Synthesis of nitrogenated heterocycles by asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)haloimines

Article abstract of DOI:10.1021/jo4014386

Highly optically enriched, protected, nitrogenated heterocycles with different ring sizes have been synthesized by a very efficient methodology consisting of the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl) haloimines followed by treatment with a base to promote an intramolecular nucleophilic substitution process. N-Protected aziridines, pyrrolidines, piperidines, and azepanes bearing aromatic, heteroaromatic, and aliphatic substituents have been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results by changing the absolute configuration of the sulfur atom of the sulfinyl group.

Full text of DOI:10.1021/jo4014386

Article
pubs.acs.org/joc
Synthesis of Nitrogenated Heterocycles by Asymmetric Transfer
Hydrogenation of N‑(tert-Butylsulfinyl)haloimines
́
Oscar Pablo, David Guijarro,* and Miguel Yus
́ ́
Departamento de Química Organica, Facultad de Ciencias and Instituto de Síntesis Organica (ISO), Universidad de Alicante,
Apartado 99, 03080 Alicante, Spain
S
* Supporting Information
ABSTRACT: Highly optically enriched, protected, nitro-
genated heterocycles with different ring sizes have been
synthesized by a very efficient methodology consisting of the
asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)-
haloimines followed by treatment with a base to promote an
intramolecular nucleophilic substitution process. N-Protected
aziridines, pyrrolidines, piperidines, and azepanes bearing
aromatic, heteroaromatic, and aliphatic substituents have
been obtained in very high yields and diastereomeric ratios up to >99:1. The free heterocycles can be easily obtained by a
simple and mild desulfinylation procedure. Both enantiomers of the free heterocycles can be prepared with the same good results
by changing the absolute configuration of the sulfur atom of the sulfinyl group.
compounds containing endocyclic imine functions.9 In the last
INTRODUCTION
■
years, several of our research activities have focused on
diastereoselective processes using enantiomerically pure N-
(tert-butylsulfinyl)imines as substrates.10 We have developed a
very effective method for the preparation of highly enantiomeri-
cally enriched aromatic and aliphatic amines by ruthenium-
catalyzed ATH of N-(tert-butylsulfinyl)ketimines in isopropyl
alcohol followed by desulfinylation of the nitrogen atom.11
Recently, we have used this hydrogen transfer based reduction
methodology as a key step to accomplish the synthesis of
optically enriched γ-, δ-, and ε-lactams from N-(tert-
butylsulfinyl)iminoesters.12 Herein we describe the application
of the ATH of N-(tert-butylsulfinyl)haloimines to the synthesis
of highly enantiomerically enriched aziridines, pyrrolidines,
piperidines, and azepanes.
The synthesis of chiral, nitrogen-containing, saturated hetero-
cycles has attracted the attention of organic chemists
worldwide.1 Some features of those compounds that make
them so interesting are that (a) they are key structures present
in many natural and synthetic products that display biological
and pharmacological activity,2 playing a crucial role in the
design of new drugs, and (b) they have found applications as
either chiral ligands or organocatalysts in asymmetric syn-
thesis.3 Among the different methods to build those
heterocyclic scaffolds in enantiomerically enriched form, the
cyclization of chiral haloamines has been shown to be very
straightforward and effective. The precursor haloamines can be
synthesized by addition or reduction methodologies from
imines bearing a chiral auxiliary bonded to the nitrogen atom.
In recent years, the tert-butylsulfinyl group has arisen as an
outstanding chiral auxiliary that leads to excellent diaster-
eoselectivities in a wide assortment of synthetic approaches4
and shows the advantage of an easy removal from the nitrogen
atom under mild acidic conditions.5 The asymmetric synthesis
of saturated nitrogenated heterocycles from N-(tert-
butylsulfinyl)haloimines has been accomplished through
addition of nucleophiles to the iminic carbon6 or, to a lesser
extent, via reduction of the CN bond with either boron or
aluminum hydrides.7
RESULTS AND DISCUSSION
■
Encouraged by the excellent results that we had obtained in the
synthesis of enantiomerically enriched amines through a
ruthenium-catalyzed ATH of sulfinylimines,11 we decided to
try to extend this methodology to the diastereoselective
reduction of N-(tert-butylsulfinyl)ketimines 2 bearing halogen
atoms that could later act as leaving groups in intramolecular
nucleophilic substitution processes that would lead to N-
protected saturated heterocycles 4 (Scheme 1). Since the
sulfinyl group can easily be removed,5 this sequence would
represent an interesting way of preparing nitrogenated
heterocyclic compounds.
Functionalized amines are appropriate substrates for the
preparation of nitrogenated heterocycles.1 A very useful
methodology for the stereoselective synthesis of chiral amines
is the asymmetric transfer hydrogenation (ATH) of imines.8
However, this reduction procedure has seldom been used as a
tool to prepare nitrogenated heterocycles, and to the best of
our knowledge, there are only a few examples reported so far
that consist of the reduction of other unsaturated heterocyclic
Our first goal was the synthesis of haloimines 2, for which we
needed the corresponding haloketones 1 as precursors. Chart 1
Received: July 2, 2013
Published: August 16, 2013
© 2013 American Chemical Society
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Scheme 1. Blueprint for the Preparation of Chiral, Saturated, N-Protected Heterocycles 4
a
Chart 1
Scheme 3. Synthesis of Haloimines 2 and ent-2e
shows all the haloketones that we have used, some of which
were commercially available (1a−1d, 1g, 1h, 1k, and 1m).
Chloroketones 1e, 1f, 1i, 1j, 1l, and 1n and bromoketones 1n′
and 1o′ were prepared from halogen-containing acid chlorides
5, as indicated in Scheme 2. First, the acid chlorides were
Scheme 2. Preparation of Haloketones 1e, 1f, 1i, 1j, 1l, 1n,
1n′, and 1o′
a
In parentheses is the yield of isolated product after column
chromatography (silica gel, hexane/ethyl acetate) based on the
starting haloketones 1. All isolated haloimines 2 and ent-2e were
b
≥95% pure (300 MHz 1H NMR). (S)-2-Methylpropane-2-
c
sulfinamide was used in this case. A mixture of geometrical isomers
with an estimated E/Z ratio = 86:14 was obtained in the crude
reaction mixture. The (E) isomer could be separated in pure form by
column chromatography (silica gel, hexane/ethyl acetate) in 27%
yield.
86:14 (E/Z) mixture of geometrical isomers was obtained, from
which the pure (E) isomer was isolated after column
chromatography. The (S)-haloimine ent-2e was also prepared
by the same procedure but using the (S)-enantiomer of 2-
methylpropane-2-sulfinamide. Unfortunately, all attempts to
prepare β-haloimines failed due to elimination processes that
led to α,β-unsaturated imines, together with some unreacted β-
haloketones.
Once we had obtained haloimines 2, we tried to reduce them
by employing our hydrogen transfer methodology. Haloimine
2e was chosen as a model substrate, and it was submitted to our
optimal reaction conditions for the ATH of N-(tert-
butylsulfinyl)ketimines:11c,d isopropyl alcohol as a hydrogen
source, a ruthenium catalyst prepared from [RuCl2(p-
cymene)]2 and the achiral ligand 2-amino-2-methylpropan-1-
ol, and a reaction temperature of 50 °C. Under these
conditions, the reduction of compound 2e was complete in 2
h. At this time, a 0.3 M solution of tert-BuOK in isopropyl
alcohol was added to the reaction flask and the mixture was
stirred at 50 °C for 1 h in order to attempt the one-pot
cyclization. Gratifyingly, the 1H NMR spectrum of the reaction
transformed into the corresponding Weinreb amides 6, which
reacted with several Grignard reagents to give, after hydrolysis,
the expected haloketones 1e, 1f, 1i, 1j, 1l, 1n, 1n′, and 1o′ in
61−93% overall yields. The starting acid chlorides were
commercially available, except for the one bearing a bromine
atom, which was prepared by treatment of the corresponding
carboxylic acid with thionyl chloride.
Having all the haloketones 1 in hand, the required
haloimines 2 were prepared by condensation of those
haloketones with (R)-2-methylpropane-2-sulfinamide in the
presence of titanium tetraethoxide under neat conditions
(Scheme 3), following our reported procedure.13 Thereby,
the expected enantiomerically pure (R)-N-(tert-butylsulfinyl)-
haloimines 2 were isolated in good yields after column
chromatography. In the case of the aliphatic imine 2m, an
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Scheme 4. One-Pot ATH−Cyclization Sequence for the Synthesis of N-Protected Aziridines 4a−4c and Pyrrolidines 4d−4j and
a
ent-4e
a
In parentheses is the yield of isolated product after column chromatography (based on the starting haloimine 2 or ent-2e) and diastereomeric ratio
(estimated from the 1H NMR spectrum of the crude reaction mixture). All isolated compounds 4 and ent-4e were ≥95% pure (300 MHz 1H NMR).
b
c
[RuCl2(p-cymene)]2 (5 mol %), 2-amino-2-methylpropan-1-ol (10 mol %), and tert-BuOK (25 mol %) were used in this reaction. (S)-
Chloroimine ent-2e was used as substrate in this reaction.
1
crude showed that the N-sulfinylpyrrolidine 4e (Scheme 4) was
the major product, with an estimated diastereomeric ratio of
99:1. After column chromatography, pyrrolidine 4e was isolated
estimation by H NMR seems to be an appropriate way to
determine the diastereoselectivities of these ATH processes.
The absolute configurations of pyrrolidines 7e and ent-7e were
determined by comparison of the sign of their optical rotation
values with the ones reported in the literature.7c As was the case
in our ATH of simple ketimines, (R)-configurated haloimines 2
led to (R)-configurated nitrogenated heterocycles.
1
in 90% yield. In order to validate the dr value estimated by H
NMR, haloimine ent-2e was submitted to the same one-pot
ATH−cyclization sequence and product ent-4e was obtained
1
with dr > 99:1 (according to the H NMR spectrum of the
reaction crude) and in 91% yield. Desulfinylation of both 4e
and ent-4e by treatment with a solution of HCl in MeOH led to
the corresponding free pyrrolidines 7e and ent-7e (Chart 2) in
Next, we studied the reaction scope by applying our one-pot
ATH−cyclization sequence to haloimines 2d−2j (Scheme 4)
with the aim of preparing some other substituted pyrrolidines.
N-Protected pyrrolidines bearing phenyl substituents with
either electron-releasing (4f) or electron-withdrawing groups
(4g) could be prepared with excellent results. We were able to
get a single crystal of compound 4g and the corresponding X-
ray structure confirmed that the stereogenic center generated in
the ATH process had the (R) absolute configuration (see
Figure 1).
Chart 2
Other pyrrolidines with aromatic substituents different from
phenyl, such as 2-naphthyl (4h) or 2-thienyl (4i), could be
prepared with equal efficiency. According to our previous
observations,11d,12 the catalyst loading for the reduction of the
aliphatic imine 2j had to be increased to ensure full conversion
of the starting material,14 but it is worth noting that the
expected aliphatic pyrrolidine 4j was obtained in 90% yield with
a 98:2 dr.
almost quantitative yields, which were then benzoylated and
analyzed by HPLC, giving ee values of 98% (for benzoylated
7e) and 99% (for benzoylated ent-7e) (see the Supporting
Information for details). These enantiomeric excesses match
very well with the diastereomeric ratios previously estimated by
1H NMR for compounds 4e and ent-4e. Therefore, the
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a higher catalyst loading was necessary to achieve complete
reduction of the aliphatic imine 2c.14
These promising results encouraged us to try to extend this
one-pot ATH−cyclization protocol to the synthesis of
piperidines and azepanes from the corresponding δ- and ε-
haloimines, respectively. However, the cyclization did not take
place under those reaction conditions: when we used δ-
chloroimine 2k as substrate, the corresponding chlorosulfina-
mide 3k was obtained instead of the expected piperidine.15
Fortunately, a two-step procedure allowed the formation of N-
protected piperidine 4k: when the ATH reaction was finished,
the usual workup was performed11c,d and the crude residue was
dissolved in THF, KHMDS was added at 0 °C, and the mixture
was stirred at the same temperature for 1 h. Under these
conditions, a highly optically enriched piperidine 4k was
isolated in 91% overall yield (Scheme 5). The same two-step
methodology applied to imine 2l yielded compound 4l with the
same good results concerning both yield and diastereoselectiv-
ity. It is worth noting that the protected aliphatic piperidine 4m
could also be obtained with a 97:3 dr using the same amount of
catalyst as for the reduction of the other aliphatic imines 2c and
2j.16
Figure 1. X-ray structure of compound 4g (for an ORTEP plot and
detailed crystallographic information, see the Supporting Information).
This one-pot ATH−cyclization routine was also applied to α-
chloroimines 2a−2c in order to try to synthesize the
corresponding chiral aziridines (Scheme 4). We were glad to
see that N-protected three-membered ring heterocycles with
either aromatic (4a and 4b) or aliphatic substituents (4c) could
be obtained in high yields and diastereomeric ratios. As before,
a
Scheme 5. ATH Followed by Treatment with KHMDS for the Synthesis of Piperidines 4k−4m and Azepanes 4n and 4o
a
In parentheses is the yield of isolated product after column chromatography (based on the starting haloimine 2) and diastereomeric ratio
b
1
1
(estimated from the H NMR spectrum of the crude reaction mixture). All isolated compounds 4 were ≥95% pure (300 MHz H NMR). The
ATH crude product was dissolved in anhydrous THF, KHMDS (1.3 equiv, 1 M solution in THF) was added at 0 °C, and the reaction mixture was
stirred at the same temperature for 1 h. [RuCl2(p-cymene)]2 (5 mol %), 2-amino-2-methylpropan-1-ol (10 mol %), and tert-BuOK (25 mol %) were
used in this reaction. The ATH crude product was dissolved in anhydrous THF, KHMDS (1.3 equiv, 1 M solution in THF) was added at 0 °C, and
c
d
the reaction mixture was stirred, allowing it to reach room temperature and then stirring overnight.
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The two-step procedure did not work for the preparation of
seven-membered ring heterocycles from ε-chloroimine 2n.
Treatment of chlorosulfinamide 3n with KHMDS failed to
form the cyclization product, even at higher temperatures and
increasing the amount of base. Fortunately, this problem could
be solved by starting from imines 2n′ and 2o′, both having a
bromine atom as a leaving group instead of a chlorine.
Treatment of bromine-containing sulfinamides 3n′ and 3o′
with KHMDS overnight at room temperature led to the
corresponding azepanes 4n and 4o in high yields and with
excellent diastereoselectivities (Scheme 5). We were able to get
an X-ray structure of compound 4n, which confirmed that the
stereogenic center generated in the ATH process had the (R)
absolute configuration (Figure 2). To the best of our
knowledge, the synthesis of azepanes through ATH processes
had never been reported so far.
aliphatic substituents can be prepared in very high yields and
optical purities. The absolute configuration of the final product
can be tuned up simply by choosing the adequate configuration
on the sulfinyl chiral auxiliary.
EXPERIMENTAL SECTION
■
General Information. All glassware was dried in an oven at 100
°C and cooled to room temperature under argon before use. All
reactions were carried out under an argon atmosphere. Haloketones
1a−1d, 1g, 1h, 1k, and 1m; (R)- and (S)-tert-BuSONH2; Ti(OEt)4
(33% TiO2 min); [RuCl2(p-cymene)]2; 2-amino-2-methylpropan-1-ol;
and all the starting materials needed for the synthesis of haloketones
1e, 1f, 1i, 1j, 1l, 1n, 1n′, and 1o′ were commercially available and were
used as received. tert-BuOK was heated in a Kugel-Rohr distillation
apparatus at 170−180 °C under vacuum for 4 h before use.
Commercially available 4 Å molecular sieves were dried in a Kugel-
Rohr distillation apparatus at 120 °C under vacuum for 5 h before use.
Commercially available anhydrous isopropyl alcohol was used as
solvent in all the transfer hydrogenation reactions. Column
chromatography was performed with silica gel 60 of 230−400 mesh.
Thin layer chromatography (TLC) was performed on precoated silica
gel plates; detection was done by UV254 light and staining with
phosphomolybdic acid (solution of 1 g of phosphomolybdic acid in 24
mL of absolute ethanol); Rf values are given under these conditions.
Melting points (mp) are uncorrected. Unless otherwise stated, NMR
samples were prepared using CDCl3 as solvent. The internal references
1
used for NMR spectra were tetramethylsilane (TMS) for H NMR
and CDCl3 for 13C NMR; chemical shifts are given in δ (ppm) and
coupling constants (J) in hertz. 13C NMR assignments were made on
the basis of DEPT experiments. Infrared (FT-IR) spectra were
obtained on a spectrophotometer equipped with an attenuated total
reflectance (ATR) accessory. Mass spectra (EI) were obtained at 70
eV; fragment ions in m/z with relative intensities (%) in parentheses
are given. HRMS were measured with electron impact (EI) ionization
at 70 eV and a double-focusing mass analyzer (magnetic and electric
fields). Optical rotation measurements and HPLC analyses were
performed at 20 °C.
Preparation of Weinreb Amides 6. General Procedure. A 2 M
NaOH aqueous solution (15 mL) was added to a suspension of
Me(MeO)NH·HCl (926 mg, 9.5 mmol) in CH2Cl2 (15 mL) at 0 °C.
Then, the corresponding acid chloride (10.0 mmol) was added
dropwise during ca. 1 min, and the reaction mixture was allowed to
reach room temperature and was stirred overnight. The reaction
mixture was extracted with CH2Cl2 (2 × 5 mL), and the combined
organic layers were washed with a 2 M NaOH aqueous solution (10
mL) and dried (Na2SO4). After filtration and evaporation of the
solvents, the expected Weinreb amides were obtained, which were
used in the next step without purification.
Figure 2. X-ray structure of compound 4n (for an ORTEP plot and
detailed crystallographic information, see the Supporting Information).
In our opinion, the methodology described herein represents
a very efficient route to prepare saturated nitrogenated
heterocycles from halogen-containing N-(tert-butylsulfinyl)-
ketimines and presents some advantages in comparison with
the few procedures found in the literature that allow a similar
transformation:7 (a) we use a catalytic ATH method to reduce
the imine function, while the reported procedures employ
stoichiometric reagents such as boron or aluminum hydrides
which could lead to the formation of side products; (b) the
achiral ligand that we use in the ruthenium catalyst is very
cheap, thus reducing the reaction costs; (c) isopropyl alcohol,
which acts as a solvent and as a hydrogen source in our ATH
reaction, is environmentally friendly and is a convenient solvent
for industrial-scale processes;17 and (d) our methodology is
more versatile, since we have been able to prepare nitrogenated
heterocycles with a variety of ring sizes.
For the preparation of bromoketones 1n′ and 1o′, 6-bromohex-
anoyl chloride was required, which was prepared by refluxing a mixture
of 6-bromohexanoic acid (2.34 g, 12.0 mmol) and SOCl2 (60.0 mmol)
in CH2Cl2 (20 mL) for 5 h. Solvent and the excess of SOCl2 were
evaporated and the residue was used directly for the synthesis of the
corresponding Weinreb amide.
Addition of Grignard Reagents to Weinreb Amides 6.
Synthesis of Haloketones 1e, 1f, 1i, 1j, 1l, 1n, 1n′, and 1o′.
General Procedure. A solution of the Grignard reagent18 (16.0
mmol) was added dropwise over a period of 40 min with the aid of a
syringe pump to a solution of the corresponding Weinreb amide (8.0
mmol) in anhydrous Et2O (30 mL) at −40 °C with vigorous stirring,
and the mixture was stirred at the same temperature for 1 h. The
temperature slowly rose to room temperature (by switching the
cryostat off and keeping the reaction flask inside the cooling bath), and
the reaction was stirred overnight. Then, a saturated aqueous NH4Cl
solution (25 mL) was carefully added (in small portions and cooling
the flask at 0 °C) and the mixture was extracted with Et2O (3 × 15
mL). The combined organic layers were dried (Na2SO4). After
filtration and evaporation of the solvent, the resulting residue was
purified by column chromatography (silica gel, hexane/ethyl acetate),
CONCLUSION
■
We have presented herein a simple, versatile, and very effective
procedure for the synthesis of highly optically enriched N-
protected aziridines, pyrrolidines, piperidines, and azepanes by
applying our ATH protocol to the diastereoselective reduction
of N-(tert-butylsulfinyl)haloimines. A one-pot ATH−cyclization
sequence enables the preparation of both aziridines and
pyrrolidines, while piperidines and azepanes become accessible
through a two-step protocol. The free saturated nitrogenated
heterocycles can be easily obtained by removal of the sulfinyl
group from the nitrogen atom under mild acidic conditions.
Nitrogenated heterocycles bearing aromatic, heteroaromatic, or
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giving the expected haloketones 1e (1.416 g, 90%), 1f (1.565 g, 92%),
1i (1.328 g, 88%), 1j (0.725 g, 61%), 1l (1.466 g, 87%), 1n (1.568 g,
93%), 1n′ (1.837 g, 90%), and 1o′ (1.939 g, 85%). Compounds 1e,19
1f,18 1i,20 1j,21 1n,22 and 1n′23 were identified by comparison of their
physical and spectroscopic data with the ones reported in the
literature. The corresponding physical, spectroscopic, and analytical
data for haloketones 1l and 1o′ follow.
Hz), 7.93, 8.02 (1H each, 2 d, J = 7.6 Hz each), 8.33 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 22.7, 29.9, 31.8, 44.8, 57.9, 124.0, 126.7,
127.6, 128.0, 128.2, 128.4, 129.3, 132.7, 134.7, 134.8, 177.8; m/z
(DIP) 335 (M+, <1), 281 (17), 279 (46), 196 (13), 169 (100), 154
(23), 153 (21), 127 (23), 57 (15); HRMS M+ found 335.1122,
C18H22ClNOS requires 335.1111.
(R)-N-(6-Chloro-2-methyl-3-hexyliden)-2-methylpropane-2-sulfi-
namide (2j). Yellow oil; Rf 0.35 (hexane/ethyl acetate 85/15); [α]D20
5-Chloro-1-(3-methylphenyl)pentan-1-one (1l). Colorless oil; Rf
0.56 (hexane/ethyl acetate 9/1); IR (neat) 3058, 1683 cm−1; 1H NMR
(300 MHz, CDCl3) δ 1.77−2.00 (4H, m), 2.41 (3H, s), 3.00 (2H, t, J
= 7.0 Hz), 3.58 (2H, t, J = 6.3 Hz), 7.29−7.41 (2H, m), 7.67−7.79
(2H, m); 13C NMR (75 MHz, CDCl3) δ 21.3, 21.5, 32.0, 37.5, 44.7,
125.2, 128.4, 128.5, 133.8, 136.8, 138.4, 199.8; m/z 212 (M+ + 2, 2),
210 (M+, 7), 134 (25), 119 (100), 91 (29); HRMS M+ found
210.0817, C12H15ClO requires 210.0811.
1
−120.5 (c 1.8, CH2Cl2); IR (neat) 1620, 1069 cm−1; H NMR (300
MHz, CDCl3) δ 1.14 (6H, d, J = 6.8 Hz), 1.24 (9H, s), 2.04−2.14
(2H, m), 2.45−3.05 (3H, m), 3.59 (2H, t, J = 6.1 Hz); 13C NMR (75
MHz, CDCl3) δ 20.1, 20.2, 22.3, 30.6, 32.4, 39.5, 44.5, 56.9, 190.0; m/
z (DIP) 251 (M+, <1), 197 (35), 195 (100), 161 (21), 110 (43), 57
(71); HRMS M+ found 251.1118, C11H22ClNOS requires 251.1111.
(R)-N-[5-Chloro-1-(3-methylphenyl)pentyliden]-2-methylpro-
pane-2-sulfinamide (2l). Yellow oil; Rf 0.31 (hexane/ethyl acetate 4/
1); [α]2D0 −18.5 (c 1.9, CH2Cl2); IR (neat) 3055, 1573, 1070 cm−1; 1H
NMR (400 MHz, CDCl3) δ 1.33 (9H, s), 1.76−1.97 (4H, m), 2.40
(3H, s), 3.07−3.41 (2H, m), 3.58−3.73 (2H, m), 7.29−7.38, 7.54−
7.73 (2H each, 2 m); 13C NMR (100 MHz, CDCl3) δ 21.5, 22.7, 25.9,
31.4, 32.2, 44.3, 57.6, 124.5, 127.9, 128.5, 132.3, 137.4, 138.3, 179.3;
m/z (DIP) 313 (M+, <1), 259 (36), 257 (100), 240 (21), 174 (23),
146 (37), 118 (26), 57 (23); HRMS M+ found 313.1278,
C16H24ClNOS requires 313.1267.
6-Bromo-1-(3-methoxyphenyl)hexan-1-one (1o′). White solid;
mp 52 °C; Rf 0.50 (hexane/ethyl acetate 9/1); IR (neat) 3054,
1
1683, 1255 cm−1; H NMR (300 MHz, CDCl3) δ 1.47−1.63, 1.73−
1.83, 1.88−1.97 (2H each, 3 m), 2.99 (2H, t, J = 7.3 Hz), 3.44 (2H, t, J
= 6.8 Hz), 3.86 (3H, s), 7.11 (1H, ddd, J = 8.1, 2.7, 0.9 Hz), 7.38 (1H,
t, J = 8.1 Hz), 7.49 (1H, dd, J = 2.7, 1.5 Hz), 7.54 (1H, m); 13C NMR
(75 MHz, CDCl3) δ 23.3, 27.8, 32.6, 33.6, 38.4, 55.4, 112.2, 119.4,
120.6, 129.5, 138.3, 159.8, 199.8; m/z 286 (M+ + 2, 9), 284 (M+, 9),
205 (48), 176 (100), 107 (26); HRMS M+ found 284.0415,
C13H17BrO2 requires 284.0412.
(R,E)-N-(6-Chloro-2-hexyliden)-2-methylpropane-2-sulfinamide
(2m).24 Yellowish oil; Rf 0.61 (hexane/ethyl acetate 1/1); [α]D20
Synthesis of Haloimines 2 and ent-2e. General Procedure.
N-(tert-Butylsulfinyl)haloimines were prepared by condensation of the
corresponding haloketones 1 with (R)-2-methylpropane-2-sulfinamide
(for 2) or (S)-2-methylpropane-2-sulfinamide (for ent-2e) following
our recently reported procedure13 as follows: a mixture of haloketone
1 (5.0 mmol), (R)- or (S)-tert-BuSONH2 (612 mg, 5.0 mmol), and
Ti(OEt)4 (2.1 mL, 10.0 mmol) was stirred overnight under argon at
72 °C (oil bath temperature). After cooling to room temperature, the
mixture was diluted with ethyl acetate (10 mL) and poured into brine
(3 mL) with rapid stirring. The resulting suspension was filtered
through a plug of Celite and the filter cake was washed with ethyl
acetate. After evaporation of the solvent, the resulting residue was
purified by column chromatography (silica gel, hexane/ethyl acetate),
giving the expected haloimines 2a (1.005 g, 78%), 2b (1.096 g, 75%),
2c (0.761 g, 64%), 2d (1.229 g, 86%), 2e (1.379 g, 92%), ent-2e (1.319
g, 88%), 2f (1.437 g, 91%), 2g (1.291 g, 85%), 2h (1.411 g, 84%), 2i
(1.124 g, 77%), 2j (0.856 g, 68%), 2k (1.319 g, 88%), 2l (1.460 g,
93%), 2m (0.321 g, 27%), 2n (1.365 g, 87%), 2n′ (1.362 g, 76%), and
2o′ (1.631 g, 84%). Compounds 2a,11b 2d,7d 2e,7c ent-2e,7c 2f,7d 2g,7d
2i,7d 2k,7d and 2n7d were identified by comparison of their physical
and spectroscopic data with the ones reported in the literature. The
corresponding physical, spectroscopic, and analytical data for
haloimines 2b, 2c, 2h, 2j, 2l, 2m, 2n′ and 2o′ follow.
1
−145.0 (c 1.3, CH2Cl2); IR (neat) 1622, 1070 cm−1; H NMR (300
MHz, CDCl3) δ 1.24 (9H, s), 1.67−1.88 (4H, m), 2.33 (3H, s), 2.37−
2.52 (2H, m), 3.55 (2H, t, J = 6.1 Hz); 13C NMR (75 MHz, CDCl3) δ
22.1, 22.5, 23.0, 31.7, 42.2, 44.6, 56.2, 184.6; m/z (DIP) 237 (M+, <1),
183 (31), 181 (100), 147 (11), 57 (48).
(R)-N-(6-Bromo-1-phenylhexyliden)-2-methylpropane-2-sulfina-
mide (2n′). Yellow oil; Rf 0.43 (hexane/ethyl acetate 4/1); [α]D20
1
−20.0 (c 1.2, CH2Cl2); IR (neat) 3056, 1590, 1070 cm−1; H NMR
(300 MHz, CDCl3) δ 1.33 (9H, s), 1.52−1.75 (4H, m), 1.85−1.94
(2H, m), 3.09−3.33 (2H, m), 3.40 (2H, t, J = 6.7 Hz), 7.38−7.52 (3H,
m), 7.84 (2H, d, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 22.7,
27.8, 28.3, 32.15, 32.2, 33.6, 57.6, 127.4, 128.6, 131.5, 137.7, 179.5; m/
z (DIP) 357 (M+, <1), 303 (100), 301 (98), 252 (10), 174 (28), 167
(19), 132 (30), 119 (25), 104 (34), 103 (24), 77 (14), 57 (32);
HRMS M+ found 357.0777, C16H24BrNOS requires 357.0762.
(R)-N-[6-Bromo-1-(3-methoxyphenyl)hexyliden]-2-methylpro-
pane-2-sulfinamide (2o′). Yellow oil; Rf 0.35 (hexane/ethyl acetate 4/
1); [α]2D0 −2.0 (c 1.6, CH2Cl2); IR (neat) 3075, 1604, 1572, 1073
cm−1; 1H NMR (400 MHz, CDCl3) δ 1.33 (9H, s), 1.51−1.62, 1.64−
1.76, 1.84−1.94 (2H each, 3 m), 3.06−3.34 (2H, m), 3.40 (2H, t, J =
6.7 Hz), 3.84 (3H, s), 7.03 (1H, d, J = 7.5 Hz), 7.35 (1H, t, J = 8.1
Hz), 7.37−7.51 (2H, m); 13C NMR (100 MHz, CDCl3) δ 22.6, 27.8,
28.2, 32.1, 32.2, 33.5, 55.3, 57.6, 112.8, 117.0, 119.7, 129.5, 139.1,
159.6, 179.2; m/z (DIP) 387 (M+, <1), 333 (56), 331 (55), 316 (25),
314 (24), 149 (100), 134 (20), 57 (22); HRMS M+ found 387.0870,
C17H26BrNO2S requires 387.0868.
(R)-N-[2-Chloro-1-(4-chlorophenyl)ethyliden]-2-methylpropane-
2-sulfinamide (2b). Yellow oil; Rf 0.69 (hexane/ethyl acetate 2/1);
1
[α]2D0 −20.0 (c 1.2, CH2Cl2); IR (neat) 3070, 1576, 1070 cm−1; H
NMR (400 MHz, CDCl3) δ 1.36 (9H, s), 5.00, 5.14 (1H each, 2 d, J =
11.0 Hz each), 7.43, 7.81 (2H each, 2 d, J = 8.6 Hz each); 13C NMR
(100 MHz, CDCl3) δ 23.2, 35.2, 59.8, 128.8, 129.0, 134.3, 138.3,
168.2; m/z (DIP) 291 (M+, <1), 237 (32), 235 (47), 201 (20), 199
(56), 151 (14), 138 (27), 137 (20), 57 (100); HRMS M+ − C4H8
found 234.9638, C8H7Cl2NOS requires 234.9625.
One-Pot ATH−Cyclization Sequence. Synthesis of Aziridines
4a−4c and Pyrrolidines 4d−4j and ent-4e. General Procedure.
A mixture of [RuCl2(p-cymene)]2 (14 mg, 0.023 mmol), 2-amino-2-
methylpropan-1-ol (4 mg, 0.045 mmol), 4 Å molecular sieves (0.3 g),
and anhydrous i-PrOH (1.5 mL) under argon was heated up to 90 °C
(oil bath temperature) for 20 min {for aliphatic haloimines 2c and 2j,
[RuCl2(p-cymene)]2 (28 mg, 0.045 mmol) and 2-amino-2-methyl-
propan-1-ol (8 mg, 0.090 mmol) were used}. During this heating
period, the initially orange reaction mixture turned into a dark red
color. The reaction was then cooled to 50 °C, and a solution of the
haloimine 2a−2j or ent-2e (0.9 mmol) in i-PrOH (6.3 mL) and tert-
BuOK (1.13 mL of a 0.1 M solution in i-PrOH, 0.113 mmol) were
successively added [for aliphatic haloimines 2c and 2j, tert-BuOK (2.25
mL of a 0.1 M solution in i-PrOH, 0.225 mmol) was used]. After
completion of the ATH reaction (generally 2 h, monitored by TLC),
tert-BuOK (3.9 mL of a 0.3 M solution in i-PrOH, 1.17 mmol) was
added to the reaction mixture and it was stirred for 1 h at 50 °C. Then,
the reaction mixture was passed through a small column of silica gel,
(R)-N-[1-Chloro-3,3-dimethyl-2-butyliden]-2-methylpropane-2-
sulfinamide (2c). Yellow oil; Rf 0.54 (hexane/ethyl acetate 4/1); [α]D20
1
−426.0 (c 1.2, CH2Cl2); IR (neat) 3068, 1601, 1076 cm−1; H NMR
(300 MHz, CDCl3) δ 1.23 (9H, s), 1.29 (9H, s), 4.25, 4.92 (1H each,
2 d, J = 10.5 Hz each); 13C NMR (75 MHz, CDCl3) δ 22.7, 27.6, 34.3,
43.1, 58.0, 182.8; m/z (DIP) 237 (M+, <1), 183 (15), 181 (38), 120
(17), 118 (53), 83 (41), 57 (100); HRMS M+ found 237.0970,
C10H20ClNOS requires 237.0954.
(R)-N-[4-Chloro-1-(2-naphthyl)butyliden]-2-methylpropane-2-
sulfinamide (2h). Yellow oil; Rf 0.41 (hexane/ethyl acetate 4/1); [α]D20
1
+31.0 (c 1.7, CH2Cl2); IR (neat) 3058, 1588, 1065 cm−1; H NMR
(400 MHz, CDCl3) δ 1.37 (9H, s), 2.14−2.32 (2H, m), 3.32−3.63
(2H, m), 3.66−3.71 (2H, m), 7.51−7.60 (2H, m), 7.86 (2H, d, J = 8.6
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the column was washed with ethyl acetate, the combined organic
phases were evaporated, and the resulting residue was purified by
column chromatography (silica gel, hexane/ethyl acetate), giving the
expected N-protected aziridines 4a−4c and pyrrolidines 4d−4j and
ent-4e with the diastereomeric ratios indicated in Scheme 4 and in the
following yields: 4a (0.185 g, 92%), 4b (0.200 g, 86%), 4c (0.148 g,
81%), 4d (0.190 g, 84%), 4e (0.215 g, 90%), ent-4e (0.217 g, 91%), 4f
(0.233 g, 92%), 4g (0.216 g, 89%), 4h (0.231 g, 85%), 4i (0.199 g,
86%), and 4j (0.176 g, 90%). Compounds 4a,7a 4b,7a 4c,6c 4d,7d 4e,6f
ent-4e,6f 4f,7d 4g,7d and 4i7d were identified by comparison of their
physical and spectroscopic data with the ones reported in the
literature. The corresponding physical, spectroscopic, and analytical
data for compounds 4h and 4j follow.
giving halosulfinamide 3k−3m, 3n′, or 3o′, which was submitted to
the cyclization step without further purification.
KHMDS (1.17 mL of a 1 M solution in THF, 1.17 mmol) was
added to a solution of the halosulfinamide 3k−3m, 3n′, or 3o′ (0.9
mmol) in anhydrous THF (4 mL) at 0 °C. For the synthesis of
piperidines 4k−4m, the reaction was then stirred for 1 h at 0 °C. For
the preparation of azepanes 4n and 4o, the cooling bath was removed
and the reaction mixture was stirred overnight at room temperature.
After completion of the cyclization step, Et2O (10 mL) and a saturated
aqueous NH4Cl solution (5 mL) were added. The mixture was
extracted with Et2O (3 × 5 mL), and the combined organic layers were
dried (Na2SO4). After filtration and evaporation of the solvent, the
resulting residue was purified by column chromatography (silica gel,
hexane/ethyl acetate), giving the expected N-protected heterocycles
4k−4o with the diastereomeric ratios indicated in Scheme 5 and in the
following yields: 4k (0.217 g, 91%), 4l (0.224 g, 89%), 4m (0.159 g,
87%), 4n (0.181 g, 72%), and 4o (0.195 g, 70%). Compound 4k7d was
identified by comparison of its physical and spectroscopic data with
the ones reported in the literature. The corresponding physical,
spectroscopic, and analytical data for compounds 4l−4o follow.
(RS,R)-N-(tert-Butylsulfinyl)-2-(3-methylphenyl)piperidine (4l).
Colorless oil; Rf 0.51 (hexane/ethyl acetate 7/3); [α]2D0 +111.0 (c
(RS,R)-N-(tert-Butylsulfinyl)-2-(2-naphthyl)pyrrolidine (4h). White
solid; mp 118 °C; Rf 0.32 (hexane/ethyl acetate 2/1); [α]2D0 +237.0 (c
1
1.5, MeOH, 98:2 dr); IR (neat) 3056, 1095, 1058 cm−1; H NMR
(400 MHz, CDCl3) δ 1.05 (9H, s), 1.77−1.96 (3H, m), 2.14−2.28
(1H, m), 3.62 (1H, dt, J = 10.7, 6.9 Hz), 3.70−3.82 (1H, m), 5.23
(1H, dd, J = 8.2, 2.1 Hz), 7.37 (1H, dd, J = 8.5, 1.6 Hz), 7.40−7.50
(2H, m), 7.69 (1H, s), 7.73−7.86 (3H, m); 13C NMR (100 MHz,
CDCl3) δ 23.0, 24.2, 36.4, 55.1, 57.4, 57.5, 124.8, 125.0, 125.5, 126.1,
127.6, 127.7, 128.2, 132.3, 133.2, 142.0; m/z (DIP) 301 (M+, <1), 245
(34), 197 (16), 160 (18), 57 (100); HRMS M+ found 301.1507,
C18H23NOS requires 301.1500.
1
1.2, MeOH, 99:1 dr); IR (neat) 3045, 1455, 1073 cm−1; H NMR
(400 MHz, CDCl3) δ 1.16 (9H, s), 1.39−1.52 (1H, m), 1.54−1.72
(3H, m), 1.97−2.08, 2.15−2.24 (1H each, 2 m), 2.37 (3H, s), 3.29
(2H, m), 4.63 (1H, t, J = 4.2 Hz), 7.06 (1H, d, J = 6.7 Hz), 7.19−7.28
(3H, m); 13C NMR (100 MHz, CDCl3) δ 20.4, 21.7, 23.0, 25.6, 31.2,
44.1, 57.3, 58.7, 124.4, 127.4, 128.1, 128.4, 138.1, 140.1; m/z (DIP)
279 (M+, 7), 223 (100), 175 (21), 91 (12), 57 (49); HRMS M+ found
279.1660, C16H25NOS requires 279.1657.
(RS,R)-N-(tert-Butylsulfinyl)-2-methylpiperidine (4m). Yellowish
oil; Rf 0.53 (hexane/ethyl acetate 3/2); [α]2D0 −36.0 (c 1.0, MeOH,
97:3 dr); IR (neat) 2971, 2932, 1455, 1360, 1073 cm−1; 1H NMR (300
MHz, CDCl3) δ 1.17 (9H, s), 1.24 (3H, d, J = 6.5 Hz), 1.42−1.81
(6H, m), 2.77−2.92 (1H, m), 3.20−3.40 (2H, m); 13C NMR (75
MHz, CDCl3) δ 19.6, 22.0, 23.4, 26.0, 34.0, 42.3, 55.0, 57.6; m/z
(DIP) 203 (M+, <1), 147 (59), 98 (11), 57 (100); HRMS M+ found
203.1339, C10H21NOS requires 203.1344.
(RS,R)-N-(tert-Butylsulfinyl)-2-phenylazepane (4n). White solid;
mp 64 °C; Rf 0.65 (hexane/ethyl acetate 4/1); [α]2D0 +271.0 (c 1.7,
CH2Cl2, > 99:1 dr); IR (neat) 3062, 1448, 1059 cm−1; 1H NMR (400
MHz, CDCl3) δ 1.02 (9H, s), 1.20−1.34, 1.58−1.67, 1.70−1.96, 2.17−
2.31 (1H, 1H, 5H, and 1H, respectively, 4 m), 3.40−3.48 (1H, m),
3.56 (1H, d, J = 15.2 Hz), 4.68 (1H, dd, J = 10.8, 5.7 Hz), 7.18−7.35
(5H, m); 13C NMR (100 MHz, CDCl3) δ 23.1, 25.3, 29.6, 30.1, 38.9,
48.0, 56.7, 57.8, 126.3, 126.4, 128.4, 145.4; m/z (DIP) 279 (M+, <1),
223 (100), 175 (45), 117 (22), 91 (80), 57 (21); HRMS M+ − C4H8
found 223.1022, C12H17NOS requires 223.1031. See the Supporting
Information for X-ray structure details.
(RS,R)-N-(tert-Butylsulfinyl)-2-isopropylpyrrolidine (4j). Colorless
oil; Rf 0.46 (hexane/ethyl acetate 7/3); [α]2D0 +19.5 (c 0.9, MeOH,
1
98:2 dr); IR (neat) 2957, 1470, 1069 cm−1; H NMR (400 MHz,
CDCl3) δ 0.89, 0.92 (3H each, 2 d, J = 6.9 Hz each), 1.20 (9H, s),
1.59−1.81 (4H, m), 2.04−2.16 (1H, m), 3.17−3.26, 3.32−3.41 (1H
each, 2 m), 3.57−3.67 (1H, m); 13C NMR (100 MHz, CDCl3) δ 16.6,
20.1, 23.4, 25.4, 26.1, 31.0, 50.5, 57.6, 62.7; m/z (DIP) 217 (M+, <1),
161 (72), 113 (14), 57 (100); HRMS M+ found 217.1509,
C11H23NOS requires 217.1500.
Removal of the Sulfinyl Group. Isolation of Pyrrolidines 7e
and ent-7e. General Procedure. Product 4e or ent-4e (133 mg, 0.5
mmol) was dissolved in a 2 M solution of HCl in methanol (7 mL;
prepared by dropwise addition of SOCl2 to methanol at 0 °C) and
stirred overnight at room temperature. Then, the solvent was
evaporated, a 2 M aqueous HCl solution (10 mL) was added, and
the mixture was extracted with ethyl acetate (3 × 10 mL). The organic
layers were discarded. The aqueous layer was basified with a buffer
solution of NH3 (2 M)/NH4Cl (2 M) (10 mL) and a 2 M aqueous
NaOH solution to ensure pH >11. The mixture was extracted with
CH2Cl2 (3 × 10 mL). The combined organic phases were dried
(Na2SO4). After filtration and evaporation of the solvent, the pure
pyrrolidine 7e (78 mg, 97%) or ent-7e (80 mg, 99%) was obtained.
Compounds 7e and ent-7e were identified by comparison of their
physical and spectroscopic data with the ones reported in the
literature.7c
(RS,R)-N-(tert-Butylsulfinyl)-2-(3-methoxyphenyl)azepane (4o).
Yellowish solid; mp 80−81 °C; Rf 0.73 (hexane/ethyl acetate 7/3);
[α]2D0 +209.0 (c 0.6, CH2Cl2, 98:2 dr); IR (neat) 3030, 1579, 1278,
Benzoylation of Pyrrolidines 7e and ent-7e. Determination
of the Enantiomeric Excess of Compounds 7e and ent-7e. A
solution of 7e or ent-7e (24 mg, 0.2 mmol) in CH2Cl2 (5 mL) was
cooled to 0 °C. An aqueous 2 M NaOH solution (5 mL) was added,
followed by benzoyl chloride (46 μL, 0.4 mmol), and the resulting
mixture was stirred for 4 h at room temperature. The organic layer was
separated, washed with an aqueous 2 M NaOH solution (2 × 5 mL),
and dried (Na2SO4). Filtration and evaporation of the solvent afforded
the corresponding benzamide (52 mg, 98%), which was analyzed by
HPLC on a ChiralCel OD-H column using a 254 nm UV detector,
10% i-PrOH in hexane as eluent, and a flow rate of 0.5 mL/min. The
retention times of the two enantiomers were 25.6 min (S) and 29.5
min (R) (see the Supporting Information for details).
Two-Step Procedure ATH + Cyclization. Synthesis of
Piperidines 4k−4m and Azepanes 4n and 4o. General
Procedure. Haloimine 2k−2m, 2n′, or 2o′ was reduced by the
same ATH procedure used for the preparation of aziridines and
pyrrolidines (see above). After completion of the ATH process
(generally 2 h, monitored by TLC), the reaction mixture was directly
passed through a small column of silica gel, the column was washed
with ethyl acetate, and the combined organic phases were evaporated,
1
1063 cm−1; H NMR (400 MHz, CDCl3) δ 1.03 (9H, s), 1.17−1.34,
1.57−1.95, 2.19−2.31 (1H, 6H and 1H, respectively, 3 m), 3.34−3.49
(1H, m), 3.56 (1H, d, J = 15.3 Hz), 3.80 (3H, s), 4.66 (1H, dd, J =
10.9, 5.7 Hz), 6.74 (1H, dd, J = 8.2, 2.3 Hz) 6.78−6.88 (2H, m), 7.23
(1H, t, J = 7.9 Hz); 13C NMR (100 MHz, CDCl3) δ 23.1, 25.2, 29.7,
30.0, 38.8, 48.1, 55.1, 56.5, 57.8, 111.3, 112.3, 118.7, 129.5, 147.1,
159.6; m/z (DIP) 309 (M+, <1), 253 (100), 205 (39), 57 (43); HRMS
M+ − C4H8 found 253.1132, C13H19NO2S requires 253.1136.
ASSOCIATED CONTENT
■
S
* Supporting Information
HPLC traces for the determination of the enantiomeric
1
excesses of pyrrolidines 7e and ent-7e; copies of H NMR
and 13C NMR spectra for haloketones 1e, 1f, 1i, 1j, 1l, 1n, 1n′,
and 1o′, haloimines 2, saturated N-protected heterocycles 4,
and free pyrrolidine 7e; crystallographic information for
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Article
Luna, A.; Chemla, F. Org. Lett. 2007, 9, 4705−4708. (f) Reddy, L. R.;
Prashad, M. Chem. Commun. 2010, 46, 222−224. (g) Louvel, J.;
compounds 4g and 4n (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
́
Botuha, C.; Chemla, F.; Demont, E.; Ferreira, F.; Perez-Luna, A. Eur. J.
Org. Chem. 2010, 2921−2926. (h) Louvel, J.; Chemla, F.; Demont, E.;
Ferreira, F.; Perez-Luna, A.; Voituriez, A. Adv. Synth. Catal. 2011, 353,
AUTHOR INFORMATION
Corresponding Author
*E-mail: dguijarro@ua.es. Fax: +34-965903549
■
́
2137−2151. (i) Cutter, A. C.; Miller, I. R.; Keily, J. F.; Bellingham, R.
K.; Light, M. E.; Brown, R. C. D. Org. Lett. 2011, 13, 3988−3991.
(j) Reddy, L. R.; Gupta, A. P.; Villhauer, E.; Liu, Y. J. Org. Chem. 2012,
77, 1095−1100. (k) Siva, S. R. N.; Srinivas, R. A.; Yadav, J. S.; Subba,
R. B. V. Tetrahedron Lett. 2012, 53, 6916−6918. (l) Senter, T. J.;
Schulte, M. L.; Konkol, L. C.; Wadzinski, T. E.; Lindsley, C. W.
Tetrahedron Lett. 2013, 54, 1645−1648. Synthesis of azepanes: (m)
See reference 6l. (n) For an example of a synthesis of an azepane from
an ε-tosyloxy imine, see the following: Brak, K.; Ellman, J. A. Org. Lett.
2010, 12, 2004−2007.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was generously supported by the Spanish Ministerio
■
de Ciencia e Innovacion
́
(MICINN; grant no. CONSOLIDER
INGENIO 2010, CSD2007-00006, CTQ2007-65218 and
CTQ2011-24151) and the Generalitat Valenciana (PROM-
ETEO/2009/039 and FEDER). O.P. thanks the Spanish
(7) Synthesis of aziridines: (a) Denolf, B.; Leemans, E.; De Kimpe,
N. J. Org. Chem. 2007, 72, 3211−3217. (b) Leemans, E.; Mangelinckx,
S.; De Kimpe, N. Synlett 2009, 1265−1268. Synthesis of pyrrolidines:
(c) Leemans, E.; Mangelinckx, S.; De Kimpe, N. Chem. Commun.
2010, 46, 3122−3124. (d) Reddy, L. R.; Das, S. G.; Liu, Y.; Prashad,
M. J. Org. Chem. 2010, 75, 2236−2246 (To the best of our knowledge,
only one example of a piperidine synthesis through reduction of an ε-
chloro-N-(tert-butylsulfinyl)ketimine with boron or aluminium
hydrides has been reported; see ref 7d).
́
Ministerio de Educacion for a predoctoral fellowship (grant
no. AP-2008-00989).
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Article
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1
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(16) The comparison of the structures of piperidines 4k−4l with 4m
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induction of the reduction step that led to the formation of the latter
has changed. However, it should be pointed out that the ATH of imine
2m followed the general reduction model established by us (see ref
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carbon atom of chlorosulfinamide 3m. The apparently different
structure of piperidine 4m is due to the fact that the chlorine atom that
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substituent of the iminic carbon (it is located on the substituent that is
trans to the sulfinyl group in 2m, whereas the substituent that bears
the chlorine atom in imines 2k and 2l is cis to the sulfinyl group).
Therefore, the cyclization step takes place in a different direction in the
case of the synthesis of 4m.
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