One-step reductive amidation of nitro arenes: Application in the synthesis of Acetaminophen

Article abstract of DOI:10.1016/j.tetlet.2005.09.196

A novel thioacetate mediated one-step reductive acetamidation of aryl nitro compounds was developed and applied to an efficient synthesis of acetaminophen. The reaction also proceeds well without a solvent in the presence of a catalytic amount of surfactant.

Full text of DOI:10.1016/j.tetlet.2005.09.196

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1861–1864
One-step reductive amidation of nitro arenes: application in
the synthesis of Acetaminophen
TM
Apurba Bhattacharya,a,* Vikram C. Purohit,a Victor Suarez,a Ritesh Tichkule,a
Gaurang Parmera and Frank Rinaldib
aDepartment of Chemistry, Texas A&M University-Kingsville, Kingsville, TX 78363, USA
bDepartment of Process Research, Bristol-Myers Squibb, Pharmaceutical Research Institute, One Squibb Drive, PO Box 191,
New Brunswick, NJ 08903-0191, USA
Received 1 September 2005; revised 16 September 2005; accepted 16 September 2005
Available online 30 January 2006
Abstract—A novel thioacetate mediated one-step reductive acetamidation of aryl nitro compounds was developed and applied to an
efficient synthesis of acetaminophen. The reaction also proceeds well without a solvent in the presence of a catalytic amount of
surfactant.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
trimethylsilanethiolate (NaSTMS). The proposed mech-
anism involved a nucleophilic attack by TMS–S(À) on
the –NO2 group followed by energetically favorable
intramolecular TMS shift from S to O and eventual
expulsion of sulfur.4 Conceptually, the strategy could
be extended to reductive amidation of NO2 by replacing
TMS–S(À) with CH3COS(À), with the acetyl group act-
ing as a TMS surrogate. Thus, sequential nucleophilic
attack of the thioacetate anion producing the acyl inter-
mediate 2a would be followed by an energetically favor-
able intramolecular acetyl shift from sulfur to oxygen
(analogous to the TMS shift) producing the second acyl
intermediate 3a; both 2a and 3a could potentially act as
in situ acetyl donor equivalents and lead directly to the
desired acetanilide after sulfur expulsion (Scheme 1).5
Aryl amides are versatile synthetic intermediates, and
are important structural elements of several drug candi-
dates.1 Traditional two-step syntheses of N-arylacet-
amides involving reduction of nitroarenes followed by
acylation via activated carboxylic acids are well docu-
mented.2 However, direct, one-step conversions of nitro
group to acetamides without the intermediacy of the
amine and the obligatory activation of carboxylic acid
are nontrivial and suffer from unwanted by-product for-
mation such as N,O-diacetylated derivatives.3 A solu-
tion to this problem originated from an earlier report
describing an efficient reduction of aromatic nitro com-
pounds to the corresponding amines employing sodium
O
O
O
O
O
O
N
O
Acyl shift
S
O
O
N
Ph
S
S
N
Ph
N
Ph
S
N
Ph
O
O
- AcO
Ph
2a
Sulfur
nitroso
3a
1
O
S
N
2a (or 3a)
- AcO
Acyl shift
NHCOCH3
Ph
Ph
N
O
S
N
O
O
Ph
Solvent
Sulfur
Ph
Scheme 1. Proposed mechanism of thioacetate mediated reductive amidation.
*
Corresponding author. Tel.: +1 361 593 2664; fax: +1 361 593 3597; e-mail: kfab002@tamuk.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.196

1862
Table 1. Thioacetate mediated acetamidation of arylnitro compounds
KSCOCH , DMF, 130 C or
A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 1861–1864
o
3
o
KSCOCH , Triton-X 405 (cat), no solvent, 130 C
3
Ar-NHCOCH
3
Ar-NO
2
2
1
Entry
1
Time (h)
% Conversiona (% yield)b
Solvent free
DMF
NO2
NO
1
2
3
2
1
2
97 (83)
98 (85)
94 (85)
96 (78)
95 (75)
95 (77)
NO2
NO2
4
5
2
2
94 (86)
95 (88)
94 (73)
95 (78)
NO2
NO
6
1
90 (60)
90 (55)
HO
NO2
7
8
1
1
90 (62)
90 (65)
88 (58)
85 (60)
OH
NO2
OH
NO2
9
2
2
1
95 (85)
95 (88)
80 (65)
94 (76)
93 (79)
70 (60)
NO2
10
11
NO2
O
NO2
12
2
92 (85)
88 (75)
Cl
Br
NO2
13
14
15
2
3
3
95 (85)
85 (75)
90 (87)
90 (78)
75 (68)
88 (75)
NO2
NO2

A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 1861–1864
1863
Table 1 (continued)
Entry
1
Time (h)
% Conversiona (% yield)b
Solvent free
DMF
16
17
18
2
3
3
80 (75)
98 (87)
95 (70)c
77 (64)
95 (78)
93 (65)c
NO2
NO2
OH
NO2
a Conversion based on GC and HPLC.
b All products exhibited satisfactory spectral properties (1H NMR and 13C NMR) fully in accord with known or expected values.9
c The isolated product was a 1:1 mixture of the expected amide and the oxazole derivative namely, 2-methyl-1-oxa-3-aza-cyclopenta[a]-
O
naphthalene
.
N
These expectations were fully realized, resulting in a sim-
ple and efficient potassium thioacetate-mediated one-
step acetamidation of various aryl nitro compounds
under essentially neutral conditions. Representative
examples are summarized in Table 1. A typical experi-
mental procedure is as follows: Under nitrogen, a stirred
mixture of potassium thioacetate (3.71 g, 32.5 mmol),
nitrobenzene (1 g, 8.1 mmol), and DMF (2.0 ml) was
heated at 130 ꢁC. The progress of the reaction was mon-
itored by HPLC and GC. After 2 h, the reaction mixture
was cooled to room temperature, brine (2 ml) was
added, and the resulting mixture was extracted with
tert-butyl methyl ether (2 · 15 ml). The combined or-
ganic layers were washed with brine (2 · 4 ml) to remove
residual DMF and filtered through a pad of charcoal
and Celite to remove any residual sulfur. Evaporation
of the solvent in vacuo produced 0.9 g of acetanilide
(83%). Although the hypothetical pathway depicted in
Scheme 1 served as a guide for designing the acetamida-
tion protocol, the mechanistic course is undoubtedly
complicated and is speculative, at best, at this point. Pre-
liminary results indicated the formation of S8 (finger-
print GC–MS) in the reaction as depicted in Scheme 1.
Under the reaction conditions, nitrosobenzene, a pro-
posed intermediate, also produced acetanilide in >95%
conversion.6 The reductive amidation of nitrobenzene
failed to proceed in thioacetic acid itself. Remarkably,
1-hydroxy-2-nitronaphthalene, when subjected to the
acetamidation conditions, afforded a mixture of the
expected amide and the corresponding oxazole-deriva-
tive, produced via cyclization of the –OH and the amide
group.
KSCOCH3 (4 equiv) in DMF under otherwise identical
conditions, was also converted to acetaminophen as a
result of the concomitant methoxy-cleavage followed
by acetamidation of the –NO2 group; p-nitrophenol
was produced as an intermediate in this process as evi-
denced by HPLC and GC–MS analysis, and p-nitrophe-
nol was the major product when 1 equiv of potassium
thioacetate was utilized.
3. Solvent-free acetamidation
Earlier, we described an efficient solvent-free synthesis
of nitroalcohols utilizing a novel dual catalytic system
consisting of a mineral base (e.g., KOH) and polyethyl-
ene glycol (PEG) type Triton-X surfactant under
homogeneous conditions.7 The crown ether-like comple-
mentary nature of the various types of Triton-X and
their differential solubilization tendencies for specific
counter-ions was demonstrated.8 Surfactant-mediated
protocols were also successfully extended to the conver-
sion of aryl nitro compounds to aryl acetamides. Thus,
solvent-free acetamidation reactions involved treating
a mixture of the aryl nitro compound (1 equiv) with
potassium thioacetate (4 equiv) in the presence of Tri-
ton-X 405 (cat) at 130 ꢁC for 3 h producing the corre-
sponding arylacetamide in good to excellent yields
(Table 1).
In summary, we have developed a novel, one-step ace-
tamidation of aryl nitro compounds. The reaction could
be performed without solvent in the presence of a cata-
lytic amount of surfactant. The acetamidation chemistry
was successfully utilized to convert p-nitrophenol in a
single step to p-hydroxyacetamide (AcetaminophenTM)
in approximately 90% conversion. Further extension of
this technology for the synthesis of various heterocycles
starting from suitably substituted aryl 2-nitro derivative
is in progress.
2. Synthesis of AcetaminophenTM
The one-step acetamidation technology was successfully
utilized to convert p-nitrophenol in a single step to p-
hydroxyacetamide (AcetaminophenTM) in >95% conver-
sion. Interestingly, p-nitroanisole, when treated with

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A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 1861–1864
4. (a) Hwuk, J. R.; Wong, F. F.; Shiao, M.-J. J. Org. Chem.
Acknowledgements
1992, 57, 5254; (b) Shiao, J.-J.; Long-Li, L.; Wei-Shan, K.;
Lin, P.-Y.; Hwu, J. R. J. Org. Chem. 1993, 58, 4742; (c) The
formation of nitrosobenzene via an alternate pathway
involving the nucleophilic attack of RS(À) on the oxygen of
the nitro functionality can not be ruled out.
Financial support provided by the Petroleum Research
Fund (PRF), National Institute of Health (NIH), Welch
Foundation, and Bristol Myers Squibb Corporation is
gratefully acknowledged.
5. (a) Average bond energy of C–S is 65 kcal/mol, C–C is
83 kcal/mol and C–Si is 83 kcal/mol; data obtained from
Michigan State University–Organic home page website
(http://www.cem.msu.edu/~reusch/OrgPage/bndenrgy.htm);
For analogous O- to C-acyl migration, see Baker–Venkata-
raman rearrangement: (b) Bowden, K.; Chehel-Amiran, M.
J. Chem. Soc., Perkin Trans. 2 1986, 2039.
6. An alternate mechanism could involve S–S bond formation
thereby delivering two electrons in the form of a hydride
(HÀ). The S–S bond formation has precedence in peptide
chemistry of cysteine. The resulting dithiane can act as an
effective acylating agent.
References and notes
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a
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