Isomerization of Trimethyl α-Keto Trithioorthocarboxylates into α,α-Bis(methylthio) Thiolcarboxylates. A New Rearrangement of Synthetic Interest

Article abstract of DOI:10.1021/jo970683+

A study was made of the isomerization reaction of a great variety of trimethyl α-keto trithioorthocarboxylates to α,α-bis(methylthio) thiolcarboxylates, intermediates of high synthetic value for the synthesis of α-arylpropionic acids. The reaction was carried out in methylene chloride in the presence of catalytic amounts of trityl perchlorate or methanesulfonic acid and was complete in 2 h at rt. In most of the investigated cases the result was positive, the yields usually being greater than 90%. Also the reaction mechanism was subjected to an experimental study.

Full text of DOI:10.1021/jo970683+

7228
J . Org. Chem. 1997, 62, 7228-7233
Isom er iza tion of Tr im eth yl r-Keto Tr ith ioor th oca r boxyla tes in to
r,r-Bis(m eth ylth io) Th iolca r boxyla tes. A New Rea r r a n gem en t of
Syn th etic In ter est
Iacopo Degani,* Stefano Dughera, Rita Fochi,* and Sonia Gazzetto
Dipartimento di Chimica Generale ed Organica Applicata dell’Universita`,
C.so M. D’Azeglio 48, I-10125 Torino, Italy
Received April 16, 1997X
A study was made of the isomerization reaction of a great variety of trimethyl R-keto trithioor-
thocarboxylates to R,R-bis(methylthio) thiolcarboxylates, intermediates of high synthetic value for
the synthesis of R-arylpropionic acids. The reaction was carried out in methylene chloride in the
presence of catalytic amounts of trityl perchlorate or methanesulfonic acid and was complete in 2
h at rt. In most of the investigated cases the result was positive, the yields usually being greater
than 90%. Also the reaction mechanism was subjected to an experimental study.
Sch em e 1
Since the accomplishment of effective procedures for
the synthesis of trimethyl R-keto trithioorthocarboxylates
1 starting from the most common derivatives of carbox-
ylic acids (i.e., esters, acyl chlorides, anhydrides, thiol
esters, and amides),1,2 research has been directed toward
the synthetic utilization of this class of essentially
unexplored compounds. The most significant findings in
this regard concern a new procedure of general validity
for the preparation of R-arylpropionic acids:3 it is well-
known that some of them are important analgesics and
antiinflammatory drugs.4
In the present work we report a study on the isomer-
ization of trimethyl R-keto trithioorthocarboxylates 1 into
methyl R,R-bis(methylthio) thiolcarboxylates 2 (Scheme
1), the fundamental, and more innovative, step of the
procedure. As a rule isomerization is easily obtained in
yields higher than 90% by stirring a solution of 1 in
anhydrous methylene chloride for about 2 h under a
nitrogen atmosphere, in the presence of catalytic amounts
of trityl perchlorate (3; procedure A: molar ratio 1:3 )
1:0.15) or methanesulfonic acid (4; procedure B: molar
ratio 1:4 ) 1:0.5). A strictly anhydrous reaction environ-
ment was maintained since, as has been demonstrated
in other research,5 the same trimethyl R-keto trithioor-
thocarboxylates 1, by treatment with soft or hard acids
in aqueous medium, give, by partial hydrolysis, methyl
R-keto thiolcarboxylates (R-CO-COSMe) in excellent
yields. The investigated reactions, the reaction condi-
tions, and the results are reported in Table 1.
From the synthetic point of view, it can be observed
that the investigated reactions, carried out in the pres-
ence of both trityl perchlorate (3; procedure A) and
methanesulfonic acid (4; procedure B), follow parallel
courses. In fact with both catalysts the isomerization
took place with all the trimethyl R-keto trithioorthocar-
boxylates 1, where R is an aryl group (entries 1-8, 11,
12, 15-22, and 25-30), the only exceptions being the
phenyl containing a chlorine or fluorine atom on the ortho
positions (entries 9, 10, 13, 14, 23, and 24). Besides,
simple aliphatic compounds gave positive results (entries
31-36), while those substituted with a chlorine or
methoxy group in the R position remain unaltered, even
on extending the reaction times and increasing the
catalyst amounts (entries 37-40). For the reactions
carried out in the presence of trityl perchlorate (3), the
final mixtures were always found to contain not only the
isomerization products but also methyl trityl sulfide (6)
and triphenylmethanol (9). The results of such reactions
(procedure A) can be rationalized by assuming that the
1 f 2 isomerization occurs through a multistep reaction
where the trityl cation acts as a methanethiolate carrier
(Scheme 2). In the first step the trityl cation would take
a methanethiolate anion from 1, giving rise to the
intermediate cation 5 and trityl methyl sulfide (6); the
methanethiolate anion would then transfer from 6 to the
carbonyl carbon of cation 5, giving rise to the oxyranic
derivative 7 and the restoration of 3. Further action of
trityl perchlorate on 7 would lead to the intermediate
cation 8, together with methyl trityl sulfide (6). Finally
these last intermediates could react, resulting in the
isomerization product 2 and the restoration of cata-
lyst 3.
The proposed reaction scheme is supported by col-
lateral experimental results: (i) the possibility of forma-
tion of the intermediate cation 5 was confirmed by the
exchange reaction between methylthio and ethylthio
groups that occurred when 1g, that does not isomerize
to 2g (entry 13), was reacted with ethyl trityl sulfide in
the presence of trityl perchlorate (3), giving at equilib-
rium the R-keto trithioorthocarboxylates 10-12 and
methyl trityl sulfide (6) (Scheme 3); (ii) that the inter-
mediate cation 8 can form was confirmed by the exchange
reaction between methylthio and ethylthio groups: in fact
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) Barbero, M.; Cadamuro, I.; Degani, I.; Dughera, S.; Fochi, R. J .
Org. Chem. 1995, 60, 6017.
(2) Degani, I.; Dughera, S.; Fochi, R.; Serra, E. J . Org. Chem. 1996,
61, 9572.
(3) Degani, I.; Dughera, S.; Fochi, R. (National Research Council of
Italy) Italian Pat. MI96A 000500, 1996; PCT/EP 97/01258 (12.03.1997).
(4) For example, see: Hamor, G. H. In Principles of Medicinal
Chemistry; Foye, W. O., Ed.; Lea & Febiger: Philadelphia, 1989;
Chapter 23 and references cited therein.
(5) Degani, I.; Dughera, S.; Fochi, R.; Gatti, A. Synthesis 1996, 467.
S0022-3263(97)00683-X CCC: $14.00 © 1997 American Chemical Society

Isomerization of Trithioorthocarboxylates
J . Org. Chem., Vol. 62, No. 21, 1997 7229
Ta ble 1. r,r-Bis(m eth ylth io) Th iolca r boxyla tes 2
yieldb (%)
molar ratio
1:3 or 1:4
reaction
time (h)
entry
R
procedure
chromatographic solventa
2
6
9
1
2
3
4
5
6
7
8
9
C6H5
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
1:0.15
1:0.5
1:0.15
1:0.5
1:0.15
1:0.5
1:0.15
1:0.5
1:0.5
1:1.5
1.0.15
1:0.5
1:0.5
1:1.5
1:0.15
1:0.5
1:0.15
1:0.5
1:0.15
1:0.5
1:0.15
1:1.5
1:0.5
1:1.5
1:0.3
1:5
1:0.15
1:0.5
1:0.15
1:0.5
1:0.2
1:0.5
1:0.2
1:1
1:0.2
1:1
1:0.5
1:1.5
1:0.5
1:1.5
2
2
4
5
2
2
2
2
9
9
2
2
9
9
2
2
2
2
2
2
2
8
9
9
7
6
2
2
2
2
2
2
2
2
2
2
9
9
9
9
PE-MeCOMe (9.5:0.5)
92
92
89
93
93
93
94
93
c
72
77
78
73
d
23
2-CH3C6H4
4-CH3C6H4
4-i-C4H9C6H4
2-FC6H4
PE-Et2O (9.8:0.2)
PE-Et2O (9.8:0.2)
PE-CH2Cl2 (7:3)
PE-Et2O (9.8:0.2)
PE-Et2O (9.8:0.2)
PE-CH2Cl2 (7:3)
PE-Et2O (9.8:0.2)
PE-Et2O (9.8:0.2)
PE-Et2O (4:1)
23
22
23
81
12
86
25
33
17
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
c
4-FC6H4
91
93
e
78
d
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-CH3OC6H4
3-C6H5 COC6H4
2,5-Cl2C6H3
3,5-Cl2C6H3
2-C10H7
e
93
94
89
94
93
93
91
94
f
69
65
77
83
d
PE-Et2O (4:1)
PE-CH2Cl2 (7:3)
PE-CH2Cl2 (7:3)
PE-CH2Cl2 (7:3)
PE-Et2O (4:1)
86
20
17
d
f
61
64
92
91
93
94
93
89
85
83
81
77
g
71
75
89
35
75
67
d
6-CH3O-2-C10H6
H
PE-CH2Cl2 (7:3)
PE-CH2Cl2 (1:1)
PE-CH2Cl2 (9:1)
PE-MeCOMe (9.5:0.5)
PE-MeCOMe (9.5:0.5)
62
20
20
85
83
CH3
n-C9H19
FCH2
g
h
h
CH3OCH2
d
a
b
d
PE ) petroleum ether (40-70 °C). Yields of pure isolated products. c The starting compounds 1e was recovered in 87% yield. Traces.
e The starting compound 1g was recovered in 86% yield. f The starting compound 1l was recovered in 82 and 98% yield, respectively, in
g
h
entries 23 and 24. The starting compound 1s was recovered in 95% yield. The starting compound 1t decomposed in entry 39; in entry
40 it was recovered in 86% yield.
when 2a was reacted with ethyl trityl sulfide in the
presence of trityl perchlorate (3), the products 13 and 14
formed at equilibrium, together with the acylic substitu-
tion products 15 and 16 and methyl trityl sulfide (6)
(Scheme 4); (iii) after the formation of the intermediate
5, the reaction proceeds to the final products, through
the rearrangement of the oxygen atom not through the
anionotropic rearrangement of the R group. In fact
starting with 1a , labeled at the carbonyl with 13C, the R
group in the isomerization product was found still bonded
to the labeled carbon atom (Scheme 5). The hypothesized
mechanism could also explain the lack of isomerization
of the trimethyl R-keto trithioorthocarboxylates 1e,g,l,s,t.
In fact an accepted opinion6a-c is that the electron-
withdrawing polar effects (inductive effects, especially
field effects) of halogens are stronger from the ortho
positions of the aryl groups than from the para and meta.
Therefore only in trithioorthocarboxylates 1e,g,l where
ortho halogens are present (entries 9, 13, and 23) are the
polar effects sufficiently intense to impede the formation
of the corresponding cationic intermediates 8e,g,l. In the
same way the missing rearrangement of entries 37 and
39 can be attributed to the electron-withdrawing polar
effects of chloro and methoxy substituents on the R-posi-
tion of the alkyl groups. On the other hand the impos-
sibility of forming the 8 type intermediates, where
electronegative atoms or groups are near the cationic
center, is indirectly confirmed by the following: reacting
ethanethiol, under acid catalysis, with ethyl R-keto
thiolcarboxylate 17 results in the corresponding R,R-
bis(ethylthio) thiolcarboxylate 19 through the formation
of the cationic intermediate 18, as is generally accepted
for thioketal formation; instead with ethyl R-keto thiol-
carboxylate 20 there is no change (Scheme 6), the
formation of the intermediate 21 not being able to take
place.
In the cases reported in Table 1 where isomerization
is promoted by methanesulfonic acid (4; procedure B), the
result being similar to when trityl perchlorate (3) is used
as catalyst, the hypothesizable reaction mechanism ap-
pears uncertain as no methanethiolate anion carrier can
be identified.7 However, even in the isomerization reac-
tion of 1a to 2a , catalyzed by 4 in the presence of carbonyl
labeled with 13C, the result is identical to that using 3
(Scheme 5). This demonstrates that even in reactions
(6) For example, see: (a) Advances in Linear Free Energy Relation-
ships; Chapman, N. B., Shorter, J ., Eds.; Plenum Press: New York,
1972; Chapter 2, and references cited therein. (b) Buckley, A.; Chap-
man, N. B.; Shorter, J . J . Chem. Soc. B 1969, 195. (c) Chapman, N.
B.; Shorter, J .; Utley, J . H. P. J . Chem. Soc. 1962, 1824.

7230 J . Org. Chem., Vol. 62, No. 21, 1997
Degani et al.
Sch em e 2
Sch em e 3
Sch em e 4
Sch em e 5
Sch em e 6
catalyzed by methanesulfonic acid no anionotropic rear-
rangement of the R group occurs; thus the mechanism
must involve intramolecular and, perhaps, intermolecu-
lar rearrangements of methanethiolate anions.
In conclusion, this study details the field of applicabil-
ity of the 1 f 2 isomerization that, as already stated,
leads easily, and in excellent yields, to intermediates of
(7) One reviewer has suggested the following Scheme to formally
interpret the reactions carried out in the presence of trityl perchlorate
(3) or methanesulfonic acid (4).
high synthetic value.3 Furthermore, the large amount
of experimental information collected has, in the case of
when the catalyst is trityl perchlorate (3), allowed us to
make a reasonable interpretation of the isomerization
mechanism; instead greater uncertainty still prevails in
the interpretation of the innermost mechanism of isomer-
ization reactions catalyzed by methanesulfonic acid (4).
However in the case of E+ ) H+ where, according to the scheme, there
should be a protonation at the carbonyl group, ab initio calculations,
carried out at the MP2/6-31G(d) level and aimed to check this
hypothesis, did not provide any conclusive information.
Exp er im en ta l Section
1H NMR and 13C NMR spectra were recorded for solutions
in CDCl3, unless otherwise noted. IR spectra were recorded

Isomerization of Trithioorthocarboxylates
J . Org. Chem., Vol. 62, No. 21, 1997 7231
for solutions in CCl4. Column chromatography and TLC were
performed on Merck silica gel 60 (70-230 mesh ASTM) and
GF 254, respectively. Petroleum ether refers to the fraction
boiling in the range 40-70 °C and is abbreviated as PE. All
of the reactions were performed in oven-dried glassware under
an atmosphere of nitrogen. Details for reactions 1-40,
chromatographic solvents, and yields of the products are listed
in Table 1. Satisfactory microanalyses were obtained for all
the new compounds.
1c: methyl 4-methylbenzoate; PE-CH2Cl2 (7:3, v/v); 93%;
bp 143-144 °C/0.3 mmHg; MS m/ z 225 (M+ - SMe); IR 1670
1
cm-1 (CO); H NMR data identical to those reported.15
1d : methyl 4-isobutylbenzoate; PE-CH2Cl2 (7:3, v/v); 95%;
bp 130-131 °C/0.4 mmHg (lit.2 bp 130-131 °C/0.4 mmHg);
MS m/ z 267 (M+ - SMe); spectral data identical to those
reported.
1e: methyl 2-fluorobenzoate; PE-Et2O (9.8:0.2, v/v); 93%;
bp 159-160 °C/0.8 mmHg; MS m/ z 229 (M+ - SMe); 1H NMR
δ 2.18 (s, 9H), 6.90-7.55 and 7.90-8.30 (2 m, 3:1, 4H); IR 1692
cm-1 (CO).
1f: methyl 4-fluorobenzoate; PE-Et2O (9.8:0.2, v/v); 92%;
mp 68-69 °C (PE); MS m/ z 229 (M+ - SMe); 1H NMR δ 2.07
(s, 9H), 6.90-7.35 and 8.40-8.75 (2 m, 1:1, 4H); IR 1672 cm-1
(CO).
1g: methyl 2-chlorobenzoate; PE-CH2Cl2 (7:3, v/v); 98%;
mp 83-84 °C (CCl4); MS m/ z 245 (M+ - SMe); 1H NMR δ
2.22 (s, 9H), 7.25-7.63 and 8.05-8.35 (2 m, 3:1, 4H); IR 1700
cm-1 (CO).
Methyl 6-methoxy-2-naphthoate,8 trityl perchlorate,9 tris-
(methylthio)methane10 and tris(ethylthio)methane11 were pre-
pared following literature procedures. All other compounds
were purchased from the Aldrich Chemical Co.
Eth yl Tr ityl Su lfid e. Ethanethiol (3.72 g, 60 mmol) was
added dropwise to a suspension of sodium hydride (1.44 g, 60
mmol) in anhydrous THF (75 mL), previously cooled with an
ice bath to 0-5 °C. After the addition was complete, the
cooling bath was removed and trityl perchlorate (3; 17.13 g,
50 mmol) was added in one portion, under stirring. After being
stirred at rt for about 30 min, GC and TLC (PE) analyses
showed that the reaction was complete. Usual workup af-
forded a crude product that was purified by chromatography
on a short column, eluting with PE. The yield of the pure title
compound was 89% (13.55 g): mp 129-130 °C (PE) (lit.12 mp
1i: methyl 4-bromobenzoate; PE-CH2Cl2 (7:3, v/v); 92%; mp
59-60 °C (PE); MS m/ z 289, 291 (M+ - SMe); 1H NMR δ 2.12
(s, 9H), 7.66 and 8.48 (2 d, 1:1, J ) 9.0, 4H); IR 1675 cm-1
(CO).
1
132 °C); MS m/ z 243 (M+ - SEt); H NMR δ 1.13 (t, J ) 7.0
1k : methyl 3-[dimethoxy(phenyl)methyl]benzoate; PE-
Et2O (9:1, v/v). The product obtained was 1-{3-[dimethoxy-
(phenyl)methyl]phenyl}-2,2,2-tris(methylthio)ethanone. Its
structure was confirmed by its 1H NMR spectrum: δ 1.98 (s,
9H), 3.08 (s, 6H), 6.90-7.70 and 8.02-8.40 (2 m, 7:2, 9H). This
acetal was treated with concd HCl (5 mL), and the reaction
mixture was stirred at rt until completion of the hydrolysis
(1 h). After usual workup, virtually pure (TLC, NMR) 1-(3-
benzoylphenyl)-2,2,2-tris(methylthio)ethanone (1k ) was ob-
tained in 93% yield: mp 119-120 °C (CCl4-PE); MS m/ z 315
(M+ - SMe); 1H NMR δ 2.05 (s, 9H), 7.10-8.00 and 8.38-
8.78 (2 m, 7:2, 9H); IR 1675 cm-1 (CO).
Hz, 3H), 2.27 (q, J ) 7.0 Hz, 2H), 7.70-7.80 (m, 15H).
Meth yl 4-Isobu tylben zoa te. Prepared by reaction of
4-isobutylbenzoyl chloride13 (9.83 g, 50 mmol) with anhydrous
methanol (100 mL). After the usual workup, the crude product
was purified by column chromatography, eluting with PE-
CH2Cl2 (7:3, v/v). The yield was quantitative (9.60 g): bp 80-
1
81 °C/0.3 mmHg; MS m/ z 192 (M+); H NMR δ 0.88 (d, J )
6.0 Hz, 6H), 1.10-2.12 (m, 1H), 2.48 (d, J ) 7.0 Hz, 2H), 3.80
(s, 3H), 7.05 and 7.80 (2 d, 1:1, J ) 8.4 Hz, 4H); IR 1732 cm-1
(CO). The title compound is mentioned in the literature,14 but
yield and physical, analytical, and spectroscopic data are not
reported.
1m : methyl 3,5-dichlorobenzoate; PE-CH2Cl2 (7:3, v/v);
95%; mp 129-130 °C (PE); MS m/ z 280 (M+ - SMe); 1H NMR
δ 2.24 (s, 9H), 7.03-7.70 and 8.32-8.50 (2 m, 1:2, 3H); IR 1680
cm-1 (CO).
Meth yl 3-[Dim eth oxy(p h en yl)m eth yl]ben zoa te. Meth-
anesulfonic acid (4; 0.96 g, 10 mmol) was added to a solution
of 3-benzoylbenzoic acid (11.30 g, 50 mmol) in anhydrous
methanol (75 mL), and the mixture was heated under a gentle
reflux until disappearance of the starting compound (5 h;
TLC: PE-Et2O, 4:1, v/v). The only product formed was methyl
3-benzoylbenzoate. The reaction mixture was cooled, and
trimethyl orthoformate (75 mL, 77 mmol) was added. After
24 h of stirring at rt, TLC analysis (PE-Et2O, 4:1, v/v) showed
the presence of the title compound as the only product. This
was isolated virtually pure (TLC, NMR) in 89% yield (12.74
g), after usual workup: mp 89-90 °C (CCl4-pentane); MS m/ z
286 (M+); 1H NMR δ 3.02 (s, 6H), 3.78 (s, 3H), 7.05-7.90 and
8.00-8.12 (2 m, 8:1, 9H); IR 1732 cm-1 (CO).
Tr im et h yl r-Ket o Tr it h ioor t h oca r b oxyla t es 1. Tri-
methyl R-keto trithioorthocarboxylates 1a ,h ,j,l,p ,r -t were
prepared following the procedures previously reported by us.1
According to the same procedures, compounds 1b,c-g,i,k ,m -
o,q were also prepared. Starting compounds and chromato-
graphic solvents used for the new preparations are listed
below, together with yields and physical and spectroscopic data
for compounds 1.
1n : methyl 2-naphthoate; PE-CH2Cl2 (7:3, v/v); 97%; mp
1
77-78 °C (PE); MS m/ z 261 (M+ - SMe); H NMR δ 2.03 (s,
9H), 7.20-7.90, 8.15-8.40, and 8.85-8.98 (3 m, 5:1:1, 7H); IR
1670 cm-1 (CO).
1o: methyl 6-methoxy-2-naphthoate;8 PE-Et2O (4:1, v/v);
94%; mp 112-113 °C (PE-CCl4); MS m/ z 291 (M+ - SMe);
1H NMR δ 2.02 (s, 9H), 3.83 (s, 3H), 6.93-7.15, 7.43-7.80,
8.18-8.45, and 8.85-8.98 (4 m, 2:2:1:1, 6H); IR 1670 cm-1
(CO).
1q: methyl acetate; PE-CH2Cl2 (1:1, v/v); 82%; mp 105-
106 °C (PE) (lit.2 mp 105-106 °C) ; MS m/ z 149 (M+ - SMe);
spectral data identical to those reported.
Meth yl r,r-Bis(m eth ylth io) Th iolca r boxyla tes 2. Rep -
r esen ta tive P r oced u r es. S-Meth yl Bis(m eth ylth io)p h e-
n ylt h ioa cet a t e (2a ). P r oced u r e A. In entry 1 (Table 1)
2,2,2-tris(methylthio)-1-phenylethanone (1a ; 2.58 g, 10 mmol)
was dissolved in anhydrous CH2Cl2 (20 mL). The colorless
solution was maintained at rt (20-25 °C), under stirring and
under an atmosphere of nitrogen. Trityl perchlorate (3; 0.51
g, 1.5 mmol) was added in one portion: a red solution was at
once obtained. Progress of the reaction was monitored by GC
and TLC (PE-MeCOMe, 9.5:0.5, v/v) analyses, and stirring
was continued for 2 h, until disappearance of the starting
compound 1a . The deep red solution was diluted with CH2Cl2
(100 mL) and then poured into 5% NaHCO3 (150 mL). The
aqueous layer was separated and extracted with CH2Cl2 (100
mL). The combined organic extracts were washed with water
(2 × 100 mL), dried over Na2SO4, and evaporated under
reduced pressure. The crude residue was column chromato-
graphed, eluting with PE-MeCOMe (9.5:0.5, v/v), to afford
three products. The first eluted product was methyl trityl
sulfide (6; 0.31 g, 72% with regard to 3): mp 106-107 °C (PE)
1b: methyl 2-methylbenzoate; PE-CH2Cl2 (7:3, v/v); 98%;
bp 160-161 °C/0.4 mmHg; MS m/ z 225 (M+ - SMe); 1H NMR
δ 2.11 (s, 9H), 2.36 (s, 3H), 7.05-7.40 and 8.05-8.35 (2 m,
3:1, 4H); IR 1680 cm-1 (CO).
(8) Basu, B.; Mukherjee, D. J . Chem. Soc., Chem. Commun. 1984,
105.
(9) Dauben, H. J .; Honnen, L. R.; Harmon, K. M. J . Org. Chem. 1960,
25, 1442.
(10) Barbero, M.; Cadamuro, I.; Degani, I.; Dughera, S.; Fochi, R.
J . Chem. Soc., Perkin Trans. 1 1993, 2075.
(11) Froling, A.; Arens, J . F. Recl. Trav. Chim. Pays-Bas 1962, 81,
1009.
(12) Schmid, M. D.; Bolliger, H. R. Helv. Chim. Acta 1954, 884.
(13) Neubert, M. E.; Fishel, D. L. In Organic Synthesis; Freeman,
J . P., Ed.; J ohn Wiley & Sons, Inc.: New York, 1990; Collect. Vol. 7,
pp 420-423.
(14) Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ayyangar, N.
R. Tetrahedron 1994, 50, 1243.
(15) Wladislaw, B.; Marzorati, L.; Biaggio, F. C. J . Org. Chem. 1993,
58, 6132.

7232 J . Org. Chem., Vol. 62, No. 21, 1997
Degani et al.
1
(lit.16 mp 106 °C); MS m/ z 243 (M+ - SMe); H NMR δ 1.82
presence of several compounds; between them, methyl trityl
sulfide (6) and ethyl trityl sulfide were the major products.
The crude residue obtained after the workup described in
procedure A was fractionated by column chromatography,
eluting with PE-CH2Cl2 (7:3, v/v). Four fractions were
collected. After evaporation of the solvent under reduced
pressure, the first fraction gave a solid substance (0.72 g)
which was a mixture of compound 6, MS m/ z 243 (M+ - SMe),
and the starting ethyl trityl sulfide, MS m/ z 243 (M+ - SEt),
in a 3:1 ratio (determined by GC). The second fraction gave
an oily substance (0.25 g) as a mixture of several products.
By GC and GC-MS analyses, the following compounds were
recognized: 1-(2-chlorophenyl)-2-(ethylthio)-2,2-bis(methylth-
io)ethanone (10), MS m/ z 259 (M+ - SMe) and 245 (M+ - SEt),
and 1-(2-chlorophenyl)-2,2-bis(ethylthio)-2-(methylthio)etha-
none (11), MS m/ z 273 (M+ - SMe) and 259 (M+ - SEt), as
major products (ratio 10:11 ) 1.7:1, determined by GC
analysis), and traces of 1-(2-chlorophenyl)-2,2,2-tris(ethylth-
io)ethanone (12), MS m/ z 273 (M+ - SEt), and S-methyl
2-chlorophenyloxothioacetate, MS m/ z 186 (M+ - CO). The
third fraction gave an oil substance (0.33 g) which was a
mixture of 10 and the starting compound 1g, in a 1.6:1 ratio.
The four fraction afforded triphenylmethanol (9; 0.11 g).
Rea ction of S-Meth yl Bis(m eth ylth io)p h en ylth ioa c-
eta te (2a ) w ith Eth yl Tr ityl Su lfid e in th e P r esen ce of
Tr ityl P er ch lor a te (3). Compound 3 (0.10 g, 0.3 mmol) was
added in one portion and under stirring to a solution of
compound 2a (0.52 g, 2 mmol) and ethyl trityl sulfide (0.61 g,
2 mmol) in anhydrous CH2Cl2 (15 mL), maintained at rt and
under an atmosphere of nitrogen: a red solution was at once
obtained. Stirring at rt was continued for 1 h, and the reaction
mixture was worked up as described in procedure A. Then
the crude residue was fractionated by column chromatography,
eluting with PE-CH2Cl2 (7:3, v/v). Four fractions were
collected. After evaporation of the solvent under reduced
pressure, the first fraction gave a solid substance (0.58 g)
which was a mixture of methyl trityl sulfide (6), MS m/ z 243
(M+ - SMe), and the starting ethyl trityl sulfide, MS m/ z 243
(M+ - SEt), in a 1.5:1 ratio (determined by GC). The second
fraction gave an oil substance (0.28 g) as a mixture of several
products. By GC and GC-MS analyses, the following com-
pounds were recognized: S-methyl (ethylthio)(methylthio)phe-
nylthioacetate (13), MS m/ z 272 (M+), 225 and 197 (M+ - SMe
and - CO), S-methyl bis(ethylthio)phenylthioacetate (14), MS
m/ z 286 (M+) and 211 (M+ - COSMe), S-ethyl bis(methylth-
io)phenylthioacetate (15), MS m/ z 272 (M+), 211 and 183 (M+
- SEt and - CO), and S-ethyl (ethylthio)(methylthio)phe-
nylthioacetate (16), MS m/ z 286 (M+), 225 and 197 (M+ - SEt
and - CO). Third and fourth fractions afforded the starting
compound 2a (0.22 g, 42%) and triphenylmethanol (9; 0.10 g),
respectively.
(s, 3H), 7.05-7.45 (m, 15H). The second eluted product was
the title compound 2a (2.37 g, 92%). The third eluted product
was triphenylmethanol (9; 0.09 g, 23% with regard to 3), mp
161-162 °C (CHCl3-PE), identical to that of an authentic
sample of commercial origin (Aldrich).
P r oced u r e B. In entry 2 (Table 1) a solution of methane-
sulfonic acid (4; 0.48 g, 5 mmol) in anhydrous CH2Cl2 (2 mL)
was added dropwise at rt (20-25 °C), during 10 min, to a
stirred solution of trithioorthocarboxylate 1a (2.58 g, 10 mmol)
in the same solvent (18 mL), maintained under an atmosphere
of nitrogen. The solution changed from colorless to yellow.
After 2 h of stirring, GC and TLC (PE-MeCOMe, 9.5:0.5, v/v)
analyses showed the disappearance of the starting compound
1a and the presence of one only product. The crude residue,
obtained after a workup identical to that described above, was
the virtually pure (TLC, GC, NMR) title compound 2a (2.37
g, 92%).
Physical properties of R,R-bis(methylthio) thiolcarboxylates
2 are as follows:
2a : bp 155-156 °C/0.3 mmHg; MS m/ z 258 (M+); 1H NMR
δ 1.97 (s, 6H), 2.24 (s, 3H), 7.05-7.32 and 7.32-7.62 (2 m,
3:2, 5H); IR 1680 cm-1 (CO).
1
2b: mp 57-58 °C (PE); MS m/ z 272 (M+); H NMR δ 1.93
(s, 6H), 2.40 and 2.42 (2 s, 1:1, 6H), 7.00-7.40 and 7.62-7.90
(2 m, 3:1, 4H); IR 1680 cm-1 (CO).
1
2c: mp 66-67 °C (PE); MS m/ z 272 (M+); H NMR δ 2.02
(s, 6H), 2.30 and 2.40 (2 s, 1:1, 6H), 7.15-7.45 and 7.50-7.85
(2 d, 1:1, J ) 8.0 Hz, 4H); IR 1680 cm-1 (CO).
2d : bp 180-181 °C/0.3 mmHg; MS m/ z 314 (M+); 1H NMR
δ 0.96 (d, J ) 6.96 Hz, 6H), 1.25-2.10 (m, 1H), 2.00 (s, 6H),
2.28 (s, 3H), 2.50 (d, J ) 6.40 Hz, 2H), 7.04 and 7.45 (2 d, 1:1,
J ) 8.2 Hz, 4H); IR 1680 cm-1 (CO).
2f: bp 159-160 °C/0.5 mmHg; MS m/ z 276 (M+); 1H NMR
δ 2.02 (s, 6H), 2.32 (s, 3H), 6.92-7.35 and 7.55-7.85 (2 m,
1:1, 4H); IR 1680 cm-1 (CO).
1
2h : mp 89-90 °C (PE); MS m/ z 292 (M+); H NMR δ 1.97
(s, 6H), 2.25 (s, 3H), 7.05 and 7.55 (2 d, 1:1, J ) 8.0 Hz, 4H);
IR 1680 cm-1 (CO).
2i: mp 100-101 °C (PE); MS m/ z 336, 338 (M+); H NMR
1
δ 1.95 (s, 6H), 2.24 (s, 3H), 7.30-7.40 (m, 4H); IR 1680 cm-1
(CO).
2j: bp 189-190 °C/0.5 mmHg; MS m/ z 288 (M+); 1H NMR
δ 1.88 (s, 6H), 2.16 (s, 3H), 3.68 (s, 3H), 6.70 and 7.40 (2 d,
1:1, J ) 8.7 Hz, 4H); IR 1680 cm-1 (CO).
2k : mp 93-94 °C (CCl4-PE); MS m/ z 362 (M+); 1H NMR δ
1.93 (s, 6H), 2.22 (s, 3H), 7.05-8.00 (m, 9H); IR 1672 cm-1
(CO).
2m : mp 110-111 °C (PE); MS m/ z 327 (M+); 1H NMR δ
2.02 (s, 6H), 2.32 (s, 3H), 7.22-7.40 and 7.50-7.65 (2 m, 1:1,
4H); IR 1680 cm-1 (CO).
Meth yl [1-13C]ben zoa te. Methanesulfonic acid (0.19 g, 2
mmol) was added to a solution of [1-13C]benzoic acid (1.23 g,
10 mmol) in anhydrous methanol (6 mL), and the reaction
mixture was heated under gentle reflux until disappearance
of the starting compound (about 5 h). Usual workup afforded
virtually pure (GC and NMR) title compound in 90% yield (1.12
g): MS m/ z 137 (M+, 38), 106 (M+ - OMe, 100); 13C NMR δ
2n : bp 210-211 °C/0.4 mmHg; MS m/ z 308 (M+); 1H NMR
δ 2.06 (s, 6H), 2.32 (s, 3H), 7.10-7.88 and 7.88-8.05 (2 m,
6:1, 7H); IR 1680 cm-1 (CO).
2o: mp 118-119 °C (CCl4-PE); MS m/ z 338 (M+); 1H NMR
δ 2.03 (s, 6H), 2.30 (s, 3H), 3.90 (s, 3H), 6.95-7.20, 7.50-7.75,
and 7.83-7.92 (3 m, 2:3:1, 6H); IR 1678 cm-1 (CO).
2p : bp 104 °C/1 mmHg (lit.10 bp 104 °C/1 mmHg); MS m/ z
182 (M+); spectral data identical to those reported.
2q: bp 100-101 °C/0.4 mmHg; MS m/ z 196 (M+); 1H NMR
δ 1.78 (s, 3H), 2.10 (s, 6H), 2.28 (s, 3H); IR 1680 cm-1 (CO).
2r : bp 163-164 °C/0.4 mmHg; MS m/ z 308 (M+); 1H NMR
δ 0.65-1.05 and 1.05-1.75 (2 m, 14:3, 17H), 1.75-2.15 (m,
2H), 2.10 (s, 6H), 2.36 (s, 3H); IR 1682 cm-1 (CO).
Rea ction of 1-(2-Ch lor op h en yl)-2,2,2-tr is(m eth ylth io)-
eth a n on e (1g) w ith Eth yl Tr ityl Su lfid e in th e P r esen ce
of Tr ityl P er ch lor a te (3). A mixture of trithioorthocarbox-
ylate 1g (0.58 g, 2 mmol) and ethyl trityl sulfide (0.61 g, 2
mmol) was dissolved in anhydrous CH2Cl2 (20 mL) under an
atmosphere of nitrogen. Trityl perchlorate (3; 0.20 g, 0.06
mmol) was added in one portion and under stirring: a brown
solution was at once obtained. Stirring at rt was continued
for 30 min. GC analysis of the reaction mixture showed the
51.87 (q, J ) 146 Hz, Me), 128.16, 129.40, and 132.70 (d, J )
13
161 Hz, CH), 130.02 (d, J 1-C,
) 74.80 Hz, 1-C), and 166.90
CO
(s, 13CO).
2,2,2-Tr is(m eth ylth io)-1-p h en yl[1-13C]eth a n on e. Pre-
pared according to the procedure reported for the synthesis of
2,2,2-tris(methylthio)-1-phenylethanone,1 starting from methyl
[1-13C]benzoate. The yield of the title compound was 91%: mp
35 °C (PE); MS m/ z 212 (M+ - SMe; 13), 153 [C(SMe)3; 100],
106 (Ph - 13CO, 57); 13C NMR δ (CD3COCD3) 13.19 (q, J )
13
140 Hz, Me), 78.72 [d, J C,
) 42.73 Hz, C(SMe)3], 128.34,
CO
13
130.40, and 133.33 (d, J ) 160 Hz, CH), 135.08 (d, J 1-C,
)
CO
57 Hz, 1-C), and 193.24 (s, 13CO).
Isom er iza t ion of 2,2,2-Tr is(m et h ylt h io)-1-p h en yl[1-
13C]eth a n on e in to S-Meth yl Bis(m eth ylth io)p h en yl[2-
13C]th ioa ceta te in th e P r esen ce of Tr ityl P er ch lor a te (3).
The reaction was carried out according to procedure A, as
described above for entry 1, starting from Ph-13CO-C(SMe)3
(0.52 g, 2 mmol) and 3 (0.10 g, 0.3 mmol) in anhydrous CH2Cl2
(16) Bredereck, H.; Gompper, R.; Seiz, H. Chem. Ber. 1957, 90, 1837.

Isomerization of Trithioorthocarboxylates
J . Org. Chem., Vol. 62, No. 21, 1997 7233
(4 mL). The following three products were isolated: 6 and 9,
respectively in yields of 78% (0.07 g) and 25% (0.02 g) with
regard to 3, and the title compound Ph-13C(SMe)2-COSMe in
88% yield (0.46 g). The structure of the last product was
confirmed by MS and 13C NMR data: MS m/ z 259 (M+; 2),
184 (M+ - COSMe, 100), 137 (M+ - COSMe, and - SMe, 13),
Eth yl r-Oxo Th iolca r boxyla tes 17 a n d 20. Rep r esen -
ta tive P r oced u r e. S-Eth yl P h en ylth ioglyoxyla te (17).
Prepared according to the procedure previously reported5 for
the hydrolysis of 2,2,2-tris(methylthio)-1-phenylethanone, start-
ing from 2,2,2-tris(ethylthio)-1-phenylethanone (3.00 g, 10
mmol) and N-bromosuccinimide (4.00 g, 22.5 mmol) in THF/
H2O (15:1, 10 mL) at rt for 30 min. Usual workup afforded
the virtually pure (TLC, GC) title compound in 92% yield (1.78
g): bp 130-131 °C/0.25 mmHg (lit.18 bp 121-122 °C/5 mmHg);
MS m/ z 194 (M+); 1H NMR δ 1.38 (t, J ) 7.0 Hz, 3H), 3.08 (q,
J ) 7.0 Hz, 2H), and 7.30-7.90 and 8.00-8.45 (2 m, 3:2, 5H);
IR 1688 cm-1 (CO).
S-Eth yl (2-F lu or op h en yl)oxoth ioa ceta te (20). Prepared
in the same way starting from 2,2,2-tris(ethylthio)-1-(2-fluo-
rophenyl)ethanone (3.18 g, 10 mmol) and N-bromosuccinimide
(6.23 g, 35 mmol) in THF/H2O (15:1, 10 mL) at rt for 30 min.
Usual workup afforded the virtually pure (TLC, GC) title
compound in 81% yield (1.72 g): bp 119-120 °C/0.3 mmHg;
MS m/ z 212 (M+); 1H NMR δ 1.50 (t, J ) 7.0 Hz, 3H), 3.21 (q,
J ) 7.0 Hz, 2H), and 7.15-8.25 (m, 4H); IR 1688 cm-1 (CO).
S-Eth yl Bis(eth ylth io)p h en ylth ioa ceta te (19). A mix-
ture of S-ethyl phenylthioglyoxylate (17; 1.94 g, 10 mmol),
H2SO4 (0.20 g, 2 mmol), and ethanethiol (25 mL) was stirred
at rt for 9 h, until GC and TLC (PE-CH2Cl2, 7:3) analyses
showed the disappearance of the starting compound. Usual
workup afforded a crude residue that was column chromato-
graphed, eluting with PE-CH2Cl2 (7:3), to afford the pure title
compound in 85% yield (2.55 g): bp 165-166 °C/0.3 mmHg;
MS m/ z 300 (M+); 1H NMR δ 1.18 (t, J ) 7.0 Hz, 6H), 1.23 (t,
J ) 7.0 Hz, 3H), 2.38 (q, J ) 7.0 Hz, 4H), 2.80 (q, J ) 7.0 Hz,
2H), and 7.05-7.32 and 7.32-7.63 (2 m, 3:2, 5H); IR 1678 cm-1
(CO).
122 (Ph - 13CS, 82); 13C NMR δ 12.77 (q, J ) 140 Hz, Me),
76.46 (s, 13C), 128.06 (d, J ) 160 Hz, CH), 136.89 (d, J 1-C,
)
13
C
13
44.08 Hz, 1-C), and 198.07 (d, J CO, ) 47.47 Hz, CO).
C
Isom er iza t ion of 2,2,2-Tr is(m et h ylt h io)-1-p h en yl[1-
13C]eth a n on e in to S-Meth yl Bis(m eth ylth io)p h en yl[2-
13C]th ioa ceta te in th e P r esen ce of Meth a n esu lfon ic Acid
(4). The reaction was carried out according to procedure B,
as described above for entry 2, starting from Ph-13CO-C(SMe)3
(0.52 g, 2 mmol) and 4 (0.10 g, 1 mmol) in anhydrous CH2Cl2
(4 mL). The only reaction product was S-methyl bis(meth-
ylthio)phenyl[2-13C]thioacetate (0.45 g, 87%).
Tr ieth yl r-Keto Tr ith ioor th oca r boxyla tes: Rep r esen -
t a t ive P r oced u r e. 2,2,2-Tr is(et h ylt h io)-1-p h en ylet h a -
n on e. [Tris(ethylthio)methyl]lithium was prepared according
to the procedure previously reported for the synthesis of
[tris(methylthio)methyl]lithium,1 by reaction of tris(ethylthi-
o)methane11 (2.45 g, 12.5 mmol) and BuLi (2.5 M solution in
hexane; 5.5 mL, 13.75 mmol) in anhydrous THF (15 mL), at
-95 °C under N2. After 2 h of stirring, a white suspension
was obtained. Then a solution of methyl benzoate (1.36 g, 10
mmol) in the same solvent (5 mL) was added dropwise during
5 min. After being stirred at -95 °C for a further 5 min, the
resulting solution was directly quenched with Et2O-water
(200 mL, 1:1). Usual workup afforded a crude reaction mixture
that was chromatographed, eluting with PE-CH2Cl2 (7:3, v/v).
The following three products were isolated. The first eluted
product was tetrakis(ethylthio)methane (0.13 g, 0.51 mmol):
mp 34-35 °C (pentane) (lit.11 mp 33-34 °C); MS m/ z 195 (M+
- SEt). The second eluted product was the title compound
The reaction of S-ethyl (2-fluorophenyl)oxothioacetate (20)
with ethanethiol and H2SO4 failed, also using a major amount
of acid (molar ratio 20:H2SO4 ) 1:1) and carrying out the
reaction at 30 °C for 24 h. After usual workup, 71% of the
starting compound was recovered; no traces of S-ethyl bis-
(ethylthio)(2-fluorophenyl)thioacetate were present (GC-MS
analysis).
(2.31 g, 77%): bp 179-180 °C/0.3 mmHg; MS m/ z 239 (M+
-
1
SEt); H NMR δ 1.22 (t, J ) 7.0 Hz, 9H), 2.65 (q, J ) 7.0 Hz,
6H), 7.10-7.45 and 8.15-8.38 (2 m, 3:2, 5H); IR 1672 cm-1
(CO). The third eluted product was 2,2-bis(ethylthio)-1-
phenylethanone (0.26 g, 11%): bp 169-170 °C/0.4 mmHg; MS
1
m/ z 240 (M+); H NMR δ 1.36 (t, J ) 7.0 Hz, 6H), 2.50-2.95
Ack n ow led gm en t. This work was supported by the
National Research Council of Italy (CNR), Progetto
Strategico “Tecnologie Chimiche Innovative” and Pro-
getto Integrato CNR (I.Co.C.E.A., Bologna)/Universita`
(Torino), and by Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica (MURST).
(m, 4H), 5.36 (s, 1H), 7.25-7.68 and 7.88-8.22 (2 m, 3:2, 5H);
IR 1688 cm-1 (CO). The two last products are known,17 but
physical, spectroscopic, and analytical data are not reported.
2,2,2-Tr is(eth ylth io)-1-(2-flu or op h en yl)eth a n on e. Pre-
pared as described above, starting from tris(ethylthio)methane
(2.45 g, 12.5 mmol), BuLi (2.5 M solution in hexane; 5.5 mL,
13.75 mmol), and methyl 2-fluorobenzoate (1.54 g, 10 mmol)
in anhydrous THF (15 mL). In this case the by products, i.e.
tetrakis(ethylthio)methane, MS m/ z 239 (M+ - SEt), and 2,2-
bis(ethylthio)-1-(2-fluorophenyl)ethanone, MS m/ z 258 (M+),
were formed only in traces. Chromatography of the crude
reaction mixture, eluting with PE-CH2Cl2 (7:3), afforded the
pure title compound in 89% yield (2.82 g): bp 142-143 °C/0.4
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
of all new compounds (3 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
1
mmHg; MS m/ z 257 (M+ - SEt); H NMR δ 1.28 (t, J ) 7.0
J O970683+
Hz, 9H), 2.80 (q, J ) 7.0 Hz, 6H), and 7.05-7.85 and 8.15-
8.55 (2 m, 3:1, 4H); IR 1698 cm-1 (CO).
(18) Lapkin, I. I.; Rodygin, A. S.; Rybakova, M. N.; Bykova, L. M.;
Belonovich, M. I. Zh. Org. Khim. 1977, 13, 996; Chem. Abstr. 1977,
87, 134344.
(17) Grossert, J . S.; Dubey, P. K. J . Chem. Soc., Chem. Commun.
1982, 1183.