Silica gel catalysed generation of episulfonium ions: A mild method for the synthesis of heterocycles

Article abstract of DOI:10.1039/b207542n

β-Carbonyloxy sulfides fragment when heated with silica or alumina to produce reactive episulfonium ion intermediates. Intramolecular activation of the leaving group and concurrent protection of a nitrogen or oxygen nucleophile via a cyclic carbamate or c

Full text of DOI:10.1039/b207542n

Silica gel catalysed generation of episulfonium ions: a mild method for
the synthesis of heterocycles
Lorenzo Caggiano, David J. Fox and Stuart Warren*
University Chemistry Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge, UK) 1st August 2002, Accepted 28th August 2002
First published as an Advance Article on the web 30th September 2002
b-Carbonyloxy sulfides fragment when heated with silica or
alumina to produce reactive episulfonium ion intermediates.
Intramolecular activation of the leaving group and con-
current protection of a nitrogen or oxygen nucleophile via a
cyclic carbamate or carbonate leads to the formation of
pyrrolidines or cyclic ethers.
gel is a mild acid and although it does not cause degradation of
ester 2 during purification at ambient temperature, when
benzoate 2 was heated in chloroform in the presence of ten times
its mass of silica gel, it reacted to form allylic sulfide 7, the
isomeric ester 5 and benzoic acid. Prolonged reaction times (4
and 8 h) increased the conversion to rearranged ester 5. After 16
h both esters were converted into allylic sulfide 7 and benzoic
acid (Table 1, entries 1–4). The [1,2]-migration of the PhS
group during the reaction suggests an episulfonium ion
intermediate, like those formed in the strong acid catalysed
rearrangements.1 The transient appearance of ester 5 is
consistent with the reversible formation of the episulfonium ion
which can be trapped by the benzoate anion bound to the silica
surface. This mechanism is consistent with the treatment of
independently synthesised ester 5 in the same reaction condi-
tions to give a similar mixture including the primary benzoate 2
approaching an equilibrium from the other direction (Table 1,
entry 5, Scheme 2). A similar silica catalysed rearrangement
occurs for a phenylselenyl acetate in which the selenium
migrated from a secondary to a primary carbon while the acetate
moved in the other direction.9
Diethyl carbamate 3 and methyl carbonate 4 were also
synthesised from alcohol 1. These compounds are also stable to
silica gel chromatography and heating, but on heating with
silica gel in chloroform they too formed allylic sulfide 7,
showing that this mild method of forming episulfonium ions is
applicable to a range of carbonyl containing leaving groups
(Scheme 2). A proportion of the carbamate also rearranged to
the tertiary carbamate 6 by PhS migration before elimination to
the olefin (Table 1, 6–11). The intermolecular recapture of the
episulfonium ion by the carbamate anion may seem surprising
given that the reaction is occurring in refluxing chloroform and
in the presence of mildly acidic silica gel, given that the
decarboxylation of carbamate ions is acid catalysed.10 Once
again the reversible nature of the isomerisation was confirmed
Many allylic sulfides and oxygen heterocycles have been
synthesised from b-hydroxy sulfides by treatment with catalytic
strong acids.1 These transformations proceed via reactive
episulfonium ions trapped by by nucleophilic opening by a
remote hydroxy group to produce a cyclic ether (Scheme 1).
Similar ether syntheses can be initiated by electrophilic iodine2
and selenium3,4 reagents forming corresponding reactive three-
membered ring intermediates from olefins.
In order to make nitrogen heterocycles via episulfonium ions
it has been necessary to reduce the basicity of the nitrogen by
attaching a tosyl group.1 This method has also been used in
similar iodonium ion5 and bromonium ion6 mediated reactions.
While this strategy gave high yields of heterocycle the removal
of the sulfonyl group to produce the free amine required
strongly reducing conditions incompatible with many func-
tional groups. Methods are available for halogen7 and sulfur8
mediated cyclisation of free amines but they involve the
addition of an electrophilic reagent to an olefin. We wished to
develop a simple method of cyclising free amines onto
stereospecifically generated episulfonium ions without strong
acid catalysis. Recently we have reported the use of the weaker
acid pyridinium p-toluene sulfonate as a catalyst in cyclo-
etherifications,1 but these conditions would still not be effective
in the cyclisation of a free amine due to the protonation of the
nucleophile. A method for generating episulfonium ions under
essentially neutral conditions was therefore needed.
It was hoped that, if the hydroxy group could be activated
sufficiently, the episulfonium ion could be formed with the aid
of a very mild non-acidic catalyst. The activated compounds
should however be stable enough for easy synthesis and
isolation in stereochemically pure fashion. Conversion of the
alcohol into an ester or related group should meet these criteria.
In order to test this proposal, alcohol1 1 was converted into
benzoate ester 2, a stable compound at ambient temperature that
could be purified by silica chromatography or heated in
chloroform at reflux without chemical change. The proven
stability of the episulfonium ion precursor to both column
chromatography and heating is vital if it is to be a useful
synthetic intermediate.
Table 1 Products from the silica gel catalysed reaction of benzoates 2 and
5 and carbamates 3 and 6 (Scheme 2)
Sulfides in reaction mixtureb
(%)
Starting
Entry
material C/Sa
Time/h
2 or 3
5 or 6
7
1
2
3
4
5
6
7
8
9
2
2
2
2
5
3
3
3
3
3
3
6
10
10
10
10
10
5
1
4
8
16
16
8
16
8
16
8
16
16
86
34
17
< 1
3
85
80
75
45
21
13
6
5
24
26
< 1
63
1
1
2
10
23
20
68
9
41
56
The formation of the episulfonium ion from benzoate 2
therefore requires a Lewis acid to coordinate to the carbonyl
group of the ester and increase its leaving group ability. Silica
> 98
34
14
19
23
45
56
67
26
5
10
10
30
30
10
10
11
12
a Silica catalyst-to-substrate ratio by mass. b Measured by NMR spectros-
copy.
Scheme 1
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CHEM. COMMUN., 2002, 2528–2529
This journal is © The Royal Society of Chemistry 2002

Scheme 4
rearranged products 5 and 6. Alternatively the nucleophile
could be the less effective alkylated-carbonate-oxygen, or
carbamate nitrogen, and decarboxylation is concurrent with, or
occurs after, the ring closure (Scheme 4). Cyclisation of alkyl
carbamates to form nitrogen heterocycles can be initiated by
selenium reagents, but in these cases nitrogen-decarboxylation
does not occur in situ.4,10–12
Scheme 2 Reagents and conditions: i, PhCOCl, pyridine, 88%; ii, NaH,
DMF; Me2NCOCl or MeOCOCl, (3) 91%; (4) 78%; iii, n-BuLi, DABCO,
THF; cyclohexanone; then PhCOCl or Me2NCOCl, (5) 5%; (6) 4%; iv,
SiO2, CHCl3, D, see Table 1.
by reaction of the primary sulfide 6 (Table 1, entry 12). Only
elimination was observed for carbonate 4.
Alumina also catalyses the reaction of the carbonyl deriva-
tives on heating, but does not do so at ambient temperature.
Other solids (TiO2, MgSO4) do not catalyse the transformation.
The choice of solvent is also important: the reaction does not
occur in solvents that reduce the activity of silica gel such as
methanol and THF, but does so in less Lewis basic solvents
(PhMe and EtOAc). Addition of water inhibits the reactions,
whereas drying the silica gel at elevated temperature in vacuo
increases the activity of the catalyst. The residual ethanol
present in commercial chloroform also inhibits the reaction. The
reactions were performed in chloroform that had been purified
by passage through a column of silica gel.
A range of cyclisation reactions in which the episulfonium
ion could be captured by an intramolecular nucleophile was
then attempted. Activation of the leaving group while temporar-
ily protecting the nucleophile could be achieved with a cyclic
carbamate or carbonate (Scheme 3). The generation of the
episulfonium ion would then be followed by a ring closure with
loss of carbon dioxide. Treatment of the cyclic carbamate 8 with
silica gel in refluxing chloroform produced the pyrrolidine 9 in
excellent yield. Filtration, washing of the silica gel and removal
of solvent produces essentially pure cyclic amine. In identical
conditions the cyclic carbonate reacted quantitatively to give a
roughly equal mixture of THF 11 and allylic sulfide 12 in
chloroform, but more cyclisation occurred in CCl4. As it is
known that the equivalent free hydroxyl group readily cyclises
to give a quantitative yield of THF,1 the silica gel reactions
indicate that the carbonate group must have an appreciable life-
time after episulfonium ion generation. For both the ether and
amine cyclisations, slow decarboxylation may occur before the
cyclisation, but this seems unlikely given the isolations of the
Scheme 5 Reagents and conditions: i, LDA, THF, 278 °C then BrCH2CN,
HMPA, 43%; ii, LiAlH4, Et2O, 99%; iii, CDI, DMF, 65%; iv, SiO2, CHCl3,
D.
The seven-membered carbamate 14 was synthesised from
ketone1 13 (Scheme 5). Treatment of this cyclic compound with
silica gel in refluxing chloroform produced a mixture of
unrearranged pyrrolidine 15 and rearranged piperidine 16
(Scheme 5). The nitrogen nucleophile attacks the proximal end
of the episulfonium ion more readily to form a five-membered
ring, than the distal end to produce a six-membered ring. In the
equivalent strong-acid-catalysed ether-cyclisation reaction, the
six-membered-ring compound is the only product, and the
reaction is under thermodynamic control. In this silica gel
catalysed process however it seems that the loss of CO2
prevents the regeneration of an episulfonium ion and that the
product ratio is controlled by the relative rates of cyclisation
rather than the ultimate stability of the products. Similar product
ratios have been observed in other non-equilibrating cyclisation
reactions.1,9
We thank the EPSRC for a grant to L. C.
Notes and references
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Scheme 3 Reagents and conditions: i, CDI, CH3CN; ii, SiO2, CHCl3, D; iii,
SiO2, CHCl3 (11+12 = 50+50) or CCl4 (11+12 = 86+14), D.
12 K. C. Nicolaou, D. A. Claremon, W. E. Barnette and S. P. Seitz, J. Am.
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