An Atom-Economical Method for the Formation of Amidopyrroles Exploiting the Self-Assembled Resorcinarene Capsule

Article abstract of DOI:10.1021/acs.orglett.0c00529

Here is reported the first example of an organocatalyzed coupling between pyrrole and isocyanates in a nanoconfined space. The hexameric resorcinarene capsule C is able to catalyze the direct coupling between isocyanates and pyrroles to give amidopyrroles

Full text of DOI:10.1021/acs.orglett.0c00529

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Letter
An Atom-Economical Method for the Formation of Amidopyrroles
Exploiting the Self-Assembled Resorcinarene Capsule
Pellegrino La Manna, Carmen Talotta,* Margherita De Rosa, Annunziata Soriente, Carmine Gaeta,
and Placido Neri*
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ABSTRACT: Here is reported the first example of an organocatalyzed coupling between pyrrole and
isocyanates in a nanoconfined space. The hexameric resorcinarene capsule C is able to catalyze the
direct coupling between isocyanates and pyrroles to give amidopyrroles with excellent yields and
selectivities. The reaction catalyzed by C prevents the use of expensive and poorly atom-economical
reagents. As in natural enzymes, the cavity of C is able to discriminate between isomeric substrates.
mide linkages are a bedrock in living systems where they
Aare continuously formed by complex natural catalytic
systems such as ribosomes.1 Additionally, amide bond
formation can be considered as one of the most exploited
reactions in the synthesis of drug candidates,2 host systems for
anion recognition,3 and materials of industrial relevance.1 The
amide bond is also found in amidopyrroles, which play
important roles in medicinal chemistry, where they act as
anticancer agents. Thus, distamycin A and its derivatives act as
inhibitors of DNA ligases, which are considered as druggable
targets in cancer therapy.4 Amidopyrroles such as N-benzyl-
Figure 1. C-undecylresorcin[4]arene 1 self-assembles to form the
hexameric resorcinarene capsule C in the presence of H2O-saturated
CDCl3. In blue are shown the bridging water molecules with H-bond-
donating free valence toward the center of the cavity of C.
and N-propargyl-1H-pyrrole-2-carboxamides show MAO in-
hibition activity.5
Traditionally, amide bond formation is obtained by acylation
of amines with carboxylic acids activated by means of coupling
reagents (e.g., DCC).1,2 This strategy uses expensive reagents
that show poor atom economy and for these reasons is
considered nonsustainable.6 On the other hand, biocatalyzed
amide-bond-forming reactions are considered as highly
sustainable.6 In fact, biocatalysts work under mild conditions
with excellent stereo- and regioselectivity, avoiding poorly
atom-economical reagents. In the last decades, scientists have
invested considerable efforts to reduce the gap between
artificial catalytic systems and their natural counterparts.7
In the past few years, several research groups have focused
their attention on the self-assembled resorcinarene capsule C
(Figure 1), which shows an internal cavity reminiscent of
natural enzyme pockets.8,9 C is formed by six resorcinarenes 1
and eight water molecules to give a self-assembled structure
sealed by 60 H-bonds with the water molecules occupying the
corners (Figure 1).9 This self-assembled capsule shows
intriguing features that make it particularly adapt for enzyme
mimicry:8 (a) it presents a π-electron-rich cavity of 1375 Å3
that can act as an enzyme pocket; (b) the inner cavity is able to
recognize neutral and cationic species and stabilize transition
states thanks to secondary interactions; (c) it behaves as a mild
Brønsted acid with a pKa value of about 5.5−6.0; (d) its inner
Received: February 10, 2020
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© XXXX American Chemical Society
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A

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cavity can establish H-bonding interactions with hosted
molecules thanks to the presence of bridging water molecules
with H-bond-donating free valence (Figure 1).8 These catalytic
features have been exploited with amazing results in the
literature.8,10,11
substrates 2a and 3a to 4aa, even after a prolonged reaction
time (Table 1, entry 1).
With these results in hand, a series of experiments were
performed in order to investigate the effects of the reaction
conditions on the efficiency of the reaction (Table 1, entries
3−6). When the reaction between 2a and 3a was performed in
the presence of a lower amount of C (15 mol %), the product
4aa was isolated in a very low yield (Table 1, entry 3). With 40
mol % C, amidopyrrole 4aa was isolated in a slightly lower
yield (85%; Table 1, entry 4) with respect to the run with 26
mol % C. Finally, a lowering of the reaction yield was observed
when the 2a/3a ratio was lowered to 2 or 1 (Table 1, entries 5
and 6). Following a standard protocol previously reported by
us and others,8,10,11 the role of capsule C in the catalysis of the
reaction in Table 1 was studied. When the reaction between 2a
and 3a in the presence of C was performed under the same
conditions but in the presence of tetraethylammonium
tetrafluoroborate (5) (Figure 2b), a known competitive guest
With regard to the synthesis of amidopyrrole derivatives, an
interesting work reported by Neumann in 199012 showed that
isocyanates can be considered as a useful vector for amide
linkage. The authors reported the reaction of trialkylstannyl-
substituted aromatic and heterocyclic compounds with aryl
isocyanates in the presence of aluminum trichloride to give N-
aryl-substituted amides.12 In a similar vein, in 1988 Katritzky13
reported the formation of amidopyrroles by reaction of C-
lithiated pyrroles with isocyanates. More recently, the
formation of amidopyrroles by rhenium-catalyzed insertion of
isocyanates into C−H bonds of heteroaromatic compounds
was reported.14 However, all of these strategies showed poor
atom economy because of the reagents necessary for the
activation of the pyrrole nucleophiles. To the best of our
knowledge, no examples have been reported in the literature
regarding the organocatalyzed formation of amidopyrroles
from pyrroles and isocyanates. Prompted by these consid-
erations, we decided to explore the organocatalyzed, atom-
economical formation of amidopyrroles by confinement of
pyrrole and isocyanate inside capsule C.15 As a preliminary
step, we started our investigation by testing the reaction
between N-methylpyrrole (2a) and phenyl isocyanate (3a)
(Table 1). Their reaction in the presence of 26 mol % capsule
C at 50 °C for 40 h in water-saturated CDCl3 afforded 4aa in
99% yield (Table 1, entry 2).
The presence of C is mandatory in order to ensure a
successful outcome of the reaction. In fact, the reaction
performed under the same conditions (Table 1, entry 2) but in
the absence of capsule C did not show any conversion of
Table 1. Optimization of the Reaction Conditions for the
a
Coupling of 2a with 3a
Figure 2. (a) Proposed mechanism for the formation of amidopyrrole
4aa inside C. (b) Proposed mechanism for the competitive inhibition
of C by tetraethylammonium tetrafluoroborate (5).
with high affinity for the inner cavity of C,8 then no hint of
product 4aa was detected in the reaction mixture (Table 1,
entry 7). Analogously, upon addition of dimethyl sulfoxide,
which can dissociate the capsule by breaking its H-bonding
network, no evidence of product 4aa was detected (Table 1,
entry 8). These results confirmed that the reaction takes place
inside the capsule C through the formation of the
heterocomplex 2a+3a@C in Figure 2.
At this point, the scope of the reaction between pyrroles and
isocyanates was studied under the optimized conditions (Table
1, entry 2) using pyrrole derivatives bearing different N
substituents (Scheme 1). In accord with the nucleophilicity
scale of typical π systems reported by Mayr and co-workers,16
the less nucleophilic unsubstituted pyrrole (2b) showed a
lower reactivity than N-methylpyrrole 2a toward isocyanate 3a,
thus requiring 72 h, rather than 40 h, to give product 4ab in
99% yield (Scheme 1). Interestingly, other N-substituted
pyrroles 2c−f (Scheme 1) gave the corresponding amidopyr-
roles by reaction with 3a in high yields but after longer reaction
times than with 2a. The reaction between isocyanate 3a and N-
b
c
entry
capsule (mol %)
2a/3a
T (°C)
t (h)
yield (%)
d
1
2
3
4
5
6
7
8
−
4
4
4
4
2
1
4
4
50
50
50
50
50
50
50
50
40
40
40
40
40
40
40
40
−
99
e f
,
26
15
40
26
26
26
26
5
85
38
11
g
−
−
h
a
Reaction conditions: 2a (0.59 M), 3a (0.15 M), H2O-saturated
CDCl3 (1.1 mL). Calculated with respect to 3a. Yield of the product
isolated by column chromatography. Only starting materials were
recovered. The same result was obtained using H2O-saturated
CHCl3. Experiments on the reusability of C under these optimized
conditions were performed, giving a positive indication of the
reusability of the capsule C. Indeed, the activity was maintained after
three cycles: run 2, 90%; run 3, 75% . The reaction was performed in
b
c
d
e
f
g
the presence of tetraethylammonium tetrafluoroborate (0.76 M).
The reaction was carried out in the presence of DMSO (0.76 M).
h
B
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d
successive prototropic equilibrium give the final amidopyrrole
product 4aa.
Scheme 1. Synthesis of Amidopyrroles 4aa−ar
Spectroscopic evidence for the encapsulation of pyrrole 2a
inside C was previously reported by our group.10 In addition,
the encapsulation of 3a was ascertained by 2D EXSY and
DOSY NMR experiments following a standard protocol
previously reported by us and others.10 In detail, the 2D
EXSY spectrum of the mixture of 3a and C in water-saturated
CDCl3 evidenced the presence of an exchange cross-peak at
3.81/7.11 ppm between the aromatic signals of isocyanate 3a
inside and outside capsule C, respectively (Figures S5 and S6).
Furthermore, the DOSY NMR experiment (Figure S7)
indicated that the aromatic protons of the encapsulated 3a,
at 3.81 ppm, showed the same diffusion coefficient as the
hexameric capsule C. Analogously, the formation of the
catalytically active 2a+3a@C heterocomplex was ascertained
by 2D EXSY and DOSY NMR experiments. In detail, an
exchange cross-peak was found at 5.27/6.19 ppm (Figure
S154) attributable to aromatic protons of 2a inside and outside
the capsule. Analogously, exchange cross-peaks were observed
at 3.09/7.12 and 3.31/7.35 ppm that were attributable to
aromatic signals of 3a inside/outside the capsule. The
generality of the procedure here described was further proved
by experiments summarized in Figure 3. In fact, ortho- and
a
b
c
Conditions reported in Table 1, entry 2, 40 h. 72 h. 96 h.
d
Reaction conditions: 2a−r (0.59 M), 3a (0.15 M), C (0.039 M),
H2O-saturated CHCl3 (1.1 mL). Yields of the products isolated by
column chromatography are shown. In the numbering scheme 4ax,
the blue and red letters refer to the pyrrole and isocyanate starting
compounds 2a−r and 3a, respectively.
phenylpyrrole (2f) gave the expected amidopyrrole 4af in 74%
yield after 96 h (Scheme 1), indicating in this way its lower
reactivity with respect to N-alkyl-substituted pyrroles 2a, 2c,
and 2d bearing smaller N substituents. Interestingly, when the
N-phenyl group of 2 was para-substituted as in 2g−j, no hint
of the corresponding products was detected in the reaction
mixtures with 3a (Scheme 1). When pyrrole 2k bearing a meta-
OMe-substitued N-phenyl group was used, the reaction with
3a gave amidopyrrole 4ak in 22% yield after 96 h. The yield
increased to 99% when isomeric 2l with the ortho-OMe-
substituted N-phenyl group was used. In a similar way, when
N-benzyl-substituted pyrroles 2m−r were investigated in the
reaction with 3a, the ortho-substituted pyrroles 2m, 2o, and 2q
showed higher reactivity than the meta-substituted isomers 2n,
2p, and 2r (Scheme 1). All of these results clearly indicated
that the formation of the catalytically active heterocomplexes
2+3a@C is favored with pyrroles 2m−r bearing ortho- or meta-
substituted phenyl groups with respect to the longer para-
substituted isomers 2g−j, which are more sterically demand-
ing.17 Overall, these results clearly indicate that, like a natural
enzyme, capsule C is able to discriminate the pair of substrates
pyrrole/phenyl isocyanate by inclusion inside its cavity. In
particular, concerning the N-phenyl- or N-benzylpyrroles,
capsule C shows the affinity scale ortho > meta > para with
regard to substitution.17 On the basis of these observations
(Scheme 1), we propose the mechanism reported in Figure 2
for the formation of amidopyrrole derivatives 4 in the
nanoconfined space of C. Initially, the heterocomplex 2+3a@
C is formed, with isocyanate 3a H-bonded to a bridging water
molecule.18 At this point, α-attack of the pyrrole to the H-
bonded activated isocyanate 3a occurs inside the capsule,
leading to intermediate I, which is stabilized through H-
bonding interactions. Then the rearomatization of I and the
Figure 3. Synthesis of amidopyrroles starting from appropriate
isocyanates 3b−j. Reaction conditions: 2a,b,e (0.59 M), 3b−j (0.15
M), C (0,039 M), water-saturated CHCl3 (1.1 mL). The yield of the
product isolated by column chromatography is given in parentheses.
(a) Starting with N-methylpyrrole (2a) and appropriate isocyanates
3b−j. (b) Starting with pyrrole (2b) and isocyanates 3b, 3f, and 3d.
(c) Starting with N-benzylpyrrole (2e) and isocyanates 3b, 3f, 3d, and
3g. In the numbering scheme 4xx, the blue and red letters refer to the
isocyanate and pyrrole starting compounds 2 and 3, respectively.
para-substituted aromatic isocyanates 3b−i were also able to
react with N-methylpyrrole 2a, leading to amidopyrroles 4(b−
i)a in high yields (Figure 3a). Notably, the large 1-naphthyl
isocyanate (3i) had also no difficulty in reacting with 2a to give
product 4ia (Figure 3a). Moreover, benzyl isocyanate (3j)
afforded amide 4ja in good yield. Analogously, unsubstituted
pyrrole 2b and N-benzylpyrrole (2e) gave the corresponding
amidopyrroles in Figure 3b,c upon reaction with the
appropriate isocyanates in the presence of capsule C.
These results indicated that the reaction is less affected by
the changes in isocyanates 3 with respect to the substituent
effects observed for pyrroles 2. In analogy with previous
results,10,11 this difference can be explained in the following
way. As reported in Figure 2a, an isocyanate substrate 3 is
involved in a strong H-bonding interaction with a bridging
water molecule of the capsule, whereas pyrrole substrate 2
interacts only through weaker van der Waals-like interactions
C
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Notes
(CH−π and π−π). Therefore, the isocyanate substrate 3, being
more tightly bound, first occupies all of the needed space in the
large capsule volume with no size discrimination. At this point,
the more loosely bound pyrrole substrate 2 can occupy only
the free space left over by 3, which is quite smaller and hence
exerts the observed size discrimination. Interestingly, iso-
cyanates did not undergo hydrolysis under the experimental
reaction conditions. This was confirmed with blank experi-
ments performed with isocyanate substrate 3a alone in water-
saturated chloroform in the presence or absence of capsule C
(see the Supporting Information), where hydrolysis product(s)
could not be detected. This behavior can be mainly ascribed to
the known low reactivity of aryl isocyanates.
In conclusion, we have here reported an example of
organocatalyzed amide bond formation that exploits the
nanoconfined space inside the hexameric resorcinarene
capsule. Thus, amidopyrroles were obtained with excellent
yields and selectivities by the direct coupling between
isocyanates and pyrroles. Like an enzyme pocket, the inner
cavity of the capsule is able to discriminate isomeric substrates.
The strategy here described is highly sustainable and prevents
the use of expensive and poorly atom-economical coupling
reagents.
The authors declare no competing financial interest.
REFERENCES
■
(1) Arthur, G. The Amide Linkage: Selected Structural Aspects in
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A.; Rescifina, A.; Gaeta, C.; Neri, P. Mild Friedel-Crafts Reactions
inside a Hexameric Resorcinarene Capsule: C-Cl Bond Activation
through Hydrogen Bonding to Bridging Water Molecules. Angew.
Chem., Int. Ed. 2018, 57, 5423−5428.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00529.
■
sı
Detailed synthetic procedures, characterization of supra-
molecular complexes with the capsule C, and 1D and 2D
NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Carmen Talotta − Laboratory of Supramolecular Chemistry,
Dipartimento di Chimica e Biologia “A. Zambelli”, Universita di
Salerno I-84084 Fisciano, Salerno, Italy; orcid.org/0000-
0002-2142-6305; Email: ctalotta@unisa.it
Placido Neri − Laboratory of Supramolecular Chemistry,
Dipartimento di Chimica e Biologia “A. Zambelli”, Universita di
Salerno I-84084 Fisciano, Salerno, Italy; orcid.org/0000-
0003-4319-1727; Email: neri@unisa.it
̀
̀
Authors
Pellegrino La Manna − Laboratory of Supramolecular
Chemistry, Dipartimento di Chimica e Biologia “A. Zambelli”,
̀
Universita di Salerno I-84084 Fisciano, Salerno, Italy
Margherita De Rosa − Laboratory of Supramolecular
Chemistry, Dipartimento di Chimica e Biologia “A. Zambelli”,
̀
Universita di Salerno I-84084 Fisciano, Salerno, Italy;
orcid.org/0000-0001-7451-5523
Annunziata Soriente − Laboratory of Supramolecular
Chemistry, Dipartimento di Chimica e Biologia “A. Zambelli”,
̀
Universita di Salerno I-84084 Fisciano, Salerno, Italy;
orcid.org/0000-0001-6937-8405
Carmine Gaeta − Laboratory of Supramolecular Chemistry,
Dipartimento di Chimica e Biologia “A. Zambelli”, Universita
di Salerno I-84084 Fisciano, Salerno, Italy; orcid.org/
0000-0002-2160-8977
̀
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00529
D
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Within a Self-Assembled Hexameric Capsule. Chem. Commun. 2015,
51, 1658−1661. (b) In the field of amide bond formation, reactions
conducted in the absence of an activating agent (e.g., DCC) but in the
presence of an excess of reagent, acetylene, and a ruthenium catalyst
are still considered as “atom-economical” in the literature.15c In our
instance, there are no activating agents, and the excess pyrrole
substrate can be easily reused. On this basis, our method can be
considered as atom-economical. (c) Krause, T.; Baader, S.; Erb, B.;
Gooßen, L. J. Atom-economic catalytic amide synthesis from amines
and carboxylic acids activated in situ with acetylenes. Nat. Commun.
2016, 7, 1−7.
(16) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Electrophilic
Alkylations in Neutral Aqueous or Alcoholic Solutions. Angew. Chem.,
Int. Ed. 2004, 43, 5402−5405.
(17) An analogous substrate selectivity was reported in ref 14. Also
see: Cavarzan, A.; Reek, J. N. H.; Trentin, F.; Scarso, A.; Strukul, G.
Substrate Selectivity in the Alkyne Hydration Mediated by NHC−
Au(I) Controlled by Encapsulation of the Catalyst Within a
Hydrogen Bonded Hexameric Host. Catal. Sci. Technol. 2013, 3,
2898−2901.
(18) The abilty of the hexameric capsule C to act as a H-bond
catalyst thanks to the presence of bridging water molecules with H-
bond free valence (see Figure 1) has been previously shown by our
groups in refs 9 and 10.
E
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