Efficient Transposition of the Sandmeyer Reaction from Batch to

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Efficient transposition of the Sandmeyer reaction from batch to continuous process Joseph D'Attoma, Titi Camara, Pierre-Louis Brun, Yves Robin, Stephane Bostyn, Frédéric Buron, and Sylvain Routier Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00318 • Publication Date (Web): 30 Nov 2016 Downloaded from http://pubs.acs.org on December 2, 2016

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Organic Process Research & Development

Efficient transposition of the Sandmeyer reaction from batch to continuous process. Joseph D’Attoma,† Titi Camara,‡ Pierre Louis Brun,‡ Yves Robin,‡ Stéphane Bostyn,§* Frédéric Buron†* and Sylvain Routier †*

†

Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, rue de

Chartres, BP 6759, 45067 Orléans Cedex 2, France. ‡

ISOCHEM, 4 rue Marc Sangnier, BP 16729, 45300 Pithiviers, France.

§

Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, avenue

de la recherche scientifique, 45071 Orléans cedex 2, France.

1 ACS Paragon Plus Environment


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TABLE OF CONTENTS GRAPHIC


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ABSTRACT. The transposition of Sandmeyer chlorination from a batch to a safe continuous flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety. KEYWORDS: Continuous process, Diazonium, Chlorination, Simplex, Scale-up.



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INTRODUCTION Diazonium salts are very versatile intermediates and reagents in organic synthesis and their chemical nature makes them an excellent leaving group in Sandmeyer,1-3 Meerwein,4,5 BalzSchiemann6,7 and pallado-catalyzed coupling chemistry.8-10 Diazonium salts are highly energetic and sensitive compounds. They react strongly to heat, light, shock, or static electricity which can lead to rapid, uncontrollable decomposition and explosion.11-14 Salt handling requires precautionary measures in the laboratory and is thus less widely used for industrial scale-up phases.15-17 However, their increasing usefulness in organic synthesis has contributed to the development of safe preparation methods .18-20 Continuous flow chemistry, which has been rapidly adopted in academic, pharmaceutical and fine chemistry laboratories. One of the main reasons for its emergence and popularity is the ability to significantly improve the safety of batch reactions.29 Improved reagent mixing, heat and mass transfer but also increased reproducibility, scale-up and automated synthetic operations explain the growing interest in this field.21-28 Sensitive and toxic reaction intermediates can be generated and directly consumed in a single process without intermediate handling or hazardous material storage. The earliest example of continuous chloro-dediazotation was demonstrated by the de Mello group in 2002 on a microfluidic chip reactor. During the past decade several studies have investigated the transposition of diazonium salt formation from batch to continuous processes but only regarding sulfonylation or hydrazine formation.30-35 Surprisingly, to the best of our knowledge, no study has yet reported the optimization of chloro-dediazotation under a continuous meso-scale process. In this study we first present transposition of the Sandmeyer chlorination reaction into a semicontinuous process using a Simplex optimization method. Starting from anilines, diazonium salts were formed under flow conditions prior to trapping this unstable intermediate and


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forming the desired chlorinated aryl derivative. We then investigated the implantation of a fully continuous process, including the generation and consumption of the diazonium entities. The scope and limitations of the process were explored using conventional substituted aryl anilines and amino heterocycles. The challenges encountered during the investigation as well as the scale-up phase are disclosed and the results discussed.

RESULTS AND DISCUSSION 1. Switch from batch to continuous-flow diazotation. Typically, the batch reaction is performed in concentrated hydrochloric and acetic acids with aqueous NaNO2.1 These experimental conditions were considered too harsh for use in a flow reactor due to the presence of corrosive reagents and strongly acidic conditions which can induce interference with chemical functions or scaffolds. However, Indeed, these conditions generate a biphasic system which interferes with the limiting factor, the solubility of organic starting materials. To work around this issue, we decided to use a homogenous system considering alkyl nitrites as universal organic diazotizing agents. Additionally, this strategy avoids acidic conditions and stabilizes the intermediate salt.36 This alternative requires the use of acetonitrile as solvent, which limits the direct transposition of the classical batch method to a flow process due to the low solubility of copper chloride. In order to avoid the risk of clogging the reactor, we conducted an initial inspection to develop a semi-continuous process involving first the synthesis of diazonium salt in continuous flow followed by the substitution of the diazo group in a flask with a heterogeneous copper chloride solution. The formation of the diazonium salt was carried out with a commercial flow chemistry device from Uniqsis®. A solution A containing 1 (1.32 mmol) in MeCN (2 mL) was introduced at 1.25 mL.min-1 and mixed using a standard Tjunction with a second solution B of tert-butyl nitrite 2 (1.44 mmol, 1.1 equiv.) in acetonitrile (2 mL) pumped at the same flow rate. The combined solution was then passed through a



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tubular 2.5 mL reactor (1 mm internal diameter, PTFE). The mixing T-junction and the coil were both submerged in a thermostatic bath to control the temperature. To determine the best experimental conditions able to quantitatively furnish the diazonium salt, the reactor outlet containing the diazo species was immediately poured into a well stirred suspension of CuCl2 in acetonitrile at 65 °C (Scheme 1) in a 250 mL round-bottom flask equipped with a condenser. In order to quantify the efficiency of the continuous process during step 1, the formation of the diazonium salt at the reactor outlet was followed by TLC. This cascade procedure offers an advantage in pressure management. The nitrogen gas production during the second step is not problematic as the final reactor is open and the flow system is not pressurized. Scheme 1. Sandmeyer reaction under semi-continuous processing mode.

2. Flow parameter optimization. The first parameter considered to generate the diazonium salt of 1 was the reaction temperature T1. Due to the instability of these species, the flow reactor was placed at 0 °C in a thermostated bath. Under these conditions and with an arbitrarily chosen 10 min. residence time, the desired compound 3 was isolated in a satisfactory 60 % yield (Table 1, entry 1). A residence time study indicated that 1 minute was a good compromise as 30 seconds led to a slight decrease in yield (entries 2, 3). To verify whether an increase in temperature would adversely affect the intermediate, the reactor was placed at 20 °C. The yield of 3 increased to 77% (entry 4) with a 1 minute holding time.


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Finally, the quantity of nitrite was adjusted and after several assays 3 was prepared in an excellent 84% yield (entry 5), in spite of the near stoichiometric quantity of tert-butylnitrite. In conclusion, with an equimolar amount of reagents and after only one minute at room temperature we were now able to induce a full conversion of aniline 1 into its diazo equivalent under a flow process. Further consumption of the intermediate was achieved in a flask with a very slight excess of copper chloride and the chlorinated derivative 3 was purified and quantified as the sole reaction product. Table 1. Parameters for the first diazonium formation. Entry Equiv. of T1 (°C) tert-butyl nitrite 2

t1 (min)

Yield of 3 (%)

1

1.5 equiv.

0

10

60

2

1.5 equiv.

0

1

74

3

1.5 equiv.

0

0.5

68

4

1.5 equiv.

20

1

77

6

1.1 equiv.

20

1

84

3. Simplex optimization of the semi-continuous process for step 2. Having in hand an optimized diazonium generation flow process leading to the chloro derivative 3 from 1, we then considered creating a full flow system including both synthesis and displacement of the diazo group by a chlorine atom. In order to achieve this goal, it was necessary to optimize each of the parameters involved in the two-step reaction. The Simplex method is an evolutionary operation technique in which a series of experiments is built in such a manner that the reaction conditions for a given experiment are controlled by the results of the preceding experiments in the series.37-39 The parameters retained for optimization were temperature, and two parameters to define the reaction, namely the amount of CuCl2 and the reaction time (Table 2).



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Table 2. Initial simplex in reduced coordinates and in real coordinates. Reduced coordinate matrix Real coordinate matrix Experiment t T CuCl2 number Xi,1 Xi,2 Xi,3 (equiv.) (min) (°C) 0

0

0

0

21

1.2

30

1

1

0

0

65

1.2

30

2

0.5

0.866

0

43

1.55

30

3

0.5

0.289

0.817

43

1.32

39

Our three dimensional simplex had four vertices represented by a tetrahedron. The experiments which constituted the first simplex were deliberately chosen within the boundary of the experimental domain in order to progress inside the domain. After the initial experiments of the first simplex, the method evolved sequentially with the addition of a new experiment, performed in the opposite direction to the worst point (w). The reduced coordinates of the new point were calculated with the following equation: xi,j = x0,j + Xi,j ×∆xj

(1)

where i corresponds to the simplex points from 0 to k, j corresponds to the variable from 1 to k, x0,j is the real coordinate for the variable j at the center of the domain studied, Xi,j corresponds to the reduced coordinate for the variable j at the point i, and ∆xj corresponds to the step size for the variable j. The step sizes and the values of the domain center are reported in Table 3 for each variable. Table 3. The control variable values at the center of the domain and their step sizes. Control variable

Value of the domain center

Step size

Unit

xi,1 (Temperature)

21

44

°C

xi,2 (CuCl2)

1.2

0.4

equiv.

xi,3 (Time)

30

10

min.


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For the simplex evolution, calculation of the new point coordinate was based on the following equation: Xr,j = Xg,j + α(Xg,j - Xw,j)

(2)

where Xr,j is the reduced coordinate of the new point for the variable j; Xg,j is the centroid of the remaining face/hyperface (i.e. the average levels for the remaining trials), and Xw,j is a rejected trial.40 Therefore, this method allowed a certain leeway in the choice of the initial step sizes that were sometimes difficult to define due to the lack of experiments at the beginning of the study. Table 4. Relation between yields and experiment number during simplex optimization (w corresponds to the worst point of the simplex and b to the best point of the simplex). Experiment number

T (°C)

CuCl2 (equiv.)

t (min)

Yield (%)

Number of simplex 1 2 3

0

21

1.2

30

54

4 (w)

1

65

1.2

30

70

1 (b)

2

2

43

1.5

30

57

3

4 (w)

3

43

1.3

39

59

2

3

4

4

80

1,5

36

82

1 (b)

2

5

82

1,1

39

86

3

1 (b)

The first simplex in table 4 showed that the best experiment was number 1 with a yield of 70 %. Experiment 0 was the worst with a yield of only 54 % of chlorinated product 3. This assay was therefore eliminated in the simplex process and the new coordinates for experiment 4 were the projection relative to this point. In the second simplex, experiment 2 was the worst with 57 % of the chlorinated product; the best result achieved was 82 % yield. Finally, a third simplex was applied, and showed that the best experiment had an 86 % yield. As the calculated temperature (108 °C) of the next simplex projection, with respect to point 5, was



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outside the feasible region (Teb

ACN

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= 82 °C at atmospheric pressure), we decided to end the

simplex evolution since: i) the temperature of the next point would be above the boiling point of the solvent; ii) the yield of 86 % was judged to correspond to the maximum yield obtained in the batch mode. To conclude, using this optimization method the yield was drastically increased from 52 % to 86 % in only five experiments.

4. Full Sandmeyer continuous process. In order to furnish a fully continuous process, the CuCl2 solubility problem had to be circumvented. Several batch assays were undertaken to identify a co-solvent to increase this solubility. Ethylene glycol (EG) was identified as an excellent co-solvent, since only 0.25 equivalent of EG increased the solubility of copper (II) chloride up to 202 g/L in acetonitrile.41 This addition of co-solvent did not interfere with the diazonium trapping step under the previously described semi-continuous process and the desired product 3 was isolated with a similar efficiency (83% yield). Consequently, a real fully continuous process was now achievable. A third pump containing a solution of CuCl2/ethylene glycol in MeCN (0.36 mol.L-1; solution C) was placed after reactor 1, using both a second standard T-junction and reactor (20 mL, 1 mm internal diameter, PTFE) (Scheme 2). With this modification, the holding time of reactor 2 was 4 min due to the total flowrate imposed by the sum of each individual throughput (solution A: 0.66 mol/l, 1.25 mL.min-1; solution B: 0.72 mol/l, 1.25 mL.min-1; solution C: 0.36 mol/l, 2.5 mL.min-1) and gave a continuous process in 5 minutes as total holding time. Additionally, the desired product 3 was isolated in an unprecedented 87 % yield, after only 5 minutes (versus 30 min in batch mode). Both of these improvements increase the attractiveness of the technology. To regulate the internal pressure in the second reactor due to the solvent heating (82 °C) and the nitrogen release, a 100 psi back pressure regulator was fitted prior to the collection flask. Further scale-up will depend on our ability to manage the pressure.


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Scheme 2. Sandmeyer reaction under the fully continuous process.

5. Extending the chemical scope. Having in hand this 3-inlet flow set-up as depicted in Scheme 2, we extended the scope of aniline derivatives to formally establish the considerable advantage of such a continuous flow process. The first tests were conducted with anilines 1-8 bearing an electro-attracting group (Table 5). The reaction efficiency was preserved, especially for acetyl compound 5 which was isolated in a quantitative yield and for nitro compound 7 in a 91 % yield.36 Nevertheless, the reaction appeared to be sensitive to the presence of an acidic function as 15 was isolated in only 50% yield (entry 7). Efficiency was partially restored with a cyano group. Yields increased again with methyl or ethyl esters to reach around 80 % in the final chloro derivatives 11 and 13. Anilines substituted with electron-donating groups such as CH3 or OMe in para position caused problems and only degradation was observed. However with additionalnitro substitution of the aromatic ring, 21 (entry 9) was isolated in 66% yield. This further confirmed that the electronic character of the aryl drives the Sandmeyer chlorination under our flow process. The less donating methyl sulfur partially restored the efficiency as 23 was isolated in average yield (entry 10).



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Table 5. Scope of the Sandmeyer reaction in aryl chlorines under continuous mode. Entry

Reactant

Product

Yield (%)

1

1

3

87

2

4

5

quant.

3

6

7

91

4

8

9

75

5

10

11

81

6

12

13

80

7

14

15

50

8

16

17

ND

9

18

19

ND

10

20

21

66

11

22

23

46

ND: Not detected. To expand the scope and identify other limits, the behavior of several amino heteroaromatic systems was investigated (Table 6). The pyridine moieties demonstrated a moderate reactivity and products 25 and 27 were isolated in 47 % and 44 % yield, respectively. Next, the procedure was tried with benzothiazole and benzoxazole rings and the reaction was fully efficient with the sulfur heterocycle 29 (entry 3), but appeared to be partially inhibited in presence of the electron rich oxygen atom (entries 4, 5). The instability 12 ACS Paragon Plus Environment

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of the diazonium salt from 2-aminopyrimidine was observed and adduct 37 was formed in only 20% yield (entry 7). A strong limitation occurred as starting amino derivative 38 was fully insoluble in acetonitrile. To solve this compatibility with the flow technology, we started from the benzyl protected nitrogen derivative 40. This protection significantly increased the solubility in acetonitrile and reactivity was partially restored. Product 41 was synthesized in 26 % yield. With an electron withdrawing N-protecting group such as a phenylsulfonyl moiety, the same behavior was observed and derivative 42 was isolated in a 23% yield (entry 9-10). Table 6. Scope of the Sandmeyer reaction in Hetaryl chlorine under continuous mode. Entry

Reactant

Product

Yield (%)

1

24

25

47

2

26

27

44

3

28

29

74

4

30

31

33

5

32

33

25

6

34

35

54

7

36

37

20

8

38

39

0a



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9

40

41

26

10

42

43

23

a) Only starting material was recovered.

6. Validation process and scale-up of the fully continuous process. To investigate the stability of the reaction process, a validation with aniline 1 was performed during 30 minutes. This step is necessary to evaluate the compatibility of the flow procedure with a large scale setup. However, as already mentioned, during the assay the generation of large quantities of nitrogen gas caused a serious breach in back pressure regulation and residence time control. In order to solve this problem, a Liquid/Gas separator vessel was designed and built.42 The reactor 2 output was collected in an external flask fitted with a screw cap GL45 with four ports (Scheme 3).

Scheme 3. Liquid/gas separator vessel. N2

BPR 100 psi

N2 pressurization Input

Output

Evacuation valve


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This home-made system was connected to a back pressure regulation of 100 psi and pressurized with nitrogen. An evacuation valve was added to stabilize the system pressure, the flow-rate and the volume in the Liquid/Gas separator (Scheme 4).

Scheme 4. Fully continuous process with L/G separator.

With this additional tool, pressure spikes were totally eliminated and the system was fully stabilized during 30 minutes (Scheme 5). The throughput rate of chlorinated product 3 was up to 5.61 g/h. Temperature monitoring in reactor 1 showed no exothermicity during the formation of the diazonium salt. This system will be very useful to design a safe, semi-industrial diazonium flow process, since the diazonium salt intermediate can be generated and directly consumed in a single one-pot continuous sequence without intermediate handling or storage of hazardous material.



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Scheme 5. System pressure with the Liquid/Gas separator.

CONCLUSION This study has shown that the transfer of the Sandmeyer reaction from batch mode to an efficient and safe continuous process is possible. First, chemometric approaches enabled the development of an efficient semi-continuous process. The implementation of the 3-inlet flow set-up made it possible to overcome the cascade step for chlorination. This continuous process also demonstrated its effectiveness with the generation of unstable diazonium salts in the synthesis of chlorinated compounds on a large scale. This scale-up also exhibited the limits of using a mechanical Back-pressure reactor (BPR), requiring us to create an online Liquid/Gas separator vessel which helped to increase the quantity of product formed while ensuring a safe process. The efficiency of the reaction was proven during 30 min without any observed exothermicity. This new fully flow procedure will undoubtedly have a major impact on the use of a safe Sandmeyer reaction in R&D research.


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EXPERIMENTAL PART General Information. 1H NMR and

13

C NMR spectra were recorded on a Bruker

DPX 250 MHz or 400 MHz instrument using CDCl3 or DMSO-d6. The chemical shifts are reported in parts per million (δ scale) and all coupling constant (J) values are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and dd (doublet doublet). Melting points are uncorrected. IR absorption spectra were obtained on a Perkin Elmer PARAGON 1000 PC and values are reported in cm-1. HRMS were recorded on a Bruker maXis mass spectrometer by the “Fédération de Recherche” ICOA/CBM (FR2708) platform. Monitoring of the reactions was performed using silica gel TLC plates (silica Merck 60 F254). Spots were visualized by UV light at 254 nm and 356 nm. Column chromatography was performed using silica gel 60 (0.063–0.200 mm, Merck).

Experimental procedure of the semi-continuous process. A solution A of aniline derivative (1.0 equiv) in MeCN (2 mL) was flowed at 1.25 ml.min-1 and mixed with a second solution B containing tBuONO (1.1 equiv.) in MeCN (2 mL) also pumped at 1.25 ml.min-1. The combined solution was then passed through a 2.5 mL linear reactor (1 mm internal diameter, PTFE). After a residence time of one minute, the solution was poured directly into a 250 mL round-bottom flask with a condenser containing a suspension of CuCl2 in acetonitrile at 65 ° C. After the flow reaction was complete, the reaction mixture was stirred for another 39 min. The entire output from the reactor was then collected and concentrated under reduced pressure, (rotary evaporator; T = 40 ◦C). The resulting mixture was extracted three times with EE (3x20 mL), dried under MgSO4, filtered and the solvents were evaporated under vacuum. The residue was purified by flash chromatography on silica gel.



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Experimental procedure of the fully continuous process. A solution A of aniline derivative (1.0 equiv; C = 0.66 mol.L-1 in MeCN for procedure A; C = 0.33 mol.L-1 in MeCN for procedure B and C = 0.33 mol.L-1 in DMF for procedure C) was flowed at 1.25 ml.min-1 and mixed using a standard T-piece with a second solution B containing tBuONO (1.1 equiv.) in MeCN (2 mL) also pumped at 1.25 ml.min-1. The combined solution was then passed through a 2.5 mL linear reactor with a residence time of one minute at room temperature. A solution C containing the CuCl2/ethylene glycol in MeCN (0.36 mol.L-1; solution C) was introduced with a third pump after reactor 1 at 2.5 ml.min-1 using a standard T-piece connected to a second reactor (20 mL, 1 mm internal diameter, PTFE). The residence time was 4 min and the temperature 82°C. The entire output from the reactor was collected and concentrated under reduced pressure, (rotary evaporator; T = 40 ◦C). The resulting mixture was extracted three times with EE (3x20 mL), dried under MgSO4, filtered and the solvents were evaporated under vacuum. The residue was purified by flash chromatography on silica gel. 4-Chloro-3-nitrotoluene (3). The reaction was carried out as described in general procedure A using 4-methyl-2-nitroaniline (200 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 98/2), the product was isolated as a yellow oil (195 mg, 87%). CAS number 89-60-1. 1H NMR (250 MHz, Chloroform-d) δ 7.66 (d, J = 1.7 Hz, 1H, Har), 7.41 (d, J = 8.3 Hz, 1H, Har), 7.31 (ddd, J = 8.2, 2.1, 0.6 Hz, 1H, Har), 2.40 (s, 3H, CH3). Conform to the literature.43 4’-Chloro-benzophenone (5). The reaction was carried out as described in general procedure A using 4′-aminoacetophenone (177 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (201 mg, 99%). CAS number 99-91-2. 1H NMR (250 MHz, Chloroform-d) δ 7.83 (d, J = 8.8 Hz, 2H, Har), 7.37 (d, J = 8.8 Hz, 2H, Har), 2.53 (s, 3H, CH3). Conform to the literature.44


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4-Chloro-nitrobenzene (7). The reaction was carried out as described in general procedure A using 4-nitroaniline (200 mg, 1.44 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (208 mg, 91%). CAS number 100-00-5. 1H NMR (250 MHz, Chloroform-d) δ 8.15 (d, J = 9.0 Hz, 2H, Har), 7.49 (d,

J = 9.2 Hz, 2H, Har). Conform to the literature.45 4-Chlorobenzonitrile (9). The reaction was carried out as described in general procedure A using 4-aminobenzonitrile (171 mg, 1.44 mmol). After purification with silica flash chromatography (EP/AE 90/10), the product was isolated as a yellow oil (148 mg, 75%). CAS number 623-03-0. 1H NMR (250 MHz, Chloroform-d) δ 7.61 (d, J = 8.9 Hz, 2H, Har), 7.47 (d, J = 8.9 Hz, 2H, Har). Conform to the literature.46 Methyl 4-chlorobenzoate (11). The reaction was carried out as described in general procedure A using methyl 4-aminobenzoate (196 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (180 mg, 81%). CAS number 1126-46-1. 1H NMR (250 MHz, Chloroform-d) δ 7.95 (s, 2H, Har), 7.40 (d, J = 8.4 Hz, 2H, Har), 3.91 (s, 3H, CH3). Conform to the literature.47 Ethyl 4-chlorobenzoate (13). The reaction was carried out as described in general procedure A using ethyl 4-aminobenzoate (212 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 95/5), the product was isolated as a yellow oil (193 mg, 80%). CAS number 7335-27-5. 1H NMR (250 MHz, Chloroform-d) δ 7.97 (d, J = 8.8 Hz, 2H, Har), 7.40 (d, J = 8.8 Hz, 2H, Har), 4.37 (q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, CH3). Conform to the literature.48 4-Chlorobenzoic acid (15). The reaction was carried out as described in general procedure A using 4-aminobenzoic acid (180 mg, 1.31 mmol).

After acidification with HCl and

trituration in EP, the product was filtered to afford a white solid (101 mg, 50%). CAS number



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74-11-3. 1H NMR (250 MHz, DMSO-d6) δ 7.93 (d, J = 8.1 Hz, 2H, Har), 7.55 (d, J = 8.0 Hz, 2H, Har). Conform to the literature.49 4-Chloro-3-nitroanisole (21). The reaction was carried out as described in general procedure A using 4-methoxy-2-nitroaniline (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (160 mg, 66%). CAS number 10298-80-3. 1H NMR (250 MHz, Chloroform-d) δ 7.41 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 3.0 Hz, 1H), 7.05 (dd, J = 8.9, 3.0 Hz, 1H), 3.85 (s, 3H). Conform to the literature.50 4-Chlorothioanisole (23). The reaction was carried out as described in general procedure A using 4-(methylthio)aniline (182 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 95/5), the product was isolated as a yellow oil (94 mg, 46%). CAS number 123-09-1. 1H NMR (250 MHz, Chloroform-d) δ 7.24 (d, J = 8.8 Hz, 2H, Har), 7.16 (d,

J = 8.9 Hz, 2H, Har), 2.45 (s, 3H, CH3). Conform to the literature.51 4-Chloropyridinium chloride (25). The reaction was carried out as described in general procedure B using 4-aminopyridine (124 mg, 1.31 mmol). After purification with silica flash chromatography (EP/AE 90/10), the product was isolated as an amorphous white solid (69 mg, 47%). CAS number 626-61-9. 1H NMR (250 MHz, Deuterium Oxide) δ 8.76 (d, J = 6.2 Hz, 2H, Har), 8.15 (d, J = 6.3 Hz, 2H, Har). Conform to the literature.52 3-Chloro-2-nitropyridine (27). The reaction was carried out as described in general procedure C using 3-amino-2-nitropyridine (91 mg, 0.66 mmol). After purification with silica flash chromatography (EP/AE 80/20), the product was isolated as a yellow oil (45 mg, 44%). CAS number 54231-32-2. 1H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 4.6, 1.5 Hz, 1H, Har), 8.00 (dd, J = 8.0, 1.5 Hz, 1H, Har), 7.55 (dd, J = 8.1, 4.6 Hz, 1H, Har). Conform to the literature.53


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2-Chlorobenzothiazole (29). The reaction was carried out as described in general procedure A using 2-aminobenzothiazole (197 mg, 1.31 mmol). After purification with silica flash chromatography (EP/AE 90/10), the product was isolated as a yellow oil (165 mg, 74%). CAS number 615-20-3. 1H NMR (250 MHz, Chloroform-d) δ 7.93 (ddd, J = 8.0, 1.4, 0.7 Hz, 1H, Har), 7.75 (ddd, J = 7.7, 1.5, 0.7 Hz, 1H, Har), 7.50 – 7.32 (m, 2H, Har). Conform to the literature.54 2-Chlorobenzoxazole (31). The reaction was carried out as described in general procedure A using 2-aminobenzoxazole (176 mg, 1.31 mmol). After purification with silica flash chromatography (EP/DCM 90/10), the product was isolated as a yellow oil (66 mg, 33%). CAS number 615-18-9. 1H NMR (250 MHz, Chloroform-d) δ 7.73 – 7.61 (m, 1H, Har), 7.56 – 7.44 (m, 1H, Har), 7.43 – 7.28 (m, 2H, Har). Conform to the literature.55 2,5-Dichloro-1,3-benzoxazole (33). The reaction was carried out as described in general procedure B using 2-Amino-5-chlorobenzoxazole (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg, 25%). CAS number 3621-81-6. 1H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, Har), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, Har), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, Har). 13C NMR (101 MHz, Chloroform-d) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH), 119.78 (CH), 111.16 (CH). HRMS [M+H]+ (EI) calcd. for C7H4Cl2NO : 187.9664 , found: 187.9663. Methyl 3-chlorothiophene-2-carboxylate (35). The reaction was carried out as described in general procedure A using methyl 3-amino-2-thiophenecarboxylate (206 mg, 1.31 mmol). After purification with silica flash chromatography (EP/AE 95/5), the product was isolated as a yellow oil (125 mg, 54%). CAS number 88105-17-3. 1H NMR (250 MHz, Chloroform-d) δ 7.46 (d, J = 5.3 Hz, 2H, Har), 7.00 (d, J = 5.3 Hz, 2H, Har), 3.88 (s, 3H, CH3). Conform to the literature.56



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2,4,6-Trichloropyrimidine (37). The reaction was carried out as described in general procedure C using 2-amino-4,6-dichloropyrimidine (107 mg, 0.66 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (24 mg, 20%). CAS number 3764-01-0. 1H NMR (250 MHz, Chloroform-d) δ 7.38 (s, 1H, Har). Conform to the literature.57 1-Benzyl-2-chloro-1H-benzoimidazole (41). The reaction was carried out as described in general procedure A using 2-amino-1-benzylbenzimidazole (293 mg, 1.31 mmol). After purification with silica flash chromatography (EP/EE 90/10), the product was isolated as a yellow oil (82 mg, 26%). CAS number 43181-78-8. 1H NMR (250 MHz, Chloroform-d) δ 7.73 – 7.65 (m, 1H, Har), 7.31 – 7.11 (m, 8H, Har), 5.36 (s, 2H, CH2). Conform to the literature.58 1-Benzyl-2-chloro-1H-benzoimidazole (42). The reaction was carried out as described in general procedure B using 2-amino-1-benzylbenzimidazole (179 mg, 0.66 mmol). After purification with silica flash chromatography (EP/AE 80/20), the product was isolated as a yellow oil (44 mg, 23%). 1H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.65 (dd, J = 7.5, 7.5 Hz, 2H), 7.54 (dd, J = 7.9, 7.9 Hz, 2H), 7.45 – 7.40 (m, 1H), 7.39 – 7.33 (m, 1H). 13C NMR (101 MHz, Chloroform-d) δ 140.91 , 138.33 , 137.61 , 135.15 , 133.79 , 129.68 , 127.50 , 125.74 , 125.26 , 119.94 , 113.86 . HRMS [M+H]+ (EI) calcd. for C13H10ClN2O2S : 293.0145, found: 293.0145.

SUPPORTING INFORMATION. Additional 1H and 13C NMR spectra for products are available in the supporting information.

AUTHOR INFORMATION Corresponding Author


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* E-mail: [email protected], [email protected] and [email protected].

ACKNOWLEDGMENT ICOA and ISOCHEM thank the Région Centre-Val de Loire “Flowsyn program” for supporting their collaboration. The ICOA team thanks the COMI FEDER and the IRON LABEX programs (ANR-11-LABX-0018-01) for their financial support.

ABBREVIATIONS BPR : Back Pressure Regulation EtOAc : ethyl acetate EE : diethylether

vs : versus mg : milligram Satd : saturated MeCN : acetonitrile MW : microwave DMF : dimethylformamide EtOH : ethanol



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Efficient Transposition of the Sandmeyer Reaction from Batch to

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