1-Alkoxyamino-2-nitroalkanes as key building blocks for a chemo- and diastereoselective synthesis of a new type of polyfunctionalized N-Alkoxypiperidine

Article abstract of DOI:10.1002/ejoc.201000540

A highly efficient conversion of β-nitrostyrenes into a new kind of functionalized N-alkoxy-2-hydroxypiperidine in two steps was developed, giving excellent yields and diastereoselectivity. The prepared compounds are the first examples of N-alkoxy-2-hydro

Full text of DOI:10.1002/ejoc.201000540

FULL PAPER
DOI: 10.1002/ejoc.201000540
1-Alkoxyamino-2-nitroalkanes as Key Building Blocks for a Chemo- and
Diastereoselective Synthesis of a New Type of Polyfunctionalized
N-Alkoxypiperidine
M. Ángeles López-García,[a] Inés Maya,[a] José G. Fernández-Bolaños,*[a]
Giovanna Bosica,[b] and Roberto Ballini*[b]
Keywords: Michael addition / Nitrogen heterocycles / Diastereoselectivity / Nitroalkanes / Alkoxyamines
A highly efficient conversion of β-nitrostyrenes into a new
kind of functionalized N-alkoxy-2-hydroxypiperidine in two
alkoxyamines to α,β-unsaturated carbonyl compounds, and
intramolecular addition of the alkoxyamino group to the car-
steps was developed, giving excellent yields and diastereo- bonyl functionality of the (non-isolated) adducts. Although
selectivity. The prepared compounds are the first examples
of N-alkoxy-2-hydroxypiperidines. The synthetic approach
involved the conjugate addition of alkoxyamines to β-nitro-
styrenes, followed by Michael addition of the isolated nitro-
three stereogenic centers are formed, only one diastereoiso-
mer was detected. This unprecedented sequence of reactions
can also be performed in a one-pot fashion.
into a number of functional groups.[11] There are a few re-
ports on the direct addition reaction of amines to nitro-
olefins;[12] however, very little attention has focused on the
addition of alkoxyamines to nitro-olefins,[13] and nothing
has been described about the addition of 1,2-nitro-N-alk-
oxyamines to α,β-unsaturated carbonyl compounds. For
these reasons, we have explored the scope and limitations
of this reaction to determine whether 1,2-nitro-N-alk-
oxyamines can act as nucleophiles in conjugate additions
through the N-alkoxyamino group or through the nitronate
anion, and to study the effect of changing an amino group
to the significantly less basic alkoxyamino group. In fact,
the pKa of protonated alkoxyamines are some 5–6 orders of
magnitude less than the parent amines.[14]
Furthermore, the formation of new bonds in the addition
of N-alkoxy-1,2-nitroamines to α,β-unsaturated carbonyl
compounds involves the generation of new stereogenic cen-
ters, which has important implications for the design of
catalytic and stereoselective reactions for the synthesis of
organic molecules with several stereogenic centers and con-
stitutes a continuing challenge for synthetic chemistry.[15,16]
Introduction
Both naturally occurring (e.g., nojirimycin) and synthetic
(e.g., noeuromycin, miglitol) polyhydroxylated piperidines
have been shown to be specific and potent inhibitors of gly-
cosidases and they possess great potential to treat a variety
of carbohydrate-mediated diseases such as diabetes, viral in-
fections including HIV, and cancer metastasis.[1–3] Most of
the methodologies described for the synthesis of these com-
pounds and chemically modified analogues, which can be
regarded as imino sugars, start from carbohydrates and re-
quire a large number of steps. Therefore, the development
of new strategies that allow the stereoselective synthesis of
hydroxylated piperidines starting from non-carbohydrate
precursors constitutes an area of current interest.[4–7] Re-
cently, hydroxylated 2-arylpiperidines have been shown to
act as inhibitors of rhamnosyl-processing enzymes and to
be potentially useful against tuberculosis.[8] In general,
functionalized piperidines and the synthetic methodologies
used for their preparation are of considerable interest.[9]
Nitroalkenes have attracted significant interest in recent
years as Michael acceptors,[10] because of the activating ef-
fect of the nitro group, as well as its easy transformation
[a] Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla,
Results and Discussion
c/ Profesor García González s/n, 41012 Sevilla, Spain
Fax: +34-954-624-960
E-mail: bolanos@us.es
In this context, we have prepared a variety of N-alkoxy-
1-aryl-2-nitroethanamines 3a–f in high yields (72–89%) by
addition of alkoxyamine hydrochlorides 2a and 2b to β-ni-
trostyrenes 1a–c at room temperature in methanol contain-
ing triethylamine (Table 1).
[b] Dipartimento di Scienze Chimiche, Università di Camerino,
via S. Agostino 1, 62032 Camerino, Italy
Fax: +39-0737-402-297
E-mail: roberto.ballini@unicam.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000540.
View this journal online at
wileyonlinelibrary.com
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Eur. J. Org. Chem. 2010, 5482–5488

Novel Polyfunctionalized N-Alkoxypiperidines
Table 1. Synthesis of N-alkoxy-2-nitro-1-arylethanamines 3a–f.
Furthermore, potassium fluoride supported on alumina
(KF/Al2O3) under solvent-free conditions has been re-
ported to be an efficient catalyst for Michael addition of
nitroalkanes to electron-deficient alkenes.[18,19] However, in
our hands, the reaction of 3a and 4a promoted by alumina
doped with KF (Table 2, entry 3), led to the formation of
by-products together with unconsumed starting material. In
contrast, the reaction did take place in neat alumina,[20] and
6a was obtained in 33% yield (Table 2, entry 4).
We also tested the reaction using, as recyclable pro-
moters, the macroreticular ion-exchange resins Amberlyst
A-21 and Amberlyst A-27, which were previously de-
scribed[21,22] as efficient catalysts in the conjugate addition
of nitroalkanes to α,β-unsaturated derivatives in the ab-
sence of any solvent. Piperidine 6a could be obtained (38%
yield) using the weakly basic resin A-21, but not with the
strongly basic resin A-27 (Table 2, entries 5 and 6).
Entry
Compound
R
RЈ
Yield [%][a]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
H
H
OMe
OMe
OH
OH
Me
Bn
Me
Bn
Me
Bn
89
87
72
84
75
82
[a] Yield of pure isolated product.
We tested commercial ISOLUTE Si-carbonate [silica tri-
We also studied the coupling of nitroalkoxyamine 3a
with methyl vinyl ketone (4a) under a range of reaction con-
ditions to explore the feasibility and chemoselectivity of this
Michael addition (Table 2). The reaction did not work
either in the absence of catalyst, or in the presence of PL-
CO3 resin, a polymer-bound equivalent of carbonate de-
signed for neutralization or for the scavenging of acids,
using different catalyst/substrate ratios (Table 2, entry 1).
Although nitroalkanes have been found to give good yields
in Michael additions by the use of a catalytic amount
2–
methylammonium carbonate; Si-TMA(CO3
)0.5], which is
a bound equivalent of tetramethylammonium carbonate
that is traditionally used as a quaternary anion-exchanger,
in the reaction. This supported base has been described as
an eco-friendly and recyclable catalyst that can be used to
generate nitronate species.[23] The use of 20 mol-% of this
catalyst at room temperature (Table 2, entry 8) was found
to be the best (59%) reaction conditions for the synthesis
of 6a.
Strong organic bases such as 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU; 1 equiv.) or 1,1,3,3-tetramethylguanidine
(TMG; 10 mol-%), in homogeneous solutions[24] in acetoni-
trile, gave good yields of 6a (78 and 79%, respectively,
Table 2, entries 11 and 12). Similarly, potassium tert-butox-
(10 mol-%)
of
cetyltrimethylammonium
hydroxide
(CTAOH),[17] this reaction, when carried out at room tem-
perature under solvent-free conditions (Table 2, entry 2), led
to the formation of a complex mixture together with start-
ing nitro derivative 3a.
Table 2. Base-catalyzed synthesis of N-alkoxypiperidine 6a from N-alkoxy-2-nitro-1-arylamines 3a.
Entry Basic catalyst
Temp. [°C]
Time [h]
Solvent
Yield [%][a]
[c]
1
2
3
4
5
6
7
8
PL-CO3 resin[b] (catalyst/substrate, 10, 20, or 30 mol-%) room temp.
6
56
2
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
CH3CN
–
[c]
CTAOH[d] (aqueous 10%, 0.3 mL/mmol; 10 mol-%)
KF-Al2O3 (200 mg/mmol)
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
60
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
–
[c]
–
Al2O3 (200 mg/mmol)
4
33
38
Amberlyst A-21 (0.5 g/mmol)
Amberlyst A-27 (0.5 g/mmol)
Isolute[e] (catalyst/substrate, 10 mol-%)
Isolute[e] (catalyst/substrate, 20 mol-%)
Isolute[e] (catalyst/substrate, 20 mol-%)
Isolute[e] (catalyst/substrate, 30 mol-%)
DBU (1 equiv.)
56
56
4
8
4
23
24
22
28
6
6
9
[c]
–
46
59
32
55
78
79
63
86
67
37
9
10
11
12
13
14
15
16
TMG[f] (catalyst/substrate, 10 mol-%)
tBuOK (catalyst/substrate, 30 mol-%)
K2CO3 (1 equiv.)
CH3CN
THF
CH3CN
CH3CN
K2CO3 (0.2 equiv.)
K2CO3 (1 equiv.)
EtOAc
[a] Yield of pure isolated product. [b] Tetraalkylammonium carbonate, polymer-bound. [c] Unconsumed starting material and formation
of by-products. [d] Ethyltrimethylammonium hydroxide. [e] Silica trimethylammonium carbonate. [f] 1,1,3,3-Tetramethylguanidine.
Eur. J. Org. Chem. 2010, 5482–5488
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J. G. Fernández-Bolaños, G. Bosica, R. Ballini
FULL PAPER
ide in tetrahydrofuran (THF) (30 mol-%) afforded 6a in 3a to act as a Michael donor, thus explaining the remark-
63% yield (Table 2, entry 13). These bases are known to able chemoselectivity of 1,2-nitro-N-alkoxyamines in reac-
promote aza-Michael addition of a range of amines to elec- tion with α,β-unsaturated ketone 4a.
tron-poor alkenes;[25,26] however, the action of these bases
It is also remarkable that, during these reaction se-
on 3a chemoselectively promoted the Michael addition
through a carbanion stabilized by the nitro group.
The best result (86%, Table 2, entry 14) was obtained
using potassium carbonate (1 equiv.) as heterogeneous pro-
moter in acetonitrile. When less potassium carbonate was
used, the yield dropped to 67% (Table 2, entry 15), whereas
when only the solvent was changed, the drop in yield was
even worse (37%; Table 2, entry 16).
It is important to note that the synthesis of 6a could
be carried out even in a one-pot fashion, directly from β-
nitrostyrene (Scheme 1). Reaction with methoxyamine hy-
drochloride in methanol containing K2CO3 (1.5 equiv.), fol-
lowed by addition, after 22 h, of methyl vinyl ketone to the
reaction mixture gave 6a (40% overall yield) after 2 h of
reaction at room temperature.
quences, although three stereogenic centers were generated
in the product piperidine 6a, only one diastereomer was ob-
1
served in the H and 13C NMR spectra, corresponding to
the racemate. The vicinal coupling constants of 6a (J3a,4a
=
12.3, J4a,5 = 12.3, J5,6 = 10.4 Hz) were consistent with a
chair conformation with the nitro and the phenyl groups in
equatorial positions. A NOESY experiment on 6a allowed
the unequivocal assignment of the configuration at C-2;
strong cross-peak correlations were observed between OH
and axial H-6, and between the methyl group and both
equatorial and axial H-3. The arrangement of the hydroxyl
group in the axial position is in agreement with the reduced
steric demand of the hydroxyl group compared with the
methyl group, and with the anomeric effect.[27,28] The trans-
diequatorial arrangement of the bulky aryl and nitro sub-
stituents might be explained by the high acidity of the hy-
drogen atom at the carbon bearing the nitro group and sub-
sequent base-catalyzed isomerization at C-5 to give the
more stable diastereoisomer.
A series of N-alkoxypiperidines 6a–d, 6g, and 6h have
been prepared in good to high yield (Table 3) from nitroalk-
oxyamines 3a–d and alkyl vinyl ketones 4a or 4b or acrolein
4c, using the conditions optimized for the synthesis of 6a
Scheme 1. One-pot synthesis of piperidine 6a from β-nitrostyrene.
These reactions led to the formation of 2-hydroxypiperi- (K2CO3, acetonitrile). These compounds, which are the first
dine 6a, most likely through the γ-nitro-δ-alkoxyamino examples of N-alkoxy-2-hydroxypiperidines, were found to
ketone 5a (not detected), formed by the conjugate addition be more stable than 2-hydroxypiperidines previously de-
of 3a to 4a, followed by intramolecular addition of the alk- scribed,[29] probably due to the lower basicity of the alk-
oxyamino group to the carbonyl functionality. The lower oxyamino moiety. When the reaction was performed on alk-
nucleophilicity of the alkoxyamino group, compared with oxyamines 3e or 3f, only extensive decomposition was ob-
that of the amino group, enables the activated methylene of served, whereas just one diastereoisomer was detected by
Table 3. K2CO3-promoted synthesis of N-alkoxypiperidines 6 and 7 from N-alkoxy-2-nitro-1-arylamines 3a–d, α,β-unsaturated aldehydes,
and ketones 4a–c.
Entry
Michael donor
Michael acceptor
Piperidine
R
RЈ
RЈЈ
Time [h]
Ratio
Yield [%][a]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
4a
4a
4a
4a
4a
4a
4b
4c
6a/7a
6b/7b
6c/7c
6d/7d
6e
H
H
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Me
Me
Me
Me
Me
Et
6
5
4
4
9
9
9
8
96:4
97:3
86:14
96:4
–
–
95:5
99:1
86
78
83
83
OMe
OMe
OH
OH
OMe
H
[b]
–
–
[b]
6f
3c
3b
6g/7g
6h/7h
70
58
H
[a] Yield after column chromatography. [b] Extensive range of by-products formed.
5484
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Eur. J. Org. Chem. 2010, 5482–5488

Novel Polyfunctionalized N-Alkoxypiperidines
oxidized in KMnO4 solution (NaOH/KMnO4/K2CO3/H2O,
1:6:40:600). Column chromatography was performed using Silica
Gel 60 (Merck, 70–230 mesh ASTM).
NMR for 6a–h. The equatorial positions of the aryl, alkyl,
and nitro groups were confirmed by the vicinal coupling
constants and by NOE experiments (Figure 1). The β-sub-
stituted enone (E)-hexan-4-en-3-one did not work well with
N-alkoxy amine 3a; no reaction was observed after 24 h at
room temperature, which was possibly due to the steric hin-
drance involved in the Michael addition.
General Procedure for the Synthesis of N-Substituted 1-Aryl-2-nitro-
ethanamines 3a–f: To a solution of β-nitroestyrenes 1a–c (3.3 mmol)
in MeOH (10 mL), alkoxyamine hydrochloride 2a–b (3.3 mmol)
and triethylamine (3.3 mmol, 0.47 mL) were added. The reaction
mixture was stirred at room temp. for 1–2 h. The solvent was re-
moved under vacuum, and the residue was purified as described
below to afford 3a–f.
N-Methoxy-2-nitro-1-phenylethanamine (3a): Reaction time 1 h; pu-
rification by column chromatography (hexane/EtOAc, 10:1); yield
585 mg, 89%; yellowish oil; Rf = 0.32 (hexane/EtOAc, 5:1). 1H
NMR (300 MHz, CDCl3): δ = 7.42–7.30 (m, 5 H, PhH), 5.88 (d,
J1,NH = 4.2 Hz, 1 H, NH), 4.89 (dd, J1,2a = 7.8, J2a,2b = 12.2 Hz, 1
H, 2a-H), 4.77 (ddd, J1,2b = 4.9 Hz, 1 H, 1-H), 4.60 (dd, J2b,1
=
4.9, J2b,2a = 12.2 Hz, 1 H, 2b-H), 3.52 (3 H, OCH3) ppm. 13C MNR
(75.5 MHz, CDCl3): δ = 135.9, 129.2, 127.7 (Ph), 78.0 (C-2), 63.1
(C-1), 62.9 (OCH ) ppm. IR (KBr): νmax = 3252, 2916, 1732, 1556,
˜
Figure 1. Significant NOE correlations of N-alkoxypiperidine 6b in
CDCl3.
3
1455, 1377 cm–1. MS (EI): m/z (%) = 196 (5) [M]+. HRMS (EI):
calcd. for C9H12N2O3 [M]+ 196.0848; found 196.0849.
A small amount of N-alkoxytetrahydropyridines 7a–h
was detected in the NMR spectra of the corresponding
piperidines (Table 3). These tetrahydropyridines were pre-
sumably formed by a dehydration reaction that took place
during chromatographic purification. The dehydration
might have occurred through an iminium cation, according
to the facile dehydration reported for the hemiaminal moi-
ety in aza-sugars.[30] The proton vicinal coupling constants
of 7a–h (J2,3 = 9.2–9.4, J3,4a = 9.2–9.4 Hz) are in agreement
N-Benzyloxy-2-nitro-1-phenylethanamine (3b): Reaction time 1 h;
purification by column chromatography (hexane/EtOAc, 10:1);
yield 782 mg, 87%; yellowish oil; Rf = 0.15 (hexane/EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 10 H, 2ϫPhH),
5.85 (d, J1,NH = 4.3 Hz, 1 H, NH), 4.87 (dd, J1,2a = 7.7, J2a,2b
=
11.8 Hz, 1 H, 2a-H), 4.81 (ddd, J1,2b = 4.7 Hz, 1 H, 1-H), 4.70,
4.65 (2ϫd, J = 11.6 Hz, 1 H each, CH2Ph), 4.57 (dd, J2b,1 = 4.7,
J2b,2a = 11.8 Hz, 1 H, 2b-H) ppm. 13C MNR (75.5 MHz, CDCl3):
δ = 137.1, 135.9, 129.2, 129.1, 128.8, 128.6, 128.3, 127.8 (2ϫPh),
78.0 (C-2), 77.2 (CH Ph), 63.2 (C-1) ppm. IR (NaCl): νmax = 3245,
˜
3
2
with a half-chair conformation H2 (Table 3).
3031, 2918, 1555, 1455, 1378 cm–1. MS (EI): m/z (%) = 272 (10)
[M]+. HRMS (EI): calcd. for C15H16N2O3 [M]+ 272.1161; found
272.1161.
Conclusions
1-(3,4-Dimethoxyphenyl)-N-methoxy-2-nitroethanamine (3c): Reac-
tion time 2 h; purification by column chromatography (hexane/
EtOAc, 5:1); yield 609 mg, 72%; yellowish oil; Rf = 0.23 (hexane/
In summary, we have developed an unprecedented, mild,
high-yielding conversion of β-nitrostyrenes into a new class
of functionalized N-alkoxypiperidines by a base-catalyzed,
two-step procedure involving 1-alkoxyamino-2-nitroalkane
intermediates. Although three stereogenic centers are
formed, only one diastereomer was detected. Moreover, the
synthesis can be performed in a one-pot procedure in satis-
1
EtOAc, 2:1). H NMR (300 MHz, CDCl3): δ = 6.90–6.82 (m, 3 H,
ArH), 5.83 (d, J1,NH = 3.3 Hz, 1 H, NH), 4.86 (dd, J1,2a = 7.7,
J2a,2b = 12.2 Hz, 1 H, 2a-H), 4.71 (ddd, J1,2b = 5.2 Hz, 1 H, 1-H),
4.57 (dd, J2b,1 = 5.2, J2b,2a = 12.2 Hz, 1 H, H-2b), 3.89, 3.87 (2ϫs,
3 H each, 2ϫOMe), 3.52 (3 H, NOCH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 149.7, 149.4, 128.2, 120.1, 111.5, 110.7
factory overall yield. Given that this procedure enables a (Ar), 78.3 (C-2), 62.9 (C-1), 62.8 (NOCH3), 56.1, 56.0 (2ϫOCH3)
ppm. IR (KBr): ν
= 3249, 2959, 2917, 2841, 2255, 1733, 1552,
˜
new route to stable 2-hydroxypiperidines bearing a versatile
nitro group, this sequence is likely to find interesting syn-
thetic applications.
max
1464, 1375 cm–1. MS (EI): m/z (%) = 256 (22) [M]+. HRMS (EI):
calcd. for C11H16N2O5 [M]+ 256.1059; found 256.1048.
N-Benzyloxy-1-(3,4-dimethoxyphenyl)-2-nitroethanamine (3d): Re-
action time 2 h; purification by column chromatography (hexane/
EtOAc, 5:1); yield 921 mg, 84%; yellowish oil; Rf = 0.39 (hexane/
EtOAc, 2:1). 1H NMR (300 MHz, CDCl3): δ = 7.4–6.8 (m, 8 H,
Experimental Section
General: 1H (300 and 500 MHz) and 13C (75.5 and 125.7 MHz)
NMR spectra were recorded with Bruker Avance-300 and Avance-
500 spectrometers. The assignments of 1H and 13C signals were
confirmed by homonuclear COSY and heteronuclear 2D correlated
spectra, respectively. Mass spectra (EI and CI) were recorded with
a Micromass AutoSpec-Q mass spectrometer. IR spectra were re-
corded with a Perkin–Elmer FTIR Paragon 500 spectrometer using
thin films on NaCl and KBr plates. Only the characteristic peaks
are quoted. TLC was performed with aluminum pre-coated sheets
(Merck, Silica Gel 60 F254); spots were visualized by UV light or
ArH, PhH), 5.81 (br. s, 1 H, NH), 4.85 (dd, J1,2a = 7.6, J2a,2b =
12.1 Hz, 1 H, 2a-H), 4.74 (m, J1,2b = 5.3 Hz, 1 H, 1-H), 4.70, 4.64
(2ϫd, J = 11.6 Hz, 1 H each, CH2Ph), 4.54 (dd, J2b,1 = 5.3, J2b,2a
= 12.1 Hz, 1 H, 2b-H), 3.86 (s, 6 H, 2ϫOCH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 149.6, 149.3, 137.1, 128.7, 128.5, 128.2,
120.1, 111.4, 110.8 (Ar, Ph), 78.2 (C-2), 77.1 (CH2Ph), 62.9 (C-1),
56.03, 56.01 (2ϫOCH ) ppm. IR (KBr): ν
= 3251, 2954, 2919,
˜
3
max
2853, 2254, 1732, 1555, 1464, 1377 cm–1. MS (EI): m/z (%) = 332
(13) [M]+. HRMS (EI): calcd. for C17H20N2O5 [M]+ 332.1372;
found 332.1381.
Eur. J. Org. Chem. 2010, 5482–5488
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5485

J. G. Fernández-Bolaños, G. Bosica, R. Ballini
FULL PAPER
1-(3,4-Dihydroxyphenyl)-N-methoxy-2-nitroethanamine (3e): Reac-
1
hexane, 1:2). Data for 6b: H NMR (500 MHz, CDCl3): δ = 7.50–
tion time 2 h; purification by column chromatography (hexane/
6.70 (m, 10 H, 2ϫPhH), 4.84 (m, 1 H, 5-H), 4.64 (d, J5,6 = 10.6 Hz,
EtOAc, 2:1); yield 565 mg, 75%; yellowish oil; Rf = 0.18 (hexane/ 1 H, 6-H), 4.37, 3.92 (2ϫd, J = 9.1 Hz, 1 H each, CH2Ph), 2.93
1
EtOAc, 2:1). H NMR (300 MHz, CDCl3): δ = 6.84–6.74 (m, 3 H, (br. s, 1 H, OH), 2.53 (dtd, J4a,4e = 14.0, J4a,3a = 12.4, J4a,5 = 12.4,
ArH), 5.59 (br. s, 3 H, 2ϫOH, NH), 4.83 (dd, J1,2a = 7.4, J2a,2b
12.1 Hz, 1 H, 2a-H), 4.66 (dd, J1,2b = 5.4 Hz, 1 H, 1-H), 4.55 (dd,
=
J4a,3e = 4.3 Hz, 1 H, 4a-H), 2.13 (m, 1 H, 4e-H), 2.09 (m, 1 H, 3e-
H), 1.85 (m, J3a,3e = 13.8 Hz, 1 H, 3a-H), 1.61 (s, 3 H, CH3) ppm.
J2b,1 = 5.4, J2b,2a = 12.1 Hz, 1 H, 2b-H), 3.52 (3 H, OCH3) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 136.6, 135.4, 129.2, 128.9,
13C NMR (75.5 MHz, CDCl3): δ = 144.3, 144.0, 128.6, 120.5, 128.51, 128.46, 128.4 (2ϫPh), 88.4 (C-5), 87.1 (C-2), 78.3 (CH2Ph),
115.9, 114.8 (Ar), 78.1 (C-2), 62.9 (C-1), 62.6 (OCH3) ppm. IR
66.2 (C-6), 33.4 (C-3), 28.3 (CH3), 25.6 (C-4) ppm. Data for 7b: 1H
(KBr): νmax = 3320, 2953, 2921, 2847, 1717, 1553, 1445, 1379 cm–1. NMR (500 MHz, CDCl3): δ = 5.14 (td, J3,4e = 5.8, J3,4a = 9.2, J2,3
˜
MS (EI): m/z (%) = 228 (8) [M]+. HRMS (EI): calcd. for
= 9.2 Hz, 1 H, 3-H), 4.74 (m, 1 H, 5-H), 4.70 (d, J2,3 = 9.2 Hz, 1
H, 2-H), 4.32, 4.14 (2ϫd, J = 9.5 Hz, 1 H each, CH2Ph), 2.81 (m,
J4a,4e = 16.6, J4a,5 = 2.5, J4a,Me = 2.5 Hz, 1 H, 4a-H), 1.96 (m, 3
H, CH3) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 100.3 (C-5),
83.5 (C-3), 78.1 (CH2Ph), 68.0 (C-2), 19.0 (C-4) ppm. IR (NaCl,
C9H12N2O5 [M]+ 228.0746; found 228.0757.
N-Benzyloxy-1-(3,4-dihydroxyphenyl)-2-nitroethanamine (3f): Reac-
tion time 2 h; purification by column chromatography (hexane/
EtOAc, 2:1); yield 823.4 mg, 82%; yellowish oil; Rf = 0.57 (CH2Cl2/
MeOH, 10:1). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 5
H, PhH), 6.76–6.68 (m, 3 H, ArH), 5.84 (br. s, 3 H, 2ϫOH, NH),
4.78 (dd, J1,2a = 7.4, J2a,2b = 12.3 Hz, 1 H, 2a-H), 4.69, 4.65 (2ϫd,
J = 11.5 Hz, 1 H each, CH2Ph), 4.64 (dd, J1,2b = 5.5 Hz, 1 H, 1-
H), 4.49 (dd, J2b,1 = 5.5, J2b,2a = 12.3 Hz, 1 H, 2b-H) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 144.4, 144.0, 136.9, 128.9, 128.7,
128.4, 128.2, 120.5, 116.0, 114.9 (Ar, Ph), 78.4 (C-2), 77.1 (CH2Ph),
Nujol): ν
= 3583, 2924, 2855, 1738, 1558, 1458, 1376 cm–1. MS
˜
max
(EI): m/z (%) = 324 (4) [M]+. HRMS (EI) for 6b: calcd. for
C19H22N2O4 [M]+ 342.1580; found 324.1570.
(2R*,5S*,6R*)-6-(3,4-Dimethoxyphenyl)-1-methoxy-2-methyl-5-
nitropiperidin-2-ol (6c) and (2R*,3S*)-2-(3,4-Dimethoxyphenyl)-1-
methoxy-6-methyl-3-nitro-1,2,3,4-tetrahydropyridine (7c): Reac-
tion time 4 h; purification by column chromatography (EtOAc/hex-
ane, 1:4 Ǟ 1:3); yield 114 mg, 83%; colorless foam; 6c/7c ratio
86:14; Rf = 0.18 (EtOAc/hexane, 1:2). Data for 6c: 1H NMR
(300 MHz, CDCl3): δ = 7.00–6.80 (m, 3 H, ArH), 4.73 (m, 1 H, 5-
H), 4.46 (d, J5,6 = 10.4 Hz, 1 H, 6-H), 3.90, 3.87 (2ϫs, 3 H each,
2ϫArOCH3), 3.08 (s, 3 H, NOCH3), 2.88 (br. s, 1 H, OH), 2.49
(dtd, J4a,4e = 14.0, J4a,3a = 12.5, J4a,5 = 12.5, J4a,3e = 4.4 Hz, 1 H,
4a-H), 2.08 (m, 1 H, 4e-H), 2.02 (m, 1 H, 3e-H), 1.77 (m, 1 H, 3a-
H), 1.51 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
149.2, 148.7, 128.9, 121.4, 111.8, 110.8 (Ar), 88.6 (C-5), 87.0 (C-2),
65.9 (C-6), 63.9 (NOCH3), 56.1, 56.0 (2ϫArOCH3), 33.3 (C-3),
28.1 (CH3), 25.5 (C-4) ppm. Data for 7c: 1H NMR (300 MHz,
CDCl3): δ = 5.06 (td, J3,4e = 5.7, J3,4a = 9.3, J3,2 = 9.3 Hz, 1 H, 3-
H), 4.73 (m, 1 H, 5-H), 4.53 (d, J2,3 = 9.3 Hz, 1 H, 2-H), 3.17 (s,
3 H, NOCH3), 2.80 (m, J4a,4e = 16.7, J4a,3 = 2.5, J4a,Me = 2.5 Hz,
1 H, 4a-H), 1.91 (m, 3 H, CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 100.2 (C-5), 84.1 (C-3), 67.5 (C-2), 63.7 (NOCH3),
62.6 (C-1) ppm. IR (KBr): ν
= 3495, 3032, 2957, 2918, 2871,
˜
max
1554, 1454, 1378 cm–1. MS (EI): m/z (%) = 304 (2) [M]+. HRMS
(EI): calcd. for C15H16N2O5 [M]+ 304.1059; found 304.1054.
General Procedure for the Synthesis of Racemic N-Alkoxypiperid-
ines 6a–h: To a solution of 3a–d (1 mmol) in CH3CN (3 mL),
K2CO3 (1 mmol) was added, then 4a–c (1.1 mmol) was slowly
added dropwise. The reaction mixture was stirred at room temp.
for 4–9 h. Once the reaction was completed (reaction monitored by
TLC), the solvent was removed under reduced pressure and the
residue was suspended in CH2Cl2 and washed with water. The col-
lected organic layers were dried (MgSO4), concentrated, and the
residue was purified as described below to afford 6a–h.
(2R*,5S*,6R*)-1-Methoxy-2-methyl-5-nitro-6-phenylpiperidin-2-ol
(6a) and (2R*,3S*)-1-(Methoxy)-6-methyl-3-nitro-2-phenyl-1,2,3,4-
tetrahydropyridine (7a): Reaction time 6 h; purification by column
chromatography (EtOAc/hexane, 1:6); yield 229 mg, 86%; colorless
foam; 6a/7a ratio 96:4; Rf = 0.41 (EtOAc/hexane, 1:2). Data for 6a:
1H NMR (500 MHz, CDCl3): δ = 7.45–7.30 (m, 5 H, PhH), 4.75
(m, 1 H, 5-H), 4.53 (d, J5,6 = 10.4 Hz, 1 H, 6-H), 3.02 (s, 3 H,
OCH3), 2.94 (br. s, 1 H, OH), 2.49 (dtd, J4a,4e = 14.0, J4a,3a = 12.3,
J4a,5 = 12.3, J4a,3e = 4.2 Hz, 1 H, 4a-H), 2.08 (m, J4e,5 = 4.4, J4e,3a
= 4.4, J4e,3e = 3.0 Hz, 1 H, 4e-H), 2.05 (m, 1 H, 3e-H), 1.78 (m,
J3a,3e = 15.0 Hz, 1 H, 3a-H), 1.51 (s, 3 H, CH3) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 136.7, 128.6, 128.4, 128.4 (Ph), 88.4 (C-
5), 86.9 (C-2), 66.1 (C-6), 63.8 (OMe), 33.3 (C-3), 28.1 (Me), 25.5
(C-4) ppm. Data for 7a: 1H NMR (500 MHz, CDCl3): δ = 5.07 (td,
J3,4a = 9.2, J2,3 = 9.2, J3,4e = 5.7 Hz, 1 H, 3-H), 4.70 (m, 1 H, 5-
28.6 (CH ), 26.1 (C-4) ppm. IR (NaCl): ν
= 3504, 2942, 1731,
˜
3
max
1550, 1512, 1444, 1376, 1262 cm–1. MS (EI): m/z (%) = 326 (27)
[M]+. HRMS (EI) for 6c: calcd. for C15H22N2O6 [M]+ 326.1478;
found 326.1485.
(2R*,5S*,6R*)-1-(Benzyloxy)-6-(3,4-dimethoxyphenyl)-2-methyl-5-
nitropiperidin-2-ol (6d) and (2R*,3S*)-1-(Benzyloxy)-2-(3,4-dimeth-
oxyphenyl)-6-methyl-3-nitro-1,2,3,4-tetrahydropyridine (7d): Reac-
tion time 4 h; purification by column chromatography (EtOAc/hex-
ane, 1:5 Ǟ 1:1); yield 103 mg, 83%; colorless foam; 6d/7d ratio 96:4;
1
Rf = 0.28 (EtOAc/hexane, 1:2). Data for 6d: H NMR (300 MHz,
CDCl3): δ = 7.25–6.75 (m, 8 H, ArH, PhH), 4.83 (m, 1 H, 5-H),
4.56 (d, J5,6 = 10.4 Hz, 1 H, 6-H), 4.39, 3.87 (2ϫd, J = 8.9 Hz, 1
H each, CH2Ph), 3.89 (s, 6 H, 2ϫArOCH3), 2.92 (br. s, 1 H, OH),
2.51 (dtd, J4a,4e = 13.5, J4a,3a = 12.6, J4a,5 = 12.6, J4a,3e = 4.5 Hz,
1 H, 4a-H), 2.12 (m, 1 H, 4e-H), 2.06 (m, 1 H, 3e-H), 1.83 (m, 1
H, 3a-H), 1.61 (s, 3 H, CH3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 149.5, 149.0, 129.0, 112.2, 111.0 (Ar), 135.5, 129.2, 128.5, 128.4
(Ph), 88.4 (C-5), 87.1 (C-2), 78.3 (CH2Ph), 66.0 (C-6), 56.1 (2ϫAr-
OCH3), 33.4 (C-3), 28.3 (CH3), 25.6 (C-4) ppm. Data for 7d: 1H
H), 4.65 (d, 1 H, 2-H), 2.80 (m, J4a,4e = 16.7, J4a,5 = 2.7, J4a,Me
=
2.3 Hz, 1 H, 4a-H), 1.92 (m, 3 H, CH3) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 100.0 (C-5), 83.8 (C-3), 67.6 (C-2), 63.5
(OMe), 28.2 (Me) ppm. IR (NaCl, Nujol): νmax = 3544, 3061, 2923,
˜
2815, 1738, 1557, 1455, 1374 cm–1. MS (EI): m/z (%) = 266 (8)
[M]+. HRMS (EI) for 6a: calcd. for C13H18N2O4 [M]+ 266.1267;
found 266.1270.
(2R*,5S*,6R*)-1-(Benzyloxy)-2-methyl-5-nitro-6-phenylpiperidin-2- NMR (300 MHz, CDCl3): δ = 5.13 (td, J3,4e = 5.8, J3,4a = 9.4, J3,2
ol (6b) and (2R*,3S*)-1-(Benzyloxy)-6-methyl-3-nitro-2-phenyl-
1,2,3,4-tetrahydropyridine (7b): Reaction time 5 h; purification by
column chromatography (EtOAc/hexane, 1:9); yield 264 mg, 78%;
white solid; m.p. 98–100 °C; 6b/7b ratio 97:3; Rf = 0.51 (EtOAc/
= 9.4 Hz, 1 H, 3-H), 4.61 (d, J2,3 = 9.4 Hz, 1 H, 2-H), 4.29, 4.17
(2ϫd, J = 9.6 Hz, 1 H each, CH2Ph), 2.80 (m, J4a,4e = 16.6, J4a,5
= 2.5, J4a,Me = 2.5 Hz, 1 H, 4a-H), 1.96 (m, 3 H, CH3) ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 100.8 (C-5), 84.5 (C-3), 78.2
5486
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5482–5488

Novel Polyfunctionalized N-Alkoxypiperidines
(CH Ph), 67.8 (C-2) ppm. IR (NaCl): ν
[2]
[3]
T. M. Cox, F. M. Platt, J. M. F. G. Aerts, in: Iminosugars: From
Synthesis to Therapeutic Applications (Eds.: P. Compain, O.
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= 3464, 2928, 1545,
max
˜
2
1513, 1458, 1361, 1251 cm–1. MS (EI): m/z (%) = 402 (2) [M]+.
HRMS (EI) for 6d: calcd. for C21H26N2O6 [M]+ 402.1791; found
402.1771.
(2R*,5S*,6R*)-6-(3,4-Dimethoxyphenyl)-2-ethyl-1-methoxy-5-nitro-
piperidin-2-ol (6g) and (2R*,3S*)-2-(3,4-Dimethylphenyl)-6-ethyl-1-
methoxy-3-nitro-1,2,3,4-tetrahydropyridine (7g): Reaction time 9 h;
purification by column chromatography (EtOAc/hexane, 1:5); yield
102 mg, 70%; yellowish syrup; 6g/7g ratio 95:5; Rf = 0.21 (EtOAc/
[4]
[5]
[6]
[7]
[8]
1
hexane, 1:2). Data for 6g: H NMR (300 MHz, CDCl3): δ = 7.08–
H. Ouchi, Y. Mihara, H. Takahata, J. Org. Chem. 2005, 70,
5207–5214.
6.75 (m, 3 H, ArH), 4.75 (m, 1 H, 5-H), 4.49 (d, J5,6 = 10.6 Hz, 1
H, 6-H), 3.90, 3.87 (2ϫs, 3 H each, 2ϫArOCH3), 3.04 (s, 3 H,
NOCH3), 2.76 (s, 1 H, OH), 2.47 (dtd, J4a,3a = 12.4, J4a,5 = 12.4,
J4a,4e = 13.9, J4a,3e = 4.7 Hz, 1 H, 4a-H), 2.11 (m, 1 H, 4e-H), 2.03
G. Danoun, J. Ceccon, A. E. Greene, J.-F. Poisson, Eur. J. Org.
Chem. 2009, 4221–4224.
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Sudagar, M. McNeil, G. S. Besra, B. G. Davis, ChemBioChem
2008, 9, 2197–2199.
(m, 1 H, 3e-H), 1.82 (m, 3 H, 3a-H, CH2CH3), 1.02 (t, JCH2,CH3
=
7.5 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ =
149.1, 148.6, 129.2, 122.1, 111.3, 110.3 (Ar), 89.2 (C-5), 88.4 (C-2),
66.0 (C-6), 63.6 (NOCH3), 56.1, 55.9 (2ϫArOCH3), 33.4 (C-3),
29.4 (CH2CH3), 25.2 (C-4), 8.6 (CH2CH3) ppm. Data for 7g: 1H
NMR (300 MHz, CDCl3): δ = 5.07 (td, J3,4a = 9.4, J2,3 = 9.4, J3,4e
= 5.7 Hz, 1 H, 3-H), 4.80 (m, 1 H, 5-H), 4.65 (d, J2,3 = 9.4 Hz, 1 H,
2-H), 3.17 (s, 3 H, NOCH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 86.4 (C-3), 68.3 (C-2), 63.4 (OCH3), 27.1 (CH2CH3), 23.0 (C-4)
[9]
a) S. Kaellstroem, R. Leino, Bioorg. Med. Chem. 2008, 16, 601–
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[10]
ppm. IR (NaCl): ν
= 3054, 2936, 1706, 1549, 1516, 1464, 1370,
˜
max
1263 cm–1. MS (EI): m/z (%) = 340 (10) [M]+. HRMS (EI) for 6g:
[11]
[12]
calcd. for C16H24N2O6 [M]+ 340.1634; found 340.1628.
(2R*,5S*,6R*)-1-(Benzyloxy)-5-nitro-6-phenylpiperidin-2-ol
(6h)
and (2R*,3S*)-1-(Benzyloxy)-3-nitro-2-phenyl-1,2,3,4-tetrahydro-
pyridine (7h): Reaction time 8 h; purification by column
chromatography (EtOAc/hexane, 1:5); yield 158 mg, 58%; syrup;
6h/7h ratio 99:1; Rf = 0.41 (EtOAc/hexane, 1:2). Data for 6h: 1H
NMR (500 MHz, CDCl3): δ = 7.52–6.77 (m, 10 H, 2ϫPhH), 5.01
(m, 1 H, 2-H), 4.79 (ddd, J4a,5 = 11.7, J5,6 = 10.4, J4e,5 = 3.8 Hz, 1
H, 5-H), 4.68 (d, J6,5 = 10.4 Hz, 1 H, 6-H), 4.37, 4.14 (2ϫd, J =
[13]
9.9 Hz, 1 H each, CH2Ph), 3.21 (s, 1 H, OH), 2.52 (dtd, J4a,4e
=
14.1, J4a,3a = 12.0, J4a,3e = 4.1 Hz, 1 H, 4a-H), 2.14 (m, 2 H, 4e-H,
3e-H), 1.87 (m, 1 H, 3a-H) ppm. 13C NMR (125.7 MHz, CDCl3):
δ = 136.2, 129.1, 128.9, 128.7, 128.6, 128.4 (Ph), 88.4 (C-5), 81.1
(C-2), 76.0 (CH2Ph), 64.0 (C-6), 27.0 (C-4), 24.1 (C-3) ppm. Data
[14]
[15]
1
for 7h: H NMR (500 MHz, CDCl3): δ = 6.29 (m, 1 H, 6-H), 5.12
H.-C. Guo, J.-A. Ma, Angew. Chem. Int. Ed. 2006, 45, 354–
366.
(td, J3,4a = 9.5, J2,3 = 9.2, J3,4e = 6.0 Hz, 1 H, 3-H) ppm. 13C NMR
[16]
[17]
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8471–8473.
(125.7 MHz, CDCl ): δ = 100.9 (C-3) ppm. IR (NaCl): νmax = 3468,
˜
3
2937, 2876, 1552, 1455, 1372 cm–1. MS (EI): m/z (%) = 328 (1)
[M]+. HRMS (EI) for 6h: calcd. for C18H20N2O4 [M]+ 328.1423;
found 328.1424.
[18]
[19]
[20]
[21]
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for all new compounds.
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[24]
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[26]
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Acknowledgments
The authors acknowledge the Spanish Ministerio de Educación y
Ciencia (MEC) (CTQ2008-02813/BQU and the integrated action
HI-2006-0131), the Junta de Andalucía (FQM134, P06-AGR-
01906), the University of Camerino, Italy and Ministero dell’Univ-
ersità e della Ricerca, Italy (MIUR). M. A. L. G. thanks the Minis-
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Eur. J. Org. Chem. 2010, 5482–5488
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5487

J. G. Fernández-Bolaños, G. Bosica, R. Ballini
FULL PAPER
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Received: April 18, 2010
Published Online: August 16, 2010
5488
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5482–5488