Base-promoted diastereoselective addition of nitromethane and nitroethane to N-tert-butylsulfinyl imines: Synthesis of N-protected α-amino acids and amino ketones

Article abstract of DOI:10.1016/j.tetasy.2014.01.010

The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO₃ under solvent-free reaction conditions gave β-nitro amine derivatives with reasonable levels of diastereoselectivity. Enantioenriched N-tert-

Full text of DOI:10.1016/j.tetasy.2014.01.010

Tetrahedron: Asymmetry 25 (2014) 362–372
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Base-promoted diastereoselective addition of nitromethane and
nitroethane to N-tert-butylsulfinyl imines: synthesis of N-protected
a-amino acids and amino ketones
⇑
⇑
M. Jesús García-Muñoz, Haythem K. Dema, Francisco Foubelo , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 December 2013
Accepted 10 January 2014
The reaction of N-tert-butylsulfinyl imines with nitromethane or nitroethane in the presence of NaHCO3
under solvent-free reaction conditions gave b-nitro amine derivatives with reasonable levels of diastere-
oselectivity. Enantioenriched N-tert-butylsulfinyl protected
sible upon oxidation of the adducts derived from nitromethane or nitroethane, respectively.
Ó 2014 Elsevier Ltd. All rights reserved.
a-amino acids or a-amino ketones are acces-
Dedicated to Professor Max Malacria on the
occasion of his 65th birthday.
1. Introduction
been reported.8 In this context, we described the diastereoselective
coupling of dimethyl malonate with N-(tert-butyl)sulfinyl imines
under solvent-free conditions and using NaHCO3 as a base pro-
moter. The resulting dimethyl 2-(1-aminoalkyl)malonates were
easily transformed successively to b-amino esters and the corre-
sponding b-lactams with high enantiomeric purity.9 Continuing
our interest in this topic, we herein report our first approach to
the base-mediated coupling of nitroalkanes and chiral N-(tert-
butyl)sulfinyl imines under mild reaction conditions. Considering
the nitro-Mannich reaction using sulfinyl imines as electrophiles,
in 2005, García Ruano, Cid et al. reported the asymmetric reaction
of N-p-toluene sulfinyl aldimines and ketimines with nitromethane
and nitroethane. They found opposite facial selectivity depending
on the reaction conditions (Scheme 1).10 However, to the best of
our knowledge, there is only one report involving the nitro-Man-
nich reaction of an N-tert-butylsulfinyl aldimine, which Lu et al.
used in one step of their synthesis of the antiviral oseltamivir
(Scheme 1).11 More recently, Liu reported on the nitro-Mannich
The addition of an organometallic compound1 or an active C–H
nucleophile to an imine is of great synthetic interest because in
this reaction together with a new functionality (the amino group),
a C–C bond is formed. Thus, if the additions are carried out in a
stereoselective fashion, enantioenriched amines, or amine deriva-
tives, would be produced. These compounds are valuable targets
for synthetic organic chemists because of their importance in agro-
chemicals, fine chemicals, and pharmaceuticals. Among the reac-
tions of imines with active C–H nucleophiles, the nitro-Mannich
(also known as aza-Henry) reaction,2 in which a nitronate anion
is involved, has received much attention over the last decade,
and as a consequence of this, new methodologies are constantly
emerging. The resulting b-nitroamine compounds, known as ni-
tro-Mannich adducts, bearing vicinal nitrogen-containing func-
tionalities in different oxidation states, are versatile
intermediates that can be easily transformed into a wide range of
interesting multifunctionalized molecules, such as 1,2-diamines3
reaction of chiral fluoroalkyl
a,b-unsaturated N-tert-butylsulfinyl
and
a
-aminocarbonyl compounds, via reduction of the nitro group
ketimines and nitromethane in the presence of 0.2 equiv of anhy-
or performing a Nef-type oxidation reaction, respectively.4 Impor-
tantly, enantiomerically pure b-nitroamine compounds have been
accessed through both metal-based and organic catalysis.5 Other
strategies to reach these compounds involve the use of chiral imi-
nes, such as N-tert-butylsulfinyl derivatives,6 which have found
high applicability in synthesis as electrophiles because both enan-
tiomers are accessible via large-scale processes7 and because the
chiral auxiliary can be easily removed under acidic conditions. In
addition, practical processes for recycling the tert-butylsulfinyl
group upon deprotection of N-tert-butanesulfinyl amines have also
drous potassium carbonate (Scheme 1).12
2. Results and discussion
In order to determine the best reaction conditions for the cou-
pling of nitromethane 2a and chiral N-tert-butanesulfinyl imines
1, we took imine (R)-1c (derived from 3-phenylpropanal) as the
model compound. Sodium iodide has recently been successfully
used as a promoter of the condensation of bromonitromethane
with imines,13 and also in the reaction of dimethyl malonate with
chiral imines 1.9 Unfortunately, no reaction occurred when 2 equiv
of nitromethane 2a and imine (R)-1c were treated with 1 equiv of
sodium iodide in THF at room temperature for 72 h (Table 1, entry
⇑
Corresponding authors. Tel.: +34 965903548; fax: +34 965 903549.
E-mail addresses: foubelo@ua.es (F. Foubelo), yus@ua.es (M. Yus).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2014.01.010

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
363
O
O
S
O
S
CH3NO2
CH3NO2
S
R2
NO2
R2
NaOH, 4Å MS
N
1 M TBAF/THF
Tol
NH
Tol
NH
R1
Tol
(10)
40 ºC, 24 h
NO2
23 °C, 1 h
R2
R1
R1
R1 = aryl, alkyl, vinyl
2 = H, aryl, alkyl
(56-99%, 74:26-62:38 dr)
Me
(25-90%, 85:15-97:3 dr)
R
Me
Me
OH
H
OH
O
CO2Et
O
O
MeNO2
(11)
Me
Me
N
Me
HN
S
NaOH, 4Å MS, 23 ºC
AcHN
S
NH2
NO2
t-Bu
O
t-Bu
O
(86%, 10:1 dr)
oseltamivir
t-Bu
t-Bu
O
S
S
N
O
MeNO2
K2CO3 (0.2 equiv), 23 ºC, 3 h
HN
NO2
R2
(12)
R1
R2
R1
R1 = CF3, CF2Cl, CF2H
R2 = Ph, 4-MeOC6H4, 4-ClC6H4, 1-naphthyl, n-C8H18
(54-95%, 95:5 dr)
Scheme 1.
Table 1
Optimization of the reaction conditions with nitromethane 2a
O
O
S
S
reaction
conditions
N
t-Bu
HN
t-Bu
NO2
CH3NO2
+
Ph
H
Ph
2a
(R)-1c
3c
Entry
Reaction conditionsa
Conversionb (%)
drc
1
2
3
4
5
6
7
8
9
CH3NO2 (2 equiv), NaI (1.1 equiv), THF (1 mL), 23 °C, 72 h
CH3NO2 (3 equiv), NaI (1.1 equiv), 23 °C, 72 h
CH3NO2 (3 equiv), NaI (1.1 equiv), 60 °C, 72 h
CH3NO2 (3 equiv), NaHCO3 (2 equiv), 23 °C, 72 h
CH3NO2 (3 equiv), NaHCO3 (2 equiv), 60 °C, 72 h
CH3NO2 (2 equiv), NaHCO3 (2 equiv), THF (1 mL), 60 °C, 72 h
CH3NO2 (2 equiv), 2 M NaOH/H2O (1.1 equiv), THF (1 mL), 23 °C, 72 h
CH3NO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg), 40 °C, 24 h
CH3NO2 (145 equiv, 1 mL), 1 M TBAF/THF (0.2 equiv), 23 °C, 1 h
0
0
0
28
95
70
0
84
100
—
—
—
90:10
92:8
73:27
—
93:7
30:70
a
b
c
All reactions were carried out using 0.2 mmol of aldimine (R)-3c.
Conversion is given based on the disappearance of the starting (R)-3c by 1H NMR.
The diastereomeric ratio was determined by 1H NMR.
1). The same result was obtained under solvent free reaction con-
ditions but using 3 equiv of nitromethane 2a and 1 equivalent of
sodium iodide for 3 days at both room temperature and 60 °C (Ta-
ble 1, entries 2 and 3). Switching from sodium iodide to sodium
bicarbonate as a base under solvent free conditions led to a low
conversion (28%) and relatively high diastereoselectivity (90:10,
Table 1, entry 4) of the expected b-nitroamine derivative 3c. The
conversion was dramatically improved upon when the sodium
bicarbonate mediated coupling was performed at 60 °C instead of
room temperature (from 28 to 95%); furthermore, a slightly higher
diastereomeric ratio was also achieved (Table 1, entry 5). Con-
versely, a lower conversion and diastereoselectivity were obtained
when the reaction was performed in THF solution at 60 °C (Table 1,
entry 6). The reaction did not take place in THF at room tempera-
ture when a stronger base, such as a 2 M aqueous solution of so-
dium hydroxide, was used (Table 1, entry 7). At this point, we
decided to apply to chiral N-tert-butylsulfinyl imine (R)-1c, the
same reaction conditions that García Ruano reported in the highly
effective asymmetric nitro-Mannich reaction of nitromethane 2a
with N-p-toluenesulfinyl imines.10 Thus, the reaction of (R)-1c in
a large excess of nitromethane 2a (reagent and solvent) with 5
equiv of sodium hydroxide in the presence of 4 Å molecular sieves
at 40 °C for 24 h led to 84% conversion and a 93:7 diastereomeric
ratio (Table 1, entry 8). Complete conversion and a significantly
lower and reversed diastereoselectivity were obtained when a
1 M THF solution of tetrabutylammonium fluoride (TBAF) was used

364
M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
at room temperature for 1 h, instead of the combination of sodium
hydroxide in the presence of 4 Å molecular sieves (Table 1, entry
9).
In order to broaden the scope of the sodium bicarbonate pro-
moted nitro-Mannich reaction we applied the optimized condi-
tions depicted in Table 1, entry 5, to different N-tert-butylsulfinyl
aldimines 1. When chiral alkyl aldimines 1 were used, b-nitro-
amine derivatives 3 were obtained in moderate to good yields
and with high diastereomeric ratios (Table 2, entries 1–6). Enantio-
meric nitro amine derivatives 3 were accessed through this meth-
odology, depending exclusively on the configuration of the sulfur
atom of the starting aldimine (Table 2, compare entries 1 and 4,
2 and 5, and 3 and 6). However, in the case of aromatic aldimine
(S)-1d derived from benzaldehyde, the expected reaction product
ent-3d was isolated in 28% yield and lower diastereoselectivity
when compared with the other aldimines (Table 2, entry 7). A pos-
sible explanation for the low yield could be that a retro nitro-Man-
nich reaction could occur to a significant extent for this aldimine
under basic conditions. Taking into account the aforementioned re-
sults, heteroaromatic aldimine (S)-1e produced the expected
Table 2
Preparation of b-nitroamine derivatives 3
O
S
O
S
N
t-Bu
HN
t-Bu
NaHCO3 (2 equiv), 60 ºC, 72 h
CH3NO2
(3 equiv)
+
NO2
R
H
R
1
2a
3
Aldimine 1
b-Nitroamine derivative 3a
Entry
1
No.
R
No.
Structure
Yieldb (%)
drc
O
S
HN
t-Bu
(R)-1a
CH3(CH2)7
3a
3b
63
93:7
Me
( )7
NO2
O
S
HN
Me
t-Bu
2
(R)-1b
i-Pr
75
90:10
NO2
Me
O
S
HN
t-Bu
3
4
(R)-1c
(S)-1a
Ph(CH2)2
3c
78
67
92:8
92:8
NO2
Ph
O
S
HN
t-Bu
CH3(CH2)7
ent-3a
Me
( )7
NO2
O
S
HN
Me
t-Bu
5
(S)-1b
i-Pr
ent-3b
72
90:10
NO2
Me
O
S
HN
t-Bu
6
7
(S)-1c
(S)-1d
Ph(CH2)2
ent-3c
ent-3d
82
28
91:9
NO2
Ph
O
S
HN
t-Bu
Ph
61:39
NO2
Ph
O
S
HN
t-Bu
NO2
8
(R)-1e
2-Benzofuryl
3e
66
72:28
O
a
b
c
All products were >95% pure (GLC and/or 300 MHz 1H NMR).
Isolated yield after column chromatography of the major diastereoisomer (silica gel, hexane/EtOAc) based on the starting aldimine 1.
The diastereomeric ratio was determined by 1H NMR.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
365
O
S
3f and 3g, respectively, in a reasonable yield for 3f and a modest
isolated yield in the case of 3g [starting ketimine (R)-1g was the
major component of the resulting reaction mixture]. However,
both reaction products were obtained with excellent diastereose-
lectivities (Fig. 1). The diastereomeric ratios exceeded the E:Z iso-
meric ratios of the starting ketimines. We have previously
observed that the indium-mediated allylation14 and propargyla-
tion15 of N-tert-butylsulfinyl methyl alkyl ketimines proceeded in
an almost diastereoselective fashion.
O
S
HN
t-Bu
N
t-Bu
Me
Me
NO2
Me
Me
3f (70%, 92:8dr)
1f
(R)-
O
S
O
S
HN
Me
t-Bu
N
t-Bu
In order to show the potential synthetic usefulness of these
b-nitroamine derivatives 3, some of them were transformed into
NO2
Me
Me
Me
N-tert-butylsulfinyl protected
a-amino acids 4 upon treatment
3g(35%, 96:4 dr)
(R)-1g
with sodium nitrite and acetic acid in dimethylformamide (DMF)
at 45 °C for 12 h (Table 3).16 After base-acid extraction, pure com-
pounds 4 were obtained in reasonable yields (no column chroma-
tography purification was needed). Remarkably, this methodology
Figure 1.
reaction product in high yield, although with moderate diastere-
oselectivity (Table 2, entry 8).
allowed the synthesis of
a-amino acid derivatives 4 with the
nitrogen bonded to a quaternary stereocenter, as in the case of
b-nitroamines 3f,g derived from ketimines (R)-1g and (R)-1f,
respectively (Table 3, entries, 4 and 5). It is noteworthy that this
variant of the Nef oxidation of primary nitroalkanes proceeds
under mild acidic conditions which are compatible with the
N-tert-butanesulfinamide acid sensitive functionality.
The N-tert-butylsulfinyl ketimines also reacted with nitrometh-
ane 2a under the optimized reaction conditions. Thus, ketimines
derived from butanone (R)-1f (obtained as an 85:15 E:Z isomeric
mixture) and 2-heptenone (R)-1g (obtained as an 83:17 E:Z iso-
meric mixture) were converted into the b-nitroamine derivatives
Table 3
Preparation of N-tert-butylsulfinyl protected
a-amino acids 4
O
S
O
S
HN
R1
t-Bu
NO2
HN
R1
t-Bu
NaNO2 (5 equiv), AcOH (6 equiv)
DMF, 45 ºC, 12 h
O
R2
R2
OH
3
4
b-Nitroamine derivative 3
a
-Amino acid derivative 4a
Entry
1
No.
R1
R2
H
No.
Structure
Yieldb (%)
O
S
HN
t-Bu
3a
CH3(CH2)7
4a
50
Me
( )7
O
OH
O
S
HN
Me
t-Bu
2
3
4
5
ent-3b
i-Pr
H
ent-4b
68
56
40
46
O
Me
OH
O
S
HN
t-Bu
3c
Ph(CH2)2
CH3(CH2)4
Et
H
4c
O
Ph
OH
O
S
HN
Me
t-Bu
3f
Me
Me
4f
Me
O
OH
O
S
HN
t-Bu
Me
3g
4g
O
Me
OH
a
All products were >95% pure (GLC and/or 300 MHz 1H NMR).
Isolated yield after acid–base extraction based on the starting b-nitroamine derivative 3.
b

366
M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
In addition, the nitro group could be reduced to an amino group
nately, the reaction did not take place under the optimized reac-
tion conditions with ketimines. In these reactions, two
stereogenic centers are generated, and the diastereomeric ratios
shown in Table 5 refer to the facial selectivity. With regard to
the second stereogenic center, an almost 1:1 mixture of epimers
was always obtained, probably due to the reaction conditions (pro-
longed reaction times in the presence of a base), considering that
an acidic proton remains in 7, so epimerization could take place
rapidly. The sterically congested aldimine (R)-1b derived from iso-
butyraldehyde along with aromatic aldimine (R)-1d derived from
benzaldehyde performed poorly to produce the expected reaction
products 7b and 7d in only 26% and 27% yield, respectively,
although with excellent diastereoselectivity in the case of the ali-
phatic imine (Table 5, entries 2 and 4). Compared to (R)-1d, the
yield obtained was much higher for the aromatic aldimine (R)-1j,
derived from o-bromobenzaldehyde, while both performed simi-
larly regarding the diastereoselectivity (Table 5, entry 7). Unfortu-
nately, it was not possible to separate, after column
chromatography the two pair of epimers for aromatic derivatives
7d and 7j (Table 5, entries 4 and 7).
by using sodium borohydride in the presence of nickel dichloride
hexahydrate.17 This transformation was exemplified by transform-
ing compound ent-3b into ent-5b, which after subsequent protec-
tion of the free amino group with benzyloxycarbonyl chloride
(CbzCl) under basic conditions produced 1,2-diamino derivative
ent-6b in 52% overall yield, based on the starting nitro compound
ent-3b (Scheme 2). Vicinal diamine derivative ent-6b could be
transformed with complete chemoselectivity involving the amino
functionalities because the protecting groups could be removed
under different reaction conditions: an acid medium for the tert-
butylsulfinyl unit and a catalytic hydrogenation for the benzyloxy-
carbonyl group.
We also studied the more challenging reaction of these chiral
N-tert-butylsulfinyl imines 1 with nitroethane 2b, due to the
formation of two stereogenic centers. We found that what we
considered the optimal reaction conditions for the addition of
nitromethane 2a to our model ketimine (R)-1c worked equally as
well with nitroethane 2b. Thus, the reaction of (R)-1c with 3 equiv
of nitroethane 2b in the presence of 2 equiv of sodium bicarbonate
at 60 °C for 72 h led to a conversion of 93% (83% isolated yield after
column chromatography) with good facial diastereoselectivity
(90:10). On the other hand, the reaction of (R)-1c in a large excess
of nitroethane 2b with 5 equiv of sodium hydroxide in the pres-
ence of 4 Å molecular sieves at 45 °C for 24 h led in this case to a
low conversion (23%) although with high facial diastereoselectivity
(95:5 dr) (Table 4, entry 2). Conversion was greatly improved upon
when working at a higher temperature for longer reaction time,
but in this case the diastereoselectivity diminished significantly
(Table 4, entry 3). A lower and reverse facial selectivity was also
observed when the reaction was carried out in a large excess of
nitroethane 2b in the presence of a substoichiometric amount of
a 1 M THF solution of TBAF (Table 4, entry 4). Considering the ste-
reogenic center bearing the nitro group, an almost 1:1 mixture of
epimers was obtained in all cases.
In order to establish the utility of the obtained b-nitroamine
derivatives 7, some of them were transformed from an epimeric
mixture into a single isomer upon oxidation by treatment with
potassium hydroxide in methanol, followed by the addition of
potassium permanganate and magnesium sulfate at 0 °C
(Table 6).18 In this way, the N-tert-butylsulfinyl protected
a-amino
ketones 8 were obtained in moderate yields. It is worth mentioning
that these mild reaction conditions prevent epimerization at the
stereogenic center adjacent to the carbonyl group.
The configuration of the newly created stereogenic center in b-
nitroamine derivatives 3 and 7 was determined by comparing the
specific rotation of ent-4b {configuration (SS,S), mp 125–128 °C,
½
a 2D3
ꢀ
¼ þ84:2 (c 1.07, CHCl3)}, with that provided in the literature
for its enantiomer (RS,R)-N-tert-butylsulfinyl-2-amino-3-methylb-
utanoic acid (D-N-tert-butylsulfinylvaline) {configuration (RS,R),
The addition of nitroethane 2b to aldimines 1 proceeded well
under the reaction conditions shown in Table 4, entry 1. Unfortu-
mp 124–126 °C, ½a D23
ꢀ
¼ ꢁ98:2 (c 1.12, CHCl3)}.19 They exhibited
identical 1H and 13C NMR spectra, and specific rotations with oppo-
O
O
O
S
S
S
NiCl2·6H2O, NaBH4
CbzCl
NaOH/H2O, CH2Cl2
HN
t-Bu
HN
t-Bu
HN
t-Bu
-5 ºC, MeOH, 15 min
Me
NO2
Me
NHCbz
Me
NH2
0 ºC, 30min
Me
ent-3b
Me
ent-6b
Me
ent-5b
Scheme 2.
Table 4
Optimization of the reaction conditions with nitroethane 2b
O
S
O
S
reaction
conditions
N
t-Bu
HN
t-Bu
+
EtNO2
NO2
*
Ph
H
Ph
*
Me
1c
(R)-
2b
7c
Entry
Reaction conditionsa
EtNO2 (3 equiv), NaHCO3 (2 equiv), 60 °C, 72 h
EtNO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg), 45 °C, 24 h
EtNO2 (280 equiv, 3 mL), NaOH (5 equiv), 4 Å MS (40 mg), 60 °C, 96 h
EtNO2 (145 equiv, 1 mL), 1 M TBAF/THF (0.2 equiv), 23 °C, 1.5 h
Conversionb (%)
drc
1
2
3
4
93 (83)
23
93
90:10
95:5
82:18
36:64
98
a
b
c
All reactions were carried out using 0.2 mmol of aldimine (R)-1c.
Conversion is given based on the disappearance of the starting (R)-1c by 1H NMR.
The diastereomeric ratio was determined by 1H NMR and refers to the facial selectivity.

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
367
Table 5
Preparation of b-nitroamine derivatives 7
O
S
O
S
NaHCO3 (2 equiv), 60 ºC, 72 h
HN
t-Bu
N
t-Bu
EtNO2
+
NO2
R
R
H
Me
2b (3 equiv)
1
7
Aldimine 1
b-Nitroamine derivative 3a
Entry
1
No.
R
No.
Structure
Yieldb (%)
drc
O
S
HN
t-Bu
(R)-1a
CH3(CH2)7
7a
66
26
80:20
>98:2
90:10
Me
NO2
( )7
Me
O
S
HN
Me
t-Bu
2
3
4
5
6
(R)-1b
(R)-1c
(R)-1d
(R)-1h
(R)-1i
i-Pr
7b
7c
7d
7h
7i
NO2
Me
Me
O
S
HN
t-Bu
Ph(CH2)2
83
NO2
Ph
Me
O
S
HN
t-Bu
Ph
27d
42:22:20:16e
NO2
Ph
Me
O
S
Me HN
t-Bu
i-Bu
57
89:11
NO2
Me
Ph
Me
O
S
HN
t-Bu
Bn
59
90:10
NO2
Me
O
S
HN
t-Bu
NO2
7
(R)-1j
2-BrC6H4
7j
51d
31:28:24:17e
Me
Br
All products were >95% pure (GLC and/or 300 MHz 1H NMR).
a
b
c
Isolated yield after column chromatography of the major pair of epimers (silica gel, hexane/EtOAc) based on the starting aldimine 1.
Diastereomeric ratio was determined by 1H NMR and refers exclusively to face selectivity.
d
e
Isolated yield after column chromatography of the four diastereoisomers (silica gel, hexane/EtOAc) based on the starting aldimine 1.
Diastereomeric ratio was determined by 1H NMR and refers to the four possible diastereoisomers.
site sign. In order to explain the stereochemical pathway of the
nucleophilic addition of the proposed sodium nitronate intermedi-
ates to chiral N-tert-butanesulfinyl imines 1, a six-membered ring
model I, with a four-membered metallacycle, in which sodium is
chelated both by the oxygen and the nitrogen atoms of the imine
moiety, is proposed (Fig. 2). Here, we assume that the nucleophilic
attack for both nitromethane and nitroethane occurs to the Si-face
of the imine unit for (RS)-isomers (Table 2, entries 1–3 and 8; Fig. 1
and Table 5) and to the Re-face in the case of (SS)-derivatives (Ta-
ble 2, entries 4–7).
3. Conclusion
We have reported that a direct nitro-Mannich-type reaction of
nitromethane 2a or nitroethane 2b and N-tert-butylsulfinyl imines
1 could be performed under solvent-free conditions in the pres-

368
M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
Table 6
Preparation of N-tert-butylsulfinyl protected
a-amino ketones 8
O
O
S
S
HN
t-Bu
1. MeOH, KOH (1 equiv), 0 ºC, 45 min
HN
t-Bu
NO2
O
2. KMnO4 (0.7 equiv), MgSO4 (0.7 equiv)
0 ºC, 4 h
R
R
Me
7
Me
8
b-Nitroamine derivative 7
a-Amino ketone derivatives 8
Entrya
No.
R
No.
Structure
Yieldb (%)
O
S
HN
t-Bu
1
7a
CH3(CH2)7
8a
44
Me
O
( )7
Me
O
S
HN
Me
t-Bu
2
3
4
5
7b
7c
7h
7i
i-Pr
8b
8c
8h
8i
10
52
39
40
O
Me
Me
O
S
HN
t-Bu
Ph(CH2)2
O
Ph
Me
O
S
Me HN
t-Bu
i-Bu
O
Me
Ph
Me
O
S
HN
t-Bu
PhCH2
O
Me
a
All products were >95% pure (GLC and/or 300 MHz 1H NMR).
Isolated yield after column chromatography (silica gel, hexane/EtOAc) based on the starting b-nitroamine derivative 7.
b
‡
4. Experimental
4.1. General
Me Me
Me
O
S
N
H
O
(RS)-tert-Butanesulfinamide and its enantiomer were a gift from
Medalchemy (>99% ee by chiral HPLC on a Chiracel AS column,
90:10 n-hexane/i-PrOH, 1.2 mL/min, k = 222 nm). TLC was per-
formed 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 (230–400
mesh). Melting points are uncorrected. Optical rotations were
measured using a polarimeter with a thermally jacketted 5 cm cell
at approximately 20 °C and concentrations (c) are given in g/
100 mL. Infrared analyses were performed with a spectrophotom-
eter equipped with an ATR component; wavenumbers are given in
cmꢁ1. Low-resolution mass spectra (EI) were obtained at 70 eV;
and fragment ions in m/z with relative intensities (%) in parenthe-
ses. High-resolution mass spectra (HRMS) were also carried out in
the electron impact mode (EI) at 70 eV and on an apparatus
equipped with a time of flight (TOF) analyzer and the samples were
ionized by ESI techniques and introduced through an ultra-high
pressure liquid chromatographer (UPLC) model. 1H NMR spectra
were recorded at 300 or 400 MHz for 1H NMR and 75 or
Na
H
N
O
+
H
_
R
I
(RS: Si-face attack)
Figure 2.
ence of NaHCO3. Aldimines and ketimines reacted in a highly dia-
stereoselective fashion with nitromethane 2a, while nitroethane
2b reacted exclusively with aldimines to produce an almost 1:1
mixture of epimers of b-nitroamine derivatives 7. The configura-
tion of the newly created stereogenic center at the carbon atom
of the imine group was determined by the configuration of the sul-
fur atom of the starting chiral imine. Enantiomerically pure
no acids and -amino ketones can be easily obtained from these
nitro-Mannich products.
a-ami-
a

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
369
100 MHz for 13C NMR, using CDCl3 as the solvent and TMS as inter-
4.3.2. (R,RS)-N-(tert-Butylsulfinyl)-3-methyl-1-nitrobutan-2-
nal standard (0.00 ppm). The data are being reported as: s = singlet,
d = doublet, t = triplet, q = quartet, p = pentet, h = heptet, m = mul-
tiplet or unresolved, br s = broad signal, coupling constant(s) in
Hz, integration. 13C NMR spectra were recorded with 1H-decou-
pling at 100 MHz and referenced to CDCl3 at 77.16 ppm. DEPT-
135 experiments were performed to assign CH, CH2, and CH3.
amine 3b
White solid; mp 39–40 °C (hexane/CH2Cl2); ½a D23
ꢀ
¼ ꢁ61 (c 1.23,
CH2Cl2); Rf 0.49 (hexane/EtOAc: 1/1); IR
m (KBr) 3157, 2962, 2925,
2871, 1555, 1469, 1379, 1042 cmꢁ1; dH 4.75 (d, J = 5.1 Hz, 2H), 4.12
(d, J = 8.5 Hz, 1H), 3.60–3.53 (m, 1H), 1.91 (h, J = 6.7 Hz, 1H), 1.25
(s, 9H), 1.00 (d, J = 6.7 Hz, 3H), 0.99 (3H, d, J = 6.8, CH3); dC 77.7
(CH2), 60.6 (CH), 56.3 (C), 30.7 (CH), 22.4, 19.1, 18.2 (CH3); LRMS
(EI) m/z 220 (M+, 1%), 132 (12), 119 (25), 90 (10), 69 (21), 57
(100); HRMS (ESI): Calculated for C9H21N2O3S (M++H) 237.1273,
found 237.1264.
4.2. General procedure for the synthesis of N-tert-butylsulfinyl
imines 1
To a solution of (R)- or (S)-tert-butanesulfinamide (0.605 g,
5 mmol) and the corresponding carbonyl compound (4.5 mmol)
in dry THF (20 mL) under argon at 23 °C was slowly added titanium
tetraethoxide (2.005 g, 1.885 mL, 9 mmol). The reaction mixture
was then stirred for 12 h at the same temperature for the alde-
hydes and at 76 °C for 5 h for the ketones. The resulting mixture
was hydrolyzed with brine (30 mL), extracted with ethyl acetate
(3 ꢂ 15 mL), dried over anhydrous MgSO4, and evaporated
(15 Torr). The residue was purified by column chromatography
(silica gel, hexane/ethyl acetate) to yield pure compounds 1. Imines
1a,20 1b,21 1c,22 1d,23 1f,14 1g,14 1h,24 1i,23 and 1j,25 were charac-
terized by comparison of their physical and spectroscopic data
with those reported in the literature. The physical, spectroscopic,
and analytical data for imine 1e follow.
4.3.3. (R,RS)-N-(tert-Butylsulfinyl)-1-nitro-4-phenylbutan-2-
amine 3c
Colorless oil; ½a D23
¼ ꢁ24 (c 1.14, CH2Cl2); Rf 0.55 (hexane/
ꢀ
EtOAc: 1/1); IR
m (film) 3298, 3026, 2955, 2923, 2854, 1550,
1375, 1240, 1045 cmꢁ1; dH 7.31–7.26 (m, 2H), 7.22–7.14 (m, 3H),
4.71 (dd, J = 13.0, 4.8 Hz, 1H), 4.61 (dd, J = 13.0, 5.3 Hz, 1H), 4.21
(d, J = 9.4 Hz, 1H), 3.80–3.74 (m, 1H), 2.86–2.79 (m, 1H), 2.72–
2.65 (m, 1H), 1.97–1.86 (m, 2H), 1.25 (s, 9H); dC 140.1 (C), 128.5,
128.2, 126.0, (CH), 79.6 (CH2), 56.3 (C), 54.2 (CH), 34.6, 31.6
(CH2), 22.4 (CH3); LRMS (EI) m/z 179 (M+ꢁt-BuSON, 12%), 136
(15), 131 (21), 104 (73), 91 (100), 90 (62), 77 (18), 65 (17); HRMS
(ESI): Calculated for
299.1429.
C
14H23N2O3S (M++H) 299.1429, found
4.2.1. (RS)-N-(tert-Butylsulfinyl)benzofuran-2-ylmethanimine 1e
4.3.4. (S,SS)-N-(tert-Butylsulfinyl)-1-nitrodecan-2-amine ent-3a
White solid; mp 125–127 °C (hexane/CH2Cl2); ½a D23
ꢀ
þ 3:9 (c
Physical and spectroscopic data were found to be same as for
1.03, CH2Cl2); Rf 0.55 (hexane/EtOAc: 1/1); IR
m
(KBr) 2971, 2962,
3a. ½a 2D3
¼ þ31 (c 1.08, CH2Cl2).
ꢀ
2922, 1599, 1292, 1127, 1081, 953, 834, 764, 691 cmꢁ1; dH 8.57
(s, 1H), 7.72–7.67 (m, 1H), 7.60 (dd, J = 8.4, 0.8 Hz, 1H), 7.48–7.42
(m, 1H), 7.34–7.28 (m, 2H), 1.30 (s, 9H); dC 156.2, 151.5 (C),
150.9, 127.9 (CH), 127.5 (C), 123.8, 122.7, 115.3, 112.2 (CH), 58.3
(C), 22.6 (CH3); LRMS (EI) m/z 193 (M+ꢁC4H8, 32%), 145 (62), 144
(31), 143 (100), 131 (74), 118 (19), 115 (36), 114 (17), 106 (13),
90 (13), 89 (27), 88 (18), 77 (16), 63 (25), 62 (15), 57 (26), 56
(11), 51 (13); HRMS (ESI): Calculated for C13H16NO2S (M++H)
250.0902, found 250.0891.
4.3.5. (S,SS)-N-(tert-Butylsulfinyl)-3-methyl-1-nitrobutan-2-
amine ent-3b
Physical and spectroscopic data were found to be same as for
3b. ½a 2D3
¼ þ59 (c 1.25, CH2Cl2).
ꢀ
4.3.6. (S,SS)-N-(tert-Butylsulfinyl)-1-nitro-4-phenylbutan-2-
amine ent-3c
Physical and spectroscopic data were found to be same as for
3c. ½a 2D3
¼ þ25 (c 1.70, CH2Cl2).
ꢀ
4.3. General procedure for the synthesis of b-nitroamine deriv-
atives 3 and 7
4.3.7. (S,SS)-N-(tert-Butylsulfinyl)-2-nitro-1-phenylethanamine
ent-3d
A
heterogeneous mixture of nitromethane 2a (186 mg,
Yellow oil; ½a 2D3
¼ þ94 (c 0.44, CH2Cl2); Rf 0.56 (hexane/EtOAc:
ꢀ
0.165 mL, 3.0 mmol) or nitroethane 2b (225 mg, 0.213 mL,
3.0 mmol), NaHCO3 (118 mg, 2.0 mmol), and the corresponding
N-tert-butylsulfinyl imine 3 (1.0 mmol) was stirred at 60 °C for
72 h. The resulting mixture was hydrolyzed with water (10 mL),
acidified with 2 M hydrochloric acid (3 mL), extracted with EtOAc
(3 ꢂ 15 mL), dried over anhydrous MgSO4, and evaporated
(15 Torr). The residue was purified by column chromatography
(silica gel, hexane/ethyl acetate) to yield pure compounds 3 and
7. Yields for compounds 3 are given in Table 2 and Figure 1, and
for compounds 7 in Table 5. Physical and spectroscopic data follow.
1/1); IR m (KBr) 3201, 3060, 3025, 2978, 2960, 2924, 1551, 1455,
1376, 1243, 1046 cmꢁ1; dH 7.42–7.33 (m, 5H), 5.10–5.06 (m, 1H),
4.85 (dd, J = 13.4, 7.3 Hz, 1H), 4.78 (dd, J = 13.4, 4.6 Hz, 1H), 4.45
(d, J = 5.0 Hz, 1H), 1.25 (s, 9H); dC 136.1 (C), 129.1, 129.0, 127.3
(CH), 80.0 (CH2), 56.8 (CH), 56.2 (C), 22.5 (CH3); LRMS (EI) m/z
165 (M+ꢁt-BuSO, 41%), 150 (10), 117 (41), 106 (49), 104 (90), 91
(29), 77 (61), 57 (100), 51 (32); HRMS (ESI): Calculated for C12H19-
N2O3S (M++H) 271.1116, found 271.1112.
4.3.8. (S,RS)-N-(tert-Butylsulfinyl)-1-(2-benzofuryl)-2-nitroethan-
amine 3e
4.3.1. (R,RS)-N-(tert-Butylsulfinyl)-1-nitrodecan-2-amine 3a
Yellow oil; ½a 2D3
ꢀ
¼ ꢁ61:9 (c 1.66, CH2Cl2); Rf 0.32 (hexane/
White solid; mp 56–57 °C (hexane/CH2Cl2); ½a D23
ꢀ
¼ ꢁ33 (c 1.21,
EtOAc: 1/1); IR
m
(KBr) 3193, 2976, 2957, 2917, 1554, 1454,
CH2Cl2); Rf 0.62 (hexane/EtOAc: 1/1); IR
m
(KBr) 3136, 2949, 2922,
1376, 1253, 1051, 812, 750 cmꢁ1; dH 7.60–7.49 (m, 1H), 7.49–
7.40 (m, 1H), 7.38–7.27 (m, 1H), 7.27–7.20 (m, 1H), 6.78 (t,
J = 0.9 Hz, 1H), 5.31–5.21 (m, 1H), 5.10 (dd, J = 13.8, 6.0 Hz, 1H),
4.99 (dd, J = 13.8, 5.2 Hz, 1H), 4.50 (d, J = 8.2 Hz, 1H), 1.27 (s, 9H);
dC 155.0, 151.9, 127.5, (C), 125.0, 123.8, 121.4, 111.3, 105.9 (CH),
77.2 (CH2), 56.7 (C), 52.6 (CH), 22.5 (CH3); LRMS (EI) m/z 206 (M+-
ꢁC4H8SO, 0.5%), 189 (73), 146 (49), 142 (31), 131 (15), 119 (19),
118 (100), 115 (54), 114 (17), 113 (11), 89 (31), 88 (10), 77 (17),
63 (26), 62 (12); HRMS (ESI): Calculated for C14H19N2O4S (M++H)
311.1066, found 311.1055.
2854, 1554, 1378, 1364, 1042 cmꢁ1; dH 4.72–4.64 (m, 2H), 4.12 (d,
J = 9.3 Hz, 1H), 3.82–3.76 (m, 1H), 1.69–1.54 (m, 2H), 1.49–1.24 (m,
12H), 1.23 (s, 9H), 0.88 (t, J = 6.7 Hz, 3H); dC 79.6 (CH2), 56.1 (C),
54.9 (CH), 32.8, 31.5, 29.1, 28.9, 28.2, 25.5 (CH2), 22.4 (CH3), 22.2
(CH2), 13.8 (CH3); LRMS (EI) m/z 187 (M+ꢁt-BuSON, 40%), 170
(17), 143 (28), 140 (25), 129 (77), 95 (35), 90 (33), 81 (46), 69
(58), 57 (69), 55 (100); HRMS (ESI): Calculated for C14H31N2O3S
(M++H) 307.2055, found 307.2049.

370
M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
4.3.9. (R,RS)-N-(tert-Butylsulfinyl)-2-methyl-1-nitrobutan-2-
4H), 1.63 (d, J = 6.9 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H), 1.31 (s, 9H),
1.28 (s, 9H); dC 140.3 (C), 128.6, 128.6, 128.4, 128.3, 126.4, 126.3,
86.3 85.7, 59.4, 58.6 (CH), 56.7, 56.6 (C), 34.9, 31.9, 31.4 (CH2),
22.8, 22.7, 16.3, 15.3 (CH3); LRMS (EI) m/z 208 (M+ꢁC4H8SO,
0,6%), 206 (11), 145 (19), 144 (11), 133 (15), 132 (26), 117 (14),
115 (10), 105 (26), 104 (57), 103 (15), 91 (100), 77 (18), 65 (17),
57 (13), 56 (14); HRMS (ESI): Calculated for C15H25N2O3S (M++H)
313.1586, found 313.1584.
amine 3f
Yellow oil; ½a 2D3
¼ ꢁ89:0 (c 1.24, CH2Cl2); Rf 0.23 (hexane/
ꢀ
EtOAc: 1/1); IR
m
(KBr) 3208, 2977, 2873, 1547, 1458, 1374, 1248,
dH 4.69 (d, J = 12.1 Hz, 1H), 4.50 (d,
1051, 939, 735 cmꢁ1
;
J = 12.1 Hz, 1H), 4.23 (s, 1H), 1.76–1.62 (m, 1H), 1.44 (s, 3H), 1.25
(s, 9H), 0.96 (t, J = 7.4 Hz, 3H); dC 83.7 (CH2), 57.3, 56.1 (C), 31.9
(CH2), 22.62, 22.54, 7.67 (CH3); LRMS (EI) m/z 180 (M+ꢁC4H8,
6%), 119 (27), 118 (9), 69 (27), 57 (100), 55 (8); HRMS (ESI): Calcu-
lated for C9H21N2O3S (M++H) 237.1273, found 237.1262.
4.3.14. (2R⁄,3R,RS)-N-(tert-Butylsulfinyl)-5-methyl-2-nitrohexan-
3-amine 7h
4.3.10. (R,RS)-N-(tert-Butylsulfinyl)-2-methyl-1-nitroheptan-2-
Diastereomeric mixture (1:1), white solid, mp 74–76 °C (hex-
amine 3g
ane/CH2Cl2); Rf 0.27 and 0.29 (hexane/EtOAc: 1/1); IR
m (KBr)
Yellow oil; ½a 2D3
ꢀ
¼ ꢁ52:3 (c 1.28, CH2Cl2); Rf 0.33 (hexane/
3229, 2958, 2927, 2870, 1545, 1456, 1388, 1364, 1036, 899 cmꢁ1
;
EtOAc: 1/1); IR
m
(KBr) 3218, 2956, 2931, 2869, 1548, 1457,
dH 5.05 (qd, J = 6.8, 2.6 Hz, 1H), 4.84 (qd, J = 6.8, 4.5 Hz, 1H), 4.29
(d, J = 10.1 Hz, 1H), 3.91 (d, J = 9.6 Hz, 1H), 3.74–3.60 (m, 1H),
3.58–3.42 (m, 1H), 1.90–1.70 (m, 2H), 1.64 (d, J = 6.9 Hz, 3H),
1.55 (d, J = 6.9 Hz, 3H), 1.51–1.41 (m, 2H), 1.26 (s, 9H), 1.25 (s,
9H), 0.94 (d, J = 1.2 Hz, 3H), 1.02–0.95 (m, 2H), 0.92 (d, J = 1.2 Hz,
3H), 0.90 (d, J = 2.2 Hz, 3H), 0.88 (d, J = 2.2 Hz, 3H); dC 86.6, 85.9,
58.6, 57.5 (CH), 56.7, 56.5 (C), 41.6, 38.5 (CH2), 24.3, 24.2 (CH),
23.4, 23.2, 22.7, 22.7, 21.2, 21.0, 15.8, 15.3 (CH3); LRMS (EI) m/z
208 (M+ꢁC4H8, 5%), 160 (7), 133 (44), 97 (15), 57 (100), 56 (11),
1374, 1048, 940 cmꢁ1
; dH 4.67 (d, J = 12.1 Hz, 1H), 4.49 (d,
J = 12.0 Hz, 1H), 4.22 (s, 1H), 1.74–1.55 (m, 2H), 1.44 (s, 3H),
1.41–1.26 (m, 6H), 1.24 (s, 9H), 0.89 (t, J = 6.6 Hz, 3H); dC 83.9
(CH2), 57.2, 56.1 (C), 39.1, 31.8 (CH2), 23.2 (CH3), 22.9 (CH2), 22.6
(CH3), 22.4 (CH2), 13.9 (CH3); LRMS (EI) m/z 222 (M+ꢁC4H8, 1%),
178 (8), 151 (10), 135 (28), 114 (34), 70 (25), 57 (100), 56 (12),
55 (13); HRMS (ESI): Calculated for
279.1742, found 279.1732.
C
12H27N2O3S (M++H)
55 (15); HRMS (ESI): Calculated for
265.1586, found 265.1584.
C
11H25N2O3S (M++H)
4.3.11. (2R⁄,3R,RS)-N-(tert-Butylsulfinyl)-2-nitroundecan-3-amine
7a
Diastereomeric mixture (1:1); colorless wax; Rf 0.36 (hexane/
4.3.15. (2R,3R⁄,RS)-N-(tert-Butylsulfinyl)-3-nitro-1-phenylbutan-
2-amine 7i
EtOAc: 1/1); IR
m (KBr) 3215, 2947, 2924, 2855, 1546, 1457, 1390,
1363, 1048 cmꢁ1; dH 5.01 (qd, J = 6.9, 2.9 Hz, 1H), 4.85 (qd, J = 6.8,
4.6 Hz, 1H), 4.23 (d, J = 9.7 Hz, 1H), 3.96 (d, J = 8.7 Hz, 1H), 3.61–
3.49 (m, 1H), 3.49–3.40 (m, 1H), 1.64 (d, J = 6.9 Hz, 3H), 1.56 (d,
J = 6.9 Hz, 3H), 1.54–1.42 (m, 4H), 1.39–1.17 (m, 42H), 0.88 (t,
J = 6.7 Hz, 6H); dC 86.4, 85.6, 60.2, 59.4 (CH), 56.6, 56.5 (C), 32.8,
31.7, 29.7, 29.3, 29.1, 29.0, 28.9 (CH2), 22.7, 22.7 (CH3), 22.6
(CH2), 16.0, 15.2, 14.1 (CH3); LRMS (EI) m/z 216 (M+ꢁC4H8SO,
9%), 187 (25), 170 (17), 168 (10), 143 (32), 142 (81), 140 (17),
111 (10), 110 (11), 104 (19), 103 (44), 97 (28), 96 (17), 95 (19),
84 (18), 83 (32), 82 (16), 81 (23), 71 (49), 70 (21), 69 (59), 68
(13), 67 (23), 64 (15), 58 (12), 57 (95), 56 (97), 55 (100), 54 (16),
Diastereomeric mixture (1:1), yellow oil; Rf 0.23 (hexane/
EtOAc: 1/1); IR
m
(KBr) 3227, 3055, 3026, 2981, 2951, 2868,
dH 7.45–7.08
1545, 1455, 1390, 1241, 1045 746, 700 cmꢁ1
;
(m, 10H), 4.92 (qd, J = 6.9, 3.7 Hz, 1H), 4.83 (qd, J = 6.9, 3.9 Hz,
1H), 4.11 (d, J = 8.8 Hz, 2H), 3.94–3.84 (m, 1H), 3.84–3.74 (m,
1H), 2.95–2.80 (m, 3H), 2.78–2.65 (m, 3H), 1.69 (d, J = 3.5 Hz,
3H), 1.67 (d, J = 3.5 Hz, 3H), 1.10 (s, 9H), 1.08 (s, 9H); dC
136.5, 136.5 (C), 129.4, 129.3, 128.7, 128.6, 127.0, 126.9, 85.8,
84.1, 61.1, 61.0 (CH), 56.5 (C), 39.6, 36.7 (CH2), 22.4, 22.4,
16.5, 15.2 (CH3); LRMS (EI) m/z 194 (M+ꢁC4H8SO, 0.8%), 119
(15), 118 (15), 117 (12), 103 (11), 92 (12), 91 (100), 65 (10);
HRMS (EI): Calculated for C14H23N2O3S (M++H) 299.1429, found
299.1428.
53 (12); HRMS (ESI): Calculated for
321.2212, found 321.2198.
C
15H33N2O3S (M++H)
4.3.12. (3R,4R⁄,RS)-N-(tert-Butylsulfinyl)-2-methyl-4-nitropen-
tan-3-amine 7b
4.4. General procedure for the synthesis of
atives 4
a-amino acid deriv-
Diastereomeric mixture (1:1); white solid, mp 88–91 °C (hex-
ane/CH2Cl2); Rf 0.28 (hexane/EtOAc: 1/1); IR
m
(KBr) 3120, 2967,
Solid NaNO2 (207 mg, 3.0 mmol) was added to a stirred solution
of compound 3 or 7 (0.50 mmol) and AcOH (150 mg, 0.143 mL,
2.50 mmol) in a 7:1 mixture of DMF and water (1.25 mL) at
23 °C. The reaction was heated at 45 °C for 12 h, after which it
was quenched with a 2 M NaOH water solution (10 mL) and ex-
tracted with CH2Cl2 (2 ꢂ 15 mL). The aqueous layer was acidified
with 2 M hydrochloric acid (12 mL) and extracted with EtOAc
(3 ꢂ 15 mL), dried over anhydrous MgSO4, and evaporated
(15 Torr) to give pure compounds 4. Yields are given in Table 3.
Physical and spectroscopic data follow.
2902, 2873, 1545, 1454, 1390, 1359, 1008, 864 cmꢁ1; dH 4.95
(qd, J = 6.9, 4.1 Hz, 1H), 4.76 (p, J = 6.8 Hz, 1H), 4.43 (d,
J = 8.1 Hz, 1H), 3.67 (d, J = 9.8 Hz, 1H), 3.56–3.46 (m, 1H), 3.12
(td, J = 7.9, 4.0 Hz, 1H), 1.93–1.82 (m. 1H), 1.81–1.72 (m, 1H),
1.69 (d, J = 6.8 Hz, 6H), 1.29 (s, 9H), 1.28 (s, 9H), 1.02 (d,
J = 6.7 Hz, 3H), 1.00-0.95 (m, 6H), 0.88 (d, J = 6.7 Hz, 3H); dC
85.2, 83.7 64.9, 64.8 (CH), 57.1, 56.9 (C), 32.3, 29.5 (CH), 23.0,
22.9, 21.2, 20.2, 18.9, 18.1, 16.5, 16.3 (CH3); LRMS (EI) m/z 194
(M+ꢁC4H8, 4%), 146 (11), 119 (39), 83 (26), 76 (10), 57 (100),
56 (21), 55 (10); HRMS (ESI): Calculated for
(M++H) 251.1429, found 251.1423.
C10H23N2O3S
4.4.1. (R,RS)-N-(tert-Butylsulfinyl)-2-aminodecanoic acid 4a
Colorless oil; ½a D23
¼ ꢁ20:2 (c 2.26, CHCl3); Rf 0.75 (MeOH/CH2-
ꢀ
4.3.13. (3R,4R⁄,RS)-N-(tert-Butylsulfinyl)-4-nitro-1-phenylpentan-
3-amine 7c
Cl2: 2/1); IR m (KBr) 3143, 2947, 2920, 2852, 1721, 1467, 1213,
1034, 900, 694 cmꢁ1; dH 9.89 (br s, 1H), 4.48 (d, J = 7.6 Hz, 1H),
3.87 (dd, J = 12.3, 6.8 Hz, 1H), 1.85–1.72 (m, 1H), 1.71–1.58 (m,
1H), 1.24–1.29 (m, 12H), 1.26 (s, 9H), 0.88 (t, J = 6.5 Hz, 3H); dC
174.9 (C), 58.7 (CH), 56.6 (C), 34.0, 31.8, 29.3, 29.1, 29.0, 25.1
(CH2), 22.7 (CH3), 22.6 (CH2), 14.0 (CH3); LRMS (EI) m/z 187 (M+-
ꢁC4H8SO, 0.4%), 131 (10), 75 (43), 57 (100); HRMS (ESI): Calculated
for C14H30NO3S (M++H) 292.1946, found 292.1935.
Diastereomeric mixture (1:1), white wax; Rf 0.28 (hexane/
EtOAc: 1/1); IR
m (KBr) 3222, 3026, 2976, 2957, 1544, 1455, 1390,
1363, 1048, 699 cmꢁ1; dH 7.37–7.06 (m, 10H), 5.04 (qd, J = 6.9,
2.8 Hz, 1H), 4.85 (qd, J = 6.8, 4.9 Hz, 1H), 4.40 (d, J = 10.1 Hz, 1H),
4.10 (d, J = 10.0 Hz, 1H), 3.63–3.51 (m, 1H), 3.42 (tt, J = 10.4,
2.8 Hz, 1H), 2.94–2.81 (m, 2H), 2.74–2.53 (m, 2H), 1.95–1.81 (m,

M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
371
4.4.2. (S,SS)-N-(tert-Butylsulfinyl)-2-amino-3-methylbutanoic
acid ent-4b
dried over anhydrous MgSO4, and evaporated (15 Torr) to give
88 mg (0.26 mmol, 52% overall yield) of compound ent-6b. Color-
White solid; mp 125–128 °C (hexane/CH2Cl2); ½a D23
ꢀ
¼ þ84:2 (c
less oil; ½a 2D3
¼ þ56 (c 1.04, CH2Cl2); Rf 0.41 (hexane/EtOAc: 1/1);
ꢀ
1.07, CHCl3); Rf 0.69 (MeOH/CH2Cl2: 1/1); IR
m
(KBr) 3269, 2958,
IR m (KBr) 3290–3245, 3057, 3035, 2960, 2928, 2872, 1705, 1535,
2929, 2872, 1721, 1384, 1257, 1024, 1014 cmꢁ1; dH 4.45 (d,
J = 7.9 Hz, 1H), 3.72 (dd, J = 7.8, 5.0 Hz, 1H), 2.16–2.05 (m, 1H),
1.31 (s, 9H), 0.98 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); dC
173.9 (C), 64.0 (CH), 56.9 (C), 32.1 (CH), 22.85, 19.3, 17.2 (CH3);
LRMS (EI) m/z 165 (M+ꢁC4H8, 17%), 119 (42), 105 (10), 72 (33),
57 (100), 56 (27).
1264, 1042, 1027 cmꢁ1; dH 7.38–7.25 (m, 5H), 6.32 (br s, 1H),
5.15–5.06 (m, 2H), 3.55–3.48 (m, 1H), 3.40 (d, J = 7.7 Hz, 1H),
3.13–3.06 (m, 2H), 1.81–1.73 (m, 1H), 1.24 (s, 9H), 0.94 (d,
J = 6.8 Hz, 3H), 0.91 (3H, d, J = 6.8, CH3); dC 157.2 (C), 136.7 (C),
128.3, 127.8, 127.7 (CH), 66.5 (CH2), 63.7 (CH), 56.25 (C), 44.35
(CH2), 31.8 (CH), 22.8, 19.5, 17.6 (CH3); LRMS (EI) m/z 205 (M+-
ꢁBnOCO, 7%), 176 (11), 91 (100), 72 (44), 65 (13), 55 (10); HRMS
4.4.3. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-4-phenylbutanoic
(ESI): Calculated for
341.1885.
C
17H29N2O3S (M++H) 431.1899, found
acid 4c
White solid; mp 88–90 °C (hexane/CH2Cl2); ½a D23
ꢀ
¼ ꢁ19:8 (c
1.00, CHCl3); Rf 0.55 (MeOH/CH2Cl2: 1/1); IR
m
(KBr) 3168,
4.6. General procedure for the synthesis of
atives 8
a-amino ketone deriv-
3021, 2957, 2928, 2864, 1724, 1455, 1245, 1210, 1105, 1036,
901, 759, 700 cmꢁ1; dH 7.36–7.07 (m, 5H), 6.61 (br s, 1H),
4.51 (d, J = 8.0 Hz, 1H), 3.97–3.84 (m, 1H), 2.81–2.60 (m, 2H),
2.21–2.05 (m, 1H), 2.04–1.90 (m, 1H), 1.30 (s, 9H); dC 174.3,
140.8 (C), 128.5, 128.4, 126.2, 58.4 (CH), 56.8 (C), 35.8, 31.5
(CH2), 22.8 (CH3); LRMS (EI) m/z 178 (M+ꢁC4H9SO, 0.6%), 164
(31), 132 (9), 117 (40), 91 (48), 77 (9), 65 (9), 57 (100); HRMS
To a solution of the corresponding b-nitroamine derivative 7
(0.4 mmol) in MeOH (2.8 mL) was added dropwise a freshly pre-
pared solution of KOH (26.4 mg, 0.4 mmol) in MeOH (4 mL) under
argon at 0 °C. After stirring for an additional 15 min, a solution of
KMnO4 (42.4 mg, 0.27 mmol) and MgSO4 (35.4 mg, 0.30 mmol) in
water (6 mL) was added dropwise. Next, the reaction mixture
was stirred for approximately 3 h at 0 °C and then filtered over a
layer of Celite using EtOAc (25 mL). The organic layer was washed
with brine (2 ꢂ 15 mL), dried with anhydrous MgSO4, and evapo-
rated (15 Torr) to give pure compounds 8. Yields are given in Ta-
ble 6. Physical and spectroscopic data follow.
(ESI): Calculated for
284.1307.
C
14H22NO3S (M++H) 284.1320, found
4.4.4. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-2-methylbutanoic
acid 4f
Yellow oil; ½a 2D3
¼ ꢁ70:1 (c 0.79, CH2Cl2); Rf 0.71 (MeOH/CH2-
ꢀ
Cl2: 1/2); IR
m (KBr) 3180, 3055, 2980, 2939, 1726, 1460, 1367,
1265, 1008, 733 cmꢁ1; dH 9.26 (br, 1H), 4.71 (s, 1H), 1.91–1.67
(m, 2H), 1.57 (s, 3H), 1.27 (s, 9H), 0.88 (t, J = 7.4 Hz, 3H); dC
176.5, 62.1, 56.4 (C), 33.1 (CH2), 23.3, 22.8, 8.12 (CH3); LRMS (EI)
m/z 161 (M+ꢁC2H4O2, 0.5%), 160 (10), 159 (97), 103 (52), 88 (15),
75 (12), 74 (61), 70 (79), 57 (100); HRMS (ESI): Calculated for C9-
H20NO3S (M++H) 222.1164, found 222.1152.
4.6.1. (R,RS)-N-(tert-Butylsulfinyl)-3-aminoundecan-2-one 8a
White wax; ½a 2D3
ꢀ
¼ ꢁ146:7 (c 1.07, CH2Cl2); Rf 0.37 (hexane/
EtOAc: 1/2); IR
m
(KBr) 3257, 2923, 2855, 1714, 1458, 1362,
1078 cmꢁ1; dH 4.53 (d, J = 5.2 Hz, 1H), 4.04 (dt, J = 6.9, 4.7 Hz,
1H), 2.25 (s, 3H), 1.91–1.71 (m, 1H), 1.73–1.51 (m, 1H), 1.23–
1.29 (m, 21H), 0.88 (t, J = 6.7 Hz, 3H); dC 206.9 (C), 63.0 (CH),
55.8 (C), 32.7, 31.7, 29.3, 29.2, 29.1 (CH2), 26.9 (CH3), 24.5 (CH2),
22.6 (CH3), 22.5 (CH2), 14.03 (CH3); LRMS (EI) m/z 189
(M+ꢁC4H9–COCH3, 32%), 142 (100), 140 (34), 84 (13), 83 (12), 70
(25), 69 (27), 57 (18), 56 (41), 55 (36); HRMS (ESI): Calculated
for C15H32NO2S (M++H) 290.2154, found 290.2163.
4.4.5. (R,RS)-N-(tert-Butylsulfinyl)-2-amino-2-methylheptanoic
acid 4g
Colorless oil; ½a D23
¼ ꢁ20:6 (c 1.77, CH2Cl2); Rf 0.76 (MeOH/CH2-
ꢀ
Cl2: 1/2); IR
m (KBr) 3173, 3046, 2956, 2929, 2871, 1721, 1525,
1460, 1151, 1025, 874, 735 cmꢁ1; dH 8.21 (br s, 1H), 4.69 (s, 1H),
1.83–1.68 (m, 2H), 1.58 (s, 3H), 1.24–1.32 (m, 15H), 0.88 (t,
J = 6.8 Hz, 3H); dC 176.7, 61.7, 56.4 (C), 40.3, 31.8 (CH2), 23.5
(CH3), 23.3 (CH2), 22.8 (CH3), 22.4 (CH2), 13.9 (CH3); LRMS (EI)
m/z 207 (M+ꢁC4H8, 0.5%), 201 (28), 145 (17), 112 (10), 89 (100),
74 (15), 57 (37); HRMS (ESI): Calculated for C12H26NO3S (M++H)
264.1633, found 264.1624.
4.6.2. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-4-methylpentan-2-
one 8b
Yellow oil; ½a 2D3
¼ ꢁ136:0 (c 0.23, CH2Cl2); Rf 0.36 (hexane/
ꢀ
EtOAc: 1/2); IR
m (KBr) 3252, 2960, 2924, 2871, 2854, 1714, 1463,
1364, 1287, 1070 cmꢁ1; dH 4.53 (d, J = 6.3 Hz, 1H), 3.91 (dd,
J = 6.4, 3.4 Hz, 1H), 2.26 (s, 3H), 2.23–2.14 (m, 1H), 1.28 (s, 9H),
1.04 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H); dC 207.0 (C), 68.4
(CH), 56.3 (C), 30.9 (CH3), 27.6 (CH), 22.9, 20.3, 15.9 (CH3); LRMS
(EI) m/z 163 (M+ꢁC4H8, 33%), 145 (13), 120 (100), 112 (15), 103
(16), 102 (16), 85 (12), 72 (20), 62 (24), 57 (100), 56 (16); HRMS
4.5. (S,SS)-N1-(Benzyloxycarbonyl)-N2-(tert-butylsulfinyl)-3-
methylbutane-1,2-diamine ent-6b
To a solution of compound ent-3b (160 mg, 0.68 mmol) and
NiCl2ꢃ6H2O (161.4 mg, 0.68 mmol) in dry MeOH (5 mL) under ar-
gon at ꢁ5 °C was slowly added NaBH4 (128.8 mg, 2.31 mmol).
The mixture was stirred at the same temperature for 25 min,
quenched with a saturated NaHCO3 aqueous solution (5 mL),
and filtered through Celite. The filtrate was concentrated under
vacuum (15 Torr), and extracted with EtOAc (3 ꢂ 15 mL), dried
over anhydrous MgSO4, and evaporated (15 Torr) to give
103.5 mg of crude diamine derivative ent-5b as a brown oil
(ESI): Calculated for
220.1362.
C
10H22NO2S (M++H) 220.1371, found
4.6.3. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-5-phenylpentan-2-
one 8c
White wax; ½a 2D3
ꢀ
¼ ꢁ99:2 (c 1.00, CH2Cl2); Rf 0.26 (hexane/
EtOAc: 1/2); IR
m
(KBr) 3262, 2955, 2925, 2859, 1713, 1455,
1361, 1062, 735, 699 cmꢁ1
; dH 7.38–7.07 (m, 5H), 4.63 (d,
J = 5.4 Hz, 1H), 4.12–4.01 (m, 1H), 2.77–2.54 (m, 2H), 2.22 (s, 3H),
2.19–2.08 (m, 1H), 2.00–1.85 (m, 1H), 1.31 (s, 9H); dC 206.6,
140.6 (C), 128.6, 128.4, 126.3, 62.5 (CH), 56.0 (C), 34.6, 30.9
(CH2), 26.9, 22.7 (CH3); LRMS (EI) m/z 176 (M+ꢁC4H9SO, 12%),
175 (100), 158 (13), 143 (10), 132 (75), 130 (22), 117 (21), 115
(48), 91 (48), 77 (11), 65 (11); HRMS (EI): Calculated for
(0.5 mmol, 74% yield). Next,
a solution of ent-5b (103 mg,
0.50 mmol) in CH2Cl2 (2 mL) was added to a 2 M NaOH aqueous
solution (1.25 mL) at 0 °C. Next, CbzCl (0.128 mg, 0.106 mL,
0.75 mmol) was added slowly to the reaction mixture and the
system was allowed to reach 23 °C over 1 h. The reaction was
quenched with brine (10 mL), extracted with EtOAc (3 ꢂ 15 mL),
C
11H13NO (M+ꢁC4H10OS) 175.0997, found 175.1002.

372
M. J. García-Muñoz et al. / Tetrahedron: Asymmetry 25 (2014) 362–372
2. For a review, see: Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887–2939.
3. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153.
4. Ono, N. The Nitro Group in Organic Synthesis; John Wiley & Sons: New York,
2001.
5. Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org. Chem. 2009,
2401–2420.
6. For recent reviews, see (a) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc.
Chem. Res. 2008, 41, 831–840; (b) Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-
Luna, A. Chem. Soc. Rev. 2009, 38, 1162–1186; (c) Robak, M. A. T.; Herbage, M.
A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.
7. (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317–1320; (b) Weix, D. A.;
Ellman, J. A. Org. Synth. 2005, 82, 157–165.
8. (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646–2650; (b)
Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suárez, J.
R.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482–3484.
9. Dema, H. K.; Foubelo, F.; Yus, M. Helv. Chim. Acta 2012, 95, 1790–1798.
10. (a) García Ruano, J. L.; Topp, M.; López-Cantarero, J.; Alemán, J.; Remuiñán, M.
J.; Cid, M. B. Org. Lett. 2005, 7, 4407–4410; (b) García Ruano, J. L.; López-
Cantarero, J.; De Haro, T.; Alemán, J.; Cid, M. B. Tetrahedron 2006, 62, 12197–
12203.
11. Weng, J.; Li, Y.-B.; Wang, R.-B.; Li, F.-Q.; Liu, C.; Chan, A. S. C.; Lu, G. J. Org. Chem.
2010, 75, 3125–3128.
12. Zhang, F.; Liu, Z.-J.; Liu, J.-T. Org. Biomol. Chem. 2011, 9, 3625–3628.
13. Rodríguez-Solla, H.; Concellón, C.; Alvarado, N.; Soengas, R. G. Tetrahedron
2012, 68, 1736–1744.
14. Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2012, 48, 2543–2545.
15. García-Muñoz, M. J.; Zacconi, F.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013,
1287–1295.
16. Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62, 234–235.
17. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159–1161.
18. Steliou, K.; Poupart, M.-A. J. Org. Chem. 1985, 50, 4971–4973.
19. Reddy, L. R.; Gupta, A. P.; Liu, Y. J. Org. Chem. 2011, 76, 3409–3425.
20. Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2008, 19, 2484–
2491.
21. (a) Mukade, T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5, 590–596; (b)
Tanuwidjaja, J.; Peltier, H. M.; Lewis, J. C.; Schenkel, L. B.; Ellman, J. A. Synthesis
2007, 3385–3391.
22. Schenkel, L. B.; Ellman, J. A. Org. Lett. 2004, 6, 3621–3624.
23. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,
1278–1284.
4.6.4. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-5-methylhexan-2-one
8h
White solid, mp 63–66 (hexane/CH2Cl2); ½a D23
¼ ꢁ168:5 (c 0.79,
ꢀ
CH2Cl2); Rf 0.36 (hexane/EtOAc: 1/2); IR
m (KBr) 3262, 2958, 2929,
2870, 1707, 1359, 1170, 1040, 887 cmꢁ1; dH 4.50 (d, J = 6.9 Hz, 1H),
4.07–3.90 (m, 1H), 2.26 (s, 3H), 1.91–1.75 (m 1H), 1.57–1.34 (m,
2H), 1.26 (s, 9H), 0.97 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H);
dC 207.7 (C), 62.1 (CH), 56.0 (C), 42.2 (CH2), 27.1 (CH3), 24.5 (CH),
23.3, 22.7, 21.4 (CH3); LRMS (EI) m/z 177 (M+ꢁC4H8, 24%), 134
(100), 117 (10), 116 (15), 78 (20), 71 (11), 57 (50); HRMS (EI): Cal-
culated for C7H15NO2S (M+ꢁC4H8) 177.0823, found 177.0848.
4.6.5. (R,RS)-N-(tert-Butylsulfinyl)-3-amino-4-phenylbutan-2-one
8i
Yellow oil; ½a 2D3
¼ ꢁ122:0 (c 1.04, CH2Cl2); Rf 0.27 (hexane/
ꢀ
EtOAc: 1/2); IR
m (KBr) 3255, 2950, 2924, 2860, 1714, 1456, 1362,
1060, 733, 699 cmꢁ1; dH 7.36–7.11 (m, 5H), 4.47 (d, J = 6.6 Hz,
1H), 4.25 (ddd, J = 8.5, 6.8, 4.9 Hz, 1H), 3.11 (dd, J = 14.0, 5.7 Hz,
1H), 2.87 (dd, J = 14.0, 7.6 Hz, 1H), 2.21 (s, 3H), 1.14 (s, 9H); LRMS
(EI) m/z 211 (M+ꢁC4H8, 5%), 120 (100), 91 (18), 57 (49); HRMS
(ESI): Calculated for
268.1364.
C
14H22NO2S (M++H) 268.1371, found
Acknowledgements
We thank the Spanish Ministerio de Ciencia e Innovación (Grant
No. CTQ2007-65218, Consolider Ingenio 2010-CSD-2007-00006
and CTQ2011-24165), the Generalitat Valenciana (Grant No. PRO-
METEO/2009/039 and FEDER) and the University of Alicante for
generous and continuous financial support.
24. Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem.
2007, 72, 10035–10044.
25. Sirvent, J. A.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013, 2461–2471.
References
1. For reviews, see: (a) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–
2569; (b) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem.
2005, 9, 1315–1392; (c) Petrini, M.; Torregiani, E. Synthesis 2007, 159–186.