Modular synthesis of triazole-containing triaryl α-helix mimetics

FULL PAPER

DOI: 10.1002/ejoc.201001531

Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

Ina Ehlers,^[a]Prantik Maity,^[a]Jeffrey Aubé,^[b]and Burkhard König*^[a]

Dedicated to Professor Henning Hopf on the occasion of his 70th birthday

Keywords: Helical structures / Peptidomimetics / Click chemistry / Nitrogen heterocycles / Protein-protein interactions

We describe novel scaffold designs for nonpeptidic α-helix

mimetics. The tricyclic scaffolds contain triazoles and repro-

duce amino acid side chains i, i+3, and i+7. The three dif-

ferent scaffolds are synthetically readily accessible, allow the

introduction of further substituents to increase the versatility,

and are suitable for library design. A modular synthesis route

using Cu^I- and Ru^II-catalyzed azide–alkyne [3+2] cycload-

ditions as central steps was developed. To demonstrate the

methodology, we have prepared a library of compounds con-

taining all three scaffolds.

(C) core system were developed (Scheme 1, below). Four

lowest-energy conformations differing in relative energies by

less than 2.5 kJmol^–1were calculated for the scaffolds A,

B, and C by density functional methods (B3LYP, 6-31G**,

Spartan program package; see the Supporting Information

for data). In one of these conformations the scaffold side

chains match the separations and relative orientations of

the key positions i, i+3, and i+7 of an idealized peptide α-

helix very well, as shown in Figure 1.

Introduction

It is still a challenge to mimic an extended region of a

protein surface defined by secondary structure motifs.

Small mimetics with geometries reproducing α-helix or β-

turn conformations have been successfully developed. α-He-

lical regions play critical roles in many protein–protein in-

teractions; the difficulty of developing such mimetics lies in

the extended region of two to four turns of a helix that is

involved in the interaction. Structural mimetics have to dis-

play the side-chain functionalities in the same spatial orien-

tation – in terms of distances and angular relationships –

as α-helixes do. Typically, one face of a helix interacts with

the protein through amino acid side chains in the positions

i, i+3 or i+4, i+7, and i+10 or i+11.^[1]Small organic scaf-

folds can replace the peptide backbone and orient the side

chains for recognition. A variety of terphenyl-like struc-

tures, many containing heterocycles, has recently been de-

veloped, largely due to the efforts of Hamilton and co-

workers.^[2]Some of these have been shown to disrupt pro-

tein interactions successfully. However, the synthesis of

many of the scaffolds is elaborate and not ideally suited to

the incorporation of chemical diversity.

Figure 1. Orientation of the i, i+3, and i+7 residues in an idealized

α-helix and comparison of their separations and relative orienta-

tions with the residues in the scaffolds A, B, and C. The triangles

connect the residues to allow direct comparison of relative separa-

tions and orientations.

Here we describe a new class of helix mimetics that is

synthetically readily accessible through incorporation of

one or two triazole rings into the scaffold design.^[3]Two

triazole-phenyl-triazole (A, B) and a phenyl-triazole-phenyl

Retrosynthetically, we envisioned that the triazoles

would be synthesized through Cu^I- or Ru^II-catalyzed [3+2]

cycloadditions between azides and terminal alkynes

(Scheme 1).^[4]It was thought that, by starting from 4-

iodoanilines, the requisite 1,4-dialkynyl-substituted benzene

intermediates could be produced through Sonogashira cou-

pling reactions, with the alkynes containing orthogonal pro-

tecting groups to allow for cleanly sequential cycload-

ditions. For the scaffold C, the alkynes would be obtained

in a Colvin rearrangement from the according aldehyde.

[a] Fakultät für Chemie und Pharmazie, Universität Regensburg,

93040 Regensburg, Germany

Fax: +49-941-943-1717

E-mail: burkhard.koenig@chemie.uni-regensburg.de

[b] Department of Medicinal Chemistry and the Chemical

Methodologies and Library Development Center, University

of Kansas, Delbert M. Shankel Structural Biology Center,

2121 Simons Drive, West Campus, Lawrence, KS 66047, USA

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201001531.

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Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

scaffolds together. Figure 2 illustrates these specific options

in the case of the scaffold B. In the scaffold C, the building

blocks containing the different side-chain substituents are

combined in the final synthesis steps, which is advantageous

for library syntheses.

Results and Discussion

Synthesis of the 1,4-Dialkynylbenzene Intermediates

Synthesis of the 1,4-dialkynylbenzene intermediates for

scaffolds A and B first entailed the selective 4-iodination of

commercially available aniline derivatives by a known litera-

ture procedure (Scheme 2).^[5]The aniline derivatives 1a–c

were thus treated with aqueous sodium hydrogencarbonate

solutions and molecular iodine at 0 °C, which afforded 2a–

c in high yields (89–95%). The alkyne substituents were in-

troduced through Pd-catalyzed Sonogashira reactions^[6]in

triethylamine. Triisopropylsilyl-protected acetylene was

chosen as the first alkyne and was coupled to 2a–c and

to commercially available 4-iodo-3-methylaniline (2d). This

gave the 4-alkynylanilines 3a–d in quantitative yields in al-

most all cases. The next step was the transformation of the

anilines into the iodoarenes 4a–d. This was accomplished

through two-step Sandmeyer-type reactions.^[7]Firstly, the

anilines were transformed with sodium nitrite into diazo-

nium salts; these were found to be unstable above 0 °C. Ac-

cordingly, they were directly iodinated with potassium

iodide without intermediate isolation. This two-step se-

quence proceeded with good yields (70–90%). Subsequent

Sonogashira couplings finally concluded the syntheses of

the 1,4-dialkynylbenzene intermediates 5a–d. Here, the cou-

plings were carried out with 2-methylbut-3-yn-2-ol^[8]to

ensure that the two alkynyl substituents in the products

bore orthogonal protecting groups. Next, the alkynols were

deprotected by heating at reflux with sodium hydroxide in

toluene. Elimination of acetone gave the 1,4-dialkynyl-sub-

stituted benzenes 6a–d, each with one deprotected alkynyl

group, in good yields (84–95%).

Scheme 1. Retrosynthetic approach to the scaffolds A, B, and C.

To demonstrate the synthesis routes, a small library con-

taining compounds with all three scaffolds was synthesized.

The individual scaffolds have distinct attributes. The scaf-

fold A, for example, can be obtained by a very short synthe-

sis through regioisomeric click reactions yielding the de-

sired geometrical arrangement. The scaffold B allows the

introduction of an additional substituent capable of influ-

encing biophysical properties, of extending the binding mo-

tif to a fourth side chain in position i+10, or of linking two

Synthesis of Azides

For the subsequent [3+2] cycloadditions a sublibrary of

azides was synthesized (Figure 3).

3-Chloropropan-1-ol (14) was treated with tert-butyl di-

carbonate (Boc₂O) and magnesium perchlorate^[9]to form

the tert-butyl ether. This chloro-substituted ether was then

transformed into the azide 7 by treatment with sodium az-

ide in DMSO at 45 °C.^[10]The overall yield for the two steps

was 76% (Scheme 3). The azides 8, 10,^[11]11,^[12]and 13^[13]

were prepared from the corresponding bromides by the

same general procedure.

Figure 2. Extended binding motif of the scaffold B (left) and two

helix mimetics connected by the linker L (right).

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Scheme 2. Synthesis of the 1,4-dialkynylbenzene intermediates 6a–d. Compound 2d was purchased.

Scheme 3. Synthesis of the azides 7 and 8.

tion mixture was neutralized with sodium acetate, and the

azide was generated by addition of sodium azide.^[16]This

reaction proceeded through the formation of the diazonium

intermediate with an overall yield of 52% for these two

steps.

Figure 3. Synthesized azides for subsequent cycloaddition.

The azide 12 (Figure 3) was prepared by a diazo transfer

reaction with use of commercially available tryptamine as

starting material.^[14]2-Azido-4-isopropyl-1-methylbenzene

(9, Scheme 4) was synthesized in a two-step procedure.

Firstly, commercially available 2-nitro-p-cymene (16) was

reduced to its corresponding aniline derivative by treatment

with a ferric chloride/zinc/dimethyl formamide/H₂O sys-

tem.^[15]The aniline derivative was then treated with hydro-

chloric acid and sodium nitrite in an ice/salt bath. The reac- Scheme 4. Synthesis of the azide 9.

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Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

Scaffold A

uent, (3) deprotection of the top alkynyl substituent, and

(4) second cycloaddition to form the top triazole ring and

at the same time to introduce the R¹substituent.

The synthesis of compounds containing the scaffold A

proceeded through the 1,4-dialkynylbenzene intermediates

6a and 6b, starting with the two-step syntheses of the 1,4-

substituted 1,2,3-triazoles 17a and 17b (Scheme 5). In these

Cu^I-catalyzed [3+2] cycloadditions, the i+7 side-chain resi-

dues were introduced. Firstly, isobutyl azide was generated

from its corresponding bromide and sodium azide in DMF

at 50 °C in a sealed flask for 15 h. In the next step, the

alkyne, sodium ascorbate, CuSO₄·5H₂O, and methanol

were added directly to the reaction mixtures. The cycload-

ditions yielded 17a and 17b. The triisopropylsilyl-protected

alkynyl groups were deprotected with TBAF to form the

unprotected alkynes 18a and 18b, which could then be used

for the final cycloadditions. The top triazole ring in each

case carries the substituent i. It is a 1,5-substituted triazole,

formed through Ru^II-catalyzed [3+2] cycloadditions^[17]be-

tween each alkyne and the azides 10, 21, and 12;

cp*RuCl(PPh₃)₂was used as catalyst, in dioxane as solvent.

The reactions went to completion on heating to 70 °C for

24 h, and the products 19a, 19b, 20, and 21 were formed

with good to moderate yields.

Cu^I-catalyzed [3+2] cycloadditions^[18]between the ter-

minal alkynes 6c and 6d and the azides 7 or 8 selectively

formed the 1,4-disubstituted triazoles 22a and 22b

(Scheme 6). The azides each contain the additional R⁴sub-

stituent that is present in this scaffold. For this position we

chose residues that should increase the polarity of the final

molecules: a protected primary alcohol and a 1,4-dioxane.

The reactions were carried out with CuSO₄·5H₂O and so-

dium ascorbate as reducing agent. Next, the triazoles 22a

and 22b were deprotonated at the 5-positions in their tri-

azole rings with nBuLi. Addition of the electrophile methyl

iodide or ethyl iodide resulted in alkylation, producing 23a

and 24b, respectively.^[19]The use of acetone as electrophile

gave the tertiary alcohol 25b. After this introduction of the

i+7 substituent, the TIPS-protected alkynyl group was de-

protected with TBAF solution to yield 26a, 27b, and 28b in

high 95–100% yields.

Scheme 6. Synthesis and modification of the bottom ring in the

scaffold B.

The final [3+2] cycloadditions were carried out in the

same fashion as described above (Scheme 7). In this case,

the azide reactants incorporate the side-chain residue i into

the scaffold. To imitate aromatic amino acids, we used the

azides 10, 11, and 12, containing naphthalene, phenyl, or

indole moieties, respectively. The synthesis of 30a, 30b, 31a,

Scheme 5. Synthesis of compounds with the scaffold A.

Scaffold B

The synthesis of compounds possessing the general and 31b concluded the synthetic route to compounds with

structure of the scaffold B, starting from the monoprotected the scaffold B. Compound 29a was prepared by using the

1,4-dialkynylbenzenes, required: (1) [3+2] cycloaddition to azide 7. To increase the polarity of this compound, the tert-

form the bottom triazole, (2) introduction of the R³substit- butyl ethers were deprotected to yield the diol 29b.

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Scheme 7. Reagents and conditions. (i) Azides N₃–R⁴(7, 10, 11, 12), CuSO₄·5H₂O, sodium ascorbate or ascorbic acid, MeOH, H₂O,

room temp.; (ii) HCl_aq, dioxane, reflux, 1.5 h.

To mimic a larger area of an α-helix, the binding motif

Alternatively, a linker for further functionalization could

has to be extended to a fourth side chain – either i+10 or be introduced. This strategy would allow incorporation of

i+11 – on the binding face of the helix. This was ac- a luminescent label or the combination of two helix mi-

complished by extending the scaffold with an additional metic scaffolds in a common binding motif. We demon-

phenyl ring to a triazole-phenyl-triazole-phenyl system. The strated this by using an alkyl linker to connect two triazole-

bottom phenyl ring orients a substituent in the meta posi- phenyl-triazole structures by use of the same synthesis

tion to reproduce the i+10 side chain correctly. The synthe- route as for the scaffold B. As linker, we used a diazido

sis route to this extended scaffold, as depicted in Scheme 8, compound that reacted through both azido moieties with

is similar to the previously described route. The additional an alkyne intermediate. (CAUTION: We suggest to treat

phenyl ring is incorporated in the azide partner of a final compounds containing more than a single azide moiety as

Cu^I-catalyzed cycloaddition, specifically 9, an azidobenzene potential serious explosion hazards and to take appropriate

carrying a meta-isopropyl substituent. The resulting triazole safety measures.) In this case, 36 was prepared from 1,8-

32 was modified with ethyl iodide under basic conditions diazidooctane and subsequently treated with ethyl iodide

to form 33 and deprotected with TBAF solution to yield and nBuLi to afford 37; deprotection with TBAF yielded

34. Finally, the last substituent was introduced by cycload- 38. The synthesis of 39 was completed by formation of the

dition, yielding compound 35, displaying four side chains.

triazoles (Scheme 9).

Scheme 8. Synthesis route to the extended scaffold B, which mimics side chains in the i, i+3, i+7, and i+10 positions.

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Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

compound 44 in 86% yield. In the final step, the i+3 residue

was introduced through electrophilic attack at the 5-posi-

tion in the triazole ring under basic conditions. The triazole

44 was treated with nBuLi, and either acetaldehyde or ethyl

iodide were then used as electrophiles to form compounds

45 and 46 and to complete the synthesis route to the scaf-

fold C.

Scheme 9. Linking of two scaffolds to double the binding motif.

Scaffold C

We designed a 6-5-6 phenyl-triazole-phenyl system in

which the top and bottom phenyl rings each carry a side

chain at the meta positions to reproduce the side chains i

and i+7 of a given helix target. These molecule fragments

could be synthesized independently and were subsequently

joined together in a triazole-forming cycloaddition to yield

the complete core structure.

To allow the subsequent cycloaddition, the top phenyl

fragment has to bear an alkyne substituent meta to the resi-

due i. The commercially available 3-bromobenzyl chloride

(40) was used as starting material and was transformed into

3-formylbenzyl chloride (41) through a halogen/metal ex-

change reaction^[20](Scheme 10). nBuLi was added to a solu-

tion of 3-bromobenzyl chloride and isopropylmagenesium

chloride in THF at 0 °C to form a triarylmagnesiate com-

plex. This complex was quenched with dry DMF to form

the desired aldehyde 41 in quantitative yield. Naphthalene

had been chosen to mimic the side chain at the position i

of the helix, so 41 was coupled with 2-naphthylboronic acid

Scheme 10. Synthesis route to the scaffold C.

Conclusions

We have developed a versatile and efficient synthetic

in a Suzuki coupling reaction. This Suzuki reaction was route to different teraryl compounds that mimic the geo-

carried out under microwave-irradiation^[21]conditions with metric arrangement of side chains in an α-helical peptide.

Pd(PPh₃)₄as catalyst and a solvent mixture of DME/H₂O As key steps the syntheses use azide–alkyne [3+2] cycload-

(2:1). The reaction mixture was heated in the microwave ditions, yielding triazoles. The three different scaffold types

oven at 100 °C for 4 h and afforded compound 42 in 70% A, B, and C were produced by starting from commercially

yield. The aldehyde 42 was transformed into its correspond- available substituted arenes. The scaffold A has a short syn-

ing homologous alkyne 43 in 74% yield through a Colvin thesis route, the scaffold B was designed to increase the ver-

rearrangement.^[22]This reaction used the lithium salt of tri- satility by inclusion of a fourth substituent, and the scaffold

methylsilyldiazomethane [TMSC(Li)N₂] to introduce the C₁C is especially well suited for library syntheses. The syn-

unit into the compound.^[23]A previously synthesized azide thetic protocols allow the introduction of a wide range of

9 was chosen for the bottom meta-substituted arene de- different substituents as required for the development of

signed to mimic the i+7 residue. The top and bottom frag- specific protein–protein interaction inhibitors and should

ments were brought together in a Cu^I-catalyzed [3+2] cyclo- therefore find application in medicinal chemistry and com-

addition between the alkyne 43 and the azide 9 to yield pound library synthesis.

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I. Ehlers, P. Maity, J. Aubé, B. König

FULL PAPER

(4 mol-%) were added to the stirred solution. The reaction mixture

was stirred until TLC showed full conversion of the starting mate-

rial. The reaction mixture was then filtered, the filtrate was washed

with diethyl ether, and the organic phase was washed with saturated

NH₄Cl solution (3ϫ) and brine. After drying with MgSO₄, the

solvent was evaporated, and the crude product was subjected to

flash column chromatography on silica gel with a hexanes/AcOEt

mixture to yield the product.

Experimental Section

General: Commercial reagents and starting materials were used

without further purification. Solvents were dried by common pro-

cedures.^[24]Flash chromatography was performed on silica gel from

Merck (70–230 mesh) and Sorbent Technologies (230–400 mesh).

Thin layer chromatography (TLC) was performed with alumina

plates coated with silica gel (Merck silica gel 60 F₂₅₄, thickness

0.2 mm) or glass plates coated with silica gel (Analtech Silica

Gel HLF 250 μm). Visualization was achieved with UV light (λ =

254 nm). Melting points were determined with a Stanford Research

System OpitMelt melting point apparatus or a Thomas Hoover

capillary melting point apparatus, are given in °C, and are uncor-

rected. NMR spectra were recorded with a Bruker Avance 300 (¹H:

300.1 MHz; ¹³C: 75.5 MHz; T = 300 K) or a Bruker Avance 400

(¹H: 400.1 MHz; ¹³C: 100.6 MHz; T = 300 K). Chemical shifts are

reported in δ (ppm) relative to external standards, and coupling

constants (J) are given in Hertz (Hz). Integration is determined as

the relative number of protons. The solvent used for each spectrum

is reported. Mass spectra were recorded with a Varian CH-5 (EI),

a Finnigan MAT 95 (CI), a Finnigan MAT TSQ 7000 (ESI), or a

Waters LCT Premier Micromass (ESI). IR spectra were recorded

with a Bio-Rad FT-IR-FTS 155 or a Perkin–Elmer FT-IR-Spec-

trometer Spectrum 100. UV/Vis spectra were recorded with a Cary

BIO 50 UV/Vis/NIR instrument (Varian). Elemental analyses were

carried out by the Microanalytical Laboratory of the University of

Regensburg.

GP4. Deprotection of 2-Methylbut-3-yn-2-ols To Yield the Free Al-

kynes: Ground sodium hydroxide was added to a solution of the

protected alkyne in toluene. The reaction mixture was heated at

reflux for 3 h or until TLC showed complete conversion. H₂O was

added, the phases were separated, and the aqueous phase was ex-

tracted twice with diethyl ether. The combined organic extracts

were washed with NH₄Cl solution (2ϫ) and brine and dried with

MgSO₄. The solvent was removed in vacuo, and the crude product

was purified by flash column chromatography on silica gel.

GP5. Cu^I-Catalyzed [3+2] Cycloadditions between Alkynes and

Azides: The alkyne (1.0 equiv.) was dissolved in methanol, and the

azide (1.1 equiv.) was added. Sodium ascorbate or ascorbic acid

(0.1 equiv.) and CuSO₄·5H₂O (0.02 equiv.) were each dissolved in

little H₂O and were added to the reaction mixture. The reaction

mixture was stirred at room temp. overnight. If TLC showed in-

complete conversion, it was heated to 65 °C. H₂O and diethyl ether

were added and the phases were separated. The aqueous phase was

extracted twice with diethyl ether, and the combined organic ex-

tracts were washed with a solution of NH₄Cl (2ϫ) and brine (2ϫ).

After drying with MgSO₄, the solvent was evaporated. The remain-

ing residue was purified by flash column chromatography on silica

gel.

General Procedures

GP1. Sonogashira Couplings between Aniline Derivatives and (Tri-

isopropylsilyl)acetylene: The aniline derivative (1.0 equiv.) was dis-

solved at room temp. under nitrogen/argon in freshly distilled (from

CaH₂) triethylamine. Bis(triphenylphosphane)palladium(II) dichlo-

ride (1 mol-%), (triisopropylsilyl)acetylene (1.0 equiv.), and cop-

per(I) iodide (2 mol-%) were added to the stirred solution. The re-

action mixture was maintained at room temp. until TLC showed

full conversion of the starting material. The reaction mixture was

filtered, and the filtrate was washed with saturated NH₄Cl solution

(3ϫ) and brine. After drying with MgSO₄, the solvent was evapo-

rated under reduced pressure, and the crude product was subjected

to flash column chromatography on silica gel with a hexanes/Ac-

OEt mixture to yield the product.

GP6. Deprotection of TIPS-Protected Alkynes: The protected al-

kyne (1 equiv.) was dissolved in THF, and a solution of TBAF in

THF (1 m, 2 equiv.) was added. After the mixture had been stirred

at room temp. for 1 h, H₂O and diethyl ether were added. The

phases were separated, and the organic phase was washed with

H₂O (3ϫ) and brine. After drying with MgSO₄, the solvent was

evaporated, and the crude product was purified by flash column

chromatography on silica gel.

GP7. Ru^II-Catalyzed [3+2] Cycloadditions: The alkyne (1.0 equiv.)

and the azide (1.0 equiv.) were dissolved in dioxane, and

cp*RuCl(PPh₃)₂(5 mol-%) was added. The reaction mixture was

stirred at 70 °C for 24 h. The solvent was removed in vacuo, and

the crude product was purified by flash column chromatography

on silica gel.

GP2. Conversion of Anilines Into Iodoarenes: The aniline derivative

(1.0 equiv.) was dissolved in concentrated hydrochloric acid in a

three-necked round-bottomed flask with internal thermometer. The

reaction mixture was cooled in an ice/NaCl bath, and a solution of

sodium nitrite (1.2 equiv.) in cooled water was slowly added drop-

wise to keep the temperature of the reaction mixture below 3 °C.

The solution was stirred at 0 °C for 1 h and was then slowly added

to a stirred solution of potassium iodide (2.5 equiv.) in water, co-

oled in an ice bath. After the mixture had been stirred at 0 °C for

2 h, ethyl acetate was added. The phases were separated, and the

aqueous phase was extracted twice with ethyl acetate. The com-

bined organic extracts were washed with H₂O, sodium metabisulfite

solution (3ϫ), and brine (2ϫ). After drying with MgSO₄, the sol-

vent was evaporated, and the crude product was purified by flash

column chromatography on silica gel with a hexanes/AcOEt mix-

ture.

GP8. Triazole Modification at the 5-Position: The triazole

(1.0 equiv.) was dissolved in dry THF under argon in a flame-dried

flask. The reaction mixture was cooled to –78 °C in an acetone/dry

ice bath, and nBuLi (1.5 equiv.) was slowly added dropwise. After

the mixture had been stirred at that temperature for 5 min, the

electrophile (4.0 equiv.) was added, and the solution was stirred at

–78 °C for 1 h. After the reaction mixture had been allowed to

warm to room temp., it was stirred at that temperature for 1 h.

H₂O was added, and the phases were separated. The aqueous phase

was extracted twice with DCM, and the combined organic extracts

were dried with MgSO₄. The solvent was evaporated under reduced

pressure, and the crude product was purified by flash column

chromatography on silica gel.

GP3. Sonogashira Coupling of Iodoarenes with 2-Methylbut-3-yn-

2-ol: The iodoarene (1.0 equiv.) was dissolved in dry THF under

nitrogen/argon at room temp. Freshly distilled (from CaH₂) DIPEA

GP9. Cu^I-Catalyzed [3+2] Cycloadditions with Small Azides: In

these two-step reactions the bromoalkane (5.0 equiv.) was dissolved

in DMF. Sodium azide (6.0 equiv.) was added, and the reaction

mixture was stirred at 50 °C for 15 h. The alkyne (1.0 equiv.) and

(4.0 equiv.),

bis(triphenylphosphane)palladium(II)

dichloride

(2 mol-%), 2-methylbut-3-yn-2-ol (1.1 equiv.), and copper(I) iodide

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Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

solutions of sodium ascorbate (0.10 equiv.) and CuSO₄·5H₂O

(0.05 equiv.) in a little H₂O were added to the formed azide. After

addition of methanol, the reaction mixtures were stirred at 50 °C

for 5 d. H₂O and diethyl ether were added, and the phases were

separated. The aqueous phase was extracted twice with diethyl

ether, and the combined organic extracts were washed with a satu-

rated solution of NH₄Cl and brine. After drying with MgSO₄, the

solvent was evaporated under reduced pressure, and the crude

product was purified by flash column chromatography on silica gel.

3-Methyl-4-[(triisopropylsilyl)ethynyl]aniline (3d): Compound 3d

was synthesized according to GP1, from 4-iodo-3-methylaniline

(500 mg, 2.15 mol), triethylamine (10 mL), PdCl₂(PPh₃)₂(15 mg,

22 μmol), (triisopropylsilyl)acetylene (0.52 mL, 2.30 mmol), and

CuI (8 mg, 43 μmol). TLC showed complete conversion of the

starting material [petroleum ether/AcOEt, 1:1; R_f= 0.65] after stir-

ring overnight. The product was obtained after flash column

chromatography on silica gel (hexanes/AcOEt 1:1) as a brown solid

(0.712 g, 100%). M.p. 52 °C. ¹H NMR (300 MHz, CDCl₃): δ =

1.10–1.12 (m, 21 H, iPr), 2.36 (s, 3 H, Ar-CH₃), 6.42 (dd, ³J = 8.23,

Synthesis of New Compounds

4

⁴J = 2.19 Hz, 1 H, ArH), 6.50 (d, J = 2.19 Hz, 1 H, ArH), 7.25

3

(d, J = 8.23 Hz, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

2-Ethyl-4-[(triisopropylsilyl)ethynyl]aniline (3a): Compound 3a was

synthesized according to GP1, from the 4-iodoaniline derivative

2a (3.70 g, 15.0 mmol) in NEt₃(70 mL), with Pd catalyst (105 mg,

0.15 mmol), (triisopropylsilyl)acetylene (3.37 mL, 15.0 mmol), and

CuI (57 mg, 0.30 mmol). After the mixture had been stirred for 2 d,

TLC showed full conversion of 2a. The crude product was purified

by flash column chromatography on silica gel (hexanes/AcOEt, 2:1;

= 11.38, 18.70, 20.96, 91.37 (C_quat), 106.52 (C_quat), 112.07, 113.22

(C_quat), 115.67, 133.68, 142.08 (C_quat), 146.53 (C_quat) ppm. IR: ν =

˜

2940, 2864, 2144, 1605, 1495 cm^–1. UV/Vis (MeCN): λ_max

(lgε)=280 nm (4.622). MS (EI): m/z (%) = 244.1 (100) [M – C₃H₇]⁺,

287.2 (63) [M]⁺. HR-MS (EI): calcd. for C₁₈H₂₉NSi [M]⁺287.2069;

found 287.2065.

1

R_f= 0.80), and 3a was obtained as a brown oil (4.54 g, 100%). H

[(3-Ethyl-4-iodophenyl)ethynyl]triisopropylsilane (4a): The synthesis

of 4a was according to GP2, with the aniline derivative 3a (4.46 g,

14.8 mmol), concentrated hydrochloric acid (15 mL), NaNO₂solu-

tion (1.23 g of NaNO₂, 17.7 mmol; in 10 mL of H₂O), and KI solu-

tion (6.14 g of KI, 37.0 mmol; in 35 mL of H₂O). The crude prod-

uct was purified by flash column chromatography on silica gel (hex-

anes/AcOEt, 10:1; R_f= 0.87), yielding 4a as a red oil (5.39 g, 88%).

¹H NMR (400 MHz, CDCl₃): δ = 1.11–1.13 (m, 21 H, iPr), 1.20

(t, ³J = 7.45 Hz, 3 H, CH₃), 2.69 (q, ³J = 7.49 Hz, 2 H, CH₂), 6.96

(dd, ⁴J = 2.02, ³J = 8.08 Hz, 1 H, ArH), 7.29 (d, ⁴J = 2.02 Hz, 1 H,

ArH), 7.73 (d, ³J = 8.08 Hz, 1 H, ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 11.28, 14.37, 18.64, 33.96, 91.67 (C_quat), 100.34 (C_quat),

3

NMR (400 MHz, CDCl₃): δ = 1.11–1.13 (m, 21 H, iPr), 1.24 (t, J

3

= 7.57 Hz, 3 H, CH₃), 2.47 (q, J = 7.57 Hz, 2 H, CH₂), 3.75 (br.

s, 2 H, NH₂), 6.57 (d, ³J = 7.83 Hz, 1 H, ArH), 7.17 (dd, ⁴J = 1.38,

³J = 8.46 Hz, 1 H, ArH), 7.18–7.19 (m, 1 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 11.41, 12.78, 18.71, 23.81, 87.10 (C_quat),

108.24 (C_quat), 113.20 (C_quat), 114.81, 127.53 (C_quat), 131.03,

132.28, 144.39 (C_quat) ppm. IR: ν = 3489, 3390, 2967, 2862, 2137,

˜

1621, 1462 cm^–1. HR-MS (ESI+): calcd. for C₁₉H₃₂NSi [M + H]⁺

302.2304; found 302.2314.

2,6-Diethyl-4-[(triisopropylsilyl)ethynyl]aniline (3b): Compound 3b

was synthesized according to GP1, by dissolving the 4-iodoaniline

derivative 2b (3.70 g, 13.5 mmol) in NEt₃(70 mL) and using Pd

catalyst (95 mg, 0.14 mmol), (triisopropylsilyl)acetylene (3.24 mL,

14.4 mmol), and CuI (52 mg, 0.27 mmol). After the mixture had

been stirred for 3 d, TLC showed full conversion of 2b. The crude

product was purified by flash column chromatography on silica gel

(hexanes/AcOEt, 2:1; R_f= 0.85), and 3b was obtained as a green-

106.21 (C_quat), 123.77 (C_quat), 130.82, 131.72, 139.19, 146.53 (C_quat

)

ppm. IR: ν = 2961, 2862, 2159, 1462 cm^–1. HR-MS (EI+): calcd.

˜

for C₁₉H₂₉ISi [M]⁺412.1083; found 412.1089.

[(3,5-Diethyl-4-iodophenyl)ethynyl]triisopropylsilane (4b): The syn-

thesis of 4b was according to GP2, with the aniline derivative 3b

(4.45 g, 13.5 mmol), concentrated hydrochloric acid (15 mL),

NaNO₂solution (1.12 g of NaNO₂, 16.2 mmol; in 10 mL of H₂O),

and KI solution (5.60 g of KI, 33.8 mmol; in 35 mL of H₂O). The

crude product was purified by flash column chromatography on

silica gel (hexanes/AcOEt, 10:1; R_f= 0.89), yielding 4b as a red-

1

brown oil (4.63 g, 100%). H NMR (400 MHz, CDCl₃): δ = 1.11–

3

1.13 (m, 21 H, iPr), 1.25 (t, J = 7.45 Hz, 6 H, CH₃), 2.49 (q, J =

7.49 Hz, 4 H, CH₂), 3.78 (br. s, 2 H, NH₂), 7.10 (s, 2 H, ArH) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 11.43, 12.83, 18.72, 24.10, 86.73

(C_quat), 108.64 (C_quat), 112.59 (C_quat), 127.25 (C_quat), 130.06, 142.13

1

brown oil (4.16 g, 70%). H NMR (400 MHz, CDCl₃): δ = 1.12–

(C_quat) ppm. IR: ν = 3500, 3406, 2956, 2868, 2142, 1621, 1459 cm^–1.

3

˜

1.14 (m, 21 H, iPr), 1.21 (t, J = 7.45 Hz, 6 H, CH₃), 2.77 (q, J =

7.49 Hz, 4 H, CH₂), 7.13 (s, 2 H, ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 11.30, 14.51, 18.67, 35.35, 91.08 (C_quat), 106.42 (C_quat),

HR-MS (ESI+): calcd. for C₂₁H₃₆NSi [M + H]⁺330.2617; found

330.2617.

107.30 (C_quat), 123.34 (C_quat), 129.34, 147.35 (C_quat) ppm. IR: ν =

˜

3-Ethyl-4-[(triisopropylsilyl)ethynyl]aniline (3c): Compound 3c was

synthesized according to GP1, by dissolving the 4-iodoaniline de-

rivative 2c (4.08 g, 16.5 mmol) in NEt₃(70 mL) and using Pd cata-

lyst (116 mg, 0.17 mmol), (triisopropylsilyl)acetylene (3.70 mL,

2956, 2862, 2148, 1462 cm^–1. HR-MS (EI+): calcd. for C₂₁H₃₃ISi

[M]⁺440.1396; found 440.1405.

[(2-Ethyl-4-iodophenyl)ethynyl]triisopropylsilane (4c): The synthesis

16.5 mmol), and CuI (63 mg, 0.33 mmol). After the mixture had of 4c was according to GP2, from the aniline derivative 3c (4.50 g,

been stirred for 3 d, TLC showed full conversion of 2c. The crude

product was purified by flash column chromatography on silica gel

(hexanes/AcOEt, 4:1; R_f= 0.58), and 3c was obtained as a yellow

oil (4.57 g, 92%). M.p. 43 °C. ¹H NMR (400 MHz, CDCl₃): δ =

14.9 mmol), concentrated hydrochloric acid (15 mL), NaNO₂solu-

tion (1.24 g of NaNO₂, 17.9 mmol; in 10 mL of H₂O), and KI solu-

tion (6.19 g of KI, 37.3 mmol; in 35 mL of H₂O). The crude prod-

uct was purified by flash column chromatography on silica gel (hex-

3

1.12–1.13 (m, 21 H, iPr), 1.22 (t, J = 7.57 Hz, 3 H, CH₃), 2.74 (q,

anes/AcOEt, 10:1; R_f= 0.89), yielding 4c as a brown oil (5.32 g,

³J = 7.57 Hz, 2 H, CH₂), 3.73 (br. s, 2 H, NH₂), 6.43 (dd, ⁴J = 87%). H NMR (400 MHz, CDCl₃): δ = 1.12–1.14 (m, 21 H, iPr),

1

3

4

2.40, J = 8.21 Hz, 1 H, ArH), 6.50 (d, J = 2.27 Hz, 1 H, ArH),

1.23 (t, ³J = 7.57 Hz, 3 H, CH₃), 2.77 (q, ³J = 7.49 Hz, 2 H, CH₂),

7.26 (d, ³J = 8.33 Hz, 1 H, ArH) ppm. ¹³C NMR (100 MHz, 7.16 (d, ³J = 8.08 Hz, 1 H, ArH), 7.46 (dd, ⁴J = 1.76, ³J = 8.08 Hz,

CDCl₃): δ = 11.43, 14.90, 18.70, 27.98, 91.01 (C_quat), 106.26 (C_quat),

1 H, ArH), 7.55 (d, ⁴J = 1.51 Hz, 1 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 11.30, 14.72, 18.64, 27.66, 94.48 (C_quat),

95.83 (C_quat), 104.48 (C_quat), 122.27 (C_quat), 134.04, 134.61, 136.98,

112.17, 112.50 (C_quat), 114.30, 134.09, 146.74 (C_quat), 148.24 (C_quat

)

ppm. IR: ν = 3467, 3373, 2939, 2868, 2142, 1621, 1459 cm^–1. HR-

˜

MS (ESI+): calcd. for C₁₉H₃₂NSi [M + H]⁺302.2304; found

302.2304.

148.58 (C_quat) ppm. IR: ν = 2967, 2857, 2153, 1467 cm^–1. HR-MS

˜

(EI+): calcd. for C₁₉H₂₉ISi [M]⁺412.1083; found 412.1090.

Eur. J. Org. Chem. 2011, 2474–2490

www.eurjoc.org

2481

I. Ehlers, P. Maity, J. Aubé, B. König

FULL PAPER

[(4-Iodo-2-methylphenyl)ethynyl]triisopropylsilane (4d): The synthe-

sis of 4d was according to GP2, with the aniline derivative 3d

(2.47 g, 8.58 mmol), concentrated hydrochloric acid (10 mL),

NaNO₂solution (710 mg of NaNO₂; 10.3 mmol, in 7 mL of H₂O),

and KI solution (3.56 g of KI, 21.4 mmol; in 15 mL of H₂O). The

crude product was purified by flash column chromatography on

(m, 21 H, iPr), 1.23 (t, ³J = 7.57 Hz, 3 H, CH₃), 1.61 (s, 6 H, CH₃),

3

2.00 (br. s, 1 H, OH), 2.79 (q, J = 7.49 Hz, 2 H, CH₂), 7.17 (dd,

3

⁴J = 1.51, J = 7.83 Hz, 1 H, ArH), 7.26–7.27 (m, 1 H, ArH), 7.37

3

(d, J = 7.83 Hz, 1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 11.33, 14.74, 18.64, 27.71, 31.45, 65.66 (C_quat), 82.12 (C_quat),

94.94 (C_quat), 95.97 (C_quat), 105.01 (C_quat), 122.58 (C_quat), 122.67

silica gel (petroleum ether/AcOEt, 2:1; R_f= 0.76), yielding 4d as

(C_quat), 128.69, 131.13, 132.57, 146.53 (C_quat) ppm. IR: ν = 3340,

˜

1

an orange-brown oil (3.09 g, 90%). H NMR (300 MHz, CDCl₃): 2956, 2862, 2148, 1462 cm^–1. HR-MS (EI+): calcd. for C₂₄H₃₆OSi

3

δ = 1.08–1.14 (m, 21 H, iPr), 2.39 (s, 3 H, ArCH₃), 7.15 (d, J =

[M]⁺368.2535; found 368.2533.

3

4

8.23 Hz, 1 H, ArH), 7.45 (dd, J = 8.09, J = 1.23 Hz, 1 H, ArH),

7.57 (d, ⁴J = 0.82 Hz, 1 H, ArH) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 11.24, 18.65, 20.56, 94.16 (C_quat), 96.31 (C_quat), 104.74

(C_quat), 122.98 (C_quat), 133.56, 134.53, 138.20, 142.54 (C_quat) ppm.

2-Methyl-4-{3-methyl-4-[(triisopropylsilyl)ethynyl]phenyl}but-3-yn-

2-ol (5d): The synthesis of 5d was according to GP3, by dissolving

the iodoarene derivative 4d (498 mg, 1.25 mmol) in dry THF

(7 mL) and using DIPEA (0.87 mL, 5.0 mmol), PdCl₂(PPh₃)₂

(17.5 mg, 0.025 mmol), 2-methylbut-3-yn-2-ol (0.14 mL,

1.4 mmol), and CuI (10 mg, 0.050 mmol). The reaction was com-

plete after stirring overnight, and the crude product was purified

by flash column chromatography on silica gel (petroleum ether/

AcOEt, 4:1; R_f= 0.36). Compound 5d was obtained as a yellow

oil (282 mg, 63%). ¹H NMR (300 MHz, CDCl₃): δ = 1.12–1.14 (m,

IR: ν = 2941, 2865, 2154, 1473 cm^–1. UV/Vis (CHCl ): λ

(lgε)

˜

3

max

= 265 nm (4.434). MS (CI-MS, NH₃): m/z (%) = 399.0 (100) [M +

H]⁺.

4-{2-Ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-2-methylbut-3-yn-2-

ol (5a): The synthesis of 5a was according to GP3, by dissolving

the iodoarene derivative 4a (5.32 g, 12.9 mmol) in dry THF

(70 mL) and using DIPEA (9.0 mL, 51 mmol), PdCl₂(PPh₃)₂

(182 mg, 0.26 mmol), 2-methylbut-3-yn-2-ol (1.40 mL, 14.2 mmol),

and CuI (99 mg, 0.52 mmol). The reaction was complete after the

mixture had been stirred for 3 d, and the crude product was puri-

fied by flash column chromatography on silica gel (hexanes/AcOEt,

4:1; R_f= 0.48). Compound 5a was obtained as a yellow oil (3.73 g,

3

21 H, iPr), 1.61 (s, 6 H, CH₃), 2.41 (s, 3 H, ArCH₃), 7.16 (dd, J

4

= 7.82, J = 1.23 Hz, 1 H, ArH), 7.25–7.27 (m, 1 H, Ar2), 7.37 (d,

³J = 7.95 Hz, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

11.28, 18.66, 20.68, 31.44, 65.64 (C_quat), 82.01 (C_quat), 94.97 (C_quat),

96.45 (C_quat), 105.27 (C_quat), 122.39 (C_quat), 123.37 (C_quat), 128.63,

132.14, 132.43, 140.47 (C_quat) ppm. IR: ν = 2941, 2864, 2150, 1491,

˜

1461 cm^–1. UV/Vis (CHCl₃): λ_max(lg ε) = 280 (4.589), 290 nm

(4.546). MS (CI, NH₃): m/z (%) = 337.2 (100) [M + H – H₂O]⁺,

355.3 (6) [M + H]⁺. HR-MS (EI): calcd. for C₂₃H₃₄OSi [M]⁺

354.2379; found 354.2374.

1

79%). H NMR (400 MHz, CDCl₃): δ = 1.11–1.13 (m, 21 H, iPr),

3

1.23 (t, J = 7.57 Hz, 3 H, CH₃), 1.63 (s, 6 H, CH₃), 1.99 (br. s, 1

3

4

3

H, OH), 2.74 (q, J = 7.57 Hz, 2 H, CH₂), 7.23 (dd, J = 1.51, J

= 8.08 Hz, 1 H, ArH), 7.29–7.31 (m, 2 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 11.31, 14.48, 18.65, 27.50, 32.46, 65.76

(C_quat), 80.56 (C_quat), 91.92 (C_quat), 98.81 (C_quat), 106.88 (C_quat),

[(3-Ethyl-4-ethynylphenyl)ethynyl]triisopropylsilane (6a): Com-

pound 6a was synthesized according to GP4. The protected alkyne

5a (5.55 g, 15.0 mmol) was dissolved in toluene (60 mL), and so-

dium hydroxide (2 g) was added. TLC showed complete conversion

after 3 h of heating at reflux, and the crude product was purified

by flash column chromatography on silica (hexanes/AcOEt, 4:1; R_f

= 0.87). As product, 6a was obtained as a brown oil (4.45 g, 95%).

¹H NMR (400 MHz, CDCl₃): δ = 1.11–1.13 (m, 21 H, iPr), 1.24

121.83 (C_quat), 123.45 (C_quat), 129.26, 131.41, 131.90, 146.10 (C_quat

)

ppm. IR: ν = 3346, 2967, 2862, 2153, 1459 cm^–1. HR-MS (EI+):

˜

calcd. for C₂₄H₃₆OSi [M]⁺368.2535; found 368.2526.

4-{2,6-Diethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-2-methylbut-3-

yn-2-ol (5b): The synthesis of 5b was according to GP3, by dissolv-

ing the iodoarene derivative 4b (4.06 g, 9.23 mmol) in dry THF

(60 mL) and using DIPEA (6.43 mL, 36.9 mmol), PdCl₂(PPh₃)₂

(130 mg, 0.185 mmol), 2-methylbut-3-yn-2-ol (0.99 mL,

10.2 mmol), and CuI (70 mg, 0.37 mmol). The reaction was almost

complete after the mixture had been stirred at room temp. for 3 d,

and the crude product was purified by flash column chromatog-

raphy on silica gel (hexanes/AcOEt, 4:1; R_f= 0.76). Compound 5b

3

(t, ³J = 7.57 Hz, 3 H, CH₃), 2.79 (q, J = 7.57 Hz, 2 H, CH₂), 3.31

3

(s, 1 H, CH), 7.25 (dd, ⁴J = 1.51, J = 7.83 Hz, 1 H, ArH), 7.31

(d, ⁴J = 1.01 Hz, 1 H, ArH), 7.38 (d, ³J = 7.83 Hz, 1 H, ArH) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 11.31, 14.62, 18.66, 27.40, 77.20,

81.99 (C_quat), 92.26 (C_quat), 106.74 (C_quat), 121.23 (C_quat), 123.98

(C_quat), 129.26, 131.45, 132.64, 146.74 (C_quat) ppm. IR: ν = 3296,

˜

2945, 2862, 2148, 1618, 1456 cm^–1. HR-MS (EI+): calcd. for

C₂₁H₃₀Si [M]⁺310.2117; found 310.2108.

1

was obtained as a white solid (1.71 g, 47%). M.p. 77 °C. H NMR

(400 MHz, CDCl₃): δ = 1.12–1.14 (m, 21 H, iPr), 1.23 (t, ³J =

7.57 Hz, 6 H, CH₃), 1.65 (s, 6 H, CH₃), 2.01 (br. s, 1 H, OH), 2.75

[(3,5-Diethyl-4-ethynylphenyl)ethynyl]triisopropylsilane (6b): Com-

pound 6b was synthesized according to GP4. The protected alkyne

5b (1.65 g, 4.16 mmol) was dissolved in toluene (30 mL), and so-

dium hydroxide (1 g) was added. TLC showed complete conversion

after 3 h of heating at reflux, and the crude product was purified

by flash column chromatography on silica gel (hexanes/AcOEt,

10:1; R_f= 0.90). Product 6b was obtained as a brown oil (1.18 g,

3

(q, J = 7.57 Hz, 4 H, CH₂), 7.15 (s, 2 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 11.32, 14.53, 18.67, 27.81, 31.48, 65.90

(C_quat), 78.99 (C_quat), 91.29 (C_quat), 102.68 (C_quat), 107.26 (C_quat),

121.20 (C_quat), 122.98 (C_quat), 128.87, 146.37 (C_quat) ppm. IR: ν =

˜

3340, 2961, 2868, 2148, 1459 cm^–1. HR-MS (EI+): calcd. for

C₂₆H₄₀OSi [M]⁺396.2848; found 396.2847.

1

84%). H NMR (400 MHz, CDCl₃): δ = 1.12–1.14 (m, 21 H, iPr),

4-{3-Ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-2-methylbut-3-yn-2-

ol (5c): The synthesis of 5c was according to GP3, by dissolving

the iodoarene derivative 4c (5.27 g, 12.8 mmol) in dry THF (70 mL)

and using DIPEA (8.90 mL, 51.1 mmol), PdCl₂(PPh₃)₂(180 mg,

0.256 mmol), 2-methylbut-3-yn-2-ol (2.50 mL, 25.5 mmol), and

CuI (98 mg, 0.51 mmol). The reaction was complete after the mix-

ture had been stirred at room temp. for 4 d, and the crude product

was purified by flash column chromatography on silica gel (hex-

anes/AcOEt, 4:1; R_f= 0.59). Compound 5c was obtained as a yel-

1.23 (t, ³J = 7.57 Hz, 6 H, CH₃), 2.79 (q, ³J = 7.49 Hz, 4 H, CH₂),

3.50 (s, 1 H, CH), 7.16 (s, 2 H, ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 11.31, 14.63, 18.67, 27.73, 80.28 (C_quat), 85.80, 91.58

(C_quat), 107.12 (C_quat), 120.68 (C_quat), 123.42 (C_quat), 128.86, 147.16

(C_quat) ppm. IR: ν = 3307, 2967, 2868, 2148, 1459 cm^–1. HR-MS

˜

(EI+): calcd. for C₂₃H₃₄Si [M]⁺338.2430; found 338.2431.

[(2-Ethyl-4-ethynylphenyl)ethynyl]triisopropylsilane (6c): Compound

6c was synthesized according to GP4. The protected alkyne 5c

(3.34 g, 9.07 mmol) was dissolved in toluene (40 mL), and sodium

1

low oil (3.49 g, 74%). H NMR (400 MHz, CDCl₃): δ = 1.12–1.14

2482

www.eurjoc.org

Eur. J. Org. Chem. 2011, 2474–2490

Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

hydroxide (1.5 g) was added. TLC showed complete conversion af-

ter 4 h of heating at reflux, and the crude product was purified by

flash column chromatography on silica (hexanes/AcOEt, 10:1; R_f

temperature for 1 h, the reaction mixture was neutralized with

NaOAc (5.50 g), and an aqueous solution of NaN₃(436 mg,

6.70 mmol, 2.0 equiv; in 7 mL of H₂O) was added dropwise over

30 min. The reaction mixture was stirred at 0 °C for an additional

1

= 0.85). Product 6c was obtained as a brown oil (2.56 g, 91%). H

3

NMR (400 MHz, CDCl₃): δ = 1.12–1.14 (m, 21 H, iPr), 1.24 (t, J 30 min, allowed to warm to room temp., and stirred at that tem-

3

= 7.57 Hz, 3 H, CH₃), 2.80 (q, J = 7.57 Hz, 2 H, CH₂), 3.13 (s, 1

perature for 1 h. The solution was extracted twice with AcOEt,

dried with MgSO₄, and concentrated. Purification by flash column

chromatography on silica gel (hexanes/AcOEt, 10:1; R_f= 0.76)

4

3

4

H, CH), 7.25 (dd, J = 1.76, J = 7.83 Hz, 1 H, ArH), 7.33 (d, J

= 1.26 Hz, 1 H, ArH), 7.39 (d, J = 7.83 Hz, 1 H, ArH) ppm. ¹³C

3

NMR (100 MHz, CDCl₃): δ = 11.31, 14.70, 18.64, 27.69, 78.28,

83.58 (C_quat), 96.34 (C_quat), 104.84 (C_quat), 121.90 (C_quat), 123.30 δ = 1.25 (d, J = 7.07 Hz, 6 H, CH₃), 2.17 (s, 3 H, Ar-CH₃), 2.89

yielded 9 as a red oil (356 mg, 61%). ¹H NMR (400 MHz, CDCl₃):

3

4

3

(C_quat), 129.18, 131.59, 132.60, 146.60 (C_quat) ppm. IR: ν = 3302,

(sept, J = 6.94 Hz, 1 H, CH), 6.91 (dd, J = 1.76, J = 7.83 Hz, 1

˜

2939, 2862, 2148, 1459 cm^–1. HR-MS (EI+): calcd. for C₂₁H₃₀Si

[M]⁺310.2117; found 310.2106.

H, ArH), 6.96 (d, J = 1.26 Hz, 1 H, ArH), 7.08 (d, J = 7.83 Hz,

1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.78, 23.94,

33.85, 115.95, 122.70, 126.88 (C_quat), 131.01, 137.95 (C_quat), 148.19

4

3

[(4-Ethynyl-2-methylphenyl)ethynyl]triisopropylsilane (6d): Com-

pound 6d was synthesized according to GP4. The protected alkyne

5d (280 mg, 0.79 mmol) was dissolved in toluene (25 mL), and so-

dium hydroxide (500 mg) was added. TLC showed complete con-

version after 3 h of reflux, and the crude product was purified by

flash column chromatography on silica gel (petroleum ether/Ac-

OEt, 4:1; R_f= 0.68). Product 6d was obtained as a brown oil

(205 mg, 87%). ¹H NMR (300 MHz, CDCl₃): δ = 1.05–1.15 (m, 21

H, iPr), 2.43 (s, 3 H, ArCH₃), 3.12 (s, 1 H, CH), 7.24 (dd, ⁴J =

(C_quat) ppm. IR: ν = 2961, 2873, 2104, 1456 cm^–1. HR-MS (EI+):

˜

calcd. for C₁₀H₁₃N₃[M]⁺175.1110; found 175.1113.

4-{2-Ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1-isobutyl-1H-1,2,3-

triazole (17a): Compound 17a was synthesized according to GP9,

with use of 1-bromo-2-methylpropane (685 mg, 5.0 mmol), sodium

azide (390 mg, 6.0 mmol), and DMF (10 mL) to preform the azide.

The next day, the alkyne 6a (310 mg, 1.0 mmol), MeOH (2 mL),

and aqueous solutions of sodium ascorbate (20 mg, 0.10 mmol)

and CuSO₄·5H₂O (13 mg, 0.05 mmol) were added. The crude prod-

uct was purified by flash column chromatography on silica gel (hex-

anes/AcOEt, 4:1; R_f= 0.49) to yield 17a as a white solid (185 mg,

3

0.68, J = 8.09 Hz, 1 H, ArH), 7.32–7.34 (m, 1 H, ArH), 7.39 (d,

³J = 7.95 Hz, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

11.27, 18.65, 20.69, 78.33, 83.46 (C_quat), 96.82 (C_quat), 105.12

(C_quat), 121.69 (C_quat), 123.99 (C_quat), 129.12, 132.18, 132.88,

1

3

45%). M.p. 71 °C. H NMR (400 MHz, CDCl₃): δ = 0.98 (d, J =

6.56 Hz, 6 H, CH₃), 1.13–1.15 (m, 21 H, iPr), 1.20 (t, ³J = 7.45 Hz,

3 H, CH₃), 2.26–2.28 (m, 1 H, CH), 2.81 (q, ³J = 7.49 Hz, 2 H,

140.55 (C_quat) ppm. IR: ν = 3309, 2942, 2865, 2152, 1489,

˜

1463 cm^–1. UV/Vis (CHCl₃): λ_max(lg ε) = 275 (4.630), 285 nm

(4.582). MS (EI): m/z (%) = 253.1 (100) [M – C₃H₇]⁺, 296.2 (23)

[M]⁺. HR-MS (EI+): calcd. for C₂₀H₂₈Si [M]⁺296.1960; found

296.1957.

3

4

3

CH₂), 4.21 (d, J = 7.32 Hz, 2 H, CH₂), 7.36 (dd, J = 1.64, J =

7.95 Hz, 1 H, ArH), 7.40 (d, ⁴J = 1.26 Hz, 1 H, ArH), 7.59 (s, 1 H,

ArH), 7.60 (d, ³J = 7.83 Hz, 1 H, ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 11.31, 15.04, 18.66, 19.84, 26.66, 29.74, 57.54, 90.90

(C_quat), 107.06 (C_quat), 122.06, 123.31 (C_quat), 129.22, 129.59,

1-Azido-3-tert-butoxypropane (7): NaN₃(1.66 g, 26 mmol,

1.5 equiv.) was added to a solution of 1-tert-butoxy-3-chloropro-

pane (2.56 g, 17 mmol, 1 equiv.) in DMSO (10 mL), and the reac-

tion mixture was stirred at 40 °C overnight. H₂O was added, and

the solution was extracted with diethyl ether (4ϫ). The combined

organic extracts were washed with brine and dried with MgSO₄.

The solvent was evaporated to yield product 7 as a colorless oil

(2.41 g, 90%). ¹H NMR (300 MHz, CDCl₃): δ = 1.18 (s, 9 H, tBu),

1.78 (m, 2 H, CH₂), 3.36–3.44 (m, 4 H) ppm. ¹³C NMR (75 MHz,

129.56 (C_quat), 132.62, 141.78 (C_quat), 146.31 (C_quat) ppm. IR: ν =

˜

2957, 2864, 2154, 1459 cm^–1. HR-MS (ESI+): calcd. for

C₂₅H₄₀N₃Si [M + H]⁺410.2991; found 410.3017.

4-{2,6-Diethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1-isobutyl-1H-

1,2,3-triazole (17b): Compound 17b was synthesized according to

GP9, with use of 1-bromo-2-methylpropane (1.01 g, 7.39 mmol),

sodium azide (576 mg, 8.86 mmol), and DMF (10 mL) to preform

the azide. The next day, the alkyne 6b (500 mg, 1.48 mmol), MeOH

(2 mL), and aqueous solutions of sodium ascorbate (29 mg,

0.15 mmol) and CuSO₄·5H₂O (18 mg, 0.07 mmol) were added. The

crude product was purified by flash column chromatography on

silica gel (hexanes/AcOEt, 4:1; R_f= 0.42) to yield 17b as a yellow

CDCl₃): δ = 27.43, 29.86, 48.59, 58.01, 72.77 (C_quat) ppm. IR: ν =

˜

2975, 2088, 1363, 1195, 1094 cm^–1. MS (EI+): m/z = 142.1 [M –

CH₃]⁺, 114.1 [M – C₃H₇]⁺.

2-(2-Azidoethyl)-1,4-dioxane (8): NaN₃(488 mg, 7.5 mmol,

1.5 equiv.) was added to a solution of 2-(2-bromoethyl)-1,4-dioxane

(976 mg, 1 equiv.) in DMSO (20 mL), and the reaction mixture was

stirred at 45 °C overnight. H₂O was added, and the solution was

extracted with diethyl ether (3ϫ). The combined organic extracts

were washed with brine and dried with MgSO₄. The solvent was

1

solid (377 mg, 58%). M.p. 76 °C. H NMR (400 MHz, CDCl₃): δ

= 0.97 (d, ³J = 6.56 Hz, 6 H, CH₃), 1.03 (t, ³J = 7.45 Hz, 6 H,

CH₃), 1.14–1.15 (m, 21 H, iPr), 2.27–2.29 (m, 1 H, CH), 2.37 (q,

³J = 7.57 Hz, 4 H, CH₂), 4.24 (d, ³J = 7.32 Hz, 2 H, CH₂), 7.24 (s,

2 H, ArH), 7.40 (s, 1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 11.38, 15.44, 18.70, 19.76, 26.81, 29.82, 57.52, 90.28 (C_quat),

107.36 (C_quat), 122.83, 123.90 (C_quat), 129.45, 129.63 (C_quat), 144.31

1

evaporated to yield product 8 as a colorless oil (727 mg, 93%). H

3

NMR (400 MHz, CDCl₃): δ = 1.34–1.36 (m, 1 H), 1.86 (dt, J =

5.22, ³J = 6.75 Hz, 2 H, CH₂), 2.02–2.12 (m, 1 H), 3.39 (t, ³J =

6.82 Hz, 2 H, CH₂), 3.73–3.80 (m, 2 H, CH₂), 4.08–4.12 (m, 2 H,

CH₂), 4.66 (m, 1 H, CH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

(C_quat), 144.35 (C_quat) ppm. IR: ν = 2967, 2862, 2153, 1459 cm^–1.

˜

HR-MS (ESI+): calcd. for C₂₇H₄₃N₃SiNa [M + Na]⁺460.3124;

found 460.3149.

25.69, 34.46, 46.58, 66.88 (2 C), 99.42 ppm. IR: ν = 2961, 2857,

˜

2093, 1138 cm^–1. MS (EI+): m/z (%) = 87.1 (100) [M – C₂H₄N₃]⁺.

4-(2-Ethyl-4-ethynylphenyl)-1-isobutyl-1H-1,2,3-triazole (18a): The

2-Azido-4-isopropyl-1-methylbenzene (9): 5-Isopropyl-2-methyl- synthesis of compound 18a was according to GP6, by dissolving

aniline (500 mg, 3.35 mmol, 1.0 equiv.) was dissolved in a 1:1 mix-

ture of concentrated hydrochloric acid (10 mL)/H₂O (10 mL). The

solution was cooled in an ice/NaCl bath, and an aqueous NaNO₂

solution (347 mg, 5.03 mmol, 1.5 equiv; in 6 mL of H₂O) was

slowly added dropwise. After the mixture had been stirred at that

17a (156 mg, 0.38 mmol) in THF (15 mL) and adding TBAF solu-

tion (1 m in THF, 0.76 mL, 0.76 mmol). After the mixture had been

stirred at room temp. for 1 h, TLC showed full conversion, and the

reaction mixture was worked up. The crude product was purified

by flash column chromatography on silica gel (hexanes/AcOEt, 4:1;

Eur. J. Org. Chem. 2011, 2474–2490

www.eurjoc.org

2483

I. Ehlers, P. Maity, J. Aubé, B. König

FULL PAPER

R_f= 0.27) to yield 18a (105 mg, 100%) as a white solid. M.p. 64 °C.

ArH), 7.43 (s, 1 H, ArH), 7.45–7.49 (m, 2 H, ArH), 7.54 (s, 1 H,

¹H NMR (400 MHz, CDCl₃): δ = 0.98 (d, ³J = 6.56 Hz, 6 H, CH₃), ArH), 7.72–7.74 (m, 1 H, ArH), 7.78 (s, 1 H, ArH), 7.79–7.81 (m,

1.20 (t, ³J = 7.57 Hz, 3 H, CH₃), 2.27 (sept, ³J = 6.82 Hz, 1 H,

2 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.20, 19.74,

26.81, 29.80, 52.12, 57.56, 122.82, 126.37, 127.34 (C_quat), 124.79,

126.33, 126.37, 126.41, 126.46, 127.66, 127.88, 128.77, 130.60

(C_quat), 132.92 (C_quat), 133.06 (C_quat), 133.16 (C_quat), 143.84 (C_quat),

3

CH), 2.81 (q, J = 7.49 Hz, 2 H, CH₂), 3.10 (s, 1 H, CH), 4.22 (d,

4

3

³J = 7.07 Hz, 2 H, CH₂), 7.38 (dd, J = 1.64, J = 7.95 Hz, 1 H,

4

ArH), 7.44 (d, J = 1.26 Hz, 1 H, ArH), 7.60 (s, 1 H, ArH), 7.62

(d, J = 8.08 Hz, 1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃):

145.11 (C_quat), 145.15 (C_quat) ppm. IR: ν = 2967, 2873, 1462,

3

˜

δ = 14.91, 19.83, 26.59, 29.74, 57.56, 77.44, 83.66 (C_quat), 121.85

1454 cm^–1. HR-MS (ESI+): calcd. for C₂₉H₃₃N₆[M + H]⁺

(C_quat), 122.11, 129.35, 129.58, 130.14 (C_quat), 132.73, 141.92 465.2767; found 465.2759.

(C_quat), 146.17 (C_quat) ppm. IR: ν = 3283, 2968, 2875, 1450 cm^–1.

˜

4-[4-(3-Benzyl-3H-1,2,3-triazol-4-yl)-2-ethylphenyl]-1-isobutyl-1H-

1,2,3-triazole (20): Compound 20 was synthesized according to

GP7, from the alkyne 18a (100 mg, 0.39 mmol), the azide 11

HR-MS (ESI+): calcd. for C₁₆H₂₀N₃[M + H]⁺254.1657; found

254.1663.

4-(2,6-Diethyl-4-ethynylphenyl)-1-isobutyl-1H-1,2,3-triazole (18b): (53 mg, 0.39 mmol), cp*RuCl(PPh₃)₂(16 mg, 20 μmol), and diox-

The synthesis of compound 18b was according to GP6, by dissolv-

ing 17b (350 mg, 0.80 mmol) in THF (20 mL) and adding TBAF

solution (1 m in THF, 1.6 mL, 1.6 mmol). After the mixture had

been stirred at room temp. for 1 h, TLC showed full conversion,

and the reaction mixture was worked up. The crude product was

purified by flash column chromatography on silica gel (hexanes/

ane (2.5 mL). Purification by flash column chromatography on sil-

ica gel (hexanes/AcOEt, 1:1; R_f= 0.40) yielded 20 as a brown vis-

cous oil (119 mg, 79%). ¹H NMR (400 MHz, CDCl₃): δ = 1.00 (d,

³J = 6.82 Hz, 6 H, CH₃), 1.12 (t, ³J = 7.57 Hz, 3 H, CH₃), 2.29

3

(sept, J = 6.82 Hz, 1 H, CH), 2.80 (q, J = 7.49 Hz, 2 H, CH₂),

3

4.24 (d, J = 7.32 Hz, 2 H, CH₂), 5.57 (s, 2 H, CH₂), 7.11–7.13 (m,

AcOEt, 4:1; R_f= 0.31) to yield 18b (209 mg, 96%) as a yellow oil. 2 H, ArH), 7.15–7.18 (m, 2 H, ArH), 7.29–7.30 (m, 3 H, ArH),

3

¹H NMR (400 MHz, CDCl₃): δ = 0.98 (d, ³J = 6.82 Hz, 6 H, CH₃), 7.62 (s, 1 H, ArH), 7.72 (d, J = 7.83 Hz, 1 H, ArH), 7.77 (s, 1 H,

3

1.04 (t, J = 7.57 Hz, 6 H, CH₃), 2.24–2.32 (m, 1 H, CH), 2.38 (q, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.80, 19.82, 26.65,

3

³J = 7.49 Hz, 4 H, CH₂), 3.08 (s, 1 H, CH), 4.25 (d, J = 7.32 Hz,

29.73, 51.84, 57.57, 122.21, 126.30, 126.62 (C_quat), 127.05, 128.11,

128.80, 129.45, 129.90, 130.81 (C_quat), 133.22, 135.59 (C_quat),

2 H, CH₂), 7.28 (s, 2 H, ArH), 7.42 (s, 1 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 15.30, 19.76, 26.75, 29.81, 57.54, 77.20, 137.93 (C_quat), 142.57 (C_quat), 145.82 (C_quat) ppm. IR: ν = 2961,

˜

83.92 (C_quat), 122.41 (C_quat), 122.81, 129.48, 129.66 (C_quat), 144.15

2868, 1454 cm^–1. HR-MS (ESI+): calcd. for C₂₃H₂₇N₆[M + H]⁺

(C_quat), 144.45 (C_quat) ppm. IR: ν = 3285, 2967, 2873, 1465 cm^–1. 387.2297; found 387.2303.

˜

HR-MS (ESI+): calcd. for C₁₈H₂₄N₃[M + H]⁺282.1970; found

3-(2-{5-[3-Ethyl-4-(1-isobutyl-1H-1,2,3-triazol-4-yl)phenyl]-1H-

282.1969.

1,2,3-triazol-1-yl}ethyl)-1H-indole (21): Compound 21 was synthe-

sized according to GP7, from the alkyne 18a (100 mg, 0.39 mmol),

the azide 12 (74 mg, 0.39 mmol), cp*RuCl(PPh₃)₂(16 mg,

20 μmol), and dioxane (2.5 mL). Purification by flash column

4-{2-Ethyl-4-[3-(naphthalen-2-ylmethyl)-3H-1,2,3-triazol-4-yl]-

phenyl}-1-isobutyl-1H-1,2,3-triazole (19a): Compound 19a was syn-

thesized according to GP7, from the alkyne 18a (100 mg,

0.39 mmol), the azide 10 (73 mg, 0.39 mmol), cp*RuCl(PPh₃)₂chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.21)

(16 mg, 20 μmol), and dioxane (2.5 mL). Purification by flash col-

umn chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.31)

yielded 19a as a slightly orange solid (160 mg, 89%). M.p. 139 °C.

yielded 21 as a brown viscous oil (91 mg, 54 %). ¹H NMR

3

(400 MHz, CDCl₃): δ = 1.00 (d, J = 6.82 Hz, 6 H, CH₃), 1.10 (t,

3

³J = 7.57 Hz, 3 H, CH₃), 2.29 (sept, J = 6.82 Hz, 1 H, CH), 2.68

¹H NMR (400 MHz, CDCl₃): δ = 0.99 (d, ³J = 6.56 Hz, 6 H, CH₃), (q, ³J = 7.49 Hz, 2 H, CH₂), 3.37 (t, ³J = 7.19 Hz, 2 H, CH₂), 4.24

1.05 (t, ³J = 7.57 Hz, 3 H, CH₃), 2.28 (sept, ³J = 6.82 Hz, 1 H,

(d, ³J = 7.32 Hz, 2 H, CH₂), 4.63 (t, ³J = 7.19 Hz, 2 H, CH₂), 6.79

3

CH), 2.75 (q, J = 7.57 Hz, 2 H, CH₂), 4.24 (d, J = 7.32 Hz, 2 H, (d, J_CH,NH= 2.27 Hz, 1 H, ArH), 6.88 (d, ⁴J = 1.51 Hz, 1 H,

4

3

CH₂), 5.72 (s, 2 H, CH₂), 7.15 (d, J = 1.51 Hz, 1 H, ArH), 7.18

ArH), 6.94 (dd, J = 1.76, J = 7.83 Hz, 1 H, ArH), 7.01 (dd, J =

(dd, ⁴J = 1.89, J = 7.95 Hz, 1 H, ArH), 7.30 (dd, J = 1.76, J =

7.07, ³J = 7.32 Hz, 1 H, ArH), 7.12 (dd, J = 7.07, J = 7.32 Hz, 1

3

8.58 Hz, 1 H, ArH), 7.44–7.49 (m, 2 H, ArH), 7.52 (s, 1 H, ArH), H, ArH), 7.25 (d, J = 7.07 Hz, 1 H, ArH), 7.30 (d, J = 8.08 Hz,

7.60 (s, 1 H, ArH), 7.70 (d, ³J = 7.83 Hz, 1 H, ArH), 7.72–7.73 (m,

1 H, ArH), 7.79–7.82 (m, 2 H, ArH), 7.80 (s, 1 H, ArH) ppm. ¹³C 7.65 (s, 1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.16,

NMR (100 MHz, CDCl₃): δ = 14.80, 19.84, 26.65, 29.76, 52.09, 19.85, 26.43, 26.68, 29.77, 48.79, 57.61, 111.17, 111.25 (C_quat),

1 H, ArH), 7.60 (d, J = 7.83 Hz, 1 H, ArH), 7.60 (s, 1 H, ArH),

3

57.61, 122.20, 124.70, 126.30, 126.34, 126.35, 126.47, 127.66, 118.14, 119.60, 122.09, 122.17, 122.45, 126.20, 126.83 (C_quat),

127.89, 128.80, 126.68 (C_quat), 129.55, 129.96, 130.86 (C_quat), 127.00 (C_quat), 129.30, 129.87, 130.46 (C_quat), 132.85, 136.08

132.91 (C_quat), 132.98 (C_quat), 133.16 (C_quat), 133.29, 138.05 (C_quat), (C_quat), 138.10 (C_quat), 142.61 (C_quat), 145.93 (C_quat) ppm. IR: ν

˜

142.64 (C_quat), 145.85 (C_quat) ppm. IR: ν = 2953, 2872, 1466,

= 3390, 2961, 2873, 1456, 1226 cm^–1. HR-MS (ESI+): calcd. for

C₂₆H₃₀N₇[M + H]⁺440.2563; found 440.2560.

˜

1427 cm^–1. HR-MS (ESI+): calcd. for C₂₇H₂₉N₆[M + H]⁺

437.2454; found 437.2456.

1-(3-tert-Butoxypropyl)-4-{3-methyl-4-[(triisopropylsilyl)ethynyl]-

4-{2,6-Diethyl-4-[3-(naphthalen-2-ylmethyl)-3H-1,2,3-triazol-4- phenyl}-1H-1,2,3-triazole (22a): The synthesis of compound 22a

yl]phenyl}-1-isobutyl-1H-1,2,3-triazole (19b): Compound 19b was

synthesized according to GP7, from the alkyne 18b (89 mg,

was according to GP5, by dissolving the alkyne 6d (720 mg,

2.43 mmol) in methanol (15 mL) and using the azide 29 (420 mg,

0.33 mmol), the azide 10 (61 mg, 0.33 mmol), cp*RuCl(PPh₃)₂2.67 mmol) and aqueous solutions of ascorbic acid (43 mg,

(13 mg, 17 μmol), and dioxane (2.5 mL). Purification by flash col-

umn chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.31)

0.24 mmol) and CuSO₄·5H₂O (12 mg, 0.049 mmol). TLC (hexanes/

AcOEt, 2:1; R_f= 0.43) showed complete conversion after stirring

yielded 19b as a white solid (130 mg, 87%). M.p. 101 °C. ¹H NMR at room temp. overnight. The crude product was purified by flash

3

(400 MHz, CDCl₃): δ = 0.98 (d, J = 6.82 Hz, 6 H, CH₃), 0.91 (t,

column chromatography on silica gel (hexanes/AcOEt, 2:1). As

³J = 7.45 Hz, 6 H, CH₃), 2.17–2.30 (m, 1 H, CH), 2.34 (q, ³J = product, 22a was obtained as a yellow oil (960 mg, 87%). ¹H NMR

7.57 Hz, 4 H, CH₂), 4.26 (d, ³J = 7.07 Hz, 2 H, CH₂), 5.71 (s, 2 H, (300 MHz, CDCl₃): δ = 1.14–1.16 (m, 21 H, iPr), 1.18 (s, 9 H, tBu),

3

CH₂), 7.00 (s, 2 H, ArH), 7.32 (dd, J = 1.89, J = 8.46 Hz, 1 H, 2.16 (tt, J = 6.17, J = 6.26 Hz, 2 H, CH₂), 2.50 (s, 3 H, ArCH₃),

2484

www.eurjoc.org

Eur. J. Org. Chem. 2011, 2474–2490

Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

3

3.38 (t, J = 5.62 Hz, 2 H, CH₂), 4.50 (t, J = 6.86 Hz, 2 H, CH₂),

7.49 (d, ³J = 7.95 Hz, 1 H, ArH), 7.55 (dd, ⁴J = 1.23, ³J = 8.09 Hz,

2:1; R_f= 0.34) yielded 24b as a white solid (282 mg, 57%). M.p.

1

67 °C. H NMR (400 MHz, CDCl₃): δ = 1.14–1.15 (m, 21 H, iPr),

1 H, ArH), 7.71–7.73 (m, 1 H, ArH), 7.78 (s, 1 H, ArH) ppm. ¹³C 1.25 (t, J = 7.57 Hz, 3 H, CH₃), 1.29 (t, J = 7.45 Hz, 3 H, CH₃),

3

NMR (75 MHz, CDCl₃): δ = 11.30, 18.67, 20.95, 27.48, 30.96, 1.33–1.37 (m, 1 H), 2.02–2.14 (m, 1 H), 2.25 (dt, ³J = 5.05, J =

3

47.59, 57.58, 72.96 (C_quat), 95.32 (C_quat), 105.62 (C_quat), 120.22, 7.19 Hz, 2 H, CH₂), 2.87 (q, J = 7.57 Hz, 2 H, CH₂), 2.89 (q, J

122.58, 122.98 (C_quat), 126.37, 130.41 (C_quat), 132.80, 141.14 = 7.57 Hz, 2 H, CH₂), 3.71–3.78 (m, 2 H, CH₂), 4.08–4.14 (m, 2

(C_quat), 147.01 (C_quat) ppm. IR: ν = 2941, 2865, 2152, 1462, 1363, H, CH₂), 4.39 (t, J = 7.19 Hz, 2 H, CH₂), 4.62 (t, J = 4.92 Hz, 1

3

˜

1196 cm^–1. UV/Vis (CHCl₃): λ_max(lgε) = 285 nm (4.618). MS (EI):

m/z (%) = 410.3 (100) [M – C₃H₇]⁺, 453.3 (45) [M]⁺. HR-MS (EI):

calcd. for C₂₇H₄₃N₃OSi [M]⁺453.3175; found 453.3171.

C₂₇H₄₃N₃OSi (453.7): calcd. C 71.47, H 9.55, N 9.26; found C

70.72, H 9.80, N 9.09.

H, CH), 7.43 (dd, J = 1.76, J = 7.83 Hz, 1 H, ArH), 7.52 (d, J

4

3

= 7.83 Hz, 1 H, ArH), 7.62 (d, J = 1.51 Hz, 1 H, ArH) ppm. ¹³C

4

NMR (100 MHz, CDCl₃): δ = 11.36, 13.39, 14.92, 16.40, 18.67,

25.65, 28.02, 35.34, 42.76, 66.84 (2 C), 94.74 (C_quat), 99.07, 105.41

(C_quat), 121.86 (C_quat), 123.83, 126.60, 131.85 (C_quat), 133.03,

134.74 (C_quat), 143.42 (C_quat), 147.02 (C_quat) ppm. IR: ν = 2935,

˜

1-[2-(1,4-Dioxan-2-yl)ethyl]-4-{3-ethyl-4-[(triisopropylsilyl)ethyn-

yl]phenyl}-1H-1,2,3-triazole (22b): The synthesis of compound 37

was according to GP5, by dissolving the alkyne 6c (1.86 g,

6.00 mmol) and the azide 8 (1.04 g, 6.60 mmol) in methanol

(50 mL) and using aqueous solutions of sodium ascorbate (119 mg,

0.60 mmol) and CuSO₄·5H₂O (30 mg, 0.12 mmol). TLC showed

complete conversion after the mixture had been stirred at room

temp. overnight followed by at 60 °C for 3 h. The crude product

was purified by flash column chromatography on silica gel (hex-

anes/AcOEt, 2:1; R_f= 0.28). Product 22b was obtained as a white

2863, 2153, 1462, 1144 cm^–1. HR-MS (ESI+): calcd. for

C₂₉H₄₆N₃O₂Si [M + H]⁺496.3359; found 496.3362.

2-(3-[2-(1,4-Dioxan-2-yl)ethyl]-5-{3-ethyl-4-[(triisopropylsilyl)-

ethynyl]phenyl}-3H-1,2,3-triazol-4-yl)propan-2-ol (25b): The synthe-

sis was according to GP8, by dissolving the triazole 22b (351 mg,

0.75 mmol) in dry THF (20 mL) and using nBuLi (2.5 m solution in

hexanes, 0.45 mL, 1.2 mmol) and dry acetone (0.22 mL, 3.0 mmol).

Purification by flash column chromatography on silica gel (hex-

anes/AcOEt, 2:1; R_f= 0.16) yielded 25b as a white solid (204 mg,

1

solid (2.66 g, 95%). M.p. 56 °C. H NMR (400 MHz, CDCl₃): δ =

52%). M.p. 112 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.14–1.15

3

1.14–1.15 (m, 21 H, iPr), 1.28 (t, ³J = 7.45 Hz, 3 H, CH₃), 1.35 (m, (m, 21 H, iPr), 1.24 (t, J = 7.57 Hz, 3 H, CH₃), 1.33–1.37 (m, 1

3

1 H), 2.02–2.14 (m, 1 H), 2.23 (dt, ³J = 4.80, J = 7.07 Hz, 2 H, H), 1.48 (s, 6 H, CH₃), 2.02–2.15 (m, 1 H), 2.32 (dt, J = 4.88, J

CH₂), 2.88 (q, J = 7.57 Hz, 2 H, CH₂), 3.71–3.77 (m, 2 H, CH₂), = 7.13 Hz, 2 H, CH₂), 2.53 (br. s, 1 H, OH), 2.85 (q, ³J = 7.57 Hz,

3

4.08–4.14 (m, 2 H, CH₂), 4.53 (t, J = 7.19 Hz, 2 H, CH₂), 4.57 (t, 2 H, CH₂), 3.73–3.80 (m, 2 H, CH₂), 4.08–4.12 (m, 2 H, CH₂), 4.70

3

³J = 4.92 Hz, 1 H, CH), 7.49 (d, ³J = 8.08 Hz, 1 H, ArH), 7.56 (t, J = 4.80 Hz, 1 H, CH), 4.78 (t, J = 7.19 Hz, 2 H, CH₂), 7.12

4

3

4

3

4

(dd, J = 1.76, J = 8.08 Hz, 1 H, ArH), 7.72 (d, J = 1.26 Hz, 1 (dd, J = 1.76, J = 7.83 Hz, 1 H, ArH), 7.21 (d, J_2,6= 1.51 Hz,

H, ArH), 7.76 (s, 1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): 1 H, ArH), 7.47 (d, ³J = 7.83 Hz, 1 H, ArH) ppm. ¹³C NMR

δ = 11.36, 14.96, 18.66, 25.62, 28.03, 35.39, 45.44, 66.86, 94.87

(C_quat), 98.92, 105.32 (C_quat), 120.09, 122.33 (C_quat), 122.73, 125.13,

(100 MHz, CDCl₃): δ = 11.35, 14.86, 18.66, 25.62, 27.85, 31.65,

35.80, 45.72, 66.86 (2 C), 69.36 (C_quat), 94.95 (C_quat), 99.81, 105.17

(C_quat), 122.64 (C_quat), 127.45, 129.93, 132.42, 133.41 (C_quat),

130.59 (C_quat), 133.22 (C_quat), 147.27 (C_quat) ppm. IR: ν = 2956,

˜

2862, 2148, 1462, 1144 cm^–1. HR-MS (ESI+): calcd. for

C₂₇H₄₂N₃O₂Si [M + H]⁺468.3100; found 497.3129.

138.58 (C_quat), 143.40 (C_quat), 146.40 (C_quat) ppm. IR: ν = 3224,

˜

2958, 2864, 2151, 1461, 1148 cm^–1. HR-MS (ESI+): calcd. for

C₃₀H₄₈N₃O₃Si [M + H]⁺526.3465; found 526.3473.

1-(3-tert-Butoxypropyl)-5-methyl-4-{3-methyl-4-[(triisopropylsilyl)-

ethynyl]-phenyl}-1H-1,2,3-triazole (23a): The synthesis was accord-

ing to GP8, by dissolving the triazole 22a (910 mg, 2.01 mmol) in

dry THF (32 mL) under N₂and using nBuLi (1.6 m solution in

hexanes, 1.89 mL, 3.02 mmol) and iodomethane (0.50 mL,

8.0 mmol). Purification by flash column chromatography on silica

1-(3-tert-Butoxypropyl)-4-(4-ethynyl-3-methylphenyl)-5-methyl-1H-

1,2,3-triazole (26a): The synthesis of compound 26a was according

to GP6, by dissolving 23a (780 mg, 1.67 mmol) in THF (50 mL)

and adding TBAF solution (1 m in THF, 3.34 mL, 3.34 mmol). Af-

ter the mixture had been stirred at room temp. for 1.5 h, TLC (pe-

troleum ether/AcOEt, 1:1; R_f= 0.46) showed full conversion, and

gel (petroleum ether/AcOEt, 2:1; R_f= 0.32) yielded 23a as a white

1

solid (832 mg, 88%). M.p. 79 °C. H NMR (300 MHz, CDCl₃): δ the reaction mixture was worked up. The crude product was puri-

= 1.13–1.15 (m, 21 H, iPr), 1.17 (s, 9 H, tBu), 2.13 (m, 2 H, CH₂),

fied by flash column chromatography on silica gel (see TLC) to

yield 26a (493 mg, 95%) as a red-brown oil. H NMR (300 MHz,

CDCl₃): δ = 1.17 (s, 9 H, tBu), 2.13 (m, 2 H, CH₂), 2.48 (s, 3 H,

1

2.47 (s, 3 H, Ar-CH₃), 2.51 (s, 3 H, Ar-CH₃), 3.38 (t, ³J = 5.76 Hz,

3

4

2 H, CH₂), 4.38 (t, J = 6.99 Hz, 2 H, CH₂), 7.43 (dd, J = 1.23,

³J = 8.09 Hz, 1 H, ArH), 7.52 (d, J = 7.95 Hz, 1 H, ArH), 7.60– Ar-CH₃), 2.50 (s, 3 H, Ar-CH₃), 3.31 (s, 1 H, CH), 3.37 (t, ³J =

3

7.61 (m, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.22,

11.30, 18.67, 21.00, 27.48, 30.73, 45.00 57.64, 72.93 (C_quat), 95.16

(C_quat), 105.66 (C_quat), 122.47 (C_quat), 123.89, 127.88, 129.23

5.62 Hz, 2 H, CH₂), 4.38 (t, J = 6.99 Hz, 2 H, CH₂), 7.44 (dd, J

= 1.37, ³J = 7.95 Hz, 1 H, ArH), 7.52 (d, ³J = 7.95 Hz, 1 H, ArH),

7.61–7.63 (m, 1 H, ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

3

4

(C_quat), 131.64 (C_quat), 132.56, 140.94 (C_quat), 143.77 (C_quat) ppm. 9.22, 20.67, 27.48, 30.71, 45.01, 57.62, 72.95 (C_quat), 81.42, 82.43

IR: ν = 2937, 2863, 2148, 1362, 1199 cm^–1. UV/Vis (CHCl ): λ

(C_quat), 120.98 (C_quat), 123.96, 127.99, 129.32, 132.16 (C_quat),

˜

3

max

(lgε) = 280 nm (4.405). MS (EI-MS): m/z (%) = 424.3 (100) [M –

C₃H₇]⁺, 467.3 (50) [M]⁺. HR-MS (EI+): calcd. for C₂₈H₄₅N₃OSi

[M]⁺467.3332; found 467.3171. C₂₈H₄₅N₃OSi (467.7): calcd. C

71.90, H 9.70, N 8.98; found C 71.61, H 9.82, N 8.73.

132.75, 141.19 (C_quat), 143.62 (C_quat) ppm. IR: ν = 2971, 2153,

˜

1362, 1195, 1072 cm^–1. UV/Vis (CHCl₃): λ_max(lg ε) = 270 nm

(4.253). MS (ESI): m/z (%) = 312.0 (61) [M + H]⁺, 623.3.5 (100) [2

M + H]⁺. HR-MS (EI+): calcd. for C₁₉H₂₅N₃O [M]⁺311.1998;

found 311.1993.

1-[2-(1,4-Dioxan-2-yl)ethyl]-5-ethyl-4-{3-ethyl-4-[(triisopropylsilyl)-

ethynyl]-phenyl}-1H-1,2,3-triazole (24b): The synthesis was accord-

ing to GP8, by dissolving the triazole 22b (486 mg, 1.0 mmol) in

dry THF (20 mL) and using nBuLi (2.5 m solution in hexanes,

0.60 mL, 1.5 mmol) and iodoethane (0.33 mL, 4.0 mmol). Purifica-

tion by flash column chromatography on silica gel (hexanes/AcOEt,

1-[2-(1,4-Dioxan-2-yl)ethyl]-5-ethyl-4-(3-ethyl-4-ethynylphenyl)-

1H-1,2,3-triazole (27b): The synthesis of compound 27b was ac-

cording to GP6, by dissolving 24b (260 mg, 0.52 mmol) in THF

(15 mL) and adding TBAF solution (1 m in THF, 1.0 mL,

1.0 mmol). After the mixture had been stirred at room temp. for

Eur. J. Org. Chem. 2011, 2474–2490

www.eurjoc.org

2485

I. Ehlers, P. Maity, J. Aubé, B. König

FULL PAPER

1.5 h, TLC showed full conversion, and the reaction mixture was

worked up. The crude product was purified by flash column

chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.33) to

3-(4-{4-[1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl]-3-methyl-

phenyl}-5-methyl-1H-1,2,3-triazol-1-yl)propan-1-ol (29b): Com-

pound 29a (100 mg, 0.205 mmol) was dissolved in dioxane (7 mL),

and HCl (4 n, 1.1 mL) was added. The reaction mixture was heated

1

yield 27b (167 mg, 95%) as a white solid. M.p. 102 °C. H NMR

3

(400 MHz, CDCl₃): δ = 1.26 (t, J = 7.57 Hz, 3 H, CH₃), 1.29 (t, at reflux for 1.5 h. The solvent was evaporated to yield the dipro-

³J = 7.45 Hz, 3 H, CH₃), 1.33–1.37 (m, 1 H), 2.02–2.14 (m, 1 H), tonated chloride salt 29b as a white solid (80 mg, 91 %). M.p.

3

2.26 (dt, J = 4.88, J = 7.26 Hz, 2 H, CH₂), 2.87 (m, 4 H), 3.29 148 °C. ¹H NMR (300 MHz, CD₃OD): δ = 2.24–2.28 (m, 4 H),

(s, 1 H, CH), 3.71–3.78 (m, 2 H, CH₂), 4.08–4.12 (m, 2 H, CH₂), 2.60 (s, 3 H, Ar-CH₃), 2.70 (s, 3 H, Ar-CH₃), 3.69–3.70 (m, 4 H),

3

4.39 (t, J = 7.19 Hz, 2 H, CH₂), 4.61 (t, J = 4.80 Hz, 1 H, CH), 4.72–4.80 (m, 4 H), 7.71–7.76 (m, 2 H, ArH), 7.92 (d, ³J = 7.95 Hz,

7.44 (dd, ⁴J = 1.76, ³J = 7.83 Hz, 1 H, ArH), 7.52 (d, ³J = 7.83 Hz,

1 H, ArH), 8.76–8.82 (m, 1 H, ArH) ppm. ¹³C NMR (75 MHz,

1 H, ArH), 7.62 (d, ⁴J = 1.26 Hz, 1 H, ArH) ppm. ¹³C NMR

CD₃OD): δ = 9.48, 21.28, 32.78, 33.74, 49.49, 51.04, 59.41, 59.60,

(100 MHz, CDCl₃): δ = 13.39, 14.70, 16.38, 25.63, 27.62, 35.31, 127.54, 127.63, 128.11 (C_quat), 129.84 (C_quat), 131.68, 132.11,

42.75, 66.83 (2 C), 81.04, 82.21 (C_quat), 99.04, 120.39 (C_quat), 136.30 (C_quat), 139.72 (C_quat), 140.68 (C_quat), 144.29 (C_quat) ppm.

123.87, 126.59, 132.35 (C_quat), 133.13, 134.81 (C_quat), 143.26

IR: ν = 3379, 2188, 1866 cm^–1. UV/Vis (H O): λ_max(lgε) = 256 nm

˜

2

(C_quat), 147.22 (C_quat) ppm. IR: ν = 3280, 2972, 2851, 1459,

(4.355). MS (ESI): m/z (%) = 357.0 (100) [M + H]⁺, 713.3 (30) [2

M + H]⁺. HR-MS (EI+): calcd. for C₁₈H₂₄N₆O₂[M]⁺356.1961;

found 356.1958. C₁₈H₂₆N₆O₂Cl₂, (429.34): calcd. C 50.35, H 6.10,

N 19.57; found C 50.07, H 5.85, N 19.39.

˜

1144 cm^–1. HR-MS (ESI+): calcd. for C₂₀H₂₆N₃O₂[M + H]⁺

340.2014; found 340.2014.

2-{3-[2-(1,4-Dioxan-2-yl)ethyl]-5-(3-ethyl-4-ethynylphenyl)-3H-

1,2,3-triazol-4-yl}propan-2-ol (28b): The synthesis of compound 28b

was according to GP6, by dissolving 25b (191 mg, 0.36 mmol) in

THF (10 mL) and adding TBAF solution (1 m in THF, 0.72 mL,

0.72 mmol). After the mixture had been stirred at room temp. for

1.5 h, TLC showed full conversion, and the reaction mixture was

worked up. The crude product was purified by flash column

3-{2-[4-(4-{1-[2-(1,4-Dioxan-2-yl)ethyl]-5-ethyl-1H-1,2,3-triazol-4-

yl}-2-ethyl-phenyl)-1H-1,2,3-triazol-1-yl]ethyl}-1H-indole (30a): The

synthesis of compound 30a was according to GP5, by dissolving

the alkyne 27b (100 mg, 0.29 mmol) and the azide 12 (61 mg,

0.32 mmol) in methanol (5 mL) and using aqueous solutions of

sodium ascorbate (6 mg, 0.03 mmol) and CuSO₄·5H₂O (2 mg,

6 μmol). TLC showed complete conversion after the mixture had

chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.20) to

1

yield 28b (133 mg, 100%) as a white solid. M.p. 138 °C. H NMR been stirred at room temp. overnight. The crude product was puri-

(400 MHz, CDCl₃): δ = 1.25 (t, ³J = 7.57 Hz, 3 H, CH₃), 1.34–1.38

fied by flash column chromatography on silica gel (hexanes/AcO-

(m, 1 H), 1.48 (s, 6 H, CH₃), 2.04–2.15 (m, 1 H), 2.33 (dt, ³J = Etm, 1:4; R_f= 0.42). Product 30a was obtained as a white solid

3

5.05, J = 7.19 Hz, 2 H, CH₂), 2.49 (br. s, 1 H, OH), 2.84 (q, J =

(126 mg, 83%). M.p. 61 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.12

(t, ³J = 7.57 Hz, 3 H, CH₃), 1.27 (t, ³J = 7.57 Hz, 3 H, CH₃), 1.34–

1.38 (m, 1 H), 2.05–2.14 (m, 1 H), 2.27 (dt, ³J = 4.80, ³J = 7.19 Hz,

2 H, CH₂), 2.68 (q, ³J = 7.49 Hz, 2 H, CH₂), 2.89 (q, ³J = 7.66 Hz,

7.57 Hz, 2 H, CH₂), 3.29 (s, 1 H, CH), 3.74–3.80 (m, 2 H, CH₂),

3

4.09–4.13 (m, 2 H, CH₂), 4.71 (t, J = 4.92 Hz, 1 H, CH), 4.79 (t,

4

3

³J = 7.32 Hz, 2 H, CH₂), 7.14 (dd, J = 1.76, J = 7.83 Hz, 1 H,

ArH), 7.23 (d, J = 1.51 Hz, 1 H, ArH), 7.48 (d, J = 7.83 Hz, 1 2 H, CH₂), 3.44 (t, ³J = 6.69 Hz, 2 H, CH₂), 3.72–3.79 (m, 2 H,

4

3

H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.64, 25.61, CH₂), 4.09–4.13 (m, 2 H, CH₂), 4.40 (t, J = 7.32 Hz, 2 H, CH₂),

3

27.45, 31.64, 35.80, 45.72, 66.88 (2 C), 69.36 (C_quat), 81.24, 81.98

(C_quat), 99.81, 121.25 (C_quat), 127.55, 129.96, 132.53, 133.94 (C_quat),

4.62 (t, J = 4.92 Hz, 1 H, CH), 4.75 (t, J = 6.82 Hz, 2 H, CH₂),

3

6.89 (d, J_CH,NH= 2.27 Hz, 1 H, CH), 7.14 (t, J = 7.45 Hz, 1 H,

3

138.60 (C_quat), 143.29 (C_quat), 146.63 (C_quat) ppm. IR: ν = 3423,

Ar), 7.22 (t, J = 7.70 Hz, 1 H, ArH), 7.24 (s, 1 H, ArH), 7.39 (d,

˜

3204, 2962, 2866, 1461, 1135 cm^–1. HR-MS (ESI+): calcd. for

C₂₁H₂₈N₃O₃[M + H]⁺370.2131; found 370.2121.

³J = 8.08 Hz, 1 H, ArH), 7.50 (dd, J = 1.76, J = 8.08 Hz, 1 H,

4

3

ArH), 7.57 (d, J = 7.57 Hz, 1 H, ArH), 7.63 (d, J = 8.08 Hz, 1

H, ArH), 7.67 (d, J = 1.51 Hz, 1 H, ArH), 8.08 (br. s, 1 H, NH)

4

1-(3-tert-Butoxypropyl)-4-{4-[1-(3-tert-butoxypropyl)-1H-1,2,3-

triazol-4-yl]-3-methylphenyl}-5-methyl-1H-1,2,3-triazole (29a): The

synthesis of compound 29a was according to GP5, by dissolving

the alkyne 26a (447 mg, 1.43 mmol) in methanol (25 mL) and using

the azide 7 (248 mg, 1.58 mmol) and aqueous solutions of ascorbic

acid (25 mg, 0.14 mol) and CuSO₄·5H₂O (9 mg, 0.03 mmol). TLC

(AcOEt, R_f= 0.42) showed complete conversion after the mixture

had been stirred at room temp. overnight and at 40 °C for 2 h. The

crude product was purified by flash column chromatography on

silica gel (AcOEt). Product 29a was obtained as a white solid

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 13.44, 15.07, 16.37, 25.63,

26.62, 26.71, 35.32, 42.76, 50.74, 66.83 (2 C), 99.08, 111.25 (C_quat),

111.44, 118.20, 119.76, 122.36 (2 C), 122.71, 124.25, 126.78 (C_quat),

127.67, 128.81 (C_quat), 129.68, 131.59 (C_quat), 134.71 (C_quat), 136.31

(C_quat), 142.17 (C_quat), 143.56 (C_quat), 146.14 (C_quat) ppm. IR: ν

˜

= 3263, 2967, 2862, 1456, 1144 cm^–1. HR-MS (ESI+): calcd. for

C₃₀H₃₆N₇O₂[M + H]⁺526.2930; found 526.2919.

2-[3-[2-(1,4-Dioxan-2-yl)ethyl]-5-(4-{1-[2-(1H-indol-3-yl)ethyl]-1H-

1,2,3-triazol-4-yl}-3-ethylphenyl)-3H-1,2,3-triazol-4-yl]propan-2-ol

(482 mg, 72%). M.p. 139 °C. ¹H NMR (300 MHz, CDCl₃): δ = (30b): Compound 30b was synthesized according to GP5, by dis-

1.18, 1.19 (2 s, 18 H, 2 tBu), 2.10–2.23 (m, 4 H), 2.51, 2.53 (2 s, 6

H, 2 ArCH₃), 3.27–3.42 (m, 4 H), 4.40, 4.54 (2 t, J = 6.99, J =

solving the alkyne 28b (148 mg, 0.40 mmol) and the azide 12

(82 mg, 0.44 mmol) in methanol (10 mL) and using aqueous solu-

4

3

6.86 Hz, 4 H, 2 H₂), 7.55 (dd, J = 1.37, J = 7.95 Hz, 1 H, ArH), tions of sodium ascorbate (8 mg, 0.04 mmol) and CuSO₄·5H₂O

3

7.69–7.70 (m, 1 H, ArH), 7.71 (s, 1 H), 7.90 (d, J = 7.95 Hz, 1 H, (2 mg, 8 μmol). TLC showed complete conversion after the mixture

ArH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 9.21, 21.57, 27.49, had been stirred at room temp. overnight. The crude product was

30.73, 30.99, 44.99, 47.46, 57.59, 57.65, 72.93 (C_quat), 72.95 (C_quat),

purified by flash column chromatography on silica (hexanes/Ac-

122.19, 124.54, 128.95, 129.17 (C_quat), 129.24 (C_quat), 129.54, OEt, 1:4; R_f= 0.20). Product 30b was obtained as a white solid

131.36 (C_quat), 135.68 (C_quat), 143.89 (C_quat), 146.43 (C_quat) ppm.

(138 mg, 63%). M.p. 131 °C. ¹H NMR (400 MHz, CDCl₃): δ =

3

IR: ν = 2972, 1361, 1197, 1076 cm^–1. UV/Vis (MeCN): λ

(lgε)

0.97 (t, J = 7.45 Hz, 3 H, CH₃), 1.30–1.34 (m, 1 H), 1.41 (s, 6 H,

˜

max

= 270 nm (4.415). MS (ESI): m/z (%) = 469.1 (100) [M + H]⁺, 937.5

CH₃), 2.01–2.11 (m, 1 H), 2.27–2.32 (m, 2 H, CH₂), 2.55 (q, J =

3

(27) [2 M + H]⁺. HR-MS (EI+): calcd. for C_{2 6}H₄₀N₆O₂7.41 Hz, 2 H, CH₂), 3.36 (t, ³J = 6.44 Hz, 2 H, CH₂), 3.71–3.76

[M]⁺468.3213; found 468.3206. C₂₆H₄₀N₆O₂(468.6): calcd. C

66.64, H 8.60, N 17.93; found C 66.64, H 8.73, N 17.94.

(m, 2 H, CH₂), 4.05–4.09 (m, 3 H, CH₂, OH), 4.67–4.71 (m, 3 H,

3

CH, CH₂), 4.76 (t, ³J = 7.19 Hz, 2 H, CH₂), 6.72 (d, J_CH,NH

=

2486

www.eurjoc.org

Eur. J. Org. Chem. 2011, 2474–2490

Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

2.02 Hz, 1 H, ArH), 7.04–7.10 (m, 2 H, ArH), 7.13–7.17 (m, 3 H,

4-{3-Ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1-(5-isopropyl-2-

3

ArH), 7.35 (d, J = 8.08 Hz, 1 H, ArH), 7.44 (d, J = 7.83 Hz, 1 methylphenyl)-1H-1,2,3-triazole (32): Compound 32 was synthe-

3

H, ArH), 7.52 (d, J = 7.83 Hz, 1 H, ArH), 9.05 (br. s, 1 H, NH)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.95, 25.58, 26.31, 26.64,

31.48, 35.75, 45.83, 50.70, 66.75 (2 C), 68.94 (C_quat), 99.78, 110.56

(C_quat), 111.60, 117.97, 119.41, 121.98, 122.70, 123.06, 126.65

(C_quat), 127.69, 129.12, 129.34 (C_quat), 130.76, 133.76 (C_quat),

sized according to GP5, by dissolving the alkyne 6c (124 mg,

0.40 mmol) and the azide 9 (84 mg, 0.48 mmol) in methanol (6 mL)

and using aqueous solutions of sodium ascorbate (8 mg,

0.04 mmol) and CuSO₄·5H₂O (2 mg, 8 μmol). TLC showed com-

plete conversion after the mixture had been stirred at room temp.

136.37 (C_quat), 139.06 (C_quat), 141.61 (C_quat), 143.19 (C_quat), 145.81 overnight. The crude product was purified by flash column

(C_quat) ppm. IR: ν = 3396, 3289, 2963, 2865, 1457, 1143 cm^–1. HR-

chromatography on silica gel (hexanes/AcOEt, 2:1; R_f= 0.67).

˜

1

MS (ESI+): calcd. for C₃₁H₃₈N₇O₃[M + H]⁺556.3036; found

556.3029.

Product 32 was obtained as a yellow oil (170 mg, 87%). H NMR

(400 MHz, CDCl₃): δ = 1.15–1.16 (m, 21 H, iPr), 1.27 (d, ³J =

3

7.07 Hz, 6 H, CH₃), 1.31 (t, J = 7.57 Hz, 3 H, CH₃), 2.22 (s, 3 H,

Ar-CH₃), 2.91 (q, ³J = 7.49 Hz, 2 H, CH₂), 2.94 (sept, ³J = 6.97 Hz,

4-[4-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-ethylphenyl]-1-[2-(1,4-di-

oxan-2-yl)ethyl]-5-ethyl-1H-1,2,3-triazole (31a): The synthesis of

compound 31a was according to GP5, by dissolving the alkyne 27b

(97 mg, 0.28 mmol) and the azide 11 (42 mg, 0.31 mmol) in meth-

anol (3 mL) and using aqueous solutions of sodium ascorbate

(6 mg, 0.03 mmol) and CuSO₄·5H₂O (2 mg, 6 μmol). TLC showed

complete conversion after the mixture had been stirred at room

temp. overnight. The crude product was purified by flash column

chromatography on silica gel (hexanes/AcOEt, 1:4; R_f= 0.52).

Product 31a was obtained as a white solid (104 mg, 79%). M.p.

3

1 H, CH), 7.23 (s, 1 H, ArH), 7.29–7.30 (m, 2 H, ArH), 7.54 (d, J

= 7.83 Hz, 1 H, ArH), 7.65 (dd, ⁴J = 1.64, ³J = 7.95 Hz, 1 H, ArH),

7.82 (d, ⁴J = 1.26 Hz, 1 H, ArH), 7.97 (s, 1 H, ArH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 11.35, 14.98, 17.42, 18.66, 23.83,

28.04, 33.53, 95.00 (C_quat), 105.31 (C_quat), 121.39, 122.51 (C_quat),

122.84, 123.92, 125.25, 128.10, 130.31 (C_quat), 130.81 (C_quat),

131.35, 133.29, 136.28 (C_quat), 147.12 (C_quat), 147.35 (C_quat), 147.98

(C_quat) ppm. IR: ν = 2956, 2862, 2142, 1459 cm^–1. HR-MS (ESI+):

˜

calcd. for C₃₁H₄₄N₃Si [M + H]⁺486.3304; found 486.3306.

1

3

117 °C. H NMR (400 MHz, CDCl₃): δ = 1.22 (t, J = 7.45 Hz, 3

H, CH₃), 1.27 (t, ³J = 7.57 Hz, 3 H, CH₃), 1.34–1.37 (m, 1 H),

5-Ethyl-4-{3-ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1-(5-iso-

3

2.04–2.16 (m, 1 H), 2.26 (dt, J = 4.88, J = 7.19 Hz, 2 H, CH₂), propyl-2-methylphenyl)-1H-1,2,3-triazole (33): The synthesis was

2.85 (q, ³J = 7.41 Hz, 2 H, CH₂), 2.89 (q, ³J = 7.49 Hz, 2 H, CH₂),

3.71–3.78 (m, 2 H, CH₂), 4.08–4.12 (m, 2 H, CH₂), 4.40 (t, ³J =

according to GP8, by dissolving the triazole 32 (150 mg,

0.31 mmol) in dry THF (10 mL) and using nBuLi (1.6 m solution

in hexanes, 0.30 mL, 0.47 mmol) and iodoethane (0.10 mL,

1.24 mmol). Purification by flash column chromatography on silica

gel (hexanes/AcOEt, 4:1; R_f= 0.65) yielded 33 as a yellow oil

(128 mg, 80%). ¹H NMR (400 MHz, CDCl₃): δ = 1.06 (t, ³J =

7.57 Hz, 3 H, CH₃), 1.15–1.16 (m, 21 H, iPr), 1.27 (d, ³J = 7.07 Hz,

6 H, CH₃), 1.31 (t, ³J = 7.45 Hz, 3 H, CH₃), 2.04 (s, 3 H, Ar-CH₃),

3

7.19 Hz, 2 H, CH₂), 4.62 (t, J = 4.80 Hz, 1 H, CH), 5.61 (s, 2 H,

CH₂), 7.30–7.33 (m, 2 H, ArH), 7.36–7.42 (m, 3 H, ArH), 7.52 (dd,

3

⁴J = 1.89, J = 7.95 Hz, 1 H, ArH), 7.57 (s, 1 H, ArH), 7.68 (d, J

= 8.33 Hz, 1 H, ArH), 7.70 (d, J = 1.76 Hz, 1 H, ArH) ppm. ¹³C

4

NMR (100 MHz, CDCl₃): δ = 13.44, 15.11, 16.39, 25.64, 26.82,

35.34, 42.75, 54.16, 66.83 (2 C), 99.09, 121.61, 124.30, 127.77,

127.96, 128.73, 129.14, 128.63 (C_quat), 129.72, 131.82 (C_quat), 2.72 (q, ³J = 7.49 Hz, 2 H, CH₂), 2.92 (q, ³J = 7.66 Hz, 2 H, CH₂),

3

134.70 (C_quat), 134.78 (C_quat), 142.30 (C_quat), 143.56 (C_quat), 147.31 2.95 (sept, J = 7.01 Hz, 1 H, CH), 7.13 (s, 1 H, ArH), 7.32–7.33

(C_quat) ppm. IR: ν = 2967, 2854, 1457, 1126 cm^–1. HR-MS (ESI+):

(m, 2 H, ArH), 7.54–7.55 (m, 2 H, ArH), 7.74 (d, J_2,6= 1.01 Hz,

1 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 11.38, 12.96,

14.96, 16.83, 18.69 (2 C), 23.86, 28.07, 33.49, 94.84 (C_quat), 105.41

(C_quat), 121.98 (C_quat), 123.80, 125.39, 126.58, 128.62, 131.10,

131.66 (C_quat), 132.88 (C_quat), 133.11, 135.11 (C_quat), 136.17 (C_quat),

4

˜

calcd. for C₂₇H₃₃N₆O₂[M + H]⁺473.2665; found 473.2666.

1-[2-(1,4-Dioxan-2-yl)ethyl]-5-ethyl-4-{3-ethyl-4-[1-(naphthalen-2-yl-

methyl)-1H-1,2,3-triazol-4-yl]phenyl}-1H-1,2,3-triazole (31b): The

synthesis of compound 31b was according to GP5, by dissolving

the alkyne 27b (75 mg, 0.22 mmol) and the azide 10 (45 mg,

0.24 mmol) in methanol (3 mL) and using aqueous solutions of

sodium ascorbate (5 mg, 0.02 mmol) and CuSO₄·5H₂O (1 mg,

4 μmol). TLC showed complete conversion after the mixture had

been stirred at room temp. overnight. The crude product was puri-

fied by flash column chromatography on silica gel (hexanes/AcOEt,

1:4; R_f= 0.49). Product 31b was obtained as a white viscous oil

147.13 (C_quat), 147.88 (C_quat), 148.01 (C_quat) ppm. IR: ν = 2956,

˜

2862, 2148, 1459 cm^–1. HR-MS (ESI+): calcd. for C₃₃H₄₈N₃Si [M

+ H]⁺514.3618; found 497.3607.

5-Ethyl-4-(3-ethyl-4-ethynylphenyl)-1-(5-isopropyl-2-methylphenyl)-

1H-1,2,3-triazole (34): The synthesis of compound 34 was accord-

ing to GP6, by dissolving 33 (112 mg, 0.22 mmol) in THF (15 mL)

and adding TBAF solution (1 m in THF, 0.44 mL, 0.44 mmol). Af-

ter the mixture had been stirred at room temp. for 1 h, TLC showed

(66 mg, 59 %). ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (t, ³J =

3

7.57 Hz, 3 H, CH₃), 1.26 (t, J = 7.57 Hz, 3 H, CH₃), 1.35 (m, 1 full conversion, and the reaction mixture was worked up. The crude

H), 2.02–2.14 (m, 1 H), 2.26 (dt, ³J = 4.96, ³J = 7.26 Hz, 2 H, product was purified by flash column chromatography on silica gel

3

CH₂), 2.85 (q, ³J = 7.49 Hz, 2 H, CH₂), 2.89 (q, J = 7.57 Hz, 2 (hexanes/AcOEt, 4:1; R_f= 0.66) to yield 34 (67 mg, 85%) as a yel-

1

3

H, CH₂), 3.71–3.78 (m, 2 H, CH₂), 4.08–4.12 (m, 2 H, CH₂), 4.40

low oil. H NMR (400 MHz, CDCl₃): δ = 1.06 (t, J = 7.50 Hz, 3

3

(t, J = 7.19 Hz, 2 H, CH₂), 4.62 (t, J = 4.80 Hz, 1 H, CH), 5.78 H, CH₃), 1.26 (d, J = 6.82 Hz, 6 H, CH₃), 1.31 (t, J = 7.57 Hz,

(s, 2 H, CH₂), 7.41 (dd, J = 1.76, J = 8.33 Hz, 1 H, ArH), 7.50– 3 H, CH₃), 2.03 (s, 3 H, Ar-CH₃), 2.73 (q, ³J = 7.66 Hz, 2 H, CH₂),

4

3

7.53 (m, 3 H, ArH), 7.61 (s, 1 H, ArH), 7.67–7.70 (m, 2 H, ArH), 2.90 (q, ³J = 7.41 Hz, 2 H, CH₂), 2.93 (sept, ³J = 6.86 Hz, 1 H,

7.79 (s, 1 H, ArH), 7.82–7.88 (m, 3 H, ArH) ppm. ¹³C NMR

CH), 3.03 (s, 1 H, CH), 7.13 (s, 1 H, ArH), 7.31–7.32 (m, 2 H,

(100 MHz, CDCl₃): δ = 13.41, 15.09, 16.36, 25.61, 26.81, 35.32, ArH), 7.55–7.56 (m, 2 H, ArH), 7.75–7.76 (m, 1 H, ArH) ppm. ¹³

C

42.72, 54.33, 66.80 (2 C), 99.05, 121.70, 124.27, 125.21, 127.24,

126.68, 126.72, 127.72, 127.77, 127.90, 129.16, 128.60 (C_quat),

NMR (100 MHz, CDCl₃): δ = 12.93, 14.72, 16.75, 17.65, 23.79,

27.63, 33.43, 81.11, 82.16 (C_quat), 120.49 (C_quat), 123.79, 125.29,

129.71, 131.79 (C_quat), 132.12 (C_quat), 133.21 (C_quat), 133.21 (C_quat), 126.52, 128.61, 131.06, 132.11 (C_quat), 132.79 (C_quat), 133.16,

134.68 (C_quat), 142.28 (C_quat), 143.52 (C_quat), 147.35 (C_quat) ppm.

135.00 (C_quat), 136.22 (C_quat), 142.86 (C_quat), 147.27 (C_quat), 147.83

IR: ν = 2967, 2851, 1454, 1138 cm^–1. HR-MS (ESI+): calcd. for

(C_quat) ppm. IR: ν = 3285, 2956, 2873, 1456 cm^–1. HR-MS (ESI+):

˜

C₃₁H₃₅N₆O₂[M + H]⁺523.2821; found 523.2822.

calcd. for C₂₄H₂₈N₃[M + H]⁺358.2283; found 358.2279.

Eur. J. Org. Chem. 2011, 2474–2490

www.eurjoc.org

2487

I. Ehlers, P. Maity, J. Aubé, B. König

3-[2-(4-{2-Ethyl-4-[5-ethyl-1-(5-isopropyl-2-methylphenyl)-1H-1,2,3- 26.50, 28.85, 30.27, 47.82, 94.74 (C_quat), 105.37 (C_quat), 121.85

FULL PAPER

triazol-4-yl]phenyl}-1H-1,2,3-triazol-1-yl)ethyl]-1H-indole (35):

Compound 35 was synthesized according to GP5, by dissolving the

alkyne 34 (55 mg, 0.15 mmol) and the azide 12 (31 mg, 0.17 mmol)

in methanol (3 mL) and using aqueous solutions of sodium ascorb-

ate (3 mg, 15 μmol) and CuSO₄·5H₂O (1 mg, 3 μmol). TLC showed

complete conversion after the mixture had been stirred at room

temp. overnight. The crude product was purified by flash column

chromatography on silica gel (hexanes/AcOEt, 1:1; R_f= 0.46).

Product 35 was obtained as a white solid (63 mg, 77 %). M.p.

(C_quat), 123.80, 126.57, 131.82 (C_quat), 133.02, 134.39 (C_quat),

143.46 (C_quat), 147.01 (C_quat) ppm. IR: ν = 2934, 2868, 2148,

˜

1462 cm^–1. HR-MS (ESI+): calcd. for C₅₄H₈₅N₆Si₂[M + H]⁺

873.6374; found 873.6404.

1,8-Bis[5-ethyl-4-(3-ethyl-4-ethynylphenyl)-1H-1,2,3-triazol-1-yl]-

octane (38): The synthesis of compound 38 was according to GP6,

by dissolving 37 (114 mg, 0.13 mmol) in THF (10 mL) and adding

TBAF solution (1 m in THF, 0.26 mL, 0.26 mmol). After the mix-

ture had been stirred at room temp. for 1 h, TLC showed full con-

version, and the reaction mixture was worked up. The crude prod-

uct was purified by flash column chromatography on silica gel (hex-

anes/AcOEt, 2:1; R_f= 0.31) to yield 38 (99 mg, 95%) as an orange

1

3

161 °C. H NMR (400 MHz, CDCl₃): δ = 1.07 (t, J = 7.45 Hz, 3

3

H, CH₃), 1.13 (t, J = 7.57 Hz, 3 H, CH₃), 1.27 (d, J = 6.82 Hz,

3

6 H, CH₃), 2.04 (s, 3 H, CH₃), 2.69 (q, J = 7.49 Hz, 2 H, CH₂),

2.74 (q, ³J = 7.49 Hz, 2 H, CH₂), 2.95 (sept, ³J = 6.88 Hz, 1 H,

1

3

oil. H NMR (400 MHz, CDCl₃): δ = 1.24 (t, J = 7.70 Hz, 6 H,

3

CH), 3.43 (t, J = 6.69 Hz, 2 H, CH₂), 4.75 (t, J = 6.82 Hz, 2 H,

CH₂), 6.87 (d, J_CH,NH= 2.27 Hz, 1 H, ArH), 7.11–7.15 (m, 2 H,

ArH), 7.20 (t, J = 7.07 Hz, 1 H, ArH), 7.27 (s, 1 H, ArH), 7.30–

3

CH₃), 1.27 (t, J = 7.57 Hz, 6 H, CH₃), 1.33–1.37 (m, 8 H), 1.90–

3

1.97 (m, 4 H), 2.85 (q, ³J = 7.41 Hz, 4 H, CH₂), 2.86 (q, ³J =

3

7.41 Hz, 4 H, CH₂), 3.28 (s, 2 H, CH), 4.22–4.29 (m, 4 H), 7.42

3

7.32 (m, 2 H, ArH), 7.38 (d, J = 8.08 Hz, 1 H, ArH), 7.56 (d, J

= 7.83 Hz, 1 H, ArH), 7.60 (dd, ⁴J = 1.76, ³J = 8.08 Hz, 1 H, ArH),

7.67 (d, ³J = 8.08 Hz, 1 H, ArH), 7.78 (d, ⁴J = 1.26 Hz, 1 H, ArH),

8.47 (br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

12.99, 15.10, 16.76, 16.79, 23.82, 26.64, 26.70, 33.45, 50.75, 111.09

(C_quat), 111.49, 118.14, 119.67, 122.26, 122.41, 122.79, 124.20,

125.34, 126.76 (C_quat), 127.63, 128.59, 128.92 (C_quat), 129.74,

131.07, 131.37 (C_quat), 132.84 (C_quat), 135.11 (C_quat), 136.12 (C_quat),

136.33 (C_quat), 142.26 (C_quat), 143.21 (C_quat), 146.08 (C_quat), 147.84

4

3

(dd, J = 1.51, J = 8.08 Hz, 2 H, ArH), 7.51 (d, J = 7.83 Hz, 2

H, ArH), 7.62 (m, 2 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 13.39, 14.66, 16.51, 27.56, 26.43, 28.84, 30.19, 47.78, 81.05,

82.13 (C_quat), 120.35 (C_quat), 123.79, 126.50, 132.82 (C_quat), 133.07,

134.44 (C_quat), 143.24 (C_quat), 147.16 (C_quat) ppm. IR: ν = 3285,

˜

2967, 2857, 1456 cm^–1. HR-MS (ESI+): calcd. for C₃₆H₄₅N₆[M +

H]⁺561.3706; found 561.3707.

1,8-Bis[4-(4-{1-[2-(1H-indol-3-yl)ethyl]-1H-1,2,3-triazol-4-yl}-3-eth-

ylphenyl)-5-ethyl-1H-1,2,3-triazol-1-yl]octane (39): Compound 39

was synthesized according to GP5, by dissolving the alkyne 38

(85 mg, 0.11 mmol, 1.0 equiv.) and the azide 12 (44 mg, 0.23 mmol,

2.2 equiv.) in methanol (5 mL) and using aqueous solutions of so-

dium ascorbate (5 mg, 0.02 mmol, 0.2 equiv.) and CuSO₄·5H₂O

(2 mg, 5 μmol, 0.04 equiv.). TLC showed complete conversion after

the mixture had been stirred at room temp. The crude product was

purified by flash column chromatography on silica gel (hexanes/

AcOEt, 1:2; R_f= 0.10). Product 39 was obtained as a green-brown

oil (42 mg, 42%). ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (t, J =

7.45 Hz, 6 H, CH₃), 1.24 (t, ³J = 7.45 Hz, 6 H, CH₃), 1.33–1.38

(C_quat) ppm. IR: ν = 3263, 2961, 2868, 1456 cm^–1. HR-MS (ESI+):

˜

calcd. for C₃₄H₃₈N₇[M + H]⁺544.3189; found 544.3153.

1,8-Bis(4-{3-ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1H-1,2,3-

triazol-1-yl)octane (36): Compound 36 was synthesized according

to GP5, by dissolving the alkyne 6c (280 mg, 0.90 mmol, 2.1 equiv.)

and the azide 13 (83 mg, 0.42 mmol, 1.0 equiv.) in methanol (5 mL)

and using aqueous solutions of sodium ascorbate (16 mg,

0.08 mmol, 0.2 equiv.) and CuSO₄·5H₂O (4 mg, 17 μmol,

0.04 equiv.). TLC showed complete conversion after the mixture

had been stirred at room temp. The crude product was purified by

flash column chromatography on silica gel (hexanes/AcOEt, 2:1; R_f

= 0.31). Product 36 was obtained as a white solid (266 mg, 78%).

M.p. 119 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.13 (m, 42 H, iPr),

1.27 (t, J = 7.57 Hz, 6 H, CH₃), 1.30–1.33 (m, 8 H, CH₂), 1.88–

1.94 (m, 4 H, CH₂), 2.87 (q, J = 7.57 Hz, 4 H, CH₂), 4.35 (t, J =

3

(m, 8 H, CH₂), 1.89–1.96 (m, 4 H, CH₂), 2.63 (q, J = 7.57 Hz, 4

3

H, CH₂), 2.85 (q, J = 7.41 Hz, 4 H, CH₂), 3.40 (t, J = 6.56 Hz,

4 H, CH₂), 4.25 (t, ³J = 7.19 Hz, 4 H, NCH₂), 4.72 (t, ³J = 6.56 Hz,

3

4 H, NCH₃), 6.83 (d, J_N,H= 1.76 Hz, 2 H, ArH), 7.11 (dd, J =

6.94, ³J = 7.45 Hz, 2 H, ArH), 7.18 (dd, J = 7.45, J = 7.78 Hz, 2

H, ArH), 7.23 (s, 2 H, ArH), 7.36 (d, ³J = 8.08 Hz, 2 H, ArH),

7.47 (dd, ⁴J = 1.38, ³J = 7.95 Hz, 2 H, ArH), 7.53 (d, ³J = 7.83 Hz,

3

7.07 Hz, 4 H, NCH₂), 7.49 (d, J = 7.83 Hz, 2 H, ArH), 7.56 (dd,

⁴J = 1.76, ³J = 8.08 Hz, 2 H, ArH), 7.72 (d, ⁴J = 1.26 Hz, 2 H,

ArH), 7.75 (s, 2 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

11.31, 14.94, 18.62, 27.99, 26.18, 28.59, 30.15, 50.26, 94.86 (C_quat),

105.28 (C_quat), 119.67, 122.27 (C_quat), 122.67, 125.06, 130.54

3

2 H, ArH), 7.61 (d, J = 8.08 Hz, 2 H, ArH), 7.64 (m, 2 H, ArH),

8.70 (br. s, 2 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

13.46, 15.02, 16.50, 26.43, 26.57, 26.67, 28.78, 30.20, 47.81, 50.72,

110.91 (C_quat), 111.52, 118.08, 119.55, 122.14, 122.43, 122.86,

124.19, 126.73 (C_quat), 127.59, 128.80 (C_quat), 129.65, 131.53

(C_quat), 134.40 (C_quat) 136.34 (C_quat), 142.16 (C_quat), 143.59 (C_quat),

(C_quat), 133.18, 147.24 (C_quat), 147.27 (C_quat) ppm. IR: ν = 2939,

˜

2857, 2148, 1459 cm^–1. HR-MS (ESI+): calcd. for C₅₀H₇₆N₆Si₂Na

[M + Na]⁺839.5568; found 839.5545.

1,8-Bis(5-ethyl-4-{3-ethyl-4-[(triisopropylsilyl)ethynyl]phenyl}-1H-

1,2,3-triazol-1-yl)octane (37): The synthesis was according to GP8,

by dissolving the triazole 36 (220 mg, 0.27 mmol) in dry THF

(20 mL) and using nBuLi (1.6 m solution in hexanes, 0.51 mL,

0.81 mmol) and iodoethane (0.20 mL, 2.16 mmol). Purification by

flash column chromatography on silica gel (hexane/AcOEt, 2:1; R_f

= 0.44) yielded 37 as an orange oil (130 mg, 56 %). ¹H NMR

(400 MHz, CDCl₃): δ = 1.14–1.15 (m, 42 H, iPr), 1.24 (t, ³J =

7.57 Hz, 6 H, CH₃), 1.28 (t, ³J = 7.57 Hz, 6 H, CH₃), 1.35–1.40

(m, 8 H), 1.91–1.95 (m, 4 H), 2.85 (q, ³J = 7.49 Hz, 4 H, CH₂),

146.02 (C_quat) ppm. IR: ν = 3258, 2967, 2857, 1454 cm^–1. HR-MS

˜

(ESI+): calcd. for C₅₆H₆₅N₁₄[M + H]⁺933.5517; found 933.5461.

3-(Naphthalen-2-ylmethyl)benzaldehyde (42): In a microwave vial,

containing a stirring bar, Na₂CO₃(1.21 g, 11.4 mmol, 2.1 equiv.)

was dissolved in H₂O (5.5 mL). The benzyl chloride derivative 41

(852 mg, 5.44 mmol, 1.0 equiv.) and DME (11.0 mL) were added,

followed by 2-naphthylboronic acid (1.12 g, 6.53 mmol, 1.2 equiv.)

and Pd(PPh₃)₄(126 mg, 0.109 mmol, 2 mol-%). The reaction mix-

ture was heated in a microwave oven at 130 °C for 4 h. H₂O was

2.88 (q, ³J = 7.49 Hz, 4 H, CH₂), 4.25 (t, ³J = 7.32 Hz, 4 H, NCH₂), added to the solution, and the phases were separated. The aqueous

7.42 (dd, ⁴J = 1.76, ³J = 7.83 Hz, 2 H, ArH), 7.52 (d, ³J = 7.83 Hz,

2 H, ArH), 7.61 (d, ⁴J = 1.26 Hz, 2 H, ArH) ppm. ¹³C NMR

phase was extracted twice with AcOEt, and the combined organic

extracts were dried with MgSO₄. The solvent was evaporated, and

(100 MHz, CDCl₃): δ = 11.34, 13.42, 14.91, 16.57, 18.65, 28.01, the crude product was purified by flash column chromatography

2488 Eur. J. Org. Chem. 2011, 2474–2490

www.eurjoc.org

Modular Synthesis of Triazole-Containing Triaryl α-Helix Mimetics

on silica gel (hexanes/AcOEt, 8:1; R_f= 0.50). Compound 42 was

AcOEt, 4:1; R_f= 0.30) yielded 45 as a colorless oil (97 mg, 59%).

¹H NMR (400 MHz, CDCl₃): δ = 1.23–1.25 (m, 9 H), 1.86 (br. s,

1 H, OH), 2.04 (s, 3 H, CH₃), 2.92 (sept, J = 6.88 Hz, 1 H, CH),

obtained as a yellow oil (937 mg, 70 %). ¹H NMR (400 MHz,

4

3

CDCl₃): δ = 4.22 (s, 2 H, CH₂), 7.30 (dd, J = 1.64, J = 8.46 Hz,

1 H, ArH), 7.44–7.52 (m, 4 H, ArH), 7.64–7.65 (m, 1 H, ArH), 4.22 (s, 2 H, CH₂), 4.90–4.97 (m, 1 H, CH), 7.18–7.19 (m, 1 H,

7.72–7.82 (m, 5 H, ArH), 9.98 (s, 1 H, CHO) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 41.45, 125.59, 126.16, 127.24, 127.33,

127.53, 127.64, 127.87, 128.36, 129.18, 129.98, 132.16 (C_quat),

ArH), 7.27–7.32 (m, 3 H, ArH), 7.35–7.46 (m, 4 H, ArH), 7.69–

7.71 (m, 2 H, ArH), 7.74–7.80 (m, 4 H, ArH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 16.93, 23.79, 23.82, 33.42, 42.04, 61.01,

133.56 (C_quat), 135.14, 136.67 (C_quat), 137.55 (C_quat), 142.15 (C_quat), 125.35, 125.71, 125.98, 126.55, 127.24, 127.52, 127.58, 127.72,

192.42 ppm. IR: ν = 3049, 2824, 1695 cm^–1. HR-MS (EI+): calcd.

128.09, 128.69 (2ϫ), 128.84, 129.47, 131.01, 131.24 (C_quat), 132.05

(C_quat), 133.03 (C_quat), 133.57 (C_quat), 135.49 (C_quat), 136.35 (C_quat),

138.45 (C_quat), 141.42 (C_quat), 144.79 (C_quat), 147.69 (C_quat) ppm.

˜

for C₁₈H₁₄O [M]⁺246.1045; found 246.1039.

2-(3-Ethynylbenzyl)naphthalene (43): Diisopropylamine (0.62 mL,

4.34 mmol, 1.2 equiv.) was dissolved in dry THF (30 mL) under

argon in a flame-dried flask. The solution was cooled to –78 °C,

and nBuLi (1.6 m solution in hexanes, 2.72 mL, 4.34 mmol,

1.2 equiv.) was slowly added dropwise. After the mixture had been

stirred at that temp. for 10 min, TMSCHN₂(2 m solution in hex-

anes, 2.17 mL, 4.34 mmol, 1.2 equiv.) was slowly added. The reac-

tion mixture was stirred at –78 °C for 30 min, and a solution of the

aldehyde 42 (890 mg, 3.61 mmol, 1.0 equiv.) in dry THF (8 mL)

was added dropwise. After stirring at –78 °C for 1 h, the reaction

mixture was heated at reflux for 3 h. H₂O was added, and the

phases were separated. The aqueous phase was extracted twice with

diethyl ether. The combined organic extracts were dried with

MgSO₄and concentrated. Purification of the crude product by

flash column chromatography (hexanes/AcOEt, 10:1; R_f= 0.62)

IR: ν = 3307, 2962, 2927, 1508, 1454 cm^–1. HR-MS (ESI+): calcd.

˜

for C₃₁H₃₂N₃O [M + H]⁺462.2545; found 462.2527.

5-Ethyl-1-(5-isopropyl-2-methylphenyl)-4-[3-(naphthalen-2-

ylmethyl)phenyl]-1H-1,2,3-triazole (46): The synthesis was accord-

ing to GP8, by dissolving the triazole 44 (150 mg, 0.36 mmol) in

dry THF (15 mL) and using nBuLi (1.6 m solution in hexanes,

0.34 mL, 0.54 mmol) and iodoethane (0.12 mL, 1.4 mmol). Purifi-

cation by flash column chromatography on silica gel (hexanes/Ac-

1

OEt, 6:1; R_f= 0.34) yielded 46 as a colorless oil (87 mg, 56%). H

NMR (400 MHz, CDCl₃): δ = 0.92 (t, ³J = 7.57 Hz, 3 H, CH₃),

3

1.25 (d, J = 7.07 Hz, 6 H, CH₃), 2.01 (s, 3 H, Ar-CH₃), 2.62 (q,

3

³J = 7.57 Hz, 2 H, CH₂), 2.94 (sept, J = 6.88 Hz, 1 H, CH), 4.24

(s, 2 H, CH₂), 7.11–7.12 (m, 1 H, ArH), 7.25–7.30 (m, 3 H, ArH),

7.36–7.47 (m, 4 H, ArH), 7.64–7.66 (m, 1 H, ArH), 7.70–7.71 (m,

2 H, ArH), 7.63–7.80 (m, 3 H, ArH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 12.91, 16.68, 16.78, 23.82, 33.45, 42.07, 124.73, 125.34,

125.36, 125.95, 127.22, 127.52, 127.58, 127.67, 127.69, 128.10,

128.36, 128.52, 128.86, 131.02, 131.77 (C_quat), 132.08 (C_quat),

132.85 (C_quat), 133.60 (C_quat), 135.14 (C_quat), 135.94 (C_quat), 138.40

1

yielded 43 as a white solid (650 mg, 74%). M.p. 56 °C. H NMR

(400 MHz, CDCl₃): δ = 3.05 (s, 1 H, CH), 4.13 (s, 2 H, CH₂), 7.22–

7.49 (m, 7 H, ArH), 7.64–7.65 (m, 1 H, ArH), 7.77–7.83 (m, 3 H,

ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 41.47, 77.07, 83.69

(C_quat), 122.17 (C_quat), 125.45, 126.04, 127.16, 127.46, 127.53,

127.61, 128.20, 128.46, 129.61, 129.98, 132.10 (C_quat), 132.63,

(C_quat), 141.56 (C_quat), 143.42 (C_quat), 147.78 (C_quat) ppm. IR: ν

˜

= 3051, 2962, 2871, 1508, 1457 cm^–1. HR-MS (ESI+): calcd. for

C₃₁H₃₂N₃[M + H]⁺446.2596; found 446.2604.

133.55 (C_quat), 137.88 (C_quat), 141.18 (C_quat) ppm. IR: ν = 3289,

˜

3054, 2906, 1599, 1480 cm^–1. HR-MS (EI+): calcd. for C₁₉H₁₄

[M]⁺242.1096; found 242.1095.

Supporting Information (see footnote on the first page of this arti-

cle): Proton and carbon NMR spectra of selected compounds.

1-(5-Isopropyl-2-methylphenyl)-4-[3-(naphthalen-2-ylmethyl)phenyl]-

1H-1,2,3-triazole (44): Compound 44 was synthesized according to

GP5, by dissolving the alkyne 43 (600 mg, 2.47 mmol) and the az-

ide 9 (477 mg, 2.72 mmol) in methanol (40 mL) and using aqueous

solutions of sodium ascorbate (49 mg, 0.25 mmol) and

CuSO₄·5H₂O (13 mg, 49 μmol). TLC showed complete conversion

after the mixture had been stirred at room temp. overnight and at

65 °C for additional 2 h. The crude product was purified by flash

column chromatography on silica gel (hexanes/AcOEt, 6:1; R_f=

0.46). Product 44 was obtained as a viscous colorless oil (888 mg,

Acknowledgments

I. E. thanks the German Academic Exchange Service (DAAD) for

supporting her work at the University of Kansas with a scholar-

ship. In addition, we thank the National Institutes of General Med-

ical Sciences for financial support through the KU CMLD center

(P50GM-69663). Support of the work by the graduate training cen-

ter of the Deutsche Forschungsgemeinschaft (GRK 760) is ac-

knowledged.

1

3

86%). H NMR (400 MHz, CDCl₃): δ = 1.26 (d, J = 6.56 Hz, 6

3

H, CH₃), 2.20 (s, 3 H, CH₃), 2.94 (sept, J = 6.94 Hz, 1 H, CH),

4.22 (s, 2 H, CH₂), 7.22–7.25 (m, 2 H, ArH), 7.28–7.29 (m, 2 H,

ArH), 7.35–7.45 (m, 4 H, ArH), 7.68–7.69 (m, 1 H, ArH), 7.75–

7.81 (m, 4 H, ArH), 7.84–7.85 (m, 1 H, ArH), 7.91 (s, 1 H, ArH)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.40, 23.84, 33.52, 42.10,

121.23, 123.74, 123.96, 125.37, 125.98, 126.47, 127.13, 127.56 (2ϫ),

127.59, 128.04, 128.13, 129.06, 129.09, 130.63 (C_quat), 130.85

(C_quat), 131.32, 132.09 (C_quat), 133.59 (C_quat), 136.33 (C_quat), 138.37

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Published Online: March 18, 2011

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Article Doi

Modular synthesis of triazole-containing triaryl α-helix mimetics

DOI: 10.1002/ejoc.201001531

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Article abstract of DOI:10.1002/ejoc.201001531

Full text of DOI:10.1002/ejoc.201001531

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