Organocatalytic strategy for hydrophenolation of gem-difluoroalkenes

Accepted Manuscript

Douglas L. Orsi, M. Ramu Yadav, Ryan A. Altman

PII:

S0040-4020(19)30406-5

https://doi.org/10.1016/j.tet.2019.04.016

TET 30261

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 2 March 2019

Revised Date: 3 April 2019

Accepted Date: 4 April 2019

Please cite this article as: Orsi DL, Yadav MR, Altman RA, Organocatalytic strategy for hydrophenolation

of gem-difluoroalkenes, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.016.

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Graphical Abstract

Organocatalytic Strategy for

Leave this area blank for abstract info.

Hydrophenolation of Gem-Difluoroalkenes

Douglas L. Orsi^a, M. Ramu Yadav^a, Ryan A. Altman^a

^aThe University of Kansas, Department of Medicinal Chemistry, Lawrence, KS 66045

1

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The image part with relationship ID rId12 was not found in the file.

Tetrahedron

journal homepage: www.elsevier.com

Organocatalytic Strategy for Hydrophenolation of Gem-Difluoroalkenes

Douglas L. Orsi^a, M. Ramu Yadav^a, and Ryan A. Altman^a

^aThe University of Kansas, Department of Medicinal Chemistry, Lawrence, KS 66045

To Steve, Congratulations on the 2018 Tetrahedon Award

☺

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful

intermediate for elaborating into more complex fluorinated compounds. Currently, most

functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based

catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or

monofluorinated products, respectively. In contrast, we present a complementary “fluorine-

retentive” reaction that exploits an organocatalytic strategy to add phenols across gem-

difluoroalkenes to deliver β,β-difluorophenethyl arylethers. The products are produced in good

Available online

Keywords:

Keyword_1

Keyword_2

Keyword_3

Keyword_4

Keyword_5

to moderate yields and selectivities, thus providing

a range of compounds that are

underrepresented in the synthetic and medicinal chemistry literature.

.

———

Corresponding author. Tel.: +1-785-864-6234; e-mail: raaltman@ku.edu

2

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1. Introduction

2. Results/Discussion

Fluorine-induced perturbations of an organic molecule’s

Standard optimization delivered improved conditions for

adding phenolic nucleophiles across gem-difluoroalkenes (Table

1). Initially, we explored similar conditions to those used for

functionalization with aryl thiols [entry 1: 25% TMG, 1,2-

dichloroethane (1,2-DCE), 80 ˚C]; however, using these

conditions, phenolic nucleophiles reacted poorly, giving no yield

of desired β,β-difluorophenethylarylether product 3 or α-

monofluorovinylether side product 4. Utilizing the same catalyst

with a higher boiling solvent and higher temperatures provided

low yield and moderate selectivity of 3 (entry 2). Considering

the intrinsic differences in acidity and nucleophilicity between

phenolic and thiophenolic nucleophiles, we explored the use of

stronger bases, such as ^tBuOK (entry 3), 1,8-

diazabicylco[5.4,0]undec-7ene (DBU, entry 4), and 1,5,7-

triazabicyclo[4.4.0]dec-5-ene (TBD, entry 5). Use of the stronger

nitrogenous bases improved the yields of product 3, but did not

greatly increase selectivity, while the inorganic ^tBuOK

selectively delivered 4. The use of stronger phosphorazine

physicochemical properties can enable new reactivities that

contrast the reactivity of the respective non-fluorinated

counterpart, as evidenced by the case of gem-difluoroalkenes.^1,2

For these substrates, the σ-withdrawing effects of the fluorine

substituents activate the difluorinated position for regioselective

attack by a variety of nucleophiles under both metal-catalyzed

and non-catalyzed nucleophilic functionalization conditions

(Figure 1).¹However, many of these reactions undergo a net

addition/elimination process that defluorinates the substrate.

Specifically, these reactions proceed through either unstable β-

fluoroanions (Figure 1a)^3-6or β-fluoroorganometal intermediates

(Figure 1b)^7-24that both undergo β-fluoride elimination and

deliver monofluorinated products.¹This elimination process can

be overridden using the nucleophile as a solvent,^25-32which

restricts use to liquid, inexpensive, and readily-available

nucleophiles. In a special case, nucleophilic attack of the

fluorinated position of a gem-difluoroalkene by a fluoride anion

delivers trifluoromethyl-containing products, though these

reactions benefit from an in situ equilibrium between the

difluoroalkene and the α-trifluormethyl anion that avoids

degradation of the organic moiety (Figure 1c).^33-38A second rare

exception involves the addition of 3-hydroxypyridine to gem-

difluoroalkenes to selectively provide the hydrophenolated

product,³⁹though this strategy was not applied to other phenolic

nucleophiles. In a more general method, the nucleophilic addition

of aryl thiols to gem-difluoroalkenes generates β,β-

difluorophenethyl arylthioethers using an organocatalytic

strategy (1,1,3,3-tetramethylguanidine, TMG, Figure 1e) without

β-fluoride elimination,⁴⁰though additional examples of “fluorine-

retentive” nucleophilic hydro-functionalization of gem-

difluoroalkenes remain elusive (Figure 1d). To complement this

reaction, we herein present a new organocatalytic system for the

regioselective nucleophilic addition reactions of phenols to gem-

difluoroalkenes that minimizes the loss of fluoride (Figure 1f).

superbases

reduced

the

selectivity

versus

α-

monofluorovinylether side product 4 (entry 6), presumably due

to degredation of desired product 3. The use of aromatic solvents

provided improved selectivity versus other solvents (entries 3,

7–10), while increased temperature and loading of TBD

improved the yield of desired product (entries 11–14). When

performed in the presence of air, the reaction generated a

complex mixture of more highly oxidized products, and ongoing

work aims to optimize conditions to selectively produce these

side products. Finally, we settled on the use of 50% TBD in 1,2-

dichlorobenzene (DCB) under N₂at 140 ˚C for 24 h as the

standard conditions (entry 15). In control reactions, subjection of

pure 3 to the optimized conditions generated mixtures of 3:4,

indicating that the product is instable to the reaction conditions.

Thus for any specific substrate, optimization of the time,

temperature, and strength of base might improve the reaction

outcome.

Table 1: Optimization of Reaction Conditions. [a] 1 (1.0

equiv., 0.10 mmol), 2 (5.0 equiv., 0.50 mmol), base (0.25 equiv.,

0.025 mmol), solvent (1.0 M, 0.10 mL), 120 ˚C, for 4 h under an

N₂atmosphere. Conversion of 1 and yields of 3 and 4 were

determined by ¹⁹F NMR analysis using α,α,α-trifluorotoluene

(TFT) as a standard (10 µL). [b] pKa in THF.^41,42[c] 80 ˚C. [d]

100 ˚C. [e] 0.50 equiv. base. [f] 140 ˚C. [g] 1 (1.0 equiv., 0.50

Figure 1: Representative Reactions of Gem-Difluoroalkenes.

3

mmol), 2 (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol),

DCB (1.0 M, 1.0 mL), 140 ˚C, for 24 h under an N₂atmosphere.

electron-deficient substrates, the standard reaction conditions

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generally delivered products in low yield and <1:1 selectivity

(9j–r), though substrates bearing 3-α,β-unsaturated carbonyl and

3-NO₂groups afforded products in sufficient yield and selectivity

(9j, k). To address this limitation, further optimization revealed

that a biphasic reaction mixture (9:1 DCB:H₂O) improved both

the selectivities and yields (9l–r). Presumably for these eletron-

deficient substrates, the water in the biphasic system (1) provided

additional protons to quench the reactive β-fluoroanion, and/or

(2) minimized degradation of the product by sequestering some

of the base in the aqueous phase. Ortho-substituted gem-

difluoroalkenes reacted inconsistently, with a 2-(4-^tBu)-Ph-

substituted substrate giving high yield (9d), a 2-Me-substituted

substrate reacting in low yield and low conversion (9h), and a

2,6–Me₂-substituted substrate not reacting at all (9i).

Using these conditions, a range of phenols were successfully

added across gem-difluoroalkenes. Reactions of various electron-

deficient phenols (Table 2, 6a–f) gave the desired β,β-

difluorophenethyl arylethers (6) in good yields (>65%) and high

selectivities (>7:1) versus the α-monofluorovinylether side

products (7). Using the standard reaction conditions, electron-

neutral and ortho-substituted phenols (3, 6g–j) delivered the β,β-

difluorophenethyl arylethers in moderate to low yields (30–50%)

and selectivities (2:1–4:1). Reactions of electron-rich phenols

delivered the anticipated products in low yields and selectivities

(6k–l), though reoptimization of the base might improve the

reactivity of these less acidic substrates. A range of useful

functional groups for further functionalization were tolerated,

like halides (6c–f) and nitrogen based functional groups (6a–b),

though an aniline-drived phenol (6l) was a poor substrate.

Table 2: Scope of Phenol Nucleophiles. Standard conditions:

1 (1.0 equiv., 0.50 mmol), 5a–o (5.0 equiv., 2.5 mmol), TBD

(0.50 equiv., 0.25 mmol), DCB (0.50 M, 1.0 mL), 140 ˚C, for 24

h under an N₂atmosphere. The selectivity of 6:7 was determined

by ¹⁹F NMR analysis of the crude reaction mixture using TFT (50

µL) as a standard and is reported in parentheses. Yields are

reported as the isolated yield of >95% pure material and

represent the average of 2 runs. [a] 1.0 equiv. TBD. [b] Contains

trifluoroethylbenzene side product.

Table 3: Scope of Gem-difluoroalkene Electrophiles. [a]

Standard conditions: 8a–r (1.0 equiv., 0.50 mmol), 5c (5.0

equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.50 M,

1.0 mL), 140 ˚C, for 24 h under an N₂atmosphere. The

selectivity of 9:10 was determined by ¹⁹F NMR analysis of the

crude reaction mixture using TFT (50 µL) as a standard and is

reported in parentheses. Yields are reported as the isolated yield

of >95% pure material and represent the average of 2 runs. [b]

Standard conditions: 8a–r (1.0 equiv., 0.50 mmol), 5c (3.0

equiv., 1.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.45 M,

0.90 mL), H₂O (0.05 M, 0.10 mL), 140 ˚C, for 24 h under an N₂

atmosphere. The selectivity of 9:10 was determined by ¹⁹F NMR

analysis of the crude reaction mixture using TFT (50 µL) as a

standard and is reported in parentheses. Yields are reported as the

isolated yield of >95% pure material and represent the average of

2 runs. [c] 4-Bromophenol used as the nucleophile. [d] Yield is

Many synthetically and biomedically useful functional groups

were tolerated on the gem-difluoroalkene substrate. Specifically,

reactions tolerated thioethers and ethers (9a–b), morpholine (9c),

nitrogen-containing functional groups (9k–l), halides (9m–p)

amides (9q), and pseudohalides (9r). Reactions of electron-rich

gem-difluoroalkenes generally afforded products in good yields

t

and high selectivities (9a–i), although aniline-based and Bu-

based gem-difluoroalkenes reacted in lower yields (9e–f). Using

4

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reported from ¹⁹F analysis of the crude reaction mixture. [e]

solvent, phenol’s pK_aof 18 disfavors deprotonation by weaker

Second run used 0.40 mmol of 8q. [f] Second run used 0.30

mmol of 8r.

bases, such as TMG (pK_a= 16), though stronger bases, such as

TBD (pK_a= 21), efficiently deprotonate and activate the phenol.

However, bases that are too strong will decompose product 3 to

generate 4. Specfically, the strong σ-electron withdrawing effect

of the gem-difluoro group and ethereal oxygen activates 3 for

elimination. Such deprotonation was observed in control

experiments involving the base-mediated decomposition of 3,

particularly with strong “superbases,” such as the phosphorazine

base P₂Et (pK_a= 25). Therefore in the present studies, TBD

provided appropriate reactivity, specifically balancing activation

of the phenol with decomposition of product. However, we note

that other currently unexplored bases might also work for this

reaction. Further, for any specific substate combination with

distinct pK_as of the phenol and product, an alternate base might

prove optimal.

Heteroaryl-substituted gem-difluoroalkenes reacted similarly

to their aryl-derived counterparts. Electron-rich heteroaryl

groups, such as indole and pyrazole, gave high selectivity (12a,

b), though the yield of pyrazole 12b was moderate. A 2-

substituted dibenzothiophene reacted in moderate yield and

selectivity (12c). When subjected to the biphasic conditions, a

pyridyl substrate gave good yield and selectivity (12d). This

series of reactions also highlighted the compatibility of

sulfonamide (12a) and acetal (12d) protecting groups.

Table 4: Scope of Heteroaryl Gem-Difluoroalkene

Electrophiles. [a] Standard conditions a: 11a–e (1.0 equiv., 0.50

mmol), 5c (5.0 equiv., 2.5 mmol), TBD (0.50 equiv., 0.25 mmol),

DCB (0.50 M, 1.0 mL), 140 ˚C, for 24 h under an N₂atmosphere.

The selectivity of 12:13 was determined by ¹⁹F NMR analysis of

the crude reaction mixture using TFT (50 µL) as a standard and is

reported in parentheses. Yields are reported as the isolated yield

of >95% pure material and represent the average of 2 runs. [b]

Standard conditions b: 11a–e (1.0 equiv., 0.50 mmol), 5c (3.0

equiv., 1.5 mmol), TBD (0.50 equiv., 0.25 mmol), DCB (0.45 M,

0.90 mL), H₂O (0.050 M, 0.10 mL), 140 ˚C, for 24 h under an N₂

atmosphere. The selectivity of 12:13 was determined by ¹⁹F

NMR analysis of the crude reaction mixture using TFT (50 µL)

as a standard and is reported in parentheses. Yields are reported

as the isolated yield of >95% pure material and represent the

average of 2 runs.

Figure 2: Plausible Reaction Mechanism.

4. Conclusion

In conclusion, we developed an organocatalytic method to

convert gem-difluoroalkenes to β,β-difluorophenethyl arylethers.

In contrast to classical syntheses of such products that require

harsh conditions^43-45and/or gaseous reagents⁴⁶and that many

times rely on functional group interconversions^47-56for generating

the fluorine-based substructure, our convergent method utilizes

only catalytic quantities of a weak amine base to add phenol

nucleophiles across gem-difluoroalkenes and deliver the desired

products in moderate to good yields and selectivities. Notably,

this reaction contrasts the many reactions of gem-difluoroalkenes

that selectively generate monofluoroalkene products.¹This

method delivers a class of products that are underrepresented in

synthetic and biomedical literature, and it tolerates many useful

functional groups for further functionalization and for medicinal

chemistry. Further efforts aim to enable the addition of other

nucleophiles, such as alkyl alcohols, to gem-difluoroalkenes, and

to expand the scope of such reactions to include aliphatic and

secondary gem-difluoroalkenes.

3. Mechanistic Considerations

The present reaction presumably operates through an addition

/ protonation sequence, in which the base plays key roles as both

a promoter and a quencher of the reaction. Initially, organic base

(B) activates the phenol pronucleophile, and subsequently, the

phenoxide nucleophile adds to the electrophilic difluorinated

carbon of the gem-difluoroalkene. This addition generates an

instable β-fluoro anionic intermediate (A) that can react via two

pathways. First, intermediate (A) can either accept a proton from

the phenol pronucleophile or from the protonated organic base

(B) to provide the desired product 3. Second, fluoride elimination

from anionic intermediate (A) can provide the undesired

monofluoroalkene 4. Alternatively, 4 can form via base-mediated

elimination of HF from 3.

5. Experimental Section

General Considerations: Unless otherwise noted, reactions

were performed under an atmosphere of air using oven-dried

glassware. Organocatalytic reactions of phenols and gem-

difluoroalkenes were performed in one-dram borosilicate glass

scintillation vials sealed with a screw-top cap containing a PTFE-

lined septum. Unless otherwise noted all other reactions were

performed in round-bottom flasks sealed with rubber septa. PTFE

syringes equipped with stainless-steel needles were used to

transfer air- and moisture-sensitive liquid reagents. Reactions

were monitored by either ¹⁹F NMR with an internal standard of

α,α,α−trifluorotoluene or by thin-layer chromatography (TLC)

Based on this presumed mechanism, the pK_aof the base

catalyst must fall within a narrow range to selectively provide 3

over 4. The base catalyst must be sufficiently basic to

deprotonate the phenol. In THF, a non-coordinating aprotic

5

on UNIPLATE Silica Gel HLF plates, visualized by quenching

of fluorescence. Normal phase column chromatography was

conducted using a automated separations system utilizing

gradient elution with VWR Common Silica Gel 60 Å, 40–60 µm.

Reverse phase column chromatography was conducted using an

automated flash chromatography system utilizing gradient elution

with a Teledyne ISCO C18 Redisep Rf Gold 50 g column.

Isolated yields reported in the manuscript represent an average of

at least 2 independent runs of final compound deemed to be at

least 95% pure by NMR. Yields reported in the supporting

information refer to a single experiment. Unless otherwise noted,

The system was sealed with three PFTE septa, and

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subsequently evacuated and backfilled with N₂three times. Dry

NMP was added via syringe transfer (PTFE syringe with oven-

dried stainless-steel needle), and the system was immersed in a

preheated 100 °C oil bath. Once no solid reagents remained

(approximately

2

min

of

heating),

potassium

bromodifluoroacetate (1.5 or 1.8 equiv.) was added portionwise

over 0.5 h, with the rate of addition controlling the evolution of

CO₂gas. Once all of the potassium bromodifluoroacetate was

added, the solution was allowed to stir for 0.5–1 h. Upon

completion, the reaction was cooled to room temperature and

then quenched with H₂O. Subsequently, Et₂O was added to the

reaction, and the mixture was washed with H₂O (five times), and

the aqueous layer was back-extracted with Et₂O (two times). The

combined organic layers were dried over Na₂SO₄and

concentrated. The crude material was dry-packed onto silica gel

and then eluted through a plug of silica gel with EtOAc:hexanes

(1:1) to remove triphenylphosphine oxide. Subsequently, H₂O₂

(30% in H₂O) was added to the mother liquor and allowed to

react for 30 min to oxidize the residual triphenylphosphine. The

organic layer was washed with H₂O (three times), dried over

Na₂SO₄, concentrated, and subjected to normal phase flash

chromatography using EtOAc and hexanes.

1

compounds were isolated in >98% purity as determined by H

and ¹⁹F NMR.

Unless otherwise noted, reagents were purchased from

commercial sources and used as received. 1,5,7-

Triazabicyclo[4.4.0]dec-5-ene (TBD) was purchased form Sigma

Aldrich. Solvents, including dimethylformamide (DMF), toluene

(PhMe), dichloromethane (DCM), methanol (MeOH),

acetonitrile (MeCN), and tetrahydrofuran (THF) were used

directly from a solvent purification system, in which solvent was

dried by passage through two columns of activated alumina

under argon. Chemical abbreviations utilized in this document

include: 1,2–Dichlorobenzene (DCB), N-methylpyrrolidine

(NMP), α,α,α-trifluorotoluene (TFT), sodium sulfate (Na₂SO₄),

magnesium sulfate (MgSO₄), ethyl acetate (EtOAc), diethyl ether

(Et₂O), ammonium chloride (NH₄Cl), ⁿbutyl lithium (ⁿBuLi),

General Procedure for the Organocatalyzed Addition of

Phenols to Gem-Difluoroalkenes (B-1): An oven-dried one-

dram vial equipped with a magnetic stir bar was charged with 1

equivalent of difluoroalkene and 5 equivalents of phenol. The

system was brought into a glovebox, and 0.5 equivalents of TBD

were added. Dry DCB (1 mL) was added via syringe transfer

(PTFE syringe with oven-dried stainless-steel needle), and the

vial was sealed with a screw-top cap containing a PTFE-lined

septum. The system was removed from the glovebox, and placed

within a heating mantle preheated to 140 ˚C and stirred for 24 h.

The reaction was cooled to room temperature, and then

standardized by adding 50 µL of TFT. The mixture was diluted

with DCM, and then stirred for 5 min. The reaction was analyzed

by ¹⁹F NMR, and then washed 3X with 1 N NaOH (aq.). The

combined aqueous layer was extracted 2X with DCM, and the

combined organic layers were dried over Na₂SO₄and

concentrated in vacuo. The residue was loaded onto celite and

then purified by flash reverse phase chromatography with

gradient elution from 98% H₂O in MeCN to 100% MeCN to

provide the desired product in >95% purity.

t

sodium hydroxide (NaOH), butyl carbonate anhydride (Boc₂O),

potassium carbonate (K₂CO₃), and hydrochloric acid (HCl).

Proton nuclear magnetic resonance (¹H NMR) and fluorine

nuclear magnetic resonance (¹⁹F NMR) were taken on a Bruker

DRX 500 spectrometer (500 and 376 MHz respectively).

Fluorine nuclear magnetic resonance (¹⁹F NMR) was taken on a

Bruker AVIII 400 Avance spectrometer (376 MHz). Proton and

carbon nuclear magnetic resonance (¹³C NMR) were taken on a

Bruker AVIII 500 Avance spectrometer with

a CPDUL

cryoprobe (500 and 126 MHz respectively). Chemical shifts (δ)

for protons are reported in parts per million (ppm) downfield

from tetramethylsilane, and are referenced to the proton

resonance of residual solvent in the NMR solvent (CHCl₃: δ =

7.26 ppm; DMSO: δ = 2.50 ppm). Chemical shifts (δ) for carbon

are reported in ppm downfield from tetramethylsilane, and are

referenced to the carbon resonance of the solvent residual peak

(CDCl₃: δ = 77.2 ppm; DMSO: δ = 39.52 ppm). Chemical shifts

for fluorine are reported in ppm upfield from

trichlorofluoromethane (0 ppm), and are referenced to added TFT

as a standard (δ = –63.77 ppm) unless otherwise specified. NMR

data are represented as follows: chemical shift (ppm), multiplicity

(s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m =

multiplet), coupling constant in Hertz (Hz), integration. High-

resolution mass determinations were obtained either by

electrospray ionization (ESI) on a Waters LCT Premier^TMmass

spectrometer or by atmospheric-pressure chemical ionization

(APCI-hexanes/PhMe) on a Waters Q-Tof Premier^TM, for which

sample plus near mass internal exact mass standard were

dissolved in hexanes, and hexanes or PhMe/hexanes were used as

ionization solvent. Infrared spectra were measured on a Perkin

Elmer Spectrum Two Fourier Transform Infrared Spectrometer

by drying samples on a diamond ATR Sample base plate.

Uncorrected melting points were measured on a Thomas Hoover

Capillary Melting Point apparatus.

General Procedure for the Organocatalyzed Addition of

Phenols to Gem-Difluoroalkenes (B-2): An oven-dried one-

dram vial equipped with a magnetic stir bar was charged with 1

equivalent of difluoroalkene and 3 equivalents of phenol. The

system was brought into a glovebox, and 0.5 equivalents of TBD

were added. Dry DCB (0.9 mL) was added via syringe transfer

(PTFE syringe with oven-dried stainless-steel needle), and the

vial was sealed with a screw-top cap containing a PTFE-lined

septum. The system was removed from the glovebox, and

distilled H₂O (0.1 mL, distilled under N₂to remove dissolved O₂)

was added via syringe transfer (PTFE syringe with oven-dried

stainless-steel needle) under N₂. The reaction was placed within a

heating mantle preheated to 140 ˚C and stirred for 24 h. The

reaction was cooled to room temperature, and then standardized

by adding 50 µL of TFT. The mixture was diluted with DCM,

and then stirred for 5 min. The reaction was analyzed by ¹⁹F

NMR, and then washed 3X with 1 N NaOH (aq.). The combined

aqueous layer was extracted 2X with DCM, and the combined

organic layers were dried over Na₂SO₄and concentrated in

vacuo. The residue was loaded onto celite and then purified by

flash reverse phase chromatography with gradient elution from

General Procedure for the Preparation of Gem-

Difluoroalkenes (A): An oven-dried 3-neck round-bottomed

flask equipped with a magnetic stir bar was charged with aryl

aldehyde (1.0 equiv.) and triphenylphosphine (1.2 or 1.5 equiv.).

6

Tetrahedron

98% H₂O in MeCN to 100% MeCN to provide the desired

Procedure B-1, 0.115 g (0.50 mmol) of compound 1 was reacted

ACCEPTED MANUSCRIPT

product in >95% purity.

with 0.298 g (2.50 mmol) of 4-hydroxybenzonitrile in the

presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.143 g (82% yield, 5% E-7b, 1% Z-

Compounds in Table 1:

5-(2,2-difluoro-2-phenoxyethyl)-1,2,3-trimethoxybenzene

(3): Following General Procedure B-1, 0.115 g (0.50 mmol) of

compound 1 was reacted with 0.236 g (2.50 mmol) of phenol in

the presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.080 g (49% yield) of desired product

1

7b) of desired product 6b as a yellow oil; H NMR (500 MHz,

CDCl₃) δ 7.62 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.4 Hz, 2 H), 6.56

(s, 2 H), 3.87 (s, 6 H), 3.85 (s, 3 H), 3.40 (t, J = 11.3 Hz, 2 H);

¹³C NMR (126 MHz, CDCl₃) δ 153.9, 153.3, 133.8, 126.9 (t, J =

3.4 Hz), 124.0 (t, J = 269.6 Hz), 121.8 (d, J = 1.8 Hz), 118.3,

117.0, 109.2, 107.7, 61.0, 56.3, 42.5 (t, J = 29.3 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ –71.23 (t, J = 11.5 Hz, 2 F); IR (film) 2940,

2842, 2253, 2231, 1596, 1505, 1464, 1424, 1360, 1325, 1296,

1253, 1241, 1210, 1173, 1156, 1129, 1068, 1004, 908, 841, 802,

732, 649 cm^-1; HRMS (ESI+) calc. for C₁₈H₁₇F₂NO₄Na (M+Na)

1

3 as a colorless solid (MP = 65–66 ˚C); H NMR (500 MHz,

CDCl₃) δ 7.32 (t, J = 7.9 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.14

(d, J = 8.0 Hz, 2 H), 6.60 (s, 2 H), 3.87 (s, 9 H), 3.39 (t, J = 11.0

Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2, 150.5, 137.6 (d,

J = 1.4 Hz), 129.4, 127.7 (t, J = 3.3 Hz), 125.6, 123.8, 121.7 (t, J

= 267.0 Hz), 107.6, 60.9, 56.2, 42.5 (t, J = 30.3 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ –70.44 (t, J = 11.0 Hz, 2 F); IR (film) 2940,

2841, 2252, 1699, 1592, 1509, 1492, 1463, 1423, 1361, 1324,

1262, 1238, 1194, 1156, 1128, 1068, 1051, 1026, 1005, 942, 909,

828, 807, 764, 749, 692, 658, 649 cm^-1; HRMS (HAPCI+) calc.

for C₁₇H₁₈F₂O₄(M+) 324.1173, found 324.1171.

1

372.1023, found 372.1026. E-7b characteristic peaks: H NMR

(500 MHz, CDCl₃) δ 5.76 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR (376

MHz, CDCl₃) δ –85.31 (d, J = 5.5 Hz, 1 F); Z-7b characteristic

peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.43 (d, J = 27.8 Hz, 1 H);

¹⁹F NMR (376 MHz, CDCl₃) δ –85.81 (d, J = 32.89 Hz, 1 F).

5-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1,2,3-

trimethoxybenzene (6c): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.408 g

(2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.145 g (72% yield) of desired product 6c as a clear

(E)-5-(2-fluoro-2-phenoxyvinyl)-1,2,3-trimethoxybenzene

(4): Following General Procedure B-1, 0.115 g (0.50 mmol) of

compound 1 was reacted with 0.236 g (2.50 mmol) of phenol in

the presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing desired product 0.024 g (16% yield,

6:1 E:Z) 4 as an orange oil; Characterization represents major E

1

oil; H NMR (500 MHz, CDCl₃) δ 7.40 (d, J = 2.5 Hz, 1 H),

1

7.27–7.25 (m, 1 H), 7.19 (dd, J = 8.8, 2.5 Hz, 1 H), 6.60 (s, 2 H),

3.87 (s, 6 H), 3.85 (s, 3 H), 3.43 (t, J = 11.0 Hz, 2 H); ¹³C NMR

(126 MHz, CDCl₃) δ 153.2, 145.3 (t, J = 1.7 Hz), 137.8, 131.3,

130.3, 128.2, 127.8, 127.0 (t, J = 3.5 Hz), 124.07 (t, J = 269.4

Hz), 123.93 (t, J = 2.0 Hz), 107.9, 61.0, 56.3, 42.4 (t, J = 29.4

Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –70.83 (t, J = 11.0 Hz, 2 F);

IR (film) 2940, 2839, 1592, 1508, 1476, 1463, 1423, 1360, 1324,

1258, 1238, 1128, 1061, 1008, 942, 867, 808, 764, 700, 666, 528

cm^-1; HRMS (HAPCI+) calc. for C₁₇H₁₆Cl₂F₂O₄(M+) 392.0394,

found 394.0424.

isomer; H NMR (500 MHz, CDCl₃) δ 7.37 (dd, J = 8.7, 7.5 Hz,

2 H), 7.17–7.14 (m, 3 H), 6.66 (s, 2 H), 5.65 (d, J = 5.6 Hz, 1 H),

3.82 (s, 3 H), 3.76 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃) δ 154.7,

154.0 (d, J = 3.5 Hz), 153.3, 130.1, 127.6 (d, J = 8.4 Hz), 124.5,

117.5, 116.3, 105.0 (d, J = 4.1 Hz), 92.7 (d, J = 38.6 Hz), 61.0,

56.1; ¹⁹F NMR (376 MHz, CDCl₃) δ –83.38 (d, J = 5.6 Hz, 1 F).

Minor Z isomer characteristic peaks: ¹H NMR (500 MHz,

CDCl₃) δ 5.24 (d, J = 28.2 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –83.80 (d, J = 28.1 Hz, 1 F).

Compounds in Table 2:

5-(2,2-difluoro-2-(3-iodophenoxy)ethyl)-1,2,3-

5-(2,2-difluoro-2-(4-nitrophenoxy)ethyl)-1,2,3-

trimethoxybenzene (6d): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.551 g

(2.50 mmol) of 3-iodophenol in the presence of 0.033 g (0.25

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.158 g (71% yield, 2% E-7d) of desired product 6d

trimethoxybenzene (6a): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.348 g

(2.50 mmol) of 4-nitrophenol in the presence of 0.066 g (0.5

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.125 g (69% yield, 3% of E-7a) of desired product 6a

1

as a brown oil; H NMR (500 MHz, CDCl₃) δ 7.53–7.50 (m, 2

1

as a dark yellow solid (MP = 117–120 ˚C); H NMR (500 MHz,

H), 7.12 (dd, J = 8.25, 2.15 Hz, 1 H), 7.03 (t, J = 8.01 Hz, 1 H),

6.56 (s, 2 H), 3.86 (s, 9 H), 3.36 (t, J = 11.08 Hz, 2 H); ¹³C NMR

(126 MHz, CDCl₃) δ 153.1, 150.7 (d, J = 2.30 Hz), 137.7 (d, J =

1.69 Hz), 134.7, 130.9, 130.7, 127.3 (t, J = 3.39 Hz), 123.8 (t, J =

267.33 Hz), 121.2, 107.6, 93.5, 60.9, 56.2, 42.4 (t, J = 29.73 Hz);

¹⁹F NMR (376 MHz, CDCl₃) δ –70.60 (t, J = 11.13 Hz, 2 F); IR

(film) 2938, 2839, 1591, 1583, 1509, 1465, 1422, 1360, 1324,

1260, 1237, 1192, 1156, 1126, 1054, 1008, 945, 910, 865, 832,

765, 750, 735, 686, 665, 649 cm^-1; MS (EI+) calc. for

C₁₇H₁₇F₂IO₄(M+) 450.0, found 449.9. E-7d characteristic peaks:

¹H NMR (500 MHz, CDCl₃) δ 5.67 (d, J = 5.7 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ –84.19 (d, J = 5.6 Hz, 1 F).

CDCl₃) δ 8.22 (d, J = 9.2 Hz, 2 H), 7.28 (d, J = 8.9 Hz, 2 H), 6.57

(s, 2 H), 3.88 (s, 6 H), 3.86 (s, 3 H), 3.42 (t, J = 11.4 Hz, 2 H);

¹³C NMR (126 MHz, CDCl₃) δ 155.4, 153.3, 145.0, 138.0, 126.8

(t, J = 3.4 Hz), 125.4, 124.0 (t, J = 269.3 Hz), 121.4 (t, J = 1.9

Hz), 116.6, 107.7, 61.0, 56.3, 42.5 (t, J = 29.3 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ ; ¹⁹F NMR (376 MHz, CDCl₃) δ –71.41 (t, J

= 11.4 Hz, 2 F); IR (film) 2940, 2841, 1614, 1592, 1522, 1509,

1492, 1461, 1424, 1346, 1325, 1301, 1238, 1209, 1157, 1124,

1060, 1009, 943, 930, 911, 853, 801, 764, 750, 723, 692, 649 cm^-

¹; HRMS (HAPCI+) calc. for C₁₇H₁₈F₂NO₆(M+H) 370.1102,

1

found 370.1099. E-7a characteristic peaks: H NMR (500 MHz,

CDCl₃) δ 5.79 (d, J = 5.8 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –85.52 (d, J = 5.9 Hz, 1 F).

5-(2-(3-chloro-2-fluorophenoxy)-2,2-difluoroethyl)-1,2,3-

trimethoxybenzene (6e): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.26 mL

4-(1,1-difluoro-2-(3,4,5-

trimethoxyphenyl)ethoxy)benzonitrile (6b): Following General

7

(2.50 mmol) of 2-fluoro-3-chlorophenol in the presence of 0.033

g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.139 g (74% yield, 5% E-7e) of desired product 6e as

a clear solid (MP = 50–51 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.23 (ddd, J = 8.1, 6.3, 1.6 Hz, 1 H), 7.19 (ddd, J = 8.3,

6.8, 1.4 Hz, 1 H), 7.01 (td, J = 8.3, 1.9 Hz, 1 H), 6.60 (s, 2 H),

3.87 (s, 6 H), 3.86 (s, 3 H), 3.43 (t, J = 11.1 Hz, 2 H); ¹³C NMR

(126 MHz, CDCl₃) δ ;153.2, 150.4, 137.7 (t, J = 1.5 Hz), 127.5,

127.0 (t, J = 3.5 Hz), 123.97, 123.96 (t J = 269.8 Hz), 123.93,

122.6, 122.3 (d, J = 15.8 Hz), 107.6, 61.0, 56.2, 42.2 (t, J = 29.4

Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –71.19 (td, J = 11.3, 5.3 Hz,

2 F), –131.17 (p, J = 6.2 Hz, 1 F); IR (film) 2941, 2842, 2253,

1705, 1595, 1509, 1483, 1462, 1424, 1360, 1325, 1275, 1260,

1243, 1181, 1156, 1129, 1069, 1027, 1004, 956, 907, 838, 821,

764, 746, 650 cm^-1; HRMS (HAPCI+) calc. for C₁₇H₁₆ClF₃₁O₄

(M+) 376.0689, found 376.0682. E-7e characteristic peaks: H

NMR (500 MHz, CDCl₃) δ 5.64 (d, J = 6.1 Hz, 1 H); ¹⁹F NMR

(376 MHz, CDCl₃) δ –85.26 (d, J = 6.1 Hz, 1 F).

the product was purified by normal-phase flash chromatography

ACCEPTED MANUSCRIPT

using a gradient of 0–10% EtOAc in hexanes with 1% PhMe,

followed by reverse-phase flash chromatography using a gradient

of 2–100% MeCN in H₂O, furnishing 0.068 g (40% yield) of

1

desired product 6h as a pale yellow oil; H NMR (500 MHz,

CDCl₃) δ 7.21 (dd, J = 8.4, 1.7 Hz, 1 H), 7.15 (t, J = 7.0 Hz, 2

H), 7.08 (dt, J = 7.5, 7.0, 1.4 Hz, 1 H), 6.60 (s, 2 H), 3.87 (s, 6

H), 3.86 (s, 3 H), 3.41 (t, J = 10.6 Hz, 2 H), 2.05 (s, 3 H); ¹³C

NMR (126 MHz, CDCl₃) δ 153.1, 148.9, 137.7 (d, J = 1.3 Hz),

131.22, 131.19, 127.8 (t, J = 3.7 Hz), 126.7, 125.5, 124.1 (t, J =

266.8 Hz), 121.9 (d, J = 1.7 Hz), 107.8, 61.0, 56.3, 42.7 (t, J =

30.7 Hz), 16.4; ¹⁹F NMR (376 MHz, CDCl₃) δ –69.81 (t, J = 10.6

Hz, 2 F); IR (film) 2939, 2840, 1591, 1508, 1494, 1460, 1423,

1360, 1324, 1262, 1238, 1177, 1156, 1126, 1091, 1042, 1009,

944, 892, 862, 832, 749, 704, 658, 618 cm^-1; HRMS (HAPCI+)

calc. for C₁₈H₂₀F₂O₄(M+) 338.1330, found 338.1320.

5-(2,2-difluoro-2-(2-isopropylphenoxy)ethyl)-1,2,3-

trimethoxybenzene (6i): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.336 mL

(2.50 mmol) of 2-isoporpylphenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.061 g (34% yield) of desired product 6i as a clear

oil; ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.26 (m, 2 H), 7.18 (dt, J

= 6.2, 2.5 Hz, 2 H), 6.64 (s, 2 H), 3.90 (s, 9 H), 3.45 (t, J = 10.3

Hz, 2 H), 2.90 (p, J = 6.9 Hz, 1 H), 1.08 (d, J = 6.9 Hz, 6 H); ¹³C

NMR (126 MHz, CDCl₃) δ 153.2, 147.6 (t, J = 1.8 Hz), 141.3,

127.9 (t, J = 3.8 Hz), 126.6, 126.5, 125.8, 124.0 (t, J = 266.4 Hz),

121.7 (t, J = 2.0 Hz), 107.8, 61.0, 56.2, 42.8 (t, J = 30.6 Hz),

26.5, 23.1; ¹⁹F NMR (376 MHz, CDCl₃) δ –69.54 (t, J = 10.4 Hz,

2 F); IR (film) 2963, 2840, 1592, 1508, 1489, 1459, 1423, 1362,

1323, 1260, 1238, 1179, 1156, 1127, 1086, 1045, 1009, 944, 892,

860, 829, 809, 752, 722, 705, 659, 603, 545, 529 ,472, 455 cm^-1;

HRMS (HAPCI+) calc. for C₂₀H₂₄F₂O₄(M+) 366.1643, found

366.1638.

5-(2-(4-bromophenoxy)-2,2-difluoroethyl)-1,2,3-

trimethoxybenzene (6f): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.432 g

(2.50 mmol) of 4-bromophenol in the presence of 0.033 g (0.25

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.137 g (68% yield, 3% E-7f) of desired product 6f (or

1

2) as a clear oil; H NMR (500 MHz, CDCl₃) δ 7.42 (d, J = 8.8

Hz, 2 H), 7.01 (d, J = 8.6 Hz, 2 H), 6.57 (s, 2 H), 3.86 (s, 9 H),

3.37 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 153.2,

149.4, 137.7 (t, J = 1.6 Hz), 132.4, 127.4, 123.7 (t, J = 267.9 Hz),

123.6, 118.6, 107.6, 60.9, 56.2, 42.4 (t, J = 29.9 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ –70.87 (t, J = 11.2 Hz, 2 F); IR (film) 2939,

2842, 2252, 1594, 1509, 1486, 1464, 1424, 1361, 1324, 1275,

1260, 1239, 1199, 1156, 1129, 1068, 1012, 908, 827, 797, 764,

744, 698, 649 cm^-1; HRMS (HAPCI+) calc. for C₁₇H₁₇BrF₂O₄

2-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-1,1'-

biphenyl (6j): Following General Procedure B-1, 0.115 g (0.50

mmol) of compound 1 was reacted with 0.426 g (2.50 mmol) of

2-phenylphenol in the presence of 0.033 g (0.25 mmol) of TBD

at 140 ˚C for 24 h. After workup with 1 N NaOH (aq.), the

product was purified by reverse-phase flash chromatography

using a gradient of 2–100% MeCN in H₂O, furnishing 0.127 g

(40 % yield, 23% E-7j, 3% Z-7j) of compound 6j as a pale oil;

¹H NMR (500 MHz, CDCl₃) δ 7.42–7.38 (m, 1 H), 7.34–7.29 (m,

7 H), 7.25 (td, J = 7.4, 1.3 Hz, 1 H), 6.35 (s, 2 H), 3.84 (s, 3 H),

3.75 (s, 6 H), 3.19 (t, J = 10.8 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 153.0, 147.5, 138.1, 135.3, 131.3, 129.6, 129.4, 128.9,

128.4, 128.0, 127.7, 127.4 (d, J = 3.8 Hz), 127.2, 125.7, 123.9 (t,

J = 269.2 Hz), 122.1 (d, J = 2.2 Hz), 107.6, 60.9, 56.1, 42.6 (t, J

= 30.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –69.38 (t, J = 10.9

Hz, 2 F); IR (film) 2938, 2839, 1754, 1699, 1591, 1507, 1479,

1460, 1422, 1359, 1324, 1275, 1259, 1235, 1188, 1155, 1125,

1045, 1010, 946, 916, 830, 748, 701, 660, 613, 569, 528 cm^-1;

HRMS (HAPCI+) calc. for C₂₃H₂₂F₂O₄(M+) 400.1486, found

400.1486. E-7j characteristic peaks: ¹H NMR (500 MHz,

CDCl₃) δ 5.61 (d, J = 6.2 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –84.18 (d, J = 6.2 Hz, 1 F); Z-7j characteristic peaks:

¹H NMR (500 MHz, CDCl₃) δ 5.06 (d, J = 28.7 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ –84.21 (d, J = 28.7 Hz, 1 F).

1

(M+) 402.0278, found 402.0267. E-7f characteristic peaks: H

NMR (500 MHz, CDCl₃) δ 5.66 (d, J = 5.7 Hz, 1 H); ¹⁹F NMR

(376 MHz, CDCl₃) δ –84.44 (d, J = 5.7 Hz, 1 F).

4-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-1,1'-

biphenyl (6g): Following General Procedure B-1, 0.115 g (0.50

mmol) of compound 1 was reacted with 0.426 g (2.50 mmol) of

4-phenylphenol in the presence of 0.033 g (0.25 mmol) of TBD

at 140 ˚C for 24 h. After workup with 1 N NaOH (aq.), the

product was purified by flash normal phase chromatography

using a gradient of hexanes to 5% PhMe and 15% EtOAc in

hexanes, furnishing 0.107 g of pure compound 6g as colorless

solid (MP = 67–70 ˚C), and 0.053 g of 80% pure compound 6g;

¹H NMR (500 MHz, CDCl₃) δ 7.56–7.54 (m, 4 H), 7.44 (t, J =

7.6 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.22 (d, J = 8.2 Hz, 2 H),

6.62 (s, 2 H), 3.88 (s, 9 H), 3.42 (t, J = 11.0 Hz, 2 H); ¹³C NMR

(126 MHz, CDCl₃) d 153.2, 149.9 (t, J = 2.1 Hz), 140.4, 138.7,

137.7 (t, J = 1.3 Hz), 128.9, 128.2, 127.7 (t, J = 3.2 Hz), 127.5,

127.2, 123.9 (t, J = 266.4 Hz), 122.0, 107.7, 61.0, 56.3, 42.6 (t, J

= 30.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –70.42 (t, J = 10.9

Hz, 2 F); IR (film) 2253, 1595, 1510, 1486, 1464, 1424, 1325,

1241, 1131, 1009, 905, 729, 650 cm^-1; HRMS (HAPCI+) calc.

for C₂₃H₂₂F₂O₄(M+) 400.1486, found 400.1478.

5-(2,2-difluoro-2-(o-tolyloxy)ethyl)-1,2,3-

trimethoxybenzene (6h): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.26 mL

(2.50 mmol) of o-cresol in the presence of 0.033 g (0.25 mmol)

of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH (aq.),

5-(2,2-difluoro-2-(4-methoxyphenoxy)ethyl)-1,2,3-

trimethoxybenzene (6k): Following General Procedure B-1,

0.115 g (0.50 mmol) of compound 1 was reacted with 0.310 g

(2.50 mmol) of 4-methoxyphenol in the presence of 0.033 g (0.25

8

Tetrahedron

ACCEPTED MANUSCRIPT

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

1-bromo-4-(1,1-difluoro-2-(4-

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.089 g (51% yield, 5% E-7k) of desired product 6k

as a colorless solid (MP = 64–66 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.05 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.59

(s, 2 H), 3.86 (s, 9 H), 3.77 (s, 3 H), 3.36 (t, J = 10.9 Hz, 2 H);

¹³C NMR (126 MHz, CDCl₃) δ 157.3, 153.1, 143.7, 137.6 (d, J =

1.4 Hz), 127.8 (d, J = 3.2 Hz), 123.8 (t, J = 266.8 Hz), 123.2,

114.4, 107.6, 60.9, 56.2, 55.6, 42.4 (t, J = 30.4 Hz); ¹⁹F NMR

(376 MHz, CDCl₃) δ –70.65 (t, J = 11.0 Hz, 2 F); IR (film) 3003,

2939, 2839, 2252, 1702, 1592, 1506, 1463, 1423, 1362, 1324,

1298, 1267, 1241, 1192, 1156, 1128, 1040, 1009, 943, 910, 842,

807, 784, 763, 735, 698, 649 cm^-1; HRMS (HAPCI+) calc. for

C₁₈H₂₀F₂O₅(M+) 354.1279, found 354.1269. E-7k characteristic

methoxyphenyl)ethoxy)benzene (9b): Following General

Procedure B-1, 0.086 g (0.50 mmol) of compound 8b was

reacted with 0.433 g (2.50 mmol) of 4-bromophenol in the

presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.097 g (56% yield) of desired product

1

9b as a peach solid (MP = 51–52 ˚C); H NMR (500 MHz,

CDCl₃) δ 7.43 (d, J = 8.9 Hz, 2 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.01

(d, J = 8.5 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.82 (s, 3 H), 3.39

(t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz, CDCl₃) δ 159.3,

149.6, 132.4, 131.6, 123.97 (t, J = 3.3 Hz), 123.91 (t, J = 267.2

Hz), 123.6 (d, J = 1.4 Hz), 118.6, 114.0, 55.3, 41.4 (t, J = 29.8

Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –71.48 (t, J = 11.2 Hz, 2 F);

IR (film) 3005, 2937, 2838, 1614, 1585, 1515, 1486, 1464, 1442,

1352, 1324, 1303, 1248, 1200, 1179, 1127, 1116, 1087, 1067,

1036, 1013, 908, 847, 821, 796, 785, 764, 736, 697, 677, 650 cm^-

¹; HRMS (HAPCI+) calc. for C₁₅H₁₃BrF₂O₂(M+) 342.0067,

found 342.0067.

1

peaks: H NMR (500 MHz, CDCl₃) δ 5.57 (d, J = 5.7 Hz, 1 H);

¹⁹F NMR (376 MHz, CDCl₃) δ –83.52 (d, J = 5.8 Hz, 1 F).

3-(1,1-difluoro-2-(3,4,5-trimethoxyphenyl)ethoxy)-N,N-

dimethylaniline (6l): Following General Procedure B-1, 0.115 g

(0.50 mmol) of compound 1 was reacted with 0.343 g (2.50

mmol) of 3-dimethylaminophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by normal-phase flash

chromatography using a gradient of 0–30% EtOAc in hexanes to

remove 3-dimethylaminophenol, followed by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.051 g (28% yield, 3% E-7l) of compound 6l as a

4-(3-(2-(2,4-dichlorophenoxy)-2,2-

difluoroethyl)phenyl)morpholine (9c): Following General

Procedure B-1, 0.112 g (0.50 mmol) of compound 8c was reacted

with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence

of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.148 g (78% yield, 6% E-10c, 1% Z-10c) of desired

1

yellow semisolid; H NMR (500 MHz, CDCl₃) δ 7.16 (t, J = 8.2

1

Hz, 1 H), 6.59 (s, 2 H), 6.55 (dd, J = 8.4, 2.5 Hz, 1 H), 6.52 (d, J

= 7.5 Hz, 1 H), 6.46 (t, J = 2.4 Hz, 1 H), 3.87 (s, 6 H), 3.86 (s, 3

H), 3.37 (t, J = 11.1 Hz, 2 H), 2.93 (s, 6 H); ¹³C NMR (126 MHz,

CDCl₃) δ 153.1, 151.7, 151.6 (t, J = 2.3 Hz), 137.6, 129.6, 127.9

(t, J = 3.2 Hz), 123.9 (t, J = 266.1 Hz), 109.7, 109.5, 107.6,

105.9, 61.0, 56.2, 42.6 (t, J = 30.6 Hz), 40.6; ¹⁹F NMR (376

MHz, CDCl₃) δ –69.93 (t, J = 11.1 Hz, 2 F); IR (film) 2938,

2840, 1699, 1608, 1592, 1505, 1460, 1423, 1358, 1324, 1263,

1236, 1126, 1045, 1003, 941, 876, 838, 812, 765, 750, 687, 668,

612, 528 cm^-1; HRMS (ESI+) calc. for C₁₉H₂₄F₂NO₄(M+H)

product 9c as a yellow solid (MP = 61–64 ˚C); H NMR (500

MHz, CDCl₃) δ 7.45 (d, J = 2.5 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1

H), 7.30–7.28 (m, 1 H), 7.23 (dd, J = 8.8, 2.5 Hz, 1 H), 7.00 (t, J

= 1.9 Hz, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 6.93 (dd, J = 8.3, 2.4

Hz, 1 H), 3.92–3.90 (m, 4 H), 3.51 (t, J = 11.2 Hz, 2 H), 3.24–

3.22 (m, 4 H); ¹³C NMR (126 MHz, CDCl₃) δ 151.4, 145.3,

132.4 (t, J = 3.4 Hz), 131.2, 130.3, 129.2, 128.3, 127.7, 124.1 (t,

J = 269.2 Hz), 124.0 (t, J = 1.9 Hz), 122.4, 118.1, 115.1, 67.0,

49.4, 42.4 (t, J = 29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –70.77

(t, J = 11.30 Hz, 2 F); IR (film) 2967, 2860, 2250, 1604, 1585,

1495, 1476, 1449, 1380, 1353, 1325, 1304, 1274, 1259, 1245,

1218, 1175, 1120, 1097, 1068, 998, 976, 908, 869, 837, 812, 763,

745, 697, 650, 618 cm^-1; HRMS (ESI+) calc. for C₁₈H₁₈Cl₂F₂NO₂

(M+H) 388.0683, found 388.0669. E-10c characteristic peaks: ¹H

NMR (500 MHz, CDCl₃) δ 5.73 (d, J = 6.3 Hz, 1 H); ¹⁹F NMR

(376 MHz, CDCl₃) δ –85.25 (d, J = 6.7 Hz, 1 F); Z-10c

1

368.1673, found 368.1662. E-7l characteristic peaks: H NMR

(500 MHz, CDCl₃) δ 5.61 (d, J = 5.5 Hz, 1 H); ¹⁹F NMR (376

MHz, CDCl₃) δ –82.25 (d, J = 5.7 Hz, 1 F).

Compounds in Table 3:

(4-(2-(2,4-dichlorophenoxy)-2,2-

1

characteristic peaks: H NMR (500 MHz, CDCl₃) δ 5.26 (d, J =

difluoroethyl)phenyl)(methyl)sulfane (9a): Following General

Procedure B-1, 0.093 g (0.50 mmol) of compound 8a was reacted

with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence

of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.112 g (68% yield, 2% E-10a) of desired product 9a

as a tan solid (MP = 69–70 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.40 (d, J = 2.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.25

(d, J = 8.4 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 1 H), 7.18 (ddd, J = 8.8,

2.5, 1.0 Hz, 1 H), 3.45 (t, J = 11.1 Hz, 2 H), 2.49 (d, J = 1.1 Hz, 3

H); ¹³C NMR (126 MHz, CDCl₃) δ 145.3, 138.3, 131.3, 131.2,

130.3, 128.4, 128.3 (t, J = 3.4 Hz), 127.7, 126.6, 124.1 (t, J = 2.0

Hz), 124.0 (t, J = 269.7 Hz), 41.7 (t, J = 29.4 Hz), 15.9; ¹⁹F NMR

(376 MHz, CDCl₃) δ –71.10 (t, J = 11.1 Hz, 2 F); IR (film) 2924,

1476, 1433, 1408, 1352, 1324, 1283, 1260, 1217, 1174, 1119,

1095, 1061, 1019, 958, 907, 868, 843, 800, 762, 733, 696, 675,

650 cm^-1; HRMS (HAPCI+) calc. for C₁₅H₁₂Cl₂F₂OS (M+)

28.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ –84.99 (d, J = 28.6

Hz, 1 F).

4'-(tert-butyl)-2-(2-(2,4-dichlorophenoxy)-2,2-

difluoroethyl)-1,1'-biphenyl (9d): Following General Procedure

B-1, 0.136 g (0.50 mmol) of compound 8d was reacted with

0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of

0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.153 g (70% yield, 3% E-10d) of desired product 9d

as a colorless solid (MP = 76–78 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.70 (s, 1 H), 7.64–7.62 (m, 3 H), 7.55 (d, J = 7.9 Hz, 2

H), 7.49 (t, J = 7.7 Hz, 1 H), 7.46 (d, J = 2.1 Hz, 1 H), 7.43 (d, J

= 7.6 Hz, 1 H), 7.31 (dd, J = 8.9, 1.3 Hz, 1 H), 7.24 (dt, J = 8.9,

1.8 Hz, 1 H), 3.63 (t, J = 11.1 Hz, 2 H), 1.45 (s, 9H); ¹³C NMR

(126 MHz, CDCl₃) δ 150.6, 145.3, 141.4, 138.1, 132.0 (t, J = 3.4

Hz), 131.3, 130.3, 129.6, 129.4, 128.9, 128.5, 127.7, 127.0,

126.6, 125.9, 124.20 (t, J = 2.1 Hz), 124.15 (t, J = 269.3 Hz),

42.3 (t, J = 29.3 Hz), 34.7, 31.5; ¹⁹F NMR (376 MHz, CDCl₃) δ –

70.80 (t, J = 11.0 Hz, 2 F); IR (film) 2964, 2250, 1476, 1352,

1

347.9954, found 347.9944. E-10a characteristic peaks: H NMR

(500 MHz, CDCl₃) δ 5.69 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376

MHz, CDCl₃) δ –85.56 (d, J = 6.1 Hz, 1 F).

9

1324, 1256, 1218, 1174, 1116, 1097, 1062, 1043, 1016, 907, 868,

837, 813, 794, 763, 734, 704, 650, 617 cm^-1; HRMS (HAPCI+)

calc. for C₂₄H₂₂Cl₂F₂₁O (M+) 434.1016, found 434.0999. E-10d

characteristic peaks: H NMR (500 MHz, CDCl₃) δ 5.83 (d, J =

6.2 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ –85.04 (d, J = 6.1

Hz, 1 F).

EtOAc in hexanes, furnishing 1.57 g (41% yield) of desired

ACCEPTED MANUSCRIPT

product 8h as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (dd,

J = 8.4, 2.0 Hz, 1 H), 7.02 (dd, J = 4.2, 2.3 Hz, 2 H), 5.34 (dd, J

= 25.6, 3.9 Hz, 1 H), 2.32 (s, 3 H), 2.27 (s, 3 H); ¹³C NMR (126

MHz, CDCl₃) δ 156.2 (dd, J = 295.2, 288.1 Hz), 137.2, 135.8

(dd, J = 4.8, 1.7 Hz), 131.1, 128.1 (dd, J = 7.9, 2.0 Hz), 127.0,

126.0 (dd, J = 6.9, 4.9 Hz), 79.3 (dd, J = 28.7, 14.9 Hz), 21.2,

20.0; ¹⁹F NMR (376 MHz, CDCl₃) δ –84.76 (dd, J = 33.1, 4.1

Hz, 1 F), –85.53 (ddd, J = 33.1, 25.5, 1.8 Hz, 1F); IR (film) 2923,

1726, 1616, 1569, 1505, 1453, 1379, 1345, 1281, 1250, 1235,

1180, 1111, 1074, 1037, 948, 917, 876, 836, 818, 765, 750, 721,

615, 581, 549, 534 cm^-1; HRMS (HAPCI+) calc. for C₁₀H₁₀F₂

(M+) 168.0751, found 168.0745.

1-(2-(4-(tert-butyl)phenyl)-1,1-difluoroethoxy)-2,4-

dichlorobenzene (9f): Following General Procedure B-1, 0.098

g (0.50 mmol) of compound 8f was reacted with 0.408 g (2.50

mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.074 g (41% yield) of desired product 9f as a clear

oil; ¹H NMR (500 MHz, CDCl₃) δ 7.43–7.40 (m, 3 H), 7.35 (d, J

= 8.1 Hz, 2 H), 7.28–7.26 (m, 1 H), 7.20 (ddd, J = 8.8, 2.5, 0.8

Hz, 1 H), 3.50 (t, J = 11.3 Hz, 2 H), 1.36 (9 H); ¹³C NMR (126

MHz, CDCl₃) δ 150.8, 145.4, 131.3, 130.4, 130.3, 128.6, 128.4,

127.7, 125.5, 124.2 (t, J = 269.8 Hz), 124.1 (t, J = 2.1 Hz), 41.7

(t, J = 29.2 Hz), 34.7, 31.5; ¹⁹F NMR (376 MHz, CDCl₃) δ –

71.02 (t, J = 11.4 Hz, 2 F); IR (film) 2965, 2869, 1477, 1352,

1325, 1274, 1260, 1218, 1175, 1159, 1124, 1097, 1062, 1026,

907, 869, 838, 805, 764, 745, 697, 651 cm^-1; HRMS (HAPCI+)

calc. for C₁₈H₁₈Cl₂F₂O (M+) 358.0703, found 358.0701.

2,4-dichloro-1-(2-(2,4-dimethylphenyl)-1,1-

difluoroethoxy)benzene (9h): Following General Procedure B-

1, 0.084 g (0.50 mmol) of compound 8h was reacted with 0.408 g

(2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.050 g (27% yield, 8% E-10h) as a pale yellow

1

semisolid; H NMR (500 MHz, CDCl₃) δ 7.40 (d, J = 2.5 Hz, 1

H), 7.25–7.22 (m, 2 H), 7.17 (dd, J = 8.8, 2.4 Hz, 1 H), 7.04 (s, 1

H), 7.01 (d, J = 7.9 Hz, 1 H), 3.50 (t, J = 11.3 Hz, 2 H), 2.40 (s, 3

H), 2.31 (s, 3 H); ¹³C (126 MHz, CDCl₃) δ 145.4 (t, J = 1.6 Hz),

137.74, 137.68, 131.7, 131.4, 131.3, 130.3, 128.5, 127.7, 127.0

(t, J = 3.1 Hz), 126.8, 124.6 (t, J = 271.0 Hz), 124.2 (t, J = 2.0

Hz), 38.6 (t, J = 29.2 Hz), 21.2, 20.0; ¹⁹F NMR (376 MHz,

CDCl₃) δ –70.43 (t, J = 11.4 Hz, 2 F); IR (film) 2923, 1702,

1618, 1583, 1508, 1476, 1382, 1347, 1311, 1258, 1217, 1126,

1095, 1060, 963, 942, 866, 810, 792, 762, 694, 673, 626, 566,

465, 455 cm^-1; MS (EI+) calc. for C₁₆H₁₁₄Cl₂F₂O (M+) 330.0,

found 330.0. E-10h characteristic peaks: H NMR (500 MHz,

CDCl₃) δ 5.83 (d, J = 6.4 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –85.72 (d, J = 6.4 Hz, 1 F).

1-(2,2-difluorovinyl)-3,5-dimethylbenzene (8g): Following

General Procedure A, 3,5-dimethylbenzaldehyde (2.10 mL, 15.0

mmol) was reacted with PPh₃(6.23 g, 22.5 mmol) and

BrCF₂CO₂K (6.05 g, 27.0 mmol). Following workup, the product

was purified by flash chromatography using a gradient of 0–10%

EtOAc in hexanes, furnishing 1.163 g (44% yield) of desired

product 8g as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 6.97 (bs,

2 H), 6.90 (bs, 1 H), 5.21 (dd, J = 26.4, 4.0 Hz, 1H), 2.32 (s, 6

H); ¹³C NMR (126 MHz, CDCl₃) δ 156.3 (dd, J = 298.2, 287.4

Hz), 138.3, 130.3 (t, J = 6.7 Hz), 128.9 (t, J = 2.2 Hz), 125.6 (dd,

J = 6.6, 3.7 Hz), 82.3 (dd, J = 28.9, 13.6 Hz), 21.4; ¹⁹F NMR

(376 MHz, CDCl₃) δ –82.39 (dd, J = 32.5, 26.5 Hz, 1 F), –84.62

(dd, J = 32.5, 4.0 Hz, 1F); IR (film) 3019, 2921, 2868, 1726,

1605, 1448, 1379, 1350, 1297, 1198, 1160, 1038, 965, 892, 851,

814, 765, 750, 715, 690, 583, 539, 515 cm^-1; HRMS (TAPCI)

calc. for C₁₀H₁₀F₂(M) 168.0751, found 168.0744.

ethyl

(E)-3-(3-(2-(2,4-dichlorophenoxy)-2,2-

(9j): Following General

difluoroethyl)phenyl)acrylate

Procedure B-1, 0.119 g (0.50 mmol) of compound 8j was reacted

with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence

of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.127 g (64% yield) of desired product 9j as a

colorless solid (MP = 70–72 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.70 (d, J = 16.0 Hz, 1 H), 7.56 (s, 1 H), 7.49 (d, J =

7.5 Hz, 1 H), 7.42–7.36 (m, 3 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.17

(dd, J = 8.8, 2.5 Hz, 1 H), 6.47 (d, J = 16.0 Hz, 1 H), 4.27 (q, J =

7.1 Hz, 2 H), 3.51 (t, J = 10.9 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H);

¹³C NMR (126 MHz, CDCl₃) δ 167.0, 145.1, 144.2, 134.8, 132.5,

132.3 (t, J = 3.4 Hz), 131.4, 130.4, 130.3, 129.1, 128.4, 127.7,

127.5, 124.1 (d, J = 1.8 Hz), 123.9 (t, J = 269.7 Hz), 118.9, 60.6,

42.0 (t, J = 29.4 Hz), 14.4; ¹⁹F NMR (376 MHz, CDCl₃) δ –70.81

(t, J = 10.9 Hz, 2 F); IR (film) 2983, 2253, 1709, 1640, 1608,

1585, 1476, 1438, 1385, 1367, 1354, 1322, 1274, 1260, 1228,

1179, 1163, 1119, 1097, 1061, 983, 909, 865, 840, 812, 763, 750,

694 cm^-1; HRMS (HAPCI+) calc. for C₁₉H₁₆Cl₂F₂O₃(M+)

400.0445, found 400.0435.

2,4-dichloro-1-(2-(3,5-dimethylphenyl)-1,1-

difluoroethoxy)benzene (9g): Following General Procedure B-

1, 0.085 g (0.50 mmol) of compound 8i was reacted with 0.408 g

(2.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.092 g (55% yield) of desired product 9i as a pale

1

yellow oil; H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 2.5 Hz, 1

H), 7.25 (d, J = 8.6 Hz, 1 H), 7.18 (dd, J = 8.8, 2.5 Hz, 1 H), 7.02

(s, 2 H), 6.97 (s, 1 H), 3.42 (t, J = 11.4 Hz, 2 H), 2.33 (s, 6 H);

¹³C NMR (126 MHz, CDCl₃) δ 145.5, 138.0, 131.3 (t, J = 3.2

Hz), 131.2, 130.3, 129.5, 128.6, 128.4, 127.7, 124.2 (t, J = 269.5

Hz), 124.1 (d, J = 2.2 Hz), 42.1 (t, J = 29.3 Hz), 21.4; ¹⁹F NMR

(376 MHz, CDCl₃) δ –70.95 (t, J = 11.4 Hz, 2 F); IR (film) 3010,

2920, 1608, 1584, 1476, 1433, 1382, 1353, 1298, 1276, 1251,

1218, 1168, 1096, 1061, 962, 866, 847, 809, 764, 751, 715, 695,

661 cm^-1; HRMS (HAPCI+) calc. for C₁₆H₁₄Cl₂F₂O (M+)

330.0390, found 330.0391.

2,4-dichloro-1-(1,1-difluoro-2-(3-

nitrophenyl)ethoxy)benzene (9k): Following General Procedure

B-1, 0.093 g (0.50 mmol) of compound 8k was reacted with

0.408 g (2.50 mmol) of 2,4-dichlorophenol in the presence of

0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

1-(2,2-difluorovinyl)-2,4-dimethylbenzene (8h): Following

General Procedure A, 2,4-dimethylbenzaldehyde (3.20 mL, 22.0

mmol) was reacted with PPh₃(8.84 g, 33.0 mmol) and

BrCF₂CO₂K (8.76 g, 40.0 mmol). Following workup, the product

was purified by flash chromatography using a gradient of 0–10%

10

Tetrahedron

ACCEPTED MANUSCRIPT

furnishing 0.083 g (47% yield, 3% E-10k, 1% Z-10k) of

CDCl₃) δ 7.49 (dd, J = 8.3, 1.7 Hz, 2 H), 7.40 (d, J = 2.3 Hz, 1

1

desired product 9k as a clear solid (MP = 96–97 ˚C); H NMR

(500 MHz, CDCl₃) δ 8.30 (d, J = 2.1 Hz, 1 H), 8.22 (dd, J = 8.3,

2.5 Hz, 1 H), 7.75 (d, J = 7.7 Hz, 1 H), 7.55 (t, J = 7.9 Hz, 1 H),

7.39 (d, J = 2.5 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 7.20 (dd, J =

8.8, 2.3 Hz, 1 H), 3.61 (t, J = 10.5 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 144.9 (d, J = 1.9 Hz), 136.9, 133.5, 131.7, 130.4, 129.5,

128.4, 127.9, 125.8, 124.1 (t, J = 2.0 Hz), 123.5 (t, J = 269.6 Hz),

123.1, 41.9 (t, J = 30.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –

70.75 (t, J = 10.6 Hz, 2 F); IR (film) 2956, 2923, 2870, 1702,

1532, 1475, 1352, 1324, 1300, 1258, 1216, 1173, 1158, 1125,

1097, 1068, 1061, 1027, 970, 908, 866, 802, 765, 34, 697, 677,

657 cm^-1; HRMS (HAPCI+) calc. for C₁₄H₉Cl₂F₂NO₃(M+)

H), 7.28 (d, J = 8.7 Hz, 2 H), 7.22 (dd, J = 8.8, 1.5 Hz, 1 H), 7.19

(dd, J = 8.8, 2.3 Hz, 1 H), 3.45 (t, J = 10.9 Hz, 2 H); ¹³C NMR

(126 MHz, CDCl₃) δ 145.2, 132.4, 131.7, 131.5, 130.6 (t, J = 3.2

Hz), 130.4, 128.5, 127.8, 124.2, 123.8 (t, J = 269.9 Hz), 122.2,

41.7 (t, J = 29.6 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –71.02 (t, J

= 10.8 Hz, 2 F); IR (film) 2925, 1701, 1583, 1476, 1433, 1408,

1384, 1350, 1260, 1217, 1099, 1073, 1061, 1014, 897, 868, 843,

799, 762, 672, 623, 565, 489 cm^-1; HRMS (HAPCI+) calc. For

C₁₄H₉BrCl₂F₂O (M+) 379.9182, found 379.9169.

2,4-dichloro-1-(1,1-difluoro-2-(2-

iodophenyl)ethoxy)benzene (9n): Following General Procedure

B-2, 0.133 g (0.50 mmol) of compound 8n was reacted with

0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of

0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.105 g (49% yield) of desired compound 9n as a

colorless solid (MP = 54–55 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.91 (dd, J = 7.9, 1.3 Hz, 1 H), 7.52 (dd, J = 7.8, 1.6

Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.35 (td, J = 7.6, 1.3 Hz, 1

H), 7.27–7.25 (m, 1 H), 7.19 (dd, J = 8.8, 2.5 Hz, 1 H), 7.01 (td, J

= 7.7, 1.7 Hz, 1 H), 3.77 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126

MHz, CDCl₃) δ 145.3, 140.0, 135.2 (t, J = 2.8 Hz), 131.8, 131.5,

130.4, 129.6, 128.7, 128.4, 127.8, 124.4, 124.1 (t, J = 270.1 Hz),

102.2, 46.1 (t, J = 29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –

69.75 (t, J = 10.8 Hz, 2 F); IR (film) 2924, 1698, 1584, 1565,

1475, 1436, 1384, 1349, 1276, 1258, 1216, 1124, 1096, 1061,

1046, 1014, 868, 811, 765, 748, 694, 671, 652, 626, 613, 566,

488, 473, 459 cm^-1; HRMS (HAPCI+) calc. for C₁₄H₉Cl₂F₂IO

(M+) 427.9043, found 427.9029.

1

346.9928, found 346.9925. E-10k characteristic peaks: H NMR

(500 MHz, CDCl₃) δ 5.73 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376

MHz, CDCl₃) δ –81.93 (d, J = 5.5 Hz, 1 F); Z-10k characteristic

peaks: ¹H NMR (500 MHz, CDCl₃) δ 5.21 (d, J = 28.0 Hz, 1 H);

¹⁹F NMR (376 MHz, CDCl₃) δ –82.18 (d, J = 27.9 Hz, 1 F).

3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)benzonitrile

(9l): Following General Procedure B-2, 0.083 g (0.50 mmol) of

compound 8l was reacted with 0.245 g (1.50 mmol) of 2,4-

dichlorophenol in the presence of 0.033 g (0.25 mmol) of TBD at

140 ˚C for 24 h. After workup with 1 N NaOH (aq.), the product

was purified by reverse-phase flash chromatography using a

gradient of 2–100% MeCN in H₂O, furnishing 0.080 g (49%

yield) of desired compound 9l as a colorless solid (MP = 81–83

1

˚C); H NMR (500 MHz, CDCl₃) δ 7.71 (d, J = 2.3 Hz, 1 H),

7.65–7.63 (m, 2 H), 7.48 (dt, J = 8.5, 4.3 Hz, 1 H), 7.39 (t, J =

2.0 Hz, 1 H), 7.24–7.18 (m, 2 H), 3.53 (t, J = 10.6 Hz, 2 H); ¹³

C

NMR (126 MHz, CDCl₃) δ 145.0, 135.2, 134.3, 133.1, 131.72,

131.66, 130.4, 129.4, 128.4, 127.8, 124.1. 123.5 (t, J = 269.9

Hz), 118.6, 112.9, 41.8 (t, J = 29.9 Hz); ¹⁹F NMR (376 MHz,

CDCl₃) δ –70.80 (t, J = 10.6 Hz, 2 F); IR (film) 3082, 2955,

2230, 1704, 1587, 1476, 1434, 1382, 1352, 1303, 1278, 1261,

1242, 1232, 1219, 1179, 1102, 1071, 1056, 1003, 976, 942, 918,

904, 873, 866, 823, 811, 800, 758, 738, 694, 644, 618, 577, 463

cm^-1; HRMS (HAPCI+) calc. for C₁₅H₉Cl₂F₂NO (M+) 327.0029,

found 327.0031.

2,4-dichloro-1-(1,1-difluoro-2-(3-

(trifluoromethyl)phenyl)ethoxy)benzene

(9o):

Following

General Procedure B-2, 0.104 g (0.50 mmol) of compound 8o

was reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in

the presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.094 g (51% yield) of desired

2-(2,2-difluorovinyl)-1,3-dimethylbenzene (8l): Following

General Procedure A, 2,6-dimethylbenzaldehyde (2.2 mL, 15.0

mmol) was reacted with PPh₃(5.91 g, 22.5 mmol) and

BrCF₂CO₂K (6.17 g, 27.0 mmol). Following workup, the product

was purified by flash chromatography using a gradient of 0–10%

EtOAc in hexanes, furnishing 0.763 g (28% yield) of desired

product 8l as a clear oil; ¹H NMR (400 MHz, CDCl₃) δ 7.14 (dd,

J = 8.6, 6.4 Hz, 1 H), 7.07 (d, J = 7.5 Hz, 2 H), 5.23 (dd, J =

27.5, 2.3 Hz, 1 H), 2.29 (s, 6 H); ¹³C NMR (126 MHz, CDCl₃)

155.0 (q, J = 291.7, 288.4 Hz), 137.5 (dd, J = 2.6, 1.4 Hz), 127.8,

127.6, 78.1 (dd, J = 27.3, 20.6 Hz), 20.5 (d, J = 2.4 Hz); ¹⁹F

NMR (376 MHz, CDCl₃) δ –83.38 (dd, J = 32.5, 27.0 Hz, 1 F), –

87.16 (dd, J = 33.1, 2.4 Hz, 1 F); IR (film) 3024, 2956, 2923,

2330, 1736, 1586, 1468, 1445, 1380, 1329, 1276, 1254, 1222,

1166, 1096, 1032, 932, 850, 802, 768, 746, 698, 599, 537 cm^-1;

HRMS (TAPCI) calc. for C₁₀H₁₀F₂(M) 168.0751, found

168.0741.

1

compound 9o as a clear oil; H NMR (500 MHz, CDCl₃) δ 7.69

(s, 1 H), 7.60 (t, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.40

(t, J = 2.0 Hz, 1 H), 7.24 (dd, J = 8.8, 1.4 Hz, 1 H), 7.19 (dd, J =

8.8, 2.4 Hz, 1 H), 3.56 (t, J = 10.7 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 145.2, 134.2, 132.6 (t, J = 3.3 Hz), 131.6, 130.4, 129.0,

128.5, 127.8, 127.6 (q, J = 4.0 Hz), 125.3, 124.9 (q, J = 3.9 Hz),

124.1, 123.8 (t, J = 269.7 Hz), 123.1, 42.1 (t, J = 29.7 Hz); ¹⁹F

NMR (376 MHz, CDCl₃, β,β,β-trifluoroethanol as standard with

ppm = –79.40) δ –64.86 (s, 3 F), –72.02 (t, J = 11.0 Hz, 2 F); IR

(film) 2949, 1584, 1477, 1454, 1435, 1354, 1329, 1257, 1202,

1166, 1126, 1100, 1076, 1062, 870, 800, 764, 751, 703, 664, 617,

564 cm^-1; HRMS (HAPCI+) calc. for C₁₅H₉Cl₂F₅O (M+)

369.9951, found 369.9934.

2,4-dichloro-1-(2-(3,5-dichlorophenyl)-1,1-

difluoroethoxy)benzene (9p): Following General Procedure B-

2, 0.105 g (0.50 mmol) of compound 8p was reacted with 0.245 g

(1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

1-(2-(4-bromophenyl)-1,1-difluoroethoxy)-2,4-

dichlorobenzene (9m): Following General Procedure B-2, 0.110

g (0.50 mmol) of compound 8m was reacted with 0.245 g (1.50

mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.113 g (59% yield) of desired compound 9m as a

colorless solid (MP = 52–53 ˚C); ¹H NMR (500 MHz,

furnishing 0.078

g

(42% yield, 1% E-10p, 1%

trifluoroethylbenzene side product) of desired compound 9p as a

1

pinkish colorless solid (MP = 46–47 ˚C); H NMR (500 MHz,

CDCl₃) δ 7.41 (d, J = 2.4 Hz, 1 H), 7.35 (t, J = 1.9 Hz, 1 H), 7.31

(d, J = 2.0 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.20 (dd, J = 8.8,

11

2.4 Hz, 1 H), 3.45 (t, J = 10.6 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 145.1, 135.1, 134.7, 131.7, 130.5, 129.3, 128.5, 128.3,

127.8, 124.1, 123.5 (t, J = 269.8 Hz), 41.7 (t, J = 30.1 Hz); ¹⁹F

NMR (376 MHz, CDCl₃) δ –70.61 (t, J = 10.6 Hz, 2 F); IR (film)

1592, 1570, 1476, 1436, 1385, 1351, 1258, 1062, 867, 800, 763,

702, 643, 565 cm^-1; HRMS (HAPCI+) calc. for C₁₄H₈Cl₄F₂O

brown oil; ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, J = 8.6 Hz,

ACCEPTED MANUSCRIPT

2 H), 7.39 (d, J = 2.4 Hz, 1 H), 7.30–7.27 (m, 2 H) 7.23 (d, J =

8.8 Hz, 1 H), 7.20 (dd, J = 8.8, 2.4 Hz, 1 H), 3.53 (t, J = 10.6 Hz,

2 H); ¹³C NMR (126 MHz, CDCl₃) δ 149.4, 145.0 (t, J = 1.7 Hz),

132.7, 132.2 (t, J = 3.5 Hz), 131.7, 130.4, 129.7, 127.8, 124.2 (t,

J = 2.1 Hz), 123.6 (t, J = 269.3 Hz), 121.5, 118.9 (q, J = 320.7

Hz), 41.6 (t, J = 29.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃, delay

time = 5 s) δ –70.80 (t, J = 10.6 Hz, 2 F), –73.85 (s, 3 F); IR

(film) 1704, 1601, 1584, 1504, 1476, 1421, 1353, 1251, 1212,

1183, 1140, 1113, 1100, 1061, 1020, 946, 890, 807, 764, 729,

694, 674, 640, 609, 579, 523, 492 cm^-1; HRMS (HAPCI+) calc.

for C₁₅H₉Cl₂F₅O₄S (M+) 449.9519, found 449.9516.

1

(M+) 369.9297, found 369.9300. E-10p characteristic peaks: H

NMR (500 MHz, CDCl₃) δ 5.75 (d, J = 5.8 Hz, 1 H); ¹⁹F NMR

(376 MHz, CDCl₃) δ –81.75 (d, J = 5.8 Hz, 1 F).

4-(2,2-difluorovinyl)-N,N-diisopropylbenzamide

(8q):

Following General Procedure A, compound 8q–1 (0.823, 3.60

mmol) was reacted with PPh₃(1.50 g, 5.30 mmol) and

BrCF₂CO₂K (1.42 g, 6.50 mmol) in NMP (2.0 mL, 2 M).

Following workup, the product was purified by flash

chromatography using a gradient of 0–30% EtOAc in hexanes,

furnishing 0.655 g (69% yield) of desired product 8q as a

Compounds in Table 4:

3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1-tosyl-1H-

indole (12a): Following General Procedure B-1, 0.167 g (0.50

mmol) of compound 11a was reacted with 0.408 g (2.50 mmol)

of 2,4-dichlorophenol in the presence of 0.033 g (0.25 mmol) of

TBD at 140 ˚C for 24 h. After workup with 1 N NaOH (aq.), the

product was purified by reverse-phase flash chromatography

using a gradient of 2–100% MeCN in H₂O, furnishing 0.209 g

(84% yield, 3% E-13a, 1% Z-13a) of desired product 12a as an

1

colorless solid (MP = 43–44 ˚C); H NMR (500 MHz, DMSO-

D₆, 25 °C) δ 7.41 (d, J = 8.1 Hz, 2 H), 7.29 (d, J = 8.2 Hz, 2 H),

5.85 (dd, J = 28.1, 4.1 Hz, 1 H), 3.61 (bs, 2 H), 1.38–1.15 (m, 12

H); ¹H NMR (500 MHz, DMSO-D₆, 60 °C) δ 7.41 (d, J = 7.9 Hz,

2 H), 7.28 (d, J = 7.9 Hz, 2 H), 5.79 (dd, J = 27.8, 4.0 Hz, 1 H),

3.64 (hept, J = 6.4 Hz, 2 H), 1.28 (bs, 12 H); ¹³C NMR (126

MHz, DMSO-D₆, 60 °C) δ 169.8, 156.1 (dd, J = 297.8, 286.2

Hz), 138.2 (t, J = 2.3 Hz), 130.5 (dd, J = 7.8, 5.8 Hz), 128.1 (dd,

J = 6.6, 3.8 Hz), 126.3, 82.3 (dd, J = 29.5, 11.8 Hz), 20.9; ¹⁹F

NMR (376 MHz, DMSO-D₆, 25 °C) δ –82.16 (dd, J = 32.1, 28.1

Hz, 1 F), –84.02 (dd, J = 32.2, 4.1 Hz, 1 F); IR (film) 3434, 2252,

2126, 1729, 1660, 1345, 1276, 1052, 1024, 1005, 822, 760, 623

cm^-1; HRMS (ESI+) calc. for C₁₅H₂₀F₂NO (M+H) 268.1513,

found 268.1500.

orange solid (MP

=

90–93 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 8.01 (d, J = 8.3 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 2 H), 7.68

(s, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 2.3 Hz, 1 H), 7.35

(t, J = 7.8 Hz, 1 H), 7.27 (t, J = 7.3 Hz, 1 H), 7.22–7.16 (m, 5 H),

3.61 (t, J = 10.8 Hz, 2 H), 2.32 (s, 3 H); ¹³C NMR (126 MHz,

CDCl₃) δ 145.1, 135.3, 135.0, 131.5, 130.8, 130.3, 130.0, 129.2,

128.5, 128.3, 127.7, 126.9, 126.3, 125.4, 125.0, 124.3 (t, J = 1.9

Hz), 123.9 (t, J = 269.4 Hz), 123.4, 119.8, 113.7, 112.8 (t, J = 3.7

Hz), 32.1 (t, J = 31.5 Hz), 21.6; ¹⁹F NMR (376 MHz, CDCl₃) δ –

70.61 (t, J = 10.9 Hz, 2 F); IR (film) 2258, 1598, 1476, 1448,

1369, 1324, 1275, 1259, 1217, 1188, 1175, 1122, 1090, 1061,

1020, 977, 908, 869, 811, 784, 765, 747, 703, 672, 750 cm^-1;

HRMS (ESI+) calc. for C₂₃H₁₈Cl₂F₂NO₃S (M+H) 496.0353,

found 496.0371. E-13a characteristic peaks: ¹H NMR (500 MHz,

CDCl₃) δ 5.82 (d, J = 3.5 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –86.14 (d, J = 3.0 Hz, 1 F); Z-13a characteristic peaks:

¹H NMR (500 MHz, CDCl₃) δ 5.42 (d, J = 29.0 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ –80.20 (d, J = 29.1 Hz, 1 F).

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-N,N-

diisopropylbenzamide (9q): Following General Procedure B-2,

0.134 g (0.50 mmol) of compound 8q was reacted with 0.245 g

(1.50 mmol) of 2,4-dichlorophenol in the presence of 0.033 g

(0.25 mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N

NaOH (aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.126 g (59% yield, 3% E-10q, 1% Z-10q) of desired

compound 9q as a orange solid (MP = 81–83 ˚C); ¹H NMR (500

MHz, CDCl₃, 25 ˚C) δ 7.40 (d, J = 7.9 Hz, 2 H), 7.37 (d, J = 2.5

Hz, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 8.9 Hz, 1 H), 7.18

(dd, J = 8.8, 2.5 Hz, 1 H), 3.74 (bs, 1 H), 3.49 (t, J = 11.0 Hz, 2

H), 1.46 (bs, 6 H), 1.21 (bs, 6 H); ¹³C NMR (126 MHz,

CDCl₃) δ 170.8, 145.2, 138.6, 132.1 (t, J = 3.2 Hz), 131.5, 130.9,

130.3, 128.5, 127.8, 126.2, 125.8, 124.2, 124.0 (t, J = 271.0 Hz),

41.99 (t, J = 29.3 Hz), 20.9; ¹⁹F NMR (376 MHz, CDCl₃) δ –

70.73 (t, J = 11.3 Hz, 2 F); IR (film) 2993, 2969, 2933, 1628,

1474, 1440, 1375, 1360, 1339, 1261, 1241, 1226, 1214, 1204,

1112, 1094, 1058, 1028, 902, 876, 856, 842, 811, 800, 771, 753,

676, 578 cm^-1; HRMS (ESI+) calc. for C₂₁H₂₃Cl₂F₂NO₂Na

(M+Na) 452.0972, found 452.0966. E-10q characteristic peaks:

¹H NMR (500 MHz, CDCl₃) δ 5.70 (d, J = 6.1 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ –84.19 (d, J = 5.9 Hz, 1 F); Z-10q

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)-1-phenyl-

1H-pyrazole (12b): Following General Procedure B-1, 0.104 g

(0.50 mmol) of compound 11b was reacted with 0.408 g (2.50

mmol) of 2,4-dichlorophenol in the presence of 0.033 g (0.25

mmol) of TBD at 140 ˚C for 24 h. After workup with 1 N NaOH

(aq.), the product was purified by reverse-phase flash

chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.081 g (44% yield) of desired product 12b as a

yellow solid (MP

=

44–46 ˚C); ¹H NMR (500 MHz,

CDCl₃) δ 7.97 (s, 1 H), 7.74 (s, 1 H), 7.70–7.68 (m, 2 H), 7.45

(dd, J = 8.6, 7.3 Hz, 2 H), 7.42 (d, J = 2.5 Hz, 1 H), 7.30–7.26

(m, 2 H), 7.20 (dd, J = 8.9, 2.5 Hz, 1 H), 3.47 (t, J = 11.0 Hz, 2

H); ¹³C NMR (126 MHz, CDCl₃) δ 145.2, 142.1, 140.1, 131.5,

130.4, 129.6, 128.4, 127.8, 127.3, 126.7, 124.2 (t, J = 1.9 Hz),

123.9 (t, J = 268.7 Hz), 119.2, 113.0 (t, J = 3.9 Hz), 31.9 (t, J =

31.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –71.98 (t, J = 11.0 Hz,

2 F); IR (film) 3053, 2927, 1601, 1576, 1505, 1476, 1431, 1403,

1385, 1343, 1258, 1215, 1187, 1120, 1097, 1062, 1042, 1017,

955, 905, 867, 838, 808, 756, 711, 691, 674, 656 cm^-1; HRMS

(ESI+) calc. for C₁₇H₁₃Cl₂F₂N₂O (M+H) 369.0373, found

369.0347.

1

characteristic peaks: H NMR (500 MHz, CDCl₃) δ 5.24 (d, J =

28.6 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ –84.28 (d, J = 29.0

Hz, 1 F).

4-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl

trifluoromethanesulfonate (9r): Following General Procedure

B-2, 0.144 g (0.50 mmol) of compound 8r was reacted with

0.245 g (1.50 mmol) of 2,4-dichlorophenol in the presence of

0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h. After workup

with 1 N NaOH (aq.), the product was purified by reverse-phase

flash chromatography using a gradient of 2–100% MeCN in H₂O,

furnishing 0.110 g (49% yield) of desired compound 9r as a light

4-(2-(2,4-dichlorophenoxy)-2,2-

difluoroethyl)dibenzo[b,d]thiophene (12c): Following General

Procedure B-1, 0.123 g (0.50 mmol) of compound 11c was

reacted with 0.408 g (2.50 mmol) of 2,4-dichlorophenol in the

12

Tetrahedron

3.

Suda, M. Tetrahedron Letters 1980, 21, 2555-2556.

presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

ACCEPTED MANUSCRIPT

4.

5.

Amii, H.; Uneyama, K. Chem Rev 2009, 109, 2119-83.

Wang, M.; Liang, F.; Xiong, Y.; Cao, S. RSC Advances

2015, 5, 11996-11999.

Hung, M.-H.; Rozen, S.; Smart, B. E. The Journal of

Organic Chemistry 1994, 59, 4332-4335.

Yokota, M.; Fujita, D.; Ichikawa, J. Org Lett 2007, 9,

4639-42.

Yu, L.; Tang, M. L.; Si, C. M.; Meng, Z.; Liang, Y.; Han,

J.; Sun, X. Org Lett 2018, 20, 4579-4583.

Yang, L.; Ji, W. W.; Lin, E.; Li, J. L.; Fan, W. X.; Li, Q.;

Wang, H. Org Lett 2018, 20, 1924-1927.

Tan, D. H.; Lin, E.; Ji, W. W.; Zeng, Y. F.; Fan, W. X.; Li,

Q. J.; Gao, H.; Wang, H. G. Advanced Synthesis &

Catalysis 2018, 360, 1032-1037.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.119 g (58% yield, 1% E-13c, 6%

unknown side product) of desired product 12c as a colorless solid

6.

1

(MP = 119–121 ˚C); H NMR (500 MHz, CDCl₃) δ 8.15 (d, J =

7.

8.0 Hz, 2 H), 7.90–7.88 (m, 1 H), 7.57 (d, J = 7.4 Hz, 1 H), 7.52–

7.47 (m, 3 H), 7.40 (s, 1 ), 7.25 (d, J = 8.8 Hz, 1 H), 7.18 (d, J =

7.9 Hz, 1 H), 3.82 (t, J = 10.9 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 145.2 (d, J = 1.7 Hz), 141.3, 139.1, 136.2, 136.0, 131.5,

130.3, 129.3, 128.7, 127.7, 127.0, 126.3 (t, J = 24.6 Hz), 124.8,

124.6, 124.4 (t, J = 1.9 Hz), 124.3 (t, J = 270.6 Hz), 122.9, 121.9,

121.3, 41.3 (t, J = 30.0 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –

69.59 (t, J = 11.0 Hz, 2 F); IR (film) 1476, 1444, 1405, 1385,

1352, 1325, 1265, 1170, 1122, 1099, 1062, 1022, 907, 842, 817,

797, 733, 706, 650, 618 cm^-1; HRMS (HAPCI+) calc. for

C₂₀H₁₂Cl₂F₂OS (M+) 407.9954, found 407.9940. E-13c

8.

9.

10.

11.

12.

13.

14.

Zhang, J.; Dai, W.; Liu, Q.; Cao, S. Org Lett 2017, 19,

3283-3286.

Zell, D.; Dhawa, U.; Muller, V.; Bursch, M.; Grimme, S.;

Ackermann, L. Acs Catalysis 2017, 7, 4209-4213.

Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi,

S.; Hosoya, T. J Am Chem Soc 2017, 139, 12855-12862.

Lu, X.; Wang, Y.; Zhang, B.; Pi, J. J.; Wang, X. X.; Gong,

T. J.; Xiao, B.; Fu, Y. J Am Chem Soc 2017, 139, 12632-

12637.

1

characteristic peaks: H NMR (500 MHz, CDCl₃) δ 5.97 (d, J =

5.7 Hz, 1 H); ¹⁹F NMR (376 MHz, CDCl₃) δ –82.77 (d, J = 5.8

Hz, 1 F).

2-(3-(2-(2,4-dichlorophenoxy)-2,2-difluoroethyl)phenyl)-5-

(1,3-dioxolan-2-yl)pyridine

(12d):

Following

General

15.

16.

17.

18.

Li, J.; Lefebvre, Q.; Yang, H.; Zhao, Y.; Fu, H. Chem

Commun (Camb) 2017, 53, 10299-10302.

Kong, L.; Liu, B.; Zhou, X.; Wang, F.; Li, X. Chem

Commun (Camb) 2017, 53, 10326-10329.

Watabe, Y.; Kanazawa, K.; Fujita, T.; Ichikawa, J.

Synthesis-Stuttgart 2017, 49, 3569-3575.

Cai, S. H.; Ye, L.; Wang, D. X.; Wang, Y. Q.; Lai, L. J.;

Zhu, C.; Feng, C.; Loh, T. P. Chem Commun (Camb) 2017,

53, 8731-8734.

Procedure B-2, 0.1446 g (0.50 mmol) of compound 11d was

reacted with 0.245 g (1.50 mmol) of 2,4-dichlorophenol in the

presence of 0.033 g (0.25 mmol) of TBD at 140 ˚C for 24 h.

After workup with 1 N NaOH (aq.), the product was purified by

reverse-phase flash chromatography using a gradient of 2–100%

MeCN in H₂O, furnishing 0.137 g (61% yield, 4% E-13d, 1% Z-

13d) of desired compound 12d as a yellow solid (MP = 84–86

1

˚C); H NMR (500 MHz, CDCl₃) δ 8.78 (d, J = 2.2 Hz, 1 H),

8.05 (s, 1 H), 7.96 (q, J = 2.7, 1.9 Hz, 1 H), 7.86 (dd, J = 8.1, 2.3

Hz, 1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.47 (d, J = 4.7 Hz, 2 H), 7.38

(d, J = 2.6 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 1 H), 7.17 (dd, J = 8.9,

2.6 Hz, 1 H), 5.91 (s, 1 H), 4.16–4.11 (m, 2 H), 4.10–4.05 (m, 2

H), 3.59 (t, J = 11.1 Hz, 2 H); ¹³C NMR (126 MHz,

CDCl₃) δ 158.0, 148.4, 145.4, 139.4, 135.1, 132.24, 132.17 (t, J =

2.9 Hz), 131.5, 131.4, 130.3, 129.5, 129.0, 128.5, 127.7, 126.6,

124.18, 124.12 (t, J = 269.6 Hz), 120.3, 102.1, 65.6, 42.3 (t, J =

29.2 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ –70.75 (t, J = 11.0 Hz,

2 F); IR (film) 2887, 1703, 1601, 1569, 1475, 1354, 1256, 1095,

1062, 1025, 982, 942, 864, 839, 799, 757, 698, 564 cm^-1; HRMS

(ESI+) calc. for C₂₂H₁₈Cl₂F₂NO₃(M+H) 452.063, found

452.0627. E-13d characteristic peaks: ¹H NMR (500 MHz,

CDCl₃) δ 5.83 (d, J = 6.0 Hz, 1 H); ¹⁹F NMR (376 MHz,

CDCl₃) δ –84.69 (d, J = 5.9 Hz, 1 F); Z-13d characteristic peaks:

¹H NMR (500 MHz, CDCl₃) δ 5.34 (d, J = 28.7 Hz, 1 H); ¹⁹F

NMR (376 MHz, CDCl₃) δ –84.63 (d, J = 28.4 Hz, 1 F).

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We thank the donors of the Herman Frasch Foundation for

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Article Doi

Organocatalytic strategy for hydrophenolation of gem-difluoroalkenes

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