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