Asymmetric synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiperidines by α-alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane

Article abstract of DOI:10.1021/jo1020807

α-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane successfully led to 2-substituted N-tert-butanesulfinyl-5-chloropentanimidates in acceptable diastereomeric ratios (dr 67/33 to 72/28) and good yields (74-86%). Subsequent reduction with NaBH₄ led to the corresponding 2-substituted N-tert-butanesulfinyl-5-chloropentylamines, which could be cyclized to a range of new chiral 3-substituted N-tert-butanesulfinylpiperidines using NaH in DMSO. Finally, the N-tert-butanesulfinylpiperidines could be efficiently deprotected to enantiomerically pure 3-alkyl- and 3-arylpiperidine hydrochlorides.

Full text of DOI:10.1021/jo1020807

pubs.acs.org/joc
Asymmetric Synthesis of Chiral N-Sulfinyl 3-Alkyl- and
3-Arylpiperidines by r-Alkylation of N-Sulfinyl Imidates with
1-Chloro-3-iodopropane
Filip Colpaert, Sven Mangelinckx,† and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering,
Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. †Postdoctoral Fellow of the Research
Foundation - Vlaanderen (FWO).
norbert.dekimpe@UGent.be
Received October 20, 2010
R-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane successfully led to 2-substituted
N-tert-butanesulfinyl-5-chloropentanimidates in acceptable diastereomeric ratios (dr 67/33 to 72/28)
and good yields (74-86%). Subsequent reduction with NaBH4 led to the corresponding 2-sub-
stituted N-tert-butanesulfinyl-5-chloropentylamines, which could be cyclized to a range of new chiral
3-substituted N-tert-butanesulfinylpiperidines using NaH in DMSO. Finally, the N-tert-butanesul-
finylpiperidines could be efficiently deprotected to enantiomerically pure 3-alkyl- and 3-arylpiperidine
hydrochlorides.
Introduction
and stereoselective R-alkylation of N-sulfinyl imidates can be
achieved leading to chiral R-substituted N-sulfinyl imidates
as useful intermediates in the synthesis of enantiopure amides
and esters.4 The significantly more nucleophilic metallo-
enamines derived from N-sulfinyl imidates were sufficiently
reactive to enable R-alkylation in contrast to metalloenamines
Piperidines are a very important class of compounds, com-
monly found in natural products and drugs.1 The piperidine
subunit can be frequently recognized in the structure of
numerous naturally occurring alkaloids and synthetic com-
pounds with interesting biological and pharmacological
properties.1e,2 For these reasons, the development of general
methods for the synthesis of enantiopure piperidine deriva-
tives has attracted considerable synthetic attention over the
last years.3 Recently, our group demonstrated that an efficient
(3) (a) Kibayashi, C. In Studies in Natural Products Chemistry. Stereo-
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A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.; McLaughlin, M. A.; Lee,
P. H.; Price, D. A. Tetrahedron 1999, 55, 8931. (j) Groaning, M. D.; Meyers,
A. I. Tetrahedron 2000, 56, 9843. (k) Leclerq, S.; Daloze, D.; Braekman, J.-C.
Org. Prep. Proced. Int. 1996, 28, 501. (l) Nadin, A. Contemp. Org. Synth.
1997, 4, 387. (m) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383.
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Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (c) Buffat, M. G. P. Tetrahedron
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234 J. Org. Chem. 2011, 76, 234–244
Published on Web 12/01/2010
DOI: 10.1021/jo1020807
r
2010 American Chemical Society

Colpaert et al.
JOCArticle
derived from N-tert-butanesulfinyl imines. Therefore, it was
envisioned that the R-alkylation of N-sulfinyl imidates with
1,3-dihalopropanes [X1(CH2)3X2; X1, X2 = halogen) could
be a valuable new approach toward the synthesis of new
chiral N-sulfinyl 3-alkyl and 3-arylpiperidines, and the results
are described herein.
Enantiopure 3-alkylpiperidines are an important group of
compounds, since their heterocyclic skeleton is present in a
large number of alkaloids.5 The importance of enantiopure
3-arylpiperidines lies in their interesting dopaminergic activ-
ity6 and their use in the treatment of various central nervous
system disorders.7 Despite the impressive advances in the
enantioselective synthesis of piperidine derivatives over the
last years,3 the preparation of enantiopure 3-arylpiperidines,
has received very little attention.8 While most enantiopure
3-arylpiperidines reported so far have been obtained by
routes involving the conventional resolution of a racemate,8a,9
Amat et al. reported recently an efficient and straightforward
procedure for the enantioselective synthesis of 3-arylpiper-
idines, involving a reduction of bicyclic δ-lactams, formed
via cyclodehydration of racemic γ-aryl-δ-oxoesters with
(R)- or (S)-phenylglycinol, a process that involves a dynamic
kinetic resolution.10 However, previously reported methods
for the preparation of enantiopure 3-alkylpiperidines, via
alkylation of a postulated rigid amide enolate derived from
bicyclic δ-lactams, could not be extended to the synthesis of
3-arylpiperidines.11 On the other hand, the R-alkylation of
N-sulfinyl imidates with X1(CH2)3X2 could afford a new
general synthetic pathway for the synthesis of enantiopure
3-alkylated and 3-arylated piperidines. Very recently, the
synthesis of chiral 3-alkyl- and 3-aryl-N-tosylpiperidines was
performed via iridium-catalyzed hydrogenation of the cor-
responding N-tosyl-1,2,3,6-tetrahydropyridines in good to
excellent enantiomeric excess.12 In contrast to chiral 2-sub-
stituted N-sulfinyl piperidines,13 no enantiopure 3-substituted
N-sulfinyl piperidines are known in literature, unless some
specific trisubstituted bicyclic examples.14 Also 4-substituted
N-sulfinyl piperidines are scarce in literature.15 Hence, the
first synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiper-
idines is described herein.
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Pelletier, S. W., Ed.; Wiley: New York, 1996; Vol. 10, Chapter 2. (b) Andersen,
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Results and Discussion
The R-alkylation of N-tert-butanesulfinyl imidates 1 with
X1(CH2)3X2 was optimized by systematically changing the
reaction conditions in the R-alkylation of N-sulfinyl imidate
(Rs)-1a and (Ss)-4 with X1(CH2)3X2 for the synthesis of
2-substituted N-sulfinyl-5-chloropentanimidates (R)-2a and
(S)-2a (Table 1). The synthesis of N-tert-butanesulfinyl imidate
(Rs)-1a was performed according to a literature procedure
via condensation of (Rs)-tert-butanesulfinamide and the cor-
responding ortho ester with a catalytic amount of p-TsOH
without solvent.4,16 Using the optimized conditions found in
our previous reported work on the R-alkylation of N-sulfinyl
imidates,4 namely treating N-tert-butanesulfinyl imidate (Rs)-1a
with 1.2 equivalents of KHMDS for 45 min at -78 °C
followed by reaction with 1.3 equivalents of Cl(CH2)3Br at
-78 °C for 1.5 h during which the temperature was allowed
to increase to room temperature, N-sulfinyl imidate (Rs)-1a
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TABLE 1. Optimization of the R-Alkylation of N-Sulfinyl Imidates (Rs)-1a and (Ss)-4 with X1(CH2)3X2
conversion of 1a
into 2a and 3a (%)a
entry
R
X1
Cl
Cl
I
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OTHP
X2
base (equiv)
temp (°C)/ time (h)
2a/3aa
dra(R)-2a/ (S)-2a
1
2
3
4
5
6
7
8
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
pTol
tBu
Br
I
I
I
I
I
I
I
I
I
I
I
I
Cl
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (2.0)
LDA (1.2)b
-78 to rt/1.5
-78 to rt/1.5
-78 to rt/1.5
-78 to rt/1.5
0/0.5
27
60
54
71
100
91
100
85
100
88
100
38
74
-
74/26
100/0
29/71
100/0
94/6
100/0
99/1
100/0
96/4
100/0
97/3
100/0
-
-
72/28
-
73/27
47/53c
60/40
59/41
70/30
58/42
70/30
70/30d
47/53
43/57
-
LDA (1.2)b
-78/1
LDA (1.5)b
-78/1
LiHMDS (1.2)
LiHMDS (1.2)
LiHMDS (2.0)
LiHMDS (2.0)
LiHMDS (2.0)e
LiHMDS (2.0)
LiHMDS (2.0)
-78/4
0/1
9
10
11
12
13
14
-78/4
-78/3 þ 0/2
-78/3 þ 0/2
-78/3 þ 0/2
-78/3 þ 0/2
-
aDetermined via 1H NMR analysis of the crude reaction mixture. bDeprotonation was performed at 0 °C. cAfter flash chromatography (Rs,R)-2a was
d
isolated in 25% yield, (Rs,S)-2a in 29% yield and a mixture of (Rs,R)-2a/(Rs,S)-2a 22/78 in 14% yield. After flash chromatography (Rs,R)-2a was
isolated in 47% yield (97% purity, 3% 3a), (Rs,S)-2a in 22% yield, a mixture of (Rs,R)-2a/(Rs,S)-2a 57/43 in 2% yield and a mixture of (Rs,R)-2a/(Rs,S)-
2a 19/81 in 6% yield. eAfter deprotonation, 2.0 equiv ZnCl2 was added at -78 °C for 15 min.
was only for 27% converted to the desired 2-substituted
N-tert-butanesulfinyl-5-chloropentanimidates 2a and to methyl
N-tert-butanesulfinyl-2-methylpent-4-enimidate 3a (Table 1,
entry 1). N-Sulfinyl imidate 3a was formed as byproduct due
to the base-induced dehydrochlorination of N-sulfinyl imidates
2a; 2a/3a 74/26. When changing the electrophile to Cl(CH2)3I,
the conversion of (Rs)-1a into 2a and 3a was increased to
60% using the same reaction conditions and no formation of
elimination product 3a was observed (Table 1, entry 2). Via
1H NMR analysis of the crude reaction mixture a diastereo-
meric ratio of (Rs,R)-2a/(Rs,S)-2a 72/28 was observed. When
switching the electrophile to I(CH2)3I the conversion of (Rs)-
1a into 2a and 3a decreased to 54%, while N-sulfinyl imidate
3a was formed as major product (2a/3a 29/71) (Table 1, entry 3).
The use of 2.0 equivalents of KHMDS resulted in a slightly
increased conversion of (Rs)-1a into 2a and 3a of 71%, while
the diastereomeric ratio was unchanged (Table 1, entry 4).
The use of LDA as base led overall to a better or complete
conversion of (Rs)-1a into 2a and 3a, but the diastereoselec-
tivity decreased (Table 1, entry 5-7). When the reaction was
performed with LiHMDS as base, after 4 h at -78 °C, (Rs)-1a
was converted for 85% in 2a (no formation of 3a) in an
acceptable diastereomeric ratio of 70/30 (Table 1, entry 8).
Applying these conditions at higher temperature led to full
conversion of (Rs)-1a into 2a and 3a, but not surprisingly the
diastereoselectivity was lowered to 58/42 and the formation
of the elimination product 3a was observed in small amounts
(Table 1, entry 9). The use of 2.0 equivalents LiHMDS im-
proved the conversion slightly when the reaction was performed
at -78 °C for 4 h (Table 1, entry 10). Therefore, the reaction
was repeated at -78 °C for 3 h, followed by 2 h at 0 °C,
leading to a complete conversion of (Rs)-1a into 2a and 3a,
while the diastereoselectivity was maintained and only a
trace amount of the elimination product 3a was formed
(Table1, entry 11). Inorder toimprove the diastereoselectivity
of the reaction, several Lewis acids were tested. When ZnCl2
was added after deprotonation only a 38% conversion was
observed, while the diastereoselectivity was lowered to 47/53
(Table 1, entry 12). The addition of BF3.OEt2 afforded a
complex mixture, and the addition of MgBr2 gave no reac-
tion. Also the addition of HMPA led to an unreacted mixture
of N-sulfinyl imidate (Rs)-1a and Cl(CH2)3I after workup.
Subsequently, with a view to improving the diastereoselec-
tivity, (SS)-methyl N-p-toluenesulfinylpropanimidate (SS)-4
was synthesized4,16 and used instead of (Rs)-1a (Table 1,
entry 13). Unfortunately, this resulted in a large decrease of
conversion (74%) and diastereoselectivity (43/57). In a last
attempt, Cl(CH2)3OTHP was used instead of Cl(CH2)3I,
unfortunately giving rise to a complex mixture (Table 1,
entry 14). Therefore, the best result was obtained upon treating
N-sulfinyl imidate (Rs)-1a with 2.0 equivalents of LiHMDS
for 45 min at -78 °C followed by reaction with 1.3 equiva-
lents of Cl(CH2)3I at -78 °C for 3 h, followed by 2 h at 0 °C,
affording 2-substituted N-tert-butanesulfinyl-5-chloropen-
tanimidates (Rs,R)-2a and (Rs,S)-2a in an acceptable dia-
stereomeric ratio of 70/30 and a trace amount of elimination
product 3a (2a/3a 97/3). After flash chromatography, com-
pound (Rs,R)-2a was isolated in 47% yield (97% purity, 3%
3a), (Rs,S)-2a in 22% yield, besides a mixture of (Rs,R)-2a/
(Rs,S)-2a 57/43 in 2% yield and a mixture of (Rs,R)-2a/(Rs,S)-
2a 19/81 in 6% yield.
Analogously, a variety of new chiral 2-substituted N-tert-
butanesulfinyl-5-chloropentanimidates 2 was prepared in
acceptable diastereomeric ratios (dr 67/33 to 72/28) and
good yields (74-86%) using the optimized reaction condi-
tions (Table 2). When the reaction was performed with
Rs-methyl N-tert-butanesulfinylbutanimidate 1b (R1 = Et)
and pentanimidate 1c (R1=n-Pr), imidates 2b and 2c were
obtained in a diastereomeric ratio of 67/33 and 71/29 respectively
(Table 2, entries 2 and 3). Unfortunately, the diastereomers
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TABLE 2. Asymmetric R-Alkylation of N-Sulfinyl Imidates 1 with Cl(CH2)3I
entry
R1
2/3a
dra(Rs,R)-2/(Rs,S)-2
yield (%)b
1
2
3
4
5
6
Me
Et
n-Pr
C6H5
4-FC6H4
4-MeOC6H4
97/3
97/3
97/3
95/5
92/8
94/6
70/30
67/33
71/29
68/32
72/28
72/28
(Rs,R)-2a (47)c, (Rs,S)-2a (22)d
2b (86)c,e
2c (74)c,f
(Rs,R)-2d (54)g, (Rs,S)-2d (23)
(Rs,R)-2e (51), (Rs,S)-2e (24)
(Rs,R)-2f (54)h
aDetermined via 1H NMR analysis of the crude reaction mixture. bIsolated yield after flash chromatography. cPurity 97%, contains 3% 3.
dAdditionally a mixture of (Rs,R)-2a/(Rs,S)-2a 57/43 and a mixture of (Rs,R)-2a/(Rs,S)-2a 19/81 was isolated respectively in 2% and 6% yield. eThe
diastereomers 2b could not be separated via flash chromatography resulting in 2b (22% dr 92/8, 38% dr 63/37, 16% dr 27/73 and 10% dr 24/76). fThe
h
diastereomers 2c could not be separated via flash chromatography resulting in 2c (74% dr 71/29). gPurity 94%, contains 6% 3d. First purification
via flash chromatography: (Rs,R)-2f (46%, 95% purity, 5% 3f) þ (Rs,R)-2f/(Rs,S)-2f 39/61 (28%), second attempt for separation of the latter mixture:
(Rs,R)-2f (8%) þ (Rs,R)-2f/(Rs,S)-2f 18/82 (20%).
of 2b and 2c could not be separated via flash chromatogra-
phy resulting in isolated diastereomeric mixtures with a yield
of 86% and 74%, respectively. Noteworthy, the stereoselec-
tivity obtained in the R-alkylation of N-tert-butanesulfinyl
imidates 1a-c (R1 = alkyl) is in analogy with the previously
reported stereoselective R-alkylation of N-sulfinyl imidates
in the synthesis of chiral R-substituted N-sulfinyl imidates,4
although the use of 1-chloro-3-iodopropane as electrophile
clearly lowers the diastereoselectivity as compared to the use
of monohalogenated electrophiles. The coordinating ability
of the additional chlorine atom of the dihalogenated electro-
phile with the metal of the metalloenamine could be an
important factor leading to a decrease in diastereoselectivity.
In the assumption that the diastereomers of (Rs)-methyl
N-tert-butanesulfinyl-5-chloro-2-arylpentanimidates 2d-f would
be better separatable, Rs-methyl N-tert-butanesulfinylaryl-
acetimidates 1d-f were synthesized.16a When the reaction was
performed with (Rs)-methyl N-tert-butanesulfinylphenyl-
acetimidate 1d (R1 = C6H5), (Rs)-methyl N-tert-butanesulfi-
nyl-5-chloro-2-phenylpentanimidates (Rs,R)-2d and (Rs,S)-
2d were obtained in a diastereomeric ratio of 68/32 (Table 2,
entry 4). In accordance with our assumption, the diastereo-
mers (Rs,R)-2d and (Rs,S)-2d could be separated by flash
chromatography, leading to the isolation of (Rs,R)-2d in
54% yield and (Rs,S)-2d in 23% yield. It has to be noted that
the separation of (Rs,R)-2d and the elimination product 3d
could not be realized, leading to (Rs,R)-2d in a purity of 94%
(contains 6% of 3d). At this stage, little attention was payed
to the presence of this trace impurity as its separation could
be easily accomplished in further steps of the synthesis of
chiral N-sulfinyl piperidines.
chloro-2-(4-methoxy)phenylpentanimidates (Rs,R)-2f and
(Rs,S)-2f in a diastereomeric ratio of 72/28 (Table 2, entry 6).
After a first purification via flash chromatography, com-
pound (Rs,R)-2f was isolated in 46% (95% purity, 5% 3f)
and additionally a mixture of diastereomers (Rs,R)-2f and
(Rs,S)-2f in a ratio of 39/61 was isolated in 28% yield. In a
second effort to separate the latter mixture via flash chro-
matography, compound (Rs,R)-2f was isolated in an addi-
tional 8% yield besides a mixture of diastereomers (Rs,R)-2f
and (Rs,S)-2f in a ratio of 18/82 in 20% yield. Noteworthy, as
compared to the R-alkylation of N-tert-butanesulfinyl imi-
dates 1a-c (R1=alkyl), a reversed stereoselectivity was
obtained in the R-alkylation of Rs-methyl N-tert-butanesul-
finylarylacetimidates 1d-f (R1 = aryl).17
In a next step, the conversion of N-sulfinyl imidate (Rs,R)-
2a to the corresponding N-sulfinyl piperidine (Rs,R)-6a via
reductive cyclization with NaBH4 was investigated (Table 3).
In a first attempt, N-sulfinyl imidate (Rs,R)-2a was treated
with 2.0 mol equiv of NaBH4 in MeOH/THF at reflux
temperature for 6 h, leading to sulfinamide (Rs,R)-5a with
77% conversion (Table 3, entry 1). When the reaction time
was increased, a mixture of sulfinamide (Rs,R)-5a and
N-sulfinyl piperidine (Rs,R)-6a was observed in a ratio of 60/40,
while still 20% of N-sulfinyl imidate (Rs,R)-2a remained
unreacted. When 5.0 equivalents NaBH4 were added to
N-sulfinyl imidate (Rs,R)-2a in MeOH/THF at reflux tempera-
ture for 1 h a full conversion to sulfinamide (Rs,R)-5a was
achieved and after flash chromatography sulfinamide (Rs,
R)-5a was isolated in 78% yield (Table 3, entry 2). Note-
worthy, the sulfinamide formed via reduction of elimination
product 3a, present as a small impurity in the starting imidate
(Rs,R)-2a, was separated via flash chromatography, result-
ing in a high purity of sulfinamide (Rs,R)-5a. In a last attempt
for reductive cyclization of N-sulfinyl imidate (Rs,R)-2a to
the corresponding N-sulfinyl piperidine (Rs,R)-6a, N-sulfinyl
imidate (Rs,R)-2a was treated with 10.0 equivalents of NaBH4,
Repeating the reaction with (Rs)-methyl N-tert-butane-
sulfinyl(4-fluorophenyl)acetimidate 1e (R1 =4-FC6H4), resulted
in the isolation of (Rs,R)-methyl N-tert-butanesulfinyl-5-
chloro-2-(4-fluorophenyl)pentanimidate (Rs,R)-2e in 51%
yield and (Rs,S)-methyl N-tert-butanesulfinyl-5-chloro-2-(4-
fluorophenyl)pentanimidate (Rs,S)-2e in 24% yield (Table 2,
entry 5). Finally, the R-alkylation of (Rs)-methyl N-tert-
butanesulfinyl(4-methoxyphenyl)acetimidate 1f (R1 = 4-
MeOC6H4), afforded (Rs)-methyl N-tert-butanesulfinyl-5-
(17) It is speculated that the nature of the R-substituent of the imidates
influences the E/Z-ratio of the lithium enolates and determines the diaste-
reomeric ratio of the reaction products.
J. Org. Chem. Vol. 76, No. 1, 2011 237

Colpaert et al.
JOCArticle
TABLE 3. Reaction of N-Sulfinyl Imidate (Rs,R)-2a with NaBH4
entry
1
reaction conditions
2a/5a/6a/7a
yield (%)b
2.0 equiv NaBH4, 4.0 equiv MeOH, THF, Δ, 6 h
þ Δ, 13 h
23/77/0/0
20/48/32/0
0/100/0/0
0/0/0/100
-
-
(Rs,R)-5a (78)
2
3
5.0 equiv NaBH4, 10.0 equiv MeOH, THF, Δ, 1 h
10.0 equiv NaBH4, 20.0 equiv MeOH, THF, Δ, 18 h
(Rs,R)-7 (56)c
aDetermined via 1H NMR analysis of the crude reaction mixture. bIsolated yields after flash chromatography. cPurity 96%, contains 4% of the amine
resulting from the reduction of the trace amount of 3a, present in the starting imidate (Rs,R)-2a.
SCHEME 1. Reduction of N-Sulfinyl Imidate (Rs,R)-2a to
Sulfinamide (Rs,R)-7 and Subsequent Deprotection to
(R)-2-Methylpentylamine Hydrochloride (R)-8
TABLE 4. Investigation of the Base-Induced Ring Closure of Sulfinamide
(Rs,R)-5a towards N-Sulfinyl Piperidine (Rs,R)-6a
entry
reaction conditions
yield (%)a
affording surprisingly sulfinamide (Rs,R)-7 (Table 3, entry 3).
After flash chromatography, sulfinamide (Rs,R)-7 was iso-
lated in 56% yield (96% purity).
1
2
3
3.0 equiv KOH, THF/H2O (1:1), Δ, 24 h
1.5 equiv LiHMDS, THF, 0 °C to rt, 7 h
1) 1.5 equiv NaI, 2-butanone, Δ, 24 h
2) 5.0 equiv NaH, THF/DMF (3:1), 0 °C
2.5 equiv NaH, DMSO, 80 °C, 2 h
-
-
-
(Rs,R)-6a (98)
After deprotection of sulfinamide (Rs,R)-7 with an excess
of dioxane HCl, (R)-2-methylpentylamine hydrochloride (R)-
4
3
aIsolated yield after flash chromatography.
8 could be isolated in 82% yield (96% purity) (Scheme 1).
Since the reductive cyclization of N-sulfinyl imidate (Rs,
R)-2a to the corresponding N-sulfinyl piperidine (Rs,R)-6a
was not successful, the base-induced cyclization of sulfin-
amide (Rs,R)-5a toward N-sulfinyl piperidine (Rs,R)-6a was
optimized (Table 4). In a first attempt, sulfinamide (Rs,R)-5a
was treated with 3.0 equivalents of KOH in THF/H2O (1:1)
at reflux temperature for 24 h according to a procedure for
the ring closure of sulfinamides to N-sulfinyl aziridines (Table 4,
entry 1).18 Unfortunately, this gave no reaction. When sulf-
inamide (Rs,R)-5a was treated with LiHMDS according to a
procedure for the ring closure of fluorinated amines to fluoro-
aziridines,19 also no reaction was observed (Table 4, entry 2).
In a next attempt, a Finkelstein reaction with NaI and
subsequent base treatment was performed on sulfinamide (Rs,
R)-5a according to a procedure for the synthesis of N-benzoyl
(R)-coniine.20 Unfortunately, a complex mixture was obtained
after the reaction with NaI. Finally, sulfinamide (Rs,R)-5a was
treated with 2.5 equivalents NaH in DMSO at 80 °C for 2 h,21
leading to N-sulfinyl piperidine (Rs,R)-6a, which was isolated in
98% yield after flash chromatography (Table 4, entry 4).
Analogously, a variety of new chiral 3-substituted N-sulfinyl
piperidines 6 was prepared in good to excellent yields via the
developed reaction conditions for the base-induced cycliza-
tion of sulfinamides 5 (Scheme 2).
These sulfinamides 5 were obtained in good to excellent
yields via reduction of the corresponding N-sulfinyl imidates
2 with NaBH4. Noteworthy, during flash chromatography
of the sulfinamides 5 (R1 = alkyl) or N-sulfinyl piperidines 6
(R1 = aryl), the amine obtained via reduction of elimination
product 3 (if present as a side product with compounds 2)
was removed, resulting in a very high purity for all chiral
3-substituted N-sulfinyl piperidines 6. Several efforts to
separate the diastereomers of 5b, 5c, 6b and 6c were not
successful, leading to a mixture of diastereomers 6b and 6c in
a diastereomeric ratio of 67/33 and 71/29, respectively.
Finally, the 3-substituted N-sulfinyl piperidines 6 were
N-deprotected by simple treatment with a 4.0 N solution of
anhydrous HCl (10.0 equiv HCl) in dioxane for 1 h at room tem-
perature in Et2O. In this way the enantiopure piperidine hydro-
chlorides 9a and 9d-f were obtained in good yield (66-99%)
after precipitation from diethyl ether (Scheme 3). Piperidine
hydrochlorides 9b and 9c were obtained in an enantiomeric ratio
of 67/33 and 71/29 (based on dr of 6b and 6c), respectively.
Piperidine hydrochloride (S)-9a is a known compound in
the literature, prepared by the asymmetric hydrogenation of
(18) Denolf, B.; Leemans, E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211.
(19) Verniest, G.; Colpaert, F.; Van Hende, E.; De Kimpe, N. J. Org.
Chem. 2007, 72, 8569.
ꢀ
(20) Friestad, G. K.; Marie, J.-C.; Suh, Y.; Qin, J. J. Org. Chem. 2006, 71,
7016.
(21) Dejaegher, Y.; Mangelinckx, S.; De Kimpe, N. J. Org. Chem. 2002,
67, 2075.
238 J. Org. Chem. Vol. 76, No. 1, 2011

Colpaert et al.
JOCArticle
SCHEME 2. Reduction of N-Sulfinyl Imidates 2 to Sulfinamides 5 and Subsequent Ring Closure to N-Sulfinyl Piperidines 6
asymmetric R-alkylation of N-sulfinyl imidates 1d-f (R1 =
SCHEME 3. Deprotection of N-Sulfinyl Piperidines 6 to
Piperidine Hydrochlorides 9
aryl) with Cl(CH2)3I. In view of the strong correspondence of
the optical rotations of compounds 9a and 9d with literature
data, together with an enatiomeric excess of >98% for the
commercially available starting material (RS)-tert-butane-
sulfinamide, an enantiomeric excess of >98% can be con-
cluded for all synthesized piperidine hydrochlorides 9, except
for compounds 9b and 9c, obtained in an enantiomeric ratio
of 67/33 and 71/29, respectively.
Conclusions
It was demonstrated that chiral 2-substituted N-tert-
butanesulfinyl-5-chloropentanimidates are formed in accep-
table diastereomeric ratios (dr 67/33 to 72/28) and good yields
(74-86%) via R-alkylation of N-sulfinyl imidates with
1-chloro-3-iodopropane. Subsequent reduction with NaBH4,
followed by cyclization of the obtained chiral 2-substituted
N-tert-butanesulfinyl-5-chloropentylamines using NaH in
DMSO, afforded the first synthesis of chiral N-sulfinyl
3-alkyl- and 3-arylpiperidines. Finally, deprotection of the
pyridines,5i and also prepared starting from a chiral lactam
involving a postulated rigid amide enolate.5l The comparison
of the optical rotations of the newly prepared piperidine
hydrochloride (R)-9a ([R]D þ3.0 (c 0.9, MeOH) vs (S)-9a
-3.0 (c 0.6, MeOH) in lit.5i) and piperidine hydrochloride
(S)-9a ([R]D -2.6 (c 0.5, MeOH) vs (S)-9a -3.0 (c 0.6, MeOH)
in lit.5i) afforded proof of the stereochemical outcome of the
asymmetric R-alkylation of N-sulfinyl imidates 1a-c (R1 =
alkyl) with Cl(CH2)3I. Piperidine hydrochlorides (R)-9d and
(S)-9d are also known compounds in the literature,10a,22 and
comparing the optical rotations of the newly prepared
piperidine hydrochloride (R)-9d ([R]D -10.7 (c 0.3, MeOH)
vs -10.3 (c 0.5, MeOH) in lit.10a) and piperidine hydrochlo-
ride (S)-9d ([R]D þ11.5 (c 0.3, MeOH) vs þ12.2 (c 0.5, MeOH)
in lit.22) afforded proof of the stereochemical outcome of the
3-substituted N-sulfinyl piperidines with dioxane HCl gave
3
rise to a new and general synthetic pathway for the synthesis
of enantiomerically pure 3-substituted piperidine hydro-
chlorides. By comparing the optical rotations of the synthe-
sized piperidine hydrochlorides with literature data from
known compounds, evidence was obtained about the stere-
ochemical outcome of the alkylation reaction.
Experimental Section
Synthesis of N-tert-Butanesulfinylphenylacetimidates 1d-f.
The synthesis of N-tert-butanesulfinyl imidates 1d-f was per-
formed according to a literature procedure via condensation of
(Rs)-tert-butanesulfinamide and the corresponding ortho ester
with a catalytic amount of p-TsOH without solvent.16a
(Rs)-Methyl N-tert-butanesulfinylphenylacetimidate 1d. Rf =
0.32 (petroleum ether/Et2O 6:4). Yellow oil, yield 88%. [R]D
-171.7 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.20 (9H,
s), 3.75 (3H, s), 3.96 (1H, d, J=14.3Hz), 4.09(1H, d, J= 14.3 Hz),
(22) Morlacchi, F.; D’Ambruoso, M.; Tortorella, V. Chim. Ind. (Milan)
1974, 56, 465.
J. Org. Chem. Vol. 76, No. 1, 2011 239

Colpaert et al.
JOCArticle
7.21-7.34 (5H, m). Anal. calcd for C13H19NO2S: C 61.63; H
7.56; N 5.53. Found: C 61.42; H 7.76; N 5.41. All spectroscopic
data were in good agreement with reported data.16a
CHCl3). IR (cm-1): νmax 1071, 1604, 2869, 2947. 1H NMR (300
MHz, CDCl3): δ 1.19 (3H, d, J = 7.2 Hz), 1.22 (9H, s),
1.56-1.89 (4H, m), 3.38 (1H, sextet, J = 7.2 Hz), 3.49-3.61
(2H, m), 3.77 (3H, s). 13C NMR (75 MHz, CDCl3): δ 17.9, 21.9,
30.2, 31.3, 36.6, 44.8, 54.1, 55.7, 179.0. MS (ES, pos. mode) m/z
(%): 268/270 (M þ Hþ, 100).
(Rs)-Methyl N-tert-Butanesulfinyl(4-fluorophenyl)acetimidate
1e. Rf = 0.29 (petroleum ether/Et2O 6:4). Yellow oil, yield 97%.
[R]D -136.8 (c 1.0, CHCl3). IR (cm-1): νmax 1173, 1158, 1221,
1
1273, 1508, 1614, 2948. H NMR (300 MHz, CDCl3): δ 1.21
(Rs,S)-Methyl N-tert-Butanesulfinyl-5-chloro-2-methylpenta-
nimidate (Rs,S)-2a. Rf=0.18 (petroleum ether/Et2O 7:3). Yellow
oil, yield 22%. [R]D -110.8 (c 1.5, CHCl3). IR (cm-1): νmax 1073,
1604, 2928, 2947. 1H NMR (300 MHz, CDCl3): δ 1.22 (9H, s),
1.24 (3H, d, J = 7.7 Hz), 1.53-1.83 (4H, m), 3.38 (1H, sextet,
J = 7.7 Hz), 3.53 (2H, t, J = 6.6 Hz), 3.77 (3H, s). 13C NMR
(75 MHz, CDCl3): δ 18.4, 22.0, 30.5, 31.3, 37.0, 44.6, 54.2, 55.8,
179.5. MS (ES, pos. mode) m/z (%): 268/270 (M þ Hþ, 100).
Anal. calcd for C11H22ClNO2S: C 49.33; H 8.28; N 5.23. Found:
C 49.13; H 8.51; N 5.37.
(9H, s), 3.75 (3H, s), 3.96 (1H, d, J = 14.3 Hz), 4.02 (1H, d, J =
14.3 Hz), 6.94-7.05 (2H, m), 7.25-7.37 (2H, m). 19F NMR (282
MHz, CDCl3): δ -115.43 to -115.54 (1F, m). 13C NMR (75
MHz, CDCl3): δ 22.0, 37.7, 54.5, 56.3, 115.5 (2C, d, J = 21.9
Hz), 130.2 (d, J = 3.5 Hz), 131.0 (2C, d, J = 8.1 Hz), 162.0 (d,
J = 245.8 Hz), 173.3. MS (ES, pos. mode) m/z (%): 272 (M þ
Hþ, 100). Anal. calcd for C13H18FNO2S: C 57.54; H 6.69; N
5.16. Found: C 57.24; H 6.85; N 5.28.
(Rs)-Methyl N-tert-Butanesulfinyl(4-methoxyphenyl)acetimidate
1f. Rf = 0.16 (petroleum ether/Et2O 6:4). Yellow oil, yield 95%.
[R]D -154.2 (c 1.2, CHCl3). IR (cm-1): νmax 751, 1033, 1074,
(Rs)-Methyl N-tert-Butanesulfinyl-5-chloro-2-ethylpentanimi-
date (Rs)-2b. Rf = 0.23 (petroleum ether/Et2O 7:3). Colorless
oil, yield 86% (97% purity, 3% 3b). The diastereomers 2b could
not be separated via flash chromatography resulting in 2b (22%
dr 92/8, 38% dr 63/37, 16% dr 27/73 and 10% dr 24/76). The
spectral data of (Rs,R)-2b and (Rs,S)-2b were obtained from the
mixture of diastereomers 2b (dr 63/37). IR (cm-1): νmax 1073,
1603, 2961. 1H NMR (300 MHz, CDCl3): (Rs,R)-2b δ 0.74 (3H,
t, J = 7.7 Hz), 1.07 (9H, s), 1.36-1.75 (6H, m), 3.08-3.21 (1H,
m), 3.36-3.45 (2H, m), 3.61 (3H, s); (Rs,S)-2b δ 0.79 (3H, t, J =
7.7 Hz), 1.06 (9H, s), 1.36-1.75 (6H, m), 3.08-3.21 (1H, m),
3.36-3.45 (2H, m), 3.61 (3H, s). 13C NMR (75 MHz, CDCl3):
(Rs,R)-2b δ 12.0, 22.0, 26.2, 29.8, 30.2, 43.9, 44.9, 54.1, 55.6,
178.6; (Rs,S)-2b δ 11.9, 22.0, 26.0, 29.7, 30.6, 43.9, 44.6, 53.9,
55.7, 178.4. MS (ES, pos. mode) m/z (%): 282/284 (M þ Hþ,
100).
1
1246, 1510, 1611, 2948. H NMR (300 MHz, CDCl3): δ 1.20
(9H, s), 3.75 (3H, s), 3.78 (3H, s), 3.89 (1H, d, J = 14.3 Hz), 4.01
(1H, d, J = 14.3 Hz), 6.81-6.90 (2H, m), 7.18-7.27 (2H, m). 13C
NMR (75 MHz, CDCl3): δ 22.0, 37.8, 54.5, 55.3, 56.2, 114.1
(2C), 126.4, 130.5 (2C), 158.7, 174.3. MS (ES, pos. mode) m/z
(%): 284 (M þ Hþ, 100). Anal. calcd for C14H21NO3S: C 59.34;
H 7.47; N 4.94. Found: C 59.51; H 7.59; N 4.96.
Synthesis of (SS)-methyl N-p-toluenesulfinylpropanimidate
(SS)-4. The synthesis of (SS)-methyl N-p-toluenesulfinylpropa-
nimidate (SS)-4 was performed according to a previous reported
procedure via condensation of (Ss)-p-toluenesulfinamide and
the corresponding ortho ester with a catalytic amount of p-TsOH
without solvent.4
(SS)-Methyl N-p-Toluenesulfinylpropanimidate (SS)-4. Rf =
0.17 (petroleum ether/Et2O 7:3). Yellow oil, 82%. [R]D þ26.7
(c 0.3, CHCl3). IR (cm-1): νmax 1069, 1294, 1593, 2946. 1H NMR
(300 MHz, CDCl3): δ 1.24 (3H, t, J = 7.2 Hz), 2.41 (3H, s), 2.74
(1H, d ꢀ q, J = 14.6, 7.2 Hz), 2.80 (1H, d ꢀ q, J = 14.6, 7.2 Hz),
3.77 (3H, s), 7.31 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.3 Hz).
13C NMR (75 MHz, CDCl3): δ 10.9, 21.5, 26.5, 54.6, 125.0 (2C),
129.8 (2C), 141.7, 144.6, 176.6. MS (ES, pos. mode) m/z (%): 226
(M þ Hþ, 100). Anal. calcd for C11H15NO2S: C 58.64; H 6.71; N
6.22. Found: C 58.52; H 6.45; N 5.93.
Synthesis of 2-Substituted N-tert-Butanesulfinyl-5-chloropen-
tanimidates 2. The synthesis of methyl N-tert-butanesulfinyl-5-
chloro-2-methylpentanimidates 2a is representative. A solution
of Rs-methyl N-tert-butanesulfinylpropanimidate (1.0 equiv,
3.00 g, 15.71 mmol) in THF (70 mL) was cooled to -78 °C. A
1.0 M solution of LiHMDS (2.0 equiv, 31.42 mL, 31.42 mmol) in
THF was slowly added and the resulting solution was stirred for
45 min at -78 °C. After deprotonation, 1-chloro-3-iodopropane
(1.3 equiv, 2.15 mL, 20.42 mmol) was added dropwise and the
reaction mixture was stirred for 3 h at -78 °C followed by
stirring at 0 °C for 2 h. The reaction was quenched at this
temperature by addition of a saturated solution of NH4Cl (3 mL)
and diluted with saturated aqueous NaHCO3 (50 mL) at room
temperature. The aqueous phase was extracted with Et2O (3 ꢀ
50 mL). The combined organic phases were dried (MgSO4),
filtered and evaporated in vacuo. The crude product was puri-
fied by flash chromatography to yield 1.98 g (7.38 mmol) of (Rs,
R)-methyl N-tert-butanesulfinyl-5-chloro-2-methylpentanimi-
date (Rs,R)-2a (97% purity, 3% 3a), 0.09 g (0.34 mmol) of a
mixture of diastereomers (Rs,R)-2a and (Rs,S)-2a in a ratio
57:43, 0.25 g (0.93 mmol) of a mixture of diastereomers (Rs,
R)-2a and (Rs,S)-2a in a ratio 19:81 and 0.92 g (3.46 mmol) of
pure (Rs,S)-methyl N-tert-butanesulfinyl-5-chloro-2-methyl-
pentanimidate (Rs,S)-2a.
(Rs)-Methyl N-tert-Butanesulfinyl-5-chloro-2-propylpentani-
midate (Rs)-2c. Rf = 0.22 (petroleum ether/Et2O 7:3). Colorless
oil, yield 74% (97% purity, 3% 3c). The diastereomers 2c could
not be separated via flash chromatography resulting in 2c (74%
dr 71/29). The spectral data of (Rs,R)-2c and (Rs,S)-2c were
obtained from the mixture of diastereomers 2c (dr 71/29). IR
(cm-1): νmax 1074, 1603, 1623, 2931, 2957. 1H NMR (300 MHz,
CDCl3): (Rs,R)-2c δ 0.92 (3H, t, J = 7.7 Hz), 1.14-1.88 (8H, m),
1.22 (9H, s), 3.28-3.39 (1H, m), 3.49-3.59 (2H, m), 3.76 (3H, s).
(Rs,S)-2c δ 0.90 (3H, t, J = 7.2 Hz), 1.14-1.88 (8H, m), 1.20
(9H, s), 3.28-3.39 (1H, m), 3.49-3.59 (2H, m), 3.75 (3H, s). 13
C
NMR (75 MHz, CDCl3): (Rs,R)-2c δ 14.1, 20.7, 22.0, 30.1, 30.2,
35.3, 42.2, 44.9, 54.0, 55.6, 178.7; (Rs,S)-2c δ 14.1, 20.6, 22.0,
30.0, 30.5, 35.1, 42.1, 44.6, 53.9, 55.7, 178.6. MS (ES, pos. mode)
m/z (%): 296/298 (M þ Hþ, 100).
(Rs,R)-Methyl N-tert-Butanesulfinyl-5-chloro-2-phenylpenta-
nimidate (Rs,R)-2d. Rf = 0.31 (petroleum ether/Et2O 7:3).
Yellow oil, yield 54% (94% purity, 6% 3d). [R]D þ33.9 (c 0.3,
CHCl3). IR (cm-1): νmax 753, 1074, 1244, 1455, 1596, 1604,
1
1628. H NMR (300 MHz, CDCl3): δ 1.21 (9H, s), 1.66-1.82
(2H, m), 1.99-2.11 (1H, m), 2.15-2.27 (1H, m), 3.54 (2H, t, J =
6.4 Hz), 3.73 (3H, s), 4.62 (1H, t, J = 7.7 Hz), 7.19-7.37 (3H,
m), 7.41-7.48 (2H, m). 13C NMR (75 MHz, CDCl3): δ 22.1,
30.1, 30.5, 44.6, 47.7, 54.5, 56.4, 127.4, 128.6 (4C), 138.1, 175.1.
MS (ES, pos. mode) m/z (%): 330/332 (M þ Hþ, 100).
(Rs,S)-Methyl N-tert-Butanesulfinyl-5-chloro-2-phenylpenta-
nimidate (Rs,S)-2d. Rf = 0.24 (petroleum ether/Et2O 7:3).
Yellow oil, yield 23%. [R]D -210.4 (c 0.3, CHCl3). IR (cm-1):
1
νmax 754, 1071, 1283, 1455, 1596, 1605, 1624. H NMR (300
MHz, CDCl3): δ 1.12 (9H, s), 1.66-1.81 (2H, m), 1.94-2.07
(1H, m), 2.15-2.27 (1H, m), 3.53 (2H, t, J = 6.4 Hz), 3.80 (3H,
s), 4.60 (1H, t, J = 7.7 Hz), 7.22-7.40 (5H, m). 13C NMR (75
MHz, CDCl3): δ 21.9, 30.4, 30.6, 44.7, 47.9, 54.6, 56.2, 127.6,
128.4 (2C), 128.9 (2C), 138.7, 175.2. MS (ES, pos. mode) m/z
(%): 330/332 (M þ Hþ, 100). Anal. calcd for C16H24ClNO2S: C
58.25; H 7.33; N 4.25. Found: C 58.02; H 7.42; N 4.46.
(Rs,R)-Methyl N-tert-Butanesulfinyl-5-chloro-2-methylpenta-
nimidate (Rs,R)-2a. Rf = 0.22 (petroleum ether/Et2O 7:3).
Yellow oil, yield 47% (97% purity, 3% 3a). [R]D -77.9 (c 1.4,
240 J. Org. Chem. Vol. 76, No. 1, 2011

Colpaert et al.
JOCArticle
(Rs,R)-Methyl N-tert-Butanesulfinyl-5-chloro-2-(4-fluorophenyl)-
pentanimidate (Rs,R)-2e. Rf = 0.33 (petroleum ether/Et2O 7:3).
Yellow oil, yield 51%. [R]D þ30.9 (c 0.5, CHCl3). IR (cm-1):
organic phases were dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash chromatography
to yield 1.05 g (4.39 mmol) of pure (Rs,R)-N-tert-butanesulfinyl-
5-chloro-2-methylpentylamine (Rs,R)-5a. N-tert-butanesulfi-
nyl-5-chloropentylamines (Rs,R)-5d-f were purified by recrys-
tallization from diethyl ether.
(Rs,R)-N-tert-Butanesulfinyl-5-chloro-2-methylpentylamine
(Rs,R)-5a. Rf = 0.26 (petroleum ether/EtOAc 2:8). Yellow crystals,
yield 78%. Mp 54.1-55.2 °C. [R]D -49.6 (c 1.1, CHCl3). IR
(cm-1): νmax 1052, 1458, 2870, 2926, 2956, 3209. 1H NMR (300
MHz, CDCl3): δ 0.94 (3H, d, J = 6.6 Hz), 1.21-1.39 and
1.50-1.92 (5H, m), 1.23 (9H, s), 2.92-3.11 (2H, m), 3.23 (1H, t,
J = 6.6 Hz), 3.54 (2H, t, J = 6.6 Hz). 13C NMR (75 MHz,
CDCl3): δ 17.6, 22.7, 29.9, 31.3, 34.0, 45.3, 51.6, 55.8. MS (ES,
pos. mode) m/z (%): 240/242 (M þ Hþ, 100). Anal. calcd for
C10H22ClNOS: C 50.09; H 9.25; N 5.84. Found: C 49.72; H 9.55;
N 5.69.
1
νmax 752, 1073, 1223, 1508, 1606, 1628, 2949. H NMR (300
MHz, CDCl3): δ 1.21 (9H, s), 1.65-1.82 (2H, m), 1.95-2.08
(1H, m), 2.13-2.26 (1H, m), 3.55 (2H, t, J = 6.6 Hz), 3.75 (3H,
s), 4.62 (1H, t, J = 8.0 Hz), 6.94-7.04 (2H, m), 7.39-7.47 (2H,
m). 19F NMR (282 MHz, CDCl3): δ -115.14 to -115.25 (1F,
m). 13C NMR (75 MHz, CDCl3): δ 22.1, 30.3, 30.5, 44.5, 46.7,
54.6, 56.5, 115.4 (2C, d, J = 21.9 Hz), 130.3 (2C, d, J = 8.1 Hz),
133.8 (d, J = 2.3 Hz), 162.1 (d, J = 245.8 Hz), 174.7. MS (ES,
pos. mode) m/z (%): 348/350 (M þ Hþ, 100). Anal. calcd for
C16H23ClFNO2S: C 55.24; H 6.66; N 4.03. Found: C 54.97; H
6.38; N 3.88.
(Rs,S)-Methyl N-tert-Butanesulfinyl-5-chloro-2-(4-fluorophenyl)-
pentanimidate (Rs,S)-2e. Rf = 0.23 (petroleum ether/Et2O 7:3).
Yellow oil, yield 24%. [R]D -199.5 (c 0.3, CHCl3). IR (cm-1):
1
(Rs,S)-N-tert-Butanesulfinyl-5-chloro-2-methylpentylamine
(Rs,S)-5a. Rf = 0.33 (petroleum ether/EtOAc 3:7). Yellow oil,
yield 72%. [R]D -58.4 (c 1.5, CHCl3). IR (cm-1): νmax 1053,
νmax 752, 1072, 1224, 1508, 1607, 2949. H NMR (300 MHz,
CDCl3): δ 1.15 (9H, s), 1.65-1.80 (2H, m), 1.89-2.03 (1H, m),
2.12-2.27 (1H, m), 3.54 (2H, t, J = 6.6 Hz), 3.79 (3H, s), 4.61
(1H, t, J = 7.7 Hz), 6.97-7.06 (2H, m), 7.30-7.38 (2H, m). 19F
NMR (282 MHz, CDCl3): δ -114.54 to -114.64 (1F, m). 13C
NMR (75 MHz, CDCl3): δ 22.0, 30.3, 30.7, 44.7, 47.0, 54.6, 56.3,
115.7 (2C, d, J = 21.9 Hz), 130.0 (2C, d, J = 8.1 Hz), 134.4 (d,
J = 3.5 Hz), 162.2 (d, J = 245.8 Hz), 174.6. MS (ES, pos. mode)
m/z (%): 348/350 (M þ Hþ, 100). Anal. calcd for C16H23-
ClFNO2S: C 55.24; H 6.66; N 4.03. Found: C 55.01; H 6.52; N
3.79.
(Rs,R)-Methyl N-tert-Butanesulfinyl-5-chloro-2-(4-methoxy-
phenyl)pentanimidate (Rs,R)-2f. Rf = 0.32 (petroleum ether/
Et2O 5:5). Yellow oil, yield 54% (46%, 95% purity, 5% 3f þ
8%, 100% purity). The spectral data of (Rs,R)-2f were obtained
from (Rs,R)-2f (8%, 100% purity). [R]D þ55.1 (c 0.4, CHCl3). IR
(cm-1): νmax 750, 1035, 1072, 1179, 1249, 1511, 1598, 2958. 1H
NMR (300 MHz, CDCl3): δ 1.21 (9H, s), 1.66-1.81 (2H, m),
1.94-2.07 (1H, m), 2.11-2.24 (1H, m), 3.53 (2H, t, J = 6.4 Hz),
3.73 (3H, s), 3.77 (3H, s), 4.55 (1H, t, J = 7.7 Hz), 6.83 (2H, d,
J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz). 13C NMR (75 MHz,
CDCl3): δ 22.1, 30.2, 30.5, 44.6, 46.7, 54.5, 55.3, 56.3, 114.0 (2C),
126.7 (2C), 130.0, 158.9, 175.6. MS (ES, pos. mode) m/z (%):
360/362 (M þ Hþ, 100). Anal. calcd for C17H26ClNO3S: C
56.73; H 7.28; N 3.89. Found: C 56.86; H 7.44; N 3.93.
(Rs,S)-Methyl N-tert-Butanesulfinyl-5-chloro-2-(4-methoxy-
phenyl)pentanimidate (Rs,S)-2f. Rf = 0.37 (petroleum ether/
Et2O 35:65). Yellow oil, yield 20% (dr (Rs,S)-2f/(Rs,R)-2f 82:18).
The diastereomer (Rs,S)-2f could not be separated via flash
chromatography from (Rs,R)-2f resulting in (Rs,S)-2f/(Rs,R)-2f
82:18. The spectral data of (Rs,S)-2f were obtained from the
mixture of diastereomers 2f (dr 82:18). IR (cm-1): νmax 752,
1034, 1072, 1178, 1248, 1510, 1600, 2951. 1H NMR (300 MHz,
CDCl3): δ 1.13 (9H, s), 1.73 (2H, quintet, J = 7.2 Hz), 1.89-2.06
(1H, m), 2.10-2.24 (1H, m), 3.53 (2H, t, J = 6.6 Hz), 3.78 (3H,
s), 3.79 (3H, s), 4.53 (1H, t, J = 7.7 Hz), 6.80-6.88 (2H, m),
7.24-7.30 (2H, m). 13C NMR (75 MHz, CDCl3): δ 21.9, 30.4,
30.6, 44.7, 47.0, 54.5, 55.3, 56.1, 114.2 (2C), 129.4 (2C), 130.6,
159.0, 175.5. MS (ES, pos. mode) m/z (%): 360/362 (M þ Hþ,
100). Anal. calcd for C17H26ClNO3S: C 56.73; H 7.28; N 3.89.
Found: C 56.48; H 7.02; N 3.70.
Synthesis of 2-Substituted N-tert-Butanesulfinyl-5-chloropen-
tylamines 5. The synthesis of (Rs,R)-N-tert-butanesulfinyl-5-
chloro-2-methylpentylamine (Rs,R)-5a is representative. To a
solution of (Rs,R)-methyl N-tert-butanesulfinyl-5-chloro-2-
methylpentanimidate (Rs,R)-2a (1.0 equiv, 1.50 g, 5.61 mmol)
in THF (30 mL) was added methanol (10.0 equiv, 1.80 g, 56.10
mmol), followed by NaBH4 (5.0 equiv, 1.06 g, 28.05 mmol). The
resulting solution was stirred for 1 h at reflux temperature and
subsequently poured into a saturated aqueous solution of NaHCO3
(30 mL) and extracted with ethyl acetate (3 ꢀ 30 mL). The combined
1
1458, 2868, 2925, 2954, 3199. H NMR (300 MHz, CDCl3): δ
0.95 (3H, d, J = 7.2 Hz), 1.17-1.33 and 1.50-1.89 (5H, m), 1.23
(9H, s), 2.84-2.96 (1H, m), 3.12-3.21 (1H, m), 3.13 (1H, t, J =
5.5 Hz), 3.53 (2H, t, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3): δ
17.6, 22.7, 30.0, 31.4, 34.0, 45.3, 51.5, 55.9. MS (ES, pos. mode)
m/z (%): 240/242 (M þ Hþ, 100). Anal. calcd for C10H22ClNOS:
C 50.09; H 9.25; N 5.84. Found: C 49.83; H 9.11; N 5.52.
(Rs)-N-tert-Butanesulfinyl-5-chloro-2-ethylpentylamine (Rs)-5b.
Rf = 0.29 (petroleum ether/EtOAc 3:7). Colorless oil, yield
93%. The diastereomers 5b could not be separated via flash
chromatography resulting in 5b (93%, dr 67/33). The spectral
data of (Rs,R)-5b and (Rs,S)-5b were obtained from the mixture
of diastereomers 5b (dr 67/33). IR (cm-1): νmax 1052, 1459, 2972,
2927, 2958, 3209. 1H NMR (300 MHz, CDCl3): (Rs,R)-5b δ 0.90
(3H, t, J = 7.2 Hz), 1.22 (9H, s), 1.23-1.55 and 1.70-1.84 (7H,
m), 2.90-3.06 (1H, m), 3.10-3.25 (2H, m), 3.54 (2H, t, J = 6.6
Hz); (Rs,S)-5b δ 0.87 (3H, t, J = 6.6 Hz), 1.22 (9H, s), 1.23-1.55
and 1.70-1.84 (7H, m), 2.90-3.06 (1H, m), 3.10-3.25 (2H, m),
3.54 (2H, t, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3): (Rs,R)-5b
δ 10.9, 22.7, 24.0, 28.3, 29.6, 40.1, 45.4, 48.4, 55.8; (Rs,S)-5b δ
10.8, 22.7, 24.0, 28.2, 29.7, 40.0, 45.4, 48.2, 55.8. MS (ES, pos.
mode) m/z (%): 254/256 (M þ Hþ, 100). Anal. calcd for
C11H24ClNOS: C 52.05; H 9.53; N 5.52. Found: C 52.17; H
9.35; N 5.67.
(Rs)-N-tert-Butanesulfinyl-5-chloro-2-propylpentylamine (Rs)-5c.
Rf = 0.27 (petroleum ether/EtOAc 3:7). Colorless oil, yield
97%. The diastereomers 5c could not be separated via flash
chromatography resulting in 5c (97%, dr 71/29). The spectral
data of (Rs,R)-5c and (Rs,S)-5c were obtained from the mixture
of diastereomers 5c (dr 71/29). IR (cm-1): νmax 1052, 1457, 2870,
2926, 2956, 3210. 1H NMR (300 MHz, CDCl3): (Rs,R)-5c and
(Rs,S)-5c δ 0.90 (3H, t, J = 6.6 Hz), 1.16-1.86 (9H, m), 1.22
(9H, s), 2.89-3.05 (1H, m), 3.10-3.23 (2H, m), 3.53 (2H, t, J =
6.6 Hz). 13C NMR (75 MHz, CDCl3): (Rs,R)-5c δ 14.4, 19.8,
22.7, 28.8, 29.6, 33.8, 38.3, 45.4, 48.7, 55.9; (Rs,S)-5c δ 14.3, 19.7,
22.7, 28.7, 29.7, 33.8, 38.3, 45.4, 48.5, 55.9. MS (ES, pos. mode)
m/z (%): 268/270 (M þ Hþ, 100). Anal. calcd for C12H26ClNOS:
C 53.81; H 9.78; N 5.23. Found: C 53.59; H 9.63; N 5.02.
(Rs,R)-N-tert-Butanesulfinyl-5-chloro-2-phenylpentylamine (Rs,R)-
5d. White crystals, yield 90% (96% purity). Mp 66.7-66.9 °C.
[R]D -19.5 (c 0.3, CHCl3). IR (cm-1): νmax 1040, 1454,
2930, 3187. 1H NMR (300 MHz, CDCl3): δ 1.09 (9H, s),
1.56-1.81 (3H, m), 1.83-1.95 (1H, m), 2.81-2.93 (1H, m),
3.13 (1H, t, J = 6.6 Hz), 3.18-3.29 (1H, m), 3.39-3.51
(3H, m), 7.15-7.37 (5H, m). 13C NMR (75 MHz, CDCl3): δ
22.6, 30.3, 30.4, 45.0, 46.8, 52.0, 55.9, 127.0, 128.2 (2C), 128.8
(2C), 141.7. MS (ES, pos. mode) m/z (%): 302/304 (M þ Hþ,
100).
J. Org. Chem. Vol. 76, No. 1, 2011 241

Colpaert et al.
JOCArticle
(Rs,S)-N-tert-Butanesulfinyl-5-chloro-2-phenylpentylamine
(Rs,S)-5d. Rf=0.44 (petroleum ether/EtOAc 3:7). Yellow oil,
yield 99%. [R]D -40.7 (c 0.2, CHCl3). IR (cm-1): νmax 731,
1055, 1454, 2957, 3220. 1H NMR (300 MHz, CDCl3): δ 1.12
(9H, s), 1.56-1.79 (3H, m), 1.84-1.98 (1H, m), 2.72-2.83
(1H, m), 3.11 (1H, d ꢀ d, J = 8.3, 5.0 Hz), 3.23-3.41 (2H, m),
3.47 (2H, t, J = 6.4 Hz), 7.21-7.37 (5H, m). 13C NMR (75
MHz, CDCl3): δ 22.7, 30.3, 30.7, 45.0, 46.8, 51.1, 55.8, 127.2,
128.0 (2C), 128.9 (2C), 141.7. MS (ES, pos. mode) m/z (%):
302/304 (M þ Hþ, 100). Anal. calcd for C15H24ClNOS: C
59.68; H 8.01; N 4.64. Found: C 59.77; H 8.15; N 4.39.
(Rs,R)-N-tert-Butanesulfinyl-5-chloro-2-(4-fluorophenyl)pentyl-
amine (Rs,R)-5e. White crystals, yield 99%. Mp 94.3-
94.6 °C. [R]D -19.2 (c 0.4, CHCl3). IR (cm-1): νmax 816,
1040, 1222, 1508, 2928, 3178. 1H NMR (300 MHz, CDCl3): δ
1.09 (9H, s), 1.53-1.76 (3H, m), 1.82-1.94 (1H, m),
2.82-2.94 (1H, m), 3.08-3.25 (2H, m), 3.38-3.44 (1H, m),
3.48 (2H, t, J = 6.1 Hz), 6.97-7.07 (2H, m), 7.13-7.20 (2H,
m). 19F NMR (282 MHz, CDCl3): δ -115.71 to -115.81 (1F,
m). 13C NMR (75 MHz, CDCl3): δ 22.6, 30.3, 30.6, 44.9, 46.2,
52.1, 55.9, 115.6 (2C, d, J = 21.9 Hz), 129.7 (2C, d, J = 6.9
Hz), 137.3 (d, J = 2.3 Hz), 161.8 (d, J = 244.6 Hz). MS (ES,
pos. mode) m/z (%): 320/322 (M þ Hþ, 100). Anal. calcd for
C15H23ClFNOS: C 56.32; H 7.25; N 4.38. Found: C 56.41; H
7.39; N 4.27.
(Rs,S)-N-tert-Butanesulfinyl-5-chloro-2-(4-fluorophenyl)pentyl-
amine (Rs,S)-5e. Rf = 0.42 (petroleum ether/EtOAc 3:7). Yellow
oil, yield 93%. [R]D -60.2 (c 0.3, CHCl3). IR (cm-1): νmax 754,
834, 1055, 1223, 1509, 2926, 3218. 1H NMR (300 MHz, CDCl3):
δ 1.13 (9H, s), 1.52-1.75 (3H, m), 1.83-1.97 (1H, m), 2.73-2.85
(1H, m), 3.13 (1H, d ꢀ d, J = 7.7, 5.5 Hz), 3.22-3.38 (2H, m),
3.47 (2H, t, J = 6.1 Hz), 6.97-7.06 (2H, m), 7.09-7.16 (2H, m).
19F NMR (282 MHz, CDCl3): δ -115.39 to -115.49 (1F, m).
13C NMR (75 MHz, CDCl3): δ 22.6, 30.2, 30.8, 44.9, 46.0, 51.1,
55.9, 115.7 (2C, d, J = 21.9 Hz), 129.3 (2C, d, J = 8.1 Hz), 137.4
(d, J = 3.5 Hz), 161.8 (d, J = 245.8 Hz). MS (ES, pos. mode) m/z
(%): 320/322 (M þ Hþ, 100). Anal. calcd for C15H23ClFNOS: C
56.32; H 7.25; N 4.38. Found: C 56.01; H 6.97; N 4.22.
10.5 Hz), 2.83 (1H, t ꢀ d, J = 11.8, 2.9 Hz), 3.26-3.36 (2H, m).
13C NMR (75 MHz, CDCl3): δ 19.3, 23.2, 26.1, 31.3, 33.0, 48.1,
53.7, 58.4. MS (ES, pos. mode) m/z (%): 204 (M þ Hþ, 100). Anal.
calcd for C10H21NOS: C 59.07; H 10.41; N 6.89. Found: C 58.79;
H 10.61; N 6.67.
(Rs,S)-N-tert-Butanesulfinyl-3-methylpiperidine (Rs,S)-6a. Rf =
0.25 (petroleum ether/Et2O 3:7). Yellow oil, yield 99%. [R]D þ6.2
1
(c 1.2, CHCl3). IR (cm-1): νmax 750, 1072, 1458, 2849, 2927. H
NMR (300 MHz, CDCl3): δ 0.88 (3H, d, J = 6.6 Hz), 0.92-1.10
and 1.46-1.84 (5H, m), 1.17 (9H, s), 2.52 (1H, d ꢀ d, J= 11.4, 10.5
Hz), 2.65 (1H, t ꢀ d, J = 12.3, 3.3 Hz), 3.26-3.38 (2H, m). 13
C
NMR (75 MHz, CDCl3): δ 19.3, 23.3, 25.5, 31.9, 33.0, 46.6, 55.3,
58.4. MS (ES, pos. mode) m/z (%): 204 (M þ Hþ, 100). Anal. calcd
for C10H21NOS: C 59.07; H 10.41; N 6.89. Found: C 59.25; H
10.56; N 6.96.
(Rs)-N-tert-Butanesulfinyl-3-ethylpiperidine (Rs)-6b. Rf = 0.42
(petroleum ether/Et2O 3:7). Colorless oil, yield 99%. The dia-
stereomers 6b could not be separated via flash chromatography
resulting in 6b (99%, dr 67/33). The spectraldataof (Rs,R)-6b and
(Rs,S)-6b were obtained from the mixture of diastereomers 6b (dr
1
67/33). IR (cm-1): νmax 1077, 1458, 2854, 2929. H NMR (300
MHz, CDCl3): (Rs,R)-6b δ 0.89 (3H, t, J = 7.2 Hz), 0.92-1.90
(7H, m), 1.17 (9H, s), 2.31 (1H, d ꢀ d, J = 12.4, 10.5 Hz), 2.87
(1H, t ꢀ d, J = 11.8, 3.3 Hz), 3.28-3.43 (2H, m); (Rs,S)-6b δ 0.89
(3H, t, J = 7.2 Hz), 0.92-1.90 (7H, m), 1.17(9H, s), 2.54 (1H, d ꢀ
d, J = 12.4, 10.5 Hz), 2.65 (1H, t ꢀ d, J = 11.8, 3.3 Hz),
3.28-3.43 (2H, m). 13C NMR (75 MHz, CDCl3): (Rs,R)-6b δ
11.3, 23.3, 26.1, 26.8, 31.0, 38.2, 48.9, 52.0, 58.4; (Rs,S)-6b δ 11.3,
23.3, 25.4, 26.8, 30.6, 38.5, 46.7, 54.2, 58.4. MS (ES, pos. mode)
m/z (%): 218 (M þ Hþ, 100). Anal. calcd for C11H23NOS: C
60.78; H 10.66; N 6.44. Found: C 60.64; H 10.43; N 6.22.
(Rs)-N-tert-Butanesulfinyl-3-propylpiperidine (Rs)-6c. Rf = 0.42
(petroleum ether/Et2O 3:7). Colorless oil, yield 96%. The diaste-
reomers 6c could not be separated via flash chromatography
resulting in 6c (96%, dr 71/29). The spectral data of (Rs,R)-6c
and (Rs,S)-6c were obtained from the mixture of diastereomers 6c
(dr 71/29). IR (cm-1): νmax 1078, 1457, 2920. 1H NMR (300 MHz,
CDCl3): (Rs,R)-6c δ 0.89 (3H, t, J = 7.2 Hz), 0.93-1.87 (9H, m),
1.17 (9H, s), 2.31 (1H, d ꢀ d, J = 12.4, 10.5 Hz), 2.86 (1H, t ꢀ d,
J = 11.8, 3.3 Hz), 3.27-3.41 (2H, m); (Rs,S)-6c δ 0.89 (3H, t, J =
7.2 Hz), 0.93-1.87 (9H, m), 1.17 (9H, s), 2.54 (1H, d ꢀ d, J = 11.6,
10.5Hz), 2.65(1H, tꢀ d, J= 12.4, 3.3 Hz), 3.27-3.41 (2H, m). 13C
NMR (75 MHz, CDCl3): (Rs,R)-6c δ 14.3, 19.9, 23.3, 26.2, 31.3,
36.2, 36.3, 48.8, 52.3, 58.4; (Rs,S)-5c δ 14.3, 19.9, 23.3, 25.5, 31.1,
36.3, 36.6, 46.7, 54.5, 58.4. MS (ES, pos. mode) m/z (%): 232 (M þ
Hþ, 100). Anal. calcd for C12H25NOS: C 62.29; H 10.89; N 6.05.
Found: C 62.15; H 10.63; N 5.97.
(Rs,R)-N-tert-Butanesulfinyl-3-phenylpiperidine (Rs,R)-6d. Rf =
0.49 (petroleum ether/Et2O 3:7). Colorless oil, yield 86%. [R]D
þ25.8 (c 0.2, CHCl3). IR (cm-1): νmax 697, 757, 944, 1073, 1360,
1454, 2929. 1H NMR (300 MHz, CDCl3): δ 1.17 (9H, s), 1.50-1.86
and 1.93-2.06 (4H, m), 2.67-2.85 (2H, m), 2.92 (1H, t ꢀ d, J =
11.6, 2.2 Hz), 3.38-3.57 (2H, m), 7.13-7.34 (5H, m). 13CNMR(75
MHz, CDCl3): δ 23.2, 25.8, 31.6, 43.6, 46.9, 54.4, 58.6, 126.7, 127.2
(2C), 128.6 (2C), 143.7. MS (ES, pos. mode) m/z (%): 266 (M þ
Hþ, 100). Anal. calcd for C15H23NOS: C 67.88; H 8.73; N 5.28.
Found: C 67.71; H 8.58; N 5.09.
(Rs,S)-N-tert-Butanesulfinyl-3-phenylpiperidine (Rs,S)-6d. Rf =
0.41 (petroleum ether/Et2O 3:7). Yellow oil, yield 93%. [R]D -37.9
(c 0.2, CHCl3). IR (cm-1): νmax 698, 757, 949, 1072, 1454, 2856,
2929. 1H NMR (300 MHz, CDCl3): δ 1.18 (9H, s), 1.54-1.84 and
1.98-2.08 (4H, m), 2.78 (1H, t ꢀ d, J = 11.0, 8.8 Hz), 2.79-2.84
(1H, m), 2.92 (1H, t ꢀ d, J = 12.1, 3.3 Hz), 3.46-3.55 (2H, m),
7.13-7.36 (5H, m). 13C NMR (75 MHz, CDCl3):δ23.2, 26.6, 31.8,
43.1, 47.6, 53.6, 58.6, 126.8, 127.1 (2C), 128.6 (2C), 143.6. MS (ES,
pos. mode) m/z (%): 266 (M þ Hþ, 100). Anal. calcd for
C15H23NOS: C 67.88; H 8.73; N 5.28. Found: C 67.97; H 8.89;
N 5.22.
(Rs,R)-N-tert-Butanesulfinyl-5-chloro-2-(4-methoxyphenyl)-
pentylamine (Rs,R)-5f. Yellow crystals, yield 99% (95% purity).
Mp 80.2-80.7 °C. [R]D -17.8 (c 0.4, CHCl3). IR (cm-1): νmax
812, 1039, 1245, 1513, 2926, 3200. 1H NMR (300 MHz, CDCl3):
δ 1.10 (9H, s), 1.57-1.77 (3H, m), 1.79-1.93 (1H, m), 2.78-2.96
(1H, m), 3.05-3.28 (2H, m), 3.36-3.44 (1H, m), 3.47 (2H, t, J =
6.1 Hz), 3.80 (3H, s), 6.82-6.93 (2H, m), 7.06-7.16 (2H, m). 13
C
NMR (75 MHz, CDCl3): δ 22.6, 30.3, 30.5, 45.1, 46.0, 52.2, 55.3,
55.9, 114.2 (2C), 129.2 (2C), 133.5, 158.5. MS (ES, pos. mode)
m/z (%): 332/334 (M þ Hþ, 100).
Synthesis of 3-Substituted N-tert-Butanesulfinylpiperidines 6.
The synthesis of (Rs,R)-N-tert-butanesulfinyl-3-methylpiperi-
dine (Rs,R)-6a is representative. To sodium hydride (2.5 equiv,
0.25 g, 10.44 mmol) was added DMSO (5 mL) and the mixture
was stirred at room temperature for 15 min. Subsequently, a
solution of (Rs,R)-N-tert-butanesulfinyl-5-chloro-2-methylpen-
tylamine (Rs,R)-5a (1.0 equiv, 1.00 g, 4.18 mmol) in DMSO
(3 mL) was added dropwise and the reaction mixture was stirred
for 2 h at 80 °C. After cooling to room temperature, the reaction
mixture was poured into water (10 mL) and extracted with
diethyl ether (3 ꢀ 15 mL). The combined organic phases were
washed with brine, dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash chromatography
to yield 0.83 g (4.09 mmol) of pure (Rs,R)-N-tert-butanesulfinyl-
3-methylpiperidine (Rs,R)-6a.
(Rs,R)-N-tert-Butanesulfinyl-3-methylpiperidine (Rs,R)-6a. Rf =
0.35 (petroleum ether/Et2O 3:7). Yellow oil, yield 98%. [R]D -11.0
(c 1.0, CHCl3). IR (cm-1): νmax 750, 1069, 1457, 2928, 2951. 1H
NMR (300 MHz, CDCl3): δ 0.88 (3H, d, J = 6.6 Hz), 0.90-1.11
and 1.52-1.83 (5H, m), 1.17 (9H, s), 2.32 (1H, d ꢀ d, J = 12.7,
242 J. Org. Chem. Vol. 76, No. 1, 2011

Colpaert et al.
JOCArticle
(Rs,R)-N-tert-Butanesulfinyl-3-(4-fluorophenyl)piperidine
(Rs,R)-6e. Rf = 0.36 (petroleum ether/Et2O 3:7). Yellow oil,
yield 99%. [R]D þ18.3 (c 0.6, CHCl3). IR (cm-1): νmax 751, 833,
0.055 g (0.40 mmol) of (R)-2-methylpentylamine hydrochloride
(R)-8 (96% purity).
(R)-2-Methylpentylamine Hydrochloride (R)-8. White crys-
tals, yield 82% (96% purity). Mp 137.2-137.5 °C. [R]D þ5.7
(c 0.3, MeOH). IR (cm-1): νmax 1509, 1610, 2972, 2913, 2957,
2993. 1H NMR (300 MHz, CDCl3): δ 0.90 (3H, t, J = 6.6 Hz),
1.06 (3H, d, J = 6.6 Hz), 1.14-1.47 (4H, m), 1.82-1.97 (1H, m),
2.66-2.82 (1H, m), 2.87-3.02 (1H, m), 8.34 (3H, br s). 13C
NMR (75 MHz, CDCl3): δ 14.1, 17.5, 19.7, 31.5, 36.2, 45.6. MS
(ES, pos. mode) m/z (%): 102 (M þ Hþ - HCl, 100).
1
1070, 1221, 1510, 2933. H NMR (300 MHz, CDCl3): δ 1.18
(9H, s), 1.56 (1H, q ꢀ d, J = 12.1, 3.9 Hz), 1.67-1.87 (2H, m),
1.94-2.05 (1H, m), 2.71-2.92 (3H, m), 3.40-3.55 (2H, m),
6.94-7.04 (2H, m), 7.13-7.21 (2H, m). 19F NMR (282 MHz,
CDCl3): δ -116.20 to -116.30 (1F, m). 13C NMR (75 MHz,
CDCl3): δ 23.2, 25.8, 31.8, 42.9, 47.0, 54.2, 58.7, 115.3 (2C, d,
J = 20.8 Hz), 128.6 (2C, d, J = 8.1 Hz), 139.3 (d, J = 3.5 Hz),
161.7 (d, J = 244.6 Hz). MS (ES, pos. mode) m/z (%): 284 (M þ
Hþ, 100). Anal. calcd for C15H22FNOS: C 63.57; H 7.82; N 4.94.
Found: C 63.72; H 7.99; N 4.97.
(Rs,S)-N-tert-Butanesulfinyl-3-(4-fluorophenyl)piperidine (Rs,S)-
6e. Rf = 0.33 (petroleum ether/Et2O 3:7). Yellow oil, yield 82%.
[R]D -44.0 (c 0.3, CHCl3). IR (cm-1): νmax 833, 1072, 1221,
1510, 2868, 2932. 1H NMR (300 MHz, CDCl3): δ 1.18 (9H, s),
1.56 (1H, q ꢀ d, J = 11.6, 3.9 Hz), 1.65-1.86 (2H, m), 1.96-2.05
(1H, m), 2.74 (1H, t ꢀ d, J = 11.6, 11.6 Hz), 2.75-2.86 (1H, m),
2.92 (1H, t ꢀ d, J = 12.0, 3.0 Hz), 3.43-3.54 (2H, m), 6.93-7.03
(2H, m), 7.10-7.19 (2H, m). 19F NMR (282 MHz, CDCl3):
δ -116.15 to -116.25 (1F, m). 13C NMR (75 MHz, CDCl3): δ
23.2, 26.5, 31.9, 42.4, 47.6, 53.6, 58.6, 115.4 (2C, d, J = 20.8 Hz),
128.5 (2C, d, J = 6.9 Hz), 139.3 (d, J = 3.5 Hz), 161.7 (d, J =
244.6 Hz). MS (ES, pos. mode) m/z (%): 284 (M þ Hþ, 100).
Anal. calcd for C15H22FNOS: C 63.57; H 7.82; N 4.94. Found: C
63.59; H 7.79; N 4.89.
Synthesis of 3-Substituted Piperidine Hydrochlorides 9. The
synthesis of (R)-3-methylpiperidine hydrochloride (R)-9a is
representative. To a solution of (Rs,R)-N-tert-butanesulfinyl-
3-methylpiperidine (Rs,R)-6a (0.50 g, 2.46 mmol) in diethyl ether
(10 mL) was added dropwise a 4.0 M solution of dioxane HCl
3
(10.0 equiv, 6.16 mL, 24.63 mmol) at room temperature. The
mixture was allowed to stir for 1 h. Then the reaction mixture
was concentrated in vacuo. Precipitation in diethyl ether af-
forded 0.32 g (2.39 mmol) of pure (R)-3-methylpiperidine
hydrochloride (R)-9a.
(R)-3-Methylpiperidine Hydrochloride (R)-9a. White crystals,
yield 97%. Mp 192.8-193.0 °C. [R]D (R)-9a þ3.0 (c 0.9, MeOH)
vs (S)-9a -3.0 (c 0.6, MeOH) in lit.5i IR (cm-1): νmax 1453, 2422,
1
2536, 2763, 2871, 2934. H NMR (300 MHz, CDCl3): δ 0.97
(3H, d, J = 6.6 Hz), 1.02-1.20 (1H, m), 1.79-2.03 (3H, m),
2.03-2.20 (1H, m), 2.46 (1H, t ꢀ d, J = 11.6, 11.6 Hz), 2.76 (1H,
t ꢀ d, J = 11.0, 11.0 Hz), 3.36 (1H, d, J = 12.1 Hz), 3.44 (1H, d, J
= 12.7 Hz), 9.37 (1H, br s), 9.55 (1H, br s). 13C NMR (75 MHz,
CDCl3): δ 19.0, 22.2, 28.5, 31.0, 43.9, 50.3. MS (ES, pos. mode)
m/z (%): 100 (M þ Hþ - HCl, 100). Anal. calcd for C6H14ClN:
C 53.13; H 10.40; N 10.33. Found: C 53.47; H 10.72; N 10.63.
(R)-9a is a known compound in literature, but no spectral data
were available.5f,23
(S)-3-Methylpiperidine Hydrochloride (S)-9a. White crystals,
yield 66%. Mp 193.1-193.3 °C. [R]D -2.6 (c 0.5, MeOH) vs
-3.0 (c 0.6, MeOH) in lit.5i,l 1H NMR (300 MHz, CDCl3): δ 0.97
(3H, d, J = 6.6 Hz), 1.02-1.19 (1H, m), 1.78-2.20 (4H, m), 2.45
(1H, t ꢀ d, J = 11.6, 11.0 Hz), 2.75 (1H, t ꢀ d, J = 11.0, 11.0
Hz), 3.36 (1H, d, J = 12.1 Hz), 3.44 (1H, d, J = 12.1 Hz), 9.38
(1H, br s), 9.59 (1H, br s). Anal. calcd for C6H14ClN: C 53.13; H
10.40; N 10.33. Found: C 52.93; H 10.22; N 10.08. All spectro-
scopic data were in good agreement with reported data.5i,l
3-Ethylpiperidine Hydrochloride 9b. White crystals, yield 99%.
Mp 147.1-147.4 °C. er 67/33 (based on dr of 6b). 1H NMR (300
MHz, CDCl3): δ 0.92 (3H, d, J = 7.2 Hz), 0.99-1.17 (1H, m),
1.19-1.42 (2H, m), 1.79-2.07 (4H, m), 2.48 (1H, t ꢀ d, J = 11.0,
11.0 Hz), 2.76 (1H, t ꢀ d, J = 11.0, 9.9 Hz), 3.40 (1H, d, J = 13.2
Hz), 3.45 (1H, d, J = 12.2 Hz), 9.34 (1H, br s), 9.61 (1H, br s).
Anal. calcd for C7H16ClN: C 56.18; H 10.78; N 9.36. Found: C
56.32; H 10.95; N 9.57. All spectroscopic data were in good
agreement with reported data.5e-g,11e
3-Propylpiperidine Hydrochloride 9c. White crystals, yield
81%. Mp 122.5-122.7 °C. er 71/29 (based on dr of 6c). IR
(cm-1): νmax 1060, 1464, 2572, 2735, 2845, 2953. 1H NMR (300
MHz, CDCl3): δ 0.90 (3H, d, J = 7.2 Hz), 1.00-1.14 (1H, m),
1.16-1.42 (4H, m), 1.75-2.13 (4H, m), 2.46 (1H, t ꢀ d, J = 10.5,
10.5 Hz), 2.75 (1H, t ꢀ d, J = 11.0, 9.9 Hz), 3.39 (1H, d, J = 14.3
Hz), 3.44 (1H, d, J = 14.3 Hz), 9.29 (1H, br s), 9.59 (1H, br s).
13C NMR (75 MHz, CDCl3): δ 14.2, 19.4, 22.3, 29.1, 33.2, 36.0,
44.4, 49.3. MS (ES, pos. mode) m/z (%): 128 (M þ Hþ - HCl,
100). Anal. calcd for C8H18ClN: C 58.70; H 11.08; N 8.56.
Found: C 58.87; H 11.11; N 8.59. 9c is a known compound in
literature, but no spectral data were available.24
(Rs,R)-N-tert-Butanesulfinyl-3-(4-methoxyphenyl)piperidine
(Rs,R)-6f. Rf = 0.28 (petroleum ether/Et2O 3:7). Yellow crys-
tals, yield 92%. Mp 71.4-71.6 °C. [R]D þ30.4 (c 0.4, CHCl3). IR
1
(cm-1): νmax 751, 828, 1037, 1071, 1245, 1513, 2852, 2932. H
NMR (300 MHz, CDCl3): δ 1.18 (9H, s), 1.56 (1H, q ꢀ d, J =
12.1, 3.9 Hz), 1.65-1.85 (2H, m), 1.94-2.03 (1H, m), 2.68-2.81
(2H, m), 2.85 (1H, t ꢀ d, J = 11.6, 11.6 Hz), 3.41-3.54 (2H, m),
3.78 (3H, s), 6.81-6.88 (2H, m), 7.10-7.17 (2H, m). 13C NMR
(75 MHz, CDCl3): δ 23.3, 25.8, 31.8, 42.7, 46.8, 54.7, 55.3, 58.6,
114.0 (2C), 128.1 (2C), 135.8, 158.4. MS (ES, pos. mode) m/z
(%): 296 (M þ Hþ, 100). Anal. calcd for C16H25NO2S: C 65.05;
H 8.53; N 4.74. Found: C 64.88; H 8.26; N 4.58.
Synthesis of (Rs,R)-N-tert-butanesulfinyl-2-methylpentyla-
mine (Rs,R)-7. To a solution of (Rs,R)-methyl N-tert-butanesul-
finyl-5-chloro-2-methylpentanimidate (Rs,R)-2a (97% purity,
3% 3a) (1.0 equiv, 0.30 g, 1.12 mmol) in THF (6 mL) was added
methanol (20.0 equiv, 0.72 g, 22.44 mmol), followed by NaBH4
(10.0 equiv, 0.42 g, 11.22 mmol). The resulting solution was
stirred for 17 h at reflux temperature and subsequently poured
into a saturated aqueous solution of NaHCO3 (5 mL) and
extracted with ethyl acetate (3 ꢀ 5 mL). The combined organic
phases were dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by flash chromatography to
yield 0.13 g (0.63 mmol) of (Rs,R)-N-tert-butanesulfinyl-2-
methylpentylamine (Rs,R)-7 (96% purity).
(Rs,R)-N-tert-Butanesulfinyl-2-methylpentylamine (Rs,R)-7.
Rf = 0.09 (petroleum ether/EtOAc 4:6). Colorless oil, yield
56% (96% purity). [R]D -55.4 (c 0.9, CHCl3). IR (cm-1): νmax
1053, 1458, 2871, 2927, 2955, 3204. 1H NMR (300 MHz,
CDCl3): δ 0.84-0.95 (3H, m), 0.91 (3H, d, J = 6.6 Hz), 1.04-
1.17 (2H, m), 1.22 (9H, s), 1.24-1.43 (2H, m), 1.57-1.70 (1H,
m), 2.92-3.06 (2H, m), 3.23 (1H, t, J = 6.6 Hz). 13C NMR (75
MHz, CDCl3): δ 14.3, 17.6, 19.9, 22.7, 34.1, 36.4, 51.7, 55.7. MS
(ES, pos. mode) m/z (%): 206 (M þ Hþ, 100).
Synthesis of (R)-2-Methylpentylamine Hydrochloride (R)-8.
To a solution of (Rs,R)-N-tert-butanesulfinyl-2-methylpentyla-
mine (Rs,R)-7 (96% purity) (0.10 g, 0.49 mmol) in diethyl ether
(2 mL) was added dropwise a 4.0 M solution of dioxane HCl
3
(23) Sliwka, H.-R.; Hansen, H.-J. Helv. Chim. Acta 1984, 67, 434.
(24) (a) Cheng, Y.-X.; Luo, X.; Tomaszewski, M. PCT Int. Appl. 2007,
WO 2007126362 A1 20071108. (b) Sadikov, V. S.; Mikbailov, A. K. Ber.
Dtsch. Chemi. Ges. B: Abh. 1928, 61b, 421.
(10.0 equiv, 1.22 mL, 4.88 mmol) at room temperature. The
mixture was allowed to stir for 1 h. Then the reaction mixture
was concentrated in vacuo. Precipitation in diethyl ether afforded
J. Org. Chem. Vol. 76, No. 1, 2011 243

Colpaert et al.
JOCArticle
(R)-3-Phenylpiperidine Hydrochloride (R)-9d. White crystals,
yield 98%. Mp 179.2-179.5 °C. [R]D -10.7 (c 0.3, MeOH) vs
-10.3 (c 0.5, MeOH) in lit.10a 1H NMR (300 MHz, CDCl3): δ
1.66 (1H, q ꢀ d, J = 12.8, 3.3 Hz), 1.94-2.25 (3H, m), 2.80-3.00
(1H, m), 2.90 (1H, t, J = 11.6 Hz), 3.26 (1H, t ꢀ m, J = 12.1 Hz),
3.47-3.62 (2H, m), 7.16-7.36 (5H, m), 9.67 (1H, br s), 9.88 (1H,
br s). Anal. calcd for C11H16ClN: C 66.83; H 8.16; N 7.08.
Found: C 66.96; H 8.33; N 7.06. All spectroscopic data were in
good agreement with reported data.10a
2.78-2.99 (2H, m), 3.26 (1H, t, J = 11.6 Hz), 3.44-3.63 (2H,
m), 7.01 (2H, t, J = 8.3 Hz), 7.17 (2H, d ꢀ d, J = 8.3, 5.5 Hz),
9.66 (1H, br s), 9.85 (1H, br s). 19F NMR (282 MHz, CDCl3):
δ -114.59 to -114.70 (1F, m). 13C NMR (75 MHz, CDCl3): δ
22.6, 30.3, 38.8, 43.9, 49.4, 115.8 (2C, d, J = 21.9 Hz), 128.5 (2C,
d, J = 8.1 Hz), 136.5 (d, J = 3.5 Hz), 162.0 (d, J = 245.8 Hz).
MS (ES, pos. mode) m/z (%): 180 (M þ Hþ - HCl, 100). Anal.
calcd for C11H15ClFN: C 61.25; H 7.01; N 6.49. Found: C 61.47;
H 7.22; N 6.52.
(S)-3-Phenylpiperidine Hydrochloride (S)-9d. White crystals,
yield 81%. Mp 178.2-178.4 °C. [R]D þ11.5 (c 0.3, MeOH)
vs þ12.2 (c 0.5, MeOH) in lit.22 1H NMR (300 MHz, CDCl3): δ
1.66 (1H, q ꢀ d, J = 12.8, 3.3 Hz), 1.91-2.25 (3H, m), 2.79-3.00
(1H, m), 2.90 (1H, t, J = 11.8 Hz), 3.25 (1H, t ꢀ m, J = 12.1 Hz),
3.48-3.65 (2H, m), 7.11-7.46 (5H, m), 9.62 (1H, br s), 9.81 (1H,
br s). Anal. calcd for C11H16ClN: C 66.83; H 8.16; N 7.08.
Found: C 66.57; H 7.97; N 7.03. All spectroscopic data were in
good agreement with reported data.22
(R)-3-(4-Fluorophenyl)piperidine Hydrochloride (R)-9e. White
crystals, yield 91%. Mp 219.8-220.0 °C. [R]D -14.7 (c 0.5,
MeOH). IR (cm-1): νmax 840, 1212, 1511, 2705, 2926. 1H NMR
(300 MHz, CDCl3): δ 1.54-1.75 (1H, m), 1.93-2.27 (3H, m),
2.76-3.01 (2H, m), 3.26 (1H, t, J = 11.0 Hz), 3.45-3.65 (2H,
m), 6.97-7.11 (2H, m), 7.12-7.23 (2H, m), 9.66 (1H, br s), 9.87
(1H, br s). 19F NMR (282 MHz, CDCl3): δ -114.57 to -114.68
(1F, m). 13C NMR (75 MHz, CDCl3): δ 22.7, 30.4, 38.9, 44.0,
49.4, 115.9 (2C, d, J = 20.8 Hz), 128.5 (2C, d, J = 8.1 Hz), 136.5
(d, J = 3.5 Hz), 162.1 (d, J = 246.9 Hz). MS (ES, pos. mode) m/z
(%): 180 (M þ Hþ - HCl, 100). Anal. calcd for C11H15ClFN: C
61.25; H 7.01; N 6.49. Found: C 61.37; H 7.15; N 6.59.
(R)-3-(4-Methoxyphenyl)piperidine Hydrochloride (R)-9f. White
crystals, yield 91%. Mp 187.6-188.0. [R]D -12.3 (c 0.4, MeOH).
IR (cm-1): νmax 834, 1033, 1246, 1444, 1514, 2722, 2931. 1H NMR
(300 MHz, CDCl3): δ 1.54-1.71 (1H, m), 1.93-2.31 (3H, m), 2.87
(2H, t ꢀ d, J = 11.6, 11.6 Hz), 3.20 (1H, t ꢀ m, J = 12.1 Hz), 3.52
(2H, t ꢀ m, J = 12.4 Hz), 3.79 (3H, s), 6.85 (2H, d, J = 8.8 Hz),
7.11 (2H, d, J = 8.8 Hz), 9.63 (1H, br s), 9.82 (1H, br s). 13C NMR
(75 MHz, CDCl3): δ 22.7, 30.4, 38.7, 43.9, 49.5, 55.3, 114.2 (2C),
127.9 (2C), 132.8, 158.8. MS (ES, pos. mode) m/z (%): 192 (M þ
Hþ - HCl, 100). Anal. calcd for C12H18ClNO: C 63.29; H 7.97; N
6.15. Found: C 63.42; H 8.04; N 6.22.
Acknowledgment. We are indebted to the Research Foun-
dation—Flanders (FWO—Vlaanderen) and Ghent Univer-
sity (BOF) for financial support.
Supporting Information Available: General experimental
1
conditions and copies of H NMR and 13C NMR spectra for
N-sulfinyl imidates 1d-f, R-alkylated N-sulfinyl imidates 2,
(SS)-methyl-N-p-toluenesulfinylpropanimidate (SS)-4, sulfin-
amides 5, N-sulfinyl piperidines 6, sulfinamide (Rs,R)-7a, (R)-2-
methylpentylamine hydrochloride (R)-8, and piperidine hydro-
chlorides 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
(S)-3-(4-Fluorophenyl)piperidine Hydrochloride (S)-9e. White
crystals, yield 99%. Mp 218.5-218.8. [R]D þ14.9 (c 0.3, MeOH).
1
IR (cm-1): νmax 840, 1212, 1511, 2706, 2926. H NMR (300
MHz, CDCl3): δ 1.55-1.72 (1H, m), 1.94-2.33 (3H, m),
244 J. Org. Chem. Vol. 76, No. 1, 2011