phosphinates via SNAr reaction

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Synthetic Methodologies for Perfluoroaryl Substituted (Diaryl)methylphosphonates, -phosphinates via SNAr reaction Kohei Fujii, Shigekazu Ito, and Koichi Mikami J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 Sep 2019 Downloaded from pubs.acs.org on September 4, 2019

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The Journal of Organic Chemistry

Synthetic Methodologies for Perfluoroaryl Substituted (Diaryl)methylphosphonates, -phosphinates via SNAr reaction Kohei Fujii, Shigekazu Ito, and Koichi Mikami* Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8552 (Japan). KEYWORDS: 1) NaHMDS THF, –78 °C, 30 min

R OR' P OR'(R) O

Ar

2) ArF - F

R = H, F

ArF OR' P OR'(R) R O up to 99% yield 100% diastereoselectivity Ar

ABSTRACT: The new synthetic methodologies for perfluoroaryl substituted (diaryl)methylphosphonates, -phosphinates via nucleophilic aromatic substitution (SNAr) were developed. Benzyl phosphonate and α-fluorobenzylphosphonate reacted with wide variety of perfluoroarenes via SNAr reaction. The reaction took place quickly and gave perfluoroarylated phosphonates in high yields. Highly diastereoselective SNAr reaction with binaphthyl-based chiral phosphinates was further achieved.

INTRODUCTION Organophosphorus compounds are useful and important compounds for organic and organometallic chemistry and exhibit a wide range of applications as ligands,1 organocatalysts2 and reagents in the Wittig and HornerWadsworth-Emmons (HWE) reaction.3 Among these phosphorus compounds, dialkyl (diarylmethyl)phosphonates possess various properties, which include biological activity4,5 and chemical luminescence.6 In organic synthesis and materials chemistry, HWE reaction with dialkyl (diarylmethyl)phosphonates is an efficient method to synthesize vinyl-based functional compounds such as potential photoproducts,7–10 OLED emitters11 and fluorescent materials12 (Figure 1). F EtO EtO O P

CF3 OH P OH O Inhibitor of Human Prostatic Acid Phosphatase

F

OEt P OEt O

Calcium Antagonistic Activity

N Me

achieved to give dialkyl (diarylmethyl)phosphonates (Figure 2, eq 3).16 Recently, Walsh has reported Pd-catalyzed direct αarylation of dialkyl benzylphosphonates (Figure 2, eq 4).17 While this reaction is available for a wide variety of benzylphosphonates, the introduction of electron-poor arenes is limited. Organocatalytic phosphonylation of o- or p-quinone methide leading to dialkyl (diarylmethyl)phosphonates has recently been developed (Figure 2, eq 5).18,19 Despite this transformation is available for a wide variety of o- or p-quinone methide, electron-poor arenes cannot be introduced because these products have phenol units. Examples to synthesize the electron-poor aryl substituted dialkyl (diarylmethyl)phosphonates include SNAr reactions between dialkyl benzylphosphonates and nitroarenes.20–22 However, there are three problems: (i) Leaving groups are necessary in dialkyl benzylphosphonates (Figure 2, eq 6).20,21 (ii) Oxidants are needed (Figure 2, eq 7).22 (iii) Nitroarenes are only allowed (Figure 2, eq 6, 7).

Chemiluminescence

Figure 1 Examples of functional dialkyl (diarylmethyl)phosphonates The conventional synthetic methodologies of dialkyl (diarylmethyl)phosphonates is Michaelis-Arbuzov reactions (Figure 2, eq 1).13,14 However, the substrate scope for this reaction is limited because of the harsh reaction conditions. Instead of this reaction, FeCl3-mediated Friedel-Crafts reaction between arenes and α-hydroxyphosphonates (Figure 2, eq 2).15 However, the problem is only electron-rich arenes can be permitted. To date, the synthesis of dialkyl (diarylmethyl)phosphonates using organometallic catalysts has been reported. One example of Cu-catalyzed reductive coupling between diethyl phosphite and tosylhydrazones has been

ACS Paragon Plus Environment

The Journal of Organic Chemistry Michaelis-Arbuzov reaction

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Br Ar

Ar Ar

Ar

P(OEt)3

+

185 °C

OEt P OEt O

(1)

OEt P OEt O

(2)

Friedel-Crafts reaction OH

Ar' FeCl3

OEt P OEt O

Ar

+

Ar

Ar'–H

Reductive coupling reaction NNHTs Ph

Ph H

Ph

+

OEt P OEt O

cat. Cu

Ph

Base

OEt P OEt O

(3)

OEt P OEt O

(4)

OEt P OEt O

(5)

Pd catalyzed -arylation Ar' cat. Pd

OEt P OEt O

Ar

+

Ar

Ar'–Br Base

Organocatalyst catalyzed conjugated addition O R R H OEt P OEt + O

Ar Organocat.

R HO

Ar

R

SNAr reaction with nitroarenes NO2 Cl OR P OR O

Ar

(6) NO2

OR P OR O

Ar

NO2

Base

+

RESULTS AND DISCUSSION We initiated our studies by evaluating the SNAr reaction between benzyl phosphonate 1a and pentafluoropyridine 2a in THF at –78 °C. First we chose NaHMDS as base because the screening of the base of the SNAr reaction between diethyl αfluorobenzylphosphonate 1b and pentafluoropyridine 2a gave the result that LDA, n-BuLi, LiHMDS, KHMDS, NaH, CsCO3 and DIPEA are not effective. The reaction afforded the product 3aa in high yield (Table 1, entry 1). Thus, the reaction time was shortened and screening of the equivalent of base and electrophile; despite reduction the amount of both base and electrophile, scarcely any lowering of the yield of 3aa (entry 2). Moreover, the yield decreased when only the equivalent of the base was increased (entry 2 vs 3). Similarly, the yield decreased when only the equivalent of the electrophile was increased (entry 2 vs 4). When the base and the electrophile were used in the same amount, the product 3aa was obtained almost quantitatively over 75 min (entry 5). 2 equivalents of base is needed because the desired product is more acidic than the substrate, so 1 equivalent of base is consumed. Table 1 Optimization of reaction conditions

O 2N Oxidant

Ar

+

OR P OR O

F

OR P OR O

Ar

(7)

R OR' P OR'(R) O

Base +

ArF–F

R Ar

2) F

1a 0.10 M

ArF OR' P OR'(R) O

1) NaHMDS (X eq), THF, –78°C, time

OEt P OEt O

Ph

This Work:SNAr reaction

Ar

Page 2 of 11

F

F ArF * P O OH * F ArF P

O OMe

Diastereoselective SNAr

Electrophilic-Fluorination Deprotection

Figure 2 Approaches toward dialkyl (diarylmethyl)phosphonates

F F

F F OEt P OEt O

3aa

Y eq

time'

entry

X

Y

time (min)

time’ (min)

yield (%)a

1

2.1

3.0

70

75

88 (74b)

2

1.1

1.1

30

45

80

3

2.2

1.1

30

45

70

4

1.1

2.2

30

45

73

5

2.0

2.0

30

45

96 (91b)

Deprotection

Synthesized by Deoxo-Fluorination

N

N

F 2a

(8)

Diastereoselective SNAr

Ph

F

F * P O OMe *

F

(9)

a : Yields were determined by 19F NMR b : Isolated yield

Perfluoroaryl groups show not only electron-withdrawing substituent effect23,24 but also unique interactions with other molecules25,26 leading to chemical biology27,28 and synthesis of functional materials.29,30 Perfluoroaryl groups are known to readily undergo SNAr reaction with various nucleophiles.31–34 Despite SNAr reactions of perfluoroarenes via α-substituted diethyl methylphosphonates have been reported, these methods cannot be applied to the synthesis of dialkyl (diarylmethyl)phosphonates because of the necessity of the electron-withdrawing group at the α-position.35,36 Herein, we report new synthetic methodologies for the synthesis of perfluoroaryl substituted dialkyl (diarylmethyl)phosphonates via SNAr reaction of diethyl benzyl-, diethyl (monofluoromehyl)phosphonates (Figure 2, eq 8). Diastereoselective SNAr reaction can be utilized for highly stereoselective perfluoroarylation of binaphthyl-based methyl phosphinate. Combination of electrophilic fluororination or deoxofluorinaiton with diastereoselective SNAr reaction should give α-perfluoroarylated chiral phosphinic acids (Figure 2, eq 9).

Under the optimized conditions, the scope of the αperfluoroarylation was evaluated (Scheme 1). Benzyl phosphonate 1a smoothly reacted with pentafluoropyridine (3aa), octafluorotoluene (3ab) and pentafluorobenzonitrile (3ae). Surprisingly, less reactive hexafluorobenzene gave perfluoroarylated phosphonate 3ac in high yield for longer reaction time. On the other hand, ethyl pentafluorobenzoate gave 3ad in moderate yield because of producing ethyl 2(diethoxyphosphoryl)-2-phenylacetate (61% isolated yield) via nucleophilic attack of the ester group and leaving pentafluorophenyl anion. Diethyl α-fluorobenzylphosphonate 1b reacted with pentafluoropyridine and octafluorotoluene to give 3ba and 3bb in moderate yields under the optimal reaction conditions (NaHMDS 1.2 eq, perfluoroarene 1.5 eq). Unfortunately, hexafluorobenzene gave 3bc in 8% yield because of the byproduct produced via double addition of diethyl α-fluorobenzylphosphonate to hexafluorobenzene.


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Scheme 1 Substrate scope 1) NaHMDS (2.0 eq), THF, –78 °C, 30 min

R OEt P OEt O

Ph

Scheme 3 Diastereoselective SNAr reactions of bis-fluorinated phosphinate

CF3 N

F Ph

F

F

F OEt P OEt O

F

OEt P OEt O 3

F F

F

F F OEt P OEt Ph O

Ph

3aa 91% 45 min

3ab 99% 45 min

F

F

F OEt P OEt O

F

F

F

F OEt P OEt O

F

N

F

F F F OEt P OEt Ph O

F Ph

3ae 82% 60 min

F

3ba 45%a 20 min

F ArF 8

ArF =

F

F

F

F

N

CF3

F

F

F 8a 15%

F F

F

F OEt P OEt O

F

F OEt P OEt O

3bb 53%a 50 min

* P O OMe *

4b

F

F Ph

F ArF

2) ArF-F (4.0 eq) –78 °C to rt, 14 h

F

3ad 38% 2h

CF3 F

* P O OMe *

F OEt P OEt O

Ph

1) NaHMDS (3.0 eq) –78 °C, THF, 30 min

F

CO2Et F

3ac 84% 2h

CN F

Ph

ArF

2) ArF-F 2 (2.0 eq), time

1 0.10 M

F

R Ph

F 8b 14%

The structure of 8b was confirmed by X-ray crystallography, indicating that the stereochemistry of 8a and 8b was (aS, R, R). Perfluoroaryl groups are positioned in a pseudoaxial orientation (Figure 3).

3bc 8%a 50min

a : NaHMDS (1.2 eq), ArF-F (1.5 eq) F3C

F

F

To investigate the diastereoselective SNAr reactions, binaphthyl based phosphinates were used as nucleophile (Scheme 2). Methyl phosphinate 4a synthesized in 5 steps from (S)-BINOL37 smoothly reacted with perfluoroarene in the presence of NaHMDS at –70 °C for elongated reaction time. The formation of three of the four diastereomers was confirmed, and mono-arylated products 5aa and 5ab were obtained with high selectivity. Then, electrophilic fluorination reaction gave α-monofluorinated compounds 6aa and 6ab in moderate yield as a single diastereomer. Second SNAr reaction gave bisarylated products as a single diastereomer 7aa in low yield and 7ab in moderate yield. Finally, electrophilic fluorination of 7aa and 7ab gave 8a and 8b in high yield as a single diastereomer.

P

O OMe

ArF P

O OMe

2) ArF-F (4.0 eq), –70°C, 24 h

1) NaHMDS (1.1 eq), THF, –70 °C, 30 min

5aa : 76%a (74:21:5)b 5ab : quantc (72:21:7)b

4a

F

ArF=

F

F 5aa-7aa

2) ArF-F (5.0 eq), –70°C to rt, 24 h

P

O OMe

6aa : 34%a (recov. 10%d) 6ab : 36%a (recov. 42%d)

F F

N F


F ArF

2) NFSI (2.0 eq), –70°C, 24 h

CF3

F F 5ab-7ab,8b

F ArF O P OMe ArF

7aa : 16%a 7ab : 64%c


F

P

F * (R)

O P

F

OMe 8b

Side View

F

F

F CF3

Top View

A reaction mechanism for the formation of 8b from 4b is shown in Scheme 4. Deprotonation of α proton by base generates the anion IM4b at pseudoequatorial position but the anion could not attack the perfluoroarenes. Configurational isomerization of pseudoequatorial anion to pseudoaxial anion IM4b’ stabilized by the interaction with p(C) → σ* (P-O)38 and/or the delocalization of the carbanion into the σ* (C-F) at the  position39 would occur. IM4b’ reacts with perfluoroarenes to give 8b’. Then the same reaction proceeds at the other α position to form 8b.

F ArF

2) NFSI (6.0 eq), –70°C, 24 h

F

*

Figure 3 X-ray structure of 8b (50% probability level)

Scheme 2 Diastereoselective SNAr reaction and Electrophilic Fluorination of binaphthyl based phosphinates 1) NaHMDS (4.0 eq), THF, –70 °C, 30 min

F (R)

O OMe

F ArF

8b : 66%a 8b : 72%a

a : Isolated yield, b : diastereomer ratio was determined by 31P NMR. Yields were determined by c : 19F NMR, d : 1H NMR

On the other hand, we evaluated the diastereoselective SNAr reaction with bis-fluorinated phosphinate 4b gave bis-arylated products 8a and 8b in moderate yield through sequential reactions with excellent diastereoselectivity (Scheme 3).


The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 4 Possible reaction mechanism of diastereoselective SNAr reactions of bis-fluorinated phosphinate

Page 4 of 11

Scheme 6 Deprotection of phosphinates 8a and 8b F ArF

F ArF NaI (20 eq)

* P O OMe *

:Base F

* O H

P

ArF F

H

* O

*

H

F

P

OMe

OMe

4b

IM4b

H

F * O P

F ArF

p(C)

OMe

+

F

*

*

(P–O)

F F OMe * * P p(C) O ArF (P–O)

IM4b'

ArF F

* O H

OMe

F

* O

*

F

P

*

P

OMe

ArF

8b'

ArF

8b

On the other hand, possible reaction mechanism for the formation of 8b from 4a is shown in Scheme 5. Mono-arylated products 5 is converted to pseudoaxial anion IM5 by base but this anion also cannot attack the NFSI. Configurational isomerization of pseudoaxial anion IM5 to pseudoequatorial anion IM5’ is occurred. IM5’ is stabilized by the π-π interaction between perfluoroaryl group and binaphthyl group, not by steric interaction between binaphtyl ring and perfluoroarenes on the basis of the X-ray crystallography (Figure 3). Pseudoequatorial anion reacts with electrophilic fluorinating reagent and gives 6. Scheme 5 Possible reaction mechanism of diastereoselective electrophilic fluorination reaction of mono-perfluoroarylated phosphinate

H H

ArF O P

ArF

H

O

* H

OMe

H

OMe

H

IM5

F O

*

P

:Base

5

H

*

P OMe Ar F

H H

O

*

F

P OMe Ar F

- interaction IM5'

9 ArF =

F F

F F

N

CF3 F

F

H

F

F ArF

8

ArF

or

F

* P O OH *

acetone, rt, 2 d

6

Furthermore, deprotection of 8a and 8b by sodium iodide smoothly proceeded and gave phosphinic acids 9a and 9b (Scheme 6). Chiral phosphinic acids 9a and 9b have C2 symmetry and are expected to show the construction of chiral environment via the steric effect of the perfluoroaryl groups at the α position.37 The catalytic activity and enantiocontrolling ability of these chiral Brønsted acid analogous will be reported in due course.

F 9a quant

F 9b 92%

In summary, we have developed new methodologies to synthesize the dialkyl (diarylmethyl)phosphonates via SNAr reaction with perfluoroarenes up to 99% yield for 75 min to 2.5 h. Furthermore, highly diastereoselective SNAr reaction has been developed by binaphthyl based chiral phosphinate. The stereochemistry of perfluorinated products was clarified by Xray analysis. Application of dialkyl (diarylmethyl)phosphonates as reagents and chiral organocatalysts is of value for further investigation.

EXPERIMENTAL SECTION General Information:1H, 13C, 31P and 19F NMR spectra were measured on Bruker AV300M spectrometers. Chemical shifts of 1H NMR were expressed in parts per million relative to the singlet ( = 7.26) for CDCl3, central line of quintet (δ = 2.50) for DMSO-d6. Chemical shifts of 13C{1H} NMR were expressed in parts per million relative to the central line of the triplet ( = 77.0) for CDCl3 central line of the septet (δ = 39.52) for DMSOd6. Chemical shifts of 31P{1H} NMR were expressed in parts per million downfield from 85% H3PO4 as an external standard ( = 0.00) in CDCl3. Chemical shifts of 19F NMR were expressed in parts per million downfield from benzotrifluoride (BTF) as an external standard ( = –63.24) in CDCl3. Analytical thin layer chromatography (TLC) was performed on glass plates pre-coated with silica-gel (Merck Kieselgel 60 F254, layer thickness 0.25 mm). Visualization was accomplished by UV light (254 nm), anisaldehyde, KMnO4, phosphomolybdic acid and 2,4-dinitrophenylhydrazine. Column chromatography was performed on KANTO Silica Gel 60N (spherical, neutral). IR spectra were measured on a JASCO FT/IR-4200 spectrometer. Mass spectra were measured on a JEOL JMS-T100CS (AccuTOF) spectrometer. Optical rotations were measured on a JASCO P-1020. All experiments were carried out under nitrogen atmosphere unless otherwise noted. Reagents:(R)-BINOL was provided from Takasago International Co. Tf2O was gifted from TOSOH F-TECH, Inc. diethyl -fluorobenzylphosphonate 1b40 Chiral methyl phosphinate 4a37 chiral dialdehyde 1241 was synthesized according to the reported procedure. Dehydrated solvent (THF) was purchased from Kanto Chemical, dried and deoxidized with GlassContour Solvent Purification System prior to use. All other reagents were purchased from Sigma-Aldrich, Kanto Chemical, Tokyo Chemical Industries, and FUJIFILM Wako Pure Chemical Corporation and used without further purification otherwise noted. Genaral procedure of SNAr reaction of diethyl benzylphosphonate. To a stirred mixture of phosphonate (0.10 mmol) in THF (1.0 mL) was added NaHMDS (0.20 mL, 1.0 M in THF, 0.20 mmol) at –78 °C, and then the mixture was stirred


Page 5 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


for 30 min. To the reaction mixture was added perfluoarene (0.20 mmol) at -78 °C. After confirming the completion of reaction by TLC analysis, the reaction mixture was warmed up to room temperature and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to give the corresponding phosphonate. diethyl ((perfluoropyridin-4yl)(phenyl)methyl)phosphonate (3aa). Colorless oil (34.2 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H, J = 6.9 Hz), 7.36-7.30 (m, 3H), 4.97 (d, 1H, 2JHP = 26.8 Hz), 4.19-4.00 (m, 4H), 1.23 (t, 3H, J = 7.1 Hz), 1.20 (t, 3H, J = 7.2 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 143.8 (dm, 1JCF = 227.3 Hz), 140.3 (dm, 1JCF = 258.8 Hz), 132.0 (d, 3JCP = 5.3 Hz), 130.9 (ttd, 2JCF = 15.0 Hz, 3JCF = 2.3 Hz, 2JCP = 2.3 Hz), 129.7 (d, 2JCP = 7.5 Hz), 129.0, 128.3, 63.7 (d, 2JCP = 6.8 Hz), 63.1 (d, 2JCP = 6.8 Hz), 41.7 (d, 1JCP = 143.3 Hz), 16.2, 16.1. 19F NMR (282 MHz, CDCl3) δ –90.3-–90.6 (m, 2F), –140.1 (t, 3JFF = 18.1 Hz). 31P{1H} NMR (122 MHz, CDCl ) δ 19.4 (d, 2J 3 PF = 84.5 Hz). FT-IR (KBr neat, cm–1) 3484, 3064, 3032, 2986, 2933, 2912, 1729, 1644, 1602, 1469, 1414, 1393, 1370, 1346, 1258, 1164, 1137, 1096, 1019, 957, 857, 800, 746, 721, 699, 648, 631, 599, 536. HRMS(ESI-TOF) Calcd for C16H16F4NO3P [M+Na]+: 400.0702, Found: 400.0712. diethyl (phenyl(2,3,5,6-tetrafluoro-4(trifluoromethyl)phenyl)methyl)phosphonate (3ab). Colorless oil (43.8 mg, 99%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H, J = 6.9 Hz), 7.37-7.28 (m, 3H), 4.97 (d, 1H, 2JHP = 27.1 Hz), 4.20-4.04 (m, 4H), 1.25 (t, 3H, J = 8.1 Hz), 1.25 (t, 3H, J = 8.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 145.2 (ddq, 1J 2 3 1 CF = 249.8 Hz, JCF = 13.6 Hz, JCP = 5.3 Hz), 144.2 (dd, JCF 2 3 = 258.0 Hz, JCF = 16.5 Hz), 132.7 (d, JCP = 4.5 Hz), 129.6 (d, 2J 4 2 CP = 7.5 Hz), 128.9, 128.2 (d, JCP = 1.5 Hz), 121.7 (td, JCF = 16.5 Hz, 2JCP = 5.3 Hz), 120.7 (q, 1JCF = 273.0 Hz), 108.9 (qt, 2J 2 2 CF = 33.0, 11.3 Hz), 63.5 (d, JCP = 6.8 Hz), 63.0 (d, JCP = 6.8 1 19 Hz), 41.0 (d, JCP = 144.0 Hz), 16.3, 16.2. F NMR (282 MHz, CDCl3) δ –56.4 (t, 3F, 4JFF = 20.7 Hz), –136.7 (s, 2F), –140.0-– 140.3 (m). 31P{1H} NMR (122 MHz, CDCl3) δ 20.2. FT-IR (KBr neat, cm-1) 3489, 3065, 2986, 2931, 2386, 2284, 1729, 1659, 1604, 1496, 1454, 1412, 1393, 1369, 1335, 1258, 1217, 1185, 1148, 1097, 1054, 1024, 982, 877, 791, 753, 713, 700, 678, 645, 614, 569, 533, 505. HRMS(ESI-TOF) Calcd for C18H16F7O3P [M+Na]+: 467.0623, Found: 467.0646. diethyl ((perfluorophenyl)(phenyl)methyl)phosphonate (3ac). Colorless oil (33.1mg, 84 %). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H, J = 7.2 Hz), 7.36-7.28 (m, 3H), 4.89 (d, 1H, 2JHP = 27.5 Hz), 4.19-3.97 (m, 4H), 1.23 (t, 3H, J = 7.1 Hz), 1.21 (t, 3H, J = 7.2 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 147.3-146.8, 144.14-143.5 (m,2C), 140.0-138.4, 136.4-135.8 (m, 2C), 133.5 (d, 3JCP = 5.4 Hz), 129.6 (d, 2JCP = 7.5 Hz), 128.9, 128.0 (d, 4JCP = 1.5 Hz), 112.2 (td, 2JCF = 16.5 Hz, 2JCP = 5.3 Hz), 63.4 (d, 2JCP = 6.8 Hz), 63.0 (d, 2JCP = 6.8 Hz), 40.4 (d, 1JCP = 144.8 Hz), 16.4, 16.3. 19F NMR (282 MHz, CDCl3) δ –138.5 (brs, 2F), –154.9 (t, 1F, 3JFF = 21.0 Hz), –161.5-–161.7 (m, 2). 31P{1H} NMR (122 MHz, CDCl ) δ 21.1. FT-IR (KBr neat, cm3 1) 3065.3, 2986.2, 2934.2, 2872.5, 1724.1, 1652.7, 1600.6, 1526.4, 1493.6, 1449.2, 1417.4, 1391.4, 1372.1, 1309.4, 1267.0, 1210.1, 1162.9, 1133.0, 1058.7, 1026.9, 985.4, 930.5, 782.0, 722.2, 697.1, 652.8, 634.5, 566.0. HRMS(ESI-TOF) Calcd for C17H16F5O3P [M+Na]+: 417.0653, Found: 417.0655.

ethyl 4-((diethoxyphosphoryl)(phenyl)methyl)-2,3,5,6tetrafluorobenzoate (3ad). Colorless oil (17.1 mg, 38%). 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H, J = 7.1 Hz), 7.37-7.29 (m, 3H), 4.96 (d, 1H, 2JHP = 27.2 Hz), 4.43 (q, 2H, J = 7.1 Hz), 4.20-3.98 (m, 4H), 1.38 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz), 1.22 (t, 3H, J = 7.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 159.6, 146.8-146.2, 143.5-142.8 (m, 4C), 133.1 (d, 3JCP = 4.5 Hz), 129.6 (d, 2JCP = 8.3 Hz), 128.8, 128.0 (d, 4JCP = 1.5 Hz), 120.2 (td, 2JCF = 15.8 Hz, 2JCP = 5.3 Hz), 112.1 (t, 2JCF = 15.8 Hz), 63.4 (d, 2JCP = 6.8 Hz), 62.9 (d, 2JCP = 7.5 Hz), 62.8, 40.9 (d, 1JCP = 144.0 Hz), 16.3, 16.2, 14.7. 19F NMR (282 MHz, CDCl3) δ –137.8 (brs, 2F), –139.5 (dd, 3JFF = 19.2 Hz, 4JFP = 10.4 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 20.7. FT-IR (KBr neat, cm-1) 3462.6, 3063.4, 2985.3, 2935.1, 2910.1, 2602.5, 2360.4, 2339.2, 1738.5, 1651.7, 1601.6, 1484.0, 1393.3, 1368.3, 1312.3, 1257.4, 1219.8, 1162.9, 1096.3, 1023.1, 981.6, 7010, 650.9, 600.7, 547.7. HRMS(ESI-TOF) Calcd for C20H21F4O5P [M+Na]+: 471.0960, Found: 471.0965. diethyl ((4-cyano-2,3,5,6tetrafluorophenyl)(phenyl)methyl)phosphonate (3ae). Colorless oil (31.9 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, 2H, J = 6.9 Hz), 7.38-7.32 (m, 3H), 4.98 (d, 1H, 2JHP = 27.9 Hz), 4.21-4.00 (m, 4H), 1.25 (t, 3H, J = 7.1 Hz), 1.22 (t, 3H, J = 7.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 144.7 (dd, 1J = 262.5 Hz, 2J = 19.5 Hz), 147.0-146.6, 143.6-143.3 (m), CF CF 132.4 (d, 3JCP = 4.5 Hz), 129.7 (d, 2JCP = 8.3 Hz), 129.1, 128.5 (d, 4JCP =0.8 Hz), 124.4 (td, 2JCF = 15.8 Hz, 2JCP = 5.3 Hz), 93.5 (tdd, 2JCF = 1.3 Hz, 3JCF = 3.0 Hz, 3JCP = 3.0 Hz), 63.8 (d, 2JCP = 8.0 Hz), 63.2 (d, 2JCP = 7.5 Hz), 41.5 (d, 1JCP = 144.0 Hz), 16.4, 16.3. 19F NMR (282 MHz, CDCl3) δ –135.3 (dd, 2F, 20.6, 17.8 Hz), –135.3 (brs, 2F). 31P{1H} NMR (122 MHz, CDCl3) δ 19.7 (t, J = 4.0 Hz). FT-IR (KBr neat, cm-1) 3064.3, 3030.6, 2986.2, 2934.2, 2910.1, 2623.7, 2393.2, 2247.6, 1964.1, 1725.0, 1650.8, 1600.6, 1493.6, 1453.1, 1393.3, 1370.2, 1344.1, 1298.8, 1260.3, 1162.9, 1096.3, 1051.0, 1025.0, 982.6, 792.6, 745.4, 700.0, 657.6, 613.3, 552.5. HRMS(ESI-TOF) Calcd for C18H16F4NO3P [M+Na]+: 424.0702, Found: 424.0719. Genaral procedure of SNAr reaction of diethyl fluorobenzylphosphonate. To a stirred mixture of diethyl fluorobenzylphosphonate (0.10 mmol) in THF (1.0 mL) was added NaHMDS (0.12 mL, 1.0 M in THF, 0.12 mmol) at –78 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added perfluoroarene (0.15mmol) at –78 °C. After confirming the completion of reaction by TLC analysis, the reaction mixture was quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1) to give the corresponding phosphonate. diethyl (fluoro(perfluoropyridin-4yl)(phenyl)methyl)phosphonate (3ba). Colorless oil (251 mg, 45%). 1H NMR (300 MHz, CDCl3) δ 7.59 (d, 2H, J = 3.6 Hz), 7.43-7.41 (m, 3H), 4.32-4.08 (m, 4H), 1.33 (t, 3H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 144.3 (dt, 1JCF = 242.3 Hz, 2JCF = 15.8 Hz), 139.6 (dd, 1JCF = 264.8 Hz, 2JCF = 35.3 Hz), 135.0 (d, 2JCF = 20.3 Hz), 131.8131.2 (m, 1C), 129.9, 128.7, 126.8-126.6 (m, 1C), 95.7 (dd, 1JCF = 186.8 Hz, 1JCP = 171.8 Hz), 65.4 (d, 2JCP = 7.5 Hz), 64.9 (d, 2J 3 3 CP = 7.5 Hz), 16.4 (d, JCP = 1.5 Hz), 16.3 (d, JCP = 1.5 Hz). 19F NMR (282 MHz, CDCl ) δ –89.9-–90.1 (m, 2F), –135.9-– 3 136.3 (m, 2F), –160.2 (dt, 1F, 2JFP = 84.0 Hz, 4JFF = 30.7 Hz). 31P{1H} NMR (122 MHz, CDCl ) δ 10.6 (d, 2J 3 PF = 84.2 Hz).



FT-IR (KBr neat, cm-1) 3064, 2987, 2935, 2871, 2360, 2339, 1735, 1644, 1539, 1460, 1416, 1393, 1371, 1266, 1206, 1162, 1014, 974, 789, 758, 695, 652, 612. HRMS(ESI-TOF) Calcd for C16H15F5NO3P [M+Na]+: 418.0607, Found: 418.0628. diethyl (fluoro(phenyl)(2,3,5,6-tetrafluoro-4(trifluoromethyl)phenyl)methyl)phosphonate (3bb). Colorless oil (131 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 7.57 (d, 2H, J = 3.5 Hz), 7.42-7.40 (m, 3H), 4.33-4.01 (m, 4H), 1.34 (t, 3H, J = 7.0 Hz), 1.26 (t, 3H, J = 7.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 146.8-146.1, 143.4-142.6 (m, 4C), 135.7 (d, 2J CF = 20.3 Hz), 129.7, 128.6, 123.1-122.5 (m, 1C), 12.06 (q, 1J 1 CF = 273.7 Hz), 110.8-110.3 (m, 1C), 95.6 (dd, JCF = 186.8 Hz, 1JCP = 172.5 Hz), 65.2 (d, 2JCP = 7.5 Hz), 64.8 (d, 2JCP = 7.5 Hz), 16.5 (d, 3JCP = 4.5 Hz), 16.4 (d, 3JCP = 5.3 Hz). 19F NMR (282 MHz, CDCl3) δ –56.6 (t, 3F, 4JFF = 20.7 Hz), –132.4-– 132.6 (m, 2F), –139.2-–140.0 (m, 2F), –159.5 (dt, 1F, 2JFP = 84.0 Hz, 4JFF = 31.7 Hz) 31P{1H} NMR (122 MHz, CDCl ) δ 11.1 (d, 2J 3 PF = 84.5 Hz). FT-IR (KBr neat, cm-1) 3564, 3500, 3066, 2988, 2935, 2916, 2873, 2360, 2339, 1658, 1603, 1489, 1451, 1417, 1393, 1371, 1336, 1268, 1228, 1189, 1153, 1017, 986, 932, 891, 782, 754, 728, 714, 697, 642. HRMS(ESI-TOF) Calcd for C18H15F8O3P [M+Na]+: 485.0529, Found: 485.0542. diethyl (fluoro(perfluorophenyl)(phenyl)methyl)phosphonate (3bc). Colorless oil (3.4 mg, 8%). 1H NMR (300 MHz, CDCl3) δ 7.54 (d, 2H, J = 3.6 Hz), 7.43-7.38 (m, 3H), 4.34-3.97 (m, 4H), 1.33 (t, 3H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.0 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 144.3 (dt, 1JCF = 242.3 Hz, 2JCF = 15.8 Hz), 139.6 (dd, 1JCF = 264.8 Hz, 2JCF = 35.3 Hz), 135.0 (d, 2JCF = 20.3 Hz), 131.8-131.2 (m, 1C), 129.9, 128.7, 126.8-126.6 (m, 1C), 95.7 (dd, 1JCF = 186.8 Hz, 1JCP = 171.8 Hz), 65.4 (d, 2JCP = 7.5 Hz), 64.9 (d, 2JCP = 7.5 Hz), 16.4 (d, 3JCP = 1.5 Hz), 16.3 (d, 3JCP = 1.5 Hz). 19F NMR (282 MHz, CDCl3) δ –133.9-–134.1 (m, 2F), –152.2 (t, 1F, 3JFF = 21.0 Hz), –158.6 (dt, 1F, 2JFP = 84.9 Hz, 4JFF = 28.7 Hz), –161.5-–161.4 (m, 2F). 31P{1H} NMR (122 MHz, CDCl3) δ 11.6 (d, 2JPF = 85.2 Hz). HRMS(ESI-TOF) Calcd for C17H15F6O3P [M+Na]+: 435.0561, Found: 435.0549. (11cS)-4-methoxy-3-(perfluoropyridin-4-yl)-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (5aa). To a stirred mixture of methyl phosphinate (4) (35.8 mg, 0.10 mmol) in THF (0.75 mL) was added NaHMDS (0.40 mL, 1.0 M in THF, 0.40 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added pentafluoropyridine (41.6 µL, 0.40 mmol) at –70 °C. After stirred 24 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the corresponding phosphinate as a white solid (5aa) (mixture of d1 and d3:30.4 mg, 60%, 16:1, d2:8.1 mg, 16%, dr = 74:21:5). d1:1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H J = 8.4 Hz), 7.96 (d, 2H, J = 9.0 Hz), 7.93 (d, 2H, J = 10.1 Hz), 7.66 (d, 1H, J = 8.3 Hz), 7.48 (dd, 2H, J = 7.7, 6.3 Hz), 7.31-7.21 (m, 5H), 5.10 (d, 1H, 2JHP = 18.9 Hz), 3.84 (d, 3H, 3JHP = 11.0 Hz), 3.40 (dd, 1H, 2JHP = 19.2, 2JHH = 14.4 Hz), 3.16 (dd, 1H, 2JHP = 17.8, 2JHH = 14.4 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 143.7 (dt, 1JCF = 246.8 Hz, 2JCF = 15.8 Hz), 141.0 (dddd, 1JCF = 282.0 Hz, 2JCF = 27.0 Hz, 3JCP = 6.8 Hz, 3JCF = 6.8 Hz), 133.9 (d, 3JCP = 3.8 Hz), 132.7 (d, 4JCP = 1.5 Hz), 132.7, 132.6 (d, 3JCP = 2.3 Hz), 131.9

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(d, 3JCP = 2.3 Hz), 131.7, 130.7 (d, 2JCP = 9.0 Hz), 129.9, 129.6, 129.2 (d, 2JCP = 7.5 Hz), 128.5-127.6 (m), 128.2, 128.1, 127.4 (d, 3JCP = 4.5 Hz), 127.3, 126.8, 126.7, 126.4, 126.3, 125.9, 123.4, 52.3 (d, 2JCP = 6.8 Hz), 39.3 (d, 1JCP = 90.0 Hz),. 36.0 (d, 1J 19 CP = 91.5 Hz). F NMR (282 MHz, CDCl3) δ –89.9 (br, 2F), –137.7 (br, 2F). 31P{1H} NMR (122 MHz, CDCl3) δ 60.6. HRMS(ESI-TOF) Calcd for C28H18F4NO2P [M+Na]+: 530.0903, Found: 530.0917. d2:1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H J = 8.4 Hz), 7.99 (d, 1H, J = 8.4 Hz), 7.95 (d, 1H, J = 8.4 Hz), 7.88 (d, 1H, J = 8.1 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.64 (d, 1H, J = 8.4 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.37 (t, 1H, J = 7.5 Hz), 7.20 (t, 1H, J = 7.2 Hz), 7.04-6.96 (m, 2H), 6.59 (d, 1H, J = 8.5 Hz), 4.73 (d, 1H, 2JHP = 22.4 Hz), 3.85 (d, 3H, 3JHP = 10.8 Hz), 3.41 (dd, 1H, 2JHP = 18.6 Hz, 2JHH = 14.4 Hz), 3.33 (dd, 1H, 2JHP = 18.6 Hz, 2JHH = 14.4 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 142.8 (ddd, 1JCF = 243.8 Hz, 2JCF = 16.5 Hz, 3JCF = 2.3 Hz), 140.0 (dddd, 1JCF = 260.3 Hz, 2JCF = 27.8 Hz, 3JCP = 6.8 Hz, 3JCF = 6.8 Hz), 134.6 (d, 3JCP = 2.3 Hz), 133.4 (d, 4JCP = 1.5 Hz), 132.8 (d, 2JCP = 6.0 Hz), 132.5 (d, 3JCP = 3.0 Hz), 132.3 (d, 4J 3 CP = 0.8 Hz), 131.9 (d, JCP = 3.0 Hz), 129.8, 129.6, 129.6128.9 (m) 129.2, 129.2, 128.2, 128.1, 128.1, 126.9, 126.9, 126.8, 126.6, 126.2 (d, 4JCP = 1.5 Hz), 124.8, 124.8, 51.5 (d, 2JCP = 6.8 Hz), 44.6 (d, 1JCP = 86.3 Hz),. 35.8 (d, 1JCP = 93.0 Hz). 19F NMR (282 MHz, CDCl3) δ –92.6 - –92.8 (m, 2F), –133.7-–134.0 (m, 2F). 31P{1H} NMR (122 MHz, CDCl3) δ 60.1. HRMS(ESITOF) Calcd for C28H18F4NO2P [M+Na]+: 530.0903, Found: 530.0930. d3:1H NMR (300 MHz, CDCl3) δ 3.77 (d, 3H, 3JHP = 10.8 Hz), other peaks are overlapped with d1. 19F NMR (282 MHz, CDCl3) both peaks are overlapped with d1. 31P{1H} NMR (122 MHz, CDCl3) δ 59.5 (3R,11cS)-3-fluoro-4-methoxy-3-(perfluoropyridin-4-yl)3,5-dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (6aa). To a stirred mixture of methyl phosphinate (5aa) (50.7 mg, 0.10 mmol) in THF (0.50 mL) was added NaHMDS (0.11 mL, 1.0 M in THF, 0.11 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added NFSI (63.1 mg, 0.20 mmol) in THF (0.50 mL) at –70 °C. After stirred 24 h, the reaction mixture was quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1 to 1/1) to give the corresponding phosphinate as a white solid (6aa) (17.9 mg, 34%). 1H NMR (300 MHz, CDCl3) δ 8.18 (d, 1H, J = 8.8 Hz), 8.06 (d, 1H, J = 8.8 Hz), 8.01 (d, 1H, J = 8.2 Hz), 7.91 (d, 1H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.2 Hz), 7.60-7.49 (m, 2H), 7.28 (t, 1H, J = 7.1 Hz), 7.24 (d, 1H, J = 5.2 Hz), 7.03 (t, 1H, J = 8.8 Hz), 6.64 (d, 1H, J = 8.4 Hz), 3.95 (d, 1H, 3JHP = 10.5 Hz), 3.57-3.33 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 143.1 (dt, 1JCF = 245.4 Hz, 2JCF = 15.8 Hz), 139.0 (dd, 1JCF = 265.5 Hz, 2JCF = 39.8 Hz), 134.9 (d, 2JCF = 20.3 Hz), 133.6, 133.4 (d, 2JCP = 5.3 Hz), 132.3 (d, 3JCP = 3.0 Hz), 131.5 (d, 4JCP = 0.8 Hz), 131.2 (d, 3JCP = 3.0 Hz), 129.9, 129.5 (d, 4JCP = 1.5 Hz), 129.2 (d, 2JCP = 6.8 Hz) 128.4, 128.0, 128.0, 127.2, 127.1-126.5 (m), 127.0, 126.8, 126.8, 126.4, 124.88, 124.8, 96.5 (dd, 1JCF = 189.8 Hz, 1JCP = 97.5 Hz), 53.7 (dd, 2JCP = 6.8 Hz, 4JCF = 3.8 Hz),. 35.3 (dd, 1JCP = 93.8 Hz, 3JCF = 3.0 Hz). 19F NMR (282 MHz, CDCl3) δ –91.6-–91.8 (m, 2F), – 130.1 (br, 2F), –175.5 (d, 1F, 2JFP = 65.7 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 51.9 (d, 2JPF = 66.5 Hz). HRMS(ESI-TOF) Calcd for C28H17F5NO2P [M+Na]+: 548.0809, Found: 548.0832 (3R,11cS)-3-fluoro-4-methoxy-3,5-bis(perfluoropyridin4-yl)-3,5-dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-


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oxide (7aa). To a stirred mixture of methyl phosphinate (6aa) (57.8 mg, 0.11 mmol) in THF (1.0 mL) was added NaHMDS (0.55 mL, 1.0 M in THF, 0.55 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added pentafluoropyridine (57.4 µL, 0.55 mmol) at –70 °C. After stirred 24 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane = 20/1/3) to give the corresponding phosphinate as a white solid (7aa) (11.6 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 8.27 (d, 1H, J = 8.6 Hz), 8.12 (d, 1H, J = 8.8 Hz), 8.06 (d, 1H, J = 8.2 Hz), 7.98 (d, 1H, J = 8.6 Hz), 7.83 (d, 1H, J = 8.2 Hz), 7.57 (t, 1H, J = 7.6 Hz), 7.43 (d, 1H, J = 8.0 Hz), 7.39 (t, 1H, J = 3.9 Hz), 7.25 (t, 1H, J = 7.7 Hz), 6.86 (d, 1H, J = 8.5 Hz), 6.59 (d, 1H, J = 8.5 Hz), 5.37 (d, 1H, 2JHP = 22.6 Hz), 3.88 (dd, 1H, 3JHP = 10.4 Hz, J = 1.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 144.4 (dt, 1JCF = 245.3 Hz, 2JCF = 16.5 Hz), 143.2 (dt, 1J 2 1 CF = 245.3 Hz, JCF = 14.3 Hz), 141.5 (d, JCF = 255.8 Hz), 139.0 (dd, 1JCF = 264.8 Hz, 2JCF = 34.5 Hz), 135.1 (d, 2JCF = 21.8 Hz), 133.8, 133.3 (d, 3JCP = 4.5 Hz), 132.2, 132.2, 131.5, 131.5, 130.5, 130.2, 128.9 (d, 3JCP = 3.0 Hz), 128.6, 127.9, 127.7, 127.6, 127.4, 126.1, 125.5 (d, 3JCP = 3.8 Hz), 125.2, 125.1-124.6 (m, 2C), 124.3, 120.9 (d, 2JCP = 15.8 Hz), 96.8 (dd, 1JCF = 189.0 Hz, 1JCP = 103.5 Hz), 54.7 (dd, 2JCP = 6.8 Hz, 4JCF = 4.5 Hz),. 40.6 (d, 1JCP = 91.5 Hz). 19F NMR (282 MHz, CDCl3) δ –88.1 (br, 1F), –88.9 (br, 1F), –90.9-–91.1 (m, 2F), –127.1 (br, 1F), – 130.3 (br, 2F), –141.1 (br, 1F), –173.6 (d, 1F, 2JFP = 69.6 Hz). 31P{1H} NMR (122 MHz, CDCl ) δ 46.2 (d, 2J 3 PF = 70.8 Hz). HRMS(ESI-TOF) Calcd for C33H16F9N2O2P [M+Na]+: 697.0698, Found: 697.0702 (3R,5R,11bS)-3,5-difluoro-4-methoxy-3,5bis(perfluoropyridin-4-yl)-3,5-dihydrodinaphtho[2,1c:1',2'-e]phosphepine 4-oxide (8a) To a stirred mixture of methyl phosphinate (7aa) (0.55 mmol) in THF (5.0 mL) was added NaHMDS (1.1 mL, 1.0 M in THF, 1.1 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added NFSI (695 mg, 2.2 mmol) in THF (5.0 mL) at –70 °C. After stirred 24 h, the reaction mixture was quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/dichloromethane = 1/1) to give the corresponding phosphinate as a white solid (8a) (252.3 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 8.14-8.04 (m, 3H), 7.97 (d, 2H, J = 8.8 Hz), 7.88 (d, 1H, J = 8.0 Hz), 7.87 (d, 1H, J = 8.1 Hz), 7.51 (d, 1H, J = 7.2 Hz), 7.46 (d, 1H, J = 7.3 Hz), 7.21 (dd, 1H, J = 8.6, 8.0 Hz), 7.16 (dd, 1H, J = 8.7, 7.4 Hz), 6.85 (d, 1H, J = 8.5 Hz), 6.71 (d, 1H, J = 8.8 Hz), 4.09 (d, 3H, 3JHP = 10.7 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 143.6 (dt, 1JCF = 243.8 Hz, 2JCF = 15.8 Hz), 143.4 (dt, 1JCF = 243.8 Hz, 2JCF = 15.8 Hz), 139.0 (dt, 1JCF = 261.0 Hz, 2JCF = 25.5 Hz, 2C), 133.3, 132.0, 131.9, 131.5, 132.3, 131.2, 131.2, 130.9, 130.9, 129.9, 129.0, 128.6-127.4 (m, 2C), 128.2, 127.9, 127.9, 127.2, 127.2, 126.4, 125.9, 122.5 (d, 2JCF = 20.3 Hz), 121.4 (d, 2JCF = 18.8 Hz), 95.7 (dd, 1JCF = 192.0 Hz, 1JCP = 104.8 Hz), 94.3 (dd, 1JCF = 193.5 Hz, 1JCP = 108.0 Hz), 55.9 (d, 2JCP = 8.3 Hz). 19F NMR (282 MHz, CDCl3) δ –90.3-–90.5 (m, 4F), –130.7 (dd, 2F, J = 23.0, 20.3 Hz), –131.2 (t, 2F, J = 18.0 Hz), –154.7 (d, 1F, 2JFP = 86.6 Hz), –160.0 (d, 1F, 2JFP = 69.9 Hz). 31P{1H} NMR (122

MHz, CDCl3) δ 36.6 (dd, 2JPF = 86.5, 73.1 Hz). FT-IR (KBr pellet, cm-1) 2364.3, 2334.4, 1734.7, 1594.8, 1456.6, 1273.8, 1045.2, 826.3, 761.7. HRMS(ESI-TOF) Calcd for C33H15F10N2O2P [M+Na]+: 715.0609, Found: 715.0597. [α]D21 = –2235.6 (c 0.005, CHCl3) (11cS)-4-methoxy-3-(2,3,5,6-tetrafluoro-4(trifluoromethyl)phenyl)-3,5-dihydrodinaphtho[2,1-c:1',2'e]phosphepine 4-oxide (5ab). To a stirred mixture of methyl phosphinate (4) (35.8 mg, 0.10 mmol) in THF (0.75 mL) was added NaHMDS (0.40 mL, 1.0 M in THF, 0.40 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added octafluorotolene (56.2 µL, 0.40 mmol) at – 70 °C. After stirred 24 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the mixture of corresponding phosphinate as a white solid (5aa) (mixture of d1:76% and d3:7%, d2:22%,). Yields were determined by 19F NMR of the crude. d1:1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H, J = 8.5 Hz), 7.96 (dd, 3H, J = 8.3, 7.4 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.51 (dd, 2H, J = 7.7, 7.0 Hz), 7.33-7.24 (m, 3H), 7.20 (d, 1H, J = 8.6 Hz), 5.12 (d, 1H, 2JHP = 19.7 Hz), 3.85 (d, 3H, 3JHP = 11.0 Hz), 3.40 (dd, 1H, 2JHP = 19.6 Hz, 2JHH = 14.1 Hz), 3.18 (dd, 1H, 2JHP = 17.4 Hz, 2JHH = 14.1 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 146.0 (dm, 1JCF = 249.0 Hz), 144.3 (dd, 1JCF = 275.3 Hz, 2JCF = 17.3 Hz), 134.0 (d, 3JCP = 3.8 Hz), 132.9 (d, 3JCP = 3.0 Hz), 132.9, 132.7 (d, 3JCP = 2.3 Hz), 132.1 (d, 3JCP = 2.3 Hz), 131.9 (d, 4JCP = 0.8 Hz), 131.0 (d, 2J 2 CP = 8.3 Hz), 129.9, 129.8 (d, JCP = 7.5 Hz), 129.6, 128.3, 128.2, 127.5, 127.4, 126.9, 126.8, 126.6, 126.4, 125.9, 123.7, 120.6 (q, 1JCF = 276.0 Hz), 119.0 (td, 2JCF = 17.3 Hz, 2JCP = 4.5 Hz), 110.3-108.6 (m, 1C), 52.4 (d, 2JCP = 6.8 Hz), 38.9. (d, 1JCP = 90.0 Hz), 36.2 (d, 1JCP = 90.8 Hz). 19F NMR (282 MHz, CDCl3) δ –56.5 (t, 3F, J = 20.7 Hz), –134.4 (br, 2F), –139.5-– 139.8 (m, 2F). 31P{1H} NMR (122 MHz, CDCl3) δ 62.3. HRMS(ESI-TOF) Calcd for C30H18F7O2P [M+Na]+: 597.0825, Found: 597.0842. d2:1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H, J = 8.48 Hz), 7.96 (dd, 2H, J = 8.4, 3.3 Hz), 7.85 (d, 1H, J = 8.2 Hz), 7.70 (d, 1H, J = 8.5 Hz), 7.63 (d, 1H, J = 8.5 Hz), 7.49 (t, 1H, J = 7.4 Hz), 7.35 (t, 1H, J = 7.1 Hz), 7.21 (t, 1H, J = 7.3 Hz), 7.01-6.96 (m, 2H), 6.57 (d, 1H, J = 8.5 Hz) 4.75 (d, 1H, 2JHP = 22.9 Hz), 3.86 (d, 3H, 3JHP = 10.9 Hz), 3.46 (dd, 1H, 2JHP = 20.0 Hz, 2JHH = 6.0 Hz), 3.33 (dd, 1H, 2JHP = 20.4 Hz, 2JHH = 5.8 Hz). 19F NMR (282 MHz, CDCl3) δ –56.8 (t, 3F, J = 23.7 Hz), –142.4-–142.7 (m, 2F), –130.1 (d, 2F). 13C{1H} NMR (75 MHz, CDCl3) δ 144.7 (dm, 1JCF = 251.3 Hz), 143.1 (dd, 1JCF = 256.5 Hz, 2JCF = 17.3 Hz), 134.4 (d, 3JCP = 2.3 Hz), 133.3 (d, 4JCP = 1.5 Hz), 133.0 (d, 2JCP = 6.0 Hz), 132.5 (d, 3JCP = 2.3 Hz), 132.2, 131.9 (d, 3JCP = 3.0 Hz), 129.6, 129.4, 129.3, 128.2, 128.0, 128.0, 126.8, 126.8, 126.5, 126.5, 126.0, 126.0, 124.9, 124.9, 120.7 (t, 2JCF = 15.0 Hz), 120.3 (q, 1JCF = 273.0 Hz), 108.3-106.9 (m, 1C), 51.4 (d, 2JCP = 6.8 Hz), 44.4 (d, 1JCP = 85.5 Hz),. 35.9 (d, 1JCP = 93.0 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 61.7. HRMS(ESI-TOF) Calcd for C30H18F7O2P [M+Na]+: 597.0825, Found: 597.0838. d3:1H NMR (300 MHz, CDCl3) δ 3.78 (d, 3H, 3JHP = 10.8 Hz), other peaks are overlapped with d1. 19F NMR (282 MHz, CDCl3) δ –139.2 (br, 2F), other peaks are overlapped with d1. 31P{1H} NMR (122 MHz, CDCl3) δ 60.7 (3R,11cS)-3-fluoro-4-methoxy-3-(2,3,5,6-tetrafluoro-4(trifluoromethyl)phenyl)-3,5-dihydrodinaphtho[2,1-c:1',2'-



e]phosphepine 4-oxide (6ab). To a stirred mixture of methyl phosphinate (5ab) (0.13 mmol) in THF (0.65 mL) was added NaHMDS (0.14 mL, 1.0 M in THF, 0.14 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added NFSI (82.0 mg, 0.26 mmol) in THF (0.65 mL) at – 70 °C. After stirred 24 h, the reaction mixture was quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1 to 1/1) to give the corresponding phosphinate as a white solid (6ab) (27.7 mg, 36%). 1H NMR (300 MHz, CDCl3) δ 8.17 (d, 1H, J = 8.8 Hz), 8.07 (d, 1H, J = 8.8 Hz), 8.00 (d, 1H, J = 8.2 Hz), 7.89 (d, 1H, J = 8.5 Hz), 7.78 (d, 1H, J = 8.2 Hz), 7.58 (d, 1H, J = 8.5 Hz), 7.52 (t, 1H, 7.5 Hz), 7.35 (t, 1H, J = 7.5 Hz), 7.24 (t, 1H, J = 7.1 Hz), 7.04 (t, 2H, J = 7.1 Hz), 6.65 (d, 1H, J = 8.8 Hz), 3.95 (dd, 1H, 3JHP = 9.5 Hz, J = 0.9 Hz), 3.53-3.33 (m, 2H). 13C{1H} NMR (75 MHz, CDCl ) δ 144.2 (dm, 1J 3 CF = 256.5 Hz), 143.2 (dd, 1JCF = 259.5 Hz, 2JCF = 18.0 Hz), 135.7 (d, 2JCF = 21.0 Hz), 133.7 (d, 3JCP = 5.3 Hz), 133.5, 132.4 (d, 3JCP = 2.3 Hz), 131.6 (d, 4JCP = 0.8 Hz), 131.3 (d, 3JCP = 3.0 Hz), 129.7 (d, 3JCP = 4.5 Hz), 129.7, 129.4 (d, 4JCP = 1.5 Hz), 129.3 (d, 3JCP = 6.8 Hz), 128.4, 127.8, 127.8, 127.1, 127.0 (d, 2JCP = 8.3 Hz), 126.7, 126.4, 125.1, 125.1, 121.7, 121.5, 121.4-120.9 (m, 1C), 119.9 (q, 1JCF = 273.0 Hz), 110.3-108.7 (m, 1C), 96.8 (dd, 1JCF = 189.8 Hz, 1JCP = 98.3 Hz), 53.6 (dd, 2JCP = 6.8 Hz, 4JCF = 3.8 Hz),. 35.4 (dd, 1JCP = 93.8 Hz, 3JCF = 3.0 Hz). 19F NMR (282 MHz, CDCl3) δ –56.7 (t, 3F, J = 22.6 Hz), –126.2 (br, 2F), –141.8 (br, 2F), –173.8 (d, 1F, 2JFP = 65.7 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 52.1 (d, 2JPF = 66.7 Hz). HRMS(ESI-TOF) Calcd for C30H17F8O2P [M+Na]+: 615.0731, Found: 615.0749. (3R,11cS)-3-fluoro-4-methoxy-3,5-bis(2,3,5,6tetrafluoro-4-(trifluoromethyl)phenyl)-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (7ab). To a stirred mixture of methyl phosphinate (6ab) (27.7 mg, 0.047 mmol) in THF (1.0 mL) was added NaHMDS (0.23 mL, 1.0 M in THF, 0.23 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added octafluorotoluene (32.9 µL, 0.23 mmol) at –70 °C. After stirred 24 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane = 20/1/3) to give the corresponding phosphinate as a white solid (7ab) (64%). Yields were determined by 19F NMR of the crude. 1H NMR (300 MHz, CDCl ) δ 8.25 (d, 1H, J = 8.9 Hz), 8.12 (d, 3 1H, J = 8.8 Hz), 8.05 (d, 1H, J = 8.2 Hz), 7.94 (d, 1H, J = 8.8 Hz), 7.81 (d, 1H, J = 8.2 Hz), 7.56 (t, 1H, J = 7.5 Hz), 7.38 (t, 2H, J = 7.3 Hz), 7.25 (t, 1H, J = 8.2 Hz), 6.87 (d, 1H, J = 8.6 Hz), 6.59 (d, 1H, J = 8.5 Hz), 5.36 (d, 1H, 2JHP = 23.1 Hz), 3.86 (dd, 1H, 3JHP = 10.4 Hz, J = 1.1 Hz) 13C{1H} NMR (75 MHz, CDCl3) δ 149.6-143.5 (br, 1C), 144.8 (d, 1JCF = 253.5 Hz), 144.3 (dm, 1JCF = 260.3 Hz), 143.3 (dd, 1JCF = 258.0 Hz, 2JCF = 16.5 Hz), 136.1 (d, 2JCF = 21.8 Hz), 133.8, 133.8, 133.5 (d, 3JCP = 4.5 Hz), 132.3, 132.3, 131.6, 130.3, 129.9, 128.9 (d, 3JCP = 3.0 Hz), 128.6, 127.8, 127.6, 127.5, 127.2, 127.1, 126.1, 125.5, 124.5, 121.1 (d, 2JCP = 15.0 Hz), 121.0-120.3 (m, 1C), 120.7 (q, 1JCF = 272.3 Hz), 119.9 (q, 1JCF = 273.8 Hz), 115.7 (td, 2JCF = 16.5 Hz, 2J = 5.3 Hz), 111.7-109.1 (m, 1C), 97.1 (dd, 1J CP CF = 190.5 Hz, 1J 2 4 CP = 102.0 Hz), 54.4 (dd, JCP = 6.8 Hz, JCF = 3.8 Hz),. 40.2

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(d, 1JCP = 91.5 Hz). 19F NMR (282 MHz, CDCl3) δ –56.5 (t, 3F, J = 21.7 Hz), –56.8 (t, 3F, J = 20.3 Hz), –123.4 (br, 1F), –126.7 (br, 2F), –137.6 (br, 2F), –139.7 (br, 1F), –141.3 (br, 2F), – 171.8 (d, 1F, 2JFP = 69.7 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 47.6 (d, 2JPF = 69.5 Hz). HRMS(ESI-TOF) Calcd for C37H16F15O2P [M+Na]+: 831.0541, Found: 831.0541. (3R,11cS)-3-fluoro-4-methoxy-3-(2,3,5,6-tetrafluoro-4(trifluoromethyl)phenyl)-3,5-dihydrodinaphtho[2,1-c:1',2'e]phosphepine 4-oxide (8b). To a stirred mixture of methyl phosphinate (7ab) (0.024 mmol) in THF (0.20 mL) was added NaHMDS (48 µL, 1.0 M in THF, 0.048 mmol) at –70 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added NFSI (44.8 mg, 0.14 mmol) in THF (0.20 mL) at – 70 °C. After stirred 24 h, the reaction mixture was quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/dichloromethane = 1/1) to give the corresponding phosphinate as a white solid (8b) (10.1 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.11-8.03 (m, 3H), 7.97 (d, 1H, J = 8.7 Hz), 7.85 (dd, 2H, J = 7.5, 6.3 Hz), 7.49 (d, 1H, J = 8.1 Hz), 7.44 (d, 1H, J = 8.1 Hz), 7.19 (dd, 1H, J = 8.1, 7.8 Hz), 7.14 (dd, 1H, J = 8.7, 7.2 Hz), 6.85 (d, 1H, J = 8.7 Hz), 6.72 (d, 1H, J = 8.1 Hz), 4.09 (d, 3H, 3JHP = 10.7 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 144.5 (dm, 1JCF = 261.0 Hz, 2C), 143.7 (d, 1JCF = 250.5 Hz, 2C), 133.4, 133.3, 133.1, 132.8, 132.3, 132.0, 131.4, 131.3, 130.7, 130.7, 129.9, 129.3, 128.1, 127.7, 127.1, 127.0, 126.7, 126.3, 122.6 (d, 2JCF = 19.5 Hz), 121.7 (d, 2JCF = 18.8 Hz), 120.4-119.4 (m, 2C) 120.0 (q, 1JCF = 273.0 Hz, 2C), 119.9 (q, 1JCF = 273.8 Hz), 111.5-109.9 (m, 2C), 96.2 (dd, 1JCF = 191.3 Hz, 1JCP = 102.8 Hz), 94.8 (dd, 1JCF = 193.5 Hz, 1JCP = 105.0 Hz) 55.9 (d, 2JCP = 8.3 Hz). 19F NMR (282 MHz, CDCl3) δ –56.8 (t 3F, 4JFF = 20.6Hz), 56.9 (t, 3F, 4JFF = 20.6Hz), –127.3-–127.3 (m, 2F), –127.8 (s, 2F), – 140.4-–140.8 (m, 4F), –152.6 (d, 1F, 2JFP = 86.6 Hz), –157.1 (d, 1F, 2JFP = 73.0 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 37.7 (dd, 2JPF = 87.1, 73.1 Hz). FT-IR (KBr pellet, cm-1) 3071.1, 2921.6, 2850.3, 2360.4, 2337.3, 1599.7, 1485.9, 1333.5, 1267.0, 1184.1, 1154.2, 1044.3, 1007.6, 754.0, 714.5. HRMS(ESI-TOF) Calcd for C37H15F16O2P [M+Na]+: 849.0452, Found: 849.0430. [α]D21 = –2751.8 (c 0.0056, CHCl3). (11bS)-3,5-dihydroxy-4-methoxy-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (12).37 To a stirred mixture of (S)-dialdehyde 11 (1.68 g, 5.4 mmol) in THF (15 mL) was added BF3･OEt2 (2.30 mL, 17.8 mmol) at 0 °C, and then the mixture was stirred for 30 min. After methyl phosphinate (7) (7.62 mL, 0.78 M in THF, 5.9 mmol) was added at 0 °C, the reaction mixture was stirred for 10 h at room temperature. After confirming the completion of reaction by TLC analysis, the reaction mixture was quenched with 1 M HClaq. The reaction mixture was extracted with ethyl acetate, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (dichloromethane/methanol = 10/1 to 5/1 to) to give the corresponding diastereomer of diol (12) as a white solid (916.7 mg, 43%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J = 8.7 Hz), 7.92 (dd, 2H, J = 7.6, 6.8 Hz), 7.78-7.74 (m, 3H), 7.44 (dd, 1H, J = 7.7, 7.3 Hz), 7.38 (dd, 1H, J = 7.6, 7.3 Hz), 7.19 (dd, 1H, J = 7.9, 7.3 Hz), 7.13 (dd, 1H, J = 8.3, 7.0 Hz), 7.05 (t, 2H, J = 8.4 Hz) 5.71 (brs, 1H), 5.01 (brs, 1H), 4.76 (dd, 1H, J = 9.2,


Page 9 of 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


8.9 Hz), 4.45 (dd, 1H, J = 8.2, 7.7 Hz), 3.66 (d, 3H, 3JHP = 9.9 Hz). 13C{1H} NMR (75 MHz, CDCl3) δ 133.8 (2C), 133.4 (d, 2C, 3JCP = 3.8 Hz), 133.1 (d, 4JCP = 2.3 Hz), 133.0 (d, 4JCP = 2.3 Hz), 131.6 (d, 2C, 4JCP = 2.3 Hz), 129.6, 129.5, 129.3 (d, 3JCP = 3.8 Hz), 128.4 (2C), 126.9 (d, 2JCP = 9.0 Hz), 126.5 (d, 3JCP = 3.8 Hz), 126.0 (d, 2JCP = 6.8 Hz), 122.1, 122.0, 121.7, 121.6, 69.5 (d, 1JCP = 96.8 Hz), 68.6 (d, 1JCP = 90.8 Hz), 54.1 (d, 2JCP = 8.3 Hz). 31P{1H} NMR (122 MHz, CDCl3) δ 51.6. FT-IR (KBr pellet, cm-1) 3282, 3060, 2954, 2360, 1507, 1458, 1219, 1159, 1085, 1057, 1034, 905, 867, 844, 750, 665, 634. HRMS(ESITOF) Calcd for C23H19O4P [M+Na]+: 413.0919, Found: 413.0921. (3R,5R,11bS)-3,5-difluoro-4-methoxy-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (4b). (11bS)-3,5-dihydroxy-4-methoxy-3,5-dihydrodinaphtho[2,1c:1',2'-e]phosphepine 4-oxide (12) (916.7 mg, 2.4 mmol) in CH2Cl2 (13.5 mL) was dropwised to the stirring dispersion of XtalFluor-E (1.70 g, 7.5 mmol) and TEA･3HF (1.66 mL, 10.2 mmol) in CH2Cl2 (10.0 mL) at 0 °C. After stirred for 1 h at room temperature, the reaction mixture was quenched with sat. aqueous NaHCO3 at 0 °C. The organic layer was extracted with CH2Cl2 and washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (diethyl ether/hexane = 5/1 to 10/1) to give the corresponding methyl phosphinate (4b) as a yellow solid (121.4 mg, 13%). 1H NMR (300 MHz, CDCl3) δ 8.02 (t, 2H, J = 8.1 Hz), 7.95 (d, 2H, J = 8.2 Hz), 7.61 (d, 1H, J = 8.4 Hz), 7.53-7.48 (m, 3H), 7.30-7.18 (m, 5H), 5.93 (dd, 1H, 2JHF = 47.9 Hz, 2JHP = 9.9 Hz), 5.71 (dd, 1H, 2JHF = 46.5 Hz, 2JHP = 10.8 Hz), 3.87 (d, 3H, 3JHP = 10.5 Hz). 13C{1H} NMR (75 MHz, CDCl ) δ 136.4 (d, 2J 3 CF = 14.5 Hz), 134.4, 134.2, 133.3 (d, 2JCF = 8.3 Hz), 129.8, 129.4, 128.4, 128.3, 127.2, 127.1, 127.0, 126.9, 126.8, 126.7, 126.7, 126.6, 126.0-125.6 (m), 90.3 (dd, 1JCF = 198.8 Hz, 1JCP = 101.3 Hz), 90.2 (dd, 1JCF = 196.5 Hz, 1JCP = 114.4 Hz), 52.9 (d, 2JCP = 7.5 Hz). 19F NMR (282 MHz, CDCl3) δ –179.5 (dd, 1F, 2JFP = 61.3, 2J 2 2 FH = 48.0 Hz), –187.4 (dd, 1F, JFP = 83.4, JFH = 46.1 Hz). 31P{1H} NMR (122 MHz, CDCl ) δ 40.3 (dd, 2J 3 PF = 84.7, 62.2 Hz). FT-IR (KBr pellet, cm-1) 2952, 2925, 2854, 2360, 2339, 1731, 1650, 1556, 1539, 1509, 1458, 1283, 1123, 1022, 854, 784, 672, 625. HRMS(ESI-TOF) Calcd for C23H17F2O2P [M+Na]+: 417.0832, Found: 417.0844. (3R,5R,11bS)-3,5-difluoro-4-methoxy-3,5bis(perfluoropyridin-4-yl)-3,5-dihydrodinaphtho[2,1c:1',2'-e]phosphepine 4-oxide (8a). To a stirred mixture of (3R,5R,11bS)-3,5-difluoro-4-methoxy-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (4b) (39.4 mg, 0.10 mmol) in THF (1.0 mL) was added NaHMDS (0.40 mL, 1.0 M in THF, 0.40 mmol) at -78 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added pentafluoropyridine (31.3 µL, 0.30 mmol) at -78 °C. After stirred 12 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1 to 5/1) to give the corresponding phosphate as a colorless solid (8a) (10.1 mg, 15%). (3R,5R,11bS)-3,5-difluoro-4-methoxy-3,5-bis(2,3,5,6tetrafluoro-4-(trifluoromethyl)phenyl)-3,5dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (8b).

To a stirred mixture of (3R,5R,11bS)-3,5-difluoro-4-methoxy3,5-dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (4b) (39.4 mg, 0.10 mmol) in THF (mL) was added NaHMDS (0.40 mL, 1.0 M in THF, 0.40 mmol) at –78 °C, and then the mixture was stirred for 30 min. To the reaction mixture was added octafluorotoluene (42.2 µL, 0.30 mmol) at –78 °C. After stirred 12 h, the reaction mixture was warmed up to rt. and quenched with sat. aqueous NH4Cl. The reaction mixture was extracted with Et2O, and organic layer was washed with brine. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1 to 5/1) to give the corresponding phosphate as a colorless solid (8b) (11.2 mg, 14%). (3R,5R,11bS)-3,5-difluoro-4-hydroxy-3,5bis(perfluoropyridin-4-yl)-3,5-dihydrodinaphtho[2,1c:1',2'-e]phosphepine 4-oxide(9a). To a stirred mixture of (3R,5R,11bS)-3,5-difluoro-4-hydroxy-3,5bis(perfluoropyridin-4-yl)-3,5-dihydrodinaphtho[2,1-c:1',2'e]phosphepine 4-oxide (8a) (4.72 mg, 0.0068 mmol) in acetone (0.75 mL) was added sodium iodide (40.0 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred for 2 days at room temperature, and quenched with 1 M HClaq. The organic layer was extracted with dichloromethane and washed with 1 M HClaq. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) and the solution of 9a in CH2Cl2 was treated with cation exchange resin (Amberlyst® 15Dry, 300w/w%). After the solution was filtered, the solvent was removed in vacuo to give the corresponding phosphinic acid as a yellowish solid (9a) (7.3 mg, quantative).1H NMR (300 MHz, actone-d6) δ 8.06 (d, 2H, J = 9.1 Hz), 8.01 (d, 2H, J = 7.5 Hz), 7.91 (d, 2H, J = 7.7 Hz), 7.44 (t, 2H, J = 5.2 Hz), 7.15 (t, 2H, J = 7.8 Hz), 6.72 (d, 2H, J = 7.2 Hz). 19F NMR (282 MHz, actone-d6) δ –95.2 (brs, 4F), –130.5 (brs, 4F), –157.0 (brs, 2F) 31P{1H} NMR (122 MHz, actone-d ) δ 24.4 (t, 2J 6 PF = 68.3 Hz). HRMS(ESI-TOF) Calcd for C32H12F10N2O2P [M-H]−: 677.0477, Found: 677.0476. (3R,5R,11bS)-3,5-dihydrodinaphtho[2,1-c:1',2'e]phosphepine 4-oxide (9b). To a stirred mixture of (3R,5R,11bS)-3,5-dihydrodinaphtho[2,1-c:1',2'-e]phosphepine 4-oxide (8b) (5.86 mg, 0.0071 mmol) in acetone (0.75 mL) was added sodium iodide (40.0 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred for 2 days at room temperature, and quenched with 1 M HClaq. The organic layer was extracted with dichloromethane and washed with 1 M HClaq. The solvent was dried over Na2SO4 and removed in vacuo. The resultant residue was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) and the solution of 9bin CH2Cl2 was treated with cation exchange resin (Amberlyst® 15Dry, 300w/w%). After the solution was filtered, the solvent was removed in vacuo to give the corresponding phosphinic acid as a yellowish solid (9b) (5.3 mg, 92%). 1H NMR (300 MHz, actone-d6) δ 8.05-7.97 (m, 4H), 7.88 (d, 2H, J = 8.7 Hz), 7.40 (d, 2H, J = 7.5 Hz), 7.13 (t, 2H, J = 7.6 Hz) 6.69 (d, 2H, J = 9.3 Hz). 19F NMR (282 MHz, acetone-d6) δ –57.4 (t, 6F, 4JFF = 21.6 Hz), –126.8 (brs, 4F), –144.6 (brs, 4F), –155.0 (brs, 2F) 31P{1H} NMR (122 MHz, actone-d ) δ 25.8 (t, 2J 6 PF = 68.4 Hz) FT-IR (KBr pellet, cm-1) 2925, 2360, 1484, 1333, 1237, 1188, 1150, 1092, 1008, 817, 753, 714. HRMS(ESI-TOF) Calcd for C36H13F16O2P [M-H]-: 811.0319, Found: 811.0359. X-ray crystallography of 8b. X-ray diffraction data were



collected on a Rigaku RAXIS-Rapid diffractometer. The structures were solved by a direct method (SHELXL-2014).42 The X-ray structure solution and refinement were carried out using the Yadokari-XG software.43 C37H15F16O2P, colorless platelet (CH2Cl2, 20 °C), MW = 826.46, crystal dimensions = 0.270  0.200  0.090 mm3, monoclinic, space group P21 (#4), a = 12.8387(14), b = 8.7580(10), c = 15.1578(18) Å,  = 107.408(3)°, V = 1626.3(3) Å3, Z = 2,  = 0.71073 Å, T = 158 K, calcd = 1.688 g cm–3, MoK = 0.213 mm–1, F000 = 824, 15609 total reflections (2max = 54.88°), index ranges = –16≤h≤16, – 10≤k≤11, –19≤l≤19, 7012 unique reflections (Rint = 0.0535), R1 = 0.0576 (I > 2(I)), 0.1030 (all data), wR2 = 0.1461 (I > 2(I)), 0.1901 (all data), S = 1.097 (553 parameters), Flack parameter = –0.03(10).

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ASSOCIATED CONTENT

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(12)

(13) (14) (15)

Supporting Information NMR spectra, X-ray crystallography data and CIF file. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

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Corresponding Author [email protected] (19)

ACKNOWLEDGMENT This work was supported by JST ACT-C Grant Number JPMJCR12Z7 and JSPS KAKENHI Grant Number 26620078.

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REFERENCES (1) (2) (3) (4)

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phosphinates via SNAr reaction

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