Microfluidic Visible-Light Paternò–Büchi Reaction of Oxindole Enol Ethers

Article abstract of DOI:10.1002/ejoc.202001057

A novel microfluidic visible-light process for the functionalisation of oxindoles is reported. The chemistry is based on the reactivity of the corresponding enol ethers, which participate in a site-, regio- and diastereoselective [2+2] heterocycloaddition (Paternò–Büchi) process. The mild reaction conditions, the use of available ketones, together with the high generality (23 examples) and robustness (up to gram scale) make this process a useful synthetic platform for the construction of structurally strained heterocycles.

Full text of DOI:10.1002/ejoc.202001057

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Microfluidic Visible-Light Paternò-Büchi Reaction of Oxindole
Enol Ethers
Authors: Pietro Franceschi, Javier Mateos, Alberto Vega Peñaloza,
and Luca Dell'Amico
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001057
Link to VoR: https://doi.org/10.1002/ejoc.202001057
01/2020

10.1002/ejoc.202001057
European Journal of Organic Chemistry
COMMUNICATION
Microfluidic Visible-Light Paternò-Büchi Reaction of Oxindole
Enol Ethers
Pietro Franceschi, Javier Mateos, Alberto Vega-Peñaloza,* and Luca Dell’Amico*[a]
[a]
P. Franceschi, J. Mateos, Dr. A. Vega-Peñaloza, Dr. L. Dell’Amico
Department of Chemical Sciences
University of Padova
Via Marzolo 1, 35131 Padova, Italy
E–mail: luca.dellamico@unipd.it,
https://dellamicogroup.com/
Abstract:
A
novel microfluidic visible-light process for the
process, known as Paternò–Büchi (PB) reaction, involves the
generation of the carbonyl excited state which reacts with diverse
types of olefins.11 We thus wondered if the oxindole enol ethers
could participate in an unprecedented PB process, delivering a
C2-C3 difunctionalised indolinic products (Scheme 1c).
functionalisation of oxindoles is reported. The chemistry is based on
the reactivity of the corresponding enol ethers, which participate in a
site-, regio- and diastereoselective [2+2] heterocycloaddition
(Paternò–Büchi) process. The mild reaction conditions, the use of
available ketones, together with the high generality (23 examples) and
robustness (up to gram scale) make of this process a useful synthetic
platform for the construction of structurally strained heterocycles.
Scheme 1. C2 vs C3 functionalisation of the oxindole scaffold. a) Metal- and
organocatalytic methods; b) light-driven and transition-metal-based methods; c)
this work – C2-C3 light-driven oxindole functionalisation.
The derivatization of biorelevant heterocyclic scaffolds is a
valuable target in organic synthesis.1 In particular, the oxindole
core is present in numerous naturally occurring compounds and
pharmaceutically active ingredients.2 Its structural modification
allows the discovery of new drug candidates and the
implementation of structure-activity-relationship studies.2d In
general, the synthetic methodologies relied on the pronucleophilic
nature of the oxindole, including: acylation, alkylation, and
condensation reactions with carbonyl compounds.1 A broad array
of electrophilic partners can be efficiently activated by means of
organo- or metal-catalysis (Scheme 1).3a Recently, the
development of new synthetic strategies towards oxindole
functionalisation has focused on the installation of the C3
quaternary center, present in a variety of natural alkaloids.1,4
Several methods have exploited the reactivity of the
corresponding oxindole enolate or enol ether.1-3 For example,
metal- or organocatalytic approaches, involving aldol-type
reactions, or 1,4-additions have been developed using oxindoles
as pronucleophiles (Scheme 1a).1,5 On the other hand, the
introduction of an aryl group at C3 can be accomplished via
transition-metal catalysis with aryl electrophiles and arylboronic
acids (Scheme 1b).6 An alternative metal-free approach for the
installation of a sp3-sp2 bond encompasses the activity of an
electron-donor-acceptor
(EDA)
complex.7
Despite
the
advancements of the field, synthetic methodologies for the
quaternisation at C3 with the concomitant modification at C2 are
still missing to date. Structural modification at both positions will
provide complex indolinic polycyclic scaffolds, with wide
occurrence in bioactive molecules.2 On the other hand, the
installation of an oxetane moiety within the oxindole scaffold is
particularly appealing thanks to the biological relevance of this
four-membered pharmacophore.8 However, this represents a
challenging synthetic target due to the high ring strain and to the
low reactivity at C2. A sustainable strategy to fill this gap can be
provided by the use of light-generated radical intermediates.9,10
In fact, under light irradiation various heterocyclic systems
effectively participate in photocycloaddition transformations with
carbonyl compounds.10 The light-driven [2+2] heterocycloaddition
The effective realization of such a general method is complicated
by several synthetic issues, including: i) the presence of light-
driven side reactions, such as the dimerization of the carbonyl
compound, ii) the site-, regio- and stereoselectivity, iii) and
possible desilylation pathways. Additionally, its possible progress
towards large-scale synthesis is hampered by the need of UV-
light sources (Hg or Xe lamps) and specific batch setups. In this
scenario, the use of a visible-light microfluidic photoreactor (MFP)
offers decisive advantages to implement a safer and more general
version of the reaction. Indeed, the MFP setup overcomes some
fundamental issues related to photochemical batch protocols,
such as: scale up, homogeneous irradiation, reproducibility and
generality.12
1
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10.1002/ejoc.202001057
European Journal of Organic Chemistry
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product, overcoming the classical limitations of UV-light driven PB
procedures.
Pietro Franceschi got his M. Sc. in Chemistry
in 2019 at the University of Padova (Italy), under
the supervision of Dr Luca Dell’Amico. Shortly
after he started his PhD in Molecular Sciences
at the same institution, under the co-supervision
of Prof. Andrea Sartorel and Dr Luca Dell’Amico.
Pietro is currently working on the development
of new light-driven methods towards the
stereoselective fixation of CO2.
We initiated our studies by testing the silyl enol ether (SEE) 1a (3
equiv.), derived from the corresponding 3-benzyloxindole, in the
presence of benzophenone 2a under a MFP equipped with a 365
nm light source.13 3-Benzyl SEE 1a was selected aiming to
generate a valuable all-carbon quaternary stereocenter within
product 3. Unfortunately, under these conditions we obtained only
12% yield of the product 3, along with the undesired
benzophenone homodimer (Table 1, entry 1). This undesired
side-product forms from the triplet (T1) excited state of 2a.14 We
thus reversed the reagent ratio, increasing the formation of 3 up
to 42% yield as single diastereoisomer (entry 2). Regrettably, its
purification was complicated by the presence of larger amounts of
ketone homodimer. A possible solution to circumvent this problem
was recently reported to be the use of visible-light emission
sources.15 In fact, under visible-light irradiation an inferior amount
of 2a T1 excited state is generated, attenuating the ketone
homodimerization and channelling the reactivity towards the
intended PB product 3. Irradiation of the same reaction mixture at
405 nm resulted in 96% yield of 3 (entry 3) and no ketone
homodimer was detected. Gratefully, we were able to reduce the
residence time up to 12 min. In this case (entry 4), the product 3
Javier Mateos obtained his M. Sc. in Organic
Chemistry from the University of Barcelona
(Spain) in 2017. Thereafter, he moved to Italy to
pursue his doctoral studies in Molecular
Sciences under the supervision of Dr Luca
Dell'Amico at the University of Padova. His
scientific interests focus on the use and
mechanistic elucidation of novel photochemical
transformations for the functionalization of
feedstock materials.
Alberto
Vega-Peñaloza
graduated
in
Pharmaceutical Chemistry at the Universidad
Michoacana (Mexico). He obtained a Ph.D. at
the CINVESTAV-IPN under the supervision of
Prof. Eusebio Juaristi. In 2014 he joined the
group of Prof. Paolo Melchiorre at ICIQ in Spain
as postdoctoral researcher. In 2018, he was
awarded the Seal of Excellence UniPD grant by
the University of Padova (Italy), where is
currently working. His main research interest
involves the development of novel organo- and photocatalytic systems to
provide sustainable synthetic methods.
was obtained in excellent yields (98%) as
a
single
diastereoisomer, boosting the performance of the system.
Interestingly, when the reaction was performed using an
equimolar mixture of reagents, the system maintained decent
level of reactivity (entry 5). Importantly, the classical batch setup
showed inferior performances (18% yield in 180 min), indicating
the key role of the MFP setup (entry 6 vs entry 4).12 As expected,
the process was completely inhibited in the absence of light (entry
7).
Table 1. Optimization of the reaction conditions.
Luca Dell’Amico completed his Ph.D. in
Organic Chemistry at the University of Parma
(Italy), under the supervision of Prof. Franca
Zanardi in 2014. He spent a research period at
the Center for Catalysis, Århus Univesity
(Denmark), working with Prof. Karl Anker
Jørgensen, and he was Marie-Curie cofound
fellow in the group of Prof. Paolo Melchiorre at
ICIQ, Tarragona (Spain). Since 2017 he started
his independent career at the Padova University
(Italy). He was awarded the G. Ciamician Medal
2019 and the Thieme Chemistry Journals Award 2020. His research focuses
on the development and mechanistic understanding of new photochemical
processes under batch and flow conditions.
We herein report the effective realisation of a microfluidic
photocatalyst-free visible-light PB process between oxindole enol
ethers and aromatic ketones under extremely mild reaction
conditions and complete atom-economy. Strained indolinic
polycycles are accessed with excellent site-, regio-, and
diastereocontrol. Remarkably, the quaternisation of C3 and the
concomitant C2 functionalisation is accomplished within a single
synthetic operation. The use of visible light guarantees a clean,
safe and efficient process. The generality of the microfluidic
method is demonstrated for a large variety of substrates (up to
>98% yield and >20ꢀ:ꢀ1 dr). Remarkably, the process can be easily
scaled up delivering up to 1.18 g of difunctionalised oxindole
[a] Reactions in PhMe at rt, 1 0.1 mmol, and 2 3 eq. (See SI). dr inferred by 1H-
NMR analysis on the crude reaction mixture. All yields refer to isolated yields.
ID = internal diameter. Boc = tert-butoxycarbonyl, TBS = tert-butyldimethylsilyl.
[b] Reaction in batch. [c] Reaction in the dark.
With the optimised reaction conditions in hand, we next evaluated
the generality of the visible-light PB process. As reported in Table
2, there is a significant tolerance for structural and electronic
variation on the oxindole enol ether. Both electron-withdrawing
(EW) and electron-donating groups (EDGs) at the ortho, meta and
para positions of the benzyl ring furnished the corresponding
2
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10.1002/ejoc.202001057
European Journal of Organic Chemistry
COMMUNICATION
tricyclic products 3, 5-10 in high yields, spanning from 64% to 98%
with complete regio- and diastereocontrol. The relative
stereochemistry of the products was inferred by X-ray on the
single crystal of compound 3. Also SEE of 3-methyl oxindole
resulted in the formation of 11 as single regio- and diastereisomer
in 98% yield. Other types of enol ethers were found competent
substrates under the microfluidic conditions, delivering products
12, 13 and 14 in 77%, 41% and 57% yield, respectively. Also
different N-protected oxindoles can participate in the reported
microfluidic PB process, delivering product 14 and 15, in 57% and
50% yield and with high fidelity (>20:1 dr). Oxindole SEEs bearing
both EW- and EDGs at different position of the oxindole core
formed the desired PB products 16 and 17 in good chemical yield
(60% and 70%). We next examined the versatility of the reaction
with respect to the ketone counterpart. Remarkably, differently
substituted benzophenones with both ED- and EWGs performed
well, delivering the corresponding products 18-23 in yields
spanning from 41% to >98% and excellent regio- and
diastereocontrol (>20:1). As limitations of the present method,
acetophenone and benzaldehyde failed to deliver the
corresponding oxetane products. This was attributed to their
extremely low absorption under visible-light.
We next assessed substrates with additional reactive double
bonds (Table 2b). Compound 24, bearing an allyl functionality,
was formed with full site-selectivity (78% yield). This encouraged
us to evaluate the possibility of extending the PB reactivity to
furan-containing enol ethers. Remarkably, product 25 formed in
74% yield as a single site-, regio- and diastereoisomer. To
understand the reason of the observed site-selectivity we
performed a competition experiment in the presence of furan 26
(Table 2c). In this case we used 2 equiv. of bezophenone 2 and 1
equiv. of 1a and 26. After 12 min product 3 formed in 63% yield
along with traces of 27, thus indicating the superior reactivity for
the oxindole-SEE double bond, despite its sterically hindered
nature.
Table 2. a) Scope of the PB reaction of oxindole enol ethers. b) Site-selective reactions in presence of additional double bonds. c) Competition experiment in the
presence of furan. TIPS = triisopropylsilyl. Cbz = carboxybenzyl.
3
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induced electron transfer (PET), from the electron-rich SEE to the
benzophenone is precluded by the high GPET (0.93 eV,
corresponding to 21.45 Kcal∙mol-1).
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In conclusion, we have disclosed that oxindole enol ethers can
engage in visible-light PB processes. Conventional limitations of
PB processes such as i) the presence of side-reactions, ii) the low
site-, regio-, and diastereoselectivity, and iii) difficult scalability,
are overcame thanks to the implementation of a MFP setup. The
method is general and can be easily applied to a variety of
different substituted oxindole-derivatives and aromatic ketones
with yields up to >98% and virtually complete site- regio- and
diastereocontrol. Finally, the reaction was scaled up converting 1
g of 3-benzyloxindole 28 into up to 1.18 g of oxetane product 3.
The utilisation of such a valuable intermediate as a building block
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[16] During the reviewing process of this manuscript two remarkable
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have appeared: a) J. Zheng, X. Dong, T. P. Yoon, Org. Lett. 2020, doi:
Keywords: synthetic photochemistry • [2+2] cycloaddition •
microfluidic photoreaction • oxindole functionalisation • flow
synthesis
4
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European Journal of Organic Chemistry
COMMUNICATION
10.1021/acs.orglett.0c02314; b) K. A. Rykaczewski, C. S. Schindler, Org.
Lett. 2020, 10.1021/acs.orglett.0c02316.
Acknowledgements
This work was supported by the CariParo Foundation, Synergy –
Progetti di Eccellenza 2018 (L.D.), and the Seal of Excellence
@unipd PLACARD (A. V.). Prof. Giorgio Pelosi is acknowledged
for performing the X-ray analysis. Chiesi Farmaceutici SpA and
Dr Ferdinando Vescovi are acknowledged for their support with
the D8 Venture X-ray equipment. Prof. Andrea Sartorel and Dr
Francesco Rigodanza are acknowledged for insightful
discussions. Stefano Mercanzin is acknowledged for technical
assistance.
5
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10.1002/ejoc.202001057
European Journal of Organic Chemistry
COMMUNICATION
From oxindole with flow. Oxindole enol ethers are engaged in microfluidic visible-light Paternò–Büchi processes, allowing the
concomitant C2-C3 functionalisation of the biorelevant heterocyclic core, in high yield and selectivity.
Key topic: Oxindole visible-light-driven functionalisation
@LucaDellAmicoLD, dellamicogroup.com
6
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