Access to gem-Difluoro Olefins via C-H Functionalization and Dual Role of Anilines

Zhen Yang, Chao Pei, and Rene M. Koenigs*

Letter

Access to gem-Diﬂuoro Oleﬁns via C−H Functionalization and Dual

Role of Anilines

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sı Supporting Information

ABSTRACT: In this Letter, we describe a simple, practical approach in which cheap CuI was used as a catalyst to introduce a gem-

diﬂuoro oleﬁn onto simple electron-rich aniline derivatives in good yield via direct C−H functionalization and a subsequent HF

elimination reaction. Detailed mechanistic studies point at a dual role of aniline derivatives in this reaction, which serve as a substrate

and a basic promoter to trigger the HF elimination step.

rganoﬂuorine compounds are an important topic in

organic chemistry and attract the interest of chemists

replacement of a carbonyl group with a gem-diﬂuoro oleﬁn can

improve the pharmacological proﬁle and reduce the in vivo

metabolism, which leads to improved bioactivity of drugs

without inﬂuencing the recognition by their biological target.

The development of eﬃcient and robust synthesis methods

due to their unique properties and wide applications ranging

from agricultural chemistry to pharmaceutical chemistry and

material sciences. Among organoﬂuorine compounds, gem-

to introduce a gem-diﬂuoro oleﬁn moiety is in high demand

diﬂuoro oleﬁns are of particular importance as electronic and

geometrical isosters of carbonyl groups (Scheme 1a). The

(

Scheme 1b,c). The gem-diﬂuoro oleﬁnation reaction via the

direct C−H functionalization of small molecules is still

underdeveloped, which may result from harsh conditions or

Scheme 1. Synthesis of gem-Diﬂuoro Oleﬁns

highly reactive intermediates that limit their applicability.

Recently, several groups developed new strategies for the

introduction of gem-diﬂuoro oleﬁns under mild reaction

conditions. A ﬁrst strategy involves the introduction of

diﬂuoromethylene using the Ruppert−Prakash reagent, the

Langlois reagent, or diﬂuoro betaines onto appropriately

functionalized reaction partners, such as diazoalkanes,

tosylhydrazones, or carbonyl groups, as pioneered by Hu and

coworkers.

Very recently, our group uncovered the ﬁrst example of a

gem-diﬂuoro oleﬁnation reaction of indole heterocycles 4 with

ﬂuorinated diazo compounds 5 via a C−H functionalization/β-

ﬂuoride elimination strategy under mild reaction conditions

(

Scheme 1b). Although signiﬁcant progress has been achieved

in the past years, one of the main limitations still resides in the

necessity of either prefunctionalized or specialized substrates,

which impacts the overall applicability. The one-step diﬂuoro

oleﬁnation reaction of simple aromatic systems via C−H

Received: July 31, 2020

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

functionalization would thus be in high demanded (Scheme

to be the optimal reaction conditions, and the gem-diﬂuoro

oleﬁn product was obtained in 75% yield (Table 1, entry 17).

An interesting observation was made with respect to additional

ligands or bases: The addition of either a phosphine ligand or

c). This strategy could streamline the synthesis of important

bioactive molecules in drug discovery to directly access

nitrogen analogues 9 of the antitubulin agent 1.

We commenced our investigations for the site-selective,

direct, one-step gem-diﬂuoro oleﬁnation of aromatic com-

pounds by studying the reaction of electron-rich N,N-dimethyl

1,10-phenanthroline resulted in almost complete inhibition of

this reaction (Table 1, entries 11 and 12); the addition of basic

additives to promote the elimination step of hydrogen ﬂuoride

resulted in substantially decreased product yields (Table 1,

entries 15 and 16). It is important to note that in all reactions,

no trace amounts of the triﬂuoromethylated reaction product

aniline 8a with 1-phenyl-2,2,2-triﬂuorodiazoethane 5a, which

would enhance the structural diversity of the currently

accessible gem-diﬂuoro oleﬁns via C−H functionalization

strategies (Scheme 1c and Table 1). Initial experiments

were observed by analysis of the crude reaction mixtures by F

NMR spectroscopy.

Table 1. Optimization of Reaction Conditions

With the optimal condition in hand, the substitution pattern

of the aniline derivative was studied next. Diﬀerent primary

alkyl chains or cyclic substituents at the nitrogen atom had

only a little inﬂuence on the eﬃciency of this gem-diﬂuoro

oleﬁnation reaction, and in all cases, the corresponding

products were obtained in good yield as a single regioisomer

no.

catalyst

solvent

T (°C)

% yield

(

Scheme 2, 9a−g). Allyl and propargyl groups (Scheme 2,

Pd(OAc) + dppbe

DCM

n.r.

trace

h,i) were well tolerated under the present reaction conditions

Rh(OAc)₂

L₁AuCl

[dppf](AuCl)₂

CuI

Scheme 2. Substrate Scope of the gem-Diﬂuoro Oleﬁnation

Reaction

DCM

CuI

CHCl₃

toluene

THF

CuOTf

CuOAc

CuCl₂

CuI

n.r.

CHCl₃

Reaction conditions: 0.2 mmol aniline 8a, 0.3 mmol 5a, and 5 mol %

catalyst were dissolved in 2.5 mL of solvent under an Ar atmosphere

at the indicated temperature and stirred until the aniline was

consumed. Yield was determined by F NMR of the crude reaction

mixture. The internal standard is triﬂuorotoluene. 12 mol % of

NaBArf and 5 mol % if 1,2-bis(diphenylphoshino)benzene (dppbe)

were added. 5 mol % of NaBArF. 10 mol % of NaBArF. 7.5 mol %

of PPh was added. 7.5 mol % of 1,10-phenanthroline. was added.

.2 mmol Cs CO was added. 0.2 mmol K CO was added.

2 3 2 3

focused on the application of diﬀerent Pd(II), Rh(II), or

Au(I) catalysts to selectively introduce the gem-diﬂuorooleﬁn

into the para position of N,N-dimethyl aniline. Pd(II)-based

catalysts that were highly eﬃcient in the functionalization of

indole heterocycles turned out to give not even trace amounts

of product in the case of N,N-dimethylaniline (Table 1, entry

). Rh(II) or Au(I) catalysts did not provide any notable

amount of the desired gem-diﬂuoro oleﬁn product (Table 1,

1,12

entries 2−4).

Surprisingly, simple CuI proved compatible,

and we could obtain the desired gem-diﬂuoro oleﬁn 9a in a

highly chemo- and regioselective manner in 28% yield without

the formation of byproducts bearing a triﬂuoromethyl group

(

Table 1, entry 6).

In subsequent studies we evaluated the inﬂuence of diﬀerent

reaction parameters, including various copper catalysts,

solvents, and temperatures (Table 1, entries 6−13). The use

of 5 mol % CuI as a catalyst in CHCl solvent at 60 °C proved

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

without any detection of cyclopropane, cyclopropene, or

rearrangement byproducts. The inﬂuence of the substitution

pattern on the phenyl ring of the aniline derivative was also

tested. The substitution of aniline in the meta position with a

methyl or methoxy group proved compatible and did not alter

the selectivity of this C−H functionalization reaction, and only

a single regioisomer was observed (Scheme 2, 9j,k). Yet a

slightly reduced yield was observed, which probably results

from steric hindrance when one neighboring substituent is

introduced. Notably, two neighboring substituents to the site

of C−H functionalization had no further detrimental eﬀect on

the reaction yield (Scheme 2, 9l). Importantly, the

introduction of an ortho substituent onto the aniline core

Scheme 3. Substrate Scope of the gem-Diﬂuoro Oleﬁnation

Reaction with Indoline and Tetrahydroquinoline

Derivatives

(Scheme 3, 14a) resulted in a complex reaction mixture, which

might be attributed to the unselective C−H functionalization

reaction. When studying diﬀerent substitution patterns on the

ﬂuorinated diazo compound, high yields were obtained in the

case of triﬂuoromethylated diazoalkanes (Scheme 2, 9m−p).

Indolines and tetrahydroquinolines are important frame-

works in natural products, and we thus studied diﬀerent N-

alkylated indoline (10) and tetrahydroquinoline (11) sub-

strates under the present reaction conditions. In all cases, we

could observe selective C−H functionalization of the aromatic

ring in the para position to nitrogen, and the corresponding

gem-diﬂuoro oleﬁns were obtained in high yield (Scheme 3,

2a−f, 13a−f). In all cases, no trace amounts of byproducts

bearing a triﬂuoromethyl group were observed. The limitations

of the present methodology lie within the substitution of the

aniline core with an electron-withdrawing ester group to both

the aniline core and the N-alkyl side chain (14b,c), which can

be explained by the reduced nucleophilicity of the aniline

derivative. A further limitation is the use of diphenyl amine

4d, amides 14e, secondary amines 14f, or heterocyclic amines

such as carbazole 15, which all gave a complex mixtures of

reaction products.

Finally, we studied this gem-diﬂuoro oleﬁnation reaction by

density functional theory (DFT) calculations to get an

understanding of the underlying reaction mechanism and

explored diﬀerent possible reaction pathways by DFT

calculation at the B3LYP-D3/6-311+G(d,p)(SDD)//B3LYP/

-31G(d)(SDD) (solvent = chloroform) level (Scheme 4). In

this context, it would be important to understand how the

elimination of HF proceeds. First, we examined the reaction of

an intermediate copper carbene complex INT2, which is

formed in an exergonic reaction (ΔG = −20.2 kcal/mol) via a

low-lying transition state with an activation free energy of 6.4

kcal/mol. (For details, see the Supporting Information.) For

the following transformation, we considered diﬀerent mecha-

nistic pathways, which might rationalize the formation of the

gem-diﬂuoro oleﬁn product, yet pathways that could account

for the transfer of an aryl-diﬂuorovinyl group do not account

for the formation of gem-diﬂuoro oleﬁn. (For details, see the

Supporting Information.) Instead, the copper carbene complex

INT2 undergoes the direct addition of N,N-dimethyl aniline

transition states and thus renders both pathways unlikely.

Similarly, the elimination of H−F from zwitterion INT3 is very

disfavored due to a high conformational strain of the transition

state that results in an activation free energy of +29.5 kcal/mol.

Very unexpectedly, N,N-dimethyl aniline was identiﬁed as a

suitable base that can readily undergo a deprotonation process

via transition state TS3 with an activation free energy of 10.6

kcal/mol. This exergonic step (ΔG = −12.7 kcal/mol) now

gives the rearomatized intermediate INT4. Subsequent

ﬂuoride elimination converts intermediate INT4 to the ﬁnal

product via a low-lying transition state TS4 with an energy

barrier of 2.6 kcal/mol, simultaneously regenerating the

a with a very low activation free energy of only 0.5 kcal/mol

to give the triﬂuoromethylated zwitterion INT3. Next, we

considered pathways of intermediate INT3, and pathways that

could lead to the formation of the triﬂuoromethylated product

were identiﬁed to proceed via high-lying transition states and

are thus unfavored. Pathways that involve deprotonation by

water molecules or cyclopropane formation can lead to either

the triﬂuoromethyl or the gem-diﬂuoro oleﬁn product, yet the

initial reaction step proceeds through energetically unfavorable

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Complete contact information is available at:

Letter

Scheme 4. DFT Studies on the Reaction Mechanism of the gem-Diﬂuoro Oleﬁnation Reaction

catalyst to continue the next catalytic cycle. The HF−N,N-

dimethyl aniline complex is likely to be cleaved by the glass

reaction tube or the silica gel column, which is not detected in

Chao Pei − Institute of Organic Chemistry, RWTH Aachen

University, D-52074 Aachen, Germany

https://pubs.acs.org/10.1021/acs.orglett.0c02568

the experiment to regenerate N,N-dimethyl aniline.

In summary, we herein report on the site-selective gem-

diﬂuoro oleﬁnation reaction of anilines, indolines, and

tetrahydroquinolines using cheap commercially available CuI

as the sole catalyst. A diverse range of gem-diﬂuoro oleﬁn

products could be accessed in good yield, even on a gram scale.

Detailed investigations by DFT calculations were performed to

rationalize this gem-diﬂuoro oleﬁnation reaction, which

suggests the nucleophilic attack of the aniline derivative to

an electrophilic copper carbene complex. Importantly, a

second molecule of the aniline derivative serves as a basic

promoter to facilitate the elimination of HF and to induce

excellent chemoselectivity in this reaction. This methodology

now provides practical and operationally simple access to the

valuable aromatic gem-diﬂuoro oleﬁn product.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

R.M.K. thanks the German Science Foundation and Dean’s

Seed Fund of RWTH Aachen for ﬁnancial support. C.P. thanks

the China Scholarship Council for the support with a Ph.D.

scholarship.

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AUTHOR INFORMATION

Corresponding Author

■

Rene M. Koenigs − Institute of Organic Chemistry, RWTH

Aachen University, D-52074 Aachen, Germany; orcid.org/

000-0003-0247-4384 ; Email: rene.koenigs@rwth-

aachen.de

Authors

Zhen Yang − Institute of Organic Chemistry, RWTH Aachen

University, D-52074 Aachen, Germany

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