Synthesis of highly functionalized 1,3-oxathioles via an unusual [4+1] annulation of α,α'-dioxothione with 1,2-diaza-1,3-dienes

Article abstract of DOI:10.1055/s-0032-1317621

The present method provides highly functionalized 1,3-oxathioles through an unusual base-promoted [4+1] annulation between α,α'-dioxothione, generated in situ from a phthalimide precursor, and 1,2-diaza-1,3-dienes. An intriguing scaffold comprised of spiro-fused oxathiole and pyrazolone components was also obtained in moderate yield. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317621

LETTER
▌2947
lSetyternthesis of Highly Functionalized 1,3-Oxathioles via an Unusual
[4+1] Annulation of α,α'-Dioxothione with 1,2-Diaza-1,3-dienes
Synthesis of Highly Functionalized 1,3-Oxathioles
Orazio A. Attanasi,*a Gianfranco Favi,a Fabio Mantellini,a Stefano Menichetti,*b Giada Moscatelli,a
Caterina Viglianisib
a
Dipartimento di Scienze della Terra, della Vita e dell’Ambiente (DiSTeVA), Sezione di Chimica Organica e delle Sostanze Organiche Naturali
(SCOSON), Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino (PU), Italy
Fax +39(722)3033441; E-mail: orazio.attanasi@uniurb.it
b
Dipartimento di Chimica ‘Ugo Schiff’ Polo Scientifico e Tecnologico, Università di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorenti-
no, Italy
Received: 15.10.20120; Accepted: 23.10.2012
matic substitution (SEAr) with a variety of phenols and
N,N-dimethylaniline to afford the corresponding alkyl, ar-
yl, or diaryl sulfides.
Abstract: The present method provides highly functionalized 1,3-
oxathioles through an unusual base-promoted [4+1] annulation be-
tween α,α'-dioxothione, generated in situ from a phthalimide pre-
cursor, and 1,2-diaza-1,3-dienes. An intriguing scaffold comprised
of spiro-fused oxathiole and pyrazolone components was also ob-
tained in moderate yield.
O
S
R
[4+2]
[4+2]
Key words: oxathioles, Michael addition, [4+1] annulation, spiro
compounds
Z
(1)
O
R
O
EDG
(2)
EDG
Heterocyclic compounds, especially those containing
five/six-membered rings, are very important units in or-
ganic and pharmaceutical chemistry. Among them, oxa-
thioles remain a relatively unexplored class of O,S-
heterocycles.1 The limited number of synthetic methods
that can be used to access such systems fall into three
groups: (i) reactions of α-diazo ketones with
thiobenzophenone2 or azibenzil/diaryldiazomethanes
with monothiobenzils,3,4 (ii) Rh(II)-catalyzed cycloaddi-
tions of carbomethoxy iodonium ylides,5 and (iii) reac-
tions of carbonyl-stabilized sulfonium ylides with
elemental sulfur.6 Surprisingly, only a few of the reported
methods are general, and many suffer from limited func-
tional group tolerance, modest regioselectivities, harsh re-
action conditions, expensive metal catalysts, or laborious
work-up. Consequently, the development of new strate-
gies for the construction of such scaffolds is highly desir-
able.
Z
S
O
O
O
R
Z
R
Z
O
S
H
H
S
DTs 2
thiophilic
'ene' addition
O
(3)
EDG
EDG
S
Z
R
SEAr
(4)
O
O
H
Scheme 1 Reactivity of α,α'-dioxothiones 2
During ongoing studies, we came to appreciate the advan-
tages of diverse 1,2-diaza-1,3-dienes (DDs, 3; Figure
1).11–15 In particular, we found that conjugated azoenes
with electron-withdrawing substituents (e.g., esters or am-
ides) on the terminal carbon and/or nitrogen (Figure 1),
were particularly suitable as versatile synthetic building
blocks because of their five-atom (3C + 2N) C4-electro-
philic nature, dense substitution patterns, and flexible
functionality that was capable of undertaking multiple
roles.
The utility of polyfunctional α-acylthiocarbonyl com-
pounds as versatile intermediates in organic synthesis is
well documented.7–10 Detailed studies on the reactivity of
α,α'-dioxothiones (DTs) 2 showed that they can act as ef-
ficient dienophiles7 (Scheme 1, equation 1), electron-poor
heterodienes8 (equation 2), as well as enophiles9 (equation
3) that are able to react with appropriate unsaturated coun-
terparts to give dihydrothiopyrans, 1,4-oxathiins, and
thiophilic ene adducts, respectively.
In addition to acting as 1,4-heterodipoles10 (Scheme 1,
equation 4), DTs have been applied in electrophilic aro-
O
1
3
N
X
5
Y
N
4
2
O
3
SYNLETT 2012, 23, 2947–2950
Advanced online publication: 16.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Figure 1 Structure of 4-alkoxy (or -dialkylamino) carbonyl-1,2-dia-
za-1,3-dienes (DDs) 3
DOI: 10.1055/s-0032-1317621; Art ID: ST-2012-D0892-L
© Georg Thieme Verlag Stuttgart · New York

2948
O. A. Attanasi et al.
LETTER
Generally, DDs can afford one to five atoms to construct mized conditions in hand, we then evaluated the scope of
cyclic molecules. Incorporation of all five atoms of the the reaction by using a variety of DDs 3a–j;17 the results
DD skeleton into pyrazolone structures has been success- are summarized in Table 1. Different 4-alkoxy or 4-(di-
fully applied in our previous work.12 As four-atom diene alkylamino)carbonyl-DDs 3 gave the corresponding oxa-
synthons, DDs have found application in both [4+1] and thioles in moderate to good yields. Different substitution
[4+2] strategies for the synthesis of dihydropyrazoles13 on the nitrogen atom of the azo group as well as variations
and pyridazines,14 respectively. In addition, they can par- of groups at C3 and C4 of the ene moiety were tolerated.
ticipate in formal [3+2]-, [4+2]-, and [5+2]-annulation re-
Table 1 Synthesis of 1,3-Oxathiole Derivatives 3a–j from DTPht 1a
actions in which two or three ring atoms (C–C or C–C–N)
and DDs 3a–ja
of the azoene component are incorporated in the final cy-
cloaddition products.15 Thus, pyrroles, pyrazole N-oxides,
R1
N
imidazoles, 2-imino-4-thiazolines, rhodanines, 2,5,6,7-
N
COR3
tetrahydro-1H-1,4-diazepin-2-ones, 5H-1,4-benzodiaze-
pines, and 2-thiohydantoins or 2-iminothiazolidinones
can be synthesized.
H
S
COR2
COR2
N
O
S
O
O
3a–j
O
O
NHCOR3
CH2Cl2, py, r.t., 2 h
R1
4a−j
O
In the present work, we wish to demonstrate that DT 2a
can behave as a C2S1O1 building block in an unusual [4+1]
annulation with DDs 3 to afford a series of highly func-
tionalized oxathioles. This observation supports our spec-
ulation of a high polarization of the thiocarbonyl moiety
in α,α'-dioxothiones 2 (Figure 2).
NPht
1a
Entry
3
R1
R2
R3
4
Yield (%)b
1
2
3a
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Et
OMe
OAll
OEt
NH2
4a
4b
4c
4d
4e
4f
58
46
51
39
52
55
51
47
69
31
NH2
3
NHPh
NHPh
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
t-BuO
O
O
O
O
4
NMe2
OMe
OEt
R
Z
R
Z
S
S
2
5
6
Figure 2 Electrophilic character of thiocarbonyl sulfur in α,α'-di-
oxothiones 2
7
3g
3h
3i
OMe
OEt
4g
4h
4i
8
Et
This process represents not only the first example of the
use of an α,α'-dioxothione as a four-atom donor partner in
the [4+1]-annulation process, but also provides access to
α,α'-disubstituted oxathiole molecules, which are under-
represented structures. The incorporation of polarizable
heteroatoms within the cyclic framework containing a
quaternary center is another important aspect of this ap-
proach to this heterocyclic architecture.
9
n-Pr
Me
OMe
NMe2
10
3j
4j
a Reaction conditions: CH2Cl2 (4 mL), r.t., 2 h, DTPht (1a; 2.0 mmol),
DD (3; 1.0 mmol), pyridine (2.0 mmol) until complete disappearance
of 3 (reaction monitored by TLC).
b Yield of isolated product.
To investigate whether DT 2a could be employed as a
partner in heterocyclic ring-forming reactions, upon addi-
tion of pyridine, α,α'-dioxothiophthalimide (DTPht) 1a in
dichloromethane at room temperature was transformed
into the transient corresponding DT 2a, which could be
directly trapped in situ with azoene 3a (Table 1). The use
of phthalimide precursors for the generation of DTs via
base-promoted 1,2-elimination is a well-documented
process.7–10,16
Mechanistically, we propose that the reaction is initiated
by nucleophilic addition (Michael addition) of DT 2a,
generated in situ, to the azoene system 3 resulting in a
nonisolable zwitterionic intermediate I. Subsequently,
five-membered cyclic product 4 would be produced by in-
tramolecular azacyclization of II through a 1,4-hydrogen
shift of I, resulting in an overall formal [4+1] cyclization
(Scheme 2).
In the presence of equimolar amounts of reagents (DTPht
1a and DD 3a), the reaction proceeded to give the highly
functionalized oxathiole 4a, albeit in low yield (27%).
When the amount of DTPht 1a (and pyridine) was in-
creased to two equivalents, the yield of the reaction also
increased to a promising 49%. Surprisingly, the yield di-
minished when the reaction was performed using three
equivalents of DTPht 1a (38%). In all cases, partial de-
composition of reagent 1a was also observed. The best re-
sult (58%) was obtained when the reaction was performed
under rigorously anhydrous conditions. With the opti-
The formation of oxathioles 4a–j as exclusive compounds
indicates that the reaction is regio- and chemoselective.
The structure of the products 4a–j was established by con-
1
sideration of the spectroscopic properties of 4a. The H
NMR spectrum of 4a in CDCl3 showed one singlet at δ =
8.78 ppm and two broad singlets at δ = 5.98 and 5.00 ppm
attributed to the protons of the semicarbazone fragment.
The 13C NMR spectrum showed six C-sp2 signals (δ =
168.5, 162.4, 158.8, 157.3, 142.2 and 101.8 ppm) and one
C-sp3 signal at δ = 96.7 ppm, consistent with the presence
of a oxathiole ring,18,19 and the IR spectrum exhibited a
Synlett 2012, 23, 2947–2950
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Highly Functionalized 1,3-Oxathioles
2949
strong band at 1648 cm–1 that could be assigned to the In conclusion, we report herein a facile base-promoted re-
C=C double bond of the oxathiole structure;19 the mass gioselective synthesis of highly functionalized 1,3-oxathi-
spectrum of 4a displayed the expected molecular ion peak oles 4 starting from α,α'-dioxothione (DT) 2a and 1,2-
(m/z 331 [M+]).
diaza-1,3-dienes (DDs) 3. The mechanism of this reaction
is proposed to be an unusual [4+1] annulation undergone
by the highly polarized carbon–sulfur double bond. A
unique scaffold 5, comprised of spiro-fused oxathiole and
pyrazolone components, was also obtained in moderate
yield. Further investigations of other applications, includ-
ing the use of other α-oxothione/activated alkene re-
agents, as well as studies on the mechanism of this
synthetic transformation are in progress.
H
S
O
O
O
NPht
py
1a
O
O
Acknowledgment
O
H
COR2
R1
S
O
This work was supported by financial assistance from the Ministero
dell’Università, dell’Istruzione e della Ricerca (MIUR) – Rome,
Università degli Studi di Urbino ‘Carlo Bo’ and Università di Firen-
ze, Italy.
2a
O
N
N
COR3
N
N
R1
S
COR2
O
COR3
3
I
[1,4]-H shift
References and Notes
(1) Wilkins, D. J. In Modern Heterocyclic Chemistry; Alvarez-
Builla, J.; Vaquero, J. J.; Barluenga, J., Eds.; Wiley-VCH:
Weinheim, 2011, 925.
(2) (a) Nikolaev, V. A.; Ivanov, A. V.; Shakhim, A. A.; Schulze,
B.; Rodina, L. L. Russ. J. Org. Chem. 2011, 47, 1911.
(b) Mataka, S.; Ishii, S.; Tashiro, M. Chem. Lett. 1977, 955.
(3) (a) Kägi, M.; Linden, A.; Mlostón, G.; Heimgartner, H.
Helv. Chim. Acta 1998, 81, 285. (b) Bak, C.; Praefcke, K.
Chem. Z. 1978, 102, 456.
O
COR2
COR2
N
O
O
O
N
O
R1
II
S
S
NHCOR3
HN
R1
O
COR3
4
Scheme 2 Tentative mechanism for the formation of 1,3-oxathioles 4
The presence of one sp3-hybridized carbon atom on the
heterocyclic skeleton together with both an electrophilic
ester group and a nucleophilic hydrazone residue at the
C2-position make these compounds attractive for subse-
quent modification. Therefore, the possibility of de-
rivatization to other α-oxathiolo-related structures was
explored. We envisaged that the α-oxathiolo hydrazone 4e
derived from tert-butoxycarbonyl-1,2-diaza-1,3-diene
(3e) might be hydrolyzed and cyclized to oxathiole-pyr-
azolone spiro compound 5 upon exposure to acidic condi-
tions. Thus, on treatment of oxathiole 4e with
trifluoroacetic acid in CH2Cl2, a novel spiro scaffold 1-
(4) Bak, C.; Praefcke, K. Chem. Ber. 1979, 112, 2744.
(5) Batsila, C.; Kostakis, G.; Hadjiarapoglou, L. P. Tetrahedron
Lett. 2002, 43, 5997.
(6) (a) Nakayama, J.; Sugiura, H.; Hoshino, M.; Kobayashi, H.
Tetrahedron Lett. 1985, 26, 2201. (b) Oka, K.; Dobashi, A.;
Hara, S. J. Am. Chem. Soc. 1981, 103, 2757.
(7) Capozzi, G.; Nativi, C.; Menichetti, S.; Rosi, A.; Valle, G.
Tetrahedron 1992, 48, 9023.
(8) (a) Menichetti, S.; Nativi, C. In Targets in Heterocyclic
Systems-Chemistry and Properties; Vol. 7; Attanasi, O. A.;
Spinelli, D., Eds.; Società Chimica Italiana: Rome, 2003,
108. (b) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.;
Raffaelli, B. Chem.–Eur. J. 1999, 1748. (c) Capozzi, G.;
Falciani, C.; Menichetti, S.; Nativi, C. J. Org. Chem. 1997,
62, 2611. (d) Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.;
Marzabadi, C.; Menichetti, S.; Nativi, C.; Tamarez, M.
Angew. Chem. 1996, 35, 777. (e) Capozzi, G.; Franck, R.
W.; Mattioli, M.; Menichetti, S.; Nativi, C.; Valle, G. J. Org.
Chem. 1995, 60, 6416.
(9) Capozzi, G.; Fragai, M.; Menichetti, S.; Nativi, C. Eur. J.
Org. Chem. 1999, 3375.
(10) Capozzi, G.; Menichetti, S.; Nativi, C. Eur. J. Org. Chem.
2000, 3653.
(11) For a review on the chemistry of DDs, see: Attanasi, O. A.;
De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.;
Perrulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009,
3109.
(12) For a recent example, see: Attanasi, O. A.; Favi, G.;
Filippone, P.; Mantellini, F.; Moscatelli, G.; Perrulli, F. R.
Org. Lett. 2010, 12, 468.
oxa-4-thia-7,8-diazaspiro[4.4]nona-2,8-dien-6-one
(5)
was formed (Scheme 3).20 Although the isolated yield was
rather moderate (38%), we were pleased to observe that a
unique scaffold comprised of spiro-fused oxathiole and
pyrazolone components could be readily obtained. To the
best of our knowledge, the only previous example of oxa-
thiole-pyrazolone spiro-derivatives was reported by El-
Saraf and co-workers.21
O
O
S
CO2Me
N
O
S
NH
N
TFA
EtO
EtO
CH2Cl2, r.t., 2 h
NHCO2t-Bu
O
O
4e
5 (38%)
(13) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jörres, M.;
Bolm, C. J. Am. Chem. Soc. 2012, 134, 6924.
(14) For some recent examples, see: (a) D’Auria, M.; Racioppi,
R.; Attanasi, O. A.; Mantellini, F. Synlett 2010, 1363.
Scheme 3 Synthesis of oxathiole-pyrazolone spiro-derivative 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2947–2950

2950
O. A. Attanasi et al.
LETTER
(b) Pitacco, G.; Attanasi, O. A.; De Crescentini, L.; Favi, G.;
Felluga, F.; Forzato, C.; Mantellini, F.; Nitti, P.; Valentin,
E.; Zangrando, E. Tetrahedron: Asymmetry 2010, 21, 617.
(c) Attanasi, O. A.; Favi, G.; Filippone, P.; Perrulli, F. R.;
Santeusanio, S. Org. Lett. 2009, 11, 309; and references
therein.
4-Ethyl 2-Methyl 2-[1-(2-Carbamoylhydrazono)ethyl]-5-
methyl-1,3-oxathiole-2,4-dicarboxylate (4a): 1H NMR
(400 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H), 2.02 (s,
3 H), 2.32 (s, 3 H), 3.84 (s, 3 H), 4.21 (q, J = 7.2 Hz, 2 H),
5.00 and 5.98 (br s, 2 H), 8.78 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 11.8 (q), 14.2 (q), 14.4 (q), 53.5 (q), 61.2 (t),
96.7 (s), 101.8 (s), 142.2 (s), 157.3 (s), 158.8 (s), 162.4 (s),
168.5 (s). IR (Nujol): 3466, 1746, 1716, 1648, 1592, 1290,
1253, 1087, 1062 cm–1. MS: m/z (%) = 331 (10), 314 (48),
288 (18), 271 (100), 243 (38), 229 (30), 199 (45), 157 (50).
Anal. Calcd for C12H17N3O6S (331.34): C, 43.50; H, 5.17; N,
12.68. Found: C, 43.64; H, 5.08; N, 12.59.
(15) For selected examples, see: (a) Attanasi, O. A.; Bartoccini,
S.; Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. J.
Org. Chem. 2012, 77, 9338. (b) Attanasi, O. A.; Bartoccini,
S.; Favi, G.; Giorgi, G.; Perrulli, F. R.; Santeusanio, S. J.
Org. Chem. 2012, 77, 1161. (c) Battistini, L.; Dell’Amico,
L.; Sartori, A.; Curti, C.; Pelosi, G.; Casiraghi, G.; Attanasi,
O. A.; Favi, G.; Zanardi, F. Adv. Synth. Catal. 2011, 353,
1966. (d) Attanasi, O. A.; De Crescentini, L.; Favi, G.;
Mantellini, F.; Nicolini, S. J. Org. Chem. 2011, 76, 8320.
(e) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Nicolini, S.;
Perrulli, F. R.; Santeusanio, S. Org. Lett. 2011, 13, 353.
(f) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.;
Santeusanio, S. J. Org. Chem. 2011, 76, 2860. (g) Attanasi,
O. A.; Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S.
Synlett 2010, 1859. (h) Attanasi, O. A.; Favi, G.; Filippone,
P.; Giorgi, G.; Lillini, S.; Mantellini, F.; Perrulli, F. R.
Synlett 2006, 2731.
(16) (a) Huang, N.-Z.; Lakshmikantham, M. V.; Cava, M. P. J.
Org. Chem. 1987, 52, 169. (b) Kirby, G. W.; Lochead, A. W.
J. Chem. Soc., Chem. Commun. 1983, 1325. (c) Harp, D. N.;
Back, T. G. J. Org. Chem. 1976, 41, 2498.
(17) Typical Procedure: To a solution of DD 3a (0.171 g, 1.0
mmol) in CH2Cl2 (4 mL) were added DTPht 1a (0.614 g, 2.0
mmol) and anhydrous pyridine (0.158 g, 2 mmol) at 25 °C.
The solution was stirred for 2 h at room temperature
(reaction monitored by TLC analysis). The solvent was
removed in vacuo and the residue was purified by column
chromatography (silica gel; cyclohexane–EtOAc, 20:80) to
give the corresponding oxathiole derivative 4a as a pale-
yellow waxy solid (0.191 g, 58%).
(18) (a) Bushby, R. J.; Mann, S. J. Chem. Soc., Perkin Trans. 1
1987, 2497. (b) Bak, C.; Praefcke, K. Chem. Ber. 1979, 112,
2744.
(19) Jacobsson, U.; Kempe, T.; Norin, T. J. Org. Chem. 1974, 39,
2722.
(20) To a solution of oxathiole 4e (0.194 g, 0.5 mmol) in CH2Cl2
(4 mL) was added TFA (0.057 g, 0.5 mmol) at 25 °C. The
solution was stirred for 2 h at r.t., the solvent was removed
in vacuo and the residue was purified by column
chromatography (silica gel; cyclohexane–EtOAc, 80:20) to
give 5 as a pale-yellow waxy solid (0.048 g, 38%).
Ethyl 2,6-Dimethyl-9-oxo-1-oxa-4-thia-7,8-diazaspiro-
[4.4]nona-2,6-diene-3-carboxylate (5): 1H NMR (400
MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H), 2.20 (s, 3 H),
2.31 (s, 3 H), 4.22 and 4.23 (q, J = 7.2 Hz, 2 H), 8.57 (s,
1 H). 13C NMR (100 MHz, CDCl3): δ = 12.7 (q), 14.2 (q),
14.3 (q), 61.4 (t), 87.8 (s), 101.7 (s), 156.9 (s), 159.0 (s),
161.8 (s), 171.7 (s). IR (Nujol): 3349, 3200, 1736, 1712,
1641, 1284, 1087 cm–1. MS: m/z (%) = 256 (35) [M]+, 213
(100), 185 (66), 141 (36). Anal. Calcd for C10H12N2O4S
(256.28): C, 46.87; H, 4.72; N, 10.93. Found: C, 46.74; H,
4.77; N, 11.01.
(21) El-Saraf, G. A.; El-Sayed, A. M.; El-Saghier, A. M. M.
Heteroat. Chem. 2003, 14, 211.
Synlett 2012, 23, 2947–2950
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