3-substituted 2-phenyl-indoles privileged structures for medicinal chemistry

Cite this: RSC Advances, 2013, 3, 945

3-Substituted 2-phenyl-indoles: privileged structures formedicinal chemistry3

Received 22nd August 2012,Accepted 1st November 2012

DOI: 10.1039/c2ra21902f

www.rsc.org/advances

Henrik Johansson, Tanja Bøgeløv Jørgensen, David E. Gloriam, Hans Brauner-Osborne and Daniel Sejer Pedersen*

Privileged structures have been used in drug discovery targeting G protein-coupled receptors (GPCR) and

other protein classes for more than 20 years. Their rich activity profiles and drug-like characteristics lend

themselves to increased productivity in hit identification and lead optimisation. Recently we discovered

two allosteric modulators 1 and 2 for the G protein-coupled receptor GPRC6A incorporating the privileged

2-phenyl-indole scaffold, functionalised at the 3-position. In order to develop new potential GPRC6A

ligands we engaged in the development of synthetic routes to provide 2-phenyl-indoles with a variety of

substituents at the indole 3-position. Herein we describe the development of optimised and efficient

synthetic routes to a series of new 2-phenyl-indole building blocks 3 to 9 and show that these can be used

to generate a broad variety of 3-substituted 2-phenyl-indoles of interest to medicinal chemists.

Introduction

Nobel laureate Sir James Black said that the most fruitful basisfor the discovery of a new drug is to start with an old.1 The useof privileged structure scaffolds in medicinal chemistryembraces the statement by Sir James Black and despite muchdebate amongst medicinal chemists regarding the validity ofthe concept within drug discovery it persists and continues togrow in popularity.2 The term ‘‘privileged structure’’ was firstcoined in relation to the progression of benzodiazepine-basedcholecystokinin receptor antagonists.3 These structures weredefined as ‘‘a single molecular framework able to provideligands for diverse receptors’’. The concept has been widelyexploited in the intervening period, particularly as a means ofproviding compound libraries with drug-like sub-structuralelements and enhanced likelihood of activity.4 The approachhas proven effective in generating hits for target receptors andoffers the promise that compounds can be successfullyoptimised, particularly in terms of selectivity, through varia-tion of the non-privileged/non-conserved parts of the struc-ture.5 A large number of privileged structures have beendescribed for GPCRs, including benzodiazepines, the 1,1-diphenylmethyl group, 4-aryl-piperidines and their spirovariants, 2-aryl-indoles, dihydropyridines, biphenyl carboxylicacids/tetrazoles (‘‘biaryl-2-acids’’) and benzimidazoles.4,6–12 In2004 we discovered a family C G protein-coupled receptor(GPCR) termed GPRC6A and initiated a medicinal chemistry

program directed at elucidating the receptor’s physiologicalfunction.13–18 GPCRs constitute a large superfamily of cell-surface proteins that are activated by a broad range ofligands19 and are known to be implicated in a plethora ofphysiological processes, making them attractive targets indrug discovery.20 We decided to employ a chemogenomicapproach using privileged structures in our search for ligandsthat could modulate the GPRC6A receptor activity.21 Ourchemogenomic approach was a success and identifiedGPRC6A antagonists 1 and 2 belonging to the 2-phenyl-indoleclass of privileged structures (Fig. 1).22–24

Department of Drug Design and Pharmacology, University of Copenhagen,

Universitetsparken 2, 2100 Copenhagen, Denmark. E-mail: [email protected];

Fax: +45-35336041

3 Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ra21902f

Fig. 1 GPRC6A antagonists 1 and 2, and the desired 3-substituted indolebuilding blocks 3–9.

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Ligands 1 and 2 are the most potent and selective allostericantagonists of GPRC6A identified to date and as such illustratethat the use of privileged structures in medicinal chemistrycan be a powerful tool for finding new receptor modulators.24

The identification of ligands 1 and 2 urged the development ofefficient methods for the synthesis of 3-substituted 2-phenyl-indoles aimed at further structure–activity relationship (SAR)studies. The 2-phenyl-indole privileged structure has in excessof 190 predicted GPCR targets in family A and C makingoptimised syntheses for new 2-phenyl-indole building blocksof general interest to medicinal chemists.21,25 The indoleheterocycle is present in a vast number of biologically activecompounds, and the chemistry of indoles has been studiedextensively.26–28 However, while 2-phenyl-indoles display manycommon features with indole itself we have discoveredsignificant differences in reactivity and stability. With the2-phenyl-indole scaffold’s status as a privileged structure thereis an evident incentive for developing the chemistry of2-phenyl-indoles further. In this work, we report optimisedsyntheses for a series of 3-substituted 2-phenyl-indole buildingblocks (3 to 9, Fig. 1) and demonstrate their utility bysynthesising a number of new potential GPRC6A receptorligands.

Results and discussion

Based on the commercial availability of a wide range of2-phenyl-indoles we decided to develop a method for selectiveacylation at the 3-position of 2-phenyl-indoles (Scheme 1 and2). The dual reactivity at the indole 1- and 3-position generallycauses selectivity issues when indoles are treated withelectrophiles. In addition, strong Lewis acid and the genera-tion of acid during acylation reactions commonly results inoligomerisation, giving laborious work-up procedures and lowyields.29–31 There are some reports of regio-selective 3-acyla-tions of indole without the need for N-protection groups, using

Grignard and zinc salts,32 ionic liquids,33 pre-activation withLewis acid (e.g. Et2AlCl,34,35 and SnCl4

29), and ZrCl4.36

However, we found that acylation methods reported to workwell with indole give highly variable results with 2-phenyl-indole. When acylation with electrophiles 12 to 14 wereattempted on 2-phenyl-indoles 10 and 11 under a wide varietyof conditions poor results were obtained generally producingcomplex mixtures (Scheme 1). The most successful synthesisof compounds 16 and 17 was achieved using titaniumtetrachloride in dichloromethane at 0 uC to give a low yieldafter tedious chromatographic purification. The followingcatalytic hydrogenation was also problematic producingmixtures of deoxygenated products and indolines but waseventually realised in a mixture of THF and acetic acid to give amoderate yield of indoles 5 and 18 (Scheme 1).24

Despite the drawbacks of the method it was initiallyacceptable for the synthesis of the first GPRC6A receptorligands.24 However, with the pressing need for comprehensiveSAR studies we found the method unsatisfactory. In contrast tothe problems encountered in the synthesis of indoles 5 and 18the synthesis of indole 6 was easily achieved by heating2-phenyl-indole in toluene with pyridine and chloroacetylchloride according to the method of Roy et al. (Scheme 2).37

The method is suitable for large-scale synthesis, gives a goodyield of indole 6 after re-crystallisation (59%, 40 g),24 andappears to be a general route to substituted 2-phenyl-indolesas exemplified by the acylation of 2-phenyl-indoles withelectron-donating (21 and 24) and electron-withdrawingsubstituents (22, Scheme 2).

Importantly, indole 6 is a shelf stable reagent, insensitive toair and moisture. Easy access to large quantities of indole 6prompted us to investigate if 6 might serve as a starting pointfor the synthesis of the desired building blocks by simplenucleophilic substitution with appropriate nucleophiles(Scheme 3).

Nucleophilic substitution was first explored as a route toacetate 15. Screening a wide range of solvents using sodium

Scheme 2 Acylation of commercially available 2-phenyl-indoles with chloroa-cetyl chloride. (i) ClCH2COCl, PhMe, pyridine, 60 uC, 6, 59%; 21, 48%, 22, 72%;24, 81%.

Scheme 1 Synthesis of indoles 5 and 18 via a acylation/catalytic hydrogenationroute. (i) Pd/C, H2, THF, AcOH, 5, 53%; 18, 63%.24

946 | RSC Adv., 2013, 3, 945–960 This journal is � The Royal Society of Chemistry 2013

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acetate as the nucleophile indicated that only polar, aproticsolvents such as DMF and DMSO allowed the reaction to takeplace at a reasonable rate (see Supporting Information (SI) fordetails3). Sodium acetate substitution in DMSO at 60 uC wassmooth and only produced a few side products. A simple work-up and purification procedure gave acetate 15 of high purityand in excellent yield (Scheme 4). Subsequent hydrolysis togive alcohol 5 was attempted under various conditions.Aqueous HCl and NaOH or NaOMe, in MeOH at 40–60 uCgave good conversion of 15 to 5 but the product was generallydifficult to purify (See SI for details3). Switching to polar,aprotic solvents gave much cleaner products and aqueous HClin THF at 50 uC was identified as the best conditions,providing 5 in good yield after chromatographic purification.Overall, this route is significantly better than that previouslyreported by us in terms of simplicity, reproducibility, cost and

yield (47%, 3 steps from 10, Scheme 1).24 The synthesis ofazide 3 was accomplished by nucleophilic substitution on 6using NaN3. A range of solvents and conditions were screenedand again fast conversion was observed in DMSO (See SI fordetails3). We found the reaction to be rapid at ambienttemperature to give azide 3 of high purity. All othernucleophiles we have employed gave no appreciable reactionat ambient temperature. Acetonitrile also provided product ofhigh purity but unlike DMSO extended heating was required tomake the reaction go to completion. The facile method ofpreparation followed by crystallisation from ethanol allows thepreparation of azide 3 of high purity on multi-gram scale inexcellent yield (.85% yield). In addition to potentiallyproviding the desired amine 4 via reduction, we examined ifazide 3 would participate in the copper catalysed Huisgencycloaddition to give 1,4-substituted 1,2,3-triazoles. Indeed,the Huisgen cycloaddition proceeds to give good yields oftriazole products (e.g. 26 and 28, Scheme 4). However, thecorrect choice of solvent proved essential for the reaction totake place. Solvent mixtures of DMSO and water provedefficient in the reaction of azide 3 with simple alkynes such asphenyl-acetylene, whilst functionalised alkynes such as 27 gaveno conversion in this reaction medium. Eventually, a tBuOH–water mixture using a catalyst loading of 15 mol% andextended reaction time was identified as the optimal condi-tions for the synthesis of triazole 28.

In stark contrast to our previous difficulties in thereduction of benzyl ethers 16 and 17 (Scheme 1) catalytichydrogenation of azide 3 was uncomplicated returning a goodyield of the desired amine 4 after chromatographic purifica-tion (Scheme 5). We found amine 4 to be unstable, inparticular under acidic conditions. Consequently, reductionand purification was run in neutral media, and we found itadvantageous to use the amine immediately after isolation. Aspart of our medicinal chemistry program on the GPRC6Areceptor we wished to synthesise amide bioisostere 32 of

Scheme 3 Proposed synthetic routes to various 3-substituted 2-phenyl-indoles.

Scheme 4 Synthesis of 2-phenyl-indole building blocks 3 and 5 from commonprecursor 6. Triazoles 26 and 28 were synthesised from azide 3 by coppercatalysed Huisgen cycloaddition. (i) DMSO, NaOAc, 60 uC, 90%; (ii) 4 M aq. HCl,THF, 50 uC, 75%; (iii) DMSO, NaN3, 90%; (iv) PhC;CH, DMSO, CuSO4?5H2O, Naascorbate, 72%; (v) 27, tBuOH, H2O, CuSO4?5H2O, Na ascorbate, 76%.

Scheme 5 Synthesis of amine 4 and subsequent coupling to give amides 31 and32. (i) Pd/C, H2, THF, 4, 76%; (ii) 29 or 30, EDCI, iPr2NEt, HOBt, DMF, 31, 62% (2steps); 32, 47% (1 step); 32, 54% (2 steps).


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known antagonist 2 (Scheme 5). To this end coupling tocarboxylic acid 30 was required. The protection of the aminefunctionality in 30 was attempted prior to coupling. However,we found protection of the amino group with variousprotecting groups to be complicated, returning complexmixtures. Reasoning that the nucleophilicity of the aminogroup is strongly reduced due to the electron-withdrawingproperties of the pyrazine ring we attempted the coupling of 30with no protection groups. Gratifyingly, amine 4 was success-fully coupled with 30 using carbodiimide chemistry to give amoderate yield of amide 32. Due to the poor stability of amine4 we examined if the crude amine could be used immediatelyafter isolation. Coupling the crude amine with carboxylic acids29 and 30 proceeded to give amides 31 and 32 in good overallyield. The use of the crude amine resulted in formation ofnumerous minor side-products but the overall yield for thesynthesis of amide 32 by this method was significantly higher(54% vs. 36%) and as such is our preferred synthetic route.

We have previously described the synthesis of GPRC6Aantagonist 1 by alkylation of indole 6 with amine 33(Scheme 6).24 Initial attempts at performing the alkylationwith K2CO3 or DBU in DMF resulted in formation of numerousside products. However, the use of a weaker base NaHCO3 inDMF gave good results. After careful optimisation it was foundthat the formation of side products could be furtherminimised in acetone or acetonitrile at 60 uC in the presenceof 20 mol% sodium iodide (See SI for details3). Although thereaction rate is higher in acetone, we favour acetonitrilebecause acetone has been observed to condense with theamine nucleophile in some instances.

Next we turned our attention to indole building block 7with a carboxylic acid at the 3-position that potentially wouldallow us to access 2-phenyl-indole amide derivatives. Synthesisof indole-3-carboxylic acids is commonly achieved via hydro-lysis of the corresponding 3-trifluroacetyl-indole.38,39 Stronglyelectrophilic acylating agents such as oxalyl chloride andtrifluoroacetic acid anhydride (TFAA) acylate indoles even atlow temperatures. Using TFAA at room temperature workedwell to provide ketone 37 but purification proved tedious andonly a moderate yield of 37 was isolated (Scheme 7).Subsequent hydrolysis of 37 did not provide carboxylic acid 7as anticipated but resulted in decarboxylation to give 2-phenyl-

indole 10 in almost quantitative yield. A possible explanationcould be that 3-acyl-indoles such as 37 are easily deprotonatedin alkaline solution.40 Thus, the generation of a delocalisedanion would retard nucleophilic attack on the ketone.41

Consequently, an extended reaction time is required to drivethe reaction to completion which is problematic becausecarboxylic acids such as 7 are known to decarboxylate underthermal conditions. This is in line with our observation, whichsuggests that carboxylic acid 7 is formed under the reactionconditions but decarboxylates relatively fast in a competingside-reaction to produce 2-phenyl-indole 10.

A possible alternative route to 2-phenyl-indole-3-carboxa-mide derivatives that eliminates the need to synthesisecarboxylic acid 7 proceeds via indole 3-glyoxyl chloride 41 thatupon heating can generate indole-3-caboxylic acid chloride toprovide indole-3-carboxamides 43 by reaction with suitableamine nucleophiles (Scheme 8).39,42,43 We hypothesised thattreating 2-phenyl-indole with oxalyl chloride at low tempera-ture followed by subsequent heating would result in decarbo-nylation, and provide a route to 2-phenyl-indole-3-carboxamides 43 following reaction with amines. In contrast

Scheme 6 Alkylation of secondary amines to provide indoles 1, 35 and 36. (i)27, 33 or 34, NaHCO3, NaI, CH3CN, 60 uC, 1, 74%; 35, 92%; 36, 81%.

Scheme 7 Synthesis of indole 3-carboxylic acid. (i) TFAA, PhMe, pyridine, 54%;(ii) NaOH (aq), 65–80 uC, 7, 0%; 10, 92%; (iii) NaClO2, H2NSO3H, NaH2PO4, THF,H2O, 0 uC, 7, 0%; 40, 83%; (iv) KMnO4, acetone, r.t. to 40 uC, 0%; (v) Boc2O,pyridine, 91%.

Scheme 8 Attempted synthesis of amides 43 and synthesis of indole-3-glyoxylamide 42. (i) ClCOCOCl, Et2O, 0 uC; (ii) a) reflux, b) R1R2NH, 0%; (iii) Bn2NH,PhMe, 87% (2 steps).


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to the difficult acylation of 2-phenyl-indole mentioned earlier,selective 3-acylation using oxalyl chloride and subsequenttreatment with secondary amines to generate 2-phenylindole-3-ylglyoxyl amides works well (e.g. 42).44,45 However, thefollowing thermal decarbonylation failed, only returningcomplex reaction mixtures with no trace of amide products43. To verify that glyoxyl chloride 41 was formed in the firststep it was trapped with dibenzylamine to obtain glyoxyl amide42 in high yield. Our results suggest that this approachtowards indole-3-carboxamides 43 is unsuitable for the2-phenyl-indole scaffold presumably due to problems in thedecarbonylation step.

Consequently, we returned our attention to the synthesis ofcarboxylic acid 7. The oxidation of N-alkylated indole-3-carbaldehyde derivatives using KMnO4

46 or Pinnick47–49

conditions have been reported. However, when applied tocommercially available 2-phenyl-indole 38 only complexmixtures with trace amounts of the desired product wereobtained (Scheme 7). Oxidation of 38 could be complicateddue to delocalisation of electrons from nitrogen to the formylgroup. To circumvent this potential problem aldehyde 38 wasBoc-protected to give indole 39.50 Gratifyingly, indole 39 wasoxidized smoothly using Pinnick conditions to give carboxylicacid 40 in high yield. Boc-protected indole 40 was synthesisedon gram-scale and easily purified by column chromatography.With carboxylic acid 40 in hand we proceeded to synthesiseanalogue 47 via carbodiimide mediated amide bond formationwith amine 33 to give a high yield of 45 (Scheme 9). To oursurprise Boc-deprotection of 45 resulted in concomitantcleavage of the morpholine amide to produce indole 46 evenunder mild conditions. To circumvent the problem the

coupling was repeated with amine 34 that was Boc- andmethyl ester-deprotected in one pot to produce indole 46which following coupling with morpholine gave analogue 47.Amides 44 to 47 produce complex NMR spectra due to thepresence of amide rotamers, which was confirmed by variabletemperature NMR experiments (See SI, compound 47 fordetails3).

Indole reacts readily with iminium ions to give aminoalk-ylation at the indole 3-position,51 and some examples with the2-phenyl-indole scaffold are also known.52,53 It is well knownthat indoles under acidic conditions react with formaldehydeto generate 3,39-diindolylmethane 52 via dehydration of3-hydroxymethylindole 49, and subsequent nucleophilic addi-tion of indole 48 (Scheme 10). Similarly, amino-alkylatedMannich products (e.g. 50) eliminate in acidic media, leadingto formation of 3,39-diindolylmethanes 52.54,55 Consideringthe reaction mechanism and the possible undesired sidereactions that may occur it is surprising that extended reactiontimes, sometimes overnight, often are reported in theliterature.52,53 Working with 2-phenyl-indole we observedextensive side product formation if the reaction was left inexcess of a few hours. Hence a short reaction time is crucial toensure a high yield of the desired product. In the casesinvestigated by us a reaction time of ,45 min after addition of2-phenyl-indole was optimal (Table 1). In this manner indoles53 to 58 were synthesised in high, reproducible yields.

For the synthesis of potential GPRC6A ligands such as 63we were interested in having access to indole building blocks 9and 61 (Scheme 11). There are several known routes totryptamine and its derivatives including reduction of indolyl-glyoxamides56 and 3-(2-nitroethylene)-indole57 with LiAlH4.However, we decided to attempt the synthesis from commer-cially available nitrile 59 reasoning that it would be possible toreduce the nitrile to provide amine 9 directly. Disappointingly,attempted reduction of 59 with LiAlH4 in THF resulted in

Scheme 9 Synthesis of analogue 47. (i) 33, 34 or morpholine, EDCI, HOBt,iPr2NEt, DMF, 44, 93%; 45, 81%; 47, 70%; (ii) HCl, ether, CH2Cl2, 46, quant.; (iii)4 M HCl, dioxane, 40 uC, 85%.

Scheme 10 Formation of 3,39-diindolylmethane 52 during acid-catalysedMannich reaction on indole.


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complex reaction mixtures, most likely due to abstraction ofthe NH proton followed by elimination of cyanide. Instead thereduction was realised under mild, catalytic conditions usingin situ generated nickel boride, from NiCl2 and NaBH4

according to the method of Caddick and co-workers.58–60

Concomitant N-Boc-protection of the primary amine gave 60 ingood yield. Simple acid catalysed Boc deprotection of 60produced primary amine 9 in high yield.

The N-methylated analogue 61 was obtained from 60 viaLiAlH4 reduction; a known method for making N-methyl-amines from ethyl-carbamates61,62 that worked similarly wellon tert-butyl-carbamate 60. Alkylation of 61 using ouroptimised conditions with alkyl chloride 6263 gave analogue63 in good yield (Scheme 11).

Conclusions

Using a chemogenomic approach we recently identifiedGPRC6A receptor antagonists 1 and 2 that incorporate the2-phenyl-indole privileged structure. During our medicinalchemistry program to optimise the properties of ligands 1 and2 we found the chemistry of 2-phenyl-indole to be markedlydifferent from that of indole. Herein we have reportedoptimised syntheses for a series of 2-phenyl-indole buildingblocks 3 to 9, functionalised at the indole 3-position.Furthermore, we have demonstrated that these buildingblocks can be used in a variety of reactions by synthesising aseries of new potential GPRC6A receptor ligands. Moreover, wehave highlighted important findings relating to the reactivityand stability of 2-phenyl-indole to aid medicinal chemists steeraround some of the pitfalls experienced by us. 2-Phenyl-indolerepresents an important privileged structure scaffold withinmedicinal chemistry with in excess of 190 predicted GPCRtargets in family A and C and as such the building blocksreported herein should be of general interest to medicinalchemists working in the GPCR field.21,25

Experimental section

General information

All anhydrous reactions were carried out in oven or flamedried glassware, under N2. Solvents were of chromatographygrade and dried using a solvent purification system (CH2Cl2,THF, DMF), with 3 Å molecular sieves (MeCN, MeOH, toluene),or by filtration through a plug of activated alumina (Al2O3)onto 3 Å molecular sieves (Et2O). Commercially acquiredchemicals were used without further purification unless statedotherwise. Thin-layer chromatography (TLC) was carried outon silica gel 60 F254 pre-coated plates and visualised using UV(254 nm), I2–SiO2, KMnO4 or Ninhydrin stain. Flash columnchromatography and dry column vacuum chromatography(DCVC)64 were carried out according to standard proceduresusing silica gel 60 (40–63 mm and 15–40 mm mesh,respectively). Aqueous sulfate buffer (pH # 2) was preparedby dissolving 1.5 mol Na2SO4 in 0.5 mol H2SO4 and adding

Table 1 Indoles 53 to 58 synthesised by Mannich reaction of indole 10 withamines 27, 33, and 64 to 67

# # R Yield (%)a

64 53 73

65 54 78

66 55 71

67 56 76

27 57 74b

33 58 73

a Isolated yield. b Solvent: dioxane/AcOH/MeOH (2/2/1, v/v/v).

Scheme 11 Synthesis of building blocks 9 and 61 and potential GPRC6A ligand63. (i) LiAlH4, THF, 0 uC to r.t., 0%; (ii) NiCl2?6H2O, NaBH4, Boc2O, MeOH, 0 uC tor.t., 66%; (iii) TFA, CH2Cl2, 83%; (iv) LiAlH4, THF, reflux, 69%; (v) 2-chloro-1-morpholinoethanone 62, NaHCO3, NaI, CH3CN, 60 uC, 73%.


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H2O to a total volume of 2000 ml. 1H NMR- and 13C NMR-spectra were recorded on 300, 400, or 500 MHz Brukerinstruments. Signals are reported in ppm (d) and solventswere used as internal standard when assigning NMR spectra.65

Coupling constants (J) are given in Hertz (Hz), rounded to thenearest 0.5 Hz. Signal assignment was made from unambig-uous chemical shifts and COSY, HSQC, HMBC and APTexperiments. Melting points are uncorrected. FT-IR (neat)signals are reported in wavenumbers (cm21). HPLC-MS wasrecorded on an Agilent 1100 system using a Xbridge C18column, 3.5 mm, 100 6 4.6 mm with UV detection at 254 nm,and an electrospray ionisation (ESI) mass detector. Mobilephase (MP) A: 0.05% HCOOH, 5% MeCN, 95% H2O (v/v/v).Mobile phase B: 0.05% HCOOH, 95% MeCN, 5% H2O (v/v/v).Flow rate: 1 ml min21. Gradient: 0–1 min: 100% MP A, 1–6min: 0 to 100% MP B in A, 6–8 min: 100% MP B. Highresolution mass spectra (HRMS) were recorded on a time offlight (TOF) MS system, coupled to an analytical HPLC and ESIdetector. HRMS HPLC was performed on a C18 column (25 cm6 4.6 mm, 5 mm) with a linear gradient (10% to 100% MeOHin H2O, containing 0.1% TFA, in 20 min, v/v) at a flow rate of 1ml min21 and UV detection at 215 nm.

2-(Methyl(2-morpholino-2-oxoethyl)amino)-1-(2-phenyl-1H-indol-3-yl)ethanone (1)

A microwave vial was charged with indole 6 (0.30 g, 1.1 mmol),NaHCO3 (0.25 g, 3.0 mmol), NaI (0.045 g, 0.3 mmol), andamine 33 (0.22 g, 1.1 mmol). MeCN (8 ml) was added and thevial was sealed and stirred at 60 uC in a heating block for 6 h.The solids were removed by filtration, washed with MeCN andthe combined organic phases were concentrated in vacuo toafford the crude tertiary amine. Purification by columnchromatography (2.5% MeOH, 0.2% aqueous NH3, inCH2Cl2, v/v) afforded a colourless film that upon addition ofEt2O and concentration in vacuo gave indole 1 as an off-white,amorphous solid (0.32 g, 74%). Rf 0.59 (5% MeOH, 0.4%aqueous NH3, in CH2Cl2, v/v). 1H NMR (500 MHz, CDCl3): d

(ppm) 9.04 (br s, 1H, Indole-NH), 8.27–8.24 (m, 1H, Indole-H4), 7.52–7.43 (m, 5H, Ph), 7.40–7.37 (m, 1H, Indole-H7), 7.31–7.27 (m, 2H, Indole-H6, H5) 3.63–3.48 (m, 8H, O(CH2CH2)2N),3.42 (s, 2H, CH2), 3.27 (s, 2H, CH2), 2.21 (s, 3H, NCH3). 13CNMR (125 MHz, CDCl3): d (ppm) 195.0, 168.9, 144.1, 135.4,132.8, 129.9, 129.6, 129.0, 127.3, 123.9, 122.8, 122.2, 114.2,111.2, 67.1, 67.0, 65.4, 59.6, 46.1, 43.1, 42.2. HPLC RT = 4.84min. MS (ESI) Found 392.2 [M + H]+. The analytical data is inagreement with that previously reported by us.24

2-Azido-1-(2-phenyl-1H-indol-3-yl)-ethanone (3)

Indole 6 (1.80 g, 6.7 mmol) was dissolved in DMSO (25 ml),sodium azide (0.52 g, 8.0 mmol) was added and the mixturewas stirred at ambient temperature for 2 h 15 min. H2O (150ml) was added and the mixture was extracted with EtOAc (4 640 ml). The combined organic phases were washed with H2Oand brine, dried over Na2SO4, filtered and concentrated invacuo to afford the crude product as a red solid. Purification byDCVC (0% to 50% EtOAc in n-heptane, v/v, 5% increments)gave azide 3 as a pale yellow solid (1.66 g, 90%). Rf 0.33 (30%EtOAc in n-heptane, v/v). Mp (uC): 127.5–130.5 (decomposed;orange plates from EtOH). 1H NMR (400 MHz, DMSO-d6): d

(ppm) 12.30 (br s, 1H, Indole-NH), 8.21–8.17 (m, 1H, Indole-H4), 7.68–7.63 (m, 2H, Ph), 7.61–7.55 (m, 3H, Ph), 7.48–7.44(m, 1H, Indole-H7), 7.29–7.23 (m, 2H, Indole-H6, H5), 4.05 (s,2H, CH2). 13C NMR (100 MHz, DMSO-d6): d (ppm) 189.8, 145.5,135.6, 132.2, 129.8, 129.7, 128.6, 126.7, 123.2, 122.2, 121.4,111.8, 111.5, 55.7. HPLC RT = 6.78 min. IR: n (cm21) 2105.HRMS (ESI) Calcd. for C16H13N4O 277.1084; Found 277.1094.

2-Amino-1-(2-phenyl-1H-indol-3-yl)-ethanone (4)

A flask was charged with indole 3 (0.25 g, 0.90 mmol), andanhydrous THF (10 ml). The flask was cooled to 0 uC using anice–water bath, flushed with N2, and 10% Pd/C (0.062 g, 0.059mmol Pd) was carefully added, and the flask was flushed withN2 followed by H2. The ice bath was removed, the flask wasfitted with a H2-balloon and the mixture was stirred vigorouslyfor 1 h 45 min. Celite and MeOH (30 ml) were added, and themixture was stirred for 45 min. The slurry was filtered througha pad of Celite, the solids washed with MeOH and the filtrateconcentrated in vacuo to afford the crude product as a pinkfilm. Purification by column chromatography (5% MeOH,0.4% aqueous NH3 in CH2Cl2, v/v) gave a pink film that uponaddition of CHCl3 and concentration in vacuo gave amine 4 asan orange solid (0.17 g, 76%). Rf 0.32 (5% MeOH, 0.4%aqueous NH3 in CH2Cl2, v/v). 1H NMR (400 MHz, CDCl3): d

(ppm) 8.70 (br s, 1H, Indole-NH), 8.35–8.32 (m, 1H, Indole-H4), 7.55–7.49 (m, 5H, Ph), 7.40–7.38 (m, 1H, Indole-H7), 7.33–7.28 (m, 2H, Indole-H6, H5), 3.57 (s, 2H, CH2). 13C NMR (100MHz, DMSO-d6): d (ppm) 196.4, 144.3, 135.6, 132.9, 129.7,129.4, 128.4, 126.9, 122.8, 121.8, 121.5, 112.3, 111.6, 50.6.HRMS (ESI) Calcd. for C16H15N2O 251.1179; Found: MH+

251.1177.

2-Hydroxy-1-(2-phenyl-1H-indol-3-yl)ethanone (5)

Indole 15 (0.60 g, 2.05 mmol) was dissolved in THF (10 ml), 4M aqueous HCl (15 ml) was added and the mixture was heatedat 50 uC for 3 h. The reaction mixture was poured intosaturated aqueous NaHCO3 (150 ml) and extracted with EtOAc(3 6 50 ml). The combined organic phases were washed withH2O and brine, dried over Na2SO4, filtered and concentrated invacuo to give a green oil. Purification by column chromato-graphy (30% EtOAc in n-heptane, v/v) gave alcohol 5 as an off-white solid (0.39 g, 75%). Rf 0.22 (30% EtOAc in n-heptane, v/v). 1H NMR (400 MHz, CDCl3): d (ppm) 8.73 (br s, 1H, Indole-NH), 8.32–8.30 (m, 1H, Indole-H4), 7.56–7.49 (m, 5H, Ph),7.41–7.39 (m, 1H, Indole-H7), 7.38–7.31 (m, 2H, Indole-H6,H5), 4.24 (d, J = 4.5, CH2), 3.84 (t, J = 4.5, 1H, OH). 13C NMR(100 MHz, CDCl3): d (ppm) 194.5, 145.4, 135.4, 132.2, 130.4,129.5, 129.1, 127.0, 124.2, 123.4, 122.3, 111.8, 111.3, 67.2.HPLC RT = 5.93 min. MS (ESI) Found 252.1 [M + H]+. The datais in agreement with that previously reported by us.24

2-(2-Phenyl-1H-indol-3-yl)ethanamine (9)

Indole 60 (0.14 g, 0.42 mmol) was dissolved in CH2Cl2 (4 ml),TFA (0.95 ml, 1.2 mmol) was added and the mixture wasstirred at ambient temperature for 7.5 h. 2 M aqueous NaOHwas added until pH 12–13 was reached, saturated aqueousNaHCO3 was added (15 ml), and the mixture was extractedwith CH2Cl2 (4 6 15 ml). The combined organic phases werewashed with brine, dried over Na2SO4, filtered and concen-


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trated in vacuo to give a colourless oil. Purification by columnchromatography (5% MeOH, 0.4% aqueous NH3 in CH2Cl2, v/v) gave primary amine 9 as a colourless foam/film (0.081 g,83%). Rf 0.25 (5% MeOH, 0.4% aqueous NH3 in CH2Cl2, v/v).1H NMR (400 MHz, CDCl3): d (ppm) 8.07 (br s, 1H, Indole-NH),7.69–7.64 (m, 1H, Indole-H4), 7.63–7.58 (m, 2H, Ph), 7.50–7.45(m, 2H, Ph), 7.40–7.35 (m, 2H, Ph, Indole-H7), 7.22 (ddd, J =8.0, 7.0, 1.0, 1H, Indole-H6), 7.17–7.13 (m, 1H, Indole-H5), 3.07(br s, 4H, CH2CH2). 13C NMR (100 MHz, CDCl3): d (ppm) 136.0,135.4, 133.3, 129.4, 129.0, 128.3, 127.8, 122.4, 119.8, 119.3,111.1, 110.7, 43.0, 28.9. HPLC RT = 4.71 min. HRMS (ESI)Calcd. for C16H17N2 237.1386; Found 237.1372.

2-Oxo-2-(2-phenyl-1H-indol-3-yl)ethyl acetate (15)

ndole 6 (1.00 g, 3.7 mmol) was dissolved in DMSO (25 ml),sodium acetate (0.36 g, 4.4 mmol) was added and the mixturewas heated at 60 uC for 3 h. Water was added and the mixturewas extracted with EtOAc (3 6 30 ml). The combined organicfractions were washed with H2O and brine, dried (NaSO4),filtered and concentrated in vacuo to afford the crude product asa brown foam. Purification by column chromatography (40%EtOAc in n-heptane, v/v) gave acetate 15 as an off-white solid(0.98 g, 90%). Rf 0.24 (30% EtOAc in n-heptane, v/v). 1H NMR(400 MHz, CDCl3): d (ppm) 8.87 (br s, 1H, Indole-NH), 8.30–8.26(m, 1H, Indole-H4), 7.57–7.44 (m, 5H, Ph), 7.40–7.35 (m, 1H,Indole-H7), 7.32–7.25 (m, 2H, Indole-H6, H5), 4.72 (s, 2H, CH2),2.08 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d (ppm) 189.4,170.6, 144.6, 135.4, 132.4, 130.2, 129.6, 129.1, 127.3, 124.0,123.1, 122.4, 112.6, 111.2, 67.7, 20.6. HPLC RT = 6.31 min. HRMS(ESI) Calcd. for C18H16NO3 294.1130; Found 294.1129.

2-Chloro-1-(2-(3-methoxyphenyl)-1H-indol-3-yl)ethanone (21)

Indole 19 (0.098g, 0.44 mmol) was dissolved in anhydroustoluene (5 mL) and flushed with nitrogen. Pyridine (0.07 ml,0.88 mmol) was added, the solution was heated at 60 uC andchloroacetyl chloride (0.07 ml, 0.88 mmol) was added dropwiseto give an orange solution. After 24 and 48 h, additional pyridine(0.07 mL, 0.88 mmol) and chloroacetyl chloride (0.07 mL, 0.88mmol) were added dropwise. After 55 h the reaction mixturewas transferred to a separation funnel with Et2O (2 6 50 ml),and washed with saturated aqueous NaHCO3 (2 6 50 ml) andbrine (2 6 50 ml). The combined organic phases were dried(Na2SO4), filtered and concentrated in vacuo to give a brown oil.Purification by DCVC (id. 4 cm; 20 ml fractions; 2 6 heptane; 0–100% EtOAc in n-heptane, v/v, 5% increments) gave indole 21(0.063 g, 48%) as a brown powder. Rf 0.55 (50% EtOAc inn-heptane, v/v). 1H NMR (300 MHz, acetone-d6): d (ppm) 11.16(br s, 1H, Indole-NH), 8.31–8.26 (m, 1H, Indole-H4), 7.53–7.46(m, 2H, ArH), 7.31–7.22 (m, 4H, ArH), 7.16–7.12 (m, 1H, ArH),4.27 (s, 2H, CH2), 3.89 (s, 3H, OCH3). 13C NMR (125 MHz,acetone-d6, APT): d (ppm) 187.9 (C), 160.8 (C), 145.7 (C), 136.6(C), 134.6 (C), 130.8 (CH), 128.4 (C), 124.4 (CH), 123.2 (CH),122.9 (CH), 122.8 (CH), 116.7 (CH), 115.8 (CH), 113.3 (C), 112.4(CH), 55.9 (CH3), 48.5 (CH2). HRMS (ESI) Calcd. forC17H15ClNO2 300.0796; Found 300.0786.

2-Chloro-1-(2-(4-chlorophenyl)-1H-indol-3-yl)ethanone (22)

Indole 20 (0.099 g, 0.44 mmol) was dissolved in anhydroustoluene (15 mL) under nitrogen. Pyridine (0.05 mL, 0.44 mmol)

was added and the solution was heated at 60 uC. Chloroacetylchloride (0.04 ml, 0.44 mmol) was added dropwise to give anorange solution. After 2 h of stirring, additional chloroacetylchloride (0.02 ml, 0.22 mmol) was added dropwise. Thereaction mixture was stirred at 60 uC for 4 h to give a yellowsuspension with a red precipitate. The reaction mixture wastransferred to a separation funnel with Et2O (2 6 50 ml), andwashed with saturated aqueous NaHCO3 (2 6 50 ml) andbrine (2 6 50 ml). The combined organic phases were driedover Na2SO4, filtered and concentrated in vacuo to give a brownoil. Purification by DCVC (id. 4 cm; 20 ml fractions; 2 6heptanes; 0–100% EtOAc in n-heptane (v/v) – 2 6 5%increments) gave indole 22 (0.095 g, 72%) as a green powder.Rf 0.65 (20% EtOAc in n-heptane, v/v). 1H NMR (300 MHz,DMSO-d6): d (ppm) 12.34 (br s, 1H, Indole-NH), 8.13–8.10 (m,1H, Indole-H4), 7.70–7.61 (m, 4H, ArH), 7.47–7.44 (m, 1H,Indole-H7), 7.29–7.21 (m, 2H, Indole-H6, H5), 4.43 (s, 2H,CH2). 13C NMR (75 MHz, acetone-d6): d (ppm) 187.4, 144.3,136.7, 136.1, 132.3, 132.0, 129.5, 128.1, 124.3, 123.1, 122.5,113.3, 112.4, 48.8.

2-Chloro-1-(6-phenyl-5H-1,3-dioxolo[4,5-f]indol-7-yl)ethanone(24)

Indole 23 (0.11 g, 0.46 mmol) was dissolved in anhydroustoluene (5 mL) and flushed with nitrogen. Pyridine (0.072 mL,0.91 mmol) was added and the solution was heated to 60 uC.Chloroacetyl chloride (0.072 ml, 0.91 mmol) was addeddropwise to give a green solution that was stirred for 24 h at60 uC to give a yellow suspension with a green precipitate. Thereaction mixture was transferred to a separation funnel withEt2O (2 6 20 ml), and washed with aqueous sulfate buffer (26 20 ml), saturated aqueous NaHCO3 (2 6 20 ml) and brine.The combined organic phases were dried over Na2SO4, filteredand concentrated in vacuo to give an orange oil. Purification byDCVC (id. 4 cm; 20 ml fractions; 2 6 heptanes; 0–40% EtOAcin n-heptane, v/v, 2–4 6 5% increments) gave indole 24 as anorange film (0.12 g, 81%). Rf 0.45 (50% EtOAc in n-heptane, v/v). 1H NMR (500 MHz, acetone-d6): d (ppm) 7.72 (s, 1H, Indole-H4), 7.68–7.66 (m, 2H, Ph), 7.59–7.57 (m, 3H, Ph), 6.96 (s, 1H,Indole-H7), 6.01 (s, 2H, OCH2), 4.18 (s, 2H, CH2Cl). 13C NMR(125 MHz, acetone-d6): d (ppm) 187.8, 146.7, 145.9, 144.2,133.6, 131.6, 130.7, 130.5, 129.7, 122.7, 113.7, 101.9, 101.4,93.0, 48.3. HRMS (ESI) Calcd. for C17H13ClNO3 314.0592;Found 314.0579.

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(2-phenyl-1H-indol-3-yl)ethanone (26)

A microwave vial was charged with indole 3 (0.150 g, 0.54mmol), sodium ascorbate (0.0108 g, 0.054 mmol), coppersulfate pentahydrate (0.0068 g, 0.027 mmol), phenyl acetylene(0.060 ml, 0.54 mmol), DMSO (4 ml) and H2O (0.5 ml). Themixture was sonicated for 10 min and then stirred at ambienttemperature for 2 h. H2O (50 ml) was added and the aqueousmixture was extracted with EtOAc (3 6 30 ml). The combinedorganic fractions were washed with H2O and brine, dried overNa2SO4, filtered and concentrated in vacuo to afford a beigesolid. Recrystallisation from EtOAc–n-hexane gave in two cropstriazole 26 as a cotton-like, white solid (0.15 g, 72%). Rf 0.44(50% EtOAc in n-heptane, v/v). Mp (uC): 233–235.5. 1H NMR


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(400 MHz, DMSO-d6): d (ppm) 12.43 (br s, 1H, Indole-NH), 8.45(s, 1H, triazole-CH), 8.20 (d, J = 7.0, 1H, Indole-H4), 7.85–7.78(m, 4H, Ph), 7.64–7.62 (m, 3H, Ph), 7.51 (d, J = 7.0, 1H, Indole-H7), 7.45 (t, J = 7.5, 2H, Ph), 7.35–7.25 (m, 3H, Indole-H6, H5,Ph), 5.41 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d (ppm)186.6, 146.0, 145.9, 135.7, 132.1, 130.8, 130.0, 129.9, 128.9,128.7, 127.8, 126.8, 125.1, 123.4, 123.1, 122.4, 121.4, 112.0,111.4, 57.0. HPLC RT = 6.76 min. HRMS (ESI) Calcd. forC24H19N4O 379.1559; Found 379.1588.

2-(Methylamino)-N-(prop-2-yn-1-yl)acetamide hydrochloride(27)

N-Boc-sarcosine (2.00 g, 10.6 mmol) was dissolved in CH2Cl2

(40 ml) and N,N-diisopropyl-ethylamine (5.2 ml, 31.5 mmol),propargylamine (0.81 ml, 12.6 mmol), N-(3- dimethylamino-propyl)-N’-ethylcarbodiimide hydrochloride (2.43 g, 12.7mmol) and DMAP (0.39 g, 3.2 mmol) were added, and themixture stirred at room temperature for 90 h. The reactionmixture was washed with aqueous sulfate buffer (3 6 40 ml),saturated aqueous NaHCO3 (2 6 40 ml) and brine, dried withNa2SO4, filtered and concentrated in vacuo, to afford the crudeamide as a white solid. The crude product was dissolved inCH2Cl2 (30 ml) and 2 M HCl 6 Et2O (10.5 ml, 21.0 mmol) wasadded. The mixture was stirred at ambient temperature for 46h and the solvent was removed under reduced pressure to givea solid that was recrystallised from absolute EtOH (20 ml),Et2O (3 ml). The solids were filtered off, washed with Et2O anddried under vacuum to give amine 27 (1.23 g, 72%). Rf 0.29(10% MeOH, 0.8% aqueous NH3 in CH2Cl2, v/v). 1H NMR (300MHz, DMSO-d6): d (ppm) 8.93 (br t, J = 5.5, 1H, NHC=O), 8.84(br s, 2H, NH2

+), 3.94 (dd, J = 5.5, 2.5, 2H, CH2C;), 3.69 (s, 2H,CH2C=O), 3.21 (t, J = 2.5, 1H, ;CH), 2.54 (s, 3H, CH3). 13C NMR(75 MHz, DMSO-d6): d (ppm) 164.7, 80.4, 73.6, 48.7, 32.7, 28.0.HRMS (ESI) Calcd. for C6H10N2O 127.0866; Found 127.0874.

2-(Methylamino)-N-((1-(2-oxo-2-(2-phenyl-1H-indol-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (28)

A flask was charged with indole 3 (0.30 g, 1.09 mmol),secondary amine 27 (0.177 g, 1.09 mmol), sodium ascorbate(0.0214 g, 0.109 mmol), copper sulfate pentahydrate (0.0136 g,0.054 mmol), tBuOH (28 ml) and H2O (4 ml), and the mixturewas sonicated for 15 min then stirred at ambient temperature.Additional sodium ascorbate (3 6 0.0215 g, 0.11 mmol after10, 24, and 29 h) and copper sulfate pentahydrate (2 6 0.014 g,0.054 mmol after 10 and 24 h) were added. After 52 h ofstirring the mixture was concentrated in vacuo and the solidstaken up in saturated aqueous NaHCO3 (150 ml) to give anemulsion which was extracted with EtOAc (10 6 30 ml) and10% MeOH in CHCl3, v/v (12 6 20 ml). The EtOAc and CHCl3

phases were respectively washed with brine, dried over Na2SO4

and filtered. The organic phases were then combined andconcentrated in vacuo to give a beige solid. Purification byDCVC (id. 4 cm; 20 ml fractions, 0–20% MeOH, 0–1.6%aqueous NH3 in CH2Cl2, v/v, 1% increments) gave triazole 28as a pale yellow foam (0.33 g, 76%). Rf 0.23 (10% MeOH, 0.8%aqueous NH3 in CH2Cl2, v/v). 1H NMR (400 MHz, CDCl3): d

(ppm) 9.20 (br s, 1H, Indole-NH), 8.33–8.31 (m, 1H, Indole-H4), 7.67–7.62 (m, 3H, Ph, NHCLO), 7.57–7.55 (m, 3H, Ph),7.47 (s, 1H, triazole-H), 7.45–7.43 (m, 1H, Indole-H7), 7.35–

7.32 (m, 2H, Indole-H6, H5), 5.13 (s, 2H, ArCOCH2), 4.51 (d, J =5.5, 2H, CH2NHCLO), 3.17 (s, 2H, CH2NHCH3), 2.37 (s, 3H,CH3). 13C NMR (100 MHz, CDCl3): d (ppm) 186.5, 171.9, 145.4,144.6, 135.5, 132.1, 130.7, 129.8, 129.5, 127.3, 124.5, 124.2,123.6, 122.5, 113.0, 111.4, 57.3, 54.6, 36.9, 34.6. HPLC RT = 4.66min. HRMS (ESI) Calcd. for C22H23N6O2 403.1877; Found403.1855.

tert-Butyl methyl(2-oxo-2-((2-oxo-2-(2-phenyl-1H-indol-3-yl)ethyl)amino)ethyl)-carbamate (31)

Amine 4 was synthesised by reduction of azide 3 (0.15 g, 0.54mmol) in THF (8 ml) using 10% Pd/C (0.040 g, 0.038 mmol Pd)as described above. The mixture was stirred at roomtemperature for 1 h to give the crude amine (0.14 g) whichwas used without further purification. The crude amine wasdissolved in anhydrous DMF (10 ml), and N-Boc-sarcosine(0.103 g, 0.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl) car-bodiimide hydrochloride (0.125 g, 0.65 mmol), 1-hydroxy-benzotriazole (0.081 g, 0.60 mmol), and N,N-diisopropyl-ethylamine (0.27 ml, 1.6 mmol) was added, and the mixturewas stirred at ambient temperature for 16.5 h. EtOAc (30 ml)was added and the mixture was washed with sulfate buffer(62), saturated aqueous NaHCO3, H2O, brine, dried overNa2SO4, filtered and concentrated in vacuo to afford a brownoil. Purification by column chromatography (45% n-heptane inEtOAc, v/v) gave amide 31 as a yellow solid (0.14 g, 62% over 2steps). Rf 0.45 (30% n-heptane in EtOAc, v/v). 1H NMR (400MHz, CDCl3): d (ppm) 9.06 (br s, 1H, Indole-NH), 8.29–8.27 (m,1H, Indole-H4), 7.52–7.38 (m, 6H, ArH, Indole-H7), 7.34–7.28(m, 2H, Indole-H6, H5), 6.97 (br m, 1H, NHCLO), 4.20 (br s,2H, CH2NHCLO), 3.84 (br s, 2H, CH2NCH3), 2.92 (s, 3H, NCH3),1.46 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3): d (ppm)189.9, 169.3, 156.1, 145.4, 135.5, 132.2, 130.2, 129.5, 129.0,127.0, 123.9, 123.1, 122.2, 112.6, 111.5, 80.8, 53.0, 48.5, 35.9,28.4. HPLC RT = 6.48 min. HRMS (ESI) Calcd. for C24H28N3O4

422.2074; Found 422.2072.

3-Amino-N-(2-oxo-2-(2-phenyl-1H-indol-3-yl)ethyl)pyrazine-2-carboxamide (32)

METHOD A. Amine 4 (0.075 g, 0.30 mmol) was dissolved inanhydrous DMF (4 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.069 g, 0.36 mmol),1-hydroxy-benzotriazole (0.045 g, 0.33 mmol),N,N-diisopropyl-ethylamine (0.16 ml, 0.90 mmol), and2-amino-pyrazinecarboxylic acid (0.050 g, 0.36 mmol) wereadded, and the mixture was stirred for 22 h at roomtemperature. EtOAc (50 ml) was added and the mixture waswashed with saturated aqueous NaHCO3, dilute sulfate buffer(20% sulfate buffer in brine, v/v), dried over Na2SO4, filteredand concentrated in vacuo to afford the crude product as ayellow oil. Purification by column chromatography (50%EtOAc in n-heptane, v/v) gave amide 32 as a pale yellow solid(0.050 g, 47%).

METHOD B. Amine 4 was synthesised by reduction of azide 3(0.25 g, 0.90 mmol) in THF (10 ml) using 10% Pd/C (0.060 g,0.059 mmol Pd) as described above. The reduction wascompleted in 80 min to give crude amine 4 (0.23 g) that wasused with no further purification. Coupling of amine 4 withcarboxylic acid 30 was carried out as described above to give


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amide 32 as a yellow solid (0.18 g, 54% over 2 steps). Rf 0.25 (50%EtOAc in n-heptane, v/v). 1H NMR (400 MHz, DMSO-d6): d (ppm)12.25 (br s, 1H, Indole-NH), 8.78 (t, J = 5.5, 1H, NHCLO), 8.22 (d, J= 2.5, 1H, pyrazine-H), 8.21–8.19 (m, 1H, Indole-H4), 7.85 (d, J =2.5, 1H, pyrazine-H), 7.72–7.70 (m, 2H, Ph), 7.61–7.59 (m, 3H,Ph), 7.47–7.45 (m, 1H, Indole-H7), 7.28–7.23 (m, 2H, Indole-H6,H5), 7.70–7.23 (br s, 2H, ArNH2), 4.18 (d, J = 5.5, 2H, CH2). 13CNMR (100 MHz, DMSO-d6): d (ppm) 190.1, 165.7, 155.1, 147.0,145.1, 135.6, 132.6, 131.0, 129.8, 129.6, 128.6, 126.8, 125.3, 123.0,122.1, 121.4, 111.83, 111.79, 47.8. HPLC RT = 6.33 min. HRMS(ESI) Calcd. for. C21H18N5O2 372.1455; Found 372.1442.

2-(Methylamino)-1-morpholinoethanone hydrochloride (33)

N-Boc-sarcosine (2.70 g, 14.3 mmol) was dissolved in CH2Cl2

(50 ml) and DMAP (0.55 g, 4.3 mmol), N,N-diisopropyl-ethylamine (7 ml, 42 mmol), morpholine (1.5 ml, 17.1 mmol),and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydro-chloride (3.28 g, 17.1 mmol) were added. The mixture wasstirred at ambient temperature for 4 days, washed with sulfatebuffer (63), saturated aqueous NaHCO3 (62), and brine. Theorganic phase was dried over Na2SO4, filtered and concen-trated in vacuo to afford the crude amide as slightly yellow oil.The crude product was dissolved in 1,4-dioxane (25 ml) and15% aqueous HCl was added (25 ml). The solution was stirredvigorously at room temperature for 22 h. Toluene was addedand the solvents removed under reduced pressure to give thecrude hydrochloric salt as a white solid. Recrystallisation fromabsolute EtOH, Et2O gave amine 33 as a white solid (1.75 g,63% over two steps). Rf 0.32 (10% MeOH, 0.8% aqueous NH3

in CH2Cl2, v/v). 1H NMR (500 MHz, DMSO-d6): d (ppm) 9.01 (s,2H, NH2

+), 4.03 (s, 2H, CH2NH2+), 3.61–3.56 (m, 4H, 2 6

CH2O), 3.49 (m, 2H, CH2NCLO), 3.37 (t, 2H, J = 4.5, CH2NCLO),2.54 (s, 3H, CH3). 13C NMR (125 MHz, DMSO-d6): d (ppm)163.9, 65.87, 65.77, 48.2, 44.5, 41.7, 32.8. The analytical data isin agreement with that previously reported by us.24

Methyl 2-(methyl(2-oxo-2-(2-phenyl-1H-indol-3-yl)ethyl)amino)acetate (35)

Synthesised according to the general procedure (see thesynthesis of 1) using indole 6 (0.50 g, 1.8 mmol), NaHCO3

(0.47 g, 5.6 mmol), NaI (0.056 g, 0.37 mmol), amine 34 (0.26 g,1.85 mmol) and MeCN (7 ml). Purification by columnchromatography (45% EtOAc, 0.2% Et3N in n-heptane, v/v)gave indole 35 as an off-white solid (0.58 g, 92%). Rf 0.29 (50%EtOAc, 0.2% Et3N in n-heptane, v/v). 1H NMR (500 MHz,CDCl3): d (ppm) 8.56 (br s, 1H, Indole-NH), 8.34–8.30 (m, 1H,Indole-H4), 7.55–7.46 (m, 5H, Ph), 7.40–7.36 (m, 1H, Indole-H7), 7.33–7.26 (m, 2H, Indole-H6, H5), 3.63 (s, 3H, COOCH3),3.61 (s, 2H, CH2), 3.40 (s, 2H, CH2), 2.38 (s, 3H, NCH3). 13CNMR (125 MHz, CDCl3): d (ppm) 195.4, 171.8, 143.9, 135.3,133.0, 129.9, 129.6, 129.0, 127.4, 123.8, 122.8, 122.5, 114.2,111.0, 64.3, 57.6, 51.5, 42.3. HPLC RT = 4.95 min. HRMS (ESI)Calcd. for C20H21N2O3 337.1547; Found 337.1536.

2-(Methyl(2-oxo-2-(2-phenyl-1H-indol-3-yl)ethyl)amino)-N-(prop-2-yn-1-yl)acetamide (36)

Synthesised according to the general procedure (see thesynthesis of 1) using indole 6 (0.50 g, 1.8 mmol), NaHCO3

(0.46 g, 5.5 mmol), NaI (0.055 g, 0.37 mmol), amine 27 (0.30 g,

1.8 mmol) and MeCN (7 ml). Purification by columnchromatography (gradient, 45% n-heptane, 0.3% Et3N inEtOAc, v/v to 30% n-heptane, 0.4% Et3N in EtOAc, v/v) gaveindole 36 as a pale yellow foam (0.54 g, 81%). Rf 0.31 (40%n-heptane, 0.2% Et3N in EtOAc, v/v). 1H NMR (500 MHz,CDCl3): d (ppm) 8.98 (br s, 1H, Indole-NH), 8.31–8.28 (m, 1H,Indole-H4), 7.87 (br t, J = 6.0, 1H, NHCLO), 7.55–7.48 (m, 5H,Ph), 7.43–7.40 (m, 1H, Indole-H7), 7.33–7.28 (m, 2H, Indole-H6, H5), 3.99 (dd, J = 6.0, 2.5, 2H, NHCH2), 3.41 (s, 2H, CH2),2.99 (s, 2H, CH2), 2.24 (s, 3H, CH3), 2.17 (t, J = 2.5, 1H, ;CH).13C NMR (125 MHz, CDCl3): d (ppm) 194.7, 171.2, 144.1, 135.4,132.8, 130.1, 129.6, 129.1, 127.3, 124.0, 123.0, 122.3, 114.1,111.2, 79.8, 71.2, 65.7, 61.2, 43.6, 28.7. HPLC RT = 4.92 min.HRMS (ESI) Calcd. for C22H22N3O2 360.1707; Found 360.1707.

2,2,2-Trifluoro-1-(2-phenyl-1H-indol-3-yl)ethanone (37)

2-Phenyl-indole (0.225 g, 1.16 mmol) was dissolved in toluene(20 ml) and pyridine (0.1 ml, 1.24 mmol) and trifluoroaceticacid anhydride (0.165 ml, 1.19 mmol) were added dropwiseunder N2 to give a yellow solution. After 1.5 h water was addedand the mixture was partitioned between saturated aqueousNaHCO3 and EtOAc. The organic phase was washed withsaturated aqueous NaHCO3, sulfate buffer and brine, driedover Na2SO4, filtered and concentrated in vacuo to give aslightly orange solid. Purification by column chromatography(20% EtOAc in n-heptane, v/v) gave indole 37 as yellow solid(0.18 g, 54%). Rf 0.26 (20% EtOAc in n-heptane, v/v). 1H NMR(300 MHz, CDCl3): d (ppm) 8.67 (br s, 1H, Indole-NH), 8.26–8.20 (m, 1H, Indole-H4), 7.60–7.35 (m, 8H, ArH, Indole-H7, H6,H5). 13C NMR (125 MHz, CDCl3, APT): d (ppm) 177.3 (quartet,2JCF = 36, CLO), 148.0 (C), 135.1 (C), 131.5 (C), 130.3 (CH), 129.6(CH), 128.5 (CH), 127.0 (C), 124.6 (CH), 123.7 (CH), 122.0 (CH),116.6 (quartet, 1JCF = 290, CF3), 111.4 (CH), 108.5 (C). HPLC RT

= 7.17. MS (ESI) Found 290.1 [M + H]+.

tert-Butyl 3-formyl-2-phenyl-1H-indole-1-carboxylate (39)

Indole 38 (1.50 g, 6.8 mmol) was dissolved in anhydrouspyridine (20 ml) and di-tert-butyl dicarbonate (1.93 g, 8.8mmol) was added to give an orange solution that was stirredunder N2. After 2 h 15 min sulfate buffer (200 ml) was addedand the slurry was extracted with EtOAc (4 6 100 ml). Thecombined organic phases were washed with sulfate buffer andbrine, dried over Na2SO4, filtered and concentrated in vacuo togive an orange solid. Recrystallisation from EtOAc gave indole39 as off-white needles that were washed with cold n-heptaneand dried (1.98 g, 91%). Rf 0.44 (20% EtOAc in n-heptane, v/v).Mp (uC): 172–173 (decomposed) 1H NMR (500 MHz, CDCl3): d

(ppm) 9.72 (s, 1H CHO), 8.40 (d, J = 7.0, 1H, Indole-H4), 8.22 (d,J = 8.0, 1H, Indole-H7), 7.51–7.40 (m, 7H Ph, Indole-H6, H5),1.27 (s, 9H C(CH3)3). 13C NMR (125 MHz, CDCl3): d (ppm)188.4, 150.0, 149.3, 136.4, 131.1, 130.2, 129.4, 128.2, 126.1,125.6, 124.9, 122.1, 119.9, 115.0, 85.1, 27.5. HPLC: RT 7.94 min.MS (ESI) Found 344.4 [M + Na]+. The analytical data is inagreement with that reported by others.50

1-(tert-Butoxycarbonyl)-2-phenyl-1H-indole-3-carboxylic acid(40)

Indole 39 (0.050 g, 0.16 mmol) was dissolved in THF (4 ml) andNaH2PO4 (0.080 g, 0.67 mmol) dissolved in water (0.4 ml), and


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sulfamic acid (0.026 g, 0.26 mmol) were added. The mixturewas cooled to 0 uC and NaClO2 (0.025 g, 0.28 mmol) dissolvedin water (0.3 ml) was added. After an additional 2.5 h sodiumchlorite (0.007 g, 0.08 mmol) was added. After a total reactiontime of 4 h sulfate buffer was added and the mixture wasextracted with CH2Cl2 (3 6 25 ml). The combined organicfractions were dried over Na2SO4, filtered and concentrated invacuo to afford a crude solid product. Purification by columnchromatography (40% EtOAc in n-heptane, v/v) gave carboxylicacid 40 as a white solid (0.044 g, 83%). Rf 0.40 (40% EtOAc inn-heptane, v/v). 1H NMR (500 MHz, CDCl3): d (ppm) 8.26–8.24(m, 1H, Indole-H4), 8.20–8.18 (m, 1H, Indole-H7), 7.47–7.35(m, 7H, Ph, Indole-H6, H5), 1.21 (s, 9H, C(CH3)3). 13C NMR(125 MHz, CDCl3, APT): d (ppm) 168.4 (C) 149.5 (C), 145.8 (C),136.2 (C), 133.3 (C), 129.8 (CH), 128.7 (CH), 127.8 (CH), 127.2(C), 125.4 (CH), 124.2 (CH), 122.1 (CH), 114.8 (CH), 110.4 (C),84.9 (C), 27.4 (CH3). HPLC RT = 7.39 min. HRMS (ESI) Calcd.for C20H18NO4Na 360.1206; Found 360.1225.

N,N-Dibenzyl-2-oxo-2-(2-phenyl-1H-indol-3-yl)acetamide (42)

2-Phenyl-indole (0.10 g, 5.2 mmol) was dissolved in anhydrousEt2O (4 ml), cooled to 0 uC and oxalyl chloride (0.075 ml, 0.68mmol) was added dropwise to give a yellow precipitate. After 1h the reaction mixture was concentrated in vacuo. Et2O (2 ml)was added and the slurry was concentrated in vacuo. Theyellow solid was dispersed in dry toluene (5 ml) and cooled to 0uC. Dibenzylamine (0.2 ml, 1 mmol) was added dropwise over10 min, and the ice bath was removed. After 1.5 h at roomtemperature the reaction was partitioned between sulfatebuffer and EtOAc. The organic phase was washed with sulfatebuffer, saturated aqueous NaHCO3 (62) and brine, dried overNa2SO4, filtered, and concentrated in vacuo to afford the crudesolid product. Recrystallisation from EtOAc gave 42 as an off-white, amorphous solid (0.10 g, 43%). The mother liquor wasconcentrated in vacuo and purified by column chromatography(40% EtOAc in n-heptane, v/v) to give additional 42 as an off-white solid (0.099 g, 43%, combined yield 87%). Rf 0.39 (40%EtOAc in n-heptane, v/v). 1H NMR (500 MHz, acetone-d6): d

(ppm) 11.39 (br s, 1H, Indole-NH), 8.15 (d, J = 8.0, 1H, Indole-H4), 7.72–7.70 (m 2H, Ar), 7.54–7.46 (m, 4H, Ar), 7.30–7.20 (m,10H, Ar, Indole-H5), 7.03–7.00 (m, 2H, Ar), 4.40 (s, 2H, CH2),4.28 (s, 2H, CH2). 13C NMR (125 MHz, acetone-d6): d (ppm)188.0, 169.3, 148.2, 137.3, 136.9, 136.8, 132.1, 131.0, 130.6,129.6, 129.4, 129.2, 129.1, 128.9, 128.5, 128.2, 128.0, 124.4,123.4, 122.3, 112.7, 111.3, 51.7, 47.4. HPLC: RT = 7.40 min.HRMS (ESI) Calcd. for C30H25N2O2 445.1910; Found 445.1896.

tert-Butyl-3-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-2-phenyl-1H-indole-1-carboxylate (44)

Indole 40 (0.50 g, 1.48 mmol) was dissolved in DMF (25 ml)and N-hydroxybenzotriazole (0.22 g, 1.63 mmol),N,N-diisopropylethylamine (0.74 ml, 4.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.34 g,1.78 mmol) and sarcosine methyl ester hydrochloride (0.22 g,1.55 mol) were added. After 21.5 h the reaction mixture wasdiluted with EtOAc (150 ml) and washed with sulfate buffer (26 100 ml), saturated aqueous NaHCO3, and brine. Thecombined organic phases were dried over Na2SO4, filteredand concentrated in vacuo to afford the crude amide as a

yellow oil. Purification by column chromatography (30%EtOAc in n-heptane, v/v) gave 44 as a colourless film (0.58 g,93%). Rf 0.26 (30% EtOAc in n-heptane, v/v). 1H NMR (500MHz, CDCl3): d (ppm) Major rotamer 8.22 (d, J = 8.5, 1H,Indole-H4), 7.65 (d, J = 7.5, 1H, Indole-H7), 7.45–7.28 (m, 7H,Ph, Indole-H6, H5), 4.46–4.42 (m, 1H, CHAHBCLO), 3.94–3.88(m, 1H, CHAHBCLO), 3.74 (s, 3H, OCH3), 2.75 (s, 3H, NCH3),1.26 (s, 9H, C(CH3)3). 13C NMR (125 MHz, CDCl3): d (ppm)Major rotamer 169.4, 167.1, 150.1, 137.1, 136.6, 133.0, 129.3,128.4, 128.1, 127.2, 125.4, 123.8, 120.0, 117.0, 115.2, 84.1, 52.3,48.7, 37.4, 27.6. HPLC RT = 7.36 min. HRMS (ESI) Calcd. forC24H27N2O5 423.1914; Found 423.1928.

1-(tert-Butoxycarbonyl)-2-phenyl-3-(methyl(2-morpholino-2-oxoethyl)carbamoyl)-1H-indole (45)

Indole 40 (0.030 g, 0.089 mmol) was dissolved in DMF (2 ml)and 1-hydroxy-benzotriazole (0.014 g, 0.1 mmol), N,N-diiso-propyl ethylamine (0.045 ml, 0.3 mmol), N-(3-dimethylamino-propyl)-N9-ethylcarbodiimide hydrochloride (0.021 g, 0.11mmol), and amine 33 (0.018 g, 0.93 mmol) were added. After20 h EtOAc and sulfate buffer was added and the phases wereseparated. The organic phase was washed with sulfate buffer,saturated aqueous NaHCO3, and brine, dried over Na2SO4,filtered and concentrated in vacuo to afford the crude amide asa solid. Purification by column chromatography (20% n-hep-tane in EtOAc, v/v) gave a colourless film. Addition of Et2O andconcentration in vacuo gave indole 45 as foamy solid (0.035 g,81%). Rf 0.18 (30% n-heptane in EtOAc, v/v). 1H NMR (500MHz, CDCl3): d (ppm) Major rotamer 8.24 (d, J = 8.0, Indole-H4), 7.70 (d, J = 8.0, 1H, Indole-H7), 7.45–7.28 (m, 7H, Ph,Indole-H6, H5), 4.67 (d, J = 15.0, 1H, CHAHBCLO), 3.85 (d, J =15.5, 1H, CHAHBCLO), 3.69–3.40 (m, 8H, 2 6 CH2CH2), 2.80 (s,3H, NCH3), 1.26 (s, 9H, C(CH3)3). 13C NMR (125 MHz, CDCl3,APT): d (ppm) 166.9 (C), 166.3 (C), 150.1 (C), 136.9 (C), 136.5(C), 133.2 (C), 129.3 (CH), 128.4 (CH), 128.0 (CH), 127.1 (C),125.4 (CH), 123.8 (CH), 120.2 (CH), 117.3 (C), 115.2 (CH), 84.0(C), 66.9 (CH2), 66.6 (CH2), 48.4 (CH2), 45.5 (CH2), 42.4 (CH2),37.4 (CH3), 27.4 (CH3). HPLC: RT = 7.00 min. HRMS (ESI)Calcd. for C27H32N3O5 478.2336; Found 478.2338.

2-(N-Methyl-2-phenyl-1H-indole-3-carboxamido)acetic acid (46)

Indole 44 (0.125 g, 0.30 mmol) was dissolved in 1,4-dioxane (4ml) and 4 M aqueous HCl (4 ml). The solution was stirred at 40uC for 28 h and the pH was adjusted to 9 with 2 M aqueousNaOH. The mixture was taken up in sulfate buffer andextracted with CH2Cl2 (4 6 40 ml). The combined organicphases were washed with brine, dried over Na2SO4, filteredand concentrated in vacuo to afford the crude product as apurple film. Purification by column chromatography (10%n-heptane, 0.2% AcOH in EtOAc, v/v) gave a slightly pink film,that upon addition of Et2O and concentration in vacuo gavecarboxylic acid 46 as foamy solid (0.077 g, 85%). Rf 0.17 (10%n-heptane, 0.2% AcOH in EtOAc, v/v). 1H NMR (500 MHz,MeOD): d (ppm) Major rotamer 7.76 (d, J = 7.5, 2H, Ph), 7.61 (d,J = 8.0, 1H, Ph), 7.46–7.43 (m, 3H, Ph), 7.39–7.35 (m, 1H, Ph),7.20–7.17 (m, 1H, Ph), 7.13–7.09 (m, 1H, Ph), 4.33 (s, 2H, CH2),2.97 (s, 3H, NCH3). 13C NMR (125 MHz, MeOD): d (ppm) Majorrotamer: 172.4, 171.9, 138.2, 137.5, 133.0, 130.0, 129.4, 128.7,128.5, 123.8, 121.6, 120.4, 112.5, 108.4, 50.0, 38.4. HPLC: RT =


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5.49 min. HRMS (ESI) Calcd. for C18H17N2O3 309.1234; Found309.1219.

N-Methyl-N-(2-morpholino-2-oxoethyl)-2-phenyl-1H-indole-3-carboxamide (47)

Indole 46 (0.058 g, 0.19 mmol) was dissolved in anhydrousDMF (2.5 ml) and N-hydroxybenzotriazole (0.028 g, 0.21mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (0.043 g, 0.23 mmol), and morpholine (58 ml,0.66 mmol) were added. After 3 days the mixture was dilutedwith EtOAc (50 ml), washed with sulfate buffer (2 6 40 ml),saturated aqueous NaHCO3 (40 ml), and brine (40 ml). Theorganic phase was dried over Na2SO4, filtered and concen-trated in vacuo to afford the crude amide as a film. Purificationby column chromatography (25% n-heptane in EtOAc, v/v)gave indole 47 as white foamy solid (0.050 g, 70%). Rf 0.17(25% n-heptane in EtOAc, v/v). 1H NMR (500 MHz, DMSO-d6): d

(ppm) Major rotamer 11.72 (s, 1H, Indole-NH), 7.82 (d, J = 7.5,2H, Ph), 7.66 (d, J = 7.5, 1H, Indole-H4), 7.47–7.42 (m, 3H, Ph,Indole-H7), 7.37 (t, J = 7.5, 1H, Ph), 7.18 (t, J = 7.5, 1H, Indole-H6), 7.09 (t, J = 7.5, 1H, Indole-H5), 4.45 (br s, 2H, CH2CLO),3.62 (br s, 4H, 2 6 CH2O), 3.53 (br s, 4H, 2 6 NCH2CH2), 2.85(s, 3H, CH3). 13C NMR (125 MHz, DMSO-d6, APT): d (ppm)Major rotamer 167.8 (C), 166.4 (C), 135.6 (C), 135.1 (C), 131.5(C), 128.7 (CH), 128.0 (CH), 127.0 (CH), 126.7 (C), 122.3 (CH),120.0 (CH), 119.5 (CH), 111.6 (CH), 108.5 (C), 66.1 (CH2), 66.0(CH2), 48.1 (CH2), 44.6 (CH2), 41.7 (CH2), 37.3 (CH3). HPLC RT

= 5.43 min. HRMS (ESI) Calcd. for C22H24N3O3 378.1812;Found: 378.1794.

2-(4-(Cyclohexanecarbonyl)piperazin-1-yl)-1-(2-phenyl-1H-indol-3-yl)ethanone (53)

Secondary amine 64 (0.23 g, 1.0 mmol) was dissolved in 1,4-dioxane (2 ml) and AcOH (1 ml). Formaldehyde (0.075 ml, 1.0mmol, 37% aqueous solution) was added, and the mixture wasstirred at room temperature for 75 min. 2-Phenyl-indole 10(0.126 g, 0.65 mmol) was added and the mixture was stirred for45 min, poured onto ice and the pH was adjusted to 13 with8% aqueous NaOH to give a white precipitate. CH2Cl2 andwater were added and the biphasic mixture was stirred for 5min. The phases were separated and the aqueous phase wasextracted with CH2Cl2 (2 6 20 ml). The combined organicphases were washed with brine, dried over Na2SO4, filtered,and concentrated in vacuo to afford a foamy solid. Purificationby DCVC (id. 4 cm; 20 ml fractions, 0–65%, EtOAc inn-heptane, v/v, 2.5% increments; 65–100% EtOAc in n-hep-tane, v/v, 5% increments; 15% MeOH, 1.2% aqueous NH3 inEtOAc, v/v) gave indole 53 as an off-white solid (0.19 g, 73%). Rf

0.47 (50% EtOAc in n-heptane, v/v). 1H NMR (400 MHz, DMSO-d6): d (ppm) 11.38 (s, 1H, Indole-NH), 7.90–7.87 (m, 2H, Ph),7.68 (d, J = 8.0, 1H, Indole-H4), 7.51 (t, J = 7.5, 2H, Ph), 7.39–7.35 (m, 2H, Ph, Indole-H7), 7.13–7.09 (ddd, J = 8.5, 7.0, 1.0,1H, Indole-H6), 7.04–7.01 (ddd, J = 8.0, 7.0, 1.0, 1H, Indole-H5), 3.64 (s, 2H, ArCH2), 3.46–3.42 (m, 4H, (CH2)2NCLO), 2.56–2.52 (m, 1H, CHCLO), 2.46–2.38 (m, 4H, (CH2CH2)2NCLO),1.89–1.60 (m, 5H, cyclohexyl-CH2), 1.36–1.09 (m, 5H, cyclo-hexyl-CH2). 13C NMR (100 MHz, DMSO-d6): d (ppm) 173.2,136.6, 135.7, 132.6, 129.6, 128.6, 128.2, 127.4, 121.5, 119.1,118.9, 111.1, 108.0, 53.1, 52.5, 51.9, 45.0, 41.2, 39.0, 29.1, 25.6,

25.1. Ca of the cyclohexane ring overlaps with DMSO, seeHSQC (Supporting Information). HPLC RT = 5.36 min. HRMS(ESI) Calcd. for C26H32N3O 402.2540; Found 402.2558.

2-(4-(Cyclopentanecarbonyl)piperazin-1-yl)-1-(2-phenyl-1H-indol-3-yl)ethanone (54)

Synthesised according to the general procedure (see synthesisof 53) using secondary amine 65 (0.214 g, 0.98 mmol), 1,4-dioxane (2 ml), AcOH (1 ml) HCHO (0.075 ml, 1.0 mmol), andindole 10 (0.126 g, 0.65 mmol). CH2Cl2 (3 6 30 ml) was usedfor extraction. Purification by DCVC (id. 4 cm; 20 ml fractions,0–10% MeOH, 0–0.8% aqueous NH3 in CH2Cl2, v/v, 0.5%increments) gave a foam/film that upon addition of EtOAc andconcentration in vacuo gave indole 54 as off-white solid (0.20 g,78%). Rf 0.47 (2% MeOH in CH2Cl2, v/v). 1H NMR (400 MHz,DMSO-d6): d (ppm) 11.38 (s, 1H, Indole-NH), 7.90–7.88 (m, 2H,ArH), 7.68 (d, J = 8.0, 1H, Indole-H4), 7.51 (t, J = 7.5, 2H, Ph),7.40–7.36 (m, 2H, Indole-H7, Ph), 7.13–7.09 (ddd, J = 8.5, 7.0,1.0, 1H, Indole-H6), 7.05–7.01 (ddd, J = 8.0, 7.0, 1.0, 1H, Indole-H5), 3.64 (s, 2H, ArCH2), 3.48–3.44 (m, 4H, (CH2)2NCLO), 2.94(m, 1H, CHCLO) 2.45–2.39 (m, 4H, (CH2CH2)2NCLO), 1.74–1.48 (m, 8H, (CH2)4). 13C NMR (100 MHz, DMSO-d6): d (ppm)173.2, 136.6, 135.7, 132.6, 129.6, 128.6, 128.2, 127.4, 121.5,119.1, 118.9, 111.1, 108.0, 53.0, 52.4, 52.0, 45.1, 41.5, 29.6,25.6. Ca of the cyclopentane ring overlaps with DMSO, seeHSQC (Supporting Information3). HPLC RT = 5.21 min. HRMS(ESI) Calcd. for C25H30N3O 388.2383; Found 388.2404.

2-(4-(Cyclobutanecarbonyl)piperazin-1-yl)-1-(2-phenyl-1H-indol-3-yl)ethanone (55)

Synthesised according to the general procedure (see synthesisof 53) using secondary amine 66 (0.199 g, 0.97 mmol), 1,4-dioxane (2 ml), AcOH (1 ml), HCHO (0.075 ml, 1.0 mmol), andindole 10 (0.127 g, 0.66 mmol). CH2Cl2 (3 6 70 ml) was usedfor extraction. Purification by DCVC (id. 4 cm; 20 ml fractions,0–60% EtOAc, 0.5% Et3N in n-heptane, v/v, 2.5% increments;60–100% EtOAc, 0.3–0.5% Et3N in n-heptane, v/v, 5% incre-ments; 15% MeOH, 1.2% aqueous NH3 in EtOAc, v/v) gaveindole 55 as an off-white solid (0.17 g, 71%). Rf 0.39 (50%EtOAc, 0.25% Et3N in n-heptane, v/v). 1H NMR (400 MHz,DMSO-d6): d (ppm) 11.38 (s, 1H, Indole-NH), 7.88 (m, 2H, Ph),7.67 (d, J = 7.5, 1H, Indole-H4), 7.51 (t, J = 7.0, 2H, Ph), 7.39–7.35 (m, 2H, Ph, Indole-H7), 7.13–7.09 (ddd, J = 8.0, 7.0, 1.0,1H, Indole-H6), 7.11 (ddd, J = 8.5, 7.0, 1.0, 1H, Indole-H5), 3.63(s, 2H, ArCH2), 3.46–3.39 (m, 2H, (CH2)2NCLO), 3.30–3.26 (m,3H, (CH2)2NCLO, CHCLO), 2.41–2.38 (m, 4H,(CH2CH2)2NCLO), 2.19–2.01 (m, 4H, 2 6 CHCH2), 1.92–1.81(m, 1H, CHCH2CHAHB), 1.76–1.67 (m, 1H, CHCH2CHAHB). 13CNMR (100 MHz, DMSO-d6): d (ppm) 171.9, 136.5, 135.7, 132.6,129.6, 128.6, 128.2, 127.4, 121.5, 119.1, 118.9, 111.1, 108.0,52.8, 52.4, 52.0, 44.6, 41.3, 36.2 24.5, 17.4. HPLC RT = 5.05 min.HRMS (ESI) Calcd. for C24H28N3O 374.2227; Found 374.2220.

Cyclopropyl(4-((2-phenyl-1H-indol-3-yl)methyl)-1,4-diazepan-1-yl)methanone (56)

Synthesised according to the general procedure (see synthesisof 53) using secondary amine 67 (0.201 g, 0.98 mmol), 1,4-dioxane (2 ml), AcOH (1 ml), HCHO (0.075 ml, 1.0 mmol), andindole 10 (0.125 g, 0.65 mmol). EtOAc was used for extraction.


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Purification by DCVC (id. 4 cm; 20 ml fractions, 0–100%EtOAc, 0–0.5% Et3N in n-heptane, v/v, 5% increments) gave acolourless film that upon addition of Et2O and concentrationin vacuo gave indole 56 as foamy white solid (0.18 g, 76%). Rf

0.30 (30% n-heptane, 0.5% Et3N in EtOAc, v/v). 1H NMR (300MHz, DMSO-d6): d (ppm) 11.34 (br s, 1H, Indole-NH), 7.89 (d, J= 7.5, 2H, Ph), 7.67 (m, 1H, Indole-H4), 7.48 (t, J = 7.0, 2H, Ph),7.38–7.35 (m, 2H, Ph, Indole-H7), 7.12–7.07 (m, 1H, Indole-H6), 7.03–6.98 (m, 1H, Indole-H5), 3.76–3.66 (m, 4H, ArCH2,(CH2)2NCLO), 3.51–3.45 (m, 2H, 2 6 CH2NCLO), 2.76 (m, 1H,CH2CHAHBN), 2.63–2.59 (m, 3H, CH2CHAHBN, CH2CH2N),1.88–1.66 (m, 3H, CH, CH2CH2N), 0.73–0.64 (m, 4H, 2 6cyclopropyl-CH2). 13C NMR (125 MHz, DMSO-d6, APT) Majorrotamer: d (ppm) 171.9 (C), 136.5 (C), 135.7 (C), 132.7 (C), 129.6(C), 128.6 (CH), 128.2 (CH), 127.4 (CH), 121.5 (CH), 119.0 (CH),118.9 (CH), 111.2 (CH), 109.2 (C), 54.9 (CH2), 53.2 (CH2), 51.7(CH2), 46.5 (CH2), 44.3 (CH2), 28.4 (CH2), 10.6 (CH), 6.9 (CH2).HPLC RT = 4.75 min. HRMS (ESI) Calcd. for C24H28N3O374.2227; Found 374.2220.

2-(Methyl((2-phenyl-1H-indol-3-yl)methyl)amino)-N-(prop-2-yn-1-yl)acetamide (57)

Synthesised according to the general procedure (see synthesisof 53) using secondary amine 27 (0.16 g, 0.98 mmol), 1,4-dioxane (2 ml), AcOH (2 ml), MeOH (1 ml), HCHO (0.075 ml,1.0 mmol), and indole 10 (0.125 g, 0.65 mmol). EtOAc was usedfor extraction. Purification by column chromatography (40%EtOAc, 0.2% Et3N in n-heptane, v/v) gave a colourless film thatupon addition of Et2O and concentration in vacuo gave 57 aspale yellow foam (0.16 g, 74%). Rf 0.34 (40% EtOAc, 0.2% Et3Nin n-heptane, v/v). 1H NMR (300 MHz, CDCl3): d (ppm) 8.19 (brs, 1H, Indole-NH), 7.73 (dd, J = 7.0, 1.0, 1H, Indole-H4), 7.63–7.59 (m, 2H, Ph), 7.53–7.38 (m, 4H, Ph, Indole-H7), 7.24–7.15(m, 2H, Indole-H6, H5), 7.06 (br t, J = 5.5, 1H, CONH), 3.90 (s,2H, ArCH2), 3.84 (dd, J = 5.5, 2.5, 2H, CLONCH2), 3.03 (s, 2H,CH2CLO), 2.32 (s, 3H, CH3), 2.17 (t, J = 2.5, 1H, ;CH). 13C NMR(75 MHz, CDCl3): d (ppm) 171.1, 136.9, 135.7, 132.7, 129.2,128.8, 128.4, 128.0, 122.4, 120.1, 119.0, 111.2, 109.2, 79.6, 71.3,59.9, 52.3, 43.7, 28.7. HPLC RT = 7.33 min. HRMS (ESI) Calcd.for C21H22N3O 332.1758; Found 332.1751.

2-(Methyl((2-phenyl-1H-indol-3-yl)methyl)amino)-1-morpholinoethanone (58)

Synthesised according to the general procedure (see synthesisof 53) using secondary amine 33 (0.121 g, 0.68 mmol), 1,4-dioxane (1 ml), AcOH (1 ml), HCHO (0.05 ml, 0.67 mmol), andindole 10 (0.10 g, 0.52 mmol). EtOAc was used for extraction.Purification by column chromatography (3% MeOH, 0.2%aqueous NH3 in CH2Cl2, v/v) gave 58 as an off-white solid (0.13g, 73%). Rf 0.37 (4% MeOH, 0.3% aqueous NH3 in CH2Cl2, v/v).1H NMR (500 MHz, MeOD): d (ppm) 7.79–7.77 (m, 2H, Ph),7.62 (d, J = 8.0, 1H, Indole-H4), 7.48 (t, J = 7.5, 2H, Ph), 7.41–7.35 (m, 2H, Ph, Indole-H7), 7.16–7.12 (m, 1H, Indole-H6),7.07–7.04 (m, 1H, Indole-H5), 3.81 (s, 2H, ArCH2), 3.53 (t, J =4.0, 2H, CH2O), 3.42 (t, J = 3.5, 2H, CH2O), 3.26 (t, J = 4.0, 2H,CH2CH2N), 3.18 (t, J = 3.0, 2H, CH2CH2N), 3.11 (s, 2H,CH2CLO), 2.36 (s, 3H, CH3). 13C NMR (125 MHz, MeOD, APT):d (ppm) 171.6 (C), 138.4 (C), 137.5 (C), 134.4 (C), 131.1 (C),129.8 (CH), 129.3 (CH), 128.7 (CH), 123.0 (CH), 120.4 (CH),

119.8 (CH), 112.2 (CH), 109.2 (C), 67.9 (CH2), 67.7 (CH2), 60.1(CH2), 52.9 (CH2), 47.1 (CH2), 43.3 (CH2), 43.2 (CH3). HPLC RT

= 4.82 min. HRMS (ESI) Calcd. for C22H25N3O2 364.2020;Found 364.2037.

tert-Butyl-(2-(2-phenyl-1H-indol-3-yl)ethyl)carbamate (60)

A 3-necked flask was charged with NiCl2 hexahydrate (0.073 g,0.3 mmol) and put under vacuum. The flask was heated with aheat-gun, until a colour-change from green to yellow wasobserved. The flask was cooled to 0 uC with an ice–water bathunder N2. Anhydrous MeOH (30 ml), indole 59 (0.70 g, 3.0mmol) and di-tert-butyl dicarbonate (1.3 g, 6.0 mmol), wereadded followed by portion-wise addition of NaBH4 (0.80 g, 21.1mmol). The ice-bath was removed and the mixture was stirredat ambient temperature for 5 h, followed by addition ofdiethylenetriamine (0.33 ml, 3.0 mmol). The mixture wasstirred for 50 min and saturated, aqueous NaHCO3 was addedfollowed by extraction with EtOAc (62). The combined organicphases were washed with NaHCO3 and brine, dried overNa2SO4, filtered and concentrated in vacuo to give the crudeproduct as a brown foam. Purification by column chromato-graphy (20% EtOAc in n-heptane, v/v) gave 60 as an off-whitesolid (0.67 g, 66%). Rf 0.26 (20% EtOAc in n-heptane, v/v). 1HNMR (500 MHz, CDCl3): d (ppm) 8.09 (br s, 1H, Indole-NH),7.67 (d, J = 7.5, 1H, Indole-H4), 7.57 (d, J = 7.5, 2H, Ph), 7.47 (t,J = 7.5, 2H, Ph), 7.40–7.36 (m, 2H, Ph, Indole-H7), 7.25–7.20(m, 1H, Indole-H6), 7.17–7.12 (m, 1H, Indole-H5), 4.59 (br s,1H, NH), 3.50–3.42 (m, 2H, CH2CH2N), 3.09 (t, J = 7.0, 2H,CH2CH2N), 1.40 (s, 9H, C(CH3)3). 13C NMR (125 MHz, CDCl3): d

(ppm) 156.0, 136.0, 135.5, 133.1, 129.2, 129.1, 128.2, 128.0,122.6, 120.0, 119.4, 111.0, 110.2, 79.2, 41.2, 28.6, 25.4. HPLC RT

= 7.28 min. HRMS (ESI) Calcd. for C21H25N2O2 337.1910;Found 337.1921.

N-Methyl-2-(2-phenyl-1H-indol-3-yl)ethanamine (61)

A 2-necked flask equipped with a water condenser was chargedwith LiAlH4 (0.075 g, 2.0 mmol). The flask was cooled to 0 uCand anhydrous THF (10 ml) was added under N2, followed byindole 60 (0.10 g, 0.30 mmol). The mixture was heated at refluxfor 5 h, cooled to 0 uC and carefully quenched by the additionof H2O (5 ml), 2 M NaOH (5 ml), H2O (15 ml) and potassiumtartrate solution (5 ml). After stirring for 30 min at roomtemperature the mixture was extracted with EtOAc (3 6 25 ml).The combined organic phases were washed with brine, driedwith Na2SO4, filtered and concentrated in vacuo to afford thecrude product as a colourless film. Purification by columnchromatography (6% MeOH, 0.5% aqueous NH3 in CH2Cl2, v/v) gave indole 61 as a colourless film (0.052 g, 69%). Rf 0.13(5% MeOH, 0.4% aqueous NH3 in CH2Cl2, v/v). 1H NMR (500MHz, CDCl3): d (ppm) 8.10 (br s, 1H, Indole-NH), 7.68 (d, J =8.0, 1H, Indole-H4), 7.60 (dd, J = 8.0, 1.0, 2H, Ph), 7.48 (t, J =7.5, 2H, Ph), 7.39–7.36 (m, 2H, Ph, Indole-H7), 7.23–7.20 (m,1H, Indole-H6), 7.16–7.13 (m, 1H, Indole-H5), 3.13 (t, J = 7.5,2H, CH2CH2N), 2.96 (t, J = 7.5, 2H, CH2CH2N), 2.42 (s, 3H,NCH3). 13C NMR (125 MHz, CDCl3): d (ppm) 136.0, 135.2,133.2, 129.4, 129.1, 128.2, 127.9, 122.5, 119.8, 119.4, 111.0,110.9, 52.7, 36.5, 25.1. HPLC RT = 4.82 min. HRMS (ESI) Calcd.for C17H18N2Na 273.1368; Found: 273.1383.


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2-Chloro-1-morpholinoethanone (62)

Morpholine was dried by filtration through a plug ofanhydrous K2CO3 prior to use. According to the method ofLilienkampf et al.63 a dry flask was charged with Et2O (40 ml)and morpholine (6.0 ml, 68 mmol). The mixture was cooled to0 uC with an ice–water bath and 2-chloroacetyl chloride (2.75ml, 34 mmol), dissolved in Et2O (20 ml) was added dropwiseover 30 min. After stirring under N2 at room temperature for45 min the precipitate was collected by filtration and washedtwice with diethyl ether. The combined organic phases wereconcentrated in vacuo affording a brown oil. Purification byKugelrohr distillation (Bp = 131 uC, 0.26 mbar) gave acolourless oil that solidified upon standing to give amide 62as white solid (3.66 g, 66%). Rf 0.30 (30% n-heptane in EtOAc,v/v). Mp (uC): 30.5–31.5. 1H NMR (400 MHz, CDCl3): d (ppm)4.04 (s, 2H, CH2Cl), 3.71–3.66 (m, 4H, 2 6 CH2O), 3.60 (t, J =4.5, 2H, CH2N), 3.51 (t, J = 5.0, 2H, CH2N). 13C NMR (100 MHz,CDCl3): d (ppm) 165.3, 66.7, 66.6, 46.8, 42.5, 40.7. The data isin agreement with that reported by others.63

2-(Methyl(2-(2-phenyl-1H-indol-3-yl)ethyl)amino)-1-morpholinoethanone (63)

A microwave vial was charged with NaI (0.006 g, 0.04 mmol),NaHCO3 (0.0335 g, 0.4 mmol), and alkyl chloride 62 (0.033 g,0.20 mmol). Indole 61 (0.050 g, 0.20 mmol) was dissolved inanhydrous MeCN (2 ml) and transferred to the vial, which wassealed and heated at 60 uC for 6 h. The solids were removed byfiltration and washed with MeCN, and the combined organicfractions were concentrated in vacuo to give a colourless film.Purification by column chromatography (5% MeOH, 0.5%Et3N in EtOAc, v/v) gave a colourless film that upon addition ofCHCl3 and concentration in vacuo gave indole 63 as off-whitesolid (0.055 g, 73%). Rf 0.34 (5% MeOH, 0.5% Et3N in EtOAc, v/v). 1H NMR (500 MHz, CDCl3): d (ppm) 8.07 (br s, 1H, Indole-NH), 7.61 (d, J = 8.0, 1H, Indole-H4), 7.56 (m, 2H, Ph), 7.48 (t, J= 7.5, 2H, Ph), 7.40–7.37 (m, 2H, Ph, Indole-H7), 7.20 (t, J = 7.0,1H, Indole-H6), 7.14 (t, J = 7.0, 1H, Indole-H5), 3.51–3.47 (m,4H, 2 6 CH2O), 3.39 (br s, 4H, 2 6 CH2NCLO), 3.19 (s, 2H,CH2CLO), 3.07 (t, J = 7.5, 2H, ArCH2), 2.78 (t, J = 7.5, 2H,ArCH2CH2), 2.30 (s, 3H, NCH3). 13C NMR (125 MHz, CDCl3): d

(ppm) 169.0, 136.0, 135.0, 133.3, 129.2, 129.1, 128.1, 128.0,122.5, 119.9, 119.2, 111.2, 111.0, 66.93, 66.91, 61.6, 57.9, 46.1,42.2, 42.1, 22.8. HPLC: RT = 4.95 min. HRMS (ESI) Calcd. forC23H28N3O2 378.2176; Found 378.2190.

Cyclohexyl(piperazin-1-yl)methanone hydrochloride (64)

N-Boc-piperazine (0.50 g, 2.7 mmol) and triethylamine (0.45ml, 3.2 mmol) were dissolved in CH2Cl2 (10 ml). The flask wasput under N2, cooled with an ice–water bath to 0 uC andcyclohexyl carboxylic acid chloride (0.36 ml, 2.7 mmol) wasadded dropwise over 10 min. The ice bath was removed andthe mixture was stirred for 1 h. The reaction mixture wastransferred to a separation funnel and washed with sulfatebuffer, saturated aqueous NaHCO3-solution, brine, dried overNa2SO4, filtered and concentrated in vacuo to give white solid.The crude product was dissolved in CH2Cl2 (10 ml), 2 M HCl 6Et2O (3.65 ml, 7.3 mmol) was added and the solution wasstirred at ambient temperature for 24 h. The solvent was

removed in vacuo to give a white solid that was recrystallisedfrom absolute EtOH. The product was isolated by filtration,washed in portions with Et2O and dried under vacuum to giveamine 64 as the hydrochloric salt (0.45 g, 71% over two steps).Rf 0.18 (5% MeOH, 0.4% aqueous NH3 in CH2Cl2, v/v). 1H NMR(300 MHz, DMSO-d6): d (ppm) 9.24 (br s, 2H, NH2

+), 3.70–3.64(m, 4H, 2 6 CH2NH2

+), 3.08–3.00 (m, 4H, 2 6 CH2NCLO),2.61–2.54 (m, 1H, CHCLO), 1.75–1.58 (m, 5H, cyclohexane-CH2), 1.36–1.09 (m, 5H, cyclohexane-CH2). 13C NMR (75 MHz,MeOD): d (ppm) 176.9, 44.8, 44.5, 43.4, 41.1, 39.5, 30.5, 27.0,26.6. HRMS (ESI) Calcd. for C11H21N2O 197.1648; Found197.1644.

Cyclopentyl(piperazin-1-yl)methanone hydrochloride (65)

Synthesised according to the general procedure (see synthesis of64) using 4-Boc-piperazine (0.50 g, 2.7 mmol), triethylamine(0.45 ml, 3.2 mmol), CH2Cl2 (10 ml) and cyclopentane-carboxylic acid chloride (0.33 ml, 2.7 mmol). The crude productwas dissolved in CH2Cl2 (10 ml) and 2 M HCl 6 Et2O (3.9 ml, 7.9mmol) was added. The mixture was stirred at ambienttemperature for 24 h, concentrated in vacuo to afford a slightlybrown solid that was recrystallised from absolute EtOH andEt2O. The solid was isolated by filtration, washed with Et2O anddried under vacuum to give amine 65 as the hydrochloric salt inthree crops (0.43 g, 74% over 2 steps). Rf 0.16 (5% MeOH, 0.4%aqueous NH3 in CH2Cl2, v/v). 1H NMR (300 MHz, DMSO-d6): d

(ppm) 9.33 (br s, 2H, NH2+), 3.74–3.64 (m, 4H, 2 6 CH2NH2

+),3.08–2.93 (m, 5H, 2 6 CH2NCLO, CHCLO), 1.80–1.47 (m, 8H,cyclopentane-CH2). 13C NMR (75 MHz, MeOD): d (ppm) 176.9,44.8, 44.5, 43.5, 41.8, 39.7, 31.0, 27.0.

Cyclobutyl(piperazin-1-yl)methanone hydrochloride (66)

A flask was charged with N-Boc-piperazine (0.50 g, 2.7 mmol),triethylamine (1.2 ml, 8.6 mmol), cyclobutane carboxylic acid(0.31 ml, 3.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbo-diimide hydrochloride (0.62 g, 3.2 mmol), DMAP (0.32 g, 2.7mmol) and CH2Cl2 (10 ml). The mixture was stirred at ambienttemperature for 44 h, CH2Cl2 was added the reaction mixturewas washed with sulfate buffer (62), saturated aqueousNaHCO3 (62), and brine. The organic phase was dried overNa2SO4, filtered and evaporated in vacuo to give a white solid.The crude product was dissolved in CH2Cl2 (10 ml) and 2 MHCl 6 Et2O (3.75 ml, 7.5 mmol) was added. The mixture wasstirred at ambient temperature for 15 h and concentrated invacuo to afford a white solid that was recrystallised fromabsolute EtOH. The solid was isolated by filtration, washedwith Et2O and dried to give amine 66 as the hydrochloric saltin two crops (0.43 g, 78% over 2 steps). Rf 0.15 (5% MeOH,0.4% aqueous NH3 in CH2Cl2, v/v) 1H NMR (400 MHz, D2O): d

(ppm) 3.86 (t, J = 5.5, 2H), 3.78 (t, J = 5.5, 2H) (2 6 CH2NH2+),

3.52 (quin, J = 8.5, 1H, CHCLO), 3.34–3.30 (m, 4 H, 2 6CH2NCLO), 2.19–2.06 (m, 4 H, 2 6 CHCH2), 1.89–1.86 (sex, J =9.5, 1H, CHCH2CHACHB), 1.74 (m, 1H, CHCH2CHACHB). 13CNMR (100 MHz, D2O-DMSO-d6): d (ppm) 178.0, 44.6, 44.5, 43.3,40.0, 38.1, 26.2, 18.8.

Cyclopropyl(1,4-diazepan-1-yl)methanone hydrochloride (67)

N-Boc-Homopiperazine (0.44 ml, 2.25 mmol) and triethyla-mine (0.44 ml, 3.15 mmol) were dissolved in CH2Cl2 (10 ml).


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The flask was put under N2, cooled to 0 uC with an ice–waterbath and cyclopropane carboxylic acid chloride (0.22 ml, 2.4mmol) was added dropwise over 10 min. After 30 min the icebath was removed and the mixture was stirred for 70 min.CH2Cl2 was added and the mixture was washed with sulfatebuffer, saturated aqueous NaHCO3, brine, dried over Na2SO4

and concentrated in vacuo to afford a slightly yellow oil. Thecrude product was dissolved in CH2Cl2 (10 ml) and 2M HCl 6Et2O (4 ml) was added. The mixture was stirred at ambienttemperature for 23 h followed by 40 uC for 18 h to give aprecipitate. The solid was isolated by filtration and recrystal-lised from absolute EtOH–Et2O. The solid was washed withportions of Et2O and dried under vacuum to afford amine 67as the hydrochloric salt (0.45 g, 98% over two steps). Rf 0.30(10% MeOH, 0.8% aqueous NH3 in CH2Cl2, v/v). 1H NMR (300MHz, DMSO-d6): d (ppm) 9.32 (br s, 2H, NH2

+), 3.92 (t, J = 5.0,1H), 3.77 (t, J = 6.0, 1H), 3.67 (t, J = 5.0, 1H), 3.52 (t, J = 6.0, 1H)(2 CHAHBNH2

+), 3.23–3.06 (m, 4H, 2 6 CH2NCLO), 2.10 (m,1H, CHCLO), 1.98–1.87 (m, 2H, CH2CH2NH2

+), 0.80–0.70 (m,4H, cyclopropane-CH2). 13C NMR (75 MHz, DMSO-d6): d (ppm)Major rotamer 172.1, 46.3, 45.3, 44.4, 41.5, 25.4, 10.9, 7.2, 7.1.HRMS (ESI) Calcd. for C9H17N2O 169.1335; Found 169.1340.

Acknowledgements

HJ thanks the Faculty of Health and Medical Sciences,University of Copenhagen for a PhD scholarship. DSP andHBO are grateful to the Danish Council for IndependentResearch, Medical Sciences for funding. TBJ thanks theLundbeck Foundation and Drug Research Academy, Facultyof Health and Medical Sciences, University of Copenhagen forfunding. DEG is grateful to the Alfred Benzon and CarlsbergFoundations for funding. The authors thank ChristianTortzen, Department of Chemistry, University of Copenhagenfor NMR assistance.

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3-substituted 2-phenyl-indoles privileged structures for medicinal chemistry

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