Development of a Continuous Flow Sulfoxide Imidation Protocol Using

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Organic Process Research & Development

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Technical Note

Development of a Continuous Flow Sulfoxide Imidation Protocol Using Azide Sources under Superacidic Conditions

Bernhard Gutmann,† Petteri Elsner,‡ Anne O'Kearney-McMullan,§ William Goundry,§ Dominique M. Roberge,*,‡ and C. Oliver Kappe*,† †

Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria ‡

§

Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland

AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom

____________________ * Corresponding authors. E-mail: [email protected], [email protected]

ACS Paragon Plus Environment


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Graphical contents entry: O H2O TMSN3 OS+

N

O 50 °C

N

0 °C N

N

Cl

fuming H2SO4

HN O S+


N N

Cl

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Abstract: The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key-step in the preparation of certain ATR kinase inhibitors. Reactions with NaN3 or TMSN3 and concentrated sulfuric acid under literature conditions provided slow reactions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C. The imidation reaction using TMSN3 as reagent was successfully performed in a flow reactor utilizing CH2Cl2/H2SO4 biphasic conditions. The mixture was subsequently quenched in-line with H2O. Phase separation, neutralization and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

Keywords: azide; continuous flow; sulfoximines, superacid



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INTRODUCTION Research on the chemistry and properties of sulfoximines was triggered by the identification of methionine sulfoximine as the agent responsible for the toxicity of wheat flour treated with nitrogen trichloride (agene).1,2 Nitrogen trichloride was used until the late 1940s for the bleaching of flour (agene process) when it was discovered that diets rich in agenized flour cause severe neurological disorders. Whitehead and Bentley accomplished the imidation of methionine sulfoxide with hydrazoic acid (HN3) in the presence of concentrated sulfuric acid and demonstrated that the product is identical with the toxic factor isolated from agene-treated proteins.2 This was the first deliberate synthesis of a sulfoximine functionality and the interest in sulfoximine chemistry has increased steadily since then.3-6 Sulfoximines contain an amphoteric nitrogen and, with two non-identical carbon substituents on the sulfur atom, a configurationally stable asymmetric sulfur moiety. Thus, the use of sulfoximines in asymmetric synthesis as reagents, chiral auxiliaries or as chiral ligands has attracted significant attention in recent years.4 Furthermore, a number of compounds containing a sulfoximine structure have been explored in medical studies and several sulfoximines have recently entered clinical trials.6 AstraZeneca is currently exploring sulfonyl-morpholinopyrimidines as inhibitors of kinases of the phosphatidylinositol 3-kinase (PI3 K) family. In particular, morpholino-pyrimidines with a sulfoximine moiety have been investigated as ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitors (compounds 3 in Scheme 1).7 Even though there is currently no clinical precedent for agents targeting ATR, inhibition of ATR was proposed as a potentially effective approach to future cancer therapy.8

Scheme 1. Preparation of Sulfoximine 2 by the HN3 Method

The shortest route for the synthesis of sulfoximines is given by a direct transfer of nitrogen onto the corresponding sulfoxides.3,9 A variety of nitrene precursors are suitable for this


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transformation,

including

O-sulfonylhydroxylamine

derivatives,

such

as

O-

mesitylsulfonylhydroxylamine (MSH), or iminoiodane reagents, such as PhI=NR (R = tosyl, trifluoroacetyl, etc.) in the presence of metals such as copper, rhodium, silver or iron.9 These reagents allow the preparation of N-protected sulfoximines, and the reactions often can be accomplished without racemization of a stereogenic sulfoxide and with retention of the configuration upon imidation.9 However, subsequent de-protection to produce the synthetically attractive free sulfoximines can be difficult and is often accompanied by a significant loss of material.10 The reaction of sulfoxides with HN3, as demonstrated in the seminal work of Whitehead and Bentley in 1951, provides free sulfoximines directly and is clearly more atom economic (HN3 method).2 This reaction is usually performed with sodium azide and sulfuric acid in CHCl3 as solvent.2,3,11-13 The method is exceedingly successful for the production of sulfoximines from sulfoxides if both carbon substituents are either methyl or aryl. In contrast, reactions with sulfoxides with more labile substituents, such as non-primary alkyl or benzyl groups, usually lead to heterolysis of the C–S bond under the strongly acidic and polar conditions.3 Only a few successful transformations of benzylic sulfoxides to the corresponding free sulfoximines by this method have been reported and the yields are often modest.5b,12 Furthermore, reactions involving azides are generally associated with severe safety concerns due to the toxicity and explosiveness of these reagents. In particular, hydrazoic acid is an exceedingly explosive and toxic compound. Despite their interesting chemical properties, their high chemical stability, profound hydrogen-bond acceptor/donor capability, and appealing physicochemical properties, sulfoximines are still severely underrepresented in organic synthesis as well as medicinal chemistry. It was speculated that the severe hazards associated with most current syntheses and the general inapplicability of these reactions for large-scale production has deterred chemists from a comprehensive exploitation of this valuable compound class.6 A continuous flow procedure for the imidation of sulfoxides has the strong potential to significantly increase the safety of these syntheses and make these compounds more accessible.14 Herein we describe the development of a continuous flow protocol for the direct synthesis of compound 2, the key-intermediate in the synthesis of ATR kinase inhibitors of type 3, from the sulfoxide 1 via the HN3 method under superacidic conditions (Scheme 1).

RESULTS AND DISCUSSION Batch Experiments Employing NaN3 and H2SO4 in Polar Solvents. Initial optimization experiments were performed with 0.2 mmol of the sulfoxide 1 in standard 1.5 mL HPLC



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vials. Since homogeneous reaction mixtures are highly preferable for continuous flow processing, initial batch reactions were performed with aqueous solutions of NaN3 and water miscible co-solvents, such as MeCN, MeOH, dioxane, AcOH and NMP. For these reactions, 0.2 mmol of the substrate were weighted into 1.5 mL HPLC vials. The vials were equipped with a stir bar and 0.4 mL of the respective solvent was added. 52 µL of a 4.4 M solution of aqueous NaN3 (1.1 equiv) and 55 µL of conc H2SO4 (5 equivalents) were then added to the reaction solution. The vials were closed and placed on a hot plate at 50 °C. Gaillard et al. reported a reaction time of around 4 h for the sulfoximidation of methyl phenyl sulfoxide at a reaction temperature of 50 °C using CHCl3 as solvent.11 However, sulfoxide 1 was fully consumed after a reaction time of only 90 min (the first sample for HPLC analysis was taken after 90 min). Methanethiol was formed in these reactions and the reaction mixtures quickly developed a highly disagreeable odor. LC-MS analysis of the reaction mixture suggested that the products formed in these reactions were exclusively derived from a Pummerer-type rearrangement and no desired sulfoximine was produced. Similarly, reactions in the absence of H2O in AcOH as solvent with various amounts of sulfuric acid provided exclusively decomposition products (Table S1 in the Supporting Information).

Batch Experiments Employing TMSN3 and Lewis Acids. Since the Pummerer rearrangement is probably favored by highly polar reaction conditions, we performed experiments using TMSN3 as reagent and various Lewis acids as catalysts in toluene as an unpolar solvent. BF3·OEt2, Yb(OTf)3, Cu(OTf)2 and ZnBr2 were investigated as catalysts (20 mol%). No reaction was observed under these conditions after a reaction time of 1 h at 50 °C. A reaction with TMSN3 in MeOH as solvent (TMSN3 quickly hydrolyzes in MeOH to release HN3), gave an un-identified side product in a slow reaction (38% after 5 h at 50 °C). Again, no desired product was formed in any of these reactions. Batch Experiments Employing Concentrated H2SO4 in CHCl3 as Solvent. By far the most common solvent for sulfoxide imidation reactions with HN3 is chloroform. Thus, further reactions were performed in chloroform under the reaction conditions reported by Pandya et al.12 In their publication the preparation of a benzylic sulfoximine in 65% yield was described. The authors mixed the benzylic sulfoxide with NaN3 in CHCl3 as solvent at room temperature. H2SO4 was then slowly added at a temperature of -20 to -25 °C under an Ar atmosphere. The reaction mixture was then further stirred at room temperature for 12 h and finally at 45 to 50 °C for 3 additional hours.


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Sulfuric acid is not soluble in CHCl3 and forms a separate, immiscible phase. In contrast, sulfoxide 1 is soluble in CHCl3, but it is protonated by H2SO4 and slowly extracted from the CHCl3 phase into the sulfuric acid phase. From the H2SO4 phase, the substrate partly precipitates as a sticky precipitate. In fact, after stirring the reaction mixture for some time at room temperature, analysis of the supernatant CHCl3 phase gave an essentially “empty” HPLC trace, indicating that all of the starting material was either extracted into the H2SO4 phase or precipitated from the mixture. Following the protocol of Pandya et al., reactions with a reaction time of 14 h at room temperature gave a conversion of 19% in the presence of 3 equivalents of NaN3. The selectivity for the product was ~53% for this reaction according to HPLC analysis at 215 nm (Table 1; for further results see Table S2 in the Supporting Information). Comparable results were obtained when the reagents were mixed directly at room temperature and the subsequent experiments were performed at a reaction temperature of 50 °C (both with NaN3 and TMSN3 as reagent). Interestingly, the decomposition of the substrate in the absence of NaN3 was faster than the actual imidation reaction in the presence of the azide (entry 2 and 4 in Table 1). Table 1. Reaction of 1 with NaN3/H2SO4 in CHCl3 at Room Temperaturea azide temp time conv 2 (equiv) [°C] [h] [%] [%] 1 NaN3 (3) rt 14 19 10 2b rt 14 60 0 c 3 NaN3 (3) 50 1 30 16 4b,c 50 1 89 0 a HPLC peak area at 215 nm. Conditions: sulfoxide 1 and NaN3 in CHCl3 were mixed with H2SO4 (6 equivalents) at -20 °C and the mixture was then further heated at room temperature (rt). bAn additional broad signal was apparent in the HPLC (for details see the Supporting Information). c Substrate and reagent were mixed at room temperature. Batch Experiments Employing Fuming H2SO4 in CHCl3 as Solvent. During our investigations we observed that the selectivity of the reaction decreased when an older bottle of concentrated sulfuric acid was used (Table S3 in the Supporting Information). We hypothesized that the lower selectivity for reactions with an older sample of H2SO4 compared to reactions with fresh H2SO4 is caused by a higher water content. Further experiments were therefore performed with fuming H2SO4 (20% SO3 content). With fuming H2SO4, the reaction worked extraordinarily well and product selectivities of up to 87% were attained after reaction times of only ~30 min at 50 °C (see Table S4 in the Supporting Information). Unfortunately,



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the reaction formed a large amount of a sticky precipitate which deposited on the vessel wall as well as on the stir-bar and rendered stirring difficult (Figure 1). Again, the reaction proceeded equally well using TMSN3 as reagent. Less precipitate was formed with TMSN3 as reagent. In fact, essentially homogenous solutions were obtained in solvents such as THF or anhydrous DME. However, no desired product was formed in these solvents (see Table S4 in the Supporting Information).

Figure 1. Reaction mixture after a reaction on a 0.4 mmol scale (3 equivalents of NaN3, 6 equivalents of fuming H2SO4). Batch Experiments Employing other Bronsted Acids in CHCl3 as Solvent. For reactions with different acids, sodium azide (3 equivalents) and the acid (6 equivalents) were mixed in CHCl3 as solvent and the starting material was then added at room temperature (0.2 mmol). The vessel was closed and heated to the desired temperature on a hot plate (Table 2). A large amount of precipitate was formed with sulfuric acid. With the other acids, the reaction mixture contained far less precipitate (probably the sodium salt of the respective acids). Only using fuming H2SO4 the product was formed with good selectivity. Interestingly, even though the pKa of MeSO3H and H2SO4 is very similar, no desired product was formed with this acid (entry 2 in Table 2). Using TMSN3 as reagent the reaction mixtures were essentially homogenous with all tested acids except of H2SO4. However, reactions with none of these acids provided any product. Instead, the main products formed in these transformations were again derived from Pummerer-type rearrangements. The reaction with CF3SO3H led to a surprisingly slow reaction considering its low pKa (entry 10 in Table 3).


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Table 2. Reaction of 1 with NaN3 or TMSN3 and Various Acids in CHCl3 at 50 °Ca azide

acid

pKa

time conv 2 [min] [%] [%] 1 NaN3 TFA -0.3 60 7 0 2 NaN3 MeSO3H -2.6 60 84 0 3 NaN3 H2SO4 (conc) -3 60 16 8 4 NaN3 H2SO4 (fuming) -3 20 98 75 AcOH 4.8 40 2 0 5 TMSN3 6 TMSN3 TFA -0.3 40 14 0 MeSO3H -2.6 40 79 0 7 TMSN3 8 TMSN3 H2SO4 (conc) -3 40 32 10 9 TMSN3 H2SO4 (fuming) -3 40 100 91 10 TMSN3 CF3SO3H -14 40 0 0 11 TMSN3 BF3·OEt2 40 71 0 a HPLC peak area at 215 nm. Conditions: sulfoxide 1 (0.2 mmol), NaN3 or TMSN3 (3 equivalents) and acid (6 equivalents) in CHCl3 were mixed at room temperature. The mixture was then further heated to 50 °C. The results presented above suggest that the sulfoximidation of 1 proceeds entirely in the H2SO4 phase. Hydrazoic acid is partly protonated in concentrated H2SO4 to form a H2N3+ species. Olah and co-workers investigated the structure and properties of the aminodiazonium ion, H2N3+, prepared by protonation of hydrazoic acid in superacids in detail.15,16 The aminodiazonium ion is fairly unstable and decomposes rather quickly under liberation of N2. Importantly, H2N3+ is a strong electrophile and was shown to have the capacity to react with aromatic compounds in an electrophilic amination.15,16 An aminodiazonium ion also might be the actual reagent for the sulfoximidation of sulfoxides (see Figure S1 in the Supporting Information). However, product was formed only in the presence of sulfuric acid and only the reaction with fuming sulfuric acid proceeded fast and cleanly (Table 2). Thus, an alternative mechanism where the azide is activated by intermediate formation of azido sulfonic acid or azido polysulfonic acid might be operating.17 Indeed, the reaction of alkali azides with gaseous SO3 was reported to give crystalline products of the composition MN3·x SO3. Upon storage under concentrated sulfuric acid, the azido polysulfonic acid forms a compound with the formula MS2O6N3 (M = Na, K).18 Reactions in Strong Acids as Solvent. Further reactions were performed in neat concentrated H2SO4 as solvent. With NaN3 as reagent, the mixture is not homogenous, presumably because of the formation of insoluble NaHSO4. On the other hand, the substrate slowly dissolves in a mixture of H2SO4/TMSN3 to give homogenous reaction solutions. Reactions in concentrated



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H2SO4 as solvent provided far better results than reactions with concentrated sulfuric acid as reagent using CHCl3 as solvent. Indeed, a product selectivity of 82% was obtained after a reaction time of 40 min at 50 °C with a ~1.5 M solution of the substrate in conc H2SO4 (entry 3 in Table 3). However, as shown in Table 3, the selectivity decreases with increasing amounts of conc sulfuric acid. Reactions in fuming sulfuric acid gave mostly decomposition while reactions in CF3SO3H or MeSO3H gave no or only slow conversion (see Table S5 in the Supporting Information).

Table 3. Reaction of 1 with Different Azide Sources in H2SO4 (conc) as Solvent at a Reaction Temperature of 50 °C (40 min Reaction Time)a azide H2SO4 conv 2 (µL) [%] [%] 1 NaN3 262 87 59 2 NaN3 524 93 10 3 TMSN3 131 91 82 4 TMSN3 262 78 43 5 TMSN3 524 75 8 a HPLC peak area at 215 nm. Conditions: azide (3 equivs) in H2SO4 (conc) were mixed with sulfoxide 1 (0.2 mmol) at room temperature. The mixture was then further heated to 50 °C. Since the sulfoxide 1 dissolves slowly in concentrated sulfuric acid at room temperature (~20 min in an ultrasonic bath for ~1.5 M solutions), a continuous flow reaction with sulfoxide 1 dissolved in sulfuric acid in one feed and neat TMSN3 in a second feed appeared feasible. However, preliminary experiments suggested that 1 slowly decomposes in conc H2SO4, rendering this approach impractical (see Table S6 in the Supporting Information).

Reactions under Biphasic CHCl3/H2SO4 Conditions. As sulfoxide 1 decomposes in neat sulfuric acid, a flow process under biphasic conditions was envisaged. Since the sulfoximidation reaction proceeds entirely in the sulfuric acid phase, the sole purpose of the inert organic phase for continuous flow reactions is to carry the reagents into the reactor (Scheme 2). To simulate such a process in batch, we dissolved the starting material and TMSN3 in CHCl3 and this mixture was then added in one shot to a well stirred solution of fuming sulfuric acid. Two separated, homogeneous phases were obtained with ~14 equivalents of H2SO4 at 50 °C (i.e. 150 µL sulfuric acid, 0.2 mmol substrate in 500 µL of CHCl3). The typical white, sticky precipitate was formed with lower amounts of H2SO4. Separate analysis of the CHCl3 and the H2SO4 phase revealed that the sulfuric acid phase contains the basic sulfoximine product 2, while the CHCl3 phase contains most of the side products. As anticipated, the reaction worked equally well using CH2Cl2 as solvent. Again, ACS Paragon Plus Environment

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the reaction was considerably faster and significantly cleaner with fuming sulfuric acid compared to reactions with conc sulfuric acid. Indeed >99% conversion was obtained with fuming sulfuric acid after a reaction time of only 10 min at 50 °C (Table S7 in the Supporting Information). After a reaction on a 0.4 mmol scale (116 mg of sulfoxide 1), the mixture was diluted with CHCl3/H2O and the phases were separated. The sulfuric acid phase was neutralized with 3 M NaOH and the free sulfoximine was finally extracted into CHCl3. This procedure provided the desired product with excellent purity (99% according HPLC at 215 nm) in 89% yield as a clear oil which solidified to a white solid upon standing (see Figure S3 for the 1HNMR). Caution: the quench of fuming sulfuric acid with H2O is extremely exothermic and

must be done very carefully, even on this small scale, to maintain the temperature at an acceptable value.

Flow Reactions. A flow reactor was assembled consisting of four syringe pumps (Syrris Asia), a 10 mL tube reactor in a water bath (PFA, 1/8’’ o.d.; 1/16’’ i.d.; 5 m length), a 2 mL tubing in an ice bath (PFA, 1/8’’ o.d.; 1/16’’ i.d.; 1 m length) and an adjustable back pressure regulator (Vapourtec). All supply lines, fittings, T- and X-pieces were made of fluoropolymers (H2SO4 is not compatible with PEEK). For the initial trials, the reaction mixture (feed A, 2 mmol substrate, 3 equivalents of TMSN3 in 5 mL CH2Cl2) was pumped into the reactor at a flow rate of 750 µL/min, while fuming sulfuric acid was pumped into the flow reactor at a flow rate of 250 µL/min. For the in-line quench and extraction, feed C and feed D carried H2O and CH2Cl2 at flow rates of 3 and 1.5 mL/min, respectively. The back pressure was adjusted to 3 bar. Distinct CH2Cl2/H2SO4 segments were formed at the entrance of the coil reactor. The sulfuric acid phase became yellow as the segments moved through the reactor and large amounts of gas were formed (N2). The gas pushed the reaction mixture out of the reactor and the residence time was thus significantly shorter than the calculated 10 min. The reaction under these conditions gave a conversion of 95% with a selectivity for the product comparable to that obtained under batch conditions (~85%). Importantly, the temperature of the cross mixer and the subsequent tubing, in which the highly exothermic quench of fuming H2SO4 was performed, did not increase above about room temperature.



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Scheme 2. Flow Set-up for Reactions under Biphasic CH2Cl2/H2SO4 Conditions

Subsequent reactions were performed at a back pressure of 7 bar. Furthermore the CH2Cl2 extraction feed (Feed D) was removed (see Figure S1 in the Supporting Information). Even at a back pressure of 7 bar, the residence time was only 7 min due to the formation of large amounts of gases and the reaction did not give complete conversion. To increase the residence time, the flow rate was finally reduced to 375 µL/min for feed A (~0.12 mmol/min substrate) and 125 µL for feed B. This gave a residence time of 14 min at a back pressure of 7 bar. A reaction on a 4 mmol scale (1.16 g of sulfoxide 1) confirmed that the reaction provides full conversion with a similar product selectivity as that obtained under batch conditions (complete conversion, 87% selectivity). However, the selectivity in the “post-steady-state” stream decreased appreciably (see Table S8 in the Supporting Information). The middle fractions were combined, the organic phase was separated, and the aqueous phase again extracted with CH2Cl2. The aqueous phase was brought to pH >7 with 5 N NaOH and reextracted with CH2Cl2. Drying of the organic phase and thorough evaporation of the solvent provided 855 mg of an off-white powder (70%). The purity of the isolated product was 96% according to HPLC (see Figure S2 in the Supporting Information). To get “steady-state yields”, 3.48 g of sulfoxide 1 (12 mmol) and 4.8 mL of TMSN3 (36 mmol) were added into a graduated cylinder and filled with CH2Cl2 to 37.5 mL. The reaction mixture was introduced into the flow reactor under the conditions described above. The effluent mixture was directed to waste. After 20 min on stream, the processed mixture was collected in a separatory funnel. The mixture was collected for 80 min in total and finally worked-up as described above to provide 2.2 g of a white powder (77%) in a HPLC purity of 90%. In total, ca 6.4 g of sulfoxide 1 and 9 g of TMSN3 were processed in the flow reactor.


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Chiral analysis of the samples produced under continuous flow conditions revealed that the chirality of (R)-1 had not been retained. It is well known that sulfoxides racemize under strongly acidic conditions (for further details see the Supporting Information).19,20

CONCLUSION In conclusion we have developed a continuous flow protocol for the imidation of a sulfoxide under superacidic conditions. Reactions with concentrated sulfuric acid under literature conditions gave a slow reaction and poor selectivity (10% product after 14 h at room temperature). In contrast, reactions with fuming sulfuric acid afforded the sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C. The imidation reaction with TMSN3 as reagent was successfully performed in a flow reactor under biphasic conditions. Dichloromethane was used to carry substrate and TMSN3 into the flow reactor. The solution was then combined with fuming sulfuric acid at 50 °C. The substrate 1 is protonated and extracted from the CH2Cl2 phase into the sulfuric acid phase, where it is converted to the corresponding sulfoximine. The mixture was subsequently quenched in-line with H2O. The organic phase contained mostly side-products, whereas the aqueous phase contained the protonated product. Phase separation, neutralization of the aqueous phase and re-extraction with an organic solvent provided the product in excellent purity and good yields, albeit with loss of chirality. Interest in sulfoximine chemistry has increased steadily since their discovery in the early 1950s,1,2 and first pharmaceuticals containing the sulfoximine moiety now enter Phase I clinical trials.6 Nevertheless, sulfoximines are still severely underrepresented in organic synthesis as well as medicinal chemistry. With the emergence of new, efficient, atomeconomic and safe synthetic protocols for the synthesis of sulfoximines, these compounds are expected to become increasingly appreciated and to play a significant role in the repertoire of synthetic and medicinal chemists.

EXPERIMENTAL SECTION General Remarks. 1H NMR spectra were recorded on a Bruker 300 MHz instrument. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. 13C NMR spectra were recorded on the same instrument at 75 MHz. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively. Analytical HPLCUV (Shimadzu LC20) analysis was carried out on a C18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5 µm) at 37 °C using a mobile phase A



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(water/acetonitrile 90:10 (v/v) + 0.1 % TFA) and B (MeCN + 0.1 % TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: linear increase from solution 5% B to 80 % B in 15 min. Low-resolution mass spectra were obtained on a Shimadzu LCMS-QP2020 instrument using electrospray ionization (ESI) in positive or negative mode. All chemicals were purchased from commercial sources and were used without further purification.

Caution: Sodium azide and TMSN3 release hydrazoic acid (HN3) in acidic media. Hydrazoic acid is a volatile, highly toxic and explosive compound. Fuming sulfuric acid is capable of causing very severe burns and reacts violently with water. Reactions with these reagents should not be undertaken without proper safety precautions put in place. Batch Experiments. Sulfoxide 1 (116 mg; 0.4 mmol) and either NaN3 or TMSN3 (3 equivalents) were mixed in 1 mL of CHCl3 in a 5 mL Pyrex screw cap reaction vial equipped with a magnetic stir bar. 300 µL of fuming sulfuric acid (20% SO3) were added to this mixture under stirring at room temperature. The vessel was sealed with a PTFE seal and a screw cap and placed on a hot plate at 50 °C. After 30 min the reaction vessel was removed from the hot plate and cooled to room temperature. The reaction mixture was quenched with H2O and extracted with CHCl3. The aqueous phase was neutralized with 5 M NaOH and extracted again with CHCl3. Drying with MgSO4 and evaporation of the solvent provided 109 mg of the product 2 as a clear liquid which solidified to a white solid upon standing (89%). ((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)methyl)(imino)(methyl)-λ6-sulfanone 2: 1H NMR (300 MHz, CDCl3) δ 6.51 (s, 1H), 4.31 (br s, 1H), 4.26 (s, 2H), 4.04 (br s, 1H), 4.00 (dd, J = 11.5, 3.7 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.68 (dd, J = 11.7, 3.0 Hz, 1H), 3.53 (td, J = 11.9, 2.9 Hz, 1H), 3.30 (td, J = 12.9, 3.7 Hz, 1H), 3.11 (s, 3H), 2.89 (s, 1H), 1.33 (d, J = 6.8 Hz, 3H);

13

C NMR (75 MHz, CDCl3) δ 162.86, 160.74, 158.89, 102.64, 70.63,

66.48, 64.90, 47.60, 42.62, 39.46, 14.01.m/z MS (pos. ESI): m/z = 305 and 307 (M+H+). Flow Experiments. 3.48 g of sulfoxide 1 (12 mmol) and 4.8 mL of TMSN3 (36 mmol) were added to a graduated cylinder and filled with CH2Cl2 to 37.5 mL (feed solution A). For the flow reactions feed A first carried CH2Cl2, feed B carried water and the quench feed C carried H2O (see Scheme 2). The flow rates for feed A, feed B and feed C were 375, 125 and 1500 µL/min. When a reaction was started, feed B was switched from water to concentrated sulfuric acid. After concentrated sulfuric acid was pumped through the reactor for ~30 min, the feed was switched to fuming sulfuric acid. This procedure avoided the direct contact of fuming sulfuric acid with water. After pumping fuming H2SO4 for ~10 to 15 min, feed A was switched from CH2Cl2 to the reagent solution. After the reagent solution was finished feed A was switched back to pure CH2Cl2. The effluent mixture was directed to waste. 20 min after


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feed A was switched from CH2Cl2 to the reagent solution, the processed mixture was collected in a separatory funnel. The mixture was collected for 80 min in total. The phases were separated and the CH2Cl2 phase was discarded. The H2O phase was again extracted with CH2Cl2, neutralized with 5 M NaOH and extracted with CH2Cl2. Drying with MgSO4 and evaporation of the solvent provided 2.2 g of the product 2 as a a white powder (77%) in a HPLC purity of 90%.

ACKNOWLEDGEMENT We acknowledge funding by NAWI Graz and the Christian Doppler Research Foundation (CDG). We are grateful to Emma J. Williams and Jerome Dubiez (AstraZeneca, Macclesfield, United Kingdom) for valuable comments.

Supporting Information Further optimization data, detailed description of the continuous flow set-up, 1H-NMR of product. This material is available free of charge via the Internet at http://pubs.acs.org.

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Development of a Continuous Flow Sulfoxide Imidation Protocol Using

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