Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

Article abstract of DOI:10.3762/bjoc.13.55

Cu- and Pd-catalyzed arylation of aminocholanes has been described for the first time. While this Cu-catalyzed protocol provides high yields in reactions of aminocholanes with iodoarenes, Pd catalysis was found to be preferable for the reactions of aminoc

Full text of DOI:10.3762/bjoc.13.55

Pd- and Cu-catalyzed approaches in the syntheses of new
cholane aminoanthraquinone pincer-like ligands
Nikolay V. Lukashev*, Gennadii A. Grabovyi, Dmitry A. Erzunov, Alexey V. Kazantsev,
Gennadij V. Latyshev, Alexei D. Averin and Irina P. Beletskaya.
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 564–570.
Department of Chemistry, Lomonosov Moscow State University,
Leninskie Gory 1-3, Moscow, 119991, Russia
doi:10.3762/bjoc.13.55
Received: 21 December 2016
Accepted: 01 March 2017
Published: 20 March 2017
Email:
Nikolay V. Lukashev* - nvlukashev@gmail.com
* Corresponding author
Associate Editor: N. Sewald
Keywords:
© 2017 Lukashev et al.; licensee Beilstein-Institut.
License and terms: see end of document.
amination; aminocholanes; bile acids; cation complexation;
Cu-catalysis; diaminoanthraquinone; Pd-catalysis
Abstract
Cu- and Pd-catalyzed arylation of aminocholanes has been described for the first time. While this Cu-catalyzed protocol provides
high yields in reactions of aminocholanes with iodoarenes, Pd catalysis was found to be preferable for the reactions of
aminocholanes with dichloroanthraquinones. UV–vis titration of bis(cholanylamino)anthraquinones with a series of cations demon-
strated their high binding affinity to Cu2+, Al3+, and Cr3+.
Introduction
Bile acids are known to ensure vital processes in vertebrate plate for design of complex molecules has become increasingly
organisms, including metabolism and fat digesting [1,2]. The popular in pharmacology, supramolecular chemistry and nano-
biological activity of bile acids is mainly based on the proper- science over recent years [4,5].
ties of their backbone. All bile acids possess a rigid cholane
skeleton with two distinct surfaces. The inward hydrophilic sur- Many macrocyclic dimeric derivatives of bile acid were de-
face (with several hydroxy groups) along with the outward scribed [6-8]. As a rule, a route to the majority of macrocyclic
hydrophobic face permit bile acids to act as facial amphiphiles structures requires multiple steps and is tedious, and the macro-
[3]. Their carboxylic and hydroxy groups can be easily modi- cyclization step generally provides low to moderate yields.
fied, and the chemistry of these processes has been thoroughly Moreover, subsequent modification of these molecules for
studied [4]. All these options make bile acids the molecules of tuning their solubility or binding ability is often difficult.
choice for many applications. The choice of bile acids as tem- Consequently, the idea of molecular pockets or jellyfish resem-
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Beilstein J. Org. Chem. 2017, 13, 564–570.
bling receptors with open “architecture” (Figure 1), which metal-catalyzed reactions were applied for the modification of
contain two or more bile acid fragments, has attracted more bile acids – cross-coupling [28,29] (Scheme 1) and Cu(I)-cata-
attention in recent years [9-16].
lyzed cycloaddition of azides to alkynes (Figure 1) [11,16,30-
32].
Bile acid, itself, can be used as a basis for ligand design [17,18].
Pincer-like ligands are capable of binding anions [18] or facili- We developed [33-35] a convenient technique for the synthesis
tate transport of anions through lipid membranes [19-22]. Some of bile acids containing dimeric compounds and macrocycles by
of similar pincer compounds can be used as receptors for Pd-catalyzed Buchwald–Hartwig amination [36]. Though this
organic molecules; e.g., polyamino derivatives based on method is often preferable for the macrocyclization in compari-
cholane skeleton can form complexes with amino acids [23] and son to classical nucleophilic substitution [28,31], it is limited to
pincer-like conjugates of deoxycholic acid and aminopyrene bile acid derivatives bearing groups with C(sp2)–Hal bonds. In
can serve as sensors for aromatic compounds [24].
addition, the use of bile acid moieties saturated with hydroxy
groups was inconvenient for the syntheses of bis(polyoxamino)
During the first decade of the XXI century, the main ap- derivatives by Pd-catalyzed amination [34,35].
proaches to cyclic and pincer cholane derivatives were based on
“classical” organic transformations (acylation, alkylation, etc.) Direct metal-catalyzed arylation of aminocholanes has not yet
[7,8,25-27]. Later, two modern synthetic approaches based on been employed in the synthesis of cholane-based ligands. Here,
Figure 1: A tripodal molecular pocket (a) [12] or jellyfish resembling receptors (b) [11,16].
Scheme 1: Example of Pd-catalyzed amination for modification of bile acid derivatives.
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we report a new and efficient synthesis of arylaminocholanes interest was drawn by the synthesis of cholane-diaminoan-
and cholane-diaminoanthraquinone derivatives by Pd- and thraquinone derivatives that can possess good complexation
Cu-catalyzed amination. Such compounds not only have cation ability, chromophoric properties, and antitumor activity as well
binding properties, but also might be easily introduced in lipid [40].
membranes to form ion channels. Appropriate close location of
lipophilic steroid fragments in bis(cholanediamino)anthra- We compared several CuI-based catalytic systems in the aryl-
quinones can be useful for non-covalent binding of lipids (such ation of amine 3b with 4-iodotoluene as a model substrate. We
as cholesterol) or other lipophilic compounds.
found out that the CuI/L-proline combination with K2CO3 led
to the target aniline 4 in excellent yield (Scheme 3). Conse-
quently, this system was used for the synthesis of bis-steroidal
arylamines 5a and 5b starting from 24-aminocholanol 3a.
Results and Discussion
Synthesis of bile acid derived ligands
A series of different 24-aminocholanols (compounds 3a–c) was
synthesized by reduction of the corresponding bile acid amides Activated chlorinated substrates, such as 1,8- and 1,5-dichloro-
with LiAlH4 (Scheme 2) [37].
anthraquinones, are very promising substrates for nucleophilic
substitution. For instance, 1,8-dichloro-9,10-anthraquinone (6a)
Cu-catalyzed amination is known to be a very efficient ap- is readily aminated by phthalimide using classical Ullmann
proach for C–N bond formation [38,39]. The availability of the conditions (15% Cu powder, quinoline, 200 °C in PhNO2) [41].
variety of inexpensive ligands for copper(I) is a crucial However, the reaction of 3c with 6a using the same conditions,
benefit in comparison to the Pd-catalyzed variant. Primary as well as the addition of stronger bases (DABCO, DIPEA,
amines of different structures can readily react with aryl DBU) afforded extremely low yields (7–12%) of aminated
halides to provide a wide range of products in excellent anthraquinones. Further attempts to apply the Cu-based catalyt-
yields. However, yet there was no evidence of the same ic system in this reaction with L-proline and other commonly
technique being applied to steroidal amines. Our particular used N,N, N,O, and O,O bidentate ligands were fruitless.
Scheme 2: Synthesis of 24-aminocholanols.
Scheme 3: Synthesis of 24-arylaminocholanols by Cu-catalyzed amination.
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Beilstein J. Org. Chem. 2017, 13, 564–570.
Previously, some of us successfully used the classic conditions under the same conditions led to the two-fold decrease in yield
of the Buchwald–Hartwig amination for the preparation of bis- of 5c. The replacement of BINAP with other phosphine ligands
amino derivatives from various dibromo- and dichloroarenes (t-Bu3P, dppf, PPF-NMe2) gave a very low turnover of Pd cata-
[42]. Thus, we adopted the well performing Pd(dba)2/BINAP lyst (up to 8 cycles).
catalytic system for the reaction of aminocholanols 3a–c with
dibromo- and dichloroarenes (Scheme 4).
The increase in reaction time (up to 65 h), reaction temperature
(120 °C, o-xylene), and change of base to K3PO4 did not show
The synthesis of aniline 5a was chosen to determine the any significant improvement in yield of 5d. Fortunately, a high
viability of Pd-catalyzed amination. Though 5a was not ob- yield of 5d (74%) was obtained by increasing the reagent con-
served in the reaction with 1,3-diiodobenzene, a good yield was centrations to 0.25 M. The adjusted conditions were successful-
obtained with 1,3-dibromobenzene. In fact, the Pd-catalyzed ly applied in the arylation of cholic acid derived amine 3c with
coupling was more efficient [43] than Ullmann-type chemistry 6a affording 34% of 5e. Thus, Pd-catalyzed amination seems to
(61% from 1,3-dibromobenzene vs 40% from 1,3-diiodoben- be a very competitive route for the preparation of arylated
zene). Since the anthraquinone skeleton is rather sensitive to aminocholanes.
strong bases, we replaced NaOt-Bu with milder Cs2CO3 in
reactions with dichlorides 6. Both 6a and 6b gave good yields Complexation of bile acid derived ligands
of aminoanthraquinones 5c (88%) and 5f (76%) under these Steroidal ligands are known to be excellent hosts for different
conditions.
ions [8]. However, we did not observe complexation of pincer
ligands 5c–e with inorganic or organic anions by NMR titration.
However, the arylation of deoxycholic acid derived amino- The attempt to increase the anion affinity for the ligands by
cholane 3b with 6a gave a surprisingly low yield of 5d (22%). exhaustive alkylation of amino groups with trimethyloxonium
We speculated that the low yield was caused by the presence of tetrafluorborate led exclusively to methylation of hydroxy
an additional hydroxy group in 3b. The formation of the alk- groups.
oxide anion on the substrate due to the thermodynamically
unfavorable equilibrium with Cs2CO3 might promote the In contrast the presence of the diaminoanthraquinone scaffold
destruction of the anthraquinone scaffold. Indeed, the addition allows for easy detection of ion binding due to the high sensi-
of an equimolar amount of iPrOH to the mixture of 3a and 6a tivity of an intensive absorption band at 550 nm to the strength
Scheme 4: Synthesis of 24-arylaminocholanols by Pd-catalyzed amination.
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Beilstein J. Org. Chem. 2017, 13, 564–570.
of intermolecular NH···O hydrogen bonds [44]. We studied the Thus, there is no appreciable dependence between the value of
influence of the various cations (Al3+, Mn2+, Fe2+, Co2+, Ni2+, the binding constants and the presence of an extra hydroxy
Zn2+, Cu2+, Ag+, Pb2+, Hg2+, Cr3+, Ga3+, Y3+, In3+) on the UV group in the cholane fragment. To the best of our knowledge a
spectrum of 5c (Figure 2). The qualitative selectivity test by complex formation of 1,8-diaminoanthraquinone derivatives
stepwise addition of 1, 2, 3, and 5 equiv of metal perchlorates in with Al and Cr salts have not been investigated earlier. The
MeCN to the solution of 5c in MeCN revealed that the majority ligands derived of 1,8-diaminoanthraquinone are convenient for
of cations did not influence the intensity of the absorption. the detection of the copper cation [45,46]: the tetradentate
However, addition of Al3+, Cr3+, and Cu2+ led to a decrease in ligand N,N’-bis(β-dimethylaminoethyl)-1,8-diaminoan-
absorption in the region of 500–600 nm and a hypsochromic thraquinone [47] demonstrate a two orders of magnitude better
shift of the maximum from 550 nm in a free ligand to 537 nm binding constant with copper cation in comparison to bidentate
(Al3+), 539 nm (Cr3+), and 535 nm (Cu2+). To establish the ligands 5c and 5d. However, the cholane skeleton in 5c and 5d
stability and stoichiometry of complexes with these metals, the can be useful for integration of these ligands into lipophilic
spectrophotometric titrations were carried out. Nonlinear membranes.
regression analysis revealed the formation of the 1:1 complex of
5c with Cu2+ and complexes with Al3+ and Cr3+ ions with dif- Conclusion
ferent stoichiometry (Table 1). The same stoichiometry and Cu- and Pd-catalyzed cross-coupling reactions were applied for
binding constants were determined for deoxycholic acid derived the preparation of arylamino derivatives of bile acids. High
ligand 5d.
yields of arylaminocholanes were achieved in copper-catalyzed
Figure 2: UV–vis spectra of 5c (50 μM solution in MeCN) before and after the addition of 5 equiv of metal perchlorates.
Table 1: Binding constants and stoichiometry of complexes of 5c and 5d with different cations.
Cation
Complex
log K
Complex
log K
Cu2+
Al3+
(5c):Cu
(5c)2:Al
(5c):Al
4.40 ± 0.06
8.25 ± 0.09
4.14 ± 0.07
8.07 ± 0.10
4.00 ± 0.08
(5d):Cu
(5d)2:Al
(5d):Al
4.03 ± 0.07
9.22 ± 0.07
3.91 ± 0.07
7.89 ± 0.06
3.85 ± 0.05
Cr3+
(5c)2:Cr
(5c):Cr
(5d)2:Cr
(5d):Cr
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Supporting Information
Experimental procedures for compounds 2–5 and UV–vis
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Acknowledgements
This work was supported by the RFBR grant 16-03-00390 and
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