Iodide-catalysed cyclization of unsaturated N-chloroamines: A new way to synthesise 3-chloropiperidines

Article abstract of DOI:10.1002/1099-0690(200209)2002:18<3171::AID-EJOC3171>3.0.CO;2-L

Tetrabutylammonium iodide is a very efficient catalyst for the cyclization of unsaturated N-chloroamines. The catalysis seems to proceed through N-iodoamine intermediates, which act as a source of iodonium ions. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200209)2002:18<3171::AID-EJOC3171>3.0.CO;2-L

FULL PAPER
Iodide-Catalysed Cyclization of Unsaturated N-Chloroamines:
A New Way to Synthesise 3-Chloropiperidines
Michael Noack[a] and Richard Göttlich*[a]
Keywords: Cyclization / Homogeneous catalysis / Nitrogen heterocycles
Tetrabutylammonium iodide is a very efficient catalyst for the
cyclization of unsaturated N-chloroamines. The catalysis
seems to proceed through N-iodoamine intermediates, which
act as a source of iodonium ions.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
Pyrrolidines and piperidines are important substructures
of a variety of biologically active compounds.[1] We are cur-
rently investigating new methods for their catalytic syn-
thesis by intramolecular addition of nitrogenϪheteroatom
bonds to double bonds.[2] In a recent publication[3] we re-
ported on the samarium() iodide catalysed cyclization of
chloro(pentenyl)amines under mild conditions.
This reaction seemed to be catalysed by iodide rather
than, as initially assumed, by samarium(). Here we give a
full report on this new reaction, describing its scope, to-
gether with a mechanistic discussion.
Results and Discussion
As reported previously, tetrabutylammonium iodide
(TBAI) efficiently catalyses the cyclization of unsaturated
chloroamines, but the reaction conditions had not been be
optimised. We therefore examined different solvents and re-
action temperatures for the cyclization of 1b. The results are
given in Scheme 1.
Chloroform is clearly the best solvent, and higher tem-
peratures seem to be necessary for efficient cyclization. To
use temperatures above the boiling point of chloroform,
1,2-dichloroethane was selected as a similar solvent. How-
ever, performance of the reaction in 1,2-dichloroethane at a
temperature of 80 °C did not improve the yield. A better
yield could be obtained by using 10 mol % of catalyst,
whilst a further increase in the amount of catalyst again
resulted in a reduced yield. In a next step we wanted to
Scheme 1. Optimization of the reaction conditions
check the generality of these optimized reaction conditions,
and therefore synthesized the chloroamines 1aϪ1o.[4]
The gem-dialkyl-substituted chloroamines 1hϪ1n were
obtained via the enamine 3 (Scheme 2), which was synthe-
sized from isobutyraldehyde and morpholine. This enamine
3 was alkylated with allyl bromide to afford aldehyde 4 after
aqueous workup. Reductive amination of aldehyde 4 gave
the amines 5hϪ5m. Amine 5n was obtained from 5l by
TMS protection of the free hydroxy group. From these sec-
ondary amines the chloroamines 1hϪ1n were obtained in
good yield by treatment with NCS.
[a]
For the synthesis of the ester-substituted chloroamine 1o,
a different approach had to be chosen (Scheme 3), as the
ester group does not survive the reductive amination. The
aldehyde 4 was therefore transformed into the oxime 6,
Organisch-Chemisches Institut der Westfälischen Wilhelms-
Universität Münster,
Corrensstr. 40, 48149 Münster, Germany
Fax: (internat.) ϩ 49-(0)251/8336529
E-mail: gottlir@uni-muenster.de
Eur. J. Org. Chem. 2002, 3171Ϫ3178  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0918Ϫ3171 $ 20.00ϩ.50/0
3171

M. Noack, R. Göttlich
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Table 1. Yields of cyclisation
Scheme 2. Synthesis of chloroamines 1hϪ1n
Scheme 3. Synthesis of chloroamine 1o
which was reduced with lithium aluminium hydride to give
amine 7. Alkylation of this amine with ethyl 3-bromopro-
pionate afforded the secondary amine 5o, which was trans-
formed into the chloroamine 1o by treatment with NCS.
These chloroamines 1aϪ1o were cyclized under the
optimized reaction conditions (Table 1, 10% TBAI, chloro-
form, 50 °C). In all cases the 3-chloropiperidines 2aϪ2o
were obtained in good yield. The cyclization does not only
produce good yields when simple alkyl-substituted chlo-
roamines are used but a variety of sensitive functional
groups neither inhibit the reaction nor are they affected in
any way. Such groups as additional double bonds (1m), es-
ters (1o), silyl ethers (1n) and even free hydroxy groups (1l)
can therefore be used in this transformation. Furthermore,
the cyclization is not sensitive to steric influences. The chlo-
roamines 1hϪ1k gave the cyclization products 2hϪ2k in
good yield, regardless of the size of R5.
The quantitative yield of 2h from the cyclization of 1h
tempted us to use this transformation for kinetic studies.
Chloroamine 1h was therefore cyclized at 50 °C in deuterated
chloroform in the presence of different amounts of TBAI.
NMR samples were taken from these reaction mixtures,
frozen in acetone/dry ice and warmed to room temperature
1
just prior to measurement of the H NMR spectrum. No
intermediates of the reaction could be detected in the spec-
tra; only signals resulting from the starting material and the
product were visible. To examine the kinetics, the product/
chloroamine ratio was determined by integration, using the
signal of TBAI as an internal standard. Figure 1 shows five Figure 1. Kinetic studies
3172
Eur. J. Org. Chem. 2002, 3171Ϫ3178

A New Way to Synthesise 3-Chloropiperidines
FULL PAPER
selected spectra with 5% TBAI, together with the measured
kinetics for 1%, 5%, 10% and 50% TBAI, respectively.
For the synthesis of the (Z)- and (E)-configured N-
chloro-4-hexenylamines 1q and 1r, a different approach was
To our surprise, the reaction proceeded best with 1% followed (Scheme 5). Chloroamine 1q was synthesized via
catalyst. An increase in the amount of catalyst also pro- the ester 9, which was obtained from but-3-en-2-ol and tri-
vided a quantitative yield, but there seemed to be an initi- ethyl orthoacetate in
a Johnson-orthoester-Claisen re-
ation period during which the reaction proceeded only arrangement.[6] Reduction of the ester 9 with lithium alumi-
slowly. The more catalyst was used, the longer was this initi- nium hydride gave the alcohol 10, which was transformed
ation period. One explanation for this observation might be into the tosylate 11. The tosyloxy group could be substi-
that iodide is only a catalyst precursor and in fact inhibits tuted with butylamine to afford the amine 5q, which was
the reaction by conproportionation with the actual catalyst, transformed into the chloroamine 1q by treatment with
which might be a more highly oxidized iodo species. For NCS.
better understanding of the mechanism and the reactive
For the synthesis of 1r, crotonic acid was brominated to
species, the stereochemical outcome of the addition to 1,2- give 12, from which (Z)-bromopropene 13 was obtained
disubstituted double bonds was of interest. We therefore by fragmentation.[7] The (Z)-propenyllithium 14 was syn-
turned our attention to the chloroamines 1pϪ1r, containing thesized from 13 by treatment with lithium powder. Cuprate
disubstituted double bonds. For the synthesis of 1p coupling[8] of this organolithium compound with 1,3-dibro-
(Scheme 4) the aldehyde 8 was prepared stereoselectively by mopropane stereoselectively gave (Z)-1-bromo-4-hexene
means of a Claisen rearrangement[5] from isobutyraldehyde 15. Substitution of the bromide with butylamine provided
and but-3-en-2-ol.
the amine 5r, which was transformed into the chloroamine
1r with NCS under standard conditions.
With the three chloroamines 1pϪ1r readily available, we
then cyclized them by application of our previously optim-
ized conditions (Scheme 6).
Scheme 4
Aldehyde 8 was reductively aminated to afford amine 5p,
which was transformed into the desired chloroamine 1p by
treatment with NCS.
Scheme 6
All three reactions produced good yields of piperidines
2pϪ2r. Furthermore, the stereochemistry of the double
bond was maintained in the product. The reaction thus pro-
ceeds through a stereospecific trans addition.
With this additional information, mechanistic discussion
is feasible. One plausible pathway would be reaction via am-
inyl radicals.[9] However, if the reaction were to proceed via
radicals, one would expect a cascade cyclization in the case
of chloroamine 1m, a reaction that we did not observe at
all. Furthermore, the stereospecificity and the initiation
period would not be explained if the reaction was radical
in nature. Therefore, a different mechanism had to be pro-
posed. The iodide might be oxidized by chloroamine to give
iodine or ICl. These compounds would conproportionate
with excess iodide, giving an explanation for the initiation
period. Furthermore, iodine and ICl are known to add to
double bonds by stereospecific trans addition,[10] as ob-
served in our reaction. If iodine or ICl were intermediates
in the reaction, one would expect a mixture of chloroamine
and iodide to be an efficient reagent for performing a halo-
lactonization. We therefore tried to achieve a halolac-
Scheme 5
Eur. J. Org. Chem. 2002, 3171Ϫ3178
3173

M. Noack, R. Göttlich
FULL PAPER
tonization of 4-pentenoic acid by addition of chlorodiethyl- nucleophilic substitution (D), affording an aziridinium
amine and catalytic amounts of TBAI (Scheme 7).
ion.[14] This exists in equilibrium with the 3-chloropi-
peridine resulting from the nucleophilic attack of a chloride
ion. Unfortunately N-iodoamines are too reactive to be dir-
ectly detected in the reaction, and we therefore have no dir-
ect evidence of their occurrence. Nevertheless, the proposed
catalytic cycle is suitable to explain all experimental obser-
vations. We are currently trying to find further evidence for
this mechanism.
Scheme 7
However, no detectable amounts of lactone were pro-
duced either under our standard conditions for the cycliza-
tion of chloroamines or on application of literature condi-
tions for halolactonizations, thereby ruling out the parti-
cipation of iodine or ICl in the catalysis.
Conclusion
In summary, we present a new, catalytic, general and mild
procedure for the cyclization of unsaturated chloroamines,
which most probably proceeds via N-iodoamines and
iodonium ions. The 3-chloropiperidines generated in this re-
action should prove to be valuable intermediates for the
synthesis of natural products. We are currently working to-
wards broadening the synthetic scope of N-chloroamines as
sources of electrophilic halonium ions.
More highly oxidized iodine species might be interme-
diates in the reaction: IIII compounds, for example, are
known to be electrophilic and to attack double bonds.[11]
However, such species also react with aromatic compounds,
and we did not find any aromatic substitution products
when we cyclized chloroamines 1aϪ1c, which each have an
aromatic nucleus in close proximity to the NϪCl group.
Such hypervalent iodine compounds can therefore be ruled
out. This leaves only one plausible reaction mechanism: the
generation of N-iodoamines. These compounds could be
formed from chloroamines by a Finkelstein reaction
(Scheme 8).
Experimental Section
General: All solvents were purified by distillation and dried, if
necessary, prior to use. As a standard solvent, tert-butyl methyl
ether (TBME) was used instead of diethyl ether in many cases. The
reactions were carried out under vacuum in heat-dried glassware
under argon. Products were purified by flash chromatography on
silica gel (40Ϫ63 µm). NMR spectra were recorded in CDCl3 with
a Bruker WM 300, a Bruker AMX 400 and a Varian Unity plus 600
spectrometer with TMS as internal standard. Mass spectra were
recorded with an MAT 8200, an MAT 8230 and a Micromars
Quattro LC spectrometer. Elemental analyses were performed with
a CHN-O Rapid from Foss-Heraeus and a Vario EL III from Ele-
mentar Analysensysteme.
2-Methyl-1-morpholinopropene (3): Morpholine (95.8 mL, 87.1 g,
1.1 mol) and a catalytic amount of p-toluenesulfonic acid were ad-
ded at 0 °C to a solution of isobutyraldehyde (90.8 mL, 72.1 g,
1.0 mol) in dichloromethane (500 mL). The solution was heated
under reflux overnight and water was removed azeotropically with
a DeanϪStark apparatus. After cooling to room temperature, the
mixture was washed with water (50 mL) and dried with sodium
sulfate. The solvent was removed and the residue was distilled in
vacuo (90Ϫ110 °C, 100 mbar) to give 2-methyl-1-morpholinoprop-
ene (3) (132.6 g, 0.94 mol, 94%) as a colorless liquid. 1H NMR
(300 MHz, CDCl3): δ ϭ 1.61, (s, with fine-splitting, 3 H), 1.68 (s,
with fine-splitting, 3 H), 2.55 (m, 4 H), 3.69 (m, 4 H), 5.30 (sept,
J ϭ 1.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 17.3,
22.1, 53.1, 66.8, 123.4, 135.3 ppm. These data are consistent with
the published spectra.
Scheme 8
As the iodine in iodoamines is in the ϩ1 oxidation state,
such compounds would conproportionate with excess iod-
ide, giving an explanation for the observed initiation period.
From studies by Jander,[12] N-iodoamines are known to be
highly reactive species. They could therefore react intramo-
lecularly with the double bond, generating an iodonium ion
A.[13] After rotation around a single bond (B) this ion could
be opened in an SN2-type manner by the nucleophilic nitro-
gen atom (C), explaining the observed stereospecificity. The
2,2-Dimethylpent-4-enal (4): A solution of the enamine 3 (60.0 g,
420 mmol) in acetonitrile (150 mL) was cooled to 0 °C. Allyl brom-
ide (40.2 mL, 56.2 g, 470 mmol) was then added and the mixture
was heated under reflux overnight. After the mixture had cooled
to room temperature, water (100 mL) and hydrochloric acid (2 ,
200 mL) were added. The organic layer was separated and the water
layer was washed three times with dichloromethane (50 mL each).
catalyst would be liberated from the cyclization product by The combined organic layers were dried with sodium sulfate, the
3174 Eur. J. Org. Chem. 2002, 3171Ϫ3178

A New Way to Synthesise 3-Chloropiperidines
FULL PAPER
solvent was removed, and the residue was distilled in vacuo (80 (m, 2 H), 5.82 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
°C, 110 mbar) to give 2,2-dimethylpent-4-enal (4, 28.6 g, 257 mmol, 25.4, 29.2, 33.8, 44.5, 49.9, 52.6, 116.5, 135.9 ppm. C11H23N
61%) as a colorless liquid. H NMR (300 MHz, CDCl3): δ ϭ 1.06 (169.31): calcd. C 78.03, H 13.69, N 8.27; found C 77.75, H 13.63,
1
(s, 6 H), 2.22 (dt, J ϭ 7.4, 1.2 Hz, 2 H), 5.06 (m, 2 H), 5.71 (m, 1
N 8.01.
13
H), 9.48 (s, 1 H) ppm.
C NMR (75 MHz, CDCl3): δ ϭ 21.0,
N-(2-Hydroxyethyl)-2,2-dimethylpent-4-enylamine (5l): B.p. 46 °C (1
mbar). H NMR (300 MHz, CDCl3): δ ϭ 0.91 (s, 6 H), 2.02 (dt,
41.3, 45.5, 118.2, 132.9, 205.3 ppm. These data are consistent with
1
the published spectra.[15]
J ϭ 7.3, 1.3 Hz, 2 H), 2.03 (s, broad, 2 H), 2.39 (s, 2 H), 2.77 (t,
with fine-splitting, J ϭ 5.4 Hz, 2 H), 3.61 (t, with fine-splitting,
J ϭ 5.4 Hz, 2 H), 5.02 (m, 2 H), 5.82 (m, 1 H) ppm. 13C NMR (75
MHz, CDCl3): δ ϭ 25.5, 34.3, 44.7, 51.7, 59.6, 60.4, 116.9, 135.3
ppm. C9H19NO (157.26): calcd. C 68.74, H 12.18, N 8.91; found C
68.35, H 11.93, N 8.70.
(E)-2,2-Dimethylhex-4-enal
(8):
Isobutyraldehyde
(62.4 g,
866 mmol) and p-toluenesulfonic acid (0.2 g) were added to a solu-
tion of 3-buten-2-ol (41.7 g, 578 mmol) in toluene (150 mL). The
reaction mixture was heated under refluxed for 48 h and the water
generated was removed in a DeanϪStark apparatus. The solvent
was then removed and the residue was distilled in vacuo (136 °C at
70 mbar) to give aldehyde 8 (48.9 g, 393 mmol, 67%) as a colorless
N-Allyl-2,2-dimethylpent-4-enylamine (5m): B.p. 102 °C (100 mbar).
1H NMR (300 MHz, CDCl3): δ ϭ 0.89 (s, 6 H), 1.12 (s, broad, 1
H), 2.01 (dt, J ϭ 7.4, 1.2 Hz, 2 H), 2.35 (s, 2 H), 3.23 (dt, J ϭ 6.0,
1.4 Hz, 2 H), 5.02 (m, 2 H), 5.12 (m, 2 H), 5.85 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 25.5, 34.2, 44.7, 53.3, 59.8, 115.4,
116.7, 135.5, 137.4 ppm.
1
liquid. H NMR (300 MHz, CDCl3): δ ϭ 1.03 (s, 6 H), 1.65 (ddd,
J ϭ 6.3, 1.5, 1.2 Hz, 3 H), 2.14 (dt, J ϭ 6.9 , 1.2 Hz, 2 H), 5.32 (m,
1 H), 5.48 (m, 1 H), 9.47 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 17.8, 21.1, 40.3, 45.9, 125.2, 129.3, 206.2 ppm. These
data are consistent with the published spectra.[16]
(E)-N-Butyl-2,2-dimethylhex-4-enylamine (5p): B.p. 126 °C
(85mbar). H NMR (300 MHz, CDCl3): δ ϭ 0.79 (s, 6 H), 0.84 (t,
General Procedure for the Reductive Amination: The primary amine
(0.11 mol) and sodium sulfate (approx. 30 g) were added to a co-
oled solution (0 °C) of the corresponding aldehyde (0.10 mol) in
dichloromethane (150 mL), and the reaction mixture was left
standing overnight. After filtration, the solvent was removed, the
residue was taken up in methanol (100 mL), and sodium borohyd-
ride (1.9 g, 50 mmol) was added in small portions at 0 °C. After
the mixture had been stirred overnight, aqueous sodium hydroxide
(25%, 50 mL) were added and the mixture was stirred for 1 h. The
organic layer was then separated and the aqueous layer was ex-
tracted three times with diethyl ether (50 mL each). The combined
organic layers were dried with sodium sulfate. After removal of the
solvent, the residue was distilled in vacuo to give the corresponding
amine as a colorless liquid.
1
J ϭ 7.2 Hz, 3 H), 1.26 (m, 2 H), 1.37 (m, 2 H), 1.59 (d, J ϭ 4.4 Hz,
3 H), 1.84 (d, 4.4 Hz, 2 H), 2.25 (s, 2 H), 2.50 (t, J ϭ 7.4 Hz, 2 H),
5.34 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 13.8, 17.7,
20.2, 25.3, 32.0, 34.1, 43.3, 50.5, 60.3, 126.8, 127.6 ppm. C12H25N
(183.34): calcd. C 78.62, H 13.74, N 7.64; found C 78.63, H 13.55,
N 7.73.
2,2-Dimethyl-N-(2-trimethylsiloxyethyl)pent-4-enylamine (5n): A so-
lution of n-butyllithium in hexane (1.6 , 20 mL, 32 mmol) was
added slowly at Ϫ78 °C to a solution of N-(2-hydroxyethyl)-2,2-
dimethylpent-4-enylamine (5l, 5.00 g, 31.8 mmol) in THF (50 mL)
and the reaction mixture was stirred for 0.5 h. Trimethylsilyl chlor-
ide (3.45 g, 31.8 mmol) was then added dropwise and the solution
was allowed to warm to room temperature overnight. The solution
was poured into a mixture of ice (100 g) and pH ϭ 7 buffer (100
mL), the phases were separated, and the aqueous phase was ex-
tracted three times with diethyl ether (50 mL each). After drying
of the combined organic layers with sodium sulfate and removal of
the solvent, the silyl ether 5n (2.47 g, 10.8 mmol, 34%) was isolated
by flash chromatography (eluent pentane/TBME, 10:1 then 3:1) as
N-Butyl-2,2-dimethylpent-4-enylamine (5h): B.p. 110 °C (110 mbar).
1H NMR (300 MHz, CDCl3): δ ϭ 0.90 (s, 6 H), 0.93 (t, J ϭ 7.3 Hz,
3 H), 1.39 (m, 5 H), 2.02 (d, J ϭ 7.5 Hz, 2 H), 2.36 (s, 2 H), 2.60
(t, J ϭ 7.0 Hz, 2 H), 5.02 (m, 2 H), 5.83 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 14.6, 21.1, 26.1, 32.9, 34.9, 45.4, 51.3, 61.1,
117.2, 136.2 ppm. HRMS: (EI, E-scan): calcd. for C11H22ClN
203.14407/205.141128; found 203.1425/205.1426. For elemental
analysis, the hydrochloride was prepared: C11H24ClN (205.77):
calcd. C 64.21, H 11.76, N 6.81; found C 63.97, H 11.47, N 6.73.
1
a yellow oil. H NMR (300 MHz, CDCl3): δ ϭ 0.13 (s, 9 H), 0.90
(s, 6 H), 1.40 (s, broad, 1 H), 2.02 (dt, J ϭ 7.4, 1.4 Hz, 2 H), 2.37
(s, 2 H), 2.71, t, 5.4 Hz, 2 H), 3.69 (t, J ϭ 5.4 Hz, 2 H), 5.02 (m, 2
13
H), 5.83 (m, 1 H) ppm. C NMR (75 MHz, CDCl3): δ ϭ 0.04,
N-Isobutyl-2,2-dimethylpent-4-enylamine (5i): B.p. 117 °C (100
mbar). 1H NMR (300 MHz, CDCl3): δ ϭ 0.88 (s, 6 H), 0.89 (d,
J ϭ 6.6 Hz, 6 H), 0.89 (s, 1 H), 1.73 (m, 1 H), 2.01 (dt, J ϭ 7.2,
1.2 Hz, 2 H, 2.32 (s, 2 H), 2.38 (d, 6.9 Hz, 2 H), 5.00 (m, 2 H), 5.82
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 20.6, 25.5, 28.0,
34.4, 44.8, 59.0, 60.3, 116.6, 135.7 ppm. C11H23N (169.31): calcd.
C 78.03, H 13.69, N 8.27; found C 77.60, H 13.55, N 8.46.
25.5, 34.4, 44.8, 52.7, 60.2, 61.7, 116.8, 135.5 ppm. C12H27NOSi
(229.44): calcd. C 62.82, H 11.86, N 6.10, found C 62.49, H 11.83,
N 5.95.
2,2-Dimethylpent-4-enal Oxime (6): Hydroxylamine hydrochloride
(1.67 g, 24 mmol) in water (1 mL) was added to a solution of so-
dium hydroxide (600 mg, 15 mmol) in water (1.5 mL), and the mix-
ture was diluted with ethanol (6 mL). Without removal of occasion-
ally precipitated sodium chloride, aldehyde 4 (2.24 g, 20 mmol) in
ethanol (50 mL) was added and the reaction mixture was left
standing overnight. Water (30 mL) was then added, the organic
layer was separated, and the aqueous layer was extracted three
times with diethyl ether (20 mL each). The combined organic layers
were dried with sodium sulfate, the solvent was removed, and the
residue was distilled in vacuo (b.p. 69 °C, 1 mbar) to yield the oxime
6 (2.29 g, 18 mmol, 90%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.06 (s, 1 H), 1.09 (s, 6 H), 2.19 (dt, J ϭ 7.4, 1.2 Hz,
N-sec-Butyl-2,2-dimethylpent-4-enylamine (5j): B.p. 109 °C (120
mbar). 1H NMR (300 MHz, CDCl3): δ ϭ 0.82 (s, broad, 1 H), 0.88
(s, 6 H), 0.88 (t, 7.5 Hz, 3 H), 1.00 (d, 6.6 Hz, 3 H), 1.35 m, 2 H),
2.00 (dt, J ϭ 7.3, 1.0 Hz, 2 H), 2.28 (d, J ϭ 11.5 Hz, 1 H), 2.38 (d,
J ϭ 11.4 Hz, 1 H), 2.45 (q, J ϭ 6.1 Hz, 1 H), 5.00 (m, 2 H), 5.82
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 10.3, 20.2, 25.6,
29.7, 34.3, 44.7, 55.5, 57.7, 116.6, 135.8 ppm. C11H23N (169.31):
calcd. C 78.03, H 13.69, N 8.27; found C 77.69, H 13.33, N 7.97.
N-tert-Butyl-2,2-dimethylpent-4-enylamine (5k): B.p. 104 °C (150
mbar). H NMR (300 MHz, CDCl3): δ ϭ 0.85 (s, 6 H), 0.89 (s, 1 2 H), 5.05 (m, 2 H), 5.76 (m, 1 H), 7.34 (s, 1 H) ppm. 13C NMR
H), 1.05 (s, 9 H), 1.99 (dt, J ϭ 7.6, 1.2 Hz, 2 H), 2.28 (s, 2 H), 5.00 (75 MHz, CDCl3): δ ϭ 25.0, 36.6, 45.3, 118.1, 133.9, 158.4 ppm.
1
Eur. J. Org. Chem. 2002, 3171Ϫ3178
3175

M. Noack, R. Göttlich
C7H13NO (127.19): calcd. C 66.11, H 10.30, N 11.01; found C (E)-1-Tosyloxy-4-hexene (11): Pyridine (15 mL, 0.15 mol) was ad-
FULL PAPER
66.03, H 10.40, N 11.12.
ded at 0 °C to a solution of toluene-4-sulfonyl chloride (29.0 g,
0.15mol) in dichloromethane (200 mL), followed by (E)-hex-4-en-
1-ol (10, 9.0 g, 90 mmol). The mixture was stirred overnight and
then poured onto ice (200 g) and stirred for another hour. Solid
sodium hydroxide was added until the pH was greater than 10. The
phases were separated, and the aqueous phase was extracted twice
with dichloromethane (50 mL each). The combined organic phases
were dried with sodium sulfate, the solvent was removed, and the
residue was purified by flash chromatography (eluent pentane/
TBME, 10:1), giving the tosylate 11 (18.2 g, 72 mmol) as a yellow
oil. 1H NMR (300 MHz, CDCl3): δ ϭ 1.58 (m, 3 H), 1.69 (m, 2
H), 2.00 (m, 2 H), 2.44 (s, 3 H), 4.02 (t, 6.4 Hz, 2 H), 5.31 (m, 2
H), 7.34 (m, 2 H), 7.79 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 17.7, 21.5, 28.6, 69.8, 126.4, 127.8, 129.0, 129.7, 133.4, 144.6
ppm. C13H18O3S (254.35): calcd. C 61.39, H 7.13; found C 61.28,
H 7.12. These data are consistent with the published spectra.[20]
2,2-Dimethylpent-4-enylamine (7): A solution of oxime 6 (2.29 g,
18 mmol) in diethyl ether (50 mL) was added dropwise at 0 °C to
a suspension of lithium aluminium hydride (1.0 g, 26 mmol) in dry
diethyl ether (100 mL). After vigorous stirring overnight, the reac-
tion mixture was poured onto ice, and solid sodium hydroxide was
added until the precipitate dissolved. The organic layer was separ-
ated, and the residue was extracted three times with diethyl ether
(50 mL each). The combined organic layers were dried with sodium
sulfate, the solvent was removed, and the residue was distilled in
vacuo (b.p. 66 °C at 100 mbar) to give the amine 7 (1.35 g,
12 mmol, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
δ ϭ 0.79 (s, 6 H), 1.71 (s, broad, 2 H), 1.90 (dt, J ϭ 7.4, 1.2 Hz, 2
H), 2.37 (s, 2 H), 4.94 (m, 2 H), 5.72 (m, 1 H) ppm. 13C NMR (75
MHz, CDCl3): δ ϭ 24.6, 34.9, 44.1, 52.9, 116.9, 135.4 ppm. These
data are consistent with the published spectra.[17]
(E)-N-Butylhex-4-enylamine (5q): The tosylate 11 (18.0 g, 71 mmol)
was added at 0 °C to butylamine (100 mL), and the mixture was
heated under reflux overnight. Excess butylamine was removed in
vacuo, and the residue was taken up in TBME (200 mL) and water
(100 mL). Aqueous sodium hydroxide (5%) was then added until
the pH was greater than 10. The phases were separated, and the
organic phase was extracted three times with aqueous sodium hy-
droxide (5%, 100 mL each) and dried with sodium sulfate. After
removal of the solvent, the product was obtained by distillation
(b.p. 145 °C, 50 mbar) as a colorless liquid, 9.1 g (59 mmol, 83%).
1H NMR (300 MHz, CDCl3): δ ϭ 0.91 (t, 7.1 Hz, 3 H), 1.04 (s,
broad, 1 H), 1.35 (m, 2 H), 1.45 (m, 2 H), 1.53 (m, 2 H), 1.64 (m,
3 H), 1.96 (m, 2 H), 2.59 (m, 4 H), 5.40 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1, 17.8, 20.7, 29.5, 29.8, 30.6, 51.8, 51.9,
124.5, 131.6 ppm. These data are consistent with the published
spectra.[21]
Ethyl 3-[(2,2-Dimethylpent-4-enyl)amino]propanoate (5o): Ethyl 3-
Bromopropionate (3.19 g, 17.6 mmol) was added at 0 °C to a solu-
tion of 2,2-dimethylpent-4-enylamine (7, 5.38 g, 47.5 mmol) in
dichloromethane (100 mL) and the solution was stirred overnight.
The reaction mixture was washed three times with aqueous sodium
hydroxide (5%, 20 mL each) and dried with sodium sulfate, and
the solvent was removed. The product was purified by flash chro-
matography (eluent pentane/TBME, 10:1 then 3:1) to yield 5o
(2.48 g, 11.6 mmol, 66%) as a yellow oil. 1H NMR (300 MHz,
CDCl3): δ ϭ 0.88 (s, 6 H), 1.26 (t, 7.1 Hz, 3 H), 1.38 (s, broad, 1
H), 2.00 (dt, J ϭ 7.5, 1.1 Hz, 2 H), 2.36 (s, 2 H), 2.49 (t, J ϭ
6.5 Hz, 2 H), 2.88 (t, J ϭ 6.5 Hz, 2 H), 4.15 (q, J ϭ 7.1 Hz, 2 H),
5.01 (m, 2 H), 5.81 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 14.3, 25.5, 34.3, 34.9, 44.7, 46.2, 60.0, 60.3, 116.8, 135.5, 177.6
ppm. C12H23NO2 (213.32): calcd. C 67.57, H 10.87, N 6.57; found
C 67.64, H 11.15, N 6.64.
2,3-Dibromobutyric Acid (12): Bromine (44.2 mL, 137 g, 0.86 mol)
was added dropwise to a suspension of crotonic acid (66.0 g, 0.767
mol) in petroleum ether (300 mL) at such a rate that the color of
the bromine quickly disappeared. To start the reaction, gentle heat-
ing with a water bath was necessary. While the bromine was added,
the crotonic acid dissolved completely and the 2,3-dibromobutyric
acid precipitated from the yellow solution as a colorless solid. After
the mixture had been stirred overnight, the solid was isolated by
filtration, washed three times with petroleum ether and dried for 4
h under vacuum to give 2,3-dibromobutyric acid (12, 162 g,
659 mmol, 86%) as a crystalline solid. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.91 (d, 6.2 Hz, 3 H), 4.40 (m, 2 H), 11.80 (s, broad,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 23.8, 44.6, 48.9, 143.8
ppm. These data are consistent with the published spectra.[22]
Ethyl (E)-Hex-4-enoate (9): Acetic acid (1 mL) was added to a mix-
ture of but-3-en-2-ol (42.9 mL, 0.50 mol) and triethyl orthoacetate
(137.0 mL, 0.75mol), and the vessel was fitted with a Liebig con-
denser. The mixture was slowly heated to 140 °C over 2 h, during
which 1 equiv. ethanol was distilled off. The temperature was then
raised to 150 °C and kept there until another equiv. of ethanol had
distilled off (approx. 3 h). The product was purified by distillation
(b.p. 93 °C, 60 mbar) to give the ester 9 (65.5 g, 0.46mol, 92%) as
a colorless liquid. 1H NMR (300 MHz, CDCl3): δ ϭ 1.26 (t, 7.2 Hz,
3 H), 1.65 (d, with fine-splitting, 4.5 Hz, 3 H), 2.33 (m, 4 H), 4.14
(q, 7.2 Hz, 2 H), 5.46 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 14.2, 17.8, 27.9, 34.4, 60.2, 126.1, 129.3, 173.2 ppm. These data
are consistent with the published spectra.[18]
(E)-Hex-4-en-1-ol (10): Lithium aluminium hydride (26 g, 0.69 mol)
was suspended in TBME (400 mL) in a 1-L flask. At 0 °C, a solu-
(Z)-1-Propenyl Bromide (13): 2,3-Dibromobutyric acid (159 g, 0.65
tion of ethyl (E)-hex-4-enoate (9, 65.5 g, 0.46 mol) in TBME (50 mol) was added in five portions at 0 °C to triethylamine (400 mL),
mL) was added slowly. The reaction mixture was stirred overnight
at room temperature and then poured onto 400 g of ice. Sulfuric
acid (50 %) was added until the precipitate dissolved. The phases
were separated and the aqueous phase was extracted three times
with TBDME (100 mL each). The combined organic phases were
dried with sodium sulfate, the solvent was removed, and the prod-
carbon dioxide being produced during the addition. After the mix-
ture had been vigorously stirred for 3 h at room temperature and
a further 3 h at 40 °C, water (300 mL) was added to the resulting
clear black solution. Concentrated hydrochloric acid (250 mL) was
then added carefully at 0 °C. The reaction mixture was left standing
overnight in a separation funnel. The organic layer was then separ-
uct was obtained from the residue by distillation (b.p. 90 °C, ated and washed first with saturated sodium hydrogencarbonate
60mbar) as a colorless liquid (29.5 g, 0.29 mol, 64%). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.65 (m, 5 H), 1.72 (s, 1 H), 2.07 (m, 2
H), 3.62 (t, 6.7 Hz, 2 H), 5.49 (m, 2 H) ppm. 13C NMR (75 MHz,
solution (20 mL) and then with brine (10 mL). After drying with
sodium sulfate, the solvent was removed and the residue was puri-
fied by distillation to give (Z)-1-bromo-1-propene (13, 40.8 g,
CDCl3): δ ϭ 17.8, 28.9, 32.5, 62.5, 125.4, 130.7 ppm. These data 337 mmol, 52%) as a colorless liquid. 1H NMR (300 MHz, CDCl3):
are consistent with the published spectra.[19]
δ ϭ 1.74 (d, 4.8 Hz, 3 H), 6.15 (m, 2 H) ppm. 13C NMR (75 MHz,
3176
Eur. J. Org. Chem. 2002, 3171Ϫ3178

A New Way to Synthesise 3-Chloropiperidines
FULL PAPER
CDCl3): δ ϭ 15.2, 108.8, 129.5 ppm. These data are consistent with 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 20.2, 25.8, 27.3, 35.8,
the published spectra.[23]
44.9, 74.7, 75.3, 117.2, 135.3 ppm.
5-[Chloro(sec-butyl)amino]-4,4-dimethylpent-1-ene (1j): 1H NMR
(300 MHz, CDCl3): δ ϭ 0.92 (s, 6 H), 0.94 (t, J ϭ 7.5 Hz, 3 H),
1.11 (d, J ϭ 6.1 Hz, 3 H), 1.35 (m, 1 H), 1.67 (m, 1 H), 2.07 (m, 2
H), 2.69 (d, J ϭ 14.8 Hz, 1 H), 2.70 (m, 1 H), 2.84 (d, J ϭ 14.8 Hz,
1 H), 5.01 (m, 2 H), 5.82 (ddt, J ϭ 16.2, 10.9, 7.5 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 11.2, 14.6, 25.6, 25.7, 27.7, 35.7,
44.8, 69.0, 71.4, 117.0, 135.5 ppm.
(Z)-1-Propenyllithium (14): (Z)-1-Propenyl bromide (13, 31.1 g,
0.257 mol), dissolved in diethyl ether (100 mL), was added drop-
wise at Ϫ50 °C to a suspension of powdered lithium (8.0 g, 1.2
mol) in diethyl ether (200 mL). After stirring for 1 h at Ϫ40 °C,
the reaction mixture was allowed to warm to room temperature.
The suspension was filtered through a reverse filter and the re-
sulting clear pale-red solution was stored at Ϫ20 °C. For deter-
mination of the concentration, 1 mL of the solution was poured
into 20 mL of 1  aqueous sulfuric acid and titrated with 0.1 
sodium hydroxide solution; 200 mL of a 1.0  solution of 14 was
obtained (77%).
5-[Chloro(tert-butyl)amino]-4,4-dimethylpent-1-ene (1k): 1H NMR
(300 MHz, CDCl3): δ ϭ 0.95 (s, 6 H), 1.20 (s, 9 H), 2.07 (dt, 7.4,
1.0 Hz, 2 H), 2.80 (s, 2 H), 5.01 (m, 2 H), 5.85 (ddt, J ϭ 16.3, 11.0,
7.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 25.7, 26.7,
34.9, 45.3, 62.5, 67.5, 116.9, 135.5 ppm.
(Z)-1-Bromohex-4-ene (15): Copper() iodide (21 g, 0.11 mol), dis-
solved in dimethyl sulfide (80 mL), was added at Ϫ78 °C to the 1.0
 (Z)-1-propenyllithium solution (200 mL, 0.2 mol). The reaction
mixture was brought to Ϫ40 °C and stirred for 15 min. 1,3-Dibro-
mopropane (22.12 g, 0.11 mol) was added to this cuprate solution,
and the reaction mixture was allowed to warm to room temperature
overnight. Saturated aqueous ammonium chloride solution (300
mL) was added at 0 °C to the resulting black suspension. After the
mixture had been stirred for 1 h, the layers were separated and the
aqueous phase was extracted twice with diethyl ether (100 mL
each). The combined organic layers were dried with sodium sulfate
and the solvent was removed. The crude (Z)-1-bromohex-4-ene (15)
was used directly in the next step without further purification.
(2E)-6-[Butyl(chloro)amino]-5,5-dimethylhex-2-ene (1p): 1H NMR
(300 MHz, CDCl3): δ ϭ 0.92 (s, 6 H), 0.93 (t, J ϭ 7.2 Hz, 3 H),
1.37 (m, 2 H), 1.59 (m, 2 H), 1.65 (m, 3 H), 1.95 (m, 2 H), 2.80 (s,
2 H), 2.90 (t, 6.9 Hz, 2 H), 5.42 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 13.9, 18.0, 19.9, 25.7, 30.3, 35.7, 43.6, 66.6, 74.8,
127.5, 127.6 ppm.
(2E)-6-[Butyl(chloro)amino]hex-2-ene: (1q): 1H NMR (300 MHz,
CDCl3): δ ϭ 0.93 (t, J ϭ 7.5 Hz, 3 H), 1.38 (m, 2 H), 1.63 (m, 2
H), 1.69 (m, 5 H), 2.02 (m, 2 H), 2.91 (m, 4 H), 5.42 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 13.9, 17.8, 20.0, 27.7, 29.7, 30.0,
63.7, 64.1, 125.4, 130.6 ppm.
(2Z)-6-[Butyl(chloro)amino]hex-2-ene: (1r): 1H NMR (300 MHz,
CDCl3): δ ϭ 0.92 (t, J ϭ 6.9 Hz, 3 H), 1.36 (m, 2 H), 1.65 (m, 2
H), 1.70 (m, 5 H), 2.07 (m, 2 H), 2.92 (m, 4 H), 5.42 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 12.7, 13.9, 20.0, 24.0, 27.8, 30.0,
64.1, 64.3, 124.5, 129.8 ppm.
(Z)-N-Butylhex-4-enylamine (5r): The crude (Z)-1-bromohex-4-ene
(15) was dissolved in dichloromethane (100 mL), and this solution
was added at 0 °C over 30 min to a mixture of n-butylamine (200
mL) in dichloromethane (300 mL). After vigorous stirring over-
night, the solvent and the excess of n-butylamine were removed.
The remainder was taken up in diethyl ether (200 mL) and water
(100 mL). Aqueous sodium hydroxide solution (5%) was added un-
til the pH was above 10. The organic layer was then separated and
dried with sodium sulfate. After removal of the solvent, the residue
was distilled (b.p. 151 °C, 50mbar) to give the amine 5r (5.31 g,
General Procedure for the Cyclization Reaction Producing 3-Chloro-
piperidines 2: The N-chloroamine (2.5 mmol) was added at 50 °C
(oil bath temperature) to a suspension of tetrabutylammonium iod-
ide (0.25 mmol) in chloroform (10 mL). The solution was kept at
this temperature for 12 h. After the mixture had cooled to room
temperature, the solvent was removed and the product was isolated
from the residue by flash chromatography.
1
34 mmol, 31% over two steps) as a colorless liquid. H NMR (300
MHz, CDCl3): δ ϭ 0.92 (t, 7.2 Hz, 3 H), 1.20 (s, broad, 1 H), 1.34
(m, 2 H), 1.47 (m, 2 H), 1.55 (m, 2 H), 1.61 (d, 6.0 Hz, 3 H), 2.08
(m, 2 H), 2.60 (m, 4 H), 5.42 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 12.6, 13.9, 20.5, 24.7, 30.0, 32.4, 49.7, 49.8, 124.0,
130.2 ppm.
5-Chloro-1-isobutyl-3,3-dimethylpiperidine (2i): 1H NMR (300
MHz, CDCl3): δ ϭ 0.86 (s, 3 H), 0.89 (d, 6.9 Hz, 6 H), 1.04 (s, 3
H), 1.32 (t, J ϭ 12.3 Hz, 1 H), 1.70 (m, 2 H), 1.93 (m, 2 H), 2.05
(d, with fine splitting, J ϭ 6.0 Hz, 2 H), 2.35 (d, J ϭ 11.1 Hz, 1
H), 3.10 (d, with fine splitting, J ϭ 9.9 Hz, 1 H), 4.07 (tt, J ϭ 11.4,
4.2 Hz, 1 H) ppm. 13C NMR (300 MHz, CDCl3):ϭ 20.6, 20.7,
25.2, 25.9, 29.3, 33.4, 48.5, 54.4, 62.8, 65.2, 66.1 ppm.
General Procedure for the Preparation of N-Chloroamines: N-Chlo-
rosuccinimide (1 equiv.) was added to a cooled (0 °C) solution of
the corresponding amine in dichloromethane. After the mixture
had been stirred for 2 h, the solvent was removed and the residue
was taken up in pentane. After removal of the solid succinimide by
filtration, the solvent was removed and the product was isolated
from the residue by flash chromatography.
1-sec-Butyl-3-chloro-5,5-dimethylpiperidine (2j): 1H NMR (400
MHz, CDCl3): δ ϭ 0.90 (t, 7.3 Hz, 3 H), 0.92 (s, 6 H), 1.04 (d, J ϭ
5.7 Hz, 3 H), 1.27 (m, 1 H), 1.31 (dd, J ϭ 12.9, 12.3 Hz, 1 H), 1.47
(m, 1 H), 1.90 (m, 2 H), 2.12 (m, 1 H), 2.23 (d, J ϭ 10.6 Hz, 1 H),
2.48 (m, 1 H), 3.04 (dd, J ϭ 11.1, 10.5 Hz, 1 H), 4.05 (m, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 11.4, 25.1, 26.8, 29.3,
29.4, 33.6, 49.09, 49.1, 56.0, 57.5, 60.9 ppm. Minor Isomer (Selected
5-[Butyl(chloro)amino]-4,4-dimethylpent-1-ene (1h): 1H NMR (300
MHz, CDCl3): δ ϭ 0.93 (t, 7.3 Hz, 3 H), 0.94 (s, 6 H), 1.38 (m, 2
H), 1.62 (m, 2 H), 2.08 (d, 8.0 Hz, 2 H), 2.85 (s, 2 H), 2.94 (m, 2
H), 5.04 (m, 2 H), 5.83 (ddt, J ϭ 12.6, 7.8, 5.4 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 13.9, 19.9, 25.7, 30.2, 35.6, 44.9,
66.6, 74.8, 117.2, 135.3 ppm.
1
Signals): H NMR (400 MHz, CDCl3): δ ϭ 1.71, 3.11, 4.32 ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 14.1, 26.5, 27.0, 33.3, 55.1, 55.4,
60.4, 62.4 ppm. MS: m/z (%) ϭ 203 (6) [Mϩ], 174 (32) [Mϩ
Ϫ
C2H5ϩ], 141 (45), 111 (16) [Mϩ Ϫ C4H9Cl], 83 (27), 71 (60), 57
(100) [C3H7Nϩ]. HRMS: (Quattro-LC, electrospray): calcd. for
C15H28ClN 203.14407; found 203.14361.
5-[Chloro(isobutyl)amino]-4,4-dimethylpent-1-ene (1i): 1H NMR
(300 MHz, CDCl3): δ ϭ 0.93 (d, 6.9 Hz, 6 H), 0.94 (s, 6 H), 1.98
(m, 1 H), 2.07 (dt, 7.5, J ϭ 1.2 Hz, 2 H), 2.67 (d, J ϭ 6.9 Hz, 2
1-tert-Butyl-3-chloro-5,5-dimethylpiperidine (2k): 1H NMR (300
H), 2.84 (s, 2 H), 5.03 (m, 2 H), 5.81 (ddt, J ϭ 17.5, 10.8, 7.2 Hz, MHz, CDCl3): δ ϭ 0.90 (s, 3 H), 0.99 (s, 3 H), 1.03 (s, 9 H), 1.29
Eur. J. Org. Chem. 2002, 3171Ϫ3178 3177

M. Noack, R. Göttlich
FULL PAPER
[5]
[6]
L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157. H. J.
Günther; E. Guntrum, V. Jäger, Liebigs Ann. Chem. 1984, 15.
F. E. Ziegler, Chem. Rev. 1988, 88, 1423.
W. S. Johnson, L. Wertheman, W. R. Bartlett, T. J. Brocksom,
T.-T. Li, D. J. Faulkner, M. R. Petersen, J. Am. Chem. Soc.
1970, 92, 741. G. V. M. Sharma, T. Shekharam, V. Upender,
Tetrahedron 1990, 46, 5665.
C. E. Fuller, D. G. Walker, J. Org. Chem. 1991, 56, 4066.
For an overview see: R. J. K. Taylor Organocopper Reagents,
Oxford University Press, Oxford, 1994.
For aminyl radicals see: F. Minisci, Synthesis 1973, 1; L. Stella,
Angew. Chem. 1982, 95, 368, Angew. Chem. Int. Ed. Engl. 1983,
22, 337; J. L. Esker, M. Newcomb, Adv. Heterocycl. Chem.
1993, 58, 1; L. Stella in Radicals in Organic Synthesis, Wiley-
VCH, Weinheim, 2001, vol. 2, p. 407 and references cited
therein.
(dd, J ϭ 12.2, 12.1 Hz, 1 H), 1.81 (d, J ϭ 11.2 Hz, 1 H), 1.91 (m,
1 H), 2.00 (dd, J ϭ 10.7, 10.4 Hz, 1 H), 2.53 (dt, J ϭ 10.7, 2.0 Hz,
1 H), 3.34 (m, 1 H), 4.01 (ddt, J ϭ 11.9, 10.6, 4.5 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 24.9, 26.4, 29.4, 33.3, 49.0, 53.4,
55.6, 56.2, 57.8 ppm. For the elemental analysis, the hydrochloride
was prepared. C11H25Cl2N (242.23): calcd. C 55.00, H 9.65, N 5.83;
found C 54.70, H 9.34, N 5.61.
[7]
[8]
trans-1-Butyl-3-chloro-2,5,5-trimethylpiperidine (2p): 1H NMR (600
MHz, CDCl3): δ ϭ 0.89 (s, 3 H), 0.90 (t, J ϭ 7.3 Hz, 3 H), 1.03 (s,
3 H), 1.26 (m, 2 H), 1.30 (d, J ϭ 5.9 Hz, 3 H), 1.37 (m, 2 H), 1.48
(dd, J ϭ 12.5, 12.4 Hz, 1 H), 1.5 (ddd, J ϭ 12.8, 12.7, 2.4 Hz, 1
H), 2.05 (d, J ϭ 11.5 Hz, 1 H), 2.18 (dq, J ϭ 9.4, 6.2 Hz, 1 H),
2.42 (dd, J ϭ 12.0, 2.3 Hz, 1 H), 2.44 (m, 1 H), 2.68 (ddd, J ϭ
13.2, 9.4, 6.4 Hz, 1 H), 3.71 (ddd, J ϭ 12.0, 9.4, 4.4 Hz, 1 H) ppm.
13C NMR (150 MHz, CDCl3): δ ϭ 14.0, 17.1, 20.5, 24.7, 26.9, 29.3,
32.5, 49.0, 53.2, 62.7, 63.5, 64.2 ppm.
[9]
[10]
[11]
See: K. E. Harding, T. H. Tiner, Compr. Org. Synth. 1991, 4,
363.
A. Varvoglis Hypervalent Iodine in Organic Synthesis, Aca-
demic Press, London, 1997. A. Varvoglis, The Organic Chem-
istry of Polycoordinated Iodine, VCH Verlagsgesellschaft,
Weinheim, 1992.
J. Jander, U. Engelhardt, G. Weber, Angew. Chem. 1962, 74, 75.
J. Jander, K. Knuth, W. Renz, Z. Anorg. Allg. Chem. 1972, 392,
143. R. Hagedorn, H. Pritzkow, J. Jander, Acta Crystallogr. B
1977, 33, 3209.
This intermediate is most probably not a zwitterion, but either
a proton or a metal salt should coordinate the amide.
This is a long-known reaction: R. C. Fuson, C. L. Zirkle, J.
Am. Chem. Soc. 1948, 70, 2760Ϫ2762. C. F. Hammer, S. R.
Heller, J. H. Craig, Tetrahedron 1972, 28, 239Ϫ253. For recent
applications of this rearrangement see: D. R. Williams, J. P.
Reddy, G. S. Amato, Tetrahedron Lett. 1994, 35, 6417. J. Cossy,
C. Dumas, D. Gomez Pardo, Eur. J. Org. Chem. 1999, 1693. J.
Cossy, O. Mirguet, D. Gomez Pardo, J.-R. Desmurs, Tetrahed-
ron Lett. 2001, 42, 5705.
R. Knorr, P. Löw, P. Hassel, Synthesis 1983, 785.
S.-C. Tsay, J. A. Robl, J. R. Hwu, J. Chem. Soc., Perkin Trans.
1 1990, 757.
Z. Dillenberger, H. Schmid, H.-J. Hansen, Helv. Chim. Acta
1978, 61, 1856.
J. Ambuehl, P. S. Pregosin, L. M. Venanzi, J. Organomet.
Chem. 1979, 181, 255.
S. E. Denmark, D. C. Forbes, D. S. Hays, J. S. DePue, R. G.
Wilde, J. Org. Chem. 1995, 60, 1391.
trans-1-Butyl-3-chloro-2-methylpiperidine (2q): 1H NMR (300
MHz, CDCl3): δ ϭ 0.92 (t, 7.5 Hz, 3 H), 1.24 (m, 2 H), 1.29 (d,
J ϭ 6.0 Hz, 3 H), 1.32Ϫ1.50 (m, 3 H), 1.61Ϫ1.70 (m, 3 H), 2.30
(m, 2 H), 2.49 (m, 2 H), 2.65 (m, 1 H), 3.66 (m, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 13.9, 16.3, 20.7, 24.9, 27.3, 35.2,
51.4, 55.6, 62.4, 63.7 ppm. C10H20ClN (189.73): calcd. C 63.31, H
10.63, N 7.38; found C 62.85, H 10.70, N 7.38.
[12]
[13]
[14]
cis-1-Butyl-3-chloro-2-methylpiperidine (2r): 1H NMR (300 MHz,
CDCl3): δ ϭ 0.91 (t, J ϭ 7.2 Hz, 3 H), 1.10 (d, J ϭ 6.3 Hz, 3 H),
1.28 (m, 2 H), 1.42 (m, 3 H), 1.86 (m, 3 H), 2.38 (m, 2 H), 2.48
(m, 2 H), 2.93 (m, 1 H), 4.14 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 14.0, 20.7, 23.5, 24.1, 28.1, 31.1, 47.7, 53.9, 58.1, 62.4
ppm. C10H20ClN (189.73): calcd. C 63.31, H 10.63, N 7.38; found
C 63.47, H 10.96, N 7.45.
[15]
[16]
Acknowledgments
We thank the Fonds der Chemischen Industrie, the Deutsche For-
schungsgemeinschaft and the SFB 424, as well as the Alfried
Krupp von Bohlen und Halbach-Stiftung, for financial support.
[17]
[18]
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[20]
[21]
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The synthesis of the chloroamines 1a؊1g has been published
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[O02129]
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Eur. J. Org. Chem. 2002, 3171Ϫ3178