Monofluoromethyl-Substituted Sulfonium Ylides: Preparation, Structure-Reactivity Study and Substrate Scope?

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Title: Monofluoromethyl-Substituted Sulfonium Ylides: Preparation, Structure-

Reactivity Study and Substrate Scope

Authors: Xin Hong, Yafei Liu, Long Lu,* and Qilong Shen*

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This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000206.

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fluorine, monofluoromethyl, electrophilic, ylide, structure-activity study

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Monofluoromethyl-Substituted Sulfonium Ylides: Preparation,

Structure-Reactivity Study and Substrate Scope

Xin Hong,^aYafei Liu,^aLong Lu,*^,band Qilong Shen*^,a

^aKey Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,

University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032

^bShanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,

Shanghai 200032

Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX

Abstract. Structure-reactivity study of a family of electrophilic monofluoromethylating reagents based on sulfonium ylide skeleton with different

steric hindrance and electron-withdrawing properties was described. These studies led us to discover two highly reactive reagents 3 with a

cyclic malonate backbone and 6 with an electron-poor 1,1,1,5,5,5-hexafluoropentane-2,4-dione backbone. The high reactivity of reagent 6

allowed to highly selectively access either C-monofluoromethylated or O-monofluoromethylated β-ketoesters in high yields by the use of

different bases. In addition, reactions of reagent 3 with a variety of nucleophiles including phenols, carboxylic acids, thiophenols or heteroaryl

nucleophiles occurred in full conversion within 10 min at room temperature and the scopes for these reactions were reported in detail.

source.^[7]While chlorofluoromethane belongs to a family of

ozone-depleting compounds and its future usage will be limited,

Background and Originality Content

Monofluoromethyl group (-CH₂F), which is generally

iodofluoromethane, which exhibits higher reactivity than

considered as bioisostere of methyl, hydroxy, thiol or amino

chlorofluoromethane, was mainly made from chlorofluoro

group,^[1]has attracted recent intense interests in the field of

-methane in low yield, even though it allowed the direct

medicinal chemistry, largely due to fluorine’s unique properties

related to its small size and strong electronegativity. It is now

well-accepted that the incorporation of fluorine might change the

target molecule’s physical properties including conformation and

dipole moment, which in turn would bring “magic effect” on the

drug candidate’s physiological properties such as lipophilicity and

metabolic stability.^[2,3]Consequently, development of efficient

methods for the preparation of monofluoromethylated

compounds is in high demand and represents a current great

challenge.

monofluoromethylation of various carbon-nucleophiles.^[8]Later

on, two radical monofluoromethylating reagents CH₂FSO₂Na (I)^[9]

and (CH₂FSO₂)₂Zn (II)^[10]that were able to monofluoromethylate

electron-poor heteroarenes or alkenes

Classic methods for the introduction of monofluoromethyl

group generally involve two different strategies.^[4]In the first

strategy, a primary alcohol was treated with a fluorinating

reagent such as DAST or its derivatives to afford the

monofluoromethylated compounds.^[5]Alternatively, in the second

strategy, an alkyl electrophile such as alkyl halide or tosylate was

nucleophilically replaced by a fluoride to generate the

corresponding monofluoromethylated compounds.^[6]A third,

direct monofluoromethylating strategy that utilizes an

electrophilic monofluoromethylating reagent to react with

various nucleophiles for the formation of monofluoromethylated

compounds, however, is less developed, owing mainly to the lack

of highly reactive electrophilic monofluoromethylating reagent.

Earlier direct monofluoromethylating strategy typically use

fluoromethyl halides (ClCH₂F or ICH₂F) as the monofluoromethyl

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First author et al.

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Figure 1 Reagents for monofluoromethylation.

step of the ylide formation reaction was the Rh-catalyzed

decomposition of the diazonium compound to generate the

corresponding carbene, if we could use a more reactive carbene

precursor, the reaction would be accelerated, and the yield of the

reaction could be improved. With these in mind, we then tried

the reaction using a carbene precursor derived from hypervalent

iodide. Notably, it was found that reaction of

were reported by Hu and Baran, respectively. Alternatively, to

expand the scope of the substrates for the introduction of the

monofluoromethyl group, three electrophilic

monofluoromethylating reagents such as S-monofluoromethyl

-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate

(III)^[11]and N-((fluoromethyl)(oxo)(phenyl)-λ⁶-sulfaneylidene)-N-

methylmethanaminium triflate or hexafluorophosphate (IV),^[12]

N,N-dimethyl-S-monofluoromethyl-S-phenylsulfoximinium

hexafluorophosphate (V),^[13]were reported. Nevertheless, the

reactivities of these reagents were moderate and the substrates

were limited mainly to heteroatom-containing nucleophiles such

as phenol, thiol, amine, phosphine, sulfonic and carboxylic acid.

To overcome these limitations, in 2017, we reported the

development of two electrophilic monofluoromethylating

reagents 1 and 2 based on sulfonium ylide skeleton that allowed

to monofluoromethylate a variety of primary, secondary and

tertiary alcohols and soft carbon nucleophiles malonate

derivatives for the first time in high yields, as well as those

heteroatom nucleophiles (Figure 1).^[14,15]We now report that the

development of a general method for the preparation of a variety

of monofluoromethylated sulfonium ylides 3-8 and structure

activity relationship studies (SAR) showed that two new reagents

3 and 6 exhibited higher reactivity than the original reagents. As a

result, the scope of the reaction can now be easily extended to

monofluoromethylate β-ketoesters. In addition, using reagent 3

as the electrophilic monofluoromethylating reagent, the reaction

time could be significantly shortened to within 15 min, which

might have potential application in the preparation of ¹⁸F-labelled

compounds.

2,2-dimethyl-5-(phenyl-λ³-iodaneylidene)-1,3-dioxane-4,6-dione

with (4-nitrophenyl)fluoromethylthioether in 1,2-dichloroethane

in the presence of 1.0 mol% Rh₂(OAc)₄occurred smoothly after 12

h at ambient temperature to give the corresponding

monofluoromethylsulfonium ylide 3 in 88% yield, as determined

by ¹⁹F NMR spectroscopy with an internal standard (Figure 2). The

reaction could be scaled up to 5.0 mmol to give ylide 3 in 46%

isolated yield. Likewise, ylide 4 was prepared in 5.0 mmol in 57%

yield. Furthermore, ylides 5 and 6 were synthesized from

reactions of 1,1,1,5,5,5-hexafluoro-3-(phenyl-λ³-iodaneylidene)

pentane-2,4-dione with (phenyl)fluoromethylthioether and

(4-nitrophenyl)fluoromethylthioether in 63% and 83% yields,

respectively. Previous efforts to synthesize reagents 5 and 6 from

the diazonium precursor 3-diazo-1,1,1,5,5,5-hexafluoropentane

-2,4-dione under various conditions were unsuccessful.^[13]

To assess whether the oxidation state of the sulfur in the ylide

will have a beneficial effect on the reactivity of the reagent, we

designed reagents 7 and 8 wherein the S atom in these two

reagents are in S(VI) oxidation state. Reagents 7 and 8 were

prepared by the reactions of dimethyl 2-diazomalonate with

1-((fluoromethyl)sulfinyl)benzene or 1-((fluoromethyl)sulfinyl)-4

-nitrobenzene in 1,2-dichloroethane in the presence of 0.5 mol%

Rh₂(OAc)₄for 12 h at ambient temperature with good yields (64%

and 40%, respectively).

Results and Discussion

Design and preparation of monofluoromethylated sulfonium

ylides. Our original method for the preparation of

monofluoromethylated sulfonium ylides involves a Rh-catalyzed

reaction of aryl monofluoromethylthioether with dimethyl

2-diazomalonate in dichloromethane at 40 ^oC for 24 h.^[16]The

reaction was quite efficient since only 0.1 mol% Rh₂(esp)₄(esp =

tetramethyl-1,3-benzenediproprionate) was required for full

conversion. With an aim to identify a more reactive electrophilic

monofluoromethylating reagent through structure activity

relationship study (SAR), we then designed a few analogs of

reagent 1 and 2 with a cyclic malonate 3 or

Figure 2 Preparation of ylides 3-8.

1H-indene-1,3(2H)-dione 4 or a more electron-poor

X-ray structures of compounds 1-3 and 6-7.

1,1,1,5,5,5-hexafluoropentane-2,4-dione backbone 5 and 6.

However, our initial efforts to synthesize these ylide derivatives

under the standard reaction conditions were unsuccessful.

Reaction of (4-nitrophenyl)fluoromethylthioether with

5-diazo-2,2-dimethyl-1,3-dioxane-4,6-dione or

Monofluoromethylsulfonium ylides 1-8 are shelf-stable, white or

yellow crystalline solids. Single crystals of ylides 1-3 and 6-7 were

obtained by slow diffusion of petroleum ether to an ethyl acetate

solution of the corresponding ylides at room temperature (Figure

3). Selected bond lengths and bond angles were shown in Table 1.

It was found that the S(1)-C(CH₂F) bond length (1.8370(18) Å) in

ylide 2 with a strong electron-withdrawing group was longer than

that in ylide 1 (1.828(2) Å), while the bond length was further

elongated with the malonate unit was replaced by a cyclic

2-diazo-1H-indene-1,3(2H)-dione were sluggish and less than 30%

conversions were observed after 72 h at 60 ^oC in

1,2-dichloroethane with 1.0 mol% rhodium catalyst loading, while

reaction using 3-diazo-1,1,1,5,5,5-hexafluoropentane-2,4-dione

did not occur at all. We reasoned that since the rate determining

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malonate group of ylide 3. Likewise, replacement of the malonate

unit in ylide 1 by a more electron-poor 1,1,1,5,5,5

Reaction conditions: β-ketoester (0.1 mmol), reagent 6 (0.2 mmol), LiOⁱPr

(0.2 mmol) in ClCH₂CH₂Cl (1.0 mL) at room temperature for 18 h; ^bYields

were determined by ¹⁹F NMR spectroscopy with trifluorotoluene as an

internal standard.

-hexafluoropentane-2,4-dione unit also led to elongate the bond

length (1.8370(18) Å in ylide 2 vs 1.8453(17) Å in ylide 6). In

addition, it was found that the S(1)-C(CH₂F) bond length in ylide 7

with S(VI) oxidation state is longer than that in ylide 1. Since the

longer S(1)-C(CH₂F) bond length indicates the weaker S(1)-C(CH₂F)

bond strength, we speculated that ylides 3-8 might exhibit higher

electrophilicity and broader substrate scope than ylides 1-2.

C-Selective monofluoromethylation of β-ketoester.^[17]In

2017, we discovered that reaction of 2-aryl or 2-alkyl-substituted

malonate derivatives reacted with reagent 2 in NMP smoothly at

room temperature after 4 h to give the corresponding

carbon-monofluoromethylated malonates in high yields.^[13]

However, our efforts to extend the reaction of β-ketoesters failed

since the reaction was rather sluggish and the formation of

desired C-monofluoromethylated product was not detected. With

the new monofluoromethylated ylides 3-8 in hand, we envisaged

that these reagents might be electrophilic enough to enable the

reaction. With these thoughts in mind, we attempted the reaction

of β-ketoester derived from α-tetralone with reagent 6 because

the S(1)-C(CH₂F) bond length in ylide 6 is the longest and likely 6 is

the most electrophilic reagent in our list. A quick screening of the

Scheme 1 Optimization of reaction of β-ketoester with reagent 6.

Ylide 1

Ylide 2

Ylide 3

Ylide 6

Figure 3 X-Ray structure of ylides 1-3 and 6-7.

Ylide 7

Table 1 Selected bond lengths and bond angles for single crystals of ylides 1-3 and 6-7.

Chin. J. Chem. 2019, 37, XXX－XXX

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Bond length (Å)

S(1)-C(Ar)

1.787(2)

Bond angle (^o)

C(CH₂F)-S(1)-C(Ar) C(CH₂F)-S(1)-C(=C)

ylide

S(1)-C(CH₂F)

1.828(2)

S(1)-C(=C)

1.716(2)

1

2

3

6

7

100.32(10)

101.90(8)

96.64(9)

106.56(10)

109.19(9)

103.16(10)

106.80(8)

108.3(5)

1.8370(18)

1.844(2)

1.7956(17)

1.792(2)

1.7097(19)

1.7040(18)

1.7359(16)

1.696(11)

1.8453(17)

1.842(9)

1.7899(17)

1.771(10)

101.24(8)

102.4(5)

C-monofluoromethylated product A in 70% yield as well as the

O-monofluoromethylated product B in 6% yield, reaction with

reagent 5 did not occur at all (Scheme 2, entries 5-6). These

results suggest the importance of the strong

electron-withdrawing group (-NO₂) on the arene moiety of the

ylide in promoting the reactivity of the reagent. To probe whether

the oxidation state of the sulfur in the ylide can further promote

the reactivity, we studied the reaction with reagents 7-8.

Nevertheless, reactions

combination of the base and the solvent disclosed that reaction in

1,2-dichloroethane using 1.0 equivalent of LiOⁱPr as the base

occurred smoothly to give the C-monofluoromethylated

β-ketoester 9a in 54% yield, while the formation of the

O-monofluoromethylated compound 10a was not observed.

Increasing the amount of LiOⁱPr and reagent 6 to 2.0 equivalents

led to the increase of the yield to 70% yield (Scheme 1, entry 1).

Switching the base to LiOH gave slightly inferior yield (62%) with

the formation of compound 10a in 4% yield (Scheme 1, entry 3).

Interestingly, when LiHMDS was used as the base, TMSF was

observed to be the main product (58% yield) and compound 9a

was formed in 32% yield (Scheme 1, entry 4). In addition, when

the reaction was conducted in an ether solvent such as dioxane,

the formation of O-monofluoromethylated compound 10a

increased significantly to 18% (Scheme 1, entry 5). Surprisingly,

when a strong organic base tert-butylimino

Scheme 2 Structure activity study (SAR) of reagents 1-8 and reagent III.

-tri(pyrrolidino)phosphorane (BTPP)^[12]was used, the reaction

occurred highly selectively to give O-monofluoromethylated

compound 10a in 60% yield (Scheme 1, entry 6).

Structure activity relationship study (SAR) of reagents 1-8.

The success in identifying the right conditions for highly

C-selective monofluoromethylation of β-ketoester promoted us

to evaluate other electrophilic monofluoromethylating reagents

under the optimized conditions. Consistent with our previous

observation, reaction of β-ketoester derived from 1-indanone

with reagents 1 and 2 occurred slowly to give the

monofluoromethylated products in less than 24% yields with a

high ratio formation of O-monofluoromethylated product B

(Scheme 2, entries 1-2). Reactions with ylide 3 or 4 bearing a

cyclic malonate or 1H-indene-1,3(2H)-dione subunit occurred

much faster and gave the C-monofluoromethylated product A as

the major product in 54-56% yields while the formation of

O-monofluoromethylated product B was generated in less than

8% yields (Scheme 2, entries 3-4). Notably, reagents 5 and 6

containing a more electron-poor

1,1,1,5,5,5-hexafluoropentane-2,4-dione backbone exhibited

dramatically different reactivity. While reaction with reagent 6

took place smoothly under the standard conditions to give the

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^aReaction conditions: β-ketoester (0.1 mmol), reagent 1-9, III (0.2 mmol),

LiOⁱPr (0.2 mmol) in ClCH₂CH₂Cl (1.0 mL) at room temperature for 18 h;

^bYields were determined by ¹⁹F NMR spectroscopy with trifluorotoluene as

an internal standard.

Scheme 4 Optimization for O-Selective monofluoromethylation of

β-ketoesters and SAR study of ylides 1-6 and 8.^a

were sluggish and the formation of monofluoromethylated

products A or B was not observed (Scheme 2, entries 7-8). As a

comparison, we also investigated the reaction of β-ketoester with

Prakash’s monofluoromethylating reagent III^[11]under the

standard conditions and found that the O-monofluoromethylated

product B was generated as the major product and the

C-monofluoromethylated product A was minor product with

yields of 68% and 28%, respectively (Scheme 2, entry 9). These

structure-activity studies suggest that decreasing the electron

density on the sulfur atom of the ylide would significantly

improve the electrophilicity of the reagent, while changing the

oxidation state of the ylide from S(IV) to S(VI) does not have a

beneficial effect on the reactivity of the reagent.

Scope of C-Selective monofluoromethylation of β-ketoesters

with reagent 6. Having elucidated the key structural factors for

the high reactivity of the monofluoromethylating reagents and

the appropriate conditions for highly C-selective

monofluoromethylating β-ketoester, we next studied the

generality of the reaction toward other β-ketoesters. In

general, β-ketoesters with both electron-donating (-OMe, Me) or

withdrawing groups (-Cl, Br, F) all reacted to give the

C-monofluoromethylated products in good to excellent yields, as

shown in Scheme 3. It was found that the yield of the reaction

was greatly affected by the steric hindrance of the ester group of

β-ketoesters derived from 1-indanone. For example, reaction of

tert-butyl ester derivative reacted in much higher yield (79%)

than that of methyl ester derivative (Scheme 3, 9b vs 9d). In

addition, the position of the substituent on β-ketoester also

affected greatly the yield of the reaction. For instance, reactions

of β-ketoesters with a methoxy group at 4-, 5- or 6-position

occurred under the standard conditions to give the

^aReaction conditions: β-ketoester (0.05 mmol), reagent 1-6, 8 (0.05

mmol), base (0.05 mmol) in solvent (0.5 mL) at room temperature for 5.0

min; ^bYields were determined by ¹⁹F NMR spectroscopy with

trifluorotoluene as an internal standard; ^cIsolated yield; ^d1.5 Equivalents of

reagent 6 was used; ^eReaction was conducted at room temperature for 2

h.

yields, respectively (Scheme 3, 9g-i). Obviously, the resonance

effect of the methoxy at 5-position enhanced the nucleophilicity

of the enolate and consequently facilitate the

C-monofluoromethylated products 9g-i in 70%, 98% and 68%

monofluoromethylation. Notably, β-ketoester derived from

estrone also reacted to give the corresponding product 9q in 90%

yield with a good diastereoselectivity (Scheme 3, 9q). Efforts to

extend the reaction to seven-membered β-ketoester, however,

failed and less than 5% conversion was observed (Scheme 3, 9r).

Likewise, reactions of linear β-ketoesters were messy and the

desired C-monofluoromethylated product was generated in less

than 5% yield (Scheme 3, 9s). Nevertheless, reaction of

α−phenyl-substituted malonate ester occurred smoothly to give

the desired C-monofluoromethylated product 9t in 77% yield

(Scheme 3, 9t).

O-Selective monofluoromethylation of β-ketoesters with

reagent 6. During the optimization for C-Selective

monofluoromethylation of β-ketoesters with reagent 6, we found

that when a strong organic base BTPP was used, the

O-monofluoromethylated compound 10a was formed exclusively,

which indicates that by choosing an appropriate base, we will be

able to control the C- or O-selectivity for the

monofluoromethylation reaction of β-ketoesters with reagent 6.

We then optimized the reaction conditions based on this initial

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discovery. Carefully monitoring the reaction by ¹⁹F NMR

spectroscopy disclosed that the reaction occurred rather fast

since full conversion was observed when the reactants and the

solvent were mixed and rushed for NMR acquisition within 5 min

(Scheme 4, entry 3). A quick screening of the solvents showed

reactions in CH₂Cl₂and dioxane occurred in high yields while

reactions in other polar solvents such as DMF, DMSO or CH₃CN

did not give the monofluoromethylated product at all (Scheme 4,

entries 2-6). Considering that the solubility of the inorganic base

in dioxane is higher than that in CH₂Cl₂, we next chose dioxane as

the solvent to examine the effect of the inorganic bases.

Nevertheless, reaction using bases such as Li₂CO₃, Na₂CO₃or

K₂CO₃occurred

Scheme 3 Scope of C-Selective monofluoromethylation of β-ketoesters with reagent 6.^a

^aReaction conditions: β-ketoester (0.3 mmol), reagent 6 (0.6 mmol), LiOⁱPr (0.6 mmol) in ClCH₂CH₂Cl (6.0 mL) at room temperature for 18 h; Isolated

yields.

sluggishly and the formation of monofluoromethylated products

were formed in less than 16% yield (Scheme 4, entries 8-10).

Interestingly, reaction using Cs₂CO₃occurred smoothly to give

product 10a in 50% yield (Scheme 4, entry 11). Further studies

showed that using other organic base such as DBU was not

effective (Scheme 4, entry 7). Finally, it was found that the yield

of the reaction could be improved to 88% when 1.5 equivalents of

reagent 6 was used (Scheme 4, entry 12).

was much less reactive and gave the O-monofluoromethylated

product in 20% yield (Scheme 4, entry 17), again highlighting the

importance of the electron-withdrawing property of the nitro

group on the reactivity of the ylide reagents. Similar to the cases

of C-selective monofluoromethylation of β-ketoesters, reagents 1

and 2 were not effective monofluoromethylating reagents for

O-Selective monofluoromethylation of β-ketoesters, giving the

product 10a in 14% and 40% yields, respectively (Scheme 4,

entries 13-14). In contrast, reactions with ylide 3 or 4 bearing a

cyclic malonate or 1H-indene-1,3(2H)-dione subunit occurred in

comparable 84% and 80% yields, respectively (Scheme 4, entries

15-16). Finally, it was found that reaction with reagent 8 occurred

At this stage, we conducted the structure activity relationship

study (SAR) for O-Selective monofluoromethylation of

β-ketoesters with monofluoromethylative ylide reagents. Not

surprisingly, reagent 5 with analogous ylide skeleton as ylide 6

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relatively slowly to give the desired compound 10a after 2.0 h at

¹⁸F-labeled monofluoromethyl vinyl ethers.

room temperature in 88% yield (Scheme 4, entry 18).

Monofluoromethylation of phenols with reagent 3. The high

efficiency of the BTPP-promoted monofluoromethylation of

β-ketoesters with regent 3 and its potential in the preparation of

¹⁸F labeled radioactive tracers in PET-CT applications prompted us

Scope for O-Selective monofluoromethylation of

β-ketoesters with reagent 3. Because of the comparable yields

for O-Selective monofluoromethylation of β-ketoesters with

reagent 6 and 3, and the easy availability of the starting material

for the preparation of ylide 3, we next studied the scope of

O-Selective monofluoromethylation of β-ketoesters with ylide 3.

As shown in Scheme 5, β-ketoesters derived from indanones with

both electron-donating group (-OMe) or electron-withdrawing

groups (-F, -Cl and -Br) all reacted smoothly to give the

corresponding monofluoromethyl vinyl ethers in high yields

(Scheme 5, 10e, 10f-h). We also found that the steric hinderance

of the ester group in the β-ketoester did not have significant

effect on the yield of the reaction. For example, β-ketoesters

bearing methyl, ethyl or isopropyl group reacted with reagent 3

under the standard conditions to give the corresponding products

10b-d in 86%, 92% and 81% yields, respectively (Scheme 5,

10b-d). Furthermore, it was found that benzolactone also reacted

under these conditions to give monofluoromethoxy-substituted

benzofuran derivative 10i in 55% yield (Scheme 5, 10i). Currently,

¹⁸F-labeled compounds have found widespread applications in

positron emission tomography-computed tomography (PET/CT)

for the diagnosis of the tumors and for the study of the

to study whether this protocol could be extended to other

nucleophiles. Since fluoroalkoxy-substituted arenes and

heteroarenes are commonly found in drug molecules, we first

studied the reaction of phenols with reagent 3. It was found that

reactions of phenols with reagent 3 occurred slightly slower than

those of β-ketoesters but full conversions were observed within

10 min at room temperature. As summarized in Scheme 6,

reactions of both electron-rich or poor phenols all reacted to give

the corresponding monofluoromethoxylated arenes in high yields.

In addition, heterophenols such as 3-hydroxy-2-nitropyridine,

4,6-dimethylpyrimidin-2-ol and 1H-benzo[d][1,2,3]triazol-1-ol also

reacted to give the desired products 11k-m in high yields.

Furthermore, because of the mild reaction conditions, various of

common functional groups including Br (11c), I (11d), cyano (11e),

enolizable ketone (11f), nitro (11g), hydroxyl (11h), ester (11i)

were compatible. Finally, the reaction was applicable to natural

molecules bearing a phenoxyl group. For example, reactions of

antioxidants pterostilbene and D-δ-tocopherol with reagent 3

occurred to give the corresponding monofluoromethoxyarenes

11n and 11o in 67% and 80% yields, respectively (Scheme 6, 11n

and 11o). The generality of the reaction toward to functionalized

(hetero)phenols strongly supports that the reaction is potentially

applicable in the preparation of monofluoromethoxylated

pharmacokinetics of the drug molecules.¹⁸In general, it was

required that the preparation of ¹⁸F-labelled tracers should be

highly efficient to full conversion within 15 mins because of the

short lifetime of radioactive ¹⁸F (t_1/2= 110 min). The high

efficiency in BTPP-promoted O-monofluoromethylation of

β-ketoesters makes it potentially applicable in the preparation of

(hetero)arenes and, more importantly, in the preparation of ¹⁸

F

labeled radioactive tracers containing a monofluoromethoxylated

(hetero)arene unit for PET-CT investigation.

Scheme 5 Scope for O-Selective monofluoromethylation of β-ketoesters

with ylide 3.^a

Monofluoromethylation of carboxylic acids with reagent 3.

Encouraged by the generality of the monofluoromethylative

reaction of β-ketoesters and (hetero)phenols, we next tried the

reaction of carboxylic acids with reagent 3 since carboxylic acids

also bear a hydroxy group. It was found that the reaction

conditions for phenols could be effectively applied to reaction

with carboxylic acids. As summarized in Scheme 7, reactions of

benzoic acids bearing both electron-donating or

electron-withdrawing groups reacted under standard conditions

^aReaction conditions: β-ketoester (0.3 mmol), reagent 3 (0.3 mmol), BTPP

(0.3 mmol) in CH₂Cl₂(2.0 mL) at room temperature for 5.0 min; Isolated

yield.

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First author et al.

Report

Scheme 6 Scope for monofluoromethylation of phenols with ylide 3.^a

observed within 10 min at room temperature. As shown in

Scheme 8, various aryl thiols and heteroaryl thiols reacted with

reagent 3 to give the corresponding monofluoromethylthioethers

in excellent yield. For instance, reactions of 4-nitrothiophenol and

benzo[d]thiazole-2-thiol with reagent 3 occurred to afford

monofluoromethylthioethers 13b and 13e in 97% and 95% yields,

respectively (Scheme 8, 13b and 13e). Likewise, reactions of

heteroaryl nitrogen nucleophiles with reagent 3 were highly

efficient and high-yielding. For example, reactions of

7H-pyrrolo[2,3-d]pyrimidine and 1H-benzo[d][1,2,3]triazole with

reagent 3 occurred under optimized conditions to give compound

Scheme 7 Scope for monofluoromethylation of carboxylic acids with

ylide 3.^a

^aReaction conditions: phenol (0.3 mmol), reagent 3 (0.3 mmol), BTPP (0.3

mmol) in CH₂Cl₂(2.0 mL) at room temperature for 10.0 min; Isolated yield.

to give the corresponding monofluoromethyl esters in good to

excellent yields. For example, reactions of 2-hydroxybenzoic acid

and 2-chloro-5-nitrobenzoic acid with reagent 3 occurred after 10

min at room temperature to afford the corresponding

monofluoromethyl esters 12j and 12h in 69% and 86% yields,

respectively (Scheme 7, 12j and 12h). Heteroaryl carboxylic acid

such as 1H-indole-2-carboxylic acid also reacted to give ester 12m

in 95% yield. Not only benzoic acids but also vinyl carboxylic acid

or aliphatic carboxylic acids reacted to give the corresponding

esters in high yields (Scheme 7, 12o-p). More importantly,

because of the higher acidity of the carboxylic acid, the carboxylic

acid derivatives containing a free hydroxy, amino or amide group

all reacted to give the monofluoromethyl esters while these

functional groups remained intact and would allow to be

connected with other pharmaceutically important structural motif

for biologic activity assessment (Scheme 7, 12f, 12j-l). Likewise,

enolizable ketone was also compatible with the reaction

conditions (Scheme 7, 12c). Furthermore, halogens such as

chloride, bromide or iodide were tolerant, that could allow to

expand the structural space of the potential drug molecules via

classic transition metal-catalyzed cross-coupling.

^aReaction conditions: carboxylic acid (0.3 mmol), reagent 3 (0.3 mmol),

BTPP (0.3 mmol) in CH₂Cl₂(2.0 mL) at 30 ^oC for 10 min; Isolated yields.

Monofluoromethylation of thiophenols and heteroaryl

nitrogen nucleophiles with reagent 3. To further expand the

scope of the nucleophiles that could react with electrophilic

monofluoromethylating reagent based on ylide skeleton, we

studied the reaction of sulfur and nitrogen nucleophilic atoms of

heteroarenes with reagent 3. However, reaction conditions

developed for phenols or carboxylic acids were not suitable for

these two types of nucleophiles. A quick survey of the commonly

used bases led us to identify that NaH was an appropriate base

for the reaction. Again, reactions of thiol and heteroaryl nitrogen

nucleophile with reagent 3 were quick and full conversions were

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Running title

Chin. J. Chem.

Scheme 8 Scope for monofluoromethylation of thiophenols and

heteroaryl nitrogen nucleophiles with ylide 3.^a

monofluoromethylated compounds. Expanding the scope of the

reaction electrophilic monofluoromethylating reagents 1-8 with

other nucleophiles are currently undergoing in our laboratory.

Experimental

General information. The ¹H, ¹⁹F NMR spectra were obtained

at 293 K on a 300 or 400 spectrometer, and chemical shifts were

recorded relative to the solvent resonance. ¹⁹F shifts were

determined relative to CFCl₃as outside standard and low field is

positive. Coupling constants are reported in hertz. The following

abbreviations were used to explain the multiplicities: s = singlet; d

= doublet; t = triplet; q = quartet; m = multiplet; br = broad.

All glassware was oven or flame dried for several hours prior

to use. Solvents were freshly degassed according to the

procedures in Purification of Laboratory Chemicals prior to use.

Deuterated solvents were purchased from Cambridge Isotope

Laboratories, Inc., and were degassed and stored over activated 4

Å molecular sieves. Unless otherwise noted, all other reagents

and starting materials were purchased from commercial sources

and used without further purification. Reagent 1 and 2 were

prepared according to our previous reported procedure.¹⁴

Likewise, reagent 9 was prepared according to previous reported

procedure.¹¹

General procedure for preparation of reagent 3. Into a 50 mL

round bottom flask equipped with a magnetic stirring bar was

added (fluoromethyl)(4-nitrophenyl)thioether (711 mg, 5.00

mmol) and 1,2-dichloroethane (30.0 mL) under an atmosphere of

nitrogen. To the mixture, Rh₂(OAc)₄(22 mg, 1.0 mol%) and

hypervalent iodonium ylide (3.1 g, 6.0 mmol,1.2 equiv.) was

added. The mixture was stirred at room temperature for 12 h.

The solvent was evaporated under vacuum and the residue was

recrystallized from ethyl acetate/petroleum ether to give ylide 3

as a white solid.

^aReaction conditions: thiophenol or heteroarene (0.3 mmol), reagent 3

(0.3 mmol), NaH (0.33 mmol) in DMF (2.0 mL) at room temperature for 10

min; Isolated yields.

14c and 14e in 88% and 68% yields, respectively (Scheme 8, 14c

and 14e). The generality and the short reaction time of the

monofluoromethylation reaction with thiols and heteroaryl

nitrogen nucleophiles suggest that the current reaction might find

applications in the preparation of ¹⁸F-labeled tracer for further

PET-CT investigations.

5-[(Fluoromethyl)(4-nitrophenyl)-λ⁴-sulfanylidene]-2,2-dimeth

yl-1,3-dioxane-4,6-dione (3). White solid (575 mg, 46%), mp: 124

–126 ^oC. ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 8.45 (d, J = 9.0

Hz, 2 H), 8.04 (d, J = 8.7 Hz, 2 H), 6.64 (dd, J = 48.2, 6.9 Hz, 1 H),

6.13 (dd, J = 44.3, 6.9 Hz, 1 H), 1.77 (s, 6 H); ¹⁹F NMR (471MHz,

CDCl₃) δ -199.70 (dd, J = 48.3, 43.8 Hz, 1 F); ¹³C NMR (126 MHz,

CDCl₃) δ 163.4, 150.5, 134.0, 129.9, 125.5, 104.9, 91.0 (d, J = 229.8

Hz), 54.1, 26.3 ppm. IR (KBr): ν_max= 3105, 2998, 1665, 1531, 1316,

1199, 1051. 915, 853, 739 cm^-1. HRMS (ESI) for C₁₃H₁₂FNO₆SNa

(M+Na⁺): Calcd: 352.0262; Found: 352.0259.

Conclusions

In summary, through structure-activity relationship study

(SAR), we successfully elucidated the key structural factors that

affect the electrophilicity and reactivity of the electrophilic

monofluoromethylating reagents based on sulfonium ylide

skeleton, and were able to identify two highly reactive

electrophilic monofluoromethylating reagents 3 and 6 based on

sulfonium ylide skeleton bearing either a cyclic malonate unit or

strong electron-withdrawing 1,1,1,5,5,5-hexafluoropentane

-2,4-dione backbone. With these two reagents, we successfully

achieved the highly selective C-monofluoromethylation or

O-monofluoromethylation of β-ketoesters by employing different

bases LiOⁱPr or BTPP. Furthermore, the high reactivity of these

reagents allowed the high efficiency monofluoromethylating

reactions of reagent 3 with a variety of nucleophiles such as

phenols, carboxylic acids, thiophenols and heteroaryl nitrogen

nucleophiles. Typically, these reactions occurred to full

conversions within 10 min, thus paving the way for their future

applications in the preparation of ¹⁸F-labeled

2-[(Fluoromethyl)(4-nitrophenyl)-λ⁴-sulfanylidene]-1H-indene

-1,3(2H)-dione (4). Yellow solid (720 mg, 57%), mp: 148 –150 ^oC.

¹H NMR (500MHz, CDCl₃, 293 K, TMS) δ 8.42 (d, J = 9.0 Hz, 2 H),

8.11 (d, J = 8.6 Hz, 2 H), 7.68 (dd, J = 5.4, 3.1 Hz, 2 H), 7.59 (dd, J =

5.4, 3.1 Hz, 2 H), 6.79 (dd, J = 47.9, 6.5 Hz, 1 H), 5.98 (dd, J = 44.3,

6.5 Hz, 1 H); ¹⁹F NMR (471MHz, CDCl₃) δ -200.24 (dd, J = 47.5, 44.6

Hz, 1 F); 1³C NMR (126 MHz, CDCl₃) δ 188.9, 150.5, 138.9, 135.1,

132.6, 130.7, 125.5, 120.8, 88.8 (d, J = 233.6 Hz), 68.3 ppm. IR

(KBr): ν_max= 3101, 1636, 1596, 1529, 1342, 1293, 852, 724 cm^-1.

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First author et al.

Report

MS (ESI): 332.0 (M+H⁺). HRMS (ESI) for C₁₆H₁₁FNO₄S (M+H⁺):

Calcd: 332.0387; Found: 332.0388.

2-(fluoromethyl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxyl

ate (9a). Colorless liquid (48 mg, 67%). Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) 8.08 (d, J = 7.9 Hz, 1 H), 7.53 (td, J = 7.5, 1.4 Hz,

1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 4.99 (dd, J =

46.6, 9.0 Hz, 1 H), 4.84 (dd, J = 46.9, 9.1 Hz, 1 H), 3.73 (s, 3 H), 3.19

(ddd, J = 16.4, 11.1, 4.7 Hz, 1 H), 3.02 (dt, J = 17.2, 4.7 Hz, 1 H),

2.65 (dt, J = 13.8, 4.7 Hz, 1 H), 2.44 (ddd, J = 13.8, 11.1, 4.8 Hz, 1

1,1,1,5,5,5-Hexafluoro-3-[(fluoromethyl)(phenyl)-λ⁴-sulfanylid

ene]pentane-2,4-dione (5). Yellow solid (1.1 g, 63%), mp: 75 –78

^oC. Eluent: ethyl acetate/petroleum ether (1:3, R_f= 0.5). ¹H NMR

(500 MHz, CDCl₃, 293 K, TMS) δ 7.70 (d, J = 7.3 Hz, 2 H), 7.67 –7.62

(m, 2 H), 6.70 (dd, J = 49.2, 7.6 Hz, 1 H), 6.06 (dd, J = 45.0, 7.6 Hz,

1 H); ¹⁹F NMR (471MHz, CDCl₃) δ -72.12 (s, 6 F), -194.31 (t, J = 47.1

Hz, 1 F); ¹³C NMR (126 MHz, CDCl₃) δ 173.6 (q, J = 36.0 Hz), 133.3,

131.0, 127.4, 125.3, 117.0 (q, J = 289.9 Hz), 94.0 (d, J = 228.5 Hz),

78.8 ppm. IR (KBr): ν_max= 3064, 2975, 1678, 1628, 1390, 1183,

1119, 1048, 768, 743 cm^-1. HRMS (ESI) for C₁₂H₈F₇O₂S (M+H⁺):

Calcd: 349.0128; Found: 349.0126.

H); ¹⁹F NMR (375 MHz, CDCl₃) δ -229.89 (t, J = 46.9 Hz, 1 F); ¹³

C

NMR (100.7 MHz, CDCl₃) δ 192.5 (d, J = 2.7 Hz), 169.7 (d, J = 6.8

Hz), 143.4, 134.1, 131.7, 128.9, 128.1, 127.0, 84.2 (d, J = 176.2

Hz), 58.5 (d, J = 20.1 Hz), 52.9, 28.4 (d, J = 4.0 Hz), 25.6 ppm. IR

(KBr): ν_max= 2956, 1737, 1688, 1602, 1487, 1313, 1241, 1221,

1016, 749 cm^-1. MS (EI): 236 (M⁺). HRMS (EI) for C₁₃H₁₃FO₃(M⁺):

Calcd: 236.0849; Found: 236.0857.

1,1,1,5,5,5-Hexafluoro-3-[(fluoromethyl)(4-nitrophenyl)-λ⁴-sul

fanylidene]pentane-2,4-dione (6). Yellow solid (8.7 g, 83%). mp:

115 –117 ^oC. ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 8.51 (d, J =

9.1 Hz, 2 H), 7.89 (d, J = 8.7 Hz, 2 H), 6.84 (dd, J = 49.4, 7.7 Hz, 1

H), 6.05 (dd, J = 44.4, 7.7 Hz, 1 H); ¹⁹F NMR (471 MHz, CDCl₃) δ

-72.18 (s, 6 F), -192.37 (dd, J= 49.3, 44.4 Hz, 1 F); ¹³C NMR (126

MHz, CDCl₃) δ 173.4 (q, J = 36.3 Hz), 150.5, 132.3, 128.0, 125.9,

116.8 (q, J = 289.9 Hz), 94.7 (d, J = 232.1 Hz), 77.2 ppm. IR (KBr):

Methyl 2-(fluoromethyl)-6-methyl-1-oxo-2,3-dihydro-1H

-indene-2-carboxylate (9b). Colorless liquid (32 mg, 45%). Eluent:

ethyl acetate/petroleum ether (1:10, R = 0.4). ¹H NMR (400 MHz,

f

CDCl₃, 293 K, TMS) 7.57 (s, 1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7.43 –

7.38 (m, 1 H), 4.87 (d, J = 48.0 Hz, 2 H), 3.70 (s, 3 H), 3.64 (d, J =

17.2 Hz, 1 H), 3.36 (d, J = 17.2 Hz, 1 H), 2.39 (s, 3 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -230.45 (t, J = 46.8 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 199.1 (d, J = 4.4 Hz), 168.9 (d, J = 9.6 Hz), 150.8, 138.1,

137.2, 135.1, 126.2, 124.8, 83.8 (d, J = 174.0 Hz), 61.5 (d, J = 21.0

Hz), 53.0, 33.9 (d, J = 3.4 Hz), 21.1 ppm. IR (KBr): ν_max= 2956,

1742, 1713, 1494, 1433, 1270, 1200, 1013, 823, 503 cm^-1. MS (EI):

236 (M⁺). HRMS (EI) for C₁₃H₁₃FO₃(M⁺): Calcd: 236.0849; Found:

236.0857.

ν

_max= 3110, 1680, 1533, 1346, 1183, 1118, 1050, 853, 740 cm^-1.

MS (ESI): 393.9 (M+H⁺). HRMS (ESI) for C₁₂H₇F₇NO₄S (M+H⁺):

Calcd: 393.9979; Found: 393.9978.

Dimethyl [(fluoromethyl)(oxido)phenyl-λ⁶-sulfanylidene]

propanedioate (7). White solid (650 mg, 64%, 3.5 mmol scale).

mp: 117–119 ^oC. Eluent: ethyl acetate/petroleum ether (1:1, R_f=

0.3). ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 7.94 (d, J = 7.9 Hz, 2

H), 7.75 (t, J = 7.4 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 2 H), 6.18 (dd, J =

Isopropyl 2-(fluoromethyl)-6-methyl-1-oxo-2,3-dihydro-1H

-indene-2-carboxylate (9c). Colorless liquid (68 mg, 90%). Eluent:

ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) 7.76 (d, J = 7.7 Hz, 1 H), 7.63 (t, J = 7.4 Hz, 1 H),

7.51 (d, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H), 4.97-5.06 (m, 1 H),

4.87 (d, J = 48.0 Hz, 2 H), 3.67 (d, J = 17.3 Hz, 1 H), 3.39 (d, J = 17.3

Hz, 1 H), 1.22 – 1.15 (m, 6 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -230.52

(t, J = 46.8 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 199.3, 167.8 (d,

J = 9.5 Hz), 153.5, 135.7, 135.0, 127.9, 126.5, 124.9, 83.8 (d, J =

173.6 Hz), 69.8, 61.4 (d, J = 20.7 Hz), 34.3 (d, J = 3.5 Hz), 21.5 ppm.

IR (KBr): ν_max= 2983, 1736, 1715, 1608, 1465, 1288, 1268, 1210,

1104, 1006, 927, 756 cm^-1. MS (EI): 250 (M⁺). HRMS (EI) for

C₁₄H₁₅FO₃(M⁺): Calcd: 250.1005; Found: 250.1003.

46.2, 8.5 Hz, 1 H), 5.86 (dd, J = 47.7, 8.5 Hz, 1 H), 3.58 (s, 6 H); ¹⁹

F

NMR (471 MHz, CDCl₃) δ -201.38 (t, J = 46.9 Hz, 1 F); ¹³C NMR (126

MHz, CDCl₃) δ 164.7, 134.2, 133.9, 123.0, 127.5, 94.3 (d, J = 232.4

Hz), 74.1, 51.4 ppm. IR (KBr): ν_max= 2952, 1706, 1650, 1436, 1309,

1222, 1086, 772, 584 cm^-1. MS (ESI): 289.0 (M+H⁺); HRMS (ESI) for

C₁₂H₁₄FO₅S (M+H⁺): Calcd: 289.0540; Found: 289.0539.

Dimethyl [(fluoromethyl)(4-nitrophenyl)oxido-λ⁶-sulfanyli

dene]propanedioate (8). White solid (670 mg, 40%, 5.0 mmol

scale). mp:165 –167 ^oC. ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ

8.49 (d, J = 9.0 Hz, 2 H), 8.15 (d, J = 8.8 Hz, 2 H), 6.21 (dd, J = 46.2,

8.7 Hz, 1 H), 5.94 (dd, J = 47.6, 8.7 Hz, 1 H), 3.65 (s, 6 H); ¹⁹F NMR

(471 MHz, CDCl₃) δ -200.77 (t, J = 46.8 Hz, 1 F); ¹³C NMR (126

MHz, CDCl₃) δ164.5, 151.1, 140.6, 128.9, 125.0, 94.5 (d, J = 233.6

Hz), 74.5, 51.8 ppm. IR (KBr): ν_max= 3015, 2954, 1708, 1642, 1533,

1436, 1315, 1222. 1087, 730, 592 cm^-1. MS (ESI): 334.0 (M+H⁺);

HRMS (ESI) for C₁₂H₁₃FNO₇S (M+H⁺): Calcd: 334.0391; Found:

334.0391.

tert-Butyl 2-(fluoromethyl)-6-methyl-1-oxo-2,3-dihydro-1H

-indene-2-carboxylate (9d). Brown liquid (65 mg, 78%). Eluent:

ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) 7.57 (s, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.41 (d, J

= 7.9 Hz, 1 H), 4.89 (dd, J = 40.0, 8.0 Hz, 1 H), 4.84 (dd, J = 40.0,

8.0 Hz, 1 H), 3.60 (d, J = 17.0 Hz, 1 H), 3.34 (d, J = 17.0 Hz, 1 H),

2.40 (s, 3 H), 1.41 (s, 9 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -230.62 (t,

J = 46.9 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 199.8 (d, J = 4.0

Hz), 167.5 (d, J = 10.3 Hz), 151.0, 137.8 136.9, 135.3, 126.1, 124.7,

83.9 (d, J = 172.8 Hz), 82.8, 62.3 (d, J = 20.3 Hz), 34.0 (d, J = 3.7

Hz), 27.8, 21.0 ppm. IR (KBr): ν_max= 2979, 2931, 1732, 1712, 1617,

1494, 1369, 1273, 1254, 1159, 1146, 1114, 1004, 843, 747, 504

cm^-1. MS (ESI): 301 (M+Na⁺). HRMS (ESI) for C₁₆H₁₉FNaO₃(M+Na⁺):

Calcd: 301.1210; Found: 301.1205.

General procedure for C-Selective monofluoromethylation of

β-ketoesters with reagent 6. Into a 25 mL Schlenk tube equipped

with a magnetic stirring bar was added β-ketoester (0.3 mmol),

LiOH or LiOⁱPr (0.6 mmol), reagent 6 (0.6 mmol) and

1,2-dichloroethane (6.0 mL). The mixture was stirred at room

temperature for 18 h. The solvent was evaporated under vacuum

and the residue was purified by flash chromatograph to give

compound 9a (48 g, 67% yield) as a colorless liquid. Methyl

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Running title

Chin. J. Chem.

Adamantyl 2-(fluoromethyl)-1-oxo-2,3-dihydro-1H-indene

1026, 761, 731 cm^-1. MS (EI): 372 (M +). HRMS (EI) for C₂₂H₂₅FO₄

(M+): Calcd: 372.1737; Found: 372.1735.

-2-carboxylate (9e). Colorless liquid (96 mg, 94%). Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.76 (d, J = 7.7 Hz, 1 H), 7.61 (t, J = 7.5 Hz, 1

H), 7.50 (d, J = 7.7 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 4.88 (dd, J =

48.0, 8.0 Hz, 1 H), 4.8 (dd, J = 48.0, 8.0 Hz, 1 H), 3.63 (d, J = 17.2

Hz, 1 H), 3.37 (d, J = 17.1 Hz, 1 H), 2.11 (s, 3 H), 2.01 (s, 6 H), 1.59

(s, 6 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -230.81 (t, J = 46.9 Hz, 1 F);

¹³C NMR (100.7 MHz, CDCl₃) δ 200.0 (d, J = 4.1 Hz), 167.1 (d, J =

10.0 Hz), 153.5, 135.5, 135.2, 127.7, 126.4, 124.8, 83.8 (d, J =

172.8 Hz), 82.9, 62.1 (d, J = 20.4 Hz), 41.0, 36.0, 34.4 (d, J = 3.6

Hz), 30.8 ppm. IR (KBr): ν_max= 2912, 2853, 1734, 1714, 1608,

1458, 1288, 1208, 1049, 1006, 756 cm^-1. MS (EI): 342 (M⁺). HRMS

(EI) for C₂₁H₂₃FO₃(M⁺): Calcd: 342.1631; Found: 346.1632.

Adamantyl 2-(fluoromethyl)-6-methoxy-1-oxo-2,3-dihydro

-1H-indene-2-carboxylate (9i). Colorless liquid (76 mg, 68%).

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR

(400 MHz, CDCl₃, 293 K, TMS) δ 7.68 (d, J = 8.6 Hz, 1 H), 6.90 (d, J

= 8.2 Hz, 2 H), 4.84 (dd, J = 48.0, 8.0 Hz, 1 H), 4.80 (dd, J = 48.0,

8.0 Hz, 1 H), 3.58 (d, J = 17.3 Hz, 1 H), 3.29 (d, J = 17.2 Hz, 1 H),

2.11 (s, 3 H), 2.02 (s, 6 H), 1.59 (s, 6 H); ¹⁹F NMR (375 MHz, CDCl₃)

δ -230.60 (t, J = 47.1 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 197.6

(d, J = 4.4 Hz), 167.3 (d, J = 9.7 Hz), 166.0, 156.6, 128.3, 126.5,

115.9, 109.5, 83.9 (d, J = 172.4 Hz), 82.7, 62.4 (d, J = 20.3 Hz),

55.7, 41.0, 36.0, 34.3 (d, J = 3.5 Hz), 30.8 ppm. IR (KBr): ν_max

=

2912, 2852, 1730, 1709, 1600, 1490, 1457, 1262, 1049, 731 cm^-1.

MS (EI): 372 (M⁺). HRMS (EI) for C₂₂H₂₅FO₄(M⁺): Calcd: 372.1737;

Found: 372.1747.

Adamantyl 2-(fluoromethyl)-6-methyl-1-oxo-2,3-dihydro-1H

-indene-2-carboxylate (9f). Colorless liquid (91 mg, 85%). Eluent:

ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.54 (s, 1 H), 7.42 (d, J = 8.9 Hz, 1 H), 7.37 (d,

J = 7.8 Hz, 1 H), 4.86 (dd, J = 48.0, 8.0 Hz, 1 H), 4.79 (dd, J = 48.0,

8.0 Hz, 1 H), 3.56 (d, J = 17.1 Hz, 1 H), 3.30 (d, J = 17.0 Hz, 1 H),

2.37 (s, 3 H), 2.10 (s, 3 H), 2.00 (s, 6 H), 1.58 (s, 6 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -230.82 (t, J = 46.9 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 199.7 (d, J = 4.1 Hz), 167.1 (d, J = 10.0 Hz), 150.9, 137.7,

136.8, 135.3, 126.0, 124.6, 83.8 (d, J = 172.7 Hz), 82.7, 62.3 (d, J =

20.5 Hz), 40.9, 35.9, 34.0 (d, J = 3.5 Hz), 30.8, 21.0 ppm. IR (KBr):

Adamantyl 2-(fluoromethyl)-5,6-dimethoxy-1-oxo-2,3

-dihydro-1H-indene-2-carboxylate (9j). White solid (106 mg, 88%),

mp: 164–165 ^oC. Eluent: ethyl acetate/petroleum ether (1:10, R_f=

0.4). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.13 (s, 1 H), 6.88 (s,

1 H), 4.82 (dd, J = 48.0, 8.0 Hz, 1 H), 4.77 (dd, J = 48.0, 8.0 Hz, 1 H),

3.94 (s, 3 H), 3.86 (s, 3 H), 3.50 (d, J = 16.9 Hz, 1 H), 3.23 (d, J =

16.9 Hz, 1 H), 2.09 (s, 3 H), 2.00 (s, 6 H), 1.57 (s, 6 H); ¹⁹F NMR

(375 MHz, CDCl₃) δ -230.66 (t, J = 47.0 Hz, 1 F); ¹³C NMR (100.7

MHz, CDCl₃) δ 198.1 (d, J = 4.3 Hz), 167.4 (d, J = 9.8 Hz), 156.2,

149.7, 149.2, 127.8, 107.2, 104.9, 83.8 (d, J = 172.6 Hz), 82.7, 62.4

(d, J = 20.4 Hz), 56.3, 56.1, 41.0, 36.0, 34.1 (d, J = 3.4 Hz), 30.82

ppm. IR (KBr): ν_max= 2913, 2853, 1728, 1702, 1591, 1502, 1458,

1317, 1274, 1248, 1221, 1113, 1049, 1007, 965, 814, 869, 732

cm^-1. MS (EI): 402 (M⁺). HRMS (EI) for C₂₃H₂₇FO₅(M⁺): Calcd:

402.1843; Found: 402.1848.

ν

_max= 2912, 2853, 1731, 1712, 1617, 1494, 1457, 1283, 1198,

1049, 1006, 966, 873, 730, 503 cm^-1. MS (EI): 356 (M⁺). HRMS (EI)

for C₂₂H₂₅FO₃(M⁺): Calcd: 356.1788; Found: 356.1787.

Adamantyl 2-(fluoromethyl)-4-methoxy-1-oxo-2,3-dihydro

-1H-indene-2-carboxylate (9g). Colorless liquid (75 mg, 67%).

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR

(400 MHz, CDCl₃, 293 K, TMS) δ 7.34 (d, J = 3.8 Hz, 2 H), 7.05 (q, J

= 4.3 Hz, 1 H), 4.87 (dd, J = 48.0, 8.0 Hz, 1 H), 4.82 (dd, J = 48.0,

8.0 Hz, 1 H), 3.90 (s, 3 H), 3.51 (d, J = 18.3 Hz, 1 H), 3.25 (d, J =

17.6 Hz, 1 H), 2.11 (s, 3 H), 2.01 (s, 6 H), 1.59 (s, 6 H); ¹⁹F NMR

(375 MHz, CDCl₃) δ -231.07 (t, J = 47.0 Hz, 1 F); ¹³C NMR (100.7

MHz, CDCl₃) δ 200.1, 167.2 (d, J = 10.4 Hz), 156.8, 142.5, 136.7,

129.3, 116.2, 115.6, 83.8 (d, J = 172.8 Hz), 82.8, 61.8 (d, J = 20.6

Hz), 55.5, 41.0, 36.0, 31.4 (d, J = 3.7 Hz), 30.8 ppm. IR (KBr): ν_max

2912, 2853, 1733, 1715, 1603, 1489, 1298, 1265, 1077, 1048,

1006, 969 cm^-1. MS (EI): 372 (M⁺). HRMS (EI) for C₂₂H₂₅FO₄(M⁺):

Calcd: 372.1737; Found: 372.1744.

Adamantyl 4-fluoro-2-(fluoromethyl)-1-oxo-2,3-dihydro-1H

-indene-2-carboxylate (9k). Yellow liquid (100 mg, 93%). Eluent:

ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR (500 MHz,

CDCl₃, 293 K, TMS) δ 7.60 (d, J = 7.5 Hz, 1 H), 7.44 – 7.38 (m, 1 H),

7.33 (t, J = 8.2 Hz, 1 H), 4.95 (dd, J = 46.6, 9.2 Hz, 1 H), 4.82 (dd, J =

47.1, 9.2 Hz, 1 H), 3.66 (d, J = 17.4 Hz, 1 H), 3.40 (d, J = 17.4 Hz, 1

H), 2.14 (s, 3 H), 2.04 (s, 6 H), 1.63 (s, 6 H); ¹⁹F NMR (471 MHz,

CDCl3) δ -118.67 (dd, J = 8.6, 5.1 Hz, 1 F), -231.11 (t, J = 47.2 Hz, 1

F); ¹³C NMR (126 MHz, CDCl₃) δ 198.8 (d, J = 2.7 Hz), 166.5 (d, J =

10.2 Hz), 159.8 (d, J = 251.1 Hz), 139.3 (d, J = 19.8 Hz), 138.0 (d, J =

4.9 Hz), 129.8 (d, J = 6.6 Hz), 121.6 (d, J = 19.4 Hz), 120.5 (d, J = 3.9

Hz), 83.5 (d, J = 172.7 Hz), 83.3, 61.9 (d, J = 20.6 Hz), 41.0, 35.9,

30.8, 30.3 (d, J = 3.8 Hz) ppm. IR (KBr): ν_max= 2913, 2854, 1739,

1719, 1619, 1593, 1482, 1246, 1218, 1048, 1005, 879, 831, 808

cm-1. MS (EI): 360 (M⁺). HRMS (EI) for C21H22F2O3 (M⁺): Calcd:

360.1537; Found: 360.1532.

=

Adamantylmethyl 2-(fluoromethyl)-5-methoxy-1-oxo-2,3

-dihydro-1H-indene-2- carboxylate (9h). Colorless liquid (108 mg,

97%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.37 (d, J = 8.3 Hz, 1 H), 7.20

(dd, J = 8.3, 2.6 Hz, 1 H), 7.16 (d, J = 2.5 Hz, 1 H), 4.87 (dd, J = 48.0,

8.0 Hz, 1 H), 4.78 (dd, J = 48.0, 8.0 Hz, 1 H), 3.52 (d, J = 16.8 Hz, 1

H), 3.27 (d, J = 16.8 Hz, 1 H), 2.10 (s, 3 H), 2.00 (s, 6 H), 1.59 (s, 6

Adamantyl 4-bromo-2-(fluoromethyl)-1-oxo-2,3-dihydro

-1H-indene-2-carboxyl-ate (9l). Yellow liquid (120 mg, 95%).

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR

(500 MHz, CDCl₃, 293 K, TMS) δ 7.80 (d, J = 8.5 Hz, 1 H), 7.73 (d, J

= 7.5 Hz, 1 H), 7.31 (t, J = 7.7 Hz, 1 H), 4.95 (dd, J = 46.6, 9.1 Hz, 1

H), 4.83 (dd, J = 47.1, 9.1 Hz, 1 H), 3.58 (d, J = 17.6 Hz, 1 H), 3.32

H); ¹⁹F NMR (375 MHz, CDCl₃) δ -230.92 (t, J = 46.9 Hz, 1 F); ¹³

C

NMR (100.7 MHz, CDCl₃) δ 199.7, 167.2 (d, J = 10.2 Hz), 159.6,

146.5, 136.4, 127.1, 125.0, 105.7, 83.8 (d, J = 172.6 Hz), 82.9, 62.7

(d, J = 20.5 Hz), 55.6, 41.0, 36.0, 33.8 (d, J = 3.5 Hz), 30.8 ppm. IR

(KBr): ν_max= 2912, 2853, 1731, 1712, 1493, 1279, 1264, 1049,

(d, J = 17.6 Hz, 1 H), 2.14 (s, 3 H), 2.04 (s, 6 H), 1.62 (s, 6 H); ¹⁹

F

Chin. J. Chem. 2019, 37, XXX－XXX

www.cjc.wiley-vch.de

First author et al.

Report

NMR (471 MHz, CDCl₃) δ -230.85 (t, J = 47.0 Hz, 1 F); ¹³C NMR (126

MHz, CDCl₃) δ 199.2 (d, J = 3.9 Hz), 166.5 (d, J = 10.8 Hz), 153.2,

138.3, 137.1, 129.6, 123.6, 121.9, 83.5 (d, J = 172.9 Hz), 83.3, 62.1

(d, J = 20.3 Hz), 41.0, 36.0, 35.6 (d, J = 3.0 Hz), 30.8 ppm. IR (KBr):

Adamantyl 6-chloro-2-(fluoromethyl)-1-oxo-2,3-dihydro

-1H-indene-2-carboxylate (9p). Colorless liquid (75 mg, 67%).

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR

(500 MHz, CDCl₃, 293 K, TMS) δ 7.74 (d, J = 2.0 Hz, 1 H), 7.60 (dd, J

= 8.2, 2.1 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.94 (dd, J = 46.6, 9.2

Hz, 1 H), 4.81 (dd, J = 47.1, 9.2 Hz, 1 H), 3.61 (d, J = 17.2 Hz, 1 H),

3.36 (d, J = 17.2 Hz, 1 H), 2.14 (s, 3 H), 2.03 (s, 6 H), 1.63 (s, 6 H);

¹⁹F NMR (471 MHz, CDCl₃) δ -230.97 (t, J = 46.8 Hz, 1 F); ¹³C NMR

(126 MHz, CDCl₃) δ 198.7 (d, J = 3.9 Hz), 166.6 (d, J = 10.7 Hz),

151.6, 136.7, 135.5, 134.2, 127.6, 124.5, 83.5 (d, J = 172.7 Hz),

83.3, 62.6, 41.0, 36.0, 34.0 (d, J = 3.8 Hz), 30.8 ppm. IR (KBr): ν_max

= 2912, 2853, 1737, 1719, 1471, 1458, 1248, 1197, 1048, 1007,

871, 728 cm^-1. MS (EI): 376 (M⁺). HRMS (EI) for C₂₁H₂₂FClO₃(M⁺):

Calcd: 376.1242; Found: 376.1252.

ν

_max= 2912, 2853, 1739, 1716, 1598, 1457, 1319, 1255, 1201,

1122, 1048, 1007, 732 cm^-1. MS (EI): 420 (M⁺). HRMS (EI) for

C₂₁H₂₂BrFO₃(M⁺): Calcd: 420.0736; Found: 420.0740.

Adamantyl 5-fluoro-2-(fluoromethyl)-1-oxo-2,3-dihydro

-1H-indene-2-carboxyl-ate (9m). White solid (86 mg, 79%), mp:

97–98 ^oC. Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4).

¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 7.79 (dd, J = 8.5, 5.3 Hz, 1

H), 7.19 (d, J = 8.4 Hz, 1 H), 7.11 (t, J = 8.6 Hz, 1 H), 4.92 (dd, J =

44.0, 8.0 Hz, 1 H), 4.82 (dd, J = 48.0, 8.0 Hz, 1 H), 3.64 (d, J = 17.4

Hz, 1 H), 3.38 (d, J = 17.4 Hz, 1 H), 2.14 (s, 3 H), 2.03 (s, 3 H), 1.62

(s, 6 H); ¹⁹F NMR (471 MHz, CDCl₃) δ -101.15 (dd, J = 15.7, 7.0 Hz,

1 F), -230.88 (t, J = 47.0 Hz, 1 F); ¹³C NMR (126 MHz, CDCl₃) δ

197.9 (d, J = 4.0 Hz), 168.6, 166.8, 166.6 (d, J = 12.4 Hz), 156.5 (d, J

= 10.6 Hz), 131.6, 127.1 (d, J = 10.8 Hz), 114.7 (dd, J = 359.2, 24.3

Hz), 83.6 (d, J = 172.7 Hz), 83.2, 62.3 (d, J = 20.3 Hz), 41.0, 36.0,

34.2 (d, J = 2.8 Hz), 30.8 ppm. IR (KBr): ν_max= 2912, 2854, 1736,

1716, 1616, 1594, 1254, 1217, 1049, 1007, 962, 731, 651 cm^-1. MS

(EI): 360 (M⁺). HRMS (EI) for C₂₁H₂₂F₂O₃(M⁺): Calcd: 360.1537;

Found: 360.1535.

16-(Fluoromethyl)-3-methoxy-13-methyl-17-oxo-7,8,9,11,12,1

3,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-16

-carboxylate (9q). Yellow solid (114 mg, 95%), mp: 105–108 ^oC.

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H NMR

(500 MHz, CDCl₃, 293 K, TMS) δ 7.22 (dd, J = 8.6, 0.9 Hz, 1 H), 6.75

(dd, J = 8.6, 2.8 Hz, 1 H), 6.68 (d, J = 2.7 Hz, 1 H), 4.72 (d, J = 47.3

Hz, 2 H), 3.80 (s, 3 H), 2.97 – 2.91 (m, 2 H), 2.50 – 2.39 (m, 2 H),

2.35 (dd, J = 13.0, 5.7 Hz, 1 H), 2.28 (td, J = 10.6, 4.3 Hz, 1 H), 2.11

– 1.92 (m, 2 H), 1.72 – 1.43 (m, 14 H), 1.06 (s, 3 H); ¹⁹F NMR (471

MHz, CDCl₃) δ -226.70 (t, J = 47.3 Hz, 1 F); ¹³C NMR (126 MHz,

CDCl₃) δ 211.9 (d, J = 2.8 Hz), 167.4 (d, J = 9.6 Hz), 157.7, 137.7,

131.8, 126.3, 113.9, 111.6, 85.1 (d, J = 175.7 Hz), 82.7, 62.2 (d, J =

20.1 Hz), 55.2, 49.5, 46.6, 43.9, 38.0, 31.8, 29.7 (d, J = 7.8 Hz),

27.9, 27.8, 26.5, 25.8, 13.9 ppm. IR (KBr): ν_max= 2977, 2932, 2837,

1750, 1721, 1609, 1576, 1500, 1455, 1369, 1281, 1248, 1147,

1042, 1014, 993, 910, 844, 733 cm^-1.

Adamantyl 5-chloro-2-(fluoromethyl)-1-oxo-2,3-dihydro

-1H-indene-2-carboxylate (9n). White solid (102 mg, 90%), mp:

132 – 134 ^oC. Eluent: ethyl acetate/petroleum ether (1:10, R_f=

0.4). ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 7.71 (d, J = 8.2 Hz, 1

H), 7.52 (s, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 4.92 (dd, J = 46.7, 9.2 Hz,

1 H), 4.80 (dd, J = 47.2, 9.2 Hz, 1 H), 3.62 (d, J = 17.3 Hz, 1 H), 3.37

(d, J = 17.3 Hz, 1 H), 2.13 (s, 3 H), 2.02 (s, 6 H), 1.62 (s, 6 H); ¹⁹

F

NMR (471 MHz, CDCl₃) δ -230.90 (t, J = 46.9 Hz, 1 F); ¹³C NMR (126

MHz, CDCl₃) δ 198.4 (d, J = 3.8 Hz), 166.6 (d, J = 10.3 Hz), 154.9,

142.2, 133.7, 128.6, 126.7, 125.8, 83.5 (d, J = 172.6 Hz), 83.2, 62.2

(d, J = 20.4 Hz), 41.0, 35.9, 34.1 (d, J = 3.6 Hz), 30.8 ppm. IR (KBr):

Diethyl 2-(fluoromethyl)-2-phenylmalonate (9t).^[14]Colorless

liquid (62 mg, 77%). Eluent: ethyl acetate/petroleum ether (1:10,

R_f= 0.4). ¹H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 7.51 – 7.28 (m, 5

H), 5.18 (s, 1 H), 5.09 (s, 1 H), 4.34 (q, J = 7.1, 2 H), 4.31 (q, J = 7.1,

2 H), 1.31 (t, J = 7.1 Hz, 6 H); ¹⁹F NMR (471 MHz, CDCl₃) δ

-223.77 (t, J = 46.7 Hz, 1 F); ¹³C NMR (126 MHz, CDCl₃) δ 168.1 (d,

J = 5.7 Hz), 134.4, 128.5, 128.2, 128.0, 84.7 (d, J = 177.7 Hz), 63.7

(d, J = 19.2 Hz), 62.2, 14.0 ppm.

ν

_max= 2912, 2853, 1736, 1716, 1600, 1580, 1457, 1422, 1295,

1206, 1070, 1049, 1007, 836, 732 cm^-1. MS (EI): 376 (M⁺). HRMS

(EI) for C₂₁H₂₂ClFO₃(M⁺): Calcd: 376.1242; Found: 376.1247.

Adamantyl 6-fluoro-2-(fluoromethyl)-1-oxo-2,3-dihydro

-1H-indene-2-carboxylate (9o). Colorless liquid (88 mg, 81%), mp:

97 – 98 ^oC. Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4).

1H NMR (500 MHz, CDCl₃, 293 K, TMS) δ 7.50 (dd, J = 8.4, 4.5 Hz, 1

H), 7.41 (dd, J = 7.4, 2.5 Hz, 1 H), 7.36 (td, J = 8.5, 2.5 Hz, 1 H), 4.93

(dd, J = 46.7, 9.1 Hz, 1 H), 4.81 (dd, J = 47.1, 9.1 Hz, 1 H), 3.60 (d, J

= 17.0 Hz, 1 H), 3.36 (d, J = 17.0 Hz, 1 H), 2.14 (s, 3 H), 2.02 (s, 6

H), 1.62 (s, 6 H); ¹⁹F NMR (471 MHz, CDCl₃) δ -113.95 (q, J = 7.5

Hz, 1 F), -231.00 (t, J = 46.9 Hz, 1 F); ¹³C NMR (126 MHz, CDCl₃) δ

199.0, 166.7 (d, J = 10.6 Hz), 162.4 (d, J = 248.7 Hz), 149.0, 136.9

(d, J = 7.7 Hz), 127.8 (d, J = 7.8 Hz), 123.3 (d, J = 23.4 Hz), 110.4,

83.5 (d, J = 172.2 Hz), 83.2, 62.8 (d, J = 20.4 Hz), 41.0, 35.9, 33.9

(d, J = 3.8 Hz), 30.8 ppm. IR (KBr): ν_max= 2913, 2854, 1737, 1716,

1488, 1457, 1296, 1262, 1214, 1048, 1007, 875, 767 cm^-1. MS (EI):

360 (M+). HRMS (EI) for C₂₁H₂₂F₂O₃(M⁺): Calcd: 360.1537; Found:

360.1534.

General procedure for O-Selective monofluoromethylation

of β-ketoesters with reagent 3. Into a 10 mL Schlenk tube

equipped with a magnetic stirring bar was added β-ketoester (0.3

mmol), BTPP (0.6 mmol), reagent 3 (0.3 mmol) and anhydrous

dichloromethane (1.0 mL). The mixture was stirred at room

temperature for 5.0 min. The solvent was evaporated under

vacuum and the residue was purified by flash chromatograph to

give compound 10a (57 mg, 80% yield) as a colorless liquid.

Methyl 1-(fluoromethoxy)-3,4-dihydronaphthalene-2-

carboxylate (10a). Colorless liquid (57 mg, 80%). Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.7). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.78 – 7.61 (m, 1 H), 7.33 – 7.22 (m, 2 H),

7.19 – 7.12 (m, 1 H), 5.63 (d, J = 55.2 Hz, 2 H), 3.79 (s, 3 H), 2.82 (t,

J = 7.8 Hz, 2 H), 2.68 (t, J = 7.9 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃)

δ -144.20 (t, J = 55.2 Hz); ¹³C NMR (100.7 MHz, CDCl₃) δ 166.6,

158.3, 138.2, 131.2, 130.1, 127.2, 126.7, 125.0, 114.9, 105.3 (d, J =

www.cjc.wiley-vch.de

Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

220.3 Hz), 51.7, 27.4, 23.9 ppm. IR (KBr): ν_max= 2993, 2950, 1712,

1619, 1282, 1199, 1127, 972, 768 cm^-1. MS (EI): 236.0 (M⁺). HRMS

(ESI) for C₁₃H₁₃FO₃(M⁺): Calcd: 236.0849; Found: 236.0851.

Methyl 7-fluoro-3-(fluoromethoxy)-1H-indene-2-carboxylate

(10g). White solid (63 mg, 87%), mp: 140–142 ^oC. Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.7). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.43 (d, J = 7.6 Hz, 1 H), 7.36 (td, J = 7.8, 4.8

Hz, 1 H), 7.09 (t, J = 8.5 Hz, 1 H), 5.94 (d, J = 53.6 Hz, 2 H), 3.83 (s,

3 H), 3.71 (s, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -120.28 (dd, J =

9.0, 4.7 Hz, 1 F), -145.49 (t, J = 53.6 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 163.9, 161.8, 158.5 (d, J = 248.5 Hz), 142.4 (d, J = 6.6 Hz),

129.3 (d, J = 6.9 Hz), 127.0 (d, J = 19.6 Hz), 117.3 (dd, J = 3.2, 1.4

Hz), 115.7 (d, J = 20.4 Hz), 115.4, 103.9 (d, J = 222.2 Hz), 51.7, 32.3

ppm. IR (KBr): ν_max= 3000, 2960, 1705, 1603, 1478, 1369, 1246,

1181, 1023, 993, 765 cm^-1. MS (EI): 240 (M⁺). HRMS (EI) for

C₁₂H₁₀F₂O₃(M⁺): Calcd: 240.0598; Found: 240.0607.

Methyl 3-(fluoromethoxy)-1H-indene-2-carboxylate (10b).^[12]

White Solid (57 mg, 86%). Eluent: ethyl acetate/petroleum ether

(1:10, R_f= 0.7). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.64 (d, J

= 5.9 Hz, 1 H), 7.45 (d, J = 5.8 Hz, 1 H), 7.43 – 7.33 (m, 2 H), 5.94

(d, J = 53.8 Hz, 2 H), 3.81 (s, 3 H), 3.66 (s, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -145.05 (t, J = 53.8 Hz); ¹³C NMR (100.7 MHz, CDCl₃) δ

164.3, 162.6, 141.8, 139.2, 128.9, 127.0, 124.3, 121.1, 114.7,

103.9 (d, J = 221.5 Hz), 51.47, 35.75 ppm.

Ethyl 3-(fluoromethoxy)-1H-indene-2-carboxylate (10c).

Colorless oil (65 mg, 92%). Eluent: ethyl acetate/petroleum ether

(1:10, R_f= 0.7). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.65 (d, J

= 6.4 Hz, 1 H), 7.46 (d, J = 6.3 Hz, 1 H), 7.45 – 7.34 (m, 2 H), 5.94

(d, J = 54.4 Hz, 2 H), 4.29 (q, J = 6.9 Hz, 2 H), 3.69 (s, 2 H), 1.66 –

0.84 (m, 3 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -145.03 (t, J = 53.9 Hz,

1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 163.9, 162.4, 141.8, 139.4,

128.9, 127.0, 124.3, 121.1, 115.3, 104.0 (d, J = 221.4 Hz), 60.3,

35.8, 14.3 ppm. IR (KBr): ν_max= 2985, 1697, 1598, 1578, 1367,

1254, 1172, 1124, 1042, 963, 758 cm^-1. MS (EI): 236 (M⁺). HRMS

(EI) for C₁₃H₁₃FO₃(M⁺): Calcd: 236.0849; Found: 236.0853.

Methyl 7-bromo-3-(fluoromethoxy)-1H-indene-2-carboxylate

(10h). White solid (79 mg, 87%), mp: 92 – 94 ^oC. Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.7). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.57 (d, J = 7.6 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1

H), 7.30 – 7.21 (m, 1 H), 5.86 (s, 2 H), 3.82 (s, 3 H), 3.61 (s, 2 H); ¹⁹

NMR (375 MHz, CDCl₃) δ -145.42 (t, J = 53.6 Hz); ¹³C NMR (100.7

MHz, CDCl₃) δ 163.9, 161.7, 141.6, 140.8, 131.9, 128.9, 120.2,

F

119.2, 115.5, 103.9 (d, J = 222.2 Hz), 51.7, 37.2 ppm. IR (KBr): ν_max

= 3003, 1711, 1593, 1564, 1440, 1360, 1332, 1286, 1232, 1185,

977, 761 cm^-1. MS (EI): 300 (M⁺). HRMS (EI) for C₁₂H₁₀BrFO₃(M⁺):

Calcd: 299.9797; Found: 299.9794.

Isopropyl 3-(fluoromethoxy)-1H-indene-2-carboxylate

(10d).^[12]Colorless oil (61 mg, 81%). Eluent: ethyl

3-Benzyl-2-(fluoromethoxy)benzofuran (10i). Colorless oil (42

mg, 55%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.7).

¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.33 (d, J = 8.2 Hz, 1 H),

7.26 – 7.19 (m, 5 H), 7.17 (dd, J = 8.0, 6.0 Hz, 2 H), 7.13 – 7.07 (m,

1 H), 5.76 (d, J = 52.6 Hz, 2 H), 3.94 (s, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -151.93 (t, J = 52.6 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

155.1, 148.9, 139.3, 129.2, 128.4, 128.3, 126.2, 123.1, 122.9,

119.4, 110.6, 101.1 (d, J = 227.6 Hz), 97.1, 28.1 ppm. IR (KBr): ν_max

= 3060, 3027, 2920, 1800, 1619, 1495, 1462, 1229, 1125, 1061,

753, 699 cm^-1. MS (EI): 256 (M⁺). HRMS (EI) for C₁₆H₁₃FO₂(M⁺):

Calcd: 256.0900; Found: 256.0903.

acetate/petroleum ether (1:10, R_f= 0.7). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.61 (dd, J = 7.1, 1.6 Hz, 1 H), 7.42 (d, J = 6.0

Hz, 1 H), 7.39 – 7.32 (m, 2 H), 5.91 (d, J = 54.0 Hz, 2 H), 5.14 (p, J =

6.2 Hz, 1 H), 3.64 (s, 2 H), 1.32 (s, 6 H); ¹⁹F NMR (375 MHz, CDCl₃)

δ -146.83 (t, J = 54.0 Hz); ¹³C NMR (100.7 MHz, CDCl₃) δ 163.4,

162.2, 141.7, 139.5, 128.8, 127.0, 124.2, 121.0, 115.8, 104.1 (d, J =

221.3 Hz), 67.7, 35.9, 22.0 ppm.

Methyl 3-(fluoromethoxy)-5-methoxy-1H-indene-2-

carboxylate (10e). Colorless oil (69 mg, 91%). Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.6). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.30 (d, J = 8.3 Hz, 1 H), 7.12 (d, J = 2.2 Hz, 1

H), 6.95 (dd, J = 8.3, 2.4 Hz, 1 H), 5.92 (d, J = 53.8 Hz, 2 H), 3.83 (s,

3 H), 3.79 (s, 3 H), 3.58 (s, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-145.03 (t, J = 53.8 Hz); ¹³C NMR (100.7 MHz, CDCl₃) δ 164.2,

162.5, 159.4, 140.5, 134.0, 125.0, 116.6, 115.8, 104.9, 04.0 (d, J =

221.4 Hz), 55.6, 51.5, 35.1 ppm. IR (KBr): ν_max= 2958, 2839, 1702,

1595, 1576, 1431, 1348, 1225, 1179, 1023, 972, 833 cm^-1. MS (EI):

252 (M⁺). HRMS (EI) for C₁₃H₁₃FO₄(M⁺): Calcd: 252.0798; Found:

252.0804.

General procedure for monofluoromethylation of phenols

with reagent 3. Into a 10 mL Schlenk tube equipped with a

magnetic stirring bar was added phenol (0.3 mmol), BTPP (0.6

mmol), reagent 3 (0.3 mmol) and anhydrous dichloromethane

(1.0 mL). The mixture was stirred at room temperature for 10.0

min. The solvent was evaporated under vacuum and the residue

was purified by flash chromatograph to give compound 11a (40

mg, 73% yield) as a colorless liquid.

1-tert-Butyl-4-(fluoromethoxy)benzene (11a).^[14]Colorless

liquid (40 mg, 73%). Eluent: petroleum ether (R_f= 0.5). ¹H NMR

(400 MHz, CDCl₃, 293 K, TMS) δ 7.37 – 7.30 (m, 2 H), 7.00 (d, J =

8.6 Hz, 2 H), 5.68 (d, J = 54.9 Hz, 2 H), 1.30 (s, 9 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -148.03 (t, J = 54.8 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 154.5, 146.4, 126.5, 116.2, 101.0 (d, J = 218.0 Hz), 31.45

ppm.

Methyl 6-chloro-3-(fluoromethoxy)-1H-indene-2-carboxylate

(10f). Colorless oil (66 mg, 86%). Eluent: ethyl acetate/petroleum

ether (1:10, R = 0.7). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.51

(d, J = 8.2 Hz, ^f1 H), 7.39 (s, 1 H), 7.32 (d, J = 9.6 Hz, 1 H), 5.91 (d, J

= 53.6 Hz, 2 H), 3.79 (s, 3 H), 3.61 (s, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -145.30 (t, J = 53.6 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

163.9, 161.7, 143.2, 137.8, 135.3, 127.6, 124.7, 122.1, 114.9,

103.9 (d, J = 222.0 Hz), 51.6, 35.6 ppm. IR (KBr): ν_max= 2953, 1742,

1715, 1599, 1435, 1321, 1252, 1207, 1106, 1039, 982, 616 cm^-1.

MS (EI): 256 (M⁺). HRMS (EI) for C₁₂H₁₀ClFO₃(M⁺): Calcd:

256.0303; Found: 256.0305.

4-(Fluoromethoxy)biphenyl (11b).^[14]Colorless liquid (56 mg,

93%). Eluent: petroleum ether (R_f= 0.45). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 7.55 – 7.53 (m, 4 H), 7.42 (t, J = 7.3 Hz, 2 H),

7.32 (t, J = 7.3 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 5.73 (d, J = 54.6

Chin. J. Chem. 2019, 37, XXX－XXX

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First author et al.

Report

Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -148.47 (t, J = 54.6 Hz, 1 F);

¹³C NMR (100.7 MHz, CDCl₃) δ 156.2, 140.4, 136.6, 128.8, 128.4,

127.1, 126.9, 116.9, 100.7 (d, J = 218.8 Hz) ppm.

IR (KBr): ν_max= 3070, 1732, 1614, 1392, 1371, 1272, 1199, 1089,

982, 868, 829, 455 cm^-1. MS (EI): 244 (M⁺). HRMS (EI) for C₁₁H₉FO₃

(M⁺): Calcd: 208.0536; Found: 208.0530.

1-Bromo-4-(fluoromethoxy)benzene (11c).^[14]Colorless liquid

(52 mg, 85%). Eluent: petroleum ether (R_f= 0.45). ¹H NMR (400

MHz, CDCl₃, 293 K, TMS) δ 7.43 (d, J = 9.0 Hz, 2 H), 6.97 (d, J = 8.6

Hz, 2 H), 5.68 (d, J = 54.4 Hz, 2 H);¹⁹F NMR (375 MHz, CDCl₃) δ

-149.17 (t, J = 54.4 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 155.9,

132.6, 118.5, 116.1, 100.7 (d, J = 219.6 Hz) ppm.

3-(Fluoromethoxy)-9H-xanthen-9-one (11j). White solid (69

mg, 94%), mp: 134 – 136 ^oC. Eluent: ethyl acetate/petroleum

ether (1:5, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.38

– 8.21 (m, 2 H), 7.69 (t, J = 7.7 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H),

7.36 (t, J = 7.5 Hz, 1 H), 7.11 (s, 1 H), 7.06 (d, J = 10.6 Hz, 1 H), 5.81

(d, J = 53.6 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -151.28 (t, J =

53.5 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 176.2, 161.4 (d, J =

2.8 Hz), 157.5, 156.2, 134.6, 128.7, 126.7, 124.1, 121.8, 117.8,

117.7, 113.7, 103.8 (d, J = 1.4 Hz), 99.7 (d, J = 222.0 Hz) ppm. IR

(KBr): ν_max= 3095, 3021, 2937, 1647, 1616, 1477, 1463, 1445,

1327, 1246, 1177, 1110, 1080, 976, 851, 764, 670 cm^-1. MS (EI):

244 (M⁺). HRMS (EI) for C₁₄H₉FO₃(M⁺): Calcd: 244.0536; Found:

244.0543.

1-(Fluoromethoxy)-4-iodobenzene (11d).^[14]Colorless liquid

(63 mg, 83%). Eluent: petroleum ether (R_f= 0.5). ¹H NMR (400

MHz, CDCl₃, 293 K, TMS) δ 7.61 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 9.0

Hz, 2 H), 5.67 (d, J = 54.4 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-149.25 (t, J = 54.3 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 156.6,

138.6, 118.9, 100.5 (d, J = 219.7 Hz), 86.4 ppm.

4-(Fluoromethoxy)benzonitrile (11e).^[14]Yellow liquid (39 mg,

85%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.5). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.65 (d, J = 9.0 Hz, 1H), 7.15

(d, J = 8.9 Hz, 1H), 5.76 (d, J = 53.6 Hz, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -151.12 (t, J = 53.5 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

159.6, 134.1, 118.5, 117.0, 107.1, 99.6 (d, J = 221.9 Hz).

3-(Fluoromethoxy)-2-nitropyridine (11k). Yellow solid (40 mg,

77%), mp: 33 – 35 oC. Eluent: ethyl acetate/petroleum ether (1:3,

R_f= 0.5). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.25 (s, 1 H),

7.76 (s, 1 H), 7.59 (s, 1 H), 5.77 (d, J = 53.0 Hz, 2 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -151.15 (t, J = 52.9 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 149.6, 144.5, 142.7, 128.9, 127.8 (d, J = 1.6 Hz), 100.8 (d,

J = 225.6 Hz) ppm. IR (KBr): ν_max= 3081, 2937, 1605, 1541, 1366,

1253, 1117, 991, 862, 814, 666 cm^-1. MS (EI): 172 (M⁺). HRMS (EI)

for C₆H₅FN₂O₃(M⁺): Calcd: 172.0284; Found: 172.0281.

1-(4-(Fluoromethoxy)phenyl)ethanone (11f).^[14]White solid

(42 mg, 84%). Eluent: ethyl acetate/petroleum ether (1:10, R_f=

0.5). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.94 (d, J = 8.9 Hz, 2

H), 7.20 – 6.98 (m, 2 H), 5.74 (d, J = 53.9 Hz, 2 H), 2.55 (s, 3 H); ¹⁹

NMR (375 MHz, CDCl₃) δ -150.42 (t, J = 53.9 Hz, 1 F); ¹³C NMR

F

1-(Fluoromethoxy)-1H-benzo[d][1,2,3]triazole (11l). Colorless

oil (21 mg, 45%). Eluent: ethyl acetate/petroleum ether (1:5, R_f=

0.5). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 6.78 (s, 1 H), 6.07 (d,

J = 51.8 Hz, 2 H), 2.43 (s, 6 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -156.64

(t, J = 51.8 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 169.8, 163.0,

115.9, 96.3 (d, J = 219.8 Hz), 23.8 ppm. IR (KBr): ν_max= 2961, 1913,

1339, 1261, 1092, 1019, 800, 418 cm^-1. MS (EI): 156.2 (M⁺). HRMS

(EI) for C₇H₉FN₂O (M⁺): Calcd: 156.0699; Found: 156.0695.

(100.7 MHz, CDCl₃) δ 196.7, 160.2, 132.6, 130.6, 116.0, 99.8 (d, J =

220.7 Hz), 26.5 ppm.

1-(Fluoromethoxy)-4-nitrobenzene (11g).^[14]Yellow solid (40

mg, 78%). Eluent: ethyl acetate/petroleum ether (1:5, R_f= 0.55).

¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.22 (d, J = 9.2 Hz, 2 H),

7.15 (d, J = 9.2 Hz, 2 H), 5.78 (d, J = 53.4 Hz, 2 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -151.57 (t, J = 53.4 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 161.2, 143.5, 125.9, 116.4, 99.6 (d, J = 222.4 Hz) ppm.

1-(Fluoromethoxy)-1H-benzo[d][1,2,3]triazole (11m). White

solid (34 mg, 68%), mp: 35–37 ^oC. Eluent: ethyl

acetate/petroleum ether (1:3, R_f= 0.5). ¹H NMR (400 MHz, CDCl₃,

293 K, TMS) δ 7.98 (d, J = 8.9 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1 H),

7.56 – 7.47 (m, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 5.95 (d, J = 52.8 Hz, 2

2-(4-(Fluoromethoxy)phenyl)ethanol (11h). Colorless oil (43

mg, 84%). Eluent: ethyl acetate/petroleum ether (1:5, R_f= 0.35).

¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.17 (d, J = 8.3 Hz, 2 H),

7.02 (d, J = 8.3 Hz, 2 H), 5.68 (d, J = 54.8 Hz, 2 H), 3.81 (t, J = 6.5

Hz, 2 H), 2.82 (t, J = 6.5 Hz, 2 H), 1.57 (s, 1 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -148.31 (t, J = 54.7 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

155.4, 133.6, 130.2, 116.8, 100.9 (d, J = 218.3 Hz), 63.6, 38.3 ppm.

IR (KBr): ν_max= 3354, 2932, 1611, 1512, 1224, 1095, 1046, 972,

825 cm^-1. MS (EI): 170 (M⁺). HRMS (EI) for C₉H₁₁FO₂(M⁺): Calcd:

170.0743; Found: 170.0742.

H); ¹⁹F NMR (375 MHz, CDCl₃) δ -149.39 (t, J = 53.3 Hz, 1 F); ¹³

NMR (100.7 MHz, CDCl₃) δ 143.5, 128.8, 128.6, 125.0, 120.1,

C

109.1, 106.8 (d, J = 237.0 Hz) ppm. IR (KBr): ν_max= 3093, 2921,

1446, 1368, 1238, 1154, 1089, 1037, 989, 742, 612 cm^-1. MS (EI):

167 (M⁺). HRMS (EI) for C₇H₆FN₃O (M⁺): Calcd: 167.0497; Found:

167.0496.

(E)-1-(4-(fluoromethoxy)styryl)-3,5-dimethoxybenzene (11n).

Purple solid (58 mg, 67%), mp: 125–128 ^oC. Eluent: ethyl

7-(Fluoromethoxy)-4-methyl-2H-chromen-2-one (11i). White

solid (58 mg, 92%), mp: 138 – 139 ^oC. Eluent: ethyl

acetate/petroleum ether (1:5, R_f= 0.7). ¹H NMR (400 MHz, CDCl₃,

293 K, TMS) δ 7.46 (d, J = 8.7 Hz, 2 H), 7.07 (d, J = 8.6 Hz, 2 H),

7.04 (d, J = 15.9 Hz, 1 H), 6.94 (d, J = 16.3 Hz, 1 H), 6.65 (d, J = 2.2

Hz, 2 H), 6.39 (t, J = 2.2 Hz, 1 H), 5.71 (d, J = 54.6 Hz, 2 H), 3.82 (s,

acetate/petroleum ether (1:5, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃,

293 K, TMS) δ 7.58 – 7.55 (m, 1 H), 7.06 – 7.00 (m, 2 H), 6.21 (s, 1

H), 5.77 (d, J = 53.7 Hz, 2 H), 2.42 (d, J = 1.2 Hz, 3 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -150.86 (t, J = 53.7 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 160.7, 159.1 (d, J = 2.9 Hz), 154.8, 152.0, 125.9, 115.8,

113.4, 113.1 (d, J = 1.2 Hz), 104.3, 99.9 (d, J = 221.6 Hz), 18.7 ppm.

6 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -148.54 (t, J = 54.6 Hz, 1 F); ¹³

NMR (100.7 MHz, CDCl₃) δ 161.0, 156.3 (d, J = 3.0 Hz), 139.3,

C

132.7, 128.2, 127.9, 127.9, 116.8, 104.5, 100.6 (d, J = 218.9 Hz),

99.9, 55.3 ppm. IR (KBr): ν_max= 3396, 2937, 2836, 1597, 1510,

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

1458, 1424, 1227, 1150, 1092, 965, 833, 737 cm^-1. MS (EI): 288

(M⁺). HRMS (EI) for C₁₇H₁₇FO₃(M⁺): Calcd: 288.1162; Found:

288.1165.

163.9, 131.9, 131.5, 129.2, 127.4, 93.8 (d, J = 221.4 Hz) ppm. IR

(KBr): ν_max= 2292, 1747, 1591, 1474, 1399, 1265, 1162, 1101,

1010, 756, 566 cm^-1. MS (EI): 232.0 (M⁺). HRMS (EI) for C₈H₆BrFO₂

(M⁺): Calcd: 231.9535; Found: 231.9539.

(R)-6-(fluoromethoxy)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-tr

imethyltridecyl)ch roman (11o). Yellow oil (116 mg, 80%). Eluent:

petroleum ether (R_f= 0.3). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS)

δ 5.50 (d, J = 55.3 Hz, 2 H), 2.66 – 2.51 (m, 2 H), 2.17 (s, 3 H), 2.14

(s, 3 H), 2.10 (s, 3 H), 1.88 – 1.72 (m, 2 H), 1.61 – 1.01 (m, 24 H),

0.92 – 0.81 (m, 12 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -148.13 (t, J =

55.3 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 148.7, 146.7, 127.6,

125.9, 123.1, 117.6, 105.1 (d, J = 218.9 Hz), 75.0, 40.0, 39.4, 37.5,

37.4, 37.3, 32.8, 32.7, 31.2, 28.0, 24.8, 24.5, 23.9, 22.7, 22.6, 21.0,

20.7, 19.8, 19.7, 13.3, 12.5, 11.9 ppm. IR (KBr): ν_max= 2926, 2867,

1460, 1401, 1377, 1248, 1166, 1128, 1102, 975 cm^-1. MS (ESI): 463

(M+H⁺). HRMS (ESI) for C₃₀H₅₂FO₂(M+H⁺): Calcd: 463.3946;

Found: 463.3947.

Fluoromethyl 3-chlorobenzoate (12e). Yellow oil (46 mg,

81%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.3). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.06 (s, 1 H), 7.97 (d, J = 7.8

Hz, 1 H), 7.61 – 7.53 (m, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 5.93 (d, J =

50.5 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -157.89 (t, J = 50.5 Hz, 1

F); ¹³C NMR (100.7 MHz, CDCl₃) δ 163.5, 134.7, 133.9 , 130.2,

130.0, 129.8, 128.1, 93.8 (d, J = 221.8 Hz) ppm. IR (KBr): ν_max

=

3074, 2994, 1749, 1577, 1473, 1429, 1279, 1252, 1116, 1011, 748

cm^-1. MS (EI): 188.1 (M⁺). HRMS (EI) for C₈H6ClFO₂(M⁺): Calcd:

188.0040; Found: 188.0046.

Fuoromethyl 4-acetamidobenzoate (12f). White solid (44 mg,

69%), mp: 153–155 ^oC. Eluent: ethyl acetate/petroleum ether

(1:10, R_f= 0.4). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.06 (d, J

= 8.6 Hz, 2 H), 7.77 – 7.43 (m, 3 H), 5.93 (d, J = 50.8 Hz, 2 H), 2.22

(s, 3 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -157.44 (t, J = 50.8 Hz, 1 F);

¹³C NMR (100.7 MHz, CDCl₃) δ 168.5, 164.0, 143.0, 131.4, 123.7,

118.7, 93.7 (d, J = 220.3 Hz), 24.7 ppm. IR (KBr): ν_max= 3314, 3274,

3191, 3123, 1740, 1683, 1596, 1538, 1410, 1322, 1261, 1179,

1160, 1096, 1001, 769 cm^-1. MS (EI): 211.1 (M⁺). HRMS (EI) for

C₁₀H₁₀FNO₃(M⁺): Calcd: 211.0645; Found: 211.0652.

General procedure for monofluoromethylation of carboxylic

acids with reagent 3. Into a 10 mL Schlenk tube equipped with a

magnetic stirring bar was added carboxylic acid (0.3 mmol), BTPP

(0.6 mmol), reagent 3 (0.3 mmol) and anhydrous

dichloromethane (1.0 mL). The mixture was stirred at room

temperature for 10.0 min. The solvent was evaporated under

vacuum and the residue was purified by flash chromatograph to

give compound 12a (55 mg, 89% yield) as a white solid.

Fluoromethyl 2-naphthoate 12a. mp: 84–86 ^oC. Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.6). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 8.68 (s, 1 H), 8.08 (dd, J = 8.7, 1.7 Hz, 1 H),

7.95 (d, J = 8.1 Hz, 1 H), 7.88 (dd, J = 8.4, 6.0 Hz, 2 H), 7.65 – 7.59

(m, 2 H), 7.55 (t, J = 7.5 Hz, 1 H), 6.01 (d, J = 50.8 Hz, 2 H); ¹⁹F NMR

(375 MHz, CDCl₃) δ -157.48 (t, J = 50.8 Hz, 1 F); ¹³C NMR (100.7

MHz, CDCl₃) δ 164.8, 135.9, 132.3, 132.0, 129.4, 128.7, 128.4,

127.7, 126.8, 125.6, 125.1, 93.9 (d, J = 220.5 Hz) ppm. IR (KBr):

Fluoromethyl 2-iodo-3-methylbenzoate (12g). Yellow solid (60

mg, 68%), mp: 33–36 ^oC. Eluent: ethyl acetate/petroleum ether

(1:10, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.55 (dd, J

= 7.6, 1.7 Hz, 1 H), 7.41 (dd, J = 7.5, 1.7 Hz, 1 H), 7.31 (t, J = 7.6 Hz,

1 H), 5.95 (d, J = 50.6 Hz, 2 H), 2.55 (s, 3 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -158.57 (t, J = 50.5 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

165.7, 143.9, 135.5, 132.9, 128.1, 127.8, 100.7, 94.1 (d, J = 221.9

Hz), 29.9 ppm. IR (KBr): ν_max= 2988, 1755, 1459, 1399, 1281,

1261, 1125, 1008, 750 cm^-1. MS (EI): 388 (M⁺). HRMS (EI) for

C₉H₈FIO₂(M⁺): Calcd: 293.9553; Found: 293.9555.

ν

_max= 2995, 1735, 1473, 1352, 1285, 1195, 1152, 1095, 1000, 782,

769 cm^-1. MS (EI): 388 (M⁺). HRMS (EI) for C₁₇H₁₅ClF₂S₂O₂(M⁺):

Calcd: 388.0170; Found: 388.0180.

Fluoromethyl 2-chloro-5-nitrobenzoate (12h). Yellow solid (60

mg, 86%), mp: 62–64 ^oC. Eluent: ethyl acetate/petroleum ether

(1:6, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.80 (d, J =

2.2 Hz, 1 H), 8.32 (dd, J = 8.7, 2.2 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H),

5.96 (d, J = 50.0 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -158.25 (t, J

= 50.0 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 161.3, 146.1, 141.7,

132.8, 129.0, 127.8, 127.1, 94.1 (d, J = 224.2 Hz) ppm. IR (KBr):

Fluoromethyl 4-cyanobenzoate (12b).^[14]White solid (50 mg,

93%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.55). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.18 (d, J = 8.7 Hz, 2 H),

7.76 (d, J = 8.7 Hz, 2 H), 5.94 (d, J = 50.3 Hz, 2 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -158.06 (t, J = 50.3 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 163.1, 132.3, 130.5, 117.6, 117.3, 94.0 (d, J = 222.7 Hz)

ppm.

ν

_max= 3118, 3097, 1751, 1609, 1518, 1463, 1357, 1276, 1164,

Fluoromethyl 4-acetylbenzoate (12c).^[14]White solid (45 mg,

77%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.55). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.15 (d, J = 8.5 Hz, 2 H), 7.99

(d, J = 8.6 Hz, 2 H), 5.93 (d, J = 50.5 Hz, 2 H), 2.61 (s, 3 H); ¹⁹F NMR

(375 MHz, CDCl₃) δ -157.94 (t, J = 50.5 Hz, 1 F); ¹³C NMR (100.7

MHz, CDCl₃) δ 197.2, 163.8, 140.9, 132.1, 130.3, 128.2, 93.9 (d, J =

221.7 Hz), 26.8 ppm.

1012, 741, 595 cm^-1. MS (EI): 233.1 (M⁺). HRMS (EI) for

C₈H₅ClFNO₄(M⁺): Calcd: 232.9891; Found: 232.9896.

Fluoromethyl 2-(4-methylbenzoyl)benzoate (12i). Yellow solid

(79 mg, 97%), mp: 65–67 ^oC. Eluent: ethyl acetate/petroleum

ether (1:10, R_f= 0.5). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.10

(d, J = 7.6 Hz, 1 H), 7.71 – 7.61 (m, 3 H), 7.57 (t, J = 7.6 Hz, 1 H),

7.39 (d, J = 7.3 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 5.67 (d, J = 50.4

Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -158.66 (t, J = 50.4 Hz, 1 F);

¹³C NMR (100.7 MHz, CDCl₃) δ 196.3, 164.0, 144.3, 142.7, 134.3,

133.2, 130.6, 129.6, 129.6, 129.3, 127.9, 127.4, 93.8 (d, J = 222.2

Hz), 21.7 ppm. IR (KBr): ν_max= 3028, 1731, 1694, 1661, 1602,

Fluoromethyl 4-bromobenzoate (12d). Yellow liquid (55 mg,

79%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.7). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.94 (d, J = 8.5 Hz, 2 H), 7.61

(d, J = 8.5 Hz, 2 H), 5.92 (d, J = 50.6 Hz, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -157.80 (t, J = 50.6 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

Chin. J. Chem. 2019, 37, XXX－XXX

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First author et al.

Report

1487, 1274, 1089, 993, 932, 748, 715 cm^-1. MS (EI): 272.1 (M⁺).

HRMS (EI) for C₁₆H₁₃FO₃(M⁺): Calcd: 272.0849; Found: 272.0856.

Hz) ppm. IR (KBr): ν_max= 3099, 3000, 1759, 1384, 1281, 1242,

1139, 1015, 916, 769, 683 cm^-1. MS (EI): 290 (M⁺). HRMS (EI) for

C₁₂H₉FO₂(M⁺): Calcd: 204.0587; Found: 204.0588.

Fluoromethyl 2-hydroxybenzoate (12j). White oil (35 mg,

69%). Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.4). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 10.29 (s, 1 H), 7.89 (dd, J =

8.0, 1.7 Hz, 1 H), 7.50 (ddd, J = 8.5, 7.2, 1.7 Hz, 1 H), 6.99 (dd, J =

Fluoromethyl 6-hydroxy-2,5,7,8-tetramethylchroman-2

-carboxylate (12o). White solid (52 mg, 62%), mp: 130–133 ^oC.

Eluent: ethyl acetate/petroleum ether (1:10, R_f= 0.3). ¹H NMR

(400 MHz, CDCl₃, 293 K, TMS) δ 5.92 – 5.47 (m, 2 H), 4.28 (s, 1 H),

2.73 – 2.64 (m, 1 H), 2.57 (dt, J = 12.0, 6.0 Hz, 1 H), 2.52 – 2.45 (m,

1 H), 2.21 (s, 3 H), 2.17 (s, 3 H), 2.08 (s, 3 H), 1.94 (td, J = 13.2,

12.0, 6.4 Hz, 1 H), 1.68 (s, 3 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-157.96 (t, J = 50.5 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 172.1,

145.4, 145.2, 1226, 1213, 118.4, 116.6, 93.5 (d, J = 221.8 Hz),

76.7, 30.3, 25.0, 20.6, 12.1, 11.7, 11.11 ppm. IR (KBr): ν_max= 3545,

2938, 1762, 1457, 1416, 1261, 1232, 1167, 1113, 1004, 790, 565

cm^-1. MS (EI): 388 (M⁺). HRMS (EI) for C₁₅H₁₉FO₄(M⁺): Calcd:

282.1267; Found: 282.1276.

8.4, 0.6 Hz, 1 H), 6.94 – 6.86 (m, 1 H), 5.94 (d, J = 50.3 Hz, 2 H); ¹⁹

NMR (375 MHz, CDCl₃) δ -157.99 (t, J = 50.4 Hz, 1 F); ¹³C NMR

(100.7 MHz, CDCl₃) δ 168.3, 162.2, 136.8, 130.2, 119.4, 117.7,

111.0, 93.5 (d, J = 223.1 Hz) ppm. IR (KBr): ν_max= 3524, 2996,

1700, 1616, 1485, 1302, 1250, 1208, 1159, 1094, 1025, 758 cm^-1.

MS (EI): 170.1 (M⁺). HRMS (EI) for C₈H₇FO₃(M⁺): Calcd: 170.0379;

Found: 170.0376.

F

Fluoromethyl 2-amino-5-methylbenzoate (12k). Yellow solid

(41 mg, 75%), mp: 155–158 ^oC. Eluent: ethyl acetate/petroleum

ether (1:10, R_f= 0.3). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.71

(s, 1 H), 7.14 (d, J = 8.3 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 1 H), 5.90 (d, J

= 51.1 Hz, 2 H), 5.61 (s, 2 H), 2.23 (s, 3 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -156.94 (t, J = 51.2 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

165.9, 149.3, 136.3, 130.8, 125.4, 116.7, 108.5, 93.3 (d, J = 219.6

Hz), 20.1 ppm. IR (KBr): ν_max= 3480, 3373, 1693, 1600, 1560,

1520, 1246, 1198, 1155, 1104, 988, 817, 786, 575 cm^-1. MS (EI):

388 (M⁺). HRMS (EI) for C₉H₁₀FNO₂(M⁺): Calcd: 183.0696; Found:

183.0695.

(2E,4E,6E,8E)-fluoromethyl 3,7-dimethyl-9-(2,6,6-trimethyl

cyclohex-1-enyl)nona-2,4,6,8-tetraenoate (12p). White solid (93

mg, 93%), mp: 80–83 ^oC. Eluent: ethyl acetate/petroleum ether

(1:10, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.07 (dd, J

= 15.0, 11.5 Hz, 1 H), 6.32 (s, 1 H), 6.28 (s, 1 H), 6.16 (s, 1 H), 6.12

(d, J = 5.0 Hz, 1 H), 5.79 (s, 1 H), 5.74 (d, J = 51.3 Hz, 2 H), 2.38 (s, 3

H), 2.06 – 1.93 (m, 5 H), 1.70 (s, 3 H), 1.61 (ddt, J = 12.4, 8.9, 4.7

Hz, 2 H), 1.51 – 1.43 (m, 2 H), 1.02 (s, 6 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -156.86 (t, J = 51.4 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

162.7, 154.7, 138.8, 135.7, 135.2, 132.5, 130.5, 128.3, 127.4,

114.2, 91.2 (d, J = 218.1 Hz), 37.6, 32.3, 31.2, 27.0, 19.8, 17.3,

12.2, 11.00 ppm. IR (KBr): ν_max= 2922, 1734, 1580, 1464, 1356,

1233, 1137, 999, 974 cm^-1. MS (EI): 388 (M⁺). HRMS (EI) for

C₂₁H₂₉FO₂(M⁺): Calcd: 332.2152; Found: 332.2154.

Fluoromethyl 2-(3-(trifluoromethyl)phenylamino)benzoate

(12l). Yellow solid (80 mg, 85%), mp: 70–73 ^oC. Eluent: ethyl

acetate/petroleum ether (1:10, R_f= 0.5). ¹H NMR (400 MHz,

CDCl₃, 293 K, TMS) δ 9.45 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 7.52 (s,

1 H), 7.49 – 7.40 (m, 3 H), 7.37 (d, J = 7.4 Hz, 1 H), 7.28 (d, J = 8.3

Hz, 1 H), 6.86 (t, J = 7.6 Hz, 1 H), 5.97 (d, J = 50.8 Hz, 2 H); ¹⁹F NMR

(375 MHz, CDCl₃) δ -62.85 (s, 3 F), -157.31 (t, J = 50.7 Hz, 1 F); ¹³

NMR (100.7 MHz, CDCl₃) δ 166.4, 147.9, 141.0, 135.4, 132.1,

C

General procedure for monofluoromethylation of

thiophenols with reagent 3. Into a 10 mL Schlenk tube equipped

with a magnetic stirring bar was added thiophenol (0.3 mmol),

NaH (0.33 mmol) and DMF (1.0 mL). The mixture was stirred at

room temperature for 15 min. Reagent 3 (0.36 mmol) was added.

The mixture was stirred at room temperature for 10.0 min. The

solvent was evaporated under vacuum and the residue was

purified by flash chromatograph to give compound 13a (50 mg,

75% yield) as a colorless liquid. 4-Bromophenyl)(fluoromethyl)

thioether (13a).^[12]Colorless liquid (50 mg, 75%). Eluent:

petroleum ether (R_f= 0.75). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS)

δ 7.46 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 5.69 (d, J = 52.7

Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -182.35 (t, J = 52.7 Hz, 1 F);

¹³C NMR (100.7 MHz, CDCl₃) δ 133.5 (d, J = 2.8 Hz), 132.4, 132.4

(d, J = 2.1 Hz), 129.6 , 88.4 (d, J = 217.3 Hz) ppm.

131.9 (q, J = 32.2 Hz), 123.0, 125.3, 120.2 (q, J = 3.9 Hz), 118.8 (q, J

= 3.8 Hz), 118.3, 114.1, 110.8, 93.5 (d, J = 221.3 Hz) ppm. IR (KBr):

ν

_max= 3316, 3003, 1701, 1605, 1529, 1337, 1258, 1116, 997, 749,

693 cm^-1. MS (EI): 313.1 (M⁺). HRMS (EI) for C₁₅H₁₁F₄NO₂(M⁺):

Calcd: 313.0726; Found: 313.0731.

Fluoromethyl 1H-indole-2-carboxylate (12m). White solid (55

mg, 95%), mp: 120– 122 ^oC. Eluent: ethyl acetate/petroleum

ether (1:10, R_f= 0.4). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 9.15

(s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 7.40 –

7.34 (m, 2 H), 7.18 (t, J = 7.5 Hz, 1 H), 5.97 (d, J = 50.8 Hz, 2 H); ¹⁹

NMR (375 MHz, CDCl₃) δ -156.81 (t, J = 50.8 Hz, 1 F); ¹³C NMR

(100.7 MHz, CDCl₃) δ 160.1, 137.6, 127.3, 126.3, 125.3, 122.9,

121.2, 112.1, 111.0, 93.7 (d, J = 221.8 Hz) ppm. MS (EI): 193.1

(M⁺). HRMS (EI) for C₁₀H₈FNO₂(M⁺): Calcd: 193.0539; Found:

193.0531.

F

(Fluoromethyl)(4-nitrophenyl)thioether (13b).^[13]Yellow solid

(54.5 mg, 97%). Eluent: ethyl acetate/petroleum ether (1:5, R_f=

0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.17 (d, J = 8.7Hz, 2

H),7.56 (d, J =8.7Hz, 2 H), 5.83 (d, J = 52.2 Hz, 2 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -184.83 (t, J = 52.1 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 146.8, 144.0 (d, J = 3.1 Hz), 128.7 (d, J = 2.3 Hz), 124.3,

86.3 (d, J = 218.6 Hz) ppm.

Fluoromethyl 3,5-bis(trifluoromethyl)benzoate (12n).

Colorless liquid (75 mg, 86%). Eluent: ethyl acetate/petroleum

ether (1:10, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.54

(s, 2 H), 8.12 (s, 1 H), 5.99 (d, J = 50.1 Hz, 2 H); ¹⁹F NMR (375 MHz,

CDCl₃) δ -63.19 (s, 6 F), -158.15 (t, J = 50.1 Hz, 1 F); ¹³C NMR

(100.7 MHz, CDCl₃) δ 162.1, 132.5 (q, J = 34.2 Hz), 130.7, 130.1,

127.2 (dt, J = 6.7, 3.4 Hz), 122.6 (q, J = 272.9 Hz), 94.0 (d, J = 224.0

(2,6-Dichlorophenyl)(fluoromethyl)thioether (13c). Colorless

liquid (61 mg, 96%). Eluent: petroleum ether (R_f= 0.75). ¹H NMR

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

(400 MHz, CDCl₃, 293 K, TMS) δ 7.42 (d, J = 8.1 Hz, 2 H), 7.31 –

7.08 (m, 1 H), 5.68 (d, J = 52.1 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃)

δ -185.47 (t, J = 52.1 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 141.2

(d, J = 2.0 Hz), 130.9, 130.2 (d, J = 1.7 Hz), 128.8, 88.1 (d, J = 221.0

Hz) ppm. (KBr): ν_max= 3078, 2943, 1567, 1556, 1320, 1188, 976,

779, 734 cm^-1. MS (EI): 210 (M⁺). HRMS (EI) for C₇H₅Cl₂FS (M⁺):

Calcd: 209.9473; Found: 209.9478.

Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 154.2, 143.1, 135.5, 130.7,

129.7, 129.1, 129.0, 124.2, 123.9, 120.5, 109.6, 81.9 (d, J = 198.7

Hz) ppm.

7-(Fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (14c).^[14]Yellow

liquid (40 mg, 88%). Eluent: ethyl acetate/petroleum ether (1:3, R_f

= 0.55). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.98 (s, 1 H), 8.93

(s, 1 H), 7.34 (d, J = 3.7 Hz, 1 H), 6.64 (d, J = 2.8 Hz, 1 H), 6.26 (d, J

= 53.3 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -163.98 (t, J = 53.3 Hz,

1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 152.6, 151.5 (d, J = 2.9 Hz),

150.1, 128.7 (d, J = 3.2 Hz), 119.5, 102.5, 81.1 (d, J = 200.3 Hz)

ppm.

(3,5-Bis(trifluoromethyl)phenyl)(fluoromethyl)thioether (13d).

Colorless liquid (72 mg, 86%). Eluent: petroleum ether (R_f= 0.75).

¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.90 (s, 2 H), 7.79 (s, 1 H),

5.79 (d, J = 52.2 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -63.12 (s, 6

F), -183.79 (t, J = 52.1 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ

137.8 (d, J = 3.0 Hz), 132.5 (q, J = 33.7 Hz), 129.7, 124.2, 121.4 (dd,

J = 7.2, 3.3 Hz), 87.1 (d, J = 219.2 Hz) ppm.

4-Chloro-7-(Fluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

(14d).^[14]White solid (47 mg, 85%). Eluent: ethyl

acetate/petroleum ether (1:3, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃,

293 K, TMS) δ 8.67 (s, 1 H), 7.37 (d, J = 3.7 Hz, 1 H), 6.67 (d, J = 2.9

Hz, 2 H), 6.23 (d, J = 52.8 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-164.58 (t, J = 52.7 Hz); ¹³C NMR (100.7 MHz, CDCl₃) δ 152.9,

151.9, 128.9, 118.36 , 106.6, 102.2, 81.5 (d, J = 201.5 Hz) ppm.

2-(Fluoromethylthio)benzo[d]thiazole (13e).^[13]Yellow solid

(57 mg, 95%). Eluent: ethyl acetate/petroleum ether (1:5, R_f=

0.7). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.96 (d, J = 8.4 Hz, 1

H), 7.80 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.35 (t, J = 7.5

Hz, 1 H), 6.16 (d, J = 51.0 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-186.75 (t, J = 51.0 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 162.5,

153.1, 135.9, 126.5, 125.2, 122.5, 121.3, 85.0 (d, J = 222.2 Hz)

ppm.

1-(Fluoromethyl)-1H-benzo[d][1,2,3]triazole (14e).^[14]White

solid (40 mg, 88%). Eluent: ethyl acetate/petroleum ether (1:3, R_f

= 0.52). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 8.10 (d, J = 8.3

Hz, 1 H), 7.65 (d, J = 8.2 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.44 (t, J

= 7.5 Hz, 1 H), 6.58 (d, J = 52.5 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃)

δ -167.97 (t, J = 52.5 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 146.6,

132.9 (d, J = 2.0 Hz), 129.0, 125.0, 120.6, 109.2, 83.5 (d, J = 204.3

Hz) ppm.

2-(Fluoromethylthio)benzo[d]oxazole (13f). Yellow solid (50.5

mg, 92%). Eluent: ethyl acetate/petroleum ether (1:5, R_f= 0.7). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.66 (d, J = 6.9 Hz, 1 H), 7.49

(d, J = 7.1 Hz, 1 H), 7.36 – 7.21 (m, 2 H), 6.16 (d, J = 50.5 Hz, 2 H);

¹⁹F NMR (375 MHz, CDCl₃) δ -188.55 (t, J = 50.5 Hz, 1 F); ¹³C NMR

(100.7 MHz, CDCl₃) δ 161.1, 152.2, 141.7, 124.8, 124.8, 119.3,

110.4, 83.9 (d, J = 223.6 Hz) ppm. (KBr): ν_max= 3071, 3026, 1508,

1454, 1327, 1238, 1141, 1101, 969, 747, 726 cm^-1. MS (EI): 183.1

(M⁺). HRMS (EI) for C₈H₆FNOS (M⁺): Calcd: 183.0154; Found:

183.0156.

1-(Fluoromethyl)-3,5-diphenyl-1H-pyrazole (14f).^[14]White

solid (67 mg, 88%). Eluent: ethyl acetate/petroleum ether (1:3, R_f

= 0.55). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.90 (d, J = 7.4

Hz, 2 H), 7.58 (d, J = 6.4 Hz, 2 H), 7.55 – 7.40 (m, 5 H), 7.38 (d, J =

7.2 Hz, 1 H), 6.75 (s, 1 H), 6.04 (d, J = 53.4 Hz, 2 H); ¹⁹F NMR (375

MHz, CDCl₃) δ -158.39 (t, J = 53.4 Hz, 1 F); ¹³C NMR (100.7 MHz,

CDCl₃) δ 153.21 (d, J = 1.9 Hz), 147.11 (d, J = 1.4 Hz), 132.7, 129.5,

129.4, 129.2, 129.0, 128.9, 128.6, 126.2, 105.3, 86.1 (d, J = 201.0

Hz) ppm.

General procedure for monofluoromethylation of heteroaryl

nitrogen nucleophile with reagent 3. Into a 10 mL Schlenk tube

equipped with a magnetic stirring bar was added heteroaryl

nitrogen nucleophile (0.3 mmol), NaH (0.33 mmol) and DMF (1.0

mL). The mixture was stirred at room temperature for 15 min.

Reagent 3 (0.36 mmol) was added. The mixture was stirred at

room temperature for 10.0 min. The solvent was evaporated

under vacuum and the residue was purified by flash

Supporting Information

The supporting information for this article is available on the

WWW under https://doi.org/10.1002/cjoc.2020xxxxx.

chromatograph to give compound 14a (47 mg, 96% yield) as a

yellow solid. 1-(Fluoromethyl)-2-methyl-1H-benzo[d]imidazole

(14a).¹²Eluent: ethyl acetate/petroleum ether (1:3, R_f= 0.6). ¹H

NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.73 – 7.60 (m, 1 H), 7.36 –

7.32 (m, 1 H), 7.27 (d, J = 3.1 Hz, 1 H), 7.26 (d, J = 3.1 Hz, 1 H), 6.03

(d, J = 53.8 Hz, 2 H), 2.62 (s, 3 H); ¹⁹F NMR (375 MHz, CDCl₃) δ

-171.17 (t, J = 53.8 Hz, 1 F); ¹³C NMR (100.7 MHz, CDCl₃) δ 151.80

(d, J = 2.9 Hz), 142.7, 134.5 (d, J = 3.2 Hz), 123.3, 123.2, 119.6,

108.8, 80.5 (d, J = 200.1 Hz), 13.4 ppm.

Acknowledgement

The authors gratefully acknowledge the financial support

from National Natural Science Foundation of China (21625206,

21632009, 21421002) and the Strategic Priority Research Program

of the Chinese Academy of Sciences (XDB20000000) for financial

support.

References

1-(Fluoromethyl)-2-phenyl-1H-benzo[d]imidazole (14b).^[14]

Colorless liquid (64 mg, 95%). Eluent: ethyl acetate/petroleum

ether (1:3, R_f= 0.6). ¹H NMR (400 MHz, CDCl₃, 293 K, TMS) δ 7.94

– 7.79 (m, 3 H), 7.61 – 7.47 (m, 4 H), 7.42 – 7.33 (m, 2 H), 6.12 (d,

J = 53.6 Hz, 2 H); ¹⁹F NMR (375 MHz, CDCl₃) δ -162.16 (t, J = 53.6

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Fluorine and Fluorinated Motifs in the Design and Application of

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www.cjc.wiley-vch.de

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Report

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Pace, V. Direct and Chemoselective Electrophilic

Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of

Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase

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Chin. J. Chem. 2019, 37, XXX－XXX

Running title

Chin. J. Chem.

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(The following will be filled in by the editorial staff)

Manuscript received: XXXX, 2019

Manuscript revised: XXXX, 2019

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Manuscript accepted: XXXX, 2019

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www.cjc.wiley-vch.de

Entry for the Table of Contents

Page No.

Monofluoromethyl-Substituted Sulfonium

Ylides: Preparation, Structure-Reactivity Study

and Substrate Scope

The development of two highly reactive reagents 3 with a cyclic malonate backbone and 6 with an

electron-poor 1,1,1,5,5,5-hexafluoropentane-2,4-dione backbone through structure-activity

relationship study (SAR) was reported. The high reactivity of reagents allowed to

monofluoromethylate β-ketoesters with high C- or O-selectivity, as well as react with a variety of

nucleophiles within 10 min at room temperature with broad substrate scope.

Xin Hong, Yafei Liu, Long Lu*, Qilong Shen*

Chin. J. Chem. 2018, template

Article Doi

Monofluoromethyl-Substituted Sulfonium Ylides: Preparation, Structure-Reactivity Study and Substrate Scope?

DOI: 10.1002/cjoc.202000206

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