Indium-mediated diastereoselective allylation of N-tert-butanesulfinyl imines derived from α-ketoesters

Article abstract of DOI:10.1016/j.tet.2016.07.020

The indium-mediated allylation of α-aldimino and -ketimino esters 3 with allylic bromides proceeds with high diastereoselectivity to yield homoallylic α-amino ester derivatives 5, in both THF and water as solvents. The reactions are diastereospecific, the stereochemical outcome depending on the configuration of both the sulfur atom of the sulfinyl group and the C[dbnd]N double bond. Of particular interest are the reaction products using ethyl bromomethylacrylate as allylating reagent because amino diesters are obtained, which can be easily transformed into enantiomerically pure α-methylidene-γ-butyrolactams 6 with an alkoxycarbonyl group on the ring bearing the nitrogen atom.

Full text of DOI:10.1016/j.tet.2016.07.020

Tetrahedron xxx (2016) 1e10
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Indium-mediated diastereoselective allylation of N-tert-
butanesulfinyl imines derived from
a-ketoesters
,
b
,
,
b
,
c
,
a,c,
ꢀ a
Edgar Macia c, Francisco Foubelo a
, Miguel Yus
*
*
a
ꢀ
Departamento de Química Organica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Instituto de Síntesis Organica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Centro de Innovacion en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
b
c
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
The indium-mediated allylation of
with high diastereoselectivity to yield homoallylic
solvents. The reactions are diastereospecific, the stereochemical outcome depending on the configura-
tion of both the sulfur atom of the sulfinyl group and the C]N double bond. Of particular interest are the
reaction products using ethyl bromomethylacrylate as allylating reagent because amino diesters are
a
-aldimino and -ketimino esters 3 with allylic bromides proceeds
Received 27 May 2016
Received in revised form 29 June 2016
Accepted 5 July 2016
a
-amino ester derivatives 5, in both THF and water as
Available online xxx
obtained, which can be easily transformed into enantiomerically pure
with an alkoxycarbonyl group on the ring bearing the nitrogen atom.
a-methylidene-g-butyrolactams 6
Dedicated to Professor Gary Posner on
occasion of his retirement
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Diastereoselective addition
Allylation
Chiral sulfinyl imines
Enantioenriched
a-amino esters
a
-Methylene- -butyrolactams
g
1. Introduction
conditions. In addition, practical processes for recycling the tert-
butanesulfinyl group upon deprotection of N-tert-butanesulfinyl
amines have also been reported.7 With regards to this, we have
described the stereoselective allylation of N-tert-butanesulfinyl
aldimines8 and ketimines9 with allylindium species and the
The addition of an allylic organometallic compound to an im-
ine or imine derivative is of great synthetic interest because
a homoallyl amine is formed. Importantly, if the allylation is car-
ried out in a stereoselective fashion, enantioenriched homoallylic
amines would be produced.1 These compounds are valuable
building blocks, because along with the carbon stereogenic centre
bonded to the nitrogen atom, the double bond of the allylic moiety
can participate in a number of further synthetically useful trans-
formations.2 Although catalytic enantioselective allylations3 using
Lewis acids or bases as chiral inductors are the ideal method of
choice for performing these transformations, more efficient and
practical protocols have been developed when the stereoselective
allylations are carried out with stoichiometric amounts of chiral
reagents,4 such as imines bearing a chiral auxiliary. In this context,
it is worth mentioning that N-tert-butanesulfinyl derivatives5
have found high applicability in synthesis as electrophiles be-
cause both enantiomers are accessible in large-scale processes6
and because the chiral auxiliary is easily removed under acidic
first one-pot
a-aminoallylation of aldehydes with chiral tert-
butanesulfinamide, allyl bromides, and indium, which provides
homoallylic amines with high chemo- and stereo-selectivity.10
Continuing our interest in this topic, we herein report our
first approach to the indium-mediated addition of allylic bromides
to N-tert-butanesulfinyl imines derived from
alkyl glyoxylate esters. These imines are precursors of
a
-ketoesters and
-amino
a
esters upon reaction with nucleophiles: The addition of arylbor-
onic acids,11 trimethylsilane pronucleophiles,12 organozinc,13 and
organomagnesium compounds14 to these imines has been already
reported, the diastereoselective reduction of N-tert-butanesulfinyl
imines derived from
a-ketoesters leading to a-amino acid de-
rivatives being also known.15 To the best of our knowledge, the
first example of allylindium intermediate additions to the N-tert-
butanesulfinyl imine derived from ethyl glyoxylate was provided
by Grigg and co-workers in their study of three-component pal-
ladiumeindium-mediated diastereoselective cascade allylation
using allenes and aryl iodides as precursors of the allylindium
* Corresponding authors. Fax: þ34 965903549; e-mail addresses: foubelo@ua.es
(F. Foubelo), yus@ua.es (M. Yus).
http://dx.doi.org/10.1016/j.tet.2016.07.020
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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E. Macia et al. / Tetrahedron xxx (2016) 1e10
2
intermediate (Scheme 1).16 More recently, the indium-mediated
allylation of the same imino ester with allylic bromides was also
performed in a saturated sodium bromide aqueous solution to
solution. Compound 3b was also accessible in almost quantitative
yield when the condensation was performed in the presence of
19
ꢁ
10 mol % of pyrrolidine and 4 A MS. The previously mentioned
reaction conditions for the formation of aldimines 3a and 3b failed to
provide condensation products when ketoesters 2cee were used as
give the expected a-amino ester derivatives in a highly diaster-
eoselective manner (Scheme 1).17
Scheme 1. Previous work on indium-mediated allylation of N-tert-butanesulfinyl imines derived from ethyl glyoxylate.
2. Results and discussion
the reactant. Fortunately, the use of 2 equiv of Ti(OEt)4 inTHF at 60 ꢀC
provided relatively high yields of imino esters 3cee (Scheme 2). The
configuration of the C]N bond of imines 3 is very important in the
study of the diastereoselective addition of allylic nucleophiles to the
imine group. This matter has not been commented on in detail in
previous publications. We assumed that aldimines 3a and 3b exhibit
E-configuration, and ketimines 3d and 3e Z-configuration, according
to their NMR spectra. However, the imine 3c derived from ethyl
pyruvate (2c) was isolated as a 6:4 mixture of E:Z diastereoisomers
which could not be separated by column chromatography. The 1H
NMR chemical shift for the t-Bu group of the minor diastereoisomer
is 1.25 ppm (1.31 ppm for the major diastereoisomer with E con-
figuration) and is coincident with the t-Bu group of 3d which
exhibited an exclusively Z configuration.
Starting sulfinyl imino esters 3 were prepared according to the
standard procedures described in the literature by reaction of
commercially available (S)-tert-butanesulfinamide 1 with aldehydes
2a,b or ketones 2cee. Thus, direct condensation of methyl (2a) or
ethyl glyoxylate (2b) and (S)-tert-butanesulfinamide (1), in the
presence of CuSO4 in dichloromethane led to iminoesters 3a and 3b,
respectively (Scheme 2).18 Methyl glyoxylate (2a) was prepared in
situ by oxidative cleavage of (þ)-dimethyl
L-tartrate and used in the
condensation step without further purification, yielding methyl
iminoester 3a in a moderate overall 30% yield. On the other hand,
ethyl imino ester 3b was prepared in high yield from freshly distilled
ethyl glyoxylate (2b) from a commercially available 50% toluene
Scheme 2. Synthesis of N-tert-butanesulfinyl iminoesters 3.
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E. Macia et al. / Tetrahedron xxx (2016) 1e10
3
The reaction of N-tert-butanesulfinyl imino ester 3a derived
from methyl glyoxylate (2a) with allyl bromide (4a, 3 equiv), in the
presence of indium metal (1.5 equiv), in THF for 6 h at room tem-
perature (Method A), led to the formation of the homoallyl amino
ester derivative 5aa as a single diastereoisomer (Table 1, entry 1).
Those are typical reaction conditions developed in our group for the
allylation of N-tert-butanesulfinyl imines.8,9 Under the same re-
action conditions, the ethyl imino ester 3b gave compound 5ba in
61% yield (Table 1, entry 4) and, when methallyl bromide (4b) was
used as the allylating reagent for 3b, compound 5bd was obtained
in 82% yield (Table 1, entry 5). Crotylation of 3a is a more chal-
lenging process, because of the regiochemistry of the addition at
total conversion occurred when the reaction was carried out in
a saturated aqueous solution of sodium bromide in the presence of
4 equiv of indium at room temperature for 48 h (Method B), leading
to amino diester derivatives 5ad and 5bd in excellent yields (Table
1, entries 3 and 6). Those were the reaction conditions developed by
Xu and Lin,17a and applied previously to the allylation of imino ester
3b by both the groups of Xu and Lin, and Babu.17b A major draw-
back of this methodology is the use of a large excess of indium
(4 equiv instead of 1.5 equiv as in Method A) which is the most
expensive component of the reaction mixture. Regarding the con-
figuration of the newly created stereogenic centres, 5ba was
assigned after comparison of the NMR spectra with those reported
in literature for the same compound17b and its enantiomer.17a ent-
5ba was unambiguously characterized after transformation into the
the most substituted g-position of the crotyl indium intermediate
took place through a six-membered cyclic transition state, leading
to an almost 2:1 mixture of syn an anti-diastereoisomers 5ac (Table
1, entry 2). Unfortunately, allylation of 3a and 3b with ethyl 2-
bromomethylacrylate (4d) did not proceed in THF at room tem-
perature (Method A) or at higher temperatures. Based on our pre-
vious experience with this allylating reagent (4d),20 we found that
known compound D-allylglycine. Thus, we assumed that the in-
dium mediated allylation proceeded through the same stereo-
chemical pathway in imines 3a and 3b, with (E,SS) configuration,
the addition of the allyl moiety taking always place at the Si face of
these systems (Table 1).
Table 1
Allylation of N-tert-butanesulfinyl imines 3a,b derived from glyoxylate esters 2a,b
Entry
Imino ester 3
Allylic bromide 4
4a (R3¼H, R4¼H)
Method
a-Amino ester 5
No.
Structure
Yield (%)a,b
1
3a
A
5aa
41
2
3a
4c (R3¼H, R4¼Me)
A
5ac
53 (66:34)c
3
4
5
3a
3b
3b
3b
4d (R3¼CO2Et, R4¼H)
B
A
A
B
5ad
5ba
5bb
5bd
79
61
82
93
4a (R3¼H, R4¼H)
4b (R3¼Me, R4¼H)
6
4d (R3¼CO2Et, R4¼H)
a
Yield was determined after column chromatography purification and is based on the starting sulfinimide 3.
b
c
In all cases the allylation proceeded with high face diastereoselectivities (>95:5) that were determined after 1H NMR analysis of the reaction crude.
Diastereomeric syn/anti ratio is given in parenthesis.
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E. Macia et al. / Tetrahedron xxx (2016) 1e10
4
The allylation of ketimines 3cee did not take place with allylic
at 60 ꢀC (Method C), to give a mixture of diastereoisomers 5ca and
5ca0, in 75 and 62% yield, respectively (Table 2, entries 1 and 2).
Importantly, there is a correlation between the E:Z isomeric ratio of
the starting ketimines 3c (6:4) and the diastereomeric mixture of
the reaction products (58:42, and 60:40). It indicates that the
allylation is stereospecific. The same correlation was observed in
the reaction of 3c with methallyl bromide (4b) and ethyl-
bromomethylacrylate (4d) (Table 2, entries 3 and 5). Taking into
bromides 4aec in the presence of 1.5 equiv of indium in THF at
room temperature (Method A). However, it proceeded effectively to
yield the expected allylated products at a higher temperature
(Method C). The indium-mediated allylation of ketimine 3c, de-
rived from ethyl pyruvate (2c) (isolated as a 6:4 mixture of E:Z
stereoisomers) was performed either in a saturated aqueous solu-
tion of sodium bromide at room temperature (Method B) or in THF
Table 2
Allylation of N-tert-butanesulfinyl imines 3cee derived from
a
-keto esters 2cee
Entry
Imino ester 3
Allylic bromide 4
Method
a
-Amino ester 5
No.
Structure
Yield (%)a
1
2
3c
3c
4a (R3¼H, R4¼H)
4a (R3¼H, R4¼H)
B
C
75 (58:42)b
62 (60:40)b
3
3c
4b (R3¼Me, R4¼H)
C
58 (60:40)b
4
5
3c
3c
4c (R3¼H, R4¼Me)
C
B
5cc
59 (46:26:14:14)b
4d (R3¼CO2Et, R4¼H)
65 (60:40)b
6
7
8
3d
3d
3e
3e
4a (R3¼H, R4¼H)
C
D
C
D
5da
5dd
60
4d (R3¼CO2Et, R4¼H)
67
4a (R3¼H, R4¼H)
45 (63:33)b
9
4d (R3¼CO2Et, R4¼H)
5ed
58
a
Yield was determined after column chromatography purification and is based on the starting sulfinimide 3.
b
Combined yield. Diastereomeric ratios are given in parenthesis and were determined after 1H NMR analysis of the reaction crude.
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5
account the stereochemical outcome for aldimines 3a and 3b (Table
1), which exhibit exclusively E configuration, we postulate that the
allylation would proceed also through the Si-face on the (E,SS)
major isomer of the imine 3c, leading to the major diastereoisomers
5ca-cd with S configuration at the 2-position (Table 2, entries 1e3
and 4). On the other hand, a complex mixture of 4 diastereoisomers
was obtained with crotyl bromide (4c). In this case, along with the
stereospecific face selectivity, a second stereogenic centre is formed
with low stereocontrol, leading in addition to syn:anti isomers
(Table 2, entry 4). In contrast, ketimines 3d and 3e were isolated as
single Z geometrical isomers, and we expected that the allylation
with allyl bromide (4a) would proceed with total face diaster-
eoselectivity. That was the case for the isopropyl derivative 3d
(Table 2, entry 6). Surprisingly, the ethyl phenylglyoxylate de-
rivative 3e led to an almost 2:1 mixture of diastereoisomers 5ea
of the imine moiety, which locates the tert-butanesulfinyl and the
ester groups axially. For these imines, the addition of the allyl
moiety takes place at the less hindered Si face (Fig. 1). The rest of
the imines (minor isomer of 3c, 3d and 3e) exhibit (E,SS) configu-
ration, and allylation should take place through a necessarily dif-
ferent pathway, because of the opposite stereochemical outcome (a
total correlation was observed between the E:Z isomeric ratio of
starting ketimines 3c, and the diastereomeric mixture of reaction
products 5caecd). The nucleophilic addition to the Re-face of im-
ines with (Z,SS) configuration could be explained by considering
a six-membered chair-like transition state II, where the indium is
coordinated by the nitrogen atom of the imine, and the tert-buta-
nesulfinyl group and R1 are located at axial positions. In the pro-
posed I and II models, we also consider that the imine and sulfinyl
units adopt the most stable s-cis conformation21 (Fig. 1).
Fig. 1. Proposed stereochemical models for the diastereoselective allylation of N-tert-butanesulfinyl iminoesters 3.
and 5ea0 when it was submitted to the same reaction conditions
(Table 2, entry 8). Finally, we found the highest yields in the ally-
lation of 3d and 3e with ethyl 2-bromomethylacrylate (4d) when
the process was carried out under solvent free reaction conditions
at room temperature (Method D), to give the expected amino di-
esters 5dd and 5ed, respectively, as single diastereoisomers (Table
2, entries 7 and 9). The allylation in a saturated aqueous solution of
sodium bromide (Method B) was far less effective for these
transformations.
We have observed that these indium-promoted allylations are
diastereospecific and the stereochemical pathways are governed by
the configuration of both the sulfur atom of the sulfinyl group and
the configuration of the C]N double bond. For that reason, two
different transition states have been proposed in order to ratio-
nalize the observed diastereoselectivities, depending on the con-
figuration of the C]N double bond, since all the sulfinyl imines
exhibit SS configuration. Thus, for imines 3a, 3b and the major
isomer of 3c with (E,SS) configuration, the allylation would proceed
through a six-membered ZimmermaneTraxler like ring model I,
with an attached five-membered metallacycle, in which indium is
chelated both by the ester carbonyl oxygen and the nitrogen atoms
Amino diesters 5dd and 5ed, derived from the allylation of
imino esters 3d and 3e, respectively, with ethyl bromomethyla-
crylate (4d), can be easily transformed into
a-methylene-g-
butyrolactams 6d and 6e in a one-pot, two-step process. First, the
tert-butanesulfinyl unit was removed under acidic conditions to
produce the ammonium salt, and after that, treatment with so-
dium ethoxide promoted the intramolecular cyclization of the
free amine. These reactions were carried out in ethanol as
solvent in order to avoid the formation of mixtures of esters
by transesterification (Scheme 3). Compounds 5 are of interest
not only because they can be transformed into the corresponding
a
-amino acid derivatives, some of them with the nitrogen
bonded to a quaternary stereocentre, but also because the allylic
moiety can participate in a number of further synthetically useful
transformations, such as cross-metathesis, epoxidation, oxidative
cleavage, Heck type reaction, cycloaddition, hydroboration,
hydroformylation, hydrogenation, hydration, ozonolysis, etc.2 In
addition, the
a,b-unsaturated lactam moiety in compounds 6
allows further structural modifications by reaction with nucleo-
philes and electrophiles, leading to more complex molecules
(Fig. 2).
Scheme 3. Synthesis of
a
-methylene-
g
-butyrolactams 6 from amino diesters 5dd and 5ed.
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6
E. Macia et al. / Tetrahedron xxx (2016) 1e10
Fig. 2. Potential applications as synthetic intermediates of compounds 5 and 6.
3. Conclusions
magnesium sulfate for 30 min, and after filtration, the solvent was
evaporated (15 Torr) to give methyl glyoxylate (2a) as a colorless
oil (0.720 g), which was used in the next step without further
purification. To a solution of the crude methyl glyoxylate (2a,
0.720 g, 8.1 mmol), and (SS)-tert-butanesulfinamide (1, 0.787 g,
6.5 mmol) in dry dichloromethane (15 mL) under argon was
added anhydrous copper(II) sulfate (1.760 g, 11.0 mmol) and the
reaction mixture was stirred at room temperature for 24 h. The
solid was filtered off, washed with ethyl acetate (3ꢂ10 mL) and the
organic layer was evaporated (15 Torr). The resulting residue was
purified by column chromatography (silica gel, hexane/ethyl ac-
etate, 6/1) to yield pure (SS,E)-methyl 2-[(tert-butanesulfinyl)im-
From the results shown here we conclude that the indium-
mediated allylation of N-tert-butanesulfinyl imines derived from
-keto esters takes place with high diastereoselectivity. In-
terestingly, the configuration of the newly created stereogenic
centre is determined by the configuration of both the sulfur atom of
the tert-butanesulfinyl unit and the C]N double bond of the imine.
Enantioenriched homoallylic a-amino esters can be prepared fol-
lowing this methodology, these compounds being synthetic in-
termediates of wide applicability.
a
ino]acetate (3a) as a colorless oil (0.372 g, 30%). Rf¼0.60 (hexane/
4. Experimental
4.1. General
30
AcOEt 2:1); [
a
]
þ173 (c 0.88, CH2Cl2);
n (film) 2957, 1750, 1735,
D
1609, 1457, 1291, 1092 cmꢁ1
; dH 1.28 [9H, s, (CH3)3], 3.94 (3H, s,
CH3), 8.02 (1H, s, CH); dC 22.7, 53.1 (CH3), 59.0 (C), 155.2 (CH), 161.6
(C); LRMS (EI) m/z 135 (Mþꢁ56, 29%), 106 (9), 103 (8), 75 (7), 59
(10), 57 (100); HRMS (ESI): calculated for C3H5NO3S (MþꢁC4H8)
134.9990, found 134.9985.
(RS)-tert-Butanesulfinamide was a gift of Medalchemy (>99% ee
by chiral HPLC on a Chiracel AS column, 90:10 n-hexane/i-PrOH,
1.2 mL/min,
l¼222 nm). TLC was performed on silica gel 60 F254
,
using aluminum plates and visualized with phosphomolybdic acid
(PMA) stain. Flash chromatography was carried out on handpacked
columns of silica gel 60 (230e400 mesh). Melting points are un-
corrected. Optical rotations were measured using a Jasco P-1030
polarimeter with a thermally jacketted 5 cm cell at approximately
23 ꢀC and concentrations (c) are given in g/100 mL. Infrared anal-
yses were performed with an ATR Jasco FT/IR-4100 spectropho-
tometer; wave numbers are given in cmꢁ1. Low-resolution mass
spectra (EI) were obtained with an Agilent GC/MS5973N spec-
trometer at 70 eV; and fragment ions in m/z with relative in-
tensities (%) in parentheses. High-resolution mass spectra (HRMS)
were also carried out in the electron impact mode (EI) at 70 eV and
on a Finnigan MAT95S spectrometer equipped with a time of flight
(TOF) analyzer and the samples were ionized by ESI techniques and
introduced through an ultra-high pressure liquid chromatography
(UPLC) model. 1H NMR spectra were recorded at 300 or 400 MHz
for 1H NMR and 75 or 100 MHz for 13C NMR with a Bruker AV300
Oxford or a Bruker AV400 spectrometers, respectively, using CDCl3
as the solvent and TMS as internal standard (0.00 ppm). The data is
being reported as: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
sept¼septet, m¼multiplet or unresolved, br s¼broad signal, cou-
pling constant(s) in Hz, integration. 13C NMR spectra were recorded
with 1H-decoupling at 100 MHz and referenced to CDCl3 at
77.16 ppm. DEPT-135 experiments were performed to assign CH,
CH2 and CH3. All reactions requiring anhydrous conditions were
performed in oven dried glassware under argon. Otherwise in-
dicated, all commercially available chemicals were purchased from
Acros or SigmaeAldrich and used without purification.
4.3. Preparation of (E,SS)-ethyl 2-[(tert-butanesulfinyl)imino]
acetate (3b)16
To a solution of the freshly distilled from a 50% solution in tol-
uene of ethyl glyoxylate (2b, 0.510 g, 5.0 mmol), and (SS)-tert-
butanesulfinamide (1, 0.665 g, 5.5 mmol) in dry dichloromethane
(15 mL) under argon was added anhydrous copper(II) sulfate
(1.760 g, 11.0 mmol) and the reaction mixture was stirred at room
temperature for 24 h. The solid was filtered off, washed with ethyl
acetate (3ꢂ10 mL) and the organic layer was evaporated (15 Torr).
The resulting residue was purified by column chromatography
(silica gel, hexane/ethyl acetate, 6/1) to yield pure (E,SS)-ethyl 2-
[(tert-butanesulfinyl)imino]acetate (3b) as a colorless oil (0.953 g,
30
93%). Rf¼0.72 (hexane/AcOEt 2:1); [
a
]
þ183 (c 0.92, CH2Cl2);
n
D
(film) 2967, 2955, 1753, 1735, 1609, 1456, 1285, 1110 cmꢁ1
;
dH 1.28
[9H, s, (CH3)3], 1.39 (3H, t, J¼7.2 Hz, CH2CH3), 4.39 (2H, q, J¼7.2 Hz,
OCH2), 8.02 (1H, s, CH); dC 14.5, 22.7 (CH3), 58.9 (C), 62.4 (CH2),
155.9 (CH), 161.1 (C); LRMS (EI) m/z 149 (Mþꢁ56, 20%), 120 (12), 117
(7), 89 (10), 73 (10), 57 (100).
4.4. General procedure for the preparation of ketimines 3cee
To a solution of the corresponding ketoester 2ced (5.5 mmol) in
dry THF (15 mL) was added (SS)-tert-butanesulfinamide (1, 0.605 g,
5.0 mmol) and titanium tetraethoxide (2.280 g, 2.095 mL,
10.0 mmol). The resulting mixture was stirred at 60 ꢀC for 6 h, and
after that quenched with brine (4.0 mL), and diluted with ethyl
acetate (3ꢂ10 mL). The resulting suspension was filtered through
a short plug of CeliteÒ and concentrated (15 Torr). The residue was
purified by column chromatography (hexane/ethyl acetate) to yield
pure compounds 3cee. Yields for these compounds 3 are given on
Scheme 2. Physical and spectroscopic data follow.
4.2. Preparation of (SS,E)-methyl 2-[(tert-butanesulfinyl)
imino]acetate (3a)
To a (þ)-dimethyl
L-tartrate (0.890 g, 5.0 mmol) solution in
diethyl ether (10 mL) was slowly added periodic acid (1.254 g,
5.5 mmol). The reaction mixture is stirred at room temperature for
2 h and after that, the solid was filtered off and washed with ethyl
acetate (3ꢂ10 mL). The organic layer was dried over anhydrous
4.4.1. (SS)-Ethyl 2-[(tert-butanesulfinyl)imino]propanoate (3c).15a
(60:40 E:Z diastereomeric mixture) yellow oil; Rf¼0.56 (hexane/AcOEt
2:1); [
a
]
30 þ151 (c 0.65, CH2Cl2);
n (film) 2980, 1725, 1629, 1458, 1365,
D
ꢀ
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ꢀ
E. Macia et al. / Tetrahedron xxx (2016) 1e10
7
1275, 1087 cmꢁ1
;
dH 1.25 [3.6H, s, (CH3)3], 1.31 [5.4H, s, (CH3)3],
2.51e2.53 (2H, m, CH2), 4.04 (1H, q, J¼5.7 Hz, CH), 4.14 (1H, d,
J¼6.3 Hz, NH), 4.22 (2H, q, J¼7.2 Hz, OCH2), 5.09e5.14 (2H, m, CH]
CH2), 5.70e5.77 (1H, m, CH]CH2); dC 14.2, 22.6 (CH3), 38.1 (CH2),
56.1 (C), 56.9 (CH), 61.8 (CH2), 118.8 (CH2), 132.4 (CH), 172.4 (C);
LRMS (EI) m/z 191 (Mþꢁ56, 15%), 167 (17), 149 (74), 100 (18), 97
(39), 95 (27), 85 (39), 83 (37), 81 (27), 71 (55), 69 (49), 57 (100), 55
(48).
1.33e1.40 (3H, m, CH2CH3), 2.34 (1.2H, s, CH3), 2.58 (1.8H, s, CH3),
4.27e4.34 (2H, m, OCH2); dC 14.0, 18.4, 22.8, 25.2 (CH3), 59.2 (C), 62.3
(CH2), 163.4, 167.3, 167.6 (C); LRMS (EI) m/z 163 (Mþꢁ56, 95%), 145 (8),
117 (46), 89 (73), 57 (100).
4.4.2. (Z,SS)-Ethyl 2-[(tert-butanesulfinyl)imino]-3-methylbutanoate
30
(3d).15a yellow oil; Rf¼0.78 (hexane/AcOEt 2:1); [
a
]
þ262 (c
D
0.60, CH2Cl2);
n
(film) 2975,1735,1625,1459,1364,1251,1089 cmꢁ1
;
4.5.4. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-4-methylpent-
4-enoate (5bb).17b Yellow oil; Rf¼0.22 (hexane/AcOEt 2:1); [
a]
D
30
dH 1.19 [3H, d, J¼6.9 Hz, CH(CH3)(CH3)], 1.20 [3H, d, J¼6.9 Hz,
CH(CH3)(CH3)], 1.25 [9H, s, (CH3)3], 1.35 (3H, t, J¼7.2 Hz, CH2CH3),
2.85 [1H, sept, J¼6.6 Hz, CH(CH3)2], 4.29e4.34 (2H, m, OCH2); dC
14.0, 18.9, 19.3, 22.5, 37.1 (CH3), 58.1 (C), 61.8 (CH2), 166.6, 174.2 (C);
LRMS (EI) m/z 191 (Mþꢁ56, 56%), 146 (12), 143 (13), 117 (100), 70
(26), 57 (59).
þ47 (c 0.88, CH2Cl2);
n
(film) 2952, 2922, 1736, 1649, 1455, 1366,
dH 1.23 [9H, s, (CH3)3], 1.29 (3H, t, J¼6.9 Hz,
1264, 1179, 1060 cmꢁ1
;
CH2CH3), 1.75 (3H, s, CH3), 2.35e2.53 (2H, m, CH2), 4.01e4.11 (2H,
m, CH, NH), 4.22 (2H, q, J¼7.2 Hz, OCH2), 4.75 (1H, br s, C]CHH),
4.83 (1H, br s, C]CHH); dC 14.1, 22.1, 29.7 (CH3), 42.4 (CH2), 56.2 (C
and CH), 61.7 (CH2), 114.5 (CH2), 140.3, 173.2 (C); LRMS (EI) m/z 205
(Mþꢁ56, 8%), 167 (15), 149 (63), 141 (30), 111 (21), 97 (30), 85 (34),
83 (38), 81 (20), 71 (46), 57 (100).
4.4.3. (Z,SS)-Ethyl 2-[(tert-butanesulfinyl)imino]-2-phenylacetate
30
(3e).15a Yellow oil; Rf¼0.85 (hexane/AcOEt 2:1); [
a]
þ108 (c
D
0.80, CH2Cl2);
n (film) 2979, 2867, 1735, 1590, 1571, 1447, 1290,
1205 cmꢁ1
;
dH 1.37 [9H, s, (CH3)3], 1.43 (3H, t, J¼7.2 Hz, CH2CH3),
4.6. General procedure for the allylation of imines 3 in H2O at
23 ꢀC (Method B)
4.43e4.52 (2H, m, OCH2), 7.28e7.55 (3H, m, ArH), 7.78e7.81 (2H, m,
ArH); dC 14.0, 23.0 (CH3), 59.5 (C), 62.3 (CH2), 127.9, 128.9, 132.6
(CH), 133.1, 163.3, 165.8 (C); LRMS (EI) m/z 207 (Mþꢁ74, 9%), 153
(37), 152 (30), 132 (6), 104 (100), 103 (77), 77 (39), 51 (27).
To a suspension of the corresponding imine 3 (0.5 mmol) in
a saturated sodium bromide aqueous solution (5 mL) was added the
corresponding allylic bromide 4 (1.5 mmol) and indium (0.232 g,
2.0 mmol). The resulting reaction mixture was stirred at 23 ꢀC for
48 h and after that, extracted with ethyl acetate (3ꢂ10 mL) and the
organic layer was dried over anhydrous magnesium sulfate and
evaporated (15 Torr). The resulting residue was then purified by
column chromatography (silica gel, hexane/ethyl acetate) to yield
pure compounds 5. Yields are given on Tables 1 and 2. Physical and
spectroscopic data follow.
4.5. General procedure for the allylation of imines 3 in THF at
23 ꢀC (Method A)
To a solution of the corresponding imine 3 (0.5 mmol) in THF
(2 mL) was added the corresponding allylic bromide 4 (1.5 mmol)
and indium (0.086 g, 0.75 mmol). The resulting suspension was
stirred at 23 ꢀC for 6 h and after that quenched with brine (4.0 mL),
extracted with ethyl acetate (3ꢂ10 mL) and the organic layer was
dried over anhydrous magnesium sulfate and evaporated (15 Torr).
The resulting residue was then purified by column chromatography
(silica gel, hexane/ethyl acetate) to yield pure compounds 5. Yields
for these compounds 5 are given on Table 1. Physical and spectro-
scopic data follow.
4.6.1. (2S,SS)-5Ethyl 1-methyl 2-[N-(tert-butanesulfinyl)amino]-4-
methylenepentanedioate (5ad). Orange oil; Rf¼0.26 (hexane/
30
AcOEt 2:1); [
a
]
þ36 (c 0.70, CH2Cl2);
n (film) 2956, 2871, 1710,
D
1630, 1518, 1457, 1368, 1214, 1147, 1059 cmꢁ1
; dH 1.21 [9H, s,
(CH3)3], 1.31 (3H, t, J¼6.9 Hz, CH2CH3), 2.68 (1H, dd, J¼13.8, 1.2 Hz,
CHH), 2.78 (1H, dd, J¼13.8, 1.2 Hz, CHH), 3.76 (3H, s, CH3),
4.10e4.26 (4H, m, NH, CHN, OCH2), 5.62 (1H, br s, C]CHH), 6.27
(1H, br s, C]CHH); dC 14.2, 22.6 (CH3), 36.8 (CH2), 52.5 (CH3), 56.3
(C), 57.1 (CH), 61.0 (CH2), 128.5 (CH2) 135.8, 166.4, 173.2 (C); LRMS
(EI) m/z 249 (Mþꢁ56, 7%), 190 (17), 158 (20), 135 (32), 115 (96), 87
4.5.1. (2S,SS)-Methyl 2-[N-(tert-butanesulfinyl)amino]pent-4-enoate
30
(5aa). Yellow oil; Rf¼0.30 (hexane/AcOEt 2:1); [
0.58, CH2Cl2);
1060 cmꢁ1
dH 1.25 [9H, s, (CH3)3], 2.50e2.55 (2H, m, CH2), 3.75
a
]
þ64 (c
D
n
(film) 2980, 2953, 1735, 1363, 1272, 1221, 1095,
;
(1H, d, J¼5.2 Hz, NH), 3.77 (3H, s, CH3), 4.04e4.09 (1H, m, CHN),
5.08e5.15 (2H, m, CH]CH2), 5.66e5.74 (1H, m, CH]CH2); dC 22.6
(CH3), 38.1 (CH2), 52.5 (CH3), 56.2 (C), 57.1 (CH), 118.8 (CH2), 132.4
(CH), 173.0 (C); LRMS (EI) m/z 177 (Mþꢁ56, 43%), 159 (20), 135
(39), 118 (54), 100 (55), 88 (26), 57 (100); HRMS (ESI): calculated
for C8H16NOS (MþꢁCO2CH3) 174.0953, found 174.0955.
(81), 69 (100); HRMS (ESI): calculated for
C11H20NO3S
(MþꢁCO2CH3) 246.1164, found 246.1158.
4.6.2. (2S,SS)-Diethyl 2-[N-(tert-butanesulfinyl)amino]-4-
methylenepentanedioate (5bd). Yellow oil; Rf¼0.24 (hexane/AcOEt
30
2:1); [
a
]
þ32 (c 1.24, CH2Cl2);
n (film) 2979, 2943, 1713, 1631,
D
1474, 1301, 1268, 1182, 1060 cmꢁ1
; dH 1.21 [9H, s, (CH3)3], 1.26e1.34
4.5.2. (2S,SS)-Methyl 2-[N-(tert-butanesulfinyl)amino]-3-
methylpent-4-enoate (5ac). (Major isomer) yellow oil; Rf¼0.36
(6H, m, 2 CH2CH3), 2.64e2.82 (2H, m, CH2), 4.11e4.26 (6H, m, 2
OCH2, CH, NH), 5.62 (1H, br s, C]CHH), 6.27 (1H, br s, C]CHH); dC
14.0, 14.2, 22.6 (CH3), 36.9 (CH2), 56.3 (C), 57.0 (CH), 61.0, 61.8
(CH2), 128.4 (CH2) 135.9, 166.4, 172.8 (C); LRMS (EI) m/z 263
(Mþꢁ56, 37%), 217 (80), 172 (39), 143 (85), 141 (100), 96 (25), 57
(67); HRMS (ESI): calculated for C10H17NO5S (MþꢁC4H8) 263.0827,
found 263.0837.
(hexane/AcOEt 2:1); [
a
]
D
30 þ55 (c 0.77, CH2Cl2);
n (film) 2957, 2870,
1735, 1638, 1437, 1207, 1070 cmꢁ1
;
dH 1.02 (3H, d, J¼5.7 Hz, CH3),
1.24 [9H, s, (CH3)3], 2.56e2.64 (1H, m, CHCH3), 3.50 (1H, d, J¼5.2 Hz,
NH), 3.74 (3H, s, CH3), 3.85 (1H, dd, J¼6.5, 4.0 Hz, CHN), 5.00e5.10
(2H, m, CH]CH2), 5.60e5.80 (1H, m, CH]CH2); dC 15.1, 22.7 (CH3),
42.0, 52.3 (CH), 56.4 (C), 62.2 (CH3), 116.1 (CH2), 138.9 (CH), 172.9
(C); LRMS (EI) m/z 191 (Mþꢁ56, 46%), 173 (14), 135 (76), 114 (30), 88
(50), 57 (100); HRMS (ESI): calculated for C9H18NOS (MþꢁCO2CH3)
188.1109, found 188.1110.
4.6.3. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2-methylpent-
4-enoate (5ca). (Major diastereoisomer) yellow oil; Rf¼0.31 (hex-
ane/AcOEt 2:1); [
a]
30 þ31 (c 0.72, CH2Cl2);
n (film) 2980, 1734, 1633,
dH 1.16 [9H, s, (CH3)3], 1.22 (3H, t,
D
1457, 1364, 1218, 1069 cmꢁ1
;
4.5.3. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]pent-4-enoate
J¼7.2 Hz, CH2CH3), 1.47 (3H, s, CH3), 2.55e2.61 (2H, m, CH2),
4.08e4.16 (3H, m, OCH2, NH), 5.05e5.09 (2H, m, CH]CH2),
5.68e5.82 (1H, m, CH]CH2); dC 13.2, 21.6, 23.1 (CH3), 44.1 (CH2),
55.1 (C), 60.6 (CH2), 60.8 (C), 118.8 (CH2), 131.1 (CH), 172.3 (C); LRMS
30
(5ba).17b Yellow oil; Rf¼0.27 (hexane/AcOEt 2:1); [
a
]
þ77 (c
D
1.96, CH2Cl2);
1075 cmꢁ1
n (film) 2952, 2928, 1735, 1642, 1465, 1365, 1185,
;
dH 1.25 [9H, s, (CH3)3], 1.29 (3H, t, J¼6.9 Hz, CH2CH3),
ꢀ
Please cite this article in press as: Macia, E.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.020

ꢀ
E. Macia et al. / Tetrahedron xxx (2016) 1e10
8
(EI) m/z 205 (Mþꢁ56, 18%), 187 (13), 163 (10), 132 (100), 114 (45), 89
(19); HRMS (ESI): calculated for C9H18NOS (MþꢁCO2CH2CH3)
188.1109, found 188.1110.
HRMS (ESI): calculated for C10H20NOS (MþꢁCO2CH2CH3) 202.1266,
found 202.1267.
4.7.2. (2R,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2,4-
4.6.4. (2R,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2-methylpent-
4-enoate (5ca0). (Minor diastereoisomer) yellow oil; Rf¼0.36
dimethylpent-4-enoate (5cb0). (Minor diastereoisomer) yellow oil;
30
Rf¼0.44 (hexane/AcOEt 2:1); [
a
]
D
þ18 (c 1.00, CH2Cl2);
n
(film)
(hexane/AcOEt 2:1); [
a
]
D
30 þ46 (c 0.79, CH2Cl2);
n
(film) 2981, 2870,
2924, 1732, 1644, 1457, 1375, 1204, 1073, 895 cmꢁ1
; dH 1.24 [9H, s,
1732, 1640, 1457, 1364, 1220, 1071 cmꢁ1
;
dH 1.16 [9H, s, (CH3)3], 1.22
(CH3)3], 1.29 (3H, t, J¼7.2 Hz, CH2CH3), 1.63 (3H, s, CH3), 1.70 (3H, br
s, CH3), 2.70e2.58 (2H, m, CH2), 4.09 (1H, s, NH), 4.14e4.25 (2H, m,
OCH2), 4.80 (1H, br s, C]CHH), 4.96 (1H, br s, C]CHH); dC 14.1, 22.7,
23.5, 24.6 (CH3), 31.9 (C), 49.4 (CH2), 56.3 (C), 61.5 (CH2), 116.6
(CH2), 140.4, 175.3 (C); LRMS (EI) m/z 219 (Mþꢁ56, 18%), 191 (9), 163
(100),157 (50),146 (95), 130 (97), 117 (41), 109 (18), 89 (92), 55 (37);
HRMS (ESI): calculated for C10H20NOS (MþꢁCO2CH2CH3) 202.1266,
found 202.1266.
(3H, t, J¼7.2 Hz, CH2CH3), 1.52 (3H, s, CH3), 2.43e2.49 (2H, m, CH2),
4.10e4.17 (3H, m, OCH2, NH), 5.01e5.06 (2H, m, CH]CH2),
5.55e5.69 (1H, m, CH]CH2); dC 13.1, 21.7, 23.2 (CH3), 43.5 (CH2),
55.0, 60.1 (C), 60.7 (CH2),118.3 (CH2),131.1 (CH),173.0 (C); LRMS (EI)
m/z 205 (Mþꢁ56, 18%), 187 (13), 163 (6), 132 (100), 114 (37), 89 (19),
57 (25); HRMS (ESI): calculated for C9H18NO2S (MþꢁCO2CH2CH3)
188.1109, found 188.1110.
4.6.5. (2S,SS)-Diethyl 2-[N-(tert-butanesulfinyl)amino]-2-methyl-4-
methylenepentanedioate (5cd). (Major diastereoisomer) orange
4.7.3. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2,3-
dimethylpent-4-enoate (5cc). (Major diastereoisomer) yellow oil;
30
oil; Rf¼0.34 (hexane/AcOEt 2:1); [
a
]
30 þ16 (c 0.57, CH2Cl2);
n
(film)
Rf¼0.44 (hexane/AcOEt 2:1); [
a]
þ55 (c 0.61, CH2Cl2);
n
(film)
D
D
2981, 1718, 1626, 1531, 1457, 1368, 1214, 1197, 1024 cmꢁ1
;
dH 1.20
2924, 1730, 1642, 1458, 1368, 1201, 1068, 894 cmꢁ1
; dH 0.99 (3H, d,
[9H, s, (CH3)3], 1.23e1.31 (6H, m, 2 CH2CH3), 1.62 (3H, s, CH3), 2.79
(1H, d, J¼13.8 Hz, CHH), 2.92 (1H, d, J¼13.8 Hz, CHH), 4.00e4.18 (4H,
m, 2 OCH2), 4.54 (1H, s, NH), 5.81 (1H, br s, C]CHH), 6.31 (1H, br s,
C]CHH); dC 14.0, 22.5, 22.6, 24.1 (CH3), 42.6 (CH2), 55.3, 57.4 (C),
61.2, 61.7, 130.3 (CH2) 135.3, 167.4, 172.9 (C); LRMS (EI) m/z 277
(Mþꢁ56, 2%), 227 (12), 204 (87), 186 (20), 163 (95), 140 (27), 114
(41), 87 (50), 69 (100); HRMS (ESI): calculated for C11H19NO5S
(MþꢁC4H8) 277.0984, found 277.0986.
J¼6.9 Hz, CH3), 1.25 [9H, s, (CH3)3], 1.29 (3H, t, J¼7.2 Hz, CH2CH3),
1.55 (3H, s, CH3), 2.40e2.55 (1H, m, CH), 4.17e4.25 (2H, m, OCH2),
4.33 (1H, br s, NH), 5.06e5.13 (2H, m, CH]CH2), 5.60e5.74 (1H, m,
CH]CH2); dC 14.1, 19.2, 22.8 (CH3), 47.4 (CH), 56.1 (C), 61.7 (CH2),
63.1 (C) 117.4 (CH2), 137.8 (CH), 174.5 (C); LRMS (EI) m/z 219
(Mþꢁ56, 5%) 203 (6), 164 (8), 146 (100), 128 (19), 98 (20), 73 (5), 55
(9);; HRMS (ESI): calculated for C10H20NOS (MþꢁCO2CH2CH3)
202.1266, found 202.1262.
4.6.6. (2R,SS)-Diethyl 2-[N-(tert-butanesulfinyl)amino]-2-methyl-4-
methylenepentanedioate (5cd0). (Minor diastereoisomer) orange
4.7.4. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2-
isopropylpent-4-enoate (5da). Yellow oil; Rf¼0.48 (hexane/AcOEt
30
oil; Rf¼0.30 (hexane/AcOEt 2:1); [
a]
30 þ25 (c 1.24, CH2Cl2);
n
(film)
2:1); [
a
]
þ26 (c 0.61, CH2Cl2);
n (film) 2961, 2923, 1725, 1366,
dH 0.98 [3H, d, J¼6.8 Hz, CH(CH3)(CH3)], 1.04 [3H,
D
D
2981, 1720, 1630, 1530, 1457, 1368, 1214, 1200, 1024 cmꢁ1
;
dH 1.17
1220, 1072 cmꢁ1
;
[9H, s, (CH3)3], 1.23e1.31 (6H, m, 2 CH2CH3), 1.53 (3H, s, CH3), 2.58
(1H, d, J¼13.8 Hz, CHH), 2.98 (1H, d, J¼13.8 Hz, CHH), 4.13e4.32 (4H,
m, 2 OCH2), 4.30 (1H, s, NH), 5.60 (1H, br s, C]CHH), 6.28 (1H, br s,
C]CHH); dC 14.0, 22.0, 22.6, 24.1 (CH3), 42.6 (CH2), 55.3, 56.4 (C),
61.2, 61.8, 130.3 (CH2) 135.3, 167.2, 174.0 (C); LRMS (EI) m/z 277
(Mþꢁ56, 3%), 232 (7), 204 (87), 186 (20), 163 (94), 140 (25), 114 (41),
d, J¼6.8 Hz, CH(CH3)(CH3)], 1.26 [9H, s, (CH3)3], 1.27e132 (3H, m,
CH2CH3), 2.23e2.32 [1H, m, CH(CH3)2], 2.74e2.77 (2H, m, CH2),
4.17e4.25 (2H, m, OCH2), 4.41 (1H, s, NH), 5.05e5.14 (2H, m, CH]
CH2), 5.63e5.72 (1H, m, CH]CH2); dC 14.2, 16.7, 17.8, 22.6 (CH3),
36.9 (CH), 38.5 (CH2), 57.0 (C), 61.5 (CH2), 69.1 (C), 118.8 (CH2), 133.1
(CH), 172.6 (C); LRMS (EI) m/z 233 (Mþꢁ56, 2%) 190 (22), 161 (15),
160 (100), 144 (23), 126 (62), 117 (40), 100 (27), 72 (8), 70 (15);
HRMS (ESI): calculated for C10H19NO3S (MþꢁC4H8) 233.1086, found
233.1090.
87 (50), 69 (100); HRMS (ESI): calculated for
C11H19NO5S
(MþꢁC4H8) 277.0984, found 277.0983.
4.7. General procedure for the allylation of imines 3 in THF at
60 ꢀC (Method C)
4.7.5. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2-phenylpent-
4-enoate (5ea). (Major diastereoisomer) yellow oil; Rf¼0.50 (hex-
To a solution of the corresponding imine 3 (0.5 mmol) in THF
(2 mL) was added the corresponding allylic bromide 4 (1.5 mmol)
and indium (0.086 g, 0.75 mmol). The resulting suspension was
stirred at 60 ꢀC for 6 h and after that, the reaction mixture was
cooled down, quenched with brine (4.0 mL), extracted with ethyl
acetate (3ꢂ10 mL) and the organic layer was dried over anhydrous
magnesium sulfate and evaporated (15 Torr). The resulting residue
was then purified by column chromatography (silica gel, hexane/
ethyl acetate) to yield pure compounds 5. Yields are given on Table
2. Physical and spectroscopic data follow.
ane/AcOEt 2:1); [
a
]
30 þ44 (c 0.50, CH2Cl2);
n (film) 3011, 2933, 1728,
D
1638, 1366, 1225, 1117, 1072 cmꢁ1
;
dH 1.20 [9H, s, (CH3)3], 1.19e1.22
(3H, m, CH2CH3), 3.23 (2H, d, J¼7.2 Hz, CH2), 4.05e4.25 (2H, m,
OCH2), 4.68 (1H, s, NH), 5.14e5.20 (2H, m, CH]CH2), 5.74e5.83
(1H, m, CH]CH2), 7.26e7.38 (5H, m, ArH); dC 14.0, 22.7 (CH3), 40.9
(CH2), 56.4 (C), 62.0 (CH2), 67.0 (C), 120.3 (CH2), 126.7, 128.1, 128.4,
131.7 (CH), 140.0, 172.7 (C); LRMS (EI) m/z 267 (Mþꢁ56, 20%), 204
(57), 203 (100), 175 (24), 157 (25), 135 (35), 131 (75), 129 (55), 91
(23), 57 (47); HRMS (ESI): calculated for C13H17NO3S (MþꢁC4H8)
267.0929, found 267.0945.
4.7.1. (2S,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2,4-
4.7.6. (2R,SS)-Ethyl 2-[N-(tert-butanesulfinyl)amino]-2-phenylpent-
4-enoate (5ea0). (Minor diastereoisomer) yellow oil; Rf¼0.42
dimethylpent-4-enoate (5cb). (major diastereoisomer) yellow oil;
30
Rf¼0.40 (hexane/AcOEt 2:1); [
a]
þ25 (c 0.60, CH2Cl2);
n
(film)
(hexane/AcOEt 2:1); [
a
]
D
30 þ52 (c 0.58, CH2Cl2);
n
(film) 3010, 3002,
dH 1.20 (3H, t,
D
2921, 1719, 1644, 1421, 1360, 1221, 1063, 736 cmꢁ1
;
dH 1.22 [9H, s,
2934, 1726, 1638, 1362, 1225, 1117, 1070 cmꢁ1
;
(CH3)3], 1.30 (3H, t, J¼7.2 Hz, CH2CH3), 1.60 (3H, s, CH3), 1.67 (3H, br
s, CH3), 2.50e2.62 (2H, m, CH2), 4.02 (1H, s, NH), 4.16e4.26 (2H, m,
OCH2), 4.74 (1H, br s, C]CHH), 4.86 (1H, br s, C]CHH); dC 14.0, 22.7,
23.5, 25.0 (CH3), 31.9 (C), 47.8 (CH2), 56.0 (C), 61.8, 115.6 (CH2),
140.2, 174.6 (C); LRMS (EI) m/z 219 (Mþꢁ56, 18%), 191 (9), 163 (80),
157 (20), 146 (100), 130 (90), 117 (41), 109 (18), 89 (92), 55 (17);
J¼7.2 Hz, CH2CH3), 1.23 [9H, s, (CH3)3], 3.13 (2H, d, J¼7.2 Hz, CH2),
4.13e4.22 (2H, m, OCH2), 4.68 (1H, s, NH), 5.18e5.24 (2H, m, CH]
CH2), 5.70e5.80 (1H, m, CH]CH2), 7.26e7.42 (5H, m, ArH); dC 14.1,
22.7 (CH3), 41.2 (CH2), 56.7 (C), 62.2 (CH2), 67.3 (C), 120.0 (CH2),
126.7, 128.3, 128.5, 132.2 (CH), 139.8, 172.4 (C); LRMS (EI) m/z 267
(Mþꢁ56, 30%), 204 (40), 203 (100), 175 (45), 157 (25), 135 (35), 131
ꢀ
Please cite this article in press as: Macia, E.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.020

ꢀ
E. Macia et al. / Tetrahedron xxx (2016) 1e10
9
(75), 129 (50), 91 (30), 57 (40); HRMS (ESI): calculated for
C
2.83 (1H, dt, J¼17.7, 2.4 Hz, CHH), 3.14 (1H, dt, J¼17.7, 2.4 Hz, CHH),
4.22 (2H, q, J¼7.2 Hz, OCH2), 5.38 (1H, br s, C]CHH), 6.01 (1H, t,
J¼2.7 Hz, C]CHH), 6.25 (1H, br s, NH); dC 14.2, 16.0, 17.0 (CH3), 29.7
(CH2), 35.8 (CH), 61.8 (CH2), 65.8 (C), 116.8 (CH2), 138.0, 169.2, 172.9
(C); LRMS (EI) m/z 183 (Mþꢁ28, 100%), 175 (20), 144 (60), 131(30),
102 (25), 58 (67); HRMS (ESI): calculated for C8H10NO3 (MþꢁC3H7)
168.0661, found 168.0667.
13H17NO3S (MþꢁC4H8) 267.0929, found 267.0932.
4.8. General procedure for the allylation of imines 3 under
solvent free reaction conditions (Method D)
A mixture of the corresponding imine 3 (0.5 mmol), ethyl
bromomethylacrylate (4d, 0.290 g, 0.210 mL, 1.5 mmol) and in-
dium (0.116 g, 1.0 mmol) was stirred at 23 ꢀC for 6 h. After that,
the reaction mixture was quenched with water (50 mL), extrac-
ted with ethyl acetate (3ꢂ10 mL) and the organic layer was dried
over anhydrous magnesium sulfate and evaporated (15 Torr). The
resulting residue was then purified by column chromatography
(silica gel, hexane/ethyl acetate) to yield pure compounds 5.
Yields are given on Table 2. Physical and spectroscopic data
follow.
4.9.2. (S)-5-Ethoxycarbonyl-3-methylene-5-phenylpyrrolidin-2-one
30
(6e). Orange oil; Rf¼0.22 (hexane/AcOEt 2:1); [
CH2Cl2);
734, 701 cmꢁ1
a
]
ꢁ2.7 (c 0.80,
D
n
(film) 3014, 2924, 1710, 1670, 1437, 1360, 1220, 1090,
dH 1.20e1.30 (3H, m, CH2CH3), 3.01 (1H, dt,
;
J¼17.1, 2.4 Hz, CHH), 3.81 (1H, dt, J¼17.1, 2.3 Hz, CHH), 4.19e4.25
(2H, m, OCH2), 5.41 (1H, br s, C]CHH), 6.07 (1H, br s, C]CHH),
6.81 (1H, br s, NH), 7.37e7.40 (5H, m, ArH); dC 14.0, 39.6, 62.4
(CH2), 65.2 (C), 117.9 (CH2), 124.4, 128.4, 129.0 (CH), 137.1, 141.0,
169.2, 171.5 (C); LRMS (EI) m/z 218 (Mþꢁ28, 100%), 172 (80), 159
(8), 144 (10), 129 (11), 104 (12), 91 (5), 77 (7); HRMS (ESI): cal-
4.8.1. (2S,SS)-Diethyl 2-[N-(tert-butanesulfinyl)amino]-2-isopropyl-
4-methylenepentanedioate (5dd). Orange oil; Rf¼0.45 (hexane/
culated for
172.0768.
C
11H10NO (MþꢁCO2CH2CH3) 172.0762, found
30
AcOEt 2:1); [
a
]
D
ꢁ8.5 (c 0.50, CH2Cl2);
n
(film) 2959, 2928, 1716,
dH 1.07 [3H, d, J¼6.9 Hz,
1625, 1456, 1366, 1260, 1155, 1026 cmꢁ1
;
CH(CH3)(CH3)], 1.08 [3H, d, J¼6.8 Hz, CH(CH3)(CH3)], 1.24 [9H, s,
(CH3)3], 1.26e1.32 (6H, m, 2 CH2CH3), 2.36 [1H, sept, J¼6.9 Hz,
CH(CH)3], 2.88e2.94 (2H, m, CH2), 4.05e4.24 (4H, m, 2 OCH2), 4.34
(1H, s, NH), 5.83 (1H, br s, C]CHH), 6.31 (1H, br s, C]CHH); dC 14.0,
14.1, 16.6, 18.0, 22.9 (CH3), 35.4 (CH), 38.0 (CH2), 57.3 (C), 61.0, 61.4
(CH2), 69.3 (C), 129.1 (CH2), 135.8 (C), 167.6 (C), 172.6 (C); LRMS (EI)
m/z 305 (Mþꢁ56, 39%), 287 (29), 259 (60), 214 (27), 185 (71), 183
(92), 174 (52), 168 (36), 145 (100), 144 (73), 138 (36), 137 (27), 117
(28), 57 (64); HRMS (ESI): calculated for C13H23NO5S (MþꢁC4H8)
305.1297, found 305.1301.
Acknowledgements
We thank the continued financial support from our Ministerio
de Ciencia e Innovacion (MCINN; projects CONSOLIDER INGENIO
2010-CDS2007-00006, CTQ2011-24165), the Ministerio de Econ-
ꢀ
omía
y Competitividad (MINECO; project CTQ2014-53695-P,
CTQ2014-51912-REDC), FEDER, the Generalitat Valenciana
(PROMETEO 2009/039, PROMETEOII/2014/017) and the University
of Alicante.
Supplementary data
4.8.2. (2S,SS)-Diethyl 2-[N-(tert-butanesulfinyl)amino]-4-methylene-
2-phenylpentanedioate (5ed). Orange oil; Rf¼0.43 (hexane/AcOEt
30
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.07.020.
2:1); [
a
]
ꢁ6.0 (c 0.70, CH2Cl2);
n (film) 3008, 2931, 1719, 1620,
D
1455, 1366, 1250, 1155, 1014 cmꢁ1
; dH 1.16e1.28 (6H, m, 2 CH2CH3),
1.23 [9H, s, (CH3)3], 3.45 (1H, d, J¼14.0 Hz, CHH), 3.54 (1H, d,
J¼14.0 Hz, CHH), 4.02e4.22 (4H, m, 2 OCH2), 4.80 (1H, s, NH), 6.03
(1H, d, J¼1.5 Hz, C]CHH), 6.36 (1H, d, J¼1.5 Hz, C]CHH), 7.33e7.39
(5H, m, ArH); dC 13.8, 14.1, 22.8 (CH3), 37.5 (CH2), 56.6 (C), 60.9
(CH2), 61.9 (CH2), 66.8 (C), 127.2, 128.2, 128.3 (CH), 131.3 (CH2),
135.0, 139.4, 167.2, 172.5 (C); LRMS (EI) m/z 339 (Mþꢁ56, 30%), 294
(10), 266 (30), 221 (37), 185 (71), 179 (100), 168 (36), 144 (43), 136
(38), 117 (28), 77 (24); HRMS (ESI): calculated for C16H21NO5S
(MþꢁC4H8) 339.1140, found 339.1157.
References and notes
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4.9. General procedure for the preparation of
butyrolactams 6
a-methylene-g-
ꢀ
ꢀ
ꢀ
ꢀ
To a solution of the corresponding amino diester derivative 5
(0.2 mmol) in ethanol (0.5 mL) was added a 4 M HCl dioxane so-
lution (0.1 mL, 0.4 mmol) at 0 ꢀC. After 30 min of stirring at the
same temperature, a 2 M sodium ethoxide ethanol solution
(0.25 mL, 0.5 mmol) was added, and the resulting mixture was
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extracted with EtOAc (3ꢂ10 mL), dried over anhydrous magnesium
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4.9.1. (S)-5-Ethoxycarbonyl-5-isopropyl-3-methylenepyrrolidin-2-
one (6d). yellow oil; Rf¼0.25 (hexane/AcOEt 2:1); [
CH2Cl2);
1041, 928 cmꢁ1
[6H, m, CH2CH3, CH(CH3)(CH3)2], 2.14 [1H, sept, J¼6.9 Hz, CH(CH)3],
a
]
30 ꢁ9.5 (c 1.50,
D
n
(film) 2965, 2926, 1733, 1702, 1660, 1463, 1370, 1252,
;
dH 0.89 [3H, d, J¼6.9 Hz, CH(CH3)(CH3)], 1.20e1.33
ꢀ
Please cite this article in press as: Macia, E.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.020

ꢀ
E. Macia et al. / Tetrahedron xxx (2016) 1e10
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ꢀ
Please cite this article in press as: Macia, E.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.020