Molecular recognition and highly responsive signaling play an important role in host
and guest interactions, which have been extensively studied in biological systems
via supramolecular host–guest mechanisms.[1] Generally, macrocyclic structures with heterocyclic ring systems possess numerous
binding sites for metal ions[2a] that provide attractive properties as molecular hosts. In the last two decades,
the scaffolds of amide cyclophanes with rigid and highly sterically encumbered structures
have been explored for their use in supramolecular chemistry.[2`]
[c]
[d] Moreover, a piperazine precursor to the macrocyclic system provides an additional
donor site with the nitrogen embedded directly in the macrocyclic backbone.
Formation of macrocycles containing amide bonds can lead to a range of pharmaceutically
interesting biological activities.[3] Moreover, the presence of amide functionalities in supramolecular structures facilitates
their use as molecular receptors[4] for molecular recognition;[5] for instance anti-HIV active macrocyclic amides.[6] In addition, cyclic amides[7] have structural rigidity, receptor selectivity, and biochemical stability. Recently,
functionalized aza-oxo-thia macrocycles bearing tetra amides have been employed as
potential antimicrobial and anticancer agents.[8] The combination of a fluorophore-tag with cyclic peptides facilitates the selective
detection of Hg(II).[9] Furthermore, the possibility of intra- and intermolecular hydrogen bonding by the
amide functionality may lead to compact conformations and functions.[10] Cyclic amides have also been used as nanomaterial devices by the formation of tubular
structures that lead to stacking and self assembly.[11] Moreover, transition-metal ions such as Ru(II), Pd(II), Ni(II), Co(II), Cu(II),
and Fe(III)[12] show selective metal ion complexation behavior with cyclic amides by formation of
stable complexes. Conversely, cyclic amides have been found to be suitable neutral
hosts for anionic guest systems.[13] Earlier, we reported cyclophanes with intra-annular amide functionalities for selective
ion transportation[14] as well as for the development of bioactive compounds.[15] Piperazine-containing cyclophanes have rarely been reported.[16]
[5c] The ability of piperazines to form hydrogen bonds with guests plays a pivotal role
in biomedical and pharmaceutical fields. The presence of a piperazine in a cyclophane[17] offers rigidity. Piperazine could act as an electron-donor group along with alkynes
in cyclic amides.[18] In this sense, piperazine-amide macrocycles with a number of binding sites as well
as with electron-rich heteroatoms such as N, S, and rigid alkynes are of potential
interest.[19] Several attempts have been made to synthesize amide cyclophanes containing piperazines,[20] but these have involved multi-step approaches, necessitating protection and deprotection
strategies, extended reaction time for cyclization, and low reaction yields.[21]
Figure 1 Structures of piperazinoamide based 1:1 and 2:2 oligomeric forms of macrocycles 1–12
Herein, we report a simple approach for the synthesis of novel amidopiperazinophanes
1–6 and 7–12 (Figure [1]) of a 1:1 and 2:2 oligomeric nature, respectively, by using propargylamine and piperazine
as skeletons through one-pot multicomponent reaction (MCR) methodology. Moreover,
this synthetic approach has advantages, including ease of manipulation, simple purification
and intrinsic atom economy. These 1:1 monomeric and 2:2 dimeric forms of amidopiperazinophanes
offer both π electron-rich donor (π = phenyl, ethynyl) and efficient hydrogen-bond
acceptor systems (tertiary amine). Our observations suggest that these amide cyclophanes
could be potential candidates for pharmaceutical applications. Moreover, our findings
open up new perspectives to design and develop supramolecular scaffolds with amide
functionalities in the macrocyclic ring by using this simple synthetic approach.
Amidopiperazinophanes can be obtained from the corresponding S-bispropargyloxy precyclophanes. The precyclophane bis-alkyne system can be constructed
from the reaction of acid chlorides and S-propargyloxy-2-aminothiophenol. Mannich reaction methodology leads to the amide macrocycles
in an effective manner by condensation of the terminal bisalkyne, piperazine, and
formaldehyde through a multicomponent reaction (MCR).
To achieve target amide macrocycles 1–12, precyclophanes 13–18 with terminal bisalkynes were used as the main building blocks with S-propargyloxy-2-aminothiophenol 19
[3b] as the other starting precursor.
Scheme 1 Reagents and conditions: (i) NEt3, CH2Cl2 (dry), 12 h: (ii) piperazine, 37–41% aq. formaldehyde, CuCl, 90 °C, 2 h. 1 (31%); 2 (37%); 3 (30%); 4 (36%); 5 (32%); 6 (30%); 7 (23%); 8 (24%); 9 (27%); 10 (30%); 11 (18%); 12 (26%); 13 (56%);. 14 (65%); 15 (59%); 16 (71%); 17 (67%); 18 (78%).
In this context, our initial aim focused on the synthesis of the precyclophanes using
various aromatic diacid chlorides including phthaloyl chloride 20, isophthaloyl chloride 21, terephthaloyl chloride 22, pyridine-2,6-dicarboxylic acid chloride 23, 5-hydroxyisophthaloyl dichloride 24, and thiophene-2,5-dicarbonyl dichloride 25. Reaction of 1.0 equiv of each diacid chloride with 2.1 equiv of S-propargyloxy-2-aminothiophenol 19 at room temperature afforded the amide precyclophanes 13, 14, and 15 in 56, 65, and 59% yields, respectively. The synthesis was extended to incorporate
hydroxyl and electron-rich heteroatoms such as N and S at the intra-annular position
of the piperazinophanes, presenting features for hydrogen bonding and stacking along
with binding sites for guest species. As a consequence, precyclophanes 16, 17, and 18 were prepared by treating S-propargyloxy-2-aminothiophenol 19 with freshly prepared pyridine-2,6-dicarbonyl dichloride 23, 5-hydroxyisophthaloyl 24, and thiophene-2,5-dicarbonyl dichloride 25 in the presence of triethylamine in dichloromethane at room temperature for 12 h
to obtain 71, 67, and 78% yields, respectively (Scheme [1]). The aromatic diacid chlorides 20–25 were synthesized according to the reported procedure.[22]
The structure of precyclophane 16 was confirmed by 1H NMR spectroscopic analysis by the appearance of long-range coupling between the
two-proton triplet at δ = 1.91 (t, J = 2.1 Hz, 2 H) for the acetylenic proton and a doublet at δ = 3.41 (d, J = 2.4 Hz, 4 H) for S-methylene proton. The amide -NH proton appeared as a singlet at δ = 10.74 in addition
to the rest of the signals for eleven aromatic protons. In the 13C NMR spectrum, compound 16 presented signals from alkyne carbons, S-methylene and N-methylene carbons at δ = 24.4, 72.4, and 79.1, respectively, the amide carbonyl carbon
resonated at δ = 161.5 and nine aromatic carbons were present. The amide carbonyl
carbon of 16 was further evidenced by the appearance of a strong absorption band at 1656 cm–1 in the IR spectrum. Finally, the precyclophane structure 16 was confirmed by the observation of a molecular ion peak at m/z 457 [M+] in the mass spectrum.
The 1H NMR spectrum of precyclophane 18 contained signals at δ = 2.21 (t, J = 2.7 Hz, 2 H), and δ = 3.49 (d, J = 2.4 Hz, 4 H) for the acetylenic and S-methylene units, respectively, with a sharp singlet at δ = 9.47 corresponding to
the two amide NH protons, in addition to signals for ten aromatic protons. The 13C NMR spectrum of precyclophane 18 displayed resonances at δ = 25.3, 72.8, and 79.4 for alkyne, S-CH2 and N-CH2 carbons, respectively, aromatic carbon signals at δ = 120.3–143.8 and a resonance
at δ = 158.8 for the amide carbonyl carbon. A molecular ion peak of precyclophane
18 was observed at m/z 462 [M+] in the mass spectrum. Further spectroscopic and analytical data matched with the
structure of the precyclophane 18.
Our aim was to extend the study to various amidopiperazines with different heteroatoms
and aromatic monocyclic spacer units. Hence, coupling of 1.0 equiv of precyclophane
13–15 with 2.0 equiv of 37–41% aqueous formaldehyde, and 1.0 equiv of piperazine in the
presence of a catalytic amount of CuCl in anhydrous dioxane at 90 °C for 2 h furnished
functionalized 1:1 oligomeric amide cyclophanes 1, 2, and 3 with propargylamine and piperazine-containing skeletons in 31, 37, and 30%, yields,
respectively, and 2:2 oligomeric cyclophane amides 7, 8, and 9 with propargylamine and piperazine skeletons in 24, 27, and 30% yields, respectively.
The proton NMR spectrum of monomeric macrocyclic amide 2 indicated the singlets at δ = 2.10, 2.87, 3.54 for the piperazinyl, S-CH2, and N-CH2 protons, respectively, and the amide proton appeared as a sharp singlet at δ = 9.97.
The rest of the signals could be attributed to the aromatic protons. The 13C NMR spectrum showed four different signals for acetylene, piperazinyl and methylene
carbons at δ = 26.2, 47.1, 51.6 and 79.3, 80.5, respectively, and a signal at δ =
163.9 for the amide carbonyl, in addition to the signals due to the aromatic carbons.
Finally, the structure was confirmed by the appearance of a molecular ion at m/z 566.
The 1H NMR spectrum of 2:2 dimeric amidopiperazinophane 8 showed a sharp singlet at δ = 2.23 for the sixteen protons of piperazinyl units,
an eight-proton singlet at δ = 2.99 for S-CH2 protons, a sharp singlet at δ = 3.55 for the N-methylene protons, signals at δ = 7.13 to 8.60 for the aromatic protons along with
the four amide protons observed as a sharp singlet at δ = 9.68. In the 13C NMR spectrum, signals at δ = 25.7, 46.8, 51.4, 79.5, 80.5 and 120.7–140.2 corresponded
to the piperazinyl, S-methylene, N-methylene, acetylenic carbons and the aromatic carbons, respectively. The amide carbonyl
carbon was observed at δ = 164.0. The structure of 2:2 oligomeric amidopiperazinophane
8 was confirmed by the appearance of a molecular ion at m/z 1132 [M+] in the mass spectrum. Similarly, the structure of the remaining 1:1 oligomeric amide
macrocycles 1, 3 and 2:2 oligomeric amidopiperazinophanes 5, 7 were confirmed by spectroscopic and analytical data.
The crystal structure of amidopiperazinophane 2 (Figure [2]) showed a relatively planar bis(2-mercaptophenyl)isophthalamide fragment linked
to the tertiary amine of the piperazine unit. The mercaptophenyl unit is highly strained
and turned away from the ring of isophthalamide by 8.18 (11) and 5.59 (10)°, at the
same time these two rings are horizontally turned towards each another by 9.10 (12)°.
Two intramolecular hydrogen bonds can be identified, generating S(5) ring motifs and
the structure is further stabilized by hydrogen bonds of C–H···S and C–H···O. The
oxygen atoms of the amide carbonyl linked to the isophthaloyl ring is disordered over
two positions with an occupancy ratio of 0.41(6):0.59(6).[23]
Figure 2 Single-crystal structure and molecular packing view of cyclophane amide 2
Our strategy was extended to the synthesis of amide piperazinophanes containing two
and four amide groups with different functional groups, as well as electron donor/acceptor
heteroatoms at intra-annular positions by introducing the pyridine-2,6-dicarbonyl,
5-hydroxyisophthaloyl and 2,5-thiophenedicarbonyl units. Thus, 1.0 equiv of precyclophane
diynes 16, 17 and 18 were treated with 37–41% aq. formaldehyde (2.0 equiv) and piperazine (1.0 equiv),
in the presence of a catalytic amount of CuCl in anhydrous dioxane at 90 °C for 2
h to form 1:1 oligomeric amide macrocycles 4, 5, 6 in 36, 32, and 30% yields, respectively, and 2:2 oligomeric amides macrocycles 10, 11 and 12 in 23, 18, and 26 yields, respectively.
The formation of 1:1 cyclophane 4 was confirmed by the appearance of an intense absorption band at 1664 cm–1 in the FTIR spectrum for the amide carbonyl. The 1H NMR spectrum displayed three sharp singlets at δ = 2.22, 3.11, and 3.66 for the
protons of the piperazinyl, S-methylene, and N-methylene units, respectively, along with a sharp singlet at δ = 10.76 for the amide
protons in the deshielded region in addition to the signals for the aromatic unit.
In the 13C NMR spectrum, signals for the piperazine carbons, methylene carbons connected to
sulfur, and nitrogen and the amide carbon at δ = 22.7, 46.8, 50.5, and 163.1, respectively,
in addition to the aromatic carbons were observed. The molecular ion was found at
m/z 567 [M+] in the mass spectrum and a satisfactory elemental analysis was obtained.
Similarly, the structure of 2:2 oligomeric cyclophane amide 10 was confirmed by 1H NMR spectroscopy through the appearance of a sharp singlet at δ = 2.34 for sixteen
protons of the piperazine skeleton, an eight proton singlet at δ = 3.02 for S-CH2 group and a singlet at δ = 3.60 for the N-CH2 protons with the rest of the signals at δ = 7.20–8.54 corresponding to the aromatic
protons. The amide protons resonated at δ = 10.71. In the 13C spectrum, signals at δ = 24.7, and 46.9, 51.4, and 79.3, 80.5 could be assigned
to the piperazinyl, acetylenic S-CH2, and N-CH2 groups, resonances between δ = 121.9 to 149.3 for the aromatic carbons and the amide
carbons appeared at δ = 161.5. The FTIR spectrum showed an absorption band at 1656
cm–1 for the amide carbonyl and a molecular ion was observed at m/z 1134 [M+] in the mass spectrum.
Analogously, the 1H NMR spectrum of the dimeric amide macrocyclic receptor 12 displayed three sharp singlets at δ = 2.36, 3.10 and 3.56 for the piperazine, S-methylene and N-methylene protons, respectively. A sharp singlet was observed at δ = 9.53 for the
four protons of the amide unit in addition to the signals for the aromatic protons.
The 13C NMR spectrum displayed carbon signals at δ = 25.7, 46.8, 51.2, 79.0, and 80.9 for
the S-CH2, N-CH2, piperazine and alkyne carbon, respectively, in addition to signals between δ = 120.5–143.8
assigned to the aromatic carbons. The amide carbonyl resonance was observed at δ =
158.8. A molecular ion was observed at m/z 1144 [M+] in the mass spectrum and its chemical composition was also evaluated by elemental
analysis.
Similarly, other structures of 1:1 oligomeric and 2:2 oligomeric cyclophane amide
5, 6 and 11 bearing strong binding sites and electron-rich donor/acceptor units were completely
characterized and confirmed by full spectroscopic and analytical analyses.
In summary, a simple approach to the synthesis of a family of amidopiperazinophane
with an intra-annular amide unit with various spacer units has been achieved with
good yields via Mannich reaction in a mild, straightforward, sequential, and rapid
one-pot multicomponent reaction (MCR).[24] All the amidopiperazonophane structures were completely characterized and confirmed
by using standard spectroscopic and analytical methods. By taking account the merits
of the synthetic strategy, our investigation will open new avenues for the design
and synthesis of novel amidopiperazinophanes, with various binding sites with electron
donor/acceptor units.
