Synthesis of 2-Acylindoles via Ag- and Cu-Catalyzed anti-Michael Hydroamination of β-(2-Aminophenyl)-α,β-ynones: Experimental Results and DFT Calculations

Article abstract of DOI:10.1021/acs.joc.8b00508

β-(2-Aminophenyl)-α,β-ynones afforded 3-unsubstituted 2-acylindoles in good yields in the presence of 20 mol % AgOTf under (microwave) MW heating. The use CuOTf as a catalyst resulted in a similar reaction outcome, generally with a lower efficiency. This transformation represents the first example of 5-endo-dig cyclization of 2-alkynylanilines bearing an acyl group linked to the triple bond. By contrast with the previously reported gold-catalyzed reaction of β-(2-aminophenyl)-α,β-ynones, which resulted in the formation of dibenzo[1,5]diazocines through a sequential process triggered by an intermolecular hydroamination, a selective intramolecular anti-Michael hydroamination was observed in the present study by silver/copper catalysis. Density functional theory calculations on the Ag-catalyzed reaction revealed that the catalyst induces an electrostatic arrangement in the TS coherent with the experimentally observed cyclization.

Full text of DOI:10.1021/acs.joc.8b00508

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Article
Synthesis of 2-acylindoles via Ag- and Cu-catalyzed
anti-Michael hydroamination of #-(2-aminophenyl)-
#,#-ynones: experimental results and DFT calculation.
Navnath D. Rode, Issam Abdalghani, Antonio Arcadi,
Massimiliano Aschi, Marco Chiarini, and Fabio Marinelli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00508 • Publication Date (Web): 14 May 2018
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Synthesis of 2-acylindoles via Ag- and Cu-catalyzed
anti-Michael hydroamination of 2-aminophenyl)-
-ynones: experimental results and DFT
calculation.
Navnath D. Rode,a Issam Abdalghani, a Antonio Arcadi,a Massimiliano Aschi,a Marco Chiarini,b
Fabio Marinellia*
aDipartimento di Scienze Fisiche e Chimiche, Università di L’Aquila, Via Vetoio- 67010
Coppito(AQ)- Italy. E-mail: fabio.marinelli@univaq.it
b Facoltà di Bioscienze e Tecnologie Agroalimentari e Ambientali, Università di Teramo, via R.
Balzarini, 1, 64100 Teramo (Te), Italy.
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
*To whom correspondence should be addressed.

ABSTRACT. -(2-aminophenyl)--ynones afforded 3-unsubstituted 2-acylindoles in good yields
in the presence of 20 mol% of AgOTf under MW heating. The use CuOTf as catalyst resulted in a
similar reaction outcome, generally with a lower efficiency. This transformation represents the first
example of 5-endo-dig cyclization of 2-alkynylanilines bearing an acyl group linked to the triple
bond. By contrast with the previously reported gold-catalyzed reaction of -(2-aminophenyl)--
ynones, that resulted in the formation of dibenzo[1,5]diazocines through a sequential process
triggered by an intermolecular hydroamination,
a
selective intramolecular anti-Michael
hydroamination was observed in the present study by mean of silver/copper catalysis. Density
Functional Theory calculation on the Ag-catalyzed reaction revealed that the catalyst induces an
electrostatic arrangement in the TS coherent with the experimentally observed cyclization.
Introduction
The indole substructure is a near-ubiquitous component in many bioactive natural products,1 and
indole scaffold occurs in a large number of commercial drugs, as well as in molecules currently
under clinical trial.2 2-Acylindoles constitute a particularly interesting class of indole derivatives,
owing to their specific pharmacological properties. For instance, 2-(4-phenoxybenzoyl)indole
derivatives have been identified as a novel structural class of calmodulin-dependent protein kinases
(CaMKII ) inhibitors.3 Moreover, 2-aroyltrimethoxyindoles have been tested as analogues of the
naturally-occurring drug Combretastatin A4, and resulted active as inhibitors of the tubulin
polymerization.4 In addition, 2-aroylindoles constitute a class of potent Histone deacetylase
inhibitors for targeted cancer therapy.5 Besides, hydrazone derivatives of acylindoles have been
6
evaluated as inhibitors of methicillin-resistant Staphylococcus aureus growth.
Furthermore, 2-
acylindoles have been recently used as useful building-blocks for the synthesis of pyrrolo[1,2-
a]indoles and pyrroloquinolines.7 Therefore, the development of practical and efficient routes

towards this useful indole derivatives is of great current interest.8 Recently, the preparation of 3-
unsubstituted 2-acylindoles has been accomplished by transition metals mediated coupling of a
preformed indole ring with aldehydes,9 oxocarboxylic acids,10 -diketones11 and with toluene
derivatives in the presence of tert-butyl hydroperoxide as oxidant.12 These procedures, although
efficient, require the presence of a directing group linked to the N1 atom of the indole, that allows
activation of C2-H bond by cyclometalation; hydrolytic cleavage is then necessaty to obtain free N-
H indole. Other recent routes towards 3-unsubstituted 2-acylindoles include the reaction of sulfur
ylides and N-(orthochloromethyl) aryl amides in the presence of cesium carbonate,13 rhodium (I)
catalyzed reductive N-cyclization of 2-vinylnitroarenes using CO as a reducing agent,14 reaction of
2-aminobenzaldehyde equivalents with bromoketones,15 Cu (I) mediated cyclization of o-
bromochalcones,16 I2-mediated intramolecular -amination of ketones17 and domino Pd-catalyzed
18
cyclization of 2-gem-dibromovinylanilines-carbonylative Suzuki coupling.
5-endo-dig cyclization of 2-alkynylaniniles
1
through transition-metals (T.M.) catalyzed
hydroamination represents an efficient and atom-economical tool for the preparation of 2-
substituted indole derivatives 2 (Scheme 1, a).19 Over the years, this simple and straightforward
methodology has been applied to the cyclization of alkynylanilines bearing a wide range of
substituents R (aryl, alkyl, vinyl and other) linked to the Csp carbon. However, no examples of 5-
endo-dig cyclization of 2-alkynylanilines with R = acyl (i.e. -(2-aminophenyl)--ynones 3,
Scheme 1, b) have been reported so far. Only one example of TBAF-assisted cyclization of a
propiolic ester (analogue of 1 with R = COOMe) has been described.20
Scheme 1. Cyclization of 2-alkynylanilines

Substrates 3 can be readily obtained via a three-step procedure consisting of (i) reaction of
aldehydes with ethynylmagnesium bromide, (ii) Sonogashira coupling of the resulting terminal
propargylic alcohol with 2-iodoaniline derivatives, (iii) oxidation;21 alternatively, carbonylative
coupling of 2-ethynylaniline with aryl iodides or vinyl triflates can be used.22 Therefore, the
development of an efficient procedure for the 5-endo-dig cyclization of 3 would nicely complement
the existing procedures for the synthesis of 2-acylindoles, with the advantage of being fully atom-
economical, without the need of protection/deprotection of the N-1 atom.
In fact, the reaction outlined in Scheme 2, b) requires a difficult anti-Michael nucleophilic addition
of the amino group to the conjugated triple bond. To the best of our knowledge, only one example
of anti-Michael 5-endo-dig hydroamination of an alkynoate ester has been reported,23 and in that
case the cyclization was favored by the particular structure of the substrate, possessing a crowded
quaternary center (gem-dimethyl effect). Alternative Michael-type cyclization of 3, affording
strained benzazetine ring,24 could also be possible, at least in principle: one example of 4-exo-dig
Pd-catalyzed intramolecular hydroamination of gem-difluoropropargylamides has been described,25
and the formation of -lactam ring was driven by the polarization of the triple bond induced by
fluorine substituents. Moreover we have recently reported that, in the presence of cationic Au(I)
complex (JonPhosAuNCMe)SbF6, substrates 3 underwent a sequential reaction, affording eight-
membered dibenzo[1,5]diazocines 5 (Scheme 2, a).26 In this case, an initial Michael-type

intermolecular hydroamination between two molecules of 3 took place preferentially, followed by
cyclization of the resulting adduct.
Consequently, development of a selective intramolecular hydroamination of substrates 3 represents
a challenging result. We wish to report here our investigation on the efficient conversion of (2-
aminophenyl)-ynones 3 into the corresponding 2-acylindoles 4 , catalyzed by AgOTf or
CuOTf (Scheme 2, b).
Scheme 2. Cyclization of (2-aminophenyl)-ynones 3
Results and Discussion
Ynone 3a was selected as model substrate, and its cyclization under different
catalyst/solvent/temperature combination was examined
(Table 1).
The anti-Michael
hydroamination failed to occur by using well-estabilished methodologies for the cyclization of 2-
alkynylaniline derivatives. For example, the formation of acylindole was not observed using PdCl2
in MeCN at 80 °C,27 (entry 1). Analogously, we failed to obtain 4a when NaAuCl4 (5 mol%) was
employed as the catalyst in EtOH at room temperature28 (entry 2), while at 80 °C (entry 3) the

nucleophilic addition of EtOH to the unsaturated alkynone took place to some extent, to give the 4-
29
ethoxy-2-phenylquinoline 6a in 26% yield.
During the optimization of our previous work,26 we
observed the formation of a small amount (12%) of acylindole 4a (together with
dibenzo[1,5]diazocine 5a), when AgOTf was used as the catalyst in toluene at 80 °C; consequently,
we attempted the use of such catalyst.30 Interestingly, partial formation of 4a occurred in the
presence of AgOTf in DMF at 100 °C, without formation of 5a (entry 4), and this solvent resulted
more effective respect to MeCN and EtOH (Table 1, entries 5-6). A better yield of 4a was observed
in dioxane (entry 7), but the ynone 3a was not recovered in this case.
Table 1. Optimization of the cyclization of 3a to give 4aa
Entry
Catalyst
(%)
Solvent
T(°C)
Time
4a (Yield
3a
(Recover
%)b
%)b
1
2
PdCl2 (10)
NaAuCl4 (5)
NaAuCl4 (5)
AgOTf (20)
AgOTf (20)
AgOTf (20)
AgOTf (20)
AgOTf (20)
AgOTf (20)
AgOTf (15)
AgOTf (10)
MeCN
EtOH
EtOH
DMF
80
r.t.
24h
24h
24h
8h
-
-
15
72
31c
65
88
26
-
3
80
-
4
100
100
100
100
100
140d
140d
140d
20
9
5
MeCN
EtOH
Dioxane
DMF
8h
6
8h
7
7
8h
38
32
84e
82
66
8
16h
15’
20’
30’
59
-
9
DMF
DMF
10
11
-
DMF
13

12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
AgSbF6 (20)
AgNO3(20)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
140d
140d
140d
140d
140d
140d
140d
140d
140d
140d
80
20’
20’
20’
20’
20’
20’
20’
20’
20’
20’
24h
15’
15’
6h
58
29
74
60
16
16
6
18
10
-
CuOTf (20)
CuCl (20)
-
CuCl2·2H2O (20)
20
-
Cu(NO3)2·3H2O
(20)
Cu(OAc)2·H2O (20)
48
81
42
51
28
12
95
-
PPh3AuNTf (5)
-
PPh3AuCl(20) +
AgOTf (15)
AuCl(20) + AgOTf
(15)
3
-
f
(JonPhosAuNCMe)
-
SbF6 (5)
(JonPhosAuNCMe)
SbF6 (5)
140d
140d
70
3g
-
none
noneh
noneh
-
THF
140d
15’
-
-
a
c
Reactions were carried out on a 0.2 mmol scale in 1.2 mL of solvent. b NMR yields. 4-ethoxy-2-phenylquinoline 6a
d
e
f
was obtained in 26% yield. MW heating. Isolated yield. Dibenzo[1,5]diazocine 5a was formed in 9% yield.
gDibenzo[1,5]diazocine 5a was formed in 25% yield and quinolone 6a was formed in 16% yield. h In the presence of 2
equiv. of 1.0 M solution of TBAF in THF, using 1 mL of solvent.
After prolonged time in DMF (entry 8), 4a was isolated in 32% yield, and the starting material 3a
was recovered in 59% yield. Very pleasingly, after microwave heating at 140 °C for 15 minutes, we
observed the complete conversion of 3a into the acylindole 4a as the sole product in high yield
(entry 9). The influence of the AgOTf loading on the reaction outcome was also tested: with 15% of
catalyst the yield was still good, while a further decrease gave worse results (entries 10-11). AgSbF6
resulted less effective than AgOTf (entry 12), and AgNO3 afforded only a scarce amount of product
(entry 13).
Then, we explored the use of other coinage metals. Cu(OTf) resulted quite effective in promoting
the desired anti-Michael hydroamination (entry 14). Also CuCl afforded the product 4a in moderate

yield (entry 15). By contrast, Cu(II) salts gave worse results (entries 16-18). Au(I) based catalysts
were completely uneffective (entries 19-23). While the catalyst showed in entries 19-21 were
previously found scarcely active also in the conversion of substrates
3
into 5,
(JonPhosAuNCMe)SbF6 in toluene at 80 °C gave good results in such transformation (as stated also
in the Introduction section and in Scheme 2).26 Surprisingly, when we used this latter catalyst DMF
at 80 °C (entry 22) and at 140 °C (entry 23) scarce formation of 5a (R = Ph) was observed, and 2-
acylindole 4a was detected in trace amounts. At 140°C quinolone 6a was also formed, likely via
Au(I)-catalyzed rearrangement31 of 3a, followed by cyclization (Scheme 3).
Scheme 3. Formation of quinolone 6a through Au(I)-catalyzed rearrangement
These results demonstrates that the reactivity of (JonPhosAuNCMe)SbF6 with substrates 3 is
dramatically influenced by the reaction medium. Finally, the near quantitative recovery of 3a
omitting the catalyst (entry 24) highlights the key role of the Ag(I) and Cu(I) catalysis in the
formation of products. We also attempted the cyclization of 3a in the presence of 1.0 M solution of
20
TBAF
using normal or MW heating (entries 25, 26); in both cases complex reaction mixtures
were obtained, without detectable formation of 4a.
Optimized conditions of entry 9 were subsequently used for exploring the scope of the reaction. As
reported in Table 2, a variety of 2-acylindoles 4 bearing aryl, heteroaryl, vinyl and alkyl group were
quickly prepared usually in good to excellent yields by AgOTf catalyzed cyclization of ynones 3a-
t,32 and only thienyl and cyclohexyl substituted products 4k and 4p were obtained in low yields.

Polysubstituted acylindoles 4q-t were also prepared starting from ynones 3q-t. We also explored
the use of CuOTf.33 Generally this catalyst resulted slightly less active respect to Ag(I) analogue,
but still produced the acylindoles 4a,b,d,g,j,o,p in synthetically useful yields. Interestingly, CuOTf
afforded the thienoyl indole 4k in better yield respect to AgOTf. It is worth noting that acylindoles
4 were obtained as sole products in all the case examined, without the formation of
dibenzodiazocines 5. Moreover, we did not observe the formation of products deriving from a
Michael-type 4-exo-dig process.
Table 2. Scope of the preparation of 2-acylindoles 4 from (2-aminophenyl)--ynones 3.a,b

Cyclization of alkynylanilines bearing a secondary alcoholic group, followed by oxidation, could be
also considered as a possible alternative route to acylindoles 4. However, cyclization of 7a resulted
difficult: reaction with NaAuCl4 at r.t28 resulted in in a very little formation of product (Scheme 4),
while the use of PdCl2 in refluxing MeCN27 resulted in the formation of a complex reaction
mixture. Also reaction of 7a with 20 mol% of AgOTf in refluxing MeCN failed: we obtained only
8% of 8a after 4h; a similar result was obtained with 20 mol% of CuOTf (9% after 6h). These
observations further demonstrate the usefulness of the present methodology.

Scheme 4. Attempts to cyclization of 7a
We also attempted the cyclization of alkynoate ester 3u (Scheme 5) but the indole 4t was obtained
in low yield using both AgOTf or CuOTf at 140 °C (condition A or B of Table 2); in both cases
starting material was not recovered. Decreasing the reaction temperature to 120 °C with AgOTf,
under otherwise identical reaction conditions, led to a similar result (21% yield). A further reduction
to 100 °C afforded 4u in 19% yield, together with recovered 3u (10% yield)
Scheme 5. Attempts to cyclization of alkynoate ester 3u.
In order to try to shed some light onto the mechanism of the Ag-catalyzed cyclization of 3 and on
the factors determining the highly selective 5-exo-dig anti Michael hydroamination pathway, we
carried out quantum-chemical calculations in the framework of Density Functional Theory.34 All

the related details are reported in the Supplementary information section. In this respect the first
question to address is as to what is the actual reactant when silver triflate (AgTf) is solubilized in
dimethylformamide. We have then studied the free energy of the reaction (1)
+
-
AgTf
+ n DMF(l) →Ag(DMF)n (sol) + Tf (sol)
(1)
(sol)
and we obtained, at 140°C, the value of -57.0 kJ/mole for n= 2 and -61 kJ/mole for n=4 indicating
that, in DMF solution silver acts as a bi-solvated cation and that Tf- does not play any relevant role,
at least in the non-highly concentrated solutions utilized in the present study. At lower temperature
(25°C) the free-energy difference becomes rather small suggesting that in this condition the tetra-
+
coordinated Ag(DMF)4 cluster is significantly populated as experimentally observed.35 It is
important to note that DMF preferentially binds to Ag+ with carbonyl oxygen, i.e. all the
investigated species obtained through N-Ag interaction have revealed much less stable. The main
question, however, deals with the stability and the chemical structure of the complexes between
solvated silver cation and 3a in DMF solution under the experimental conditions. There are,
obviously, different possibilities depending on the preferential binding site of Ag+ with the 3a,
(NH2, oxygen or C-C triple bond) and on the number of solvating DMF molecules possibly bound
to Ag+. Some of the relevant structures of [3a-Ag-DMFn]+ systems (with n=0, 1 and 2) are reported
in Figure 1. In the same Figure we have also schematically reported the most accessible Transition
Structures (see below).

Figure 1. Schematic view of of [3a-Ag-DMFn]+ systems (n=0, 1 and 2) and standard free energy of
+
formation at 140°C in dmf solution with respect to Ag(DMF)2 + 3a species.
It is interesting to note that the affinity of silver cations toward 3a is not outstanding and hence it
would be rather difficult to isolate stable complexes at significant concentrations in the
experimental conditions. At the same time the most stable intermediates turned out to be the
structure Ia with the silver cation coordinated to nitrogen and oxygen. We also localized all the
plausible TS structures, with a different number of explicit DMF molecules bound to silver cation.
Thermochemical calculations (showing standard free energy barriers of +35 kcal/mole with n=0,
+
+33 kcal/mole with n=2 and +30 kcal/mol with n=1 with respect to the free reactants Ag(DMF)2
and 3a) clearly indicate that only the TS with one DMF molecule (TSc in Figure 1) may play a
kinetic role in the present conditions. On the basis of the above results we can conclude that
+
Ag(DMF)2 and 3a, in pre-equilibrium with rather unstable intermediate complexes, evolve to the
cyclic structure IIIa through a single-step path schematically depicted in Figure 2, and subsequent
exoergonic protodemetallation affords the final products. In the same Figure we have also reported
the atomic charges and bond lengths in the transition state TSc in which we observe that the
presence of silver cation induces a correct electrostatic arrangement for the observed cyclization.36

Figure 2. Lowest energy reaction path, with atomic charges (in red) and selected bond lengths in
the transition state TSa
To confirm the validity of the proposed model we also estimated the half-life of 3a at the
experimental initial concentration (0.2 M) and using a pseudo-first order rate constant (silver
concentration of 0.1M). calculated according to the standard Eyring theory with transmission
coefficient equal to 1. We obtained a calculated half-life of about 6400 s which, although higher
than the experimental value, reveals rather satisfactory considering all the unavoidable systematic
errors present in our calculations.
Conclusions
We have reported here the first example of 5-exo-dig cyclization of 2-alkynylanilines bearing an
acyl group on the triple bond, through a selective anti-Michael intramolecular hydroamination. Free
N-H indoles were obtained, and derivatization of nitrogen was unnecessary in this alternative
approach to 2-acylindoles. The use of silver and copper triflates vs. (JonPhosAuNCMe)SbF6
resulted in divergent cyclization paths starting from substrates 3. DFT calculations, carried out for
the Ag-catalyzed reaction, have shown that the process is characterized by a very strong
thermodynamic driving force and that it takes place in two steps by overcoming a barrier

characterized by a TS in which Ag+ is coordinated by both carbon atom of the alkyne moiety, with
different bond lengths, and by a single DMF molecule. Analysis of the atomic charges at the TS
reveals that the presence of Ag(I) induces an electrostatic arrangement coherent with the
experimentally observed anti-Michael hydroamination. A similar result was also obtained with
Cu(I), whose details are also reported in the Supplementary Information.
Experimental Section
General remarks
Unless otherwise stated, all starting materials, catalysts, and solvents were commercially available
1
and were used as purchased. H NMR and 13C NMR spectra were recorded at 400 and 100.6 MHz
in CDCl3 (unless otherwise stated). Chemical shifts are reported in ppm relative to tetramethylsilane
or referenced to the chemical shifts of residual solvent resonances (CDCl3 at 77.04 ppm for 13C).
The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, dt = doublet of triplet, td = triplet of doublet, bs = broad signal.
HRMS spectra were recorded using a MALDI-TOF spectrometer. -(2-aminophenyl)--ynones
3a37, 3b-c,21 3d,38 3e,29 3f,21 3g-i,29 3j-k,21 3m,22 3n-r,21 3s-t26 and -(2-aminophenyl)--ynoate
3u26 are known compounds and were prepared as reported (see Supporting Information for the
related structures). Ynone 3l was prepared using a reported procedure,21 through Sonogashira
coupling of 2-iodoaniline with
(E)-1-(furan-2-yl)pent-1-en-4-yn-3-ol 9l (obtained from the
corresponding aldehyde via Grignard reaction) to give 7l and subsequent oxidation. Compounds 7a
1
was prepared as reported.37 Compound 8a was not isolated, and its yield was determined by H
NMR of the reaction mixture (1,3,5-trimethoxybenzene as internal standard) through comparison
with reported spectrum.39 Indoles 4a, 4b, 4e, 4f, 4g, 4h, 4j, 4k, 4o, 4q, 4u and quinolone 6a are
known compounds.
Computational details.
All the calculations were performed in the framework of Density Functional Theory (DFT) using
the CAM-B3LYP functional40 in conjunction with 6-31+G* basis set and with the Los Alamos
National Laboratory Effective Core Potential with a double-zeta basis set (lanl2dz)41 for silver.
Larger basis set, 6-311+G*, was utilized for performing single point calculations onto the structures

more significant (i.e. showing lower formation free energies at the CAM-B3LYP/6-31+G* level).
All the structures were first optimized and then characterized as minima or first order saddle points
calculating the harmonic frequencies. Free energy calculations were finally obtained at the
temperature of interest by calculating for each structure the partition function in the ideal-gas
approximation, at the temperatures of interest, using the geometries, the associated frequencies and
considering as reference state the concentration of 1.0 mole/liter at the pressure of 1.0 bar. The
excess free energy, i.e. the effect of the solvent, was taken into account using a mean-field approach
according to the Polarizable Continuum Model (PCM)42 as implemented in the Gaussian 09
software.43 On the purpose, the experimental dielectric constant44 and density45 of DMF were
utilized at 140°C. The atomic charges were evaluated through standard fitting procedures.46 All the
details concerning the optimized structures and the free-energy calculations are reported in the
Supplementary Information section.
1
(E)-1-(furan-2-yl)pent-1-en-4-yn-3-ol 9l. Yield: 1.15 g, 95 %; H NMR (400 MHz, CDCl3): δ
7.38–7.36 (m, 1H), 6.64 (d, J = 15.7 Hz, 1H), 6.40–6.24 (m, 3H), 5.05 (d, J = 5.5 Hz, 1H), 2.64 (dd,
J = 2.2, 0.5 Hz, 1H), 2.44 (br s, 1H); 13C NMR (100.6 MHz, CDCl3): δ 151.7, 142.5, 125.9, 120.3,
111.4, 109.4, 82.6, 74.6, 62.3. HRMS m/z (ESI) positive ion, calculated for C9H8KO2:
[M+K]+ 187.0161, Found: 187.0159
(E)-5-(2-aminophenyl)-1-(furan-2-yl)pent-1-en-4-yn-3-ol 7l. Yield: 415 mg, 87 %; 1H NMR
(400 MHz, CDCl3): δ 7.39 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 6.4, 1.5 Hz, 1H), 7.17–7.13 (m, 1H),
6.72–6.66 (m, 3H), 6.41–6.33 (m, 3H), 5.32 (J = 4.7, 1.2 Hz, 1H), 3.50 (br s, 2H, NH2); 13C NMR
(100.6 MHz, CDCl3): δ 151.8, 148.0, 142.5, 132.3, 130.0, 126.5, 120.0, 118.0, 114.5, 111.45,
111.42, 109.4, 93.2, 83.1, 63.1. HRMS m/z (ESI) positive ion, calculated for C15H13KNO2: [M+K]+
278.0583, Found: 278.0583.
(E)-5-(2-aminophenyl)-1-(furan-2-yl)pent-1-en-4-yn-3-one 3l. Yield: 250 mg, 63 %; Yellow
1
solid; H NMR (400 MHz, CDCl3): δ 7.62 (d, J = 15.8 Hz, 1H), 7.57–7.56 (m, 1H), 7.43 (dt, J =
7.9, 1.4 Hz, 1H), 7.26–7.22 (m, 1H), 6.79–6.70 (m, 4H), 6.55-6.53 (m, 1H), 4.45 (br s, 2H, NH2);
13C NMR (100.6 MHz, CDCl3): δ 177.3, 150.7, 150.1, 145.8, 133.6, 133.2, 132.4, 126.1, 118.0,

116.9, 114.7, 112.9, 104.0, 93.1, 89.1. HRMS m/z (ESI) positive ion, calculated for C15H11KNO2:
[M+K]+ 276.0427, Found: 276.0422.
General procedure for the synthesis of 2-acylindoles 4
A sealed microwave vial was charged with -(2-aminophenyl)-ynone 3 (0.22 mmol) and
AgOTf (20 mol%) in anhydrous DMF (1.2 mL). After prestirring for 1 min at room temperature,
0
the reaction mixture was irradiated with microwaves at 140 C for 15 min. After completion of the
reaction (as monitored by TLC), the reaction mixture was diluted with a H2O (10 mL), and
extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (hexanes/ ethyl acetate 90:10 v/v) to obtain 2-acylindole 4.
(1H-indol-2-yl)(phenyl)methanone 4a.18 Yield (Procedure A): 42 mg, 84%; (Procedure B): 37 mg,
74%; 1H NMR (400 MHz, CDCl3): δ 9.66 (br s, 1H), 8.00 (d, J = 8.3 Hz, 2H), 7.72 (dd, J = 8.1, 0.8
Hz, 1H), 7.65–7.60 (m, 1H), 7.59–7.56 (m, 3H), 7.37 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.18–7.14 (m,
2H); 13C NMR (100.6 MHz, CDCl3): δ 187.3, 138.0, 137.7, 134.3, 132.4, 129.3, 128.5, 127.8,
126.5, 123.2, 121.0, 112.9, 112.3.
(1H-indol-2-yl)(m-tolyl)methanone 4b.47 Yield (Procedure A): 38 mg, 76 %; (Procedure B): 34.5
1
mg, 69%; H NMR (400 MHz, CDCl3): δ 9.32 (br s, 1H), 7.81–7.47 (m, 3H), 7.43–7.38 (m, 4H),
7.19–7.15 (m, 2H), 2.47 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 187.4, 138.4, 138.0, 137.5,
134.5, 133.2, 129.7, 128.3, 127.8, 126.49, 126.48, 123.2, 121.0, 112.7, 112.2, 21.5.
1
Ethyl 3-(1H-indole-2-carbonyl)benzoate 4c. Yield (Procedure A): 36 mg, 72 %; H NMR (400
MHz, CDCl3): δ 9.53 (br s, 1H), 8.67–8.66 (m, 1H), 8.30 (dt, J = 7.9, 1.6 Hz, 1H), 8.18 (dt, J =
8.00, 1.6 Hz, 1H), 7.74 (dd, J = 8.00, 1.1 Hz, 1H), 7.64 (ddd, J = 7.8, 7.2, 0.9 Hz, 1H), 7.51 (dd, J =
7.9, 0.9 Hz, 1H), 7.40 (ddd, J = 7.8, 7.2, 1.2 Hz, 1H), 7.20–7.16 (m, 2H), 3.98 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): δ 186.2, 166.3, 138.2, 137.7, 134.0, 133.3, 133.2, 130.5, 130.3, 128.8, 127.7,

126.9, 123.4, 121.2, 113.2, 112.3, 52.5. HRMS m/z (ESI) positive ion, calculated for C17H13KNO3:
[M+K]+ 318.0533, Found: 318.0530.
1-(4-(1H-indole-2-carbonyl)phenyl)ethan-1-one 4d. Yield (Procedure A): 34 mg, 68 %;
1
(Procedure B): 33 mg, 66 %; H NMR (400 MHz, CDCl3): δ 9.61 (br s, 1H), 8.09 (dd, J = 8.7 Hz,
4H), 7.74–7.71 (m, 1H), 7.52–7.49 (m, 1H), 7.40 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.20–7.15 (m, 2H),
2.69 (s, 3H); 13C NMR (100.6 MHz, CDCl3): δ 197.6, 186.4, 141.7, 139.6, 137.9, 134.1, 129.4,
128.4, 127.7, 127.0, 123.4, 121.3, 113.4, 112.3, 26.9. HRMS m/z (ESI) positive ion, calculated for
C17H13KNO2: [M+K]+ 302.0583, Found: 302.0582.
1
(1H-indol-2-yl)(4-methoxyphenyl)methanone 4e.18 Yield (Procedure A): 45 mg, 90 %; H NMR
(400 MHz, CDCl3): δ 9.60 (br s, 1H), 8.05 (dd, J = 8.6, 1.8 Hz, 2H), 7.72 (dd, J = 7.9, 1.7 Hz, 1H),
7.49 (dd, J = 8.0, 0.5 Hz, 1H), 7.36 (td, J = 8.2, 0.9 Hz, 1H), 7.18–7.14 (m, 2H), 7.03 (dd, J = 8.6,
1.8, 2H), 3.91 (s, 3H); 13CNMR (100.6 MHz, CDCl3): δ 185.9, 163.2, 137.3, 134.5, 131.6, 130.7,
127.8, 126.2, 123.1, 120.9, 113.8, 112.2, 111.9, 55.5.
1
(2-Bromophenyl)(1H-indol-2-yl)methanone 4f.48 Yield (Procedure A): 44 mg, 88 %; H NMR
(400 MHz, CDCl3): δ 9.38 (br s, 1H), 7.71–7.65 (m, 2H), 7.54–7.37 (m, 5H), 7.15 (ddd, J = 8.0,
7.0, 1.0 Hz, 1H), 6.88 (dd, J = 2.1, 1.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ 187.0, 139.7,
138.2, 134.5, 133.5, 131.4, 129.4, 127.5, 127.1, 126.9, 123.4, 121.2, 120.0, 114.4, 112.4.
(4-Chlorophenyl)(1H-indol-2-yl)methanone 4g.18 Yield (Procedure A): 37 mg, 74 %; (Procedure
B): 35 mg, 70%; 1H NMR (400 MHz, CDCl3): δ 9.54 (br s, 1H), 7.96 (dd, J = 8.6, 1.8 Hz, 2H), 7.72
(dd, J = 8.1, 0.9 Hz, 1H), 7.59–7.45 (m, 3H), 7.39 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.20–7.14 (m,
2H); 13C NMR (100.6 MHz, CDCl3): δ 185.8, 138.8, 137.6, 136.3, 134.0, 130.6, 128.8, 127.7,
126.8, 123.3, 121.2, 112.8, 112.2.
(1H-indol-2-yl)(naphthalen-1-yl)methanone 4h.16 Yield (Procedure A): 44 mg, 88 %;1H NMR
(400 MHz, CDCl3): δ 10.07 (br s, 1H), 8.34–8.24 (m, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.96–7.85 (m,
2H), 7.66–7.61 (m, 1H), 7.60–7.48 (m, 4H), 7.34 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.12 (ddd, J = 8.0,
7.0, 1.0 Hz, 1H), 6.96 (dd, J = 2.1, 1.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ 188.9, 138.2,
136.0, 135.7, 133.8, 131.5, 130.8, 128.4, 127.9, 127.6, 127.3, 126.8, 126.5, 125.5, 124.3, 123.3,
121.0, 113.9, 112.5.
1
(1H-indol-2-yl)(3-(trifluoromethyl)phenyl)methanone 4i. Yield (Procedure A): 41 mg, 82 %; H
NMR (400 MHz, CDCl3): δ 9.39 (br s, 1H), 8.25 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.89-7.87 (m,
1H), 7.75–7.66 (m, 2H), 7.50 (dd, J = 7.6, 1.1 Hz, 1H), 7.41 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.21–

7.15 (m, 2H); 13C NMR (100.6 MHz, CDCl3): δ 185.6, 138.6, 137.8, 133.8, 132.3 ( q, J = 1.2 Hz),
130.1 (q, J = 33 Hz), 129.1 , 128.8 ( q, J = 3.8 Hz), 127.7, 127.1, 126.0 (q, J = 3.9 Hz), 124.7 (q, J =
272 Hz), 123.4, 121.4, 113.3, 112.3. HRMS m/z (ESI) positive ion, calculated for C16H10F3NNaO:
[M+Na]+ 312.0612, Found: 312.0613.
Furan-2-yl(1H-indol-2-yl)methanone 4j.47 Yield (Procedure A): 33 mg, 66 %; (Procedure B): 33
1
mg, 66 %; H NMR (400 MHz, CDCl3): δ 9.31 (br s, 1H), 7.82–7.69 (m, 3H), 7.51–7.44 (m, 2H),
7.37 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.18 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.65 (dd, J = 3.6, 1.7 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): δ 172.6, 152.7, 146.5, 137.2, 133.5, 128.0, 126.5, 123.4,
121.0, 118.6, 112.5, 112.1, 111.4.
(1H-indol-2-yl)(thiophen-2-yl)methanone 4k.47 Yield (Procedure A): 8 mg, 16 %; (Procedure B):
1
17 mg, 34 %; H NMR (400 MHz, CDCl3): δ 9.49 (br s, 1H), 8.06 (dd, J = 3.8, 1.2 Hz, 1H), 7.74
(ddd, J = 6.5, 6.1, 1.0 Hz, 2H), 7.50 (dd, J = 8.4, 0.9 Hz, 1H), 7.45 (dd, J = 2.2, 1.0 Hz, 1H), 7.38
(ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.24 (dd, J = 4.9, 3.8 Hz, 1H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H);
13C NMR (100.6 MHz, CDCl3): δ 177.9, 142.5, 137.4, 134.1, 133.2, 133.0, 128.1, 127.8, 126.4,
123.2, 121.1, 112.2, 110.7.
1
(E)-3-(furan-2-yl)-1-(1H-indol-2-yl)prop-2-en-1-one 4l. Yield (Procedure A): 33 mg, 66 %; H
NMR (400 MHz, CDCl3): δ 9.46 (br s, 1H), 7.75–7.65 (m, 2H), 7.56 (d, J = 1.7 Hz, 1H), 7.48–7.42
(m, 2H), 7.38–7.36 (m, 2H), 7.16 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 6.74 (d, J = 3.6 Hz, 1H), 6.53 (dd,
J = 3.3, 2.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ 180.9, 151.7, 145.0, 137.8, 136.6, 129.2,
127.8, 126.4, 123.2, 121.0, 119.3, 116.3, 112.7, 112.2, 109.4. HRMS m/z (ESI) positive ion,
calculated for C15H11KNO2: [M+K]+ 276.0427, Found: 276.0429.
(4-(tert-butyl)cyclohex-1-en-1-yl)(1H-indol-2-yl)methanone 4m. Yield (Procedure A): 28 mg, 56
1
%; H NMR (400 MHz, CDCl3): δ 9.38 (br s, 1H), 7.71–7.68 (m, 1H), 7.44 (d, J = 8.2 Hz, 1H),
7.33 (ddd, J = 8.3, 7.1, 1.1 Hz, 1H), 7.14 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H), 7.08 (dd, J = 1.2, 1.1 Hz,
1H), 7.02–6.99 (m, 1H), 2.76–2.70 (m, 1H), 2.43–2.29 (m, 2H), 2.13–1.99 (m, 2H), 1.45–1.37 (m,
1H), 1.30–1.19 (m, 1H), 0.94 (s, 9H); 13C NMR (100.6 MHz, CDCl3): δ 188.3, 140.7, 138.4, 137.2,
134.4, 127.6, 125.8, 122.9, 120.7, 112.1, 110.6, 43.6, 32.3, 27.8, 27.2, 25.9, 23.5. HRMS m/z (ESI)
positive ion, calculated for C19H24NO: [M+H]+ 282.1858, Found: 282.1857.
1
1-(1H-indol-2-yl)hexan-1-one 4n. Yield (Procedure A): 46 mg, 92%; H NMR (400 MHz, CDCl3):
δ 9.52 (br s, 1H), 7.71 (dd, J = 7.2, 1.1 Hz, 1H), 7.46–7.44 (m, 1H), 7.34 (ddd, J = 8.3, 7.1, 1.1 Hz,
1H), 7.21 (dd, J = 1.1 Hz, 1H), 7.15 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 2.95 (t, J = 7.6 Hz, 2H), 1.85–
1.77 (m, 2H), 1.42–1.35 (m, 4H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ 193.9,

137.4, 135.3, 127.6, 126.2, 123.0, 120.9, 112.3, 109.2, 38.4, 31.6, 24.9, 22.5, 14.0. HRMS m/z
(ESI) positive ion, calculated for C14H17KNO: [M+K]+ 254.0947, Found: 254.0940.
(1H-indol-2-yl)(thiophen-2-yl)methanone 4o.17 Yield (Procedure A): 37.5 mg, 75 %; (Procedure
1
B): 27.5 mg, 55 %; H NMR (400 MHz, CDCl3): δ 9.48 (br s, 1H), 7.70 (dd, J = 8.1, 1.0 Hz, 1H),
7.45 (dt, J = 2.7, 0.9 Hz, 1H), 7.34 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.21 (dd, J = 2.1, 0.9 Hz, 1H),
7.15 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 3.01 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3): δ 194.1, 137.3, 134.9, 127.6, 126.2, 123.0, 120.9, 112.3, 108.9, 31.5, 8.8.
cyclohexyl(1H-indol-2-yl)methanone 4p. Yield (Procedure A): 16 mg, 32%; (Procedure B): 14.5
mg, 29 %; 1H NMR (400 MHz, CDCl3): δ 9.11 (br s, 1H), 7.71 (dd, J = 7.2, 1.1 Hz, 1H), 7.43 (d, J
= 8.4 Hz, 1H), 7.34 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 7.26–7.24 (m, 1H), 7.15 (ddd, J = 8.2, 7.1, 1.2
Hz, 1H), 3.24–3.16 (m, 1H), 1.96–1.89 (m, 4H), 1.64–1.54 (m, 4H), 1.46–1.24 (m, 2H); 13C NMR
(100.6 MHz, CDCl3): δ 197.1, 137.3, 134.4, 127.6, 126.2, 123.0, 120.9, 112.3, 108.9, 46.5, 29.8,
25.9. HRMS m/z (ESI) positive ion, calculated for C15H17KNO: [M+K]+ 266.0947, Found:
266.0947.
1
(6-chloro-1H-indol-2-yl)(phenyl)methanone 4q.48 Yield (Procedure A): 41 mg, 82 %; H NMR
(400 MHz, CDCl3): δ 9.49 (br s, 1H), 7.99 (dd, J = 8.3, 1.3 Hz, 2H), 7.69–7.59 (m, 2H), 7.59–7.51
(m, 2H), 7.51–7.48 (m, 1H), 7.15–7.13 (m, 2H); 13C NMR (100.6 MHz, CDCl3): δ 187.0, 137.7,
135.0, 132.6, 132.5, 129.2, 128.6, 126.3, 124.2, 122.2, 112.6, 112.0.
1
(6-fluoro-1H-indol-2-yl)(phenyl)methanone 4r. Yield (Procedure A): 34 mg, 68 %; H NMR (400
MHz, CDCl3): δ 9.41 (br s, 1H), 7.98 (dd, J = 7.8, 1.6 Hz, 2H), 7.68–7.63 (m, 2H), 7.56–7.52 (m,
2H), 7.16–7.14 (m, 2H), 6.96 (ddd, J = 8.8, 6.7, 2.3 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): δ
186.9, 162.4 (d, JC-F = 244 Hz), 137.8, 135.08 (d, JC-F = 3.7 Hz), 132.5, 129.2, 128.6, 124.6 (d, JC-F
=
10.5 Hz), 124.4 (d, JC-F = 1.1 Hz), 113.08, 113.06, 110.9 (d, JC-F = 27.6 Hz), 98.1 (d, JC-F = 27.6 Hz).
HRMS m/z (ESI) positive ion, calculated for C15H10FKNO: [M+K]+ 278.0383, Found: 278.0381.
1
1-(5,7-dimethyl-1H-indol-2-yl)hexan-1-one 4s. Yield (Procedure A): 46 mg, 92 %; H NMR (400
MHz, CDCl3): δ 9.00 (br s, 1H), 7.32 (s, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.98 (s, 1H), 2.92 (t, J = 7.7
Hz, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 1.82–1.74 (m, 2H), 1.39–1.34 (m, 4H), 0.91 (t, J = 7.7 Hz, 3H);
13C NMR (100.6 MHz, CDCl3): δ 193.8, 135.6, 135.1, 130.5, 128.6, 127.4, 121.2, 119.7, 109.2,
38.3, 31.6, 25.1, 22.5, 21.4, 16.7, 14.0. HRMS m/z (ESI) positive ion, calculated for C16H21KNO:
[M+K]+ 282.1260, Found: 282.1259.
1
1-(6-fluoro-1H-indol-2-yl)propan-1-one 4t. Yield (Procedure A): 31 mg, 62 %; H NMR (400

MHz, CDCl3): δ 9.46 (br s, 1H), 7.40 (dd, J = 9.0, 4.3 Hz, 1H), 7.34 (dd, J = 6.8, 2.3, 1H), 7.17 (dd,
J = 2.2, 1.3 Hz, 1H), 7.11 (dt, J = 9.0, 6.7, 2.3 Hz, 1H), 3.01 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.4 Hz,
3H); 13C NMR (100.6 MHz, CDCl3): δ 194.0, 158.1 (d, JC-F = 236 Hz), 136.3, 133.8, 127.7 (d, JC-F
= 10.3 Hz), 115.3 (d, JC-F = 26.9 Hz), 113.2 (d, JC-F = 9.7 Hz), 108.6 (d, JC-F = 5.9 Hz), 107.3 (d, JC-F
= 23.4 Hz), 31.6, 8.6. HRMS m/z (ESI) positive ion, calculated for C11H10FKNO: [M+K]+
230.0383, Found: 230.0384.
Methyl 5-chloro-1H-indole-2-carboxylate 4u.49
Yield (Procedure A): 9 mg, 18 %; 1H NMR (400 MHz, CDCl3): δ 8.95 (br s, 1H), 7.67 (s, 1H), 7.35
(d, J = 8.7 Hz, 1H), 7.31–7.25 (m, 2H), 7.15 (d, J = 1.5 Hz, 1H), 3.95 (s, 3H); 13C NMR
(100.6MHz, CDCl3): δ 162.1, 135.1, 128.4, 126.6, 126.0, 121.8, 112.98, 112.93, 108.1, 52.2.
2-phenylquinolin-4(1H)-one 6a.50
1
Yield: 8 mg, 16 %; H NMR (400 MHz, DMSO): δ 11.75 (br s, 1H), 8.11 (dd, J = 8.1, 1.1 Hz, 1H),
7.84–7.77 (m, 3H), 7.67 (ddd, J = 8.4, 7.0, 1.5 Hz, 1H), 7.61–7.53 (m, 3H), 7.34 (t, J = 7.5 Hz, 1H),
6.34 (s, 1H); 13C NMR (100.6 MHz, DMSO): δ 177.0, 150.0, 140.5, 134.2, 131.8, 130.4, 129.0,
127.4, 124.9, 124.7, 123.2, 118.7, 107.3.
1
Supporting Information Available. a) Structure of 3a-t, copies of H and 13C NMR spectra of all
1
new compounds and copies of H spectra of known acylindoles and quinolone 6a. b) Details of
DFT calculations. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment
The authors are grateful for financial support from the Università dell’Aquila. M. A. wishes to
thank CINECA (Italy) for the grant Iscra-Class C (code IscrC_CCAE).
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