New synthesis of semisquaric acid derivatives via chlorinated N-(cyclobutylidene)amines

Article abstract of DOI:10.1021/jo0502044

The synthesis and reactivity of new chlorinated AT-(cyclobutylidene)amines leading to new synthetic pathways toward various substituted cyclobutenediones is described.

Full text of DOI:10.1021/jo0502044

New Synthesis of Semisquaric Acid
Derivatives via Chlorinated
N-(Cyclobutylidene)amines
Guido Verniest, Jeroen Colpaert, Karl W. To¨rnroos,† and
Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural
and Applied Biological Sciences, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
norbert.dekimpe@ugent.be
Received February 1, 2005
FIGURE 1. (Semi)squarates and related physiologically active
cyclobutenediones
though the starting cyclobutanone is commercially avail-
able, the low overall yield (10%) makes this procedure of
no preparative use. Other synthetic methods are based
on the skeletal functionalization of (semi)squaric acid.2,6,7
The synthesis and reactivity of new chlorinated N-(cyclobu-
tylidene)amines leading to new synthetic pathways toward
various substituted cyclobutenediones is described.
Semisquaric acid or 3-hydroxy-3-cyclobutene-1,2-dione
3 has been isolated from the maize molds Fusarium
moniliforme and Gibberella fujikuroi as a sodium and
potassium salt (pKa ) 0.88).8 These salts were named
moniliformin (4) and are toxic for mammals and possess
plant growth regulating and phytotoxic effects.9,10 Since
the discovery of moniliformin, it served as a “lead”
compound to synthesize numerous analogues which
showed interesting physiological properties. Squaric acid
derivatives were patented for their application in the
treatment of chronic inflammatory diseases such as
asthma, multiple sclerosis, and rheumatoid arthritis.11
Dibutylsquarate 5 can be used as a therapy for alopecia
areata, a kind of hair loss.12,13 More general, positive
results have been obtained in medicinal chemistry by the
use of the squaryl group as a carboxylate isosteric group
to enhance biological activity.14 Squarates possess also
a strong chelating ability to metal ions.15
Cyclobutenediones have interested organic chemists for
a long time because of their intriguing molecular skel-
eton, suggesting specific properties and reactivities such
as a high ring tension and consequent enhanced electro-
philicity. Indeed, since the first synthesis of 3-hydroxy-
4-phenylcyclobutenedione 11 via a cycloaddition of phen-
ylacetylene with trifluorochloroethene and subsequent
hydrolysis, numerous studies have been performed on
this type of compounds.2 Hydroxylated cyclobutenediones,
e.g., 2 (squaric acid) and 3 (semisquaric acid) (Figure 1),
have been synthesized via an acidic hydrolysis of poly-
halogenated or polyalkoxylated cyclobutenes obtained by
a thermal or photochemical [2 + 2]-cycloaddition of
ketenes or ketene analogues to perhalogenated or alkoxy-
lated alkenes and alkynes.2-4 Often, difficult procedures
or not readily available starting materials are used to
get to these compounds. A 2,2,4,4-tetrabromination of
cyclobutanone yielded semisquaric acid after dehydro-
bromination and successive aqueous hydrolysis.5 Al-
More recently, significant research is focused on mono-
and diamino-substituted cyclobutenediones, or (semi)-
squaramides, which is reflected in the large number of
* Corresponding author. Tel: +32 (0)9 264 59 51. Fax: +32 (0)9
264 62 43.
(6) Schmidt, A. H.; Maibaum, H. Synthesis 1987, 134.
(7) Schmidt, A. H.; Schmidt, G.; Diedrich, H. Synthesis 1990, 579.
(8) Springer, J. P.; Clardy, J.; Cole, R. J.; Kirksey, J. W.; Hill, R.
K.; Carlson, R. M.; Isidor, J. L. J. Am. Chem. Soc. 1974, 96, 2268.
(9) Burka, L. T.; Doran, J.; Wilson, B. J. Biochem. Pharmacol. 1982,
31, 79.
† Department of Chemistry, University of Bergen, Allegaten 41, 5007
Bergen, Norway.
(1) Smutny, E. J.; Roberts, J. D. J. Am. Chem. Soc. 1955, 77, 3420.
(2) For reviews: (a) Frauenrath, H. In Houben-Weyl Methoden der
Organische Chemie; Kropf, H., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, New York, 1993; Vol. E15.2. (b) de Meijere, A.;
Kozhushkov, S. I.; Butenscho¨n, H. In Houben-Weyl Methods of Organic
Chemistry; de Meijere, A., Ed.; Georg Thieme Verlag: Stuttgart-New
York, 1997; Vol. E17f. (c) Schmidt, A. H. Synthesis 1980, 961. (d)
Schmidt, A. H.; Ried, W. Synthesis 1978, 1. (e) Knorr, H.; Ried, W.
Synthesis 1978, 649. (f) Schmidt, A. H.; Ried, W. Synthesis 1978, 869.
(3) Bellus, D. J. Am. Chem. Soc. 1978, 100, 8026.
(4) Raasch, M. S.; Miegel, R. E.; Castle, J. E. J. Am. Chem. Soc.
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Chem. Abstr. 1976, 86, 72011.
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J. P.; Happle, R.; Nigel, J.; Tobin, D. J. Eur. J. Dermatol. 2000, 10,
443.
10.1021/jo0502044 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/26/2005
J. Org. Chem. 2005, 70, 4549-4552
4549

SCHEME 1
patents concerning this topic. For instance, semisquara-
mide 6 and derivatives showed potent paralytic activities
(Figure 1).16 Other semisquaramides display smooth
muscle relaxation (7)17 and antimigraine activities.18
In addition, diaminocyclobutenediones have been the
subject of considerable research and resulted in phar-
macologically interesting compounds, such as pibutidine
8, a histamine H2 receptor antagonist19 and EAA-090 9,
a neuroprotectant with potential as a treatment for brain
damage resulting from stroke.20 Besides the above-
mentioned physiological properties of cyclobutenediones,
these compounds also proved to be powerful synthetic
building blocks for the synthesis of a variety of carbo-
and heterocycles, such as quinones, furanones, xantho-
nes, cyclopentenediones, phenols, and 2-pyridones.21
The present report describes the application of N-
(cyclobutylidene)amines in the synthesis of different
semisquarates and semisquaramides. It is surprising that
no monocyclic N-(3-arylcyclobutylidene)alkylamines have
been described so far, which makes the study of these
compounds worthwhile. In addition, halogenated N-
(cyclobutylidene)amines in general have barely been
studied. Besides theoretical calculations,22 only one paper
was found concerning halogenated N-(cyclobutylidene)-
amines. This paper deals with the synthesis of the N-tert-
butylimine of a benzo-annelated 2,2-dichlorocyclobu-
tanone.23 Other publications deal with the synthesis and
reactivity of enamines24 or oximes25 which are a com-
pletely different classes of compounds.
SCHEME 2
Readily available 3-substituted 2,2-dichlorocyclobu-
tanones 1026 were dehalogenated with zinc in acetic acid
prior to the conversion to imines 12 because a direct
imination of dichlorinated cyclobutanones 10 was not
successful and resulted in complex reaction mixtures. In
contrast, dehalogenated cyclobutanones 1127 were easily
(14) Butera, J. A.; Antane, M. M.; Antane, S. A.; Argentieri, T. M.;
Freeden, C.; Graceffa, R. F.; Hirth, B. H.; Jenkins, D.; Lennox, J. R.;
Matelan, E.; Norton, N. W.; Quagliato, D.; Sheldon, J. H.; Spinelli,
W.; Warga, D.; Wojdan, A.; Woods, M. J. Med. Chem. 2000, 43, 1187;
Chem. Abstr. 2000, 132, 317624.
iminated using titanium(IV) chloride as an activating and
dehydrating agent, resulting in new imines 12 (Scheme
1). The reaction of these new compounds with 4.5 equiv
of NCS in refluxing CCl4 for 30 min resulted in a 2,2,4,4-
tetrachlorination toward novel imines 13 in high yields.
To verify whether these tetrachlorinated imines could be
used as precursors for 3-hydroxy-4-phenylcyclobutene-
dione 1,28 N-(2,2,4,4-tetrachloro-3-phenylcyclobutylidene)-
isopropylamine was treated with aqueous oxalic acid,
HCl, or H2SO4.
(15) Seitz, G.; Imming, P. Chem. Rev. 1992, 92, 1227.
(16) Shinada, T.; Nakagawa, Y.; Hayashi, K.; Corzo, G.; Nakajima,
T.; Ohfune, Y. Amino Acids 2003, 24, 293.
(17) Butera, J. A.; Lennox, J. R.; Jenkins, D. J. PCT Int. Appl. WO
2000034230 A1 20000615, 2000; Chem. Abstr. 2000, 133, 43244.
(18) Srinivas, N. R.; Shyu, W. C.; Soong, C. W.; Greene, D. J. Pharm.
Sci. 1998, 87, 1170.
(19) Higuchi, A.; Isobu, Y.; Kijima, H.; Kiuchi, Y.; Saito, T. Jpn Kokai
Tokkyo Koho JP 11092372 A2 19990406, 1999; Chem. Abstr. 1999, 130,
316615.
Much to our surprise, a considerable amount of dehy-
drochlorinated imine 14 was recovered after workup
(Scheme 2). Even when 13a was treated with an excess
of 80% aq H2SO4 at room temperature, a dehydrohalo-
genation occurred toward N-(2,4,4-trichloro-3-phenyl-2-
cyclobutenylidene)isopropylamine 14 which appeared to
be quite stable and was only partially converted to the
hydrolyzed cyclobutenone 15 after 20 h. Eventually, a
complete hydrolysis of imine 13a toward 3-hydroxy-4-
phenylcyclobutenedione 1 was established under very
harsh hydrolytic conditions, i.e., 90% aq H2SO4 at
80-90 °C for 15 h (yield 72%). To develop a most efficient
pathway toward 4-phenylsemisquaric acid 1, attempts
were performed to chlorinate 2,2-dichloro-3-phenylcy-
clobutanone with the use of NCS or trichloroisocyanuric
(20) Childers, W. E., Jr.; Abou-Gharbia, M. A.; Magid, A.; Moyer, J.
A.; Zaleska, M. M. Drugs Future 2002, 27, 633638; Chem. Abstr. 2002,
139, 16866.
(21) (a) Ohno, M.; Yamamoto, Y.; Eguchi, S. Synlett 1998, 1167. (b)
Taing, M.; Moore, H. W. J. Org. Chem. 1996, 61, 329. (c) Sun, L.;
Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 12473. (d) Zhang, S.;
Liebeskind, L. S. J. Org. Chem. 1999, 64, 4042. (e) Liebeskind, L. S.;
Fengl, R. W. J. Org. Chem. 1990, 55, 5359 and references therein. (f)
Shinada, T.; Ooyama, Y.; Hayashi, K.-I., Ohfune, Y. Tetrahedron Lett.
2002, 43, 6755.
(22) Ding W.-J.; Fang, D.-C. J. Org. Chem. 2001, 66, 6673.
(23) Roedig, A.; Ganns, E. M. Liebigs Ann. Chem. 1982, 406.
(24) (a) Kristol, D.; Shapiro, R. J. Org. Chem. 1973, 38, 1470. (b)
Madsen, J. O.; Lawesson, S.-O. Tetrahedron 1974, 30, 3481.
(25) Gsell, L.; Gehret, J. C. Eur. Pat. Appl. EP 39308 A1 19811104,
1981; Chem. Abstr. 1981, 96, 85116.
(26) (a) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879.
(b) Chaumeil, H.; Le Drain, C. Helv. Chim. Acta 1996, 79, 1075. (c)
Cagnon, J. R.; Marchand-Brynaert, J.; Ghosez, L. J. Braz. Chem. Soc.
1996, 7, 371.
(27) (a) Hassner, A.; Dillon, J. L., Jr. J. Org. Chem. 1983, 48, 3382.
(b) Dehmlow, E. V.; Bueker, S. Chem. Ber. 1993, 126, 2759.
(28) Chickos, J. S. J. Org. Chem. 1973, 38, 3642.
4550 J. Org. Chem., Vol. 70, No. 11, 2005

SCHEME 3
SCHEME 4a
a n.d.: yield not determined (unstable compounds; the reaction
mixture was used as such for further transformation).
SCHEME 5a
acid. Because both methods were unsuccessful, cyclobu-
tanone 10a (R1 ) Ph) was treated with chlorine gas in
CHCl3 in the presence of DMF-HCl. Under the reaction
conditions used, no tetrachlorocyclobutanone was de-
tected during the course of the reaction, but instead,
trichlorocyclobutenone 15 was obtained in good yield. A
final hydrolysis of the obtained cyclobutenone 15 indeed
yielded 4-phenylsemisquaric acid 1 in good yield (Scheme
2). This new synthesis is more efficient and easier to
perform as compared to other procedures reported in the
present literature.2
In an approach to reach 4-substituted 3-alkoxycy-
clobutenediones, tetrachlorinated imines 13 were treated
with 4 equiv of a 2-4 M solution of various sodium
alkoxides in the respective alcohols (Scheme 3). The
resulting trialkoxycyclobutenylimines 16 originated from
an initial dehydrohalogenation toward imines 14 followed
by a 3-fold substitution of the remaining chlorine atoms
by the respective alkoxides. Unfortunately, the reaction
of N-(3-butylcyclobutylidene)amine 13e resulted in a
tarry reaction mixture which could not be purified. In
contrast, this reaction pathway proceeded very smoothly
when using N-(3-arylcyclobutylidene)amines 13a-d. The
obtained new cyclobutenimines 16 were efficiently hy-
drolyzed in a biphasic CH2Cl2/aq 2 M HCl system toward
3-alkoxy-4-arylcyclobutenediones 1729 in high yields. This
method provides alkyl 4-arylsemisquarates directly, with-
out the need for a transformation of semisquaric acid to
the vinylogous esters. Methyl 4-phenylsemisquarate was
easily converted to the corresponding N-isopropylsemi-
squaramide 18 by reaction with isopropylamine at room
temperature.
Encouraged by these results, efforts were made to
apply this synthetic methodology to unsubstituted cy-
clobutanone 19, which should lead to semisquarates in
a very straightforward manner. Commercially available
cyclobutanone was reacted with NCS, trichloroisocyanu-
ric acid or chlorine gas, but unfortunately, in no cases
could a clean reaction mixture be obtained. The reaction
resulted in a mixture of compounds which could not be
separated by distillation or column chromatography. In
a n.d.: yield not determined (unstable compounds; the reaction
mixture was used as such for further transformation).
contrast, the reaction of N-(cyclobutylidene)amines
20a30-e, which were prepared from cyclobutanone, with
5 equiv of NCS in dry tetrachloromethane nicely resulted
in N-(2,2,4,4-tetrachlorocyclobutylidene)amines 21 in
good yields (Scheme 4). Attention must be drawn to the
fact that N-(cyclobutylidene)amines 20 are low-boiling,
heat- and moisture-sensitive compounds which have to
be used for further transformation immediately after
isolation. In particular, imines 20b and 20c, derived from
less sterically hindered amines, could not be stored even
at low temperature (-20 °C). Nevertheless, when used
directly in the chlorination reaction, no special precau-
tions had to be taken. Treatment of the chlorinated
imines 21 with an excess of 4 M sodium methoxide in
methanol did not yield the expected N-(2,4,4-trimethoxy-
2-cyclobutenylidene)alkylamines, but gave compounds 29
(Scheme 5). The formation of these compounds can be
rationalized by an initial Michael addition of methoxide
to the intermediate N-(trichlorocyclobutenylidene)amine
23 and subsequent dehydrochlorination and substitution
of the remaining chloro atoms by methoxide. The inter-
mediates 24 and 25 and the resulting imines 28 could
not be isolated even when using a nonaqueous workup.
J. Org. Chem, Vol. 70, No. 11, 2005 4551

Instead, cyclobutenones 29 resulting from the hydrolysis
of imines 28 were obtained after aqueous workup. The
structural assignment of these compounds was confirmed
by an X-ray analysis of the isopropyl derivative 29a,
which was purified by recrystallization from Et2O/CCl4/
CH2Cl2 50:50:5.
After hydrolysis of the vinylogous amides 29 with
aqueous HCl, crystalline semisquaramides 30a-e31 were
isolated and purified by chromatography in good yields.
Due to the low stability of n-propyl- and isobutylamino
intermediates 20b,c, 21b,c and 29b,c, a rapid synthesis
of 30b and 30c was necessary, without purification of
the intermediates. In that way, an overall yield of about
30% for squaramides 30b,c and ca. 40-45% for deriva-
tives 30a,d,e could be accomplished starting from com-
mercially available cyclobutanone.
In conclusion, it can be stated that an evaluation of
the synthetic utility of chlorinated N-(cyclobutylidene)-
amines, a virtually unknown class of compounds, emerged
in new straightforward syntheses of various semi-
squarates and new semisquaramides. The latter com-
pounds are of particular interest having in mind the
renewed attention focused on these compounds which
often display potent physiological activities. In addition,
an efficient synthesis of 4-phenylsemisquaric acid was
developed via initial chlorination of 2,2-dichloro-3-phe-
nylcyclobutanone and subsequent hydrolysis.
Acknowledgment. We are indebted to the IWT
(Flemish Institute for the Promotion of Scientific-
Technological Research in Industry), the FWO-Flanders,
and Ghent University (GOA) for financial support.
Supporting Information Available: General experimen-
1
tal conditions; H NMR, 13C NMR, IR, MS, and EI analytical
(29) (a) Reed, M. W.; Pollard, D. J.; Perri, S. T.; Lafayette, F.; Moore,
H. W. J. Org. Chem. 1988, 53, 2477. (b) Thorpe, J. E. J. Chem. Soc.,
Sect. B 1968, 12, 1534. (c) Schmidt, A. H.; Kircher, G.; Maus, S.; Bach,
H. J. Org. Chem. 1996, 61, 2085.
(30) Logothetis, L. A. J. Am. Chem. Soc. 1965, 87, 749.
(31) Schmidt, A. H.; Debo, M.; Wehner, B. Synthesis 1990, 3, 237.
data for compounds 12-18, 20, 21, 29, and 30; X-ray crystal-
lographic data for compound 29a. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0502044
4552 J. Org. Chem., Vol. 70, No. 11, 2005