Reduction of 5-(bromomethyl)-1-pyrrolinium bromides to 2-(bromomethyl)pyrrolidines and their transformation into piperidin-3-ones through an unprecedented ring expansion-oxidation protocol

Article abstract of DOI:10.1016/j.tetlet.2008.07.112

3,3-Dialkyl-5-(bromomethyl)-1-pyrrolinium bromides, prepared via bromocyclization of N-(2,2-dialkyl-4-pentenylidene)amines by means of bromine in dichloromethane, were reduced to 4,4-dialkyl-2-(bromomethyl)pyrrolidines for the first time using borane dimethyl sulfide in dichloromethane. Furthermore, the latter 2-(bromomethyl)pyrrolidines were transformed into the corresponding piperidin-3-ones through an unprecedented ring expansion-oxidation protocol in dimethylsulfoxide in the presence of potassium carbonate. Reduction of 5,5-dialkylpiperidin-3-ones by means of sodium borohydride in methanol afforded 5,5-dialkyl-3-hydroxypiperidines in good yields.

Full text of DOI:10.1016/j.tetlet.2008.07.112

Tetrahedron Letters 49 (2008) 6039–6042
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reduction of 5-(bromomethyl)-1-pyrrolinium bromides
to 2-(bromomethyl)pyrrolidines and their transformation into piperidin-3-
ones through an unprecedented ring expansion-oxidation protocol
*
Matthias D’hooghe, Jan Baele, Jan Contreras, Mark Boelens, Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
3,3-Dialkyl-5-(bromomethyl)-1-pyrrolinium bromides, prepared via bromocyclization of N-(2,2-dialkyl-
4-pentenylidene)amines by means of bromine in dichloromethane, were reduced to 4,4-dialkyl-2-(bro-
momethyl)pyrrolidines for the first time using borane dimethyl sulfide in dichloromethane. Furthermore,
the latter 2-(bromomethyl)pyrrolidines were transformed into the corresponding piperidin-3-ones
through an unprecedented ring expansion-oxidation protocol in dimethylsulfoxide in the presence of
potassium carbonate. Reduction of 5,5-dialkylpiperidin-3-ones by means of sodium borohydride in meth-
anol afforded 5,5-dialkyl-3-hydroxypiperidines in good yields.
Received 2 July 2008
Revised 18 July 2008
Accepted 21 July 2008
Available online 24 July 2008
Keywords:
1-Pyrrolinium salts
Piperidin-3-ones
3-Hydroxypiperidines
Ring expansion
Ó 2008 Elsevier Ltd. All rights reserved.
From a synthetic point of view, electrophile-induced cycliza-
tions constitute a powerful methodology for the preparation of
a large variety of functionalized azaheterocyclic compounds.1 In
this respect, N-(2,2-dialkyl-4-pentenylidene)amines have been
proven to be excellent substrates for electrophile-induced cycli-
zation reactions affording a variety of aziridines, pyrrolidines
and piperidines via intermediate cyclic iminium salts.2 Previ-
ously, the reduction of this type of 5-(bromomethyl)-1-pyrrolin-
ium salts has been performed using classical reducing agents
such as sodium borohydride in methanol and lithium aluminium
hydride in THF or diethyl ether, resulting in the isolation of
piperidines as the major reaction components instead of pyrrol-
idines.2h,i The observed ring enlargement has been explained
date, the only approach towards 2-(bromomethyl)pyrrolidines
starting from 5-(bromomethyl)-1-pyrrolinium salts involves a
two-step procedure in which these pyrrolinium bromides are
first ring expanded into 3-methoxypiperidines upon treatment
with sodium methoxide in methanol and subsequent reduction,3
followed by ring contraction of the latter 3-methoxypiperidines
by means of boron(III) bromide.2h
Biologically spoken, the 3-hydroxypiperidine motif is of interest
due to its presence in a large number of natural products with a
range of bioactivities.4 Among others, cassine, deoxocassine,
pseudoconhydrine, spectalin, prosophylline, prosopinine, febrifu-
gine and prosafrinine are important representatives of this partic-
ular class of piperidine alkaloids.4
HO
HO
HO
HO
N
H
(CH2)10COMe
N
H
N
H
(CH2)9COEt
(-)-Cassine
(+)-Pseudoconhydrine
(+)-Prosopinine
considering an intramolecular substitution of bromide by nitro-
gen in the initially formed 2-(bromomethyl)pyrrolidines, giving
rise to intermediate bicyclic aziridinium salts which suffer from
ring opening at the more hindered aziridine carbon atom. To
In the literature, a variety of synthetic approaches towards 3-
hydroxypiperidines are known, including nucleophilic cycliza-
tions of pentylamines bearing a suitable leaving group at the
5-position,5 radical cyclization reactions,6 intramolecular Michael
reactions,7 Diels–Alder reactions,8 and reductions of 3-hydroxy-
pyridines9 or piperidin-3-ones.10 Furthermore, a convenient en-
try into 3-hydroxypiperidines has been described based on the
* Corresponding author. Tel.: +32 92645951; fax: +32 92646243.
E-mail address: norbert.dekimpe@UGent.be (N. De Kimpe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.112

6040
M. D’hooghe et al. / Tetrahedron Letters 49 (2008) 6039–6042
ring expansion of 2-(hydroxymethyl)pyrrolidines via intermedi-
ate bicyclic aziridinium salts upon initial activation of the hydro-
xyl group.11a,b
chloroimines towards the corresponding secondary b-chloroam-
ines, as the use of complex metal hydrides only leads to aziridines
instead.15 Probably, the less alkaline properties of borane as com-
pared to ionic reducing agents such as LiAlH4 or NaBH4 can account
for these observations. Up to now, borane dimethyl sulfide has not
been used for the reduction of cyclic iminium salts towards the
corresponding tertiary amines.
In the present Letter, the straightforward one-step reduction of
3,3-dialkyl-5-(bromomethyl)-1-pyrrolinium bromides, obtained
via bromocyclization of N-(2,2-dialkyl-4-pentenylidene)amines,
towards the corresponding 2-(bromomethyl)pyrrolidines is de-
scribed for the first time using borane dimethyl sulfide in dichloro-
methane. Furthermore, the latter 2-(bromomethyl)pyrrolidines
were transformed into piperidin-3-ones in dimethylsulfoxide
through an unprecedented ring expansion-oxidation protocol. Sub-
sequent reduction of these piperidin-3-ones with sodium borohy-
dride led to 3-hydroxypiperidines.
In the next stage, the reactivity of 2-(bromomethyl)pyrrol-
idines 4 with regard to the oxidant dimethylsulfoxide (DMSO)
was investigated as a potential entry into pyrrolidine-2-carbalde-
hydes, which are known to be attractive synthons for further
elaboration.16 The oxidation of organic halides to the corre-
sponding carbonyl compounds comprises a well-known transfor-
mation in organic synthesis. Several methods have been
developed to carry out this conversion such as the Hass–Bender
reaction,17 the Kröhnke reaction18 and the Kornblum reaction,19
although all these procedures are limited in scope and require
high reaction temperatures. In order to circumvent these limita-
tions, improved variants of the Kornblum oxidation of alkyl ha-
lides to aldehydes and ketones by means DMSO have been
In the literature, two different methodologies are known for the
preparation of N-(2,2-dialkyl-4-pentenylidene)amines 2, both
starting from isobutyraldehyde 1 (R2 = Me) and from cyclohexane-
carbaldehyde
four-step approach involving imination with tert-butylamine,
-alkylation using lithium diisopropylamide (LDA) and allyl bro-
1 a
(R2–R2 = (CH2)5). The first method entails
a
mide, hydrolysis of the imine by aqueous oxalic acid and imination
of the aldehyde utilizing a primary amine R1NH2.12 As the direct
allylation of the starting aldehydes with allyl bromide and LDA is
not a selective process and leads to intractable reaction mixtures,
a detour via N-tert-butyl imines is required and offers a suitable
and flexible way for the synthesis of the desired imines 2. Alterna-
described.20 In analogy, 2-(bromomethyl)pyrrolidines
4 were
stirred in DMSO at 30 °C for 14 h in the presence of 2 equiv of
potassium carbonate, resulting in full consumption of the start-
ing material. However, spectroscopic analysis of the obtained
reaction products revealed their molecular structure to be piper-
idin-3-ones 5 instead of pyrrolidine-2-carbaldehydes (Scheme 2,
crude yields). The addition of potassium carbonate appeared to
be essential, as piperidin-3-ones 5 were isolated in very low
yields (10%) if no K2CO3 was used.
tively, imines 2 can be accessed more easily through direct
a -ally-
lation of the required aldehydes 1 via a Claisen rearrangement
using allyl alcohol in the presence of p-toluenesulfonic acid in p-
cymene,13 followed by an imination step (Scheme 1). Treatment
of the thus obtained
bromine in dichloromethane at 0 °C for 15 min afforded 5-bromo-
methyl-1-pyrrolinium bromides quantitatively (Scheme 1),
which were used immediately and as such for further elaboration
due to their instability.
Subsequently, the reduction of cyclic iminium salts 3 towards
the corresponding 2-(bromomethyl)pyrrolidines 4 was envisaged.
As mentioned before, the reduction of 5-(bromomethyl)-1-pyrro-
linium salts by means of classical reducing agents such as NaBH4
or LiAlH4 results in ring expansion to piperidines.2h,i In order to
prepare the desired 2-(bromomethyl)pyrrolidines 4, 1-pyrrolinium
bromides 3 were treated with 1 equiv of borane dimethyl sulfide in
dichloromethane at 0 °C for 1 h, followed by the addition of
10 equiv of an aqueous solution of sodium hydroxide (0.5 M) to
convert the in situ formed stable amine-borane complex to the free
amine (Scheme 1).14 The use of borane dimethyl sulfide as a mild
c
,d-unsaturated imines 2 with 1.02 equiv of
Whereas many reports on the synthesis and application of
piperidin-3-ones bearing an electron-withdrawing group at nitro-
gen (usually acyl) are available in the literature,21 often associated
with the preparation of biologically relevant target compounds,
less information can be found regarding the synthesis of N-alkylpi-
peridin-3-ones. The latter piperidones are usually prepared via oxi-
dation of 3-hydroxypiperidines22 or acid hydrolysis of the
vinylether moiety in 5-methoxy-1,2,3,4-tetrahydropyridines,3,23
although also the cyclization of 4-(alkoxycarbonylmethylami-
no)butanoates has been described.24
From a mechanistic point of view, the following rationale can be
suggested. Apparently, 2-(bromomethyl)pyrrolidines 4 are first
transformed into intermediate bicyclic aziridinium salts 7 (in equi-
librium with the corresponding 3-bromopiperidines), which are
converted into piperidines 8 upon ring opening with dimethylsulf-
oxide, either via direct nucleophilic ring opening at the substituted
aziridine carbon atom or via initial spontaneous ring opening and
3
reducing agent has been reported before for the reduction of
a-
1) 0.67 equiv allyl alcohol
p-TsOH
p-cymene, Δ
R1
Br
1.02 equiv
R1
H
O
N
Br2
N
H
R2
Br
H
R2
2) 1 equiv R1NH2
MgSO4
CH2Cl2, Δ, 1 h
CH2Cl2
0 ºC, 15 min
R2 R2
R2
R2
3 (100%)
1
2
.
R1
N
1) 1 equiv BH3 Me2S
CH2Cl2, 0 ºC, 1 h
Br
R2
2) 10 equiv NaOH (0.5 M)
0 ºC - r.t., 30 min
R2
4a (R1 = tBu, R2 = Me, 74%)
4b (R1 = iPr, R2 = Me, 37%)
4c (R1 = tBu, R2-R2 = (CH2)5, 85%)
4d (R1 = sBu, R2 = Me, 87%)
Scheme 1.

M. D’hooghe et al. / Tetrahedron Letters 49 (2008) 6039–6042
6041
R1
N
R1
N
R1
N
2 equiv K2CO3
2 equiv NaBH4
MeOH, r.t., 1 h
Br
R2
R2
R2
R2
R2
DMSO, 30 ºC, 14 h
O
OH
R2
4
5a (R1 =
t
Bu, R2 = Me, 82%)
6a (85%)
6b (73%)
6c (50%)
6d (62%)
5b (R1 = iPr, R2 = Me, 94%)
5c (R1 =
5d (R1 =
t
Bu, R2-R2 = (CH2)5, 91%)
Bu, R2 = Me, 81%)
s
Scheme 2.
R1
N
R1
N
N
N
Br
3 equiv KOSiMe3
Br
Br
R2
R2
R2
4
R2
7
THF, Δ, 2 h
OH
4a
6a (71%)
DMSO
R1
N
R1
N
aq. workup
N
N
Br
Me
S
R2
R2
R2
R2
OSiMe3
O
Me
Me3SiO
O
H
7a
9
8
5
Scheme 4.
Scheme 3.
The spectral data of piperidine 6a obtained via both pathways were
judged to be identical.
subsequent substitution of the thus formed carbenium ion.
Abstraction of the acidic proton at the oxygenated carbon atom
by potassium carbonate results in the liberation of dimethylsulfide
and piperidin-3-ones 5 (Scheme 3).
It should be mentioned that in some cases a substantial amount
(upto 50%) of 3-hydroxypiperidines 6 was obtained along with
piperidin-3-ones 5 after heating of pyrrolidines 4 (e.g., 4c and d)
in DMSO, which might be the result of an incomplete oxidation
reaction or direct hydrolysis of the strained intermediates 7, prob-
ably due to water present in DMSO. As the isolation of 3-piperi-
In summary, the electrophile-induced cyclization of N-(2,2-dial-
kyl-4-pentenylidene)amines by means of bromine in dichloro-
methane furnished 3,3-dialkyl-5-(bromomethyl)-1-pyrrolinium
bromides, which were reduced into 4,4-dialkyl-2-(bromo-
methyl)pyrrolidines for the first time using borane dimethyl sul-
fide in dichloromethane. The latter 2-(bromomethyl)pyrrolidines
were transformed into the corresponding piperidin-3-ones
through an unprecedented ring expansion-oxidation protocol by
heating in dimethylsulfoxide in the presence of potassium carbon-
ate. Finally, reduction of 5,5-dialkylpiperidin-3-ones using sodium
borohydride in methanol afforded 3-hydroxypiperidines in good
yields.
dones
5 in analytically pure form by means of column
chromatography was unsuccessful, their immediate reduction
was performed by means of 2 equiv of sodium borohydride in
methanol, affording the corresponding 3-hydroxypiperidines 6a–
d in good yields after 1 h at room temperature (Scheme 2).25 In-
deed, 3-piperidones are fairly labile substances which are better
handled as their hydrohalides.26
References and notes
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(halomethyl)pyrrolidines, in which 2-(iodomethyl)pyrrolidines
were converted into mixtures of the corresponding 2-(hydroxy-
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2 h (Scheme 4). This approach provides an improved alternative for
the above-mentioned literature protocol. The direct conversion of
pyrrolidine 4a to piperidine 6a proceeds through the formation
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a
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Tetrahedron: Asymmetry 2007, 18, 1667; (e) Calveras, J.; Casas, J.; Parella, T.;
Joglar, J.; Clapes, P. Adv. Synth. Catal. 2007, 349, 1661; (f) Stragies, R.;
Osterkamp, F.; Zischinsky, G.; Vossmeyer, D.; Kalkhof, H.; Reimer, U.; Zahn,
G. J. Med. Chem. 2007, 50, 3786; (g) Koch, D.; Maechling, S.; Blechert, S.
Tetrahedron 2007, 63, 7112; (h) Uttamchandani, M.; Liu, K.; Panicker, R. C.; Yao,
31.5, 46.7, 53.4, 54.5, 58.5, 66.7. IR (NaCl): m
OH = 3330 cmÀ1. MS (70 eV): m/z (%):
185 (M+, 7); 170 (100); 94 (11); 70 (14); 58 (14); 57 (33); 56 (11); 55 (13). Anal.
Calcd for C11H23NO: C, 71.30; H, 12.51; N, 7.56. Found: C, 71.47; H, 12.66; N, 7.41.
26. (a) Blicke, F. F.; Krapcho, J. J. Am. Chem. Soc. 1952, 74, 4001; (b) Easton, N. R.;
Bartron, L. R.; Meinhofer, F. L.; Fish, V. B. J. Am. Chem. Soc. 1953, 75, 2086.
27. Williams, D. R.; Osterhout, M. H.; McGill, J. M. Tetrahedron Lett. 1989, 30, 1331.