Single Cu(I)-Photosensitizer Enabling Combination of Energy-Transfer and Photoredox Catalysis for the Synthesis of Benzo[ b]fluorenols from 1,6-Enynes

DOI: 10.1021/acs.orglett.1c01427

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Organic Letters p. 4478 - 4482 (2021)

Update date:2022-08-03

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Authors:

Zheng, Limeng

Xue, Han

Zhou, Bingwei

Luo, Shu-Ping

Jin, Hongwei

Liu, Yunkui

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Article abstract of DOI:10.1021/acs.orglett.1c01427

An efficient, mild, and atom-economical synthesis of benzo[b]fluorenols from 1,6-enynes has been developed under photocatalytic conditions. A single P/N heteroleptic Cu(I)-photosensitizer might exhibit both energy-transfer and photoredox catalytic activities in the formation of benzo[b]fluorenols.

Full text of DOI:10.1021/acs.orglett.1c01427

pubs.acs.org/OrgLett

Letter

Single Cu(I)-Photosensitizer Enabling Combination of Energy-

Transfer and Photoredox Catalysis for the Synthesis of

Benzo[b]ﬂuorenols from 1,6-Enynes

Limeng Zheng, Han Xue, Bingwei Zhou, Shu-Ping Luo, Hongwei Jin, and Yunkui Liu*

Cite This: Org. Lett. 2021, 23, 4478 −4482

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ABSTRACT: An eﬃcient, mild, and atom-economical synthesis of benzo[b]ﬂuorenols from 1,6-enynes has been developed under

photocatalytic conditions. A single P/N heteroleptic Cu(I)-photosensitizer might exhibit both energy-transfer and photoredox

catalytic activities in the formation of benzo[b]ﬂuorenols.

It is well-known that photocatalytic reactions can be

n the past several decades, visible light-driven photocatalytic

I_{reactions have received extensive attention and emerged as}classiﬁed into two categories according to diﬀerent mechanistic

pathways: (1) energy-transfer (EnT) reactions in which

photocatalysts merely transfer their absorbed energy to target

substrates and no electron-transfer events occur between

them;⁶(2) electron-transfer reactions in which photocatalysts

undergo single electron-transfer (SET) events to target

substrates or cocatalysts and they thus are termed as

photoredox catalysts.¹⁻³So far, in most of the reported

photocatalytic reactions, a certain photocatalyst achieves either

an energy-transfer or a photoredox catalytic cycle. To the best

of our knowledge, there are few examples in which a certain

photocatalyst achieves both the desired energy absorption

(EA) and photoredox catalytic activity within a designed

reaction.⁷We envision that it may be very attractive to take full

advantage of photocatalyst’s EA and photoredox activities

within a single photocatalytic reaction; thus unprecedented

transformations would be anticipated to be achieved. Due to

our continued interest in the development of highly eﬃcient

photocatalytic reactions involving P/N heteroleptic Cu(I)-

an important and useful platform for the construction of

complex molecules owing to their mild, environmentally

benign, and highly selective manner.¹⁻³In this regard, the

noble and heavy transition-metal-centered complexes, for

example, ruthenium(II)- and iridium(III)-centered polypyridyl

complexes, are the most commonly used photocatalysts

because of their long lifetime of excited states, strong energy

absorption in the visible light region, and desirable redox

potentials for triggering radical reactions.^1e,fHowever, the high

toxicity, expensive costs, and limited abundance of Ru and Ir

impede the large scale application of such photocatalysts in

organic synthesis. To circumvent the above-mentioned

problems, one way is to explore organo-photocatalyts;²the

other way is to explore photocatalysts based on metals with

advantages of low toxicity, inexpensive costs, and rich

abundance on earth. Recently, copper-based photocatalysts

have been proven to meet the criteria and have received

increasing attention.³Gratifyingly, they not only could replace

Ir- and Ru-based photosensitizers to promote some photo-

catalytic reactions⁴but also could achieve unique photo-

catalytic reactions that are diﬃcult to realize with the Ir- or Ru-

centered photocatalysts.⁵Thus, one can reasonably expect that

more and more novel transformations will be achieved with

copper-based photocatalysts under visible-light-driven catalysis

conditions.

Received: April 26, 2021

Published: May 14, 2021

https://doi.org/10.1021/acs.orglett.1c01427

Org. Lett. 2021, 23, 4478−4482

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Letter

photosensitizers,^5a,bherein we reveal that a combination of the

EA and photoredox activities of a P/N heteroleptic Cu(I)-

photosensitizer (PS 1) enabled the mild and eﬃcient

construction of benzo[b]ﬂuorenols from 1,6-enynes in

moderate to high yields in one-pot manner (Scheme 1a).

Table 1. Optimization of the Reaction Conditions

Scheme 1. Various Synthetic Routes for the Construction of

Benzo[b]ﬂuorenols

photosensitizer

(5 mol %)

yield of 2a

entry

amine (3.0 equiv)

solvent

(%)

PS 1

Et₃N

MeCN

PS 1

PS 2

PS 3

Ru(bpy)₃Cl₂·

6H₂O

Et₃N

Benzo[b]ﬂuorenone derivatives including benzo[b]ﬂuorenols

represent a class of important polycyclic compounds that have

a broad spectrum of biological or pharmaceutical properties.⁸

Previously, Hu et al. reported the synthesis of benzo[b]-

ﬂuorenols via a Pd-catalyzed intramolecular cyclization/

aromatization/carbonyl reduction of 1,6-enynes in the

presence of stoichiometric amounts of 3-bromoprop-1-yne

under a high temperature of 130 °C (Scheme 1b);^8fin 2017,

Liu et al. developed a multistep synthesis of benzo[b]ﬂuorenols

involving a DBU-catalyzed intramolecular cyclization of 1,6-

diynyl carbonates at 80 °C followed by an alcoholysis of the

resulting benzo[b]ﬂuorene carbonates (Scheme 1c).^8gOur

protocol for the construction of benzo[b]ﬂuorenols has

characteristic advantages of mild reaction conditions and

high atom economy.

Initially, 1,6-enyne 1a was chosen as the model substrate to

optimize the reaction conditions (Table 1). When 1a was

treated with 3 equiv of Et₃N in MeCN in the presence of 5 mol

% PS 1 under N₂atmosphere protection and blue LED

irradiation for 20 h, benzo[b]ﬂuorenol 2a was unexpectedly

obtained in 64% LC yield (entry 1, Table 1). Controlled

experiments indicated that photocatalyst, light irradiation, and

amine are indispensable for the formation of 2a (entries 2−4,

Table 1). Among a range of photocatalysts and amines

screened, P/N heteroleptic Cu(I)-photosensitizer PS 1

exhibited the highest catalytic eﬃciency and Me₂NH

(dissolved in THF, 2.0 M) was proven to be the best choice

of amine (entries 1, 5−18, Table 1). Solvent screening

experiments indicated that MeCN was the most suitable

medium for the reaction (entries 18−21, Table 1). It was

found that 3.0 equiv of Me₂NH was just enough for getting

satisfactory yield of 2a, while 2.0 or 4.0 equiv of Me₂NH led to

a decreased yield of 2a (entries 22 and 23 vs 18, Table 1).

Attempts to decrease the catalyst loading to 2.5 mol % resulted

in a poor outcome (entry 24 vs 18, Table 1). The use of 10

mol % PS 1 did not improve the yield of 2a (entry 25 vs 18,

Table). Under the optimized reaction conditions of entry 18 in

Table 1, a 1 mmol scale synthesis of 2a was also carried out,

and 2a could be obtained in 80% yield (entry 18, Table 1).

With the optimized reaction conditions in hand, we set out

to investigate the scope of 1,6-enynes 1 (Scheme 2). The R¹

groups on the phenyl ring A were ﬁrst examined. It was found

that the substrates with electron-donating R¹groups generally

underwent the annulation more smoothly and aﬀorded higher

Rose Bengal

PS 1

Et₃N

DIPEA

(n-Pr)₃N

TMEDA

n-butyamine

piperidine

tetrahydropyrrole

N-ethylaniline

(n-Bu)₂NH

(n-Pr)₂NH

Me₂NH

Me₂NH (2.0)

Me₂NH (4.0)

Me₂NH

MeCN

THF

toluene

DMF

MeCN

PS 1

18 PS 1

92(86 , 80 )

PS 1

PS 1 (2.5)

PS 1 (10.0)

Me₂NH

Reaction conditions: 1a (0.3 mmol), photocatalyst (5 mol % based

on 1a), amine (3.0 equiv based on 1a; Me₂NH was dissolved in THF

(2 M)), and solvent (6 mL) with 15 W blue LED light for 20 h under

N₂atmosphere unless otherwise noted. Yields were determined by

LC analysis. Without light irradiation. Trace. Isolated yield is

shown in parentheses. Yield of 1 mmol scale synthesis of 2a.

yields of products than those with electron-withdrawing R¹

groups (2a−2c, 2e, 2f, and 2h vs 2d and 2g, Scheme 2). In

addition, when the aromatic ring A was 1-naphthalenyl or 2-

thiophenyl moiety, the reaction also proceeded smoothly,

aﬀording the desired products in 67% and 69% yield,

respectively (2i and 2j, Scheme 2). Next, we examined the

generality of 1,6-enyne 1 with diﬀerent substituents R²on the

phenyl ring B. It was found that the introduction of electron

donating groups into the phenyl ring B was necessary for

getting acceptable yields of products (2k−2o, Scheme 2). It is

interesting that a pyridine-derived 1,6-enyne 1p was also viable

for the reaction, and the desired product was obtained in 57%

yield (2p, Scheme 2). Finally, we examined the reactivity of

1,6-enynes with various R³groups. Generally, substrates

possessing aryl or heteroaryl R³groups performed better and

delivered higher yields of products than those containing

aliphatic R³ones (2q−2x vs 2z, Scheme 2). When R³was a

heterocycle moiety, for example, 3-thiophenyl group, the

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Scheme 2. Substrate Scope for 1,6-Enynes 1

Scheme 3. Mechanistic Experiments

reaction also worked well and delivered the desired product in

a high yield of 90% (2y, Scheme 2).

To gain insight into the possible reaction mechanism, several

mechanistic experiments were carried out (Scheme 3). First,

the model reaction of 1a was interrupted midway, and 37%

yield of 2a was obtained along with small amount of 3a (10%

yield) (eq 1, Scheme 3). If 1a was subjected to the standard

conditions except in the absence of Me₂NH, then only 3a was

obtained in 95% yield (eq 2, Scheme 3). When the preparative

3a was subjected to the standard conditions, 2a was obtained

in 93% yield (eq 3, Scheme 3). These results indicated that 3a

might be an intermediate in this transformation. We could not

detect [4 + 2] cyclization intermediate 5 (vide infra, Scheme 4)

and 2za when we subjected 1a and 1za, respectively (eq 4,

Scheme 3), to the standard conditions. Fortunately, we

detected and isolated [4 + 2] cyclization intermediate 2zb

when 1zb was used as the starting material (eq 5, Scheme 3).

Next, deuterium-labeling experiments were conducted. When

the reaction of 1a was run under the standard conditions

except in the presence of 3.0 equiv of D₂O, deuterium-

incorporated 2a-d₁, which contains 17% D-enrichment of the

methyne hydrogen at the 11-position was obtained in 87%

yield (eq 6, Scheme 3). In addition, we synthesized 1a-d₆and

subjected it to the standard reaction conditions. To our

surprise, in the resulting 2a-d₆, a 22% D-enrichment of the

methyne hydrogen at the 11-position was also observed (eq 7,

Scheme 3). These results indicated that hydrogen on the

phenyl ring A or the residue H₂O in the reaction medium may

be the hydrogen source of the methyne moiety at the 11-

position of 2a. In addition, Stern−Volmer studies between 1a

and PS 1 indicated that the energy transfer process from PS 1

to 1a occurred (see Figure S3 in SI). Finally, radical scavenging

experiments indicated that the model reaction of 1a could not

be inhibited in the presence of 2.0 equiv of TEMPO, BHT, or

1,1-diphenylethylene (eq 8, Scheme 3, see SI).

Scheme 4. Proposed Mechanism

First, upon irradiation, PS 1 transferred its absorbed energy to

1a, and triplet intermediate 4 was formed, which readily

underwent an intramolecular [4 + 2] cyclization to produce

intermediate 5.^6,9Then upon energy transfer from PS 1 or

direct excitation by light, intermediate 5 may be converted into

its excited triplet species 6, which may undergo an intra-

molecular HAT (hydrogen atom transfer) process to ﬁnally

deliver 2a (path a).^10,11,12aAlternatively, an intermolecular

HAT process between the excited triplet species 6 and

intermediate 5 may also possibly occur (path b).^10,12Thus,

intermediate 7 and 3a may be produced. Upon aromatization,

7 could be ﬁnally converted to 2a. Furthermore, 3a could be

Based on the experimental results and previous litera-

ture,^6,9−14a possible mechanism is proposed in Scheme 4.

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converted to the excited state 3a* by light. Then both 3a

(E_p/2(3a/3a^−•) = −1.26 V vs SCE; see SI) and 3a* may

undergo SET reduction by the excited state Cu(I)*

(E_1/2(Cu^II/Cu^I*) = −1.37 V vs SCE^5b) to give 8 and an

oxidative Cu(II) species (E_1/2(Cu^II/Cu^I) = +1.27 V vs SCE^5b),

which could be reduced back to Cu(I) by Me₂NH

(E_p/2[(Me)₂NH^•+/(Me)₂NH] = +1.03 V vs SCE¹³).¹⁴

Compound 8 could be further reduced and ﬁnally transferred

to 2a.

In summary, we have successfully developed a mild and

atom-economical preparation of benzo[b]ﬂuorenols from 1,6-

enynes enabled by a P/N heteroleptic Cu(I)-photosensitizer.

The P/N-heteroleptic Cu(I)-photosensitizer played a key role

in the reaction by merging both energy-transfer and photo-

redox catalytic activities in the reaction. Further studies on the

exploration of novel reactions via combination of energy-

transfer and photoredox catalysis of P/N heteroleptic Cu(I)-

photosensitizers are still underway in our laboratory.

ACKNOWLEDGMENTS

■

We are grateful to the Natural Science Foundation of China

(No. 21772176 and 22001231) and the Natural Science

Foundation of Zhejiang Province (No. LY20B020013 and

LQ20B020012) for ﬁnancial support.

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ASSOCIATED CONTENT

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Corresponding Author

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Yunkui Liu − State Key Laboratory Breeding Base of Green

Chemistry-Synthesis Technology, College of Chemical