Chemoselective one-pot reductive deamination of aryl amines

Article abstract of DOI:10.1016/S0040-4039(01)01027-9

A one-pot deamination of a wide variety of substituted anilines is described. The process involves a diazotization-dediazotization utilizing acetic acid, sodium nitrite, and sodium bisulfite- inexpensive, 'green' reagents. The process occurs quickly under mild conditions, tolerates sensitive functionality, and gives products in modest-to-good yields (16-88%).

Full text of DOI:10.1016/S0040-4039(01)01027-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5367–5369
Chemoselective one-pot reductive deamination of aryl amines
a
b
a,b,
Otto J. Geoffroy, Thomas A. Morinelli and G. Patrick Meier *
a
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
b
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina,
Charleston, SC 29425, USA
Received 15 May 2001; accepted 4 June 2001
Abstract—A one-pot deamination of a wide variety of substituted anilines is described. The process involves a diazotization-
dediazotization utilizing acetic acid, sodium nitrite, and sodium bisulfite- inexpensive, ‘green’ reagents. The process occurs quickly
under mild conditions, tolerates sensitive functionality, and gives products in modest-to-good yields (16–88%). © 2001 Elsevier
Science Ltd. All rights reserved.
Deamination of aryl amines is an important reaction
that has been the focus of synthetic investigations for
over 100 years. It is used primarily as a method for
many of these reactions proceed via radicals and thus
suffer from problems common to these intermediates
1
4a
6
such as dimerization,
extraction of iodine from aryl iodides.
halogen scrambling, and
13
removal of amines after they have been utilized for
directing electrophilic aromatic substitution reactions.
The transformation is typically achieved by a two-step
process involving diazotization followed by reduction
with various inorganic or organic reductants including
Recently we needed to utilize an amine-directed nuclear
iodination followed by a deamination for the synthesis
of a series of thromboxane A mimetics as exemplified
2
2
hypophosphorous acid, various alcohols such as etha-
in Scheme 1.
3
4
5
nol, nitric oxide, triphenylphosphine, a variety of
structurally related amides including N,N-dimethylfor-
Since both the starting material and final products
contain sensitive functionalities, we explored several
mild processes for removing the amine. The approach
that we initially found best for our compounds utilized
6
7
mamide, a variety of amines including triethylamine,
8
9
10
alkyl nitrites, trichlorosilane and ferrocene. Many of
these reductants have also been developed for use in
1
1
catalysed as well as uncatalyzed procedures. Finally,
there are two methods that have been developed as
a mild diazotization method (AcOH, NaNO , ethanol,
2
water), followed by an in situ reduction by ethanol
‘
one-pot’ reactions: the direct diazotization–dediazo-
1
a
12
(24°C), as described in Kornblum’s review. These
reductions proceeded in modest to good yield, required
long reaction times at room temperature (12–32 h), and
gave variable amounts of ethyl ethers derived both
from displacement of the diazonium salt and some of
the substituents. The rates of the reactions were faster
in refluxing ethanol, but resulted in lower yields of the
desired product.
tization with sodium nitrite in hypophosphorous acid
and the reaction with alkyl nitrites in dimethyl for-
8
a
mamide. One problem with many of these methodolo-
gies is that they require the initial preparation of
unstable aryldiazonium salts. A second problem is that
frequently the reduction processes do not proceed well
with electron donating groups in the para position or
1,4b
with any substituent in the meta position.
Finally,
Scheme 1.
*
Corresponding author.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01027-9

5
368
O. J. Geoffroy et al. / Tetrahedron Letters 42 (2001) 5367–5369
Bisulfite reduction15
Table 1.
ArNH2
Ethanol reduction14,15
Yield (%) Time (h)
62
Yield (%)
Time (h)
1
2
-I, 4-CO CH3
1
8391
18
32
24
24
38
24
24
24
24
24
24
2
7
2
2
2
-I, 5-OCH3
-I
2
3
72
34
2
6
20
4
4
4
2
4
4
4
64
53
67
0
80
a
b
2
2
4
2
3
2
-I, 4-OH
4
5
6
7
8
16
82
88
83
73
67
26
-CN, 3-Cl
69
69
75
0
-CO CH3
-F, 4-Cl
-OCH3
2
-I, 4-I, 5-SO H
9
10
60
5
3
c
0.5d
RPPG(4-NH , 3-I)F
2
a
1
8% of the corresponding ethyl ether was isolated.
b
c
A red tarry material was the only product obtained.
Single letter code for amino acids.
Monitoring the reaction showed the reaction gave a maximum yield at 0.5 hr which decreased with time, 3.2% at 18 h and 2.2% at 24 h.
d
1
b
Bisulfite is a little known reducing agent for diazo-
view to the ability of this process to provide selective
deuteration and to explore the mechanism of the reac-
tion: reaction with CD CO D, NaDSO , and C H OD
1a,14
nium ions that has not been extensively explored.
Since bisulfite is such a mild reducing agent and the
corresponding acid is a weak acid, we explored the
ability of a mixture of bisulfite and nitrite to effect the
simultaneous diazotization and reductive dediazotiza-
tion of aryl amines (Scheme 2).
3
2
3
2
5
gave product with exclusive (>95%) substitution of
deuterium for the amine and indicates that the hydro-
gen is not provided by the alkyl portion of the alcohol.
meta-Substitution, which typically decreases the yields
1
,4b
in alcohol or hypophosphorous acid reductions,
The anilines were dissolved in a solution of ethanol,
water, and acetic acid at 24°C and a solution of sodium
nitrite in water was added followed immediately by
addition of aqueous solution of sodium bisulfite. The
reaction was faster (1–20 h), cleaner, and consistently
gave higher yields of the desired deaminated products
than our previous method (Table 1).
does not appear to significantly influence this reaction
as indicated by the good yields from the reactions of
compounds 2, 5, 8, and 9. Even compounds that can
form diazo-quinones (4), and usually give lower yields
1
of the deaminated products, gave a modest yield of the
deaminated product. The application of this process to
highly functionalized compounds, such as the synthesis
of peptides containing iodinated phenylalanines, is also
successful as seen in the diazotization–dediazotization
of compound 10.
Several features of the process are significant. Starting
materials with functionality ortho to the intermediate
diazonium group (1, 2, 3, 5, 7, 9, and 10), which have
been shown to undergo displacement in other reduction
In summary, this report describes a one-pot, simultan-
eous diazotization–dediazotization of a wide variety of
substituted anilines to give the deaminated product.
The process utilizes inexpensive and relatively environ-
mentally benign reagents—acetic acid, sodium nitrite,
and sodium bisulfite. The process occurs quickly, gives
products in modest-to-good yields (16–88%), and is
successful even in sensitive compounds such as peptides
or those with leaving groups ortho to the diazonium
ion.
1
schemes , gave good yields of the desired product and
minor amounts of the corresponding ethers. Compound
4
is the exception to this observation, with 16% of the
desired product and 18% of the ether being isolated.
However the corresponding reduction process with eth-
anol gave only tarry material. Additionally, no halo-
gen-scrambling was detected (replacement of the
diazonium ion with iodine from the deaminated
product), suggesting that if the reaction proceeds via a
radical intermediate, trapping by the hydrogen of the
bisulfite is faster than the reaction with the aryl iodides.
The source of the hydrogen was briefly studied with a
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