Calix[6]arene-based Br?nsted acids for molecular recognition and catalysis

Article abstract of DOI:10.1039/d0ob02393k

We report the synthesis of a versatile trifluoromethylsulfonamide calix[6]arene derivative with Br?nsted acid features which can influence both molecular recognition and catalytic application. Indeed, in low polarity media, the trifluoromethyl-containing

Full text of DOI:10.1039/d0ob02393k

Organic &
Biomolecular Chemistry
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PAPER
Calix[6]arene-based Brønsted acids for molecular
recognition and catalysis†
Cite this: Org. Biomol. Chem., 2021,
19, 1546
Gianpiero Cera, * Federica Cester Bonati, Margherita Bazzoni,
Andrea Secchi * and Arturo Arduini
*
We report the synthesis of a versatile trifluoromethylsulfonamide calix[6]arene derivative with Brønsted
acid features which can influence both molecular recognition and catalytic application. Indeed, in low
polarity media, the trifluoromethyl-containing supramolecular wheel is able to respond to the complexa-
tion with charged species as a function of its selective ion-pair recognition. In parallel, the enhanced
acidity is the key to promote Michael additions of indoles to nitroalkenes under pseudo-physiological
reaction conditions (H2O, 37 °C).
Received 1st December 2020,
Accepted 20th January 2021
DOI: 10.1039/d0ob02393k
rsc.li/obc
hosting molecules via the hydrophobic effect and as catalysts
Introduction
thanks to their acidic sulfonic moieties.9 In contrast, TSAs
Calix[6]arenes represent a fascinating class of macrocycles that exploit their versatile hydrogen-bonding domain to influence
has been extensively employed as a platform to construct syn- both an ion-pair selective formation of pseudorotaxanes and
thetic receptors for neutral and charged species.1 In this the promotion of catalytic transformations. However, their
context, the possibility that this macrocycle could be functio- function is governed by the nature of the substituent on the
nalised regioselectively prompted our research group to intro-
duce a new class of non-palindromic wheels which are able to
bind di- and monocationic species in a programmed manner.2
This finding led to exploiting the reactivity of heteroditopic
calix[6]arenes for the synthesis of oriented (pseudo)rotaxanes
and stimuli-responsive prototypes of molecular machines.3 In
fact, the threading process that guides the formation of
inclusion complexes with viologen salts is highly dominated
by hydrogen bonding interactions.4 Also, in apolar media, phe-
nylureido groups are able to separate the ion pair of the bipyri-
dinium salt, thus dictating the threading of the axle inside the
π-rich aromatic cavity. More recently, we demonstrated how
aromatic sulfonamide moieties5 could be employed as binding
sites for counterion-dependent molecular recognition of dica-
tionic viologen salts.6 Remarkably, this class of trisulfonamide
calix[6]arenes (TSA) could serve as Brønsted acid catalysts for
the Friedel–Crafts-type alkylation reactions in polar protic
organic media.7 These findings are of high importance in the
field of calix[6]arene chemistry since, to the best of our knowl-
edge, only hexasulfonated calix[6]arene derivatives display com-
parable properties (Fig. 1, a).8 These Brønsted acids, extensively
employed in supramolecular chemistry, are able to work as
Università di Parma, Dipartimento di Scienze Chimiche, della Vita e della
Sostenibilità Ambientale, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
E-mail: gianpiero.cera@unipr.it, andrea.secchi@unipr.it, arturo.arduini@unipr.it
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Comparing the reactivity of hexasulfonated calix[6]arenes with
d0ob02393k
heteroditopic trisulfonamido (TSA) analogues.
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arene ring. In fact, electron-donating groups are crucial to pro-
moting a highly selective rearrangement of the host in the
presence of tight ion-pairs. In contrast, only TSAs, substituted
at the para-position with three nitro groups, were able to work
as effective catalysts (Fig. 1, b).
Prompted by these findings, and inspired by the unique
physical and chemical properties of the trifluoromethyl
group,10 we now introduce a new calix[6]arene derivative with
the upper ring functionalised with three triflyl-amide moieties
(Fig. 1, c). This wheel displays a unified reactivity that allows
its function both as a receptor for selective ion-pair reco-
gnition and as a highly efficient catalyst for the Michael
addition to nitroalkenes.
Results and discussion
At the outset of the investigation, following established proto-
cols,6 we synthesised a new calix[6]arene derivative F from a
known trioctyloxy trinitro derivative TN (Scheme 1).
Its conformation in solution was subsequently investigated.
In apolar solvents, F is present as a mixture (2 : 1) of two con-
formations in a slow exchange at the NMR timescale (see
Fig. S2 and 3 in the ESI†). The major one was established to be
a typical pseudo cone as reflected by its AX system of two doub-
2
Fig. 2 The Gutmann–Beckett plot showing the influence of TSAs (3
equiv.) on TEPO (1 equiv.) in C6D6 as expressed by the variations in the
chemical shift of the 31PNMR spectrum when compared to the refer-
ence TEPO.
lets with a geminal coupling of J = 15.3 Hz of the methylene
groups of the calix[6]arene ring. The second, minor one, was
attributed to a “distorted” pseudo cone conformer. This is
characterised by a moderate “down-field” shift (0.5 ppm) of
the two methoxy groups in a 2 : 1 ratio analogously to what we
previously observed for this class of compounds. Having now
at our disposal a family of diversely substituted TSA calix[6]
arenes which were previously synthesised in our preliminary
studies (Fig. 2, A–E),6,7 we decided to investigate the influence
of the substitution pattern on their eventual, relative Brønsted
acidity.11 To this end, we compared their interactions with a
weak Lewis base such as triethylphosphino oxide (TEPO) in
apolar solvents. Indeed, it is known that a rapid formation of a
hydrogen bond complex would lead to a single downfield shift
of the 31P NMR signal. Taking as a reference the 31P NMR of
TEPO (5 mM in C6D6), we thus constructed a Gutman–Beckett
plot (Fig. 2).12 Quite expectedly, the para-nitro substituted E
was the most acidic (ΔδPP = 8.7 ppm) along the series of
the aromatic sulfonamides that we described in our previous
work. However, the newly developed TSA F, outcompeted all
the other parental TSA calix[6]arenes with a remarkable shift
of ΔδPP = 11.7 ppm, highlighting the role of the trifluoro-
methyl group in increasing the Brønsted acidity of the supra-
molecular wheel.
It became interesting at this stage to evaluate if this
enhanced acidity could deplete the ability of F to form
inclusion complexes with bipyridinium salts. Hence, we per-
formed spectrophotometric titrations using DOV·2OTs as the
guest. The formation of a CT band at 270 nm and an apparent
stability constant log K1:1 of 3.5 suggested the formation of a
pseudorotaxane complex.13
This value, one order of magnitude lower with respect to
aromatic TSA pseudorotaxanes, prompted us to compare the
apparent stability constants with the corresponding ΔδPP
values. We obtained a linear correlation that explains the
reduced stability of the complex in terms of enhanced
Brønsted acidity of the TSA rather than a depletion of the
π-electron-density of the calix[6]arene cavity (Fig. 3).
Subsequently, we equilibrated a solution of F in CDCl3 in
the presence of a previously employed viologen salt derivative
(DOV·2OTs) at 298 K. The 1H-NMR analysis of the resulting
yellow mixture highlighted the fairly selective formation of a
pseudorotaxane P[F(pC) . DOV]2OTs in which the host adopts
a partial cone conformation (pC/C ∼ 4 : 1, Fig. 4).
The main features of the 1H-NMR spectrum included a sub-
stantial downfield shift (1.5–2 ppm) and the splitting in two
Scheme 1 Synthesis of the trifluoromethyl sulfonamido calix[6]arene
TSA F.
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features of the electron-rich TSAs A and C (entry 5). This
remarkable effect could be attributed to the limited steric hin-
drance offered by the trifluoromethyl groups which allow an
efficient stabilisation of the partial cone conformation. Such a
manifold occurs by hydrogen-bonding interactions operated
by a tosylate counterion that acts as a bridge between two adja-
cent trifluoromethylsulfonamide moieties.6 Encouraged by the
features of F, we subsequently attempted the complexation
using a parental viologen-based axle with two iodides as the
weaker coordinating counterions (DOV·2I).
A marked difference was now observed. The NMR analysis
showed that F is still able to form a pseudorotaxane, but
majorly adopting a cone conformation (pC/C ∼ 1 : 2, entry 5).13
Hence, in an analogy with the parental TSA A (entry 7), calix[6]
arene wheel F is still able to selectively respond to the com-
plexation with viologen based axles, with a conformational
rearrangement dictated by the nature of the ion-pair.14
Once having demonstrated that the relative higher acidity of
F could be still exploited to control the conformation of the
newly developed calix[6]arene wheel, we moved our attention
to its catalytic application.15 In particular, one of the most
encountered challenges in supramolecular organic chemistry
is the development of catalytic methodologies that are able to
mimic the high performances offered by biological pro-
cesses.16 In this context, enzymes could be considered as the
most powerful supramolecular machines due to their ability to
promote organic transformations with incredible levels of
Fig. 3 Log K1:1 vs. ΔδPP values for P[(A, C–F) . DOV]2OTs.
signals in a 2 : 1 ratio (£ + $) of the methoxy groups.
Furthermore, also in this case, the two doublets of the methyl-
ene bridge split into three couples of doublets, one of those
(a/a′ couple) suffered a considerable shift of the 13C NMR reso-
nances to δ 35.3 ppm, denotative of an inversion point associ-
ated with a methoxy-substituted ring (Fig. S5 and related
spectra in the ESI†). Interestingly, the increased Brønsted
acidity of F, should have led to a drop in the partial cone vs.
cone selectivity as previously demonstrated for aromatic-substi-
tuted TSAs (Table 1, entries 1–4). Nevertheless, complexation
of F with viologen-based axles, which presents tight ion pairs
such as DOV·2OTs, occurs with a selectivity that parallels the
Fig. 4 1H-NMR spectra (400 MHz, 298 K of (a) DOV·2OTs in CD3CN, (b) pseudorotaxane P[F(pC) . DOV]2OTs in CDCl3, (c) calixarene F in CDCl3.
Bottom-right: schematic representation of F and P[F(pC) . DOV]2OTs. The color of the ovals/rectangle indicate the relative position of the phenolic
substituent with respect to the plane defined by the bridging methylene groups (hexagon), i.e. black upward, white downward. The rectangle ident-
ifies the phenolic ring substituted with the octyloxy chains while the circle those with the methoxy groups.
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Table 1 Ion-pair selective pseudorotaxane formation using TSA A, C–E
and F
Table 2 Optimisation of reaction conditions
Entrya
Calix[6]arene
Conv. [%]
Yields [%]
1
2
3
4
5
6
7
—
A
B
C
D
E
45
75
74
61
75
86
100
69
73
12
(42)
69
71
56
72
82
96
66
70
(8)
Entry
TSA
X
ΔδPP
pC : C
1
2
3
4
5
6
7
A (R = 4-MeC6H4)
C (R = 4-MeOC6H4)
D (R = 4-ClC6H4)
E (R = 4-NO2C6H4)
F (R = CF3C6H4)
F (R = CF3C6H4)
A (R = 4-MeC6H4)
OTs
OTs
OTs
OTs
OTs
I
6.3
4.0
7.7
∼5 : 1a
∼5 : 1a
∼4 : 1a
∼3 : 1a
∼4 : 1
F
8
G
H
F
9b
10c
8.1
11.7
11.7
6.3
∼1 : 2
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), calix[6]arene
(5 mol%), H2O (0.5 ml, 0.4 M), 37 °C, 16 h, isolated yields. Yields cal-
culated by 1H-NMR integration using 1,3,5-trimethoxybenzene as an
internal standard are shown in brackets. b H (15 mol%) was employed.
c Using toluene (0.5 ml, 0.4 M) as the solvent.
I
∼1 : 2a
a See ref. 6.
selectivity and efficiency.17 As a consequence of the ability of
TSAs to engage in strong hydrogen bonding interactions with
water in the solid state,7 we thus investigated the possibility of
developing a synthetic protocol for a Michael addition of
indoles 2 to conjugate alkenes 1,18 using water as the safest
and environmentally low-impact solvent.
Indeed, after having identified water at 37 °C as the
optimal, quasi-physiological reaction conditions for the cataly-
sis,19 we started the screening of the previously synthesised
TSAs.
.
of the supramolecular wheel. This effect, in turn, results in an
Interestingly, in all the cases under study, “on-water” con- enhanced rate of catalysis. The crucial role of the solvent was
ditions associated with the use of TSAs (5 mol% loading) led finally investigated by performing the reaction in a low-polarity
to a notable acceleration of the reactivity.20 Aromatic sulfona- solvent such as toluene, which led to poor conversion of the
mides A–C substituted at the para-position with EDG groups starting material (entry 10). This effect could be attributed to
formed nitroalkane 3aa with moderate to good yields (entries the presence of a homodromic intra-annular H-bonding
2–4, Table 2). Even better results were obtained with TSAs domain,21 which is responsible for the pseudo-cone confor-
bearing EWG groups such as chlorine (D) and the previously mation and made the acidic NH bonds of TSA F unable to
employed nitro group (E). In fact, 3aa was isolated with 72% promote a catalytic turnover.
and 82% yields, respectively (entries 5 and 6). To our delight, F
Subsequently, in order to evaluate the applicability of the
led to the complete consumption of nitrostyrene 1a and the methodology, we subjected a family of nitroalkenes 1 and
corresponding product was delivered with the excellent yield indoles 2 to the optimised reaction conditions (Table 3).
of 96% (entry 7).
Unsubstituted and substituted nitrostyrenes 1b–g were
Control experiments were subsequently performed. The use smoothly converted into products 3ba–ga with high yields
of the well-established triphenylureido calix[6]arene G led to a (70–94%). The method proved to be highly performant in the
marked decrease in the performance of the catalysis (66%, presence of both EDGs and EWGs such as halogens too.
entry 8) due to its intrinsic lower acidity. In parallel, mono- An aliphatic nitroalkene 1h was still applicable to the catalysis
meric trifluoromethylsulfonamide H followed suit (70%, entry leading to 3ha in slightly diminished yields (86%). Diversely
9). For the sake of comparison, we measured the relative substituted indoles could be employed too. So, indoles bearing
Brønsted acidity of H with the Gutmann–Beckett method (see EDGs such as an ether or hydroxyl group led to the corres-
Fig. S4 in the ESI†). Hence, we found a lower shift of the 31P ponding products 3bb–bc in excellent yields (95% and 93%,
NMR resonance (ΔδPP(H) = 7.01 vs. ΔδPP(F) = 11.7 ppm), which respectively). Interestingly, while inherently less reactive
suggested a cooperative effect of the trifluoromethyl function- indoles 2d–f were found poorly prone to the transformation
alities in TSA F as being responsible for the increased acidity using E (in MeOH at 50 °C), here the use of the newly opti-
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Table 3 Scope for the Michael addition
Fig. 5 (a) Model reaction performed in the presence of a competitive
guest and (b) outcome of the catalysis with TSAs; NMR conversion (%) in
red, isolated yields (%) in blue.
model reaction in the presence of a competitive binder such as
dioctyl viologen ditosylate (DOV·2OTs). The reaction yielded
the corresponding product 3aa in comparable yields (94%,
NMR yields), excluding the ability of TSAs to catalyse the
Michael addition inside the cavity (Fig. 5a, and S7 in the ESI†).
We thus tried to correlate both conversions and yields
obtained in the optimisation table with the relative Brønsted
acidities calculated using the Gutmann–Beckett approach.
Interestingly, a linear correlation was observed, suggesting
the reactivity of the catalyst to be a function of the enhanced
Brønsted acidity of F (Fig. 5b).
As for the mechanism, we proposed an outer-sphere mani-
fold in which cooperative trifluorosulfonamide moieties are
able to engage in H-bond interactions with the nitro com-
pound, lowering its activation barrier and thus promoting the
nucleophilic attack of the indoles.22 However, the presence of
a background reactivity23 prompts us to not exclude a supra-
molecular amplification of the acidity of the medium due to a
hydrogen-bonding network established between the acidic sul-
fonamide moieties and water.24
mised protocol was beneficial for the outcome of the catalysis.
Hence, differently substituted halogenated indoles led to pro-
ducts 3bd–bf in good to high yields (78–89%). Finally, the
method proved amenable also in the presence of N-protected
indole derivatives 2g–h, with compounds 3ag–ah transformed
in high yields (91–93%, respectively).
The feature of the catalytic methodology led us to interro-
gate whatever the π-rich aromatic cavity of the calix[6]arene F
could have a role in promoting the transformation, as for
example by threading the nitroalkene reactant.‡ Towards this
end, despite the low solubility of F in water, we performed the
Conclusions
We report an exhaustive investigation on the role of Brønsted
acidity in the working mode of TSA calix[6]arenes. In particu-
lar, we demonstrated how the modified physical and chemical
properties, associated with the presence of trifluoromethyl-
sulfonamide moieties, could still be exploited to design ion-
pair selective supramolecular receptors, in low polarity sol-
vents. Furthermore, these features allow a dichotomous mani-
‡TSAs are not able to thread nitrostyrenes both in polar (MeOD)7 and in low
polarity solvents (CDCl3, see Fig. S8 in the ESI†). We attempted to investigate the
eventual complexation of TSA F and 1a in D2O by 1H-NMR analysis. However,
these reagents are not soluble enough (up to 60 °C) in this medium.
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fold for TSAs, promoting a widely applicable catalytic Michael 138.4, 136.6, 130.8, 126.2, 125.9, 122.6, 121.6, 119.8, 119.2,
addition to nitrolefines with high levels of efficiency, under 118.8, 114.6, 111.4, 109.8, 79.7, 55.3, 41.6, 15.6. ESI-MS: m/z [M
pseudo physiological reaction conditions. These findings + H]+ calcd for C18H19N2O3: 311.14; found: 311.19.
provide a deeper understanding of the reactivity of this novel
3-(1-(2,5-Dimethoxyphenyl)-2-nitroethyl)-1H-indole (3da)26
class of supramolecular wheels and pave the way for a broader
application both as receptors and as Brønsted acid catalysts.
General procedure was followed using 1d (0.2 mmol, 41.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3da (57.3 mg, 88%) as a yellow wax. 1H NMR
(400 MHz, CD2Cl2) δ = 8.29 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H),
Experimental
7.41 (d, J = 8.2 Hz, 1H), 7.25–7.18 (m, 2H), 7.10 (ddd, J = 7.9,
In a glass tube, 1 (0.2 mmol), 2 (0.6 mmol), and F (8.9 mg,
7.1, 0.9 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.81 (dd, J = 8.9, 3.1
5 mol%) were successively added. Distilled H2O (0.5 ml, 0.4 M)
Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 5.58 (dd, J = 8.7, 7.1 Hz, 1H),
was added and the reaction mixture placed in a pre-heated oil
5.15–4.97 (m, 2H), 3.92 (s, 3H), 3.69 (s, 3H). 13C NMR
bath at 37 °C. After 16 h, the reaction mixture was cooled to
(101 MHz, CD2Cl2) δ = 153.6, 151.16, 136.40, 128.60, 126.43,
room temperature and CH2Cl2 (10 ml) was added. The mixture
122.44, 121.97, 119.66, 118.75, 115.70, 113.71, 112.02, 111.76,
was concentrated under reduced pressure and the crude puri-
111.32, 78.15, 56.00, 55.47, 35.52. ESI-MS: m/z [M + H]+ calcd
fied by column chromatography on silica gel. All the desired
for C18H19N2O4: 327.13; found: 327.17.
products are known compounds which were characterised by
the comparison of their analytical data with those reported in
previous literature.
4-(1-(1H-Indol-3-yl)-2-nitroethyl)-N,N-dimethylaniline (3ea)25
General procedure was followed using 1e (0.2 mmol, 38.4 mg).
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1H-indole (3aa)25
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ea (42.9 mg, 66%) as a yellow solid. M. p. =
General procedure was followed using 1a (0.2 mmol, 35.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3aa (56.9 mg, 96%) as a white solid. M. p. =
1
130–132 °C. H NMR (400 MHz, CD2Cl2) δ = 8.26 (s, 1H), 7.48
(d, J = 7.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.23–7.19 (m, 3H),
7.12 (d, J = 2.3 Hz, 1H), 7.10–7.05 (m, 1H), 6.76–6.66 (m, 2H),
5.14–5.05 (m, 2H), 5.00–4.89 (m, 1H), 2.94 (s, 6H). 13C NMR
(101 MHz, CD2Cl2) δ = 150.0, 136.5, 128.3, 126.7, 126.2, 122.5,
121.3, 119.6, 118.9, 115.1, 112.6, 111.3, 80.0, 40.8, 40.3.
ESI-MS: m/z [M + H]+ calcd for C18H20N3O2: 310.16; found:
310.18.
1
155–157 °C. H NMR (400 MHz, CD2Cl2) δ = 8.28 (s, 1H), 7.46
(d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.33–7.28 (m, 2H),
7.25–7.19 (m, 1H), 7.15–7.04 (m, 2H), 6.94–6.87 (m, 2H),
5.20–5.07 (m, 2H), 4.97 (dd, J = 11.7, 8.0 Hz, 1H), 3.81 (s, 3H).
13C NMR (101 MHz, CD2Cl2) δ = 159.0, 136.5, 131.4, 128.8,
126.1, 122.5, 121.4, 119.7, 118.8, 114.7, 114.1, 111.4, 79.8, 55.2,
40.8. ESI-MS: m/z [M + H]+ calcd for C17H17N2O3: 297.12;
found: 297.11.
3-(1-(4-Chlorophenyl)-2-nitroethyl)-1H-indole (3fa)25
General procedure was followed using 1f (0.2 mmol, 36.6 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3fa (55.3 mg, 92%) as a yellow solid. M. p. =
108–111 °C. 1H NMR (400 MHz, CD2Cl2) δ = 8.32 (s, 1H),
7.48–7.38 (m, 2H), 7.38–7.31 (m, 4H), 7.25 (t, J = 7.6 Hz, 1H),
7.14–7.09 (m, 2H) 5.21 (t, J = 8.2 Hz, 1H), 5.13 (dd, J = 12.3, 8.2
Hz, 1H), 4.99 (dd, J = 12.5, 8.2 Hz, 1H). 13C NMR (101 MHz,
CD2Cl2) δ = 138.2, 136.5, 133.2, 129.3, 129.0, 125.9, 122.7,
121.6, 119.9, 118.7, 113.8, 111.5, 79.4, 40.9. ESI-MS: m/z [M +
H]+ calcd for C16H14ClN2O2: 301.07; found: 301.06.
3-(2-Nitro-1-phenylethyl)-1H-indole (3ba)25
General procedure was followed using 1b (0.2 mmol, 29.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ba (49.8 mg, 94%) as an off-white solid. M. p. =
1
98–102 °C. H NMR (400 MHz, CD2Cl2) δ = 8.30 (s, 1H), 7.48
(d, J = 7.9 Hz, 1H), 7.44–7.35 (m, 4H), 7.34–7.29 (m, 2H), 7.23
(t, J = 7.6 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 7.10 (t, J = 7.6 Hz,
1H), 5.22 (t, J = 7.9 Hz, 1H), 5.14 (dd, J = 12.3, 7.6 Hz, 1H), 5.02
(dd, J = 12.3, 8.4 Hz, 1H). 13C NMR (101 MHz, CD2Cl2) δ =
139.6, 136.5, 128.8, 127.8, 127.5, 126.1, 122.6, 121.6, 119.8,
118.7, 114.3, 111.4, 79.6, 41.5. ESI-MS: m/z [M + H]+ calcd for
C16H15N2O2: 267.11; found: 267.14.
3-(1-(4-Bromophenyl)-2-nitroethyl)-1H-indole (3ga)25
General procedure was followed using 1g (0.2 mmol, 45.4 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ga (62.1 mg, 90%) as an off-white solid. M. p. =
3-(1-(3-Methoxy-4-methylphenyl)-2-nitroethyl)-1H-indole (3ca)7
General procedure was followed using 1c (0.2 mmol, 38.6 mg). 120–122 °C. 1H NMR (400 MHz, CD2Cl2) δ = 8.32 (s, 1H),
Purification by column chromatography (n-hex/EtOAc 95 : 5) 7.54–7.48 (m, 2H), 7.43 (dd, J = 7.5, 3.2 Hz, 2H), 7.31–7.26 (m,
yielded 3ca (56.8 mg, 92%) as a yellow wax. 1H NMR (400 MHz, 2H), 7.26–7.20 (m, 1H), 7.14–7.07 (m, 2H), 5.25–5.17 (m, 1H),
CD2Cl2) δ = 8.22 (s, 1H), 7.46 (dd, J = 8.0, 1.0 Hz, 1H), 7.35 (dt, 5.12 (dd, J = 12.3, 7.4 Hz, 1H), 4.98 (dd, J = 12.3, 8.4 Hz, 1H).
J = 8.3, 0.8 Hz, 1H), 7.18–7.15 (m, 1H), 7.08–7.02 (m, 3H), 6.82 13C NMR (101 MHz, CD2Cl2) δ = 138.7, 136.5, 131.9, 129.6,
(d, J = 1.7 Hz, 1H), 6.80 (s, 1H), 5.12 (t, J = 8.0 Hz, 1H), 5.06 125.9, 122.7, 121.6, 121.3, 119.9, 118.7, 113.7, 111.5, 79.3, 41.0.
(dd, J = 12.3, 8.0 Hz, 1H), 4.95 (dd, J = 12.3, 8.0 Hz, 1H), 3.75 ESI-MS: m/z [M + H]+ calcd for C16H14BrN2O2: 345.02; found:
(s, 3H), 2.14 (s, 3H). 13C NMR (150 MHz, CD2Cl2) δ = 158.1, 345.03.
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3-(1-Cyclohexyl-2-nitroethyl)-1H-indole (3ha)25
134–137 °C. H NMR (400 MHz, CD2Cl2) δ = 8.40 (s, 1H), 7.60
(s, 1H), 7.43–7.28 (m, 7H), 7.17 (d, J = 1.8 Hz, 1H), 5.22–5.05
(m, 2H), 5.00 (dd, J = 12.2, 8.0 Hz, 1H). 13C NMR (101 MHz,
CD2Cl2) δ = 139.1, 135.1, 128.9, 127.9, 127.7, 127.6, 125.4,
122.9, 121.3, 114.0, 113.0, 112.9, 79.5, 41.3. ESI-MS: m/z [M +
H]+ calcd for C16H14BrN2O2: 345.03; found: 345.06.
General procedure was followed using 1h (0.2 mmol, 31.0 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ha (46.6 mg, 90%) as a yellow wax. 1H NMR
(400 MHz, CD2Cl2) δ = 8.27 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H),
7.42 (d, J = 8.1 Hz, 1H), 7.29–7.20 (m, 1H), 7.16 (td, J = 7.6, 7.1,
1.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 4.89 (dd, J = 11.9, 5.9 Hz,
1H), 4.78 (dd, J = 11.9, 10.0 Hz, 1H), 3.70 (dt, J = 9.9, 6.6 Hz,
1H), 1.98–1.75 (m, 3H), 1.75–1.61 (m, 3H), 1.39–0.97 (m, 5H).
13C NMR (101 MHz, CD2Cl2) δ = 136.3, 126.9, 122.4, 122.1,
119.5, 119.0, 113.2, 111.4, 78.7, 41.9, 40.6, 31.2, 30.5, 26.3.
ESI-MS: m/z [M + H]+ calcd for C16H21N2O2: 273.16; found:
273.13.
6-Chloro-3-(2-nitro-1-phenylethyl)-1H-indole (3bf)28
General procedure was followed using 1b (0.2 mmol, 29.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3bf (46.4 mg, 77%) as a yellow wax. 1H NMR (400 MHz,
CD2Cl2) δ = 8.33 (s, 1H), 7.44–7.41 (m, 1H), 7.40–7.35 (m, 5H),
7.35–7.29 (m, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.06 (dd, J = 8.6, 1.8
Hz, 1H), 5.19 (t, J = 7.9 Hz, 1H), 5.11 (dd, J = 12.3, 7.8 Hz, 1H),
5.00 (dd, J = 12.3, 8.1 Hz, 1H). 13C NMR (101 MHz, CD2Cl2) δ =
139.2, 136.8, 128.9, 128.4, 127.7, 127.6, 124.81, 122.3, 120.4,
119.8, 114.6, 111.3, 79.5, 41.4. ESI-MS: m/z [M + H]+ calcd for
C16H14ClN2O2: 301.07; found: 301.03.
3-(2-Nitro-1-phenylethyl)-1H-indol-5-ol (3bb)27
General procedure was followed 1b (0.2 mmol, 29.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3bb (53.6 mg, 95%) as a yellow solid. M. p. = 122–126 °C.
1H NMR (400 MHz, CD2Cl2) δ = 8.20 (s, 1H), 7.40–7.35 (m, 4H),
7.35–7.29 (m, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 2.3 Hz,
1H), 6.84 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.7, 2.3 Hz, 1H),
5.17–5.05 (m, 2H), 5.04–4.94 (m, 1H), 4.82 (s, 1H). 13C NMR
(101 MHz, CD2Cl2) δ = 149.7, 139.5, 131.7, 128.9, 127.7, 127.5,
126.8, 122.6, 113.6, 112.4, 112.1, 103.1, 79.5, 41.5. ESI-MS: m/z
[M + H]+ calcd for C16H15N2O3: 283.11; found: 283.07.
3-(1-(4-Methoxyphenyl)-2-nitroethyl)-1-methyl-1H-indole (3ag)29
General procedure was followed using 1a (0.2 mmol, 35.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ag (56.2 mg, 91%) as a whitish oil. 1H NMR
(400 MHz, CD2Cl2) δ = 7.47 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.2
Hz, 1H), 7.32–7.19 (m, 3H), 7.09 (t, J = 7.4 Hz, 1H), 6.96 (s, 1H),
6.90 (d, J = 7.2 Hz, 2H), 5.20–5.06 (m, 2H), 5.02–4.90 (m, 1H),
3.81 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, CD2Cl2) δ =
159.0, 137.3, 131.6, 128.8, 126.5, 126.1, 122.1, 119.2, 118.8,
114.1, 113.0, 109.5, 79.8, 55.2, 40.8, 32.7. ESI-MS: m/z [M + H]+
calcd for C18H19N2O2: 311.14; found: 311.17.
5-Methoxy-3-(2-nitro-1-phenylethyl)-1H-indole (3bc)25
General procedure was followed using 1b (0.2 mmol, 29.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3bc (55.2 mg, 93%) as a yellow solid. M. p. =
137–140 °C. 1H NMR (400 MHz, CD2Cl2) δ = 8.22 (s, 1H),
7.44–7.36 (m, 4H), 7.35–7.26 (m, 2H), 7.09 (d, J = 2.6 Hz, 1H),
6.89 (s, 1H), 6.87 (d, J = 2.4 Hz, 1H), 5.21–5.13 (m, 2H), 5.02
(dd, J = 12.0, 8.3 Hz, 1H), 3.80 (s, 3H). 13C NMR (101 MHz,
CD2Cl2) δ = 154.2, 139.5, 131.6, 128.9, 127.8, 127.5, 126.5,
122.3, 113.9, 112.5, 112.1, 100.6, 79.5, 55.7, 41.5. ESI-MS: m/z
[M + H]+ calcd for C17H17N2O3: 297.12; found: 297.09.
1-Benzyl-3-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-indole (3ah)29
General procedure was followed using 1a (0.2 mmol, 35.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3ah (71.6 mg, 93%) as a whitish oil. 1H NMR
(400 MHz, CD2Cl2) δ = 7.49 (d, J = 7.9 Hz, 1H), 7.39–7.29 (m,
6H), 7.21 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.10 (d, J =
7.8 Hz, 2H), 6.92 (d, J = 7.3 Hz, 2H), 5.35 (s, 2H), 5.19 (t, J = 7.8
Hz, 1H), 5.16–5.07 (m, 1H), 5.02–4.93 (m, 1H), 3.82 (s, 3H). 13
C
5-Fluoro-3-(2-nitro-1-phenylethyl)-1H-indole (3bd)27
NMR (101 MHz, CD2Cl2) δ = 159.0, 137.6, 136.9, 131.5, 128.8,
128.7, 127.6, 126.9, 126.7, 125.6, 122.3, 119.5, 119.1, 114.2,
113.8, 110.0, 79.9, 55.2, 50.1, 40.9. ESI-MS: m/z [M + H]+ calcd
for C24H23N2O3: 387.17; found: 387.19.
General procedure was followed using 1b (0.2 mmol, 29.8 mg).
Purification by column chromatography (n-hex/EtOAc 95 : 5)
yielded 3bd (50.7 mg, 89%) as a yellow wax. 1H NMR
(400 MHz, CD2Cl2) δ = 8.35 (s, 1H), 7.41–7.30 (m, 6H), 7.21 (d,
J = 2.1 Hz, 1H), 7.10 (d, J = 9.7 Hz, 1H), 6.98 (td, J = 9.1, 2.1 Hz,
1H), 5.20–5.07 (m, 2H), 5.01 (dd, J = 11.1, 7.0 Hz, 1H). 13C
1
Conflicts of interest
NMR (101 MHz, CD2Cl2) δ = 157.7 (d, JC–F = 234 Hz), 139.2,
5
133.0, 128.9, 127.7, 127.6, 126.5 (d, JC–F = 10 Hz), 123.3, 114.4
There are no conflicts to declare.
6
4
2
(d, JC–F = 5 Hz), 112.2 (d, JC–F = 11 Hz) 110.9 (d, JC–F = 26
Hz), 103.7 (d, JC–F = 24 Hz), 79.5, 41.4. ESI-MS: m/z [M + H]+
3
calcd for C16H14FN2O2: 285.10; found: 285.11.
Acknowledgements
5-Bromo-3-(2-nitro-1-phenylethyl)-1H-indole (3be)25
The authors thank Centro Interdipartimentale di Misure of the
General procedure was followed using 1b (0.2 mmol, 29.8 mg). University of Parma for NMR measurement and B.Sc. student
Purification by column chromatography (n-hex/EtOAc 95 : 5) Nicholas Grassi for experimental support. Chiesi Farmaceutici
yielded 3be (58.6 mg, 85%) as a white solid. M. p. = SpA is acknowledged for the support for the D8 Venture. This
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work was supported by the Italian MIUR (PRIN 20173L7W8 K).
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