Advances in the Solid-Phase Synthesis of Pyrimidine Derivatives

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Review

Advances in the Solid Phase Synthesis of Pyrimidine Derivatives Aparna E P, and Devaky K S ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00172 • Publication Date (Web): 04 Jan 2019 Downloaded from http://pubs.acs.org on January 6, 2019

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ACS Combinatorial Science

Advances in the Solid Phase Synthesis of Pyrimidine Derivatives Aparna E.P, Devaky K. S.* School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala 686560, India, Fax: 91-481- 27310, Ph: 9496720967

Graphical abstract In this review we discuss solid phase synthesis of diversely substituted and fused pyrimidine derivatives using various types of polystyrene supports. The synthetic procedures depend on the type of pyrimidine derivative synthesised and the nature of the functional polymer used.

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

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Advances in the Solid Phase Synthesis of Pyrimidine Derivatives Aparna E.P, Devaky K. S.* School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala 686560, India, Fax: 91-481- 27310, Ph: 9496720967 ABSTRACT This review describes the existing synthetic approaches for the solid-phase synthesis (SPS) of differently substituted and fused pyrimidine derivatives. These synthetic strategies are classified on the basis of the different synthetic routes leading to the particular type of pyrimidine heterocycle formed. The review discusses the application of a variety of polystyrene derived supports for the construction of pyrimidine rings.

The effect of

microwave heating on the solid-phase synthesis is also addressed in the review. KEYWORDS: Solid-phase synthesis, pyrimidine derivatives, microwave irradiation. 

INTRODUCTION

Heterocyclic compounds are molecules having cyclic structure containing at least one atom such as sulfur, oxygen or nitrogen in addition to carbon as part of the ring and they constitute the largest family of organic compounds. Nitrogen containing heterocycles especially pyrimidines form an important class of heterocyclic compounds.1-3 Heterocycles containing pyrimidine ring has wide occurrence in nature.4 Nucleic acid bases like thymine, cytosine and uracil and many natural products such as vitamins (thiamine) are pyrimidine derivatives. Many pyrimidine derivatives find applications in biological and clinical field.2-3, 5 For example, drugs containing pyrimidine moieties such as barbituric acid and veranal are used as hypnotics.6 Many compounds containing

fused pyrimidine systems

act as

pharmacophores, e.g., deazapurines, a class of pyrrolo[3,2-d]pyrimidines, act as antagonists toward adenosine receptor subtypes7,8 and inhibitors of enzymes.9-12 Fused pyrimidine systems, like 1,2,4-triazolo[1,5-a]pyrimidine and thiazolo[4,5-d]pyrimidine-5,7-dione, find extensive applications in biological fields.13-26 Most of the polyaminopyrimidines are important therapeutic agents,27particularly aminopyrimidines are major components in drugs such as Gleevec (a tyrosine kinase inhibitor) and the hypocholesterolemic agent rosuvastatin.28,29 Recently, arylimidazo-pyrimidines appear to be essential in the pathology of Alzheimer’s disease for detecting β-amyloid (Aβ) plaques in the brain.

Many marine

alkaloids have shown inherent biological activity due to the presence of dihydropyrimidinone 2 ACS Paragon Plus Environment

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moiety.30 Thus nitrogen containing heterocycles, especially pyrimidines, have been accepted as special in pharmacophores. This review discusses the different strategies employed in the solid phase synthesis of substituted pyrimidines oving to their broad range of applications. Combinatorial chemistry has emerged as an integral part of research in the synthesis of new pharmacophores by using “split and pool” protocols in association with solid-phase synthesis,31-40 which was expanded from Merrifield’s polymer supported peptide synthesis to the field of small organic molecules. Traditionally developed methods for the synthesis of drug libraries are too slow and costly to effectively address the needs of drug discovery. In recent decades, solid-phase synthesis has been exploited to overcome this problem by synthesising libraries of molecules that are biologically active as well as powerful alternative method for the optimization of potential drug candidates.41-45 One of the most important features of solid-phase organic synthesis in drug discovery is the elimination and purification of intermediates allowing the rapid synthesis of libraries of structurally related compounds. In the solid phase organic synthesis the product work-up is easy and could be achieved by simple procedures like filtration and washings. Further, the reaction can be driven to completion by the use of excess soluble reagents without causing separation problems leading to increased product yield. Reactions that are impractical in solution phase are also carried out in solid-phase mechanism.46,47 Application of microwave irradiation to chemical reactions has introduced a new dimension to solid-phase synthesis to aid the development of new, ecofriendly, synthetic protocols. From an environmental point of view, microwave reactions proceed via "dry media reaction" and "solvent less synthesis" mechanisms and play an important role in protecting the environment in addition to providing an increased yield of products by minimizing decomposition.48-51 Solid-phase synthesis accelerates the production of targeted compounds by eliminating purification and isolation of intermediates whereas microwave heating reduces the time required for completion of the reaction. Combining the two methods can lead to increased reaction rates, reduced reaction periods and use of limited amounts of solvents or no solvent, better yields and higher purities. Many classical reactions under microwave irradiation perform better than reactions under conventional heating.50,51 In polymer supported reactions the progress of a reaction is greatly influenced by the first immobilization step of a reagent or a substrate to the polymer, the key step of solid-phase strategy and it mainly depends on the nature of the polymer support and the functional group/groups present on it. Depending on the reactive functional groups present on the polymer support, the procedures for the construction of the pyrimidine core also vary. Some literature reports on the effect of microwave heating on the solid-phase synthesis are also 3 ACS Paragon Plus Environment


described in the manuscript. Reviews on the solid-phase synthesis of heterocycles have been published in many journals52,53 and in several books.46,47 However, an exclusive review on the solid-phase synthesis, of a particular heterocycle viz. pyrimidine, comprising most of the synthetic strategies has not been published. The present review describes the different methods for the synthesis of simple and fused pyrimidine ring systems by solid phase strategy.



SOLID-PHASE SYNTHESIS OF SUBSTITUTEDPYRIMIDINES

The pyrimidine moiety is one of the most prevalent heterocycle in naturally occurring biologically important compounds. The pyrimidine core is purported to play the role as the active centre for various biological activities and substituents on the pyrimidine core fine tunes its activity. Polyaminopyrimidines are very important in pharmaceutical chemistry and have a number of applications as therapeutic agents. Alkyl, aryl, and heteroaryl substituted pyrimidines inhibit the activity of certain enzymes and are the major component of a variety of drugs like trimethoprim, pyrantel embonate and tisopurine. Therefore the methods for synthesising such compounds gain great attention.5 

Solid-phase synthesis of disubstituted pyrimidines

The synthesis of a pyrimidine containing drug viz. imatinib 7 on Merrifield resin 1 was published by Leonetti et al.54 The reaction was started by converting resin 1 to AMEBA resin 2 by 4-hydroxy-2-methoxybenzaldehyde under microwave irradiation and such linker immobilization strategy was not reported earlier. Reductive amination of the resin 2by 4methyl-3-nitroaniline and further acylation of product 3 afforded resin 4. Substitution of chlorine present in 4 by N-methylpiperazine and successive guanylation of product 5 gave the guanidine intermediate 6 and was further cyclized with 3-dimethylamino-1-pyridin-3-ylpropenone. Finally, the product 7 isolated from resin 6 by TFA cleavage method was obtained in good yield (nearly 65%) and high purity (Scheme 1). Leonetti and co-workers evaluated all the final products as libraries of BCR-ABL kinase.


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NH2 CH2Cl

PS

CHO

HO PS

PS

O

NaH, DMF, MW, 120 oC, 5 min

Cl

NO2 CH3 (i)Ti(OiPr)4, TEA, THF, 12 h

CHO

OCH3

OCH3 2

CH3 NO2

N H

(ii) NaBH(OCOCH3)3, DCM, 4 h

PS

O

OCH3 3

1 CH3 Cl

N CH3

NO2

(i) ClCH2C6H4COCl

(i) NMPRZ, DMF, DIPEA, MW, 100 oC, 5 min

N

DIPEA, DMF, 3 h

(i) bis-(N-alloc)-methylthio pseudourea, HgCl2, TEA, DMF, 0 oC, 10 min

NH2

N

(ii) SnCl2, DMF, MW, 100 oC, 5 min

O

PS

N

(ii) Pd(PPh3)4, PhSiH3, DCM, 1 h

O

O PS

4

O 5

N CH3 N

H N

N

NH2 NH

N

(i) nitrobenzene, BEMP, MW, 120 oC, 50 min (ii) TFA,DCM 1 h

O

PS

N

N

H N

N

O

N

H N

N

N O

7

O 6

PS

= Polystyrene support

Scheme 1.Solid-phase synthesis of imatinib by Leonetti et al. 

Solid-phase synthesis of trisubstitutedpyrimidines

Agarwal et al. have reported the SPS of 2,4,6-trisubstituted pyrimidine derivatives, which function as anti-infecting agents, on Merrifield resin.55 Initially, an aldehyde function was attached to the chloromethylated resin 1 through an ether linkage and the resulting resin 8 on reaction with acetophenones afforded the corresponding chalcone attached resin 9. The resin bound pyrimidines 10 were obtained in the next step by the reaction of different amidines or guanidines with resin 9. Finally trisubstituted pyrimidines 11 were cleaved from the resin 10 using TFA/DCM mixture (Scheme 2). Agarwal et al. was successful in synthesising trisubstituted pyrimidines showing antimalarial and antitubercular activity by this method. Out of thirty pyrimidine derivatives synthesised twenty three compounds exhibited in vitro antimalarial activity in the range 0.25-2µg/mL. More over sixteen derivatives have shown antitubercular activity in the range 1-25µg/mL and the slight variation in activities was observed with change in substituents. 5 ACS Paragon Plus Environment


HO PS

PS

H3C

NaOMe, DMF, 48 h, rt

R

R

NH

R

HO

NH2

H2N

NaOMe, DMF, 30 h, 80 oC

9

R

O 8

O

PS

CHO

80 oC, 40 h

1

O

O

CHO NaH, DMF

Cl

Page 6 of 63

O

TFA/DCM, 1 h

N

PS

N

N

NH2

NH2

10

N

11

Scheme 2.Solid-phase synthesis of trisubstituted pyrimidines by Agarwal et al.

Montebugnoli and co-workers reported the synthesis of chlorodiaminopyrimidines, by selective aminodechlorination of 4-amino-2,6-dichloropyrimidines, both in solution and solid-phase conditions.

56,57

The SPS strategy started by immobilizing N-protected 4-amino-

2,6-dichloropyrimidines on Merrifield resin 1. R1 N N

O

HO

O PS

Cl N

R1

Cl

Cl

DMF, 1 h, 60 0C

1

O

PS

O

N

Cl

N

O

N

12

Cl DMF, 25-60 oC

R2R3NH, DIEPA R1 PS

O

O

N O

R1

Cl

N

PS

R2

N

R3

14

+

N R2

N

R1

Cl

N

R2 N

N

R3

N Cl

NaHCO3, H2O

R1 N

N O

TFA,DCM

H

O

+

N

13

O

H

N

R2 N

N

R3

N

R3

Cl

15

16

Scheme 3.Solid-phase synthesis of chlorodiaminopyrimidines by Montebugnoli et al.

Resulted

resin

12

on

amination

by

dialkylamines

afforded

resin

bound

chlorodiaminopyrimidines 13 and 14. Regioisomeric chlorodiaminopyrimidines 15 and 16, released from the resin by TFA treatment, were obtained in good yield (>80%) (Scheme 3). Out of the two sets of pyrimidine derivatives, Montebugnoli obtained 2,4-diamino isomer as the major product. 6 ACS Paragon Plus Environment

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The synthesis of pyrimidine derivatives from chalcone immobilized Wang resin was reported by Katritzky et al.58 Hydroxyacetophenones bound resin 18, prepared by treating Wang resin 17 with 4-hydroxyacetophenone, triphenylphosphine and DIAD under Mitsunobu condition, on treatment with aromatic aldehydes resulted in corresponding chalcone resins 19. Acetamidines were allowed to react with resin 19 provided resin bound pyrimidines 20, and the products were isolated from the resin after TFA treatment (Scheme 4). Katritzky successfully synthesised a series of pyrimidine derivatives 21 with high purity in excellent yields (79 – 93%) using different chalcone immobilized resins 19. O

O

OH O PS

PS

17

O

PS

PS L

HO

OH

R1

O

H

NaOMe, THF

O

PPh3, DIAD, NMM

17

18 R2

1

R

NH R2

O L

L

R2

NH2

PS

DMA, 100 oC, 24 h

N L

N

O

19

20

N

N R1

TFA, DCM rt, 1 h

R1

HO

21

Scheme 4.Solid-phase synthesis of trisubstituted pyrimidines byKatritzky et al.

Weber and co-workers suggested a new method for the synthesis of aminopyrimidines from 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene resin.59 The reaction procedure starts with condensation of an aliphatic amine with the aldehyde resin 22 and subsequent reduction to yield the aminoresin 23. In the second step, 2-alkyl-4,6-dichloropyrimidines were reacted with the resin 23 in the presence of DIEA in DMF at room temperature resulting in the polymer-bound pyrimidine 24. This aromatic nucleophilic substitution reaction is one of the key steps in this reaction mechanism. The resin bound aminopyrimidine intermediate 24 was then treated with TFA/DCM mixture affording 2-alkyl-4-chloro-6-aminopyrimidine derivative 25 in good to excellent yield (91 to 99%). The target compound 2-alkyl-4,6diaminopyrimidines

27

was

produced

from

polymer

bound

2-alkyl-4-chloro-6-

aminopyrimidines 24 by a sequential aromatic substitution reaction with various aliphatic amines and subsequent cleavage of the resulting resin 26 (Scheme 5). Weber et al. applied 2(4-formyl-3 methoxyphenoxy)ethyl linker strategy for the synthesis of aminopyrimidines, and lithium amide as the nucleophile for chlorine displacement, they declared that such an approach had not been reported. 7 ACS Paragon Plus Environment


Cl CHO

PS

N

PS

R1 N

DIPEA, DMF, rt

Cl N

23

DMF, AcOH, rt

H

PS

N R2

R

N H

PS

Na(OAc)3BH

O

Cl

1

R1NH2

Page 8 of 63

TFA, DCM rt

R1 HN N

N

R

25

24 R3R4NH R1 HN

R3 N N

TFA/DCM, rt

R4

80-100 oC, n-BuOH, 140 h

R1 N

PS

R3 N N

N

N 2

R2

22

Cl

R4

N 2

R2

R

27

26

Scheme 5.Solid-phase synthesis of diaminopyrimidines by Weber et al.

Microwave assisted solid-phase synthesis is an emerging and interesting field. One noticeable contribution to this area was from Pellegrino et al. for the synthesis of a molecular library of heterocyclic derivatives and many of them are useful as therapeutic agents.60 They started the synthesis by the coupling of the rink amide resin 28 with 3-hydroxybenzoic acid in EDC/HCl. The product polymer bound 3-hydroxybenzamide 29 on reaction with bromomethyl ketones resulted in 30 which on further treatment with DMF in DMA under microwave irradiation produced resin bound enaminoketones 31. NH2 OCH3

O

PS

H N

O

OCH3

O

L PS

O

OH

HO

L PS

EDC.HCl Anhydrous DMF, rt

NH2

PS

L

O

O O

N H 30

R1

DMF/DMA DMF, MW 120 oC, 1 h

PS

L

O O

N H

N H 29

28 O

OH

R1

(i) R2C(=NH)NH2, BEMP, HMPA, DMF, MW, 150 oC, 30 min (ii) TFA/DCM, rt

N 31

R1COCH2Br DBU, HMPA Anhydrous DMF MW, 140 oC, 30 min

R1

O H2N

O

32

N N

R2

Scheme 6. Solid-phase synthesis of trisubstituted pyrimidine derivatives by Pellegrino et al.

The resin 31on reaction with amidines in DMF under microwave irradiation at 150 ℃ for 30 min afforded resin bound pyrimidines which on cleavage gave the pyrimidine derivatives 32 in good yield (50–70%) (Scheme 6).The yields were found to be considerably enhanced (69-73%) when the reaction was carried out under microwave irradiation. All the synthesised products are reported to be therapeutic agents. 8 ACS Paragon Plus Environment

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Obrech et al. reported the synthesis of 2,4,6-trisubstituted pyrimidines on a polystyrene support.61 In this method the Merrifield resin 1 on reaction with thiourea in ethanolic medium resulted in resin-bound thiouronium salt 33. Resin-bound pyrimidine-carboxylic acids 34 were synthesised by cyclocondensation of acetylenic ketones with resin 33 in the presence of DIEA in DMF. The alkylthio group present in resin 33 was converted to corresponding sulfones 35 by m-CPBA in DCM. Finally cleavage by pyrrolidine in dioxane at room temperature yields trisubstituted pyrimidines 36 in excellent yields and high purity (96-99%) (Scheme 7). By applying solid-phase protocol with multicomponent reaction sequences along with multidirectional cleavage steps, diverse pyrimidine derivatives in a parallel array were achieved by Obrech et al. (i)

R

NH.HCl PS

1

Cl

Thiourea Dioxane/ethanol, 85 oC, 15 h

S

PS

COOH

COOtBu N

(i-Pr)2EtN, DMF, rt, 24 h

NH2

33

O

COOH

DCM, rt, 15 h

PS

S N O O

R

S

N

R

34

COOH

N m-CPBA

PS

(ii) 50 % CF3COOH, DCM, rt, 15 h

N

Pyrrolidine Dioxane, rt, 6 h

35

N

N

R

36

Scheme 7.Solid-phase synthesis of trisubstituted pyrimidines by Obrech et al.

Porcheddu and co-workers synthesised 2,4,5-trisubstituted pyrimidines using β-keto esters or β-keto amides on a solid supported piperazine 37 by "catch and release" method.62 Initially, resin bound β-enaminone 40 was synthesised by heating solid supported piperazine 36 with N-formylimidazole dimethyl acetal 38 and β-keto ester 39 using CSA catalyst in DMF for 48 h. The obtained resin 40 was then refluxed with guanidine in basic medium for 2 h afforded the aimed pyrimidines 41in pure form with excellent yields (Scheme 8).



Page 10 of 63

N

PS

N

N CH(OCH3)2 38 CSA (cat) + DMF, 80 oC, 48 h

NH

37

R

Y O

N

PS

N

R1 Y

O

O

NH+NO3R3 H2N N R2

R2 N NaOEt, THF/EtOH, R3 2 h, Reflux

R

R1

R N

Y R

N 41

O

1

40

O 39

Scheme 8.Solid-phase synthesis of trisubstituted pyrimidines by Porcheddu et al.

Porcheddu and co-workers synthesised a variety of resin bound piperazine tethered β-keto esters/β-keto amides which on further reaction with guanidine derivatives afforded a variety of pyrimidine derivatives (in excellent yields, 83-94%) and they could increase the yield by carrying out the reaction in microwave irradiation condition. Font et al. developed a new method for the solid-phase synthesis of 2,6-disubstituted-4alkoxypyrimidine derivatives.63 Initially, 6-alkoxy-2-mercaptopyrimidin-4-ones 42 was immobilized on Merrifield resin 1in presence of triethylamine in DMF. The obtained resin 43 when subjected to alkylation using phenacyl bromides in the presence of TMG resulted in resin bound 4-alkoxypyrimidine derivatives 44. Oxidation of resin 44 with m-CPBA followed by cleavage with N-nucleophiles in dioxane afforded the desired product, 2-amino-4-alkoxy pyrimidines 45 in good yield (32-72%) and purity greater than 95% (Scheme 9). Font et al. cited the use of 4-alkylpyrimidines as potential pesticides and as cyclin-dependent kinase inhibitors. O

O PS

Cl

HN

+

N

HS

1

R

Et3N DMF, rt

HN PS

N

S

O

R

TMG/DMF, rt

43

42

Ar

Br

Ar

O Ar

O O

N PS

S

(i) m-CPBA DCM, rt 1 2

N

R

(ii) R R NH Dioxane, 60-80 oC

O

N R1

N R2

N

R

45

44

Scheme 9.Solid-phase synthesis of trisubstituted pyrimidines by Font et al.

Barillari et al. employed nucleophilic aromatic substitution for the synthesis of diaminosubstituted pyrimidines on solid-phase.57,

64

Initially, 4-amino-6-chloro-2-methylpyrimidine

was immobilized on p-nitrophenyl carbonate Wang resin 46 by NaH in THF. The resulted 10 ACS Paragon Plus Environment

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pyrimidine bound resin 47on treatment with 4-phenylbutylamine in the presence of TEA in nbutyl alcohol at 80 ℃ for 24 h afforded the targeted pyrimidine bound resin 48 which on TFA cleavage provided corresponding trisubstituted pyrimidines 49 with high yield and purity (Scheme 10). Barillari et al. was successful in synthesising a library of twenty four diamino substituted pyrimidines using four differently substituted pyrimidines and six amines. The attraction of p-nitrophenyl carbonate Wang resin is the shorter cleavage time and milder cleavage conditions when compared with rink resin. NH2 NO2

O O

N

O

PS

Cl

O

NH

46

O

TEA, n-BuOH, 80 oC N

O PS

H2N

N

NaH, THF, rt, 24 h

O

PS

O

N

Cl

47 NH2

NH N

N

TFA/DCM N

N

N H 48

N H 49

Scheme 10.Solid-phase synthesis of trisubstituted pyrimidines by Barillari et al.

Masquelin and co-workers illustrate the synthesis of 2,4,5-trisubstituted pyrimidines using commercially available ketene derivatives by both solution phase and solid-phase strategies.65 Initially, thiourea immobilized Merrifield resin 33 on reaction with ketene derivatives (ethoxymethylidene)malononitrile 50 in the presence of DIEA in DMF formed resin bound pyrimidine 51. The alkylthio group present in resin 51 was converted to corresponding sulfones by m-CPBA in DCM and subsequent cleavage of resulted resins by pyrrolidine in dioxane at room temperature yielded tetrasubstituted pyrimidines 52 in good yields (78%) and high purity (99.5 %) (Scheme 11).

NH.HCl PS

S

NH2 33

EtO

CN 50

CN

(i-Pr)2EtN, DMF, 0 oC, rt

CN

N PS

S

N 51

NH2

(i) m-CPBA, DCM, rt (ii) Pyrrolidine, Dioxane, rt

CN

N N

N 52

Scheme 11.Solid-phase synthesis of trisubstituted pyrimidines by Masquelin et al.


NH2




Page 12 of 63

Solid-phase synthesis of tetrasubstituted pyrimidines

Masquelin et al. synthesised 2,4,5,6-tetrasubstituted pyrimidines also.65 The procedure involves

the

condensation

of

thiouronium

anchored

resin

33

and

[bis(methylthio)methylidene]malononitrile 53 to resin bound pyrimidine 54. Oxidation of 54 and subsequent cleavage of resulted resin yielded tetrasubstituted pyrimidines 55 and 56 in good yields (Scheme12).

NH.HCl PS

S

NH2 33

MeS

CN

MeS

CN 53

SMe N PS

S

(i-Pr)2EtN, DMF, 0 oC, rt

SMe CN NH2

N 54

(i) m-CPBA, DCM, rt

(ii) Pyrrolidine, Dioxane, rt

CN

N

(i) m-CPBA, DCM, rt N

N

NH2

55

(ii) Pyrrolidine, Dioxane, rt

N CN

N N

N

NH2

56

Scheme 12.Solid-phase synthesis of tetrasubstituted pyrimidines by Masquelin et al.

Matloobi and co-workers optimized the reaction conditions and synthesised tetrasubstituted pyrimidine derivatives using solid phase strategy.66 They treated Merrifield resin 1 with dihydropyrimdine-2-thiones 57 and the resulted resin 58 on aromatisation and subsequent oxidation by oxone yielded resin 60 (Scheme 13). Various nucleophiles were then allowed to react with resin 60 to afford the corresponding pyrimidine derivatives 61 with medium yield and purity lower than 85%. Matloobi obtained highly diverse pyrimidine core even with unreactive nucleophiles.


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O PS

Cl

Ph

Me

1

DMF, K2CO3

NH

+ EtO N H

S

PS

H N

S

N

S

Me

Ph

Ph

MW, 130 oC, 30 min

O

58 Oxone, H2O, DMF

OEt

N

CAN, H2O, DCM

OEt

N

MW, 160 oC, 30 min

57 PS

Me

O O PS S N

o

MW, 150 C, 45 min

Me OEt

N

O

Ph

O

O Piperidine, EtOH MW, 100 oC, 10 min

Ph N

EtO Me

61

60

59

N

N

Scheme 13.Solid-phase synthesis of tetrasubstituted pyrimidine by Matloobi et al.

The importance of α,β-unsaturated ketones as intermediates for the synthesis of four different templates (namely pyrimidines, DHPMs, pyridines, and pyrazoles) on the solid support was revealed by Marzinzik et al.67 Initially 4-carboxybenzaldehyde was immobilized on the rink amide resin 28 using 4-carboxybenzaldehyde in presence of DIC with 1hydroxybenzotriazole. Resulted resin 62 was converted to the corresponding polymer supported chalcone derivatives 63 by treating with substituted acetophenones. Reaction of appropriate amidines with resin 63 afforded the desired pyrimidine derivatives on the polymer support. Finally, the product 64 was separated from the polymer with excellent purity greater than 95% (Scheme 14). Marzinzik and co-workers explored the importance of α,β-unsaturated ketone immobilized polymers as a diversifying agent in the synthetic chemistry of N-heterocycles. HO PS

L

NH2

CHO

O

DIC, HOBt, DMA, rt, 1 h

28

CHO PS

L

H N

R1COCH2R2, LiOH.H2O DME, rt, 16 h

O 62

R3

NH O PS

L

R1

H N

2

R O

63

H2N

R3

(i) DMA, 100 °C, 16 h H2N (ii) 20% TFA/DCM, O rt, 15 min

N

N R1 2

R 64

Scheme 14.Solid-phase synthesis of tetrasubstituted pyrimidine derivatives by Marzinzik et al.

Kumar et al. employed solid-phase syntheses for preparing structurally diverse substituted pyrimidines under three-component reaction conditions.68 At first, resin immobilized thiouronium salt 33 (synthesised from Merrifield resin with thiourea in DMF at 80 ℃) was shaken with ethyl cyanoacetate and substituted aromatic aldehydes for 30 h in DMF in the 13 ACS Paragon Plus Environment


Page 14 of 63

presence of K2CO3 at 80 ℃ yielding pyrimidine attached resin 65. Oxidation of resin 65 by m-CPBA and further cleavage with different amines afforded the desired product tetrasubstituted pyrimidines 66 (Scheme 15). Kumar et al. were successful in synthesising a combinatorial library of eighty tetrasubstituted pyrimidines in excellent yield (80-90%). The synthesised tetrasubstituted pyrimidines were reported to be pharmaceutically very important as antituberculosis agents. NH.HCl PS

S

NH2

33

OH

NCCH2COOHC2H5

N

K2CO3

+

DMF, 80 oC, 30 h

Ar-CHO

CN

PS

S

N

Ar

65

OH

(i) m-CPBA DCM, rt, 18 h

CN

N

RHN (ii) RNH2 DCM, 40 oC, 10 h

N

Ar

66

Scheme 15.Solid-phase synthesis of tetrasubstitutedpyrimidine derivatives by Kumar et al.

Chauhan et al. reported the solid-phase synthesis of tetrasubstituted pyrimidines.69 The synthetic procedure involves the reaction of resin 33 with ethyl cyanoacetate and substituted aromatic aldehydes under basic conditions to afford resin bound pyrimidine 67. Pyrimidine derivatives 68 were then cleaved from resin 67 by n-butylamine followed by oxidation with m-CPBA (Scheme 16). All the synthesised compounds were reported to exhibit high degree of biological activity. O NH.HCl PS

S 33

NH2

H3C

O

OH CN

Ar-CHO, K2CO3 DMF, 80 oC, 24 h

PS

N S

CN N

67

R

(i) m-CPBA, DCM, rt, 15 h (ii) n-Bu-NH2, DCM, 40 oC, 10 h

OH NC R

N N

NH(CH2)3CH3

68

Scheme 16.Solid-phase synthesis of tetrasubstituted pyrimidines by Chauhan et al.



SOLID-PHASE SYNTHESIS OF PYRIMIDINONES

Pyrimidinones are a significant component of many marine alkaloids and are important pharmacologically as privileged structures in drug research. Pyrimidinone system possesses inherent properties like calcium channel modulating, adrenergic agonistic, mitotic kinesin inhibiting, antibacterial, fungicidal, etc.70 Dankers et al reported two conventional methods for the modification of peptides by ureidopyrimidinone (UPy) moieties on the solid support.71 In the first method, peptides were modified with UPy units at the N-terminal amino acid. The peptides were synthesised on 14 ACS Paragon Plus Environment

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Wang resin by conventional SPPS and the N-terminus of resulted resin bound peptides 69 were deprotected and the corresponding product 70 was allowed to react with UPy units produced the corresponding UPy peptides 71. The product UPy modified peptides 72 were cleaved from the solid support after deprotecting the Fmoc group, in moderate to good yield in the range 50-75% (Scheme 17). PS

PS

L O

tBu O O H N N H ButOOCH2C O

O N H

H N O

HN HN NH Fmoc

OH OH O HN

O

DMF, 20 min N Fmoc H

NH2

O

69

PS

O

L O

NH

(i) Pipiridine

O HN

O

HN 72

H N

70

O

HN

NH

O N H

HN HN NH Fmoc

N

O H N

O H N N O H ButOOCH2C O O

NH

HOOCH2C

H2N

tBu O

Piperidine

O

O

L O

tBu O

(ii) TFA/H2O, 6 h

O

O O

H N

N

N H

BuOtOC

N

HN N H N

H N O

O N H

H N O

HN HN NH Fmoc

O

DMF, 16 h, 50 oC O

O N H

HN N H N

O

71

Scheme 17.Solid-phase synthesis of ureidopyrimidinonepeptide byDankers et al.

Whereas in the second method UPy coupling took place at ε-position of the amino acid just next to C-terminal amino acid and resulted UPy modified peptides possess free N-terminal amino group. The UPy-peptide was cleaved from the solid support using TFA/TIS/water mixture and isolated in moderate yield. This modification method of peptides with UPy moieties, reported by Dankers et al., is a work of special importance because easy functionalization of N-termini of peptides is possible. The resulted peptides are reported to have applications in biomedical field and in tissue engineering. The UPy-functionalized peptides also find applications in the manufacturing of supramolecular materials as per Dankers reports. Reports are available on alkyl and aryl substituted pyrimidines by Cesar et al. using polymer bound benzamidine resin (modified Wang resin) 73.72 First resin 73was condensed with ethyl cyanoacetate in DMF or 2-methoxyethanol solvent afforded resin bound pyrimidine 74. Cesar et al. varied the choice of base with solvent. Potassium t-butoxide was added as the base when DMF was used as solvent and sodium methoxide as the base in 215 ACS Paragon Plus Environment


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methoxyethanol establishing the best solvent base combination. The product 6-amino-2-(4hydroxyphenyl)-3H-pyrimidin-4-one 75 was released from the resin using TFA mediated cleavage mechanism and attained high yield (85%) in 2-methoxyethanol compared with DMF (20%) (Scheme 18). By repeating the reaction with a variety of 1,3-dielectophiles Cesar achieved structurally diverse pyrimidine derivatives. O PS

O

EtO NH2

PS

CN

O

HO

H N

80 oC, 16 h

O

rt, 1 h

N

NH

H N

TFA/DCM N

NH2

73

O

NH2

74

75

Scheme 18.Synthesis of 6-amino-2-(4-hydroxyphenyl)-3H-pyrimidin-4-one by Cesar et al.

Hamper and co-workers described the synthesis of trisubstituted pyrimidin-6-one-5carboxylic acids and pyrimidin-4-ones derivatives as novel compounds from modified Wang resin 76 (Treatment of the Wang resin with Meldrum’s acid and further esterification of the product following Knoevenagel condensation provided substituted methylene malonate bound Wang resin.73 Reaction of aromatic and branched aliphatic aldehydes with methylene malonate bound Wang resin produced alkylidene malonate resins 76). Resin 76 on cyclocondensation with N-substituted amidines (prepared by Pinner synthesis from nitriles) yielded the resin bound dihydropyrimidinones 77 and 77a. On oxidation 77 was converted to resin bound pyrimidinone 78. Finally, on TFA cleavage dihydropyrimidin-4-one-5-carboxylic acids 79 were obtained in good yield (46 & 54%). The resin 77a on prolonged treatment with TFA resulted in dihydropyrimidin-4-one with low yield (Scheme 19).

O PS

L

NH

O 2

O

OCH2CF3

NH2

PS

DMA, 70 oC, 6 h

R1

76

R

O L

O

O TFA

N

O R1

R2

N H

N

HO R1

77 CAN O

O

O TFA

N

HO R1

N H 79

L PS

DMA, rt, 12 h

O N

N

O

R2

N H 77 a TFA

O

R1

R2

O

N H

R2

R1

78

Scheme 19.Solid-phase synthesis of pyrimidinone derivatives by Hamper et al. 16 ACS Paragon Plus Environment

N H 80

R2

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Hamper repeated the whole reaction sequence with another functionalized resin viz. benzylidene malonate resin and trisubstituted pyrimidin-4-one-5-carboxylic acids were produced in good yield. Regioselectivity of cyclization mechanism was also checked by Hamper during the synthesis and the two regioisomeric pyrimidinone carboxylic acids obtained were confirmed by ROESY1D and gHMBC NMR experiments. By this method, a library was synthesised using eight aldehydes, three nitriles, and four amines forming a combinatorial set of 96 pyrimidinones. Gross et al. reported a simple and efficient procedure for the solid-phase synthesis of 4,6diaryl DHPM derivatives under three-component Biginelli conditions.74 In general, selective immobilization of reactants on the solid support was essential for the synthesis of a particular DHPM derivative under Biginelli conditions. Different reactants like urea/thiourea, β-keto ester, S-linked isothiouronium salt etc., can be used for immobilization on the polymer support. In the procedure developed by Gross et al. β-keto amides were immobilized on the solid support 81. Initially, 4-ethoxybenzaldehyde 82 and urea/thiourea 83 were allowed to react in the presence of catalytic amounts of toluene-4-sulfonic acid at 95 °C for 1 h. A bisureide intermediate was formed which reacted with resin 84 at 95 °C for 12 h. The resulted DHPM derivatives 90 were cleaved from the resin using TFA and obtained in high yield with good purity (Scheme 20). O PS

L

N H

O 81

O

Ar1

O

H +

Ar2

O 82

+

(i)TsOH, i-PrOH H 2N

NH2 83

(ii)TFA/DCM

Ar1

H 2N Ar2

NH N H

O

84

Scheme 20. Solid-phase synthesis of 4,6-diaryl-3,4-dihydropyrimidine derivatives by Gross et al.

Kong et al. reported the synthesis of pyrimidine derivatives from sodium benzenesulfinate functionalized polystyrene solid support 85.75 They targeted a variety of biologically important pyrimidine derivatives including pyrimidine-2-ones and pyrimidine-2-thiones. At first, the resin 85 was allowed to react with benzyl bromide in DMF and the resulted sulfone linker on resin 86 is versatile and offers various on-resin functionalization reactions with extra modifications. The resin 86 on alkylation with styrene epoxides gave polymer-bound 3benzenesulfonyl-1,3-diphenylpropan-1-ol 87, subsequent oxidation with Jones reagent produced polymer-bound 3-benzenesulfonyl-1,3-diphenylpropan-1-one 88, which on treatment with a variety of diamides in basic medium produced a series of pyrimidine 17 ACS Paragon Plus Environment


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derivatives 89 and 90 by simultaneous cyclization and cleavage mechanisms (Scheme 21). From α-Bungarotoxin (α-BTX) radioligandassay report, Kong revealed that all the products act as efficient neuronal sodium channels blockers. O PS

SO2Na

R1

BrCH2R1

PS

NBu4I, KI, DMF, rt

R2

S OO

85

R3

O O S

PS

LiCH2SOCH3

R2

86

87

R3

R1 OH

Jones reagent, Acetone, 0 oC

R4

R4 N

HN

N

1

NH2

PS

3

R

O O S 2

R

X

X R1

H2N

NH2

3

NH R3

X = O or S

R2

O

89

R

90

N

R1

R

R2

R4

88

Scheme 21. Solid-phase synthesis of tetrasubstituted pyrimidinones/thiopyrimidinones by Kong et al.

The synthesis of 3,4-dihydropyrimidine-2-one derivatives from sodium benzenesulfinate resin was also carried out by Li et al.76 Firstly 1% DVB cross-linked polystyrene sodium sulfinate 85 was acidified to polymer-supported phenylsulfinic acid 91 using con.HCl, which on

further

treatment

with

aldehydes

and

thiourea/urea

gave

polymer-supported

(benzenesulfonyl substituted) thiourea/urea 92. The resin 92 underwent cyclizationdehydration process with enolates of 1,3-dicarbonyl compounds in the presence of TsOH.H2O producing substituted 3,4-dihydro-1H-pyrimidine-2-ones 93. The reaction of resin 92 with β-keto acids in the presence of pyrrolidine gave another class of compounds like dihydropyrimidine carboxylic acids 94 (Scheme 22). One major advantage of this method observed by Li et al. was the extra high purity (>95% by NMR) of the products. The separated products were obtained in highly pure form and not required further purification.


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HCl

SO2Na

PS

SO2H

PS

DMF/H2O 91

85

X R1CHO, DMF O R1

O R2

X

O OH

R2

R2

SO2 X

PS

KOH, EtOH, TsOH

R1

R3

N H

X=O or S

NH2

O R3

HN

H2N

N H

NH2

R1

O

R2

HN

Pyrrolidine, THF, TsOH

92

93

OH

N H

X

O 94

Scheme 22.Solid-phase synthesis of dihydropyrimidinones by Li et al.

Aucagne et al. have described the solid-phase synthesis of diverse pyrimidine nucleosides from 2'-deoxyuridine95.77 This strategy started by the attachment of a modified linker coupled deoxyuridine moiety 97 to aminomethyl polystyrene resin 98 using Nhydroxybenzotriazole activated ester. Transesterification of the resin bound product 99 and introduction of iodo group to heterocyclic moiety produced resin bound 5-iodo-2'deoxyuridine 100. O But

O N

O

HO HO

O

O

O

NH

But

DCM, 3 h, rt

O

96

95

(i) Ac2O, pyridine, 4 h, rt

(ii) CF3CO2H/DCM, 15 h, rt O

O O O PS

O

O

N Me

O

O O

N Me

O HO

O

I

O

AcO

O 97

MeONa, MeOH, 24 h, rt

O O

HO

N

HO

O

AcO

O

O

I

NH

N

NH

N

O

O

Et3N, HOBt, dioxane, 5 h, rt

99

O

O

NHMe 98

AcO

O

PS

NH

N

(i) Ac2O, pyridine, 18 h, rt (ii) I2/CAN

PS

O

HO

O

O

NH

N

O

O

O

CO2H

O

NH

O 101

100

Scheme 23.Solid-phase synthesis of pyrimidine nucleosides by Aucagne et al.

Various Pd-mediated reactions such as Heck, Sonogashira, Stille, etc., were applied for the modification and subsequent release of substituted nucleosides 101 (Scheme 23). From the reaction yields, the authors concluded that Sonogashira and Stille reaction conditions were well suitable for the solid-phase synthesis of nucleosides compared with Heck and Suzuki19 ACS Paragon Plus Environment


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Miyaura conditions. This method is applicable for the synthesis of other nucleoside analogues and the substitution of the nucleoside core having highly diverse structures. Parlato and co-workers described the synthesis of 5,6-disubstituted pyrimidinone derivatives on a variety of polymer supports.78 Initially, a thiouronium salt anchored resin 33 condensed with various β-keto esters in the presence of Ca(OH)2 producing respective pyrimidinone bound resins 102. The pyrimidinone moiety was departed from resin 102 using different cleavage mechanisms. When oxone was used as the cleaving agent in dioxane/water solvent, a sulfone intermediate was formed which underwent nucleophilic cleavage with water forming 5,6-disubstituted pyrimidine-2,4(1H,3H)-diones 103 (69 to 99% yield). When the same oxidation reaction was conducted in methanolic solution the product formed was 5,6-disubstituted 2-methoxypyrimidin-4(3H)-ones 104 with 72 to 85% yield (Scheme 24). O Oxone Dioxane/H2O

O R

EtO NH.HBr PS

S 33

NH2

O

PS

H2O/EtOH

S

O

R

HN

R1

Ca(OH)2

Reflux

O

N

R

HN

R1

N R1 H 103 R

R1

102 Oxone CH3OH, Reflux

O

N HN 104

OCH3

Scheme 24. Solid-phase synthesis of di- and tri-substituted pyrimidinones by Parlato et al.

Parlato repeated the synthesis using Wang resin with a benzylic spacer. Benzylic-type cleavage of the resin bound product using TFA/DCM mixture yielded the corresponding 5,6disubstituted 2-thioxo-2,3-dihydropyrimidin-4(1H)-ones in 72 to 80% yield. The same synthesis was carried out on a hydrophilic tentagel resin also. The demerit of the method reported by Parlato et al. was poor yield and purity of the product. The product contained certain by products from the polymer support itself. The first report on the solid-phase synthesis of substituted imidazolidinones and pyrimidinones by an intramolecular cyclization reaction promoted by DIC was given by Wang et al.79 In the first step, a resin-bound dipeptide 105 was synthesised from rink amide resin 28. For pyrimidine synthesis, N-Fmoc-alanine was used as the second amino acid in the peptide residue of resin 105. The synthesised dipeptides 105 were acylated using aryl isothiocyanate producing corresponding resin bound thiourea 106. The resin 106 was then subjected to an intramolecular cyclization reaction in the presence of DIC to afford the resin bound product 107. Under conventional method, the completion of reaction required two 20 ACS Paragon Plus Environment

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days with the assistance of heating at 90℃, whereas microwave irradiation reduced the reaction time from two days to four minutes. In final step TFA mediated cleavage of resin 107 resulted trisubstituted pyrimidinones 108 with high yield (90%) and moderate purity (Scheme 25). Wang and co-workers successfully attained DIC promoted intramolecular cyclization for the synthesis of N-heterocycles. L

PS

(i) 25% piperidine, 15 min (ii) Dipeptide

NH-Fmoc

PS

R1

H N

L

N H

O

28

O

R3

aryl isothiocyanate NH2

R2

DIEA, 6 h

105 R2

PS

L

1

R

H N O

O N H

R3

S 4

N H

R2

N H

R

O

DIC, DMF MW, 4 min

PS

L

N H

106

R3

O N R1

107

NH

N 95% TFA/H2O 2h

N

R4

HN

R1 NH

N

R3

2

O

O

2

R

R4

108

Scheme 25.Solid-phase synthesis of tetrasubstituted pyrimidinones by Wang et al.

Kappe and co-workers developed a method for the synthesis of functionalized 4-aryl-3,4dihydropyrimidine-5-carboxylates using polymer-bound thiouronium salt 33 as the starting material (Scheme 26).80 NH.HCl

O X RO C 2

+

PS

Me

S 33

109

NH2

CS2CO3 NMP, 75 oC, 16 h

RO2C

(i) Dioxane, EtOH, AcOH Reflux, 16 h NH

(ii) TFA, EtSH, DCM, rt, 16 h

N Z (iii) Dioxane, MeCN, H NH4OH, Reflux, 8 h Z = O or S or NH 111

PS

H N

S N

Me

(i) Cl-COR1, Pyridine, DCM, 0 oC, rt, 6 h

Me CO2R X

(ii) TFA, EtSH,DCM, rt, 16 h

110

X RO2C

N

COR1

Me

N Z H Z = O or S or NH 112

Scheme 26.Solid-phase synthesis of dihydropyrimidinone derivatives by Kappe et al.

Initially, polymer-bound thiouronium salt 33 was condensed with unsaturated β-keto esters 109 under basic medium resulted in resin bound 1,4-dihydropyrimidines 110. Resin 110 was subjected to multi-directional cleavage steps which incorporate an additional diversity and afforded the desired DHPM derivative 111 with excellent purity (>95%) and high yield (77%). Acylation of the resin 110 at the N3 position with electrophiles under basic condition 21 ACS Paragon Plus Environment


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and the further multidirectional cleavage resulted in another attractive group of DHPMs 112 that are pharmacologically active.



SOLID-PHASE SYNTHESIS OF IMIDAZOPYRIMIDINES

Imidazopyrimidines and imidazopyridine moieties are found in phosphodiesterase inhibitors, benzodiazepine receptor ligands, gonadotropin releasing hormone antagonists. Imidazopyrimidines exhibit antiviral, antiulcer, antibacterial, antifungal and herbicidal properties and act as non glucoside base inhibitors. Many imidazopyrimidine derivatives are potent inducible nitricoxide synthase dimerisation inhibitors.81 Kazzouli et al. described the solid-phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines on rink amide resin having both acid and base labile linker.82 Initially, rink amide resin 28 was converted to resin 113 by 3-iodobenzoic acid using a peptidic coupling mechanism. Resin bound α-bromoketone 114 was achieved from resin 113 by the reaction of N-bromosuccinimide. Subsequent reaction of resin 114 with various 2aminopyrimidines in DMF resulted in corresponding pyrimidine resins 115. The desired product, imidazo[1,2-a]pyrimidines 116 were then cleaved from resin 115 and purified (Scheme 27). Both acidic and basic cleavage strategies are applicable because of the compatibility of resin for both acid and base labile linkers. O I

HO PS

L

O

NHFmoc

PS (i) Piperidine, DMA (ii) TBTU, HOBt, Et3N, DMAP, 1,4-dioxane, 48 h

28

O

N

H2N

N

L

I

N H

(i) tributyl(1-ethoxyvinyl)tin, Ph3As, Pd2(dba)3, 1,4-dioxane, 50 °C, 24 h (ii) NBS, THF/H2O, 1h

PS

R

N N

O L

O Br

N H 114

113

N PS

O L

HN

N

R

N O

TFA/DCM

N

R

N

H2N

DMF, rt, 72 h 115

116

Scheme 27. Solid-phase synthesis of imidazo[1,2-a]pyrimidine derivatives by Kazzouli et al.

Soh et al. described the synthesis of 2-(benzylthio)imidazo[1,2-a]pyrimidin-5(1H)-ones on bromomethyl resin 118.83 β-Keto ester, 117 was reacted with thiourea to afford 5,6disubstituted-2-mercaptopyrimidin-4-one intermediate, which immediately react with resin 22 ACS Paragon Plus Environment

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118 under microwave irradiation conditions provided resin bound pyrimidines 119. The resin 119 on reaction with bromoacetonitrile resulted in resin 120 which on subsequent selfcyclization with benzyl thiol followed by cleavage from the solid support yielded 2(benzylthio)imidazo[1,2-a] pyrimidin-5(1H)-ones 121 (Scheme 28). The product formed was reported to have high purity and yields in the range 10-61%. N-Alkylation and formylation were used to diversify the synthesised 2-(benzylthio)imidazo[1,2-a]pyrimidin-5(1H)-ones. By using microwave irradiation, reaction time for the completion of SPS was shortened from a couple of days to 80 min. O O

S

O

R2

OEt

+ H2N

NH2

R1 117

(i) NaOEt, EtOH/DMF MW, 130 oC, 30 min (ii)

PS

R1

HN PS

S

BrCH2CN, TEA, EtOH/DMF R2

N

Br

MW, 120 oC, 20 min

119

118 MW, 100 oC, 10 min O

O 1

NC PS

R

N S

N

R2

BnSH, t -BuOK, MW t - BuOH, 40 oC, 20 min

R1 2

R

H N

N H

S N

121

120

Scheme 28.Solid-phase synthesis of substituted imidazopyrimidines by Soh et al.



SOLID-PHASE SYNTHESIS OF PYRAZOLOPYRIMIDINES

Pyrazolopyrimidines are a class of heterocyclic compounds with broad spectrum biological activities. They constitute the central core of a variety of chemical compounds including a few pharmaceuticals and pesticides. Many of them are potent to prevent cell cycle arrest and tumour growth in human medulloblastoma cells. Pyrazolo[3,4-d]pyrimidines derivatives have been explored for their inhibitory activity towards various protein kinase enzymes and their role as anticancer agents.84,85 Liao and co-workers described the sold phase synthesis of pyrazolo[3,4-d]pyrimidine derivatives via aza-Wittig/electrocyclic ring closure reaction on rink resin 28.86 One of the noticeable attractions of this work was, the by product, toxic triphenylphosphine oxide from the aza-Wittig reaction, could be easily separated by a simple wash. Initially, the precursor 122 was hydrolysed to 123 and attached to resin 28 forming the corresponding resin bound intermediate 124 which was then allowed to react with various primary amines to get resin bound imines 125. Resin bound aza-ylide 126, synthesised from resin 125 by reaction with 23 ACS Paragon Plus Environment


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triphenylphosphine in dichloromethane, on further reaction with isocyanate underwent azaWittig/electrocyclic ring closure reaction and the product pyrazolo[3,4-d]pyrimidine 128 was separated from resin 127 and purified by HPLC (Scheme 29). By varying the nucleophiles, a library of products were generated and all are reported to have moderate to good yield (775%). L PS

N

N N3

NaOH EtOH/THF/H2O

COOEt CHO

R1 N PS

R1NH2

R1 N PS

N3

NH

N R2

NH N

O

DIC, HOBt, DMF

CHO

PS

N

127

R2NCO DCM

N

N R2 N

H2N O

N

126

R1 N

N

N

NH O

TFA/DCM

N

P(Ph)3

L

DCM

N3

NH

124

R1 N

125

N

PS

OHC

O

PPh3

N

N

O

COOH

123

L

THF, CH(OCH3)3

L

28

N

N3

122

L

N

NH2

N

N

128

Scheme 29. Solid-phase synthesis of pyrazolo[3,4-d]pyrimidines by Liao et al.

Tan et al. described the solid-phase synthesis of both 6-oxopurines and pyrazolo[3,4d]pyrimidines on Wang resin 17.87 6-Chloropurines or 4-chloro-1H-pyrazolo[3,4d]pyrimidines 129 were immobilized Wang resin 17 using DABCO. In the next step selective N9-alkylation of 130 was conducted under Mitsunobu conditions and an amino group was introduced to the C2 position via Suzuki or Sonogashira coupling. Finally, the product 132 was cleaved from the resin 131 with 30% TFA in DCM (Scheme 30).

N H2N

L

OH 17 (i) DABCO, DMF PS

Cl

PS

N 129

(ii) NaH, DMF

O

PS

R1OH, PPh3

N

N N H

L

H2N

N N

N H

DIAD, THF

L

OH

O

N H2N

N N

N

TFA/DCM

N H2N

1 131 R

130

N N

N

1 132 R

Scheme 30. Solid-phase synthesis of pyrazolo[3,4-d]pyrimidines by Tan et al.

All the synthesised products were subjected to examine their effects on multidrug resistance protein 4 (MRP4/ABCC4) facilitated effluxes. From the study, Tan 24 ACS Paragon Plus Environment

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observed that four members out of the synthesised derivatives were active in inhibiting MRP4-mediated efflux of bimane-glutathione conjugate and shows the property to reverse MRP4-mediated resistance to the anticancer drug 6-thioguanine. The reversal of resistance was gained without any effects on the uptake and metabolism of 6-thioguanine. The authors successfully synthesised pyrimidine derivatives that are biologically very active. Heo and co-workers reported the synthesis of a 1-aryl-1H-pyrazolo[3,4-d]pyrimidine based

compound,

N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-

carboxamide, by solid-phase strategy.88 Initially, the 1-aryl-1H-pyrazolo[3,4-d]pyrimidine backbone was synthesised by a solution phase protocol and used for further reactions in solidphase synthesis. The procedure involves the reductive amination of AMEBA (acidsensitive methoxybenzaldehyde) resin 133 (synthesised from Merrifield resin 1) to isobutylamine immobilized AMEBA resin 134 and attachment of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4d]pyrimidin-4-one-6-carboxylic acid to resin 134 in the presence of EDC and HOAt in DMF at room temperature. Benzylaminated intermediate resin 136 was produced from 135 by BOP mediated amination in presence of DIEA as the base in DMF at room temperature. Finally, resin 136 was subjected to TFA cleavage in DCM affords the desired product 137 in 71% yield (Scheme 31). By varying the functional groups present in pyrimidine and amine, Heo and co-workers successfully synthesised a library of twenty four biologically active pyrimidine derivatives in moderate to good yields in a high-throughput fashion. O OMe CHO

Cl

PS

1

OMe CHO

HO NaBH(OAc)3

EDC, HOAt PS

DCE, rt, 21 h

O

N N

OMe

H2N PS

DMF, rt, 19 h

N H

O

134

133

OMe

PS

O

N

O HN 135

N PS

N N

N

O

N

O

BOP, DIEPA DMF, rt, 13 h

N

EDC, HOAt DMF, rt, 19 h

N

TFA/DCM

N

rt, 1h

N

O N

HN

HN

O

O OH

HN

NH2

OMe

NH N

136

Scheme 31.Solid-phase synthesis of pyrazolopyrimidines by Heo et al.


137

N

N




Page 26 of 63

SOLID-PHASE SYNTHESIS OF PYRIDOPYRIMIDINES

Pyridopyrimidine derivatives exhibit potent and significant pharmacological properties and many of them act as inhibitors in cyclic nucleotide synthesis. Their applications include antihistamines, antiseptic, antiarrhytmic, antirheumatic and anti-inflammatory activities.89 Gordeev and co-workers found out the application of Knoevenagel condensation chemistry for the synthesis of pyrido[2,3-d]pyrimidine derivatives on the polymer support.90 They used a hydroxyl functionalized polymer as the solid support. In their work, the actual reaction started from a β-keto ester modified resin 138, prepared by acetoacetylation of the Wang resin 17 with diketene in the presence of DMAP catalyst. Resin 138 on Knoevenagel condensation

with

benzaldehyde

afforded

a

benzylidene

resin

139

which

on

cyclocondensation with 6-aminouracils producedpyrido[2,3-d]pyrimidines 140 (Scheme 32). The authors observed that SPS strategy was crucial for the synthesis of pyrido[2,3d]pyrimidines because of the reduced reactivity of 6-aminouracils in solution phase method. The product achieved by Gordeev et al. in SPS strategy has good yield and are highly pure (91%).

R2

PS

L

17

O OH

O O

DMAP, DCM

PS

L

O

O Me

O 138

1

R

O H

Piperidine i-PrOH-C6H6

PS

L

Me

O R1

R2

(i)CAN, DMA

O

139

(ii) TFA/DCM

R1

O

N NH2 R3

O

O

O N

O OH

N N R3

N

Me

140

Scheme 32. Solid-phase synthesis of pyrido[2,3-d]pyrimidines by Gordeev et al.

An attractive class of heterocyclic compounds such as 4-methyl-pyrido[2,3-d]pyrimidin-7one based library with two diversity points was achieved by Angiolini et al. by a combinatorial expansion mechanism.91 The procedure started from the intermediate, 4methyl-pyrido-[2,3-d]pyrimidin-7-one scaffold, essential for both solution and solid-phase methods. The intermediate was first converted to corresponding chloride derivatives 141 and coupled with the N-alkylaminomethyl resin 142 derived from Merrifield resin. Oxidation of the resultant polymer supported intermediate 143 gave a sulfone intermediate tethered resin 144 which on aromatic substitution with different amines resulted in resin bound pyridopyrimidines 145. Finally, the product 146 was separated from the polymer support by


Page 27 of 63 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


TFA method (Scheme 33). Angiolini claimed that this work presents the first combinatorial expansion on this versatile scaffold (4-methyl-pyrido[2,3-d]pyrimidin-7-one). CH3

CH3

N N

O

PS

N

TFA/DCM, rt, 2 h N

S

N H 142

N

S

oxalyl chloride, DMF, DCM, rt, 2 h

N

O

R3

R3

PS

N

DCM, TEA, rt, 12 h O

O

OtBu

O

O

N

S

N N

Cl

141

143

CH3

m-CPBA, DCM, rt, 1.5 h R3

CH3

PS

N

N 1

R

N

N

N

R3 O

PS

TFA/DCM, rt, 1.25 h

O

N

R1R2NH, TEA, THF, 60 oC, 1 h

O

R2

R2 O O

N

R3

146

O

R1

N

145

O O S

N

N

H

N

N

N

N

CH3

CH3

144

Scheme 33. Solid-phase synthesis of pyrido[2,3-d]pyrimidines by Angiolini et al

Schell et al. suggested the synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones with three points of diversity on commercially available rink amide resin 28, the N-alkylated form of rink amide resin (Scheme 34).92 L

PS

1

N H

1

R

PS

N L

R1 PS

Cl

N R1

NH

2

THF, rt

28 O

1

(Bt C(=NH)Bt + Bt C(=NH)Bt )

1

O 2

R NH2

N Bt

Cl

DMA, rt

148

Bt

Cl

DIEA, rt 147

DIEA Cl

N R1

NMP, 95 oC

R2

PS

PS

149

O R3R4NH

PS

N L

N R2

N N R2 150

N L

Cl

O

N R1

O

O N

NH

N L

N

Cl

N R1

N L

Cl

Cl

N

N R4

R3

95% TFA/H2O

N R1

151

N H

N R2

N

N R4

R3

152

Scheme 34.Solid-phase synthesis of trisubstituted pyridopyrimidines by Schell et al.



Page 28 of 63

Resin-bound secondary amines 28, obtained as a reductive amination product of rink amide resin, was treated with di(benzotriazolyl) methenimine and subsequent acylation of the product 147 with 2,6-dichloronicotinoyl chloride provided resin 148. Benzotriazole moiety present in 148 was replaced using 2-t-butyl-1,1,3,3-tetramethylguanidine (Barton’s base) and further cyclization of product 149 afforded resin bound pyrimidines 150. Substitution of chlorine present in resin 150 by a dialkylamino group resulted in resin 151. Finally, resin 151 was subjected to TFA cleavage and the targeted product trisubstituted 1H-pyrido[2,3d]pyrimidin-4-ones 152 was obtained in good yield (31-71%) and purity (50-95%). The synthesised N-heterocycles were found to have significant biological application as therapeutic agents. Synthesis of pyridopyrimidine by Molina et al. is an interesting one.93 In the first step ethyl α-azido-β-(2-pyridyl)acrylate 154 undergo Staudinger reaction with polymer bound triphenylphosphine 153 yielding polymer bound iminophosphorane 155. The resin 155 underwent an aza-Wittig reaction with aromatic isocyanates resulting carbodiimides 157, through the formation of an intermediate 156,

which was further electrocyclized with

simultaneous cleavage to corresponding pyrido[1,2-c]pyrimidine derivatives 158 (Scheme 35). All the synthesised compounds were reported to be efficient superoxide scavengers and anti-inflammatory agents by Molina et al.

N PS

PPh3

+

DCM, rt

N N3

153

PS

Ph3P N

COOEt

COOEt

Ar-NCO, DCM, rt

155

154 N PS

Ph3P N O

COOEt N Ar

Solid CO2 or CS2

N Ar N C N

COOEt

157

156

Toluene, 90 oC

N N Ar

N

COOEt

158

Scheme 35. Solid-phase synthesis of pyrido[1,2-c]pyrimidines by Molina et al.

Solid-phase synthesis of structurally diverse dihydropyrido[2,3-d]pyrimidines on Merrifield resin 1 under microwave irradiation conditions were reported by Agarwal and coworkers.94 Initially, the resin 1 was modified with aldehydes functional groups, and product 159 was treated with 6-amino-1,3-dimethyluracil 160 and an active methylene compound 161 under microwave irradiation. The resulted resin 162 on TFA cleavage afforded 28 ACS Paragon Plus Environment

Page 29 of 63 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


dihydropyrido[2,3-d]pyrimidines 163. Agarwal et. al. synthesised a series dihydropyrido[2,3d]pyrimidine derivatives using different active methylene compounds with yields in the range 82–92% (Scheme 36).

Me

HO PS

1

Cl

PS

O

NaH, NMP, MW, 15 min

N

O

CHO

CHO

O

O N NH2 Me 160

+

R1

R

161

CH3COOH, MW, 4 S 159

O Me O

OH

TFA/DCM, rt, 30 min

PS

R1

N N Me

N H

R''

162

O Me O

R1

N N Me

N H

R

163

Scheme 36. Solid-phase synthesis of pyrido[1,2-c]pyrimidines by Agarwal et al.



SOLID-PHASE SYNTHESIS OF PYRIMIDOPYRIMIDINE

Pyrimidopyrimidine derivatives are biologically important as antiallergic, antitumor, antipyretic, anti-inflammatory and antiparasitic agents. Virgilio et al. also have reported the inhibitory activity of pyrimidopyrimidines in cellular proliferation and motility induced by hprune in breast cancer.95 Srivastava et al. described the solid-phase synthesis of pyrimido[4,5-d]pyrimidine derivatives. Polymer bound 2-(alkylthio)-4-aminopyrimidine-5-carbonitrile 164 was used as starting material for the synthesis of diverse pyrimido[4,5-d]pyrimidine derivatives (Scheme 37).96



Page 30 of 63

O CN

N PS

S

N

N KOH, EtOH

NH2

Partial hydrolysis

164 Urea, 120 oC

Thiourea, 120 oC

NH2 N PS

S

N

N H

N O

PS

S

165a

S

S

N N

N O

166

PS

S

N N

N

S N H 169b

O N

N

N S H 167

Ph

Raney Ni/H2, MeOH O

N N

O

N H

N

169a

NH2

N N H

PS

O Ph

Raney Ni/H2, MeOH

Raney Ni/H2, MeOH

NH2

N

N

165b

Raney Ni/H2, MeOH

N

N H

NH2

O

N N

N

168 PhNCO, Diphenyl ether, PhNCS, Diphenyl ether, 259 oC 259 oC

NH2

N

S

PS

NH2

N H

Ph O

170

N

N N

N H

Ph O

171

Scheme 37.Solid-phase synthesis of substituted pyrimidopyrimidines by Srivastava et al.

Firstly resin 164 was treated with urea and thiourea resulted in resin 165a and 165b and further hydrogenation with Raney nickel in methanol afforded 4-aminopyrimido[4,5d]pyrimidine 2(1H)-one 166 and 4-aminopyrimido[4,5-d]pyrimidine 2(1H)-thione 167. Resin 164 was also converted to polymer-bound 2-(alkylthio)-4-aminopyrimidine-5-carboxamide 168 by partial hydrolysis of the cyano group which on treatment with phenyl isocyanate or phenyl isothiocyanate afforded resin 169a and 169b, further hydrogenation resulted 3phenylpyrimido[4,5-d]pyrimidine-lH-2,4-dione 170 and 3-phenylpyrimido[4,5-d]pyrimidinelH-4-one-2-thione 171. 

SOLID-PHASE SYNTHESIS OF PYRROLOPYRIMIDINES

Pyrrolopyrimidines come under an attractive class of compounds and exhibit superfluous biological activities due to their similarity to pyrimidines and purines. They are medically important as antagonists toward adenosine receptor subtypes and inhibit the activity of various enzymes.97 The first report on the solid-phase synthesis of pyrrolo[3,2-d]pyrimidine on Merrifield resin was described by Rombouts et al.98 Initially Merrifield resin 1 was modified to an amino resin 172 by a cystamine linker, 2-aminoethanethiolate in DMF (Scheme 38).


Page 31 of 63 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


O 2-aminoethanethiol hydrochloride Cl

PS

1

PS

S O

PS

NaH, DMF, 48 h, rt

NH2

S

CO2Bn

NHR

NH 174

(ii) Cs2CO3, DMF, 12 h

PS

(i) Et3N.HBr, 50 °C, (ii) THF/MeCN, 24 h

172

(i) Cl3CCOCl, dioxane, 70 °C, 4 h

N

CO2Bn N PhF

S

PS

O R

N N

N H

O

S

R3NCO, DCM CO2Bn rt, 12 h NH

H N 173

(i) m-CPBA, DCM, rt, 1 h

O

(ii) t-BuONa, THF, 0 °C, 1 h CO2Bn

R

H N N O

N H

CO2B n

176

175

Scheme 38. Solid-phase synthesis of substituted pyrrolo[3,2-d]pyrimidines by Rombouts et al.

Resin 172 on reaction with 4-oxo-N-(PhF)prolinate afforded resin bound 4-aminopyrrole2-carboxylate 173. Different isocyanates were allowed to react with 173 to form resin bound ureidopyrroles 174 which was then converted to pyrrolo[3,2-d]pyrimidines by a “2- step” process. The resin bound urea 174 was treated with trichloroacetyl chloride in dioxane, then with dried Cs2CO3 resulted in the formation of resin-bound pyrrolo[3,2-d]pyrimidines 175 which was then oxidised using m-CPBA in DCM and product was cleaved from the resin by sodium t-butoxide in THF. Rombouts obtained biologically significant pyrrolo[3,2d]pyrimidines 176 having alkyl and aryl substituents at the N3 position in high purity (90100%) with a disadvantage of relatively low product yield (42-50%). Synthesis of pyrrole fused pyrimidine on functionalized Merrifield resin was reported by Fridkin et al.99 The procedure involves the conversion of Merrifield resin containing a cystamine linker 172 to resin-bound aminopyrrole 178 by 4-oxo-N-(PhF)-proline benzyl ester 177. The resin 178 on treatment with ethyl or 2,4-dimethoxyphenyl isocyanates resulted in corresponding ureidopyrrole resins 179. Cyclization of resin 179 by haloform reaction produced resin bound pyrrolo[3,2-d]pyrimidines 180 and further diversification at positions N3, N5 and C6 by alkylation in basic medium produced resins 181 and 182. The product 183 was cleaved from the resin by safety-catch approach (Scheme 39). Fridkin successfully employed this procedure for the synthesis of twenty three chemical entities of pyrrolo[3,2d]pyrimidines with excellent purities (61-98%).



Page 32 of 63

R1

O

CO2Bn PhF

NH2

PS S

PS

177

Et3N, Et3N.HBr, THF/CH3CN, 50 °C, 24 h

172

NH

R2-N=C=O

R1

S

PS S

DCM, rt, 12 h 178

CO2Bn

N H

O

R1

N

R2HN PS

PS

S Cl3CCOCl

N

O

dioxane, 70 °C, 4 h

N R2

179

O

R3X CO2Bn

Cs2CO3, DMF, rt, 12 h

N R

O

R2

O

(i) m-CPBA, DCM, rt, 1 h o

N O

N R3

R4

LiOH CO2Bn

THF/H2O/MeOH, 70 °C, 12 h

181

S N

N R3

2

180

O

R1

N

O

PS R1

CO2Bn

S

R1

N H

N H

(ii) n-BuONa, THF, 1 h, 0 C

R5 N

O R2

N O

R1 O N R3

R4

183

182

Scheme 39. Solid-phase synthesis of pyrrolo[3,2-d]pyrimidines by Fridkin et al.

Lee et al. reported a new procedure for the synthesis of suitably functionalized pyrrolo[2,3-d]pyrimidine structures that act as inhibitors of α-helix-mediated protein-protein interactions.100 Initially, an efficient solid-phase synthesis of structurally diverse 2,4,6,7tetrasubstituted pyrrolo[2,3-d]pyrimidine derivatives on rink amide resin 28 was discussed. In their procedure, the resin 28 was first acylated with bromoacetic acid (BAA) under microwave irradiation to corresponding bromofunctionalized resin 184 which on treatment with a primary amine gave resin 185. As a result of repeating acylation and substitution reactions, resin bound peptoid 186 was formed. The intermediate 186 was allowed to couple with 4,6-dichloro-2-(methylthio)pyrimidine-carbaldehyde producing resin 187 which underwent an intramolecular aldol reaction and subsequent dimethylamination at C4 resulted in resin bound bicyclic pyrrolopyrimidine 188. Oxidation of resin 188 and further amine displacement reaction resulted in resin bound 2,6,7-trisubstituted pyrrolo[2,3-d]pyrimidines 189. The product, 190 released from resin 189 using TFA cleavage with good yield (80%) offers a greater diversification at four substitution positions (Scheme 40). During the formation of pyrrolopyrimidine ring, DMF was optimized as the efficient solvent, because cyclization reaction was feasible only in DMF.


Page 33 of 63 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


O

O L

PS

NH2

BAA, DIC DMF, rt

28 O

PS

Br

N H

PS

DMF, rt

L

N H

O

Cl N N

O S

DIEA, THF, rt 12 h

PS

L

N H

R1 NH

R1 N

(i) BAA, DIC

O

PS

(ii) R2NH2

L

(ii) R3NH2, DIEA, NMP, 170 oC, 12 h

PS

N

PS

N

DBU, DMF/MeOH

S

L

L

O

N

N R1

N

N

R2

N S

188 O

O O

R2

O

H N

90 oC

R2

H N

NH O

186

187 (i) m-CPBA, NaHCO3 THF/H2O, rt

N H

Cl

H N

R1 N

O

185

184

H Cl

L

R1NH2

N

N R1

N 2

R

N

TFA rt, 2 h

N S O O

189

H2N O

N N R1 R2 190

N N N

HN R3

Scheme 40. Solid-phase synthesis of pyrrolo[2,3-d]pyrimidines by Lee et al.



SOLID-PHASE SYNTHESIS OF PURINES Purines systems regulate many physiological processes and are used in cancer

treatment. They are a major component of drugs used for the treatment of cardiovascular and central nervous system complaints.101 Lucrezia and co-workers suggested a new solid-phase strategy for the synthesis of various substituted purines from 4,6-dichloro-5-nitropyrimidine on rink amide resin 28.102 The strategy started with the immobilization of 4,6-dichloro-5-nitropyrimidine on the amide resin 28 by DIEA. In the next step, resin bound triamino intermediate 193 was accomplished by the substitution of chlorine atom present in resin 191 by a nitro group and subsequent reduction of resin 192 by lithium aluminium hydride in the presence of aluminium chloride. The resin bound triamino intermediate 193 was then treated with isothiocyanates in the presence of DCC giving corresponding resin attached 8-aminopurines 194. The product 195 was then separated from the resin and purified (Scheme 41). They were successful in synthesising a series of substituted purines from triamino intermediate by the reaction with a series of substituted formamides and aldehydes.



Page 34 of 63

Cl NO2

N L

PS

N

NH2

Cl

PS

DMF, DIEA, rt, 2 h

28

L

NO2

N N

L

R-NH2

NH

PS

L

NH

N

Cl

NH2

N N 193

N H

R

(i) R1-N=C=S, benzene, 80 oC, 15 min

NO2

N

DMF, DIEA, rt, 2 h

192

191

PS

NH

PS

L

N H

LiAlH4-AlCl3 THF, rt, 12 h

R

NH2

NH N

N

o

(ii) DCC, 80 C, 12 h

NHR1

N R

N

N

N

TFA/DCM rt, 20 min

NHR1

N N R 195

194

Scheme 41.Solid-phase synthesis of substituted purines by Lucrezia et al.

Magdalena et al. gave the first report on mixed purine-pyrimidine-4'-alkoxy-2'deoxynucleosides from nucleoside 4'-5'-enolacetates.103 In their report, the oligonucleotides were first synthesised by GeneSyn synthesizer using UNYLINKER porous glass and standard

phosphoramidite

approach

and

further

modified

to

corresponding

4'-

alkoxyoligonucleotides. All the modified products are found to functions as RNA mimics.

The report on the synthesis of purines on Merrifield resin functionalized by 2-sulfanyl ether linker was given by Gibson et al.104 The reactions were carried out on the polymer supports with different degrees of cross-linking and varying chlorine loading capacities. The product yields were higher with resins having lower cross linking and chlorine loading capacities. At first 6-amino-2-sulfanylpyrimidin-4(3H)-one immobilized resin 196 was treated with sodium nitrite in acetic acid afforded resin 197 which was reduced to 198 and further cyclization with biacetyl gave corresponding dimethylpteridinedione 199. The product 200 was cleaved from the resin using m-CPBA. 2-Amino, 2-allylamino, and 2-pyrrolidinylderivatives were isolated by same procedure (Scheme 42). In the case of resin with lower cross linking and chlorine loading capacities, they applied an alternative cleavage strategy called DDO oxidation. In all cases, Gibson and co-workers obtained products with good yield (84-90%).


Page 35 of 63 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


O

O

HN PS

S

N

NH2

196

HN

NaNO2

PS

HOAc, DMF, rt, 24 h

S

O NO

N

NH2

197

DMF, 40 oC, 20 h

DMF, 80 oC, 18 h

N

HN PS

S

N 199

PS

S

N

NH2

198

O

O (MeO)3CH–Ac2O

NH2

HN

Na2S2O4

DDO, acetone, rt, 3 h N COMe

N

HN

Nu

N COMe Nu = Amines/ N - pyrrolidinyl Nu

N

200

Scheme 42.Solid-phase synthesis of substituted purines by Gibson et al.

Aminomethylpolystyrene resin 201 with backbone amide linker was used as the solid support by Vanda and co-workers.105 At first aldehyde functionalized polystyrene 22 underwent reductive amination with propylamine yielding the amine immobilized resin 210. Polymer supported alanine derivative 202 was synthesised from resin 201 by acylation with Fmoc-Ala-OH and subsequent deprotection with piperidine. Resin 202 was then arylated with 4,6-dichloro-5-nitropyrimidine and substitution of chlorine present in product resin 203 with a secondary amine gave the resin 204. Reduction of resin 204 with sodium dithionite and further thermal cyclization of the resulted resin 205 with benzaldehyde afforded polymer supported purine derivative 206. The acidic cleavage of the resin 206 produced the targeted product (S)-2-(8-phenyl-6-(piperidin-1-yl)-9H-purin-9-yl)-N-propylpropanamide 207 with good yield (7-61%) and high purity (Scheme 43). The optically pure pyrimidine derivatives synthesised by Vanda exhibit anticancer properties against breast carcinoma and myelogenous leukemia cell lines MCF7 and K562.



Page 36 of 63

Cl

CHO

PS

22

(i) R1NH2, AcOH, DMF, rt, 16 h (ii) NaBH(OAc)3, rt, 4 h

H N

PS

(i) Fmoc-amino acid, HOBt, DIC, DMF, DCM, rt, 16 h (ii) Piperidine, DMF, rt, 30 min

R1

201

PS

NH2

N R1

NO2

N

O R2

Cl

N

DIPEA, DMF, rt, 16 h

202 4

N O PS

NO2 NH

N R1

O N R1

PS

N

NH2 NH

5

R CHO, DMSO

R2

O N R1

PS

205

N

R4 N

N

R3

N R2

Na2S2O4, K2CO3 TBAHS, DCM, H2O, rt, 16 h

204

R4 N

N

MW, 100 °C, 60 min

NO2

R2

N

R3

R3

NH

N R1

R

N

N

O

DMF, 60 oC, 16 h

2

R4 N

R N

N

R3R4NH

N

203

PS

Cl

N

TFA/DCM O

rt, 2 h

R5

HN R1

206

R3

N N R5

R2

207

Scheme 43.Solid-phase synthesis of purine derivatives by Vanda et al.

Vankova et al. described the solid-phase synthesis of purine-hydroxyquinolinone bisheterocycles on aminomethylated polystyrene resin equipped with an acid-labile linker (4(4-formyl-3-methoxyphenoxy)butyric

acid)208.106

Initially,

primary

amines

were

immobilized on resin 208 by reductive amination and the resulted resin 209 on arylation with 2,6-dichloropurine afforded resin 219. N9 alkylation of resin bound purine 210 by alkyl iodide in the presence of DBU and subsequent substitution of chlorine atom resulted resin 211. The resin 211on reaction with aliphatic diamines in diethylene glycol diethyl ether afforded resin 212. Acylation of resin 212 with 3-amino-4-(methoxycarbonyl)benzoic acid gave an intermediate bound resin 213 which on saponification with potassium trimethylsilanolate yielded corresponding carboxylic acid resin 214. On esterification with haloketones of aliphatic, aromatic or heterocyclic character resulted in resin 215. On acidic cleavage resin 215 underwent a cyclization reaction resulting in the formation of product bisheterocycles 216 with high purity (65-98%) and good yield (12-98%) (Scheme 44). In the case of the nitro group bearing derivatives Vankova applied another cyclization method where the cyclization was performed using acetic acid. The present strategy was very successful for the synthesis of purine-hydroxyquinolinone bisheterocycles, with four diversity positions, excellent substrates for biological research.


Page 37 of 63 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


O H N

PS

PS

L

O

R1NH2, NaBH(OAc)3

PS

O

L

O

O

208 PS

L

N

H2N

X

N H O

N H

R1

2,6-Dichloropurine

N R2

N

N

N

DIEA, THF, 50 oC

Cl

209

PS

L

3-amino-4-(methoxycarbonyl) benzoic acid DIC, HOBt, DCM, DMF, rt

N

N

N H2N

X

N H

PS

R1 NH2-X-NH2, (CH2OH)2

N R2

N

L

N

PS

TMSOK, THF, rt, 24 h

L

N

HN H2N

N H O

N

N

Haloketones

N R2

HN

DIEA, DMF, rt, 2 h

N H O

H2N O

214

X

O

N

211

N R2

HN AcOH, Reflux, 3 h

HO

R1 N

N HN

R3

R3

HOOC

N R2

N

R1

215

O

N

Cl

N

N

1

N

N X

R

L

R1

N

150 oC, 24 h

212

PS

N H

N 210

R2I, DBU, DMSO, 50 oC

N

213

H3COOC

AcOH/DMF, rt, 4h

L

R1

N HN

PS

R1

N

H N

X

N H O

N

N R2

216 O

x = Spacer

Scheme 44.Synthesis of purine-hydroxyquinolinone bisheterocycles by Vankova et al.



SOLID-PHASE SYNTHESIS OF QUINAZOLINES

Quinazoline derivatives are used in agrochemical and veterinary industries. Quinazolines are important pharmaceutically as anticancer, antiviral and antibacterial agents. Derivatives of quinazoline such as quinazolinediones are ligands and act as inhibitors of the enzymes PARP and tankyrase that are important pharmaceutically.107 An efficient methodology for the traceless solid-phase synthesis of derivatives of quinazoline was developed by Fulopova et al.108 Fulopova and co-workers carried out the synthesis

from

three

components

namely

Fmoc-protected

α-amino

acids,

2-

nitrobenzenesulfonyl chlorides and α-bromoacetophenones. In the first step, Fmoc-protected α-amino acid was immobilized on Wang resin 17. The resin bound amino acid was deprotected and allowed to react with 2-nitrobenzenesulfonyl chlorides, the newly formed sulfonamide intermediates 217 underwent Fukuyama alkylation with substituted αbromoacetophenones providing polymer-supported acyclic alkylated sulphonamides 218. The product 218 on treatment with DBU and subsequent base catalysed C-C coupling, converted the intermediate indazole oxides to quinazolines 219. Treatment of resin 219 with 50% TFA in DCM released corresponding quinazoline carboxylates 220 into solution. The cleaved 37 ACS Paragon Plus Environment


Page 38 of 63

products were purified in aqueous ammonium acetate buffer-acetonitrile by reversed-phase HPLC and following decarboxylation affording 4-benzoylquinazolines 221as the major product with 8-56% yield and purityin the range 51-70% (Scheme 45). Fulopova effectively synthesised pharmacologically important pyrimidine derivatives with three points of diversity under mild reaction conditions. R2

O2N L

OH

PS

17

(i) Fmoc-amino acid, DMAP, DIC, DCM, DMF, rt, 12 h (ii) Piperidine, DMF, rt, 15 min PS (iii) 2-Nos-Cl, 2,6-lutidine, DCM, rt, 12 h

O DBU, DMF rt, 30 min

PS

L O

R1

H N

O

O O2S NH

C6H5COCH2Br DIEA, DMF, rt, 12 h

R1

PS

L

O

218

R3 TFA /DCM rt, 1 h

2

R1

N H

O

NH4Ac OH

N 2

R

O

N

R1

221

220

219

R3

O

R3

O N

R

R3

O O2S N R1

217

R2

N O

L

R2

O2N

Scheme 45 Solid-phase synthesis of quinazoline derivatives by Fulopova et al.

Kisseljova et al. modified the above described method by amino functionalizing Wang resin 17 with 2-(Fmoc-amino)ethanol by trichloacetimidate activation method.109 The Fmoc group was then removed and the product resin 222 on reaction with 2-Nos-Cl(2nitrobenzenesulfonylchloride) and subsequent Fukuyama alkylation with a series of benzyl alcohols under Mitsunobu conditions resulted in resin-bound N-benzylsulfonamides 223. The resin 223 was subjected to DBU in DMF and finally, the product 224 was cleaved from the resin by TFA method (Scheme 46).

PS

L

(i) CCl3CN, DBU, DCM, 1 h Fmoc-ethanolamine, BF3EtO, THF, 30 min OH

PS

(ii) Piperidine, DMF, 15 min

17

L R1 222

(i) 2-Nos-Cl, 2,6-lutidine, DCM, 16 h

1

(i) DBU, DMF, 80 oC, 5 h N N

(ii) Benzyl alcohol, PPh3, DIAD, THF, 2 h

R3

R3

R2

NH2

R

PS

L

(ii) TFA/DCM, rt, 1 h 1

R

N

SO2 NO2

R2

223 224

Scheme 46.Solid-phase synthesis of substituted quinazolines by Kisseljova et al.


Page 39 of 63 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


Benzhydrylamine is a promising intermediate in the synthesis of nitrogenous heterocycles proved by the author from the above mentioned method. Cyebasek et al. reported the solid-phase synthesis of 3-amino-4H-quinolizin-4-ones and fused

3-amino-4H-pyrimidin-4-ones

on

Wang

resin

17.110

Initially,

N-

benzyloxycarbonylglycine ethyl ester was immobilized on Wang resin and the product 225 on further treatment with Bredereck's reagent resulted in corresponding polymer-bound ethyl (Z)-2-benzyloxycarbonylamino-3-(dimethylamino)prop-2-enoate 226. Cyclization of product to polymer bound 3-amino-4H-quinolizin-4-ones 227 and fused 3-amino-4H-pyrimidin-4ones 228 was achieved by treatment with suitable nucleophiles in acidic medium. Finally, deprotection and cleavage of resin released the product with high purity but (25-83%) moderate yield (19-39%) (Scheme 47). O PS

L

OH

+

N C O

COOEt

toluene, 80 °C

L

PS

O

9h NH2

O PS

L

O

N H

COOEt

COOEt

t-BuOCH(NMe2)2 toluene, 90 °C, 11 h

225

17 NMe2

N H

N

O

N PS

L

N H

O

AcOH, 90 °C, 10 h

N N

TFA/DCM, rt

O

H2N

N O 228

227 226

Scheme 47.Solid-phase synthesis of substituted quinazolines by Cyebasek et al.

Solid-phase

synthesis

of

benzo-fused

pyrimidine-2,4-diones

namely

quinazoline-2,4-diones (QDs) from urea immobilized Sasrin resin has been published by Gordeev et al.111 In the given strategy urea immobilized Sasrin resin 230 was synthesised by acylating the resin bound amino acids 229 with activated carbamates. Alternative pathway used by Gordeev for the immobilization of urea includes the treatment of aniline derivative with resin bound activated carbamates. In the next step resin 230 was subjected to heterocyclization,

to

corresponding

resin

bound

QDs

231,

by

heating

with

tetramethylguanidine (TMG) in NMP. Finally, the QDs 232 were cleaved from the resin by TFA and had 90-95% yield. The resin 231was also subjected to alkylation via a Mitsunobutype reaction resulting in another product, N'-substituted QD 233, with moderate yield (Scheme 48). The synthetic method illustrated was successful in synthesising heterocyclic scaffolds having high chemical and structural diversity.



O O L

PS

R N

O

O OMe

2

R

PS

NH2

NCO

R1

L

H N

O 1

R

DMF, Py

229

230

Page 40 of 63

O

HN R2

MeO O

TMG, NMP, 55-65 °C, 12 h R1

O

OH

N

R2 N R3

(i) R3OH, DIAD, PPh3 ,THF

O

O

(ii) TFA/DCM

O L PS

H N

O

R2

N

O R1

TFA/DCM

O H

N

R2 N H

O

O

O

232

231

233

R1

O

Scheme 48. Solid-phase synthesis of substituted quinazoline-2,4-diones by Gordeev et al.

Srivastava and co-workers described the solid-phase synthesis of 2-aminoquinazolinebased compounds.112 The procedure involves the attachment of 2-nitrobenzadehydehyde 234 on the rink amide resin 28. The nitro group present in resin 235 was reduced to amino group and the resulted resin 236 was cyclized, with cyanogen bromide, to resin bound quinazolines 237. The product 3,4-dihydroquinazoline-2-amine 238 was cleaved from the resin 237 by TFA mediated mechanism and has high yield and purity (Scheme 49). Srivastava et al. repeated the same synthetic procedure using rink resin modified with amino acids such as Nεaminocaproic acid, p-aminobenzoic acid, γ-aminobutyric acid, 3-aminobenzoic acid, etc., to introduce diversity. In all such cases, 2-aminoquinazoline-based compounds were obtained with high yield (>95%) and purity (>85%).

L PS

OHC O2N

28

AcOH/TMO NaCNBH3, rt, 3 h

R1

NH2 + 234

BrCN DMF: EtOH (2:1), rt, 16 h

PS

L

H2N

L PS

N H O2N

SnCl2.2H2O

R1

DMF, rt, 5 h

PS

L

235

N

R1 N

R 1

236 HN

50% TFA/DCM rt, 2 h

N H H2N

H2N

237

R1 H N

Br 238

Scheme 49.Solid-phase synthesis of 2-aminoquinazolines by Srivastava et al.


Page 41 of 63 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


But when they repeated the same reaction with the α-amino acid alanine, instead of the desired product 2-amino-3-(2'-amino-2'-oxoethyl)-3,4-dihydroquinazolin-1-ium bromide, 3methyl-1,5-dihydroimidazo[2,1-b]quinazoline-2(3H)-one was formed as the major product. They explained the formation of the unexpected product as: the interaction of free amine, formed from cyanogen bromide, with resin bound alanine leading to two sequential cyclization reactions affording a tricyclic backbone as the major product. According to Srivastava, all the synthesised compounds are pharmacologically very important as they reduced the risk of thrombosis. The solid-phase synthesis of 2-amino-substituted 3H-quinazoline-4-ones via an aza-Wittig reaction of iminophosphoranes was developed by Zhang et al.113 Here iminophosphorane anchored polystyrene support 153 was used as solid support. Treatment of primary amines with isatoic anhydride 239 produced N-substituted benzamide 240. Then a modified Kirsanov reaction was carried out, in which polymer-supported triphenylphosphine 153 was allowed to react with 240 to give polymer tethered iminophosphorane 241. On heating with isocyanates resin 241 was converted to a carbodiimide intermediate 242 which underwent intramolecular cyclization resulting in the targeted quinazolinederivatives 243 in excellent yield (74-88%) and purity (61-96%) (Scheme 50). O

O O

N H 239

O

RNH2 DMAP/DMF rt, 8 h

R1NCO, Toluene/ Xylene

PPh2

PS

NHR NH2 240

153 C2Br2Cl4/TEA/DCM Ar, reflux, 5 h

PS

Ph2P N RHN O 241 O

O

N

NHR

Ar, reflux, 8-24 h

N C NR1

N

R NHR1

243

242

Scheme 50.Synthesis of 2-amino-substituted 3H-quinazoline-4-ones by Zhang et al.

This simple and conventional method, developed by Zhang et al., is applicable for the synthesis of substituted quinazolines that are biologically important as thymidylate synthase inhibitors, tumour necrosis factor (TNF)- α inhibitors, histamine H2 antagonists, etc. The solid-phase synthesis of quinazolines with three diversity positions and application of this synthetic method for combinatorial synthesis was reported by Krupkova and coworkers.114 The synthesis was carried out on acylated rink amide resin as well as alkylated 41 ACS Paragon Plus Environment


Page 42 of 63

BAL resin or ethanolamine-derivatized Wang resin 244. Initially, 2-nitrobenzenesulfonyl chlorides were immobilized on the resin 244 and N-alkylation of the product 245 was carried out using α-bromoketones. The formed alkylated resins 246 were then subjected to DBU producing an indazole-oxide resin 247 which further transformed to quinazoline resin 248. Finally, the product 249 was released by TFA method (Scheme 51) and this method offers a simple and convenient preparation of quinazolines by the base-catalyzed mechanism. O PS

L

H N

O

Fmoc

244

R2

O

(i) Piperidine, DMF, rt, 15 min

L

PS

H N

O

SO2Cl

(ii)

O

R2COCH2Br

SO2

NO2 DMF, rt, 0.5-7 h

L PS

O N

O

SO2 NO2

1

NO2 R1 Lutidine,DCM, rt, 12 h

R

R1

245

246 DBU,DMF, rt, 30 min

R2

O

O TFA/DCM

N

R1

OH

N 249

O

rt, 1 h

PS

L

O

N

O

R1

N

DBU,DMF, rt 10 min - 12 h

O R2 248

L PS

O

O N N

R1

O R2 247

Scheme 51.Solid-phase synthesis of substituted quinazolines by Krupkova et al.

Weber et al. reported the solid-phase synthesis of 6-hydroxy-2,4-diaminoquinazolines.115 Initially, 6-hydroxy-7-methoxyquinazoline scaffold 251 was synthesised in solution-phase (either from 4,5-dimethoxy-2-nitrobenzoic acid under basic medium and subsequent reduction or by selective demethylation of 6,7-dimethoxy-2,4(1H, 3H)-quinazolindione) andimmobilized on a resin having an o-methoxybenzyl alcohol functionality 250 under Mitsunobu conditions. C4 Amination of the resulted resin 252 afforded resin bound 4aminoquinazoline derivative253 which on further amination with unbranched secondary amines at 90 ℃ in n-BuOH afforded the 2,4-diaminoquinazolines attached resin 254. Finally, the targeted product 255 was separateded from the resin by TFA cleavage (91-96% yield) (Scheme 52). By a Tecancombitec synthesizer Weber successfully synthesised a library of quinazoline derivatives using commercially available cyclic six-membered secondary amines. The synthesised derivatives are reported to exhibit important pharmacological applications as reversible inhibitors of the gastric (HC/KC)-ATPase, antagonists of the neurokinin-2 receptors, etc.


Page 43 of 63 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


O

PS

CH3

+

H3C OH

O

PS

Cl HO

N N

250

THF, 10-15 C, 24 h

Cl

NHR1R2

Cl

o

O

CH3

DIAD, PPh3 O H3C

251

N

O

N

THF, rt, 24 h Cl

252 O

PS

R1

N

O H3C

O

PS

CH3

NHR3R4 , n-BuOH

R2

o

100 C, 48 h

O

N

O

N

CH3

H3C

O

Cl

253

R1 R1

R2 TFA/DCM 2 h, rt N R3 N N R4 254 N

N

HO H3C

R2 N

O

N

N R4

R3

255

Scheme 52.Solid-phase synthesis of substituted diaminoquinazolines by Weber et al.

Solid-phase synthesis of quinazoline-2,4-diones having various electron-withdrawing substituents on the aromatic ring was reported by Okuzumi et al. Derivatized 4-(4-formyl-3methoxyphenoxy)butyryl amide 256 resin was used as polymer support.116 At first, the resin 256 underwent acylation with 4-nitrophenylacetic acid and the reduction of the nitro group provides solid supported arylamine 257. Coupling of resin 257with substituted anthranilic acids in the presence of DIC or HOAt produced resin 258 which on carbonylation with N,N′carbonyldiimidazole in decalin at 95 ℃ gave corresponding quinazolidine-2,4-diones attached resin 259. Finally, the quinazolidine derivatives 260 were separated from the resin 259 by TFA cleavage (Scheme 53). By varying solid supported alkylamines and substituted anthranilic acids a variety of quinazolidine derivatives were obtained with high yield (7689%) and purity (90-95%). Highly pure products were achieved by using anthranilic acids having electron withdrawing substituents. Okuzumi was successful in synthesising quinazoline-2,4-dione derivatives with electron-withdrawing substituents on the aromatic ring. X

O NH2

NO2 HO

NH L PS

256

O

N L

(i) DIC, HOAt NMP, 25 oC, 16 h (ii) SnCl2.2H2O NMP, 25 oC, 16 h

N

OH NH2

O

DIC, HOAt NMP, 25 oC, 16 h

PS

257

N L

O PS

258 O

O N

NH NH2

X

O

X NH

N

N N

N 95% TFA/H2O

O

Decalin, 95 oC, 16 h N L

X

O NH O

25 oC, 1 h

O

N H

259

O 260

PS

Scheme 53. Solid-phase synthesis of substituted quinazolines-2,4-diones by Okuzumi et al. 43 ACS Paragon Plus Environment


Page 44 of 63

Makino et al. reported an excellent procedure for the solid-phase synthesis of 2,4disubstituted 1,2,4-benzothiadiazin-3-one-1,1-dioxides.77,78, 116 The resin 261, obtained from reductive

amination

of

4-(4-formyl-3-methoxyphenoxy)butyryl

resin

with

1-

aminomethylnaphthalene, was used as polymer support (Scheme 54). The procedure involves the acylation of the resin 261 with 4-nitrophenylacetic acid and subsequent reduction of the nitro group producing solid supported arylamine 262. The product 262 then underwent sulfonylation by solid-phase Fukuyama-Mitsunobu alkylations, with 2-nitrobenzenesulfonyl chlorides in 2,6-di-t-butyl-4-methylpyridine/DCM mixture giving solid supported 2nitrobenzenesulfonamides 263. Nitro group present in 263 was then reduced with SnCl2 and further cyclization of resulted resin 264 with N,N′-carbonyldiimidazole produced resin bound 1,2,4-benzothiadiazin-3-one-1,1-dioxides 265. An extra point of diversity was introduced to 265 by N-alkylation affording resin 266 which on TFA cleavage released the products 267 and 268 from the solid support in good yield (71-90%) and purity. Makino improved the above strategy for the synthesis of 2-aminoquinazolin-4-ones also.117

NO2

HO NH L

DIC, HOAt

N L

NMP/EtOH

25 oC, 16 h

261

R1

SnCl2.2H2O

O PS

O

NH2

PS

o

25 C, 16 h

O

O S

Cl

NO2

2,6-di-t-But-4-methylpyridine DCM, 25 oC, 16 h

PS

262 R1 O S O NH

R1 O S NH

O

NO2

O NH2

N

N L

NMP/EtOH 25 oC, 16 h

O

N L

PS

O O S N

N L

265

R1

NH

N L

R2

O 266 PS

R1 O O S N

95% TFA/H20 25 oC, 1 h

O N H

N O

R1 O O S N

95% TFA/H20 25 oC, 1 h

PS

O O S N

R2 X DIEA/NMP 25 oC, 16 h

O PS

O

NH O

N

DCM, 25 oC, 16 h

264

R1

263

N

N

SnCl2.2H2O

N

R2

O

O

N H

O

268

267

Scheme 54.Solid-phase synthesis of fused pyrimidines by Makino et al.


Page 45 of 63 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


In their work, the previously synthesised aryl amines were coupled with 2-azidobenzoic acid and subsequent aza-Wittig reaction with 2-methoxycarbonylphenyl isocyanate gave resin attached phenylisocyanate derivative. The treatment of the product with secondary amines produced resin bound 2-aminoquinazolin-4-ones. Finally the product, 2aminoquinazolin-4-one was cleaved from the resin using TFA method. Kesarwani et al. developed a new procedure for the solid-phase synthesis, of imidazoquinazolinone-based compounds with three points of diversity, on rink amide resin.118 Initially amino acid immobilized rink amide resin was treated with 2nitrobenzaldehyde and succeeding reduction of the nitro group to an amine. Resulted resin 269 on reaction with aryl isothiocyanates produced resin bound thiourea 270 which was converted to resin bound quinazoline 271 by DIC in DCM. Second cyclization and cleavage was achieved by 10% AcOH in DCM resulted in the formation of the desired imidazoquinazolinones 272 with high purity (77-96%) and good to moderate yields (70-90%) (Scheme 55). PS

L

R1

H N O

N H H2N 269

R2 R3NCS 16 h, rt

PS

L

R1

H N O

PS

N H HN S 270

DIC

2

R

DCM, 12 h NHR3

L

H N

O

R1

N

HN 3

R

10 % AcOH/ DCM N 271

R2

16 h, rt

R1 O

N N R3

N

R2

272

Scheme 55.Solid-phase synthesis of imidazoquinazolinone derivatives by Kesarwani et al.

Using this strategy, a library of fifteen imidazoquinazolinones were synthesised by an Advanced Chemtech Multiple Organic Synthesizer. Imidazoquinazolinones are medically very important as useful drugs. Hassanein and co-workers evaluated the pharmacological activities of imidazoquinazolinones using indomethacin as reference drug.119 Hassanein observed imidazoquinazolinones are a promising class of compounds possessing analgesic activity, antiinflammatory effect and reasonable COX-2 selectivity. Most of the synthesised quinazolinone derivatives obeyed 'Lipinski's rule of five' and exhibited pharmacokinetic properties. The first synthesis of 2,4-diaminoquinazoline derivative named prazosin 277 by solidphase strategy was developed by Wilson et al.120 Initially carboxyl polystyrene 273 was converted to acyl isothiocyanate resin 274 by treating with (COCl)2 in DCM and further with Bu4NNCS in THF/DCM mixture. The resin 274 on treatment with 2-amino-4,5dimethoxybenzonitrile in NMP affords resin 275, which was treated with 1-(2-furoyl)45 ACS Paragon Plus Environment


Page 46 of 63

piperazine and EDC in the presence of base to form resin-bound guanidine 276.Prazosin 277 was separated from resin 276 by TFA cleavage and was obtained in 24 % yield (Scheme 56). A library of 2,4-diaminoquinazolineswith yields in the range 24-74% was synthesised by using the Quest 210 Synthesizer by varying amines and 2-amino-4,5-dimethoxybenzonitriles with morpholine. (i) COCl2, DCM

CO2H

PS

(ii) Bu4NNCS, DCE/THF

O PS

MeO

NH2

MeO

CN

N C S

273

O

S

OMe OMe

NH2

N TFA/H2O

N

DCE, (i-Pr)2NEt, CHCl3, 24 h

CN

CN

H N

N NH

O

H N

275

PS

O

H N

NMP, rt, 3 h

274

O

PS

OMe OMe

N O

80 oC, 16 h

MeO

N

MeO

N

N

O N

O

277

O

276

Scheme 56.Solid-phase synthesis of prazosin by Wilson et al.

Yu et al. reported the solid-phase synthesis of 2-arylamino-substituted quinazolinones on p-methylbenzhydrylamine (MBHA) resin 28 using the “tea-bag” methodology.121-124 At first resin 28 was coupled with o-nitrobenzoic acid and the nitro group present in resultant resin 278 was reduced by tin(II) chloride to corresponding amino resin 279. The resin 279 was converted to resin bound thiourea 280 by arylisothiocyanate. Guanidine resin 290 was accomplished by the reaction of resin 280 with Mukaiyama's reagent (2-chloro-1methylpyridinium iodide) and a primary amine. Intramolecular cyclization and simultaneous cleavage of resin 281 by HF resulted in the formation 2-amino-substituted quinazolinones 282 (58-85% yield) (Scheme 57). COOH

R1

NO2 L PS

NH2

28 HN S PS L

HN H N O 280

HOBt, DIC

PS

DMF, rt, 12 h

L

R2 R1

Mukaiyama’s reagent Amine, DMF, rt, 12 h

O2N H N

R1

SnCl2

PS

L

DMF, rt, 12 h

H2N H N

R1

ArNCS DCM, rt, 12 h

O

O 278

279

R3 HN N HN H PS N L O

R2 R1

O o

HF, 0 C, 1.5 h

N

1

R

N

281

Scheme 57.Solid-phase synthesis of substituted quinazolines by Yu et al. 46 ACS Paragon Plus Environment

282

R3 N H

R2

Page 47 of 63 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


A library of 2-amino-substituted quinazolinone derivatives were synthesised by using various 2-nitrobenzoic acid derivatives, arylisocyanates, and amines. All the synthesised derivatives were biologically very active and had useful therapeutic implications. Gopalsamy et al. reported the solid-phase synthesis of substituted 2-amino-4(1H)quinazolinones.125 The procedure involves the immobilization of Fmoc protected amino acid on Wang resin 17 using HOBT and DIC as coupling agents in DMF in presence of DMAP. The resultant resin was deprotected using piperidine and the resin 283 formed on reaction with Fmoc-isothiocyanate afforded resin bound Fmoc protected thiourea. Removal of the Fmoc protecting group resulted in resin 284 which on reaction with methyl iodide gave polymer bound S-methylthiopseudourea 285. Resin 285 was converted to polymer bound quinazolinone 286 by isatoic anhydride in DMAC. 2-Amino substituted quinazoline-4-ones 287 were released from the resin by TFA in DCM with yields in the range 80-95% (Scheme 58). Libraries of biologically active quinazolinone derivatives were synthesised by Gopalsamy using various amines and isatoic anhydrides. O

L PS

OH + HO 17 O

L PS

O

R

R

NHFmoc

O

R

NH2

(i) FmocNCS, DMF, rt, 20 h (ii) 20% piperidine, DMF, rt, 20 min

283 O

H N

NH2

O L

L

PS

(ii) 20% piperidine, DMF, rt, 20 min

MeI DMF, rt, 18 h

284 S

PS

O

(i)HOBt/DIC/DMAP, DMF, rt, 18 h

O

R

PS

286

R

HO TFA/DCM 1

R

N

O

N

R1

NH2

rt, 1 h

R NH

DMAC, 80 oC,18 h R2 N

N R1

O

O

O O

SCH3 285 O

R2 N

H N

L

R2 N O

287

Scheme 58.Solid-phase synthesis of aminoquinazoline derivatives by Gopalsamy et al.

Dener et al. developed the synthesis of 2,4-diaminoquinazoline on modified Merrifield resin.126 First, 2-methoxy-4-hydroxybenzaldehyde was immobilized on the Merrifield resin 1using cesium carbonate in DMA. The resulted aldehyde resin 288 was converted to a resin bound secondary amine 289 by treating with R1-NH2. Resin 289 on reaction with dichloroquinazoline

and

DIEA

afforded

(4-amino-2-chloroquinazolinyl)polystyrene

derivative 290. Introduction of a second amine building block to resin 290 was accomplished by heating with secondary amines. TFA cleavage of resin 290 and 292 in the presence of a cation scavenger, triethylsilane, produced corresponding aminoquinazolines 291and 293 in



Page 48 of 63

17 to 67% yields (Scheme 59). Dener repeated the synthesis with other resins such as Wang, rink amide, etc. OCH3 CHO

OCH3 CHO

Cl

PS

Cs2CO3, KI, DMA, 60-65 °C

1

R1

PS

Cl

N

N

OCH3

N

TFA/DCM

N

(ii) NaBH4, THF/EtOH

288

NH

H3CO H3CO

O

HO

Cl

OCH3 N

PS

OCH3 (i) R1NH2, (MeO)3CH, THF

R1

H3CO H3CO

N H

R1

O 298

PS

Cl N N

Cl

PS

N H

(i-Pr)2NEt, THF, 60 °C

R1

289

290

291

R2R3NH, DMA, 135-140 °C 3

R1

R 2 N R

N

OCH3 TFA/DCM

N PS

OCH3 N

H3CO

1

NH

H3CO

R

N N 293

N R3

R2

292

Scheme 59.Solid-phase synthesis of diaminoquinazoline derivatives by Dener et al.



SOLID-PHASE SYNTHESIS OF THIAZOLOPYRIMIDINES

Thiazolopyrimidinederivatives

are

mainly

used

in

biomedical

industries.

Thiazolopyrimidines are a major component of various biologically active molecules and are used in the treatment of arthritis, multiple sclerosis, asthma etc.127 The studies carried out by Lee et al. were interesting as they reported a new strategy for the synthesis of thiazolopyrimidines on Merrifield resin 1.128The procedure was based on the immobilization of dipotassium cyanodithioimidocarbonate 294 on Merrifield resin 1 and the formed polymer supported cyanocarbonimidodithioate 295 on reaction with ethyl 2bromoacetate yielded thiazole amino ester resin 296. Reaction of isocyanate with resin 296 went on easily under microwave irradiation condition giving thiazolourea resin 306. Cyclization followed by alkylation of the resin 297 resulted in polymer bound thiazolo[4,5d]pyrimidine-5,7-dione 298. The product 298 was oxidised by m-CPBA and the desired product, thiazolo[4,5-d]pyrimidine-5,7-dione 299, was obtained (21-34%) by desulfonation and simultaneous cleavage of resin 298 (Scheme 60). The substituents R1and R2 on the thiazolo[4,5-d]pyrimidine-5,7-dione affect the properties and yield of the product. Lee evaluated pharmacological properties of the synthesised compounds using Lipinski's Rule as


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the reference. Interestingly Lee observed that all the synthesised compounds were within reasonable oral acceptable drug ranges.

N PS

Cl +

KS

1

N DMF rt

SK

PS

S

294 O

PS

CN

N

CN

OEt

Br O

SH

PS

295

150 0C

OEt

S 296

O

R2

NH

PS

NaH, DMF, rt OEt

S

S

80 0C

NHR1

S

N

Et3N, DMF

R1-NCO, MW

NH2

O

S

2

R -X

O

N

N

N

S

O

R1

O

297

298

(i) m-CPBA DCM, rt

R1

(ii) R3R4NH, Et3N 80 0C

O

R4

S

N

N N R2

N

R3

299

Scheme 60. Solid-phase synthesis of thiazolo[4,5-d]pyrimidines by Lee et al.

The first report on the synthesis of thermally stable pyrimidine derivatives from resinbound cyclic malonic acid ester 302 was published by Huang et al.129 Initially Merrifield resin 1 reacted with sodium ethyl acetoacetate affording β-keto ester resin 300 which on decarboxylation yielding corresponding ketone resin 301. About 78% of resin 301 was converted to resin-bound cyclic malonic acid ester 302 by malonic acid in acetic anhydride. PS

sodium ethyl acetoacetate

Cl

O

o

DMF, 80 C, 16 h

1

EtO

PS

DMSO NaCl 140 oC, 48 h

O

PS

CH2CH2COCH3 301

300 O O

Malonic acid Acetic anhydride

O

PS

R1HN O

NH2

O

PS

NHR1

O

304

1

R

220-240 0C, 20 min HC(OEt)3 reflux, 6 h

N S

2

R

NH2

O N

2

R S

O N H

O PS

N H

O

HC(OEt)3 reflux, 20 h

302

X

O

X

O 303

O

N

R1

R1

20 min

N X H X = O or S 306

O N

220-240 0C

R1

N

S

R2 305

Scheme 61.Solid-phase synthesis of thiazolopyrimidine derivatives by Huang et al.

Subsequent treatment of resin 302 with 2-aminobenzothiazole or 2-amino-4methylthiazole and thermal cyclization of resultant resin 303 released the product 3-methyl49 ACS Paragon Plus Environment


Page 50 of 63

5H-thiazolo[3,2-a]pyrimidin-5-one 305 with 77-86 % yield. Similarly, reaction of resin 302 with urea or thiourea resulted in the formation of resin 304 which on thermal cyclization (at 220-240 ℃) gave another series of pyrimidine derivatives 306 (65-82 %) (Scheme 61). The polymer-bound ketone could easily be regenerated for reuse after cleavage. The major limitation observed by Huang was the limited applicability of the method to thermally stable heterocycles because of the requirement of high temperature for thermal cyclization. 

SOLID-PHASE SYNTHESIS OF TRIAZOLOPYRIMIDINES

Triazolopyrimidines exhibit a range biological activity. Triazolopyrimidines are important medicinally as coronary vasodilators, antihypertensive agents, leishmanicides, antibiotics, adenosine A2a antagonists, immunosuppressants, antitumor agents, fungicides, etc.130 Synthesis of 1,2,4-triazolo[1,5-a]pyrimidines was reported by Cavallaro et al. The synthesis commenced with PL-FMP (CHO functionalized PS) resin 22.131 In the first step, the resin 22was converted to amine attached resin 307 by treating with a primary amine in the presence of sodium triacetoxyborohydride. The polymer bound amine 307 on reaction with diphenoxycyanoimidate yielded the phenylisourea resin 308 which was cyclized to triazole resin 309 and subsequent Michael addition with ethyl (ethoxymethylene)cyanoacetate NH2 NCN

1

PS

R NH2, DMF, NaBH(OAc)3

CHO

N H

PS

cat. AcOH

22

O

PhO

EtO PS

70% AcOH NMP, 98 °C

PS

N R1

N

N H

N

N N2H4

OPh

PS

NMP, 75 °C

308

O PS

DMF, rt, 3 h

N N

N

N

R1

N

PS

COOEt

N

CN

R1

PS

N R1

N

N N

Cl POCl3, pyridine

N

N H 314

PS

N

DCE, rt,15 min

R2

30% TFA/DCE

HN

N

N

N H

N

R2R3NH NMP, 80 °C

313

R3

N N N

R1

N

N N N

R1

N H

R3 N

COOEt

N N

311

312 R2

NH N

309

310 KH-MDS

N R1

NH2

N NH R1

OPh

DIEA, DMAP NMP, 75 °C

307

N

EtO

R1

NCN

N

N H 315

Scheme 62. Solid-phase synthesis of triazolo[1,5-a]pyrimidines by Cavallaro et al.

affording resin bound Michael adduct 310. Cyclization of resin 310, with potassium bis(trimethylsilyl)amide in DMF, to resin-bound triazolopyrimidinone 311and further 50 ACS Paragon Plus Environment

Page 51 of 63 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


reaction

in

the

presence

of

phosphorus

oxychloride

resulted

in

resin-bound

chlorotriazolopyrimidine 312. Polymer bound diamino-triazolopyrimidines 313 were obtained by substitution of the chlorine present in 312 by dialkylamino group. Finally, cleavage of the resin 314 gave 1,2,4-triazolo[1,5-a]pyrimidines 315 in 7 to 25% yields (Scheme 62). The authors observed that all the synthesised compounds were biologically significant as antimalarial agents, antihypertensive agents and coronary vasodilators. 

SOLID-PHASE SYNTHESIS OF XANTHINES

Xanthines are pharmacologically important as they are the major component of drugs which are used as bronchodilators, phosphodiesterase inhibitors, CFTR chloride-channel activators. They form a biologically significant class of compounds that can act as anticonvulsants, nootropics and used for the treatment of disease such as migraine.132 Synthesis of xanthine derivatives, on Wang resin 17, containing substituents at the N1, N3, N7 and C8 positions were reported by He et al.133 HO L PS

OH

17

Br O

PS

L

DCC, DMAP DMF, rt, 5 h

t-BuOK, t-BuOH DMF, rt, 2 h

L

Br

O 316 O

PS

O

O H2N

PS

R1NH2

L

THF, rt, 12 h

N

R1

PS

L

3

R NCO

PS

L

R N H

319

O

N

R 1

R 2

N

N

HN 3

N

318 R1 N

O

o-Xylene 120 -125 oC, rt

O

DBU, THF, rt, 12 h

317 O

R2

N H

O

1

R N

O

R2 NC N C OEt

O

R2

(i) NaOEt, THF, 3 R MeOH N (ii) R4X, DIEA, O THF

320

O

R1 N

N R4

N

R2

321

Scheme 63.Solid-phase synthesis of substituted xanthines by He et al.

Initially resin 17 was converted to benzyl bromoacetate resin 316 by bromoacetic acid and further reaction with many primary amines resulted in N-substituted benzyl carbamate resin 317. Resin 317 was then converted to benzyl N-methylenecyanamide N-substituted carbamate resin 318 by ethoxymethylenecyanamide or methyl ethoxymethylenecyanamide. On cyclization with t-BuOK, resin 318 produced 5-amino-(3-substituted)imidazole-4carboxylic acid benzyl ester resin 319. The reaction of various isocyanates with resin 319 in o-xylene resulted in the formation of 5-(3-substituted ureido)imidazole-4-carboxylic acid benzyl ester resin 320 which underwent a simultaneous cyclization-cleavage reaction and following one pot N-alkylation resulting in fully substituted xanthines 321 with an average



Page 52 of 63

yield of 75% (Scheme 63). He et al. successfully synthesised a set of 22 xanthines having four diversity positions. He et al. developed the synthesis of 1,3-substituted xanthines on the PS-MB-CHO resin.134 Firstly the aldehyde functionalized resin 322 was converted to N-(2-methoxy-4phenoxybenzyl)glycine ethyl ester resin 323 by reductive amination. The product 323 was then

treated

with

NaOEt

in

EtOH

yielding

polymer-supported

4-amino-5-

ethoxycarbonylimidazole 324. OMe PS

(i) NH2CH2COOEt.HCl DMF, RT, 30 min

O

OMe PS

O

(ii) TEA, NaB(OAc)3H 1% HOAc, DMF, rt, 24 h

O 322

323

(i) NC-N=CHOEt DMF/EtOH, rt, 24 h

OMe PS

OEt

N H

(ii) NaOEt, DMF/EtOH rt, 24 h

O

OMe O

O

1

OEt

N

NH2

N

324

R NCX

PS

o-Xylene,120 oC, 24 h

O

O N 325

OMe PS

N N 326

N

PS

DIEA, DMF, R1 rt, 24 h

N H

NaOEt MeOH/THF, reflux, 12 h

NH X

NHR1

OMe

R2X O

O

OEt

N

O O

O N N

X 327

N N R2

R1

90% TFA/DCM rt, 12 h

R1 X

X

N

H N

N N R2 328

Scheme 64. Solid-phase synthesis of 1,3-substituted xanthines by He et al.

In the next step different isocyanates/isothiocyantes were allowed to react with resin 324 affording

ethyl

4-(3-substituted)ureido-1-(2-methoxy-4-phenoxybenzyl)imidazole-5-

carboxylate resin 325. Cyclization of 325 with NaOEt yielded resin bound N1-substituted-7(2-methoxy-4-phenoxybenzyl)xanthine 326. After N-alkylation of resin 326 and the TFA cleavage of there sulted resin 327 afforded the final xanthines 328 in moderate yield (1764%) and high purities (Scheme 64). Thus He and co-workers developed the first solid-phase synthetic route for the synthesis of 1,3-disubstituted xanthines and successfully synthesised a series of twelve xanthines. Lee et al. developed an eight step synthetic protocol for the synthesis of tetrasubstituted xanthines on Merrifield resin 1.135The reaction commenced with the immobilizationof Ncyano-N-substituted-carbamidothioate 329 on Merrifield resin 1 (Scheme 65).


Page 53 of 63 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


N

CN

NaS

N H 329

Cl

PS

R1 N PS

S

o

DMF, 60 C

1

OEt

Br

CN

N

O K2CO3

NH R1

PS

PS

S N R1

OEt

R2NCO SnCl2.2H2O

S

PS

N R1

Toluene, 60 oC

O

DMF, 60 oC

OEt

DBU

O

Acetone, rt

N PS

R3 N

PS

DMF, 60 oC

S N R1

S N R1

N

(i) m-CPBA, DCM, rt

R2

(ii) R4SH, Et3N DCE, 60 oC

O

O N

R2

O 334

O

O

H N

N

NaOEt

333

332

R3X, K2CO3

NH

N

OEt

331

H N R2

O NH2

N R1

DMF, 45 oC

330

N

S

CN

R4

N N R1

R3 N

O N

R2

O 336

335

Scheme 65.Solid-phase synthesis of tetrasubstituted xanthines by Lee et al.

The resulted resin 330 on reaction with ethyl-2-bromoacetate afforded resin 331which was further converted to an imidazole bound resin 332 by aThorpe-Ziegler-type reaction promoted by DBU. The resin 332 was then allowed to react with selected isocyanates in toluene using SnCl2.H2O as Lewis acid catalyst to give the urea resin 333. Intramolecular cyclization of resin 333 was achieved by NaOEt in DMF at 60 ℃. Third diversity position was then introduced to the resulted xanthine bound resin 334 by reacting with selected alkyl halides under basic conditions in DMF. The resin attached trisubstituted xanthine 335 was treated with m-CPBA in DCM to afford the sulfone resin. Finally, the product 336 was detached from resin 335 with simultaneous introduction of an additional diversity position by n-propylthiol in DCE at 60 ℃. The same reaction was repeated under microwave irradiation condition by replacing n-propylthiol with amines in DMSO at 120 ℃. By using various Ncyano-N'-substituted carbamidothioates, isocyanates, alkyl halides, and nucleophiles (thiols or amines) Lee and co-workers successfully synthesised tetrasubstituted xanthines by an eight step process with yields in the range 7- 83%. 

CONCLUSION

Pyrimidine residue is an important structural component in many biologically active natural products and plays a key role in medicinal and synthetic chemistry. The synthesis of pyrimidine derivatives via different synthetic routs is an inevitable part in the field of pharmaceutical research. This review summarizes studies on solid-phase synthesis of 53 ACS Paragon Plus Environment


Page 54 of 63

pyrimidine derivatives that possess biological and pharmacological activities. The syntheses of pyrimidine core itself like aminopyrimidines, dihydropyrimidines, di-, tri- and tetrasubstituted pyrimidines and pyrimidine ring fused with other rings such as pyridine, pyrrole, pyrazole, thiazole, etc., are described. Solid-phase synthesis of pyrimidine derivatives using different polymer supports based on Merrifield, Wang and rink amide resins following a variety of synthetic procedures are also described. The effects of microwave on the synthetic transformations are also discussed. ACKOWLEDGEMENT The authors gratefully acknowledge the financial support received from University Grants Commission, India, by awarding junior and senior research fellowships to E.P. Aparna. 

AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected]. Phone: 9496720967. Fax: 91-481- 27310 Basic polymer supports mentioned in the review Structure of polymer supports used

Name of polymer support

CH2Cl

PS

Merrifield resin

1

OH O

Wang resin

PS

17 CHO

PS

Aldehyde resin

22 NH2 OCH3 PS

Rink amide resin

H N 28

O

OCH3

O

SO2Na

PS

Sodium benzenesulfinate resin

85

PPh3

PS

Polymer bound triphenylphosphine

153


Page 55 of 63 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




ABBREVIATIONS

AMEBA

-

Acid sensitive methoxybenzaldehyde

BEMP

-

2-t-Butylimino-2-diethylamino-1,3-dimethyl-perhydro1,3,2-diazaphosphorine

BOP

-

Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

CAN

-

Ceric ammonium nitrate

CSA

-

Camphorsulphonic acid

DABCO

-

1,4-Diazabicyclo-[2.2.2]octane

DBU

-

1,8-Diazabicyclo[5.4.0]undec-7-ene

DCM

-

Dichloromethane

DDO

-

Dimethyldioxirane

DHPM

-

Dihydropyrimidine

DIC

-

N,N′-diisopropylcarbodiimide

DIAD

-

Diisopropyl azodicarboxylate

DIEA

-

Diisopropylethylamine

DMAP

-

4-Dimethylaminopyridine

DMF

-

N,N-dimethylformamide

DVB

-

Divinylbenzene

EDC

-

N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide

ELSD

-

Evaporative light-scattering detector

ESI-MS

-

Electrospray ionization mass spectrometry

FT-IR

-

Fourier transform infrared spectroscopy

gHMBC

-

Heteronuclear Multiple Bond Correlation

HMPA

-

Hexamethylphosphoramide

HPLC

-

High-performance liquid chromatography

LC/MS

-

Liquid Chromatography - Mass Spectrometry

m-CPBA

-

m-Chloroperbenzoic acid

NMP

-

N-Methylpyrrolidine-2-one

NMPRZ

-

N-Methylpiperazine

NMR

-

Nuclear Magnetic Resonancespectroscopy

Nos-Cl

-

2-Nitrobenzenesulfonylchloride

MS

-

Mass spectroscopy

PL-FMP

-

4-Formyl-3-methoxyphenoxymethyl)polystyrene 55 ACS Paragon Plus Environment


QDs

-

Quinazoline-2,4-diones

RPLC

-

Reversed Phase Liquid Chromatography

SPS

-

Solid phase synthesis

t-BuOK

-

Potassium t-butoxide

TEA

-

Triethylamine

TFA

-

Trifluroacetic acid

TIS

-

Triisopropylsilane

TMG

-

Tetramethylgnanidine

TsOH

-

p-Toluenesulfonic acid

UPy

-

2-Ureido-4(1H)-pyrimidinone

REFERENCES Garcia,V. M.; Torroba, T., Sulfur-nitrogen heterocycles. Molecules 2005, 10 (2), 318-320. 2. Katritzky, A. R.; Rees, C. W., Comprehensive heterocyclic chemistry Pergamon press: 1984. 3. Elderfield, R. C., Heterocyclic compounds: Six-membered heterocycles containing two hetero atoms and their benzo derivatives J. Wiley: 1957; Vol. 6. pp. 564-600. 4. Lagoja, I. M., Pyrimidine as constituent of natural biologically active compounds. Chemistry & Biodiversity 2005, 2 (1), 1-50. 5. Selvam, T. P.; James, C. R.; Dniandev, P. V.; Valzita, S. K., A mini review of pyrimidine and fused pyrimidine marketed drugs. Research in Pharmacy 2012, 2 (4), 1-9. 6. Sharma, V.; Chitranshi, N.; Agarwal, A. K., Significance and biological importance of pyrimidine in the microbial world. Int. J. Med. Chem.2014, 2014,1-32. 7. Grahner, B.; Winiwarter, S.; Lanzner, W.; Mueller, C. E., Synthesis and structureactivity relationships of deazaxanthines: analogs of potent A1-and A2-adenosine receptor antagonists. J. Med. Chem. 1994, 37 (10), 1526-1534. 8. Romeo, G.; Russo, F.; De Blasi, A., Synthesis of novel 5H‐pyrimido[5,4‐b]indole‐(1H,3H)-2,4‐diones as potential ligands for the cloned α1‐adrenoceptor subtypes. J. Heterocycl. Chem. 2001, 38 (2), 391-395. 9. Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Hanson, J. C.; Kicska, G. A.; Sauve, A. A.; Schramm, V. L.; Tyler, P. C., 8-Aza-immucillins as transition-state analogue inhibitors of purine nucleoside phosphorylase and nucleoside hydrolases. J. Med. Chem. 2003, 46 (1), 155-160. 10. Bantia, S.; Miller, P. J.; Parker, C. D.; Ananth, S. L.; Horn, L. L.; Kilpatrick, J. M.; Morris, P. E.; Hutchison, T. L.; Montgomery, J. A.; Sandhu, J. S., Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)-a novel potent and orally active immunosuppressive agent. Int. J. Immunopharmacol. 2001, 1 (6), 1199-1210. 11. Pathak, V. P., Selective formation of pyrrolo [3,2-d] pyrimidines from methyl [(Nbenzoyl-S-methylisothiocarbamoyl)amino]-1H-pyrrole-2-carboxylate.Org. Process Res. Dev. 2000, 4 (2), 129-130. 12. Stamford, A. W., Phosphodiesterase 5 inhibitors. Annu. Rep. Med. Chem. 2002, 37, 53-64.

1.


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Advances in the Solid-Phase Synthesis of Pyrimidine Derivatives

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