TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: a Process

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TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: a Process for the Synthesis of Dihydroisobenzofuran Derivatives Yulei Zhao, Zheng Zhang, Xu Liu, Zongkang Wang, Ziping Cao, Laijin Tian, Mingbo Yue, and Jinmao You J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02842 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 5, 2019

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The Journal of Organic Chemistry

TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: a Process for the Synthesis of Dihydroisobenzofuran Derivatives Yulei Zhao*,† Zheng Zhang,† Xu Liu,† Zongkang Wang,† Ziping Cao,† Laijin Tian,† Mingbo Yue† and Jinmao You*,†,‡ †

Key Laboratory of Life-Organic Analysis, Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural

Medicine, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273165, Shandong, China ‡

Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese

Academy of Science, Xining, 810001, China

O

R1

HN

NR1

R4

R3

O

or

TBAF (0.2 eq., 1 mol/L in THF)

R2 + R1NH2

R3

THF, rt or 35 oC in air

R4 R

2

Transition-metal-free Mild reaction conditions

Selective O-Nucleophilic Excellent yields

F

R4 R

3

O

R2 19 examples (from enaminones) 95% - >99% yields

N

TBAF

Broad substrate scope High atom economy

Abstract: A novel methodology for the stereoselective synthesis of dihydroisobenzofuran derivatives is described in this paper. The procedure was realized by the bifunctional TBAF catalyzed selective Onucleophilic cyclization of enaminone with intramolecular alkyne under mild and non-metal-mediated conditions. The results of control experiment suggested that the cation-π interaction and basicity, offered by TBAF, might be indispensable for the isomerization of enaminone and the formation of carbon-oxygen bond. ■ INTRODUCTION Tetrabutylammonium fluoride (TBAF) is well known as a soluble source of fluoride and a mild base.1 It was also widely used as a reagent for the cleavage of silyl ethers.2 In recent years, TBAF has been extensively used as basic catalyst,3 fluorinated reagent,4 or used for reduction reactions,5 elimination reaction,6 cyclization reaction,7b-c etc.7 However, the above properties or applications were more focused on the contribution of the fluoride anion in TBAF. Recently, the role of ACS Paragon Plus Environment

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tetrabutylammonium has become a research focus.8 Cation-π interaction is a intermolecular force.9,10 Tetraalkylammonium ion was found to have noteworthy catalytic activity for the cyclization of alkyne.8 Lepore et al. presented the direct evidence for the ammonium cation-π interaction with the triple bond of alkynes by Raman spectroscopy.8b They also utilized TBAF as the unique catalyst to provide versatile approaches for the synthesis of isoxazoline,8c pyrazoline8c and nonracemic azaproline derivatives8a by the cyclization of alkyne substrates. Nevertheless, there is still a need of experimental evidence for the unique characteristics of tetrabutylammonium cation-π interaction with alkyne. Dihydroisobenzofuran structure acts as a core skeleton in many natural products, bioactive compounds

or

functional

molecules,11

for

example,

xylarinol

B,11a

escitalopram,11b

matriisobenzofuran,11c thunberginol F 7-O-β-D-glucopyranoside11d and functional material.11e-f Nowadays, the efficient synthetic routes to dihydroisobenzofuran derivatives are usually by performing at high temperatures12,14 or using metal-catalyzed approaches,13 while non-metal-mediated methods under mild reaction conditions are rarely reported.14 Yamada et al. reported an elegant silver-catalyzed C-C bond formation with carbon dioxide to afford dihydroisobenzofuran derivatives (Scheme 1, a).13a Liu et al. developed an excellent addition/elimination reaction of exo-cyclic enol ether with imine to prepare dihydroisobenzofuran derivatives at 110 oC (Scheme 1, b).14a Despite of the achievements introduced above, there is a great desire for the synthesis of dihydroisobenzofuran by novel methods with readily available starting materials and inexpensive non-metallic catalyst under mild conditions. Enaminones as versatile building blocks, have a wide range of synthetic applications, including selective C-,15 N-16 and O-nucleophilic cyclization17 reactions. Among them, the selective Onucleophilic cyclization provided some novel non-metal-mediated methodologies to synthesize heterocyclic

compounds.

For

example,

Cui

et

al.

developed

a

versatile

base-promoted

cycloisomerization of enaminone derivatives for the preparation of benzo[b][1,4]oxazepines (Scheme 1, c) 17c and pyridines.17a

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The Journal of Organic Chemistry a) by Yamada's group

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AgOAc (0.1 eq.) DBU (2.0 eq.) CO2 (1.0 MPa)

O R3 R1

esterification

o

MeCN, 30 C 1-24 h

R2

O

R3

MeI

OMe R1

O R2

b) by Liu's group R3 R1

t-BuOK (1.2 eq.)

O

+

R

3

N

R4

THF, 110 oC, 3 h

R2

R1

O R2

c) by Cui's group X

O

Cs2CO3 (2.0 eq.)

R3 NH R2

O R1

R1

R3

NMP, 120 oC N2,18 h

O attack N

R2

X = F, Cl, Br or I d) Our previous work: O CuCl (10 mol%) BPO

R3 N

R

R2

DMAc, 80 oC, N2

1

O

HN

R3

R1

HN

AgNO3 (10 mol%) NH2R1

R1

R3

DMF, 80 oC, air R2

O

R2

e) This work: O

R1

HN

R4

R3 2 (0.4 mmol) O R

or

R2

o

THF, rt or 35 C + R1NH2

3

R4 1

NR1 TBAF (0.2 eq., 80 uL, 1 mol/L in THF)

R4 R3

O attack

O R2

R2

Scheme 1. Construction of dihydroisobenzofuran structures

As part of our ongoing efforts to develop new methodology for the construction of carbo- and heterocyclic compounds,18 we previously disclosed synthetic methods involving chemoselective tandem reactions for the synthesis of α-naphthylamines and indeno[1,2-c]pyrrolones starting from (oalkynyl)phenyl enaminones (Scheme 1, d).19 Further, we designed (o-terminal alkynyl)phenyl enaminone 2a’ (Scheme 2) and envisioned that it might be feasible to prepare other potentially useful ring-fused cyclic products via a Csp2-H functionalization. However, when TBAF was used to remove trimethylsilyl, no 2a’ was observed and C-nucleophilic cyclization product (such as, 3a) was not detected. Interestingly, during this procedure, an unexpected selective O-nucleophilic cyclization process was realized instead to afford dihydroisobenzofuran structure (Scheme 2, 4a). In this process, only one geometric isomer was observed. The unexpected discovery motivated our further exploration. In this paper, we reported a bifunctional TBAF catalyzed selective O-nucleophilic cyclization of


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enaminone to synthesize dihydroisobenzofurans via a possible tetrabutylammonium cation-π interaction process (Scheme 1, e). N Ph O

NHPh

O

TBAF (1.5 eq., 0.6 mL, 1 mol/L in THF)

NHPh

O NHPh +

+

O

THF, rt, 10 min, air 2a

2a'

TMS

0% Deprotection

0.4 mmol

3a 0% C attack

4a >99% O attack

Scheme 2. Unexpected discovery ■ RESULTS AND DISCUSSION Our subsequent studies focused on the reaction of (Z)-1-(2-(phenylethynyl)phenyl)-3-(ptolylamino)prop-2-en-1-one (2b) in the presence of catalytic amounts of TBAF (20 mol %) in various solvents (Table 1, entries 1-4). Tetrahydrofuran (THF) was found to be the optimal solvent to perpare the desired dihydroisobenzofuran (4b) in a near-quantitative yield (entry 3, >99%, 2 h). However, no reaction occurred with acetonitrile as the solvent (entry 4). When the reaction was carried out at 25 oC, the yield of 4b decreased to 92% even after 5 h (entry 5). When the temperature was increased to 50 oC, some partial isomerizations were observed and the nuclear magnetic resonance (NMR) characterization of the product presented an unclean spectrum (entry 6). A lower yield (75%) was obtained with 0.2 eq. of potassium hydroxide as the catalyst (entry 7). Surprisingly, other common Brønsted base or quaternary ammonium salt such as triethylamine, sodium carbonate, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB) and tetrabutylammonium iodide (TBAI) were ineffective for the formation of 4b (entries 8-12). In order to clarify the effective catalytic species, control experiment was carried out. Upon the treatment of 2b with TBAB and CsF at 35 oC, 4b was isolated in 72% yield (entry 13). Nevertheless, no reaction occurred only with CsF as the catalyst (entry 13). These results (entries 3, 11, 13 and 14) suggested that both fluoride anion and tetrabutylammonium cation might be indispensable for this procedure. When the reaction was carried out with 0.2 eq. of TBAF·3H2O as the catalyst, the reaction was slowed down. However, it was found that 4b could also be isolated in 95% yield with 19 h (entry 15). ACS Paragon Plus Environment

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Table 1. Optimization of the reaction conditionsa Me

Me N

O

HN Cat. (0.2 eq.)

O

Solvent, x oC, air 2b (0.4 mmol) Ph

4b

Ph

Entry

Solvent

Temp. (oC)

Cat.

1

DCM

35

TBAFb

-

5

63

2

EtOAc

35

TBAFb

-

5

82

3

THF

35

TBAFb

-

2

>99

4

MeCN

35

TBAFb

-

5

NR

5

THF

25

TBAFb

-

5

92

6

THF

50

TBAFb

-

2

-c

7

THF

35

KOH

-

4

75

8

THF

35

Et3N

-

6

NR

9

THF

35

Na2CO3

-

6

NR

10

THF

35

TBAC

-

6

NR

11

THF

35

TBAB

-

6

NR

12

THF

35

TBAI

-

6

NR

13

THF

35

TBAB

CsF (2.0)

4

72

14

THF

35

-

CsF (2.0)

6

NR

15

THF

35

TBAF· 3H2O

-

19

95

16

THF

35

-

NaH (1.2)

8

32

17

THF

35

NaH (1.2)

15-crown-5 (1.2)

2

70

18

THF

35

TBAC

NaH (1.2)

2

>99

19

THF

35

TBAB

NaH (1.2)

2

>99

20

THF

35

Na2CO3

15-crown-5 (0.2)

2

NR

21

THF

35

TBAC

Na2CO3 (2.0)

2

NR

22

THF

35

NaF

15-crown-5 (0.2)

2

NR

23

THF

35

Bu4NOHd

-

2

83

24

THF

35

HF

-

2

trace

25

THF

35

TfOH

-

2

NR

26

THF

35

HF+TBAB

-

2

NR

Additive (y eq.) Time (h) Yield (%)

a

Solvent (0.1 M), 2b (0.4 mmol), Cat. (0.2 equiv.) were added to a Schlenk tube in air. b 80 uL TBAF (1 mol/L in THF) was used in the reaction. c The isomerization was observed by NMR analysis. NR = no reaction. d 50wt.% in water.


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When the reaction was carried out by using NaH (1.2 eq.) as the base, 4b was obtained with only a yield of 32% after 8 h (entry 16). But the addition of 15-crown-5 led to an increased yield to 70% after 2 h (entry 17). However, a near-quantitative yield of 4b was observed with TBAC or TBAB as the catalyst in the presence of NaH (1.2 eq.) (entries, 18 and 19). These results mentioned above (entries 1619) implied that the ammonium salt not only played a role of phase transfer catalysis, but also conducted an additional catalytic activity. When the reaction was performed with Na2CO3 and 15-crown-5 (entry 20) or TBAC and Na2CO3 (entry 21), no substantial effect was detected. The failure of Na2CO3 could be due to its lower basicity of carbonate (entry 20) or poor solubility in THF (entry 21). Therefore, to increase the solubility of sodium salt, 15-crown-5 was also employed. However, no reaction was observed in the presence of NaF and 15-crown-5 (entry 22), which further illustrated that it was indispensable for the tetraalkylammonium to cycloisomerization (entry 22 vs 3). When the reaction was carried out with Bu4NOH (0.2 eq.), 4b could be isolated with a yield of 84% (entry 23). The above results (entries 3, 10-12 and 23) indicated that a properly alkaline anion is also important for the reaction. In addition, it has been proved that acidic conditions are ineffective to the cyclization reaction (entries 24-26). With the optimal reaction conditions determined (Table 1, entry 3), the substrate scope was then examined (Table 2). A range of substituted (o-alkynyl)phenyl enaminones 2 were suitable for the reaction, offering the corresponding products 4a-4s in excellent yields (95% - >99%). Firstly, the electronic effect of the substituent R1 was investigated (4b-4f). The substrates with electron-donating (such as, 4c, R1 = p-OMePh, >99%) or electron-withdrawing (such as, 4e, R1 = p-ClPh, 95%) groups were all tolerable to furnish corresponding products in excellent yields. Treatment of the substrate bearing a 2-naphthyl group furnished 4g in 98% yield. The steric effect the electronic effect of the substituent R1 was also examined (entries 4h-4j). When R1 was large steric hindrance group, the desired dihydroisobenzofuran could also be obtained in excellent yield (such as, 4h, R1 = 2,6-diisopropyl phenyl, 98%). Subsequently, the R2 substituents were examined (4k-4m). Excellent yields of the ACS Paragon Plus Environment

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corresponding dihydroisobenzofurans could be isolated irrespective of the presence of electron-donating (4k, R2 = 3,4,5-trimethoxyphenyl, 96%) or electron-withdrawing (4m, R2 = p-ClPh, 97%) groups on the benzene ring. Nevertheless, when alkyl (such as, R2 = n-butyl) instead of aryl was used, nearly no reaction occurred under the optimal reaction conditions. Then, the effect of different R3 substituents was investigated. It was found that a methyl-, dimethoxy- or fluoro-substituted substrates were all tolerable for the reaction, offering 4n, 4o and 4p in 95%, 95% and 97% yield, respectively. For substituents R4, an aryl substituent (such as, phenyl group) offered 4q in 96% yield. In addition, special examination was performed on desired product bearing terminal olefin moiety. The corresponding (o-alkynyl)phenyl enaminones 2 (R2 = trimethylsilyl) could be smoothly transformed into terminal olefin products in excellent yields (4r, >99%; 4a, >99%; 4s, 95%). Structural identification of 4q was performed by X-ray crystallography.20 Our method also involved a new method for the synthesis of conjugated aldehydes. When R1 was nbutyl group, a conjugated aldehyde 5 was obtained in 92% yield under the standard reaction condition (Scheme 3). The formation of 5 indicated that alkyl-substituted imine showed good hydrolysis reactivity after the cyclization reaction. In addition, the synthetic value of the dihydroisobenzofuran based imine 4 was exemplified by the selective reduction of 4b to furnish a new dihydroisobenzofuran derivative 6 in 85% yield (Scheme 4). It is expected that product 6 could be further elaborated to other cyclic products, according to the known procedures of deriving allyl or alkenyl substituted aromatic amines,21 which is under investigation in our laboratory. It is noticeable that the one-pot tandem reaction strategy is feasible. A one-pot TBAF catalyzed conjugate addition/cycloisomerization reaction was carried out with ynone22 and aniline 7 to directly furnish dihydroisobenzofuran 4b in 83% yield (Scheme 5). This procedure involved two distinct nucleophilic catalytic steps using the same tetraalkylammonium fluoride catalyst.


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Table 2. The scope of the reactiona O

NR1

R1

HN

TBAF (0.2 eq., 80 uL, 1 mol/L in THF)

R4

R3

R4 R3

o

O

THF, 35 C, air R2 2 (0.4 mmol)

R2 4

Me

OMe

N

O 4b

Cl

N

N

O 4c

Ph

2 h, >99%

N

O 4d

Ph

2 h, >99%

O 4e

Ph

Ph

2 h, >99%

2 h, 95%

Br N

N

O 4f

N

O 4g

Ph

2 h, 96%

N

O 4h

Ph

O 4i

Ph 1 h, 98%b

2 h, 98% N Ph

Ph 1 h, 98%b

N Ph

N Ph

N O

Br

OMe

O 4j

O

O

OMe 4k

Ph

4l

OMe

4m

3 h, 96%

1 h, >99%b

2 h, 95%

Me

OMe

N Ph

N

Cl 2 h, 97%

N

Ph

N

MeO O

O

Me 4n

MeO 4o

Ph

O 4p

OMe

N

O

O 4r

O

4a

15 min, >99%c,d

Ph 4 h, 96%

Cl

N Ph

N

4q

Ph 1 h, 97%b

1 h, 95%

3 h, 95%

O

F Ph

4s

15 min, >99%c,d

4q

30 min, 95%c,d

a

b

The reactions were carried out under the optimized reaction conditions. Isolated yield. 0.5 eq. of TBAF was used. c R2 = trimethylsilyl (TMS), 1.0 eq. of TBAF was used. d The reactions were carried out at room temperature.

O O

HN


O

THF, 35 oC, 10 h, air Ph

Ph

2t (0.2 mmol)

5 (92%)

Scheme 3. Formation of conjugated aldehyde 5

Me N

Me

TsOH H2O (1 eq.) NaBH4 (4 eq.)

O Ph 4b (0.3 mmol)

EtOH, 25 oC 2.5 h

HN

O Ph 6 (85%)


8

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Scheme 4. Synthesis of the reduction product 6

Me

O

N


NH2 +

THF, 35 oC, 6 h

Me

O

Ph 1a (0.2 mmol)

7 (1.0 eq.)

4b (83%)

Me O

Ph

HN

TBAF

TBAF rearrangement cyclization

conjugate addition Ph

Scheme 5. One-pot conjugate addition/cycloisomerization tandem reaction

Based on the reported work23 and our experimental results, a plausible mechanism is demonstrated with model substrates 1a and 7 as outlined in Scheme 6. Initially, enaminone 2b was generated via a conjugate addition (1a to 2b). Subsequently, the hydrogen atom on the nitrogen of enaminone was removed by fluoride anion (A to B).3 Then, the in-situ generated oxygen anion attacked the alkyne moiety (B to C, 5-exo-dig), which might be activated by the cation-π interaction,8b to furnish C. Alternatively, tetrabutylammonium cation may also serve as a non-coordinating cation to stabilize enolate that formed upon deprotonation of the starting material. Finally, the further protonation process occurred to offer the target molecule 4b. Me

F

O Michael-type addition

O

HN

+ TBAF

O

H

Me N

Me 1a

Ph

7

H 2N

2b

A

Ph

Ph

Me Me

O

N Protonation

5-exo-dig NR4

R Ph B NR3 Cation- Interaction

Me

N

N

O

C Ph

O

4b Ph

Scheme 6. The possible reaction mechanism ■ CONCLUSION In conclusion, we developed a novel bifunctional TBAF catalyzed selective O-nucleophilic cyclization of enaminone for the synthesis of dihydroisobenzofuran derivatives. This procedure featured ACS Paragon Plus Environment

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a possible cation-π interaction as the activated process and fluoride anion as a Brønsted base. The developed procedure provides an atom-economic and highly efficient method for the preparation of dihydroisobenzofurans with excellent yields under mild conditions. One-pot conjugate addition/ cycloisomerization tandem reaction was successfully implemented under the same condition. Our laboratory is making ongoing efforts to explore this cycloisomerization reaction for the synthesis of various types of carbo- or heterocyclic compounds. ■ EXPERIMENTAL SECTION General Methods. All reactions were carried out in air except noted. The TBAF (1 mol/L in THF) was

purchased from Sigma-Aldrich Co. and Sun Chemical Technology (Shanghai) Co., Ltd. Anhydrous tetrahydrofuran was distilled from sodium and benzophenone. Unless noted, all commercial reagents were used without further purification. Reactions were monitored by thin layer chromatography using UV light to visualize the course of reaction. Purification of reaction products was carried out by flash chromatography on silica gel (300~400 mesh). 1H NMR spectra were recorded at 500 or 400 MHz, 13C NMR spectra were recorded at 125 or 100 MHz, and in CDCl3, (CD3)2SO, (CD3)2CO, CD2Cl2 or C6D6 (containing 0.03% TMS) solutions. 1H NMR spectra were recorded with Me4Si (δ = 0.00) as the internal reference and

13C

NMR spectra were recorded with CDCl3 (δ = 77.00), DMSO-d6 (δ = 39.52),

(CD3)2CO (δ = 29.84), CD2Cl2 (δ = 54.00) or C6D6 (δ = 128.06) as the internal reference. Highresolution mass spectra were obtained using a Bruker Maxis Impact mass spectrometer with a TOF (for ESI) analyzer. Single crystal X-ray diffraction data was collected in Bruker SMARTAPEX diffractiometers with molybdenum cathodes. Preparation of compounds 2 The compounds 2 were prepared according to the literature methods.19 To a solution of 719 (4.4 mmol) in MeOH (5 mL) in an oven-dried vial was added NH2R1 (1.02 eq.) and then stirred at room temperature in the air for 1-2 h until 7 had disappeared by TLC analysis. Then, the mixture was filtered, and the filter cake was washed with methanol (5 mL). The pure filter cake 2 was collected and dried. (If the filtrate still containing a small amount of 2 in individual substrates ACS Paragon Plus Environment

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judging by TLC, the small amount of product could be recovered by column chromatographic purification using petroleum ether/ethyl acetate (from 15/1 to 5/1, v/v) as the eluent.) Compounds 2b-g, 2k-m and 2o are known compounds19 and the spectroscopic data are in agreement with that previously reported. The analytical data of other products 2 are as follows. (Z)-3-(phenylamino)-1-(2-((trimethylsilyl)ethynyl)phenyl)prop-2-en-1-one (2a). Yellow solid; 88% yield (1.24 g); mp 113-115 oC; 1H NMR (400 MHz, CDCl3): δ 12.06 (d, J = 12.4 Hz, 1H), 7.69-7.67 (m, 1H), 7.55-7.53 (m, 1H), 7.47-7.34 (m, 5H), 7.13-7.08 (m, 3H), 6.19 (d, J = 7.9 Hz, 1H), 0.25 (s, 9H); 13C{1H}

NMR (100 MHz, CDCl3): δ 193.1, 144.3, 143.4, 140.6, 134.0, 130.0, 128.8, 128.4, 123.9,

120.7, 116.6, 104.1, 100.0, 98.1, -0.6; HRMS (ESI) calcd for C20H22NOSi [M+H]+: 320.1465, found 320.1469. (Z)-3-((2,6-diisopropylphenyl)amino)-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one

(2h).

Yellow

solid; 90% yield (1.61 g); mp 99-101 oC; 1H NMR (500 MHz, CDCl3): δ 11.66 (d, J = 12.5 Hz, 1H), 7.76-7.74 (m, 1H), 7.62-7.60 (m, 1H), 7.52-7.50 (m, 2H), 7.42-7.39 (m, 2H), 7.33-7.26 (m, 4H), 7.20 (d, J = 7.6 Hz, 2H), 6.94-6.90 (m, 1H), 6.06 (d, J = 7.5 Hz, 1H), 3.32-3.27 (m, 2H), 1.24 (d, J = 6.9 Hz, 12H);

13C{1H}

NMR (125 MHz, CDCl3): δ 192.5, 153.3, 144.5, 143.4, 136.2, 133.1, 131.4, 129.6,

128.3, 128.3, 128.2, 127.6, 123.8, 123.5, 120.6, 95.8, 93.8, 88.9, 28.4, 23.8; HRMS (ESI) calcd for C29H30NO [M+H]+: 408.2322, found 408.2316. (Z)-3-((4-(tert-butyl)phenyl)amino)-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one (2i). Yellow solid; 93% yield (1.55 g); mp 141-143 oC; 1H NMR (500 MHz, CDCl3): δ 12.10 (d, J = 12.3 Hz, 1H), 7.737.72 (m, 1H), 7.62-7.60 (m, 1H), 7.54-7.51 (m, 2H), 7.49-7.47 (m, 1H), 7.43-7.33 (m, 7H), 7.08 (d, J = 8.7 Hz, 2H), 6.15 (d, J = 7.8 Hz, 1H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 193.0, 147.2, 144.8, 143.2, 138.0, 133.5, 131.7, 130.0, 128.6, 128.6, 128.5, 126.8, 123.6, 120.8, 116.4, 97.5, 94.2, 88.8, 34.1, 31.1; HRMS (ESI) calcd for C27H26NO [M+H]+: 380.2009, found 380.2006. (Z)-3-((2-bromophenyl)amino)-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one (2j). Brownish oil; 84% yield (1.49 g); 1H NMR (500 MHz, CDCl3): δ 12.37 (d, J = 11.8 Hz, 1H), 7.77-7.75 (m, 1H), 7.61-7.58 ACS Paragon Plus Environment

11


Page 12 of 24

(m, 2H), 7.54-7.52 (m, 2H), 7.49-7.45 (m, 1H), 7.43-7.38 (m, 2H), 7.35-7.28 (m, 4H), 7.21 (d, J = 8.2 Hz, 1H), 6.94-6.91 (m, 1H), 6.30 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 193.0, 142.5, 142.4, 138.7, 133.5, 133.2, 131.5, 130.1, 128.5, 128.5, 128.4, 128.3, 128.3, 124.0, 123.3, 120.8, 114.6, 112.8, 99.4, 94.3, 88.7; HRMS (ESI) calcd for C23H17BrNO [M+H]+: 402.0488, found 402.0494. (Z)-1-(4-methyl-2-(phenylethynyl)phenyl)-3-(p-tolylamino)prop-2-en-1-one (2n). Yellow solid; 90% yield (1.39 g); mp 143-144 oC; 1H NMR (500 MHz, CDCl3): δ 12.08 (d, J = 12.0, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.34-7.33 (m, 3H), 7.22-7.20 (m, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.19 (d, J = 8.0 Hz, 1H), 2.39 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 192.3, 144.3, 140.1, 140.1, 137.9, 133.9, 133.3, 131.5, 130.2, 129.3, 128.5, 128.3, 123.5, 120.6, 116.4, 97.3, 93.8, 89.1, 21.1, 20.7; HRMS (ESI) calcd for C25H22NO [M+H]+: 352.1696, found 352.1690. (Z)-1-(4-fluoro-2-(phenylethynyl)phenyl)-3-((4-methoxyphenyl)amino)prop-2-en-1-one (2p). Yellow solid; 95% yield (1.55 g); mp 119-122 oC; 1H NMR (500 MHz, CDCl3): δ 12.12 (d, J = 12.3 Hz, 1H), 7.75-7.72 (m, 1H), 7.54-7.52 (m, 2H), 7.43-7.39 (m, 1H), 7.36-7.35 (m, 3H), 7.29-7.27 (m, 1H), 7.117.09 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.12 (d, J = 7.7 Hz, 1H), 3.80 (s, 3H); 13C{1H}

NMR (125 MHz, CDCl3): δ 190.9, 163.1 (d, JC-F = 249.2 Hz), 156.6, 145.5, 139.3 (d, JC-F = 3.1

Hz), 133.8, 131.7, 130.8 (d, JC-F = 9.2 Hz), 128.9, 128.5, 123.0, 123.0, 119.8 (d, JC-F = 22.9 Hz), 118.2, 115.9 (d, JC-F = 21.3 Hz), 115.1, 96.8, 95.2, 87.9 (d, JC-F = 2.8 Hz), 55.7; HRMS (ESI) calcd for C24H19FNO2 [M+H]+: 372.1394, found 372.1390. (Z)-3-phenyl-3-(phenylamino)-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one (2q). Yellow solid; 85% yield (1.49 g); mp 118-120 oC; 1H NMR (500 MHz, CDCl3): δ 12.79 (s, 1H), 7.81-7.79 (m, 1H), 7.617.59 (m, 1H), 7.42-7.40 (m, 2H), 7.36-7.32 (m, 5H), 7.29-7.27 (m, 1H), 7.25-7.21 (m, 4H), 7.15-7.12 (m, 2H), 7.01-6.98 (m, 1H), 6.82 (d, J = 7.8 Hz, 2H), 6.38 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 190.9, 160.7, 143.2, 139.5, 135.7, 133.3, 131.5, 129.7, 129.6, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 124.1, 123.2, 120.6, 101.3, 94.3, 89.0; HRMS (ESI) calcd for C29H22NO [M+H]+: 400.1696, found 400.1699. ACS Paragon Plus Environment

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(Z)-3-((4-methoxyphenyl)amino)-1-(2-((trimethylsilyl)ethynyl)phenyl)prop-2-en-1-one (2r). Yellow solid; 88% yield (1.35 g); mp 95-96 oC; 1H NMR (500 MHz, CDCl3): δ 12.11 (d, J = 12.2 Hz, 1H), 7.69-7.67 (m, 1H), 7.53-7.52 (m, 1H), 7.39-7.33 (m, 3H), 7.07-7.04 (m, 2H), 6.92-6.89 (m, 2H), 6.14 (d, J = 7.7 Hz, 1H), 3.80 (s, 3H), 0.24 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 192.0, 156.4, 145.0, 143.2, 133.8, 133.7, 129.5, 128.6, 128.2, 120.4, 118.0, 115.0, 104.1, 99.7, 97.3, 55.6, -0.2; HRMS (ESI) calcd for C21H24NO2Si [M+H]+: 350.1571, found 350.1576. (Z)-3-((4-chlorophenyl)amino)-1-(2-((trimethylsilyl)ethynyl)phenyl)prop-2-en-1-one

(2s).

Yellow

solid; 90% yield (1.40 g); mp 110-112 oC; 1H NMR (500 MHz, CDCl3): δ 12.04 (d, J = 12.0 Hz, 1H), 7.68-7.66 (m, 1H), 7.54-7.52 (m, 1H), 7.40-7.34 (m, 3H), 7.32-7.29 (m, 2H), 7.05-7.03 (m, 2H), 6.21 (d, J = 7.8 Hz, 1H), 0.24 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 192.8, 143.6, 142.8, 139.0, 133.8, 129.9, 129.8, 128.7, 128.6, 128.2, 120.5, 117.5, 103.9, 100.0, 98.5, -0.3; HRMS (ESI) calcd for C20H21ClNOSi [M+H]+: 354.1075, found 354.1073. (Z)-3-(butylamino)-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one (2t). Brownish oil; 79% yield (1.05 g); 1H NMR (500 MHz, CDCl3): δ 10.34 (s, 1H), 7.67-7.65 (m, 1H), 7.56-7.55 (m, 1H), 7.51-7.48 (m, 2H), 7.35-7.31 (m, 5H), 6.93-6.89 (m, 1H), 5.79 (d, J = 7.4 Hz, 1H), 3.28-3.24 (m, 2H), 1.62-1.56 (m, 2H), 1.43-1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H);

13C{1H}

NMR (125 MHz, CDCl3): δ 191.1, 153.7,

143.5, 133.0, 131.4, 129.1, 128.2, 128.1, 128.0, 123.5, 120.3, 94.0, 93.4, 89.0, 48.9, 33.0, 19.6, 13.6; HRMS (ESI) calcd for C21H22NO [M+H]+: 304.1696, found 304.1691. Synthesis of dihydroisobenzofurans 4 In air, to a vial were added 2 (0.4 mmol), THF (3 mL) and TBAF (the corresponding amount of TBAF, see: Table 2; 1 mol/L in THF). The mixture was stirred at room temperature or 35 oC till 4 disappeared by TLC analysis. The resulting mixture was concentrated under reduced pressure and subjected

to

column

chromatography

for

purification

directly,

using

petroleum

ether/dichloromethane/triethylamine (160/20/0.9 to 100/100/1) as the eluent.


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(E)-2-((Z)-3-methyleneisobenzofuran-1(3H)-ylidene)-N-phenylethan-1-imine

(4a).

Yellow

solid;

>99% yield (98 mg); mp 72-74 oC; 1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.65-7.58 (m, 2H), 7.40-7.36 (m, 2H), 7.22-7.18 (m, 3H), 6.47 (d, J = 9.6 Hz, 1H), 5.29 (d, J = 2.6 Hz, 1H), 5.06 (d, J = 2.7 Hz, 1H);

13C{1H}

NMR (100 MHz,

DMSO-d6): δ 160.1, 157.4, 155.6, 152.7, 133.4, 132.7, 132.0, 130.9, 129.6, 126.1, 122.2, 121.6, 121.2, 99.4, 86.7; HRMS (ESI) calcd for C17H14NO [M+H]+: 248.1070, found 248.1065. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(p-tolyl)ethan-1-imine(4b).

Yellow

solid; >99% yield (134 mg); mp 149-151 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.80 (d, J = 9.5 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.68-7.65 (m, 1H), 7.61-7.58 (m, 1H), 7.46-7.43 (m, 2H), 7.30-7.27 (m, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.70 (s, 1H), 6.57 (d, J = 9.5 Hz, 1H), 2.34 (s, 3H); 13C{1H} NMR (125 MHz, CD2Cl2): δ 159.9, 154.6, 151.0, 150.0, 135.7, 135.0, 134.5, 131.9, 131.1, 129.8, 129.6, 129.1, 128.7, 127.1, 121.2, 120.9, 120.0, 101.8, 100.0, 20.7; HRMS (ESI) calcd for C24H20NO [M+H]+: 338.1539, found 338.1541. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(4-methoxyphenyl)ethan-1-imine (4c). Yellow solid; 99% yield (140 mg); mp 118-120 oC;1H NMR (500 MHz, DMSO-d6): δ 8.81 (d, J = 9.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.66-7.63 (m, 1H), 7.60-7.55 (m, 1H), 7.46-7.43 (m, 2H), 7.30-7.26 (m, 3H), 7.01-6.99 (m,2H), 6.68 (s, 1H), 6.55 (d, J = 9.5 Hz, 1H), 3.79 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 158.9, 157.8, 152.7, 150.4, 145.1, 134.3, 134.2, 131.4, 131.2, 130.0, 129.0, 128.8, 127.1, 122.1, 121.8, 120.5, 114.6, 101.8, 100.0, 55.3; HRMS (ESI) calcd for C24H20NO2 [M+H]+: 354.1489, found 354.1495. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-phenylethan-1-imine (4d). Yellow solid; 99% yield (128 mg); mp 106-108 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.80 (d, J = 9.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.68-7.65 (m, 1H), 7.61-7.58 (m, 1H), 7.46-7.42 (m, 4H), 7.30-7.23 (m, 4H), 6.71 (s, 1H), 6.59 (d, J = 9.5 Hz, 1H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 159.7, 154.9, 152.3, 150.3, 134.3, 134.2, 131.6, 131.1, 130.0, 129.3, 129.0,


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128.8, 127.2, 125.7, 121.9, 120.8, 120.5, 102.1, 99.7; HRMS (ESI) calcd for C23H18NO [M+H]+: 324.1383, found 324.1386. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(4-chlorophenyl)ethan-1-imine (4e). Yellow solid; 95% yield (136 mg); mp 149-151 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.79 (d, J = 9.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.69-7.66 (m, 1H), 7.61-7.58 (m, 1H), 7.48-7.43 (m, 4H), 7.30-7.27 (m, 3H), 6.72 (s, 1H), 6.58 (d, J = 9.5 Hz, 1H); 13C{1H}

NMR (125 MHz, DMSO-d6): δ 160.2, 155.7, 151.1, 150.3, 134.4, 134.2, 131.8, 131.0, 130.1,

129.9, 129.2, 129.1, 128.9, 127.3, 122.6, 122.0, 120.5, 102.4, 99.6; HRMS (ESI) calcd for C23H17ClNO [M+H]+: 358.0993, found 358.0997. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(4-bromophenyl)ethan-1-imine (4f). Yellow solid; 96% yield (154 mg); mp 130-132 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.77 (d, J = 9.5 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.68-7.65 (m, 1H), 7.60-7.57 (m, 3H), 7.45-7.42 (m, 2H), 7.29-7.28 (m, 1H), 7.21-7.19 (m, 2H), 6.71 (s, 1H), 6.57 (d, J = 9.5 Hz, 1H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 160.2, 155.7, 151.5, 150.3, 134.4, 134.2, 132.1, 131.8, 131.0, 130.0, 129.1, 128.9, 127.2, 123.0, 122.0, 120.5, 118.1, 102.4, 99.6; HRMS (ESI) calcd for C23H17BrNO [M+H]+: 402.0488, found 402.0490. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(naphthalen-2-yl)ethan-1-imine (4g). Yellow solid; 98% yield (146 mg); mp 147-149 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.89 (d, J = 9.6 Hz, 1H), 8.32-8.30 (m, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.96-7.94 (m, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.70-7.67 (m, 1H), 7.64-7.61 (m, 1H), 7.59-7.53 (m, 3H), 7.41-7.38 (m, 2H), 7.27-7.24 (m, 1H), 7.21 (d, J = 7.0 Hz, 1H), 6.77 (d, J = 9.5 Hz, 1H), 6.72 (s, 1H);

13C{1H}

NMR (125 MHz, DMSO-d6): δ 160.0, 155.4, 150.3, 149.5, 134.4, 134.2, 133.6, 131.7,

131.1, 130.0, 129.0, 128.8, 128.5, 127.6, 127.2, 126.6, 126.4, 125.7, 125.3, 123.4, 122.0, 120.5, 112.8, 102.3, 99.9; HRMS (ESI) calcd for C27H20NO [M+H]+: 374.1539, found 374.1535.


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Page 16 of 24

(E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(2,6-diisopropylphenyl)ethan-1imine (4h). Yellow solid; 98% yield (160 mg); mp 145-147 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.47 (d, J = 9.5 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.4 Hz, 2H), 7.707.67 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.32 (m, 2H), 7.24-7.21 (m, 1H), 7.17 (d, J = 7.7 Hz, 2H), 7.117.07 (m, 1H), 6.70 (s, 1H), 6.67 (d, J = 9.6 Hz, 1H), 3.03-2.97 (m, 2H), 1.16 (d, J = 6.9 Hz, 12H); 13C{1H}

NMR (125 MHz, DMSO-d6): δ 160.3, 158.0, 150.8, 150.0, 137.9, 134.8, 134.7, 132.2, 131.5,

130.5, 129.3, 129.2, 127.7, 124.5, 123.4, 122.5, 121.0, 102.5, 99.6, 27.8, 24.1; HRMS (ESI) calcd for C29H30NO [M+H]+: 408.2322, found 408.2313. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(4-(tert-butyl)phenyl)ethan-1-imine (4i). Yellow solid; 98% yield (149 mg); mp 145-147 oC; 1H NMR (500 MHz, C6D6): δ 9.14-9.11 (m, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.24-7.21 (m, 2H), 7.07-7.01 (m, 3H), 6.96-6.93 (m, 1H), 6.87-6.84 (m, 1H), 6.46-6.43 (m, 1H), 6.01 (s, 1H), 1.26 (s, 9H); 13C{1H}

NMR (125 MHz, C6D6): δ 159.7, 154.5, 151.3, 151.2, 148.8, 135.1, 135.1, 132.3, 130.5, 129.6,

129.4, 129.0, 127.4, 126.5, 121.3, 121.3, 120.0, 102.2, 101.1, 34.5, 31.6; HRMS (ESI) calcd for C27H26NO [M+H]+: 380.2009, found 380.2011. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N-(2-bromophenyl)ethan-1-imine (4j). Yellow solid; >99% yield (159 mg); mp 155-156 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.70 (d, J = 9.7 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.70-7.67 (m, 2H), 7.62-7.59 (m, 1H), 7.47-7.40 (m, 3H), 7.28-7.22 (m, 2H), 7.17-7.14 (m, 1H), 6.74 (s, 1H), 6.68 (d, J = 9.7 Hz, 1H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 160.7, 156.9, 150.9, 150.2, 134.5, 134.1, 132.7, 131.9, 130.9, 130.1, 129.1, 129.0, 128.8, 127.3, 126.8, 122.2, 120.5, 120.2, 118.0, 102.5, 99.5; HRMS (ESI) calcd for C23H17BrNO [M+H]+: 402.0488, found 402.0494. (E)-N-phenyl-2-((Z)-3-((Z)-3,4,5-trimethoxybenzylidene)isobenzofuran-1(3H)-ylidene)ethan-1imine (4k). Yellow solid; 96% yield (159 mg); mp 158-160 oC; 1H NMR (500 MHz, CD2Cl2): δ 8.84 (d, J = 9.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.51-7.48 (m, 1H), 7.39-7.36 (m, 2H), 7.24-7.21 (m, 1H), 7.14 (d, J = 7.5 Hz, 2H), 7.10 (s, 2H), 6.33 (d, J = 10.0 Hz, ACS Paragon Plus Environment

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1H), 6.23 (s, 1H), 3.83 (s, 6H), 3.80 (s, 3H); 13C{1H} NMR (125 MHz, CD2Cl2): δ 161.3, 156.2, 153.9, 150.9, 138.3, 135.7, 132.0, 131.8, 130.5, 130.1, 129.7, 126.3, 121.9, 121.2, 120.4, 106.7, 102.8, 100.1, 61.1, 56.4; HRMS (ESI) calcd for C26H24NO4 [M+H]+: 414.1700, found 414.1690. (E)-2-((1Z,3Z)-3-(naphthalen-2-ylmethylene)isobenzofuran-1(3H)-ylidene)-N-phenylethan-1-imine (4l). Yellow solid; 95% yield (142 mg); mp 143-146 oC; 1H NMR (500 MHz, C6D6): δ 8.96 (d, J = 9.4 Hz, 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.39-7.36 (m, 1H), 7.34-7.31 (m, 4H), 7.22-7.19 (m, 2H), 7.14 (d, J = 7.9 Hz, 1H), 7.05-7.02 (m, 2H), 7.00-6.97 (m, 1H), 6.91-6.88 (m, 1H), 6.78 (s, 1H), 6.42 (d, J = 9.4 Hz, 1H); 13C{1H} NMR (125 MHz, C6D6): δ 159.9, 155.3, 153.7, 152.2, 135.1, 134.5, 132.4, 132.1, 130.9, 130.7, 129.5, 129.5, 129.3, 126.3, 126.2, 126.0, 125.9, 124.1, 121.6, 121.4, 120.2, 101.2, 98.0; HRMS (ESI) calcd for C27H20NO [M+H]+: 374.1539, found 374.1542. (E)-2-((Z)-3-((Z)-4-chlorobenzylidene)isobenzofuran-1(3H)-ylidene)-N-phenylethan-1-imine (4m). Yellow solid; 97% yield (139 mg); mp 170-172 oC; 1H NMR (500 MHz, CD2Cl2): δ 8.89 (d, J = 9.5 Hz, 1H), 7.82-7.78 (m, 3H), 7.75 (d, J = 7.5 Hz, 1H), 7.60-7.59 (m, 1H), 7.56-7.55 (m, 1H), 7.48-7.45 (m, 2H), 7.42-7.40 (m, 2H), 7.30-7.26 (m, 3H), 6.37 (d, J = 9.5 Hz, 1H), 6.30 (s, 1H); 13C{1H} NMR (125 MHz, CD2Cl2): δ 160.1, 155.3, 152.5, 151.3, 134.8, 133.1, 132.5, 131.8, 131.2, 130.2, 129.8, 129.2, 128.8, 125.8, 121.3, 121.0, 120.0, 100.6, 100.1; HRMS (ESI) calcd for C23H17ClNO [M+H]+: 358.0993, found 358.0995. (E)-2-((Z)-3-((Z)-benzylidene)-5-methylisobenzofuran-1(3H)-ylidene)-N-(p-tolyl)ethan-1-imine (4n). Yellow solid; 95% yield (134 mg); mp 155-156 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.78 (d, J = 9.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84-7.81 (m, 3H), 7.45-7.41 (m, 3H), 7.30-7.23 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 6.65 (s, 1H), 6.49 (d, J = 9.5 Hz, 1H), 2.48 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (125 MHz, C6D6): δ 159.8, 154.7, 151.5, 151.4, 141.1, 135.5, 135.3, 135.2, 130.9, 130.2, 130.0, 129.6, 129.0, 127.3, 121.5, 121.1, 120.2, 101.9, 100.5, 21.6, 21.0; HRMS (ESI) calcd for C25H22NO [M+H]+: 352.1696, found 352.1696.


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(E)-2-((Z)-3-((Z)-benzylidene)-5,6-dimethoxyisobenzofuran-1(3H)-ylidene)-N-phenylethan-1-imine (4o). Yellow solid; 95% yield (146 mg); mp 201-203 oC; 1H NMR (500 MHz, DMSO-d6): δ 8.76 (d, J = 9.6 Hz, 1H), 7.80 (d, J = 7.5 Hz, 2H), 7.63 (s, 1H), 7.56 (s, 1H), 7.44-7.40 (m, 4H), 7.26-7.21 (m, 4H), 6.59 (s, 1H), 6.51 (d, J = 9.6 Hz, 1H), 3.93 (s, 3H), 3.89 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 160.2, 155.0, 152.9, 152.4, 151.5, 150.7, 134.6, 129.3, 128.8, 128.6, 128.1, 126.8, 125.4, 124.1, 120.8, 103.2, 102.1, 100.7, 98.4, 56.1; HRMS (ESI) calcd for C25H22NO3 [M+H]+: 384.1594, found 384.1590. (E)-2-((Z)-3-((Z)-benzylidene)-5-fluoroisobenzofuran-1(3H)-ylidene)-N-(4-methoxyphenyl)ethan-1imine (4p). Yellow solid; 97% yield (144 mg); mp 155-157 oC; 1H NMR (500 MHz, (CD3)2CO): δ 8.89 (d, J = 9.4 Hz, 1H), 8.04-8.01 (m, 1H), 7.90 (d, J = 7.4 Hz, 2H), 7.72-7.70 (m, 1H), 7.45-7.42 (m, 2H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 3H), 7.00-6.98 (m, 2H), 6.62 (s, 1H), 6.37 (d, J = 9.4 Hz, 1H), 3.84 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ 164.6 (d, JC-F = 247.5 Hz), 158.3, 152.5, 149.9 (d, JC-F = 4.9 Hz), 145.6, 137.0 (d, JC-F = 10.4 Hz), 134.4, 129.2, 128.6, 128.1, 127.2, 123.7 (d, JC-F = 9.7 Hz), 122.1, 117.8 (d, JC-F = 24.9 Hz), 114.3, 106.6 (d, JC-F = 25.3 Hz), 102.7, 100.1, 54.8; HRMS (ESI) calcd for C24H19FNO2 [M+H]+: 372.1394, found 372.1387. (E)-2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)-N,1-diphenylethan-1-imine

(4q).

Yellow solid; 96% yield (153 mg); mp 193-194 oC; 1H NMR (500 MHz, C6D6): δ 8.08-8.06 (m, 2H), 7.27-7.25 (m, 3H), 7.19 (d, J = 8.1 Hz, 2H), 7.10-7.05 (m, 7H), 7.01-6.96 (m, 2H), 6.93-6.90 (m, 1H), 6.81-6.78 (m, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.92 (s, 1H), 5.90 (s, 1H); 13C{1H} NMR (125 MHz, C6D6): δ 163.4, 157.3, 152.7, 150.8, 141.2, 135.2, 134.5, 132.5, 130.4, 130.3, 129.5, 129.3, 129.3, 129.2, 128.9, 128.5, 127.1, 124.1, 121.4, 121.2, 119.9, 102.4, 93.7; HRMS (ESI) calcd for C29H22NO [M+H]+: 400.1696, found 400.1700. (E)-N-(4-methoxyphenyl)-2-((Z)-3-methyleneisobenzofuran-1(3H)-ylidene)ethan-1-imine

(4r).

Yellow solid; >99% yield (110 mg); mp 104-106 oC; 1H NMR (500 MHz, (CD3)2CO): δ 8.76 (d, J = 9.5 Hz, 1H), 7.94-7.93 (m, 1H), 7.87-7.85 (m, 1H), 7.63-7.58 (m, 2H), 7.22 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.28 (d, J = 9.5 Hz, 1H), 5.15 (d, J = 3.0 Hz, 1H), 4.99 (d, J = 3.0 Hz, 1H), 3.81 (s, 3H); 13C{1H}

NMR (125 MHz, (CD3)2CO): δ 159.8, 159.2, 158.5, 153.6, 146.6, 134.2, 133.9, 132.0, 131.2, ACS Paragon Plus Environment

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123.0, 122.2, 121.8, 115.2, 100.6, 85.4, 55.7; HRMS (ESI) calcd for C18H16NO2 [M+H]+: 278.1176, found 278.1171. (E)-N-(4-chlorophenyl)-2-((Z)-3-methyleneisobenzofuran-1(3H)-ylidene)ethan-1-imine

(4s).

Yellow solid; 95% yield (107 mg); mp 105-107 oC; 1H NMR (500 MHz, CD2Cl2): δ 8.75 (d, J = 9.5 Hz, 1H), 7.70 (d, J = 7.0 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 7.56-7.49 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 6.19 (d, J = 9.5 Hz, 1H), 5.01 (s, 2H); 13C{1H} NMR (125 MHz, CD2Cl2): δ 160.8, 158.0, 156.5, 151.6, 134.0, 133.4, 131.6, 131.2, 130.5, 129.5, 122.8, 121.6, 121.1, 99.5, 85.6; HRMS (ESI) calcd for C17H13ClNO [M+H]+: 282.0680, found 282.0685. Synthesis of compound 5. In air, to a vial were added 2t (60.7 mg, 0.2 mmol), THF (2 mL) and TBAF (40 uL, 0.04 mmol, 1.0 mol/L in THF). The mixture was stirred at 35 oC for 10 h. The resulting mixture was concentrated under reduced pressure and subjected to column chromatography for purification directly, using petroleum ether/dichloromethane/triethylamine (175/25/1) as the eluent. 2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)acetaldehyde (5). Yellow solid; 92% yield (46 mg); mp 119-121 oC; 1H NMR (500 MHz, DMSO-d6): δ 10.33 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.78-7.75 (m, 1H), 7.64-7.61 (m, 1H), 7.507.47 (m, 2H), 7.35-7.32 (m, 1H), 6.87 (s, 1H), 6.26 (d, J = 8.1 Hz, 1H);

13C{1H}

NMR (125 MHz,

DMSO-d6): δ 187.9, 166.0, 149.9, 134.7, 133.7, 133.2, 130.3, 130.2, 129.4, 129.0, 127.8, 123.0, 120.6, 104.3, 99.7; HRMS (ESI) calcd for C17H13O2 [M+H]+: 249.0910, found 249.0912. Synthesis of compound 6. In air, to a vial were added 4b (101.2 mg, 0.3 mmol), EtOH (6 mL), NaBH4 (45.4 mg, 1.2 mmol), and TsOHH2O (57.0 mg, 0.3mmol). The mixture was stirred at 25 oC for 2.5 h. Then, the reaction mixture was diluted with H2O (30 mL), and extracted with ethyl acetate (20 mL×3). Subsequently, the combined extracts were washed with brine and dried over anhydrous Na2SO4. After filtration, the ACS Paragon Plus Environment

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volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (silica gel, petroleum ether/ethyl acetate =10/1) to give pure 6. N-(2-((Z)-3-((Z)-benzylidene)isobenzofuran-1(3H)-ylidene)ethyl)-4-methylaniline

(6).

Yellow

solid; 85% yield (87 mg); mp 103-104 oC; 1H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.41-7.34 (m, 4H), 7.22-7.20 (m, 1H), 7.01 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 6.10 (s, 1H), 5.42 (t, J = 6.9 Hz, 1H), 4.27 (d, J = 6.9 Hz, 2H), 3.90 (s, br., 1H), 2.24 (s, 3H);

13C{1H}

NMR (125 MHz, DMSO-d6): δ 151.9, 150.9, 146.4, 135.0, 133.7, 131.8,

129.6, 129.4, 128.7, 128.3, 126.3, 124.2, 120.4, 120.2, 112.4, 99.1, 98.7, 38.9, 20.0; HRMS (ESI) calcd for C24H22NO [M+H]+: 340.1696, found 340.1693. Experimental Procedure for the TBAF-Catalyzed Tandem Reaction of 1a and 7. In air, to an oven-dried vial were added 1a (46.1 mg, 0.2 mmol), THF (2 mL), 7 (21.4 mg, 0.2 mmol) and TBAF (80 uL, 0.08 mmol, 1.0 mol/L in THF). Then, the mixture was stirred at 35 oC for 6 h. The resulting mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, petroleum ether/dichloromethane/triethylamine = 150/30/1) to give pure 4b in 83% yield (56.0 mg).

■ ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 1H

and 13C NMR spectra for new compounds (PDF)

Crystallographic details for compound 4q (CIF)

■ AUTHOR INFORMATION Corresponding Author *(Yulei Zhao) E-mail: [email protected] *(Jinmao You) E-mail: [email protected]. ACS Paragon Plus Environment

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Notes The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS We thank the Shandong Natural Science Foundation (ZR2018BB026, ZR2018JL013), the National Natural Science Foundation of China (21475075) and the Doctoral Start-Up Scientific Research Foundation of Qufu Normal University.

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Generated 1,4-Oxazepine. J. Org. Chem. 2017, 82, 9515. (c) Shen, J.; Xue, L.; Lin, X.; Cheng, G.; Cui, X. The base-promoted synthesis of multisubstituted benzo[b][1,4]oxazepines. Chem. Commun. 2016, 52, 3292. (18) (a) Zhao, Y.; Xu, M.; Zheng, Z.; Yuan, Y.; Li, Y. Tertiary amine self-catalyzed intramolecular Csp3–H functionalization with in situ generated allenes for the formation of 3-alkenyl indolines. Chem. Commun. 2017, 53, 3721. (b) Zhao, Y.; Cao, Z.-Y.; Zeng, X.-P.; Shi, J.-M.; Yu, Y.-H.; Zhou, J. Asymmetric sequential Au(I)/chiral tertiary amine catalysis: an enone-formation/cyanosilylation sequence to synthesize optically active 3-alkenyloxindoles from diazooxindoles. Chem. Commun. 2016, 52, 3943. (c) Cao, Z.-Y.; Zhao, Y.; Zhou, J. Sequential Au(I)/chiral tertiary amine catalysis: a tandem C-H functionalization of anisoles or a thiophene/asymmetric Michael addition sequence to quaternary oxindoles. Chem. Commun. 2016, 52, 2537. (d) Zhao, Y.; Yuan, Y.; Wang, X.; Li, Y. Synthesis of Polycyclic Benzo[b]indolo[3,2,1-de]acridines via Sequential Allenylation, Diels−Alder Cyclization, and Hydrogen Migration Reaction. J. Org. Chem. 2017, 82, 11198. (19) Zhang, F.; Qin, Z.; Kong, L.; Zhao, Y.; Liu, Y.; Li, Y. Metal/Benzoyl Peroxide (BPO)Controlled Chemoselective Cycloisomerization of (o‑Alkynyl)phenyl Enaminones: Synthesis of α‑Naphthylamines and Indeno[1,2‑c]pyrrolones. Org. Lett. 2016, 18, 5150. (20) CCDC 1861936 (21) (a) Ye, J.-H.; Zhu, L.; Yan, S.-S.; Miao, M.; Zhang, X.-C.; Zhou, W.-J.; Li, J.; Lan, Y.; Yu, D.-G. Radical Trifluoromethylative Dearomatization of Indoles and Furans with CO2. ACS Catal. 2017, 7, 8324. (b) Ye, J.-H.; Song, L.; Zhou, W.-J.; Ju, T.; Yin, Z.-B.; Yan, S.-S.; Zhang, Z.; Li, J.; Yu, D.-G. SelectiveOxytrifluoromethylation of Allylamineswith CO2. Angew. Chem. Int. Ed. 2016, 55, 10022. (c) Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Synthesis of 2(1H)‑Quinolinones via Pd-Catalyzed Oxidative Cyclocarbonylation of 2‑Vinylanilines. Org. Lett. 2013, 15, 1998. (22) Our previous studies on the transformation of ynone derivatives, see: (a) Z. Cao, H. Zhu, X. Meng, L. Tian, G. Chen, X. Sun, You, J. Silver-Catalyzed Domino Reaction of ortho-Carbonylated AlkynylSubstituted Arylaldehydes with Conjugated Dienes: Stereoselective Access to Indanone-Fused Cyclohexenes. J. Org. Chem. 2016, 81, 12401. (b) Cao, Z.; Zhu, H.; Meng, X.; Guan, J.; Zhang, Q.; Tian, L.; Sun, X.; Chen, G.; You, J. Metal-Free Reaction of ortho-Carbonylated Alkynyl-Substituted Arylaldehydes with Common Amines: Selective Access to Functionalized Isoindolinone and Indenamine Derivatives. Chem. - Eur. J. 2016, 22, 16979. (c) Cao, Z.; Zhu, H.; Meng, X.; Tian, L.; Sun, X.; Chen, G.; You, J. Gold-Catalyzed Reaction of ortho-Alkynylarylaldehydes with Conjugated Dienes: An Efficient Access to Highly Strained Tetracyclic Bridgehead Olefins. Chem. - Eur. J. 2016, 22, 9125. (23) Ref. (8a), (8b), (8c), (19) and Fustero, S.; Fernández, B.; Bello, P.; del Pozo, C.; Arimitsu, S.; Hammond, G. B. Intramolecular Hydroamination of Difluoropropargyl Amides: Regioselective Synthesis of Fluorinated β- and γ-Lactams. Org. Lett. 2007, 9, 4251. ACS Paragon Plus Environment

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TBAF-Catalyzed O-Nucleophilic Cyclization of Enaminones: a Process

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