Visible Light/Tertiary Amine Promoted Synergistic Hydroxydifluoroacetamidation of Unactivated Alkenes under Air

DOI: 10.1021/acs.orglett.0c04216

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Organic Letters p. 617 - 622 (2021)

Update date:2022-07-29

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Authors:

Huang, Panyi

Jin, Can

Shi, Xiayue

Sun, Bin

Yan, Zhiyang

Yu, Chuanming

Zhu, Rui

Zhuang, Xiaohui

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Article abstract of DOI:10.1021/acs.orglett.0c04216

An efficient and novel method for regioselective hydroxydifluoroacetamidation of alkenes with bromodifluoroacetamides has been achieved via a tandem radical pathway mediated by photoredox catalysis under metal-free conditions. This transformation proceeded smoothly in the presence of Rhodamine 6G, affording a series of α,α-difluoro-γ-hydroxyacetamides in moderate to excellent yields. The significant advantages of this protocol are the low-cost photocatalyst, readily available starting materials, synthetic convenience, and wide functional group compatibility.

Full text of DOI:10.1021/acs.orglett.0c04216

pubs.acs.org/OrgLett

Letter

Visible Light/Tertiary Amine Promoted Synergistic

Hydroxydiﬂuoroacetamidation of Unactivated Alkenes under Air

Bin Sun,^§Rui Zhu,^§Xiaohui Zhuang, Xiayue Shi, Panyi Huang, Zhiyang Yan, Chuanming Yu,

and Can Jin *

Cite This: Org. Lett. 2021, 23, 617 −622

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ABSTRACT: An eﬃcient and novel method for regioselective hydroxydiﬂuoroacetamidation of alkenes with bromodiﬂuor-

oacetamides has been achieved via a tandem radical pathway mediated by photoredox catalysis under metal-free conditions. This

transformation proceeded smoothly in the presence of Rhodamine 6G, aﬀording a series of α,α-diﬂuoro-γ-hydroxyacetamides in

moderate to excellent yields. The signiﬁcant advantages of this protocol are the low-cost photocatalyst, readily available starting

materials, synthetic convenience, and wide functional group compatibility.

Scheme 1. Introduction of the RCF₂Group into Alkenes

he diﬂuoromethylene (CF₂) group is a privileged

pesticides,²and

T_{structural motif in pharmaceuticals,}

materials science³because it can dramatically aﬀect the

physical, chemical, and biological properties of organic

molecule.⁴Over the past few years, the signiﬁcance of

diﬂuoroalkyl compounds has inspired chemists to develop

novel methods for the construction of C−CF₂bonds.⁵Among

these, difunctionalization of alkenes is regarded as one of the

most powerful tools for the synthesis of diﬂuoroalkylated

compounds as it can realize the rapid synthesis of structurally

diverse molecules. By employing this strategy, diﬂuoroalkyla-

tion of alkenes has been well-established, accompanied by

simultaneous γ-functionalization such as arylation,⁶oxylation,⁷

thiolation,⁸benzeneselenolation,⁹and halogenation (Scheme

1, a).¹⁰According to the existing reports, synthesis of CF₂R-

containing molecules via difunctionalization of styrene-type

alkenes has been studied extensively, while it would be more

interesting to achieve diﬂuoroalkylation of unactivated alkenes,

like aliphatic oleﬁns.

Alcohol, which is considered as a reactive center for

functional group interconversions, plays a vital role in organic

synthesis,¹¹and thus, preparation of alcohols from simple

starting materials is one of the key transformations in organic

reactions. In the past several years, a few strategies for selective

hydroxydiﬂuoroalkylation of styrene have been established for

the synthesis of CF₂R-containing alcohols (Scheme 1, b).¹²

For example, Qing^12aand Akita^12brespectively developed a

convenient method for synthesis of CF₂H-containing alcohol

via visible light induced hydroxydiﬂuoromethylation of styrene

by employing water as the nucleophile. Recently, Xu^12c

reported a mild method for preparation of α-hydroxy amides

Received: December 21, 2020

Published: December 29, 2020

https://dx.doi.org/10.1021/acs.orglett.0c04216

Org. Lett. 2021, 23, 617−622

617

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Letter

through hydroxydiﬂuoromethylation of electron-deﬁcient

alkene (acrylamides) mediated by electrochemical catalysis.

Although several successful strategies have been disclosed, the

more diﬃcult task of hydroxydiﬂuoroalkylation of unactivated

aliphatic alkene still remained elusive, which could be

explained by the unfavored oxidation of the aliphatic carbon

radical to the corresponding carbocation.

Table 1. Optimization of the Reaction Conditions

entry

photocatalyst

additive

solvent

yields (%)

Na₂-Eosin Y

Eosin B

Eosin Y

Rose Bengal

fac-Ir(ppy)₃

Acr⁺-MesClO₄

Rhodamine 6G

Ru(bpy)₃Cl₂

methylene blue

Rhodamine 6G

PMDETA

DIPEA

DCE

DCM

CH₃CN

DMSO

DMF

N.D.

trace

N.D.

Our group has widely developed green and eﬃcient methods

for photoredox catalyzed C−H functionalization in the past

several years.¹³As our pioneering works for diﬂuoroalkylation,

BrCF₂R-type derivatives were demonstrated to be easily

activated under photocatalytic conditions to generate the

diﬂuoroalkyl radical while eliminating a bromide anion.

Meanwhile, dioxygen, which is known as an ideal cheap and

environmentally friendly oxidant, could act as a potential

hydroxy source because it is capable of interacting with a

carbon-centered radical.¹⁴We speculated that the carbon

radical generated through radical addition between ·CF₂R and

aliphatic alkene would be initially trapped by O₂rather than

being oxidized to the carbocation, which is crucial for achieving

the hydroxydiﬂuoroalkylation of unactivated alkene. Herein,

we describe the ﬁrst example of an aerobic hydroxydiﬂuor-

oacetamidation of aliphatic alkenes with bromodiﬂuoroaceta-

mides mediated by photoredox catalysis via employing

inexpensive Rhodamine 6G as a photocatalyst.

−

DMAP

DBU

DABCO

PMDETA

DCE

Initially, we employed allylbenzene (1a) and the easily

prepared 2-bromo-2,2-diﬂuoro-N-phenylacetamide (2a) as

model substrates to evaluate the reaction parameters such as

the photocatalyst, solvent, and additive. Satisfactorily, the

desired product 3aa was obtained in 31% yield when the

reaction was carried out in the presence of Na₂-Eosin Y and

PMDETA in DCE with irradiation of a 10 W 545−550 nm

LED for 12 h (Table 1, entry 1). Subsequently, various

photocatalysts, including Eosin B, Eosin Y, Rose Bengal, fac-

Rhodamine 6G

(1) Reaction conditions: unless otherwise noted, all reactions were

performed with 1a (0.6 mmol), 2a (0.2 mmol), additive (0.4 mmol),

and photocatalyst (1 mol %) in solvent (2 mL) under air atmosphere,

irradiated by a 10 W LED for 12 h; (2) 545−550 nm for Na₂-Eosin Y,

Eosin B, Eosin Y, Rose Bengal, Rhodamine 6G; 400−405 nm for

Acr⁺-MesClO₄⁻, fac-Ir(ppy)₃; 455−460 nm for Ru(bpy)₃Cl₂.

Ir(ppy)₃, Acr⁺-MesClO₄, Rhodamine 6G, Ru(bpy)₃Cl₂, and

−

Isolated yield based on 2a. 1a (2 mL). 1a (0.2 mmol), 2a (0.4

mmol). Without photocatalyst. Without organoamine. Without

light.

methylene blue were also studied (Table 1, entries 2−9).

Among them, the Rhodamine 6G exhibited a better catalytic

eﬃciency, and the yield of 3aa could be dramatically increased

to 56% (Table 1, entry 7). A series of commonly available

solvents such as DCM, CH₃CN, DMSO, and DMF was then

tested for this reaction, but none of them could give a better

result compared with DCE (Table 1, entries 10−13). To our

delight, the isolated yield of 3aa was increased to 76% when

the allylbenzene was employed as solvent (Table 1, entry 14).

The eﬀects of other additives were then examined, and the

results showed that DIPEA only could give a much lower yield,

while DMAP, DBU, and DABCO were not eﬀective at all

(Table 1, entries 15−18). The further optimization for the

yield of product based on alkene was also studied, and the

result revealed that the product could be obtained only in a

yield of 25% when the ratio of 1a and 2a was adjusted to 1:2

(Table 1, entry 19). Control experiments indicated that

photocatalyst, visible light, and organoamine were all

indispensable for this transformation (Table 1, entries 20−22).

With the optimized conditions in hand, the substrate scope

of this visible-light-induced aerobic hydroxydiﬂuoroacetamida-

tion of alkenes was investigated, and this method exhibited

good substrate compatibility and remarkable selectivity. As

shown in Scheme 2, the allylbenzene with electron-donating

(methyl or methoxy) or electron-withdrawing (ﬂuoro) groups

on the benzene ring were all suitable for this reaction, giving

the α,α-diﬂuoro-γ-hydroxy-acetamides (3ba−3da) in moderate

to good yields. In addition, the eﬀect of carbon chain length on

this reaction was also studied. The results showed that the

examined oleﬁns, including but-3-en-1-ylbenzene, pent-4-en-1-

ylbenzene, and hex-5-en-1-ylbenzene, all exhibited moderate

reactivity in this transformation (3ea−3ga), aﬀording the

corresponding products in 52 to 59% yields. The naphthalene

substituted alkene 1h also worked well, delivering the desired

product 3ha in 71% yield. It was noteworthy that the normal

aliphatic oleﬁn without a benzene ring, such as pent-1-ene, hex-

1-ene, and oct-1-ene, still led to the desired product in

moderate yields (3ia−3ka). Apart from the chain alkene, cyclic

alkene (cyclohexene) was also viable for this protocol, giving

the product 3la in a yield of 48%. Furthermore, functionalized

aliphatic alkenes containing a hydroxy or bromo group were

then employed for this transformation. Screening revealed that

free hydroxyl group was compatible with the reaction

conditions, and the corresponding product 3ma was obtained

in a yield of 54%. Accidentally, alkenes with the easy leaving

group, such as 5-bromopent-1-ene, gave the ﬁve-membered

cyclic ether 3na in 57% yield via the elimination of hydrogen

bromide caused by intramolecular substitution, and the

anticipated hydroxydiﬂuoroacetamidation product was not

observed. A range of styrenes bearing either an electron-

donating (methoxy) or electron-withdrawing (chloro) group

on the aryl ring also could be transformed into the

corresponding hydroxydiﬂuoroacetamidation products 3oa,

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Scheme 2. Substrate Scope of Alkenes

Scheme 3. Substrate Scope of Bromodiﬂuoroacetamides

Reaction conditions: 1 (2 mL), 2a (0.2 mmol), Rhodamine 6G (1

mol %, 0.002 mmol), and PMDETA (0.4 mmol) was irradiated with

an LED (545−550 nm) in air atmosphere at room temperature for 12

h. Isolated yields.

Reaction Conditions: 1a (2 mL), 2 (0.2 mmol), Rhodamine 6G (1

mol %, 0.002 mmol) and PMDETA (0.4 mmol) was irradiated with a

LED (545−550 nm) in air atmosphere at room temperature for 12 h.

Isolated yields.

3pa, and 3qa in 76, 73, and 72% yields, respectively. The α-

substituted alkene α-methylstyrene reacted smoothly, aﬀording

the desired product 3ra in a yield of 69%. Conjugated diene 1s

was readily converted to the desired α,α-diﬂuoro-γ-hydrox-

yacetamides product 3sa in moderate yield. Additionally, the

photocatalytic protocol presented herein was also easily

extended to nonconjugated diene 1t, which demonstrated its

wide substrate tolerance.

After the scope of alkenes was examined, a variety of N-aryl

bromodiﬂuoroacetamides was then investigated via the

hydroxydiﬂuoroacetamidation with allylbenzene 1a under the

standard conditions, and the results are summarized in Scheme

3. It was found that the substrates bearing either electron-

donating (methyl, methoxy, isopropyl) or electron-withdraw-

ing (ﬂuoro, chloro, bromo) groups on the para-position of the

benzene ring all could produce the corresponding products in

moderate to good yields (3ab−3ag). The eﬀect on the position

of substituents on the phenyl was then studied, and the results

showed that either meta-substituted or ortho-substituted

derivatives all exhibited good tolerance for this reaction,

providing the products 3ah−3ak in 60−73% yields. The

bromodiﬂuoroacetamides with multisubstituents on the phenyl

ring also worked well to give the corresponding products 3al

and 3am in satisﬁed yields. Subsequently, several other aryl

groups were demonstrated to be tolerated well for this

transformation. For example, compounds 2n−2r bearing a

naphthalene group aﬀorded the difunctionalization products

(3an−3ar) in moderate to good yields. In addition, we found

that substrates 2s−2u with quinoline moieties also could work

satisfactorily, aﬀording the products 3as−3au in 57−78%

yields. Finally, the pyridinyl-containing compound 2v was

tested for this reaction, and the desired product 3av was

obtained in a satisfactory yield.

To gain insights into the mechanism of this reaction, some

control experiments were performed (Scheme 4). A radical

scavenger, 2,6-di-tert-butyl-4-methyphenol (BHT), was ﬁrst

applied to the standard reaction system, and the trans-

formation was totally inhibited (Scheme 4, a). Subsequently, a

similar result was obtained when another radical scavenger

TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was employed

in same reaction system, and to our delight, the adduct

between TEMPO and RCF₂radical was successfully detected

by ESI- MS (Scheme 4, b). These results suggested that the

reaction might proceed via a radical mechanism. In addition,

this transformation could not proceed well when it was

conducted under N₂atmosphere, indicating that oxygen was

crucial for this reaction (Scheme 4, c, d). The Stern−Volmer

ﬂuorescence quenching experiments revealed that the excited

Rhodamine 6G was quenched by PMDETA, while 2-bromo-

2,2-diﬂuoro-N-phenylacetamide 2a exhibited much less of an

eﬀect (Figure S4 −S5, see Supporting Information).

619

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Org. Lett. 2021, 23, 617−622

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Letter

In summary, we succeeded in developing a synthetically

valuable method for the hydroxydiﬂuoroacetamidation of

unactivated alkenes by employing a photocatalytic system

under metal-free conditions, aﬀording novel access to α,α-

diﬂuoro-γ-hydroxyacetamides. This transformation proved to

be compatible with a wide range of aliphatic alkenes, and

bromodiﬂuoroacetamides bearing various functional groups

also exhibited good tolerance. Furthermore, this protocol

featured mild conditions, low cost, excellent regioselectivity,

and simple operation.

Scheme 4. Radical Inhibitor Experiment

ASSOCIATED CONTENT

* Supporting Information

■

sı

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c04216.

Experimental details and spectroscopic data for new

compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

■

Can Jin − Collaborative Innovation Center of Yangtze River

Delta Region Green Pharmaceuticals, Zhejiang University of

Technology, Hangzhou 310014, P.R. China; College of

Pharmaceutical Sciences, Zhejiang University of Technology,

Hangzhou 310014, P.R. China; orcid.org/0000-0003-

1997-6209; Email: jincan@zjut.edu.cn

According to the above-mentioned observations and

previous literature reports,¹⁵we could speculate a plausible

mechanism for this reaction as follows (Scheme 5). Irradiation

Scheme 5. Proposed Mechanism

Authors

Bin Sun − Collaborative Innovation Center of Yangtze River

Delta Region Green Pharmaceuticals, Zhejiang University of

Technology, Hangzhou 310014, P.R. China

Rui Zhu − College of Pharmaceutical Sciences, Zhejiang