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Rapid Access to Novel 1,2,3-Triazolo-Heterocyclic Scaffolds via Tandem Knoevenagel Condensation/AzideAlkyne 1,3-Dipolar Cycloaddition Reaction in One Pot Ram Awatar Maurya, Praveen Reddy Adiyala, D Chandrasekhar, Chada Narsimha Reddy, Jeevak Sopanrao Kapure, and Ahmed Kamal ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2014 Downloaded from http://pubs.acs.org on June 21, 2014

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ACS Combinatorial Science

Rapid Access to Novel 1,2,3-TriazoloHeterocyclic Scaffolds via Tandem Knoevenagel Condensation/Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in One Pot Ram Awatar Maurya,* Praveen Reddy Adiyala, D. Chandrasekhar, Chada Narsimha Reddy, Jeevak Sopanrao Kapure, and Ahmed Kamal*

O

O O

+ O R2

R2

R2 Piperidinium acetate R1 EtOH, rt

N3

N

N AcOH

N

N Reflux

AcO R1 33 examples; 78-93% yield; high atom economy

ACS Paragon Plus Environment

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Rapid Access to Novel 1,2,3-Triazolo-Heterocyclic Scaffolds

via

Tandem

Knoevenagel

Condensation/Azide-Alkyne

1,3-Dipolar

Cycloaddition Reaction in One Pot Ram Awatar Maurya,* Praveen Reddy Adiyala, D. Chandrasekhar, Chada Narsimha Reddy, Jeevak Sopanrao Kapure, and Ahmed Kamal* Division of Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India KEYWORDS: Knoevenagel condensation, azide-alkyne cycloaddition, tandem reaction, triazole, pyrazolo-pyridine, β-carboline, isoquinoline ABSTRACT:

H O

O

+

R1

O R2

N3

Piperidinium acetate (one eq.) Ethanol, rt

O

R2

R2 N N N

AcOH

N OAc

Reflux

R1

R1

33 examples; 78-93% yield; high atom economy


1

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An operationally simple, one pot, two-step cascade method has been developed to afford biologically important fused 1,2,3-triazolo-heterocyclic scaffolds from 2-alkynyl aryl(heteroaryl) aldehydes and phenacyl azides. This unique atom economical transformation engages four reactive centres (aldehyde, alkyne, active methylene, and azide) under metal-free catalysis. INTRODUCTION The azide-alkyne 1,3-dipolar cycloaddition reaction has attracted an enormous amount of interest over the past decade. Today it is widely used in classical organic/combinatorial synthesis,1 medicinal chemistry/drug discovery programs,2 and has also made a major impact in polymer/material science,3 and in the field of chemical biology.4 The ease and efficiency of this reaction has been recognized in organic/aqueous solvents over a range of temperature varying from ambient to heating.5 Moreover, both terminal and internal alkynes have been efficiently used as compatible substrate with a high order of regioselectivity. In addition to the intermolecular format, many research groups have demonstrated intramolecular version of azidealkyne 1,3-dipolar cycloaddition reaction.6 However, most of the reported intramolecular strategies of the azide-alkyne 1,3-dipolar cycloaddition have largely utilized terminal alkyne in a multi-step format to facilitate the reaction with limited applications to internal alkynes.7 Intramolecular azide-alkyne cycloaddition provides an elegant access to interesting two annulated cyclic ring system. Thus, developing one pot, novel tandem process for intramolecular azide/internal alkyne 1,3-dipolar cycloaddition would open a rapid access to diverse heterocyclic scaffold.8 Efficient transformation of simple substrates into structurally novel and multifarious heterocycles constitutes a great challenge in organic chemistry. Tandem reactions which allow formation of multiple bonds in one pot operation have been recognised as a powerful tool to address these


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concerns.9 Presented in this letter is a tandem process which involves an intermolecular Knoevenagel condensation-intramolecular azide/internal alkyne 1,3-dipolar cycloaddition reaction in one pot that eventually leads to very interesting fused 1,2,3-triazolo-heterocycles. The strategy has been generalized on three distinct substrates bearing indole, pyrazole, and benzene core motifs. We have also demonstrated efficient conversion of fused 1,2,3-triazolo-heterocycles into β-carboline, pyrazolo-pyridine, and isoquinolines. These heterocycles are very important scaffolds as they are found in numerous synthetic and natural products of biological and pharmacological interest (Figure 1).10 HO O RO

N N H

R1

OH

OH Pyridindolol (beta-galactosidase inhibitor)

N

N N

N

N

Ph Cl

R

3-(2-Pyridinyl)isoquinoline Pyrazolo-pyridines (Selective Inhibitors of A1 Adenosine Receptors) (Adenosine A3 Receptor Ligands)

Figure 1. Chemical structure of some biologically important β-carboline, pyrazolo-pyridine, and isoquinoline.

RESULTS AND DISCUSSION Indole is considered as a privileged scaffold and is found in a plethora of synthetic and natural products of medicinal interest.11 Starting from 2-(arylethynyl)-indole-3-carbaldehyde 1

and

phenacyl azide 2, the proposed tandem Knoevenagel condensation-azide/internal alkyne 1,3dipolar cycloaddition reaction should lead to the formation of fused 1,2,3-triazolo-β-carbolines 3. Thus, firstly we sought to optimize the reaction by taking 1-benzyl-2-(phenylethynyl)-1Hindole-3-carbaldehyde 1{1} and 2-azido-1-phenylethanone 2{1} as reaction partners (Table 1).


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Table 1. Optimization of one pot, tandem Knoevenagel condensation-azide/internal alkyne 1,3-dipolar cycloaddition reaction.a O

O O

H + N

Ph N3

Ph

Ph

Ph

Catalyst Solvent

N Ph

2{1}

1{1}

Entry

Catalyst/additive

Catalyst/additi

Solvent

N

N N

Ph 3{1,1}

Temperature

3{1,1} (%)b

ve mol%

a

Yield of

1

Piperidine

20

Ethanol

rt

12

2

Piperidine

20

Ethanol

reflux

NI

3

DBU

20

Ethanol

rt

8

4

NaOH

20

Ethanol

rt

NI

5

p-TsOH

20

Ethanol

rt

NI

6

AcOH

20

Ethanol

rt

NI

7

Sc(OTf)3

20

Ethanol

rt

NI

8

PA

20

Ethanol

rt

35

9

PA

50

Ethanol

rt

55

10

PA

100

Ethanol

rt

88

11

PA

150

Ethanol

rt

88

12

PA

100

Ethanol

reflux

87

13

PA

100

Acetonitrile

rt

81

14

PA

100

Methanol

rt

87

b

1{1} (0.20 mmol), 2{1} (0.20 mmol), solvent (2.0 ml), catalyst, stir, 24 h. Isolated unoptimized yields. NI = Not isolated. rt = room

temperature. PA = Piperidinium acetate

A number of base (piperidine, DBU, NaOH) and acid [p-TsOH, AcOH, Sc(OTf)3] catalysts were attempted but none of them lead to a satisfactory yield of 3{1,1} either at ambient temperature or under reflux condition (Table 1, entry 1-7). Under basic conditions, substrate 1{1} remained largely unreacted whereas 2{1} was fully consumed. A careful survey of the literature revealed that the anion obtained after deprotonation of active methylene 2{1} with a base undergoes decomposition.12 We were pleased to achieve complete conversion of both 1{1} and 2{1} (TLC) and high yield of 3{1,1} using piperidinium acetate as an additive (100 mol%) at ambient


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temperature (Table 1, entry 10).13 The structure of 3{1,1} was assigned with the help of ESI-MS, 1

H NMR,

13

C NMR, IR, and HRMS data [IR spectra of 3{1,1} did not show any band

corresponding to azide and alkyne; 13C NMR of 3{1,1} did not show any alkyne carbon in typical acetylene region].

Refluxing the reaction mixture or further increasing the amount of the

additive (150 mol%) did not lead to any improvement. Methanol and acetonitrile were also found suitable solvents for the reaction. O H AcO

O Piperidinium acetate

H N Bn 1{1}

N N Bn 4{1}

-H 2O Ph

N3

Ph 2a -AcOH

Ph

N COPh N Bn

N N N Ph

5{1}

- Piperidine (as piperidinium acetate)

COPh N Bn

N3

N3

N Bn

6{1}

Ph

6'{1}

3{1,1}

COPh Ph

O

N

- Piperidine (as piperidinium acetate)

Ph N Bn

N

N N

Ph 7{1}

Scheme 1. A plausible mechanism for piperidinium acetate mediated tandem Knoevenagel condensationazide/internal alkyne 1,3-dipolar cycloaddition reaction.

Piperidinium acetate mediated reaction can be explained as depicted in Scheme 1. Substrate 1{1} reacts with piperidinium acetate to yield an imininium acetate 4{1} which is attacked by enol 2{1} leading to the formation of 5{1}. The intermediate 5{1} might lead to the formation of 3{1,1} in two different pathways depending on whether piperidine is lost before or after azide/alkyne 1,3-dipolar cycloaddition reaction. It is not easy for the Knoevenagel adduct 6’{1}


5

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to undergo intramolecular azide/alkyne cycloaddition due to azide/alkyne proximity limitations. Since 6’{1} (and even 6{1}) was never isolated in our reaction conditions, it might be assumed either 6{1} was preferentially formed or reaction proceeded via alternative pathway where elimination of piperidine occurred after azide/alkyne cycloaddition. However, a possibility of piperidine mediated isomerisation of 6’{1} to 6{1} cannot be ruled out.

O

R2

O O

H + R

N R

Methanol

N3 R1

N N N

Piperidinium acetate

2

N R

2

1

R1

3

O

O H

Ph

1{1}

H

H

N

Ph

O

O

H N

3{1,1} R = Bn, R1 = Ph, R2 = Ph (88%) 3{1,2} R = Bn, R1 = Ph, R2 = 4-Cl-C6 H4 (83%) 3{1,3} R = Bn, R1 = Ph, R2 = 4-F-C6H4 (91%) 3{1,4} R = Bn, R1 = Ph, R2 = 4-MeO-C6 H4 (86%) 3{1,5} R = Bn, R1 = Ph, R2 = 4-Ph-C6 H4 (90%) 3{1,6} R = Bn, R1 = Ph, R2 = 4-Me-C6 H4 (80%) 3{1,7} R = Bn, R1 = Ph, R2 = 3-MeO-C6 H4 (82%) 3{1,8} R = Bn, R1 = Ph, R2 = 4-(pyrrolidin-1-yl)phenyl (80%) 3{2,1} R = Bn, R1 = 4-MeC6H4, R2 = Ph (81%) 3{2,2} R = Bn, R1 = 4-MeC6H4, R2 = 4-Cl-C6H4 (80%) 3{2,5} R = Bn, R1 = 4-MeC6H4, R2 = 4-Ph-C6H4 (83%) 3{2,6} R = Bn, R1 = 4-MeC6H4, R2 = 4-Me-C6H4 (81%) 3{3,2} R = Bn, R1 = n-pentyl, R2 = 4-Cl-C6 H4 (80%) 3{3,6} R = Bn, R1 = n-pentyl, R2 = 4-Me-C6 H4 (81%) 3{4,2} R = Me, R1 = n-pentyl, R2 = 4-Cl-C6 H4 (78%) 3{4,6} R = Me, R1 = n-pentyl, R2 = 4-Me-C6H4 (80%)

N

N

Ph

Ph

1{2}

1{3}

1{4}

Diversity points in substrate 1 O

O N3

Cl

2{1}

N3 2{2}

O

N3

F

O

O

O

2{3}

N3

O 2{4}

O

N3

Ph 2{5}

N3 2{6}

O

O N3 2{7}

N3

N 2{8}

Diversity points in substrate 2

Figure 2. Synthesis of a library of fused 1,2,3-triazolo-β-carbolines 3 through tandem Knoevenagel condensationazide/internal alkyne 1,3-dipolar cycloaddition reaction. Bn = PhCH2, values in parenthesis represent isolated unoptimized yields.


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Having optimized the tandem strategy with the substrates 1{1} and 2{1}, a series of fused 1,2,3triazolo-β-carbolines 3 (Figure 2) were synthesized in high yields following the same protocol. It should be noted that azide-alkyne click reaction smoothly proceeded without any metal catalyst at ambient temperature making the process environmentally benign. In all of the reactions, a single new spot appeared on TLC and Knoevenagel adduct (corresponding to 6’{1} or 6{1}) was never obtained in any case. O N N Ph

H

8

Ar 1 +

O

Piperidinium acetate one equivalent Ethanol, rt, 24 h

N

N Ph

O Ar 2 2

Ar 2

N

N N

Ar 1 N3

9

Ar 1 = Ph, Ar2 = Ph (93%) Ar 1 = Ph, Ar2 = 4-Cl-C 6 H4 (90%) Ar 1= Ph, Ar 2 = 4-F-C 6H 4 (89%) Ar 1 = Ph, Ar2 = 4-MeO-C6 H 4 (88%) Ar 1 = Ph, Ar2 = 4-Ph-C6 H4 (89%) Ar 1 = 4-Me-C 6H 4, Ar2 = Ph (91%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-Cl-C6 H4 (93%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-F-C 6H 4 (90%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-MeO-C 6 H4 (85%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-Ph-C 6H 4 (91%)

O

O H

N

9{1,1} 9{1,2} 9{1,3} 9{1,4} 9{1,5} 9{2,1} 9{2,2} 9{2,3} 9{2,4} 9{2,5}

H

N N Ph

N Ph

8{1}

8{2}

Diversity points in substrate 8

Scheme 2. Synthesis of fused pyrazole-1,2,3-triazolopyridyls library through tandem Knoevenagel condensationazide/internal alkyne 1,3-dipolar cycloaddition reaction. Values in parenthesis represent isolated unoptimized yields.

Next we focused our attention towards synthesizing fused pyrazole-1,2,3-triazolopyridyls 9 by reacting 5-(arylethynyl)-1H-pyrazole-4-carbaldehyde 8 with phenacyl azides 2 using piperidinium acetate as an additive (Scheme 2). To our delight, substrate 8 smoothly reacted with phenacyl azides 2 in ethanol at room temperature using one equivalent piperidinium acetate as an additive leading to high yields of fused pyrazole-1,2,3-triazolopyridyls 9. All the reactions


7

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proceeded straightforwardly leading to a clean single spot on TLC with no side products. A series of fused pyrazole-1,2,3-triazolopyridyls 9 were successfully synthesized using the optimized protocol. Next we explored the scope of the tandem process using 2-(arylethynyl)benzaldehyde 10 as substrates.

In

contrast

to

indole

and

pyrazole

substrates,

the

reaction

of

2-

(phenylethynyl)benzaldehyde 10{1} with 2-azido-1-(4-fluorophenyl)ethanone 2{3} in ethanol using one equivalent piperidinium acetate remained incomplete even after 96 h. However, refluxing the reaction mixture for 24 h led to the complete consumption of both substrates (10{1} & 2{3}) yielding 11{1,3} (89%) (Scheme 3). Next, a series of fused 1,2,3-triazoloisoquinolines 11 were synthesized by refluxing 2-alkynylaryl aldehydes 10 and phenacyl azides 2 in ethanol using one equivalent of piperidinium acetate as an additive. O H O Ar 1

10 + N3 2

Ar 2 N N N

EtOH, reflux, 24 h

O Ar 2

Piperidinium acetate (one equivalent)

Ar1

11

11{1,2} 11{1,3} 11{1,4} 11{2,2} 11{2,3} 11{2,4} 11{2,5}

Ar 1 = Ph, Ar 2 = 4-Cl-C6 H 4 (85%) Ar 1 = Ph, Ar 2 = 4-F-C 6 H4 (89%) Ar 1 = Ph, Ar 2 = 4-MeO-C 6H 4 (82%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-Cl-C6 H4 (89%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-F-C 6H 4 (91%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-MeO-C 6H 4 (78%) Ar 1 = 4-Me-C 6H 4, Ar2 = 4-Ph-C 6 H4 (89%)

Scheme 3. Synthesis of 1,2,3-triazoloisoquinoline library through tandem Knoevenagel condensation-azide/internal alkyne 1,3-dipolar cycloaddition. Values in parenthesis represent isolated unoptimized yields.

Fused 1,2,3-triazolo-heterocycles 3, 9 & 11 are very interesting heterocycles in terms of their biological and pharmacological potentials since they bear privileged scaffolds (β-carboline, pyrazolo-pyridine & isoquinoline) as a part of their chemical structure. Moreover we found that these fused 1,2,3-triazolo-heterocycles 3, 9 & 11 could be converted to β-carboline 12, pyrazolopyridine 13 & isoquinoline 14 by refluxing the corresponding precursor in acetic acid. Thus,


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these new fused heterocycles provide efficient and alternative routes for β-carboline, pyrazolopyridine & isoquinoline (Scheme 4).

O O O

R''

Cl

R'

N

N AcOH

N N N

O

Cl

Ref lux, 12 h

R

N OAc N Bn Ph 12{1,2} (95%) Corresponding precursor = 3{1,2}

N N Ph

OAc

13{1,2} (96%) Corresponding precursor = 9{1,2}

OAc Ph 14{2,5}, R'' = 4-biphenyl (95%) Corresponding precursor = 11{2,5}

Scheme 4. Conversion of fused 1,2,3-triazolo-heterocycles to corresponding β-carboline, pyrazolo-pyridine, and isoquinoline. Values in parenthesis represent isolated unoptimized yields.

CONCLUSION An atom economical, tandem, four centred, one pot, two step method has been developed leading to the formation of structurally novel diverse heterocyclic scaffolds. The generality and scope of the strategy has been demonstrated on three distinct substrates (indole, pyrazole, and benzene). Furthermore, efficient conversion of these heterocyles into various other pharmacologically important β-carboline, pyrazolo-pyridine, and isoquinoline has been illustrated. EXPERIMENTAL General information. All the reagents and chemicals were purchased from commercial sources and used without further any purification. Anhydrous solvents were purchased from SigmaAldrich Company and used without further any purification. Common laboratory solvents (LR grade) were purchased from domestic suppliers. Analytical thin layer chromatography was performed with E. Merck silica gel 60 F aluminium plates and visualized under UV 254 nm.


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NMR spectra were measured with Brucker 300, 500, and 600 MHz, and Varian 400 MHz instruments. Chemical shifts are reported in δ units, parts per million (ppm) downfield from TMS. Coupling constants (J) are in hertz (Hz) and are unadjusted; therefore, due to limits in resolution, in some cases there are small differences (

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