Indium-mediated aza-Henry reaction of imines: Access to 2-nitroamines

Article abstract of DOI:10.1002/ejoc.201200304

A new method has been developed to obtain 2-nitroamines by an indium-promoted reaction of bromonitromethane with a variety of imines. On the strength of these results, the reaction was also performed with 2-bromo-2-nitropropanes to afford 2,2-dialkyl-2-nitroamines. Moreover, the indium-mediated reaction of 1-bromo-1-nitroethane and imines afforded 1-methyl-2-nitroamines with remarkably high anti selectivity. The use of chiral sugar-derived imines furnished the corresponding 2-nitroamines with excellent stereoselectivity. A new method to obtain 2-amines by reaction of bromonitromethane with a variety of imines, 2-bromo-2-nitropropanes and chiral sugar-derived aldehydes, promoted by indium is reported. This is the first example of the preparation of 2,2-dialkyl-2-nitroamines by addition to imines. The sugar-derived aldehydes furnished the corresponding 2-nitroamines with excellent stereoselectivity. Copyright

Full text of DOI:10.1002/ejoc.201200304

Job/Unit: O20304
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Date: 27-06-12 09:57:12
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FULL PAPER
DOI: 10.1002/ejoc.201200304
Indium-Mediated Aza-Henry Reaction of Imines: Access to 2-Nitroamines
Raquel G. Soengas,*[a,b] Sandrina Silva,[a] Amalia M. Estévez,[b] Juan C. Estévez,[b]
Ramón J. Estévez,[b] and Humberto Rodríguez-Solla[c]
Keywords: Synthetic methods / Nucleophilic addition / Aza-Henry reactions / Indium / Amines
A new method has been developed to obtain 2-nitroamines
by an indium-promoted reaction of bromonitromethane with
a variety of imines. On the strength of these results, the reac-
tion was also performed with 2-bromo-2-nitropropanes to af-
ford 2,2-dialkyl-2-nitroamines. Moreover, the indium-medi-
ated reaction of 1-bromo-1-nitroethane and imines afforded
1-methyl-2-nitroamines with remarkably high anti selecti-
vity. The use of chiral sugar-derived imines furnished the cor-
responding 2-nitroamines with excellent stereoselectivity.
far, both racemic and asymmetric methods for the reactions
with various nitroalkanes have been carried out by using
inorganocatalysts,[9] organocatalysts[10] or chiral Lewis acid
catalysts of ytterbium,[11] aluminium,[12] copper[13] and
zinc[14] metals.
Despite the considerable synthetic effort and the ad-
vances made in this area, there are still limitations to the
applicability of the aza-Henry reaction. The vast majority
of the known procedures are restricted to imines derived
from non-enolizable aldehydes, typically aromatic ones. The
reason is that enolizable aldehyde-derived azomethines tend
to undergo α-deprotonation rather than addition. Among
the numerous literature examples, only a few aza-Henry re-
actions have been reported that give good selectivity for a
broad range of reaction partners.
A valuable alternative to carry out the aza-Henry reac-
tion with enolizable aldehydes would be the development of
new, less basic nitronates derived from those metals charac-
terized by the low basicity of their organometallic com-
pounds. Taking advantage of the low basicity of the samar-
ium reagents,[15] we recently described a reaction of bromo-
nitromethane with a variety of imines under very mild con-
ditions promoted by SmI2 to afford nitroamines.[16] The use
of substoichiometric amounts of SmI2 to generate a ni-
tronate intermediate is inconsistent with the typical role of
SmI2 as a monoelectronic reducing agent in a Barbier-type
process through metallation of the C–Br bond. Thus, the
proposed mechanism for the synthesis of nitroamines in-
volves initiation by the release of iodide from traces of SmI3
that are present in tetrahydrofuran (THF) solutions of
SmI2.
Introduction
The aza-Henry (or nitro-Mannich) reaction involves nu-
cleophilic addition of nitroalkanes to imines. This reaction
results in the formation of a carbon–carbon bond with con-
comitant generation of a β-nitroamine. By using this reac-
tion a wide variety of other organic compounds can be de-
rived by functional transformations of the nitro group into
other chemical functionalities, such as amines,[1] carbonyl
groups,[2] hydroxylamines[3] and oximes or nitriles.[4]
The aza-Henry reaction has long been known[5] and pro-
vides access to valuable functionalized structural motifs
such as 1,2-diamines.[6] It is therefore conceivable that ef-
forts may have been devoted over the years to improve
yields and stereocontrol. Surprisingly, significant success
was not achieved until very recently. Unlike the addition of
nitronates to aldehydes, the addition to imines is not ther-
modynamically favored. Anderson et al. reasoned that, be-
cause nitronates are quite inert toward Schiff bases, the aid
of a Lewis or Brønsted acid is required, and they reported
an improved version of the classical nitro-Mannich reac-
tion.[7] Subsequently, in 1999, Shibasaki et al. described the
first asymmetric aza-Henry reaction in which binaph-
thoxide (binol)-based heterobimetallic complexes of ytter-
bium and aluminium were used as catalysts.[8]
Since Anderson and Shibasaki’s pioneering work, the
aza-Henry reaction has attracted considerable attention. So
[a] Departament of Chemistry & QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
E-mail: rsoengas@ua.pt
[b] Centro Singular de Investigación en Química Biológica y
Materiales Moleculares, Campus Vida, Universidad de
Santiago de Compostela,
In connection with this work on the SmI2-mediated aza-
Henry reaction and our previous work on the indium-medi-
ated Henry reaction,[17] we decided to investigate an alter-
native approach based on a Barbier-type addition of α-
bromo-α-nitroalkanes to imines. Our aim was to develop an
indium-promoted aza-Henry reaction, taking advantage of
Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain
[c] Departamento de Química Orgánica e Inorgánica, Facultad de
Química, Universidad de Oviedo,
Julián Clavería 8, 33071 Oviedo, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200304.
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the very low first ionization energy of indium(0), which classical ionic nitro-Mannich reaction usually fails to give
makes it an ideal candidate for use in single electron trans- the desired products and only additions of nitromethane to
fer (SET) reactions. This property, together with the sta- imines have been reported in the literature. As expected,
bility of In0 to oxygen and water, has prompted exhaustive according to the proposed ionic mechanism, the SmI2-me-
studies focused on the chemistry of indium with organic diated reaction of sterically hindered bromonitroalkanes
molecules in the past several years.[18]
with imines failed to give the corresponding nitroamines
(Table 2, Entries 2 and 5), and the unreacted starting mate-
rial was recovered in both cases.
Results and Discussion
Table 2. Synthesis of 2,2-alkyl-2-nitroamines 5a–d.
Initially, we studied the addition reaction of bromoni-
tromethane to imine 1a promoted by indium. The best re-
sults were achieved with solutions of 1 equiv. of imine 1a,
1 equiv. of indium and 1.5 equiv. of bromonitromethane 2
in THF under sonication at room temp. for 4 h. It is note-
worthy that no reaction occurred in the absence of sonic-
ation. On other hand, shorter reaction times resulted in
lower conversion rates. By using these optimal reaction con-
ditions, the reaction of bromonitromethane 2 and achiral
N-(p-methoxyphenyl)imines 1b–e derived from commer-
cially available aldehydes was carried out (Scheme 1). As
shown by the results in Table 1, under these conditions ali-
phatic linear imine 1b and branched imines 1d and 1e, ali-
cyclic imine 1c and aromatic imine 1a were efficiently con-
verted into their corresponding 2-nitroamines 3a–3e.
Entry
Imine
R
Nitroamine
Yield[a]
1
1a
1a
1b
1c
1c
1d
C6H5
C6H5
CH3(CH2)6
C6H11
C6H11
iBu
5a
49
2[b]
3
[c]
[c]
5b
81
4
5c
78
[c]
[c]
5[b]
6
5d
69
[a] Isolated yield of pure compounds 5 after column chromatog-
raphy relative to compounds 1. [b] Reaction mediated by samarium
diiodide (1 equiv. imine, 1 equiv. 2-bromonitropropane, 1 equiv.
SmI2). [c] No reaction took place under these conditions.
However, because the mechanism for the indium-medi-
ated addition of bromonitroalkanes to imines is an SET
mechanism, 4 was successfully added to imines (Scheme 2).
As shown in Table 2, the reaction of imines 1a–d with 4
under the same reaction conditions described previously
gave 2-nitroamines 5a–d (Table 2, Entries 1, 3, 4 and 6).
Scheme 1. Indium-mediated reaction of imines 1a–e and bromoni-
tromethane 2.
Table 1. Synthesis of 2-nitroamines 3a–e.
Entry
Imine
R
Nitroamine
Yield[a]
Scheme 2. Indium-mediated reaction of imines 1a–d and 2-bromo-
2-nitropropane (4).
1
2
3
4
5
1a
1b
1c
1d
1e
C6H5
CH3(CH2)6
C6H11
iBu
3a
3b
3c
3d
3e
61
82
80
78
68
Given these satisfactory results, we decided to extend our
studies to the conformationally restricted bromonitroalkane
6, which is a highly valuable reagent for the preparation of
iPr
[a] Isolated yield of pure compounds 3 after column chromatog-
raphy relative to compounds 1.
branched-chain
derivatives
of
biological
interest
(Scheme 3).[20]
Regarding the mechanism of these indium-mediated
transformations, it should be noted that in contrast to the
SmI2-mediated reaction of bromonitromethane with imines,
which is promoted by the iodide released by traces of SmI3,
the synthesis of nitro alcohols 3a–e by using 1.0 equiv. of
indium is consistent with the typical role of indium as a
monoelectronic reducing agent. In fact, recent studies on
the structure of the intermediates formed upon sonication
of mixtures of bromonitroalkanes and indium in THF sug-
gested the formation of a RInIII-type transient species.[19]
Reaction of the indium species with aldehydes would give
rise, after work-up, to the corresponding 2-nitroamines.
Scheme 3. Indium-mediated reaction of imines 1b–c, e–f and 5-
bromo-2,2-dimethyl-5-nitro-1,3-dioxane (6).
5-Bromo-2,2-dimethyl-5-nitro-1,3-dioxane (6), which is
In subsequent experiments aimed at extending these easily prepared from the commercially available insecticide
studies to include hindered 1-bromo-1-nitroalkanes, the bronopol[21] (2-bromo-2-nitropropane-1,3-diol), reacted
case of 2-bromo-2-nitropropane (4) was considered. Be- with imines 1b–c, e–f to give the corresponding nitroamines
cause sterically-hindered nitroalkanes are less reactive, the 7b–c, e–f in moderate to good yields (Table 3).
2
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Indium-Mediated Aza-Henry Reaction of Imines
Table 3. Synthesis of 2,2-alkyl-2-nitroamines 7b–c, e–f.
The excellent anti diastereoselectivity obtained can be ex-
plained in terms of a lowered C–N antibonding orbital that
would bring about increased stabilization of a Felkin–Anh
antiperiplanar nucleophilic addition of the organoindium
species to the imine carbonyl,[22] as shown in Figure 2.
Entry
Imine
R
Nitroamine
Yield[a]
1
2
3
4
1b
1c
1e
1f
CH3(CH2)6
C6H11
iPr
7b
7c
7e
7f
79
75
64
38
pMeOC6H4
[a] Isolated yield of pure compounds 7 after column chromatog-
raphy relative to compounds 1.
The satisfactory results obtained in the synthesis of race-
mic 2-nitroamines 3, 5 and 7 prompted us to test the useful-
ness of this methodology for the synthesis of enantiopure
2-nitroamines. Our preliminary studies were carried out
with a panel consisting of chiral imines 1g–i (Figure 1),
which upon indium-mediated reaction with bromoni-
tromethane (2), 2-bromo-2-nitropropane (4) or 5-bromo-
2,2-dimethyl-5-nitro-1,3-dioxane (6) under the same reac-
tion conditions as before, provided 2-nitroamines 3g–i, 5g–
i and 7g–i (Scheme 4, Table 4).
Figure 2. Felkin–Anh model for the attack on sugar imines 1g–i.
The expected anti selectivity was confirmed by analysis
of the NMR spectroscopic data for nitroamine 3h and of a
sample obtained by debromination[23] of the known bromo-
nitroamine 8[16] (Scheme 5).
Scheme 5. Debromination of bromonitroamine 8.
Chiral enantiopure diamines are useful synthetic inter-
mediates and are of great interest for the development of
new chiral ligands for asymmetric synthesis. Particularly ap-
propriate for those purposes are 1,2-diamines containing a
sugar residue.[24] The resulting nitroamines 3g–i, 5g–i and
7g–i could be suitable starting materials for the preparation
of orthogonally protected sugar-derived diamines. To illus-
trate this synthetic possibility, reduction of compound 3h
to the corresponding diamine was investigated (Scheme 6).
Although there are numerous protocols for the reduction of
nitro compounds to amines,[25] the reduction of β-ni-
troamines is more complicated because of the inherent in-
stability of this functional group.[26] SmI2 has been widely
used as a mild reductant for the conversion of β-ni-
troamines to 1,2-diamines.[27] N-Diphenylphosphanyl-β-ni-
troamines have been reduced with Zn/NH4Cl[28] and with
catalytic In with Zn as a stoichiometric reductant.[29]
Figure 1. Chiral imines 1g–i.
Scheme 4. Indium-mediated reaction of imines 1g–i and bromo-
alkanes 2, 4 and 6.
Table 4. Synthesis of enantiopure 2-nitroamines 3g–i, 5g–i and
7g–i.
Entry Aldehyde
Bromo-
2-Nitroamine
Yield[a] syn/anti[b]
nitroalkane
1
2
3
4
5
6
7
8
9
1g
1h
1i
2
4
6
2
4
6
2
4
6
3g
5g
7g
3h
5h
7h
3i
85
78
80
79
70
71
75
72
71
1:4
1:5
1:5
1:4
1:6
1:6
1:3
1:5
1:6
Scheme 6. Reduction of β-nitroamine 3h and preparation of or-
thogonally protected diamine 9.
5i
7i
[a] Isolated yields of epimeric mixtures of pure 2-nitroamines after
column chromatography relative to compounds 1. [b] syn/anti ratio
was determined by 300 MHz 1H NMR spectroscopic analysis of
the corresponding crude products.
In our case, treatment of nitroamine 3h with SmI2/H2O
in the presence of pyrrolidine[30] afforded the corresponding
1,2-diamine 9 in good yield and without any loss of the
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sodium hydrogen carbonate, diluted with water (10 mL) and ex-
tracted with diethyl ether (3ϫ25 mL). The combined organic layers
were dried with magnesium sulfate, filtered and the solvent was
evaporated in vacuo. The residue was purified by flash column
chromatography with mixtures of ethyl acetate/hexane as eluants
to give the pure compounds shown in Tables 1, 2, 3 and 5.
stereochemical integrity (Table 5). Similarly, the reduction
can also be carried out with Zn powder in 2-propanol/dilute
HCl. This procedure gave the 1,2-diamine 9 in moderate
yield.
Table 5. Synthesis of diamine 9.
Entry
Conditions
Yield[a]
4-Methoxy-N-(2-nitro-1-phenylethyl)benzenamine (3a): Brown oil.
1H NMR (300 MHz, CDCl3): δ = 7.61–7.24 (m, 5 H), 6.73 (d, J =
9.0 Hz, 2 H), 6.58 (d, J = 9.0 Hz, 2 H), 6.23 (d, J = 7.4 Hz, 1 H),
5.09 (t, J = 6.7 Hz, 1 H), 4.69 (d, J = 6.7 Hz, 2 H), 3.71 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.1 (C), 139.6 (C),
137.9 (C), 129.2 (2ϫ CH), 128.5 (CH), 126.4 (2ϫ CH), 115.6 (2ϫ
CH), 114.8 (2ϫ CH), 80.0 (CH2), 57.7 (CH), 55.6 (CH3) ppm. MS
(ESI+): m/z (%) = 273 (4) [M + H]+, 213 (7), 212 (100), 124 (7).
1
2
SmI2/H2O/pyrrolidine
Zn/1 m HCl
87
69
[a] Isolated yield of pure compound 9 after column chromatog-
raphy relative to compound 3h.
HRMS (ESI+): calcd. for C15H17N2O3 [M + H]+ 273.1239; found
+
Conclusions
273.1233. IR (neat): ν = 3375, 1554, 1511, 1378, 1243 cm–1. R =
˜
f
In conclusion, we report a new synthetic route to 2-ni-
troamines. The process involves the indium-mediated ad-
dition of 1-bromo-1-nitroalkanes to imines. This strategy
constitutes a promising and convenient alternative to the
classical aza-Henry reaction. The approach is very simple
from an experimental point of view and, because bases are
not required, it is not subject to the limitations of the classi-
cal aza-Henry reaction. In addition, this approach may
have many advantages with respect to a previously reported
samarium-mediated Henry reaction of imines with bromo-
nitromethane, which failed to give the desired 2-nitroamines
when hindered bromonitroalkanes were employed.
0.23 (hexane/AcOEt, 3:1).
4-Methoxy-N-(1-nitrononan-2-yl)benzenamine (3b): Brown oil. 1H
NMR (300 MHz, CDCl3): δ = 6.80 (d, J = 8.5 Hz, 2 H), 6.64 (d,
J = 8.5 Hz, 2 H), 4.51 (dd, J = 11.5, 4.9 Hz, 1 H), 4.41 (dd, J =
11.5, 5.7 Hz, 1 H), 3.98–3.87 (m, 1 H), 3.75 (s, 3 H), 1.71–1.27 (m,
12 H), 0.88 (t, J = 6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.9 (C), 139.9 (C), 115.3 (2ϫ CH), 115.0 (2ϫ CH), 78.0
(CH2), 55.6 (CH3), 53.5 (CH), 32.8 (CH2), 31.6 (CH2), 29.2 (CH2),
28.9 (CH2), 25.8 (CH2), 22.5 (CH2), 13.9 (CH3) ppm. MS (ESI+):
m/z (%) = 295 (100) [M + H]+, 234 (5), 214 (4), 201 (7). HRMS
(ESI+): calcd. for C16H27N2O3 [M + H]+ 295.2022; found
+
295.2016. IR (neat): ν = 3380, 1550, 1513, 1381, 1243 cm–1. R =
˜
f
0.48 (hexane/EtOAc, 5:1).
Regarding the stereoselective version of this new ap-
proach to 2-nitroamines, promising results were achieved
when chiral sugar-derived imines 1g–i were treated with
bromonitroalkanes 2, 4 and 6, with the anti 2-nitroamines
obtained as major isomers in all cases. The corresponding
2-nitroamines can be easily reduced to afford the corre-
sponding sugar-derived 1,2-diamines.
A systematic study of the mechanistic and stereochemical
aspects of this new and highly promising access to 2-ni-
troamines is currently in progress. The development of an
indium-catalytic procedure is also underway.
N-(1-Cyclohexyl-2-nitroethyl)-4-methoxybenzenamine (3c): Brown
oil. 1H NMR (300 MHz, CDCl3): δ = 6.76 (d, J = 9.0 Hz, 2 H),
6.65 (d, J = 9.0 Hz, 2 H), 4.72 (dd, J = 12.3, 5.2 Hz, 1 H), 4.46
(dd, J = 12.3, 7.4 Hz, 1 H), 4.08–4.04 (m, 1 H), 3.73 (s, 3 H), 2.73
(s, 11 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.7 (C), 141.0
(C), 115.0 (2ϫ CH), 114.9 (2ϫ CH), 75.7 (CH2), 60.9 (CH), 55.7
(CH3), 43.0 (CH), 34.7 (2ϫ CH2), 25.2 (CH2), 21.6 (2ϫ CH2) ppm.
MS (ESI+): m/z (%) = 279 (6) [M + H]+, 234 (19), 216 (100), 214
+
(28). HRMS (ESI+): calcd. for C15H23N2O3 [M + H]+ 279.1709;
found 279.1703. Rf = 0.22, (hexane/EtOAc, 3:1).
4-Methoxy-N-(4-methyl-1-nitropentan-2-yl)benzenamine
(3d):
1
Brown oil. H NMR (300 MHz, CDCl3): δ = 6.76 (d, J = 9.1 Hz,
2 H), 6.65 (d, J = 9.0 Hz, 2 H), 4.70 (dd, J = 12.5, 1.7 Hz, 1 H),
4.45 (dd, J = 12.5, 1.8 Hz, 1 H), 4.15–4.05 (m, 1 H), 3.72 (s, 3 H),
1.74–1.48 (m, 1 H), 1.28–1.23 (m, 2 H), 0.95 (t, J = 7.2 Hz, 3 H),
0.88 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
152.6 (C), 140.9 (C), 114.9 (2ϫ CH), 114.8 (2ϫ CH), 76.1 (CH2),
75.1 (CH), 74.7 (CH), 55.6 (CH3), 32.1 (CH), 23.3 (CH2), 8.0
(CH3), 7.7 (CH3) ppm. MS (ESI+): m/z (%) = 275 [M + Na]+, (100),
270 [M + NH4]+, (47), 253 [M + H]+, (12), 209 (6), 206 (4). HRMS
Experimental Section
General: Reactions under sonication were carried out in a Selecta
cleaning bath (320 W) at 20 °C. Melting points were determined
with a Kofler Thermogerate apparatus. Specific rotations were re-
corded on a JASCO DI-370 optical polarimeter. Nuclear magnetic
resonance spectra were recorded with Varian Mercury 300 or Var-
ian Inova 500 spectrometers. Mass spectral data were obtained with
+
(ESI+): calcd. for C13H21N2O3 [M + H]+ 253.1552; found
a
Hewlett–Packard 5988A mass spectrometer. Thin-layer
253.1548. Rf = 0.53, (hexane/EtOAc, 1:1).
chromatography (TLC) was performed by using Merck GF-254
type 60 silica gel and ethyl acetate/hexane mixtures as eluants; the
TLC spots were visualized with Hanessian mixture. Column
chromatography was carried out by using Merck-type 9385 silica
gel.
4-Methoxy-N-(3-methyl-1-nitrobutan-2-yl)benzenamine (3e): Brown
oil. 1H NMR (300 MHz, CDCl3): δ = 6.79 (d, J = 7.2 Hz, 2 H),
6.64 (d, J = 7.2 Hz, 2 H), 4.48 (d, J = 5.9 Hz, 1 H), 4.12 (q, J =
7.1 Hz, 1 H), 3.89–3.74 (m, 2 H), 3.70 (s, 3 H), 1.29–1.23 (m, 1 H),
1.03 (apparent t, J = 7.0 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.8 (C), 140.3 (C), 115.2 (2ϫ CH), 115.0 (2ϫ CH),
76.5 (CH2), 58.9 (CH), 55.7 (CH3), 30.4 (CH), 19.0 (CH3), 18.1
(CH3) ppm. MS (ESI+): m/z (%) = 239 (100) [M + H]+, 232 (29),
General Procedure for the Reaction of Bromonitroalkanes and
Imines: To a suspension of indium powder (0.5 mmol) in THF
(1 mL) was added the bromonitroalkane (0.75 mmol) and the mix-
ture was sonicated for 20 min. The corresponding aldimine
(0.5 mmol) was added and sonication was continued for a further
4 h. The reaction mixture was neutralized with saturated aqueous
+
208 (20), 176 (24). HRMS (ESI+): calcd. for C12H19N2O3 [M +
H]+ 239.1396; found 239.1390. Rf = 0.53, (hexane/EtOAc, 3:1).
4
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Indium-Mediated Aza-Henry Reaction of Imines
4-Methoxy-N-(2,2-dimethyl-2-nitro-1-phenylethyl)benzenamine (5a): (CH2), 25.5 (CH3), 21.4 (CH3) ppm. MS (ESI+): m/z (%) = 379.22
1
+
Brown oil. H NMR (300 MHz, CDCl3): δ = 7.34–7.25 (m, 5 H),
(15) [M + H]+, 124.08. HRMS (ESI+): calcd. for C20H31N2O3 [M
6.66 (d, J = 9.1 Hz, 2 H), 6.51 (d, J = 9.1 Hz, 2 H), 4.85 (s, 1 H),
4.25 (br. s, 1 H), 3.67 (s, 3 H), 1.61 (s, 3 H), 1.62 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.9 (C), 140.3 (C), 137.5 (C), 128.7
(2ϫCH), 128.5 (CH), 128.3 (2ϫ CH), 115.8 (2ϫ CH), 114.8 (2ϫ
CH), 91.4 (C), 65.9 (CH), 55.7 (CH3), 25.7 (CH3), 21.0 (CH3) ppm.
MS (ESI+): m/z (%) = 301.15 (75) [M + H]+, 124.07 (100). HRMS
+ H]+ 379.2233; found 379.2227. Rf = 0.29, (hexane/EtOAc, 5:1).
4-Methoxy-N-[2-methyl-1-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)prop-
yl]benzenamine (7e): Brown oil. H NMR (300 MHz, CDCl3): δ =
1
6.74 (d, J = 8.9 Hz, 2 H), 6.63 (d, J = 8.9 Hz, 2 H), 4.72 (d, J =
12.9 Hz, 2 H), 4.25 (d, J = 12.9 Hz, 2 H), 3.75–3.78 (m, 1 H), 3.74
(s, 3 H), 1.88–1.74 (m, 1 H), 1.51 (s, 3 H), 1.47 (s, 3 H), 0.98–0.81
(m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.1 (C), 142.0
(C), 115.1 (2 ϫ CH), 114.5 (2 ϫ CH), 101.2 (C), 94.5 (C), 63.3
(CH2), 63.1 (CH2), 55.9 (CH3), 53.4 (CH), 27.2 (CH), 25.2 (CH3),
24.5 (CH3), 18.4 (CH3), 16.6 (CH3) ppm. MS (ESI+): m/z (%) =
+
(ESI+): calcd. for C17H21N2O3 [M + H]+ 301.1547; found
301.1537. Rf = 0.29, (hexane/AcOEt, 7:1).
4-Methoxy-N-(2,2-dimethyl-1-nitrononan-2-yl)benzenamine
(5b):
1
Brown oil. H NMR (300 MHz, CDCl3): δ = 6.82 (d, J = 8.9 Hz,
2 H), 6.53 (d, J = 8.9 Hz, 2 H), 3.80 (s, 1 H), 3.76 (br. s, 1 H), 3.71
(s, 3 H), 1.64–1.13 (m, 18 H), 0.93–0.82 (m, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.3 (C), 138.7 (C), 115.8 (2ϫ CH), 114.3
(2ϫ CH), 91.5 (C), 62.7 (CH), 55.9 (CH3), 32.0 (CH2), 29.9 (CH2),
29.3 (CH2), 28.2 (CH2), 26.5 (CH2), 25.1 (CH3), 22.9 (CH2), 22.8
(CH3), 14.3 (CH3) ppm. MS (ESI+): m/z (%) = 323.23 (12) [M +
339.19 (31) [M + H]+. HRMS (ESI+): calcd. for C17H27N2O5 [M
+
+ H]+ 339.1920; found 339.1929. Rf = 0.30, (hexane/EtOAc, 5:1).
4-Methoxy-N-[(4-methoxyphenyl)(2,2-dimethyl-5-nitro-1,3-dioxan-
5-yl)methyl]benzenamine (7f): Brown oil. 1H NMR (300 MHz,
CDCl3): δ = 7.85–7.82 (m, 2 H), 7.26–7.19 (m, 2 H), 6.99–6.90 (m,
4 H), 4.50 (dd, J = 12.5, 4.0 Hz, 2 H), 4.38–4.32 (m, 1 H), 4.25
(dd, J = 12.5, 4.0 Hz, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 1.46 (s, 3
H), 1.42 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.0 (C),
145.2 (C), 132.0 (C), 130.2 (2ϫ CH), 129.4 (C) 122.0 (2ϫ CH),
114.3 (2ϫ CH), 114.1 (2ϫ CH), 99.1 (C), 59.7 (2ϫ CH2), 55.5
(CH3), 55.4 (CH3), 25.3 (CH3), 21.2 (CH3) ppm. MS (ESI+): m/z
(%) = 403.19 (40) [M + H]+ . HRMS (ESI+ ): calcd. for
C21H27N2O6+ [M + H]+ 403.1869; found 403,1858. Rf = 0.41, (hex-
ane/EtOAc, 5:1).
H]+. HRMS (ESI+): calcd. for C18H31N2O3 [M + H]+ 323.2335;
found 323.2342. Rf = 0.28, (hexane/EtOAc, 9:1).
+
N-(1-Cyclohexyl-2,2-dimethyl-2-nitroethyl)-4-methoxybenzenamine
(5c): Brown oil. 1H NMR (300 MHz, CDCl3): δ = 6.76 (d, J =
9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 3.80 (s, 1 H), 3.74 (s, 3 H),
3.54 (br. s, 1 H), 1.80–1.64 (m, 4 H), 1.62 (s, 3 H), 1.60 (s, 3 H),
1.32–0.79 (m, 7 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.3
(C), 142.9 (C), 115.1 (2 ϫ CH), 114.3 (2 ϫ CH), 92.2 (C), 65.3
(CH), 55.9 (CH3), 40.9 (CH), 33.6 (CH2), 28.4 (CH2), 26.7 (CH2),
26.3 (CH2), 26.1 (CH2), 25.2 (CH3), 23.2 (CH3) ppm. MS (ESI+):
m/z (%) = 307.20 (29) [M + H]+, 124 (100). HRMS (ESI+): calcd.
1-O-tert-Butyldimethylsilyl-5,6-deoxy-2,3-di-O-isopropylidene-5-
[(p-methoxyphenyl)amino]-6-nitro-α-D-mannofuranose and L-Gulo-
furanose (3 g): Orange oil. [α]2D6 = +7.5 (c = 1.4, in CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 6.78 (d, J = 8.7 Hz, 4 H), 6.71 (d,
J = 8.7 Hz, 4 H), 5.64 (d, J = 1.7 Hz, 2 H), 5.33 (s, 1 H), 5.30 (s,
1 H), 4.82–4.65 (m, 4 H), 4.60–4.53 (m, 4 H), 4.42–4.32 (m, 2 H),
4.17 (dd, J = 7.5, 2.4 Hz, 1 H); 4.10 (dd, J = 7.1, 1.7 Hz, 1 H), 3.72
(s, 3 H), 3.71 (s, 3 H), 1.50 (s, 3 H), 1.48 (s, 3 H), 1.29, (s, 6 H),
0.89 (s, 9 H), 0.88 (s, 9 H), 0.12 (s, 3 H), 0.11 (s, 3 H), 0.09 (s, 3
H), 0.08 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): major isomer
d-manno (anti): δ = 153.1 (C), 139.3 (C), 116.5 (2ϫ CH), 115.2
(CH), 114.6 (2ϫ CH), 112.2 (C), 101.0 (CH), 86.6 (CH), 79.4 (CH),
75.2 (CH2), 55.2 (CH3), 52.5 (CH), 25.7 (CH3), 25.3 (3ϫ CH3),
24.3 (CH3), 17.5 (C), –4.8 (CH3), –5.8 (CH3) ppm; minor isomer
l-gulo (syn): δ 152.8 (C), 139.7 (C), 116.5 (2ϫ CH), 115.2 (CH),
114.6 (2ϫ CH), 112.4 (C), 101.0 (CH), 79.0 (CH), 78.0 (CH), 76.1
(CH2), 55.2 (CH3), 53.0 (CH), 25.5 (CH3), 25.3 (3ϫ CH3), 23.9
(CH3), 17.5 (C), –4.7 (CH3), –5.7 (CH3) ppm. MS (ESI+): m/z (%)
= 491 (2) [M + Na]+, 469 (100) [[M + H]+], 408 (13), 337 (9).
HRMS (ESI+): calcd. for C22H37N2O7Si+ [M + H]+ 469.2370;
found 469.2365. Rf = 0.53, (hexane/AcOEt, 3:1).
for C17H27N2O3 [M + H]+ 307.2016; found 307.2027. Rf = 0.29,
(hexane/EtOAc, 9:1).
+
4-Methoxy-N-(2,2,4-trimethyl-1-nitropentan-2-yl)benzenamine (5d):
1
Brown oil. H NMR (300 MHz, CDCl3): δ = 6.75 (d, J = 9.0 Hz,
2 H), 6.62 (d, J = 9.0 Hz, 2 H), 3.97 (br. s, 1 H), 3.93 (s, 1 H), 3.74
(s, 3 H), 1.73–1.64 (m, 1 H), 1.61 (s, 3 H), 1.57 (s, 3 H), 1.34 (d, J
= 6.8 Hz, 1 H), 2.01 (d, J = 6.8 Hz, 1 H), 0.89, 0.86, 0.84, 0.81 (4s,
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.3 (C), 142.3 (C),
115.1 (2ϫ CH), 114.0 (2ϫ CH), 92.6 (C), 59.4 (CH), 55.9 (CH3),
42.0 (CH2), 24.9 (CH), 24.1 (CH3), 24.0 (CH3), 22.4 (CH3), 21.6
(CH3) ppm. MS (ESI+): m/z (%) = 281.18 (100) [M + H]+, 258.18
+
(82). HRMS (ESI+): calcd. for C15H25N2O3 [M + H]+ 281.1860;
found 281.1855. Rf = 0.30, (hexane/EtOAc, 9:1).
N-[1-(2,2-Dimethyl-5-nitro-1,3-dioxan-5-yl)octyl]-4-methoxyaniline
(7b): Brown oil. 1H NMR (300 MHz, CDCl3): δ = 6.82 (d, J =
8.9 Hz, 2 H), 6.52 (d, J = 8.9 Hz, 2 H), 4.77 (d, J = 13.2 Hz, 2 H),
4.27 (d, J = 13.2 Hz, 2 H), 3.76 (s, 1 H), 3.75 (br. s, 1 H), 3.71 (s,
3 H), 1.53 (s, 3 H), 1.37 (s, 3 H), 1.35–1.18 (m, 12 H), 0.93–0.82
(m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.1 (C), 141.2
(C), 115.8 (2ϫ CH), 115.1 (2ϫ CH), 99.8 (C), 93.9 (C), 32.7 (CH2),
29.9 (CH2), 29.3 (CH2), 28.2 (CH2), 26.5 (2ϫ CH3), 25.3, (CH2),
22.9 (CH2), 14.2 (CH3) ppm. MS (ESI+): m/z (%) = 395.25 (17) [M
+ H]+. HRMS (ESI+): calcd. for C21H35N2O5+ [M + H]+ 395.2546;
found 395.2555. Rf = 0.30, (hexane/EtOAc, 5:1).
3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-[(p-methoxyphenyl)-
amino]-6-nitro-α-D
-glucofuranose (3h): Yellow oil. [α]2D7 = –9.2 (c =
1
0.6 in CHCl3). H NMR (500 MHz, CDCl3): δ = 7.34–7.12 (m, 5
H), 6.54 (d, J = 9.0 Hz, 2 H), 6.34 (d, J = 9.0 Hz, 2 H), 5.83 (d, J
= 3.6 Hz, 1 H), 4.67 (dd, J = 13.1, 3.9 Hz, 1 H), 4.59–4.44 (m, 3
H), 4.42–4.38 (m, 1 H), 4.24–4.17 (m, 3 H), 4.02 (d, J = 3.1 Hz, 1
H), 3.73 (s, 3 H), 1.47 (s, 3 H); 1.31 (s, 3 H) ppm. 13C NMR
N-[Cyclohexyl(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)methyl]-4-meth-
oxyaniline (7c): Brown oil. H NMR (300 MHz, CDCl3): δ = 6.79 (125 MHz, CDCl3): δ = 153.3 (C), 139.3 (C), 136.9 (C), 128.4
1
(d, J = 8.9 Hz, 2 H), 6.64 (d, J = 8.9 Hz, 2 H), 4.58 (d, J = 12.6 Hz,
1 H), 4.43 (d, J = 12.6 Hz, 1 H), 4.08 (d, J = 12.6 Hz, 2 H), 3.80
(2ϫCH), 128.0 (CH), 127.9 (2ϫ CH), 116.3 (2ϫ CH), 114.9 (2ϫ
CH), 112.1 (C), 104.9 (CH), 81.9 (CH), 81.2 (CH), 79.9 (CH), 75.8
(s, 1 H), 3.75 (s, 3 H), 3.65 (br. s, 1 H), 1.72–1.45 (m, 4 H), 1.38 (s, (CH2), 72.1 (CH2), 55.6 (CH3), 51.9 (CH), 26.7 (CH3), 26.2
3 H), 1.35 (s, 3 H), 1.30–0.92 (m, 7 H) ppm. 13C NMR (75 MHz, (CH3) ppm. MS (ESI+): m/z (%) = 445 (100) [M + H]+, 444 (1),
CDCl3): δ = 152.5 (C), 142.3 (C), 115.2 (2ϫ CH), 114.4 (2ϫ CH), 316 (5), 289 (1), 288 (21). HRMS (ESI+): calcd. for C23H29N2O7
+
99.4 (C), 90.7 (C), 63.3 (CH2), 63.1 (CH2), 61.7 (CH), 55.8 (CH3), [M + H]+ 445.1975; found 445.1969. Rf = 0.28, (hexane/AcOEt,
39.5 (CH), 33.8 (CH2), 27.0 (CH2), 26.6 (CH2), 26.1 (CH2), 26.0 3:1).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20304
/KAP1
Date: 27-06-12 09:57:12
Pages: 9
R. G. Soengas et al.
FULL PAPER
6,7-Dideoxy-1,2:3,4-di-O-isopropylidene-6-[(p-methoxyphenyl)- calcd. for C25H33N2O7 [M + H]+ 473.2282; found 473.2270. Rf =
+
amino]-7-nitro-glycero-β-
D
-galacto-heptose (3i): Orange oil. [α]2D0
=
0.31, (hexane/AcOEt, 5:1).
1
+12.1 (c = 0.7 in CHCl3). H NMR (300 MHz, CDCl3): δ = 6.80–
6.65 (m, 8 H), 5.59 (d, J = 3.1 Hz, 1 H), 5.56 (d, J = 3.1 Hz, 1 H),
4.87 (dd, J = 8.0, 2.3 Hz, 1 H), 4.81 (dd, J = 7.8, 3.0 Hz, 1 H), 4.67
(dd, J = 7.9, 4.4 Hz, 1 H), 4.61–4.57 (m, 3 H), 4.44–4.40 (m, 1 H),
4.38 (dd, J = 4.9, 1.1 Hz, 1 H); 4.35 (dd, J = 4.8, 1.1 Hz, 1 H), 4.32
(dd, J = 3.0, 1.4 Hz, 1 H), 4.29 (dd, J = 3.0, 1.4 Hz, 1 H), 4.28–
4.27 (m, 2 H), 4.12 (dd, J = 3.4, 1.0 Hz, 1 H), 3.95 (dd, J = 3.6,
1.0 Hz, 1 H), 3.74 (s, 6 H), 1.46 (s, 8 H), 1.33–1.32 (m, 13 H), 1.29
(s, 4 H) ppm. 13C NMR (75 MHz, CDCl3): major isomer d-glycero
(anti) δ 153.5 (C), 139.8 (C), 117.0 (2ϫ CH), 114.9 (2ϫ CH), 109.4
(C), 108.8 (C), 96.3 (CH), 75.1 (CH2), 71.1 (CH), 70.9 (CH), 70.7
(CH), 67.0 (CH), 55.6 (CH3), 54.6 (CH), 25.8 (CH3), 25.7 (CH3),
24.8 (CH3), 24.0 (CH3) ppm; minor isomer l-glycero (syn): δ =
153.0 (C), 139.9 (C), 115.1 (2ϫ CH), 115.0 (2ϫ CH), 109.6 (C),
108.9 (C), 96.5 (CH), 76.0 (CH2), 70.9 (2ϫ CH), 70.4 (CH), 65.4
(CH), 55.6 (CH3), 54.8 (CH), 25.8 (2ϫ CH3), 24.8 (CH3), 24.0
(CH3) ppm. MS (ESI+): m/z (%) = 447 (5) [M + Na]+, 424 (100)
[M + H]+ , 386 (22), 364 (26). HRMS (ESI+ ): calcd. for
C20H29N2O8+ [M + H]+ 425.1924; found 425.1918. Rf = 0.46, (hex-
ane/AcOEt, 3:1).
(6R)-6,7-Dideoxy-6-deoxy-1,2:3,4-di-O-isopropylidene-6-[(p-meth-
oxyphenyl)amino]-6-(1-methyl-1-nitroethyl)-β-D-galacto-heptose (5i):
1
Yellow oil. H NMR (300 MHz, CDCl3): δ = 6.96–6.57 (m, 4 H),
5.44 (d, J = 5.0 Hz, 1 H), 4.75 (d, J = 13.4 Hz, 1 H), 4.58–4.53 (m,
1 H), 4.34–4.34 (m, 2 H), 4.14 (d, J = 13.4 Hz, 1 H), 4.05 (d, J =
13.4 Hz, 1 H), 3.75 (s, 3 H), 1.54 (s, 3 H), 1.48 (s, 3 H), 1.35 (s, 6
H), 1.30 (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.8 (C), 141.2 (C), 115.1 (2ϫ CH), 115.0 (2ϫ CH), 109.3
(C), 99.6 (C), 96.4 (CH), 91.7 (C), 70.8 (CH), 70.7 (CH), 64.0 (CH),
63.5 (CH), 57.1 (CH), 55.8 (CH3), 26.2 (CH3), 25.9 (CH3), 25.2
(CH3), 24.9 (CH3), 24.5 (CH3), 21.8 (CH3) ppm. MS (ESI+): m/z
(%) = 453.22 ([M + H]+, 100). HRMS (ESI+): calcd. for
C22H33N2O8+ [M + H]+ 453.2237; found 453.2246. Rf = 0.46, (hex-
ane/AcOEt, 3:1).
1-O-tert-Butyldimethylsilyl-5-deoxy-2,3-di-O-isopropylidene-5-[(p-
methoxyphenyl)amino]-5-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)-α-D-
lyxofuranose (7 g): Orange oil. [α]2D4 = –26.2 (c = 2.2 in CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 6.80–6.58 (m, 8 H), 5.34 (s, 1 H, 1-
Hanti), 5.24 (s, 1 H, 1-Hsyn), 4.81–4.67 (m, 3 H), 4.65–4.49 (m, 3
H), 4.44–4.42 (m, 2 H), 4.38–4.25 (m, 4 H), 4.24–4.12 (m, 2 H),
4.11–3.98 (m, 3 H), 3.93 (dd, J = 9.2, 3.3 Hz, 1 H), 3.74 (2s, 6 H),
1.52 (s, 3 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H), 1.33 (s, 3
H), 1.25 (s, 6 H), 1.13 (s, 3 H), 0.89 (s, 9 H), 0.87 (s, 9 H), 0.16 (s,
3 H), 0.14 (s, 3 H), 0.11 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.8 (C), 152.5 (C), 141.1 (2ϫ C), 115.1 (2ϫ CH), 115.0 (2ϫ
CH), 114.7 (2ϫ CH), 114.6 (2ϫ CH), 112.7 (C), 112.4 (C), 101.6
(CH), 101.0 (CH), 99.3 (C), 98.7 (C), 91.7 (C), 91.6 (C), 86.3 (CH),
86.0 (CH), 80.8 (CH), 80.6 (CH), 80.2 (CH), 75.3 (CH), 63.8 (CH2),
63.6 (CH2), 63.4 (CH2), 60.5 (CH2), 55.8 (CH3), 55.5 (CH3), 54.1
(2ϫ CH), 27.6 (CH3), 26.4 (2ϫ CH3), 25.9 (CH3), 25.7 (4ϫ CH3),
25.2 (CH3), 24.9 (2ϫ CH3), 23.9 (CH3), 21.1 (CH3), 19.6 (CH3),
18.0 (2ϫ C), –4.3 (CH3), –4.6 (CH3), –5.3 (CH3), –5.6 (CH3) ppm.
MS (ESI+): m/z (%) = 569.29 ([M + H]+, 100), 430.20 (35). HRMS
(ESI+): calcd. for C27H45N2O9Si+ [M + H]+ 569.2889; found
569.2871. Rf = 0.30, (hexane/AcOEt, 7:1).
1-O-tert-Butyldimethylsilyl-5-deoxy-2,3-di-O-isopropylidene-5-[(p-
methoxyphenyl)amino]-5-(1-methyl-1-nitroethyl)-α-D-lyxofuranose
(5 g): Major isomer 5R (anti): orange oil. [α]2D4 = +101.4 (c = 0.9
1
in CHCl3). H NMR (300 MHz, CDCl3): δ = 6.78–6.69 (m, 4 H),
5.22 (s, 1 H), 4.75 (dd, J = 5.8, 3.4 Hz, 1 H), 4.65–4.56 (m, 2 H),
4.45 (d, J = 5.8 Hz, 1 H), 3.95 (dd, J = 9.3, 3.4 Hz, 1 H), 3.73 (s,
3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), 1.52 (s, 3 H), 1.24 (s, 3 H), 0.87
(s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.4 (C), 141.4 (C), 114.9 (4ϫ CH), 112.6 (C), 101.6
(CH), 90.8 (C), 86.4 (CH), 80.6 (2ϫ CH), 57.9 (CH3), 55.8 (CH),
26.5 (CH3), 26.3 (3ϫ CH3), 25.5 (CH3), 25.3 (CH3), 22.8 (CH3),
18.0 (C), –4.4 (CH3), –5.5 (CH3) ppm. MS (ESI+): m/z (%) = 497.27
(100) [M + H]+. HRMS (ESI+): calcd. for C24H41N2O7Si+ [M +
H]+ 497.2683; found 497.2678. Rf = 0.35, (hexane/AcOEt, 7:1).
Minor isomer 5S (syn): orange oil. [α]2D4 = –71.8 (c = 0.9 in CHCl3).
1H NMR (300 MHz, CDCl3): δ = 6.74 (d, J = 9.0 Hz, 2 H), 6.64
(d, J = 9.0 Hz, 2 H), 5.34 (s, 1 H), 4.65 (dd, J = 5.8, 4.0 Hz, 1 H),
4.54–4.46 (m, 1 H), 4.42 (d, J = 5.8 Hz, 1 H), 3.91 (d, J = 4.0 Hz,
1 H), 3.79–3.68 (m, 4 H), 1.63 (s, 3 H), 1.61 (s, 3 H), 1.25 (s, 3 H),
1.14 (s, 3 H), 0.88 (s, 9 H), 0.12 (s, 3 H), 0.11 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.1 (C), 142.0 (C), 114.6 (4ϫ CH),
112.5 (C), 101.0 (CH), 93.1 (C), 86.2 (CH), 81.0 (CH), 76.7 (CH)
56.7 (CH3), 55.9 (CH), 25.7 (2ϫ CH3), 25.6 (CH3), 25.5 (CH3),
24.9 (CH3), 24.1 (CH3), 20.5 (CH3), 18.0 (C), –4.3 (CH3), –5.2
(CH3) ppm. MS (ESI+): m/z (%) = 497.27 (100) [M + H]+. HRMS
(ESI+): calcd. for C24H41N2O7Si+ [M + H]+ 497.2678; found
497.2673. Rf = 0.29, (hexane/AcOEt, 9:1).
3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-5-[(p-methoxyphenyl)-
amino]-5-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)-α-D-xylofuranose
(7h): Major isomer 5R (anti): orange oil. [α]2D4 = –67.4 (c = 0.8 in
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.22–7.13 (m, 3 H), 6.76
(d, J = 8.9 Hz, 2 H), 6.74–6.70 (m, 2 H), 6.53 (d, J = 8.9 Hz, 2 H),
5.95 (d, J = 3.7 Hz, 1 H), 4.70–4.54 (m, 2 H), 4.49 (d, J = 3.7 Hz,
1 H), 4.37 (d, J = 13.0 Hz, 1 H), 4.30–4.25 (m, 2 H), 4.21 (d, J =
3.4 Hz, 1 H), 4.12 (d, J = 11.7 Hz, 1 H), 3.98 (br. s, 1 H), 3.78 (d,
J = 3.4 Hz, 1 H), 3.75 (s, 3 H), 3.71 (s, 1 H), 1.46 (s, 3 H), 1.39 (s,
3 H), 1.33 (s, 3 H), 1.30 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.9 (C), 141.6 (C), 136.3 (C), 128.2 (2ϫ CH), 128.0 (CH),
127.08 (2ϫ CH), 114.7 (4ϫ CH), 112.5 (C), 104.8 (CH), 98.7 (C),
92.0 (C), 83.4 (CH), 80.8 (CH), 81.3 (CH), 72.0 (CH2), 63.3 (CH2),
60.4 (CH2), 56.4 (CH3), 55.6 (CH), 27.4 (CH3), 26.9 (CH3), 26.4
(5R)-3-O-Benzyl-6-deoxy-1,2-O-isopropylidene-5-[(p-methoxyphen-
yl)amino]-5-(1-methyl-1-nitroethyl)-α-
D-xylofuranose (5h): Yellow
oil. 1H NMR (300 MHz, CDCl3): δ = 7.38–7.28 (m, 3 H), 7.15–
(CH3), 19.5 (CH3) ppm. MS (ESI+): m/z (%) = 545.25 (100) [M +
7.12 (m, 2 H), 6.67–6.61 (m, 4 H), 5.86 (d, J = 3.7 Hz, 1 H), 4.67– H]+. HRMS (ESI+): calcd. for C28H37N2O9 [M + H]+ 545.2499;
+
4.50 (m, 1 H), 4.43 (d, J = 3.7 Hz, 1 H), 4.24 (d, J = 11.3 Hz, 1
H), 4.04 (dd, J = 9.6, 3.0 Hz, 1 H), 3.87–3.82 (m, 2 H), 3.68 (s, 3
H), 3.36 (d, J = 9.6 Hz, 1 H), 1.70 (s, 3 H), 1.67 (s, 3 H), 1.49 (s,
found 545.2441. Rf = 0.32, (hexane/AcOEt, 3:1). Minor isomer 5S
(syn): orange oil. H NMR (300 MHz, CDCl3): δ = 7.32–7.29 (m,
3 H), 7.15–7.11 (m, 2 H), 6.68 (d, J = 9.1 Hz, 2 H), 6.62 (d, J =
1
3 H), 1.28 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.7 9.1 Hz, 2 H), 5.88 (d, J = 3.5 Hz, 1 H), 4.81 (d, J = 13.6 Hz, 1 H),
(C), 140.9 (C), 137.4 (C), 128.4 (2ϫ CH), 127.8 (CH), 127.6 (2ϫ 4.43 (d, J = 3.5 Hz, 1 H), 4.38–4.29 (m, 2 H), 4.28–4.23 (m, 2 H),
CH), 115.1 (2ϫ CH), 114.9 (2ϫ CH), 111.9 (C), 105.3 (CH), 91.2
4.15 (d, J = 9.0 Hz, 1 H), 4.10–3.93 (m, 3 H), 3.91 (d, J = 2.7 Hz,
(C), 82.2 (CH), 80.9 (CH), 80.8 (CH), 71.5 (CH2), 57.9 (CH), 55.8 1 H), 3.71 (s, 3 H), 1.47 (s, 3 H), 1.38 (s, 3 H), 1.34 (s, 3 H), 1.28
(CH3), 27.1 (CH3), 26.3 (CH3), 24.2 (CH3), 23.5 (CH3) ppm. MS (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.9 (C), 140.7
(ESI+): m/z (%) = 473.23 (100) [M + H]+, 406 (69). HRMS (ESI+):
(C), 137.2 (C), 128.5 (2ϫ CH), 128.0 (CH), 128.0 (2ϫ CH), 115.1
6
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Indium-Mediated Aza-Henry Reaction of Imines
(4ϫ CH), 112.5 (C), 105.5 (CH), 99.3 (C), 91.8 (C), 82.4 (CH), CDCl3): δ 153.0 (C), 140.1 (C), 137.3 (C), 129.0 (2ϫCH), 128.6
80.8 (CH), 80.4 (CH), 72.0 (CH2), 63.7 (CH2), 63.0 (CH2), 55.8 (CH), 128.0 (2ϫCH), 116.7 (2ϫCH), 115.0 (2ϫCH), 112.2 (C),
(CH3), 54.7 (CH), 27.0 (CH3), 26.6 (CH3), 25.9 (CH3), 21.1 104.8 (CH), 81.9 (CH), 81.4 (CH), 81.2 (CH), 71.9 (CH2), 55.8
(CH3) ppm. Rf = 0.28 (hexane/AcOEt, 3:1).
(CH3), 41.8 (CH2), 31.1 (CH), 26.8 (CH3), 26.2 (CH3) ppm. MS
(ESI+): m/z (%) =415.22 ([M + H]+, 100). HRMS (ESI+): calcd.
(6R)-6,7-Dideoxy-6-deoxy-1,2:3,4-di-O-isopropylidene-6-[(p-meth-
oxyphenyl)amino]-6-(2,2-dimethyl-5-nitro-1,3-dioxan-5-yl)-β-D-gal-
for C23H31N2O10 [M + H]+ 415.2227; found 415.2228. Rf = 0.39,
+
(CH2Cl2/MeOH, 9:1).
1
acto-heptose (7i): Orange oil. [α]2D0 = +12.1 (c = 0.7 in CHCl3). H
NMR (300 MHz, CDCl3): δ = 6.80–6.65 (m, 8 H), 5.59 (d, J =
3.1 Hz, 1 H), 5.56 (d, J = 3.1 Hz, 1 H), 4.87 (dd, J = 8.0, 2.3 Hz,
1 H), 4.81 (dd, J = 7.8, 3.0 Hz, 1 H), 4.67 (dd, J = 7.9, 4.4 Hz, 1
H), 4.61–4.57 (m, 3 H), 4.44–4.40 (m, 1 H), 4.38 (dd, J = 4.9,
1.1 Hz, 1 H); 4.35 (dd, J = 4.8, 1.1 Hz, 1 H), 4.32 (dd, J = 3.0,
1.4 Hz, 1 H), 4.29 (dd, J = 3.0, 1.4 Hz, 1 H), 4.28–4.27 (m, 2 H),
4.12 (dd, J = 3.4, 1.0 Hz, 1 H), 3.95 (dd, J = 3.6, 1.0 Hz, 1 H), 3.74
(s, 6 H), 1.46 (s, 8 H), 1.33–1.32 (m, 13 H), 1.29 (s, 4 H) ppm. 13C
NMR (75 MHz, CDCl3): major isomer δ = 153.5 (C), 139.8 (C),
117.0 (2ϫCH), 114.9 (2ϫCH), 109.4 (C), 108.8 (C), 96.3 (CH),
75.1 (CH2), 71.1 (CH), 70.9 (CH), 70.7 (CH), 67.0 (CH), 55.6
(CH3), 54.6 (CH), 25.8 (CH3), 25.7 (CH3), 24.8 (CH3), 24.0
(CH3) ppm; minor isomer; δ 153.0 (C), 139.9 (C), 115.1 (2ϫCH),
115.0 (2ϫCH), 109.6 (C), 108.9 (C), 96.5 (CH), 76.0 (CH2), 70.9
(2 ϫ CH), 70.4 (CH), 65.4 (CH), 55.6 (CH3), 54.8 (CH), 25.8
(2 ϫ CH3), 24.8 (CH3), 24.0 (CH3) ppm. MS (ESI+): m/z (%) =
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for nitroamines 3, 5
and 7 and diamines 9 and 10.
Acknowledgments
This work was supported by the Spanish Ministry of Science and
Innovation (MICINN) (CTQ2008-06493, CTQ2009-08490 and
CTQ2010-14959) and by the Xunta de Galicia (research project
CN2011/037). Thanks are also due to the University of Aveiro, to
the Fundação para a Ciência e a Tecnologia (FCT) and the Fundo
Europeu de Desenvolvimento Regional (FEDER) for funding the
Organic Chemistry Research Unit. R. S. thanks the FCT for a “In-
vestigador Auxiliar” position. S. S. thanks FCT for post-doctoral
grant SFRH/BPD/64812/2009. A. M. E. thanks the Spanish MIC-
INN for an FPU grant. Prof. Artur Silva, Prof. José Cavaleiro, and
Dr. João Tomé are acknowledged for helpful discussions.
525.24 ([M + H]+, 100). HRMS (ESI+): calcd. for C25H37N2O10
+
[M + H]+ 525.2448; found 525.2441. Rf = 0.46, (hexane/AcOEt,
3:1).
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1
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1
(59 mg, 69%) as an amorphous beige solid. H NMR (300 MHz,
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6.6 Hz, 1 H), 1.43 (s, 3 H), 1.19 (s, 3 H) ppm. 13C NMR (75 MHz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. G. Soengas et al.
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Received: March 12, 2012
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20304
/KAP1
Date: 27-06-12 09:57:12
Pages: 9
Indium-Mediated Aza-Henry Reaction of Imines
Aza-Henry Reactions
A new method to obtain 2-amines by reac-
tion of bromonitromethane with a variety
of imines, 2-bromo-2-nitropropanes and
chiral sugar-derived aldehydes, promoted
by indium is reported. This is the first ex-
ample of the preparation of 2,2-dialkyl-2-
nitroamines by addition to imines. The su-
gar-derived aldehydes furnished the corre-
sponding 2-nitroamines with excellent
stereoselectivity.
R. G. Soengas,* S. Silva, A. M. Estévez,
J. C. Estévez, R. J. Estévez,
H. Rodríguez-Solla ............................ 1–9
Indium-Mediated Aza-Henry Reaction of
Imines: Access to 2-Nitroamines
Keywords: Synthetic methods / Nucleo-
philic addition / Aza-Henry reactions / In-
dium / Amines
Eur. J. Org. Chem. 0000, 0–0
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9