Synthesis of sp 3-Enriched β-Fluoro Sulfonyl Chlorides

SYNTHESIS

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2021, 53, 1771–1784

paper

1771

en

R. Gurbanov et al.

Paper

Synthesis

Synthesis of sp³-Enriched -Fluoro Sulfonyl Chlorides

Rustam Gurbanov^a

Andriy Sokolov^a,b

Sergey Golovach^a

Kostiantyn Melnykov^a,b

Alexey V. Dobrydnev^a,b

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Oleksandr O. Grygorenko*^a,b

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^aEnamine Ltd., Chervonotkatska Street 78, Kyiv

02094, Ukraine

www.enamine.net

^bTaras Shevchenko National University of Kyiv,

Volodymyrska Street 60, Kyiv 01601, Ukraine

gregor@univ.kiev.ua

OTeMalerakisClaoSgnhrrdreergvsocOphr.o@eGnnudrknyinogivgoN.rkAaeietunivtokh.onuoarl University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine

Received: 29.10.2020

Accepted after revision: 13.11.2020

Published online: 15.12.2020

be largely underrepresented in the literature.^7,8Thus, the

parent 2-fluoroethanesulfonyl chloride has been described

in several papers; the methods used for its preparation in-

cluded Cl₂-mediated oxidation of -fluoroethyl thiocya-

nate,^8athiouronium tosylate,^8band tert-butyl sulfide

(Scheme 1).^8cIn turn, the latter substrates were prepared

via nucleophilic substitution starting from 2-fluoroethanol.

Additional to that, a few substituted -fluoro sulfonyl chlo-

rides,⁹as well as -fluoro alkyl sulfides¹⁰considered as pre-

cursors to ones, are mentioned in the literature.

DOI: 10.1055/s-0040-1706101; Art ID: ss-2020-t0036-op

Abstract A three-step approach to the synthesis of sp³-enriched -

fluoro sulfonyl chlorides starting from alkenes is reported. The method

was successfully applied to a wide range of acyclic and cyclic substrates,

bearing either an exocyclic or an endocyclic double bond. The proce-

dure worked with a wide range of substrates and tolerated a number of

functional and protecting groups. Moreover, the target cyclic com-

pounds were obtained as single cis diastereomers on a multigram scale.

The title compounds are promising building blocks for drug discovery

that can be used to obtain sp³-enriched -fluoro and ,-unsaturated

sulfonamides.

refs. 7−9

+

NH₂

SO₂Cl

F

SX

F

LG

F

OH

F

X = CN, t-Bu,

Key words organosulfur compounds, organofluorine compounds,

oxidation, sulfonyl chlorides, building blocks

NH₂

LG = Br, OTs

this work

R³

R²

SO₂Cl

R³

R²

SAc

R³

Br

Sulfonamides have taken an outstanding part in drug

discovery for many years. First of all, the sulfonamide bond

is considered as an amide bioisostere, although conforma-

tional properties of these structural units are rather differ-

ent.¹Another remarkable feature of the sulfonamide motif

is its stability under physiological conditions: thus, only a

few known enzymes are able to hydrolyze the SO₂–N bond.²

It is not surprising therefore that sulfonamides were intro-

duced into the pharmaceutical market as early as in the

first half of the 20th century (the well-known ‘sulfa

drugs’).³These antibacterial drugs earned their creator, Ger-

hard Domagk, a Nobel Prize in 1939.⁴Since then, more than

a hundred sulfonamide-containing drugs have been ap-

proved and used over the world.⁵

Taking into account the importance of sulfonamides in

drug discovery, as well as in line with ongoing trends to-

wards the synthesis of advanced sulfonyl halide building

blocks,⁶we have turned our attention to (hetero)aliphatic

sulfonyl chlorides bearing a single fluorine atom at the -

position (4). Surprisingly, this compound class appeared to

R²

F

2

F

R²

R¹

F

3

R¹

4

1

Scheme 1 Synthesis of -fluoro sulfonyl chlorides

In this work, we propose an alternative strategy for the

preparation of sp³-enriched -fluoro sulfonyl chlorides,

which is similar to a three-step approach to aliphatic -

alkoxy sulfonyl chlorides described by us previously and

based on alkoxybromination of the corresponding alkenes

1.^6cSimilarly to the latter approach, the key step of the pro-

posed method might include bromofluorination of 1,

whereas to install the sulfonyl chloride moiety, nucleophilic

substitution of the bromine atom by thioacetate anion and

subsequent oxidative chlorination were envisaged. Twenty-

three alkenes 1a–x, significantly varied in structure, were

studied as the substrates for the proposed reaction se-

quence to establish its scope and limitations (Figure 1).

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1772

R. Gurbanov et al.

Paper

Synthesis

First of all, acyclic substrates were studied, namely sty-

rene (1a) and 3-methoxy-2-methylprop-1-ene (1b). The

first step, i.e. bromofluorination, was carried out upon ac-

tion of Et₃N·3HF and NBS in CH₂Cl₂according to slightly

modified literature procedures.¹¹The reaction led to prod-

ucts 2a and 2b exclusively formed according to Mar-

kovnikov’s rule.^11aFurther steps, i.e. KSAc-mediated prepa-

ration of -fluoro ethanethioates 3a and 3b, as well as their

oxidative chlorination upon action of N-chlorosuccinimide

(NCS) and aqueous HCl, were performed following the well-

established protocols.^6cThus, the corresponding -fluoro

sulfonyl chlorides 4a and 4b were isolated in 64% and 66%

overall yield, respectively (Table 1, entries 1 and 2).

bromofluorination of cyclooctene (1u). The crude product

contained a number of impurities (including some isomeric

bromofluorocyclooctanes); possibly, transannular reactions

(common in medium-sized rings¹²) were responsible for

that. In this regard, cyclooctene (1u) was bromofluorinated

at lowered temperature (–20 °C) with 1,3-dibromo-5,5-di-

methylhydantoin (DBDMH) and Py·HF as a source of the

fluoride. This improvement allowed preparation of the tar-

get product 2u in nearly quantitative yield (98%; Table 1,

entry 21).

In general, bromofluorination of alkenes 1 proceeded

smoothly and gave the desired products in moderate to

good yields. The yields of the products correlated with their

lipophilicity and (partially) volatility, obviously due to loss-

es upon workup of the reaction mixture.

Ph

The next step, i.e. nucleophilic substitution of the bro-

mine atom with thioacetate anion, was performed in DMF

upon heating and provided the corresponding -fluoro

thioacetates 3 in up to 99% yield (Table 1). This method

worked well with the substrates derived from mono- and

disubstituted (vicinal and geminal) alkenes, and neither he-

teroatom position nor ring size had a tangible impact on its

outcome. However, fine-tuning of the reaction temperature

was necessary to attain optimal yield of the products. The

reaction followed an S_N2 mechanism; thus, syn-3e,f and cis-

3q–w products were obtained from the corresponding anti-

2e,f and trans-2q–w isomeric substrates (Table 1; entries 5,

6, and 17–23). At the same time, tri- (2x) and tetrasubsti-

tuted (2g) -fluoro bromides (Table 1, entries 7 and 24) did

not participate in nucleophilic substitution, affording side

elimination products instead.

NPhth

Ph

1e

OMe

1b

SO₂Me

Ph

1a

Ph

1f

1d

1g

1c

1h

1j

1i

1k

EtO₂C

Boc

N

O

Boc

N

1l

1n

1o

1p

N

Boc

O

1q

1r

1s

1t

1u

1v

1w

1x

Figure 1 Alkenes 1a–x – starting materials for this study

These successful results prompted us to extend the sub-

strate scope with other acyclic as well as carbo- and hetero-

cyclic alkenes (Figure 1). Many of the starting materials

shown in Figure 1 were available commercially; functional-

ized alkenes 1c and 1d were obtained from 3-chloro-2-

methylprop-1-ene (5) (Scheme 2), whereas carbo- and het-

erocyclic alkenes 1h–l,n–p were synthesized by Wittig ole-

fination of the corresponding cyclic ketones 6 (Scheme 3).

Analogously to the case of 1a and 1b, fluorobromination

of alkenes 1c,d,h–l and 1n–p led to Markovnikov-type

products 2c,d,h–p, which were obtained in 38–99% yield

(Table 1; entries 3, 4, and 8–16). In turn, alkene 1l was con-

verted into a ca. 1:1 mixture of diastereomeric products 2l

and 2m that were separated by column chromatography

(Table 1, entries 12 and 13).

Ultimately, the oxidative chlorination of 3 proceeded in

a straightforward manner under typical conditions (NCS, aq

HCl, MeCN, 0 °C to rt), and the target -fluoro sulfonyl chlo-

rides 4 were obtained in up to 97% yield (Table 1). Dimin-

ished yields were observed only for the products bearing

MeSO₂Na, DMSO, 65 °C, 12 h

MeO₂S

86%

1c

Cl

5

PhthNK, DMSO, 55 °C, 12 h

NPhth

91%

1d

Scheme 2 Synthesis of functionalized alkenes 1c and 1d

Since the mechanism of the bromofluorination probably

includes formation of bromonium ions, the reaction should

occur as an anti addition.^11aIndeed, under the aforemen-

tioned conditions, trans--methylstyrene (1e) and stilbene

(1f) were converted into anti--fluoro bromides (2e,f), and

cyclic substrates 1q–x bearing an endocyclic double bond

gave trans--fluoro bromides 2q–x exclusively, in 59–94%

yield (Table 1; entries 5, 6, and 17–24). Nevertheless, the

developed procedure turned out to be inappropriate for the

Method A (for 1h–k,p):

Ph₃P=CH₂, DMSO, rt, 3 h

R¹

R²

75−89%

O

Method B (for 1l,n,o):

Ph₃P=CH₂, THF, 10 °C to rt, 2 h

95−98%

R²

6

1h–l,n–p

for R¹, R², and yields see Table 1

Scheme 3 Synthesis of alkenes 1h–l and 1n–p

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R. Gurbanov et al.

Paper

Synthesis

acid-labile groups [i.e., Boc-protected derivatives 4n (13%),

4o (39%), and 4v (30%), as well as tetrahydrofuran 4w

(45%)]. Intriguingly, the stilbene-derived -fluoro thio-

acetate 3f failed to give the corresponding sulfonyl chloride,

resulting in a complex mixture of side products.

Notably, cyclic derivatives 4q–w were obtained as pure

cis diastereomers (Table 1, entries 17–23), which was con-

firmed by NOE experiments with products 4s and 4v (Fig-

ure 2). In addition, the configuration of sulfonyl chloride

4m was also confirmed by NOE experiments.

Table 1 Synthesis of -Fluoro Sulfonyl Chlorides 4^a

R¹

F

Br

F

SAc

R³

F

SO₂Cl

R³

Et₃N^.3HF, NBS, CH₂Cl₂

5 °C to rt, overnight

NCS, aq HCl, MeCN

0 °C to rt, 2 h

KSAc, DMF, Δ, 12 h

R¹

R²

R³

R²

1

2

3

4

Entry Alkene 1

Yield (%)^b-Fluoro bromides 2

Yield (%) -Fluoro thioacetates 3

Temp (°C) Yield (%) -Fluoro sulfonyl chlorides Yield (%)

4

F

Ph

SO₂Cl

SAc

Br

1

–

85

40

50

96

78

83

Ph

1a

2a

3a

4a

F

MeO

SAc

MeO

SO₂Cl

MeO

Br

2

–

N/A^c

38

79^d

MeO

Me

1b

2b

3b

4b

F

MeSO₂

Br

MeSO₂

SAc

MeSO₂

SO₂Cl

MeSO₂

3

86

91

50

55

25

95

76

92

Me

1c

2c

3c

4c

F

NPhth

SAc

NPhth

Br

NPhth

SO₂Cl

NPhth

4

43

Me

1d

2d

F

3d

F

4d

F

Ph

5

–

69

71

45

76

78

91

–

1e

SO₂Cl

Br

SAc

2e

F

3e

F

4e

Ph

SAc

Ph

6

–

1f

Br

2f

3f

F

Br

7

8

9

–

68

82

–

1g

1h

2g

SAc

Br

SO₂Cl

83

85

30

40

88

87

90

79

F

2h

2i

3h

3i

4h

4i

SAc

Br

F

1i

1j

Br

SAc

SO₂Cl

10

11

89

87

73

50

90

95

80

F

4j

2j

3j

Br

SAc

N/A^c

71^d

F

2k

4k

1k

3k

1774

R. Gurbanov et al.

Paper

Synthesis

Table 1 (continued)

Entry Alkene 1

Yield (%)^b-Fluoro bromides 2

Yield (%) -Fluoro thioacetates 3

Temp (°C) Yield (%) -Fluoro sulfonyl chlorides Yield (%)

4

Br

SO₂Cl

EtO₂C

SAc

EtO₂C

12

30

35

41

99

90

50

40

45

50

93

97

72

99

70

77

89

13

39

73

F

2l

3l

4l

EtO₂C

98

1l

SAc

SO₂Cl

EtO₂C

13

F

3m

2m

4m

SAc

Br

SO₂Cl

Boc N

Boc

N

Boc N

14

96

F

1n

3n

4n

2n

SO₂Cl

Br

SAc

Boc N

15

95

F

1o

2o

3o

4o

Br

SAc

SO₂Cl

O

16

75

F

2p

4p

1p

3p

F

17

–

59

82

70

N/A^c

92^d

97

SO₂Cl

F

1q

SAc

F

Br

2q

3q

3r

4q

4r

F

18

–

82

SO₂Cl

SAc

Br

2r

1r

F

19

–

91

94

98^e

40

46

71

75

85

90

70

65

–

92

97

53

64

82

–

63

83

56

30

45

–

SO₂Cl

F

SAc

Br

1s

2s

3s

3t

3u

4s

4t

4u

F

20

–

SO₂Cl

SAc

Br

1t

2t

F

21

–

SO₂Cl

SAc

Br

1u

2u

F

Boc

N

Boc

N

Boc

N

Boc

N

22

23

24

–

SO₂Cl

Br

SAc

1v

2v

3v

4v

F

O

SO₂Cl

Br

SAc

1w

3w

2w

4w

F

–

Br

1x

2x

^aRelative configurations are shown.

^bCompounds 1c and 1d were prepared according to Scheme 2. Compounds 1h–l and 1n–p were prepared according to Scheme 3 using Methods A and B.

^cThe product was used in the next step without purification.

^dYield over two steps.

^eReaction conditions: DBDMH, Py·HF, CH₂Cl₂, –20 °C to rt, overnight.

1775

R. Gurbanov et al.

Paper

Synthesis

,-unsaturated (8b) sulfonamides, the former one was the

major product (Table 2, entries 7 and 8). Importantly, no re-

action occurred when an additional amount of the nucleo-

phile was added to the obtained mixture of 7a and 8a, and

the mixture left at room temperature overnight. Therefore,

the elimination of HF occurred from the starting material

4h and not from the product 7a.

F

H

SO₂Cl

H

EtO₂C

H

F

H

N

H

Boc

SO₂Cl

H

F

SO₂Cl

4v

4s

4m

Figure 2 Important NOE correlations observed for 4m, 4s, and 4v

In conclusion, we have developed a general and efficient

three-step approach to the preparation of sp³-enriched -

fluoro sulfonyl chlorides starting from acyclic and car-

bo(hetero)cyclic alkenes. The method worked well with

mono- and disubstituted alkenes (vicinal and geminal) ex-

cept for diaryl-substituted ones; it was not fruitful with tri-

and tetrasubstituted substrates. Owing to low molecular

weight and sp³-enrichment, as well as conformational re-

striction, -fluoro sulfonyl chlorides meet the requirements

for renowned criteria as building blocks for lead-oriented

synthesis.¹³The obtained compounds can be used for the

preparation of -fluoro and (especially) ,-unsaturated

sulfonamides (that are not readily available by other meth-

ods), both being useful for early drug discovery programs.

Next, we turned our attention to the preparation of the

corresponding sulfonamides. For this purpose, 4h was cho-

sen as a model sulfonyl chloride, whereas ammonia and an-

iline were used as model nucleophiles. It was found that the

sulfonylation with 4h was accompanied with -elimination

to a great extent, so that the target -fluoro sulfonamides 7

were formed together with the corresponding ,-unsatu-

rated sulfonamides 8. Toward this end, a series of experi-

ments were performed in order to find the favorable reac-

tion conditions. Particularly, the effect of the solvent and

the temperature were studied primarily (Table 2).

Table 2 Optimization of the Sulfonylation Reaction Conditions

F

SO₂NHR

RNH₂, solvent

Solvents were purified according to standard procedures.¹⁴All start-

ing materials were obtained from Enamine Ltd. and UORSY. Melting

points were measured on an MPA100 OptiMelt automated melting

point system. Analytical TLC was performed using Polychrom SI F254

plates. Column chromatography was performed using Merck silica gel

60 (230–400 mesh) as the stationary phase. ¹H, ¹⁹F, and ¹³C NMR spec-

tra were recorded on an Agilent ProPulse 600 spectrometer (600 MHz

for ¹H NMR and 151 MHz for ¹³C NMR), a Bruker 170 Avance 500 spec-

trometer (at 500.1 MHz, 470.6 MHz, and 125.8 MHz for ¹H, ¹⁹F, and

¹³C nuclei, respectively) or Varian Unity Plus 400 spectrometer (at

400.4 MHz, 376.5 MHz, and 100.7 MHz for ¹H, ¹⁹F, and ¹³C nuclei, re-

spectively). Chemical shifts are reported in ppm downfield from TMS

as an internal standard. Elemental analyses were performed at the

Laboratory of Organic Analysis, Department of Chemistry, Taras

Shevchenko National University of Kyiv. Mass spectra were recorded

on an Agilent 1100 LCMSD SL instrument [chemical ionization (APCI),

electrospray ionization (ESI)] or Agilent 5890 Series II 5972 GCMS in-

strument [electron impact ionization (EI)]. HRMS analyses were con-

ducted on an Agilent 1260 Infinity UHPLC instrument coupled with

an Agilent 6200 Accurate Mass TOF mass spectrometer.

+

SO₂Cl

SO₂NHR

temperature, time

4h

7

8

Entry

R

Reaction conditions

Products (ratio)^a

1

2

3

4

5

6

H

Ph

aq NH₃, rt, 20 min

7a + 8a (1:6)

7a + 8a (1:10)

7a + 8a (1:12)^b

7a + 8a (1:3)

7a + 8a (1:2.5)

aq NH₃, 0 °C to rt, 20 min

aq NH₃, 0 °C, 1 h

NH₃, THF, rt, 30 min^c

NH₃, THF, –30 °C, 30 min^c

PhNH₂(1 equiv), i-Pr₂NEt (1.1

equiv), THF, –30 °C, overnight

7b + 8b (1:1) and by-

products

7

8

Ph

PhNH₂(1 equiv), AcONa (1 equiv),

AcOH, rt, overnight

7b + 8b (1.6:1)

PhNH₂(1.2 equiv), AcONa (1.5

equiv), AcOH, rt, overnight

7b + 8b (1.7:1)^d

^aIn the crude product, according to ¹H NMR spectra.

^bPure 8a was isolated in 52% yield.

^cA solution of NH₃was added to a solution of 4h.

^dA mixture of 7b and 8b (1.7:1 ratio) was isolated in 73% total yield.

2-Methyl-3-(methylsulfonyl)prop-1-ene (1c)¹⁵

MeSO₂Na (5.11 g, 50 mmol) and 3-chloro-2-methylprop-1-ene (5)

(4.53 g, 50 mmol) were dissolved in anhydrous DMF (150 mL), and

the resulting mixture was heated at 65 °C for 12 h. The volatiles were

evaporated under reduced pressure; the remainder was diluted with

water (200 mL) and extracted with EtOAc (2 × 100 mL). The combined

organic layers were washed with brine (2 × 50 mL), dried (Na₂SO₄),

and evaporated under reduced pressure, affording pure 1c; yield: 5.77

g (86%).

Upon sulfonylation of ammonia in aqueous media, low-

ering the temperature increased the content of ,-unsatu-

rated derivative 8a up to 12:1 ratio (Table 2, entries 1–3).

Contrary to that, THF media and reverse addition of the re-

agents (an ammonia solution was added to a solution of 4h)

facilitated the formation of -fluoro sulfonamide 7a and in-

creased its content upon lowering the temperature, al-

though 8a still was the major product (up to 1:2.5 ratio of

7a and 8a; Table 2, entries 4 and 5). In its turn, the best re-

sults for the sulfonylation of aniline were obtained in AcOH

media at room temperature using AcONa as a base. Al-

though this also resulted in a mixture of -fluoro (7b) and

2-(2-Methylallyl)isoindoline-1,3-dione (1d)¹⁶

Potassium phthalimide (9.26 g, 50 mmol) and 3-chloro-2-methyl-

prop-1-ene (5) (4.53 g, 50 mmol) were dissolved in anhydrous DMF

(150 mL), and the resulting mixture was heated at 55 °C for 12 h. The

1776

R. Gurbanov et al.

Paper

Synthesis

volatiles were evaporated under reduced pressure, and the remainder

was diluted with water (200 mL). The precipitate formed was filtered,

washed with water, and dried, affording pure 1d; yield: 9.16 g (91%).

-Fluoro Bromides 2a–t and 2v–x; General Procedure

Et₃N·3HF (20.2 g, 125 mmol) was added to a solution of alkene 1a–

l,n–t,v–x (50 mmol) in CH₂Cl₂(100 mL), and the resulting mixture

was cooled to 5 °C. Then, NBS (10.7 g, 60 mmol) was added portion-

wise at 5 °C, and the reaction mixture was stirred at rt overnight.

Then, it was poured onto an ice–water mixture (200 g). The organic

layer was separated, washed with saturated aq NaHCO₃(3 × 50 mL),

dried (Na₂SO₄), and evaporated under reduced pressure, affording

pure product (2a,g,i,o,p,r–t), or crude product which was purified by

distillation (2e,h,j,q,w,x), column chromatography (2c,l–n,v), recrys-

tallization (2d,f), or used without purification (2b,k).

Alkenes 1h–k and 1p; Method A; General Procedure

NaH (60% dispersion in mineral oil; 2.40 g, 60 mmol) was washed

with hexane under argon atmosphere and dissolved carefully in an-

hydrous DMSO (100 mL) at 60 °C. The resulting solution was cooled to

15 °C, Ph₃PMeI (23.4 g, 58 mmol) was added under argon atmosphere,

and the mixture was allowed to react for 20 min. The corresponding

ketone 6 (50 mmol) was added dropwise at rt, and the resulting solu-

tion was stirred for 3 h at rt. The alkene formed was removed from

the reaction mixture under reduced pressure and condensed in a liq-

uid nitrogen cooled vacuum trap. The vacuum trap was sealed, re-

moved, and allowed to equilibrate to rt. The product retrieved from

the vacuum trap was pure enough so that no further purification was

required.

(2-Bromo-1-fluoroethyl)benzene (2a)^11d

Yield: 6.57 g (85%) from 4.00 g of styrene (1a); yellowish oil.

1-Bromo-2-fluoro-3-methoxy-2-methylpropane (2b)

The crude product was used in the subsequent step without further

characterization; yield: 9.03 g from 5.00 g of 1b; yellowish liquid.

Methylenecyclobutane (1h)^17a

Yield: 8.07 g (83%) from 10.0 g of cyclobutanone; colorless liquid.

1-Bromo-2-fluoro-2-methyl-3-(methylsulfonyl)propane (2c)

The product was purified by column chromatography (gradient CHCl₃

to EtOAc); yield: 3.76 g (38%) from 5.70 g of 1c; yellowish oil.

¹H NMR (400 MHz, CDCl₃):  = 3.72 (t, J = 12.5 Hz, 1 H), 3.60 (t, J = 16.3

Methylenecyclopentane (1i)^17a

Yield: 8.30 g (85%) from 10.0 g of cyclopentanone; colorless liquid.

Hz, 2 H), 3.40 (t, J = 16.3 Hz, 1 H), 2.97 (s, 3 H), 1.71 (d, J = 22.0 Hz, 3

H).

Methylenecyclohexane (1j)^17a,b

Yield: 13.1 g (89%) from 15.0 g of cyclohexanone; colorless liquid.

¹³C NMR (101 MHz, CDCl₃):  = 92.0 (d, J = 177.7 Hz), 60.0 (d, J = 24.0

Hz), 43.6 (d, J = 6.2 Hz), 36.9 (d, J = 28.5 Hz), 23.8 (d, J = 23.3 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –143.3.

Methylenecycloheptane (1k)^17c

Yield: 8.55 g (87%) from 10.0 g of cycloheptanone; colorless liquid.

Anal. Calcd for C₅H₁₀BrFO₂S: C, 25.76; H, 4.32; S, 13.75. Found: C,

26.07; H, 4.45; S, 13.69.

4-Methylenetetrahydro-2H-pyran (1p)^17d

Yield: 7.35 g (75%) from 10.0 g of dihydro-2H-pyran-4(3H)-one; yel-

lowish liquid.

2-(3-Bromo-2-fluoro-2-methylpropyl)isoindoline-1,3-dione (2d)

The product was purified by recrystallization (hexane–t-BuOMe,

1:1); yield: 3.21 g (43%) from 5.0 g of 1d; yellowish powder; mp 70–

72 °C.

Alkenes 1l, 1n, and 1o; Method B; General Procedure

t-BuOK (6.73 g, 60 mmol) was dissolved in anhydrous THF (100 mL),

and the resulting solution was cooled to 0 °C. Then, Ph₃PMeI (22.2 g,

55 mmol) was added under argon atmosphere, and the reaction mix-

ture was stirred at 0 °C for 30 min. A solution of ketone 6 (50 mmol)

in anhydrous THF (30 mL) was added dropwise maintaining the tem-

perature below 10 °C. The mixture was allowed to react at rt for 2 h

and then evaporated under reduced pressure. The residue was sub-

jected to flash chromatography (hexane–t-BuOMe, 1:1), affording

pure title product.

¹H NMR (500 MHz, CDCl₃):  = 7.99–7.84 (m, 2 H), 7.79–7.65 (m, 2 H),

4.03 (dt, J = 19.6, 3.3 Hz, 2 H), 3.63–3.46 (m, 2 H), 1.54 (dd, J = 19.6, 3.3

Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 167.6, 133.9, 131.4, 123.2, 93.5 (d, J =

180.9 Hz), 43.3 (d, J = 25.7 Hz), 36.3 (d, J = 27.3 Hz), 21.9 (d, J = 23.3

Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –148.9.

Anal. Calcd for C₁₂H₁₁BrFNO₂: C, 48.02; H, 3.69; N, 4.67. Found: C,

48.03; H, 3.97; N, 4.37.

Ethyl 4-Methylenecyclohexanecarboxylate (1l)^17e

anti-(2-Bromo-1-fluoropropyl)benzene (2e)^11f

Yield: 14.5 g (98%) from 15.0 g of ethyl 4-oxocyclohexanecarboxylate;

yellowish oil.

The product was purified by distillation; bp 37 °C/0.1 mmHg; yield:

20.3 g (69%) from 16.0 g of 1e; yellowish liquid.

tert-Butyl 3-Methyleneazetidine-1-carboxylate (1n)^17f

Yield: 11.4 g (96%) from 12.0 g of tert-butyl 3-oxoazetidine-1-carbox-

ylate; yellowish oil.

anti-(1-Bromo-2-fluoroethane-1,2-diyl)dibenzene (2f)

The product was purified by recrystallization (hexane); yield: 3.30 g

(71%) from 3.00 g of 1f; white powder; mp 123–124 °C.

¹H NMR (400 MHz, CDCl₃):  = 7.46–7.19 (m, 10 H), 5.84 (dd, J = 46.0,

6.7 Hz, 1 H), 5.12 (dd, J = 14.8, 6.7 Hz, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 136.8, 136.5 (d, J = 20.5 Hz), 129.2,

128.9, 128.8, 128.4, 128.3, 126.8 (d, J = 6.2 Hz), 95.5 (d, J = 181.7 Hz),

54.6 (d, J = 28.2 Hz).

tert-Butyl 4-Methylenepiperidine-1-carboxylate (1o)^17d

Yield: 11.3 g (95%) from 12.0 g of tert-butyl 4-oxopiperidine-1-car-

boxylate; yellowish oil.

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Synthesis

¹⁹F NMR (376 MHz, CDCl₃):  = –170.1.

Anal. Calcd for C₉H₁₅BrFNO₂: C, 40.32; H, 5.64; N, 5.22. Found: C,

40.41; H, 5.91; N, 5.45.

Anal. Calcd for C₁₄H₁₂BrF: C, 60.24; H, 4.33. Found: C, 60.00; H, 4.63.

tert-Butyl 4-(Bromomethyl)-4-fluoropiperidine-1-carboxylate

2-Bromo-3-fluoro-2,3-dimethylbutane (2g)^11g

(2o)^11c

Yield: 12.4 g (68%) from 8.42 g of 1g; yellowish crystals.

Yield: 15.00 g (99%) from 10.0 g of 1o; yellowish oil.

1-(Bromomethyl)-1-fluorocyclobutane (2h)^11b

4-(Bromomethyl)-4-fluorotetrahydro-2H-pyran (2p)

Yield: 12.7 g (90%) from 7.0 g of 1p; yellowish liquid.

The product was purified by distillation; bp 64 °C/38 mmHg; yield:

13.3 g (68%) from 8.00 g of 1h; yellowish liquid.

¹H NMR (400 MHz, CDCl₃):  = 3.83 (dd, J = 11.4, 3.7 Hz, 2 H), 3.68 (td,

J = 11.4, 3.7 Hz, 2 H), 3.44 (d, J = 18.5 Hz, 2 H), 1.92–1.83 (m, 2 H),

1.83–1.67 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 90.6 (d, J = 178.0 Hz), 63.5, 39.0 (d, J =

26.4 Hz), 34.1 (d, J = 21.4 Hz).

1-(Bromomethyl)-1-fluorocyclopentane (2i)^11b

Yield: 14.9 g (82%) from 8.25 g of 1i; yellowish liquid.

1-(Bromomethyl)-1-fluorocyclohexane (2j)^11b

¹⁹F NMR (470 MHz, CDCl₃):  = –160.9.

The product was purified by distillation; bp 60 °C/7 mmHg; yield:

19.2 g (73%) from 13.00 g of 1j; yellowish liquid.

Anal. Calcd for C₆H₁₀BrFO: C, 36.57; H, 5.12. Found: C, 36.47; H, 5.19.

1-(Bromomethyl)-1-fluorocycloheptane (2k)

trans-1-Bromo-2-fluorocyclobutane (2q)

The crude product was used in the subsequent step without further

The product was purified by distillation; bp 116 °C/760 mmHg; yield:

purification; yield: 7.62 g from 5.00 g of 1k; yellowish liquid.

16.7 g (59%) from 10.0 g of 1q; colorless liquid.

¹H NMR (500 MHz, CDCl₃):  = 4.93 (dq, J = 54.9, 7.6 Hz, 1 H), 4.40–

4.21 (m, 1 H), 2.51–2.38 (m, 2 H), 2.07–1.95 (m, 1 H), 1.85–1.76 (m, 1

H).

Ethyl (1r,4r)-4-(Bromomethyl)-4-fluorocyclohexanecarboxylate

(2l)

The product was purified by column chromatography (hexane–EtOAc,

10:1; R_f= 0.4); yield: 4.77 g (30%) from 10.0 g of 1l; yellow liquid.

¹³C NMR (126 MHz, CDCl₃):  = 92.0 (d, J = 227.2 Hz), 43.1 (d, J = 22.2

Hz), 27.2 (d, J = 19.4 Hz), 22.3 (d, J = 18.7 Hz).

¹H NMR (400 MHz, CDCl₃):  = 4.09 (q, J = 7.1 Hz, 2 H), 3.40 (d, J = 17.3

Hz, 2 H), 2.21 (t, J = 11.9 Hz, 1 H), 2.11–2.00 (m, 2 H), 1.91–1.82 (m, 2

H), 1.82–1.67 (m, 2 H), 1.52 (td, J = 13.8, 4.5 Hz, 1 H), 1.42 (td, J = 13.8,

4.5 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 3 H).

¹⁹F NMR (376 MHz, CDCl₃):  = –162.5.

Anal. Calcd for C₄H₆BrF: C, 31.40; H, 3.95; Br, 52.23. Found: C, 31.65;

H, 3.67; Br, 52.09.

¹³C NMR (126 MHz, CDCl₃):  = 174.8, 92.0 (d, J = 177.2 Hz), 60.4, 42.0,

39.3 (d, J = 27.6 Hz), 32.7 (d, J = 22.5 Hz), 23.9, 14.2.

¹⁹F NMR (376 MHz, CDCl₃):  = –160.2.

trans-1-Bromo-2-fluorocyclopentane (2r)^11e

Yield: 20.1 g (82%) from 10.0 g of 1r; colorless liquid.

Anal. Calcd for C₁₀H₁₆BrFO₂: C, 44.96; H, 6.04. Found: C, 45.34; H, 6.39.

trans-1-Bromo-2-fluorocyclohexane (2s)^11d,e

Yield: 20.1 g (91%) from 10.0 g of 1s; brown oil.

Ethyl (1s,4s)-4-(Bromomethyl)-4-fluorocyclohexanecarboxylate

(2m)

trans-1-Bromo-2-fluorocycloheptane (2t)^11e

Yield: 22.9 g (94%) from 12.0 g of 1t; brown oil.

The product was purified by column chromatography (hexane–EtOAc,

10:1; R_f= 0.2); yield: 5.33 g (35%) from 10.0 g of 1l; yellowish liquid.

¹H NMR (400 MHz, CDCl₃):  = 4.11 (q, J = 7.1 Hz, 2 H), 3.47 (d, J = 20.0

Hz, 2 H), 2.53 (t, J = 5.2 Hz, 1 H), 1.93–1.75 (m, 8 H), 1.22 (t, J = 7.1 Hz,

3 H).

¹³C NMR (101 MHz, CDCl₃):  = 174.6, 92.8 (d, J = 177.2 Hz), 60.4, 39.2,

38.7 (d, J = 26.3 Hz), 31.3 (d, J = 21.9 Hz), 23.7 (d, J = 4.9 Hz), 14.2.

tert-Butyl trans-3-Bromo-4-fluoropyrrolidine-1-carboxylate (2v)

The product was purified by column chromatography (gradient hex-

ane to t-BuOMe); yield: 3.17 g (40%) from 5.0 g of 1v; yellowish oil;

ca. 1:1 mixture of rotamers.

¹H NMR (500 MHz, CDCl₃):  = 5.17 (dd, J = 51.6, 4.0 Hz, 1 H), 4.34 (dd,

¹⁹F NMR (376 MHz, CDCl₃):  = –154.3.

J = 11.6, 4.0 Hz, 1 H), 4.00–3.81 (m, 3 H), 3.77–3.57 (m, 1 H), 1.47 (s, 9

Anal. Calcd for C₁₀H₁₆BrFO₂: C, 44.96; H, 6.04; Br, 29.91. Found: C,

45.01; H, 6.10; Br, 29.79.

H).

¹³C NMR (126 MHz, CDCl₃):  = 153.8, 95.6 (d, J = 184.7 Hz) and 94.8

(d, J = 184.5 Hz), 79.8, 52.5 and 52.1, 49.5 (d, J = 22.0 Hz) and 49.1 (d,

J = 22.4 Hz), 46.3 (d, J = 26.4 Hz) and 45.6 (d, J = 26.9 Hz), 28.0.

tert-Butyl 3-(Bromomethyl)-3-fluoroazetidine-1-carboxylate (2n)

¹⁹F NMR (376 MHz, CDCl₃):  = –165.5.

The product was purified by column chromatography (gradient hex-

ane to t-BuOMe); yield: 6.50 g (41%) from 10.0 g of 1n; yellowish oil.

¹H NMR (500 MHz, CDCl₃):  = 4.08 (dd, J = 20.6, 10.3 Hz, 2 H), 3.98

(dd, J = 16.5, 10.3 Hz, 2 H), 3.66 (d, J = 20.6 Hz, 2 H), 1.43 (s, 9 H).

Anal. Calcd for C₉H₁₅BrFNO₂: C, 40.32; H, 5.64; N, 5.22. Found: C,

40.18; H, 5.56; N, 5.13.

¹³C NMR (126 MHz, CDCl₃):  = 155.5, 89.0 (d, J = 212.2 Hz), 80.0, 58.4

(2 C), 33.7 (d, J = 27.1 Hz), 27.9.

¹⁹F NMR (376 MHz, CDCl₃):  = –152.2.

trans-3-Bromo-4-fluorotetrahydrofuran (2w)

The product was purified by distillation; bp 84 °C/76 mmHg; yield:

11.1 g (46%) from 10.0 g of 1w; colorless liquid.

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R. Gurbanov et al.

Paper

Synthesis

¹H NMR (500 MHz, CDCl₃):  = 5.29 (dd, J = 53.2, 3.5 Hz, 1 H), 4.43–

S-(2-Fluoro-2-methyl-3-(methylsulfonyl)propyl) Ethanethioate

4.34 (m, 2 H), 4.34–4.23 (m, 1 H), 4.14–4.00 (m, 2 H).

(3c)

¹³C NMR (126 MHz, CDCl₃):  = 97.2 (d, J = 185.8 Hz), 73.8, 71.1 (d, J =

22.9 Hz), 47.2 (d, J = 25.9 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –164.7.

The reaction mixture was stirred at 50 °C.

Yield: 0.92 g (25%) from 3.75 g of 2c; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 3.56–3.38 (m, 2 H), 3.29 (ddd, J = 38.1,

21.2, 14.9 Hz, 2 H), 2.99 (s, 3 H), 2.39 (s, 3 H), 1.65 (d, J = 21.2 Hz, 3 H).

Anal. Calcd for C₄H₆BrFO: C, 28.43; H, 3.58. Found: C, 28.31; H, 3.64.

¹³C NMR (126 MHz, CDCl₃):  = 193.3, 93.1 (d, J = 176.1 Hz), 60.6 (d, J =

24.1 Hz), 43.1 (d, J = 6.6 Hz), 39.0 (d, J = 25.8 Hz), 30.0, 23.2 (d, J = 23.6

Hz).

trans-2-Bromo-1-fluoro-1-methylcyclohexane (2x)^11h

The product was purified by distillation; bp 52 °C/20 mmHg; yield:

37.4 g (71%) from 26.0 g of 1x; colorless liquid.

¹⁹F NMR (376 MHz, CDCl₃):  = –143.4.

Anal. Calcd for C₇H₁₃FO₃S₂: C, 36.83; H, 5.74; S, 28.09. Found: C, 36.87;

H, 5.74; S, 28.45.

trans-1-Bromo-2-fluorocyclooctane (2u)^11d

Cyclooctene (1u) (4.30 g, 39 mmol) and Py·HF (7.73 g, 78 mmol) were

dissolved in CH₂Cl₂(80 mL) and the resulting solution was cooled to

–20 °C. Then, DBDMH (11.2 g, 39 mmol) was added portionwise at

–20 °C, and the reaction mixture was allowed to stir at rt overnight.

Then, it was poured onto an ice–water mixture (200 g), and the or-

ganic layer was separated, washed with saturated aq NaHCO₃(3 × 40

mL), dried (Na₂SO₄), and evaporated under reduced pressure, afford-

ing pure 2u as a brown oil; yield: 8.00 g (98%).

S-(3-(1,3-Dioxoisoindolin-2-yl)-2-fluoro-2-methylpropyl) Ethane-

thioate (3d)

The reaction mixture was stirred at 55 °C.

Yield: 3.41 g (95%) from 3.65 g of 2d; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 7.89–7.84 (m, 2 H), 7.77–7.71 (m, 2 H),

4.02–3.82 (m, 2 H), 3.33–3.20 (m, 2 H), 2.38 (s, 3 H), 1.37 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 193.9, 167.7, 133.8, 131.4, 123.1, 94.8

(d, J = 178.8 Hz), 44.0 (d, J = 25.4 Hz), 35.5 (d, J = 24.8 Hz), 30.0, 21.6 (d,

J = 23.6 Hz).

-Fluoro Ethanethioates 3a–f and 3h–w; General Procedure

KSAc (17.1 g, 150 mmol) was added to a solution of fluoro bromide

2a–f,h–w (50 mmol) in anhydrous DMF (150 mL), and the resulting

mixture was stirred at the temperature given below for the prepara-

tion of each ethanethioate for 12 h. Then, it was cooled to rt, poured

onto an ice–water mixture (200 g), and extracted with t-BuOMe (3 ×

100 mL). The combined organic layer was washed with brine (2 × 100

mL), dried (Na₂SO₄), and evaporated under reduced pressure, afford-

ing pure title product, which was used in the subsequent step with-

out further purification (3a–d,h–w), or crude product which was pu-

rified by either distillation (3e) or column chromatography (3f).

¹⁹F NMR (376 MHz, CDCl₃):  = –147.1.

Anal. Calcd for C₁₄H₁₄FNO₃S: C, 56.94; H, 4.78; N, 4.74; S, 10.86.

Found: C, 57.11; H, 5.10; N, 4.52; S, 10.90.

syn-(1-Fluoro-1-phenylpropan-2-yl) Ethanethioate (3e)

The reaction mixture was stirred at 45 °C.

The product was purified by distillation; bp 61 °C/0.5 mmHg; yield:

6.70 g (76%) from 9.0 g of 2e; yellowish oil.

¹H NMR (500 MHz, CDCl₃):  = 7.44–7.31 (m, 5 H), 5.47 (dd, J = 46.3,

6.8 Hz, 1 H), 4.06 (dquint, J = 20.5, 6.8 Hz, 1 H), 2.29 (s, 3 H), 1.32 (dd,

J = 6.8, 2.5 Hz, 3 H).

S-(2-Fluoro-2-phenylethyl) Ethanethioate (3a)

The reaction mixture was stirred at 40 °C.

¹³C NMR (151 MHz, CDCl₃):  = 194.3, 137.3 (d, J = 20.9 Hz), 128.6 (d,

J = 2.5 Hz), 128.2, 126.1 (d, J = 7.4 Hz), 95.3 (d, J = 178.3 Hz), 43.8 (d, J =

24.2 Hz), 30.6, 17.5 (d, J = 2.5 Hz).

Yield: 4.92 g (96%) from 5.25 g of 2a; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 7.44–7.34 (m, 5 H), 5.49 (dd, J = 47.3,

8.3 Hz, 1 H), 3.51–3.39 (m, 1 H), 3.33–3.22 (m, 1 H), 2.37 (s, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.4, 138.0 (d, J = 20.1 Hz), 128.4 (d,

J = 1.8 Hz), 128.2, 125.1 (d, J = 6.7 Hz), 92.2 (d, J = 175.0 Hz), 35.0 (d, J =

26.2 Hz), 30.1.

¹⁹F NMR (376 MHz, CDCl₃):  = –178.1.

Anal. Calcd for C₁₁H₁₃FOS: C, 62.24; H, 6.17; S, 15.10. Found: C, 62.49;

H, 6.52; S, 15.32.

¹⁹F NMR (376 MHz, CDCl₃):  = –175.1.

syn-(2-Fluoro-1,2-diphenylethyl) Ethanethioate (3f)

Anal. Calcd for C₁₀H₁₁FOS: C, 60.58; H, 5.59; S, 16.17. Found: C, 60.50;

H, 5.58; S, 16.49.

The reaction mixture was stirred at 45 °C.

The product was purified by column chromatography [gradient hex-

ane (100) to EtOAc (30:70)]; yield: 2.30 g (78%) from 3.00 g of 2f; yel-

low oil.

S-(2-Fluoro-3-methoxy-2-methylpropyl) Ethanethioate (3b)

The reaction mixture was stirred at 50 °C.

¹H NMR (400 MHz, CDCl₃):  = 7.36–7.11 (m, 10 H), 5.74 (dd, J = 46.2,

5.7 Hz, 1 H), 5.07 (dd, J = 21.0, 5.7 Hz, 1 H), 2.27 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 193.2, 138.2, 137.2 (d, J = 20.9 Hz),

128.8, 128.6, 128.5, 128.1, 127.8, 126.1 (d, J = 7.0 Hz), 95.0 (d, J = 181.7

Hz), 53.4 (d, J = 23.1 Hz), 30.4.

Yield: 8.24 g (79%) from 5.0 g of 1b; brown liquid.

¹H NMR (400 MHz, CDCl₃):  = 3.42 (d, J = 20.0 Hz, 2 H), 3.37 (s, 3 H),

3.29–3.13 (m, 2 H), 2.34 (s, 3 H), 1.32 (d, J = 20.0 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 194.5, 95.4 (d, J = 174.4 Hz), 76.4, 59.6,

34.6 (d, J = 25.3 Hz), 30.4, 21.0 (d, J = 23.5 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –150.5.

¹⁹F NMR (376 MHz, CDCl₃):  = –176.7.

Anal. Calcd for C₁₆H₁₅FOS: C, 70.05; H, 5.51; S, 11.69. Found: C, 69.93;

H, 5.64; S, 11.64.

Anal. Calcd for C₇H₁₃FO₂S: C, 46.65; H, 7.27; S, 17.79. Found: C, 46.83;

H, 7.63; S, 18.09.

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Paper

Synthesis

S-((1-Fluorocyclobutyl)methyl) Ethanethioate (3h)

The reaction mixture was stirred at 30 °C.

¹H NMR (500 MHz, CDCl₃):  = 4.11 (q, J = 7.1 Hz, 2 H), 3.15 (d, J = 19.6

Hz, 2 H), 2.36 (s, 3 H), 2.23 (tt, J = 12.0, 3.5 Hz, 1 H), 2.03–1.95 (m, 2

H), 1.86 (d, J = 13.6 Hz, 2 H), 1.75 (qd, J = 13.6, 3.5 Hz, 2 H), 1.46 (td, J =

13.6, 4.6 Hz, 1 H), 1.38 (td, J = 13.6, 4.6 Hz, 1 H), 1.23 (t, J = 7.1 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.7, 175.0, 93.3 (d, J = 174.9 Hz),

60.3, 42.0, 38.2 (d, J = 24.6 Hz), 33.1 (d, J = 22.3 Hz), 30.4, 23.9, 14.2.

Yield: 4.27 g (88%) from 5.00 g of 2h; brown liquid.

¹H NMR (400 MHz, CDCl₃):  = 3.29 (d, J = 24.3 Hz, 2 H), 2.34 (s, 3 H),

2.33–2.20 (m, 2 H), 2.12–2.00 (m, 2 H), 1.85–1.73 (m, 1 H), 1.60–1.49

(m, 1 H).

¹³C NMR (101 MHz, CDCl₃):  = 195.2, 95.2 (d, J = 214.9 Hz), 35.6 (d, J =

23.9 Hz), 33.0 (d, J = 21.2 Hz), 30.5, 11.2 (d, J = 13.4 Hz).

¹⁹F NMR (470 MHz, CDCl₃):  = –157.5.

Anal. Calcd for C₁₂H₁₉FO₃S: C, 54.94; H, 7.30; S, 12.22. Found: C, 54.90;

H, 6.95; S, 12.08.

¹⁹F NMR (376 MHz, CDCl₃):  = –128.1.

Anal. Calcd for C₇H₁₁FOS: C, 51.83; H, 6.84; S, 19.76. Found: C, 52.07;

H, 7.14; S, 19.56.

Ethyl (1s,4s)-4-((Acetylthio)methyl)-4-fluorocyclohexanecarbox-

ylate (3m)

The reaction mixture was stirred at 50 °C.

S-((1-Fluorocyclopentyl)methyl) Ethanethioate (3i)

The reaction mixture was stirred at 40 °C.

Yield: 2.05 g (97%) from 2.15 g of 2m; brown oil.

¹H NMR (400 MHz, CDCl₃):  = 4.06 (qt, J = 7.2, 1.8 Hz, 2 H), 3.13 (d, J =

21.2 Hz, 2 H), 2.45 (t, J = 5.2 Hz, 1 H), 2.28 (s, 3 H), 1.79 (q, J = 5.2 Hz, 4

H), 1.72–1.60 (m, 4 H), 1.17 (tt, J = 7.2, 1.8 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 194.5, 174.4, 94.2 (d, J = 174.2 Hz),

60.3, 39.2, 37.1 (d, J = 24.2 Hz), 31.8 (d, J = 21.9 Hz), 30.4, 23.6 (d, J =

5.1 Hz), 14.2.

Yield: 12.3 g (87%) from 14.5 g of 2i; brown liquid.

¹H NMR (500 MHz, CDCl₃):  = 3.30 (d, J = 20.6 Hz, 2 H), 2.36 (s, 3 H),

2.03–1.88 (m, 2 H), 1.88–1.75 (m, 2 H), 1.74–1.55 (m, 4 H).

¹³C NMR (126 MHz, CDCl₃):  = 195.0, 105.3 (d, J = 176.3 Hz), 37.1 (d,

J = 23.3 Hz), 36.4 (d, J = 26.6 Hz), 30.4, 24.0.

¹⁹F NMR (470 MHz, CDCl₃):  = –138.6.

¹⁹F NMR (376 MHz, CDCl₃):  = –151.3.

Anal. Calcd for C₈H₁₃FOS: C, 54.52; H, 7.43; S, 18.19. Found: C, 54.58;

H, 7.71; S, 17.99.

Anal. Calcd for C₁₂H₁₉FO₃S: C, 54.94; H, 7.30; S, 12.22. Found: C, 54.75;

H, 7.03; S, 12.26.

S-((1-Fluorocyclohexyl)methyl) Ethanethioate (3j)

The reaction mixture was stirred at 50 °C.

tert-Butyl3-((Acetylthio)methyl)-3-fluoroazetidine-1-carboxylate

(3n)

The reaction mixture was stirred at 40 °C.

Yield: 4.61 g (90%) from 5.25 g of 2j; brown liquid.

¹H NMR (500 MHz, CDCl₃):  = 3.17 (d, J = 20.4 Hz, 2 H), 2.36 (s, 3 H),

1.90–1.80 (m, 2 H), 1.64–1.52 (m, 5 H), 1.50–1.37 (m, 2 H), 1.28–1.18

(m, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.6, 94.2 (d, J = 173.7 Hz), 37.8 (d, J =

24.5 Hz), 33.9 (d, J = 21.8 Hz), 30.1, 24.6, 21.4 (d, J = 2.8 Hz).

Yield: 2.47 g (72%) from 3.50 g of 2n; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 4.03 (dd, J = 19.4, 10.5 Hz, 2 H), 3.88

(dd, J = 19.4, 10.5 Hz, 2 H), 3.40 (d, J = 19.4 Hz, 2 H), 2.39 (s, 3 H), 1.43

(s, 9 H).

¹³C NMR (126 MHz, CDCl₃):  = 193.6, 155.6, 90.2 (d, J = 209.1 Hz),

79.8, 58.8 (2 C), 33.5 (d, J = 25.4 Hz), 30.1, 27.9.

¹⁹F NMR (470 MHz, CDCl₃):  = –153.4.

¹⁹F NMR (376 MHz, CDCl₃):  = –147.8.

Anal. Calcd for C₉H₁₅FOS: C, 56.81; H, 7.95; S, 16.85. Found: C, 57.13;

H, 7.95; S, 16.78.

Anal. Calcd for C₁₁H₁₈FNO₃S: C, 50.17; H, 6.89; N, 5.32; S, 12.17.

Found: C, 49.88; H, 6.63; N, 4.95; S, 11.91.

S-((1-Fluorocycloheptyl)methyl) Ethanethioate (3k)

The reaction mixture was stirred at 50 °C.

tert-Butyl 4-((Acetylthio)methyl)-4-fluoropiperidine-1-carboxyl-

ate (3o)

Yield: 6.55 g (71%) from 5.0 g of 1k; brown oil.

The reaction mixture was stirred at 45 °C.

¹H NMR (500 MHz, CDCl₃):  = 3.20 (d, J = 20.6 Hz, 2 H), 2.37 (s, 3 H),

2.00–1.91 (m, 2 H), 1.78–1.59 (m, 6 H), 1.55–1.48 (m, 2 H), 1.46–1.38

(m, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.7, 98.4 (d, J = 172.7 Hz), 38.8 (d, J =

24.9 Hz), 37.6 (d, J = 23.5 Hz), 30.1, 29.1, 21.7 (d, J = 5.5 Hz).

Yield: 14.7 g (99%) from 15.0 g of 2o; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 4.03–3.75 (m, 2 H), 3.14 (d, J = 19.9 Hz,

2 H), 2.98 (t, J = 13.1 Hz, 2 H), 2.33 (s, 3 H), 1.81 (t, J = 10.9 Hz, 2 H),

1.62–1.48 (m, 2 H), 1.41 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.0, 154.1, 92.6 (d, J = 174.9 Hz),

79.3, 39.0 (2 C), 37.8 (d, J = 24.2 Hz), 33.3 (d, J = 21.4 Hz), 30.0, 28.0.

¹⁹F NMR (376 MHz, CDCl₃):  = –159.9.

¹⁹F NMR (376 MHz, CDCl₃):  = –152.5.

Anal. Calcd for C₁₀H₁₇FOS: C, 58.79; H, 8.39; S, 15.69. Found: C, 58.65;

H, 8.25; S, 15.83.

Anal. Calcd for C₁₃H₂₂FNO₃S: C, 53.59; H, 7.61; N, 4.81; S, 11.00.

Found: C, 53.58; H, 7.78; N, 4.52; S, 11.33.

Ethyl (1r,4r)-4-((Acetylthio)methyl)-4-fluorocyclohexanecarbox-

ylate (3l)

The reaction mixture was stirred at 50 °C.

S-((4-Fluorotetrahydro-2H-pyran-4-yl)methyl) Ethanethioate (3p)

The reaction mixture was stirred at 50 °C.

Yield: 1.19 g (93%) from 1.30 g of 2l; brown oil.

Yield: 5.12 g (70%) from 7.50 g of 2p; brown oil.

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¹H NMR (500 MHz, CDCl₃):  = 3.84–3.76 (m, 2 H), 3.67 (td, J = 11.5,

2.6 Hz, 2 H), 3.19 (d, J = 20.2 Hz, 2 H), 2.37 (s, 3 H), 1.82–1.75 (m, 3 H),

1.70 (td, J = 13.0, 5.3 Hz, 1 H).

¹H NMR (500 MHz, CDCl₃):  = 4.67 (dtt, J = 45.7, 8.1, 3.7 Hz, 1 H), 3.69

(tt, J = 8.1, 4.4 Hz, 1 H), 2.28 (s, 3 H), 2.19–2.11 (m, 1 H), 2.05–1.94 (m,

2 H), 1.91–1.75 (m, 4 H), 1.67–1.52 (m, 4 H), 1.47–1.40 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.2, 91.7 (d, J = 175.0 Hz), 63.1, 37.5

(d, J = 24.2 Hz), 34.0 (d, J = 21.4 Hz), 30.1.

¹⁹F NMR (376 MHz, CDCl₃):  = –158.0.

¹³C NMR (126 MHz, CDCl₃):  = 194.9, 144.2, 93.3 (d, J = 165.2 Hz),

43.4, 31.0 (d, J = 22.3 Hz), 30.4, 30.2 (d, J = 4.8 Hz), 27.0 (d, J = 9.1 Hz),

24.5, 21.8 (d, J = 10.0 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –161.2.

Anal. Calcd for C₈H₁₃FO₂S: C, 49.98; H, 6.82; S, 16.68. Found: C, 49.87;

H, 7.21; S, 16.28.

Anal. Calcd for C₁₀H₁₇FOS: C, 58.79; H, 8.39; S, 15.69. Found: C, 58.77;

H, 8.16; S, 15.54.

S-(cis-2-Fluorocyclobutyl) Ethanethioate (3q)

tert-Butyl cis-3-(Acetylthio)-4-fluoropyrrolidine-1-carboxylate

(3v)

The reaction mixture was stirred at 70 °C.

The crude product was used in the subsequent step without further

purification; yield: 15.5 g from 16.7 g of 2q; brown liquid.

The reaction mixture was stirred at 70 °C.

Yield: 1.04 g (64%) from 1.65 g of 2v; brown oil; ca. 1:0.9 mixture of

rotamers.

S-(cis-2-Fluorocyclopentyl) Ethanethioate (3r)

The reaction mixture was stirred at 70 °C.

¹H NMR (500 MHz, CDCl₃):  = 5.08 (dd, J = 53.0, 4.0 Hz, 1 H), 4.00 (d, J

= 33.0 Hz, 1 H), 3.92–3.66 (m, 2 H), 3.61 (d, J = 39.9 Hz, 1 H), 3.27 (q, J

= 10.4 Hz, 1 H), 2.37 (s, 3 H), 1.45 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃):  = 193.9, 153.5 and 153.4, 92.3 (d, J =

180.4 Hz) and 91.8 (d, J = 181.1 Hz), 79.7, 51.9 (d, J = 23.0 Hz) and 51.4

(d, J = 23.0 Hz), 47.7 and 47.0, 43.6 (d, J = 18.5 Hz) and 43.1 (d, J = 18.5

Hz), 30.1, 28.0.

Yield: 7.96 g (82%) from 10.0 g of 2r; brown liquid.

¹H NMR (500 MHz, CDCl₃):  = 5.00 (dt, J = 54.1, 3.7 Hz, 1 H), 3.78–

3.41 (m, 1 H), 2.34 (s, 3 H), 2.14–1.88 (m, 4 H), 1.73 (d, J = 10.8 Hz, 2

H).

¹³C NMR (126 MHz, CDCl₃):  = 195.2, 144.2, 95.5 (d, J = 176.5 Hz),

46.2 (d, J = 18.3 Hz), 31.5 (d, J = 21.8 Hz), 28.7, 21.2.

¹⁹F NMR (376 MHz, CDCl₃):  = –180.5.

¹⁹F NMR (376 MHz, CDCl₃):  = –184.4.

Anal. Calcd for C₁₁H₁₈FNO₃S: C, 50.17; H, 6.89; N, 5.32; S, 12.17.

Found: C, 49.84; H, 7.04; N, 5.32; S, 12.18.

Anal. Calcd for C₇H₁₁FOS: C, 51.83; H, 6.84; S, 19.76. Found: C, 51.52;

H, 6.59; S, 19.38.

S-(cis-4-Fluorotetrahydrofuran-3-yl) Ethanethioate (3w)

The reaction mixture was stirred at 65 °C.

S-(cis-2-Fluorocyclohexyl) Ethanethioate (3s)

The reaction mixture was stirred at 75 °C.

Yield: 2.87 g (82%) from 3.60 g of 2w; brown liquid.

Yield: 8.96 g (92%) from 10.0 g of 2s; brown liquid.

¹H NMR (500 MHz, CDCl₃):  = 5.15 (dt, J = 45.7, 8.1 Hz, 1 H), 4.17 (t,

J = 8.1 Hz, 1 H), 4.10 (d, J = 3.1 Hz, 1 H), 4.07–4.02 (m, 1 H), 3.96 (s, 1

H), 3.64 (ddt, J = 10.6, 8.1, 3.1 Hz, 1 H), 2.36 (s, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 194.4, 92.8 (d, J = 181.8 Hz), 73.3 (d, J =

23.6 Hz), 69.8, 44.7 (d, J = 17.4 Hz), 30.4.

¹H NMR (500 MHz, CDCl₃):  = 4.74 (ddd, J = 48.7, 4.6, 2.3 Hz, 1 H),

3.66 (ddt, J = 29.6, 10.2, 2.3 Hz, 1 H), 2.33 (s, 3 H), 2.08–1.98 (m, 1 H),

1.81–1.69 (m, 3 H), 1.68–1.54 (m, 2 H), 1.53–1.39 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.8, 90.5 (d, J = 173.3 Hz), 45.1 (d, J =

18.9 Hz), 30.6 (d, J = 21.0 Hz), 30.2, 27.4, 24.9, 19.1.

¹⁹F NMR (376 MHz, CDCl₃):  = –182.6.

¹⁹F NMR (376 MHz, CDCl₃):  = –190.0.

Anal. Calcd for C₆H₉FO₂S: C, 43.89; H, 5.53; S, 19.53. Found: C, 44.06;

H, 5.71; S, 19.17.

Anal. Calcd for C₈H₁₃FOS: C, 54.52; H, 7.43; S, 18.19. Found: C, 54.90;

H, 7.39; S, 18.32.

-Fluoro Sulfonyl Chlorides 4a–e and 4h–w; General Procedure

S-(cis-2-Fluorocycloheptyl) Ethanethioate (3t)

The reaction mixture was stirred at 85 °C.

Yield: 20.3 g (97%) from 21.5 g of 2t; brown oil.

¹H NMR (500 MHz, CDCl₃):  = 4.83 (ddd, J = 47.5, 6.6, 2.3 Hz, 1 H),

3.81 (ddt, J = 29.6, 10.2, 2.3 Hz, 1 H), 2.33 (s, 3 H), 2.00–1.84 (m, 3 H),

1.79–1.68 (m, 3 H), 1.64–1.56 (m, 3 H), 1.53–1.47 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 194.9, 94.1 (d, J = 173.9 Hz), 47.8 (d, J =

19.9 Hz), 32.4 (d, J = 21.6 Hz), 30.2, 28.3 (d, J = 4.7 Hz), 26.5, 25.8, 20.6

(d, J = 7.1 Hz).

A solution of fluoro ethanethioate 3a–e,h–w (50 mmol) in MeCN (45

mL) was added dropwise to a cold (0 °C) stirred solution of NCS (20.0

g, 150 mmol) and concd HCl (7.5 mL, 75 mmol) in MeCN (150 mL),

maintaining the temperature below 5 °C. After the addition was fin-

ished and no more exothermic reaction was observed, the solution

was stirred at rt for an additional 1 h. The resulting mixture was dilut-

ed with water (200 mL) and extracted with CH₂Cl₂(3 × 100 mL). The

combined organic layer was washed with brine (2 × 100 mL), dried

(Na₂SO₄), and evaporated under reduced pressure, affording pure

product 4a–e,h,i,k–m,o–s,w, or crude product 4j,n,t–v which was pu-

rified by column chromatography.

¹⁹F NMR (376 MHz, CDCl₃):  = –180.7.

Anal. Calcd for C₉H₁₅FOS: C, 56.81; H, 7.95; S, 16.85. Found: C, 56.86;

H, 7.89; S, 16.99.

2-Fluoro-2-phenylethanesulfonyl Chloride (4a)

Yield: 4.12 g (78%) from 4.70 g of 3a; yellow liquid.

S-(cis-2-Fluorocyclooctyl) Ethanethioate (3u)

The reaction mixture was stirred at 90 °C.

Yield: 4.14 g (53%) from 8.0 g of 2u; brown oil.

¹H NMR (400 MHz, CDCl₃):  = 7.58–7.42 (m, 3 H), 7.42–7.30 (m, 2 H),

6.13 (ddd, J = 47.3, 9.3, 2.3 Hz, 1 H), 4.42–4.28 (m, 1 H), 3.99 (ddd, J =

28.9, 14.9, 2.3 Hz, 1 H).

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Synthesis

¹³C NMR (126 MHz, CDCl₃):  = 135.4 (d, J = 20.1 Hz), 130.1 (d, J = 1.9

Hz), 129.3, 125.6 (d, J = 6.4 Hz), 88.1 (d, J = 182.1 Hz), 70.4 (d, J = 27.1

Hz).

¹³C NMR (151 MHz, CDCl₃):  = 134.6 (d, J = 20.4 Hz), 130.2 (d, J = 2.5

Hz), 129.1, 126.9 (d, J = 5.8 Hz), 92.2 (d, J = 183.2 Hz), 75.0 (d, J = 24.6

Hz), 13.1 (d, J = 2.5 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –175.6.

¹⁹F NMR (376 MHz, CDCl₃):  = –167.9.

MS (APCI): m/z = 203 [M – H]^–(for the corresponding sulfonic acid).

MS (APCI): m/z = 217 [M – H]^–(for the corresponding sulfonic acid).

Anal. Calcd for C₈H₈ClFO₂S: C, 43.15; H, 3.62; S, 14.40. Found: C,

43.49; H, 3.23; S, 14.57.

Anal. Calcd for C₉H₁₀ClFO₂S: C, 45.67; H, 4.26; S, 13.55. Found: C,

45.49; H, 4.37; S, 13.62.

2-Fluoro-3-methoxy-2-methylpropane-1-sulfonyl Chloride (4b)

(1-Fluorocyclobutyl)methanesulfonyl Chloride (4h)

Yield: 7.73 g (83%) from 8.20 g of 3b; yellow liquid.

Yield: 4.45 g (90%) from 4.30 g of 3h; colorless oil.

¹H NMR (400 MHz, CDCl₃):  = 4.26–4.11 (m, 2 H), 3.61 (dd, J = 12.4,

10.5 Hz, 1 H), 3.50 (dd, J = 21.7, 10.5 Hz, 1 H), 3.41 (s, 3 H), 1.63 (d, J =

21.7 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃):  = 93.1 (d, J = 180.5 Hz), 76.0 (d, J = 25.4

Hz), 69.8 (d, J = 26.6 Hz), 59.6, 21.9 (d, J = 22.7 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –149.8.

MS (APCI): m/z = 185 [M – H]^–(for the corresponding sulfonic acid).

¹H NMR (400 MHz, CDCl₃):  = 4.16 (d, J = 19.7 Hz, 2 H), 2.60–2.40 (m,

4 H), 2.07–1.92 (m, 1 H), 1.75–1.62 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃):  = 93.3 (d, J = 218.6 Hz), 70.7 (d, J = 24.5

Hz), 33.4 (d, J = 21.5 Hz), 12.0 (d, J = 10.5 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –134.6.

MS (EI): m/z = 131 [M – HF – Cl]⁺, 67 [M – SO₂Cl – HF]⁺.

Anal. Calcd for C₅H₈ClFO₂S: C, 32.18; H, 4.32; S, 17.18. Found: C,

32.12; H, 4.15; S, 17.36.

Anal. Calcd for C₅H₁₀ClFO₃S: C, 29.35; H, 4.93; S, 15.67. Found: C,

29.64; H, 4.88; S, 15.33.

(1-Fluorocyclopentyl)methanesulfonyl Chloride (4i)

2-Fluoro-2-methyl-3-(methylsulfonyl)propane-1-sulfonyl Chlo-

ride (4c)

Yield: 11.0 g (79%) from 12.2 g of 3i; yellow liquid.

¹H NMR (400 MHz, CDCl₃):  = 4.18 (d, J = 17.9 Hz, 2 H), 2.30–2.17 (m,

2 H), 1.93–1.72 (m, 6 H).

¹³C NMR (151 MHz, CDCl₃):  = 101.6 (d, J = 183.3 Hz), 72.3 (d, J = 26.2

Hz), 37.7 (d, J = 23.0 Hz), 23.3.

¹⁹F NMR (376 MHz, CDCl₃):  = –142.8.

MS (APCI): m/z = 181 [M – H]^–(for the corresponding sulfonic acid).

Yield: 0.76 g (76%) from 0.90 g of 3c; yellow crystals; mp 60–62 °C.

¹H NMR (400 MHz, CDCl₃):  = 4.59–4.45 (m, 2 H), 3.77–3.55 (m, 2 H),

3.04 (s, 3 H), 1.87 (d, J = 22.8 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 90.96 (d, J = 182.2 Hz), 70.37 (d, J =

25.6 Hz), 60.31 (d, J = 24.0 Hz), 43.97 (d, J = 5.3 Hz), 25.72 (d, J = 23.2

Hz).

Anal. Calcd for C₆H₁₀ClFO₂S: C, 35.92; H, 5.02; S, 15.98. Found: C,

35.99; H, 4.82; S, 15.67.

¹⁹F NMR (376 MHz, CDCl₃):  = –139.5.

MS (EI): m/z = 133 [M – SO₂Cl – HF]⁺.

Anal. Calcd for C₅H₁₀ClFO₄S₂: C, 23.77; H, 3.99; S, 25.37. Found: C,

23.77; H, 3.87; S, 25.24.

(1-Fluorocyclohexyl)methanesulfonyl Chloride (4j)

The product was purified by column chromatography (gradient hex-

ane to EtOAc); yield: 4.82 g (95%) from 4.50 g of 3j; yellow oil.

¹H NMR (400 MHz, CDCl₃):  = 4.03 (d, J = 16.6 Hz, 2 H), 2.16–2.02 (m,

2 H), 1.72–1.45 (m, 7 H), 1.34–1.19 (m, 1 H).

¹³C NMR (101 MHz, CDCl₃):  = 93.2 (d, J = 181.9 Hz), 73.9 (d, J = 25.9

Hz), 34.9 (d, J = 22.0 Hz), 24.4, 21.5 (d, J = 2.9 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –153.7.

MS (APCI): m/z = 195 [M – H]^–, 175 [M – HF – H]^–(for the correspond-

3-(1,3-Dioxoisoindolin-2-yl)-2-fluoro-2-methylpropane-1-sulfo-

nyl Chloride (4d)

Yield: 3.19 g (92%) from 3.20 g of 3d; white crystals; mp 161–163 °C.

¹H NMR (400 MHz, CDCl₃):  = 7.89 (dd, J = 5.5, 3.1 Hz, 2 H), 7.77 (dd,

J = 5.5, 3.1 Hz, 2 H), 4.28–4.13 (m, 2 H), 4.11–3.95 (m, 2 H), 1.76 (d, J =

21.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 168.0, 134.6, 131.6, 123.9, 92.9 (d, J =

185.5 Hz), 71.4 (d, J = 25.1 Hz), 45.3 (d, J = 26.9 Hz), 22.4 (d, J = 23.2

Hz).

ing sulfonic acid).

Anal. Calcd for C₇H₁₂ClFO₂S: C, 39.16; H, 5.63; S, 14.93. Found: C,

39.23; H, 5.59; S, 14.72.

¹⁹F NMR (376 MHz, CDCl₃):  = –147.5.

MS (APCI): m/z = 280 [M – HF – H]^–(for the corresponding sulfonic

acid).

(1-Fluorocycloheptyl)methanesulfonyl Chloride (4k)

Yield: 3.40 g (80%) from 3.80 g of 3k; yellow liquid.

Anal. Calcd for C₁₂H₁₁ClFNO₄S: C, 45.08; H, 3.47; N, 4.38; S, 10.03.

Found: C, 44.96; H, 3.42; N, 4.77; S, 10.34.

¹H NMR (400 MHz, CDCl₃):  = 4.07 (d, J = 15.9 Hz, 2 H), 2.25–2.12 (m,

2 H), 2.00 (ddd, J = 25.4, 15.9, 10.0 Hz, 2 H), 1.81–1.62 (m, 4 H), 1.60–

1.41 (m, 4 H).

¹³C NMR (126 MHz, CDCl₃):  = 97.3 (d, J = 180.5 Hz), 74.6 (d, J = 26.6

Hz), 38.4 (d, J = 23.2 Hz), 29.1, 21.7 (d, J = 5.3 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –138.5.

MS (APCI): m/z = 209 [M – H]^–(for the corresponding sulfonic acid).

syn-1-Fluoro-1-phenylpropane-2-sulfonyl Chloride (4e)

Yield: 552 mg (91%) from 540 mg of 3e; yellow crystals; mp 42–43 °C.

¹H NMR (500 MHz, CDCl₃):  = 7.52–7.41 (m, 3 H), 7.41–7.32 (m, 2 H),

5.79 (dd, J = 46.2, 7.3 Hz, 1 H), 4.19 (dquint, J = 9.6, 7.3 Hz, 1 H), 1.36

(d, J = 7.3 Hz, 3 H).

Anal. Calcd for C₈H₁₄ClFO₂S: C, 42.01; H, 6.17; S, 14.02. Found: C,

42.02; H, 5.81; S, 13.64.

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Synthesis

Ethyl (1r,4r)-4-((Chlorosulfonyl)methyl)-4-fluorocyclohexanecar-

(4-Fluorotetrahydro-2H-pyran-4-yl)methanesulfonyl Chloride

boxylate (4l)

(4p)

Yield: 1.05 g (77%) from 1.25 g of 3l; yellow crystals; mp 54–55 °C.

Yield: 3.95 g (73%) from 4.80 g of 3p; yellow crystals; mp 72–73 °C.

¹H NMR (400 MHz, CDCl₃):  = 4.12 (q, J = 7.1 Hz, 2 H), 4.03 (d, J = 15.9

Hz, 2 H), 2.33–2.20 (m, 3 H), 1.99–1.90 (m, 2 H), 1.84 (qd, J = 12.5, 3.0

Hz, 2 H), 1.71 (td, J = 13.6, 4.5 Hz, 1 H), 1.61 (td, J = 13.6, 4.5 Hz, 1 H),

1.24 (t, J = 7.1 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃):  = 174.4, 91.9 (d, J = 182.4 Hz), 73.8 (d, J =

26.2 Hz), 60.6, 41.3, 33.8 (d, J = 22.3 Hz), 23.5, 14.2.

¹H NMR (400 MHz, CDCl₃):  = 4.05 (d, J = 17.9 Hz, 2 H), 3.86 (dd, J =

11.5, 5.0 Hz, 2 H), 3.75 (t, J = 11.5 Hz, 2 H), 2.12–1.98 (m, 3 H), 1.93

(ddt, J = 17.9, 13.8, 5.0 Hz, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 90.6 (d, J = 182.8 Hz), 73.5 (d, J = 24.9

Hz), 62.9, 34.9 (d, J = 21.4 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –158.8.

MS (APCI): m/z = 197 [M – H]^–, 177 [M – HF – H]^–(for the correspond-

¹⁹F NMR (376 MHz, CDCl₃):  = –156.7.

MS (APCI): m/z = 167 [M – SO₂Cl – HF]⁺.

ing sulfonic acid).

Anal. Calcd for C₁₀H₁₆ClFO₄S: C, 41.89; H, 5.62; S, 11.18. Found: C,

42.20; H, 5.29; S, 11.36.

Anal. Calcd for C₆H₁₀ClFO₃S: C, 33.26; H, 4.65; S, 14.80. Found: C,

33.53; H, 4.62; S, 14.91.

Ethyl (1s,4s)-4-((Chlorosulfonyl)methyl)-4-fluorocyclohexanecar-

boxylate (4m)

cis-2-Fluorocyclobutane-1-sulfonyl Chloride (4q)

Yield: 17.3 g (92%) from 16.7 g of 2q; yellowish oil.

Yield: 1.07 g (89%) from 1.10 g of 3m; yellow oil.

¹H NMR (400 MHz, CDCl₃):  = 5.35 (dq, J = 52.2, 7.1 Hz, 1 H), 4.70–

4.47 (m, 1 H), 2.93–2.76 (m, 1 H), 2.75–2.62 (m, 1 H), 2.62–2.44 (m, 1

H), 2.40–2.21 (m, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 84.6 (d, J = 227.7 Hz), 72.9 (d, J = 19.0

Hz), 28.9 (d, J = 22.1 Hz), 18.3 (d, J = 9.0 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –175.8.

MS (APCI): m/z = 117 [M – HCl – F]⁺.

¹H NMR (400 MHz, CDCl₃):  = 4.13 (q, J = 7.1 Hz, 2 H), 4.05 (d, J = 17.8

Hz, 2 H), 2.60 (t, J = 4.8 Hz, 1 H), 2.05–1.86 (m, 8 H), 1.25 (t, J = 7.1 Hz,

3 H).

¹³C NMR (126 MHz, CDCl₃):  = 174.2, 92.9 (d, J = 182.3 Hz), 72.9 (d, J =

25.1 Hz), 60.6, 38.4, 32.1 (d, J = 21.8 Hz), 23.2 (d, J = 4.2 Hz), 14.2.

¹⁹F NMR (376 MHz, CDCl₃):  = –153.7.

MS (APCI): m/z = 267 [M – H]^–(for the corresponding sulfonic acid).

Anal. Calcd for C₄H₆ClFO₂S: C, 27.84; H, 3.50; S, 18.57. Found: C,

27.77; H, 3.81; S, 18.20.

Anal. Calcd for C₁₀H₁₆ClFO₄S: C, 41.89; H, 5.62; S, 11.18. Found: C,

42.13; H, 5.51; S, 11.34.

cis-2-Fluorocyclopentane-1-sulfonyl Chloride (4r)

Yield: 42.4 g (97%) from 38.0 g of 3r; yellowish oil.

¹H NMR (400 MHz, CDCl₃):  = 5.47 (dt, J = 52.5, 3.8 Hz, 1 H), 4.08 (dtd,

J = 27.2, 9.4, 3.8 Hz, 1 H), 2.64–2.48 (m, 1 H), 2.44–2.31 (m, 1 H), 2.29–

2.12 (m, 2 H), 2.04–1.81 (m, 2 H).

¹³C NMR (101 MHz, CDCl₃):  = 93.3 (d, J = 185.4 Hz), 78.1 (d, J = 17.7

Hz), 32.4 (d, J = 21.4 Hz), 25.7, 21.4.

¹⁹F NMR (376 MHz, CDCl₃):  = –186.7.

tert-Butyl 3-((Chlorosulfonyl)methyl)-3-fluoroazetidine-1-car-

boxylate (4n)

The product was purified by column chromatography (hexane–t-BuOMe,

1:1; R_f= 0.3); yield: 0.33 g (13%) from 2.30 g of 3n; yellow oil.

¹H NMR (400 MHz, CDCl₃):  = 4.28 (d, J = 19.2 Hz, 2 H), 4.29–4.15 (m,

4 H), 1.43 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃):  = 155.7, 87.6 (d, J = 215.4 Hz), 81.0, 68.9

(d, J = 24.5 Hz), 59.6, 59.4, 28.3.

MS (EI): m/z = 87 [M – SO₂Cl]⁺, 67 [M – SO₂Cl – HF]⁺.

¹⁹F NMR (376 MHz, CDCl₃):  = –151.9.

MS (APCI): m/z = 170 [M – C₄H₈– CO₂+ H]⁺(for the corresponding

Anal. Calcd for C₅H₈ClFO₂S: C, 32.18; H, 4.32; S, 17.18. Found: C,

32.53; H, 4.08; S, 17.58.

sulfonic acid).

Anal. Calcd for C₉H₁₅ClFNO₄S: C, 37.57; H, 5.25; N, 4.87; S, 11.14.

Found: C, 37.60; H, 5.38; N, 4.48; S, 10.76.

cis-2-Fluorocyclohexane-1-sulfonyl Chloride (4s)

Yield: 6.38 g (63%) from 8.90 g of 3s; yellow crystals; mp 44–48 °C.

¹H NMR (400 MHz, CDCl₃):  = 5.44 (dd, J = 49.5, 3.9 Hz, 1 H), 3.63

(ddd, J = 29.6, 12.7, 4.2 Hz, 1 H), 2.39–2.30 (m, 1 H), 2.30–2.15 (m, 2

H), 2.08–1.98 (m, 1 H), 1.73–1.58 (m, 2 H), 1.58–1.34 (m, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 85.5 (d, J = 180.4 Hz), 77.3 (d, J = 10.2

Hz), 30.9 (d, J = 21.0 Hz), 24.4, 22.4, 18.6.

¹⁹F NMR (376 MHz, CDCl₃):  = –134.6.

MS (EI): m/z = 101 [M – SO₂Cl]⁺, 81 [M – SO₂Cl – HF]⁺.

tert-Butyl 4-((Chlorosulfonyl)methyl)-4-fluoropiperidine-1-car-

boxylate (4o)

Yield: 5.92 g (39%) from 14.0 g of 3o; yellow crystals; mp 99–100 °C.

¹H NMR (400 MHz, CDCl₃):  = 4.04 (d, J = 17.0 Hz, 2 H), 4.09–3.96 (m,

2 H), 3.09 (td, J = 12.2, 11.6 Hz, 2 H), 2.12 (t, J = 11.6 Hz, 2 H), 1.88–

1.71 (m, 2 H), 1.44 (d, J = 2.0 Hz, 9 H).

¹³C NMR (151 MHz, CDCl₃):  = 154.4, 91.4 (d, J = 182.5 Hz), 80.2, 73.1

(d, J = 24.9 Hz), 38.9 (2 C), 34.2 (d, J = 21.4 Hz), 28.3.

Anal. Calcd for C₆H₁₀ClFO₂S: C, 35.92; H, 5.02; S, 15.98. Found: C,

35.74; H, 5.40; S, 16.23.

¹⁹F NMR (376 MHz, CDCl₃):  = –160.3.

MS (APCI): m/z = 296 [M – H]^–(for the corresponding sulfonic acid).

cis-2-Fluorocycloheptane-1-sulfonyl Chloride (4t)

Anal. Calcd for C₁₁H₁₉ClFNO₄S: C, 41.84; H, 6.06; N, 4.44; S, 10.15.

Found: C, 41.66; H, 5.72; N, 4.04; S, 10.18.

The product was purified by column chromatography (hexane–t-BuOMe,

1:1; R_f= 0.5); yield: 18.7 g (83%) from 20.0 g of 3t; yellow liquid.

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¹H NMR (400 MHz, CDCl₃):  = 5.61 (dd, J = 48.7, 3.4 Hz, 1 H), 3.60

(ddd, J = 26.2, 10.7, 3.4 Hz, 1 H), 2.47–2.38 (m, 1 H), 2.38–2.17 (m, 2

H), 2.03–1.89 (m, 1 H), 1.86–1.70 (m, 3 H), 1.69–1.61 (m, 1 H), 1.60–

1.49 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃):  = 88.0 (d, J = 182.3 Hz), 78.8 (d, J = 21.8

Hz), 33.1 (d, J = 21.5 Hz), 26.1, 25.5, 22.5 (d, J = 4.7 Hz), 21.5 (d, J = 3.0

Hz).

1-Cyclobutylidenemethanesulfonamide (8a)

-Fluoro sulfonyl chloride 4h (200 mg, 1.07 mmol) was added to ice-

cold 25% aq ammonia (10 mL), and the reaction mixture was stirred at

0 °C for 1 h. Then, it was extracted with CH₂Cl₂(6 × 10 mL), and the

combined organic layer was dried (Na₂SO₄) and evaporated to dryness

under reduced pressure. The residue was dispersed in hexane (10 mL),

stirred at reflux for 5 min, and filtered. This operation was repeated

twice more, affording 8a as a colorless solid; yield: 81 mg (52%); mp

94–96 °C.

¹H NMR (400 MHz, CDCl₃):  = 6.12 (s, 1 H), 4.67 (s, 2 H), 3.13 (t, J = 8.2

Hz, 2 H), 2.86 (t, J = 8.2 Hz, 2 H), 2.10 (quint, J = 8.2 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 161.5, 121.1, 32.2, 31.8, 17.5.

MS (EI): m/z = 147 [M]⁺.

¹⁹F NMR (376 MHz, CDCl₃):  = –188.7.

MS (EI): m/z = 95 [M – SO₂Cl – HF]⁺.

Anal. Calcd for C₇H₁₂ClFO₂S: C, 39.16; H, 5.63; S, 14.93. Found: C,

39.28; H, 5.38; S, 14.70.

cis-2-Fluorocyclooctane-1-sulfonyl Chloride (4u)

HRMS (ESI): m/z [M + H]⁺calcd for C₅H₁₀NO₂S: 148.0432; found:

148.0427.

The product was purified by column chromatography (gradient hex-

ane to t-BuOMe); yield: 2.50 g (56%) from 4.0 g of 3u; yellow liquid.

¹H NMR (400 MHz, CDCl₃):  = 4.76 (ddt, J = 45.1, 8.4, 4.1 Hz, 1 H), 3.69

(dd, J = 8.4, 4.1 Hz, 1 H), 2.62–2.43 (m, 2 H), 2.25–2.10 (m, 1 H), 2.09–

1.95 (m, 3 H), 1.92–1.72 (m, 4 H), 1.68–1.58 (m, 1 H), 1.55–1.46 (m, 1

H).

¹³C NMR (101 MHz, CDCl₃):  = 91.6 (d, J = 168.0 Hz), 75.5, 31.5 (d, J =

22.8 Hz), 29.1 (d, J = 23.2 Hz), 25.8, 25.4, 22.3 (d, J = 7.6 Hz), 20.7 (d, J =

9.7 Hz).

Anal. Calcd for C₅H₉NO₂S: C, 40.80; H, 6.16; N, 9.52; S, 21.78. Found: C,

40.68; H, 6.31; N, 9.71; S, 21.42.

1-(1-Fluorocyclobutyl)-N-phenylmethanesulfonamide (7b) and 1-

Cyclobutylidene-N-phenylmethanesulfonamide (8b)

Sulfonyl chloride 4h (200 mg, 1.07 mmol) was dissolved in AcOH (2

mL), then PhNH₂(120 mg, 1.29 mmol) and AcONa (132 mg, 1.61

mmol) were added, and the resulting mixture was stirred at rt over-

night. Then, it was diluted with water (5 mL) and extracted with CH-

Cl₃(3 × 2 mL). The combined organic layer was washed with water (3

× 1 mL), dried (Na₂SO₄), and evaporated under reduced pressure, af-

fording the crude product, which was subjected to HPLC purification

[Chromatorex 18 SMB100-5T 100 × 19 mm, 5 m column; linear gra-

dient water–MeCN, 70:30 (0 min) to 45:55 (5 min); 30 mL/min flow]

followed by recrystallization (hexane) to give a 1.7:1 mixture of 7b

and 8b as a colorless solid; yield: 184 mg (73%); mp 61–62 °C. Further

separation of the obtained mixture was not successful.

¹⁹F NMR (376 MHz, CDCl₃):  = –167.3.

MS (EI): m/z = 109 [M – SO₂Cl – HF]⁺.

Anal. Calcd for C₈H₁₄ClFO₂S: C, 42.01; H, 6.17; S, 14.02. Found: C,

42.33; H, 6.49; S, 13.63.

tert-Butyl cis-3-(Chlorosulfonyl)-4-fluoropyrrolidine-1-carboxyl-

ate (4v)

The product was purified by column chromatography (hexane–t-BuOMe,

1:1; R_f= 0.3); yield: 0.33 g (30%) from 1.0 g of 3v; yellow liquid; ca.

1:0.8 mixture of rotamers.

¹H NMR (400 MHz, CDCl₃):  = 5.55 (dt, J = 52.3, 3.5 Hz, 1 H), 4.42–

4.27 (m, 1 H), 4.22–4.03 (m, 2 H), 3.99–3.82 (m, 1 H), 3.69–3.54 (m, 1

H), 1.48 (s, 9 H).

¹³C NMR (151 MHz, CDCl₃):  = 153.5, 90.1 (d, J = 189.4 Hz) and 89.3

(d, J = 189.9 Hz), 81.3 and 81.2, 74.2 (d, J = 18.4 Hz) and 73.7 (d, J =

16.7 Hz), 52.2 (d, J = 23.2 Hz) and 51.9 (d, J = 22.4 Hz), 44.7, 28.3.

¹⁹F NMR (376 MHz, CDCl₃):  = –189.5 and –189.9.

MS (EI): m/z = 195 [M – C₄H₈– HCl]⁺.

Spectroscopic Data for 7b

¹H NMR (500 MHz, CDCl₃):  = 7.39–7.12 (m, 5 H), 6.58 (s, 1 H), 3.42

(d, J = 20.3 Hz, 2 H), 2.56–2.35 (m, 4 H), 1.97–1.88 (m, 1 H), 1.64–1.55

(m, 1 H).

¹³C NMR (126 MHz, CDCl₃):  = 129.5, 125.8, 121.9, 94.5 (d, J = 212.3

Hz), 54.7 (d, J = 22.3 Hz), 33.7 (d, J = 22.5 Hz), 11.9 (d, J = 11.7 Hz).

¹⁹F NMR (376 MHz, CDCl₃):  = –137.1.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₅FNO₂S: 244.0808; found:

244.0806.

Anal. Calcd for C₉H₁₅ClFNO₄S: C, 37.57; H, 5.25; N, 4.87; S, 11.14.

Found: C, 37.76; H, 5.36; N, 4.61; S, 10.76.

Spectroscopic Data for 8b

¹H NMR (500 MHz, CDCl₃):  = 7.39–7.12 (m, 5 H), 6.73 (s, 1 H), 5.99

(q, J = 2.3 Hz, 1 H), 3.07–2.92 (m, 2 H), 2.86–2.74 (m, 2 H), 2.00 (quint,

J = 8.1 Hz, 2 H).

¹³C NMR (126 MHz, CDCl₃):  = 136.5, 129.3, 125.1, 121.1, 118.1, 32.6,

32.0, 29.7.

cis-4-Fluorotetrahydrofuran-3-sulfonyl Chloride (4w)

Yield: 1.45 g (45%) from 2.80 g of 3w; yellowish oil.

¹H NMR (400 MHz, CDCl₃):  = 5.60 (ddd, J = 53.6, 4.9, 3.5 Hz, 1 H),

4.59–4.54 (m, 1 H), 4.53–4.43 (m, 1 H), 4.43–4.35 (m, 1 H), 4.29 (dd,

J = 24.9, 11.5 Hz, 1 H), 4.05 (ddd, J = 33.5, 11.5, 3.5 Hz, 1 H).

¹³C NMR (101 MHz, CDCl₃):  = 90.6 (d, J = 191.8 Hz), 75.4 (d, J = 16.7

Hz), 73.7 (d, J = 23.5 Hz), 67.2.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₁H₁₄NO₂S: 224.0745; found:

224.0742.

¹⁹F NMR (376 MHz, CDCl₃):  = –189.9.

MS (APCI): m/z = 89 [M – SO₂Cl]⁺.

Funding Information

Anal. Calcd for C₄H₆ClFO₃S: C, 25.47; H, 3.21; S, 17.00. Found: C,

25.68; H, 3.38; S, 17.03.

The work was funded by Enamine Ltd. Additional funding from the

Ministry of Education and Science of Ukraine, Grant No. 19BF037-03

(A.V.D. and O.O.G.) is also acknowledged.

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Paper

Synthesis

Acknowledgment

(8) (a) Saunders, B. C.; Stacey, G. J.; Wilding, I. G. E. J. Chem. Soc.

1949, 773. (b) Howell, W. C.; Millington, J. E.; Pattison, F. L. M.

J. Am. Chem. Soc. 1956, 78, 3843. (c) Bunyagidj, C.; Piotrowska,

H.; Aldridge, M. H. J. Chem. Eng. Data 1981, 26, 344.

(9) (a) Wang, L.; Pratt, J. K.; McDaniel, K. F.; Dai, Y.; Fidanze, S. D.;

Hasvold, L.; Holms, J. H.; Kati, W. M.; Liu, D.; Mantei, R. A.;

McClellan, W. J.; Sheppard, G. S.; Wada, C. K. US 2014162971,

2014. (b) Mao, Z.; Ma, D.; Ge, Y.; Ren, X.; Li, Y. CN 105622469,

2016. (c) Dai, W.; Xi, N.; Li, M.; Zhang, T.; Li, X.; Hu, H.; Chen,

W.; Wang, T.; Liu, J. WO 201748675, 2017. (d) Braun, M.-G.;

Gibbons, P.; Lee, W.; Ly, C.; Rudolph, J.; Schwarz, J.; Ashkenazi,

A.; Fu, L.; Lai, T.; Wang, F.; Beveridge, R.; Zhao, L. WO

2018166528, 2018.

The authors thank Prof. Andrey A. Tolmachev for his encouragement

and support, Mr. Vitaliy Polovinko for 2D NMR and NOE experiments,

and Mr. D. V. Bylina for HRMS measurements.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706101.

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Article Doi

Synthesis of sp 3-Enriched β-Fluoro Sulfonyl Chlorides

DOI: 10.1055/s-0040-1706101

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Full text of DOI:10.1055/s-0040-1706101

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