Indium-mediated debromination of gem -bromonitroalkanes under mild conditions in aqueous medium

Article abstract of DOI:10.1055/s-0033-1339030

gem-Bromonitroalkanes are efficiently reduced into the corresponding dehalogenated products in excellent yields with indium metal in the presence of a palladium(0) catalyst and indium(III) chloride in aqueous medium. The addition of bromonitromethane to c

Full text of DOI:10.1055/s-0033-1339030

LETTER
▌1561
lIenttedr ium-Mediated Debromination of gem-Bromonitroalkanes under Mild
Conditions in Aqueous Medium
Indium-Mediated Debromination of gem-Bromonitroalkanes
Rita C. Acúrcio, 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: 15.03.2014; Accepted after revision: 08.04.2014
um-promoted procedure for the reduction of gem-bromo-
nitroalkanes that would avoid using highly toxic tri-n-
butyltin hydride.
Abstract: gem-Bromonitroalkanes are efficiently reduced into the
corresponding dehalogenated products in excellent yields with indi-
um metal in the presence of a palladium(0) catalyst and indium(III)
chloride in aqueous medium. The addition of bromonitromethane to
carbohydrate-derived aldehydes or imines, followed by debromina-
tion of the intermediate bromonitro compounds represents an ex-
tremely efficient method for the stereoselective preparation of
nitrosugars.
The very low first ionization energy of indium(0) makes
it an ideal candidate to be used in single-electron transfer
(SET) reactions.15 This property, together with its stability
toward oxygen and water, has prompted exhaustive stud-
ies focused on indium-mediated carbon–carbon bond-
forming reactions16 and reductions of functional groups.17
Various reactions in which a carbon–halogen bond is re-
duced by indium have been reported.18 However, to the
best of our knowledge, the indium-promoted transforma-
tion of gem-halonitroalkanes into nitroalkanes has not
been described to date.
Key words: reductive dehalogenation, indium, bromonitroalkanes,
nitroalkanes, nitrosugars
Nitroalkanes are important synthons for the preparation of
more complex molecules. Under basic conditions, they
readily form a nitronate anion that can undergo aldol reac-
tions with aldehydes and ketones (Henry reaction),1 or im-
ines (aza-Henry reaction),2 and additions to α,β-
unsaturated carbonyl compounds (Michael reaction).3
Moreover, a wide variety of other organic compounds can
be accessed by transformations of the nitro group into oth-
er chemical functionalities, such as amines,4 carbonyl
groups,5 hydroxylamines6 and oximes or nitriles.7
Herein, we describe a novel dehalogenation reaction of 2-
bromo-2-nitroalkan-1-ols and 2-bromo-2-nitroamines
promoted by indium metal in the presence of tetrakis(tri-
phenylphosphine)palladium(0) [Pd(PPh3)4] as the catalyst
and indium(III) chloride (InCl3) in aqueous medium.19
To determine the optimum reaction conditions, we first
used a model substrate, 2-bromo-1-cyclohexyl-2-nitroeth-
anol (1a), and various reagent systems (Scheme 1, Table
1).
gem-Bromonitroalkanes are useful analogues of nitroal-
kanes and have been employed in organic synthesis as
precursors of aliphatic nitro derivatives, with the aim of
improving diastereoselection and avoiding dimerization.8
For example, the enantioselective conjugate addition of
gem-bromonitroalkanes to α,β-unsaturated ketones fol-
lowed by debromination of the resulting products, afford-
ed the corresponding nitroalkanes with excellent
enantioselectivity.9 Similarly, debromination of the enan-
tiopure products arising from the addition of bromonitro-
methane to aldehydes or imines gave the corresponding
nitroalkanols10 or nitroamines,11 whilst preserving the ab-
solute configuration at the β-position. Radical dehaloge-
nation promoted by tri-n-butyltin hydride has been widely
used to transform gem-halonitroalkanes into nitroal-
kanes.12
OH
OH
NO2
NO2
Pd(PPh3)4, In, InCl3
Br
1a
2a
Scheme 1 Indium-mediated reductive debromination of 2-bromo-1-
cyclohexyl-2-nitroethanol (1a)
Thus, treatment of bromoalkanol 1a with indium powder
(200 mol%) and indium(III) chloride (50 mol%) in the
presence of tetrakis(triphenylphosphine)palladium(0) (2
mol%) in a 2:1 (v/v) mixture of tetrahydrofuran–water af-
forded the desired nitroalkane product 2a in 93% yield
(Table 1, entry 1).20,21
During our recent investigations on the use of bromonitro-
methane in organic synthesis,13 we became interested in
the use of gem-bromonitrosugars as precursors of the cor-
responding enantiopure nitrosugars. This, combined with
our long-term interest in the use of indium in organic
chemistry,14 prompted us to initiate a search for an indi-
The reaction did not occur in the absence of either indi-
um(III) chloride or indium (Table 1, entries 2 and 3). The
indium/indium(III) chloride reagent system in the absence
of Pd(PPh3)4 reduced the C–Br bond at a very low rate, re-
sulting in a poor yield of 2a (Table 1, entry 4). Employing
other solvent systems also led to poor results (Table 1, en-
tries 5–7). When zinc metal was used instead of indium,
the reaction did not proceed (Table 1, entry 8).
SYNLETT 2014, 25, 1561–1564
Advanced online publication: 13.05.2014
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9
3
6
-
5
2
1
4
1
4
3
7
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2
0
9
6
DOI: 10.1055/s-0033-1339030; Art ID: st-2014-d0230-l
© Georg Thieme Verlag Stuttgart · New York

1562
R. C. Acúrcio et al.
LETTER
The interest in this procedure lies in the better diastereose-
lection achieved on the addition of bromonitromethane to
aldehydes and imines, rather than on the addition of sim-
pler nitromethane. Thus, the addition of nitromethane to
sugar aldehydes13a–c,e or imines11a,13d,f gave moderate to
good diastereoselectivity, while the addition of bromoni-
tromethane resulted in excellent anti-selectivity.13d,g Ac-
cordingly, the sequence of bromonitromethane
addition/debromination would be predicted to afford the
anti-isomers with superior diastereoselection than the ad-
dition of nitromethane alone. In order to prove our hy-
pothesis, we explored the sequence of bromonitromethane
addition/debromination on several sugar-derived alde-
hydes and imines 3g–l. The corresponding nitrosugars
2g–l were obtained in good yields and with excellent dia-
stereoselectivities (Scheme 3, Table 3).24 The absolute
configurations were established by comparison with the
literature data on nitrosugars 2g–l.
Table 1 Optimization of the Conditions for the Synthesis of 1-Cyclo-
hexyl-2-nitroethanol (2a)
Entry
Reagentsa
Solvent
Yield
1
2
3
4
5
6
7
8
Pd(PPh3)4, In, InCl3
Pd(PPh3)4, In
THF–H2O
THF–H2O
THF–H2O
THF–H2O
DMF–H2O
MeOH–H2O
H2O
93%
NR
Pd(PPh3)4, InCl3
In, InCl3
NR
13%
32%
28%
21%
NR
Pd(PPh3)4, In, InCl3
Pd(PPh3)4, In, InCl3
Pd(PPh3)4, In, InCl3
Pd(PPh3)4, Zn, InCl3
THF–H2O
a Ratio of bromonitroalkanol/Pd(PPh3)4/metal/InCl3 = 1:0.02:2:0.5.
NR = no reaction.
The observed stereochemistry of products 2 can be ex-
plained by assuming Felkin–Ahn-type addition of the bro-
monitronate anion. The stereochemistry at the β-nitro
position is preserved during the dehalogenation reaction.
Given this satisfactory result (Table 1, entry 1), the indi-
um-mediated reductive elimination was applied to various
gem-halonitro compounds (Scheme 2, Table 2), the requi-
site starting materials being readily prepared by reactions
A mechanistic proposal for the debromination process is
of aldehydes or imines with bromonitromethane.10,11a,22 depicted in Scheme 4. Thus, treatment of gem-bromoni-
After aqueous work-up, the intermediate bromonitro de- troalkanes 1 with indium(I), generated in situ by the reac-
rivatives were submitted, without any further purification, tion of indium metal and indium(III) chloride, in the
presence of a catalytic amount of palladium(0) would gen-
erate indium nitronate intermediates 4, hydrolysis of
which would afford the corresponding nitroalkanes 2.
Even though the role of palladium(0) is not clear, it is
probably involved in some kind of palladium insertion
into the C–Br bond, which would facilitate the metalla-
tion.
to the debromination reaction.
As shown by the results compiled in Table 2, the
Pd(PPh3)4/In/InCl3 system was effective for the reductive
dehalogenation of various 2-bromo-2-nitro intermediates
in aqueous medium, affording the corresponding nitroal-
kanes 2a–f in good to excellent yields.23 Accordingly, the
combination of a sodium iodide catalyzed addition fol-
lowed by dehalogenation was an effective procedure for
the preparation of nitroalkanes from either aldehydes or
imines.
1) BrCH2NO2, NaI
2) Pd(PPh3)4, In, InCl3
Y
YH
NO2
H
sugar
sugar
1) BrCH2NO2, NaI
3
2
Y
2) Pd(PPh3)4, In, InCl3
YH
Scheme 3 Addition of bromonitromethane to sugar-derived alde-
hydes and imines 3g–l followed by an indium-mediated reductive de-
bromination
NO2
R
H
R
3
2
Scheme 2 Addition of bromonitromethane to aldehydes and imines
3 followed by an indium-mediated reductive debromination
In + 1/2 InCl3
YH
L
YH
H3O+
Table 2 Synthesis of Nitroalkanes 2a–f
YH
3/2 InCl
Pd(0)
In
Br
NO2
R
L
NO2
R
R
Entry
Substrate
R
Y
Product
Yield
NO2
2
1
4
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
c-C6H11
n-C7H15
Ph
O
O
O
O
2a
2b
2c
2d
2e
2f
93%
90%
51%
83%
72%
78%
Scheme 4 Mechanistic proposal for the conversion of 1 into 2
In summary, we have developed an easy, efficient and
general reductive debromination procedure for converting
gem-bromonitroalkanes into the corresponding nitroal-
kanes using a palladium(0) catalyst, indium metal and in-
dium(III) chloride. The reactions proceeded smoothly
i-Bu
c-C6H11 NPMPa
n-C7H15 NPMPa
a NPMP = N-p-methoxyphenyl
Synlett 2014, 25, 1561–1564
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indium-Mediated Debromination of gem-Bromonitroalkanes
1563
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Table 3 Synthesis of Nitrosugars 2g–l
Entry Substrate Sugar
Y
Product dr
Yielda
O
O
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1
3g
O
O
2g
2h
95:5 83%
O
O
O
O
2
3
4
3h
3i
>98:2 88%
O
NPMPb 2i
>98:2 69%
>98:2 81%
O
OBn
O
TBSO
3j
O
2j
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Synthesis 2003, 63.
O
O
O
5
6
3k
3l
NPMPb 2k
>98:2 65%
95:5 81%
BnO
O
2l
O
a Yield of isolated product after column chromatography based on the
starting aldehyde or imine 3.
b NPMP = N-p-methoxyphenyl
under mild conditions in neutral aqueous medium, pre-
serving the stereochemistry of any existing stereogenic
centers. In combination with the sodium iodide catalyzed
addition of bromonitromethane to aldehydes or imines,
the present method offers an efficient alternative for the
stereoselective preparation of nitrosugars.
Acknowledgment
Thanks are due to the University of Aveiro, Fundação para a Ciên-
cia e a Tecnologia (FCT) and FEDER for funding the Organic Che-
mistry Research Unit (project PEst-C/QUI/UI0062/2013) and the
Portuguese National NMR Network (RNRMN). R.S. thanks the
FCT for an ‘Investigador Auxiliar’ position.
(16) Allylations: (a) Araki, S.; Kamei, T.; Hirashita, T.;
Yamamura, H.; Kawai, M. Org. Lett. 2000, 2, 847. (b) Tan,
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Soc. 2003, 125, 2958. (c) Propargylations: Isaac, M. B.;
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(d) Alkynylations: Augé, J.; Lubin-Germain, N.;
Seghrouchni, L. Tetrahedron Lett. 2002, 43, 5255.
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(20) Nitroalkanes 2; General Procedure
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
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NaI (0.12 mmol, 0.15 equiv) was added to a stirred solution
of bromonitromethane (0.8 mmol, 1 equiv) and the
corresponding aldehyde 3 (0.8 mmol, 1 equiv) in THF
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1561–1564

1564
R. C. Acúrcio et al.
LETTER
(10 mL), and the resulting mixture was stirred at r.t. for 5 h.
After this period, the mixture was quenched with aq HCl (10
mL, 0.1 M) and extracted with Et2O (1 × 20 mL). The
combined extracts were washed with sat. aq Na2S2O3
solution (1 × 20 mL), dried over Na2SO4, filtered and the
solvent removed under reduced pressure to afford the crude
1-bromo-1-nitroalkan-2-ol. In metal (183 mg, 1.6 mmol),
InCl3 (88 mg, 0.4 mmol) and Pd(PPh3)4 (18 mg, 2 mol%)
were added to a solution of the 1-bromo-1-nitroalkan-2-ol
(0.8 mmol) in THF–H2O (2:1, 6 mL). After stirring the
mixture at r.t. for 12 h, it was quenched with HCl (3 mL,
1 M), diluted with H2O (25 mL) and extracted with Et2O
(3 × 25 mL). The combined organic extracts were dried over
Na2SO4, filtered and the solvent removed under reduced
pressure to afford the nitroalkanes 2.
(23) N-(1-Cyclohexyl-2-nitroethyl)-4-methoxybenzenamine
(2e)
Brown oil; Rf = 0.22 (hexane–EtOAc, 3:1). 1H NMR (300
MHz, CDCl3): δ = 6.76 (d, J = 9.0 Hz, 2 H), 6.65 (d, J = 9.0
Hz, 2 H), 4.72 (dd, J = 12.3, 5.2 Hz, 1 H), 4.46 (dd, J = 12.3,
7.4 Hz, 1 H), 4.08–4.04 (m, 1 H), 3.73 (s, 3 H), 2.73 (s, 11
H). 13C NMR (75 MHz, CDCl3): δ = 152.7 (C), 141.0 (C),
115.0 (2 × CH), 114.9 (2 × CH), 75.7 (CH2), 60.9 (CH), 55.7
(CH3), 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
C15H23N2O3: 279.1709; found: 279.1703.
(24) 7-Deoxy-1,2:3,4-di-O-isopropylidene-7-nitro-D-glycero-
β-D-galacto-heptopyranose (2g)
Yellow oil; Rf = 0.20 (hexane–EtOAc, 3:1); [α]D20 –49.4
(c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.49 (d,
J = 5.0 Hz, 1 H), 4.78 (apparent d, J = 11.2 Hz, 1 H), 4.65
(dd, J = 8.0, 2.5 Hz, 1 H), 4.51–4.47 (m, 2 H), 4.43 (dd,
J = 8.0, 2.0 Hz, 1 H), 4.34 (dd, J = 4.9, 2.5 Hz, 1 H), 3.73
(dd, J = 8.2, 2.0 Hz, 1 H), 2.89 (d, J = 5.9 Hz, 1 H), 1.51 (s,
3 H, CH3), 1.46 (s, 3 H, CH3), 1.37 (s, 3 H, CH3), 1.32 (s, 3
H, CH3). 13C NMR (75 MHz, CDCl3): δ = 109.6, 108.9,
96.2, 78.1, 70.6, 70.5, 70.1, 67.7, 67.4, 25.9, 24.8, 24.3. MS
(ESI): m/z (%) = 342 (24) [M + Na]+, 337 (100) [M + NH4]+,
320 (19) [M + H]+, 262 (48).
(21) 1-Cyclohexyl-2-nitroethanol (2a)
Yellow oil; Rf = 0.30 (hexane–EtOAc, 5:1). 1H NMR (300
MHz, CDCl3): δ = 4.45–4.33 (2 m, 3 H), 1.73–0.90 (m, 11
H). 13C NMR (75 MHz, CDCl3): δ = 79.3, 72.8, 41.4, 27.9,
26.1, 25.9, 25.7, 22.8.
(22) Concellón, J. M.; Rodríguez-Solla, H.; Concellón, C.;
García-Granda, S.; Díaz, M. R. Org. Lett. 2006, 8, 5979.
Synlett 2014, 25, 1561–1564
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