Tetrahedron 64 (2008) 8585–8603

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Tetrahedron 64 (2008) 8585–8603

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 845

Recent advances in the synthesis of purine derivatives and their precursors

Michel LegraverendUMR176 CNRS, Institut Curie, Bat. 110 Centre Universitaire, 91405 Orsay, France

a r t i c l e i n f o

Article history:Received 19 May 2008Available online 3 June 2008

Keywords:Purine librariesPurine chemistryATP analoguesEnzyme inhibitorsReceptor antagonists

Abbreviations: ATP, adenosine 50-triphosphate; GTcyclic guanosine 30 ,50-monophosphate; AcCoA, acetyflavin adenine dinucleotide; PAPS, 30-phosphoadenos

E-mail address: [email protected].

0040-4020/$ – see front matter � 2008 Elsevier Ltd.doi:10.1016/j.tet.2008.05.115

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85862. Functionalisation at position 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8586

2.1. Functionalisation of the purine ring from guanosine, via a 6-arylsulfonate intermediate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85862.2. Preparation of C-6-arylpurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85872.3. Synthesis of 6-amidopurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85872.4. Substitution reactions of 6-chloropurine and 2-amino-6-chloropurine with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8588

3. Functionalisation at position 9: preparation of 9-substituted purine derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85893.1. Regioselective and stereoselective coupling of 6-(substituted-imidazol-1-yl)purines with 1-chloro-20-deoxyribose . . . . . . . . . . . . . . . . . . . . . . . . . . 85893.2. Michael addition of adenine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85903.3. Arylation at N-9 of 7-deazapurines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85903.4. Arylation at N-9 of purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85903.5. Mitsunobu alkylation at N-9 position with either primary or secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85913.6. Use of an aminoalkane and pyrimidine precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8591

4. Functionalisation at N-1, N-3, N-7 and C-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85924.1. Preparation of xanthine derivatives from 6-aminouracils (Traube synthesis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85924.2. Synthesis of purines from an imidazole precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85924.3. Solid-phase synthesis of xanthine derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85924.4. Synthesis of N-1,N-7-disubstituted purines from 6-chloropurine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8595

5. Functionalisation at position 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85955.1. Pyrimidine precursors of 2,6,8,9-tetrasubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85955.2. Synthesis of 2,6,8,9-tetrasubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85965.3. Synthesis of 7-deazapurines (pyrrolo[2,3-d]pyrimidines) from pyrimidine precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8597

6. Functionalisation at position 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85986.1. Synthesis of 8,9-disubstituted adenines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85986.2. Synthesis of 2,8,9-trisubstituted adenines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8598

6.2.1. Synthesis of 2,8,9-trisubstituted adenine inhibitors of HSP90 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85986.2.2. 8-Aryl-9-methyladenine derivatives from a 4,6-dichloropyrimidine precursor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8599

P, guanosine 50-triphosphate; GDP, guanosine 50-diphosphate; cAMP, cyclic adenosine 30 ,50-monophosphate; cGMP,l-coenzyme A; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; FAD,ine 50-phosphosulfate; SAM, 50-S-adenosyl methionine.fr

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M. Legraverend / Tetrahedron 64 (2008) 8585–86038586

6.3. Synthesis of 6,7,8-trisubstituted purines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85996.4. Preparation of 6,8-disubstituted purine analogues: thiazolopyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8600

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8600References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8601Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8603

1. Introduction

The purine ring is the most ubiquitous nitrogen-containingheterocycle in nature,1 since, besides the numerous purine de-rivatives found in various marine organisms and plants, it is thecore structure of adenine and guanine in nucleic acids (RNA andDNA). In addition, purines are involved in many metabolic pro-cesses as cofactors associated with a great number of enzymes andreceptors, notably ATP, GTP, GDP, cAMP, cGMP, AcCoA, NAD, NADP,FAD, PAPS and SAM,1,2 which play key roles at different phases ofthe cell cycle, in cell signalling and other fundamental biologicalprocesses.3 It should be noted that all of these associated proteinscontain a purine recognition pocket and, consequently, purinederivatives have long been developed to selectively inhibit orantagonise each of these enzymes and receptors. Indeed, a greatvariety of di-, tri- or tetrasubstituted purines described in the lit-erature have been found to be potent inhibitors of chaperoneHSP90, protein kinases (MAP, Src and Cdk), sulfotransferases,phosphodiesterases and microtubule assembly, inducers of in-terferon and dedifferentiation and antagonists of adenosine re-ceptors and corticotropin-releasing hormone receptors.2 This widerange of biological activities displayed by purines is conferred bya judicious choice of the nature of the substituents that can becombined on the N-1, C-2, N-3, C-6, N-7, C-8 and N-9 centres (Fig. 1).

N

N NH

N1

2

3

6 7

8

9

Figure 1. Purine (imidazo[4,5-d]pyrimidine) ring.

With such an easy access to so much structural diversity, thepurine core has become a privileged structure in medicinalchemistry,4 and an important scaffold in the preparation of com-binatorial libraries. In general, two strategies are applied for thepreparation of purine libraries. In the first procedure, a preformedpurine ring loaded with various reactive functionalities is directlymodified, which allows good regiocontrol at C-2, C-6, C-8 and N-9.Alternatively, substituted pyrimidine or imidazole precursors arefunctionalised, generating the second heterocycle of the purine corein the process with better regiocontrol at N-1, N-3, N-7 and N-9.

OHO

N

HO

1

N

N

NH

O

BOP (1.5 equiv)DIPEA (2.0 equiv)R-NH2 (1.2-5.0 equivDMF/EtOH(65-99%)

3

X

X = OH, H

Scheme

Following a previous article, which highlights the interest inpurines as inhibitors and modulators of key biological targets,2 thegoal of the present article is to review recent advances in thesynthesis of purine derivatives, with particular emphasis onmethods that can lead to purine libraries.

2. Functionalisation at position 6

6-Aminopurines are traditionally obtained in four steps froma nucleoside precursor in a process, which requires protection ofthe sugar moiety followed by halide formation, often under harshconditions. Interestingly, Wan and co-workers5 have recently de-scribed the synthesis of several 6-aminopurine derivatives 2 in onestep and high yield from unprotected inosine 1 (X¼OH) (Scheme 1),by BOP-mediated amination.

Polycyclic aromatic hydrocarbons (PAH) are potent mutagensand carcinogens that are challenging synthetic targets. This methodalso allowed the synthesis of PAH derivative 3 from 20-deoxy-inosine 1 (X¼H) as well as the rare DNA constituent 4 in almostquantitative yield.

Under these conditions, several 6-substituted purines 2a–h(Table 1, entries 1–8) were prepared from unprotected inosine inhigh yield from various aryl- or benzylamines.

Using similar reaction conditions, the acetyl-protected inosine 5led to the corresponding 6-substituted-9-(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)-purines 6a–g (Scheme 2, Table 2, entries 1–7).

2.1. Functionalisation of the purine ring from guanosine, viaa 6-arylsulfonate intermediate

The use of a 6-arylsulfonate for C–C bond formation withboronic acids at room temperature on the purine ring was reportedfor the first time in 2005.6 This palladium-catalysed cross-couplingreaction of nucleoside arylsulfonates and arylboronic acids re-quired the use of a ligand and could be generalised to variousboronic acids (Scheme 3).

The starting compound, 6-arylsulfonyl-30,50-bis-O-(tert-butyl-dimethylsilyl)-20-deoxyguanosine 7, was synthesised from 20-deoxyguanosine in high yield, in the presence of Et3N and DMAP,with 2,4,6-trimethylphenylsulfonyl chloride.

OHO

N

HO

N

N

N

HN

)

: R =X = H

R

2: R = alkyl, aryl

NH2

O4: R =X = H

98%

(PAH adduct)

(rareDNA constituent)

X

1.

Table 2Amination of sugar-protected inosine

Entry Amine Reaction conditions Product (%) Yield (%)

1 Bn-NH2 rt, <1 h 6a 98

2 NH2 rt, overnight 6b 99

3 NH2 rt, overnight 6c 99

4 NH rt, overnight 6d 87

5 O NH rt, overnight 6e 70

6NH2 rt, overnight

then 80 �C, 10 h6f 78

7

O

NH2rt, 48 h 6g 74

OAcO

N

AcO OAc

N

N

NH

O

OAcO

N

AcO OAc

N

N

N

HN

BOP (1.2 equiv)DIPEA (1.5 equiv)R-NH2DMF, rt

R

6a-g5

Scheme 2.

ORO

N

RO

N

N

N

O

NH2

SO

O

B(OH)2

X

Ligand-PdTHP or PhMert, or 45 °C

7 : R = TBDMS

Scheme

Table 1Amination of sugar-unprotected inosine and 20-deoxyinosine

Entry X Amine Methoda Product Yield (%)

1 OH Bn–NH2 A 2a 992 H Bn–NH2 A 2b 99

3 OHNH2

B 2c 91

4 OHNH2

B 2d 74

5 OH

O

NH2B 2e 81

6 OH

O

NH2

PhB 2f 85

7 OHNH2

B 2g 65

8 OHNH2 B 2h 72

a A: BOP (1.2 equiv), DIPEA (1.5 equiv), RNH2 (1.2 equiv), rt; B: BOP (1.5 equiv),DIPEA (2 equiv), RNH2 (5 equiv), rt, overnight, then 60 or 80 �C.

M. Legraverend / Tetrahedron 64 (2008) 8585–8603 8587

Of the nucleoside arylsulfonates evaluated, the O-6-(2,4,6-tri-methylphenyl)sulfonate 7 proved to be optimal in cross-couplingreactions with tetrahydropyran (THP) as the best solvent, to form 8.

2.2. Preparation of C-6-arylpurines

It has been proposed that DNA containing C-6-arylpurines couldexhibit unusual properties,7 prompting a number of studies on theintroduction of substituted aryl moieties at the C-6 position of thepurine ring in recent years. For example, Lakshman and co-workershave synthesised a wide variety of C-6-arylpurine 20-deoxyribo-sides 10a–g via the Pd-mediated Suzuki–Miyaura cross-couplingof arylboronic acids with C-6 halonucleosides 9 (Scheme 4 andTable 3).

For several C-6 arylations, the chloronucleoside gave highercoupling yields than the bromo analogue (see Table 3). With aryl-boronic acids containing electron-withdrawing groups performingless well, several ligands were tested, but the system Pd(OAc)2/K3PO4/2-(dicyclohexylphosphino)biphenyl was found to besuperior.7

Hocek and co-workers have reported8 that the regioselectivityof the Suzuki–Miyaura cross-coupling of 2,6-dihalopurines (11 and14) with 1 equiv of phenylboronic acid is dependent on the halogenat position 2. Thus, 9-benzyl-2,6-dichloropurine 11 gave 12, theproduct of cross-coupling at position 6, whereas the correspondingiodopurine 14 gave the 2-arylpurine derivative 15. In the presenceof 3 equiv of phenylboronic acid, both halogenopurines led to 9-benzyl-2,6-diphenylpurine 13 in high yield (Scheme 5).

The scope of this reaction was extended to substituted phenyl-and heteroarylboronic acids.9,10 A high yield (70%) of 2-chloro-6-(3-pyridyl)purine 17d was obtained from 2,6-dichloropurine 16 with1 equiv of 3-pyridylboronic acid in an aqueous phase (H2O/MeCN2:1). It is interesting to note that no protection at N-9 was necessary(Scheme 6 and Table 4),9 although the regioselectivities and yieldsat position 6 (17a–d) were inferior to those under the previouslydescribed conditions (toluene, K2CO3, Pd(PPh3)4, 100 �C, 8–20 h;Scheme 5) as the unwanted 2,6-disubstituted products 18a,b werealso observed.

Various 6-aryl-, 6-heteroaryl-, 6-phenylethynyl- or 6-styr-ylpurines 20a–e have also been prepared by Stille couplings on theparent halopurine 19a,b, and were found to be antimycobacterialagents (Scheme 7, and Table 5).11

2.3. Synthesis of 6-amidopurines

Olomoucine, roscovitine and purvalanol A and B are well-knownrepresentatives of the 2,6-diaminopurine class of molecules thatexhibit a great variety of biological activities against CDKs and otherenzymes and receptors.2 Large libraries of 2,6,9-trisubstituted pu-rines bearing an amino substituent at positions 2 and 6 have beensynthesised.12–20 These derivatives are easily obtained from various2,6-dihalogenopurines, the halogen at position 6 (Cl or Br) beingmore reactive than that at position 2 (F, Cl, Br or I) under SNArconditions.

ORO

N

RO

N

N

N

NH2

X

PCy2

8

Ligand:

3.

Table 3Synthesis of C-6 aryl 20-deoxynebularine derivatives

Arylboronic acid Time (h) Product Yield (%) Arylboronic acid Time (h) Product Yield (%)

Phenylboronic acid 1a 10a 91 Phenylboronic acid 1.5b 10a 914-Methoxyphenylboronic acid 1.5a 10b 69 4-Methoxyphenylboronic acid 1.5b 10b 693-Methoxyphenylboronic acid 1a 10c 73 3-Nitrophenylboronic acid 1.5b 10e 732-Ethoxyphenyboronic acid 19.5a 10d 62 4-Acetylphenylboronic acid 1.5b 10f 623-Nitrophenylboronic acid 1.5a 10e 59 3-Thiopheneboronic acid 8b 10g 594-Acetylphenylboronic acid 8.5a 10f 493-Thiopheneboronic acid 6a 10g 58

a X¼Br.b X¼Cl.

ORO

N

RO

N

ORO

N

RO

N

R = TBDMSPCy2

Ligand:

9 10a-g

N

N

X

N

N

R

1.5 equiv arylboronic acid2 equiv K3PO4

10 mol% Pd(OAc)2

15 mol% Ligandanhyd dioxane

Scheme 4.

N

N

N

N

Cl

Cl

N

N

N

N

Cl

I

N

N

N

N

Ph

Cl

N

N

N

N

Ph

Ph

N

N

N

N

Cl

Ph

PhB(OH)2 (1 equiv)

PhB(OH)2 (1 equiv)

77%

81%

PhB(OH)2 (3 equiv)

PhB(OH)2 (3 equiv)

84 %

88 %

Conditions:PhMe, K2CO3,Pd(PPh3)4Ar, 100 °C, 8-20 h

11 12

13

1514

Scheme 5.

NH

N

N

N

Cl

Cl

C6H4B(OH)2 or3-pyrB(OH)2 (1 equiv)Pd(OAc)2, Cs2CO3,(3-NaO3SC6H4)3P

16

Armicrowave irradiation

Scheme


On the contrary, 6-amido-2-aminopurines are not so easilyobtained and this perhaps explains why the biological activities ofsuch derivatives have not been explored to date. Recently, theregioselective syntheses of 6-amidopurine derivatives 22 and 24from 2,6-dihalogenopurines 21 and 23, respectively, haveappeared, which give convenient access to this type of derivative(Scheme 8).21

Furthermore, the halogen at position 2 can then be substitutedby amines under SNAr conditions from fluoropurine 22 or Pd(0)-mediated coupling from the corresponding iodo derivative 24. Afurther Pd(0)-catalysed cross-coupling at position 2 in 24 is alsopossible with boronic acids or alkynes.

2.4. Substitution reactions of 6-chloropurine and 2-amino-6-chloropurine with nucleophiles

Substitution reactions of 6-halogenopurines with nucleophiles,particularly amines, have been widely exploited in medicinalchemistry, for example, in the synthesis of ATP analogues.22 A li-brary of 6-O-alkylguanine derivatives has been synthesised ascyclin-dependent kinase 1 and 2 inhibitors.23,24 Recently, a rapid,high-yielding nucleophilic displacement reaction of 6-chloropurine25 and 2-amino-6-chloropurine 26 with various nucleophilesunder microwave irradiation has been described (Scheme 9 and

NH

N

N

N

Cl

(N)X

+NH

N

N

N

(N)X

(N)

X17a-d 18a-b

X= H, 4-MeO, 3-NO2

6.

Table 4The Suzuki–Miyaura reactions of 2,6-dichloro-9H-purine

Boronic acid Equiv Product Yield (%)

Phenyl 1 17a 5518a 5

4-Methoxyphenyl 1 17b 5718b 6

3-Nitrophenyl 1 17c 263-Pyridyl 1 17d 70

N

N

N

N

Cl

N

N

N

N

R'

RR'-SnBu3 (1.5 equiv)(Ph3P)2Pd(Cl)2DMF

R

19a: R = H19b: R = NH2

20a: R = H; R' = Ph-C20b: R = NH2; R' = Ph-C20c: R = NH2; R' = (E)-PhCH20d: R = NH2; R' = Ph20e: R = H; R' = 2-Furyl

Scheme 7.

Table 5Pd-catalysed coupling between purines 19a,b and organotin reagents

Starting material Product Temperature (�C) Time (h) Yield (%)

19a 20a 75 2.5 7719b 20b 80 21 6419b 20c 100 21 7719b 20d 110 24 3019a 20e 95 17 93

N

N N

N

Cl

F

N

N N

NNH

F

O

R

Pd2(dba)3/ XantphosCs2CO3, dioxane, 100 °C

RCONH2, 1 equiv

N

N N

NCl

I

N

N N

NNH

I

O

RRCONH2, 3 equivNaH, 3 equiv, DMF

0 °C to rt, 2-4 h

R = Ph 85%R = 4-Cl-Ph 78 %R = 4-OMe-Ph 69%R = 2-OH-Ph 74%R = i-Bu 70%

R = Ph 50%R = 4-Cl-Ph 56 %R = i-Bu 35%

21 22

23 24

Scheme 8.

nucleophile, solvent

microwave irradiationN

N

N

N

Cl

HR N

N

N

N

R

HH2N

25: R = H26: R = NH2

27

26

Scheme 9.

Table 6Reaction of 2-amino-6-chloropurine with nucleophiles

Nucleophile Solvent Molarproportionofnucleophile

Temperature(�C)

Time(min)

R (27) Yield(%)

NH2Bn Nosolvent

10 110 15 NHBn 93

NH2(CH2)3Me Nosolvent

20 80 15 NH(CH2)3Me 84

CyNH2 Nosolvent

30 130 1 NHCy 94

PhNH2 Nosolvent

10 130 5 NHPh 96

PhNH2 Nosolvent

10 130 5 NHPh 48

Morpholine Nosolvent

10 90 1 N-Morpholyl

99

Piperidine Nosolvent

10 90 1 Piperidyl 93

MeONa NMP 3 100 1 OMe 99EtONa DMSO 3 100 2 OEt 83EtONa NMP 3 100 3 OEt 98BnOH DMSO 3 100 1 OBn 74PhONa DMSO 4 150 10 OPh 96MeSNa DMF 2.2 90 1 SMe 91MeSNa NMP 3 90 1 SMe 99PhSNa DMF 2 80 1 SPh 99


Table 6).25 This method is particularly suitable for the rapid con-struction of libraries of purines with a high diversity at position 6.In a few minutes, 6-substituted purines 27 were obtained from 26and primary amines, including anilines, and secondary amines, aswell as O- and S-nucleophiles, including MeONa, EtONa, PhONa,MeSNa and PhSNa.

In 2007, Liu and Robins26 reported a complete study of SNArreactions between 6-fluoro-, 6-chloro-, 6-bromo-, 6-iodo- and 6-alkylsufonylpurine nucleosides and nitrogen, oxygen and sulfurnucleophiles. In several cases, 6-halogenopurines do not follow theclassical order of reactivity for SNAr reactions of 1-halogeno-2,4-dinitrobenzenes (F>Cl>Br>I); the reactivity at C-6 in purinesclearly depends on the leaving group and the nucleophile. For ex-ample, the relative ease of displacement with a weakly basic aryl-amine (aniline) was inverted (I>Br>Cl>>F), as compared tobenzylamine (F>Br>Cl>I) (Table 7).

Table 7Orders of leaving group reactivities with various 6-substituted purines

Nucleophile Reactivity

BuNH2 F>RSO2>Br>Cl>IMeOH/DBU RSO2>F>BrzCl>Ii-PentSH/DBU RSO2>F>BrzI>ClPhNH2 I>Br>RSO2>Cl>FPhNH2/TFA F>RSO2>I>Br>Cl

3. Functionalisation at position 9: preparation of 9-substituted purine derivatives

3.1. Regioselective and stereoselective coupling of 6-(substituted-imidazol-1-yl)purines with 1-chloro-20-deoxyribose

Alkylation of purines usually results in the formation of regio-isomeric mixtures of N-7- and N-9-alkylpurines. The desired N-9compound is normally the major product, but the formation ofsignificant amounts of the N-7 isomer, as well as other alkylationproducts, is often observed.27 Glycosylation of purines suffers froma similar lack of regioselectivity with the additional problem thatcomplex diastereomeric mixtures may be encountered.


This traditional problem in purine chemistry was recentlysolved by Robins and co-workers.27–29 Unsubstituted heteroarylrings appended at C-6 of purines adopt essentially coplanar ringalignments, and it was reasoned that the proton above the N-7atom would prevent any N-7 alkylation. Indeed, the N-9 regio-specific glycosylation of purine acceptors with furanosyl and pyr-anosyl sugar donors was improved by the presence of an imidazolesubstituent at position 6 of the purine ring (28). Such purines un-dergo regiospecific N-9 glycosylation, but the stereoselectivity ofglycosylation (a or b) was still dependent on the solvent used forthe glycosylation reaction. Such derivatives (28) were readily pre-pared, improving the solubility and solvation of the purine in mixedsolvents. Glycosylation of the 6-sodium salts of (imidazol-1-yl)purines 28 with a protected chlorosugar proceeded with highregioselectivity (100%) and stereoselectivity (98%) in high yield(>90%) to afford exclusively the b anomer-N-9 regioisomers 29(Scheme 10).29 Ammonolysis of the imidazolium salts 30, gener-ated in situ from 29 with BnCl and NaI, gave high yields of theadenine derivative, Cladribine 31, a clinical anticancer drug.

N

N

N

Cl NH

N

N

N

N

N

Cl N

N

N

O

TolO

TolO

N

N

N

Cl N

N

N

O

TolO

TolO

I

1) NaH/MeCN

2) chlorosugar

BnI/MeCN60 °C, 1.5 h

NH3/MeOH60 °C, 11 h

N

NCl N

N

O

HO

HO

NH2

cladribine:31

R R R

R = Pr, iPr, Bu, Pent...

28

29 30

Scheme 10.

N

N NCl

N

N NHCl

Ar(Het)

(a) pyridine/Cu(OAc)2, ArB(OH)24 Å MS, 3 dfor aryl introduction

(b) CuI, Cs2CO3/N,N-dimethyl-cyclohexane-1,2-diamine,140 °C, DMF, 24 hfor heteroaryl introduction

35 36

Scheme 12.

N

NCl NH

N

Cl

N

NCl N

N

Cl

R

Cu(OAc)2 (anhyd.)4 Å MSEt3N, DCM

B(OH)2

R

16 37

Scheme 13.

3.2. Michael addition of adenine

Highly efficient Michael addition reactions of adenine 32 to a,b-unsaturated esters 33 under microwave irradiation to form 34a–d have been reported (Scheme 11),30 where it was unnecessary toprotect the exocyclic amino group, due to its relatively weak

N

N N

N

NH2

H

R1 R2

CO2R3

+DABCO/TBAB

microwaveirradiation200-300 W8-12 min

32 33

Scheme

nucleophilic character. Similarly, coupling of 6-chloropurine (25)with benzyl acrylate in DMF, in the presence of base (DIEA) at roomtemperature, gave the 9-substituted product in 74% yield.31 Fur-thermore, methyl, ethyl, or tert-butylacrylate also react regiose-lectively with 6-chloropurine under microwave irradiation in waterto give the 9-substituted products in good yield.32

These authors noted that, again, no protection was necessary ifamino or hydroxy groups were present in the molecule, and thatthe purine was exclusively alkylated at N-9.32

3.3. Arylation at N-9 of 7-deazapurines

Lam–Chan33 or Buchwald34 coupling conditions can be appliedto perform N-arylation of the N-7 atom of pyrrolo[2,3-d]pyrimi-dines such as 35 to form 36 (Scheme 12). The Lam–Chan protocolwas applicable for the introduction of meta- and para-substitutedaryl rings, but it could not be extended to ortho-substituted arylrings or heterocyclic systems. In these cases, the transformationwas carried out using the Buchwald procedure. The pyridine/Cu(OAc)2 combination was found to be optimal for the Lam–Chanreaction, while the use of Cs2CO3/N,N-dimethylcyclohexane-1,2-diamine at 140 �C in DMF gave superior results for the Buchwaldprocedure.35

3.4. Arylation at N-9 of purines

In 2001, Ding and co-workers36 described one of the first N-9arylations of purines such as 16 via boronic acid/cupric acetate/NEt3

in dichloromethane to form 37 (Scheme 13 and Table 8).Bakkestuen and Gundersen later described37 a regioselective N-

9 arylation of purines 38 using arylboronic acids 39 in the presenceof Cu(II) and an organic base. Trials revealed phenanthroline to give

N

N N

N

NH2

R1

R2

CO2R334a-d

34 R1 R2 R3

a H H Etb H H n-Buc H Me Et

d Me H Et

11.

Table 8N-9 Arylation of purine

N-9 Aryl substituent Yield (%) N-9 Aryl substituent Yield (%)

45 Me 47

OMe

O Me

43

O44

N

N NH

N

ClN

N N

N

Cl

25 42

OH

O

O

O

BtDPS O

O

O

tBDPS

1) PPh3, DEADTHF, 0 °C2) -78 °C, purine,c-C5H10

(78%)

41

+


significantly higher yields of 40 than triethylamine or pyridine(Scheme 14 and Table 9).

Under these conditions, 2-amino-6-chloropurine 26 did notreact, due to solubility problems. N-9 Arylation was, however,possible with various boronic acids in comparable conditions

Table 9Cu-mediated reaction between purines 38 and arylboronic acids 39

X Y R1 R2 Yield (%)

H Cl H H 71H Cl H CH3 68H Cl H OCH3 52H Cl H Cl 41H Cl Cl H 73Cl Cl H H 52Cl Cl H CH3 48NH2 Cl H H 42H NH2 H H No reactionH SCH3 H H 76H SH/SPh H H 81H 2-Thienyl H H 68

N

NX NH

NY N

NX N

NY

Cu(OAc)2 (anhyd.)4 Å MS,phenanthroline, DCM, 4 d

B(OH)2

R1

R2

R1 R238 39 40

+

Scheme 14.

Scheme 15.

N

N N

NCl

25

44

N OHBoc

O

NBoc

O

PPh3, DEADTHF, rt

43

MMTr+ MMTr

Scheme 16.

N

N NH

N

O

45

NH

Ac

O

NPh

PhHN

N N

N

O

H2NR

1) DIAD, PPh3, THF, 70 °C, twice

2) 1:1 NH3-H2O/MeOH, 60 °C 2 hR-OH+

46

Scheme 17.

(Cu(OAc)2/pyridine/molecular sieves/CH2Cl2) and with good yields(41–81%) on condition that the reaction was carried out on the bis-Boc-amino 6-chloropurine derivative.38

At present, these arylations have been achieved with phenyl-and substituted phenylboronic acids (Table 9). Other conditionsmay be needed to generalise this reaction with heteroarylboronicacids. The use of Cs2CO3/N,N-dimethylcyclohexane-1,2-diamine/Het-X at 140 �C in DMF was, however, recently found to be theoptimum conditions to introduce heterocyclic systems on thepyrrole nitrogen of various pyrrolo[2,3-d]pyrimidines (7-deazapurines).35

It is noteworthy that this copper(II)-mediated N-9 arylationmethodology greatly enhances the structural diversity of possiblepurine libraries, since other methods, such as anionic alkylationwith an alkyl halide, Mitsunobu alkylation and various glycosyla-tion reactions, do not allow regioselective N-9 arylation.

3.5. Mitsunobu alkylation at N-9 position with either primaryor secondary alcohols

Nucleoside analogues are generally prepared either by directcoupling of a base with a carbon substrate or by construction ofpurines and pyrimidines from aminoalkanes. The first route usually

involves fewer steps and gives higher overall yields. All of thereported approaches, however, do not work efficiently with elec-tron-rich purines, such as guanine, due to side reactions.

The triphenylphosphine-diethyl (or -diisopropyl) azodicarbox-ylate Mitsunobu inversion procedure has become very useful tosynthesise nucleoside analogues.39–44 Thus analogues 42 and 44have been synthesised from 6-chloropurine 25 and alcohols 41 and43, respectively (Schemes 15 and 16).

This alkylation reaction tolerates virtually any alcohol withoutadditional acidic hydrogens (pKa<10–12).12 The large number ofcommercially available alcohols offers a considerable diversity inlibraries of N-9 substituted purine derivatives.45

Coupling of unprotected guanine with alcohols under Mitsu-nobu conditions has, however, been reported to be impossible,probably due to a solubility problem with THF, the best solvent forthe Mitsunobu reaction.46,47

Although successful coupling of various alcohols with 2-amino-6-chloropurine was reported by Toyota and co-workers in 1993,46 itwas only recently that a general method for highly N-9 regiose-lective and high-yield coupling of a series of alcohols with a pro-tected guanine (45) to form 46a–j was reported (Scheme 17 andTable 10).47 This method was applied to various 2- or 6-(di)chloropurines.

This method is compatible with a very large range of substratesand allows stereochemical control of the couplings, as shown bythe isolation of a single diastereoisomer when a diastereoisomericalcohol was employed.47

3.6. Use of an aminoalkane and pyrimidine precursors

Condensation of guanidine 47 and ethyl aminomalonate 48 un-der basic conditions led to 2,5-diamino-4,6-dihydroxypyrimidine

Table 10Reaction substrate scope in the guanine–alcohol coupling

Alcohol Product Yield (%)

OHTBSO 46a 86

OH 46b 85

OH 46c 83

OH 46d 85

OH46e 76

OH46f 81

OH46g 72

OH46h 78

OH 46i 74

OHTBSO

46j 84


49, which is a precursor of 2-amino-6-chloropurines 51, via the 2,5-diamino-4,6-dichloropyrimidine 5048,49 (Scheme 18) bearing an N-9substituent arising from substitution of one chlorine atom in 50 bya primary amine.16,19,48

CH2N

NH2

47

NHNH2

OO

OO

48

N

N

ONH2H

H2N OH

N

N

ClNH2

H2N Cl

N

N

Cl

H2N N

N

R

1) R-NH2

2) ethylorthoformate

49

5051

EtONa, EtOH

POCl3

+

R = i-Pr, Me, c-C5H9,c-C6H11, Bn

Scheme 18.

The synthesis of pyrimidine 49 was performed on a 37-g scale in65% yield, while the subsequent chlorination was achieved in aPOCl3/benzyltriethylammonium chloride/PCl5/MeCN mixture inonly 32% yield.48 An improvement of this chlorination was reportedin 200049 using the Vilsmeier reagent, which gave the bis[(dime-thylamino)methylene]amino derivative of 50. This derivative had tobe carefully hydrolysed in acidic conditions to give 50 in 42% yieldfrom 49.

HN

N NH2

O

O

HN

N NH2

O

O

BrBr2, NaHCO3

MeOH

RNH2,microwaveirradiation

120 °C10 min

52 53

a: R = nBu, b: R = Bn, c: Re: R = o-PyCH2, f: R = m-P

Scheme

4. Functionalisation at N-1, N-3, N-7 and C-8

4.1. Preparation of xanthine derivatives from 6-aminouracils(Traube synthesis)

Xanthines constitute an important class of pharmacologicallyactive compounds, which are commonly used for their effects asmild stimulants, bronchodilators, phosphodiesterase inhibitors,CFTR chloride-channel activators and adenosine receptorantagonists.50

The syntheses of xanthines from 6-aminouracils, such as 52,generally involve multistep reactions and require tedious chro-matographic separations, which limit the synthesis of a largenumber of compounds. In addition, the Traube synthesis is gener-ally incompatible with the introduction of complex N-sub-stituents,51 although interesting xanthine derivatives have beenprepared from 5-bromo-6-aminouracil 53 (Scheme 19), 5,6-di-aminouracil such as 56 (Scheme 20),52,53 and N-1(or N-3) mono-substituted-5,6-diaminouracil (Scheme 19).54

In the present example, the cyclisation step (54a–f to 55a–f) wascarried out under microwave irradiation (Scheme 19).

Novel 1,3-dipropyl-8-(1-heteroarylmethyl-1H-pyrazol-4-yl)-xanthine derivatives such as 59, 61a,b and CVT-5440 have beensynthesised55,56 as potent and selective A2B adenosine receptorantagonists or inverse agonists56 (Scheme 20). These targets weresynthesised in a similar fashion from 56 by coupling the corre-sponding carboxylic acids 57, 60 and 4-benzyloxybenzoic acid inthe presence of a coupling agent (EDCI, EDAC). The ring closure ofthe intermediate pyrimidines (e.g., 58) was effected by treatmentwith aqueous NaOH to afford 59, 61a or 62, the CVT-5440 precursor.

CVT-5440 (Scheme 20) is a high-affinity A2B adenosine receptorantagonist for the potential treatment of asthma.57

4.2. Synthesis of purines from an imidazole precursor

An alternative approach to the synthesis of xanthines fromaminouracils is to use an imidazole starting material. A solution-phase synthesis of a xanthine substituted at the N-1 and N-7 posi-tions was achieved from benzyl alcohol 63 as a substitute for Wangresin (Scheme 21).50 The N-substituted glycine benzyl ester 65 wasobtained by reacting 63 with bromoacetic acid to give 64, which inturn, could be treated with butylamine in THF to provide 65. Treat-ment of 65 with ethoxymethylene cyanamide gave intermediate 66,which upon reaction with a strong base underwent imidazole ringformation to afford 67. Imidazole 67 was treated with an isocyanateto provide 68 in 90% yield before subsequent ring closure with NaOEtto give the 1,7-disubstituted xanthine 69 in 90% yield.

The new synthetic procedure summarised in Scheme 21 allowedthe preparation on solid support of di-, tri-, or tetrasubstitutedxanthines 75 (Scheme 22).50

4.3. Solid-phase synthesis of xanthine derivatives

The versatility of this chemistry was illustrated by the prepa-ration of a library of 22 di-, tri- or tetrasubstituted xanthines

HN

N NH2

O

O

HN

N

O

O N

NR

SHNHR

EtOC(O)SKMW, 120 °C

10 min

54 a-f 55 a-f

= PhCH2CH2, d: R = p-F-PhCH2CH2,yCH2

19.

N

N NH2

O

O

NH2

N

N NH2

O

O

HN

O

NN

57

56

58

EDCI,MeOH, rt

92%

O

NN

HO

N

N

O

O

59

N

HN

NN2 N NaOH, MeOH

reflux, 80 %

N

N

O

O60

61a: R = OH2) NaOH, 70 °C

NNHO

O O OEt

O

N

HN

N N

O R

O

61b: R =HN

amine, DMFHOBt, EDAC

N

N

O

O N

HN

O

62

1) 4-benzyloxybenzoicacid, EDCI, MeOH

2) NaOH 2 N,MeOH, 70 °C

Ph

N

N

O

O N

HN

O

R

R =

N

N

O

OCVT-5440 Me

, EDAC, MeOH

1)

O

O

Scheme 20.

OH HOCCH2Br, DDCO

DMAP, DMFO

OBr

O

O HN

BuBuNH2, THF

O

ONBu

NCN

NC-N=CHOEtTHF

O

O

N

N

H2N

ButBuOK, tBuOH

DMFO

O

N

N

HN

Bu

NH

OHex

C6H13NCOo-xylene

N

NH

N

NO

Bu

O

HexNaOEtTHF/MeOH

63 64 65

66 6768

69

Scheme 21.

OH HOCCH2Br, DDCO

DMAP, DMFO

OBr O

O HN R1

R1NH2, THF

O

ONR1

NCN

NC-N=COEtDBU, THF

O

O

N

N

H2N

R1tBuOK, tBuOHDMF

O

O

N

N

HN

R1

NH

OR3

R3NCO

o-xylene

N

N N

NO R1

O

R31) NaOEt THF/MeOH

Wang resin

R2R2

R2R2

R2

R4

2) R4X, DIEA, THF

70 71

72 73 74

75

Scheme 22.


Table 11Library of substituted xanthines

N

NH

N

NO

HexBu

O

75a 35%

N

NH

N

NO Bu

O

75b 35%

N

NH

N

NO

PhBu

O

75c 34%

N

NH

N

N

OBn

Bu

O

75d 29%

N

NH

N

N

OHex

Bn

O

75e 25%

N

NH

N

NO

PhBn

O

75f 30%

N

NH

N

NO

BnBn

O

75g 23%

N

NH

N

N

O Bn

O

75h 27%

N

N N

NO

PhBn

O

75i 20%

N

N N

NO

PhBn

O

75j 19%

N

N N

NO Bn

O

75k 20%

N

N N

NO Bn

O

75l 19%

N

N N

NO Bn

O

75m 23%

N

N N

NO Bn

O

Bn75n 24%

N

N N

NO

PhBn

O

75o 23%

N

N N

N

OPh

Bn

O

Bn75p 20%

N

NH

N

NO

O

75q 16%

N

NH

N

NO

Ph

O

75r 15%

N

N N

N

O

O

Bn75s 14%

N

N N

NO

Ph

O

75t 14%

N

NH

N

NO

OPh

75u 7%

N

N N

N

O

OPh

75v 6%

N

N

OH

N

N

CH2

OHH2N

R

N

N

CH2Ph

OH

Ph

77: R = CONH276: R = CN

CH(NH)NH2.HCl

N

N

O

N

N

CH2

OH

Ph

HNOE

CH3I, K2CO3,DMF, rt

78

79

2-MeOCH2CH2OHreflux

NOE: nuclear overhauser effect

Scheme 23.

CEtO

OCN C

EtO

OCN

NH2

EtOMeC(OEt)3

100 °C

80 81

Scheme

83

N

NH

O

N

N

O

R

84

Me1) RNCO, NEt3, PhH, 100 °C2) NaOMe, MeOH, reflux, 73%

R = Et, i-Pr

Scheme 25.


(75a–v) (Table 11). The solid-phase synthesis (70–75, Scheme 22)was adapted from preliminary solution-phase studies (Scheme 21).The overall yields obtained were 14–35%, indicating an averageyield of �75% for each step of the solid-phase reaction, for all butthe most encumbered analogues (75u and 75v).

Imidazole precursors such as 7658 allow the synthesis of purinesbearing substituents at N-1, C-8 and N-9 (77–79), as outlined inSchemes 23–25.

H2N

C

N

NCO

CN

N

Me

OEtMe

EtO

OBnNH2

EtOH, 80 °C

82 83

24.

N

NH

O

O

S

N

N

86

OO DMB

N

N

O

O

S

N

N

OO DMB

R3

R3-X

K2CO3, DMF

HN

N

O

O N

NDMB

R3

KOtBu

THF, 0 °C

R1-X

K2CO3, DMFN

N

O

O N

NDMB

R3

R1N

N

O

O N

HN

R3

R1 90% TFACH2Cl2

87

888990

DMB = 2,4-dimethoxybenzyl

O

H2N

O

N

NEtDMB

85

90

R7-X

K2CO3, DMFN

N

O

O N

N

R3

R1R7

91

R1 = Me, All, BnR3 = Me, Bn, EtOHR7 = Me, Et

Scheme 26.


5-Aminoimidazole derivatives such as 83 can be elaborated ina few steps from 80 and ethyl 2-aminocyanoacetate 81 via 82, asshown in Scheme 24.59

Aminoimidazole 83 was treated with various isocyanates(RNCO), setting the stage for cyclisation step in methanol/MeONaunder reflux to afford 1,8,9-trisubstituted xanthines 84(Scheme 25).59,60

Recently, an elegant synthesis from aminoimidazole 85 ofa key precursor (86) of functionalised xanthines was reported51

that does not need to use isocyanates to introduce the N-1 sub-stituents (Scheme 26). This method, which allows maximumflexibility for modification at N-1 (88/89), N-3 (86/87) and N-7 (90/91) is based on the selective removal of each N-protectinggroup under mild conditions. This allows efficient access toa range of disubstituted xanthines with the less common 1,7- and3,7-substitution patterns, as well as 1,3,7-trisubstituted de-rivatives (91) (Scheme 26), from a common precursor 86. N-3Protection can be achieved, if required, with allylmethyl chloridein the presence of K2CO3, and cleaved under neutral conditionsby Pd(0) catalysis.

Table 12Library of N-1,N-7-disubstituted purines

N

N N

NO

BuBu

97a 18%

N

N N

NO

Bu

97b 17%

N

N N

NO

BuPh

97c 15%

N

N N

NO

HeptBn

97f 18%

N

N N

NO

BnBu

97g 14%

N

N N

N

O Bu

97k 13%

N

N N

NO Bu

97l 27%

4.4. Synthesis of N-1,N-7-disubstituted purines from6-chloropurine

N-1,N-7-Disubstituted purines 97a–o (Table 12) can be syn-thesised in five steps from 6-chloropurine 25 and 92 via an initialMichael addition. Subsequent acid-catalysed hydrolysis of 93afforded 94 that was N-1-alkylated with butyl iodide to give 95.Quaternisation of 95 occurred on heating with further BuI to afford96, which gave 97, the N-9 deprotected product, in the presence ofammonia (Scheme 27).31

This methodology, developed on solid-phase, has permitted thesynthesis of a library of 15N-1,N-7-disubstituted purines in 13–27%overall yield (average yield of 70% for each step) (Table 12).


5.1. Pyrimidine precursors of 2,6,8,9-tetrasubstituted purines

Pyrimidines are versatile substrates for the synthesis of vari-ously substituted purines. Pyrimidine synthesis from amidines

N

N N

NO

Hept

97d 20%

N

N N

NO

HeptBu

97e19%

N

N N

NO

Bn

97h 16%

N

N N

NO Bu

97i 18%

N

N N

NO Bn

97j 13%

N

N N

N

O Bn

97m 20%

N

N N

NO Bu

97n 15%

N

N N

NO Bn

97o 16%

Ph O

ODIEA, DMF

N

N N

N

Cl

OO

Ph

HN

N N

NO

OO

Ph

85% HCOOH

N

N N

NO

OO

Bu

BuI, DBUDMF, rt

N

N N

N

O

OO

Ph

BuBuI, DBU

DMF, 70° C

BuI

NH3/MeOH

92 93 94

95 96

97a: R = R' = Bu

25

N

N N

NO

RR'

Ph

Scheme 27.

CNHR2

NH2

O

EtO

OEtO

N

N

OH

OHR2

H N

N

Cl

ClR2

NO2EtONa, EtOH

2) POCl3

98

R2 = H, Me102 : R2 = H103 : R2 = Me

R

99 a: R = H99 b: R = NO2

+

100 : R2 = H101 : R2 = Me

1) HNO3

Scheme 28.

N

N Cl

NO2

Cl

106

S

HN

N OH

O

HS

105

thiourea, EtONaEtOH

99b

NO2

Scheme 30.


constitutes a very efficient strategy to prepare 2-substituted pu-rines, due to the great variety of commercially available alkyl, arylor heterocyclic amidines (Scheme 28),61,62 which provide the firstpoint of structural diversity.61,63 For example, amidines 98 werecondensed with diethyl malonate (99a) in the presence of sodiumethoxide to obtain the 4,6-dihydroxypyrimidines 100 and 101.Controlled nitration with fuming nitric acid and chlorination withphosphorus oxychloride afforded the corresponding dichloropyr-imidines (102 and 103) in good yields.62

Replacement of diethyl malonate by ethyl cyanoacetate 80 in analkaline medium provides a 6-aminopyrimidinone 104 (Scheme29), another interesting purine precursor.64–67

CH2N S

NH2O

O NN

N

OHH

HS NH2

thiourea 80 104

+

Scheme 29.

Diethyl nitromalonate 99b has not been widely used to syn-thesise 5-nitropyrimidines, since, as shown above, good yields forthe nitration of dioxopyrimidines 102 or 103 are obtained.

In the case of the 2-thiopyrimidine derivative 105, however,Harnden and Hurst have observed that the use of commercial diethylnitromalonate might be a better strategy than the nitration of 2-methylthiopyrimidine-4,6-diol.68 The 5-nitropyrimidine-2-thiol (105)was obtained in 41% yield, the low yield being the result of the effect ofthe 5-nitro group on the hydrolytic stability of the 2-mercapto sub-stituent (Scheme 30). A methylation of 105 gave the 2-methylthioderivative in 64% yield, which was chlorinated to give 106 in good yield.

5.2. Synthesis of 2,6,8,9-tetrasubstituted purines

A synthesis of tetrasubstituted purines has been reported from4,6-dichloro-2-methyl-5-nitropyrimidine (103), itself prepared

according to a literature procedure.69,70 The second point of di-versity is introduced by the substitution of one chlorine atom of the5-aminopyrimidine 107 by various amines (see Section 5.1 andScheme 28 for the first point of diversity).71 Incorporation of analkylthio group at the 6-position in 103 or 108 led to 110 or 109,respectively (Scheme 31). Cyclisation with aldehydes in the pres-ence of FeCl3 afforded 111, which was oxidised to the correspondingsulfone 112 for displacement by various amines to give the thirdpoint of diversity (113) (Scheme 32). The fourth point of diversity atposition C-8 can be introduced with aldehydes (Scheme 32).

The 2-methylthiopyrimidine 106 (Scheme 30) constitutes aninteresting starting material towards libraries of 2,6,8,9-tetrasub-stituted purines with complete regiospecificity at every step, in-cluding a wide variety of substituents at the 9 position.72,73

This liquid-phase methodology (Schemes 31 and 32) was vali-dated by the synthesis of a 216-member 2,6,8,9-tetrasusbstitutedpurine library (113) (Scheme 32),74 and was applied recently onsolid support75 (114–119) to build a library of 24 purines (120)(Scheme 33).

Substitution of the methyl sulfone at position 2 can be achievedeasily on the pyrimidines 117, which leads to 2-amino-substitutedpyrimidines 118. On the contrary, it should be noted that substitutionby amine nucleophiles of 2-methyl- or 2-phenylsulfonylpurines isconsidered to be difficult.73,75–77 Functionalisations at position 2 inpurines are otherwise carried out from 2-halogenopurines, since 2-halogens (F, Cl, Br, I) are generally less reactive than the 6-halogen inSNAr. Whitfield and co-workers noted in 2003 that SNAr displace-ment reactions of 6-O-alkyl-2-fluoropurine with various weak

N

N Cl

NO2

Cl

103

N

N Cl

NH2

Cl

N

N NH

NH2

Cl

reduction first approach

substitution first approach

R2 N

N NH

NH2

S

R2

Ph

N

N NH

NO2

S

R2

Ph

R2 = n-Bu, i-Bu, Cy2-furyl-CH2, Bn, Ph

Fe/HClBnSH, Et3Nn-BuOH, 100 °C

R2NH2then BnSH, rt

Fe/NH4Cl

107 108

109

103

110

n-BuNH2n-BuOH, Et3N

100 °C

Scheme 31.

N

N N

N

S

R2

Ph

R3

R3-CHOFeCl3/SiO2 N

N N

N

S

R2

Ph

R3

OO

N

N N

N

HN

R2

R4

R3

R4-NH2(excess)109

111 112 113

mCPBACH2Cl2

Scheme 32.

O NH

R1 NR1

N

N Cl

NO2

S

NR1

N

N NH

NO2

S R2

NR1

N

N NH

NO2

SR2

OO

NR1

N

N NH

NH2

HN R2

NR1

N

NHN N

N

R2

R4

HNR1

N

NHN N

N

R2

R4

106, DIEATHF, 1 h, rt

9:1 TFA/H2Ort, 3 h

(ArgoGel-MB) 114

115 116

117 118 119 120

R1NH2Na(OAc)3BHDCE, rt

R2-NH2DIEATHF, 1 h, rt

OxoneNaHCO324 h, rt

R3-NH21 h, rt

R4-C(OMe)3H+ , 80 °C

CrCl2

R3 R3 R3

Scheme 33.


nucleophiles (anilines) were dramatically accelerated in the pres-ence of trifluoroacetic acid and 2,2,2-trifluoroethanol as solvent.78

5.3. Synthesis of 7-deazapurines (pyrrolo[2,3-d]pyrimidines)from pyrimidine precursors

7-Deazapurines (pyrrolo[2,3-d]pyrimidines)79 are among themost intensively studied purine analogues and display variousbiological activities. A number of synthetic strategies are availableincluding their preparation from various pyrimidineprecursors.80,81

Compounds 124–128 (Scheme 34) were synthesised as potentialthymidylate synthase inhibitors, from the key intermediate,2-amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine 123,82,83

(itself prepared from diaminopyrimidin-4-one 121 and chloro-acetone 122) to which various arylthiols were conveniently

attached at the 5-position via a modification of an oxidative thiolationprocedure reported by Gangjee and co-workers (Scheme 34).79,82

Similarly, 7-deazapurines may be obtained from pyrimidinesbearing adjacent amino and vinyl functionalities, e.g., 131. The dif-ferent reactivities of the three halogens of the pyrimidine 129 allowa regioselective amination to give 130, followed by a regioselectiveStille coupling to yield the intermediates 131. A thermal cyclisationstep in acetic acid affords the desired pyrrolo[2,3-d]pyrimidines132 (Scheme 35).35

Pyrrolo[2,3-d]pyrimidines have also been prepared from 5-allyl-2-amino-4,6-dichloropyrimidine 133, itself obtained from guani-dine and ethyl allylmalonate in two steps.84 An ozonolysis of 133leads to the aldehyde 134, which is protected as the diethylacetalderivative 135. A monosubstitution by a primary amine gives 136,which is cyclised to the 7-deazapurines 137 in dilute aqueoushydrochloric acid (Scheme 36).84

HN

N

O

HN

N NH

O

H2N NH2 H2NMeO

Cl+

NaOAc/H2O

100 °CMe

I2, EtOH/H2O (2/1)

100-110 °C; arylthiolHN

N NH

O

H2NMe

S

121 122 123 124: R = 3',4'-diF

125: R = 3',5'-diF

126: R = 3',5'-diCF3

127: R = 3',5'-diNO2

128: R = 3',5'-diCl

R

Scheme 34.

R = Me, Bn

N

N Cl

Br

Cl Pd(PPh3)2, PhMe, 110 °C, 24 h

N

N NH

Br

ClR

RNH2

THF, rt, 12 h

N

N NHClR

OEt

AcOH, 120 °C, 2 hN

NCl NR

131129 130

132

Bu3SnCH:CHOEt

Scheme 35.

N

N Cl

CH2

H2N

Cl

N

N Cl

CH2

H2N

Cl O

133 134 135

N

N Cl

CH2

H2N

ClHC

O O

N

N NH

CH2

H2N

ClHC

O O

R

N

NH2N N

R

Cl

136 137

HCl-H2O, rt

O3, -78 °C

MeOH-AcOEtEtOH, H+

RNH2, BuOH

NEt3, 100 °C, 2 d

R =HO

HO

HO

HO OH

HO

HO OHOH, ,

Scheme 36.



6.1. Synthesis of 8,9-disubstituted adenines

The highly potent water-soluble protein chaperone HSP90 in-hibitor 138 (R¼t-BuCH2) (Fig. 2) is an 8,9-disubstituted adenine,which induced inhibition of tumour growth.85 It is synthesised inthree steps from adenine by alkylation at position 9 followed bybromination at position 8 with Br2 in a mixture of THF, AcOH andH2O. Exchange of the bromo atom of 139 for a sulfur and sub-stitution of the thionoadenine 140 (Scheme 37) by the phenyldiazoderivative 141 gave intermediates 142.

N

N N

NNH2

(CH2)n

S

OI

NHR138

Figure 2.

The alcohol function of 143 is then revealed to create the mesylleaving group required for subsequent amination.

Further HSP90 inhibitors 146 and 149 can be synthesisedaccording to two related strategies starting from di- or tri-aminopyrimidines 144 or 147 (Schemes 38 and 39). In the firstsequence, the butyl substituent of 146 is introduced prior to thecyclisation of 145 and before amination at C-6 with NH3 (Scheme38). Alternatively, the butyl substituent of 149 can be introduced atthe last step from the 4,5,6-triaminopyrimidine precursor 147(Scheme 39),85 via cyclisation of the amido intermediate 148.

6.2. Synthesis of 2,8,9-trisubstituted adenines

6.2.1. Synthesis of 2,8,9-trisubstituted adenine inhibitors of HSP90Commercially available 2,4,5,6-tetraaminopyrimidine 150

(Scheme 40) and 2-fluoroadenine 152 (Scheme 40) have beenfeatured in strategies towards the preparation of libraries of func-tionalised 2-fluorinated purines, from which very potent 8-aryl-sulfanyl-adenine inhibitors of HSP90 were synthesised.86

Interestingly, the fluorine atom at C-2 increased the solubility and

N

N

NH2

N

N

(CH2)3

Br

OAc

N

N

NH2

N

HN

(CH2)3

S

OAc

N

N

NH2

N

N

(CH2)3

S

OR

OIthiourea, n-BuOH

reflux, 3 h (88%)

O I

N2 BF4141

DMSO, rt, 24 h (51%)

139 140142: R = Ac

143: R = H138

1) mesylation2) amination

Scheme 37.

N

N NH

NH2

Cl

N

N N

NNH2

N

N NH

HN

Cl

O

O

O

O

O

TsCl, Et3N, DCE40 °C, 16 h (71%)

NH3, MeOH120 °C, 3 d(80%)

144 145 146

2,5-(MeO)2C6H3CH2CO2H

Scheme 38.

N

N

NH2NH2

NH2

N

N

NH2

NH2

HN

OO N

N N

NNH2

O

NMP, 40-50 °C,(98%)

1) MeONan-BuOH, reflux2 h, (75%)2) BuI, Cs2CO3DMF, rt, 16 h(54%)

147 148 149

3-MeOC6H4CH2CO2H.HCl

Scheme 39.

N

N

NH2NH2

H2N NH2

N

N

NH2

H2N N

N

H

SH

150 151

CS2, NaHCO3

H2O/EtOH, reflux

N

N

NH2

F N

N

H

N

N

NH2

F N

N

R

Br2) NBS, DMF, rt, 80%

1) ROTs, Cs2CO3, DMF80 °C, 50%

152 153

N

N N

NNH2

R

SF

154

R: 2-iprOCH2CH2, Bu,pent-4-ynylR': H, Cl

O O

O

R'

Scheme 40.


potency of the resulting inhibitors. Cyclisation of 150 in CS2 gavethe purinethiol 151 before reaction with aryl iodides and alkylationat N-9 afforded the 8-arylsulfanyl-adenines 154. Transformationof the C-2-amino group to fluorine in 151 with HF/pyridine inthe presence of sodium nitrite86 gave the 2-fluoroadenines 154.Similarly, the target 2-fluoroadenines 154 were synthesised from 2-fluoroadenine 152 after alkylation at N-9 with tosylates, bromina-tion at C-8 with N-bromosuccinimide giving 153 and thioarylationat C-8 in DMF/K2CO3.

6.2.2. 8-Aryl-9-methyladenine derivatives from a 4,6-dichloropyrimidine precursor

Treatment of N-1-(4,6-dichloro-5-nitropyrimidin-2-yl)aceta-mide 155 with an aqueous solution of methylamine neutralisedwith acetic acid gave the monomethylamino derivative in good

yield before nitro reduction with Raney nickel afforded the diaminoderivative 156. The Schiff base 157, obtained by condensation of 156with an aldehyde, was directly converted by oxidative ring clo-sure87 into 2-amino-8-aryl-6-chloropurine 158, which was furtherfunctionalised to 159 (Scheme 41).88

Considerable diversity can thus be introduced at C-8, N-9 andC-2 with aldehydes, amines and alkynes, respectively.

6.3. Synthesis of 6,7,8-trisubstituted purines

N-7-Substituted purines can be synthesised by direct alkylationof 6-chloropurine 25, but, in this case, N-7- and N-9-substitutedpurines are obtained as a mixture of regioisomers (see Section 3.1).Liu and co-workers have recently reported an efficient and regio-specific strategy to prepare N-7-substituted purines (Scheme 42).89

N

N Cl

NO2

Cl

AcHNN

N NH

NH2

Cl

AcHNMe

1) 40% MeNH2, AcOH/THF2) H2, Raney Ni/MeOH

N

N

Cl

H2N N

N

Me

Ar

ArCHOAcOH/MeOH

N

N NH

NCl

AcHNMe

Ar

1) FeCl3/EtOH

2) HCl/H2O-THFN

N

NH2

N

N

Me

Ar

R'

155 156 157

158 159

Ar: Ph, 2-furyl, 2-thienyl, 2-pyridyl, 2-FPh, 3-FPh, 4-FPh, 3-ClPh, 4-ClPh, 3-CNPh...R': c-C4H10(OH), c-C5H8(OH), c-C7H12(OH)

Scheme 41.

Table 13Reaction of 4,6-dichloro-5-aminopyrimidine with aryl isothiocyanates

Entry Isothiocyanate R1 Product Yield (%)

1 168 Ph– 175 922 169 2,6-Me2Ph– 176 903 170 p-MePh– 177 934 171 p-MeOPh– 178 955 172 p-CF3Ph– 179 826 173 p-NO2Ph– 180 507 174 3-Pyridyl– 181 80


This method is based on the mono-amination of pyrimidines 161with ethanolic ammonia in a sealed tube at 120 �C, followed bydisplacement of the second chloro group with an excess of thio-phenol in refluxing n-butanol, leading to the intermediates 163.Cyclisation in the presence of a carboxylic acid or an aldehyde gave7,8-disubstituted purines 164. The strong electron-donating effectof the newly introduced amino group in pyrimidines 162 preventsa second amination.

N

N

Cl

Cl

NHR1

N

N

SAr

N

NR2

160

R1-XNaH

NH3 N

N

Cl

NH2

NHR1 PhSH N

N

SPh

NH2

NHR1

161 162 163

R1

164

R2COOHor R2CHO N

N

N

N

NR2

R1

R3 R4

1) mCPBA

2) R3R4NH

165

N

N

Cl

Cl

NH2

7

9

Scheme 42.

A 40-membered library of 6,7,8-trisubstituted purines (165) wasconstructed, demonstrating the potential utility of this regiospecificstrategy.

6.4. Preparation of 6,8-disubstituted purine analogues:thiazolopyrimidines

Thiazolopyrimidines are widely used bioisosteres of the purinebase (Scheme 43) and this heterocycle can be obtained in one step

ArH2N

N

N Cl

NH2

NH

n-BuOH

Et3N, 80 °C(80%)

160

166

Ph

4

Ar

R1

N C S

168-174 MeCN, 50 °C, 16 hCs2CO3 (2 eq)

N

N S

N

Cl

NHR1

175-181

Ar = 3,4,5-(MeO)3Ph-

Scheme

by the reaction of a purine precursor, 4-chloro-5,6-diaminopyr-imidine (166), with isothiocyanates or by the reaction of 5-amino-4,6-dichloropyrimidine 160 with isothiocyanates (Scheme 43 andTable 13).90

These compounds (175–181) are interesting 6,8-disubstitutedpurine analogues that can be obtained in one or two steps froma readily available pyrimidine precursor (160).

The thiazolopyrimidines 175–181 can be aminated at the laststep under microwave irradiation to give the disubstituted thia-zolopyrimidine derivatives 182.

7. Conclusions

The purine motif is a privileged substructure, which is recog-nised by an enormous number of proteins.91 This biological rele-vance and the occurrence of the purine heterocycle in nature makeit an attractive target for chemical modification. Being one of themost studied heterocycles in medicinal chemistry, a wide range of

N

N S

NNHAr

NHPh

167

N C S

DBU, DMF8 h (20%)

R2 NH2

acid or basemicrowave irradiation,150 °C

N

N S

NNH

NHR1

R2

182

R1: see table 13R2: 3,4,5-(MeO)3PhCH2-,Me-(CH2)3-, t-Bu-, Ph-, p-MeOPh,m-ClPh-, p-NO2Ph-

43.


chemical reactions can now be applied, opening up the possibilityof building large libraries of new molecules bearing a great di-versity of functions in seven directions around its small core. Recentadvances in purine chemistry have been illustrated in this review,either by new synthetic routes or by improvements of known re-actions, which widen the scope, and allow better regioselectivitywith a higher yield. This article highlights the potential for com-binatorial chemistry on the purine ring; for example, with only twonon-identical substituents and seven possible points of attachment,as many as 42 different regioisomeric disubstituted purines can beenvisaged. Thus, while much of the purine chemical space remainsto be explored, the recent advances in purine chemistry should leadto more potent and specific inhibitors of known biological targetsand pave the way to new inhibitors or antagonists of targets thathave yet to be described. In conclusion, purines offer an exceptionalscaffold for the synthesis of relevant tools in biology througha combination of the high level of regio-functionalisation and thediversity of the chemistries that are possible with this heterocycle.

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dron 64 (2008) 8585–8603 8603
M. Legraverend / Tetrahe
Biographical sketch

Michel Legraverend was born in Saint-Pair-sur-Mer, Normandy, France. After receiv-ing a first degree (DEUG) in Chemistry and Biology at the University of Caen, he com-pleted further studies (Maitrise and DEA) in Chemistry and Molecular Biology at theUniversity of Paris-sud in Orsay. He carried out graduate studies at the CNRS, ICSNat Gif sur Yvette under the supervision of Prof. E. Lederer. He joined the laboratoryof Medicinal Chemistry and Biology, Applied Pharmacology Section of Dr. David Johns,with Dr. Robert I. Glazer, from 1977 to 1979, at the National Cancer Institute, NIH, Be-thesda, MD. He joined the laboratory of Chemical Pharmacology of Dr. Emile Bisagni atthe Institut Curie, Orsay, France, where he completed his doctoral studies (University ofParis XI, Orsay) and obtained a researcher position at INSERM, France. He worked thenunder the directorship of Dr. David S. Grierson (1998–2006) and presently with Dr. M.-P.Teulade-Fichou. His current research interest includes the search of new methods forthe synthesis of polysubstituted purines, as inhibitors of various targets involved in thecell cycle and cell signalling.

Tetrahedron 64 (2008) 8585–8603

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