Silver-Catalyzed Nucleophilic Addition of Î²-Dicarbonyls to Isocyano

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Silver-Catalyzed Nucleophilic Addition of #-Dicarbonyls to Isocyano Group: Facile Access to Indolin-3-ol Derivatives Zhongyan Hu, Lingjuan Zhang, Juanjuan Li, Wenhui Yang, Qianwen Wei, and Xianxiu Xu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03058 • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 9, 2019

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The Journal of Organic Chemistry

Silver-Catalyzed Nucleophilic Addition of -Dicarbonyls to Isocyano Group: Facile Access to Indolin-3-ol Derivatives Zhongyan Hu,† Lingjuan Zhang, ‡,* Juanjuan Li, ‡ Wenhui Yang, ‡ Qianwen Wei,† and Xianxiu Xu†,* †College

of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of

Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China. ‡School

of Chemistry & Material Science, Shanxi Normal University, Linfen, Shanxi 041004, China

ABSTRACT: A domino silver-catalyzed intermolecularly nucleophilic addition of -dicarbonyls to

isocyano group and cyclization of imidoyl silver sequence was developed for the direct and efficient synthesis of indolin-3-ol derivatives. This domino transformation tolerates a range of readily available o-acyl arylisocyanides and 1,3-dicarbonyls under operationally simple procedure. Triple roles of silver carbonate are demonstrated in this reaction: 1) activation of isocyano group, 2) formation of enolate, and 3) promotion the nucleophilic reactivity of imidoyl intermediate.

R2

R1

O O

NC

+ O

R4

Ag2CO3 (15 mol%)

R3

dioxane 80 C

R2

R1 OH O N H

R4 R3

O

 Catalytic activation of isocyano group  Functional group tolerance  Triple role of Ag2CO3  24 examples

INTRODUCTION Indolin-3-ol moiety is present in a number of bioactive natural products and synthesized molecules.1 Indolin-3-ol derivatives also serve as versatile building blocks in organic synthesis.1,2 Given the

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significance of these scaffolds, their synthesis has drawn considerable attention in recent years.3-8 In 2003, Liu and McWhorter reported an elegant work for the synthesis of 3-substituted 2-aryl-3H-indol-3-ols by the nucleophilic addition of Grignard reagents to 2-aryl-3H-indol-3-ones.3 Later, copper-catalyzed arylation of indolin-2,3-ones with arylboronic acids4 and oxidation of 2-aryltryptamine derivatives5 were well developed for the preparation of indolin-3-ol derivatives. Recently,

transition

metals

Pd,6

Au,7

or

Ag8

catalyzed

cyclization

of

1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols has been proven to be an efficient protocol for the assembly of indolin-3-ol derivatives. As versatile building blocks,9 isocyanides have recently been employed in the assembly of indolio-3-ol derivatives. In 2010, Kobayashi and co-workers reported the synthesis of indol-3-ols from the nucleophilic addition of the reactive Grignard reagents to 2-acyl arylisocyanides (Scheme 1c).10 Only 12 examples of aliphatic and aromatic magnesium bromides were used in this transformation, where the functional group tolerance is limited. In 2018, Cheng and co-workers developed a Pd-catalyzed one-pot three-component reaction of isonitriles, oxygen and N-tosylhydrazones to access 3-substituted 2-amino-3H-indol-3-ols (Scheme 1d).11 In spite of these research efforts, exploiting the direct synthetic strategy for the efficient construction of indolin-3-ols remains highly desirable. Scheme 1. Recent Protocols for the Synthesis of Indolin-3-ols.


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a) Indolin-3-ols synthesis by Au and Pd catalyzed cyclization R OH

R OH

R OH I

ArI, [Pd]

[Au], NIS ref 7

N Ts

ref 6

NHTs

Ar

N Ts

b) Indolin-3-ols synthesis by Ag catalyzed cyclization 1

R2 OH

R

AgOAc R3

NHTs

R2 OH

R1

N Ts

ref 8

R3

c) 3H-indol-3-ols synthesis by addition of isocyanides with organomagnesium R2

R1 O

R3MgBr

+

NC

R2

THF

R1 OH R3

ref 10

12 examples R3 = Me, Et, Ar

N

d) 3H-indol-3-ols synthesis by one-pot reaction of hydrazones, isonitriles, and O2 R1 NNHTs

+

NH2

R2 NC

1) PdCl2(dppe) PPh3, LiOH 2) O2

HO R1 NHR2

ref 11

N

e) This work: catalytic -addition of o-acyl arylisocyanides with 1,3-dicarbonyls R2

R1

O O +

NC

R4

Ag2CO3 (15 mol%)

R3

dioxane, 80 C

R2

O

 Catalytic activation of isocyano group  Triple role of Ag2CO3

R1 OH O N H

R4 R3

O

 Broad substrate scope  Functional group tolerance

We have devoted our efforts on isocyanide chemistry for years.12 Very recently, we employed o-acyl arylisocyanides as 1,5-dielectronphiles to react with ammonium acetate for the synthesis of quinazoline derivatives.13 In this domino process ammonia acts as a dinucleophile to react with isocyano and acyl groups, respectively. We conceived that imidoyl intermediate, generated from o-acyl arylisocyanides with a carbon nucleophile, could undego intramolecular nucleophilic addition to the o-acyl group to construct a five-membered ring,14 deliverying the highly functinalized indolin-3-ol derivatives. As our continuous interest in isocyanide chemistry,15 we herein report a facile silver-catalyzed direct nucleophilic addition of -dicarbonyls to the isocyano group of o-acyl arylisocyanides for the efficient synthesis of indolin-3-ol derivatives (Scheme 1d). This domino transformation tolerates a wide range of o-acyl arylisocyanides and various 1,3-dicarbonyles. Notably, the catalytic silver carbonate plays triple roles: 1) activation of isocyano group, 2) formation of enolate, and 3) promotion the nucleophilic reactivity of imidoyl intermediate. Among the reactivities of isocyanide, -addition plays a vital role in a large number of 3 ACS Paragon Plus Environment


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isocyanide-based reactions,9 including the well-known multicomponent Passerini16 and Ugi reactions.17 Mechanistically, these transformations are initiated by the nucleophilic reactivity of isocyanides, where isocyanides act as nucleophiles to attack the electrophiles, results the nitrilium intermediate which can further react with a nucleophile to provide the -adduct.9,16,17 Compared with the pronounced nucleophilicity, isocyanides are not reactive electrophiles.9a A few examples of reaction with highly reactive organometallic nucleophiles such as Grignard reagents,10,18 organolithiums,19 organozincs20 were documented to date. The reaction of o-alkynylaryl isocyanides with nucleophiles to generate quinolines by a tandem nucleoaddition and cyclization sequence was documented.21 Additionally, the electrophilicity of isocyanides can also be activated by Lewis acid in some insertion reactions.22 Notably, Hong’s group recently developed novel strategies to improve the electrophilicity of isocyanides by the in situ formation of more reactive formimidate23 or transient imidoyl-imidazole intermediate.24 The formal nucleophilic addition of ketones to isocyanides was realized for the preparation of enaminones. In contrast, the silver-catalyzed reaction of -dicarbonyls with o-acyl arylisocyanides (Scheme 1d) developed by our research group also represents a direct and simple protocol for the activation of isocyanides.

RESULTS AND DISCUSSION Initially,

the

reaction

between

(2-isocyanophenyl)(phenyl)methanone

1a13,25

and

5,5-dimethylcyclohexane-1,3-dione 2a was investigated by varying the metal salts, solvents and temperatures to optimize the protocol (Table 1). When substrates 1a and 2a were treated with Ag2CO3 (30 mol%) in dioxane at 80 ºC for 0.5 h, 3-phenylindolin-3-ol 3a was obtained in 78% yield (entry 1). Solvent screening revealed that 1,4-dioxane gave the higher yield of product 3a (entries 1–3). It was found that silver salts were effective for the tandem addition reaction (entries 1–6 vs entries 7 and 8). Whereas other metal salts such as CuI and CuCl were inert to the reaction in which the desired 3-phenylindolin-3-ol 3a was not detected (entries 7–8). Lower reaction temperatures were also detrimental to the production of the target product 3a (entries 9 and 10 vs entry 1). The amount of 4 ACS Paragon Plus Environment

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catalyst could be reduced to 15 mol% without decreasing the product yield (entries 11–13). We also found that the addition of base have no remarkable effect on the tandem reaction (entry 14). After screening the reaction conditions, the optimal system for this reaction involved Ag2CO3 (15 mol%) in 1,4-dioxane at 80 °C (Table 1, entry 12).

Table 1. Optimization of the Reaction Conditionsa O

O

HO PhO Cat. Sol.

Ph

time, 80 C

NC

O 2a

1a

entry

N H

O 3a

catalyst (mol %)

solvent

time (min)

Yield of 3a (%)b

1

Ag2CO3 (30)

dioxane

20

78

2

Ag2CO3 (30)

CH3CN

20

47

3

Ag2CO3 (30)

EtOH

40

45

4

Ag(TFA) (30)

dioxane

90

24

5

AgF (30)

dioxane

30

35

6

AgNO3 (30)

dioxane

60

41

7

CuI (30)

dioxane

30

0

8

CuCl (30)

dioxane

30

0

9c

Ag2CO3 (30)

dioxane

60

61

10d

Ag2CO3 (30)

dioxane

40

65

11

Ag2CO3 (20)

dioxane

30

85

12

Ag2CO3 (15)

dioxane

30

85

13

Ag2CO3 (10)

dioxane

30

60



14e

Ag2CO3 (15)

dioxane

15

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82

aReaction bIsolated

conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst, solvent (2 mL), air atmosphere. yields. cAt 40 ºC. dAt 60 ºC. eLi2CO3 (30 mol%) was added.

With the optimal conditions in hand, the scope of substrates with regard to different acyl arylisocyanide 1 was first explored to evaluate the generality and limitation of the tandem reaction (Scheme 2). Satisfyingly, the reaction of 2-acyl arylisocyanides 1 bearing various substitutes at 3-, 4-, 5- and 6-position of benzene ring (1b–k), performed well to give the desired indolin-3-ols 3a–k in good yields. Additionally, the R1 group of isocyanides 1 was tolerated both electron-rich and -poor aryl group (3l and 3m), whereas, 2-acyl arylisocyanides 1 with aliphatic R1 groups also gave the 3-alkyl substituted indolin-3-ols 3n–p albeit with slight lower yields. It is worth mentioning that halogen functionality is tolerated in this reaction (3b–e, 3g–i and 3k), which could be used as a handle for further modification. Furthermore, 1 mmol scale synthesis of indolin-3-ol 3a was carried out, obtaining 3a in comparably high yield (83%). Scheme 2. Scope of 2-Acyl Arylisocyanides 1.a,b


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O

HO R1 O

O Ag2CO3 (15 mol%)

1

R

R2

+

NC

1,4-dioxane, 80 °C

Cl HO PhO

N H

N H 3d, 80%

O 3c, 81%

HO PhO

F

N H 3e, 81%

Me

N H

Cl

O

3h, 70%

HO PhO N H

O 3f, 78%

O

HO PhO

HO PhO

HO PhO N H

O 3b, 75%

O

N H O 3g, 74%

Br

N H

O 3a, 85% (83%)c HO PhO

O

3

2a

HO PhO

Br

N H

O

1

Cl

R2

HO PhO F

N H O 3i, 78%

HO PhO

HO PhO

OH O N H

Me

3j, 76%

O

Cl

N H

O

3k, 79%

N H 3l, 60% O

Cl R OH O OHO N H

O 3m, 67% a1

N H

O 3n, R = Me, 41% 3o, R = n-Bu, 42%

OH O N H

O

3p, 43%

(0.3 mmol), 2 (0.6 mmol) and Ag2CO3 (15 mol%) in 1,4-dioxane (2 mL) at 80 ºC for 30 min. yields. c1 mmol scale synthesis (288 mg 3a was obtained).

bIsolated

Then the scope of 1,3-dicarbonyl compounds 2 was further explored. As depicted in Scheme 3, various 1,3-dicarbonyls were tolerated in this reaction, including cyclo-1,3-dione 2b, acetoacetone 2c, 3,5-heptanedione 2d, dibenzoylmethane 2e, acetoacetate 2f, dimethyl malonate 2g, Meldrum's acid 2h and dimethyl barbituric acid 2i, and the corresponding indolin-3-ols 3q–x were obtained in good to high yields. In the case of indolin-3-ol 3u, a mixture of two isomers (ratio is 4:1) was obtained in a high combined yield. The structrure of 3w was confirmed by single-crystal X-ray diffraction analysis.26 Scheme 3. Scope of 1,3-Dicarbonyl Compounds 2a,b



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O

HO Ph O Ph

O

O

+

Ag2CO3 (15 mol%) N H

1,4-dioxane, 80 °C

NC 1a HO PhO

HO PhO

N H

N H

HO PhO

N H

O 3q, 85%

N H

O 3r, 70%

HO PhO

HO PhO

Ph Ph

N H

OMe OMe

O

3v, 63% HO PhO

O

N H

Et

HO PhO

OEt

O 3u (4:1), 79%

3t, 54%

Et

O 3s, 71%

N H

O

HO PhO

O 3

2

N O

N H

O

O 3w, 81%

3w (CCDC 1866731)

N O

3x, 80%

a1a

(0.3 mmol), 2 (0.6 mmol) and Ag2CO3 (15 mol%) in 1,4-dioxane (2 mL) at 80 ºC for 30 min. bIsolated yields.

To gain insight into the mechanism of the tandem α-addition process, control experiments were performed (Scheme 4). When 2.0 equiv of TEMPO was added to the standard reaction, 3a was obtained in 82% yield (Scheme 4, eq 1). This result indicated that this domino process probably does not proceed via a radical pathway. Moreover, the reaction between 1a and 2a was performed under the standard conditions at an N2 atmosphere, 3a was obtained in comparable yield (Scheme 4, eq 2). This result shown that adventitious H2O or O2 are not involved in the Ag-catalyzed nucleophilic addition process. Scheme 4. Control Experiments O

O

O

Ph + 1a

Ph OH O Ag2CO3 (15mol%) 1,4-dioxane, 80°C

NC

TEMPO (2.0 equiv) 81%

2a

(1) N H

3a

O

Ph OH O

O

O Ph

NC 1a

O

+ 2a

Ag2CO3 (15mol%) 1,4-dioxane, 80°C N2, 82%

(2) N H

O 3a


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On the basis of above experiment results and related literature precedents,14,25,27,28 a plausible reaction mechanism is proposed in Scheme 5 (exemplified by the generation of 3a). The coordination of Ag2CO3 to o-acyl arylisocyanide 1a forms a silver complex I with the enhanced reactivity of isocyano group.14,25,27 Meanwhile, Ag2CO3 coordinates to dicarbonyl 2a, followed by the abstraction of a proton, to generate the nucleophilic enolate silver complex II.28 Nucleophilic addition of the intermediate II to complex I produces the imidoyl silver intermediate III.14,25 Then cyclization of imidoyl silver III by the nucleophilic addition to the acyl group generates the intermediate IV,12a, 14, 25 which is protonated to regenerate the catalyst Ag2CO3 and simultaneously affords the final product 3a. From the whole process, it can be concluded that silver carbonate plays a triple role: 1) activation of isocyano group by coordination; 2) generation of the nucleophilic enolate by deprotonation of 1,3-dicarbonyls; and 3) formation of the reactive imidoyl silver intermediate that facilitates the intramolecular cyclization. Scheme 5. Plausible Reaction Mechanism. O

O

Ag2CO3

NC 1a O

N

AgCO3-

Ag O

O Ag

AgCO3-

Ag

I

Ag2CO3

O

Ph

Ph

Ph

N Ag2CO3

O

O

O III

AgHCO3

2a

II Ag Ph O O N IV

O

AgHCO3

HO PhO N

Ag2CO3

O V

1,3-H shift

HO PhO N H 3a

O

CONCLUSION In summary, a facile silver-catalyzed direct nucleophilic addition of -dicarbonyls to the isocyano group of o-acyl arylisocyanides has been successfully developed for the efficient synthesis of indolin-3-ol derivatives. This domino transformation was initiated by the nucleophilic addition of



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enolate to the Ag-activated isocyanide group, which tolerates a wide range of o-acyl arylisocyanides and various cyclic and linear 1,3-dicarbonyles. Notably, silver carbonate plays a triple role in this domino reaction, activation of isocyano group and generation of enolate as well as formation and transformation of the reactive imidoyl silver intermediate.

EXPERIMENTAL

SECTION

General Information. All reagents were purchased from commercial sources and used without further purification, unless otherwise indicated. All reactions were monitored by TLC, which was performed on precoated aluminum sheets of silica gel 60 (F254). The products were purified by flash column chromatography on silica gel (300−400 mesh). Melting points were uncorrected. 1H NMR and 13C{1H}

NMR spectra were recorded at 25 ºC on a Varian 400 MHz and 100 MHz, respectively, and

TMS as the internal standard. All chemical shifts are given in ppm. High-resolution mass spectra (HRMS) were obtained using a microTOF II focus spectrometer (ESI). The starting materials o-acyl arylisocyanides 1a-p were prepared according literatures13,24.

General procedure for the synthesis of 3 (taking 3a as an example). To a mixture of (2-isocyanophenyl)(phenyl)methanone 1a (62.1 mg, 0.3 mmol) and 5,5-dimethylcyclohexane-1,3-dione 2a (84.1 mg, 0.6 mmol) in 1,4-dioxane (2 mL) at 80 ºC was added Ag2CO3 (12.4 mg, 0.045 mmol). After the reaction was finished as indicated by TLC (reaction time, 20 min), the resulting mixture was poured into water (10 mL) and extracted with DCM (CH2Cl2, 10 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the crude product with flash column chromatography (petroleum ether : EtOAc = 12 : 1) to give 3a (88.5 mg, 85%).


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2-(3-Hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3a). Pale yellow solid. 88.5 mg, 85% yield (0.3 mmol scale); 288 mg, 83% yield (1 mmol scale). m.p. 155-157 oC. 1H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.03 (s, 3H), 2.20-2.29 (m, 2H), 2.50 (s, 2H), 7.07-7.12 (m, 2H), 7.21-7.26 (m, 5H), 7.40 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 1.2 Hz, 1H), 13.69 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 27.8, 28.3, 30.5, 51.9, 51.9, 85.4, 107.0, 112.6, 123.5, 124.5, 125.9, 127.6, 128.2, 129.3, 136.2, 139.6, 140.5, 177.0, 198.5, 200.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H21NNaO3 ([M+Na]+) 370.1414, Found 370.1425. 2-(4-Chloro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3b). Pale yellow solid. 85.6 mg, 75% yield. m.p. 172-175 oC. 1H NMR (CDCl3, 400 MHz) δ 0.80 (s, 3H), 0.93 (s, 3H), 2.08-2.18 (m, 2H), 2.37 (s, 2H), 6.93-6.96 (m, 2H), 7.13-7.18 (m, 4H), 7.34 (d, J = 7.2 Hz, 2H), 8.14 (s, 1H), 13.64 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 27.7, 28.3, 30.4, 51.9,

52.0, 86.4, 106.9, 110.9, 125.4, 127.1, 127.4, 127.7, 130.8, 131.9, 132.8, 136.8, 141.8, 177.3, 198.5, 200.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20ClNNaO3 ([M+Na]+) 404.1024, Found 404.1033. 2-(5-Bromo-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3c).

Pale yellow solid. 103.3 mg, 81% yield. m.p. 204-206 oC. 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 3H), 1.02 (s, 3H), 2.19-2.28 (m, 2H), 2.49 (s, 2H), 6.97 (d, J = 8.0 Hz, 1H), 7.23-7.30 (m, 3H), 7.35-7.39 (m, 4H), 7.97 (s, 1H), 13.66 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 27.8, 28.3, 30.4, 51.9, 51.9, 85.3, 107.2, 113.8, 118.8, 123.5, 127.9, 127.9, 128.4, 132.3, 138.2, 138.7, 139.9, 176.5, 198.5, 200.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20BrNNaO3 ([M+Na]+) 448.0519, Found 448.0524. 2-(5-Chloro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3d).

Pale yellow solid. 91.5 mg, 80% yield. m.p.161-163 oC. 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 3H), 1.02 (s, 3H), 2.19-2.28 (m, 2H), 2.49 (s, 2H), 7.02 (d, J = 8.8 Hz, 1H), 7.20-7.29 (m, 5H), 7.38 (d, J = 7.2 Hz, 2H), 7.98 (s, 1H), 13.67 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 27.8, 28.3, 30.4, 51.9,

51.9, 85.3, 107.2, 113.4, 123.5, 125.1, 127.9, 128.4, 129.4, 131.3, 137.9, 138.2, 139.9, 176.7, 198.5, 200.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20ClNNaO3 ([M+Na]+) 404.1024, 11 ACS Paragon Plus Environment


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Found 404.1034. 2-(5-Fluoro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3e).

Pale yellow solid. 88.7 mg, 81% yield. m.p.161-163 oC. 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 3H), 1.02 (s, 3H), 2.19-2.29 (m, 2H), 2.49 (s, 2H), 6.92-6.97 (m, 2H), 7.06 (dd, J = 8.4 Hz, J = 4.0 Hz, 1H), 7.21-7.29 (m, 3H), 7.37-7.39 (m, 2H), 8.04 (s, 1H), 13.72 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 27.8, 28.3, 30.5, 51.9, 51.9, 85.4 (d, J = 2.1 Hz), 107.1, 112.5 (d, J = 25.5 Hz), 113.4 (d, J = 8.5 Hz), 115.9 (d, J = 25.5 Hz), 123.5, 127.9, 128.4, 135.5 (d, J = 2.2 Hz), 138.3 (d, J = 8.5 Hz), 140.0, 159.8 (d, J = 244.6 Hz), 173.2 (d, J = 1.8 Hz), 198.5, 200.5. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20FNNaO3 ([M+Na]+) 388.1319, Found 388.1314. 2-(3-Hydroxy-3-(p-tolyl)indolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3f). Pale yellow solid. 84.5 mg, 78% yield. m.p. 155-157 oC. 1H NMR (CDCl3, 400 MHz) δ 0.95 (s, 3H), 1.02 (s, 3H), 2.18-2.28 (m, 5H), 2.45 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.19-7.28 (m, 3H), 7.37-7.40 (m, 2H), 8.04 (s, 1H), 13.69 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 21.1, 27.8, 28.3,

30.5, 51.9, 51.9, 85.4, 106.8, 112.3, 123.6, 125.2, 127.5, 128.2, 136.0, 136.4, 137.2, 140.7, 176.8, 198.3, 200.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C23H23NNaO3 ([M+Na]+) 384.1570, Found 384.1581. 2-(6-Bromo-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3g).

Pale yellow solid. 94.3 mg, 74% yield. m.p.196-198 oC. 1H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.02 (s, 3H), 2.20-2.29 (m, 2H), 2.50 (s, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.20-7.29 (m, 5H), 7.35-7.38 (m, 2H), 7.90 (d, J = 0.8 Hz, 1H), 13.62 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 27.9, 28.3, 30.5, 52.0, 52.0, 85.1, 99.9, 107.4, 115.9, 122.7, 123.5, 125.9, 127.9, 128.4, 128.7, 135.2, 140.1, 141.0, 177.1, 198.7, 200.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20BrNNaO3 ([M+Na]+) 448.0519, Found 448.0528. 2-(6-Chloro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3h).

Pale yellow solid. 80.0 mg, 70% yield. m.p. 196-198 oC. 1H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.02 (s, 3H), 2.20-2.29 (m, 2H), 2.50 (s, 2H), 7.05 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.20-7.29 (m,3H), 7.35-7.38 (m, 2H), 7.91 (s, 1H), 13.62 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 28.5, 30.9, 51.5, 51.6, 110.7, 117.4, 124.3, 128.3, 130.2, 133.1, 134.4, 137.4, 140.1, 141.4, 148.4, 195.7, 196.9, 199.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20ClNNaO3 ([M+Na]+) 404.1024, Found 404.1036. 2-(6-Fluoro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3i). Pale yellow solid. 85.4 mg, 78% yield. m.p.161-163 oC. 1H NMR (CDCl3, 400 MHz) δ 0.96 (s, 3H), 1.03 (s, 3H), 2.20-2.29 (m, 2H), 2.50 (s, 2H), 6.75 (t, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.16 (dd, J = 13.2 Hz, J = 5.2 Hz, 1H), 7.20-7.28 (m, 3H), 7.37 (d, J = 7.6 Hz, 2H), 7.90 (s, 1H), 13.62 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 27.9, 28.3, 30.5, 52.0, 52.0, 84.9, 100.8 (d, J = 27.4 Hz),


Page 13 of 23 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


107.4, 112.2 (d, J = 22.8 Hz), 123.5, 125.7 (d, J = 9.8 Hz), 127.7, 128.3, 131.8 (d, J = 2.9 Hz), 140.4, 140.9 (d, J = 11.8 Hz), 162.1 (d, J = 246.0 Hz), 177.7, 198.7, 200.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20FNNaO3 ([M+Na]+) 388.1319, Found 388.1308. 2-(3-Hydroxy-6-methyl-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3j). Pale yellow solid. 82.3 mg, 76% yield. m.p. 196-198 oC. 1H NMR (CDCl3, 400 MHz) δ 0.94 (s, 3H), 1.01 (s, 3H), 2.18 (d, J = 16.8 Hz, 1H), 2.23 (d, J = 16.8 Hz, 1H), 2.32 (s, 3H), 2.48 (s, 2H), 6.88 (d, J = 7.6 Hz, 1H) 6.92 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.19-7.26 (m, 3H), 7.38 (d, J = 8.4 Hz, 2H), 7.98 (s, 1H), 13.62 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 21.4, 27.8, 28.3, 30.5, 51.9, 52.0, 85.3, 107.0, 113.2, 123.5, 124.2, 126.6, 127.5, 128.2, 133.5, 139.7, 139.8, 140.8, 177.3, 198.4, 200.5. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C23H23NNaO3 ([M+Na]+) 384.1570, Found 384.1564. 2-(7-Chloro-3-hydroxy-3-phenylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3k).

Pale yellow solid. 90.3 mg, 79% yield. m.p. 165-167 oC. 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 3H), 0.95 (s, 3H), 2.14-2.21 (m, 2H), 2.43 (s, 2H), 6.93 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 7.13-7.20 (m, 4H), 7.30 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 13.65 (s, 1H).

13C{1H}

NMR (CDCl3, 100

MHz) δ 27.9, 28.2, 30.5, 52.0, 52.1, 86.4, 107.7, 117.7, 122.8, 123.6, 126.7, 127.8, 128.4, 129.2, 137.6, 137.8, 140.1, 176.3, 198.7, 200.6. HRMS (ESI-TOF) (m/z): Calcd for C22H20ClNNaO3 ([M+Na]+) 404.1024, Found 404.1012. 2-(3-Hydroxy-3-(p-tolyl)indolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3l). Pale yellow solid. 76.0 mg, 60% yield. m.p. 155-157 oC. 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.03 (s, 3H), 2.26 (s, 2H), 2.27 (s, 3H), 2.49 (s, 2H), 7.04-7.10 (m, 4H), 7.24-7.29 (m, 4H), 7.96 (s, 1H), 13.68 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 21.0, 27.9, 28.3, 30.5, 52.0, 52.0, 85.4, 107.0, 112.5, 123.4, 124.4, 125.9, 129.0, 129.2, 136.5, 137.2, 137.6, 139.5, 177.2, 198.5, 200.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C23H23NNaO3 ([M+Na]+) 384.1570, Found 384.1583. 2-(3-(4-Chlorophenyl)-3-hydroxyindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione

(3m).

Pale yellow solid. 76.6 mg, 67% yield. m.p. 155-157 oC. 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 3H), 1.03 (s, 3H), 2.22-2.31 (m, 2H), 2.50 (s, 2H), 7.08-7.12 (m, 2H), 7.20-7.29 (m, 4H), 7.31-7.34 (m, 2H), 7.99 (s, 1H), 13.67 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 27.9, 28.2, 30.5, 51.9, 52.0, 85.1, 106.9, 112.7, 124.5, 125.1, 126.0, 128.5, 129.6, 133.4, 135.8, 139.3, 139.6, 176.4, 198.6, 200.6. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C22H20ClNNaO3 ([M+Na]+) 404.1024, Found 404.1016. 2-(3-Hydroxy-3-methylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3n). Pale yellow solid. 35.1 mg, 41% yield. m.p. 146-148 oC. 1H NMR (CDCl3, 400 MHz) δ 1.08 (s, 3H), 1.12 (s, 3H), 1.69 (s, 3H), 2.44-2.58 (m, 4H), 7.08 (d, J = 8.0 Hz, 1H), 7.20-7.24 (m, 1H), 7.28-7.32 (m, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 13.68 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 24.8, 27.9, 28.2, 30.4,



Page 14 of 23

51.9, 52.7, 82.1, 106.7, 112.5, 123.1, 125.7, 129.2, 136.2, 139.5, 177.7, 199.3, 200.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C17H19NNaO3 ([M+Na]+) 308.1257, Found 308.1254 2-(3-Hydroxy-3-propylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3o). Pale yellow solid. 39.5 mg, 42% yield. m.p. 146-148 oC. 1H NMR (CDCl3, 400 MHz) δ 0.77 (t, J = 7.2 Hz, 3H), 0.94-1.04 (m, 2H), 1.08 (s, 3H), 1.12 (s, 3H), 2.02-2.10 (m, 2H), 2.43-2.57 (m, 4H), 7.06 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.27-7.33 (m, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 13.74 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 13.9, 16.9, 28.0, 28.2, 30.5, 40.0, 52.0, 52.7, 85.3, 107.1 112.4, 123.8, 125.6, 129.3, 134.7, 140.4, 177.8, 199.4, 200.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C19H23NNaO3 ([M+Na]+) 336.1570, Found 336.1568. 2-(3-Hydroxy-3-propylindolin-2-ylidene)-5,5-dimethylcyclohexane-1,3-dione (3p). Pale yellow solid. 39.5 mg, 42% yield. m.p. 146-148 oC. 1H NMR (CDCl3, 400 MHz) δ 0.36 (d, J = 6.8 Hz, 3H), 1.06 (s, 3H), 1.09 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 2.46-2.54 (m, 5H), 7.06 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 13.84 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 15.7, 16.8, 27.9, 28.2, 30.4, 33.8, 52.0, 52.7, 88.5, 107.1

112.4, 125.1, 125.2, 129.3, 132.0, 141.1, 178.8, 199.5, 200.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C19H23NNaO3 ([M+Na]+) 336.1570, Found 336.1571. 2-(3-Hydroxy-3-phenylindolin-2-ylidene)cyclohexane-1,3-dione (3q). Pale yellow solid. 81.4 mg, 85% yield. m.p. 155-157 oC. 1H NMR (CDCl3, 400 MHz) δ 1.85-1.93 (m, 2H), 2.35-2.93 (m, 2H), 2.57-2.66 (m, 2H), 7.06-7.12 (m, 2H), 7.21-7.28 (m, 5H), 7.38-7.40 (m, 2H), 8.03 (s, 1H), 13.78 (s, 1H). 13C{1H}

NMR (CDCl3, 100 MHz) δ 19.0, 38.3, 38.4, 85.6, 108.0, 112.6, 123.6, 124.6, 126.0, 127.6,

128.3, 129.4, 136.4, 139.6, 140.5, 177.6, 199.0, 201.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C20H17NNaO3 ([M+Na]+) 342.1101, Found 342.1096. 3-(3-Hydroxy-3-phenylindolin-2-ylidene)pentane-2,4-dione (3r). Pale yellow solid. 64.5 mg, 70% yield. m.p. 177-179 oC. 1H NMR (CDCl3, 400 MHz) δ 2.00 (s, 3H), 2.36 (s, 3H), 6.57 (s, 1H), 7.00-7.06 (m, 2H), 7.13(d, J = 7.2 Hz, 1H), 7.20-7.29 (m, 4H), 7.33-7.35 (m, 2H), 12.56 (s, 1H). 13C{1H}

NMR (CDCl3, 100 MHz) δ 30.4, 31.5, 84.6, 111.6, 113.7, 124.4, 124.5, 127.6, 128.1, 129.4,

135.5, 140.3, 140.5, 172.5, 197.1, 203.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C19H17NNaO3 ([M+Na]+) 330.1101, Found 330.1102. 3-(3-Hydroxy-3-phenylindolin-2-ylidene)heptane-3,5-dione (3s). Pale yellow solid. 64.5 mg, 70% yield. m.p. 181-183 oC. 1H NMR (CDCl3, 400 MHz) δ 0.58 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H), 1.89-1.99 (m, 1H), 2.42-2.63 (m, 3H), 6.54 (s, 1H), 6.97-7.02 (m, 2H), 7.10-7.12 (m, 1H), 7.18-7.27 (m, 4H), 7.33 (d, J = 7.2 Hz, 2H), 12.35 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 8.8, 9.7, 35.2, 37.6, 84.3, 111.3, 112.9, 124.2, 124.4, 124.6, 127.6, 128.0, 129.4, 135.4, 140.2, 140.7, 171.3, 200.8, 208.0. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C21H21NNaO3 ([M+Na]+) 358.1414, Found 358.1417.


Page 15 of 23 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


2-(3-Hydroxy-3-phenylindolin-2-ylidene)-1,3-diphenylpropane-1,3-dione (3t). Pale yellow solid. 69.8 mg, 54% yield. m.p. 207–209 oC. 1H NMR (CDCl3, 400 MHz) δ 6.92-6.99 (m, 3H), 7.03-7.13 (m, 8H), 7.21-7.29 (m, 5H), 7.34 (d, J =7.2 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H), 12.34 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 84.8, 109.5, 111.6, 124.1, 124.6, 127.4, 127.6, 127.8, 127.9, 128.1, 128.8, 129.4, 130.8, 131.7, 135.7, 139.8, 140.4, 140.5, 141.6, 174.3, 196.4, 198.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C29H21NO3 ([M+Na]+) 454.1414, Found 454.1398. (E)/(Z)-Ethyl 2-(3-hydroxy-3-phenylindolin-2-ylidene)-3-oxobutanoate (3u). Pale yellow solid. 79.9 mg, 79% yield. 1H NMR (CDCl3, 400 MHz) δ 0.93 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 0.69H), 2.07 (s, 0.68H), 2.37 (s, 3H), 3.84-3.92 (m, 2H), 4.24-4.37 (m, 0.46H), 6.78 (s, 1H), 6.92-7.00 (m, 2.46H), 7.12-7.22 (m, 4.12H), 7.24-7.28 (m, 2.41H), 7.37-7.41 (m, 2.52H), 11.23 (s, 0.2H), 12.77 (s, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ 13.5, 14.0, 30.3, 31.0, 60.5, 61.0, 84.4, 84.6, 102.3, 102.6,

110.9, 111.3, 123.8, 124.0, 124.1, 124.1, 124.3, 124.3, 127.3, 127.4, 127.9, 128.0, 129.1, 129.2, 134.8, 135.2, 140.1, 140.4, 140.8, 169.0, 169.7, 173.0, 174.0, 197.9, 201.4. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C20H19NNaO4 ([M+Na]+) 360.1206, Found 360.1207. Dimethyl 2-(3-hydroxy-3-phenylindolin-2-ylidene)malonate (3v). Pale yellow solid. 64.1 mg, 63% yield. m.p. 180-183 oC. 1H NMR (CDCl3, 400 MHz) δ 3.32 (s, 3H), 3.78 (s, 3H), 6.52 (s, 1H), 6.91-6.95 (m, 2H), 7.13-7.26 (m, 5H), 7.40-7.42 (m, 2H), 10.89 (s, 1H).

13C{1H}

NMR (CDCl3, 100

MHz) δ 51.6, 52.0, 84.1, 92.7, 110.5, 123.4, 124.3, 124.5, 127.4, 128.0, 129.3, 134.3, 140.6, 141.0, 168.7, 169.0, 172.3. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C19H17NNaO5 ([M+Na]+) 362.0999, Found 362.1000. 5-(3-Hydroxy-3-phenylindolin-2-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3w). Pale yellow solid. 85.3 mg, 81% yield. m.p. 199-201 oC. 1H NMR (CDCl3, 400 MHz) δ 1.51 (s, 3H), 1.67 (s, 3H), 7.10 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.24-7.31 (m, 5H), 7.40-7.41 (m, 3H), 11.92 (s, 1H). 13C{1H}

NMR (CDCl3, 100 MHz) δ 25.5, 27.1, 85.0, 85.1, 104.3, 112.4, 123.7, 124.6, 125.9, 128.0,

128.4, 129.6, 135.7, 139.2, 140.0, 164.0, 166.2, 177.8. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C20H17NNaO5 ([M+Na]+) 374.0999, Found 374.0987. 5-(3-Hydroxy-3-phenylindolin-2-ylidene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

(3x).

Pale yellow solid. 86.9 mg, 80% yield. m.p. 197-199 oC. 1H NMR (CDCl3, 400 MHz) δ 3.17 (s, 3H), 3.39 (s, 3H), 7.11 (d, J = 6.8 Hz, 2H), 7.25-7.30 (m, 5H), 7.43 (d, J = 7.2 Hz, 2H), 7.76 (s, 1H), 13.04 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ 28.0, 28.2, 86.0, 90.7, 112.4, 123.4, 124.6, 125.9, 127.7, 128.5, 129.5, 136.2, 139.1, 140.6, 151.0, 163.1, 165.6, 177.9. Mass Spectrometry: HRMS (ESI-TOF) (m/z): Calcd for C20H17N3NaO4 ([M+Na]+) 386.1111, Found 386.1105.

ASSOCIATED CONTENT Supporting Information.



Page 16 of 23

The Supporting Information is available free of charge on the ACS Publications website.

Copies of NMR spectra of compounds 3 and crystal data of compound 3w (PDF)

X-ray structure and data of compound 3w (CIF)

AUTHOR INFORMATION Corresponding Author E-Mail: [email protected] E-Mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS Financial support of this research provided by the NNSFC (21672034) is greatly acknowledged.

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Synthesis

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(E)-2-Arylmethylidene-N-tosylindolines

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(E)-2-Arylmethylidene-N-tosyl/nosyltetrahydroquinolines: Access to 2-Substituted Indoles and Quinolines. J. Org. Chem. 2012, 77, 5108.



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(7) Kothandaraman, P.; Mothe, S. R.; Toh, S. S. M.; Chan, P. W. H. Gold-Catalyzed Cycloisomerizations of 1-(2-(Tosylamino)phenyl)prop-2-yn-1-ols to 1H-Indole-2-carbaldehydes and (E)-2-(Iodomethylene)indolin-3-ols. J. Org. Chem. 2011, 76, 7633. (8) Susanti, D.; Koh, F.; Kusuma, J. A.; Kothandaraman, P.; Chan, P. W. H. Silver Acetate Catalyzed

Hydroamination

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Silver-Catalyzed Nucleophilic Addition of Î²-Dicarbonyls to Isocyano

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