Cyclization reactions of vicinal dianions with 1,2-dielectrophiles: Synthesis and properties of the first 2,3-diiminothietanes

Article abstract of DOI:10.1039/a906913e

Reaction of dilithiated ethyl thioglycolate with bis(imidoyl chloride)s of oxalic acid afforded the first 2,3-diiminothietanes, which underwent ring expansion reactions upon treatment with ethyl thioglycolate or dimethyl acetylene-dicarboxylate.

Full text of DOI:10.1039/a906913e

Cyclization reactions of vicinal dianions with 1,2-dielectrophiles: synthesis and
properties of the first 2,3-diiminothietanes†
Peter Langer*a and Manfred Döringb
a
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen,
Germany. E-mail: planger@uni-goettingen.de
Institut für Anorganische und Analytische Chemie der Universität Jena, August-Bebel-Strasse 2, 07743 Jena,
b
Germany
Received (in Cambridge, UK) 25th August 1999, Accepted 14th October 1999
Reaction of dilithiated ethyl thioglycolate with bis(imidoyl
chloride)s of oxalic acid afforded the first 2,3-diiminothi-
etanes, which underwent ring expansion reactions upon
treatment with ethyl thioglycolate or dimethyl acetylene-
dicarboxylate.
1 equiv. of the dianion. However, a change of the reaction
conditions (slow addition of the dianion to 2a) and of the work-
up procedure (filtration under inert conditions rather than
aqueous work-up) did not provide the desired product 4. Similar
disappointing results were obtained when the dianion of prop-
2-enethiol was employed.
Four-membered ring lactams and lactones represent pharmaco-
logically important compounds which, due to their ring strain,
readily undergo ring-expansion or -opening reactions.1 To the
best of our knowledge, azetidine-2,3-diones represent the only
known heterocycles which combine the biologically significant
structural features of a four-membered ring and a 1,2-dione
subunit.2 Due to their high reactivity, oxetanes and thietanes
containing a 1,2-dione subunit are unknown to date. However,
a few examples of the corresponding heterocyclic 1,2-diimines
have been reported.3,4 We envisaged that reaction of 1,2-di-
anions with oxalic acid dielectrophiles could provide a
convenient synthesis of four-membered ring heterocycles
containing a 1,2-dione or related subunit. Much to our surprise,
until recently cyclization reactions of oxalic acid dielectrophiles
with 1,1-, 1,2-, 1,3- or 1,4-dianions had not been reported.5 This
is presumably due to the fact that these reactions can suffer from
several drawbacks, such as overaddition of the nucleophile,
expulsion of CO or decomposition. We have recently shown
that bis(imidoyl chloride)s of oxalic acid [Cl2C2(NR)2] repre-
sent useful C2 building blocks in cyclization reactions with
1,3-dianions.6 Herein we report that bis(imidoyl chloride)s can
be cyclized with 1,2-dianions equally successfully. To the best
of our knowledge, these transformations represent the first
examples of cyclization reactions of 1,2-dianions with 1,2-di-
electrophiles to date.7
Much to our satisfaction, reaction of bis(imidoyl chloride) 2a
with the dianion of ethyl thioglycolate 5b9b afforded the
2,3-diiminothietane 6a in 30% yield (Scheme 2).‡ Thietane 6a
could be readily isolated by chromatography as it represented
the only Et2O-soluble product formed in the reaction. In
contrast, reaction of 5b with oxalyl chloride or diethyl oxalate
gave polymeric material under a variety of conditions. In
contrast to the open-chained derivative Me(PhHN)CNCH-
CO2Et, thietane 6a adopted a 3-iminopropionate- rather than a
3-aminocrotonate structure, presumably for electronic reasons.
Variable temperature 1H NMR (CDCl3) showed that
2,3-diiminothietane 6a represented a structurally mobile com-
pound due to E/Z isomerization of the imino group at C-3.§
Interestingly, treatment of bis(imidoyl chloride)s 2b,c with
the dianion 5b resulted in formation of the 1,2-dithioles 7b and
7c in 41 and 40% yields, respectively (Scheme 2).10 The
formation of the dithioles 7 can be explained by initial
cyclization to give the 2,3-diiminothietanes 6, subsequent ring
opening, addition of a second equivalent of the dianion,
cyclization and expulsion of EtOAc.
In order to elucidate the mechanism of the conversion of
2,3-diiminothietanes 6 into the bisthioles 7, cycloaddition
reactions of 6a were studied. When a toluene solution of
thietane 6a and dimethyl acetylenedicarboxylate (DMAD) was
stirred at 80 °C for 12 h, the yellow coloured thioimino ether 9
was isolated in 64% yield (Scheme 3). The formation of
cycloadduct 9 can be explained by initial ring-opening of
thietane 6a to give the 1,4-zwitterionic intermediate 8 and
subsequent regioselective cyclization of the latter with
DMAD.¶ Bisthiole 7a was isolated in 58% yield when a toluene
Our first aim was the preparation of 2,3-diiminothietanes by
reaction of dilithiated thiols with bis(imidoyl chloride)s.4,8
Unfortunately, treatment of bis(imidoyl chloride) 2a with the
dianion of BnSH 1b9a gave a complex reaction mixture from
which the cyclic disulfide 3 was isolated in low yield (Scheme
1). Formation of 3 can be explained by initial condensation of
2a with 2 equiv. of 1b and subsequent oxidative cyclization.
The yield of 3 could be improved by the use of 2 rather than only
Scheme 1
† Dedicated to Professor A. Zeeck on the occasion of his 60th birthday.
Scheme 2
Chem. Commun., 1999, 2439–2440
This journal is © The Royal Society of Chemistry 1999
2439

158.99 (C, SCNTol), 167.39 (C, CO2Et); nmax(KBr)/cm21 2980 (w), 1738
(s), 1655 (m), 1641 (m), 1505 (s), 1268 (s), 1235 (m), 1125 (m), 1030 (m),
823 (m); m/z (CI, H2O) 353 (M+ + 1), 236 (M+ + 1 2 TolN·C), 203 (M+ +
1 2 TolNNCNS) (Calc. for C20H20N2O2S: C, 68.16; H, 5.72; N, 7.94. Found:
C, 68.51; H, 5.79; N, 8.07%).
§ From 90 to 60 °C the 1H NMR spectra exhibited only one set of signals.
By cooling, broadening of the signals and coalescence (60 °C) were
observed giving rise to two signals each for the CH, CH2 and CH3 group
with the integration ratio 1+5. Singlets were detected for the CH groups and
multiplets were detected for the CH2 groups, both for the major and the
minor component. The free energy of activation of this process (DG‡
=
74.0 kJ mol21) lies in the range of typical activation barriers for E/Z
isomerizations of imines.
Scheme 3
solution of 6a and of ethyl thioglycolate 5a was stirred for 12 h
at 80 °C. This experiment suggested that intermediate 8 was not
only involved in the formation of the cycloadduct 9 but also in
the conversion of the 2,3-diiminothietanes 6a–c into the
bisthioles 7a–c.
¶ To the best of our knowledge, open-chained 1,4-zwitterions related to 8
have not been reported so far. In contrast, 1,3-zwitterions have been
previously discussed as intermediates in the chemistry of thietanes, see refs.
4(a) and 8(c). The mass spectrum of 6a exhibited characteristic fragment
peaks (loss of electroneutral TolNNCNS) which independently supported the
existence of intermediate 8. Cleavage of the carbon–sulfur bond of a
2-iminothietane has been observed during the thermal rearrangement of the
latter to an a,b-unsaturated thioamide, see ref. 8(b).
The influence of the heteroatoms of the 1,2-dianion on the
regiochemistry of cyclization was next studied. No cyclization
could be induced in the reaction of bis(imidoyl chloride) 2a with
the dianion of ethyl lactate, presumably due to the lower
nucleophilicity of the oxygen relative to the sulfur atom. In
contrast, reaction of 2a,b with the dianion of ethyl hippurate
1011 afforded the 6-imino-6H-1,3-oxazines 11a,b by regio-
selective cyclization via the carbon and the oxygen atom of the
dianion (Scheme 4). The regioselectivity of this reaction, which
was carried out under kinetic conditions, can be explained by
the higher electron density at the oxygen rather than at the
nitrogen atom of the dianion or, alternatively, by initial
formation of a four-membered ring and subsequent ring
expansion. Similar to bisthioles 7a–c, oxazines 11a,b represent
masked 1,2,3,4-tetracarbonyl systems containing strong intra-
molecular hydrogen bonds (N–H…O).
1 J. A. Pono and S. L. Schreiber, in Comprehensive Organic Synthesis, ed.
B. M. Trost, Pergamon, Oxford, 1991, vol. 5, p. 151; J. Mattay, R.
Conrads and R. Hoffmann, in Houben-Weyl, ed. G. Helmchen, R. W.
Hoffmann, J. Mulzer and E. Schaumann, 4th edn., Thieme, Stuttgart,
1995, vol. E21c, p. 3133.
2 L. A. Paquette, R. R. Rothhaar, M. Isaac, L. M. Rogers and R. D.
Rogers, J. Org. Chem., 1998, 63, 5463; J. D. Buynak, H. B. Borate,
G. W. Lamb, D. D. Khasnis, C. Husting, H. Isom and U. Siriwardane,
J. Org. Chem., 1993, 58, 1325.
3 Only a single report related to the synthesis of 2,3-diiminooxetanes has
appeared: H.-J. Kabbe, Angew. Chem., 1968, 80, 406; Angew. Chem.,
Int. Ed. Engl., 1968, 7, 389.
4 For the preparation of a triiminothietane, see: (a) G. L’abbé and L.
Huybrechts, J. Chem. Soc., Chem. Commun., 1979, 161; for the
preparation of a 2,4-diiminothietane, see (b) G. L’abbé and J.-P. Dekerk,
Tetrahedron Lett., 1979, 3213; (c) H. J. Bestmann, Angew. Chem., 1977,
89, 370; Angew. Chem., Int. Ed. Engl., 1977, 16, 358.
5 P. Langer and M. Stoll, Angew. Chem., 1999, 111, 1919; Angew. Chem.,
Int. Ed., 1999, 38, 1803.
6 P. Langer, M. Döring, H. Görls and R. Beckert, Liebigs Ann./Recl.,
1997, 2553; P. Langer and M. Döring, Synlett, 1998, 396; P. Langer and
M. Döring, Synlett, 1998, 399; P. Langer, J. Wuckelt, M. Döring and R.
Beckert, Eur. J. Org. Chem., 1998, 1467.
7 For reactions of 1,2-dianions with 1,3-dielectrophiles, see: K. G.
Bilyard, P. J. Garratt, R. Hunter and E. Lete, J. Org. Chem., 1982, 47,
4731; for the preparation of b-lactams by reaction of 1,3-amide dianions
with CH2I2, see: K. Hirai and Y. Iwano, Tetrahedron Lett., 1979,
2031.
8 Only a few 2-iminothietanes have been prepared so far: (a) A. Dondoni,
A. Batagha, P. Giorgianni, G. Gilli and M. Sacerdoti, J. Chem. Soc.,
Chem. Commun., 1977, 43; (b) J. Mulzer and T. Kerkmann, Angew.
Chem., 1980, 92, 470; Angew. Chem., Int. Ed. Engl., 1980, 19, 466; (c)
E. Schaumann, M. Möller and G. Adiwidjaja, Chem. Ber., 1988, 121,
689; (d) M. Sakamoto, T. Ishida, T. Fujita and S. Watanabe, J. Org.
Chem., 1992, 57, 2419.
9 (a) K. H. Geiß, D. Seebach and B. Seuring, Chem. Ber., 1977, 110,
1833; (b) K. Tanaka, N. Yamagishi, R. Tanikaga and A. Kaji, Chem.
Lett., 1977, 471.
Scheme 4
P. L. thanks Professor A. de Meijere for his support. Financial
support from the Fonds der Chemischen Industrie (scholarship
and funds for P. L.) is gratefully acknowledged.
Notes and references
‡ Preparation of 6a: A THF solution of LDA (2.5 equiv.) was prepared by
addition of BuLi (9.4 ml, 1.6 M solution in hexane) to a THF solution (15
ml) of diisopropylamine (2.1 ml) at 0 °C. To this solution TMEDA (2.3 ml)
and ethyl thioglycolate (0.54 ml) were added at 240 °C. The deep yellow
solution was stirred at 0 °C for 2 h and subsequently transferred to a THF
solution (80 ml) of 2a (1.8 g) at 278 °C. The temperature was allowed to
rise to ambient and the mixture was stirred for 2 h at 20 °C. The solvent was
removed in vacuo and the residue was purified by chromatography (silica
gel, Et2O–light petroleum = 1+10 ? 1+3) to give 634 mg (30%) of a yellow
solid, mp 110 °C (decomp.); dH(CDCl3, 200 MHz) 0.98 (t, J 7, 3 H,
CH2CH3), 2.32, 2.34 (s, 6 H, Tol-CH3), 4.94 (m, 2 H, CH2CH3), 5.33 (s, 1
H, CHCO2Et), 6.95–7.25 (m, 8 H, Tol); dC(CDCl3, 50 MHz) 13.62
(CH2CH3), 21.01, 21.18 (Tol-CH3), 54.47 (CH, CHCO2Et), 62.21
(CH2CH3), 121.44, 122.37, 129.75, 129.99 (CH, Tol), 136.66, 137.34 (C,
Tol-C to CH3), 142.95, 143.25 (C, Tol-C to N), 157.00 (C, CHCNTol),
10 Heterocyclic bisthioles are present in natural products, for example in
the antibiotic thiolutine: H.-D. Stachel and K. Zeiler, Liebigs Ann.,
1995, 2011.
11 A. P. Krapcho and E. A. Dundulis, Tetrahedron Lett., 1976, 2205.
Communication 9/06913E
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Chem. Commun., 1999, 2439–2440