Broadening the synthetic scope of the iron(III)-Catalyzed aza-prins cyclization

Article abstract of DOI:10.1002/ejoc.200901372

The nature and influence of the N-sulfonyl group in azaPrins cyclization and the reactivity of the six-membered azacycle generated has been studied. The aza-Prins cyclization of γ,δ-unsaturated amines with a tosyl group at the nitrogen atom produces 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines with a halovlnyl function, extraordinarily stable to further derivatization and detosylation conditions. To modulate the reactivity of such aza-cycles, a general study of the azaPrins cyclization reaction was performed with several sulfonamides. Ring formation occurs satisfactorily with both N-nosyl and N-mesylamines providing optimal conditions for further synthetic transformations. To exemplify the scope of this methodology, a short synthesis of the alkaloid coniine was successfully carried out.

Full text of DOI:10.1002/ejoc.200901372

FULL PAPER
DOI: 10.1002/ejoc.200901372
Broadening the Synthetic Scope of the Iron(III)-Catalyzed Aza-Prins
Cyclization
Rubén M. Carballo,[a] Guillermo Valdomir,[a] Martín Purino,[a] Víctor S. Martín,*[a] and
Juan I. Padrón*[a,b]
Keywords: Iron / Homogeneous catalysis / Sulfonamides / Cyclization / Heterocycles
The nature and influence of the N-sulfonyl group in aza-
Prins cyclization and the reactivity of the six-membered aza-
cycle generated has been studied. The aza-Prins cyclization
of γ,δ-unsaturated amines with a tosyl group at the nitrogen
atom produces 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyr-
idines with a halovinyl function, extraordinarily stable to fur-
ther derivatization and detosylation conditions. To modulate
the reactivity of such aza-cycles, a general study of the aza-
Prins cyclization reaction was performed with several sulfon-
amides. Ring formation occurs satisfactorily with both N-no-
syl and N-mesylamines providing optimal conditions for fur-
ther synthetic transformations. To exemplify the scope of this
methodology, a short synthesis of the alkaloid coniine was
successfully carried out.
and co-workers in this field[3] opened the way to Overman
and co-workers to develop an excellent methodology that
Introduction
The Prins cyclization reaction is one of the most power- has been applied in the synthesis of several natural prod-
ful methodologies for generating heterocycles through con- ucts.[4]
comitant carbon–heteroatom and carbon–carbon bond for-
Recently we described the direct aza-Prins cyclization re-
mation, showing great potential in organic synthesis.[1] The action between γ,δ-unsaturated tosylamines and aldehydes
aza-Prins cyclization is the nitrogen version of the reaction, in the presence of inexpensive, environmentally friendly,
which permits a rapid access to aza-cycles of natural and and stable iron(III) halides to give six-membered aza-cycles
synthetic products, but it has received less attention than 3 and 5 in good-to-excellent yields (Scheme 1). The process
the oxygen version.[2] The pioneering work of Speckamp is based on the consecutive generation of a γ-unsaturated
Scheme 1. Aza-Prins cyclization of γ,δ-unsaturated tosylamines.
iminium ion and subsequent nucleophilic attack by the un-
[a] Instituto Universitario de Bio-Orgánica “Antonio González”,
Universidad de La Laguna,
saturated C–C bond.[5] Homoallyl(tosyl)amine (1) gave
trans-2-alkyl-4-halo-1-tosylpiperidine 3 as the major iso-
mer. In addition, the alkyne aza-Prins cyclization reaction
between homopropargyl(tosyl)amine (4) and aldehydes gave
2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines 5 as the
only cyclic products.
A further step in the optimization of the Prins cyclization
reaction was the development of a catalytic version in which
the stoichiometric amounts of the iron(III) halide were re-
c/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife,
Spain
Fax: +34-922-318579
E-mail: vmartin@ull.es
[b] Instituto de Productos Naturales y Agrobiología-CSIC,
c/Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife,
Spain
Fax: +34-922-260135
E-mail: jipadron@ipna.csic.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901372.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2304–2313

Iron(III)-Catalyzed Aza-Prins Cyclization
placed. The key finding for this protocol was the catalytic
effect of a combination of the iron source [FeX3 or Fe-
(acac)3] and TMSCl.[6] This catalytic method also allows
the construction of chloro-, bromo-, and iodo-substituted
heterocycles by choosing a suitable combination of the
iron(III) source, the corresponding trimethylsilyl halide, and
the solvent.[7] Overall, this process leads to the formation
of one carbon–carbon bond, one heteroatom–carbon bond,
one halogen–carbon bond, and a ring in a regioselective
and efficient manner (Scheme 2).
Scheme 3. Chemical stability of 2-isobutyl-4-chloro-1-tosyl-1,2,5,6-
tetrahydropyridine. Reagents and conditions: a) RuCl3·H2O (7 mol-
%), NaIO4, EtOAc/CH3CN/H2O (3:3:1), 0 °C; b) tert-BuLi, Et2O;
c) H2, Pd/C, EtOAc; d) Na, naphthalene, DME, –78 °C.
Scheme 2. Iron-catalyzed aza-Prins cyclization of γ,δ-unsaturated
tosylamines.
On the other hand, in our research directed at the devel-
opment of novel antitumor drugs[8] we have determined the
antiproliferative activity of a series of trans-2-alkyl-4-halo-
piperidines 3 and 2-alkyl-4-halo-1,2,5,6-tetrahydropyridines
5. These in vitro activities were examined in the human so-
lid tumor cell lines A2780 (ovarian cancer), SW1573 (non-
small cell lung cancer), and WiDr (colon cancer). The val-
ues of the biological activities revealed that, in general, ana-
logues of 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridine 5
are more potent than derivatives of trans-2-alkyl-4-halopip-
eridine 3. A remarkable selectivity of the most active aza
compound 7 for the resistant cell line WiDr was observed
(Figure 1).
The high stability of sulfonamides, although rendering
them attractive candidates for general amine protection,
clearly poses the conundrum of their eventual removal, usu-
ally at a late stage in a synthetic scheme. Thus, there is a
widespread perception that the N-tosyl group is difficult to
remove. In fact, this depends on the substrate type, experi-
mental conditions (usually harsh), and the functional
groups present in the molecule.[12] In our case we assumed
that methods involving radical mechanisms are not compat-
ible with the halogen groups in the aza-cycle. Moreover, we
suspected that the N-tosyl group may have a direct influ-
ence on the reactivity of the rest of the functional groups.
In this article we describe our studies on the influence of
N-sulfonyl groups on the aza-Prins cyclization reaction and
subsequent derivatization of the six-membered ring. We
used p-nitrobenzenesulfonyl (nosyl) and methanesulfonyl
(mesyl) and compared these with our previous results ob-
tained with the p-toluenesulfonyl group (tosyl). We found
that the nosyl and mesyl sulfonamide groups had advan-
tages over the tosyl group. The nosyl group led to improved
selectivity of the reaction and was easily removed in the
presence of the halogen and halovinyl function. The smaller
mesyl group permitted aza-Prins cyclization, giving very
good yields, and had a positive influence on the derivati-
zation of the resulting aza-cycles.
Figure 1. Structures of antiproliferative six-membered aza-cycles.
To test the reactivity of this kind of aza-cycle and with
the obtention of large diverse synthetic libraries to be evalu-
ated as bioactive compounds as a final objective,[9] we de-
cided to derivatize this kind of heterocycle, particularly the
2-alkyl-4-halo-1,2,5,6-tetrahydropyridines 5. Based on our
previous results with six-membered oxa-cycles, we applied
the strategy to the halovinyl double bond and attempted to
remove the protecting tosyl group.[8a,10]
Results and Discussion
Unfortunately, all attempts at dihydroxylation and N-
The general aim of this study was to find stable sulfon-
sulfonyl deprotection were fruitless.[11] Under hydrogena- amides that could be used in the aza-Prins cyclization, that
tion and dehalogenation conditions, the chlorovinyl system permitted the further derivatization of the six-membered
was also stable. The methods used to remove the N-tosyl aza-cycles, and that were more easily deprotected than the
group were also fruitless (Scheme 3).
tosyl group.
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Juan I. Padrón et al.
FULL PAPER
Use of the N-Nosyl Group in the Aza-Prins Cyclization
Reaction
2.0 equiv. of TMSCl were necessary (Table 1, entry 10).
With regard to catalyst loading, 15 mol-% of FeX3 and
20 mol-% of Fe(acac)3 were found to provide the best con-
ditions (Table 1, entries 7 and 10).
Because of the inefficient conditions required for the re-
moval of N-tosyl groups, we first decided to explore the
replacement of the N-tosyl group by other more labile N-
sulfonyl groups. We focused our efforts on p-nitrobenz-
enesulfonyl (nosyl) because its removal proceeds under
much milder conditions, that is, by the attack of a thiophen-
olate anion at the sulfonyl ipso position.[13]
Table 1. Synthesis of 2-alkyl-4-halo-1-nosyl-1,2,5,6-tetrahydropyr-
idines from homopropargyl(nosyl)amine and aldehydes using
iron(III) salts as catalysts.
To initiate our study, we synthesized the homopropargyl-
and homoallyl(nosyl)amines starting from the correspond-
ing homopropargyl and homoallyl alcohols. The syntheses
proceeded via the corresponding phthalimides, obtained by
Mitsunobu reaction,[14] hydrolysis, and further sulfonylation
(Scheme 4).
Entry
R
X
RCHO
[equiv.]
FeX3
[mol-%] [mol-%]
Fe(acac)3 TMSX
%
[equiv.] Yield[a]
1
2
3
4
5
6
7
8
9
10
iBu
iBu
iBu
iBu
iBu
iBu
iBu
iBu
iBu
iBu
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1.0
1.2
1.5
1.5
1.0
1.2
1.5
1.0
1.2
2.0
100
100
100
150
10
10
15
0
0
0
0
0
65[b]
69[b]
80[b]
91[b]
65[b]
70[b]
86[b]
47[b]
50[b]
83[b]
0
0
0
0
0
0
10
10
20
0
1.0
1.2
1.5
1.0
1.5
2.0
0
0
Scheme 4. Synthesis of γ,δ-unsaturated nosylamines. Reagents and
conditions: a) i) Phthalimide, PPh3/DEAD, THF, 0 °C, ii)
NH2NH2·H2O, EtOH/∆, b) NsCl/Et3N, CH2Cl2.
11
12
13
iBu
iBu
iBu
Br
Br
Br
1.5
1.5
2.0
150
15
0
0
0
20
0
1.5
2.0
74[c]
97[c]
83[c]
14
15
16
Bn
Bn
Bn
Cl
Cl
Cl
1.5
1.5
2.0
150
15
0
0
0
20
0
1.5
2.0
49[d]
29[d]
35[d]
As a model study for the optimization of the reaction
conditions, we first chose the alkyne aza-Prins cyclization
of homopropargyl(nosyl)amine (8) and isovaleraldehyde to
give 2-alkyl-4-halo-1-nosyl-1,2,5,6-tetrahydropyridines 10
(Table 1, entries 1–10). We used our previously described
conditions based on stoichiometric amounts of FeCl3 and
the catalytic systems FeX3/TMSX or Fe(acac)3/TMSX.[5,6]
We found complete conversion to the desired product when
an excess of aldehyde was used (Table 1, entries 4, 7, and
17
18
19
Ph
Ph
Ph
Cl
Cl
Cl
1.5
1.5
2.0
150
15
0
0
0
20
0
1.5
2.0
14[e]
14[e]
18[e]
[a] Isolated yield. [b] 10a: R = iBu, X = Cl. [c] 10b: R = iBu, X =
Br. [d] 10c: R = Ph, X = Cl. [e] 10d: R = Ph, X = Br.
Compared with the N-tosyl aza-cycles, we obtained sim-
10). In the stoichiometric reaction an excess of FeX3 was ilar yields when isovaleraldehyde was used. However, 2-
necessary to obtain better yields (Table 1, entries 3 vs. 4). phenylacetaldehyde and benzaldehyde gave lower yields.[5,6]
With the FeX3/TMSCl system, we found that it was pos-
With these results in hand, we extended our studies to
sible to increase the yields with 1.5 equiv. of TMSCl homoallyl(nosyl)amine as the unsaturated amine. Table 2
(Table 1, entries 6 and 7), whereas with Fe(acac)3/TMSCl summarizes the results obtained in this study.
Table 2. Cyclization of homoallyl(nosyl)amine and aldehydes using iron(III) salts as catalysts.[a]
Entry
R
X
% Yield (11/12)
FeX3/TMSX[c]
Fe(acac)3/TMSX[d]
[b]
FeX3
a
b
c
iBu
iBu
Bn
Ph
Cl
Br
Cl
Cl
96 (Ͼ99:1)
84 (Ͼ99:1)
32 (90:10)
56 (85:15)
80 (Ͼ99:1)
70 (Ͼ99:1)
26 (90:10)
74 (85:15)
88 (Ͼ99:1)
84 (Ͼ99:1)
67 (90:10)
67 (90:10)
d
[a] For the best reaction conditions see the Supporting Information. [b] Reaction conditions: 9 (1.0 equiv.), 2 (1.0 equiv.), FeX3 (1.0 equiv.),
CH2Cl2 (0.1 ), room temp., 1 h. [c] Reaction conditions: 9 (1.0 equiv.), 2 (1.5 equiv.), FeX3 (0.1 equiv.), TMSX (1.0 equiv.), CH2Cl2
(0.1 ), room temp., 2–12 h. [d] Reaction conditions: 9 (1.0 equiv.), 2 (1.0 equiv.), Fe(acac)3 (0.075 equiv.), TMSX (1.0 equiv.), CH2Cl2
(0.1 ), room temp., 2–12 h.
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Iron(III)-Catalyzed Aza-Prins Cyclization
With homoallyl(nosyl)amine (9), the three promoter sys- Table 3. Synthesis of 2-alkyl-4-halo-1-mesyl-1,2,5,6-tetrahydropyr-
idines from homopropargyl(mesyl)amine and aldehydes using
tems gave similar yields and diastereoselectivity (Table 2).
In all cases, the trans diastereomer 11 was obtained as the
iron(III) salts as catalysts.[a]
major stereoisomer and its stereochemistry was established
by NOE experiments.[15] The stability of the γ-unsaturated
iminium ion controls the stereochemical course of the al-
kene Prins cyclization reaction. Thus, the more stable E im-
inium intermediate led to the more stable trans isomer. The
Z iminium ion becomes a more stable intermediate when R
Entry
R
X
% Yield
bears an aromatic ring. This fact explains the increase in
the cis isomer when an aromatic ring is used. Interestingly,
all the trans compounds were more stable than their corre-
sponding cis isomers.[5] The best promoter system was Fe-
(acac)3/TMSX, which worked well with both aliphatic and
aromatic aldehydes. Catalyst loadings of 10 mol-% of FeCl3
and 7.5 mol-% of Fe(acac)3 were found to be optimal
(Table 2). With the nosyl group the aza-Prins cyclization
gave better diastereoselectivity but the yields were slightly
lower.[16]
The removal of the N-nosyl group under previously re-
ported conditions[12a] was satisfactorily performed leaving
intact the halovinyl system. However, the halovinyl moiety
continued to be unreactive under other derivatization con-
ditions (Scheme 5).
[b]
FeX3
FeX3/TMSX[c] Fe(acac)3/TMSX[d]
a
b
c
iBu
iBu
Bn
Ph
Cl
Br
Cl
Cl
82
82
61
18
80
82
55
14
78
79
57
18
d
[a] For the best reaction conditions, see the Supporting Infor-
mation. [b] Reaction conditions: 15 (1.0 equiv.), 2 (1.0 equiv.), FeX3
(1.0 equiv.), CH2Cl2 (0.1 ), room temp., 1 h. [c] Reaction condi-
tions: 15 (1.0 equiv.), 2 (1.0 equiv.), FeX3 (0.1 equiv.), TMSX
(1.0 equiv.), CH2Cl2 (0.1 ), room temp., 2–12 h. [d] Reaction con-
2 (1.5 equiv.), Fe(acac)3 (0.15 equiv.),
TMSX (1.5 equiv.), CH2Cl2 (0.1 ), room temp., 2–12 h.
ditions: 15 (1.0 equiv.),
With N-(but-3-enyl)methanesulfonamide (17) the aza-
Prins cyclization worked very well, affording as the major
compound the trans diastereomer 18 in excellent yields. The
best promoter system was FeX3/TMSX, which gave almost
quantitative yields with isovaleraldehyde and 2-phenylace-
taldehyde (Table 4, entries a–c). This promoter system also
worked well with aromatic aldehydes (Table 2 and Table 4,
entry d). With N-mesylamines the yields of the aza-Prins
cyclization reactions increased and the stereoselectivities de-
creased with respect to N-nosylamines (Table 2). In the case
of aldehydes with an aromatic ring, the trans/cis (18/19) ra-
tios were the same as those observed with N-tosyl- and N-
nosyl-protected amines (Table 4, entries c and d).[5,6]
Scheme 5. Deprotection of 4-chloro-2-isobutyl-1-nosyl-1,2,5,6-
tetrahydropyridine and trans-4-chloro-2-isobutyl-1-nosylpiperidine.
Reagents and conditions: a) K2CO3/CH3CN, DMSO/PhSH, 50 °C;
b) [RuCl3·H2O] (7 mol-%), NaIO4, EtOAc/CH3CN/H2O (3:3:1),
0 °C; c) tBuLi, Et2O.
Table 4. Cyclization of homoallyl(mesyl)amine and aldehydes using
iron(III) salts as catalysts.[a]
Use of the N-Mesyl Group in the Aza-Prins Cyclization
Reaction
Although we succeeded in removing the N-nosyl group,
the reactivity of the halovinyl system of the protected amine
continued to be too low for practical use. Thus, we pon-
dered the use of methanesulfonyl (mesyl) as the protecting
group because of its small size and the expectation of a
positive influence on the reactivity of the halovinyl system.
The γ,δ-unsaturated mesylamines were synthesized in good
yields following a similar protocol to that described in
Scheme 4.[17] The next step was to check the alkyne aza-Prins
cyclization using N-(but-3-ynyl)methanesulfonamide (15) as
the nucleophile. The results of this study are summarized in
Table 3. We found that the corresponding 2-alkyl-4-halo-1-
mesyl-1,2,5,6-tetrahydropyridines 16 were formed in good
yields. The three promoter systems worked well giving almost
the same yields as those obtained with the nosyl series.
Entry
R
X
% Yield (18/19)
FeX3/TMSX[c] Fe(acac)3/TMSX[d]
[b]
FeX3
a
b
c
iBu
iBu
Bn
Ph
Cl
Br
Cl
Cl
99 (90:10)
99 (90:10)
97 (90:10)
56 (85:15)
99 (90:10)
99 (85:15)
99 (85:15)
76 (85:15)
99 (88:12)
90 (87:13)
75 (85:15)
58 (85:15)
d
[a] For the best reaction conditions, see the Supporting Infor-
mation. [b] Reaction conditions: 17 (1.0 equiv.), 2 (1.0 equiv.), FeX3
(1.0 equiv.), CH2Cl2 (0.1 ), room temp., 1 h. [c] Reaction condi-
tions: 17 (1.0 equiv.), 2 (1.0 equiv.), FeX3 (0.1 equiv.), TMSX
(1.0 equiv.), CH2Cl2 (0.1 ), room temp., 2–12 h. [d] Reaction con-
ditions: 17 (1.0 equiv.),
TMSX (1.5 equiv.), CH2Cl2 (0.1 ), room temp., 2–12 h.
2 (1.5 equiv.), Fe(acac)3 (0.15 equiv.),
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Juan I. Padrón et al.
FULL PAPER
With these results in hand, we moved forward to explore hydroxylation of the tetrahydropyridine 20, giving the diol
the deprotection of the N-mesyl group and the derivati- 22 as the sole stereoisomer. Furthermore, 20 was hydroge-
zation of the halovinyl system.
nated by using Pd(OH)2/C as the catalyst to give the piper-
The reductive cleavage of the N-mesyl group was carried idine 23 in 83% yield, which was also synthesized by cata-
out with Red-Al leading to the demesylated tetrahydropyr- lytic transfer hydrogenation of 4-chloro-6-isobutyl-1-(meth-
idine 13 in 42% yield.[18] Unfortunately, under these condi- ylsulfonyl)-1,2,3,6-tetrahydropyridine (16). Hydrogenation
tions, the dehalogenated N-mesyltetrahydropyridine 20 was of the chlorovinyl system was possible in 96% yield by using
also obtained as a minor compound in 22% yield ammonium formate as the hydrogen source.
(Scheme 6). However, 6-isobutyl-1-mesyl-1,2,3,6-tetra-
As we can see from Scheme 6, the N-mesyltetrahydropyr-
hydropyridine (20) was obtained as the sole product by idines are probably more reactive than the corresponding
using LiAlH4 instead of Red-Al as the reducing agent.[19] N-tosyl and N-nosyl derivatives due to the smaller volume
From these experiments it can be concluded that the pres- of the N-mesyl group compared with the N-tosyl and N-
ence of the chloro has a direct influence on the cleavage nosyl groups.[20]
of the N-mesyl group. In fact, N-mesyl deprotection was
Finally, to explore the synthetic scope of this methodol-
successful when the chlorovinyl system was not present in ogy and concomitantly to broaden the library of potential
the six-membered ring (Scheme 7).
bioactive compounds, we synthesized the racemic coniine
by using the homopropargyl- and homoallyl(mesyl)amine
approaches (Scheme 7). Thus, the tetrahydropyridine 24
was obtained in 85% yield from an alkyne aza-Prins cycli-
zation reaction using FeCl3 as the promoter and butanal as
the aldehyde. The chlorovinyl system in 24 was hydroge-
nated by using Pd(OH)2/C as the catalyst and ammonium
formate as the hydrogen source, which gave the N-mesylpip-
eridine 25 in 90% yield. Deprotection of the N-mesyl group
with Red-Al in toluene led to (R,S)-coniine hydrochloride
(27) in 85% yield. The approach through the alkene aza-
Prins cyclization using the catalytic system FeCl3/TMSCl
led to the piperidine 26 in 72% yield. The N-mesylpiperid-
ine 25 was obtained in 90% yield by treatment with
Bu3SnH and AIBN.
Scheme 6. Deprotection and reactivity of the 4-chloro-2-isobutyl-
1-mesyl-1,2,5,6-tetrahydropyridine. Reagents and conditions: a)
Red-Al, C7H8, 13/20 (2:1) 64%; b) RuCl3·H2O (7 mol-%), NaIO4,
EtOAc/CH3CN/H2O (3:3:1), 0 °C, 75%; c) LiAlH4/THF, 75%; d)
OsO4/NMO, THF/H2O (1:1), 85%; e) Pd(OH)2/C, HCO2NH4,
MeOH, 65 °C, 96%; f) Pd(OH)2/C, H2, MeOH, 83%.
Conclusions
We have shown the direct influence of the N-sulfonyl
group on the reactivity of the halovinyl system of six-mem-
bered-ring aza-cycles. The halovinyl reactivity increases as
the volume of the sulfonyl group decreases. Thus, the tetra-
With regard to the reactivity of the halovinyl system, we hydropyridines protected with the smaller N-mesyl group
first looked at dihydroxylation. When the chlorovinyl aza- are chemically more reactive than the corresponding N-to-
cycle 16 was submitted to ruthenium-catalyzed cis hydroxyl- syl or N-nosyl derivatives. The combination of a readily
ation, the trans-3-hydroxy-2-isobutyl-1-(methylsulfonyl)pip- available and inexpensive iron source [Fe(acac)3 or FeX3]
eridin-4-one (21) was stereoselectively produced as the sole and TMSCl catalyzed the aza-Prins cyclization of γ,δ-un-
stereoisomer.[8a] An additional functionality was incorpo- saturated (alkyne and alkene) sulfonamides with different
rated into the aza-cycle framework by osmium-catalyzed cis aldehydes. The reaction worked very well with N-tosyl, N-
Scheme 7. Synthesis of (R,S)-coniine by the aza-Prins cyclization reaction. Reagents and conditions: a) FeCl3, CH2Cl2, 85%; b) Pd(OH)2/
C, HCO2NH4, MeOH, 65 °C, 90%; c) Red-Al, C7H8, 85%; d) FeCl3/TMSCl, CH2Cl2, 72%; e) AIBN, Bu3SnH, THF, ∆, 90%.
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Iron(III)-Catalyzed Aza-Prins Cyclization
chloride (7.20 g, 32.4 mmol) were added to a solution of but-3-
yn-1-amine[21] (2.85 g, 27 mmol) in CH2Cl2 (135 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature and
then diluted with CH2Cl2 and washed with H2O, dried with
MgSO4, and concentrated. This crude reaction mixture was puri-
fied by flash silica gel column chromatography (n-hexane/EtOAc
solvent systems) to give 8 (5.47 g, 21.6 mmol) in 80% yield.[22]
nosyl, and N-mesyl groups. With the N-nosyl group, the
aza-Prins cyclization reaction led to better diastereoselectiv-
ity and its deprotection was possible keeping intact the
halovinyl system of the aza-cycle, which is essential for bio-
logical activity. With the N-mesyl group, further derivati-
zation of the six-membered ring and sulfonyl deprotection
were possible.
N-(But-3-enyl)-4-nitrobenzenesulfonamide [Homoallyl(nosyl)amine,
9]: Et3N (11.34 mL, 81 mmol) and 4-nitrobenzene-1-sulfonyl chlo-
ride (7.20 g, 32.4 mmol) were added to a solution of but-3-en-1-
amine[23] (2.90 g, 27 mmol) in CH2Cl2 (135 mL) at 0 °C. The reac-
tion mixture was allowed to warm to room temperature and then
diluted with CH2Cl2 and washed with H2O, dried with MgSO4,
and concentrated. This crude reaction mixture was purified by flash
silica gel column chromatography (n-hexane/EtOAc solvent sys-
tems) to give 9 (4.84 g, 18.9 mmol) in 70% yield. 1H NMR (CDCl3,
300 MHz): δ = 8.37 (d, J = 8.9 Hz, 2 H), 8.0 (d, J = 8.8 Hz, 2 H),
5.62 (m, 1 H), 5.07 (m, 2 H), 4.47 (br. s, 1 H), 3.09 (q, J = 6.5 Hz,
2 H), 2.24 (d, J = 6.7 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 149.8 (C), 145.7 (C), 133.4 (CH), 128.1 (2 CH), 124.2 (2 CH),
Experimental Section
General: 1H NMR spectra were recorded at 300, 400, and 500 MHz
and 13C NMR spectra were recorded at 75 and 100 MHz (VTU
298.0 K). Chemical shifts are reported in parts per million. The
residual solvent peak was used as an internal reference. For analyti-
cal thin-layer chromatography, silica gel ready-foils were used and
developed with 254 nm UV light and/or by spraying with a solution
of ninhydrin (10% w/v in EtOH) or vanillin in EtOH/H2SO4/AcOH
(15:1:1.3) and heating at 200 °C. Column chromatography was per-
formed using silica gel (0.015–0.04 mm) and n-hexane/EtOAc sol-
vent systems. All reagents were obtained from commercial sources
and used without further purification. Solvents were dried and dis-
tilled before use.
118.5 (CH ), 42.0 (CH ), 33.5 (CH ) ppm. FTIR (CHCl ): ν =
˜
2
2
2
3
3263.6, 1519.5, 1345.6, 1309.7, 1159.5 cm–1. C10H12N2O4S (256.28):
calcd. C 46.87, H 4.72, N 10.93; found C 46.95, H 4.56, N 10.86.
N-(But-3-ynyl)methanesulfonamide [Homopropargyl(mesyl)amine,
15]: Et3N (11.34 mL, 81 mmol) and methanesulfonyl chloride
(2.6 mL, 32.4 mmol) were added to a solution of but-3-yn-1-amine
(2.85 g, 27 mmol) in CH2Cl2 (135 mL) at 0 °C. The reaction mix-
ture was allowed to warm to room temperature and then diluted
with CH2Cl2 and washed with H2O, dried with MgSO4, and con-
centrated. This crude reaction mixture was purified by flash silica
gel column chromatography (n-hexane/EtOAc solvent systems) to
give 15 (2.79 g, 18.9 mmol) in 70% yield. 1H NMR (CDCl3,
300 MHz): δ = 4.95 (br. s, 1 H), 3.27 (dd, J = 6.4, 12.9 Hz, 2 H),
2.98 (s, 3 H), 2.47 (td, J = 2.7, 6.5 Hz, 2 H), 2.06 (t, J = 2.6 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 80.3 (C), 70.8 (C), 41.5
General Procedure for the FeX3-Promoted Nosyl Aza-Prins Cycliza-
tion Reactions [Homopropargyl(nosyl)amine]: Anhydrous FeX3
(1.5 equiv.) was added in one portion to a solution of homopropar-
gyl(nosyl)amine (1.0 equiv.) and aldehyde (1.5 equiv.) in dry CH2X2
(0.1 ). The reaction was stirred at room temperature until analysis
by TLC showed complete formation of the product. The reaction
was then quenched by the addition of water with stirring and ex-
tracted with CH2Cl2. The combined organic layers were dried with
MgSO4 and the solvent was removed under reduced pressure. This
crude reaction mixture was purified by flash silica gel column
chromatography (n-hexane/EtOAc solvent systems).
General Procedure for the FeX3/TMSX-Catalyzed Nosyl Aza-Prins
Cyclization Reactions: Anhydrous FeX3 (0.15 equiv.) and TMSX
(1.5 equiv.) were added to a solution of homopropargyl(nosyl)
amine (1.0 equiv.) in dry CH2X2 (0.1 ). Aldehyde (1.5 equiv.) was
then added to the reaction mixture, which was stirred at room tem-
perature until analysis by TLC showed complete formation of the
product. The reaction was then quenched by the addition of water
with stirring and extracted with CH2Cl2. The combined organic
layers were dried with MgSO4 and the solvent was removed under
reduced pressure. This crude reaction mixture was purified by flash
silica gel column chromatography (n-hexane/EtOAc solvent sys-
tems).
(CH ), 40.6 (CH ), 20.1 (CH ) ppm. FTIR (CHCl ): ν = 3277.3,
˜
2
3
2
3
1307.1, 1142.9, 640.5, 516.6 cm–1. C5H9NO2S (147.20): calcd. C
40.80, H 6.16, N 9.52; found C 40.50, H 6.25, N 9.46.
N-(But-3-enyl)methanesulfonamide [Homoallyl(mesyl)amine, 17]:
Et3N (3.9 mL, 27.9 mmol) and methanesulfonyl chloride (7.2 g,
870 µL) were added to a solution of but-3-en-1-amine (1.0 g,
9.3 mmol) in CH2Cl2 (43 mL) at 0 °C. The reaction mixture was
allowed to warm to room temperature and then diluted with
CH2Cl2 and washed with H2O, dried with MgSO4, and concen-
trated. This crude reaction mixture was purified by flash silica gel
column chromatography (n-hexane/EtOAc solvent systems) to give
17 (765 mg, 5.12 mmol) in 55% yield. 1H NMR (CDCl3,
300 MHz): δ = 5.75 (m, 1 H), 5.16 (m, 2 H), 4.40 (br. s, 1 H), 3.20
(br. d, J = 6.4 Hz, 2 H), 2.95 (s, 3 H), 2.33 (d, J = 6.2 Hz, 2 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 133.9 (CH), 118.1 (CH2), 42.0
General Procedure for the Fe(acac)3/TMSX-Catalyzed Nosyl Aza-
Prins Cyclization Reactions: Fe(acac)3 (0.2 equiv.) and TMSX
(2.0 equiv.) were added to a solution of homopropargyl(nosyl)-
amine (1.0 equiv.) in dry CH2X2 (0.1 ). Aldehyde (2.0 equiv.) was
then added to the reaction mixture, which was stirred at room tem-
perature until analysis by TLC showed complete formation of the
product. The reaction was then quenched by the addition of water
with stirring and extracted with CH2Cl2. The combined organic
layers were dried with MgSO4 and the solvent was removed under
reduced pressure. This crude reaction mixture was purified by flash
silica gel column chromatography (n-hexane/EtOAc solvent sys-
tems).
(CH ), 40.2 (CH ), 34.0 (CH ) ppm. FTIR (CHCl ): ν = 3289.5,
˜
2
3
2
3
2934.1, 1641.9, 1315.8, 1150.2 cm–1. C5H11NO2S (149.21): calcd. C
40.25, H 7.43, N 9.39; found C 39.99, H 7.63, N 9.19.
Final Products
4-Chloro-6-isobutyl-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyr-
idine (10a): (Table 1, entries 1–10). 1H NMR (CDCl3, 300 MHz): δ
= 8.32 (d, J = 8.7 Hz, 2 H), 7.99 (d, J = 8.7 Hz, 2 H), 5.77 (br. s,
1 H), 4.47 (br. s, 1 H), 3.92 (dd, J = 5.3, 14.8 Hz, 1 H), 3.29 (m, 1
H), 2.02 (m, 2 H), 1.69 (sept, J = 6.7 Hz, 1 H), 1.43 (m, 2 H), 0.93
(m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 149.7 (C), 146.5
(C), 129.5 (C), 127.9 (2 CH), 124.8 (CH), 124.1 (2 CH), 53.0 (CH),
43.2 (CH2), 38.5 (CH2), 30.4 (CH2), 24.4 (CH), 22.4 (CH3), 22.0
Starting Materials
N-(But-3-ynyl)-4-nitrobenzenesulfonamide [Homopropargyl(nosyl)-
amine, 8]: Et3N (11.34 mL, 81 mmol) and 4-nitrobenzene-1-sulfonyl
Eur. J. Org. Chem. 2010, 2304–2313
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2309

Juan I. Padrón et al.
FULL PAPER
(CH ) ppm. FTIR (CHCl ): ν = 2951.2, 1655.7, 1527.4, 1349.3,
8.8 Hz, 2 H), 8.02 (d, J = 8.8 Hz, 2 H), 7.27 (m, 5 H), 5.42 (br. s,
1 H), 3.96 (m, 2 H), 3.15 (m, 1 H), 2.78 (br. d, J = 13.6 Hz, 1 H),
2.06–1.87 (m, 2 H), 1.61 (m, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 149.7 (C), 146.3 (C), 136.4 (C), 128.9 (2 CH), 127.9
(2 CH), 127.6 (CH), 126.2 (2 CH), 124.4 (2 CH), 56.4 (CH), 51.9
˜
3
3
1317.6, 1159.5, 739.8 cm–1. C15H19ClN2O4S (358.84): calcd. C
50.21, H 5.34, N 7.81; found C 50.42, H 5.30, N 7.62.
4-Bromo-6-isobutyl-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyr-
1
idine (10b): (Table 1, entries 11–13). H NMR (CDCl3, 300 MHz):
(CH), 41.6 (CH ), 38.2 (CH ), 35.2 (CH ) ppm. FTIR (CHCl ): ν =
˜
2
2
2
3
δ = 8.32 (d, J = 8.9 Hz, 2 H), 7.98 (d, J = 8.9 Hz, 2 H), 5.59 (br.
s, 1 H), 4.41 (m, 1 H), 3.87 (m, 1 H), 3.30 (td, J = 6.5, 13.6 Hz, 1
H), 2.12 (m, 2 H), 1.68 (m, 1 H), 1.14 (m, 2 H), 0.91 (m, 6 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 149.7 (C), 146.4 (C), 129.0 (CH),
2939.5, 1519.6, 1341.2, 1319.2, 1159.2, 567.6 cm–1. C17H17ClN2O4S
(380.85): calcd. C 53.61, H 4.50, N 7.36; found C 53.80, H 4.65, N
7.40.
127.9 (2 CH), 124.1 (2 CH), 118.8 (C), 54.1 (CH), 43.0 (CH2), 39.1 cis-4-Chloro-1-(4-nitrophenylsulfonyl)-2-phenylpiperidine
(12d):
(CH2), 32.5 (CH2), 24.4 (CH), 22.4 (CH3), 22.0 (CH3) ppm. FTIR (Table 2, entry d). H NMR (CDCl3, 300 MHz): δ = 8.17 (d, J =
(CHCl ): ν = 3103.5, 1650.9, 1528.9, 1343.4, 1159.5, 610.9 cm–1. 9.0 Hz, 2 H), 7.68 (d, J = 9.0 Hz, 2 H), 7.13 (m, 5 H), 4.79 (t, J =
1
˜
3
C15H19BrN2O4S (403.29): calcd. C 44.67, H 4.75, N 6.95; found C
44.70, H 4.72, N 6.99.
6.0 Hz, 1 H), 4.20 (sept, J = 4.1 Hz, 1 H), 4.00 (m, 1 H), 3.56 (m,
1 H), 2.51 (m, 1 H), 2.36–2.19 (m, 2 H), 2.00 (m, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 149.4 (C), 146.0 (C), 137.8 (C), 128.0
(2 CH), 128.0 (2 CH), 127.5 (CH), 127.2 (2 CH), 123.7 (2 CH),
58.1 (CH), 53.2 (CH), 41.8 (CH2), 39.2 (CH2), 34.2 (CH2) ppm.
6-Benzyl-4-chloro-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyr-
1
idine (10c): (Table 1, entries 14–16). H NMR (CDCl3, 300 MHz):
δ = 8.12 (d, J = 8.9 Hz, 2 H), 7.71 (d, J = 8.9 Hz, 2 H), 7.26 (m, 3
H), 7.11 (m, 2 H), 5.79 (br. s, 1 H), 4.70 (m, 1 H), 3.86 (dd, J =
6.3, 14.8 Hz, 1 H), 3.19 (m, 1 H), 2.90 (dd, J = 1.0, 7.0 Hz, 2 H),
2.36 (m, 1 H), 2.10 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 149.6 (C), 146.0 (C), 136.2 (C), 130.5 (C), 129.2 (2 CH), 128.5
(2 CH), 127.8 (2 CH), 126.8 (CH), 124.1 (2 CH), 124.0 (CH), 55.8
FTIR (CHCl ): ν = 2921.5, 1524.6, 1341.2, 1310.2, 1159.9,
˜
3
601.6 cm–1. C17H17ClN2O4S (380.85): calcd. C 53.61, H 4.50, N
7.36; found C 53.56, H 4.68, N 7.55.
4-Chloro-6-isobutyl-1,2,3,6-tetrahydropyridine (13): PhSH (432 µL,
4.2 mmol), K2CO3 (800 mg, 5.6 mmol), and DMSO (0.7 mL) were
added to a stirred solution of 4-chloro-6-isobutyl-1-(4-nitrophen-
ylsulfonyl)-1,2,3,6-tetrahydropyridine (10a; 500 mg, 1.4 mmol) in
dry MeCN (16.8 mL). The reaction mixture was stirred at 50 °C
for 24 h and then the solvent was removed under reduced pressure.
The crude reaction mixture was purified by flash silica gel column
chromatography (EtOAc/n-hexane solvent systems) to afford com-
pound 13 (207 mg, 1.18 mmol, 85%). 1H NMR (CDCl3,
300 MHz): δ = 5.75 (br. s, 1 H), 3.39 (m, 1 H), 3.16 (ddd, J = 3.1,
5.8, 12.5 Hz, 1 H), 2.91 (ddd, J = 4.8, 8.5, 12.7 Hz, 1 H), 2.40 (m,
1 H), 2.20 (m, 1 H), 1.74 (sept, J = 6.5 Hz, 1 H), 1.50 (s, 1 H), 1.30
(m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 130.4 (C), 128.4 (CH), 52.6 (CH),
44.8 (CH2), 42.6 (CH2), 33.4 (CH2), 24.3 (CH), 22.8 (CH3), 22.0
(CH), 40.9 (CH ), 39.0 (CH ), 31.1 (CH ) ppm. FTIR (CHCl ): ν
˜
2
2
2
3
=
2975.4, 1652.4, 1527.4, 1349.4, 1317.3, 1156.7 cm–1.
C18H17ClN2O4S (392.86): calcd. C 55.03, H 4.36, N 7.13; found C
55.09, H 4.35, N 7.21.
trans-4-Chloro-2-isobutyl-1-(4-nitrophenylsulfonyl)piperidine (11a):
1
(Table 2, entry a). H NMR (CDCl3, 300 MHz): δ = 8.35 (d, J =
8.8 Hz, 2 H), 8.00 (d, J = 8.8 Hz, 2 H), 4.24 (q, J = 6.9 Hz, 1 H),
4.05 (m, 1 H), 3.88 (m, 1 H), 3.10 (t, J = 13.3 Hz, 1 H), 2.04 (m,
2 H), 1.66 (m, 1 H), 1.55–1.23 (m, 4 H), 0.88 (m, 6 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 149.7 (C), 146.8 (C), 127.9 (2 CH),
124.3 (2 CH), 52.4 (CH), 52.0 (CH), 40.4 (CH2), 39.1 (CH2), 38.6
(CH2), 35.3 (CH2), 24.6 (CH), 22.3 (CH3), 22.0 (CH3) ppm. FTIR
(CHCl ): ν = 2963.2, 1526.3, 1347.2, 1319.3, 1156.7, 746.3 cm–1.
˜
3
(CH ) ppm. FTIR (CHCl ): ν = 2955.7, 2921.5, 1604.9, 1527.5,
˜
3
3
C15H21ClN2O4S (360.86): calcd. C 49.93, H 5.87, N 7.76; found C
50.06, H 6.01, N 7.55.
1048.6 cm–1. C9H16ClN (173.68): calcd. C 62.24, H 9.29, N 8.06;
found C 62.25, H 9.18, N 8.13.
trans-4-Bromo-2-isobutyl-1-(4-nitrophenylsulfonyl)piperidine (11b):
(Table 2, entry b). H NMR (CDCl3, 300 MHz): δ = 8.35 (d, J =
trans-4-Chloro-2-isobutylpiperidine (14): PhSH (432 µL, 4.2 mmol),
K2CO3 (800 mg, 5.6 mmol), and DMSO (0.7 mL) were added to a
stirred solution of trans-4-chloro-2-isobutyl-1-(4-nitrophenylsulfo-
nyl)piperidine (11; 500 mg, 1.39 mmol) in dry MeCN (16.8 mL).
The reaction mixture was stirred at 50 °C for 24 h and then the
solvent was removed under reduced pressure. The crude reaction
mixture was purified by flash silica gel column chromatography
(EtOAc/n-hexane solvent systems) to afford compound 14 (207 mg,
1
7.7 Hz, 2 H), 8.00 (d, J = 8.2 Hz, 2 H), 4.16 (br. s, 2 H), 3.82 (m,
1 H), 3.10 (t, J = 13.7 Hz, 1 H), 2.13 (br. d, J = 8.4 Hz, 2 H), 1.89
(m, 1 H), 1.67 (m, 1 H), 1.41 (m, 3 H), 0.85 (br. s, 6 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 149.7 (C), 146.7 (C), 127.9 (2 CH),
124.3 (2 CH), 53.1 (CH), 42.7 (CH), 41.2 (CH2), 39.5 (CH2), 38.8
(CH2), 36.1 (CH2), 24.5 (CH), 22.3 (CH3), 22.1 (CH3) ppm. FTIR
(CHCl ): ν = 2954.3, 1529.4, 1355.3, 1311.4, 1147.0, 600.2 cm–1.
˜
3
1
1.18 mmol, 85%). H NMR (CDCl3, 300 MHz): δ = 4.53 (br. s, 1
C15H21BrN2O4S (405.31): calcd. C 44.45, H 5.22, N 6.91; found C
44.56, H 5.35, N 6.72.
H), 3.12 (m, 1 H), 4.05 (m, 1 H), 2.91 (dt, J = 3.3, 12.1 Hz, 1 H),
2.05 (br. s, 1 H), 1.92 (m, 3 H), 1.56 (m, 2 H), 1.22 (m, 2 H), 0.90
(s, 3 H), 0.88 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 57.9
(CH), 47.7 (CH), 45.3 (CH2), 40.5 (CH2), 40.3 (CH2), 33.9 (CH2),
trans-2-Benzyl-4-chloro-1-(4-nitrophenylsulfonyl)piperidine
(11c):
(Table 2, entry c). 1H NMR (CDCl3, 300 MHz): δ = 8.13 (d, J =
8.5 Hz, 2 H), 7.60 (d, J = 8.5 Hz, 2 H), 7.18 (m, 5 H), 4.52 (br. s,
1 H), 4.38 (br. d, J = 5.8 Hz, 1 H), 3.76 (br. d, J = 14.1 Hz, 1 H),
3.62 (t, J = 12.9 Hz, 1 H), 3.17 (m, 2 H), 2.04 (m, 4 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 149.3 (C), 146.0 (C), 138.2 (C), 129.1
(2 CH), 128.4 (2 CH), 127.8 (2 CH), 126.4 (CH), 123.9 (2 CH),
54.3 (CH), 54.1 (CH), 38.6 (CH2), 35.9 (CH2), 34.0 (CH2), 33.2
24.0 (CH), 22.8 (CH ), 22.2 (CH ) ppm. FTIR (CHCl ): ν =
˜
3
3
3
3409.2, 2958.8, 2869.9, 1628.9, 1022.7 cm–1. C9H18ClN (175.70):
calcd. C 61.52, H 10.33, N 7.97; found C 61.66, H 10.20, N 7.99.
4-Chloro-6-isobutyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine
(16a): (Table 3, entry a). 1H NMR (CDCl3, 300 MHz): δ = 5.87 (br.
s, 1 H), 4.26 (br. s, 1 H), 3.89 (dd, J = 6.4, 14.9 Hz, 1 H), 3.25 (br.
t, J = 12.2 Hz, 1 H), 2.84 (s, 3 H), 2.59 (m, 1 H), 2.19 (br. d, J =
17.9 Hz, 1 H), 1.71 (m, 1 H), 1.49 (m, 1 H), 1.36 (m, 1 H), 0.92
(m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 129.8 (C), 125.7
(CH ) ppm. FTIR (CHCl ): ν = 2927.7, 1522.3, 1344.8, 1310.1,
˜
2
3
1156.7, 690.7 cm–1. C18H19ClN2O4S (394.87): calcd. C 54.75, H
4.85, N 7.09; found C 54.99, H 4.90, N 7.15.
trans-4-Chloro-1-(4-nitrophenylsulfonyl)-2-phenylpiperidine
(Table 2, entry d). H NMR (CDCl3, 300 MHz): δ = 8.36 (d, J = 24.4 (CH), 22.5 (CH ), 22.0 (CH ) ppm. FTIR (CHCl ): ν =
(11d): (CH), 52.3 (CH), 43.1 (CH2), 39.9 (CH3), 38.3 (CH2), 31.0 (CH2),
1
˜
3
3
3
2310
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2304–2313

Iron(III)-Catalyzed Aza-Prins Cyclization
2931.9, 1659.2, 1326.9, 1150.4, 775.0, 611.4 cm–1. C10H18ClNO2S s, 1 H), 4.26 (m, 1 H), 3.86 (br. d, J = 12.8 Hz, 1 H), 3.12 (m, 1
(251.77): calcd. C 47.70, H 7.21, N 5.56; found C 47.71, H 7.37, N H), 2.95 (m, 1 H), 2.82 (m, 1 H), 2.22 (m, 5 H), 1.98 (m, 1 H), 1.86
5.56.
(m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 137.7 (C), 128.9
(2 CH), 128.6 (2 CH), 126.8 (CH), 55.8 (CH), 52.6 (CH), 40.0
(CH2), 40.0 (CH3), 39.0 (CH2), 36.7 (CH2), 36.4 (CH2) ppm. FTIR
4-Bromo-6-isobutyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine
(16b): (Table 3, entry b). 1H NMR (CDCl3, 300 MHz): δ = 6.10 (br.
s, 1 H), 4.20 (br. s, 1 H), 3.83 (dd, J = 6.2, 14.7 Hz, 1 H), 3.26 (br.
t, J = 12.4 Hz, 1 H), 2.83 (s, 3 H), 2.68 (m, 1 H), 2.32 (m, 1 H),
1.70 (m, 1 H), 1.48 (m, 1 H), 1.35 (m, 1 H), 0.92 (s, 3 H), 0.90 (s,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 129.7 (CH), 118.9 (C),
53.3 (CH), 42.9 (CH2), 39.8 (CH3), 38.9 (CH2), 33.1 (CH2), 24.3
(CHCl ): ν = 2915.2, 1449.3, 1328.6, 1145.3, 743.6, 571.2 cm–1.
˜
3
C13H18ClNO2S (287.81): calcd. C 54.25, H 6.30, N 4.87; found C
54.23, H 6.39, N 4.61.
trans-4-Chloro-1-(methylsulfonyl)-2-phenylpiperidine (18d): (Table 4,
entry d). 1H NMR (CDCl3, 300 MHz): δ = 7.34 (m, 5 H), 5.33 (br.
s, 1 H), 4.00 (m, 1 H), 3.90 (br. d, J = 14.6 Hz, 1 H), 3.09 (m, 1
H), 2.96 (s, 3 H), 2.87 (br. d, J = 13.6 Hz, 1 H), 2.17 (m, 2 H), 1.89
(m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 137.1 (C), 128.9
(2 CH), 127.4 (CH), 126.3 (2 CH), 55.8 (CH), 52.4 (CH), 41.1
(CH), 22.5 (CH ), 21.9 (CH ) ppm. FTIR (CHCl ): ν = 2953.7,
˜
3
3
3
1658.2, 1329.36, 1147.5, 619.5 cm–1. C10H18BrNO2S (296.22):
calcd. C 40.55, H 6.12, N 4.73; found C 40.65, H 6.29, N 4.74.
6-Benzyl-4-chloro-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine
(16c): (Table 3, entry c). 1H NMR (CDCl3, 300 MHz): δ = 7.30–
7.19 (m, 5 H), 5.84 (br. s, 1 H), 4.54 (br. s, 1 H), 3.86 (dd, J = 5.3,
13.9 Hz, 1 H), 3.19 (m, 1 H), 2.87 (m, 2 H), 2.63 (m, 1 H), 2.41 (s,
3 H), 2.19 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 136.9
(C), 130.7 (C), 129.3 (2 CH), 128.4 (2 CH), 126.8 (CH), 124.5 (CH),
55.7 (CH), 40.6 (CH2), 39.9 (CH3), 38.7 (CH2), 31.8 (CH2) ppm.
(CH ), 40.8 (CH ), 38.6 (CH ), 35.8 (CH ) ppm. FTIR (CHCl ): ν
˜
2
3
2
2
3
= 2869.5, 1449.3, 1323.8, 1141.6, 784.2, 706.4 cm–1. C12H16ClNO2S
(273.78): calcd. C 52.64, H 5.89, N 5.12; found C 53.00, H 6.09, N
5.18.
6-Isobutyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine
(20):
4-Chloro-6-isobutyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridine
(16; 100 mg, 0.39 mmol) was added to a stirred solution of LiAlH4
(18 mg, 0.47 mmol) in dry THF (0.5 mL) at room temperature. The
reaction mixture was stirred until TLC showed complete conver-
sion of the substrate and then quenched by the addition of water
(carefully added). MgSO4 was then added. The reaction mixture
was filtered through a Celite pad and the solvent was removed un-
der reduced pressure. This crude reaction mixture was purified by
flash silica gel column chromatography (EtOAc/n-hexane solvent
systems) to afford compound 20 (63 mg, 0.29 mmol, 75%). 1H
NMR (CDCl3, 300 MHz): δ = 5.83 (m, 1 H), 5.74 (m, 1 H), 4.14
(s, 1 H), 3.84 (dd, J = 6.4, 14.6 Hz, 1 H), 3.20 (m, 1 H), 2.84 (s, 3
H), 2.31 (m, 1 H), 1.97 (m, 1 H), 1.77 (sept, J = 6.6 Hz, 1 H), 1.52
(m, 1 H), 1.37 (m, 1 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.93 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 128.6 (CH),
124.5 (CH), 51.4 (CH), 43.4 (CH2), 39.6 (CH3), 37.6 (CH2), 24.3
FTIR (CHCl ): ν = 2937.6, 1646.5, 1329.4, 1148.4, 678.6 cm–1
C13H16ClNO2S (285.79): calcd. C 54.63, H 5.64, N 4.90; found C
54.58, H 5.73, N 4.75.
.
˜
3
4-Chloro-1-(methylsulfonyl)-6-phenyl-1,2,3,6-tetrahydropyridine
(16d): (Table 3, entry d). 1H NMR (CDCl3, 300 MHz): δ = 7.38 (m,
5 H), 6.04 (br. s, 1 H), 5.47 (br. s, 1 H), 3.81 (m, 1 H), 3.19 (m, 1
H), 2.78 (m, 1 H), 2.62 (m, 3 H), 2.37 (m, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 137.5 (C), 131.2 (C), 128.6 (2 CH), 128.4
(CH), 128.1 (2 CH), 123.2 (CH), 56.7 (CH), 39.4 (CH3), 38.4
(CH ), 31.8 (CH ) ppm. FTIR (CHCl ): ν = 2945.2, 1660.5, 1339.4,
˜
2
2
3
1150.8, 554.6 cm–1. C12H14ClNO2S (271.76): calcd. C 53.03, H
5.19, N 5.15; found C 53.13, H 5.29, N 5.15.
trans-4-Chloro-2-isobutyl-1-(methylsulfonyl)piperidine
(18a):
(Table 4, entry a). 1H NMR (CDCl3, 300 MHz): δ = 4.09 (m, 2 H),
3.75 (br. d, J = 11.7 Hz, 1 H), 3.04 (br. t, J = 2.7, 15.0 Hz, 1 H),
2.86 (s, 3 H), 2.10 (t, J = 12.7 Hz, 2 H), 1.83 (m, 2 H), 1.54 (m, 2
H), 1.31 (m, 1 H), 0.90 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 52.7 (CH), 51.7 (CH), 40.6 (CH3), 39.9 (CH2), 39.2 (CH2), 39.1
(CH2), 35.9 (CH2), 24.6 (CH), 22.4 (CH3), 21.9 (CH3) ppm. FTIR
(CH), 23.2 (CH ), 22.6 (CH ), 22.0 (CH ) ppm. FTIR (CHCl ): ν =
˜
2
3
3
3
2934.2, 1645.3, 1334.4, 1155.9, 916.9 cm–1. C10H19NO2S (217.33):
calcd. C 55.27, H 8.81, N 6.44; found C 55.30, H 8.80, N 6.47.
(2SR,3SR,4RR)-2-Isobutyl-1-(methylsulfonyl)piperidine-3,4-diol (22):
N-Methylmorpholine N-oxide (NMO; 191 mg, 1.41 mmol) and
OsO4 (cat.) were added to a stirred solution of 6-isobutyl-1-(meth-
ylsulfonyl)-1,2,3,6-tetrahydropyridine (20; 100 mg, 0.47 mmol) in
THF (1.5 mL) and H2O (1.5 mL) at room temperature. The reac-
tion mixture was stirred until TLC showed complete conversion of
the substrate and then quenched by the addition of Na2S2O4 and
diluted with AcOEt. The mixture was dried with MgSO4, filtered,
and the solvent removed under reduced pressure. The crude reac-
tion mixture was purified by flash silica gel column chromatog-
raphy (EtOAc/n-hexane solvent systems) to afford compound 22
(100 mg, 0.40 mmol, 85%). 1H NMR (CDCl3, 300 MHz): δ = 4.16
(m, 1 H), 3.86 (m, 1 H), 3.74 (m, 2 H), 3.06 (m, 4 H), 2.74 (br. s,
1 H), 2.10 (br. s, 1 H), 1.82 (m, 1 H), 1.68 (m, 2 H), 1.52 (m, 1 H),
1.20 (m, 1 H), 0.93 (d, J = 6.0 Hz, 3 H), 0.92 (d, J = 6.0 Hz, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 70.4 (CH), 66.2 (CH),
57.3 (CH), 40.3 (CH3), 38.8 (CH2), 37.5 (CH2), 27.6 (CH2), 24.4
(CHCl3):
ν
˜
=
2954.5, 1326.2, 1152.3, 785.3, 567.5 cm–1.
C10H20ClNO2S (253.79): calcd. C 47.33, H 7.94, N 5.52; found C
47.34, H 8.22, N 5.53.
cis-4-Chloro-2-isobutyl-1-(methylsulfonyl)piperidine (19a): (Table 4,
entry a). H NMR (CDCl3, 300 MHz): δ = 4.49 (m, 1 H), 4.09 (q,
J = 6.7 Hz, 1 H), 3.62 (br. d, J = 13.4 Hz, 1 H), 3.47 (br. t, J =
2.5, 12.1 Hz, 1 H), 2.88 (s, 3 H), 2.23–1.57 (m, 7 H), 0.93 (m, 6
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 54.4 (CH), 50.1 (CH),
41.1 (CH2), 40.5 (CH3), 35.4 (CH2), 34.4 (CH2), 33.3 (CH2), 25.1
1
(CH), 22.3 (CH ), 22.0 (CH ) ppm. FTIR (CHCl ): ν = 2950.5,
˜
2
2
3
1332.2, 1149.3, 788.3, 565.5 cm–1. C10H20ClNO2S (253.79): calcd.
C 47.33, H 7.94, N 5.52; found C 47.53, H 7.84, N 5.72.
trans-4-Bromo-2-isobutyl-1-(methylsulfonyl)piperidine
(18b):
(Table 4, entry b). 1H NMR (CDCl3, 300 MHz): δ = 4.23 (m, 1 H),
4.08 (br. s, 1 H), 3.70 (br. d, J = 14.5 Hz, 1 H), 3.05 (m, 1 H), 2.87
(s, 3 H), 2.25–1.87 (m, 4 H), 1.55 (m, 2 H), 1.33 (m, 1 H), 0.90 (m,
6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 52.5 (CH), 43.6 (CH),
40.8 (CH2), 40.7 (CH3), 40.1 (CH2), 38.9 (CH2), 36.7 (CH2), 24.6
(CH), 23.0 (CH ), 21.6 (CH ) ppm. FTIR (CHCl ): ν = 3470.6,
˜
3
3
3
2956.2, 2932.6, 1308.7, 1145.2 cm–1. C10H21NO4S (251.34): calcd.
C 47.79, H 8.42, N 5.57; found C 47.65, H 8.37, N 5.44.
(CH), 22.4 (CH ), 22.0 (CH ) ppm. FTIR (CHCl ): ν = 2944.5,
˜
3
3
3
1326.2, 1147.4, 665.0, 539.9 cm–1. C10H20BrNO2S (298.24): calcd.
2-Isobutyl-1-(methylsulfonyl)piperidine (23): Pd(OH)2/C (20%,
28 mg, 0.04 mmol) and HCO2NH4 (500 mg, 7.9 mmol) were added
C 40.27, H 6.76, N 4.70; found C 40.41, H 7.00, N 4.72.
trans-2-Benzyl-4-chloro-1-(methylsulfonyl)piperidine (18c): (Table 4, to a stirred solution of 4-chloro-6-isobutyl-1-(methylsulfonyl)-
entry c). 1H NMR (CDCl3, 300 MHz): δ = 7.26 (m, 5 H), 4.40 (br. 1,2,3,6-tetrahydropyridine (16; 100 mg, 0.395 mmol) in dry MeOH
Eur. J. Org. Chem. 2010, 2304–2313
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2311

Juan I. Padrón et al.
FULL PAPER
(3.9 mL) at room temperature. The reaction mixture was stirred at
65 °C for 14 h. Then it was allowed to cool down to room tempera-
ture and the mixture was diluted with AcOEt (5 mL), filtered, and
the solvent removed under reduced pressure. The crude reaction
mixture was purified by flash silica gel column chromatography
(EtOAc/n-hexane solvent systems) to afford compound 23 (83 mg,
tion mixture was purified by flash silica gel column chromatog-
raphy (n-hexane/EtOAc solvent systems) to afford compound 26
(115.7 mg, 0.48 mmol, 72%). 1H NMR (CDCl3, 400 MHz): δ =
4.14 (m, 2 H), 3.83 (br. d, J = 12.4 Hz, 1 H), 3.09 (t, J = 12.8 Hz,
1 H), 2.92 (s, 3 H), 2.18 (m, 2 H), 1.94 (dt, J = 5.2, 12.8 Hz, 1 H),
1.81 (dq, J = 4.9, 12.8 Hz, 1 H), 1.65 (m, 1 H), 1.50 (m, 1 H), 1.38
0.38 mmol, 96%). 1H NMR (CDCl3, 300 MHz): δ = 4.05 (m, 1 H), (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3,
3.65 (br. d, J = 13.7 Hz, 1 H), 3.01 (t, J = 12.7 Hz, 1 H), 2.85 (s, 3 75 MHz): δ = 53.8 (CH), 52.8 (CH), 40.9 (CH3), 40.1 (CH2), 39.2
H), 1.60 (m, 8 H), 1.36 (m, 1 H), 0.92 (m, 6 H) ppm. 13C NMR (CH2), 36.2 (CH2), 32.6 (CH2), 19.7 (CH2), 13.7 (CH3) ppm. FTIR
(CDCl3, 75 MHz): δ = 50.6 (CH), 40.5 (CH3), 40.1 (CH2), 38.4
(CHCl3):
ν
˜
=
2960.6, 1327.7, 1149.8, 670.1, 537.3 cm–1.
(CH2), 28.2 (CH2), 25.0 (CH2), 24.6 (CH), 22.4 (CH3), 22.3 (CH3)
C9H18ClNO2S (239.76): calcd. C 45.08, H 7.57, N 5.84; found C
18.3 (CH ) ppm. FTIR (CHCl ): ν = 2941.6, 2872.2, 1326.4, 45.40, H 7.18, N 6.20.
˜
2
3
1145.2, 773.2 cm–1. C10H21NO2S (219.34): calcd. C 54.76, H 9.65,
1-(Methylsulfonyl)-2-propylpiperidine (25) (26 as Starting Material):
α,αЈ-Azoisobutyronitrile (AIBN) (13 mg, 0.08 mmol) and tributyl-
tin hydride (210 µL, 0.78 mmol) were added to a stirred solution
of 4-chloro-2-propyl-1-(methylsulfonyl)piperidine (26; 94 mg,
0.39 mmol) in dry toluene (4 mL) at room temperature. The reac-
tion mixture was heated at reflux for 3 h. Then it was allowed to
cool to room temperature, and the solvent was removed under re-
duced pressure. The crude reaction mixture was purified by flash
silica gel column chromatography (EtOAc/n-hexane solvent sys-
tems) to afford compound 25 (73 mg, 0.35 mmol, 90%).
N 6.39; found C 54.70, H 9.63, N 6.43.
4-Chloro-1-(methylsulfonyl)-6-propyl-1,2,3,6-tetrahydropyridine (24):
Anhydrous FeCl3 (1.47 g, 9.05 mmol) was added in one portion to
a solution of homopropargyl(mesyl)amine (1.3 g, 9.05 mmol) and
butyraldehyde (650 mg, 9.05 mmol) in dry CH2Cl2 (0.1 ). The re-
action mixture was stirred at room temperature until analysis by
TLC showed complete formation of the product. The reaction mix-
ture was then quenched by the addition of water with stirring and
extracted with CH2Cl2. The combined organic layers were dried
with MgSO4, and the solvent was removed under reduced pressure.
This crude reaction mixture was purified by flash silica gel column
chromatography (n-hexane/EtOAc solvent systems) to give 24
2-Propylpiperidine (RS-Coniine, 27): Red-Al (3.5  in toluene,
2.4 mL, 7.3 mmol) was added to a stirred solution of 1-(methyl-
sulfonyl)-2-propylpiperidine (25; 300 mg, 1.46 mmol) in toluene
(1.5 mL) at room temperature. The reaction mixture was stirred
until TLC showed complete conversion of the substrate and then
it was quenched by the addition of water (carefully added) and
diluted with diethyl ether (5 mL). Then HCl (5%) was added and
the water layer was separated. NaOH (5%) and diethyl ether were
added to this layer. The organic layer was separated and dried with
MgSO4 and the solvent was removed under reduced pressure. This
alkaloid 27 (203 mg, 1.24 mmol, 85%) was isolated as the hydro-
chloride salt.[24]
1
(1.83 g, 7.69 mmol) in 85% yield. H NMR (CDCl3, 300 MHz): δ
= 5.90 (br. s, 1 H), 4.20 (s, 1 H), 3.91 (dd, J = 4.7, 11.1 Hz, 1 H),
3.25 (m, 1 H), 2.85 (s, 3 H), 2.60 (m, 1 H), 2.20 (dd, J = 3.5,
13.4 Hz, 1 H), 1.55 (m, 2 H), 1.43 (m, 2 H), 0.93 (t, J = 2.4 Hz, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 129.9 (C), 125.5 (CH),
54.1 (CH), 40.0 (CH3), 39.7 (CH2), 36.5 (CH2), 31.3 (CH2), 19.3
(CH ), 13.7 (CH ) ppm. FTIR (CHCl ): ν = 2956.2, 1652.3, 1327.4,
˜
2
3
3
1150.9, 785.5 cm–1. C9H16ClNO2S (237.75): calcd. C 45.47, H 6.78,
N 5.89; found C 45.48, H 6.74, N 5.84.
Supporting Information (see also the footnote on the first page of
this article): Optimization tables, 1H and 13C NMR spectra for the
homoallyl and homopropargyl sulfonamides 8, 9, 15, and 17 and
the compounds of Tables 1–4 as well as for compounds 13, 14 and
20–25.
1-(Methylsulfonyl)-2-propylpiperidine (25) (24 as Starting Material):
Pd(OH)2/C (20%, 516 mg, 0.74 mmol) and HCO2NH4 (39.4 g,
147.4 mmol) were added to a stirred solution of 4-chloro-1-
(methylsulfonyl)-6-propyl-1,2,3,6-tetrahydropyridine (24; 1.75 g,
7.37 mmol) in dry MeOH (74 mL) at room temperature. The reac-
tion mixture was stirred at 65 °C for 14 h. Then it was allowed to
cool to room temperature and the mixture was diluted with AcOEt
(90 mL), filtered, and the solvent removed under reduced pressure.
The crude reaction mixture was purified by flash silica gel column
chromatography (EtOAc/n-hexane solvent systems) to afford com-
Acknowledgments
This research was supported by the Ministerio de Ciencia e Innova-
ción (MICINN) of Spain, co-financed by the European Regional
Development Fund (Project CTQ2008-06806-C02-01/BQU), the
Ministerio de Sanidad y Consumo (MSC) (Projects RTICC RD06/
0020/1046 and RD06/0020/0041), the Agencia Canaria de In-
vestigación, Innovación y Sociedad de la Información (ACIISI) of
the Canary Islands (Project PI 2007/022), the Fundación Canaria
de Investigación y Salud (FUNCIS) (Grant REDESFAC PI 01/06),
the Consejo Superior de Investigaciones Científicas (CSIC) (Project
PIE 200880I032) and the Fundación Instituto Canario de In-
vestigación del Cáncer (FICIC) (Grant-G.I. No. 08/2007). R. M. C.
thanks the Ministerio de Educación y Ciencia (MEC) for a predoc-
toral fellowship. G. V. thanks the Agencia Nacional de investiga-
ción e Innovación (ANII) of Uruguay for a predoctoral fellowship.
M. P. was supported by the Programme Alban, the European
Union Programme of High Level Scholarships for Latin America
(scholarship no. E07D402567AR).
1
pound 25 (1.36 g, 6.63 mmol, 90%). H NMR (CDCl3, 300 MHz):
δ = 3.94 (br. s, 1 H), 3.65 (br. d, J = 14.2 Hz, 1 H), 2.99 (t, J =
13.0 Hz, 1 H), 2.84 (s, 3 H), 1.61 (m, 6 H), 1.48 (m, 2 H), 1.32 (m,
2 H), 0.91 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 52.6 (CH), 40.7 (CH), 40.4 (CH2), 31.8 (CH2), 28.2 (CH2), 25.2
(CH ), 19.7 (CH ), 18.5 (CH ) 13.9 (CH ) ppm. FTIR (CHCl ): ν
˜
2
2
2
3
3
= 2941.8, 2868.8, 1356.9, 1156.8, 775.8 cm–1. C9H19NO2S (205.32):
calcd. C 52.65, H 9.33, N 6.82; found C 52.64, H 9.32, N 6.89.
trans-4-Chloro-1-(methylsulfonyl)-2-propylpiperidine (26): Anhy-
drous FeX3 (10.9 mg, 0.07 mmol) and TMSCl (72.8 mg,
0.67 mmol) were added to a solution of homoallyl(mesyl)amine
(100 mg, 0.67 mmol) in dry CH2Cl2 (0.1 ). Butyraldehyde
(72.5 mg, 1.01 mmol) was then added to the reaction mixture,
which was stirred at room temperature until analysis by TLC
showed complete formation of the product. The reaction was then
quenched by the addition of water with stirring and extracted with
CH2Cl2. The combined organic layers were dried with MgSO4 and
the solvent was removed under reduced pressure. This crude reac-
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See the Supporting Information.
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Received: November 26, 2009
Published Online: March 9, 2010
Eur. J. Org. Chem. 2010, 2304–2313
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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