Reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide heterocyclic system: A combined experimental and theoretical study

Article abstract of DOI:10.1002/chem.200800433

The reactivity of the 4-amino-5H-1,2-oxathiole-2,2-dioxide (or β-amino-γ-sultone) heterocyclic system has scarcely been studied. Here we describe the reactivity of this system towards electrophiles and amines on readily available model substrates differently substituted at the C-5 position. A variety of C-electrophiles, carbonyl electrophiles (such as acyl chlorides, isocyanates, or aldehydes) and halogen or nitrogen electrophiles have been explored. Both the C-3 and 4-amino positions of the β-amino-γ- sultone system are able to undergo electrophilic reactions, and the reaction products depend on the electrophile used and on the reaction conditions. On the other hand, nucleophilic attack of amines occurs at the C-4 position of the β-amino-γ-sultone system only in spiranic substrates bearing alicyclic substituents at the C-5 position. A comparative computational study between spiranic and non-spiranic substrates suggests that conformational changes, undergone on intermediate compounds, account for the observed reactivity differences. Moreover, these conformational changes seem to bring about an increase of electron density on the N-4 and C-3 atoms of the enaminic system, and a possible enhancement in the reactivity of spiranic substrates towards electrophiles in the presence of amines. Experimental data consistent with this predicted enhanced reactivity is also presented.

Full text of DOI:10.1002/chem.200800433

DOI: 10.1002/chem.200800433
Reactivity of the 4-Amino-5H-1,2-Oxathiole-2,2-Dioxide Heterocyclic
System: A CombinedExperimental andTheoretical Study
Sonia de Castro,[a] M. Teresa Peromingo,[a] Angel E. Lozano,[b]
[a]
María-JosØ Camarasa,[a] andSonsoles Velµzquez*
Abstract: The reactivity of the 4-
amino-5H-1,2-oxathiole-2,2-dioxide (or
b-amino-g-sultone) heterocyclic system
has scarcely been studied. Here we de-
scribe the reactivity of this system to-
wards electrophiles and amines on
readily available model substrates dif-
ferently substituted at the C-5 position.
A variety of C-electrophiles, carbonyl
electrophiles (such as acyl chlorides,
isocyanates, or aldehydes) and halogen
or nitrogen electrophiles have been ex-
plored. Both the C-3 and 4-amino posi-
tions of the b-amino-g-sultone system
are able to undergo electrophilic reac-
tions, and the reaction products depend
on the electrophile used and on the re-
action conditions. On the other hand,
nucleophilic attack of amines occurs at
the C-4 position of the b-amino-g-sul-
tone system only in spiranic substrates
bearing alicyclic substituents at the C-5
position. A comparative computational
study between spiranic and non-spiran-
ic substrates suggests that conforma-
tional changes, undergone on inter-
mediate compounds, account for the
observed reactivity differences. More-
over, these conformational changes
seem to bring about an increase of
electron density on the N-4 and C-3
atoms of the enaminic system, and a
possible enhancement in the reactivity
of spiranic substrates towards electro-
philes in the presence of amines. Ex-
perimental data consistent with this
predicted enhanced reactivity is also
presented.
Keywords: density functional calcu-
lations
· heterocycles · reactive
intermediates · spiro compounds ·
sultones
Introduction
1,2-oxathiole-2,2-dioxide (or b-amino-g-sultone) heterocyclic
system, first reported by us in 1988,[4] was generated by
treatment of a-mesyloxynitriles of sugars under non-nucleo-
philic basic conditions. The mechanism involves deprotona-
tion of the alkylsulfonate moiety at the a-position, in a basic
medium, and attack of the carbanion, thus generated, on the
cyano group through an intramolecular aldol-type cyclocon-
densation to give, eventually, the cyclic enamine system.
This unexpected synthetic event (the expected reaction
would have been a b-elimination to leave a cyano group at-
tached to a double bond) was later extended to other a-me-
syloxynitriles of sugars,[5] and non-carbohydrate templates
(adamantane derivatives).[6] We also reported the applica-
tion of this reaction to nucleoside templates, which led to
the discovery of a unique class of potent and specific anti-
HIV-1 agents called TSAO derivatives.[7–9] This aldol-type
cyclo-condensation was later renamed by other researchers
as a CSIC reaction (carbanion-mediated sulfonate intramo-
lecular cyclisation reaction) and further used with other al-
kanesulfonate or alkanesulfonamide substrates.[10–12]
Sultones are versatile heterocyclic intermediates, the
chemistry, industrial applications, and biological properties
of which continue to be of interest.[1] Even though recent
chemical literature on saturated g-sultones has been de-
scribed,[2] research on the chemistry of a,b-unsaturated-g-
sultones,[3] and particularly of b-amino-substituted represen-
tatives of this family, is much more scarce. The 4-amino-5H-
[a] Dr. S. de Castro, M. T. Peromingo, Dr. M.-J. Camarasa,
Dr. S. Velµzquez
Instituto de Química MØdica (C.S.I.C.)
C/Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)915-644-853
E-mail: iqmsv29@iqm.csic.es
[b] Dr. A. E. Lozano
Instituto de Ciencia y Tecnología de Polímeros (C.S.I.C.)
Juan de la Cierva 3, 28006 Madrid (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800433, and contains general
experimental methods, synthesis and characterisation of compounds
4b, 5b, 6, 10b, 13, 21, 22, 24, 27, 28, 30a, 30b, 31b, 32b, 37–42, 44–46,
48–51, and 53, plus an additional figure showing the general structure
of TSAO nucleosides.
The potentially rich chemical reactivity embodied in the
b-amino-g-sultone heterocyclic ring has been investigated,
although not in detail.[10a] Various synthetic studies for the
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FULL PAPER
direct and selective functionalisation of the C-3 or the
amino positions of the enamine system on TSAO com-
pounds have been performed.[13,14] However, the presence of
tert-butyldimethylsilyl groups (TBDMS) at positions 2’ and
5’, sensitive to basic and acid media, respectively, but essen-
tial for the antiviral efficacy of the TSAO compounds, re-
stricted the selection of smooth reaction conditions compati-
ble with such groups. The corresponding b-keto-g-sultone,
obtained by hydrolysis,[6,10a] has been transformed to b-
amino and b-keto sulfonic acids by reductive opening of the
ring.[11b] Moreover, chloroformylation of the b-keto-g-sul-
tone system led to unsaturated b-chloro-a-formyl-g-sultone
derivatives, which are useful intermediates for the synthesis
of heterocyclic compounds.[15] Finally, opening of the 4-
amino-5H-1,2-oxathiole-2,2-dioxide system on sugar deriva-
tives has also been carried out with a nucleophilic base such
as methanolic sodium methoxide.[5]
In this current work we describe the chemical reactivity of
the enamine system of the b-amino-g-sultone heterocyclic
ring on easily available simple model substrates, which
would allow exploration of a wider range of reaction condi-
tions than in TSAO derivatives. The behaviour of this
system towards electrophiles of different nature and amines
has been investigated. Our results revealed that the reactivi-
ty towards amines is highly dependent on the nature of the
C-5 substituents of the substrate. We also discuss the experi-
mentally observed chemical reactivity differences in the
light of molecular calculations. This study is able to justify
the experimental results based on electronic and geometrical
features of reactive and intermediate compounds. A further
analysis of these intermediates suggests an enhanced reactiv-
ity of spiranic substrates towards electrophiles, in the pres-
ence of bases, in comparison with non-spiranic substrates.
Experimental data consistent with this predicted enhance-
ment of reactivity is also presented.
which involved cyanohydrine formation from the corre-
sponding commercially available ketones, followed by mesy-
lation and final ring closure with an appropriate base. Thus,
reaction of 1,3-diphenyl-2-propanone (1a) with sodium cya-
nide and sodium hydrogencarbonate in ether/water, accord-
ing to previously described conditions,[5,8,10a] afforded the cy-
anohydrine 2a (40%) together with unreacted starting ma-
terial (40%; Scheme 1). Better yields were obtained through
the TMS-protected cyanohydrines procedure.[16,17] Thus,
treatment of 1a with trimethylsilyl cyanide in the presence
of a catalytic amount of BF3·Et2O, followed by deprotection
of the trimethylsilyl cyanohydrine 3a with 3n hydrochloric
acid, afforded the cyanohydrine 2a in 70% yield. Further
improvement of this reaction was achieved when equimolec-
ular amounts of BF3·Et2O were used. Under these condi-
tions the two-step method could be performed in a one-pot
procedure and the cyanohydrine 2a was obtained in higher
yields (90%). Reaction of 2a with mesyl chloride (slowly
added at 08C) in dichloromethane, with triethylamine as
base at room temperature, gave the desired alkyl sulfonate
derivative 4a in low yield (25%) and the ketone derivative
1a (40%), used as starting material. Conversion of the cya-
nohydrine back to the ketone material could be avoided
when the mesyl chloride was slowly added at À208C and
the reaction was then stirred at 08C. The desired alkyl sulfo-
nate derivative 4a was then obtained in 80% yield. The cyc-
lisation-base step in TSAO derivatives is usually carried out
either with Cs2CO3 or DBU.[7–9] Compound 4a failed to cy-
clise by using DBU as the base. Instead, b-elimination of
the tertiary mesylate group was observed (compound 6,[18]
Scheme 1). However, the b-amino-g-sultone derivative 5a
was readily obtained when Cs2CO3 or NaH were used as
bases (80% or 62% yield, respectively).
The synthesis of b-amino-g-sultone derivative 5b, bearing
a benzyl and an ethyl substituent at the C-5 position, was
carried out in a similar way, using these conditions and start-
ing from commercially available 1-phenyl-2-butanone 1b
(Scheme 1). The 1H NMR spectra of compounds 5a,b
showed the presence of two singlets at 6.33 and 5.21 ppm
for 5a, and at 6.19 and 5.40 ppm for 5b. The high-field sig-
nals disappeared on rapid exchange with D2O and were as-
signed to the NH2 group. The downfield singlets that disap-
peared on slow exchange with D2O were assigned to H-3.
The slow exchange could be due to an imine-enamine tauto-
meric equilibrium.[5]
Results andDiscussion
The b-amino-g-sultone derivatives 5a,b were selected as
simple and readily available substrates for our studies
(Scheme 1). We first focused on achieving optimal reaction
conditions for the synthesis of the dibenzyl derivative 5a,
The b-amino-g-sultone ring has two electron-rich centres
at C-3 and 4-amino, respectively. We first examined the re-
activity of the model b-amino-g-sultone derivatives 5a,b to-
wards C-electrophiles such as alkyl halides. Thus, reaction of
5b with benzyl bromide in the presence of NaH at room
temperature afforded the 4-N- and 3-C-benzylated deriva-
tives 7 (21%) and 8 (10%) together with the N,C-dialkylat-
ed compound 9a (15%) and unreacted starting material
(Scheme 2). Longer reaction times and increasing amounts
of the electrophile and the base (1 or 2 additional equiva-
lents) afforded, exclusively, the N,C-dialkylated derivative
9a in a 51% yield. Similarly, reaction of 5b with methyl
Scheme 1.
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S. Velµzquez et al.
out at room temperature overnight, a mixture of compounds
12 (17%), 13 (10%) and unreacted starting material (40%)
was obtained. Formation of compound 13 could be ex-
plained by a second Michael addition of enamine 12 to
methyl propiolate. Prolonged reaction time or increased
equivalents of the electrophile and of the base led to the de-
composition of the starting material, but did not increase
the yields of the products. Interestingly, when the reaction
between 5b and methyl propiolate was carried out in the
presence of NaH as the base, the N-acylated derivative 14
was obtained in 40% yield.
To avoid acylation of the 4-amino group in the presence
of NaH, methyl propiolate was replaced by acrylonitrile as
the Michael acceptor. When model sultone 5b was reacted
with two equivalents of acrylonitrile in the presence of NaH
at room temperature for one hour, mixtures of the N,C-di
and the tri-Michael adducts 15 and 16 were isolated
(Scheme 2). Reduced amounts of acrylonitrile and base
(1 equiv) afforded mixtures of the N- and C-monoalkylated
17 and 18 and the N,C-dialkylated compound 16
(Scheme 2). Polyalkylation of the enamine system could be
explained by the higher reactivity of the Michael acceptor
(acrylonitrile vs methyl propiolate).
Reaction of the model b-amino-g-sultone derivatives 5a,b
with carbonyl electrophiles, such as isocyanates, occurs ex-
clusively at the 4-amino group of the enamine system in
good yields. Thus, reaction of 5a with chlorosulfonyl isocya-
nate in acetonitrile, followed by treatment with aqueous
NaHCO3, gave the 4-unsubstituted ureido derivative 19 in
46% yield (Scheme 3). Similarly, reaction of 5a,b with an
excess of ethoxycarbonyl or benzoyl isocyanate, in dry ace-
tonitrile at 808C, afforded the corresponding 4’’-N-acyl sub-
stituted ureido derivatives 20 (93%), 21 (60%), and 22
(81%) in good yields.
Scheme 2.
iodide in the presence of KOH also afforded the N,C-dialky-
lated derivative 9b in 47% yield. These results were similar
to those obtained in TSAO nucleosides.[13] We next studied
the reaction of 5a with dimethylformamide dimethylacetal
to give the protected amino compound, and its reaction with
alkyl halides in order to alkylate regioselectively the C-3 po-
sition of the sultone ring. The 4-dimethylaminomethylen-
amino derivatives 10a,b were easily prepared in excellent
yields (97%) by the condensation reaction of 5a,b with an
excess of dimethylformamide dimethylacetal.[19] However,
all attempts to alkylate 10a,b with methyl iodide in the pres-
ence of different bases (NaH or KOH) were unsuccessful
and unreacted starting material was recovered, in spite of
the expected increased nucleophilicity of C-3 due to the
electron-donating effect of the dimethylaminomethylen-
ACHTREUNG
model substrates with a,b-unsaturated reagents (Michael ac-
ceptors) as C-electrophiles. It appears that in this case alky-
lation of the enamine system, in the presence of DMAP,
takes place exclusively through the amine, albeit in low
yields. Thus, treatment of sultone 5b with 1.2 equivalents of
methyl propiolate in acetonitrile in the presence of DMAP
at 08C for two hours gave a 10:1 mixture of E/Z Michael
adducts 12 (Scheme 2) in 17% yield, together with unreact-
ed starting material (45%). When this reaction was carried
Scheme 3.
Treatment of compound 5b with an excess of benzoyl
chloride and DMAP as base in acetonitrile afforded the N-
benzoyl derivative 23 in 71% yield (Scheme 3) after a pro-
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Heterocyclic System Reactivity
FULL PAPER
longed reaction time (4 days) at room temperature. When
this reaction was carried out in a pressure reaction vessel at
808C (general N-acylation conditions used in TSAO nucleo-
side derivatives),[14] the initially observed N-acyl group of 23
underwent migration to the enaminic C-3 carbon to give the
C-acylated product 24 after three hours, in good yield
(69%). It should be noted that N-acylation of the b-amino-
g-sultone heterocyclic system at room temperature or C-acy-
lation with acyl chlorides has never been observed previous-
ly in TSAO nucleoside derivatives.[14]
could be considered as useful intermediates for further func-
tionalisation of this heterocycle.
Modifications at the 4-position of the b-amino-g-sultone
heterocyclic system, which have been previously reported to
work smoothly in this system, such as acid hydrolysis of the
enamino system,[6,10a,12] or substitution of this amino group
by other amines through transamination reactions[14] were
next addressed in our substrates (Scheme 5). In good agree-
Other carbonyl electrophiles such as aldehydes (previ-
ously unexplored in TSAO nucleoside substrates) react with
model sultone derivatives 5a,b exclusively at the C-3 posi-
tion of the enamine system (Scheme 3). Reaction of 5b with
benzaldehyde in dry THF in the presence of NaH at low
temperature (À788C) afforded the 3-hydroxyphenylmethyl
derivative 25 in low yield. Interestingly, when 5a,b was re-
acted with benzaldehyde under similar conditions at 708C,
the 3-benzoyl derivatives 26 and 24 were obtained in 88 and
77% yield, respectively. Similarly, reaction of 5b with 2-fur-
aldehyde and cyclohexanaldehyde at 708C afforded the 3-
acyl derivatives 27 and 28 in good yields (74 and 73%, re-
spectively). However, reaction of 5a,b with acetaldehyde,
propanaldehyde or unsaturated aldehydes, such as croton-
A
Scheme 5.
starting material was observed.
We next investigated the behaviour of the model sub-
strates 5a,b towards other electrophiles, such as halogen or
nitrogen electrophiles (Scheme 4). Compounds 5a,b reacted
with halogen electrophiles, also exclusively at the C-3 posi-
tion of the enamine system, in good yields. Bromo and iodo
substituents were easily introduced by using Johnsonꢁs con-
ditions,[20] which involves iodine in basic medium. Thus,
treatment of 5a with iodine in ethanol, and sodium bicar-
bonate as base, afforded the 3-iodo derivative 29 in 70%
yield. Similarly, reaction of 5a,b with bromine in ethanol
yielded the 3-bromo derivatives 30a,b in excellent yields (98
and 95%, respectively). On the other hand, nitrosation of
5a,b with sodium nitrite in acetic acid at 08C gave the
purple 3-nitroso derivatives 31a,b in 81 and 61% yield, re-
spectively (Scheme 4). These 3-functionalised derivatives
ment with previous results, hydrolysis of compounds 5a,b
with 1n HCl in methanol afforded the expected b-keto-g-
sultone derivatives 32a,b (Scheme 5) in good yields (85 and
76%, respectively). Alternative methods for the synthesis of
the b-keto-g-sultone heterocyclic system involved cyclisation
of a-(carboxyethyl)alkyl alkanesulfonates.[21]
1H and 13C NMR spectra of compounds 32a,b revealed
that they exist in solution in the keto (A) or enol (B) forms
1
depending on the choice of solvent. In CDCl3, the H NMR
spectra of 32a,b showed the disappearance of the singlets
assigned to the 4-NH2 and the H-3, and the presence of a
new AB system at d=2.99 and 3.23 ppm, corresponding to
the H-3 of the keto form A. In 13C NMR, the chemical shifts
for the C-4 ketone carbonyl are at d=200.6 and 200.8 ppm,
which are typical values for ketone carbonyls. However, in
1
[D6]DMSO, the H NMR spectra of 32a,b showed a broad
singlets at d=12.75 and 12.84 ppm, respectively, exchangea-
ble with D2O, which were assigned to the hydroxyl protons
of the corresponding enol tautomers (B). The singlets at d=
5.86 ppm for 32a and d=6.03 ppm for 32b were assigned to
the H-3 vinyl protons of the corresponding enol tautomers.
In 13C NMR, the enolic C-4 carbon appears at d=166.2 ppm
for 32a and d=166.2 ppm for 32b. These results indicate
that in [D6]DMSO, compounds 32a,b exist in enol form.
However, in contrast with TSAO derivatives,[14] trans-
amination reactions of 5a,b with an excess of H-Gly-
OMe.HCl or H-b-Ala-OMe.HCl as amines, heated in meth-
anol under reflux in a sealed tube for several days were un-
successful, and unreacted starting material was recovered
(Scheme 5).
Scheme 4.
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S. Velµzquez et al.
The marked reactivity difference found between the
TSAO sultone system (in which the sultone moiety is fused
to the C-3’ position of the ribose ring of TSAO nucleosides,
Figure 1 below, Supporting Information) and the model sub-
strates 5a,b in the reactions with amines prompted us to in-
vestigate whether the spiranic (TSAO nucleosides) or non-
spiranic nature of the model substrates 5a,b could explain
the experimental reactivity differences. Thus, the spiro-fused
compounds 40, 41 and 42 (Scheme 6) containing the b-
Scheme 6.
amino-g-sultone moiety were chosen as simple spiranic
models and were subjected to transamination reactions. The
synthesis of the simpler derivatives 40 and 41, fused to a cy-
clopentane or a tetrahydrofuran ring, was carried out in a
similar way to that described for the model substrates 5a,b,
starting from the appropriate commercially available cyclic
ketone 34 and 35,[22] by cyanohydrine formation, mesylation
and base cyclisation. Thus, treatment of 34 and 35[22] with
trimethylsilyl cyanide in the presence of one equivalent of
BF3·Et2O afforded the corresponding cyanohydrines, which
were subsequently reacted with mesyl chloride in the pres-
ence of triethylamine as base to yield the desired alkyl sulfo-
nate derivatives 37 and 38 (72 and 63% overall yield, re-
spectively). Reaction of 37 and 38 with Cs2CO3 gave the de-
sired fused spiro sultone derivatives 40 and 41 in good yields
(91 and 70%, respectively). The spiro sultone compound 42
(Scheme 6) fused to a N-benzyl-3-pyrrolidine ring was simi-
larly prepared by reaction of N-benzyl-3-pyrrolidinone (36)
with potassium cyanide in water at 08C, in the presence of
sodium bicarbonate,[23] followed by mesylation (mesyl chlo-
ride/triethylamine) and base-cyclisation (Cs2CO3) to give the
desired fused spiro derivative 42 in good yield.
Interestingly, reaction of spiro sultone derivatives 40–42
with an excess of amines such as glycine or b-alanine ester
hydrochlorides in methanol under reflux, in a sealed tube
for 24 h, afforded the N-alkyl derivatives 43–46 (Scheme 7)
in moderate to good yields (40, 76, 67, and 62%, respective-
ly). Thus, remarkable differences in the reactivity of the b-
amino-g-sultone heterocyclic system towards amines be-
tween spiranic and non-spiranic substrates were observed.
Theoretical studies, mentioned below, were carried out to
rationalise these reactivity differences. As will be comment-
ed below, these studies further suggest that interaction of a
tertiary amine, and consequently a base, on the C-4 position
brings about an increase in the reactivity of spiranic sub-
strates towards electrophiles. To test this prognosis, the reac-
tivity of model spiranic b-amino-g-sultone derivatives 40–42
Scheme 7.
towards electrophiles, such as benzoyl chloride or methyl
propiolate, in the presence of DMAP as base, was next com-
pared with that of model non-spiranic substrates 5a,b. Inter-
estingly, spiro sultone derivatives 40–42 reacted with ben-
zoylchloride in the presence of DMAP in dry acetonitrile
very rapidly and efficiently (Scheme 7). It took only 1–5 h at
room temperature to go to completion, affording the N-ben-
zoyl derivatives 47–49 in good yields (70, 71, and 78%
yields, respectively). Thus, the rate of these N-benzoylations
was dramatically increased in spiro sultone derivatives at
room temperature (1–5 h for 40–42 compared with four days
for compound 5b). At higher temperature (808C in a sealed
tube) treatment of compound 42 with benzoylchloride and
DMAP in dry acetonitrile gave the expected C-benzoyl de-
rivative 50 in three hours in 67% yield. However, reaction
of the simpler spiro sultone derivatives 40 and 41 under sim-
ilar conditions with benzoylchloride and DMAP at 808C led
to product decomposition. Finally, reaction of compounds
40–42 with methyl propiolate and DMAP in acetonitrile at
À208C for 1–6 h gave a mixture of the N-alkylated deriva-
tives of E and Z configuration 51–53 (Scheme 7) in higher
yields than that of model non-spiranic substrates (45–57%
yield for 40–42 vs. 17% yield for compounds 5a,b). There-
fore, the reactivity of the enaminic system of spiro sultone
derivatives 40–42 towards benzoyl chloride, methyl propio-
late or amines appears to be higher than that of non-spiranic
substrates 5a,b.
Theoretical study: A comparative computational study be-
tween spiranic and non-spiranic b-amino-g-sultone sub-
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Heterocyclic System Reactivity
FULL PAPER
strates was carried out in order to rationalise the experimen-
tal results described in this paper. All the b-amino-g-sultone
compounds (Am) together with their corresponding (E)-
and (Z)-imine tautomers (Im) were modelled by means of
DFTB3LYP/6-31G(d) calculations to determine the tauto-
mer populations and their geometrical features.
The DFT quantum-mechanical calculations showed the
relative Gibbs energy of the different tautomers to follow
the order depicted in Scheme 8. The tendency in free energy
indicates that the most stable isomer for all studied com-
pounds is that of the amine. However, when the substituents
on C-5 are not alicyclics, the imine tautomers have free
energy values close to that found for the 4-amino one
(DGAm ꢀDGIm2 >DGIm1).
linear chains, the conformational change when the system
goes from the amine tautomer to the imine ones is easily
achieved. However, when R1 and R2 form an alicyclic
moiety, this conformational change is more difficult to ach-
ieve, because both cycles, joined by a spiranic carbon, are
mutually hindering, and an energetic and synergic agree-
ment between both cycles has to be accomplished to permit
successful proton transfer.
On calculating the Mulliken and ESP charges by compu-
tational chemistry methods, it is observed that the b-amino-
g-sultone ring has two electron-rich atoms centred on the C-
3 and 4-amino atoms (Figure 2). HOMO energy values,
Figure 2. HOMO representation of amine tautomer (left) and (Z)-imine
tautomer of 40 (right).
close to À6.5 eV for the 4-amino derivatives and near 7.0 eV
for the (Z)- and (E)-imine tautomers, indicate that these
molecules have a slightly hard behaviour and that the amine
nitrogen atom is more nucleophilic than the imine ones.
Also, the HOMO electron density for the amine tautomer is
mainly centred on the C-3 and 4-amino atoms, with the
higher electron density placed on C-3, no matter which com-
pound is analyzed. For the imine compounds, the HOMO
electron density, even though it is more delocalised, is
mainly centred on the NH imine moiety having the C-3
atom with lower electron density than the nitrogen one.
Therefore, the reactivity towards electrophiles will depend
on the ratio of tautomers present in the reaction system.
Thus, attending to electronic features, the 4-amino tauto-
mers will react towards electrophiles both on the nitrogen
and C-3 atoms, even though the product ratio should be
slightly displaced to the reaction on N-4, whilst the (E)- or
(Z)-imine tautomers will react mostly at the N-4 position.
In Scheme 9 the plausible reactions for b-amino-g-sultone
derivatives and their corresponding tautomers with electro-
philes are shown. This scheme also depicts the relative equi-
librium constants of the obtained product ratio. To justify
the latter scheme derived from the analysis of the HOMO
frontier orbital, quantum calculations were also carried out
to model these electrophilic reactions on the C-3 and 4-
amino positions. It could be observed that both positions are
able to undergo electrophilic reactions. When an ethyl
cation, chosen as an electrophilic probe for the sake of sim-
plicity, was allowed to interact with the compound described
in this paper, the intermediate state of the attack on the C-3
position had higher energy than that of the attack on the 4-
Scheme 8. Gibbs energy orders for b-amino-g-sultone tautomers.
In geometric terms, the differences between the diverse
tautomers are important. Thus, the five-membered sultone
cycle of the amine tautomer is almost flat, with the sulfur
and carbon atoms C-3, C-4 and C-5 forming a plane, where-
as the oxygen atom of the cycle forms a rough envelope
conformation. This oxygen atom has a flap angle higher
than 1758 in relation to that plane. Regarding the imine con-
formations, the sultone ring forms a more real envelope con-
formation in which the flap atom is placed, in this case, on
the sulfur atom (Figure 1). This conformational change, as
commented below, seems to be responsible for the peculiar
reactivity of these chemical systems towards several mole-
cules. Also, the conformational divergence depends on the
substituents at the C-5 position. Thus, when R1 and R2 are
Figure 1. Molecular modelling, B3LYP/6–31G(d) geometry for 4-amino
tautomer of 41 (left) and (Z)-imine tautomer of 41 (right).
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9625

S. Velµzquez et al.
Figure 3. LUMO representation of amine tautomer (left) and (Z)-imine
tautomer of 40 (right).
transpositions necessary to rationalise the interconversion
between the amino and imine tautomers.
The dramatic difference in reactivity of spiranic versus
non-spiranic sultone derivatives towards amines as nucleo-
philes cannot be explained by considering solely the frontier
orbitals of these substrates and nucleophiles. Therefore, a
computational study of the reactions by nucleophiles to-
wards the 4-amino-1,2-oxathiole-2,2-dioxide heterocyclic
systems was carried out. For the sake of simplicity, the trans-
amination reactions were modelled by placing an ammonia
molecule (as a simple amine probe) near the C-2 position.
In this context, the ammonia nucleophile moiety was placed
at 2.0 Š, calculating the optimised geometry for two
models: one simulating the attack from the top, and the
other from the bottom of the five-membered sultone ring
plane.
As shown in Scheme 10, for the non-spiranic sultone com-
pounds it was not possible to find any energy minimum or
intermediate state for the reaction of NH3 with the amino-
derivative, because the nucleophile was ejected from the ini-
tial distance to distances larger than 3.5 Š, showing that this
molecule is not able to interact with the C-4 carbon. Howev-
er, NH3 was able to interact in all the spiranic compounds,
forming an intermediate compound (I) that was able to
progress towards the transamination compound. The inter-
mediate I is only produced when the ammonia molecule in-
teracts with the C-4 position through one side (top position
of Scheme 10). This intermediate state showed a contorted
conformation on the sultone ring, which is not flat, showing
an envelope conformation with the spiranic carbon being
the flap atom (E5). This state is stabilised because the other
ring also undergoes a conformational change. Both coordi-
Scheme 9. Electrophilic reactions of b-amino-g-sultone derivatives and
their corresponding tautomers.
amino one (Scheme 9). However, the final state of the
attack on the 4-amino position had the lowest free energy.
Also, it was found by thermodynamic reasoning that the
attack on the C-3 position of the imine moiety is reversible,
resembling the tautomerism of the proton, and hence, in-
stead of a proton making the interchange, the electrophile
seems to be able to jump from the C-3 position to the 4-
amino one. These calculations are thus capable of justifying
the obtained experimental results. After the first electrophil-
ic reaction, another one is possible on the other reactive po-
sition. In conclusion, both C-3 and 4-amino positions will be
capable of undergoing electrophilic reactions, and the reac-
tion products will depend on the substrate, the used electro-
phile (soft or hard) and the reaction conditions (pH, temper-
ature, time, etc.).
Theoretical studies of b-amino-g-sultone substrates to-
wards nucleophiles were also performed. LUMO diagrams
show the C-4 position to be the most favourable for attack
by nucleophiles (Figure 3). Also, the lobes of the LUMO
centred on the C-3 and 4-amino positions allow justification
of the feasibility of these systems to undergo the proton
Scheme 10.
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Chem. Eur. J. 2008, 14, 9620 – 9632

Heterocyclic System Reactivity
FULL PAPER
nated changes are able to
lessen the energy of the system,
producing the intermediate
was placed at 2.0 Š from the C-4 position. Again, similar in-
termediate states to those found above were obtained only
for spiranic compounds. In this case, the lowest DGS inter-
mediate was that derived from 41 (DGS =65.91 kcalmolÀ1),
whilst the highest one corresponded to 40 (DGS =89.23 kcal
molÀ1). As an example, the geometry conformation of the
intermediate state derived from 41 is depicted in Figure 6.
The obtained geometry is analogous to the geometry of the
intermediate of the reaction with NH3. However, the distan-
compound
(Figure 4).
The
lowest relative Gibbs energies
for the intermediate compounds
(DGS =DGintermediateÀDGreactives
=
DGintermediateÀDGsultoneÀDGNH
)
3
were found for the intermedi-
ates derived from 41 (DGS =
50.32 kcalmolÀ1) and 42 (DGS =
48.21 kcalmolÀ1), being slightly
higher for 40 (DGS =57.32 kcal
molÀ1). The progress of the re-
action is easily achieved by
transfer of a proton from the
NH3 group to the NH2 one,
with release of the protonated
group, NH3. The stage resultant
ces N
N
N
termediates resulting from the interaction with NMe3. Thus,
in absolute terms, the electronic interaction is lower than
that obtained for the reaction with ammonia.
Figure 4. Molecular model of
the resultant intermediate (I)
of the reaction between 42 and
NH3.
of the proton transfer matches with the attack on the non-
reactive side, and hence the NH3 is released, yielding the
transamination product. Evidently, if the nucleophile is an
amine (RNH2), the resultant compound is the transamina-
tion product, in which the resultant moiety placed on C-4 is
NHR.
Furthermore, the conformational change mentioned
above, needed to produce the intermediate compound (I,
Scheme 10), may bring about an increase of electron density
on the N-4 and C-3 atoms. In particular, the HOMO graph
(Figure 5) indicates that the highest electron density is locat-
Figure 6. Geometry of the intermediate state resultant of the interaction
between 41 and NMe3.
Again, the electron density is mainly located on the C-3
and N-4 atoms. Thus, after the interaction of the nucleophile
(NMe3), the 4-amino group is geometrically out of plane
with a structure like an aliphatic amine (sp3) with enhanced
reactivity and capable of reacting under mild conditions
with electrophilic entities. Also, the C-3 position showed the
HOMO highest density, and, therefore, may be able to react
with the same electro-deficient systems. The enhancing of
reactivity is evident from observation of the HOMO energy.
The HOMO energy is À6.59 eV for 41, À5.60 eV for NMe3,
and À5.05 eV for the intermediate compound. This lower
EHOMO of the intermediate compound means a higher reac-
tivity towards electrophiles, which has been supported ex-
perimentally, as mentioned before. The reactivity of posi-
tions C-3 and N-4 will depend on the electrophile used and
the reaction conditions. Paying attention to this result, the
reactivity of these systems is explained and summarised in
Scheme 11.
Figure 5. HOMO graph of the intermediate state I resultant of the reac-
tion between 41 and NH3.
ed on the C-3 carbon. Also, the amine group attached to
that carbon is out of the plane of the sultone envelope, its
nature being more sp3, and thus more reactive to electro-
philes. As an example, the HOMO graph for the intermedi-
ate compound derived from 41 is portrayed in Figure 5.
This increase of electron density on the N-4 and C-3
atoms, on the intermediate state resulting from the interac-
tion of a nucleophile on C-4, may anticipate an enhanced re-
activity of spiranic substrates towards electrophiles in the
presence of amines as bases, compared with the non-spiranic
substrates. Thus, a similar computational study replacing the
ammonia molecule by a tertiary amine as a base was carried
out. In this case, NMe3 was used as a simple probe and it
Conclusion
The reactivity of the readily available 4-amino-5H-1,2-oxa-
thiole-2,2-dioxide (b-amino-g-sultone) heterocyclic system
toward electrophiles and amines has been studied. One of
the interesting features of the system is its ambident nucleo-
philicity: nucleophilic reaction can take place at the site of
the enaminic carbon atom (C-3) and/or the primary amino
nitrogen atom, depending on the nature of the electrophile
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9627

S. Velµzquez et al.
corded with a spectrometer operating at 75, 100, and 125 MHz. Analyti-
cal thin-layer chromatography (TLC) was performed on silica gel 60 F254
.
Separations on silica gel were performed by preparative centrifugal circu-
lar thin-layer chromatography (CCTLC) on a Chromatotron (Kiesegel
60 PF254 gipshaltig, layer thickness of 1 mm, flow rate of 5 mLminÀ1).
Flash column chromatography was performed with silica gel 60 (230–400
mesh). Liquid chromatography was performed using a force flow (flash
chromatography) HPFC Horizon system with Flash 25m cartridges (KP-
Sil Silica, 60 Š, 40–63 mm).
Triethylamine, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, acetoni-
trile, and ethanol were dried by heating under reflux over calcium hy-
dride. Tetrahydrofuran was dried by heating under reflux over sodium/
benzophenone.
2-Benzyl-2-hydroxy-3-phenylpropionitrile (2a)
Method A: NaHCO3 (79 mg, 0.94 mmol) and sodium cyanide (24 mg,
0.48 mmol) were added to a solution of 1a (100 mg, 0.48 mmol) in diethyl
ether (2 mL)/water (1 mL). The mixture was stirred at room temperature
for 40 h. The organic layer was separated and the aqueous phase was fur-
ther extracted with diethyl ether (2”10 mL). The combined organic ex-
tracts were dried and evaporated to dryness. The residue was purified by
column chromatography (hexane/ethyl acetate 1:2), to give 2a (45 mg,
40%) as a white amorphous solid. 1H NMR (300 MHz, (CD3)2CO): d=
2.96 (s, 4H), 6.49 (brs, 1H), 7.42 ppm (m, 10H). The slowest moving
band afforded 40 mg (40%) of unreacted starting material (1a).
Scheme 11. Geometrical and electronic (EHOMO) parameters for the inter-
mediate resulting from the reaction of spiranic compounds with electro-
philes (E1, E2) in the presence of a base (top) along with its reaction
products (bottom).
Method B: Trimethylsilyl cyanide (130 mL, 0.96 mmol) and boron trifluor-
ide diethyl etherate (12 mL, 0.096 mmol) were added to a solution of 1a
(100 mg, 0.48 mmol) in dichloromethane (5 mL). The mixture was stirred
at room temperature for 0.5 h. The solvent was evaporated to dryness. A
solution of 3n HCl (5 mL) was added and the resulting suspension was
stirred at room temperature for 12 h. Volatiles were removed and the res-
idue, thus obtained, was dissolved in ethyl acetate (10 mL) and washed,
successively, with aqueous NaHCO3 (2”5 mL) and brine (2”5 mL). The
organic layer was dried (Na2SO4), filtered, and evaporated to dryness.
The final residue was purified by CCTLC on the Chromatotron (hexane/
ethyl acetate, 1:2) to give 2a (80 mg, 70%) as a white foam.
and the reaction conditions. On the other hand, amines
react at the C-4 position of the heterocycle through an ex-
change with the amino function only in spiranic substrates
bearing alicyclic substituents at the C-5 position. Theoretical
studies indicate that the reactivity of spiranic systems to-
wards amines is primarily controlled by conformational
changes on intermediate compounds. Furthermore, the cal-
culations predict an enhanced reactivity of spiranic sub-
strates towards electrophiles in the presence of amines. This
increase of reactivity on spiranic derivatives comes from the
interaction of an electron-rich moiety, such as an amine at
the C-4 position. This interaction brings about a conforma-
tional change with breaking of the planarity of the sultone
ring, which increases the reactivity of the C-3 and N-4 posi-
tions towards electrophiles. This is supported by experimen-
tal results, which indicated that the rate or yields of the re-
action of spiranic substrates with electrophiles, such as ben-
zoyl chloride or methyl propiolate in the presence of a terti-
ary amine (DMAP), were dramatically increased when com-
pared with model non-spiranic substrates. These studies
represent a clear example of how an electronic interaction is
able to induce conformational changes that lead to inter-
mediate states with increase reactivity.
Method C: Trimethylsilyl cyanide (400 mL, 3 mmol) and boron trifluoride
diethyl etherate (253 mL, 2 mmol) were added to solution of 1a (420 mg,
2 mmol) in dichloromethane (5 mL). The mixture was stirred at room
temperature for 2 h and the solvent was evaporated to dryness. The resi-
due, thus obtained, was dissolved in ethyl acetate (10 mL), washed with
brine (2”5 mL) and dried (Na2SO4). After filtration and evaporation of
the solvent, the residue was purified by CCTLC on the Chromatotron
(hexane/ethyl acetate, 1:2) to give 2a (430 mg, 90%) as a white foam.
2-Benzyl-2-(methanesulfonyloxy)-3-phenylpropionitrile
(4a):
Et3N
(1.9 mL, 14 mmol) was added to a solution of 2a (600 mg, 2.2 mmol) in
dry dichloromethane (5 mL). The mixture was cooled to À308C and
methanesulfonyl chloride (460 mL, 6 mmol) was slowly added. The mix-
ture was stirred at À208C for 1 h and at 08C for an additional hour. Vola-
tiles were removed and the residue was dissolved in ethyl acetate
(10 mL) and washed successively with water (10 mL) and brine (2”
10 mL). The organic phase was dried (Na2SO4), filtered and evaporated
to dryness. The final residue was purified by flash column chromatogra-
phy on silica gel (hexane: ethyl acetate, 10:1) to give 4a (0.55 g, 80%) as
a white amorphous solid. 1H NMR (200 MHz, (CD3)2CO): d=2.85 (s,
3H), 3.42 and 3.47 (AB system, J=9.4 Hz, 4H), 7.38 ppm (m, 10H); IR
(film): n˜ =2541 cmÀ1; elemental analysis calcd (%) for C17H17NO3S: C
64.74, H 5.43, N 4.44, S 10.17; found: C 64.44, H 5.09, N 4.67, S 9.98. The
slowest moving band afforded 30 mg (5%) of unreacted starting material
(2a).
Experimental Section
4-Amino-5,5-dibenzyl-5H-1,2-oxathiole-2,2-dioxide (5a): Caesium car-
bonate (490 mg, 1.5 mmol) was added to a suspension of 4a (310 mg,
1 mmol) in dry acetonitrile (3 mL), and the mixture was stirred at room
temperature for 2 h. Solvent was removed and the residue, thus obtained,
was dissolved in ethyl acetate (20 mL) and washed successively with
water (10 mL) and brine (2”10 mL). The organic phase was dried
(Na2SO4) and filtered, followed by evaporation of the solvent. The resi-
due was purified by CCTLC on the Chromatotron (hexane/ethyl acetate,
3:1) to give 5a (270 mg, 80%) as a white solid. M.p. (toluene): 225–
Chemical procedures: Melting points were determined in a Reichert-
Jung Thermovar hot-stage microscope equipped with a polarizer. IR
spectra were obtained on a Perkin–Elmer Spectrum One spectrophotom-
eter. Microanalyses were carried out on a CHN-O-RAPID instrument.
Mass spectra were measured on
equipped with an electrospray source (LC/MC HP 1100). 1H NMR spec-
tra were recorded with spectrometer operating at 300, 400, and
500 MHz with Me4Si as the internal standard. 13C NMR spectra were re-
a quadropole mass spectrometer
a
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Chem. Eur. J. 2008, 14, 9620 – 9632

Heterocyclic System Reactivity
FULL PAPER
2268C; 1H NMR (200 MHz, (CD3)2CO): d=3.12 and 3.35 (AB system,
J=14.5 Hz, 4H), 5.21 (s, 1H), 6.33 (brs, 2H, NH2), 7.30 ppm (m, 10H);
13C NMR (50 MHz, (CD3)2CO): d=43.4, 90.1, 92.2, 128.2, 129.1, 132.1,
135.9, 142.5, 158.5 ppm; IR (film): n˜ =3501, 3407 cmÀ1; MS (ES+): m/z:
316.1 [M+1]+, 338.1 [M+Na]+, 631.2 [2M+1]+, 653.2 [2M+Na]+; ele-
mental analysis calcd (%) for C17H17NO3S: C 64.74, H 5.43, N 4.44, S
10.17; found: C 64.50, H 5.03, N 4.12, S 10.03.
on an Horizon system (hexane/ethyl acetate 1:1) to give 10a (115 mg,
97%) as
a white solid. M.p. (dichloromethane/hexane): 181–1828C;
1H NMR (300 MHz, (CD3)2CO): d=3.05 and 3.22 (AB system, J=
13.5 Hz, 4H), 3.18 (s, 6H), 5.76 (s, 1H), 7.25 (m, 10H), 7.88 ppm (s, 1H);
13C NMR (50 MHz, (CD3)2CO): d=35.3, 41.2, 43.4, 95.0, 98.5, 127.9,
128.9, 132.2, 136.5, 159.0, 165.7 ppm; MS (ES+): m/z: 371.3 [M+1]+; ele-
mental analysis calcd (%) for C20H22N2O3S: C 64.84, H 5.99, N 7.56, S
8.66; found: C 64.56, H 5.62, N 7.33, S 8.28.
4-Benzylamino-5-benzyl-5-ethyl-5H-1,2-oxathiole-2,2-dioxide, 4-amino-
3,5-dibenzyl-5-ethyl-5H-1,2-oxathiole-2,2-dioxide and 4-benzylamino-3,5-
dibenzyl-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (7, 8 and 9a): A solution of
5b (100 mg, 0.40 mmol) and NaH (21 mg, 0.88 mmol) in dry THF (5 mL)
was stirred at room temperature for 10 min. Then, benzylbromide
(147 mL, 0.99 mmol) was added and the mixture was stirred at room tem-
perature for 19 h and neutralised with acetic acid to pHꢁ7. The residue
obtained after evaporation was purified by HPFC on a Horizon system
(hexane/ethyl acetate, 2:1). From the fastest moving band 9a (25 mg,
15%) was isolated as a white amorphous solid. M.p. (hexane/ethyl ace-
tate): 187–1888C; 1H NMR (500 MHz, (CD3)2CO): d=1.03 (t, J=7.0 Hz,
3H), 1.91 (m, 1H), 2.18 (m, 1H), 3.35 (s, 2H), 3.55 and 3.63 (AB system,
J=18.3 Hz, 2H), 4.24 (ABX system, J=5.9 and 15.6 Hz, 1H), 4.25 (ABX
system, J=7.4 and 15.6 Hz, 1H), 6.42 (ABX system, J=5.9 and 7.4 Hz),
1H, 6.98 (d, J=7.3 Hz, 2H), 7.16 (t, J=7.3 Hz, 1H), 7.22 (t, J=7.3 Hz,
2H), 7.33 ppm (m, 10H); 13C NMR [125 MHz, (CD3)2CO] d=7.9, 28.4,
30.7, 44.3, 47.6, 92.2, 97.9, 126.9, 127.3, 127.8, 128.2, 128.4, 128.8, 129.2,
129.5, 131.9, 135.5, 140.4, 140.5, 151.4 ppm; MS (ES+): m/z: 434.3
[M+1]+, 451.3 [M+H2O]+, 889.3 [2M+Na]+; elemental analysis calcd
(%) for C26H27NO3S: C 72.03, H 6.28, N 3.23, S 7.40; found: C 71.89, H
5.99, N 3.00, S 7.12.
Reaction of sultone 5b with methyl propiolate
5-Benzyl-5-ethyl-4-[(E)-2-(methoxycarbonyl)vinyl]amino-5H-1,2-oxa-
thiole-2,2-dioxide ((E)-12) and (Z)-12:
A solution of 5b (100 mg,
0.39 mmol), methyl propiolate (42 mL, 0.47 mmol) and DMAP (57 mg,
0.47 mmol) in dry acetonitrile (10 mL) was stirred at 08C for 2 h. The sol-
vent was removed and ethyl acetate was added (5 mL) and the mixture
was washed with 0.1n HCl (2”5 mL) and brine (2”5 mL). The organic
layer was dried, filtered and evaporated to dryness. The final residue was
purified by CCTLC on the Chromatotron (hexane/ethyl acetate, 1:2) to
give a 90:10 mixture (20 mg, 17%) of (E)-12 and (Z)-12 as a white foam.
Data for (E)-12: 1H NMR (300 MHz, (CD3)2CO): d=0.90 (t, J=7.5 Hz,
3H), 1.85 (m, 1H), 2.03 (m, 1H), 3.25 (s, 2H), 3.65 (s, 3H), 5.52 (d, J=
13.4 Hz, 1H), 6.54 (s, 1H), 7.25 (m, 5H), 7.55 (dd, J=11.2, 13.4 Hz, 1 H),
8.87 ppm (d, J=11.2 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=23.3, 28.9,
44.7, 51.8, 92.4, 95.9, 102.2, 127.8, 128.1, 128.5, 128.7, 130.9, 133.0, 139.7,
151.4, 167.0 ppm; IR (film): n˜ =3405, 1716 cmÀ1; MS (ES+): m/z: 338.0
[M+1]+, 360.0 [M+Na]+, 697.0 [2M+Na]+; elemental analysis calcd (%)
for C16H19NO5S: C 56.96, H 5.68, N 4.15, S 9.50; found: C 56.67, H 5.31,
N 4.01, S 9.42.
Data for (Z)-12: 1H NMR (300 MHz, (CD3)2CO): d=3.78 (s, 3H), 5.23
(d, J=6.3 Hz, 1H), 6.41 ppm (s, 1H). The slowest moving band afforded
42 mg (42%) of unreacted starting material (5b).
1
The next moving band gave 28 mg (21%) of 7 as a white foam. H NMR
(300 MHz, (CD3)2CO): d=0.87 (t, J=7.2 Hz, 3H), 1.74 (m, 1H), 2.03 (m,
1H), 3.25 (s, 2H), 4.31 (d, J=5.5 Hz, 2H), 5.40 (s, 1H), 6.69 (brt, J=
5.5 Hz, 1H; NH), 7.35 ppm (m, 10H); 13C NMR (100 MHz, (CD3)2CO):
d=6.8, 28.9, 44.1, 48.9, 87.6, 92.1, 127.1, 127.8, 128.1, 128.8, 131.1, 134.9,
137.5, 157.1 ppm; MS (ES+): m/z: 344.3 [M+1]+, 366.3 [M+Na]+, 709.1
[2M+Na]+; elemental analysis calcd (%) for C19H21NO3S: C 66.45, H
6.16, N 4.08, S 9.34; found: C 66.23, H 5.99, N 3.89, S 8.97.
5-Benzyl-5-ethyl-4-propioloylamino-5H-1,2-oxathiole-2,2-dioxide (14): A
solution of 5b (100 mg, 0.39 mmol) and NaH 60% dispersion in mineral
oil (32 mg, 0.78 mmol) in dry THF (5 mL) was stirred at room tempera-
ture for 1 h. Methyl propiolate (69 mL, 0.78 mmol) was added and the
mixture was stirred at room temperature for 3 h. Solvent was removed
and the residue was dissolved in ethyl acetate (5 mL) and the mixture
was washed with water (2”5 mL) and brine (2”5 mL). The organic layer
was dried (Na2SO4), filtered and evaporated to dryness. The final residue
was purified by CCTLC on the Chromatotron (hexane/ethyl acetate, 4:1)
to give 14 (48 mg, 40%) as a white solid. M.p. (hexane/ethyl acetate):
136–1378C; 1H NMR (400 MHz, (CD3)2CO): d=0.87 (t, J=7.3 Hz, 3H),
1.85 (m, 1H), 2.17 (m, 1H), 3.28 and 3.36 (AB system, J=14.5 Hz, 2H),
4.06 (s, 1H), 7.22 (s, 1H), 7.27 (m, 5H), 10.20 ppm (brs, 1H; NH);
13C NMR (100 MHz, (CD3)2CO): d=7.0, 28.8, 43.5, 76.7, 79.0, 93.8, 107.0,
127.7, 128.6, 131.3, 134.4, 146.0, 151.0 ppm; IR (film): n˜ =3508, 2305,
1707 cmÀ1; MS (ES+): m/z: 306.0 [M+1]+, 633.2 [2M+Na]+; elemental
analysis calcd (%) for C15H15NO4S: C 59.00, H 4.95, N 4.59, S 10.50;
found: C 58.83, H 5.00, N 4.37, S 10.11.
The slowest moving band afforded 13 mg (10%) of 8 as a white foam.
1H NMR (500 MHz, (CD3)2CO): d=0.93 (t, J=7.5 Hz, 3H), 1.82 (m,
1H), 2.08 (m, 1H), 3.25 (s, 2H), 3.58 and 3.63 (AB system, J=17.3 Hz,
2H), 5.83 (brs, 2H; NH2), 7.16 (d, J=7.3 Hz, 2H), 7.19 (m, 1H), 7.20 (m,
2H), 7.30 ppm (m, 5H); 13C NMR (125 MHz, (CD3)2CO): d=14.4, 27.6,
44.3, 92.0, 100.1, 126.9, 127.7, 128.7, 128.9, 129.0, 131.8, 135.5, 138.3,
152.3 ppm; MS (ES+): m/z: 344.3 [M+1]+, 361.2 [M+H2O]+, 366.2
[M+Na]+, 709.2 [2M+Na]+; elemental analysis calcd (%) for
C19H21NO3S: C 66.45, H 6.16, N 4.08, S 9.34; found: C 66.32, H 6.01, N
3.87, S 9.31.
5,5-Dibenzyl-3-methyl-4-methylamino-5H-1,2-oxathiole-2,2-dioxide (9b):
A solution of 5a (100 mg, 0.32 mmol) and KOH (54 mg, 0.90 mmol) in
dry 1,4-dioxane (15 mL) was stirred at room temperature for 15 min.
Then MeI (126 mL, 0.90 mmol) was added. The mixture was stirred at
room temperature for 24 h, neutralised with acetic acid and concentrated
to dryness. The residue was treated with ethyl acetate (2”5 mL) and
brine (5 mL). The organic phase was dried (Na2SO4), filtered and evapo-
rated to dryness. The residue was purified by CCTLC on the Chromato-
tron (hexane/ethyl acetate, 1:1) to give 9b (30 mg, 27%) as a white amor-
phous solid. M.p. (hexane/ethyl acetate): 213–2148C; 1H NMR
(300 MHz, (CD3)2CO): d=1.90 (s, 3H), 3.03 (d, J=5.1 Hz, 3H), 3.05 and
3.26 (AB system, J=14.5 Hz, 4H), 6.81 (br s, 1H; NH), 7.25 ppm (m,
10H); 13C NMR (50 MHz, (CD3)2CO): d=7.1, 29.8, 41.9, 88.9, 126.1,
126.3, 130.0, 134.4, 142.1 ppm; MS (ES+): m/z: 344.2 [M+1]+, 366.6
[M+Na]+, 711.3 [2M+Na]+; elemental analysis calcd (%) for
C19H21NO3S: C 66.45, H 6.16, N 4.08, S 9.34; found: C 66.21, H 6.01, N
3.87, S 9.11.
Reaction of sultone 5b with acrylonitrile
Method A (2equivalents of acrylonitrile and NaH) : A solution of sultone
5b (100 mg, 0.39 mmol) and NaH 60% dispersion in mineral oil (32 mg,
0.78 mmol) in dry THF (4 mL) was stirred at room temperature for
15 min. Acrylonitrile (52 mL, 0.78 mmol) was added and the mixture was
stirred at room temperature for 1 h. The solvent was removed under
vacuum and the residue was dissolved in ethyl acetate (5 mL). The mix-
ture was washed with water (2”10 mL) and brine (10 mL). The organic
layer was dried (Na2SO4), filtered and evaporated to dryness. The final
residue was purified by flash chromatography on silica gel (pentane/ethyl
acetate, 1:1). From the fastest moving band, 5-benzyl-3-(2-cyanoethyl)-4-
bis-(2-cyanoethyl)amino-5-ethyl-5H-1,2-oxathiole-2,2-dioxide
(15)
(35 mg, 25%) was isolated as
a
white foam. 1H NMR (400 MHz,
(CD3)2CO): d=1.10 (t, J=7.2 Hz, 3H), 1.92 (ddd, J=5.2, 11.2, 14.8 Hz,
1H), 2.15 (m, 1H), 2.20–2.51 (m, 5H), 2.54–2.66 (m, 1H), 2.82 (m, 2H),
3.04 (t, J=6.4 Hz, 2H), 3.44 and 3.48 (AB system, J=15.2 Hz, 2H), 4.17
(td, J=6.4, 14.8 Hz, 1H), 4.36 (td, J=6.4, 15.2 Hz, 1H), 7.36 ppm (m,
5H); 13C NMR (100 MHz, (CD3)2CO): d=8.2, 12.0, 12.3, 20.3, 26.7,
28.7, 40.5, 48.6, 65.8, 96.3, 119.3, 119.4, 119.8, 129.2, 129.6, 131.7, 134.9,
168.5 ppm; MS (ES+): m/z: 435.2 [M+Na]+, 413.3 [M+1]+; elemental
5,5-Dibenzyl-4-[(dimethylamino)methylen]amino-5H-1,2-oxathiole-2,2-
dioxide (10a): N,N-Dimethylformamide dimethyl acetal (170 mL,
1.28 mmol) was added to a solution of 5a (100 mg, 0.32 mmol) in dry
DMF (10 mL). The reaction mixture was stirred at 408C for 40 min. The
solvent was evaporated to dryness and the residue was purified by HPFC
Chem. Eur. J. 2008, 14, 9620 – 9632
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9629

S. Velµzquez et al.
analysis calcd (%) for C21H24N4O3S: C 61.14, H 5.86, N 13.58, S 7.77;
found: C 61.08, H 5.79, N 13.72, S 7.58.
3399, 3222, 1744 cmÀ1; MS (ES+): m/z: 431.0 [M+1]+, 453.0 [M+Na]+,
882.9 [2M+Na]+; elemental analysis calcd (%) for C21H22N2O6S: C 58.59,
H 5.15, N 6.51, S 7.45; found: C 58.33, H 4.91, N 6.33, S 7.39.
The slowest moving band afforded 5-benzyl-3-(2-cyanoethyl)-4-(2-cya-
noethyl)amino-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (16) (15 mg, 15%) as
a white foam. 1H NMR (400 MHz, (CD3)2CO): d=0.92 (t, J=7.6 Hz,
3H), 1.78 (m, 1H), 2.09 (m, 2H), 2.57–2.72 (m, 2H), 2.89 (m, 3H), 3.26
(s, 2H), 3.85 (q, J=6.4 Hz, 2H), 6.19 (brt, J=5.6 Hz, 1H), 7.30 ppm (m,
5H); 13C NMR (100 MHz, (CD3)2CO): d=7.5, 18.2, 19.0, 20.1, 29.8, 41.0,
44.9, 92.4, 98.4, 118.9, 119.7, 127.9, 128.9, 131.9, 135.3, 150.2 ppm; MS
(ES+): m/z: 382.3 [M+Na]+; elemental analysis calcd (%) for
C18H21N3O3S: C 60.15, H 5.89, N 11.69, S 8.92; found: C 60.21, H 5.96, N
11.75, S 9.14.
4-Benzoylamino-5-benzyl-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (23): Ben-
zoyl chloride (140 mL, 1.20 mmol) was added to a solution of 5a (100 mg,
0.40 mmol) and DMAP (217 mg, 1.78 mmol) in dry acetonitrile (5 mL).
The mixture was stirred at room temperature for 4 days. Salts were fil-
tered and solvent was evaporated and ethyl acetate was added. The or-
ganic layer was successively washed with 1n HCl (2”5 mL) and brine
(2”5 mL), dried (Na2SO4), filtered and evaporated to dryness. The final
residue was purified by CCTLC on the Chromatotron (hexane/ethyl ace-
tate, 5:1) to yield 100 mg (71%) of 23 as a white foam. 1H NMR
(400 MHz, (CD3)2CO): d=0.93 (t, J=7.2 Hz, 3H), 1.86–1.96 (m, 1H),
2.30–2.39 (m, 1H), 3.40 and 3.47 (AB system, J=14.4 Hz, 2H), 7.25–7.33
(m, 2H), 7.45–7.66 (m, 4H), 7.61–7.67 (m, 2H), 7.86–7.89 (m, 1H), 8.03–
8.05 (m, 2H), 9.58 ppm (brs, 1H); 13C NMR (100 MHz, (CD3)2CO): d=
8.5, 30.0, 44.9, 95.4, 106.8, 129.0, 129.9, 130.0, 131.4, 132.4, 132.7, 134.6,
134.7, 135.5, 136.0, 148.6, 168.6 ppm; MS (ES+): m/z: 358.3 [M+1]+; ele-
mental analysis calcd (%) for C19H19NO4S: C 63.85, H 5.36, N 3.92, S
8.97; found: C 63.91, H 5.41, N 4.09, S 9.06.
Method B (1 equivalent of acrylonitrile and NaH): A solution of sultone
5b (100 mg, 0.39 mmol) and NaH 60% dispersion in mineral oil (16 mg,
0.39 mmol) in dry THF (4 mL) was stirred at room temperature for
15 min. Acrylonitrile (26 mL, 0.39 mmol) was added and the mixture was
stirred at room temperature overnight. Solvent was removed and the res-
idue was dissolved in ethyl acetate (10 mL) and the mixture was washed
with water (2”10 mL) and brine (10 mL). The organic layer was dried
(Na2SO4), filtered and evaporated to dryness. The final residue was puri-
fied by flash chromatography on silica gel (pentane/ethyl acetate, 1:1)
From the slowest moving band a 2:1 mixture of 5-benzyl-3-(2-cyanoeth-
yl)-4-(2-cyanoethyl)amino-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (16) and
5-benzyl-4-(2-cyanoethyl)amino-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (17)
(49 mg, 41%) was obtained as a white foam. Compound 17: 1H NMR
(400 MHz, (CD3)2CO): d=0.85 (t, J=7.3 Hz, 3H), 1.78 (m, 1H), 2.15 (m,
1H), 2.86 (m, 2H), 3.26 (s, 2H), 3.85 (q, J=6.5 Hz, 2H), 5.63 (s, 1H),
6.16 (brt, 6.4 Hz, 1H), 7.25–7.34 ppm (m, 5H); MS (ES+): m/z: 307.5
[M+1]+.
4-Amino-3-benzoyl-5-benzyl-5-ethyl-5H-1,2-oxathiole-2,2-dioxide
(24):
Benzoyl chloride (140 mL, 1.20 mmol) was added to a solution of 5b
(100 mg, 0.39 mmol) and DMAP (217 mg, 1.78 mmol) in dry acetonitrile
(5 mL). The mixture was stirred in an Ace pressure tube for 3 h at 808C.
Salts were filtered and solvent was evaporated and ethyl acetate was
added. The organic layer was successively washed with 1n HCl (2”
5 mL) and brine (2”5 mL), dried (Na2SO4), filtered and evaporated to
dryness. The final residue was purified by CCTLC on the Chromatotron
(dichloromethane/methanol, 25:1) to yield 97 mg (69%) of 24 as a white
amorphous solid. M.p. (hexane/ethyl acetate): 201–2028C; 1H NMR
(300 MHz, (CD3)2CO): d=0.97 (t, J=7.5 Hz, 3H), 1.88 (m, 1H), 2.24 (m,
1H), 3.33 and 3.43 (AB system, J=14.2 Hz, 2H), 7.23–7.90 (m, 10H),
8.25 (brs, 1H; NH), 9.51 ppm (brs, 1H; NH); 13C NMR (75 MHz,
(CD3)2CO): d=7.9, 29.5, 44.8, 91.6, 105.5, 128.5, 128.8, 129.4 132.2, 132.9,
135.2, 140.4, 169.5, 188.5 ppm; IR (film): n˜ =3462, 1630 cmÀ1; MS (ES+):
m/z: 358.1 [M+1]+, 375.2 [M+H2O]+, 380.0 [M+Na]+, 737.2 [2M+Na]+;
elemental analysis calcd (%) for C19H19NO4S: C 63.85, H 5.36, N 3.92, S
8.97; found: C 63.69, H 5.25, N 3.88, S 9.12.
The fastest moving band afforded 49 mg (40%) of 4-amino-5-benzyl-3-
(2-cyanoethyl)-5-ethyl-5H-1,2-oxathiole-2,2-dioxide (18) as a white foam.
1H NMR (300 MHz, (CD3)2CO): d=0.91 (t, J=7.2 Hz, 3H), 1.69–1.85
(m, 1H), 1.97–2.11 (m, 1H), 2.51–2.57 (m, 2H), 2.69–2.75 (m, 2H), 3.24
(s, 2H), 6.21 (bs, 2H) 7.26–7.32 ppm (m, 5H); 13C NMR (100 MHz,
(CD3)2CO): d=8.5, 17.6, 19.9, 30.4, 45.6, 93.3, 99.3, 120.7, 128.8, 129.7,
132.8, 136.4, 154.0 ppm; MS (ES+): m/z: 307.2 [M+1]+; elemental analy-
sis calcd (%) for C15H18N2O3S: C 58.80, H 5.92, N 9.14, S 10.47; found: C
58.95, H 5.94, N 9.35, S 10.53.
4-Amino-5-benzyl-5-ethyl-3-(a-hydroxybenzyl)-5H-1,2-oxathiole-2,2-di-
oxide (25): A solution of 5b (100 mg, 0.39 mmol) in dry THF (5 mL),
previously degassed under an argon atmosphere, was reacted with NaH
60% dispersion in mineral oil (32 mg, 0.78 mmol) and the mixture was
stirred at room temperature for 10 min. The mixture was cooled to
À788C, benzaldehyde (79 mL, 0.78 mmol) was added and the mixture was
stirred for 10 min. After quenching the reaction with water (2 mL), the
solvent was evaporated to dryness. The final residue was purified by
CCTLC on the Chromatotron (hexane/ethyl acetate, 2:1). The faster
moving band afforded 25 (15 mg, 10%) as an amorphous solid. M.p.
(hexane/ethyl acetate): 141–1438C; 1H NMR (300 MHz, (CD3)2CO): d=
0.78 (t, J=7.2 Hz, 3H), 1.64 (m, 1H), 1.95 (m, 1H), 3.23 (s, 2H), 5.19
(brs, 1H), 5.62 (s, 1H), 5.81 (brs, 2H), 7.29 (m, 8H), 7.52 ppm (m, 2H);
13C NMR (100 MHz, (CD3)2CO): d=7.1, 28.6, 44.1, 67.1, 90.8, 103.1,
126.8, 127.4, 127.7, 128.4, 128.5, 131.5, 135.3, 142.5, 153.1 ppm; IR (film):
5,5-Dibenzyl-4-ureido-5H-1,2-oxathiole-2,2-dioxide (19): Chlorosulfonyl
isocyanate (111 mL, 1.28 mmol) was added to a cooled (À308C) solution
of 5a (100 mg, 0.32 mmol) in dry dichloromethane (5 mL), previously de-
gassed under an argon atmosphere. The resulting mixture was stirred at
À308C for 20 min. Then, the reaction was quenched (NaHCO3) and the
organic layer was separated. The aqueous layer was extracted several
times with ethyl acetate (3”10 mL). The combined organic layers were
washed with water (2”5 mL) and brine (2”5 mL), was dried (Na2SO4),
filtered and evaporated to dryness. The residue was purified by CCTLC
on the Chromatotron (ethyl acetate/methanol, 6:1) yielding 54 mg (46%)
of compound 19 as a white solid. M.p. (toluene): 147–1488C; 1H NMR
(300 MHz, (CD3)2CO): d=3.10 and 3.24 (AB system, J=13.8 Hz, 4H),
6.04 (brs, 2H; NH2), 6.66 (s, 1H), 7.23 (m, 10H), 8.71 ppm (brs, 1H;
NH); 13C NMR (50 MHz, (CD3)2CO): d=43.8, 92.3, 100.8, 128.2, 129.4,
131.9, 135.4, 149.5, 155.0 ppm; IR (film): n˜ =3687, 3504, 1772 cmÀ1; MS
(ES+): m/z: 359.1 [M+1]+, 376.1 [M+H2O]+, 381.1 [M+Na]+, 717.2
[2M+1]+, 739.1 [2M+Na]+; elemental analysis calcd (%) for
C18H18N2O4S: C 60.32, H 5.06, N 7.82, S. 8.95; found: C 60.00, H 4.91, N
7.55, S 8.77.
n˜ =3583, 3497, 3395 cmÀ1
;
MS (ES+): m/z: 382.0 [M+Na]+, 741.2
[2M+Na]+; elemental analysis calcd (%) for C19H21NO4S: C 63.49, H
5.89, N 3.90, S 8.92; found: C 63.32, H 5.71, N 3.72, S 8.67.
4-Amino-3-benzoyl-5,5-dibenzyl-5H-1,2-oxathiole-2,2-dioxide (26): A so-
lution of 5a (100 mg, 0.32 mmol), in dry THF (5 mL) under argon, was
reacted with NaH 60% dispersion in mineral oil (26 mg, 0.64 mmol) at
room temperature for 10 min. Then, benzaldehyde (65 mL, 0.64 mmol)
was added and the mixture was refluxed for 10 min. After quenching the
reaction with methanol (2 mL), the solution was stirred at room tempera-
ture for 5 min. The solvent was evaporated and the residue was dissolved
in ethyl acetate (5 mL). The organic layer was successively washed with
1n HCl (2”5 mL) and brine (2”5 mL), dried (Na2SO4), filtered and
evaporated to dryness. The final residue was purified by CCTLC on the
Chromatotron (hexane/ethyl acetate, 10:1) to give 26 (118 mg, 88%) as a
white amorphous solid. 1H NMR (400 MHz, (CD3)2CO): d=3.27 and
5,5-Dibenzyl-4-ethoxycarbonylureido-5H-1,2-oxathiole-2,2-dioxide (20):
Ethoxycarbonyl isocyanate (99 mL, 0.96 mmol) was added to a solution of
5a (100 mg, 0.32 mmol) in dry acetonitrile (6 mL). The reaction mixture
was stirred in an Ace pressure tube for 2.5 h at 1008C. Solvent was re-
moved to dryness. The final residue was purified by CCTLC on the Chro-
matotron (hexane/ethyl acetate, 2:1) to give 20 (127 mg, 93%) as a white
solid. M.p. (hexane/ethyl acetate): 193–1948C; 1H NMR (500 MHz,
(CD3)2CO): d=1.34 (t, J=7.3 Hz, 3H), 3.28 (s, 4H), 4.35 (q, J=7.3 Hz,
2H), 6.83 (s, 1H), 7.28 (m, 10H), 9.88 (brs, 1H; NH), 10.46 ppm (brs,
1H; NH). 13C NMR (125 MHz, (CD3)2CO): d=13.9, 42.9, 63.3, 91.5,
104.0, 127.6, 128.5, 131.0, 133.7, 146.3, 149.8, 155.7 ppm; IR (film): n˜ =
9630
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9620 – 9632

Heterocyclic System Reactivity
FULL PAPER
3.55 (AB system, J=14.5 Hz, 4H), 7.34 (m, 12H), 7.52 (m, 1H), 7.74 (m,
2H), 8.20 (brs, 1H; NH), 9.21 ppm (brs, 1H; NH); 13C NMR (100 MHz,
CDCl3): d=42.8, 89.7, 105.5, 127.8, 128.0, 128.6, 128.7, 131.5, 132.2, 134.3,
139.5, 168.3, 187.5 ppm; MS (ES+): m/z: 420.1 [M+1]+, 437.1 [M+H2O]+,
861.1 [2M+Na]+; elemental analysis calcd (%) for C24H21NO4S: C 68.72,
H 5.05, N 3.34, S 7.64; found: C 68.39, H 4.91, N 3.11, S 7.22.
IR (film): n˜ =3429, 1733 cmÀ1; MS (ES+): m/z: 276.0 [M+1]+, 573.3
[2M+Na]+; elemental analysis calcd (%) for C11H17NO5S: C 47.99, H
6.22, N 5.09, S 11.65; found: C 48.03, H 6.18, N 5.19, S 11.59.
4-Amino-3-benzoyl-1-oxa-2-thiaspiro
A
(47):
Benzoyl chloride (124 mL, 1.08 mmol) was added to a solution of 40
(100 mg, 0.36 mmol) and DMAP (176 mg, 1.44 mmol) in dry acetonitrile
(5 mL). The mixture was stirred at room temperature for 5 h. Salts were
filtered and solvent was evaporated and ethyl acetate was added. The or-
ganic layer was successively washed with 1n HCl (2”5 mL) and brine
(2”5 mL), dried (Na2SO4), filtered and evaporated to dryness. The final
residue was purified by CCTLC on the Chromatotron (hexane/ethyl ace-
tate, 3:1) to yield 108 mg (70%) of 47 as a white foam. 1H NMR
(300 MHz, (CD3)2CO): d=1.87–203 (m, 6H), 2.35 (m, 2H), 7.35 (s, 1H),
7.45 (m, 5H), 9.53 ppm (brs, 1H); 13C NMR (100 MHz, (CD3)2CO): d=
25.3, 397.8, 38.0, 40.3, 85.1, 101.5, 128.3, 128.9, 130.1, 131.2, 134.3, 135.0,
145.5, 168.3 ppm; MS (ES+): m/z: 294 [M+1]+, 316 [M+Na]+; elemental
analysis calcd (%) for C14H15NO4S: C 57.32, H 5.15, N 4.77, S 10.93;
found: C 57.29, H 5.29, N 4.99, S 11.04.
4-Amino-5,5-dibenzyl-3-iodo-5H-1,2-oxathiole-2,2-dioxide (29):
A 5%
solution of iodine in ethanol was added dropwise to a solution of 5a
(100 mg, 0.32 mmol) and NaHCO3 (267 mg, 3.2 mmol) in dry ethanol
(10 mL), until the colour of the reaction mixture remained light brown.
Then, solvent was evaporated and the residue was treated with cold
(48C) ethyl acetate (30 mL), cold (48C) brine (15 mL) and cold (48C)
5% aqueous NaHSO3 solution (7 mL). The organic layer was separated
and the aqueous layer was extracted with cold (48C) ethyl acetate (3”
10 mL). The combined organics were washed with brine (3”5 mL), dried
(Na2SO4), filtered and evaporated to dryness. The final residue was puri-
fied by CCTLC on the Chromatotron (hexane/ethyl acetate, 1:1) to give
29 (99 mg, 70%) as a white solid. M.p. (toluene): 223–2248C; 1H NMR
(300 MHz, (CD3)2CO): d=3.16 and 3.38 (AB system, J=14.3 Hz, 4H),
6.49 (brs, 2H), 7.25 ppm (m, 10H); 13C NMR (100 MHz, (CD3)2CO): d=
43.1, 44.0, 93.8, 127.9, 128.8, 131.6, 134.9, 158.6 ppm; MS (ES+): m/z:
442.1 [M+1]+, 904.9 [2M+Na]+; elemental analysis calcd (%) for
C17H16INO3S: C 46.27, H 3.65, N 3.17, S 7.27; found: C 46.00, H 3.54, N
3.01, S 6.98.
1,6-Dioxa-4-[(E)-2-(methoxycarbonyl)vinyl]amino-2-thiaspiro[4.4]non-3-
N
ene-2,2-dioxide ((E)-52) and( Z)-52: According to the method described
in the journal for the preparation of 12, a solution of 41 (100 mg,
0.52 mg), methyl propiolate (57 mL, 0.64 mmol) and DMAP (78 mg,
0.64 mmol) in dry acetonitrile (10 mL) was stirred at À208C for 1.5 h.
The solvent was removed and ethyl acetate was added (5 mL) and the
mixture was washed with 0.1n HCl (2”5 mL) and brine (2”5 mL). The
organic layer was dried, filtered and evaporated to dryness. The final resi-
due was purified by CCTLC on the Chromatotron (hexane/ethyl acetate,
1:2) to give a 93:12 mixture (82 mg, 57%) of (E)-52 and (Z)-52.
Data for (E)-52: 1H NMR (300 MHz, (CD3)2CO): d=2.29 (m, 1H), 2.62
(m, 2H), 3.69 (s, 3H), 3.98–4.23 (m, 3H), 5.59 (d, J=13.8 Hz, 1H), 6.49
(s, 1H), 7.74 (d, J=13.8 Hz, 1H), 8.82 ppm (brs, 1H); 13C NMR
(75 MHz, CDCl3): d=38.4, 52.2, 105.3, 119.8, 141.4, 148.3, 168.3 ppm.
4-Amino-5,5-dibenzyl-3-nitroso-5H-1,2-oxathiole-2,2-dioxide
(31a):
Sodium nitrite (44 mg, 0.64 mmol) was slowly added over 30 min to a so-
lution of 5a (100 mg, 0.32 mmol) in acetic acid (8 mL)/water (0.8 mL)/
methanol (1 mL) at 108C. The reaction mixture was stirred at 108C for
4 h and the solvent was removed. The residue was neutralised with a sa-
turated aqueous solution of NaHCO3 to pHꢁ7, and it was extracted with
ethyl acetate (2”10 mL). The combined organic layers were dried
(Na2SO4), filtered and evaporated to dryness. The final residue was puri-
fied by CCTLC on the Chromatotron (hexane/ethyl acetate, 6:1) to give
31a (89 mg, 81%) as a blue solid. M.p. (dichloromethane/hexane): 198–
1998C; 1H NMR (200 MHz, (CD3)2CO): d=3.30 and 3.61 (AB system,
J=14.5 Hz, 4H), 7.31 ppm (m, 10H); 13C NMR (50 MHz, (CD3)2CO):
d=42.1, 88.5, 88.7, 127.2, 127.9, 130.5, 130.7, 132.7, 132.8, 168.4 ppm. IR
(film): n˜ =3484, 3407, 1653 cmÀ1; MS (ES+): m/z: 345.0 [M+1]+; elemen-
tal analysis calcd (%) for C17H16N2O4S: C 59.29, H 4.68, N 8.13, S 9.31;
found: C 59.01, H 4.60, N 7.89, S 9.00.
Data for (Z)-52: 1H NMR (300 MHz, (CD3)2CO): d=3.71 (s, 3H), 5.63
(d, J=8.0 Hz, 1H), 6.31 (s, 1H), 6.38 (d, J=8.0 Hz, 1H), 9.15 ppm (brs,
1H); MS (ES+): m/z: 276.3 [M+1]+; elemental analysis calcd (%) for
C10H13NO6S: C 43.63, H 4.76, N 5.09, S 11.65; found: C 43.59, H 4.70, N
5.19, S 11.42.
Computational methods: Computational chemistry was carried out by
first drawing the molecules in the desktop of Cerius2 and optimising the
structures at the AM1 level of theory. Subsequently, electronic energies
and structures were calculated by full optimisation, without any geomet-
rical constraint, by using the Beckeꢁs three-parameter hybrid functional[24]
and using the Lee et al.[25] correlation functional with the 6-31G(d) basis
set (B3LYP/6-31G(d)).[26] Frequency calculations were used for all mini-
mised structures to ensure that satisfactory minima were obtained.
HOMO energies, zero-point electronic energies and CGhelp charges
(CGHelp) were determined by doing a single-point calculation with the
hybrid B3LYP/6-31G+(d,f).[27] Semiempirical model (AM1) calculations
were performed with MOPAC version 6.0.[28] The Gaussian 03 and Gaus-
sian 98W program packages were used throughout this work.[29] Molecu-
lar graphs and pictures were achieved with the GaussView[30] and Argus-
lab programs.[31]
5,5-Dibenzyl-4-oxo-1,2-oxathiolane-2,2-dioxide (32a): A solution of 5a
(100 mg, 0.32 mmol) in 1n HCl in methanol (17 mL) was stirred at room
temperature for 14 h. The solvent was removed under vacuum and the
residue was dissolved in ethyl acetate. The mixture was washed with
water (10 mL), brine (10 mL), and NaHCO3 (10 mL). The organic layer
was dried (Na2SO4), filtered and evaporated to dryness. The final residue
was purified by CCTLC on the Chromatotron (hexane/ethyl acetate,
10:1) to give 32a (85 mg, 85%) as a white solid. M.p. (ethanol/water):
78–798C; Tautomer A: 1H NMR (300 MHz, CDCl3): d=3.02 and 3.23
(AB system, J=14.2 Hz, 4H), 3.03 (s, 2H), 7.17 ppm (m, 10H); 13C NMR
(100 MHz, CDCl3): d=41.5, 53.8, 100.2, 127.9, 128.7, 130.8, 132.7,
200.6 ppm; IR (film): n˜ =1764, 1369 cmÀ1
;
Tautomer B: 1H NMR
(400 MHz, (CD3)2SO): d=3.02 and 3.17 (AB system, J=13.9 Hz, 4H),
5.86 (s, 1H), 7.27 (m, 10H), 12.84 ppm (brs, 1H); 13C NMR (100 MHz,
(CD3)2SO): d=41.4, 91.8, 94.8, 127.0, 128.0, 130.7, 134.1, 166.2 ppm; MS
(ES+): m/z: 317.0 [M+1]+, 334.0 [M+H2O]+, 339.0 [M+Na]+, 655.2
[2M+Na]+; elemental analysis calcd (%) for C17H16O4S: C 64.54, H 5.10,
S 10.14; found: C 64.32, H 4.87, S 9.87.
Acknowledgements
We thank the Spanish MEC (project SAF2006-12713-C02), the European
Commission (project HPAW-CT-2002-90001) and the Spanish CICYT
(project MAT2004-01946) for financial support.
4-Methoxycarbonylethylamino-1-oxa-2-thiaspiro[4.4]non-3-ene-2,2-diox-
A
ide (43): A solution of 40 (100 mg, 0.53 mmol) and H-b-Ala-OMe·HCl
(221 mg, 1.59 mmol) in methanol (5 mL) was stirred in an Ace pressure
tube for 24 h at 1008C. The solvent was evaporated and the residue was
purified by HPFC on a Horizon system (dichloromethane/methanol,
200:1) to give 43 (58 mg, 40%) as a white solid. M.p. (hexane/ethyl ace-
tate): 98–998C; 1H NMR (300 MHz, CDCl3): d=1.79–1.99 (m, 6H), 2.18
(m, 2H), 2.63 (t, J=6.3 Hz, 2H), 3.33 (q, J=6.3 Hz, 2H), 3.72 (s, 3H),
4.84 (brt, J=6.3 Hz, 1H), 5.27 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=25.1, 32.5, 38.2, 38.6, 41.1, 52.5, 86.8, 97.2, 157.9, 172.9 ppm.
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Received: March 10, 2008
Revised: June 6, 2008
Published online: September 9, 2008
9632
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Chem. Eur. J. 2008, 14, 9620 – 9632