A convenient one-pot preparation of stable equivalents of cyclobutane-1,2-dione and cyclobutanetrione

Article abstract of DOI:10.1080/00397910701845308

A very short, high-yielding, one-pot procedure has been developed for the preparation of half-protected cyclobutane-1,2-dione. This compound is much more stable than cyclobutane-1,2-dione itself and allowed further transformation to give diprotected cyclobutanetrione equivalents. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701845308

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A Convenient One‐Pot Preparation of Stable
Equivalents of Cyclobutane‐1,2‐dione and
Cyclobutanetrione
a
a
a
a
Geoffrey Deguest , Laurent Bischoff , Corinne Fruit & Francis Marsais
a
Laboratoire de Chimie Organique Fine et Hétérocyclique,
Mont‐Saint‐Aignan, Cedex, France
Published online: 22 Feb 2008.
To cite this article: Geoffrey Deguest , Laurent Bischoff , Corinne Fruit & Francis Marsais (2008) A Convenient
One‐Pot Preparation of Stable Equivalents of Cyclobutane‐1,2‐dione and Cyclobutanetrione, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:6,
841-847, DOI: 10.1080/00397910701845308
To link to this article: http://dx.doi.org/10.1080/00397910701845308
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Synthetic Communications , 38: 841–847, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845308
A Convenient One-Pot Preparation of Stable
Equivalents of Cyclobutane-1,2-dione and
Cyclobutanetrione
Geoffrey Deguest, Laurent Bischoff, Corinne Fruit,
and Francis Marsais
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique, Mont-Saint-
Aignan Cedex, France
Abstract: A very short, high-yielding, one-pot procedure has been developed for the
preparation of half-protected cyclobutane-1,2-dione. This compound is much more
stable than cyclobutane-1,2-dione itself and allowed further transformation to give
diprotected cyclobutanetrione equivalents.
Keywords: cyclobutanediones, dithiolanes, dithianes, spiro compounds
INTRODUCTION
Cyclobutane derivatives are widely used compounds, especially for biochemi-
cal purposes. For example, the 1-amino-1-cyclobutanecarboxylic acid has
[1]
often been incorporated into peptides as a constrained aminoacid. Most
syntheses of this ring proceed via dialkylation of an enolate with a 1,3-diha-
lopropane. Other routes to four-membered rings proceed via cyclobutanone
derivatives. Cyclobutanone itself is a stable but costly substance. Cyclo-
butane-1,2-dione is hardly used, because its high instability makes it
very difficult to handle. Moreover, its synthesis was described from 1,2-
cyclobutenediol bis(trimethylsilyl)ether, itself having a high propensity for
hydrolysis and ring contraction.
Received in Poland June 27, 2007
Address correspondence to Laurent Bischoff, Laboratoire de Chimie Organique
Fine et H e´ t e´ rocyclique, CNRS-UMR 6014, IRCOF-INSA Rouen, Universit e´ de
Rouen, B.P. 08, 76131, Mont-Saint-Aignan, Cedex, France. E-mail: laurent.
bischoff@insa-rouen.fr
8
41

8
42
G. Deguest et al.
In this article, we describe a one-pot synthesis of half-protected
cyclobutanedione, which represents a stable and easy-to-handle surrogate
for cyclobutanedione. A subsequent transformation afforded a diprotected
cyclobutanetrione equivalent.
RESULTS AND DISCUSSION
[2]
Cyclobutanedione was first described in 1971. The authors mention the
great instability of this compound, which requires protection from light to
avoid rapid polymerization. Their synthesis started with the radical
reduction of a dialkyl succinate with molten sodium in the presence of tri-
methylsilyl chloride (TMSCl) for the trapping of the methoxide anion
[
2c]
released during the process.
For instance, reduction of diethyl succinate
afforded 1,2-bis(trimethylsilyl)cyclobutene with a 78% yield. Unfortunately,
the latter is very sensitive to moisture and must be handled carefully,
because traces of water lead to ring contraction. As the synthesis was very
tedious and required extreme care to avoid degradation of both compounds,
we developped an efficient, one-pot synthesis of cyclobutanedione, half-
protected as its mono-dithiane derivative 3.
Starting from dimethyl succinate, we used the reduction conditions
[
3]
described in the literature, but we adapted the protocol to a one-pot
procedure, leading directly to compound 3. As depicted in Scheme 1, a
solution of dimethyl succinate and TMSCl was added slowly, under argon,
to an exact 4 molar equivalents of molten sodium in refluxing toluene. As a
very exothermic reaction immediately took place, there was no accumulation
of metallic sodium in the presence of the reagents, thus avoiding hazardous
evolution. In addition, sodium was completely consumed during the
1
addition of the reagents, making the workup safier. H NMR spectrum of an
aliquot of the toluene solution obtained at the end of the addition showed a
very clean, 1:2 mixture of bis(trimethylsilyl)cyclobutene 1 (d ¼ 2.07
and 0.04 ppm) and MeOTMS (d ¼ 3.3 and 0.13 ppm). This solution was
subsequently cooled to 2708C, diluted with pentane, and treated with
Scheme 1. One-pot synthesis of half-protected cyclobutanedione 3.

Half-Protected Cyclobutane-1,2-dione
843
Scheme 2. Diprotected equivalents of cyclobutanetrione.
[
2]
bromine.
After heating under reflux, a clean 1:2:2 mixture of
cyclobutane-1,2-dione 2, MeOTMS, and TMS-Br (d ¼ 0.59 ppm) was
1
obtained as indicated by H NMR spectra. At this stage, no isolation of
unstable cyclobutane-1,2-dione was required.
The presence of 2 molar equivalents of TMSBr by-product in the solution
proved very useful in the next step of the synthesis. As described in the litera-
ture, ketones were protected as their dithioketals under mild reaction conditions
[
4]
[5]
[6]
in the presence of BF3 catalytic I2 or when using a bis S-TMS derivative
instead of the dithiol. Our results showed that or the presence of 2 molar equiv
of TMSBr provided the accurate amount required for the rapid consumption of
water during the thioketal formation. Thus, direct treatment of the cyclobutane-
1
,2-dione solution with propanedithiol in the presence of a catalytic amount of
iodine afforded a mixture of product 3, along with remaining TMS-OMe and
presumably (not measured) hydrogen bromide. Concentration in vacuo
afforded half-protected 1,2-cyclobutanedione 3, which was easily purified by
means of column chromatography, in 87% yield from dimethyl succinate.
This material is stable and can be stored for months at 48C.
We further used this compound as a precursor of a synthetic equivalent of
cyclobutanetrione, in which ketones at C1 and C3 were both protected. A con-
venient preparation of ketones is illustrated by the double electrophilic sulfenyla-
[
7]
tion of enolates. For this purpose, the double-sulfenylating agents 4a and 4b
[8]
were prepared, using ionic exchange resin–supported thiotosylate but with a
resin slightly different than that described. In the presence of lithiated hexam-
ethyldisylazane (LiHMDS), the cyclobutanone underwent a smooth deprotona-
tion. Electrophilic sulfenylation allowed the introduction of the third ketone
equivalent as its dithioketal in moderate yield (Scheme 2). According to the
[
9]
literature, a dithiolane can be deprotected selectively, in the presence of a
dithiane, which remains unchanged. For this reason, we alsoprepared the unsym-
metrical compound 5a, in which both ketones are orthogonally protected.
CONCLUSION
As a conclusion, we have developped a very short, safe, and easy experimental
method for the synthesis of cyclobutanedione and cyclobutanetrione

8
44
G. Deguest et al.
derivatives. This procedure was illustrated by the synthesis of half-protected
cyclobutanone 3, which can be handled safely without polymerization. A
third ketone, as its protected form, can also be introduced by means of electro-
philic sulfenylation.
EXPERIMENTAL
Caution: extreme care must be taken while handling liquid sodium, because of its
pyrophoric character. In addition, a magnetic or mechanical stirring bar coated
with poly tetrafluoro ethylene (PTFE) must be avoided, because explosive
[1c]
reactions were previously reported between this material and liquid sodium.
1,2-Cyclobutanedione Monodithiane 3
A three-neck, round-bottom flask equiped with a glass mechanical stirrer was
charged with sodium (7.2 g, 315 mmol) and 250 mL of dry toluene under an
argon atmosphere. This suspension was heated under reflux and vigorous
mechanical stirring (glass mechanical stirrer), until fine drops of liquid
sodium were obtained in the solvent. A mixture of dimethyl succinate
(
9.9 mL, 75 mmol) and freshly distilled TMSCl (note that traces of HCl can
[
1c]
result in explosions ) in 120 mL of dry toluene was added dropwise
during 2 h. A thick precipitate of NaCl was obtained. The latter was
decanted, and the supernatant was canulated in another round-bottom flask
under argon. NaCl was rinsed twice with dry toluene, and the whole
solution was cooled to 2708C, protected from light with an aluminium foil.
Caution: at this stage of the reaction, traces of sodium may remain in the
precipitated NaCl, which requires treatment with absolute ethanol before
discarding.
This solution was diluted with pentane (150 mL), then cooled to 2708C
and treated with bromine (3.89 mL, 75 mmol), which upon dropwise addition
led to an exothermic reaction. At the end of the addition, the reaction mixture
was heated to 408C during 2 h.
After cooling to room temperature, 1,3-propanedithiol (9.1 mL, 90 mmol),
and then iodine (1.9 g, 7.5 mmol) were added, and stirring was continued for
2 h. Evaporation of the solvent and TMS by-products gave almost pure 3 as a
brown solid. The latter was subjected to column chromatography through
silica gel eluting with ethyl acetate/cyclohexane 1/4, Rf ¼ 0.7, affording 3
(
11.4 g, 87%) as a light brown solid.
1
H NMR (CDCl , 300 MHz): 1.9 (m, 1H), 2.0 (t, J ¼ 8.3, 2H), 2.1 (m, 1H),
3
2
.60 (t, J ¼ 3.4, 1H), 2.63 (t, J ¼ 4.1, 1H), 3.35 (t, J ¼ 8.3, 2H), 3.45 (td,
1
3
J ¼ 2.7, 14.7, 2H); C NMR (CDCl , 75 MHz): 24.8, 26.3, 28.1, 42.9, 60.9,
3
2
01.2; IC(þ)MS (MHþ ) m/z ¼ 175, Anal. calcd. for C H OS : C, 48.24;
7
10
2
H, 5.78; S, 36.80. Found: C, 48.13; H, 5.75; S, 36.87.

Half-Protected Cyclobutane-1,2-dione
845
Polymer-Supported Sodium 4-Methylbenzenesulfonothioate
Sulfur (10.7 g, 0.33 mol) was added to a stirred solution of p-toluenesulfinic
acid sodium salt (50 g, 0.33 mol) in pyridine (200 mL). The reaction
mixture was stirred for 48 h, then filtrated and evaporated to obtain sodium
thiotosylate in a quantitative yield (69.9 g, 100%). This compound (10 g,
0
2
.048 mol) was added to a strong acid resin (Lewatit Monoplus MP500,
00 g, 1.1 meq/ml). Water (250 mL) was added, and the suspension was
stirred at room temperature for 18 h. The mixture was filtered and washed
with water and acetone to furnish the resin-supported thiotosylate (268 g,
1
00%).
1
,2-Bis-tosylsulfanyl-ethane 4a
1
,2-Dibromoethane (1.66 mL, 19.2 mmol) was added to a stirred suspension
of the resin-supported thiotosylate (62 g) in anhydrous toluene (100 mL).
The reaction mixture was refluxed for 20 h, then filtred and washed with
toluene. The crude extracts were evaporated and submitted to flash chromato-
graphy through silica gel, eluting with ethyl acetate/cyclohexane 1/4
1
(
Rf ¼ 0.5) to obtain 4a as a yellow oil (7.56 g, 98%). H NMR (CDCl ,
3
3
00 MHz): 2.37 (s, 6H), 3.17 (s, 4H), 7.28 (d, J ¼ 8.4, 4H), 7.76
1
3
(
d, J ¼ 8.4, 4H); C NMR (CDCl , 75 MHz): 21.8, 35.0, 127.1, 129.9,
3
1
C, 47.74; H, 4.51; S, 31.86. Found: C, 47.69; H, 4.44; S, 31.94.
41.3, 145.3; IC(þ)MS (MHþ ) m/z ¼ 403 Anal. calcd. for C H O S :
1
6 18 4 4
1
,3-Bis-tosylsulfanyl-propane 4b
The same procedure was applied to the synthesis of 4b, starting from 1,3-
dibromopropane (2 mL, 19.2 mmol). Flash chromatography through silica
gel was conducted with dichloromethane/cyclohexane 4/1 (Rf ¼ 0.4) to
1
yield 4b (7.98 g, 97%) as a yellow solid. H NMR (CDCl , 300 MHz): 2.0
3
(
q, J ¼ 7 Hz, 2H), 2.45 (s, 6H), 2.99 (t, J ¼ 7 Hz, 4H), 7.35 (d, J ¼ 8.3 Hz,
1
3
4
3
H), 7.78 (d, J ¼ 8.3 Hz, 4H); C NMR (CDCl , 75 MHz): 21.6, 28.0,
3
3.9, 127.0, 129.9, 141.5, 145.1; IC(þ)MS (MHþ ) m/z ¼ 417. Anal.
calcd. for C H O S : C, 49.01; H, 4.84; S, 30.79 Found: C, 48.89; H,
1
7 20 4 4
4
.80; S, 30.84.
2
,4-Bis-dithianyl-cyclobutanone 5a
To a stirred solution of 1M LiHMDS (1.15 mL, 1.15 mmol) in 10 mL
anhydrous THF at –788C, 3 (100 mg, 0.57 mmol) in anhydrous THF (5 mL)
was added dropwise. The reaction mixture was stirred for 20 min at –788C,

8
46
G. Deguest et al.
then 1,2-bis-tosylsulfanyl-ethane 4a (274 mg, 0.68 mmol) in anhydrous THF
5 mL) was added dropwise and kept for an additional 20 min at –788C. The
(
mixture was allowed to reach room temperature and stirred for 3 h. Neutraliz-
ation of the reaction mixture with 1M citric acid and extractive workup with
diethyl ether (5 ꢀ 20 mL) afforded a crude product, which was purified by
flash chromatography through silica gel, eluting with ethyl acetate/cyclo-
hexane 1/4 (Rf ¼ 0.8). Compound 5a (74 mg, 49%) was obtained as a
1
white solid. H NMR (CDCl , 300 MHz): 1.81 (m, 1H), 2.10 (m, 1H), 2.50
3
1
3
(
s, 2H), 2.58 (t, J ¼ 3.7 Hz, 1H), 2.63 (t, J ¼ 3.7 Hz, 1H), 3.4 (m, 6H);
C
NMR (CDCl , 75 MHz): 25.7, 28.8, 41.6, 64.8, 76.9, 202.0; IC(þ)MS
3
(
MHþ ) m/z ¼ 265. Anal. calcd. for C H OS : C, 40.88; H, 4.57; S,
9
12
4
4
8.50. Found: C, 40.82; H, 4.53; S, 48.52.
2-Dithianyl-l,4-dithiolanylcyclobutanone 5b
The previous procedure, applied to the synthesis of 5b, starting from 3 and
using compound 4b (283 mg, 0.68 mmol) (100 mg, 0.57 mmol), and
followed by flash chromatography with ethyl acetate/cyclohexane 1/4
1
(
Rf ¼ 0.8), afforded compound 5b (76 mg, 48%). H NMR (CDCl3,
3
2
2
00 MHz): 1.90 (m, 2H), 2.15 (s, 2H), 2.2 (m, 2H), 2.68 (t, J ¼ 3.4, 2H),
1
3
.70 (t, J ¼ 4.0, 2H), 3.55 (td, J ¼ 2.5, 4H); C NMR (CDCl , 75 MHz):
3
4.8, 27.3, 42.9, 57.2, 198.7; IC(þ)MS (MHþ ) m/z ¼ 279. Anal. calcd.
for C H OS : C, 43.13; H, 5.07; S, 46.06. Found: C, 43.11; H, 5.04; S, 46.12.
4
1
0
14
ACKNOWLEDGMENTS
The authors thank the Minist e` re de I’Education Nationale, Enseignement
Sup e´ rieur et Recherche (MENESR) for a grant to G. Deguest.
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