Difunctionalization of Alkynones by Base-Mediated Reaction with α,α-Dithioketones

Yajie Yang, Lu Cheng, Mengdan Wang, Liqiang Yin, Ye Feng, Chengyu Wang,* and Yanzhong Li *

Letter

Difunctionalization of Alkynones by Base-Mediated Reaction with

α ,α -Dithioketones

Cite This: Org. Lett. 2021, 23, 5339 −5343

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sı Supporting Information

ABSTRACT: A novel 1,2-difunctionalization of alkynones via an

umpolung strategy for the synthesis of tetrasubstituted oleﬁns has

been developed. This procedure is realized by a formal C−C σ-bond

cleavage reaction of cyclic α,α-dithioketones and subsequent

deprotection. Notable features of this approach include excellent

yields, mild reaction conditions, a broad substrate scope, and

operational simplicity.

lkynes, one of the most prevalent classes of organic

compounds, are widely used as building blocks for the

synthesis of many functional materials and pharmaceutical

molecules. Arguably, among the various transformation

reactions of alkynes, one-pot 1,2-difunctionalization of internal

alkynes is an eﬃcient approach for the synthesis of

tetrasubstituted alkene derivatives, especially those bearing

Figure 1. Biologically active compounds containing tetrasubstituted

oleﬁns.

four functional groups (Scheme 1a). Most of these reactions

required transition metal catalysis. For instance, Gaunt’s group

creatively realized Cu-catalyzed electrophilic carbotriﬂation of

alkynes to form highly substituted tetrasubstituted alkenyl

triﬂates. A gold-catalyzed intermolecular difunctionalization

of alkynes with aryl diazonium salts without any external

oxidants and photosensitizers under visible-light irradiation

was presented by Hashmi’s group. In addition, a few studies

concerning transition metal-free difunctionalization of internal

alkynes have also been reported. For example, Greaney and co-

workers developed the eﬃcient metal-free aminoarylation of

internal alkynes to yield tetrasubstituted enaminoates in a

single step. A practical multicomponent synthesis of highly

substituted vinyl ethers via iodo(III) etheriﬁcation of alkynes

with iodine(III) electrophiles and alcohols was disclosed by

Scheme 1. Difunctionalization of Alkynes

Yoshikai’s group. Although great progress has been made in

the past few decades, almost all of the reported alkyne

difunctionalization reactions are simultaneous incorporations

of two functional groups of opposite polarity onto the diﬀerent

carbon atoms of the CC bonds. In this context, installing

two functional groups of the same polarity on the internal

alkynes remains a challenge and has rarely been reported

except with the help of transition metal catalysis.

Carbonyl and formyl functional groups are important and

are used ﬂexibly for subsequent modiﬁcation and trans-

formations. Thus, installing carbonyl and formyl groups

Received: May 14, 2021

Published: July 6, 2021

2021 American Chemical Society

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Org. Lett. 2021, 23, 5339−5343

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Letter

Table 1. Optimization of the Synthesis of 3a

Scheme 2. Scope of Alkynone 1 for the Bifunctionalization

Reaction

a,b

entry

1a:2a

base

solvent

yield (%)

1:1

1:1.2

1:1

2.0 equiv of Cs CO

DMSO

DMF

DMA

toluene

DMSO

2.0 equiv of Cs CO

2.0 equiv of CsF

2.0 equiv of K CO

2.0 equiv of BuOK

2.0 equiv of Cs CO

1.5 equiv of Cs CO

Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), solvent (2.0

mL), base, reaction in air, 1 h. Isolated yields. N . No reaction.

simultaneously on the adjacent carbon atoms of CC bonds

is very appealing, and they serve as a platform for producing

various highly functionalized tetrasubstituted alkenes. How-

ever, installation of these groups is a great challenge because of

their identical electrophilic character. Phenylglyoxal, an ideal

bifunctional molecule containing both carbonyl and formyl

groups, makes it possible to introduce carbonyl and formyl

groups across CC bonds via formal C−C σ-bond cleavage

reactions. Nevertheless, phenylglyoxal has rarely been exam-

ined as the bifunctional group source in organic synthesis

despite its high reactivity. We considered trying to reverse the

electronic property of the formyl carbon in phenylglyoxal

through the strategy of polarity reversal, that is the protection

of the formyl group with 1,3-dithiane, because the 1,3-

dithianes are usually regarded as precursors of sulfur-stabilized

acyl anion equivalents (umpolung reactivity) and widely used

as nucleophiles in alkylation, epoxide ring opening, and

Michael addition reactions. We envisaged that such protected

Reactions were conducted by employing 1 (0.3 mmol) to react with

phenylglyoxal might undergo nucleophilic attack to electron

deﬁcient alkynes such as alkynones, followed by intramolecular

addition to the CO bond of phenylglyoxal to give a

cyclobutenol intermediate. In addition, ring opening of the

cyclobutenol intermediate might give rise to difunctionalized

alkynes bearing both carbonyl and thiolyl groups simulta-

neously (Scheme 1b). It is known that tetrasubstituted oleﬁns

have been widely explored for liquid crystal and materials

a (0.3 mmol) in 3 mL of DMSO with 2.0 equiv of Cs CO at room

2 3

temperature under N . Isolated yields. The isomer ratios were taken

from the H NMR spectrum. Keto:enol ratio of 1:0.7. Keto:enol

ratio of 0.3:1. Keto:enol ratio of 1:0.3. Keto:enol ratio of 1:0.4.

optimize the reaction conditions, we screened other parame-

ters systematically. The same yield of 3a was obtained when

the 1a:2a was changed to 1:1.2 (entry 2). A survey of diﬀerent

research and are found in many pharmaceutical compounds

such as Tamoxifen, idoxifene, and etacstil (Figure 1). We

report herein a base-promoted 1,2-difunctionalization of

alkynes via the C−C σ-bond cleavage reaction of cyclic α,α-

dithioketones, which provides potential access to tetrasub-

stituted oleﬁns.

bases was conducted, including CsF, K CO , and BuOK, and

the yields of 3a all decreased dramatically (entries 3−5,

respectively). An almost quantitative yield of the desired

product 3a was obtained when the reaction was conducted

under a nitrogen atmosphere (entry 6). Conducting the

reaction in solvents such as DMF, DMA, and toluene

decreased the yield (entries 7−9, respectively). In addition,

decreasing the loading of Cs CO impaired this reaction with a

To test our hypothesis, we carried out the investigation by

employing 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one

(

1a) to react with (1,3-dithian-2-yl)(phenyl)methanone (2a)

using Cs CO as the base and DMSO as the solvent at room

temperature (Table 1). The desired product 3a was isolated in

lower yield of 94% (entry 10). On the basis of the experimental

data presented above, 2.0 equiv of Cs CO as the base and

6% yield (entry 1). According to H NMR, the H signal of

the enol−OH shifted to 17−18 ppm, indicating the formation

of a hydrogen bond with the carbonyl oxygen. To further

DMSO as the solvent at room temperature under a N₂

atmosphere proved to be the optimized reaction conditions.

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Org. Lett. 2021, 23, 5339−5343

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Letter

Scheme 3. Scope of α,α-Dithioketone 2 for the

Bifunctionalization Reaction

Scheme 5. Transformations of Products

adjacent to the triple bond, various electron-withdrawing

groups such as 4-F, 4-Cl, 3-Cl, 4-Br, and 4-I and an electron-

donating group (4-OMe) introduced onto the aryl ring were all

suitable substrates to produce 3o−3t in high yields. Similarly,

substrates with 2-thienyl and 2-furyl groups could also be

Reactions were conducted by employing 1b (0.3 mmol) to react

employed in this transformation. An alkyl-substituted R group

with 2 (0.3 mmol) in 3 mL of DMSO with 2.0 equiv of Cs CO at

room temperature under N . Isolated yields. Keto:enol ratio of 0.1:1.

The isomer ratio was taken from the H NMR spectrum.

(C H and C H ) also resulted in the corresponding products

w and 3x in 67% and 73% yields, respectively.

Finally, the substituent scope of R in the α,α-dithioketone

was examined (Scheme 3). Various electron-withdrawing and

electron-donating aryl groups were found to be suitable for this

reaction, delivering good yields of the products (3y−3ac).

Notably, the strong electron-withdrawing group CN could also

be introduced into the desired product 3ad. Dithioketones

with naphthyl and thienyl substitution also provided the

products 3ae and 3af in 99% and 98% yields, respectively.

Scheme 4. Possible Mechanism for the Formation of 3a

Alkyl-substituted R groups (n-Pr and i-Pr) also worked

smoothly, providing the corresponding products 3ag and 3ah

in 96% and 87% yields, respectively.

On the basis of the literature precedent, a possible

mechanistic pathway for the formation of product 3a is

depicted in Scheme 4. First, dithioacetal 2a is readily

deprotonated to form carbanion A in the presence of a base,

which subsequently attacks alkynone 1a resulting in allene

intermediate B. Following that, an intramolecular nucleophilic

addition/four-membered ring-opening cascade occurs to

provide intermediate D, which undergoes further hydrolysis

to aﬀord product 3a.

With the optimized conditions in hand (Table 1, entry 6),

we investigated the substrate scope of ynones. As shown in

Scheme 2, we explored ynones with diﬀerent substituents (R )

attached to the carbonyl and found that alkynones with both

electron-donating and electron-withdrawing groups on the

phenyl ring were compatible, oﬀering excellent yields of the

desired products 3a−3h. X-ray crystallographic analysis

unambiguously conﬁrmed the structure of 3b as a Z form in

the enol form. Subsequently, the sterically demanding 1-

naphthyl- and 2-naphthyl-substituted ynones were also ex-

plored and gave the corresponding products 3i and 3j with

To demonstrate the versatility of the strategy, further

transformations of the products were carried out. At ﬁrst, we

tried to dethioacetalize the products. Due to the enol

isomerization, the product 3c mainly exists in an enol

structure. As a result, under the hydrolysis condition, the

corresponding carboxylic acid was produced and further

nucleophilic addition gave the highly functionalized γ-

high yields of 93% and 96%, respectively. The H NMR

spectrum of 3j showed that two isomers were obtained because

of keto−enol isomerization. Notably, heteroaryl motifs such as

N-methyl-2-indolyl, N-tosyl-2-pyrrolyl, and 3-furyl were well

tolerated, providing products 3k−3m, respectively. Even the

hydroxybutenolide 4c (Scheme 5a). When the substituents

R and R of substrates 1 and 2 were diﬀerent, a mixture of two

isomers (4a and 4a′) was obtained (Scheme 5b). Indeed, γ-

hydroxybutenolide is a vital core extensively found in natural

products and bioactive molecules. At 80 °C, 3f bearing an o-

alkyl R substituent ( Bu) worked well to furnish the desired

product 3n, albeit with a reduced yield. For R substituents

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Org. Lett. 2021, 23, 5339−5343

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Letter

bromo-substituted phenyl ring could be converted to

chromone derivative 5 almost quantitatively (Scheme 5c).

In summary, we have developed a versatile and highly

eﬃcient base-promoted alkyne difunctionalization reaction via

the formal C−C σ-bond cleavage reaction of cyclic α,α-

dithioketones. This reaction proceeds under mild conditions

with a broad substrate scope, yielding tetrasubstituted oleﬁns

in excellent yields. This procedure represents the ﬁrst example

of installing two electrophiles on the triple bond simulta-

neously without transition metal catalysis with operational

simplicity.

ACKNOWLEDGMENTS

■

The authors thank the National Natural Science Foundation of

China (Grants 21871087 and 21702088) and the Open

Research Fund of Key Laboratory of Polar Materials and

Devices, Ministry of Education, for ﬁnancial support.

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AUTHOR INFORMATION

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Corresponding Authors

0791−10811. (i) Tian, P. P.; Cai, S. H.; Liang, Q. J.; Zhou, X. Y.;

Yanzhong Li − School of Chemistry and Molecular

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00241, China; Key Laboratory of Polar Materials and

Devices, Ministry of Education, East China Normal

University, Shanghai 200241, China; orcid.org/0000-

002-2898-3075; Email: yzli@chem.ecnu.edu.cn

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Chengyu Wang − School of Chemistry and Chemical

Engineering, Linyi University, Linyi, Shandong 276000,

China; orcid.org/0000-0002-9189-1069;

Email: wangchengyu@lyu.edu.cn

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Yajie Yang − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China;

orcid.org/0000-0002-3782-1131

Lu Cheng − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China

Mengdan Wang − School of Chemistry and Molecular

Engineering, East China Normal University, Shanghai

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Liqiang Yin − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China

Ye Feng − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China

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The authors declare no competing ﬁnancial interest.

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