One-pot three-component barbier-type reaction for the synthesis of β-nitroamines

Article abstract of DOI:10.1055/s-0033-1339486

The combination of an aldehyde, bromonitromethane, and p-methoxyaniline in the presence of tin(II) chloride and titanium tetraethoxide allows a straightforward access to β-nitroamine derivatives. The use of solid paraformaldehyde results in the amino methylation of methylnitronate. On the other hand, chiral sugar-derived aldehydes furnished the corresponding nitrosugars in high yields and stereoselectivities.

Full text of DOI:10.1055/s-0033-1339486

LETTER
ꢀ1949
letter
One-Pot Three-Component Barbier-Type Reaction for the Synthesis of
ꢁ-Nitroamines
Barbier-Type Reaction for the Synthesis of ꢁ-Nitroamines
Raquel G. Soengas,* Artur M. S. Silva*
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt; E-mail: rsoengas@ua.pt
Received: 24.06.2013; Accepted: 30.06.2013
In this context, three-component Grignard–Barbier-type
reactions involving carbonyl compounds, nitrogen nu-
cleophiles, and nitronates as carbon nucleophiles would
be particularly attractive in assembling carbon–carbon
Abstract: The combination of an aldehyde, bromonitromethane,
and p-methoxyaniline in the presence of tin(II) chloride and titani-
um tetraethoxide allows a straightforward access to ꢀ-nitroamine
derivatives. The use of solid paraformaldehyde results in the amino
methylation of methylnitronate. On the other hand, chiral sugar-de- bonds around the carbonyl group and directly generating
rived aldehydes furnished the corresponding nitrosugars in high
a ꢀ-nitroamine function.
yields and stereoselectivities.
Herein we describe the first one-pot Barbier-type reaction
Key words: one-pot reaction, ꢀ-nitroamine, bromonitroalkane,
of aldehydes and bromonitromethane in the presence of an
aza-Henry reaction, aminomethylation
amine such as p-methoxyaniline to provide ꢀ-nitroamines.
This methodology should prove particularly useful in cas-
es where the intermediates imines are unstable.
The aza-Henry (or nitro-Mannich) reaction involves nu-
Since the indium-mediated reaction of aldehydes and bro-
monitroalkanes was reported,12 chemoselectivity has been
an important issue. For practical reasons, is not recom-
mended to use an excess of the amine, so a non-negligible
concentration of aldehyde is expected in the equilibrium
mixture. In order to minimize the concentration of alde-
hyde in the equilibrium we decided to investigate the use
titanium tetraethoxide as additive.13
cleophilic addition of nitroalkanes to imines,1 and results
in the formation of a carbon–carbon bond with concomi-
tant generation of a ꢀ-nitroamine function. From the re-
sulting ꢀ-nitroamines, a wide variety of other organic
compounds can be derived by functional transformations
of the nitro group into other chemical functionalities, such
as amines,2 carbonyl groups,3 hydroxylamines4 and ox-
imes or nitriles.5 In this regard, significant efforts have
been devoted over the years to improve yields and stereo-
control.6 Surprisingly, significant success has not been
achieved until recent years and only a few aza-Henry re-
actions have been reported that give good results for a
broad range of reaction partners. We have been particular-
ly interested in the Barbier-type addition of bromonitroal-
kanes to imines, an alternative to the classic aza-Henry
reaction which performs better in terms of yields, diaste-
reoselectivity and substrate scope.7 Continuing our inter-
est in this topic, we aimed at the development of a one-pot
reaction for the direct synthesis of ꢀ-nitroamines from al-
dehydes.
In a preliminary experiment, a mixture of benzaldehyde
(1a; 0.50 mmol), p-methoxyaniline (3; 0.45 mmol), and
indium metal (0.50 mmol) in THF (2 mL) was stirred at
room temperature in the presence of titanium tetraethox-
ide (0.50 mmol). After one hour, bromonitromethane (2)
was added (0.60 mmol) and the mixture was sonicated for
six hours. These conditions afforded a rather sluggish re-
action, with the crude product mixture containing only
traces of the desired ꢀ-nitroamine 4a, along with some ꢀ-
nitroalkanol 5a and unreacted benzaldehyde (1a). Given
this unsatisfactory result and taking into account that
tin(II) chloride can also promote the addition of bromoni-
tromethane to imines,14 we decided to investigate the use
of tin(II) chloride without sonication for the addition of
the bromonitromethane (Scheme 1). Thus, a mixture of
benzaldehyde (1a; 0.50 mmol), p-methoxyaniline (3; 0.45
mmol), and tin(II) chloride (0.50 mmol) in THF (1 mL)
was stirred at room temperature in the presence of an ad-
ditive. After one hour, bromonitromethane (2) was added
(0.50 mmol) and the mixture was stirred for a further four
hours (Table 1).
During the past several years, interest in the development
of one-pot reactions for the sustainable synthesis of organ-
ic compounds has grown exponentially.8 The use of one-
pot conversions, without intermediate recovery steps,
drastically reduces operating time and costs as well as
consumption of solvents and energy.9 Among the avail-
able one-pot transformations, multicomponent10 Gri-
gnard–Barbier-type reactions are attracting much interest,
on account of their usefulness in the preparation of allyl-
amines and propargylamines.11
In the absence of any additive (Table 1, entry 2), a large
amount of the corresponding ꢀ-nitroalcohol 5a was de-
tected along with the desired ꢀ-nitroamine 4a. The addi-
tion of a drying agent such as sodium sulfate (Table 1,
entry 3) led to an almost 1:1 mixture of ꢀ-nitroamine 4a
and ꢀ-nitroalcohol 5a. Gratifyingly, it was found that tita-
nium(IV) salts effectively promoted the reaction to afford
SYNLETT 21709013, 2415, 1949–1952
Advanced online publication: 07.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339486; Art ID: ST-2013-D0580-L
© Georg Thieme Verlag Stuttgart · New York

1950
R. G. Soengas, A. M. Silva
LETTER
OMe
Table 2 Synthesis of ꢀ-Nitroamines 4b–g from Aldehydes 1b–g
OMe
+
Br
NO2
OH
[M]
Entry
1
R
4
Yield (%)a
2
additive
HN
NO2
O
Ph
THF
NO2
4a
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
p-CNC6H4
C6H11
i-Pr
4b
4c
4d
4e
4f
62
75
72
77
69
71
68
61
Ph
Ph
H
NH2
5a
3
1a
Scheme 1 One-pot reaction of bromonitromethane (2), benzalde-
hyde (1a) and p-methoxyaniline
(CH2)6Me
i-Bu
ꢀ-nitroamine 4a (Table 1, entries 4–7). The best results,
regarding both yield and chemoselectivity, were obtained
in the presence of two equivalents of titanium tetraethox-
ide and two equivalents of tin(II) chloride (Table 1, entry
7). The excellent chemoselectivity is noteworthy, since
full conversion of the aldehyde into the imine was not
achieved before the addition of bromonitromethane.
1g
1h
1i
Bn
4g
4h
4i
CO2Et
H
a Isolated yield of analytically pure compounds.
Table 1 Screening Conditions for the Metal-Promoted Addition of
Bromonitromethane (2) to Benzaldehyde (1a) in the Presence of p-
Methoxyaniline
the methylnitronate resulted leading to the formation of 2-
nitroethylamine 4g (Table 2, entry 8). In general, poly-
meric precursors of formaldehyde, such as paraformalde-
hyde, are poorly reactive but there are a few examples in
the literature in which paraformaldehyde is reactive
enough to be used directly, including the hydroxymethyl-
ation of nitroalkanes.17 To the best of our knowledge, this
is the first example of the monoaminomethylation of
methylnitronate. The nitro-Mannich aminomethylation of
nitroalkanes has long been known,18 although it has re-
ceived scant attention recently.19 The Mannich reaction on
nitromethane under classical conditions does not stop at
the monosubstitution stage, but instead results in disubsti-
tution. As a consequence, the synthesis of 2-nitroethyl-
amines as previously reported, required a multistep
procedure, involving Henry reaction of nitromethane with
formaldehyde, acid-catalyzed dehydration, and Michael
addition of an amine to the resulting nitroethylene.20
Entry Promoter (mol%) Additive (mol%)
4a (%)a 5a (%)a
1
2
3
4
5
6
7
In (100)
Ti(OEt)4 (100)
–
5
14
27
57
49
73
78
9
41
32
24
28
0
SnCl2 (100)
SnCl2 (100)
SnCl2 (100)
SnCl2 (100)
SnCl2 (100)
SnCl2 (100)
Na2SO4 (500)
Ti(OEt)4 (100)
Ti(Oi-Pr)4 (100)
Ti(OEt)4 (200)
Ti(OEt)4 (100)
0
a Conversion was determined by 1H NMR.
Given these satisfactory results, the generality of the na-
ture of the aldehyde was investigated (Table 2). Thus, a
mixture of the corresponding aldehyde 1b–i (0.50 mmol),
p-methoxyaniline (3; 0.45 mmol), tin(II) chloride (1.00
mmol) and titanium tetraethoxide (1.00 mmol) in THF (2
mL) was stirred at room temperature.15 After one hour,
bromonitromethane (2) was added (0.50 mmol) and the
mixture was stirred for further four hours. In all the cases,
the corresponding ꢀ-nitroamines 4b–i were obtained in
good yields (Scheme 2).16
The satisfactory results obtained in the synthesis of race-
mic ꢀ-nitroamines 4a–h and ꢀ-nitroethylamine 4i prompt-
ed us to test the usefulness of this methodology for the
synthesis of enantiopure ꢀ-nitroamines. Thus, the above
conditions were also applied to the reaction of chiral alde-
hydes 1j–l with bromonitromethane (2; Table 3). Indeed,
when the reaction was carried out in the presence of p-me-
thoxyaniline, tin(II) chloride, and titanium tetraethoxide
in the conditions described above, the corresponding ni-
troamines 4j–l were isolated in good yields (Scheme 3).21
OMe
Br
NO2
O
OMe
OMe
OMe
Br
NO2
SnCl2
2
SnCl2
Ti(OEt)4
2
HN
HN
Ti(OEt)4
O
THF
NO2
4b–i
NO2
THF
R
H
R
R
NH2
3
R
H
NH2
3
1b–i
1j–l
4j–l
major isomer anti
Scheme 2 Tin(II)-mediated addition of bromonitromethane (2) to al-
dehydes 1 in the presence of p-methoxyaniline (3)
Scheme 3 Tin(II)-mediated addition of bromonitroalkane 2 to chiral
sugar aldehydes 1h–j in the presence of p-methoxyaniline (3)
Interestingly, when the reaction was carried out with
formaldehyde in its polymeric form, aminomethylation of
Synlett 2013, 24, 1949–1952
© Georg Thieme Verlag Stuttgart · New York

LETTER
Barbier-Type Reaction for the Synthesis of ꢀ-Nitroamines
1951
Stereoselectivity in these cases was a major concern, since high stereoselectivity. This approach has many advantag-
the reaction was conducted in the presence of tin and tita- es, as it results in reductions in operating time and costs as
nium, both of which species could act as Lewis acids.22 well as consumption of solvents and energy. Moreover,
Despite our concerns, we observed the same diastereose- the procedure described herein is particularly useful in
lectivity as that previously reported for the aza-Henry- cases where the intermediates imines are unstable.
type addition of bromonitroalkanes to preformed p-me-
thoxyphenylimines.7 In all cases, nitroamines 4 were ob-
tained as mixtures of the anti and syn isomers in which the
Acknowledgment
Thanks are due to the University of Aveiro, Fundação para a Ciên-
cia e a Tecnologia (FCT), the European Union, QREN, FEDER and
COMPETE for funding the Organic Chemistry Research Unit (QO-
PNA) (project PEst-C/QUI/UI0062/2013) and the Portuguese Na-
tional NMR Network (RNRMN). R.S. thanks the FCT for an
‘Investigador Auxiliar’ position.
major isomer is the anti-ꢀ-nitroamine. The stereochemical
outcome of the reaction was determined by comparison of
spectroscopic data with those of previously characterized
diamines.
Table 3 Synthesis of Carbohydrate-Based ꢀ-Nitroamines 4j–l from
Sugar Aldehydes 1j–l
Supporting Information for this article is available online at
Entry
1
R
4
Yield Ratio
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimginrtSatonIuipfogtrimornat
(%)
anti/syn
O
References and Notes
TBSO
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1
1j
4j
62
5:1
O
O
O
O
O
2
3
1k
1l
4k
4l
75
72
4:1
3:1
O
OBn
O
O
O
O
(3) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
(4) García Ruano, J. L.; López-Cantarero, J.; de Haro, T.;
Alemán, J.; Cid, M. B. Tetrahedron 2006, 62, 12197.
(5) Czekelius, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2005,
44, 612.
a Isolated yield of analytically pure compounds.
The excellent anti diastereoselectivity obtained can be ex-
plained in terms of a lowering of the C–N antibonding or-
bital, which would bring about increased stabilization of a
Felkin–Anh antiperiplanar nucleophilic addition of the or-
ganotin species to the imine, as shown in Figure 1.23
(6) Marqués-López, E.; Merino, P.; Tejero, T.; Herrera, R. P.
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4339. (b) Rodríguez-Solla, H.; Concellón, C.; Alvaredo, N.;
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(11) Kouznetsov, V. V.; Vargas Méndez, L. Y. Synthesis 2008,
491.
MeO
Cl
Cl
O
Sn
N
H
–
O
+N
O
R
R
H
Figure 1 Felkin–Anh model for the attack on sugar imines
In summary, multicomponent reaction of a range of alde-
hydes, tin(II) chloride, p-anisidine, and bromonitrometh-
ane was found to afford ꢀ-nitroamines in high yields. The
use of formaldehyde in polymeric form results in the ami-
nomethylation of the methylnitronate anion. To the best of
our knowledge, this is the first example of such a mono-
aminomethylation reported in the literature. When applied
to chiral sugar-derived aldehydes, this methodology al-
lows the preparation of carbohydrate ꢀ-nitroamines with
(12) (a) Soengas, R. G.; Estévez, A. M. Eur. J. Org. Chem. 2010,
5190. (b) Soengas, R. G.; Estévez, A. M. Tetrahedron Lett.
2012, 53, 570. (c) Rodríguez-Solla, H.; Soengas, R. G.;
Alvaredo, N. Synlett 2012, 23, 2083. (d) Soengas, R. G.;
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Silva, A. M. S. Tetrahedron 2013, 69, 3425.
(13) González-Gómez, J. C.; Medjahdi, M.; Foubelo, F.; Yus, M.
J. Org. Chem. 2010, 75, 6308.
(14) Mahasneh, A. S.; Qaraqe, H. Z. Naturforsch., B 2005, 60b,
797.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1949–1952

1952
R. G. Soengas, A. M. Silva
LETTER
(15) General Procedure for the Synthesis of ꢁ-Nitroamines 4:
To a solution of the corresponding aldehyde (0.50 mmol) in
anhyd THF (1 mL), Ti(OEt)4 (1.00 mmol) was added,
followed by SnCl2 (1.00 mmol) and p-anisidine (0.45
mmol). After 1 h, bromonitromethane (0.50 mmol) was
added and the reaction mixture was stirred at r.t. over a
period of 4 h. The excess of Ti(OEt)4 was then decomposed
by the slow addition of a solution of brine. The resulting
suspension was filtered through a pad of Celite® and the pad
washed with EtOAc. The organic layer was separated and
washed with aq 1 M HCl, H2O, aq sat. solution of HNaCO3
and brine, dried over Na2SO4 and concentrated under
vacuum. The residue was purified by flash column
chromatography eluting with mixtures of EtOAc–hexane to
yield ꢀ-nitroamines 4.
(d, J = 8.9 Hz, 2 H, Ar), 6.61 (d, J = 7.2 Hz, 2 H, Ar), 4.32–
4.59 (m, 2 H), 3.76–3.86 (m, 5 H). 13C NMR (75 MHz,
CDCl3): ꢁ = 153.0 (C), 140.0 (C), 115.0 (2 × CH), 114.8 (2
× CH), 74.3 (CH2), 55.7 (OMe), 42.3 (CH2). MS (ESI+): m/z
(%) = 197 (100) [M + H]+, 180 (21), 90 (12). IR (neat): 3400,
1558, 1375 cm–1.
(17) (a) Otero, J. M.; Soengas, R. G.; Estévez, J. C.; Estévez, R.
J.; Watkin, D. J.; Evinson, E. L.; Nash, R. J.; Fleet, G. W. J.
Org. Lett. 2007, 9, 623. (b) Soengas, R. G.; Estévez, A. M.
Synlett 2010, 2625.
(18) Senkus, M. J. Am. Chem. Soc. 1946, 68, 10.
(19) (a) Geue, R. J.; Hambley, T. W.; Harrowfield, J. M.;
Sargeson, A. M.; Snow, M. R. J. Am. Chem. Soc. 1984, 106,
5478. (b) Supriya, S.; Raghavan, A.; Vijayaraghavan, V. R.;
Subramanian, J. Polyhedron 2007, 26, 3388.
(20) Heath, R. L.; Rose, J. D. J. Chem. Soc. 1947, 1486.
(21) Analytical Data of 3-O-Benzyl-5,6-dideoxy-1,2-O-
isopropylidene-5-p-methoxyphenylamino-6-nitro-ꢂ-D-
glucofuranose (4k): yellow oil; Rf 0.28 (hexane–EtOAc,
3:1); [ꢂ]D27 –9.2º (c = 0.6 in CHCl3). 1H NMR (500 MHz,
CDCl3): ꢁ = 7.12–7.34 (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), 4.44–4.59 (m, 3 H), 4.38–4.42 (m, 1
H), 4.17–4.24 (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). 13C NMR (125 MHz, CDCl3):
ꢁ = 153.3 (C), 139.3 (C), 136.9 (C), 128.4 (2 × CH), 128.0
(CH), 127.9 (2 × CH), 116.3 (2 × CH), 114.9 (2 × CH), 112.1
(C), 104.9 (CH), 81.9 (CH), 81.2 (CH), 79.9 (CH), 75.8
(CH2), 72.1 (CH2), 55.6 (Me), 51.9 (CH), 26.7 (Me), 26.2
(Me). MS (ESI+): m/z (%) = 445 (100) [M + H]+, 444 (1), 316
(5), 289 (1), 288 (21). HRMS (ESI+): m/z [M + H]+ calcd for
[C23H29N2O7]+: 445.1975; found: 445.1969. IR (neat): 3380,
1556, 1513, 1377, 1241 cm–1.
(16) As examples of the obtained ꢀ-nitroamines, we present the
analytical data:
4-Methoxy-N-(2-nitro-1-phenylethyl)benzenamine (4a):
brown oil; Rf 0.23 (hexane–EtOAc, 3:1). 1H NMR (300
MHz, CDCl3): ꢁ = 7.24–7.61 (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).
13C NMR (75 MHz, CDCl3): ꢁ = 153.1 (C), 139.6 (C), 137.9
(C), 129.2 (2 × CH), 128.5 (CH), 126.4 (2 × CH), 115.6 (2 ×
CH), 114.8 (2 × CH), 80.0 (CH2), 57.7 (CH), 55.6 (Me). MS
(ESI+): m/z (%) = 273 (4) [M + H]+, 213 (7), 212 (100), 124
(7). HRMS (ESI+): m/z [M + H]+ calcd for [C15H17N2O3]+:
273.1239; found: 273.1233. IR (neat): 3375, 1554, 1511,
1378, 1243 cm–1.
N-(1-Cyclohexyl-2-nitroethyl)-4-methoxybenzenamine
(4c): brown oil; Rf 0.22 (hexane–EtOAc, 3:1). 1H NMR (300
MHz, CDCl3): ꢁ = 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), 4.04–4.08 (m, 1 H), 3.73 (s, 3 H), 2.73 (s, 11
H). 13C NMR (75 MHz, CDCl3): ꢁ = 152.7 (C), 141.0 (C),
115.0 (2 × CH), 114.9 (2 × CH), 75.7 (CH2), 60.9 (CH), 55.7
(Me), 43.0 (CH), 34.7 (2 × CH2), 25.2 (CH2), 21.6 (2 × CH2).
MS (ESI+): m/z (%) = 279 (6) [M + H]+, 234 (19), 216 (100),
214 (28). HRMS (ESI+): m/z [M + H]+ calcd for
(22) It is known that the stereochemical outcome of the indium-
mediated allylation of N-tert-butanesulfinyl imines can be
highly dependent on the presence of Lewis acids or bases.
See: Lin, G.-Q.; Xu, M.-H.; Zhong, Y. W.; Sun, X.-W. Acc.
Chem. Res. 2008, 41, 831.
(23) (a) Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199.
(b) Anh, N. T.; Eisenstein, O.; Lefour, J.-M.; Dau, M.-E. J.
Am. Chem. Soc. 1973, 95, 6146. (c) Anh, N. T.; Eisenstein,
O. Nouv. J. Chim. 1977, 1, 61.
[C15H23N2O3]+: 279.1709; found: 279.1703. IR (neat): 3389,
1553, 1513, 1384, 1243 cm–1.
4-Methoxy-N-(2-nitroethyl)aniline (4i): orange oil; Rf 0.48
(hexane–EtOAc, 3:1). 1H NMR (300 MHz, CDCl3): ꢁ = 6.81
Synlett 2013, 24, 1949–1952
© Georg Thieme Verlag Stuttgart · New York