Synthesis and functionalization of N-sulfinyl imines: Sonogashira reaction and copper-catalyzed azide-alkyne cycloaddition

Accepted Manuscript Synthesis and Functionalization of N-Sulfinyl Imines: Sonogashira Reaction and Copper-catalyzed Azide-alkyne Cycloaddition Frederico B. Souza, Stanley N.S. Vasconcelos, Joel S. Reis, Daniel C. Pimenta, Hélio Stefani PII: DOI: Reference:

S0040-4039(17)30149-1 http://dx.doi.org/10.1016/j.tetlet.2017.01.107 TETL 48610

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

31 December 2016 26 January 2017 30 January 2017

Please cite this article as: Souza, F.B., Vasconcelos, S.N.S., Reis, J.S., Pimenta, D.C., Stefani, H., Synthesis and Functionalization of N-Sulfinyl Imines: Sonogashira Reaction and Copper-catalyzed Azide-alkyne Cycloaddition, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.107

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Synthesis and Functionalization of N-Sulfinyl Imines: Sonogashira Reaction and Copper-catalyzed Azide-alkyne Cycloaddition

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Frederico B. Souza, Stanley N. S. Vasconcelos, Joel S. Reis, Daniel C. Pimenta and Hélio Stefani∗

1

Tetrahedron Letters journal homepage: www.elsevier.com

Synthesis and Functionalization of N-Sulfinyl Imines: Sonogashira Reaction and Copper-catalyzed Azide-alkyne Cycloaddition Frederico B. Souza, a Stanley N. S. Vasconcelos, a Joel S. Reis, a Daniel C. Pimenta.b Hélio Stefania* a

Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo – SP, Brasil Instituto Butantã, São Paulo – SP – Brasil Corresponding author: [email protected], Tel. 55 11 3091-3654

b

ARTICLE INFO

ABSTRACT

Article history: Received Received in revised form Accepted Available online

A small library of novel molecules was generated using a rapid and efficient methodology for the synthesis of N-sulfinyl imine triazole compounds. The process involves a coupling step from the Sonogashira cross-coupling reaction and then, in a one-step reaction, deprotection of the trimethylsilyl group and triazole heterocyclic ring formation using a microwave reactor.

2009 Elsevier Ltd. All rights reserved. Keywords: N-sulfinyl imines Sonogashira reaction Heterocycle Cycloaddition Triazole

1. Introduction N-Sulfinyl imines are of significant research attention because they are considered building blocks for more complex molecules, where it is desirable to obtain amines, since many drugs and drug candidates have this functionality.1 Some examples of the use of these compounds as substrates, in order to be added to the electrophilic position to generate different amines, are in the synthesis of α-amino acids,2 α-amino phosphonates,3 aziridine carboxylates4 and aziridine phosphonates.5 In addition to their building block functionality, studies have also shown their use in reactions as important chiral ligands.6,7 Thus, we decided to investigate the possibility of working with these compounds, not for the addition of some type of nucleophile, but instead for making a functionalization on a molecule so that we can obtain our N-sulfinyl imine product with the triazole heterocyclic ring. The importance of the unnatural triazole heterocycle ring in various fields of science,8–10 whether in medical chemistry,11–13 materials science14,15 or biochemistry16,17, is already well known.18 Although click chemistry is a concept that encompasses several reactions that meet the requirements,19,20 the most common of these reactions is the Cu(I)-catalyzed version of the Hüisgen 1,3-dipolar cycloaddition reaction between alkynes and azides for the synthesis of triazole scaffolds. The ever increasing advances in the field of click chemistry have made it a powerful strategy for the development and optimization of drug candidates. Thus, by knowing some of the pharmaceutical properties that triazole rings may present as an antiviral, antibacterial or antiHIV (Figure 1), and the possibility of performing biological experiments to test the compounds synthesized by us, a small

library of N-sulfinyl imine triazole compounds was prepared using a quick and simple methodology. H O O S N

N

N

N N N

N

O OH O Antibacterial

N N

N O

Anti-HIV

Figure 1. Structures of biologically active 1,2,3-triazoles. The use of microwave radiation as an alternative source of energy for conducting organic synthesis is widely accepted as it often has several beneficial factors, which consequently generate improvements in the synthetic process.21–23 Specifically, we note the reduction of reaction time since microwave radiation can use a temperature and pressure greater than in a conventional system, higher yields due mainly to fewer by-products and reproducibility since there is extreme precision in the cavity of the equipment in relation to the parameters used, such as temperature, pressure and energy.24 Results and Discussion We first synthesized the starting material, the N-sulfinyl imine 125 using freshly prepared LiHMDS26 with the commercially available menthyl-p-toluenesulfinate and finally, pbromobenzaldehyde. The product was obtained after recrystallization in n-pentane, with 72% of yield.

2

Tetrahedron other nitrogen base pentamethyldiethylenetriamine gave a moderate yield (Table 1, entry 6).

With this compound in hand, we began the screening to find the best conditions for the Sonogashira cross-coupling reaction using the N-sulfinyl imine 1 together with ethynyltrimethylsilane in the presence of palladium catalysts, copper salts, N,Ndiisopropylethylamine and tetrahydrofuran, and microwave source of energy to obtain the sulfinimine 3 as product.27 Before starting the screening, we tested this reaction in microwave and ultrasound, the first being shown to be more effective in conducting the reaction once the yield was higher in 4%. Table 1. Screening of Sonogashira coupling reaction conditions

After this step, we began the screening of the catalysts. The first to be tested was copper and we tried it in different oxidation states. Copper iodide continued to show the best results (Table 1, entry 5), but we can see that when used copper (II) sources, it was necessary to add sodium ascorbate to promote the reduction of copper II to copper I, since when this was not the case, the yield of the reaction decreased dramatically (Table 1, entries 11– 12). Finally, we tested the different sources of palladium catalysts. We also use them in different oxidation states (0 and II) and what proved to be better as a reaction condition was the tetrakis(triphenylphosphine)palladium(0) (Table 1, entry 18). Once the conditions were optimized for the Sonogashira reaction, we focused our attention on finding the best conditions for the copper-catalyzed azide-alkyne cycloaddition and the first parameter to be evaluated was the copper catalyst.

a

Entry

“Cu”

Catalyst

Base

Solvent

Yield (%)

1

CuI

Pd(PPh3)2Cl2

DIPEA

DMF

71

2

CuI

Pd(PPh3)2Cl2

DIPEA

ACN

42

3

CuI

Pd(PPh3)2Cl2

DIPEA

THF

72

4

CuI

Pd(PPh3)2Cl2

DIPEA

Toluene

nr

5

CuI

Pd(PPh3)2Cl2

Et3N

THF

76

6

CuI

Pd(PPh3)2Cl2

PMDTA

THF

68

7

CuI

Pd(PPh3)2Cl2

Cs2CO3

THF

49

8

CuCl

Pd(PPh3)2Cl2

Et3N

THF

59

9

CuBr

Pd(PPh3)2Cl2

Et3N

THF

64

10

CuCN

Pd(PPh3)2Cl2

Et3N

THF

66

11

CuSO4

Pd(PPh3)2Cl2

Et3N

THF

The copper-catalyzed azide-alkyne cycloaddition of the sulfinimine 3 with an organic azide (4a-m) using a source of copper catalyst, nitrogen base and solvent, preceded by the deprotection of the trimethylsilyl group using TBAF in a one-pot reaction in order to obtain the triazole heterocyclic ring 5a.28 Table 2. Screening of CuAAC conditions

Entry

“Cu”

Additive

Solvent

Yield(%)a

1

CuSO4

Na Asc

DMF

89

2

CuSO4

-

DMF

18

3

CuI

Na Asc

DMF

77

4

CuI

-

DMF

75

5

CuCl

-

DMF

63

6

CuBr

-

DMF

68

7

CuCN

-

DMF

71

62

8

Cu(OAc)2

Na Asc

DMF

54

CuSO4

49b

12

Cu(OAc)2

Pd(PPh3)2Cl2

Et3N

THF

43b

13

CuI

Pd2(dba)3

Et3N

THF

70

14

CuI

Pd(dppf)Cl2.

Et3N

THF

48

CH2Cl2 15

CuI

Pd(OAc)2

Et3N

THF

16

CuI

Pd(PPh3)4

Et3N

THF

81

9

Na Asc

ACN

81

17

CuI

PEPPSITM-iPr

Et3N

THF

73

10

CuSO4

Na Asc

THF

76

18

CuI

Pd(acac)2

Et3N

THF

45

11

CuSO4

Na Asc

DCM

69

a

Yields refer to the isolated product b Sodium ascorbate was used in the reaction

We varied the conditions by changing the solvents (Table 1, entries 1–4), copper catalyst, base (Table 1, entries 5–7), copper source (Table 1, entries 7–12) and finally, the palladium catalyst (Table 1, entries 13–18). As we can see from Table 1, the best solvent to conduct the reaction was polar aprotic THF (Table 1, entry 3). We also tried the non-polar solvent toluene (Table 1, entry 4), polar aprotic DMF (Table 1, entry 1) and polar protic methanol (Table 1, entry 2). When the best solvent for the reaction was obtained, we started the screening of the bases. We tested both organic and inorganic bases and obtained an improvement in yield when the base used was triethylamine (Table 1, entry 5). The lowest yield occurred when using cesium carbonate (Table 1, entry 7) and the

a

Yields refer to the isolated product

As we can see from Table 2, we used different sources of copper in oxidation states of I and II, however, the case of copper sulphate (II) together with the reducing agent sodium ascorbate presented the highest yield (Table 2, entry 1). The use of sodium ascorbate to obtain the product in a good yield has been shown to be even more essential since, when it is not used, the product is generated in much a lower yield (Table 2, entry 2). The efficacy and justification of the use of sodium ascorbate was proved when it is added in sources of copper in oxidation state I , showing that in this case it is not necessary since the yield is almost the same. We next proceeded to the screening of the solvents. We used acetonitrile (Table 2, entry 9), tetrahydrofuran (Table 2, entry 10) and dichloromethane (Table 2, entry 11), but dimethylformamide

3 remained the solvent that produced the best reaction conditions (Table 2, entry 1). After confirming that both attempted reactions were successfully performed, namely, the Sonogashira coupling and CuACC, we saw the possibility of carrying out the one-pot triazole ring synthesis in a domino reaction once some reagents and solvents used coincided in the reactions, except for the palladium catalyst and TBAF (Scheme 1).

Scheme 1. One-pot triazole synthesis attempt Unfortunately, after many attempts, we still did not achieve the desired product and decided to follow the synthetic route that we had already defined. The first change was the attempted formation of the coupling product promoted in the microwave reactor, which was shown to be effective, since the yield was 4% higher than when done in batch. In addition, we tried to do the reaction with ultrasound, but microwave radiation continued to show the best result. After determining the optimal conditions for the one-pot deprotection of trimethylsilyl group and [3+2] cycloaddition reaction of alkyne and organoazide, we explored the generality of the protocol, as indicated in Table 3. We decided to use arylazides since our research group is interested in fluorescent compounds,29 so aromatics substituents would increase the conjugation of the molecule, increasing the likelihood of a positive result. Table 3. Exploring the scope of N-sulfinyl imine triazole synthesis.

By analyzing Table 3, we can see that all reactions generated products with yields considered moderate to good, but as expected, the substituents attached to the aromatic ring have electron influences that interfere with the reaction. The lowest yields were obtained with groups that exhibit electronwithdrawing characteristics, such as p-NO2 (Table 3, entry 5k) and p-CF3 (Table 3, entry 5f). The substituents connected to the ring with electron donor characteristics generated the triazole products with higher yields, such as p-OMe (Table 3, entry 5c) and the heterocyclic thiazole (Table 3, entry 5d). Neutral groups also gave products in good yields, like phenyl (Table 3, entry 5i) and naphthyl (Table 3, entry 5g). We also synthesized triazoles containing para-position halogens (Table 3, entries 5e-5j-5l), which leaves a possible future functionalization open in the molecule. Triazole compounds were synthesized from the aryl azides derived from salicylic acid (Table 3, entry 5h) and the oxazoline heterocyclic ring (Table 3, entry 5m).

Acknowledgments The authors are grateful for financial support provided by the FAPESP, São Paulo Research Foundation, Brazil (grant numbers 2012/00424-2 and 2016/05260-9 to FBS), the National Council for Scientific and Technological Development (CNPq), Brazil, for a fellowship (306119/2014-5 to HAS) and FINEP, Brazil, (grant number 01.09.0278.04 to DCP). References and notes 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12.

13. 14. 15.

16.

17. 18. 19. 20. 21. 22.

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Tetrahedron 23. Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron, 2001, 57, 9225. 24. de la Hoz, A.; Díaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev., 2005, 34, 164. 25. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62, 2555. 26. General procedure for the LiHMDS synthesis: Add an excess of HMDS (compared to n-BuLi, 1.1 eq.) in anhydrous THF 1ml/mmol, under nitrogen atmosphere. The solution must be cooled to -78 ºC and after that, the n-BuLi is added slowly to the reaction. When the addition is finished, the solution is allowed to warm to 0 ºC and stirred for 15 min. 27. General procedure for the Sonogashira cross-coupling reaction: Compound 1 (1 eq.) in THF (1 mL/mmol), ethynyltrimethylsilane (1.2 eq.), cooper iodide (12 mol%), tetrakis(triphenylphosphine)palladium(0) (4 mol%), triethylamine (3 eq.) were placed in a 10-mL SiC vial, sealed with a PTFEcoated silicon septum and closed with a snap cap made of PEEK. A stir bar coated with PTFE was placed inside the vial for proper homogenization. The reaction tube was placed inside the cavity of an Anton-Paar microwave synthesis system, operated at 80 ºC, a power of 100 W and a pressure of 5 bar for 30 min. After completion of the reaction, NH4Cl solution was added and extracted with EtOAC (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. Purification was accomplished by chromatography on silica gel eluted with Hex/EtOAc (5 %). 28. General procedure for the copper-catalyzed azide-alkyne cycloaddition: Compound 3 (1 eq.) in DMF (5 mL/mmol), copper sulphate (1 eq.), sodium ascorbate (1 eq.) and organoazide (1.1 eq.) were placed in a 10-mL SiC vial, sealed with a PTFE-coated silicon septum and closed with a snap cap made of PEEK. A stir

bar coated with PTFE was placed inside the vial for proper homogenization. The reaction tube was placed inside the cavity of an Anton-Paar microwave synthesis system, operated at 80 ºC, a power of 100 W and a pressure of 5 bar for 20 min. After completion of the reaction, NH4Cl solution was added and extracted with EtOAC (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. Purification was accomplished by chromatography on silica gel eluted with Hex/EtOAc (40 %). Compound 5b: Yield 73%, yellow oil. 1H NMR (300 MHz, CDCl3-d) δ 8.73 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H) 8.01 (d, J = 8.4 Hz, 1H) 7.80 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H) 7.70 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.79 (t, J = 8.3 Hz, 1H)7.55 (d, J = 8.3 Hz, 2H), 2.40 (s, 3H). 13C NMR (75 MHz, CDCl3-d) δ 159.42, 145.83, 138.27, 136.48, 132.77, 132.57, 132.29, 131.94, 130.81, 129.88, 128.49, 128.15, 127.40, 125.32, 124.66, 119.65, 111.57, 52.13, 21.08.HRMS (ESITOF) m/z calcd for C22H17N5O3S + H+: 431,1052. Found: 431,1059. 29. Vasconcelos, S.N.S; Rodrigues, A.C.B; Bastos, E.L; Stefani, H.A. Chemistry Select, 2016, 6, 1287.

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Highlights Synthesis and Functionalization of N-Sulfinyl Imines: Sonogashira Reaction and Copper-catalyzed Azide-alkyne Cycloaddition Frederico B. Souza, a Stanley N. S. Vasconcelos, a Joel S. Reis, a Daniel C. Pimentab and Hélio Stefania a

Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo - SP, Brasil. bInstituto Butantã, São Paulo – SP, Brasil Corresponding Author: [email protected]; Tel 55 11 3091-3654

-Sonogashira cross-coupling reaction -Copper-catalyzed azide-alkyne cyclization -Synthesis of N-sulfinyl imine triazole.

*Corresponding author. Tel.: +55 11 3091 3654; Fax: +55 11 3815 441; e-mail: [email protected] (H.A. Stefani)