Scalable Approach to Fluorinated Heterocycles with Sulfur Tetrafluoride (SF4)

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Scalable Approach to Fluorinated Heterocycles with Sulfur

Tetraﬂuoride (SF₄)

Serhii Trofymchuk,^#Maksym Bugera,^#Anton A. Klipkov, Volodymyr Ahunovych, Bohdan Razhyk,

Sergey Semenov, Andrii Boretskyi, Karen Tarasenko, and Pavel K. Mykhailiuk *

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ABSTRACT: A general approach to ﬂuorinated (hetero)aromatic

derivatives is elaborated. The key reaction is a deoxoﬂuorination of

substituted acetophenones with sulfur tetraﬂuoride (SF₄). In contrast

to previous deoxoﬂuorination methods, this transformation is fast,

scalable (up to 70 g), and high-yielding. More than 100 novel or

previously hardly accessible ﬂuorinated heterocycles, interesting for

medicinal chemistry and agrochemistry, were synthesized.

sponding transformation of less active acetophenones is also

known, but often problematic, however.²¹There are many

precedents in the literature on deoxoﬂuorination of ﬁve- and

six-membered heteroaromatic alkyl ketones with DAST (4)

morph-DAST (5, O(CH₂CH₂)₂NSF₃) or its analogues, yet

these examples are not systematic and are often a result of

individual extensive optimization.²²⁻²⁴For example, previously

our colleagues synthesized pyridine 6a from ketone 6 and

DAST (8 equiv) in 40% yield.^22gThe reaction was slowit

took place during 14 days. Two additional representative

examples from a patent literature are additionally provided on

Scheme 1. Deoxoﬂuorination of ketone 7 with morph-DAST

was described to provide the desired product 7a in 12% yield

after 28 days.²⁵Reaction of ketone 8 was even slower: the

authors performed it during 48 days! After every week, a new

portion of morph-DAST was added to the mixture. In total, 21

equiv of morph-DAST were used. From our personal

experience, this is a typical situation for deoxoﬂuorination of

substituted acetophenones. In general, these reactions are slow

and addition of new portions of DAST (or its analogues) is

required regularly. Heating, however, usually does not speed up

the needed transformation, but rather leads to extensive

formation of side productsﬂuorostyrenes (Scheme 1).

INTRODUCTION

■

Fluorine-containing hetero(aromatic) compounds are popular

in drug discovery¹⁻³and agrochemistry.⁴Scientists often

incorporate ﬂuorine atom(s) or ﬂuoroalkyl group(s) into

bioactive agents mostly to ﬁne-tune their lipophilicity, aﬀect

pK_avalues of the neighboring functional groups, or increase

metabolic stability.⁵⁻⁹Among all ﬂuoroalkyl groups, the most

popular ones are triﬂuoromethyl and diﬂuoromethyl. Indeed,

more than 70 drugs contain the triﬂuoromethyl group, and at

least 5 drugsthe diﬂuoromethyl one.¹⁰

The 2,2-diﬂuoroethyl substituent (Figure 1) is less common

in drug discovery. Nonetheless, heteroaromatic compounds

with 2,2-diﬂuoroethyl group were already validated in medicinal

chemistry as valuable bioisosteres of anisoles.¹¹For example,

replacement of methoxy group in diuretic agent 1a with CF₂Me

substituent gave compound 1b with improved potency and

better metabolic stability.¹²Analogous replacement in anti-

malarial agent 2a resulted in 1 order of magnitude more active

derivative 2b.¹³Replacement of methoxy group in antidiabetic

agent 3a led to an extreme boost in potency to provide

compound 3b.¹⁴

In recent years, several novel synthetic methods to access

hetero(aromatic) derivatives with CF₂Me group appeared.¹⁵⁻¹⁷

Worth noting is a radical approach with MeCF₂SO₂Na

developed in 2018 by Baran and co-workers.¹⁵The most

popular one, however, is still deoxoﬂuorination of (hetero)-

aromatic ketones with diethylaminosulfur triﬂuoride (DAST,

SF₃NEt₂)¹⁸or its dialkyl analogues. The reaction of aromatic

substrates with active carbonyl groupbenzaldehydes¹⁹or

ketoesters²⁰proceeds smoothly (Scheme 1). The corre-

Received: June 28, 2021

https://doi.org/10.1021/acs.joc.1c01518

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The Journal of Organic Chemistry

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Scheme 1. Deoxoﬂuorination of (Hetero)aromatic Ketones:

State of the Art

Figure 1. Fluoroalkyl groupsCF₃, CF₂H, CF₂Mein medicinal

chemistry.

As a supplier of building blocks, we often received requests

from various pharmaceutical and agrochemical companies for

these compounds. Therefore, we needed to develop a practical

method to them. Previously, we described general procedures

for deoxoﬂuorination of aliphatic and hetero(aromatic)

carboxylic acids with sulfur tetraﬂuoride.^26,27In this work, we

would like to disclose our achievements on deoxoﬂuorination of

hetero(aromatic) ketones with SF₄. These results summarize

our eﬀorts during the last 5 years.

ﬂuorostyrene (Scheme 2). Reaction with sulfur tetraﬂuoride

in liquid hydrogen ﬂuoride (HF), however, was clean and fast.

After 16 h, we isolated the needed product 8a in 92% yield.

After some optimization, we found that the amount of sulfur

tetraﬂuoride could be safely reduced to 1.7 equiv (Scheme 2,

entry 10). Also, following the previously elaborated protocol,

we could also generate hydrogen ﬂuoride in situ by adding

water to the reaction mixture (Scheme 2, entry 12). Both

protocols worked ﬁne, and in future, we used them both

allowing some ﬂexibility. Importantly, the procedure was

scalable, and we could easily synthesize 20 g of product 8a in

one run. After standard workup, the compound was isolated

from the reaction mixture by simple distillation.

In 1958, Smith from DuPont ﬁrst used sulfur tetraﬂuoride²⁸

for deoxoﬂuorination of various carbonyl groups.²⁹In 1960,

deoxoﬂuorination of acetophenone with sulfur tetraﬂuoride was

described.³⁰Subsequently, other examples of deoxoﬂuorination

of substituted acetophenones appeared, but those examples

were rare and nonsystematic.³¹This is especially true for

heterocyclic derivatives.³²In this work, we report the ﬁrst

systematic study of deoxoﬂuorination of hetero(aromatic)

methyl ketones, (Het)Ar-C(O)Me, with sulfur tetraﬂuoride

to access medchem-relevant 2,2-diﬂuoroethyl derivatives

(Het)Ar-CF₂Me. To the best of our knowledge, no such

studies we reported before.

Caution! Sulfur tetraﬂuoride (SF₄) and hydrogen ﬂuoride

(HF) are highly toxic. Special care and an additional technical

training must be taken before working with them.

Scope. Having an optimized procedure in hand, we next

studied its scope. Indeed, diversely substituted acetophenones

7−21 easily gave the needed gem-diﬂuoro-substituted products

7a−21a (Scheme 3). With selected ketones 10 and 12, we also

performed control experiments with DAST and morph-DAST,

and in both cases, only low conversions were observed. Heating

of the reaction mixture did not signiﬁcantly help, but rather

facilitated formation of side ﬂuorostyrenes. With substrate 18,

RESULTS AND DISCUSSION

■

Optimization. First, we tried deoxoﬂuorination of substrate

8 using common reagentsEt₂NSF₃(DAST) and O-

(CH₂CH₂)₂NSF₃(morph-DAST). The reactions were per-

formed in dichloromethane. Both of them were slow and did

not go to completion within 3 days. Heating also did not help,

but rather led to formation of side products including

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a

Scheme 2. Optimization of Deoxoﬂuorination of Ketone 8

Scheme 3. Deoxoﬂuorination of Aromatic Ketones

a

b

1

Determined by H NMR. Isolated yield.

standard protocol with sulfur tetraﬂuoride in hydrogen ﬂuoride

led to polymerization. We could, however, obtain the needed

product 18a in 10% yield using catalytic amount of water

instead of adding an excess of hydrogen ﬂuoride.

It is also interesting to note that keto-sulfonic acid 20,

PhC(O)CH₂SO₃H, smoothly aﬀorded gem-diﬂuoro-substi-

tuted sulfonyl ﬂuoride 21aa class of compounds especially

popular today in organic synthesis and chemical biology

(Scheme 3).³³Standard reaction of ketone 21 with DAST

and morph-DAST led to polymerization only. Reaction of

substituted benzophenone 22 with both DAST and morph-

DAST led to low conversions. Reaction with sulfur tetra-

ﬂuoride, in turn, gave the desired ﬂuorinated product 22a in

72% yield. Importantly, all syntheses were performed on a

multigram scale.

Next, deoxoﬂuorination of heterocyclic ketones with sulfur

tetraﬂuoride was elaborated (Scheme 4). Ketones with the

fragment of pyrazole (23−26), imidazole (27, 28), and thiazole

(29−34) gave the desired products 23a−34a in 53−88% yield.

Worth noting is that pyrazole 26 and imidazoles 27, 28 had free

NH-groups, and required no N-protection. Thiazole 32 had free

amino group that was also compatible with reaction conditions.

Control experiments of ketones 24, 26−28 with DAST or

morph-DAST gave only low conversion of products. Reaction

of keto-ester 25 with DAST on the other hand led to the

formation of a complex mixture having the corresponding

ﬂuoroalkene.

The elaborated protocol was not without limitations. We

could not convert thiophenes 36−38 and furane 39 into the

needed products (Scheme 4). In all cases, extensive polymer-

ization was observed, presumably via initial protonation of

C(2)-atom by hydrogen ﬂuoride. Substrate 35 was the only

example of thiophene-containing ketone that we could convert

into the desired product 35a. The corresponding reaction with

DAST did not proceed at room temperature, and under heating

led to polymerization.

b

c

SF₄(3.0 equiv), water (0.5 equiv) instead of hydrogen ﬂuoride. SF₄

d

e

(3.0 equiv). 20 °C. Water (0.05 equiv) instead of hydrogen ﬂuoride,

40 °C, 48 h. SF₄(6.0 equiv), water (1.0 equiv) instead of HF, 20 °C,

120 h. Hydrogen ﬂuoride (30.0 equiv). Reaction conditions: (i)

ketone (1.0 equiv), SF₄(1.7 equiv), hydrogen ﬂuoride (10.0 equiv),

20 °C, 16 h; (ii) workup; (iii) distillation. [DAST]: ketone (1.0

equiv), Et₂NSF₃(3.0 equiv), CH₂Cl₂, 20 °C, 16 h. [mDAST]: ketone

(1.0 equiv), O(CH₂CH₂)₂NSF₃(3.0 equiv), CH₂Cl₂, 20 °C, 16 h.

f

g

a

54 with DAST gave only complex mixture, but the

corresponding transformation with sulfur tetraﬂuoride aﬀorded

the needed product 54a in 82% yield. Pyrazine 55 and indazole

56 were also successfully converted into the diﬂuorinated

derivatives 55a, 56a in 61−72% yield. Reaction of ketone 57

with two aromatic substituentsphenyl and pyridylwith

DAST or morph-DAST did not proceed at all, even under

Chloro-, bromo-, and ﬂuoro-substituted pyridyl ketones 40−

53 were also easily converted into the corresponding gem-

diﬂuoro-substituted products 40a−53a in 60−92% yields using

sulfur tetraﬂuoride (Scheme 4). Reaction of pyridyl keto-ester

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a

Scheme 4. Deoxoﬂuorination of Heteroaromatic Ketones

b

c

d

e

f

g

SF₄(3.0 equiv). 80 °C, 72 h. 35 °C, 144 h. 40 °C, 96 h. SF₄(25.0 equiv), water (1 equiv) instead of HF, 20 °C, 2 weeks. O(CH₂CH₂)₂NSF₃

h

a

(5.0 equiv), neat, 60 °C, 24 h. SF₄(6.0 equiv). Reaction conditions: (i) ketone (1.0 equiv), SF₄(1.7 equiv), hydrogen ﬂuoride (10.0 equiv), 20

°C, 16 h; (ii) workup; (iii) distillation. [DAST]: ketone (1.0 equiv), Et₂NSF₃(3.0 equiv), CH₂Cl₂, 20 °C, 16 h. [morph-DAST]: ketone (1.0

equiv), O(CH₂CH₂)₂NSF₃(3.0 equiv), CH₂Cl₂, 20 °C, 16 h.

heating. Deoxoﬂuorination with sulfur tetraﬂuoride, however,

allowed preparation of product 57a in 69% yield.

react with inactive (hetero)aromatic ketones (via intermediate

I-1) to form intermediate I-2. This is the reason why the

reaction of (hetero)aromatic ketones with DAST is much

Next, we performed deoxoﬂuorination of functionalized

heterocyclic triﬂuoromethyl ketones into the pentaﬂuoroethyl-

substituted products (Scheme 5).^34,35Pyridyl ketones 58−65

smoothly aﬀorded the desired C₂F₅-substituted derivatives

58a−65a in 62−91% yield. We also could convert thiophenes

66, 67 into the desired products 66a, 67a in good yields of 69−

74%. Reaction of 66 and 67 with DAST gave no product. The

only limitation of this approach was furan 68, and we could not

obtain the needed product.

+

slower: no active Lewis acid (SF₃). Next, intermediate I-2

reacts with an excess of ﬂuoride (or hydrodiﬂuoride) anion to

give the target ArCF₂Me product. With low concentration of

ﬂuoride anion, however, intermediate I-2 can also eliminate

proton to give the side productﬂuoroalkene (Scheme 6). The

latter is a typical situation for deoxoﬂuorination of ketones with

DAST or its analogues: no external HF.

Modiﬁcations. Having synthesized diﬂuoro- and penta-

ﬂuoro-substituted (hetero)aromatic derivatives depicted on

Schemes 3−5, we wanted also to highlight their representative

modiﬁcations into the corresponding ﬂuorinated building

Mechanism. From the mechanistic standpoint, sulfur

tetraﬂuoride reversibly reacts with hydrogen ﬂuoride to give

an active SF₃⁺cation which is a strong Lewis acid. The latter can

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Scheme 5. Deoxoﬂuorination of Heterocyclic

Triﬂuoromethyl Ketones

Scheme 7. Modiﬁcations of gem-Diﬂuoroalkyl Heterocycles

23a, 25a, and 54a

a

obtained in 25 g scale in a single run. Worth noting is that this is

principally a novel approach to ﬂuorocinnamic acids.³⁶

Fluorinated pyrazoles are very popular in agrochemistry,³⁷

drug discovery,³⁸and coordination chemistry as ligands for

transition metals.³⁹Therefore, we next performed bromination

of pyrazole 23a in acetic acid to give bromide 71a in 85% yield

(Scheme 7). Reaction of 23a with N-iodosuccinimide (NIS)

similarly aﬀorded iodide 72 in 68% yield. [Pd]-catalyzed

carbonylation of the latter in methanol, followed by saponiﬁed

with LiOH gave interesting pyrazole−carboxylic acid 73 in 71%

combined yield. The synthesis was performed on 30 g scale.

Representative lithiation of bromide 15a with BuLi followed

by addition of dimethylformamide (DMF) gave aldehyde 74 in

81% yield (Scheme 8). Treatment of the intermediate lithium

b

Ketone hydrate was ﬁrst dehydrated into ketone, which next reacted

c

according to standard procedure. Ketone hydrate (1.0 equiv), SF₄(3

a

equiv), 90 °C, 48 h. Reaction conditions: (i) ketone (1.0 equiv), SF₄

(1.7 equiv), hydrogen ﬂuoride (10.0 equiv), 20 °C, 16 h; (ii) workup;

(iii) distillation.

Scheme 6. Mechanism of Deoxoﬂuorination of

Heteroaromatic Ketones with Sulfur Tetraﬂuoride in

Hydrogen Fluoride

Scheme 8. Modiﬁcations of Bromide 15a

blocks that could be directly used in medchem and agro-

chemical projects.

salt with sulfur dioxide and subsequent oxidation with sulfuryl

chloride gave sulfonyl chloride 75 in 84% yield. Finally, [Pd]-

catalyzed reaction of bromide 15a with B₂Pin₂gave the

corresponding boron derivative 76 in 78% yield.

Reaction of pyridyl-2-chlorides with CsF in dimethyl

sulfoxide (DMSO) under heating gave pyridyl-2-ﬂuoride 40b,

44b, 49b, 58b, 61b, and 63b (Scheme 9) in excellent yields

Reaction of compound 25a with 1,8-diazabicyclo[5.4.0]-

undec-7-ene (DBU) led to elimination of hydrogen ﬂuoride.

Saponiﬁcation of the crude product with LiOH gave

ﬂuoroacrylic acid 69 in 55% combined yield (Scheme 7).

Analogous transformation of substrate 54a gave ﬂuoroacrylic

acid 70 in 50% combined yield. The product was subsequently

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(Halex process).⁴⁰These types of structures are often used as

arylating agents in agrochemistry (Acynonapyr, Scheme 9).⁴

Scheme 10. Synthesis of Fluoroalkyl-Substituted

Heteroaromatic Carboxylic Acids

a

Scheme 9. Synthesis of Fluoroalkyl-Substituted Pyridyl

Fluorides

(Hetero)aromatic carboxylic acids with diverse ﬂuoroalkyl

groups are also popular in agrochemistry and drug discovery

(Fluopyram and Cyclobutriﬂurame, Scheme 10). Therefore, we

converted several representative bromides from Schemes 3−5

into the corresponding carboxylic acids (Scheme 10). We used

two main protocols for that. Bromide 7a was treated with nBuLi

followed by addition of dry carbon dioxide to aﬀord acid 7c in

77% yield. Analogously, acids 11c, 15c, 48c, 64c, and 65c were

obtained. Thiazole 31a, however, was carbonylated in methanol

using [Pd]-catalysis and saponiﬁed to aﬀord the needed acid

31c in 73% yield. Following that method, carboxylic acids 19c,

42c, 45c, and 50c were additionally obtained. For bromide 61a,

the best result was achieved with transmetallation with iPrMgCl

followed by addition of carbon dioxide. The desired carboxylic

acid 62c was obtained in 60% yield.

b

Et₂O instead of THF. [Pd]: (i) bromide (1.0 equiv), NEt₃(1.05

equiv), Pd(dppf)Cl₂(0.02 equiv), MeOH, CO (40 atm), 110 °C, 12

h. (ii) aq. NaOH (1.2 equiv); (iii) aq. HCl. [iPrMgBr]: (i) bromide

(1.0 equiv), iPrMgBr (1.03 equiv), THF, 0 °C, 1 h; (ii) dry CO₂(15

a

equiv); (iii) aq. HCl. Reaction conditions: (i) bromide (1.0 equiv),

BuLi (1.05 equiv), tetrahydrofuran (THF), −80 °C, 1 h; (ii) dry CO₂

(15 equiv); (iii) aq. HCl.

Triﬂuoromethyl-substituted anilines and aminoheterocycles

are widespread in drug discovery and especially in agro-

chemistry (Bistriﬂuron, Fluometuron, Enasidenib, and Fluazi-

namSchemes 11 and 12). Therefore, we also synthesized

here several ﬂuoroalkyl-substituted anilines and aminohetero-

cycles from substrates obtained before. For that, we used three

diﬀerent protocols depending on availability of starting

materials. For example, nitrobenzenes 9a, 10a, and 17a were

easily reduced into the desired anilines 9d, 10d, and 17d

(Scheme 11). Worth noting is that aniline 9d was stable only as

a hydrochloride salt. In the form of a free base, it decomposed

immediately.

Reaction of 2-pyridyl ﬂuoride 40b with liquid ammonia in

tetrahydrofurane under heating smoothly gave the correspond-

ing 2-aminopyridine 40d in 82% yield (Scheme 12). Following

similar logic, synthesis of 2-aminopyridines 43d, 58d, 59d, and

63d was also undertaken.

Curtius reaction of carboxylic acid 15c with (PhO)₂P(O)N₃

in tert-butanol, followed by acidic N-Boc cleavage gave aniline

15d in 63% yield. The product was stable only as a

hydrochloride; in the form of a free base, it decomposed.

Using that tactic, aminopyridines 48d, 50d, and 62d were also

obtained (Scheme 13).

Deoxoﬂuorination strategy described in this work not only

allowed the synthesis of new compounds, but also signiﬁcantly

facilitated preparation of known ones. For example, previous

synthesis of compounds 6a−8a with DAST or morph-DAST

took from 2 weeks to 2 months (Schemes 1 and 14). The

current protocol with sulfur tetraﬂuoride, in turn, allowed the

practical synthesis of all three compounds in up to 70 g scale

during 1 day (Scheme 13).

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a

Scheme 11. Synthesis of Fluoroalkyl-Substituted Anilines

Scheme 13. Synthesis of Fluoroalkyl-Substituted Anilines

b

(i) Acyl chloride (1.0 equiv), NaN₃(1.5 equiv), water−acetone =

a

1:1, 10 °C; (ii) tBuOH, reﬂux, 12 h; (iii) HCl in dioxane. Reaction

conditions. [DPPA]: (i) acid (1.0 equiv), (PhO)₂P(O)N₃(1.05

equiv), NEt₃(1.05 equiv), tBuOH, reﬂux, 12 h; (ii) HCl in dioxane.

Scheme 14. Comparison of Deoxoﬂuorination Protocols

a

Reaction conditions: (i) nitrobenzene (1.0 equiv), NH₄Cl (0.36

equiv), Fe (3.6 equiv), aq. HCl, iPrOH, reﬂux, 1 h; (ii) distillation.

[Pd]: bromide (1.0 equiv), AcCl (1.05 equiv), 10% Pd/C (0.1 equiv),

H₂(1 atm), MeOH, 20 °C, 12 h.

a

Scheme 12. Synthesis of Fluoroalkyl-Substituted Anilines

benzaldehydes and aromatic ketoesters, however, acetophe-

nones are much less active. Therefore, the deoxoﬂuorination is

often problematic: reactions are slow (up to 2 months), require

permanent addition of new portions of DAST (or analogues),

and lead to extensive formation of side productsﬂuorostyr-

enes. In this work, we elaborated a practical method to

(hetero)aromatic derivatives with CF₂Me group and analogues

with sulfur tetraﬂuoride (SF₄). Deoxoﬂuorination of the

corresponding ketones was performed in the presence of

water or hydrogen ﬂuoride. In contrast to previous approaches,

the reaction is fast and high-yielding. Using that method, we

were able to synthesize >100 of new or previously hardly

available ﬂuorinated (hetero)aromatics for the direct use in

medicinal chemistry and agrochemistry. Moreover, the method

not only allowed the preparation of new compounds but also

b

a

70 °C. Reaction conditions. [NH₃]: ﬂuoride (1.0 equiv), liquid

NH₃(10 equiv), THF, 90 °C, 24 h.

CONCLUSIONS

■

(Hetero)aromatic compounds with CF₂Me group are valuable

bioisosteres of anisoles in medicinal chemistry.¹²⁻¹⁴Never-

theless, synthetic approaches to them are still limited. The main

method relies on deoxoﬂuorination of acetophenones with

DAST (SF₃NEt₂) and its analogues. In strict contrast to active

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(126 MHz, CDCl₃) δ 150.7, 139.2 (t, J = 4 Hz), 137.1 (t, J = 9 Hz),

133.5 (t, J = 28 Hz), 122.9 (t, J = 248 Hz), 122.3, 33.6 (t, J = 25 Hz),

15.5 (t, J = 4 Hz) ppm. ¹⁹F{¹H} NMR (470 MHz, CDCl₃) δ −106.3

(s) ppm. GCMS (M) 250. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₉H₁₁BrF₂N 250.0043; found 250.0031.

General Procedure B (Reaction with SF₄/H₂O). 7a as an

example. Scale: 0.1 mol.

signiﬁcantly facilitated the synthesis of the new ones (Schemes

1 and 14).

With the results provided in this work, we believe that in the

nearest future, ﬂuorinated heterocycles with CF₂Me group will

play a solid role in medicinal chemistry and agrochemistry

projects.

1-Bromo-2-(1,1-diﬂuoroethyl)benzene (7a). Compound 7 (19.90

g, 0.10 mol, 1.0 equiv) was placed in a 500 mL autoclave made of

Hastelloy nickel alloy. The reaction vessel was cooled down by liquid

nitrogen and H₂O (0.9 mL, 0.05 mol, 0.5 equiv) was added. Then, SF₄

(32.40 g, 0.30 mol, 3.0 equiv) was condensed into a reaction vessel.

Cooling bath was removed, and the mixture was allowed to warm up to

a room temperature. It was then stirred for 16 h at room temperature.

The gaseous products were vented oﬀ into a trap with a solution of

NaOH (1 M). The residue was poured onto a suspension of NaHCO₃

and ice (500 g) (for products with no basic centers, just ice can be

used) extracted with MTBE, and an organic extract was washed with

saturated aq. NaHCO₃(500 mL). The organic layer was separated,

dried over Na₂SO₄, and ﬁltered under reduced pressure to aﬀord the

desired product. The ﬁnal product was puriﬁed by distillation. Yield:

19.01 g, 0.086 mol, 86%, yellow oil. General procedure A. Yield: 19.45

g, 0.088 mol, 88%. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J = 13.5,

7.9 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 2.07 (t, J

= 18.4 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 137.1 (t, J

= 26 Hz), 135.0, 131.2, 127.5, 127.2 (t, J = 9 Hz), 121.4 (t, J = 242

Hz), 119.8 (t, J = 4 Hz), 24.9 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −87.9 (s) ppm. GCMS (M) 221. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₈H₈BrF₂220.9777; found 220.9771.

1-Bromo-2-(1,1-diﬂuoroethyl)-4-ﬂuorobenzene (8a). General

EXPERIMENTAL SECTION

■

General Considerations. All chemicals were provided by

Enamine Ltd. (www.enamine.net). All solvents were treated according

to standard methods. All reactions were monitored by thin-layer

chromatography (TLC) and were visualized using UV light. Product

puriﬁcation was performed using silica gel column chromatography.

TLC characterization was performed with precoated silica gel GF254

(0.2 mm), while column chromatography characterization was

1

performed with silica gel (100−200 mesh). H NMR spectra were

recorded at 400, 500, or 600 MHz (Varian); ¹⁹F NMR spectra were

recorded at 376 MHz (Varian) and ¹³C NMR spectra were recorded at

100, 126 or 151 MHz (Varian). ¹H NMR chemical shifts are calibrated

using residual undeuterated solvents CHCl₃(δ = 7.26 ppm) or DMSO

(δ = 2.50 ppm). ¹³C NMR chemical shifts for ¹³C NMR are reported

relative to the central CHCl₃(δ = 77.16 ppm) or DMSO (δ = 39.52

ppm). ¹⁹F NMR chemical shifts are calibrated using CFCl₃as an

internal standard. Coupling constants are given in hertz. High-

resolution mass spectra (HRMS) were recorded on an Agilent LC/

MSD TOF mass spectrometer by electrospray ionization time-of-ﬂight

(ESI-TOF) reﬂectron experiments.

Caution! Sulfur tetraﬂuoride (SF₄) and hydrogen ﬂuoride (HF) are

highly toxic. Special care and additional technical training must be

taken before working with them.^41,42

1

procedure B. Yield: 22.47 g, 0.094 mol, 94%, red oil. H NMR (400

MHz, CDCl₃) δ 7.60 (dd, J = 8.7, 5.2 Hz, 1H), 7.34 (dd, J = 9.4, 3.0

Hz, 1H), 7.00 (td, J = 8.3, 3.0 Hz, 1H), 2.05 (t, J = 18.4 Hz, 3H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 161.9 (d, J = 248 Hz), 139.2 (td,

J = 27, 7 Hz), 136.4 (d, J = 8 Hz), 120.6 (t, J = 242 Hz), 118.3 (d, J =

22 Hz), 115.0 (dt, J = 26, 10 Hz), 113.9 (q, J = 4 Hz), 24.6 (t, J = 28

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.4 (s, 2F), −114.0

(s, 1F) ppm. GCMS (M) 239. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₈H₇BrF₃238.9683; found 238.9680.

1-(1,1-Diﬂuoroethyl)-3-nitrobenzene (10a). Modiﬁed general

procedure A: SF₄(3.0 equiv). Yield: 15.33 g, 0.082 mol, 82%, brown

solid, m.p. = 45-46 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J =

8.3 Hz, 1H), 8.32 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 8.0 Hz,

1H), 2.04 (t, J = 19.1 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 147.8, 138.9 (t, J = 28 Hz), 131.3 (t, J = 6 Hz), 130.7,

125.0, 122.4 (t, J = 239 Hz), 119.5 (t, J = 6 Hz), 24.7 (t, J = 28 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −85.5 (s) ppm. GCMS

(M) 187. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₈F₂NO₂

188.0523; found 188.0514.

General Procedure A (Reaction with SF₄/HF). 9a as an example.

Scale: 0.1 mol.

1-(1,1-Diﬂuoroethyl)-2-nitrobenzene (9a). Compound 9 (16.5 g,

0.10 mol, 1.0 equiv) was placed in a 500 mL autoclave made of

Hastelloy nickel alloy. The reaction vessel was cooled down by liquid

nitrogen and anhydrous liquid HF (20.1 mL, 1.00 mol, 10.0 equiv) was

added. Then, SF₄(18.36 g, 0.17 mol, 1.7 equiv) was condensed into a

reaction vessel. The cooling bath was removed, and the mixture was

allowed to warm up to a room temperature. It was then stirred for 16 h

at room temperature. The gaseous products were vented oﬀ into a trap

with aqueous solution of NaOH (1 M). The residue was poured onto a

suspension of NaHCO₃and ice (500 g) (for products with no basic

centers, just ice can be used) extracted with methyl tert-butyl ether

(MTBE), and an organic extract was washed with saturated aq.

NaHCO₃(500 mL). The organic layer was separated, dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure to aﬀord

the desired product. The ﬁnal product was puriﬁed by distillation.

Yield: 15.90 g, 0.085 mol, 85%, yellow oil. ¹H NMR (400 MHz,

DMSO-d₆) δ 7.90 (d, J = 7.9 Hz, 1H), 7.83−7.71 (m, 3H), 2.10 (t, J =

19.1 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ 147.6,

132.4, 131.9, 129.2 (t, J = 28 Hz), 127.6 (t, J = 7 Hz), 123.9, 121.5 (t, J

= 241 Hz), 25.8 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆) δ −84.3 (s) ppm. Gas chromatography mass spectrometry

(GCMS) (M) 187. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₈H₈F₂NO₂188.0523; found 188.0520.

2-Bromo-3-(1,1-diﬂuoro-2-methylpropyl)pyridine (6a). A solution

of 6 (2.00 g, 0.0087 mol, 1.0 equiv) in CH₂Cl₂(10 mL) was placed in

an autoclave made of Hastelloy nickel alloy. The reaction vessel was

cooled down by liquid nitrogen and H₂O (0.32 g, 0.0174 mol, 2.0

equiv) was added. Then, SF₄(4.70 g, 0.0435 mol, 5.0 equiv) was

condensed into a reaction vessel. Cooling bath was removed, and the

mixture was allowed to warm up to a room temperature. It was then

stirred for 16 h at room temperature. The gaseous products were

vented oﬀ into a trap with aqueous solution of NaOH (1 M). NaHCO₃

was added, and the mixture was ﬁltered. The ﬁnal product was puriﬁed

by distillation. Yield: 1.52 g, 0.0061 mol, 70%, yellow oil, b.p. = 59−61

°C at 0.5 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 3.5 Hz,

1H), 7.84 (dd, J = 7.7, 1.3 Hz, 1H), 7.34 (dd, J = 7.6, 4.7 Hz, 1H),

3.08−2.86 (m, 1H), 1.01 (d, J = 6.9 Hz, 6H) ppm. ¹³C{¹H} NMR

1-Bromo-3-(1,1-diﬂuoroethyl)benzene (11a). General procedure

1

A. Yield: 16.35 g, 0.074 mol, 74%, green oil. H NMR (400 MHz,

CDCl₃) δ 7.65 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.8 Hz,

1H), 7.30 (t, J = 7.8 Hz, 1H), 1.91 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 137.2 (t, J = 26 Hz), 135.0, 131.2, 127.6,

127.2 (t, J = 9 Hz), 122.6 (t, J = 242 Hz), 119.8 (t, J = 4 Hz), 24.9 (t, J

= 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.6 (s) ppm.

GCMS (M) 221. We could not obtain reliable HRMS for this

compound. GC/MS (EI): m/z (%) 204.90 (100%), 206.90 (97.78%),

219.90 (46.82%), 221.90 (46.15%), 126.00 (23.67%).

1-Bromo-3-(1,1-diﬂuoroethyl)-5-ﬂuorobenzene (12a). Modiﬁed

general procedure A: SF₄(3.0 equiv). Yield: 14.58 g, 0.061 mol, 61%,

1

colorless oil, b.p. = 71-72 °C at 15 mmHg. H NMR (400 MHz,

CDCl₃) δ 7.45 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 8.7 Hz,

1H), 1.90 (t, J = 18.1 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 162.6 (d, J = 252 Hz), 141.9 (td, J = 28, 8 Hz), 124.1 (td, J =

6, 3 Hz), 123.1 (d, J = 9 Hz), 120.6 (d, J = 24 Hz), 120.4 (td, J = 241, 2

Hz), 111.4 (dt, J = 23, 6 Hz), 26.0 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −88.8 (s, 2F), −109.7 (s, 1F) ppm. GCMS (M)

239. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₇BrF₃238.9683;

found 238.9675.

H

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1-(1,1-Diﬂuoroethyl)-4-nitrobenzene (13a). General procedure A.

Yield: 17.02 g, 0.091 mol, 91%, yellow solid, m.p. = 52−53 °C. H

(qt, J = 277, 5 Hz), 118.3 (td, J = 246, 3 Hz), 43.3 (h, J = 30 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −62.0 (t, J = 10.0 Hz), −94.1 (q,

J = 9.9 Hz) ppm. GCMS (M) 289. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₉H₇BrF₅288.9651; found 288.9655.

1

NMR (400 MHz, CDCl₃) δ 8.29 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7

Hz, 2H), 1.95 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 148.9, 144.4 (t, J = 27 Hz), 126.1 (t, J = 6 Hz), 124.0, 121.0

(t, J = 241 Hz), 26.0 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −89.5 (s) ppm. GCMS (M) 187. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₈H₈F₂NO₂188.0523; found 188.0526.

2,2-Diﬂuoro-2-phenylethane-1-sulfonyl Fluoride (21a). Modiﬁed

general procedure A: HF (30.0 equiv). Yield: 16.35 g, 0.073 mol, 73%,

1

colorless oil, b.p. = 75−76 °C at 0.5 mmHg. H NMR (400 MHz,

CDCl₃) δ 7.59−7.42 (m, 5H), 4.16 (td, J = 12.9, 3.3 Hz, 2H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 133.6 (t, J = 25 Hz), 131.6,

129.2, 125.1 (t, J = 6 Hz), 117.0 (t, J = 249 Hz), 58.1 (td, J = 33, 19

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ 63.7 (t, J = 13.0 Hz),

−94.5 (d, J = 12.5 Hz) ppm. GCMS (M) 224. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₈H₈F₃O₂S 225.0197; found 225.0184.

Diﬂuorobis(4-nitrophenyl)methane (22a). General procedure B.

2,4-Dichloro-1-(1,1-diﬂuoroethyl)benzene (14a). General proce-

1

dure A. Yield: 14.81 g, 0.067 mol, 67%, colorless oil. H NMR (400

MHz, DMSO-d₆) δ 7.77 (s, 2H), 7.65 (d, J = 8.5 Hz, 3H), 7.56 (d, J =

8.4 Hz, 3H), 2.03 (t, J = 19.0 Hz, 9H) ppm. ¹³C{¹H} NMR (151 MHz,

DMSO-d₆) δ 135.7, 133.3 (t, J = 26 Hz), 131.5, 131, 128.5 (t, J = 9

Hz), 127.7 (d, J = 7 Hz), 121.1 (t, J = 241 Hz), 24.1 (t, J = 28 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −85.9 (s) ppm. GCMS

(M) 221. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₇Cl₂F₂

210.9893; found 210.9897.

1-Bromo-4-(1,1-diﬂuoroethyl)benzene (15a). Modiﬁed general

procedure A: T = 20 °C, t = 4 h. Yield: 8.84 g, 0.04 mol, 40%,

green oil. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J = 8.4 Hz, 2H), 7.38

(d, J = 8.4 Hz, 2H), 1.90 (t, J = 18.1 Hz, 3H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 137.3 (t, J = 27 Hz), 131.9, 126.6 (t, J = 6 Hz),

124.2 (t, J = 2 Hz), 121.6 (t, J = 239 Hz), 26.0 (t, J = 30 Hz) ppm.

⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.4 (s) ppm. GCMS (M) 221.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₈BrF₂220.9777;

found 220.9782.

1

Yield: 21.17 g, 0.072 mol, 72%, white solid, m.p. = 143−145 °C. H

NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 8.6 Hz, 4H), 7.72 (d, J = 8.7

Hz, 4H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 149.3, 142.5 (t, J =

29 Hz), 127.1 (t, J = 6 Hz), 124.2, 118.9 (t, J = 245 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −91.7 (s) ppm. GCMS (M) 294. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₁₃H₉F₂N₂O₄295.0530; found

295.0535.

5-(1,1-Diﬂuoroethyl)-1-methyl-1H-pyrazole (23a). Modiﬁed gen-

eral procedure A: SF₄(3.0 equiv). Yield: 12.85 g, 0.088 mol, 88%,

brown oil, b.p. = 55−56 °C at 15 mmHg. ¹H NMR (400 MHz,

CDCl₃) δ 7.39 (s, 1H), 6.37 (s, 1H), 4.01 (s, 3H), 2.03 (t, J = 18.2 Hz,

3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 138.1 (t, J = 29 Hz),

137.8, 117.5 (t, J = 234 Hz), 106.5 (t, J = 5 Hz), 38.5, 24.2 (t, J = 27

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −85.9 (s) ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₆H₉F₂N₂147.0734; found

147.0726.

2-Bromo-1-chloro-4-(1,1-diﬂuoroethyl)benzene (16a). Modiﬁed

general procedure A: SF₄(3.0 equiv). Yield: 18.36 g, 0.072 mol, 72%,

1

colorless oil, b.p. = 100−102 °C at 15 mmHg. H NMR (400 MHz,

CDCl₃) δ 7.76 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.38 (dd, J

= 8.3, 1.7 Hz, 1H), 1.90 (t, J = 18.1 Hz, 3H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃) δ 138.3 (t, J = 28 Hz), 136.3, 130.6, 130.4 (t, J = 6 Hz),

125.0 (t, J = 6 Hz), 122.8, 120.7 (t, J = 240 Hz), 26.0 (t, J = 30 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.4 (s) ppm. GCMS

(M) 255. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₇BrClF₂

254.9388; found 254.9392.

3-(1,1-Diﬂuoroethyl)-1-methyl-1H-pyrazole (24a). Modiﬁed gen-

eral procedure A: T = 80 °C, t = 72 h, the mixture was heated in an oil

bath. Yield: 7.74 g, 0.053 mol, 53%, colorless oil, b.p. = 63−65 °C at 15

mmHg. ¹H NMR (400 MHz, DMSO-d₆) δ 7.76 (d, J = 1.9 Hz, 1H),

6.43 (d, J = 1.3 Hz, 1H), 3.86 (s, 3H), 1.95 (t, J = 18.7 Hz, 3H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 147.8 (t, J = 33 Hz), 132.2,

119.5 (t, J = 231 Hz), 102.6, 38.7, 23.6 (t, J = 27 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, DMSO-d₆) δ −82.0 (s) ppm. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₆H₉F₂N₂147.0734; found 147.0738.

1-Nitro-3-(1,1,2,2-tetraﬂuoroethyl)benzene (17a). General proce-

1

dure A. Yield: 18.29 g, 0.082 mol, 82%, yellow oil. H NMR (400

MHz, CDCl₃) δ 8.47−8.39 (m, 2H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (t, J

= 7.9 Hz, 1H), 6.00 (t, J = 54.0 Hz, 1H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃) δ 148.4, 132.7 (t, J = 6 Hz), 131.7 (t, J = 26 Hz), 130.1,

126.4, 122.2 (t, J = 7 Hz), 114.8 (tt, J = 249, 30 Hz), 110.0 (tt, J = 251,

44 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −113.4 (s, 2F),

−134.1 (s, 2F) ppm. GCMS (M) 223. HRMS (ESI-TOF) m/z: [M +

NH₄]⁺calcd for C₈H₉F₄N₂O₂241.0595; found 241.0611.

1-Bromo-4-(1,1-diﬂuoropropyl)benzene (18a). Modiﬁed general

procedure B: H₂O (0.05 equiv), T = 40 °C, t = 48 h, the mixture was

heated in an oil bath. Yield: 2.35 g, 0.01 mol, 10%, yellow oil. ¹H NMR

(400 MHz, CDCl₃) δ 7.55 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.4 Hz,

2H), 2.12 (tq, J = 15.1, 7.5 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H) ppm.

¹³C{¹H} NMR (101 MHz, CDCl₃) δ 136.4 (t, J = 27 Hz), 131.7, 127.0

(t, J = 6 Hz), 124.1, 123.1 (t, J = 242 Hz), 32.4 (t, J = 28 Hz), 6.9 (t, J =

5 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −98.1 (s) ppm.

GCMS (M) 235. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₉H₁₀BrF₂234.9934; found 234.9911.

1-Bromo-4-(1,1,2,2-tetraﬂuoroethyl)benzene (19a). General pro-

cedure B. Yield: 24.67 g, 0.096 mol, 96%, brown oil, b.p. = 61−63 °C at

20 mmHg. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.2 Hz, 2H),

7.43 (d, J = 8.4 Hz, 2H), 5.91 (tt, J = 54.2, 2.1 Hz, 1H) ppm. ¹³C{¹H}

NMR (151 MHz, CDCl₃) δ 132.1, 128.8 (t, J = 25 Hz), 128.3 (t, J = 6

Hz), 126.3, 115.4 (tt, J = 248, 29 Hz), 110.1 (tt, J = 251, 44 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −109.6 to −117.9 (m), −131.2

to −138.5 (m) ppm. GCMS (M) 257. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₈H₆BrF₄256.9589; found 256.9584.

1-Bromo-4-(1,1,3,3,3-pentaﬂuoropropyl)benzene (20a). Modi-

ﬁed general procedure B: SF₄(6.0 equiv), H₂O (1.0 equiv), T = 20

°C, t = 120 h. Yield: 28.03 g, 0.097 mol, 97%, yellow oil. ¹H NMR (400

MHz, CDCl₃) δ 7.60 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H),

3.14−2.78 (m, 2H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 134.5

(t, J = 26 Hz), 132.1, 126.8 (t, J = 6 Hz), 125.3 (t, J = 2.0 Hz), 123.3

Ethyl 3,3-Diﬂuoro-3-(1-methyl-1H-pyrazol-5-yl)propanoate

(25a). A solution of 25 (9.80 g, 0.05 mol, 1.0 equiv) in CH₂Cl₂(30

mL) was placed in an autoclave made of Hastelloy nickel alloy. The

reaction vessel was cooled down by liquid nitrogen and HF (26 mL,

1.25 mol, 25.0 equiv) was added. Then, SF₄(32.40 g, 0.30 mol, 6.0

equiv) was condensed into a reaction vessel. Cooling bath was

removed, and the mixture was allowed to warm up to a room

temperature. It was then stirred for 16 h at room temperature. The

gaseous products were vented oﬀ into a trap with a solution of NaOH

(1 M). NaHCO₃was added, and the mixture was ﬁltered. The ﬁnal

product was puriﬁed by distillation. Yield: 7.09 g, 0.0325 mol, 65%,

1

yellow oil, b.p. = 95−96 °C at 0.5 mmHg. H NMR (400 MHz,

CDCl₃) δ 7.42 (s, 1H), 6.43 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.03 (s,

3H), 3.33 (t, J = 14.9 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 165.8 (d, J = 6 Hz), 137.9, 136.3 (t, J = 29

Hz), 115.7 (t, J = 240 Hz), 107.1 (t, J = 5 Hz), 61.7, 43.0 (t, J = 28 Hz),

38.7, 14.1 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −89.0 (s) ppm.

GCMS (M) 218. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₉H₁₃F₂N₂O₂219.0945; found 219.0940.

4-(1,1-Diﬂuoroethyl)-1H-pyrazole (26a). Modiﬁed general proce-

dure A: T = 80 °C, t = 72 h, the mixture was heated in an oil bath.

Yield: 8.18 g, 0.062 mol, 62%, beige solid. ¹H NMR (400 MHz,

CDCl₃) δ 11.34 (s, 1H), 7.74 (s, 2H), 1.96 (t, J = 17.9 Hz, 3H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 131.8, 121.0 (t, J = 16 Hz), 119.3

(t, J = 210 Hz), 25.9 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −80.2 (s) ppm. Liquid chromatography mass spectrometry

(LCMS) (M + H)⁺133. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₅H₇F₂N₂133.0577; found 133.0580.

4-(1,1-Diﬂuoroethyl)-1H-imidazole (27a). Modiﬁed general pro-

cedure A: T = 35 °C, t = 144 h, the mixture was heated in an oil bath.

Yield: 8.58 g, 0.065 mol, 65%, gray solid, m.p. = 56−57 °C. ¹H NMR

I

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(400 MHz, CDCl₃) δ 11.38 (br s, 1H), 7.73 (s, 1H), 7.28 (s, 1H), 2.00

(t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 137.5

(t, J = 31 Hz), 135.9, 119.3 (t, J = 233 Hz), 115.3 (t, J = 5 Hz), 24.3 (t,

J = 28 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −85.6 (s) ppm.

LCMS (M − H)⁻131. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₅H₇F₂N₂133.0577; found 133.0582.

5-Bromo-2-(1,1-diﬂuoroethyl)-1H-imidazole (28a). Modiﬁed gen-

eral procedure A: T = 40 °C, t = 96 h, the mixture was heated in an oil

bath. Yield: 14.77 g, 0.07 mol, 70%, beige solid, m.p. = 123−124 °C.

¹H NMR (400 MHz, CDCl₃) δ 10.19 (br s, 1H), 7.11 (s, 1H), 2.08 (t,

J = 18.7 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 143.1 (t, J

= 34 Hz), 117.4, 117.0 (t, J = 235 Hz), 114.8, 23.1 (t, J = 26 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −87.1 (s) ppm. LCMS (M + H)⁺

212. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₅H₆BrF₂N₂:

210.9682; found: 210.9688.

2-(1,1-Diﬂuoroethyl)thiazole (29a). General procedure A. Yield:

11.92 g, 0.08 mol, 80%, colorless oil. ¹H NMR (400 MHz, DMSO-d₆)

δ 8.03 (d, J = 3.0 Hz, 1H), 7.99 (s, 1H), 2.12 (t, J = 18.9 Hz, 3H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 163.4 (t, J = 34 Hz), 143.3,

123.2, 119.4 (t, J = 236 Hz), 23.2 (t, J = 26 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, DMSO-d₆) δ −79.6 (s) ppm. GCMS (M) 149. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₅H₆F₂NS: 150.0189; found:

150.0185.

4-Bromo-2-(1,1-diﬂuoroethyl)thiazole (30a). General procedure

A. Yield: 18.47 g, 0.081 mol, 81%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.38 (s, 1H), 2.12 (t, J = 18.4 Hz, 3H) ppm. ¹³C{¹H} NMR

(151 MHz, CDCl₃) δ 165.5 (t, J = 36 Hz), 125.8, 119.6, 118.4 (t, J =

238 Hz), 23.5 (t, J = 26 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−82.6 (s) ppm. GCMS (M) 228. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₅H₅BrF₂NS: 227.9294; found: 227.9289.

2-Chloro-3-(1,1-diﬂuoroethyl)pyridine (40a). General procedure

A. Yield: 13.10 g, 0.074 mol, 74%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.46 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.32 (dd, J

= 7.7, 4.8 Hz, 1H), 2.07 (t, J = 18.5 Hz, 3H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃) δ 150.7, 148.5, 136.1 (t, J = 9 Hz), 132.3 (t, J = 28 Hz),

122.4, 120.2 (t, J = 242 Hz), 24.4 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −89.6 (s) ppm. LCMS (M + H)⁺178. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇ClF₂N: 178.0235; found:

178.0230.

2-Chloro-4-(1,1-diﬂuoroethyl)pyridine (41a). General procedure

A. Yield: 12.04 g, 0.068 mol, 68%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.77 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.40 (d, J =

8.0 Hz, 1H), 2.01 (t, J = 18.7 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 156.0 (t, J = 31 Hz), 151.3, 139.8, 125.7, 120.3 (t, J = 239

Hz), 118.1 (t, J = 4 Hz), 23.2 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −91.3 (s) ppm. GCMS (M) 177. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₇H₇ClF₂N: 178.0235; found: 178.0227.

2-Bromo-4-(1,1-diﬂuoroethyl)pyridine (42a). General procedure

1

A. Yield: 14.43 g, 0.065 mol, 65%, yellow oil. H NMR (400 MHz,

CDCl₃) δ 8.46 (d, J = 5.1 Hz, 1H), 7.60 (s, 1H), 7.36 (d, J = 4.8 Hz,

1H), 1.90 (t, J = 18.3 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 150.9, 148.9 (t, J = 28 Hz), 142.8, 124.1 (t, J = 6 Hz), 120.6

(t, J = 241 Hz), 118.6 (t, J = 5 Hz), 25.6 (t, J = 29 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −91.6 (s) ppm. GCMS (M) 222. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇BrF₂N: 221.9730; found:

221.9733.

4-(1,1-Diﬂuoroethyl)-2,5-diﬂuoropyridine (43a). General proce-

1

dure A. Yield: 12.53 g, 0.07 mol, 70%, colorless oil. H NMR (400

MHz, CDCl₃) δ 8.13 (s, 1H), 7.11 (t, J = 3.9 Hz, 1H), 2.01 (t, J = 18.7

Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.4 (d, J = 238

Hz), 155.1 (m), 138.8 (m), 136.4 (dd, J = 28, 16 Hz), 118.5 (t, J = 242

Hz), 107.1 (dt, J = 44, 8 Hz), 24.6 (td, J = 28, 2 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −70.7 (d, J = 28.5 Hz), −90.5 (d, J = 10.4

Hz), −136.0 (dt, J = 28.2, 10.4 Hz) ppm. GCMS (M) 179. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₆F₄N: 180.0436; found:

180.0449.

2-Chloro-5-(1,1-diﬂuoroethyl)pyridine (44a). General procedure

A. Yield: 13.63 g, 0.077 mol, 77%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.52 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz,

1H), 1.94 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 147.1 (t, J = 7 Hz), 143.9, 135.2 (t, J = 6 Hz), 133.3 (t, J = 28

Hz), 128.1, 120.6 (t, J = 240 Hz), 25.9 (t, J = 29 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −88.6 (s) ppm. LCMS (M + H)⁺178.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇ClF₂N: 178.0235;

found: 178.0228.

2-Bromo-5-(1,1-diﬂuoroethyl)pyridine (45a). General procedure

A. Yield: 18.87 g, 0.085 mol, 85%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.52 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz,

1H), 1.94 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 147.1 (t, J = 7 Hz), 143.9 (t, J = 2 Hz), 135.2 (t, J = 6 Hz),

133.3 (t, J = 28 Hz), 128.1, 120.6 (t, J = 240 Hz), 25.9 (t, J = 29 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.6 (s) ppm. GCMS

(M) 222. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇BrF₂N:

221.9730; found: 221.9713.

2-Chloro-5-(1,1,2,2-tetraﬂuoroethyl)pyridine (46a). General pro-

cedure A. Yield: 17.47 g, 0.082 mol, 82%, colorless oil. ¹H NMR (400

MHz, CDCl₃) δ 8.58 (s, 1H), 7.82 (dd, J = 8.3, 2.3 Hz, 1H), 7.47 (d, J

= 8.4 Hz, 1H), 5.97 (t, J = 54.2 Hz, 1H) ppm. ¹³C{¹H} NMR (151

MHz, CDCl₃) δ 155.0, 148.2 (t, J = 7 Hz), 137.2 (t, J = 6 Hz), 124.8 (t,

J = 25 Hz), 124.4, 114.8 (tt, J = 249, 30 Hz), 109.9 (tt, J = 251, 44. Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −113.7(s, 2F), −134.1 (s,

2F) ppm. GCMS (M) 213. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₇H₅ClF₄N: 214.0047; found: 214.0024.

2-Bromo-4-(1,1-diﬂuoroethyl)thiazole (31a). Yield: 14.36 g, 0.063

mol, 63%, yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 2.00

(t, J = 18.5 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 152.8

(t, J = 33 Hz), 137.2, 121.2 (t, J = 5 Hz), 118.4 (t, J = 237 Hz), 24.2 (t,

J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.3 (s) ppm.

GCMS (M) 228. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₅H₅BrF₂NS: 227.9294; found: 227.9299.

4-(1,1-Diﬂuoroethyl)thiazol-2-amine (32a). General procedure A.

1

Yield: 12.46 g, 0.076 mol, 76%, yellow solid, m.p. = 57−59 °C. H

NMR (400 MHz, CDCl₃) δ 6.71 (s, 2H), 5.48 (br s, 2H), 1.91 (t, J =

18.3 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 168.9, 148.0

(t, J = 31 Hz), 118.9 (t, J = 236 Hz), 106.5 (t, J = 6 Hz), 24.2 (t, J = 28

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −86.7 (s) ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₅H₇F₂N₂S: 165.0298; found:

165.0294.

2-Chloro-5-(1,1-diﬂuoroethyl)thiazole (33a). General procedure

1

A. Yield: 14.09 g, 0.077 mol, 77%, yellow oil. H NMR (400 MHz,

CDCl₃) δ 7.66 (s, 1H), 2.04 (t, J = 17.8 Hz, 3H) ppm. ¹³C{¹H} NMR

(151 MHz, CDCl₃) δ 154.1, 139.8 (t, J = 6 Hz), 137.4 (t, J = 32 Hz),

118.3 (t, J = 237 Hz), 25.4 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −76.9 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₅H₅ClF₂NS: 183.9799; found: 183.9794.

2-Bromo-5-(1,1-diﬂuoroethyl)thiazole (34a). General procedure

1

A. Yield: 18.24 g, 0.08 mol, 80%, yellow oil. H NMR (400 MHz,

CDCl₃) δ 7.67 (s, 1H), 2.04 (t, J = 17.8 Hz, 3H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 141.2 (t, J = 6 Hz), 139.2 (t, J = 32 Hz), 138.4,

118.2 (t, J = 237 Hz), 25.5 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −76.8 (s) ppm. GCMS (M) 228. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₅H₅BrF₂NS: 227.9294; found: 227.9291.

Methyl 4-(2,5-Dichlorothiophen-3-yl)-4,4-diﬂuorobutanoate

(35a). Modiﬁed general procedure B: SF₄(25.0 equiv), H₂O (1.0

equiv), T = 20 °C, t = 2 weeks. Yield: 22.18 g, 0.077 mol, 77%, yellow

oil. ¹H NMR (400 MHz, CDCl₃) δ 6.86 (s, 1H), 3.70 (s, 3H), 2.65−

2.48 (m, 4H) ppm. ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.2, 133.6

(t, J = 30 Hz), 127.3, 125.6 (t, J = 6 Hz), 124.7 (t, J = 5 Hz), 119.5 (t, J

= 244 Hz), 52.0, 32.9 (t, J = 27 Hz), 27.1 (t, J = 4 Hz) ppm. ¹⁹F{¹H}

NMR (470 MHz, CDCl₃) δ −92.8 (t, J = 15.8 Hz) ppm. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₉H₉Cl₂F₂O₂S: 288.9668; found:

288.9671.

3-(1,1-Diﬂuoroethyl)-5-ﬂuoropyridine (47a). General procedure

1

A. Yield: 11.75 g, 0.073 mol, 73%, brown oil. H NMR (400 MHz,

CDCl₃) δ 8.57 (d, J = 17.1 Hz, 2H), 7.54 (d, J = 8.6 Hz, 1H), 1.96 (t, J

= 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.2 (d, J

= 266 Hz), 142.4 (d, J = 5 Hz), 139.7 (d, J = 23 Hz), 120.2 (t, J = 240

Hz), 119.9 (t, J = 6 Hz), 119.7 (t, J = 6 Hz), 25.9 (t, J = 29 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.4, −126.0 ppm. GCMS (M)

J

https://doi.org/10.1021/acs.joc.1c01518

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

161. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇F₃N: 162.0531;

found: 162.0523.

27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −92.0 (s) ppm.

GCMS (M) 144. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₆H₇F₂N₂: 145.0577; found: 145.0572.

3-Bromo-5-(1,1-diﬂuoroethyl)pyridine (48a). General procedure

1

A. Yield: 19.31 g, 0.087 mol, 87%, yellow oil. H NMR (400 MHz,

5-Bromo-3-(1,1-diﬂuoroethyl)-1-methyl-1H-indazole (56a). Gen-

eral procedure A. Yield: 10.68 g, 0.061 mol, 61%, yellow solid, m.p. =

79−82 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.51 (dd, J =

8.9, 1.3 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.07 (s, 3H), 2.17 (t, J = 18.5

Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 140.2 (t, J = 35

Hz), 139.8, 130.2, 124.0, 121.9, 119.6 (t, J = 232 Hz), 115.1, 110.8,

36.1, 23.8 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−84.2 (s) ppm. GCMS (M) 175. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₆H₇F₂N₂: 145.0577; found: 145.0572.

CDCl₃) δ 8.77 (s, 1H), 8.70 (s, 1H), 7.98 (s, 1H), 1.97 (t, J = 18.2 Hz,

3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 152.4, 144.6 (t, J = 6

Hz), 135.5 (m), 135.4, 120.8, 120.2 (t, J = 241 Hz), 25.9 (t, J = 29 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.7 ppm. GCMS (M)

222. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇BrF₂N:

221.9730; found: 221.9721.

2-Chloro-6-(1,1-diﬂuoroethyl)pyridine (49a). General procedure

A. Yield: 12.74 g, 0.072 mol, 72%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.48 (d, J = 5.1 Hz, 1H), 7.44 (s, 1H), 7.32 (d, J = 5.0 Hz,

1H), 1.90 (t, J = 18.3 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 152.4, 150.5, 149.3 (t, J = 29 Hz), 120.4 (t, J = 6 Hz), 120.0

(t, J = 241 Hz), 118.2 (t, J = 5 Hz), 25.6 (t, J = 29 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −91.6 (s) ppm. LCMS (M + H)⁺178.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇ClF₂N: 178.0235;

found: 178.0231.

2-Bromo-6-(diﬂuoro(phenyl)methyl)pyridine (57a). Modiﬁed

general procedure A: SF₄(3.0 equiv). Yield: 19.60 g, 0.069 mol,

1

69%, gray solid, m.p. = 59−60 °C. H NMR (400 MHz, CDCl₃) δ

7.67−7.56 (m, 4H), 7.55−7.48 (m, 1H), 7.47−7.37 (m, 3H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 156.5 (t, J = 32 Hz), 142.2,

139.3, 136.1 (t, J = 27 Hz), 130.3, 129.4, 128.6, 126.0 (t, J = 5.9 Hz),

119.1 (t, J = 4.4 Hz), 116.9 (t, J = 245 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −95.9 (s) ppm. LCMS (M + H)⁺285. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₁₂H₉BrF₂N: 283.9886; found:

283.9881.

2-Bromo-6-(1,1-diﬂuoroethyl)pyridine (50a). General procedure

1

A. Yield: 19.76 g, 0.089 mol, 89%, yellow oil. H NMR (400 MHz,

CDCl₃) δ 7.71−7.58 (m, 2H), 7.55 (d, J = 7.6 Hz, 1H), 2.01 (t, J =

18.7 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 156.5 (t, J =

31 Hz), 141.8, 139.5, 129.5, 120.2 (t, J = 239 Hz), 118.4 (t, J = 4 Hz),

23.2 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −91.2

(s) ppm. GCMS (M) 222. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₇H₇BrF₂N: 221.9730; found: 221.9723.

2-(1,1-Diﬂuoroethyl)-5-ﬂuoropyridine (51a). General procedure

A. Yield: 10.63 g, 0.066 mol, 66%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.47 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 8.7, 4.3 Hz, 1H), 7.49

(td, J = 8.4, 2.8 Hz, 1H), 2.01 (t, J = 18.6 Hz, 3H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 160.0 (d, J = 259 Hz), 151.7 (td, J = 31, 4 Hz),

137.7 (d, J = 25 Hz), 123.8 (d, J = 19 Hz), 121.1 (q, J = 4 Hz), 119.9 (t,

J = 238 Hz), 23.4 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −89.8 (d, J = 3.2 Hz, 2F), −125.3 (t, J = 3.0 Hz, 1F) ppm.

GCMS (M) 161. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₇H₇F₃N: 162.0531; found: 162.0523.

2-Chloro-3-(perﬂuoroethyl)pyridine (58a). General procedure A.

Ketone hydrate was ﬁrst dehydrated into ketone, which next reacted

according to the standard procedure. Yield: 17.33 g, 0.075 mol, 75%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.60 (d, J = 4.6 Hz, 1H),

7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.42 (dd, J = 7.8, 4.8 Hz, 1H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 152.7, 149.7, 139.0 (t, J = 8 Hz),

123.9 (t, J = 24 Hz), 122.3, 118.1 (qt, J = 287, 38 Hz), 111.5 (tq, J =

257, 40 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −83.8 (s, 3F),

−113.1 (s, 2F) ppm. GCMS (M) 231. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₇H₄ClF₅N: 231.9952; found: 231.9958.

5-Bromo-2-ﬂuoro-3-(perﬂuoroethyl)pyridine (59a). Modiﬁed gen-

eral procedure A: ketone hydrate (1.0 equiv), SF₄(3.0 equiv), T = 90

°C, t = 48 h, the mixture was heated in an oil bath. Yield: 23.23 g, 0.079

mol, 79%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H),

8.11 (dd, J = 7.9, 2.3 Hz, 1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃)

δ 159.1 (dt, J = 248, 3 Hz), 152.8 (d, J = 16 Hz), 142.5 (t, J = 7 Hz),

119.6 (qt, J = 286, 38 Hz), 116.8 (d, J = 5 Hz), 113.4 (q, J = 29 Hz),

111.2 (tdd, J = 257, 41, 7 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃)

δ −84.9 (d, J = 10.3 Hz, 3F), −115.1 (dd, J = 17.6, 1.8 Hz, 2F) ppm.

GCMS (M) 294. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₇H₃BrF₆N: 293.9353; found: 293.9350.

2-Chloro-4-(perﬂuoroethyl)pyridine (60a). Ketone hydrate was

ﬁrst dehydrated into ketone, which next reacted according to standard

procedure. Yield: 17.79 g, 0.077 mol, 77%, colorless oil. ¹H NMR (400

MHz, CDCl₃) δ 8.60 (d, J = 5.1 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J = 5.1

Hz, 1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 152.8, 150.9,

140.0 (t, J = 26 Hz), 121.9 (t, J = 7 Hz), 119.4 (t, J = 6 Hz), 116.7 (qt, J

= 290, 39 Hz), 111.8 (tq, J = 256, 39 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −84.9 (s, 3F), −117.4 (s, 2F) ppm. GCMS (M) 231.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₄ClF₅N: 231.9952;

found: 231.9949.

5-Chloro-2-(1,1-diﬂuoroethyl)pyridine (52a). General procedure

1

A. Yield: 10.62 g, 0.06 mol, 60%, colorless oil. H NMR (400 MHz,

CDCl₃) δ 8.59 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 8.4, 2.3 Hz, 1H), 7.61

(d, J = 8.4 Hz, 1H), 2.00 (t, J = 18.6 Hz, 3H) ppm. ¹³C{¹H} NMR

(126 MHz, CDCl₃) δ 153.7 (t, J = 30 Hz), 148.4, 136.9, 133.4, 121.7

(t, J = 239 Hz), 120.6 (t, J = 4 Hz), 23.3 (t, J = 27 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −90.8 ppm. GCMS (M) 177. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₇ClF₂N: 178.0235; found:

178.0231.

5-Bromo-2-(1,1-diﬂuoroethyl)pyridine (53a). General procedure

A. Yield: 20.42 g, 0.092 mol, 92%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.69 (s, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.55 (d, J = 8.4

Hz, 1H), 2.00 (t, J = 18.6 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 154.0 (t, J = 30 Hz), 150.6, 139.9, 122.2, 121.0 (t, J = 4 Hz),

119.9 (t, J = 239 Hz), 23.3 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −91.0 (s) ppm. GCMS (M) 222. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₇H₇BrF₂N: 221.9730; found: 221.9728.

Ethyl 3,3-Diﬂuoro-3-(pyridin-3-yl)propanoate (54a). Modiﬁed

general procedure A: SF₄(3.0 equiv). Yield: 17.63 g, 0.082 mol,

82%, yellow oil, b.p. = 85−86 °C at 0.5 mmHg. ¹H NMR (400 MHz,

CDCl₃) δ 8.77 (s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 7.9 Hz,

1H), 7.37 (dd, J = 7.7, 5.0 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.26 (t, J

= 14.5 Hz, 2H), 1.16 (d, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 166.0 (t, J = 7 Hz), 151.4, 146.9 (t, J = 7 Hz), 133.4 (t,

J = 6 Hz), 132.1 (t, J = 26 Hz), 123.2, 119.0 (t, J = 245 Hz), 61.5, 44.4

(t, J = 30 Hz), 14.1 ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −92.6

(s) ppm. LCMS (M + H)⁺216. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₁₀H₁₂F₂NO₂: 216.0836; found: 216.0815.

2-Chloro-5-(perﬂuoroethyl)pyridine (61a). General procedure A.

1

Yield: 14.32 g, 0.062 mol, 62%, colorless oil. H NMR (400 MHz,

CDCl₃) δ 8.64 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, 1H), 7.49

(s, 1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 155.7, 148.1 (t, J =

6 Hz), 137.0 (t, J = 6 Hz), 124.7, 124.1 (t, J = 25 Hz), 118.8 (qt, J =

286, 39 Hz), 113.5 (tq, J = 255, 39 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, CDCl₃) δ −85.4 (s, 3F), −115.9 (s, 2F) ppm. GCMS (M) 231.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₄ClF₅N: 231.9952;

found: 231.9949.

3-Bromo-5-(perﬂuoroethyl)pyridine (62a). Modiﬁed general pro-

cedure A: ketone hydrate (1.0 equiv), SF₄(3.0 equiv), T = 90 °C, t =

48 h, the mixture was heated in an oil bath. Yield: 24.29 g, 0.088 mol,

88%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 1.0 Hz,

1H), 8.77 (s, 1H), 8.05 (s, 1H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 154.6, 145.9 (t, J = 6 Hz), 137.0 (t, J = 6 Hz), 126.6 (t, J = 25

Hz), 120.9, 118.8 (qt, J = 286, 38 Hz), 111.1 (tq, J = 256, 39 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −85.2 (s, 3F), −115.9 (s, 2F)

2-(1,1-Diﬂuoroethyl)pyrazine (55a). General procedure A. Yield:

1

10.37 g, 0.072 mol, 72%, yellow oil. H NMR (400 MHz, CDCl₃) δ

8.95 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 2.03 (t, J = 18.7

Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 150.8 (t, J = 30

Hz), 146.1, 143.8, 141.7 (t, J = 5 Hz), 120.7 (t, J = 239 Hz), 23.2 (t, J =

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ppm. GCMS (M) 276. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₇H₄BrF₅N: 275.9447; found: 275.9441.

3-Fluoro-3-(pyridin-3-yl)acrylic Acid (70). General procedure C.

Yield: 4.18 g, 0.025 mol, 50%, beige solid, m.p. = 198−199 °C. H

1

NMR (400 MHz, DMSO-d₆) δ 12.34 (br s, 1H), 8.96 (s, 1H), 8.70 (d,

J = 4.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 7.9, 4.8 Hz,

1H), 6.36 (d, J = 36.3 Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 164.5, 162.1 (d, J = 273 Hz), 151.8, 146.5 (d, J = 8 Hz),

133.1 (d, J = 7 Hz), 126.4 (d, J = 27 Hz), 123.8, 100.3 (d, J = 6 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −101.8 (s) ppm. LCMS

(M + H)⁺168. HRMS (ESI-TOF) m/z: [M +Na]⁺calcd for

C₈H₆FNNaO₂: 190.0280; found: 190.0283.

2-Chloro-6-(perﬂuoroethyl)pyridine (63a). General procedure A.

Ketone hydrate was ﬁrst dehydrated into ketone, which next reacted

according to the standard procedure. Yield: 19.64 g, 0.085 mol, 85%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (t, J = 7.9 Hz, 1H),

7.65 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H) ppm. ¹³C{¹H} NMR

(151 MHz, CDCl₃) δ 152.2, 148.2 (t, J = 26 Hz), 140.0, 127.7, 120.8

(t, J = 4 Hz), 117.9 (qt, J = 287, 37 Hz), 111.5 (tq, J = 256, 38 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −83.6 (s, 3F), −117.8 (s,

2F) ppm. GCMS (M) 231. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₇H₄ClF₅N: 231.9952; found: 231.9946.

2-Bromo-6-(perﬂuoroethyl)pyridine (64a). General procedure A.

Ketone hydrate was ﬁrst dehydrated into ketone, which next reacted

according to the standard procedure. Yield: 23.74 g, 0.086 mol, 86%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.84−7.55 (m, 3H) ppm.

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 148.6 (t, J = 26 Hz), 142.6,

139.5, 131.5, 121.1 (t, J = 4 Hz), 118.8 (qt, J = 287, 37 Hz), 109.6 (tq, J

= 256, 38 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −83.6 (s,

3F), −117.8 (s, 2F) ppm. GCMS (M) 276. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₇H₄BrF₅N: 275.9447; found: 275.9436.

5-Bromo-2-(perﬂuoroethyl)pyridine (65a). Modiﬁed general pro-

cedure A: ketone hydrate (1.0 equiv), SF₄(3.0 equiv), T = 90 °C, t =

48 h, the mixture was heated in an oil bath. Yield: 25.12 g, 0.091 mol,

91%, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1H), 8.03

(d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H) ppm. ¹³C{¹H} NMR (126

MHz, CDCl₃) δ 151.6, 146.4 (t, J = 26 Hz), 140.2, 124.4, 123.4, 118.9

(qt, J = 287, 37 Hz), 112.3 (qt, J = 255, 38 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −83.7 (s, 3F), −117.7 (s, 2F) ppm. GCMS (M)

276. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₄BrF₅N:

275.9447; found: 275.9437.

4-Bromo-2-(perﬂuoroethyl)thiophene (66a). General procedure

A. Yield: 19.39 g, 0.069 mol, 69%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.48 (s, 1H), 7.37 (s, 1H) ppm. ¹³C{¹H} NMR (126 MHz,

CDCl₃) δ 132.7 (t, J = 5 Hz), 130.9 (t, J = 29 Hz), 127.3, 118.7 (qt, J =

286, 39 Hz), 112.48 (tq, J = 221, 33 Hz), 110.7 ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −85.2 (s, 3F), −106.4 (s, 2F) ppm. GCMS (M)

281. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₆H₃BrF₅S:

280.9059; found: 280.9065.

2-Bromo-4-(perﬂuoroethyl)thiophene (67a). General procedure

A. Yield: 20.79 g, 0.074 mol, 74%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 7.63 (s, 1H), 7.20 (s, 1H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 130.4 (t, J = 27 Hz), 129.3 (t, J = 7 Hz), 127.8, 118.9 (qt, J =

286, 39 Hz), 114.8, 112.1 (tq, J = 253, 39 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −85.3 (s, 3F), −111.4 (s, 2F) ppm. GCMS (M)

281. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₆H₃BrF₅S:

280.9059; found: 280.9054.

General Procedure C (Elimination of HF). 69 as an example.

(E)-3-Fluoro-3-(1-methyl-1H-pyrazol-5-yl)acrylic Acid (69). To a

solution of 25a (10.90 g, 0.05 mmol, 1.0 equiv) in dry CH₂Cl₂(120

mL) was added DBU (17.60 g, 0.05 mol, 1.0 equiv) dropwise at 0 °C.

The solution was stirred for 2 h. The mixture was diluted with water

(50 mL). The organic layer was separated and washed with a solution

of citric acid (50 mL), brine (50 mL), dried over Na₂SO₄, ﬁltered, and

evaporated under reduced pressure. The residue was suspended in

hexane overnight and ﬁltered. A pure trans-isomer was obtained. The

crude product was dissolved in a mixture of THF (50 mL) and water

(50 mL) and LiOH·H₂O (2.10 g, 0.05 mol, 1.0 equiv) was added to

the mixture. The mixture was washed with CH₂Cl₂(2 × 30 mL). The

organic layer was separated, and the aqueous layer was acidiﬁed with

H₂SO₄. The precipitate was ﬁltered and dried. Yield: 4.68 g, 0.0275

mol, 55%, white solid, m.p. = 59−60 °C. ¹H NMR (400 MHz, DMSO-

d₆) δ 12.11 (br s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 5.78 (d, J = 36.3 Hz,

1H), 3.86 (s, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ

165.0, 160.8 (d, J = 269 Hz), 137.3 (d, J = 7 Hz), 130.5 (d, J = 6 Hz),

113.8 (d, J = 31 Hz), 95.1 (d, J = 5 Hz), 38.9 ppm. ¹⁹F{¹H} NMR (376

MHz, DMSO-d₆) δ −95.0 (s) ppm. LCMS (M − H)⁻169. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₈FN₂O₂: 171.0570; found:

171.0563.

4-Bromo-5-(1,1-diﬂuoroethyl)-1-methyl-1H-pyrazole (71). To a

solution of 23a (7.30 g, 0.05 mol, 1.0 equiv) and sodium acetate (4.51

g, 0.055 mol, 1.1 equiv) in acetic acid (150 mL) at 0 °C was added

bromine (8.00 g, 0.05 mol, 1.0 equiv). The mixture was warmed to

room temperature and stirred for 16 h. The reaction mixture was

neutralized with saturated aqueous Na₂CO₃and extracted with EtOAc

(5 × 200 mL). The organic layers were combined, dried over Na₂SO₄,

ﬁltered, and concentrated under reduced pressure. The ﬁnal product

was puriﬁed by distillation. Yield: 9.56 g, 0.0425 mol, 85%, colorless

1

oil, b.p. = 58−59 °C at 0.5 mmHg. H NMR (400 MHz, CDCl₃) δ

7.41 (s, 1H), 4.01 (s, 3H), 2.12 (t, J = 19.3 Hz, 3H) ppm. ¹³C{¹H}

NMR (126 MHz, CDCl₃) δ 140.0, 134.7 (t, J = 30 Hz), 118.2 (t, J =

237 Hz), 93.5 (t, J = 4 Hz), 40.5, 25.1 (t, J = 27 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −82.1 (s) ppm. GCMS (M) 225. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₆H₈BrF₂N₂: 224.9839; found:

224.9832.

5-(1,1-Diﬂuoroethyl)-4-iodo-1-methyl-1H-pyrazole (72). To a

solution of 23a (51.10 g, 0.35 mol, 1.0 equiv) in acetic acid (400

mL) were added triﬂuoroacetic acid (TFA) (39.90 g, 0.35 mol, 1.0

equiv) and NIS (78.75 g, 0.35 mol, 1.0 equiv). The mixture was heated

at 70 °C for 16 h. The reaction mixture was neutralized with saturated

aqueous Na₂CO₃and extracted with EtOAc (5 × 300 mL). The

organic layers were combined, dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. The crude product was puriﬁed

by column chromatography (hexane/EtOAc, 9:1). Yield: 64.74 g,

0.238 mol, 68%, colorless oil, b.p. = 73−74 °C at 0.5 mmHg. ¹H NMR

(400 MHz, CDCl₃) δ 7.46 (s, 1H), 4.03 (t, J = 1.8 Hz, 3H), 2.09 (t, J =

18.9 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 145.0, 137.5

(t, J = 31 Hz), 118.4 (t, J = 238 Hz), 57.0 (t, J = 4 Hz), 40.5 (t, J = 5

Hz), 25.8 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−82.6 (s) ppm. GCMS (M) 272. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₆H₈F₂IN₂: 272.9700; found: 272.9692.

5-(1,1-Diﬂuoroethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid

(73). To a solution of 72 (59.84 g, 0.22 mol, 1.0 equiv) in MeOH

(400 mL), Et₃N (23.33 g, 0.231 mol, 1.05 equiv) and cat. Pd(dppf)Cl₂

× CH₂Cl₂(3.59 g, 0.0044 mol, 0.02 equiv) were added in a steel

autoclave. The resulted mixture was stirred with CO at 40 atm pressure

at 110 °C for 12 h. The mixture was ﬁltered through SiO₂. The ﬁltrate

was concentrated, dissolved in THF (200 mL) and LiOH (15.84 g,

0.66 mol, 3.0 equiv) was added. The mixture was stirred at room

temperature overnight. The solution was partially concentrated under

reduced pressure and diluted with MTBE. The organic layer was

separated, and the aqueous layer was acidiﬁed with aq. HCl to pH ∼ 2.

The desired acid was extracted with EtOAc, dried over Na₂SO₄, and

concentrated under reduced pressure. Yield: 30.02 g, 0.158 mol, 71%,

1

beige solid, m.p. = 123−124 °C. H NMR (400 MHz, DMSO-d₆) δ

12.75 (s, 1H), 7.83 (s, 1H), 3.96 (t, J = 2.8 Hz, 3H), 2.14 (t, J = 19.3

Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 162.9, 140.7,

138.5 (t, J = 32 Hz), 119.3 (t, J = 240 Hz), 114.2, 40.4 (t, J = 6 Hz),

24.5 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ

−82.4 (s) ppm. LCMS (M + H)⁺191. HRMS (ESI-TOF) m/z: [M +

Na]⁺calcd for C₇H₈F₂N₂NaO₂: 213.0452; found: 213.0439.

4-(1,1-Diﬂuoroethyl)benzaldehyde (74). To a solution of 15a

(11.05 g, 0.05 mol, 1.0 equiv) in THF (150 mL) was added nBuLi (2.5

M solution in hexane, 20.6 mL, 0.0515 mol, 1.03 equiv) dropwise at

−80 °C. The reaction mixture was stirred at −80 °C for 1 h, and then

added DMF (4.56 g, 0.0625 mol, 1.25 equiv). The reaction mixture

was slowly warmed up to room temperature and a 10% HCl solution

(55 mL) was added. The mixture was diluted with MTBE (100 mL),

washed with water (2 × 50 mL). The organic layer was dried over

L

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Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The ﬁnal

product was puriﬁed by distillation. Yield: 6.84 g, 0.0405 mol, 81%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H), 7.94 (d, J =

8.0 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 1.94 (t, J = 18.2 Hz, 3H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 191.6, 143.9 (t, J = 27 Hz),

137.4, 130.0, 125.6 (t, J = 6 Hz), 121.4 (t, J = 240 Hz), 26.0 (t, J = 29

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −89.4 (s) ppm. GCMS

(M) 169. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₉H₉F₂O:

171.0621; found: 171.0624.

9, 5 Hz), 132.1 (td, J = 28, 5 Hz), 120.6 (t, J = 239 Hz), 109.7 (d, J =

38 Hz), 25.9 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−66.3 (s, 1F), −87.5 (d, J = 2.4 Hz, 2F) ppm. LCMS (M + H)⁺162.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd C₇H₇F₃N: 162.0531; found:

162.0535.

2-(1,1-Diﬂuoroethyl)-6-ﬂuoropyridine (49b). General procedure

1

D. Yield: 6.12 g, 0.038 mol, 76%, colorless oil. H NMR (400 MHz,

CDCl₃) δ 8.33 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.07 (s,

1H), 1.93 (t, J = 18.3 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 164.0 (d, J = 240 Hz), 151.8 (td, J = 29, 8 Hz), 148.8 (d, J =

15 Hz), 120.0 (td, J = 241, 3 Hz), 117.4 (q, J = 5 Hz), 106.0 (dt, J = 40,

6 Hz), 25.6 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ

−66.2 (s, 1F), −91.5 (s, 2F) ppm. GCMS (M) 161. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd C₇H₇F₃N: 162.0531; found: 162.0528.

2-Fluoro-3-(perﬂuoroethyl)pyridine (58b). General procedure D.

4-(1,1-Diﬂuoroethyl)benzenesulfonyl Chloride (75). To a solution

of 15a (11.05 g, 0.05 mol, 1.0 equiv) in THF (100 mL) was added

nBuLi (2.5 M in hexane, 20.6 mL, 0.0515 mol, 1.03 equiv) dropwise

under argon at −80 °C. The mixture was stirred for 1 h at −80 °C and

a solution of SO₂(4.80 g, 0.075 mol, 1.5 equiv) in THF (100 mL) was

added slowly to the mixture. The mixture was stirred for 30 min at 0

°C and SO₂Cl₂(6.75 g, 0.05 mol, 1 equiv) was added slowly to the

mixture. The mixture was stirred overnight at room temperature and

diluted with MTBE (200 mL). The solution was washed with water (2

× 100 mL), dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure. The ﬁnal product was puriﬁed by distillation. Yield:

1

Yield: 7.53 g, 0.035 mol, 70%, colorless oil. H NMR (400 MHz,

CDCl₃) δ 8.46 (d, J = 4.1 Hz, 1H), 8.03 (t, J = 8.3 Hz, 1H), 7.38 (dd, J

= 6.6, 5.7 Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.3

(dt, J = 247, 3 Hz), 151.9 (d, J = 15 Hz), 140.2 (t, J = 7 Hz), 121.7 (d, J

= 5 Hz), 118.9 (qt, J = 286, 38 Hz), 111.9 (q, J = 26 Hz), 113.1 (m)

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −64.3 (s, 1F), −80.6 to

−91.9 (m, 3F), −109.6 to −119.9 (m, 2F) ppm. GCMS (M) 215.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd C₇H₄F₆N: 216.0248; found:

216.0243.

1

10.10 g, 0.042 mol, 84%, white solid, m.p. = 123−124 °C. H NMR

(400 MHz, CDCl₃) δ 8.12 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz,

2H), 1.96 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 145.5, 145.1 (t, J = 27 Hz), 127.6, 126.4 (t, J = 6 Hz), 120.8

(t, J = 241 Hz), 26.1 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

CDCl₃) δ −90.0 (s) ppm. LCMS (RSO₃H − H)⁻221. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₈H₈ClF₂O₂S: 240.9902; found:

240.9908.

2-Fluoro-5-(perﬂuoroethyl)pyridine (61b). General procedure D.

1

Yield: 7.85 g, 0.0365 mol, 73%, colorless oil. H NMR (400 MHz,

CDCl₃) δ 8.50 (s, 1H), 8.09−7.92 (m, 1H), 7.10 (dd, J = 8.6, 2.9 Hz,

1H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 165.6 (d, J = 246 Hz),

147.3 (m), 144.2 (m), 123.2 (td, J = 25, 5 Hz), 118.8 (qt, J = 286, 39

Hz), 113.5 (tq, J = 119, 39 Hz), 110.3 (d, J = 38 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −62.4 (s, 1F), −85.5 (s, 3F), −115.3 (s,

2F) ppm. GCMS (M) 215. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

C₇H₄F₆N: 216.0248; found: 216.0252.

2-Fluoro-6-(perﬂuoroethyl)pyridine (63b). General procedure D.

Yield: 8.60 g, 0.04 mol, 80%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.01 (q, J = 7.7 Hz, 1H), 7.63 (dd, J = 7.5, 1.6 Hz, 1H), 7.18

(dd, J = 8.3, 2.6 Hz, 1H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ

163.2 (d, J = 245 Hz), 146.6 (m), 142.7 (d, J = 8 Hz), 119.8 (d, J = 4

Hz), 118.8 (qt, J = 287, 37 Hz), 113.5 (d, J = 36 Hz), 109.6 (tq, J =

255, 39 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −64.8 (s, 1F),

−83.7 (s, 3F), −117.9 (s, 2F) ppm. GCMS (M) 215. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd C₇H₄F₆N: 216.0248; found: 216.0253.

General Procedure E (n-BuLi, CO₂). 7c as an example. Scale: 0.05

mol.

2-(4-(1,1-Diﬂuoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-

borolane (76). To a solution of 15a (4.42 g, 0.02 mol, 1.0 equiv) in

dioxane (100 mL) were added KOAc (9.80 g, 0.10 mol, 5.0 equiv) and

bis(pinacolato)diboron (5.59 g, 0.022 mol, 1.1 equiv). A steam of

argon was passed through the mixture for 10 min and Pd(dppf)Cl₂·

CH₂Cl₂, (0.82 g, 0.001 mol, 0.05 equiv) was added to the mixture. The

solution was heated at 95 °C for 12 h under argon. The mixture was

concentrated, diluted with CH₂Cl₂, and ﬁltered through a plug of SiO₂.

The ﬁltrate was washed with water (2 × 100 mL), brine (100 mL),

dried over Na₂SO₄, ﬁltered, and concentrated under reduced pressure.

The ﬁnal product was puriﬁed by column chromatography (hexane/

EtOAc, 8:2). Yield: 4.18 g, 0.0156 mol, 78%, yellow solid, m.p. = 47−

49 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 7.8 Hz, 2H), 7.50

(d, J = 7.9 Hz, 2H), 1.91 (t, J = 18.2 Hz, 3H), 1.35 (s, 12H) ppm.

¹³C{¹H} NMR (151 MHz, CDCl₃) δ 140.9 (t, J = 26 Hz), 135.0, 123.9

(t, J = 6 Hz), 121.9 (t, J = 239 Hz), 84.2, 26.1 (t, J = 30 Hz), 25.0 ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −88.9 (s) ppm. GCMS (M) 268.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₁₄H₂₀BF₂O₂: 269.1524;

found: 269.1515.

General Procedure D (Reaction with CsF). 40b as an example.

Scale: 0.05 mol.

3-(1,1-Diﬂuoroethyl)-2-ﬂuoropyridine (40b). To a solution of 40a

(8.85 g, 0.05 mol, 1.0 equiv) in DMSO (120 mL) was added CsF (8.00

g, 0.0525 mol, 1.05 equiv) at room temperature. The mixture was

stirred at 120 °C in an oil bath with a thermocouple overnight. The

mixture was diluted with water (300 mL) and extracted with EtOAc (3

× 100 mL). The combined organic layers were washed with water (3 ×

100 mL) and brine (1 × 100 mL), dried over Na₂SO₄, ﬁltered, and

concentrated under reduced pressure. Yield: 5.72 g, 0.0355 mol, 71%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 4.6 Hz, 1H),

8.00 (t, J = 8.5 Hz, 1H), 7.28 (dd, J = 7.3, 5.0 Hz, 1H), 2.03 (t, J = 18.6

Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.0 (dt, J = 242,

5 Hz), 149.3 (d, J = 15 Hz), 137.7 (td, J = 7, 3 Hz), 121.5 (d, J = 5 Hz),

120.5 (q, J = 57, 29 Hz), 119.3 (td, J = 240, 6 Hz), 24.8 (td, J = 28, 4

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −67.4 (s, 1F), −89.0

(d, J = 10 Hz, 2F) ppm. GCMS (M) 161. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd C₇H₇F₃N: 162.0531; found: 162.0534.

2-(1,1-Diﬂuoroethyl)benzoic Acid (7c). A three-neck round-

bottom ﬂask was equipped with a dropping funnel, thermometer,

air-bubbles counter, and ﬁlled with argon. Compound 7a (11.05 g,

0.05 mol, 1.0 equiv) with dry THF (150 mL) was loaded to the ﬂask

and cooled to −80 °C, and a solution of n-BuLi (2.5 M in hexane, 21

mL, 0.0525 mol, 1.05 equiv) was added dropwise. The mixture was

stirred for 1 h at the same temperature and crashed dry ice was added

(33.00 g, 0.75 mol, 15.0 equiv). The cooling bath was removed, and

mixture was stirred at room temperature for 12 h, then diluted with

water, and concentrated. The residue was dissolved in water, and

washed with MTBE (3 × 50 mL). The separated water layer was

acidiﬁed with aq. HCl to pH ∼ 4, and the formed precipitate was

collected by ﬁltration. Yield: 7.16 g, 0.0385 mol, 77%, yellow solid,

1

m.p. = 80−81 °C. H NMR (400 MHz, CDCl₃) δ 11.30 (br s, 1H),

7.79 (d, J = 7.6 Hz, 1H), 7.67−7.56 (m, 2H), 7.52 (t, J = 7.3 Hz, 1H),

2.14 (t, J = 18.4 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ

174.3, 137.6 (t, J = 27 Hz), 131.6, 129.8, 129.7, 129.6 (t, J = 3 Hz),

126.3 (t, J = 8 Hz), 122.2 (t, J = 241 Hz), 26.9 (t, J = 29 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −84.5 (s) ppm. LCMS (M −

H)⁻185. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₉H₉F₂O₂:

187.0571; found: 187.0578.

5-(1,1-Diﬂuoroethyl)-2-ﬂuoropyridine (44b). General procedure

D. Yield: 5.88 g, 0.0365 mol, 73%, colorless oil. ¹H NMR (400 MHz,

CDCl₃) δ 8.39 (s, 1H), 8.01−7.82 (m, 1H), 6.99 (dd, J = 8.5, 2.8 Hz,

1H), 1.95 (t, J = 18.2 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz,

CDCl₃) δ 164.3 (d, J = 242 Hz), 145.1 (dt, J = 16, 7 Hz), 138.3 (dt, J =

3-(1,1-Diﬂuoroethyl)benzoic Acid (11c). General procedure E.

1

Yield: 7.63 g, 0.041 mol, 82%, white solid, m.p. = 108−110 °C. H

NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 8.14−7.94 (m, J = 8.6

Hz, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 2.00 (t, J =

18.9 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 166.6,

M

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137.8 (t, J = 27 Hz), 131.3, 130.8, 129.3, 129.1 (t, J = 6 Hz), 125.1 (t, J

= 6 Hz), 122.0 (t, J = 238 Hz), 25.0 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, CDCl₃) δ −88.4 (s) ppm. LCMS (M − H)⁻185. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₉H₉F₂O₂: 187.0571; found:

187.0575.

H)⁺188. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₈F₂NO₂:

188.0523; found: 188.0514.

6-(1,1-Diﬂuoroethyl)picolinic Acid (50c). General procedure F.

Yield: 6.45 g, 0.0345 mol, 69%, beige solid, m.p. = 76−77 °C. ¹H NMR

(400 MHz, CDCl₃) δ 10.31 (br s, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.11

(t, J = 7.8 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 2.06 (t, J = 18.6 Hz, 3H)

ppm. ¹³C{¹H} NMR (151 MHz, CDCl₃) δ 163.5, 154.7 (t, J = 31 Hz),

145.9, 140.1, 125.1, 124.0 (t, J = 4 Hz), 120.0 (t, J = 240 Hz), 23.4 (t, J

= 27 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −88.4 (s)

ppm. LCMS (M + H)⁺188. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₈H₈F₂NO₂: 188.0523; found: 188.0528.

5-(Perﬂuoroethyl)nicotinic Acid (62c). A three-neck round-bottom

ﬂask was equipped with a dropping funnel, thermometer, air-bubbles

counter, and ﬁlled with argon. Compound 62a (13.80 g, 0.05 mol, 1.0

equiv) with dry THF (150 mL) was loaded to the ﬂask cooled to 0 °C,

and a solution of iPrMgBr (0.75 M in THF, 69 mL, 0.0515 mol, 1.03

equiv) was added dropwise. The mixture was stirred for 1 h at the same

temperature, and crashed dry ice was added (33.00 g, 0.75 mol, 15.0

equiv). The cooling bath was removed, and mixture was stirred at

room temperature for 6 h, then diluted with water, and concentrated.

The residue was dissolved in water and washed with MTBE (3 × 50

mL). The separated water layer was acidiﬁed with aq. HCl to pH ∼ 4,

and the formed precipitate was collected by ﬁltration. Yield: 7.23 g,

0.03 mol, 60%, yellow solid, m.p. = 139−140 °C. ¹H NMR (400 MHz,

DMSO-d₆) δ 14.00 (br s, 1H), 9.35 (s, 1H), 9.17 (s, 1H), 8.44 (s, 1H)

ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ 164.8, 154.1, 150.5 (t, J

= 6 Hz), 134.8 (t, J = 6 Hz), 127.1, 123.4 (t, J = 24 Hz), 118.4 (qt, J =

286, 39 Hz), 111.6 (tq, J = 116, 39 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, DMSO-d₆) δ −84.7 (s, 3F), −114.9 (s, 2F) ppm. LCMS (M +

H)⁺242. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₅F₅NO₂:

242.0240; found: 242.0236.

4-(1,1-Diﬂuoroethyl)benzoic Acid (15c). General procedure E.

1

Yield: 6.60 g, 0.0355 mol, 71%, white solid, m.p. = 183−184 °C. H

NMR (400 MHz, DMSO-d₆) δ 13.22 (s, 1H), 8.04 (d, J = 8.3 Hz, 2H),

7.68 (d, J = 8.2 Hz, 2H), 1.98 (t, J = 18.9 Hz, 3H) ppm. ¹³C{¹H} NMR

(101 MHz, DMSO-d₆) δ 166.7, 141.3 (t, J = 27 Hz), 132.3, 129.7,

125.0 (t, J = 6 Hz), 122.1 (t, J = 238 Hz), 25.0 (t, J = 28 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −86.0 (s) ppm. LCMS (M −

H)⁻185. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₉H₉F₂O₂:

187.0571; found: 187.0568.

General Procedure F ([Pd]-Carbonylation). 19c as an example.

Scale: 0.05 mol.

4-(1,1,2,2-Tetraﬂuoroethyl)benzoic Acid (19c). To a solution of

19a (12.85 g, 0.05 mol, 1.0 equiv) in MeOH (150 mL), Et₃N (5.30 g,

0.0525 mol, 1.05 equiv) and cat. Pd(dppf)Cl₂× CH₂Cl₂(0.82 g, 0.001

mol, 0.02 equiv) were added in a steel autoclave. The resulted mixture

was stirred with CO at 40 atm pressure at 110 °C for 12 h. The mixture

was ﬁltered through SiO₂, treated with 10% aq. NaOH (1.2 equiv) and

left stirred at room temperature overnight. The solution was partially

concentrated under reduced pressure and diluted with MTBE. The

organic layer was separated, and the aqueous layer was acidiﬁed with

aq. HCl to pH ∼ 2. The desired acid was extracted with EtOAc, dried

over Na₂SO₄, and concentrated under reduced pressure. Yield: 7.55 g,

0.034 mol, 68%, white solid, m.p. = 196−197 °C. ¹H NMR (400 MHz,

DMSO-d₆) δ 13.41 (br s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.3

Hz, 2H), 6.82 (tt, J = 52.4, 4.0 Hz, 1H) ppm. ¹³C{¹H} NMR (151

MHz, DMSO-d₆) δ 166.4, 134.2, 133.2 (t, J = 24 Hz), 129.8, 126.5 (t, J

= 6 Hz), 116.2 (tt, J = 55, 28 Hz), 110.0 (tt, J = 249, 39 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −114.6 (t, J = 6.4 Hz),

−136.8 (t, J = 6.4 Hz) ppm. LCMS (M − H)⁻221. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₉H₇F₄O₂: 223.0382; found: 223.0377.

4-(1,1-Diﬂuoroethyl)thiazole-2-carboxylic Acid (31c). General

procedure F. Yield: 7.04 g, 0.0365 mol, 73%, white solid, m.p. =

92−93 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 14.33 (br s, 1H), 8.39

(s, 1H), 2.04 (t, J = 19.0 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 160.5, 160.3, 152.6 (t, J = 32 Hz), 125.1 (t, J = 4 Hz),

119.0 (t, J = 236 Hz), 23.7 (t, J = 27 Hz) ppm. ¹⁹F{¹H} NMR (376

MHz, DMSO-d₆) δ −85.1 (s) ppm. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₆H₆F₂NO₂S: 194.0087; found: 194.0082.

6-(Perﬂuoroethyl)picolinic Acid (64c). Modiﬁed general procedure

E: solventEt₂O. Yield: 10.24 g, 0.0425 mol, 85%, white solid, m.p. =

1

131−132 °C. H NMR (400 MHz, DMSO-d₆) δ 13.74 (br s, 1H),

8.35−8.27 (m, 2H), 8.19−8.11 (m, 1H) ppm. ¹³C{¹H} NMR (151

MHz, DMSO-d₆) δ 165.0, 149.2, 146.0 (t, J = 26 Hz), 140.2, 128.0,

125.1, 118.5 (qt, J = 287, 38 Hz), 110.0 (tq, J = 255, 38 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −82.8 (s, 3F), −116.3 (s, 2F)

ppm. LCMS (M + H)⁺242. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₈H₅F₅NO₂: 242.0240; found: 242.0244.

6-(Perﬂuoroethyl)nicotinic Acid (65c). Modiﬁed general procedure

E: solventEt₂O. Yield: 9.76 g, 0.0405 mol, 81%, white solid, m.p. =

141−142 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 13.92 (br s, 1H), 9.23

(s, 1H), 8.55 (dd, J = 8.1, 1.5 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H) ppm.

¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ 165.1, 150.6, 148.8 (t, J = 25

Hz), 139.4, 129.8, 122.3, 118.5 (qt, J = 287, 37 Hz), 110.1 (tq, J = 254,

38 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −82.7 (s, 3F),

−116.4 (s, 2F) ppm. LCMS (M + H)⁺242. HRMS (ESI-TOF) m/z:

[M + H]⁺calcd for C₈H₅F₅NO₂: 242.0240; found: 242.0246.

2-(1,1-Diﬂuoroethyl)aniline Hydrochloride (9d). To a solution of

AcCl (4.12 g, 0.0525 mol, 1.05 equiv) in MeOH (400 mL) were added

9a (9.35 g, 0.05 mol, 1.0 equiv) and 10% Pd/C (0.5 g). The mixture

was hydrogenated at atmospheric pressure and cooled with ice water

until the absorption of hydrogen ceased. The mixture was ﬁltered. The

ﬁltrate was concentrated under reduced pressure. The solid residue

was washed with MTBE (2 × 50 mL) and dried. Yield: 9.00 g, 0.0465

mol, 93%, yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (br s,

3H), 7.58−7.29 (m, 3H), 7.18 (t, J = 7.4 Hz, 1H), 2.04 (t, J = 19.2 Hz,

3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 135.0, 131.2, 126.8

(t, J = 7 Hz), 123.6, 123.1 (t, J = 239 Hz), 122.1, 25.0 (t, J = 28 Hz)

ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −84.6 (s) ppm. HRMS

(ESI-TOF) m/z: [M + H]⁺calcd for C₈H₁₀F₂N: 158.0781; found:

158.0774.

4-(1,1-Diﬂuoroethyl)picolinic Acid (42c). General procedure F.

1

Yield: 5.24 g, 0.028 mol, 56%, white solid, m.p. = 149−150 °C. H

NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J = 5.0 Hz, 1H), 8.12 (s, 1H),

7.80 (s, 1H), 2.02 (t, J = 19.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 165.7, 150.4, 150.0, 146.3 (t, J = 28 Hz), 122.2 (t, J = 5

Hz), 121.1 (t, J = 239 Hz), 119.7 (t, J = 6 Hz), 24.4 (t, J = 27 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −88.5 (s) ppm. HRMS (ESI-

TOF) m/z: [M + H]⁺calcd for C₈H₈F₂NO₂: 188.0523; found:

188.0518.

5-(1,1-Diﬂuoroethyl)picolinic Acid (45c). General procedure F.

1

Yield: 6.36 g, 0.034 mol, 68%, beige solid, m.p. = 158−160 °C. H

NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.23−8.00 (m, 2H), 2.05

(t, J = 19.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ

165.9, 151.3, 145.8 (t, J = 6 Hz), 135.0 (t, J = 27 Hz), 134.1 (t, J = 6

Hz), 124.2, 121.5 (t, J = 238 Hz), 24.7 (t, J = 28 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, DMSO-d₆) δ −89.3 (s) ppm. LCMS (M + H)⁺188.

HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₈H₈F₂NO₂: 188.0523;

found: 188.0509.

5-(1,1-Diﬂuoroethyl)nicotinic Acid (48c). General procedure E.

3-(1,1-Diﬂuoroethyl)aniline Hydrochloride (10d). To a boiled

solution of 10a (9.35 g, 0.05 mol, 1.0 equiv) and NH₄Cl (1.07 g, 0.02

mol, 0.4 equiv) in a mixture of iPrOH (200 mL), H₂O (10 mL) and

con. HCl (1 mL) was added Fe (10.08 g, 0.18 mol, 3.6 equiv) in

portions. The mixture was stirred under reﬂux for 20 min, and a hot

solution was ﬁltered through SiO₂. The ﬁltrate was concentrated under

reduced pressure. The solid residue was dissolved in EtOAc (200 mL)

1

Yield: 6.73 g, 0.036 mol, 72%, beige solid, m.p. = 194−195 °C. H

NMR (400 MHz, DMSO-d₆) δ 13.73 (br s, 1H), 9.18 (s, 1H), 9.02 (s,

1H), 8.36 (s, 1H), 2.07 (t, J = 19.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126

MHz, DMSO-d₆) δ 165.5, 151.6, 149.7 (t, J = 6 Hz), 133.2, 132.9 (t, J

= 27 Hz), 126.5, 121.4 (t, J = 238 Hz), 24.7 (t, J = 28 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −85.7 (s) ppm. LCMS (M +

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and washed with water (100 mL) and brine (100 mL), then dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The whole

product was dissolved in 5 M HCl in dioxane (150 mL) and stirred at

room temperature for 1 h and concentrated under reduced pressure.

(126 MHz, CDCl₃) δ 154.5, 153.1, 139.7 (t, J = 8 Hz), 119.4 (qt, J =

287, 40 Hz), 112.5 (tq, J = 255, 40 Hz), 107.5 (t, J = 24 Hz), 107.2

ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −84.9 (s, 3F), −115.4 (s,

2F) ppm. LCMS (M + H)⁺292. HRMS (ESI-TOF) m/z: [M + H]⁺

calcd for C₇H₅BrF₅N₂: 290.9556; found: 290.9552.

1

Yield: 7.55 g, 0.039 mol, 78%, yellow solid, m.p. = 203−204 °C. H

6-(Perﬂuoroethyl)pyridin-2-amine (63d). General procedure G.

Yield: 3.60 g, 0.017 mol, 85%, white solid, m.p. = 69−70 °C. ¹H NMR

(400 MHz, DMSO-d₆) δ 7.58 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.3 Hz,

1H), 6.66 (s, 1H), 6.51 (s, 2H) ppm. ¹³C{¹H} NMR (151 MHz,

DMSO-d₆) δ 159.8, 144.2 (t, J = 25 Hz), 138.2, 118.8 (qt, J = 287, 39

Hz), 112.0 (tq, J = 253, 37 Hz), 111.9, 109.3 (t, J = 5 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −82.8 (s, 3F), −116.8 (s, 2F)

ppm. LCMS (M + H)⁺213. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₇H₆F₅N₂: 213.0451; found: 213.0446.

4-(1,1-Diﬂuoroethyl)aniline Hydrochloride (15d). To a solution of

NaN₃(1.95 g, 0.03 mol, 1.5 equiv) in a mixture of H₂O/acetone 1:1

(50 mL) was added 4-(1,1-diﬂuoroethyl)benzoyl chloride (4.09 g, 0.02

mol, 1.0 equiv) dropwise at 10 °C. The mixture was stirred for 1 h and

partially concentrated under reduced pressure without heating. The

residue was extracted with MTBE (3 × 50 mL). The combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated under

reduced pressure without heating. The residue was added to boiled t-

BuOH (50 mL) dropwise. The mixture was heated under reﬂux

overnight and concentrated under reduced pressure. The residue was

dissolved in 5 M HCl in dioxane (30 mL), and the resulting precipitate

was ﬁltered. Yield: 2.44 g, 0.0126 mol, 63%, yellow solid, m.p. = 157−

159 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (br s, 3H), 7.76 (d, J

= 8.2 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 1.95 (t, J = 18.3 Hz, 3H) ppm.

¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 135.3, 130.3, 126.1 (t, J = 6

Hz), 122.7, 121.1 (t, J = 238 Hz), 25.0 (t, J = 29 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, DMSO-d₆) δ −84.3 (s) ppm. HRMS (ESI-TOF) m/

z: [M + H]⁺calcd for C₈H₁₀F₂N: 158.0781; found: 158.0777.

General Procedure H (Curtius Reaction). 50d as an example.

Scale: 0.05 mol.

NMR (400 MHz, DMSO-d₆) δ 9.76 (br s, 3H), 7.61−7.55 (m, 1H),

7.53 (d, J = 5.6 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 1.96 (t, J = 18.9 Hz,

3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 138.7 (t, J = 27

Hz), 134.1, 130.2, 124.2, 123.2 (t, J = 5 Hz), 120.8 (t, J = 238 Hz),

118.5 (t, J = 6 Hz), 25.0 (t, J = 29 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz,

DMSO-d₆) δ −85.4 (s) ppm. HRMS (ESI-TOF) m/z: [M + H]⁺calcd

for C₈H₁₀F₂N: 158.0781; found: 158.0785.

3-(1,1,2,2-Tetraﬂuoroethyl)aniline (17d). To a boiled solution of

17a (9.35 g, 0.05 mol, 1.0 equiv) and NH₄Cl (1.07 g, 0.02 mol, 0.4

equiv) in a mixture of iPrOH (200 mL), H₂O (10 mL) and con. HCl

(1 mL) was added Fe (10.08 g, 0.18 mol, 3.6 equiv) in portions. The

mixture was stirred under reﬂux for 20 min and a hot solution was

ﬁltered through SiO₂. The ﬁltrate was concentrated under reduced

pressure. The solid residue was dissolved in EtOAc (200 mL) and

washed with water (100 mL) and brine (100 mL), then dried over

Na₂SO₄, ﬁltered, and concentrated under reduced pressure. The ﬁnal

product was puriﬁed by distillation. Yield: 9.41 g, 0.041 mol, 82%,

colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.41−7.25 (m, 1H), 6.94

(d, J = 7.7 Hz, 1H), 6.92−6.57 (m, 2H), 5.89 (tt, J = 54.1, 2.9 Hz, 1H),

3.83 (br s, 2H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ 149.1,

130.2 (t, J = 24 Hz), 129.40, 116.6 (tt, J = 54, 27 Hz), 116.5, 112.6 (t, J

= 6 Hz), 110.9 (tt, J = 249, 40 Hz), 110.6 (t, J = 7 Hz) ppm. ¹⁹F{¹H}

NMR (376 MHz, CDCl₃) δ −114.8 (s, 2F), −134.9 (s, 2F) ppm.

LCMS (M + H)⁺194. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₈H₈F₄N: 194.0593; found: 194.0590.

General Procedure G (Reaction with NH₃). 40d as an example.

Scale: 0.02 mol.

3-(1,1-Diﬂuoroethyl)pyridin-2-amine (40d). To a solution of 40b

(3.22 g, 0.02 mol, 1.0 equiv) in THF (100 mL), liquid ammonia (3.40

g, 0.20 mol, 10.0 equiv) was added at −20 °C. The reaction mixture

was heated to 90 °C for 24 h in an autoclave. The reaction was cooled

to room temperature, and the solvent was removed under reduced

pressure. The residue was puriﬁed by column chromatography. Yield:

6-(1,1-Diﬂuoroethyl)pyridin-2-amine Hydrochloride (50d). Com-

pound 50a (11.10 g, 0.05 mol, 1.0 equiv) was dissolved in tBuOH (150

mL). Et₃N (5.30 g, 0.0525 mol, 1.05 equiv) and (PhO)₂P(O)N₃

(15.13 g, 0.055 mol, 1.05 equiv) were added to the solution. The

mixture was heated at reﬂux for 15 h, cooled to room temperature, and

concentrated under reduced pressure. The residue was dissolved in

EtOAc (200 mL) and washed with a sat. solution of NaHCO₃(100

mL), water (100 mL), and brine (100 mL). The organic layer was

dried over Na₂SO₄, ﬁltered, and concentrated. The crude product was

puriﬁed by column chromatography (gradient, hexane/EtOAc). The

whole product was dissolved in 5 M HCl in dioxane (100 mL) and

stirred at room temperature overnight. The mixture was concentrated

under reduced pressure. Yield: 5.14 g, 0.0325 mol, 65%, white solid,

1

2.59 g, 0.0164 mol, 82%, orange solid, m.p. = 78−79 °C. H NMR

(400 MHz, CDCl₃) δ 8.11 (d, J = 4.2 Hz, 1H), 7.55 (d, J = 7.6 Hz,

1H), 6.68 (t, J = 5.4 Hz, 1H), 4.96 (br s, 2H), 1.96 (t, J = 18.6 Hz, 3H)

ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 155.3, 149.8, 134.6 (t, J = 7

Hz), 122.7 (t, J = 238 Hz), 116.4 (t, J = 27 Hz), 113.7, 23.7 (t, J = 29

Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, CDCl₃) δ −90.0 (s) ppm. LCMS

(M + H)⁺159. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for

C₇H₉F₂N₂: 159.0734; found: 159.0730.

4-(1,1-Diﬂuoroethyl)-5-ﬂuoropyridin-2-amine (43d). Modiﬁed

general procedure G: T = 70 °C. Yield: 2.68 g, 0.0152 mol, 76%,

yellow solid, m.p. = 64−65 °C. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97

(s, 1H), 6.58 (d, J = 4.0 Hz, 1H), 6.18 (s, 2H), 1.95 (t, J = 19.2 Hz,

3H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 157.0, 148.2 (dt, J

= 242, 4 Hz), 135.7 (d, J = 25 Hz), 133.4 (td, J = 28, 12 Hz), 119.8 (t, J

= 239 Hz), 103.7 (t, J = 7 Hz), 24.2 (t, J = 28 Hz) ppm. ¹⁹F{¹H} NMR

(376 MHz, DMSO-d₆) δ −88.6 (d, J = 11.8 Hz, 2F), −151.5 (t, J =

11.8 Hz, 1F) ppm. LCMS (M + H)⁺177. HRMS (ESI-TOF) m/z: [M

+ H]⁺calcd for C₇H₈F₃N₂: 177.0640; found: 177.0636.

1

m.p. = 153−154 °C. H NMR (400 MHz, DMSO-d₆) δ 8.25 (br s,

3H), 7.87 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 7.2

Hz, 1H), 2.06 (t, J = 19.3 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 156.3, 142.3, 119.1 (t, J = 240 Hz), 114.6, 108.2 (t, J = 6

Hz), 23.2 (t, J = 26 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, D₂O) δ

−92.2 (s) ppm. LCMS (M + H)⁺159. HRMS (ESI-TOF) m/z: [M +

H]⁺calcd for C₇H₉F₂N₂: 159.0734; found: 159.0725.

5-(1,1-Diﬂuoroethyl)pyridin-3-amine (48d). General procedure H.

1

Yield: 5.29 g, 0.0335 mol, 67%, white solid, m.p. = 204−205 °C. H

NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H),

7.80 (s, 1H), 2.02 (t, J = 19.3 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz,

DMSO-d₆) δ 148.0, 136.7 (t, J = 29 Hz), 127.0, 124.3 (t, J = 6 Hz),

123.2 (t, J = 6 Hz), 120.4 (t, J = 240 Hz), 24.4 (t, J = 27 Hz) ppm.

¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −86.8 (s) ppm. LCMS (M +

H)⁺159. HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₇H₉F₂N₂:

159.0734; found: 159.0738.

3-(Perﬂuoroethyl)pyridin-2-amine Hydrochloride (58d). General

procedure G. The ﬁnal compound was dissolved in 5 M dioxane and

concentrated under reduced pressure. Yield: 4.22 g, 0.017 mol, 85%,

1

white solid, m.p. = 127−128 °C. H NMR (400 MHz, DMSO-d₆) δ

8.38 (d, J = 5.4 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.10 (br s, 2H),

7.08−6.93 (m, 1H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ

152.4, 144.5, 143.8, 118.7 (dt, J = 78, 40 Hz), 114.8 (m), 112.1, 107.9

(t, J = 25 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆) δ −84.2 (s,

3F), −113.9 (s, 2F) ppm. LCMS (M + H)⁺213. HRMS (ESI-TOF)

m/z: [M + H]⁺calcd for C₇H₆F₅N₂: 213.0451; found: 213.0457.

5-Bromo-3-(perﬂuoroethyl)pyridin-2-amine (59d). Modiﬁed gen-

eral procedure G: T = 70 °C. Yield: 4.60 g, 0.0158 mol, 79%, white

5-(Perﬂuoroethyl)pyridin-3-amine (62d). General procedure H.

1

Yield: 7.63 g, 0.036 mol, 72%, white solid, m.p. = 198−199 °C. H

NMR (400 MHz, DMSO-d₆) δ 8.53 (br s, 2H), 8.35−8.21 (m, 2H),

7.71 (s, 1H) ppm. ¹³C{¹H} NMR (151 MHz, DMSO-d₆) δ 147.2,

133.2, 127.5, 125.7 (t, J = 25 Hz), 121.7, 118.3 (qt, J = 77, 38 Hz),

111.1 (tq, J = 255, 39 Hz) ppm. ¹⁹F{¹H} NMR (376 MHz, DMSO-d₆)

δ −84.6 (s, 3F), −115.2 (s, 2F) ppm. LCMS (M + H)⁺213. HRMS

1

solid, m.p. = 102−104 °C. H NMR (400 MHz, CDCl₃) δ 8.26 (s,

1H), 7.71 (d, J = 2.1 Hz, 1H), 5.10 (br s, 2H) ppm. ¹³C{¹H} NMR

O

https://doi.org/10.1021/acs.joc.1c01518

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(ESI-TOF) m/z: [M + H]⁺calcd for C₇H₆F₅N₂: 213.0451; found:

(4) MacBean, C., Ed. The Pesticide Manual; British Crop Production

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Looking Beyond Intuition. Science 2007, 317, 1881−1886.

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Chemistry. J. Med. Chem. 2008, 51, 4359−4369.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c01518.

■

sı

(7) O’Hagan, D. Understanding Organofluorine Chemistry. An

Introduction to the C −F Bond. Chem. Soc. Rev. 2008, 37, 308−319.

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Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330.

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N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem.

2015, 58, 8315−8359.

¹H, ¹³C, and ¹⁹F NMR spectra for all compounds and

additional experimental details including photographs of

experimental setup (PDF)

AUTHOR INFORMATION

Corresponding Author

(10) Sub-structure search was performed at www.drugbank.ca.

(11) Meanwell, N. A. Fluorine and Fluorinated Motifs in the Design

and Application of Bioisosteres for Drug Design. J. Med. Chem. 2018,

61, 5822−5880.

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Verkman, A. S. Nanomolar Potency and Metabolically Stable

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55, 5942−5950.

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White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.;

Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.;

Jiménez-Díaz, M. B.; Gamo, F. J.; Goldsmith, E. J.; Charman, W. N.;

Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.;

Charman, S. A.; Phillips, M. A. Structure-Guided Lead Optimization of

Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium

falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical

Candidate Potential. J. Med. Chem. 2011, 54, 5540−5561.

■

Pavel K. Mykhailiuk − Enamine Ltd., 02094 Kyiv, Ukraine;

orcid.org/0000-0003-1821-9011;

Email: pavel.mykhailiuk@gmail.com; www.enamine.net

Authors

Serhii Trofymchuk − Enamine Ltd., 02094 Kyiv, Ukraine;

Institute of Organic Chemistry, NAS of Ukraine, 02094 Kyiv,

Ukraine

Maksym Bugera − Enamine Ltd., 02094 Kyiv, Ukraine; V.P.

Kukhar Institute of Bioorganic Chemistry and Petrochemistry,

NAS of Ukraine, 02094 Kyiv, Ukraine

Anton A. Klipkov − Enamine Ltd., 02094 Kyiv, Ukraine; V.P.

Kukhar Institute of Bioorganic Chemistry and Petrochemistry,

NAS of Ukraine, 02094 Kyiv, Ukraine

(14) Piotrowski, D. W.; Futatsugi, K.; Warmus, J. S.; Orr, S. T. M.;

Freeman-Cook, K. D.; Londregan, A. T.; Wei, L.; Jennings, S. M.;

Herr, M.; Coffey, S. B.; Jiao, W.; Storer, G.; Hepworth, D.; Wang, J.;

Lavergne, S. Y.; Chin, J. E.; Hadcock, J. R.; Brenner, M. B.; Wolford, A.

C.; Janssen, A. M.; Roush, N. S.; Buxton, J.; Hinchey, T.; Kalgutkar, A.

S.; Sharma, R.; Flynn, D. A. Identification of Tetrahydropyrido[4,3-

d]Pyrimidine Amides as a New Class of Orally Bioavailable TGR5

Agonists. ACS Med. Chem. Lett. 2013, 4, 63−68.

(15) Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.;

Shabat, D.; Baran, P. S. Direct Synthesis of Fluorinated Hetero-

arylether Bioisosteres. Angew. Chem., Int. Ed. 2013, 52, 3949−3952.

(16) Patrick, T. B.; Flory, P. A. Direct Fluorination of Aryl Ketone

Hydrazones. J. Fluorine Chem. 1984, 25, 157−164.

(17) Mathey, F.; Bensoam, J. Reactions de l ’hexafluorure de

Molybdene Avec Les Aldehydes et Les Cetones Fonctionnels.

Tetrahedron 1975, 31, 391−401.

Volodymyr Ahunovych − Enamine Ltd., 02094 Kyiv,

Ukraine; V.P. Kukhar Institute of Bioorganic Chemistry and

Petrochemistry, NAS of Ukraine, 02094 Kyiv, Ukraine

Bohdan Razhyk − Enamine Ltd., 02094 Kyiv, Ukraine

Sergey Semenov − Enamine Ltd., 02094 Kyiv, Ukraine

Andrii Boretskyi − UORSY, Ukrorgsyntez Ltd., 02002 Kyiv,

Ukraine

Karen Tarasenko − V.P. Kukhar Institute of Bioorganic

Chemistry and Petrochemistry, NAS of Ukraine, 02094 Kyiv,

Ukraine; Chemspace LLC, 02094 Kyiv, Ukraine

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01518

Author Contributions

^#S.T. and M.B. contributed equally to this work.

(18) (a) Middleton, W. J. New Fluorinating Reagents. Dialkylami-

nosulfur Fluorides. J. Org. Chem. 1975, 40, 574−578. (b) Markovskij,

L. N.; Pashinnik, V. E.; Kirsanov, A. N. Application of Dialkylamino-

sulfur Trifluorides in the Synthesis of Fluoroorganic Compounds.

Synthesis 1973, 787−789.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

(19) (a) Messina, P. A.; Mange, K. C.; Middleton, W. J. Aminosulfur

Trifluorides: Relative Thermal Stability. J. Fluorine Chem. 1989, 42,

137−143. (b) Lal, G. S.; Fez, G. P.; Pesaresi, R. J.; Prozonic, F. M.

Bis(2-Methoxyethyl)Aminosulfur Trifluoride: A New Broad-Spectrum

Deoxofluorinating Agent with Enhanced Thermal Stability. Chem.

Commun. 1999, 215−216. (c) Beaulieu, F.; Beauregard, L. P.;

Courchesne, G.; Couturier, M.; Laflamme, F.; L’Heureux, A.

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Crystalline Deoxofluorinating Reagents. Org. Lett. 2009, 11, 5050−

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M. Aminodifluorosulfinium Salts: Selective Fluorination Reagents with

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Discovery of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride as a

Deoxofluorinating Agent with High Thermal Stability as Well as

Unusual Resistance to Aqueous Hydrolysis, and Its Diverse

Fluorination Capabilities Including Deoxofluoro-Arylsulfinylation

The authors are grateful to Enamine Ltd. for ﬁnancial support.

P.K.M. is grateful to I. Sadkova for the help with the preparation

of the manuscript, and to Dr. Denis Bylina for HRMS analysis.

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R

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Scalable Approach to Fluorinated Heterocycles with Sulfur Tetrafluoride (SF4)

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