Controlled photo-flow oxidative reaction (UV-FOR) platform for ultra-fast phthalide and API synthesis

Article abstract of DOI:10.1039/c8gc02320d

An integrated photo-flow oxidative reaction (UV-FOR) platform approach is presented for the synthesis of phthalides. The current protocol is catalyst-free, and uses economical and abundant hydro-carbons and hydrocarbon derivatives such as benzoic acid, benzene, and xylene, as starting materials. The reaction is performed using oxygen as a green oxidant in a time- and labour-efficient manner. This integrated approach has been shown to be successful in making a UV-FOR platform suitable for the on-demand synthesis of phthalides and their further syntheses to 2-arylmethylbenzoic acids and arylogous Michael addition products under relatively mild conditions. The current protocol was further extended to the gram scale synthesis of an ischemic stroke-relevant active pharmaceutical ingredient (API), 3-N-butylphthalide (NBP), in a continuous flow process.

Full text of DOI:10.1039/c8gc02320d

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Controlled photo-flow oxidative reaction (UV-FOR)
platform for ultra-fast phthalides and API synthesis
Dnyaneshwar Aand,‡ Sanjeev Karekar,‡ Bhushan Mahajan, Amit B. Pawar, Ajay K
Singh*
Received 31st May 2018,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract. An integrated photo-flow oxidative reaction (UV-FOR) building blocks for medicinal chemistry.3 Over the past few decades,
platform approach is
presented for the
varietites of methods have been developed in the synthesis of
phthalides such as oxidative lactonization (of ortho-
alkynylbenzaldehydes, 1,2- benzenedimethanol, and o-alkyl
aromatic carboxylic acid/ester),4-6 reduction of phthalic anhydrides
or phthalaldehydic acids,7-9 oxidation,10 nucleophilic addition,11
synthesis
of
phthalides.
The
current protocol is
catalyst-free, uses
condensation,12
substitution,13
cycloaddition,15
photocyclization etc.2,
electrophilic
and
nucleophilic
aromatic
economical
abundant
and
hydro-
cyclocarbonylation,14
benzannulation/
electrocyclization,17
rearrangement,16
18-21
carbon(s) as starting
materials (benzoic
Although, noble metal (Ru, Rh, Ir, Pd)
catalyzed approaches, appear to be the best and thus are of
22-24
acid,
xylene). The reaction
was performed
benzene,
particular interest.2,
However, the high price and limited
availability of these precious metals have spurred interest in metal-
free systems among the scientific community, especially photo-
oxidation, due to very similarities with natural process.25, 26 In this
using oxygen as
green oxidant in
a
a
time- and labour-efficient manner. This context, Schmalz et al. reported photo-oxidative lactonization
integrated approach is shown to be making the UV-FOR platform reactions of 2-benzoylbenzaldehyde. Due to high price and less
suitable for on-demand of phthalides and their further elaboration availability of starting materials, long reaction time (72 h) makes it
to 2-arylmethylbenzoic acids and arylogous Michael addition as less efficient process and alternatively to improve efficiency they
products under relatively milder conditions. The current protocol have used toxic NaCN as a catalyst.27 However, it becomes more
was further extended to gram scale synthesis of ischemic stroke critical for utilizing cyanide salt in API synthesis.28 To date, it is still
relevant active pharmaceutical ingredient (API), viz. 3-N- challenging to develop a catalyst-free protocol for phthalide
Butylphthalide (NBP) under continuous flow process.
synthesis employing economical abundant hydrocarbon as starting
material (o-methylsubstituted ketone),29-33 and oxygen as a green
oxidant, which will enables to expand the versatility with broad
ranging of phthalides toward the inaccessible level. However, the
first step of the process involves the activation of relatively inert
Csp3-H bond, and it subsequent oxidation to aldehyde functionality
Introduction
Phthalides have a long history in natural products/pharmaceuticals
and biologically active compounds and have been used in all areas,
from academia to industry.1, 2 The Phthalides are bicyclic nucleus
derived from the fusion of a γ-lactone with a benzene unit and are
considered as valuable pharmacological compounds and versatile
35
selectively without overoxidation.34, Pfau et al. reported batch
photo-oxidation reaction of 2-methylbenzophenones. However, it
results in formation of mixture of products which make this
protocol non-viable to due lack of selectivity in the product
formation.36 Therefore, there has been no clear-cut solutions for
controlled photo-oxidative phthalide synthesis in batch system.
Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad, India.
E-mail: ajaysingh015@gmail.com; ajaysingh015@iict.res.in
Therefore, scientific and
industrial use of photo-oxidative
†Electronic Supplementary Information (ESI) available: [method, chemical
phthalides formation has faced serious problems, which turned
away many potential workers in this field.
compound
DOI: 10.1039/x0xx00000x
‡These authors contributed equally.
information,
detailed
spectral
characterization].
See
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Scheme 1 Phthalides in bioactive molecules and evaluation of accessible methods (S, R, E, and S represent sampling, reaction, extraction,
and separation).
In this context, it is highly desirable to develop a safe and an
efficient chemical approach for controlled synthesis of phthalides
under a metal-free, acid or base-free and eco-efficient manner.
The continuous flow platform has emerged as an efficient
synthetic tool with attractive advantages such as high surface-to
volume ratio, and multi-step synthesis, excellent mass and heat
transfer, enhanced photo-irradiation, which leads to an
enhancement in selectivity and a reduction in the reaction
time.37-40 The strategies to predict and design integrated
platform capable of the effective oxidation necessitate a deeper
understanding of the factors such as multi-phasic reaction, one-
flow multi step reaction, safety operations, reliable scale-up,
complete integrated system that influence the reaction.41, 42 In
specific, a reduced mass transfer limitation and well-defined
interfacial areas achieved in gas−liquid segmented flows have
been utilized for chemical43 and physical screening of gas−liquid
processes. We have adapted segmented flow of uniformly sized
oxygen gas bubbles separated with liquid segments, which led to
reduced axial dispersion and provided control over mass transfer
time, volume fractions occupied by gases and liquids, and
gas−liquid Interfaces.44 To address the above mentioned
challenges, we decided to exploit flow technologies technologies
to achieve improved irradiation compared with a batch reactor
(Scheme 1).25, 26
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Table 1 Optimization of O2 segmental flow reaction to synthesize
phthalide (4) in catalyst free methods.
ratio of 2a: O2 and residence time furnished mixture of 3a (19-
58%) and 4a (10-65%) (Table 1, entries 2-4). Although we have
observed poor selectivity, the combined yields of 3a and 4a were
greatly improved as compared to entry 1. Next, we investigated
the dilution effect with the hypothesis that the aldehyde (3a)
intermediate could terminate the reaction; for the long exposure
time to convert to 4a. Expectedly, diluted reactant 2a gave
excellent combined yield with improved selectivity of 4a (82%)
(Table 1, entries 8&9). When reaction pressure was set at 145 psi
and reactor volume was fixed at 13.3 mL, the desired product 4a
formed in 92% yield (table 1, entry 11). When air was used as
oxygen source, it resulted in the lower yield of the product (table
1, entry 12). Notably, only medium pressure lamp is suitable for
the reaction (Supporting infromation Table 1, entries 13-15);
which may be due to fact that reactant molecules could able to
absorb 310-390 nm wavelength of light as confirmed by UV-
Visible spectroscopy (supporting information fig. S4). Assured of
the feasibility of the photo-flow system for practical applications,
we next investigated the solvent effect. The use of either of
DMSO or chlorobenzene as a solvent led to the complete
conversion and excellent selectivity within 12.1 min, whereas
1,4-dioxane, toluene, DCM, ethyl acetate, methanol, acetone,
and hexane failed to produce the desired product in appreciable
yield (see the supporting information). Moreover, to our
surprise, we could see formation of 4a product with poor
selectivity, when DCM, MeCN, and DMF was employed as a
solvent. Preferentially, we used DMSO instead of chlorobenzene
due to the latter’s toxic behavior and laborious column
chromatography separations.
Entry Flow rate µL/min Retention
% Yieldj
time (min.)
2a
O2
3a
4a
1a
95
70
12.3
5.6
5
3
2a
60
300
200
100
300
200
100
200
200
1000
1000
1000e
-
38
31
49
19
58
21
25
15
5
10
3a
20
9.1
18
4a
20
16.7
6.5
41
5a
10
NA
24
6a
10
9.5
7a
10
18.5
8.5
65
8b
40
71
9b
20
9.2
82
10c
11d
12c
16f
100
100
100
batch
12.1
12.1
12.1
4320
89
3
92 (85)
32
11
42
12
Reaction condition: (a) 2a (0.025 M) in DMSO, reactor loop
volume 2 mL; pressure 40 psi; medium pressure lamp (250 W),
(b) 2a (0.0125 M) in DMSO, reactor volume 2 mL, pressure 40 psi,
medium pressure lamp (250 W); (c) 2a: 0.0125 M in DMSO;
reactor volume 13.3 mL, medium pressure lamp (250 W); [d] 2a
(0.0125 M) in DMSO; reactor volume 13.3 mL, BPR (145 psi),
medium pressure lamp (250 W); [e] 2a (0.0125 M) in DMSO;
reactor volume 13.3 mL, BPR (145 psi), medium pressure lamp
(250 W), air [f] batch reactor, 2a (0.025 M) in DMSO, reactor
volume 50 mL, O2 gas balloon, medium pressure (250 W); [j]
yields are determined by GC-MS analysis with dodecane as
internal standard, at least three measurements were taken to
obtain an average yield; yield in parenthesis indicated isolated
yield.
After optimizing the reaction parameters for the synthesis
of phthalide, we were interested to develop the integrated total
process strategy (reaction, quenching, extraction and separation)
for the selective removal of waste chemicals/solvent in order to
reduce tedious workup steps. Due to the high boiling point (189
oC) of DMSO, it was troublesome to remove DMSO under
vacuum to isolate the products. To overcome this problem, we
switched from less volatile DMSO solvent to highly volatile
o
dichloromethane (DCM, boiling point 40 C) after the reaction in
the continuous flow. We adopted liquid–liquid extraction of
droplet microfluidics to isolate the synthesized phthalides in
DCM from the DMSO mixture, followed by separation of the
DCM mixture using a phase microseparator embedded with
hydrophobic PTFE membrane (Supporting Figure 32 & 33).37, 45 It
is well known that water is well miscible with DMSO to become a
hydrophilic aqueous-like phase, but immiscible with hydrophobic
DCM. To induce a sufficient difference in the polarity of
DMSO/water and DCM for conducting droplet-based extraction,
water was first infused at different flow rates to the DMSO
mixture coming from the photo-flow reactor at T-junction to
form a homogeneous DMSO/water phase in the PTFE capillary,
where we encountered tube-clogging, presumably due to the
insolubility of phthalides in water/DMSO mixture at the given
ratio. To solve this problem, we replaced the T-junction with X-
junction and connected the inlets of water and DCM (Fig. 1), for
Initialy, we infused the solution of 2-methylbenzophenone
2a (0.025 M) as a model substrate in dimethyl sulfoxide (DMSO)
and oxygen in a segmented-flow manner using a leak proof
syringe into a homemade photo-flow reactor to synthesize 3-
phenylisobenzofuran-1(3H)-one (Table 1, Supporting Movie S1).
The passage of a solution under stoichiometric molar ratios of
1.24 (O2/2-methylbenzophenone) through a 2 mL PFA coil held at
30 oC and was irradiated at medium pressure lamp with a 250 W
UV lamp at a 0.095 mLmin-1 flow rate (residence time = 12.3 min)
which led to the generation of typically brownish color solution
with 3% yield of the desired product 4a. The use of various molar

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Fig. 1 Synthesis of Phthalides; Reaction condition: UV medium pressure lamp 250 W; Substituted ketones (2): 0.0125 M in DMSO, reactor
volume 13.3 mL, PFA tubing (id: mm and length 17 meter), Temperature 25±5. Yields are based on isolated yield.
1
the formation of an organic–aqueous droplet, and real time
extraction through a PTFE capillary (id = 1 mm, length = 2.6 m,
vol. = 2 mL). Important factors for the extraction efficiency are
the flow-rate ratio of water to DCM and the contact time, as
determined by the capillary length for a given flow rate. A 2:1
ratio (1 mLmin-1 for water and 100 mLmin-1 for DCM) and 1.7 min
retention time were sufficient for the extraction of synthesized
phthalides. As shown in Fig. 1, the biphasic stream leaving the
extraction stage was separated into aqueous and organic
streams with a microseparator. A homemade polyethene film
and high density polyethylene (HDPE)-based microseparator was
constructed with a PTFE film membrane placed in the middle of
the separator. The salient features of the home made
microseparator are its easy fabrication and its excellent
mechanical, thermal, and chemical stability (see the supporting
information). In contrast, a metal-based microseparator is not
only difficult to fabricate, but also could be subject to possible
corrosion. Only the phthalide-containing organic phase wets the
thin fluoropolymer membrane (pore size = 0.45 m) and is
allowed to pass through the holes to the bottom of the
separator, thereby completing the DCM–water separation.
Complete separation can be achieved by regulating the back
pressures, thereby allowing transfer of the purified phthalide in
DCM to the microreactor (Fig. 1).
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Fig. 2 On demand synthesis: reaction condition for synthesis of 5a: methanol (flow rate 100 lmin-1) cylindrical shape cartridge (6 cm
length  0.3 cm diameter), temperature (RT); pressure 145 bar; 10% Pd/C (80 mg); reaction condition for synthesis of 6a: stock solution
o
of B: chalcone (0.0115 M in toluene) + KOH (10 mol%) + 18-crown-6 ether (10 mol%); PFA tubing (id: 1 mm and length 13 m) at 0 C.
Yields are based on overall isolated yield.
After the development of fully integrated process for the
synthesis of phthalide, we were interested to test the scope and
limitation of this strategy. As shown in Figure 1, we have
successfully developed the UV-FOR conditions (photo-oxidation
and cyclization (12.1 min), and extraction/separation (1.8 min)
that has emerged as a superior alternative for photo-oxidation of
o‑alkylphenyl ketones for the synthesis of phthalides with good
to excellent yields (70-91% yields). A range of substrates having
electron-donating and electron-withdrawing substituents as
starting materials (substituted o‑alkylphenyl ketones, 2b-2l) were
well tolerated furnishing the required phthalides in good yields.
It is worth to mention that in these substrates exclusive site
selective oxidation of the methyl group ortho to the carbonyl was
observed without affecting the other aromatic methyl
substituents (4b-4l).
lignans.17, 49 This reductive cleavage of phthalides can mostly be
performed by the hydrogen molecule (H2) with palladium on
carbon.50, 51 However, molecular H2 is dangerous to handle and
requires extreme care during the process to avoid any disasters
caused by even small leakage during production, storage, and
53
transportation.52, Therefore, it would be highly desirable to
develop a safer protocol and in our view, H-cube is the best
option.54 Prior to a connect multi-valve system for various
compounds synthesis, we separately optimized the reaction
conditions for continuous one-flow synthesis of 2-
arylmethylbenzoic acids.47 2-Arylmethylbenzoic acid was
obtained in overall good yield (~82%) (Fig. 2, 5a) in 16 min by the
fully integrated UV-FOR platform (phthalides generation (12.1
min), extraction and separation (1.8 min), and in situ
hydrogenation (2.1 min). In contrast, the traditional batch
methods require several hours/days to produce 2-
arylmethylbenzoic acid.55
Next, we were interested to demonstrate the practicability
of our present integrated UV-FOR platform for the synthesis of 3-
N-butylphthalide which is an ischemic stroke relevant natural
products. 3-N-Butylphthalide (NBP) is a class of compounds
which are mostly isolated from the seeds of Apium graveolens
Linn, and does not always meet demand. Therefore,
supplementing NBP with a synthetic manufacturing process from
more abundant precursors is a promising way.46 For this purpose,
substrate 2m was prepared from readily available 2-
methylbenzoic acid through a known procedure.47 The present
UV-FOR platform provides a simple and straightforward access to
NBP from easily synthesized starting material 2m, and O2 with
70% yields. As pointed out earlier, photochemistry has a great
potential for continuous chemical manufacturing and the
strategies introduced here are applicable to produce NBP in gram
scale.48 By using this UV-FOR platform, continuous for three days
one can able to gram scale synthesis of NBP.
Scheme 2 Proposed reaction pathway.
Late stage functionalization (LSF) holds the potential to
revolutionize the logic of chemical synthesis and open new ways
to formulate innovative natural products and medicines.56,
57
The reductive cleavage of phthalides is an important
reaction for the synthesis of 2-arylmethylbenzoic acid, which are
valuable intermediates in the synthesis of anthrones,
isoquinoline, polycyclic aromatic hydrocarbons, and natural
Recently, arylogous Michael addition reactions represents one of
the best method to functionalize phthalides with highly improved
diastereoselectivities.58 We have chosen chalcone and 3-

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phenylisobenzofuran-1(3H)-one as the model substrates for late enolization system, multi-step reaction, toxic or noxious regents.
stage functionalization of pthalides.47 Control of several parameters More importantly, the system provided here would enable a future
such as temperature, retention time, catalyst amount, solvent automation of laboratory and industry to produce on-demand
system etc were necessary to fine-tune the reaction system. Finally, chemicals in the areas of drug discovery, natural products, materials
we found that within 60 min (phthalides generation (12.1 min), synthesis and biology.
extraction and separation (1.8 min), and arylogous Michael addition
(51.0 min), gave overall 80% yield with 96.5:3.5
diastereoselectivities of (6a). The conventional batch process
required 24-72 h time (phthalide synthesis (12-60 h), extraction (1-3
h), separation (2-12 h), and arylogous Michael addition (5-20 h).58
After having optimal flow conditions for all the steps, we have
successfully inter-connected all the reactors to make a completely
integrated UV-FOR platform for multi-step synthesis of 2-
arylmethylbenzoic acid and arylogous Michael addition reaction
with 80% and 82% yields respectively.47
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
A.K.S. thanks Department of Science and Technology, New Delhi
(Govt. of India) (DST), New Delhi, for the INSPIRE Faculty Award and
Early Carrier Research Award. Financial assistance received from
the DST and Science and Engineering Research Board (SERB) by
sponsoring project no. DST/INSPIRE/04/2016/000247 and
ECR/2017/000208 are gratefully acknowledged. One of the authors
(Sanjeev Karekar) is thankful to Council of Scientific & Industrial
Research (CSIR), New Delhi, for providing Junior Research
Fellowship (JRF). We gratefully acknowledge Director, CSIR-IICT for
his support and encouragement.
In order to determine the reaction mechanism, several control
experiments were performed.47 In the beginning of the reaction, 2a
is oxidized to a aldehyde species 3a by the photo-oxidation and
subsequently, isomerization of 3a to 4a via multi-step pathways as
proposed in Scheme 2. We observed sequential multistep oxidation
in the early stage of reaction (2 min), and again this was confirmed
using control experiments.47 Then we looked at the possibility of a
free-radical pathway, and verification of its origin. For this purpose,
we added radical scavengers such as tetramethylpiperidine-N-oxide
(TEMPO) to the reaction mixture under identical reaction
conditions. As expected, we could not get any desired product.
However, our attempt to trap and isolate benzyl radical with
TEMPO were unsuccessful. This suggests that the current photo-
oxidation reactions may be proceed via a free radical pathway.
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Green Chemistry
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DOI: 10.1039/C8GC02320D
Green Chemistry
COMMUNICATION
Table of Contents
we have developed a time-efficient, integrated and continuous flow
platform for real-time, high-throughput studies of phthalide and API
synthesis from ketone−O2 reactions.
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