Preparation of α-amino ketones, β-amino hydroxylamines using asymmetric aza-Henry reactions of N-p-tolylsulfinylimines with nitroethane

Article abstract of DOI:10.1016/j.tet.2006.10.021

N-Sulfinylimines derived from aromatic and aliphatic aldehydes react with nitroethane and NaOH, yielding mainly two diastereoisomeric β-nitroamines as the result of a highly diastereoselective reaction and further epimerization of the carbon linked to the

Full text of DOI:10.1016/j.tet.2006.10.021

Tetrahedron 62 (2006) 12197–12203
Preparation of a-amino ketones, b-amino hydroxylamines using
asymmetric aza-Henry reactions of N-p-tolylsulfinylimines
with nitroethane
*
Jose Luis Garcıa Ruano, Jesus Lopez-Cantarero, Teresa de Haro,
´
ꢀ
ꢀ
ꢀ
Jose Aleman and M. Belen Cid
*
ꢀ
ꢀ
ꢀ
´
Departamento de Quımica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
ꢀ
ꢀ
Received 31 August 2006; revised 3 October 2006; accepted 10 October 2006
Available online 30 October 2006
Abstract—N-Sulfinylimines derived from aromatic and aliphatic aldehydes react with nitroethane and NaOH, yielding mainly two diaste-
reoisomeric b-nitroamines as the result of a highly diastereoselective reaction and further epimerization of the carbon linked to the nitro group.
The resulting b-nitroamines are used as precursors of N-sulfonyl a-amino methyl ketones and b-amino hydroxylamines.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
N-p-tolylsulfinylimines from aliphatic and aromatic alde-
hydes as well as from ketones, even when they have enol-
izable protons.8 Depending on the reaction conditions
employed (NaOH or TBAF) we were able to obtain as the
major product one of the two possible diastereoisomers.
Diastereoselective and enantioselective versions of the aza-
Henry (or nitro-Mannich) reaction are recently attracting a
great deal of attention.1–3 This interest is due to the forma-
tion of optically pure b-nitroamines, which are attractive
targets in asymmetric synthesis mainly due to their possible
but not always easy conversion to diamines.4 Additionally,
the nitro moiety can be transformed into other interesting
functional groups like carbonyl groups,5 hydroxylamines,6
and oximes or nitriles7 (Scheme 1).
As a part of our ongoing investigations on the asymmetric
aza-Henry reaction, we present herein the results obtained
when these N-p-tolylsulfinylimines are treated with nitro-
ethane under the conditions previously optimized with nitro-
methane, and the transformation of the resulting b-nitro
sulfinylamines into other compounds of interest such as
a-amino methyl ketones and b-amino hydroxylamines.
Activator
Activator
HN
N
R2
NO2
R4-CH2NO2
R1
R2
R1
2. Results and discussion
R4
N-Sulfinylimines 1a–i have been obtained by condensation
of the corresponding aldehydes and ketones with (S)-N-p-
tolylsulfinylamide following the Ti(OEt)4 Davis’ protocol9
with slight modifications in the work-up.10
NH2
R2
NH2
R2
NH2
R2
NH2
R1
NHOH
R1
R1
X
R4
R4
R4
X=O, NOH
Aza-Henry reactions of N-sulfinylimines 1 with EtNO2, un-
der the same reaction conditions optimized when MeNO2
was used as nucleophile,8 led to a mixture of diastereoiso-
mers (Table 1). The four possible ones were obtained with
very low diastereoselectivity with the aromatic N-sulfinyl-
aldimine 1a using TBAF as the base (entry 1) with no
improvement by lowering the reaction temperature. Never-
theless, when this reaction was carried out in the presence
of NaOH, diastereoisomers 2a and 3a were clearly pre-
dominant and can be easily separated from 4a and 5a by
simple crystallization in ether (entry 2). A similar result was
Scheme 1. Aza-Henry reaction and some interesting transformations.
We have recently reported the asymmetric diastereoselective
aza-Henry reaction of nitromethane with a wide variety of
Keywords: Asymmetric synthesis; Diastereoselectivity; Imines; Amines;
Sulfoxides.
* Corresponding authors. Tel./fax: +34 91 497 3966 (J.L.G.R.); tel.: +34 91
497 5505; fax: +34 91 484 0784 (M.B.C.); e-mail addresses: joseluis.
garcia.ruano@uam.es; belen.cid@uam.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.021

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12198
Table 1. Aza-Henry reaction of nitroethane with N-sulfinylaldimines (Ss)-1a–g
O
NHSOTol
NO2
NHSOTol
NO2
NHSOTol
NO2
NHSOTol
NO2
S
Tol
N
EtNO2
+
+
+
R1
R1
R1
R1
H
R1
1
2
3
4
5
Entry
Substrate’s R1
s.m./prod
Conditions
Conv [%]a
t [h]
0.5
Ratio of products 2/3/4/5a
Yieldb (2/3) [%]
1
2
C6H5
C6H5
a
a
Method B
Method A
95
81
28:13:38:21
50:44:3:3
92 (2–5)
75 [43 (2a)/32 (3a)]
36
70d (58:42)
3
4
5
6
7
8
p-CNC6H4
p-MeOC6H4
PhCH]CH
Me
Me
i-Pr
b
c
d
e
e
f
Method A
Method A
Method A
Method A
Method A, Yb(Oi-Pr)3 (1 equiv)
Method A
100
74
93
94
93
62
26
66
72
17
24
138
51:41:3:5
55:41:2:2
51:40:6:3c
91 (2+3):5:4
42:40:9:9
83:17
82 [45 (2b)/37 (3b)]
68 [40 (2c)/28 (3c)]
70 [36 (2d)/34 (3d)]
80e
Not determined
48f (83:17)
42d (93:7)
9
i-Pr
f
NaOH (5 equiv), 40 ꢁC
73
168
81:19
34g
ꢁ
˚
Method A: EtNO2 (solvent), NaOH (5 equiv), 4 A MS, 40 C. Method B: EtNO2 (solvent), TBAF.
Determined by 1H NMR.
After flash chromatography.
a
b
c
Determined after isolation of products by flash chromatography.
After crystallization in ether.
After chromatography the ratio 2e/3e was 55.2:44.8 (determined by HPLC).
Recovered starting material: 17%.
Recovered starting material: 15%.
d
e
f
g
obtained with other aromatic imines 1b,c, a,b-unsaturated
1d, and the aliphatic N-sulfinylimine 1e, derived from ace-
taldehyde (entries 3–6). In the later case, the addition of
Yb(Oi-Pr)3 produced a deleterious effect on the stereoselec-
tivity of the reaction (entry 7).11 The bulkier aliphatic i-Pr
substituent required longer reaction times to afford the b-ni-
troamines with higher stereoselectivity (entry 8). The results
in entries 8 and 9 clearly illustrate that the isolated yields de-
creased when the reactions were carried out in the absence of
molecular sieves, which could suggest that they have some
role in preventing the hydrolysis of the N-sulfinylimine, by
absorbing the water generated by the HOꢀ.
conditions affording the corresponding b-nitroamines in
very low yields.12 Finally, N-sulfinylketimines failed to
undergo aza-Henry reaction with nitroethane under the same
reaction conditions.
The absolute configurations of compounds 2f and 3a were
respectively established as (Ss, 1S,2S) and (Ss, 1S,2R) by
X-ray crystallography (Fig. 1). The major diastereoisomers
2 obtained in the reactions carried out in the presence of
NaOH have been assigned the same configurations as 2f
by assuming that all imines should evolve through the
same stereochemical course.13
The bulky tert-butyl N-sulfinylimine reacts with nitroethane
under both catalyzed (Yb(Oi-Pr)3) and uncatalyzed
When compounds 2a and 3a were treated independently
with nitromethane using NaOH as well as TBAF, a mixture
Figure 1. X-ray structure of 2f and 3a.

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12199
NHSO2Tol
NO2
NHSO2Tol
NO2
of 2a and 3a was obtained in both cases (Scheme 2). It indi-
cates that the carbon bearing the nitro group is easily epimer-
izable under both reaction conditions. The fact that no traces
of the compounds resulting from the aza-Henry reaction
with nitromethane were detected in the latter experience, de-
spite the presence of nitromethane as solvent, also indicates
that retro aza-Henry reaction is not taking place under these
conditions. The above results suggest that the lack of stereo-
selectivity observed in these reactions could be due to the
epimerization under the reaction conditions, and therefore
it is not easily avoidable. The use of only 1 equiv of
NaOH after 40 h affords the same mixture of diastereoiso-
mers, but the conversion decreases to 64%.
NHSO2Tol
O
i)
ii)
2 + 3
+
R
R
R
6
7
8
73% (ee= 80,HPLC16) 8a
90% (ee> 99, HPLC16) 8e
R=Ph 2a : 3a = 58/42
R=Me 2e : 3e = 56/44
100%
98%
Scheme 3. Preparation of a-amino ketones 8a and 8e. (i) m-CPBA, CH2Cl2,
rt–0 ꢁC, 30 min, 90%; (ii) (a) t-BuOK/t-BuOH, rt, 10 min; (b) EtOAc,
KMnO4, 0 ꢁC, 2 h 30 min.
NHSOTol
i
NHOH
2a
Ph
63%
9a
NHSOTol
NHOH
NHSOTol
NH2
i
ii
3a
NHSOTol
Ph
MeNO2, NaOH
Ph
35%
89%
NO2
2a
+
3a
Ph
Ph
2a
4 A MS
40 °C, 20 h
11a
10a
69 / 31
NHSOTol
NHOH
NHSOTol
i
NOH
2f
+
i-Pr
NHSOTol
NO2
3a
i-Pr
MeNO2, TBAF
rt, 20 m
2a
+
3a
dr= 97:3
9f
48%
12f 8%
55 / 45
Scheme 4. Preparation of b-amino hydroxylamines. (i) Al/Hg (3 equiv),
40 min; (ii) Al/Hg (10 equiv), 65 h.
Scheme 2. Isomerization of 2a into 3a.
The high selectivity observed at the new chiral center bear-
ing the sulfinamide moiety when NaOH was used as the base
is in agreement with the proposed model for the reactions
with nitromethane8 and could be attributed to a rigid transi-
tion state in which both reacting partners were coordinated
to the metal, as outlined in Figure 2. The S configuration
of the sulfoxide favors the TS leading the (Ss, S) diastereo-
isomer (I in Fig. 2), since the TS affording the (Ss, R) diaste-
reoisomer (II in Fig. 2) would be destabilized by the steric
interactions of the bulky p-tolyl group.
When compounds 2a and 3a, which can be obtained by flash
chromatography in 43 and 32% yields, respectively, were
independently treated for 40 min with aluminum amalgam18
(3 equiv) in THF/H2O at rt, the corresponding hydroxyl-
amines 9a and 10a could be isolated in 63 and 89% yields,
respectively, after flash chromatography. Prolonging the re-
action times of 3a and using 10 equiv of aluminum amalgam
the 1,2-diamine 11a was obtained in 35% yield. When the
b-nitroamine 2f, with aliphatic substituents, was submitted
to the same reaction conditions hydroxylamine 9f could be
isolated in 48% yield along with 8% of the oxime 12f.
Several synthetic manipulations of the b-nitroamines 2 and 3
can be envisioned (Schemes 3 and 4). All the attempts
carried out to transform the nitro group in the sulfinyl b-
nitroamines 2 and 3 into a carbonyl one were unsuccessful.
However, this transformation could be easily achieved from
the corresponding sulfonyl b-nitroamines 6 and 7 (easily
prepared from 2 and 3 by oxidation with m-CPBA). Thus,
the reaction of a mixture of 6a and 7a with t-BuOK/
t-BuOH and subsequent addition of KMnO4 afforded the
corresponding ketone 8a in 73% yield and 80% ee.14 This
loss of optical purity can be explained through epimerization
of the stereogenic center once the ketone is formed, due to
the acidity at the a position.15 This acidity is lower when
R is an aliphatic chain and thus ketone 8e is obtained opti-
cally pure (ee>99%) from b-nitroamines 2e and 3e follow-
ing the same procedure.16 Therefore, ketones 8a and 8e are
obtained in 51 and 63% yields, respectively, from the corre-
sponding sulfinylimines 1a and 1e employing only one final
chromatographic purification.17
3. Conclusions
In summary, the aza-Henry reaction of N-sulfinylimines
derived from aromatic and aliphatic aldehydes with nitro-
ethane and NaOH takes place to afford the corresponding
b-nitroamines as a mixture of two major diastereoisomers
(2 and 3) as a consequence of the easy epimerization at the
carbon linked to the nitro group. The synthetic interest of
these compounds is illustrated with several transformations.
After separation of the minor isomers (4 and 5) by crystalli-
zation of the crude, b-nitroamines 2 and 3 are transformed
into N-sulfonyl a-amino methyl ketones 8 in good yields.
Reduction of the nitro group using aluminum amalgam
provides b-amino hydroxylamines in moderate to good
yields.
4. Experimental
4.1. General
Tol
O
H
O
S
O
+
H
O
S
.
Na
Tol
N
N
Na
.
O
N
R
(Me) H
N
O
1H NMR and 13C NMR spectra were acquired in a Bruker
spectrometer at 200 or 300 MHz and 75 MHz, respectively.
THF and CH2Cl2 were distilled from sodium-benzophenone
and P2O5, respectively. Melting points were measured using
a Gallemkamp apparatus in open capillary tubes. Optical
(Me) H
+
.
.
R
.
.
I
II
Figure 2. Transition states involved in aza-Henry reactions of nitromethane
and nitroethane with N-sulfinylaldimines in the presence of NaOH.

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12200
rotations were recorded in cells with 10 cm path length on
a Perkin–Elmer 241 MC polarimeter. Flash column chroma-
tography was performed using silica gel Merk-60 (230–400
mesh) or RedisepÔ normal phase columns in an Isco
CombiFlash instrument. All reagents were purchased from
Aldrich. All the N-sulfinylimines and ketimines were syn-
thesized using Davis’ methodology9 with slight modifica-
tions in the work-up.10
method A at 40 ꢁC after 26 h in 45 and 37% yields, respec-
tively, after flash chromatography (hex/EtOAc 2:1). Data of
2b as a mixture 2b/3b¼85:15; white solid, mp: 78 ꢁC; [a]D20
+236 (c 0.5, CHCl3); 1H NMR (300 MHz): d 7.70 (d,
J¼7.7 Hz, 2H), 7.52–7.34 (m, 6H), 5.13 (d, J¼7.67 Hz,
1H), 4.80–4.78 (m, 1H), 4.66–4.61 (m, 1H), 2.45 (s, 3H),
1.37 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz): d 142.1,
141.9, 139.5, 132.4, 129.7, 127.8, 125.2, 117.8, 112.1,
1
86.2, 59.6, 21.2, 17.2. Data of 3b: H NMR (300 MHz):
4.2. General procedure for the aza-Henry reaction of
(S)-N-sulfinylimines by using NaOH. (Method A)
d 7.70 (d, J¼8.3 Hz, 2H), 7.56–7.34 (m, 6H), 4.94–4.75
(m, 3H), 2.45 (s, 3H), 1.49 (d, J¼6.6 Hz, 3H); 13C NMR
(75 MHz): d 142.8, 142.3, 132.7, 129.4, 127.7, 125.5,
125.4, 117.0, 113.0, 87.0, 59.5, 21.4, 14.2.
Powdered NaOH (2 mmol) was added to a slurry of the cor-
responding N-sulfinylimine (0.4 mmol) and the same weight
˚
of 4 A MS in EtNO2 (5.7 mL) at rt. The reaction mixture was
stirred at the indicated temperature and reaction time speci-
fied in each case (Table 1). All reactions were monitored by
TLC (hex/EtOAc 2:1), the mixture was filtrated through a
short pad of silica gel, and the crude purified by flash chro-
matography.
4.2.3. (1S,2S,(S)S)-N-(p-Tolylsulfinyl)-2-nitro-1-(4-meth-
oxyphenyl)-propylamine (2c) and (1S,2R,(S)S)-N-(p-
tolylsulfinyl)-2-nitro-1-(4-methoxyphenyl)-propylamine
(3c). These compounds were obtained following the general
method A at 40 ꢁC after 66 h in 40 and 28% yields, respec-
tively, after flash chromatography (hex/EtOAc 2:1). Data
of 2c: yellow oil; [a]2D0 +89 (c 0.5, CHCl3); 1H NMR
(300 MHz): d 7.52 (d, J¼8.2 Hz, 2H), 7.32–7.25 (m, 4H),
6.94 (d, J¼8.8 Hz, 2H), 4.80–4.65 (m, 3H), 3.82 (s, 3H),
2.43 (s, 3H), 1.33 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz):
d 160.0, 142.0, 141.5, 129.8, 129.0, 128.0, 125.4, 114.3,
86.7, 59.6, 55.3, 21.4, 15.0. Data of 3c: colorless oil; [a]D20
4.2.1. (1S,2S,(S)S)-N-(p-Tolylsulfinyl)-2-nitro-1-phenyl-
propylamine (2a) and (1S,2R,(S)S)-N-(p-tolylsulfinyl)-2-
nitro-1-phenyl-propylamine (3a). These compounds were
obtained following the general method A and method B.
Method A: at 40 ꢁC after 36 h as a mixture 2a/3a/others¼
50:44:3:3. After flash chromatography 2a and 3a were
obtained in 43 and 32% yields, respectively. Crystallization
from ether of the crude provides a mixture of 2a and 3a
in 70% combined yield (2a/3a¼58:42). Method B: a 1 M
solution of TBAF (66 mL) was added to a solution of the
corresponding N-sulfinylimine (0.328 mmol) in EtNO2
(4.7 mL) at rt. The reaction mixture was stirred for 0.5 h.
The reaction was monitored by TLC (hex/EtOAc 2:1), the
mixture (2a/3a/4a/5a¼28:13:38:21) was filtrated through
a short pad of silica gel, the solvent evaporated, and the crude
purified by flash chromatography. Data of the major diaste-
reoisomer 2a: white solid; mp: 123–125 ꢁC; [a]D20 +153 (c
0.2, CHCl3); IR: 3184, 1554, 1455, 1389, 1360, 1089,
1
+135 (mixture 3c/2c/4c or 5c¼86:10:4, c 2, CHCl3); H
NMR (300 MHz): d 7.57 (d, J¼8.5 Hz, 2H), 7.34–7.24 (m,
4H), 6.92 (d, J¼8.7 Hz, 2H), 4.84–4.75 (m, 3H), 3.65 (s,
3H), 2.43 (s, 3H), 1.46 (d, J¼6.6 Hz, 3H); 13C NMR
(75 MHz): d 160.0, 141.8, 141.1, 129.4, 129.0, 128.2,
125.4, 114.6, 87.5, 60.2, 55.3, 21.4, 16.9.
4.2.4. (1S,2S,(S)S)-N-(p-Tolylsulfinyl)-1-nitro-2-methyl-
4-phenylbut-3-en-2-amine (2d) and (1S,2R,(S)S)-N-(p-
tolylsulfinyl)-1-nitro-2-methyl-4-phenylbut-3-en-2-
amine (3d). These compounds were obtained following the
general method A at 40 ꢁC after 72 h in 36 and 34% yields,
respectively, after flash chromatography (hex/EtOAc 2:1).
Data of 2d: yellow oil; [a]2D0 +134 (c 0.8, CHCl3); IR
1057 cmꢀ1
;
1H NMR (300 MHz): d 7.53 (d, J¼8.3 Hz,
2H), 7.42–7.30 (m, 7H), 4.94 (br d, J¼6.4 Hz, 1H), 4.80
(dq, J¼8.1, 6.6 Hz, 1H), 4.69 (dd, J¼8.1, 6.6 Hz, 1H),
2.43 (s, 3H), 1.33 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz):
d 141.8, 140.9, 136.6, 129.7, 129.2, 129.0, 127.7, 125.4,
87.3, 60.6, 21.4, 17.0; MS (FAB) m/z 319.1 (M+1, 81),
154 (32), 139 (100); HRMS [M+1]: calcd for
C16H19N2O3S: 319.1116; found: 319.1124. Anal. Calcd for
C16H18N2O3S: C, 60.36; H, 5.70; N, 8.80; S, 10.07. Found:
C, 60.56; H, 5.84; N, 8.40; S, 9.62. Data of the minor diaste-
reoisomer 3a: mp: 120 ꢁC; [a]D20 +160 (c 0.2, CHCl3); IR:
3196, 2924, 1554, 1389, 1361, 1088, 1051 cmꢀ1; 1H NMR
(300 MHz): d 7.57 (d, J¼8.1 Hz, 2H), 7.40–7.31 (m, 7H),
4.95–4.86 (m, 2H), 4.79 (dq, J¼6.8, 5.0 Hz, 1H), 2.43 (s,
3H), 1.46 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz):
d 142.0, 141.3, 136.3, 129.8, 129.0, 128.9, 127.6, 125.4,
86.6, 60.0, 21.4, 14.9; MS (FAB) m/z 319.1 (M+1, 45),
154 (28), 139 (100); HRMS [M+1]: calcd for
C16H19N2O3S: 319.1116; found: 319.1115.
(film): 3196, 2924, 1545, 1088, 1056 cmꢀ1 1H NMR
;
(300 MHz): d 7.60 (d, J¼8.2 Hz, 2H), 7.42–7.20 (m, 7H),
6.73 (d, J¼15.8 Hz, 1H), 6.13 (dd, J¼15.8, 7.8 Hz, 1H),
4.77–4.58 (m, 2H), 4.46–4.32 (qd, J¼6.8, 1.0 Hz, 1H),
2.42 (s, 3H), 1.51 (d, J¼6.4 Hz, 3H); 13C NMR
(75 MHz): d 142.0, 141.1, 135.8, 135.5, 129.7, 128.7,
128.6, 126.8, 125.5, 123.9, 85.9, 58.8, 21.4, 16.2; MS
(FAB) m/z 345 (M+1, 55), 139 (100), 154 (10); [M+1]:
calcd for C18H21N2O3S: 345.1272; found: 345.1282. Data
of 3d: colorless oil; [a]2D0 +143 (c 0.81, CHCl3); 1H
NMR (300 MHz): d 7.61 (d, J¼8.3 Hz, 2H), 7.43–7.29
(m, 7H), 6.75 (d, J¼15.8 Hz, 1H), 6.16 (dd, J¼15.8,
8.1 Hz, 1H), 4.69–4.57 (m, 2H), 4.43–4.34 (ddd, J¼6.5,
4.1, 1.1 Hz, 1H), 2.43 (s, 3H), 1.51 (d, J¼6.8 Hz, 3H);
13C NMR (75 MHz): d 142.0, 141.3, 136.4, 135.6, 129.8,
128.7, 128.6, 126.9, 125.5, 122.6, 86.0, 58.2, 21.4, 15.4;
MS (FAB) m/z 345 (M+1, 9), 139 (100), 154 (24);
[M+1]: calcd for C18H21N2O3S: 345.1272; found:
345.1279.
4.2.2. (1S,2S,(S)S)-N-(p-Tolylsulfinyl)-2-nitro-1-(4-nitrile-
phenyl)-propylamine (2b) and (1S,2R,(S)S)-N-(p-tolyl-
sulfinyl)-2-nitro-1-(4-nitrilephenyl)-propylamine (3b).
These compounds were obtained following the general
4.2.5. (2S,3S,(S)S)-N-(p-Tolylsulfinyl)-3-nitrobutan-2-
amine (2e) and (2S,3R,(S)S)-N-(p-tolylsulfinyl)-3-nitro-
butan-2-amine (3e). These compounds were obtained

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12201
following the general method A at 40 ꢁC after 17 h as a
2e/3e/others¼91:5:4 mixture in an 80% combined yield of
2e and 3e after flash chromatography (CombiFlash) as
a 2e/3e¼55.2:44.8 mixture (determined by HPLC with a
ChiralpakÒ AD, hex/i-PrOH¼93:7, 0.7 mL/min, T¼25 ꢁC,
major diastereomer tR¼27.3 min, minor diastereomer
tR¼32.9 min). Data of the mixture: IR (film): 3196, 1550,
30 min in 100% yield. Data of 6a: white solid; mp:
171 ꢁC; [a]D20 +68 (c 0.375, CHCl3); IR (film): 3255, 1598,
1458, 1388, 1359, 1165, 1092, 1068 cmꢀ1 1H NMR
;
(300 MHz): d 7.54 (d, J¼8.4 Hz, 2H), 7.22–7.01 (m, 7H),
5.8 (br d, J¼9.3 Hz, 1H), 4.89–4.75 (m, 2H), 2.35 (s, 3H),
1.51 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz): d 143.7,
136.7, 135.1, 128.7, 128.8, 127.1, 127.2, 86.2, 60.3, 21.4,
15.56.
1389, 1452, 1391, 1363, 1088, 1058 cmꢀ1 1H NMR
;
(300 MHz): d 7.55 (d, J¼7.9 Hz, 2H 2e), 7.51 (d,
J¼7.9 Hz, 2H 3e), 7.28 (br d, 2H 2e and 2H 3e), 4.73 (br
d, J¼8.9 Hz, 1H 2e and 1H 3e), 4.45–4.36 (m, 1H 2e and
1H 3e), 3.77–3.58 (m, 1H 2e and 1H 3e), 2.40 (s, 3H 2e
and 3H 3e), 1.37–1.31 (4d, 6H 2e and 6H 3e); MS (FAB)
m/z 257.1 (M+1, 59), 139 (100), 55 (16); HRMS [M+1]:
calcd for C11H17N2O3S: 257.0960; found: 257.0973. Anal.
Calcd for C11H16N2O3S: C, 51.54; H, 6.29; N, 10.93; S,
12.51. Found: C, 51.76; H, 6.32; N, 10.65; S, 12.27. Data
of the major diastereoisomer 2e: 13C NMR (75 MHz):
d 141.8, 140.7, 129.7, 125.7, 86.7, 51.3, 21.4, 18.4, 14.9.
Data of the minor diastereoisomer 3e: 13C NMR
(75 MHz): d 141.7, 140.3, 129.6, 125.8, 87.0, 51.1, 20.0,
15.6, 14.2.
4.3.2. (1S,2R)-N-(p-Tolylsulfonyl)-2-nitro-1-phenylpro-
pylamine (7a). This compound was obtained following the
general method for oxidation starting from 3a at 0 ꢁC after
30 min in 100% yield. Data of 7a: white solid; mp: 156–
157 ꢁC; [a]D20 +55 (c 0.10, CHCl3); IR (film): 3419, 1551,
1
1458, 1389, 1321, 1162, 1089 cmꢀ1; H NMR (300 MHz):
d 7.54 (d, J¼8.2 Hz, 2H), 7.30–6.95 (m, 7H), 5.50 (br d,
J¼9 Hz, 1H), 4.78 (m, 2H), 2.38 (s, 3H), 1.62 (d,
J¼6.5 Hz, 3H); 13C NMR (75 MHz): d 143.7, 136.7,
134.9, 129.5, 128.8, 128.7, 127.41, 126.8, 86.0, 60.2, 21.4,
15.7.
4.3.3. (1S,2S)-N-(p-Tolylsulfonyl)-2-nitrobutylamine (6e)
and (1S,2R)-N-(p-tolylsulfonyl)-2-nitrobutylamine (7e).
These compounds were obtained following the general
method at 0 ꢁC after 45 min in 98% yield. Data of the mix-
ture 6e and 7e: IR (film): 3277, 1552, 1439, 1394, 1334,
4.2.6. (3S,4S,(S)S)-N-(p-Tolylsulfinyl)-2-methyl-4-nitro-
pentan-3-amine (2f). This compound was obtained follow-
ing the general method A at 40 ꢁC after 138 h as a 2f/
3f¼83:17 mixture in 48% yield after flash chromatography
(CombiFlash) recovering 17% of starting material 1f. Com-
pound 2f was obtained as a 93:7 mixture after crystallization
in ether. Data of the diastereoisomer 2f: white solid; mp:
115–116 ꢁC; [a]D20 +33 (c 1, CHCl3); IR (film): 3197,
1
1093, 1034 cmꢀ1; H NMR (300 MHz): d 7.76–7.73 (m,
4H), 7.31 (br d, J¼8.1 Hz, 4H), 5.42–5.37 (m, 2H), 4.59
(qd, J¼6.8, 1.7 Hz, 1H), 4.49 (qd, J¼1.9, 1.6 Hz, 1H),
3.80–3.69 (m, 2H), 2.42 (s, 6H), 1.50 (d, J¼6.8 Hz, 3H),
1.49 (d, J¼6.9 Hz, 3H), 1.04 (d, J¼6.9 Hz, 3H), 1.02 (d,
J¼6.8 Hz, 3H); 13C NMR (75 MHz): d 150.0, 143.9,
137.4, 130.0, 127.0, 127.0, 86.2, 86.2, 53.5, 52.1, 51.6,
21.5, 17.5, 16.7, 15.4, 15.3.
1549, 1454, 1389, 1362, 1089, 1061 cmꢀ1 1H NMR
;
(300 MHz): d 7.62 (d, J¼8.1 Hz, 2H), 7.31 (d, J¼7.9 Hz,
2H), 4.90–4.80 (m, 1H), 4.72 (d, J¼9.4 Hz, 1H), 3.27
(ddd, J¼9.3, 7.3, 4.5 Hz, 1H), 2.41 (s, 3H), 1.83 (sept,
J¼6.9 Hz, 1H), 1.61 (d, J¼6.9 Hz, 3H), 1.06 (d, J¼6.9 Hz,
3H), 1.03 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz):
d 142.5, 141.9, 129.7, 125.3, 83.7, 64.4, 31.8, 21.4, 20.1,
19.2, 17.9; MS (FAB) m/z 285 (M+1, 55), 139 (100), 55
(21); HRMS [M+1]: calcd for C13H21N2O3S: 285.1273;
found: 285.1281. Anal. Calcd for C13H20N2O3S: C, 54.91;
H, 7.09; N, 9.85; S, 11.28. Found: C, 55.0; H, 6.94; N,
9.56; S, 11.00.
4.4. Procedure for preparing N-sulfonyl a-amino
methyl ketones (8)
The corresponding nitro sulfone (0.075 mmol), obtained by
oxidation of p-tolylsulfinylnitroamines with m-CPBA
(1.2 equiv) in CH2Cl2 (0.5 mL) at 0 ꢁC, was dissolved in
3 mL of t-BuOH at 60 ꢁC and added to a solution of
t-BuOK (0.26 mmol) in 1 mL of t-BuOH at rt. The mixture
was stirred under argon atmosphere for 10 min while cooling
to rt and then 18 mL of ethyl acetate was added and the re-
action mixture was cooled to 0 ꢁC. Immediately, a solution
of KMnO4 (0.11 mmol) in 5.4 mL of water at 0 ꢁC was
added to the mixture and stirred vigorously for 2 h 30 min
at 0 ꢁC, whereupon 0.3 mL of 1 M solution of H2SO4 was
added at once and stirred for 5 min, then 0.15 mL of 1 M
solution of sodium bisulfite (NaHSO3) was added until the
solution turns colorless. The two layers were separated and
the aqueous layer was extracted with ethyl acetate (2ꢂ
4 mL). The combined organic layers were washed with
ice-cold water (2ꢂ4 mL) and brine and then dried over
MgSO4 anhydride. The crude was purified by flash chroma-
tography (hex/EtOAc¼90:10–70:30).
4.3. Typical procedure for the oxidation of p-tolyl-
sulfinylamines to p-tolylsulfonylamines
m-CPBA (0.12 mmol) was added to a solution of the corre-
sponding sulfinylamine (0.1 mmol) in CH2Cl2 (0.5 mL) at
rt. The reaction mixture was stirred at 0 ꢁC for 30–50 min.
The reactions were monitored by TLC (hex/EtOAc 3:1)
and when the reaction was completed, CH2Cl2 (1 mL)
was added, the organic phase was washed with NaHSO3
(2ꢂ1 mL) and the aqueous phase was extracted with
CH2Cl2 (2ꢂ1 mL). The organic extracts were washed with
a saturated solution of NaHCO3 (2ꢂ1 mL). The organic
layer was dried over anhydrous MgSO4 and the solvent evapo-
rated, obtaining the corresponding pure sulfonylamines
without further purification.
4.4.1. (S)-(D)-N-(p-Tolylsulfonyl)-3-amino-3-phenyl-2-
propanone (8a).15 Yield: 73%; mp: 157 ꢁC (Ref. 15 136–
137 ꢁ C); ee¼80%; [a]D20 +202 (c 0.8, CHCl3) [Ref. 15
[a]2D0 +287 (c 0.8, CHCl3)]. The enantiomeric excess of
ketone 8a has been determined by HPLC with a ChiralpakÒ
4.3.1. (1S,2S)-N-(p-Tolylsulfonyl)-2-nitro-1-phenylpro-
pylamine (6a). This compound was obtained following the
general method for oxidation starting from 2a at 0 ꢁC after

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12202
AD column (hex/i-PrOH¼90:10, 1 mL/min, T¼25 ꢁC),
minor enantiomer tR¼37.1 min (10%), major enantiomer
tR¼41.8 min (90%).
194 (100), 109 (17), 139 (21), 83 (43); HRMS [M+1]: calcd
for C13H22N2O2S: 271.1486; found: 271.1495.
4.4.2. (S)-(D)-N-(p-Tolylsulfonyl)-amino-2-butanone
(8e). Yield: 90%; mp: 93–94 ꢁC; [a]D20 +57 (c 0.6, CHCl3);
IR (film): 3269, 1721, 1428, 1420, 1050, 1088,
Acknowledgements
We thank the Spanish Government for financial support
(Grants BQU2003-04012 and CTQ2005-07328).
1050 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.72 (d,
;
J¼8.0 Hz, 2H), 7.30 (d, J¼8.0 Hz, 2H), 5.6 (br d,
J¼6.3 Hz, 1H), 3.93 (quin, J¼7.2 Hz, 1H), 2.43 (s, 3H),
2.11 (s, 3H), 1.35 (d, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d 205.6, 143.6, 136.9, 129.7, 127.1, 57.7, 26.2,
21.5, 18.8; MS (FAB+) m/z: 242.0 (M+1, 100), 198.0 (42),
155.0 (38), 136.0 (37), 91.0 (47); HRMS [M+1]: calcd for
C11H15NO3S: 242.0851; found: 242.0852. The enantiomeric
excess of ketone 8e (>99%) has been determined by HPLC
with a ChiralpakÒ AD column (hex/i-PrOH¼90:10, 1 mL/
min, T¼25 ꢁC), tR¼21.8 min.
References and notes
1. (a) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K.
J. Org. Chem. 1998, 63, 9932; (b) Anderson, J. C.; Peace, S.;
Pih, S. Synlett 2000, 850; (c) Anderson, J. C.; Blake, A. J.;
Howell, G. P.; Wilson, C. J. Org. Chem. 2005, 70, 549; (d)
Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-
Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69,
8168; (e) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R.
Org. Biomol. Chem. 2003, 1, 4275; (f) Baricordi, N.; Benetti,
S.; Biondini, G.; De Risi, C.; Pollini, G. P. Tetrahedron Lett.
2004, 45, 1373.
4.5. Procedure for preparing b-amino hydroxylamines
Aluminum amalgam (48 mg) was added to a solution of the
corresponding sulfinylnitroamine (0.12 mmol) in THF/H2O
(9:1) (11.7 mL). The reaction mixture was stirred at rt for
40 min whereupon it was filtrated through a short pad of
Celite and the crude purified by flash chromatography
(hex/EtOAc¼1:2).
2. Enantioselective version using metallic catalyst: (a) Yamada, K.;
€
Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem. 1999,
111, 3713; Angew. Chem., Int. Ed. 1999, 38, 3504; (b) Yamada,
K.; Moll, G.; Shibasaki, M. Synlett 2001, 980; (c) Nishiwaki,
N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 2992; (d) Knudsen, K. R.; Risgaard,
T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem.
Soc. 2001, 123, 5843; (e) Knudsen, K. R.; Jørgensen, K. A. Org.
Biomol. Chem. 2005, 3, 1362; (f) Anderson, J. C.; Howell, G. P.;
Lawrence, R. M.; Wilson, C. J. Org. Chem. 2005, 70, 5665.
3. Enantioselective organocatalytic reactions: (a) Nugent, B. J.;
Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
3418; (b) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625; (c) Yoon, T. P.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2005, 44, 466; (d) Palomo, C.; Oiarbide, M.;
4.5.1. (1S,2S,(S)S)-N-(p-Tolylsulfinyl)-2-hydroxylamine-
1-phenylpropylamine (9a). Yield: 63%; [a]2D0 +74 (c 1.7,
CHCl3); IR (film): 3251, 2100, 1650, 1492, 1455, 1087,
1042 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.54 (d,
;
J¼8.2 Hz, 2H), 7.42–7.32 (m, 7H), 5.49 (br d, J¼2.8 Hz,
1H), 4.44 (dd, J¼9.4 and 2.8 Hz, 1H), 2.97 (dq, J¼9.4 and
6.5 Hz, 1H), 2.40 (s, 3H), 1.05 (d, J¼6.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 142.1, 141.4, 140.3, 129.5,
128.6, 128.2, 128.0, 125.5, 61.5, 61.4, 21.3, 15.4;
MS (FAB+) m/z: 305.0 (M+1, 33), 106 (100), 57 (49);
HRMS [M+1]: calcd for C16H20N2O2S: 305.1327; found:
305.1330.
ꢀ
Laso, A.; Lopez, R. J. Am. Chem. Soc. 2005, 127, 17622; (e)
Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi,
L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975; (f)
Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V.
Tetrahedron 2006, 62, 375; (g) Xu, X.; Furukawa, T.; Okino,
T.; Miyabe, H.; Takemoto, Y. Chem.—Eur. J. 2006, 12, 466.
4. Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. 1998,
110, 2724; Angew. Chem., Int. Ed. 1998, 37, 2581;
Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151.
5. Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
6. Luzio, F. A.; Fitch, R. W. J. Prakt. Chem. 2000, 342, 498–501;
For some b-amino hydroxylamines with interesting biological
properties, see: Hogg, J. H.; Ollmann, I. R.; Haeggstrtm, J. Z.;
Wetterholm, A.; Samuelsson, B.; Chi-Huey Wong, C.-H.
Bioorg. Med. Chem. 1995, 3, 1405.
4.5.2. (1S,2R,(S)S)-N-(p-Tolylsulfinyl)-2-hydroxylamine-
1-phenylpropylamine (10a). Yield: 89%; [a]2D0 +78 (c 0.2,
CHCl3); IR (film): 3251, 1632, 1492, 1453, 1089,
1054 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.67 (d,
;
J¼8.2 Hz, 2H), 7.42–7.32 (m, 7H), 5.07 (br t, J¼3.5 Hz,
1H), 4.95 (br d, J¼3.1 Hz, 1H), 3.40 (dq, J¼6.7 and
4.0 Hz, 1H), 2.43 (s, 3H), 0.69 (d, J¼6.7 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d 142.0, 141.7, 139.3, 129.7,
128.5, 127.6, 127.5, 125.4, 61.2, 57.4, 21.4, 10.8;
MS (FAB+) m/z: 305.0 (M+1, 39), 289 (55), 219 (26);
HRMS [M+1]: calcd for C16H20N2O2S: 305.1323; found:
305.1322.
7. Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005,
44, 612.
´
ꢀ
ꢀ
8. Garcıa Ruano, J. L.; Topp, M.; Lopez-Cantarero, J.; Aleman, J.;
4.5.3. (3S,4S,(S)S)-N-(p-Tolylsulfinyl)-2-methyl-4-hy-
droxylamine-pentan-3-amine (9f). Yield: 48%; [a]2D0 +83
(c 0.9, CHCl3); IR (film): 3352, 2089, 1645, 1492, 1464,
ꢀ
Remuin˜an, M. J.; Cid, M. B. Org. Lett. 2005, 7, 4407.
9. (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998,
27, 13 and references cited therein; (b) Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedron 2004, 60, 8003 and references cited
therein; (c) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005,
8398; (d) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984; (e) Weix, D. J.; Shi, Y.; Ellman, J. A.
J. Am. Chem. Soc. 2005, 127, 1092.
1087, 1045, 1015 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d 7.66 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H), 4.30 (br
d, J¼6.9 Hz, 1H), 3.32–3.26 (m, 1H), 2.79 (dq, J¼9.7 and
6.4 Hz, 1H), 2.41 (s, 3H), 1.89 (quind, J¼6.8 and 2.5 Hz,
1H), 1.24 (d, J¼6.4 Hz, 3H), 1.11 (d, J¼6.81 Hz, 3H),
0.79 (d, J¼6.7 Hz, 3H); MS (FAB+) m/z: 271.2 (M+1, 46),

´
J. L. Garcıa Ruano et al. / Tetrahedron 62 (2006) 12197–12203
12203
´
ꢀ
10. Garcıa Ruano, J. L.; Aleman, J.; Cid, M. B.; Parra, A. Org. Lett.
(b) Adam, W.; Roschmann, K. J.; Saha-Moller, C. R. Eur. J.
Org. Chem. 2000, 557.
2005, 7, 179.
11. Qian, Ch.; Gao, F.; Chen, R. Tetrahedron Lett. 2001, 42, 4673.
12. It is noteworthy that in this case when the reaction was carried
out using 0.2 equiv of TBAF, a mixture of the corresponding
sulfones was obtained, whereas the use of 1 equiv of TBAF
affords all four possible diastereoisomers in 38% overall yield.
13. Complete X-ray data of compounds 3a and 2f have been depos-
ited at the Cambridge Crystallographic Data Centre as CCDC
298296 and CCDC 298297, respectively.
14. Kornblum, N.; Ericson, A. S.; Nelly, W. J.; Henggeler, B.
J. Org. Chem. 1982, 4534.
15. Ketone 8a has been already described in: (a) Davis, F. A.;
Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393;
16. The enantiomeric excesses of ketones 8a and 8e have been
determined by HPLC with a ChiralpakÒ AD column (hex/
i-PrOH¼90:10, 1 mL/min, T¼25 ꢁC).
17. a-Amino ketones are valuable building blocks in asymmetric
synthesis and are not not easily accesible in enantiomerically
pure form. See Ref. 15a and references cited therein.
18. (a) Corey, E. J.; Vlattas, I.; Andersen, N. H.; Hardin, K. J. Am.
Chem. Soc. 1968, 90, 3245; (b) Nakagawa, M.; Kodato, S.;
Kakayama, K.; Hino, T. Tetrahedron Lett. 1987, 28, 6281;
For a recent publication dealing with the difficulties of reduc-
tion of nitro groups, see: Anderson, J. C.; Chapman, H. A.
Synthesis 2006, 3309.