1-(2,5-dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl esters as highly efficient chemoselective acylating reagents

Article abstract of DOI:10.1055/s-1999-3529

1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl esters 4f-k were prepared in yields usually greater than 90%, by reacting acyl chlorides with 1-(2,5-dichlorophenyl)-2,2-bis(methylsulfanyl)ethanone enolate. These esters were demonstrated to be excellent chemoselective reagents for the acylation of amines, alcohols, thiols, pyrrole and indole. From all the acylation reactions the dimethyl α-oxo dithioacetal 2d, recyclable for the preparation of esters 4f-k, could be recovered in 90-100% yield.

Full text of DOI:10.1055/s-1999-3529

1200
PAPER
1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl Esters as Highly Efficient
Chemoselective Acylating Reagents†
Iacopo Degani,* Stefano Dughera, Rita Fochi,* Emanuela Serra
Dipartimento di Chimica Generale ed Organica Applicata dell’Università, C.so M. D’Azeglio 48, I-10125 Torino, Italy
Fax +39(11)6707642; E-mail: fochi@silver.ch.unito.it
Received 12 February 1999
This paper reports an easy, no-risk preparation, and the
Abstract: 1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl es-
properties, of a new class of vinyl esters that can be used
ters 4f–k were prepared in yields usually greater than 90%, by re-
as efficient chemoselective acylating agents of amines, al-
acting
acyl
chlorides
with
1-(2,5-dichlorophenyl)-2,2-
cohols, phenols, thiols, pyrrole and indole. In previous re-
bis(methylsulfanyl)ethanone enolate. These esters were demon-
strated to be excellent chemoselective reagents for the acylation of search,7,8 reactions of esters, acyl chlorides, anhydrides,
amines, alcohols, thiols, pyrrole and indole. From all the acylation
reactions the dimethyl a-oxo dithioacetal 2d, recyclable for the
thiol esters and amides with [tris(methylsulfanyl)meth-
yl]lithium or [bis(methylsulfanyl)methyl]lithium led us
preparation of esters 4f–k, could be recovered in 90–100% yield.
to, among other things, the preparation of dimethyl a-oxo
Key words: vinyl esters, chemoselective acylating reagents,
dithioacetals 2. In a study aimed at developing the syn-
amides, esters, thiol esters
thetic potential of these compounds, we thought to turn
some of them into the corresponding vinyl esters 4 that
can be used as new acylating agents. The conversion was
The last few decades have seen the proposal of a great va-
riety of acylating agents to fulfill, in the specific field of
acylation reactions, the increasing demand for selective
reagents able to react in mild conditions. Starting from the
late 1940s descriptions were given of numerous reagents
belonging to the class of vinyl esters 1, destined, frequent-
ly, to the chemical as well as the enzymatic acylation of
different types of amines, alcohols, thiols, enolizable car-
bonyl compounds, carboxylic acids, amino acids and pep-
tides. The isopropenyl acetate1 (1; R1 = H, R2 = R3 = Me)
was described first, and this was followed by 1-methoxy-
vinyl esters2 (1; R1 = H, R2 = OMe, R3 = Me, Ar), 1-
ethoxy-2-(trimetylsilyl)vinyl esters3 (1; R1 = SiMe3, R2 =
OEt, R3 = alkyl, Ph), various isopropenyl esters4 (1; R1 =
H, R2 = Me, R3 = alkyl, alkenyl, Ph), 1-butylvinyl esters4a
(1; R1 = H, R2 = Bu, R3 = substituted alkyl), 1-ethoxyvinyl
esters5 (1; R1 = H, R2 = OEt, R3 = alkyl, substituted alkyl)
and vinyl esters1g,6 (1; R1 = R2 = H, R3 = alkyl, Ph). The
synthetic value of these vinyl esters lies just in their pro-
viding selective acylation reactions in mild conditions,
unlike the most common acylating agents such as acyl
chlorides and anhydrides. On looking through the litera-
ture it can be seen that it is difficult to make a comparative
evaluation of the performance distinguishing the various
classes of vinyl esters 1. However, the effort that has been
put into making these reagents easily accessible is very
evident. In fact their preparation shows significant limita-
tions due to the use of high-risk reagents such as potential-
ly explosive intermediates with an acetylenic structure
and toxic catalysts based on mercury salts.
easily carried out by reacting acyl chlorides 3 with the
enolates of a-oxo dithioacetals 2 (molar ratio 3:2 = 1:1) in
anhydrous THF at room temperature for 30 min (Scheme
1). Vinyl esters 4 were always obtained in high yield (Ta-
ble 1).
Scheme 1
A preliminary, comparative evaluation of the acylating
properties of vinyl esters 4 was made, reacting the esters
to reflux with benzylamine (5) in THF, in a molar ratio of
1:1 (Scheme 2). Table 2 gives the results. Entries 1–4
show that the rate of the benzoylation reactions (4, R2 =
Ph) of benzylamine is dramatically affected by the elec-
tronic effects of R1. In fact, compared to the case where R1
= Ph (entry 1), the reaction rate decreases if there is an
electron donor group on the phenyl (entry 2), instead it in-
creases if there are electron withdrawing groups on the
phenyl (entries 3, 4), according to the sequence R1 = 4-
MeOC6H4 <<< Ph << 4-ClC6H4 < 2,5-Cl2C6H3. Further-
more, in entries 4–9, where R1 = 2,5-Cl2C6H3, all the reac-
tions, checked regularly throughout their development,
essentially required the same time to reach completion.
Thus in these cases the rate of the acylation of benz-
ylamine suffered neither the electronic effects nor the ster-
2
R
O
3
1
O
R ,H
R
1
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl Esters as Chemoselective Acylating Reagents
1201
ic effects of R2. This behavior of esters 4 is consistent with
a tetrahedral mechanism, where the elimination of the
leaving group is the slow step of the reaction. One impor-
tant aspect from the synthetic point of view can be seen in
entries 4–9: along with amides 6, there was always a high
yield of the dimethyl a-oxo dithioacetal 2d that can be re-
cycled to prepare vinyl esters 4f–k.
1
R
O
MeS
2
O
+
Ph
R
NH
2
SMe
4
5
1. THF, reflux
2. H O
2
Thus, considering our synthetic aims, we chose, on the ba-
sis of the above results, the 1-(2,5-dichlorophenyl)-2,2-
bis(methylsulfanyl)vinyl esters from among the examined
vinyl esters 4, these acylating agents appearing certainly
promising and significant enough to submit to further in-
vestigations. First the research was developed by studying
reactions between the vinyl ester 4f and several represen-
tative amines or the corresponding lithium amides in THF
at reflux (Table 3). The butylamine and cyclohexylamine
(Table 3: entries 1, 2) behaved in almost the same way as
the benzylamine (Table 2: entry 4). Instead, attempts at
the benzoylation of the dibutylamine and aniline with
O
O
MeS
1
2
Ph
+
NH
R
R
SMe
2
6
Scheme 2
Table 1 Vinyl Esters 4a–k
Com-
R1
R2
Yieldb
(%)
MS
mpc (°C) or
IR
1H NMR, d, J (Hz)
pounda
m/z (M+) bp (°C)/Torr n CO cm-1
MeS (s, 3H)
Others
e
e
e
4a
4b
Ph
Ph
Ph
100
84
316
254
75–76d
Me
148/0.5f
1775
1760
1748
2.16, 2.28
2.19, 2.34
2.54, 2.60
2.16 (s, 3H); 7.20–8.10
(m, 5H)
4c
Ph
t-Bu
85
98
296
346
50–51
70–71
1.28 (s, 9H); 7.20–7.55
(m, 5H)
4d
4-MeOC6H4
Ph
4.02 (s, 3H); 6.90–7.15,
7.55–7.85, 8.16–8.42
(3 m,1:2:1, 9H)
4e
4f
4-ClC6H4
Ph
98
100
100
350
384
414
69–70
93–94
95–96
1748
1748
1742
2.23, 2.31
2.27, 2.37
2.25, 2.35
7.10–7.68; 7.92–8.22
(2 m, 3.5:1, 9H)
2,5-Cl2C6H3
2,5-Cl2C6H3
Ph
7.10–7.60; 7.90–8.10
(2 m, 3:1, 8H)
4g
4-MeOC6H4
3.85 (s, 3 H); 6.95
(d, J = 9.6, 2H);
7.15–7.55 (m, 3 H); 8.05
(d, J = 9.6, 2H)
4h
4i
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
4-ClC6H4
2-thienyl
Me
94
98
97
89
418
390
322
364
118–119
96–97
1748
1745
1778
1760
2.27, 2.35
2.20, 2.30
2.20, 2.27
2.36, 2.48
7.20–7.55 (m, 5 H); 8.05
(d, J = 9.6, 2H)
7.00–7.35, 7.50-7.70,
7.85–8.00 (3 m, 3:2:1, 6H)
4j
168/0.7
73–74
2.12 (s, 3 H); 7.20–7.35,
7.35–7.50 (2 m, 2:1, 3H)
4k
t-Bu
1.40 (s, 9 H); 6.98–7.44,
7.44–7.57 (2 m, 2:1, 3H)
a
Satisfactory microanalyses were obtained: C, ± 0.11; H, ± 0.06; Cl, ± 0.08; S, ± 0.10.
b Yield of pure product.
c
Crystallization solvent: PE.
d
Lit.8 mp 75–76°C.
e
Spectral data identical to those reported.8
Lit.12 bp 127–129°C/0.35 Torr.
f
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

1202
I. Degani et al.
PAPER
4f did not produce the corresponding amides, not even in Later on, given what is known in the literature, namely
trace amounts (entries 3, 7); also the piperidine was benz- that a certain number of vinyl esters can acylate various
oylated in low yield (entry 5). The results in themselves alcohols and phenols,1,5,6 we investigated the possibility
show the selective behavior of the ester 4f in the acylation of realizing the acylation of these classes of compounds
of various types of amines. Furthermore the reactions re- using the esters 4a,f,j,k. Exploratory trials were first car-
ported in entries 9 and 10 directly demonstrate that the es- ried out by heating 4f in THF at reflux with benzyl alco-
ter 4f is able to selectively acylate aliphatic primary amino hol, or phenol, for many hours in the presence or absence
groups in the presence of aliphatic secondary amino of methanesulfonic acid. All such acylation attempts
groups (entry 9) and aromatic amino groups (entry 10). failed. Instead, putting 4f into 1,2-dichloroethane at re-
However, the ester 4f is able to benzoylate lithium dibut- flux, with benzyl alcohol in the presence of methane-
ylamide, lithium piperidylamide and lithium phenylamide sulfonic acid, led to the thiol ester 9. Evidently the
in good to very good yield (entries 4, 6, 8). Another aspect conversion of 4f to 9 took place through the formation of
that is certainly useful from the synthetic point of view is 8 by the acid-catalyzed addition of H2O (coming from
that both steps of the ester 4f formation and amine acyla- moisture) and the successive elimination of methanethiol
tion can be carried out with a one pot reaction; N-benzyl- (Scheme 3). The behavior of the ester 4f towards alcohols
benzamide and N-(4-aminobenzyl)benzamide were is different from that of the other known vinyl esters in
obtained in this way, in yields of 98% and 96% respec- that protonation occurs in position 1, not in position 2, due
tively (see experimental section).
to the formation of the cation 7, strongly stabilized by two
methylsulfanyl groups. Therefore in the case of the ester
4f, the protonation of the vinyl system hinders its acylat-
ing action instead of favoring it. However the acylation re-
actions of the hydroxy groups to obtain the esters 12 were
easily realized by reacting in THF, with a standard reflux
of 1 h, the lithium salts of primary, secondary and tertiary
alcohols and phenols (10) with the vinyl ester 4a (Scheme
4; Table 4: entries 1–4) and 4f,j,k (Table 4: entries 5–20).
In cases that could be compared, the best yields were ob-
tained with the esters 4f,j,k. Also in these reactions there
was the recovery, in excellent yields, of the recyclable a-
oxo dithioacetals 2a,d. With thiols the behavior of the es-
ters 4a,f,j,k was analogous to that in reactions with alco-
hols and phenols. In fact, positive results were obtained
only with the thiolate anions 11 (Scheme 4), resulting in
thiol esters 13 in good yield (Table 4: entries 21–27).
Ar
O
O
Ar
MeS
MeS
+
H
O
O
Ph
Ph
+
SMe
SMe
4f
7
H O,
2
_
+
H
Ar
O
Ar
O
MeS
HO
MeS
_
MeSH
O
O
Ph
Ph
O
SMe
9
8
Ar = 2,5-Cl C H
6 3
2
Scheme 3
Another group of reactions studied concerned the benz-
oylation with 4f of substrates containing two different po-
tentially acylable groups (Scheme 5). Also in these reac-
Table 2 Acylation of Benzylamine (5) with Vinyl Esters 4a,d–k
Entry
n°
Ester
4
R2
Timea
(h)
Prod-
uct
Yieldb (%)
MS
mpc (°C)
[Lit. mp (°C)]
m/z (M+)
6
2
1
2
3
4
5
6
7
8
9
4a
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
48
24
12
4
4
4
4
4
4
6a
6a
6a
6a
6b
6c
6d
6e
6f
84
21
2a, 75
2b, 18
2c, 79
2d, 95
2d, 96
2d, 96
2d, 96
2d, 94
2d, 92
189
189
189
189
241
245
217
149
191
106–107d
106–107d
100
97
96
96
95
96
92
106–107d
106–107d
4-MeOC6H4
4-ClC6H4
2-thienyl
Me
128–129e [128–131]13
167–168f [164.35–165.35]14
120–121g [119–120]15
61–62h [61–62]4b
81.5–82.5h [82–83]4a
4j
4k
t-Bu
a At reflux.
b Yield of pure product isolated by column chromatography.
c Crystallization solvent: CH2Cl2-PE.
d Physical and spectral data are identical to those of an authentic sample of commercial origin (Aldrich).
e IR: n = 1678 cm–1 (CO). 1H NMR: d = 3.84 (s, 3H); 4.60 (d, J = 5.6 Hz, 2H); 6.90, 7.78 (2 d, J = 8.5 Hz, 4H); 7.38 (m, 5H).
f IR: n = 1678 cm–1 (CO). 1H NMR: d = 4.60 (d, J = 5.6 Hz, 2H); 7.38 (m, 5H); 7.39, 7.75 (2 d, J = 8.5 Hz, 4H).
g IR: n = 1672 cm–1 (CO). 1H NMR: d = 4.60 (d, J = 5.6 Hz, 2H); 6.92–7.12, 7.32, 7.35–7.58 (3 m, 1:5:2, 8H).
h
Spectral data identical to those reported.4b
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl Esters as Chemoselective Acylating Reagents
1203
3
HO
+
(14)
4a,f,j,k
+
R
X
Li
NH
A)
2
O
B) 14
+ BuLi
10 (X = O)
11 (X = S)
HO
HS
NH
Ph
Ph
+
2d
A: 97%; B: 94%
15
THF,
reflux
HS
NH
(16)
A)
O
2
B) 16
+ BuLi
O
4f
NH
+
2d
3
R
2
A: 97%; B: 94%
17
X
R
2a,d
+
12 (X = O)
13 (X = S)
4-HOC H
OH (18)
6
4
O
+
BuLi
Scheme 4
4-HOC H
6
Ph
+
2d
O
4
87%
19
Scheme 5
tions the chemoselectivity of 4f was well evident. In fact
2-aminoethanol (14) and the corresponding lithium salt
both underwent selective benzoylation to nitrogen, pro-
viding, exclusively, N-(2-hydroxyethyl)benzamide (15). In conclusion, the research led to the following results:
Analogously both 2-aminoethanethiol (16) and the corre- i) preparation of a new family of vinyl esters, the 1-(2,5-
sponding lithium salt gave, exclusively, N-(2-sulfanyleth- dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl esters 4 (R1
yl)benzamide (17). Another example of the = 2,5-Cl2C6H3); ii) it was demonstrated that these vinyl es-
chemoselectivity of 4f is seen in its reaction with the lith- ters act in mild conditions as selective acylating agents of
ium salt of 4-(hydroxymethyl)phenol (18). The only reac- various amine classes, also in the presence of other poten-
tion product was the ester 19.
tially acylable groups; iii) these vinyl esters are excellent
acylating agents also towards alcohols, phenols, thiols,
pyrrole and indole, when they are in salt form. Further-
more it should be stressed that as acylating agents, and
compared to the known vinyl esters, the 1-(2,5-dichlo-
Two last cases studied are the reaction of 4f with the lith-
ium salts of pyrrole and indole; the corresponding prod-
ucts of N-benzoylation were easily obtained in yields of
88% and 89% respectively (see experimental section).
Table 3 Benzoylation of Amines and Lithium Amides with the Vinyl Ester 4f
Entry Amine
n°
Lithium
amide
Timea Product
(h)
Yieldb (%)
MS
mp (°C) or bp (°C)/Torr
m/z (M+) [Lit. mp (°C) or bp
(°C)/Torr]
product 2d
1
2
3
4
5
6
7
8
9
BuNH2
c-C6H11NH2
Bu2NH
3
5
24
24
24
4
24
5
4
BuNHCOPh
97
95
93
96
177
203
38–39c,d [39.5–40.5]9
147–148e,f [147]9
c-C6H11NHCOPh
g
-
Bu2N Li+
Bu2NCOPh
c-C5H10NCOPh
74
21
91
71
25
94
233
189
189
124/0.3h [110/0.25]16
48e,i [48]9
c-C5H10NH
-
c-C5H10N Li+
c-C5H10NCOPh
48e,i [48]9
g
PhNH2
-
PhNH Li+
PhNHCOPh
MeNHCH2CH2NHCOPh
4-H2NC6H4CH2NHCOPh 100
74
71
96
93
197
148l
226
164–165e,j
oil
MeNHCH2CH2NH2
4-H2NC6H4CH2NH2
87k
10
5
142e,m [142–143]17
a
At reflux.
b
Yield of pure product isolated by column chromatography.
c Crystallization solvent: pentane.
d IR: n = 1672 cm–1 (CO). 1H NMR: d = 0.70–1.12, 1.12–1.80, 3.10–3.55, 6.95–7.30, 7.30–7.60 (5 m, 3:4:2:3:2).
e Crystallization solvent: CH2Cl2-PE.
f IR: n = 1660 cm–1 (CO). 1H NMR: d = 0.95–2.30, 3.80–4.45, 7.45–7.85, 7.85–8.15 (4 m, 10:1:3:2).
g
The reaction failed.
h Spectral data identical to those reported.16
i Spectral data identical to those reported.3a
j
Physical and spectral data identical to those of an authentic sample of commercial origin (Aldrich).
k Isolated as picrate.
l M+ - MeNH.
m IR: n = 1662 cm–1 (CO). 1H NMR identical to that reported.17
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

1204
I. Degani et al.
PAPER
Table 4 Acylation of Lithium Salts of Alcohols and Thiols (10 and 11)
En- Ester R3
Timea Product 12 or 13 Yieldb (%)
MS
m/z
mp (°C) or bp (°C)/ IR
Torr [Lit. mp (°C)
n CO
(M+) or bp (°C)/Torr] cm–1
1H NMR, d, J (Hz)
try
4
in 10 or 11
(h)
prod-
uct
2
n°
1
4a
4a
PhCH2
1 (r.t.) PhCOOCH2Ph
83
2a, 91
2a, 93
212
141–142/0.3c
2
C6H13-CH(Me)
1
PhCOOCH(Me)- 85
234
148/8
1722 0.90–1.30, 1.30–2.10,
5.10–5.60, 7.45–7.80,
8.00–8.35
C6H13
[90/0.6]9
(5 m, 3:13:1:3:2)
d
3
4a
t-Bu
1
2
PhCOOBu-t
72
2a, 90
178
100/10
1720
[96/2]9
4
5
6
4a
4f
4f
Ph
PhCOOPh
72
93
88
2a, 78
2d, 91
2d, 93
198
212
206
69c,e
PhCH2
n-C6H13
1 (r.t.) PhCOOCH2Ph
141–142/0.3c
d
1 (r.t.) PhCOOC6H13-n
106/0.3
1722
[138/8.5]9
7
4f
C6H13-CH(Me)
1
PhCOOCH(Me)- 85
C6H13
2d, 91
234
148/8
1722 0.90–1.30, 1.30–2.10,
5.10–5.60, 7.45–7.80,
8.00–8.35
[90/0.6]9
(5 m, 3:13:1:3:2)
d
8
9
4f
4f
t-Bu
1
PhCOOBu-t
86
2d, 89
178
100/10
1720
[96/2]9
Ph
1
1
PhCOOPh
90
86
2d, 93
2d, 91
198
232
69c,e
10 4f
4-ClC6H4
PhCOOC6H4Cl
87–88e
1752 7.20–7.85, 8.20–8.45
(2 m, 7:2)
[88]9
11 4j
12 4j
13 4j
PhCH2
1 (r.t.) MeCOOCH2Ph
87
2d, 93
2d, 89
2d, 89
150
63–64/0.35c
134/8c
n-C12H25
1 (r.t.) MeCOOC12H25-n 85
229f
173f
g
g
C6H13-CH(Me)
1
MeCOOCH(Me)- 88
C6H13
82/10
[84/15]9
14 4j
15 4j
t-Bu
1
1
MeCOOBu-t
74
83
2d, 91
2d, 88
117f
215
97/760c
4-BrC6H4
MeCOOC6H4Br
113–114/0.3
1762 2.43 (s, 3H); 7.20, 7.75
[129–130/15]9
(2 d, J = 9.0, 4H)
16 4k
17 4k
PhCH2
1
1
t-BuCOOCH2Ph 87
t-BuCOOC6H13-n 87
2d, 95
2d, 88
192
76–77/3.8
1731 1.28 (s, 9H); 5.36
(s, 2H); 7.65 (m, 5H)
[67–70/2]20
n-C6H13
187f
74/8
1735 0.75–1.75 (m, 11H);
1.13 (s, 9H); 4.05
[204/760]21
(t, J = 3.0, 2H)
18 4k
C6H13-CH(Me)
1
t-BuCOOCH
(Me)-C6H13
81
2d, 84
215f
92/8
1730 1.00–1.20 (m, 6H);
1.35 (s, 9H);
[114/20]16
1.30–1.80, 4.80–5.20
(2 m, 10:1, 11H)
19 4k
20 4k
21 4a
t-Bu
24
1
t-BuCOOBu-t
t-BuCOOC6H4F
PhCOSCH2Ph
66
90
87
2d, 84
2d, 91
2a, 95
159f
196
228
76–77/20
1723 1.38, 1.43 (2 s, 1:1)
[75–78/20-21]22
h
4-FC6H4
PhCH2
67–68/0.3
1755
[oil]23
1
39–40i
1667 4.38 (s, 2H);
7.32–7.80, 8.05–8.30
(2 m, 8:2, 10H)
[39.5]9
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl Esters as Chemoselective Acylating Reagents
1205
Table 4 (continued))
En- Ester R3
Timea Product 12 or 13 Yieldb (%)
MS
m/z
mp (°C) or bp (°C)/ IR
Torr [Lit. mp (°C)
n CO
(M+) or bp (°C)/Torr] cm–1
1H NMR, d, J (Hz)
try
4
in 10 or 11
(h)
prod-
uct
2
n°
22 4f
23 4f
24 4f
PhCH2
1
1
1
PhCOSCH2Ph
89
2d, 93
228
152
194
39–40i
1667 4.38 (s, 2H);
7.32–7.80, 8.05–8.30
[39.5]9
(2 m, 8:2, 10H)
Me
PhCOSMe
87
2d, 80
2d, 89
70–71/0.3
1660 2.48 (s, 3H);
[210–212/760]9
7.30–7.62, 7.80–8.15
(2 m, 3:2, 5H)
C2H5-CH(Me)
PhCOSCH(Me)- 82
C2H5
128/8
1670 1.38 (t, J = 6.5, 3H);
1.76 (d, J = 6.5, 3H);
1.75–2.35, 3.75–4.40,
7.45–7.85, 8.00–8.30
(4 m, 2:1:3:2, 8H)
[150/20]9
j
j
25 4f
26 4j
Ph
1
1
PhCOSPh
93
82
2d, 93
2d, 89
214
188
55-56e
[56-57]9
n-C8H17
MeCOSC8H17-n
104/8
1702 1.22–1.53, 1.53–2.30
(2 m, 15H);
[116–117/10]9
2.70 (s, 3H); 3.24
(t, J = 6.5, 2H)
k
27 4k
n-C8H17
4
t-BuCOSC8H17-n 85
2d, 88
230
124/6
1.20–1.48, 1.48–2.00
[110–111/5]25
(2 m, 1:4, 15H);
1.65 (s, 9H); 3.18
(t, J = 6.5, 2H)
a At reflux, unless otherwise noted.
b Yield of pure product.
c Physical and spectral data are identical to those of an authentic sample of commercial origin (Aldrich).
d 1H NMR identical to that reported.18
e Crystallization solvent: PE.
f M+ + 1.
g Spectral data identical to those reported.19
h 1H NMR identical to that reported.23
i Crystallization solvent: pentane.
j Spectral data identical to those reported.24
k 1H NMR identical to that reported.25
rophenyl)-2,2-bis(methylsulfanyl)vinyl esters have the
following advantageous features: i) a facile, low-cost and
no-risk preparation; ii) mild conditions of the acylation re-
actions; iii) easy procedures; iv) high yields; v) recovery,
in yields usually greater than 90%, from all the acylation
reactions of the dimethyl a-oxo dithioacetal 2d, recycla-
ble for the preparation of the vinyl esters.
thanol, sodium methanethiolate, anhyd THF and 1,2-dichloroethane
were purchased from Aldrich Chemical Co. 2-Sulfanylethylamine
was purchased from Fluka Chemical Co.
Dimethyl a-Oxo Dithioacetals 2a–d
Prepared according to the procedure previously reported by us.7
Vinyl Esters 4a–k; 1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfa-
nyl)vinyl Benzoate (4f); Typical Procedure
A solution of 1-(2,5-dichlorophenyl)-2,2-bis(methylsulfanyl)eth-
anone (2d; 2.81 g, 10 mmol) in anhyd THF (10 mL) was added
dropwise over 5 min to a suspension of NaH (0.26 g, 11 mmol) in
the same solvent (5 mL), under stirring and under N2. An exother-
mic reaction with hydrogen evolution immediately occurred and a
yellow solution was obtained. After 10 min, a solution of benzoyl
chloride (3, R2 = Ph; 1.41 g, 10 mmol) in THF (5 mL) was added in
one portion. Soon the solution changed from yellow to colorless and
a white precipitate began to separate. Stirring was maintained for a
further 1 h until GC and TLC analyses (PE/CH2Cl2, 3:2, v/v)
showed the disappearance of the starting compound and the pres-
ence of one only product. The mixture was treated with Et2O/H2O
1H NMR and IR spectra were recorded respectively for solutions in
CDCl3 and CCl4, unless otherwise noted. 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 N2.
Details for the reactions and yields of the products are listed in the
Tables 1–4. All the products gave satisfactory physical and spectral
(MS, 1H NMR and IR) data.
Acyl chlorides 3, BuLi (2.5 M solution in hexane), NaH, amines, al-
cohols, thiols, aminoethanol, 4-hydroxymethylphenol, 2-sulfanyle-
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1206
I. Degani et al.
PAPER
(200 mL, 1:1). The aqueous layer was separated and extracted again
with Et2O (50 mL). The combined organic extracts were washed
with 5% aq NaOH (2 x 50 mL) and then with H2O (2 x 50 mL), dried
(Na2SO4), and evaporated under reduced pressure. The white solid
N-[2-(Methylamino)ethyl]benzamide
Oil; MS: m/z = 148 (M+ – MeNH). In this case the reaction products,
i.e. the title compound and the dithioacetal 2d, could not be separat-
ed by column chromatography. Picric acid (1.14 g, 5 mmol) was
dissolved, by heating, in anhyd Et2O (50 mL) and a solution of the
crude reaction residue in the same solvent (10 mL) was added in one
portion. The picrate of the title compound precipitated immediately
as a yellow substance, which was gathered by filtration, washed
with Et2O (5 mL) and dried under reduced pressure (1.78 g, 87%):
mp 159–161 °C (from Me2CO/PE).
1
substance obtained was the virtually pure (TLC, H NMR) title
compound 4f (3.85 g, 100% yield); MS: m/z = 384 (M+). It was used
in the next step without further purification. A sample was purified
for the analyses: mp 93–94 °C (from PE).
Yields, physical and spectral data for vinyl esters 4a–k are reported
in Table 1.
IR (KBr): n = 1610, 1638 cm–1 (CO).
1H NMR (CD3COCD3): d = 2.62 (s, 3 H), 2.95–3.28, 3.28–3.75 (2
Acylation of Amines, Alcohols, Phenols and Thiols with Vinyl
Esters 4; Typical Procedures. N-Benzylbenzamide (6a)
In entry 4 of Table 2 a solution of 1-(2,5-dichlorophenyl)-2,2-
bis(methylsulfanyl)vinyl benzoate (4f; 1.93 g, 5 mmol) in anhyd
THF (8 mL) was added in one portion with stirring, to a solution of
benzylamine (5; 0.54 g, 5 mmol) in the same solvent (2 mL). The
resulting solution was heated under reflux for 4 h, until GC and TLC
analyses (PE/Et2O, 1:1, v/v) showed the disappearance of the start-
ing compounds and the presence of only two products. The mixture
was poured into cold sat. aq NaCl (80 mL) and extracted with Et2O
(2 x 80 mL). After drying (Na2SO4) and removal of the solvent un-
der reduced pressure, the crude residue was chromatographed on a
short column, eluting with PE/Et2O (1:1, v/v). The first eluted prod-
uct was 1-(2,5-dichlorophenyl)-2,2-bis(methylsulfanyl)ethanone
(2d; 1.33 g, 95%). The second eluted product was the pure (GC,
TLC, 1H NMR) title compound 6a (1.02 g, 97%): mp 106–107 °C
(from CH2Cl2/PE); MS: m/z = 211 (M+); physical and spectral data
are identical to those of an authentic sample of commercial origin
(Aldrich).
m, 1:1, 4 H), 7.30–7.60, 7.60–7.95 (2 m, 3:2, 5 H), 8.72 (s, 2 H).
Anal. Calcd for C16H17N5O8 (407.34): C, 47.18; H, 4.21; N, 17.19.
Found: C, 47.10; H, 4.23; N, 17.10.
After evaporation of the organic solution, virtually pure 2d was ob-
tained in 96% yield (1.35 g).
Yields, physical and spectral data for amides are reported in Tables
2 and 3.
N-Benzoylpyrrole
The mixture was prepared according to the procedure described for
the preparation of N-benzoylpiperidine, starting from pyrrole (0.34
g, 5 mmol), BuLi (2 mL, 5 mmol) and 4f (1.93 g, 5 mmol) in anhyd
THF (10 mL). The reaction was complete after 1 h of stirring at r.t.
The crude residue obtained after the above workup was chromato-
graphed on a short column, eluting with PE/Et2O (9.9:0.1, v/v), to
afford 2d (1.22 g, 87%) and the title compound (0.75 g, 88%): bp
104 °C / 0.27 mmHg (Lit.9 bp 276 °C / 715 mmHg).
Entries 1–3 and 5–9 of Table 2 and entries 1, 2, 5, 9 and 10 of Table
3 were performed according to the same procedure. Under the same
conditions entries 3 and 7 of Table 3 failed.
IR: n = 1710 cm–1 (CO).
1H NMR: d = 6.25 (m, 2H), 7.17 (m, 2H), 7.35–7.40, 7.40–8.25 (2
m, 3:2, 5H).
The two steps of preparation of 4f and benzoylation of benzylamine
(5) can be carried out with a one-pot reaction. In this case a solution
of 5 (0.54 g, 5 mmol) in anhyd THF (2 mL) was added to the mix-
ture containing 4f (1.93 g, 5 mmol), prepared as described above in
the representative procedure to obtain vinyl esters. The reaction was
complete after 4 h of reflux under stirring. Workup described above
afforded the dithioacetal 2d and the title compound 6a, in yield of
100% (1.40 g) and 98% (1.03 g), respectively.
MS: m/z = 171 (M+).
Benzoylation of indole was also made in an analogous manner.
Chromatography of the crude residue using PE/CH2Cl2 (7:3, v/v) as
eluent, afforded 2d (1.28 g, 91%) and N-benzoylindole (0.98 g,
89%): mp 68–69 °C (from CH2Cl2/PE) (Lit.9 mp 67–68 °C).
IR: n = 1694 cm–1 (CO).
1H NMR: d = 6.72 (d, J = 4.5 Hz, 1H), 7.37 (d, J = 4.5 Hz, 1H),
7.45–7.95, 8.38–8.62 (2 m, 8:1, 9H).
According to the same procedure N-(4-aminobenzyl)benzamide
was obtained in 96% yield (1.08 g).
MS: m/z = 221 (M+).
N-Benzoylpiperidine
Benzyl Benzoate (12; R2 = Ph, R3 = PhCH2)
In entry 6 of Table 3 a solution of BuLi (2.5 M solution in hexane;
2 mL, 5 mmol) was added dropwise during 5 min, using a syringe
and under stirring, to a solution of piperidine (0.42 g, 5 mmol) in an-
hyd THF (2 mL), previously cooled at 0 °C with an ice bath. The
cooling bath was removed, and the solution was allowed to warm to
r.t. After 15 min, a solution of 4f (1.93 g, 5 mmol) in anhyd THF (8
mL) was added in one portion and the mixture was heated under re-
flux for 4 h, until GC and TLC analyses (PE/Et2O, 1:1, v/v) showed
the disappearance of the starting compounds and the presence of
only two products. After a workup identical to that described above,
the crude residue was chromatographed on a short column, eluting
with PE/Et2O (1:1, v/v). The first eluted product was dithioacetal 2d
(1.32 g, 94%). The second eluted product was the pure (GC, TLC,
1H NMR) title compound (0.86 g, 91%): mp 47–48 °C (from
CH2Cl2/pentane) (Lit.9 mp 48 °C); MS: m/z = 189 (M+); spectral
data identical to those reported.3a
In entry 5 of Table 4 a solution of BuLi (2 mL, 5 mmol) was added
as described above to a solution of benzyl alcohol (0.54 g, 5 mmol)
in anhyd THF (5 mL), previously cooled at 0–5 °C. After the addi-
tion was complete, the solution was allowed to warm to r.t. and
stirred for 15 min. A solution of vinyl ester 4f (1.93 g, 5 mmol) in
anhyd THF (5 mL) was added in one portion. Stirring at r.t. was
maintained for a further 1 h until disappearance of the starting com-
pounds (GC; TLC: PE/Et2O, 9.8:0.2, v/v). The crude residue ob-
tained after the above workup was treated with cold pentane (3 mL)
and the insoluble substance was gathered by filtration. It was virtu-
ally pure (GC, TLC, 1H NMR) dithioacetal 2d (1.28 g, 91%). After
evaporation of pentane under reduced pressure, the virtually pure
1
(GC, TLC, H NMR) title compound was obtained in 93% yield
(0.99 g): bp 141–142 °C / 0.3 mmHg; MS: m/z = 212 (M+); physical
and spectral data are identical to those of an authentic sample of
commercial origin (Aldrich).
Entries 4 and 8 of Table 3 were also performed according to the
above procedure.
Entries 6–20 of Table 4 were performed according to the same pro-
cedure. In entries 9 and 10 dithioacetal 2d was separated by the es-
ters, i.e., phenyl benzoate and 4-chlorophenyl benzoate, by
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PAPER
1-(2,5-Dichlorophenyl)-2,2-bis(methylsulfanyl)vinyl Esters as Chemoselective Acylating Reagents
1207
chromatography of the crude residues on short columns, eluting
with PE/Et2O (9.8:0.2, v/v).
Anal. Calcd for C16H12O3Cl2 S (355.24): C, 54.10; H, 3.40; Cl,
19.96; S, 9.02. Found: C, 54.14; H, 3.45; Cl, 20.06; S, 8.93.
Phenyl Benzoate (12; R2 = R3 = Ph)
In entry 4 of Table 4 the mixture prepared as described above
starting from BuLi (2 mL, 5 mmol), phenol (0.47 g, 5 mmol) and
Benzoylation of Bifunctional Compounds 14, 16, 18
N-(2-Hydroxyethyl)benzamide (15)
Procedure A. A solution of vinyl ester 4f (1.93 g, 5 mmol) in anhyd
THF (8 mL) was added in one portion and under stirring, to a solu-
tion of aminoethanol (14; 0.30 g, 5 mmol) in the same solvent (2
mL), and the mixture was heated under reflux. The reaction was
complete after 4 h (GC; TLC: PE/Et2O, 1:1, vv). A workup identical
to that described above for the preparation of N-benzylbenzamide,
afforded a crude residue that was chromatographed on a short col-
umn, eluting with PE/Et2O (1:1, v/v). The first eluted product was
dithioacetal 2d (1.35 g, 96%). The second eluted product was the
pure (GC, TLC, 1H NMR) title compound 15 (0.80 g, 97%): mp 50–
51 °C (from PE) (Lit.9 mp 50 °C).
1-phenyl-2,2-(dimethylsulfanyl)vinyl benzoate (4a; 1.58 g,
5
mmol) in THF (10 mL) was heated under reflux. The reaction was
complete after 2 h. Because of the solubility of dithioacetal 2a in
pentane, the crude residue obtained after the usual workup was col-
umn chromatographed, eluting with PE/Et2O (9.5:0.5, vv). The first
eluted product was the title compound (0.71 g, 72%): mp 69 °C
(from PE); MS: m/z = 198 (M+); physical and spectroscopic data are
identical to those of an authentic sample of commercial origin (Al-
drich). The second eluted product was dithioacetal 2a (0.83 g,
78%).
Entries 1–3 of Table 4 were performed in the same conditions.
IR: n = 1670 and 3040 cm–1 (CO and OH).
1H NMR: d = 3.30–3.90 (m, 4H), 4.08 (br s, 1H; it disappeared after
treatment with D2O), 7.20–7.60, 7.60–8.05 (2 m, 3:2, 5H).
Details for the reaction conditions, yields, physical and spectral data
for esters 12 are reported in Table 4.
S-Benzyl Thiobenzoate (13; R2 = Ph, R3 = PhCH2)
MS: m/z = 165 (M+).
In entry 22 of Table 4 a solution of vinyl ester 4f (1.93 g, 5 mmol) in
anhyd THF (5 mL) was added at r.t., in one portion and under stir-
ring, to a suspension of lithium phenylmethanethiolate, prepared
at 0–5 °C starting from phenylmethanethiol (0.62 g, 5 mmol) in an-
hyd THF (5 mL) and BuLi (2 mL, 5 mmol). After 15 min at r.t., the
mixture was heated under reflux for 1 h, until disappearance of the
starting compounds (GC; TLC: PE/Et2O, 9.5:0.5, vv). Workup de-
scribed above for the preparation of benzyl benzoate afforded the
virtually pure dithioacetal 2d (1.31 g, 93%) and the title compound
(0.99 g, 89%): mp 39–40 °C (from pentane) (Lit. mp9 39.5 °C); MS:
m/z = 228 (M+).
Procedure B. A solution of BuLi (2 mL, 5 mmol) was added drop-
wise during 5 min, using a syringe and under stirring, to a solution
of 14 (0.30 g, 5 mmol) in anhyd THF (3 mL), previously cooled at
0 °C with an ice bath. The cooling bath was removed, and the yel-
low solution obtained was allowed to warm to r.t. After 15 min, a
solution of 4f (1.93 g, 5 mmol) in anhyd THF (8 mL) was added in
one portion. Stirring was maintained for a further 1 h, until comple-
tion of the reaction. The above workup afforded 2d (1.37 g, 98%)
and the pure title compound 15 (0.78 g, 94%).
N-(2-Sulfanylethyl)benzamide (17)
Entries 21,23–27 were performed according to the same procedure.
In entry 21 the vinyl ester was 4a. In entry 23 commercially avail-
able (Aldrich) sodium methanethiolate was used. Reactions carried
out with phenylmethanethiol and thiophenol in the absence of BuLi,
failed.
Procedure A. The reaction was carried out as described in the above
procedure A, starting from 2-aminoethanethiol (16) (0.38 g, 5
mmol) and vinyl ester 4f (1.93 g, 5 mmol) in anhyd THF (10 mL).
The reaction was complete after 4 h of reflux (GC; TLC: PE/Et2O,
1:1, vv). The above workup afforded 2d (1.35 g, 96%) and 17 (0.88
g, 97%): mp 69–70 °C (from pentane) (Lit.10 mp 70 °C).
Details for the reaction conditions, yields, physical and spectral data
for thiol esters 13 are reported in Table 4.
IR: n = 1656 cm–1 (CO).
1H NMR: d = 1.42 (t, J = 8.0 Hz, 1H; it disappeared after treatment
with D2O), 2.76 (q, J = 6.5 Hz, 2H), 3.63 (q, J = 6.5 Hz, 2H), 7.20–
7.63, 7.72–8.00 (2 m, 3:2, 5H).
Attempts to Benzoylate Benzyl Alcohol and Phenol with 4f in
the Presence or Absence of Methanesulfonic Acid
Procedure A. A mixture of benzyl alcohol (0.54 g, 5 mmol) and 4f
(1.93 g, 5 mmol) in anhyd THF (10 mL) was refluxed for 24 h. GC-
MS analysis showed the presence of the only starting compounds
that were recovered in 95% (1.85 g) and 82% (0.45 g) yields, re-
spectively.
MS: m/z = 181 (M+).
Procedure B. According to the procedure B described above for the
synthesis of 15, the mixture was prepared starting from BuLi (2 mL,
5 mmol), 2-aminoethanethiol (16) (0.38 g, 5 mmol) and 4f (1.93 g,
5 mmol) in anhyd THF (10 mL). The reaction was complete after 1
h of stirring at r.t. Compounds 2d and 17 were obtained in 89%
(1.25 g) and 94% (0.85 g) yields, respectively.
Attempts to benzoylate phenol under these conditions also failed.
The reactions failed also using anhyd dioxane instead of THF.
Procedure B. Methanesulfonic acid (0.48 g, 5 mmol) was added to
the mixture of benzyl alcohol (0.54 g, 5 mmol) and 4f (1.93 g, 5
mmol) in anhyd 1,2-dichloroethane (10 mL). After 2 h of reflux,
GC-MS analysis showed the disappearance of the starting com-
pounds and the presence of one only major product 9 and traces of
dithioacetal 2d and benzyl benzoate. The crude residue obtained af-
ter the usual workup was chromatographed through a small column,
eluting with PE/Et2O (9.5:0.5, v/v), to afford the thiol ester 9 in 70%
yield (1.25 g): bp 204–205 °C / 0.25 mmHg.
IR: n = 1697 and 1738 cm–1 (2 CO).
1H NMR: d = 2.47 (s, 3H), 7.23 (s, 1H), 7.60–8.10, 8.40–8.78 (2 m,
6:2, 8H).
4-Hydroxybenzyl Benzoate (19)
The mixture constituted of a solution of 4-hydroxymethylphenol
(18; 0.62 g, 5 mmol), BuLi (2 mL, 5 mmol) and 4f (1.93 g, 5
mmol) in anhyd THF (10 mL), was prepared as described for the
above preparation of 15 (procedure B) and then heated under reflux.
After 1 h, the reation was complete. The above workup afforded 2d
(1.27 g, 91%) and the title compound 19 (1.00 g, 87%): mp 70–71
°C (from CHCl3/pentane) (Lit.11 mp 81–82 °C).
IR: n = 1743, 3613 cm–1 (CO and OH).
1H NMR: d = 1.80 (s, 1H; it disappeared after treatment with D2O),
4.74 (s, 2H), 7.08–7.75, 8.10–8.35 (2 m, 7:2, 9H).
MS: m/z = 307 (M+ – SMe).
MS: m/z = 228 (M+).
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York

1208
I. Degani et al.
PAPER
(6) Chen, S. -T.; Chen, S. -Y.; Chen, S. -J.; Wang, K. -T.
Tetrahedron Lett. 1994, 35, 3583.
(7) Barbero, M.; Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.
J. Org. Chem. 1995, 60, 6017.
Acknowledgement
This work was supported by the National Research Council of Italy
(CNR), and by Ministero dell’Università e della Ricerca Scientifica
e Tecnologica (MURST).
(8) Degani, I.; Dughera, S.; Fochi, R.; Serra, E. J. Org. Chem.
1996, 61, 9572.
(9) Dictionary of Organic Compounds on CD-ROM, version 6:2;
Chapman & Hall Electronic Publishing Division: London,
1998.
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Article Identifier:
1437-210X,E;1999,0,07,1200,1208,ftx,en;Z01499SS.pdf
Synthesis 1999, No. 7, 1200–1208 ISSN 0039-7881 © Thieme Stuttgart · New York