section 4.33.2.2.4),

894

Five-membered Rings containing Three Oxygen or Sulfur Atoms

the conversion of 1,2-diols into their cyclic sulfite esters enables a stereochemical investigation of optically active diols by chiroptical methods to be carried out (74JOC2073). Ethylene sulfite has been patented as a hydroxyethylating agent in organic syntheses (48USP2448767), as a spinning solvent for polyacrylonitrile (55USP2706674, 56USP2752318), as starting material for the production of polyesters (57BRP781169, 62BEP610763) or polyurethanes (65BEP659395), and as a component in scrubbing liquids for removing hydrogen sulfide from gaseous mixtures (62BRP902256). Other applications include incorporation in washing liquids for purification of polyalkenes (62BRP903077), in detergents (62GEP1124962), in photographic emulsions (63GEP1159760) and in textile auxiliaries (66GEP1223397). Further patents describe the potential application of ethylene sulfite or derivatives thereof as accelerators for aminoplastic molding compositions (61BRP866440), as vulcanization accelerators (64FRP1379555), as components in hair dying agents (71USP3565571) and as preservatives for black-white developers (73USP3713826, 73GEP2203225). Anthraquinone dyes with a cyclic sulfite ester group may be used for dyeing polyester fibers (72GEP2121525). 1,3,2Dioxathiolane-2-thiones are reported to increase the lubricating properties of mineral oils (67USP3357993). Finally, l,3,2-dioxathiolan-4-one 2-oxides (anhydrosulfites of a-hydroxy carboxylic acids) have been patented as monomeric starting materials for the production of homopolymers (57USP28115H) and copolymers (72GEP2162157). 1,3,2-Dioxathiolane 2,2-dioxides (cyclic sulfate esters of 1,2-diols) are used in practice like sultones to introduce acid substituents into nitrogen heterocycles (48BSF1002), especially into cyanine dyes (58GEP1028718). Fluorinated derivatives are useful in the treatment of textiles such as cotton to impart wash and wear characteristics (62USP3055913). The conversion of cyclic sulfates into resinous film-forming polymers has been likewise patented (64USP3154526). 1,2,5-Oxadithiolane 2,2,5,5-tetroxide, i.e. 1,2-ethanedisulfonic anhydride, as well as its benzo derivative, may be used to improve the dyeing characteristics of polyesters with basic dyes (71JAP7142631).

4.33.5.2 Natural Occurrence and Special Modes of Formation Experimental studies have shown that ozone-alkene reactions in the gas phase likewise proceed via intermediate formation of 1,2,3-trioxolanes (primary ozonides) whose spontaneous decomposition then as a rule leads to a variety of subsequent products, including 1,2,4-trioxolanes (8DA3807). Because ozone is present in the atmosphere (from 0.02 p.p.m. at sea level up to 0.2 p.p.m. and more in industrial and urbanized areas), reactions of Table 12 Occurrence of 1,2,4-Trithiolane Derivatives Substituent at position 3

H Me

Me Me Et Ph a c

5 a

H Me b

Et

b

Prib

Et b Ph c

Occurrence

Ref.

Red alga Chondria californica Mushroom Boletus edulis Dry red beans Grape leaves Potato oil Rapeseed protein heated in water Roasted filberts Pork meat Cooked beef

76JOC2465 73MI43302 75MI43301 75MI43302 70MI43300 76MI43302 72MI43304 72TH43300 68CI(L)1639 70MI43301 72MI43305 79MI43301 76MI43303 B-78MI43303 B-78MI43303 79P1397 74CC906

Cooked mutton Cooked chicken Meat extract Meat extract Onion Allium cepa Guinea-hen weed Petiveria alliacea

Besides 1,2,4-trithiolane, the 1- and 4-oxides were also isolated from Chondria californica. Mixture of cis and trans isomers. cis Isomer (trithiolaniacin).

Five-membered Rings containing Three Oxygen or Sulfur Atoms

895

this type can proceed wherever alkenes occur or are emitted. For example, the blue haze that forms over some densely vegetated areas is attributed to aerosols formed by the ozone oxidation of the hydrocarbons (mainly terpenes) released by the plants. In industrial and urbanized areas, alkenes arising from automobile exhaust gases and their photochemical reactions are the most important source of unsaturated hydrocarbons. Therefore, ozonealkene reactions and the products formed play a significant role in environmental chemistry (B-78MI43302) (for biological consequences of these reactions, cf. Section 4.33.5.3). 1,2,4-Trithiolanes have been identified in some plant species as well as in the flavor of various food products, especially in those prepared from meat {cf. Table 12). These aroma compounds are formed as a rule only during cooking or roasting of meat by reaction of simple degradation products {e.g. H2S and aldehydes) of proteins and carbohydrates. Indeed, a series of model experiments has demonstrated that the thermal decomposition of sulfurcontaining amino acids such as cysteine, both in the presence (73MI43300, 73MI43301) and in the absence of carbohydrates (76MI43301) yields, among a variety of other components, typical flavor constituents of heated meat. Thus the most frequently occurring derivative, 3,5-dimethyl-l,2,4-trithiolane (126), was shown to result from the oxidation of bis(lmercaptoethyl) sulfide (205) which is a key product formed in the reaction of acetaldehyde with hydrogen sulfide (74MI43303). Reactions of this type play an important role in the manufacture of artificial roasting flavors from cysteine and other amino acids (68USP3365306). Derivatives of 1,3,2- and 1,4,2-dioxathiolane as well as of 1,2,3- and 1,2,5-oxadithiolane have not been observed in nature. Me

Me S Me"

[O]

- <

1 SH (205)

S

SH

-2[H] '

1

Me'"'

s

(126)

4.33.5.3 Biological Activity The high toxicity of ozone to man and animals is in part connected with the formation and subsequent reactions of ozonides in the organism. In particular, fatty acid ozonides are suggested to be intermediates in ozone intoxications. Thus methyl oleate ozonide causes in vitro the formation of methaemoglobin and loss of cellular thiols. It furthermore catalyzes the formation of disulfide-linked interchain polymers between haemoglobin and ovalbumin and induces, like other fatty acid ozonides, pathological alterations (Heinz bodies) in erythrocytes (75MI43303). This finding may explain the protective effects of antioxidants and thiol-generating systems against ozone-produced toxicants (75MI43304). As possible constituents in air pollution {cf. Section 4.33.5.2), ozonides and their decomposition products cannot only injure the health of man and animals but also damage plants (52MI43300, 59MI43300). The powerful germicidal effect of ozonides at very low concentrations may be used for their detection in the air (68MI43300). Ozonized olive oil was found to possess wound-healing (47MI43300) as well as bactericidal and fungicidal properties (47MI43301). Disinfectants containing ozonides have been likewise described (55MI43300, 64GEP1166975). In the 1,2,4-trithiolane series, relatively little information on biological activity, including toxic effects, is available. The average concentrations of the flavoring substance 3,5dimethyl-1,2,4-trithiolane (126) in food products (maximum up to 0.3 p.p.m.) are generally recognized as safe (78MI43304). 3,5-Bis[bis(isopropoxycarbonyl)methylene]-l,2,4-trithiolane (57), which forms as a photochemical degradation product of the fungicide isoprothiolane (diisopropyl l,3-dithiolan-2-ylidenemalonate), was found to be inactive in the reverse mutation systems of Ames' Salmonella strains (79MI43301). Some 1,2,4-trithiolane derivatives have been patented as fungicides (65GEP1192452) and antimalarial agents (71USP3578682, 72USP3694498).

Five-membered cyclic sulfites and sulfates are of toxicological relevance due to their potential bioalkylating properties. Ethylene sulfate (18) is more toxic than dimethyl sulfate (75JPR943); like the latter and other alkylating agents, it induces local malignant tumors after subcutaneous injection (74MI43304) and proved to be a weak mutagen both in vitro and in vivo (77MI43303). Copyright © 1984 Elsevier Ltd.

Comprehensive Heterocyclic Chemistry