Development of a Scalable Process for the Crop Protection Agent

Feb 20, 2015 - Initially designed to control a broad spectrum of sap-feeding insects, Isoclast has shown no signs of cross-resistance to existing comm...
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Development of a Scalable Process for the Crop Protection Agent Isoclast Kim E. Arndt,‡ Douglas C. Bland,*,† Nicholas M. Irvine,‡ Stacey L. Powers,† Timothy P. Martin,‡ James Russell McConnell,† David E. Podhorez,† James M. Renga,‡ Ronald Ross,‡ Gary A. Roth,† Brian D. Scherzer,† and Todd W. Toyzan† †

Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States Process Chemistry, Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States

‡

ABSTRACT: A scalable process to the insecticide Isoclast manufactured by Dow AgroSciences LLC is described. The process involves the de novo construction of a fully elaborated pyridine sulfide using enamine-mediated cyclization followed by two efficient and inexpensive oxidations to introduce the sulfoximine.

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INTRODUCTION Isoclast Active (1, Scheme 1) is a fast acting sap-feeding insecticide commercialized by Dow AgroSciences in 2013.1

ring construction to produce functionalized pyridine ring systems exist in the literature.4 However, examples of 6(trifluoromethyl)pyridines prepared by de novo methods are relatively rare, particularly those that can be readily functionalized to produce useful intermediates for the preparation of Isoclast.5 Several different approaches were explored, but the most promising of those from a chemical complexity and commercial feasibility standpoint was enamine-mediated Michael additions. This article will discuss our cyclization studies focused on enamines derived from 3-(methylthio)butanal (6) to make pyridine sulfide 10, followed by the development and scale-up of conditions for the inexpensive introduction of the sulfoximine to make Isoclast.

Scheme 1. Discovery Chemistry Route to Isoclast Active (1)

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RESULTS AND DISCUSSION A very attractive intermediate in the synthesis of Isoclast was the trifluoromethylpyridine with a fully elaborated alkyl sulfide side chain, 10 (Scheme 2). It was envisioned that this compound could likely be obtained from commercially available 3-(methylthio)butanal (6), a secondary amine (7), a 2-trifluoroacetyl vinyl ether (9), and an ammonia source.

Initially designed to control a broad spectrum of sap-feeding insects, Isoclast has shown no signs of cross-resistance to existing commercial products.2 The first synthesis of Isoclast was accomplished by a fourstep sequence starting from commercially available 5chloromethyl-2-(trifluoromethyl)pyridine (2, Scheme 1).1a Chloride displacement with sodium methyl mercaptide gave the sulfide (3) in good yield, followed by the conversion to the sulfilimine (4) with cyanamide and iodobenzene diacetate. The sulfilimine (4) was then oxidized to the corresponding sulfoximine (5) with m-chloroperoxybenzoic acid (mCPBA) in aqueous ethanol under basic conditions. Finally, lowtemperature methylation with iodomethane and potassium hexamethyldisilazide gave Isoclast as a mixture of diastereomers. The overall yield (four chemical steps) was a low 2.4% after isolation by silica gel chromatography. Although this route was optimized to provide gram quantities of Isoclast for initial field trials, an aggressive commercialization plan included rapidly escalating kilogram sample requirements. Since the cost of 5-chloromethyl-2-(trifluoromethyl)pyridine (2) was considered to be prohibitive for scale-up, an investigation of alternative starting points for this material was initiated using existing proprietary pyridine building blocks.3 Concurrently, efforts also began surveying various de novo pyridine synthesis routes. Numerous examples of de novo © XXXX American Chemical Society

Scheme 2. Enamine Michael/Cyclization Approach to Pyridine Sulfide

Received: January 12, 2015

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Several cyclic and noncyclic enamines were compared in a small/quick qualitative study in order to explore the effect of R1 and R2. The noncyclic secondary amines used in the study consisted of dimethyl, diethyl, dipropyl, and di-isopropyl (Scheme 2). In all cases, low yields of pyridine sulfide 10 were observed along with significant quantities of 11. The cyclic secondary amines included pyrrolidine, piperazine, piperidine, and morpholine. In these cases, as suggested in the literature, pyrrolidine was significantly superior.6 A third small qualitative study explored R4 of enone 9 as a variable (Me, Et, i-Pr, n-Bu, i-Bu, t-Bu, and cyclohexyl). For reasons not clear to us, ethyl and isopropyl vinylogous esters were superior to the others. The use of aldehyde 6, pyrrolidine, and 4-ethoxy-1,1,1-trifluorobut-3-en-2one (9, R4 = Et) initially afforded pyridine sulfide 10 in about 55% yield following silica gel chromatography. Additionally, higher yields of pyridine sulfide 10 (increases of 5−10%) were obtained when enamine 13 (derived from pyrrolidine) was added to 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (9, R4 = Et) versus adding enone 9 to enamine 13 (Scheme 3). Early sulfoximine analogue syntheses by the discovery chemists introduced the sulfilimine functionality by first reaction of a sulfide with sodium azide in H2SO4 to give the corresponding unsubstituted sulfilimine, followed by alkylation with cyanogen bromide. A later procedure was developed using iodobenzene diacetate and cyanamide,7 which was used during small sample preparations (Scheme 1, 3 to 4). Perhaps the most troublesome aspect of the original synthesis of Isoclast was the oxidation of the sulfilimine to the corresponding sulfoximine. Although mCPBA and potassium carbonate were used successfully to produce numerous small-scale samples, we found chemical yields for this reaction to be unpredictable upon scale-up. As with the sulfilimine chemistry, we believed that cost, together with safety concerns, made this approach unsuitable for large-scale sample production. Dimethyldioxirane produced from oxone and acetone under phase transfer conditions8 was used successfully on small scale, but it was rejected for scale-up based on economic and reactive chemistry concerns. Initial efforts were focused on catalytic ruthenium-based sodium periodate oxidations.9 This method proved to be more robust than the mCPBA approach and was eventually scaled to multikilograms. Initial Kilogram Scale-Up. As described above, the original de novo synthesis of pyridine sulfide 10 utilized acetonitrile as solvent for enamine formation, Michael addition to give diene 15, and subsequent ammonium acetate cyclization. The original synthesis used about 2.5 equiv of pyrrolidine in acetonitrile. Upon scale-up, toluene was the preferred solvent for enamine formation because dehydration of this system was more efficient and thus allowed for the use of about 1.1 equiv of pyrrolidine (Scheme 3). The reaction was worked up by simple filtration followed by rotary evaporative removal of the toluene. The Michael addition and cyclization chemistry worked well in acetonitrile and were not altered for this sample campaign. The workup consisted of dilution of the reaction mixture with water followed by extraction with hexane. Solvent removal followed by vacuum distillation provided pure pyridine sulfide 10 in 65− 70% yield (based on aldehyde 6). As had been observed previously, the major impurity generated by this chemistry was enamine-one 16. This impurity was generated during the enamine mediated Michael addition to enone 14 and was easily removed by distillation of pyridine sulfide 10.

Scheme 3. Pyrrolidine Enamine/Michael addition/ Cyclization Approach to Pyridine Sulfide

Several comments about the analytical procedures used to monitor this chemistry are appropriate at this time. Enamine 13 was unstable toward GC analysis. Since it has a weak chromaphore, HPLC with UV detection was difficult. The most effective method for monitoring the conversion of aldehyde 6 to enamine 13 was 1H NMR analysis. Since analysis of enamine 13 was difficult via chromatographic methods, again, the best way to monitor the reaction of 13 with enone 14 was 1H NMR. Each of the vinyl protons of enone 14, enamine 13, the two major isomers of intermediate 15, and impurity 16 can be observed in the downfield region of the NMR spectra. Since intermediate 15 has a strong chromaphore, its disappearance can be monitored by normal-phase HPLC (UV detection) during the course of the cyclization reaction. Pyridine sulfide 10 was prepared in multiple runs using 1 L reaction equipment (see Experimental Section). In addition, an analytical standard of sulfide 10 was prepared for use in quantitative analyses. Pyridine sulfide (10) process streams were assayed via GC analysis using dibutyl phthalate as the internal standard. The iodobenzene diacetate procedure proved to be an excellent way to form sulfilimine 17 (Scheme 4). The reactants Scheme 4. Oxidation of Pyridine Sulfide 10 to Isoclast Active (1)

were mixed together in acetonitrile at 10 °C, and the mixture was allowed to warm to room temperature. Near 20 °C, a mild exotherm occurred, which raised the temperature into the low 30s, and during this time, the mixture became a clear light orange solution. LC analysis would indicate >98% area conversion to the more polar sulfilimines 17. Workup involved addition of water followed by three extractions of the acetonitrile/water sulfilimine (17) solution with hexanes to remove the majority of byproduct iodobenzene. Solvent exchange into dichloromethane gave a sulfilimine solution ready for the following oxidation. Additional LC analysis indicated two sulfilimine isomers were present in a 30:70 area ratio. These isomers could be separated and characterized (see Experimental Section). Although providing a well-controlled and high-yielding synthesis of 17, the use of iodobenzene diacetate presented the problems of B

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of enone 14 with enamine 13 gave a much lower yield for the cyclization step. It was assumed that some of the toluene must be removed in order to azeotropically dry the toluene/13 solution and remove excess pyrrolidine prior to reaction with enone 14. In the early process development stages, the Michael reaction and subsequent cyclization were conducted in acetonitrile. Subsequently, it was determined that toluene may be substituted for acetonitrile with no deleterious effect on the yield of 10. The use of toluene provided two major process advantages. First, the toluene solution of enamine 13 may be used directly in the following Michael reaction. Second, the workup of the post cyclization reaction was simplified. In our previous workup, the post cyclization acetonitrile solution of pyridine sulfide 10 was diluted with water and extracted with several portions of hexanes. The hexanes were then removed on a rotary evaporator. The current workup consists of washing the postcyclization toluene solution once with water followed by removal of the toluene by rotary evaporation. The concentrated crude sulfide is then purified by vacuum distillation. The average yield from aldehyde 6 was 66% following distillation with an average purity of 98 wt % (GC internal standard method). The distillation bottoms were composed of unidentified tars and impurity 16. Differential scanning calorimetry (DSC) and accelerated rate calorimetry (ARC) data on the distillation bottoms indicated a potential exothermic decomposition starting as low as 170 °C. For this reason, distillations were kept at an internal pot temperature of less than 155 °C. The 66% yield over this three-step sequence was noteworthy when one considers the number of bonds being formed and broken while utilizing a minimal number of physical operations. Oxidation of Pyridine Sulfide 10 to Sulfilimine 17. With the anticipation of further scale-up and eventual manufacture, an alternative synthesis of sulfilimine 17 was desired. Two main routes are commonly used to prepare sulfilimines,9 involving either an oxidative imination of a sulfide or a nucleophilic displacement of the corresponding sulfinimidoyl halide (halosulfonium intermediate). There are few literature examples7 for the formation of N-cyanosulfilimines from sulfides. Discovery chemists introduced this functionality by first reaction of a sulfide with sodium azide in H2SO4 to give the unsubstituted sulfilimine, followed by alkylation with cyanogen bromide. As described above, a later procedure was developed using iodobenzene diacetate and cyanamide, which was used during sample campaigns. Both of these routes are examples of the oxidative imination approach to sulfilimines, and they proceed through postulated nitrene intermediates. The first route was unattractive by virtue of potentially explosive sodium azide and the use of the highly toxic alkylating agent cyanogen bromide. In the second route, a postulated cyanonitrene intermediate was generated. Although it is a well-behaved and high-yielding procedure, the high cost and uncertain availability of iodobenzene diacetate suggested the search for an alternative procedure. In addition, this procedure presented the problematic disposal or recycle of a large quantity of iodobenzene on a process scale. Swern reported the generation and interception of this cyanonitrene intermediate from N-sodio-N-chlorocyanamide to form Ncyanosulfilimines.10 However, N-sodio-N-chlorocyanamide was generated below −50 °C using t-butyl hypochlorite, and it did not appear to be attractive from a manufacturing perspective. Therefore, work was focused on the second approach to

using an expensive reagent as well as disposal or recycle of large quantities of iodobenzene on a process scale. Sulfilimine 17 was next oxidized to Isoclast using a catalytic amount of RuCl3 with a full equivalent of NaIO4 in a CH2Cl2/ water two-phase system (Scheme 4). The sodium periodate was mixed with water, followed by addition of ruthenium(III) chloride. To this dark mixture was added the CH2Cl2/ sulfilimine (17) solution over about 2 h with rapid stirring. The reaction was exothermic, with the temperature maintained below 30 °C by control of the addition rate. At the onset of addition, a vigorous off-gassing occurred, which subsided within 5 min. A black color formed on the exposed glass surface of the reaction vessel and also up into the N2 bubbler. The cause of this off-gassing and black color formation was not known; however, it was possibly a result of in situ formation of volatile ruthenium tetroxide. Over the course of the sulfilimine (17) addition, the reaction mixture became black and very thick. During some runs, the oxidation would appear to stall. In these cases, the reaction could be coaxed to completion by the addition of more RuCl3 and/or NaIO4. Workup of this thick dark mixture needed to be performed immediately upon completion of the oxidation. If the reaction mixture was allowed to sit, then product 1 would start to crystallize from the mixture, compounding problems with its isolation. When the oxidation was complete, as determined by LC analysis, more water was added to the mixture to affect phase separation. This phase separation was hindered by a large amount of black rag, and a flashlight had to be used for interface determination. The rag/aqueous layer was re-extracted with CH2Cl2. The organics were then combined, water was added, and excess oxidant was destroyed by the addition of aqueous sodium metabisulfite. The organics were concentrated, and the gray paste-like solid recrystallized from hot 2-propanol to give Isoclast as a gray solid, with yields generally in the upper 70% range across the two step oxidation procedure from pyridine sulfide 10. In this manner, about 200 g of Isoclast could be prepared. It should be noted that the grey color of the product was caused by residual ruthenium. The ruthenium level in the material was about 270 ppm, as determined via neutron activation analysis. Although this oxidation of sulfilimine 17 to the desired product, Isoclast, provided acceptable yield, the processing issues encountered during workup, the iodine waste generated, and the observations made during this oxidation would make the use of RuCl3/NaIO4 a poor candidate for further scale-up. Second-Generation Process Development. Synthesis of Pyridine Sulfide 10. During the course of our initial sample campaign, it became evident that we could not meet the required long-term cost of manufacturing utilizing the chemistry described above. The original synthesis of pyridine sulfide 10 worked well and required only minor modifications in order to deliver a more streamlined process. Our original preparation of enamine 13 used 1.1 equiv of pyrrolidine, potassium carbonate, and toluene as the solvent. Upon completion of the reaction, the potassium carbonate was removed by filtration, and the toluene was removed by rotary evaporation. For future sample campaigns, we demonstrated that not all of the toluene needed to be removed prior to forwarding enamine 13 to the Michael reaction with enone 14. Concentration of the toluene/enamine mixture (ca. 35 °C/20 mmHg) to approximately 45−55 wt % 13 provided a solution that could be used directly in the Michael reaction. One experiment in which no toluene was removed prior to reaction C

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to the reaction mixture resulted in more sulfoxide (19) formation. The promising results with calcium hypochlorite prompted a reinvestigation using sodium hypochlorite, which would eliminate insoluble calcium salt precipitation. Higher concentration bleach solutions (10−12 wt %) are known to lose strength over time, which might explain the problem using commercial pool bleach. The reaction was subsequently conducted using commercial bleach (6 wt %, 5.7% active via titration). On a 1 mmol scale, cyanamide was dissolved in acetonitrile and cooled to 0 °C, and the bleach was added. After stirring cold for 15 min, sulfide 10 (dissolved in acetonitrile) was added and allowed to warm to room temperature. LC analysis indicated sulfide 10 was gone, with major sulfilimine 17 isomers present and only 6% (area LC) sulfoxide 19 isomers. The mechanism and kinetics for the formation of sulfilimines have been discussed7 and appear to be quite complicated. A simplified mechanism is proposed in Scheme 5 and is based upon analogy with the Mann−Pope reaction for the formation of N-p-tosylsulfilimines. The chlorinating agent (bleach) can react with the cyanamide to give chlorocyanamide or directly with sulfide 10, leading to a chlorosulfonium intermediate 18. Pyridine sulfide 10 can also react with the chlorocyanamide to give the analogous chlorosulfonium intermediate 18. These chlorosulfonium intermediates 18 are believed to react with their counterion (or water), leading to sulfilimine 17 and sulfoxide 19. The apparent competition (rates) of these two pathways will determine the ratio of sulfilimine 17 to sulfoxide 19. Further studies led to a change in the order of addition of the reagents, which simplified the scale-up of this process. It was found that sulfide 10 could be premixed with the cyanamide in acetonitrile and cooled, followed by adding bleach, eliminating one continuous slow addition. The reaction was quickly scaled (0.5 mol), and the original workup procedure (extraction into CH2Cl2) was modified to accommodate the new NaMnO4 oxidation (discussed in the following section). However, sulfoxide (19) levels were found to have increased from 6% (area LC) on the 1 mmol scale to 7−9% (area LC) on the larger scales. The reasons for this increase were not known. Two 0.1 mol reactions were conducted using 50% aqueous cyanamide instead of the solid form. In addition to the lower cost, use of this solution would make loading into larger vessels more convenient and safer. However, in both cases, the level of sulfoxide 19 increased to 12−13% (area LC). The initial increase in water concentration appeared to have a detrimental effect on this reaction. Oxidation of Sulfilimine 17 to Isoclast. Of particular interest from a process scale-up perspective was the need to replace ruthenium chloride/sodium periodate in the final oxidation step. Although ruthenium chloride/sodium periodate gave the desired final product in good yields, there have been several caveats to this process. Removal of the entrained ruthenium species in the final product requires treatment with alumina followed by recrystallization from 2-propanol. Also, noticeable off-gassing and deposition of a black residue into the headspace of the reactor has been observed while running this chemistry. In addition, difficulties encountered during workup and phase separation of the reaction mixture dictated an alternative synthetic procedure. There are some literature examples12 that describe the use of potassium permanganate as an oxidant in the formation of sulfoximines. However, none of these references contain

sulfilimines, which involved nucleophilic displacement of a generated sulfonium halide intermediate. A qualitative screening study was undertaken in the laboratory that involved the generation of a sulfonium halide intermediate 18 (Scheme 5) and its subsequent displacement Scheme 5. Possible Mann−Pope Type Pathway for Sulfilimine Formation

with cyanamide or its sodium salt. The variables studied included halogenating agent (N-chlorosuccinimide, trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin, and Nbromosuccinimide), nucleophile (cyanamide or sodium salt), solvent, order of addition of reagents, and temperature. The goal of this study was to rapidly identify a potential synthesis of sulfilimine 17, which could later be developed into a procedure suitable for scale-up. The reaction mixtures were analyzed by HPLC (see Experimental Section for conditions), looking for disappearance of sulfide 10 and formation of sulfilimine isomers 17. The major byproducts formed during these reactions were the sulfoxide isomers 19, which were always present in >10% area. In some cases, sulfoxides 19 proved to be the major product. As a consequence, a successful procedure using these halogenating agents was not realized. The formation of cyanosulfilimines using 4 equiv of I2 with cyanamide and sodium t-butoxide appeared in the literature11 after the completion of this current study. Earlier research indicated that sodium hypochlorite solution (bleach) could be used with cyanamide in acetonitrile to give sulfilimine 17. When this experiment was repeated using commercial pool bleach obtained locally, significant amounts (>10% area LC) of sulfoxides 19 were obtained, and large amounts of unreacted sulfide 10 remained. Use of larger quantities of bleach to drive the reaction to completion resulted in the formation of ketone 20. Apparently under alkaline conditions (Scheme 6), the sulfimimine undergoes isomerScheme 6. Plausible Pathway to Ketone 20

ization and hydrolysis to the ketone (20). The use of solid calcium hypochlorite appeared to give better conversion to sulfilimine 17 with less formation of sulfoxides 19, but the reactions could not be forced to completion. Over the course of the reaction, calcium salts would gum out and eventually prevent good mixing of the reaction mixture. Addition of water D

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filtered, and the product was isolated as described in the Experimental Section. Several impurities have been observed in the starting sulfilimine solution and the crude isolated sulfoximine product. Figure 1 summarizes the main impurities than can be easily

examples of substrates with pyridine ring functionality or a nitrile group on the sulfilimine nitrogen. With respect to Isoclast, some preliminary work demonstrated that catalytic reaction of sulfilimine 17 with 4 equiv of peracetic acid and 6 mol % of manganese dioxide (MnO2) generated Isoclast in about 56% yield of crude isolated product. While these preliminary experiments were encouraging, MnO2 is known to be a catalyst for peroxide decomposition. It was noticed during this experiment that the reaction temperature increased quickly, and a water bath was needed to moderate the internal temperature. During this reaction, a purple color was observed (possibly indicating the presence of a Mn7+ species). This prompted efforts to study Mn7+ (e.g., some permanganate salt) for the final oxidation step. Either sodium or potassium permanganate should feasibly work equally in this oxidation step; however, the cheaper sodium salt was chosen based on the cost of future scale-up. Commercial 40 wt % aqueous sodium permanganate was utilized for these studies. The studies began with looking at two-phase liquid−liquid oxidations. A previously prepared solution (using the iodobenzene diacetate route) of sulfilimine 17 in methylene chloride (∼11−15 wt %) was utilized for these initial process studies. This sulfilimine solution was cooled in an ice−water bath, and then the aqueous permanganate solution (1 mol equiv) was slowly added via an addition funnel. It was determined that running the reaction with about 0.95 mol equiv of permanganate relative to sulfilimine 17 gave clean conversion, acceptable yields, and a manageable workup scheme. The reaction was very exothermic, so the permanganate addition rate was adjusted to maintain the internal reaction temperature at the desired setting (typically, 10−20 °C). The reaction mixture was analyzed by reverse-phase HPLC, and the reaction was subsequently quenched with sodium bisulfite to remove excess oxidant. The organic layer was separated and concentrated on a rotovap to obtain crude Isoclast as a white solid. One concern with this oxidation strategy was the manganese byproducts formed during the redox chemistry. As the permanganate reagent was slowly added, the Mn7+ species presumably became reduced to MnO2. Over time, as the permanganate was slowly added, the reaction mixture became more viscous from manganese byproduct formation. This brown precipitate exhibited fine particles that were difficult to filter quickly as well as remove entrained sulfoximine product. In addition, the MnO2 precipitate exhibited a willing propensity to deposit a thick rind layer onto the walls of the glass reactor. From a scale-up perspective, formation of such a thick rind layer could possibly insulate the reaction mixture from the appropriate heat transfer needed by the cooling jacket in larger reaction vessels. It was found that by reversing the addition order of reagents and running the reaction more dilute these process issues were eliminated. Using this approach, the reaction vessel was charged with 40 wt % sodium permanganate followed by additional water and methylene chloride (see Experimental Section for details), and then the sulfilimine/methylene chloride solution was slowly added via addition funnel. The addition rate was adjusted so that the internal reaction temperature could be maintained between 10 and 20 °C. The solution viscosity appeared lower with this reverse addition approach. When the bisulfite quench was added to the reaction vessel, there was no apparent rind layer after 30 min of additional stirring. The reaction was then

Figure 1. Potential relevant impurities associated with the Isoclast process.

detected by HPLC. Sulfoxide 19 was a byproduct formed during the preparation of sulfilimine 17. Sulfone 21 was the direct oxidation product of sulfoxide 19 during the permanganate chemistry. Controlling the formation of sulfone 21 could be achieved through suppressing the amount of sulfoxide 19 formation during the sulfilimine preparation. Sulfilimine 22 was likely formed when sulfilimine 17 was exposed to more acidic reaction conditions. Formation of this impurity could likely be suppressed by controlling the pH of the reaction. Methyl ketone 20 was an impurity that was ubiquitous to both oxidation steps. Methyl ketone (20) formation can be suppressed by controlling the pH during permanganate oxidation of sulfilimine 17. The biggest breakthrough in understanding pH dependence came from the following observations. Observation 1: When pure/crystalline sulfilimine isomers are dissolved into methylene chloride and then treated with 40 wt % sodium permanganate (usual reaction concentration), there was considerably more generation of methyl ketone 20 than in the standard process. Observation 2: Most of the sulfilimine/methylene chloride solutions utilized for permanganate oxidations were prepared from the iodobenzene diacetate chemistry. Toward the end of the permanganate studies, an alternative oxidation approach to preparing the sulfilimine using commercial bleach was under development (see previous discussion). When these sulfilimine solutions (prepared from bleach) where subject to the permanganate oxidation conditions, a higher percent area by HPLC analysis of methyl ketone 20 was observed as compared to that from the standard process. During the sodium permanganate oxidations, sodium hydroxide was generated, leading to a highly alkaline mixture. Under these conditions, methyl ketone 20 formation was observed. In the iodobenzene diacetate route to sulfilimine 17, 2 equiv of acetic acid are generated from this oxidation step and carried through to the permanganate oxidation, in effect neutralizing the sodium hydroxide that was formed. If sulfilimine/methylene chloride solutions prepared from the bleach route were subsequently spiked with acetic acid, then the permanganate oxidation gave clean conversion to the desired sulfoximines with very little methyl ketone present. Therefore, further oxidations required the addition of acetic acid to the sulfilimine solutions prior to slow addition to the aqueous permanganate. Oxidations to Prepare Isoclast. As previously mentioned, Isoclast was produced utilizing the iodobenzenediacetate oxidation of pyridine sulfide 10 to sulfilimine 17 followed by sodium permanganate oxidation in CH2Cl2 to the desired product. During the early stages of process development, the E

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to room temperature and stirred for about 5 h. A small sample was removed and analyzed via 1H NMR, which indicated that the reaction was complete. The mixture was filtered, and the solid was washed with toluene. The filtrate was concentrated on the rotary evaporator (20 mmHg/35 °C), leaving 13 as a pale yellow liquid (677 g). The material was used in the subsequent step. 1H NMR (300 MHz, CDCl3/major isomer >95%) δ 1.33 (d, J = 6.6 Hz, 3H), 1.81 (m, 4H), 2.00 (s, 3H), 2.99 (m, 4H), 3.22 (m, 1H), 3.98 (dd, J = 13.5, 9.0 Hz, 1H), 6.26 (d, J = 13.5 Hz, 1H). 5-[1-(Methylthio)ethyl]-2-(trifluoromethyl)pyridine (10). A 1 L three-necked, round-bottomed flask was fitted with a condenser, a mechanical stirrer, and an addition funnel. The vent from the condenser was connected to a 2 L trap that could be purged with N2. The vent from the trap went to a 1 L jacketed (cold water) flask with a subsurface dip tube. The 1 L flask contained 10% bleach. The vent from the 1 L flask was connected to a recirculating scrubber column packed with 1/4 in. ceramic saddles. Bleach was pumped through this scrubber column. The column was vented in a hood. The system was purged with N2 via the 2 L purge trap. To the reaction vessel were added CH3CN (694 g) and ETFBO (9, 737 g, 4.39 mol). The solution was cooled to below 15 °C, and then the enamine (8, 677 g, ca. 3.95 mol) was added dropwise, keeping the temperature at or below 15 °C. The dark reaction mixture was warmed to room temperature and stirred overnight. A small sample was removed and analyzed by 1H NMR. The NMR spectra indicated that the reaction was complete. To the vessel was added ammonium acetate (461 g, 5.98 mol), and the dark slurry was heated at 80 °C and held there for 30 min. At that time, HPLC analysis indicated that the reaction was complete (less than 1% 15 remained). The dark mixture was cooled to room temperature and sparged with N2 for 1.5 h. Acetonitrile (128 g), water (485 g), and hexane (502 g) were added. After stirring for 30 min, the phases were separated, and the aqueous phase was extracted again with hexane (365 g). The combined organic phases were concentrated on the rotary evaporator (20 mmHg, 35 °C), leaving a very dark liquid. The material was distilled through a 12 cm Vigreux column, and product 10 was collected at about 90 °C overhead temperature at 2 mmHg as a yellow liquid (593 g, >98 wt % via internal standard GC assay). 1 H NMR (400 MHz, CDCl3) δ 1.63 (d, J = 7.2 Hz, 3H), 1.95 (s, 3H), 3.94 (q, J = 7.1 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.0, 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H). GC-MS m/z (% relative intensity, ion) 221 (30%, M+), 174 (100%), 154 (85%). N-Cyano-S-[1-(6-trifluoromethyl-3-pyridinyl)ethyl]-Smethylsulfilimine (17).13 Procedure 1. In a 3 L four-necked, round-bottomed flask, a mixture of 221 g (1.0 mol) of 5-[1(methylthio)ethyl]-2-(trifluoromethyl)pyridine (10) and 42 g (1.0 mol) of cyanamide in 1200 mL of acetonitrile was cooled below 10 °C with an ice bath. To this solution was added 322 g (1.0 mol) of iodobenzene diacetate all at once. The yellow slurry was allowed to stir below 10 °C for 10 min, and then the ice bath was removed. The reaction mixture slowly warmed to room temperature over 1.5 h and then slowly exothermed from 22 to 30 °C over the next 0.5 h. The reaction was now a clear orange solution. The reaction mixture was allowed to return to room temperature, when LC analysis indicated that there was 97% purity). 14 was purchased from Solvay (>98% purity). Sodium permanganate was purchased from the Carus Corporation. Iodobenzene diacetate was purchased from Deepwater Chemical. All solvents were HPLC grade and purchased from Fisher Scientific. All other raw materials were ACS grade purchased from Aldrich Chemical. The pyridine sulfide (10) could be assayed by GC analysis using dipropyl phthalate as the internal standard: Agilent HP-1 (30 m × 0.32 mm, 0.25 μm film), temp 1 = 50 °C, time 1 = 2 min, rate = 30 °C/min, temp 2 = 300 °C, 24 psi He pressure. The disappearance of diene 15 could be monitored using normal-phase HPLC: Zorbax RX-SIL (4.6 × 250 mm, 5 μm), 60% hexane/40% t-butylmethyl ether, 1 mL/min, 225 nm detection. GC/MS analyses were conducted using an Agilent 5975 Inert mass selective detector at 70 eV ionization potential. The GC column and temperature program are as described above. Isoclast Active (1) and sulfilimine 17 could be assayed by HPLC using o-toluic acid as the internal standard: Agilent Zorbax RX-C8 (250 mm × 4.6 mm, 5 μm), 25% solvent A = 90:10:0.1 CH3CN/CH3OH/formic acid, 75% solvent B = 90:10:0.1 water/CH3OH/formic acid, 1 mL/min, 32 °C, 230 or 260 nm. NMR spectra were recorded on a Bruker Avance 400 MHz (400.13 MHz for 1H; 100.62 for 13C) or a Bruker 300 MHz (300.13 MHz for 1H; 75.5 MHz for 13C) instrument. Chemical shifts are reported in parts per million (ppm) (δ) relative to tetramethylsilane. Multiplicities are reported as follows: s (singlet), d (doublet), t (triplet), and m (multiplet). Coupling constants (J) are reported in Hz. 3-(Methylthio)-1-(pyrrolidin-1-yl)-1-butene (13). A 5 L three-necked, flask round-bottomed flask with thermowell was fitted with a N2 inlet/addition funnel, a mechanical stirrer, and a stopper. After the vessel was flushed with N2, it was loaded with granular potassium carbonate (278 g, 2.01 mol), toluene (2091 g), and pyrrolidine (317 g, 4.45 mol). The slurry was cooled to about 10 °C, and the aldehyde 6 (411 g, 3.99 mol) was added dropwise, keeping the temperature at or below 15 °C. After the addition was complete, the mixture was warmed F

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The organics were combined, and this acetonitrile/sulfilimine solution was used directly in the following oxidation. LC analysis indicated a 95 area % (40:54 ratio) of two sulfilimines isomers. N-Cyano-S-[1-(6-trifluoromethyl-3-pyridinyl)ethyl]-Smethylsulfoximine (1).14 Procedure 1. To 1500 mL of water was added 214 g (1.0 mol) of sodium periodate, and the mixture was stirred for 15 min. Initially, the solids dissolved to give a cloudy mixture, but they later reappeared toward the end of 15 min (hydrate?). To this white mixture was added 930 mg (4.5 mmol) of ruthenium(III) chloride hydrate, and the dark brown mixture was stirred for 5 min. To this rapidly stirred mixture was added dropwise a solution of ∼1.0 mol sulfilimine in 1000 mL of dichloromethane over 1.75 h. Note that during the first several minutes of sulf ilimine solution addition a vigorous of f-gassing was seen, as evidenced by rapid bubbling through the N2 bubbler. Also at this time, a black residue would form on the exposed surfaces of the reaction f lask along with black color formation in the N2 bubbler. The cause of this off-gassing and black color formation was not known. The temperature during this addition rose from 16 to 29 °C. During some of these oxidations, a thick flocculent solid would form; in others, the reaction remained fairly thin with a minimal amount of solids present. The reaction mixture was monitored by LC analysis, and in some of the oxidations, additional small portions of sodium periodate would need to be added to complete the sulfilimine to sulfoximine oxidation. The reason why some of the oxidations stalled before completion was not known. Upon completion, the reaction mixture was transferred to a 5 L round-bottomed flask with mechanical stirrer and bottom drain, and 1.5 L of water was added. After stirring for 10 min, the mixture was allowed to settle, and the layers were separated (dark mixture with solids present; a flashlight was used to aid in determining the interface). The aqueous mixture was reextracted with 200 mL of dichloromethane, and the aqueous mixture was discarded. The organics were combined and returned to the workup vessel, and 500 mL of water was added. Excess oxidant was destroyed by adding ∼40 mL of an aqueous solution of sodium metabisulfite, testing the mixture with starch iodide paper. The layers were separated, and the organics were dried over MgSO4, filtered, and concentrated in vacuo to give a paste-like gray solid. This solid was heated and dissolved in 500 mL of hot 2-propanol, and the flask was placed in a refrigerator overnight. The slurry was filtered and rinsed with 2-propanol to give 260 g of a gray solid. The solid was air-dried in a hood overnight and further dried in a vacuum oven at 40 °C to give 217 g (78% yield for two steps) of a gray solid; 30:70 (area) ratio of isomers by LC analysis. Purification for Analytical Sample. The gray color (ruthenium) could be removed from the product by treatment with neutral alumina. Contact time should be kept to a minimum to prevent isomerization of the sulfoximine isomers. For example, 385 g of the gray sulfoximine [98 area % (31:67 ratio) of isomers by LC] was heated and dissolved in 2.5 L of EtOAc. To this dark solution was added 190 g of neutral alumina (Aldrich, Brockmann I, neutral activated), and the mixture was stirred for 10 min. The mixture was filtered warm through Celite, concentrated in vacuo, and air-dried in a hood to give 378 g of a light tan solid [99 area % (32:67 ratio) of isomers by LC]. A total of 1128 g of sulfoximine treated in the above manner was heated and dissolved in 2.5 L of i-PrOH. The solution was allowed to slowly cool to 30 °C with stirring. The mixture was filtered at 30 °C and rinsed with 2-propanol to

solution of sodium metabisulfite, testing the mixture with starch iodide paper. To the mixture was added 800 mL of hexanes, and the mixture was stirred for 5 min and separated. The bottom aqueous layer was returned to the flask, 400 mL of water was added followed by 400 mL of hexanes, and the mixture was stirred for 5 min and separated. The aqueous was again returned to the round-bottomed flask and extracted a third time with 400 mL of hexanes. The hexane extracts (containing the bulk of iodobenzene) were discarded. The aqueous layer was concentrated in vacuo (to remove acetonitrile) until a cloudy two-phase mixture was obtained. This mixture was extracted two times (700 mL, 300 mL) with dichloromethane, and the organics were combined and dried overnight over MgSO4. After filtration, the dichloromethane solution (1560 g) was used directly in the following oxidation. LC analysis indicated a 92 area % (28:64 ratio) of two sulfilimines isomers. Purification of the Two Sulfilimine Isomers. Isomer A. Sulfilimine solution from a typical reaction (40 mL, ∼16 wt % theory) was concentrated in vacuo and exposed to high vacuum to give a thick orange/amber oil. This oil was dissolved in 10 mL of EtOAc, and 10 mL of hexanes was added. To the cloudy mixture was added 1 mL of EtOAc to give back a clear solution. The flask was scratched with a glass rod to induce crystallization. The mixture was cooled in a refrigerator for 1 h, filtered, and exposed to high-vacuum drying to give 1.2 g of a white powder. mp 115−117 °C. >99% (area) LC of the first eluting isomer. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 2 Hz, 1H), 8.15 (dd, J = 8, 2 Hz, 1H), 8.02 (d, J = 8 Hz, 1H), 4.73 (q, J = 7 Hz, 1H), 2.66 (s, 3H), 1.77 (d, J = 7 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 150.89, 146.61 (q, J = 34.3 Hz), 139.16, 133.33, 122.89, 120.80, 120.56 (m), 120.16, 56.35, 30.49, 14.93. Isomer B. The filtrate from above was concentrated in vacuo to give a thick amber oil [LC analysis indicated an 82 area % 15:67 ratio) of two sulfilimines isomers]. This oil was purified by flash chromatography on silica, eluting with 5% EtOH in CHCl3. Some minor colored material was discarded first. The major sulfilimine isomer (second eluting isomer by LC) was collected next, concentrated in vacuo, and exposed to highvacuum drying to give 3.2 g of thick amber oil. This oil was slurried and scratched with 20 mL of Et2O, cooled in a refrigerator, filtered, and exposed to high-vacuum drying to give 2.48 g of a white powder. mp 78−80 °C. >99% (area) LC of the second eluting isomer. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2 Hz, 1H), 8.22 (dd, J = 8, 2.0 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 4.78 (q, J = 7 Hz, 1H), 2.74 (s, 3H), 1.75 (d, J = 7 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 150.50, 146.61 (q, J = 34.3 Hz), 138.58, 134.99, 122.83, 120.89 (m), 120.61, 120.10, 56.84, 29.82, 12.64. Procedure 2. In a 2 L four-necked, round-bottomed flask a solution of 110.6 g (0.475 mol, 95% assay) of 5-[1(methylthio)ethyl]-2-(trifluoromethyl)pyridine and 25.2 g (0.6 mol) of cyanamide in 600 mL of acetonitrile was cooled to −5 °C with a salt/ice bath. To this solution was added 750 g (0.575 mol) of 5.7 wt % aqueous commercial bleach dropwise over 45 min, with the temperature kept below 0 °C. The yellow reaction mixture was allowed to stir at −1 °C for 30 min. To the light orange mixture was added 9.5 g (0.05 mol) of sodium metabisulfite in 25 mL of water to destroy any remaining oxidant, and the two-phase mixture was allowed to settle. An insoluble material was present in the aqueous phase. This aqueous phase was re-extracted with 2 × 50 mL of acetonitrile. G

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within 5 min. The mixture was stirred cold for 1 h and filtered to give 147.6 g of a white solid. The product was air-dried in a hood for 2 days to give 116.5 g of product and was further dried in a vacuum oven at 35 °C to give 116.5 g (88% yield) of a white powder. LC analysis indicated a 95 area % (43:52 ratio) of two isomers, with the major impurity being the sulfone (3.5% area).

give 1397 g of an off-white solid. This material was dried in a hood overnight and then exposed to vacuum oven drying at 40 °C to give 1052 g of an off-white powder. mp 116−128 °C. 34:66 area ratio of isomers by LC. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.26 (m, 1H), 8.03 (d, J = 8 Hz, 1H), 5.37 (m, 1H), 3.49, 3.47 (2s, 3H), 1.88 (m, 3H). Procedure 2. In a 5 L four-necked, round-bottomed flask, a mixture of 400 mL of dichloromethane, 400 mL of water, and 320 mL (1.25 mol) of a 40% aq solution of NaMnO4 (Aldrich) was cooled to 13 °C with an ice bath. To this rapidly stirred mixture was added dropwise a solution of (∼1.0 mol) sulfilimine in 1000 mL of dichloromethane (∼1560 g) over 1.75 h. During this time, the ice bath was lowered or raised to maintain a reaction temperature of 13−20 °C. A gritty film appeared to form on portions of the round-bottomed flask. A 10 min postreact LC sample indicated no remaining sulfilimine starting material. After stirring for 30 min at 15 °C, a solution of 570 g (3.0 mol, 3 equiv) of sodium metabisulfite in 900 mL of water was added with rapid stirring over 1.5 h: Note that this is very exothermic, as the temperature rose from 15 to 28 °C rapidly at first. The dark reaction mixture color gradually lightened, and a brownish flocculent mixture was obtained by the conclusion of bisulfite addition. No film or rind remained on the flask sides at this point. The mixture was stirred at room temperature (23 °C) for 30 min and was then filtered through Whatman coarse wet-strengthened filter paper. The brown paste-like solid was patted down and rinsed with two wet cake volumes of dichloromethane (wet cake wt 500 g). The clear two-phase mixture was transferred to a 4 L separatory funnel, and the bottom organics were collected. The aqueous layer was re-extracted with 30 mL of dichloromethane, and the organics were combined with the first cut (∼1800 mL volume). The solution was concentrated in vacuo to give 275 g of a white solid. This solid was air-dried overnight in a hood to give 260 g and finally in a vacuum oven at 40 °C to give 259 g (93% yield) of a white solid. LC analysis indicated a 98 area % (30:68 ratio) of two isomers. Procedure 3. In a 2 L four-necked, round-bottomed flask, a mixture of 100 mL of acetonitrile, 200 mL of water, and 160 g (0.45 mol) of a 40% aq solution of NaMnO4 (Aldrich) was cooled to 15 °C with an ice bath. To this rapidly stirred mixture was added dropwise a solution of (∼0.475 mol) sulfilimine in ∼700 mL of acetonitrile over 50 min. During this time, the ice bath was lowered or raised to maintain a reaction temperature near 19 °C. The reaction was allowed to postreact for 45 min. The dark mixture was cooled to 12 °C, and a solution of 171 g (0.9 mol) of sodium metabisulfite in 300 mL of water was added with rapid stirring over 15 min: Note that this very exothermic, as the reaction temperature rose from 12 to 28 °C rapidly at first. The dark reaction mixture color gradually lightened, and an off-white flocculent mixture was obtained by the conclusion of bisulfite addition. A small dark rind remained on the flask sides at this point, but it dissipated within 10 min. The mixture was stirred at room temperature (23 °C) for 30 min and was then filtered through Whatman filter paper. The off-white solid was rinsed with 50 mL of acetonitrile. The clear two-phase mixture was transferred to a 2 L separatory funnel, and the bottom aqueous layer was discarded. The upper yellow organic layer was concentrated in vacuo to ∼50 wt % product. At this point, the product was a two-phase mixture, and a small amount of crystalline material could be seen on the sides of the flask. This mixture was poured onto 300 mL of rapidly stirred water in an ice bath, and the white insoluble phase solidified

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (989) 638-6946. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank analytical sciences group within Dow for developing process analytical methods.

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DEDICATION This article is dedicated in memory of Kim Arndt, whose passion and energy for process chemistry development have inspired many of his colleagues.

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REFERENCES

(1) (a) Loso, M. R.; Nugent, B. M.; Huang, J. X.; Rogers, R. B., Zhu, Y.; Renga, J. M.; Hegde, V. B.; Demark, J. J. Insecticidal N-substituted (6-haloalkylpyridin-3-yl)alkyl sulfoximines. US Patent 7,687,634 B2, 2010. (b) Loso, M. R.; Watson, G. B.; Babcock, J.; Kramer, V. J.; Zhu, Y.; Nugent, B. M.; Thomas, J. D. Modern Crop Protection Compounds, 2nd ed.; John Wiley & Sons, Inc.: New York, 2012; Vol. 3, p 1226. (2) Zhu, Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang, J. X.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent, B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler, J.; Meade, T.; Thomas, J. D. J. Agric. Food Chem. 2011, 59, 2950. (3) Ross, R.; Renga, J. M.; Bland, D. C.; Roth, G.; Fung, A. P.; Davis, C. S. Methods for preparing 3-substituted-6-trifluoromethylpyridines from 6-trichloromethyl halogenated pyridines. US Patent 8,785,650 B2, 2014. (4) For a review, see Henry, G. D. Tetrahedron 2004, 60, 6043. (5) (a) Cooke, J. W. B.; Coleman, M. J.; Caine, D. M.; Jenkins, K. P. Tetrahedron Lett. 1998, 39, 7965. (b) Desrosiers, J. N.; Kelly, C. B.; Fandrick, D. R.; Nummy, L.; Campbell, S. J.; Wei, X.; Sarvestani, M.; Lee, H.; Sienkiewicz, A.; Sanyal, S.; Zeng, X.; Grinberg, N.; Ma, S.; Song, J. J.; Senanayake, C. H. Org. Lett. 2014, 16, 1724. (6) Cook, G. A. Enamines: Synthesis, Structure and Reactions; Marcel Dekker, Inc.: New York, 1988; p 7. (7) Kemp, J. E. G.; Ellis, D.; Closier, M. D. Tetrahedron Lett. 1979, 20, 3781. (8) Gaggero, N.; D’Accolti, L.; Colonna, S.; Curci, R. Tetrahedron Lett. 1997, 38, 5559. (9) (a) Gilchrist, T. L.; Moody, C. J. Chem. Rev. 1977, 77, 409. (b) Oae, S.; Furukawa, N. Sulfilimines and Related Derivatives; American Chemical Society: Washington, DC, 1983. (c) Reggelin, M.; Zur, C. Synthesis 2000, 1, 1. (10) Hutchins, M. G. K.; Swern, D. J. Org. Chem. 1982, 47, 4847. (11) Mancheno, O. G.; Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809. (12) (a) Kresze, G.; Wustrow, B. Chem. Ber. 1962, 95, 2652. (b) Claus, P. K.; Rieder, W.; Hofbauer, P.; Vilsmaier, E. Tetrahedron 1975, 31, 505. (c) Claus, P. K.; Hofbauer, P.; Rieder, W. Tetrahedron Lett. 1974, 15, 3319. (d) Johnson, C. R.; Rigau, J. J. J. Org. Chem. 1968, 33, 4340. (e) Shimizu, H.; Sugimoto, A.; Kataoka, T.; Hori, M. Heteroat. Chem. 1995, 6, 167. (13) Podhorez, D. E.; Ross, R., Jr.; McConnell, J. R. Process for the preparation of certain substituted sulfilimines. US Patent 7,868,027 B2, 2011.

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(14) (a) Arndt, K. E.; Bland, D. C.; Podhorez, D. E.; McConnell, J. R. Process for the oxidation of certain substituted sulfilimines to insecticidal sulfoximines. US Patent 7,511,149 B2, 2009. (b) Bland, D. C.; Adaway, T. J.; Podhorez, D. E. Process for the Preparation of Certain Substituted Sulfilimines. US Patent 8,193,222 B1, 2012. (15) Isoclast is a trademark of The Dow Chemical Company (DOW) or an affiliated company of Dow.

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