Atypical oxidation reaction by thionyl chloride: Easy two-step synthesis of N-alkyl-1,4-dithiines

Article abstract of DOI:10.1080/00397910600943600

Easy two-step synthesis of a series of dithiines was performed from succinic anhydride via cyclization of the corresponding 4-(alkylamino)-4- oxobutanoic acids (succinamic acids). The reaction, carried out in polar aprotic solvents, gave 4,8-dithiine-indacene-1,3,5,7-tetraones (diimides 3) via 3,7-bis-4,8-dithia-indacene-1,5-diones (diisoimides 2), which could be isolated. Surprisingly, in this reaction, thionyl chloride appeared as an oxidant, and this process seemed to be useful for the syntheses of S-containing heterocyclic compounds such as 1,4-dithiins. A mechanistic pathway was considered. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600943600

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Atypical Oxidation Reaction by Thionyl
Chloride: Easy Two‐Step Synthesis of
N‐Alkyl‐1,4‐dithiines
Alain Valla a , Dominique Cartier a , Frédéric Zentz a & Roger Labia a
a Chimie et Biologie des Substances Naturelles CNRS , Quimper, France
Published online: 24 Nov 2006.
To cite this article: Alain Valla , Dominique Cartier , Frédéric Zentz & Roger Labia (2006) Atypical Oxidation
Reaction by Thionyl Chloride: Easy Two‐Step Synthesis of N‐Alkyl‐1,4‐dithiines, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:23, 3591-3597, DOI:
10.1080/00397910600943600
To link to this article: http://dx.doi.org/10.1080/00397910600943600
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Synthetic Communicationsw, 36: 3591–3597, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943600
Atypical Oxidation Reaction by Thionyl
Chloride: Easy Two-Step Synthesis of
N-Alkyl-1,4-dithiines
´ ´
Alain Valla, Dominique Cartier, Frederic Zentz, and
Roger Labia
Chimie et Biologie des Substances Naturelles CNRS, Quimper, France
Abstract: Easy two-step synthesis of a series of dithiines was performed from succinic
anhydride via cyclization of the corresponding 4-(alkylamino)-4-oxobutanoic acids
(succinamic acids). The reaction, carried out in polar aprotic solvents, gave 4,8-
dithiine-indacene-1,3,5,7-tetraones (diimides 3) via 3,7-bis-4,8-dithia-indacene-1,5-
diones (diisoimides 2), which could be isolated. Surprisingly, in this reaction,
thionyl chloride appeared as an oxidant, and this process seemed to be useful for the
syntheses of S-containing heterocyclic compounds such as 1,4-dithiins. A mechanistic
pathway was considered.
Keywords: Dithiine, imide, isoimide, thionyl chloride
In previous works,[1–3] we have reported on the syntheses and the biological
properties of a series of maleimides and succinimides. To obtain other
derivates possessing higher biological activities, we have studied the cycliza-
tion of 4-(alkylamino)-4-oxobutanoic acids 1 (acyl chlorides), easily obtained
from aliphatic amines and succinic anhydride. Surprisingly, the cyclization of
these via the acyl chlorides, generated by thionyl chloride, did not lead to the
corresponding succinimides (Fig. 1).
Received in the U.K. January 17, 2006
Address correspondence to Alain Valla, Chimie et Biologie des Substances
´
Naturelles FRE 2125 CNRS 6, rue de l’Universite 29000, Quimper, France. E-mail:
alain.valla@cegetel.net
3591

3592
A. Valla et al.
Figure 1.
The reaction, carried out in polar aprotic solvents such as dioxane, gave
4,8-dithiine-indacene-1,3,5,7-tetraones (diimides 3) via 3,7-bis-4,8-dithia-
indacene-1,5-diones (diisoimides 2). The diisoimides 2 could be considered
as the kinetically controlled compounds and may be isolated (as rose
crystals) only when they had a low solubility in the reaction medium.
Otherwise, a rapid isomerization occurred and led to the (green) diimides 3,
which were always insoluble (Fig. 2).
Several publications have been devoted to the ring conformation and
electronic properties of 1,4-diithins, and it was also reported that 1,4-dithiins
could be used as synthons (dienophiles) in cycloaddition reactions.[4]
In the literature, only a few articles referred to the syntheses of
1,4-dithiines,[5–12] and we chose an easy two-step process, depicted by Michaılidis
¨
et al.[13]
This methodology, which was reported without experimental details, has
also been used for the preparation of the ethyl, propyl, and t-butyl derivatives
by Hayakawa et al.[14] and Kim et al.[15]
In these reports, no mechanistic pathway was suggested. Only one patent
described a biological use of some 1,4-dithiin-2,3,5,6-tetracarboxydiimides as
anthelmintics.[16]
This situation prompted us to investigate the mechanistic pathway of this
reaction.
CHEMISTRY
Taking in account our experimental data, we proposed a mechanistic pathway
involving the conversion of the succinamic acids 1 into isosuccinimides 4,
Figure 2. a) R ¼ benzyl, b) R ¼ cyclohexyl, c) R ¼ isopropyl, d) R ¼ propyl, and
e) R ¼ butyl.

Atypical Oxidation Reaction by Thionyl Chloride
3593
Figure 3.
which reacted with thionyl chloride to provide sulfochlorides 5. Two linked
molecules of these furnish the disulfoxides 6. Two concomitant attacks of
the Cl anion (liberated in the mixture in the precedent stage) led to the disulf-
oxides 7, which, via a Pummerer-like reaction and simultaneous elimination
of HCl, led to the diisomaleimide-dithiines 2 (Fig. 3). These isomerize to
the more stable dithiines 3.
A comparable reaction has been depicted by Higa and Krubsack[17] (Fig. 4).
Thionyl chloride, in this reaction, appeared as an oxidant, and this process
seemed to be useful for the syntheses of S-containing heterocyclic compounds
such as 1,4-dithiins. Furthermore, the products were easily isolated and
directly recrystallized.
Figure 4.

3594
A. Valla et al.
EXPERIMENTAL
Melting points were taken on a Leitz 350 heated-stage microscope and are not
1
corrected. H NMR spectra were recorded at 400 MHz on Bruker Avance
DPX 400 and Bruker WP80 DS instruments. Chemical shifts were reported
in parts per million (ppm) (d) relative to TMS. IR spectra were run on a
Bruker IF 55 spectrometer.
General Procedure for the Preparation of Compounds 1
Succinic anhydride (15 mmol) was dissolved into 10 mL of dioxane, and
15 mmol of the correspondent amine in 10 mL of dioxane were slowly
added. The solution was warmed at 808C for 30 min, and the succinamic
acid 1 crystallized by cooling. The white crystals were filtered off, dried,
and recrystallized from dioxane.
Data
la: mp 1448C (lit.: 137.5–138.2[18]) (85%). IR (KBr): nCO 1691; 1642 cm21
.
1H NMR. (DMSO d-6): 4.27 (m, 2H, CH2); 2.46 (m, 2H, CH2); 2.38 (m, 2H,
CH2); 7.30 (m, 5H, Ar). Anal. calc. for C11H13NO3: C, 63.76; H, 6.32; N, 6.76;
O, 23.16; found: C, 63.51; H, 6.41; N, 6.68; O, 23.4.
1b: mp 1718C (lit.: 166.5–167[18]) (90%). IR (KBr): nCO 1697; 1642 cm21
.
1H NMR (CD3COCD3): 2.56 (t, J ¼ 7 Hz, 2H, CH2); 2.44 (t, J ¼ 7 Hz, 2H,
CH2); 1.89 (m, 3H, CH2 þ CH cyclohexane); 1.72 (m, 2H, CH2 cyclohexane);
1.59 (m, 2H, CH2 cyclohexane); 1.33 (m, 2H, CH2 cyclohexane); 1.19 (m, 4H,
2 ꢀ CH2cyclohexane). Anal. calc. for C10H17NO3: C, 60.28; H, 8.60; N, 7.03;
O, 24.09; found: C, 60.01; H, 8.80; N, 6.88; O, 24.31.
1c: mp 1088C (lit.: 105–107[18,19]) (90%). IR (KBr): nCO 1731; 1641 cm21
.
1H NMR (DMSO d-6): 3.80 (m, 1H, CH); 2.40 (t, J ¼ 7 Hz, 1H, CH2); 2.26
(t, 2H, J ¼ 7 Hz, CH2); 1.02 (d, 6H, CH3). Anal. calc. for C7H13NO3: C,
52.82; H, 8.23; N, 8.80; O, 30.15; found: C, 52.69; H, 8.44; N, 8.69; O, 30.18.
1d: mp 1018C[14] (85%). IR (KBr): nCO 1714; 1642 cm21. 1H NMR (DMSO
d-6): 2.98 (m, 2H, CH2); 2.41 (t, J ¼ 7 Hz, 2H, CH2); 2.29 (t, 2H, J ¼ 7.2 Hz,
CH2); 1.39 (m, 2H, CH2); 0.83 (t, 6H, J ¼ 7.2 Hz, CH3). Anal. calc. for
C7H13NO3: C, 52.82; H, 8.23; N, 8.80; O, 30.15; found: C, 52.72; H, 8.42;
N, 8.65; O, 30.21.
1e: mp 968C[20] (85%). IR (KBr): nCO 1695; 1650 cm21 1H NMR (DMSO
d-6): 3.02 (m, 2H, CH2); 2.40 (t, J ¼ 7.2 Hz, 2H, CH2); 2.28 (t, 2H,

Atypical Oxidation Reaction by Thionyl Chloride
3595
J ¼ 7.2 Hz, CH2); 1.35 (m, 2H, CH2); 1.26 (m, 2H, CH2); 0.86 (t, 6H,
J ¼ 7.2 Hz, CH3). Anal. calc for C8H15NO3: C, 55.47; H, 8.73; N, 8.09; O,
27.71; found: C, 55.22; H, 8.99; N, 7.82; O,27.97.
General Procedure for the Preparation of Compounds 2
Succinamic acid (1 g) was dissolved into 10 mL of ether, and 13 mL of thionyl
chloride was slowly added. The solution was allowed to sit at rt for 6 h, and the
diisoimide was filtered off, washed with 2 ꢀ 5 mL of ether, and recrystallized.
Data
1
2a: Rose crystal, mp: 2108C. IR: nCO 1791, 1696 cm21. H NMR (CDCl3):
4.78 (s, 4H, CH2); 7.31–7.38 (m, 10H, Ar). 13C NMR (DMSO d6): CO:
163.1; CN: 162.5; Cq: 134.3, 129.2, 127.3; CH: 129.0, 128.6, 127.7; CH2:
43.0. Anal. calc. for C22H14N2O4S2: C, 60.82; H, 3.25; N, 6.45; O, 14.73;
S, 14.76; found: C, 60.60; H 3.3; N, 6.42; O, 15.03; S, 14.64.
1
2b: Rose crystals, mp: 2288C. IR: nCO 1789, 1774, 1701 cm21. H NMR
(CDCl3): 1.23–2.13 (m, 20H, CH2); 3.75–3.82 (m, 2H, CH). 13C NMR
(DMSO d6): CO: 160.5; CN: 130.2; Cq: 127.5, 126.5; CH: 49.7; CH2: 32.5,
25.0, 24.9. Anal. calc. for C20H22N2O4S2: C, 57.39; H, 5.30; N, 6.69;
O,15.28; S, 15.32; found: C, 57.21; H, 5.53; N, 6.42; O, 15.73; S, 15.11.
General Procedure for the Preparation of Compounds 3
Succinamic acid (1g) was dissolved into 10 mL of dioxane, and 13 mL of
thionyl chloride was slowly added. The solution was allowed to sit at rt for
6 h, and the diisoimide was filtered off, washed with 2 ꢀ 5 mL of ether, and
recrystallized.
Data
1
3a: Green pellets, mp: 2248C. IR: nCO 1712. 1697 cm21. H NMR (CDCl3):
4.64 (s, 4H, CH2); 7.31–7.35 (m, 10H, Ar). 13C NMR (DMSO d6): CH2:
41.95; Cq: 135.9, 134.2; CH: 132.1, 128.8, 127.8; CO: 164.3. Anal. calc.
for C22H14N2O4S2: C, 60.82; H, 3.25; N, 6.45; O, 14.73; S, 14.76; found:
C, 60.60; H, 3.52; N, 6.43; O, 14.91; S, 14.54.
1
3c: Green pellets, mp: 2208C. IR: nCO 1713, 1696 cm21. H NMR (DMSO
d-6): 1.35 (d, 12H, CH3, J ¼ 6.9 Hz); 4.23–4.30 (m, 2H, CH) 13C NMR

3596
A. Valla et al.
(DMSO d6) CO: 164.0; Cq: 130.3; CH: 43.6; CH3: 19.6. Anal. calc. for
C14H14N2S2: C, 49.69; H, 4.17; N, 8.28; O, 18.99; S, 18.99; S, 18.95;
found: C, 49.54; H, 4.28; N, 8.00; O, 19.03; S, 19.15.
1
3d: Green pellets, mp: 2228C. IR: nCO 1714, 1693 cm21. H NMR (DMSO
d-6): 0.88 (t 6H, CH3, J ¼ 7.09 Hz). 13C NMR (DMSO d6): CO: 164.3; Cq:
130.4; CH2: 21.0, 40.4; CH3: 11.1. Anal. calc. for C14H14N2O4S2: C, 49.69;
H, 4.17; N, 8.28; O, 18.99; S, 18.95; found: C, 49.30; H, 4.27; N, 8.12; O,
19.34; S, 18.97
3e: Green pellets, mp: 2888C. IR: nCO 1713, 1693 cm21 1H NMR (DMSO
d-6): 0.91 (t 6H, CH3, J ¼ 7.35 Hz); 1.26–1.35 (m, 4H, CH2); 1.51–1.58
(m, 4H, CH2); 3.49 (t, 4H, CH2, J ¼ 7.05 Hz). 13C NMR (DMSO d6): CO:
164.3; Cq: 130.4; CH2: 19.3, 29.6, 40.4; CH3: 13.4. Anal. calc. for
C16H18N2O4S2: C, 52.44; H, 4.95; N, 7.64; O, 17.46; S, 17.50; found: C,
52.22; H, 5.15; N, 7.51; O, 17.75; S, 17.37.
ACKNOWLEDGMENTS
We gratefully acknowledge Dr. Masson and Dr. Gulea (Laboratoire de Chimie
´
Moleculaire et Thio-organique, Caen, France) for helpful discussions about
the mechanistic pathway.
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