Synthesis, biological activity, and SAR of antimycobacterial 2- and 8-substituted 6-(2-furyl)-9-(p-methoxybenzyl)purines

Bioorganic & Medicinal Chemistry 15 (2007) 7144–7165

Synthesis, biological activity, and SAR of antimycobacterial

2- and 8-substituted 6-(2-furyl)-9-(p-methoxybenzyl)purines

Morten Brændvang and Lise-Lotte Gundersen^*

Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway

Received 20 March 2007; revised 26 June 2007; accepted 6 July 2007

Available online 22 August 2007

Abstract—A number of 6-(2-furyl)-9-(p-methoxybenzyl)purines carrying a variety of substituents in the 2- or 8-position have been

synthesized and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. It is demonstrated that

sterical hindrance in the purine 8-position reduces activity and that C-8 should be unsubstituted. In the purine 2-position small,

hydrophobic substituents are beneﬁcial. The electronic properties of the 2-substituents appear to have only a minor inﬂuence on

bioactivity. The compounds studied exhibit low toxicity toward mammalian cells (VERO cells) and are essentially inactive toward

Staphylococcus aureus and Escherichia coli. The most active and selective antimycobacterial in the series detected to date is the novel

2-methyl-6-furyl-9-(p-methoxybenzyl)purine with MIC = 0.20 lg/mL against M. tuberculosis and IC₅₀against VERO cells >62.5 lg/

mL. Also the novel 2-ﬂuoro analog and the previously known 2-chloro compound, both with MIC = 0.39 lg/mL, are highly inter-

esting drug candidates.

1. Introduction

class of antimycobacterial purines.⁶The most active

compounds contain an electron rich aryl group, prefer-

ably 2-furyl-, in the purine 6-position, and a benzyl

group at N-9. The benzylic moiety should not be substi-

tuted in the ortho- or a-positions, but several substitu-

ents in the meta- and para-positions are well tolerated.

A p-methoxy group seems to be very favorable. This

substituent generally increases antimycobacterial activ-

ity and decreases toxicity toward mammalian cell. Some

of the most active and selective antimycobacterial pur-

ines, 1a and 1b, are shown in Figure 1. As can be seen

from Figure 1, the introduction of chlorine in the purine

2-position signiﬁcantly enhances antimycobacterial

activity in vitro, and the same trend is seen for several

6-aryl-9-benzylpurines.¹We have now further explored

synthesis, antibacterial activity, and SAR for 2-substituted

We have previously reported that certain 6,9-disubsti-

tuted purines are potent inhibitors of Mycobacterium

tuberculosis (Mtb) in vitro.¹Our antimycobacterial pur-

ines display several properties which make them highly

interesting as potential drugs against tuberculosis; high

selectivity toward Mtb compared to other microorgan-

isms, activity against several drug-resistant strains of

Mtb, generally low toxicity toward mammalian cells,

and ability to aﬀect Mtb inside macrophages. Even

though the mode of action for this class of antimycobac-

terials has not yet been established, our ﬁndings point

toward a novel target. For treatment of mycobacterial

infections, organism-speciﬁc agents, preferably with a

novel mechanism of action in order to avoid develop-

ment of resistance as long as possible, are recom-

mended.²WHO³and others⁴list antimycobacterial

purines among compounds that should be pursued fur-

ther (discovery research) as potential TB-drugs.⁵

In preceding papers, we have discussed SAR for the sub-

stituent in the purine 6-position^1eand at N-9^1b,dfor our

Keywords: Antimicrobial agent; Purine; Tuberculosis.

*

Corresponding author. Tel.: +47 22857019; fax: +47 22855507;

e-mail: l.l.gundersen@kjemi.uio.no

Figure 1. Structure of potent antimycobacterial purines.

doi:10.1016/j.bmc.2007.07.034

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7145

6-(2-furyl)-9-(p-methoxybenzyl)purines. Analogs substi-

tuted at C-8 have been synthesized and evaluated as

antimycobacterials as well.

diacylated or sulfonylated depending on the reaction

conditions to give compounds 6–9. Coupling of the

N²-benzylated purine 3c with 2-furyl(tributyl)tin led to

compound 10.

2. Chemistry

Synthesis of 2-alkylamino-6-furylpurines by reductive

acylation of compound 4, as reported for the prepara-

tion of other 2-alkylaminopurines,⁹met with little

success. Instead we prepared the methyl- and dimethy-

laminopurines 11 and 12 from the 2-chloropurine 1b

(Scheme 2). Compound 1b was reacted with methyl-

amine to give the N-methylaminopurine 11 and reaction

with the HCl salt of glycine methylester gave compound

12. A similar reaction on a 2-chloropurine is reported to

take place at room temperature,¹⁰but in our case a reac-

tion temperature of 85 ꢁC was required. Reaction of

compound 1b with sodium methylthiolate gave the

2-methylthio derivative 13, which could be oxidized with

mCPBA selectively to the sulfoxide 14 or sulfone 15

depending on the reaction conditions.

Because the introduction of chlorine in the 2-position of

6-aryl-9-benzylpurines generally enhances antimycobac-

terial activity (see above), we were interested in the anti-

mycobacterial activity of other 2-halopurines. We have

recently reported the synthesis of the 2-ﬂuoropurine

1c⁷(Fig. 1), and that of the 2-iodo analog 5 is shown

in Scheme 1. N-Alkylation of 2-amino-6-chloropurine

2 with 4-methoxybenzyl chloride gave the desired com-

pound 3a together with the N-7 alkylated isomer 3b

(Scheme 1). Minor amounts of the dialkylated product

3c could also be isolated. Compound 3a was converted

to the 2-amino-6-(2-furyl)purine 4, a key compound in

the syntheses of several 2-substituted 6-(2-furyl)purines

(Scheme 1). The 2-iodopurine 5 was prepared from the

aminopurine 4 by treatment with isoamylnitrite and diio-

domethane. However, compound 5 was only isolated in

40% yield due to tedious separation from the 2-iso-

amyloxypurine formed as a by-product under these

reaction conditions. Attempts to prepare the corre-

sponding 2-bromopurine by the bromination method

published by Nair,⁸or several modiﬁcations of the origi-

nal procedure, failed because complete separation of the

desired product from 2-alkoxypurine by-products was

not achieved. Synthesis of the bromo analog, or the 2-

iodo compound 5, employing the same strategy as in

the reported synthesis of 2-ﬂuoropurine 1c, was also

not successful.⁷The aminopurine 4 could be mono- or

We have recently reported the synthesis of the 2-nitrop-

urine 16 and its facile conversion to the 2-ﬂuoropurine

1c.⁷We report here that nitropurine 16 can also easily

be converted to other 2-substituted purines (Scheme 3).

Treatment of compound 16 with tetrabutylammonium

hydroxide at room temperature gave the 2-oxopurine

17. 2-Oxopurines are traditionally synthesized under

more harsh conditions, that is, treatment of 2-chloro-

purines with hydrochloric acid, cleavage of certain

alkoxypurines, treatment of methylthiopurines with

hydrogen peroxide, or diazotation–hydrolysis of amino-

purines.¹¹Alternatively, 2-oxopurines are available in

several steps from cytosine.¹²

Scheme 1. Reagents and conditions: (a) p-CH₃O–C₆H₄–CH₂Cl, K₂CO₃, DMF; (b) (2-furyl)SnBu₃, (Ph₃P)₂PdCl₂, DMF, 90 ꢁC; (c) CH₂I₂,

isoamylONO, 85 ꢁC; (d) Ac₂O, Et₃N, toluene, D; (e) Ac₂O, toluene, D; (f) CH₃SO₂Cl, pyridine; (g) CH₃SO₂Cl, DMAP, Et₃N, CH₂Cl₂.

7146

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

Scheme 2. Reagents and conditions: (a) CH₃NH₂, H₂O, THF, 85 ꢁC; (b) H₂NCH₂CO₂CH₃ÆHCl, Et₃N, DMF, 85 ꢁC; (c) CH₃SNa, DMF, 90 ꢁC;

(d) m-CPBA (1.0 equiv), CH₂Cl₂, ꢀ10 ꢁC; (e) m-CPBA (2.3 equiv), CH₂Cl₂.

Scheme 3. Reagents and conditions: (a) Bu₄NOH, H₂O, THF; (b) ROH, KF; (c) ROH, KCN; (d) CH₃ONa, CH₃OH, D.

2-Chloropurine 1b could be converted to the corre-

sponding 2-methoxypurine 18a by treatment with so-

dium methoxide in methanol at reﬂux temperature

(Scheme 3). Since it is known that a 2-nitro group in cer-

tain purines have been displaced by nucleophiles, such

as methanol,¹³we also explored the possibility of con-

verting nitropurine 16 into a variety of 2-alkoxypurines

18. The results are presented in Table 1. 2-Nitropurine

16 did not react with methanol at room temperature,

but compound 16 was easily converted to the 2-meth-

oxyderivative 18 when potassium ﬂuoride or potassium

cyanide was added. The reaction with methanol took

place at ambient temperature; the other alcohols ex-

plored required heating. Both primary and secondary

alkoxy groups, as well as the phenoxy group, could be

introduced to the purine 2-position. Generally the con-

version was faster in the presence of potassium cyanide

compared to potassium ﬂuoride, but both salts could be

used to synthesize compounds 18 in generally high

yields. Only very minor amounts of 2-ﬂuoro- or 2-cya-

nopurines were formed in these reactions.

Purines 19, carrying an alkyl-, alkenyl- or aryl-substitu-

ent in the 2-position, were easily available by Stille- or

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

Table 1. Synthesis of 2-alkoxypurines 18 from 2-nitropurine 16

7147

ROH

Additive

Temperature (ꢁC)

Time (h)

Yield (%), 18^a

CH₃OH

EtOH

None

50

rt

24

50

1.5

6

No react.

87, 18a

75, 18a

93, 18a

98, 18a

16, 18a

90, 18a

82, 18b

94, 18b

74, 18c

94, 18c

KF, satd soln, ca. 56 equiv

KCN, satd soln, ca. 37 equiv

KF, satd soln, ca. 56 equiv

KCN, satd soln, ca. 37 equiv

KF, 4 equiv

rt

50

1.5

50

1.5

48

4

KCN, 4 equiv

50

70

KF, satd soln, ca. 6 equiv

KCN, satd soln, ca. 1.8 equiv

KF, 4 equiv

EtOH

50

n-PrOH

i-PrOH

n-BuOH

BnOH

97 (D)

82 (D)

100

6

KCN, 4 equiv

KF, 4 equiv

2

b

48

7

—

KCN, 4 equiv

KF, 4 equiv

53, 18d

81, 18e

95, 18e

71, 18f

83, 18f

65, 18g

68, 18g

KCN, 4 equiv

KF, 4 equiv

24

2.5

21

1.5

BnOH

PhOH

KCN, 4 equiv

KF, 4 equiv

KCN, 4 equiv

^aYield of isolated compound.

^bNot obtained pure, contaminated with 2-ﬂuoropurine 1c.

Negishi coupling of 2-chloropurine 1b with the desired

organometallic reagent (Scheme 4).¹⁴The 2-acetylpurine

20 was formed by hydrolysis of the enol ether 19h, and

2-cyanopurine 21 was available from compound 1b by

treatment of zinc cyanide in the presence of palla-

dium(0).¹⁵Sonogashira coupling of compound 1b with

trimethylsilylacetylene, followed by cleavage of the

TMS-group, aﬀorded the ethynylpurine 23.

Elevated temperature (120 ꢁC) was required for the for-

mation of the acetylene 22 (Scheme 4), and Sonogashira

coupling of the chloropurine 1b with propyne was not

successful. On the other hand, 2-iodopurines 24 and 5

reacted with propyne in a sealed tube to give alkynes

25 and 26 (Scheme 5). The reaction on the dihalopurine

24 was performed at 0 ꢁC to minimize formation of

dipropynylpurine.

Scheme 4. Reagents and conditions: (a) RZnX, Pd-complex, THF; (b) RSnR⁰, (Ph₃P)₂PdCl₂, DMF, 90 ꢁC; (c) HCl(aq), acetone; (d) Zn(CN)₂,

3

(Ph₃P)₄Pd, NMP, 120 ꢁC; (e) TMSC„CH, (Ph₃P)₂PdCl₂, CuI, Et₃N, DMF, 120 ꢁC; (f) K₂CO₃, MeOH, CH₂Cl₂.

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M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

Scheme 5. Reagents and conditions: (a) CH₂I₂, isoamylONO, 85 ꢁC; (b) CH₃C„CH, (Ph₃P)₂PdCl₂, CuI, Et₃N, CH₃CN; (c) (2-furyl)SnBu₃,

(Ph₃P)₂PdCl₂, DMF, 90 ꢁC.

2-Triﬂuoromethylpurines have been synthesized from

the corresponding 2-iodopurines by treatment with

‘CF₃Cu’, generated in situ from Zn, CF₃Br, and CuI,

but the reaction required the extremely toxic co-solvent

HMPA.¹⁶Hence, we decided to prepare the target 29

(Scheme 6) from 6-chloro-2-triﬂuoromethylpurine 27¹⁷

by N-alkylation followed by Stille coupling.

In order to avoid problems with regioselectivity in the

cross-coupling of the dichloropurine 31b, we also syn-

thesized compound 32b from the furylpurine 1a by lith-

iation followed by trapping with hexachloroethane.

However lithiation in the furyl ring was also observed

and compound 35b was isolated in minor amounts.

Lithiation of compound 1a followed by trapping with

1,2-dibromo-1,1,2,2-tetrachloroethane gave the 8-bro-

mopurine 32c. No reaction at the furyl ring could be ob-

served. Also the 8-methylpurine 32a could be formed

selectively from 1a, and the dimethylated compound

was formed when an excess of methyl iodide was used.

The total yields of compounds 32a and 32b from 6-chlo-

ropurine 30 are approximately the same from both syn-

thetic sequences employed. The 8-bromopurine 32c can

only be prepared via the furylpurine 1a, since couplings

on 8-bromo-6-chloropurines take place preferably at

C-8.¹⁸

After synthesizing 6-furyl-9-(p-methoxybenzyl)purines

carrying a variety of substituents in the purine 2-posi-

tion, we turned to synthesis of 8-substituted analogs

(Scheme 7). 6-Chloropurine 30 was lithiated at C-8

and trapped with methyl iodide or hexachloroethane

to give compound 31, which was subjected to Stille cou-

pling to give 6-furylpurines 32a and 32b. In the synthesis

of compound 32b, mild conditions were used in order to

achieve selective coupling in the 8-position,¹⁸but a small

amount of the difurylpurine 32d was formed. Com-

pound 32b was converted to the methoxypurine 33. A

minor amount of the oxopurine 34 was also isolated.

We believe that compound 34 is formed by cleavage of

the methoxypurine 33 and not directly from chloropu-

rine 32b. We have previously observed low hydrolytic

stability of certain other 8-methoxypurines.¹⁹

2.1. Biological activity

The 2- and 8-substituted 6-furylpurines were screened

for antibacterial activity against M. tuberculosis H₃₇Rv

and the results are presented in Tables 2 and 3. For

Scheme 6. Reagents and conditions: (a) p-CH₃O–C₆H₄–CH₂Cl, K₂CO₃, DMF; (b) (2-furyl)SnBu₃, (Ph₃P)₂PdCl₂, DMF, 90 ꢁC.

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7149

Scheme 7. Reagents and conditions: (a) LDA, THF, ꢀ78 ꢁC; (b) CH₃I, THF, ꢀ78 ꢁC, rt; (c) C₂Cl₆, THF, ꢀ78 ꢁC; (d) (2-furyl)SnBu₃, (Ph₃P)₂PdCl₂,

DMF, 90 ꢁC; (e) (2-furyl)SnBu₃, [(2-furyl)₃P]₄Pd, DMF, 50 ꢁC; (f) CH₃ONa, CH₃OH, D; (g) CBrCl₂CBrCl₂, THF, ꢀ78 ꢁC, rt.

compounds displaying MIC against Mtb 6 6.25 mg/mL,

toxicity toward mammalian cells (VERO cells) was also

determined (Tables 2 and 3). Selected compounds were

screened against Staphylococcus aureus and Escherichia

coli as well (Tables 2 and 3).

compounds examined were less active than the parent

compound 1a. Again, low toxicity toward VERO cells

and low activity against other bacteria were observed.

From the results presented in Table 2, it can be seen that

the introduction of a polar substituent at C-2 resulted in

reduced antimycobacterial activity. Compounds with p-

Several 2-substituted purines exhibited inhibitory activ-

ity against Mtb (Table 2). Compared to the previously

examined 2-chloropurine 1b, ﬂuoropurine 1c was

equally active (MIC = 0.39 lg/mL) and the methylpu-

rine 19a slightly more active (MIC = 0.20 lg/mL). Also

the introduction of a methoxy (18a MIC = 0.78 lg/

mL) and a methylthio group (13a MIC = 0.78 lg/mL)

in the 2-position increased antimycobacterial activity

somewhat compared to the unsubstituted compound

1a (MIC = 1.56 lg/mL). The 2-ethylpurine 19b was

found to be equally active as the parent compound 1a.

For all 2-substituted compounds examined, the MICs

against other bacteria, S. aureus (Gram positive) and

E. coli (Gram negative), were >32 lg/mL. This conﬁrms

our previous observation that the 6-aryl-9-benzylpurines

are highly selective against Mtb.

values²⁰< 0

generally

exhibited MIC

against

Mtb > 6.25 mg/mL. Exceptions were the methoxy group

(p = ꢀ0.02, MIC 18a = 0.78 lg/mL) and the acetyl

group (p = ꢀ0.55, MIC 20 = 6.25 lg/mL). We have pre-

viously found low tolerance for polar substituents

(p < 0) on the benzyl group in 6-aryl-9-benzylpurines.^1d

Mtb contains a thick and waxy cell wall, which may pre-

clude eﬃcient penetration of the more polar

compounds.

Purines carrying C-2 substituents with diﬀerent elec-

tronic properties (F, Cl, OMe, SMe, and Me) exhibit

high inhibitory activity against Mtb, indicating that

the electronic properties of the substituents have

only minor inﬂuence on the antimycobacterial

activity.

In most cases examined, the active 2-substituted antimy-

cobacterial purines exhibited low toxicity toward mam-

malian cells (VERO cells). For 2-methylpurine 19a, a

selectivity index (IC₅₀VERO cells : MIC Mtb) greater

than 313 was calculated. The 2-ethynylpurine 23 was,

however, highly toxic to VERO cells (IC₅₀= 0.14 lg/

mL). Also the ethenylpurine 19g and methylthiopurine

13a displayed relatively high toxicity (IC₅₀< 10 lg/mL).

It is worth mentioning that we previously observed an

increase in toxicity toward VERO cells when the meth-

ylthio substituent was introduced in the benzylic para-

position of related structures.^1d

Substituent size, on the other hand, appears to be much

more important for biological activity. Both in the alk-

oxy/aryloxy-series (compounds 18) and the alkyl/alke-

nyl/aryl series (compounds 19), the activity generally

decreases as the size of the 2-substituent increases. The

iodopurine 5 is also much less active than chloro- 1b

or ﬂuoro-analog 1c. Introduction of unsaturations in a

C-2 side chain appears not to be favorable. Activity

against Mtb was found to be ethyl (19b,

MIC = 1.56 lg/mL) > ethenyl (19g, MIC = 3.13 lg/

mL) > ethynyl (23, MIC 6.25 = lg/mL). Our results

indicate that the not yet identiﬁed target for the antimy-

cobacterial purines contains a pocket that can accom-

modate relatively small and hydrophobic C-2

substituents.

Introduction of a substituent at C-8 in 6-furyl-9-(p-

methoxybenzyl)purine 1a turned out not to have a posi-

tive eﬀect on antimycobacterial activity (Table 3). All

7150

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

Table 2. Antibacterial activity against M. tuberculosis, S. aureus, and E. coli, and cytotoxic activity against VERO cells for 2-substituted purines^a

Compound

X

% Inhibition of MIC

MIC S. aureus MIC E. coli

IC₅₀VERO Selectivity

M. tuberculosis M. tuberculosis (ATCC 25923) (ATCC 25922) cells (lg/mL) index

(ATCC 27294)

at 6.25 lg/mL

concd.

H

₃₇Rv (lg/mL)^b(lg/mL)^c

(lg/mL)^d

(SI = IC₅₀: MIC

M. tuberculosis)

1a

1b

–H

–Cl

97^e

98^e

97

43

60

0

1.56^e

0.39^e

0.39

n.d.

0.78

n.d.

0.78

n.d.

0.20

1.56

n.d.

>6.25

n.d.

6.25

3.13

>6.25

6.25

n.d.

6.25

n.d.

6.25

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

>62.5^e,f

>10^e,f

>10

n.d.

3.05

n.d.

>62.5^f

n.d.

>62.5^f

n.d.^g

n.d.

>10^f

8.85

n.d.

>10^f

n.d.

>10^f

n.d.

0.14

n.d.

>40

>26

n.d.

3.9

1c

5

–F

–I

–NH₂

4

6

–NHCOCH₃

–N(COCH₃)₂

–NHSO₂CH₃

–N(SO₂CH₃)₂

–NHCH₂–p-C₆H₄–OCH₃

–NHCH₃

–N(CH₃)₂

–SCH₃

7

8

30

0

9

10

5

11

12

77

34

98

60

0

13

14

–SOCH₃

–SO₂CH₃

–NO₂

n.d.

>80

n.d.

>313

n.d.

>1.6

2.82

n.d.

>1.6

n.d.

>1.6

n.d.

0.02

n.d.

15

16

56

42

97

89

73

53

76

59

72

99

60

97

62

96

99

91

99

37

97

69

97

42

82

17

–OH

–OCH₃

18a

18b

18c

18d

18e

18f

18g

19a

19b

19c

19d

19e

19f

19g

19h

19i

19j

20

–OCH₂CH₃

–O(CH₂)₂CH₃

–OCH(CH₃)₂

–O(CH₂)₃CH₃

–OCH₂Ph

–OPh

–CH₃

–CH₂CH₃

–CH(CH₃)₂

–(CH₂)₃CH₃

–c-Propyl

–c-Pentyl

–CH@CH₂

–C(OEt)@CH₂

–Ph

–(2-Furyl)

–COCH₃

–CN

21

23

–C„CH

–C„CCH₃

–CF₃

26

29

^aFor a general structure, see Figure 2.

^bMIC Rifampin 0.25 lg/mL.

^cMIC Gentamycin 0.03 lg/mL.

^dMIC Gentamycin 0.125 lg/mL.

^eTaken from Ref. 1d.

^fLow solubility precludes determination at higher concentration.

^gSolubility in tissue culture to low to determine IC₅₀

.

The results presented in Table 3 demonstrate that C-8,

in the class of purines studied, should be unsubstituted.

Again, it seems like sterical factors are the most impor-

tant. The compounds containing the larger substituents

(Br 32c, 2-furyl 32d) are the least active antimycobacte-

rials. C-8 substituents may inﬂuence the spatial orienta-

tion of the N-9 benzyl group. 8-Substituted purine

nucleosides often prefer the syn conformation whereas

the unsubstituted analogs prefer the anti conforma-

tion.²¹Previously we observed that introduction of

substituents to the benzylic ortho- or a-positions of the

benzyl group also resulted in reduced activity.^1dIt

appears that the benzylimidazole part of the molecules

is extremely sensitive to sterical hindrance and substituents

that may interfere with the conformation of the benzyl

group required for binding to target must be avoided.

Figure 3 summarizes our current knowledge on SAR

regarding antimycobacterial 6-aryl-9-benzylpurines.

3. Conclusions

We have synthesized a number of 6-(2-furyl)-9-(p-meth-

oxybenzyl)purines carrying a variety of substituents in

the purine 2- or 8-position and determined their ability

to inhibit growth of M. tuberculosis in vitro. The results

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7151

Table 3. Antibacterial activity against M. tuberculosis, S. aureus, and E. coli, and cytotoxic activity against VERO Cells for 8-substituted purines^a

Compound

X

Y

% Inhibition of

M. tuberculosis

(ATCC 27294)

MIC M. tuberculosis

₃₇Rv (lg/mL)^b

MIC S. aureus

(ATCC 25923)

(lg/mL)^c

MIC E. coli

(ATCC 25922)

(lg/mL)^d

IC₅₀VERO

cells (lg/mL)

H

at 6.25 lg/mL concd

32a

32b

32c

32d

33

–CH₃

–Cl

–Br

–H

93

90

40

0

6.25

>6.25

n.d.

3.13

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>32

n.d.

>62.5^e

n.d.

–H

–(2-Furyl)

–OCH₃

–OH

n.d.

–H

95

64

72

10

>10^e

n.d.

34

35a

35b

–CH₃

–Cl

–CH₃

–Cl

n.d.

^aFor a general structure, see Figure 2.

^bMIC Rifampin 0.25 lg/mL.

^cMIC Gentamycin 0.03 lg/mL.

^dMIC Gentamycin 0.125 lg/mL.

^eLow solubility precludes determination at higher concentration.

show that sterical hindrance at C-8 reduces activity, and

the 8-position should be unsubstituted. In the purine 2-

position small, hydrophobic substituents are beneﬁcial.

The electronic properties of the 2-substituents appear

to have little inﬂuence on bioactivity. Generally the

compounds studied exhibited low toxicity toward mam-

malian cells and were essentially inactive toward S. aur-

eus and E. coli. The most active and selective

antimycobacterial in the series detected to date is 2-

methyl-6-furyl-9-(p-methoxybenzyl)purine 19a with

MIC = 0.20 lg/mL against Mtb and IC₅₀against VERO

cells > 62.5 lg/mL. Also the 2-ﬂuoro 1c and the previ-

ously known 2-chloro analog 1b, both with

MIC = 0.39 lg/mL, are highly interesting drug

candidates.

compounds were prepared as previously described: 6-(2-

furyl)-9-(4-methoxyphenylmethyl)-9H-purine 1a.^1d

2-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

1b,^1d2-ﬂuoro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine 1c,⁷2-nitro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 16,⁷6-chloro-2-triﬂuoromethyl-

1H-purine 27,¹⁷and 6-chloro-9-(4-methoxyphenylmeth-

yl)-9H-purine 30.^1dAll other reagents were commercially

available and used as received. Activities against M.

tuberculosis,¹S. aureus,²³E. coli,²³and VERO cells¹

were determined as reported before.

4.1. 2-Amino-6-chloro-9-(4-methoxyphenylmethyl)-9H-

purine (3a) and 2-amino-6-chloro-7-(4-methoxyphenyl-

methyl)-7H-purine (3b)

Potassium carbonate (2.49 mg, 18.0 mmol) and 2-ami-

no-6-chloro-9H-purine 2 (1.02 g, 6.00 mmol) were stir-

red in dry DMF (25 mL) at ambient temperature

under N₂. After 20 min, 4-methoxyphenylmethyl chlo-

ride (1.63 mL, 12.0 mmol) was added. The resulting mix-

ture was stirred for 16 h, ﬁltered, and evaporated in

vacuo. The isomers 3a and 3b were separated by ﬂash

chromatography on silica gel eluting with CH₂Cl₂/

MeOH (19:1). Various amounts of compound 3c could

also be isolated depending on the amount of heat em-

ployed in the evaporation of the reaction mixture.

4. Experimental

The ¹H NMR spectra were recorded at 600 MHz with a

Bruker AV 600 instrument, at 500 MHz with a Bruker

Avance DRX 500 instrument, at 300 MHz with a Bru-

ker Avance DPX 300 instrument, or at 200 MHz with

a Bruker Avance DPX 200 instrument or a Varian Gem-

ini 200 instrument. The ¹H decoupled ¹³C NMR spectra

were recorded at 150, 125, 75 or 50 MHz using instru-

ments mentioned above. ¹⁹F NMR spectra were re-

corded at 188 MHz with the Avance DPX 200

instrument using CCl₃F in CDCl₃as reference (d

0 ppm). Mass spectra under electron impact conditions

(EI) were recorded at 70 eV ionizing voltage with a

VG Prospec instrument and are presented as m/z (%

rel int.). Elemental analyses were performed by Ilse Bee-

tz Mikroanalytisches Laboratorium, Kronach, Ger-

many. Melting points were determined with a C.

Reichert melting point apparatus and are uncorrected.

4.1.1. 2-Amino-6-chloro-9-(4-methoxyphenylmethyl)-9H-

purine (3a).²⁴Yield: 917 mg (53%), colorless powdery

˚

DMF was distilled from BaO and stored over 4 A molsi-

eve. Triethylamine, diisopropylamine, pyridine, dichlo-

romethane, and acetonitrile were distilled from CaH₂,

and THF from Na/benzophenone. Toluene was dried

over Na-wire. N-Methylpyrrolidine (NMP) was

purchased on SureSeal bottles from Aldrich and used

as received. The Grignard reagents used were titrated

using salicylaldehyde phenylhydrazone.²²The following

Figure 2. General structures of purines discussed in Table 2 (com-

pounds I) and in Table 3 (compounds II).

7152

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

Figure 3. Summary of SAR knowledge for 6-aryl-9-benzylpurines.

crystals, mp 178 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 3.78

(s, 3H, CH₃), 5.15 (br s, 4H, CH₂and NH₂), 6.86 (d,

J = 8.6 Hz, 2H, Ar), 7.20 (d, J = 8.6 Hz, 2H, Ar), 7.68

(s, 1H, H-8); ¹³C NMR (CDCl₃, 50 MHz) d 46.7

(CH₂), 55.3 (CH₃), 114.4 (CH in Ar), 125.1 (C-5),

126.9 (C-1 in Ar), 129.2 (CH in Ar), 142.0 (C-8), 151.1

(C-4/C-6), 153.7 (C-4/C-6), 159.1 (C-4 in Ar), 159.6

(C-2); MS-EI m/z (rel %) 291/289 (6/18 M⁺), 121 (100),

91 (2), 78 (4), 77 (3); HRMS: Found 289.0730, Calcd

for C₁₃H₁₂ClN₅O 289.0732.

was stirred at 90 ꢁC under N₂for 16 h, cooled, and evap-

orated in vacuo. A saturated solution of potassium ﬂuo-

ride in methanol (10 mL) was added and the mixture

was stirred at ambient temperature for at least 4 h and

evaporated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/hex-

ane (1:1) followed by EtOAc/hexane (2:1) and ﬁnally

pure EtOAc; yield 189 mg (88%), colorless crystals, mp

1

235–237 ꢁC (dec). H NMR (CDCl₃, 200 MHz) d 7.77

(s, 3H, CH₃), 5.10 (br s, 2H, NH₂), 5.19 (s, 2H, CH₂),

6.61 (dd, J = 3.6 and 1.6 Hz, 1H, H-4 in furyl), 6.85

(d, J = 8.6 Hz, 2H, Ar), 7.22 (d, J = 8.6 Hz, 2H, Ar),

7.70 (m, 2H, H-5 in furyl and H-8), 7.77 (br d,

J = 3.6 Hz, 1H, H-3 in furyl); ¹³C NMR (DMSO-d₆,

50 MHz) d 45.1 (CH₂), 55.0 (CH₃), 112.3 (C-4 in furyl),

113.9 (CH in Ar), 116.2 (C-3 in furyl), 121.6 (C-5), 128.6

(CH in Ar), 128.8 (C-4 in Ar), 142.2 (C-8), 145.2 (C-5 in

furyl), 145.4 (C-6), 149.3 (C-2 in furyl), 153.6 (C-4),

158.6 (C-2), 160.2 (C in Ar); MS-EI m/z (rel %) 321

(55, M⁺), 121 (100), 91 (3), 78 (5), 77 (5); HRMS: Found

321.1234, Calcd for C₁₇H₁₅N₅O₂321.1226.

4.1.2. 2-Amino-6-chloro-7-(4-methoxyphenylmethyl)-7H-

purine (3b).²⁴Yield: 361 mg (21%), colorless crystals,

mp 225–227 ꢁC. ¹H NMR (DMSO-d₆, 300 MHz) d

3.67 (s, 3H, CH₃), 5.43 (s, 2H, CH₂), 6.63 (br s, 2H,

NH₂), 6.86 (m, 2H, Ar), 7.09 (m, 2H, Ar), 8.50 (s, 1H,

H-8); ¹³C NMR (DMSO-d₆, 75 MHz) d 48.7 (CH₂),

55.1 (CH₃), 114.1 (CH in Ar), 114.7 (C-5), 128.1 (CH

in Ar), 128.8 (C-1 in Ar), 142.3 (C-6/C-2), 149.8 (C-8),

158.8 (C-4 in Ar), 160.0 (C-2/C-6), 164.4 (C-4); MS-EI

m/z (rel %) 291/289 (3/13, M⁺), 121 (100), 91 (2), 78

(6), 77 (5); HRMS: Found 289.0730, Calcd for

C₁₃H₁₂ClN₅O 289.0730.

4.3. 6-(2-Furyl)-9-iodo-9-(4-methoxyphenylmethyl)-9H-

purine (5)

4.1.3. 6-Chloro-9-(4-methoxyphenylmethyl)-2-(4-meth-

oxyphenylmethylamino)-9H-purine (3c). Colorless nee-

dles, mp 161–164 ꢁC. H NMR (CDCl₃, 200 MHz) d

A mixture of 2-amino-6-(2-furyl)-9-(4-methoxyphenylm-

ethyl)-9H-purine 4 (80 mg, 0.25 mmol), diiodomethane

(2.5 mL), and isoamyl nitrite (670 lL, 5.00 mmol) was

heated at 85 ꢁC for 75 min. After cooling, the solution

was evaporated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/

hexane (2:1); yield 43 mg (40%), colorless oil. Crystalli-

zation from CH₂Cl₂–acetone aﬀorded an analytical sam-

1

3.815 (s, 3H, CH₃), 3.824 (s, 3H, CH₃), 4.65 (br s, 2H,

CH₂NH), 5.18 (s, 2H, CH₂), 5.75 (br s, 1H, NH),

6.84–6.90 (m, 4H, Ar), 7.21–7.34 (m, 4H, Ar), 7.71 (s,

1H, H-8); ¹³C NMR (CDCl₃, 50 MHz) d 45.4 (CH₂),

46.8 (CH₂), 55.3 (2· CH₃), 113.9 (CH in Ar), 114.3

(CH in Ar), 124.5 (C-5), 127.2 (C in Ar), 128.7 (CH in

Ar), 129.4 (CH in Ar), 130.9 (C in Ar), 141.3 (C-8),

151.0 (C-4/C-6), 153.6 (C-4/C-6), 158.69 (C in Ar),

158.74 (C in Ar), 159.6 (C-2); MS-EI m/z (rel %) 411/

409 (14/39, M⁺), 290 (7), 288 (22), 136 (2), 121 (100);

Anal. Found: C, 61.41; H, 4.83; N, 17.00.

C₂₁H₂₀ClN₅O₂requires C, 61.54; H, 4.92; N, 17.09%.

1

ple, colorless crystalline compound, mp 145–148 ꢁC. H

NMR (CDCl₃, 300 MHz) d 3.80 (s, 3H, OCH₃), 5.33 (s,

2H, CH₂), 6.65 (dd, J = 3.5 and 1.7 Hz, 1H, H-4 in fur-

yl), 6.89 (d, J = 8.7 Hz, 2H, Ar), 7.27 (d, J = 8.7 Hz, 2H,

Ar), 7.77 (d, J = 1.7 and 0.7 Hz, 1H, H-5 in furyl), 7.82

(dd, J = 3.5 and 0.7 Hz, 1H, H-3 in furyl), 7.91 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 46.9 (CH₂), 55.2

(OCH₃), 112.7 (C-4 in furyl), 114.4 (CH in Ar), 118.4

(C-3 in furyl), 119.6 (C-2), 126.5 (C-1 in Ar), 128.0 (C-

5), 129.5 (CH in Ar), 144.1 (C-8), 146.5 (C-5 in furyl),

146.6 (C-6), 148.7 (C-2 in furyl), 152.8 (C-4), 159.8 (C-

4 in Ar); MS-EI m/z (rel %) 432 (56, M⁺), 305 (2), 184

(2), 121 (100), 106 (2); Anal. Found: C, 47.29; H, 3.15;

N, 12.89. C₁₇H₁₃IN₄O₂requires C, 47.24; H, 3.03; N,

12.96%.

4.2. 2-Amino-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-

purine (4)²⁵

2-(Tributylstannyl)furan (0.26 mL, 0.80 mmol) was

added to a solution of 2-amino-6-chloro-9-(4-methoxy-

phenylmethyl)-9H-purine 3a (195 mg, 0.67 mmol) and

bis(triphenylphosphine)palladium(II) chloride (24 mg,

0.034 mmol) in DMF (5 mL). The resulting mixture

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7153

4.4. N-[6-(2-Furyl)-9-(4-methoxybenzyl)-9H-purine-2-yl]-

acetamide (6)

4.6. 6-(2-Furyl)-2-methylsulfonylamino-9-(4-methoxyphenyl-

methyl)-9H-purine (8)

A stirred suspension of 2-amino-6-(2-furyl)-9-(4-meth-

(80 mg, 0.25 mmol)

A solution of methanesulfonyl chloride (259 lL,

oxyphenylmethyl)-9H-purine

4

3.33 mmol) was added dropwise to a suspension of

2-amino-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-pur-

ine 4 (106 mg, 0.33 mmol) in pyridine (3 mL). The sus-

pension was stirred at ambient temperature for 24 h,

poured into ice water (40 mL), and extracted with

CH₂Cl₂(2· 30 mL). The combined organic extracts

were washed with satd aq NH₄Cl (40 mL), water

(40 mL), satd aq NH₄Cl (40 mL), and brine (40 mL),

dried (MgSO₄), and evaporated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel elut-

ing with CH₂Cl₂gradually increasing the amount of ace-

tone to CH₂Cl₂/acetone (9:1); yield 30 mg (23%),

colorless crystals, mp 127–128 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 3.47 (s, 3H, SO₂CH₃), 3.76 (s, 3H,

OCH₃), 5.27 (s, 2H, NCH₂), 6.62 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in furyl), 6.85 (d, J = 8.7 Hz, 2H, Ar),

7.25 (d, J = 8.7 Hz, 2H, Ar), 7.71 (dd, J = 1.7 and

0.6 Hz, 1H, H-5 in furyl), 7.78 (dd, J = 3.5 and 0.6 Hz,

1H, H-3 in furyl), 7.93 (s, 1H, H-8), 8.02 (br s, 1H,

NH); ¹³C NMR (CDCl₃, 75 MHz) d 41.7 (SO₂CH₃),

47.1 (CH₂), 55.3 (OCH₃), 112.7 (C-4 in furyl), 114.5

(CH in Ar), 118.1 (C-3 in furyl), 125.3 (C-5), 126.9

(C-1 in Ar), 129.5 (CH in Ar), 143.6 (C-8), 146.3 (C-5

in furyl), 146.8 (C-6/C-2), 149.3 (C-2 in furyl), 152.4

(C-2/C-6), 153.1 (C-4), 159.8 (C-4 in Ar); MS-EI m/z

(rel %) 399 (19, M⁺), 321 (3), 320 (4), 200 (3), 121

(100); Anal. Found: C, 53.95; H, 4.55; N, 17.44.

C₁₈H₁₇N₅O₄S requires C, 54.13; H, 4.29; N, 17.53%.

and triethylamine (174 lL, 1.25 mmol) in toluene

(2 mL) was heated at reﬂux. Acetic anhydride

(236 lL, 2.50 mmol) was added and the reaction mix-

ture was heated at reﬂux for 22 h, cooled, and evap-

orated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with CH₂Cl₂/

acetone (9:1) followed by CH₂Cl₂/acetone (7:3); yield

47 mg (52%), oﬀ-white crystalline compound, mp

167–168 ꢁC. ¹H NMR (CDCl₃, 300 MHz) d 2.55 (s,

3H, CH₃CO), 3.75 (s, 3H, OCH₃), 5.26 (s, 2H,

NCH₂), 6.61 (dd, J = 3.5 and 1.7 Hz, 1H, H-4 in fur-

yl), 6.85 (d, J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz,

2H, Ar), 7.71 (dd, J = 1.7 and 0.7 Hz, 1H, H-5 in

furyl), 7.75 (dd, J = 3.5 and 0.7 Hz, 1H, H-3 in fur-

yl), 7.91 (s, 1H, H-8), 8.27 (br s, 1H, NH); ¹³C

NMR (CDCl₃, 75 MHz)

d 25.1 (CH₃CO), 46.9

(NCH₂), 55.3 (OCH₃), 112.6 (C-4 in furyl), 114.4

(CH in Ar), 117.6 (C-3 in furyl), 125.1 (C-5), 127.0

(C-1 in Ar), 129.5 (CH in Ar), 143.7 (C-8), 146.0

(C-5 in furyl), 146.5 (C-6), 149.5 (C-2 in furyl),

152.7 (C-2), 153.0 (C-4), 159.7 (C-4 in Ar), 171.0

(C@O); MS-EI m/z (rel %) 363 (100, M⁺), 348 (6),

322 (4), 321 (21), 320 (3), 121 (99); Anal. Found:

C, 62.65; H, 4.74; N, 19.13. C₁₉H₁₇N₅O₃requires

C, 62.80; H, 4.72; N, 19.27%. 2-(N,N-Diacetylami-

no)-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

7 was also isolated; yield 39 mg (38%), data see

below.

4.7. 6-(2-Furyl)-2-(N,N-Dimethylsulfonylamino)-9-(4-

methoxyphenylmethyl)-9H-purine (9)

4.5. 2-(N,N-Diacetylamino)-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine (7)

Triethylamine (464 lL, 3.33 mmol) was added to a

suspension of 2-amino-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 4 (106 mg, 0.33 mmol) and 4-

(N,N-dimethylamino)pyridine (4.0 mg, 0.033 mmol) in

CH₂Cl₂(5 mL). A solution of methanesulfonyl chloride

(259 lL, 3.33 mmol) was added dropwise. The resulting

solution was stirred at ambient temperature for 4 h,

poured into ice water (40 mL), and extracted with

CH₂Cl₂(2· 25 mL). The combined organic extracts

were washed with water (25 mL) and brine (2·

25 mL), dried (MgSO₄), and evaporated in vacuo. The

product was puriﬁed by ﬂash chromatography on silica

gel eluting with CH₂Cl₂/acetone (29:1) followed by

CH₂Cl₂/acetone (19:1); yield 87 mg (55%), colorless

powdery crystals, mp 234–236 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 3.72 (s, 6H, 2· SO₂CH₃), 3.78 (s, 3H,

OCH₃), 5.33 (s, 2H, NCH₂), 6.64 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in furyl), 6.88 (d, J = 8.7 Hz, 2H, Ar),

7.25 (d, J = 8.7 Hz, 2H, Ar), 7.70 (br s, 1H, H-5 in fur-

yl), 7.79 (d, J = 3.5 Hz, 1H, H-3 in furyl), 8.04 (s, 1H, H-

8); ¹³C NMR (CDCl₃, 75 MHz) d 44.5 (2· SO₂CH₃),

47.3 (CH₂), 55.3 (OCH₃), 112.8 (C-4 in furyl), 114.6

(CH in Ar), 118.4 (C-3 in furyl), 126.3 (C-1 in Ar),

127.9 (C-5), 129.5 (CH in Ar), 145.8 (C-8), 146.6 (C-5

in furyl), 147.0 (C-6/C-2), 149.2 (C-2 in furyl), 149.7

(C-2/C-6), 153.3 (C-4), 159.9 (C-4 in Ar); MS-EI m/z

(rel %) 477 (6, M⁺), 399 (8), 398 (6), 122 (3), 121

A stirred suspension of 2-amino-6-(2-furyl)-9-(4-meth-

oxyphenylmethyl)-9H-purine 4 (160 mg, 0.50 mmol) in

toluene (4 mL) was heated at reﬂux for 24 h. Acetic

anhydride (472 lL, 5.00 mmol) was added. After

additional 24 h reﬂux, the solution was cooled and

evaporated in vacuo. The product was isolated by

ﬂash chromatography on silica gel eluting with

CH₂Cl₂/acetone (9:1); yield 151 mg (74%), colorless

crystalline compound, mp 187–189 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 2.28 (s, 6H, 2· CH₃CO), 3.71

(s, 3H, OCH₃), 5.27 (s, 2H, NCH₂), 6.60 (dd,

J = 3.5 and 1.7 Hz, 1H, H-4 in furyl), 6.80 (d,

J = 8.7 Hz, 2H, Ar), 7.21 (d, J = 8.7 Hz, 2H, Ar),

7.70 (dd, J = 1.7 and 0.7 Hz, 1H, H-5 in furyl),

7.85 (dd, J = 3.5 and 0.7 Hz, 1H, H-3 in furyl),

8.06 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d

26.3 (2· CH₃CO), 47.0 (NCH₂), 55.1 (OCH₃), 112.7

(C-4 in furyl), 114.3 (CH in Ar), 118.7 (C-3 in furyl),

126.5 (C-1 in Ar), 127.4 (C-5), 129.4 (CH in Ar),

145.6 (C-8), 146.3 (C-5 in furyl), 147.2 (C-6), 148.7

(C-2 in furyl), 153.2 (C-2/C-4), 153.4 (C-4/C-2),

159.7 (C-4 in Ar), 172.1 (2· C@O); MS-EI m/z (rel

%) 405 (34, M⁺), 363 (70), 349 (17), 348 (80), 321

(12), 121 (100); Anal. Found: C, 62.35; H, 4.82; N,

17.17. C₂₁H₁₉N₅O₄requires C, 62.22; H, 4.72; N,

17.27%.

7154

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

(100); Anal. Found: C, 47.69; H, 4.14; N, 14.71.

C₁₉H₁₉N₅O₆S₂requires C, 47.79; H, 4.01; N, 14.67%.

3.75 mmol) and 2-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 1b (112 mg, 0.33 mmol) in DMF

(3 mL) and the reaction mixture was heated in a sealed

tube under N₂at 85 ꢁC for 15 h. After cooling the pre-

cipitate was ﬁltered oﬀ and the solution evaporated in

vacuo, and the residue was dissolved in CH₂Cl₂

(15 mL). Again, the precipitate was ﬁltered oﬀ, and the

solution was evaporated in vacuo. The residue was puri-

ﬁed by ﬂash chromatography on silica gel eluting with

CH₂Cl₂/acetone (19:1); yield 95 mg (82%), colorless

crystalline compound, mp 163–164 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 3.27 (s, 6H, N(CH₃)₂), 3.75 (s,

3H, OCH₃), 5.18 (s, 2H, NCH₂), 6.57 (dd, J = 3.4 and

1.7 Hz, 1H, H-4 in furyl), 6.83 (d, J = 8.7 Hz, 2H, Ar),

7.25 (d, J = 8.7 Hz, 2H, Ar), 7.62 (br d, J = 3.4 Hz, H-

3 in furyl), 7.67 (s, 1H, H-8), 7.70 (br s, 1H, H-5 in fur-

yl); ¹³C NMR (CDCl₃, 75 MHz) d 37.4 [N(CH₃)₂], 46.1

(NCH₂), 55.2 (OCH₃), 111.9 (C-4 in furyl), 114.2 (CH in

Ar), 115.2 (C-3 in furyl), 121.3 (C-5), 128.1 (C-1 in Ar),

129.4 (CH in Ar), 140.9 (C-8), 145.1 (C-5 in furyl), 146.1

(C-6), 151.2 (C-2 in furyl), 154.3 (C-4), 159.4 (C-4 in Ar),

159.7 (C-2); MS-EI m/z (rel %) 349 (100, M⁺), 334 (7),

321 (3), 320 (14), 121 (52); Anal. Found: C, 65.28; H,

5.41; N, 20.05. C₂₁H₁₉N₅O₄requires C, 65.32; H, 5.48;

N, 20.04%.

4.8. 6-(2-Furyl)-2-(4-methoxyphenylmethylamino)-9-(4-

methoxyphenylmethyl)-9H-purine (10)

The title compound was prepared by Stille coupling on

6-chloro-9-(4-methoxyphenylmethyl)-2-(4-methoxyphe-

nylmethylamino)-9H-purine 3c (0.70 mmol) as described

for compound 4 above. EtOAc/hexane (1:1) followed by

EtOAc/hexane (2:1) were used for ﬂash chromatogra-

phy; yield 262 mg (85%), colorless crystals, mp 153–

154 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 3.75 (s, 3H,

CH₃), 3.76 (s, 3H, CH₃), 4.63 (br d, J = 5.8 Hz, 2H,

CH₂NH), 5.16 (s, 2H, CH₂) 6.09 (br s, 1H, NH), 6.59

(dd, J = 3.4 and 1.6 Hz, 1H, H-4 in furyl), 6.78–6.84

(m, 4H, Ar), 7.16–7.31 (m, 4H, Ar), 7.70 (m, 1H, H-5

in furyl), 7.71 (s, 1H, H-8), 7.79 (br d, J = 3.4 Hz, 1H,

H-3 in furyl); ¹³C NMR (CDCl₃, 50 MHz) d 45.3

(CH₂), 46.4 (CH₂), 55.2 (2· CH₃), 112.5 (C-4 in furyl),

113.8 (CH in Ar), 114.2 (CH in Ar), 117.7 (C-3 in furyl),

122.1 (C-5), 127.5 (C-1 in Ar), 128.7 (CH in Ar), 129.4

(CH in Ar), 131.2 (C-1 in Ar), 141.9 (C-8), 145.8 (C-

6), 145.9 (C-5 in furyl), 148.6 (C-2 in furyl), 154.3 (C-

4), 158.1 (C-2/C-4 in Ar), 158.6 (C-2/C-4 in Ar), 159.4

(C-2/C-4 in Ar); MS-EI m/z (rel %) 441 (100, M⁺), 426

(4), 320 (67), 136 (6), 121 (64); HRMS: Found

441.1780, Calcd for C₂₅H₂₃N₅O₃441.1801. Anal.

Found: C, 68.02; H, 5.28; N, 15.09. C₁₇H₁₅N₅O₂re-

quires C, 68.04; H, 5.25; N, 15.86%.

4.11. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-methyl-

thio-9H-purine (13)

A

solution of 2-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 1b (341 mg, 1.00 mmol) and so-

dium methythiolate (1.05 g, 15.0 mmol) in dry DMF

(8 mL) was heated at 90 ꢁC under N₂for 1.5 h and

cooled. The reaction mixture was diluted with water

(5 mL) and EtOAc (10 mL), the phases were separated,

and the aqueous phase extracted with EtOAc (4·

25 mL). The combined organic extracts were washed

with brine (2· 50 mL) and dried (MgSO₄). The product

was puriﬁed by ﬂash chromatography on silica gel elut-

ing with EtOAc/hexane (1:1); yield 255 mg (72%), pale

yellow crystals, mp 147–148 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 2.62 (s, 3H, SCH₃), 3.71 (s, 3H, OCH₃),

5.24 (s, 2H, CH₂), 6.57 (dd, J = 3.5 and 1.8 Hz, 1H,

H-4 in furyl), 6.80 (d, J = 8.7 Hz, 2H, Ar), 7.21 (d,

J = 8.7 Hz, 2H, Ar), 7.70 (m, 1H, H-5 in furyl), 7.71

(dd, J = 3.5 and 0.7 Hz, 1H, H-3 in furyl), 7.84 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 14.6 (SCH₃), 46.5

(CH₂), 55.1 (OCH₃), 112.3 (C-4 in furyl), 114.2 (CH in

Ar), 117.0 (C-3 in furyl), 125.4 (C-5), 127.1 (C-1 in

Ar), 129.4 (CH in Ar), 142.9 (C-8), 145.6 (C-6), 145.8

(C-5 in furyl), 149.7 (C-2 in furyl), 152.8 (C-4), 159.5

(C-4 in Ar), 165.8 (C-2); MS-EI m/z (rel %) 352 (56,

M⁺), 231 (8), 121 (100), 78 (4), 77 (5); Anal. Found:

C, 61.30; H, 4.56; N, 15.86. C₁₈H₁₆N₄O₂S requires C,

61.35; H, 4.58; N, 15.90%.

4.9. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-(N-meth-

ylamino)-9H-purine (11)

A

solution of 2-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 1b (112 mg, 0.33 mmol) in THF

(3 mL) and 40% methylamine in water (3 mL) was stir-

red under N₂in a sealed tube at 85 ꢁC for 15 h. After

cooling the solution was evaporated in vacuo. The prod-

uct was puriﬁed by ﬂash chromatography on silica gel

eluting with CH₂Cl₂/acetone (19:1) followed by

CH₂Cl₂/acetone (9:1); yield 95 mg (86%), oﬀ-white crys-

1

talline compound, mp 144–145 ꢁC. H NMR (CDCl₃,

300 MHz) d 3.06 (d, J = 5.1 Hz, 3H, NCH₃), 3.76 (s,

3H, OCH₃), 5.20 (s, 2H, NCH₂), 5.32 (br s, 1H, NH),

6.58 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 in furyl), 6.84

(d, J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz, 2H, Ar),

7.67 (br s, H-5 in furyl and H-8), 7.73 (dd, J = 3.5 and

0.7 Hz, 1H, H-3 in furyl); ¹³C NMR (CDCl₃, 75 MHz)

d 28.8 (NCH₃), 46.2 (NCH₂), 55.3 (OCH₃), 112.2 (C-4

in furyl), 114.2 (CH in Ar), 116.4 (C-3 in furyl), 122.4

(C-5), 127.9 (C-1 in Ar), 129.4 (CH in Ar), 140.9 (C-

8), 145.1 (C-5 in furyl), 146.5 (C-6), 150.0 (C-2 in furyl),

154.1 (C-4), 159.5 (C-4 in Ar), 160.2 (C-2); MS-EI m/z

(rel %) 335 (100, M⁺), 320 (1), 214 (3), 121 (81), 106

(1); Anal. Found: C, 64.48; H, 4.97; N, 21.27.

C₁₈H₁₇N₅O₂requires C, 64.47; H, 5.11; N, 20.88%.

4.12. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-methylsulﬁnyl-

9H-purine (14)

4.10. 2-(N,N-Dimethylamino)-6-(2-furyl)-9-(4-methoxy-

phenylmethyl)-9H-purine (12)

A solution of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-2-

methylthio-9H-purine 13a (88 mg, 0.25 mmol) in

CH₂Cl₂(2 mL) was cooled to ꢀ10 ꢁC, before a cold

solution of m-CPBA (21.6 mg, 0.125 mmol) in CH₂Cl₂

Triethylamine (1.05 mL, 7.50 mmol) was added to a

mixture of glycine methyl ester hydrochloride (471 mg,

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7155

(1 mL) was added dropwise, and the mixture was stirred

for 30 min. Additional m-CPBA (21.6 mg, 0.125 mmol)

in CH₂Cl₂(1 mL) was added and the mixture stirred

for 30 min. The solution was washed with 5% aq

Na₂S₂O₄(10 mL), satd aq NaHCO₃(10 mL), and brine

(10 mL). The dried (MgSO₄) solution was evaporated

and the product was puriﬁed by ﬂash chromatography

on silica gel eluting with EOAc/hexane (4:1) followed

by CH₂Cl₂/MeOH (19:1); yield 73 mg (79%), colorless

oil which was crystallized from EtOAc–hexane, mp

186–187 ꢁC. ¹H NMR (CDCl₃, 300 MHz) d 3.01 (s,

3H, SOCH₃), 3.77 (s, 3H, OCH₃), 5.45 (s, 2H, CH₂),

6.65 (dd, J = 3.5 and 1.7 Hz, 1H, H-4 in furyl), 6.87

(d, J = 8.7 Hz, 2H, Ar), 7.29 (d, J = 8.7 Hz, 2H, Ar),

7.77 (dd, J = 1.7 and 0.6 Hz, 1H, H-5 in furyl), 7.86

(dd, J = 3.5 and 0.6 Hz, 1H, H-3 in furyl), 8.08 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 40.7 (SOCH₃),

47.2 (CH₂), 55.3 (OCH₃), 112.8 (C-4 in furyl), 114.5

(CH in Ar), 118.7 (C-3 in furyl), 126.4 (C-1 in Ar),

128.3 (C-5), 129.8 (CH in Ar), 145.6 (C-8), 146.2 (C-

6), 146.7 (C-5 in furyl), 149.1 (C-2 in furyl), 153.0 (C-

4), 159.9 (C-4 in Ar), 166.8 (C-2); MS-EI m/z (rel %)

368 (6, M⁺), 352 (9), 322 (3), 249 (13), 121 (100); Anal.

Found: C, 58.64 H, 4.57; N, 15.05. C₁₈H₁₆N₄O₃S re-

quires C, 58.68; H, 4.38; N, 15.21%.

(8 mL) was heated at 50 ꢁC until the purine dissolved

and cooled to ambient temperature. Tetrabutylammo-

nium hydroxide (670 lL, 1.0 mmol, 1.5 M in water)

was added drop wise over 20 min. The resulting mixture

was stirred at ambient temperature for 48 h. Satd aq

NH₄Cl (20 mL) and water (20 mL) were added and

the mixture extracted with CH₂Cl₂(4· 40 mL). The

combined organic extracts were washed with water

(20 mL) and brine (20 mL), dried (MgSO₄), and evapo-

rated in vacuo. The product was puriﬁed by ﬂash chro-

matography on silica gel eluting with CH₂Cl₂/EtOH

(19:1) followed by CH₂Cl₂/EtOH (9:1); yield 116 mg

(72%), pale yellow crystalline compound, mp 239–

1

240 ꢁC. H NMR (DMSO-d₆, 300 MHz) d 3.72 (s, 3H,

OCH₃), 5.24 (s, 2H, NCH₂), 6.80 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in furyl), 6.90 (d, J = 8.7 Hz, 2H, Ar),

7.29 (d, J = 8.7 Hz, 2H, Ar), 7.79 (dd, J = 3.5 and

0.7 Hz, H-3 in furyl), 7.90 (dd, J = 1.7 and 0.7 Hz, H-5

in furyl), 8.37 (s, 1H, H-8), 11.8 (br s, 1H, NH/OH);

¹³C NMR (CDCl₃, 75 MHz) d 46.1 (NCH₂), 55.2

(OCH₃), 113.4 (C-4 in furyl), 114.4 (C-3 in Ar), 118.8

(C-5), 120.1 (C-3 in furyl), 127.0 (C-1 in Ar), 129.5 (C-

2 in Ar), 137.4 (C-6/C-2), 143.7 (C-2 in furyl), 145.8

(C-8), 147.8 (C-5 in furyl), 158.2 (C-2/C-6), 159.5 (C-

4), 159.7 (C-4 in Ar); MS-EI m/z (rel %) 322 (39, M⁺),

121 (100), 91 (3), 78 (6), 77 (6); HRMS: Found

322.1069 Calcd for C₁₇H₁₄N₄O₃322.1066.

4.13. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-methyl-

sulfonyl-9H-purine (15)

4.15. 6-(2-Furyl)-2-methoxy-9-(4-methoxyphenylmethyl)-

9H-purine (18a)

A solution of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-2-

methylthio-9H-purine 13a (70 mg, 0.20 mmol) in

CH₂Cl₂(3 mL) was cooled to 0 ꢁC, before a cold solu-

tion of m-CPBA (77.7 mg, 0.45 mmol) in CH₂Cl₂

(3 mL) was added dropwise. The mixture was stirred

at ambient temperature for 21 h before cold 10% aq

Na₂S₂O₄(6 mL) was added. After 15 min, the mixture

was diluted with CH₂Cl₂(10 mL), the phases were sepa-

rated, and the organic layer was washed with satd aq

NaHCO₃(2· 10 mL) and brine (20 mL). The dried

(MgSO₄) solution was evaporated and the product was

puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/hexane (4:1); yield 50 mg (65%), colorless

crystalline compound, mp 184–185 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 3.45 (s, 3H, SO₂CH₃), 3.76 (s,

3H, OCH₃), 5.41 (s, 2H, CH₂), 6.65 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in furyl), 6.85 (d, J = 8.7 Hz, 2H, Ar),

7.27 (d, J = 8.7 Hz, 2H, Ar), 7.78 (m, H-5 in furyl),

7.84 (br d, J = 3.5 Hz, 1H, H-3 in furyl), 8.17 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 39.7 (SO₂CH₃),

47.5 (CH₂), 55.3 (OCH₃), 112.9 (C-4 in furyl), 114.6

(CH in Ar), 119.1 (C-3 in furyl), 126.1 (C-1 in Ar),

129.2 (C-5), 129.8 (CH in Ar), 146.2 (C-6), 146.8 (C-

8), 147.2 (C-5 in furyl), 149.0 (C-2 in furyl), 152.2 (C-

4), 159.5 (C-2), 159.9 (C-4 in Ar); MS-EI m/z (rel %)

384 (45, M⁺), 369 (3), 305 (2), 121 (100), 91 (2); Anal.

Found: C, 56.32; H, 4.26; N, 14.33. C₁₈H₁₆N₄O₄S re-

quires C, 56.24; H, 4.20; N, 14.57%.

A

mixture of 2-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 1b (299 mg, 0.88 mmol) in a

0.7 M solution of sodium methoxide in methanol

(15 mL) was stirred at reﬂux under N₂-atm for 4 h,

cooled, and poured into cold satd aq NH₄Cl. Most of

the methanol was removed by evaporation in vacuo

and the aqueous mixture was extracted with EtOAc

(5· 20 mL). The combined organic layers were dried

(MgSO₄) and evaporated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/hexane (2:1); yield 223 mg (75%), colorless

1

crystals, mp 167–169 ꢁC. H NMR (CDCl₃, 200 MHz)

d 3.74 (s, 3H, CH₃), 4.08 (s, 3H, CH₃), 5.25 (s, 2H,

CH₂), 6.60 (m, 1H, H-4 in furyl), 6.83 (d, J = 8.6 Hz,

2H, Ar), 7.24 (d, J = 8.6 Hz, 2H, Ar), 7.71 (br s, 1H, fur-

yl), 7.72 (s, 1H, furyl/H-8), 7.84 (s, 1H, furyl/H-8); ¹³C

NMR (CDCl₃, 50 MHz) d 46.6 (CH₂), 55.1 (CH₃),

55.3 (CH₃), 112.3 (C-4 in furyl), 114.3 (CH in Ar),

116.7 (C-3 in furyl), 124.6 (C-5), 127.2 (C-1 in Ar),

129.3 (CH in Ar), 143.0 (C-8), 145.9 (C-5 in furyl),

147.0 (C-2 in furyl/C-6), 150.2 (C-2 in furyl/C-6), 154.2

(C-4), 159.6 (C-4 in Ar), 162.0 (C-2); MS-EI m/z (rel

%) 336 (56, M⁺), 321 (2), 121 (100), 78 (4), 77 (4); Anal.

Found: C, 64.06; H, 4.73; N, 16.27. C₁₈H₁₆N₄O₃re-

quires C, 64.28; H, 4.80; N, 16.66%.

4.16. General procedure for the synthesis of 2-alkoxyp-

urines 18 from 2-nitropurine (16)

4.14. 6-(2-Furyl)-2-hydroxy-9-(4-methoxyphenylmethyl)-

9H-purine (17)

A mixture of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-2-

nitro-9H-purine 16 (88 mg, 0.25 mmol) and KF or

KCN (amount see Table 1) in the desired alcohol

A mixture of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-2-

nitro-9H-purine 16 (176 mg, 0.50 mmol) in THF

7156

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

(10 mL) was stirred at the temperature and for the time

given in Table 1. The reaction mixture was evaporated,

and the product was puriﬁed by ﬂash chromatography

on silica gel eluting with CH₂Cl₂/acetone (19:1). Yields,

see Table 1.

4.16.4. 2-Butoxy-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (18e). Colorless crystals, mp 113 ꢁC. ¹H

NMR (CDCl₃, 300 MHz) d 0.94 (t, J = 7.4 Hz, 3H,

CH₃), 1.43–1.56 (m, 2H, CH₂), 1.76–1.85 (m, 2H,

CH₂), 3.72 (s, 3H, OCH₃), 4.43 (t, J = 6.7 Hz, 2H,

OCH₂), 5.22 (s, 2H, NCH₂), 6.56 (dd, J = 3.5 and

1.8 Hz, 1H, H-4 in furyl), 6.80 (d, J = 8.7 Hz, 2H, Ar),

7.20 (d, J = 8.7 Hz, 2H, Ar), 7.68–7.71 (m, 2H, H-3

and H-5 in furyl), 7.81 (s, 1H, H-8); ¹³C NMR (CDCl₃,

75 MHz) d 13.8 (CH₃), 19.1 (CH₂), 30.9 (CH₂), 46.4

(NCH₂), 55.1 (OCH₃), 67.6 (OCH₂), 112.2 (C-4 in fur-

yl), 114.2 (CH in Ar), 116.6 (C-3 in furyl), 124.4 (C-5),

127.3 (C-1 in Ar), 129.3 (CH in Ar), 142.9 (C-8), 145.7

(C-5 in furyl), 147.0 (C-6), 150.1 (C-2 in furyl), 154.2

(C-4), 159.5 (C-4 in Ar), 161.8 (C-2); MS-EI m/z (rel

%) 378 (21, M⁺), 349 (6), 335 (6), 322 (16), 121 (100);

Anal. Found: C, 66.37; H, 5.85; N, 14.79. C₂₁H₂₂N₄O₃

requires C, 66.65; H, 5.86; N, 14.81%.

4.16.1. 2-Ethoxy-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (18b). Colorless crystalline compound, mp

137–138 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 1.47 (t,

J = 7.1 Hz, 3H, CH₃), 3.77 (s, 3H, OCH₃), 4.53 (q,

J = 7.1 Hz, 2H, OCH₂), 5.27 (s, 2H, NCH₂), 6.61

(dd, J = 3.3 and 1.9 Hz, 1H, H-4 in furyl), 6.85 (d,

J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz, 2H, Ar),

7.72–7.73 (m, 2H, H-3 and H-5 in furyl), 7.85 (s,

1H, H-8); ¹³C NMR (CDCl₃, 75 MHz)

d 14.5

(CH₃), 46.5 (NCH₂), 55.2 (OCH₃), 63.6 (OCH₂),

112.3 (C-4 in furyl), 114.3 (CH in Ar), 116.6 (C-3

in furyl), 124.5 (C-5), 127.3 (C-1 in Ar), 129.4 (CH

in Ar), 142.9 (C-8), 145.9 (C-5 in furyl), 147.1 (C-

6), 150.2 (C-2 in furyl), 154.3 (C-4), 159.6 (C-4 in

Ar), 161.7 (C-2); MS-EI m/z (rel %) 350 (41, M⁺),

335 (12), 322 (3), 321 (3), 121 (100); Anal. Found:

C, 64.83; H, 5.31; N, 15.77. C₁₉H₁₈N₄O₃requires

C, 65.13; H, 5.18; N, 15.99%.

4.16.5. 2-Benzyloxy-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (18f). Colorless crystalline compound, mp

122 ꢁC. ¹H NMR (CDCl₃, 300 MHz) d 3.74 (s, 3H,

OCH₃), 5.24 (s, 2H, NCH₂), 5.54 (s, 2H, OCH₂), 6.60

(dd, J = 3.5 and 1.8 Hz, 1H, H-4 in furyl), 6.81 (d,

J = 8.7 Hz, 2H, Ar), 7.19 (d, J = 8.7 Hz, 2H, Ar),

7.27–7.36 (m, 3H, H-3 and H-4 in Ph), 7.50–7.55 (m,

2H, H-2 in Ph), 7.71–7.75 (m, 2H, H-3 and H-5 in furyl),

7.84 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d 46.5

(NCH₂), 55.2 (OCH₃), 69.4 (OCH₂), 112.3 (C-4 in fur-

yl), 114.3 (CH in Ar), 116.8 (C-3 in furyl), 124.7 (C-5),

127.3 (C-1 in Ar), 127.8 (CH in Ph), 128.3 (CH in Ph),

129.3 (CH in Ar), 136.9 (C-1 in Ph), 143.1 (C-8), 145.9

(C-5 in furyl), 147.1 (C-6), 150.1 (C-2 in furyl), 154.2

(C-4), 159.6 (C-4 in Ar), 161.4 (C-2); MS-EI m/z (rel

%) 412 (68, M⁺), 335 (9), 306 (22), 291 (47), 121 (100);

Anal. Found: C, 69.97; H, 4.78; N, 14.01. C₂₃H₁₈N₄O₃

requires C, 69.89; H, 4.89; N, 13.58%.

4.16.2. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-propoxy-

9H-purine (18c). Colorless oil. Evaporation from acetone–

hexane gave colorless crystals, mp 119 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 1.06 (t, J = 7.4 Hz, 3H, CH₃), 1.81–

1.93 (m, 2H, CH₂), 3.75 (s, 3H, OCH₃), 4.41 (t,

J = 6.8 Hz, 2H, OCH₂), 5.26 (s, 2H, NCH₂), 6.59 (dd,

J = 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.84 (d, J = 8.8 Hz,

2H, Ar), 7.23 (d, J = 8.8 Hz, 2H, Ar), 7.71–7.73 (m, 2H,

H-3 and H-5infuryl), 7.83(s, 1H, H-8); ¹³C NMR (CDCl₃,

75 MHz) d 10.6 (CH₃), 22.2 (CH₂), 46.5 (NCH₂), 55.3

(OCH₃), 69.5 (OCH₂), 112.3 (C-4 in furyl), 114.3 (CH in

Ar), 116.7 (C-3 in furyl), 124.5 (C-5), 127.3 (C-1 in Ar),

129.4 (CH in Ar), 142.9 (C-8), 145.8 (C-5 in furyl), 147.1

(C-6), 150.2 (C-2 in furyl), 154.3 (C-4), 159.6 (C-4 in Ar),

161.9 (C-2); MS-EI m/z (rel %) 364 (27, M⁺), 335 (9), 334

(3), 322 (14), 121 (100); Anal. Found: C, 66.15; H, 5.53;

N, 15.29. C₂₀H₂₀N₄O₃requires C, 65.92; H, 5.53; N,

15.38%.

4.16.6. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-phenoxy-

9H-purine (18g). After completing reaction, the mixture

was cooled to ambient temperature and CH₂Cl₂(50 mL)

was added to the residue. The solution was washed with

satd aq Na₂CO₃(4· 25 mL), water (25 mL), brine (2·

25 mL), dried (MgSO₄), and evaporated in vacuo. The

residue was dissolved in CH₂Cl₂(50 mL), washed with

aq NaOH (4· 25 mL, pH 10), water (25 mL), and brine

(25 mL), dried (MgSO₄), and evaporated in vacuo. The

product was puriﬁed by ﬂash chromatography on silica

gel eluting with CH₂Cl₂followed by CH₂Cl₂/acetone

(19:1) and CH₂Cl₂/acetone (9:1). Colorless crystalline

compound, mp 133–135 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 3.73 (s, 3H, OCH₃), 5.11 (s, 2H, NCH₂),

6.56 (dd, J = 3.5 and 1.7 Hz, 1H, H-4 in furyl), 6.78

(d, J = 8.8 Hz, 2H, Ar), 7.14 (d, J = 8.8 Hz, 2H, Ar),

7.19–7.28 (m, 3H, Ph), 7.36–7.43 (m, 2H, Ph), 7.65

(dd, J = 3.5 and 0.8 Hz, 1H, H-3 in furyl), 7.69 (dd,

J = 1.7 and 0.8 Hz, 1H, H-5 in furyl), 7.89 (s, 1H, H-

8); ¹³C NMR (CDCl₃, 75 MHz) d 46.8 (NCH₂), 55.2

(OCH₃), 112.4 (C-4 in furyl), 114.2 (CH in Ar), 117.1

(C-3 in furyl), 121.5 (CH in Ph), 124.7 (CH in Ph),

125.2 (C-5), 126.9 (C-1 in Ar), 129.1 (CH in Ph), 129.7

(CH in Ar), 143.5 (C-8), 146.1 (C-5 in furyl), 147.3 (C-

6), 149.9 (C-2 in furyl), 153.5 (C-1 in Ph), 154.0 (C-4),

4.16.3. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-isop-

ropoxy-9H-purine (18d). Oﬀ-white crystalline com-

1

pound, mp 145–146 ꢁC. H NMR (CDCl₃, 300 MHz)

d 1.42 (d, J = 6.2 Hz, 6H, 2· CH₃), 3.75 (s, 3H,

OCH₃), 5.24 (s, 2H, NCH₂), 5.40 [sept, J = 6.2 Hz,

1H, CH(CH₃)₂], 6.61 (dd, J = 3.4 and 1.8 Hz, 1H,

H-4 in furyl), 6.83 (d, J = 8.7 Hz, 2H, Ar), 7.23 (d,

J = 8.7 Hz, 2H, Ar), 7.70–7.71 (m, 2H, H-3 and H-5

in furyl), 7.82 (s, 1H, H-8); ¹³C NMR (CDCl₃,

75 MHz)

d 21.9 (2· CH₃), 46.5 (NCH₂), 55.2

(OCH₃), 70.4 [CH(CH₃)₂], 112.2 (C-4 in furyl), 114.3

(CH in Ar), 116.5 (C-3 in furyl), 124.3 (C-5), 127.3

(C-1 in Ar), 129.4 (CH in Ar), 142.8 (C-8), 145.8

(C-5 in furyl), 147.2 (C-6), 150.3 (C-2 in furyl),

154.3 (C-4), 159.6 (C-4 in Ar), 161.3 (C-2); MS-EI

m/z (rel %) 364 (26, M⁺), 349 (14), 322 (12), 306

(9), 121 (100); Anal. Found: C, 65.80; H, 5.41; N,

15.54. C₂₀H₂₀N₄O₃requires C, 65.92; H, 5.53; N,

15.38%.

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7157

159.6 (C-4 in Ar), 161.1 (C-2); MS-EI m/z (rel %) 398

(52, M⁺), 381 (1), 278 (2), 277 (7), 121 (100); Anal.

Found: C, 69.49; H, 4.67; N, 13.84. C₂₃H₁₈N₄O₃re-

quires C, 69.34; H, 4.55; N, 14.06%.

the top of a silica gel column. The product was puriﬁed

by ﬂash chromatography eluting with CH₂Cl₂/acetone

(19:1); yield 133 mg (80%), colorless oil, crystallized

from CH₂Cl₂-hexane, mp 119–120 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 1.43 (t, J = 7.6 Hz, 3H, CH₃),

3.13 (q, J = 7.6 Hz, 2H, CH₂) 3.74 (s, 3H, OCH₃), 5.32

(s, 2H, NCH₂), 6.60 (dd, J = 3.5 and 1.7 Hz, 1H, H-4

in furyl), 6.83 (d, J = 8.7 Hz, 2H, Ar), 7.25 (d,

J = 8.7 Hz, 2H, Ar), 7.70–7.72 (m, 1H, H-5 in furyl),

7.82 (br d, J = 3.5 Hz, 1H, H-3 in furyl), 7.93 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 13.2 (CH₃), 32.6

(CH₂), 46.5 (NCH₂), 55.2 (OCH₃), 112.3 (C-4 in furyl),

114.3 (CH in Ar), 117.0 (C-3 in furyl), 126.3 (C-5), 127.3

(C-1 in Ar), 129.5 (CH in Ar), 143.6 (C-8), 145.4 (C-6),

145.5 (C-5 in furyl), 149.8 (C-2 in furyl), 152.6 (C-4),

159.6 (C-4 in Ar), 166.6 (C-2); MS-EI m/z (rel %) 334

(63, M⁺), 319 (4), 121 (100), 78 (5), 77 (5); Anal. Found:

C, 68.08; H, 5.39; N, 16.55. C₁₉H₁₈N₄O₂requires C,

68.25; H, 5.43; N, 16.76%.

4.17. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-methyl-

9H-purine (19a)

Zinc bromide (1.40 mL, 1.44 mmol, 1.03 M in THF) was

added dropwise to a stirred solution of methyllithium

(1.0 mL, 1.4 mmol, 1.4 M in diethyl ether) and THF

(2 mL) at ꢀ78 ꢁC under N₂. After stirring for 1 h, the

cooling bath was removed and the mixture was stirred

at ambient temperature for 20 min. A solution of 2-

chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-pur-

ine 1b (248 mg, 0.73 mmol), in dry THF (8 mL) was

added followed by a solution of tetrakis(triphenylphos-

phine)palladium(0) [generated in situ from tris-

(diphenylmethylideneacetone)dipalladium chloroform

adduct (16 mg, 0.016 mmol) and triphenylphosphine

(31 mg, 0.12 mmol)] in dry THF (4 mL). The resulting

mixture was heated at reﬂux for 21 h and cooled to

ambient temperature. Satd aq NH₄Cl (10 mL) was

added and the aq phase was extracted with EtOAc (2·

25 mL). The combined organic extracts were washed

with brine (2· 20 mL), dried (MgSO₄), and evaporated.

The product was puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/hexane (2:1); yield

189 mg (81%), colorless crystals, mp 127–130 ꢁC. ¹H

NMR (CDCl₃, 200 MHz) d 2.85 (s, 3H, CH₃), 3.76 (s,

3H, OCH₃), 5.32 (s, 2H, CH₂), 6.61 (dd, J = 3.6 and

1.8 Hz, 1H, H-4 in furyl), 6.85 (d, J = 8.8 Hz, 2H, Ar),

7.23 (d, J = 8.8 Hz, 2H, Ar), 7.72 (br d, J = 3.6 Hz,

1H, H-3 in furyl), 7.81 (s, 1H, H-5 in furyl/H-8), 7.90

(s, 1H, H-5 in furyl/H-8); ¹³C NMR (CDCl₃, 50 MHz)

d 26.3 (CH₃), 46.5 (CH₂), 55.3 (OCH₃), 112.4 (C-4 in

furyl), 114.4 (CH in Ar), 117.1 (C-3 in furyl), 126.3

(C-5), 127.2 (C-1 in Ar), 129.3 (CH in Ar), 143.6 (C-

8), 145.48 (C-5 in furyl), 145.54 (C-6), 149.7 (C-2 in fur-

yl), 152.6 (C-4), 159.6 (C-4 in Ar), 162.4 (C-2); MS-EI m/

z (rel %) 320 (47, M⁺), 305 (3), 122 (8); Anal. Found: C,

67.29; H, 4.83; N 16.92. C₁₈H₁₆N₄O₃requires C, 67.49;

H, 5.03; N, 17.49%.

4.19. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-(1-methyl-

ethyl)-9H-purine (19c)

The title compound was prepared by Negishi coupling

between 1-methylethylzinc bromide (generated from 1-

methylethylmagnesium bromide 327 lL, 0.50 mmol,

1.53 M in THF) and 2-chloro-6-(2-furyl)-9-(4-methoxy-

phenylmethyl)-9H-purine 1b (85 mg, 0.25 mmol) as de-

scribed for compound 19b above. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/hexane (2:1); yield 66 mg (76%), oﬀ-white

crystalline solid, mp 123 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 1.47 (d, J = 6.9 Hz, 6H, 2· CH₃), 3.39 [sept,

J = 6.9 Hz, 1H, CH(CH₃)₂], 3.75 (s, 3H, OCH₃), 5.33 (s,

2H, NCH₂), 6.60 (dd, J = 3.5 and 1.7 Hz, 1H, H-4 in

furyl), 6.84 (d, J = 8.7 Hz, 2H, Ar), 7.29 (d,

J = 8.7 Hz, 2H, Ar), 7.72 (dd, J = 1.6 and 0.7 Hz, 1H,

H-5 in furyl), 7.77 (dd, J = 3.5 and 0.7 Hz, 1H, H-3 in

furyl), 7.94 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz)

d 22.2 (CH₃), 37.6 (CH), 46.6 (NCH₂), 55.2 (OCH₃),

112.2 (C-4 in furyl), 114.3 (CH in Ar), 116.4 (C-3 in fur-

yl), 126.5 (C-5), 127.5 (C-1 in Ar), 129.5 (CH in Ar),

143.6 (C-8), 145.5 (C-6), 145.6 (C-5 in furyl), 150.4 (C-

2 in furyl), 152.7 (C-4), 159.6 (C-4 in Ar), 170.0 (C-2);

MS-EI m/z (rel %) 348 (51, M⁺), 333 (31), 320 (7), 149

(3), 121 (100); Anal. Found: C, 68.82; H, 5.77; N,

16.14 C₂₀H₂₀N₄O₂requires C, 68.95; H, 5.79; N,

16.08%.

4.18. 2-Ethyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-

purine (19b)

ZnBr₂(1.0 mL, 1.0 mmol, 1.0 M in THF) was added to

[1,1-bis(diphenylphosphino) ferrocene]dichloro-palla-

dium(II) complex with CH₂Cl₂(1:1) (20 mg,

0.025 mmol). After cooling to ꢀ78 ꢁC, ethylmagnesium

bromide (610 lL, 0.50 mmol, 0.82 M in THF) was

added dropwise over 15 min, and the resulting mixture

was stirred for an additional 15 min at ꢀ78 ꢁC before

a solution of 2-chloro-6-(2-furyl)-9-(4-methoxyphenylm-

ethyl)-9H-purine 1b (170 mg, 0.50 mmol) in THF (5 mL)

was added. After 1 h, the mixture was allowed to reach

ambient temperature and stirred for 15 h. Satd aq

NH₄Cl (20 mL) was added and the resulting mixture

was extracted with EtOAc (3· 30 mL). The organic

phase was washed with water (30 mL) and brine

(30 mL). The dried (MgSO₄) solution was evaporated

together with a small amount of silica and added at

4.20. 2-n-Butyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (19d)

The title compound was prepared by Negishi coupling

between n-butylzinc bromide (generated from n-BuLi,

280 lL, 0.50 mmol, 1.80 M in hexane) and 2-chloro-6-

(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

1b

(85 mg, 0.25 mmol) as described for compound 19b

above. The product was puriﬁed by ﬂash chromatogra-

phy on silica gel eluting with EtOAc/hexane (2:1); yield

1

39 mg (43%), colorless crystalline solid, mp 103 ꢁC. H

NMR (CDCl₃, 300 MHz) d 0.96 (t, J = 7.3 Hz, 3H,

CH₃), 1.42–1.49 (m, 2H, CH₂) 1.85–1.93 (m, 2H,

CH₂), 3.09–3.14 (m, 2H, CH₂), 3.76 (s, 3H, OCH₃),

7158

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

5.33 (s, 2H, NCH₂), 6.61 (dd, J = 3.5 and 1.7 Hz, 1H, H-

4 in furyl), 6.85 (d, J = 8.7 Hz, 2H, Ar), 7.26 (d,

J = 8.7 Hz, 2H, Ar), 7.73 (m, 1H, H-5 in furyl), 7.84

(br d, J = 3.5 Hz, 1H, H-3 in furyl), 7.93 (s, 1H, H-8);

¹³C NMR (CDCl₃, 75 MHz) d 14.0 (CH₃), 22.5 (CH₂),

31.2 (CH₂), 39.2 (CH₂), 46.6 (NCH₂), 55.2 (OCH₃),

112.4 (C-4 in furyl), 114.3 (CH in Ar), 117.0 (C-3 in fur-

yl), 126.3 (C-5), 127.3 (C-1 in Ar), 129.5 (CH in Ar),

143.7 (C-8), 145.5 (C-6), 145.6 (C-5 in furyl), 149.8 (C-

2 in furyl), 152.6 (C-4), 159.6 (C-4 in Ar), 165.9 (C-2);

MS-EI m/z (rel %) 362 (7,M⁺), 347 (4), 333 (9), 320

(83), 121 (100); Anal. Found: C, 70.01; H, 6.25; N,

15.52. C₂₁H₂₂N₄O₂requires C, 69.59; H, 6.12; N,

15.46%.

kis(triphenylphosphine)palladium(0) [generated in situ

from tris(dibenzylideneacetone)dipalladium (5.7 mg,

6.25 lmol)

and

triphenylphosphine

(13.1 mg,

0.050 mmol)] in THF (1 mL) was added. The resulting

mixture was then reﬂuxed for 21 h, cooled, and worked

up as described for compound 19b above. The product

was puriﬁed by ﬂash chromatography on silica gel elut-

ing with CH₂Cl₂/acetone (19:1); yield 57 mg (61%),

colorless oil. Evaporation from acetone–hexane gave

colorless crystalline compound, mp 114–115 ꢁC. ¹H

NMR (CDCl₃, 300 MHz) d 1.63–1.79 (m, 2H, CH₂),

1.79–1.95 (m, 2H, CH₂), 1.95–2.08 (m, 2H, CH₂),

2.08–2.21 (m, 2H, CH₂), 3.77 (s, 3H, OCH₃), 5.33 (s,

2H, NCH₂), 6.61 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 in

furyl), 6.85 (d, J = 8.7 Hz, 2H, Ar), 7.28 (d, J = 8.7 Hz,

2H, Ar), 7.73 (dd, J = 1.8 and 0.7 Hz, H-5 in furyl),

7.76 (br d, J = 3.5 Hz, H-3 in furyl), 7.94 (s, 1H, H-8);

¹³C NMR (CDCl₃, 75 MHz) d 26.0 (2· CH₂), 33.5 (2·

CH₂), 46.6 (NCH₂), 48.9 (CH), 55.3 (OCH₃), 112.3 (C-

4 in furyl), 114.4 (CH in Ar), 116.5 (C-3 in furyl),

126.5 (C-5), 127.6 (C-1 in Ar), 129.6 (CH in Ar), 143.6

(C-8), 145.5 (C-5 in furyl), 150.4 (C-2 in furyl), 152.8

(C-4), 159.7 (C-4 in Ar), 169.1 (C-2), C-6 was hidden;

MS-EI m/z (rel %) 374 (44, M⁺), 346 (27), 333 (75),

253 (5), 225 (4), 121 (100); Anal. Found: C, 70.53; H,

5.98; N, 15.01. C₂₂H₂₂N₄O₂requires C, 70.57; H, 5.92;

N, 14.96%.

4.21. 2-Cyclopropyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (19e)

The title compound was prepared by Negishi coupling

between cyclopropylzinc bromide (generated from

cyclopropylmagnesium bromide 1.14 mL, 0.44 M,

0.50 mmol) and 2-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 1b (85 mg, 0.25 mmol) as de-

scribed for compound 19b above. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with CH₂Cl₂/acetone (19:1); yield 62 mg (72%), colorless

oil. Evaporation from acetone–hexane gave colorless

crystalline compound, mp 115–116 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 1.02–1.09 (m, 2H, CH₂), 1.18–

1.25 (m, 2H, CH₂), 2.42 (tt, J = 8.1 and 4.8 Hz, 1H,

CH), 3.76 (s, 3H, OCH₃), 5.27 (s, 2H, NCH₂), 6.60

(dd, J = 3.4 and 1.7 Hz, 1H, H-4 in furyl), 6.84 (d,

J = 8.7 Hz, 2H, Ar), 7.24 (d, J = 8.7 Hz, 2H, Ar),

7.71–7.74 (m, 2H, H-5 and H-3 in furyl), 7.89 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 10.7 (2· CH₂),

18.3 (CH), 46.5 (NCH₂), 55.2 (OCH₃), 112.3 (C-4 in fur-

yl), 114.3 (CH in Ar), 116.4 (C-3 in furyl), 126.4 (C-5),

127.4 (C-1 in Ar), 129.5 (CH in Ar), 143.3 (C-8), 145.4

(C-6), 145.5 (C-5 in furyl), 150.3 (C-2 in furyl), 152.9

(C-4), 159.6 (C-4 in Ar), 166.5 (C-2); MS-EI m/z (rel

%) 346 (78, M⁺), 331 (4), 239 (2), 225 (6), 121 (100);

Anal. Found: C, 69.37; H, 5.18; N, 16.12. C₂₀H₁₈N₄O₂

requires C, 69.35; H, 5.24; N, 16.17%.

4.23. 2-Ethenyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (19g)

The title compound was prepared by Stille coupling

between 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmeth-

yl)-9H-purine 1b (341 mg, 1.00 mmol) and ethenyl(trib-

utyl)stannane (350 lL, 1.20 mmol) as described for

compound 4 above. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/hex-

ane (2:1); yield 254 mg (76%), colorless crystals, mp

1

94–95 ꢁC. H NMR (CDCl₃, 300 MHz) d 3.79 (s, 3H,

OCH₃), 5.38 (s, 2H, NCH₂), 5.74 (dd, J = 10.5 and

1.9 Hz, 1H, @CH₂), 6.65 (dd, J = 3.5 and 1.8 Hz, 1H,

H-4 in furyl), 6.73 (dd, J = 17.3 and 1.9 Hz, 1H,

@CH₂), 6.88 (d, J = 8.7 Hz, 2H, Ar), 7.07 (dd, J = 17.3

and 10.5 Hz, 1H, @CH), 7.30 (d, J = 8.7 Hz, 2H, Ar),

7.77 (dd, J = 1.8 and 0.7 Hz, 1H, H-5 in furyl), 7.83

(dd, J = 3.5 and 0.7 Hz, 1H, H-3 in furyl), 7.99 (s, 1H,

H-8); ¹³C NMR (CDCl₃, 75 MHz) d 46.6 (NCH₂),

55.2 (OCH₃), 112.4 (C-4 in furyl), 114.4 (CH in Ar),

116.8 (C-3 in furyl), 122.4 (@CH₂), 127.1 (C-5), 127.3

(C-1 Ar), 129.5 (CH in Ar), 136.9 (@CH), 144.4 (C-8),

145.6 (C-5 in furyl), 145.6 (C-6), 150.1 (C-2 in furyl),

152.7 (C-4), 158.9 (C-2), 159.7 (C-4 in Ar); MS-EI m/z

(rel %) 332 (60, M⁺), 317 (3), 121 (100), 78 (6), 77 (6);

Anal. Found: C, 69.01; H, 4.84; N, 16.67. C₁₉H₁₆N₄O₂

requires C, 68.66; H, 4.85; N, 16.86%.

4.22. 2-Cyclopentenyl-6-(2-furyl)-9-(4-methoxyphenyl-

methyl)-9H-purine (19f)

A round-bottomed ﬂask with condenser was charged

with magnesium turnings (243 mg, 10.0 mmol) and a

few crystals of I₂. A solution of cyclopentyl bromide

[2 mL of a solution of cyclopentyl bromide (1.49 g,

10.0 mmol) in dry THF (10 mL)] was added. The stirred

mixture was heated gently to start the reaction. The rest

of the cyclopentyl bromide solution was added at a rate

to keep gentle reﬂux. The mixture was stirred for addi-

tional 2 h, cooled, and ﬁltered under N₂, and the result-

ing cyclopentylmagnesium bromide was titrated.

Cyclopentylmagnesium bromide (1.00 mL, 0.50 M,

0.50 mmol) was cooled to 0 ꢁC and ZnBr₂(500 lL,

1.00 M, 0.50 mmol) was added. The mixture was

stirred 1 h at room temperature before a solution of 2-

chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

1b (85 mg, 0.25 mmol) in dry THF (1.5 mL) and tetra-

4.24. 2-(1-Ethoxyvinyl)-6-(2-furyl)-9-(4-methoxyphenyl-

methyl)-9H-purine (19h)

The title compound was prepared by Stille coupling

between 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmeth-

yl)-9H-purine 1b (170 mg, 0.50 mmol) and 1-(ethoxyvi-

nyl)tributylstannane (203 lL, 0.60 mmol) as described

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7159

for compound 4 above. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/

hexane (1:1); yield 155 mg (82%), colorless powdery

crystals, mp 144–145 ꢁC. H NMR (CDCl₃, 200 MHz)

1.8 Hz, 1H, H-4 in 2-furyl), 6.63 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in 6-furyl), 6.85 (d, J = 8.7 Hz, 2H,

Ar), 7.27 (d, J = 8.7 Hz, 2H, Ar), 7.39 (dd, J = 3.4 and

0.7 Hz, 1H, H-3 in 2-furyl), 7.63–7.64 (m, H-5 in 2-fur-

yl), 7.75–7.76 (m, H-5 in 6-furyl), 7.83 (dd, J = 3.5 and

0.6 Hz, 1H, H-3 in 6-furyl), 7.94 (s, 1H, H-8); ¹³C

NMR (CDCl₃, 75 MHz) d 46.7 (CH₂), 55.2 (OCH₃),

112.0 (C-4 in 2-furyl), 112.4 (C-4 in 6-furyl), 112.7 (C-

3 in 2-furyl), 114.4 (CH in Ar), 117.2 (C-3 in 6-furyl),

126.7 (C-5), 127.0 (C-1 in Ar), 129.6 (CH in Ar), 144.3

(C-8), 144.6 (C-5 in 2-furyl), 145.9 (C-5 in 6-furyl),

146.1 (C-2/C-4/C-6), 149.9 (C-2 in 6-furyl), 152.3 (C-2

in 2-furyl), 152.6 (C-2/C-4/C-6), 152.7 (C-4/C-2/C-6),

159.7 (C-4 in Ar); MS-EI m/z (rel %) 372 (55, M⁺),

357 (2), 121 (100), 78 (6), 77 (6); Anal. Found: C,

67.89; H, 4.50; N, 14.89. C₂₁H₁₆N₄O₃requires C,

67.73; H, 4.33; N, 15.05%.

1

d 1.53 (t, J = 7.0 Hz, 3H, CH₃), 3.77 (s, 3H, OCH₃),

4.06 (q, J = 7.0 Hz, 2H, OCH₂), 4.63 (d, J = 1.9 Hz,

1H, =CH₂), 5.38 (s, 2H, NCH₂), 5.77 (d, J = 1.9 Hz,

1H, @CH₂), 6.61 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 fur-

yl), 6.86 (d, J = 8.7 Hz, 2H, Ar), 7.29 (d, J = 8.7 Hz,

2H, Ar), 7.73 (m, 1H, H-5 in furyl), 7.78 (dd, J = 3.5

and 0.7 Hz, 1H, H-3 in furyl), 7.96 (s, 1H, H-8); ¹³C

NMR (CDCl₃, 125 MHz) d 14.4 (CH₃), 46.8 (NCH₂),

55.2 (OCH₃), 64.1 (OCH₂), 89.4 (=CH₂), 112.3 (C-4 in

furyl), 114.4 (CH in Ar), 116.8 (C-3 in furyl), 127.0

(C-1 in Ar), 127.4 (C-5), 129.7 (CH in Ar), 144.6 (C-

8), 145.6 (C-6), 145.7 (C-5 in furyl), 150.1 (C-2 in furyl),

152.6 (C-4), 156.2 (C-2), 157.9 (@CO), 159.7 (C-4 in Ar);

MS-EI m/z (rel %) 376 (4, M⁺), 362 (16), 361 (69), 332

(15), 331 (15), 121 (100); Anal. Found: C, 67.16; H,

5.50; N, 14.78. C₂₁H₂₀N₄O₃requires C, 67.01; H, 5.36;

N, 14.88%.

4.27. 2-Acetyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (20)

A mixture of 2-(1-ethoxyvinyl)-6-(2-furyl)-9-(4-meth-

oxyphenylmethyl)-9H-purine 19h (87 mg, 0.23 mmol),

acetone (1.6 mL), and 1 M HCl (0.4 mL) was stirred

for 20 h at ambient temperature, before water (5 mL)

was added and the mixture was extracted with EtOAc

(4· 15 mL). The combined organic extracts were washed

with satd aq NaHCO₃(10 mL) and brine (10 mL), dried

(MgSO₄), and evaporated. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/

hexane (2:1); yield 68 mg (85%), colorless powdery crys-

4.25. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-phenyl-

9H-purine (19i)

The title compound was prepared by Stille coupling

between 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmeth-

yl)-9H-purine 1b (125 mg, 0.367 mmol) and trimethyl-

(phenyl)stannane (100 lL, 0.55 mmol) as described for

compound 4 above. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/hex-

ane (1:3), followed by EtOAc/hexane (1:2) and EtOAc/

hexane (1:1); yield 122 mg (87%), colorless crystalline

compound, mp 140–142 ꢁC. ¹H NMR (CDCl₃,

300 MHz) d 3.72 (s, 3H, OCH₃), 5.35 (s, 2H, NCH₂),

6.64 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 in furyl), 6.83

(d, J = 8.7 Hz, 2H, Ar), 7.28 (d, J = 8.7 Hz, 2H, Ar),

7.42–7.53 (m, 3H, Ph), 7.78 (dd, J = 1.8 and 0.8 Hz,

H-5 in furyl), 7.82 (dd, J = 3.5 and 0.8 Hz, H-5 in furyl),

7.97 (s, 1H, H-8), 8.61–8.64 (m, 2H, Ph); ¹³C NMR

(CDCl₃, 75 MHz) d 46.7 (NCH₂), 55.2 (OCH₃), 112.3

(C-4 in furyl), 114.4 (CH in Ar), 116.4 (C-3 in furyl),

127.0 (C-5), 127.5 (C-1 in Ar), 128.3 (CH in Ph), 128.4

(CH in Ph), 129.5 (CH in Ar), 130.1 (CH in Ph), 138.1

(C-1 in Ph), 144.4 (C-8), 145.8 (C-5 in furyl), 145.8 (C-

6), 150.8 (C-2 in furyl), 153.1 (C-4), 158.9 (C-2), 159.7

(C-4 in Ar); MS-EI m/z (rel %) 382 (70, M⁺), 367 (4),

121 (100), 78 (5), 77 (7); Anal. Found: C, 72.27; H,

4.82; N, 14.73. C₂₃H₁₈N₄O₂requires C, 72.24; H, 4.74;

N, 14.65%.

1

tals, mp. 166–167 ꢁC. H NMR (CDCl₃, 200 MHz) d

2.87 (s, 3H, CH₃), 3.74 (s, 3H, OCH₃), 5.42 (s, 2H,

CH₂), 6.63 (dd, J = 3.5 and 1.8 Hz, 1H, H-4 in furyl),

6.84 (d, J = 8.6 Hz, 2H, Ar), 7.26 (d, J = 8.6 Hz, 2H,

Ar), 7.76 (dd, J = 1.6 and 0.7 Hz, 1H, H-5 in furyl),

7.81 (dd, J = 3.5 and 0.6 Hz, 1H, H-3 in furyl), 8.13 (s,

1H, H-8); ¹³C NMR (CDCl₃, 125 MHz) d 27.2 (CH₃),

47.1 (CH₂), 55.2 (OCH₃), 112.6 (C-4 in furyl), 114.4

(CH in Ar), 117.6 (C-3 in furyl), 126.6 (C-1 in Ar),

128.9 (C-5), 129.7 (CH in Ar), 145.7 (C-6), 146.3 (C-5

in furyl), 146.6 (C-8), 149.7 (C-2 in furyl), 152.5 (C-4),

154.5 (C-2), 159.8 (C-4 in Ar), 197.7 (C@O); MS-EI

m/z (rel %) 348 (55, M⁺), 333 (7), 305 (2), 121 (100),

91 (3); Anal. Found: C, 65.38; H, 4.66; N, 15.86.

C₁₉H₁₆N₄O₃requires C, 65.51; H, 4.63; N, 16.08%.

4.28. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-9H-purine-

2-carbonitrile (21)

A mixture of zinc cyanide (70 mg, 0.60 mmol), 2-chloro-

6-(2-furyl)-9-(4-methoxy-phenylmethyl)-9H-purine 1b

(170 mg, 0.50 mmol) and tetrakis(triphenylphosphine)-

palladium(0) [generated in situ from tris(diphenylmethy-

lideneacetone)dipalladium (32 mg, 0.035 mmol) and

triphenylphosphine (73 mg, 0.28 mmol)] in dry NMP

(4 mL) was stirred at 120 ꢁC under N₂for 24 h and

cooled, before 2 M aq ammonia (5 mL) was added.

The mixture was extracted with EtOAc (3· 20 mL),

and the combined organic extracts were washed with

2 M aq ammonia (15 mL) and brine (20 mL), dried

(MgSO₄), and evaporated in vacuo. The product was

isolated by ﬂash chromatography on silica gel eluting

4.26. 2,6-(Di-2-furyl)-9-(4-methoxyphenylmethyl)-9H-

purine (19j)

The title compound was prepared by Stille coupling be-

tween 2,6-dichloro-9-(4-methoxyphenylmethyl)-9H-pur-

ine (77 mg, 0.25 mmol) and 2-(tributylstannyl)furan

(236 lL, 0.75 mmol) as described for compound 4

above. The product was puriﬁed by ﬂash chromatogra-

phy on silica gel eluting with EtOAc/hexane (1:1); yield

69 mg (74%), oﬀ-white powdery crystals, mp 155–

156 ꢁC. ¹H NMR (CDCl₃, 300 MHz) d 3.75 (s, 3H,

OCH₃), 5.38 (s, 2H, CH₂), 6.56 (dd, J = 3.4 and

7160

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

with CH₂Cl₂/acetone (19:1); yield 112 mg (68%), color-

less crystals, mp 205–207 ꢁC. ¹H NMR (CDCl₃,

500 MHz) d 3.78 (s, 3H, OCH₃), 5.37 (s, 2H, CH₂),

6.67 (dd, J = 3.4 and 1.5 Hz, 1H, H-4 in furyl), 6.88

(d, J = 8.6 Hz, 2H, Ar), 7.29 (d, J = 8.6 Hz, 2H, Ar),

7.79 (br s, H-5 in furyl), 7.87 (br d, J = 3.5 Hz, 1H, H-

3 in furyl), 8.17 (s, 1H, H-8); ¹³C NMR (CDCl₃,

125 MHz) d 47.5 (CH₂), 55.3 (OCH₃), 113.0 (C-4 in fur-

yl), 114.6 (CH in Ar), 116.4 (CN), 119.2 (C-3 in furyl),

126.1 (C-1 in Ar), 129.2 (C-5), 129.8 (CH in Ar), 137.6

(C-6/C-2), 146.6 (C-2/C-6), 146.6 (C-8), 147.1 (C-5 in

furyl), 148.6 (C-2 in furyl), 151.7 (C-4), 160.0 (C-4 in

Ar); MS-EI m/z (rel %) 331 (26, M⁺), 121 (100), 91

(4), 78 (6), 77 (5); HRMS: Found 331.1056 Calcd for

C₁₈H₁₃N₅O₂331.1069; Anal. Found: C, 65.08; H, 3.94;

N, 20.76. C₁₈H₁₃N₅O₂requires C, 65.25; H, 3.95; N,

21.14%.

¹H NMR (CDCl₃, 300 MHz) d 3.09 (s, 1H, „CH),

3.75 (s, 3H, OCH₃), 5.31 (s, 2H, NCH₂), 6.62 (dd,

J = 3.5 Hz, J = 1.7 Hz, 1H, H-4 in furyl), 6.85 (d,

J = 8.7 Hz, 2H, Ar), 7.24 (d, J = 8.7 Hz, 2H, Ar), 7.74

(m, 1H, H-5 in furyl), 7.82 (br d, J = 3.5 Hz, H-3 in fur-

yl), 8.03 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d

46.8 (NCH₂), 55.3 (OCH₃in Ar), 74.4 („CH), 82.6

(C„CH), 112.6 (C-4 in furyl), 114.5 (CH in Ar), 117.9

(C-3 in furyl), 126.8 (C-1 in Ar), 127.7 (C-5), 129.6

(CH in Ar), 145.2 (C-2), 145.3 (C-8), 146.2 (C-6),

146.3 (C-5 in furyl), 149.2 (C-2 in furyl), 152.1 (C-4),

159.8 (C-4 in Ar); MS-EI m/z (rel %) 330 (54, M⁺),

315 (3), 121 (100), 78 (6), 77 (6); Anal. Found: C,

69.26; H, 4.37; N, 16.71. C₁₉H₁₄N₄O₂requires C,

69.08; H, 4.27; N, 16.96%.

4.31. 6-Chloro-2-iodo-9-(4-methoxyphenylmethyl)-9H-

purine (24)

4.29. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-trimeth-

ylsilylethynyl-9H-purine (22)

2-Amino-6-chloro-9-(4-methoxyphenylmethyl)-9H-pur-

ine 3a (290 mg, 1.00 mmol), diiodomethane (10 mL),

and isoamyl nitrite (2.7 mL, 20 mmol) were heated at

85 ꢁC for 75 min. After cooling, the solution was evap-

orated in vacuo, dissolved in EtOAc (30 mL), washed

with brine (2· 15 mL), dried (MgSO₄), and evaporated

in vacuo. The product was puriﬁed by ﬂash chromatog-

raphy on silica gel eluting with EtOAc/hexane (2:1);

yield 197 mg (49%), colorless oil. ¹H NMR (CDCl₃,

300 MHz) d 3.79 (s, 3H, OCH₃), 5.31 (s, 2H, CH₂),

6.89 (d, J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz, 2H,

Ar), 7.90 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d

47.5 (CH₂), 55.2 (OCH₃), 114.4 (CH in Ar), 116.5 (C-

2), 125.8 (C-1 in Ar), 129.6 (CH in Ar), 131.2 (C-5),

144.9 (C-8), 150.0 (C-6), 152.4 (C-4), 159.8 (C-4 in

Ar); MS-EI m/z (rel %) 402/400 (16/46, M⁺), 136 (2),

121 (100), 78 (8), 77 (6); Anal. Found: C, 39.07; H,

2.60; N, 13.91. C₁₃H₁₀CIN₄O requires C, 38.98; H,

2.52; N, 13.99%.

A mixture of CuI (9.5 mg, 0.050 mmol), bis(triphenyl-

phosphine)palladium(II) chloride (17.5 mg, 0.025 mmol),

2-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-

purine 1b (170 mg, 0.50 mmol), triethylamine (250 lL,

1.79 mmol), and ethynyltrimethylsilane (139 lL,

1.00 mmol) in dry DMF (1.5 mL) was heated at

120 ꢁC for 5 h in a sealed tube. After cooling, the solu-

tion was evaporated in vacuo, dissolved in CH₂Cl₂

(20 mL), and ﬁltered through a plug of silica gel (5 g)

eluting with CH₂Cl₂/acetone (7:3) (100 mL). The solu-

tion was evaporated in vacuo and the product was puri-

ﬁed by ﬂash chromatography on silica gel eluting with

CH₂Cl₂/acetone (39:1); yield 82 mg (41%), oﬀ-white

crystalline compound, mp 155–157 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 0.26 (s, 9H, TMS), 3.71 (s, 3H,

OCH₃), 5.31 (s, 2H, NCH₂), 6.58 (dd, J = 3.5 and

1.7 Hz, 1H, H-4 in furyl), 6.80 (d, J = 8.7 Hz, 2H, Ar),

7.17 (d, J = 8.7 Hz, 2H, Ar), 7.70 (m, 1H, H-5 in furyl),

7.79 (br d, J = 3.5 Hz, H-3 in furyl), 7.96 (s, 1H, H-8);

¹³C NMR (CDCl₃, 75 MHz) d ꢀ0.4 (TMS), 46.6

(NCH₂), 55.2 (OCH₃), 92.1 (C„), 103.2 (C„), 112.5

(C-4 in furyl), 114.4 (CH in Ar), 117.8 (C-3 in furyl),

126.7 (C-1 in Ar), 127.4 (C-5), 129.4 (CH in Ar), 145.1

(C-8), 145.8 (C-6/C-2), 146.0 (C-5 in furyl), 149.1 (C-2

in furyl), 152.0 (C-4), 159.7 (C-4 in Ar), C-2 or C-6

was hidden; MS-EI m/z (rel %) 402 (56, M⁺), 387 (9),

251 (3), 121 (100), 108 (2); Anal. Found: C, 65.66; H,

5.53; N, 13.88. C₂₂H₂₂N₄O₂Si requires C, 65.65; H,

5.51; N, 13.92%.

4.32. 6-Chloro-9-(4-methoxyphenylmethyl)-2-propynyl-

9H-purine (25)

Propyne (41 mg, 1.02 mmol) was condensed at ꢀ78 ꢁC

in a sealed tube. CuI (3.9 mg, 0.021 mmol), bis(triphen-

ylphosphine)palladium(II)

chloride

(5.4 mg,

0.008 mmol), triethylamine (0.50 mL), and a solution

of 6-chloro-2-iodo-9-(4-methoxyphenyl)-9H-purine 24

(82 mg, 0.205 mmol) in dry CH₃CN (1.5 mL) were

added. The tube was sealed and the mixture was stirred

at 0 ꢁC for 2 h. The reaction mixture was cooled to

ꢀ78 ꢁC, the ﬂask was opened, and the reaction mixture

was allowed to reach room temperature under N₂. The

mixture was diluted with CH₂Cl₂(5 mL) and evaporated

in vacuo. The product was puriﬁed by ﬂash chromatog-

raphy on silica gel eluting with EtOAc/hexane (1:1) fol-

lowed by EtOAc/hexane (2:1) and EtOAc/hexane (4:1);

yield 46 mg (72%), colorless crystalline compound, mp

148–150 ꢁC. ¹H NMR (CDCl₃, 300 MHz) d 2.14 (s,

3H, CH₃), 3.79, (s, 3H, OCH₃), 5.35 (s, 2H, CH₂),

6.88 (d, J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz, 2H,

Ar), 8.00 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d

4.4 (CH₃), 47.3 (CH₂), 55.3 (OCH₃), 78.7 (C„), 86.5

(C„), 114.6 (CH in Ar), 126.2 (C-1 in Ar), 129.5 (CH

4.30. 2-Ethynyl-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (23)

A mixture of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-2-

trimethylsilylethynyl-9H-purine 22 (120 mg, 0.298 mmol)

and K₂CO₃(413 mg, 3.13 mmol) in CH₂Cl₂(2.5 mL)

and MeOH (2.5 mL) was stirred for 1.5 h at ambient

temperature, diluted with CH₂Cl₂(20 mL), washed with

brine (3· 15 mL), dried (MgSO₄), and evaporated in va-

cuo. The product was puriﬁed by ﬂash chromatography

on silica gel eluting with CH₂Cl₂/acetone (9:1); yield

72 mg (73%), oﬀ-white powdery crystals, mp 155 ꢁC.

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7161

in Ar), 130.5 (C-5), 145.4 (C-8), 145.9 (C-6/C-2), 150.8

(C-2/C-6), 151.8 (C-4), 160.0 (C-4 in Ar); MS-EI m/z

(rel %) 314/312 (18/47, M⁺), 297 (3), 121 (100), 78 (8),

77 (7); Anal. Found: C, 61.45; H, 3.93; N, 17.80.

C₁₆H₁₃ClN₄O requires C, 61.44; H, 4.19; N, 17.91%.

crystalline compound, mp 104–106 ꢁC. ¹H NMR

(CDCl₃, 300 MHz) d 3.78 (s, 3H, OCH₃), 5.41 (s, 2H,

CH₂), 6.88 (d, J = 8.7 Hz, 2H, Ar), 7.30 (d, J = 8.7 Hz,

2H, Ar), 8.18 (s, 1H, H-8); ¹³C NMR (CDCl₃,

75 MHz) d 48.0 (CH₂), 55.3 (OCH₃), 114.7 (CH in

Ar), 119.3 (q, J_CF= 275 Hz, CF₃), 125.7 (C-1 in Ar),

129.9 (CH in Ar), 132.6 (C-5), 146.9 (C-8), 149.8 (q,

J_CF= 38 Hz, C-2), 151.6 (C-4/C-6), 151.7 (C-6/C-4),

160.1 (C-4 in Ar); ¹⁹F NMR (CDCl₃, 188 MHz)

ꢀ69.20 (CF₃); MS-EI m/z (rel %) 344/342 (12/36, M⁺),

121 (100), 91 (3), 78 (7), 77 (6); Anal. Found: C, 49.55;

H, 3.23; N, 16.35 C₁₄H₁₀ClF₃N₄O requires C, 49.07;

H, 2.94; N, 16.35%.

4.33. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-(1-propy-

nyl)-9H-purine (26)

Method A. The title compound was prepared by Stille

coupling between 6-chloro-9-(4-methoxyphenylmethyl)-

2-(1-propynyl)-9H-purine 25 (29 mg, 0.093 mmol) and

2-(tributylstannyl)furan (35 lL, 0.11 mmol) as described

for compound 4 above. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with

CH₂Cl₂/acetone (19:1); yield 18 mg (56%), oﬀ-white

crystalline compound, mp 158–160 ꢁC. ¹H NMR

(CDCl₃, 200 MHz) d 2.12 (s, 3H, CH₃), 3.76 (s, 3H,

OCH₃), 5.35 (s, 2H, NCH₂), 6.61 (dd, J = 3.5 Hz,

J = 1.7 Hz, 1H, H-4 in furyl), 6.85 (d, J = 8.7 Hz, 2H,

Ar), 7.23 (d, J = 8.7 Hz, 2H, Ar), 7.73 (m, 1H, H-5 in

furyl), 7.82 (dd, J = 3.5 and 0.6 Hz, H-3 in furyl), 7.96

(s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d 4.5 (CH₃),

46.6 (NCH₂), 55.2 (OCH₃), 79.7 (C„), 84.6 (C„),

112.5 (C-4 in furyl), 114.4 (CH in Ar), 117.6 (C-3 in fur-

yl), 126.8 (C-1 in Ar), 127.1 (C-5), 129.5 (CH in Ar),

144.7 (C-8), 146.0 (C-5 in furyl), 146.1 (C-6/C-2), 146.6

(C-2/C-6), 149.2 (C-2 in furyl), 152.1 (C-4), 159.7 (C-4

in Ar); MS-EI m/z (rel %) 344 (100, M⁺), 330 (2), 329

(10), 315 (2), 121 (78); Anal. Found: C, 69.71; H, 4.78;

N, 16.20. C₂₀H₁₆N₄O₂requires C, 69.76; H, 4.68; N,

16.27%.

4.34.2. 6-Chloro-7-(4-methoxyphenylmethyl)-2-triﬂuo-

romethyl-7H-purine (28b). Yield: 93 mg (18%), colorless

1

powdery crystals, mp 173–175 ꢁC. H NMR (CDCl₃,

300 MHz) d 3.78 (s, 3H, OCH₃), 5.65 (s, 2H, CH₂),

6.89 (d, J = 8.7 Hz, 2H, Ar), 7.15 (d, J = 8.7 Hz, 2H,

Ar), 8.31 (s, 1H, H-8); ¹³C NMR (CDCl₃, 75 MHz) d

50.7 (CH₂), 55.3 (OCH₃), 114.8 (CH in Ar), 119.3 (q,

J_CF= 275 Hz, CF₃), 123.5 (C-1 in Ar), 125.5 (C-5),

129.0 (CH in Ar), 144.0 (C-6), 150.2 (q, J_CF= 38 Hz,

C-2), 150.8 (C-8), 160.1 (C-4 in Ar), 162.0 (C-4); MS-

EI m/z (rel %) 344/342 (7/23, M⁺), 121 (100), 91 (2), 78

(5), 77 (4); Anal. Found: C, 49.31; H, 3.34; N, 16.44.

C₁₄H₁₀ClF₃N₄O requires C, 49.07; H, 2.94; N, 16.35%.

4.35. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-2-triﬂuo-

romethyl-9H-purine (29)

The title compound was prepared by Stille coupling

between 6-chloro-9-(4-methoxyphenylmethyl)-2-triﬂu-

oromethyl-9H-purine 28a (130 mg, 0.38 mmol) and 2-

(tributylstannyl)furan (143 lL, 0.46 mmol) as described

for compound 4 above. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/

hexane (1:1) followed by EtOAc/hexane (2:1); yield

118 mg (83%), colorless crystals, mp 149–150 ꢁC. ¹H

NMR (CDCl₃, 200 MHz) d 3.78 (s, 3H, OCH₃), 5.41

(s, 2H, CH₂), 6.66 (dd, J = 3.6 and 1.7 Hz, 1H, H-4 in

furyl), 6.88 (d, J = 8.6 Hz, 2H, Ar), 7.30 (d, J = 8.6 Hz,

2H, Ar), 7.79 (m, 1H, H-5 in furyl), 7.89 (br d,

J = 3.5 Hz, 1H, H-3 in furyl), 8.13 (s, 1H, H-8); ¹³C

NMR (CDCl₃, 75 MHz) d 47.2 (CH₂), 55.3 (OCH₃),

112.8 (C-4 in furyl), 114.5 (CH in Ar), 118.7 (C-3 in fur-

yl), 120.0 (q, J_CF= 275 Hz, CF₃), 126.4 (C-1 in Ar),

128.8 (C-5), 129.7 (CH in Ar), 146.1 (C-8), 146.2 (C-

6), 146.8 (C-5 in furyl), 149.1 (C-2 furyl), 150.4 (q,

J_CF= 36.5 Hz, C-2), 152.1 (C-4), 159.9 (C-4 in Ar);

¹⁹F NMR (CDCl₃, 188 MHz) ꢀ69.3 (CF₃); MS-EI m/z

(rel %) 374 (40, M⁺), 187 (2), 121 (100), 91 (2), 78 (4);

Anal. Found: C, 57.97; H, 3.82; N, 15.15.

C₁₈H₁₃F₃N₄O₂requires C, 57.76; H, 3.50; N, 14.97%.

Method B. Propyne (476 mg, 11.9 mmol) was condensed

at ꢀ78 ꢁC in a sealed tube. CuI (2.2 mg, 0.0116 mmol),

bis(triphenylphosphine)palladium(II) chloride (4.9 mg,

0.007 mmol), a solution of 6-(2-furyl)-2-iodo-9-(4-meth-

oxyphenylmethyl)-9H-purine 5 (50 mg, 0.12 mmol) in

dry CH₃CN (1 mL), and triethylamine (0.50 mL,

3.6 mmol) were added. The tube was sealed and the mix-

ture was stirred at ambient temperature for 24 h. The

reaction mixture was cooled to ꢀ78 ꢁC, the ﬂask was

opened, and the reaction mixture was allowed to reach

ambient temperature under N₂. The mixture was evapo-

rated in vacuo and the product was puriﬁed by ﬂash

chromatography on silica gel eluting with CH₂Cl₂/ace-

tone (19:1); yield 25 mg (63%).

4.34. 6-Chloro-9-(4-methoxyphenylmethyl)-2-triﬂuoro-

methyl-9H-purine (28a) and 6-chloro-7-(4-methoxyphe-

nylmethyl)-2-triﬂuoromethyl-7H-purine (28b)

Potassium carbonate (610 mg, 4.41 mmol) and 6-chloro-

2-triﬂuoromethyl-9H-purine 27 (328 mg, 1.47 mmol) in

dry DMF (10 mL) were stirred at ambient temperature

under N₂for 20 min, before 4-methoxyphenylmethyl

chloride (400 lL, 2.95 mmol) was added. The resulting

mixture was stirred for 16 h, ﬁltered, and evaporated

in vacuo. The isomers were separated by ﬂash chroma-

tography on silica gel eluting with EtOAc/hexane (1:1).

4.36. 6-Chloro-9-(4-methoxyphenylmethyl)-8-methyl-9H-

purine (31a)

6-Chloro-9-(4-methoxyphenylmethyl)-9H-purine 30 (137 mg,

0.50 mmol) in THF (2 mL) was added dropwise to

a stirred solution of LDA [generated in situ from

diisopropylamine (0.11 mL, 0.77 mmol) and n-BuLi

(0.44 mL, 0.7 mmol, 1.6 M in hexane)] in THF (2 mL)

4.34.1. 6-Chloro-9-(4-methoxyphenylmethyl)-2-triﬂuo-

romethyl-9H-purine (28a). Yield: 206 mg (41%) colorless

7162

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

at ꢀ78 ꢁC under N₂. After stirring for 1 h at ꢀ78 ꢁC,

iodomethane (0.31 mL, 5.0 mmol) was added dropwise

and the resulting mixture was stirred at ꢀ78 ꢁC for

3.5 h, gradually warmed to ambient temperature over

2 h, and stirred at ambient temperature for 15 h. Satd

aq NH₄Cl (15 mL) was added and the mixture was ex-

tracted with EtOAc (2· 25 mL). The combined organic

extracts were washed with brine (20 mL), dried

(MgSO₄), and evaporated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/hexane (2:1); yield 96 mg (67%), colorless

7.09 (d, J = 8.6 Hz, 2H, Ar), 7.72 (br s, 1H, H-5 in fur-

yl), 7.76 (br d, J = 3.4 Hz, 1H, H-3 in furyl), 8.88 (s, 1H,

H-2); ¹³C NMR (CDCl₃, 50 MHz) d 14.9 (CH₃), 45.4

(CH₂), 55.2 (OCH₃), 112.4 (C-4 in furyl), 114.3 (CH in

Ar), 116.5 (C-3 in furyl), 127.3 (C-1 in Ar), 127.6 (C-

5), 128.4 (CH in Ar), 145.4 (C-5 in furyl), 145.7 (C-6),

149.9 (C-2 in furyl), 151.8 (C-2), 153.5 (C-4/C-8), 154.3

(C-4/C-8), 159.3 (C-4 in Ar); MS-EI m/z (rel %) 320

(77, M⁺), 305 (8), 213 (1), 160 (3), 121 (100); HRMS:

Found 320.1276, Calcd for C₁₈H₁₆N₄O₂320.1273; Anal.

Found: C, 67.30; H, 5.02; N 17.26. C₁₈H₁₆N₄O₂requires

C, 67.75; H, 5.22; N, 17.49%.

1

crystals, mp 121–123 ꢁC. H NMR (CDCl₃, 200 MHz)

d 2.59 (s, 3H, CH₃), 3.76 (s, 3H, OCH₃), 5.36 (s, 2H,

CH₂), 6.83 (d, J = 8.6 Hz, 2H, Ar), 7.12 (d, J = 8.6 Hz,

2H, Ar), 8.70 (s, 1H, H-2); MS-EI m/z (rel %) 290/288

(10/30, M⁺), 275 (1), 273 (4), 246 (1), 121 (100); HRMS:

Found 288.0776, Calcd for C₁₄H₁₃ClN₄O 288.0778;

Anal. Found: C, 58.36; H, 4.44. C₁₄H₁₃ClN₄O requires

C, 58.82; H, 4.54%.

Method B: LDA [generated from diisopropylamine

(0.085 mL, 0.60 mmol) and n-BuLi (0.34 mL,

0.55 mmol, 1.6 M in hexane)] in THF (2 mL) was added

dropwise to a stirred solution of 6-(2-furyl)-9-(4-meth-

oxyphenylmethyl)-9H-purine 1a (153 mg, 0.50 mmol)

in THF (10 mL) at ꢀ78 ꢁC under N₂. After stirring for

50 min at ꢀ78 ꢁC, iodomethane (0.62 mL, 1.0 mmol)

was added dropwise and the resulting mixture was stir-

red at ꢀ78 ꢁC for 5 h, gradually warmed to ambient

temperature over ca. 2 h and stirred at ambient temper-

ature for ca. 15 h. Satd aq NH₄Cl (15 mL) was added

and the mixture was extracted with EtOAc (3·

25 mL). The combined organic extracts were washed

with brine (2· 20 mL), dried (MgSO₄), and evaporated

in vacuo. The product was puriﬁed by ﬂash chromatog-

raphy on silica gel eluting with EtOAc/hexane (2:1);

yield 110 mg (69%).

4.37. 6,8-Dichloro-9-(4-methoxyphenylmethyl)-9H-purine

(31b)

6-Chloro-9-(4-methoxyphenylmethyl)-9H-purine 30 (275 mg,

1.00 mmol) in THF (4 mL) was added dropwise to a

stirred solution of LDA [generated in situ from diisopro-

pylamine (0.21 mL, 1.50 mmol) and n-BuLi (0.88 mL,

1.40 mmol, 1.6 M in hexane)] in THF (4 mL) at

ꢀ78 ꢁC under N₂. After stirring for 1 h at ꢀ78 ꢁC, a

solution of hexachloroethane (473 mg, 2.00 mmol) in

THF (4 mL) was added dropwise and the resulting mix-

ture was stirred at ꢀ78 ꢁC for 2 h, and 10 min without

cooling. Satd aq NH₄Cl (15 mL) was added and the

mixture was extracted with EtOAc (2· 25 mL). The

combined organic extracts were washed with brine

(20 mL), dried (MgSO₄) and evaporated in vacuo. The

product was puriﬁed by ﬂash chromatography on silica

gel eluting with EtOAc/hexane (1:1) followed by EtOAc/

hexane (1:3); yield 251 mg (81%), colorless crystals,

mp 110–112 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 3.73

(s, 3H, OCH₃), 5.38 (s, 2H, CH₂), 6.81 (d, J = 8.5 Hz,

2H, Ar), 7.30 (d, J = 8.5 Hz, 2H, Ar), 8.72 (s, 1H,

H-2); ¹³C NMR (CDCl₃, 50 MHz) d 47.1 (CH₂), 55.3

(OCH₃), 114.3 (CH in Ar), 126.0 (C-1 in Ar), 129.6

(CH in Ar), 130.5 (C-5), 144.1 (C-8), 149.4 (C-6),

152.0 (C-2), 152.4 (C-4), 159.7 (C-4 in Ar); MS-EI m/z

(rel %) 312/310/308 (1/10/16, M⁺), 273 (2), 121 (100),

78 (5), 77 (5); Anal. Found: C, 50.24; H, 3.11; N

17.83. C₁₃H₁₀Cl₂N₄O requires C, 50.50; H, 3.26; N,

18.12%.

4.39. 8-Chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (32b)

MethodA: A mixture of tris(diphenylmethylideneacetone)-

dipalladium chloroform adduct (23 mg, 0.022 mmol) and

tri(2-furyl)phosphine (37 mg, 0.16 mmol) in DMF (8 mL)

was stirred at ambient temperature under N₂-atm for

15 min., before 6,8-dichloro-9-(4-methoxyphenylmeth-

yl)-9H-purine 31b (228 mg, 0.74 mmol) and 2-furyl(tribu-

tyl)tin (0.28 mL, 0.88 mmol) were added. The resulting

mixture was stirred for 18 h at 50 ꢁC and evaporated in va-

cuo. The residue was dissolved in acetonitrile (30 mL) and

washed with hexane (15· 10 mL). The acetonitrile layer

was evaporated and the product was isolated by ﬂash

chromatography on silica eluting with EtOAc/hexane

(1:5) followed by EtOAc/hexane (1:2); yield 118 mg

(47%), colorless small needles, mp 156–157 ꢁC. ¹H

NMR (CDCl₃, 200 MHz) d 3.76 (s, 3H, OCH₃), 5.41 (s,

2H, CH₂), 6.64 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in furyl),

6.84 (d, J = 8.4 Hz, 2H, Ar), 7.33 (d, J = 8.4 Hz, 2H, Ar),

7.74 (br s, 1H, H-5 in furyl), 7.80 (br d, J = 3.4 Hz, 1H, H-

3 in furyl), 8.94 (s, 1H, H-2); ¹³C NMR (CDCl₃, 50 MHz)

d 46.4 (CH₂), 55.3 (OCH₃), 112.6 (C-4 in furyl), 114.2 (CH

in Ar), 117.6 (C-3 in furyl), 126.6 (C-1 in Ar), 127.2 (C-5),

129.5 (CH in Ar), 143.2 (C-6/C-8), 144.5 (C-6/C-8), 145.9

(C-5 in furyl), 149.0 (C-2 in furyl), 152.7 (C-2), 153.1 (C-

4), 159.6 (C-4 in Ar); MS-EI m/z (rel %) 342/340 (10/30,

M⁺), 170 (1), 121 (100), 78 (4), 77 (5); Anal. Found: C,

59.54; H, 3.84; N 16.57. C₁₇H₁₃ClN₄O₂requires C,

59.92; H, 3.84; N, 16.44%. Fractions containing 6,8-di-

(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine 32d (see

below) were also isolated.

4.38. 6-(2-Furyl)-9-(4-methoxyphenylmethyl)-8-methyl-

9H-purine (32a)

Method A: The title compound was prepared by Stille

coupling on 6-chloro-9-(4-methoxyphenylmethyl)-8-

methyl-9H-purine 31a (0.65 mmol) as described for

compound 4 above and the product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/hex-

1

ane (2:1); yield 176 mg (85%), colorless wax. H NMR

(CDCl₃, 200 MHz) d 2.56 (s, 3H, CH₃), 3.72 (s, 3H,

OCH₃), 5.34 (s, 2H, CH₂), 6.61 (dd, J = 3.4 and

1.8 Hz, 1H, H-4 in furyl), 6.79 (d, J = 8.6 Hz, 2H, Ar),

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

7163

Method B: LDA [generated from diisopropylamine

(0.13 mL, 0.89 mmol) and n-BuLi (0.51 mL, 0.81 mmol,

1.6 M in hexane)] in THF (4 mL) was added dropwise to

a stirred solution of 6-(2-furyl)-9-(4-methoxyphenylm-

ethyl)-9H-purine 1a (227 mg, 0.74 mmol) in THF

(10 mL) at ꢀ78 ꢁC under N₂. After stirring for 55 min

at ꢀ78 ꢁC, hexachloroethane (350 mg, 1.48 mmol) in

THF (4 mL) was added dropwise and the resulting mix-

ture was stirred at ꢀ78 ꢁC for 3 h and without cooling

for 15 min. Satd aq NH₄Cl (15 mL) was added and

the mixture was extracted with EtOAc (3· 25 mL).

The combined organic extracts were washed with brine

(2· 20 mL), dried (MgSO₄), and evaporated in vacuo.

The product was puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/hexane (1:5) followed by

EtOAc/hexane (1:2); yield 137 mg (54%). 8-Chloro-6-

(5-chloro-2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

35b (41 mg, 15%) was also isolated (data see below).

on silica gel eluting with acetone/hexane (1:4); yield

65 mg (24%), oﬀ-white crystalline solid, mp 134–

136 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 3.72 (s, 3H,

OCH₃), 5.76 (s, 2H, CH₂), 6.60 (dd, J = 3.6 and

1.8 Hz, 1H, H-4 in furyl), 6.65 (dd, J = 3.4 and 1.6 Hz,

1H, H-4 in furyl), 6.77 (d, J = 8.6 Hz, 2H, Ar), 7.16

(d, J = 8.6 Hz, 2H, Ar), 7.27 (br d, J = 3.6 Hz, 1H, H-

3 in furyl), 7.66 (m, 1H, H-5 in furyl), 7.74 (m, 1H, H-

5 in furyl), 7.94 (br d, J = 3.4 Hz, 1H, H-3 in furyl),

8.94 (s, 1H, H-2); ¹³C NMR (CDCl₃, 50 MHz) d 46.5

(CH₂), 55.2 (OCH₃), 112.4 (C-4 in furyl), 112.6 (C-4 in

furyl), 114.1 (CH in Ar), 114.9 (C-3 in furyl), 117.6

(C-3 in furyl), 128.1 (C-1 in Ar and C-5), 128.4 (CH in

Ar), 144.7 (C-8), 144.8 (C-5 in furyl), 145.5 (C-6 and

C-5 in furyl), 149.4 (2· C-2 in furyl), 152.4 (C-2),

153.5 (C-4), 159.1 (C-4 in Ar); MS-EI m/z (rel %) 372

(43, M⁺), 265 (1), 121 (100), 78 (5), 77 (6); Anal. Found:

C, 67.92; H, 4.44; N 15.30. C₂₁H₁₆N₄O₃requires C,

67.73; H, 4.33; N, 15.05%.

4.40. 8-Bromo-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine (32c)

4.42. 6-(2-Furyl)-8-methoxy-9-(4-methoxyphenylmethyl)-

9H-purine (33)

LDA [generated from diisopropylamine (0.17 mL,

1.2 mmol) and n-BuLi (0.69 mL, 1.1 mmol, 1.6 M in

hexane)] in THF (4 mL) was added dropwise to a stirred

solution of 6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-

purine 1a (306 mg, 1.00 mmol) in THF (20 mL) at

ꢀ78 ꢁC under N₂. After stirring for 50 min at ꢀ78 ꢁC,

a solution of 1,2-dibromo-1,1,2,2,-tetrachloroethane

(651 mg, 2.00 mmol) in THF (2 mL) was added drop-

wise and the resulting mixture was stirred at ꢀ78 ꢁC

for 5 h, gradually warmed to ambient temperature over

ca. 4 h, and stirred at ambient temperature for ca. 14 h.

Satd aq NH₄Cl (15 mL) was added and the mixture was

extracted with EtOAc (3· 25 mL). The combined organ-

ic extracts were washed with brine (2· 20 mL), dried

(MgSO₄), and evaporated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/hexane (1:5) followed by EtOAc/hexane

(1:1); yield 153 mg (45%), colorless crystals, mp 150–

151 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d 3.74 (s, 3H,

OCH₃), 5.39 (s, 2H, CH₂), 6.62 (dd, J = 3.4 and

1.8 Hz, 1H, H-4 in furyl), 6.81 (d, J = 8.6 Hz, 2H, Ar),

7.30 (d, J = 8.6 Hz, 2H, Ar), 7.68 (br s, 1H, H-5 in fur-

yl), 7.72 (br d, J = 3.4 Hz, 1H, H-3 in furyl), 8.81 (s, 1H,

H-2); ¹³C NMR (CDCl₃, 50 MHz) d 47.2 (CH₂), 55.3

(OCH₃), 112.6 (C-4 in furyl), 114.2 (CH in Ar), 117.8

(C-3 in furyl), 126.8 (C-1 in Ar), 128.5 (C-5), 129.4

(CH in Ar), 133.0 (C-8), 144.4 (C-6), 145.9 (C-5 in furyl),

149.0 (C-2 in furyl), 152.7 (C-2), 153.0 (C-4), 159.5 (C-4

in Ar); MS-EI m/z (rel %) 386/384 (15/15, M⁺), 305 (6),

121 (100), 78 (5), 77 (5); HRMS: Found 384.0220, Calcd

for C₁₇H₁₃BrN₄O₂3840222; Anal. Found: C, 53.25; H,

3.47; N 14.04. C₁₇H₁₃BrN₄O₂requires C, 53.01; H,

3.40; N, 14.54%.

A

mixture of 8-chloro-6-(2-furyl)-9-(4-methoxyphe-

nylmethyl)-9H-purine 32b (205 mg, 0.60 mmol) in a

0.7 M solution of sodium methoxide in methanol

(10 mL) was stirred at reﬂux under N₂-atm for 4 h,

cooled, and poured into cold satd aq NH₄Cl (10 mL).

Most of the methanol was removed by evaporated in va-

cuo and the aqueous mixture was extracted with EtOAc

(4· 20 mL). The combined organic layers were dried

(MgSO₄) and evaporation in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting

with acetone/hexane (2:7); 111 mg (55%), colorless crys-

tals, mp 143–144 ꢁC. ¹H NMR (CDCl₃, 200 MHz) d

3.75 (s, 3H, OCH₃), 4.28 (s, 3H, OCH₃), 5.18 (s, 2H,

CH₂), 6.61 (dd, J = 3.4 and 1.8 Hz, 1H, H-4 in furyl),

6.82 (d, J = 8.6 Hz, 2H, Ar), 7.31 (d, J = 8.6 Hz, 2H,

Ar), 7.72 (br s, 1H, H-5 in furyl), 7.81 (br d,

J = 3.4 Hz, 1H, H-3 in furyl), 8.81 (s, 1H, H-2); ¹³C

NMR (CDCl₃, 50 MHz) d 44.2 (CH₂), 55.2 (OCH₃),

57.5 (OCH₃), 112.2 (C-4 in furyl), 114.0 (CH in Ar),

115.9 (C-3 in furyl), 126.1 (C-5), 127.7 (C-1 in Ar),

129.3 (CH in Ar), 141.3 (C-6), 145.6 (C-5 in furyl),

149.4 (C-2 in furyl), 150.7 (C-2), 152.3 (C-4), 158.3 (C-

8), 159.2 (C-4 in Ar); MS-EI m/z (rel %) 336 (34, M⁺),

168 (1), 121 (100), 78 (4), 77 (5); Anal. Found: C,

64.28; H, 4.69; N, 16.38. C₁₈H₁₆N₄O₃requires C,

64.28; H, 4.80; N, 16.66%. 6-(2-Furyl)-8-hydroxy-9-(4-

methoxyphenylmethyl)-9H-purine 34 54 mg (28%) was

also isolated (data see below).

4.43. 6-(2-Furyl)-8-hydroxy-9-(4-methoxyphenylmethyl)-

9H-purine (34)

1

Colorless crystals, mp 249–251 ꢁC. H NMR (CDCl₃,

4.41. 6,8-Di(2-furyl)-9-(4-methoxyphenylmethyl)-9H-pur-

ine (32d)

200 MHz) d 3.75 (s, 3H, OCH₃), 5.07 (s, 2H, CH₂),

6.61 (dd, J = 3.2 and 1.8 Hz, 1H, H-4 in furyl), 6.83

(d, J = 8.8 Hz, 2H, Ar), 7.28 (br d, J = 3.2 Hz, 1H, H-

3 in furyl), 7.45 (d, J = 8.8 Hz, 2H, Ar), 7.64 (br s, 1H,

H-5 in furyl), 8.65 (s, 1H, H-2), 8.97 (br s, 1H, NH);

¹H NMR (DMSO-d₆, 600 MHz) d 3.70 (s, 3H, OCH₃),

4.96 (s, 2H, CH₂), 6.73 (m, 1H, H-4 in furyl), 6.88 (d,

Fractions containing a mixture of the title compound

and 8-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-

9H-purine 32b (from the synthesis of 32b by method

A, see above) were subjected to ﬂash chromatography

7164

M. Brændvang, L.-L. Gundersen / Bioorg. Med. Chem. 15 (2007) 7144–7165

J = 8.4 Hz, 2H, Ar), 7.29–7.31 (m 3H, H-3 in furyl and

Ar), 7.91 (s, 1H, H-5 in furyl), 8.55 (s, 1H, H-2), 11.66

(br s, 1H, NH); ¹³C NMR (DMSO-d₆, 150 MHz) d

42.1 (CH₂), 55.0 (OCH₃), 111.9 (C-3 in furyl), 112.4

(C-4 in furyl), 113.9 (CH in Ar), 115.3 (C-5), 128.4 (C-

1 in Ar), 129.0 (CH in Ar), 132.3 (C-6), 145.5 (C-5 in fur-

yl), 149.6 (C-2 in furyl), 150.4 (C-2), 150.5 (C-4), 153.4

(C-8), 158.7 (C-4 in Ar); MS-EI m/z (rel %) 322 (35,

M⁺), 122 (4), 121 (100), 78 (1), 77 (2); Anal. Found:

C, 63.28; H, 4.52; N, 17.15. C₁₇H₁₄N₄O₃requires C,

63.35; H, 4.38; N, 17.38%.

3.45; N 15.18. C₁₇H₁₂Cl₂N₄O₂requires C, 54.43; H,

3.22; N, 14.93%.

Acknowledgment

Antimycobacterial data were provided by the Tubercu-

losis Antimicrobial Acquisition and Coordinating Facil-

ity (TAACF) through a research and development

contract with the US National Institute of Allergy and

Infectious Diseases. We are grateful for all help pro-

vided by Dr. Cecil Kwong and co-workers. Other anti-

bacterial data were provided by University Hospital

North Norway, Department of Microbiology. The Nor-

wegian Research Council is gratefully acknowledged for

partial ﬁnancing of the Bruker Avance instruments used

in this study.

4.44. 9-(4-Methoxyphenylmethyl)-8-methyl-(5-methyl-2-

furyl)-9H-purine (35a)

To a stirred solution of LDA [generated from diisopro-

pylamine (0.25 mL, 1.74 mmol) and n-BuLi (0.91 mL,

1.45 mmol, 1.6 M in hexane)] in THF (4 mL) at

ꢀ78 ꢁC under N₂was added dropwise a solution of

6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-purine

1a

References and notes

(177 mg, 0.58 mmol) in THF (12 mL). After stirring

for 1 h at ꢀ78 ꢁC, iodomethane (0.36 mL, 5.8 mmol)

was added dropwise and the resulting mixture was stir-

red at ꢀ78 ꢁC for 6 h, gradually warmed to ambient

temperature over ca. 2 h, and stirred at ambient temper-

ature for ca. 15 h. Satd aq NH₄Cl (15 mL) was added

and the mixture was extracted with EtOAc (3·

25 mL). The combined organic extracts were washed

with brine (2· 20 mL), dried (MgSO₄), and evaporated

in vacuo. The product was puriﬁed by ﬂash chromatog-

raphy on silica gel eluting with EtOAc/hexane (1:1);

1. (a) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu,

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G.; Gundersen, L.-L.; Nissen-Meyer, J.; Rise, F.; Spils-

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1

yield 106 mg (55%), oﬀ-white wax. H NMR (CDCl₃,

3. Hudson, A.; Imamura, T.; Gutteridge, W.; Kanyok, T.;

Nunn, P. The current anti-TB drug research and devel-

opment pipeline. TDR/PRD/TB/0.31W, 2003.

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200 MHz) d 2.44 (s, 3H, CH₃), 2.50 (s, 3H, CH₃), 3.68

(s, 3H, OCH₃), 5.28 (s, 2H, CH₂), 6.20 (d, J = 3.4 Hz,

1H, H-4 in furyl), 6.75 (d, J = 8.6 Hz, 2H, Ar), 7.06

(d, J = 8.6 Hz, 2H, Ar), 7.73 (d, J = 3.4 Hz, 1H, H-3 in

furyl), 8.84 (s, 1H, H-2); ¹³C NMR (CDCl₃, 125 MHz)

d 14.0 (CH₃), 14.7 (CH₃), 45.2 (CH₂), 55.1 (OCH₃),

109.2 (C-4 in furyl), 114.2 (CH in Ar), 118.9 (C-3 in fur-

yl), 127.1 (C-5), 127.3 (C-1 in Ar), 128.4 (CH in Ar),

144.0 (C-6), 147.9 (C-2 in furyl), 151.8 (C-2), 153.0 (C-

4), 153.8 (C-8), 156.0 (C-5 in furyl), 159.3 (C-4 in Ar);

MS-EI m/z (rel %) 334 (53, M⁺), 319 (5), 291 (1), 277

(2), 121 (100); HRMS: Found 334.1434, Calcd for

C₁₉H₁₈N₄O₂334.1430.

6. For other examples of antimycobacterial purines, see: (a)

Alksnis, E.; Korneeva, D.; Lukevics, E. Chem. Hetero-

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4.45. 8-Chloro-6-(5-chloro-2-furyl)-9-(4-methoxyphenyl-

methyl)-9H-purine (35b)

Isolated in 15% yield in the synthesis of 32b (Method B).

Colorless microcrystalline solid, mp 166–168 ꢁC. ¹H

NMR (CDCl₃, 200 MHz) d 3.76 (s, 3H, OCH₃), 5.40

(s, 2H, CH₂), 6.43 (d, J = 3.6 Hz, 1H, H-4 in furyl),

6.83 (d, J = 8.6 Hz, 2H, Ar), 7.33 (d, J = 8.6 Hz, 2H,

Ar), 7.82 (d, J = 3.6 Hz, 1H, H-3 in furyl), 8.94 (s, 1H,

H-2); ¹³C NMR (CDCl₃, 50 MHz) d 46.5 (CH₂), 55.3

(OCH₃), 109.7 (C-4 in furyl), 114.2 (CH in Ar), 120.0

(C-3 in furyl), 126.6 (C-1 in Ar), 127.0 (C-5), 129.5

(CH in Ar), 141.0 (C-6/C-8/C-5 in furyl), 143.28 (C-6/

C-8/C-5 in furyl), 143.32 (C-6/C-8/C-5 in furyl), 148.1

(C-2 in furyl), 152.6 (C-4), 152.7 (C-2), 159.6 (C-4 in

Ar); MS-EI m/z (rel %) 378/376/374 (1/10/15, M⁺), 121

(100), 91 (3), 78 (5), 77 (5); Anal. Found: C, 54.87; H,

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Article Doi

Synthesis, biological activity, and SAR of antimycobacterial 2- and 8-substituted 6-(2-furyl)-9-(p-methoxybenzyl)purines

DOI: 10.1016/j.bmc.2007.07.034

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Full text of DOI:10.1016/j.bmc.2007.07.034

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