Synthesis of indomethacin analogues for evaluation as modulators of MRP activity

Bioorganic& Medicinal Chemistry 9 (2001) 745±762

Synthesis of Indomethacin Analogues for Evaluation as

Modulators of MRP Activity

Anita R. Maguire,^a,ÃStephen J. Plunkett,^aSebastien Papot,^aMartin Clynes,^b

Robert O'Connor^band Samantha Touhey^b

^aDepartment of Chemistry, University College Cork, Cork, Ireland

^bNational Cell and Tissue Culture Centre, Dublin City University, Glasnevin, Dublin 9, Ireland

Received 4 September 2000; accepted 31 October 2000

AbstractÐSynthesis of a range of indomethacin analogues, required for investigation in combination toxicity assays, bearing both

Earlier work^1ahas established that a number of NSAIDs,

including indomethacin and sulindac, have the ability to

potentiate the toxicity of a range of anticancer drugs

such as doxorubicin, vincristine and VP-16, especially in

MRP-expressing cell lines such as DLKP and A549

while this eect was not evident in P-gp expressing cell

lines such as DLKPA. Signi®cantly, the activity in

enhancing the toxicity of the anticancer drugs does not

appear to be directly related to cyclooxygenase (COX)

inhibition as a number of NSAIDs which are known to

act as COX inhibitors do not display this eect. Two

other groups have reported similar results with indo-

methacin in MRP expressing cell lines.^1b,c

was 1-benzyl-5-methoxy-2-methylindole-3-acetamide 2;

when the side chain was modi®ed to a carboxylic acid 3,

improved anti-in¯ammatory activity resulted. In an

exhaustive study, Shen and co-workers prepared a further

350 analogues to determine the structure±activity rela-

tionship. The result of this study was four candidates

that went forward for clinical evaluation (Fig. 1), and of

these MK-615, later to receive the generic name indo-

methacin, proved to be the most eective anti-in¯amma-

tory agent in human subjects. Signi®cantly, in terms of

anti-in¯ammatory activity, both benzyl and benzoyl sub-

stituents on the indole nitrogen atom were tolerated.

The biological mechanisms of action of indomethacin

and other NSAIDs have been extensively studied;

cyclooxygenase (COX) inhibition is their principal

mode of action.⁴Indomethacin, in common with most

other NSAIDs, has been shown to inhibit both COX-1

and COX-2 isoforms; the gastrotoxicity associated with

this class of compounds is believed to be due to COX-1

inhibition and accordingly extensive searching for selec-

tive COX-2 inhibitors has been undertaken in recent

years.⁵Indeed, the indomethacin derivative in which the

benzoyl group is replaced by a 4-bromobenzyl group 7

has been reported as a highly selective COX-2 inhi-

bitor.⁶

To explore this eect and, in particular, to determine

SAR in potentiating the toxicity of anticancer drugs, a

range of indomethacin analogues was synthesised and

their activity tested in our screens (hereafter described

as combination toxicity assays). Indomethacin 1 was a

logical candidate for investigation as its structure is very

amenable to modi®cation to establish the in¯uence of the

various substituents, for example the role of the 5-meth-

oxy, 2-methyl and chloro substituents, in addition to the

importance of the N-benzoyl substituent, can be explored

through synthesis and testing of appropriate analogues.

Indomethacin 1 was developed by Shen and co-workers

in the Merck, Sharp and Dohme Research Laboratories

in the early 1960's.^2,3Signi®cantly, the lead compound

^ÃCorresponding author. Tel.: +353-21-490 2125; fax: +353-21-427

4097; e-mail: a.r.maguire@ucc.ie

PII: S0968-0896(00)00292-3

746

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

Figure 1.

However, some NSAIDs also inhibit other enzymes,

including phospholipase A₂(PLA₂). In 1978, Kaplan

and co-workers found that indomethacin 1 inhibits PLA₂

from rabbit polymorphonuclear leukocytes,⁷while more

recent reports have studied the inhibitory abilities of other

NSAIDs.⁸Development of selective inhibitors of human

PLA₂, based on N-benzyl derivatives of indomethacin,

has attracted considerable attention recently, including

work by Kreft and co-workers⁹at Wyeth-Ayerst and

Shevitz, Bach and co-workers^10À12at Lilly.

Bach and co-workers.^10À12These compounds were selec-

ted to allow systematicinvestigation of the in¯uence of

each of the structural components of indomethacin on the

enhancement of cytotoxicity of doxorubicin and other

anticancer agents in the combination toxicity assays. SAR

in this study were not necessarily expected to be identical

to SAR in indomethacin analogues for anti-in¯amma-

tory eects, COX and PLA₂inhibition. Therefore,

inclusion of compounds which are known COX inhibi-

tors (both COX-1 and COX-2 inhibitors including the

selective COX-2 inhibitor 7), and selective PLA₂inhi-

bitors with very little COX inhibition 26±29, allowed us

to investigate if there was any correlation between the

results obtained in this study, and previously studied

bioactivity pro®les of indomethacin analogues, thereby

providing information on the mode of action of MRP

inhibition.

A number of studies have considered the lipoxygenase

and cycloxygenase-inhibitory properties of NSAIDs,

including indomethacin, aspirin and sulindac, and their

eects on tumour growth and promotion.¹³While this

work was underway, a report by Levy and co-workers

of indomethacin-mediated reversal of MDR in cell lines

expressing MRP appeared.^1b

Synthesis of N-benzyl indomethacin analogues

In this paper, the synthesis of a range of indomethacin

derivatives is described; the results of their biological

evaluation in the enhancement of cytotoxicity of anti-

cancer agents in MRP-expressing cell lines will be descri-

bed elsewhere.¹⁴

The ®rst class of compounds selected for investigation

were N-benzyl derivatives of indomethacin; based on

the precedent for COX and PLA₂inhibition with

N-benzyl derivatives of indomethacin outlined above, it

was of interest to determine whether these derivatives

would result in enhancement of the cytotoxicity of

doxorubicin and other anti-cancer agents in the combi-

nation toxicity assays.

Results and Discussion

The indomethacin derivatives synthesised during this

work are summarised in Figure 2 and can be considered

in three distinct groups; compounds 4, 5 and 7±11 and

13±20 are N-benzyl indole acetic acid derivatives, com-

pounds 21±25 are N-benzoyl derivatives closely related

in structure to indomethacin and compounds 26±29 are

examples of the selective PLA₂inhibitors developed by

The ®rst compounds investigated were simple N-benzyl

indole-3-acetic acid derivatives 8±11 to establish if this

substructure of indomethacin were sucient for activ-

ity. These were prepared by benzylation of indole-3-

acetic acid in the presence of sodium hydride in DMF as

illustrated in Scheme 1.¹⁵Given the extensive structural

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

747

Figure 2.

748

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

Scheme 1.

modi®cation compared to indomethacin, it was not

surprising that these compounds did not prove active in

the combination toxicity assays.

the ¯uoro substituent to the 3-position (16±18). The

selective COX-2 inhibitor 7⁶was included in this study.

To explore the in¯uence of the 2-methyl and 5-methoxy

substituents, the N-4-chlorobenzyl derivatives 19 and

20, in which one of these groups is absent in each, were

prepared by benzylation of 5-methoxyindole-3-acetic

acid 31 and 2-methylindole-3-acetic acid 32, respec-

tively, with 4-chlorobenzyl chloride (Scheme 3).

A series of N-benzyl derivatives 4, 5, 7, 13±18, which

were much more closely related structurally to indo-

methacin 1 than 8±11, was prepared by benzylation of

the commercially available 5-methoxy-2-methylindole-3-

acetic acid 30 as illustrated in Scheme 2. Benzyl chlorides

and benzyl bromides 12 were used as precursors, depend-

ing on which was more readily available, with no notice-

able eect on the outcome of the benzylation. A pure

sample of each of the N-benzyl derivatives was obtained

by recrystallisation or chromatographic puri®cation. This

series allowed investigation of the in¯uence, in the

combination toxicity assay, of the nature of the 4-sub-

stituent (halo, methyl, methylthio or unsubstituted) on

the benzyl group (4, 5, 7, 13±15), and also the impact of

moving the chloro substituent to the 2- or 3-position, or

Synthesis of N-benzoyl indomethacin analogues

Whereas the syntheses of N-benzyl indomethacin ana-

logues were achievable in a simple one-step process, this

was not the case for the indomethacin analogues where

the N-benzoyl unit is retained. Direct N-benzoylation of

a commercially available indole nucleus is not feasible,

and thus such compounds must be synthesised by an

alternative route. The synthesis of indomethacin developed

Scheme 2.

Scheme 3.

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

749

by Yamamoto oers an elegant entry to these com-

pounds as outlined in Scheme 4.¹⁶para-Methoxyphenyl-

hydrazine 33 is treated with acetaldehyde in toluene at

0 ^ꢀC to give the hydrazone 34. This may then be ben-

zoylated at the N¹-position to give the N¹,N¹-dis-

ubstituted hydrazone 35, which upon treatment with

gaseous hydrogen chloride aords the hydrazine

hydrochloride 36. Subsequent cyclisation with levulinic

acid 37 in the classic Fischer indole synthesis provides

indomethacin 1.

benzoyl chloride to produce 38 and 39 respectively.

Benzoylation of the hydrazone 43 with 4-chlorobenzoyl

chloride was conducted in ether forming 44 in good

yield. Despite Yamamoto's report¹⁶that the benzoy-

lated hydrazone 35 precipitated out from the reaction

medium and was separable by simple ®ltration, this never

proved to be the case with 38, 39 and 44. Instead, it was

necessary to quench the reactions and obtain these pro-

ducts by ¯ash column chromatography. Each of the

benzoylated hydrazones were obtained as a single isomer.

Based on this syntheticroute the indomethaicn ana-

logues 21, 22 and 25 were prepared (Schemes 4 and 5) to

allow investigation of the signi®cance of the chloro and

methoxy substituents on the activity in the combination

toxicity assay. Both 4-methoxyphenylhydrazine 33 and

phenylhydrazine 42 were easily protected as their acetal-

dehyde hydrazones 34 and 43, respectively. Hydrazone 34

was benzoylated with benzoyl chloride and 4-bromo-

Each of the N¹,N¹-disubstituted hydrazones 38, 39 and

44 was easily converted to the corresponding hydrazine

hydrochlorides 40, 41 and 45 with gaseous hydrogen

chloride. Here, the hydrazone was dissolved in toluene/

methanol and when an excess of hydrogen chloride was

bubbled through the solution for 1 h at 0 ^ꢀC the desired

hydrazine hydrochloride could be obtained in good

yield and used without further puri®cation. To eect the

Scheme 4.

Scheme 5.

750

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

Fischer Indole synthesis, each of the three disubstituted

hydrazine hydrochlorides 40, 41 and 45 was, in turn,

reacted with levulinic acid 37 in acetic acid to give the

desired indomethacin analogues 21, 22 and 25 (Schemes

4 and 5). While the reaction proceeded eciently at 70±

80^oC with the methoxy substituted derivatives 40 and

41, re¯ux in acetic acid was necessary to form 25

re¯ecting the decreased activity in the absence of the

methoxy substituent. The dechloro derivative of indo-

methacin 21 and the bromo derivative of indomethacin

22 were obtained by recrystallisation; the demethoxy

derivative of indomethacin 25 was puri®ed by ¯ash col-

umn chromatography. The compounds were fully

characterised and displayed spectroscopic characteristics

very similar to those of indomethacin 1 as expected.

when reacted with p-benzoquinone in nitromethane

gave the 3-(carbomethoxy)-2-methyl-1-(phenylmethyl)-

5-hydroxyindole 48 in 47% yield and its 2-ethyl homo-

logue 49 in 53% yield. The products in both cases were

separable by simple ®ltration and could be used without

further puri®cation.

Before the 3-methyl ester can be reduced, the 5-hydroxy

function must be ®rst protected. Treatment of indoles

48 and 49 with methyl iodide under phase transfer con-

ditions resulted in the alkylated products 50 and 51.

These 5-methoxyindoles were recrystallised from iso-

propanol to give 50 (57%) and 51 (61%). Reduction of

the 3-methyl ester side chain could now proceed. This

was achieved with lithium aluminium hydride in THF at

room temperature following the procedure described by

Martinelli and co-workers,²¹the reactions proceeding

cleanly to aord alcohols 52 and 53 without further

need for puri®cation.

To determine the signi®cance of the carboxylic acid moi-

ety, the indomethacin derivatives 23 and 24 were prepared

as outlined in Scheme 6. While these compounds may

hydrolyse in vivo to release indomethacin, their solubility

and transport properties would be expected to be very

dierent to those of the free acid 1. The methyl ester 23

and the p-tolyl amide 24 were prepared via coupling with

methanol and p-toluidine, respectively, in the presence of

DCC and DMAP.

Elaboration of the 3-hydroxymethyl function to an

acetamide was achieved in two steps. Conversion of 52

and 53 to the cyanoindoles 54 and 55 was achieved with

cyanotrimethylsilane as nucleophile in the presence of

boron tri¯uoride etherate. Puri®cation was easily

achieved by elution through a silica gel plug to give 54 in

72% yield and 55 in 71% yield. Hydrolysis of the cyano

function was accomplished with powdered potassium

hydroxide in re¯uxing tert-butanol. Chromatographic

puri®cation of the 2-ethylindoleacetamide 57 by chro-

matography gave the product in 66% yield, while its

2-methyl homologue 56, which was prepared on a larger

scale, was puri®ed by two recrystallisations followed by

chromatography of the concentrated mother liquor to

give the product in an overall yield of 70%. Cleavage of

the 5-methoxy protecting group was achieved cleanly by

treatment with boron tribromide solution in dichloro-

methane at 0 ^ꢀC to give the 5-hydroxyindoleacetamides

58 (88%) and 59 (98%) without further puri®cation.

Synthesis of the N-benzyl indoleacetamide derivatives

The N-benzyl indoleacetamide derivatives 26±29 were the

next targets selected on the basis of the recent interest in

these compounds as selective PLA₂inhibitors with very

low COX inhibition.^12bDetermination of the activity of

these compounds in the combination toxicity assays

would be of interest, to establish if there is any correla-

tion between this study, PLA₂inhibition and COX inhi-

bition. Martinelli and co-workers²¹have reported a

practical synthetic route to 29 employing a Nenitzescu

reaction as the key step, and this approach was employed

in this work for the synthesis of each of the compounds

26±29 as summarised in Scheme 7.

Elaboration at the 5-position could now commence.

While Martinelli and co-workers²¹had conducted the

alkylation of 59 to 63 under phase transfer conditions,

in this work each of the alkylations to form 60±63 were

conducted using sodium hydride in DMF following the

conditions described by Bach and co-workers.^12bAlkyla-

tion with ethyl 4-bromobutyrate proceeded in reasonable

yield to give the chain-extended products 60 and 61 in 38

and 49% yields, respectively, after chromatographic

puri®cation. In both cases unreacted starting material

The enamino esters 46 and 47 were easily prepared in

quantitative yields by condensing benzylamine with

methyl acetoacetate and methyl propionylacetate in the

presence of a catalytic amount of p-toluenesulphonic

acid and could be used without further puri®cation. The

Nenitzescu cyclisation of the enamino esters with

p-benzoquinone is the key step in this syntheticstrategy

forming the indole nucleus with the desired 1,2,3,5-

substituent pattern. Thus the enamino esters 46 and 47

Scheme 6.

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

751

Scheme 7.

was recovered and could be reused resulting in corrected

yields of 47 and 58%, respectively. Saponi®cation with

aqueous sodium hydroxide and subsequent acidi®cation

with hydrochloric acid gave the PLA₂inhibitors 26 in

80% yield and 27 in 67% yield.

both cases, the starting material was completely con-

sumed. The 2-methylindoleacetamide 62 was obtained

in 58% yield after chromatographic puri®cation. When

the crude product from the reaction leading to the 2-

1

ethylindoleacetamide 63 was analysed by H and ¹³C

NMR spectroscopy, it was found to be essentially pure,

being contaminated only with DMF, and thus it was

used in the next step without further puri®cation. How-

ever, a 100 mg sample was reserved and puri®ed by

chromatography to give an analytically pure sample,

with an overall yield of 65%.

In order to obtain the phosphonicacid analogues 28 and

29, the bromo phosphonate 64 was synthesised by an

Arbuzov reaction of trimethylphosphite with an excess of

dibromopropane.²²The phosphonate side-chain was then

attached to the 5-hydroxyindoleacetamides 58 and 59 in a

similar fashion to before: treatment ®rst with sodium

hydride, then with the (bromopropyl)phosphonate 64

aords 62 and 63 in reasonable yield (Scheme 7). In

Cleavage of the phosphonate ester function was

achieved with iodotrimethylsilane in dichloromethane/

752

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

acetonitrile at room temperature. The intermediate tri-

methylsilyl phosphonate esters give, upon methanol

work-up, the desired phosphonicacids 28 and 29. The

2-methyl derivative 28 was obtained in 67% yield after

recrystallisation (ethyl acetate:acetonitrile:acetic acid:

water 21/7/7/9), while the 2-ethyl derivative 29 was

obtained in 35% yield after recrystallisation from the

same solvent mixture.

phosphorus pentoxide. Dry solvents were prepared by

re¯uxing over a drying agent under an inert atmosphere:

THF was dried over sodium/ benzophenone, ether and

toluene were dried over calcium hydride. Dimethylforma-

mide was distilled from calcium hydride under reduced

pressure (ca 15 mm Hg) and stored over activated

molecular sieves.

1-Benzylindole-3-acetic acid 8. To a slurry of sodium

hydride (60% dispersion in mineral oil; 0.55g, 13.8mmol,

2.4 equiv) in dry DMF (10 mL) under nitrogen at 0 ^ꢀC was

added indole-3-acetic acid (1.00 g, 5.71mmol) in one por-

tion. Stirring at 0 ^ꢀC was continued for 30min. Benzyl

bromide (0.82 mL, 6.84mmol, 1.2 equiv) was added in

one portion and stirring continued for 1 h. The reaction

was quenched by pouring into ice±water (ca 100 mL),

the resultant mixture acidi®ed with 10% hydrochloric

acid and the crude product obtained by ®ltration.

Recrystallisation (ether/ethanol) aorded the title com-

pound as a white solid (0.4459 g, 29.5%).

In summary, a series of indomethacin analogues has

been prepared to allow investigation of SAR in combi-

nation toxicity assays. All of the compounds were tested

for their ability to inhibit MRP-1-mediated drug eux,

as measured by the enhancement of adriamycin toxicity

in a miniaturised 96-well acid-phosphatase-based assay

in a human lung carcinoma cell line, DLKP.²³Indo-

methacin, which we have shown to be a potent MRP-1

inhibitor was used as a positive control.^1aThe deriva-

tives 4, 7, 14, 18, 21, 22, 25, 26 and 27 all displayed

MRP-1 inhibitory activity. It was found that the use of N-

benzyl in place of the N-benzoyl group did not abolish

MRP-1 inhibitory activity but the stringency of the

requirements for substituents in the phenyl ring was much

greater in the absence of the carbonyl group. The com-

pounds were also assayed for COX-1, COX-2 and GST

inhibitory activity as indomethacin is a potent inhibitor

of all three enzymes. The results indicated that there were

dierent structural requirements for inhibition of each of

the dierent molecular targets. These results will be dis-

cussed in more detail in a future paper outlining the full

biological properties of the agents.¹⁴

Mp 153±154 ^ꢀC (lit.¹⁵148 ^ꢀC); ꢀ_max(KBr)/cm^À13000±

2500 (OH), 1702 (CO); ¹H NMR (270 MHz, CDCl₃) d

7.10±7.63 (m, 10H, indole-H and Ph), 5.27 (s, 2H, N-

CH₂), 3.80 (s, 2H, CH₂CO₂H); ¹³C NMR (67.8 MHz,

CDCl₃) d 177.8 (CO), 137.3 (i-Ph), 136.6 (C7a), 128.8,

126.9 (o- and m-Ph), 127.9 (C3a), 127.6, 127.3 (C2 and

p-Ph), 122.1 (C5), 119.6, 119.1 (C4 and C6), 109.8 (C7),

106.9 (C3), 50.0 (N-CH₂), 31.0 (CH₂CO₂H); m/z 265

(M⁺, 8%), 149 (12), 91 (28), 84 (66), 49 (100); (found:

C, 76.7; H, 6.0; N, 5.4. C₁₇H₁₅NO₂requires C, 77.0; H,

5.7; N, 5.3%).

1-(4-Chlorobenzyl)indole-3-acetic acid 9. The procedure

followed was as detailed above, using: para-chlorobenzyl

chloride (1.10 g, 6.84mmol, 1.2 equiv). Upon acidi®ca-

tion, the crude product was extracted with dichloro-

methane (50 mL), the organiclayer washed with water

(3Â50 mL) and brine (50 mL), dried (MgSO₄), evapo-

rated and concentrated in vacuo. Recrystallisation

(ether/ethanol) aorded the title compound as a pale

yellow solid (0.6925 g, 40.5%).

Experimental

High ®eld ¹H and ¹³C NMR spectra were recorded on a

Jeol GSX FT spectrometer at 270.05 and 67.80 MHz,

1

respectively. Low ®eld H NMR spectra were recorded

on a Jeol PMX60SI (60 MHz) spectrometer. Spectra

recorded in CDCl₃are reported in parts per million

from internal tetramethylsilane. Spectra recorded in

DMSO-d₆are reported in parts per million from inter-

nal 3-(trimethylsilyl)propionic-2,2,3,3-d₄acid, sodium

salt. Coupling constants are reported in Hertz. The ³¹P

and ³¹C NMR spectra of 28 were recorded on a Jeol

Eclipse+400 spectrometer. Mass spectra were recorded

on a Kratos Pro®le HV-4 double focusing high resolu-

tion mass spectrometer. Elemental analyses were recor-

ded on a Perkin-Elmer 240 elemental analyser. IR

spectra were recorded on a Perkin-Elmer Paragon 1000

FT-IR spectrometer as liquid ®lms, chloroform (CHCl₃)

solutions or potassium bromide (KBr) discs. Melting

points were recorded on a Thomas Hoover capillary

melting point apparatus and are uncorrected.

Mp 146±148 ^ꢀC; ꢀ_max(KBr)/cm^À13300±2500 (OH),

1

1713 (CO); H NMR (270 MHz, CDCl₃) d 7.00±7.63

(m, 9H, indole-H and C₆H₄), 5.23 (s, 2H, CH₂), 3.80 (s,

2H, CH₂CO₂H); ¹³C NMR (67.8 MHz, CDCl₃) d 177.6

(CO), 136.5 (i-Ph), 135.9 (C7a), 133.5 (p-Ph), 129.0,

128.4 (o- and m-Ph), 127.9 (C3a), 127.1 (C2), 122.3 (C5),

119.8, 119.2 (C4 and C6), 109.7 (C7), 107.2 (C3), 49.4

(N-CH₂), 31.0 (CH₂CO₂H); m/z 299, 301 (M⁺[^35/37Cl],

32%), 255 (31), 125 (100); (found: C, 67.8; H, 4.9; N,

4.65; Cl, 11.4. C₁₇H₁₄NClO₂requires C, 68.1; H, 4.7; N,

4.7; Cl, 11.8%).

Thin layer chromatography was performed on DC-

Alufoilen Kieselgel 60F₂₅₄0.2 mm plates (Merck) and

visualised under UV light and with a vanillin stain.

Flash column chromatography was performed using

Kieselgel 60 (Merck) 230±400 mesh.

1-(4-Bromobenzyl)indole-3-acetic acid 10. The procedure

followed was as detailed above, using: para-bromobenzyl

bromide (1.71 g, 6.84mmol, 1.2 equiv). Recrystallisation

of the crude product (ether/ethanol) aorded the title

compound as a pale yellow solid (0.4493 g, 22.9%).

All solvents were distilled before use: hexane from cal-

cium chloride, dichloromethane and ethyl acetate from

Mp 147±149 ^ꢀC; ꢀ_max(KBr)/cm^À13000±2500 (OH),

1710 (CO); H NMR (270 MHz, CDCl₃) d 6.85±7.63

1

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

753

(m, 9H, indole-H and C₆H₄), 5.21 (s, 2H, CH₂), 3.78 (s,

2H, CH₂CO₂H); ¹³C NMR (67.8 MHz, CDCl₃) d 177.6

(CO), 136.4 (C7a), 131.9 (m-Ph), 128.5 (o-Ph), (i-Ph

not seen), 128.0 (C3a), 127.1 (C2), 122.3 (C5), 121.6 (p-

Ph), 119.7, 119.2 (C4 and C6), 109.7 (C7), 107.2 (C3),

49.5 (N-CH₂), 30.9 (CH₂CO₂H); m/z 343, 345 (M⁺(^79/

⁸¹Br], 30%), 299 (30), 224 (60), 125 (100); (found: C,

59.0; H, 4.3; N, 3.8; Br, 23.1. C₁₇H₁₄NBrO₂requires C,

59.3; H, 4.1; N, 4.1; Br, 23.2%).

CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 177.3 (CO),

154.4 (C5), 136.3 (p-Ph), 135.1, 133.1, 131.5, 128.1

(4ÂqC), 129.0, 127.3 (o- and m-Ph), 111.2, 109.8 (C4

and C6), 103.8 (C3), 100.5 (C7), 55.9 (CH₃O), 46.2 (N±

CH₂), 30.4 (CH₂CO₂H), 10.4 (CH₃).

1-(4-Bromobenzyl)-5-methoxy-2-methylindole-3-acetic acid

7. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (328.8 mg, 1.5

mmol), para-bromobenzyl bromide (281.2 mg, 1.35 mmol,

0.9 equiv), which was added dropwise via syringe as a

solution in DMF (1 mL), sodium hydride (60% disper-

sion in mineral oil; 144.0 mg, 3.6 mmol, 2.4 equiv) and

DMF (4 mL). Flash column chromatography (chloro-

form/methanol 15:1) aorded the title compound as a

pale yellow solid (119.6 mg, 20.5%).

1-(4-Methoxybenzyl)indole-3-acetic acid 11. The pro-

cedure followed was as detailed above, using: para-

methoxybenzyl bromide (0.93 mL, 6.84mmol, 1.2 equiv).

Recrystallisation of the crude product (ether/ethanol)

aorded the title compound as a pale yellow solid

(0.7957 g, 47.2%).

Mp 133±135 ^ꢀC; n_max(KBr)/cm^À13300±2200 (OH), 1712

(CO); ¹H NMR (270MHz, CDCl₃) d 6.79±7.62 (m, 9H,

indole-H and C₆H₄), 5.20 (s, 2H, N±CH₂), 3.78 (s, 2H,

CH₂CO₂H), 3.76 (s, 3H, CH₃O); ¹³C NMR (67.8 MHz,

CDCl₃) d 177.6 (CO), 159.1 (p-Ph), 136.5 (C7a), 129.3 (i-

Ph), 128.3 (o-Ph), 127.9 (C3a), 127.1 (C2), 122.0 (C5),

119.5, 119.0 (C4 and C6), 114.2 (m-Ph), 109.8 (C7), 106.7

(C3), 55.3 (CH₃O), 49.5 (N±CH₂), 31.0 (CH₂CO₂H); m/z

295 (M⁺, 10%), 251 (17), 121 (100); (found: C, 72.7; H,

6.2; N, 4.4. C₁₈H₁₇NO₃requires C, 73.2; H, 5.8; N, 4.7%).

Mp 191±192 ^ꢀC; n_max(KBr)/cm^À13300±2500 (OH), 1700

(CO); ¹H NMR (270 MHz, CDCl₃) d 6.77±7.35 (m, 7H,

indole-H and C₆H₄), 5.20 (s, 2H, N±CH₂), 3.84 (s, 3H,

CH₃O), 3.72 (s, 2H, CH₂CO₂H), 2.29 (s, 3H, CH₃); ¹³C

NMR (67.8 MHz, CDCl₃) d 177.7 (CO), 154.4 (C5),

136.8, 135.0, 132.3, 128.1 (4ÂqC), 132.5, 127.7 (o- and

m-Ph), 121.1 (p-Ph), 111.1, 109.7 (C4 and C6), 104.0

(C3), 100.5 (C7), 55.9 (CH₃O), 46.2 (N±CH₂), 30.5 (CH₂

CO₂H), 10.3 (CH₃); m/z 387, 389 (M⁺[^79/81Br], 1%), 239

(25), 121 (68), 78 (94), 63 (100); (found: C, 59.0; H, 5.0; N,

3.9. C₁₉H₁₈NBrO₃requires C, 58.8; H, 4.7; N, 3.6%).

1-Benzyl-5-methoxy-2-methylindole-3-acetic acid 13. The

procedure followed was as detailed above, using: 5-meth-

oxy-2-methylindole-3-acetic acid (328.8 mg, 1.5 mmol),

benzyl chloride (207 mL, 1.8 mmol, 1.2 equiv), sodium

hydride (60% dispersion in mineral oil; 144.0 mg, 3.6

mmol, 2.4 equiv) and DMF (4 mL). Flash column chro-

matography (chloroform/methanol 20:1) aorded the title

compound as a pale yellow solid (175.0 mg, 37.7%).

1-(4-Fluorobenzyl)-5-methoxy-2-methylindole-3-acetic acid

14. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (328.8mg, 1.5

mmol), para-¯uorobenzyl bromide (187 mL, 1.5 mmol,

1.0 equiv), which was added dropwise via syringe,

sodium hydride (60% dispersion in mineral oil; 144.0 mg,

3.6 mmol, 2.4 equiv) and DMF (5 mL). Flash column

chromatography (chloroform/methanol 20:1) aorded

the title compound as a white solid (140.8 mg, 28.7%).

Mp 169±173 ^ꢀC; n_max(KBr)/cm^À13300±2500 (OH),

1

1700 (CO); H NMR (270 MHz, CDCl₃) d 6.73±7.25

(m, 8H, indole-H and Ph), 5.22 (s, 2H, N-CH₂), 3.81 (s,

3H, CH₃O), 3.69 (s, 2H, CH₂CO₂H), 2.26 (s, 3H, CH₃);

¹³C NMR (67.8 MHz, CDCl₃) d 177.6 (CO), 154.3

(C5), 137.8, 153.2, 131.7, 128.1 (4ÂqC), 127.3 (p-Ph),

128.8, 125.9 (o- and m-Ph), 111.0, 109.9 (C4 and C6),

103.7 (C3), 100.4 (C7), 55.9 (CH₃O), 46.7 (N±CH₂), 30.5

(CH₂CO₂H), 10.4 (CH₃); m/z 309 (M⁺, 82%), 264 (70),

173(37), 158 (38), 91 (100); (Found: C, 73.4; H, 6.15; N,

4.2. C₁₉H₁₉NO₃requires C, 73.8; H, 6.2; N, 4.5%).

Mp 167±169 ^ꢀC; n_max(KBr)/cm^À13300±2500 (OH),

1

1686 (CO); H NMR (270 MHz, CDCl₃) d 6.74±7.07

(m, 7H, indole-H and C₆H₄), 5.21 (s, 2H, N±CH₂), 3.83

(s, 3H, CH₃O), 3.71 (s, 2H, CH₂CO₂H), 2.28 (s, 3H,

CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 177.1 (CO),

162.1 (d, J_CF246, C4⁰), 154.4 (C5), 135.0, 133.5, 131.5,

128.1 (4ÂqC), 127.6 (d, ³J_CF8.7, C2⁰and C6⁰), 115.7 (d,

²J_CF22.4, C3⁰and C5⁰), 111.1, 109.8 (C4 and C6), 103.8

(C3), 100.5 (C7), 55.8 (CH₃O), 46.2 (N±CH₂), 30.4 (CH₂

CO₂H), 10.4 (CH₃); m/z 327 (M⁺, 2%), 283 (5), 205

(19), 109 (17), 84 (73), 49 (100); (found: C, 69.9; H, 5.6;

N, 4.0; F, 5.7. C₁₉H₁₈NFO₃requires C, 69.7; H, 5.5; N,

4.3; F, 5.8%).

1-(4-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid

4. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (219.2 mg,

1

mmol), para-chlorobenzyl chloride (193.2 mg, 1.2 mmol,

1.2 equiv), sodium hydride (60% dispersion in mineral

oil; 96.0 mg, 2.4 mmol, 2.4 equiv) and DMF (5 mL).

Recrystallisation of the crude product (ether/ethanol)

aorded the title compound as a pale yellow solid (141.1

mg, 41.1%).

1-(4-Methylthiobenzyl)-5-methoxy-2-methylindole-3-acetic

acid 5. The procedure followed was as detailed above,

using: 5-methoxy-2-methylindole-3-acetic acid (438.5mg,

2 mmol), para-methylthiobenzyl chloride¹⁷(414.4 mg, 2.4

mmol, 1.2 equiv), which was added dropwise as a solu-

tion in DMF (1 mL), sodium hydride (60% dispersion

in mineral oil; 192.0 mg, 4.8 mmol, 2.4 equiv) and DMF

(5 mL). Flash column chromatography (chloroform/

methanol 20:1) aorded a dark orange solid that was

further puri®ed by recrystallisation (dichloromethane/

Mp 185±187 ^ꢀC; n_max(KBr)/cm^À13200±2500 (OH),

1

1706 (CO); H NMR (270 MHz, CDCl₃) d 6.74±7.25

(m, 7H, indole-H and C₆H₄), 5.22 (s, 2H, N-CH₂), 3.84

(s, 3H, CH₃O), 3.72 (s, 2H, CH₂CO₂H), 2.29 (s, 3H,

754

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

hexane), giving the title compound as an o-white solid

(119.2 mg, 16.8%).

1 mmol), ortho-chlorobenzyl chloride (147 mL, 1.2 mmol,

1.2 equiv), sodium hydride (60% dispersion in mineral

oil; 96.0 mg, 2.4 mmol, 2.4 equiv) and DMF (5 mL).

Recrystallisation of the crude product (dichloro-

methane/hexane) aorded the title compound as a white

solid (119.2 mg, 34.7%).

Mp 159±160 ^ꢀC (lit.¹⁸155±56.5 ^ꢀC); n_max(KBr)/cm^À1

3300±2500 (OH), 1709 (CO); ¹H NMR (270MHz,

CDCl₃) d 6.74±7.16 (m, 7H, indole-H and C₆H₄), 5.22 (s,

2H, N-CH₂), 3.84 (s, 3H, CH₃O), 3.72 (s, 2H, CH₂CO₂H),

2.42 (s, 3H, CH₃S), 2.30 (s, 3H, CH₃); ¹³C NMR

(67.8 MHz, CDCl₃) d 176.9 (CO), 154.4 (C5), 137.5,

135.1, 131.6, 128.1 (4ÂqC), 134.8 (p-Ph), 127.2, 126.5 (o-

and m-Ph), 111.1, 109.9 (C4 and C6), 103.6 (C3), 100.5

(C7), 56.0 (CH₃O), 46.4 (N±CH₂), 30.4 (CH₂CO₂H), 15.9

(CH₃S), 10.4 (CH₃); m/z 355 (M⁺, 17%), 311 (12), 137

(100); (found: C, 67.5; H, 6.2; N, 4.2; S, 8.8.

C₂₀H₂₁NSO₃requires C, 67.6; H, 6.0; N, 3.9; S, 9.0%).

Mp 193±196 ^ꢀC; n_max(KBr)/cm^À13300±2400 (OH),

1

1702 (CO); H NMR (270 MHz, CDCl₃) d 6.98±7.41

(m, 5H, C₆H₄and 4-H), 6.77 (dd, J 8.6, 2.4, 1H, 6-H),

6.23 (d, J 7.6, 1H, 7-H), 5.32 (s, 2H, N±CH₂), 3.85 (s,

3H, CH₃O), 3.76 (s, 2H, CH₂CO₂H), 2.28 (s, 3H, CH₃);

¹³C NMR (67.8 MHz, CDCl₃) d 176.7 (CO), 154.6

(C5), 135.2 (C2⁰), 131.9, 131.6, 128.2 (3ÂqC), 129.4,

128.7, 127.4, 127.0 (C3⁰, C4⁰, C5⁰and C6⁰), 111.3, 109.7

(C4 and C6), 103.9 (C3), 100.6 (C7), 55.9 (CH₃O), 44.6

(N±CH₂), 30.4 (CH₂CO₂H), 10.2 (CH₃); m/z 343

(M⁺[³⁵Cl], 1%), 299 (8), 125 (19), 84 (75), 49 (100).

1-(4-Methylbenzyl)-5-methoxy-2-methylindole-3-acetic acid

15. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (400mg, 1.82

mmol), para-methylbenzyl bromide (405mg, 2.19mmol,

1.2 equiv), sodium hydride (60% dispersion in mineral

oil: 175.2 mg, 4.38 mmol, 2.4 equiv) and DMF (5 mL).

Recrystallisation of the crude product (methanol) aor-

ded the title compound as a white solid (70 mg, 12%).

1-(3-Fluorobenzyl)-5-methoxy-2-methylindole-3-acetic acid

18. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (548.1 mg, 2.5

mmol), meta-¯uorobenzyl bromide (363mL, 3 mmol, 1.2

equiv), sodium hydride (60% dispersion in mineral oil;

240.0 mg, 6 mmol, 2.4 equiv) and DMF (5 mL). Recrys-

tallisation (dichloromethane/hexane) aorded the title

compound as a white solid (350.2 mg, 42.8%).

Mp 189±190^ꢀC; n_max(KBr)/cm^À13300±2500 (OH), 1698

(CO); ¹H NMR (270MHz, CDCl₃) d 7.32±6.74 (m, 7H,

indole-H and C₆H₄), 5.22 (s, 2H, N-CH₂), 3.84 (s, 3H,

CH₃O), 3.72 (s, 2H, CH₂CO₂H), 2.30 (s, 3H, CH₃), 2.28 (s,

3H, CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 177.8 (CO),

154.2 (C5), 136.9, 135.2, 134.7, 131.6 (4ÂqC), 129.4, 125.9

(o- and m-Ph), 127.9 (p-Ph), 111.0, 110.0 (C4 and C6),

103.3 (C3), 100.2 (C7), 55.9 (CH₃O), 46.6 (N±CH₂), 30.5

(CH₂CO₂H), 21.0 (CH₃), 10.4 (CH₃); m/z 323 (M⁺, 74%),

278 (67), 105 (100); (found: C, 73.91; H, 6.51; N, 4.17;

C₂₀H₂₁NO₃requires C, 74.28; H, 6.39; N, 4.33%).

Mp 182±183 ^ꢀC; n_max(KBr)/cm^À13300±2200 (OH),

1

1702 (CO); H NMR (270 MHz, CDCl₃) d 6.61±7.26

(m, 7H, indole-H and C₆H₄), 5.25 (s, 2H, N-CH₂), 3.85

(s, 3H, CH₃O), 3.73 (s, 2H, CH₂CO₂H), 2.30 (s, 3H,

CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 176.4 (CO),

163.2 (d, J_CF246, C3⁰), 154.4 (C5), 140.5 (d, J_CF7.5,

3

C1⁰), 135.0, 131.5, 128.1 (3ÂqC), 130.4 (d, ³J_CF7.5, C5⁰),

121.5 (d, ⁴J_CF2.5, C6⁰), 114.3, 113.0 (2 d, ²J_CF21.2, ²J_CF

21.2, C2⁰and C4⁰), 111.2, 109.7 (C4 and C6), 103.9 (C3),

100.5 (C7), 55.9 (CH₃O), 46.4 (N±CH₂), 30.3

(CH₂CO₂H), 10.4 (CH₃); m/z 327 (M⁺, 84%), 282 (100),

117 (88), 109 (77); (found: C, 70.1; H, 5.5; N, 4.3; F, 6.1.

C₁₉H₁₈NFO₃requires C, 69.7; H, 5.5; N, 4.3; F, 5.8%).

1-(3-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid

16. The procedure followed was as detailed above, using:

5-methoxy-2-methylindole-3-acetic acid (219.2 mg,

1

mmol), meta-chlorobenzyl chloride (148mL, 1.2 mmol, 1.2

equiv), sodium hydride (60% dispersion in mineral oil;

96.0 mg, 2.4 mmol, 2.4 equiv) and DMF (5 mL). Recrys-

tallisation of the crude product (dichloromethane/hexane)

aorded the title compound as a white solid (157.1 mg,

45.7%).

1-(4-Chlorobenzyl)-5-methoxyindole-3-acetic acid 19.

The procedure followed was as detailed above, using:

5-methoxyindole-3-acetic acid (410.4 mg, 2 mmol), para-

chlorobenzyl chloride (386.5 mg, 2.4 mmol, 1.2 equiv),

sodium hydride (60% dispersion in mineral oil; 192.0 mg,

4.8 mmol, 2.4 equiv) and DMF (5 mL). Flash column

chromatography (chloroform/methanol 20:1) aorded a

pale yellow solid that was further puri®ed by recrys-

tallisation (dichloromethane/hexane), giving the title

compound as a white solid (185.6 mg, 28.1%).

Mp 177±179 ^ꢀC; n_max(KBr)/cm^À13200±2500 (OH),

1

1710 (CO); H NMR (270 MHz, CDCl₃) d 6.74±7.22

(m, 7H, indole-H and C₆H₄), 5.23 (s, 2H, N-CH₂), 3.85

(s, 3H, CH₃O), 3.73 (s, 2H, CH₂CO₂H), 2.28 (s, 3H,

CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 176.8 (CO),

154.4 (C5), 139.9 (C3⁰), 135.0, 134.8, 131.5, 128.1

(4ÂqC), 130.1, 127.6, 126.1, 124.1 (C2⁰, C4⁰, C5⁰and

C6⁰), 111.2, 109.8 (C4 and C6), 103.9 (C3), 100.5 (C7),

55.9 (CH₃O), 46.3 (N±CH₂), 30.3 (CH₂CO₂H), 10.4

(CH₃); m/z 343 (M⁺[³⁵Cl], 1%), 299 (12), 125 (16), 84

(68), 43 (100); (found: C, 65.9; H, 5.4; N, 4.0.

C₁₉H₁₈NClO₃requires C, 66.4; H, 5.3; N, 4.1%).

Mp 145±146 ^ꢀC; n_max(KBr)/cm^À13300±2400 (OH),

1

1706 (CO); H NMR (270 MHz, CDCl₃) d 6.81±7.27

(m, 8H, indole-H and C₆H₄), 5.20 (s, 2H, N-CH₂), 3.84

(s, 3H, CH₃O), 3.77 (s, 2H, CH₂CO₂H); ¹³C NMR (67.8

MHz, CDCl₃) d 177.3 (CO), 154.3 (C5), 135.9 (p-Ph),

133.5, 131.7, 128.3 (3ÂqC), 128.7, 128.1 (o- and m-Ph),

127.8 (C2), 112.6, 110.6 (C4 and C6), 106.6 (C3), 100.9

(C7), 55.9 (CH₃O), 49.6 (N±CH₂), 31.0 (CH₂CO₂H); m/

z 329, 331 (M⁺[^35/37Cl], 14%), 284 (12), 127 (19), 125

(60), 69 (82), 41 (100); (found: C, 65.9; H, 5.2; N, 4.3;

1-(2-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid

17. The procedure followed was as detailed above,

using: 5-methoxy-2-methylindole-3-acetic acid (219.2mg,

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

755

Cl, 11.0. C₁₈H₁₆NClO₃requires C, 65.55; H, 4.9; N,

4.25; Cl, 10.75%).

hydrazone (1.00 g, 6.09 mmol) in pyridine (5 mL) under

nitrogen at 0 ^ꢀC was added benzoyl chloride (1.42 mL,

12.2mmol, 2.0 equiv) in one portion. Stirring at rt was

continued for 3 h. The reaction mixture was partitioned

between water (50 mL) and dichloromethane (30 mL). A

®ne, white, insoluble solid was removed by suction ®ltra-

tion, washing with a portion of dichloromethane (20 mL).

The ®ltrate was placed in a separatory funnel, the

1-(4-Chlorobenzyl)-2-methylindole-3-acetic acid 20. The

procedure followed was as detailed above, using:

2-methylindole-3-acetic acid (378.4 mg, 2 mmol), para-

chlorobenzyl chloride (386.5 mg, 2.4 mmol, 1.2 equiv),

sodium hydride (60% dispersion in mineral oil; 192.0 mg,

4.8 mmol, 2.4 equiv) and DMF (10 mL). Flash column

chromatography (chloroform/methanol 20:1) aorded a

pale yellow solid that was further puri®ed by recrys-

tallisation (dichloromethane/hexane), giving the title

compound as a white solid (229.2 mg, 36.5%).

organiclayer removed, dried (MgSO ), evaporated and

4

concentrated in vacuo. Flash column chromatography

(hexane/ethyl acetate 1:1) aorded the title compound

as a clear, orange oil (0.88 g, 54.1%).

n_max(®lm)/cm^À11660 (CO); ¹H NMR (60 MHz,

CDCl₃) d 6.9±8.2 (m, 9H, C₆H₄and Ph), 6.8 (q, J 5, 1H,

NCHCH₃), 3.7 (s, 3H, CH₃O), 1.8 (d, J 5, 3H, N

CHCH₃).

Mp 182±184 ^ꢀC; n_max(KBr)/cm^À13300±2200 (OH),

1

1706 (CO); H NMR (270 MHz, CDCl₃) d 6.86±7.58

(m, 8H, indole-H and C₆H₄), 5.26 (s, 2H, N±CH₂), 3.76

(s, 2H, CH₂CO₂H), 2.31 (s, 3H, CH₃); ¹³C NMR (67.8

MHz, CDCl₃) d 177.0 (CO), 136.3 (p-Ph), 134.4, 133.2,

127.7 (3ÂqC), 129.0, 127.4 (o- and m-Ph), 121.5 (C5),

119.8, 118.2 (C4 and C6), 109.1 (C7), 104.2 (C3), 46.1 (N±

CH₂), 30.3 (CH₂CO₂H), 10.3 (CH₃); m/z 313, 315

(M⁺[^35/37Cl], 14%), 268 (20), 127 (36), 125 (100);

(found: C, 69.1; H, 5.5; N, 4.6; Cl, 11.3. C₁₈H₁₆NClO₂

requires C, 68.9; H, 5.1; N, 4.5; Cl, 11.3%).

Acetaldehyde N¹-(4-bromobenzoyl)-N¹-(4-methoxyphenyl)

hydrazone 39. The procedure followed was as detailed

above, using: acetaldehyde 4-methoxyphenylhydrazone

(0.94 g, 5.74 mmol), 4-bromobenzoyl chloride (2.52 g,

11.47 mmol, 2.0 equiv), which was added in one portion,

and pyridine (10 mL). Flash column chromatography

(hexane/ethyl acetate 7:5) aorded the title compound

as an orange solid (1.212 g, 60.8%).

Acetaldehyde 4-methoxyphenylhydrazone 34.^16aTo a

slurry of 4-methoxyphenylhydrazine (5.967 g, 43.2 mmol)

in toluene (40 mL) under nitrogen at 0 ^ꢀC was added a

solution of acetaldehyde (3.62 mL, 64.8 mmol, 1.5 equiv)

in toluene (7 mL) dropwise. Stirring at rt was continued

for 30 min. The solution was decanted through a ¯uted

®lter paper into a RB-¯ask, evaporated and concentrated

in vacuo. Bulb-to-bulb distillation (140 ^ꢀC/0.6 mm Hg)

aorded the title compound as a clear yellow liquid

(4.5290 g, 63.8%; E and Z isomers formed in a 1:1 ratio).

n_max(®lm)/cm^À11662 (CO); ¹H NMR (270 MHz,

CDCl₃) d 7.67, 7.55 (ABq, J 10.0, 4H, MeOC₆H₄), 7.10,

7.01 (ABq, J=8.9, 4H, BrC₆H₄), 6.82 (q, J=5.4, 1H,

NCHCH₃), 3.84 (s, 3H, CH₃O), 1.88 (d, J=5.1, 3H,

NCHCH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 169.2

(CO), 159.9, 134.4, 124.7 (3ÂqC, 1 qC not seen), 131.4,

130.6, 130.3 (3ÂCH, 1 CH not seen), 115.4 (CN), 55.5

(CH₃O), 18.5 (CH₃).

Acetaldehyde N¹-(4-chlorobenzoyl)-N¹-phenylhydrazone

44. The procedure followed was as detailed above, using:

acetaldehyde phenylhydrazone (1.00g, 7.45mmol),

4-chlorobenzoyl chloride (0.95 mL, 7.45mmol, 1.0 equiv),

pyridine (0.60 mL, 7.45mmol, 1.0 equiv) and ether (10

mL). Flash column chromatography (hexane/ethyl ace-

tate 1:1) aorded the title compound as a clear, orange

oil (1.3519 g, 66.5%).

n_max(®lm)/cm^À13302 (NH), 2936 (CH); ¹H NMR

(270 MHz, CDCl₃) d 6.75±7.06 (m, 5.5H, C₆H₄, NH and

NCH(CH₃) one isomer), 6.62 (q, J 5.7, 0.5H, N

CH(CH₃) one isomer), 3.74, 3.75 (2 s, 3H, CH₃O, E and

Z isomers), 1.94, 1.81 (2 d, J 5.1, 5.7, 3H, NCH(CH₃), E

and Z isomers); ¹³C NMR (67.8 MHz, CDCl₃) d 153.8,

153.5 (p-Ph, E and Z isomers), 139.7, 139.5 (i-Ph, E and

Z isomers), 138.3, 136.8 (o- and m-Ph), 114.1, 113.9

(CN, E and Z isomers), 55.4 (CH₃O), 12.0 (CH₃).

n_max(®lm)/cm^À11663 (CO); ¹H NMR (60 MHz,

CDCl₃) d 7.0±7.8 (m, 9H, C₆H₄and Ph), 6.7 (q, J=5,

1H, NCHCH₃), 1.8 (d, J=5, 3H, NCHCH₃).

Acetaldehyde phenylhydrazone 43. The procedure fol-

lowed was as detailed above, using: phenylhydrazine

(10.82 g, 0.1 mol), acetaldehyde (8.4 mL, 0.15 mol, 1.5

equiv) and toluene (40 mL). Bulb-to-bulb distillation of

the crude product (66±80 ^ꢀC/0.25±0.45 mm Hg) aorded

a yellow oil, which upon trituration with hexane recrys-

tallised. The title compound was obtained as a yellow

crystalline solid by ®ltration (3.57 g, 26.6%; E and Z

isomers formed in a 3:2 (or 2:3) ratio).

N¹-Benzoyl-N¹-(4-methoxyphenyl)hydrazine hydrochloride

40. An excess of gaseous hydrogen chloride was bub-

bled through a solution of acetaldehyde N¹-benzoyl-N¹-

(4-methoxyphenyl)hydrazone (442.0 mg, 1.65 mmol) in

toluene (20 mL) and methanol (1 mL) at 0 ^ꢀC for 1 h.

Excess hydrogen chloride was removed under reduced

pressure (ca 15 mm Hg) for 30 min and the solvent eva-

porated. The contents were swirled with a little toluene

and ®ltered by suction aording the title compound as a

white solid without further puri®cation (267.0 mg,

58.1%).

Mp 66±82 ^ꢀC; ¹H NMR (60 MHz, CDCl₃) d 6.4±7.3 (m,

7H, C₆H₅, NH and NCH(CH₃)), 1.7 [minor], 1.9

[major] (2 d, J 5, 3H, NCH(CH₃), E and Z isomers).

Acetaldehyde N¹-benzoyl-N¹-(4-methoxyphenyl)hydrazone

38. To a solution of acetaldehyde 4-methoxyphenyl-

Mp 170±172 ^ꢀC; n_max(KBr)/cm^À13300±2300 (NH⁺₃),

1680 (CO).

756

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

N¹-(4-Bromobenzoyl)-N¹-(4-methoxyphenyl)hydrazine

hydrochloride 41. The procedure followed was as detailed

above, using: acetaldehyde N¹-(4-bromobenzoyl)-N¹-(4-

methoxyphenyl)hydrazone (1.212 g, 3.49 mmol), aord-

ing the title compound as a white solid without further

puri®cation (1.0216 g, 81.8%).

hexane) aorded the title compound as a white solid

(0.1923 g, 28.5%).

Mp 160±162 ^ꢀC (lit.²⁰162±164^ꢀC); n_max(KBr)/cm^À13300±

2500 (OH), 1697 (carboxyl CO), 1677 (amide CO); ¹H

NMR (270 MHz, CDCl₃/acetone-d₆) d 7.69, 7.61 (ABq,

J=6.6, 4H, C₆H₄), 7.03 (d, J=2.7, 1H, 4-H), 6.93 (d,

J=8.9, 1H, 7-H), 6.66 (dd, J=9.2, 2.4, 1H, 6-H), 3.82 (s,

3H, CH₃O), 3.69 (s, 2H, CH₂), 2.36 (s, 3H, CH₃); ¹³C

NMR (67.8 MHz, CDCl₃/acetone-d₆) d 171.0 (carboxyl

CO), 167.5 (amide CO), 155.4 (C5), 134.9, 134.0,

130.1, 126.6, 112.3 (5ÂqC, 1 qC not seen), 131.6, 129.2 (o-

and m-Ph), 114.1, 110.8 (C4 and C6), 100.8 (C7), 54.6

(CH₃O), 12.3 (CH₃), a-CH₂signal at d ꢁ29 ppm obscured

by acetone-d₆peaks; m/z 401, 403 (M⁺[^39/81Br], 51%), 185

(92), 183 (100); (found: C, 56.4; H, 4.3; N, 3.55; Br, 19.6.

C₁₉H₁₆NBrO₄requires C, 56.7; H, 4.0; N, 3.5; Br, 19.9%).

Mp 167±169 ^ꢀC; n_max(KBr)/cm^À13000±2500 (NH⁺₃),

1670 (CO).

N¹-(4-Chlorobenzoyl)-N¹-phenylhydrazine hydrochloride

45. The procedure followed was as detailed above,

using: acetaldehyde N¹-(4-chlorobenzoyl)-N¹-phenyl-

hydrazone (1.209 g, 4.43 mmol), aording the title com-

pound as a white solid without further puri®cation

(1.120 g, 89.2%).

Mp 183±192 ^ꢀC; n_max(KBr)/cm^À13000±2500 (NH⁺₃),

1680 (CO).

1-(4-Chlorobenzoyl)-2-methylindole-3-acetic acid 25. The

procedure followed was as detailed above, using: N¹-(4-

chlorobenzoyl)-N¹-phenylhydrazine hydrochloride (0.989

g, 3.49 mmol), levulinicaicd (0.487 g, 4.19 mmol, 1.2

equiv) and acetic acid (5 mL). In this case the reaction

was conducted at re¯ux for 5 h. Flash column chroma-

tography (chloroform/methanol 10:1) aorded the title

compound as a white solid (0.287 g, 27.6%).

1-Benzoyl-5-methoxy-2-methylindole-3-acetic acid 21.

N¹-Benzoyl-N¹-(4-methoxyphenyl)hydrazine hydrochlor-

ide (338 mg, 1.21 mmol), levulinicaicd (169 mg, 1.48

mmol, 1.2 equiv) and acetic acid (5 mL) were placed in a

RB-¯ask ®tted with a re¯ux condenser and heated at

80 ^ꢀC under nitrogen for 3 h. The reaction solution was

allowed to cool to rt overnight. The reaction mixture

was partitioned between water (25 mL) and dichloro-

methane (25 mL), the organiclayer removed and the

aqueous extracted with a further portion of dichloro-

methane (25 mL). The combined organics were washed

with water (3Â25 mL) and extracted with saturated

aqueous sodium bicarbonate solution (2Â25mL). The

combined aqueous extracts were acidi®ed (ꢁ20mL 10%

hydrochloric acid) and the resultant mixture extracted

with dichloromethane (2Â25mL). The combined organic

extracts were dried (MgSO₄), evaporated and con-

centrated in vacuo. Recrystallisation of the crude product

(acetone/water) aorded the title compound as a white

solid (180.6 mg, 46.2%).

n_max(KBr)/cm^À13500±2500 (OH), 1686 (CO); ¹H

NMR (270 MHz, CDCl₃) d 6.83±7.58 (m, 8H, C₆H₄and

indole-H), 3.50 (s, 2H, CH₂), 2.23 (s, 3H, CH₃); ¹³C

NMR (67.8 MHz, CDCl₃) d 178.3 (carboxyl CO),

169.0 (amide CO), 140.4 (p-Ph), 137.2, 136.3, 134.7,

130.5 (4ÂqC), 132.3, 130.0 (o- and m-Ph), 124.0, 123.6

(C4 and C5), 119.2 (C6), 114.5 (C7), 113.0 (C3), 31.0

(CH₂), 13.3 (CH₃).

Methyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-

acetate 23. To a solution of 1-(4-chlorobenzoyl)-5-meth-

oxy-2-methylindole-3-acetic acid (358mg, 1.0 mmol) and

4-dimethylaminopyridine (12 mg, 0.1 mol, 10 mol%) in

dichloromethane (10 mL) at 0^ꢀC was added, ®rst, metha-

nol (0.40 mL, 10mmol, 10 equiv) in one portion, and sec-

ond, a solution of dicyclohexylcarbodiimide (227 mg,

1.1 mmol, 1.1 equiv) in dichloromethane (10 mL) drop-

wise. Stirring was continued at rt for 2 h. The reaction

mixture was cooled to 0 ^ꢀC, ®ltered through Celite and the

®ltrate evaporated and concentrated in vacuo. Flash col-

umn chromatography (hexane/ethyl acetate 3:1) aorded

the title compound as a pale yellow solid (292mg, 78.6%).

Mp 175±176 ^ꢀC (lit.¹⁹176±177 ^ꢀC); n_max(KBr)/cm^À1

3500±3000 (OH), 1731 (carboxyl CO), 1645 (amide

1

CO); H NMR (270 MHz, CDCl₃/acetone-d₆) d 7.48±

7.72 (m, 5H, C₆H₅), 7.01 (d, J=2.4, 1H, 4-H), 6.91 (d,

J=8.9, 1H, 7-H), 6.64 (dd, J=8.9, 2.4, 1H, 6-H), 3.82

(s, 3H, CH₃O), 3.69 (s, 2H, CH₂), 2.36 (s, 3H, CH₃); ¹³

C

NMR (67.8 MHz, CDCl₃/acetone-d₆) d 171.5 (carboxyl

CO), 168.8 (amide CO), 155.5 (C5), 135.3, 130.6,

130.2, 112.2 (4ÂqC, 1 qC not seen), 132.1 (p-Ph), 129.0,

128.2 (o- and m-Ph), 114.4, 111.0 (C4 and C6), 100.9

(C7), 55.0 (CH₃O), 12.6 (CH₃), a-CH₂signal at d

ꢁ29 ppm obscured by acetone-d₆peaks; m/z 323 (M⁺,

49%), 105 (100), 77 (21); (found: C, 70.2; H, 5.2; N, 4.4.

C₁₉H₁₇NO₄requires C, 70.6; H, 5.3; N, 4.3%).

n

_max(KBr)/cm^À11732 (ester CO), 1682 (amide CO);

¹H NMR (270 MHz, CDCl₃) d 7.74, 7.56 (ABq, J=5.1,

4H, C₆H₄), 7.06 (d, J=2.4, 1H, 4-H), 6.96 (d, J=8.9,

1H, 7-H), 6.77 (dd, J=8.9, 2.7, 1H, 6-H), 3.93 (s, 3H,

5-CH₃O), 3.80 (ester CH₃O), 3.77 (s, 2H, CH₂), 2.48 (s,

3H, CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 171.2 (ester

CO), 168.2 (amide CO), 156.1 (C5), 139.2, 135.9,

134.0, 130.8, 130.7, 112.5 (6ÂqC), 131.1, 129.4 (o- and

m-Ph), 114.9, 111.6 (C4 and C6), 101.4 (C7), 55.7 (5-

CH₃O), 52.1 (ester CH₃O), 30.1 (CH₂), 13.2 (CH₃).

1-(4-Bromobenzoyl)-5-methoxy-2-methylindole-3-acetic

acid 22. The procedure followed was as detailed above,

using: N¹-(4-bromobenzoyl)-N¹-(4-methoxyphenyl)hydra-

zine hydrochloride (0.500 g, 1.40 mmol), levulinic acid

(0.195 g, 1.68 mmol, 1.2 equiv) and acetic acid (5 mL).

The reaction mixture was heated at 70±80^ꢀC for 6 h.

Recrystallisation of the crude product (dichloromethane/

N-Tolyl 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-

3-acetamide 24. To a solution of 1-(4-chlorobenzoyl)-5-

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

757

methoxy-2-methylindole-3-acetic acid (358mg, 1.0mmol),

toluidine (118 mg, 1.1 mmol, 1.1 equiv), and 4-

dimethylaminopyridine (12 mg, 0.1 mmol, 10 mol%), in

dichloromethane (10 mL) at 0 ^ꢀC was added a solution

of dicyclohexylcarbodiimide (227.0mg, 1.1 mmol, 1.1

equiv) in dichloromethane (5 mL) dropwise. Stirring at rt

was continued for 3 h. The reaction mixture was cooled to

0 ^ꢀC, ®ltered through Celite and the ®ltrate evaporated and

concentrated in vacuo. Flash column chromatography

(hexane/ethyl acetate 8:1, 4:1, 2:1 then 1:1) aorded an

orange solid that was further puri®ed by recrystallisa-

tion (ether/ethanol), giving the title compound as on o-

white solid (142.6 mg, 31.9%).

(40 mL) at rt under nitrogen was added a solution of

methyl 3-(phenylmethyl)amino-2-pentenoate (15.00 g,

68.1 mmol) in nitromethane (20 mL) dropwise over

30 min. Stirring at rt was continued for 48 h. The reac-

tion mixture was cooled to 0 ^ꢀC in an ice-bath, ®ltered,

washed with cold nitromethane (ꢁ50mL) aording the

title compound as a pale brown solid (11.32g, 53.7%)

after drying in vacuo that was used without subsequent

puri®cation. However, an analytical sample was obtained

thus: a portion of the product (2.89 g) was suspended in

1,2-dichloroethane (10 mL) and the mixture re¯uxed for

30 min. Filtration of the hot mixture aorded a pale

brown solid (1.68 g).

n_max(KBr)/cm^À13283 (NH), 1686 and 1654 (2Âamide

Mp 191±193 ^ꢀC (lit.²¹194±195 ^ꢀC); n_max(KBr)/cm^À13281,

1646, 1142; ¹H NMR (270MHz, CDCl₃) d 6.72-7.67 (m,

8H, indole-H and C₆H₅), 5.34 (s, 2H, N±CH₂), 3.93 (s,

3H, CO₂CH₃), 3.14 (q, J=7.5, 2H, CH₂CH₃), 1.18 (t,

J=7.4, 3H, CH₂CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d

166.3, (CO), 155.6 (C5), 151.4, 136.6, 131.5, 127.9

(4ÂqC), 128.9, 125.8 (o- and m-Ph), 127.7 (p-Ph), 111.7,

110.7 (C4 and C6), 106.6 (C7), 103.1 (C3), 50.8 (CO₂CH₃),

46.7 (N±CH₂), 19.3 (CH₂CH₃), 13.8 (CH₂CH₃).

1

CO); H NMR (270 MHz, CDCl₃) d 7.68, 7.49 (ABq,

J=6.8, 4H, C₆H₄Cl), 7.05±7.29 (m, 4H, C₆H₄CH₃), 6.95

(d, J=2.2, 1H, 4-H), 6.88 (d, J=8.6, 1H, 7-H), 6.71 (dd,

J=9.0, 2.6, 1H, 6-H), 3.80 (s, 3H, CH₃O), 3.78 (s, 2H,

CH₂), 2.44 (s, 3H, 2-CH₃), 2.28 (s, 3H, C₆H₄CH₃); ¹³C

NMR (67.8 MHz, CDCl₃) d 168.3, 168.0 (2ÂCO),

156.4 (C5), 139.6, 136.6, 134.8, 134.3, 133.5, 130.9,

130.2, 115.2 (8ÂqC), 131.2, 129.4, 129.2, 120.2, 112.5

(5ÂCH, 1 CH not seen), 100.7 (C7), 55.7 (CH₃O), 33.2

(CH₂), 20.8 (C₆H₄CH₃), 13.3 (2-CH₃).

3-(Carbomethoxy)-2-methyl-1-(phenylmethyl)-5-hydroxy-

indole 48. The procedure followed was as detailed above,

using: a solution of benzoquinone (14.54g, 0.134 mol, 1.38

equiv) in nitromethane (50 mL) and a solution of methyl

3-(phenylmethyl)amino-2-butenoate (20.00g, 0.974 mol)

in nitromethane (25 mL). Stirring at rt under nitrogen was

continued for 66 h. The title compound was obtained as a

pale brown solid (13.73 g, 47.7%). A portion (2.50 g)

was re¯uxed in 1,2-dichloroethane (5 mL) for 1 h and

the resultant mixture ®ltered whilst hot to give an ana-

lytical sample (0.87 g) as a pale brown solid.

Methyl 3-(phenylmethyl)amino-2-pentenoate 47. A solu-

tion of methyl propionylacetate (12.6 mL, 0.1 mmol),

benzylamine (11.4 mL, 0.105 mmol, 1.05 equiv) and

p-toluenesulphonicacid monohydrate (0.95 g, 5 mmol, 5

mol%) in toluene (50 mL) was re¯uxed under Dean±

Stark conditions under nitrogen for 3 h. The reaction

solution was cooled in an ice-bath to ꢁ10 ^ꢀC, the ®ne

white crystalline precipiate that formed was removed by

®ltration, and the ®ltrate evaporated and concentrated

in vacuo aording the title compound as a clear orange

liquid (21.1 g, 95.7%) that was used without subsequent

puri®cation.

Mp 191±193 ^ꢀC; n_max(CHCl₃)/cm^À13016, 1676, 1118; ¹H

NMR (270 MHz, DMSO-d₆) d 8.99 (s, 1H, OH), 6.63±

7.42 (m, 8H, indole-H and C₆H₅), 5.43 (s, 2H, N-CH₂),

3.81 (s, 3H, CO₂CH₃), 2.65 (s, 3H, CH₃); ¹³C NMR

(67.8 MHz, DMSO-d₆) d 165.4, (CO), 152.8 (C5), 144.9,

137.2, 136.5, 130.3 (4ÂqC), 128.6, 126.1 (o- and m-Ph),

127.2 (p-Ph), 111.6, 110.7 (C4 and C6), 105.4 (C7), 102.5

(C3), 50.3 (CO₂CH₃), 45.8 (N±CH₂), 11.8 (CH₃).

¹H NMR (270 MHz, CDCl₃) d 8.93 (s, 1H, NH), 7.18±

7.37 (m, 5H, C₆H₅), 4.56 (s, 1H, CCHÀCO), 4.43 (d,

J=6.2, 2H, N±CH₂), 3.64 (s, 3H, OCH₃), 2.23 (q, J=7.5,

2H, CH₂CH₃), 1.12 (t, J=7.4, CH₂CH₃); ¹³C NMR

(67.8 MHz, CDCl₃) d 171.2 (CO), 167.0 (C3), 138.8

(i-Ph), 128.7, 126.9, (o- and m-Ph), 127.4 (p-Ph), 81.0

(C2), 49.9 (N-CH₂), 25.1 (CH₂CH₃), 12.1 (CH₂CH₃).

3-(Carbomethoxy)-2-ethyl-1-(phenylmethyl)-5-methoxy-

indole 51. To a mixture of 3-(carbomethoxy)-2-ethyl-1-

(phenylmethyl)-5-hydroxyindole (11.31 g, 36.56 mmol)

and tetrabutylammonium bromide (1.179g, 3.66mmol,

10mol%) in water (100mL) was added a 50% aq solution

of sodium hydroxide (35 mL) and methyl iodide (6.83 mL,

0.110 mol, 3.0 equiv). This heterogeneous mixture was

brought to re¯ux, resulting in a dark brown solution, and

re¯ux continued for 30min. Once cooled to rt, the reac-

tion mixture was extracted with ethyl acetate (3Â85mL),

the combined extracts washed with brine (150mL), dried

(MgSO₄), evaporated and concentrated in vacuo to a

pale brown solid (10.82 g). Recrystallisation of the crude

product (iso-propanol) aorded the title compound as

colourless crystals (7.160 g, 60.6%).

Methyl 3-(phenylmethyl)amino-2-butenoate 46. The pro-

cedure followed was as detailed above, using: methyl

acetoacetate (10.8 mL, 0.1 mol). The title compound was

obtained as a clear orange liquid (20.1 g, 97.8%) that

was used without subsequent puri®cation.

¹H NMR (270 MHz, CDCl₃) d 8.93 (s, 1H, NH), 7.13±

7.38 (m, 5H, C₆H₅), 4.54 (s, 1H, CCH±CO), 4.42 (d,

J=6.2, 2H, N-CH₂), 3.63 (s, 3H, OCH₃), 1.91 (s, 3H,

CH₃); ¹³C NMR (67.8 MHz, CDCl₃) d 170.9 (CO),

161.9 (C3), 138.7 (i-Ph), 128.8, 126.7, (o- and m-Ph),

127.4 (p-Ph), 82.9 (C2), 50.0 (N-CH₂), 19.3 (CH₃).

3-(Carbomethoxy)-2-ethyl-1-(phenylmethyl)-5-hydroxy-

indole 49. To a solution of freshly recrystallised benzo-

quinone (10.17 g, 93.9 mmol, 1.38 equiv) in nitromethane

Mp 100±101 ^ꢀC (lit.²¹102±103 ^ꢀC); n_max(CHCl₃)/cm^À1

2950, 1689, 1480, 1462, 1439, 1120; ¹H NMR (270 MHz,

758

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

DMSO-d₆) d 6.78±7.53 (m, 8H, indole-H and C₆H₅),

5.51 (s, 2H, N±CH₂), 3.84 (s, 3H, CO₂CH₃), 3.79 (s, 3H,

CH₃O), 3.11 (q, J=7.4, 2H, CH₂CH₃), 1.06 (t, J=7.4,

3H, CH₂CH₃).

2.31 (s, 3H, CH₃); ¹³C NMR (67.8 MHz, DMSO-d₆) d

153.4 (C5), 138.6, 134.9, 131.2, 128.0 (4ÂqC), 128.5,

126.2 (o- and m-Ph), 127.0 (p-Ph), 111.9 (C3), 109.9 (C4

and C6), 100.6 (C7), 55.3 (CH₃O), 53.9 (CH₂OH), 45.8

(N-CH₂), 10.0 (CH₃).

3-(Carbomethoxy)-2-methyl-1-(phenylmethyl)-5-methoxy-

indole 50. The procedure followed was as detailed above,

using: 3-(carbomethoxy)-2-methyl-1-(phenylmethyl)-5-

hydroxy-indole (12.99 g, 43.98 mmol), tetrabutylammo-

nium bromide (1.418 g, 4.40 mmol, 10 mol%), water

(125 mL), 50% aq sodium hydroxide solution (42 mL)

and methyl iodide (8.21 mL, 0.132 mol, 3.0 equiv). The

crude product was obtained as a pale brown solid that

upon recrystallisation (iso-propanol) aorded the title

compound as beige crystals (7.775 g, 57.2%).

3-(Cyanomethyl)-2-ethyl-1-(phenylmethyl)-5-methoxy-

indole 55. To a solution of boron tri¯uoride etherate

(4.06 mL, 32.1 mmol, 3.0 equiv) and cyanotrimethylsilane

(5.70 mL, 42.7 mmol, 4.0 equiv) in dichloromethane (65

mL) at 0 ^ꢀC under nitrogen in a three-necked RB-¯ask

®tted with a thermometer and a dropping funnel was

added a solution of 3-(hydroxymethyl)-2-ethyl-1-(phe-

nylmethyl)- 5-methoxyindole (3.156 g, 10.7 mmol) in di-

chloromethane (15 mL) dropwise at such a rate that the

internal temperature was maintained at <7 ^ꢀC. Stirring

at 0 ^ꢀC was continued for 1 h. The reaction was quen-

ched by the addition of satd aq sodium bicarbonate

solution (10 mL) and stirring at rt continued for 45min.

The organiclayer was separated, washed with 1 M

hydrochloric acid (25 mL), satd aq sodium bicarbonate

solution (25 mL) and brine (25 mL), dried (MgSO₄),

evaporated and concentrated in vacuo to a brown oil

(2.194 g). Elution of the crude product through a silica

gel plug with dichloromethane (500 mL) aorded the

title compound, after evaporation and concentration in

vacuo, as a light amber semi-solid (2.319 g, 71.3%).

Mp 127±128 ^ꢀC; n_max(CHCl₃)/cm^À13007, 2950, 1688,

1482, 1415, 1119; ¹H NMR (270 MHz, DMSO-d₆) d

6.78±7.54 (m, 8H, indole-H and C₆H₅), 5.48 (s, 2H, N-

CH₂), 3.84 (s, 3H, CO₂CH₃), 3.79 (s, 3H, CH₃O), 2.67

(s, 3H, CH₃); ¹³C NMR (67.8 MHz, DMSO-d₆) d 165.4,

(CO), 155.2 (C5), 145.2, 137.1, 131.1, 126.9 (4ÂqC),

128.7, 126.0 (o- and m-Ph), 127.3 (p-Ph), 111.3, 111.1

(C4 and C6), 103.3 (C7), 103.0 (C3), 55.3 (CH₃O), 50.5

(CO₂CH₃), 45.9 (N±CH₂), 11.8 (CH₃).

3-(Hydroxymethyl)-2-ethyl-1-(phenylmethyl)-5-methoxy-

indole 53. To a slurry of lithium aluminium hydride

(2.46 g, 64.9 mmol, 3.0 equiv) in THF (50 mL) at rt under

nitrogen was added a solution of 3-(carbomethoxy)-2-

ethyl-1-(phenylmethyl)-5-methoxyindole (7.00 g, 21.6

mmol) in THF (15 mL) dropwise and stirring continued

for 17 h. The reaction was quenched by the sequential

addition of water (2.5 mL), 15% aq sodium hydroxide

solution (2.5 mL) and water (7.5 mL). The resultant

mixture was stirred at rt for 30 min during which the

grey slurry was transformed to a ®ne white solid and a

clear yellow solution. This mixture was ®ltered, the ®l-

trate dried (MgSO₄), evaporated and concentrated in

vacuo to give the title compound (4.24 g, 66.4%) with-

out further puri®cation as a yellow oil that solidi®ed

upon standing.

n_max(CHCl₃)/cm^À13012, 2249, 1486, 1454, 1157; ¹H

NMR (270MHz, DMSO-d₆) d 6.70±7.31 (m, 8H, indole-

H and C₆H₅), 5.40 (s, 2H, N±CH₂), 4.04 (s, 2H, CH₂CN),

3.76 (s, 3H, CH₃O), 2.78 (q, J=7.6, 2H, CH₂CH₃), 1.05

(t, J=7.4, 3H, CH₂CH₃).

3-(Cyanomethyl)-2-methyl-1-(phenylmethyl)-5-methoxy-

indole 54. The procedure followed was as detailed above,

using: a solution of boron tri¯uoride etherate (5.84 mL,

46.1mmol, 3.0 equiv) and cyanotrimethylsilane (8.19 mL,

61.4 mmol, 4.0 equiv) in dichloromethane (90 mL) and a

solution of 3 - (hydroxymethyl) - 2 - methyl - 1 - (phenyl-

methyl)-5-methoxyindole (4.32 g, 15.4 mmol) in di-

chloromethane (25 mL). Work up in a similar fashion

aorded the crude product as a dark red semi-solid

(4.266 g) that, upon elution through a silica gel plug with

dichloromethane (700 mL), gave the title compound as a

light yellow semi-solid (3.233 g, 72.5%).

Mp 69±72 ^ꢀC (lit.²¹69±70 ^ꢀC); n_max(CHCl₃)/cm^À13008,

1485, 1454, 1158; ¹H NMR (270MHz, DMSO-d₆) d 6.63±

7.30 (m, indole-H and C₆H₅), 5.37 (s, 2H, N±CH₂), 4.61

(s, 3H, CH₂OH; accidental equivalence), 3.76 (s, 3H,

CH₃O), 2.74 (q, J=7.5, 2H, CH₂CH₃), 1.05 (t, J=7.6,

3H, CH₂CH₃).

n_max(CHCl₃)/cm^À13004, 2249, 1487, 1454, 1157; ¹H

NMR (270MHz, DMSO-d₆) d 6.72±7.32 (m, 8H, indole-

H and C₆H₅), 5.36 (s, 2H, N±CH₂), 4.03 (s, 2H, CH₂CN),

3.78 (s, 3H, CH₃O), 2.33 (s, 3H, CH₃); ¹³C NMR

(67.8 MHz, DMSO-d₆) d 154.1 (C5), 138.5, 135.4, 131.4,

127.2 (4ÂqC), 128.9, 126.4 (o- and m-Ph), 127.4 (p-Ph),

119.6 (CN), 110.9, 110.8 (C4 and C6), 100.3 (C7), [C3

not seen], 55.7 (CH₃O), 46.2 (N±CH₂), 12.5 (CH₂CN),

10.2 (CH₃).

3-(Hydroxymethyl)-2-methyl-1-(phenylmethyl)-5-methoxy-

indole 52. The procedure followed was as detailed above,

using: a slurry of lithium aluminium hydride (2.85 g,

75.2 mmol, 3.0 equiv) in THF (50 mL) and a solution of 3-

(carbomethoxy)-2-methyl-1-(phenylmethyl)-5-methoxy-

indole (7.75 g, 25.1 mmol) in THF (30 mL). Work up in

a similar fashion aorded the title compound as a yel-

low solid (4.45 g, 63.0%) without further puri®cation.

3-(Amidomethyl)-2-ethyl-1-(phenylmethyl)-5-methoxyin-

dole 57. To a solution of 3-(cyanomethyl)-2-ethyl-1-(phe-

nylmethyl)-5-methoxyindole (2.307 g, 7.58mmol) in tert-

butanol (30 mL) was added powdered potassium hydrox-

ide (2.127 g, 37.9 mmol, 5.0 equiv) and the mixture

re¯uxed under nitrogen for 1 h. Once cooled to rt, the

n

_max(KBr)/cm^À13500±2700 (OH), 2923, 1447, 1147; ¹H

NMR (270 MHz, DMSO-d₆) d 6.61±7.30 (m, 8H,

indole-H and C₆H₅), 5.33 (s, 2H, N±CH₂), 4.60 (s, 3H,

CH₂OH; accidental equivalence), 3.75 (s, 3H, CH₃O),

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

759

reaction mixture was partitioned between ethyl acetate

(75 mL) and brine (75mL). The organiclayer was sepa-

rated, washed with brine (75mL), dried (MgSO₄), evapor-

ated and concentrated in vacuo. Flash column chroma-

tography (dichloromethane/ethyl acetate 1:2) aorded the

title compound as a pale yellow solid (1.680g, 66.2%).

above, using: 3 - (amidomethyl) - 2 - methyl - 1 - (phenyl-

methyl)-5-methoxyindole (2.32 g, 7.52mmol) in dichloro-

methane (25 mL) and boron tribromide (1.0 M solution

in dichloromethane; 22.6 mL, 22.6 mmol, 3.0 equiv).

Work-up in a similar fashion (a further portion of di-

chloromethane, ꢁ125 mL, was added prior to the aqu-

eous washes to eect complete dissolution of the crude

product) aorded the title compound as a brown solid

(1.941 g, 87.7%) without further puri®cation.

n_max(CHCl₃)/cm^À13514, 3398, 3008, 1671 (CO),

1485, 1154; ¹H NMR (270 MHz, DMSO-d₆) d 6.63±7.30

(m, 10H, indole-H, C₆H₅and NH₂), 5.36 (s, 2H, N±

CH₂), 3.74 (s, 3H, CH₃O), 3.44 (s, 2H, 3-CH₂), 2.73 (q,

J=7.4, 2H, CH₂CH₃), 1.04 (t, J=7.4, 3H, CH₂CH₃).

n_max(CHCl₃)/cm^À13600±3100 (OH), 3513, 3398, 3008,

1669 (CO), 1483, 1454, 1153; ¹H NMR (270 MHz,

DMSO-d₆) d 8.59 (br s, 1H, OH), 6.50±7.31 (m, 10H,

indole-H, C₆H₅and NH₂), 5.29 (s, 2H, N±CH₂), 3.37 (s,

2H, 3-CH₂), 2.26 (s, 3H, CH₃); ¹³C NMR (67.8 MHz,

DMSO-d₆) d 172.8 (CO), 150.6 (C5), 138.8, 134.4,

130.6 (3ÂqC, 1 qC not seen), 128.5, 126.2 (o- and m-

Ph), 126.9 (p-Ph), 110.2, 109.5 (C4 and C6), 105.1 (C3),

102.7 (C7), 45.8 (N±CH₂), 31.7 (3-CH₂), 10.2 (CH₃).

3-(Amidomethyl)-2-methyl-1-(phenylmethyl)-5-methoxy-

indole 56. The procedure followed was as detailed above,

using: 3-(cyanomethyl)-2-methyl-1-(phenylmethyl)-5-

methoxyindole (3.113 g, 10.7 mmol), powdered potas-

sium hydroxide (3.01 g, 53.6 mmol, 5.0 equiv) and tert-

butanol (40 mL). Work up in a similar fashion gave the

crude product as a yellow solid (2.956 g). Recrystallisation

(ethyl acetate) aorded the product as colourless crystals

(1.139g). Concentration of the mother liquor and sub-

sequent recrystallisation (hexane/dichloromethane) aor-

ded the product as pale yellow crystals (0.725 g).

Concentration of the mother liquor and subsequent

¯ash column chromatography (ethyl acetate then ethyl

acetate/methanol 20:1) aorded the product as a pale

yellow solid (0.463 g). Combination of the three materi-

als aorded the title compound (2.327 g, 70.4%).

Dimethyl (3-bromopropyl)phosphonate 64.²²Trimethyl-

phosphite (2.38 mL, 20.1 mmol) and 1,3-dibromopro-

pane (10.2 mL, 0.105 mol, 5.0 equiv) were placed in a

RB-¯ask ®tted with a re¯ux condenser and heated to

150 ^ꢀC (external temperature) in an oil-bath for 30min.

Once cooled to rt, the excess dibromopropane was

removed by distillation (60±62^ꢀC/ꢁ15mm Hg) and the

title compound obtained by bulb-to-bulb distillation

(120 ^ꢀC/0.1 mm Hg) as a clear, colourless liquid (1.668 g,

35.9%).

n_max(CHCl₃)/cm^À13514, 3398, 3003, 1671 (CO),

1486, 1454, 1154; ¹H NMR (270 MHz, DMSO-d₆) d

6.64±7.30 (m, 10H, indole-H, C₆H₅and NH₂), 5.33 (s,

2H, N±CH₂), 3.75 (s, 3H, CH₃O), 3.45 (s, 2H, 3-CH₂),

2.29 (s, 3H, CH₃); ¹³C NMR (67.8 MHz, DMSO-d₆) d

172.8 (CO), 153.5 (C5), 138.5, 134.8, 131.2, 128.1

(4ÂqC), 128.2, 126.1 (o- and m-Ph), 126.9 (p-Ph), 109.7

(C4 and C6), 105.6 (C3), 100.8 (C7), 55.4 (CH₃O), 45.9

(N±CH₂), 31.6 (3-CH₂), 10.1 (CH₃).

n_max(®lm)/cm^À13464, 2955, 1232, 1031; ¹H NMR

(270MHz, CDCl₃) d 3.76 (d, J=_PH11.0, 6H, (CH₃O)₂

3

PO), 3.48 (t, J=7.4, 2H, CH₂Br), 1.83±2.01, 2.06±2.24 (2

m, 4H, CH₂CH₂PO); ¹³C NMR (67.8 MHz, CDCl₃) d

2

52.4 (d, ²J=_CP6.2, (CH₃O)₂PO), 33.4 (d, J=_CP18.6,

3

CH₂CH₂PO), 25.9 (d, J_CP=4.9, CH₂Br), 23.5 (d,

¹J=_CP142.9, CH₂PO).

Ethyl 4[3-(amidomethyl)-2-ethyl-1-(phenylmethyl)-indol-

5-yl]oxy]butanoate 61. To a solution of 3-(amido-

methyl)-2-ethyl-1-(phenylmethyl)-5-hydroxyindole (894

mg, 2.90 mmol) in DMF (5 mL) at rt under nitrogen was

added sodium hydride (60% dispersion in mineral oil;

139 mg, 3.48 mmol, 1.2 equiv) in one portion. Stirring at

rt was continued for 1 h. Ethyl 4-bromobutyrate (415 mL,

2.90 mmol) was added in one portion and stirring at rt

was continued for 2 h. The reaction was quenched with

water (10 mL) and extracted with dichloromethane

(15 mL). The organiclayer was separated, the aqueous

layer extracted with dichloromethane (10 mL), the com-

bined organics washed with water (3Â25mL) and brine

(25 mL), dried (MgSO₄), evaporated and concentrated in

vacuo to a brown oil. Flash column chromatography (di-

chloromethane/iso-propanol 20:1, 10:1 then 5:1) aorded

the title compound as a beige solid (600.5 mg, 49.0%;

57.6% based on recovered starting material) and

unreacted starting material was recovered (133.3 mg).

3-(Amidomethyl)-2-ethyl-1-(phenylmethyl)-5-hydroxy-

indole 59. To a solution of 3-(amidomethyl)-2-ethyl-1-

(phenylmethyl)-5-methoxyindole (1.622g, 5.03mmol) in

dichloromethane (35 mL) at 0^ꢀC under nitrogen was

added boron tribromide (1.0 M solution in dichloro-

methane; 15.1 mL, 15.1mmol, 3.0 equiv) dropwise. Stir-

ring at rt was continued for 3 h. The reaction solution was

diluted with dichloromethane (50 mL) and quenched with

water (75 mL). The organiclayer was separated, washed

with sat. aq ammonium chloride solution (75 mL), brine

(75 mL), dried (Na₂SO₄), evaporated and concentrated

in vacuo aording the title compound as a pale brown

solid (1.551 g, 98.2%) without further puri®cation.

n_max(CHCl₃)/cm^À13500±3100 (OH), 3512, 3396, 3006,

1668 (CO), 1482, 1454, 1153; ¹H NMR (270MHz,

DMSO-d₆) d 8.61 (br s, 1H, OH), 6.49±7.30 (m, 10H,

indole-H, C₆H₅and NH₂), 5.31 (s, 2H, N±CH₂), 3.39 (s,

2H, 3-CH₂), 2.70 (q, J=7.4, 2H, CH₂CH₃), 1.03 (t, J=

7.4, 3H, CH₂CH₃).

¹H NMR (270MHz, DMSO-d₆) d 6.62±7.30 (m, 10H,

indole-H, C₆H₅and NH₂), 5.35 (s, 2H, N±CH₂), 4.07 (q,

J=7.1, 2H, CH₃CH₂OCO), 3.96 (t, J=6.2, 2H, g-CH₂),

3.43 (s, 2H, 3-CH₂), 2.73 (q, J=7.4, 2H, 2-CH₂CH₃),

3-(Amidomethyl)-2-methyl-1-(phenylmethyl)-5-hydroxy-

indole 58. The procedure followed was as detailed

760

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

2.47 (t, J=7.0, 2H, a-CH₂), 1.97 (qn, J=6.8, 2H,

b-CH₂), 1.18 (t, J=7.2, 3H, CH₃CH₂OCO), 1.03 (t,

J= 7.4, 3H, 2-CH₃CH₂).

mmol) in DMF (20 mL), sodium hydride (60% disper-

sion in mineral oil; 0.391 g, 9.78 mmol, 1.2 equiv) and

dimethyl (3-bromopropyl)phosphonate (1.883 g, 8.15

mmol). Work up in a similar fashion gave the crude

product as a light brown solid. A portion (100 mg) of

this material was puri®ed by ¯ash column chromato-

graphy (dichloromethane/iso-propanol 7:1 then 5:1)

aording an analytically pure sample (63.8 mg, overall

yield 64.8%).

Ethyl 4-[3-(amidomethyl)-2-methyl-1-(phenylmethyl)-indol-

5-yl]oxy]butanoate 60. The procedure followed was as

detailed above, using: 3-(amidomethyl)-2-methyl-1-

(phenylmethyl)-5-hydroxyindole (950 mg, 3.23 mmol) in

DMF (10 mL), sodium hydride (60% dispersion in

mineral oil; 155 mg, 3.87 mmol, 1.2 equiv) and ethyl

4-bromobutyrate (415 mL, 3.23 mmol). Work up in a

similar fashion gave the crude product as a brown oil.

Flash column chromatography (dichloromethane/iso-

propanol 20:1, 10:1 then 5:1) aorded the title com-

pound as a beige solid (506.5 mg, 38.4%; 47.3% based

on recovered starting material) and unreacted starting

material was recovered (178.6 mg).

¹H NMR (270 MHz, DMSO-d₆) d 6.65±7.31 (m, 10H,

indole-H, C₆H₅and NH₂), 5.35 (s, 2H, N±CH₂), 4.00 (t,

3

J=5.7, 2H, g-CH₂), 3.64 (d, J_PH=14.8, 6H, (CH₃O)₂

P=O), 3.44 (s, 2H, 3-CH₂), 2.73 (q, J=7.4, 2H, 2-

CH₂CH₃), 1.80±2.01 (m, 4H, a- and b-CH₂), 1.04 (t,

J=7.4, 3H, 2-CH₂CH₃); ¹³C NMR (67.8 MHz, DMSO-

d₆) d 172.7 (CO), 152.4 (C5), 140.5, 138.7, 131.3, 128.3

(4ÂqC), 128.4, 125.9 (o- and m-Ph), 126.9 (p-Ph), 110.5,

110.0 (C4 and C6), 105.3 (C3), 102.4 (C7), 67.8 (d,

n_max(CHCl₃/cm^À13514, 3399, 3002, 1727 (ester CO),

1

2

1672 (amide CO), 1485, 1156; H NMR (270 MHz,

³J_CP=17.4, g-CH₂), 51.9 (d, J_CP=6.2, (CH₃O)₂PO),

DMSO-d₆) d 6.67±7.35 (m, 10H, indole-H, C₆H₅and

NH₂), 5.38 (s, 2H, N±CH₂), 4.12 (q, J=7.1, 2H, CH₃

CH₂OCO), 4.01 (t, J=6.3, 2H, g-CH₂), 3.47 (s, 2H,

3-CH₂), 2.52 (t, J=7.3, 2H, a-CH₂), 2.34 (s, 3H, CH₃),

2.02 (qn, J=6.8, 2H, b-CH₂), 1.22 (t, J=7.3, 3H,

CH₃CH₂OCO); ¹³C NMR (67.8 MHz, DMSO-d₆) d

172.7, 172.5 (2ÂCO), 152.4 (C5), 138.6, 134.8, 131.2,

128.1 (4ÂqC), 128.4, 126.1 (o- and m-Ph), 126.9 (p-Ph),

110.1, 109.7 (C4 and C6), 105.7 (C3), 101.9 (C7), 67.0

(g-CH₂), 59.7 (CH₃CH₂OCO), 45.8 (N-CH₂), 31.5

(3-CH₂), 30.2 (a-CH₂), 24.5 (b-CH₂), 14.0 (CH₃CH₂

OCO), 10.2 (CH₃).

45.9 (N-CH₂), 31.4 (3-CH₂), 22.3 (d, ²J_CP=4.9, b-CH₂),

1

20.2 (d, J_CP=139, a-CH₂), 17.3 (2-CH₂CH₃), 14.4

(2-CH₂CH₃).

4-[3-(Amidomethyl)-2-ethyl-1-(phenylmethyl)-indol-5-yl]-

oxy]butanoic acid 27. To a solution of ethyl 4-[3-(ami-

domethyl) - 2 - ethyl - 1 - (phenylmethyl) - indol - 5 - yl]oxy]

butanoate (403.9 mg, 0.956 mmol) in ethanol (15 mL) at

rt was added a 1 M aq solution of sodium hydroxide

(2 mL). Stirring at rt was continued for 2 h. The reaction

mixture was evaporated to dryness, water (10 mL) added

and the resultant mixture acidi®ed with 10% hydrochlo-

ricacid ( ꢁ1 mL). The crude product was extracted with

ethyl acetate (ꢁ200 mL), the organiclayer separated,

washed with brine (50 mL), dried (MgSO₄), evaporated

and concentrated in vacuo. This material was swirled

with ether/methanol (3±4 mL/6 drops), allowed to settle,

the liquor carefully removed by pipette, and the residual

solid dried in vacuo to give the title compound as an o-

white solid (254.2 mg, 67.4%).

Dimethyl [3-[3-(amidomethyl)-2-methyl-1-(phenylmethyl)-

indol-5-yl]oxy]-propyl]phosphonate 62. The proc edure fol-

lowed was as detailed above, using: 3-(amidomethyl)-2-

methyl-1-(phenylmethyl)-5-hydroxyindole (1.103 g, 3.75

mmol) in DMF (10 mL), sodium hydride (60% disper-

sion in mineral oil; 180 mg, 4.50 mmol, 1.2 equiv) and

dimethyl (3-bromopropyl)phosphonate (0.866 g, 3.75

mmol). Work up in a similar fashion gave the crude

product as a light brown oil. Flash column chromato-

graphy (dichloromethane/iso-propanol 9:1 then 9:2)

aorded the title compound as an o-white solid (0.964g,

57.9%).

Mp 196±198 ^ꢀC (lit.^12b196±199 ^ꢀC); n_max(KBr)/cm^À1

3548 (NH), 3600±2200 (OH), 2965, 1715 (carboxyl

CO), 1644 (amide CO), 1487, 1044; ¹H NMR

(270 MHz, DMSO-d₆) d 6.63±7.35 (m, 10H, indole-H,

C₆H₅and NH₂), 5.35 (s, 2H, N±CH₂), 3.96 (t, J=6.3,

2H, g-CH₂), 3.44 (s, 2H, 3-CH₂), 2.73 (q J=7.4, 2H,

CH₂CH₃), 2.40 (t, J=7.2, 2H, a-CH₂), 1.91±2.03 (m, 2H,

b-CH₂), 1.04 (t, J=7.4, 3H, CH₂CH₃); ¹³C NMR

(67.8 MHz, DMSO-d₆) d 174.1, 172.7 (2ÂCO), 152.5

(C5), 140.4, 138.7, 131.2, 128.2 (4ÂqC), 128.4, 125.9 (o-

and m-Ph), 126.8 (p-Ph), 110.4, 110.0 (C4 and C6),

105.2 (C3), 102.0 (C7), 67.1 (g-CH₂), 45.8 (N±CH₂),

31.4 (3-CH₂), 30.2 (a-CH₂), 24.5 (b-CH₂), 17.3

(CH₂CH₃), 14.4 (CH₂CH₃); (found: C, 69.9; H, 6.9; N,

7.4. C₂₃H₂₆N₂O₄requires C, 70.0; H, 6.6; N, 7.1%).

n_max(CHCl₃)/cm^À13515, 3399, 3002, 1671 (CO), 1485,

1

1156, 1039; H NMR (270MHz, DMSO-d₆) d 6.71±7.37

(m, 10H, indole-H, C₆H₅and NH₂), 5.40 (s, 2H, N±CH₂),

3

4.05 (t, J=5.5, 2H, g-CH₂), 3.68 (d, J=_PH15.1, 6H,

(CH₃O)₂P=O), 3.48 (s, 2H, 3-CH₂), 2.35 (s, 3H, CH₃),

1.90±2.06 (m, 4H, a- and b-CH₂); ¹³C NMR (67.8 MHz,

DMSO-d₆) d 174.2 (CO), 153.9 (C5), 140.1, 136.4, 132.9,

129.7 (4ÂqC), 130.0, 127.8 (o- and m-Ph), 128.5 (p-Ph),

111.8, 111.3 (C4 and C6), 107.3 (C3), 103.7 (C7), 69.3 (d,

³J=_CP16.2, g-CH₂), 53.5 (d, ²J=_CP6.2, (CH₃O)₂P=O),

2

47.4 (N-CH₂), 33.1 (3-CH₂), 23.9 (d, J_CP=3.7, b-CH₂),

22.0 (d, ¹J_CP=139, a-CH₂), 11.7 (CH₃).

4-[3-(Amidomethyl)-2-methyl-1-(phenylmethyl)-indol-5-yl]-

oxy]butanoic acid 26. To a solution of ethyl 4-[3-(ami-

domethyl)-2-methyl-1-(phenylmethyl)-indol-5-yl]oxy]-

butanoate (495.9 mg, 1.21 mmol) in ethanol (40 mL) at rt

was added a 1 M aq solution of sodium hydroxide

(3 mL). Stirring at rt was continued for 19 h. The reaction

Dimethyl [3-[3-(amidomethyl)-2-ethyl-1-(phenylmethyl)-

indol-5-yl]oxy]-propyl]phosphonate 63. The procedure

followed was as detailed above, using: 3-(amidomethyl)-

2-ethyl-1-(phenylmethyl)-5-hydroxyindole (2.513 g, 8.15

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

761

mixture was evaporated to dryness, water (10 mL)

added and the resultant mixture acidi®ed with 10%

hydrochloric acid (ꢁ1 mL). The crude product was

obtained by ®ltration, stirred with boiling ethyl acetate

(50 mL) for 5 min, cooled to ꢁ5 ^ꢀC and ®ltered to give,

after drying (50 ^ꢀC/1.0 mm Hg, 3 h), the title compound

as an o-white solid (368.0 mg, 79.7%).

was as detailed above, using: sodium iodide (5.86 g,

39.1 mmol, 6.0 equiv), chlorotrimethylsilane (4.96 mL,

39.1 mmol, 6.0 equiv) and acetonitrile (35 mL). A portion

of the iodotrimethylsilane solution (20 mL, 3.0 equiv)

was added to a solution of dimethyl [3-[3-(amido-

methyl)-2-ethyl-1-(phenylmethyl)-indol-5-yl]oxy]propyl]

phosphonate (3.793 g, 6.51 mmol) in dichloromethane

(50 mL) in one portion and stirring at rt under nitrogen

continued for 1.5 h. Work up in a similar fashion gave the

crude product as an orange solid. Recrystallisation (ethyl

acetate:acetonitrile:acetic acid:water 21:7:7:9) aorded the

title compound as a pale brown solid (0.970g, 34.6%).

Mp 232±234 ^ꢀC (lit.^12b218±221 ^ꢀC); n_max(KBr)/cm^À1

3548 and 3345 (NH), 3600±2200 (OH), 2962, 2917, 1729

(carboxyl CO), 1641 (amide CO), 1578, 1473, 1161,

1

1038; H NMR (270 MHz, DMSO-d₆) d 6.65±7.33 (m,

10H, indole-H, C₆H₅and NH₂), 5.35 (s, 2H, N±CH₂),

3.97 (t, J=6.3, 2H, g-CH₂), 3.44 (s, 2H, 3-CH₂), 2.40 (t,

J=7.2, 2H, a-CH₂), 2.31 (s, 3H, CH₃), 1.90±2.01 (m,

2H, b-CH₂); ¹³C NMR (67.8 MHz, DMSO-d₆) d 174.1,

172.6 (2ÂCO), 152.5 (C5), 138.5, 134.7, 131.3, 128.1

(4ÂqC), 128.4, 126.1 (o- and m-Ph), 126.9 (p-Ph), 110.2,

109.7 (C4 and C6), 105.7 (C3), 101.9 (C7), 67.2 (g-CH₂),

45.8 (N±CH₂), 31.5 (3-CH₂), 30.4 (a-CH₂), 24.6 (b-

CH₂), 10.1 (CH₃).

Mp 190±192 ^ꢀC (lit.²¹194±196 ^ꢀC); n_max(KBr)/cm^À1

3600±2400 (OH), 3457 (N±H), 2361, 1654 (CO), 1487,

1

1154; H NMR (270 MHz, DMSO-d₆) d 6.64±7.38 (m,

10H, indole-H, C₆H₅and NH₂), 5.35 (s, 2H, N±CH₂),

4.00 (t, J=6.3, 2H, g-CH₂), 3.44 (s, 2H, 3-CH₂), 2.73 (q,

J=7.4, 2H, 2-CH₂CH₃), 1.63±1.78, 1.87±2.00 (2 m, 4H,

a- and b-CH₂), 1.04 (t, J=7.4, 3H, 2-CH₂CH₃); ¹³C NMR

(67.8 MHz, DMSO-d₆) d 172.8 (CO), 152.5 (C5), 140.4,

138.7, 131.2, 128.2 (4ÂqC), 128.4, 125.9 (o- and m-Ph),

126.8 (p-Ph), 110.4, 110.0 (C4 and C6), 105.2 (C3), 102.3

[3-[3-(Amidomethyl)-2-methyl-1-(phenylmethyl)-indol-5-yl]

oxy]propyl]phosphonic acid 28. To a solution of sodium

iodide (2.55 g, 10.0 mmol, 9.0 equiv) in acetonitrile

(13 mL) at rt under nitrogen in a 20 mL narrow, straight-

walled ¯ask (a new B19 cone sealed at the end by a

glassblower is ideal) was added chlorotrimethylsilane

(2.16 mL, 17.0 mmol, 9.0 equiv) in one portion. A ®ne

white precipitate formed immediately and was allowed

to settle over 15 min aording a clear yellow solution of

iodotrimethylsilane. To a solution of dimethyl [3-[3-

(amidomethyl)-2-methyl-1-(phenylmethyl)-indol-5-yl]-

oxy]propyl]-phosphonate (842 mg, 1.89 mmol) in di-

chloromethane (20 mL) at rt under nitrogen was added a

portion of the iodotrimethylsilane solution (5 mL, 3.0

equiv) in one portion. Stirring at rt was continued for

1.5 h. The reaction contents were evaporated to dryness

and the residue stirred with methanol (10 mL) for 10min,

resulting in a white suspension. Evaporation and con-

centration in vacuo aorded the crude product. Recrys-

tallisation (ethyl acetate/acetonitrile/acetic acid/water

21:7:7:9) aorded the title compound as a white solid

(531 mg, 67.3%).

3

(C7), 68.2 (d, J_CP=16.1, g-CH₂), 45.8 (N±CH₂), 31.4

1

2

(3-CH₂), 24.1 (d, J_CP=145, a-CH₂), 23.1 (s, J_CP=0,

b-CH₂), 17.3 (2-CH₂CH₃), 14.4 (2-CH₂CH₃); (found: C,

61.6; H, 6.3; N, 6.4. C₂₂H₂₇N₂PO₅requires C, 61.4; H,

6.3; N, 6.5%).

Acknowledgements

BioResearch Ireland and DCU Education Trust are

gratefully acknowledged for ®nancial support for this

work.

References

1. (a) Duy, C. P.; Elliot, C. J.; O'Connor, R. A.; Heenan,

M. M.; Coyle, S.; Cleary, I. M.; Kavanagh, K.; Verhaegen, S.;

O'Loughlin, C. M.; NicAmhlaoibh, R.; Clynes, M. Eur. J.

Cancer 1998, 34, 1250. (b) Draper, M. P.; Martell, R. L.; Levy,

S. B. Br. J. Cancer 1997, 75, 810. (c) Roller, A.; Bahr, O. R.;

Streer, J.; Winter, S.; Heneka, M.; Deininger, M.; Meyer-

mann, R.; Naumann, U.; Gulbins, E.; Weller, M. Biochem.

and Biophys. Res. Comm. 1999, 259, 600.

2. For an introduction, see: Shen, T.-Y. In Non-steroidal Anti-

im¯ammatory Drugs; Grattini, S., Dukes, M. N. G., Eds;

Excerpa Medica Foundation: Amsterdam, 1965; p 13.

3. For a detailed review, see: Shen, T.-Y.; Winter C. A. In

Advances in Drug Research; Harper, N. J., Simmonds, A. B.

(Eds.); Academic: London, 1977; Vol. 12, p 89.

Mp 201±203 ^ꢀC (lit.^12b201±203 ^ꢀC); n_max(KBr)/cm^À1

3600±2400 (OH), 3455 (N±H), 2928, 1655 (CO), 1489,

1

1154; H NMR (270 MHz, DMSO-d₆) d 6.66±7.32 (m,

10H, indole-H, C₆H₅and NH₂), 5.34 (s, 2H, N±CH₂),

4.01 (t, J=6.5, 2H, g-CH₂), 3.44 (s, 2H, 3-CH₂), 2.31 (s,

3H, CH₃), 1.83±2.01, 1.64±1.76 (2 m, 4H, a- and b-

CH₂); ¹³C NMR (100.54 MHz, DMSO-d₆) d 174.9

(CO), 153.1 (C5), 138.8, 135.9, 131.9, 128.6 (4ÂqC),

129.1, 126.7 (o- and m-Ph), 127.7 (p-Ph), 111.0, 110.5 (C4

4. Vane, J. R.; Botting, R. M. Scand. J. Rheumatol 1996, 25, 9.

5. Hawkey, C. J. Lancet 1999, 353, 307.

3

6. Black, W. C.; Bayly, C.; Belley, M.; Chan, C.-C.; Charleson,

S.; Denis, D.; Gauthier, J. Y.; Gordon, R.; Guay, D.; Kargman,

S.; Lau, C. K.; Leblanc, Y.; Mancini, J.; Ouellet, M.; Percival,

D.; Roy, P.; Skorey, K.; Tagari, P.; Vickers, P.; Wong, E.; Xu,

L.; Prasit, P. Bioorg. Med. Chem. Lett. 1996, 6, 725.

and C6), 105.6 (C3), 102.6 (C7), 69.0 (d, J_CP=17.7, g-

CH₂), 46.5 (N±CH₂), 31.9 (3-CH₂), 24.4 (d, ¹J_CP=137, a-

2

CH₂), 23.3 (s, J_CP=0, b-CH₂), 10.6 (CH₃); ³¹P NMR

(161.83 MHz, DMSO-d₆, phosphoricacid external refer-

ence) d 27.5; (found: C, 60.3; H, 5.9; N, 6.3. C₂₁H₂₅

N₂PO₅requires C, 60.6; H, 6.05; N, 6.7%).

7. Kaplan, L.; Wiess, J.; Elsbach, P. Proc. Natl. Acad. Sci.

USA 1978, 75, 2955.

8. Makela, A.; Kuusi, T.; Schroder, T. Scand. J. Clin. Lab.

È

[3-[3-(Amidomethyl)-2-ethyl-1-(phenylmethyl)-indol-5-yl]

oxy]propyl]phosphonic acid 29. The procedure followed

Invest. 1997, 57, 401. Lobo, I. B.; Hoult, J. R. S. Agents

Actions 1994, 41, 111.

762

A. R. Maguire et al. / Bioorg. Med. Chem. 9 (2001) 745±762

9. Kreft, A.; Nelson, J.; Musser, J.; Failli, A.; Shah, U.;

Kubrak, D.; Banker, A.; Stean, R.; Schiehser, G.; Strum, R.;

Holloway, D.; Bauer, J.; Sung, M.-L.; Marshall, L.; Glaser, K.

Agents Actions 1993, 39 (Special Conference Issue), C33.

10. For an overview, see: Mihelich, E. D.; Carlson, D. G.;

Fox, N.; Song, M.; Shevitz, R. W.; Snyder, D. W. Prog. Surg

1997, 24, 140.

11. For a detailed review, see: Schevitz, R. W.; Bach, N. J.;

Carlson, D. G.; Chirgadze, N. Y.; Clawson, D. K.; Dillard,

R. D.; Draheim, S. E.; Hartley, L. W.; Jones, N. D.; Mihelich,

E. D.; Olkowski, J. L.; Snyder, D. W.; Sommers, C.; Wery, J.-P.

Nature Struct. Biol. 1995, 2, 458.

12. For a detailed account of the chemistry and pharmacol-

ogy, see: Dillard, R. D.; Bach, N. J.; Draheim, S. E.; Berry, D.

R.; Carlson, D. G.; Chirgadze, N. Y.; Clawson, D. K.; Hart-

ley, L. W.; Johnson, L. M.; Jones, N. D.; McKinney, E. R.;

Mihelich, E. D.; Olkowski, J. L.; Schevitz, R. W.; Smith, A.

C.; Snyder, D. W.; Sommers, C. D.; Wery, J.-P. J. Med. Chem.

1996, 39, (a) 5119; (b) 5137; (c) 5159.

13. (a) For leading reviews, see: Marnett, L. J. Cancer

Research 1992, 52, 5575. (b) Ara, G.; Teicher, B. A. Pros-

taglandins, Leukotrienes Essent. Fatty Acids 1996, 54, 3.

14. Touhey, S.; O'Connor, R.; Plunkett, S. J.; Maguire, A. R.;

Clynes, M. Biochemical Pharmacology, submitted for publication.

15. Ihara, M.; Noguchi, K.; Fukumoto, K.; Kametani, T.

Tetrahedron 1985, 41, 2109.

16. (a) Yamamoto, H. J. Org. Chem. 1967, 32, 3693. (b)

Yamamoto, H. Chem. Pharm. Bull 1968, 16, 17.

17. Samanen, J. M.; Brandeis, E. J. Org. Chem. 1988, 53, 561.

18. Sarett, L. H.; Shen, T.-Y. (Merck and Co., Inc.). US

Patent 3,196,162.

19. Sletzinger, M.; Gal, G.; Chemerda, J. M. (Merck and Co.,

Inc.) Fr. Patent 1,540,725, see: Chem. Abs. 1969, 71, 81161u.

20. Yamamoto, H.; Nakao, K.; Maruyama, I. (Sumitomo

Chemical Co., Ltd.) Japan. Patent 15,092 67, (see: Chem. Abs.

1968, 68, 104976t).

21. Pawlak, J. M.; Khau, V. V.; Hutchison, D. R.; Martinelli,

M. J. J. Org. Chem. 1996, 61, 9055.

22. Adapted from: Germanaud, L.; Brunel, S.; Chevalier, Y.;

Le Perchec, P. Bull. Soc. Chim. Fr. 1988, 699. For an alter-

native synthesis, see: Ornstein, P. A. Org. Prep. Proc. Int.

1988, 20, 371.

23. Martin, A.; Clynes, M. In Vitro Cell Dev. Biol. 1991, 27A,

183.

Article Doi

Synthesis of indomethacin analogues for evaluation as modulators of MRP activity

DOI: 10.1016/S0968-0896(00)00292-3

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0968-0896(00)00292-3

Full text of DOI:10.1016/S0968-0896(00)00292-3

Products guided by the article

R&D Labs maybe for 3446-67-1

Relevant to this article

Hot Product