Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine-2,4

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Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3d]Pyrimidine-2,4-Diones Via One-Pot Three Component Reactions Shaik Karamthulla, Asim Jana, and Lokman Hakim Choudhury ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.6b00147 • Publication Date (Web): 30 Dec 2016 Downloaded from http://pubs.acs.org on January 2, 2017

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ACS Combinatorial Science

Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine-2,4-Diones

Via

One-Pot

Three Component Reactions Shaik Karamthulla,a,b Asim Janaa and Lokman H. Choudhurya* a

Department of Chemistry, Indian Institute of Technology Patna, Bihar, Patna-8001103,

INDIA b

Department of Chemistry, Rayalaseema University, Kurnool, Andhra Pradesh-518007,

INDIA E-mail; [email protected] NH2 O R O

S R1 R1

N

Ar N R

N H

O

MW, 130 oC 20 min AcOH

Ar

R OH + OH

O

CN

N N R

4

O O

CN

O

SH

NH2

Method A/B

R

CN

N

O

Ar N R

N H 5 Method-B EtOH, MW 80 oC, 15 minutes

Method-A EtOH, Reflux 5-8 h

ABSTRACT: A simple and novel method for the synthesis of 5,6-disubstituted pyrrolo[2,3d]pyrimidine-2,4-diones has been reported using

arylglyoxal based three component

reactions. Under microwave heating conditions, arylglyoxal, 6-amino uracil or its derivatives reacts with various thiols in acetic acid medium to provide a series d]pyrimidine-2,4-diones

(4)

of

pyrrolo[2,3-

having a thioether and an aryl ring in 5 and 6 positions

respectively. On the other hand reaction of arylglyoxal, amino uracil and malononitrile in place of thiols, provided corresponding

5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-

diones (5) with selectively converting one of the -CN to -CONH2 group both in conventional (method A) and microwave heating conditions (method B). This methodology is a simple and

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efficient protocol for the synthesis of diverse 5,6-disubstituted pyrrolo[2,3-d]pyrimidine2,4-diones from the readily available starting materials in good yields.

KEYWORDS: Arylglyoxal monohydrates, 6-Aminouracil derivatives, Thiols, Malononitrile, 5,6-disubstituted pyrrolo[2,3-d]pyrimidines, Microwave assisted reactions

INTRODUCTION Pyrrolo[2,3-d]pyrimidine scaffolds are abundant in various natural products as well as in synthetic drugs.1 Due to their resemblance to purines and pyrimidines, pyrrolo[2,3d]pyrimidine scaffolds exhibit diverse biological activities such as antitumor,2 antifolates,3 anti-viral,4 analgesic,5 antagonist to receptors,6 anti-microbial,7 antifungal,8 anticancer,9 antibiotics,10 antiproliferative,11 antipyretic, anti-inflammatory, as well as anticonvulsant activities.12 Moreover, pyrrolo[2,3-d]pyrimidine derivatives are also potent inhibitors of protein kinases such as the enzyme Janus Kinase 3 (JAK 3) and hence they are useful for the treatment of a wide range of immunological disorders.13

A wide range of clinically approved drugs have pyrrolo[2,3-d]pyrimidine core. e.g. Pemetrexed, a chemotherapy drug used for the treatment of pleural mesothelioma and nonsmall cell lung cancer14 and Tofacitinib a drug used for the treatment of psoriasis, rheumatoid arthritis (RA), and inflammatory bowel disease.15 Likewise, biologically active nucleosides such as Sangivamycin and Toyacamycin exhibit antimicrobial, antiparasitic, antiviral, and antineoplastic activities.16 Pyrrolo[2,3-d]pyrimidine and its oligoarylene analogues also exhibit strong UV-blue fluorescence and are used as fluorescent functional materials.17

Considering their wide range of biological activities and pharmaceutical importance we realized the scopes to develop better and efficient synthetic methodologies for the synthesis 2 ACS Paragon Plus Environment

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of novel pyrrolo[2,3-d]pyrimidine derivatives. Literature survey reveals that there are only limited methods known for the synthesis of pyrrolo[2,3-d]pyrimidine core. Some of the useful methods for the synthesis of pyrrolo[2,3-d]pyrimidines include reaction of α-halo carbonyl compounds with 2,6-diaminopyrimidin-4-on,18 three-component reactions of 6aminouracil derivatives, arylglyoxal and dimedone in the presence of catalytic amount of acetic acid,19 one-pot three component reaction of 6-amino-pyrimidine-2,4-dione derivatives, aldehydes and nitro methane using CuFe2O4 magnetic nanoparticles,20 one-pot microwave assisted three component coupling reaction of 6-amino-1,3-dimethyluracil, aryl amines and arylglyoxal monohydrates21 etc..

Microwave heating reduces reaction time drastically usually from several hours to minutes, and also allows chemists to use this technique to synthesize diverse molecules in less time, as a result microwave heating has gained huge popularity in organic synthesis.22 It is also more efficient in terms of energy consumption with compared to conventional heating, minimizes cost, as well as provides clean products in good to excellent yields. Multicomponent reactions (MCRs) in tandem with microwave-assisted chemistry offers many advantages in terms of purity, selectivity, chemical yield, enhanced reaction rates and simplicity.23 Considering the merits of microwave heating in MCRs, very recently we have explored this strategy for the synthesis of diverse heterocycles.24 In continuation of our work on arylglyoxal-based MCRs herein, we report a convenient three component reactions to access disubstituted pyrrolo[2,3d]pyrimidine derivatives as shown in Scheme 1.



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NH2 O R O

S R1 R1

N

Ar N R

N H

O

SH


O Ar

R OH + OH

4

O

CN

N N R

O O

CN

NH2

Method A/B


R O

CN

N

Ar N R

N H 5 Method-B EtOH, MW 80 oC, 15 minutes

Scheme 1. Multicomponent synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine2,4-Diones

RESULTS AND DISCUSSION The preliminary investigation for this MCR was initiated by the reaction of phenylglyoxal monohydrate 1{1}, 6-amino-1,3-dimethyluracil 2{1} and 2-mercaptopyrimidine 3{1} under microwave heating conditions. The reaction mixture having 1:1:1 equivalent mixture of 1{1}, 2{1} and 3{1) was tested in the presence of various solvents and catalysts and the results are summarized in Table 1. Under catalyst-free microwave heating conditions when this model reaction was tried in water, only 21% of the desired product 4{1,1,1} was obtained. Changing solvent from water to ethanol and keeping all other parameters same

provided only trace

amount of the product. Next to optimize the reaction conditions; the model reaction was tried in the presence of 20-mol% of various acidic catalysts such as para-toluene sulfonic acid (PTSA), iodine and acetic acid at 120 oC, for 20 minutes under microwave irradiation. Moderate yields of 4 {1,1,1} were obtained in these cases (Table 1, entry 3-5). Interestingly, when amount of acetic acid was increased to 100 mol% slightly better yield was observed (Table 1, entry 6). Next, the model reaction was checked using solvents (EtOH+AcOH; 1:1), (H2O +AcOH; 1:1) and only AcOH. Interestingly, for this MCR, acetic acid was found as the best solvent among all the screened solvents. Keeping reaction temperature at 130 oC for 20 minutes in acetic acid as solvent cum promoter provided the optimum yield (89%) of this reaction (Table 1, entry 10). 4 ACS Paragon Plus Environment

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Table 1: Optimization of reaction conditions for compound 4{1,1,1}a O O OH

Ph

OH

N

Entry

+ N

+ N

O

1{1}

SH

2{1}

Solvent

Solvent Catalyst Temperature

N O

MW

O

N H

N

3{1}

Catalyst (mol

N

N

N

NH2

S

4{1,1,1}

Temp (o C)

%)

Time

Yield b(%)

(min)

1

Water

----

120

20

21

2

EtOH

----

120

20

trace

3

EtOH

PTSA (20)

120

20

41

4

EtOH

I2 (20)

120

20

26

5

EtOH

AcOH (20)

120

20

38

6

EtOH

AcOH (100)

120

20

52

7

EtOH- AcOH

----

120

20

64

----

120

20

69

mixture( 1:1 ) 8

Water- AcOH mixture( 1:1 )

9

AcOH

----

120

20

78

10

AcOH

----

130

20

89

a

Reaction conditions: phenylglyoxal monohydrate (1.0 mmol), 2-marcaptopyrimidine (1.0 mmol),

and

6-amino-1,3-dimethyluracil (1.0 mmol). bIsolated yield.

After establishing the optimized reaction conditions, a series of disubstituted pyrrolo[2, 3d]pyridinedione derivatives were successfully synthesized under the given reaction conditions and the results are summarized in the Table 2. It was found that a wide range of arylglyoxals bearing either electron-donating or electron-withdrawing substituents like -F, OMe, -NO2, on the phenyl ring are suitable for this three component reaction and the corresponding three component products were obtained in good yields using both 6-amino1,3-dimethyluracil and 6-aminouracil. To extend the scope of this methodology, disubstituted arylglyoxal such as 3,4-(methylenedioxy)phenylglyoxal and bulky arylglyoxal such as 65 ACS Paragon Plus Environment


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methoxynaphthylglyoxal were also tested and the corresponding three component products were obtained in good yields. Next the variability of other thiols such as 2-marcapto pyridine, thiophenol, 4-methyl thiophenol and 4-methoxy thiophenol were tested and

the

corresponding desired three component products 4{1,1,2}, 4{1,1,3}, 4{1,1,4}, 4{1,1,5} and 4{5,1,4} were obtained in good yields. Structures of all the starting materials used in the three component reaction for the preparation of pyrrolo[2,3-d]pyridinedione derivatives tethered with aryl and thioether group is shown in Figure 1.

Arylglyoxal monohydrate 1: O

O

O OH OH

OH

F

1{1}

1{2}

O

O OH

OH

MeO

1{3} O OH

OH

O

OH

O2N

OH

OH

OH

O

1{6}

1{5}

1{4}

OH

MeO

6-AminoUracile 2: O

N

H N

O

N

HN

NH2

NH2

O

O

2{1}

2{2}

Thiols 3: SH N

3{1}

N

SH

SH

SH

SH

Me

OMe

N

3{2}

3{3}

3{4}

3{5}

Figure 1. Substrates used in the multicomponent synthesis of compounds 4. 6 ACS Paragon Plus Environment

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Table 2: Three component synthesis of pyrrolo[2,3-d]pyrimidinediones (4)a O

O OH

Ar

RN

+ OH

O

Entry

O +

N R

NH2

R1

Yieldb

Product

(%)

AcOH

SH

RN o

MW, 130 C 20 min Entry

O

S

N 89

O

N 78

N H

N

4{1,1,1}

OMe 4{6,1,1}

N O

N O

S

F

85

N

HN

7

N H

N

O

S

N

N 2

76

N H

N H

O

4{1,2,1}

4{2,1,1}

N O

S

N O

O

OMe N

S

N

N 3

85

8

N H

O

O

N H

N

N H

52

9

S

O

N H

N H 4{3,2,1}

N 5

S

N O

N

N O

O O

N

N H

80

N

HN

4{4,1,1}

O

OMe

N O

NO2 N

63

4{2,2,1}

N 4

F N H

N S

N

HN

4{3,1,1}

O

(%)

N

6

N H

N

Yieldb

N

N

1

N H

N R

Product

O

S

Ar

O

N O

S R1

82

10

S

HN O

N

O O

N H

73

N H 4{5,2,1}

4{5,1,1}



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N O

S

O

N

HN 11

O

N H

N H

OMe

74

S

N

14

70

O

N H

N

4{1,1,4}

4{6,2,1}

N O

S

O

N 12

O

N

N H

68

15

N O

74

N

O

O

S

N

13

70

N

N H

N H 4{1,1,5}

4{1,1,2}

O

OMe S

S

N 16

O

O O

N

71

N H 4{5,1,4}

4{1,1,3} a

Reaction conditions: arylglyoxal monohydrate (1 mmol), thiols (1 mmol), and 6-aminouracil

derivatives (1 mmol), in acetic acid at 130 oC. bIsolated yield.

After the successful demonstration of this methodology next we wanted to replace thiol by a C-nucleophile malononitrile in this three component reactions. When the three component reaction of phenylglyoxal monohydrate, 6-amino-1,3-dimethyluracil and malononitrile in ethanol under microwave heating conditions were tried in the absence of any catalyst or promoter, a novel product [2-cyano-2-(1,3-dimethyl-2,4-dioxo-6-phenyl-2,3,4,7-tetrahydro1H-pyrrolo[2,3-d]pyrimidin-5-yl)acetamide] with pyrrolo[2,3-d]pyrimidinedione core was obtained in good yield. Interestingly, in this three component reaction, one of the two cyano groups of malononitrile hydrolyzed into a corresponding amide group. By using this three component approach a series of 2-cyano-2-(1,3-dimethyl-2,4-dioxo-6-aryl-2,3,4,7-tetrahydro1H-pyrrolo[2,3-d]pyrimidin-5-yl)acetamides 5a to 5e were prepared using both microwave and conventional heating conditions in ethanol and the results are summarized in Table 3. 8 ACS Paragon Plus Environment

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Table 3: Three component synthesis of pyrrolo[2,3-d]pyrimidinedionesa NH2 O O Ar

OH OH

Entry

CN

N +

O

Method-A EtOH, Reflux 5-8 h Method-B EtOH, MW 80 oC, 15 minutes

N

NH2

Time

Yield (%)b

(h)

Method A

+

CN

OO

CN

N O

Ar N

N H Yield (%)c

Product

Method B

NH2 O O 1

6

CN

N

82

O

76

N H

N

5a

NH2 O O 2

6

CN

N

85

80

OMe

82

N H

N

O

F

5b

NH2 O O

CN

N 3

5

90

O

N H

N

5c

NH2 O O 4

8

CN

N

82

O

O O

75

N H

N

5d

NH2 O O 5

8

CN OMe

N

78

O

N

71

N H 5e



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a

Reaction conditions: arylglyoxal monohydrate (1.0 mmol), malononitrile (1.0 mmol), and 6-amino-

1,3-dimethyluracil (1.0 mmol), in ethanol under reflux conditions (method A) or microwave heating conditions (80 oC, 15 minutes method B). bIsolated yield in case of Method A. cIsolated yield in case of Method B.

Finally, we tried to check the suitability of this three component reaction in gram scale synthesis. Interestingly, product

5a was obtained in 80% yield within 15 minutes while

performing the reaction in 10 mmol scale (using 1.52 gm of phenylglyoxal monohydrate) under microwave conditions. Similarly, under conventional heating (method B) using 10 mmol scale of the same reaction provided 73 % yield of 5a.

On the basis of the above-described results, the most probable reaction pathways for the formation of 4 and 5 using the three-component reactions are depicted in Scheme 2. For the formation of 4, initially intermediate A will form by the reaction of arylglyoxal and aminouracil derivative in the presence of acid. Nucleophilic addition of thiol with intermediate A will provide B, which undergoes intramolecular cyclization and followed by dehydration will give the desired product 4. While in the case of malononitrile, Knoevenagel condensation of arylglyoxal 1 with malononitrile gives intermediate C. Michael addition of 6-amino-1,3-dimethyluracil to intermediate C will provide intermediate D, which can undergo intramolecular cyclization and finally leading to the formation of 5.


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Scheme 2. Proposed Reaction Pathway O CN

N

O

CN Ar

CN

NH2

OH

O

Ar

RN O

OH

C

O

RN

O Ar

R N

O

O

N R

NH

H+

RSH

O

SR

A

NR H2N

O

N R

O

N

NC H

O

O

RN

O NH2

N R

B

O

N R

NH D

Ar

H+

H+

O NC H

O RN O

O

O

NC

-H2O

SR

RN

NH

N Ar H E

N R

O

Ar N R

N H

4

O NH2

RN O

Ar

RN

Ar N H

N R 5

CONCLUSIONS In conclusion we have demonstrated an efficient, one-pot method for the expeditious synthesis of novel pyrrolo[2,3-d]pyrimidine derivatives via three component reactions. The notable features of this methodology are easily available starting materials, no need of column chromatographic separation/purification, short reaction time, good yields and useful for the easy access of diverse pyrrolo[2,3-d]pyrimidine derivatives.



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ASSOCIATED CONTENT *Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxxxxxxxxxxx Experimental details and spectroscopic characterization of all the compounds and 1H and 13C spectra for all products. (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected], [email protected]

ACKNOWLEDGMENTS S.K is thankful to CSIR for his fellowship (SRF). Authors are grateful to IIT Patna for the financial support for carrying out this work. We are also thankful

to SAIF IIT Patna for

providing HRMS data.

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Pyrrolo[2,3-d]pyrimidines.

Unexpected

Products

in

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(a)

Mishra,

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Adv., 2016, 6, 24464-24469; (b) Karamthulla, S; Khan, M. N.; Choudhury, L. H. Microwave-Assisted Synthesis of Novel 2,3-Disubstituted Imidazo[1,2-A]Pyridines Via One-Pot Three Component Reactions. RSC Adv., 2015, 5, 19724-19733; (c) Karamthulla, S.; Pal, S.; Khan, M. N.; Choudhury, L. H. On-Water Synthesis of Novel Trisubstituted 1,3-Thiazoles via Microwave-Assisted Catalyst-Free Domino Reactions. RSC Adv. 2014, 4, 37889-37899.



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

Synthesis of Novel d]Pyrimidine-2,4-Diones Reactions

5,6-Disubstituted Pyrrolo [2,3Via One-Pot Three Component

Shaik Karamthulla,a,b Asim Janaa and Lokman H. Choudhurya* NH 2 O R O

S R1 R1

N

Ar N

N H

R


O Ar

R OH + OH

O

CN

N N

NH 2

Method A/B

One-pot Metal-free Conditions

R O


CN

N

Ar N R

R

4 16 examples

O O

CN

O

SH

N H 5 Method-B EtOH, MW 80 oC, 15 minutes 5 examples

ACS Paragon Plus Environment

Page 18 of 18

Synthesis of Novel 5,6-Disubstituted Pyrrolo [2,3-d]Pyrimidine-2,4

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