The newborn surface of dull metals in organic synthesis. Bismuth-mediated solvent-free one-step conversion of nitroarenes to azoxy- and azoarenes

Article abstract of DOI:10.1021/jo0203645

When milled together with bismuth shots, nitroarenes are readily converted to azoxy- and/or azoarenes depending on substrates and conditions employed. Simple extraction with organic solvent followed by evaporation of the resulting dark pasty solid gave the product in good yield.

Full text of DOI:10.1021/jo0203645

SCHEME 1
Th e New bor n Su r fa ce of Du ll Meta ls in
Or ga n ic Syn th esis. Bism u th -Med ia ted
Solven t-F r ee On e-Step Con ver sion of
Nitr oa r en es to Azoxy- a n d Azoa r en es
Shinobu Wada, Mika Urano, and Hitomi Suzuki*
Department of Chemistry, School of Science and
Technology, Kwansei Gakuin University,
Gakuen 2-1, Sanda 669-1337, J apan
hsuzuki@ksc.kwansei.ac.jp
Received J une 3, 2002
arenes 2 and/or azoarenes 3 in good yield. Both metals
are cheap and easy to handle. Lead is toxic, but bismuth
is not. Some bismuth salts are orally taken as medicines
for intestinal disorders.4 A black slurry in situ generated
from bismuth chloride and zinc5 or sodium borohydride6
in organic solvent was previously used for the reduction
of nitroarenes to azoxyarenes. The active species involved
therein was taken as free bismuth by the authors, but
possible involvement of low valent bismuth, bismuthane
(BiH3), borane, nascent hydrogen, or electrochemical
process on a binary metal system cannot be excluded.
Aromatic azoxy compounds are key materials for
electronic devices based on their liquid crystalline prop-
erties, while azo compounds are important as the back-
bone for a variety of dyestuffs. Azoxyarenes 2 are
obtained directly from nitroarenes 1 by heating with
alcoholic KOH,7 sodium alkoxide,8 or zinc/NaOH,9 reduc-
tion with sodium borohydride,10 lithium aluminum hy-
dride11 or sodium arsenite,12 treatment with magne-
sium,13 samarium,14 or thallium metal15 in alcohol,
catalytic reduction over palladium,16 alkaline reduction
with phosphine17 or glucose,18 and electrochemical reduc-
tion.19 Aromatic azo compounds 3 are directly obtainable
from nitro compounds 1 by reduction with zinc/NaOH,20
lithium aluminum hydride21 or dicobalt octacarbonyl,22
Abstr a ct: When milled together with bismuth shots, ni-
troarenes are readily converted to azoxy- and/or azoarenes
depending on substrates and conditions employed. Simple
extraction with organic solvent followed by evaporation of
the resulting dark pasty solid gave the product in good yield.
When a metal is mechanically crushed, the newborn
metal surface should be highly activated and immediately
react with atmospheric oxygen and moisture to form a
thin film of metal oxide/hydroxide, which protects the
metal from further oxidative degradation. With the
decrease of metallic nature, however, such protective
action will be moderated and the activated metal surface
could survive for a short while enough to react with a
neighboring molecular species other than those of atmo-
spheric origin. With this idea in mind, we have examined
the reaction of in situ pulverized metals with a series of
organic compounds under completely dry conditions.
Chemical activation of metals has been extensively
studied and widely employed in organic synthesis.1
However, mechanical activation of metals has been
investigated mainly from physicochemical point of view,2
and only few attempts have so far been made to exploit
it in organic transformations.3 In this paper, we wish to
report a solvent-free one-step conversion of aromatic nitro
compounds 1 to azoxy ones 2 (Scheme 1) based on the
nascent surface of dull metals such as bismuth and lead.
Numerous papers have been published on the solid-phase
reactions that involve the supported reagents, solid acid/
base catalysts, immobilized enzymes or imprinted solid
materials, but all of these deal with the cold and static
solid surface. The present results are concerned with the
hot and newborn solid surface and should provide a novel
aspect of solvent-free organic reactions.
(4) For a review of bismuth-based medicines, see: Briand, G. G.;
Burford, N. Chem. Rev. 1999, 99, 2601-2657.
(5) Borah, H. N.; Prajapati, D.; Sandhu, J . S.; Ghosh, A. C.
Tetrahedron Lett. 1994, 35, 3167-3170.
(6) Ren, P.; Pan, S.; Dong, T.; Wu, S. Synth. Commun. 1996, 26,
3903-3908.
(7) Newbold, B. T. J . Chem. Soc. 1961, 4260.
(8) Suter, C. M.; Dains, F. B. J . Am. Chem. Soc. 1928, 50, 2733-
2739.
(9) Olah, G.; Pavlath, A.; Kuhn, I. Acta Chim. Acad. Sci. Hung. 1955,
7, 71-84; Chem. Abstr. 1956, 50, 11262d.
(10) (a) Shine, H. J .; Mallory, H. E. J . Org. Chem. 1962, 27, 2390-
2391. (b) Weill, C. E.; Panson, G. S. J . Org. Chem. 1956, 21, 803.
(11) Dewar, M. J . S.; Goldberg, R. S. Tetrahedron Lett. 1966, 2717-
2720.
Among several metals of moderate hardness or brittle-
ness that are available commercially in the form of shots
or grains, bismuth and lead have been found to exhibit
a unique ability to deoxygenate nitroarenes 1 to azoxy-
(12) Bigelow, H. E.; Palmer, A. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. 2, pp 57-59.
(13) Zechmeiser, L.; Rom, P. J ustus Liebigs Ann. Chem. 1929, 468,
117-132; Chem. Abstr. 1929, 23, 2171.
(14) Hou, Z.; Fujiwara, Y.; Taniguchi, H. J . Org. Chem. 1988, 53,
3118-3120.
(1) For a review, see: Fu¨rstner, A. Angew. Chem., Int. Ed. Engl.
1993, 32, 164-189.
(15) McKillop, A.; Raphael, R. A.; Taylor, E. C. J . Org. Chem. 1970,
35, 1670-1672.
(2) For a review, see Gaffet, E.; Bernard, F.; Niepce, J .-C.; Charlot,
F.; Gras, C.; Le Caer, G.; Guichard, J .-L.; Delcroix, P.; Mocellin, A.;
Tillement, O. J . Mater. Chem. 1999, 9, 305-314.
(3) (a) Harrowfield, J . M.; Hart, R. J .; Whitaker, C. R. Aust. J . Chem.
2001, 54, 423-425. (b) Rowlands, S. A.; Hall, A. K.; McCormick, P.
G.; Street, R.; Hart, R. J .; Ebell, G. F.; Donecker, P. Nature 1994, 367,
223.
(16) Busch, M.; Schulz, K. Chem. Ber. 1929, 62B, 1458-1466.
(17) Buckler, S. A.; Doll, L.; Lind, F. K.; Epstein, M. J . Org. Chem.
1962, 27, 794-798.
(18) Galbraith, H. W.; Degering, E. F.; Hitch, E. F. J . Am. Chem.
Soc. 1951, 73, 1323-1324.
(19) De Groot, H.; Van den Heuvel, E.; Barendrecht, E.; J anssen,
L. J . J . Ger. Pat. 3,020,846, 1980; Chem. Abstr. 1981, 94, 54,934s.
10.1021/jo0203645 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002
8254
J . Org. Chem. 2002, 67, 8254-8257

TABLE 1. Rea ction of p-Nitr oa n isole 1a a n d Bism u th
Sh ots u n d er Differ en t Con d ition s
SCHEME 2
product ratioa conversion yieldb
run
conditions
2a /3a
(%)
(%)
1
2
3
4
5
6
under air
78/22
100/0
17/83
100/0
100/0
100/0
∼100
∼100
∼100
∼100
∼100
∼100
∼100
under airc
7d
under N2
under O2
1 drop of hexane added
1 drop of benzene added
∼100
∼100
91d
∼100
Determined by 1H NMR. Based on conversion. c Powdery
a
b
d
bismuth (∼100 mesh) was used. Isolated yield.
and by high-temperature reaction with ethanolamines.23
Heating aromatic nitro compound and aniline at high
temperature in the presence of powdered alkali also leads
to azo compound.24 A variety of multistep indirect routes
are available for aromatic azo compounds, which include
diazonium coupling, condensation of nitrosoarene with
aromatic amine or azide, mild oxidation of aromatic
amines, etc.25 However, all known preparative methods
involve the wet process based on solution chemistry.
4-Nitroanisole 1a , commercial bismuth shots (Kishida,
ca. 1 mm) and small stainless balls were placed in a
stainless steel cylinder (1.2 × 4 cm) with a screw cap and
gently shaken on a laboratory ball-mill apparatus at a
rate of 30 Hz/s for 1.5 h at room temperature. The
resulting dark gray to near black powder or pasty solid
was extracted with ethyl acetate by trituration. The
extract was filtered on a thin bed of a Celite and
evaporated to leave a mixture of 4,4′-dimethoxyazoxy-
benzne 2a and 4,4′-dimethoxyazobenzene 3a in a 78:22
ratio in almost 100% combined yield (Table 1, run 1). The
insoluble black powder was a mixture of bismuth and
bismuth oxide which, thanks to the low reduction poten-
tial of bismuth, can be readily converted to the original
metal simply by heating under an atmosphere of such
reducing gases as hydrogen, carbon monoxide, and
methane.26
this ratio in favor of azoxyarene 2a (Table 1, runs 5 and
6). When the bismuth shot was replaced by a commercial
powdery bismuth (Ishizu; -100 mesh, 99.99% purity), the
reaction came to a halt at low conversion and most of
the starting material was recovered intact (run 2). These
observations demonstrate a crucial role of the nascent
bismuth surface in the reductive dimerization of ni-
troarene 1a to azoxy- and azoarenes 2a and 3a .
The reaction of 2,2′-dinitrobiphenyl 4 with bismuth
shots was quite slow and incomplete, giving benzo[c]-
cinnoline N-oxide 5 in 90% yield based on conversion.
However, by replacing bismuth with lead (Ishizu; 99.999%
purity), nitroarene 4 readily underwent reductive cy-
clization to form benzo[c]cinnoline 6 in 95% isolated yield
(Scheme 2). These polycyclic azaarenes were previously
prepared by the reduction of 4 with lithium aluminum
hydride,27 sodium borohydride28 or samarium metal,14
oxidation of 2,2′-diaminobiphenyl with sodium perbo-
rate,29 and photochemical cyclodehydrogenation of azoben-
zene 2a in concentrated sulfuric acid.30
The reductive dimerization of nitroarenes by bismuth
metal is highly dependent on the nature of a substituent
group present in aromatic ring. When the substituent is
alkyl, alkoxy, or halogen, azoxybenzenes 2a -i are ob-
tained in good isolated yield. In contrast, the electron-
withdrawing substituents such as acyl, acyloxy, and nitro
groups suppressed the reaction. As expected, the presence
of hydroxy and carboxy functions inhibited the reaction
(Table 2).
The reaction vessel was not airtight and so, with an
intention to exclude the influence of atmospheric oxygen,
the milling was carried out under an atmosphere of
nitrogen. As expected, the product composition shifted
considerably toward the azo compound at the expense of
the azoxy compound (2a /3a ) 17:83). To our surprise,
however, the addition of a drop of an inert organic solvent
such as hexane or benzene to the nitroarene-bismuth
mixture prior to milling led to the complete reversal of
Among several other metals commercially available in
the form of shots or grains, which included tin, manga-
nese, copper, aluminum, antimony, and lead, only the last
metal showed satisfactory deoxygenating ability and gave
acceptable results. The oxidation-reduction potentials
of these metals follow the order Al > Mn > Sn > Pb > H
> Sb > Bi > Cu.31 When the lead shots were subjected
to ball-milling in the presence of 1a , azo compound 3a
was obtained as the sole product in 96% isolated yield
(Table 3, run 3). Little or no azoxy compound could be
detected. This is consistent with the more reactive nature
of lead as compared to bismuth, but at variance with the
previous report that nitroarenes are reduced to azoxy-
(20) (a) Shine, H. J .; Chamness, J . T. J . Org. Chem. 1963, 28, 1232-
1236. (b) Bigelow, H. E.; Robinson, D. B. Organic Syntheses; Wiley:
New York, 1955; Collect. Vol. III, pp 103-104.
(21) (a) Nystrom, R, F.; Brown, W. G. J . Am. Chem. Soc. 1948, 70,
3738-3740. (b) Badger, G. M.; Seidler, J . H.; Thomson, B. J . Chem.
Soc. 1951, 3207-3211.
(22) Alper, H.; Paik, H.-N. J . Organomet. Chem. 1979, 172, 463-
466.
(23) Meltsner, M.; Kirshenbaum, J .; Stempel, A. J . Am. Chem. Soc.
1938, 60, 1236-1237.
(24) Martynoff, M. Compt. Rend. Acad. Sci. Paris 1946, 223, 747-
749; Chem. Abstr. 1947, 41, 2400f.
(25) For
a
survey of aromatic azo compounds, see: (a) Lang-
(27) Badger, G. M.; Seidler, V. H.; Thomson, B. J . Chem. Soc. 1951,
3207-3211.
Fugmann, S. Houben-Weyl Methoden der Organischen Chemie, Band
E/6d, Teil 1; Klamann, D., Ed.; Georg Thieme: Stuttgart, 1992; pp
119-142. (b) Schundehutte, K. H. Ibid. Band X/3; Stroh, R., Ed.; Georg
Thieme: Stuttgart, 1965; pp 211-465.
(26) (a) Gmelin Handbuch der Anorganischen Chemie, Band 19;
Lippert, W., et al., Ed.; Georg Thieme: Stuttgart, 1964; p 646; (b) Band
III; Friedheim, C., Ed.; 1908; Georg Thieme: Stuttgart, p 955.
(28) Smith, W. B. J . Heterocycl. Chem. 1987, 24, 745-748.
(29) Corbett, J . F.; Holt, P. F. J . Chem. Soc. 1961, 3695-3699.
(30) Badger, D. M.; Drewer, R. J .; Lewis, G. E. Aust. J . Chem. 1963,
16, 1042-1050.
(31) Emsley, J . The Elements, 3rd ed; University Press: Oxford,
1998.
J . Org. Chem, Vol. 67, No. 23, 2002 8255

TABLE 2. Red u ction of Va r iou s Nitr oa r en es w ith
Bism u th Sh ots u n d er a Hexa n e Va p or a
SCHEME 3
nitroarene
product ratiob 2/3
conversionc (%)
yieldd (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k -q
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
100/0
0/100
-
91
86
∼100
∼100
∼100
∼100
∼100
∼100
∼100
∼100
∼100
∼100
0
∼100
89
98
43
∼100
92
63
∼100
0
a
b
3/4 in Table 1 and runs 5/6 in Table 3, where the product
ratios 2/3 were reversed in the presence of an additive.
Consistent with this Scheme, the milling of 2a with
bismuth shots readily gave a quantitative yield of 3a . The
electron-donating substituent would facilitate the nu-
cleophilic attachment of the oxygen atom of the nitro
function onto the newborn bismuth surface in a push-
pull manner, but the electron-withdrawing group would
disfavor such a process. Thus, p-dinitrobenzene 1n does
not react with bismuth shots under the conditions
employed, but p-nitrosonitrobenzene was readily con-
verted to 4,4′-dinitroazobenzene 3n . Therefore, the con-
version of the nitro group to the nitroso group is most
likely the key step of this overall transformation. When
an equimolar mixture of two different nitroarenes 1a and
1b was milled together with bismuth, two symmetrical
and one unsymmetrical azoxyarenes were formed in an
approximate ratio of 1:1:1. This observation contrasts
with the previous reports that symmetrical azoxyben-
zenes were always obtained as the major product from
the reaction of differently substituted nitrosobenzene and
N-phenylhydroxylamine due to the rapid equilibrium
between these two substrates in solution.34 Interestingly
enough, parent nitrobenzene 1j contrasts in its behavior
to substituted nitrobenzenes 1a -i, producing not the
expected azoxybenzene 2j but azobenzene 3j as the sole
product. This may be taken to reflect some topological
feature of the newborn solid surface, on which less bulky
1j can settle down better to be transformed to 3j beyond
2j. Attempts to trap a nitrene or nitrenoid species failed,
precluding its possible intermediacy in the formation of
azoxy- and/or azoarenes.
The present methodology was successfully extended to
the single-step synthesis of long-chain 4-alkoxyazoxyare-
nes 9 from the corresponding nitro compounds 8 (Table
4). Compounds 9a -h are long known for their liquid
crystalline property.35 The reaction was clean and the
yield based on conversion was almost quantitative. The
unsatisfactory conversion observed with nitroarenes hav-
ing an alkoxy chain longer than eight carbon units may
be attributed to inefficient mixing, but it may also reflect
some role played by the longer alkoxy chain in the
reduction of nitroarenes 8 on the structured solid surface.
The product was always azoxy compound irrespective of
the presence or absence of an additive. Prolonged reaction
For details, see the Experimental Section. Determined by 1H
NMR. c Isolated yield. Based on conversion.
d
TABLE 3. Red u ction of Nitr oa r en es 1a , 1g, a n d 1j w ith
Differ en t Meta l Gr a in s or Sh ots
run substrate metal additive product ratioa 2/3 yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1f
1f
1f
1j
1a
1a
1a
Bi
hexane
hexane
100/0
60/40
0/100
100/0
95/5
91
89
96
∼100
71
94
0
Pb
Pb
Bi
Pb
Pb
Sb
Sn
Mn
Al
hexane
hexane
0/100
0
0
0
10
a
b
Determined by 1H NMR. Refer to isolated compounds. Not
optimized. Reaction time was 1.5 h.
arenes by heating with lead in DMF under reflux.32 In
the reaction with metallic lead, however, care should be
taken when opening the reaction vessel, since the result-
ing black powdery mixture was liable to catch fire in
contact with air. Lead was probably converted to an
inflammable lower oxide or so during the reductive
dimerization of nitroarene 1a . Such spontaneous ignition
was never observed with bismuth. Antimony belongs to
the same family as bismuth, but it was quite reluctant
to react with nitroarenes.
The formation of azoxyarene 2 from nitroarene 1 under
aqueous conditions has been known to proceed via the
stepwise reduction processes from 1 to nitrosoarene 7 to
N-arylhydroxylamine, followed by the dehydrative cou-
pling of the last two species to produce 2.33 Under the
present completely dry conditions, however, no proton
source is available. Therefore, the deoxygenative dimer-
ization of nitroarenes on the activated bismuth surface
is most likely to proceed according to the pathway
illustrated in Scheme 3.
Nitroarene 1 is adsorbed and deoxygenated on the
newborn bismuth surface to form nitrosoarene 7 as the
initial product, which then couples with another molecule
of 7 to afford azoxyarene 2. In the presence of oxygen or
some additive, part of active metal surface would be
occupied or destroyed by these molecular species and
further reduction will be suppressed. In the absence of
these, however, the reaction goes further to produce
azoarene 3. This interpretation is substantiated by runs
(34) (a) Oae, S.; Fukumoto, T.; Yamaguchi, M. Bull. Chem. Soc. J pn.
1963, 36, 728-729. (b) Shemyakin M. M.; Maimind, V. I.; Vaichunaite,
B. K. Izvest. Akad. Nauk SSSR., Otdel. Khim. Nauk 1957, 1260-1262;
Chem. Abstr. 1958, 52, 6231.
(35) Weygand, C.; Gabler, R. J . Prakt. Chem. 1940, 155 (2), 332-
341.
(32) Azoo, J . A.; Grimshaw, J . J . Chem. Soc. C 1968, 2403-2405.
(33) Pizzolatti, M. G.; Yunes, R. A. J . Chem. Soc., Perkin Trans. 2
1990, 759-764.
8256 J . Org. Chem., Vol. 67, No. 23, 2002

TABLE 4. Red u ction of Lon g-Ch a in
4-Alk oxyn itr oa r en es w ith Bism u th Sh ots
laboratory ball milling apparatus (Retsch mixer mill, MM200;
Retsch GmbH, Haan, Germany). Chromatographic purification
of products were performed with Wakogel 200 (100-200 mesh)
using hexanes-EtOAc (1-5:1) as the eluting solvent. All prod-
ucts are known and were identified by comparison of melting
points and 1H NMR, IR, and/or MS spectra with those of
authentic samples or literature data.35,36
Caution: Care should be taken when the ball milling reduc-
tion of nitroarenes is carried out using lead shots. The resulting
black powder and pasty solid often catch fire in contact with
air.
carbon chain
length () n)
conversiona
yieldb
(%)
Red u ction of Nitr oa r en es w ith Bism u th Sh ots u n d er
Millin g Con d ition s. Rep r esen ta tive P r oced u r e. 4-Nitroani-
sole (1a , 0.076 g; 0.50 mmol), bismuth shots (0.865 g, 4.13 mmol;
Kishida, ca. 1 mm; 99.999% purity), and two stainless balls were
placed in a stainless cylinder (5 mL volume) and a drop of hexane
was added just before closing a screw cap. The reaction vessel
was shaken on a ball mill apparatus at a rate of 30 Hz/s. The
cylinder considerably warmed by mechanical friction. After 1.5
h, milling was stopped and the resulting gray to near black
powder or pasty solid was extracted with ethyl acetate by
trituration. The combined extracts were filtered on a thin Celite
bed and evaporated to leave 4,4′-dimethoxyazoxybenzene 2a
(0.059 g, 91%) as yellow crystals, mp 120-122 °C (lit.32 mp 118-
119 °C).
substrate
(%)
8a
8b
8c
8d
8e
8f
2
4
5
6
7
8
10
12
79
91
82
97
87
20
44
25
∼100
∼100
∼100
∼100
∼100
∼100
∼100
∼100
8g
8h
a
Refer to isolated compounds. Reactions were not optimized.
b
All products are known.35 Based on conversion.
time did not improve conversion but favored the decom-
position of azoxy to azo compound. Replacement of
bismuth by lead resulted in the formation of an identified
third product in addition to the expected azoxy and azo
compounds. The reported yields of azoxy compounds 9
are in the range 45-88%.35 In ordinary solution chem-
istry, the alkyl chain length does not seem to influence
much on the product yield.
In summary, a convenient and effective one-pot pro-
cedure has been developed for the solvent-free one-step
conversion of nitroarenes to azoxyarene and/or azoarenes.
The reaction is clean and highly chemoselective, manipu-
lation is simple, reaction time is short, and yield is
generally good. Extension of the present methodology to
other functional group transformations is under way.
Red u ction of Nitr oa r en es w ith Lea d Sh ots u n d er Mill-
in g Con d ition s. Rep r esen ta tive P r oced u r e. 2,2′-Dinitrobi-
phenyl (4, 0.0288 g; 0.118 mmol), lead shots (0.172 g, 0.832
mmol; Ishizu, ca. 0.5 mm; 99.999% purity), and two stainless
balls were placed in a stainless cylinder (5 mL volume) and
shaken on a ball mill apparatus at a rate of 30 Hz/s. After 1.5
h, milling was stopped, and the resulting black pasty product
was extracted with ethyl acetate by trituration. The combined
extracts were filtered on a thin Celite bed and evaporated to
leave a pale yellow solid, which was chromatographed on silica
gel using a mixture of hexane/ethyl acetate (2:1) to give benzo-
[c]cinnoline 6 (0.020 g, 92%) as pale yellow needles, mp 157-
158 °C (lit.14 mp 157-158 °C).
Under the similar conditions using bismuth shots, compound
4 was converted slowly to benzo[c]cinnoline N-oxide 5, mp 137-
138 °C (lit.14 mp 139-140 °C). The yield based on unrecovered
material was around 90%.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR data of
azoxy and azo compounds obtained (2, 3, 5, and 6). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Exp er im en ta l Section
Reagents and metal shots were all reagent-grade commercial
products and used as obtained. Long-chain alkoxy nitroarenes
8 were prepared by the reaction of p-nitrophenol and long-chain
alkyl bromides in DMF in the presence of potassium carbonate.
Ball milling was carried out in a stainless cylinder (1.2 × 4 cm;
5 mL volume) using stainless balls of 7 mm diameter on a
J O0203645
(36) Dictionary of Organic Compounds, 5th ed; Chapman: London
1982; and supplement volumes.
J . Org. Chem, Vol. 67, No. 23, 2002 8257