Parallel solid-phase synthesis of diaryltriazoles

Article abstract of DOI:10.3762/bjoc.8.115

A series of substituted diaryltriazoles was prepared by a solid-phase-synthesis protocol using a modified Wang resin. The copper(I)-or ruthenium(II)-catalyzed 1,3-cycloaddition on the polymer bead allowed a rapid synthesis of the target compounds in a parallel fashion with in many cases good to excellent yields. Substituted diaryltriazoles resemble a molecular structure similar to established terphenyl-alpha-helix peptide mimics and have therefore the potential to act as selective inhibitors for protein-protein interactions.

Full text of DOI:10.3762/bjoc.8.115

Parallel solid-phase synthesis of diaryltriazoles
Matthias Wrobel1, Jeffrey Aubé2 and Burkhard König*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1027–1036.
1Fakultät für Chemie und Pharmazie, Universität Regensburg,
D-93040 Regensburg, Germany, Fax: +49 9419431717 and
2Department of Medicinal Chemistry and the Chemical Methodology
and Library Development Center, University of Kansas, Delbert M.
Shankel Structural Biology Center, 2121 Simons Drive, West
Campus, Lawrence, KS 66047, USA
doi:10.3762/bjoc.8.115
Received: 13 April 2012
Accepted: 13 June 2012
Published: 06 July 2012
This article is part of the Thematic Series "Recent developments in
chemical diversity".
Email:
Burkhard König* - burkhard.koenig@chemie.uni-regensburg.de
Guest Editor: J. A. Porco Jr.
* Corresponding author
© 2012 Wrobel et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chemical diversity; Huisgen cycloaddition; library synthesis;
peptidomimetics; solid phase synthesis; triazole
Abstract
A series of substituted diaryltriazoles was prepared by a solid-phase-synthesis protocol using a modified Wang resin. The copper(I)-
or ruthenium(II)-catalyzed 1,3-cycloaddition on the polymer bead allowed a rapid synthesis of the target compounds in a parallel
fashion with in many cases good to excellent yields. Substituted diaryltriazoles resemble a molecular structure similar to estab-
lished terphenyl-alpha-helix peptide mimics and have therefore the potential to act as selective inhibitors for protein–protein inter-
actions.
Introduction
The α-helix was the first-described secondary structure of peptide-based compounds [8], can be overcome by compounds
peptides discovered by Linus Pauling in 1951 [1]. With about stabilized by non-natural amino acids [9] or cross-linked
30% of the amino acids in proteins being part of α-helices [2], it between side chains and the backbone [10]. Replacement of the
is the most common secondary structure found in proteins [3]. complete backbone by a nonpeptidic scaffold, which positions
Protein–protein as well as protein–DNA and protein–RNA side chains in the typical i, i+3 and i+7 arrangement of an
interactions often involve α-helices as recognition motifs on α-helix is another successful strategy [11]. Horwell pioneered
protein surfaces [4]. These helices are important targets for new this type of peptidomimetics and showed that 1,6-disubstituted
drugs, but stabilization of the helix folding for small structures indanes can imitate the helix residues i and i+1 [12,13].
with less than 15 residues still remains a challenge [5,6]. Thus, Hamilton reported a 3,2′,2″-substituted terphenyl scaffold with
new attempts have been made to design low-molecular-weight a spatial orientation that mimics the i, i+3 and i+7 moieties on
ligands that disrupt protein–protein interactions [7]. For the surface of an α-helical peptide [14]. Inspired by the
example, fast proteolytic degradation observed with small terphenyl-based α-helix mimetics 1, several related compounds
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Results and Discussion
Synthesis of azide-functionalized Wang
resins
Two azide-functionalized resins were prepared for the solid-
phase synthesis of diaryl-triazoles. The commercially
available 4-(bromomethyl)benzoic acid (5) was converted into
azide 6 in anhydrous DMF with sodium azide under
heating. Coupling to Wang resin in dichloromethane, by using
DIC and DMAP as coupling reagents, gave resin 7 in quantitat-
ive yield (Scheme 2) [18]. Commercially available 4-azidoben-
zoic acid (8) gave resin 9 in an analogous esterification of a
Wang resin.
Scheme 1: Terphenyl scaffold 1 [13,14]; oxazole-pyridazine-piper-
azine 2 [14,15] and aryl-triazoles 3 and 4 [15,16] as α-helix mimetics.
Solid-phase synthesis of diaryltriazoles
The conditions for the solid-phase synthesis of diaryltriazoles
containing three or more adjacent aryl rings (Scheme 1), such as on functionalized Wang resin 7 were optimized by using five
2, were reported [15]. However, the synthesis of substituted different alkynes 10a–e, containing acyclic or cyclic aliphatic
triaryl compounds can be tedious, and the predictability of their moieties, simple arenes and 1-(but-3-yn-2-yl)-3-(4-chloro-
potency and selectivity as inhibitors is still limited. We have phenyl)-1-methylurea (10c) as an example of a more complex
recently reported the synthesis of triazole-based α-helix alkyne. The azide–alkyne [3 + 2] cycloaddition was catalyzed
mimetics 3 and 4 [16], which are efficiently available through with copper(II) sulfate pentahydrate and L-ascorbic acid in
azide–alkyne cycloadditions [17]. We now report the use of this DMF overnight at room temperature. A solution of EDTA was
chemistry to prepare libraries of potential inhibitors of added to remove the remaining copper cations from the resin.
protein–protein interactions.
Resin cleavage under acidic conditions with TFA in DCM gave
Scheme 2: Synthesis of azido-functionalized resins 7 and 9.
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
compounds 11a–e in moderate to excellent overall yields of converted quantitatively, but elimination of water occurred in
57 to 90% (Table 1). Due to the solid phase synthesis protocol the presence of TFA. The dehydrated products were obtained in
the crude material purity was typically high, ranging from 70 to 57 and 71%. The remaining material was the corresponding
90%. Alkyne 10d and 10e bearing hydroxy groups were hydroxylated product.
Table 1: Copper-catalyzed [2 + 3] cycloadditions of resin-bound azide 7 with five terminal alkynes.
terminal alkyne 10
product 11
yield [%]
63
10a
11a
90
10b
11b
81
10c
11c
57
71
10d
10e
11d
11e
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Parallel synthesis of a compound library
yields (88–99%). Resin 9 was used in reaction 2 under other-
A larger compound library was prepared by using resins 7 and wise identical reaction conditions. The use of an aromatic azide
9, 15 different terminal alkynes 10f–t and either copper or leads to more rigid products containing three adjacent aromatic
ruthenium-catalyzed [2 + 3] cycloadditions. The three reactions rings: The central triazole and the phenyl ring of the benzoic
and the obtained products 11 (reaction 1), 12 (reaction 2) and 13 acid as constant structural elements and the third ring consisting
(reaction 3) are summarized in Table 2.
either of substituted benzenes, heteroarenes or a polycyclic
aromatic compound. Lower product yields were obtained in this
Reaction 1 follows the established protocol and, gave after series of compounds, ranging from 21 to 63%. The lower re-
removal of the copper salts with a solution of EDTA and TFA activity of the aromatic azide and the increased steric demand
cleavage, the corresponding products in good to quantitative may explain the decrease in yield in comparison to that of the
Table 2: Copper-catalyzed [2 + 3] cycloadditions of resin bound azide 7 with five terminal alkynes. Compounds 13, with the exception of 13f, were
only characterized during compound library synthesis, by HPLC–MS analysis.
alkyne 10
product after cleavage from resin (yield)
reaction 2
resin 9,
catalyst CuSO4
reaction 1
resin 7, catalyst CuSO4
reaction 3
resin 7, catalyst Cp·RuCl(PPh3)2
10f
11f (95%)
13a not obtained
12a (49%)
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Table 2: Copper-catalyzed [2 + 3] cycloadditions of resin bound azide 7 with five terminal alkynes. Compounds 13, with the exception of 13f, were
only characterized during compound library synthesis, by HPLC–MS analysis. (continued)
10g
11g (99%)
13b (43%)
12b (44%)
10h
11h (97%)
13c (89%)
12c (45%)
10i
11i (98%)
13d (89%)
12d (44%)
10j
11j (98%)
13e (90%)
12e (41%)
10k
11k (97%)
13f (48%)
12f (21%)
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Table 2: Copper-catalyzed [2 + 3] cycloadditions of resin bound azide 7 with five terminal alkynes. Compounds 13, with the exception of 13f, were
only characterized during compound library synthesis, by HPLC–MS analysis. (continued)
10l
11l (98%)
13g (94%)
12g (52%)
10m
11m (88%)
13h (96%)
12h (38%)
10n
11n (98%)
13i (80%)
12i (41%)
10o
11o (97%)
13j (82%)
12j (63%)
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Table 2: Copper-catalyzed [2 + 3] cycloadditions of resin bound azide 7 with five terminal alkynes. Compounds 13, with the exception of 13f, were
only characterized during compound library synthesis, by HPLC–MS analysis. (continued)
10p
11p (99%)
13k (89%)
12k (47%)
10q
11q (98%)
13l (89%)
12l (40%)
10r
11r (98%)
13m (92%)
12m (61%)
10s
13n (95%)
11s (94%)
12n (26%)
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Table 2: Copper-catalyzed [2 + 3] cycloadditions of resin bound azide 7 with five terminal alkynes. Compounds 13, with the exception of 13f, were
only characterized during compound library synthesis, by HPLC–MS analysis. (continued)
10t
13o (74%)
11t (96%)
12o not obtained
former series of compounds. The formation of the compound
Table 3: Ruthenium-catalyzed [2 + 3] cycloadditions of resin-bound
12o, bearing a particularly bulky substituent, was not observed.
Replacing the copper(I) catalyst by a ruthenium(II) complex
allows the preparation of regioisomers in reaction 3. Instead
of the 1,4-disubstituted triazoles obtained from copper(I) catal-
ysis, the complex pentamethylcyclopentadienylbis(tri-
phenylphosphine)ruthenium(II) chloride leads to 1,5-disubsti-
tuted triazole compounds [19]. 4-(Azidomethyl)benzoic acid
functionalized Wang resin 7 and the alkynes 10f–t were reacted
in DMF at 70 °C overnight, and the products 13b–o were
obtained after TFA cleavage from the resin in moderate to good
yields ranging from 43–96%. Only compound 13a could not be
obtained. The proton NMR analysis allows us to clearly distin-
guish between 1,4- and 1,5-disubstituted triazoles due to a char-
acteristic shift of the triazole proton resonance. The triazole
proton of the 1,4-disubstituted ring in compound 11k shows a
1H NMR resonance at δ = 8.71 (400 MHz, DMSO-d6), while
the resonance signal for the triazole proton of product 13f is
observed at δ = 8.00 (400 MHz, DMSO-d6). Compounds 13,
with the exception of compound 13f, were only characterized
by mass spectrometry during the synthesis of the compound
library.
azide 7 with three disubstituted alkynes.
alkyne
product 15 (yield)a
14a
15a (78%)
The copper-mediated [2 + 3] cycloadditions are restricted to
terminal alkynes. However, the ruthenium-catalysis allows
the use of internal alkynes. In preliminary work, resin 7 was
therefore reacted with internal alkynes 14a–c and pentamethyl-
cyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride
as catalyst in DMF at 70 °C overnight followed by TFA
cleavage [20]. LC–MS analysis of the crude product revealed
the formation of compounds 15a–c in high yields of 78–98%
(Table 3).
14b
15b (84%)
14c
Conclusion
Diaryltriazoles were obtained in an efficient three-step solid-
15c (98%)
aYields based on LC–MS; compound 12b was used as standard.
phase procedure. Immobilization of aromatic azides on
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
commercial Wang resin followed by copper(I)- or resin) for 2 h at room temperature. Subsequently, the catalyst
ruthenium(II)-catalyzed 1,3-cycloaddition and subsequent complex pentamethylcyclopentadienylbis(triphenylphos-
cleavage of the product from the resin gave the target structures phine)ruthenium(II) chloride, Cp·RuCl(PPh3)2, (5 mol %) and
in good to excellent yields with the possibility to introduce a either a terminal or an internal alkyne (4 equiv) were added.
wide variety of different substituents. The alternative use of After the reaction mixture was stirred for 22 h at 70 °C, the
copper or ruthenium catalysis for the on-bead cycloaddition resin was washed with dimethylformamide, methanol and
gives regioisomeric products, which extends the diversity of the dichloromethane (each solvent 3 × 2 mL/100 mg resin).
compound collection. The method may find application in the
combinatorial search for selective protein–protein inhibitors. To GP 4 – Cleavage of solid-phase resin-bound molecules with
that end, most of the compounds prepared herein were TFA: The swollen resin was treated with a 1:4 mixture of tri-
submitted to the Molecular Libraries Small Molecular Reposi- fluoroacetic acid and dichloromethane (1 mL/100 mg resin).
tory for ongoing inclusion in high-throughput screening activi- After being stirred for 10 min at room temperature, the cleaved
ties.
product was rinsed out of the resin using dichloromethane
(1.5 mL/100 mg resin). The resin was treated once more with
the 20% trifluoroacetic acid solution (1 mL/100 mg resin),
stirred for 10 min at room temperature and washed with
Experimental
General procedures
GP 1 – Coupling of benzoic acid derivatives 6 and 8 on dichloromethane (3 × 1 mL/100 mg resin). The solvent was
Wang resin: Wang resin (1 equiv) was preswollen in evaporated and the product was dried in high vacuum for 4 h.
dichloromethane (0.8 mL/100 mg resin) for 2 h at room
temperature. Subsequently, both coupling reagents N,N′-diiso- 4-(Azidomethyl)benzoic acid (6) [21]: The synthetic proce-
propylcarbodiimide (3.5 equiv) and dimethylaminopyridine dure leading to this literature-known compound was improved.
(0.5 equiv) were added. After the addition of the benzoic acid 4-(Bromomethyl)benzoic acid (5, 1.2 g, 5.58 mmol, 1.0 equiv)
derivative 6 or 8 (2.5 equiv) the reaction mixture was stirred for and sodium azide (907 mg, 13.95 mmol, 2.5 equiv) were
20 h at room temperature. The resin was first washed with suspended in 25 mL of anhydrous dimethylformamide under a
dimethylformamide, methanol and dichloromethane (each nitrogen atmosphere. After the reaction mixture was stirred for
solvent 3 × 0.8 mL/100 mg resin), and then dried in high 15 h at 50 °C the solvent was evaporated. The colorless residue
vacuum for 3 h.
was dissolved in 90 mL of water and the solution was treated
with 17 mL of hydrochloric acid (c 1 mol/L). The precipitate
GP 2 – Huisgen 1,3-dipolar cycloaddition of solid-phase- was separated with a Büchner funnel, dissolved in
immobilized azides with terminal alkynes by copper(I) dichloromethane and dried over potassium sulfate. After filtra-
catalysis: An azide-functionalized Wang resin 7 or 9 (1 equiv) tion, and evaporation of the solvent, 4-(azidomethyl)benzoic
was preswollen in dimethylformamide (1.5 mL/100 mg resin) acid (6, 880 mg, 4.97 mmol, 89%) was yielded as a colorless
for 2 h at room temperature. The copper(I) catalyst was solid and dried in high vacuum overnight; mp 135.6–136.6 °C;
prepared in situ by using L-ascorbic acid (0.5 equiv) as 1H NMR (300 MHz, CDCl3) δ 4.46 (s, 2 H, H-6), 7.44 (d, 3JHH
reducing agent and copper(II) sulfate pentahydrate (10 mol %). = 8.4 Hz, 2H, H-4), 8.14 (d, 3JHH = 8.3 Hz, 2H, H-3); 13C
After the terminal alkyne (4 equiv) was added, the reaction mix- NMR (75 MHz, CDCl3) δ 54.3 (−, 1C, C-6), 128.0 (+, 2C, C-4),
ture was stirred for 22 h at room temperature. The resin was 129.1 (Cq, 1C, C-2), 130.8 (+, 2C, C-3), 141.5 (Cq, 1 C, C-5),
washed with dimethylformamide, methanol and 171.4 (Cq, 1C, C-1); IR (cm−1) : 2933 (w), 2880 (w), 2817
dichloromethane (each solvent 2 mL/100 mg resin). The (w), 2656 (w), 2110 (m), 2086 (m), 1950 (w), 1682 (s), 1293
remaining copper cations were complexed and removed by (s), 1239 (s), 707 (s), 545 (s); EIMS m/z: 177.0 (40) [M]+, 148.0
using a solution of ethylenediaminetetraacetic acid disodium (80) [M − N2]+, 135.0 (100) [M − N3]+; Anal. calcd for
salt. For this purpose, a 1:1 mixture of dimethylformamide and C8H7N3O2: C, 54.24; H, 3.98; N, 23.72; found: C, 54.28; H,
disodium EDTA (aq., sat.) was added to the resin and stirred for 4.25; N, 23.75.
10 min at room temperature. Again washing steps with water,
dimethylformamide, methanol and dichloromethane (each
Supporting Information
solvent 3 × 2 mL/100 mg resin) were carried out.
Supporting Information File 1
Experimental details and spectra.
GP 3 – Huisgen 1,3-dipolar cycloaddition of solid-phase-
immobilized azides with terminal or internal alkynes by
ruthenium(II) catalysis: The azide functionalized Wang resin
(1 equiv) was preswollen in dimethylformamide (2 mL/100 mg
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-115-S1.pdf]
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Beilstein J. Org. Chem. 2012, 8, 1027–1036.
Acknowledgments
License and Terms
We thank Ben Neuenswander for carrying out the purification
of library members. Financial support from the National Insti-
tute of General Medical Sciences (KU CMLD center, P50
GM69663).
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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