Unusual reactivity of N-acyl imides: N-aroyl-1,2,4-dithiazolidine-3,5- diones as acyl isocyanate equivalents

Article abstract of DOI:10.1039/b814677b

Crystalline samples of three N-aroyl-1,2,4-dithiazolidine-3,5-diones have been prepared as the first examples of a novel class of compound that displays the reactivity of an acyl isocyanate when treated with nucleophiles.

Full text of DOI:10.1039/b814677b

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Unusual reactivity of N-acyl imides: N-aroyl-1,2,4-dithiazolidine-3,5-diones
as acyl isocyanate equivalents†
Mark E. Wood,*a Victoria M. Annisa and Clifford D. Jonesb
Received 22nd August 2008, Accepted 18th September 2008
First published as an Advance Article on the web 1st October 2008
DOI: 10.1039/b814677b
Crystalline samples of three N-aroyl-1,2,4-dithiazolidine-3,5-
diones have been prepared as the first examples of a novel class
of compound that displays the reactivity of an acyl isocyanate
when treated with nucleophiles.
Recent studies in our laboratory have shown that N-alkyl-1,2,4-
Fig. 2 N-Aroyl-1,2,4-dithiazolidine-3,5-diones as possible acyl iso-
cyanate equivalents.
dithiazolidine-3,5-diones 1 can be prepared, using straightforward
procedures,1,2 from the parent heterocycle 2.3,4 Most significantly,
they can be regarded as protected isocyanates 3, the latter func-
tionality being revealed on treatment with triphenylphosphine,
under anhydrous conditions (Scheme 1).
The logical approach to the preparation of N-acyl imides
involves the treatment of the appropriate N-H imide with an
acid chloride, under basic conditions. Indeed, Titherley and
Hicks reported the preparation of N-benzoyl phthalimide in 1906
by the reaction between phthalimide and benzoyl chloride in
pyridine, from which the desired product was precipitated by
the addition of ethanol.11 Attempts to modify this methodology
for the use of 1,2,4-dithiazolidine-3,5-dione 2 failed to give the
desired product with benzoyl chloride and similar approaches
using other bases such as Hu¨nig’s base, caesium carbonate and
potassium tert-butoxide also failed. It was found, however, that
the desired reaction could be effected in dichloromethane using
poly(4-vinylpyridine) as an insoluble base to simplify purification.
Using this methodology, three novel N-aroyl-1,2,4-dithiazolidine-
3,5-diones 5 were prepared (Scheme 2 and Table 1).†
Scheme
1
N-Alkyl-1,2,4-dithiazolidine-3,5-diones as isocyanate
equivalents.
Acyl isocyanates 4 (Fig. 1) are very useful reagents, not only for
the preparation of N-acyl ureas and N-acyl carbamates but also for
the construction of a wide range of heterocycles by virtue of their
ability to readily undergo addition to unsaturated compounds.5–7
Such reagents are, however, considerably more reactive than their
N-alkyl counterparts 3, which can present substantial problems
with their handling and long-term storage. A relatively small
number of generally applicable methods are available for their
preparation, most notably the reaction of acid chlorides with
silver8 or sodium9 cyanate and the treatment of primary amides
with oxalyl chloride.10
Scheme 2 N-Aroylation of 1,2,4-dithiazolidine-3,5-dione. Reagents and
conditions: poly (4-vinylpyridine) (1 equiv.), CH2Cl2, 0 ◦C to reflux, 24 h.
The crude products obtained were found (by 1H and 13C
NMR) to be very impure and they generally contained significant
quantities of the primary amides corresponding to the acid
Fig. 1 N-Acyl isocyanates.
Table 1 Preparation of N-aroyl-1,2,4-dithiazolidine-3,5-diones
In view of our previous work, we initiated studies into the
preparation of hitherto unknown‡ N-aroyl-1,2,4-dithiazolidine-
3,5-diones 5 as possible acyl isocyanate 4 equivalents (Fig. 2).
Entry
1
Ar
Product
Yield (%)
22
5a
aSchool of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker
Road, Exeter, UK EX4 4QD. E-mail: m.e.wood@exeter.ac.uk; Tel: +44
1392 263450
2
3
5b
5c
18
14
bAstraZeneca, Cancer and Infection Chemistry, Mereside, Alderley Park,
Macclesfield, UK SK10 4TG
† Electronic supplementary information (ESI) available: General ex-
perimental procedure for the preparation of 5a–5c and analyti-
cal/spectroscopic data for these compounds. See DOI: 10.1039/b814677b
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Table 2 N-Aroyl urea formation from N-aroyl-1,2,4-dithiazolidine-3,5-
chlorides used. The fact that the quantity of the amide increased
on attempting to remove by-products using aqueous sodium
bicarbonate solution suggested that they were the result of
hydrolytic cleavage of the heterocycle in the products 5. Despite
attempts to exclude all water from the reaction mixtures by its
azeotropic removal from the poly(4-vinylpyridine) with benzene
prior to use, we could not significantly reduce the quantity of amide
by-product formed and attempts to purify the crude reaction
products by chromatography on silica gel unsurprisingly led to
apparent complete decomposition of the required products 5.
Fortunately, however, the N-aroyl-1,2,4-dithiazolidine-3,5-diones
5 proved to be highly crystalline and whilst they could only be
obtained in relatively low yields, they could be crystallised in
an analytically pure form from chloroform, by slow diffusion of
pentane, layered carefully above the solution. Interestingly, it was
clear that the crude products resulting from the reactions carried
out at reflux contained significantly fewer by-products than those
from reactions carried out at lower temperatures. The resulting
crystalline solids have subsequently been stored in air for several
months with no noticeable decomposition.
Preparation of 4-methoxybenzoyl isocyanate 4b from N-(4-
methoxybenzoyl)-1,2,4-dithiazolidine-3,5-dione 5b by desulfuri-
sation with solid-supported triphenylphosphine was attempted
at 40, 80 and 110 ◦C in dichloromethane, benzene and toluene
respectively (Scheme 3). Shorter reaction times appeared to result
in no reaction, 5b still being present, and extended reaction periods
(up to 48 h) gave 4-methoxybenzamide 6 (Fig. 3) as the only
isolable product after filtering off the solid-supported reagent and
evaporation of the solvent, despite care being taken to exclude
moisture at all times.
diones and primary amines
Entry
1
Ar
R
Solvent
THF
Product
Yield (%)
86
tBu
10a
2
3
4
5
tBu
THF
THF
PhMe
THF
10b
10c
10d
10e
64
57
71
64
tBu
dione 8 (Fig. 3) would be a very good leaving group in this
system, giving similar reactivity. When treated with a range of
primary amines 9 (in THF or toluene under reflux), however,
5a–c gave the corresponding N-aroyl ureas 10 in reasonable
yields, apparently produced by nucleophilic attack at a carbonyl
group of the heterocyclic ring rather than the exocyclic carbonyl
group as originally expected (Scheme 4). The results for these
experiments are summarised in Table 2 and they suggest that N-
aroyl-1,2,4-dithiazolidine-3,5-diones 5 are capable of reacting as
acyl isocyanate 4 equivalents.
Scheme 4 N-Aroylurea formation from N-aroyl-1,2,4-dithiazolidine-
3,5-diones and primary amines. Reagents and conditions: amine (1 equiv.),
THF or PhMe, reflux, 24 h.
Scheme 3 Attempted is isocyanate generation from N-(4-methoxyben-
zoyl)-1,2,4-dithiazolidine-3,5-dione. Reagents and conditions: solid-sup-
ported triphenylphosphine (1.3 equiv.), solvent (CH2Cl2, C6H6 or PhMe),
reflux, 24–48 h.
A secondary amine (morpholine, 11) gave a similar result
on reaction with N-(4-methoxybenzoyl)-1,2,4-dithiazolidine-3,5-
dione 5b (Scheme 5) and 4-nitrobenzyl alcohol 12 also produced
the corresponding N-(4-methoxybenzoyl)urethane 13 under es-
sentially identical conditions (Scheme 6).
Fig. 3 4-Methoxybenzamide, N-(trifluoroacetyl)succinimide and the
conjugate base of 1,2,4-dithiazolidine-3,5-dione.
Scheme 5 N-Aroylurea formation from N-(4-methoxybenzoyl)-1,2,4-
dithiazolidine-3,5-dione and morpholine. Conditions: THF, reflux, 18 h.
Given the ability of N-(trifluoroacetyl)succinimide 7 (Fig. 3) to
act as an “active ester-type” reagent for trifluoroacetylation,12 the
reactivity of N-aroyl-1,2,4-dithiazolidine-3,5-diones 5a–c towards
amines and alcohols was investigated. In view of the low pKa
value of 2 (pKa = 2.85, I = 0.163, 25.6 ◦C)13 compared with that
Alkaline hydrolysis of N-alkyl-1,2,4-dithiazolidine-3,5-diones
1 is believed to occur via nucleophilic attack of hydroxide at
a carbonyl group of the heterocycle15 and nitrogen nucleophiles
are also known to form ureas directly with these compounds,1,16
suggesting the mechanism shown in Scheme 7 is appropriate
◦
of succinimide (pKa = 9.59, I = 0.5, 25 C),14 it was initially
anticipated that the conjugate base of 1,2,4-dithiazolidine-3,5-
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Acknowledgements
We thank AstraZeneca and EPSRC for funding to V. M. A., the
EPSRC National Mass Spectrometry Service Centre (Swansea,
UK) for mass spectra and Dr Stephen J. Simpson (Exeter, UK)
for NMR work.
Notes and references
Scheme 6 N-Aroylcarbamate formation from N-(4-methoxybenzoyl)-
1,2,4-dithiazolidine-3,5-dione and 4-nitrobenzyl alcohol. Conditions:
THF, reflux, 24 h.
‡ We previously reported (tentatively) the possible preparation of N-
benzoyl 1,2,4-dithiazolidine-3,5-dione,1 however, the studies described
herein revealed that our original structural assignment was incorrect.
1 M. E. Wood, D. J. Cane-Honeysett, M. D. Dowle, S. J. Coles and M. B.
Hursthouse, Org. Biomol. Chem., 2003, 1, 3015.
2 D. J. Cane-Honeysett, M. D. Dowle and M. E. Wood, Tetrahedron,
2005, 61, 2141.
3 G. Zumach and E. Ku¨hle, Angew. Chem., Int. Ed. Engl., 1970, 9, 54.
4 L. Chen, T. R. Thompson, R. P. Hammer and G. Barany, J. Org. Chem.,
1996, 61, 6639.
5 B. A. Arbuzov and N. N. Zobova, Synthesis, 1974, 461.
6 B. A. Arbuzov and N. N. Zobova, Synthesis, 1982, 433.
7 For more recent examples of heterocycle synthesis using N-acyl
isocyanates, see: Y. Hari, T. Iguchi and T. Aoyama, Synthesis, 2004,
1359; Y. Hari, T. Iguchi and T. Aoyama, Synthesis, 2005, 2147.
8 A. J. Hill and W. M. Degnan, J. Am. Chem. Soc., 1940, 62, 1595.
9 M.-Z. Deng, P. Caubere, J. P. Senet and S. Lecolier, Tetrahedron, 1988,
44, 6079.
10 A. J. Speziale and L. R. Smith, J. Org. Chem., 1962, 27, 3742.
11 A. W. Titherley and W. L. Hicks, J. Chem. Soc., 1906, 89, 708.
12 A. R. Katritzky, B. Yang, G. Qiu and Z. Zhang, Synthesis, 1999, 55.
13 D. J. Cane-Honeysett, M. D. Dowle and M. E. Wood, Synlett, 2000,
1622.
Scheme 7 Proposed mechanism for nucleophilic ring-opening of N-aroyl-
1,2,4-dithiazolidine-3,5-diones.
for N-aroyl-1,2,4-dithiazolidine-3,5-diones 5 behaving as acyl
isocyanates 4.
In summary, we have demonstrated the first method for the
preparation of N-aroyl-1,2,4-dithiazolidine-3,5-diones 5, a novel
class of compound that shows the reactivity of an acyl isocyanate
4 in reactions with amine and alcohol nucleophiles. Whilst there is
clearly room for improvement in the method for the preparation
and isolation of these compounds, they represent a potentially
very useful, crystalline and air stable alternative to a difficult to
handle, yet important, class of reagent.
14 M. J. Blais, O. Enea and G. Berthon, Thermochim. Acta, 1977, 20, 335.
15 G. Barany and R. B. Merrifield, J. Am. Chem. Soc., 1980, 102, 3084.
16 M. Planas, E. Bardaj´ı, K. J. Jensen and G. Barany, J. Org. Chem., 1999,
64, 7281.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 4099–4101 | 4101
©