B2pin2-Catalyzed Difluoroalkylation of

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Copper/B2pin2-Catalyzed Difluoroalkylation of Methylenecyclopropanes with Bromodifluorinated Acetates and Acetamides: One-pot Synthesis of CF2-Containing Dihydronaphthalene Derivatives Chuang Liu, Yan-Jie Yang, Jun-Ying Dong, Mingdong Zhou, Lei Li, and He Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01106 • Publication Date (Web): 26 Jul 2019 Downloaded from pubs.acs.org on July 27, 2019

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The Journal of Organic Chemistry

Copper/B2pin2-Catalyzed Difluoroalkylation of Methylenecyclopropanes with Bromodifluorinated Acetates and Acetamides: One-pot Synthesis of CF2Containing Dihydronaphthalene Derivatives Chuang Liu, Yan-Jie Yang, Jun-Ying Dong, Ming-Dong Zhou, Lei Li* and He Wang* School of Chemistry and Materials Science, Liaoning Shihua University, Fushun 113001, P. R. China

Abstract: A novel copper/B2pin2-catalyzed difluoroalkylation of methylenecyclopropanes with bromodifluorinated acetates and acetamides via tandem radical process involving ringopening/intramolecular cyclization has been reported. This protocol is not only tolerated to a diverse range of substrates, but also applicable to the synthesis of useful difluoromethylated compounds. Moreover, the reaction could be performed on a gram scale with high yield, which opens up the possibility for practical applications. R1 R

R1 + BrCF2COR2

Cu(I)/B2pin2

CF2COR2

R 80 C 29 examples up to 93% yield  One-pot to CF2-containing dihydronaphthalenes via tandem radical process  Readily available substrate and broad scope

Introduction Dihydronaphthalene derivatives are useful synthetic building blocks and widely present in various medicines and natural products.1 They have explicitly exhibited fascinating biological activities and used as fluorescent ligands for the estrogen receptor.2 On the other hand, organofluorine compounds play significant roles in pharmaceutical, agrochemical and material sciences.3 Thus, the incorporation of a fluorinated group into dihydronaphthalene derivatives has attracted a lot of attention.4-6 Among them, the remarkable CF3-containing

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dihydronaphthalene derivatives have been synthesized through a copper-catalyzed tandem trifluoromethylation/cyclization of internal alkynes with Togni’s reagent or Umemoto’s reagent (Scheme 1a).5 In contrast, the construction of CF2-containing dihydronaphthalene derivatives has rarely been reported.6 For instance, the Zhang group reported a palladium-catalyzed Hecktype fluoroalkylation reaction of alkenes (Scheme 1b).[6e] Recently, Cheng has made significant advances in the development of visible-light-promoted difuoroalkylation/C-H annulation cascade reaction of cyclopropyl olefins by iridium catalyst (Scheme 1c).[6c] Given that the gemdifluoromethylene group (CF2) can act as a potential bioisostere of hydroxy groups or a carbonyl group, and enhance the acidity of the neighboring group, dipole moments, and conformational changes,7 the development of novel methods with generality and practicality for the construction of CF2-containing dihydronaphthalene derivatives is highly desirable. Fu's and Xiao's works R2

R2 [Cu]

R1

n

X

CF3

R1

[CF3+]

X

(a)

n

Zhang's work R1 + R3F2C X

R R2

[Pd] Xantphos

R1 CF2R3

R

(b)

R2

Cheng's work R +

Ar

R X

[Ir]

R = CF2COR1, CHFCO2Et, CF3 (c) CH2CN, CH(CO2Et)2

LEDs

This work R1 R

R1 2 + BrCF2COR

Cu(I)/B2pin2

CF2COR2 R

Scheme 1. Synthesis of fluorine-containing dihydronaphthalene derivatives. Over the past decades, transition-metal catalyzed radical difluoromethylation has emerged as a powerful strategy for the introduction of gem-difluoro group to organic molecules.8


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Recently, a series of copper-catalyzed difluoroalkylation reactions have been explored for the construction of C-CF2 bonds.9 The difluoroalkyl (CF2)-radical, a powerful intermediate in organic synthesis, could also be readily generated via copper catalysis, which has been widely employed in addition reactions and cross-coupling reactions. Owing to high ring strain and reactivity, methylenecyclopropanes (MCPs) are a type of interesting building blocks and widely used in organic synthesis.10 In particular, the fluorination of MCPs has been explored extensively to construct useful fluorine-containing scaffolds recently.11 For example, the Shi group reported an elegant copper(I)-catalyzed intramolecular trifluoromethylation of MCPs for the one-pot synthesis of CF3-containing dihydronaphthalene derivatives.5b As part of our interest in C-CF2 bond-forming reactions,12 we herein report a copper/B2pin2-catalyzed difluoroalkylation of MCPs with bromodifluorinated reagents for the synthesis of CF2containing dihydronaphthalene derivatives. Results and Discussion We initiated our investigation on the reaction of MCPs 1a with ethyl bromodifluoroacetate 2a (Table 1). Using CuCl as a catalyst, dtbbpy as ligand, and B2pin2 as the additive, the cascade reaction afforded the desired product 3a in 80% yield using NaHCO3 in 1,4-dioxane at 80 °C (entry 1). Variation of Cu(I) and Cu(II) species indicated that CuBr was superior to the other copper salts (entries 1-6). Other ligands such as 1,10-phenanthroline (1,10-phen), 2,2′bipyridine (bpy), N,N′-dimethylethylenediamine (DMEDA) did not promote this reaction, and afforded 3a in low yield (entries 7-9). After a screening of several parameters (for more details, see SI, Table S1), the reaction proceeded well and gave 3a in 84% yield when CuBr (10 mol %)/dtbbpy (10 mol %) was used in combination with B2pin2 (30 mol %) and NaHCO3 in



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1,4-dioxane at 80 °C for 16 h (entry 2). Control experiments revealed that both the catalyst and an inert atmosphere are crucial for the success of this transformation, and the omission of dtbbpy, B2pin2, or NaHCO3 led to rather poor conversion (entries 10-14). Table 1. Optimization of Reaction Conditionsa

+ BrCF2CO2Et

1a t

catalyst (10 mol %) ligand (10 mol %) B2pin2 (30 mol %) base (2 equiv) solvent (1.0 mL) 80 C, N2, 16 h

2a t

Bu

CF2CO2Et

3aa

Bu NH HN

N

N

N L1

N

N L2

N L3

entry

cat.

ligand

yield (%)b

1

CuCl

L1

80

2

CuBr

L1

84

3

CuI

L1

54

4

CuCl2

L1

74

5

CuBr2

L1

80

6

Cu(OAc)2

L1

64

7

CuBr

L2

32

8

CuBr

L3

27

9

CuBr

L4

19

10c

-

L1

0

11d

CuBr

-

15

12e

CuBr

L1

13


L4

Page 5 of 35 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


aReaction

13f

CuBr

L1

10

14g

CuBr

L1

0

conditions: 1a (0.2 mmol), 2a (0.4 mmol), B2pin2 (30 mol %), cat. (10 mol %), ligand

(10 mol %), and base (2.0 equiv) in a solvent (1.0 mL) under N2 at 80 °C for 16 h. bIsolated yield. cNo copper catalyst was used. dNo ligand was used. eNo B2Pin2 was used. fNo base was used. gUnder air. With the optimized conditions in hand, the scope and generality of a series of MCPs was then evaluated. As shown in Scheme 2, the tandem cyclization reaction could proceed well to afford corresponding products in moderate to high yields. Diphenylmethylenecyclopropanes bearing different electron-donating and halogen groups at the para-position of the phenyl ring reacted efficiently to give the CF2-containing dihydronaphthalenes 3aa-3af in good yields. Next, MCPs containing one phenyl group have been proved to be suitable for this transformation. Mono-and di-substituted MCPs bearing various functional groups, such as methyl, methoxy, benzyloxy, halogen, and trifluoromethyl groups were viable for this transformation in moderate to good yields (3ga-3sa). Among them, subjection of the substrates 1g, 1k, 1m, and 1r to the standard conditions gave moderate yields. As these substrates represent weak stability at room temperature, we assume the partially decomposition of substrates may occur under 80 °C, which might be responsible for the low yields of products. Furthermore, substrates containing an alkyl group also gave the desired product in 37% and 45% yields (3ta and 3ua), respectively. However, changing the cyclopropyl group to cyclobutyl group (1v) failed to afford the product in the present reaction system. To demonstrate the synthetic practicality of this catalytic system, synthesis of product 3aa on a 5 mmol scale was conducted and a 79% isolated yield was



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achieved.

R

R

1

+ BrCF2CO2Et

1

2a

CuBr (10 mol %) dtbbpy (10 mol %) B2pin2 (30 mol %) NaHCO3 (2 equiv) 1,4-dioxane (1.0 mL) 80 oC, N2,16 h

Me

Me

3aa, 84%, 79%c

Cl

Br

MeO

Me 3ha, 62%d 66% (3ha:8ha90:10)e

CF2CO2Et

CF2CO2Et

OBn 3la, 70%d 75% (3la:8la91:9)e

3ka, 46%d 49% (3ka:8ka91:9)e

Br

Me

MeO

CF2CO2Et

CF2CO2Et

CF2CO2Et

CF2CO2Et

CF2CO2Et

3ga, 43%d 47% (3ga:8ga87:13)e

3ja, 72%d 78% (3ja:8ja=92:8)e

CF2CO2Et

F 3da, 66%

F3C

Br

Br 3ma, 44%d 45% (3ma:8ma93:7)e

F

CF2CO2Et

CF2CO2Et

CF2CO2Et

3ia, 61%d 68% (3ia:8ia90:10)e

OMe

CF2CO2Et

3ca, 84%

3fa, 73%

Cl

8

Br

3ea, 86%

R1

R

CF2CO2Et

CF2CO2Et

Br

EtO2CF2C

1

3

3ba, 75%

CF2CO2Et

R

R

CF2CO2Et

CF2CO2Et

Cl

CF2CO2Et

OBn 3oa, 66%d 72% (3oa:8oa92:8)e

OMe 3na, 67% CF2CO2Et

CF2CO2Et

OMe 3pa, 83% CF2CO2Et Me

Br

OBn Cl Cl 3qa, 63%d 3ra, 46%d 67% (3qa:8qa85:15)e 59% (3ra:8ra90:10)e

Me

Br 3sa, 72%d 77% (3sa:8sa93:7)e

3ta, 37%d 40% (3ta:8ta85:15)e

CF2CO2Et n

Pr

3ua, 45%d 48% (3ua:8ua85:15)e

1v, (no reaction)

Scheme 2. Scope of MCPs. aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), B2pin2 (30 mol %), CuBr (10 mol %), dtbbpy (10 mol %), and NaHCO3 (2.0 equiv) in a 1,4-dioxane (1.0 mL) under N2 at 80°C for 16 h. bIsolated yield. cReaction was performed with 5 mmol of 1a. d After the reaction, the mixture was treated by AgNO3 (0.08 mmol) in EtOH and refluxed for 10 h to remove byproduct 8. e The ratio product 3/byproduct 8 was determined by the crude 1H NMR and 19F NMR spectroscopy of isolated mixture.


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Given the importance of the gem-difluoromethylene group, we next turned our attention to the scope of bromodifluoroacetamides (Scheme 3). Various N,N-disubstituted amides, such as diethylamine, pyrrolidine, piperidine, and morpholine, were proven to be viable difluoroalkylation reagent as well, furnishing the CF2-containing dihydronaphthalenes in good yields (3ab-3ae). Comparable yields were obtained for the N-substituted anilines 3ag-3ai, implying that the presence of a free N-H bond in bromodifluoroacetamides has no significant impact on this reaction. CuBr (10 mol %) dtbbpy (10 mol %) B2pin2 (30 mol %)

O +

R2

BrF2C

1a

F F NEt2

3ab, 64% O

F F

F F N

O Ph

O Ph

3ac, 61%

3ad, 84%

F F

N O Ph

H N

F F Ph

O Ph

3ae, 61% F F

3

N

O Ph

O Ph 3ah, 93%

O Ph

3af, 71% F

H N Br

R2

O Ph

NaHCO3 (2 equiv) 1,4-dioxane (1.0 mL) 80 oC, N2,16 h

2

F F

F F

H N Me

3ag, 76%

F H N O Ph

CF3

3ai, 72%

Scheme 3. Scope of bromodifluoroacetamides. aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), B2pin2 (30 mol %), CuBr (10 mol %), dtbbpy (10 mol %), and NaHCO3 (2.0 equiv) in a 1,4-dioxane (1.0 mL) under N2 at 80°C for 16 h. bIsolated yield. The product 3aa could be reduced with NaBH4 in anhydrous THF to yield compound 4aa (Scheme 4, eq 1). NBS-promoted oxidation of product 3aa in EtOH led to the formation of



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CF2-containing naphthalene 5aa in 65% yield (Scheme 4, 2). Considering the valuable CF2H moiety,13 removal of the ester moiety was achieved to provide difluoromethylated compound 7aa in 53% yield (Scheme 4, eq 3). To gain some insight into the catalytic mechanism, radical trapping experiments were then carried out. The standard reaction was found to be completely suppressed by radical inhibitors 2,2,6,6,-tetramethyl-1-piperidinyloxy (TEMPO) and 1,1diphenylalkene, suggested that a radical process might be involved in this reaction. (Scheme 4, eq 4). CF2CO2Et Ph

CF2CH2OH NaBH4

3aa

4aa, 85% CF2CO2Et Ph

CF2CO2Et NBS EtOH, rt, 2 h

3aa

5aa, 65%

Ph 3aa

Ph 1a

(2)

Ph

CF2CO2Et

Ph

(1)

Ph

EtOH, rt, 2 h

CF2H

CF2CO2H 1M K2CO3 MeOH, rt, 2 h

Ph

CsF NMP, N2, 170 C, 3 h

6aa, 94% CuBr (10 mol %) dtbpy (10 mol %) B2pin2 (30 mol %) BrCF2CO2Et NaHCO3 (2 equiv) 1,4-dioxane (1.0 mL) 80 oC, N2,16 h 2a

Ph

(3)

7aa, 53%

3aa TEMPO: 0% 1,1-diphenylethylene: 0%

N O

(4)

CF2CO2Et detected by GCMS

Scheme 4. Derivatives (derivatization) of CF2-containing dihydronaphthalenes and mechanistic studies On the basis of our experimental results and the previous mechanistic investigations,[5b, 9b] a plausible mechanism is suggested starting from LCuIX complex A (Scheme 5). The CuI-Bpin species B is generated between A and B2pin2 in the presence of NaHCO3. Subsequently, a single electron transfer (SET) from species B to bromodifluorinated reagent 2 gives the intermediate


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C and a CF2COR2 radical D. Addition of radical D to MCPs 1 with a ring-opening process delivers radical intermediate E, which undergoes intramolecular radical cyclization to generate intermediate F. The intermediate F could be oxidized by intermediate D, followed by proton abstraction to afford the product 3 in the presence of base.

BrCF2COR2 2

CF2COR2 C

R1

R 1

NaHCO3

CF2COR2

X Bpin L CuII Bpin R Br D

L CuI Bpin

LCuX B2pin2

A

B H CF2COR2

E

base

R1

R

R1

CF2COR2

3

R1

R F

Scheme 5. Postulated Mechanism. In summary, we have described a copper/B2pin2-catalyzed system to construct CF2containing dihydronaphthalenes from easily available MCPs and bromodifluorinated reagents. This catalytic system tolerates a broad scope of substrates with good reaction efficiency. The products were successfully applied in the synthesis of a series of useful difluoromethylated compounds. This protocol also holds promise for application in drug chemistry. Experimental Section General Information. All chemicals were obtained from commercial sources and were used as received unless otherwise noted. 1H, 13C and 19F NMR spectra were recorded using CDCl3 or DMSO-d6 as a solvent on a 400 MHz spectrometer at 298 K. The chemical shift is given in dimensionless δ values and is frequency referenced relative to TMS in 1H and


13C

NMR


spectroscopy. HRMS data were obtained via ESI mode with a TOF mass analyzer. All solvents were obtained from commercial sources and were used as received. Column chromatography was performed on silica gel (300-400 mesh) using ethyl acetate (EA)/petroleum ether (PE). Synthesis of MCPs 1. Method 1: KOtBu (2.53 g, 22.5 mmol) was added at room temperature in three portions (7.5 mmol each) to a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (4.64 g, 10 mmol) in dry THF (45 mL). After the solution was stirred at room temperature for 30 min. The orange solution was then refluxed for 2 h before aryl ketones (10 mmol) was added and stirring was continued at 65 °C for overnight. The reaction mixture was quenched by brine (20 mL) at room temperature, the aqueous layer was extracted with hexane (3 × 10 mL). The combined organic layers were washed with brine (4 × 10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by flash column chromatography over silica gel with PE / EA to afford the corresponding product 1. Method 2: To a suspension of 0.85 g of NaH (53% suspension in mineral oil) in 20 ml 1,2dimethoxyethane, 3-bromopropyltriphenylphosphonium bromide (4.64 g, 10 mmol) was added at room temp under N2, and then two drops of EtOH were added. This mixture was stirred for 6 h at 60-70 °C. Aryl ketones (10 mmol) was added and the mixture was stirred at 70 ℃ for an additional 5 h. The mixture was poured into ice-water and extracted with hexane. The hexane extract was dried and concentrated. The crude reaction mixture was purified by flash column chromatography over silica gel with PE / EA to afford the corresponding product 1. MCPs 15b,14 and bromodifluoroamides 29f,15 were synthesized according to the literatures.


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MCPs 1a, 1b, 1c, 1d, 1e;14f 1f, 1t;14a 1g, 1l, 1n;5b 1h, 1i, 1j, 1p, 1m, 1s, 1v;14c 1k,14b 1o,14e 1r;14d and 2a, 2b, 2c, 2d, 2e;15 2f, 2g, 2h9f were reported in previous literatures, MCPs 1q, 1u and bromodifluoroamide 2i were reported for the first time and their physical data and spectroscopic were presented as follow: 2-(Benzyloxy)-4-bromo-1-(cyclopropylidenemethyl)benzene (1q). White solid; m.p. 88-89 °C; yield: 376.8 mg (60%); 1H NMR (400 MHz, CDCl3) δ 7.65-7.63 (m, 1H), 7.47-7.44 (m, 2H), 7.43-7.38 (m, 2H), 7.37-7.26 (m, 1H), 7.13-7.07 (m, 3H), 5.07 (s, 2H), 1.38-1.34 (m, 2H), 1.171.12 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 155.0, 135.8, 127.9, 127.4, 126.9, 126.7, 125.8, 124.4, 123.3, 119.9, 115.0, 110.7, 69.8, 3.2, 0.0. HRMS (ESI) m/z: [M+Na]+ Calcd for C17H15BrONa+ 337.0198, found 337.0191. (1-Cyclopropylidenebutyl)benzene (1u). Yellow oil; yield: 244.2 mg (71%); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 2H), 7.22-7.18 (m, 1H), 2.65-2.61 (m, 2H), 1.62-1.52 (m, 2H), 1.40-1.36 (m, 2H), 1.15-1.11 (m, 2H), 0.93-0.89 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.0, 126.9, 125.9, 125.1, 124.7, 119.4, 34.7, 20.5, 12.8, 3.6, 0.0. HRMS (ESI) m/z: [M+Na]+ Calcd for C13H16Na+ 195.1144, found 195.1136. 2-Bromo-2,2-difluoro-N-(4-(trifluoromethyl)phenyl)acetamide (2i). White solid; m.p. 142-143 °C; yield: 412.3 mg (65%); 1H NMR (400 MHz, CDCl3) δ 7.99 (br, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.7 (t, J = 27.7 Hz), 138.3, 128.2 (q, J = 32.8 Hz), 126.7 (q, J = 3.8 Hz), 123.7 (q, J = 270.2 Hz), 120.3, 111.1 (t, J = 314.8 Hz). HRMS (ESI) m/z: [M+Na]+ calcd for C9H5BrF5NONa+ 339.9367, found 339.9358. Synthesis of CF2-containing dihydronaphthalenes 3. MCPs (1, 0.2 mmol), ethyl bromodifluoroacetate (2a, 0.4 mmol), B2pin2 (30 mol %), CuBr (10 mol %), dtbbpy (10 mol %),



and NaHCO3 (2 equiv) was added in 1,4-dioxane (1 mL), and stirred under N2 in an oil bath heated at 80°C for 16 h. After the reaction, 1,4-dioxane was removed under reduced pressure, EtOH (1 mL) was then added, followed by addition of AgNO3 (0.4 mmol). The mixture was further stirred under reflux for 10 h. Purification was finally performed by flash column chromatography on silica gel using EtOAc and petroleum ether to give the desired product 3. Note: When using MCPs containing only a phenyl group as the substrate, a difluoroalkylsubstituted homoallylic halide by-product 8 was observed. Since product 3 and by-product 8 represent the same Rf in chromatography, the reaction mixture was further treated with AgNO3 to convert by-product 8 to the corresponding difluoroalkyl-substituted homoallylic nitrates and difluoroalkyl-substituted homoallylic ethers. (For more details please see below the characterization of 9ja and 10ja). Following this procedure, a gram-scale synthesis of 3aa were conducted in a 75 ml pressure resistant tube sealed using 5 mmol 1a and 10 mmol 2a with other chemicals scale-up proportionally base 1a, and stirred under N2 in an oil bath heated at 80°C for 16 h. Afterwards, the reaction mixture was evaporated to remove the solvent, followed by adding brine (20 mL) and ethyl acetate (15 mL) to the resulting slurry mixture. The organic layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers ware further dried over anhydrous sodium sulphate (Na2SO4), filtered over a sintered funnel and evaporated to dryness. The crude product was finally purified by flash chromatography over silica gel with PE / EA = 200:1 to afford the corresponding product 3aa (1.3 g, yield: 79%). Ethyl 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)acetate (3aa). Yellow oil; yield:


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54.8 mg (84%); 1H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 3H), 7.12-7.11 (m, 2H), 7.10-7.07 (m, 2H), 6.99-6.94 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.87 (q, J = 7.2 Hz, 2H), 2.89 (t, J = 8.0 Hz, 2H), 2.58 (t, J = 8.0 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (t, J = 34.2 Hz), 141.2 (t, J = 6.9 Hz), 136.4, 136.1, 135.4, 130.3 (t, J = 2.1 Hz), 128.5, 128.2 (d, J = 23.3 Hz), 127.9, 127.8, 127.3 127.2, 126.5, 113.7 (t, J = 247.3Hz), 62.7, 27.9, 22.2 (t, J = 5.0 Hz), 13.7. 19F NMR (377 MHz, CDCl3) δ -96.3. HRMS (ESI) m/z: [M+Na]+ calcd for C20H18F2O2Na+ 351.1167, found 351.1162. Ethyl 2,2-Difluoro-2-[6-methyl-1-(p-tolyl)-3,4-dihydronaphthalen-2-yl]acetate (3ba). Yellow oil; yield: 53.6 mg (75%); 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J = 8.0, 2H), 7.04-7.01 (m, 3H), 6.84 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 2.91 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.88 (t, J = 34.3 Hz), 141.2 (t, J = 7.2 Hz), 138.5, 137.4, 136.1, 133.5, 133.0, 130.1 (t, J = 2.0 Hz), 128.5, 128.1, 127.2, 127.1 (t, J = 23.5 Hz), 127.0, 113.9 (t, J = 246.9 Hz), 62.6, 27.9, 22.2 (t, J = 5.0 Hz), 21.3, 21.2, 13.7. 19F NMR (377 MHz, CDCl3) δ -95.9. HRMS (ESI) m/z: [M+Na]+ calcd for C22H22F2O2Na+ 379.1480, found 379.1488. Ethyl

2,2-Difluoro-2-(6-methoxy-1-(4-methoxyphenyl)-3,4-dihydronaphthalen-2-yl)acetate

(3ca). Yellow solid; m.p. 40-41 °C; yield: 65.0 mg (84%); 1H NMR (400 MHz, CDCl3) δ 7.087.05 (m, 2H), 6.92-6.88 (m, 2H), 6.74 (t, J = 1.6 Hz, 1H), 6.56 (d, J = 1.6 Hz, 2H), 3.93 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 2.96 (t, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (t, J = 34.5 Hz), 159.7, 159.2, 140.8 (t, J = 7.1 Hz), 138.2, 131.6 (d, J = 2.1 Hz), 128.7 (m), 125.8 (t, J = 23.6 Hz), 114.0 (t, J = 245.9 Hz), 113.3, 113.2, 111.1, 62.6, 55.3, 55.2, 28.4, 22.0 (t, J = 5.0 Hz), 13.7. 19F NMR



(377 MHz, CDCl3) δ -95.2. HRMS (ESI) m/z: [M+Na]+ calcd for C22H22F2O4Na+ 411.1378, found 411.1367. Ethyl 2,2-Difluoro-2-(6-fluoro-1-(4-fluorophenyl)-3,4-dihydronaphthalen-2-yl)acetate (3da). Yellow oil; yield: 48.4 mg (66%); 1H NMR (400 MHz, CDCl3) δ 7.14-7.06 (m, 4H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.73 (td, J = 8.4, 2.8 Hz, 1H), 6.54 (dd, J = 8.4, 5.6 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (t, J = 34.4 Hz), 162.6 (d, J = 248.2 Hz), 162.4 (d, J = 246.0 Hz), 139.5 (d, J = 7.0 Hz), 138.8 (d, J = 8.1 Hz), 132.2 (d, J = 3.6 Hz), 131.9 (dt, J = 8.1, 2.2 Hz), 131.5 (d, J = 3.4 Hz), 129.0 (d, J = 8.7 Hz), 127.9 (td, J = 23.4, 2.4 Hz), 115.1 (d, J = 21.5 Hz), 114.5 (d, J = 21.8 Hz), 113.6 (t, J = 248.0 Hz), 113.1 (d, J = 21.3 Hz), 62.8, 27.9 (d, J = 1.7 Hz), 22.1 (t, J = 5.0 Hz), 13.8. 19F NMR (377 MHz, CDCl3) δ -96.5, -112.6, -113.7. HRMS (ESI) m/z: [M+Na]+ calcd for C20H16F4O2Na+ 387.0979, found 387.0984. Ethyl 2-(6-chloro-1-(4-chlorophenyl)-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ea). Yellow oil; yield: 68.4 mg (86%); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.92 (t, J = 8.0 Hz, 2H), 2.62 (t, J = 8.0 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 34.3 Hz), 139.3 (t, J = 6.5 Hz), 137.9, 134.6, 134.4, 134.1, 133.5, 131.4 (t, J = 2.2 Hz), 128.9 (t, J = 23.1 Hz), 128.4, 128.3, 127.4, 126.6, 113.5 (t, J = 248.8 Hz), 63.0, 27.6, 22.2 (t, J = 4.9 Hz), 13.8. 19F NMR (377 MHz, CDCl3) δ -97.0. HRMS (ESI) m/z: [M+Na]+ calcd for C20H16Cl2F2O2+Na+ 419.0388, found 419.0381. Ethyl 2-(6-bromo-1-(4-bromophenyl)-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3fa). White solid; m.p. 116-117 °C; yield: 71.3 mg (73%); 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J


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= 8.0 Hz, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H), 7.04-7.01 (m, 2H), 6.456.42 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H), 2.92 (t, J = 8.0 Hz, 2H), 2.61 (t, J = 8.0 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 34.3 Hz), 139.3 (t, J = 6.4 Hz), 138.1, 135.1, 133.9, 131.7, 131.3, 130.3, 129.6, 129.0 (t, J = 23.0 Hz), 128.6, 122.8, 122.3, 113.5 (t, J = 249.1 Hz), 63.0, 27.5, 22.3 (t, J = 4.9 Hz), 13.8. 19F NMR (377 MHz, CDCl3) δ 97.1. HRMS (ESI) m/z: [M+Na]+ calcd for C20H16Br2F2O2Na+) 506.9377, found 506.9369. Ethyl 2-(3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ga). Yellow oil; yield: 21.9 mg (43%); 1H NMR (400 MHz, CDCl3) δ 7.24-7.17 (m, 2H), 7.15-7.12 (m, 2H), 6.87 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.88 (t, J = 8.0 Hz, 2H), 2.47-2.42 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (t, J = 35.2 Hz), 135.5, 131.9, 130.5 (t, J = 23.6 Hz), 128.9, 128.7 (t, J = 9.1 Hz), 127.7, 127.6, 126.8, 113.7 (t, J = 248.3 Hz), 63.0, 27.4, 21.3 (t, J = 2.8 Hz), 14.0.

19F

NMR (377 MHz, CDCl3) δ -107.3. HRMS (ESI) m/z: [M+Na]+ calcd for

C14H14F2O2Na+ 275.0854, found 275.0861. Ethyl 2,2-Difluoro-2-(6-methyl-3,4-dihydronaphthalen-2-yl)acetate (3ha). Yellow oil; yield: 33.0 mg (62%); 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.84 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.83 (t, J = 8.0 Hz, 2H), 2.44-2.40 (m, 2H), 2.33 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.9 (t, J = 35.3 Hz), 139.0, 135.5, 129.35 (t, J = 23.7 Hz), 129.2, 128.6 (t, J = 8.9 Hz), 128.5, 127.7, 127.4, 113.8 (t, J = 248.1 Hz), 63.0, 27.5, 21.4, 21.3 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -107.0. HRMS (ESI) m/z: [M+Na]+ calcd for C15H16F2O2Na+ 289.1011, found 289.1018. Ethyl 2-(6-chloro-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ia). Yellow oil; yield: 35.0 mg (61%); 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J = 8.0, 2.0 Hz, 1H), 7.14 (s, 1H), 7.06



(d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H), 2.46-2.41 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.7 (t, J = 35.0 Hz), 137.3, 134.3, 130.9 (t, J = 23.6 Hz), 130.4, 128.8, 127.8, 127.6 (t, J = 9.1 Hz), 126.9, 113.5 (t, J = 248.7 Hz), 63.1, 27.3, 21.0 (t, J = 2.8 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -107.3. HRMS (ESI) m/z: [M+Na]+ calcd for C14H13ClF2O2Na+ 309.0464, found 309.0469. Ethyl 2-(6-bromo-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ja). Yellow oil; yield: 47.5 mg (72%); 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H), 2.45-2.40 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.6 (t, J = 35.0 Hz), 137.5, 131.1 (t, J = 23.7 Hz), 130.8, 130.6, 129.9, 129.0, 127.7 (t, J = 9.1 Hz), 122.5, 113.4 (t, J = 248.7 Hz), 63.1, 27.2, 21.0 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -107.4. HRMS (ESI) m/z: [M+Na]+ calcd for C14H13BrF2O2Na+ 352.9959, found 352.9963. Ethyl 2,2-Difluoro-2-(6-(trifluoromethyl)-3,4-dihydronaphthalen-2-yl)acetate (3ka). Yellow oil; yield: 29.4 mg (46%); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.93 (t, J = 8.0 Hz, 2H), 2.512.46 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.48 (t, J = 34.6 Hz), 136.1, 135.1, 133.3 (t, J = 23.5 Hz), 130.5 (q, J = 32.1 Hz), 127.7, 127.4 (t, J = 9.0 Hz), 124.3 (q, J = 3.8 Hz), 124.0 (q, J = 270.5 Hz), 123.8 (q, J = 4.0 Hz), 113.3 (t, J = 248.9 Hz), 63.2, 27.2, 21.1 (t, J = 2.8 Hz), 13.9. 19F NMR (377 MHz, CDCl3) δ -62.7, -107.4. HRMS (ESI) m/z: [M+Na]+ calcd for C15H13F5O2Na+) 343.0728, found 343.0736. Ethyl 2-(8-(benzyloxy)-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3la). Yellow oil; yield: 50.2 mg (70%); 1H NMR (400 MHz, CDCl3) δ 7.43-7.36 (m, 4H), 7.35-7.30 (m, 2H),


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7.15 (t, J = 8.0 Hz, 1H), 6.78 (t, J = 7.6 Hz, 2H), 5.08 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H), 2.45-2.41 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0 (t, J = 34.8 Hz), 155.0, 137.3, 136.9, 129.6, 129.3 (t, J = 23.6 Hz), 128.6, 128.0, 127.3, 123.2 (t, J = 9.4 Hz), 121.1, 120.3, 114.0 (t, J = 247.5 Hz), 110.4, 70.3, 63.0, 27.8, 20.8 (t, J = 2.8 Hz), 13.9. 19F NMR (377 MHz, CDCl3) δ -106.4. HRMS (ESI) m/z: [M+Na]+ calcd for C21H20F2O3Na+ 381.1273, found 381.1272. Ethyl 2-(8-bromo-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ma). Yellow oil; yield: 29.1 mg (44%); 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.26-7.25 (m, 1H), 7.10-7.03 (m, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.87 (t, J = 8.0 Hz, 2H), 2.45-2.41 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 163.6 (t, J = 34.8 Hz), 138.14, 132.8 (t, J = 23.8 Hz), 131.2, 131.1, 129.8, 127.3 (t, J = 9.3 Hz), 126.8, 123.5, 113.5 (t, J = 248.5 Hz), 63.2, 28.3, 21.0 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -107.1. HRMS (ESI) m/z: [M+Na]+ calcd for C14H13BrF2O2Na+ 352.9959, found 352.9956. Ethyl 2-(5,8-Dimethoxy-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3na). Yellow oil; yield: 41.9 mg (67%); 1H NMR (400 MHz, CDCl3) δ 7.27-7.26 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.79 (s, 6H), 2.84 (t, J = 8.4 Hz, 2H), 2.41-2.35 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.95 (t, J = 35.0 Hz), 150.4, 150.3, 129.4 (t, J = 23.6 Hz), 125.0, 123.0 (t, J = 9.3 Hz), 121.8, 113.9 (t, J = 247.9 Hz), 111.9, 108.8, 62.9, 56.0, 55.9, 20.3, 20.2 (d, J = 3.0 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -106.9. HRMS (ESI) m/z: [M+Na]+ calcd for C16H18F2O4Na+ 335.1065, found 335.1063. Ethyl

2-(8-(benzyloxy)-5-methyl-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate


(3oa).


Page 18 of 35

Yellow oil; yield: 49.0 mg (66%); 1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 6H), 7.02 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.06 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 2.78 (t, J = 8.4 Hz, 2H), 2.45-2.41 (m, 2H), 2.21 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0 (t, J = 35.1 Hz), 153.5, 137.1, 135.2, 131.2, 128.6, 128.5 (t, J = 23.9 Hz), 127.9, 127.4, 127.2, 123.5 (t, J = 9.3 Hz), 121.1, 114.1 (t, J = 247.2 Hz), 110.0, 70.4, 62.9, 24.2, 20.5 (t, J = 2.8 Hz), 18.8, 13.9. 19F NMR (377 MHz, CDCl3) δ -106.4. HRMS (ESI) m/z: [M+Na]+ calcd for C22H22F2O3Na+ 395.1429, found 395.1424. Ethyl 2-(5-bromo-8-methoxy-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3pa). Yellow solid; m.p. 34°C; yield: 59.6 mg (83%); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8 Hz, 1H), 7.25 (t, J = 2.0 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.94 (t, J = 8.4 Hz, 2H), 2.45-2.41 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (t, J = 34.9 Hz), 155.1, 135.9, 133.0, 129.7 (t, J = 23.8 Hz), 122.8, 122.5 (t, J = 9.3 Hz), 114.6, 113.6 (t, J = 248.3 Hz), 110.6, 63.0, 55.7, 27.5, 20.6 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -107.0. HRMS (ESI) m/z: [M+Na]+ calcd for C15H15BrF2O3+Na+ 383.0065, found 383.0072. Ethyl

2-(8-(benzyloxy)-6-bromo-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate

(3qa).

Yellow solid; m.p. 46 °C; yield: 55.2 mg (63%); 1H NMR (400 MHz, CDCl3) δ 7.43-7.32 (m, 5H), 7.23 (s, 1H), 6.95-6.93 (m, 2H), 5.05 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 2.81 (t, J = 8.0 Hz, 2H), 2.44-2.38 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.8 (t, J = 34.9 Hz), 155.4, 138.7, 136.1, 129.6 (t, J = 24.0 Hz), 128.7, 128.2, 127.4, 123.4, 122.8, 122.5 (t, J = 9.4 Hz), 120.2, 113.9, 113.8 (t, J = 247.8 Hz), 70.6, 63.0, 27.6, 20.7 (t, J = 2.8 Hz), 13.9.

19F



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C21H19BrF2O3Na+ 459.0378, found 459.0383. Ethyl 2-(6,8-dichloro-3,4-dihydronaphthalen-2-yl)-2,2-difluoroacetate (3ra). White solid; m.p. 48 °C; yield: 29.5 mg (46%); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 2.0 Hz, 1H), 7.23-7.21 (m, 1H), 7.06 (dd, J = 2.0, 1.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.85 (t, J = 8.0 Hz, 2H), 2.462.42 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.45 (t, J = 34.7 Hz), 139.0, 134.3, 133.3, 132.8 (t, J = 23.8 Hz), 128.2, 127.6, 126.4, 123.9 (t, J = 9.3 Hz), 113.32 (t, J = 248.8 Hz), 63.2, 28.0, 20.8 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ 107.2. HRMS (ESI) m/z: [M+Na]+ calcd for C14H12Cl2F2O2Na+ 343.0075, found 343.0079. Ethyl 2-(8-bromo-6-methyl-3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3sa). Yellow oil; yield: 49.7 mg (72%); 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.21 (s, 1H), 6.91 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.82 (t, J = 8.0 Hz, 2H), 2.43-2.39 (m, 2H), 2.29 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.7 (t, J = 34.6 Hz), 140.3, 137.9, 131.6 (t, J = 23.9 Hz), 131.5, 128.4, 127.8, 127.2 (t, J = 9.4 Hz), 123.3, 113.6 (t, J = 248.3 Hz), 63.1, 28.4, 21.0 (t, J = 2.8 Hz), 20.9, 14.0. 19F NMR (377 MHz, CDCl3) δ -106.8. HRMS (ESI) m/z: [M+Na]+ calcd for C15H15BrF2O2Na+ 367.0116, found 367.0127. Ethyl 2,2-Difluoro-2-(1-methyl-3,4-dihydronaphthalen-2-yl)acetate (3ta). Yellow oil; yield: 19.7 mg (37%); 1H NMR (400 MHz, CDCl3) δ 7.39-7.37 (m, 1H), 7.27-7.20 (m, 2H), 7.16-7.14 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.47-2.42 (m, 2H), 2.21 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.4 (t, J = 36.0 Hz), 136.4, 135.8, 135.7 (t, J = 7.6 Hz), 128.3-128.1 (m), 127.3 (t, J = 22.9 Hz), 127.2, 126.6, 124.1, 114.4 (t, J = 249.4 Hz), 62.9, 28.1, 22.7 (t, J = 5.9 Hz), 15.5 (t, J = 2.9 Hz), 14.0. 19F NMR (377 MHz, CDCl3) δ -101.1. HRMS (ESI) m/z: [M+Na]+ calcd for C15H16F2O2Na+ 289.1011, found 289.1017.



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Ethyl 2,2-difluoro-2-(1-propyl-3,4-dihydronaphthalen-2-yl)acetate (3ua). Yellow oil; yield: 26.5 mg (45%); 1H NMR (400 MHz, CDCl3) δ 7.39-7.37 (m, 1H), 7.25-7.20 (m, 2H), 7.19-7.15 (m, 1H), 4.32 (q, J = 7.2 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.51-1.44 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.5 (t, J = 36.0 Hz), 140.5 (t, J = 5.1 Hz), 137.2, 134.3, 128.1, 127.5, 127.0 (t, J = 22.8 Hz), 126.5, 124.3, 114.47 (t, J = 249.5 Hz), 62.9, 30.6 (t, J = 2.6 Hz), 28.3, 22.9, 22.8 (t, J = 6.0 Hz), 14.1, 13.9. 19F NMR (377 MHz, CDCl3) δ -100.2. HRMS (ESI) m/z: [M+Na]+ calcd for C17H20F2O2Na+ 317.1324, found 317.1332. N,N-Diethyl-2,2-difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)acetamide (3ab). Yellow oil; yield: 45.5 mg (64%); 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 3H), 7.20-7.15 (m, 4H), 7.06-7.01 (m, 1H), 6.63 (d, J = 8.0 Hz, 1H), 3.29 (q, J = 7.2 Hz, 2H), 3.20 (q, J = 7.2 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.64 (t, J = 8.0 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.59 (t, J = 30.5 Hz), 139.4 (t, J = 5.9 Hz), 137.5, 136.1, 135.7, 129.7 (t, J = 2.3 Hz), 129.4 (t, J = 22.1 Hz), 128.2, 127.8, 127.4, 127.2, 126.4, 116.6 (t, J = 251.1 Hz), 42.1 (t, J = 4.2 Hz), 41.6, 28.0, 23.3 (t, J = 4.6 Hz), 14.0, 12.4. 19F NMR (377 MHz, CDCl3) δ -92.4. HRMS (ESI) m/z: [M+Na]+ calcd for C22H23F2NONa+ 378.1640, found 378.1648. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one

(3ac).

Yellow oil; yield: 43.0 mg (61%); 1H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 3H), 7.20-7.15 (m, 4H), 7.05-7.01 (m, 1H), 6.60 (d, J = 7.6 Hz, 1H), 3.33 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H), 1.83-1.76 (m, 2H), 1.74-1.67 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.8 (t, J = 31.0 Hz), 140.0 (t, J = 7.2 Hz), 136.8,


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136.2, 135.5, 123.0 (t, J = 1.9 Hz), 129.4 (t, J = 23.5 Hz), 128.3, 127.8, 127.7, 127.2, 127.1, 126.4, 115.8 (t, J = 249.9 Hz), 47.2, 46.4 (t, J = 4.7 Hz), 27.9, 26.4 (t, J = 14.4 Hz), 23.2, 22.7 (t, J = 4.8 Hz). 19F NMR (377 MHz, CDCl3) δ -93.9. HRMS (ESI) m/z: [M+Na]+ calcd for C22H21F2NONa+ 376.1483, found 376.1488. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)-1-(piperidin-1-yl)ethanone

(3ad).

Yellow oil; yield: 61.7 mg (84%); 1H NMR (400 MHz, CDCl3) δ 7.39-7.32 (m, 3H), 7.20-7.15 (m, 4H), 7.06-7.00 (m, 1H), 6.62 (d, J = 5.6 Hz, 1H), 3.36 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 8.0 Hz, 2H), 2.95- (t, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H), 1.61-1.55 (m, 2H), 1.52-1.45 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.2 (t, J = 30.1 Hz), 139.9 (t, J = 6.8 Hz), 136.9, 136.1, 135.6, 129.8 (t, J = 2.2 Hz), 129.0 (t, J = 22.8 Hz), 128.3, 127.8, 127.7, 127.4, 127.2, 126.5, 116.1 (t, J = 248.3 Hz), 46.9 (t, J = 3.6 Hz), 43.9, 28.0, 26.1, 25.3, 24.4, 22.9 (t, J = 4.5 Hz).

19F


C23H23F2NO+Na+ 390.1640, found 390.1643. 2,2-Difluoro-1-morpholino-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)ethanone (3ae). White solid; m.p. 119-120 °C; yield: 45.0 mg (61%); 1H NMR (400 MHz, CDCl3) δ 7.40-7.33 (m, 3H), 7.20-7.16 (m, 4H), 7.08-7.02 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 3.61 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 4.8 Hz, 2H), 3.45 (t, J = 4.4 Hz, 2H), 3.33 (t, J = 4.4 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H), 2.63 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.5 (t, J = 30.6 Hz), 140.4 (t, J = 7.0 Hz), 136.7, 136.1, 135.4, 129.8 (t, J = 2.1 Hz), 128.5, 128.4 (t, J = 22.7 Hz), 127.9, 127.8, 127.4, 127.3, 126.5, 116.0 (t, J = 248.3 Hz), 66.5, 66.4, 46.5 (t, J = 3.7 Hz), 42.9, 27.9, 22.7 (t, J = 4.6 Hz). 19F NMR (377 MHz, CDCl3) δ -91.2. HRMS (ESI) m/z: [M+Na]+ calcd for C22H21F2NO2Na+ 392.1433, found 392.1437.



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2,2-Difluoro-N-phenyl-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)acetamide (3af). White solid; m.p. 120-121 °C; yield: 53.3 mg (71%); 1H NMR (400 MHz, CDCl3) δ 7.33-7.22 (m, 8H), 7.197.17 (m, 4H), 7.15- 7.11 (m, 1H), 7.04-7.00 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.1 (t, J = 30.4 Hz), 141.3 (t, J = 6.5 Hz), 137.0, 136.1, 136.0, 135.3, 130.1 (d, J = 2.1 Hz), 129.0, 128.9 (d, J = 22.9 Hz), 128.5, 128.0, 127.7, 127.3, 127.1, 126.4, 125.2, 119.8, 115.1 (t, J = 253.1 Hz), 27.9, 22.9 (t, J = 5.3 Hz). 19F NMR (377 MHz, CDCl3) δ -97.2. HRMS (ESI) m/z: [M+Na]+ calcd for C24H19F2NONa+ 398.1327, found 398.1330. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)-N-(p-tolyl)acetamide

(3ag).

White

solid; m.p. 121-122 °C; yield: 59.1 mg (76%); 1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m, 3H), 7.21-7.15 (m, 7H), 7.09 (d, J = 8.0 Hz, 2H), 7.04-7.00 (m, 1H), 6.59 (d, J = 8.0 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H), 2.31 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.9 (t, J = 30.1 Hz), 141.2 (t, J = 6.3 Hz), 137.1, 136.1, 135.3, 134.9, 133.6, 130.1 (t, J = 2.0 Hz), 129.4, 129.0 (t, J = 23.0 Hz), 128.5, 127.9, 127.7, 127.3, 127.0, 126.4, 119.8, 115.2 (t, J = 253.1 Hz), 27.9, 22.9 (t, J = 5.3 Hz), 20.9. 19F NMR (377 MHz, CDCl3) δ -97.3. HRMS (ESI) m/z: [M+Na]+ calcd for C25H21F2NONa+ 412.1483, found 412.1483. N-(4-bromophenyl)-2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)acetamide

(3ah).

White solid; m.p. 118-119 °C; yield: 84.4 mg (93%); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.8 Hz, 2H), 7.30-7.16 (m, 10H), 7.05-7.00 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 2.99 (t, J = 8.0 Hz, 2H), 2.75 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.1 (t, J = 30.5 Hz), 141.5 (t, J = 6.8 Hz), 136.8, 136.0, 135.2, 135.1, 131.9, 130.2 (d, J = 2.0 Hz), 128.8 (t, J = 23.2 Hz), 128.6, 128.0, 127.8, 127.4, 127.0, 126.5, 121.3, 117.9, 115.0 (t, J = 254.3 Hz), 27.8, 22.7


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(t, J = 5.4 Hz). 19F NMR (377 MHz, CDCl3) δ -96.6. HRMS (ESI) m/z: [M+Na]+ calcd for C24H18BrF2NONa+ 476.0432, found 476.0445. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)-N-(4(trifluoromethyl)phenyl)acetamide (3ai). White solid; m.p. 156-157 °C; yield: 63.8 mg (72%); 1H

NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.32 (s, 1H),

7.29-7.17 (m, 7H), 7.05-7.01 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 3.00 (t, J = 8.0 Hz, 2H), 2.76 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.4 (t, J = 30.6 Hz), 141.7 (t, J = 7.0 Hz), 139.2 (q, J = 1.3 Hz), 136.8, 136.0, 135.1, 130.2 (t, J = 1.9 Hz), 128.7, 128.0, 127.9, 127.4, 127.1, 127.0 (q, J = 32.7 Hz), 126.5, 126.2 (q, J = 3.8 Hz), 123.9 (q, J = 270.0 Hz), 119.5, 115.0 (t, J = 252.6 Hz), 27.8, 22.6 (t, J = 5.4 Hz). 19F NMR (377 MHz, CDCl3) δ -62.2, -96.5. HRMS (ESI) m/z: [M+Na]+ calcd for C25H18F5NONa+ 466.1201, found 466.1209. Synthesis of compound 4aa. A round flask was equipped with a magnetic stir bar, 3aa

(0.2 mmol), NaBH4 (0.3 mmol), and EtOH (1.0 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting solution was added HCl (2.5M, 0.5 mL). The reaction mixture was extracted with CH2Cl2 (10 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, After removal of the solvent under reduced pressure, the residue was purified by silica-gel column chromatography to give 4aa. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)ethanol (4aa). Yellow oil; yield: 48.6 mg (85%); 1H NMR (400 MHz, CDCl3) δ 7.41-7.33 (m, 3H), 7.19-7.15 (m, 4H), 7.05-7.01 (m, 1H), 6.58 (d, J = 7.6 Hz, 1H), 3.64 (td, J = 13.6, 6.8 Hz, 2H), 2.92 (t, J = 8.0 Hz, 2H), 2.56 (t, J = 8.0 Hz, 2H), 1.76 (t, J = 6.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.1 (t, J = 5.6 Hz), 138.2, 135.9, 135.8, 129.6 (t, J = 2.4 Hz), 129.0 (t, J = 22.6 Hz), 128.2, 127.9, 127.3,



127.2, 127.1, 126.5, 121.5 (t, J = 242.4 Hz), 64.8 (t, J = 31.5 Hz), 28.0, 23.5 (t, J = 5.3 Hz). 19F NMR (377 MHz, CDCl3) δ -101.6. HRMS (ESI) m/z: [M+Na]+ calcd for C18H16F2ONa+ 309.1061, found 309.1065. Synthesis of compound 5aa. A round flask was equipped with a magnetic stir bar, 3aa (0.2 mmol), NBS (0.6 mmol), and 1,4-dioxane (1.0 mL). The resulting mixture was stirred for 2 h at room temperature. After removal of the solvent under reduced pressure, the residue was purified by silica-gel column chromatography to give 5aa. Ethyl 2,2-difluoro-2-(1-phenylnaphthalen-2-yl)acetate (5aa). Yellow oil; yield: 42.2 mg (65%); 1H

NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 1H), 7.93-7.89 (m, 2H), 7.56-7.52 (m, 1H),

7.47-7.44 (m, 3H), 7.41-7.32 (m, 2H), 7.27-7.25 (m, 2H), 3.95 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.7 (t, J = 34.0 Hz), 139.2 (t, J = 5.0 Hz), 135.9, 134.3, 133.1, 131.3 (d, J = 1.6 Hz), 128.8 (t, J = 23.1 Hz), 128.2, 128.1, 127.9, 127.8, 127.3, 127.1, 126.7, 121.8 (t, J = 8.4 Hz), 113.6 (t, J = 249.0 Hz), 62.8, 13.6.19F NMR (377 MHz, CDCl3) δ -94.4. HRMS (ESI) m/z: [M+Na]+ calcd for C20H16F2O2+Na+ 349.1011, found 349.1013. Synthesis of compound 6aa. A round flask was equipped with a magnetic stir bar, 3aa (0.2 mmol), K2CO3 (1M, 0.6 mL), and MeOH (0.6 mL). The resulting mixture was stirred overnight at room temperature. The resulting solution was added HCl (2.5M, 0.5 mL), and stirred at room temperature for 8 h. The reaction mixture was extracted with CH2Cl2 (10 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the corresponding product 6aa. 2,2-Difluoro-2-(1-phenyl-3,4-dihydronaphthalen-2-yl)acetic acid (6aa). White solid; m.p.


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112 °C; yield: 56.4 mg (94%); 1H NMR (400 MHz, CDCl3) δ 8.85 (br, 1H), 7.34-7.31 (m, 3H), 7.20 (d, J = 4.0 Hz, 2H), 7.21-7.14 (m, 2H), 7.08-7.02 (m, 1H), 6.64 (d, J = 7.6 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.9 (t, J = 33.6 Hz), 140.3 (t, J = 5.6 Hz), 137.3, 136.2, 135.4, 129.8 (d, J = 2.4 Hz), 128.9, 128.4, 128.1, 127.9, 127.8, 126.9, 114.4 (t, J = 248.2 Hz), 27.6, 22.9 (t, J = 4.6 Hz). 19F NMR (377 MHz, DMSO-d6) δ -97.4. HRMS (ESI) m/z: [M+Na]+ calcd for C18H14F2O2Na+ 323.0854, found 323.0862.

Synthesis of compound 7aa. The 6aa (0.2 mmol) and CsF (1.0 mmol) were dissolved in 1.0 mL of NMP. The reaction mixture was stirred at 170 °C in an atmosphere of nitrogen for 5 h. After cooling to room temperature, water (3.0 mL) was added to the reaction mixture. Organic materials were extracted for three times with ethyl acetate and the combined organic layer were washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by silica-gel column chromatography to give 7aa. 3-(Difluoromethyl)-4-phenyl-1,2-dihydronaphthalene (7aa). Yellow oil; yield: 27.1 mg (53%); 1H

NMR (400 MHz, CDCl3) δ 7.46-7.38 (m, 3H), 7.22-7.18 (m, 4H), 7.09-7.05 (m, 1H), 6.70

(d, J = 7.6 Hz, 1H), 6.07 (t, J = 55.6 Hz, 1H), 2.95 (d, J = 8.0 Hz, 1H), 2.62-2.57 (m, 2H). 13C{1H}

NMR (100 MHz, CDCl3) δ 141.5 (t, J = 10.8 Hz), 136.5, 136.1 (t, J = 1.6 Hz), 134.7,

129.9 (t, J = 1.6 Hz), 128.8 (t, J = 23.7 Hz), 128.6, 128.5, 128.0, 127.6, 127.3, 126.5, 114.3 (t, J = 229.7 Hz), 27.7, 19.6 (t, J = 2.7 Hz). 19F NMR (377 MHz, CDCl3) δ -115.4. HRMS (ESI) m/z: [M+Na]+ calcd for C17H14F2Na+ 279.0956, found 279.0951. Characterization of compound 9ja and 10ja. MCPs (1j, 4×0.2 mmol), ethyl



bromodifluoroacetate (2a, 4×0.4 mmol), B2pin2 (30 mol %), CuBr (10 mol %), dtbbpy (10 mol %), and NaHCO3 (2 equiv) was added in 1,4-dioxane (4×1 mL), and stirred under N2 for 16 h at 80°C. After the reaction, 1,4-dioxane was removed under reduced pressure, EtOH (4 mL) was then added, followed by addition of AgNO3 (0.16 mmol). The mixture was further stirred under reflux for 10 h. Purification was finally performed by flash column chromatography on silica gel using EtOAc and petroleum ether to give the desired product 3ja and by-products (9ja and 10ja). The ratio of 3ja to 8ja was validated unambiguously by crude 1H NMR spectroscopy. Note: When using MCPs containing only a phenyl group as the substrate, a difluoroalkylsubstituted homoallylic halide by-product 8ja was observed. Since product 3ja and by-product 8ja represent the same Rf in chromatography, the reaction mixture was further treated with AgNO3 to convert by-product 8ja to the corresponding difluoroalkyl-substituted homoallylic nitrate 9ja and difluoroalkyl-substituted homoallylic ether 10ja. Ethyl (Z)-3-(4-bromobenzylidene)-2,2-difluoro-5-(nitrooxy)pentanoate (9ja). Yellow oil; yield: 13.8 mg (4%); 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 4.55 (t, J = 7.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.5 (t, J = 34.8 Hz), 135.0 (t, J = 9.2 Hz), 133.0, 132.1, 130.1, 128.7 (t, J = 22.6 Hz), 123.0, 114.0 (t, J = 251.5 Hz), 70.0, 63.5, 24.6 (t, J = 2.1 Hz), 13.9. 19F NMR (377 MHz, CDCl3) δ -104.2. HRMS (ESI) m/z: [M+Na]+ calcd for C14H14BrF2NO5Na+ 415.9916, found 415.9929. Ethyl (E)-3-(4-bromobenzylidene)-5-ethoxy-2,2-difluoropentanoate (10ja). Yellow oil; yield: 11.3 mg (4%); 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.55 (t, J = 7.2 Hz, 2H), 3.45 (q, J = 7.2 Hz, 2H), 2.66 (t,


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J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.6 (t, J = 34.9 Hz), 133.7, 132.9 (t, J = 9.5 Hz), 131.7, 131.0 (t, J = 21.8 Hz), 130.6, 122.4, 114.5 (t, J = 251.1 Hz), 68.2, 66.3, 63.1, 27.4 (d, J = 1.9 Hz), 15.1, 14.0. 19F NMR (377 MHz, CDCl3) δ -101.2. HRMS (ESI) m/z: [M+Na]+ calcd for C16H19BrF2O3Na+ 399.0378, found 399.0379. ASSOCIATED CONTENT SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI: jo-2019-01106f. Reaction optimization; mechanistic study; structural determination of 3ca; 1H, 13C NMR and 19F

NMR spectra of all the new compounds (PDF).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. * E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We acknowledge financial supports from the National Natural Science Foundation of China (21702087, and 21801105), Natural Science Foundation of Liaoning Province (2015020196, 20170520353, and 20180510033), the Program for Liaoning Innovative Talents in University (LR2017021), Research Project Fund of Liaoning Provincial Department of Education



(L2017LQN010 and L2017LZD001 ), Talent Scientific Research Fund of Liaoning Shihua University (2016XJJ-078 and 2016XJJ-079), the open project of Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (No.130028836 and 130028911 ). References (1) (a) Teponno, R. B.; Kusari, S.; Spiteller, M. Recent advances in research on lignans and neolignans. Nat. Prod. Rep. 2016, 33, 1044-1092. (b) Nono, E. C. N.; Mkounga, P.; Kuete, V.; Marat, K.; Hultin, P. G.; Nkengfack, A. E. Pycnanthulignenes A−D, Antimicrobial Cyclolignene Derivatives from the Roots of Pycnanthus angolensis. J. Nat. Prod., 2010, 73, 213-216. (c) Voets, M.; Antes, I.; Scherer, C.; Müller-Vieira, U.; Biemel, K.; MarchaisOberwinkler, S.; Hartmann, R. W. Synthesis and Evaluation of Heteroaryl-Substituted Dihydronaphthalenes and Indenes: Potent and Selective Inhibitors of Aldosterone Synthase (CYP11B2) for the Treatment of Congestive Heart Failure and Myocardial Fibrosis. J. Med. Chem., 2006, 49, 2222-2231. (d) Azhar-Ul, H.; Malik, A.; Anis, I.; Khan, S. B.; Ahmed, E.; Ahmed, Z.; Nawaz, S. A.; Choudhary, M. I. Enzymes Inhibiting Lignans from Vitex negundo. Chem. Pharm. Bull., 2004, 52, 1269-1272. (2) (a) Magoulas, G. E.; Papaioannou, D. Bioinspired Syntheses of Dimeric Hydroxycinnamic Acids (Lignans) and Hybrids, Using Phenol Oxidative Coupling as Key Reaction, and Medicinal Significance Thereof. Molecules 2014, 19, 19769-19835. (b) Silva, L. F.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C. Iodine(III)-Promoted Ring Contraction of 1,2-Dihydronaphthalenes: A Diastereoselective Total Synthesis of (±)Indatraline. Org. Lett., 2007, 9, 1433-1436. (c) Scribner, A. W.; Haroutounian, S. A.; Carlson, K. E.; Katzenellenbogen, J. A. 1-Aryl-2-pyridyl-3,4-dihydronaphthalenes: Photofluorogenic


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