Artigo - Síntese Direta de Paracetamol 2014

Green Chemistry COMMUNICATION Cite this: DOI: 10.1039/c4gc00166d Received 30th January 2014, Accepted 27th March 2014 DOI: 10.1039/c4gc00166d www.rsc.org/greenchem Amidation of phenol derivatives: a direct synthesis of paracetamol (acetaminophen) from hydroquinone† Roxan Joncour,a Nicolas Duguet,a Estelle Métay,a Amadéo Ferreirab and Marc Lemaire*a A direct synthesis of paracetamol (acetaminophen) from hydro- quinone has been developed using ammonium acetate as an amidating agent. The reaction proceeds in acetic acid at elevated temperatures without any metallic catalyst. Under these con- ditions, paracetamol was obtained with high yield and selectivity (>95%). The reaction has also been carried out on the multi-gram scale (44 g of hydroquinone) and a potential process has been pro- posed based on the recycling of the solvent and by-products. This amidation protocol has also been extended to other phenol derivatives. Introduction N-Arylamides are ubiquitous in biologically active molecules and are widely encountered in pharmaceuticals (e.g., atorvasta- tin, imatinib) and agrochemicals. Among the plethora of syn- thetic methods developed so far,1 the direct creation of the C–N bond through cross-coupling of arylhalides (I, Br, Cl) or pseudohalides (OTf, OTs, OMs, etc.) with primary or secondary amides offers one of the best options in terms of versatility. These amidation methods are mainly catalyzed by palladium (Buchwald–Hartwig cross-coupling)2 and copper (Ullmann– Goldberg condensation).3 Alternatively, N-arylamides could be prepared through the Chan–Lam–Evans cross-coupling using arylboronic derivatives under oxidative conditions (Scheme 1).4 Although these methods are robust and well-established, it is necessary to incorporate the leaving group beforehand on the aromatic coupling partner which finally ends up in the waste. Consequently, the atom-economy of the overall process remains modest. N-Acetyl-para-aminophenol (APAP), commonly known as paracetamol or acetaminophen, is a representative of the N-arylamide class. This product is one of the most consumed drugs worldwide with a global production of more than 100 000 tons per year.5 However, the relative simplicity of its structure makes this molecule a low added value compound with an estimated production cost of 3–4 euros per kg.6 Hence, the paracetamol synthesis requires a limited number of steps with excellent efficiencies and high atom-economies. In this context, the aforementioned cross-coupling technologies have not found their place yet. Over the last century, many routes have been explored for the paracetamol production but all those which have emerged industrially are based on the acetyl- ation of para-aminophenol (PAP) as the final stage (Scheme 2). That is the reason why the access to this key intermediate has been the focus of numerous studies. First, para-aminophenol could be obtained by nitration of chlorobenzene, followed by hydrolysis under alkaline con- ditions (and subsequent acidification) and hydrogenation of the corresponding para-nitrophenol (Scheme 2, Route 1).7 This approach requires 3 steps from chlorobenzene (4 from benzene) and generates many salts which induce a modest atom economy of about 38%.8 The alternative approach in which para-nitrophenol is prepared by direct nitration of phenol also provides para-aminophenol in 4 steps from benzene, but provides a process with an improved atom economy of about 54% (Scheme 2, Route 2). In both cases, the nitration leads to a significant proportion of the unwanted ortho-isomer that could not be avoided. A second possibility Scheme 1 Main routes for direct amidation. †Electronic supplementary information (ESI) available: Calculation of atom- economies, the HPLC method, general procedures and characterization data of products. See DOI: 10.1039/c4gc00166d aLaboratoire de CAtalyse SYnthèse et ENvironnement (CASYEN), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS, UMR-5246, Université Claude Bernard Lyon 1, 43 boulevard du 11 novembre 1918, Bât. Curien/ CPE, 69622 Villeurbanne, France. E-mail: marc.lemaire.chimie@univ-lyon1.fr; Fax: +33-472-43-14-08; Tel: +33-472-43-14-07 bMinakem SAS, 145 chemin des Lilas, 59310 Beuvry-la-Forêt, France This journal is © The Royal Society of Chemistry 2014 Green Chem. Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online View Journal involves the hydrogenation of nitrobenzene to phenylhydroxyl- amine that is transformed under acidic conditions to the desired para-aminophenol via a Bamberger rearrangement (Scheme 2, Route 3).9 Although more attractive than route 1, this latter route suffers from moderate selectivity (aniline is obtained as a by-product) and the generation of large quan- tities of sulphate salts that reduces the overall atom-economy (about 52% based on benzene).8 Several attempts have been made to substitute the corrosive and polluting sulphuric acid by solid acids but low selectivities are generally obtained.10 Therefore, there is still an incentive to develop a greener process for the paracetamol production. One of the most promising routes in terms of atom- economy is the direct amidation of hydroquinone with acet- amide since it generates only water as the by-product. It should be noted that hydroquinone is industrially produced by direct oxidation of phenol which is also used as a starting material for the production of para-nitrophenol (Scheme 2, Route 2). Gopinathan et al. have shown that hydroquinone could react with acetamide at elevated temperatures (280–300 °C) in the presence of solid acid catalysts such as zeolite β or a heteropolyacid.11 Under these conditions, parace- tamol was obtained with 86% yield. Qiu et al. have also used a H-SZM-5 zeolite catalyst at 300 °C, confirming the difficulty to activate this reaction probably due to the relatively poor nucleophilicity of acetamide.12 We have previously described the nucleophilic substitution of phenol derivatives – including hydroquinone – with alcohols to give access to aromatic ethers under Brønsted or Lewis acid catalysis at 115 °C.13 As this nucleophilic substitution could also be carried out using aniline, we envisioned that the reac- tion could work with acetamide. Unfortunately, all attempts to incorporate the acetamido group failed under our con- ditions.14 We now report here an alternative method for the direct synthesis of paracetamol from hydroquinone using ammonium acetate as an amidating agent.15 Both starting materials are relatively cheap and available in bulk quantities. The proposed route gives access to paracetamol without salt production and water as the by-product. Results and discussion Inspired by the early work of Bean and Donovan,16 who described the amination of hydroquinone using a mixture of diammonium phosphate and ammonia at 200 °C, we focussed our attention on the use of ammonium acetate for the amida- tion of hydroquinone. It was anticipated that the production of para-aminophenol in the presence of the acetate counter- anion would lead to the desired acetamido functionality (Scheme 3). Thus, hydroquinone (HQ) was treated with a stoichiometric amount of ammonium acetate at 180 °C for 15 hours under solvent-free conditions.17 Satisfyingly, a 63% conversion of hydroquinone to a 91 : 9 mixture of APAP and PAP was achieved with 68% selectivity (Table 1, entry 1). When heated at 220 °C, the reaction was almost complete (98%) but the overall selectivity dramatically dropped to 42% (Table 1, entry 2). This could be explained by the formation of diarylamines that have been identified by LC-MS (Fig. 1). These by-products are probably formed by the reaction of para-aminophenol with hydroquinone and further acetylation and/or acetamidation. We hypothesized that diarylation occurs when working at high concentrations. Therefore, hydroquinone was treated with 3.3 equivalents of ammonium acetate at 180 °C. Under these con- Scheme 3 Proposed route for paracetamol. Scheme 2 Commercial routes for paracetamol production. Table 1 Optimization of reaction conditionsa Entry Temp. (°C) AcONH4/HQ (mol. ratio) Conv.b (%) Selec.b APAP + PAP (%) APAP/PAPb (mol. ratio) 1 180 1/1 63 68 91/9 2 220 1/1 98 42 83/17 3 180 3.3/1 58 94 87/13 4 180 10/1 48 >95 85/15 5 200 10/1 65 >95 85/15 6 220 10/1 98 >95 79/21 a Reaction conditions: hydroquinone (40–100 mmol), AcONH4, 15 hours. b Determined by HPLC. Communication Green Chemistry Green Chem. This journal is © The Royal Society of Chemistry 2014 Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online ditions, the selectivity increased to 94% (Table 1, entry 3) and was further improved to >95% when working with 10 equi- valents (Table 1, entry 4). Meanwhile, the conversion of hydro- quinone slightly dropped from 63 to 48% and the ratio between APAP and PAP remained relatively constant (around 85 : 15). Finally, the increase of the temperature to 200 °C slightly improved the conversion (65%) and a further increase to 220 °C led to 98% conversion. However, acetylation of para- aminophenol was incomplete (79–85%) in both cases (Table 1, entries 5 and 6). In order to increase the acetylation of para-aminophenol to paracetamol, we then turned our attention to the use of acetic acid as an acylating agent. Thus, hydroquinone was reacted under the previously optimized conditions in the presence of acetic acid (5 equiv.) at 220 °C for 15 hours. Pleasingly, the conversion of hydroquinone was 96% and the global selectivity reached >95% (Table 2, entry 1). More importantly, neither para-aminophenol nor its diarylamine derivatives could be detected under these conditions confirming its full acetylation to paracetamol. However, the use of a large excess of ammonium acetate still compromises this route for potential industrial applications. Decreasing its amount to 2 and 1.2 equivalents led to lower conversions (85% and 76%, respecti- vely) while the selectivity and the ratio between APAP and PAP were hardly altered (Table 2, entries 2 and 3). The same obser- vations were made when using 2 equivalents of ammonium acetate and only one equivalent of acetic acid at 180 °C (Table 2, entry 4). Finally, a 2 : 5 mixture of ammonium acetate and acetic acid was selected as a compromise which preserved high selecti- vity with an acceptable conversion (Table 2, entry 2). From a mechanistic point of view, the reaction of hydro- quinone with ammonium acetate could produce para-amino- phenol as an intermediate which could be directly acetylated to acetyl-para-aminophenol in the presence of acetic acid. In this sequence, the formation of paracetamol is accompanied with the production of two molecules of water (Scheme 4, Route 1). However, an alternative mechanism pathway could not be ruled out under our conditions. Indeed, at elevated temperatures, ammonium acetate could be first dehydrated to acetamide and could further react with hydroquinone to produce one molecule of paracetamol along with one molecule of water (Scheme 4, Route 2). This hypothesis has been con- firmed by Noyes and Goebel who have shown that ammonium acetate could be dehydrated to acetamide at 220 °C with 84% conversion, and the equilibrium could be obtained in less than one hour.18 In order to probe whether ammonium acetate or acetamide acts as the nucleophile, we carried out the amidation of hydro- quinone with 10 equivalents of acetamide for 15 hours at 220 °C. Under these conditions, a conversion of 27% was obtained with 84% APAP + PAP selectivity (Table 3, entry 1). This result indicates that acetamide is a less efficient amidat- ing agent than ammonium acetate and corroborates the find- ings of Gopinathan11 and Qiu.12 Indeed, ammonium acetate Table 2 Amidation of hydroquinone in acetic acida Entry AcONH4 (equiv.) AcOH (equiv.) Conv. HQb (%) Selec.b APAP + PAP (%) APAP/PAPb (mol. ratio) 1 10 5 96 >95 100/0 2 2 5 85 >95 100/0 3 1.2 5 76 >95 100/0 4c 2 1 32 >95 99/1 a Reaction conditions: hydroquinone (20–100 mmol), AcONH4, 220 °C, 15 hours. b Determined by HPLC. c Reaction was performed at 180 °C for 15 hours. Scheme 4 Potential mechanism pathways. Fig. 1 Diarylamine by-products detected by LC-MS. Table 3 Amidation of hydroquinone with acetamidea Entry Conditions Conv. HQb (%) Selec.b APAP + PAP (%) APAP/PAPb (mol. ratio) 1 AcNH2: 10 eq. 27 84 94/6 2 CH3CONH2: 2 eq. 56 >95 100/0 AcOH: 5 eq. 3 CH3CONH2: 1 eq. 82 >95 100/0 AcONH4: 1 eq. H2O: 1 eq. CH3COOH: 5 eq. a Reaction conditions: hydroquinone (20–40 mmol), 220 °C, 15 hours. b Determined by HPLC. Green Chemistry Communication This journal is © The Royal Society of Chemistry 2014 Green Chem. Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online gave 98% conversion with >95% selectivity under similar con- ditions (Table 1, entry 6). Then, hydroquinone was treated with 2 equivalents of acetamide and 5 equivalents of acetic acid to give 56% conversion and >95% selectivity (Table 3, entry 2). It should be noted that ammonium acetate gave 85% conversion, proving once again its superiority as an amidating agent (Table 2, entry 2). The presence of acetic acid appears to be essential for the conversion indicating that it could act as both an acylating agent and a catalyst. Finally, the amidation of hydroquinone has been carried out in acetic acid (5 equivalents) using a 1/1/1 mixture of acet- amide–ammonium acetate–water in order to simulate the in situ dehydration of ammonium acetate. In this case, the conversion reached 82% and the overall selectivity was found superior to 95% (Table 3, entry 3). It should be added that no para-aminophenol was detected. This result indicates that both mechanism pathways could be followed under these conditions but with a predominant character for route 1 (Scheme 4). In order to evaluate the potential of this process on a larger scale, a batch of paracetamol was prepared under optimized conditions. Thus, 44 g (0.4 mol) hydroquinone was treated with 63 g ammonium acetate in 114 mL of acetic acid at 230 °C.19 After 15 hours, HPLC analysis of the reaction mixture revealed 93% conversion of hydroquinone. Acetic acid was dis- tillated from the reaction mixture and recovered with 85% yield. After cooling, paracetamol precipitated and 53 g (88%) was recovered by filtration. HPLC of the crude product showed that the purity was higher than 99% (Fig. 2).20 The filtrate was also analyzed by HPLC and a 2 : 1 mixture of acetamide and ammonium acetate was obtained. This mixture could be reused in another batch along with 1 equi- valent of ammonium acetate and 1 equivalent of water as pre- viously shown (Table 3, entry 3). Thus, we have proven that paracetamol can be prepared from hydroquinone with high yields and selectivity. The recycling of the solvent and the reac- tant allows the reduction of the practical E factor of this method. The overall process is depicted in Scheme 5. Scope and limitations In order to assess the synthetic utility of this protocol, a range of phenol derivatives was treated with ammonium acetate in the presence of acetic acid at 220 °C for 15 hours. The results are shown in Table 4. Di- or tri-hydroxybenzenes were first con- sidered. Resorcinol gave 70% conversion and the corres- ponding (mono)acetamide was obtained with 50% isolated yield (Table 4, entry 1). However, catechol gave only 10% con- version and a poor 9% yield (Table 4, entry 2). Phloroglucinol (1,3,5-trihydroxybenzene) reacted completely giving an insolu- ble solid that has not been characterized yet. We assumed that this substrate is very reactive towards nitrogenated nucleo- philes21 and gave a polyaromatic compound. Then, 1-naphthol Fig. 2 HPLC chromatogram of the crude paracetamol. Scheme 5 Amidation of hydroquinone in the medium scale. Table 4 Amidation of phenol derivativesa Entry Phenol derivative Product Conv.b (%) Isolated yield (%) 1 70 50 2 10 9 3 — 100 0c 4 42 36 5 72 56 a Reaction conditions: phenol derivative (40 mmol), AcONH4 (80 mmol), AcOH (200 mmol), 220 °C, 15 hours. b Determined by 1H NMR. c Formation of an insoluble solid. Communication Green Chemistry Green Chem. This journal is © The Royal Society of Chemistry 2014 Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online 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. 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. 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. Notes and references 1 (a) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606–631; (b) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405–3415. 2 For leading references, see: (a) W. C. Shakespeare, Tetra- hedron Lett., 1999, 40, 2035–2038; (b) J. Yin and S. L. Buchwald, Org. Lett., 2000, 2, 1101–1104; (c) J. Yin and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 6043–6048; (d) L. Jiang and S. L. Buchwald, in Metal-Catalyzed Cross- Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004. 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. 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. 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Green Chemistry Communication This journal is © The Royal Society of Chemistry 2014 Green Chem. Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online 11 S. Gopinathan, C. Gopinathan, J. Kuruvilla, S. A. Pardhy and P. Ratnasamy, US, 5,856,575, 1999, to CSIR. 12 J. Qiu, J.-G. Wang and J.-X. Dai, Huaxue Shijie, 2010, 51, 606–608. 13 C. Cazorla, E. Pfordt, M.-C. Duclos, E. Métay and M. Lemaire, Green Chem., 2011, 13, 2482–2488. 14 Unpublished results. 15 Our results were first published as a patent: M. Lemaire, R. Joncour, N. Duguet, E. Métay and A. Ferreira, Procédé de préparation de dérivés d’acétamidophényle, Fr. Demande, 1359972 A1 20131014, 2013. 16 F. R. Bean and T. S. Donovan, US, 2,376,112, 1945, to Eastman Kodak Company. 17 Ammonium acetate (mp = 114 °C) is melted at such a temp- erature and therefore can act as both a reagent and a solvent. 18 W. A. Noyes and W. F. Goebel, J. Am. Chem. Soc., 1922, 44, 2286–2295. 19 The scale-up was carried out at 230 °C in order to obtain a higher conversion of hydroquinone. Indeed, a low concen- tration of hydroquinone facilitates the precipitation of the product from the reaction mixture and furnishes a higher purity of paracetamol. 20 See the ESI† for detailed HPLC conditions. 21 Phloroglucinol reacts smoothly with hydroxylamine at room temperature to give the corresponding trioxime, see: J. C. Bottaro, R. Malhotra and A. Dodge, Synthesis, 2004, 499–500. Communication Green Chemistry Green Chem. This journal is © The Royal Society of Chemistry 2014 Published on 22 April 2014. Downloaded by Gebze Institute of Technology on 12/05/2014 08:04:44. View Article Online