Eco-friendly reductive acetamidation of arylnitro compounds by thioacetate anion through in situ catalytic regeneration: application in the synthesis of Acetaminophen

Article abstract of DOI:10.1016/j.tetlet.2006.03.057

A novel one-step reductive acetamidation of arylnitro compounds mediated by thioacetate anion in thioacetic acid via in situ catalytic regeneration was developed and applied to an efficient synthesis of Acetaminophen.

Full text of DOI:10.1016/j.tetlet.2006.03.057

Tetrahedron Letters 47 (2006) 3221–3223
Eco-friendly reductive acetamidation of arylnitro compounds by
thioacetate anion through in situ catalytic regeneration:
application in the synthesis of AcetaminophenTM
Apurba Bhattacharya,a,* Victor Suarez,a Victoriano Tamez, Jr.a and Jiejun Wub
aDepartment of Chemistry, Texas A&M University-Kingsville. Kingsville, TX 78363, USA
bJ & J Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
Received 20 December 2005; accepted 9 March 2006
Available online 29 March 2006
Abstract—A novel one-step reductive acetamidation of arylnitro compounds mediated by thioacetate anion in thioacetic acid via
in situ catalytic regeneration was developed and applied to an efficient synthesis of AcetaminophenTM.
Ó 2006 Elsevier Ltd. All rights reserved.
Earlier we reported a simple and highly efficient potas-
sium thioacetate mediated one-pot conversion of aryl
nitro compounds to aryl acetamides.1 The reactions
are conducted by employing potassium thioacetate
(4 equiv) as a nucleophile in dipolar aprotic solvents or
in a solvent-free environment in the presence of catalytic
amounts of polyethylene glycol (PEG) type surfactants
such as Triton-X.2 Although the acetamidation proceeds
well with useful levels of conversion and efficiency, its
utility is limited by the use of a large amount of rela-
tively expensive potassium thioacetate. The process is
also encumbered by excessive amounts of environmen-
tally unacceptable salt-waste formation, leading to com-
plex isolation as well as high disposal cost. Furthermore,
use of stoichiometric amounts of the highly nucleophilic
thioacetate anion results in unwanted nucleophilic dis-
placement of halogens as well as dealkylative methoxy
cleavage in electron-poor aromatic systems. This report
describes a facile and cost-effective surfactant-mediated
one-pot reductive acetamidation of aryl nitro derivatives
utilizing inexpensive thioacetic acid in conjunction with
catalytic amounts of base such as potassium carbonate
through in situ catalytic regeneration of thioacetate
anion as the nucleophile. The presence of catalytic
potassium carbonate is essential; no reductive acetami-
dation was observed in its absence in thioacetic acid
under otherwise identical conditions.3 The need for such
methodology originated from our Industry–University
collaborative research program directed towards devel-
oping efficient and environmentally friendly pharmaceu-
tical processes.4
The mechanism proposed for the reductive acetamida-
tion involves a sequential nucleophilic attack of the thio-
acetate anion on the nitro function producing the acyl
intermediate 2a followed by an energetically favorable
intramolecular acetyl shift from S to oxygen 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 expul-
sion (Scheme 1).1,5 Since thioacetic acid is a stronger
acid (pKa = 3.33) than acetic acid (pKa = 4.76), it
occurred to us that the acetate anion generated in the
scheme should deprotonate thioacetic acid, regenerating
the thioacetate anion thereby rendering the process cat-
alytic with respect to thioacetate anion. Thus, conceptu-
ally, the process could be carried out in thioacetic acid
itself in the presence of catalytic amount of a base such
as potassium carbonate. These expectations were fully
realized resulting in an efficient, solvent-free, one-pot
acetamidation of aryl nitro compounds utilizing a
unique acid–base system consisting of thioacetic acid
in conjunction with catalytic amounts of potassium car-
bonate under essentially salt-free conditions.
The catalytic nitroamidation protocol involves treating
a mixture of the aryl nitro compound (1 equiv) with
thioacetic acid (4–8 equiv) and potassium carbonate
*
Corresponding author. Tel.: +1 361 593 2664; fax: +1 361 593
3597; e-mail: kfab002@tamuk.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.057

3222
A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 3221–3223
O
O
O
O
O
N
Ph
2a
O
O
S
Acyl shift
O
O
N
Ph
S
S
N
Ph
N
Ph
S
N
Ph
O
O
- AcO
Sulfur
nitroso
3a
1
O
S
N
- AcO
2a (or 3a)
Acyl shift
NHCOCH3
Ph
Ph
N
O
S
N
Ph
O
O
Ph
Solvent
Sulfur
Scheme 1. Proposed mechanism of thioacetate mediated reductive amidation.
(5 mol %) at 150 °C. The reaction was monitored by
HPLC until completion. Since the reaction is conducted
in the absence of a large amount of a strong sulfur
nucleophile, it obviates the shortcomings associated
with the undesired nucleophilic displacement of aryl
halides or dealkylative methoxy cleavage by thioace-
tate anion (Table 1, entries 4, 5, 6 and 9) thereby essen-
tially complementing the nucleophilic protocol reported
earlier.1 The presence of Triton-X is imperative; the
reactions conducted without Triton-X 405 was consider-
ably slower (three to five times) under otherwise identi-
cal conditions.2 The process is essentially salt-free and
is performed neat; the product is directly obtained by
distillative removal of thioacetic acid. No exhaustive
workup to remove the large amounts of salt was neces-
sary, thus leading to significant process simplicity. These
conditions were successfully applied to prepare various
arylacetamides from a representative group of aryl
nitro compounds in good yields (Table 1). The one-step
acetamidation technology was successfully utilized to
convert p-nitrophenol in a single step to p-hydroxyacet-
amide (AcetaminophenTM or TylenolÒ) in 78% yield. A
typical experimental procedure is as follows: Under
nitrogen, a stirred mixture of 4-chloro-1-nitrobenzene
(1 g, 6.35 mmol), thioacetic acid (1.93 g, 25.39 mmol),
K2CO3 (0.050 g, 0.36 mmol), and dry Triton-X 405
(0.010 g) was heated at 150 °C. The progress of the reac-
tion was monitored by HPLC and GC. After 4 h the
reaction was cooled to room temperature, and acetone
(8 mL) was added and filtered through a sintered glass
funnel. Evaporation of the acetone in vacuo produced
0.975 g of N-(4-chloro-phenyl)-acetamide (91%). It needs
to be stressed that the mechanism depicted in Scheme 1
although served as a guide for designing the salt-free pro-
tocol, is hypothetical at best, and the mechanistic course
is undoubtedly complicated and is yet to be established.
Preliminary results indicated the formation of S8 (finger-
print GCMS) in the reaction as depicted in the scheme.
When nitrosobenzene (a proposed intermediate in the
reaction) was subjected under the reaction conditions,
acetanilide was produced in 80% yield providing indirect
support for the hypothesis (entry 13).
In conclusion, we have developed an efficient, salt-free
environmentally friendly one-pot acetamidation of aryl
nitro compounds under essentially non-nucleophilic con-
ditions. The reaction is performed without solvent in the
presence of catalytic amounts of surfactant and base. The
acetamidation chemistry was successfully utilized to con-
vert p-nitrophenol in a single step to p-hydroxyacetamide
(AcetaminophenTM or TylenolÒ) in good yield. The fact
that the reactions proceed to high conversions, selectivity
and vessel efficiency renders the process practical and eco-
nomically attractive and demonstrates yet another facet
Table 1. Thioacetate anion promoted acetamidation of arylnitro compounds via in situ catalytic regeneration6
CH COSH, K CO (cat), Triton-X 405 (cat), no solvent, 150 ºC
3
2
3
Ar-NHCOCH
3
Ar-NO
2
1
2
Entry
Substrate (Ar)
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1-Isopropyl-4-nitrobenzene
1-Ethyl-4-nitrobenzene
4-Nitrotoluene
2-Bromo-4-nitrotoluene
4-Chloro-1-nitrobenzene
1-Bromo-2-nitrobenzene
Nitrobenzene
4-Nitrophenol
4-Nitroanisole
2,3-Dichloro-1-nitrobenzene
2-Nitrophenol
2-Nitroaniline
N-(4-Isopropyl-phenyl)-acetamide
N-(4-Ethyl-phenyl)-acetamide
N-p-Tolyl-acetamide
N-(3-Bromo-4-methyl-phenyl)-acetamide
N-(4-Chloro-phenyl)-acetamide
N-(2-Bromo-phenyl)-acetamide
N-Phenyl acetamide
N-(4-Hydroxy-phenyl)-acetamide
N-(4-Methoxy-phenyl)-acetamide
N-(2,3-Dichloro-phenyl)-acetamide
N-(2-Hydroxy-phenyl)-acetamide
N-(2-Amino-phenyl)-acetamide
N-Phenyl acetamide
114
67
67
5
77
84
69
99
93
81
76
78
67
78
73
28
80
4
13
14
18
67
14
18
10
1
Nitrosobenzene

A. Bhattacharya et al. / Tetrahedron Letters 47 (2006) 3221–3223
3223
M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 2001, 955; (k) Blackie, J. A.; Turner, N. J.; Wells,
A. S. Tetrahedron Lett. 1997, 38, 3043.
of the utility of the surfactant-mediated solvent-free
technology in organic synthesis.
4. The program was aimed at giving the BS/MS level students
exposure to pharmaceutical process R&D in an academic
setting. Chemical & Engineering News; Education Concen-
trate pp 41, July 23 issue, 2001.
Acknowledgements
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) Hwuk, J. R.; Wong, F. F.; Shiao, M.-J. J. Org. Chem.
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 cannot be ruled out.; (d) Average
bond energy of C–S is 65 kcal/mol and C–C is 83 kcal/mol;
Data obtained from Michigan State University—Organic
homepage website (http://www.cem.msu.edu); For analo-
gous O- to C–acyl migration, see Baker–Venkataraman
rearrangement: (e) Bowden, K.; Chehel-Amiran, M. J.
Chem. Soc., Perkin Trans. 2 1986, 2039; (f) 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
cystein. The resulting dithiane can act as an effective
acylating agent.
References and notes
1. (a) Bhattacharya, A. Abstracts of Papers, 229th National
Meeting of the American Chemical Society, San Diego,
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C.; Suarez, V.; Tichkule, R.; Parmer, G.; Rinaldi, F.
Tetrahedron Lett. 2006, 47, 1861.
2. Bhattacharya, A.; Purohit, V. C.; Rinaldi, F. Org. Proc.
Res. Dev. 2003, 7, 254.
3. For traditional two-step synthesis of amides see: (a)
Nishimura, S. Bull. Chem. Soc. Jpn. 1961, 34, 32; (b)
Adams, R.; Cohen, F. L. Org. Syn. Coll. 1932, 1, 240; (c)
Mendennhall, G. D.; Smith, P. A. S. Org. Syn. Coll. 1973,
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6. (a) All of the compounds gave a 13C resonance of
169 2 ppm, indicative of the amide carbon and
a
resonance at 24 2 ppm indicative of the acetamide
methyl. The 13C and 1H NMR spectra were consistent with
the predictions made by CNMR and HNMR programs
(ACD/Labs,V8.0); (b) For all the compounds GCMS
analysis (Shimadzu QP5050A) in EI mode provided simi-
larity index match of >90% compared to the authentic
samples in the NIST-98 database.