Short Articles
Bull. Chem. Soc. Jpn., 77, 1027–1028 (2004) 1027
Ethyl Acetate as a Pro-Reducing
Agent in an One-Pot Reductive
Deamination of Nitroanilines
Valeriy A. Bacherikov, May-Jane Wang,
Shu-Yun Cheng, Ching-Huang Chen,
1
ꢀ
Kuo-Tung Chen, and Tsann-Long Su
Laboratory of Bioorganic Chemistry, Institute of Biomedical
Sciences, Academia Sinica, Taipei 115, Taiwan
Scheme 1. Conversion of mono and dinitro substituted
anilines to corresponding benzenes.
1Department of Medicinal Chemistry, College of Pharmacy,
Taipei Medical University, Taipei 110, Taiwan
H2SO4 solution by using EtOAc instead of EtOH. The result in-
dicated that EtOAc can be a useful agent for hydrodeamination.
This prompted us to study the reductive deamination of various
nitro-substituted anilines by our new method (20% H2SO4/
NaNO2/EtOAc, Method 1) and compared that with a similar
procedure previously developed by Par e´ et al.11 (i.e., conc.
H SO /NaNO /EtOH, Method 2) for the dediazonization of
Received September 25, 2003; E-mail: tlsu@ibms.sinica.edu.tw
The one-pot reductive deamination of mono or dinitro
substituted anilines to the corresponding nitrobenzenes by us-
ing ethyl acetate or ethanol was compared. It revealed that
ethyl acetate is more suitable for the reductive deamination
of mononitroanilines, while ethanol is more appropriate for
dinitroanilines.
2
4
2
4-methyl-2,6-dinitroaniline (1c).
Aniline derivatives bearing dinitro and mononitro func-
tion(s) (1a–1e and 1f–1i, respectively) were used for our stud-
ies. In Method 1, the reductive deamination was carried out by
adding finely powdered NaNO2 to a mixture of aniline, 20%
ꢁ
H2SO4 and EtOAc (1:1 v/v) at 50–55 C (internal temperature)
(Method 1). However in Method 2 the pulverized NaNO2 was
The replacement of a diazonium group by hydrogen (hydro-
dediazoniation) via a reduction process has been widely utiliz-
ed as an indirect method for removing an amino group from the
added portionwise at a rate to keep the internal temperature at
ꢁ
80 C to a suspension of nitroanilines in a mixture of conc.
1
aromatic ring. The reductive deamination involves a com-
pleteness of diazoniation, followed with reduction. The pro-
posed mechanism of reductive deamination by forming a radi-
H2SO4 and EtOH. The deaminated products (2) were isolated
from the organic layer in satisfactory yield either by recrystal-
lization or column chromatography (Table 1).
2
cal intermediate was further confirmed later by Wassmundt et
3
As shown in Table 1, the deaminated products derived from
the mononitro-substituted anilines 1f–1i were obtained in good-
to-high yield by Method 1 depending upon the position of the
nitro group to the amino function. The higher yield of the de-
aminated products was observed from the substituted meta-ni-
troanilines 1g and 1i than that from the para-nitroanilines, 1f
and 1h. However, EtOAc was less effective in the reaction of
1h than other mononitroanilines (1f, 1g, and 1i). It also revealed
that in the reactions of mononitro substituted anilines 1f–i, a
significant substituent effect (methoxy vs chloro) was not ob-
served. Reductive deamination of the dinitro substituted ani-
lines by Method 1 (i.e., 1c or 1d ! 2c and 1e ! 2e) was un-
expected in low yield. The amount of 2e obtained was depend-
ent on the addition rate of NaNO2. In general, a higher yield of
the product could be obtained when the internal reaction tem-
al. The first step of reductive deamination involves the forma-
tion of diazonium salt, which can be readily generated by treat-
1
ing amine with sodium nitrite in mineral acid, liquid nitrogen
4
5,6
dioxide, and other agents. The second step, hydrodediazo-
niation, can be furnished by using common reducing agents
1
1
5
7,8
such as alcohols, hypophosphorous acid, DMF, and other.
During the course of our research, we synthesized 3,5-di-
nitrophenol (2a) as an intermediate for constructing biological
active compounds. Compound 2a was synthesized from s-trini-
ꢁ
9
trobenzene under drastic conditions (AlCl3/120 C). To avoid
using explosive s-trinitrobenzene, we prepared 2a from 5-ace-
toxy-2-acetylamino-1,3-dinitrobenzene (1a) by following a
previously described method with modification (Scheme 1).10
Compound 1a was hydrolyzed by conc. H2SO4 to give the in-
termediate 4-amino-3,5-dinitrophenol (1b), which was not iso-
lated, and subsequently reacted with NaNO2 in boiling EtOH
for 3–5 h to yield the desired phenol 2a. However, the inter-
mediate 1b was poorly soluble in the reaction medium and re-
quired a long refluxing time (ca. 3–5 h) to complete the reac-
tion. To improve the solubility of 1b, EtOAc was added to
the reaction mixture. Under such conditions the reaction went
smoothly and finished within a short period of time (ca. 0.5
h). Based on this finding, we were able to directly convert 1a
into 2a in good yield (74%) in a one-pot reaction in a 20%
ꢁ
perature was kept approximately at 50 C during the addition
of NaNO2. It should be noted here that the reaction proceeded
slowly, or afforded a complicated mixture of products when
conc. H2SO4 was used in Method 1. To prove EtOAc is in-
volved in deamination process, we studied the products formed
from this agent under the reaction conditions described above
1
by H NMR spectroscopy method. Thus, EtOAc was treated
ꢁ
with 20% H2SO4 in the presence of NaNO2 at 50 C for 10
min, the organic and aqueous layers were separated and then
subjected to NMR measurements. Ethanol and acetic acid (each
Published on the web May 6, 2004; DOI 10.1246/bcsj.77.1027