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and 2-naphthol were converted to their corresponding acet-
amides with 42 and 72% conversion and with 36 and 56% iso-
lated yield, respectively (Table 4, entries 4 and 5). Finally,
phenol and other derivatives such as 4-chloro- and 4-nitro-
phenol and 2,6-xylenol were subjected to the same conditions.
Unfortunately, these substrates were totally inactive and were
recovered unaltered.
The fact that dihydroxybenzenes are by far more reactive
than monohydroxybenzenes has already been noted in the
nucleophilic substitution of phenol derivatives with alcohols.13
In that case, we postulated that the mechanism proceeds via
a Wheland-type intermediate involving dearomatisation of
the benzene or naphthalene rings. In the context of this ami-
dation protocol, the reactivity could also be correlated with the
potential ketonization of the phenol derivatives and with the
reactivity of the corresponding ketones towards ammonium
acetate.
3 For selected reviews, see: (a) S. V. Ley and A. W. Thomas,
Angew. Chem., Int. Ed., 2003, 42, 5400–5449; (b) K. Kunz,
U. Scholz and D. Ganzer, Synlett, 2003, 2428–2439;
(c) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev.,
2004, 248, 2337–2364; (d) F. Monnier and M. Taillefer,
Angew. Chem., Int. Ed., 2009, 48, 6954–6971.
4 For recent reviews, see: (a) K. Sanjeeva Rao and T.-S. Wu,
Tetrahedron, 2012, 68, 7735–7754; (b) J. X. Qiao and
P. Y. S. Lam, Synthesis, 2011, 829–856; (c) D. M. T. Chan
and P. Y. S. Lam, in Boronic Acids, ed. D. G. Hall, Wiley-
VCH, Weinheim, 2005, pp. 315–361.
5 China and India are the two main producers of paraceta-
mol with more than 110 000–115 000 tons per year to which
should be added the production of other countries in the
Asia-Pacific region. The rest of the production comes from
the USA for an approximate 30 000–35 000 tons per year.
The production of paracetamol in Europe ceased in 2009.
6 Accurately estimating the production cost of paracetamol is
not a simple task as it depends on the route chosen by the
manufacturer. Notably, the main differences lie in the
selected starting material and the selected technology for
the reduction (H2 versus Fe/HCl) of either para-nitrophenol
or nitrobenzene.
7 For the recent literature on the platinum-catalysed hydrogen-
ation of nitrophenol, see: (a) M. Takasaki, Y. Motoyama,
K. Higashi, S.-H. Yoon, I. Mochida and H. Nagashima, Org.
Lett., 2008, 10, 1601–1604; (b) M. Li, L. Hu, X. Cao, H. Hong,
J. Lu and H. Gu, Chem. – Eur. J., 2011, 17, 2763–2768;
(c) K. Xu, Y. Zhang, X. Chen, L. Huang, R. Zhang and
J. Huang, Adv. Synth. Catal., 2011, 353, 1260–1264;
(d) F. Cárdenas-Lizana, C. Berguerand, I. Yuranov and
L. Kiwi-Minsker, J. Catal., 2013, 301, 103–111.
Conclusions
In conclusion, we have reported a direct synthesis of paraceta-
mol from hydroquinone using ammonium acetate in acetic
acid. The reaction proceeds at elevated temperatures in the
absence of a metallic catalyst and gives excellent selectivity
(>95%). The reaction has also been demonstrated on the
multi-gram scale and a potential process including recycling
of acetic acid has been evaluated. In this context, the proposed
route gives access to paracetamol without salt production and
water as the by-product. Furthermore, this amidation protocol
has also been extended to a small range of phenol derivatives
with low to moderate isolated yields (9–50%). Finally, these
results gave us insights into the potential intermediates but
further studies will be necessary to fully describe the mechan-
ism of this transformation.
8 See the ESI† for the calculation of theoretical atom-
economies.
9 For the recent literature using sulphuric acid, see:
(a) D. C. Caskey and D. W. Chapman, US, 4,571,437, 1986,
to Mallinckrodt; (b) C. V. Rode, M. J. Vaidya and
R. V. Chaudhari, Org. Process Res. Dev., 1999, 3, 465–470;
(c) C. V. Rode, M. J. Vaidya, R. Jaganathan and
R. V. Chaudhari, Chem. Eng. Sci., 2001, 56, 1299–1304;
(d) J. M. Nadgeri, N. S. Biradar, P. B. Patil, S. T. Jadkar,
A. C. Garade and C. V. Rode, Ind. Eng. Chem. Res., 2011, 50,
5478–5484.
Acknowledgements
The authors would like to thank Minakem and the Association
Nationale de la Recherche et de la Technologie (ANRT) for
financial support through a CIFRE grant (2011/1190) for R. J.
10 For the recent literature using solid acid catalysts, see:
(a) R. V. Chaudhari, S. S. Divekar, M. J. Vaidya and
C. V. Rode, US, 6,028,227, 2000, to CSIR; (b) T. Komatsu
and T. Hirose, Appl. Catal., A, 2004, 276, 95–102;
(c) S. Wang, Y. Ma, Y. Wang, W. Xue and X. Zhao, J. Chem.
Technol. Biotechnol., 2008, 83, 1466–1471; (d) P. Liu, Y. Hu,
M. Ni, K. You and H. Luo, Catal. Lett., 2010, 140, 65–68;
(e) S. Wang, Y. Wang, Y. Gao and X. Zhao, Chin. J. Catal.,
2010, 31, 637–644; (f) A. Deshpande, F. Figueras,
M. Lakshmi Kantam, K. Jeeva Ratnam, R. Sudarshan Reddy
and N. S. Sekhar, J. Catal., 2010, 275, 250–256; (g) S. Wang,
Y. Jin, B. He, Y. Wang and X. Zhao, Sci. China Chem., 2010,
53, 1514–1519.
Notes and references
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