Selective five- and six-membered cyclic amine syntheses via capture of episulfonium ions

Article abstract of DOI:10.1039/b503068b

The method involving the capture of episulfonium ions for the selective synthesis of five- and six-membered cyclic amine was analyzed. Exchange of the methyl carbamate group for a dinitro-benzamide allowed determination of the more stable cyclic product,

Full text of DOI:10.1039/b503068b

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C O M M U N I C A T I O N
Selective five- and six-membered cyclic amine syntheses via capture
of episulfonium ions
David J. Fox, Thomas J. Morley, Sarah Taylor and Stuart Warren*
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW.
E-mail: sw134@cam.ac.uk
Received 1st March 2005, Accepted 1st March 2005
First published as an Advance Article on the web 14th March 2005
Amide nitrogens open episulfonium ions to form pyrro-
lidines or piperidines selectively, depending on the nitrogen
substituent, in either reversible or irreversible reactions.
The ring closure reactions of b-hydroxy sulfides and their deriva-
tives containing pendant nucleophiles produce cyclic ethers,
lactones, sulfides, amines,1 carbamates and carbonates by the
intramolecular trapping of an episulfonium ion.2 In the majority
of cases, five- or six-membered heterocycles are produced, and
in strong-acid catalysed cyclo-etherifications, the more thermo-
dynamically stable ring size is formed in a reversible reaction.2
Related nitrogen reactions generally occur with irreversible ring-
closure,3–11 although thermodynamic control of stereochemistry,
rather than ring-size, can occur using iodonium ions.6
Scheme 2 Reagents and conditions: i, LDA, THF, HMPA, then
BrCH2CN, 62%; ii, LiAlH4, Et2O, 98%; iii, X = CO2Me: ClCO2Me,
Et3N, CH2Cl2, 76%; X = CO2Bn: ClCO2Bn, Et3N, CH2Cl2, 56%; X =
CO2Ph: ClCO2Ph, Et3N, CH2Cl2, 71%; X = Ts: TsCl, Et3N, CH2Cl2,
68%; X = CHO: HCO2COtBu, Et3N, THF, 80%; iv, Amberlyst-15,
CDCl3, see Table 1.
The rearrangement of carbamate 1 in the presence of silica
gel to give a mixture of five- and six-membered cyclic amines
2 (“unrearranged” where the sulfur has not migrated) and 3
(“rearranged” where the sulfur has migrated) probably occurs
with irreversible ring-closure as CO2 is lost (Scheme 1).1 The use
of nitrogen nucleophiles with less labile electron-withdrawing
groups may result in reversible ring closures. Cyanomethylation
and reduction of ketone2 4 gave amine 5 which could be acylated
to give alkyl-carbamates 6a–c, sulfonamide 6d and formamide
6e. Methyl carbamate 6a was treated with Amberlyst-15 acid
resin and a mixture of cyclic products 7a and 8a was initially
formed (Scheme 2). Prolonged treatment did indeed result
in the equilibration of the mixture to give a single product,
establishing the reversible addition of a nitrogen nucleophile to
an episulfonium ion (Table 1). Exchange of the methyl carbamate
group for a dinitro-benzamide allowed determination of the
more stable cyclic product, the pyrrolidine-amide, by X-ray
crystallography (10, Scheme 3).†
Scheme 3 Reagents and conditions: i, NH2NH2, KOH, 80%; ii,
HCO2COtBu, Et3N, THF, 56%. X-Ray structure of the 3,5-dinitroben-
zamide 10 of pyrrolidine 9 (ellipsoids at 50% probability).
Fig.
1
X-Ray structure of sulfonamide 7d (ellipsoids at 50%
probability).†
Scheme 1
Reactions of carbamate esters 6b and 6c also produced single
products on prolonged treatment with acid. Sulfonamide 6d
reacted to give a mixture of products that equilibrated to form
only the five-membered ring (Fig. 1). Formamide 6e initially
reacted to form an allylic sulfide by elimination of water,2 but
reprotonation reproduced the episulfonium ion that ring closed
to produce an unchanging ratio (15 : 85) of products 7e and
8e. The major product was subsequently deformylated and the
crystal structure of the hydrochloride salt of amine 11 established
that the six-membered ring was the major product in the ring
closure (Scheme 4).
Scheme 4 Reagents and conditions: i, NH2NH2, KOH, 60%. X-Ray
structure of the HCl salt of piperidine 11 (ellipsoids at 50% probability).†
The increased stability of unrearranged five-membered ring
7a compared to rearranged six-membered ring 8a is in direct
contrast to the related cyclic ethers 12 and 13 where the ring size
is dominated by the “downhill” migration of the sulfur to the
less substituted carbon (Scheme 5).2 This complete turnover
of the dominance of sulfur in a five- to six-membered-ring
equilibrium is not known in simple cyclic ethers, and therefore
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 9 – 1 3 7 1
1 3 6 9
©

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Table 1 Cyclisation of amides 6 (Scheme 2)
Amide
Acyl group X
Cyclisation time/h
Conversion (%)a
Product ratio 7 : 8 (%)a
Yield (%)b
6a
6a
6b
6b
6b
6c
6c
6d
6d
6e
6e
CO2Me
CO2Me
CO2Me
CO2Ph
CO2Ph
CO2Bn
CO2Bn
Tosyl
2
17
120
18
120
18
120
2
ca.25
100
100
100
100
100
100
15
34 : 66
40 : 60
100 : 0
45 : 55
100 : 0
93 : 7
100 : 0
33 : 67
100 : 0
15 : 85
14 : 86
—
—
84
—
80
—
88
—
56
—
10
Tosyl
CHO
CHO
60
19
190
100
67
100
a by NMR; b isolated yield.
the equilibration of the piperidines to the pyrrolidines was
surprising. In carbamates 8a–c the steric compression of the
acyl group and the equatorial methyl group may destabilise
the six-membered rings compared to the pyrrolidine isomers
(Scheme 5). This destabilisation does not occur in ether 13.
lactam product. Reduction and acylation produced carbamate
8a. In this case the inclusion of the carbonyl inside the ring
restricts the ring-closing reaction to give only the six-membered
lactam. Possibly the additional restriction in torsional angles
supplied by the amide of precursor 14 precludes the formation
of the five-membered ring.
Previous methods involving the capture of episulfonium
ions1,2 have not proved useful for the selective synthesis of
piperidines. Placing the acyl group within the ring results in
the selective formation of a six-membered ring (15) while an
exocyclic acyl group leads to the formation of a five-membered
ring (7). In both cases the electron withdrawing functionality
can be removed providing selective syntheses of pyrrolidine 9 or
piperidine 11.
Scheme 5
Prolonged treatment of formamides 7e and 8e with acid
did not lead to their interconversion in chloroform at 40 ◦C,
and in d8-toluene at 100 C, independently synthesised pyrro-
◦
Acknowledgements
lidine 7e (Scheme 3) only partially equilibrated to give a six-
membered ring. This establishes that formamides 7e and 8e
are far less labile than the carbamates and sulfonamides, and
do not equilibrate in the ring-closing reactions. All of the
ring-closure reactions in Table 1 indicate that six-membered
rings are formed faster than five-membered rings. Generally,
in irreversible five- versus six-membered-ring closures onto
iodonium5,6 and selenonium8–10 ions, amide nitrogens attack
the more substituted4,5,9 or benzylic4,8 electrophilic carbon. This
indicates that the nitrogen favours attack at a more cation-
like carbon. This is in contrast to sulfur-mediated ring-closure
reactions where oxygen attacks the less substituted carbon in
non-equilibrating conditions.2
We thank the EPSRC (T. J. M.) and Trinity College, Cambridge
(S. T.) for studentships. We also thank Dr John Davies for
crystallography and the EPSRC for financial assistance towards
the purchase of the Nonius CCD diffractometer.
Notes and references
† Crystal Data for 10: C20H21N3O5S, M = 415.46, orthorhombic, space
˚
group P212121, a = 6.04760(10), b = 10.1799(3), c = 32.0263(9) A,
3
U = 1971.67(9) A , Z = 4, l(Mo–Ka) = 0.202 mm−1, 7221 reflections
˚
measured at 180(2) K using an Oxford Cryosystems Cryostream cooling
apparatus, 3248 unique (Rint = 0.033); R1 = 0.033, wR2 = 0.073 [I >
2r(I)]. Absolute structure parameter −0.08(8). The structure was solved
with SHELXS-97, and refined with SHELXL-97.11
Amide 14, also made from ketone 4, is similar to amide 6 but
has the carbonyl of the amide as part of the main carbon chain
(Scheme 6). Treatment of this amide with acid led to a single
Crystal Data for 7d: C20H25NO2S2, M = 375.53, orthorhombic, space
˚
group Pca2(1), a = 15.717(3), b = 6.1884(12), c = 39.420(8) A, U =
3
3834.1(13) A , Z = 8, l(Mo–Ka) = 0.291 mm−1, 11360 reflections
˚
measured at 180(2) K using an Oxford Cryosystems Cryostream cooling
apparatus, 5387 unique (Rint = 0.044); R1 = 0.042, wR2 = 0.098 [I >
2r(I)]. The structure was solved with SHELXS-97, and refined with
SHELXL-97.11
Crystal Data for 11·HCl: C13H20ClNS, M = 257.81, orthorhombic, space
˚
group Pbca, a = 8.5638(3), b = 14.0302(5), c = 23.1201(9) A, U =
3
2777.92(18) A , Z = 8, l(Mo–Ka) = 0.401 mm−1, 13217 reflections
˚
measured at 180(2) K using an Oxford Cryosystems Cryostream cooling
apparatus, 3144 unique (Rint = 0.058); R1 = 0.070, wR2 = 0.193 [I >
2r(I)]. The structure was solved with SHELXS-97, and refined with
SHELXL-97.11
CCDC reference numbers 261090–261092. See http://www.rsc.org/
suppdata/ob/b5/b503068b/ for crystallographic data in CIF or other
electronic format.
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BrCH2CO2Et, 37%; ii, NaOH, H2O, MeOH; iii, DCC, NHS, THF then
NH3, H2O, 95% (2 steps); iv, NaBH4, MeOH, 62%; v, TFA, toluene,
74%; vi, LiAlH4, Et2O; vii, ClCO2Me, Et3N, CH2Cl2, 63% (2 steps).
Trans. 1, 2001, 37.
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1 3 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 9 – 1 3 7 1

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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 3 6 9 – 1 3 7 1
1 3 7 1