Rapid production of benzazole derivatives by a high-pressure and high-temperature water microflow chemical process

A high-pressure and high-temperature (HPHT) water microflow chemical process was utilized for the synthesis of benzazole derivatives. The current approach enables the extremely rapid production of various 2-arylbenzazoles including benzimidazoles, benzoxazoles, and benzthiazole in excellent yields.


Figure S1. Microflow Reaction System for Benzazoles Production.
Optimization of reaction conditions for benzazoles synthesis was performed by controlling the following parameters; 1) temperatures at the start/end positions of microreactor, which were set at the same values to each other, 2) pressure through the back pressure regulator, 3) reactor volume by changing length of SUS316 tube with fixed inner diameter of 0.5 mm.The fluctuation of temperature and pressure was controlled within 0.8 ºC and 0.2 MPa, respectively, which were to be considered as experimental errors.For all the experiments, flow rates of water and substrates solution were kept constant at 4.5 and 0.5 mL/min, respectively.Under the working conditions, Reynolds number and residence time of the fluid in the microreactor at various temperature and pressure were estimated as described below.Density and viscosity data from "NIST Chemistry Webbook" were utilized for these calculations.
Reynolds number (Re) was calculated based on equation (1).

Graphical representation of
where t: residence time (s), r: inner diameter of microreactor SUS316 tube (= 0.5 mm), L: length of microreactor SUS316 tube (cm), ρ w : density of water at certain temperature/pressure (g/cm 3 ), F total : total flow rate of pumps (g/min).
Graphical representation of residence time using reactor of 450 cm length (0.88 cm 3 ) at various temperatures/pressures is shown in Figure S2 (c).
Analysis of product mixtures was performed by GC-MS/MS (Varian 1200L), GC-FID (Agilent Technologies 5973 GC).For the quantitative analysis, the multipoint calibration curves were produced using the authentic samples with n-alkanes (carbon number is 12 16) as internal standard.

1-1. Typical Procedure for Benzazoles Production by Dehydration
For production of 1,2-diphenyl-1H-benzo[d]imidazole 2a by dehydration, N-methylpyrrolidone (NMP) solution of N-[2-(phenylamino)phenyl]benzamide 1a of required molar concentration was placed in Tank 2 (substrate solution tank).Then, the solution in the tank was introduced into the syringe pump and applied to high pressure/-temperature water on the course of operation.The collected materials were dissolved in EtOAc with addition of internal standard, then followed by GC analysis.
The results of screening process conditions were summarized in Table S1.a Yields were determined by GC-FID analysis using n-hexadecane as an internal standard.Section 1-1.The results of screening process conditions were summarized in Table S2.
Table S2  a Reactor volume = 0.88 cm 3 .b Yields were determined by GC-FID analysis using n-hexadecane as an internal standard.c Residence time was estimated based on the equation (2).

Typical Procedure of Control Experiments
1.25 mmol of N-[2-(phenylamino)phenyl]benzamide (1a) was placed in 100 mL flask, and H 2 O/NMP (22.5 mL/2.5 mL) was added.Then the solution was stirred at 120 ºC in hot bath.After stirred for 24 h, the solution was cooled to room temperature.The solution was diluted by EtOAc with addition of n-hexadecane as an internal standard, followed by GC analysis.
For the other conditions in control experiments, solvent sets of H 2 O (25 mL; Table 2, Reynolds number at various temperatures/pressures is shown in Figure S2 (b).Applied conditions in this investigation (pressure = 30~45 MPa; temperature = 350~445 ºC) correspond to the estimated Reynolds number of approximately >3.0 × 10 3 .

b
Residence time was estimated based on the equation (2).

Figure S2 .
Figure S2.Some Calculated Parameters at Various Temperature and Pressure: (a) values of ionic products based on Marshall and Franck equation S1 ; (b) Reynolds number estimated by the equation (1); (c) residence time in reactor of 0.88 cm 3 volume, estimated by the equation (2).

Table S3 .
Screening of Process Conditions for Production of 2-Phenylbenzoxazole (2b) by N-Acylation/Dehydration Sequential Condensation Process.a