Applicability of aluminum amalgam to the reduction of arylnitro groups

Article abstract of DOI:10.1016/j.tetlet.2020.152575

An array of arylnitro compounds with various functionality were treated with freshly-prepared aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and disappearance of starting material occurring over 20–30 min. The workup of the reductions involves only removal of the insoluble by-products by filtration followed by concentration. Only in some cases is chromatography required to secure the pure product. The desired arylamines are furnished in quantities of 25–100 mg, which in some cases, could be taken on to the next reaction without further purification. Reductions of 4-nitrobenzyl derivatives of carbohydrates or nucleosides were selective in affording the corresponding 4-aminobenzyl products. To show applicability in click chemistry, selected aminobenzyl products are directly azidated to yield products that were then used in click reactions to afford the corresponding 1,2,3-triazoles.

Full text of DOI:10.1016/j.tetlet.2020.152575

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Applicability of aluminum amalgam to the reduction of arylnitro groups
Paige J. Monsen, Frederick A. Luzzio
PII:
S0040-4039(20)31074-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152575
TETL 152575
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 September 2020
11 October 2020
15 October 2020
Please cite this article as: Monsen, P.J., Luzzio, F.A., Applicability of aluminum amalgam to the reduction of
arylnitro groups, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152575
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Applicability of aluminum amalgam to the
reduction of arylnitro groups
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Paige J. Monsen and Frederick A. Luzzio
17 examples
-rapid
-mild
-selective
NH2
NO2
Al(Hg)
R
R
THF/H2O (9:1)
rt
-inexpensive
30-60 minutes

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Applicability of aluminum amalgam to the reduction of arylnitro groups
Paige J. Monsena and Frederick A. Luzzioa,
a Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +1-502-852-7323; fax: +1-502-852-8149; e-mail: faluzz01@louisville.edu
Article history:
Received
An array of arylnitro compounds with various functionality were treated with freshly-prepared
aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The
Received in revised form
Accepted
Available online
Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and
disappearance of starting material occurring over 20-30 minutes. The workup of the reductions
involves only removal of the insoluble by-products by filtration followed by concentration. Only
in some cases is chromatography required to secure the pure product. The desired arylamines are
furnished in quantities of 25-100 mg, which in some cases, could be taken on to the next
reaction without further purification. Reductions of 4-nitrobenzyl derivatives of carbohydrates or
nucleosides were selective in affording the corresponding 4-aminobenzyl products. To show
applicability in click chemistry, selected aminobenzyl products are directly azidated to yield
products that were then used in click reactions to afford the corresponding 1,2,3-triazoles.
Keywords:
Aluminum amalgam
Arylnitro groups
Azides
Click chemistry
Reduction
2009 Elsevier Ltd. All rights reserved.
1. Introduction
three separate prostaglandin syntheses, the Corey group did in
fact establish the applicability of Al(Hg) to the reduction of
The reduction of arylnitro groups to the corresponding
arylamino products constitutes a widespread and significant
transformation in organic synthesis.1-3 Considering the process is
the most direct for the preparation of substituted aniline
derivatives, the most desirable protocols allow for the presence of
sensitive protecting groups as well as easily-reducible functional
groups, heterocycles and heteroatoms. The reduction of arylnitro
compounds can utilize a gamut of metals in conjunction with
either hydrogen gas or water as well as metal/metalloid hydrides,
in situ H2 generation and redox and related processes.3 However,
a common denominator in most of the recent developments is the
generation of less metallic and solvent waste which can favor
greener and more economical and atom-efficient processes. As a
consequence of searching for rapid, reliable, selective and
inexpensive methods for the reduction of arylnitro groups to the
corresponding arylamino groups under mild and neutral
conditions, we were surprised to discover that there have been no
reports or systematic studies of aluminum amalgam [Al(Hg)] in
accomplishing such a routine process. Early studies by Keck4,5
demonstrated the usefulness of aluminum amalgam in cleaving
intramolecular N-O bonds to amino alcohols and resulted in a
well-received protocol that was used as a pivotal step in many
total syntheses (Figure 1).6-10 Our later studies of aluminum
amalgam [Al(Hg)]-mediated reductions included the conversions
of imides to hydroxylactams11 and nitroalkanols to the
corresponding amino alkanols (Figure 1).12,13 While the latter
study was focused on minimizing both oxime formation and the
retro-Henry (retro-aldol) side reactions, it did not reach beyond
reduction of the nitroalkyl group inherent in the nitroalkanol
functionality. However, during the course of reports describing
complex nitro aliphatic nitro intermediates.14a-c Interestingly, the
Corey prostaglandin intermediates carried nitrile and dithiane
functionality which survived the reduction.14c Later, the Keck-
type reductions along with our results with nitroalkanols
established the applicability for the generation of aminoalcohol
intermediates. For any substrate, the advantage of the amalgam is
that the reduction is run under neutral conditions. Hence, the
employment of acid or basic extraction is also avoided and
therefore an acylating agent for the amino group can be added to
the reaction mixture at the conclusion of the reaction.12 While our
earlier experiences with nitroalkanol Al(Hg) reductions12,13
demonstrated that power ultrasound was effective in increasing
reactivity by dispersing the aluminum through shock wave-
induced microfragmentation, we determined that sonication was
1979 Keck [4]
1994 Luzzio [12]
OH
O2N
R
OH
H2N
R
OH
R
Al(Hg)
Al(Hg)
O
N
R
R
NHR
1991 Luzzio [11]
This Work
O
N
O
OH
N
NO2
NH2
Al(Hg)
Al(Hg)
R
R
R
R
O
Figure 1. Al(Hg)-mediated reductive cleavage of nitrogen-oxygen
bonds4 and application of the process to reduce imides to
hydroxylactams11 and nitroalkanols.12
not a necessary expedient in arylnitro reductions.

2
Tetrahedron Letters
2. Results and discussion
Table 1. Al(Hg) reduction of various arylnitro substrates to
corresponding arylamines.
The preparation and use of the aluminum amalgam used in the
studies described herein is a simple reproducible process
whereby food-grade aluminum foil is briefly treated with
aqueous mercuric chloride solution and the amalgam is then
introduced to a THF/water solution of the substrate to be reduced
(See Supplementary data). Our initial examination of the Al(Hg)
reduction of the arylnitro substrates was carried out under non-
ultrasonic conditions and involved the transformation of simple
monofunctionalized nitroaryls to establish reaction conditions
and compatibility (Table 1). The nitrotoluene 1 (Table 1, entry 1)
responded as anticipated and gave the p-toluidine 2 (>99%) after
a simple filtration through a glass frit to remove oxidized
aluminum species followed by concentration. The isomeric ortho,
meta and para benzylic alcohols 3, 5 and 7 (Table 1, entries 2-4)
were reduced to the corresponding arylamino benzylic alcohols 4,
6 and 8, all in excellent yields with no cleavage of the benzylic
oxygen bond or adjustment in acidity or basicity during the
workup to secure the products. Despite the propensity for
naphthalenes or substituted naphthalenes to reduce under
electron-transfer conditions, 1-nitronaphthalene 9 (Table 1, entry
5) was cleanly reduced to 2-aminonaphthalene 10 (90%) without
any ring reduction. However, using minimal amounts (2 weight-
equiv) of Al(Hg) in the reduction of 9, we observed a 74% yield
of the corresponding hydroxylamine in contrast to complete
conversion to the amine product using seven weight equivalents
of aluminum. Benzylic ethers of nitrophenols 11 and 13 (Table 1,
entries 6, 7) were reduced smoothly to the corresponding
aminoaryl ethers 12 and 14 respectively (>99%) with no benzylic
cleavage. Compatibility with carbonyl groups is always a
concern when evaluating the selectivity of nitro group reductions,
and along with aldehyde groups, simple substrates bearing amide,
ketone and ester groups were evaluated. Reduction of 4-
nitrosalicylaldehyde 15 (Table 1, entry 8) resulted in significant
reduction to the aminobenzylic alcohol 16 (36%). However,
protection of the aldehyde function of 15 through the acetal
derivative 17 (Table 1, entry 9) followed by Al(Hg) reduction
provided the corresponding aminoaryl acetal 18 (57%). N-
Arylamide functionality remains intact during the Al(Hg)
reduction as exemplified by the clean conversion of N-(3-
NO2
Al (Hg)
NH2
R
R
conditionsa
Entry
1
Substrate
Product
Yieldb (%)
>99
NO2
NH2
1
3
2
4
OH
NO2
OH
2
3
>99
>99
NH2
OH
OH
NH2
NO2
6
5
OH
OH
4
5
>99
90
O2N
H2N
7
8
NH2
NO2
10
9
NO2
NH2
6
7
>99
>99
BnO
BnO
11
13
12
14
NH2
NO2
PMBO
PMBO
O
H
HO
OH
OH
8
9
36
57
O2N
H2N
15
16
O
O
O
O
OH
OH
H2N
O
O2N
O
18
17
10
11
96
80
N
H
NO2
N
H
NH2
nitrophenyl)acetamide 19 (Table 1, entry 10) to
N-(3-
19
20
aminophenyl)acetamide 20 (96%). Selectivity of the nitro group
over amide groups bearing benzylic carbonyls was observed with
substrates 21 and 23 (Table 1, entries 11, 12) thereby affording
the corresponding aminoaryl amides 22 (80%) and 24 (94%)
respectively. Similar to the reduction of aldehyde 15, 4-
Nitroacetophenone 25 (Table 1, entry 13) gave the corresponding
aminoacetophenone 26 (43%) which was accompanied by
carbonyl reduction to 1-(4-amino)phenylethanol.
F
F
O
O
N
N
H
H
H2N
O2N
22
21
O
O
N
N
O
12
13
94
43
O
O
H2N
O2N
24
26
23
25
O
The Al(Hg)-mediated reduction fits into click chemistry15
schemes quite effectively whereby the products bearing the
newly-formed arylamino group can be directly azidated after
filtration of the reaction mixture to give the cycloaddition click
partners (Table 2). When the geraniol p-nitrobenzoate 27 (Table
2, entry 1) was submitted to the reduction-azidation sequence
(NaNO2/NaN3/AcOH/H2O), the corresponding geranyl (4-
azido)benzoate product 28 was obtained (27%) but accompanied
with decomposition products. Quite possibly, the multiple sites of
unsaturation of the geranyl moiety was not compatible with the
azidization sequence. The 4-nitrobenzylic ether of 4-chloro-3-
methylphenol 29 (Table 2, entry 2) was reduced followed by
direct azidation to provide the 4-(azidobenzyl)chlorophenolic
ether 30 (52%). No benzylic cleavage or hydrodechlorination by-
products accompanied the desired product. The
H2N
O2N
aConditions: Al(Hg)/THF:H2O (9:1)/rt, 30-60 min.
bYields are for isolated purified products.
4-(nitrobenzyl)glycosyl tetraacetate 31 (Table 2, entry 3)
responded well to the Al(Hg) reduction-azidation sequence and
delivered the corresponding 4-(azidobenzyl)glycoside 32 (77%).
Similarly, the N3-4-(nitrobenzyl)cyclo-pentylidene uridine 33
(Table 2, entry 4) was submitted to reduction-azidation and
provided the N3-4-azidobenzyl derivative 34 (63%).
Further utilization of the 4-(azidobenzyl)-chlorophenolic ether
30,
the
azidobenzyl
glycoside
32,
and
N3-
(azidobenzyl)nucleoside 34 in the copper-mediated ‘click’
cycloaddition reaction is easily facilitated and further
Table 2. Reduction-azidation of selected arylnitro derivatives to the corresponding arylazido products

3
NO2
NH2
N3
Al (Hg)
NaNO2/NaN3
conditionsb
R
R
R
conditionsa
Entry
1
Substrate
Product
Yieldc (%)
27
O
O
O
O
N3
O2N
28
27
Cl
Cl
O
O
2
3
52
77
O2N
N3
29
30
OAc
OAc
NO2
N3
O
O
AcO
AcO
AcO
AcO
O
O
OAc
OAc
31
32
O
N
O
N
N
N
HO
HO
O
NO2
O
N3
O
O
4
63
O
O
O
O
33
34
aConditions: Al(Hg)/THF:H2O (9:1)/rt, 30-60 min.
bConditions: NaNO2/NaN3/AcOH:H2O (1:1)/0 ˚C to rt, 30-90 min.
cIsolated purified yield of azido product over two steps from the starting nitro substrate.
demonstrates the utility of the Al(Hg) reduction-azidation
sequence in delivering click products 35, 36 and 38 (Scheme 1).
Our choice of 4-ethynylfluorobenzene as the click partner for 35
and 36 was influenced by its desirable reactivity in an earlier
study where it was utilized in the design of click biofilm
inhibitors.16,17 Thus, the 4-azidobenzyl ether 30 was reacted with
4-ethynylfluorobenzene in the presence of copper II sulfate
pentahydrate and sodium ascorbate (THF/H2O, 2:1) which
provided the fluorophenyltriazole 35 (81%). The preparation of
triazolylbenzylgycoside 36 exemplifies the generation of unique
glycoconjugates which are made possible by the employment of
diverse glycosyl azide derivatives.18 Under the same conditions as
the preparation of 35, the 4-(azidobenzyl)glycosyl tetraacetate 32
was reacted with 4-ethynylfluorobenzene to afford the
triazolylbenzylglycoside 36 (81%) (Scheme 1). The interest in
bridged nucleosides as prodrugs and crosslinked oligonucleotides
as transcription factor traps19, 20 prompted us to evaluate the N3-4-
(azidobenzyl)uridine derivative 34 as a click co-reactant with the
N3-propargyl derivative 37. Accordingly, the click reaction of 34
and 37, mediated with the same reagent system as 3035 and
3236 provided the N3-N3' cross-linked triazole derivative 38
(98%). Click products 35, 36, 38 were characterized as the 1,4-
‘anti’-substituted triazoles in which the regiochemistry is
consistent with the copper (I)-catalyzed mechanism.21
3. Conclusion
In summary, the Al(Hg) reduction of arylnitro compounds to
the corresponding arylamines represents a significant departure
from established methods such as metal hydride, catalytic
hydrogenation or in situ hydrogen generation. The reduction of
selected substrates demonstrates the varied applicability of the
Al(Hg) system-especially during the course of a process wherein
the product is directly taken on to the next reaction. The
aluminum amalgam protocol is particularly useful in click
chemistry whereby the amine product is directly taken on to the
azide cycloaddition partner. From our vantage point, the lone
drawback associated with the use of aluminum amalgam is the
employment of mercury (II) chloride in its preparation. The
toxicity of mercury salts is well-known,22 and the use of many
heavy metal-derived reagents precludes substantial scale-up in
both research and industrial settings. Despite the toxicity of many
mercury-derived systems, however, they will always find use in
situations in which procurement of the target compound is of
highest priority.23
Cl
O
F
30
F
N
N
CuSO4•5H2
Na-Asc
O
N
THF/H2O (2:1)
35, 81%
r.t.
24 h
N
N
OAc
F
N
F
32
O
CuSO4•5H2O
Na-Asc
THF/H2O (2:1)
r.t.
AcO
AcO
O
OAc
Funding in part was provided by a University of Louisville
Dissertation Completion Fellowship and NIH/NIDCR
1R01DE023206. Acknowledgement is made to the NSF
(CHE1726633) for support of the Indiana University Mass
Spectrometry Facility.
36, 81%
24 h
O
N
O
N
N
N
HO
N
O
N
O
N
O
O
N
CuSO4•5H2O
Na-Asc
HO
O
O
N
O
O
THF/H2O (2:1)
OH
34
+
r.t.
24 h
O
O
O
References and notes
O
O
37
1.
2.
Smith, M. B. Compendium of Organic Synthetic Methods; Wiley:
New York, 2014; Vol. 13, pp 299-301.
Larock, R. C. Comprehensive Organic Transformations-A Guide to
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1999; pp 821-828. doi:10.1039/c5ra10076c
38, 98%
Scheme 1. Click reactions of selected substrates 30, 32, 34 to give
triazole products 35, 36, 38.
Acknowledgments
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Supplementary Data
Supplementary data features detailed experimental
procedures, characterization data (1H and 13C NMR, FTIR, and
HRMS data), and copies of spectra is provided.