A new, simple synthesis of N-tosyl pyrrolidines and piperidines

Article abstract of DOI:10.1055/s-2006-942488

Iodocyclization of unsaturated tosylamides promoted by Oxone oxidation of KI afforded, in good yields, N-tosyl iodopyrrolidines and piperidines. A new, simple method for the conversion of alcohols to tosylamides is presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942488

2760
PAPER
A New, Simple Synthesis of N-Tosyl Pyrrolidines and Piperidines
S
ynthesis of
N
-
Tosyl
P
a
yrrolidines
r
and Pipe
i
ridinesa Carla Marcotullio,*a Valerio Campagna,a Silvia Sternativo,a Ferdinando Costantino,b Massimo Curinia
a
b
Received 25 January 2006; revised 18 April 2006
gle SN2 substitution, again using alcohols as starting ma-
terial. The process is outlined in Scheme 1.
Abstract: Iodocyclization of unsaturated tosylamides promoted by
Oxone® oxidation of KI afforded, in good yields, N-tosyl iodopyr-
rolidines and piperidines. A new, simple method for the conversion
of alcohols to tosylamides is presented.
In preliminary experiments we prepared potassium tosyl-
amide in situ by heating 1.5 equivalents each of KOH and
Key words: pyrrolidines, piperidines, Oxone®, iodocyclization, p-toluenesulfonamide in DMF. Following complete dis-
toluenesulfonamides
solution of the base, one equivalent of mesylate 2, pre-
pared from commercial (S)(+)-2-octanol 1, in DMF was
added dropwise. Purification of the reaction mixture ob-
tained after one hour gave the desired tosylamide 3 in 80%
Pyrrolidines and piperidines are important heterocyclic
cores of several natural products1 and, as such, have al-
ways attracted the attention of chemists. As a result of this
interest, several synthetic methodologies have been devel-
oped,2 with one of the most common being the cyclization
of alkenes bearing an internal nucleophile, using electro-
philes such as H+, Pd2+, PhS+ or PhSe+. Iodocyclization of
homoallylic tosylamides has been shown to be a smooth
method for the preparation of pyrrolidines.3 One of the
most frequently used ways to perform such a reaction is to
use an excess of I2 together with either NaHCO3 or K2CO3
in acetonitrile.3 However, considering the environmental
hazards associated with the transport, handling and stor-
age of halogens,4 an alternative methodology has been
sought.
yield with an enantiomeric excess of 94% (chiral HPLC).9
NHTs
OH
OMs
5
5
5
1
2
3
Scheme 1 Preparation of tosylamides
The results described above indicated that the transforma-
tion of alcohols into their corresponding tosylamides, fol-
lowing our procedure, proceeds stereospecifically with
inversion of configuration. The same methodology was
applied to the mesylate 5, prepared from commercial (E)-
3-hexen-1-ol (4), to give the tosylamide 6 in 80% yield.
In our ongoing studies on the capability of Oxone® (potas-
sium monopersulphate) to oxidize iodide ions to iodine/
hypoiodide,5 we applied the Oxone®–KI system to the io-
docyclization of unsaturated tosylamides.
The overall yield of the transformation was 71%, which is
slightly better than that reported for the conversion of al-
cohol 4 into the tosylamide 6 through the Mitsunobu reac-
tion.3 The new procedure was then used to prepare
tosylamides from a range of primary and secondary alco-
hols, obtained by reduction of the corresponding commer-
cial ketones (Table 1). It should be noted that the former
transformations were as efficient as those reported previ-
ously, both in terms of reaction times and yields.
In order to demonstrate the applicability of this new ap-
proach, we required a series of unsaturated tosylamides.
Several procedures are available for their synthesis. They
are easily prepared from primary amines by reaction with
p-toluenesulfonyl chloride,6 as well as from alcohols
through Mitsunobu reactions;7 however, such reactions
are limited by the commercial availability of primary un-
saturated amines and the use of expensive reagents. An-
other method for tosylamide synthesis involves the
reaction of potassium p-toluenesulfonamide with iodides,
prepared from alcohols via the corresponding tosylates.8
This reaction occurs with a double SN2 reaction and re-
sults in an overall retention of configuration. We wish to
report a modification of this procedure that was developed
in order to more easily prepare tosylamides through a sin-
Having developed a reliable route to the tosylamides, we
turned our attention to their iodocyclization. In our previ-
ous work on the iodolactonization and iodoetherification
of unsaturated acids and alcohols,5a we performed the cy-
clization of such substrates using Oxone® and KI in a 4:1
H2O–MeCN solution. In the present experiment, howev-
er, we discovered that these conditions were not effective
enough to result in any ring closure of tosylamide 6 and,
even after 24 hours, only unreacted starting material was
recovered. This low activity is probably due to protona-
tion of the amide under the highly acidic reaction condi-
tions employed.
SYNTHESIS 2006, No. 16, pp 2760–2766
x
x.
x
x
.
2
0
0
6
Since we have already shown that performing iodide oxi-
dation using Oxone® under heterogeneous conditions is
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-942488; Art ID: T01306SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of N-Tosyl Pyrrolidines and Piperidines
2761
10
possible,5b,5c we anticipated that the use of wet Al2O3
was achieved by single-crystal X-ray determination.11 It
would allow neutralization of the acidic medium and should be noted that in the structure of N-tosyl 2-iodoethyl
hence permit the nitrogen to act as a nucleophile on the cy- pyrrolidine 34 (Figure 1) the iodine and nitrogen atoms
clic iodonium cation.
are clearly in the anti position, demonstrating that the cy-
clization of 17 occurs in a stereospecific anti manner.
Preliminary experiments showed that when an equimolar
amount of KI was added to Oxone® supported on wet
Al2O3 in CHCl3 at room temperature, a deep purple color
quickly developed, clearly indicating the formation of I2.
Subsequent slow addition of 6 gave, after usual workup,5b
N-tosyl 2-ethyl-3-iodo pyrrolidine 30 in 85% yield.
The trans relationship between the iodine and the ethyl
group was established by comparison with reported spec-
troscopic data,3 and led us to conclude that the cyclization
proceeds through the same classical mechanism of iodine-
induced cyclization already reported3 (Scheme 2).
I
I
+
N
TsHN
TsHN
Ts
Scheme 2 Proposed mechanism for the iodocyclization
The cyclization of tosylamide 9, under the same condi-
tions, smoothly provided N-tosyl 2-iodomethyl pyrroli-
dine 31 in 87% yield; however, (Z)-tosyl amide 12 did not
give the expected cyclized product 32 even after 24 hours.
This result could be seen to reinforce our hypothesis that
the cyclization occurs in a concerted manner since, as pre-
viously reported for the cyclization of (Z)-olefinic tosyl
amides,3 the substituent at the double bond (namely the
ethyl group) should be in a pseudoaxial position for cy-
clization to occur.
Figure 2 X-ray structure of compound 34
We turned our attention to the cyclization of secondary to-
syl amides. Upon treatment with the Oxone®–Al2O3–KI
system previously used, compound 20 gave 35, in one
hour, as a 1:3.8 mixture of cis:trans diastereoisomers
(NMR) in 95% yield. Compound 23, however, gave the
dehydrohalogenated compound 36 as a mixture 1:1.4 of
trans:cis diastereoisomers (NMR) in 80% yield, instead of
the expected iodo pyrrolidine 37.
Cyclization of compound 14 gave an octahydro-1H-in-
dole derivative. The cis stereochemistry of iodine and H-
7a was established by the multiplicity and coupling con-
1
stant value of H-7a (dd, J = 5.7, 8.4 Hz) in the H NMR
While iodocyclizations have been routinely used for the
preparation of N-tosyl pyrrolidines, no examples of cy-
clizations induced by iodine on unsaturated tosyl amides
leading to N-tosyl piperidines have been described.
Komatsu12 obtained 2-iodomethyl N-tosyl piperidine 38
as a side product. To test if our procedure could be effec-
tive in the preparation of tosyl piperidines, we prepared 26
starting from the commercial alcohol 24.
spectrum of 33. Molecular modeling confirmed that these
values could exist only if H-7a and iodine are in a cis re-
lationship, indicating an anti nitrogen attack on the cyclic
iodonium ion.
I
Treatment of 26 with the Oxone®–Al2O3–KI combination
gave 38 smoothly in 83% yield. TLC analysis of the reac-
tion of tosyl amide 29, however, showed that though the
starting material disappeared within 45 minutes, the single
spot that was formed proved to be too complex to identify.
N
Ts
37
N
Ts
32
I
Figure 1 Expected products from the cyclization of compounds 12
and 23
In summary, we have developed a straightforward method
for the synthesis of N-tosyl amides and demonstrated that
the Oxone®–KI induced cyclization of unsaturated N-to-
syl amides provides a useful and simple method for the
preparation of pyrrolidines and piperidines.
Cyclization of tosylamide 17 produced a single diaste-
reomer in 82% yield, however since it was impossible to
establish the correct stereochemistry by either one- or
two-dimensional NMR, a definitive proof of the structure
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York

2762
M. C. Marcotullio et al.
PAPER
Table 1 Tosylamide Synthesis and Cyclization
Starting material
Mesylate
Tosylamide (Yield)
Overall yield Cyclization product
Yield, [time (min)]
–
NHTs
OMs
OH
69%
71%
–
5
5
5
(80%)
3
1
2
I
30
31
85 (45)
TsHN
HO
MsO
N
(80%)
6
5
8
4
Ts
I
71%
71%
87% (40)
N
TsHN
HO
MsO
(83%)
9
7
Ts
–
–
MsO
HO
NHTs
(81%)
12
10
11
I
33
84% (50)
82% (45)
NHTs
NH2
N
(90%)
14
13
Ts
72%
68%
34
35
N
TsHN
HO
MsO
MsO
I
(80%)
17
16
19
Ts
15
18
I
95% (60)
cis:trans
1:3.8
N
TsHN
HO
(80%)
20
Ts
80% (60)
cis:trans
1.4:1
63%
69%
36
38
N
TsHN
HO
MsO
(77%)
Ts
21
24
22
25
23
I
83% (30)
TsHN
N
MsO
HO
(83%)
Ts
26
TsHN
63%
–
–
HO
MsO
(73%)
29
28
27
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Tosyl Pyrrolidines and Piperidines
2763
1H and 13C NMR spectra were recorded in CDCl3 on a Bruker AC
200 spectrometer at 200 MHz and 50 MHz, respectively in the Fou-
rier transform mode, or on a Bruker Avance-DRX 400 spectrometer
at 400 MHz and 100.62 MHz, respectively. Residual solvent signals
were used as internal references. Optical rotations were measured
with a Jasco DIP-1000 digital polarimeter. The enantiomeric excess
was determined by chiral HPLC performed on an HP 1100
[Chiracel OD-H column (0.046 mm × 250 mm), UV detector at 220
nm; (0.5 mL/min, hexane–IPA, 93:7), r.t. = 17.02 C; er = 96.8:3.2].
(S)-(+)-2-octanol was purchased from Fluka (er: S:R ≥99.5:0.5 by
GC). Elemental analyses were carried out on a Carlo Erba Model
1106 Elemental Analyzer. Column chromatography was performed
using Merck silica gel 60 (70–120 mesh). TLC was performed on
Anal. Calcd for C8H16O: C, 74.94; H, 12.58. Found: C, 74.97; H,
12.54.
Preparation of Primary Mesylates; General Procedure
To a stirred solution of the alcohol (1 mmol) and MsCl (1.2 mmol)
in CH2Cl2 (5 mL), at 0 °C, Et3N (5 mmol) was added dropwise. Af-
ter 1 h the reaction mixture was diluted with H2O (10 mL) and ex-
tracted with CH2Cl2 (3 × 5 mL). The combined organic layers were
washed with H2O (2 × 5 mL), brine (2 × 5 mL), dried (Na2SO4) and
evaporated. All mesylates obtained were pure by TLC and NMR
analysis, and were used without further purification. Samples sub-
mitted for elemental analysis were purified by short column chro-
matography (CH2Cl2).
Merck silica gel 60 F254
.
(3E)-Hex-3-en-1-yl Methanesulfonate (5)14
Preparation of 6-Methylhept-5-en-1-ol (27)
Yield: 89%.
To a stirred and cooled (0 °C) soln of methyl 6-methylhept-5-
enoate13 (800 mg, 5.13 mmol) in dry Et2O (16 mL), LiAlH4 (390
mg, 10.26 mmol) was added in portions. The resulting mixture was
stirred at the same temperature until TLC showed complete disap-
pearance of the starting material. Sat. aq NH4Cl (5 mL) was added,
followed by EtOAc (5 mL). Acidification of the mixture with 2 N
HCl led to disappearance of the gray precipitates. The organic phase
was separated and the aqueous layer was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with sat. aq
NaHCO3 (2 × 5 mL), H2O (2 × 5 mL) and brine (2 × 5 mL), dried
(Na2SO4) and evaporated. The residue was purified by silica gel col-
umn chromatography (CH2Cl2–MeOH, 19:1).
13C NMR (200 MHz): d = 13.5, 25.5, 28.8, 37.4, 69.7, 122.5, 136.3.
Anal. Calcd for C7H14O3S: C, 47.17; H, 7.92. Found: C, 47.20; H,
7.90.
Pent-4-en-1-yl Methanesulfonate (8)15
Yield: 86%.
13C NMR (50 MHz): d = 28.1, 29.4, 37.2, 69.4, 116.0, 136.6.
Anal. Calcd for C6H12O3S: C, 43.88; H, 7.37. Found: C, 43.92; H,
7.34.
(3Z)-Hex-3-en-1-yl Methanesulfonate (11)16
Yield: 88%.
Yield: 600 mg (91%).
1H NMR (200 MHz): d = 1.20–1.50 (m, 2 H), 1.55–1.65 (m, 2 H),
1.58 (s, 3 H), 1.69 (s, 3 H), 2.01 (q, J = 7.0 Hz, 2 H), 3.64 (t, J = 6.8
Hz, 2 H), 5.11 (m, 1 H).
13C NMR (50 MHz): d = 17.7, 25.7, 25.9, 27.7, 32.4, 62.9, 124.4,
131.7.
13C NMR (50 MHz): d = 14.9, 20.6, 27.2, 37.4, 69.3, 122.1, 135.8.
Anal. Calcd for C7H14O3S: C, 47.17; H, 7.92. Found: C, 47.22; H,
7.88.
(4E)-Hex-4-en-1-yl Methanesulfonate (16)17
Yield: 90%.
Anal. Calcd for C8H16O: C, 74.94; H, 12.58. Found: C, 74.90; H,
12.60.
All analytical and spectroscopic data were in agreement with report-
ed values.
Preparation of Secondary Alcohols; General Procedure
To a stirred solution of the ketone (1 mmol) in EtOH (10 mL) a so-
lution of NaBH4 (0.5 mmol) in H2O (1 mL) was added dropwise.
After 1 h the reaction mixture was treated with acetone (1 mL) and
after 5 min, diluted with H2O (5 mL), acidified to pH 4 with HCl
(4%) and extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with sat. aq NaHCO3 (2 × 5 mL), H2O (2 × 5
mL) and brine (2 × 5 mL), dried (Na2SO4) and evaporated. The
crude product was purified by silica gel column chromatography
(CH2Cl2–MeOH, 19:1).
Hex-5-en-1-yl Methanesulfonate (25)
Yield: 83%.
1H NMR (200 MHz): d = 1.49–1.70 (m, 2 H), 1.75–1.90 (m, 2 H),
2.10–2.20 (m, 2 H), 3.03 (s, 3 H), 4.27 (t, J = 6.6 Hz, 2 H), 4.98–
5.12 (m, 2 H), 5.70–5.90 (m, 1 H).
13C NMR (50 MHz): d = 24.6, 28.5, 32.9, 37.3, 69.9, 115.2, 137.9.
Anal. Calcd for C7H14O3S: C, 47.17; H, 7.92. Found: C, 47.21; H,
7.89.
Hex-5-en-2-ol (18)
Yield: 90%.
1H NMR (200 MHz): d = 1.17 (d, J = 6.2 Hz, 3 H), 1.4–1.6 (m,
2 H), 2.0–2.2 (m, 2 H), 3.80 (sext, J = 6.2 Hz, 1 H), 4.8–5.1 (m,
2 H), 5.7–5.9 (m, 1 H).
13C NMR (50 MHz): d = 23.4, 30.1, 38.2, 67.6, 114.7, 138.5.
6-Methylhept-5-en-1-yl Methanesulfonate (28)
Yield: 86%.
1H NMR (200 MHz): d = 1.35–1.55 (m, 2 H), 1.60 (s, 3 H), 1.69 (s,
3 H), 1.65–1.85 (m, 2 H), 2.02 (q, 2 H), 3.00 (s, 3 H), 4.23 (t, J = 6.5
Hz, 2 H), 5.09 (m, 1 H).
13C NMR (50 MHz): d = 17.9, 25.8, 25.9, 27.5, 28.9, 37.6, 70.5,
123.9, 132.5.
Anal. Calcd for C6H12O: C, 71.95; H, 12.08. Found: C, 71.92; H,
12.10.
Anal. Calcd for C9H18O3S: C, 52.40; H, 8.79. Found: C, 52.45; H,
8.75.
6-Methylhept-5-en-2-ol (21)
Yield: 92%.
Preparation of Secondary Mesylates; General Procedure
To a stirred solution of the alcohol (1 mmol) in pyridine (1 mL),
MsCl (1.2 mmol) was added dropwise. After 2 h the reaction mix-
ture was diluted with H2O (10 mL), acidified to pH 4 with HCl (5%)
and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were washed with H2O (2 × 5 mL), brine (2 × 5 mL), dried (Na2SO4)
1H NMR (200 MHz): d = 1.23 (d, J = 6 Hz, 3 H), 1.4–1.6 (m, 2 H),
1.66 (s, 3 H), 1.73 (s, 3 H), 2.11 (m, 2 H), 3.84 (m, 1 H), 5.17 (m,
1 H).
13C NMR (50 MHz): d = 17.7, 23.4, 24.5, 25.7, 39.1, 67.9, 124.0,
132.4.
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York

2764
M. C. Marcotullio et al.
PAPER
and evaporated. The crude residue was used without further purifi-
cation. Samples submitted for elemental analysis were purified by
short column chromatography (CH2Cl2).
All analytical and spectroscopic data were in agreement with report-
ed values.3
N-[(4E)-Hex-4-en-1-yl](4-methylphenyl)sulfonamide (17)
Yield: 80%.
1-Methylheptyl Methanesulfonate (2)
Yield: 86%.
1H NMR (200 MHz): d = 1.55 (quint, J = 7 Hz, 2 H), 1.64 (d,
J = 4.7 Hz, 3 H), 1.99 (q, J = 7 Hz, 2 H), 2.47 (s, 3 H), 2.97 (q,
J = 6.5 Hz, 2 H), 4.45 (t, J = 4.5 Hz, 1 H), 5.2–5.7 (m, 2 H), 7.35 (d,
J = 7 Hz, 2 H), 7.77 (d, J = 7 Hz, 2 H).
1H NMR (200 MHz): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.2–1.5 (m, 8 H),
1.42 (d, J = 6.3 Hz, 3 H), 1.7–1.9 (m, 2 H), 3.00 (s, 3 H), 4.80 (sext,
J = 6.2 Hz, 1 H).
13C NMR (50 MHz): d = 14.0, 21.2, 22.6, 25.1, 28.9, 31.6, 36.7,
38.7, 80.5.
13C NMR (50 MHz): d = 18.1, 21.8, 29.5, 30.0, 42.9, 126.4, 127.4,
129.9, 137.3, 143.6.
Anal. Calcd for C9H20O3S: C, 51.89; H, 9.68. Found: C, 51.86; H,
9.71.
Anal. Calcd for C13H19NO2S: C, 61.63, H, 7.56; N, 5.53. Found: C,
61.60; H, 7.58; N, 5.50.
1-Methylpent-4-en-1-yl Methanesulfonate (19)18
Yield: 85%.
N-(1-Methylpent-4-en-1-yl)(4-methylphenyl)sulfonamide (20)
Yield: 80%.
All analytical and spectroscopic data were in agreement with report-
ed values.
1H NMR (200 MHz): d = 0.99 (d, J = 6.6 Hz, 3 H), 1.44 (q, J = 7.5
Hz, 2 H), 1.9–2.1 (m, 2 H), 2.41 (s, 3 H), 6.41 (sept, J = 6.7 Hz,
1 H), 4.64 (d, J = 8.3 Hz, 1 H), 4.80 (m, 2 H), 5.51 (m, 1 H), 7.32
(d, J = 8.4 Hz, 2 H), 7.75 (d, J = 8.2 Hz, 2 H).
1,5-Dimethylhex-4-en-1-yl Methanesulfonate (22)
Yield: 82%.
13C NMR (50 MHz): d = 21.7, 29.9, 36.8, 49.8, 115.3, 127.3, 129.9,
1H NMR (200 MHz): d = 1.44 (d, J = 6.2 Hz, 3 H), 1.63 (s, 3 H),
1.71 (s, 3 H), 1.78 (m, 2 H), 2.11 (q, J = 7.2 Hz, 2 H), 3.01 (s, 3 H),
4.84 (m, 1 H), 5.12 (m, 1 H).
13C NMR (50 MHz): d = 17.7, 21.2, 23.7, 25.7, 36.7, 38.6, 80.0,
122.6, 132.9.
137.9, 138.6, 143.4.
Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53. Found: C,
61.62; H, 7.54; N, 5.56.
N-(1,5-Dimethylhex-4-en-1-yl)(4-methylphenyl)sulfonamide
(23)
Yield: 77%.
Anal. Calcd for C9H18O3S: C, 52.40; H, 8.79. Found: C, 52.37; H,
8.75.
1H NMR (200 MHz): d = 1.08 (d, J = 6.5 Hz, 3 H), 1.3–1.5 (m,
2 H), 1.55 (s, 3 H), 1.77 (s, 3 H), 1.91 (quint, J = 6.9 Hz, 2 H), 2.46
(s, 3 H), 3.34 (quint, J = 6.7 Hz, 1 H), 4.49 (d, J = 7.6 Hz, 1 H), 4.96
(br s, 1 H), 7.33 (d, J = 8 Hz, 2 H), 7.80 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz): d = 17.9, 21.8, 21.9, 23.7, 25.9, 37.7, 50.1,
126.7, 127.3, 129.9, 138.5, 143.4.
Preparation of Tosylamides; General Procedure
KOH (1.5 mmol) was dissolved in DMF (1 mL) at 120 °C and tosyl-
amide (1.5 mmol) was added to the resulting solution. After 30 min
a solution of the mesylate (1 mmol) in DMF (1 mL) was added. Af-
ter 1 h the reaction mixture was cooled, diluted with H2O (10 mL)
and extracted with Et2O (4 × 5 mL). The combined organic layers
were washed with H2O (3 × 5 mL), brine (3 × 5 mL), dried (MgSO4)
and evaporated. The crude product was purified by silica gel col-
umn chromatography (hexane–EtOAc, 9:1).
Anal. Calcd for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98. Found: C,
63.98; H, 8.27; N, 4.95.
N-Hex-5-enyl(4-methylphenyl)sulfonamide (26)19
Yield: 83%.
N-Oct-2-yl(4-methylphenyl)sulfonamide (3)
13C NMR (50 MHz): d = 21.5, 25.7, 28.9, 33.1, 43.0, 114.8, 126.4,
Yield: 80%.
1H NMR (200 MHz): d = 0.86 (t, J = 7 Hz, 3 H), 1.04 (d, J = 6.5 Hz,
3 H), 1.2–1.4 (m, 10 H), 2.44 (s, 3 H), 3.30 (quint, J = 6.5 Hz, 1 H),
4.29 (d, J = 8.7 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 2 H), 7.77 (d, J = 7.8
Hz, 2 H).
129.7, 136.9, 138.2, 143.3.
Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53. Found: C,
61.60; H, 7.52; N, 5.56.
13C NMR (50 MHz): d = 14.1, 21.5, 21.9, 22.5, 25.4, 28.9, 29.7,
31.7, 37.4, 50.0, 127.1, 129.6, 138.3, 143.0.
N-[6-Methyl(hept-5-en-1-yl)](4-methylphenyl)sulfonamide (29)
Yield: 73%.
1H NMR (200 MHz): d = 1.15–1.30 (m, 2 H), 1.30–1.45 (m, 2 H),
1.57 (s, 3 H), 1.66 (s, 3 H), 1.91 (q, J = 6.6 Hz, 2 H), 2.43 (s, 3 H),
2.93 (q, J = 6.9 Hz, 2 H), 4.15 (t, J = 6.9 Hz, 1 H), 5.01 (m, 1 H),
7.31 (d, J = 8.1 Hz, 2 H), 7.75 (d, J = 8.1 Hz, 2 H).
13C NMR (50 MHz): d = 17.6, 21.5, 25.7, 26.7, 27.3, 29.0, 43.1,
122.3, 127.1, 129.7, 131.8, 136.9, 143.2.
Anal. Calcd for C15H25NO2S: C, 63.57; H, 8.89; N, 4.94. Found: C,
63.53; H, 8.87; N, 4.97.
N-[(3E)-Hex-3-en-1-yl](4-methylphenyl)sulfonamide (6)
Yield: 80%.
All analytical and spectroscopic data were in agreement with report-
ed values.3
Anal. Calcd for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98. Found: C,
64.07; H, 8.20; N, 5.00.
N-Pent-4-en-1-yl(4-methylphenyl)sulfonamide (9)
Yield: 83%.
N-(2-Cyclohex-1-en-1-ylethyl)(4-methylphenyl)sulfonamide
(14)
To a stirred solution of commercial 2-cyclohexenylethanamine (300
mg, 2.4 mmol) in CH2Cl2 (10 mL) and Et3N (0.5 mL) was added,
dropwise, a solution of TsCl (503 mg, 2.6 mmol) in CH2Cl2 (2 mL).
The reaction was monitored by TLC and upon disappearance of the
starting material, the reaction mixture was washed with sat.
All analytical and spectroscopic data were in agreement with report-
ed values.8
N-[(3Z)-Hex-3-en-1-yl](4-methylphenyl)sulfonamide (12)
Yield: 81%.
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Tosyl Pyrrolidines and Piperidines
2765
NaHCO3 (2 × 5 mL) The organic phase was extracted with CH2Cl2
(3 × 5 mL) and the combined organic layers were washed with brine
(2 × 5 mL), dried (Na2SO4) and evaporated. Tosylamide 14 was
pure by TLC and NMR and was used without further purification.
Samples for elemental analysis were purified on a short column of
SiO2 (CH2Cl2–EtOAc, 19:1).
2-(Iodomethyl)-5-methyl-1-[(4-methylphenyl)sulfonyl]pyrroli-
dine (35)
Yield: 95%.
1H NMR (400 MHz): d (cis isomer) = 1.10 (d, J = 6.4 Hz, 3 H), 1.5–
1.6 (m, 2 H), 2.0–2.2 (m, 2 H), 2.46 (s, 3 H), 3.20 (dd, J = 9.3, 10.5
Hz, 1 H), 3.68 (dd, J = 3.2, 9.3 Hz, 1 H), 3.7–3.8 (m, 2 H), 7.38 (d,
J = 7.8 Hz, 2 H), 7.77 (d, J = 7.8 Hz, 2 H).
Yield: 90%.
1H NMR (200 MHz): d = 1.51 (m, 4 H), 1.72 (m, 2 H), 1.93 (m,
2 H), 2.06 (t J = 6.8 Hz, 2 H), 2.43 (s, 3 H), 2.99 (m, 2 H), 4.86 (br
s, 1 H), 5.37 (br s, 1 H), 7.31 (d, J = 7.3 Hz, 2 H), 7.77 (d, J = 7.2
Hz, 2 H).
13C NMR (50 MHz): d = 21.5, 22.6, 23.3, 25.1, 27.5, 37.4, 40.7,
124.5, 127.1, 128.8, 133.5, 136.9, 143.3.
13C NMR (100 MHz): d (cis isomer) = 11.7, 21.0, 29.2, 30.7, 58.6,
62.4, 127.5, 129.7, 138.8, 143.7.
1H NMR (400 MHz): d (trans isomer) = 1.18 (d, J = 6.4 Hz, 3 H),
1.5–1.6 (m, 2 H), 2.0–2.2 (m, 2 H), 2.45 (s, 3 H), 3.08 (dd, J = 9.6,
10.7 Hz, 1 H), 3.80 (dd, J = 2.8, 9.6 Hz, 2 H), 4.0–4.1 (m, 1 H), 4.14
(quint, J = 6.4 Hz, 1 H), 7.35 (d, J = 8 Hz, 2 H), 7.76 (d, J = 8 Hz,
2 H).
13C NMR (100 MHz): d (trans isomer) = 9.9, 20.3, 26.6, 30.5, 57.5,
61.1, 126.9, 129.6, 138.9, 143.2.
Anal. Calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01. Found: C,
64.50; H, 7.55; N, 4.97.
Cyclization of p-Toluenesulfonamides; General Procedure
Oxone® (5 mmol) was added to a stirred suspension of wet Al2O3
(10 g) in CHCl3 (25 mL). KI (5 mmol) was then added and the re-
sulting deep purple suspension was stirred for 10 min before tosyla-
mide (1 mmol), in CHCl3 (2.5 mL) was added dropwise. The
reaction was monitored by TLC and, upon completion, the mixture
was filtered under vacuum and the solution washed with saturated
NaHSO3 (2 × 10 mL) and brine (2 × 10 mL). The organic layer was
dried (Na2SO4) and concentrated. All the cyclized compounds were
pure by TLC and NMR analysis, but samples for elemental analysis
were purified on a short SiO2 column chromatography (CH2Cl2–
EtOAc, 98:2).
Anal. Calcd for C13H18INO2S: C, 41.17; H, 4.78; N, 3.69. Found: C,
41.20; H, 4.76; N, 3.71.
2-Isopropenyl-5-methyl-1-[(4-methylphenyl)sulfonyl]pyrroli-
dine (36)
Yield: 80%.
1H NMR (400 MHz): d (trans isomer) = 1.26 (d, J = 6.4 Hz, 3 H),
1.5–1.7 (m, 2 H), 1.54 (s, 3 H), 1.7–1.8 (m, 2 H), 3.96 (s, 3 H), 4.21
(quint, J = 6.6 Hz, 1 H), 4.30 (d, J = 8.5 Hz, 1 H), 4.77 (br s, 1 H),
4.84 (br s, 1 H), 7.26 (d, J = 8 Hz, 2 H), 7.73 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz): d (trans isomer) = 18.3, 20.9, 22.8, 29.6,
31.9, 57.3, 64.7, 112.7, 127.3, 129.1, 134.8, 143.3.
1H NMR (400 MHz): d (cis isomer) = 1.39 (d, J = 6.4 Hz, 3 H), 1.5–
1.7 (m, 2 H), 1.79 (s, 3 H), 2.0–2.2 (m, 2 H), 2.45 (s, 3 H), 3.82
(sext, J = 6 Hz, 1 H), 4.02 (t, J = 6.7 Hz, 1 H), 4.91 (br s, 1 H), 5.09
(br s, 1 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.74 (d, J = 7.9 Hz, 2 H).
2-Ethyl-3-iodo-1-[(4-methylphenyl)sulfonyl]pyrrolidine (30)
Yield: 85%.
All analytical and spectroscopic data were in agreement with re-
ported values.3
13C NMR (100 MHz): d (cis isomer) = 18.7, 21.5, 22.8, 29.8, 31.8,
57.7, 66.6, 111.8, 127.5, 129.6, 135.0, 144.9.
2-(Iodomethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine (31)
Yield: 87%.
Anal. Calcd for C15H21NO2S: C, 64.48; H, 7.58; N, 5.01. Found: C,
64.51; H, 7.53; N, 5.04.
All analytical and spectroscopic data were in agreement with report-
ed values.13
2-Iodomethyl-1-[(4-methylphenyl)sulfonyl]piperidine (38)
Yield: 83%.
3a-Iodo-1-[(4-methylphenyl)sulfonyl]octahydro-1H-indole (33)
Yield: 84%.
All analytical and spectroscopic data were in agreement with report-
ed values.12
1H NMR (400 MHz): d = 1.43 (m, 2 H), 1.74 (m, 2 H), 2.15 (m,
2 H), 2.27 (m, 2 H), 2.44 (s, 3 H), 2.51 (m, 2 H), 3.51 (dd, J = 8.3,
9.5 Hz, 1 H), 3.69 (ddd, J = 3.2, 8.0, 9.5 Hz, 1 H), 3.92 (dd, J = 5.7,
8.4 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.89 (d, J = 7.9 Hz, 2 H).
13C NMR (100 MHz): d = 21.6, 22.3, 24.1, 31.9, 40.6, 42.5, 47.1,
52.6, 70.0, 127.7, 129.6, 133.6, 143.4.
Crystal Structure Determination of 34
Single crystal diffraction data collection of 34 was carried out on an
XCALIBUR Oxford Instruments diffractometer equipped with a
CCD detector, at the Dipartimento di Scienze della Terra - Univer-
sity of Perugia, using graphite monochromated Mo-Ka-radiation,
and operating at 50 kV and 30 mA. To maximize the reciprocal
space coverage, a combination of w and j scans was used, with a
step size of 0.5° and a time of 50 s/frame. The distance between the
crystal and the detector was 60.4 mm.
Anal. Calcd for C15H20INO2S: C, 44.45; H, 4.97; N, 3.46. Found: C,
44.43; H, 4.94; N, 3.49.
2-(1-Iodoethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine (34)
Yield: 82%.
1H NMR (400 MHz): d = 1.39–1.44 (m, 1 H), 1.77–1.92 (m, 3 H),
1.89 (d, J = 7.0 Hz, 3 H), 2.46 (s, 3 H), 3.13–3.17 (m, 1 H), 3.37–
3.40 (m, 2 H), 4.76–4.80 (m, 1 H), 7.36 (d, J = 7.5 Hz, 2 H), 7.77
(d, J = 7.5 Hz, 2 H).
13C NMR (100 MHz): d = 20.5, 24.4, 25.1, 30.4, 36.9, 49.4, 65.5,
127.5, 129.8, 135.2, 143.7.
Data were corrected for absorption using SADABS. The structure
was solved by direct methods and refined by full-matrix least-
squares against F2 using all data, with the SHELXTL software
package. Non-H atoms were refined anisotropically; H atoms were
placed in calculated positions.
CCDC 292928; Empirical formula C13H18INO2S; Formula weight
379.23; Crystal system = orthorhombic; Space group P212121 (no.
19); z-8; a = 6.310(1), b = 12.357(2) c = 19.561(3) Å;
V = 1521.7(4) Å3, D (calculated) = 1.655 Mg/m3, Absorption coef-
ficient 2.236 mm–1, F(000) 752; 2qmax = 24.99°; Reflections collect-
ed 12601; Independent reflections 2517 [R(int) = 0.0987]; 164
Anal. Calcd for C13H18INO2S: C, 41.17; H, 4.78; N, 3.69. Found: C,
41.20; H, 4.76; N, 3.66.
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York

2766
M. C. Marcotullio et al.
PAPER
Parameters; Final R indices [1863 with I > 2 sigma (I)] R1 = 0.089,
wR2 = 0.0887; S = 1.180 (all data); Largest diff. peak and hole 0.75
and –0.67 e Å–3.
(7) (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.
1972, 94, 679. (b) Henry, J. R.; Marcin, L. R.; McIntosh, M.
C.; Scola, P. M.; Harris, G. D. Jr.; Weinreb, S. M.
Tetrahedron Lett. 1989, 30, 5709. (c) Mitsunobu, O.
Synthesis 1981, 1. (d) Hughes, D. L. Org. Prep. Proced. Int.
1996, 28, 127.
Acknowledgment
(8) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org.
Chem. 1994, 59, 4172.
Financial support from MIUR, National Project ‘Sviluppo di pro-
cessi ecocompatibili nella sintesi organica’ is gratefully acknowled-
ged.
(9) Compound 3 showed [a]D24 +4.06 (c 2.15, CH2Cl2). This
value is comparable with the [a] value of the same
tosylamide prepared from commercial (R)-2-octyl amine by
reaction with p-toluenesulfonyl chloride {[a]D23 +5.0 (c 1.7,
CH2Cl2)}.
References
(1) For examples, see: O’Hagan, D. Nat. Prod. Rep. 2000, 17,
435.
(2) Mitchenson, A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1
2000, 2862; and references cited therein.
(3) Jones, A. D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc.,
Perkin Trans. 1 2001, 1182.
(10) Hirano, M.; Oose, M.; Morimoto, T. Chem. Lett. 1991, 331.
(11) CCDC reference number 292928.
(12) Minakata, S.; Kano, D.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2002, 4, 2097.
(13) Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem.
2004, 783.
(4) Clark, J. H.; Ross, J. C.; Macquarrie, D. J.; Barlow, S. J.;
Bastock, T. W. J. Chem. Soc., Chem. Commun. 1997, 1203.
(5) (a) Curini, M.; Epifano, F.; Marcotullio, M. C.; Montanari,
F. Synlett 2004, 368. (b) Curini, M.; Epifano, F.;
Marcotullio, M. C.; Rosati, O. Tetrahedron Lett. 2002, 43,
1201. (c) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati,
O.; Rossi, M. Tetrahedron 1999, 55, 6211.
(14) Porter, N. A.; Funk, M. O.; Gilmore, D.; Isaac, R.; Nixon, J.
J. Am. Chem. Soc. 1976, 98, 6000.
(15) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757.
(16) Esch, P. M.; Boska, I. M.; Hiemstra, H.; De Boer, R. F.;
Speckamp, W. N. Tetrahedron 1991, 47, 4039.
(17) Clive, D.; Hisaindee, S. J. Org. Chem. 2000, 65, 4923.
(18) Porter, N. A.; Zuraw, P. J. J. Org. Chem. 1984, 49, 1345.
(19) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982,
104, 2444.
(6) Greene, T. W.; Wutz, P. G. M. In Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991, 379.
Synthesis 2006, No. 16, 2760–2766 © Thieme Stuttgart · New York