Ultrasound-assisted rapid reduction of nitroaromatics to anilines using gallium metal

Article abstract of DOI:10.1080/00397911.2020.1743317

The reduction of nitroaromatic compounds to anilines is widely used throughout organic synthesis. Typical methods of performing this transformation utilize hydrogenation over a pyrophoric catalyst or a finely divided reducing metal, which often affords heterogeneous mixtures that are difficult to purify. Herein, we report for the first time the use of gallium metal as a reducing agent in organic synthesis. The reaction proceeds under aerobic conditions and affords homogeneous mixtures for a convenient workup. Using this method, twelve anilines were obtained in 33% to quantitative yields with short reaction times of 10-60 minutes.

Full text of DOI:10.1080/00397911.2020.1743317

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Ultrasound-assisted rapid reduction of
nitroaromatics to anilines using gallium metal
Ian Bento, Mabel Bernaldez, Ryden Noguchi & Joel Kawakami
To cite this article: Ian Bento, Mabel Bernaldez, Ryden Noguchi & Joel Kawakami (2020):
Ultrasound-assisted rapid reduction of nitroaromatics to anilines using gallium metal, Synthetic
Communications, DOI: 10.1080/00397911.2020.1743317
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2020.1743317
Ultrasound-assisted rapid reduction of nitroaromatics to
anilines using gallium metal
Ian Bento, Mabel Bernaldez, Ryden Noguchi, and Joel Kawakami
Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu, HI, USA
ABSTRACT
ARTICLE HISTORY
The reduction of nitroaromatic compounds to anilines is widely used
throughout organic synthesis. Typical methods of performing this
transformation utilize hydrogenation over a pyrophoric catalyst or a
finely divided reducing metal, which often affords heterogeneous
mixtures that are difficult to purify. Herein, we report for the first
time the use of gallium metal as a reducing agent in organic synthe-
sis. The reaction proceeds under aerobic conditions and affords
homogeneous mixtures for a convenient workup. Using this method,
twelve anilines were obtained in 33% to quantitative yields with
short reaction times of 10-60 minutes.
Received 18 October 2019
KEYWORDS
Aniline; gallium; metal;
nitroaromatic; reducing;
reduction; ultrasound
GRAPHICAL ABSTRACT
Introduction
The reduction of nitroaromatics to anilines remains an interesting organic transform-
[
1a]
[1b,c]
ation mediated by metals
or nonmetals.
The need for an aerobic and non-
pyrophoric condition led to the investigation of methods involving indium as the
[
2]
reducing metal. Nitroaromatic reduction using indium produced minor amounts of
anilines and mostly unreacted starting material. In addition, the crude reaction mixture
afforded a colloidal, heterogeneous suspension making for a difficult workup, a problem
[
3]
[4]
[5]
often observed using tin, aluminum, zinc and iron as the reducing metal. We
[
6a–d]
were intrigued to find scarce reports for using gallium,
a lighter metal within the
same group as indium, as the reducing metal and no report of it for the reduction of
nitroaromatic compounds.
CONTACT Joel Kawakami
jkawakam@chaminade.edu
Natural Sciences and Mathematics, Chaminade University
of Honolulu, Honolulu, HI 96816, USA.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
I. BENTO ET AL.
Table 1. The reduction of nitroaromatic compounds to afford anilines using gallium in acidic etha-
nolic solution.
1
2
3
a
b
Entry
R
R
R
Method
Time (min.)
Yield
1
2
3
4
5
6
7
8
9
H
H
Me
H
Cl
H
H
H
H
H
Me
H
H
H
Br
I
A
A
B
C
C
C
C
C
B
C
C
C
10
15
15
20
15
20
50
15
20
30
50
60
Quant
Quant
85%
79%
99%
82%
68%
93%
99%
73%
79%
33%
H
Me
H
H
H
H
H
H
H
CN
CH
2
CN
OH
OBn
1
1
1
a
0
1
2
H
H
H
H
H
CO
2
Me
Ac
Nitroaromatic compounds were suspended in 1.5 N HCl in EtOH with 4 equiv. of Ga metal and sonicated until a homo-
geneous mixture was obtained. Work-up proceeded by (A) neutralization with NaOH and sonication followed by
extraction with DCM; (B) neutralization with 2 M phosphate buffer (pH ¼ 7.6) followed by extraction from Rochelle’s
salt (aq) with DCM; (C) Neutralization with NaOH followed by extraction from Rochelle’s salt (aq) with DCM.
b
Isolated yields after chromatography on silica gel
Results and discussion
Initial attempts to use gallium in the reduction of nitroaromatic compounds produced
only minute amounts of the aniline product with the bulk of the reaction material con-
sisting of unreacted gallium metal. The use of acid to dissolve the metal was not suc-
[
7]
cessful. However, the use of an acid with sonication resulted in rapid dissolution of
the gallium metal with complete conversion of nitroaromatic compounds to anilines in
high yields. This reaction requires 4 equivalents of gallium metal, dissolved in 1.5 N
HCl in ethanol as the optimized conditions. Critical to the success of the reaction was
the complete dissolution of the gallium metal through ultrasonication. The dissolved
gallium species in excess has yet to be elucidated. Attempts to substitute ethanol for
water failed due to the insolubility of the nitroaromatic starting materials. Also, dimin-
ishing the concentration of HCl or substitution with formic, trifluoroacetic, p-toluene-
sulfonic or triflic acids resulted in lower yields of the aniline product. Replacing gallium
with indium under these optimized conditions failed to afford appreciable amounts of
the aniline product. The optimized conditions were applied to an array of nitroaromatic
compounds (Table 1). The reduction of nitroarenes proceeded rapidly. Product yields
were slightly lower for substrates bearing an electron withdrawing substituent (entries 7,
11 and 12). Chemoselectivity was observed in the reduction of nitro groups in the pres-
ence of a halogen atom (entries 4–6), a cyano group (entries 7 and 8), and a benzyl
ether, or an ester (entries 10 and 11). The reduction proceeded well in the presence of a
phenol functional group (entry 9). A slight decrease in yield is observed from the
increased steric demand of an ortho methyl group (entry 3) relative to its less hindered
meta and para counterparts (entries 1 and 2). The moderate yield observed for the

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SYNTHETIC COMMUNICATIONS
3
Scheme 1. Tandem in-situ nitro reduction followed by reductive amination.
Scheme 2. Nitro reduction of indoles. Reduction of 7 was performed on a gram-scale.
reduction of a nitro group in the presence of a ketone (entry 12) was primarily ascribed
to the subsequent reductive amination with the aniline product. The simultaneous imine
formation represents a limitation to this method. However, this side reaction inspired
us to develop a creative tandem in-situ amination reaction as evidenced by performing
the reduction of 3-nitrochlorobenzene in the presence of benzaldehyde (Scheme 1). The
aqueous work up was optimized to afford a homogeneous biphasic extraction using
DCM, avoiding a difficult heterogeneous mixture.
The method was applied to several heteroaromatic compounds. The reaction pro-
ceeded well in the presence of indoles (Scheme 2). The reduction of nitroindoles 5 and
7
afforded the corresponding anilines in good yields. Aniline 8 was isolated in 58% yield
on a gram scale. Further scale up is feasible with several reaction vessels running in par-
allel in a single sonicator, all with rapid reaction times (<30 min).
Conclusion
The rapid reduction of nitroaromatic compounds with gallium as the reducing metal
afforded anilines in high yields, and was shown to tolerate several functional groups
susceptible to reduction. The reaction used non-pyrophoric reagents and did not require
the need for a scrupulous anhydrous solution or inert atmosphere conditions. Gallium
with its low melting point was easily handled as a molten liquid after heating in a warm
water bath. Unlike other metals such as aluminum, zinc and tin, the reduction with gal-
lium afforded a homogeneous solution for a less problematic workup.
Experimental
The following is a representative example. p-toluidine (2A): To a 25 mL round-bottom
flask containing molten gallium (313 mg, 4.48 mmol, 4.0 equiv.) were added 4-nitroto-
luene (154 mg, 1.12 mmol, 1.0 equiv.), EtOH (11.2 mL), and 12 N HCl (aq) (1.4 mL).

4
I. BENTO ET AL.
The flask was sonicated at r.t. for 15 min. The reaction mixture was basified with
.74 M NaOH (aq) (8 mL), and sonicated for 10 min at r.t. to break up any precipitate
2
formed. The reaction mixture was transferred to a 125 mL separatory funnel, diluted
with water (20 mL) and extracted with DCM (3 ꢀ 20 mL). The combined extracts were
dried over anhydrous Na SO , passed through a short plug of silica gel, and solvent was
2
4
removed by rotary evaporation to afford a colorless solid as the product (2A) in quanti-
1
tative yield. H NMR (300 MHz, CDCl ) d 6.97 (d, J ¼ 8.3 Hz, 2H), 6.61 (d, J ¼ 8.3 Hz,
3
þ
2
H), 3.53 (br s, 2H), 2.24 (s, 3H) ppm. ESI-MS (m/z): 108.4 [M þ H] .
1
Supporting Information: Full experimental detail, H spectra, MP, and LCMS-FIA
þ
(
ESI ) can be found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
We would like to thank Hawai’i Pacific University of the use of their nuclear magnetic resonance
instrument. Also, our thanks to Dr. Paul Helquist at University of Notre Dame and Dr. David
Kingston at Virginia Tech for useful commentaries while preparing our manuscript.
Funding
The work was supported by grants from the Alana Dung Research Foundation and NIH NIGMS
INBRE under [Award number: P20GM103466].
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