Comparison of the reactivity of β-thiolactones and β-lactones toward ring-opening by thiols and amines

Article abstract of DOI:10.1039/c2ob25640a

An investigation into the comparative reactivity of simple β-lactones and β-thiolactones toward a thiol and a primary amine is reported. A simple 3-mercaptomethyl-2-oxetanone is found to undergo rearrangement in the presence of aqueous base to give the corresponding thietane-3-carboxylic acid rather than the 3-hydroxymethyl-2-thietanone. Implications for the use of β-thiolactones in bioorganic and medicinal chemistry are discussed.

Full text of DOI:10.1039/c2ob25640a

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PAPER
Comparison of the reactivity of β-thiolactones and β-lactones toward ring-
opening by thiols and amines†
Amandine Noel,a Bernard Delpecha and David Crich*a,b
Received 29th March 2012, Accepted 14th June 2012
DOI: 10.1039/c2ob25640a
An investigation into the comparative reactivity of simple β-lactones and β-thiolactones toward a thiol and
a primary amine is reported. A simple 3-mercaptomethyl-2-oxetanone is found to undergo rearrangement
in the presence of aqueous base to give the corresponding thietane-3-carboxylic acid rather than the
3-hydroxymethyl-2-thietanone. Implications for the use of β-thiolactones in bioorganic and medicinal
chemistry are discussed.
Introduction
We are interested in the chemistry of the β-thiolactones (2-thieta-
nones) as surrogates for the β-lactones and β-lactams in bio-
organic and medicinal chemistry,1,2 and as precursors3 to
substituted monothioacids for use in coupling reactions.4 An
integral part of this investigation is the study of the reactivity and
stability of these under-explored5–30 sulfur-based heterocycles,
whose longer carbon–sulfur bonds cause them to adopt puckered
conformations1,13,31–33 closer to the cyclobutanones than to their
oxygen and nitrogen counterparts. One way to approach this
problem and to put the chemistry of the β-thiolactones in context
is to carry out direct comparisons with that of the more familiar
β-lactones. Accordingly, we describe an investigation into the
relative stabilities and reactivities of simple β-thiolactones and
β-lactones toward nucleophilic ring opening reactions.
Scheme 1 Formation and opening of the β-lactone 3.
Results and discussion
Treatment of commercial 2,2-bis(hydroxymethyl)butyric acid 1
with mesitylenesulfonyl chloride and triethylamine in dichloro-
methane at −20 °C enabled isolation of the β-lactone 2 in 34%
yield (Scheme 1). Mitsunobu reaction with thioacetic acid,34,35
diethyl azodicarboxylate, and commercial 4-(heptadecafluorode-
cyl)phenyl diphenylphosphine36,37 then led to the thioester 3 in
59% yield. Treatment of 3 with hydrazine in acetonitrile enabled
selective cleavage of the thioester and resulted in the isolation of
the mercaptomethyl-β-lactone 4 in 87% yield (Scheme 1).
Treatment of the acetylthiomethyl-β-lactone 3 with hot 6 N
HCl, following a literature precedent for opening of β-lactones
under acidic conditions,57 enabled isolation of the hydrolysis
product 5 in 31% yield in a process complicated by nucleophilic
ring opening by chloride anion. The use of 48% tetrafluoroboric
acid in place of 6 N HCl resulted in a cleaner reaction mixture
and enabled isolation of 5 in 71% yield (Scheme 1).
In a series of experiments intended to probe the relative kine-
tics of ring closure of β-lactones and β-thiolactones, the hydro-
xymercapto acid 5 was exposed to a variety of typical
condensation reagents and the crude reaction mixtures examined
for the formation of 4 and/or 7 (Scheme 2) by both IR and NMR
spectroscopy. In all cases the reaction mixtures were complex,
showing, in addition to the β-thiolactone 7 (CvO stretch
aCentre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, 1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
bDepartment of Chemistry, Wayne State University, Detroit, MI 48202,
USA. E-mail: Dcrich@chem.wayne.edu; Fax: +(01) 313 577 8822;
Tel: +(01) 313 577 6203
1730 cm−1), traces of the lactone 4 (CvO stretch 1810 cm−1
)
†Electronic supplementary information (ESI) available: Full experimen-
1
tal details, characterization data and copies of H and 13C NMR spectra.
and a number of other products which rendered isolation
See DOI: 10.1039/c2ob25640a
difficult. Eventually, careful purification of the crude reaction
6480 | Org. Biomol. Chem., 2012, 10, 6480–6483
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Fig. 1 The cyclization of 5 with trifluoroacetic anhydride. (a) 1H NMR
1
1
1
of 8 (crude product), (b) H NMR of 4, (c) H NMR of 7, (d) H NMR
of the crude reaction mixture.
chlorides. Indeed, the low yield of the β-lactone 2 (Scheme 1)
can be accounted for in part by competing sulfonylation of a
hydroxyl group that is best explained by an intramolecular trans-
fer from a carboxyl/sulfonyl mixed anhydride. While quantita-
tive results could not be obtained from these reaction mixtures,
inspection of the IR and NMR spectra of the crude reaction mix-
tures nevertheless leads us to the reasonable conclusion that in
activated forms of 5, such as the mixed anhydride 6, 4-exo-trig
cyclization to form the β-thiolactone 7 is faster than that to form
the β-lactone 4. Conversely, 6-exo-trig cyclization from 6
appears to be faster for the harder alcohol than for the softer
thiol. We can not completely rule out the possibility that the
6-exo-trig trifluoroacetyl transfer process is also more rapid at
sulfur, giving the thioester 12 (Scheme 2), and that this is then
followed by a second acyl shift to the alcohol giving ester 9.
However, the lack of evidence for the formation of 12 combined
with Occam’s razor leads us to prefer the direct transfer of the
trifluoroacetyl group from 6 to the alcohol giving 9.
Scheme 2 Cyclization of the hydroxymercapto acid 5 with trifluoro-
acetic anhydride.
mixture arising from cyclization with trifluoroacetic anhydride
and triethylamine enabled the isolation of the β-thiolactone 7 in
10% yield (Scheme 2) along with the trifluoroacetyl ester 9 of
the starting hydroxymercapto acid 5, which could not be isolated
pure, but which was identified following esterification and loss
of the trifluoroacetyl group to give 10. The trifluoroacetylated
β-thiolactone 8 was tentatively identified in the crude cyclization
reaction mixture as a major product (Scheme 2, Fig. 1). The
identity of this trifluoroacetyl-β-thiolactone 8 was confirmed
when treatment of a crude isolate of mercaptoacid 9 was cyclized
with EDCI and pentafluorophenol (Scheme 2). When a crude
reaction mixture from the cyclization of 5 with trifluoroacetic
anhydride was treated with 4-nitrobenzoyl chloride, the β-thio-
lactone derivative 11 was isolated in 11% yield (Scheme 2),
somewhat consistent with the 10% yield of 7. Evidently, the
4-exo-trig cyclization of the initial mixed anhydride 6 to give ulti-
mately either the β-lactone 4 or the β-thiolactone 7 is relatively
slow due to the highly sterically hindered nature of the carboxyl
group. A competing 6-exo-trig cyclization leading to the transfer
of the trifluoroacetyl group and formation of the acid 9 was
observed as the major pathway. Activation of this acid with
further trifluoroacetic anhydride then provides the esterified
β-thiolactone 8. While the chemistry is exemplified for cycliza-
tion with trifluoroacetic anhydride, similar problems were
encountered with other dehydration reagents, including sulfonyl
Rearrangement of mercaptomethyl-β-lactone 4 to the corre-
sponding hydroxymethyl-β-thiolactone 7 was attempted under a
variety of conditions to no avail. However, treatment of 4 with
a mixture of 1 M aqueous sodium hydroxide and THF gave a
1
crude reaction mixture whose H NMR spectrum was devoid of
signals arising from 4 or 7, but which contained a major
product, formed in approximately 40% yield. Extractive work up
and acidification enabled isolation of this product, albeit only in
5% yield, and its identification as 3-ethylthietan-3-carboxylic
acid 13 (Scheme 3), with the low yield reflecting difficulties in
isolation. In view of the fact that thiolates are well-known to
open β-lactones by SN2 attack at the β-position, this remarkable
reaction might be viewed as an intramolecular SN2-like process
involving a bicyclo[2.2.0]hexane-like transition state made poss-
ible by the relatively long C–S bonds, both existing and incipient
(Scheme 3, path a). Alternatively, taking note of the widely
accepted stepwise zwitterionic intermediate model for the extru-
sion of CO2 from β-lactones,38–48 it may be considered as arising
from trapping of a transient zwitterionic form of the lactone
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Scheme 3 Possible mechanisms for the formation of thietanecar-
boxylic acid 13.
Fig. 2 Kinetic profile for the reaction of β-lactone 14 and β-thiolactone
15 with butanethiol.
Scheme 4 Opening of β-lactone 14 and β-thiolactone 15 with
butanethiol.
(Scheme 3, path b). While the elucidation of the mechanism of
formation of 13 from 4 must await further work, the formation
of 13 serves to underline the preference of β-lactones toward
nucleophilic ring opening at the β-position by soft
nucleophiles49–56 even though the nucleophile is ideally placed
for attack on the carbonyl centre. The attempted conversion of
the hydroxymethyl-β-thiolactone 7 to the mercaptomethyl-
β-lactone 4 under a variety of basic and Lewis acidic conditions
was not productive.
We next turned our attention to intermolecular competition
reactions for the opening of β-lactones and β-thiolactones by
simple nucleophiles. Thus, an equimolar mixture of 3-benzyl-2-
oxetanone 1458 and its thio analog 1512 in acetonitrile was
heated to 75 °C in the presence of 10 equivalents of butanethiol
and the progress of the reactions monitored by LC-MS. Separate
experiments demonstrated both substrates to react with the thiol
cleanly in the SN2-like mode and provided authentic samples of
the respective products 16 and 17 (Scheme 4). Plotting of the
concentrations of 14–17 against time for the competition reaction
(Fig. 2) and standard data analysis according to a pseudo-first
order kinetic scheme revealed the β-thiolactone 15 to be cleaved
to 17 with a half-life of 5.6 h, under conditions when the conver-
sion of the β-lactone 14 was essentially zero.
A similar competition between 14 and 15 for reaction with
isobutylamine was complicated by the parallel existence of the
SN2 and acylation pathways for the opening of the β-lactone by
the amine to give 18 and 19 in 27 and 71% yield, respectively,
consistent with literature precedents (Scheme 5).59,60 The β-thio-
lactone 15 followed a unique reaction path with the amine
leading to the formation of the amide 20, again consistent with
Scheme 5 Opening of β-lactone 14 and β-thiolactone 15 with
isobutylamine.
the literature precedents,3,12 that was complicated only by sub-
sequent disulfide formation to give 21 (Scheme 5).
Despite these complications, it proved possible to conduct
competition experiments in dichloromethane at room temperature
leading to the plots illustrated in Fig. 3 from which it is evident
that the thiolactone 15 reacts (t1/2 = 0.04 h) more rapidly with
isobutylamine than lactone 14 (t1/2 = 1.78 h) and, furthermore,
that the two modes of reaction of the lactone 14 proceed with
approximately equal rates. Unfortunately, attempts to perform
similar competition experiments with methanol as the nucleo-
phile have so far failed, owing to complications arising from
slow reactions in the absence of catalysis or heat, and polymeriz-
ation on heating or with catalysis by acid or base, consistent with
earlier literature reports on the reactions of simple β-lactones
with methanol.61,62
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