A new synthesis of 2-substituted-1,3-dithianes from trichloromethyl compounds

Article abstract of DOI:10.1016/j.tetlet.2006.12.066

Trichloromethyl compounds are efficiently converted into 1,3-dithianes upon reaction with a disodium 1,3-propanedithiolate-1,3-propanedithiol mixture in DMF solution at 0 °C. This synthesis is limited to those substrates where the substituent attached to the trichloromethyl group is an electron-withdrawing group.

Full text of DOI:10.1016/j.tetlet.2006.12.066

Tetrahedron Letters 48 (2007) 1201–1204
A new synthesis of 2-substituted-1,3-dithianes
from trichloromethyl compounds
a
a
a
Nancy Gonz a´ lez Rivera, David Corona Becerril, Carlos Guadarrama-P e´ rez,
b
b
a,
*
Adrian Covarrubias-Zu n˜ iga, Jos e´ Gustavo Avila-Z a´ rraga and Mois e´ s Romero-Ortega
a
Departamento de Qu ı´ mica Org a´ nica, Facultad de Qu ı´ mica, Universidad Aut o´ noma del Estado de M e´ xico,
Paseo Col o´ n/Paseo Tollocan, Toluca Estado de M e´ xico, Mexico
b
Facultad de Qu ı´ mica, Universidad Nacional Aut o´ noma de M e´ xico, Ciudad Universitaria, DF, Mexico
Received 10 November 2006; revised 4 December 2006; accepted 12 December 2006
Abstract—Trichloromethyl compounds are efficiently converted into 1,3-dithianes upon reaction with a disodium 1,3-propanedi-
thiolate-1,3-propanedithiol mixture in DMF solution at 0 ꢀC. This synthesis is limited to those substrates where the substituent
attached to the trichloromethyl group is an electron-withdrawing group.
ꢁ
2006 Elsevier Ltd. All rights reserved.
The generation of 1,3-dithianes is an important process
in modern synthetic organic chemistry. Among the
complexes generated by the desulfurization of 2-alky-
nyl-1,3-ditianes. In the context of developing a syn-
1
7e
most important characteristics of these compounds, is
their stability under both acidic and basic conditions
thetic utility of trichloromethyl compounds, we have
reported that a variety of this substrates bearing elec-
tron-withdrawing groups react with sodium thiopheno-
2
and their potential utility in organic synthesis as acyl
carbanion equivalents in carbon–carbon bond forming
8
a
8b
late or sodium thiolacetate in the presence of the
thiol to give the corresponding phenylthiomethyl or
thiolacetylmethyl derivatives. Given that in at least
3
,4
reactions. In general, 1,3-dithianes are prepared by
Br o¨ nsted or Lewis acid catalyzed condensation of
aliphatic or aromatic aldehydes with 1,3-propanedithiol
8
c
one instance, a bisphenylthiomethyl species was an
intermediate in the formation of the phenylthiomethyl
compound, it was reasonable to expect that 1,3-dithi-
anes should be obtainable from trichloromethyl com-
pounds and 1,3-propanedithiol under appropriate
conditions.
5
a
5b
5c
5i
using for example, PTSA,
BF –OEt ,
ZnCl2,
3
2
5
d
5e
5f
5g
5h
ZrCl –SiO , LiBF4, InCl , NBS, I , Y(OTf)3
4
2
3
2
5
j
6
or RuCl3. Recently, Ricci reported a facile synthesis
of chiral oxazolidine-1,3-dithianes and their use as
ligands for asymmetric catalysis. Although some of
these syntheses are carried out under mild conditions,
all of them necessarily require the use of aldehydes.
Interestingly, although a great variety of methods are
known for the preparation of 2-acyl-1,3-dithianes, the
most important, is the direct acylation of 2-lithio-1,3-
dithiane derivatives with nitriles or alkyl chlorofor-
The initial experiments were carried out using the tri-
9
chloroacetylpyrrole 1a (Scheme 1). As expected, the
reaction of 1a with 6 equiv of 1,3-propanedithiol and
4 equiv of sodium hydride in anhydrous THF at room
temperature did indeed give the 1,3-dithiane 2a, but only
in a 24% yield. The major product isolated (64%) was
the 3-mercaptopropylthiomethyl compound 3a. Addi-
tionally, disulfide 5 was also obtained.
7
a–c
mates.
Additionally, Rozen reported that 2-ethoxy-
carbonyl-1,3-dithianes reacted with BrF to form the
3
d
7
corresponding a,a-difluoro derivatives, and Takeda
developed the preparation of alkylcyclopropanes by
the reaction of terminal olefins with the alkylcarbene
It was thought that the reductive cleavage of 2a (Scheme
2
) might be a function of temperature and therefore low
temperature conditions were studied.
Keywords: Trichloromethyl compounds; 2-Trichloroacetylpirrole; 1,3-
Propapnedithiol; 1,3-Dithiane derivatives.
*
Corresponding author. Tel.: +52 722 2175109; fax: +52 722
173890; e-mail: romero.ortega@usa.net
The reaction of 1a with 5 equiv of 1,3-propanedithiol
and 3 equiv of sodium hydride in anhydrous THF at
2
0040-4039/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.066

1202
N. G. Rivera et al. / Tetrahedron Letters 48 (2007) 1201–1204
S
NaH
+
N
H
S
N
H
S
SH
+
S S
o
THF, 25 C
O
O
5
2a
3a
CCl3
+
N
H
SH SH
O
Cl
NaH
THF, - 40 o
1
a
2a
+
C
N
H
Cl
O
4
a
Scheme 1. Reductive reaction of 1a.
S
S
S
N
H
S
N
S
S
N
S
S
O
O
O
S
S
H
H
2
a
SH SH
3a
+
5
Scheme 2. Reductive cleavage of 2a.
ꢀ
40 ꢀC rapidly produced (20 min) dichloromethylpyr-
role 4a as the major product (71%) and only traces of
,3-dithiane 2a. After considerable experimentation it
ditions trichloromethyl compounds 1b–f were also rap-
idly and efficiently converted into the corresponding
1,3-dithianes 2b–f (Table 1). Several aspects of the data
given in Table 1 deserve comment. Firstly, this method
is operationally simple. Secondly, although the reaction
is very useful for the preparation of the 1,3-dithianes
from trichloromethyl compounds, it is limited to those
1
was found that reaction of 1a with 5 equiv of 1,3-pro-
panodithiol and 8 equiv of sodium hydride in DMF
solution at ꢀ5 ꢀC reproducibly gave 2a as the major
1
0
product (Table 1, entry 1). Under these optimized con-
Table 1. Formation of 1,3-dithianes 2 from trichloromethyl compounds 1
NaH
R
O
CCl3
+
S
S
SH SH
o
DMF, 0 C
1
R
2
R =
O
O
O
O
N
H
N
H
a
b
c
d
CH3
N
CO CH
N
N
2
3
CH3
CN
H
N
N
N
CO CH
2
3
e
f
g
h
i
a
Entry
Substrate
Time (min)
Product
Yield (%)
Mp (ꢀC)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
20
30
15
15
25
15
5
2a
2b
92
82
85
92
88
132–133
87–88
Oil
150–152
Oil
2c
2d
2e
2f
2g
90
b
113–114
Oil
1g
1h
1i
No reaction
No reaction
a
Yields refer to pure isolated products, properly characterized by spectral data.
Difficulties were encountered to obtain the product in a pure form.
b

N. G. Rivera et al. / Tetrahedron Letters 48 (2007) 1201–1204
1203
cases where the substituent attached to the trichloro-
methyl group is a carbonyl moiety (entries a–d) or an
electron-withdrawing heterocyclic system (e.g., entries
e and f). However, with trichloroacetonitrile (entry g),
the reaction was very fast even at low temperatures
and difficulties were encountered to obtain the product
in a pure form. The reaction fails to occur with com-
pounds such as trichlorotoluene (entry h) and chloro-
form (entry i), where such activation is absent. Lastly,
this method may offer a strategically similar but tacti-
cally complementary alternative for the preparation of
Tetrahedron Lett. 1996, 37, 4621; (e) Yadav, J. S.; Reddy,
B. S.; Pandey, S. K. Synlett 2001, 238; (f) Yadav, J. S.;
Reddy, B. S.; Pandey, S. K. Synth. Commun. 2002, 32, 715;
(
g) Kamal, A.; Chouhan, G. Synlett 2002, 474; (h)
Firouzabadi, H.; Iranpoor, H.; Hazarkhani, H. J. Org.
Chem. 2001, 66, 7527; (i) Kanta, D. S. Tetrahedron Lett.
2
004, 45, 2339; (j) Tetrahedron Lett. 2004, 45, 7719.
6
. Capito, E.; Bernardi, L.; Comes-Franchini, M.; Fini, F.;
Fochi, M.; Polliano, S.; Ricci, A. Tetrahedron: Asymmetry
2005, 16, 3232.
7. (a) Seebach, D. Synthesis 1969, 1, 17; (b) Corey, E. J.;
Erickson, B. W. J. Org. Chem. 1971, 36, 3553; (c) Smith,
A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37, 365; (d)
Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003,
1
,3-dithianes bearing an electron-withdrawing group at
C-2 without the use of aldehydes.
6
8, 8287; (e) Takeda, T.; Kuroi, S.; Ozaki, M.; Tsubouchi,
A. Org. Lett. 2004, 6, 3207.
In summary, we have demonstrated that trichloromethyl
compounds, bearing a highly carbanion stabilizing sub-
stituent, are efficiently converted into the corresponding
8
. (a) Romero-Ortega, M.; Fuentes, A.; Gonz a´ lez, C.;
Morales, D.; Cruz, R. Synthesis 1999, 225; (b) Romero-
Ortega, M.; Reyes, H.; Covarrubias-Z u´ n˜ iga, A.; Cruz, R.;
Avila-Zarraga, J. G. Synthesis 2003, 2765; (c) Guzm a´ n,
A.; Romero, M.; Talam a´ s, F. X.; Villena, R.; Greenhouse,
R.; Muchowski, J. M. J. Org. Chem. 1996, 61, 2470.
1
,3-dithiane derivatives using a disodium 1,3-propanedi-
thiolate-1,3-propanedithiol mixture in DMF solution at
0
ꢀC. This process is expected to be particularly useful in
those instances where the heteroaryl or the a-carbonyl
aldehydes, the usual precursors of these 1,3-dithiane
derivatives, are not readily available.
9. 2-Trichloroacetylpyrole 1a, ethyl trichloroacetate 1c, tri-
chloroacetonitrile 1g, trichlorotoluene 1h, 1,3-propane-
dithiol and sodium hydride were purchased from Aldrich
and used as received. Compounds 1b, 1d–f were synthe-
8
sized by literature methods.
1
0. Typical procedure: To a stirred suspension of sodium
hydride (50% suspension in mineral oil) (384 mg, 8 mmol)
in anhydrous DMF (25 mL) under argon, was added 1,3-
propanedithiol (541 mg, 0.5 mL, 5 mmol) in DMF (5 mL)
at room temperature. After 10 min, the reaction mixture
was cooled to 0 ꢀC and 2-trichloroacetylpyrrole 1a
Acknowledgments
Financial support for this research from ‘Coordinaci o´ n
de Investigaci o´ n y Estudios Avanzados de la Universi-
dad Aut o´ noma del Estado de M e´ xico’ (Clave 1915/
004) is gratefully acknowledged. The authors wish to
thank Professor Joseph M. Muchowski from UNAM
for helpful discussions and his interest in our work.
(
212 mg, 1 mmol) in DMF (5 mL) was added dropwise.
2
The reaction was stirred under argon for 20 min at 0 ꢀC
and monitored by TLC (hexane:AcOEt, 80:20). The
reaction was quenched with satd aq ammonium chloride
solution, the product was extracted with AcOEt
(
2 4
3 · 50 mL), the organic layer was dried over Na SO .
Following solvent removal in vacuo, the product was
purified by silica gel column chromatography (hexane–
AcOEt, 85:15) to afford pure 2-(2 -pyrroloyl)-1,3-dithiane
References and notes
0
1
2
. (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1969, 8, 639;
b) Grobel, B. T.; Seebach, D. Synthesis 1977, 357; (c)
Bulman Page, O. C.; Van Niel, M. B.; Prodger, J. C.
Tetrahedron 1989, 45, 7643.
. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991; pp
2
a 187 mg (88%) as a solid, mp 132–133 ꢀC (hexanes–
(
1
dichloromethane). H NMR (300 MHz, CDCl ) d: 2.05–
3
2
.19 (m, 2H), 2.71 (dt, 2H), 3.46 (dt, 2H), 4.86 (s, 1H), 6.30
13
(
m, 1H), 6.92 (m, 1H), 7.08 (m, 1H). C (75 MHz, CDCl
3
)
d: 184.11, 128.69, 125.91, 116.96, 111.10, 42.75, 29.70,
+
2
7.05, 25.25. EIMS m/z 213 (M , 45), 119 (100).
1
3
78–207; (b) Corey, E. J.; Seebach, D. J. Org. Chem. 1966,
1, 4097; (c) Eliel, E. L.; Morris-Natschke J. Am. Chem.
Compound 2b was purified by silica gel chromatography
using hexane–AcOEt 97:3, it was obtained as a solid, mp
Soc. 1984, 106, 2937.
1
8
7–88 ꢀC
(hexanes–dichloromethane).
H
NMR
3
. (a) Corey, E. J.; Seebach, D. J. Org. Chem. 1975, 40, 231;
(
300 MHz, CDCl
3
) d: 1.96–2.20 (m, 2H), 2.62–2.83 (m,
H), 3.37 (td, 2H), 5.16 (s, 1H), 7.42–7.61 (m, 3H), 7.92–
(
1
b) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl.
965, 4, 1075, 1077.
. (a) Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31,
815; (b) Hauptmann, H.; Campos, M. M. J. Am. Chem.
Soc. 1950, 72, 5815; (c) Seebach, D.; Kolb, M. Chem. Ind.
2
7
1
1
3
.97 (m, 2H). C (75 MHz, CDCl
28.6, 42.4, 26.3, 25.0. EIMS m/z 224 (M , 20), 119 (100).
3
) d: 192.6, 134.5, 133.3,
4
+
5
Compound 2c was purified by silica gel chromatography
using hexane–AcOEt 95:5, it was obtained as an oil, H
NMR (300 MHz, CDCl ) d: 1.32 (t, 3H), 1.96–2.20 (m,
1
(London) 1974, 687; (d) Ong, B. S. Tetrahedron Lett. 1980,
4225; (e) Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24,
1289; (f) Ku, B.; Oh, D. Y. Synth. Commun. 1989, 19, 433;
3
2
H), 2.60 (m, 2H), 3.41 (m, 2H), 4.17 (s, 1H), 4.24 (c, 2H).
1
3
C (75 MHz, CDCl
3
) d: 169.8 (C), 61.6, 40.0, 25.9, 25.0,
+
(
(
g) Ong, B. S.; Chan, T. H. Synth. Commun. 1977, 7, 283;
h) Corey, E. J.; Simoji, K. Tetrahedron Lett. 1983, 24,
1
4.0. EIMS m/z 192 (M , 65), 119 (100). Compound 2d
was purified by silica gel chromatography using hexane–
1
9
1
69; (i) Komatsu, N.; Uda, M.; Suzuki, H. Synlett 1995,
84; (j) Choudray, B. M.; Sudha, Y. Synth. Commun.
996, 2993.
AcOEt 70:30, it was obtained as a solid, mp 150–152 ꢀC.
1
3
H NMR (300 MHz, CDCl ) d: 2.11 (m, 2H), 2.73 (m,
2
7
1
1
H), 3.38 (m, 2H), 5.01 (s, 1H), 7.28–7.32 (m, 2H), 7.40–
.43 (m, 1H), 7.99 (d, 1H), 8.36–8.39 (m, 1H), 8.73 (br,
H). C (75 MHz, CDCl
23.9, 122.9, 122.5, 114.7, 111.4. 46.66, 29.39, 27.82, 25.48.
5
. (a) Djerassi, C.; Gorman, M. J. Am. Chem. Soc. 1953, 75,
704; (b) Wilson, G. E., Jr.; Huang, M. G.; Schloman, W.
3
1
3
3
) d: 191.2, 136.2, 131.7, 126.0,
W. J. Org. Chem. 1968, 33, 21343; (c) Evans, D. A.;
Truesdale, L. K.; Grimm, K. G.; Nesbit, S. L. J. Am.
Chem. Soc. 1977, 99, 5009; (d) Pantey, H. K.; Margan, S.
+
EIMS m/z 263 (M , 12), 144 (100). Compound 2e was

1204
N. G. Rivera et al. / Tetrahedron Letters 48 (2007) 1201–1204
purified by silica gel chromatography using hexane– using hexane–AcOEt 95:5; it was obtained as a solid, mp
1
1
AcOEt 85:15, it was obtained as an oil. H NMR
300 MHz, CDCl ) d: 2.12–2.20 (q, J = 5.58 Hz, 2H),
113–114 ꢀC (hexanes–dichloromethane).
H
NMR
(
(300 MHz, CDCl ) d: 211–217 (m, 2H), 2.81–2.90 (m,
3
3
2
1
1
2
.73–2.84 (m, 2H), 3.58–3.66 (m, 2H), 3.95 (s, 3H), 4.01 (s,
2H), 3.20 (s, 3H), 3.23 (s, 3H), 3.28–3.33 (m, 2H), 4.89 (s,
1
3
13
H), 5.30 (s,1H), 9.18 (s, 1H). C (75 MHz, CDCl
3
) d:
1H), 8.52 (s, 1H), C (75 MHz, CDCl
3
) d: 175.1 (C),
), 36.3 (CH ),
28.7 (CH ), 25.4 (CH ). EIMS m/z 242 (M , 12), 209
71.6, 171.5, 165.3, 163.5, 159.5, 118, 53.3, 52.98, 43.23,
165.87 (CH), 164.2 (C), 49.3 (CH), 36.4 (CH
2
2
+
+
8.9, 28.1, 26.2. EIMS m/z 314 (M , 5), 210 (100).
3
2
Compound 2f was purified by silica gel chromatography
(100).