A Brief History Behind the Most Used Local Anesthetics

Home , Bupivacaine, Etidocaine, Eucaine, Levobupivacaine, Mepivacaine, Procaine

Tetrahedron xxx (xxxx) xxx

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Tetrahedron report XXX A brief history behind the most used local anesthetics

* Marco M. Bezerra, Raquel A.C. Leao,~ Leandro S.M. Miranda, Rodrigo O.M.A. de Souza

Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, 21941-909, Brazil article info abstract

Article history: The chemistry behind the discovery of local anesthetics is a beautiful way of understanding the devel- Received 13 April 2020 opment and improvement of medicinal/organic chemistry protocols towards the synthesis of biologically Received in revised form active molecules. Here in we present a brief history based on the chemistry development of the most 16 September 2020 used local anesthetics trying to draw a line between the ﬁrst achievements obtained by the use of Accepted 18 September 2020 cocaine until the synthesis of the mepivacaine analogs nowadays. Available online xxx © 2020 Elsevier Ltd. All rights reserved.

Keywords: Anesthetics Medicinal chemistry Organic synthesis Mepivacaíne

Contents

1. Introduction ...... 00 1.1. Pain and anesthesia ...... 00 1.2. Ancient techniques to achieve anesthesia ...... 00 1.3. The objective of this work ...... 00 2. Cocaine ...... 00 2.1. Scientific explorations in South America ...... 00 2.2. The interest in coca leaves ...... 00 2.3. Albert Niemann isolates cocaine ...... 00 2.4. Cocaine’s popularity ...... 00 2.5. The discovery of local anesthesia ...... 00 2.6. Cocaine’s rise and decline on local anesthesia ...... 00 2.7. Essential characteristics of a local anesthetic candidate ...... 00 3. Eucaines ...... 00 3.1. Cocaine as a model for novel local anesthetics ...... 00 3.2. Importance, effects, and disadvantages of the eucaines ...... 00 4. Benzocaine ...... 00 4.1. The discovery of benzocaine ...... 00 4.2. Nitro reducing methods ...... 00 4.3. Catalytic hydrogenation methods ...... 00 4.4. Amination of aryl halides ...... 00 4.5. Alternative methods ...... 00 4.6. Benzocaine limitations ...... 00 5. Procaine ...... 00 5.1. The invention of procaine ...... 00 5.2. The original synthesis ...... 00

Please cite this article as: M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al., A brief history behind the most used local anesthetics, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131628 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

5.3. A modern catalytic hydrogenation method ...... 00 5.4. Copper-mediated C-N coupling ...... 00 5.5. Sustainable oxidation method ...... 00 5.6. Dealkylating amination of secondary alcohols ...... 00 5.7. Limitations of procaine ...... 00 6. Tetracaine...... 00 6.1. Invention of tetracaine ...... 00 6.2. The original synthesis ...... 00 6.3. Catalytic hydrogenation of amides ...... 00 6.4. Continuous flow photoredox amination of aryl halides ...... 00 6.5. Limitations of tetracaine ...... 00 7. Lidocaine...... 00 7.1. The invention of lidocaine ...... 00 7.2. The original synthesis ...... 00 7.3. Ugi tricomponent reactions ...... 00 7.4. Transamidation methods ...... 00 7.5. Batch and continuous flow processes ...... 00 7.6. Across-the-world automated synthesis of lidocaine ...... 00 7.7. Challenges involving the discovery of new local anesthetics ...... 00 8. Mepivacaine family ...... 00 8.1. Invention of the mepivacaine family ...... 00 8.2. The original syntheses ...... 00 8.3. The a-C-H carbamoylation method ...... 00 8.4. Stereospecific synthesis of levobupivacaine ...... 00 8.5. The asymmetric synthesis of mepivacaine family via a “cation-pool” strategy ...... 00 8.6. Continuous flow telescoped hydrogenation ...... 00 8.7. Perspectives on the synthesis of mepivacaine family ...... 00 9. Conclusion ...... 00 Declaration of competing interest ...... 00 Acknowledgement ...... 00 References ...... 00

1. Introduction mepivacaine, bupivacaine, and ropivacaine.

1.1. Pain and anesthesia 2. Cocaine

Pain is a subjective experience that has both physical and psy- 2.1. Scientiﬁc explorations in South America chological origins. This sensation is part of the human condition, however, since the dawn of civilization, humanity has tried to The emperor Francis I of Austria (1768e1835) aspired to restore develop tools to deal with pain. Anesthesia is a state of numbness of his power after the Napoleonic wars, so he arranged the marriage of the senses that can be achieved in two ways: through the loss of his daughter with the heir to the Portuguese throne, which was consciousness, induced by general anesthetics, or by blocking pain located in Rio de Janeiro at the time. A team of Austrian scientists conduction in part of the body, what is called local anesthesia. accompanied the newly married into South America, ventured the sub-continent for years, and gathered precious research on its 1.2. Ancient techniques to achieve anesthesia natural resources [4,5].

The ﬁrst strategies to achieve local anesthesia involved physical 2.2. The interest in coca leaves methods, such as electric shocks, cooling, and pressure [1]. Addi- tionally, today we know that some abundant natural products, such Years later, the stimulant properties of Peruvian coca leaves as menthol, thymol, and eugenol have mild anesthetic properties provoked the curiosity of renowned chemists as Friedrich Wohler€ [2,3]. However, none of these molecules or techniques enabled (1800e1882). The plant abounded in South America, so Wohler€ painless dental treatments, obstetric procedures, and major sur- requested a large sample of coca leaves to a friend, who was about geries. These advances in medicine were made possible thanks to to sail around the globe on board of SS Novara serving an Austrian the discovery of local anesthetics. scientiﬁc expedition [6,7]. Wohler€ delegated his student, Albert Niemann (1834e1861), to investigate the substances present in 1.3. The objective of this work coca leaves [8].

This article aims to present the most relevant local anesthetics 2.3. Albert Niemann isolates cocaine through time starting with cocaine until ropivacaine. This work is divided into two parts: the first one is a historical review of cocaine Niemann isolated an alkaloid, baptized it cocaine, and illustrated and its first synthetic analogs, the eucaines; the second part is a the numbness it caused in 1860: “The solutions have an alkaline review of the synthetic methodologies developed throughout the reaction, a bitterish taste, promote the flow of the saliva, and leave years to prepare benzocaine, procaine, tetracaine, lidocaine, upon the tongue a peculiar numbness, followed by a sensation of

2 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx cold” [9,10]. bicyclic structure. Therefore, chemists invented simplified analogs of ecgonine, such as 4-hydroxy-1,2,2,6,6-pentamethylpiperidine-4- 2.4. Cocaine’s popularity carboxylic acid (4) and 2,2,6-trimethylpiperidin-4-ol (5)(Scheme 2). These molecules were used by George Merling to synthesize Cocaine-based drinks spread throughout the world after the first synthetic local anesthetics, a-eucaine (6), and b-eucaine Niemman’s discovery; Even Pope Leo XIII (1810e1903) com- (7), in 1896 (Fig. 1)[30e32]. mended Vin Mariani, a popular tonic wine at the time, in recog- nition of its benefits [11]. 3.2. Importance, effects, and disadvantages of the eucaines

2.5. The discovery of local anesthesia The eucaines were received with enthusiasm among physicians [33e36]. The eucaine’s effects were similar to those observed in The Peruvian Physician Moreno y Maíz tested cocaine in animals cocaine, both had similar duration and produced smarting when and detected its peripheral effect at the first study on the alkaloid, injected [36]. The b-eucaine was considered superior to a-eucaine conducted in 1868 [12,13]. Twelve years later, Basil von Anrep because the first was not eyeing irritating and remained stable injected cocaine under his skin and declared its efficacy as an when sterilized by boiling [33]; these advantages made b-eucaine anesthetic [14,15]. Despite these observations, local anesthesia important during world war I [37]. arose years later; Carl Koller - influenced by Sigmund Freud, his colleague and cocaine enthusiast [16e18] - anesthetized a patient’s 4. Benzocaine eye with cocaine, operated his glaucoma, and placed a milestone in medical surgery [19e21]. 4.1. The discovery of benzocaine

2.6. Cocaine’s rise and decline on local anesthesia Benzocaine (9) is an ethyl ester of 4-aminobenzoic acid discovered as a local anesthetic by the pharmacist Eduard Ritsert in Cocaine anesthesia popularized among surgeons [22], who 1903 [38]. It was firstly synthesized in 1898 when Limpricht invented numerous techniques to anesthetize increasingly broader reduced the nitro group of ethyl 4-nitrobenzoate (10) using parts of the human body [23e25]; Some doctors believed it was ammonium sulfide (Scheme 3)[39]. harmless [26]. However, important reports exposed dozens of Since then, benzocaine became a good target molecule for deaths associated with cocaine use and it changed the perception of studies on nitro reduction, amination of aryl halides, and alterna- doctors and society [27]. Cocaine proved to be unsafe, but local tive methods to obtain anilines. Some other works were committed anesthesia was too valuable to be forsaken. Since then, chemists specifically in the improvement of benzocaine synthesis, finding have pursued new local anesthetics that fit the demand for more efficient methods, or investing in enabling technologies. increasingly complex medical procedures. 4.2. Nitro reducing methods 2.7. Essential characteristics of a local anesthetic candidate Treating nitro-compounds with metals in acidic media is a The new substances should present five essential characteristics simple technique to obtain amines and anilines. Basa and co- to be considered a successful local anesthetic, accordingly to Dr. workers developed an efficient one-pot nitro reduction/esterifica- Braun, a German physician that studied novel local anesthetics in tion using tin and hydrogen chloride; this synthesis started from 4- the early XX century [28,29]. nitrobenzoic acid (11) and afforded benzocaine (9) in a 93% yield (Scheme 4)[40]. 1) A lower degree of toxicity than cocaine in proportion to its local Following works explored a broad scope of nitroarenes, anesthetic power; including benzocaine, to find milder reaction conditions and 2) Sufficient solubility in water. The solutions should be stable, that different metals, - as indium [41,42], tellurium [43], and iron [44]- is, they should keep without deterioration and capable of ster- obtaining yields between 90 and 95% for the local anesthetic. ilization by boiling; The Wang’s method is a successful example of nitro reduction; 3) Absence of any sign of irritation. There should be no injury to the the author reduced ethyl p-nitrobenzoate using a simple autoclave tissues. The local anesthetics should be easily absorbed without containing nanosized activated iron powder and tap water; causing any after-effects, such as hyperemia, inflammation, in- Benzocaine was obtained in 94% after 2 h at 120 C(Scheme 5)[44]. filtrations, or necroses; Alternatively, the reductions with metal chlorides in protic 4) Compatibility with epinephrine (a vasoconstrictor that in- solvents can be carried out in milder temperatures and pHs. Some creases the duration of anesthesia); works studied the synthesis of benzocaine and other anilines, 5) Rapid penetration of the mucous membrane, and sustainability evaluating the chemoselectivity of the proposed methods. The for medullary anesthesia. authors used titanium tetrachloride [45], tin (II) chloride [46], and A molecule capable of accomplishing these five points would be ferric chloride [47] under diverse reaction conditions, obtaining considered a great candidate to be the next blockbuster local benzocaine in 85e98% yields. anesthetic. Kumar and co-workers revisited an old but atom economic method for the highly chemoselective nitro reduction of nitro- 3. Eucaines arenes: mixing the substrate with a 57% HI aqueous solution and heating it at 90 C for 2 e 4 h. This method affords benzocaine in a 3.1. Cocaine as a model for novel local anesthetics 60% yield (Scheme 6)[48] - which is far from being excellent, but its speed and simplicity make it noteworthy. Chemists inspired themselves in cocaine structure (1) to search A few works investigated the synthesis of benzocaine and a for new synthetic local anesthetics. Cocaine is composed of two broad scope of anilines using NaBH4 in combination with catalysts; moieties: the ecgonine ring (2) and the benzoic acid (3)(Scheme 1). Yanada and co-workers used the reducing agent in presence of The ecgonine ring synthesis would be challenging due to its MoO3 and Na2SeO3 [49]; Yoon and co-workers used a borohydride

3 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 1. Retrosynthesis of cocaine (1) leading to ecgonine (2) and benzoic acid (3).

Scheme 2. Molecular simpliﬁcation of ecgonine ring (2) leading to the analogs 4-hydroxy-1,2,2,6,6-pentamethylpiperidine-4-carboxylic acid (4) and 2,2,6-trimethylpiperidin-4-ol (5).

Scheme 6. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) promoted by a 57% HI aqueous solution. Fig. 1. Chemical structures of a-eucaine (7) and b-eucaine (8).

exchange resin in combination with Ni(OAc)2 [50]; Gohain and co- workers used NaBH4 in combination with ammonium sulfate [51]; Prathap and co-workers used NaBH4 with NiCl2 in an aqueous solution of TEMPO-oxidized cellulose [52]. The goal of these works was to study the chemoselectivity of the methods by preparing a large variety of anilines. These methods require a large excess of NaBH4, which is not optimal under the perspective of benzocaine synthesis, despite the yields between 82 and 97% and the mild reaction conditions. Scheme 3. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) described Füldner and co-workers developed an efﬁcient photocatalyzed by Limpritch. nitro reduction. The authors used a blue light LED as (Scheme 7)a light source, PbBiO2X(X¼ Cl, Br) as a heterogeneous photocatalyst and triethanolamine as an electron donor; this method afforded benzocaine from ethyl 4-nitrobenzoate in 95% yield [53].

4.3. Catalytic hydrogenation methods

Catalytic hydrogenation is the most efficient and atom economic strategy to reduce the nitro group and obtain benzocaine. Adams and Cohen firstly investigated the catalytic hydrogenation of ethyl 4-nitrobenzoate (10), using a PtO catalyst in ethanol under 3 atm fi 2 Scheme 4. One-pot esteri cation/nitro reduction of 4-nitrobenzoic (11) acid produc- e ing benzocaine (9). H2 pressure. The authors obtained benzocaine (9)in91100% yields in gram scale (Scheme 8)[54]. Other studies used benzocaine as a target to investigate the chemoselectivity of the reduction of nitroarenes, exploring different catalysts, ligands, and supports [55e60]. Regarding benzocaine synthesis, these methods did not provide great advances in reaction time, H2 pressure, or yields. Glycerol and hydrazine can also be used as a hydrogen source to nitro reduction. Gawande and co-workers used Fe-Ni magnetic nanoparticle catalyst and glycerol to produce benzocaine (9) in 94% yield (Scheme 9)[61]. This method has two major advantages: the fi Scheme 5. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) using an catalyst can be easily recovered by ltration and glycerol is a safer autoclave reactor. reagent than hydrogen gas.

4 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 7. Photocatalyzed nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9). Scheme 11. Amination of ethyl 4-iodobenzoate (12) promoted by a CuI catalyst.

and efﬁcient alternative to the classic nitro reductions. The major advantages are high yields and mild reaction conditions; These reactions require a metallic catalyst - palladium or copper - and a nitrogen source. Hori investigated the effect of Pd(dba)2 catalyst in combination with a titanium-nitrogen complex prepared from molecular nitrogen, to synthesize benzocaine and a broad scope of anilines; This method afforded benzocaine in 32% yield [67]. Pos- Scheme 8. Hydrogenation of ethyl 4-nitrobenzoate (10) to benzocaine (9) catalyzed by terior works investigated other nitrogen sources as Zn(N(SiMe3)) PtO2. [68] and ammonia gas [69], obtaining benzocaine in 93e94% yields. Tao studied the action of a CuI catalyst in the synthesis of benzocaine and a broad scope of anilines; the author used 2,2,2- triﬂuoroacetamide as a nitrogen source and obtained the local anesthetic from ethyl 4-iodobenzoate (12) in 99% yield (Scheme 11) [70]. Subsequent works investigated different nitrogen sources and Cu (I) salts [71e73], obtaining benzocaine in 89e97% yields.

Scheme 9. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) using 4.5. Alternative methods glycerol as a hydrogen donor. Alternative transformations can also afford benzocaine and Hydrazine offers broader catalyst alternatives: Shi synthesized other anilines using unconventional reagents and different raw benzocaine using hydrazine and a nickel-iron mixed oxide catalyst materials. In recent work, Wang and co-workers developed an Ag- fl [62]. Zhao used a cobalt-promoted molybdenum carbide catalyst catalyzed amination of uoroarenes using the simple salts Ag2CO3 [63]. Lin used a metal-free carbon nanotubes catalyst [64]. Patil and K2S2O8, and NaN3 as a nitrogen source, obtaining benzocaine fl used immobilized iron metal containing ionic liquid as a catalyst from ethyl 4- uorobenzoate (13) in 89% yield (Scheme 12)[74]. This strategy requires longer reaction times and higher temperatures - [65]. These methods afforded benzocaine in yields between 94 and 100%. 20 h reaction at 120 C - when compared to the previously Jensen developed a continuous flow mobile reactor unit for demonstrated transmetalation method but enables the preparation fl transfer hydrogenations. The system afforded benzocaine in 99% of anilines from aryl uorides. yield, in laboratory scale, using Pd/C as the catalyst (Scheme 10). In previous work, Chatterjee demonstrated that is also possible The entire reactor and its components fitted inside a suitcase, to prepare benzocaine and other anilines via amination of boronic fl resulting in a setup weighing less than 10 kg. Aside from the acids; this metal-free amination requires [Bis(tri uoroacetoxy) exceptional mobility, this continuous flow system provides better iodo]benzene (PIFA), N-Bromosuccinimide (NBS) and cyanamide, thermal and pressure control, and it is safer when compared to a affording benzocaine in 83% yield [75]. conventional batch hydrogenator [66]. The previous transformations were concerned about the amino group preparation. Verma and co-workers demonstrated a simple and efficient method to prepare a broad scope of esters, starting 4.4. Amination of aryl halides from alcohols, via photochemical C-H activation catalyzed by an oxo-vanadium-graphitic carbon nitride (VO@g-C3N4). The authors The amination of aryl halides via transmetalation is a modern prepared benzocaine (9) starting from (4-aminophenyl)methanol

Scheme 10. Continuous ﬂow catalytic hydrogenation of ethyl 4-nitrobenzoate (10) producing benzocaine (9) in a suitcase-sized reactor.

5 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

5.2. The original synthesis

Originally, procaine (17) was obtained in two steps. The first step was the esterification of the 4-nitrobenzoyl chloride (18) with 2- (diethylamino)ethan-1-ol (19), resulting in the intermediate nitrocaine (20); the last step was the nitro reduction promoted by tin and concentrated hydrochloric acid, furnishing procaine (17) fl Scheme 12. Amination of ethyl 4- uorobenzoate (13) promoted by Ag2CO3/K2S2O8. (Scheme 15)[78].

5.3. A modern catalytic hydrogenation method

Similar to benzocaine, some authors also used procaine as a target to study the chemoselectivity of reducing agents. Gholinejad and co-workers used a naturally occurring clay, clinochlore, as a catalyst for a nitro reduction via NaBH4; the authors reduced nitrocaine at room temperature, in a 6 h reaction, affording procaine in 93% yield [79]. Zhang and co-workers studied a catalytic Scheme 13. Photochemical oxidation of (4-aminophenyl)methanol (14) promoted by an oxo-vanadium-graphitic carbon nitride catalyst. hydrogenation method for nitroarenes using a catalyst containing CoNx and CoyZnS supported on N-doped porous carbon; the reduction of nitrocaine was carried at 90 C and 5 bar H2 pressure, (14) by mixing the starting material with H2O2 under a 40 Watt furnishing procaine in 99.9% yield after 3 h [60]. domestic bulb, affording the local anesthetic in 85% yield (Scheme 13)[76]. 5.4. Copper-mediated C-N coupling A recent methodology developed by Qiu and co-workers transformed naturally occurring phenols and its derivatives into Maejima and co-workers developed a copper-mediated C-N anilines. The authors used cheap reducing agents to obtain coupling reaction; the authors reacted 2-(diethylamino)ethyl 4- benzocaine (9) and other anilines. The reaction requires high bromobenzoate (21) with metallic copper, 2-aminoethanol, and temperature, a large excess of hydrazine, and substoichiometric TMSN3 at 95 C for 24 h, obtaining procaine in 63% yield (Scheme amounts of NaBH4 and Pd/C; the authors started from ethyl 4- 16)[80]. The conventional nitro reductions give higher yields and hydroxybenzoate (15) obtained benzocaine (9) in 32% yield offer better atom economy, but the metal-catalyzed C-N coupling (Scheme 14)[77]. strategies must always be considered as an option because it opens the possibility of using aryl halides as starting materials. 4.6. Benzocaine limitations 5.5. Sustainable oxidation method A great number of authors visited benzocaine synthesis throughout the decades, studying new catalysts, inventing new Fang developed a metal-free method for the oxidation of nitro transformations, and exploring new technologies. The small size, alkyl arenes to carboxylic acids using O2 and NaOH/EtOH mixture. simplicity, and practical value of this local anesthetic are essential The authors synthesized procaine (17) in three steps: the oxidation to its importance in organic synthesis. However, unlike the previ- of 4-nitrotoluene (22), affording 4-nitrobenzoic acid (23) in 65% ﬁ ously mentioned eucaines, benzocaine does not have an aliphatic yield; then, the telescoped esteri cation and catalytic hydrogena- free amine portion and because of that it is poorly water-soluble; tion of 4-nitrobenzoic acid (23), affording procaine (17) in 91% yield so, benzocaine was limited to topic anesthesia and could not be a (Scheme 17)[81]. This method is highly atom economic and can be substitute to the eucaines. considered a sustainable approach for the synthesis of procaine.

5.6. Dealkylating amination of secondary alcohols 5. Procaine Liu and co-workers developed a novel transformation to obtain 5.1. The invention of procaine anilines using procaine (17) synthesis as a practical example; the dealkylating amination is successful in transforming secondary Procaine is another ester of 4-aminobenzoic acid, invented by alcohols into anilines. The reaction requires NaN3 and triﬂuoro- Alfred Einhorn in 1905 [78]. Procaine’s preeminent characteristic acetic acid (TFA); procaine was obtained in 63% yield from 2- was a great safety; therefore, despite being less potent than cocaine (diethylamino)ethyl 4-(1-hydroxyethyl)benzoate (23) after reac- or the eucaines, it was considered a superior local anesthetic [28]. tion at 40 C for 4 h (Scheme 18). This new transformation enables Sanoﬁ launched procaine in the same year it was invented, under different strategies to obtain procaine, avoiding nitro reduction. the trade name of Novocaine; this product dominated the market of local anesthesia for approximately four decades. 5.7. Limitations of procaine

Procaine, benzocaine, and other 4-aminobenzoic acid derivatives share similar synthetic challenges, due to its structural resemblances. So, some works may present solutions that apply to multiple anesthetics. The major difference between procaine and benzocaine is the diethylamine moiety present in the ﬁrst one; this basic group enhances hydrophilicity, enabling the use of procaine as an injectable solution, and plays an important role in the potency Scheme 14. Synthesis of benzocaine (9) starting from ethyl 4-hydroxybenzoate (15). of the anesthetic. But high hydrophilicity is related to a short

6 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 15. Two-step synthesis of procaine (17) described by Einhorn; ﬁrstly, the esteriﬁcation of 4-nitrobenzoyl chloride (18) followed by the nitro reduction of nitrocaine (20).

Scheme 16. C-N coupling of 2-(diethylamino)ethyl 4-bromobenzoate (21) promoted by metallic copper.

Scheme 17. Metal-free oxidation of 4-nitrotoluene (22) and telescoped esteriﬁcation-reduction of 4-nitrobenzoic acid (11).

Scheme 18. Dealkylating amination of 2-(diethylamino)ethyl 4-(1-hydroxyethyl)benzoate (23). duration of the anesthesia, which is the major weakness of procaine 6.2. The original synthesis [82]. So, chemists looked for a molecule that could deliver a longer effect. According to the original synthesis, Eisleb prepared tetracaine (24) in two steps, starting from sodium 4-aminobenzoate (25): the ﬁrst step was the amine alkylation using 1-bromobutane furnishing the intermediate 4-(butylamino)benzoic acid (26); the second step 6. Tetracaine was the esteriﬁcation with dimethylethanolamine (27), affording tetracaine (24)(Scheme 19). 6.1. Invention of tetracaine

Tetracaine is also a 4-aminobenzoic acid derivative, invented by 6.3. Catalytic hydrogenation of amides Otto Eisleb in 1930 [83]. Its structure was inspired in procaine, with two main differences: tetracaine had a dimethylamino group, Yuan developed a method for the catalytic hydrogenation of instead of a diethylamino; and most important, tetracaine had an n- amides to amines using a [Ru(H)(CO)(Triphos)] catalyst. The au- butyl group attached to the aromatic nitrogen. These aspects made thors synthesized tetracaine (24) in two steps: ﬁrstly, the catalytic tetracaine be the longer-acting local anesthetic available at the hydrogenation of ethyl 4-butyramidobenzoate (28), affording the time. However, it was very toxic. Especially dangerous in surgeries intermediate ethyl 4-(pent-1-en-2-ylamino)benzoate (29) in 89% that required larger volumes of anesthetic [84]. yield; then, the transesteriﬁcation with 2-(dimethylamino)ethanol

7 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 19. Original synthesis of procaine described by Otto Eisleb.

Scheme 20. Amide reduction of 4-butyramidobenzoate (28) followed by transesteriﬁcation of ethyl 4-(pent-1-en-2-ylamino)benzoate (29).

(27), furnishing tetracaine (24) in 85% yield (Scheme 20)[85]. This drug that would eventually overcome both procaine and tetracaine method is a consistent alternative to the classic N-alkylation using had its development marked by serendipity and systematic work. 1-bromobutane but requires one more reaction step. A similar approach was developed by Pan, who prepared 7. Lidocaine tetracaine in an 83% overall yield applying the same transformations in a metal-free approach. The authors reduced the 7.1. The invention of lidocaine amide precursor to the amine using B(C6F5)3 in place of the Ruthenium catalyst [86]. The Swedish chemists’ Nils Lofgren€ and Bengt Lundqvist invented lidocaine in 1943 and it had an unprecedented chemical 6.4. Continuous flow photoredox amination of aryl halides structure for a local anesthetic. At the time, the chemists were synthesizing analogs of isogramine - casually reported as a mild In recent work, Park developed a continuous flow photoredox local anesthetic after a researcher prepared it by mistake [88,89]. € amination of aryl halides using Ni (II) salts and Ru(bpy)3(PF6)2 as After a systematic selection of drug candidates, Lofgren and catalysts. The authors obtained tetracaine (24) in 84% yield in one Lundqvist identified lidocaine, an amino-amide derivative from step, starting from 2-(dimethylamino)ethyl 4-bromobenzoate (21) 2,6-xylidine, as their best local anesthetic [90,91]. Lidocaine was (Scheme 21)[87]; the residence time is short - only 10 min - and the superior to procaine in safety and comparable to tetracaine in small amount of Ru catalyst needed - only 0,02% - argues for its duration [84]; it was so valuable that the company that launched economic viability. lidocaine, Astra AB, became one of the biggest pharmaceutical companies in the world [88,92]. 6.5. Limitations of tetracaine 7.2. The original synthesis Tetracaine was the only option in long-duration surgeries for almost fifteen years. The discovery of novel local anesthetics that Originally, Lofgren€ and Lundqvist obtained lidocaine (30)intwo shared only the positive aspects of procaine and tetracaine was steps: the first step was the acylation of 2,6-xylidine (31) using 2- challenging and would require radical structural modifications. The chloroacetyl chloride (32) to afford the intermediate 2-chloro-N- (2,6-dimethylphenyl)acetamide (33)in70e80% yield; the next step was the amine alkylation between the 33 and diethylamine (34), furnishing lidocaine (30) in quantitative yields (Scheme 22)[91].

7.3. Ugi tricomponent reactions

Adolph and co-workers developed a photo catalyzed tricomponent Ugi reaction using a 100 W Hg lamp and Pt/TiO2 as a photocatalyst; this methodology used 2-isocyano-1,3-dimethyl (35) benzene and diethylamine (34) as starting materials and afforded lidocaine (30) in 82% yield after a 24 h reaction (Scheme Scheme 21. Continuous ﬂow photoredox amination of 2-(dimethylamino)ethyl 4- 23)[93]. bromobenzoate (21) affording tetracaine (24). The described method is a photocatalyzed version of the original

8 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 22. Original synthesis two-step synthesis of lidocaine; ﬁrstly, the acylation of 2,6-xylidine; then, the amine alkylation of 2-chloro-N-(2,6-dimethylphenyl)acetamide (33).

platform could produce 810 doses per day of a 2% lidocaine hydrochloride solution [97]. The compact continuous-flow platform developed by Adamo and co-workers produced the same 810 lidocaine doses per day as the previously mentioned manufacturing platform. The refrigerator-sized factory was able to alternate the production of lidocaine hydrochloride, diphenhydramine hydrochloride, diaz- epam, and fluoxetine hydrochloride by reconfiguring the synthesis modules. The processes were carried out via a multi-step contin- fl Scheme 23. Photocatalized tricomponent Ugi reaction starting from 2-isocyano-1,3- uous- ow synthesis followed by isolation, crystallization, and dimethyl (35) to produce lidocaine (30). formulation systems, able to deliver the medicine on-demand. The authors also chose the classic synthetic strategy, using 2,6-xylidine, 2-chloroacetyl chloride, and diethylamine as starting materials. The Ugi’s lidocaine synthesis, which obtained the local anesthetic in a reaction follows through two tubular reactors: the acylation step 78% yield after 70 h [94]. The Ugi reaction is a useful way to produce occurs in the first one, in 18.4 min residence time; the substitution lidocaine under mild conditions; this strategy shifts the complexity step occurs in the second one, in 17.7 min, furnishing lidocaine in of the synthesis to the preparation of the isonitrile. 90% yield (Scheme 26)[98].

7.4. Transamidation methods 7.6. Across-the-world automated synthesis of lidocaine

Srinivas and co-workers developed an efficient, simple, and Fitzpatrick and co-workers developed a delocalized synthesis of sustainable method for the synthesis of various amides via trans- lidocaine. Using the cloud, servers located in Tokyo, Japan auton- amidation. The methodology required a stoichiometric amount of omously optimized the synthesis conditions in laboratories in K2S2O8 in aqueous media, heating the reagents at 100 C for 10 min Cambridge, UK; A researcher controlled the process from Los with microwave irradiation or conventional thermal conditions. Angeles, USA via an internet connection. This work opened new The authors used 2,6-xylidine (31) and 2-(diethylamino)acetamide possibilities in the API synthesis; this approach frees the researcher (36) as starting materials furnishing lidocaine (30) in a 95% yield or producer from the obligation of having a fixed location, and the (Scheme 24)[95]. time can be spent more efficiently, once the system is autono- Another transamidation was reported by Guangchen and co- mously optimized, with minimal researcher intervention [99]. workers, who synthesized lidocaine (30) and a broad scope of amides under mild conditions. The authors started from 2,6- 7.7. Challenges involving the discovery of new local anesthetics xylidine (31) and phenyl diethylglycinate (37), using LiHMDS to produce lidocaine (30) in 91% yield (Scheme 25)[96]. The pro- The modern approaches that use lidocaine as a target reflect the cedure is transition-metal-free, operationally simple, and carried at importance of this local anesthetic. Even nowadays it is extremely room temperature. popular due to its safety and versatility. The high standards established by lidocaine demanded that the next generation of local 7.5. Batch and continuous flow processes anesthetics should be even more efficient.

Monbaliu and co-workers designed a pharmaceutical 8. Mepivacaine family manufacturing platform for the synthesis of lidocaine hydrochloride. The authors used the classic synthetic strategy - using 2,6- 8.1. Invention of the mepivacaine family xylidine, 2-chloroacetyl chloride, and diethylamine as starting materials - and developed an advanced end-to-end puriﬁcation, The next family of local anesthetics arose, once again, in Swe- extraction, reactive crystallization, antisolvent cooling crystalliza- den. Bo af Ekenstam synthesized Mepivacaine and Bupivacaine, tion, and aqueous liquid formulation processes. The manufacturing both launched as racemic mixtures; as well as levobupivacaine and

Scheme 24. Transamidation of 2-(diethylamino)acetamide (36) and 2,6-xylidine (31) promoted by K2S2O8.

9 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 25. Transamidation of phenyl diethylglycinate (37) and 2,6-xylidine (31) promoted by LiHMDS.

Scheme 26. Multi-step continuous flow synthesis of lidocaine (30) in a compact and reconfigurable system. ropivacaine, launched as enantiomerically pure products 8.4. Stereospecific synthesis of levobupivacaine [100e102]. These local anesthetics are amino-amides derivatives from 2,6-xylidine, like lidocaine. However, the free amino group in Adger and co-workers reported a five-step synthesis of levo- the mepivacaine family is an alkylated piperidine ring; The length bupivacaine, starting from the protected L-Lysine. Firstly, the Cbz-L- of the alkyl chain indicates the local anesthetic - mepivacaine has a Lysine (45) was treated with NaNO2 and NaOAc in acetic acid, methyl group, ropivacaine an n-propyl group, and bupivacaine/ yielding the intermediate (S)-6-acetoxy-2-(((benzyloxy)carbonyl) levobupivacaine an n-butyl group. Mepivacaine is similar to lido- amino)hexanoic acid (46); The second step was the amide coupling caine concerning potency and duration [100]; Bupivacaine, though, via carbodiimide between 46 and 2,6-xylidine (31), furnishing the is three times more potent than mepivacaine and offers a much intermediate (S)-5-(((benzyloxy)carbonyl)amino)-6-((2,6- longer effect [103]. Ropivacaine and levobupivacaine gained space dimethylphenyl)amino)-6-oxohexyl acetate (47); then, occurred after the discovery that (R) enantiomers of the mepivacaine family the acetoxy hydrolysis followed by tosylation affording the tosy- are related to a higher incidence of cardiac arrest [104,105], so the lated intermediate (S)-5-(((benzyloxy)carbonyl)amino)-6-((2,6- (S) enantiomers were presented as a safer option [106]. dimethylphenyl)amino)-6-oxohexyl 4-methylbenzenesulfonate (48); in the fourth step, the 48 suffered a one-pot deprotection/ 8.2. The original syntheses cyclization via catalytic hydrogenation promoted by H2 and Pd/C, furnishing (S)-42; Lastly, the authors reacted (S)-42 with 1- Originally, Ekenstam proposed a two-step synthesis starting bromobutane, furnishing levobupivacaine ((S)-40) in 38% overall from 2,6-xylidine (31) and racemic piperidine-2-carboxylic acid yield (Scheme 29)[108]. (38), or the optical isomer (S)-piperidine-2-carboxylic acid ((S)-38), This work applied simple chemical transformations and low- to produce mepivacaine (39), bupivacaine (40), ropivacaine ((S)- cost starting materials to stereospecifically produce levobupiva- 41), and levobupivacaine ((S)-40). The strategy involves the amide caine; The number of steps could be a downside of this strategy. coupling via acid chloride between 2,6-xylidine (31) and the racemic 38 or optically pure carboxylic acid (S)-38, furnishing the 8.5. The asymmetric synthesis of mepivacaine family via a “cation- intermediate N-(2,6-dimethylphenyl)piperidine-2-carboxamide pool” strategy (42) or the (S)-enantiomer (S)-42; then, the racemic or optically pure intermediate is N-alkylated with the suitable alkyl halide to Shankaraiah and co-workers developed a “cation-pool” strategy afford the correspondent local anesthetic (Scheme 27)[101,102]. for the asymmetric synthesis of (S)-mepivacaine ((S)-39), levobupivacaine ((S)-40), and ropivacaine ((S)-41). The authors applied 8.3. The a-C-H carbamoylation method anodic oxidation and soft nucleophiles to prepare an (S)-pipecolic acid precursor, tert-butyl (S)-2-(2-cyanopiperidin-1-yl)-2- Yoshimitsu and co-workers developed the synthesis of mepi- oxoacetate (49), used in the synthesis of the local anesthetics. The vacaine via a-C-H carbamoylation; The authors mixed the readily first step is the telescoped acidic hydrolysis followed by amidation available N-methylpiperine (43) with 2,6-dimethylpheylisocyanate with 2,6-xylidine (31) via EDC/HOBt, affording the intermediate (44) and Et3B at room temperature for 42 h, obtaining 52% yield of (S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide ((S)-42); the mepivacaine (39)(Scheme 28). This approach presented only alkylation of the piperidine ring with formaldehyde/NaCNBH3,1- moderate yields, but it shifts the complexity of the synthesis to the bromopropane or 1-bromobutane leads to (S)-mepivacaine ((S)- xylidine moiety, avoiding the amidation/alkylation steps, present in 39), ropivacaine ((S)-41) or levobupivacaine ((S)-40), respectively, the classic strategy [107]. in yields between 80 and 85% (Scheme 30)[109].

10 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 27. Original synthesis of mepivacaine (39), bupivacaine (40), ropivacaine ((S)-41) and levobupivacaine ((S)-40) described by Ekenstam.

8.6. Continuous ﬂow telescoped hydrogenation

Suveges and co-workers developed a fast method to synthesize the mepivacaine (39), bupivacaine (40) and rac-ropivacaine (41) using continuous ﬂow technology. The authors accomplished a telescoped catalytic hydrogenation/reductive amination using a continuous-ﬂow H-Cube reactor; the methanolic solution of N- (2,6-dimethylphenyl)picolinamide (50) in the presence of a suit- Scheme 28. Synthesis of mepivacaine (39) via a-C-H carbamoylation using N-meth- able aliphatic aldehyde e formaldehyde, propionaldehyde or ylpiperine (43) and 2,6-dimethylpheylisocyanate (44) as starting materials.

Scheme 29. Stereospeciﬁc synthesis of levobupivacaine ((S)-40) starting from L-lysine (45).

11 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Scheme 30. Synthesis of (S)-mepivacaine ((S)-39), ropivacaine ((S)-41) or levobupivacaine ((S)-40) via ‘cation-pool’ strategy.

Scheme 31. Continuous flow telescoped catalytic hydrogenation/reductive amination for the synthesis of mepivacaine (39), bupivacaine (40) and rac-ropivacaine (41). butyraldehyde - was pumped through a 10% Pd/C cartridge, under safer than cocaine. hydrogen pressure - the H-Cube system generates hydrogen in-situ, The discovery of new technologies for the synthesis of these providing a safer and more convenient reaction setup. The racemic molecules can be analyzed in parallel to the history of local anes- local anesthetics were obtained in yields between 80 and 89% thesia. The growing concern with sustainability, automation, and (Scheme 31)[110]. machine learning highlights the importance of tools such as catalysis, flow chemistry, and cloud-based servers to the improve- 8.7. Perspectives on the synthesis of mepivacaine family ment of organic synthesis processes. These approaches associated with the study of novel transformations can revolutionize the way The mepivacaine family is widely used in modern surgery, local anesthetics are produced and delivered to the patients. especially in long-duration procedures. The major challenges present in the synthesis of these local anesthetics are the development Declaration of competing interest of methods for the amide bond formation that are milder, safer, more sustainable; the study of new methods to the asymmetric The authors declare that they have no known competing synthesis of (S)-piperidine-2-carboxylic acid; and the exploration financial interests or personal relationships that could have of novel synthetic strategies and technologies that could allow appeared to influence the work reported in this paper. different or more efficient routes. The previously depicted works addressed some of these challenges, but there is still room for new Acknowledgement ideas. Authors thanks CAPeS, CNPq and FAPERJ for financial support. 9. Conclusion References After the isolation of cocaine and the experiments of Carl Koller, humanity was faced with local anesthesia, a tool that could no [1] M.E. Ring, The history of local anesthesia, J. Calif. Dent. Assoc. 35 (2007) 275e282. longer be left out. Local anesthetics are a disruptive technology that [2] G. Haeseler, D. Maue, J. Grosskreutz, J. Bufler, B. Nentwig, S. Piepenbrock, has enabled the medical practice to effectively perform various R. Dengler, M. Leuwer, Voltage-dependent block of neuronal and skeletal surgical procedures, such as ophthalmic, obstetric, dental opera- muscle sodium channels by thymol and menthol, Eur. J. Anaesthesiol. | EJA 19 (2002). https://journals.lww.com/ejanaesthesiology/Fulltext/2002/08000/ tions, among others. Cocaine served as a model for the posterior Voltage_dependent_block_of_neuronal_and_skeletal.5.aspx. local anesthetics. The new molecules should be more effective and [3] C.-K. Park, K. Kim, S.J. Jung, M.J. Kim, D.K. Ahn, S.-D. Hong, J.S. Kim, S.B. Oh,

12 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Molecular mechanism for local anesthetic action of eugenol in the rat tri- selective reduction of aromatic nitro compounds: ethyl 4-aminobenzoate: geminal system, PAIN® 144 (2009) 84e94, https://doi.org/10.1016/ (benzoic acid, 4-amino-, ethyl ester), Org. Synth. 81 (2003) 188e194. j.pain.2009.03.016. [43] R.H. Khan, Tellurium mediated reduction of aromatic nitro groups, J. Chem. [4] E.S. Ramírez, A.J. Lacombe, As relaçoees entre a Austria e o Brasil 1815-1889, Res. 2000 (2000) 290e291. 1a, Companhia Editora Nacional, Saeo Paulo, 1968. [44] L. Wang, P. Li, Z. Wu, J. Yan, M. Wang, Y. Ding, Reduction of nitroarenes to [5] F.B. Clemente, M.K.M. Carrion, T.S. Dedecek, Relaçoes~ diplomaticas entre aromatic amines with nanosized activated metallic iron powder in water, Brasil e Austria, no período de 1822 a 1889, Relaçoes~ Int. No Mundo Atual 1 Synthesis 2003 (2003) 2001e2004. (2000) 89e108. [45] J. George, S. Chandrasekaran, Selective reduction of nitro compounds with [6] S.B. Karch, A brief history of cocaine, 2o, Boca Raton, FL, 2017. titanium (II) reagents, Synth. Commun. 13 (1983) 495e499. [7] C. Pumberger, Die Berichte der Wiener Zeitung über die Weltumsegelung der [46] F.D. Bellamy, K. Ou, Selective reduction of aromatic nitro compounds with Novara in den Jahren 1856e1860, Universitat€ Wien, 2013. stannous chloride in non acidic and non aqueous medium, Tetrahedron Lett. [8] F. Wohler,€ Ueber eine organische Base in der Coca, Ann. Chem. Pharm. 114 25 (1984) 839e842. (1860) 213e217. [47] D.G. Desai, S.S. Swami, S.B. Hapase, Rapid and inexpensive method for [9] A. Niemann, Ueber eine neue organische Base in den Cocablattern,€ Arch. reduction of nitroarenes to anilines, Synth. Commun. 29 (1999) 1033e1036. Pharm. (Weinheim) 153 (1860) 129e155, https://doi.org/10.1002/ [48] J.S.D. Kumar, M.M. Ho, T. Toyokuni, Simple and chemoselective reduction of ardp.18601530202. aromatic nitro compounds to aromatic amines: reduction with hydriodic [10] A. Niemann, On the alkaloid and other constituents of coca leaves, Am. J. acid revisited, Tetrahedron Lett. 42 (2001) 5601e5603. Pharm. 33 (1861) 122e126. [49] K. Yanada, R. Yanada, H. Meguri, Promoting effect of na2SeO3 on the activity [11] E.I. Eger, L.J. Saidman, R. Westhorpe, The wondrous story of anesthesia. of MoO3 catalyst for nitroarenes reduction to amines with sodium borohy- http://public.eblib.com/choice/publicfullrecord.aspx?p¼1466718, 2014. dride, Tetrahedron Lett. 33 (1992) 1463e1464. [12] T. Moreno y Maïz, Recherches chimiques et physiologiques sur l’erythoxilum [50] N.M. Yoon, J. Choi, Reduction of nitro compounds with borohydride ex- coca du perou et la cocaïne, 1868. change resin-nickel acetate, Synlett (1993) 135e136. [13] E. Marret, M. Gentili, F. Bonnet, Moreno y Maïz: a missed rendezvous with [51] S. Gohain, D. Prajapati, J.S. Sandhu, A new and efficient method for the se- local anesthesia, Anesthesiol. Anesthesiol. 100 (2004) 1321e1322. lective reduction of nitroarenes: use of ammonium sulphate-sodium boro- [14] B. Anrep, Ueber die physiologische Wirkung des Cocaïn, Pflüger Arch. für die hydride,, Chem. Lett. 24 (1995) 725e726. Gesammte Physiol. des Menschen und der Thiere 21 (1880) 38e77. [52] K.J. Prathap, Q. Wu, R.T. Olsson, P. Diner, Catalytic reductions and tandem [15] S.M. Yentis, K.V. Vlassakov, Vassily von Anrep, forgotten pioneer of regional reactions of nitro compounds using in situ prepared nickel boride catalyst in anesthesia, Anesthesiology 90 (1999) 890e895. nanocellulose solution, Org. Lett. 19 (2017) 4746e4749. [16] S. Freud, Über coca, Cent. Feur Die Gesammte Ther 2 (1884) 290e314. [53] S. Füldner, P. Pohla, H. Bartling, S. Dankesreiter, R. Stadler, M. Gruber, [17] D. Galbis-Reig, Sigmund Freud, Carl Koller, The controversy surrounding the A. Pfitzner, B. Konig,€ Selective photocatalytic reductions of nitrobenzene discovery of local anesthesia, Int. Congr. Ser 1242 (2002) 571e575, https:// derivatives using PbBiO2X and blue light, Green Chem. 13 (2011) 640e643. doi.org/10.1016/S0531-5131(02)00606-4. [54] R. Adams, F.L. Cohen, Ethyl p-Aminobenzoate, Org. Synth. 8 (1928) 66, [18] A. dos Reis Jr, Sigmund Freud (1856-1939) and Karl Koller€ (1857-1944) and https://doi.org/10.1002/0471264180.os008.19. the discovery of local anesthesia, Brazilian J. Anesthesiol 59 (2009) 244e257. [55] M. Takasaki, Y. Motoyama, K. Higashi, S.-H. Yoon, I. Mochida, H. Nagashima, [19] C. Koller, On the use of cocaine for producing anaesthesia on the eye, Lancet Chemoselective hydrogenation of nitroarenes with carbon nanofiber- 124 (1884) 990e992, https://doi.org/10.1016/S0140-6736(02)28859-5. supported platinum and palladium nanoparticles, Org. Lett. 10 (2008) [20] H. Knapp, Cocaine and its Use in Ophthalmic and General Surgery, Putnam, 1601e1604. New York, 1885. [56] Y. Motoyama, K. Kamo, H. Nagashima, Catalysis in polysiloxane gels: [21] C. Koller, Historical notes on the beginning of local anesthesia, J. Am. Med. platinum-catalyzed hydrosilylation of polymethylhydrosiloxane leading to Assoc. 90 (1928) 1742e1743. reusable catalysts for reduction of nitroarenes, Org. Lett. 11 (2009) [22] R. Matas Local, Regional Anesthesia, A retrospect and prospect,, Am. J. Surg. 1345e1348. 25 (1934) 189e196, https://doi.org/10.1016/S0002-9610(34)90158-6. [57] P. Lara, A. Suarez, V. Colliere, K. Philippot, B. Chaudret, Platinum N-hetero- [23] R.J. Hall, Hydrochlorate of cocaine, New York Med. J. 40 (1884) 643e645. cyclic carbene nanoparticles as new and effective catalysts for the selective http://hdl.handle.net/2027/nnc2.ark:/13960/t4nk6259b. hydrogenation of nitroaromatics, ChemCatChem 6 (2014) 87e90, https:// [24] J. Corning, Spinal anaesthesia and local medication of the cord with cocaine, doi.org/10.1002/cctc.201300821. New York Med. J. 42 (1885) 483. [58] Y. Ren, H. Wei, G. Yin, L. Zhang, A. Wang, T. Zhang, Oxygen surface groups of [25] A. Bier, Versuche über Cocainisierung des Rückenmarkes, Dtsch. Zeitschrift activated carbon steer the chemoselective hydrogenation of substituted Für Chir. 51 (1899) 361e369. nitroarenes over nickel nanoparticles, Chem. Commun. 53 (2017) [26] J.B. Mattison, Cocaine poisoning, Indian Med. Gaz. 30 (1895) 82. 1969e1972. [27] J.B. Mattison, Cocaine dosage and cocaine addiction, Lancet 129 (1887) [59] X. Shi, X. Wang, X. Shang, X. Zou, W. Ding, X. Lu, High Performance, Active, 1024e1026, https://doi.org/10.1016/S0140-6736(00)49824-7. Sites of a ceria-supported palladium catalyst for solvent-free chemoselective [28] H. Braun, Ueber einige neue ortliche€ anaesthetica (stovain, alypin, novocain), hydrogenation of nitroarenes, ChemCatChem 9 (2017) 3743e3751. Dtsch. Medizinische Wochenschrift 31 (1905) 1667e1671. [60] G. Zhang, F. Tang, X. Wang, P. An, L. Wang, Y.-N. Liu, Co, N-codoped porous [29] C.N. Le Brocq, Report ON the local anaesthetics recommended as substitutes carbon-supported Co y ZnS with superior activity for nitroarene hydroge- for cocaine, Br. Med. J. 1 (1909) 783e785, https://doi.org/10.1136/ nation, ACS Sustain. Chem. Eng. 8 (2020) 6118e6126. bmj.1.2517.783. [61] M.B. Gawande, A.K. Rathi, P.S. Branco, I.D. Nogueira, A. Velhinho, [30] E. Fischer, Ueber das Triactonamin und seine Homologen, Berichte Der Dtsch. J.J. Shrikhande, U.U. Indulkar, R. V Jayaram, C.A.A. Ghumman, N. Bundaleski, Chem. Gesellschaft 17 (1884) 1788e1799. Regio-and chemoselective reduction of nitroarenes and carbonyl compounds [31] G. Merling, Eucain, Berichte Der Dtsch. Pharm. Gesellschaft 6 (1896) over recyclable magnetic Ferrite nickel nanoparticles (Fe3O4 Ni) by using 173e176. glycerol as a hydrogen source, Chem. Eur J. 18 (2012) 12628e12632. [32] G. Merling, The synthetic production of eucaine, Am. Drug. Pharm. Rec. 29 [62] Q. Shi, R. Lu, L. Lu, X. Fu, D. Zhao, Efficient reduction of nitroarenes over (1897) 292. nickel-iron mixed oxide catalyst prepared from a nickel-iron hydrotalcite [33] J.C. Clemesha, Eucain B - a further note on new local anesthetics, Buffalo precursor, Adv. Synth. Catal. 349 (2007) 1877e1881. Med. J. 36 (1897) 845e847. [63] Z. Zhao, H. Yang, Y. Li, X. Guo, Cobalt-modified molybdenum carbide as an [34] P. Dolbeau, in: A Contribution to the Study of Anaesthesia in Ocular Surgery efficient catalyst for chemoselective reduction of aromatic nitro compounds, by Means of Eucaine B, The University of Paris, 1897. Green Chem. 16 (2014) 1274e1281, https://doi.org/10.1039/C3GC42049C. [35] Eucaine Lohmann, B as a local anaesthetic in surgery, Ther. Monatshefte. [64] Y. Lin, S. Wu, W. Shi, B. Zhang, J. Wang, Y.A. Kim, M. Endo, D.S. Su, Efficient (1897) 427. and highly selective boron-doped carbon materials-catalyzed reduction of [36] P. Silex, Zwei neue locale anasthetica,€ Ther. Monatshefte (1897) 216e217. nitroarenes, Chem. Commun. 51 (2015) 13086e13089. [37] M.R.S. Creese, Martha Annie Whiteley (1866-1956): chemist and Editor, Bull. [65] N.M. Patil, T. Sasaki, B.M. Bhanage, Immobilized iron metal-containing ionic Hist. Chem. 20 (1997) 42e45. liquid-catalyzed chemoselective transfer hydrogenation of nitroarenes into [38] E. Ritsert, Aromatic Esters and Process of Making the Same, 1903. US748101. anilines, ACS Sustain. Chem. Eng. 4 (2016) 429e436. [39] H. Limpricht, Ueber die Verbindungen aus Benzoylchlorid oder Phtalyl- [66] R.K. Jensen, N. Thykier, M. V Enevoldsen, A.T. Lindhardt, A high mobility chlorid und den Estern der drei Oxybenzoes€ auren,€ Justus Liebigs Ann. Chem. reactor unit for R&D continuous flow transfer hydrogenations, Org. Process 303 (1898) 274e289. Res. Dev. 21 (2017) 370e376. [40] S.C. Basa, C. Srinivasulu, One-pot process for benzocaine from p-nitrobenzoic [67] K. Hori, M. Mori, Synthesis of nonsubstituted anilines from molecular ni- acid, Org. Prep. Proced. Int. 13 (1981) 424e425. trogen via transmetalation of arylpalladium complex with Titanium ni- [41] C.J. Moody, M.R. Pitts, Indium as a reducing agent: reduction of aromatic trogen fixation complexes, J. Am. Chem. Soc. 120 (1998) 7651e7652. nitro groups, Synlett 1998 (1998) 1028. [68] D.-Y. Lee, J.F. Hartwig, Zinc trimethylsilylamide as a mild ammonia equiva- [42] B.K. Banik, I. Banik, F.F. Becker, Indium/ammonium chloride-mediated lent and base for the amination of aryl halides and triflates, Org. Lett. 7

13 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

(2005) 1169e1172. [96] G. Li, M. Szostak, Highly selective transition-metal-free transamidation of [69] G.D. Vo, J.F. Hartwig, Palladium-catalyzed coupling of ammonia with aryl amides and amidation of esters at room temperature, Nat. Commun. 9 (2018) chlorides, bromides, iodides, and sulfonates: a general method for the 1e8. preparation of primary arylamines,, J. Am. Chem. Soc. 131 (2009) [97] J.-C.M. Monbaliu, T. Stelzer, E. Revalor, N. Weeranoppanant, K.F. Jensen, 11049e11061. A.S. Myerson, Compact and integrated approach for advanced end-to-end [70] C.-Z. Tao, J. Li, Y. Fu, L. Liu, Q.-X. Guo, Copper-catalyzed synthesis of primary production, purification, and aqueous formulation of lidocaine hydrochlo- arylamines from aryl halides and 2, 2, 2-trifluoroacetamide, Tetrahedron ride, Org. Process Res. Dev. 20 (2016) 1347e1353. Lett. 49 (2008) 70e75. [98] A. Adamo, R.L. Beingessner, M. Behnam, J. Chen, T.F. Jamison, K.F. Jensen, J.- [71] J. Kim, S. Chang, Ammonium salts as an inexpensive and convenient nitrogen C.M. Monbaliu, A.S. Myerson, E.M. Revalor, D.R. Snead, On-demand source in the Cu-catalyzed amination of aryl halides at room temperature, continuous-flow production of pharmaceuticals in a compact, reconfigurable Chem. Commun. (2008) 3052e3054. system, Science (80-. ) 352 (2016) 61e67. [72] D. Wang, Q. Cai, K. Ding, An efficient copper-catalyzed amination of aryl [99] D.E. Fitzpatrick, T. Maujean, A.C. Evans, S. V Ley, Across-the-World auto- halides by aqueous ammonia, Adv. Synth. Catal. 351 (2009) 1722e1726. mated optimization and continuous-flow synthesis of pharmaceutical agents [73] C. Tao, W. Liu, A. Lv, M. Sun, Y. Tian, Q. Wang, J. Zhao, Room-temperature operating through a cloud-based server, Angew. Chem. Int. 57 (2018) copper-catalyzed synthesis of primary arylamines from aryl halides and 15128e15132, https://doi.org/10.1002/anie.201809080. aqueous ammonia, Synlett (2010) 1355e1358. [100] B. af Ekenstam, B. Egner, L.R. Ulfendahl, K.G. Dhuner, O. Oljelund, Trials with [74] Y. Wang, C. Wei, R. Tang, H. Zhan, J. Lin, Z. Liu, W. Tao, Z. Fang, Silver-cata- carbocaine: a new local anaesthetic drug,, Br. J. Anaesth. 28 (1956) 503e506. lyzed intermolecular amination of fluoroarenes, Org. Biomol. Chem. 16 [101] B. af Ekenstam, B. Egner, G. Pettersson, N-alkyl pyrrolidine and N-alkyl (2018) 6191e6194. piperidine carboxylic acid amides, Acta Chem. Scand. 11 (1957) 1183e1190, [75] N. Chatterjee, M. Arfeen, P.V. Bharatam, A. Goswami, A metal and base-free https://doi.org/10.3891/acta.chem.scand.11-1183. chemoselective primary amination of boronic acids using cyanamidyl/aryl- [102] B. af Ekenstam, C. Bovin, L-N-n-propylpipecolic acid-2,6-xylidide and cyanamidyl radical as aminating species: synthesis and mechanistic studies method for preparing the same, WO8500599, 1985. by density functional theory, J. Org. Chem. 81 (2016) 5120e5127. [103] F. Henn, R. Brattsand, Some Pharmacological and Toxicological properties of [76] S. Verma, R.B.N. Baig, C. Han, M.N. Nadagouda, R.S. Varma, Oxidative ester- a new long-acting local analgesic, LAC-43 (Marcaine), in comparison with ification via photocatalytic CeH activation, Green Chem. 18 (2016) 251e254. mepivacaine and tetracaine, Acta Anaestheol. Scand. 21 (1966) 9e30. [77] Z. Qiu, L. Lv, J. Li, C.-C. Li, C.-J. Li, Direct conversion of phenols into primary [104] G.A. Albright, Cardiac arrest following regional anesthesia with etidocaine or anilines with hydrazine catalyzed by palladium, Chem. Sci. 10 (2019) bupivacaine, Anesthesiology 51 (1979) 285e287. 4775e4781. [105] J.E. Heavner, Cardiac toxicity of local anesthetics in the intact isolated heart [78] A. Einhorn, Alkamin esters of para-aminobenzoic acid, US812554, 1905. model: a review, Reg. Anesth, Pain Med. 27 (2002) 545e555, https://doi.org/ [79] M. Gholinejad, E. Oftadeh, M. Shojafar, J.M. Sansano, B.H. Lipshutz, Syner- 10.1053/rapm.2002.36458. gistic effects of ppm levels of palladium on natural clinochlore for reduction [106] B.F. Tullar, Optical isomers of mepivacaine and bupivacaine, J. Med. Chem. 14 of nitroarenes, ChemSusChem. 12 (2019) 4240e4248, https://doi.org/ (1971) 891e892. 10.1002/cssc.201901535. [107] T. Yoshimitsu, K. Matsuda, H. Nagaoka, K. Tsukamoto, T. Tanaka, Radical [80] T. Maejima, Y. Shimoda, K. Nozaki, S. Mori, Y. Sawama, Y. Monguchi, H. Sajiki, fixation of functionalized carbon resources: a-sp3C H carbamoylation of One-pot aromatic amination based on carbonenitrogen coupling reaction tertiary amines with aryl isocyanates, Org. Lett. 9 (2007) 5115e5118. between aryl halides and azido compounds, Tetrahedron 68 (2012) [108] B. Adger, U. Dyer, G. Hutton, M. Woods, Stereospecific synthesis of the 1712e1722, https://doi.org/10.1016/j.tet.2011.12.058. anaesthetic levobupivacaine, Tetrahedron Lett. 37 (1996) 6399e6402, [81] K. Fang, G. Li, Y. She, Metal-free aerobic oxidation of nitro-substituted https://doi.org/10.1016/0040-4039(96)01357-3. alkylarenes to carboxylic acids or benzyl alcohols promoted by NaOH, [109] N. Shankaraiah, R.A. Pilli, L.S. Santos, Enantioselective total syntheses of J. Org. Chem. 83 (2018) 8092e8103, https://doi.org/10.1021/acs.joc.8b00903. ropivacaine and its analogues, Tetrahedron Lett. 49 (2008) 5098e5100. [82] T. Gordh, T.E. Gordh, K. Lindqvist, Lidocaine: the origin of a modern local [110] N.S. Suveges, R.O.M.A. De Souza, B. Gutmann, C.O. Kappe, Synthesis of anesthetic, Anesthesiol. J. Am. Soc. Anesthesiol. 113 (2010) 1433e1437, mepivacaine and its analogues by a continuous flow tandem https://doi.org/10.1097/ALN.0b013e3181fcef48. M.D.Ph.D.-M.Sc.-M.D. HydrogenationReductive amination strategy, Eur. J. Org. Chem. Eur. J. Org. [83] O. Eisleb, Beta-dimethylaminoethyl ester of para-butylamino-benzoic acid, Chem (2017). US1889645, 1932. [84] T. Gordh, Xylocain - a new local analgesic, Anaesthesia 4 (1949) 4e9. [85] M. Yuan, J. Xie, Q. Zhou, Boron lewis acid promoted ruthenium-catalyzed hydrogenation of amides: an efficient approach to secondary amines, ChemCatChem 8 (2016) 3036e3040. [86] Y. Pan, Z. Luo, J. Han, X. Xu, C. Chen, H. Zhao, L. Xu, Q. Fan, J. Xiao, B (C6F5) 3- catalyzed deoxygenative reduction of amides to amines with ammonia Prof. Rodrigo O. M. A. de Souza has a degree at the borane, Adv. Synth. Catal. 361 (2019) 2301e2308. Pharmacy School of Federal University of Rio de Janeiro [87] B.Y. Park, M.T. Pirnot, S.L. Buchwald, Visible light-mediated (hetero) aryl (UFRJ) and PhD at the Institute of Natural Products amination using Ni (II) salts and photoredox catalysis in flow: a synthesis of Research. He is coordinating the Biocatalysis and Organic Tetracaine, J. Org. Chem. 85 (2020) 3234e3244. Synthesis group at the Chemistry Institute of UFRJ since [88] M.H. Holmdahl, Xylocain (lidocaine, lignocaine), its discovery and Gordh’s 2010 with Prof. Leandro S. M. Miranda, and have been contribution to its clinical use, Acta Anaesthesiol. Scand. 42 (1998) 8e12, working on process development for API synthesis as well https://doi.org/10.1111/j.1399-6576.1998.tb04979.x. as introducing continuous-flow methodologies on bio- [89] J.A.W. Wildsmith, J.-R. Jansson, From cocaine to lidocaine: great progress catalytic process. with a tragic ending, Eur. J. Anaesthesiol. 32 (2015). https://journals.lww. com/ejanaesthesiology/Fulltext/2015/03000/From_cocaine_to_lidocaine__ Great_progress_with_a.1.aspx. [90] H. Erdtman, N. Lofgren,€ Über eine neue Gruppe von lokalanasthetisch€ wirksamen Verbingdungen, Sven. Kem. Tidskr. 49 (1937) 163e174. [91] N. Lofgren,€ B. Lundqvist, Alkyl Glycinanilides, 1948, 2441498. [92] A.J. Johansson, Inga Fischer-Hjalmars (1918-2008): Swedish pharmacist, humanist, and pioneer quantum chemist, J. Chem. Educ. 89 (2012) 1274e1279, https://doi.org/10.1021/ed300024g. [93] C.M. Adolph, J. Werth, R. Selvaraj, E.C. Wegener, C. Uyeda, Dehydrogenative transformations of imines using a heterogeneous photocatalyst, J. Org. Chem. 82 (2017) 5959e5965. Prof. Leandro S. de M. Miranda has a degree at the [94] I. Ugi, S. Cornelius, Process for preparing amino-carboxylic acid amides, Pharmacy School of Federal University of Rio de Janeiro US3247200, 1966. (UFRJ) and PhD at the Institute of Natural Products [95] M. Srinivas, A.D. Hudwekar, V. Venkateswarlu, G.L. Reddy, K.A.A. Kumar, Research He is coordinating the Biocatalysis and Organic R.A. Vishwakarma, S.D. Sawant, A metal-free approach for transamidation of Synthesis group at the Chemistry Institute of UFRJ since amides with amines in aqueous media,, Tetrahedron Lett. 56 (2015) 2010 with Prof. Rodrigo O. M. A. de Souza and have been 4775e4779. working on the development of synthetic organic methods towards API synthesis.

14 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Dr. Raquel A. C. Leao~ has a PhD in chemistry from Flu- Msc Marco Macena has a degree at the Pharmacy School minense Federal University and have been working as of Federal University of Rio de Janeiro and is actually staff scientist at the Biocatalysis and Organic Synthesis working to obtain his PhD on new strategies towards the group since 2013. Her main research focus is on applying synthesis of cheap anesthetics compounds. continuous-ﬂow chemistry to API synthesis, on single and multi-step processes.