Continuous flow photochemical and thermal multi-step synthesis of bioactive 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

Article abstract of DOI:10.3390/molecules24244527

An effective multi-step continuous flow approach towards N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones, including the local anesthetic compound AL-12, has been realized. Compared to the traditional decoupled batch processes, the combined photochemical–thermal–thermal flow setup rapidly provides the desired target compounds in superior yields and significantly shorter reaction times.

Full text of DOI:10.3390/molecules24244527

molecules
Article
Continuous Flow Photochemical and Thermal
Multi-Step Synthesis of Bioactive
3-Arylmethylene-2,3-Dihydro-1H-Isoindolin-1-Ones
Saira Mumtaz 1 , Mark J. Robertson 1 and Michael Oelgemöller 1,2,
*
1
College of Science and Engineering, James Cook University, Townsville, QLD 4811, Australia;
saira.mumtaz@my.jcu.edu.au (S.M.); mark.robertson@jcu.edu.au (M.J.R.)
Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4-bis,
9000 Gent, Belgium
2
*
Correspondence: michael.oelgemoeller@jcu.edu.au; Tel.: +61-7-4781-4543
Academic Editor: Yasuharu Yoshimi
Received: 17 November 2019; Accepted: 10 December 2019; Published: 11 December 2019
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: An effective multi-step continuous flow approach towards N-diaminoalkylated
3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones, including the local anesthetic compound AL-12,
has been realized. Compared to the traditional decoupled batch processes, the combined
photochemical–thermal–thermal flow setup rapidly provides the desired target compounds in
superior yields and significantly shorter reaction times.
Keywords: photochemistry; photodecarboxylation; phthalimide; continuous-flow photochemistry;
multi-step synthesis; arylmethylene isoindolinones
1. Introduction
Due
3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones has been widely studied [
many synthetic pathways developed, the photodecarboxylative benzylation of phthalimides
represents a mild and efficient access to these important target compounds [ ]. Subsequently, this
photobenzylation has been successfully applied as a key step in the synthesis of the cardiovascularly
active AKS-186 and the local anesthetic AL-12 (Scheme 1) [ ]. The syntheses protocols involved
to
their
broad
biological
activities,
the
synthesis
of
1,2]. Among the
3,4
5,6
utilize conventional step-by-step batch procedures. Examples of photodecarboxylations involving
phthalimides in circulating or continuous-flow reactors have also been realized [7,8].
MeO
OH
NEt2 . HCl
N
N
O
O
AL-12
AKS-186
Scheme 1. Examples of bioactive 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones.
Flow chemistry allows for the continuous manufacturing of target compounds under controlled
conditions [
9
,
10]. This technology has proven particularly beneficial for photochemical transformation
13]. Flow operation
as it permits effective light utilization and protection of photoactive products [11
–
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www.mdpi.com/journal/molecules

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furthermore enables easy coupling of individual reaction steps without the need for isolation
and purification of intermediates (‘telescoping’) [14]. A growing number of multi-step processes
incorporating a photochemical key-step have already been described [15]. Following this development,
we have successfully established a three-step one-flow process for the continuous synthesis of a series
of N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones.
2. Results
2.1. Synthesis Optimization
The
3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones
of the readily available N-(bromoalkyl)phthalimides (
corresponding benzylated hydroxyl phthalimidines (
three-step
synthesis
of
the
desired
N-diaminoalkylated
6
is outlined in Scheme 2. Initial photobenzylation
1
) with arylactetates (
2
) produces the
Subsequent
4
) as key intermediates.
acid-catalyzed dehydration [16], followed by amination with the corresponding secondary amines
(5) [17] yields the desired target compounds 6.
Scheme 2. Synthesis of N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones.
Under batch conditions, the photodecarboxylation, dehydration, and amination steps were
performed in three different solvents, i.e., acetone/pH 7 buffer, dichloromethane and DMF [6]. To avoid
a switch of solvents under continuous flow conditions, a common solvent for all three reaction steps
was desirable. N-(2-Bromoethyl)phthalimide (1a), phenylacetate (2a) and diethylamine (5a) were thus
chosen as model reagents for a solvent study. Following the original reaction protocols, each step for
the synthesis of 6a was conducted separately in batch in acetone, DMF and/or acetonitrile, respectively
(Table 1). Dichloromethane was omitted due to the poor solubility of most reagents in this solvent. For
the photodecarboxylation, pH 7 buffer (33 vol%) was used as a co-solvent to minimize side-reactions
(entries I–III) [3]. Overall, acetonitrile was found to be the most suitable solvent as it gave acceptable to
good conversions for all three reaction steps without the formation of noticeable by-products (entries
II, V, and VIII). The acid catalyzed dehydration step produced large amounts of the aldol-condensation
product of acetone [18], which was difficult to remove (entry IV).
Table 1. Solvent optimization study.
Entry
Solvent
Time [h]
Conversion [%] a
Photodecarboxylation
acetone b
acetonitrile b
DMF b
I
II
III
3
3
3
87
80
45
Dehydration
IV
V
VI
acetone
acetonitrile
DMF
5
5
5
37 c
83
80
Amination
VII
VIII
IX
acetone
acetonitrile
DMF
5
5
5
46
53
55
a
Determined by 1H-NMR analysis ( 3%); b pH 7 buffer as co-solvent; c Aldol-condensation product of acetone as
±
a by-product.

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2.2. Flow Reactor Design
Photodecarboxylative additions in continuous-flow mode were initially investigated using a
previously described in-house capillary reactor [19]. The reactor used a transparent fluorinated
ethylene propylene (FEP) capillary wrapped around a Pyrex body with a single 8 W UVB fluorescence
tube at its center. This photoreactor module was subsequently coupled via a FEP T-junction with a
thermal loop. Following a reactor concept reported by Horie and co-workers [20], the capillary coil of
this thermal module was placed in an ultrasonic bath in order to prevent precipitation of the rather
non-polar dehydration products 4. Finally, the reactor system was expanded into a three component
setup coupled through FEP T-junctions (Figure 1). Micro-FEP tubing was used for the first and the
second loop (each with an I.D. of 0.8 mm, a length of 10 m, and an internal volume of 5 mL), whereas a
wider tubing diameter was chosen for the third module (I.D. of 1.58 mm, length of 10 m, and internal
volume of 19.6 mL). Reactant solutions were injected into the reaction streams with syringe pumps
between each reactor. A strongly basic ion exchange resin cartridge (ca. 50 mL) was placed between
the second and third reactor module to remove excess of acid after the dehydration step. A similar
approach was described by DeLaney et al. for the removal of base [21]. Heating was achieved in the
third step by submerging the capillary coil in a water bath. The reactor components are described in
detail in the Supplementary Materials.
H2SO4 solution
5
HNR'2
(
) solution
80oC
)))
hν
IE-resin
1 + 2
solution
6
Photoreactor loop
Ultrasonic loop
Thermal loop
(I.D.: 0.8 mm, 5 mL) (I.D.: 0.8 mm, 5 mL)
(I.D.: 1.6 mm, 19.6 mL)
(a)
(b)
) Actual in-house multi-step flow reactor module (A: photo reactor, B:
Figure 1.
(a
) Flow scheme; (
b
ultrasonic reactor, C: ion exchange resin cartridge, D: thermal reactor, E: product collection flask, F1–3:
syringe pumps, G1/2: T-junctions).
2.3. Continuous-Flow Operations
2.3.1. Photodecarboxylation
Representative examples of the photodecarboxylative addition reaction were initially carried out
under flow conditions with the aim to obtain high to complete conversions (Scheme 3 and Table 2).
Previously degassed mixtures of the corresponding N-(bromoalkyl)phthalimides (1a and
arylactetate (2a ) were injected into the capillary photoreactor and the product solution was collected
externally in a round bottom flask. An excess of arylacetate was utilized to suppress competing simple
decarboxylations (-CO2H -H exchange) [22]. When pH 7 buffer-acetone was used as the reaction
medium, complete conversions were achieved with a residence time of 20 min (corresponding to a
reagent flow rate of 0.25 mL/min) and the benzylated hydroxyl phthalimidines 4a were isolated in
b) and
–d
↔
–
e
good to high yields of 80%–95% (entries I–V). Prolonged residence times of 30 min (reagent flow rates
of 0.17 mL/min) were required in pH 7 buffer-acetonitrile solutions but likewise furnished the desired
target compounds 4a–e in high yields of 83%–91% (entries VI–X).

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Scheme 3. Photodecarboxylative additions of arylactetates to N-(bromoalkyl)phthalimides.
Table 2. Experimental results for photodecarboxylative addition reactions under flow conditions.
Entry
n
R
Residence Time [min]
pH 7 Buffer-Acetone
Yield of 3 [%]
I
II
III
IV
V
2
2
3
3
3
H
4-MeO
H
4-Me
4-F
20
20
20
20
20
87 (3a)
85 (3b)
95 (3c)
80 (3d)
89 (3e)
pH 7 Buffer-Acetonitrile
VI
VII
VIII
IX
2
2
3
3
3
H
4-MeO
H
4-Me
4-F
30
30
30
30
30
83 (3a)
85 (3b)
91 (3c)
83 (3d)
90 (3e)
X
2.3.2. Photodecarboxylation-Dehydration Coupling
The photoaddition step was subsequently coupled with the first thermal reactor loop (Scheme 4
and Table 3). The initial photoreaction mixture in pH 7 buffer-acetonitrile was pumped through the
photoreactor module at 0.17 mL/min, resulting in a residence time of 30 min. A 1:1 mixture of a 10 M
solution of sulfuric acid and acetonitrile was injected in a FEP T-junction into the effluent at a flow
rate of 0.17 mL/min. The combined reaction stream was pumped through a FEP capillary submerged
in an ultrasonic bath and the product mixture was collected externally in a flask. After workup and
isolation, the corresponding 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones 4a
–
e
were obtained in
good to high yields of 83%–94% with near complete E-selectivity (E:Z
≥
9:1), as confirmed by 1H-NMR
spectroscopic analysis [16].
Scheme 4. Photodecarboxylation with subsequent dehydration.

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Table 3. Experimental results for tandem-photodecarboxylation-dehydration reactions under
flow conditions.
Yield of 4 [%] b
Entry
n
R
Residence Times [min] a
I
II
III
IV
V
2
2
3
3
3
H
4-MeO
H
4-Me
4-F
30 + 15
30 + 15
30 + 15
30 + 15
30 + 15
91 (4a)
90 (4b)
83 (4c)
86 (4d)
94 (4e)
a
For photochemical and thermal reaction steps; b Near complete E-selectivity as determined by 1H-NMR analysis.
2.3.3. In Series Multistep Flow Operation
The entire three-step procedure was consequently realized in the combined
photochemical–thermal–thermal flow setup shown in Figure 1 (Scheme 5 and Table 4). As
before, the initial photodecarboxylative addition was performed in the photoreactor and the
subsequent dehydration in the thermal ultrasonic module. The effluent stream from the dehydration
loop entered a cartridge containing strongly basic Dowex 1-X8 ion exchange resin against gravity from
the bottom, effectively neutralizing excess amounts of acid. A solution of the corresponding amine
5a or
b in acetonitrile was subsequently introduced into the reagent stream in a FEP T-junction at a
flow rate of 0.25 mL/min. The combined solution entered a FEP capillary submerged in a water bath
kept at 80 ◦C and the product solution was collected externally in a flask. The integrated assembly
provided the desired target compounds 6a–e in good overall yields of 73%–77%, among them the local
anesthetic AL-12 in its neutral form (entry II). The acidic workup conditions caused near complete
conversion into the Z-stereoisomer of 6a–e (Z:E ≥ 9:1) [6].
Scheme 5. Photodecarboxylation with subsequent dehydration and amination.
Table 4. Experimental results for multistep photodecarboxylation-dehydration-amination reactions
under flow conditions.
Yield of 6 [%] b
Entry
n
R
R’
Residence Times [min] a
I
II
III
IV
V
2
2
3
3
3
H
4-MeO
H
4-Me
4-F
Et
Et
Me
Et
30 + 15 + 33
30 + 15 + 33
30 + 15 + 33
30 + 15 + 33
30 + 15 + 33
75 (6a)
73 (6b)
75 (6c)
77 (6d)
75 (6e)
Et
a For the photochemical and both thermal reaction loops, excluding connecting tubes and cartridge; b Near complete
Z-selectivity as determined by 1H-NMR analysis.
3. Discussion
Even though acetone was the best solvent for the photodecarboxylative addition, the acidic
conditions of the subsequent dehydration step led to the formation of its corresponding aldol
condensation product, which demanded additional time- and resource-intensive separation. Attempt
to use super activated acidic aluminum oxide as a solid catalyst instead failed and showed little to
no conversion to the dehydration products 4a
–
e. The removal of DMF required higher temperatures
during evaporation, which caused partial degradation of the photoproducts 3a
–
e
and necessitated
subsequent purification. Acetonitrile was thus chosen as the solvent for all three reaction steps as it
gave good conversions and could be removed easily. The photodecarboxylations in acetonitrile under

Molecules 2019, 24, 4527
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flow conditions imposed a somewhat longer residence time of 30 min to reach complete conversions,
which was most likely caused by its differing photoactivation mode. Photoreactions of phthalimides in
acetonitrile follow a direct excitation pathway, whereas the corresponding transformations in acetone
involve triplet-sensitization [23].
The photodecarboxylative addition in the simple in-house flow device required residence times
of 20 and 30 min to achieve complete conversions. This respectable performance is best explained
by the advanced operation and design features of the microcapillary reactor [24]. The narrow path
length, i.e., inner diameter of the capillary, of just 0.8 mm allowed for effective light penetration
throughout the reaction mixture. Due to the central position of the 8 W fluorescent tube (inside-out
irradiation), all light is furthermore directed onto the reaction capillary, thus resulting in efficient light
1
utilization [25]. However, only approx.
/3 of the length of the fluorescent tube (23 cm) was covered
by the capillary tube (48 windings over 7.8 cm) in the current flow photoreactor, which leaves room for
future improvements.
Dehydrations of the photoproducts 3a
–e readily furnished the corresponding olefins 4a–e with near
complete E-selectivity. Using DFT calculations, Kise et al. [26] and independently Li and Janesko [27
]
showed that the E-isomers of N-substituted 3-arylmethyleneisoindolin-1-ones are thermodynamically
more stable than their Z-counterparts. The current results are in line with these findings. Ultrasonic
irradiation effectively prevented precipitation of the dehydration products 4a–e and hence clogging,
pressure build-up and eventual rupture of the capillary [28].
The one-flow approach required a switch from acidic conditions in the dehydration to basic
conditions in the final amination step. Initial attempts to use excess amounts of amine to neutralize
the sulfuric acid were unsatisfactory. Instead, a cartridge filled with an ion exchange resin as an acid
scavenger was introduced between the thermal loops [29,30]. After several trials, strongly basic Dowex
1-X8 ion exchange resin was found optimal.
Under coupled-flow conditions, amination was achieved rapidly with a residence time of 33
min due to the superior heat transfer inside the small diameter of the capillary [31]. The target
N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones 6a–e were isolated by first
converting them into their corresponding hydrochloride salts and subsequent neutralization. This
procedure caused near complete isomerization to the Z-isomers, presumably via an acylaminium
cationic intermediate [32]. The same isomerization was also observed during alternative column
chromatographic purification of compounds 6a–e on silica gel [6].
In comparison with the original decoupled three-step synthesis, the developed one-flow protocol
gave higher overall yields and furnished the desired compounds 6a–e in shorter time (Table 5). The
continuous process only required a single workup, isolation and purification step, which subsequently
reduced losses of intermediate products [33]. It should be noted however that the reaction volumes
and starting concentrations differed between the two reaction modes. While the overall process time,
i.e., the time to pump the complete reaction volume through the entire device, is naturally significantly
longer than the actual residence time, flow operation generates the final products 6a–e continuously.
The reaction scale can also be increased easily by simply changing the starting reagent volumes.
Table 5. Comparison of flow vs. batch performances.
Compound
Batch [7]
Flow
Reaction timea
Overall yields of 6a–e [%]
9 h
28–45
78 min b
72–77
a
Excluding time required for workup, isolation and purification; b Overall residence time, excluding connecting
tubes and cartridge.

Molecules 2019, 24, 4527
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4. Materials and Methods
4.1. Experimental Procedures
General experimental details and spectroscopic data can be found in the supporting information.
All batch processes and compounds 3a 4a , and 6a have been previously described in detail.
–
e,
–
e
–e
The spectroscopic data are in full agreement with those reported in the literature [6].
4.1.1. Photodecarboxylations under Flow Conditions
The lamp inside the flow photoreactor was allowed to warm up for 10 min. Twenty milliliters of a
degassed solution of the respective potassium arylacetate (0.66 mmol) and N-(bromoalkyl)phthalimide
(0.33 mmol) in acetone-pH 7 buffer or acetonitrile-pH 7 buffer (2:1) were pumped through the flow
photoreactor loop. The reaction mixture and 20 mL of fresh organic wash solvent were collected in
a flask. After the addition of water (25 mL), most of the organic solvent was removed via rotary
evaporation at low temperatures (water bath <30 ◦C). The remaining reaction mixture was subsequently
extracted with CH2Cl2 (3
×
40 mL) and the combined organic layers were washed with saturated
40 mL). After drying over MgSO4 and filtration, the reaction
NaHCO3 (2 40 mL) and brine (1
×
×
mixture was evaporated to dryness on a rotary evaporator at low temperatures (<30 ◦C) and the solid
product obtained was dried in vacuum. When necessary, the crude product was purified by titruration
or column chromatography [6].
4.1.2. Coupled Photodecarboxylative Addition and Dehydration under Flow Conditions
The reaction was started as described in Section 4.1.1. After 20 min run time, 20 mL of a 1:1 mixture
of acetonitrile and 10 M H2SO4 were injected into the effluent stream. The combined reaction mixture
was pumped through a FEP capillary submerged in an ultrasonic bath. The final product and 30 mL of
wash acetonitrile were collected at the exit of the thermal capillary. The collected reaction mixture was
diluted with water (25 mL) and extracted with CH2Cl2 (3
washed with brine (25 mL) and dried over MgSO4. Evaporation and drying in vacuum furnished the
desired product. When necessary, the crude product was purified by column chromatography [6].
×
25 mL). The combined organic layers were
4.1.3. In Series Photodecarboxylative Addition with Thermal Dehydration and Amination under Flow
Conditions
The reaction was started as described in Section 4.1.2. The effluent from the thermal ultrasonic
reactor loop was passed through a cartridge filled with strongly basic Dowex 1-X8 ion exchange resin
(20–50 mesh, ca. 50 mL). After another 20 min run time, a mixture of 2 mL of dialkylamine in 38 mL of
acetonitrile was injected into the reaction stream. The combined reaction mixture is passed through a
FEP capillary submerged in a water bath at 80 ◦C. The final product and 60 mL of wash acetonitrile
were collected at the exit of the reactor sequence. The collected reaction mixture was diluted with
water (50 mL) and acidified using 1 M HCl solution. The solution was subsequently washed with
ethyl acetate (50 mL). The aqueous layer containing the target compound (as a hydrochloride salt) was
then basified to pH 10 using ammonia solution and extracted with CH2Cl2 (3
×
25 mL). The combined
organic phase was collected, washed with brine (50 mL) and dried over MgSO4. The organic layer was
evaporated by rotary evaporation and further dried in vacuum. When necessary, the crude product
was further purified by column chromatography [6].

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5. Conclusions
The
continuous
three-step
synthesis
of
N-diaminoalkylated
3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones was successfully realized in a one-flow
reactor. Compared to the conventional batch processes, the one-flow system exhibited superior isolated
yields. This is mainly caused by a reduction of isolation and purification steps. The developed reaction
protocols may be transferred to more advanced and custom-designed continuous flow tandem reactors
such as the Vapourtec UV-150 module [8,34]. The process furthermore demonstrates the synthesis
potential of arylacetic acids [35] as well as photodecarboxylations [36–38].
Supplementary Materials: Technical information on the flow reactor setup, further experimental details and
spectroscopic data can be found online.
Author Contributions: S.M. conducted the experiments. M.J.R. assisted with the chemical analysis and
interpretation of results. M.O. supervised the project and prepared the manuscript.
Funding: This research was funded by the Australian Research Council (ARC), grant number DP130100794.
Acknowledgments: S.M. thanks the Higher Education Commission Pakistan for providing a Scholarship under
the International Research Support Initiative Program.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3a–e, 4a–e, and 6a–e are available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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