E - Z isomerization of 3-benzylidene-indolin-2-ones using a microfluidic photo-reactor

Article abstract of DOI:10.1039/d0ra05288d

Here, we report controlled E-Z isomeric motion of the functionalized 3-benzylidene-indolin-2-ones under various solvents, temperature, light sources, and most importantly effective enhancement of light irradiance in microfluidic photoreactor conditions. S

Full text of DOI:10.1039/d0ra05288d

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E–Z isomerization of 3-benzylidene-indolin-2-
ones using a microfluidic photo-reactor†
Cite this: RSC Adv., 2020, 10, 28630
ab
a
Veeramalla Ganeshab and Ajay K. Singh
*
*
Chada Raji Reddy,
Here, we report controlled E–Z isomeric motion of the functionalized 3-benzylidene-indolin-2-ones under
various solvents, temperature, light sources, and most importantly effective enhancement of light irradiance
in microfluidic photoreactor conditions. Stabilization of the E–Z isomeric motion is failed in batch process,
which might be due to the exponential decay of light intensity, variable irradiation, low mixing, low heat
exchange, low photon flux etc. This photo-m-flow light driven motion is further extended to the
establishment of a photostationary state under solar light irradiation.
Received 16th June 2020
Accepted 21st July 2020
DOI: 10.1039/d0ra05288d
rsc.li/rsc-advances
Functionalized 3-benzylidene-indolin-2-ones are an important ones remains
structural motif in organic chemistry and are embedded in (Scheme 1).
a challenging task and highly desirable
many naturally occurring compounds.1 They found wide
On the other hand, selective E/Z stereo-isomerization of
applications in molecular-motors,2 energy harvesting dyes,3 alkenes has been well established using various methods in the
pharmaceutical chemistry (sunitinib, tenidap),4 protein kinase presence of light stimuli,15a cations,15b halogens or elemental
inhibitors,5 pesticides,6 avors,7 and the fragrance industry.8 In selenium,16 palladium-hydride catalyst,10 cobalt-catalyst,17 Ir-
the last few decades, numerous protocols have been developed catalyst,18 organo-catalysts.19 Among these, light-induced pho-
for the synthesis of novel indolin-2-ones. For instance, palla- tostationary E/Z stereoisomerization is very attractive, due to its
dium (Pd)-catalysed intramolecular hydroarylation of N-aryl- close proximity towards the natural process. In recent years,
propiolamides,9 Knoevenagel condensation of oxindole and several light-driven molecular motors (controlled motion at the
aldehyde,10 two-step protocols such as Ni-catalyzed CO2 inser- molecular level), molecular propellers,20 switches,21 brakes,22
tion followed by coupling reaction,11 Pd-catalysed C–H turnstiles,23 shuttles,24 scissors,25 elevators,26 rotating
functionalization/intramolecular
alkenylation,12
Pd(0)/ modules,27 muscles,28 rotors,29 ratchets,30 and catalytic self-
monophosphine-promoted ring–forming reaction of 2- propelled objects have been developed.31 Further, equipment's
(alkynyl)aryl isocyanates with organoboron compound, and relying on molecular mechanics were rapidly developed,
others.13
particularly in the area of health care.
Knoevenagel condensation is one of the best methods for the
preparation of 3-benzylidene-indolin-2-ones, but oen it gives
mixture of E/Z isomeric products. Otherwise, noble metal-
catalysed protocols received enormous interest. However, the
limited availability, high price, and toxicity of these metals
diminished their usage in industrial applications. Therefore,
several research groups have been engaged in search of an
alternative greener and cleaner approach under metal-free
conditions. To address the diastereoisomeric issue, Tacconi
et al. reported a thermal (300–310 ꢀC) isomerization reaction of
3-arylidene-1,3-dihydroindol-2-ones,14 which suffers from poor
reaction efficiency and E/Z selectivity. Therefore, trans-
formations controlling E/Z ratio of 3-benzylidene-indolin-2-
aDivision of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500007, India. E-mail: rajireddy@iict.res.in;
ajaysingh015@iict.res.in
bAcademy of Scientic and Innovative Research (AcSIR), Ghaziabad 201002, Uttar
Pradesh, India
Scheme 1 Functionalized 3-benzylidene-indolin-2-ones and alkenes
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra05288d
in bioactive compounds and the accessible methods.
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syntheses, excellent mass and heat transfer, which lead to
signicant decrease the reaction time with improved yield or
selectivity over batch reactors.33a,34 To address the aforemen-
tioned challenges, it is essential to develop a highly efficient
photo-microchemical ow approach for the controlled isomer-
ization of functionalized 3-benzylidene-indolin-2-ones in
catalyst-free and an environment friendly manner.
Results and discussion
The required substrate, (E)-3-benzylideneindolin-2-one (3a), was
synthesised following the literature Knoevenagel condensation
procedure (details in ESI†).14 As most of the E to Z isomerization
of alkenes are contra-thermodynamic in nature, to appropri-
ateness for the photostationary state, electromagnetic radia-
tion, irradiance time, temperature, solvent, and aptness of
reactor needs to be optimized. Accordingly, we were interested
to nd the suitable electromagnetic radiation which can
interact with the starting materials. In this regard, the UV-
Visible absorption spectrum of the 3a in DMF is tested, which
showed absorption peak close to output spectrum of the
medium pressure Hg lamp (Fig. 1). It suggests that the medium
pressure Hg lamp is suitable for the photo-chemical reaction.
Next, the residence time in photo-ow condition is optimized,
using a solution of 3a (0.25 M) in DMF solvent and infuse into
a homemade photo-ow reactor through the leak-proof syringes
to the synthesis of (Z)-3-benzylideneindolin-2-one 4a (Table 1,
entry 1). The solution 3a, passing through a commercially
available high purity peruoroalkoxy (PFA) tubing (inner
Fig. 1 UV-Vis spectroscopy of the (E)-3-benzylideneindolin-2-one
(3a) and (Z)-3-benzylideneindolin-2-one (4a) in DMF solvent.
Till date, controlled photo-isomerization of functionalized 3-
benzylidene-indolin-2-ones is one of the puzzling problems to
the scientic community. Photochemical reactions in batch
process have serious drawbacks with limited hot-spot zone due
to inefficient light penetration with increasing light path
distance through the absorbing media, and the situation
becomes poorer when the reactor size increases.32,33 In contrast,
the capillary microreactor platform has emerged as an efficient
the articial tool with impressive advantages, such as excellent
photon ux, uniform irradiation, compatibility with multi-step
Table 1 Preliminary study for a photo-flow isomerization of oxyindole under a standard light conditiona
Yielde (%)
Residence time
(min)
4a
3a
Entry
Flow rate (mL minꢁ1
)
Temp. (ꢀC)
(Z-isomer)
(E-isomer)
1
2
3
4
5
6
7
8
100
200
50
20
10
20
20
10
20
15.7
7.8
31.4
78.5
157
78.5
78.5
157
78.5
960
30
30
30
30
30
20
10
10
10
10
10
12
7
18
44
44
56
88
93
82
56
56
44
76 (71)f
76
18
NA
76
24 (19)f
24
82
100
24
9b
10c
11d
NA
100
78.5
a
Reaction conditions: 3a: 0.25 M in dimethylformamide (DMF) solvent, reactor volume 1.57 mL (PFA tubing id 1000 mm and 2 meter length), light
source medium pressure 250 W Hg lamp. Reaction conditions: Light source blue LED (4 W, light out-put 465 nm; 10 lux per cm2, brand name
Lizone). Reaction conditions: Batch process. Reaction conditions: Reactor volume 7.85 mL. Reaction conditions: Yields are based on the
LC-MS. f Isolated yield in parenthesis.
b
c
d
e
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Having the preliminary optimized photo-ow process system
for the isomerization reaction of 3-benzylideneindolin-2-one
(3a), we turned our attention towards integrating one-ow
process to reduce the laborious extraction and the work-up to
get 4a from the DMF solution, as depicted in Fig. 3.33a,36 Due to
high boiling point of the solvent, DMF (153 ꢀC), it is difficult to
evaporate to obtain the product using rotary evaporator. Thus,
we switched to extract the product with low boiling solvent,
(dichloromethane (DCM)/diethyl ether (DEE)/and industrial
favourable t-butyl methyl ether (MTBE)), to favourably isolate
the product as a separable mixture of 4a and 3a. It is well-known
phenomenon that DMF (hydrophilic solvent) prefers to move
into aqueous-phase and is partially miscible with DCM (rela-
tively hydrophobic solvent). As a result, water (ow rate ¼ 1.25
mL minꢁ1) and extracting solvent DCM (ow rate ¼ 1.25
mL minꢁ1) were infused into an X-junction to the DMF mixture
that owed from the exit of the photo-reactor to form the
aqueous-organic droplet in the PTFE capillary to accomplish the
extraction of isomer 4a into the DCM droplet within 0.2 min
residence time (see ESI Video S1†). Next, to separate the
aqueous organic droplet, we were adapted our previously
designed and commercialized continuous ow liquid–liquid
micro-separator.37 Notably, the completion of the DCM–water
separation obtained in 0.1 min of the residence time. Notably,
additional sodium sulphate or magnesium sulphate is not
needed to dry the product.
Fig. 2 Time profile. Reaction condition: 3a: 0.25 M in DMF, reactor
volume 1.57 mL (PFA tubing) light source medium pressure 250 W Hg
lamp; conversions are based on LC-MS analysis.
diameter (id) ¼ 1000 mm, length ¼ 2 meter, volume ¼ 1.57 mL)
ꢀ
held at 30 C was irradiated with 250 W medium pressure UV
lamp at a 100 mL minꢁ1 ow rate (irradiation time ¼ 15.7 min)
which typically leads to the formation of the brownish colour
solution having 12% (yield) of the 4a product (Table 1, entry 1).
Next, the reactions at various temperatures and residence times
were carried out to nd the optimal condition, with an
improved yield of 4a (Table 1, entries 2 to 6). To our delight, 4a
was obtained in 76% yield at 10 ꢀC with 20 mL minꢁ1 ow rate in
DMF solvent along with 3a (24%), separable by column chro-
matography (Table 1, entry 7, Fig. S2†). Moreover, the increment
of the residence time 78.5 to 157 min failed to increase the yield
of 4a (Table 1, entry 8, Fig. 2) by providing the energy-efficient
photo-ow system. Further, when the medium pressure 250 W
Hg lamp was replaced with blue LED 4 W, the desired product
4a formed only in 18% yield (Table 1, entry 9). The reaction in
batch process under the ow-optimized stock solution condi-
tion failed to produce any desired product 4a (Table 1, entry 10),
which may be due to the exponential decay of light intensity in
bulk solution, low light irradiation, low mixing, low heat
exchange and low photon ux.35
In order to improve the photo-ow reaction efficiency, we
next investigated the effect of solvents (Table S1†) and found
that both. DMF and DMA as good solvents to provide a decent
yield in the isomerization at 10 ꢀC in 1.3 h, while hexane failed
to stabilize the photo stationary state. Having the optimized
controlled-photostationary state in hand on milligram scale, we
next moved toward the process intensication reactor in gram
scale. The scale-up synthesis of 4a was examined using 7.85 mL
volume reactor by the extension ((inner diameter (id) ¼ 1000
mm, length ¼ 10 meter) of PFA tubing (Table 1, entry 11). The
long tubing reactors were irradiated with a medium pressure
lamp to maintain the adequate light intensity, and the solution
of 3a was passed to the reactor with a ow rate of 100 mL minꢁ1
,
Fig. 3 Reaction condition: 3a: 0.25 M in DMF, reactor volume 7.8 mL
(PFA tubing id 1000 mm and 10 meter length) light source medium
pressure 250 W Hg lamp; yields are based on isolated Z-isomer and
parenthesis yield based on isolated E-isomer.
although maintaining 10 ꢀC to produce 4a in 76% yield,
resulting in ca. 6.0 g dꢁ1 productivity (see ESI Video S1†).
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Fig. 4 Isomerization under the solar irradiation. Reactor volume 7.8 mL (PFA tubing id 1000 mm and 10 meter length) light source sunlight; yield
is based on isolated yields.
Aer the successful development of an integrated system for controlled condition as well mixture of light (solar irradiance)
the photostationary state for the conversion of 3- condition to form the desired functionalised (Z)-3-
benzylideneindolin-2-one (3a) to 4a, we next examined the benzylideneindolin-2-ones. This integrated platform can be
scope and limitations of the continuous ow system as well as useful to those syntheses where the photostationary state for E–
the effect of the directing group. Toward this, a few electron- Z isomerization involves in drug discovery, natural products,
releasing and electron-withdrawing 3-benzylideneindolin-2- biology, energy, and environmental chemistry. Genuine-time
one derivatives were prepared using substituted aldehydes. reaction control for photostationary state for E–Z isomeriza-
Notably, the methyl (3b), methoxy (3c), nitro (3d), cyano (3e), tion under unstable irradiance (cloudy or rainy days) work is
uoro (3f), chloro (3g), bromo (3h) substituted 3- under progress in our laboratory.
benzylideneindolin-2-ones underwent photostationary state to
afford the corresponding Z-isomer derivatives 4b to 4h, in good
yield (53–71%).
Conflicts of interest
Having explored the photostationary state for E–Z isomeri-
zation under xed wavelength, as an articial light source,
temperature, and solvent conditions, we became interested to
develop the photostationary state under the sunlight irradiation
(to save the power and present domain application).33a The
homemade cylindrical shape capillary reactor is suitable only
The authors declare no competing nancial interest.
Acknowledgements
One of the authors (V. G.) is thankful to the Council of Scientic
&
Industrial Research (CSIR), New Delhi, for providing
for the laboratory-controlled condition. Hence,
a novel
a University Grant Commission-Senior Research Fellowship
(UGC-SRF). A. K. S. thanks Department of Science and Tech-
nology, New Delhi (Govt. of India) (DST), New Delhi, for the
INSPIRE Faculty Award (DST/INSPIRE/04/2016/000247) and
Early Carrier Research Award (ECR/2017/000208). CSIR-IICT
Communication No. IICT/Pubs./2020/116.
arrangement of capillary microreactor needed for highly effi-
cient solar light harvesting, which is unprecedented. The newly
designed solar panel microreactor (details fabrication is
provided in ESI, Fig. S3†) was placed on roof-top to expose to
daylight (the average amount of solar emission 5.25 kW h per
m2per day in Hyderabad, India, manually controlled light
intensity > 50 000 lux) to verify the photostationary state of 3a.38
As shown in Fig. 4, the solution of 3a in DMF (0.25 M) infused
into the solar panel PFA capillary microreactor with a syringe
pump. It was observed that the optimal conversion to 4a was
50% (isolated yield) in the presence of sunlight. Though the
isomerization is low, the overall strategy minimized the labo-
rious extraction and separation process with 0.166 g hꢁ1
productivity.
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