Regioselective Synthesis of 1-Sulfanyl-and 1-Selanylindolizines

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Regioselective Synthesis of 1-Sulfanyl- and 1-Selanylindolizines Filipe Vinícius Penteado Scaranaro, Caroline Signorini Gomes, Gelson Perin, Cleisson S Garcia, Cristiani F Bortolatto, Cesar A Brüning, and Eder J. Lenardao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00871 • Publication Date (Web): 03 May 2019 Downloaded from http://pubs.acs.org on May 3, 2019

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The Journal of Organic Chemistry

Regioselective Synthesis of 1-Sulfanyl- and 1-Selanylindolizines Filipe Penteado,a Caroline S. Gomes,a Gelson Perin,a Cleisson S. Garcia,b Cristiani F. Bortolatto,b César A. Brüningb and Eder J. Lenardãoa,* a

Laboratório de Síntese Orgânica Limpa - LASOL - CCQFA - Universidade Federal de Pelotas -

UFPel - P.O. Box 354 - 96010-900, Pelotas, RS, Brazil. b

Laboratório de Bioquímica e Neurofarmacologia Molecular – LABIONEM - CCQFA - Universidade

Federal de Pelotas - UFPel - 96010-900, Pelotas, RS, Brazil. * Email: [email protected]

ABSTRACT We describe herein a new approach to prepare unprecedented bioactive indolizine motifs decorated with organosulfur and organoselenium groups. A total of twelve 1sulfanylindolizines and two 1-selanylindolizines were prepared in excellent yields by an intramolecular annulation of easily prepared chalcogen-containing pyridinium salts. The reaction is fast (1 h at 70 oC or 5 min under sonication) and transition metal-free, using glycerol as a green solvent.

INTRODUCTION Nitrogen-containing heterocycles are among the most important classes of natural occurring compounds, being mainly found in the form of alkaloids. Their crucial role is closely linked to the biological applicability in pharmaceutical industry, being present in countless drugs, high-performance materials and dyes.1 Among the diversity of heterocyclic derivatives, indolizines are privileged structures, which started to be studied after the 1960s, when camptothecin (A, Figure 1) was extracted from Camptotheca acuminata, known in China as “happy tree”. This molecule has a potent anticancer activity, trapping the topoisomerase I, preventing thus the DNA replication of cancer cells.2 Over the following few decades, two camptothecin analogues, topotecan (B) and irinotecan (C), have reached the shelves as two important anticancer drugs for the treatment of ovarian, lung, breast and colon cancers (Figure 1).2b Besides, several studies have demonstrated that synthetic analogues of indolizines are effective against several pathologies, presenting a diversity of biological activities, including anticancer,3 anti-histaminic,4 antimicrobial5 and antitubercular.6

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Camptothecin and its derivatives bioactive analogues

N

O

O

HO

N

N

O

Me camptothecin A

Et

Me N Me

Bu

S Me CO2H Me

topotecan B

MeO

HO

F

N

O HO

irinotecan C

O

CO2H

F

N OH H E

O

Bioactive sulfanylindolizine derivatives.

O SePh

N

OMe

S D

Cl

O

Me

MeO

N

Cl

N Me

Bioactive chalcogen-containing heterocycles t

N

O

O

N

N

O

HO

O

Me

N

O Bu

N

S

Bu

S

i

N

F MeO2S G 3-sulfanylindolizine anti-inflammatory activity

Pr

H 1-sulfanylindolizine treatment of intraocular hypertension

Figure 1. Bioactive natural and synthetic heterocyclic compounds.

On the other hand, organochalcogen compounds (sulfur and selenium-containing) belong to a class of molecules with a wide range of applications. The importance of these compounds is linked to their use as building blocks in the construction of complex structures, as a catalyst in many selective reactions and to their biological activities.7-10 When combined with heterocyclic systems, the organochalcogen can present interesting pharmacological properties. For example, the 3-sulfanylindole derivatives D and E have demonstrated a powerful anticancer activity, inhibiting the tubulin polymerization in breast carcinoma cells,9 while 4-selanylquinoline derivative F exhibits a potent anti-inflammatory activity, superior to Meloxicam®, a worldwide marketed drug for the treatment of inflammatory processes (Figure 1).10 In this context, sulfur-containing indolizines have been emerging as an important class of bioactive molecules.11-12 For example, the 3-sulfanylindolizine derivative G is a potent antiinflammatory, acting as an antagonist of CRTH2, which is a prostaglandin receptor that, when activated, triggers physiological and pathological responses associated with allergy and inflammation.11a Studies from the beginning of the 1990s showed that the 1-sulfanylindolizine compound H was efficient in reducing and controlling the intraocular pressure, with potential use in the treatment of intraocular hypertension (Figure 1).12


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Despite the high potential of these compounds in medicinal chemistry, only recently a general approach to access 3-sulfanylindolizines and 1,3-bis-sulfanylindolizines was disclosed, by Cao, Zhou and co-workers.13 The C-H/S-H cross-coupling of indolizines and thiols in the presence of an excess of H2O2, afforded selectively moderate to good yields of 3-sulfanylindolizines. By replacing the oxidant with TBHP and adding KI as a catalyst, the authors were able to prepare 1,3-bis-sulfanylindolizines in poor to excellent yields. The selective synthesis 1-sulfanylindolozines, however, is not trivial and from the best of our knowledge, a general methodology to prepare this class of compounds is unprecedented in the literature. Obviously, this has been a barrier in drug discovery studies involving this interesting class of compounds. Therefore, the development of an efficient and selective protocol to access 1-sulfanylindolozines is mandatory for the prospection of new bioactive 1sulfanylindolozines and for the study of their chemical and physicochemical properties. Herein, we report our results on the selective synthesis of the title compounds via benchstable and easy to handle sulfur-containing pyridinium salts, under mild reaction conditions. The results in the application of this new strategy to the selenium analogues to prepare hitherto unknown 1-selanylindolozines are also presented. RESULTS AND DISCUSSION Initially, based on preview reports,14 we envisioned the synthesis of 2-phenyl-1(phenylthio)indolizine

3a

through

a

one-pot

procedure,

by

the

base-promoted

condensation/cyclization of 2-[(phenylthio)methyl]pyridine 1a and 2-bromoacetophenone 2a (Scheme 1). A brief optimization study was performed, in which the effect caused by different bases, solvent mixtures and the reaction time were evaluated; however, the desired product was obtained in a maximum yield of only 36% (Table S1, line 4, in the Supporting Information). In general, most of the pyridinium salt 1a was recovered in the end of these reactions, while the substrate 2a was completely consumed through a parallel self-condensation reaction (confirmed by GC-MS analyses of the crude mixture). In order to achieve the product 3a in an acceptable yield, we decided to change our initial strategy by performing the reaction in two steps, following the one-pot protocol reported by Clososki and co-workers for the synthesis of 2,5-diaryl-indolizines.14a Thus, the key intermediate pyridinium salt 4a was previously prepared from equimolar amounts of 1a and 2a in refluxing acetone for 5 h. Following, the solvent was evaporated and the resulting solid was subjected to a base-promoted condensation/cyclization step, using K2CO3 (1 equiv) in



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H2O (1.0 mL) at 70 ºC, for 8 h. Fortunately, the desired product 3a was accessed in 65% yield, almost double the previous best result (Scheme 1). SPh

O N

SPh +

1a, 0.3 mmol

acetone reflux, 5 h step 1 2a, 0.3 mmol

N

Br

Ph

SPh

Br

K2CO3 (1 equiv) H2O, 70 ºC 8h step 2

Ph

O 4a key intermediate pyridinium salt

N

Ph

3a, 65%

Scheme 1. One-pot synthesis of the 1-sulfanylindolizine 3a.

Encouraged by this remarkable improvement, we have decided to isolate the key reaction intermediate 4a, using this species as starting material to reach the desired product 3a. Thus, the pyridinium salt 4a was treated with aqueous K2CO3 (1 equiv) for 1 h at 70 ºC, delivering the desired product 3a in an excellent yield of 95% (Scheme 2). SPh

SPh

N Ph

Br O

K2CO3 (1 equiv) H2O, 70 ºC 1h

N

Ph

3a, 95%

4a, 0.3 mmol

Scheme 2. Pyridinium salt 4a as starting material to access 3a.

Based on this excellent outcome, we decided to carry out an optimization study of the base-promoted

intramolecular

condensation/cyclization

of

1-(2-oxo-2-phenylethyl)-2-

[(phenylthio)methyl]pyridin-1-ium bromide 4a to give 2-phenyl-1-(phenylthio)indolizine 3a (Table 1). Thus, potassium carbonate (K2CO3, 1 equiv) was chosen as the standard base and several polar protic and aprotic solvents were used in the reaction medium instead water (Table 1, entries 2-7). The reaction was conducted smoothly in the presence of the nonconventional solvents PEG-400 and glycerol, affording the expected product 3a in quantitative yields (Table 1, entries 6 and 7). Glycerol, a coproduct from the biodiesel production,15 is considered a green solvent, in view of its biodegradability and low toxicity.16,17 Considering these aspects, glycerol was chosen as the solvent for the following studies. The reaction was also carried out in the presence of AcOK instead K2CO3 and a remarkable decrease in the reaction efficiency was observed, accessing the product 3a in a moderate yield of 54% (Table 1, entry 8). In the absence of base, the starting material 4a was completely recovered after 1 h of stirring at 70 oC

(Table 1, entry 9). Additionally, it was confirmed that heating is crucial to the process, since


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when the reaction was conducted at room temperature it was observed a notable decreasing in its efficiency, with 3a being obtained in only 33% yield (Table 1, entry 10). Table 1. Optimization study in the synthesis of 3a from pyridinium salt derivative 4a.a

SPh

N Ph

Br

SPh base solvent, 70 ºC 1h

O

Ph

N 3a

4a, 0.3 mmol

entry

base (1 equiv) solvent (1.0 mL)

yield (%)b

1

K2CO3

H 2O

95

2

K2CO3

DMSO

76

3

K2CO3

DMF

65

4

K2CO3

MeCN

68

5

K2CO3

EtOH

90

6

K2CO3

PEG-400

>99

7

K2CO3

glycerol

>99

8

AcOK

glycerol

54

9

-

glycerol

NR

10c

K2CO3

glycerol

33

11d

K2CO3

glycerol

>99

A mixture of 4a (0.3 mmol) and the base (1.0 equiv) in the solvent was stirred at 70 ºC for 1 h. b Yield obtained by column chromatography. c The reaction was conducted at room temperature. d The reaction was conducted under ultrasonic irradiation (20 kHz, 60% amplitude) for 5 min, reaching the final temperature of 110 ºC. a

Finally, based on the recent growing of industrial applications of ultrasound irradiation,18 as well as, on our recent interest in the use of this alternative energy source to promote organic transformations,17h,19 a mixture of 4a and K2CO3 in glycerol was

subjected to

sonication (a probe sonicator was used) and the reaction progress was followed by TLC. After only 5 min of sonication (20 kHz, 60% of amplitude), the starting material 4a was completely converted to the desired product 3a, thus dramatically reducing the reaction time compared to the conventional (oil bath) heating (Table 1, entry 7 vs 11). Thus, the best reaction condition to prepare 2-phenyl-1-(phenylthio)indolizine 3a consists in the treatment of a solution of 1-(2-



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oxo-2-phenylethyl)-2-[(phenylthio)methyl]pyridin-1-ium bromide 4a (0.3 mmol) in glycerol (1.0 mL) with K2CO3 (1.0 equiv) under conventional heating for 1 h at 70 ºC (Method A) or sonication for 5 min (Method B). With the aim to verify the scope and limitations of this new protocol to access chalcogeno-indolizines, we have prepared a total of fourteen pyridinium salts 4, twelve of them decorated with organosulfur and two with organoselenium groups (Table 2). As it can be seen on Table 2, the desired salts 4a-n were obtained in moderate to very good yields, with the alkyl-thioether derivatives 4j-l (R = C3H7) and the electron-deficient ones 4g-I (R = 4FC6H4) showing a lower reactivity. 2-[(Phenylselanyl)methyl]pyridine 1e (YR = SeC6H5) was a good substrate for the reaction, affording the expected selenium-containing pyridinium salts 4m (R1 = H) and 4n (R1 = 4-Cl) in 62% and 67% yields, respectively (Table 2). Table 2. Synthesis of pyridinium salts 4a-n.a O YR + R1

N

1 Y = S, Se

R1

Br

N

R1

N

Br O

S

O

4

O

R1

S

Br

O 4a: R1 = H, 80% 4b: R1 = Me, 77% 4c: R1 = Cl, 79%

N

Br

2

SPh

N O

R1

S

Br

OMe

4d: R1 = H, 83% 4e: R1 = Me, 81% 4f: R1 = Cl, 86%

4j: R1 = H, 56% 4k: R1 = Me, 59% 4l: R1 = Cl, 50%

YR

N

R1

70 ºC, 24 h

Br

R1

EtOAc

N Br

F

4g: R1 = H, 71% 4h: R1 = Me, 75% 4i: R1 = Cl, 75%

SePh

4m: R1 = H, 62% 4n: R1 = Cl, 67%

O

A mixture of 2-(methylchalcogenyl)-pyridine 1 (0.5 mmol) and 2-bromoacetophenone derivative 2 (0.6 mmol) in ethyl acetate (3.0 mL) was stirred at 70 ºC for 24 h. The resulting precipitate was filtered off, washed with ethyl acetate and dried using a vacuum pump. a

The next step of the study was to examine the scope and limitations of the cyclization reaction, evaluating the influence of different substituents both at the sulfur atom and at the carbonyl in the salt 4. A comparative study between conventional heating and sonication was also conducted, to verify the efficiency and generality of our protocol. As shown in Table 3, it was evaluated the effect of the presence of electron-donating and electron-withdrawing


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groups (EDG and EWG) in the phenyl unit directly bonded to the carbonyl group (Ar = 4MeC6H4 and 4-ClC6H4), combining them with different alkyl and aryl groups directly bonded to the sulfur atom (R = alkyl and aryl). Regarding the S-phenyl derivatives 4a-c (R = C6H5), it can be easily noticed that the presence of an EDG in 4b (Ar = 4-MeC6H4) decreases the electrophilicity of the carbonyl reaction site, affording the product 3b in a lower yield compared to 3a. The presence of an EWG in 4c (Ar = 4-ClC6H4), however, did not cause a significant changing in the reactivity of the substrate, affording the expected product 3c in similar yields to 3a. The effect of the electronic density of the aryl group connected to the carbonyl was less pronounced when the electron-rich p-methoxyphenylthio group was present (R = 4-MeOC6H4S), as in salts 4d-f. For instance, 3d (Ar = C6H5), 3e (Ar = 4-MeC6H4) and 3f (Ar = 4-ClC6H4) were obtained in 94%, 93% and 98% yields, respectively through the Method A (Table 3). On the other hand, the presence of an EWG in the S-aryl moiety, as in 4g-i (R = 4FC6H4) negatively influenced the reactivity, giving the respective 2-substituted indolizines 3g-i in lower yields compared to those derivatives from 4a-f using the Method A. For example, 1[(4-fluorophenyl)thio]-2-phenylindolizine 3g (Ar = C6H5) was obtained in 84% yield under the conditions of Method A, while 3h (Ar = 4-MeC6H4) was isolated in 83%. As expected, the electron-poor p-chlorophenyl-substituted salt 4i (Ar = 4-ClC6H4) was more reactive, affording the respective indolizine 3i in 91% yield. The alkyl thioethers 4j-l were considerably less reactive compared to the S-aryl ones, affording the respective products 3j-I in lower yields than the aryl analogues. Regarding the aryl group connected to the carbonyl moiety in the starting S-alkyl thioether salt 4, electron-neutral 4j (Ar = C6H5) and electron-rich 4k (Ar = 4MeC6H4) presented a similar reactivity, with the respective indolizines 3j and 3k being obtained in 76% and 74% yields under conventional heating (Method A). Better results were obtained starting from the electron-poor thioether 4l (Ar = 4-ClC6H4), which afforded the expected product 3l in 90% yield by Method A. As it can be seen in Table 3, the reaction time was reduced to only 5 min using sonication (Method B), giving the expected products in slightly higher yields than those obtained under conventional heating for 1 h (Method A). In view of the high potential of selenium-containing heterocycles in medicinal chemistry and materials science,7 we decided to extend our protocol to the synthesis of the until now unprecedented 1-selanylindolizine derivatives 3m and 3n. Fortunately, when the seleniumcontaining pyridinium salts 4m and 4n were submitted to the optimal reaction conditions (Methods A and B), the expected Se-containing products 3m and 3n were obtained in excellent yields (up to 99%) using both Methods, A and B (Table 3). It is worth to mention



Page 8 of 26

that our approach is limited to aromatic -bromo-ketones 2, once the alkyl analogues would generate, in the pyridinium intermediate 4, a second site with acidic hydrogen atoms, allowing parallel intermolecular condensation reactions (see Scheme 4 for a plausible reaction mechanism). Table 3. Study of the reaction scope of the synthesis of chalcogeno-indolizines 3a-n.a

YR

N Br

Ar

YR

K2CO3 (1.0 equiv) glycerol (1 mL) Method A: 70 ºC, 1 h Method B: US (20 kHz), 5 min

O 4a-n, 0.3 mmol


N

Ar

3a-n R = alkyl, aryl Y = S, Se

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SPh

SPh

Ph

N

SPh Me

N 3b Method A: 86% Method B: 91%

3a Method A: 95% Method B: 99%

3c Method A: 97% Method B: 98%

OMe

OMe

S

S Me

N

3d Method A: 94% Method B: 93% F

3f Method A: 98% Method B: 99%

F

F

S Ph

S Me

N

3i Method A: 91% Method B: 98%

S

S N

Cl

N

3h Method A: 83% Method B: 87%

3g Method A: 84% Method B: 86%

Cl

N

3e Method A: 93% Method B: 95%

S N

OMe

S Ph

N

Cl

N

Ph

S Me

N

3j Method A: 76% Method B: 82%

3l Method A: 90% Method B: 95%

3k Method A: 74% Method B: 77% SePh

SePh Ph N 3m Method A: 95% Method B: 99%

Cl

N

N

Cl

3n Method A: 97% Method B: 98%

Method A = In a round-bottomed flask were added the substrate 4a-n (0.3 mmol), K2CO3 (1.0 equiv) and glycerol (1.0 mL), and the mixture was stirred for 1 h at 70 ºC. Method B = In a round-bottomed flask were added the substrate 4a-n (0.3 mmol), K2CO3 (1.0 equiv) and glycerol (1.0 mL), and the system was sonicated for 5 min (20 kHz, 60 % of amplitude), reaching the final temperature of 110 ºC. In both methods the reaction yields were determined after isolation by column chromatography. a

To show the synthetic usefulness of this protocol, a gram-scale synthesis of indolizine 3c was performed using the Method A (4.0 mmol of 4c was used). Satisfactorily, the desired product 3c was obtained in 94% yield, demonstrating the synthetic applicability of the developed methodology (Scheme 3).



Cl

SPh

N Br

Page 10 of 26

SPh

K2CO3 (1.0 equiv) glycerol (3 mL) Method A: 70 ºC, 1 h

Cl

N

O 3c (1.26 g, 94%)

4c (1.73 g, 4 mmol)

Scheme 3. Gram-scale synthesis of 3c.

Based on several studies reported in the literature for similar cyclizations,14,20 and in our own findings, a plausible reaction mechanism for the synthesis of 1-chalcogenylindolizines 3 from 4 is proposed (Scheme 4). Initially, carbonate acts as a Bronsted base abstracting a proton from the C-sp3 adjacent to the -SPh group, leading to the sulfur-stabilized carbanion intermediate I,21 which undergoes an intramolecular annulation via a nucleophilic attack from the carbanion to the pendent carbonyl, giving the cyclic intermediate II. Following, a second proton in the α-sulfur position is abstracted, supplying the electronic deficiency on the nitrogen atom and affording the intermediate III. Protonation of intermediate III forms the onium ion derivative IV, that undergoes elimination of water, stablishing the aromaticity of the product 3a (Scheme 4). PhS

O

Br

SPh

N

-HCO3

H 4a

Ph

O CO3-2

SPh N 3a

Ph

Br

SPh

N

H

+

N I

Ph

II

Br

H H

Ph

- KBr - H2CO3 SPh

- H 2O - HCO3

OH2 N CO3-2

H HCO3 OH

H H IV

SPh H+

Ph

OH N H H

Ph

III

Scheme 4. Plausible reaction mechanism for the synthesis of 3a.

Considering that compounds with indolizine moiety have been demonstrated many biological activities,3-6 we evaluated the scavenger activity of some 1-chalcogenylindolizines against the radical 2,20-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid (ABTS•+), according to Re and co-workers.22 Excess of reactive oxygen species (ROS) formed in cells, such as superoxide anion radical (O2•-), hydroxyl radical (HO•), hydrogen peroxide (H2O2), singlet oxygen (1O2), and lipid peroxyl (RO•), could oxidatively damage lipids, proteins and DNA. This imbalance in the ROS has been postulated to be responsible for ageing and to play an


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important role in the pathogenesis of a great number of diseases, including inflammation, atherosclerosis, diabetes, coronary diseases, stroke, Parkinson’s disease, Alzheimer’s disease and carcinogenesis.23-25 Compounds that present ABTS•+ radical scavenger have the potential to neutralize the ROS which is generated in cell. In fact, ABTS•+ has been largely used for the determination of the scavenger mechanism of antioxidant compounds.26,27

Figure 2. ABTS•+ radical-scavenger effect of 1-chalcogenylindolizines. Data are reported as mean ± SEM for 3-4 independent experiments for each compound. Results are expressed as percentage of control. Ascorbic acid was used as positive control. C: control; V: vehicle.

The 1-sulfanylindolozines 3a, 3b, 3c, 3f and 3i and 1-selanylindolizine 3n presented a significant gradual scavenger activity of ABTS•+ from the concentration of 5 µM, as showed in Figure 2. The IC50 (concentration that inhibits 50% of ABTS•+) values and the maximal inhibition (Imax) were similar among the compounds (Table S2, in Supporting Information). These results pointed out the effectiveness of 1-chalcogenylindolizines to reduce radicals by electron transfer.22 Remarkably, the scavenger activity of 1-chalcogenylindolizines was similar to the positive control ascorbic acid, a well-known antioxidant compound and the most effective aqueous-phase antioxidant in human blood plasma of major importance for protection against diseases and degenerative processes caused by oxidative stress.28 In this way, these new 1-chalcogenylindolizines could be interesting to be studied in the treatment of oxidative stress-related diseases. Conclusion In summary, we described herein an easy, rapid and efficient methodology to access the promising bioactive class of unpublished 1-chalcogenylindolizines in good to excellent yields. This methodology uses glycerol as a cheap, widely available and green solvent,



Page 12 of 26

promoting the reaction medium efficiently by solubilizing the whole substrates. In addition, this intramolecular annulation of chalcogen-containing pyridinium salts was satisfactorily accelerated by ultrasound irradiation, decreasing the reaction time from 1 hour, under conventional heating, to only 5 minutes, keeping similar yield ranges or even enhancing the product yields in some cases. Showing ABTS•+ scavenger activity, 1-chalcogenylindolizines could be potential agents against oxidative stress-related diseases in order to improve human health. Taken together, the features of this protocol make it a green and robust method to prepare unpublished bioactive 1-chalcogenylindolizines. EXPERIMENTAL General Information The reactions were monitored by TLC carried out on Merk silica gel (60 F254) by using UV light as visualization agent and the mixture between 5% of vanillin in 10% of H2SO4 under heating conditions as developing agents. Merck silica gel (particle size 0.040-0.063 mm) was used to flash chromatography. Hydrogen nuclear magnetic resonance spectra (1H NMR) were obtained at 400 MHz on A Bruker Avance III HD spectrometer. The spectra were recorded in CDCl3 and DMSO-d6 solutions. The chemical shifts are reported in ppm, referenced to tetramethysilane (TMS) as the external reference. Hydrogen coupling patterns are described as singlet (s), doublet (d), triplet (t), doublet of doublets (dd), doublet of doublet of doublets (ddd) and multiplet (m). Coupling constants (J) are reported in Hertz. Carbon-13 nuclear magnetic resonance spectra (13C NMR) were obtained at 100 MHz on Bruker Nuclear Ascend 400 spectrometers. The chemical shifts are reported in ppm, referenced to the solvent peak of CDCl3 or DMSO-d6. Electrospray ionization (ESI-QTOF) high resolution mass spectrometry (EMAR) analyzes were performed on a Bruker Daltonics micrOTOF-Q II instrument in positive mode. The samples were solubilized in HPLC grade acetonitrile and injected into the APCI source via a syringe at a flow rate of 5.0 μL min-1. The following instrument parameters were applied: the capillary and cone voltages were adjusted to +3500 V and -500 V, respectively, with a desolvation temperature of 180 °C. Compass 1.3 software for micrOTOF-Q II (Bruker Daltonics, USA) was used for data acquisition and processing. Data were collected in the m/z range of 50-1200 at the rate of two sweeps per second. The ultrasound-promoted reactions were performed using a Cole Parmer-ultrasonic processor Model CPX 130, with a maximum power of 130 W, operating at an amplitude of 60% and a frequency of 20 kHz. The temperature of the reactions under US was monitored using a Incoterm digital infrared thermometer Model Infraterm (Brazil).


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General procedure for the synthesis of 2-[(sulfanyl)methyl]pyridines 1: In a two-necked 25 mL round-bottomed flask containing a solution of pyridin-2-ylmethanol (0.110 g; 1.0 mmol) in DCM (3.0 mL) at 0 ºC (ice bath) under stirring, SOCl2 (0.236 g; 2.0 mmol) in DCM (3.0 mL) was added dropwise. After the addition, the system was kept at 0 ºC and it was stirred for additional 2 h. Then, the solvent was evaporated under reduced pressure and the residue was dried using a vacuum pump to give the desired 2-(chloromethyl)pyridine in quantitative yield. Following, thiol (1.2 mmol), K2CO3 (0.138 g; 1.0 mmol) and MeCN (3.0 mL) were added into the flask, and the resulting mixture was stirred for 12 h at room temperature. After this time, the mixture was poured out into water (10 mL) and extracted with ethyl acetate (3x 10 mL). The organic layer was separated, and the residual water was removed with anhydrous MgSO4. The solvent was removed under reduced pressure and the desired 2[(sulfanyl)methyl]pyridines derivatives 1 were purified by chromatography column of silica gel using a 8:2 mixture of hexanes/ethyl acetate. The expected starting materials 1 were obtained in a yield range of 80% to 95% and the spectral data are in agreement with those of literature.29 General procedure for the synthesis of 2-[(phenylselanyl)methyl]pyridine 1: In a 25 mL round-bottomed double necked flask containing a solution of diphenyl diselenide (0.6 mmol) in EtOH (3.0 mL). Following, the system was saturated with argon and cooled to 0 ºC, and NaBH4 (1.2 equiv) was added to the yellow solution in several portions. After the addition, the reaction was vigorously stirred at 0 ºC, and after around 30 min, the solution became colorless, indicating the total cleavage of the Se-Se bond. Then, a solution of 2(chloromethyl)pyridine (1.0 mmol) in EtOH (3.0 mL) was added dropwise. After the end of the addition, the mixture was stirred at room temperature for additional 12 h. After this time, the mixture was poured out into water (10 mL) and extracted with ethyl acetate (3x 10 mL). The organic layer was separated, dried over Mg2SO4 and the solvent evaporated under reduced pressure.

The

desired

2-[(phenylselanyl)methyl]pyridine

was

purified

by

column

chromatography using a 8:2 solution of hexane/ethyl acetate, being isolated in 90% yield. The spectral data are in agreement with those of literature.30 General procedure for the preparation of the chalcogen-containing pyridinium salts derivatives 4a-n: In a round-bottomed flask were added the 2-(methylchalcogenyl)-pyridines 1 (0.5 mmol; see SI for the synthesis of 1), 2-bromoacetophenone derivatives 2 (0.6 mmol) and ethyl acetate (3.0 mL) as the solvent. The resulting solution was vigorously stirred at 70 ºC (oil bath), and along the process it was observed the formation of a white precipitate. After



Page 14 of 26

24 h, the formed precipitate was filtered off, washed with ethyl acetate (3x 2 mL) to removing unreacted starting materials and other soluble impurities. The solvent was removed under reduced pressure. 1-(2-Oxo-2-phenylethyl)-2-[(phenylthio)methyl]pyridin-1-ium bromide (4a): Yield: 0.160 g (80%); white solid; mp 219-221 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.04 (dd, J = 6.2, 1.1 Hz, 1H); 8.50 (td, J = 7.8, 1.3 Hz, 1H); 8.19 – 8.17 (m, 2H); 8.15 – 8.11 (m, 1H); 7.85 – 7.80 (m, 2H); 7.71 – 7.67 (m, 2H); 7.33 - 7.27 (m, 5H), 6.72 (s, 2H); 4.89 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.5, 153.7, 148.7, 146.0, 134.6, 133.7, 131.8, 131.1, 129.4, 129.2, 129.0, 128.6, 128.2, 126.2, 63.0, 34.8. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C20H18BrNOS, 320.1103; found, 320.1099. 1-(2-Oxo-2-(p-tolyl)ethyl)-2-[(phenylthio)methyl]pyridin-1-ium bromide (4b): Yield: 0.159 g (77%); white solid; mp 194-197 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.04 – 9.02 (m, 1H); 8.50 (td, J = 7.8, 1.2 Hz, 1H); 8.14 – 8.07 (m, 3 H); 7.83 (dd, J = 8.0, 1.0 Hz, 1H); 7.50 (d, J = 8.0 Hz, 2H); 7.33 - 7.27 (m, 5H); 6.68 (s, 2H); 4.88 (s, 2H); 2.46 (s, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.0, 153.6, 148.7, 146.0, 145.4, 131.8, 131.2, 131.1, 129.6, 129.4, 129.2, 128.7, 128.2 126.2, 62.9, 34.8, 21.4. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C21H20BrNOS, 334.1260; found, 334.1260. 1-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[(phenylthio)methyl]pyridin-1-ium bromide (4c): Yield: 0.171 g (79%); white solid; mp 201-203 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.00 (dd, J = 6.2, 1,1 Hz, 1H); 8.49 (td, J = 7.8, 1.4 Hz, 1H); 8.18 (d, J = 8.7 Hz, 2H); 8.14 – 8.10 (m, 1H); 7.82 – 7.77 (m, 3H); 7.33 - 7.27 (m, 5H); 6.66 (s, 2H); 4.84 (s, 2H).

13C{1H}

NMR

(DMSO-d6, 100 MHz) δ (ppm) 189.7, 153.7, 148.7, 146.1, 139.5, 132.5, 131.8, 131.1, 130.5, 129.4, 129.2, 129.2, 128.2, 126.3, 62.9, 34.8. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C20H17BrClNOS, 354.0714; found, 354.0717. 2-{[(4-Methoxyphenyl)thio]methyl}-1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide (4d): Yield: 0.178 g (83%); white solid; mp 194-197 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.04 – 9.03 (m, 1H); 8.47 (td, J = 7.8, 1.1 Hz, 1H); 8.19 – 8.11 (m, 3H); 7.73 – 7.80 (m, 1H); 7.71 – 7.67 (m, 2H); 7.63 (dd, J = 7.9, 0.9 Hz, 1H); 7.21 (d, J = 8.7 Hz, 2H); 6.86 (d, J = 8.7 Hz, 2H); 6.68 (s, 2H); 4.75 (s, 2H); 3.73 (s, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.6, 159.8, 154.0, 148.6, 145.8, 135.3, 134.6, 133.7, 129.5, 129.0, 128.6, 126.1, 120.7, 114.8, 62.8, 55.3, 36.3. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C21H20BrNO2S, 350.1209; found, 350.1210.


Page 15 of 26 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-{[(4-Methoxyphenyl)thio]methyl}-1-[2-oxo-2-(p-tolyl)ethyl]pyridin-1-ium

bromide

(4e): Yield: 0.180 g (81%); white solid; mp 207-209 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.02 (dd, J = 6.2, 1.2 Hz, 1H); 8.47 (td, J = 7.8, 1.4 Hz, 1H); 8.14 – 8.12 (m, 1H); 8.08 (d, J = 8.2 Hz, 2H); 7.63 (dd, J = 8.0, 1.3 Hz, 1H); 7.49 (d, J = 8.2 Hz, 2H); 7.20 (d, J = 8.8 Hz, 2H); 6.86 (d, J = 8.8 Hz, 2H); 6.63 (s, 2H); 4.74 (s, 2H); 3.73 (s, 3H); 2.46 (s, 3H).

13C{1H}

NMR

(DMSO-d6, 100 MHz) δ (ppm) 190.0, 159.8, 153.9, 148.7, 145.8, 145.3, 135.3, 131.2, 129.5, 128.7, 126.0, 120.8, 114.8, 62.7, 55.3, 36.3, 21.3. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C22H22BrNO2S, 364.1366; found, 364.1364. 1-[2-(4-Chlorophenyl]-2-oxoethyl)-2-{[(4-methoxyphenyl)thio]methyl}pyridin-1-ium bromide (4f): Yield: 0.200 g (86%); white solid; mp 208-209 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.02 (dd, J = 6.2, 1.0 Hz, 1H); 8.47 (td, J = 7.8, 1.3 Hz, 1H); 8.19 (d, J = 8.6 Hz, 2H); 8.15 – 8.11 (m, 1H); 7.78 (d, J = 8.6 Hz, 2H); 7.62 (dd, J = 8.0, 1.2 Hz, 1H); 7.20 (d, J = 8.8 Hz, 2H); 6.86 (d, J = 8.8 Hz, 2H); 6.66 (s, 2H); 4.73 (s, 2H); 3.73 (s, 3H).

13C{1H}

NMR

(DMSO-d6, 100 MHz) δ (ppm) 189.8, 159.8, 154.0, 148.6, 145.9, 139.5, 135.3, 132.5, 130.5, 129.5, 129.2, 126.1, 120.7, 114.8, 62.8, 55.3, 36.3. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C21H19BrClNO2S, 384.0820; found, 384.0819. 2-{[(4-Fluorophenyl)thio]methyl}-1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide (4g): Yield: 0.170 g (71%); white solid; mp 225-228 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.00 – 8.99 (m, 1H); 8.48 (td, J = 7.8, 1.3 Hz, 1H); 8.17 – 8.10 (m, 3H); 7.82 – 7.80 (m, 1H); 7.71 – 7.67 (m, 3H); 7.36 – 7.32 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H); 6.64 (s, 2H); 4.80 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.6, 162.2 (d, J = 246.5 Hz), 153.6, 148.8, 146.1, 135.3 (d, J = 8.5 Hz), 134.7, 133.7, 129.5, 129.1, 128.6, 126.4 (d, J = 2.9 Hz), 126.3, 116.3 (d, 21.9 Hz), 62.9, 35.6. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C20H17BrFNOS, 338.1009; found, 338.1024. 2-{[(4-Fluorophenyl)thio]methyl}-1-[2-oxo-2-(p-tolyl)ethyl]pyridin-1-ium bromide (4h): Yield: 0.162 g (75%); white solid; mp 220-223 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.02 (m, 1H); 8.49 (td, J = 7.9, 1.2 Hz, 1H); 8.15 – 8.07 (m, 3H); 7.72 (dd, J = 7.9, 0.9 Hz, 1H); 7.49 (d, J = 8.1 Hz, 2H); 7.36 – 7.32 (m, 1H); 7.16 (t, J = 8.8 Hz, 2H); 6.65 (s, 2H); 4.84 (s, 2H); 2.46 (s, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.1, 162.2 (d, J = 246.5 Hz), 153.4, 148.8, 146.0, 145.4, 135.2 (J = 8.5 Hz), 131.2, 129.5, 129.5, 128.7, 126.4 (J = 3.4 Hz), 126.2, 116.3 (d J = 22.1 Hz), 62.8, 35.6, 21.3. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C21H19BrFNOS, 352.1166; found, 352.1167. 1-[2-(4-Chlorophenyl)-2-oxoethyl]-2-{[(4-fluorophenyl)thio)]ethyl}pyridin-1-ium

(4i):

Yield: 0.162 g (75%); white solid; mp 202-204 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.02



Page 16 of 26

(s, 1H); 8.50 (s, 1H); 8.20 – 8.14 (m, 3H); 7.79-7.72 (m, 3H); 7.34 (s, 2H); 7.17 (s, 2H); 6.68 (s, 2H); 4.83 (s, 2H).

13C{1H}

NMR (DMSO-d6, 100 MHz) δ (ppm) 189.8, 162.1 (d, J = 246.5

Hz), 153.6, 148.7, 146.1, 139.5, 135.2 (J = 8.5 Hz), 132.4, 130.5, 129.5, 129.2, 126.4, 126.3, 126.3, 116.3 (d J = 22.1 Hz), 62.9, 35.6. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C20H16BrClFNOS, 372.0620; found, 372.0619. 1-(2-Oxo-2-phenylethyl)-2-[(propylthio)methyl]pyridin-1-ium bromide (4j): Yield: 0.102 g (56%); white solid; mp 162-164 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.04 – 9.02 (m, 1H); 8.70 (td, J = 7.8, 1.0 Hz, 1H); 8.29 (d, J = 7.2 Hz, 1H); 8.22 – 8.19 (m, 1H); 8.13 (d, J = 7.3 Hz, 2H); 7.79 (t, J = 7.4 Hz, 1H); 7.67 (t, J = 7.7 Hz, 2H); 6.61 (s, 2H); 4.42 (s, 2H); 2.32 (t, d = 7.2 Hz, 2H); 1.40 (sex, J = 7.2 Hz, 2H); 0.79 (t, J = 7.2, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.3, 154.5, 148.7, 146.5, 134.6, 133.6, 129.6, 129.0, 128.5, 126.2, 62.9, 32.4, 31.6, 21.7, 13.0. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C17H20BrNOS, 286.1260; found, 286.1262. 1-[2-Oxo-2-(p-tolyl)ethyl]-2-[(propylthio)methyl]pyridin-1-ium bromide (4k): Yield: 0.112 g (59%); white solid; mp 175-177 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.99 (dd, J = 6.2, 1.0 Hz, 1H); 8.69 (td, J = 7.9, 1.3 Hz, 1H); 8.27 – 8.25 (m, 1H); 8.21 – 8.17 (m, 1H); 8.02 (d, J = 8.0 Hz, 2H); 7.47 (d, J = 8.0 Hz, 2H); 6.54 (s, 2H); 4.39 (s, 2H); 2.44 (s, 3H); 2.31 (t, J = 7.2 Hz, 2H); 1.39 (sex, J = 7.2 Hz, 2H); 0.79 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 186.7, 151.1, 145.7, 143.5, 142.3, 128.1, 126.5, 125.6, 123.1, 59.7, 29.4, 28.6, 18.7, 18.3, 10.0. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C18H22BrNOS, 300.1416; found, 300.1421. 1-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[(propylthio)methyl]pyridin-1-ium (4l): Yield: 0.100 g (50%); white solid; mp 165-168 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.00 (dd, J = 6.1, 0.8 Hz, 1H); 8.70 (td, J = 7.9, 1.2 Hz, 1H); 8.28 – 8.26 (m, 1H); 8.22 – 8.13 (m, 3H); 7.76 (d, J = 8.6 Hz, 2H); 6.58 (s, 2H); 4.40 (s, 2H); 2.30 (t, J = 7.2 Hz, 2H); 1.40 (sex, J = 7.2 Hz, 2H); 0.80 (t, J = 7.3 Hz, 3H).

13C{1H}

NMR (DMSO-d6, 100 MHz) δ (ppm) 189.4, 154.5, 148.7,

146.6, 139.4, 132.4, 130.4, 129.6, 129.1, 126.2, 62.8, 32.4, 31.6, 21.7, 13.0. HRMS (APCIQTOF) m/z: [M - Br]+ calcd for C17H19BrClNOS, 320.0870; found, 320.0868. 1-(2-Oxo-2-phenylethyl)-2-[(phenylselanyl)methyl]pyridin-1-ium (4m): Yield: 0.138 g (62%); white solid; mp 193-195 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.97 – 8.95 (m, 1H); 8.38 – 8.35 (m, 1H); 8.15 – 8.02 (m, 3H); 7.83 – 7.79 (m, 1H); 7.70 – 7.67 (m, 2H); 7.52 (d, J = 7.7 Hz, 1H); 7.40 – 7.26 (m, 5H); 6.61 (s, 2H); 4.72 (s, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz) δ (ppm) 190.3, 155.2, 148.2, 145.5, 135.0, 134.6, 133.7, 129.3, 129.1, 128.8, 128.6,


Page 17 of 26 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


126.0, 125.7, 62.9, 26.7. HRMS (APCI-QTOF) m/z: [M - Br]+ calcd for C20H18BrNOSe, 368.0549; found, 320.0566. 1-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[(phenylselanyl)methyl]pyridin-1-ium (4n): Yield: 0.161 g (67%); white solid; mp 185-186 ºC. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.97 (d, J = 5.9 Hz, 1H); 8.37 (t, J = 7.5 Hz, 1H); 8.17 (d, J = 8.5 Hz, 2H); 8.06 – 8.03 (m, 1H); 7.77 (d, J = 8.5 Hz, 2H); 7.53 (d, J = 7.7 Hz, 1H); 7.40 – 7.26 (m, 5H); 6.63 (s, 2H); 4.74 (s, 2H). 13C{1H}

NMR (DMSO-d6, 100 MHz) δ (ppm) 189.5, 155.2, 148.2, 145.6, 139.4, 135.0, 132.5,

130.5, 129.3, 129.1, 129.1, 128.8, 126.0, 125.7. 62.9, 26.7. HRMS (APCI-QTOF) m/z: [M Br]+ calcd for C20H18BrNOSe, 402.0157; found, 402.0153. General procedure to the preparation of 1-chalcogenylindolizines 3a-n: In a roundbottomed flask were added the 2-methylchalcogenyl-pyridinium salts 4a-n (0.3 mmol), K2CO3 (1 equiv) and glycerol (1.0 mL) as solvent. After that, the solution was submitted to vigorous stirring, at 70 ºC for 1 h (oil bath, Method A), or submitted to ultrasonic irradiation (20 kHz, 60% of amplitude) for 5 min (Method B). At the end of the reaction, the solution was poured into water (10 mL) and extracted with ethyl acetate (3x 10 mL). The organic layer was separated, the residual water was removed with Mg2SO4, and it was concentrated under vacuum. Finally, the desired products 3a-n were purified by column chromatography using a mixture of hexanes/ethyl acetate (95/5) as the eluent. 2-Phenyl-1-(phenylthio)indolizine (3a): Yield Method A: 0.086 g (95%); Method B: 0.089g (99%); beige solid; mp 66-68 ºC. Data for compound 3a obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.86 (d, J = 6.9 Hz, 1H); 7.56 – 7.54 (m, 2H); 7.49 – 7.47 (m, 2H); 7.27 – 7.23 (m, 2H); 7.19 – 7.15 (m, 1H); 7.07 – 7.03 (m, 2H); 6.94 – 6.91 (m, 3H); 6.72 (ddd, J = 9.0, 6.6, 0.8 Hz, 1H); 6.51 (td, J = 6.9, 1.0 Hz, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ

(ppm) 140.6, 137.4, 134.2, 133.2, 128.7, 128.3, 127.0, 125.5, 125.1, 124.4, 119.7, 118.0, 111.9, 111.7, 94.6. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H15NS, 302.0998; found, 302.1002. 1-(Phenylthio)-2-(p-tolyl)indolizine (3b): Yield Method A: 0.081 g (86%); Method B: 0.086g (91%); brown solid; mp 75-77 ºC. Data for compound 3b obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.86 (d, J = 6.7 Hz, 1H); 7.48 – 7.43 (m, 4H); 7.08 – 7.04 (m, 4H); 6.93 – 6.91 (m, 3H); 6.74 – 6.70 (m, 1H); 6.52 – 6.49 (m, 1H); 2.25 (s, 3H).

13C{1H}

NMR

(CDCl3, 100 MHz) δ (ppm) 140.7, 137.4, 136.7, 133.3, 131.2, 129.1, 128.7, 128.5, 125.5, 125.1, 124.3, 119.6, 117.9, 111.8, 111.6, 94.5, 21.1. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C21H18NS, 316.1154; found, 316.1156.



Page 18 of 26

2-(4-Chlorophenyl)-1-(phenylthio)indolizine (3c): Yield Method A: 0.097 g (97%) Method B: 0.098g (98%); white solid; mp 95-97 ºC. Data for compound 3c obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.87 (d, J = 6.8 Hz, 1H); 7.50 – 7.46 (m, 4H); 7.21 (d, J = 8.5 Hz, 2H); 7.08 – 7.04 (m, 2H); 6.96 – 6.89 (m, 3H); 6.76 – 6.73 (m, 1H); 6.52 (td, J = 6.8, 1.0 Hz, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ (ppm) 140.3, 137.6, 133.0, 132.6, 131.9, 129.9,

128.8, 128.5, 125.5, 125.1, 124.5, 120.0, 118.0, 112.1, 111.7, 94.6. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H14ClNS, 336.0608; found, 336.0609. 1-[(4-Methoxyphenyl)thio]-2-phenylindolizine (3d): Yield Method A: 0.094 g (94%); Method B: 0.093g (93%); yellow solid. mp 83-85 ºC. Data for compound 3d obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.86 (d, J = 6.7 Hz, 1H); 7.58 – 7.52 (m, 3H); 7.46 (s, 1H); 7.29 – 7.16 (m, 3H); 6.89 – 6.86 (m, 2H); 6.75 – 6.71 (m, 1H); 6.64 – 6.62 (m, 2H); 6.51 (t, J = 6.7 Hz, 1H); 3.62 (s, 3H).

13C{1H}

NMR (CDCl3, 100 MHz) δ (ppm) 157.4,

137.3, 134.3, 133.0, 131.2, 128.8, 128.3, 127.2, 127.0, 125.5, 119.6, 118.0, 114.5, 111.8, 111.6, 96.2, 55.3. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C21H17NOS, 332.1104; found, 332.1103. 1-[(4-Methoxyphenyl)thio]-2-(p-tolyl)indolizine (3e): Yield Method A: 0.093 g (93%); Method B: 0.095g (95%); brown solid; mp 85-87 ºC. Data for compound 3e obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.84 (d, J = 6.9 Hz, 1H); 7.51 (d, J = 9.0 Hz, 1H); 7.46 (d, J = 8.0 Hz, 2H); 7.43 (s, 1H); 7.08 (d, J = 8.0 Hz, 2H); 6.88 (d, J = 8.9 Hz, 2H); 6.72 (ddd, J = 9.0, 6.6, 0.9 Hz); 6.63 (d, J = 8.9 Hz, 2H); 6.49 (td, J = 6.9, 1.1 Hz, 1H); 3.62 (s, 3H); 2.26 (s, 3H).

13C{1H}

NMR (CDCl3, 100 MHz) δ (ppm) 157.3, 137.3, 136.7, 133.1,

131.3, 131.3, 129.0, 128.6, 127.1, 125.4, 119.4, 117.9, 114.5, 111.7, 111.4, 96.0, 55.2, 21.2. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C22H19NOS, 346.1260; found, 346.1260. 2-(4-Chlorophenyl)-1-[(4-methoxyphenyl)thio]indolizine (3f): Yield Method A: 0.107 g (98%); Method B: 0.108 g (99%); beige solid.; mp 101-103 ºC. Data for compound 3f obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.85 (d, J = 6.9 Hz, 1H); 7.54 – 7.48 (m, 3H); 7.43 (s, 1H); 7.23 (d, J = 8.5 Hz, 2H); 6.87 (d, J = 8.8 Hz, 2H); 6.77 – 6.73 (m, 1H); 6.63 (d, J = 8.8 Hz, 2H); 6.52 (td, J = 6.9, 1.1 Hz, 1H); 3.63 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 157.5, 137.4, 132.9, 132.8, 131.7, 130.9, 129.9, 128.5, 127.2, 125.5, 119.8, 118.0, 114.5, 112.0, 111.5, 96.2, 55.3. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C21H16ClNOS, 366.0713; found, 366.0714. 1-[(4-Fluorophenyl)thio]-2-phenylindolizine (3g): Yield Method A: 0.080 g (84%); Method B: 0.082 g (86%); brown oil. Data for compound 3g obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.89 (d, J = 6.9 Hz, 1H); 7.55 – 7.48 (m, 4H); 7.29 – 7.25 (m, 2H); 7.22 –


Page 19 of 26 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


7.18 (m, 2H); 6.89 – 6.86 (m, 2H); 6.78 – 6.74 (m, 3H); 6.54 (td, J = 6.9, 1.0 Hz, 1H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 160.6 (d, J = 243.3 Hz), 137.4 , 135.5 (d, J = 2.9 Hz), 134.1, 133.1, 128.7, 128.3, 127.1, 126.9 (d, J = 7.8 Hz), 125.6, 119.9, 117.8, 115.7 (d, J = 21.9 Hz), 111.9, 111.8, 95.1. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H14FNS, 320.0904; found, 320.0905. 1-[(4-Fluorophenyl)thio]-2-(p-tolyl)indolizine (3h): Yield Method A: 0.083 g (83%); Method B: 0.086 g (87%); brown oil. Data for compound 3h obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.90 (d, J = 6.9 Hz, 1H); 7.50 – 7.43 (m, 4H); 7.09 (d, J = 7.9 Hz, 2H); 6.91 – 6.86 (m, 2H); 6.80 – 6.74 (m, 3H); 6.55 (td, J = 6.9, 1.2 Hz, 1H); 2.28 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 160.6 (d, J = 243.3 Hz), 137.3, 136.8, 135.6 (d, J = 3.2 Hz), 133.2, 131.1, 129.1, 128.5, 126.8 (d, J = 7.7 Hz), 125.5, 119.8, 117.8, 115.7 (d, J = 22.1 Hz), 111.8, 111.6, 95.0, 21.2. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C21H16FNS, 334.1060; found, 334.1060. 2-(4-Chlorophenyl)-1-[(4-fluorophenyl)thio]indolizine (3i): Yield Method A: 0.097 g (91%); Method B: 0.104 g (98%); brown oil. Data for compound 3i obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.98 (d, J = 6.9 Hz, 1H); 7.60 – 7.56 (m, 4H); 7.33 (d, J = 8.5 Hz, 2H); 6.97 – 6.92 (m, 2H); 6.89 – 6.84 (m, 3H); 6.65 (td, J = 6.9, 1.1 Hz, 1H).

13C{1H}

NMR

(CDCl3, 100 MHz) δ (ppm) 160.7 (d, J = 243.7 Hz), 137.5, 135.2 (d, J = 2.9 Hz), 133.1, 132.6, 131.8, 129.9, 128.5, 126.9 (d, J = 7.7 Hz), 125.6, 120.1, 117.9, 115.8 (d, J = 22.1 Hz), 112.1, 111.8, 95.1. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H13ClFNS, 354.0514; found, 354.0514. 2-Phenyl-1-(propylthio)indolizine (3j): Yield Method A: 0.061 g (76%); Method B: 0.066 g (82%); brown oil. Data for compound 3j obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.81 (d, J = 6.9 Hz, 1H); 7.75 – 7.73 (m, 2H); 7.61(d, J = 9.0 Hz, 1H); 7.37 – 7.33 (m, 3H); 7.26 – 7.22 (m, 1H); 6.72 (ddd, J = 9.0, 6.6, 0.8 Hz, 1H); 6.46 (td, J = 6.9, 1.1 Hz, 1H); 2.39 (t, J = 7.3 Hz, 2H); 1.31 (sex, J = 7.3 Hz, 2H); 0.75 (t, J = 7.3 Hz, 3H).

13C{1H}

NMR

(CDCl3, 100 MHz) δ (ppm) 136.8, 134.9, 132.5, 128.8, 128.2, 126.8, 125.3, 118.5, 118.3, 111.3, 111.2, 99.2, 39.5, 22.7, 13.2. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C17H17NS, 268.1154; found, 268.1153. 1-(Propylthio)-2-(p-tolyl)indolizine (3k): Yield Method A: 0.062 g (74%); Method B: 0.065 g (77%); dark green oil. Data for compound 3k obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.80 (d, J = 6.9 Hz, 1H); 7.64 (d, J = 8.0 Hz, 2H); 7.60 (d, J = 9.0 Hz, 1H); 7.35 (s, 1H); 7.16 (d, J = 8.0 Hz, 2H); 6.71 (ddd, J = 9.0, 6.6, 0.9 Hz, 1H); 6.45 (td, J = 6.9, 1.1 Hz, 1H); 2.39 (t, J = 7.3 Hz, 2H); 2.32 (s, 3H); 1.32 (sex, J = 7.2 Hz, 2H); 0.76 (t, J = 7.3 Hz, 3H).



13C{1H}

Page 20 of 26

NMR (CDCl3, 100 MHz) δ (ppm) 136.8, 136.4, 132.5, 132.0, 129.0, 128.7, 125.2,

118.4, 118.2, 111.2, 111.1, 99.1, 39.5, 22.8, 21.2, 13.2. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C18H19NS, 282.1310; found, 282.1311. 2-(4-Chlorophenyl)-1-(propylthio)indolizine (3l): Yield Method A: 0.081 g (90%); Method B: 0.086 g (95%); dark green oil. Data for compound 3l obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.82 (d, J = 6.9 Hz, 1H); 7.70 (d, J = 8.6 Hz, 2H); 7.60 (d, J = 9.0 Hz, 1H); 7.37 (s, 1H); 7.32 (d, J = 8.6 Hz, 2H); 6.73 (ddd, J = 9.0, 6.6, 0.9 Hz, 1H); 6.48 (td, J = 6.9, 1.2 Hz, 1H); 2.37 (t, J = 7.3 Hz, 2H); 1.30 (sex, J = 7.3 Hz, 2H); 0.76 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 136.9, 133.4, 132.7, 131.2, 130.0, 128.4, 125.3, 118.8, 118.3, 111.5, 111.1, 99.2, 39.5, 22.7, 13.2. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C17H16ClNS, 302.0765; found, 302.0767. 2-Phenyl-1-(phenylselanyl)indolizine (3m): Yield Method A: 0.099 g (95%); Method B: 0.104 g (99%); white solid.; 85-88 ºC. Data for compound 3m obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.86 (d, J = 6.9 Hz, 1H); 7.56 – 7.54 (m, 2H); 7.49 – 7.47 (m, 2H); 7.27 – 7.23 (m, 2H); 7.19 – 7.15 (m, 1H); 7.07 – 7.03 (m, 2H); 6.94 – 6.91 (m, 3H); 6.72 (ddd, J = 9.0, 6.6, 0.8 Hz, 1H); 6.51 (td, J = 6.9, 1.0 Hz, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ

(ppm) 137.6, 135.3, 134.8, 133.7, 129.1, 128.9, 128.2, 127.9, 127.0, 125.4, 125.2, 119.6, 119.1, 112.0, 111.8, 91.6. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H15NSe, 351.0475; found, 351.0472. 2-(4-Chlorophenyl)-1-(phenylselanyl)indolizine (3n): Yield Method A: 0.112 g (97%); Method B: 0.113 g (98%); white solid.; mp 98-99 ºC. Data for compound 3n obtained by Method A: 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.92 (d, J = 6.9 Hz, 1H); 7.59 (d, J = 9.0 Hz, 1H); 7.52-7.50 (m, 3H); 7.29 (d, J = 8.4 Hz, 2H); 7.13-7.04 (m, 5H); 6.81-6.78 (m, 1H); 6.596.56 (m, 1H).

13C{1H}

NMR (CDCl3, 100 MHz) δ (ppm) 137.7, 135.0, 133.3, 132.9, 132.4,

130.2, 129.0, 128.3, 127.8, 125.4, 119.8, 119.0, 111.9, 91.5. HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C20H14ClNSe, 383.997; found, 383.9971. Gram-scale synthesis of 3c: In a round-bottomed flask were added the 1-(2-(4chlorophenyl)-2-oxoethyl)-2-((phenylthio)methyl)pyridin-1-ium bromide 4c (1.73 g, 0.3 mmol), K2CO3 (1 equiv) and glycerol (3.0 mL) as solvent. After that, the solution was submitted to vigorous stirring, at 70 ºC for 1 h (oil bath, Method A). At the end of the reaction, the solution was poured into water (20 mL) and extracted with ethyl acetate (3x 15 mL). The organic layer was separated, the residual water was removed with Mg2SO4, and it was concentrated under vacuum. Finally, the residue was purified by column chromatography using a mixture of hexanes/ethyl acetate (95/5) as the eluent, to give the product 3c (1.26 g, 94%).


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Bioassays General procedure for the ABTS•+assay Determination of the ABTS•+ radical-scavenging effect of compounds was performed according to the method of Re and co-workers,22 with some modifications. The ABTS was dissolved in water to 7mM concentration and the ABTS radical cation (ABTS•+) was produced by reacting ABTS stock solution with potassium persulfate (2.45 mM final concentration) and allowing the mixture to stand in the dark at room temperature for 12–16 h before use. In the day of assay, the pre-formed ABTS•+ radical solution was diluted 1:88 (1.0 mL ABTS•+ radical + 87.0 mL 10 mM potassium phosphate buffer, pH 7.0) to give an absorbance value of 0.7 at 734 nm. Solutions of 1-chalcogenylindolizines 3 and ascorbic acid were freshly prepared in DMSO and deionized water, respectively. In brief, ABTS•+ radical was added to a medium containing the compounds 3a, 3b, 3c, 3f, 3i, 3n or ascorbic acid (1-25 μM). The media were incubated for 30 min at 25 °C. The decrease in absorbance was measured at 734 nm, which depicted the scavenging activity of compounds against ABTS•+ radical. Ascorbic acid was used as a positive control. Statistical analysis was performed using a one-way ANOVA followed by the Newman-Keuls test. Values of p < 0.05 were considered statistically significant. The IC50 values (the concentration of an inhibitor in which the response is reduced by half) were calculated by linear regression from individual experiments using “GraphPad Software” (GraphPad software, San Diego, CA, USA). The IC50 values were reported as means accompanied by their 95 % confidence limits. Maximum inhibition (Imax - maximum percentage that an inhibitor reduced a response) was calculated at the most effective dose used. Conflicts of Interest There are no conflicts to declare. Acknowledgements The authors are grateful to CNPq, FAPERGS and FINEP for the financial support. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. CNPq is also acknowledged for Fellowships to G.P. and E.J.L.. Associated Content Supporting Information: Tables S1 and S2 and figures of the NMR spectra (1H, 13C{1H}) of all the synthesized compounds are found in the SI file.



Page 22 of 26

Notes and References 1. (a) Quin, L. D.; Tyrell, J. A. Fundamentals of Heterocyclic Chemistry, Wiley-VCH, Weinheim, 2010. (b) Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. Modern Heterocyclic Chemistry, Wiley-VCH, Weinheim, 2010. (c) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry, ed. Pergamon Press, Oxford, 1984. (d) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic Chemistry II, ed. Pergamon Press, Oxford, 1996. (e) Gomtsyan, A. Chem. Heterocycl. Comp. 2012, 48, 7-10. (f) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893-930. 2. (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888-3890. (b) Ulukan, H.; Swaan, P. W. Drugs 2002, 62, 20392057. 3. (a) Butler, M. S. Nat. Prod. Rep. 2005, 22, 162-195. (b) Bloch, W. M.; Derwent-Smith, S. M.; Issa, F.; Morris, J. C.; Rendina, L. M.; Sumby, C. J. Tetrahedron 2011, 67, 9368-9375. (b) Shen, Y. M.; Lv, P. C.; Chen, W.; Liu, P. G.; Zhang, M. Z.; Zhu, H. L. Eur. J. Med. Chem. 2010, 45, 3184-3190. 4. (a) Cingolani, G. M.; Claudi, F.; Massi, M.; Venturi, F. Eur. J. Med. Chem. 1990, 25, 709712. (b) Chai, W.; Breitenbucher, J. G.; Kwok, A.; Li, X.; Wong, V.; Carruthers, N. I.; Lovenberg, T. W.; Mazur, C.; Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med. Chem. Lett. 2003, 13, 1767-1770. 5. (a) Darwish, E. S. Molecules 2008, 13, 1066-1078. (b) Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C.; Samanta, A.; Banerjee, S.; Mondal, N. B. Eur. J. Med. Chem. 2011, 46, 2132-2140. 6. (a) Darwish, E. S. Molecules 2008, 13, 1066-1078. (b) Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C.; Samanta, A.; Banerjee, S.; Mondal, N. B. Eur. J. Med. Chem. 2011, 46, 2132-2140. 7. (a) Lenardão, E. J.; Santi, C.; Sancineto, L. New Frontiers on Organoselenium Compounds Springer: Cham, Switzerland, 2018. (b) Jain, V. K.; Priyadarsini; K. I. (Eds.) Organoselenium Compounds in Biology and Medicine: Synthesis, Biological and Therapeutic Treatments Royal Society of Chemistry: Croydon, UK, 2017. (c) Santi, C. (Ed.) Organoselenium Chemistry between Synthesis and Biochemistry, Bentham Books, 2014, DOI 10.2174/97816080583891140101. (d) Alberto, E. E.; Braga, A. L. Activation of Peroxides by Organoselenium Catalysts: A Synthetic and Biological Perspective, In: Derek, W. J.; Risto, L. (Eds.) Selenium and Tellurium Chemistry: From Small Molecules to Biomolecules and Materials. Springer: Berlin, 2011, pp. 251-283. (e) Wirth, T. (Ed.)


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O N

YR

+

Ar

Br

EtOAc 70 ºC, 24 h 50-86%

Y = S, Se R = Ph, 4-OMe-C6H4, 4-F-C6H4, Pr Ar = Ph, 4-Me-C6H4, 4-Cl-C6H4

YR

N Ar

Br O

key intermediate

K2CO3 (1 equiv) glycerol

Page 26 of 26

YR

Ar N 70 ºC (oil bath), 1 h or US (20 kHz), 5 min exclusively 1-substituted !! 74-99% 14 examples


Regioselective Synthesis of 1-Sulfanyl-and 1-Selanylindolizines

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