Synthesis of 3-(Organochalcogen) Chalcogenazolo Indoles via

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Synthesis of 3-(Organochalcogen) Chalcogenazolo Indoles via Cascade Cyclization of N-alkynylindoles Thaís Prochnow, Adriano Maroneze, Davi Fernando Back, and Gilson Zeni J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00052 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 4, 2019

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The Journal of Organic Chemistry

Synthesis of 3-(Organochalcogen) Chalcogenazolo Indoles via Cascade Cyclization of N-alkynylindoles Thaís Prochnow,† Adriano Maroneze,† Davi Fernando Back‡ and Gilson Zeni†,* †Laboratório

de Síntese, Reatividade, Avaliação Farmacológica e Toxicológica

de Organocalcogênios and

‡Laboratório

de Materiais Inorgânicos, CCNE,

UFSM, Santa Maria, Rio Grande do Sul, 97105-900, Brazil *E-mail:

[email protected]

Abstract A

transition

metal-free

one-pot,

three-steps

protocol

combining

N-

alkynylindoles, n-butyllithium, elemental selenium and an electrophile source was developed to allow the synthesis of 3-(organoselanyl) selenazolo indoles. Substrate scope was studied by varying the structure of N-alkynylindoles and the electrophile source. This sequential reaction proceeded selectively through an initial intramolecular 5-endo-dig mode with two new carbon-selenium bonds formation in a one-pot procedure. The reaction conditions were also compatible with elemental sulfur and tellurium, which led to construct 3-(alkylthio) thiazolo indoles and 3-(alkyltelluro) tellurazolo indoles, respectively. In addition, it was also

demonstrated

that

a

series

of

dichalcogenides

derived

from

1

ACS Paragon Plus Environment

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

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chalcogenazoloindoles ring could be easily prepared via oxidation of chalcogenolate anion in contact with air. Keywords: cyclization, heterocycles, selenides, indoles, selenazoles. Introduction In the recent years, the environmental issues and costs have encouraged the chemists to study alternatives to develop new synthetic methodologies using transition metal-free conditions. Transition metal-free protocols are one of the most interesting tools for the development of innovative synthetic methods of heterocycles.1 Although heterocycles can be efficiently produced using transition-metal catalyzed cyclization reactions,2 much effort has been devoted to the development of cyclization reactions under absence of these catalysts. Among these various methods, the cyclization of either saturated or unsaturated substrates using base- or acid-catalyzed reactions,3 carbon-hydrogen bond activation,4 radical5 and electrophilic cyclization reactions,6 electrochemical processes,7 the use of ionic liquids as solvents8 and microwave irradiated reactions9 are the most straightforward approaches. These approaches are also efficient routes to functionalized indoles.10 Indoles are studied for more than one hundred years because the impressive number of the therapeutic properties over wide range of targets11 and because they are useful as synthetic intermediaries for commercially accessible materials.12 Although, the synthesis of 2-organoselanyl indoles is described,13 their reaction as precursors for the preparation of indole-fused selenium-heterocycle compounds has not been reported.

Selenium-heterocycle compounds are a source of interesting

biological properties including antibacterial,14 anti-apoptotic,15 anti-tumoral,16 2


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hepatoprotective,17 anticonvulsant, antioxidant,18 antinociceptive and antiallodynic.19 The wide range of application of indoles and selenium-heterocycles prompted us to join these two structures in a three-steps one-pot, transition metal-free cyclization for the synthesis of 3-(alkylselanyl) selenazolo indoles 2. To achieve this goal, we postulated that 2-indolylselenolate anion could be generated by the abstraction of hydrogen acid at the C2 position via metalation of N-alkynylindoles 1, followed by the addition of two equivalents of elemental selenium. The hydroselenation of carbon-carbon of the alkyne could lead to 3(organoselanyl) selenazolo indoles 2 via trapping of second selenolate anion with an electrophile source (Scheme 1). 1. n-BuLi

R1

2. Se(0)

N

R1

SeLi Se(0) N

R1 N

1

LiSe R2

Se R2

R3Br

R1 N 2

R3Se

Se R2

R2

Scheme 1 Results and Discussion The starting N-alkynylindoles 1 were readily available by using the coppercatalyzed coupling reaction between indoles with haloalkynes.20 Following our knowledge that lithium anions react easily with elemental selenium to form selenolates, which can reduce triple bonds via hydroselenation,21 the lithiation of N-alkynylindole 1a (0.5 mmol) was initially carried out by the addition of nbutyllithium (1.2 equiv) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental selenium (2.0 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After that, the mixture was 3



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warmed to 0 ºC to the addition of 1-bromobutane (1.0 equiv) and the reaction was continued for 1 h. Following this reaction condition, the 3-(butylselanyl) selenazolo indole 2a was obtained together with the starting material 1a. The purification by flash column chromatography led to 57% yields of the product 2a (Table 1, entry 1). The recovering of the starting material indicated that the reaction could require a greater amount of elemental selenium.

When we

increased the amount of elemental selenium to 2.5 equiv, the yield of the reaction increased to 62% (Table 1, entry 2). In the latter condition, the starting material was still recovered.

Thus, the further increase of amount of n-

butyllithium to 1.3 equiv led to good yield of 2a (Table 1, entry 3); however, the use of 1.5 equiv did not improve the reaction results (Table 1, entry 4). Next, we investigated the amount of 1-bromobutane by using 1.5 equiv; however, it did not provide any improvement in the yield (Table 1, entries 5). We then tried to study the influence of temperature on the reaction conditions. For these purposes, we changed the temperature of the n-butyllithium and elemental selenium addition to 0 0C and the final temperature of the reaction to 65 0C; however, these changes did not increase the yield of 2a (Table 1, entries 6-8). These findings in the optimization study indicated that the best yield of 3(butylselanyl) selenazolo indole 2a was obtained when N-alkynylindole 1a (0.5 mmol) was treated with n-BuLi (1.3 equiv) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental selenium (2.5 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. The mixture was warmed to 0 ºC to the addition of 1-bromobutane (1.1 equiv) and the reaction was continued for 1 h at room temperature (Table 1, entry 3). 4


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Table 1. Effect of different reaction parameters on the preparation of 3(butylselanyl) selenazolo indole 2a.a 1. n-BuLi

R1

2. Se(0)

N

R1

SeLi Se(0) N

N

1

LiSe

a

Se

n-BuBr R1

R2

N 2 n-BuSe

Se R2

R2

R2

entry

R1

n-BuLi (equiv)

Se(0) (equiv)

n-BuBr (equiv)

2a yield (%)b

1

1.2

2.0

1.1

57

2

1.2

2.5

1.1

62

3

1.3

2.5

1.1

71

4

1.5

2.5

1.1

23

5

1.3

2.5

1.5

70

6

1.3

2.5

1.1

56c

7

1.3

2.5

1.1

48d

8

1.3

2.5

1.1

30e

The reaction was performed by the addition of n-butyllithium to a solution of N-

alkynylindole 1a (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental selenium was added at -78 °C and allowed to react at room temperature over 1 h. After the mixture was warmed to 0 ºC and 1-bromobutane was added and the reaction was continued for 1 h at room temperature. 5



b

Yields were determined for purified products after column chromatography.

c

The n-butyllithium and elemental selenium were added at 0 0C.

d

The 1-bromobutane was added at -78 °C.

e

The reaction was kept at 65 °C for 1h after the addition of 1-bromobutane.

Page 6 of 39

After the study to determine the optimal conditions, various N-alkynylindoles, alkyl halides and a series of elemental sulfur, selenium and tellurium were used in different combinations to define the scope and limitations of our methodology. The results shown in Table 2 indicate that it was quite general and the indoles 2 were obtained in moderate to good yields. In all cases, the desired products were found to have trace amount of starting material and diorganyl dichalcogenides as side products that can be easily separated by flash column chromatography. The analysis of Table 2 indicates that the reaction occurred efficiently starting from N-alkynylindoles having neutral, electron-donating or electron-withdrawing groups directly bonded to the aryl group in alkynes, indicating that electronic effects did not significantly influence the reaction yields. However, the reaction with N-alkynylindoles having aryl groups with substituent at the ortho-position failed to give the desired indoles, which can be attributed to the influence of the steric effects (Table 2, entries 1-10). Electrondonating substituents, such as Me and MeO at the indole ring were also compatible with optimized conditions affording the 3-(butylselanyl) selenazolo indoles 2i and 2j in moderate to good yields (Table 2, entries 11 and 12). In the reaction with N-alkynylindoles 1m and 1n, having a halogen at the indole ring, we did not observe the formation of desired product. In these cases, the non halogenated indole products were obtained as the byproduct, probably by the 6


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further lithium-halogen exchanged reaction (Table 2, entry 13 and 14).22 The Nalkynylindole 1o, having an electron-withdrawing cyano group, was also a suitable substrate affording the product in good yield under optimized conditions (Table 2, entry 15). We then extended the scope of this methodology to other alkyl bromides, which were also suitable electrophilic source giving the corresponding 3-(alkylselanyl) selenazolo indoles 2l-n in comparable yields to 1-bromobutane (Table 2, entries 16-18).

The scope of this cyclization was

further studied applying the reaction conditions described in Table 1, entry 3 to elemental sulfur as the chalcogen source. However, these reaction conditions failed to afford the desired products because the elemental sulfur did not react with indolyllithium intermediate. This probably occurred because sulfur is less reactive in the oxidative addition step and usually less nucleophilic than the corresponding selenium compounds for the cyclization step.

This negative

result indicated the need for an adjustment in the reaction condition. In the course of sulfur addition, we observed that the reactions changed the color from a clear yellow solution, before the addition of elemental sulfur, to an opaque yellow solution after the elemental sulfur addition.

The formation of

chalcogenolate anion is easily identified by the visual appearance of a clear solution, typically a yellow solution. Thus, the presence of an opaque yellow solution clearly showed that sulfur was not consumed in the reaction medium. Thus, the elemental sulfur (1.3 equiv) was added at 0 ºC, instead of -78 ºC and allowed to react at reflux, instead of 0 ºC, over 1 h. Next, the mixture was warmed to 0 ºC and 1-bromobutane was added and the reaction was continued for 1 h at room temperature. This change led to the formation of desired 3(butylthio) thiazolo indole 2o in 50% yield (Table 2, entry 19). The reaction 7



Page 8 of 39

conditions were compatible with other substrates, such as 1-bromopropane and with N-alkynylindole having a methyl group at the para-position; however, it did not work with the chlorine atom at the para-position (Table 2, entries 20-22). In order to extend the scope of the cyclization, we also applied the optimal conditions to the elemental tellurium. The N-alkynylindoles 1a, 1g and 1i were cyclized to give the 3-(alkyltelluro) tellurazolo indoles corresponding 2r-u in moderate to good yields (Table 2, entries 23-26). Regarding the substrates having alkyl group at the alkyne, we found a limitation in this methodology. For example, no product was observed with N-alkynylindole having a butyl group directly bonded to alkyne and any change in the reaction conditions was found to be effective to give the products. Finally, we applied the optimized conditions on a scale-up reaction. Thus, the cyclization of N-alkynylindole 1a in a 5 mmol scale was carried out under optimized reaction conditions leading to the formation of 1.65 g (77% yield) of 3-(butylselanyl) selenazolo indole 2a (Scheme 2). Table 2. Synthesis of 3-(organochalcogen) chalcogenazolo indoles 2.a R1

N

R2

1. n-BuLi (1.3 equiv), THF - 78 ºC (0.16 h), 0 °C (0.5 h) 2. Y(0) (2.5 equiv), -78 ºC to r.t., 1 h 3. R3Br (1.1 equiv), 0 ºC to r.t., 1 h

R1 N R3Y

Y R2

3-(organochalcogen) Entry

N-alkynylindole

Y(0)

R3Br chalcogenazolo indoles 2

8


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N 1a

1

Se

Se

N

n-BuBr

n-BuSe 2a, 71%

N

2

Se

N

1b

Se

CH3

n-BuBr

n-BuSe 2b, 60%

CH3

N

3

1c

Se

N Se

n-BuBr

n-BuSe 2c, 61%

CH3

CH3

N

4

N

1d OCH3

Se

Se

OCH3

n-BuBr

n-BuSe not observed

N

5

1e

N Se

Se

n-BuBr

n-BuSe 2d, 35%

OCH3

OCH3

9



Page 10 of 39

N

6

N

1f

Se

Cl

Se

Cl

n-BuBr

n-BuSe not observed

N 1g

7

N Se

Se

n-BuBr

n-BuSe 2e, 50%

Cl

Cl

N

8

Se

N

1h

Se

CF3

n-BuBr

n-BuSe 2f, 50%

CF3

N 1i

9

N Se

Se

n-BuBr

n-BuSe 2g, 45%

F

F

N

10

1j

N Se

Se

n-BuBr

n-BuSe 2h, 54%

10


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H3C H3C

N

11

1k

Se

Se

N

n-BuBr

n-BuSe 2i, 40%

H3CO H3CO

N

12

1l

Se

Se

N

n-BuBr

n-BuSe 2j, 60%

Br Br

N

13

1m

Se

N Se

n-BuBr

n-BuSe not observed

I

I

N

14

1n

N Se

n-BuBr

Se

n-BuSe not observed

CN CN

N

15

Se

1o

n-BuBr

N

Se

n-BuSe 2k, 60%

16

1a

Se

n-PrBr

N

Se

n-PrSe 2l, 50%

11



17

1a

Se

Page 12 of 39

Se

N n-HeptBr

n-HeptSe 2m, 51%

18

1a

Se

Se

N

BnBr

BnSe 2n, 40%

19b

1a

S

S

N

n-BuBr

n-BuS 2o, 50%

20b

1a

S

S

N

n-PrBr

n-PrS 2p, 60%

21b

1c

S

S

N n-BuBr

n-BuS 2q, 41%

22b

S

N 1g

S

n-BuBr

n-BuS not observed

23

1a

Te

CH3

N

Cl

Te

n-BuBr

n-BuTe 2r, 65%

12


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24

1a

Te

N

n-HeptBr

Te

n-HeptTe 2s, 63%

25

1g

Te

Te

N n-BuBr

n-BuTe Cl

2t, 54%

26

1i

Te

Te

N n-BuBr

n-BuTe F

2u, 42% a

The reaction was performed by the addition of n-butyllithium (1.3 equiv) to a

solution of N-alkynylindole (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental chalcogen (2.5 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After the mixture was warmed to 0 ºC and 1-bromobutane (1.1 equiv) was added and the reaction was continued for 1 h at room temperature. b

The elemental sulfur (1.3 equiv) was added at 0 ºC and allowed to react under

reflux over 1 h.

N

1. n-BuLi (1.3 equiv), THF, - 78 ºC 2. Se(0) (2.5 equiv), -78 ºC to r.t 3. n-BuBr (1.1 equiv), 0 ºC to r.t, 1 h

N n-BuSe

Ph 1a (5 mmol)

Se Ph

2a, 1.65g (77%)

Scheme 2

13



Page 14 of 39

Mechanism Proposal To gain information on the reaction mechanism, we tried to block the cyclization step by trapping the first selenolate anion. To achieve this goal we made two modifications; reduced the amount of elemental selenium and changed the temperature of elemental selenium addition. Thus, the elemental selenium (1.1 equiv) was added at -78 °C and allowed to react under this temperature until the reaction became completely clear. After that, 1-bromobutane (1.1 equiv) was added at -78 °C and allowed to react for 1 h under this temperature. A sample of this reaction was taken and analyzed by GCMS indicating the formation of 3(butylselanyl) selenazoloindole 2a, 2-butylselanyl-N-alkynylindole 3 and the presence of the starting material 1a. However, all attempts to separate 2a and 3 were unsuccessful (Scheme 3). This result is significant because it indicates that the formation of 3-(butylselanyl) selenazoloindole 2a occurs via an anionic process, in which the N-alkynylindole selenolate could be the key intermediary for this cyclization. Thus, we postulate that the formation of 3-(butylselanyl) selenazoloindoles 2 proceeds through an initial hydrogen abstraction from the C-2 position of the N-alkynylindole to give the 2-indolyl lithium intermediate I, which reacts with elemental selenium, affording the key intermediate Nalkynylindole selenolate II. This intermediate promotes the reduction of carboncarbon triple bond, followed by the reaction with a second equiv of elemental selenium to give the second selenolate anion III. The trap of selenolate III with alkyl halides affords the 3-(alkylselanyl) selenazoloindole 2 (Scheme 4).

14


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1. n-BuLi (1.1 equiv), THF, - 78 ºC N 1a

+

N

2. Se(0) (1.1 equiv), -78 ºC

1a

3. n-BuBr (1.1 equiv), -78 ºC

N 2a n-BuSe

Sen-Bu

+

Se Ph

N 3

Ph

Ph

Ph

Scheme 3

n-BuLi

R1

N

R1

Li

Se(0)

N

1

R1 II

I R2

Se(0)

R2

R1 N 2

SeLi N

R3Br

Se

N

2

R3Se

R1

R

III

LiSe

R2

Se R2

Scheme 4 Reactivity of 3-(butylselanyl) selenazoloindole Because of the potential pharmacological applications23 and versatility as synthetic intermediates in organic synthesis,24 the development of methods for the synthesis of diorganyl diselenides has been the subject of extensive studies. Among various methods for the synthesis of these compounds, the use of Grignard reactions is one of the most practical and efficient procedure. However, this methodology is widely applied for the synthesis of diorganyl diselenides of the relatively simple structure.

Having demonstrated that N-

alkynylindole selenolate can be trapped with electrophile species and knowing that selenolates can be easily oxidized to diselenides in contact with air, we envisioned that through the methodology described in this study, diselenides derived from selenazoloindole ring could be easily prepared. For this purpose, 15



Page 16 of 39

n-butyllithium (1.3 equiv) was added to a solution of N-alkynylindoles (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental selenium (1.1 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After quenching with aqueous solution of NH4Cl and stirring for 2h under air, the selenazoloindolyl diselenides 4a-c were obtained in moderate to good yields (Scheme 5). The reaction conditions can be also applied to the elemental tellurium leading to the preparation of corresponding ditellurides 4d-f (Scheme 5).

R1 R1

N

R2

N

Ph

Se

Ph

H3C

N

Ph

Te

N

4d - 45%

Se Se Se

Ph

Y N

F

Se Se

CH3

N

N H3C

Te

F

N

Se

4c - 44%

Te

Te Te

R1

Se

N

4b - 62%

Te

Te Te

R2

Se

N

4a - 65%

N

Y

R2

Y

Se

Se Se

Y

N

1. n-BuLi (1.3 equiv), THF - 78 ºC (0.16 h), 0 °C (0.5 h) 2. Y(0) (2.5 equiv), -78 ºC to r.t., 1 h 3. NH4Cl, air

Te

N

CH3

N

4e - 36%

Te Te Te

N

4f - 47%

16


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Scheme 5 Conclusion In summary we developed a methodology to prepare 3-(organoselanyl) selenazolo indoles in which the 2-indolylselenolate anion, generated in situ, promoted a hydroselenation of carbon-carbon bond of alkyne, followed by trapping of second selenolate anion with an electrophile source, leading to the product. The same one-pot, three-steps cascade protocol was applied to the elemental sulfur and tellurium furnishing 3-(butylthio) thiazolo indoles and 3(alkyltelluro) tellurazolo indoles, respectively. The versatility of the methodology was also studied by the preparation of dichalcogenides derived from chalcogenazoloindole ring, which were easily prepared via oxidation of chalcogenolate anion in contact with air.

Furthermore, the feature of this

methodology includes the simple and easy preparation of N-alkynylindoles, the use of transition metal-free conditions and the generality of the reaction conditions, which allowed the construction of two classes of chalcogen containing heterocycles, selectively prepared in good yields from the same starting materials. All compounds prepared were characterized by 1H and

13C

NMR spectroscopy, and the structures of 2o and 4a (CCDC 1884217 and 1884218) were elucidated by X-ray crystallography, which confirmed the formation of five-membered heterocycle via a 5-endo-dig cyclization process. However, they were not detected by CGMS analysis. Experimental Section Materials and Methods 17



Page 18 of 39

Proton nuclear magnetic resonance spectra (1H NMR) were obtained on a NMR spectrometer at 400 MHz. Spectra were recorded in CDCl3 solutions. Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl3 or tetramethylsilane (TMS) as the external reference. Data are reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz and integrated intensity. Carbon-13 nuclear magnetic resonance spectra (13C NMR) were obtained on a 400 NMR spectrometer at 100 MHz. Spectra were recorded in CDCl3 solutions. Chemical shifts are reported in ppm, referenced to the solvent peak of CDCl3. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), t (triplet), quart (quartet), quint (quintet), sex (sextet), dd (double doublet) and m (multiplet). The

77Se

NMR experiment was

carried out using capillary tube with diphenyl diselenide as external reference. High resolution mass spectra were recorded on a mass spectrometer using electrospray ionization (ESI). Column chromatography was performed using Silica Gel (230-400 mesh). Thin layer chromatography (TLC) was performed using Gel GF254, 0.25 mm thickness. For visualization, TLC plates were either placed under ultraviolet light, or stained with iodine vapor, or acidic vanillin. Most reactions were monitored by TLC for disappearance of starting material. The following solvents were dried and purified by distillation from the reagents indicated: tetrahydrofuran from sodium with a benzophenone ketyl indicator. All other solvents were ACS or HPLC grade unless otherwise noted. Air- and moisture-sensitive reactions were conducted in flame-dried or oven dried glassware equipped with tightly fitted rubber septa and under a positive atmosphere of dry nitrogen or argon. Reagents and solvents were handled using standard syringe techniques. The starting N-alkynylindoles 1 were readily 18


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available by using the copper-catalyzed coupling reaction between indoles with haloalkynes.20 General

Procedure

for

the

Synthesis

of

3-(organochalcogenyl)

chalconazolo indoles 2a-u. n-Butyllithium (0.26 mL of 2.5 M solution in hexane, 0.65 mmol, 1.3 equiv) was added to a solution of N-alkynylindoles (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental chalcogen (2.5 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After the mixture was warmed to 0 ºC and alkyl halides (1.1 equiv) was added and the reaction was continued for 1 h at room temperature. After quenching with H2O and extraction with ethyl acetate (3 × 5 mL), the combined organic layers were dried over MgSO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel. 3-(Butylselanyl)-2-phenyl-[1,3]selenazolo[3,2-a]indole (2a): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.153 g (71%), mp 52-55 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.888.85 (m, 1H), 7.61-7.58 (m, 1H), 7.54-7.51 (m, 2H), 7.44-7.34 (m, 3H), 7.247.13 (m, 2H), 6.66 (d, J = 0.8 Hz, 1H), 2.75 (t, J = 7.2 Hz, 2H), 1.50-1.41 (m, 2H), 1.19-1.11 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H).

13C

{1H} NMR (CDCl3, 100

MHz): δ (ppm) 134.8, 133.6, 133.6, 132.7, 130.6, 130.1, 128.4, 128.3, 121.2, 119.5, 119.1, 114.9, 112.6, 97.2, 31.4, 30.1, 22.4, 13.4.

77Se

NMR (77 MHz, in

CDCl3 with diphenyl diselenide as external reference) δ (ppm) 437.6, 185.4. MS (EI. 70 eV. m/z (relative intensity)): 435 (33), 434 (22), 432 (100), 429 (57), 374

19



Page 20 of 39

(73), 217 (63), 169 (30), 89 (33). HRMS (ESI-TOF) m/z calcd for C20H20NSe2 [M + H]+: 433.9926. Found: 433.9930. Procedure for the Large Scale Synthesis of 3-(Butylselanyl)-2-phenyl[1,3]selenazolo[3,2-a]indole (2a): n-Butyllithium (2.6 mL of 2.5 M solution in hexane, 6.5 mmol, 1.3 equiv) was added to a solution of N-alkynylindoles (1.08 g, 5 mmol) in THF (10 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental chalcogen (0.98 g, 2.5 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After the mixture was warmed to 0 ºC and alkyl halides (0.76 g, 1.1 equiv) was added and the reaction was continued for 1 h at room temperature. After quenching with H2O and extraction with ethyl acetate (3 × 5 mL), the combined organic layers were dried over MgSO4, and concentrated

under

vacuum.

The

product

was

isolated

by

column

chromatography (hexane was eluent) as a yellow solid. Yield: 1.65 g, 77%. 3-(Butylselanyl)-2-m-tolyl-[1,3]selenazolo[3,2-a]indole (2b): The product was isolated by column chromatography (hexane was eluent) as a yellow oil. Yield: 0.134 g (60%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.88 (d, J = 8.6 Hz, 1H), 7.62-7.58 (m, 1H), 7.32-7.16 (m, 6H), 6.66 (s, 1H), 2.76 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.45 (quint, J = 7.3 Hz, 2H), 1.16 (sex, J = 7.3 Hz, 2H), 0,73 (t, J = 7,2 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 137.9, 134.5, 133.6, 133.4,

132.5, 131.1, 130.4, 129.1, 128.1, 127.6, 121.1, 119.4, 119.0, 114.5, 112.5, 97.0, 31.2, 30.0, 22.4, 21.4, 13.4. HRMS (ESI-TOF) m/z calcd for C21H22NSe2 [M + H]+: 448.0083. Found: 448.0092.

20


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3-(Butylselanyl)-2-(p-tolyl)-[1,3]selenazolo[3,2-a]indole (2c): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.136 g (61%), mp 71-74 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.888.85 (m, 1H), 7.61-7.58 (m, 1H), 7.43-7.39 (m, 2H), 7.23-7.13 (m, 4H), 6.65 (s, 1 H), 2.76 (t, J = 7.3 Hz, 2H), 2.40 (s, 3H), 1.45 (quint, J = 7.5 Hz, 2H), 1.16 (sex, J = 7.5 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H).

13C {1H}

NMR (CDCl3, 100 MHz):

δ (ppm) 138.4, 133.5, 132.5, 131.7, 130.3(2C), 129.0(2C), 121.1, 119.3, 119.0, 114.4, 112.4, 97.0, 31.3, 29.9, 22.5, 21.3, 13.4. MS (EI. 70 eV. m/z (relative intensity)): 449 (28), 448 (22), 447 (100), 443 (56), 388 (74), 310 (49), 230 (51), 115 (36), 77 (13). HRMS (ESI-TOF) m/z calcd for C21H22NSe2 [M + H]+: 448.0083. Found: 448.0075. 3-(Butylselanyl)-2-(4-methoxyphenyl)-[1,3]selenazolo[3,2-a]indole (2d): The product was isolated by column chromatography (hexane was eluent) as a brown oil. Yield: 0.081 g (35%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.89-8.85 (m, 1H), 7.61-7.58 (m, 1H), 7.46-7.43 (m, 2H), 7.24-7.13 (m, 2H), 6.96-6.93 (m, 2H), 6.65 (d, J = 0.8 Hz, 1H), 3.85 (s, 3H), 2.75 (t, J = 7.3 Hz, 2H), 1.45 (quint, J = 7.3 Hz, 2H), 1.17 (sex, J = 7.3 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (CDCl3, 100 MHz): δ (ppm) 159.7, 133.5, 132.5, 131.7, 130.2, 127.1, 121.1, 121.1, 119.3, 119.0, 114.3, 113.7, 112.5, 97.0, 55.3, 31.3, 30.0, 22.5, 13.4. HRMS (ESI-TOF) m/z calcd for C21H22NOSe2 [M + H]+: 464.0032. Found: 464.0039. 3-(Butylselanyl)-2-(4-chlorophenyl)-[1,3]selenazolo[3,2-a]indole (2e): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.116 g (50%), mp 75-78 °C. 1H NMR (CDCl3, 400 MHz): δ 21



Page 22 of 39

(ppm) 8.87-8.83 (m, 1H), 7.62-7.58 (m, 1H), 7.46-7.36 (m, 4H), 7.25-7.14 (m, 2H), 6.67-6.65 (m, 1H), 2.75 (t, J = 7.3 Hz, 2H), 1.45 (quint, J = 7.3 Hz, 2H), 1.15 (sex, J = 7.3 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H).

13C


MHz): δ (ppm) 134.3, 133.5, 133.2, 133.2, 132.6, 131.7, 128.5(2C), 121.3, 119.6, 119.1, 115.3, 112.5, 97.4, 31.3, 30.1, 22.4, 13.4.

77Se

NMR (77 MHz, in

CDCl3 with diphenyl diselenide as external reference) δ (ppm) 438.37, 184.49. MS (EI. 70 eV. m/z (relative intensity)): 469 (26), 467 (70), 219 (21), 377 (26), 375 (100), 373 (97), 331 (45), 241 (33), 89(29). HRMS (ESI-TOF) m/z calcd for C20H19ClNSe2 [M + H]+: 467.9536. Found: 467.9544. 3-(Butylselanyl)-2-(3-(trifluoromethyl)phenyl)-[1,3]selenazolo[3,2-a]indole (2f): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.125 g (50%), mp 76-79 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.90-8.82 (m, 1H), 7.85-7.78 (m, 1H), 7.73-7.50 (m, 4H), 7.297.14 (m, 2H), 6.69 (s, 1H), 2.78 (t, J = 7.2 Hz, 2H), 1.44 (quint, J = 7.3 Hz, 2H), 1.15 (sex, J = 7.3, 2H), 0.72 (t, J = 7.3 Hz, 3H).

13C


MHz): δ (ppm) 135.6, 133.9, 133.5, 132.6, 130.7 (quart, J = 32.4 Hz), 128.8, 127.3 (quart, J = 3.8 Hz), 126.6 (quart, J = 289.8 Hz), 124.96 (quart, J = 3.8 Hz), 121.5, 119.7, 119.2, 116.1, 112.5, 97.5, 31.30, 30.2, 22.4, 13.3.

77Se

NMR

(77 MHz, in CDCl3 with diphenyl diselenide as external reference) δ (ppm) 438.4, 184.5. MS (EI. 70 eV. m/z (relative intensity)): 501 (69), 500 (12), 499 (75), 440 (61), 363 (76), 285 (100), 207 (69). HRMS (ESI-TOF) m/z calcd for C21H19F3NSe2 [M + H]+: 501.9800. Found: 501.9784. 3-(Butylselanyl)-2-(4-fluorophenyl)-[1,3]selenazolo[3,2-a]indole (2g): The product was isolated by column chromatography (hexane was eluent) as a 22


Page 23 of 39 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


yellow oil. Yield: 0.101 g (45%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.87-8.41 (m, 1H), 7.61-7.58 (m, 1H), 7.54-7.39 (m, 2H), 7.29-7.05 (m, 4H), 6.65 (s, 1H), 2.74 (t, J = 7.2 Hz, 2H), 1.42 (quint, J = 7.3 Hz, 2H), 1.14 (sex, J = 7.3 Hz, 2H), 0.72 (t, J = 7.2 Hz, 3H).

13C {1H}

NMR (CDCl3, 100 MHz): δ (ppm) 162.2 (d, J =

249.1 Hz), 133.5, 132.6, 132.4 (d, J = 8.4 Hz), 130.7 (d, J = 3.2 Hz), 129.0, 121.3, 119.6, 119.2, 115.4 (d, J = 21.7 Hz), 115.2, 112.5, 97.3, 31.3, 30.1, 22.5, 13.5. HRMS (ESI-TOF) m/z calcd for C20H19FNSe2 [M + H]+: 451.9832. Found: 451.9839. 3-(Butylselanyl)-2-(naphthalen-2-yl)-[1,3]selenazolo[3,2-a]indole (2h): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.130 g (54%), mp 97-100 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.90-8.88 (m, 1H), 7.97-7.95 (m, 1H), 7,90-7,82 (m, 3H), 7,67-7,61 (m, 2H), 7.56-7.48 (m, 2H), 7.28-7.16 (m, 2H), 6.69 (d, J = 0.8 Hz, 1H), 2.75 (t, J = 7.2 Hz, 2H), 1,50-1,37 (m, 2H), 1,15-1,05 (m, 2H), 0,66 (t, J = 7,2 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 133.6, 133.5, 132.9, 132.9, 132.6, 132.1, 130.1, 129.9, 128.1, 128.0, 127.8, 127.7, 126.6, 126.5, 121.2, 119.5, 119.1, 115.0, 112.5, 97.2, 31.3, 30.0, 22.4, 13.3. HRMS (ESI-TOF) m/z calcd for C24H22NSe2 [M + H]+: 484.0083. Found: 484.0090. 3-(Butylselanyl)-7-methyl-2-phenyl-[1,3]selenazolo[3,2-a]indole

(2i):

The

product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.089 g (40%), mp 89-91 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.73-8.70 (m, 1H), 7.54-7.50 (m, 2H), 7.43-7.35 (m, 4H), 6.99-6.96(m, 1H), 6.57(s, 1H), 2.74 (t, J = 7.3 Hz, 2H), 2.47 (s, 3H), 1.4 (quint, J = 7.3 Hz, 2H), 1.15 (sex, J = 7.3 Hz, 2H), 0.72 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR (CDCl3, 23



Page 24 of 39

100 MHz): δ (ppm) 134.8, 133.5, 133.0, 132.0, 130.6 (2C), 130.5, 129.7, 128.3, 128.3, 121.0, 118.8, 112.2, 96.8, 31.4, 30.0, 22.5, 21.5, 13.4. MS (EI. 70 eV. m/z (relative intensity)): 449 (31), 448 (23), 447 (100), 387 (49), 310 (55), 231 (61), 168 (36), 102 (18). HRMS (ESI-TOF) m/z calcd for C21H22NSe2 [M + H]+: 448.0083. Found: 448.0091. 3-(Butylselanyl)-7-methoxy-2-phenyl-[1,3]selenazolo[3,2-a]indole (2j): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.139 g (60%), mp 90-93 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.73 (d, J = 9.1 Hz, 1H), 7.52-7.49 (m, 2H), 7.44-7.32 (m, 3H), 7.04 (d, J = 2.6 Hz, 1H), 6.80 (dd, J = 9.1, 2.6 Hz, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 2.72 (t, J = 7.3 Hz, 2H), 1.43 (quint, J = 7.3 Hz, 2H), 1.4(sex, J = 7.3 Hz, 2H), 0.71 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 154.9, 134.7, 134.1,

133.3, 130.5, 128.8 (2C), 128.2, 128.2(2C), 113.2, 109.1, 100.8, 96.9, 55.6, 31.3, 29.9, 22.4, 13.3. HRMS (ESI-TOF) m/z calcd for C21H22NOSe2 [M + H]+: 464.0032. Found: 464.0027. 3-(Butylselanyl)-2-phenyl-[1,3]selenazolo[3,2-a]indole-8-carbonitrile (2k): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.137 g (60%), mp 88-91 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.13 (dt, J = 8.6, 0.9 Hz, 1H), 7.58-7.52 (m, 3H), 7.47-7.39 (m, 3H), 7.20 7.15 (m, 1H), 6.91 (s, 1H), 2.73 (t, J = 7.3 Hz, 2H), 1.50-1.40 (m, 2H), 1.19-1.12 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm)

134.0, 133.6, 130.5, 130.5 (2C), 128.8, 128.5, 128.3, 126.3, 118.7, 118.7, 118.1, 116.8, 101.0, 96.1, 31.3, 30.2, 22.4, 13.3.

77Se

NMR (77 MHz, in CDCl3

24


Page 25 of 39 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


with diphenyl diselenide as external reference) δ (ppm) 452.3, 185.6. HRMS (ESI-TOF) m/z calcd for C21H19N2Se2 [M + H]+: 458.9879. Found: 458.9872. 2-Phenyl-3-(propylselanyl)-[1,3]selenazolo[3,2-a]indole (2l): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.105 g (50%), mp 107-110 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.89 (d, J = 8.3 Hz, 1H), 7.64-7.51 (m, 3H), 7.46-7.36 (m, 3H), 7.26-7.14 (m, 2H), 6.67 (s, 1H), 2.73 (t, J = 7.3 Hz, 2H), 1.49 (sex, J = 7.3 Hz, 2H), 0.74 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 134.6, 133.5, 132.5,

130.6(2C), 128.3, 128.2 (2C), 121.2, 119.4, 119.1, 114.7, 112.5, 97.0, 32.3, 22.7, 14.0. MS (EI. 70 eV. m/z (relative intensity)): 421 (31), 420 (20), 419 (100), 417 (94), 374 (84), 292 (83), 216 (68), 89 (83). HRMS (ESI-TOF) m/z calcd for C19H18NSe2 [M + H]+: 419.9770. Found: 419.9779. 3-(Heptylselanyl)-2-phenyl-[1,3]selenazolo[3,2-a]indole (2m): The product was isolated by column chromatography (hexane was eluent) as a light brown solid. Yield: 0.121 g (51%), mp 42-45 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.89-8.85 (m, 1H), 7.62-7.57 (m, 1H), 7.54-7.50 (m, 2H), 7.43-7.34 (m, 3H), 7.24-7.14 (m, 2H), 6.66 (s, 1H), 2.74 (t, J = 7.2 Hz, 2H), 1.50-1.40 (m, 2H), 1.19-1.04 (m, 8H), 0.82 (t, J = 7.2 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ

(ppm) 134.7, 133.5, 133.5, 132.5, 130.5, 130.2, 128.3, 128.2, 121.1, 119.4, 119.1, 114.7, 112.5, 97.1, 31.5, 30.3, 29.2, 29.2, 28.6, 22.5, 14.0. MS (EI. 70 eV, m/z (intensidade relativa)): 475 (62), 473 (53), 375 (50), 295 (58), 217 (100), 89 (45). HRMS (ESI-TOF) m/z calcd for C23H26NSe2 [M + H]+: 476.0396. Found: 476.0388.

25



Page 26 of 39

3-(Benzylselanyl)-2-phenyl-[1,3]selenazolo[3,2-a]indole (2n): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.093 g (40%), mp 115-118 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.86 -8.83 (m, 1H), 7.56-7.52 (m, 1H), 7.20-7.09 (m, 5H), 7.03-6.96 (m, 5H), 6.656.62 (m, 2H), 6.57 (d, J = 0.9 Hz, 1H), 3.84 (s, 2H).13C {1H} NMR (CDCl3, 100 MHz): δ (ppm) 136.9, 134.2, 133.5, 133.4, 133.0, 132.0, 130.3, 128.8, 128.3, 128.2, 127.9, 127.0, 121.2, 119.6, 119.2, 114.4, 112.3, 97.8, 33.4. HRMS (ESITOF) m/z calcd for C23H18NSe2 [M + H]+: 467.9770. Found: 467.9762. General procedure for the one-pot synthesis of thiazolo[3,2-a]indoles. nButyllithium (0.26 mL of 2.5 M solution in hexane, 0.65 mmol, 1.3 equiv) was added to a solution of N-alkynylindoles (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental sulfur was added at 0 ºC, and allowed to react at reflux over 1 h. After the mixture was warmed to 0 ºC and alkyl halides (1.1 equiv) was added and the reaction was continued for 1 h at room temperature. After quenching with H2O and extraction with ethyl acetate (3 × 5 mL), the combined organic layers were dried over MgSO4, and concentrated

under

vacuum.

The

residue

was

purified

by

column

chromatography on silica gel. 3-(Butylthio)-2-phenylthiazolo[3,2-a]indole (2o): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.085 g (50%); mp 65-68 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.59 (d, J = 8.2 Hz, 1H), 7.69-7.62 (m, 3H), 7.46-7.36 (m, 3H), 7.26-7.15 (m, 2H), 6.56 (s, 1H), 2.77 (t, J = 7.3 Hz, 2H), 1.43-1.33 (m, 2H), 1.22-1.10 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ 26


Page 27 of 39 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


(ppm) 135.2, 132.6, 132.1, 131.1, 131.1, 129.7(2C), 128.5, 128.4, 121.3, 119.5, 119.4, 112.1, 91.6, 35.4, 30.6, 21.4, 13.4. HRMS (ESI-TOF) m/z calcd for C20H20NS2 [M + H]+: 338.1037. Found: 338.1040. 2-Phenyl-3-(propylthio)thiazolo[3.2-a]indole (2p): The product was isolated by column chromatography (hexane was eluent) as a light brown solid. Yield: 0.097 g (60%), mp 97-100 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.61-8.58 (m, 1H), 7.69-7.62 (m, 3H), 7.47-7.36 (m, 3H). 7.27-7.16 (m, 2H), 6.56 (s, 1H), 2.74 (t, J = 7.3 Hz, 2H), 1.47-1.36 (m, 2H), 0.74 (t, J = 7.3 Hz, 3H).

13C

{1H}

NMR (CDCl3, 100 MHz): δ (ppm) 135.2, 132.6, 132.1, 131.5, 131.1, 129.8, 128.5, 128.4, 121.3, 121.2, 119.5, 119.4, 112.1, 91.6, 37.6, 22.1, 12.9. MS (EI. 70 eV. m/z (intensidade relativa)): 324 (24), 323 (100), 280 (87), 279 (50), 247 (27), 121 (32), 89 (18). HRMS (ESI-TOF) m/z calcd for C19H18NS2 [M + H]+: 324.0881. Found: 324.0875. 3-(Butylthio)-2-(p-tolyl)thiazolo[3,2-a]indole (2q): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.072 g (41%); mp 73-77 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.60-8.56 (m, 1H), 7.66-7.52 (m, 3H), 7.26-7.14 (m, 4H), 6.54 (d, J = 0.8 Hz, 1H), 2.77 (t, J = 7.2, 2H), 2.40 (s, 3H), 1.40 (quint, J = 7.3 Hz, 2H), 1.19 (sex, J = 7.3 Hz, 2H), 0.72 (t, J = 7.3Hz, 3H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 138.6, 135.3,

132.7, 131.7, 131.2, 129.6, 129.3, 129.2, 121.3, 121.0, 119.5, 119.4, 112.2, 91.6, 35.5, 30.8, 21.5, 21.4, 13.5. HRMS (ESI-TOF) m/z calcd for C21H22NS2 [M + H]+: 352.1194. Found: 352.1186. 3-(Butyltellanyl)-2-phenyl-[1,3]tellurazolo[3,2-a]indole (2r):

27



Page 28 of 39

The product was isolated by column chromatography (hexane was eluent) as an orange oil. Yield: 0.173 g (65%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.229.17 (m, 1H), 7.56-7.53 (m, 1H), 7.38-7.33 (m, 5H), 7.24-7.20 (m, 1H), 7.157.09 (m, 1H), 6.68 (d, J = 0.8 Hz, 1H), 2.71 (t, J = 7.4 Hz, 2H), 1.52 (quint, J = 7.3 Hz, 2H), 1.15 (sex, J = 7.3 Hz, 2H), 0.74 (t, J = 7.3 Hz, 3H).

13C

{1H} NMR

(CDCl3, 100 MHz): δ (ppm) 140.8, 136.9, 132.5, 130.6, 129.2, 128.4, 127.9, 121.6, 121.0, 119.5, 118.7, 113.6, 107.3, 100.3, 32.85, 24.71, 13.38, 13.22. HRMS (ESI-TOF) m/z calcd for C20H20NTe2 [M + H]+: 533.9720. Found: 533.9728. 3-(Heptyltellanyl)-2-phenyl-[1,3]tellurazolo[3,2-a]indole (2s): The product was isolated by column chromatography (hexane was eluent) as an orange oil. Yield: 0.172 g (63%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.19 (d, J = 8.0 Hz, 1H); 7,55 (d, J = 8,0 Hz, 1H); 7,44-7,31 (m, 5H); 7.25-7.18 (m, 1H), 7.15-7.09 (m, 1H), 6.69 (s, 1H), 2.76-2.67 (m, 2H), 1.26-1.05 (m, 9H), 0.83-0.77 (m, 4H). 13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 140.8, 136.9, 132.5, 130.5 (2C),

128.4(2C), 127.9, 121.4, 121.0, 119.5, 118.7, 113.6, 107.3, 31.6, 31.5, 30.8, 28.5, 22.6, 14.1, 13.6. HRMS (ESI-TOF) m/z calcd for C23H26NTe2 [M + H]+: 576.0190. Found: 576.0196. 3-(Butyltellanyl)-2-(4-chlorophenyl)-[1,3]tellurazolo[3,2-a]indole

(2t):

The

product was isolated by column chromatography (hexane was eluent) as an orange oil. Yield: 0.153 g (54%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.20-9.16 (m, 1H), 7.57 -7.53 (m, 1H), 7.36-7.21 (m, 5H), 7.16 -7.10 (m, 1H), 6.68 (d, J = 0.8 Hz, 1H), 2.72 (t, J = 7.3 Hz, 2H), 1.53 (quint, J = 7.3 Hz, 2H), 1.14 (sex, J = 7.3 Hz, 2H), 0.75 (t, J = 7.3 Hz, 3H).

13C {1H}

NMR (CDCl3, 100 MHz): δ (ppm) 28


Page 29 of 39 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


139.3, 136.9, 133.7, 132.5, 131.8, 128.6, 121.2, 121.1, 119.9, 119.6, 118.7, 113.6, 107.6, 100.9, 32.85, 24.69, 13.38, 13.34. HRMS (ESI-TOF) m/z calcd for C20H19ClNTe2 [M + H]+: 567.9330. Found: 567.9337. 3-(Butyltellanyl)-2-(4-fluorophenyl)-[1,3]tellurazolo[3,2-a]indole (2u): The product was isolated by column chromatography (hexane was eluent) as an orange solid. Yield: 0.115 g (42%), mp 60-65 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.19 (d, J = 8.6 Hz, 1H), 7.58-7.54 (m, 1H), 7.35-7.30 (m, 2H), 7.25-7.04 (m, 1H), 6.71-6.68 (m, 3H), 2.73 (t, J = 7.4 Hz, 2H), 1.59-1.51 (m, 2H), 1.211.13 (m, 2H), 0.76 (t, J = 7.3 Hz, 3H). 13C {1H} NMR (CDCl3, 100 MHz): δ (ppm) 162.33 (d, J = 248.1 Hz), 136.87 (d, J = 3.0 Hz), 132.46, 132.17 (d, J = 8.4 Hz), 128.45, 128.37, 121.33, 121.08, 120.10, 119.56, 118.71, 115.39 (d, J = 21.9 Hz), 113.56, 107.44, 100.99, 32.84, 24.68, 13.33, 13.27. HRMS (ESI-TOF) m/z calcd for C20H19FNTe2 [M + H]+: 551.9626. Found: 551.9614. General procedure for the one-pot synthesis of selenazolo[3.2-a]indol-3il)diselane and tellurazolo[3.2-a]indol-3-yl)ditellane. n-Butyllithium (0.26 mL of 2.5 M solution in hexane, 0.65 mmol, 1.3 equiv) was added to a solution of N-alkynylindoles (0.5 mmol) in THF (3 mL) at -78 °C for 10 min, under an inert atmosphere and then warming the mixture to 0 °C while stirring for 30 min at this temperature. The elemental chalcogen (2.5 equiv) was added at -78 °C and allowed to react at room temperature over 1 h. After quenching with 2 mL of saturated NH4Cl solution and allowed to oxidize under air for 2 hour. After this time, the mixture was diluted with ethyl acetate (3 × 2 mL) and washed whit saturated NH4Cl solution (3 x 2 mL), the combined organic layers were dried over MgSO4, and concentrated under vacuum. The 29



Page 30 of 39

residue was purified by column chromatography on silica gel. 1,2-bis(2-Phenyl[1,3]selenazolo[3,2-a]indol-3-yl)diselane (4a): The product was isolated by column chromatography (hexane/ethyl acetate 90:5 as eluent) as a dark red solid. Yield: 0.122 g (65%). mp 123-126 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.29 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.26-7.09 (m, 8H), 6.98-6.89 (m, 6H), 6.60 (s, 2H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 135.9, 133.5,

133.2, 133.1, 132.5, 129.8, 128.5, 128.0 (2C), 121.2, 119.8, 119.1, 111.9, 97.4. HRMS (ESI-TOF) m/z calcd for C32H21N2Se4 [M + H]+: 752.8366. Found: 752.8375. 1.2-bis(2-(p-Tolyl)-[1.3]selenazolo[3.2-a]indol-3-yl)diselane

(4b):

The

product was isolated by column chromatography (hexane/ethyl acetate 90:5 as eluent) as a dark red solid. Yield: 0.120 g (62%). mp 114-117 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.32 (d, J = 8.5 Hz, 2H), 7.56-7.54 (m, 2H), 7.187.14 (m, 2H), 6.94 (t, J = 7.8 Hz, 2H), 6.87 (s, 8H), 6.58-6.56 (m, 2H), 2,24 (s, 6H).

13C

{1H} NMR (CDCl3. 100 MHz): δ (ppm) 138.6. 136.3. 133.3. 133.1.

132.6. 130.7. 129.7. 128.8. 121.1. 119.9. 119.0. 113.2. 112.1. 97.4. 21.2. HRMS (ESI-TOF) m/z calcd for C34H25N2Se4 [M + H]+: 780.8679. Found: 780.8684. 1.2-bis(2-(4-Fluorophenyl)-[1.3]selenazolo[3.2-a]indol-3-yl)diselane

(4c):

The product was isolated by column chromatography (hexane/ethyl acetate 90:5 as eluent) as a dark red solid. Yield: 0.085 g (44%). mp 92-95 °C. 1H NMR (CDCl3, 400 MHz): δ (ppm) 8.32 (d, J = 8.4 Hz, 2H), 7.61-7.58 (m, 2H), 7.227.17 (m, 2H), 7.00-6.88 (m, 6H), 6.81-6.73 (m, 4H), 6.63-6.63 (m, 2H).

13C {1H}

NMR (CDCl3, 100 MHz): δ (ppm) 162.68 (d, J = 249.5 Hz), 134.74, 133.19, 30


Page 31 of 39 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


132.74, 132.53, 131.51 (d, J = 8.4 Hz), 129.43 (d, J = 3.4 Hz), 121.40, 120.04, 119.33, 115.15 (d, J = 22.0 Hz), 112.04, 97.68, HRMS (ESI-TOF) m/z calcd for C32H19F2N2Se4 [M + H]+: 788.8177. Found: 788.8168. 1.2-bis(2-Phenyl-[1.3]tellurazolo[3.2-a]indol-3-yl)ditellane (4d): The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.088 g (45%). mp 162-165 °C. 1H NMR (CDCl3. 400 MHz): δ (ppm) 7.82 (s, 2H), 7.63-7.55 (m, 4H), 7.35-7.33 (m. 6H), 7.29-7.25 (m, 2H), 7.18-7.10 (m, 4H), 6.68 (s, 2H). 13C {1H} NMR (CDCl3, 100 MHz): δ (ppm) 136.8, 134.6, 131.1, 129.0, 127.5, 126.8, 121.0, 120.4, 119.9, 119.0, 116.2, 114.4, 110.4, 106.5. HRMS (ESI-TOF) m/z calcd for C32H21N2Te4 [M + H]+: 952.7954. Found: 952.7961. 1.2-bis(2-(p-Tolyl)-[1.3]tellurazolo[3.2-a]indol-3-yl)ditellane

(4e):

The

product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.088 g (36%). mp 135-137 °C. 1H NMR (CDCl3. 400 MHz): δ (ppm) 7.81 (s, 2H), 7.63-7.55 (m, 4H), 7.26 -7.23 (m, 2H), 7.19-7.10 (m, 8H), 13C

6.68 (s, 2H), 2.35 (s, 6H).

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 137.5,

134.6, 134.0, 131.1, 129.7, 126.7, 120.9, 120.4, 119.4, 119.0, 116.2, 114.6, 110.3, 106.3, 21.12. HRMS (ESI-TOF) m/z calcd for C34H25N2Te4 [M + H]+: 980.8267. Found: 980.8278. 1.2-bis(2-(Naphthalen-2-yl)-[1.3]tellurazolo[3.2-a]indol-3-yl)ditellane

(4f):

The product was isolated by column chromatography (hexane was eluent) as a yellow solid. Yield: 0.247 g (47%). mp 196-199 °C. 1H NMR (CDCl3, 400 MHz): 7.99 (s, 2H), 7.87-7.84 (m, 4H), 7.70-7.61 (m, 8H), 7.54-7.49 (m, 4H), 7.26-7.18 (m, 4H), 6.76 (s, 2H).

13C

{1H} NMR (CDCl3, 100 MHz): δ (ppm) 134.9, 134.4, 31



Page 32 of 39

133.9, 132.8, 131.4, 128.6, 127.8, 127.7, 126.8, 126.1, 126.1, 124.2, 21.1, 120.61, 120.5, 119.1, 116.0, 114.5, 110.4, 106.8, HRMS (ESI-TOF) m/z calcd for C40H25N2Te4 [M + H]+: 1052.8267. Found: 1052.8270. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ORCID Gilson Zeni: 0000-0003-1290-6478 Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We are grateful to FAPERGS, CAPES and CNPq for financial support. CNPq and CAPES are also acknowledged for the fellowships (T. P., A. M. and G.Z.). Supporting Information The

Supporting

Information

is

available

free

of

charge

on

the

https://pubs.acs.org/ at DOI: XXXX 1H

and 13C NMR spectra for all new compounds and X-ray results and crystal

data for compounds 2o and 4a (1884217 and 1884218). References

32


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Silver-Nanoparticle-Catalyzed

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Spiroindolenines via a 5-exo-dig Spirocyclization ACS Catal. 2016, 6, 81568161. (f) Della Ca’, N.; Fontana, M.; Motti, E.; Catellani, M. Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C-H Bond 34


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fungi:

structure

diversity,

biological

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chemoenzymatic synthesis Nat. Prod. Rep. 2010, 27, 57-78. 12. (a) Owczarczyk, Z. R.; Braunecker, W. A.; Garcia, A.; Larsen, R.; Nardes, A. M.; Kopidakis, N.; Ginley, D. S.; Olson, D. C. 5,10-Dihydroindolo[3,2-b]indoleBased Copolymers with Alternating Donor and Acceptor Moieties for Organic 35



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Three-Component

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Phenylselenophthalimide and Styrenes Org. Lett. 2009, 9, 5263-5266.

36


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Regio-

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Stereospecific 37



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Cyclizations of N-Alkynylindoles Angew. Chem., Int. Ed. 2017, 56, 1338713391. (b) Sato, A. H.; Ohashi, K.; Ito, K.; Iwasawa, T. Regio- and stereoselective synthesis of 1-(1-halovinyl)-1H-indoles from 1-ethynyl-1Hindoles with in situ generated HX Tetrahedron Lett. 2013, 54, 2878-2881. 21. Zeni, G.; Stracke, M. P. Nogueira, C. W.; Braga, A. L.; Menezes, P. H.; Stefani, H. A. Hydroselenation of Alkynes by Lithium Butylselenolate: An Approach in the Synthesis of Vinylic Selenides Org. Lett. 2004, 6, 1135-1138. 22. Shirejini, S. Z.; Mohammadi, A. Halogen–Lithium Exchange Reaction Using an Integrated Glass Microfluidic Device: An Optimized Synthetic Approach Org. Process Res. Dev. 2017, 21, 292-303. 23. (a) Nogueira C. W.; Rocha J. B. Toxicology and pharmacology of selenium: emphasis on synthetic organoselenium compounds Arch Toxicol. 2011, 85, 1313-1359. (b) Nogueira, C. W.; Rocha, J. B. T. Diphenyl Diselenide a JanusFaced Molecule J. Braz. Chem. Soc. 2010, 21, 2055-2071. (c) Eduardo E. Alberto, E. E.; Nascimento, V.; Braga, A. L. Catalytic Application of Selenium and Tellurium Compounds as Glutathione Peroxidase Enzyme Mimetics J. Braz. Chem. Soc. 2010, 21, 2032-2041. 24. (a) Ivanova, A.; Arsenyan, P. Rise of diselenides: Recent advances in the synthesis of heteroarylselenides Coord. Chem. Rev. 2018, 370, 55-68. (b) Godoi, M. G.; Paixão, M. W.; Braga, A. L. Chiral organoselenium-transitionmetal catalysts in asymmetric transformations Dalton Trans. 2011, 40, 1134711355. Graphical Table of Contents 38


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R1

N

3

R1

1. n-BuLi

R -X

R1

N

Y = S, Se, Te 2

R

Y0

R2

R3Y

YLi

2. Y0

N

Y

air oxidation R2

Y N

R1

R2 Y

Y

N

R2

Y

1

R

39


Synthesis of 3-(Organochalcogen) Chalcogenazolo Indoles via

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