Regio- and stereoselective aminopentadienylation of carbonyl compounds

Article abstract of DOI:10.1021/jo402854z

A simple and robust protocol is detailed for the preparation of enantioenriched α-substituted (1,4-pentadien-3-yl)amine derivatives. The methodology involves the addition of an in situ formed pentadienyl indium reagent to chiral tert-butylsulfinimines, previously formed in the same pot. The addition takes place with excellent γ-regio- and diastereoselectivity for a wide range of carbonyl compounds, including α-unsubstituted aldehydes and methyl alkyl ketones. The catalytic hydrogenation of the sulfinamines obtained provides a convenient access to chiral α-substituted (3-pentyl)amines. The hydroboration-oxidation of the α-(1,4-pentadien-3- yl)amine derivatives, followed by a cyclization under Mitsunobu conditions, takes place with an excellent diastereoselectivity governed by the chiral sulfinyl group.

Full text of DOI:10.1021/jo402854z

Article
pubs.acs.org/joc
Regio- and Stereoselective Aminopentadienylation of Carbonyl
Compounds
Irene Bosque, Emine Bagdatli,† Francisco Foubelo, and Jose C. Gonzalez-Gomez*
́
́
Departamento de Quımica Organica, Facultad de Ciencias and Instituto de Sıntesis Organica (ISO), Universidad de Alicante, Apdo.
́
́
99, 03080 Alicante, Spain
S
* Supporting Information
ABSTRACT: A simple and robust protocol is detailed for the
preparation of enantioenriched α-substituted (1,4-pentadien-3-
yl)amine derivatives. The methodology involves the addition of
an in situ formed pentadienyl indium reagent to chiral tert-
butylsulfinimines, previously formed in the same pot. The
addition takes place with excellent γ-regio- and diastereose-
lectivity for a wide range of carbonyl compounds, including α-
unsubstituted aldehydes and methyl alkyl ketones. The catalytic hydrogenation of the sulfinamines obtained provides a
convenient access to chiral α-substituted (3-pentyl)amines. The hydroboration−oxidation of the α-(1,4-pentadien-3-yl)amine
derivatives, followed by a cyclization under Mitsunobu conditions, takes place with an excellent diastereoselectivity governed by
the chiral sulfinyl group.
situ formed 2,4-pentadienyl indium reacts smoothly with a
range of carbonyl compounds, including α,β-unsaturated
aldehydes and ketones, in DMF or aqueous media also with
excellent γ selectivity.11
INTRODUCTION
■
Pentadienylmetals can suffer from metallotropic 1,3- or 1,5-
rearrangements and upon reaction with electrophiles can give
rise to three possible regioisomers: the α, γ, and ε adducts. The
addition to aldehydes or ketones of pentadienyl reagents of
Mg,1 Be,2 Zn,3 Sn,4 Si,5 and B6 has been examined under
different conditions. The regioselectivity differs from one case
to another, but the γ adduct is the main product in most cases.
Many of the protocols examined are limited by the use of
hazardous or moisture-sensitive reagents, which complicates
their manipulation or makes these procedures poorly reliable.
Importantly, the alcohols obtained in the γ-pentadienylation of
carbonyl compounds have proven to be valuable building
blocks in the synthesis of more complex molecules.7
The development of new practical methodologies for the γ-
regioselective addition of pentadienyl metal reagents to imines
is driven by the potential of the corresponding adducts in the
construction of more complex molecules. An elegant example
was recently illustrated by the group of Martin during the
synthesis of racemic Pseudotabersonine.12 This natural product
was prepared from the adduct obtained by addition of a
pentadienyl aluminum reagent to the corresponding aromatic
imine (Scheme 2). Importantly, the same scaffold is present in
other Aspidosperma alkaloids such as Aspidospermidine and
Pandoline.
The pentadienylation of imines, using tributylpentadienyltin
and Lewis acids (i.e., InCl3) as additives, was studied by the
group of Nishigaichi.8 In their work, the authors found that N-
phenyl imines afford the ε adduct as the only regioisomer,
presumably by Lewis acid activation of the imine and
nucleophilic attack of the pentadienyltin species through an
acyclic transition state. Remarkably, with less basic N-tosyl
imines, the only regioisomer isolated was the corresponding γ
adduct. The formation of this compound was explained by
considering that, after transmetalation, the resulting pentadie-
nylindium intermediate coordinates to the iminic nitrogen and
reacts through a cyclic transition state (Scheme 1).
The indium-mediated Barbier-type reaction is superior to the
aforementioned procedures, due to its experimental simplicity
and because toxic reagents are avoided.9 In this context Araki
and co-workers examined the addition of 2,4-pentadienyl
indium derivatives, under Barbier conditions, observing the
exclusive formation of γ adducts in the addition to carbonyl
compounds.10 Soon after, the group of Fallis observed that in
At the outset of this work, we were not aware of any
stereocontrolled addition of pentadienyl indium reagent to
imine derivatives.13 In this context we decided to expand the
scope of our indium-mediated aminoallylation of aldehydes14
with chiral tert-butylsulfinamide15 by using a pentadienyl
indium reagent, generated in situ. This approach would allow
the regio- and stereoselective formation of chiral α-substituted
(1,4-pentadien-3-yl)amines, which could act as building blocks
for other interesting target molecules.
RESULTS AND DISCUSSION
■
The one-pot protocol developed in our research group for the
α-aminoallylation of aldehydes was implemented to prepare
several enantioenriched α-substituted (1,4-pentadien-3-yl)-
amines. In this case, the required pentadienyl bromide was
Received: December 23, 2013
Published: February 3, 2014
© 2014 American Chemical Society
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Scheme 1. Addition of Tributylpentadienyltin Reagent to Imines Catalyzed by InCl3
Scheme 2. Pentadienylation of Imines in the Construction of Natural Product Scaffolds
e
prepared by reaction of commercially available penta-1,4-dien-
3-ol with PBr3 in diethyl ether at 0 °C for 1 h. Our
methodology involves the formation of the corresponding
imine by condensation of an aldehyde with enantiopure N-tert-
butylsulfinamide in the presence of Ti(OEt)4 and indium
powder at room temperature. After 1 h, the prepared
pentadienyl bromide was added to the reaction mixture and
the temperature was increased to 60 °C. Under these
conditions, a range of aldehydes was examined (Table 1).
Benzaldehyde afforded the corresponding γ adduct 4a in only
14% yield as an inseparable mixture of 9:1 diastereoisomers.16
Better yields and good diastereoselectivities were achieved with
more electron-deficient aromatic substrates such as 3- and 4-
chlorobenzaldehyde (2b,c), although the bulkier 2-chloroben-
zaldehyde afforded product 4d in poorer yield. The α-branched
cyclohexanecarbaldehyde gave a 74:26 mixture of γ/α adducts.
The major γ regioisomer 4e was isolated in good yield after
column chromatography. Importantly, the configuration at the
newly formed stereogenic center in 4e was confirmed to be R
by X-ray crystal diffraction analysis (see the Supporting
Information), which fits with our working model that predicts
addition of the allylic reagent onto the si face of the (RS)-
sulfinimine (Table 1). We were pleased to observe that α-
unsubstituted aldehydes (2f−l), which are more challenging
substrates with other allylic organometallic species due to their
easy enolization, reacted well with this protocol. Notably, the
presence of halogen atoms was tolerated in the substrates (2b−
d,g) and only γ adducts were isolated in good yields and with
excellent diasteroselectivity. The 1,2-addition product (4j) was
isolated exclusively when cinnamaldehyde was examined.
Furthermore when (S)-citronellal was examined with either
enantiomer of the N-tert-butylsulfinamide, products 4k,l were
both obtained in very good yields and diastereoselectivities.
The configuration at the newly stereogenic center formed was
controlled by the chiral sulfur atom without remarkable
matched or mismatched effect.
Table 1. Aminopentadienylation of Aldehydes
a
The crude reaction mixture showed a 74:26 mixture of γ and α
b
c
adducts. ent-4h and ent-4i were also synthesized using ent-1. Signals
corresponding to diastereoisomers are not observed in the 13C NMR
d
e
spectra. In this case, ent-1 was used. Isolated yields and
diastereomeric ratios (1H NMR spectroscopy) after column
chromatography are shown.
Encouraged by the good results reported for the indium-
mediated allylation of tert-butylsulfinyl ketimines,17 we decided
to apply our pentadienylation methodology to ketones
(Scheme 3). In this case the formation of the corresponding
ketimines required an increase of the temperature to 60 °C and
of the reaction time to 8 h, whereupon 5-bromo-1,3-pentadiene
was added. That the indium powder was still active after the
imine formation confirms the stability of the metal in the
presence of moisture and/or ethanol at 60 °C. Aliphatic methyl
ketones examined under these conditions (5a−c) afforded γ
adducts exclusively (6a−c) in good yields and with excellent
diastereoselectivities.18
In order to evaluate the efficiency of this one-pot protocol,
we isolated the tert-butylsulfinyl imine of 2-heptanone (72%)
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a
Scheme 3. Aminopentadienylation of Methyl Alkyl Ketones
Scheme 4. Catalytic Hydrogenation of Pentadienyl Amines
4f and 6a
processes related to single-electron transfers are more
reasonable in these cases (i.e., pinacol-like coupling reactions).
Given the occurrence of pyrrolidines in natural and synthetic
bioactive compounds, we considered it of interest to develop a
new entry to stereodefined 2,2,3-trisubstituted pyrrolidines.
With this in mind, we submitted α-substituted pentadienyl
amines 6b,c to a hydroboration−oxidation sequence using an
excess of 9-borabicyclo[3.3.1]nonane (9-BBN). The corre-
sponding diols (9b,c; Scheme 5) were obtained in good yields
and were submitted to Mitsunobu reaction conditions to
explore the differentiation of the diastereotopic hydroxyethyl
groups upon cyclization.23 We were pleased to observe that the
corresponding pyrrolidines (10b,c) were obtained with
excellent diastereoselectivities and were isolated in very good
yields as single isomers after column chromatography.24 To
elucidate the configuration of the new stereocenter, compound
10c was transformed by conventional methods into the more
rigid benzoyl derivative 11. After the assignment of all signals of
a
1
Isolated yields and diastereomeric ratios (determined by H NMR
spectroscopy) after column chromatography are shown.
and submitted this to indium-mediated pentadienylation in
THF. Under these conditions compound 6b was isolated in
only 44% yield (32% over two steps), 2-heptanone being
recovered as the major side product from a competitive
hydrolytic process. We thus reasoned that the presence of
Ti(OEt)4 improved the conversion of the intermediate imine
by minimizing its hydrolysis. Moreover, the presence of Ti(IV)
could also accelerate the pentadienylation process versus
hydrolysis. In Scheme 3 we propose a hypothetically more
stable [4.4.0] bicyclic transition state where the indium metal is
coordinated to an alkoxy ligand acting as a bridge with a
titanium center bonded to the oxygen atom of the sulfinyl
group. The combination of In(III) and Ti(IV) in the same
transition state might account for a more efficient Lewis acid
activation. Importantly, we have found the same degree and
sense of diastereoselection for the one-pot methodology and
the two-step procedure. More importantly, while the
intermediate imine was isolated as an 83:17 mixture of E/Z
isomers, compound 6b was obtained as a single isomer.
Consequently, we reasoned that a dynamic kinetic resolution
takes place where the E/Z imines can rapidly interconvert in
the presence of Lewis acids.19 The major diastereoisomer is
formed from the addition of the pentadienyl indium reagent
onto the si face of the (RS,E)-imine, as previously observed in
the two-step protocol.20,21
At this point we decided to explore some synthetic
applications of the obtained enantioenriched pentadienyl
amines. Hydrogenation of both double bonds was accom-
plished for substrates 4f and 6a using PtO2 as a catalyst. The
sulfinyl group remained intact under these reaction conditions.
thereby avoiding the deprotection of the amine functionality.22
The corresponding amines 7 and 8 were obtained in excellent
yields without any detectable epimerization (Scheme 4). To the
best of our knowledge, chiral amines α-substituted with a 3-
pentyl moiety have not been reported so far. It is worth noting
that a direct addition of 3-pentyl organometallic reagents to
imines would be sterically disfavored and reduction or other
1
the H NMR spectra of compound 11 (COSY and HSQC
experiments were used), relevant NOEs were identified that
clearly indicated a trans relationship between the methine
proton and the methyl group. For a better understanding of this
diastereoselective cyclization, we removed the chirality of the
sulfinyl group by oxidation with m-CPBA and submitted the
obtained sulfonamide 12 to the same Mitsunobu reaction
conditions. This reaction afforded a 1:1 diastereomeric mixture
of pyrrolidines 13 and 14, accompanied by the tetrahydropyran
byproduct 15 (see the Experimental Section). Oxidation of
pyrrolidine 10b took place smoothly to afford pyrrolidine 13 as
a single isomer. This experiment demonstrates that the chirality
of the sulfinyl group is essential for achieving a good
diastereoselection in this Mitsunobu cyclization.
This excellent diastereoselectivity is noteworthy, since both
alkyl groups attached to the quaternary center exhibit similar
steric bulkiness. Accordingly, we reasoned that this unexpect-
edly high diastereoselection should be supported on kinetic
grounds. To account for the key role of the chiral sulfinyl group
in the diastereoselection, we postulate two possible transition
states where the oxygen of the sulfinyl group is hydrogen-
bonded to the remained hydroxyethyl group. The pyrrolidine
ring formation takes place from the transition state that avoids
nonbonding interactions of the tert-butyl group with the
substituents attached to C-2 (Scheme 6).
CONCLUSION
■
The aminopentadienylation of carbonyl compounds with chiral
tert-butylsulfinamide and in situ formed pentadienylindium
reagent provides a convenient access to chiral α-substituted
amines with a 1,4-pentadien-3-yl unit from readily available
starting materials. The protocol made use of In(0) and
Ti(OEt)4, which are nontoxic and do not require a careful
exclusion of moisture and/or air. This methodology accom-
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Scheme 5. Preparation of trans-(2,2,3)-Trisubstituted Pyrrolidines Fully Stereocontrolled by the Chiral tert-Butylsulfinyl Group
Scheme 6. Plausible Explanation for the Diastereoselective Mitsunobu Cyclization
60 °C for 3 min, ramp from 60 to 270 °C at 15 °C/min, hold at 270
°C for 10 min. Mass spectra (EI) were obtained at 70 eV; fragment
ions are given in m/z with relative intensities (%) in parentheses.
HRMS analyses were also carried out in the electron impact mode
(EI) at 70 eV using a quadrupole mass analyzer or in the electrospray
modates electron-poor aromatic aldehydes, α,β-unsaturated
aldehydes, and α-branched aliphatic aldehydes and is
particularly efficientin terms of yields and diastereoselectiv-
itieswith α-unsubstituted aldehydes and methyl alkyl
ketones. Catalytic hydrogenation of some of the pentadienyl
amines obtained allowed the formation of enantioenriched α-
tertiary or quaternary 3-pentyl amines, which are otherwise
difficult to prepare. Moreover, the hydroboration−oxidation of
selected examples of pentadienyl amines, followed by a
cyclization of the obtained amino diol under Mitsunobu
reaction conditions, furnished the corresponding trans-2,2,3-
trisubstituted pyrrolidines with excellent diastereoselectivity. It
was demonstrated that the chirality of the sulfinyl group was
essential for this high diastereoselection.
1
ionization mode (ESI) using a TOF analyzer. H NMR spectra were
recorded at 300 or 400 MHz, using CDCl3 or CD3CN as the solvent
and TMS as an internal standard (0.00 ppm); the data are reported as
s (singlet), d (doublet), t (triplet), m (multiplet or unresolved), and br
(broad signal), with coupling constant(s) in Hz and the integration.
1
13C NMR spectra were recorded with H decoupling at 101 MHz
using the solvent signal as reference (77.16 ppm for CDCl3). DEPT-
135 experiments were performed to assign CH, CH2, and CH3.
2,4-Pentadienyl Bromide (3).25 To a stirred solution of PBr3
(190 μL, 2 mmol) in dry Et2O (2.5 mL) under an Ar atmosphere was
added 1,4-pentadien-3-ol (485 μL, 5 mmol) dropwise over ca. 2 min at
0 °C. The resulting solution was stirred at 0 °C until the starting
material disappeared (followed by GC: starting alcohol, tR = 2.2 min;
product, tR = 4.0 min). The reaction was carefully quenched by the
addition of brine (1 mL). The layers were separated, and the organics
were washed sequentially with a saturated solution of NaHCO3 (×3)
and brine, dried over MgSO4, and filtered. The volatiles were carefully
removed at 40 °C under atmospheric pressure. The product was
obtained as a colorless oil (447 mg, 60%, 97 wt % in Et2O): 1H NMR
(300 MHz, CDCl3) δ 6.46−6.22 (m, 2H), 5.90 (dt, J = 13.0, 7.8 Hz,
1H), 5.28 (d, J = 14.9 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.03 (d, J =
7.6 Hz, 2H).
EXPERIMENTAL SECTION
■
General Remarks. (RS)-N-tert-Butylsulfinyl amine 1 and its
enantiomer (ent-1) were a gift of Medalchemy (>99% ee by chiral
HPLC on a Chiracel AS column, n-hexane/i-PrOH 90/10, 1 mL/min,
λ 222 nm). TLCs were performed on silica gel 60 F254 using aluminum
plates and were visualized with phosphomolybdic acid (PMA) or
ninhydrin stain. Flash chromatography was carried out on hand-
packed columns of silica gel 60 (230- 400 mesh). Melting points are
uncorrected. Optical rotations were measured using a polarimeter with
a thermally jacketed 5 cm cell at approximately 20 °C, and
concentrations (c) are given in g/100 mL. Infrared analyses were
performed with a spectrophotometer equipped with an ATR
component; wavenumbers are given in cm−1. GC analyses were
obtained with an HP-5 column (30 m × 0.25 mm, i.d. 0.25 μm) and an
EI (70 EV) detector. The temperature program was as follows: hold at
General Procedure for the Synthesis of Sulfinamides 4. In a
dry flask was placed (RS)-N-tert-butylsulfinamide (1, 61 mg, 0.5 mmol)
followed by indium powder (71 mg, 0.63 mmol). The reaction vessel
was evacuated and put under an Ar atmosphere. Then a solution of the
corresponding aldehyde (0.55 mmol) in dry THF (1 mL) and
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Ti(OEt)4 (225 μL, 1 mmol) were added successively and the reaction
mixture was stirred under Ar for 1 h at 23 °C. After this time, 2,4-
pentadienyl bromide (110 mg, 0.75 mmol) was added to the mixture,
and it was heated to 60 °C for 3 h. The mixture was allowed to reach
room temperature and was carefully added over a stirred mixture of 4/
1 EtOAc/brine (50 mL). The resulting white suspension was filtered
through a short pad of Celite, washed with EtOAc and the organics
were concentrated under reduced pressure. The resulting suspension
was diluted in 4/1 EtOAc/hexane (50 mL) and filtered again through
Celite, and the organics were concentrated under reduced pressure.
(RS,S)-N-tert-Butylsulfinyl-1-phenyl-2-vinylbut-3-en-1-amine
(4a). The crude product was prepared from PhCHO following the
general procedure and purified by column chromatography (7/3
hexane/EtOAc). The expected product was obtained as a yellow oil
according to 1H NMR): [α]D20 = −113.8° (c 0.60, CHCl3); Rf = 0.29
(7/3 hexane/EtOAc); IR ν 3281, 3079, 2978, 2959, 1634, 1573, 1473,
1363, 1062, 919, 730 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38−7.32
(m, 2H), 7.25 (td, J = 7.5, 1.5 Hz, 1H), 7.22−7.17 (m, 1H), 5.84 (ddd,
J = 17.1, 10.2, 8.7 Hz, 1H), 5.74 (ddd, J = 17.4, 10.4, 7.3 Hz, 1H), 5.28
(dd, J = 10.2, 1.4 Hz, 1H), 5.21 (d, J = 17.1 Hz, 1H), 5.02 (d, J = 10.4
Hz, 1H), 4.97 (dt, J = 17.1, 1.4 Hz, 1H), 4.94 (s, 1H), 3.86 (s, 1H),
3.18 (dd, J = 15.1, 7.4 Hz, 1H), 1.17 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 137.8 (C), 136.9 (CH), 136.1 (CH), 134.4 (C), 129.8
(CH), 129.7 (CH), 128.7 (CH), 126.7 (CH), 119.3 (CH2), 117.7
(CH2), 56.1 (CH), 55.9 (C), 55.1 (CH), 22.7 (CH3); CG tR = 15.5
min.; LRMS (EI) m/z (%) 189 (30), 187 (100), 170 (7), 142 (6), 141
(13), 140 (10), 139 (30), 138 (21), 128 (6), 67 (5); HRMS (ESI)
calcd for C16H23NOSCl 312.1189, found 312.1187.
1
20
(19 mg, 14%, 90:10 dr according to H NMR): [α]D = −121.5° (c
(RS,1R)-N-tert-Butylsulfinyl-1-cyclohexyl-2-vinylbut-3-en-1-
amine (4e). The crude product prepared from cyclohexanecarbalde-
hyde was obtained as a mixture of α- and γ-allylic products (26:74
according to 1H NMR) following the general procedure. The desired γ
product was purified by column chromatography (9/1 hexane/
EtOAc), giving a colorless wax (78 mg, 55%, single diastereoisomer
1.3, CHCl3); Rf = 0.12 (8/2 hexane/EtOAc); IR ν 3280, 3079, 2958,
1
1634, 1455, 1056, 917 cm−1; for the major diastereoisomer H NMR
(300 MHz, CDCl3) δ 7.38−7.28 (m, 5H), 5.81 (ddd, J = 17.0, 10.2,
9.0 Hz, 1H), 5.57 (ddd, J = 17.3, 10.5, 7.1 Hz, 1H), 5.33−5.20 (m,
2H), 5.03−4.88 (m, 2H), 4.28 (dd, J = 8.7, 1.5 Hz, 1H), 3.92 (br s,
1H), 3.07 (dd, J = 16.2, 8.4 Hz, 1H), 1.18 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 139.7 (C), 137.7 (CH), 136.4 (CH), 128.9 (CH),
128.3 (CH), 127.9 (CH), 119.0 (CH2), 117.5 (CH2), 60.2 (CH), 56.0
(CH), 55.8 (C), 22.8 (CH3); CG tR = 14.6 min; LRMS (EI) m/z (%)
154 (13), 153 (100), 137 (7), 136 (25), 129 (8), 105 (21), 104 (25),
77 (11); HRMS (EI) calcd for C16H23NOS − C4H8 221.0874, found
221.0888.
1
20
according to H NMR): [α]D = −72.8° (c 0.73, CHCl3); Rf = 0.20
(8/2 hexane/EtOAc); IR ν 3292, 3232, 3075, 2978, 2924, 2852, 1638,
1449, 1363, 1059, 995, 912, 752 cm−1; 1H NMR (300 MHz, CDCl3) δ
5.94−5.81 (m, 2H), 5.21−5.07 (m, 4H), 3.32 (d, J = 5.3 Hz, 1H),
3.15−3.05 (m, 2H), 1.79−1.48 (m, 6H), 1.23 (s, 9H), 1.21−0.97 (m,
5H). 13C NMR (101 MHz, CDCl3) δ 138.6 (CH), 138.1 (CH), 117.4
(CH2), 117.3 (CH2), 62.7 (CH), 56.5 (C), 52.0 (CH), 40.7 (CH),
31.5 (CH2), 27.8 (CH2), 26.7 (CH2), 26.6 (CH2), 26.3 (CH2), 23.1
(CH3); CG tR = 14.7 min; LRMS (EI) m/z (%) 227 (7), 160 (24),
159 (100), 144 (59), 96 (31), 95 (53), 94 (11), 81 (32), 79 (11), 77
(28), 68 (13), 67 (22), 55 (18); HRMS (EI) calcd for C16H29NOS −
C4H8 227.1344, found 227.1339.
(RS,1S)-N-tert-Butylsulfinyl-1-(4-chlorophenyl)-2-vinylbut-3-
en-1-amine (4b). The title compound was prepared from p-
Chlorobenzaldehyde following the general procedure and purified by
column chromatography (7/3 hexane/EtOAc). The expected product
was obtained as a yellow oil (102 mg, 66%, single diastereoisomer
according to 1H NMR): [α]D20 - 150.7° (c 0.69, CHCl3); Rf = 0.20 (7/
3 hexane/EtOAc); IR ν 3277, 3080, 2979, 2959, 1737, 1635, 1597,
(RS,4R)-N-tert-Butylsulfinyl-3-vinyltridec-1-en-4-amine (4f).
The crude product (93:7 dr according 1H NMR) prepared from
decanal following the general procedure was purified by column
chromatography (9/1 hexane/EtOAc). The expected product was
obtained as a yellow oil (150 mg, 90%, 98:2 dr according to 1H
1
1490, 1062, 1013, 919, 828 cm−1; H NMR (300 MHz, CDCl3) δ
7.33−7.27 (m, 2H), 7.24−7.18 (m, 2H), 5.78 (ddd, J = 17.0, 10.2, 9.0
Hz, 1H), 5.54 (ddd, J = 17.4, 10.4, 7.2 Hz, 1H), 5.30 (dd, J = 10.3, 1.6
Hz, 1H), 5.24 (ddd, J = 17.1, 1.6, 0.7 Hz, 1H), 5.00 (dt, J = 10.4, 1.3
Hz, 1H), 4.93 (dt, J = 17.2, 1.3 Hz, 1H), 4.26 (dd, J = 8.6, 1.3 Hz, 1H),
3.91 (s, 1H), 3.02 (dd, J = 16.4, 8.6 Hz, 1H), 1.17 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ 138.3 (C), 137.4 (CH), 136.1 (CH), 133.7 (C),
130.2 (CH), 128.6 (CH), 119.3 (CH2), 117.9 (CH2), 59.5 (CH), 56.1
(CH), 55.9 (C), 22.7 (CH3); CG tR = 16.0 min; LRMS (EI) m/z (%)
189 (33), 187 (100), 170 (5), 157 (3), 142 (5), 141 (14), 140 (10),
139 (33), 138 (21), 128 (4), 67 (5); HRMS (ESI) calcd for
C16H23NOSCl (M + H) 312.1189, found 312.1185.
20
NMR): [α]D = −50.3° (c 1.01, CHCl3); Rf = 0.23 (8/2 hexane/
EtOAc); IR ν 3290, 3209, 3077, 2954, 2924, 2854, 1635, 1466, 1362,
1
1065, 999, 914, 721 cm−1; H NMR (300 MHz, CDCl3) δ 5.86−5.80
(m, 1H), 5.80−5.74 (m, 1H), 5.27−5.07 (m, 4H), 3.42 (d, J = 7.0 Hz,
1H), 3.32−3.23 (m, 1H), 3.16 (dd, J = 13.5, 7.3 Hz, 1H), 1.56−1.50
(m, 1H), 1.32−1.23 (m, 15H), 1.21 (s, 9H), 0.88 (t, J = 6.9 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 137.8 (CH), 136.4 (CH), 119.1
(CH2), 117.2 (CH2), 58.8 (CH), 56.2 (C), 53.3 (CH), 32.0 (CH2),
31.5 (CH2), 29.7 (CH2), 29.7 (CH2), 29.5 (CH2), 29.4 (CH2), 25.6
(CH2), 22.9 (CH3), 22.8 (CH2), 14.3 (CH3); CG tR = 16.3 min;
LRMS (EI) m/z (%) 271 (7), 270 (1), 222 (11), 204 (16), 203 (100),
156 (7), 95 (14), 84 (30), 70 (48), 55 (20); HRMS (EI) calcd for
C19H37NOS − C4H8 271.1970, found 271.1973.
(RS,1S)-N-tert-Butylsulfinyl-1-(3-chlorophenyl)-2-vinylbut-3-
en-1-amine (4c). The title compound was prepared from m-
chlorobenzaldehyde following the general procedure and purified by
column chromatography (7/3 hexane/EtOAc). The expected product
was obtained as a colorless oil (129 mg, 83%, 90:10 dr according to 1H
(RS,4R)-N-tert-Butylsulfinyl-8-bromo-3-vinyloct-1-en-4-
20
1
NMR): [α]D = −105.8° (c 0.72, CHCl3); Rf = 0.30 (7/3 hexane/
amine (4g). The crude product (94:6 dr according to H NMR)
prepared from 5-bromopentanal26 following the general procedure was
purified by column chromatography (8/2 hexane/EtOAc). The
expected product was obtained as a yellow oil (122 mg, 73%, single
EtOAc); IR ν 3276, 3217, 2978, 2960, 1634, 1597, 1574, 1474, 1316,
1
1056, 920, 752 cm−1; H NMR (400 MHz, CDCl3) δ 7.29−7.27 (m,
1H), 7.27−7.24 (m, 2H), 7.19−7.14 (m, 1H), 5.78 (ddd, J = 17.1,
10.2, 9.0 Hz, 1H), 5.56 (ddd, J = 17.4, 10.4, 7.2 Hz, 1H), 5.30 (dd, J =
10.2, 1.4 Hz, 1H), 5.25 (dd, J = 17.1, 0.7 Hz, 1H), 5.04−4.99 (m, 1H),
4.95 (dt, J = 17.2, 1.3 Hz, 1H), 4.26 (dd, J = 8.6, 1.2 Hz, 1H), 3.91 (s,
1H), 3.03 (q, J = 8.4 Hz, 1H), 1.19 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 142.0 (C), 137.3 (CH), 136.0 (CH), 134.3 (C), 129.5
(CH), 128.7 (CH), 128.1 (CH), 127.2 (CH), 119.4 (CH2), 118.0
(CH2), 59.7 (CH), 56.0 (CH), 55.9 (C), 22.7 (CH3); CG tR = 15.8
min; LRMS (EI) m/z (%) 189 (38), 188 (10), 187 (100), 170 (12),
157 (4), 142 (6), 141 (13), 140 (10), 139 (28), 138 (20), 128 (5), 67
(5); HRMS (ESI) calcd for C16H23NOSCl 312.1189, found 312.1186.
(RS,1S)-N-tert-Butylsulfinyl-1-(2-chlorophenyl)-2-vinylbut-3-
en-1-amine (4d). The title compound was prepared from o-
chlorobenzaldehyde following the general procedure and purified by
column chromatography (7/3 hexane/EtOAc). The expected product
was obtained as a colorless oil (33 mg, 21%, single diastereoisomer
1
20
diastereoisomer according to H NMR): [α]D = −52.4° (c 1.13,
CHCl3); Rf = 0.27 (7/3 hexane/EtOAc); 1H NMR (300 MHz,
CDCl3) δ 5.87−5.69 (m, 2H), 5.36−5.05 (m, 4H), 3.45 (dd, J = 6.8,
5.1 Hz, 1H), 3.40 (t, J = 6.6 Hz, 2H), 3.32−3.22 (m, 1H), 3.16 (dd, J =
14.2, 6.9 Hz, 1H), 1.96−1.76 (m, 2H), 1.68−1.54 (m, 2H), 1.49−1.29
(m, 2H), 1.22 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 137.6 (CH),
136.1 (CH), 119.4 (CH2), 117.5 (CH2), 58.4 (CH), 56.2 (C), 53.2
(CH), 33.8 (CH2), 32.6 (CH2), 30.6 (CH2), 24.2 (CH2), 22.9 (CH3);
CG tR = 15.4 min; LRMS (EI) m/z (%) 281 (4), 279 (4), 214 (9), 213
(100), 212 (10), 211 (97), 200 (7), 144 (10), 104 (8), 95 (11), 85 (5),
84 (38), 83 (4), 81 (22), 79 (9), 77 (17), 69 (14), 68 (24), 67 (45), 56
(12), 55 (18), 53 (12); HRMS (EI) calcd for C14H26BrNOS − C4H8
279.0292, found 279.0290.
(RS,2R)-N-tert-Butylsulfinyl-1-phenyl-3-vinylpent-4-en-2-
1
amine (4h). The crude product (97:3 dr according H NMR) was
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20
prepared from phenylethanal, following the general procedure, and
purified by column chromatography (8/2 hexane/EtOAc). The
expected product was obtained as a yellow oil (102 mg, 70%, 98:2
dr according to 1H NMR): [α]D20 = −21.1° (c 0.73, CHCl3); Rf = 0.29
(7/3 hexane/EtOAc); IR ν 3291, 3074, 2981, 1495, 1455, 1216, 1057,
NMR): [α]D = −31.5° (c 0.93, CHCl3); Rf = 0.32 (7/3 hexane/
EtOAc); IR ν 3288, 3080, 2958, 2928, 1635, 1457, 1363, 1059, 1001,
917, 798 cm−1; H NMR (300 MHz, CDCl3) δ 5.90−5.70 (m, 2H),
1
5.31−5.20 (m, 2H), 5.15 (dt, J = 4.5, 1.6 Hz, 1H), 5.11 (dt, J = 11.0,
1.6 Hz, 1H), 5.08−5.02 (m, 1H), 3.44−3.31 (m, 2H), 3.26 (t, J = 6.9
Hz, 1H), 1.96 (q, J = 7.3 Hz, 2H), 1.66 (d, J = 1.0 Hz, 3H), 1.59 (s,
3H), 1.57−1.52 (m, 1H), 1.35−1.23 (m, 4H), 1.21 (s, 9H), 0.85 (d, J
= 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 137.8 (CH), 135.7
(CH), 131.2 (C), 124.7 (CH), 119.8 (CH2), 116.7 (CH2), 57.9 (CH),
56.2 (C), 53.9 (CH), 38.9 (CH2), 37.8 (CH2), 28.5 (CH), 25.7
(CH3), 25.4 (CH2), 22.7 (CH3), 18.7 (CH3), 17.7 (CH3); CG tR =
15.5 min; LRMS (EI) m/z (%) 220 (33), 201 (12), 193 (23), 178
(45), 168 (5), 152 (76), 137 (49), 121 (38), 109 (100), 96 (44), 81
(97), 69 (89), 55 (35); HRMS (EI) calcd for C19H35NOS − C4H8
269.1813, found 269.1808.
1
921, 747 cm−1; H NMR (300 MHz, CDCl3) δ 7.31−7.13 (m, 5H),
5.99−5.79 (m, 2H), 5.36−5.12 (m, 4H), 3.59 (ddd, J = 13.6, 8.2, 4.7
Hz, 1H), 3.44 (d, J = 7.2 Hz, 1H), 3.22 (dd, J = 12.2, 7.3 Hz, 1H), 2.91
(dd, J = 14.0, 4.9 Hz, 1H), 2.60 (dd, J = 13.9, 9.0 Hz, 1H), 1.04 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 138.9 (C), 136.9 (CH), 136.2
(CH), 129.5 (CH), 128.2 (CH), 126.2 (CH), 119.5 (CH2), 117.8
(CH2), 60.8 (CH), 56.0 (C), 52.4 (CH), 38.2 (CH2), 22.5 (CH3); CG
tR = 16.4 min; LRMS (EI) m/z (%) 235 (5), 167 (5), 146 (5), 145
(8), 144 (100), 128 (6), 104 (24), 92 (7), 91 (35), 81 (19), 68 (4);
HRMS (EI) calcd for C17H25NOS − C4H8 235.1031, found 235.1032.
(SS,2S)-N-tert-Butylsulfinyl-1-phenyl-3-vinylpent-4-en-2-
amine (ent-4h). The title compound was prepared from (SS)-N-tert-
butylsulfinamide (ent-1) following the same general procedure, giving
a yellow oil (100 mg, 69%). Physical and spectroscopic data were
(SS,4S,6S)-N-tert-Butylsulfinyl-6,10-dimethyl-3-vinylundeca-
1,9-dien-4-amine (4l). The product was prepared from (S)-
citronellal and ent-1, following the general procedure, and purified
by column chromatography (8/2 hexane/EtOAc). The expected
product was obtained as a yellow oil (137 mg, 84%, >97:3 dr according
20
found to be the same as for 4h, except for the optical rotation: [α]D
20
to 13C NMR): [α]D = +30.5° (c 1.02, CHCl3); Rf = 0.28 (7/3
= +20.4° (c 1.2, CHCl3).
hexane/EtOAc); IR ν 3290, 3077, 2958, 2924, 1635, 1456, 1362, 1059,
1001, 916, 794 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.87 − 5.74 (m,
2H), 5.32−5.21 (m, 2H), 5.18−5.05 (m, 3H), 3.43−3.34 (m, 2H),
3.24 (t, J = 8.2 Hz, 1H), 2.00 (td, J = 15.0, 6.8 Hz, 1H), 1.94−1.83 (m,
1H), 1.68 (d, J = 1.0 Hz, 3H), 1.60 (s,3H), 1.45−1.35 (m, 3H), 1.21
(s, 9H), 1.19−1.13 (m, 1H), 1.13−1.01 (m, 1H), 0.89 (d, J = 6.7 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 137.4 (CH), 136.0 (CH), 131.2
(C), 124.7 (CH), 119.6 (CH2), 117.0 (CH2), 57.6 (CH), 56.1 (C),
53.3 (CH), 39.3 (CH2), 35.6 (CH2), 28.7 (CH), 25.7 (CH3), 25.1
(CH2), 22.7 (CH3), 20.4 (CH3), 17.7 (CH3); CG tR = 15.6 min;
LRMS (EI) m/z (%) 220 (33), 201 (12), 193 (25), 178 (47), 168 (5),
152 (77), 137 (47), 121 (35), 109 (100), 96 (44), 81 (92), 69 (86), 55
(35); HRMS (EI) calcd for C19H35NOS − C4H8 269.1813, found
269.1819.
General Procedure for the Synthesis of Sulfinamides 6. In a
dry flask was placed (RS)-N-tert-butylsulfinamide (1; 61 mg, 0.5
mmol) followed by indium powder (71 mg, 0.63 mmol). The reaction
vessel was evacuated and put under an Ar atmosphere. Then a solution
of the corresponding ketone (0.55 mmol) in dry THF (1 mL) and
Ti(OEt)4 (281 μL, 1.25 mmol) were added successively and the
reaction mixture was stirred under an Ar atmosphere for 12 h at 65 °C.
At this time 2,4-pentadienyl bromide (154 mg, 1.05 mmol) was added
to the mixture, and it was heated to 65 °C for 7 h. The mixture was
warmed to room temperature and was carefully added over a stirring
mixture of 4/1 EtOAc/brine (20 mL). The resulted white suspension
was filtered through a short pad of Celite and washed with EtOAc, and
the organics were concentrated under reduced pressure. The resulting
suspension was diluted in 4/1 EtOAc/hexane (20 mL) and filtered
again through Celite, and the organics were concentrated under
reduced pressure.
(RS,3R)-N-tert-Butylsulfinyl-1-phenyl-4-vinylhex-5-en-3-
amine (4i). Compound 4i was prepared from 3-phenylpropanal
following the general procedure. After purification by column
chromatography (8/2 hexane/EtOAc), the expected product was
obtained as a yellow oil (130 mg, 85%, 97:3 dr according to 1H
20
NMR): [α]D = −61.5° (c 0.85, CHCl3); Rf = 0.17 (8/2 hexane/
EtOAc); IR ν 3286, 3079, 2977, 2950, 1635, 1602, 1455, 1057, 917
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.34−7.29 (m, 2H), 7.27−7.14
(m, 3H), 5.88−5.71 (m, 2H), 5.34−5.23 (m, 2H), 5.23−5.11 (m, 2H),
3.56 (d, J = 7.1 Hz, 1H), 3.35 (tdd, J = 7.2, 5.3, 3.6 Hz, 1H), 3.24 (dd,
J = 13.9, 6.9 Hz, 1H), 2.82−2.73 (m, 1H), 2.61 (ddd, J = 13.7, 10.4,
6.3 Hz, 1H), 1.99−1.89 (m, 1H), 1.72−1.60 (m, 1H), 1.28 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 142.0 (C), 137.7 (CH), 136.0 (CH),
128.6 (CH), 128.5 (CH), 126.1 (CH), 119.6 (CH2), 117.4 (CH2),
58.3 (CH), 56.3 (C), 53.3 (CH), 33.6 (CH2), 32.0 (CH2), 23.0
(CH3).; CG tR = 16.3 min; LRMS (EI) m/z (%) 249 (M+ − C4H8, 8),
181 (18), 145 (8), 133 (11), 132 (10), 118 (12), 117 (81), 96 (24), 92
(10), 91 (100), 81 (5), 77 (8), 67 (9), 65 (10); HRMS (EI) calcd for
C18H27NOS − C4H8 249.1187, found 249.1176.
(SS,3S)-N-tert-Butylsulfinyl-1-phenyl-4-vinylhex-5-en-3-
amine (ent-4i). The title compound was prepared from (SS)-N-tert-
butylsulfinamide (ent-1) following the same general procedure, giving
a colorless oil (122 mg, 80%, 97:3 dr according to 1H NMR). Physical
and spectroscopic data were found to be the same as for 4i, except for
20
the optical rotation: [α]D = +56.4° (c 1.7, CHCl3).
(RS,1E,3R)-N-tert-Butylsulfinyl-1-phenyl-4-vinylhexa-1,5-
dien-3-amine (4j). Compound 4j was prepared from cinnamalde-
hyde following the general procedure. After purification by column
chromatography (9/1 hexane/EtOAc), the expected product was
1
obtained as a white solid (109 mg, 72%, 97:3 dr according to H
20
NMR): mp 47.9−50.0 °C; [α]D = +133.5° (c 1.01, CHCl3); Rf =
(RS,3R)-N-tert-Butylsulfinyl-3-methyl-4-vinylhex-5-en-3-
amine (6a). From 2-butanone, the expected product was obtained
following the general procedure as a colorless crystal (75 mg, 62%,
97:3 dr according 1H NMR) after column chromatography (9/1
hexane/EtOAc): mp 35.2−36.8 °C; [α]D20 = −66.6° (c 0.72, CHCl3);
Rf = 0.37 (7/3 hexane/EtOAc); IR ν 3292, 3075, 2976, 2940, 1632,
0.30 (7/3 hexane/EtOAc); IR ν 3281, 3079, 2977, 1635, 1363, 1059,
1
966, 918, 752 cm−1; H NMR (300 MHz, CDCl3) δ 7.42−7.28 (m,
4H), 7.27−7.22 (m, 1H), 6.61 (d, J = 15.8 Hz, 1H), 5.98 (dd, J = 15.9,
8.0 Hz, 1H), 5.95−5.75 (m, 2H), 5.32−5.12 (m, 4H), 3.99 (td, J = 7.2,
2.6 Hz, 1H), 3.67 (d, J = 2.7 Hz, 1H), 3.05 (q, J = 7.3 Hz, 1H), 1.23 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 137.2 (CH), 136.7 (C), 136.5
(CH), 133.9 (CH), 128.7 (CH), 128.0 (CH), 127.9 (CH), 126.7
(CH), 118.5 (CH2), 118.3 (CH2), 59.1 (CH), 55.8 (C), 54.3 (CH),
22.8 (CH3); CG tR = 16.7 min; LRMS (EI) m/z (%) 228 (5), 181 (6),
180 (11), 179 (97), 162 (5), 141 (5), 131 (13), 130 (100), 129 (8),
117 (12), 116 (88), 115 (39), 103 (11), 91 (14), 78 (5), 77 (17), 67
(6); HRMS (EI) calcd for C18H25NOS − C4H8 247.1031, found
247.1040.
1
1457, 1380, 1176, 1059, 1001, 919, 732 cm−1; H NMR (300 MHz,
CDCl3) δ 5.98−5.75 (m, 2H), 5.24−5.10 (m, 4H), 3.49 (s, 1H), 2.98
(t, J = 8.6 Hz, 1H), 1.66 (dq, J = 14.7, 7.4 Hz, 1H), 1.56 (dq, J = 14.5,
7.3 Hz, 1H), 1.29 (s, 3H), 1.21 (s, 9H), 0.87 (t, J = 7.4 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 136.8 (CH), 136.2 (CH), 118.8 (CH2),
118.1 (CH2), 59.2 (C), 57.5 (CH), 56.2 (C), 30.6 (CH2), 24.1 (CH3),
23.0 (CH3), 7.5 (CH3); GC tR = 12.2 min; LRMS (EI) m/z (%) 176
(16), 122 (5), 121 (6), 120 (100), 102 (21), 81 (10), 71 (5), 67 (10),
57 (17); HRMS (ESI) calcd for C13H26NOS (M+ + 1) 244.1735,
found 244.1728.
(RS,4R,6S)-N-tert-Butylsulfinyl-6,10-dimethyl-3-vinylundeca-
1,9-dien-4-amine (4k). The product was prepared from (S)-
citronellal, following the general procedure, and purified by column
chromatography (8/2 hexane/EtOAc). The expected product was
obtained as a yellow oil (139 mg, 86%, >97:3 dr according to 13C
(RS,4R)-N-tert-Butylsulfinyl-4-methyl-3-vinylnon-1-en-4-
amine (6b). From 2-heptanone (75 μL, 0.53 mmol), the expected
product was obtained following the general procedure as a colorless oil
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(93 mg, 65%, single diastereoisomer according to 1H NMR) after
(RS,4R)-N-tert-Butylsulfinyl-1-hydroxyl-3-(2′-hydroxyethyl)-
4-methylnonan-4-amine (9b). The homoallylamine 6b (171 mg,
0.6 mmol) was dissolved in dry THF (0.2 mL) under an Ar
atmosphere and cooled to 0 °C. A solution of 9-BBN (0.5 M in THF,
7.2 mL, 3.6 mmol) was added dropwise over ca. 10 min. The stirred
mixture was heated for 15 h at 60 °C. After the mixture was cooled to
0 °C, a solution of NaOH (1.6 mL, 2 M) was carefully added and, after
5 min, H2O2 solution (30 wt %/v, 1 mL) was added. The mixture was
stirred for 15 h at 60 °C and then cooled to room temperature. The
organic phase was collected, and the aqueous phase was extracted with
EtOAc (×3). The organics were dried over MgSO4, filtered, and
concentrated to give the crude diol. After column chromatography
(98/2 EtOAc/MeOH) the pure product 9b was obtained as a colorless
oil (115 mg, 60%, single diastereoisomer according to 1H NMR):
[α]D20 = −30.5° (c 0.95, CHCl3); Rf = 0.16 (98/2 EtOAc/MeOH); IR
ν 3301, 2953, 2933, 2870, 1457, 1363, 1098, 1012, 935, 753 cm−1; 1H
NMR (300 MHz, CDCl3) δ 3.82−3.71 (m, 3H), 3.71−3.53 (m, 2H),
3.42 (br s, 1H), 3.12 (br s, 1H), 2.00−1.82 (m, 4H), 1.54−1.31 (m,
6H), 1.28 (s, 3H), 1.27−1.23 (m, 3H), 1.21 (s, 9H), 0.89 (t, J = 6.9
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 62.3 (CH2), 61.3 (C), 61.0
(CH2), 56.1 (C), 41.5 (CH), 38.5 (CH2), 34.0 (CH2), 33.4 (CH2),
32.4 (CH2), 23.3 (CH3), 22.9 (CH3), 22.8 (CH2), 22.6 (CH2), 14.0
(CH3); GC tR = 15.8 min; LRMS (EI) m/z (%) 163 (5), 161 (83),
160 (11), 134 (10), 129 (44), 128 (69), 115 (11), 114 (100), 112
(10), 111 (21), 110 (14), 105 (30), 91 (20), 85 (11), 84 (14), 83 (21),
82 (15), 81 (21), 71 (18), 70 (20), 69 (28), 67 (24), 57 (32), 55 (60);
HRMS (ESI) calcd for C16H36NO3S (M+ + 1) 322.2416, found
322.2418.
20
column chromatography (9/1 hexane/EtOAc): [α]D = −63.8° (c
0.98, CHCl3); Rf = 0.33 (7/3 hexane/EtOAc); IR ν 3297, 3075, 2954,
1
2935, 1632, 1456, 1380, 1178, 1064, 1002, 914, 731 cm−1; H NMR
(300 MHz, CDCl3) δ 5.93−5.78 (m, 2H), 5.27−5.17 (m, 2H), 5.16−
5.10 (m, 2H), 3.50 (s, 1H), 2.97 (t, J = 8.5 Hz, 1H), 1.67−1.43 (m,
2H), 1.40−1.30 (m, 2H), 1.30 (s, 3H), 1.28−1.20 (m, 4H), 1.20 (s,
9H), 0.88 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 136.8
(CH), 136.1 (CH), 118.7 (CH2), 118.1 (CH2), 59.0 (C), 57.7 (CH),
56.1 (C), 38.0 (CH2), 32.2 (CH2), 24.5 (CH3), 22.9 (CH3), 22.6
(CH2), 22.5 (CH2), 14.1 (CH3); GC tR = 13.9 min; LRMS (EI) m/z
(%) 229 (4), 163 (6), 162 (13), 161 (100), 159 (5), 158 (49), 144
(5), 118 (9), 110 (6), 105 (23), 97 (15), 95 (10), 91 (7), 67 (12), 57
(12), 55 (12); HRMS (ESI) calcd for C16H32NOS (M+ + 1) 286.2205,
found 286.2201.
(RS,3R)-N-tert-Butylsulfinyl-3-methyl-1-phenyl-4-vinylhex-5-
en-3-amine (6c). From 4-phenyl-2-butanone, the expected product
was obtained following the general procedure as a colorless oil (115
1
mg, 72%, single diastereoisomer according to H NMR) after column
20
chromatography (9/1 hexane/EtOAc): [α]D = −74.2° (c 0.73,
CHCl3); Rf = 0.34 (7/3 hexane/EtOAc); IR ν 3076, 3025, 2977, 2953,
1
2867, 1632, 1603, 1455, 1381, 1063, 1063, 1002, 747 cm−1; H NMR
(300 MHz, CDCl3) δ 7.32−7.12 (m, 5H), 5.99−5.79 (m, 2H), 5.34−
5.11 (m, 4H), 3.62 (br s, 1H), 3.07 (t, J = 8.6 Hz, 1H), 2.73−2.54 (m,
2H), 1.93 (ddd, J = 14.2, 10.9, 6.4 Hz, 1H), 1.80 (ddd, J = 14.2, 11.2,
7.0 Hz, 1H), 1.39 (s, 3H), 1.24 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 142.4 (C), 136.6 (CH), 135.9 (CH), 128.6 (CH), 128.5 (CH),
126.1 (CH), 119.3 (CH2), 118.4 (CH2), 58.9 (C), 58.0 (CH), 56.4
(C), 40.5 (CH2), 29.5 (CH2), 24.5 (CH3), 23.1 (CH3); GC tR = 16.6
min; LRMS (EI) m/z (%) 263 (8), 196 (7), 195 (56), 178 (5), 159
(14), 158 (38), 147 (47), 146 (21), 132 (15), 131 (25), 110 (29), 95
(6), 92 (9), 9 (100), 83 (18), 87 (11), 65 (11); HRMS (ESI) calcd for
C19H30NOS (M++1) 320.2048, found 320.2039.
(RS,3R)-N-tert-Butylsulfinyl-1-hydroxyl-3-(2′-hydroxyethyl)-
4-methyl-6-phenylhex-4-amine (9c). From 6c (191 mg, 0.6
mmol), the expected product was obtained following the same
procedure used for 9b, as a colorless wax (136 mg, 64%, single
1
20
diastereoisomer according to H NMR): [α]D = −39.9° (c 0.80,
CHCl3); Rf = 0.15 (98/2 EtOAc/MeOH); IR ν 3271, 2949, 1454,
1363, 1031, 730 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33−7.27 (m,
1H), 7.27−7.22 (m, 1H), 7.22−7.09 (m, 3H), 4.09 (s, 1H), 4.02−3.81
(m, 1H), 3.81−3.72 (m, 2H), 3.69−3.49 (m, 2H), 2.74−2.54 (m, 2H),
2.03−1.84 (m, 3H), 1.81−1.72 (m, 2H), 1.49−1.39 (m, 2H), 1.38 (s,
3H), 1.23 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 142.3 (C), 128.6
(CH), 128.4 (CH), 126.1 (CH), 62.1 (CH2), 61.3 (C), 61.0 (CH2),
56.3 (C), 41.4 (CH), 41.1 (CH2), 34.0 (CH2), 33.6 (CH2), 29.9
(CH2), 23.4 (CH3), 23.0 (CH3); GC tR = 17.22 min; LRMS (EI) m/z
(%) 323 (12), 289 (10), 275 (20), 249 (13), 207 (8), 202 (14), 201
(82), 176 (11), 159 (41), 157 (11), 153 (17), 148 (12), 146 (15), 131
(34), 129 (100), 105 (32), 103 (11), 101 (54), 91 (72), 77 (14);
HRMS (ESI) calcd for C19H34NO3S (M+ + 1) 356.2259, found
356.2270.
(RS,4R)-N-tert-Butylsulfinyl-3-ethyltridecan-4-amine (7). To a
solution of compound 4f (65 mg, 0.20 mmol) in EtOAc (6 mL) was
added PtO2 (6 mg, 10 mol %), and the mixture was placed under a
hydrogen atmosphere. The mixture was vigorously stirred at room
temperature for 15 h. The catalyst was removed by filtration through a
pad of Celite, with more EtOAc as eluent. The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography (9/1 hexane/EtOAc), to give the expected product as
20
a colorless oil (62 mg, 93%): [α]D = −38.6° (c 0.79, CHCl3); Rf =
0.54 (7/3 hexane/EtOAc); IR ν 3243, 2957, 2923, 2871, 2854, 1462,
1
1362, 1056, 753 cm−1; H NMR (300 MHz, CDCl3) δ 3.20 (dt, J =
7.4, 4.4 Hz, 1H), 3.02 (d, J = 7.6 Hz, 1H), 1.43−1.30 (m, 5H), 1.30−
1.17 (m, 16H), 1.14 (s, 9H), 0.87 (t, J = 7.3 Hz, 6H), 0.81 (t, J = 6.8
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 58.4 (CH), 56.0 (C), 46.2
(CH), 32.4 (CH2), 32.0 (CH2), 29.7 (CH2), 29.7 (CH2), 29.6 (CH2),
29.4 (CH2), 26.6 (CH2), 22.9 (CH3), 22.8 (CH2), 22.5 (CH2), 22.1
(CH2), 14.2 (CH3), 12.4 (CH3), 12.3 (CH3); GC tR = 13.4 min;
LRMS (EI) m/z (%) 203 (16), 186 (17), 157 (12), 156 (100), 154
(6), 100 (12), 97 (7), 91 (33), 84 (11), 83 (19), 71 (11), 70 (14), 69
(12), 56 (15), 55 (19); HRMS (ESI) calcd for C19H42NOS (M+ + 1)
332.2987, found 332.2993.
(RS,2R,3R)-N-tert-Butylsulfinyl-2-methyl-2-pentyl-3-(2′-
hydroxyethyl)pyrrolidine (10b). The corresponding diol 9b (160
mg, 0.5 mmol) was dissolved in dry THF (1.7 mL) under an Ar
atmosphere and cooled to 0 °C. PPh3 (157 mg, 0.6 mmol) was added
to the reaction mixture followed by a DIAD solution in THF (1 mL,
0.6 M). The reaction mixture was stirred for 15 h at 25 °C. All volatiles
were removed under reduced pressure before purification by column
chromatography (99/1, EtOAc/MeOH) to give the corresponding
pure product 10b as a colorless oil (101 mg, 67%, 96:4 dr crude, single
(RS,3R)-N-tert-Butylsulfinyl-4-ethyl-3-methylhexan-3-amine
(8). Compound 8 was obtained from compound 6a (49 mg, 0.2
mmol), following the same procedure used to obtain 7, as a colorless
1
20
stereoisomer after purification according H NMR): [α]D = −62.5°
20
(c 1.05, CHCl3); Rf = 0.29 (98/2 EtOAc/MeOH); IR ν 3385, 2954,
oil (45 mg, 92%): [α]D = −55.7° (c 0.79, CHCl3); Rf = 0.34 (7/3
1
hexane/EtOAc); IR ν 3237, 2961, 2875, 1464, 1379, 1362, 1178, 1052,
937, 920 cm−1; 1H NMR (300 MHz, CDCl3) δ 3.16 (br s, 1H), 1.67−
1.51 (m, 4H), 1.35−1.26 (m, 1H), 1.22 (s, 3H), 1.20 (s, 9H), 1.19−
1.08 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H), 0.88 (t,
J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 61.7 (C), 55.9 (C),
50.4 (CH), 31.4 (CH2), 23.9 (CH3), 23.1 (CH2), 23.0 (CH2), 22.9
(CH3), 14.6 (CH3), 14.0 (CH3), 8.2 (CH3); GC tR = 12.6 min; LRMS
(EI) m/z (%) 191 (36), 176 (19), 162 (8), 127 (98), 126 (28), 120
(64), 119 (9), 102 (16), 97 (10), 85 (68), 72 (13), 71 (100), 57 (74),
55 (10); HRMS (ESI) calcd for C13H30NOS (M+ + 1) 248.2048,
found 248.2037.
2932, 2871, 1458, 1377, 1361, 1035, 1017, 955 cm−1; H NMR (300
MHz, CDCl3) δ 3.78 (m, 2H), 3.65 (dd, J = 16.0, 8.2 Hz, 1H), 2.78
(dd, J = 16.6, 9.7 Hz, 1H), 2.10−1.95 (m, 2H), 1.91−1.45 (m, 6H),
1.44−1.25 (m, 6H), 1.22 (s, 9H), 1.17 (s, 3H), 0.89 (t, J = 6.7 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 69.3 (C), 61.9 (CH2), 57.4 (C),
41.2 (CH), 39.9 (CH2), 39.8 (CH2), 32.8 (CH2), 32.6 (CH2), 29.5
(CH2), 24.7 (CH3), 23.3 (CH2), 22.8 (CH2), 21.7 (CH3), 14.2
(CH3); GC tR = 14.83 min; LRMS (EI) m/z (%) 184 (11), 166 (10),
129 (9), 128 (100), 126 (11), 111 (16), 110 (14), 97 (10), 96 (14), 84
(11), 82 (13), 71 (12), 55 (15); HRMS (ESI) calcd for C16H34NO2S
(M+ + 1) 304.2310, found 304.2302.
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(RS,2R,3R)-N-tert-Butylsulfinyl-3-(2-hydroxyethyl)-2-methyl-
2-(2-phenylethyl)pyrrolidine (10c). From compound 9c (106 mg,
0.3 mmol), the expected product was obtained following the same
procedure to obtain compound 10b, as a colorless oil (75 mg, 75%,
96:4 dr crude, single diastereoisomer after purification according to 1H
(M++1, 1), 322 (13), 241 (7), 234 (29), 202 (35), 115 (9), 114 (100),
57 (28); HRMS (ESI) calcd for C16H36NO4S (M+ + 1) 338.2361,
found 338.2357.
(2R,3R)-N-tert-Butylsulfonyl-2-methyl-2-pentyl-3-(2′-
hydroxyethyl)pyrrolidine (13). Compound 13 was obtained from
compound 10b (90 mg, 0.13 mmol) following the same procedure
used to obtain compound 12. A single diastereoisomer was obtained as
a colorless wax (40 mg, 95%, 96:4 dr crude, single diastereoisomer
20
NMR): [α]D = −40.4° (c 1.10, CHCl3); Rf = 0.21 (98:2 EtOAc/
MeOH); IR ν 3370, 3025, 2960, 1602, 1455, 1362, 1031, 750 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.37−7.24 (m, 2H), 7.24−7.12 (m,
20
according to 1H NMR after purification): [α]D = −5° (c 070,
3H), 3.82 (t, J = 9.5 Hz, 1H), 3.79−3.68 (m, 1H), 3.62 (dd, J = 15.8,
8.5 Hz, 1H), 2.83 (dd, J = 17.1, 9.7 Hz, 1H), 2.67 (t, J = 8.5 Hz, 2H),
2.14 (s, 1H), 2.08−1.94 (m, 2H), 1.91−1.78 (m, 2H), 1.78−1.58 (m,
1H), 1.58−1.48 (m, 1H), 1.47−1.35 (m, 1H), 1.26 (s, 9H), 1.22 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 142.4 (C), 128.6 (CH), 128.4
(CH), 126.0 (CH), 69.3 (C), 61.6 (CH2), 57.8 (C), 41.2 (CH), 41.2
(CH2), 40.0 (CH2), 32.7 (CH2), 29.9 (CH2), 29.4 (CH2), 24.9 (CH3),
21.8 (CH3); GC tR = 17.3 min; LRMS (EI) m/z (%) 230 (9), 207
(17), 202 (25), 200 (21), 186 (24), 172 (12), 159 (36), 158 (32), 131
(24), 127 (43), 126 (41), 118 (16), 117 (25), 108 (11), 105 (10), 92
(11), 91 (100), 33 (65), 32 (71),l 77 (11), 68 (17), 56 (17), 55 (24);
HRMS (ESI) calcd for C19H32NO2S (M+ + 1) 338.2154, found
338.2142.
CHCl3); Rf = 0.16 (7/3 hexane/EtOAc); IR ν 3489, 2956, 2930, 2871,
1
1465, 1298, 1116, 752 cm−1; H NMR (300 MHz, CDCl3) δ 3.83−
3.73 (m, 1H), 3.72−3.65 (m, 1H), 3.64−3.54 (m, 1H), 3.24 (td, J =
9.9, 6.5 Hz, 1H), 2.99 (br s, 1H), 2.25−2.10 (m, 1H), 2.10−1.89 (m,
2H), 1.78−1.61 (m, 2H), 1.61−1.50 (m, 1H), 1.50−1.42 (m, 1H),
1.40 (s, 9H), 1.37−1.34 (m, 1H), 1.32 (s, 3H), 1.31−1.15 (m, 5H),
0.88 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 72.1 (C),
61.9 (C), 67.8 (CH2), 49.8 (CH2), 42.5 (CH), 39.5 (CH2), 33.0
(CH2), 32.4 (CH2), 28.9 (CH2), 25.6 (CH3), 24.33 (CH2), 22.8
(CH2), 22.6 (CH3), 14.2 (CH3); GC tR = 18.0 min; LRMS (EI) m/z
(%) 248 (13), 184 (7), 129 (8), 128 (100), 111 (6), 57 (22); HRMS
(ESI) calcd for C16H34NO3S (M+ + 1) 320.2259, found 320.2270.
(2R,3S)- and (2R,3R)-N-tert-Butylsulfonyl-2-methyl-2-pentyl-
3-(2′-hydroxyethyl)pyrrolidine (13 and 14). A 1/1 mixture of
compounds 13 and 14 was obtained from compound 12 (100 mg,
0.15 mmol) following the same procedure described for 10b, as a
(2R,3R)-N-benzoyl-3-(2-hydroxyethyl)-2-methyl-2-(2-
phenylethyl)pyrrolidine (11). Pyrrolidine 10c (20 mg, 0.05 mmol)
was dissolved in dry MeOH (0.5 mL) at 0 °C, and a 4 M solution of
HCl in dioxane (50 μL) was added dropwise over 1 min. After the
mixture was stirred for 1 h, the solvent was removed under reduced
pressure and the hydrochloride was dissolved in CH2Cl2 (1 mL) and
cooled to 0 °C. A solution of NaOH (2 M, 1 mL) was added, followed
by benzoyl chloride (7 μL, 0.06 mmol), and the reaction mixture was
stirred at 25 °C for 15 h. The product was extracted with CH2Cl2 and
washed sequentially with NaOH (2 M) and brine. The organics were
dried over MgSO4, filtered, and concentrated under reduced pressure.
After column chromatography (7/3 hexane/EtOAc), the expected
product 11 was obtained as a colorless oil (15 mg, 90%, single
1
colorless oil (47 mg, 50% yield): H NMR (300 MHz, CDCl3) δ
3.85−3.72 (m, 2H), 3.71−3.53 (m, 4H), 3.44 (dd, J = 16.4, 8.1 Hz,
1H, 14), 3.24 (dd, J = 16.3, 9.8 Hz, 1H, 13), 2.25−2.10 (m, 1H),
2.10−1.94 (m, 4H), 1.93−1.46 (m, 10H), 1.45 (s, 3H, 14), 1.40 (s,
18H), 1.32 (s, 3H, 13), 1.32−1.01 (m, 11H), 0.88 (t, J = 6.5 Hz, 6H).
(4R)-N-tert-Butylsulfonyl-1-(4′-oxacyclohexyl) heptan-2-
amine (15). Compound 15 (20%) was obtained as a byproduct in
the reaction that gave compounds 13 and 14: Rf = 0.50 (7/3 hexane/
1
EtOAc); IR ν 3289, 2952, 2928, 1457, 1299, 1121, 952 cm−1; H
NMR (300 MHz, CDCl3) δ 4.11−3.98 (m, 2H), 3.48−3.29 (m, 3H),
1.88 (tt, J = 12.1, 3.2 Hz, 1H), 1.78−1.44 (m, 7H), 1.40 (s, 9H), 1.35
(s, 3H), 1.33−1.16 (m, 7H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 68.4 (C), 63.5 (CH2), 60.3 (CH2), 53.6 (C), 44.9
(CH), 38.4 (CH2), 32.3 (CH2), 27.8 (CH2), 27.3 (CH2), 24.7 (CH3),
23.2 (CH2), 22.8 (CH2), 21.2 (CH3), 14.2 (CH3); GC tR = 16.6 min;
LRMS (EI) m/z (%) 248 (15), 234 (30), 178 (7), 128 (43), 114
(100), 57 (39); HRMS (ESI) calcd for C16H34NO3S (M+ + 1)
320.2259, found 320.2263.
1
20
diastereoisomer according to H NMR after purification): [α]D
=
−61.5° (c 1.00, CHCl3); Rf = 0.31 (1/1 hexane/EtOAc); IR ν 3406,
1
3025, 2930, 1612, 1415, 1265 cm−1; H NMR (300 MHz, CDCl3) δ
7.45−7.35 (m, 5H), 7.31−7.27 (m, 1H), 7.26−7.21 (m, 3H), 7.20−
7.12 (m, 1H), 3.79 (dt, J = 15.6, 6.1 Hz, 1H), 3.68 (dt, J = 10.1, 7.5
Hz, 1H), 3.46−3.29 (m, 2H), 2.97−2.81 (m, 1H), 2.72−2.60 (m, 2H),
2.37 (dddd, J = 13.9, 11.1, 5.8, 3.1 Hz, 1H), 2.01−1.90 (m, 1H), 1.85−
1.42 (m, 5H), 1.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.8
(C), 142.6 (C), 139.0 (C), 129.4 (CH2), 128.7 (CH2), 128.5 (CH2),
128.5 (CH2), 126.4 (CH2), 125.9 (CH2), 66.8 (C), 61.8 (CH2), 50.9
(CH2), 41.7 (CH), 37.8 (CH2), 32.0 (CH2), 30.5 (CH2), 28.6 (CH2),
19.6 (CH3); GC tR = 22.5 min; LRMS (EI) m/z (%) 244 (01), 231
(23), 230 (39), 207 (28), 188 (14), 187 (12), 106 (9), 105 (100), 91
(9), 77 (25); HRMS (ESI) calcd for C22H28NO2 (M+ + 1) 338.2120,
found 338.2129.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures and a CIF file giving H and 13C NMR spectra for
compounds 3−15 and crystallographic data for compound 4e
(CDCC 971541). This material is available free of charge via
the Internet at http://pubs.acs.org.
(4R)-N-tert-Butylsulfonyl-1-hydroxyl-3-(2′-hydroxyethyl)-4-
methylnonan-4-amine (12). The sulfinyl compound 9b (112 mg,
0.35 mmol) was dissolved in dry CH2Cl2 (0.05 M) and placed under
an Ar atmosphere. The solution was cooled to 0 °C, and m-CPBA (73
mg, 0.42 mmol) was added. The reaction mixture was stirred for 1 h at
0 °C, with full conversion being observed by TLC. The reaction
mixture was quenched by adding a saturated aqueous solution of
NaHSO3 and a saturated aqueous solution of NaHCO3, the layers
were separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. After column chromatography
(1/1 hexane/EtOAc) the expected product was obtained as a colorless
oil (112 mg, 95%, single diastereoisomer according to 1H NMR):
AUTHOR INFORMATION
Corresponding Author
*E-mail for J.C.G.-G.: josecarlos.gonzalez@ua.es.
■
Present Address
†Faculty of Science and Arts, Cumhuriyet Campus, Ordu
University, 52200 Ordu, Turkey.
Notes
The authors declare no competing financial interest.
20
[α]D = −5° (c 0.60, CHCl3); Rf = 0.14 (1/1 hexane/EtOAc); IR ν
ACKNOWLEDGMENTS
We thank the Spanish Ministerio de Ciencia e Innovacion
■
1
3443, 2953, 2872, 1468, 1287, 1117, 1049, 735 cm−1; H NMR (300
́
MHz, CDCl3) δ 4.37 (s, 1H), 3.84−3.60 (m, 4H), 2.01−1.74 (m, 4H),
1.63−1.39 (m, 4H), 1.38 (s, 9H), 1.34 (s, 3H), 1.31−1.16 (m, 5H),
0.87 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 64.3 (C),
62.1 (CH2), 61.3 (CH2), 60.1 (C), 39.7 (CH), 38.9 (CH2), 33.2
(CH2), 32.5 (CH2), 32.3 (CH2), 24.6 (CH3), 23.1 (CH2), 22.8 (CH2),
21.5 (CH3), 14.3 (CH3); GC tR = 17.6 min; LRMS (EI) m/z (%) 338
(CTQ2011-24165) for financial support. I.B. acknowledges the
Generalitat Valenciana for a predoctoral fellowship (ACIF/
2011/159). E.B. acknowledges the Council of Higher
Education- Turkey for a postdoctoral fellowship (16.10.12-
̈
B.09.6.YOK.0.71.01-207.02-12285).
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Article
reaction. In the case of aldimines it seems more reasonable to place the
vinylic group in an equatorial position; however, gauche interactions
along C2−C3 are more severe with ketimines. In fact, during the
addition of pentadienyl indium reagents to α,β-unsaturated ketones a
transition state was proposed where the vinylic group occupies an axial
position; see: Villalva-Servín, N. P.; Melekov, A.; Fallis, A. G. Synthesis
2003, 5, 790.
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́
ez-Gom
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́
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́
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Ellman, J. Tetrahedron 1999, 55, 8883.
(20) This dynamic kinetic resolution was also observed in the simple
indium-mediated allylation of isolated tert-butylsulfinyl ketimines, and
we assigned the absolute configurations of compounds 6a−c assuming
the same mode of addition (see ref 17).
(21) In these hypothetical transition states we did not define the
geometry of the internal double bond of the pentadienyl moiety
because it is not relevant to the stereochemical outcome of the
1804
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