Inverse electron demand hetero diels-alder reactions of solid supported α-acilthiones

Article abstract of DOI:10.1080/10426500590912277

A solid supported dienic α,α′-dioxothione, obtained from the corresponding resin-linked β-chetoester, is able to react with vinyl ethers to give chemo- and regiospecifically the expected oxathiin cycloadducts. Trans-esterification allowed a quantitative and very clean cleavage of the products from the solid support. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/10426500590912277

Phosphorus, Sulfur, and Silicon, 180:1327–1331, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500590912277
Inverse Electron Demand Hetero Diels–Alder Reactions
of Solid Supported α-Acilthiones
Stefano Menichetti
Mattia Mori
Cristina Nativi
Dipartimento di Chimica Organica, Polo Scientifico Universita` di
Firenze, Sesto Fiorentino, Firenze, Italy
A solid supported dienic α,αꢀ-dioxothione, obtained from the corresponding resin-
linked β-chetoester, is able to react with vinyl ethers to give chemo- and regiospecifi-
cally the expected oxathiin cycloadducts. Trans-esterification allowed a quantitative
and very clean cleavage of the products from the solid support.
Keywords Diels–alder reactions; dioxothione; oxathiins; solid phase synthesis
INTRODUCTION
In the past few years we demonstrated the utility of the phthalim-
idesulfenyl chloride (PhthNSCl, Phth = Phthaloyl)-mediated genera-
tion of α-oxothiones and several related thiocarbonyl species.1 This
methodology is based on the electrophilic introduction of the N-
thiophthalimide group on a suitable α-functionalized carbon nucle-
ophile followed by base-catalyzed formation of the carbon-sulfur double
bond via phthalimide anion elimination (Scheme 1).
By applying this procedure to β-diketons, β-ketoesters, and N-
sulfonyl-β-iminoesters, it is possible to generate the corresponding
α,αꢀ-difunctionalized tioketones, which behave as efficient electron-poor
dienes in chemo- and regiospecific and highly stereoselective inverse
electron demand Diels–Alder reactions with a plethora of electron-rich
alkenes, to give oxathiin cycloadducts with interesting synthetic appli-
cations (Scheme 1).1,2
Received July 9, 2004; accepted October 5, 2004.
Work was carried out in the framework of the National Project “Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni” and supported by the MIUR (Ministero
Istruzione Universita` e Ricerca) and by the University of Firenze.
Address correspondence to Stefano Menichetti, Dipartimento di Chimica Organica,
Polo Scientifico Universita´ di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino,
Firenze, Italy. E-mail: stefano.menichetti@unifi.it
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S. Menichetti et al.
SCHEME 1
Among the features required in a successful synthetic protocol, the
possibility of its exploitation on solid phase is nowadays particularly
appreciated.
In this communication we report our preliminary results on the gen-
eration of a solid supported α,αꢀ-dioxothione from a β-ketoester func-
tionalized resin.
RESULTS AND DISCUSSION
β-Ketoesters are among the more versatile reagents in organic syn-
thesis, and consequently several methods have been reported for their
loading on solid support.3 For this project we decided to use the Wang
resin on which the β-ketoester moiety can be introduced by either sim-
ple trans-esterification with t-butylacetoacetate or using an acyl Mel-
drum’s acid derivative.3 Both procedures gave the expected modified
1
resin 1 as demonstrated by FTIR and H NMR analysis even though,
in our hands, the trans-esterification protocol was more convenient
(Scheme 2).
The next step was the sulfenylation with PhthNSCl, which was
the crucial point of the procedure because the co-formation of HCl
could degrade Wang resin. The reaction was performed using 1.5
equiv of PhthNSCl, in dry CH2Cl2 at rt, and FTIR analysis showed
the formation of the linked α,αꢀ-dioxothiophthalimide 2 without ev-
idence of cleavage of the intermediates from the resin either under
this condition or using an excess (3 equiv) of the sulfenyl chloride
(Scheme 2).
The final step was the generation of the solid-supported dioxothione
3 by reaction with a base. In a first attempt, functionalized resin 2 was

Hetero Diels–Alder Reactions
1329
SCHEME 2
reacted with pyridine (1 equiv) in the presence of an excess of ethyl
vinyl ether 4 in CHCl3 at 60◦C for 22 h. The formation of the supported
oxathiin cycloadduct 5 was confirmed by spectroscopic analysis and
eventually by cleavage from the resin with MeONa in THF,4 which
allowed us to isolate cycloadduct 6 in 23% yield as a pure compound
(Scheme 2).
Several example of Diels–Alder reactions on solid phase have been
reported5 but, to the best of our knowledge, this is the first example
of a hetero cycloaddition involving a solid-supported thioketone. More-
over, it must be considered that in this reaction the diene is a reactive
intermediate that has to be generated on the resin and trapped by the
electron-rich dienophile.
Crucial improvements to the methodology were obtained using a
one-step procedure. Thus the resin-linked β-ketoester 1 was reacted
in CH2Cl2 with PhthNSCl and, in sequence, with Et3N and 4,6 and the
mixture heated at 60◦C for 19 h. The same cleavage with an excess of
MeONa in THF (5 h at rt) of the oxathiin modified resin 5 afforded the
pure cycloadduct 6 in 81% yield (Scheme 2). Because the Wang resin
requires five reactions (trans-esterification, sulfenylation, dioxothione
generation, cycloaddition, and cleavage) to the final product 6, the over-
all yield indicates that every step occurs with an almost quantitative
conversion.
Using resin 1 as a suitable source of the supported dienic dioxoth-
ione 3, the reaction was carried out with vinyl ethers 7–9 under the
aforementioned conditions and, in any case, the expected oxathiin cy-
cloadducts 10–12 (Table I) were isolated as single isomers in satisfac-
tory yield and as pure compounds directly from the washing of the resin
after cleavage.

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S. Menichetti et al.
TABLE I Oxathiins 6, 10–12 Prepared by Hetero Diels–Alder
Reactions of a α,αꢀ-Dioxothione on Solid Phase
Dienophile
Product
Yielda
81%
50%b
53%b
40%b
aIsolated yield of the pure command (>95% by 1H NMR) after cleavage.
bIsolated yield on a single run without optimization.
Together with their spectroscopic data, the definitive attribution of
the structural identity of derivatives 6, 10–12 was easily achieved by
comparison with authentic samples obtained in solution using the 3-
oxo-2-thioxo-butyric acid methyl ester1 as diene.
CONCLUSION
In conclusion the phthalimidesulfenyl chloride-mediated synthesis of
α,αꢀ-dioxothiones can be successfully applied on solid phase. Using a
β-ketoester functionalized Wang resin, it is possible to generate in situ
an α-oxothione that participates as electron-poor diene to hetero Diels–
Alder reactions with vinyl ethers. The solid-supported cycloadducts
can be quantitatively cleaved from the resin by trans-esterification,
which afforded the required oxathiins, which do not deserve further
purification.
The application of this methodology to other dienophiles as well as
different sulfur-containing dienes is under investigation.

Hetero Diels–Alder Reactions
1331
REFERENCES
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[4] Cleavage using the acid condition usually reported for Wang resin (i.e., TFA/CH2Cl2)
caused extensive decomposition of the cycloadducts with ring opening of the oxathiin
ring.
[5] a) B. A. Lorsbach and M. J. Kurth, Chem. Rev., 99, 1549 (1999); b) J. Yli-Kauhaluoma,
Tetrahedron, 57, 7053 (2001) and references cited therein.
[6] To a pre-swelled suspension of resin 1 (153 mg, loading 1.1 mmol/g, 0.17 mmol) in
dry CH2Cl2 (2.5 mL), PhthNSCl (75 mg, 0.35 mmol) in dry CH2Cl2 (1.5 mL) and dry
Et3N (44 mg, 0.43 mmol) were added in succession. After 20 min at rt, vinyl ether
4 (62 mg, 0.86 mol) was introduced and the mixture heated at 60◦C for 19 h. The
resin was washed with CH2Cl2, MeOH, Et2O ed again CH2Cl2, (3 × 8 mL each), and
dried under vacuum. Oxathiin functionalized resin 5 thus obtained (170 mg, load-
ing 0.93 mmol/g, 0.16 mmol) was swelled in dry THF (6 mL) and freshly prepared
MeONa (0.5 mL, 1.58 M in MeOH) was added to the mixture kept at rt for 5 h. The
resin was washed with CH2Cl2, Et2O, and CH2Cl2 (3 × 8 mL each), the collected or-
ganic phase washed with H2O (50 mL), saturated NH4Cl (2 × 30 mL), and dried
over anhydrous Na2SO4. Evaporation of the solvent gave cycloadduct 6 as pure
compound by 1H NMR, identified also by comparison with an authentic sample.1
1H NMR (200 MHz, CDCl3) δ: 1.25 (t, J = 7.5 Hz, 3H), 2.32 (s, 3H), 2.76–2.94 (AB
part of an ABX system, JAB = 13.5 Hz, 2H), 3.64–3.76 (m, 1H), 3.73 (s, 3H), 3.84–3.96
(m, 1H); 5.24 (X part of an ABX system, J = 4.0 and 2.0 Hz, 1H).