Visible Light-Promoted Friedel-Crafts-Type Chloroacylation of Alkenes to β-Chloroketones

Alkenes to β ‑Chloroketones

Letter

Visible Light-Promoted Friedel−Crafts-Type Chloroacylation of

Dilip V. Patil, Hun Young Kim, and Kyungsoo Oh*

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00788

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sı Supporting Information

ABSTRACT: The photoredox chloroacylation of alkenes has been

developed as a substitute for the Friedel−Crafts acylation of alkenes

to β-chloroketones. The direct generation of acyl radical species

from acid chlorides under the photoredox conditions allows the

formation of β-chloroketones without dehydrochlorination with the

help of KHCO . The synthetic utility of the current method is

demonstrated in the one-pot synthesis of dihydroisoxazole, dihydropyrazole, and dihydropyrimidine-2-thione in 1 mmol scale.

riedel−Crafts acylations of aromatic compounds are

conditions. Thus, the synthetic access to β-chloroketones is

important synthetic tools in organic synthesis. While

currently limited to the BiCl -catalyzed chlorination of β-

silyloxy ketones using TMSCl, the SiCl

hydrochlorination of α,β-unsaturated ketones, and the aryl

cyclopropane-opening in the HCl/HNO /O conditions. The

facile dehydrochlorination pathway of β-chloroketones neces-

sitates neutral reaction conditions; however, such reaction

conditions are not currently available in the Friedel−Crafts

acylation reactions of alkenes. In 2017, the Xu group

investigated the addition of acyl radical species from acid

chlorides to electron-deﬁcient alkenes under the photolytic

the aromatization of the sigma complex provides the driving

force to give aromatic ketones as products, the Friedel−Crafts

acylation of alkynes renders a facile access to either alkynyl

/PhOH-promoted

ketones or β-chlorovinyl ketones (Scheme 1a). The utilization

of alkenes, however, routinely provides the α,β-unsaturated

ketones due to the instability of β-chloroketones under acidic

Scheme 1. Visible-Light-Promoted Friedel−Crafts-Type

Chloroacylation Approaches to β -Chloroketones

conditions, where the formations of fused pyran derivatives

and 3,3-dialkyl 2-oxindole derivatives were achieved without

chlorine incorporation (Scheme 1b). Similarly, the Tang group

in 2018 applied the acyl radical addition to alkynyl esters to

give 3-acylcoumarins in good yields. Recently, the Ngai group

developed the proton-coupled electron-transfer (PCET)-

mediated chloroacylation of alkenes, where the 2,6-di-t-butyl-

-methyl-pyridine was used to form the corresponding *Py-

HCl as a PCET catalyst. The PCET process promotes the α-

chloro-α-hydroxy benzyl radical addition to an alkene to give

the radical intermediates. The subsequent 1,3-chlorine shift

gives α,β-unsaturated ketones after the dehydrochlorination of

β-chloroketone intermediates. While the Ngai’s work formally

constitutes the photolytic Friedel−Crafts acylation of alkenes,

the isolation of β-chloroketones was only achieved for two

substrates after a reverse phase HPLC puriﬁcation. Similarly,

the Zhu group in 2017 disclosed the decarboxylative cross-

coupling of α-keto acids and styrenes via a tandem

Received: March 2, 2020

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

ﬂuorination−protodeﬂuorination under the photolytic con-

the presence of 2 mol % fac-Ir(ppy) photocatalyst, various

ditions to give α,β-unsaturated ketones. In 2019, the Xu

group reported the atom-transfer radical cyclization reaction

under visible-light photocatalytic conditions, where the

reaction solvents were examined (entries 1−8). Among the

solvents tested, the use of DCE and THF provided the desired

β-chloroketones 3a in 51−53% yields (entries 4 and 5). The

utilization of other photocatalysts revealed that the current

chlorine atom was incorporated into the substrates.

Motivated by the lack of direct synthetic methods to β-

chloroketones via the Friedel−Crafts acylations of alkenes, a

new photoredox approach was pursued under mild conditions.

Given that the acid chloride can photolytically generate the

chloroacylation reaction was not eﬀected by Ir(ppy)

PF , Ru(bpy) (PF , Eosin Y, and Rose Bengal catalysts

entries 9−12). The employment of an inorganic base was

crucial, as the nature of the base dramatically changed the

(dtbbpy)-

)

6 2

(

reaction outcome. Thus, the use of KHCO improved the

acyl radical species, the visible light-promoted chloroacyla-

tion of alkenes was envisioned for the synthesis of β-

chloroketones (Scheme 1c). Herein, we report an atom

economical synthetic route to β-chloroketones using the

visible-light-promoted Friedel−Crafts-type chloroacylation of

alkenes. It is noteworthy that the developed photoredox

conditions are mild enough to give ready access to β-

chloroketones without eﬀecting the dehydrochlorination.

The photochemical chloroacylation of alkenes using acid

chlorides was projected to generate two radical species: the

acyl radical from acid chlorides and the benzyl radical from the

addition of the acyl radical to alkenes. Thus, to investigate the

photochemical chloroacylation of alkenes using the acyl radical

pathway, a suitable photoredox condition was sought using

benzoyl chloride 1a and 4-methylstyrene 2a (Table 1). First, in

isolated yield of 3a to 57% (entry 13); however, the

employment of more basic inorganic bases such as K CO

dramatically reduced the formation of 3a to a 29% yield, and

the enone 4a was formed in an 8% yield (entry 14). The

dehydrochlorination of 3a was more pronounced upon using

an organic base, 2,6-lutidine (entry 15), and other inorganic

and organic bases completely shut down the reaction (see the

Supporting Information for details). Further optimization was

performed by using increased amounts of benzoyl chloride 1a,

KHCO , and fac-Ir(ppy) , where the desired β-chloroketone

a was obtained in 74% yield (entries 16 and 17). The control

experiments conﬁrmed the photoredox nature of the reaction

with respect to fac-Ir(ppy) and light (entries 18 and 19). The

reaction exclusively provided the enone 4a in the absence of

any added base (entry 20).

With the optimized photoredox conditions for Friedel−

Crafts-type chloroacylation of alkenes, the substrate scope of

acid chlorides and alkenes was examined (Scheme 2). The use

Table 1. Optimization of Visible-Light-Promoted Friedel−

Crafts-Type Chloroacylation of Alkene

Scheme 2. Substrate Scope of Friedel−Crafts-Type

Chloroacylation of Alkenes by Photoredox Catalysis

yield (%)

entry

photocat.

fac-Ir(ppy)₃

solvent

base

acetone

PhCH₃

EtOAc

DCE

NaHCO₃

KHCO₃

fac-Ir(ppy)₃

THF

CH CN

1,4-dioxane

2-Me-THF

THF

Ir(ppy) (dtbbpy)PF

Ru(bpy) (PF )

6 2

Eosin Y

Rose Bengal

fac-Ir(ppy)₃

K CO

2,6-lutidine

KHCO₃

Isolated yield of the corresponding β-chloro alcohols after reduction

using NaBH . The crude yields of 3 are in parentheses.

fac-Ir(ppy)₃

THF

of styrene derivatives with diﬀerent electronic characters

provided the desired β-chloroketones 3a−3d in 68−77%

yields. While the crude yields of 3 were higher, the column

chromatography of the β-chloroketones resulted in the loss of

products due to the facile dehydrochlorination. The halogen

and ester-containing styrenes provided the β-chloroketones

3e−3h in 55−66% yields, clearly demonstrating the functional

Reaction using 1a (0.4 mmol), 2a (0.2 mmol), base (0.4 mmol), and

photocatalyst (2 mol %) in 4 mL of solvent (0.05 M) at ambient

temperature under an argon atmosphere and blue LED lights for 24 h.

Isolated yields after column chromatography. Use of 1a (3 equiv)

and KHCO (3 equiv). Use of fac-Ir(ppy) (4 mol %). Without

light.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

group compatibility in the current photoredox conditions.

Other styrene derivatives could also be employed to give the

corresponding products 3i−3l; however, the 4-phenyl

substituted β-chloroketone 3i could not be puriﬁed by column

chromatography due to the facile HCl elimination. Thus, the in

situ reduction of the ketone moiety was necessary to give the

corresponding β-chloro alcohol (vide infra). The cyclic alkenes

such as 1,2-dihydronaphthalene and indene provided the anti-

selective β-chloroketones 3m and 3n in 57−63% yields. The

substrate scope of acid chlorides revealed that the electron-

withdrawing group-containing acid chlorides were better suited

for the chloroacylation of alkenes; thus, while 4′-methyl

substituted β-chloroketone 3o was obtained in 54% yield, the

halogen-substituted acid chlorides provided the corresponding

β-chloroketones 3p−3r in 73−78% yields. Such an electronic

eﬀect was not apparent for 3′-substituted-β-chloroketones 3s

and 3t, leading to lower yields of the products. The optimized

photoredox chloroacylation conditions could be applied to

naphthoyl and heteroaroyl chlorides to give modest yields of

the products 3u−3w. While the halide and ester moieties were

tolerated under the reaction condition to give the products

While the Ngai group’s PCET process utilized the formation

of α-chloro-α-hydroxy benzyl radical species followed by

chlorine 1,3-shift, the acyl radical pathway has been proposed

in the work of Xu and co-workers, despite the use of 2,6-

lutidine. Thus, the mechanism of the current Friedel−Crafts-

type chloroacylation was investigated (Scheme 4). The

Scheme 4. Control Experiments and the Proposed

Mechanism for Photoredox Catalysis

x−3z, the limitation of the current chloroacylation of the

alkenes includes the intolerance of aliphatic acid chlorides and

nonstyrene-type alkenes. Also, the use of functionalized acid

chloride and styrene with aldehyde and amide moieties was not

successful, possibly due to the competing photolytical

pathways of aldehyde and amide moieties.

The synthetic utilization of β-chloroketone 3a is illustrated

in Scheme 3. While our optimized reaction condition in 0.3

Scheme 3. One-Pot Synthetic Utilization of β-

Chloroketones

mmol at 0.05 M required 4 mol % of fac-Ir(ppy) loading to

give 3a in 74% yield, the photocatalyst loading could be

lowered to 2 mol % at an increased concentration to give 3a in

a slightly lower yield of 65%. Thus, the reaction at 1 mmol

scale at 0.1 M concentration smoothly proceeded with 2 mol %

introduction of a radical inhibitor, TEMPO, into the reaction

mixture provided the acyl-captured TEMPO 9a in addition to

benzoic anhydride 10a. The formation of 10a was observed

from the reaction mixture as byproducts, and the inadvertent

presence of moisture and molecular oxygen was responsible for

the formation of 10a. A thorough degassing of the reaction

solvent reduced the formation of 10a, and our control

experiment conﬁrmed that 10a was unable to produce the acyl

radical species under the optimized photoredox conditions.

Our attempts to capture the benzyl radical species were

partially successful upon using a Hantzsch ester as a hydrogen

donor to give the saturated ketone 12a; however, the use of a

weak nucleophile such as TsNH₂failed to intercept the

benzylic cation intermediate, possibly due to the facile

of fac-Ir(ppy) in 24 h, and the in situ treatment of 3a with

NaOAc led to the enone 4a in 61% yield. The NaBH₄

reduction of the β-chloroketone 3a also provided the β-chloro

alcohol 5a in 60% yield. The direct synthetic access to

heterocyclic compounds such as dihydroisoxazole 6a, dihy-

dropyrazole 7a, and dihydropyrimidine-2-thione 8a was also

accomplished in 47−62% yields. Thus, the current photolytic

Friedel−Crafts-type chloroacylation approach provides the

facile combination of acid chlorides and alkenes that could be

further in situ transformed to other heterocyclic compounds.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Complete contact information is available at:

Letter

interception of the chloride anion species. The acyl radical

species was only generated in the presence of a light source, as

in the light on/oﬀ experiment in Scheme 4; thus, the radical

chain reaction is highly unlikely. On the basis of the control

experiments, a plausible reaction mechanism is proposed: the

https://pubs.acs.org/10.1021/acs.orglett.0c00788

Notes

The authors declare no competing ﬁnancial interest.

irradiation of fac-Ir(ppy) with blue visible lights generates

the photoexcited state of *Ir(ppy) that could be oxidized by

ACKNOWLEDGMENTS

red

■

benzoyl chloride 1a (E = −1.26 V vs SCE) to a Ir(IV)

IV/III

This research was supported by the National Research

Foundation of Korea (NRF) grants funded by the Korean

government (MSICT) (NRF-2015R1A5A1008958 and NRF-

species (E₁_/₂

= −1.73 V vs SCE) and an acyl radical A.

The addition of the acyl radical A to the alkene 2 generates the

benzyl radical species B that could be stabilized by an adjacent

phenyl group. The loss of reactivity for aliphatic alkenes

illustrates the importance of such a radical-stabilizing eﬀect.

019R1A2C2089953).

lII

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■

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Experimental procedures and characterization data for

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Kyungsoo Oh − Center for Metareceptome Research, Graduate

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6974, Republic of Korea; orcid.org/0000-0002-4566-

573 ; Email: kyungsoooh@cau.ac.kr

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Org. Lett. XXXX, XXX, XXX−XXX

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15) The use of cyclohexene, hept-1-ene, and vinylcyclohexane failed

(

to deliver the desired β-chloroketones. Upon prolonged photolytic

conditions, the benzoyl chloride slowly decomposed to benzoic

anhydride.

(16) The acyl radical generation from 4-formylbenzoyl chloride

under the optimized conditions was not successful, whereas the 4-

formylbenzoyl chloride was recovered intact after 24 h. The use of

N,N-dimethyl-4-vinylbenzamide primarily led to the decomposition

under the optimized conditions within 12 h.

(17) Under the optimized reaction concentration (0.05 M in THF),

the 4 mol % fac-Ir(ppy)₃was completely soluble; however, the

insoluble KHCO somewhat slowed down the reaction conversion.

Upon scaling up the reaction to 1 mmol of 1a using a ﬂask instead of

vials, the reaction mixture was better exposed to the blue LEDs. The

utilization of larger reaction vessels allowed the use of less catalyst

loading (2 mol %) in an increased concentration (0.10 M), where the

reaction time could be shortened within 24 h.

(18) The reaction mixture was degassed by ﬂowing argon through

the reaction solution for 10 min before applying the blue LEDs. The

reaction without degassing led to the formation of 3a in 55% as

opposed to 74% with the degassing.

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20) Our measurement of the cyclic voltammetry of benzoyl

red

chloride (E = −1.26 V vs Ag/AgCl) in the Supporting Information

red

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(

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22) The pH measurement of the reaction mixture at the early stage

of the reaction was not informative due to the heavy presence of

moisture-sensitive benzoyl chloride 1a. However, the pH measure-

ment of the reaction mixture after about 50% consumption of 1a

consistently demonstrated the neutral conditions (pH = 7). Also, the

β-chloroketone 3a was kept at neutral pH conditions by KHCO after

the reaction, which was crucial for the prevention of dehydrochlori-

nation of 3a (Table 1, entry 20).

(23) The loss of the product 3 to chalcone derivatives was observed

upon silica gel column chromatography in 10−90%. To prevent the

HCl elimination, the top of silica gel column was packed with