Preparation of indium nitronates and their Henry reactions

Article abstract of DOI:10.1039/c4ob01468e

Indium nitronates were readily prepared from commercially available nitroalkanes by transmetallation of the corresponding lithium nitronates with indium salts. The Henry reaction of this indium organometallics with aldehydes afforded β-nitroalkanols in moderate to high yields. The use of chiral sugar aldehydes furnished the corresponding carbohydrate-derived β-nitroalkanols with excellent stereoselectivity.

Full text of DOI:10.1039/c4ob01468e

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Preparation of indium nitronates and their Henry
reactions†
Cite this: Org. Biomol. Chem., 2014,
12, 8593
Raquel G. Soengas,* Rita Acúrcio and Artur M. S. Silva*
Received 12th July 2014,
Accepted 11th September 2014
DOI: 10.1039/c4ob01468e
www.rsc.org/obc
Indium nitronates were readily prepared from commercially avail- and indium powder.9 The approach is very simple from the
able nitroalkanes by transmetallation of the corresponding lithium experimental point of view and, as bases are not required, it is
nitronates with indium salts. The Henry reaction of this indium not subject to the limitations of the classical Henry reaction.
organometallics with aldehydes afforded β-nitroalkanols in mode- In addition, reaction of aldehydes and hindered α,α-dialkyl-
rate to high yields. The use of chiral sugar aldehydes furnished the bromonitro alkanes afforded the corresponding 1,1-alkyl-1-
corresponding carbohydrate-derived β-nitroalkanols with excel- nitroalkan-2-ols in good yields. However, the application of
lent stereoselectivity.
this methodology is limited by the difficult access to α-bromo-
nitroalkanes: just a few are commercially available and they are
considerably more expensive than nitroalkanes.
The preparation of organoindium reagents has attracted
the attention of organic chemists, due to their low toxicity10
and their synthetic utility for carbon–carbon bond for-
mation.11 The synthesis of organoindium reagents can be
achieved not only by reaction between an organic halide and
an indium metal12 but also by reaction of aluminum,13 mag-
nesium,14 or lithium15 organometallics with indium halides.
In this paper we report a new and straightforward preparation
of indium nitronates from nitroalkanes via reaction of the
corresponding lithium nitronates with indium trichloride and
their Henry reactions with carbonyl compounds.
Introduction
The nitro-aldol reaction, often known as the Henry reaction, is
a powerful carbon–carbon bond-forming reaction.1 The classi-
cal Henry reaction, which involves the base-catalysed reaction
of nitroalkanes and aldehydes, has been widely used in syn-
thesis.2 Nevertheless, the classical nitro-aldol reaction does
suffer from some important drawbacks:3 (1) poor stereochemi-
cal control, due to the reversibility of the reaction;4 (2) low
yields, mainly when either the starting carbonyl compound or
the resulting 2-nitro alcohols are base-sensitive; (3) sensitive-
ness to steric factors, causing sterically hindered nitro alkanes
to be less reactive, usually failing to give the desired nitro-aldol
products in good yields.5 Hence, the nitroaldol condensation Results and discussion
of α,α-dialkylnitroalkanes6 has not been widely used in
In our preliminary studies, the reaction of nitromethane 1a
organic synthesis, despite the usefulness of the resulting 1,1-
alkyl-1-nitroalkan-2-ols.7
with benzaldehyde 2a was assessed. Thus, the lithium nitro-
nate generated by the reaction of nitromethane 1a and n-BuLi
was readily transmetalated with indium trichloride in THF at
−78 °C to give the corresponding indium nitronate. Further
reaction with benzaldehyde gave the β-nitroalkanol 3a in 71%
yield (Table 1, entry 1).16
As shown by the results compiled in Table 1, under the
above conditions, aromatic aldehydes 2b–d, linear aldehydes
2e–f and alicyclic aldehyde 2g were efficiently converted into
their corresponding β-nitroalkanols (Table 1, entries 2–7).
High yields were obtained, except for the electron-rich aryl
aldehyde 1b, which, as expected, proved to be substantially
less reactive and yielded the corresponding adduct 3c in only
39% yield (Table 1, entry 2). This process tolerates a broad
In order to circumvent these limitations, there is recent
interest in the development of alternative procedures for the
preparation of 2-nitroalkan-1-ols that obviate the use of bases.8
Our group reported a promising and convenient alternative to
the classical nitroaldol (Henry) reaction, consisting of the
addition of indium nitronates to aldehydes where indium
nitronates were generated in situ from α-bromonitroalkanes
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal.
E-mail: artur.silva@ua.pt, rsoengas@ua.pt; Fax: +351 234 370084;
Tel: +351 234 370714
†Electronic supplementary information (ESI) available: Full experimental details
and NMR spectra for compounds 3. See DOI: 10.1039/c4ob01468e
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Table 1 Synthesis of β-nitroalkanolsa
Entry
1
R1
R2
2
R3
3
syn/antib
Yieldc (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
—
—
—
—
—
—
—
71
39
81
75
85
69
83
4-MeO-C6H4
4-CN-C6H4
2-NO2-C6H4
n-C7H15
CO2Et
2g
c-C6H12
3g
8
1a
H
H
2h
3h
—
63
9
1b
1c
CH3
CH3
2a
2e
Ph
3i
3j
—
—
58
55
10
n-C7H15
11
1d
2i
H
3k
—
71
12
13
14
15
1e
1ed
1e
1f
CH3
CH3
CH3
CH2OBn
H
H
H
H
2a
2a
2g
2a
Ph
Ph
c-C6H12
Ph
3l
3l
3m
3n
33/67
33/67
27/73
30/70
60
59
79
61
a Reactions were carried out with the appropriate nitroalkane (3 mmol), indium trichloride (1 mmol), n-butyllithium (3 mmol), and the aldehyde
(2 mmol) overnight at room temperature. b Determined by 1H NMR. c Isolated yield. d Ethanol was added (3 mmol) before the coupling with the
aldehydes.
scope of functional groups, including a cyano group (Table 1,
entry 3), a nitro group (Table 1, entry 4) or an ester group
(Table 1, entry 6). Moreover, the reaction of nitromethane and
formyl chromone 2h afforded exclusively the corresponding
Henry adduct in good yield, and the 1,4-addition product was
not detected in the crude reaction mixture (Table 1, entry 8).17
In subsequent experiments aimed at extending these studies
to include other nitroalkanes, hindered 1,1′-dialkylnitro-
alkanes were considered first. Thus, the reaction of 2-nitropro-
pane 1b and nitrocyclopentane 1c with benzaldehyde 2a and
octanal 2e, respectively, afforded the corresponding β-nitroalk-
anols 3i and 3j in good yields (Table 1, entries 9 and 10). It is
also worth mentioning the good results obtained by the reac-
tion of nitrocyclohexane 1d with solid paraformaldehyde.
Under these conditions, the hydroxymethylated product 3k
was obtained in 71% yield (Table 1, entry 11).
The addition of nitroethane 1e to aldehydes resulted in
moderate anti-selectivity (Table 1, entries 12 and 14), identical
to those obtained when nitroethane indium nitronate was gen-
erated from bromonitroalkanes and indium(0).9c Similarly, the
reaction of indium nitronate, derived from ethyl O-benzyl-
nitroethanol 1f, with benzaldehyde 2a afforded the corres-
ponding nitroalkanol 3k in good yield and moderate anti-
selectivity (Table 1, entry 15).18
Scheme 1 Proposed mechanism for the synthesis of β-nitroalkanols 3.
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The observed anti-selectivity could be explained according
to a chelation-control model. According to our proposition,
indium metallation of intermediate lithium nitronate 4,
readily generated from nitroalkene 1 and n-butyllithium,
renders specie 5 (Scheme 1). For the reaction of intermediate 5
with aldehydes, we suggest intramolecular chelation of the
metallic centre producing a rigid chair-like state.
Table 2 Synthesis of (E)-2-(2-nitrovinyl)phenols
The predominant formation of the anti-isomers over
the syn-isomers could be explained based on the higher
stability of the pseudochair transition state I leading to the
anti-isomer.19
In contrast to lithium organometallics, organoindium
reagents are known to be tolerable to active hydrogen. In order
to demonstrate the intermediacy of indium nitronates, ethanol
was added to the reaction mixture before the coupling with the
aldehyde. In this case, neither the yield nor the diastereo-
selectivity decreased (Table 1, entry 13). In a further experi-
ment aimed to confirm the intermediacy of indium nitronates
and their stability to active hydrogen, the reaction of nitro-
methane 1a and hydroxyaldehydes was investigated. Unexpect-
edly, the reaction of nitromethane 1a with salicylaldehyde 2j
afforded (E)-2-(2-nitrovinyl)phenol 6a in a 73% yield (Table 2,
entry 1). The extension of this reaction to 2-hydroxybenzalde-
hydes 2k and 2l gave the corresponding (E)-2-(2-nitrovinyl)
phenols 6b and 6c, respectively (Table 2, entries 2 and 3). 2-(2-
Nitrovinyl)phenols have been used as substrates in sequential
Michael and acetalization reactions for the preparation of
4-nitromethylchromans, which have wide range of uses in
pharmaceutical chemistry.20 However, the methods described
for their synthesis to date only gave low to moderate yields,
limiting their usefulness as starting materials in the synthesis
of drug intermediates. The present methodology is a con-
venient alternative to the diastereoselective synthesis of (E)-2-
(2-nitrovinyl)phenols in good yields.
Entry
2
R1
R2
6
E/Z
Yielda (%)
1
2
3
2j
2k
2l
H
Cl
H
H
H
OMe
6a
6b
6c
>98 : 2
>98 : 2
>98 : 2
73
78
62
a Isolated yield.
Scheme 2 Proposed mechanism for the synthesis of (E)-2-(2-nitrovi-
nyl)phenols 6.
Table 3 Synthesis of chiral sugar-derived β-nitroalkanols
Entry
1
1
R1
H
R2
H
2
R3
3
1R/1Sa
2R/2Sa
Yieldb (%)
71
1a
2m
3o
89/11
—
2
1a
H
H
2n
2o
3p
87/13
—
75
3
4
1c
1e
3q
3r
90/10
96/4
—
52
67
CH3
H
15/85
a Determined by 1H NMR. b Isolated yield.
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A plausible mechanism would involve elimination of the
intermediate indium alcoholate 7 by the action of the 2-alkoxy
group, producing (E)-nitroalkene 6a (Scheme 2).
H. Hattori, Appl. Catal., A, 2003, 247, 65–74; (h) R. Ballini,
D. Fiorini, M. V. Gil and A. Palmieri, Tetrahedron, 2004, 60,
2799–2804.
The satisfactory results obtained in the synthesis of racemic
nitro alcohols 3 prompted us to test the usefulness of this
methodology for the synthesis of enantiopure 1-nitroalkan-2-
ols. Our studies were carried out with chiral sugar aldehydes
2m–o, which upon reaction with indium nitronates of nitro-
alkanes 1 under the same reaction conditions as above, pro-
vided the corresponding 1-nitroalkan-2-ols 3o–r in moderate to
good yields and good diastereomeric ratios (see Table 3).21
The major diastereomers were always those predicted by
the Felkin–Anh model. Upon addition of nitroethane 1e, the
anti diastereoselectivity is also excellent (Table 3, entry 4).
In conclusion, we have developed a new route to form
indium nitronates directly from nitroalkanes by deprotonation
with n-BuLi followed by transmetalation with indium trichlo-
ride. This method provides easier access to indium nitronates
compared with the existing procedures that need α-bromo-
7 (a) D. Crich, K. Ranganathan, S. Rumthao and M. Shirai,
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stereoselectivity. The use of 2-hydroxybenzaldehydes allows
establishment of a new diastereoselective synthesis of (E)-2-(2-
nitrovinyl)phenols in good yields.
11 (a) Z.-L. Shen, S.-Y. Wang, Y.-K. Chok, Y.-H. Xu and
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and aldehydes. n-Butyllithium (1.6 M in hexane, 2.0 mL,
3.1 mmol) was added to a stirred solution of anhydrous
indium trichloride (221 mg, 1.0 mmol) and nitroalkane 1
(3.0 mmol) in THF (4 mL) at −78 °C. The mixture was
stirred for 10 min, after which time aldehyde 2 (2.0 mmol)
was added. The reaction mixture was warmed to room
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temperature and left overnight. The reaction was quenched
with 1 M HCl (10 mL), and the product was extracted with
diethyl ether (3 × 20 mL). The organic extracts were washed
with water and brine, and concentrated. The residue was
purified by flash column chromatography in mixtures of
ethyl acetate–hexane when necessary to obtain pure
nitroalkanols 3. The products 3a,9a 3b,9a 3c,9e 3d,8a 3e,9a
3f,2c 3g,9a 3i,9a 3k,9d 3l,9c 3m9c and 3n18 are known com-
pounds. 2-(1-Nitrocyclopentyl)octan-1-ol (3j): clear oil. 1H
NMR (CDCl3, ppm): 0.81 (t, J = 6.9 Hz, 3 H, –CH3),
1.16–1.20 (m, 12 H), 1.62–1.76 (m, 5 H), 2.02–2.12 (m, 1 H),
2.24–2.38 (m, 1 H), 2.46–2.58 (m, 1 H), 3.75 (d, 1 H, J =
10.3 Hz, H-1). 13C NMR (CDCl3, ppm): 14.1 (CH3), 22.6, 24.6,
24.8, 26.3, 29.2, 31.8, 32.5, 33.7, 35.6 (10 × CH2), 75.9 (CH),
103.6 (C). MS (ESI+) m/z (%) 244 ([M + H]+, 40); HRMS (ESI+)
calc. for [C13H26NO3]+ [M + H]+ 244.1907, found: 244.1925.
17 J. M. Rodríguez and M. D. Pujol, Tetrahedron Lett., 2011,
52, 2629–2632.
CH3, anti), 1.26 (s, 3 H, CH3, syn), 1.38 (s, 3 H, CH3, anti),
1.40 (s, 3 H, CH3, syn), 1.54–1.67 (m, 8 H, syn + anti),
1.85–1.96 (m, 2 H, syn + anti), 2.10–2.20 (m, 2 H, syn +
anti), 2.35–2.42 (m, 2 H, syn + anti), 2.54–2.62 (m, 2 H,
syn + anti), 3.96–4.50 (m, 4 H, syn + anti), 4.25–4.28 (m,
2 H, syn + anti), 4.36–4.66 (m, 6 H, syn + anti), 5.84 (d, J =
3.8 Hz, 1 H, H-1, anti), 5.90 (d, J = 3.8 Hz, 1 H, H-1, syn),
7.16–7.32 (m, 10 H, Ar–H, syn + anti). 13C NMR (CDCl3,
ppm) major isomer: 23.8, 24.5 (2 × CH2), 26.4, 26.8 (2 ×
CH3), 33.4, 35.9 (2 × CH2), 72.2 (CH2), 72.8, 79.6, 81.4, 82.6
(4 × CH), 102.6 (C), 105.3 (CH), 112.0 (C), 128.0 (2 × CH),
128.4 (CH), 128.8 (2 × CH), 136.9 (C). MS (ESI+) m/z (%) 394
([M + H]+, 19); HRMS (ESI+) calc. for [C20H28NO7]+ [M + H]+
394, 1860, found: 394, 1852. 3-O-Benzyl-1,2-O-isopro-
pylidene-5-(1-nitroethyl)-α-D-xylofuranose (3r): clear oil.
1H-NMR (CDCl3, ppm): 1.24 (s, 6 H, 2 × CH3, syn + anti),
1.38 (s, 6 H, 2 × CH3, syn + anti), 1.48 (d, J = 6.8 Hz, 3 H,
CH3, anti), 1.55 (d, J = 6.8 Hz, 3 H, CH3, syn), 3.88–3.94 (m,
2 H, syn + anti), 4.02–4.07 (m, 2 H, syn + anti), 4.37–4.72
(m, 6 H, syn + anti), 5.82 (d, J = 3.7 Hz, 1 H, H-1, anti), 5.91
(d, J = 3.7 Hz, 1 H, H-1, syn), 7.18–7.32 (m, 10 H, Ar–H,
syn + anti). 13C NMR (CDCl3, ppm) major isomer anti: 11.4,
26.3, 26.9 (3 × CH3), 65.8 (CH), 72.3 (CH2), 68.5, 79.1, 80.9,
82.1, 83.8, 105.2 (6 × CH), 112.0 (C), 128.0 (2 × CH), 128.4
(CH), 128.8 (2 × CH), 137.1 (C). MS (ESI+) m/z (%) 354 ([M +
H]+, 22); HRMS (ESI+) calc. for [C17H24NO7]+ [M + H]+ 354,
1547, found: 354, 1552.
18 T. Nitabaru, A. Nojiri, M. Kobayashi, N. Kumagai and
M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 13860–13869.
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J., 1997, 3, 20–28.
20 D. B. Ramachary and R. Sakthidevi, Org. Biomol. Chem.,
2010, 8, 4259–4265.
21 The products 3o9a and 3p9a are known compounds. 3-O-
Benzyl-1,2-O-isopropylidene-5-(1-nitrocyclopentanyl)-α-D-xylo-
furanose (3q): clear oil. 1H-NMR (CDCl3, ppm): 1.23 (s, 3 H,
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