Synthesis of tripodal and hexapodal pyrazole- and benzimidazole-bearing compounds

DOI: 10.1055/s-0033-1338518

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Synthesis p. 3341 - 3348 (2013)

Update date:2022-08-03

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Koch, Niklas

Mazik, Monika

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Article abstract of DOI:10.1055/s-0033-1338518

The syntheses of eight new tripodal and hexapodal benzimidazole- and pyrazole-bearing compounds, which are all potentially applicable for use as artificial receptors, are described. The prepared compounds contain either bromo-substituted heteroaromatic ri

Full text of DOI:10.1055/s-0033-1338518

PRACTICAL SYNTHETIC PROCEDURES

▌3341

practical synthetic procedures

Synthesis of Tripodal and Hexapodal Pyrazole- and Benzimidazole-Bearing

Compounds

Synthesis of Tripodal and Hexapodal Compounds

Niklas Koch, Monika Mazik*

Institut für Organische Chemie, Technische Universität Bergakademie Freiberg, Leipziger Strasse 29,

09596 Freiberg, Germany

Fax +49(3731)393170; E-mail: monika.mazik@chemie.tu-freiberg.de

PSP

Received: 30.04.2013; Accepted after revision: 11.07.2013

261

Abstract: The syntheses of eight new tripodal and hexapodal benzimidazole- and pyrazole-bearing compounds, which are all potentially

applicable for use as artificial receptors, are described. The prepared compounds contain either bromo-substituted heteroaromatic rings, able

to participate in halogen-bonding interactions, or their analogues lacking the bromo substituents. Furthermore, the preparation of a new tris-

benzimidazolium cage is included in this work. All used practical synthetic procedures are facilely accomplishable and provide the products

in good to excellent yields. In addition, slightly modified, simplified synthetic procedures for five known tripodal compounds, which lead

to better yields than those previously reported, are also detailed.

Key words: triethylbenzene scaffold, trimethoxybenzene scaffold, tripodal receptors, hexapodal receptors, cyclophanes

R¹

X =

R¹

R¹= H, Me

R¹

OMe

R¹

R = OMe

R = CH₂Br

procedure B

procedure A or B

X =

75–98%

87–96%

MeO

OMe

R¹= H, Br

R¹

R¹= H, Me

R¹

R¹= H, Me

R = Et

procedure C

procedure A, B or C

X =

77–96%

32%

R¹

3Br^–

X =

¹= H, Br

Scheme 1 Procedures for the practical preparation of tripodal and hexapodal pyrazole- and benzimidazole-bearing compounds

lecular chemistry. Compounds bearing heterocyclic rec-

ognition sites such as benzimidazole and pyrazole units

Introduction

The design and development of artificial tripodal recep- are reported to be effective in the molecular recognition of

tors for the selective recognition of cations, anions^1a,band ions.^1a,2–4Moreover, our group has shown that pyrazole-

neutral molecules^1c,drepresents an active area in supramo- and benzimidazole-based receptors are also useful in car-

bohydrate recognition for both neutral^5aand anionic sub-

strates.^5bIt should also be noted that a hexapodal receptor

SYNTHESIS 2013, 45, 3341–3348

bearing pyrazole units is reported to be effective in the

Advanced online publication: 29.08.2013

DOI: 10.1055/s-0033-1338518; Art ID: SS-2013-Z0324-PSP

recognition of ion pairs.⁶

3342

N. Koch, M. Mazik

PRACTICAL SYNTHETIC PROCEDURES

In this paper, we describe the syntheses of eight new benz- which are widely used as building blocks for supramolec-

imidazole- and pyrazole-based compounds that enforce ular systems. To provide a complete description of the

tripodal or hexapodal topologies (compounds 1–4, 6, 8, 12 preparation of the tripodal bromo-substituted derivatives

and 13; see Figure 1 and Scheme 1) and which are all po- and their non-brominated analogues, slightly modified

tentially applicable for use as artificial receptors. The pre- synthetic procedures for the known compounds 5, 7, 9–11

pared compounds contain either bromo-substituted are also included. In the case of the synthesis of com-

heteroaromatic rings, able to participate in halogen-bond- pound 7, we observed the formation of the previously un-

ing interactions, or their analogues lacking the bromo sub- reported trisbenzimidazolium cage 14 [prepared as the

stituents. The tripodal compounds are based on the tribromide salt 14a and the tris(hexafluorophosphate) salt

trimethoxybenzene or triethylbenzene scaffold, both of 14b], which is also part of this work.

MeO

OMe

MeO

OMe

MeO

OMe

MeO

·3X^–

14a: X^–= Br^–

14b: X^–= PF₆

–

Figure 1 Structures of the benzimidazole- and pyrazole-bearing compounds described in this work

Synthesis 2013, 45, 3341–3348

PRACTICAL SYNTHETIC PROCEDURES

Synthesis of Tripodal and Hexapodal Compounds

3343

The pyrazole-containing compounds 9–11 are reported to azole (19), 3,5-dimethyl-1H-pyrazole (20) and 1H-

be selective receptors for ammonium ions^2a,band have pyrazole (22) (see Scheme 2 and Scheme 3). The reaction

been used as building blocks in the self-assembly of a of hexakis(bromomethyl)benzene (23)¹¹with the bromo-

three-dimensional cage,⁷whereas compound 5 was de- substituted pyrazoles 18 and 19 gave the hexapodal com-

scribed as an intermediate in the synthesis of a phloroglu- pounds 12 and 13, respectively (see Scheme 4).

cinol model compound.⁸The benzimidazole-bearing

For the syntheses of compounds 1–13, we tested three

methods. In procedure A, adopted from a previously de-

compound 7 has been described as an anion receptor with

perchlorate binding preference.^2cThese previously report-

scribed synthesis of hexakis[(1H-pyrazol-1-yl)meth-

ed, interesting applications show the potential of these

yl]benzene,⁶the employed benzimidazole or pyrazole was

structurally rather simple molecules and clarifies the need

deprotonated with finely ground sodium hydroxide in

for facile syntheses of related compounds.

N,N-dimethylformamide (DMF) before reaction with the

corresponding bromomethyl-substituted benzene com-

pound (15, 21 or 23). The reaction mixture was stirred un-

der mild heating, then poured into ice water. While

Scope and Limitations

unreacted starting materials remain in the water/DMF

mixture, the desired products precipitate as fluffy solids

The tripodal compounds 1–11, containing a trimethoxy-

benzene- or triethylbenzene-derived core, were prepared

and can be easily collected by filtration with a Büchner

via reactions of 1,3,5-tris(bromomethyl)-2,4,6-trimeth-

funnel (to complete the precipitation, the mixtures can be

oxybenzene (15)⁹or 1,3,5-tris(bromomethyl)-2,4,6-trieth-

kept in a fridge overnight). To free the product from DMF,

the filter cake has to be washed thoroughly with water and

ylbenzene (21)¹⁰with commercially available

benzimidazole and pyrazole derivatives, such as 2-bromo-

then dried in a desiccator. With this procedure, the trieth-

1H-benzimidazole (16), 1H-benzimidazole (17), 4-bro-

ylbenzene-based compounds 8–10 and the hexapodal de-

mo-1H-pyrazole (18), 4-bromo-3,5-dimethyl-1H-pyr-

rivative 13 were synthesized in very good to excellent

MeO

OMe

MeO

OMe

MeO

B, 75%

88%

OMe

B, 98%

OMe

B, 86%

MeO

OMe

MeO

OMe

MeO

B, 77%

OMe

MeO

OMe

Scheme 2 Synthesis of the trimethoxybenzene-based compounds. Reagents and conditions: (B) NaH (4.5 equiv), MeCN, r.t.

Synthesis 2013, 45, 3341–3348

3344

N. Koch, M. Mazik

PRACTICAL SYNTHETIC PROCEDURES

90%

A, 93%

C, 77%

A, 96%

85%

32%

B, 89%

NaPF₆

MeOH

r.t., 24 h

75%

·3X^–

14a: X^–= Br^–

–

14b: X^–= PF₆

Scheme 3 Syntheses of the triethylbenzene-based compounds. Reagents and conditions: (A) NaOH (4 equiv), DMF, 70 °C; (B) NaH (4.5

equiv), MeCN, r.t.; (C) DIPEA (3.3 equiv), THF, MeCN, r.t.

A, 96%

B, 87%

Scheme 4 Syntheses of the pyrazole-bearing hexapodal compounds 12 and 13. Reagents and conditions: (A) NaOH (7 equiv), DMF, 70 °C;

(B) NaH (6.6 equiv), MeCN, r.t.

yields. The yield of 9 was 96%, raised from the literature of the trimethoxybenzene-containing compounds could

yields of 60%⁷and 65%,^2a,bwhile 10 was obtained in 85% be synthesized in satisfactory yields with this method.

yield in a single step, using the commercially available 4-

Procedure B revealed the most general application spec-

trum. It was possible to synthesize the tripodal triethyl-

benzene- and trimethoxybenzene-based compounds 1–5,

7 and 11, as well as the hexapodal compound 12, in good

bromo-3,5-dimethyl-1H-pyrazole (19), compared to the

earlier 71% yield in two steps.^2a,bCompounds 8 and 13

have not been previously reported. It is notable that none

Synthesis 2013, 45, 3341–3348

PRACTICAL SYNTHETIC PROCEDURES

Synthesis of Tripodal and Hexapodal Compounds

3345

to excellent yields. With procedure B, the yields of the starting materials provided the desired compounds in sim-

known compounds 5, 7 and 11 could be improved from ilarly high yields. The prepared compounds are able to

60% to 77% for 5,⁸from 85% to 90% for 7,^2cand from participate in multiple noncovalent interactions, including

73% to 89% for 11.^2a,bThis procedure is a modified ver- halogen-bonding interactions, and are all potentially ap-

sion of the procedure previously described for the synthe- plicable for use as artificial receptors.

sis of 5 and 9–11.^2a,b,8The deprotonation of the

heterocyclic unit with sodium hydride was undertaken in

MeCN and THF were purchased as ‘AcroSeal Extra Dry Solvents’

anhydrous acetonitrile before the corresponding bromo-

methyl-substituted benzene derivative was added, and the

mixture was stirred at room temperature under nitrogen

(in the synthesis reported previously, THF^2a,bor DMF⁸

was used as the solvent). Then, the reaction was quenched

by the addition of water, the mixture was extracted with

chloroform and the product was purified by flash chroma-

tography on silica gel using a chloroform–methanol mix-

ture as the eluent. In the case of 2, the addition of hexane

to the eluent was necessary for the complete separation

from the remaining 1H-benzimidazole (17).

from Acros Organics. DMF was dried over CaH₂and distilled under

N₂atmosphere before use. All other chemicals were commercially

available of reagent grade (Acros Organics, Sigma Aldrich or

ABCR) and used without further purification, unless otherwise not-

ed. Analytical TLC was performed on commercial Merck plates

coated with silica gel (TLC Silica Gel 60 F₂₅₄) and the silica gel used

for flash chromatography was Merck Kieselgel 60. Melting points

were measured on a Mettler Toledo MP50 Melting Point System

apparatus and are uncorrected. ¹H and ¹³C NMR spectra were deter-

mined for solutions in CDCl₃or DMSO-d₆with TMS, δ = 0.00 ppm

as an internal standard on Bruker DRX-400 ([¹H]: 399.97 MHz,

[¹³C]: 100.57; at 25 °C), Bruker AV III-400 ([¹H]: 400.40 MHz,

[¹³C]: 100.68 MHz; at 25 °C) and Bruker DRX-500 ([¹H]: 500.13

MHz, [¹³C]: 125.76 MHz; at 22 °C) instruments. HRMS data were

measured on Finnigan MAT 95x (EI-MS and EI-HRMS) and

Finnigan 95XL Thermo (ESI-HRMS) mass spectrometers. Elemen-

tal analyses were determined on an Elementar Analysesysteme

Vario Micro Cube.

The last method, procedure C, employs N,N-diisopropyl-

ethylamine (DIPEA) as the base and tetrahydrofuran–ace-

tonitrile as the solvent. This procedure emerged to be the

most facile one for the synthesis of compound 6, because

of the very easy workup, resulting from the precipitation

of the desired compound from the employed solvent mix-

ture during the reaction. The workup consisted only of

collection of the solid by filtration and washing with tet-

rahydrofuran. Although the yield of 77% is at the lower

end of the scale relative to other yields in this work, the

quick workup along with no need for further chromato-

graphic purification (such as in procedure B) makes this

route to 6 notable.

Compounds 8–10 and 13; General Procedure (Procedure A)

The corresponding pyrazole derivative 18, 19 or 22 (4 or 7 equiv)

was dissolved in alkaline DMF [containing NaOH (4 or 7 equiv)]

and the solution was stirred for 30 min at r.t. The bromomethyl-sub-

stituted benzene derivative 21 or 23 (1 equiv) was added and the re-

action mixture was stirred for 24–48 h at 70 °C. The solution was

cooled to r.t., then poured into ice water (50 mL), and the resulting

precipitate was collected by filtration, washed thoroughly with H₂O

(3 × 15 mL) and dried in a desiccator.

1,3,5-Tris[(4-bromo-1H-pyrazol-1-yl)methyl]-2,4,6-triethyl-

benzene (8)

The reaction of compound 21 (200 mg, 0.45 mmol) with 4-bromo-

1H-pyrazole (18; 267 mg, 1.81 mmol) in DMF [5 mL, containing

NaOH (73 mg, 1.81 mmol)] afforded compound 8 as a white solid

(reaction time: 24 h); yield: 270 mg (93%); mp 144 °C.

¹H NMR (400 MHz, CDCl₃): δ = 0.95 (t, J = 7.6 Hz, 9 H), 2.72 (q,

J = 7.6 Hz, 6 H), 5.40 (s, 6 H), 7.06 (s, 3 H), 7.50 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 15.16, 23.48, 50.31, 93.27,

Interestingly, if procedure C is used for the preparation of

7, the expected tripodal compound is not recovered as the

precipitate; rather, the reaction provided the correspond-

ing trisbenzimidazolium cage as its tribromide salt 14a,

which was converted into the corresponding tris(hexaflu-

orophosphate) salt 14b. Closely related cage compounds

have been reported as selective anion receptors¹²and, as

their copper(I) and silver(I) complexes,¹³as N-heterocy-

clic carbene derivatives.

128.35, 130.03, 140.12, 146.34.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₄H₂₈Br₃N₆: 638.99007;

found: 638.99060.

In summary, we have reported three possible practical

synthetic procedures for the preparation of new tripodal

trimethoxybenzene-based (1–4) and triethylbenzene-

based (6, 8) compounds, as well as new hexapodal com-

pounds (12, 13), bearing either bromo-substituted benz-

Anal. Calcd for C₂₄H₂₇Br₃N₆: C, 45.10; H, 4.26; N, 13.15. Found:

C, 45.30; H, 4.13; N, 13.11.

1,3,5-Tris[(1H-pyrazol-1-yl)methyl]-2,4,6-triethylbenzene (9)

imidazole/pyrazole units or their analogues lacking the The reaction of compound 21 (810 mg, 1.84 mmol) with 1H-pyr-

azole (22; 500 mg, 7.34 mmol) in DMF [10 mL, containing NaOH

bromo substituents. In addition, the preparation of the new

trisbenzimidazolium cage 14 [as the tribromide and the

tris(hexafluorophosphate) salts 14a,b] was included in

this work. All used procedures are facilely accomplish-

able and provided the desired products in good to excel-

lent yields. For the known compounds 5, 7 and 9–11, we

have suggested slightly modified syntheses that simplify

the reaction procedures and lead to better yields than those

(294 mg, 7.34 mmol)] afforded compound 9 as a white solid (reac-

tion time: 24 h); yield: 710 mg (96%); mp 125 °C.

¹H NMR (400 MHz, CDCl₃): δ = 0.96 (t, J = 7.6 Hz, 9 H), 2.72 (q,

J = 7.6 Hz, 6 H), 5.45 (s, 6 H), 6.20 (t, J = 2.0 Hz, 3 H), 6.98 (d,

J = 2.2 Hz, 3 H), 7.55 (d, J = 1.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 15.18, 23.31, 49.59, 105.57,

127.81, 130.44, 139.48, 146.05.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₄H₃₁N₆: 403.26047; found:

previously reported. The scale-up of the presented proce-

dures to a gram scale can be performed with ease. Reac-

tions conducted with a doubled or tripled amount of the

403.26069.

Anal. Calcd for C₂₄H₃₀N₆: C, 71.61; H, 7.51; N, 20.88. Found: C,

71.36; H, 7.59; N, 20.92.

Synthesis 2013, 45, 3341–3348

3346

N. Koch, M. Mazik

PRACTICAL SYNTHETIC PROCEDURES

1,3,5-Tris[(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-

2,4,6-triethylbenzene (10)

1,3,5-Tris[(1H-benzimidazol-1-yl)methyl]-2,4,6-trimethoxy-

benzene (2)

The reaction of compound 21 (500 mg, 1.13 mmol) with 4-bromo-

3,5-dimethyl-1H-pyrazole (19; 794 mg, 4.53 mmol) in DMF [10

mL, containing NaOH (181 mg, 4.53 mmol)] afforded compound

10 as a white solid (reaction time: 24 h); yield: 697 mg (85%); mp

156 °C.

The reaction of compound 15 (200 mg, 0.45 mmol) with 1H-benz-

imidazole (17; 238 mg, 2.01 mmol) and NaH (60% dispersion in

mineral oil; 80 mg, 2.01 mmol) in MeCN (5 mL) afforded com-

pound 2 as a white solid (reaction time: 3 d; column chromatogra-

phy: CHCl₃–MeOH–hexane, 1:1:1 v/v/v, R_f= 0.47); yield: 220 mg

(88%); mp >194 °C (dec).

¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, J = 7.5 Hz, 9 H), 2.12 (s,

9 H), 2.15 (s, 9 H), 2.71 (q, J = 7.5 Hz, 6 H), 5.19 (s, 6 H).

¹H NMR (500 MHz, CDCl₃): δ = 3.51 (s, 9 H), 5.31 (s, 6 H), 7.25–

7.30 (m, 6 H), 7.45–7.51 (m, 3 H), 7.76–7.82 (m, 3 H), 7.93 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 38.43, 63.40, 109.85, 120.41,

¹³C NMR (100 MHz, CDCl₃): δ = 10.46, 12.27, 14.63, 23.72, 48.07,

94.46, 130.00, 137.06, 145.38, 145.79.

120.46, 122.39, 123.29, 133.63, 143.08, 143.64, 160.36.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₃H₃₁N₆O₃: 559.24522;

HRMS (ESI): m/z [M + H]⁺calcd for C₃₀H₄₀Br₃N₆: 723.08402;

found: 723.08420.

found: 559.24518.

Anal. Calcd for C₃₀H₃₉Br₃N₆: C, 49.81; H, 5.43; N, 11.62. Found:

C, 49.45; H, 5.39; N, 11.94.

Anal. Calcd for C₃₃H₃₀N₆O₃: C, 70.95; H, 5.41; N, 15.04. Found: C,

70.65; H, 5.39; N, 14.93.

Hexakis[(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl]ben-

zene (13)

The reaction of compound 23 (200 mg, 0.31 mmol) with 4-bromo-

3,5-dimethyl-1H-pyrazole (19; 386 mg, 2.20 mmol) in DMF [5 mL,

containing NaOH (88 mg, 2.20 mmol)] afforded compound 13 as a

white solid (reaction time: 48 h); yield: 365 mg (96%); mp 289 °C.

¹H NMR (400 MHz, CDCl₃): δ = 1.98 (s, 18 H), 2.04 (s, 18 H), 5.24

(s, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 10.21, 12.26, 49.23, 94.52,

136.42, 137.13, 145.75.

1,3,5-Tris[(4-bromo-1H-pyrazol-1-yl)methyl]-2,4,6-trimeth-

oxybenzene (3)

The reaction of compound 15 (300 mg, 0.67 mmol) with 4-bromo-

1H-pyrazole (18; 444 mg, 3.02 mmol) and NaH (60% dispersion in

mineral oil; 121 mg, 3.02 mmol) in MeCN (10 mL) afforded com-

pound 3 as a white solid (reaction time: 3 d; column chromatogra-

phy: CHCl₃–MeOH, 20:1 v/v, R_f= 0.56); yield: 325 mg (75%); mp

115 °C.

¹H NMR (500 MHz, CDCl₃): δ = 3.64 (s, 9 H), 5.31 (s, 6 H), 7.42

(s, 3 H), 7.50 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 46.18, 62.88, 93.27, 120.29,

129.68, 139.59, 160.59.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₁H₂₂Br₃N₆O₃: 644.92785;

found: 644.92774.

HRMS (ESI): m/z [M + H]⁺calcd for C₄₂H₄₉Br₆N₁₂: 1200.92434;

found: 1200.92419.

Anal. Calcd for C₄₂H₄₈Br₆N₁₂: C, 42.03; H, 4.03; N, 14.00. Found:

C, 42.16; H, 4.13; N, 13.89.

Compounds 1–5, 7, 11 and 12; General Procedure (Procedure

Anal. Calcd for C₂₁H₂₁Br₃N₆O₃: C, 39.10; H, 3.28; N, 13.03. Found:

C, 39.16; H, 3.15; N, 12.84.

To the corresponding benzimidazole or pyrazole 16–20 (4.5 or 6.6

equiv), dissolved under N₂atmosphere in anhyd MeCN, NaH (60%

dispersion in mineral oil, 4.5 or 6.6 equiv) was added and the mix-

ture was stirred for 30 min at r.t. Then, the bromomethyl-substituted

benzene derivative 15, 21 or 23 (1 equiv) was added and the reac-

tion mixture was stirred for up to 5 d at r.t. under N₂atmosphere.

The reaction was quenched with H₂O (10 mL) and extracted with

CHCl₃(3 × 10 mL). The organic layers were combined, dried over

MgSO₄and filtered, and the solvent was removed under reduced

pressure. The residue was purified by silica gel column chromatog-

raphy using CHCl₃–MeOH or CHCl₃–MeOH–hexane as the eluent.

1,3,5-Tris[(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)methyl]-

2,4,6-trimethoxybenzene (4)

The reaction of compound 15 (300 mg, 0.67 mmol) with 4-bromo-

3,5-dimethyl-1H-pyrazole (19; 529 mg, 3.02 mmol) and NaH (60%

dispersion in mineral oil; 121 mg, 3.02 mmol) in MeCN (10 mL) af-

forded compound 4 as a white solid (reaction time: 4 d; column

chromatography: CHCl₃–MeOH, 10:1 v/v, R_f= 0.76); yield: 480

mg (98%); mp 195 °C.

¹H NMR (400 MHz, CDCl₃): δ = 2.14 (s, 9 H), 2.24 (s, 9 H), 3.48

(s, 9 H), 5.13 (s, 6 H).

1,3,5-Tris[(2-bromo-1H-benzimidazol-1-yl)methyl]-2,4,6-tri-

methoxybenzene (1)

¹³C NMR (100 MHz, CDCl₃): δ = 10.34, 12.34, 43.60, 62.33, 93.92,

119.92, 137.44, 145.54, 160.00.

The reaction of compound 15 (200 mg, 0.45 mmol) with 2-bromo-

1H-benzimidazole (16; 397 mg, 2.01 mmol) and NaH (60% disper-

sion in mineral oil; 80 mg, 2.01 mmol) in MeCN (5 mL) afforded

compound 1 as a white solid (reaction time: 3 d; column chromatog-

raphy: CHCl₃–MeOH, 15:1 v/v, R_f= 0.53); yield: 306 mg (86%);

mp >160 °C (dec).

¹H NMR (400 MHz, CDCl₃): δ = 3.61 (s, 9 H), 5.35 (s, 6 H), 6.44

(d, J = 8.1 Hz, 3 H), 6.50 (ddd, J = 1.2, 7.2, 8.2 Hz, 3 H), 7.09 (ddd,

J = 1.2, 7.2, 8.1 Hz, 3 H), 7.62 (d, J = 8.1 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 39.93, 63.97, 109.80, 119.15,

119.42, 122.46, 123.33, 130.47, 134.70, 142.81, 160.35.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₃H₂₈Br₃N₆O₃: 796.97352;

found: 796.97364.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₇H₃₄Br₃N₆O₃: 729.02180;

found: 729.02325.

Anal. Calcd for C₂₇H₃₃Br₃N₆O₃: C, 44.47; H, 4.56; N, 11.52. Found:

C, 44.29; H, 4.54; N, 11.33.

1,3,5-Tris[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-2,4,6-tri-

methoxybenzene (5)

The reaction of compound 15 (300 mg, 0.67 mmol) with 3,5-di-

methyl-1H-pyrazole (20; 290 mg, 3.02 mmol) and NaH (60% dis-

persion in mineral oil; 121 mg, 3.02 mmol) in MeCN (10 mL)

afforded compound 5 as a white solid (reaction time: 4 d; column

chromatography: CHCl₃–MeOH, 10:1 v/v, R_f= 0.58); yield: 254

mg (77%); mp 167 °C.

¹H NMR (400 MHz, CDCl₃): δ = 2.14 (s, 9 H), 2.23 (s, 9 H), 3.46

(s, 9 H), 5.11 (s, 6 H), 5.75 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 11.16, 13.54, 42.46, 62.14,

Anal. Calcd for C₃₃H₂₇Br₃N₆O₃: C, 49.84; H, 3.42; N, 10.57. Found:

C, 49.90; H, 3.34; N, 10.30.

104.89, 120.48, 139.32, 146.86, 159.72.

Synthesis 2013, 45, 3341–3348

PRACTICAL SYNTHETIC PROCEDURES

Synthesis of Tripodal and Hexapodal Compounds

3347

HRMS (ESI): m/z [M + H]⁺calcd for C₂₇H₃₇N₆O₃: 493.29217;

found: 493.29249.

washed thoroughly with THF and dried in vacuo. The desired com-

pound 6 was obtained as a white solid; yield: 1.38 g (77%); mp

252 °C.

¹H NMR (400 MHz, CDCl₃): δ = 1.07 (br s, 9 H), 2.83 (q, J = 7.5

Hz, 6 H), 5.53 (s, 6 H), 6.31 (br s, 6 H), 7.12 (t, J = 7.8 Hz, 3 H),

7.65 (d, J = 8.1 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 15.05, 23.91, 45.68, 110.67,

119.67, 122.47, 123.31, 129.96, 130.38, 134.98, 143.44, 146.57.

MS (EI, 70 eV): m/z = 790 [M⁺], 709, 593, 397, 317.

HRMS (EI): m/z [M⁺] calcd for C₃₆H₃₃Br₃N₆: 786.03113; found:

Anal. Calcd for C₂₇H₃₆N₆O₃: C, 65.83; H, 7.37; N, 17.06. Found: C,

65.94; H, 7.48; N, 17.11.

1,3,5-Tris[(1H-benzimidazol-1-yl)methyl]-2,4,6-triethylben-

zene (7)

The reaction of compound 21 (500 mg, 1.13 mmol) with 1H-benz-

imidazole (17; 603 mg, 5.10 mmol) and NaH (60% dispersion in

mineral oil; 204 mg, 5.10 mmol) in MeCN (10 mL) afforded com-

pound 7 as a white solid (reaction time: 5 d; column chromatogra-

phy: CHCl₃–MeOH, 15:1 v/v, R_f= 0.44; yield: 564 mg (90%); mp

173 °C.

786.03085.

Anal. Calcd for C₃₆H₃₃Br₃N₆: C, 54.77; H, 4.21; N, 10.65. Found:

C, 55.03; H, 4.04; N, 10.58.

¹H NMR (400 MHz, CDCl₃): δ = 0.97 (t, J = 7.6 Hz, 9 H), 2.69 (q,

J = 7.6 Hz, 6 H), 5.41 (s, 6 H), 7.31–7.40 (m, 6 H), 7.44–7.47 (m, 6

H), 7.84 (dd, J = 1.7, 6.9 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 15.38, 23.70, 42.94, 109.24,

120.82, 122.72, 123.33, 130.11, 133.96, 141.07, 144.06, 146.41.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₆H₃₇N₆: 553.30742; found:

553.30771.

Trisbenzimidazolium Tribromide 14a

To 1H-benzimidazole (17; 442 mg, 3.74 mmol), dissolved in THF–

MeCN (4:1, 15 mL), DIPEA (0.64 mL, 3.74 mmol) was added and

the mixture was stirred for 1 h at r.t. Then, compound 21 (500 mg,

1.13 mmol) was added and the reaction mixture was stirred for 48 h

at r.t. The resulting precipitate was collected by filtration, washed

thoroughly with THF and dried in vacuo. Compound 14a was ob-

tained as a white solid; yield: 180 mg (32%); mp >290 °C (dec).

Anal. Calcd for C₃₆H₃₆N₆: C, 78.23; H, 6.57; N, 15.21. Found: C,

77.85; H, 6.51; N, 15.04.

¹H NMR (400 MHz, DMSO-d₆): δ = 1.07 (t, J = 7.4 Hz, 18 H), 2.46

(q, J = 7.5 Hz, 12 H), 5.75 (s, 12 H), 6.17 (s, 3 H), 7.94 (dd, J = 3.2,

6.4 Hz, 6 H), 8.43 (dd, J = 3.2, 6.4 Hz, 6 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 15.87, 22.48, 45.11, 114.64,

127.87, 128.88, 132.51, 133.89, 148.57.

HRMS (ESI): m/z [M³⁺] calcd for C₅₁H₅₇N₆: 251.15428; found:

251.15435.

1,3,5-Tris[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-2,4,6-trieth-

ylbenzene (11)

The reaction of compound 21 (500 mg, 1.13 mmol) with 3,5-di-

methyl-1H-pyrazole (20; 490 mg, 5.10 mmol) and NaH (60% dis-

persion in mineral oil; 204 mg, 5.10 mmol) in MeCN (10 mL)

afforded compound 11 as a white solid (reaction time: 4 d; column

chromatography: CHCl₃–MeOH, 15:1 v/v, R_f= 0.63); yield: 491

mg (89%); mp 197 °C.

¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, J = 7.6 Hz, 9 H), 2.13 (s,

9 H), 2.14 (s, 9 H), 2.77 (q, J = 7.6 Hz, 6 H), 5.18 (s, 6 H), 5.76 (s,

3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 11.34, 13.43, 14.56, 23.69, 46.93,

105.43, 130.62, 138.98, 144.94, 147.20.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₀H₄₃N₆: 487.35437; found:

487.35452.

Anal. Calcd for C₅₁H₅₇Br₃N₆: C, 61.64; H, 5.78; N, 8.46. Found: C,

61.43; H, 5.67; N, 8.54.

Trisbenzimidazolium Tris(hexafluorophosphate) 14b

Trisbenzimidazolium tribromide 14a (300 mg, 0.30 mmol) was dis-

solved in hot MeOH (10 mL) and a soln of sodium hexafluorophos-

phate (458 mg, 2.73 mmol) in MeOH (5 mL) was added. The

mixture was stirred for 24 h at r.t., during which time a white pre-

cipitate formed. The precipitate was collected by filtration, washed

thoroughly with MeOH and dried in vacuo. Product 14b was ob-

tained as a white solid; yield: 270 mg (75%); mp >300 °C.

Anal. Calcd for C₃₀H₄₂N₆: C, 74.03; H, 8.70; N, 17.27. Found: C,

74.16; H, 8.68; N, 17.18.

¹H NMR (400 MHz, DMSO-d₆): δ = 1.08 (t, J = 7.4 Hz, 18 H), 2.43

(q, J = 7.1 Hz, 12 H), 5.72 (s, 12 H), 6.15 (s, 3 H), 7.94 (dd, J = 3.2,

6.3 Hz, 6 H), 8.38 (dd, J = 3.1, 6.4 Hz, 6 H).

¹³C NMR (100 MHz, DMSO-d₆): δ = 15.82, 22.47, 45.02, 114.61,

127.95, 128.79, 132.60, 133.74, 148.68.

HRMS (ESI): m/z [M³⁺] calcd for C₅₁H₅₇N₆: 251.15428; found:

251.15477.

Hexakis[(4-bromo-1H-pyrazol-1-yl)methyl]benzene (12)

The reaction of compound 23 (300 mg, 0.47 mmol) with 4-bromo-

1H-pyrazole (18; 458 mg, 3.12 mmol) and NaH (60% dispersion in

mineral oil; 125 mg, 3.12 mmol) in MeCN (10 mL) afforded com-

pound 12 as a light-orange solid (reaction time: 4 d; column chro-

matography: CHCl₃–MeOH, 15:1 v/v, R_f= 0.73); yield: 424 mg

(87%); mp 224 °C.

¹H NMR (400 MHz, CDCl₃): δ = 5.56 (s, 12 H), 7.01 (d, J = 0.6 Hz,

6 H), 7.41 (d, J = 0.5 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 49.94, 94.08, 129.44, 137.69,

Anal. Calcd for C₅₁H₅₇F₁₈N₆P₃: C, 51.52; H, 4.83; N, 7.07. Found:

C, 51.56; H, 4.89; N, 6.98.

140.71.

HRMS (ESI): m/z [M + H]⁺calcd for C₃₀H₂₅Br₆N₁₂: 1032.73621;

found: 1032.73657.

Supporting Information for this article is available online at

http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi

tgioSrantnugIifoop

itmnatr

Anal. Calcd for C₃₀H₂₄Br₆N₁₂: C, 34.91; H, 2.34; N, 16.29. Found:

C, 35.04; H, 2.40; N, 16.18.

References

Compounds 6 and 14a; Procedure C

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1,3,5-Tris[(2-bromo-1H-benzimidazol-1-yl)methyl]-2,4,6-tri-

ethylbenzene (6)

To 2-bromo-1H-benzimidazole (16; 1.47 g, 7.48 mmol), dissolved

in THF–MeCN (4:1, 20 mL), DIPEA (1.27 mL, 7.48 mmol) was

added and the mixture was stirred for 1 h at r.t. Then, compound 21

(1 g, 2.27 mmol) was added and the reaction mixture was stirred for

7 d at r.t. The resulting precipitate was collected by filtration,

Synthesis 2013, 45, 3341–3348

3348

N. Koch, M. Mazik

PRACTICAL SYNTHETIC PROCEDURES

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Synthesis 2013, 45, 3341–3348

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