HFIP-Catalyzed Difluoroalkylation of Propargylic Alcohols to Access Tetrasubstituted Difluoroalkyl Allenes

Tetrasubstituted Di ﬂ uoroalkyl Allenes

Letter

HFIP-Catalyzed Diﬂuoroalkylation of Propargylic Alcohols to Access

Jinshan Li, Wenxue Xi, Saimei Liu, Chenxi Ruan, Xiaochun Zheng, Jianguo Yang, Lei Wang,

and Zhiming Wang*

Cite This: https://doi.org/10.1021/acs.orglett.1c02659

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sı Supporting Information

ABSTRACT: A hexaﬂuoroisopropanol (HFIP)-catalyzed diﬂuoroalkylation of propargylic alcohols with diﬂuoroenoxysilanes to

access structurally diverse tetrasubstituted diﬂuoroalkyl allenes has been developed. This convenient procedure enables the rapid

construction of highly functionalized multisubstituted ﬂuorinated allenes in a mild and straightforward way. Furthermore, the

synthetic potential of this methodology has been demonstrated by the facile synthesis of various structurally interesting ﬂuorine-

containing molecules such as gem-diﬂuorosubstituted dihydropyran, tetrasubstituted CF H-allene, and multisubstituted ﬂuorinated

cyclopentanone derivatives.

llenes are the core substructures of numerous natural

products and pharmaceuticals and are synthetically robust

Scheme 1. Synthetic Strategies toward Tetrasubstituted

Diﬂuoroalkyl Allenes

building blocks for the construction of diverse complex

molecules. Therefore, the development of more eﬃcient

and convenient methods for the synthesis of functionalized

allenes from simple starting materials is highly desirable.

Meanwhile, the introduction of ﬂuorine atoms or ﬂuoroalkyl

groups into molecules could have a broad impact on the

physicochemical characteristics and biological activities of the

parent targets, and thus the synthesis of ﬂuorinated allenes is

of great value for medicinal chemistry and drug development.

Furthermore, polyunsaturated hydrocarbons featuring the

distinct properties of allenes would allow a large variety of

1c,f

structure reorganizations for further applications. However,

in comparison with the well-developed methods for the

synthesis of di- or trisubstituted diﬂuoroalkyl allenes, the

synthetic strategies for accessing tetrasubstituted diﬂuoroalkyl

allenes have been much less exploited. In 2019, Wang and

coworkers developed a Ni-catalyzed 1,4-carboﬂuoroalkylation

of 1,3-enynes to access tetrasubstituted diﬂuoroalkyl allenes

using diﬂuoroalkyl halides (Scheme 1a). In 2020, Bao and

Received: August 10, 2021

coworkers reported a metal-free synthesis of tetrasubstituted

diﬂuoromethyl allenes via the 1,1,4-trifunctionalization of 1,3-

enynes with N-ﬂuorobenzenesulfonimide (NFSI) as the

ﬂuorination source (Scheme 1b). Thus the development of

new eﬃcient strategies for the synthesis of multiply function-

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

alized tetrasubstituted diﬂuoroalkyl allenes using easily

available reaction partners is highly desirable.

Table 1. Regioselective 1,4-Nucleophilic Diﬂuoroalkylation

of α,β-Enones

Among the established methods to construct allenes, the

direct transformation of propargylic alcohols or their

derivatives represents one of the most eﬃcient approaches

with great successes achieved. Great eﬀorts have been devoted

to the preparation of challenging multisubstituted allene

derivatives by trapping the in-situ-generated allenic carboca-

tion intermediates from propargylic alcohols with diﬀerent

types of nucleophiles. Usually, stronger nucleophiles are

yield (%)

required to inhibit the Meyer−Schuster rearrangement

byproduct. In sharp contrast, no attempt has been made

for the synthesis of multisubstituted ﬂuorinated allenes with

ﬂuorinated nucleophiles, which is mainly due to their relatively

low electron density and poor nucleophilicity. Therefore, the

rearrangement side reaction must be eﬃciently suppressed to

successfully obtain the targeted ﬂuorinated allene product. In

our recent studies, we found for the ﬁrst time that

hexaﬂuoroisopropanol (HFIP) could act as an ideal catalyst

to form the ﬂuorinated carbon−carbon bond with high

entry

catalyst

solvent

time (h)

Cu(OTf)₂

DCM

HFIP

DCE

BF ·OEt₂

trace

HFIP

TFE

eﬃciency. Inspired by this interesting investigation, along

with our continuing interest in developing new strategies for

the synthesis of ﬂuorine-containing molecules, we envisioned

PrOH

that the HFIP-catalyzed strategy would bring great oppor-

tunities to eﬃciently access structurally diverse tetrasubstituted

diﬂuoroalkyl allenes with diﬂuoroenoxysilanes as diﬂuoroalky-

<1 min

HFIP

lating reagents (Scheme 1c). Additionally, the coexistence of

allene and diﬂuoroketone multifunctional structural units in

the products could provide versatile handles for the further

synthesis of structurally interesting ﬂuorine-containing mole-

cules.

MeNO₂

toluene

Reaction conditions: 1a (0.5 mmol), 2a (1.05 equiv), and catalyst

(10 mol %) in solvent (3.0 mL) at room temperature. Isolated yields.

HFIP was used as a solvent. ND, not detected.

With the above understanding in mind, we ﬁrst examined

the reaction between propargylic alcohol 1a and diﬂuoroenox-

ysilane 2a by employing diﬀerent Lewis acids (Cu(OTf) , BF ·

With the optimized reaction conditions in hand, we

investigated the substrate scope of the preparation of

tetrasubstituted diﬂuoroalkyl allenes 3. As shown in Scheme

2, a series of propargylic alcohols and diﬂuoroenoxysilanes with

both electron-donating and electron-withdrawing substituents

proved to be compatible for this HFIP-catalyzed reaction.

First, propargylic alcohols bearing diﬀerent substituents at the

γ-position were evaluated. It was found that propargylic

alcohols bearing electron-donating groups aﬀorded the desired

products (3c, 3d, and 3g) in a higher yield than the substrates

bearing electron-withdrawing groups (3b and 3f). A

substituent at the ortho position of the phenyl ring gave a

lower yield (3e, 72% yield), indicating that the steric eﬀect had

a great inﬂuence on the reaction. Then, the propargylic

alcohols derived from a range of substituted diaryl ketones

were used as the substrate (1h−1p). All of these propargylic

alcohols were well tolerated under standard conditions and

aﬀorded the expected products (3h−3p) in moderate to good

yields (64−87% yields). Subsequently, diﬂuoroenoxysilanes

with electron-donating or electron-deﬁcient groups were

evaluated, and the corresponding products could be obtained

in good yields (3q−3u). Heteroaryl-substituted propargylic

alcohol was also well-tolerated for this method to aﬀord the

desired allene product (3v). Unfortunately, propargylic

alcohols derived from ﬂuorenone 3w were found to be

unsuitable for this reaction, and the propargylic alcohol was

recovered, which was probably due to the large steric

hindrance of the ﬂuorenyl group. For the alkyl-substituted

OEt ) or a Brønsted acid (diphenyl phosphate A) as a

comparison (Table 1, entries 1−3). Under the action of these

catalysts, the reaction usually gave both the allene product 3a

and the rearrangement product 4a simultaneously. Changing

the catalyst to more mild hydrogen-bonding organocatalysts

such as urea B and thiourea C did not give better results

(

entries 4 and 5). Considering the remarkable ability of HFIP

11,12

to enhance the reaction eﬃciency

and its good catalytic

performance for the construction of a ﬂuorinated carbon−

carbon bond in our previous study, HFIP was then employed

as a promising catalyst to access the desired tetrasubstituted

diﬂuoroalkyl allene products with high selectivity. As expected,

the reaction proceeded smoothly to aﬀord the allene product

a in 86% yield (entry 6). Other ﬂuoroalcohols, such as

triﬂuoroethanol (TFE), hexaﬂuoro-2-methylisopropanol D,

hexaﬂuoro-2-phenylisopropanol E, and 2,2,3,3-tetraﬂuorobuta-

nediol F, could also promote the selectivity toward the target

allene product, although in lower yields (entries 7−10).

Furthermore, the strong hydrogen-bonding donor ability and

the unique eﬀects of ﬂuorine atoms in HFIP were

demonstrated by the obtained results when HFIP was replaced

by the corresponding ether G or isopropanol (entries 11 and

2). Interestingly, the reaction could proceed almost

instantaneously when using HFIP as a solvent (entry 13).

Further screening of other solvents did not give higher yields

(

entries 14−16). Thus the optimal reaction conditions were

established to be the use of HFIP (10 mol %) as the catalyst in

dichloromethane (DCM) at room temperature, as shown in

entry 6.

propargyl alcohol 1x (R = R = Me), both the allene product

3x (42% yield) and the direct hydroxyl-substituted product 3x′

(34% yield) were obtained. Unfortunately, the benzyl-

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 2. Scope of the Diﬂuoroalkylation of Propargylic

Alcohols with Diﬂuoroenoxysilanes

substituted diﬂuoroenoxysilane 2y was found to be unsuitable

for this reaction, probably due to the low nucleophilicity of the

alkyl-substituted reactant.

After successfully developing a convenient approach for the

synthesis of tetrasubstituted diﬂuoroalkyl allenes, we then

focused our attention on the potential applications of these

multisubstituted ﬂuorinated allenes. Considering the fact that

allenes are widely used as key building blocks for constructing

more complex substructures and the versatile performance of

−10

α,α-diﬂuoroketones in organoﬂuorine chemistry,

the

synthesized highly functionalized allene should provide huge

potential for building various ﬂuorinated motifs. As shown in

Scheme 3, a gram-scale experiment has been conducted to

Scheme 3. Gram-Scale Experiment and Diversiﬁed

Synthesis of Functionalized CF -Containing Dihydropyran

Derivatives

demonstrate the synthetic utility of this protocol in the ﬁrst

place. The reduction of 3m with NaBH proceeded eﬃciently,

delivering the ﬂuorinated β-allenol 5 in 96% yield. More

importantly, the subsequent acid-catalyzed or electrophile-

mediated cyclization of 5 with p-toluenesulfonic acid (PTSA),

N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), Se-

lectﬂuor, or PhSeCl enabled the facile synthesis of a series of

gem-diﬂuorosubstituted dihydropyran derivatives (6−10) that

are otherwise diﬃcult to access, which provides a new

synthetic strategy to access these bioactively important

ﬂuorinated six-membered heterocycles.

The synthesis of CF H-containing molecules has attracted

great attention in recent years due to their widespread

applications in the ﬁelds of pharmaceuticals, agrochemicals,

and material sciences. However, the reported routes for the

synthesis of CF H-allenes usually require a multistep synthesis

procedure. Previous works by our group have demonstrated

that diﬂuoroenoxysilanes could serve as ideal reagents to

selectively and eﬃciently incorporate the CF H group into the

ortho position of the sulfur group in chalcogenides, which

prompted us to construct a tetrasubstituted CF H-allene by

the simple treatment of diﬂuoroalkyl allene 3m with a strong

base through the Haller−Bauer reaction. Surprisingly, unlike

the previous studies, this C−C bond cleavage reaction is highly

Reaction conditions: propargylic alcohol 1 (0.5 mmol), diﬂuor-

oenoxysilane 2 (1.05 equiv), and HFIP (10 mol %) in DCM (3.0 mL)

dependent on the solvent. The desired tetrasubstituted CF H-

at room temperature.

allene 11 could be obtained only with MeCN as solvent

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

318000, P. R. China; orcid.org/0000-0002-6583-3826;

Letter

(

Scheme 4). When the solvent was changed to MeOH, an

Email: wzmmol@hotmail.com, zhiming@tzc.edu.cn

unexpected highly substituted ﬂuorinated cyclopentanone

Authors

Scheme 4. Synthesis of Tetrasubstituted CF H-Allene and

Fluorinated Cyclopentanone Derivative

Jinshan Li − Advanced Research Institute and Department of

Chemistry, Taizhou University, Taizhou 318000, P. R.

China; orcid.org/0000-0001-8033-5932

Wenxue Xi − Advanced Research Institute and Department of

Chemistry, Taizhou University, Taizhou 318000, P. R.

China

Saimei Liu − Advanced Research Institute and Department of

Chemistry, Taizhou University, Taizhou 318000, P. R.

China

Chenxi Ruan − School of Resources and Chemical Engineering,

Sanming University, Sanming 365004, P. R. China

Xiaochun Zheng − Advanced Research Institute and

Department of Chemistry, Taizhou University, Taizhou

18000, P. R. China

product 12 (X-ray conﬁrmed) was obtained instead of the

Jianguo Yang − Advanced Research Institute and Department

of Chemistry, Taizhou University, Taizhou 318000, P. R.

China; orcid.org/0000-0003-4268-7384

Lei Wang − Advanced Research Institute and Department of

Chemistry, Taizhou University, Taizhou 318000, P. R.

China; orcid.org/0000-0001-6580-7671

CF H-allene product, which is otherwise diﬃcult to prepare via

the reported synthetic routes. On the basis of the

experimental result, a plausible mechanism for the formation

of this ﬂuorinated cyclopentanone is outlined in Scheme 4.

First, diﬂuoroalkyl allene 3m is attacked by the hydroxyl anion

to produce the intermediate I. The keto−enol tautomerism of

intermediate I delivers intermediate II. Subsequently, the

ﬂuorinated pent-2-ene-1,4-dione intermediate III may be

generated through a β-F elimination process. Finally, intra-

molecular nucleophilic attack of the remote carbonyl group

provides the observed ﬂuorinated cyclopentanone product 12.

In summary, a straightforward method to access a

structurally diverse array of tetrasubstituted diﬂuoroalkyl

allenes from readily available propargylic alcohols and

diﬂuoroenoxysilanes under HFIP catalysis has been developed.

This reaction features a simple operation, mild reaction

conditions, and good functional group tolerance. The key to

the success of this reaction is the utilization of HFIP as a

powerful catalyst to suppress the rearrangement side reaction

of propargylic alcohols. Various useful ﬂuorine-containing

compounds such as gem-diﬂuorosubstituted dihydropyran,

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c02659

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Natural Science Foundation of Zhejiang

Province (no. LQ20B020005), Leading Innovative and

Entrepreneur Team Introduction Program of Zhejiang (no.

019R01005), and Joint Fund of Zhejiang Provincial Natural

Science Foundation (no. LTZ21B020001).

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