Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-(Chlorosulfonyl)benzoate: An Example of Inhibiting Parallel Side Reactions

Article abstract of DOI:10.1021/acs.oprd.6b00238

An expeditious process for the highly efficient synthesis of methyl 2-(chlorosulfonyl)benzoate was described, which involved the continuous-flow diazotization of methyl 2-aminobenzoate in a three-inlet flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side reaction such as hydrolysis was decreased eminently from this continuous-flow process even at a high concentration of hydrochloric acid. The mass flow rate of methyl 2-aminobenzoate was 4.58 kg/h, corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.

Full text of DOI:10.1021/acs.oprd.6b00238

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Communication
Continuous-Flow Diazotization for Efficient Synthesis of Methyl 2-
Chlorosulfonyl)benzoate: an Example of Inhibiting Parallel Side-reactions
Zhiqun Yu, Hei Dong, Xiaoxuan Xie, Jiming Liu, and Wei-Ke Su
(
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00238 • Publication Date (Web): 17 Nov 2016
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ContinuousꢀFlow Diazotization for Efficient Synthesis
of Methyl 2ꢀ(Chlorosulfonyl)benzoate: an Example of
Inhibiting Parallel Sideꢀreactions
†
†
†
‡
,†,‡
Zhiqun Yu, Hei Dong, Xiaoxuan Xie, Jiming Liu, and Weike Su*
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†
National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative
Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P.R. China
‡
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China
*
Correspondent. Tel: (+86)57188320899. Eꢀmail: pharmlab@zjut.edu.cn.
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Abstract:
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An expeditious process for the highly efficient synthesis of methyl 2ꢀ(chlorosulfonyl)benzoate was
described, which involved the continuousꢀflow diazotization of methyl 2ꢀaminobenzoate in a 3ꢀinlet
flow reactor via a cross joint followed by chlorosulfonylation in the tandem tank reactor. The side
reaction such as hydrolysis was decreased eminently from this continuousꢀflow process even at high
concentration of hydrochloric acid. The mass flow rate of methyl 2ꢀaminobenzoate was 4.58 kg/h,
corresponding to an 18.45 kg/h throughput of diazonium salt solution. The potential of inhibiting
parallel side reactions by conducting in a flow reactor was successfully demonstrated in this method.
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Key Words: Diazotization, Continuousꢀflow, Parallel sideꢀreaction, Chlorosulfonylation.
Introduction
Sulfonyl chlorides are versatile precursors for the synthesis of many pharmaceutically active
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compounds, including sulfonamides , sulfonylfluorides , sulfonate esters , sulfones , and sulfinic acids .
Among which, methyl 2ꢀ(chlorosulfonyl)benzoate is a key intermediate for the synthesis of important
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intermediates and biological active compounds (Figure 1), such as Saccharin , HNO donor ,
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farnesyltransferase inhibitor and acetohydroxyacid synthase inhibitor .
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Figure 1. Compounds derived from the methyl 2ꢀ(chlorosulfonyl)benzoate moiety.
Preparation of methyl 2ꢀ(chlorosulfonyl)benzoate was summarized in two different synthetic routes
(
Scheme 1). In the Route I, 2ꢀsulfobenzoic anhydride was treated with phosphorus pentachloride and
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methanol to give the desired products in excellent yield . Nonetheless, the application of this method
was relatively limited due to the lack of availability of raw materials. As a consequence, the
diazotization of methyl 2ꢀaminobenzoate followed by chlorosulfonylation in Route II was established as
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the compatible method for the synthesis of target compound .
Scheme 1. Synthetic routes of methyl 2-(chlorosulfonyl)benzoate
Diazotization of methyl 2ꢀaminobenzoate could be easily conducted under aqueous solution of
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sodium nitrite and hydrochloric acid at low temperature (such as 0 C). The resulting diazonium salt was
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then subjected to the stepwise sulphination and oxidationꢀchlorination with SO /Cl /CuCl , or
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oneꢀstep copperꢀcatalyzed chlorosulfonylation with userꢀfriendly reagent NaHSO . We adopted the
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latter method for the synthesis of methyl 2ꢀ(chlorosulfonyl)benzoate. The proposed mechanism
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the reaction sequence is shown in Scheme 2. The aryl diazonium chloride 2 is first reduced to the
diazenyl radical 3a by the Cu(I) catalyst; liberation of nitrogen generates the aryl radical 3b. This radical
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species could then attack the SO molecule generated in situ to yield 3c, which Cu(II) was reduced to
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Cu(I) and the catalytic cycle was completed with chloride anion combining to yield the sulfonyl
chloride adduct 3. However, this approach did engender important safety concerns due to the highly
explosive diazonium salt which may decomposed intensively under a relatively high temperature while
releasing heat and outꢀgassing. To reduce the safety hazards, we envisioned the development of a
continuousꢀflow process for the multistep synthesis of methyl 2ꢀ(chlorosulfonyl)benzoate.
Continuousꢀflow technology offers significant benefits over batch methods, including precise control of
temperature, stoichiometry, and residence time; high reproducibility; easy scale up, and commendable
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inhibition of consecutive side reactions . The increase in surface area to volume ratio under flow
conditions renders massive heat transfer. Finally, safety hazards in handling exothermic reactions
associated with explosive intermediates are minimized owing to the reduced volume in the vessel of
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continuous flow reaction .
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Scheme 2. Proposed mechanism for chlorosulfonylation reaction.
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There have been several reports on generating diazonium salts as reactive intermediates (followed by
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iododeamination, chlorodeamination, azo dyes, and chlorosulfonylation) using micro flow technology .
Compared to a micrometerꢀscale reactor, a millimeterꢀscale reactor, due to its relatively high
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productivity, is easier to proceed in industrial production . Our group has been committed to develop
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the continuous diazotization process in millimeterꢀscale , and herein, we describe a continuousꢀflow
diazotization process for synthesis of methyl 2ꢀ(chlorosulfonyl)benzoate under mild condition (Scheme
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).
Scheme 3. Adapted synthetic route of methyl 2-(chlorosulfonyl)benzoate
Results and discussions
Initial design of continuous-flow process.
Under the safety consideration, DSC measurement has been carried out and the results (details can be
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found in supporting information) revealed that diazonium salt solution is relative stable at around 20 C.
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Then the diazonium salt gradually decomposed as the increasement of temperature. When it arrived at
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0 C, the heat release rate became much higher where the rate of decomposition speed up as well. Heat
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release reached a maximum number at 113 C. The total heat released from diazonium salt solution is
about 437 kJ/kg, indicating diazotization as a potential hazardous procedure. Therefore, continuousꢀflow
diazotization process is highly demanded. For a continuousꢀflow process, the fluidity of reagents is
another important factor that has to be considered. In this procedure, water solubility of the diazonium
salt is very good while the target product is agglomeration of the particles, and tends to clumped
together.
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So the initial process was designed with a combination of continuousꢀflow diazotization and batch
quench process (Scheme 4). In this design, two peristaltic pumps (P , P , Baoding Longer, China)
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loaded with pump tubing connected by a Tꢀjoint that was connected to reaction tube (Hastelloy C276 ,
mm i.d., 5 mm o.d.). The reaction tube was immersed in a thermostat controlled water bath. Reaction
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temperature inside the reactor was monitored by temperature sensors (four sensors distributed uniformly
in reaction tube). The temperature profile was completed smoothly, due to the much higher circulation
flow rate of water bath in contrast to the flow rate of the reactants, which would lead reactor to reach the
near isothermal conditions. A pressure sensor was installed to monitor the backpressure in the reactor. In
case the pressure was abnormal, the pumps would be stopped immediately so that the pump tubing
won’t get ruptured. Solution A of methyl 2ꢀaminobenzoate in concentrated hydrochloric acid together
with solution B of 40 wt % aqueous sodium nitrite were prepared and pumped into the reaction tube.
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The flow rates were 122.8 mL/min and 46.7 mL/min respectively and the molar ratio of methyl
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ꢀaminobenzoate: HCl : NaNO was 1.0 : 3.0 : 1.1. After a residence time (τ ) in reaction tube, diazo
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solution flowed into the tank at atmospheric pressure which was placed with aqueous NaHSO (1.5
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equiv, 15 wt %), hydrochloric acid (2.0 equiv, 37 wt %) and CuCl (0.01 equiv) beforehand. Tail gas was
absorbed by aqueous sodium hydroxide. The chlorosulfonylation reaction was stirred by a mechanical
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agitator at 0 C for about 5 h till the reaction ended , and about 1.4 equiv of excess HCl was left
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(balanced equations can be found in supporting information) to maintain acidic condition. The
suspended solid was then collected by vacuum filtration, washed with water and dried under vacuum at
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below 35 C to give crude product. Unfortunately, an undesired hydrolysis byꢀproduct 6 (Scheme 5) was
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mainly obtained when τ = 10 s, T = 25 C. The similar results were observed even reaction temperature
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T ) and residence time (τ ) were varied.
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Scheme 4. Initial design of continuous-flow process
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Solution A is including methyl 2ꢀaminobenzoate (2.59 M) with 3.0 equiv of concentrated hydrochloric acid (37 wt %)
under a flow rate of 122.8 mL/min; solution B is aqueous sodium nitrite (7.48 M) under a flow rate of 46.7 mL/min.
Reaction tube is a Hastelloy C276 tube with 3 mm i.d. and 5 mm o.d.. Aqueous solution of NaHSO (1.5 equiv, 15
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wt %), hydrochloric acid (2.0 equiv, 37 wt %) and CuCl (0.01 equiv) are preꢀplaced in the collection tank.
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Scheme 5. Plausible formation of byꢀproducts through hydrolysis.
It’s plausible that inhibiting the hydrolysis of ester had priority in this work. The possible origins of
byꢀproduct 6 were shown in Scheme 4. In theory, the raw material 1, intermediate 2, and product 3
could be hydrolyzed with the treatment of hydrochloric acid. In order to figure out the main hydrolysis
rate law, test experiments of 1 were conducted. Material 1 was added into hydrochloric acid at given
concentrations and temperatures, samples were collected and then poured into ice water at definite time
intervals in which the resulting products were analyzed by HPLC. The results were shown in Figure 2. It
was found that the hydrolysis rate of methyl 2ꢀaminobenzoate increased significantly with increasing
temperature. Hydrolysis rate was enhanced remarkably with prolonged reaction time at high
concentration of hydrochloric acid while no obvious hydrolysis (less than 1%) occurred at low
concentration of hydrochloric acid. In a word, hydrolysis hardly occurred at low concentration of
hydrochloric acid, or at high concentration together with very short residence time. Considering that 2
and 3 were presented in low concentration of hydrochloric acid at low temperature, byꢀproduct 6 was
mainly derived from 4. In other words, the aniline has been hydrolyzed before diazotization, which was
a fatal flaw of initial design process.
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Figure 2. Hydrolysis of 1 in different concentrations of hydrochloric acid at various temperatures.
Further design of continuous-flow process.
Based on previously experimental dada, we decided to restrain the hydrolysis side reaction by
reducing the concentration of hydrochloric acid. However, reducing the initial concentration of reagents
by adding water will cause more waste water. Thus a converged route of three feed streams flowed into
the reactor was designed. showed The continuousꢀflow reactor experimental setup was displayed in
Scheme 6, in which two peristaltic pumps (P , P ) loaded with tubing connected by a Tꢀjoint that was
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connected to reaction tube I (Hastelloy C276, 3 mm i.d., 5 mm o.d.). The third pump (P ) loaded with
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tubing connected by another Tꢀjoint that was connected to reaction tube II (Hastelloy C276, 3 mm i.d., 5
mm o.d.). The reaction tubes were immersed in two thermostat controlled water baths, respectively.
Reaction temperature inside the reactor was monitored by temperature sensors (four sensors distributed
uniformly in reaction tube). Two pressure sensors were used to monitor the backpressure in the reactor,
and if the pressure was abnormal, the pumps would be stopped immediately so that the pump tubing
won’t rupture. Solution A of concentrated hydrochloric and solution B of 40 wt %aqueous sodium nitrite
were pumped into the reaction tube with the flow rates of 124.9 mL/min and 73.6 mL/min, respectively.
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The concentration of hydrochloric acid was diluted when contacted with each other. After a residence
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time (τ ) in reaction tube I, material C of methyl 2ꢀaminobenzoate was introduced into tube II with a
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flow rate of 67.5 mL/min where diazotization took place. After another residence time (τ ), diazo
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solution was outflowed from the reaction tube and accumulated in collection tank, which was placed
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with aqueous NaHSO (1.5 equiv, 15 wt %), hydrochloric acid (2.0 equiv, 37 wt %) and CuCl (0.01
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equiv) beforehand. For a same molar flow ratio of diazotization, the stoichiometry in the quench tank
was not changed compared with initial design process. After the reaction was completed, product was
obtained by the same method as initial design process.
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Scheme 6. Further design of continuous-flow process .
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Solution A is hydrochloric acid (37 wt %) with a flow rate of 124.9 mL/min; solution B is 7.48 M aqueous sodium
nitrite with a flow rate of 73.6 mL/min; material C is liquid methyl 2ꢀaminobenzoate with a flow rate of 67.5 mL/min.
Reaction tube I and II are Hastelloy C276 tube with 3 mm i.d and 5 mm o.d.. Aqueous solution of NaHSO (1.5 equiv,
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5 wt %), hydrochloric acid (2.0 equiv, 37 wt %) and CuCl (0.01 equiv) are pre placed in the collection tank.
The optimization of experimental parameters was systematically investigated by varying the reaction
temperature and residence time under convenient continuousꢀflow conditions. According to the
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sequence of Scheme 6, T and τ were investigated firstly while T = 25 C, τ = 10 s and molar flow
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ratio of 1 : NaNO = 1.0 : 1.1. As shown in Figure 3, the yield of 3 was decreased with increasing
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temperature (T ), and also prolonged residence time (τ ). In order to find out the reason, another set of
1
1
experiments were carried out (using the reactor system as shown in Scheme 6). Molar flow ratio of
o
NaNO was increased by increasing flow rate of P when τ = 1 s, T = 25 C, τ = 10 s, tube length was
2
2
1
2
2
adjusted to maintain the definite residence time, and results were shown in Figure 4. The yield increased
0
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1
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9
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7
8
9
0
o
by increasing molar flow ratio of NaNO at relatively high T (25 C), but no significant change
2
1
o
o
occurred at low T (ꢀ5 C). In addition, as increasing amount of NaNO at 25 C, azoꢀcoupling
1
2
byꢀproduct (Figure 5) was minimized significantly (HPLC area percent decreased from 8% to 1%).
Considering that the unstable nitrous acid generated in tube I is prone to be decomposed at relatively
high temperature, we thus attributed the reason of diminished yield to the decomposition of nitrous acid.
Overall, preventing decomposition of nitrous acid was another steppingstone of the work.
Figure 3. The effect of T and τ on the yield.
1
1
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Figure 4. The effect of molar flow ratio of NaNO to 1 on the yield.
2
O
O
N
O
N
O
NH
2
7
Figure 5. Structure of azoꢀcoupling byꢀproduct.
Advanced design of continuous-flow process.
In account of restraining hydrolysis of ester, inhabiting decomposition of nitrous acid and conducting
the reaction at moderate temperature, an advanced design process was carried out. The advanced
experimental setup was displayed in Scheme 7, three pumps (P , P , P ) loaded with tubing connected
1
2
3
by a crossꢀjoint that was connected to reaction tube (Hastelly C276, 3 mm i.d., 5 mm o.d.). The reaction
tube was immersed in thermostat controlled water bath. Reaction temperature inside the reactor was
detected by temperature sensors (four sensors distributed uniformly in reaction tube). A pressure sensor
was used to evaluate the backpressure in the reactor. While the pressure was abnormal, the pumps would
be turned off immediately so that the pump tubing won’t get ruptured. Concentrated hydrochloric acid
(solution A), 40 wt % aqueous solution of sodium nitrite (solution B) and methyl 2ꢀaminobenzoate
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(
material C) were pumped into the reaction tube. The following steps were introduced as previous.
Hydrochloric acid was diluted when all reagents mixed with each other, and the generation of nitrous
acid and diazotization were carried out simultaneously. With reaction conditions: molar flow ratio of 1 :
HCl : NaNO was 1.0 : 3.0 : 1.1, the results from optimized condition was concluded in Figure 6. The
2
0
1
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9
0
o
yield of 3 was increased to 90% when T = 20 C and τ = 20 s. The azo byproduct was minimized to <
1
1
22
0
.1% . Both long τ with high T and short τ with low T led to the decreasement of yield. The
1 1 1 1
acceleration of reaction rate was observed with increasement of temperature, while higher temperature
along with longer residence time resulted in the decomposition of diazonium salt. At low temperature
and shorter residence time, the conversion of amine was not completely achieved.
a
Scheme 7. Advanced design of continuous-flow process
O
O
2
SO Cl
a
Solution A is hydrochloric acid (37 wt %) with a flow rate of 124.9 mL/min; solution B is 7.48 M aqueous sodium
nitrite with a flow rate of 73.6 mL/min; material C is liquid methyl 2ꢀaminobenzoate with a flow rate of 67.5 mL/min.
Reaction tube is Hastelloy C276 tube with 3 mm i.d and 5 mm o.d.. Aqueous NaHSO (1.5 equiv, 15 wt %),
3
hydrochloric acid (2.0 equiv, 37 wt %) and CuCl (0.01 equiv) are pre placed in the collection tank.
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49
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51
52
53
54
55
56
57
58
59
60
Figure 6. Effect of diazotization reaction temperature and residence time on the yield.
With optimum continuousꢀflow diazotization in hand, chlorosulfonylation conditions were
investigated. The reaction temperature was studied firstly. As displayed in Figure 7a, a slight
o
improvement on the yield was achieved while the reaction temperature was kept at 20 C. However,
higher temperature provided lower product yield with the assumption that the diazonium salt might be
decomposed and the product could be hydrolyzed under such condition.
Figure 7. Effect of parameters towards the yield of chlorosulfonylation.
Next, the amount of sodium bisulfite and cuprous chloride were examined respectively with
o
optimized conditions. Chlorosulfonylation reactions were conducted at 20 C. Figure 7b revealed the
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effect of the amount of sodium bisulfite, in which the yield increased with increasing amount of sodium
bisulfite before a max value was reached and continued increasing affected scarcely on the yield. Figure
7
c showed the effect of the amount of cuprous chloride, and similar effect was observed.
Chlorosulfonylation reaction was insufficient with the lack of sodium bisulfite or cuprous chloride.
Finally, the yield of 3 was improved to 93% when molar equivalents of sodium bisulfite and cuprous
chloride were employed in 1.75 and 0.01 equiv respectively.
0
1
2
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4
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9
0
o
Though it was proved to be stable at 20 C by DSC measurement and diazonium salt was still
accumulated in the collection tank, temperature profile of chlorosulfonylation was investigated. As
shown in Figure 8, reaction temperature was nearly invariant at constantꢀtemperature water bath
o
condition, while reaction temperature was increased at intervals of 10 C during the first 90 min and
o
intervals of 3 C during the next 3 h under adiabatic condition. In brief, the exothermic process of
chlorosulfonylation was conducted smoothly, and the chlorosulfonylation reaction was relatively safe at
the condition of external heat transfer.
Figure 8. Temperature curve of chlorosulfonylation reaction.
To emphasize the advantage of continuousꢀflow synthesis, the comparison between continuousꢀflow
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technology and batch manner was summarized in Table 1. Based on the analysis of hydrolysis, diluted
concentration of hydrochloric acid and low diazotization reaction temperature were chosen in batch
experiment, i.e. sodium nitrite and methyl 2ꢀaminobenzoate were added to hydrochloric acid (20 wt%)
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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6
o
simultaneously affording diazonium salt at 0−5 C. The same sulfonylation conditions with advanced
0
1
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3
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9
0
design process were adopted to obtain product 3 with high yields. It should be pointed out this advanced
continuousꢀflow process is able to perform well in the condition of concentrated hydrochloric acid.
Table 1. Comparison of diazotization in different operate manners
operate manner
concentration of
hydrochloric acid (%)
reaction
reaction time
yield
of 3
(%)
temperature
o
( C)
Stirred for 0.5 h after
addition of NaNO2
batch
20
0−5
84
further design flow process
advanced design flow process
37
37
25
20
13 s
20 s
85
93
Conclusion
In summary, a practical continuousꢀflow diazotization process for the synthesis of methyl
ꢀ(chlorosulfonyl)benzoate from methyl 2ꢀaminobenzoate was developed. The in situ generated nitrous
2
acid for diazotization in a 3ꢀinlet flow reactor via a cross joint was found to be crucial for inhibiting
potential side reaction such as hydrolysis. The optimized continuousꢀflow diazotization could proceed
smoothly at high concentration of hydrochloric acid and moderate temperature, avoiding the
inconvenience arised from batch technology. The continuousꢀflow technology was demonstrated to
restrain parallel sideꢀreactions in a practical and efficient manner. The process could be potentially
applied for the preparation of analogous compounds from lowꢀmelting point anilines.
Experimental section:
All the chemical reagents were purchased from commercial sources and used without further
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purification. Melting points were determined on a Buchi 540 melting point apparatus and uncorrected.
The MS and HRMS data were recorded by Thermo LCQ advantage and Bruker II OTOFMS
1
13
respectively. The IR data was determined by Therno Nicolet AVATA 370. H NMR and C NMR
spectra were recorded on Varian 400 MHz spectrometer using tetramethylsilane (TMS) as the internal
standard. Highꢀperformance liquid chromatography (HPLC) analysis was carried out on an Agilent 1200
system. The moisture was detective by Metrohm 870 KF Titrino Plus water meter.
0
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General Procedure of Hydrolysis Experiment. Hydrochloric acid (0.3 mol) with definite
concentration was placed in a 250 mL three neck round bottom flask which was immersed in a water
bath at definite temperature. Methyl 2ꢀaminobenzoate (2.0 g, 13.2 mmol) was poured into the flask. The
mixture was stirred vigorously by a mechanical agitator. Samples (1 mL each time) were collected at
definite time intervals and poured into ice water (10 g) as soon as possible to quench reaction. Then
samples were analyzed by HPLC (Agilent 1200 system equipped with a Cꢀ18 250 mm × 4.0 mm
column and detected at 254 nm, eluted with 70 : 30 CH OH/H O at 0.8 mL/min).
3
2
23
Continuous-flow Experimental Procedure of Advanced Design . As shown in scheme 7, solution
A of hydrochloric acid (592 g, 37 wt %, 6.0 mol), solution B of aqueous sodium nitrite (380 g, 40 wt %,
2
.2 mol) and solution C of methyl 2ꢀaminobenzoate (302 g, 2.0 mol) were pumped into the flow reactor
via a cross joint by P , P and P at the flow rates of 124.9 mL/min, 73.6 mL/min and 67.5 mL/min,
1
2
3
o
respectively. After a residence time of 20 s at 20 C in reaction tube (Hastelloy C276 tube with 3 mm i.d.
and 5 mm o.d.), reaction mixture outflowed the tube (backpressure of the reactor was about 0.08 MPa)
and accumulated in the collection tank at atmospheric pressure (filled with 2428 g of 15 wt % aqueous
o
NaHSO , 395 g concentrated hydrochloric acid and 1.98 g of CuCl, preꢀcooled to 0 C), which was
3
o
stirred by a mechanical agitator. Then increase the reaction temperature to 20 C, and the reaction was
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maintained for 5 h. Tail gas was absorbed by sodium hydroxide solution. Then the suspended solid was
collected by vacuum filtration, washed with water (2 × 300 mL), and dried under vacuum at below 35
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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o
24
C to give 447 g crude solid product in 95% isolated yield with 98% purity and about 0.5% moisture .
HPLC conditions: Agilent 1200 system equipped with a XBꢀC18 250 mm × 5.0 mm column and
detected at 210 nm, eluted with 58 : 42 CH CN/H O at 1.0 mL/min.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
+
1
Characterization data of compound 3: Mp: 58−60 °C. MS (M+Na ): 257. H NMR (CDCl , 400 MHz)
3
1
3
δ/ppm: 8.15 (d, J = 8.0 Hz, 1H, ArꢀH), 7.81−7.71 (m, 3H, ArꢀH), 3.99 (s, 3H, ꢀCH ). C NMR (CDCl ,
3
3
1
00 MHz) δ/ppm: 53.4, 129.1, 130.1, 131.5, 132.4, 135.2, 141.7, 166.2.
+
Characterization data of compound 7: Mp: 118−120 °C. MS (M+H ): 314. HRMS (ESI) m/z: Calcd
+
ꢀ1
for C H N NaO , (M + Na ): 336.0960. Found: 336.0899. IR (KBr) ν/cm : 3447, 3339, 1717, 1714,
1
6
15
3
4
1
1699, 1594. H NMR (CDCl , 400 MHz) δ/ppm: 8.50 (s, 1H, ArꢀH), 7.88 (d, J = 8.8 Hz, 1H, ArꢀH),
3
7
.76 (d, J = 7.6 Hz, 1H, ArꢀH), 7.60 (d, J = 8.0 Hz, 1H, ArꢀH), 7.54 (t, J = 7.2 Hz, 1H, ArꢀH), 7.41 (t, J
7.2 Hz, 1H, ArꢀH), 6.71 (d, J = 9.2 Hz, 1H, ArꢀH), 6.28 (br s, 2H, ꢀNH ), 3.91 (s, 3H, ꢀCH ), 3.89 (s,
=
2
3
1
3
3H, ꢀCH ). C NMR (CDCl , 100 MHz) δ/ppm: 168.2, 168.0, 152.9, 151.6, 143.4, 131.7, 131.2, 129.4,
3
3
1
28.8, 128.0, 126.3, 118.9, 117.1, 109.8, 52.3, 51.9.
Acknowledgment
We are grateful to the Public Projects of Zhejiang Province (No. 2016C33071) and the National
Natural Science Foundation of China (No. 21406203 and No. 21276237) for financial support.
Supporting Information
1
13
DSC on diazonium salt solution; photos of equipment sets; copies of H/ C NMR, HPLC, MS,
HRMS, IR spectrums for compounds; balanced equations for calculation of excess acid
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(
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(c) Wootton, R. C. R.; Fortt, R.; de Mello, A. J. Lab Chip 2002, 2, 5−7. (d) MaletꢀSanz, B.; Madrzak, J.;
Ley, S. V.; Baxendale, I. R. Org. Biomol. Chem. 2010, 8, 5324−5332. For more reviews on diazonium
and diazo compounds in flow, see: (e) Mueller, S. T. R.; Wirth, T. ChemSusChem 2015, 8, 245−250. (f)
Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. −Eur. J. 2015, 21, 2298−2308.
(16) Browne, D. L.; Baxendale, I. R.; Ley, S. V. Tetrahedron 2011, 67, 10296−10303.
(17) (a) Yu, Z. Q.; Lv, Y.W.; Yu, C. M. Org. Process Res. Dev. 2012, 16, 1669−1672. (b) Yu, Z. Q.; T.
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G.; Xie. X. X.; Zhou, P. C.; Lv, Y. W.; Su, W. K. Org. Process Res. Dev. 2015, 19, 892−896. (c) Yu, Z.
Q.; Lv, Y. W.; Yu, C. M.; Su, W. K. Org. Process Res. Dev. 2013, 17, 438−442. (d) Yu, Z. Q.; Xie, X.
X.; Dong, H.; Liu, J. M.; Su, W. K. Org. Process Res. Dev. 2016, 20, 774−779.
(18) Hastelloy C276 has a good performance of corrosionꢀresistant in concentrated hydrochloric acid
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and it would not accelerate the decomposition of diazonium salt, similar result has been reported in
reference 11. Because of the poor performance of heat transfer, plastic pipe was not recommended at
such conditions.
(19) Before starting reaction, the pumps were calibrated with corresponding materials. During the
reaction, mass flow rates were monitored by the decrease of three materials’ weights. Overall, the feed
solutions are on balances. One exception was after longꢀterm use, the accuracy of flow rate decreased
because of fatigue damage on pump tubing. The peristaltic pump is pulsatile, and the stoichiometry was
affected apparently at low rotation speed, but not affected obviously at high rotation speed, so thinner
pump tubing and high revolution were suggested.
(20) Reaction was monitored by wineꢀred color resulted from reaction between diazonium salt and
1
ꢀaminoꢀ8ꢀnaphtholꢀ3,6ꢀdisulfonic acid. In this process, another 0.5 h agitation was maintained after no
color change.
(21) All yields in Figure 3, 4, 6, 7 and Table 1 were assay yields.
(22) Diazotization reaction end point can be determined by the existence of azo byproduct, because if
diazotization isn’t complete, the aniline will react with the dizaonium salt to form azo byproduct.
(23) The experimental duration of this process was only 4 min, and the longest duration run among our
optimization was only tens of minutes. We focused on establishing a process for synthesis of target
product and optimizing reaction parameters to modify yield, so we haven’t considered running the
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labꢀscale system for a long duration. A more than 10 min duration experiment can be achieved by using
larger volume of flasks, however the service life of pump tubing was only tens to hundreds of hours, and
the flow accuracy decreased with longer running time. Much longer duration (such as 1000s of hours)
experiment can be achieved by using more industrial equipment including pumps, automated control
system, etc. just like the BalzꢀSchiemann reaction equipment displayed in supporting information.
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(24) The sulfonyl chloride product is easily hydrolyzed to sulfonic acid byproduct by moisture, so
keeping a relative low temperature during drying is necessary. However, about 1.5% sulfonic acid
byproduct was still detected.
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