Continuous-flow process for the synthesis of 5-amino-1,2,3,4

Subscriber access provided by TULANE UNIVERSITY

Full Paper

Continuous-flow process for the synthesis of 5amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol Zhiyong Tan, Zhen-Hua Li, Guoqiang Jin, and Chuanming Yu Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00281 • Publication Date (Web): 20 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organic Process Research & Development

Continuous-flow process for the synthesis of 5-amino-1,2,3,4-tetrahydro-1,4-methano-napht halen-9-ol Zhiyong Tana, Zhenhua Lia,* Guoqiang Jina, and Chuanming Yub* Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Chao Wang Road 18th, 310014, Hangzhou, P. R. China b National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region, Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China a

Email: [email protected]; [email protected]

ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Table of Contents graphic


Page 2 of 20

Page 3 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Abstract. In this article, we described a safe and practical process for the synthesis of 5-amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol (1) via a continuous-flow reactor. The primary procedures in this process involved not merely the produce of isoamyl nitrite but also the temperature-programmed Diels-Alder reaction by aryne (derived from 2-amino-6-nitrobenzonic acid) with cyclopentadiene in the series flow reactor. The continuous-flow process minimized the accumulation of dangerous isoamyl nitrite and energetic diazonium salt, and the entire reaction time was hold down to 250 s.

Keywords. Continuous-flow reaction, Isoamyl nitrite, Diazotization, Diels–Alder reaction, Aryne



Page 4 of 20

1. Introduction Benzonorbornadienes play increasingly important roles in areas of synthetic organic chemistry, catalysis, supermolecule, material science and medicinal chemistry.1 The Diels-Alder reaction of arynes with diene is an efficient route to benzonorbornadienes. In recent decades, many compounds such as anthranilic acids, fluoroanisole, bis-(2-iodophenyl)-mercury, 2-(trimethylsilyl)-aryl triflates, triynes, etc have been utilized to produce the aryne species.2 Among them, inexpensive and convenient anthranilic acids has an enormous appeal which is regarded as a classical aryne precursor. Intriguingly, this process is industrially unattractive, for it’s highly dangerous and often has low yield, especially in large-scale manufacture.3 It is because

of

certain

unstable

reactive

species

like

diazotization

reagent,

benzenediazonium and aryne. The objective of this account is to develop a safe and efficacious way to generate arynes with anthranilic acids. 2-amino-6-nitrobenzonic acid (2) was chosen for this study, and its Diels-Alder reaction product (1) is an important intermediate for the synthesis of some popular drugs such as benzovindiflupry and isopyrazam.4 Preparation of 1 can be finished by diazotization of 2-amino-6-nitrobenzonic acid to form diazonium salt, which is intended to develop the final product by the liberation of nitrogen and carbon dioxide . Presently, literatures references about this process mostly focus on bench-scale in batch vessel.5 A serious drawback of this method is the hazardous nature of alkyl nitrites and diazonium compounds. Alkyl nitrites are easily to form explosive mixtures with air or oxygen due to they are air sensitive, light sensitive and flammable.6 What’s more, the energetic intermediates 3 and 4 are extremely unstable.7 When run under conditions of comparatively high temperature or non-uniform stirring environment, they may produce explosions of great violence. Imperfect mixture in the large vessel may bring about the undesired products as a result of the superior reactivity of the diazonium intermediate salt and aryne (Scheme 1). As a part of our uninterrupted efforts to study continuous-flow processes, we determined to adapt the continuous flow synthesis technology to manufacture of 1 to


Page 5 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


address these safety issues.8 Continuous-flow technology has some promising advantages over batch methods, including precise regulate of stoichiometry, short holding time, low backmixing, high repeatability, easy industrialized, and generally better yields.9 By increasing surface-to-volume ratio under flow conditions, the mass and heat transfer can be improved considerably. Moreover, potential safety problems in operating exothermic reactions combined with energetic intermediates are minimized because of the much smaller on-line volume.10 2. Results and Discussion Switch from Batch to Continuous-Flow Esterification. Isoamyl nitrite is widely used in pharmaceutical chemicals, and the study of diazotization with isoamyl nitrite has already been carried out.11 As such, a large number of methods for the synthesis of isoamyl nitrite have been documented.12 One of the most economical methods is to take NaNO2/HCl as the esterifying reagent. Nevertheless, large amounts of yellow smoke spewed from the batch vessel during the pilot production process. Then, in this paper, it was hypothesized that isoamyl nitrite decomposed violently in the vessel and released highly toxic nitric oxide. The reason lies in the strong action of back mixing on isoamyl nitrite and hydrochloric acid solution. Therefore, it is important to separate isoamyl nitrite from the reaction vessel in time. Several groups have investigated the use of the continuous system for the generation and online separation of potentially hazardous products.13 Analogously, we utilized a continuous-flow reactor to produce isoamyl nitrite, and the reaction mixture was separated in a liquid-liquid separator under nitrogen protection, which maintained the least possible on-line volume of isoamyl nitrite.



Scheme 1. Schematic for the preparation of isoamyl nitrite a

Isoamylol in 1.1 equivalent of hydrochloric acid flow through P1; aqueous solution of sodium nitrite flow through P2 . Residence loop I is a PTFE tube with 1.5 mm i.d. and 3 mm o.d.. The static mixer (PTFE, 1.5 mm i.d., 3 mm o.d., 10 mm length, two mixing elements with a twist angle of 90°) and loop I were in the same thermostatic bath. The liquid-liquid separator is a separating funnel with a jacket in which the cooling fluid at 0 °C can be passed. a

The continuous-flow setup is shown in Scheme 1. Two individual feed streams (a mixture of isoamylol and hydrochloric acid; aqueous solution of sodium nitrite) were introduced into a loop reactor (PTFE, 1.5 mm i.d., and 3 mm o.d.) via a T-joint (PTFE, 1.5 mm i.d.) and static mixer by two peristaltic pumps (P1, P2, Baoding Longer, China), respectively. The dosage of isoamylol, hydrochloric acid and sodium nitrite was put in-line with their ratios in batch.12c In particular, the static mixer and reaction loop was sink into the constant-temperature bath, and the reaction mixture flowed into a liquid-liquid separator. Then, the organic phase was applied to the next step directly, and the water phase was removed by the valve. The test parameters were methodically explored through the variation of holding time (τ1) and temperature (T1). 4.5 M isoamylol in 1.1 equivalent of hydrochloric acid flow through P1 with a velocity of 1.0 mL/min, and 5.5 M sodium nitrite solution flow through P2 with a velocity of 0.9 mL/min. The purity of isoamyl nitrite became one of the most important indexes since we expected the isoamyl nitrite to be used for the next step directly after extraction by the liquid-liquid separator under nitrogen protection. The results were exhibited in Figure 1. The maximum purity of 96% (GC isoamylol content: 3%) was gained when τ1 = 200 s and T1 = 0 °C, and an excellent yield of 94% was achieved in the meanwhile. Neither long τ1 with high T1 nor short τ1 with low T1 can improve the purity of isoamyl nitrite. The increase of the temperature could quicken the rate of the


Page 6 of 20

Page 7 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


esterification reaction. Nonetheless, higher temperature together with longer holding time leaded to the reduction of purity. The dosage of sodium nitrite was subsequently investigated. Molar flow ratios of isoamylol to sodium nitrite were differed by means of accommodating the flow rate of sodium nitrite solution. The results showed that sodium nitrite seemed to be slightly higher than 1.05 equiv, while much fewer doses leaded to the low conversion rate of isoamylol.

Figure 1. Effect of temperature and holding time on esterification. The purity of isoamyl nitrite were detected by GC chromatography.

Switch from Batch to Continuous-Flow Diazotation. With esterification parameters in hand, we undertook the optimization of Diels-Alder reaction with aryne. For abounding industrial procedures covered, the diazotization of aromatic amines had been well studied.14 In the reported procedure for the conversion of 2 to 1, 18 equivalents of cyclopentadiene were added, and the mixture was heated to reflux overnight. Then, the reaction mixture was filtered, and 1 was gained in 58% yield after column chromatographic separation.5a,15 The drawbacks of this process are chiefly in the safety concerns and low yield, and therefore the method for producing aryne by heating 2 failed to get the attention of industry. Several mechanistic pathways have been considered to account for the various byproducts when benzenediazonium 2-carboxylate is allowed to decompose in the presence of nucleophilic reagents.16 Many undesired coupling products may be formed easily in the inadequate stirring vessel (Scheme 2). Apparently, side reactions were mainly caused by 3 and 4, and the application of the flow reaction technology is a powerful



tool to minimize these side reactions. At present, many reports on continuous-flow diazotization followed by different functional reaction such as chlorosulfonylation, iododeamination and azo dyes have been published.17 Surprisingly, to the best of our knowledge, no study has yet described the optimization of Diels-Alder reaction of aryne (derived from decomposition of benzenediazonium 2-carboxylates) under a continuous mesoscale process.18 According to our previous works on continuous processes of diazotization using millimeter scale reactors,8 herein, we plan to apply this technology to the synthesis of 1. Scheme 2. The reaction mechanism of 1 from 2-amino-6-nitrobenzonic acid

Before we set about developing the continuous-flow diazotation, preliminary experiments in batch manner were conducted to verify the method. To avoid hydrolysis of reactive intermediate 3 and 4 to hydroxybenzene as much as possible, we needed anhydrous diazotization reaction instead of traditional diazotization in the acidic aqueous solution. Preliminary optimization experiments showed that acid environment is essential to facilitate the diazotization.19 As indicated by the results, acid additives could improve the yield of 1 (Table 1, entries 1 and 2). Nevertheless, we clearly observed a yield decrease when increasing the acidity of the additives (Table 1, entries 3). The possible reason was that hydrogen ion could not only assist in the formation of diazonium salt, but accelerate the decomposition of isoamyl nitrite (Table 1).20 There was an improved product yield of 1 with our preliminary optimization, and these trials signified a bright possibility to switch to continuous-flow. But these conditions were too harsh for directly use in a flow reactor due to the low solube diazonium salt 3.


Page 8 of 20

Page 9 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Screening acid additives of cycloaddition in batch Entrya

Additive

Yield(%)

Purityb(%)

1 2 3 4

none CH3COOH CCl3COOH CF3COOH

37 72 67 64

96 95 95 95

condition: 2 (0.1 mol), cyclopentadiene (3 equiv.), isoamyl nitrite (1.1 equiv.), additive (1.0 equiv.), 50 °C. bThe analysis of crude 1 based on HPLC. aReaction

In order to avoid being clogged, we designed an initial program to develop a semi-continuous process involving first the synthesis of diazonium salt in continuous flow followed by the Diels-Alder reaction in a flask with cyclopentadiene. Choosing a proper solvent is of great importance to our further experiments. Experiments were done with the continuous-flow system as depicted in Scheme 3; several inactive solvents, diethylene glycol dimethyl ether (ether), toluene (aromatic), ethyl acetate (ester), and 1,2-dichloroethane (halogenated hydrocarbon) were evaluated in this study. 5.4 mL solvent was added to every 1g of 3. As the experimental results suggested, diethylene glycol dimethyl ether (DG) was an ideal medium since DG had better solubility for 3 than other solvents thereby avoiding the pipe plugging. In addition to that, DMF and DMSO had a good solubility to 3, however they can react with 4.21 After the reaction solvent was selected, further improvement of this project began with continuous diazotization, followed by cycloaddition reaction in batch. The figure of simple experimental instrument was shown in Scheme 3. The device contained two plunger metering pumps (P3, P4, PTFE, WOOK, China) to introduce the feed streams of 2 and isoamyl nitrite, respectively. A T-joint (Hastelloy SS316L, 2 mm i.d.) was coupled with the reaction loop (Hastelloy SS316L, 2 mm i.d., and 4 mm o.d.). The solution from loop II then got into a T-joint and incorporated with a stream of cyclopentadiene, which was transfered by pump (P5, PTFE, WOOK, China). The molar flow ratio among 2, nitrite, and cyclopentadiene was established in terms of their equivalents in batch. Then, the mixture entered a stirring reaction vessel, which



is kept warm at 50 °C. After the reaction was completed, the solvent was removed from the reaction mixture by distillation, and the residues refluxed in hexane to extract the crude product 1. What calls for special attention is that the formation of intermediate 3 with the improper solvent would cause serious pipe clogging. What’s more, 3 was potentially shock sensitive and may violently detonate when dry, and it ought to be kept wet with solvent at all times. Scheme 3. Schematic for the preparation of 1a

Isoamylol in 1.1 equiv of hydrochloric acid flow through P1; solution of sodium nitrite

a

flows through P2; 2-amino-6-nitrobenzonic acid in DG flow through P3; isoamyl nitrite flow through P4; cyclopentadiene flow through P5. Residence loop I is a PTFE tube with 1.5 mm i.d. and 3 mm o.d., Residence loop II is an SS316L tube with 2 mm i.d. and 4 mm o.d..

We systematically investigated the experimental parameters by shifting holding time (τ2) and temperature (T2). 1.0 M 2 in 1.0 equivalent of acetic acid in DG were pumped by P3 (15.0 mL/min). Isoamyl nitrite was pumped by P4 (1.6 mL/min), and 10.0 M cyclopentadiene was pumped by P5 (4.5 mL/min). The cycloaddition reaction conditions were in-line with the batch methods (50 °C). The results were shown in figure 2, and the yield was increased with time, but reach a maximum after a lengthy holding time at less than 5 °C. When the temperature was higher than 10 °C, the yield was noticeably decreased. That came out of the rate of side reaction overwhelmed the subsequent Diels-Alder reaction. Increasing the reaction temperature could bring about the violent decomposition of diazonium salt 3 to byproducts (Scheme 2). The highest yield of 75% was gained when τ2 = 20 s and T2 = 0 °C.


Page 10 of 20

Page 11 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. Effect of temperature and holding time on diazotization. Yields of 1 were calculated from 2

The dosage of isoamyl nitrite was subsequently investigated. Molar flow ratios of isoamyl nitrite to 2 changed when aligning the flow rate of isoamyl nitrite. Experiment data were exhibited in Table 2. A lightly excessive isoamyl nitrite (1.02 equiv) was allowed. The yield of 1 was decreased when too much isoamyl nitrite was loaded. Reasons were that excessive isoamyl nitrite may drive the decomposition of diazonium, and an overdose of isoamylol, from the decomposition of isoamyl nitrite, would have a competitive side reaction with 4.21 Table 2.

Effect of the isoamyl nitrite amount

Isoamyl nitrite/2 a

Yieldb (%)

1.00 1.01 1.02 1.03 1.04

70 72 75 75 73

aMolar bYields

flow ratios of isoamyl nitrite to 2 . of 1 were calculated from 2.

Advanced Continuous-Flow Process. The continuous-flow procedure of esterification and diazotization was victoriously running. But, the improved the yield of 1 was still not obvious, and the safety issue caused by diazonium accumulation failed to be completely abolished. An improved procedure was then drafted (Scheme 4). Diazonium 3 and intermediate 4 were formed in different conditions in the



temperature-programmed loop reactor. Excellent results were obtained by the flowing 1.0 M 2 solution together with isoamyl nitrite for a holding time of 20 s at 0 °C. It was followed by the introduction of 10.0 M cyclopentadiene into the tube reactor and then the mixture proceeded to the Diels-Alder reaction in Loop III. The reaction solution discharged from Loop III was poured continuously into the collection vessel which doesn't require constant temperature. Residence loop III was immersed in a hot oil bath, and the temperature was controlled by a thermostat. The nitrogen and carbon dioxide released in the cycloaddition step may give rise to uncontrollable holding time in a flow reactor. Thus, a back-pressure regulator (BPR) was selected to be installed in the tail of the reactor, and the back pressure was set to 100 psi. The flow rate of three solutions were 15.0, 1.6, and 4.5 mL/min, respectively. The molar flow ratio of 2 to isoamyl nitrite to cyclopentadiene was 1.0:1.02:3.0. The loop II and loop III were of the same specification (Hastelloy SS316L, 2 mm i.d., and 4 mm o.d.). On the premise of keeping the same flow rates, holding time (τ3) was researched by changing the tube length. The temperature (T3) of Loop III was explored according to the batch process (50 °C). With these restructuring, the yield of 1 was increased to 85% in 99% purity when τ3 = 30 s, T3 = 120 °C.22 Scheme 4. Schematic of the advanced experimental setup for the preparation of 1a

4.5 M isoamylol in 1.1 equiv of hydrochloric acid flow through P1; 5.5 M aqueous solution of sodium nitrite flow through P2; 1 M 2-amino-6-nitrobenzonic acid in DG flow through P3; isoamyl nitrite flow through P4; 10 M cyclopentadiene flow through P5. Residence loop I is a PTFE tube with 1.5 mm i.d. and 3 mm o.d., Residence loop II and III are an SS316L tube with 2 mm i.d. and 4 mm o.d.. a

To underline the advantages of the aforementioned optimal flow program, a comparison with the reaction performance in the batch manner was shown. It was evident that this advanced continuous-flow process has many advantages in this


Page 12 of 20

Page 13 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Diels-Alder reaction (Table 3). Experimental details can be found in the Experimental Section. Table 3. The comparison of the batch process with a continuous process Methods

Batch

Continuous-flow

Yield(%)

72

85

Purity(%)

95

99 Diazotization:

Reaction

hours

time

20 s Cycloaddition: 30 s

3. Conclusion In summary, we have set up an expeditious and high-yielding process for the synthesis

of

5-amino-1,2,3,4-tetrahydro-1,4-methano-naphthalen-9-ol

via

a

continuous-flow reactor. Adopting flow technology to minimized safety issues caused by isoamyl nitrite and unstable diazonium salt intermediate has become an efficacious way. This continuous process readily adapt to the manufacture of benzonorbornadiene derivatives and can easily be scaled up with several high-throughput reactors in parallel.

4. Experimental section 4.1. General Compound 2 was provided by Hangzhou Beyond & Upgrade Technology Co., Ltd., and all other chemicals were purchased from commercial sources and were used without further purification. Melting points were determined on a Büchi 540 melting point apparatus and were uncorrected. 1H (600 MHz) NMR,

C (100 MHz) NMR

13

spectra were recorded on a Varian spectrometer in CDCl3 using tetramethylsilane (TMS) as internal standards. Mass spectra were measured with a low-resolution MS instrument using ESI ionization. HPLC analysis was carried out on an Agilent HPLC system (series 1200, Agilent Technologies, Germany) equipped with Agilent Welch Welchrom-C18 reversed-phase column (250 mm × 4.6mm, 5 μm). A mobile phase of



acetonitrile and water (80:20) was used at a flow rate of 1.0 mL/min and a column temperature of 25 °C. The UV detector was set at 230 nm to analyze the column effluent. The HPLC analysis data was reported in area % and not adjusted to weight %. Gas chromatography (GC) analysis was carried out on an Agilent 7890B gas chromatograph. GC conditions: nitrogen pressure (0.06 MPa), injection temp.: 200 °C, detector temp.: 210 °C, oven: 60 °C. 4.2. Synthesis of isoamyl nitrite with continuous-flow process As shown in Scheme 1, isoamylol (88 g, 1.0 mol), aqueous hydrogen chloride (111.5 g, 1.1 mol ), and sodium nitrite (72.4 g, 1.05 mol) in 115 g H2O were pumped into the flow reactor via a T-joint and a static mixer by P1 and P2 at flow rates of 1 mL/min and 0.9 mL/min, respectively, after a holding time of 200 s at 0 °C in residence loop I (PTFE, 1.5 mm i.d., 3 mm o.d.), the mixture flowed through the outlet and accumulated in the liquid-liquid separator. The water layer is continuously separated and the organic layer is continuously collected. After the flow reaction was finished, isoamyl nitrite as pale yellow liquid in 94% yield and 96% purity was obtained. 4.3. Synthesis of 5-nitro-1,4-dihydro-1,4-methano-naphthalene(1) in batch Acetic acid (9 g, 0.15 mol) was diluted with 70 mL of dichloromethane. This solution was held at 40 °C while a solution of 2 (27.3 g, 0.15 mol) and cyclopentadiene (14.85 g, 0.45 mol) in acetone (60 mL), and isoamyl nitrite (18.43 g, 1.05 mol) was respectively and simultaneously added dropwise within 1 h, then stirring at 50 °C for 3 h. The reaction mixture was cooled to 25 °C, filtered through a pad of Celite, and evaporated. The resulting brown oil was refluxing 3 times with hexane (150 mL), gave 19.9 g of 1 (mp 44.1-45.3 °C), which was dried in vacuum drying oven. Yield: 72%. Spectral data: 1H NMR (600 MHz, Chloroform-d) δ 7.67 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.04 (dd, J = 8.4, 7.2 Hz, 1H), 6.86 (m, 2H), 4.84 (s, 1H), 3.99 (m, 1H), 2.35 (dt, J = 7.8, 1.2 Hz, 1H), 2.27 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, Chloroform-d) δ 155.73, 148.66, 144.38, 143.84, 142.10, 126.32, 125.43, 119.39, 69.17, 50.32. MS m/z (ESI): 187.1 M+. 4.4. Synthesis of 5-nitro-1,4-dihydro-1,4-methano-naphthalene (1) with advanced


Page 14 of 20

Page 15 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Continuous-flow process. As shown in Scheme 4, 2-amino-6-nitrobenzoic acid (273 g, 1.5 mol), acetic acid (90 g, 1.5 mol ) in 1420 g of DG, and isoamyl nitrite (soaking up the organic layer from liquid-liquid separator) were pumped into the flow reactor via a T-joint by P3 and P4 at flow rates of 15.0 and 1.6 mL/min, respectively, after a holding time of 20 s at 0 °C in residence loop II (Hastelloy SS316L, 2 mm i.d., 4 mm o.d.); cyclopentadiene (297 g, 4.5 mol) in 425 g DG was introduced into the reactor via T-joint by P5 at a flow rate of 4.5 mL/min and contacted with diazonium salt, after another holding time of 30 s at 120 °C in residence loop III (Hastelloy SS316L, 2mm i.d., 4 mm o.d.) and the mixture flowed through the end of the loop and discharged the solution into the collection vessel. The pressure in reactor was regulated under 100 psi by a BPR. DG and cyclopentadiene was recovered by distillation and the resulting brown oil was refluxing 3 times with hexane (1500 mL). 242 g of crude product 1 as pale yellow solid in 86% yield and 99.3% HPLC purity was obtained. P3 the measurement range of 50.00 mL/min, P4 and P5 had a measurement range of 10.000 mL/min. All plunger metering pumps were set a built-in automatic pressure shut-down device to prevent reactor from overpressure. ASSOCIATED CONTENT Supporting Information H/13C NMR, and HPLC spectra for compound 1; GC spectra for isoamyl nitrite.

1

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected] ORCID

Zhen-Hua Li: 0000-0002-8092-3571 Chuanming Yu: 0000-0002-1345-0778 Notes

The authors declare no competing financial interest



Acknowledgment This work was supported by the National Natural Science Foundation of China (21376221 and 21506190).We thank Dr. Zhiqun Yu and Mr. Xiaoxuan Xie for helpful discussions and input.

References

1. (a) Wang, B. U.; Turner, D. A.; Zujovic´, T.; Hadad, C. M.; Badjic´, J. D. The Role of Chirality in Directing the Formation of Cup-Shaped Porphyrins and the Coordination Characteristics of such Hosts, Chem. Eur. J. 2011, 17, 8870 – 8881. (b) Xu, M. H.; Tu, J. L.; Franzini, R. M. Rapid and Efficient Tetrazine-Induced Drug Release from Highly Stable Benzonorbornadiene Derivatives, Chem. Commun. 2017, 53, 6271-6274. (c) Medina, J. M.; Ko, J. H.; Maynard, H. D.; Garg, N. K. Expanding the ROMP Toolbox: Synthesis of Air-Stable Benzonorbornadiene Polymers by Aryne Chemistry, Macromolecules 2017, 50, 580−586. (d) Xu, M.; Galindo-Murillo, R.; Cheatham, T. E. III.; Franzini, R. M. Dissociative Reactions of Benzonorbornadienes with Tetrazines: Scope of Leaving Groups and Mechanistic Insights, Org. Biomol. Chem. 2017, 15, 9855–9865. 2. (a) Wentrup, C. The Benzyne Story, Aust. J. Chem. 2010, 63, 979–986. (b) Pindur, U.; Kim, Y.S. New Electrophilic Reactions of 2,2'-bisindolyls with Acid Chlorides and Carbodienophiles, J. Hetero. Chem. 1996, 33, 623-631. (c) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. Synthesis of Dihydronaphthalenes via Aryne Diels-Alder Reactions: Scope and Diastereoselectivity, J. Am. Chem. Soc. 2005, 127, 15028-15029. 3. (a) Friedman, L.; Logullo, F. M. Arynes via aprotic diazotization of anthranilic acids, J. Org. Chem. 1969, 34, 3089-3092. (b) Petrillo, G.; Novi, M.; Garbarino, G.; Dell’Erba, C. A Mild and Efficient SRN1 Approach to Diaryl Sulfides from Arenediazonium Tetrafluoroborates, Tetrahedron, 1986, 42, 4007-4016. 4. (a) Villani, S. M.; Ayer, K.; Cox, K. D. Molecular Characterization of the sdhB Gene and Baseline Sensitivity to Penthiopyrad, Fluopyram, and Benzovindiflupyr


Page 16 of 20

Page 17 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


in Venturia Inaequalis, Plant Dis. 2016, 100, 1709-1716. (b) Kuznetsov, D.; Cazenave, A. B.; Rambach, O.; Camblin, P.; Nina, M.; Leipner, J. Foliar Application of Benzovindiflupyr Shows Non-Fungicidal Effects in Wheat Plants, Pest manag. Sci. 2018, 74, 665-671. (c) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, C. Sedaxane, Isopyrazam and Solatenol: Novel Broad-Spectrum Fungicides Inhibiting Succinate Dehydrogenase (SDH)-synthesis Challenges and Biological Aspects, Chimia. 2015, 69, 425-434. 5. (a) Dumeunier, R.; Tombler, H. Process for the Preparation of Pyrazole Caraoxylic Acid Amides, Patent WO 2011/131543, 2011. (b) Gribkov, D.; Stohler, R.; Vettiger, T.; Rommel, M. Process for the Preparation of Pyrazole Caraoxylic Acid Amides, Patent WO 2011/131546, 2011. 6. Yasuo Seto Alkyl nitrites, Drugs and Poisons in Humans. Springer, Berlin, Heidelberg, 2015,153-158, DOI:10.1007/3-540-27579-7_17. 7. Roya,T.; Biju, A. T. Recent advances in molecular rearrangements involving aryne intermediates, Chem. Commun., 2018, 54, 2580--2594. 8. (a) Guo, S. Z.; Yu, Z. Q.; Yu, C. M. Kilogram-Scale Synthesis of 2,4-Dichloro-5-fluorobenzoic Acid by Air Oxidation under the Continuous-Flow Process, Org. Process Res. Dev. 2018, 22, 252-256. (b) Yu, Z. Q.; Zhou, P.C.; Liu, J. M.; Wang, W. Z.; Yu, C. M.; Su, W. K. Continuous-Flow Process for Selective Mononitration of 1-Methyl-4-(methylsulfonyl)benzene, Org. Process Res. Dev. 2016, 20, 199-203. (c) Yu, Z. Q.; Lv, Y. W.; Yu, C. M.; Su, W. K. A High-Output, Continuous Selective and Heterogeneous Nitration of p-Difluorobenzene, Org. Process Res. Dev., 2013, 17, 438–442. (d) Yu, Z. Q.; Lv, Y. W.; Yu, C. M. A Continuous Kilogram-Scale Process for the Manufacture of o-Difluorobenzene, Org. Process Res. Dev., 2012, 16, 1669–1672. 9. (a) Hessel, V. Novel Process Windows - Gate to Maximizing Process Intensification via Flow Chemistry, Chem. Eng. Technol. 2009, 32, 1655-1681.(b) Wahab, B.; Ellames, G.; Passey, S.; Watts, P. Synthesis of Substituted Indoles Using Continuous flow Micro Reactors, Tetrahedron 2010, 66, 3861-3865. (c) Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Rencurosi,



A. Reaction of Grignard Reagents with Carbonyl Compounds under Continuous flow Conditions, Tetrahedron 2010, 66, 3242-3247. (d) Wegner, J.; Ceylan, S.; Kirschning, A. Flow Chemistry - A Key Enabling Technology for (Multistep) Organic Synthesis, Adv. Synth. Catal. 2012, 354, 17-57. (e) Wiles, C.; Watts, P. Continuous Flow Reactors: a Perspective, Green Chem. 2012, 14, 38-54. 10. (a) Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Continuous Flow Nitration of Benzaldehyde, Org. Process Res. Dev. 2009, 13, 999-1002. (b) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.; Smith, C. D. Multistep Synthesis Using Modular Flow Reactors: Bestmann-Ohira Reagent for the Formation of Alkynes and Triazoles, Angew. Chem., Int. Ed. 2009, 48, 4017-4021. 11. Perkin, A. G.; Steven, A. B. A product of the action of isoamyl nitrite on pyrogallol, J. Chem. Soc., Trans. 1906, 89, 802-808. 12. (a) Khakyzadeh, V.; Vahidian, H. R.; Salarian, A. A.; Zolfigol, M. A. Synthesis, Modeling and Optimization of Cyanide Antidote (3-methylbutyl) Nitrite using Response Surface Methodology, Res. Chem. Intermed. 2016, 42, 2391-2398 (b) Soloveichik, S. Process for the Production of Nitrous Esters, Patent US 1954/27114606A, 1954 (c) McDonough, J. A.; Johnston, D. W.; Thompson, P. M. Point of use Generation of Amyl Nitrite, Patent US 2013/8987496B1, 2013 (d) Karrer, P.; Balzano, S. Method for Preparing Alkyl Nitrites, Patent US 2003/0149292A1, 2003. (e) Yuan, X. J.; Li, Y.; Li, W. L.; Dong, L. Y. ; Wang, K.; Fan, X.; Xia, W.; Hu, Y. R.; Xu, H. Y. Method and apparatus for preparing C1-C4 alkyl nitrite, Patent CN 2017/106831439 A, 2017. 13. (a) Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V. Taming Hazardous Chemistry by Continuous Flow Technology, Chem. Soc. Rev., 2016, 45, 4892--4928. (b) Castano, B.; Gallo, E.; Cole-Hamilton, D.; Dal Santo, V.; Psaro, R.; Caselli, A.; Continuous flow asymmetric cyclopropanation reactions using Cu(I) complexes of Pc-L-star ligands supported on silica as catalysts with carbon dioxide as a carrier, Green Chem., 2014, 16(6), 3202–3209. (c) Delville, M. M. E.; van Hest, J. C. M.; Rutjes, F. P. J. T. Ethyl diazoacetate synthesis in flow, Beilstein J. Org. Chem., 2013, 9, 1813–1818.


Page 18 of 20

Page 19 of 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


14. Zollinger, H. Diazo Chemistry I: Aromatic and Heteroaromatic Compounds; Wiley-VCH: Weinheim, Germany, 1994. 15. Snow, R. A.; Cottrell, D. M.; Paquette, L. A. Demonstration and Analysis of Bridging Regioselectivity Operative during di-π-methane Photorearrangement of Ortho-Substituted Benzonorbornadienes and anti-7,8-benzotricyclo[4.2.2.02,5]deca -3,7,9-trienes, J. Am.Chem. Soc. 1977, 99, 3734-3744. 16. Buxton, P. C.; Fensome, M.; Heaney, H.; Mason, K.G. Benzyne Formation and the

Stepwise

Decomposition

of

Benzenediazonium-2-carboxylate:

A

Re-Investigation, Tetrahedron, 1995, 51, 2959-2968. 17. (a) Hessel, V. Novel Process Windows - Gate to Maximizing Process Intensification via Flow Chemistry, Chem. Eng. Technol. 2009, 32, 1655-1681.(b) Wahab, B.; Ellames, G.; Passey, S.; Watts, P. Synthesis of Substituted Indoles Using Continuous flow Micro Reactors, Tetrahedron 2010, 66, 3861-3865. (c) Riva, E.; Gagliardi, S.; Mazzoni, C.; Passarella, D.; Rencurosi, A.; Vigo, D.; Rencurosi, A. Reaction of Grignard Reagents with Carbonyl Compounds under Continuous flow Conditions, Tetrahedron 2010, 66, 3242-3247. (d) Wegner, J.; Ceylan, S.; Kirschning, A. Flow Chemistry - A Key Enabling Technology for (Multistep) Organic Synthesis, Adv. Synth. Catal. 2012, 354, 17-57. (e) Wiles, C.; Watts, P. Continuous Flow Reactors: a Perspective, Green Chem. 2012, 14, 38-54. (f) Yu, Z. Q.; Tong, G.; Xie, X. X.; Zhou, P. C.; Lv, Y. Y.; Su, W. K. Continuous-Flow Process for the Synthesis of 2-Ethylphenylhydrazine Hydrochloride, Org. Process Res. Dev. 2015, 19, 892-896. 18. Browne, D. L.; Wright, S.; Deadman, B. J.; Dunnage, S.; Baxendale, I. R.; Turner, R. M.; Ley, S. V. Continuous flow reaction monitoring using an on-

line

miniature mass spectrometer, Rapid Commun. Mass Spectrom. 2012, 26, 1999–2010 19. Logullo, F. M.; Seitz, A. H.; Friedman, L. Benzenediazonium-2-Carboxylate and Biphenylene, Org. Synth. 1968, 48, 12-7. 20. Yunker, M. H.; Szulczewski, D.; Higuchi, T. Kinetics of the Degradation of Isoamyl Nitrite in Ampuls I, J. Am. Pharm. Assoc. 1958, 47, 613-620.



21. (a) Okuma, K.; Nojima, A.; Nakamura, Y.; Matsunaga, N.; Nagahora, N.; Shioji, K. B. Reaction of Benzyne with Formamides and Acetylimidazole, Chem. Soc. Jpn. 2011, 84, 328-332. (b) Liu, F. L.; Chen, J. R.; Zou, Y. Q.; Wei, Q.; Xiao, W. J. Three-Component Coupling Reaction Triggered by Insertion of Arynes into the S=O Bond of DMSO, Org. Lett. 2014, 16, 3768-3771.(c) Li, H.Y.; Xing, L.J.; Lou, M.M.; Wang, H.; Liu, R.-H.; Wang, B. Reaction of Arynes with Sulfoxides, Org. Lett. 2015, 17, 1098-1101. 22. The yield was based on the amount of 2-amino-6-nitrobenzonic acid. and the purity was detected by HPLC (see supporting information).


Page 20 of 20

Continuous-flow process for the synthesis of 5-amino-1,2,3,4

Recommend Documents