Aza-Henry Reaction with Nitrones, an Under-Explored Transformation

Article abstract of DOI:10.1002/ejoc.201801823

Nitromethylation of nitrones occurred efficiently in CH₃NO₂ in the presence of tetramethylammonium fluoride or triazabicyclodecene as promoters. The obtained adducts might be conveniently transformed into vicinal diamines. The process was extended to nitroethane and nitropropane affording mixtures of syn and anti stereoisomers with low diastereoselectivity.

Full text of DOI:10.1002/ejoc.201801823

A Journal of
Accepted Article
Title: Aza-Henry reaction with nitrones, an under-explored
transformation
Authors: Gatien Messire, fabien massicot, alexis vallee, jean-luc vasse,
and Jean-Bernard Behr
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801823
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801823
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
Aza-Henry reaction with nitrones, an under-explored
transformation
Gatien Messire,[a] Fabien Massicot,[a] Alexis Vallée,[a] Jean-Luc Vasse,[a] and Jean-Bernard Behr*[a]
Abstract: nitromethylation of nitrones occurred efficiently in CH3NO2
in the presence of tetramethylammonium fluoride or
been reported over the years and no systematic exploration of
such transformation has been attempted.7 The contrasting
results obtained during nitromethylation of nitrones in these early
investigations (modest yields or conversion) possibly hampered
its wider development. In this study, we explored the scope and
limitations of the reaction with a series of achiral and chiral
nitrones, providing a basis for future work in this field in view of
enantioselective transformations.
triazabicyclodecene as promoters. The obtained adducts might be
conveniently transformed into vicinal diamines. The process was
extended to nitroethane and nitropropane affording mixtures of syn
and anti stereoisomers with low diastereoselectivity.
.
Introduction
Synthetic tools to access the 1,2-diamine structural motif are of
importance due to its prevalence in biologically active natural
products, in medicinal chemistry, as well as in the core structure
of catalysts used in asymmetric synthesis.1 Among the methods
giving access to the N-C-C-N sequence,2 the addition of -
nitrogen C-nucleophiles such as nitroalkanes to imines or imine
equivalents has been exploited and enantioselective versions
were recently developed.3 However, these transformations are
usually restricted to a number of reactive imines or require
formation or pre-activation of the imine in situ, as exemplified by
the cross-dehydrogenative addition of nitromethane to tertiary
amines.4 The direct addition of nitromethane to unactivated
imines (aza-Henry or nitro-Mannich type reactions) has been
attempted only recently using 3,4-dihydroisoquinoline 1 (Figure
1) as a model substrate.3c Enantioselective aza-Henry reaction
with the same imine proved possible by using bi-functional
thiourea catalysts, which afforded the nitro amine product in
optimal 77% ee.3d Surprisingly, there are few examples reporting
the use of nitrones as imine surrogates in aza-Henry reactions.
Nitrones such as 2 are conveniently prepared by oxidation of the
corresponding amines and are often obtained as easy to handle
and stable crystalline compounds.5 Furthermore, the highly
polarized double bond of nitrones is responsible for their high
electrophilic character and for their susceptibility to nucleophilic
addition of organometallic reagents.6 Hence, nitrones have been
used as key substrates in the synthesis of designingly
functionalized iminosugars.6a-c But to the best of our knowledge
only four examples of aza-Henry reactions with nitrones have
Figure 1. Structures of key compounds 1-3.
Results and Discussion
Optimization, scope of bases. As
a prelude of our
investigation, nitrone 2 was chosen as the model substrate.
Compound 2 is easily prepared from tetrahydroisoquinoline and
its derivatives have valuable biological interests especially the 1-
(aminomethyl)-1,2,3,4-tetrahydroiso-quinolines
3.8,9
(+)-
Praziquantel (PZQ) 3a is the main drug prescribed against all
Schistosoma species and, as such, is indicated in the list of
essential drugs of WHO.9 Retrosynthetically, compounds 3 might
be obtained from 2 by initial addition of nitroalkanes and
subsequent reduction. In most cases the reactive nitronate is
generated by a base, among which amines, hydroxides or
alcoholates are the most widely used.10 We began our study
with the treatment of nitrone 2 and nitromethane with sodium
ethanolate in ethanol, reiterating conditions that have been
used in initial assays.7 After 24 h no addition product could be
detected in the reaction mixture and 2 was entirely recovered
(Table 1, entry 1).
[a]
G. Messire, Dr F. Massicot, A. Vallée, Dr J.-L. Vasse, Prof. J.-B.
Behr, Université de Reims Champagne-Ardenne, Institut de Chimie
Moléculaire de Reims, CNRS UMR 7312, FR CNRS 3417, 51687
Reims Cedex 2, France. E-mail: jb.behr@univ-reims.fr
https://www.univ-reims.fr/icmr/
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
tetramethylammonium fluoride (TMAF) was used as the base
(0.25 equivalent) in CH3NO2 as the solvent, conversion reached
66% and 2-hydroxy-1-nitromethyl-1,2,3,4-tetrahydroisoquinoline
4 was isolated in 28% yield. The recovery of only a small portion
of the formed product was explained by oxidation of 4 into
ketonitrone 5 in the presence of air oxygen. Exploration of
various reaction conditions (amount of TMAF, reaction time, see
Table 1) allowed to increase the yield up to 75% and led to the
following conclusions: (a) an excess of TMAF is needed to
ensure substantial conversion, 1.6 equivalents appearing as the
upper limit (entries 2-6); (b) for a given amount of TMAF, the
conversion reached a plateau and no further evolution was
observed even after prolonged reaction time, maximum
conversion being obtained with 1.6 equiv of TMAF after 2.5 h
(see in the following section the plots of conversion vs time); (c)
complete conversion could not be achieved even with 2 molar
ratio of TMAF; remaining nitrone was still present in the crude
reaction mixture, to a small extent though; (d) the presence of
MeOH as a co-solvent significantly impacted the conversion
(entry 7), most likely due to a profound depletion of the pKa of
fluoride in methanol; (e) lowering the amount of nitromethane to
Entry
Base
(equiv.)
EtONa (2)
Solvent
Time
(h)
24
Conversion
Yield
(%)c,d
–
(%)
0b
1
2
3
4
5
6
7
8
9
EtOHa
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
MeOHf
TMAF (0.25)
TMAF (1.0)
TMAF (1.3)
TMAF (1.6)
TMAF (2.0)
TMAF (1.6)
TMAF (1.6)
24e
6e
66
84
90
96
96
27
66
18
28
47
57
74
73
–
2.5e
2.5e
2.5e
2.5
2.5
2.5
THFg
–
CH3NO2
–
TMAF.4 H2O
(1.6)h
CH3NO2
75
10
TBAF.3 H2O
(1.6)
2.5
96
TBAOH (1.6)i
2.5
2.5
2.5
2.5
6e
50
92
36
87
93
52
13
–
61
–
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
MeOHf
11
12
13
14
15
16
17
DBU (1.6)
5-6
equivalents
reduced
conversion
(entry
8);
(f)
tetrabutylammonium fluoride trihydrate (TBAF.3H2O) was as
efficient as anhydrous TMAF but hydrated TMAF (TMAF.4H2O)
gave very low conversion, certainly because of insolubility of this
reagent in nitromethane (entries 9,10).
TBD (0.3)
67
TBD (1.6)
TBD (1.6)
68
–
Other bases such as tetraethylammonium hydroxide,13 NEt3,14
MeONa (1.6)
2.5
2.5
19
DABCO,15 DBU,16 guanidines,17 CsOH,3e MeONa,18 K2CO3 or
K2CO3 (1.6) +
TBABr (0.3)h
CH3NO2
–
CsF20 have been used in the literature as nitronate precursors,
in the presence of phase-transfer catalysts when needed. Thus
the scope of bases was explored here (entries 11-18) with 2
under the optimal conditions stated above (1.6 equiv of base vs
nitrone, nitromethane as the solvent, 2.5 h under argon). It was
found that only DBU and TBD gave satisfactory results, with
almost complete conversion and 61% and 68% isolated yield
respectively (entries 12 and 15). Conversely, no reaction
occurred in the presence of NEt3, DABCO, CsOH, MeONa or
K2CO3 under analogous conditions (results not shown in table 1).
With TBD, the reaction occurred at slower rate than with TMAF,
reaching maximal conversion after 6 h (see the supporting
information). The importance of the amount of base was
reinvestigated with TBD showing that sub-molar quantities were
insufficient for acceptable conversion (entry 13). Other bases
gave unsatisfactory results due either to low solubility in
nitromethane (CsOH, MeONa, K2CO3, CsF) or to low reactivity
(NEt3, DABCO). However, with the addition of methanol as co-
solvent, hydroxide (entry 11) and methoxide (entry 16) proved
moderately efficient, giving rise to almost 50% conversion.
18
19
CsF (1.6)h
CH3NO2
2.5
2.5
13
0b
–
–
CsF (1.6) +
H2O /
CH3NO2
TBABr (0.3)h
–
20
21
22
CsF (1.6) +
CH3NO2
CH3NO2
CH3NO2
CH3NO2
2.5
24
54
81
80
0b
TBABr (0.3)h
CsF (1.6) +
52
64
–
TBABr (0.3)h
CsF (1.6) +
TBABr (1)f
16
23
TBABr (1)
2.5
a
In the presence of 2 equiv. of nitromethane. No further evolution of the
reaction after this time; maximum conversion reached.
b The reaction product was not detected in the 1H NMR spectrum of the crude.
c Isolated yield (chromatography on silica gel) of pure 4.
d – means that the yield was not determined, due to low conversion.
e No further evolution after this time (maximum conversion reached)
f A mixture of MeOH/CH3NO2 (1/2) was used as the solvent.
g In the presence of 6 equiv. of nitromethane.
h Heterogeneous reaction mixture due to insoluble material.
i Methanolic solution of TBAOH was used (1M).
Gratifyingly, phase-transfer catalysis (PTC) conditions using
tetrabutylammonium bromide (TBABr) as the transfer agent
provided a good solution to address the solubility issue of CsF.
A traditional liquid–liquid biphasic system (water/nitromethane),
in which the reagents partitioned between aqueous (CsF) and
organic (TBABr, nitrone) phases, completely disrupted the
reactivity of CsF (entry 19). Nevertheless, in the absence of
water, fluoride could be smoothly transferred with TBABr from
solid CsF in suspension into the organic liquid phase. Catalysis
occurred with 0.3 equivalent TBABr but at slower rate in this
Table 1. Optimization of nitromethylation of nitrone 2.
Due to its peculiar basicity in non-aqueous solvents, fluoride
anion is a good alternative for the removal of C-H acidic
hydrogens in aprotic solvents.11 Ammonium fluorides have
notably been used to initiate Henry reaction with sugar-derived
aldehydes and chiral quaternary ammonium fluorides proved
their efficiency in enantioselective carbon-carbon bond formation
reactions
with
nitromethane.12
Hence,
when
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
heterogeneous system (entries 20-21), 81% conversion being
reached after 24h with 52% isolated yield. Here again, formation
of nitrone 5 as a by-product, favored by prolonged reaction
period, accounted for the unsatisfactory low yield. By increasing
the amount of TBABr to 1 equivalent, 80% conversion was
obtained in 16 h and the addition product was isolated in 64%
yield (entry 22). A control reaction with TBABr alone showed, as
expected, that a neutral ammonium species is not able to initiate
the reaction by itself (entry 23).
CHCl3 and partially deuterated CH3NO2 was also evidenced in
the NMR spectrum, as a result of release of nitromethane and
fluoride mediated proton-deuterium exchange with CDCl3.21b
Such a retroaddition is a problem encountered as well in more
classical Henry or aza-Henry transformations.22
conversion vs time/equiv TMAF
100
TMAF (0.3 equiv)
90
80
Course of the reaction. In the experiments above with the most
convenient bases TMAF or TBD, unsatisfactory yields were
observed in situations where conversion stagnated at low ratios
or where a significant amount of oxidation product 5 formed.
Both trends were addressed by supplementary experiments.
TMAF (0.6 equiv)
70
60
TMAF (1 equiv)
50
40
30
20
10
0
TMAF (1.6 equiv)
TMAF (2.0 equiv)
Firstly, the ease of oxidation of hydroxylamine
4
was
demonstrated by simply mixing it in the standard reaction
conditions (TMAF 1.6 equiv, CH3NO2 as the solvent), without
flushing the system with argon (Scheme 1). After 3 days,
complete disappearance of the hydroxylamine occurred with
concomitant formation of nitrone 5. The oxidation of
hydroxylamines by air oxygen is usually metal-catalyzed, but the
formation of a conjugated system might account here for the
ease of such a process in the absence of any metal.21a
Conversely, compound 4 was not susceptible to oxidation when
it was kept under argon, either in solution or neat.
0
10
20
reaction time (h)
Figure 2. Time-course of the aza-Henry reaction of 2 with various amounts
of TMAF.
The kinetic of the reaction was also studied with TBD and with a
heterogeneous (CsF/TBABr) system, affording analogous plots
showing dose-dependent maximal conversions (see the
supporting information).23
Enlarging the scope of nitrones and nitroalkanes. Aza-Henry
reaction was applied to
a series of nitrones with varied
structures (Table 2), by using either TMAF or TBD as the
promoter. Acyclic nitrones such as 6-824 afforded the expected
products in modest yields, due to competing formation of a
(bis)nitromethyl alkane. Aldehydes afford such bis(nitromethyl)
adducts as well.25 Here, 1,1-bis(nitromethyl)heptan was obtained
in 65% yield from 6 by using TMAF as the base. TBD tuned the
ratio in favour of hydroxylamine 6a (51% isolated yield). Under
the same conditions nitrones 7 and 8 gave only 16% and 47%
respectively of the expected aza-Henry adduct. Retro-aza-
Michael reaction followed by Michael addition to the intermediate
nitro alkene might account for the formation of bis(nitromethyl)
adducts from targeted hydroxylamines.
Better results were obtained with glyceraldehyde-derived
nitrone 9, which was converted into hydroxylamine 9a in 58%
yield with TBD. The reaction afforded two inseparable
diastereoisomers in equal amount (dr 55 : 45). Satisfyingly,
cyclic nitrones 10-13 were converted in good yields into their
nitromethyl adducts, either with TMAF or with TBD. Best results
were obtained with carbohydrate-derived nitrones 12-13, which
afforded 12aR and 13aR in high yield and diastereoselectivity.
Addition to nitrone 12 proved completely stereoselective
whereas O-benzylated 13aR was obtained from 13 as a 10:2.7
inseparable mixture of isomers.
Scheme 1. Stability of nitromethyl isoquinoline 4.
Secondly, a kinetic study of the reaction course was attempted
using various ratios of TMAF (Figure 2). The results show that
the transformation is quite rapid, reaching a plateau conversion
after 5 h with 0.3 equiv or after 1-2 h with one equivalent or more.
However, no further evolution could be noticed even after
prolonged reaction period. Having in mind the need for a large
excess of CH3NO2 to help conversion, these experiments
suggest that nitromethylation of nitrones is a reversible process.
1
Reversion of 4 to starting nitrone 2 was monitored by H NMR
spectroscopy (scheme 1 and supporting information). In the
absence of base, nitromethyl adduct 4 was stable in CDCl3 (0.2
mmol/mL) for 24h; no starting nitrone could be detected. But
after addition of TMAF, the reaction returned nitrone 2 in several
hours, in a very clean manner. The concomitant formation of
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
a d.r. = 55:45. b only one isomer detected by NMR. c d.r. = 79:21 in favour of the (2R) isomer. d epimerization occurs in solution, affording the (2S) isomer as the
only product after several days
Table 2. Aza-Henry reaction applied to acyclic or cyclic nitrones.
Due to solubility issues with TMAF in nitropropane, TBAF was
engaged as an alternative base. From nitrone 2,
The preferential (2R) configuration of the newly formed
stereocenter in both structures was assessed by nOe
experiments (see Supporting Information) and is consistent
with nucleophilic attack from the Re side. With such cyclic
nitrones, facial approach of the reactant is governed by steric
hindrance of the neighboring C-3 substituent, as observed in
previous studies with nitrones 12 or 13.26 However, whereas
12aR proved configurationally stable, 13aR epimerized after
several days in solution (CDCl3) to 13aS (see Supporting
Information). Such an isomerization process with iminosugars
bearing acidic C-H at C-α to C-2 has already been observed
and might result from retro-Michael/Michael equilibration.27
hydroxylamines 14 (71%, TMAF) and 15 (35%, TBAF) were
obtained in nitroethane and nitropropane, respectively, as
mixtures of the two possible diastereomers. After HPLC
separation of syn- and anti-14, each single stereoisomer re-
equilibrated in solution to the initial 65/35 composition. The
addition of nitroethane and nitropropane to chiral nitrone 13
afforded 16 and 17 respectively as mixtures of syn/anti (2R)-
isomers, in good yields (91% for 16 and 83% for 17, TBD as a
base). Stereochemical stability of 16 was studied further. In
solution, the 58/42 mixture of epimers remained stable with
no emergence of additional stereoisomers, as would happen
from
a C-2 epimerizing retro-Michael/Michael process.
Next, nitrones 2 and 13 were used as models to assay
However, as for 14, a pure sample of HPLC-separated syn or
nitroethane and nitropropane as nucleophiles (Scheme 2).
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
anti-16 evolved in solution into the original mixture, due to
epimerization of the -C(CH3)(H)-NO2 stereocenter.28
Scheme 2. Reaction of 2 and 13 with nitroethane and nitropropane.
Reagents and conditions: i) TMAF, 2.5 h, rt; ii) TBD, 6 h, rt, iii) TBAF.3H2O,
2.5 h, rt.
Encouraged by these results, we applied the aza-Henry
reaction of nitrones to the synthesis of biologically relevant
targets (Scheme 3). Thus, iminosugar 18 was prepared in a
single step (39% yield) from hydroxylamine 12aR.
Hydrogenolysis of both nitro and N-hydroxy functions was
performed concomitantly to hydrolysis of isopropylidenes in
the presence of hydrochloric acid. After neutralization of the
reaction mixture, diamine 18 was purified by chromatography
on silica gel (CHCl3/MeOH/NH4OH 0.8M, 5/5/1).
Scheme 3. synthesis of iminosugar 18 and of PZQ 3a.
Recent tension regarding supply of PZQ, the only effective
drug to treat schistosomiasis, stimulated a renewed interest in
straightforward synthetic accesses. When raised to 500 mg-
scale, nitromethylation of 2 afforded 4 in 93% yield, the
hydrogenolysis of which gave the known vicinal diamine 19
(62%).29 Regioselective acylation under conditions from the
literature29 gave 20 in 60% yield. Terminal cyclization with
chloroacetyl chloride under phase transfer catalysis using
benzyltriethyammonium chloride afforded Praziquantel in
Conclusions
Overall, our study comprises an extensive analysis of the
aza-Henry reaction applied to nitrones. The results show that
the transformation is reversible and requires a large excess of
nitromethane to secure high conversion. Ammonium fluorides
or strong organic bases such as TBD are convenient
promoters. Alternatively, phase-transfer catalysis gave also
acceptable yields, which opens the door to various
enantioselective strategies of the reaction under kinetic
conditions, either with chiral ammonium fluorides,12b chiral
Brønsted bases32 or by using cinchona alkaloids as PT
catalysts.33 Nitroethane or nitropropane proved also possible
C-nucleophiles, affording mixtures of isomerisable ß-alkyl-ß-
nitro-hydroxylamines. The reaction was exploited for the
synthesis of unprecedented diamino-iminosugar 18 as well as
for that of PZQ, the latter requiring four atom-economic steps
starting from nitrone 2 and nitromethane. Our synthesis of
PZQ affords an alternative to other processes and provides
the advantage of chemical diversity through the use of other
nitroalkanes.
56%
overall
yield.4b,30
Concerning
the
overall
reduction/deprotection strategy to aminomethyl derivatives 18
and 19 it should be pointed out that such diamines are also
accessible via addition of cyanide ion to nitrones followed by
hydrogenolysis, as demonstrated by Goti for related
polyhydroxylated cyclic nitrones.31
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
250 MHz) δ 0.80 (t, 3J = 7.5 Hz, 3H, CH3‒CH2), 1.25‒1.52 (m, 9H,
CH3‒(CH2)4‒CHaHb), 1.65‒1.70 (m, 1H, CH3‒(CH2)4‒CHaHb), 2.70 (s,
3H, CH3‒N(OH)), 3.30‒3.45 (m, 1H, CH), 4,38 (dd, 2J = 12.5 Hz, 3J =
4.7 Hz, 1H, CHaHb‒NO2), 4,74 (dd, 2J = 12.5 Hz, 3J = 7.6 Hz, 1H,
CHaHb‒NO2), 6.52 (br s, 1H, OH); 13C NMR (CDCl3, 62.5 MHz) δ 14.0
(CH3‒CH2), 22,5 (CH2), 26.1 (CH2), 27.4 (CH2), 29.2 (CH2), 31.6
(CH2), 44.3 (CH3‒N(OH)), 65.8 (CH), 75.9 (CH2‒NO2); HRMS (ESI+)
m/z calcd for C9H21N2O3 [M + H]+ 205.1552, found 205.1550.
Experimental Section
General information
N-(1-Nitrononan-2-yl)-N-octylhydroxylamine (7a). According to
general procedure, obtained after nitromethylation of
7
and
Reactants and reagents were purchased from standard suppliers
(Sigma-Aldrich, Alfa-Aesar, Fischer Scientific) and were used without
further purification. All reactions were conducted under Ar atmosphere
using anhydrous solvents, air- or moisture-sensitive reagents and
products were stored at -20°C under Ar. Silica gel F254 (0.2 mm) was
used for TLC plates, detection being carried out by spraying with an
alcoholic solution of phosphomolybdic acid or an aqueous solution of
KMnO4 (2%) / Na2CO3 (4%), followed by heating. Reactions were
monitored either by TLC or by 1H-NMR. Conversion was deduced
from the relative amount of nitrone vs products (hydroxylamine +
oxidation product, if any) in the 1H-NMR spectrum, after analysis of
small aliquots of the reaction mixture quenched under the standard
conditions. Column chromatography was performed over silica gel M
9385 (40-63 µm) Kieselgel 60. NMR spectra were recorded on Bruker
AC 250 (250 MHz for 1H, 62.5 MHz for 13C), 500 (500 MHz for 1H, 125
MHz for 13C) or 600 (600 MHz for 1H, 150 MHz for 13C)
spectrometers. Chemical shifts are expressed in parts per million
purification of the resulting residue by chromatography on silica gel
(dichloromethane / diethyl ether / petroleum ether 1:1:8); yellow oil; 1H
NMR (CDCl3, 250 MHz) δ 0.85‒0.90 (m, 6H, 2 CH3), 1.20‒1.35 (m,
21H, 10 CH2, CH‒CHaHb‒CH2), 1.43‒1.53 (m, 2H, CH2), 1.68‒1.76
(m, 1H, CH‒CHaHb‒CH2), 2.61 (dt, 2J = 12.5 Hz, 3J = 7.5 Hz, 1H,
CHaHb‒N(OH)), 2.79 (dt, 2J = 12.5 Hz, 3J = 7.5 Hz, 1H, CHaHb‒
N(OH)), 3.35‒3.45 (m, 1H, CH), 4.37 (dd, 2J = 12.0 Hz, 3J = 5.0 Hz,
1H, CHaHb‒NO2), 4.71 (dd, 2J = 12.0 Hz, 3J = 8.0 Hz, 1H, CHaHb‒
NO2), 4.81 (br s, 1H, OH); 13C NMR (CDCl3, 62.5 MHz) δ 14.1 (CH3),
14.1 (CH3), 22.6 (CH2), 22.7 (CH2), 26.4 (CH2), 26.8 (CH2), 27.0
(CH2), 27.6 (CH2), 29.1 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2),
31.8 (CH2), 31.9 (CH2), 56.2 (CH2‒N(OH)), 64.7 (CH), 76.4 (CH2‒
NO2); HRMS (ESI+) m/z calcd for C17H37N2O3 [M + H]+ 317.2804,
found 317.2809.
N-Benzyl-N-(1-nitrononan-2-yl)hydroxylamine (8a). According to
general procedure, obtained after nitromethylation of
8
and
(ppm) and were calibrated to the residual solvent peak for 1H and 13
C
purification of the resulting residue by chromatography on silica gel
(dichloromethane / diethyl ether / petroleum ether 1:1:8); yellow oil; 1H
NMR (CDCl3, 500 MHz) δ 0.90 (t, 3J = 5 Hz, 3H, CH3), 1.21‒1.44 (m,
10H, CH3‒(CH2)5), 1.48‒1.57 (m, 1H , CH‒CHaHb‒CH2), 1.79‒1.89
(m, 1H , CH‒CHaHb‒CH2), 3.50‒3.55 (m, 1H, CH), 3.82 (d, 2J = 13.0
Hz, 1H, CHaHb‒Ph), 3.98 (2J = 13.0 Hz, 1H, CHaHb‒Ph), 4,42 (dd, 2J
= 12.0 Hz, 3J = 5.0 Hz, 1H, CHaHb‒NO2), 4.76 (dd, 2J = 12.0 Hz, 3J =
8.0 Hz, 1H, CHaHb‒NO2), 4.80 (br s, 1H, OH), 7.27‒7.40 (m, 5H, 5
CHar); 13C NMR (CDCl3, 125 MHz) δ 14.2 (CH3), 22.8 (CH2), 26.5
(CH2), 26.9 (CH2), 29.2 (CH2), 29.7 (CH2), 31.9 (CH2), 60.7 (CH2‒Ph),
64.3 (CH), 76.5 (CH2‒NO2), 127.7 (CHar), 128.6 (CHar), 129.2
(CHar), 137.4 (CIVar); HRMS (ESI+) m/z calcd for C16H27N2O3 [M +
H]+ 295.2022, found 295.2029.
N-Benzyl-N-(1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitro-ethyl-
hydroxylamine (9a, mixture of two inseparable diastereoisomers)
According to general procedure, obtained after nitromethylation of 9
and purification of the resulting residue by chromatography on silica
gel (diethyl ether / petroleum ether 4:6); colorless oil; 1H NMR (CDCl3,
250 MHz) δ 1.34 (s, 3H), 1.37 (s, 3H), 1.39 (s, 3H), 1.41 (s, 3H), 3.65‒
3.80 (m, 2H), 3.87‒4.08 (m, 7H), 4.12‒4.18 (m, 1H), 4.28‒4.35 (m,
1H), 4.49‒4.57 (m, 2H), 4.64 (dd, 2J = 13.0 Hz, 3J = 4.0 Hz, 1H), 4.82
(dd, 2J = 13.0 Hz, 3J = 8.5 Hz, 1H), 4.96‒5.04 (m, 2H), 5.17 (br s, 1H),
7.28‒7.34 (m, 10H, 10 CHar); 13C NMR (CDCl3, 62.5 MHz) δ 25.1
(CH3), 25.3 (CH3), 26.5 (CH3), 26.6 (CH3), 61.7 (CH2), 62.1 (CH2),
64.1 (CH), 66.2 (CH2), 66.8 (CH), 68.2 (CH2), 72.4 (CH2), 72.8 (CH2),
73.3 (CH), 74.2 (CH), 108.9 (CIV), 110.1 (CIV), 127.9 (CHar) 127.9
(CHar), 128.7 (CHar), 128.7 (CHar), 129.2 (CHar), 129.3 (CHar),
129.5 (CHar), 136.9 (CIVar); m/z calcd for C14H20N2O5Na [M + Na]+
319.1270, found 319.1264.
2,2-Dimethyl-5-(nitromethyl)pyrrolidin-1-ol (10a). According to
general procedure, obtained after nitromethylation of 10 and
purification of the resulting residue by chromatography on silica gel
(diethyl ether / petroleum ether 4:6); yellow oil; 1H NMR (CDCl3, 250
MHz) δ 1.10 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.50‒1.69 (m, 3H, CH2‒
CHaHb‒CH), 1.90‒2.22 (m, 1H, CHaHb‒CH), 3.53‒3.75 (m, 1H, CH),
4.49 (dd, 2J = 13.5 Hz, 3J = 7.0 Hz, 1H, CHaHb‒NO2), 4.61 (dd, 2J =
13.5 Hz, 3J = 7.0 Hz, 1H, CHaHb‒NO2), 4.80 (br s, 1H, OH); 13C NMR
(CDCl3, 62.5 MHz) δ 18.6 (CH3), 22.7 (CH2‒ CH2‒CH), 27.0 (CH3),
34.0 (CH2‒CH2‒CH), 61.9 (CH), 64.0 (CIV), 79.3 (CH2NO2); m/z calcd
for C7H15N2O3 [M + H]+ 175.1083, found 175.1081.
6,7-Dimethoxy-1-(nitromethyl)-3,4-dihydroisoquinolin-2(1H)-ol
(11a). According to general procedure, obtained after nitromethylation
of 11 and purification of the resulting residue by chromatography on
silica gel (diethyl ether / petroleum ether 6:4); pale yellow solid; mp
102°C; 1H NMR (CDCl3, 500 MHz) δ 2.87‒2.90 (m, 2H, CH2‒CH2‒
N(OH)), 3.19‒3.24 (m, 1H, CHaHb‒N(OH)), 3.32‒3.37 (m, 1H, CHaHb‒
spectra. Coupling constants are in Hz and splitting pattern
abbreviations are: br, broad; s, singlet; d, doublet; t, triplet; m,
multiplet. DEPT 1D NMR experiment, COSY, HSQC, and HMBC 2D
NMR experiments were used to confirm the NMR peak assignments
for compounds 4, 6−19. Optical rotations were determined at 20 °C
with a Perkin-Elmer Model 241 polarimeter in chloroform. High
Resolution Mass Spectra (HRMS) were performed on Q-TOF Micro
micromass positive ESI (CV = 30 V). Melting points (mp) were
determined on a Tottoli apparatus and were uncorrected.
Nitrone 10 is commercially available. All other nitrones were prepared
according to known protocols from either the corresponding amines
by using sodium tungstate-H2O2 (2) or oxone (7 and 11) as oxydizing
agent,5a,b or by condensation of aldehydes with hydroxylamines
(6,8,9)5c or by intramolecular dispacement from oximes (12,13).5d
Their NMR spectra are given in the Supporting Information
General procedure for the nitroalkylation of nitrones 2, 6‒13.
To a solution of nitrone 2, 6‒13 (0.35 mmol, 1 equiv) in nitroalkane
(380 µL, 20 equiv for nitrones 2, 6-11; 950 µL, 50 equiv for nitrones 12
and 13) at room temperature under argon was added the base (0.56
mmol, 1.6 equiv.). The solution was stirred during 2.5 to 6h depending
on the base. The reaction mixture was quenched with a saturated
aqueous solution of NH4Cl and extracted three times with
dichloromethane. The combined organic layers were dried (MgSO4)
and the solvent removed under reduced pressure. The residue was
purified by chromatography on silica gel to afford the corresponding
aza-Henry adducts 4, 6a‒13a and 14‒17 and eventually the
(bis)nitromethyl alkanes 6b and 7b.
1-(Nitromethyl)-3,4-dihydroisoquinolin-2(1H)-ol (4). According to
general procedure, obtained after nitromethylation of
2
and
purification of the resulting residue by chromatography on silica gel
(diethyl ether / petroleum ether 1:1) as a yellow oil; 1H NMR (CDCl3,
250 MHz) δ 2.95‒3.05 (m, 2H, CH2‒CH2‒N(OH)), 3.20‒3.30 (m, 1H,
CHaHb‒N(OH)), 3.37‒3.47 (m, 1H, CHaHb‒N(OH)), 4.76‒4.93 (m, 3H,
CH‒CH2‒NO2), 6.25 (br s, 1H, OH), 7.17‒7.27 (m, 4H, 4 CHar); 13C
NMR (CDCl3, 62.5 MHz) δ 26.7 (CH2‒CH2‒N(OH)), 52.0 (CH2‒
N(OH)), 64.9 (CH), 78.0 (CH2‒NO2), 126.3 (CHar), 126.7 (CHar),
127.7 (CHar), 129.0 (CHar), 131.6 (CIVar), 134.3 (CIVar); HRMS
(ESI+) m/z calcd for C10H13N2O3 [M + H]+ 209.0926, found 209.0919.
N-Methyl-N-(1-nitrooctan-2-yl)hydroxylamine (6a). According to
general procedure, obtained after nitromethylation of
6
and
purification of the resulting residue by chromatography on silica gel
(diethyl ether / petroleum ether 1:1); colorless oil; 1H NMR (CDCl3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
N(OH)), 3.84 (s, 3H, CH3), 3.84 (s, 3H, CH3), 4.71‒4.84 (m, 3H, CH‒
N(OH) and CH2‒NO2), 6.43 (br s, 1H, OH), 6.56 (s, 1H, CHar), 6.59
(s, 1H, CHar); 13C NMR (CDCl3, 125 MHz) δ 26.2 (CH2‒CH2‒N(OH)),
51.5 (CH2‒N(OH)), 55.9 (CH3), 56.1 (CH3), 64.6 (CH), 78.0 (CH2‒
NO2), 108.9 (CHar), 111.2 (CHar), 122.9 (CIVar), 126.4 (CIVar), 147.8
(CIVar‒OMe), 148.5 (CIVar‒OMe); m/z calcd for C12H17N2O5 [M + H]+
269.1137, found 269.1134.
Hz, 3H, CH3), 2.80 (dt, 2J = 17.2 Hz , 3J= 5.5 Hz, 1H, CHaHb‒CH2‒
N(OH)), 2.99‒3.05 (m, 1H, CHaHb‒CH2‒N(OH)), 3.27 (dt, 2J = 12.6
Hz, 3J = 5.7 Hz, 1H, CHaHb‒N(OH)), 3.43‒3.49 (m, 1H, CHaHb‒
N(OH)), 4.70 (d, 3J = 7.1 Hz, 1H, CH‒N(OH)), 4.83‒4.91 (m, 1 H, CH‒
NO2), 6.68 (br s, 1H, OH), 7.03 (d, 3J = 7.5 Hz, 1H, CHar), 7.12‒7.24
(m, 3H, 3 CHar); 13C NMR (CDCl3, 125 MHz) δ 6.4 (CH3), 25.4 (CH2‒
CH2‒N(OH)), 50.4 (CH2‒N(OH)), 69.2 (CH‒N(OH)), 84.8 (CH‒NO2),
126.1 (CHar), 127.8 (CHar), 128.3 (CHar), 128.9 (CHar), 130.7
(CIVar), 134.7 (CIVar); m/z calcd for C11H15N2O3 [M + H]+ 223.1083,
found 223.1089.
(3aS,4S,6R,6aR)-4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyl-6-(nitromethyl)dihydro-3aH-[1,3]dioxolo[4,5-c]pyrrol-5(4H)-ol
(12aR). According to general procedure, obtained after
nitromethylation of 12 and purification of the resulting residue by
chromatography on silica gel (diethyl ether / petroleum ether 4:6);
colorless solid; mp 150°C; [훼]2퐷0 ‒17 (c 0.4, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 1.30 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.46 (s, 3H, CH3),
1.54 (s, 3H, CH3), 3.13 (t, 1H, 5CH), 3,59 (q, 3J = 5.0 Hz, 1H, 2CH),
3.96 (dd, 2J = 10.0 Hz, 3J = 5.0 Hz, 1H, 7CHaHb), 4.08 (dd, 2J = 10.0
1-(1-Nitropropyl)-3,4-dihydroisoquinolin-2(1H)-ol
(15A,
minor
diastereoisomer). According to general procedure, obtained as minor
product after nitropropylation of 2 and purification of the resulting
residue by chromatography on silica gel (diethyl ether / petroleum
ether 3:7); yellow oil; 1H NMR (CDCl3, 500 MHz) δ 0.87 (t, 3J = 7.3 Hz,
3H, CH3), 1.48‒1.55 (m, 1H, CHaHb‒CH3), 2.32‒2.41 (m, 1H, CHaHb‒
CH3), 2.75‒2.84 (m, 1H, CHaHb‒CH2‒N(OH)), 2.95‒3.09 (m, 1H,
CHaHb‒CH2‒N(OH)), 3.08‒3.15 (m, 1H, CHaHb‒N(OH)), 3.44‒3.50
(m, 1Hb, CHaHb‒N(OH)), 4.67 (dt, 3J = 10.6 Hz, 3J = 3.0 Hz, 1H, CH‒
NO2), 4.77 (d, 3J = 3.0 Hz, 1H, CH‒N(OH)), 5.96 (br s, 1H, OH), 7.09‒
7.24 (m, 4H, 4 CHar). 13C NMR (CDCl3, 125 MHz) δ 11.3 (CH3), 20.8
(CH2‒CH3), 28.1 (CH2‒ CH2‒N(OH)), 53.7 (CH2‒N(OH)), 70.6 (CH‒
N(OH)), 93.6 (CH‒NO2), 126.4 (CHar), 126.7 (CHar), 127.4 (CHar),
128.8 (CHar), 132.6 (CIVar), 135.0 (CIVar); m/z calcd for C12H17N2O3
[M + H]+ 237.1239, found 237.1235.
3
Hz, J = 5.0 Hz, 1H, 7CHaHb), 4.25‒4.31 (m, 2H, 4CH and 6CH), 4.50‒
4.52 (t, 1H, 3CH), 4.64‒4.73 (m, 2H, CH2‒NO2), 5.5 (br s, 1H, OH);
13C NMR (CDCl3, 125 MHz) δ 25.3 (CH3), 25.4 (CH3), 26.540 (CH3),
27.3 (CH3), 66.3 (7CH2), 70.1 (2CH), 74.4 (5CH), 75.5 (CH2‒NO2), 76.5
(4CH), 77.5 (6CH), 77.6 (3CH), 110.3 (CIV), 114.5 (CIV); m/z calcd for
C13H22N2O7Na [M + Na]+ 341.1325, found 341.1336.
(2R,3R,4R,5R)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-
(nitromethyl)pyrrolidin-1-ol (13aR). According to general procedure,
obtained as major product after nitromethylation of 13 and purification
of the resulting residue by chromatography on silica gel (diethyl ether /
petroleum ether 4:6); colorless oil; 1H NMR (CDCl3, 500 MHz) δ 3.41‒
3.45 (m, 1H, 5CH), 3.60‒3.68 (m, 2H, 6CH2), 3.93‒3.95 (m, 1H, 3CH),
3.96‒3.98 (m, 1H, 4CH), 4.10‒4.14 (m, 1H, 2CH), 4.40‒4.58 (m, 7H,
CHaHb‒NO2 and 3 CH2‒Ph), 4.90 (dd, 2J = 10.0 Hz, 3J = 5.0 Hz,
CHaHb‒NO2), 5.99 (br s, 1H, OH), 7.25‒7.34 (m, 15H, 15 CHar); 13C
NMR (CDCl3, 125 MHz) δ 67.1 (2CH), 68.5(6CH2), 70.7 (5CH), 71.9
(CH2‒Ph), 72.1 (CH2‒Ph), 73.4 (CH2‒NO2), 73.5 (CH2‒Ph), 83.0
(3CH), 83.3 (4CH), 127,8 (CHar), 127.9 (CHar), 128.0 (CHar), 128.0
(CHar), 128.1 (CHar), 128.1 (CHar), 128.6 (CHar), 128.6 (CHar),
128.6 (CHar), 137.4 (CIVar), 137.6 (CIVar) 137.9 (CIVar); m/z calcd for
C27H30N2O6Na [M + Na]+ 501.2002, found 501.2011.
1-(1-Nitropropyl)-3,4-dihydroisoquinolin-2(1H)-ol
(15B,
major
diastereoisomer). According to general procedure, obtained as major
product after nitropropylation of 2 and purification of the resulting
residue by chromatography on silica gel (diethyl ether / petroleum
ether 3:7); yellow oil; 1H NMR (CDCl3, 500 MHz) δ 0.92 (t, 3J = 7.3 Hz,
3H, CH3), 1.74‒1.81 (m, 1H, CHaHb‒CH3), 2.02‒2.13 (m, 1H, CHaHb‒
CH3), 2.74 (dt, 2J = 17.0 Hz, 3J = 5.0 Hz, 1H, CHaHb‒CH2‒N(OH),
2.81 (dt, 2J = 17.0 Hz, 3J = 3.5 Hz, 1H, CHaHb‒CH2‒N(OH), 3.29‒3.40
(m, 1H, CHaHb‒N(OH)), 3.43‒3.52 (m, 1H, CHaHb‒N(OH)), 4.52 (td,
3J = 11.1 Hz, 3J = 3.0 Hz, 1H, CH‒NO2), 4.59 (d, 3J = 8.7 Hz, 1H, CH‒
N(OH)), 6.33 (br s, 1H, OH), 7.09‒7.27 (m, 4H, 4 CHar); 13C NMR
(CDCl3, 125 MHz) δ 10.7 (CH3), 24.2 (CH2‒CH3), 24.7 (CH2‒CH2‒
N(OH)), 49.1 (CH2‒N(OH)), 68.5 (CH‒N(OH)), 92.6 (CH‒NO2), 126.0
(CHar), 127.9 (CHar), 129.0 (CHar), 129.1 (CHar), 130.7 (CIVar),
134.6 (CIVar); m/z calcd for C12H17N2O3 [M + H]+ 237.1239, found
237.1235.
(2R,3R,4R,5R)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-((R)-1-
nitroethyl)pyrrolidin-1-ol (16A, minor diastereoisomer). According to
general procedure, obtained as minor product after nitroethylation of
13 and purification of the resulting residue by chromatography on
silica gel (diethyl ether / petroleum ether 4:6);TLC : diethyl ether /
petroleum ether 4:6; colorless oil; 1H NMR (CDCl3, 500 MHz) δ 1.59
(d, 3J = 6.8 Hz, 3 H, CH3), 3.49‒3.54 (m, 1H, 6CHaHb), 3.62‒3.67 (m,
2H, 5CH and 2CH), 3.72‒3.79 (m, 1H, 6CHaHb), 4.04‒4.08 (m, 2H,
3CH and 4CH), 4.42‒4.65 (m, 6H, 3 CH2‒Ph), 4.81‒4.87 (m, 1H, CH‒
NO2), 5.63 (br s, 1H, OH), 7.30‒7.37 (m, 15H, 15 CHar); 13C NMR
(CDCl3, 125 MHz) δ 15.2 (CH3), 67.4 (6CH2), 70.5 (5CH), 71.6 (2CH),
71.7 (CH2‒Ph), 72.0 (CH2‒Ph), 73.4 (CH2‒Ph), 82.4 (CH‒NO2), 82.6
(3CH), 83.8 (4CH), 127.8‒128.5 (15 CHar), 137.6 (CIVar), 137.7
(CIVar), 138.0(CIVar); m/z calcd for C28H32N2O6 [M + H]+ 493.2339,
found 493.2333.
(2R,3R,4R,5R)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-((R)-1-
nitroethyl)pyrrolidin-1-ol (16B, major diastereoisomer). According to
general procedure, obtained as major product after nitroethylation of
13 and purification of the resulting residue by chromatography on
silica gel (diethyl ether / petroleum ether 4:6); colorless oil; 1H NMR
(CDCl3, 500 MHz) δ 1.54 (d, 3J = 6.8 Hz, 3H, CH3), 3.61‒3.67 (m, 2H,
6CHaHb and 5CH), 3.72‒3.79 (m, 2H, 6CHaHb and 2CH), 3.97 (dd, 3J =
7.0 Hz, 3J = 2.5 Hz, 1H, 4CH), 4.08‒4.12 (m, 1H, 3CH); 4.42‒4.65 (m,
6H, 3 CH2‒Ph), 4.95‒5.01 (m, 1H, CH‒NO2), 5.98 (br s, 1H, OH),
7.30‒7.37 (m, 15H, 15 CHar). 13C NMR (CDCl3, 125 MHz) δ 16.7
(CH3), 66,7 (6CH2), 69.5 (5CH), 71.5 (2CH), 71.6 (CH2‒Ph), 71.8
(CH2‒Ph) and 73.4 (CH2‒Ph), 83.2 (3CH), 83.3 (CH‒NO2), 83.7
(4CH), 127.77‒128.51 (15 CHar), 137.3 (CIVar), 137.6 (CIVar) and
137.98 (CIVar); m/z calcd for C28H32N2O6 [M + H]+ 493.2339, found
493.2333.
(2R,3R,4R,5S)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-
(nitromethyl)pyrrolidin-1-ol (13aS). Present in the reaction mixture as
a minor product after nitromethylation of 13 and purification of the
resulting residue by chromatography on silica gel (diethyl ether /
petroleum ether 4:6); colorless oil; 1H NMR (CDCl3, 500 MHz) δ 3.18‒
3.22 (m, 1H, 5CH), 3.65‒3.68 (m, 2H, 6CH2), 3.76‒3.78 (m, 1H, 4CH),
3.82‒3.85 (m, 1H, 2CH), 4.06‒4.08 (m, 1H, 3CH), 4.38‒4.57 (m, 6H, 3
CH2‒Ph), 4.65 (dd, 2J = 10.0 Hz, 3J = 5.0 Hz, CHaHb‒NO2), 4.77 (dd,
2J = 10.0 Hz, 3J = 8.0 Hz, CHaHb‒NO2), 5.81 (br s, 1H, OH), 7.24‒
7.31 (m, 15H, 15 CHar); 13C NMR (CDCl3, 125 MHz) δ 67.4 (2CH),
69.3 (6CH2), 71.8 (CH2‒Ph), 71.9 (CH2‒Ph), 72.8 (CH2‒NO2), 72.9
(5CH), 73.5 (CH2‒Ph), 80.1 (3CH), 81.3 (4CH), 127,8 (CHar), 127.9
(CHar), 127.9 (CHar), 128.0 (CHar), 128.1 (CHar), 128.2 (CHar),
128.4 (CHar), 128.5 (CHar), 128.5 (CHar), 128.6 (CHar), 128.6
(CHar), 128.7 (CHar), 128.8 (CHar),137.2 (CIVar), 137.6 (CIVar) 137.8
(CIVar); m/z calcd for C27H30N2O6Na [M + Na]+ 501.2002, found
501.2008.
1-(1-Nitroethyl)-3,4-dihydroisoquinolin-2(1H)-ol
(14A,
minor
diastereoisomer). According to general procedure, obtained as minor
product after nitroethylation of 2 and purification of the resulting
residue by chromatography on silica gel (diethyl ether / petroleum
ether 3:7); yellow oil; 1H NMR (CDCl3, 500 MHz) δ 1.37 (d, 3J = 6.6
Hz, 3H, CH3), 2.72‒2.81 (m, 1H, CHaHb‒N(OH)), 3.02‒3.10 (m, 2H,
CH2‒CH2‒N(OH)), 3.35‒3.43 (m, 1H, CHaHb‒N(OH)), 4.87‒4.91 (m,
2H, CH‒NO2 and CH‒N(OH)), 6.10 (br s, 1H, OH), 7.12‒7.25 (m, 4H,
4 CHar); 13C NMR (CDCl3, 125 MHz) δ 11.9 (CH3), 28.8 (CH2‒CH2‒
N(OH)), 54.5 (CH2‒N(OH)), 70.9 (CH‒N(OH)), 86.3 (CH‒NO2), 126.2
(CHar), 126.9 (CHar), 127.5 (CHar), 128.9 (CHar), 132.7 (CIVar),
135.7 (CIVar); m/z calcd for C11H15N2O3 [M + H]+ 223.1083, found
223.1078.
1-(1-Nitroethyl)-3,4-dihydroisoquinolin-2(1H)-ol
(14B,
major
diastereoisomer). According to general procedure, obtained as major
product after nitroethylation of 2 and purification of the resulting
residue by chromatography on silica gel (diethyl ether / petroleum
ether 3:7); yellow oil; 1H NMR (CDCl3, 500 MHz) δ 1.48 (d, 3J = 6.8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
(2R,3R,4R,5R)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-((R)-1-
nitropropyl)pyrrolidin-1-ol (17A, minor diastereoisomer). According
to general procedure, obtained as minor product after nitropropylation
of 13 and purification of the resulting residue by chromatography on
silica gel (diethyl ether / petroleum ether 4:6); colorless oil; 1H NMR
(CDCl3, 500 MHz) δ 0.91 (t, 3J = 7.3 Hz, 3H, CH3), 1.76‒1.83 (m, 1H,
CHaHb‒CH3), 1.95‒2.02 (m, 1H, CHaHb‒CH3), 3.54‒3.58 (m, 1H,
6CHaHb), 3.63‒3.78 (m, 3H, 6CHaHb, 2CH and 5CH), 4.02‒4.04 (m, 1H,
3CH), 4.06‒4.07 (m, 1H, 4CH), 4.40‒4.63 (m, 6H, 3 CH2‒Ph), 4.75‒
4.81 (m, 1H, CH‒NO2), 5.39 (br s, 1H, OH), 7.21‒7.35 (m, 15H, 15
CHar); 13C NMR (CDCl3, 125 MHz) δ 10.4 (CH3), 24.1 (CH2‒CH3),
67.6 (6CH2), 70.8 (5CH), 71.5 (2CH), 71.8 (CH2‒Ph), 71.9 (CH2‒Ph),
73.5 (CH2‒Ph), 82.6 (3CH), 84.3 (4CH), 90.7 (CH‒NO2), 127.8‒128.6
(15 CHar), 137.4 (CIVar), 137.7 (CIVar), 138.0 (CIVar); m/z calcd for
C29H34N2O6Na [M + Na]+ 529.2315, found 529.2321.
equiv),
2
N
HCl (0.560 mL, 1.12 mmol,
1
equiv) and
cyclohexanecarbonyl chloride (0.224 mL, 1.68 mmol, 1.5 equiv) and
was obtained as a pale yellow solid (183 mg, 60%); mp 104‒106 °C
(lit.[29] 111‒113°C); 1H NMR (CDCl3, 600 MHz) δ 1.03‒1.24 (m, 5H),
1.57‒1.87 (m, 5H), 2.05‒2.15 (m, 1H), 2.79‒2.88 (m, 2H), 3.05‒3.09
(m, 1H, CHaHb‒NH), 3.19‒3.23 (m, 1H, CHaHb‒NH), 3.37 (ddd, 2J =
14 Hz, 3J = 9.1 Hz, 3J = 4.5 Hz, 1H, CHaHb‒NH‒CO), 3.84 (ddd, 2J =
14.0 Hz, 3J = 6.4 Hz, 3J = 3.3 Hz, 1H, CHaHb‒NH‒CO), 4.19 (dd, 3J =
9 Hz, 3J = 2.7 Hz, 1H, CH‒NH), 5.75 (br s, 2H), 6.83 (br s, 1H, NH‒
CO), 7.09‒7.10 (m, 1H, CHar), 7.16‒7.19 (m, 2H, 2 CHar), 7.22‒7.24
(m, 1H, 1 CHar); 13C NMR (CDCl3, 150 MHz) δ 25.83 (CH2), 25.85
(CH2), 26.04 (CH2), 28.7 (CH2), 29.64 (CH2), 29.69 (CH2), 39.54
(CH2‒NH), 43.16 (CH2‒NH‒CO), 45.49 (CH‒CO), 55.3 (CH‒NH),
126.6 (CHar), 126.84 (CHar), 127.1 (CHar), 129.3 (CHar), 134.4
(CIVar), 134.6 (CIVar), 176.90 (CO).
(2R,3R,4R,5R)-3,4-bis(Benzyloxy)-2-((benzyloxy)methyl)-5-((R)-1-
nitropropyl)pyrrolidin-1-ol (17B, major diastereoisomer). According
to general procedure, obtained as major product after nitropropylation
of 13 and purification of the resulting residue by chromatography on
silica gel (diethyl ether / petroleum ether 4:6); colorless oil; 1H NMR
(CDCl3, 500 MHz) δ 0.96 (t, 3J = 7.3 Hz, 3H, CH3), 1.89‒1.95 (m, 1H,
CHaHb‒CH3), 2.08‒2.17 (m, 1H, CHaHb‒CH3), 3.54‒3.57 (m, 1H,
2CH), 3.63‒3.78 (m, 3H, 6CH2 and 5CH), 3.97 (dd, 3J = 7.1 Hz, 3J =
2.5 Hz, 1H, 4CH), 4.19 (dd, 3J = 7.1 Hz, 3J = 2.5 Hz, 1H, 3CH), 4.40‒
4.63 (m, 6H, 3 CH2‒Ph), 4.75‒4.81 (m, 1H, CH‒NO2), 5.22 (br s, 1H,
OH), 7.21‒7.35 (m, 15H, CHar); 13C NMR (CDCl3, 125 MHz) δ 10.8
(CH3), 23.7 (CH2‒CH3), 66.7 (6CH2), 69.4 (5CH), 71.1 (2CH), 71.6
(CH2‒Ph), 72.1 (CH2‒Ph), 73.5 (CH2‒Ph), 83.3 (3CH), 84.5 (4CH),
89.6 (CH‒NO2), 127.8‒128.5 (CAR), 137.7 (CIVar), 137.8 (CIVar), 138.1
(CIVar); m/z calcd for C29H34N2O6Na [M + Na]+ 529.2315, found
529.2321.
(+)-Praziquantel (PZQ) (3a). PZQ was prepared according to the
literature30,4b from 20 (55 mg, 0.202 mmol, 1 equiv), sodium hydroxide
(50% in water, 0.097 mL, 1.21 mmol, 6.0 eq), chloroacetyl chloride
(25 mg, 0.017 mL, 0.222 mmol, 1.1 eq) and Benzyltriethylammonium
chloride (4.6 mg, 0.020 mmol, 0.1 eq) and was obtained as a pale
yellow solid (35 mg, 56%); mp 133°C (lit.[31] 132‒134°C); 1H NMR
(CDCl3, 500 MHz) δ 1.24‒1.34 (m, 3H), 1.48‒1.60 (m, 2H), 1.72‒1.85
(m, 5H), 2.47 (tt, 3J = 11.5 Hz, 3J = 3.1 Hz, 1H), 2.77‒2.84 (m, 2H),
2.87‒3.02 (m, 2H), 4.08 (d, 2J = 17.5 Hz, 1H), 4.48 (d, 2J = 17.5 Hz,
1H), 4.79‒4.87 (m, 2H), 5.17 (dd, 2J = 13.1 Hz, 3J = 2.5 Hz, 1H),
7.18‒7.33 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 25.7, 28.7, 29.,
29.2, 39.1, 40.8, 45.1, 49.0, 55.0, 125.5 CHar, 127.0 CHar, 127.5
CHar, 129.3 CHar, 132.8 (CIVar), 134.7 (CIVar), 164.4 (CO), 174.8
(CO).
Supporting Information (see footnote on the first page of
this article) plots representing time-course of the aza-Henry
reaction with TBD or under PTC conditions, NMR monitoring
of retro-aza-Henry of 4 and isomerization of 13aR, NOESY
spectra for 12aR,13aR,13aS, copies of 1H- and 13C-NMR
spectra of nitrones 2, 5-9, 11-13, of products 3a, 4, 6a-13a,
14-20 and of dinitromethyl adducts.
(2R,3R,4S,5S)-2-(Aminomethyl)-5-((R)-1,2-
dihydroxyethyl)pyrrolidine-3,4-diol (18). To a solution of 12aR (106
mg, 0.333 mmol, 1 equiv) in dry methanol (5 mL) under argon was
added 10 wt. % Pd/C (35 mg, 0.033 mmol, 0.1 equiv) and 6 N HCl (1
mL). The suspension was stirred 48 h under hydrogen (1 bar) then
filtered over Celite. The Celite was rinsed with methanol and the
filtrate was concentrated under reduced pressure to eliminate HCl.
Amberlyst A-26 resin (OH-) was added to the residue in solution in
methanol (5 mL) until reaching basic conditions, then the crude was
filtered and evaporated under reduced pressure. Purification of the
resulting residue on silica gel (CHCl3 / MeOH / NH4OH 0.8M 5:5:1)
afforded 18 as a yellow oil (25 mg, 39%). [훼]2퐷0 +3.6 (c 0.56, MeOH);
1H NMR (CD3OD, 500 MHz) δ 2.65 (dd, 2J = 12.8 Hz, 3J = 7.0 Hz, 1H,
CHaHb‒NH2), 2.81 (dd, 2J = 12.8 Hz , 3J = 5.0 Hz, 1H, CHaHb‒NH2),
2.88‒3.04 (m, 1H, 2CH), 3.08 (dd, 3J = 5.2 Hz, 3J = 4.0 Hz, 1H, 5CH),
3.53‒3.63 (m, 2H, 7CH2), 3.65‒3.71 (m, 2H, 3CH and 6CH), 3.87 (m,
1H, 4CH); 13C NMR (CD3OD, 125 MHz) δ 45.3 (CH2‒NH2), 65.5
(2CH), 65.6 (5CH), 65.7 (7CH), 72.8 (6CH), 74.3 (4CH), 75.1 (3CH); m/z
calcd for C7H17N2O4 [M + H]+ 193.1188, found 193.1189.
Acknowledgements
We thank the CNRS and Univ. Reims Champagne Ardenne
for financial support. GM is grateful to URCA and GRAND
REIMS for a doctoral allocation. We also thank Dr. E. Riguet,
Dr. Dominique Harakat, Anthony Robert and Freddy Vignibe
for their contribution to some aspects of this project.
(1,2,3,4-Tetrahydroisoquinolin-1-yl)methanamine
(19).
To
a
Keywords: nitrones • reactivity • aza-Henry • nitromethylation
• vicinal diamines
solution of 4 (289 mg, 1.39 mmol, 1 equiv) in dry methanol (8 mL)
under argon was added 10 wt. % Pd/C (148 mg, 0.139 mmol, 0.1
equiv) and 6 N HCl (2 mL). The suspension was stirred 24 h under
hydrogen (1 bar) then filtered over Celite. The Celite was rinsed with
methanol and the filtrate was concentrated under reduced pressure to
eliminate HCl. Amberlyst A-26 resin (OH-) was added to the residue in
solution in methanol (5 mL) until reaching basic conditions; filtration
and evaporation under reduced pressure afforded 1929 as a brown oil
(139 mg, 62%), which was used without further purification; 1H NMR
(CD3OD, 250 MHz) δ 2.84 (t, 3J = 5.6 Hz, 2H, CH2‒CH2‒NH), 3.07‒
3.28 (m, 4H, CH2‒NH, CH2‒NH2), 4.20 (dd, 3J = 9.5 Hz, 3J = 4 Hz,
1H, CH‒NH), 7.15‒7.26 (m, 4H, 4 CHar). 13C NMR (CD3OD, 125
MHz) δ 29.7 (CH2‒CH2‒NH), 39.6 (CH2‒NH), 44.3 (CH2‒NH2), 54.5
(CH‒NH), 127.5 (CHar), 127.5 (CHar), 128.3 (CHar), 130.7 (CHar),
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+
H]+
N-((1,2,3,4-Tetrahydroisoquinolin-1-yl)methyl)cyclohexane-
carboxamide (20). 20 was prepared according to the literature29 from
19 (0.181 g, 1.12 mmol, 1 equiv), pyridine (0.121 mL, 1.51 mmol, 1.35
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
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10.1002/ejoc.201801823
European Journal of Organic Chemistry
SHORT COMMUNICATION
Entry for the Table of Contents
Layout 2:
FULL PAPER
Text for Table of Contents (about 350 characters)
Comprehensive study of the addition of nitroalkanes to
nitrones was conducted. The reaction proved efficient with
TMAF or TBD as bases, in the presence of a large excess
of RCH2NO2. Phase-transfer catalysis gave also
acceptable yields. Nitroethane or nitropropane afforded
mixtures of isomerisable diastereomers. The reaction was
applied to the synthesis of biologically relevant
compounds.
Key topic : nitrone reactivity
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