Radical Carbonylation Mediated by Continuous-Flow Visible-Light Photocatalysis: Access to 2,3-Dihydrobenzofurans

Article abstract of DOI:10.1021/acs.orglett.8b01971

The annulative carbonylation of alkenyl-tethered arenediazonium salts using visible-light photocatalysis in continuous flow is described. The method furnishes a diverse series of novel acetate-functionalized 2,3-dihydrobenzofurans at room temperature and

Full text of DOI:10.1021/acs.orglett.8b01971

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical Carbonylation Mediated by Continuous-Flow Visible-Light
Photocatalysis: Access to 2,3-Dihydrobenzofurans
Nenad Micic† and Anastasios Polyzos*,‡
†School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
‡CSIRO Manufacturing, Research Way, Clayton, Victoria 3168, Australia
S
* Supporting Information
ABSTRACT: The annulative carbonylation of alkenyl-
tethered arenediazonium salts using visible-light photo-
catalysis in continuous flow is described. The method
furnishes a diverse series of novel acetate-functionalized 2,3-
dihydrobenzofurans at room temperature and moderate CO
pressure (25 atm), delivering these products in a short time
with straightforward scale-up. This continuous flow and free-
radical approach overcomes the limitation of traditional Pd-catalyzed annulative carbonylation, giving valuable 2,3-
dihydrobenzofurans in a predictable and regioselective manner.
has been applied to the synthesis of acetaldehyde-function-
nnulative carbonylation is an attractive strategy for the
1
Asynthesis of carbonyl-containing N- or O-heterocycles. alized O-heterocycles using organostannane reagents (Scheme
1b).6 The limitations of traditional free-radical carbonylation
The intramolecular Heck-type annulative carbonylation of
methods relate to the low regioselective control over the
cyclization pathway, the requirement for high-pressure CO
(>80 bar), and a strong radical acceptor coupling partner.
These factors have encouraged the development of improved
methods for radical carbonylation. In 2015, Xiao reported a
single example of free-radical annulative alkoxycarbonylation of
2-allyloxybenzenediazonium salt mediated by organophotor-
edox catalysis.7 This marked a notably different reactivity
manifold to previous radical methods, as simple nucleophiles
could be engaged as coupling partners. Despite this milestone,
the photoredox-mediated carbonylative cyclization of alkenyl-
tethered aryl(pseudo)halides has not been developed. This is
likely due to the practical and safety implications arising from
the use of CO gas at high pressures (≥80 atm) and the
requirement of specialized autoclave photoreactors, impairing
accessibility and scalability.
allyl-2-iodophenyl ethers and amines provides a direct route to
acetaldehyde-functionalized benzofuran, benzopyran, indoline,
and tetrahydroisoquinoline derivatives.2 A limitation of this
approach relates to multiple product distribution derived from
competitive biscarbonylation, carbometalation, and β-hydride
elimination pathways following oxidative addition.3 This
protocol is particularly challenging for the synthesis of
pharmaceutically relevant 2,3-dihydrobenzofurans (Scheme
1a).4
Free-radical carbonylation offers an advantageous alternative
to Pd-catalyzed carbonylation of aryl (pseudo)halides.5 The
radical-mediated carbonylation of alkenyl-tethered aryl halides
Scheme 1. Synthesis of Acetate-Functionalized 2,3-
Dihydrobenzofurans via Annulation/Alkoxycarbonylation
Cascade
In this letter we report a method for the annulative
carbonylation of alkenyl-tethered arenediazonium salts using
visible-light photocatalysis in continuous flow processing
(Scheme 1c). Our approach provides access to 3-acetate-
substituted 2,3-dihydrobenzofurans under mild reaction
conditions with significant chemo- and regioselectivity. The
application of continuous flow processing permits short
reaction times (200 s), low partial pressure of gaseous CO
(25 atm), and straightforward scale-up.
We proposed that the 3-acetate-functionalized 2,3-dihydro-
benzofurans could be generated from allyloxy-tethered
benzenediazonium tetrafluoroborate (I) via a photoredox
catalysis manifold (Scheme 2). Diazonium tetrafluoroborates
Received: June 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
time in the photoreactor was set to 200 s. High dilution
conditions were necessary to decrease unwanted intermolec-
ular radical addition, particularly for intermediates III and
IV.11
Scheme 2. Reaction Design for the Radical Annulation/
Alkoxycarbonylation under Photoredox Conditions
We embarked on our investigation by screening a selection
of organic and transition metal photoredox catalysts (Table 1).
a
Table 1. Selected Optimization Experiments
b
entry
deviation from scheme conditions
yield (%)
are attractive aryl (pseudo)halide radical precursors due to
their mild reduction potential (E° ∼ 0 V vs SCE)8 and
convenient preparation. Single electron reduction from the
excited state photocatalyst (PC*) to the allyloxy-tethered
arenediazonium salt I induces homolytic cleavage of a C−N
bond, generating the aryl radical II and oxidized photocatalyst
(PC•+). Intramolecular radical alkene addition furnishes the
primary alkyl radical intermediate III. Trapping of the alkyl
radical with CO gives the acyl radical IV. Single electron
oxidation of the acyl radical by the oxidized photocatalyst
(PC•+) results in the regeneration of the photocatalyst (PC)
and the formation of the acylium ion V. Reaction of the
acylium ion with an alcohol affords the 3-acetate 2,3-
dihydrobenzofuran VI.
The application of flow processing was anticipated to reduce
reaction time and mediate carbonylation at reduced partial
pressures of CO relative to the batch reaction. Moreover,
continuous flow photochemistry has been established as a
viable tool to improve the efficiency of photochemical
transformations.9 Accordingly, a flow chemistry platform was
developed to comprise a CO gas delivery system and tubular
flow photoreactor. The flow configuration was comprised of a
commercially available Teflon AF-2400 tube-in-tube reactor
operating as a gas addition module (GAM) and was connected
to a tubular flow photoreactor (Figure 1) (see Supporting
Information (SI)). The AF-2400 GAM continuously delivers
CO gas to a reaction stream in a controlled, safe, and
reproducible manner.10
1
2
3
4
5
6
7
8
9
no deviation
74
67
65
8
53
64
47
69
85 (73)
85
trace
n.d.
Ru(bpy)3Cl2·6H2O (1 mol %)
fluorescein (1 mol %)
eosin Y (1 mol %), green 14 W LEDs
0.04 M concentration
MeCN/MeOH (95:5)
10 equiv of MeOH
100 s photoreactor residence time
0.5 mol % [Ir]
0.5 mol % [Ir], CO (35 atm)
no catalyst
10
11
12
no light
a
Unless otherwise noted, reactions were carried out with 1a (0.2
mmol), [Ir(dtbbpy)(ppy)2]PF6 (1 mol %), MeOH (10 mL), CO (25
atm), irradiation (450 nm LED, 14 W), room temperature, 200 s. bpy
= 2,2′-bipyridine; ppy = 2-phenylpyridine; dtbbpy = 4,4′-di-tert-butyl-
b
2,2′-bipyridine. 1H NMR yields determined with maleic acid as the
internal standard. Isolated yields in parentheses.
In the latter, Ru and Ir photocatalysts form stable complexes
with CO, leading to catalyst deactivation under high pressures
of CO.12 We anticipated that the lower CO pressures engaged
under flow conditions potentially alleviate this unwanted
deactivation pathway for transition metal photocatalysts.
Accordingly, [Ir(dtbbpy)(ppy)2]PF6 was initially screened,
and the catalyst afforded the desired methoxycarbonylated
product 2a in good yield (entry 1). The archetypal ruthenium
photocatalyst, Ru(bpy)3Cl2·6H2O, provided 2a in a slightly
lower yield of 67%. In contrast, organophotocatalysts (entries
3−4, refer to SI for comprehensive catalyst screen) furnish 2a
in lower yields relative to the transition metal dyes, suggesting
that the Ir and Rh photocatalysts were not deactivated by CO
under the flow conditions. Increasing the concentration of 1a
resulted in polymerized byproducts (entry 5). The concen-
tration of nucleophile (methanol) was reduced to 5% (v/v)
with only a slight reduction in yield. However, stoichiometric
quantities of alcohol resulted in poor yields (entries 6−7).
Volumetric flow rates higher than 0.15 mL/min afforded
complete conversion of the arenediazonium salt with a
reduction in alkoxycarbonylated product, suggesting that the
increased flow rate through the GAM did not result in
saturation of the liquid phase with CO (entry 8). Longer
residence times did not lead to an appreciable increase in yield.
Reducing the catalyst loading to 0.5 mol % proved beneficial,
affording the desired ester 2a in excellent yield (entry 9). The
pressure of CO was modulated, and increasing the pressure of
CO gas to 35 atm did not result in an increase in carbonylated
products, implying intermolecular alkene addition of inter-
Figure 1. Schematic of the continuous flow platform with gas−liquid
photoreactor.
The initial conditions for method development required
methanolic solutions of 2-allyloxybenzenediazonium tetrafluor-
oborate (1a) and photocatalyst to be pumped through the
GAM (0.15 mL/min), enriched with CO at 25 atm, then
irradiated with blue light at room temperature to give methyl
2-(2,3-dihydrobenzofuran-3-yl)acetate (2a). The residence
B
DOI: 10.1021/acs.orglett.8b01971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mediate III was no longer a significant competing reaction
pathway (entry 10). Control reactions showed that both
irradiation and photocatalyst are required (entries 11−12).
Notably, full conversion of 1a was observed for the
[Ir(dtbbpy)(ppy)2]PF6, Ru(bpy)3Cl2·6H2O, and fluorescein-
Scheme 4. Scope of Arenediazonium Tetrafluoroborate
Allyloxy Ethers
a
1
catalyzed reactions. H NMR analysis of the crude reaction
mixtures identified trace amounts 3-methyl-2,3-dihydrobenzo-
furan, suggesting the competitive reduction of 1a may be
occurring under the reaction conditions.
With the optimal reaction conditions established, the scope
of the developed transformation was explored (Scheme 3).
a
Scheme 3. Reaction Scope of Alcohol Coupling Partner
a
Reaction conditions: 1m−u (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6
(0.5 mol %), nBuOH/MeCN 1:1 v/v (10 mL), CO (25 atm),
irradiation (450 nm LED, 14 W), room temperature, 200 s, isolated
yields.
at the C5 position did not furnish the carbocyclized products
in appreciable quantities (see SI).
The generality of the reaction was further demonstrated
through the compatibility of unsaturated ortho-tethered
arenediazonium salts with the standard reaction conditions
(Figure 2).
a
Reaction conditions: 1a (0.2 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.5
mol %), ROH/MeCN (10 mL), CO (25 atm), irradiation (450 nm
b
LED, 14 W), room temperature, 200 s, isolated yields. No MeCN v/
c
d
v as cosolvent. 50% v/v MeCN used as cosolvent. 95% v/v MeCN
used as cosolvent.
First, primary, secondary, and tertiary alkyl alcohol coupling
partners were investigated, and each class of alcohol yielded
the corresponding ester in excellent yield, regardless of steric
bulk (2a−2f). Phenol, known to form azo compounds with
addition to arenediazonium salts,13 formed the corresponding
ester product 2h in a satisfactory yield. Alcohols with C−H
bonds susceptible to radical abstraction were tolerated without
quenching of the alkyl radical (2h−k).14 Alcohols with internal
alkenes furnished unsaturated ester 2k with retention of double
bond stereochemical configuration, and halogenated alcohols
were compatible with the reaction conditions (2l), permitting
further functionalization.
Figure 2. Extension of the annulation/alkoxycarbonylation reaction to
ortho-tethered arenediazonium salts. Reaction conditions: 3a−c (0.2
n
mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.5 mol %), BuOH/MeCN 1:1 v/v
(10 mL), CO (25 atm), irradiation (450 nm LED, 14 W), room
temperature, 200 s, isolated yields are given.
We next turned our attention to evaluating the scope of the
arenediazonium allyl ethers (Scheme 4). Weakly donating and
electron-withdrawing substituents afforded the desired radical
annulation/carbonylation product in good to excellent yields
(2m−2t). In contrast to Pd-catalyzed carbonylation, bromo,
chloro, and fluoro substituents were compatible, with no
observable competitive biscarbonylation or dehalohydrogen-
ated products detected by H NMR. Methoxy substitution at
the C6 position (2u) was achieved in acceptable yield;
unfortunately, methoxy, phenoxy, and acetamide substitution
The use of methallyloxy derivative 3a furnished the 3-
acetate-functionalized 2,3-dihydrobenzofuran 4a, with an all-
carbon quaternary center at the C3 position, in good yield.
Access to acetate-functionalized benzofuran 4b and chromane
4c could be realized through the use of propargyloxy and 1-
butenyloxy substitution, respectively.
The scale up of high-pressure dilute photochemical
multiphase reactions in batch presents significant challenges.
To demonstrate the facile scalability of the developed flow
1
C
DOI: 10.1021/acs.orglett.8b01971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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protocol, the reaction was scaled by a factor of 20. To facilitate
a preparative scale reaction, the GAM and photoreactor
volumes were increased by a factor of 3 (see SI). Operating in
the continuous flow regime, 4.0 mmol of 1a was processed to
afford the ethyl ester 2b in 72% isolated yield.
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In summary, we have developed a continuous-flow, visible-
light photoredox catalytic approach for the annulative
alkoxycarbonylation of alkenyl-tethered arenediazonium salts.
Continuous-flow processing enabled significant process in-
tensification compared to batch and facile scale-up. The
developed method was applied to the synthesis of a diverse
library of 3-acetate-functionalized 2,3-dihydrobenzofurans.
This work exemplifies our strategy to overcome the challenges
associated with Pd-catalyzed annulative carbonylation through
a free-radical approach under mild reaction conditions. Work is
currently underway in our laboratory to expand the general
scope of visible-light photocatalytic carbonylation reactions
using the continuous-flow platform.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01971.
Experimental procedures, compound characterization
data, and NMR spectra for all compounds (PDF)
(13) Haghbeen, K.; Tan, E. W. J. Org. Chem. 1998, 63, 4503−4505.
(14) Luo, Y. Comprehensive Handbook Of Chemical Bond Energies;
CRC Press: Boca Raton, FL, 2007.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anastasios.polyzos@unimelb.edu.au.
ORCID
Anastasios Polyzos: 0000-0003-1063-4990
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N. Micic acknowledges the University of Melbourne,
Melbourne Research Scholarship (MRS). A. Polyzos acknowl-
edges the University of Melbourne and CSIRO for the joint
Establishment Grant.
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D
DOI: 10.1021/acs.orglett.8b01971
Org. Lett. XXXX, XXX, XXX−XXX