Synthesis of Amines, Carbamates and Amides by Multi-Step Continuous Flow Synthesis

Article abstract of DOI:10.1002/ejoc.201700906

We report the continuous flow synthesis of acyl azides in various continuous flow systems and demonstrate that liquid–liquid separation may be incorporated to prepare anhydrous solutions of the acyl azide, which may be subsequently reacted with appropriate nucleophiles to prepare amines, carbamates and amides within a fully integrated multi-step process in high yields (> 80 %). Interesting effects were also observed when preparing carbamates with long chain alcohols, whereby as the chain length of the alcohol increased the products could be made in high yield even without incorporation of the liquid–liquid separation module.

Full text of DOI:10.1002/ejoc.201700906

A Journal of
Accepted Article
Title: Synthesis of amines, carbamates and amides via multi-step
continuous flow synthesis
Authors: Paul Watts and Cloudius Sagandira
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700906
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700906
Supported by

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Synthesis of amines, carbamates and amides via multi-step continuous flow synthesis
Cloudius R. Sagandira and Paul Watts*
Nelson Mandela Metropolitan University, University Way, Port Elizabeth, 6031, South Africa.
Email: Paul.Watts@nmmu.ac.za
Abstract
We report the continuous flow synthesis of acyl azides in various continuous flow systems and
demonstrate that liquid-liquid separation may be incorporated to prepare anhydrous solutions of
the acyl azide, which may be subsequently reacted with appropriate nucleophiles to prepare
amines, carbamates and amides within a fully integrated multi-step process in high yields
(>80%). Interesting effects were also observed when preparing carbamates with long chain
alcohols, whereby as the chain length of the alcohol increased the products could be made in
high yield even without incorporation of the liquid-liquid separation module.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Introduction
Reactions involving azides represent an important but hazardous process. These reactions are
extremely exothermic and it is hence difficult to control the temperature of such reactions when
performed on a large scale. In addition, some azides are explosive which adds future complexity
to their synthesis. Flow reactors have a considerable attraction for exothermic reactions because
the high surface to volume ratio of the reactor enables excellent temperature control of the
process.1–3
Regarding alkyl azides, Kopach et al.4 illustrated the synthesis of benzyl azide derivative 2 in a
continuous flow system by an efficient nucleophilic substitution reaction between the
corresponding benzyl chloride 1 and sodium azide (Scheme 1).4 The reactor system was a 316-
stainless steel system with tubing measuring 0.64 mm (I.D.) and 63.1 mm long, having an
internal volume of 20 ml. The GC oven containing the reactor was maintained at 90 °C and 200
psi of N2 was applied to the outlet of the reaction system. The two reagents were pumped into a
T-shaped fitting just outside the oven and mixed, before they flowed through the reactor. A
residence time of 20 min in the reactor afforded 97 % conversion at 90 °C. The product solution
was collected for a batch work-up, to give the product in 94% isolated yield.
N3
X
OH
NaN3 / H2O
DMSO
+
H3C
CH3
H3C
CH3
H3C
CH3
1
2
Scheme 1. Reaction of sodium azide and 3,5-bis-(trifluoromethyl)benzyl halides.
In comparison, Delville et al.5 synthesised benzyl azide 5 from benzylamine 3 using imidazole-
1-sulfonyl azide hydrochloride 4 as the diazo transfer reagent (Scheme 2) in a 92 µL internal
volume glass reactor. It had two mixing units of the folding flow type incorporated and the
reactor temperature was controlled by Peltier elements. In case of short reaction times, a 7.0 µL
internal volume glass reactor was used. This reactor did not have mixing units because of the
inherent short diffusion distances which led to efficient mixing. The optimal reaction conditions
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
were found to be room temperature, 600 s residence time and imidazole-1-sulfonyl azide
hydrochloride/benzylamine stoichiometric ratio of 3:4. A GC yield of 97 % was obtained and
after batch work-up a yield of 73 % of was obtained.
4
O
N
S
N3
Cl
HN
DiPEA/ZnCl2
MeOH/CH2Cl2 (3:10)
O
N3
H2N
5
3
Scheme 2. Diazotransfer reaction on benzylamine.
The first multi-step continuous flow synthesis was reported by Ley and co-workers6 through the
preparation of a natural product oxomaritidine. Product isolation at all the intermediate stages
was not necessary unlike in the batch process which was time consuming and wasteful as a result
of the laborious laboratory manipulations involved.6
Acyl azides are also of significant application in synthesis. Johan et al.3 illustrated the synthesis
of carbamoyl azides 7 via Curtius rearrangement from corresponding aromatic aldehydes 6 using
iodine azide (Scheme 3) as the key reagent. The authors used tetrabutylammonium azide for the
in situ generation of iodine azide. The reactor had a capillary volume of 192 µL and optimum
conditions were found to be 26 min residence time and a temperature of 80 °C. The product
yields were found to be in the range of 21-44 %.3
O
O
O
-N3
80 °C
-N2
IN3
R
R N C O
N
N3
R
H
R
N3
H
7.5 µL/min
7
6
R = Ph (Substituted or unsubstituted)
Scheme 3. Carbomyl azides synthetic route.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Ley and co-workers7 used an azide-containing monolith in a flow system for conducting Curtius
rearrangement reactions via acid chloride inputs. They prepared azide functionalised monolithic
columns to facilitate Curtius rearrangement reactions within flow systems. Azide ions were
immobilised onto ion exchange resins to increase its safety profile, as these polymers supported
azide systems can handle shock, impact and exposure hazards which are posed by azides
themselves. The isocyanate formed as a result of Curtius rearrangement reaction was then
subsequently trapped with various nucleophiles resulting in the respective products, however it
needs to be emphasised that this approach of using immobilised azides is not suitable for the
large scale synthesis of such compounds.7 Baumann et al.8 used mesofluidic flow reactors to
perform Curtius rearrangement reactions of carboxylic acids in the presence of
diphenylphosphoryl azide (DPPA) and trapped the intermediate isocyanate with various
nucleophiles. Figure 1 shows the general setup for the Curtius rearrangement of carboxylic acids
under continuous flow condition. A mixture of triethylamine, appropriate nucleophile and
carboxylic acid was pumped into the system through channel 1 and DPPA into channel 2. Both
solutions were prepared in acetonitrile and a temperature of 120 °C and a residence time between
20-50 min was used to ensure complete conversion. Amberlyst 21 (A-21) and Amberlyst 15 (A-
15) were used as in-line scavengers for this process. The authors used a Biotage V10 solvent
evaporator that enabled direct isolation of a wide range of products in both high yield (>75 %)
and excellent purity.8 Although the scavenger systems allow easy synthesis on a small scale,
again the methodology is not suitable for the synthesis of larger quantities of product.
Figure 1. General scheme for Curtius rearrangement of carboxylic acids.
A pioneering example, where an acyl azide was prepared and consumed in situ in a potentially
scalable fashion, was reported by Jensen et al.,9 where an acyl chloride 8 was reacted with
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
sodium azide to give the organic azide 9, which was then heated to form an isocyanate 10 in the
Curtius reaction followed by alcohol addition to yield carbamate 11 (Scheme 4). The phase-
transfer reaction between aqueous azide and acid chloride to produce the organic azide was
performed in a silicon microreactor. An inline micro-separator with a selectively wetted porous
membrane was used for the subsequent continuous separation of the aqueous and organic
mixture. The membrane is exclusively wetted by the organic phase, preventing the aqueous
phase from passing through resulting in quantitative separation of the two phases.12,51 Organic
azides from the first step in the microreactor were subsequently heated giving isocyanates via
Curtius rearrangement. The generated nitrogen was subsequently removed out of the system
using a gas/liquid separator.9 They formed carbamates in the third step by contacting the
generated isocyanate with different alcohols in the third microreactor.
O
O
Cl
O
N3
R1OH
Heat
NaN3
R
R1
RNCO
N
O
R
R
H
8
9
10
11
R = Ph and R1 = Alkyl group
Scheme 4. Multi-step synthetic process of carbamate.
When contacting benzoyl chloride in toluene (0.36 M) with a solution of sodium azide (0.4 M)
they observed that the conversion of benzoyl chloride to benzoyl azide was a function of
residence time (65 % conversion at 90 min residence time and 98 % conversion at 200 min
residence time). A T-mixer was added upstream of the first reactor to improve mixing. Residence
time was increase by adding tubing before the first reactor. The Curtius rearrangement step
proved to be the limiting step in increasing productivity of the overall system. However, adding a
second reactor while operating at double the flow rate can mitigate this limitation. The authors
achieved 99 % conversion at 90 °C using 12 mg of H-mordenite solid acid catalyst at, compared
to the uncatalysed conversion 91.2 % at the same residence time (60 min) and temperature.9 The
reaction between an alcohol and isocyanate was rapid and 96-99 % of carbamate was obtained.
Productivity range of 80-120 mg was achieved per day depending the type of the carbamate
synthesised working at a flow rate of 1 µL/min for each of the aqueous (0.4 M) and organic (0.36
M) reagents. Although this system was very elegant, clearly the throughput was small.9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
As part of our ongoing program into local drug manufacture, we were interested in further
studying the in situ synthesis of acyl azide chemistry in continuous flow systems with a view to
conducting multistep synthesis of amines 15, carbamates 16 and amides 17 via Curtius
rearrangement and subsequent reaction (Scheme 5). In order to ensure that all processes were
scalable, we wished to only use solution phase synthesis methodology.
NH2
15
O
H 2
R
O
H
N
O
O
ROH
N C O
C
O
NaN3 (aq)
Heat
Cl
N3
16
R
C
O
12
14
13
O
H
O
C
R
N
H
17
Scheme 5. In situ acyl azide synthesis and consumption.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Results and Discussion
Optimisation of benzoyl azide synthesis. As a model, the reaction between benzoyl chloride 12
and sodium azide 18 to afford benzoyl azide 13 was used (Figure 2) to optimise the reaction
conditions. In our preliminary experiments, benzoyl chloride (0.1 M) in acetone was reacted with
aqueous sodium azide (0.1 M) in a 19.5 µl Labtrix SOR-mixer glass reactor (Chemtrix) at 25 °C
and a flow rate of 10 µl/min for each reagent was used. As anticipated the benzoyl azide 13
successfully reacted in good conversions (96 %); the extent of the reaction was confirmed by GC
and HPLC against a characterised synthetic benzoyl azide standard.
Figure 2. Schematic manifold used for benzoyl azide synthesis and optimisation studies.
A comprehensive study on the effects of different solvents, temperature, molar ratios and
residence time was conducted to optimise the reaction. Table 1 summarises the screening results
(Figure 2).
Table 1. Condition screening and optimisation of model reaction in flow.
Run
12/18a
Solvent for 12
12/Mb
T/ºC
Rt/s
Conv.c
1
2
3
4
6
1/1.1
1/1.1
1/1.1
1/1.1
1/1.1
Acetone
Acetonitrile
Toluene
0.05
0.05
0.05
0.05
0.1
25
25
25
80
25
117
117
117
117
117
100
100
25
Acetonitrile
Acetonitrile
97
100
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
7
8
1/1.1
1/1.1
1/1
Acetonitrile
Acetonitrile
Acetonitrile
Toluene
0.05
0.025
0.05
0.05
0.05
0.05
50
25
25
50
25
25
117
117
117
117
11.7
11.7
100
100
97
9
10
11
12
1/1.1
1/1.1
1/1.1
45
Acetonitrile
Toluene
100
7
13
14
1/1.1
1/1.1
Acetone
Toluene
0.05
0.05
25
25
11.7
200
100
38
a Molar equivalent
b Feed concentration of 12
c Conversion towards benzoyl azide
0.11 M aqueous sodium azide stock solution was prepared to achieve 1:1.1 reacting ratio
In initial studies, acetone and acetonitrile were found to be good solvents for benzoyl chloride as
they all afforded full conversions whilst toluene afforded a conversion of only 25 % using a
molar ratio of 1/1.1 of 12/18, at 25 °C and a residence time of 117 s (Table 1: entries 1, 2 and 3).
Full conversion was also achieved using both acetone and acetonitrile when the residence time
was reduced by a factor of ten to 11.7 s; however as expected in toluene a lower conversion of
only 7 % was obtained (entries 11, 12 and 13). The poor conversions in toluene may be
attributed to the fact that it is immiscible in water, which is the solvent for the sodium azide,
consequently meaning that the reagents did not have enough contact in the reactor for the
reaction to proceed successfully unlike when water miscible solvents were used as the mixing
efficiency provided by the Chemtrix SOR-mixer reactor 3227 was good enough to successfully
achieve full conversions. An increase in temperature from 25 to 50 °C, while maintaining the
same molar ratio, concentration and residence time resulted in an increase in conversion from 25
% to 45 % for the reaction in toluene (entries 3 and 10).
Full conversion was still achieved at elevated temperatures of 50 °C in acetonitrile (entry 7) and
conversely the conversion decreased to 97 % when the temperature was elevated to 80 °C while
maintaining the same reagents molar ratio, concentrations and residence time (entry 4). The drop
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
in conversion is as a result of decomposition of benzoyl azide to form benzoyl isocyanate, which
is also known as the Curtius rearrangement. Zabalov and Tiger10 reported an onset temperature
for thermal decomposition of acyl azides of around 70-80 °C, which was also echoed by
Baumann et al.11 Further experiments showed that an increase in residence time from 117 s to
200 s in toluene, while maintaining the same reagents molar ratio, concentrations and
temperature resulted in an increase in conversion from 25 % to 38% (entry 3 and 14). A small
excess of sodium azide (1.1 equiv.) was necessary to ensure full conversions in acetonitrile
(entry 2).
Equimolar ratios of the reagents afforded 97 % conversion (entry 9). Varying benzoyl azide
concentration between 0.025M and 0.1 M while maintaining the same reagents molar ratio,
temperature and residence time did not have any notable effect on conversions (entries 2, 6 and
8). It should be mentioned that some precipitates were observed when carrying out the reaction
in acetone starting at 0.05 M concentration of the benzoyl chloride and became more evident at
0.1 M. This eventually resulted in the system blockage, however it allowed us to collect enough
sample for analysis before complete blockage. We concluded that the precipitation was as a
result of incompatibility between aqueous sodium azide and acetone.
In summary, the reaction proceeded smoothly and in a very clean manner affording full
conversions when acetonitrile was the solvent of choice for benzoyl chloride 12. The reaction
was successful at 25 °C, molar ratio of 1:1.1 where sodium azide 18 was slightly in excess. 11.7
s was the residence time of choice for this reaction as it was the shortest time investigated. From
an industry perspective it is ideal to use short residence time (high reagents flow rates) as it
enhances the throughput of the process. Concentrations higher than 0.1 M were investigated
however they were characterised by eventual system blockages.
Other continuous flow systems for benzoyl azide synthesis. Having successfully prepared benzoyl
azide in a continuous flow system using acetonitrile as the solvent for benzoyl chloride 12 at the
aforementioned conditions, the next step was to develop a simpler continuous flow system that
can efficiently synthesise benzoyl azide 13. Taking advantage of the fact that the reaction
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
proceeded well at 25 °C and short residence time, we investigated the reaction using a T-mixer
only at room temperature (Figure 3).
Figure 3. Schematic diagram of a simple continuous flow system for benzoyl azide.
Benzoyl chloride 12 (0.1 M) in acetonitrile and sodium azide 18 (0.11 M) in water were each
pumped at 50 µl/min flow rate through the continuous flow system at room temperature
affording benzoyl azide 13 in full conversions. A T-mixer and a 20 cm tube (125 µm ID) was
enough for the reaction to proceed successfully, meaning that there was no need for the SOR-
mixer glass reactor for this reaction. Investigations of the synthesis of benzoyl azide 13 in a
simple continuous flow system were motivated by the fact that we wanted to carry out
subsequent reactions after in situ preparation of the azide. So there was always a need of
simplifying the system at each step if possible in order to avoid a complicated and clumsy
continuous flow system for multistep synthesis.
Curtius rearrangement: Acyl azides to isocyanates. Thermal decomposition of acyl azides,
commonly known as the Curtius rearrangement, is one of the classic reactions in organic
chemistry. The Curtius rearrangement can be carried out with or without a catalyst; however in
the absence of a catalyst the reaction is known to be predominantly dependent on
temperature.9,10,12 Lewis acids are usually used to catalyse this reaction to reduce
residence/reaction time.10,13,14 Catalyst free Curtius rearrangement will be investigated in this
project in order to simplify the system; however we are aware that this may require higher
temperatures.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Benzoyl azide Curtius rearrangement in acetonitrile. After successfully carrying out benzoyl
azide synthesis using just a T-mixer and tube (Figure 3) we added a glass reactor downstream
which was meant to be heated for the Curtius rearrangement; the system was then fitted with a
10 Bar back pressure regulator (Figure 4). Benzoyl chloride 12 (0.1 M) in acetonitrile and
sodium azide 18 (0.11 M) in water were pumped at various flow rates (to effect residence times
of 11.7 s, 23.4 s and 117 s) through the continuous flow system to determine the effects of
residence time on the Curtius rearrangement in the heated microreactor. Benzoyl azide 13, which
was formed after the T-mixer in full conversions (based on our previous results described
earlier), was subsequently pumped into a heated (30-190°C) glass micro reactor, forming phenyl
isocyanate 14 and an amine (Aniline) 15.
Figure 4. Proposed schematic diagram for multistep phenyl isocyanate synthesis in a continuous
flow system.
In our attempt to synthesise phenyl isocyanate 14 via the Curtius rearrangement of benzoyl azide
13 formed in situ upon heating, we however observed that aniline 15 was the main product
formed in the reaction. We realised that the reaction did not stop at the phenyl isocyanate
formation as we desired; since there was water in the system it acted as a nucleophile thereby
reacting with phenyl isocyanate 14 affording aniline 15, which was confirmed by a characterised
synthetic standard. The effects of temperature and residence time on aniline synthesis are shown
in Figure 5; which illustrates that both temperature and residence time have a direct relationship
with aniline formation in this reaction. Generally, an increase in temperature and residence time
resulted in an increase in the amount of the aniline 15 formed. 11.7 s residence time (Curtius
rearrangement and subsequent aniline synthesis) afforded a maximum conversion of 55 % at 190
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
°C and a ten times longer residence time (117 s) afforded a maximum conversion of 94 % at the
same temperature 190 °C.
100
5 l/min ( 117s)
25 l/min ( 23.4s)
50 l/min (11.7 s)
80
60
40
20
0
20
40
60
80
100
120
140
160
180
200
Temperature (oC)
Figure 5. Effect of temperature and residence time on aniline formation.
The Curtius rearrangement was found to be the limiting step for the whole multistep process as it
determined the residence time in the system and also the temperature for second reactor. The first
step (benzoyl azide synthesis from benzoyl chloride) in acetonitrile afforded full conversion at
11.7 s residence time however to achieve good conversion towards aniline via the Curtius
rearrangement of benzoyl azide, we had to settle for a 50 times longer residence time (585 s, 9.75
min, 1 µl/min for each reagent) and a temperature of 150 °C for the Curtius rearrangement in the
multistep aniline synthesis. The phenyl isocyanate reacted with water affording aniline 15 at 98
% conversion over all steps.
Given the inherent dangers in the handling of organic azides, one of our aims was to prepare
benzoyl azide 13 in situ and without isolation, to conduct subsequent reactions to give more
complex products such as amines 15, carbamates 16 and amides 17 (Scheme 5). The formation
of aniline in our attempt to just do the Curtius rearrangement towards phenyl isocyanate 14 was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
an apparent misfortune, which led to some interesting observations since amines (aniline) 15
were one of our target compounds. However, this development to an extent was not welcomed
since it would always push the reaction towards aniline 15 formation as long as water is present
in the system, consequently meaning that other compounds such as carbamates 16 and amides 17
would not be achieved. This therefore meant that water had to be eliminated from the system
just after benzoyl azide 13 formation before the Curtius rearrangement, or replace water with a
solvent which will not react with phenyl isocyanate 14. In an effort to eliminate water from the
system, we incorporated a Zaiput15 liquid-liquid separator after forming benzoyl azide 13 at the
T-mixer, before it entered the heated glass reactor for the Curtius rearrangement (Figure 6).
Figure 6. Water removal from the system attempt using a Zaiput liquid/liquid separator.
Benzoyl chloride 12 (0.1 M) in acetonitrile and sodium azide 18 (0.11 M) in water were pumped
at 1 µl/min into the system affording 9.75 min residence time in the glass microreactor. The
micro reactor was heated at 150 °C for the Curtius rearrangement reaction to take place after
benzoyl azide 13 was formed in full conversion at the T-mixer and water elimination by a
liquid/liquid separator. The separator did not work for our system as aniline 15 was still formed
(98 %). This meant that water went through the membrane and reacted with phenyl isocyanate 14
hence it failed to separate the aqueous phase from the organic phase effectively. We elucidated
that the miscibility of acetonitrile and water was the root cause of this failure.
Acetonitrile can be replaced with toluene as a solvent for benzoyl chloride as it is immiscible in
water. This may enhance the chances of success in elimination of water using a Zaiput
liquid/liquid separator from the system; however results of preliminary reactions of benzoyl
azide synthesis in a toluene/water solvent system showed very poor conversions compared to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
acetonitrile/water solvent system (Table 1). These observations had initially made us choose
acetonitrile as benzoyl chloride solvent over toluene only until we faced the aforementioned
challenges upon performing the Curtius rearrangement reaction. However, using a continuous
flow system in Figure 7, a catalytic amount sodium dodecylbenzenesulfonate (SDS) (0.05%) was
used to achieve full conversions towards benzoyl azide 13 using toluene as benzoyl chloride 12
(0.1 M) solvent and NaN3 18 in water (0.11 M) at 25 °C and 117 s residence time compared to 25
% conversion of the uncatalysed reaction (Table 1) using the same glass microreactor as above
(Design 3227).
Figure 7. Schematic manifold used for benzoyl azide synthesis in toluene using SDS as a
catalyst in Labtrix flow system.
SDS was used as a phase transfer catalyst (PTC) to successfully promote the formation of
benzoyl azide 13. However, in the presence of SDS the Zaiput liquid/liquid separator failed to
efficiently remove water probably because the SDS lowers the interfacial tension16 in the
toluene/water solvent system thus making it difficult to separate the phases. Consequently, the
benzoyl azide synthesis using toluene as a solvent in the absence of a catalyst was hence further
optimised in a continuous flow system.
Benzoyl azide optimisation in toluene. Preliminary experiments had shown that benzoyl azide
synthesis in toluene required longer residence times than reactions performed in acetonitrile. We
therefore switched using a FlowSyn 2 ml internal volume glass reactor (0.5 mm channel
diameter). The larger channel diameter allowed us to optimise the reaction at higher
concentrations (0.5 M) without encountering blockages (Figure 8). Benzoyl chloride 12 (0.5 M)
in toluene and sodium azide 18 (0.55 M) in water were prepared in separate FlowSyn reagent
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
delivery bottles. An experimental domain (Table 2) was established after numerous reactions
were performed in the continuous flow system at various residence times and temperatures.
Figure 8. Schematic manifold for benzoyl azide synthesis optimisation in toluene.
Table 2. Experimental domain.
Variable
Minimum
Maximum
Temperature (⁰ C)
Residence Time (Min)
25
5
95
20
Observations (Table 1) demonstrated that benzoyl azide synthesis in toluene was dependant on
flow rate and temperature. Benzoyl azide is known to start decomposing from 70-80 °C,11–13
however we were still keen to investigate the conversion effects above these temperatures. The
experimental domain was further used to create a central composite design (CCD) to
systematically execute the experiments. A total of 12 experiments were created from the CCD
and all these experiments were performed as triplicates. The CCD was generated from the
experimental domain (Table 2) to carry out benzoyl azide optimisation studies in a continuous
flow system. Optimisation studies were carried out by varying temperature and residence time;
the results are shown in Table 3. The data was analysed using Statistica software obtaining a 3-D
surface response (Figure 9).
Table 3. CCD experimental output and observations.
Run
Temp.
Res. Time Exp.1 Conversion
Exp.2
Exp.3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
(⁰ C)
35
35
85
85
60
60
25
95
60
60
60
60
(Min)
(%)
22
10
89
59
71
25
12
95
32
32
32
32
Conversion (%) Conversion (%)
1
2
14.3
5.6
14.3
5.6
20.0
5.0
7.7
7.7
7.7
7.7
7.7
7.7
20
8
20
10
89
59
71
24
13
96
32
32
32
33
3
88
59
72
21
14
97
32
32
32
32
4
5
6
7
8
9
10
11
12
Figure 9. 3-D surface plot for benzoyl azide synthesis in toluene.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
From the 3-D surface plot, it can be deduced that both temperature and residence time have
influence on conversion towards benzoyl azide 13. Generally higher temperatures and longer
residence times afforded better conversions. The 3-D plot can be illustrated by means of profile
plots (2-D) where the effect that temperature and residence time have on conversion towards
benzoyl azide 13 can be easily visualised and explained. Profile plots are used to investigate the
effect of one given variable over its complete range while the other variable is kept constant.
Below are the temperature and residence time profile plots (Figure 10 and 11) respectively.
120
25 oC
60 oC
95 oC
100
80
60
40
20
0
4
6
8
10
12
14
16
18
20
22
Residence Time (Min)
Figure 10. Residence time effect on % conversion profile plot.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
20 Min
7.69 Min
5 Min
100
80
60
40
20
0
20
30
40
50
60
70
80
90
100
o
Temperature ( C)
Figure 11. Temperature effect on % conversion profile plot.
In general conversion towards benzoyl azide 13 increases as residence time increases (Figure 10)
and also with an increase in temperature following a sigmoidal curve (Figure 11). As shown by
sigmoid shaped curves in Figure 11, there is a slow increase in conversion initially as
temperature increases from 25-40 °C followed by a sharp increase in conversion from
temperatures beyond 40 °C to 70 °C where an almost linear relationship was displayed between
temperature and conversion. Beyond 70 °C, conversion increased slowly as temperature
increased until it reached a constant optimum point. This observation can be explained by the
fact that benzoyl azide decomposition is reported to start around 70-80 °C meaning that beyond
70 °C, benzoyl azide decomposition may be occurring as indicated by the slow increase in
conversions towards benzoyl azide 13. Conversion increases as residence time increases at any
given temperature; for example, at 95 °C, the conversion is 99 % at 20 min, 93 % at 7.69 min
and 84 % at 5 min residence time.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Reaction optimisation was our aim of these investigations. The 3-D surface plot and profile plots
show that the predicated optimum conversion towards benzoyl azide 13 is 99 % at 95 °C using a
20 min residence time. However, for further studies we selected the ‘optimum conditions’ to be
95 °C and 7.69 min residence time (0.13 ml/min flow rate for each reagent) which affords
conversion of 93 %. Our motivation behind this was from an industrial perspective, as doing this
reaction at a residence time which is 2.6 times shorter has only a tiny effect of reaction
efficiency. Jensen et al.9 achieved 65 % conversion towards benzoyl azide at room temperature
at 90 min residence time, of which our approach had much shorter residence time and produced
better conversions.
Continuous flow synthesis of various acyl azides. Using the abovementioned conditions (95
°C and 7.69 min residence time) and the same continuous flow system, various acyl azides were
synthesised to investigate the chemical reaction behaviour of different acyl chlorides 19 with
sodium azide 18 towards their respective acyl azides 20. These investigations were done using
the 2 ml FlowSyn system (Figure 12) where an acyl chloride 19 (0.5 M) in toluene and sodium
azide 18 (0.55 M) in water were prepared into separate FlowSyn reagent bottles. Using the
continuous flow system, various acyl azides were synthesised (Table 4).
Figure 12. Continuous flow system for acyl azide synthesis.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Table 4. Various acyl azides synthesis in continuous flow using the previous condition.
Entry
Substrate
a Product
c Conversion %
1
92
2
3
4
5
6
7
96
48 (65)
96
90
34 (51) b
94
a All reactions used 1 equiv. acyl chloride in toluene (0.5M) and 1.1 equiv. NaN3 in water (0.55 M)
b % Conversion at 20 min residence time and 95 °C
c Conversion determined by GC-FID and HPLC (UV-Vis)
According to the results in Table 4, aromatic acyl chlorides with electron withdrawing groups
(EWG) afforded higher conversions to the corresponding acyl azides compared with electron
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
donating groups (EDG) (Compare entry 1, 2 and 3) as expected. Comparing entry 1 and entry 5,
cinnamoyl chloride afforded better conversions than benzoyl chloride because of the α, β-
unsaturated double bond attached to the carbonyl carbon of cinnamoyl chloride. To investigate
whether the substrate conversion in entry 3 and 6 was limited by the reaction conditions or not,
we performed the reaction at a lower flow rate (0,05 ml/min, 20 min residence time), keeping the
rest of the variables constant. Hence, we effectively increased residence time by a factor of 2.6
and conversion increased to 65 % and 51 % respectively. These observations showed that it
possible to get higher conversions even when EDG are involved although at a longer residence
time than when EWD groups are attached to the phenyl moiety.
Incorporating a liquid-liquid separator into multi-step syntheses. The benzoyl chloride 12
solvent was changed from acetonitrile to toluene in benzoyl azide 13 synthesis to enable the use
of a liquid/liquid separator, in order to facilitate water elimination from the system prior to
Curtius rearrangement. The use of toluene rather than acetonitrile however significantly
increased the residence time needed for benzoyl azide synthesis. As clearly illustrated water
removal in the system after benzoyl azide 13 synthesis was very important for the success of
subsequent reactions in the multistep synthesis towards compounds such as carbamates and
amides via Curtius rearrangement (phenyl isocyanate 14) otherwise an amine (aniline) will be
afforded. A FlowSyn continuous flow system with a glass mixer block and a 10 ml stainless steel
coil reactor was utilised (Figure 13).
Figure 13 Use of Liquid/liquid separator towards Curtius rearrangement reaction.
Benzoyl chloride 12 (0.5 M) in toluene and sodium azide 18 (0.55 M) in water were prepared in
separate FlowSyn reagent bottles. Each reagent was pumped at 0.13 ml/min and the reactor
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
temperature was kept at 95 °C for the first reactor (7.69 min residence time) to allow benzoyl
azide 13 synthesis. A Zaiput liquid/liquid separator was used to remove the aqueous phase in the
system beforeanhydrous benzoyl azide 13a underwent Curtius rearrangement in the 10 ml
stainless steel coil reactor (38.5 min residence time) held at temperatures in the range of 70-150
°C, to afford phenyl isocyanate 14. The system was used under 10 Bar pressure to allow
superheating to prevent the solvent boiling. The effect of temperature on the conversion of
benzoyl chloride to phenyl isocyanate via the Curtius rearrangement of benzoyl azide 13a
formed in situ is shown in Figure 14 below.
120
100
80
60
40
20
0
60
80
100
120
140
160
Temperature (oC)
Figure 14. Temperature effect on Curtius rearrangement reaction in a continuous flow system at
38.5 min residence time in the heated coil reactor.
As illustrated in Figure 14, conversion of benzoyl chloride 13 towards phenyl isocyanate 14 in
the stainless steel coil reactor was a function of temperature at 38.5 min residence time.
Conversion increased with increase in temperature reaching full conversion at 130 °C. This
observation was as expected since the Curtius rearrangement only occurs in the presence of heat
above 70 °C.9,13 Jensen et al.9 reported 99 % benzoyl azide conversion towards phenyl
isocyanate at 60 min residence time (105 °C). We managed to obtain full conversion at a lower
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
residence time (38.5 min, 130 °C) than Jensen et al,9 (60 min, 105 °C) by pressuring the system
which allowed us to superheat the reaction to higher temperatures. The liquid/liquid separator
successfully removed the aqueous phase after the first step which leads to the successful Curtius
rearrangement. These developments made it possible to react the phenyl isocyanate with
different nucleophiles of our choice in a continuous flow system, affording compounds such as
carbamates and amides as discussed below.
Multi-step continuous flow synthesis of amines, carbamates and amides. As above-
mentioned, given the inherent dangers in the handling of organic azides, one of our aims was to
prepare benzoyl azide 13 in situ and without isolation conduct subsequent reactions to give more
complex products such as amines 15, carbamates 16 and amides 17 via Curtius rearrangement of
benzoyl azide 13 into phenyl isocyanate 14 (Scheme 5). The amine (aniline 15) was the only
product when acetonitrile was used as solvent for benzoyl chloride 12 as the liquid/liquid
separator failed to eliminate water from the system. However, solvent change to toluene enabled
effective use of the liquid/liquid separator making it possible to trap the phenyl isocyanate 14
with nucleophiles such as alcohols and carboxylic acids yielding carbamates 16 and amides 17
respectively in good conversions (Figure 15).
Figure 15 General continuous flow system used in multi-step synthesis of carbamates and
amides via Curtius rearrangement.
Benzoyl chloride 12 (0.5 M) in toluene and sodium azide 18 (0.55 M) in water were prepared in
FlowSyn reagent bottles and each reagent was pumped at 0.13 ml/min and the reactor
temperature was kept at 95 °C for the first reactor (7.69 min residence time) to allow benzoyl
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
azide synthesis 13. A liquid/liquid separator was used to remove the aqueous phase from the
system before either an alcohol or carboxylic acid (0.5 M) in toluene was pumped into the
system at 0.13 ml/min flow rate. This mixture entered the 130 °C coil reactor at a total flow rate
of 0.39 ml/min (25.6 residence time) for the Curtius rearrangement reaction and subsequent
trapping of the resultant phenyl isocyanate 14 with the pre-introduced nucleophiles (alcohols and
carboxylic acids) affording carbamates 16 and amides 17 respectively. Figure 16 is a summary
of carbamates synthesised via Curtius rearrangement using respective alcohols (ethanol,
propanol, butanol, hexanol and octanol) using the aforementioned conditions. Good conversions
and good isolated yield were afforded in the multistep synthesis of carbamates 21 - 25 (94 %),
for example the isolated yield for the carbamate 21 was 92 %.
O
O
HN
N
O
N
O
O
O
H
H
23
22
21
O
O
O
O
NH
25
NH
24
Figure 16 Various carbamates and their respective % conversions synthesised in a continuous
flow system via Curtius rearrangement.
It was interesting to note that some carbamates were successfully synthesised in good
conversions without incorporating a liquid/liquid separator in the continuous flow system (Figure
17) when toluene was used as a solvent.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Figure 17 Carbamate synthesis in the absence of a liquid/liquid separator.
Benzoyl chloride 12 (0.5 M) in toluene and sodium azide 13 (0.55 M) in water were each
pumped through the system at 0.13 ml/min flow rate and the reactor temperature was kept at 95
°C for the first reactor (7.69 min residence time) to allow benzoyl azide 13 synthesis. An alcohol
26 (0.5 M) in toluene was pumped into the system at 0.13 ml/min flow rate. This mixture entered
the 130 °C coil reactor at a total flow rate of 0.39 ml/min (25.6 residence time) for the Curtius
rearrangement reaction and subsequent trapping of the resultant phenyl isocyanate with
appropriate alcohols giving carbamates 16. Figure 18 shows the conversions afforded from
various alcohols without the use of a liquid/liquid separator to remove water in the system.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
100
80
60
40
20
0
Ethanol
Propanol
Butanol
Hexanol
Octanol
Alcohol
Figure 18 Carbamate synthesis in a continuous flow system without a liquid/liquid separator.
It shows that conversion of alcohols towards respective carbamates using a continuous flow
system generally increases with increase in the hydrocarbon chain length of the alcohol. Using
ethanol and propanol, no respective carbamates were synthesised, instead aniline was produced
via reaction of the phenyl isocyanate with water in the system. However, some considerable
conversions towards respective carbamates were achieved using butanol (12 %), hexanol (57 %)
and octanol (79 %). Hydrophobicity of alcohols increases with an increase in hydrocarbon
chains. Ethanol and propanol are miscible in water where miscibility decreases with hydrocarbon
chain length. Therefore, the contact between the organic phase and aqueous phase in the system
is diminished as the hydrocarbon chain length of the added alcohol increases which has a
positive impact on reaction towards carbamates. The reaction will occur in the organic phase as
phenyl isocyanate contact with water will be minimal thus favouring carbamates synthesis. We
noted that the formation of the unwanted aniline decreased as the hydrocarbon chain length
increased. However, this continuous flow system (Figure 17) produced carbamates at lower
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
conversion at higher temperatures compared to the one in Figure 15 where a liquid/liquid
separator was used as no aniline was formed at all. This might be because solubility of toluene
increased with temperature therefore inciting miscibility between the organic phase and aqueous
phase resulting in some water to react with phenyl isocyanate. Hence conversion towards the
target carbamates is decreased in this case.
Multi-step continuous flow synthesis of amides. Under the conditions used in the continuous
flow system (Figure 15), the phenyl isocyanate formed in situ via Curtius rearrangement of
benzoyl azide was trapped with an appropriate carboxylic acid to produce amides 17. Figure 19
summarises the amides 27-30 prepared in good conversions (80 - 85 %) and the isolated yield for
amide 28 was 83%, demonstrating minimum loss on work-up.
HN
N
H
O
O
27
28
O
O
N
NH
H
29
30
Figure 19. Various amides and their respective % conversions synthesised in a continuous flow
system via Curtius rearrangement.
Optimising the last step (phenyl isocyanate reaction with carboxylic acid) was not a target in this
research. However, conversion towards amides can be enhanced by using bases such as
triethylamine as these bases deprotonate carboxylic acids, forming more reactive carboxylate
ions, which are better nucleophiles. Hence better conversions will be obtained in the presence of
a base in the last step of the multistep synthesis.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Conclusion
Given the inherent dangers in the handling of organic azides, we managed to perform continuous
multistep synthesis of amines, amides and carbamates via Curtius rearrangement of benzoyl
azide formed in situ. Continuous multistep synthesis of aniline in acetonitrile was successfully
performed in the absence of a liquid/liquid separator where benzoyl azide synthesis was effected
from benzoyl chloride and aqueous sodium azide at room temperature using a T-mixer followed
by Curtius rearrangement and subsequent trapping of the resultant phenyl isocyanate with water
in a glass micro reactor at 150 °C and 9.75 min residence time yielding 98 % conversion towards
aniline. We successfully achieved continuous multistep synthesis of carbamates and amides in
toluene at 94 % and 80 - 85 % conversion respectively. Compared to literature Our approach was
effective as we achieved benzoyl azide synthesis in toluene (92 % conversion) at a much shorter
residence time (7.69 min) than literature precedent (98 % conversion, room temperature and 200
min residence time)9 by increasing the reaction temperature and ensuring efficient mixing
throughout the system. Curtius rearrangement in the absence of a catalyst was successfully
achieved in full conversion at shorter residence time 25.6 min by pressurizing the system
allowing superheating without solvent boiling. Jensen et al 9 achieved 91 % conversion at 90 °C
and 60 min residence time, however full conversion was only attained in the presence of a
catalyst under these conditions. The preparation of carbamates with long chain alcohols was
achieved in high yield even without the incorporation of the liquid-liquid separation module.
Therefore, our work demonstrated the use of a simple network of micro reactors, inline
separation and in situ generation and consumption of hazardous intermediates such as
isocyanates. Multivariate optimisation of benzoyl azide synthesis in continuous flow systems
was successfully performed.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700906
European Journal of Organic Chemistry
Experimental procedures
General experimental methods
All reagents were obtained from commercial sources and used as supplied without further
purification. All solvents were analytical or HPLC grade and were used as supplied. Nuclear
magnetic resonance (NMR) spectra were recorded at room temperature as solutions in deuterated
chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6). A Bruker spectrometer was
used to record the spectra and the chemical shifts are reported in parts per million (ppm) with
coupling constants in Hertz (Hz). Infra-red spectra were recorded from 4000-500 cm-1 using a
Bruker spectrometer and peaks (Vmax) reported in wavenumbers (cm-1). Agilent gas
chromatography (7820A) fitted with a HP-1 (Crosslinked Methyl Siloxane 30m x 0.32mm x 0.25
µm) column using nitrogen as carrier gas was used to record GC data. High performance liquid
chromatography (HPLC) data was obtained using Agilent 1100 with a UV/Vis detector and a
Zorbax C18, 10µm, 4,6mm x 250mm column. Continuous flow reactions were performed on a
Labtrix® Start system and a Uniquis FlowSyn system and reactions were monitored by HPLC-
UV/Vis and GC.
Flow systems
The Labtrix Start system equipped with glass microreactor (Model 3227, 3223, 3023 and 3022),
reactor holder, standard syringe pump, 1 mL SGE gastight syringes, polyetheretherketone
(PEEK) tubing (1/32” OD x 125 µm ID), an IDEX 10 bar backpressure regulator. The Uniqsis
FlowSyn system with a 2mL borosilicate glass reactor, aluminum coil reactor,
polytetrafluoroethylene (PTFE) tubing (1 mm OD x 0.7 mm ID) and 20 Bar Upchurch back
pressure reactor.
Benzoyl azide synthesis in the The Labtrix ® Start system
Sodium azide 18 was dissolved in water and benzoyl chloride 12 dissolved in appropriate
solvents to be screened (acetone, toluene or acetonitrile). The molar ratios and concentration of
these solutions varied as described. The sodium azide solution and benzoyl chloride solutions
were pumped through the Labtrix flow system (Figure 2). The product 13 sample was extracted
This article is protected by copyright. All rights reserved.