Synthesis of 4-substituted-1,2-dihydroquinolines by means of gold-catalyzed intramolecular hydroarylation reaction of n-ethoxycarbonyl-n-propargylanilines

Article abstract of DOI:10.3390/molecules26113366

An alternative Au(I)-catalyzed synthetic route to functionalized 1,2-dihydroquinolines is reported. This novel approach is based on the use of N-ethoxycarbonyl protected-Npropargylanilines as building blocks that rapidly undergo the IMHA reaction affording the 6-endo cyclization product in good to high yields. In the presence of N-ethoxycarbonyl-N-propargyl-metasubstituted anilines, the regiodivergent cyclization at the ortho-/para-position is achieved by the means of catalyst fine tuning.

Full text of DOI:10.3390/molecules26113366

molecules
Article
Synthesis of 4-Substituted-1,2-Dihydroquinolines by Means of
Gold-Catalyzed Intramolecular Hydroarylation Reaction of
N-Ethoxycarbonyl-N-Propargylanilines
Antonio Arcadi 1 , Andrea Calcaterra 2 , Giancarlo Fabrizi 2, Andrea Fochetti 2, Antonella Goggiamani 2,*,
Antonia Iazzetti 2,*, Federico Marrone 2, Vincenzo Marsicano 1 , Giulia Mazzoccanti 2 and Andrea Serraiocco 2
1
Dipartimento di Scienze Fisiche e Chimiche, Università degli Studi di L’Aquila, 67100 Coppito, Italy;
antonio.arcadi@univaq.it (A.A.); vincenzo.marsicano@graduate.univaq.it (V.M.)
Dipartimento di Chimica e Tecnologie del Farmaco, Dipartimento di Eccellenza 2018–2022,
2
Sapienza Università di Roma, 00185 Rome, Italy; andrea.calcaterra@uniroma1.it (A.C.);
giancarlo.fabrizi@uniroma1.it (G.F.); andrea.fochetti@uniroma1.it (A.F.); federico.marrone@uniroma1.it (F.M.);
giulia.mazzoccanti@uniroma1.it (G.M.); andrea.serraiocco@uniroma1.it (A.S.)
*
Correspondence: antonella.goggiamani@uniroma1.it (A.G.); antonia.iazzetti@uniroma1.it (A.I.)
Abstract: An alternative Au(I)-catalyzed synthetic route to functionalized 1,2-dihydroquinolines is
reported. This novel approach is based on the use of N-ethoxycarbonyl protected-N-propargylanilines
as building blocks that rapidly undergo the IMHA reaction affording the 6-endo cyclization product in
good to high yields. In the presence of N-ethoxycarbonyl-N-propargyl-meta-substituted anilines, the
regiodivergent cyclization at the ortho-/para-position is achieved by the means of catalyst fine tuning.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Arcadi, A.; Calcaterra, A.;
Fabrizi, G.; Fochetti, A.; Goggiamani,
A.; Iazzetti, A.; Marrone, F.;
Keywords: gold catalysis; intramolecular hydroarylation; 1,2-dihydroquinolines
Marsicano, V.; Mazzoccanti, G.;
Serraiocco, A. Synthesis of
4-Substituted-1,2-Dihydroquinolines
by Means of Gold-Catalyzed
Intramolecular Hydroarylation
Reaction of N-Ethoxycarbonyl-N-
Propargylanilines. Molecules 2021, 26,
3366. https://doi.org/10.3390/
molecules26113366
1. Introduction
4-Substituted-1,2-dihydroquinolines represent key structural units in a variety of
naturally occurring products/pharmaceuticals and are used as building blocks in organic
synthesis [
are known, [
cal approaches using mild reaction conditions remains an active research area [
1
–
5
1
]. Many methods for the synthesis of functionalized 1,2-dihydroquinolines
], but due to their pharmaceutical relevance, the development of practi-
11].
6
–
Academic Editor: Michal Szostak
Among them, the transition metal-catalyzed as well as the metal-free mediated intramolec-
ular hydroarylation (IMHA) reactions involving the activation of the N-substituted-N-
propargyl anilines carbon–carbon triple bond by using an electrophilic source have been
extensively used [12
IMHA of N-tosyl-N-propargylanilines was explored and the corresponding 4-substituted-
1,2-dihydroquinoline derivatives were efficiently isolated (Scheme 1a) [14 16]. Alter-
natively these latter products can be obtained by the sequential catalyzed IMHA/Pd-
catalyzed cross-coupling of 3-bromo-2-propynyl-N-tosylanilines, which afforded the corre-
sponding 4-substituted-1,2-dihydroquinoline derivatives [17,18]. However, the behavior
Received: 7 May 2021
Accepted: 1 June 2021
Published: 2 June 2021
,13]. In particular, the synthetic potential of gold catalysis in the
–
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
of the substituent attached to N-propargylaniline nitrogen has a significant impact on
the reaction outcome. While N-propargylanilines bearing the more easily removable 2-
nitrobenzenesulfonyl (Ns) nitrogen protecting group underwent the gold-catalyzed IMHA
to give the corresponding dihydroquinoline in good yield, subjection of the N-Boc pro-
tected derivatives under the same reaction conditions afforded the divergent formation of
an oxazolidinone derivative as the exclusive product [16]. Moreover, 1-azaspirotrienone
derivatives were produced exclusively instead of the expected dihydroquinolines when N-
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
(4-methoxyphenyl)-N-(3-substituted-2-propyn-1-yl)triflamides were reacted with 2 equiv.
◦
of ICl in CH2Cl2 at
−
78 C for 0.5 [19]. As part of our ongoing interest on the devel-
opment of efficient atom-economical routes of heterocycles by means of gold-catalyzed
IMHA [20–22], we envisaged that the introduction of the more suitable ethyl carbamate
Molecules 2021, 26, 3366. https://doi.org/10.3390/molecules26113366
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3366
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protecting group could allow for some of the drawbacks of the previously reported gold-
catalyzed IMHA of N-substituted-N-propargylanilines (Scheme 1b) to be overcome. The
carbamate motif, indeed, in addition to being widely known as excellent protecting groups
for amines in organic synthesis, has received a great deal of attention in drug design and
medicinal chemistry for its application in the construction of drugs and prodrugs [23].
.
Scheme 1. Gold(I)-catalyzed IMHA of N-tosyl- (a) vs. N-ethoxy carbonyl-N-propargylanilines (b).
Herein, we report the results of our investigations.
2. Results and Discussion
We started our study by examining the transformation of the N-ethoxycarbonyl-
N-propargylaniline 1a into 2a under different reaction conditions. The results of this
preliminary screening are summarized in Table 1.
Table 1. Screening optimal conditions for the IMHA of the N-ethoxycarbonyl-N-propargylaniline 1a a
.
◦
Entry
Catalyst
T ( C)
Solvent
Time (h)
2a (Yield %)
b
1
2
3
4
5
6
PtCl2
NaAuCl4
JPAu(CH3CN)SbF6
JPAu(CH3CN)SbF6
JPAu(CH3CN)SbF6
JPAuCl/AgNTf2
80
80
80
100
100
80
EtOH
EtOH
24
48
1
4.5
0.75
3.5
-
-
c
DCM d
CHCl3d
CHCl3
CH2Cl2
98
70 e
86 f
94
a
Reactions were carried out on a 0.35 mmol of 1a in 2 mL of solvent in the presence of 0.014 mmol of the catalyst.
1a was recovered in 30% yield, ethyl 3-oxo-3-phenylpropyl(phenyl)carbamate 3a was isolated in 35% yield; c 1a
b
was recovered in 18% yield, 3a was isolated in 75% yield; d Commercial anhydrous solvent; e 3a was isolated in
21% yield; f 3a was isolated in 7% yield.

Molecules 2021, 26, 3366
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As shown, the IMHA of 1a occurred in almost quantitative yield in the presence of the
commercially available JohnPhosAu(MeCN)SbF6 catalyst (4 mol %) in anhydrous DCM at
80 ◦C (Table 1, entry 3) [15,16].
About the same result was obtained using the catalytic system JPAuCl/AgNTf2
(
Table 1, entry 6) while slightly poorer results were observed when CHCl3 was used as the
solvent instead of DCM (Table 1, entries 4, 5). In this latter solvent, the hydration derivative
ethyl 3-oxo-3-phenylpropyl(phenyl)carbamate 3a was isolated to some extent (Figure 1).
Figure 1. Structure of the hydration derivative 3a.
In contrast with the good efficiency showed by NaAuCl4 2H2O in the sequential
·
alkylation/gold-catalyzed annulation reactions of anilines with propargylic bromide deriva-
tives providing quinoline scaffolds in ethanol [24], this gold salt was ineffective as the
catalyst of the IMHA of N-ethoxycarbonyl-N-propargylaniline 1a, affording only the for-
mation of the hydration product 3a in good yield (Table 1, entry 2) [25]. Starting material 1a
was recovered in almost quantitative yield when PtCl2 was used as the catalyst in ethanol
(Table 1, entry 1) [26].
Then, to briefly explore the influence of the protecting group on the reaction outcome,
we used the optimized reaction condition for the cyclization of the N-propargylaniline
derivatives 4a and 4b (Scheme 2).
a
Scheme 2. JPAu(CH3CN)SbF6 catalyzed IMHA of N-propargylaniline derivatives 4a and 4b
.
a
Compound 4b was recovered in almost quantitative yield when the reaction was carried out in the
absence of the catalyst.
As shown by the results reported in Scheme 2, the N-trifluoroacetyl-N-propargylaniline
derivative failed to undergo the desired gold-catalyzed IMHA to give the corresponding di-
◦
hydroquinoline 5a in the presence of 4 mol % of JPAu(CH3CN)SbF6 in DCM at 80 C. Inter-
estingly, under the same reaction conditions, the simple N-(3-phenylprop-2-yn-1-yl)aniline
4b underwent a complete gold-catalyzed IMHA, but the 4-phenyl-1,2-dihydroquinoline 5b
(25% yield) was prone to be partially oxidized under the reaction conditions to give the
corresponding 4-phenylquinoline 6b (56% yield). The partial oxidation of 5b to 6b occurs
even under a nitrogen atmosphere. Furthermore, we observed the formation of 7b, which
was isolated in 7% of yield (see Figure 2) [27].

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Figure 2. Structure of the 4-phenylquinoline 6b and 4-phenyl-1,2,3,4-tetrahydroquinoline 7b obtained
from compound 4b in the condition reported in Scheme 2.
Subsequently, we continued to establish the scope and the generality of gold(I)
catalyzed-IMHA reactions of aryl-substituted N-ethoxycarbonyl-N-propargylanilines
1 in
terms of ring substitution. The utilization of electron-deficient substrates and the control of
the regioselectivity of substituted aromatics remain challenges of gold(I) catalyzed-IMHA
reactions of aryl-substituted N-propargylanilines. To that end, a range of readily accessible
derivatives 1a
presence of the JohnPhosAu(CH3CN)SbF6 as the catalyst. The outcomes of such studies are
shown in Table 2. The 4-arylsubstituted-1,2-dihydroquinoline derivatives were isolated
–j
were prepared and then subjected to the IMHA in CH2Cl2 at 80 ◦C in the
2
in high yields both when the electron donating –OMe group or the strong withdrawing
–COOMe were introduced into the para-position of the aromatic ring attached to the alkyne
(Table 2, entries 2, 3). Conversely, the introduction of substituents onto the aromatic
ring attached to the nitrogen moiety had a different pronounced effect according to their
electronic features. The formation of the target 4-aryl-1,2-dihydroquinoline derivative
2
efficiently occurred by the introduction of an electron-donating group on the phenyl ring
para to the nitrogen and in the para position of both aromatic rings of the starting aryl-
substituted propargylic aniline derivatives (Table 2, entries 4–6). Moreover, the IMHA was
also allowed in almost quantitative yield in the presence of the –Me group on the phenyl
ring para to the nitrogen and of a withdrawing carbonyl in the para position of the other
aryl group (Table 2, entry 7). In absolute agreement with considerations of the positive
effect of electronic releasing groups on the aromatic ring attached to the nitrogen on the
gold-catalyzed IMHA of substrate 1, substrate 1h bearing two methyl groups on the same
benzene nucleus was smoothly converted to the corresponding 1,2-dihydroquilonine 2h in
about quantitative yield either by the gold-catalyzed IMHA (Table 2, entry 8). Substrate
1i, possessing a Cl-substituent on the same aromatic ring, cyclized as expected to afford
the corresponding dihydroquinoline derivative 2i in moderate yield (Table 2, entry 9).
The formation of the IMHA products occurred only in low yield in the presence of the
strong electron-withdrawing CF3-substituent probably due to the poorer coordination of
the alkyne moiety with the gold catalyst (Table 2, entry 10).
With regard to the regiochemical outcome, the meta-substituted derivatives 1k
underwent the para-position cyclization to give the corresponding 1,2-dihydroquinolines
2k in the presence of JohnPhosAu(CH3CN)SbF6 (catalyst ). Fine tuning factors such as
valency state, counterion, and auxiliary ligand in homogeneous gold catalysis is imperative
–n mainly
–n
A
in controlling the product divergence [28]. Indeed, for compounds 1k–l, the para-position
cyclization was revealed to be enhanced in the presence of catalyst A0 bearing NTf2 as
counterion (catalyst A0, entries 2 and 6). The electron-rich tri-isopropylphenyl ring on the
−
ligand and the slightly more strongly coordinated NTf2 jointly lower the electrophilicity of
the gold center. On the other hand, the regiodivergent cyclization to the sterically hindered
ortho-position to give the regioisomeric 1,2-dihydroquinolines 20k
–n
resulted governed by
the electron-deficient ligand features, according to the literature (Table 3) [29].

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Table 2. Scope of the gold(I)-catalyzed IMHA of the N-ethoxycarbonyl-N-propargylanilines 1 a.
Entry
R
R2
1
Time (h)
2 (Yield %)
1
2
3
4
5
6
7
8
9
H
H
H
H
OMe
COMe
H
a
b
c
d
e
f
g
h
i
1
18
2
2
1
5
1
1
24
2a (98)
2b (82)
2c (99)
2d (82)
2e (99)
2f (68) b
2g (99)
2h (99)
2i (56) c
2j (10) d
4-OMe
4-Me
4-Me
4-Me
3,5-(Me)2
4-Cl
H
OMe
COMe
H
H
OMe
10
4-CF3
j
24
a
Reactions were carried out on 0.35 mmol scale of
1
in 2 mL of CH2Cl2; b The starting alkyne 1f was recovered in
8% yield; c The starting alkyne 1i was recovered in 18% yield; d The starting alkyne 1j was recovered in 60% yield.
Very likely, the control of ortho/para site-selectivity in these substrates is the result of
the different coordination modes of the gold catalyst influenced by sterics and electronics
of the auxiliary ligand. The prowess of electron-rich bulk ligands in pushing the π-system
toward the para C–H bond through a Au(I)-bicoordinate activation was also explored
in the 6-endo-dig gold catalyzed hydroarylation of functionalized N-aryl alkynamides
(Figure 3) [30].
Figure 3. Ligand control of ortho/para site-selectivity.
Indeed, according to the literature [13], the gold catalyzed IMHA proceeds through a
Friedel–Crafts type mechanism:
undergoes an electrophilic aromatic substitution to give the Wheland-type intermediate
η I, which
2-coordination of alkyne moiety affords complex
II. This latter, after aromatization and protodeauration would give the product 2. The
proposed mechanism is outlined in the Scheme 3.

Molecules 2021, 26, 3366
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Table 3. Ortho- vs. para-position annulation in the gold(I)-catalyzed IMHA of the N-ethoxycarbonyl-
N-propargylanilines 1k–n a.
0
Overall Yield (%) b
Entry
R1
R2
Catalyst
2/2
(Ratio) c
1
2
3
4
A
A
B
C
99
99
90
67
(67/33)
(94/6)
(44/56)
(46/54)
0
0
OMe
H
2k/2 k
5
6
7
8
A
A
B
C
99
99
99
86
(61/39)
(75/25)
(54/46)
(54/46)
0
0
OMe
OMe
COMe
OMe
2l/2 l
9
A
70
73
83
77
(91/9)
(91/9)
(63/37)
(51/49)
0
10
11
12
A
0
2m/2 m
B
C
13
14
15
16
A
A
B
C
85
75
99
72
(88/12)
(64/36)
(40/60)
(19/81)
0
0
COMe
COMe
COOMe
COMe
2n/2 n
17
18
19
20
A
88
90
70
82
(88/12)
(65/35)
(33/67)
(20/80)
0
A
0
2o/2 o
B
C
a
Reactions were carried out on 0.35 mmol of 1k
regioisomers 2 + 20; c The isomeric ratio was determined by 1H NMR analyses.
–n
in 2 mL in CH2Cl2; b Overall yield refers to the mixture of

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Scheme 3. Proposed Friedel–Crafts mechanism for the Au(I)-catalyzed cyclization of N-substituted-
N-propargylanilines.
3. Materials and Methods
3.1. General Information
All the commercially available reagents, catalysts, bases, and solvents were used as
purchased without further purification. Reaction products 2a
on a pad of SiO2 using AcOEt, while reaction products 2f 2i and 2j were purified by
chromatography on SiO2 (25–40 m), eluting with n-hexane/AcOEt mixtures. Reaction
products 2k/20k 2o/20o were obtained as isomeric mixtures by filtration on a pad of SiO2
–e and 2g–h were filtered
,
µ
–
using AcOEt to eliminate the catalysts before calculating the isomeric ratio by 1H NMR.
When possible, to obtain suitable NMR spectra of each compound, the isomeric mixtures
were further purified by semi-preparative HPLC under normal phase condition using
a Nucleodur 100–5 column (762,007.100) and eluting with n-hexane/AcOEt mixtures.
1H NMR (400.13 MHz), 13C NMR (100.6 MHz), and 19F spectra (376.5 MHz) were recorded
with a Bruker Avance 400 spectrometer. Splitting patterns were designed as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). IR spectra were
recorded with a Jasco FT/IR-430 spectrometer. HRMS were recorded with an Orbitrap
Exactive Mass spectrometer with ESI source. Melting points were determined with a Büchi
B-545 apparatus and are uncorrected.
3.2. Synthetic Procedures
3.2.1. Preparation of Substrates 1
Substrates were prepared as described in the Supplementary Materials.
3.2.2. Preparation of Derivatives 2: Typical Procedure for the Preparation of the Ethyl
4-Phenylquinoline-1(2H)-Carboxylate 2a
A Carousel Tube Reactor (Radley Discovery Technology) equipped with a magnetic
stirring bar was charged with ethyl phenyl(3-phenylprop-2-yn-1-yl)carbamate 1a (97.8 mg,
0.35 mmol, 1 equiv.), CH2Cl2 (2 mL), JohnPhosAu(MeCN)SbF6 (10.8 mg, 0.014 mmol,
0.04 equiv.), and sealed. Then, the reaction mixture was stirred at 80 ◦C and monitored by
TLC until the disappearance of the starting material. After 1 h, the obtained mixture was
cooled at room temperature and concentrated under reduced pressure. The residue was
filtered on a pad of SiO2 to afford 97.1 mg of ethyl 4-phenylquinoline-1(2H)-carboxylate 2a
(99% yield).

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Compound 2a: yield: 99% (97.1 mg); yellow oil; IR (neat): 2912, 1707, 1380 cm−1
1H NMR (400.13 MHz) (CDCl3):
= 7.69 (d, J = 7.4 Hz, 1H), 7.45–7.36 (m, 5H), 7.31–7.27 (m,
1H), 7.12–7.05 (m, 2H), 6.07 (t, J = 4.5 Hz, 1H), 4.51 (d, J = 4.5 Hz, 2H), 4.33 (q, J = 7.1 Hz,
2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
= 154.2 (q), 138.9 (q), 137.3
;
δ
δ
(q), 129.3 (q), 128.8 (CH), 128.5 (CH), 127.9 (CH), 127.7 (CH), 126.1 (CH), 124.2 (CH), 124.1
(CH), 123.4 (CH), 62.3 (CH2), 43.1 (CH2), 14.7 (CH3); MS (EI ion source): m/z (%) = 279
(18, [M+]), 206 (100), 204 (62), 102 (21); HRMS: m/z [M + Na]+ calcd. for C18H17NO2Na:
302.1152; found: 302.1152.
3.3. Characterization Data
3.3.1. Characterization Data of Compound 1a–o
Characterization data of substrate 1 are reported in the Supplementary Materials.
3.3.2. Characterization Data of Compound 2b–j, 2l–o, 20l–20o
Compound 2b. Yield: 82% (88.9 mg); yellow oil; IR (neat): 2980, 1699, 1608, 1510,
1051 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.56 (bd, J = 7.7 Hz, 1H), 7.19 (d, J = 8.8 Hz,
2H), 7.18–7.15 (m, 1H), 7.01 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 1H), 6.95 (dt, J1 = 7.2 Hz, J2 = 1.2 Hz,
1H), 6.84 (d, J = 8.8 Hz, 2H), 5.91 (t, J = 4.5 Hz, 1H), 4.37 (d, J = 4.5 Hz, 2H), 4.20 (q, J = 7.1 Hz,
2H), 3.76 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 159.4 (q), 154.2
(q), 138.4 (q), 137.4 (q), 131.3 (q), 130.0 (CH), 129.5 (q), 127.6 (CH), 126.1 (CH), 124.15 (CH),
124.08 (CH), 122.5 (CH), 113.9 (CH), 62.2 (CH2), 55.4 (CH3), 43.1 (CH2), 14.7 (CH3); MS (EI
ion source): m/z (%) = 309 (47, [M+]), 280 (93), 236 (100), 221 (21), 192 (20); HRMS: m/z
[M + Na]+ calcd. for C19H19NO3Na: 332.1257; found: 332.1261.
Compound 2c. Yield: 99% (111.3 mg); white solid; m.p. = 110–111 ◦C; IR (neat): 2977,
1698, 1604, 1484 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.98 (d, J = 8.5 Hz, 2H), 7.67–7.65
(m, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.30–7.25 (m, 1H), 7.06–6.99 (m, 2H), 6.10 (t, J = 4.6 Hz, 1H),
4.49 (d, J = 4.6 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR
(100.6 MHz) (CDCl3):
δ = 197.8 (q), 154.2 (q), 143.9 (q), 138.3 (q), 137.4 (q), 136.6 (q), 129.1
(CH), 128.7 (CH), 128.1 (CH), 126.0 (CH), 124.6 (CH), 124.4 (CH), 120.6 (q), 62.4 (CH2), 43.1
(CH2), 26.8 (CH3), 14.7 (CH3); MS (EI ion source): m/z (%) = 321 (27, [M+]), 292 (71), 248
(100), 205 (28); HRMS: m/z [M + H]+ calcd. for C20H20NO3: 322.1438; found: 322.1431.
Compound 2d. Yield: 82% (88.6 mg); pale yellow oil; IR (neat): 2980, 1702, 1491,
1382 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.56–7.53 (m, 1H), 7.40–7.33 (m, 5H), 6.81
(dd, J1 = 8.9 Hz, J2 = 2.9 Hz, 1H), 6.60 (d, J = 2.9 Hz, 1H), 6.06 (t, J = 4.5 Hz, 1H), 4.44 (d,
J = 4.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR
(100.6 MHz) (CDCl3):
δ = 156.2 (q), 154.4 (q), 138.9 (q), 138.8 (q), 130.51 (q), 130.47 (q),
128.8 (CH), 128.5 (CH), 127.9 (CH), 125.2 (CH), 113.0 (CH), 111.6 (CH), 62.1 (CH2), 55.6
(CH3), 43.2 (CH2), 14.7 (CH3); MS (EI ion source): m/z (%) = 309 (21, [M+]), 280 (24), 236
(100), 193 (36), 165 (19), 63 (30); HRMS: m/z [M + H]+ calcd. for C19H20NO3: 310.1438;
found: 310.1443.
−1
Compound 2e. Yield: 99% (101.4 mg); orange oil; IR (neat): 2981, 1697, 1493, 1378 cm
;
1H NMR (400.13 MHz) (CDCl3):
δ
= 7.53–7.52 (m, 1H), 7.42–7.34 (m, 5H), 7.07 (dd,
J1 = 8.3 Hz, J2 = 1.4 Hz, 1H), 6.86 (bd, J = 1.4 Hz, 1H), 6.02 (t, J = 4.5 Hz, 1H), 4.45 (d,
J = 4.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR
(100.6 MHz) (CDCl3):
δ = 154.2 (q), 139.1 (q), 139.0 (q), 134.8 (q), 133.8 (q), 129.1 (q), 128.8
(CH), 128.5 (CH), 128.4 (CH), 127.8 (CH), 126.5 (CH), 124.0 (CH), 123.5 (CH), 62.2 (CH2),
43.1 (CH2), 21.1 (CH3), 14.7 (CH3); MS (EI ion source): m/z (%) = 293 (39, [M+]), 264
(49), 220 (100), 204 (55), 63 (29); HRMS: m/z [M + H]+ calcd. for C19H20NO2: 294.1489;
found: 294.1491.
Compound 2f. Yield: 68% (77.2 mg); yellow oil; IR (neat): 2980, 2836, 1702, 1608, 1509,
1463 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.53–7.51 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H),
7.07 (dd, J1 = 8.3 Hz, J2 = 1.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.89 (bd, J = 1.6 Hz, 1H), 5.97
(t, J = 4.5 Hz, 1H), 4.43 (d, J = 4.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.24 (s, 3H),
1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 159.3 (q), 154.2 (q), 138.5 (q),

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134.8 (q), 133.7 (q), 131.4 (q), 129.9 (CH), 129.3 (CH), 128.3 (CH), 126.5 (CH), 123.9 (CH),
122.7 (q), 113.9 (CH), 62.1 (CH2), 55.4 (CH3), 43.1 (CH2), 21.1 (CH3), 14.7 (CH3); MS (EI
ion source): m/z (%) = 323 (43, [M+]), 294 (87), 250 (100), 235 (20), 207 (17); HRMS: m/z
[M + H]+ calcd. for C20H22NO3: 324.1594; found: 324.1597.
Compound 2g. Yield: 96% (112.4 mg); orange wax; IR (neat): 2980, 2243, 1705, 1596,
1494 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.99 (d, J = 8.4 Hz, 2H), 7.54–7.52 (m, 1H),
7.45 (d, J = 8.4 Hz, 2H), 7.11–7.07 (m, 1H), 6.79 (bd, J = 1.4 Hz, 1H), 6.08 (t, J = 4.4 Hz, 1H),
4.46 (d, J = 4.4 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 1.34 (t, J = 7.1 Hz,
3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 197.9 (q), 154.2 (q), 144.0 (q), 138.3 (q), 136.5 (q),
134.8 (q), 133.9 (q), 129.6 (CH), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.5 (q), 126.3 (CH),
124.1 (CH), 62.3 (CH2), 43.1 (CH2), 26.8 (CH3), 21.1 (CH3), 14.7 (CH3); MS (EI ion source):
m/z (%) = 351 (M+, 31), 322 (50), 278 (14), 157 (46), 134 (100), 114 (62); HRMS: m/z [M + H]+
calcd. for C21H22NO3: 336.1594; found: 336.1598.
Compound 2h. Yield: 99% (106.3 mg); yellow oil; IR (neat): 2979, 1703, 1608, 1557,
1376, 1271 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ
= 7.28–7.14 (m, 6H), 6.68 (s, 1H), 6.01
(t, J = 5.2 Hz, 1H), 4.20–4.14 (m, 4H), 2.26 (s, 3H), 1.65 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz) (CDCl3):
= 153.9 (q), 141.8 (q), 139.9 (q), 139.1 (q), 137.3 (q), 135.3
δ
(q), 129.0 (CH), 128.5 (CH), 127.4 (CH), 127.2 (CH), 125.8 (q), 125.3 (CH), 122.4 (CH), 62.1
(CH2), 42.6 (CH2), 23.0 (CH3), 21.5 (CH3), 14.7 (CH3); MS (EI ion source): m/z (%) = 307 (20,
[M+]), 278 (27), 234 (100), 218 (18); HRMS: m/z [M + H]+ calcd. for C20H22NO2: 308.1645;
found: 308.1649.
Compound 2i. Yield: 56% (61.7 mg); pale yellow oil; IR (neat): 2981, 2847, 1702, 1594,
1
1481 cm−1; H NMR (400.13 MHz) (CDCl3):
δ = 7.59 (bd, J = 8.1 Hz, 1H), 7.43–7.36 (m,
3H), 7.33–7.30 (m, 2H), 7.21 (dd, J1 = 8.7 Hz, J2 = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.06
(t, J = 4.5 Hz, 1H), 4.47 (d, J = 4.5 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz) (CDCl3):
δ = 153.9 (q), 138.1 (q), 135.6 (q), 130.7 (q), 129.5 (CH), 128.61
(CH), 128.60 (CH), 128.0 (CH), 127.4 (CH), 125.7 (CH), 125.3 (CH), 124.4 (q), 62.3 (CH2),
43.0 (CH2), 14.5 (CH3). MS (EI ion source): m/z (%) = 313 (30, [M+]), 284 (72), 240 (100), 204
(62), 176 (19); HRMS: m/z [M + H]+ calcd. for C18H17ClNO2: 314.0942; found: 314.0952.
Compound 2j. Yield: 10% (13.0 mg); colorless oil; IR (eat): 2919, 2848, 1710, 1609,
1382, 1051 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 7.77 (bd, J = 8.5 Hz, 1H), 7.49 (dd,
J1 = 8.6 Hz, J2 = 1.6 Hz, 1H), 7.33 (bd, J = 1.6 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.94 (d,
J = 8.8 Hz, 2H), 6.04 (t, J = 4.5 Hz, 1H), 4.48 (d, J = 4.5 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H),
3.86 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 159.7 (q), 153.9 (q),
140.4 (q), 137.8 (q), 130.4 (q), 129.9 (q), 129.7 (CH), 126.1 (q, q, J = 32.5 Hz), 124.5 (CH, q,
J = 3.7 Hz), 124.20 (q, q, J = 270.3 Hz), 124.19 (CH), 123.7 (CH), 123.1 (CH, q, J = 3.7 Hz),
114.2 (CH), 62.7 (CH2), 55.5 (CH3), 43.2 (CH2), 14.6 (CH3); 19F NMR (376.5 MHz) (CDCl3):
δ
=
−
62.3; MS (EI ion source): m/z (%) = 377 (26, [M+]), 348 (77), 304 (100), 289 (14), 261
(18); HRMS: m/z [M + Na]+ calcd. for C20H18F3NO3Na: 400.1131; found: 400.1119.
Isomeric mixture 2k
20k. Overall yield (catalyst A): 99% (107.2.0 mg); 2k 20k = 67/33;
+
/
overall yield (catalyst A0): 99% (107.1 mg); 2k 20k = 94/6; overall yield (catalyst B): 90%
/
(97.1 mg); 2k/20k = 44/56; overall yield (catalyst C): 67% (72.7 mg); 2k/20k = 46/54.
2k: orange oil; IR (Neat): 2980, 2243, 1705, 1596, 1494 cm−1; 1H NMR (400.13 MHz)
(CDCl3):
1H), 5.80 (t, J = 4.5 Hz, 1H), 4.38 (d, J = 4.6 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 1.27
(t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
= 159.1 (q), 154.1 (q), 139.2 (q), 138.7
δ = 7.29–7.21 (m, 6H), 6.90 (d, J = 8.7 Hz, 1H), 6.52 (dd, J1 = 8.7 Hz, J2 = 2.6 Hz,
δ
(q), 138.6 (q), 128.8 (CH), 128.5 (CH), 127.8 (CH), 127.0 (CH), 122.5 (q), 120.4 (CH), 110.2
(CH), 109.7 (CH), 62.3 (CH2), 55.5 (CH3), 43.3 (CH2), 14.7 (CH3). MS (EI ion source): m/z
(%) = 309 (0.2, [M+]), 235 (100), 220 (17), 204 (29), 191 (24), 165 (15); HRMS: m/z [M + Na]+
calcd. for C19H19NO3Na: 332.1257; found: 332.1260.
20k: colorless oil; IR (neat): 2982, 1708, 1610, 1504, 1466 cm−1; 1H NMR (400.13 MHz)
(CDCl3):
J = 5.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.43 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR
(100.6 MHz) (CDCl3): = 156.2 (q), 153.9 (q), 141.5 (q), 139.8 (q), 137.8 (q), 128.3 (CH), 127.7
δ = 7.36–7.24 (m, 6H), 6.69 (d, J = 8.9 Hz, 1H), 6.08 (t, J = 5.1 Hz, 1H), 4.33 (d,
δ

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(CH), 126.68 (CH), 126.62 (CH), 124.5 (CH), 118.6 (q), 117.0 (CH), 108.4 (CH), 62.2 (CH2),
55.5 (CH3), 42.7 (CH2), 14.7 (CH3); MS (EI ion source): m/z (%) = 309 (42, [M+]), 280 (51),
236 (100), 220 (51), 193 (15); HRMS: m/z [M + Na]+ calcd. for C19H19NO3Na: 332.1257;
found: 332.1260.
Isomeric mixture 2l
overall yield (catalyst A0): 99% (120.9); 2l
(121.9 mg); 2l
20l = 54/46; overall yield (catalyst C): 86% (105.5 mg); 2l
wax; IR (KBr): 3060, 2922, 1680, 1593, 1480, 1232 cm−1
Reported NMR spectra refer to an isomeric mixture 2l
signals were assigned to each specific isomer while 13C NMR signals were not assigned.
+
20l. Overall yield (catalyst A): 98% (120.4 mg); 2l
20l = 75/29; overall yield (catalyst B): 99%
20l = 54/46; yellow
/
20l = 61/39;
/
/
/
.
+
20l in the ratio 54/46; 1H NMR
1H NMR (400.13 MHz) (CDCl3) (selected signals):
δ = 7.89 (d, J = 8.4 Hz, 2H 2l), 7.81
(d, J = 8.4 Hz, 2H 20l), 7.35 (d, J = 8.4 Hz, 2H 2l), 7.24–7.17 (m, 1H 2l + 4H 20l), 6.84 (d,
J = 8.6 Hz, 1H 2l), 6.59 (d, J = 9.0 Hz, 1H 20l), 6.52 (dd, J1 = 8.6 Hz, J2 = 2.6 Hz, 1H 2l), 6.03
(t, J = 5.0 Hz, 1H 20l), 5.87 (t, J = 4.6 Hz, 1H 2l), 4.39 (d, J = 4.6 Hz, 2H 2l), 4.25–4.15 (m,
2H 2l + 4H 20l), 3.74 (s, 3H 2l), 3.32 (s, 3H 20l), 2.54 (s, 3H 2l), 2.53 (s, 3H 20l), 1.29–1.23 (m,
3H 2l + 3H 20l); 13C NMR (100.6 MHz) (CDCl3):
δ = 198.1, 197.9, 159.4, 156.0, 154.1, 153.9,
146.7, 144.1, 139.8, 138.7, 138.1, 137.1, 136.6, 135.5, 129.0, 128.8, 128.7, 128.0, 126.93, 126.90,
126.0, 121.9, 121.7, 117.9, 117.1, 110.4, 109.9, 108.2, 62.43, 62.39, 55.6, 55.4, 43.2, 42.7, 26.85,
26.79, 14.8, 14.7; MS (EI ion source): m/z (%) = 351 (51, [M+]), 322 (63), 278 (100), 262 (23),
235 (20), 43 (23); HRMS: m/z [M + H]+ calcd. for C21H22NO4: 352.1543; found: 352.1536.
Isomeric mixture 2m
+ /
20m. Overall yield (catalyst A): 70% (83.0 mg); 2m 20m = 91/9;
overall yield (catalyst A0): 73% (86.5 mg); 2m 20m = 91/9; overall yield (catalyst B): 83%
/
(98.6 mg); 2m/20m = 63/37; overall yield (catalyst C): 77% (91.8 mg); 2m/20m = 51/49.
Compound 2m. Colorless oil; IR (Neat): 2915, 1711, 1577, 1386, 1244 cm−1; 1H NMR
(400.13 MHz) (CDCl3):
δ = 7.27–7.24 (m, 3H), 7.00 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.8 Hz,
2H), 6.60 (dd, J1 = 8.6 Hz, J2 = 2.6 Hz, 1H), 5.84 (t, J = 4.5 Hz, 1H), 4.43 (d, J = 4.5 Hz,
2H), 4.28 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR
(100.6 MHz) (CDCl3):
δ = 159.3 (q), 159.0 (q), 154.1 (q), 138.6 (q), 138.2 (q), 131.6 (q), 129.9
(CH), 127.0 (CH), 122.7 (q), 119.6 (CH), 113.9 (CH), 110.2 (CH), 109.6 (CH), 62.2 (CH2), 55.5
(CH3), 55.4 (CH3), 43.2 (CH2), 14.7 (CH3); MS (EI ion source): m/z (%) = 339 (1, [M+]), 265
(100), 250 (13), 222 (10), 207 (15); HRMS: m/z [M + K]+ calcd. for C20H21NO4K: 378.1102;
found: 378.1095.
Compound 20m. Colorless oil; IR (neat): 2915, 1694, 1609, 1381, 1239, 1042 cm−1
;
1H NMR (400.13 MHz) (CDCl3):
δ = 7.26–7.24 (m, 1H), 7.17 (t, J = 8.2 Hz, 1H), 7.08 (d,
J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.9 Hz, 1H), 5.93 (t, J = 5.1 Hz, 1H), 4.20
(d, J = 5.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.37 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz) (CDCl3):
δ = 158.6 (q), 156.3 (q), 153.9 (q), 140.0 (q), 137.2 (q), 134.1
(q), 128.3 (CH), 127.8 (CH), 123.6 (CH), 118.7 (q), 117.0 (CH), 113.1 (CH), 108.4 (CH), 62.3
(CH2), 55.7 (CH3), 55.5 (CH3), 42.7 (CH2), 14.7 (CH3); MS (EI ion source): m/z (%) = 339 (66,
[M+]), 310 (67), 266 (100), 251 (23); HRMS: m/z [M + H]+ calcd. for C20H22NO4: 340.1543;
found: 340.1539.
Isomeric mixture 2n
+ /
20n. Overall yield (catalyst A): 85% (112.9 mg); 2n 20n = 88/12;
overall yield (catalyst A0): 75% (99.7); 2n 20n = 64/36; overall yield (catalyst B): 99%
/
(131.6 mg); 2n/20n = 40/60; overall yield (catalyst C): 72% (95.1 mg); 2n/20n = 19/81.
Compound 2n: pale yellow solid; m.p. = 140–141 ◦C; IR (neat): 2930, 1751, 1657, 1583,
1298 cm−1; 1H NMR (400.13 MHz) (CDCl3):
δ = 8.27 (bs, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.62
(dd, J1 = 8.2 Hz, J2 = 1.7 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.21 (t,
J = 4.5 Hz, 1H), 4.53 (d, J = 4.5 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 2.60 (s, 3H),
1.37 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 197.3 (q), 166.7 (q), 153.9 (q),
142.8 (q), 137.7 (q), 137.3 (q), 136.4 (q), 132.6, (q) 129.9 (CH), 129.8 (CH), 128.7 (CH), 126.9
(q), 125.9 (CH), 124.4 (CH), 123.9 (CH), 62.5 (CH2), 52.2 (CH3), 43.0 (CH2), 26.7 (CH3), 14.5
(CH3); MS (EI ion source): m/z (%) = 379 (67, [M+]), 350 (15), 306 (100), 290 (52), 264 (70),
204 (26); HRMS: m/z [M + Na]+ calcd. for C22H21NO5Na: 402.1312; found: 402.1312.

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1
Compound 20n: yellow oil; IR (neat): 2919, 1725, 1599, 1268, 1023 cm−1; H NMR
(400.13 MHz) (CDCl3): = 7.90 (d, J = 8.5 Hz, 2H), 7.77 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H),
7.23–7.19 (m, 3H), 6.21 (t, J = 5.2 Hz, 1H), 4.33 (d, J = 5.2 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.84
(s,3 H), 2.00 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
= 202.2 (q),
δ
δ
166.7 (q), 153.6 (q), 145.4 (q), 139.8 (q), 139.5 (q), 138.0 (q), 129.9 (q), 129.1 (CH), 127.6 (CH),
127.3 (CH), 127.1 (q), 126.7 (CH), 123.9 (CH), 62.5 (CH2), 52.1 (CH3), 42.4 (CH2), 29.1 (CH3),
14.5 (CH3); MS (EI ion source): m/z (%) = 379 (58, [M+]), 350 (100), 306 (95), 264 (44), 204
(36), 43 (27); HRMS: m/z [M + Na]+ calcd. for C22H21NO5Na: 402.1312; found: 402.1310.
Isomeric mixture 2o
+ /
20o. Overall yield (catalyst A): 88% (112.0 mg); 2o 20o = 88/12;
overall yield (catalyst A0): 90% (114.3); 2o 20o = 65/35; overall yield (catalyst B): 70%
/
(89.0 mg); 2o/20o = 33/67; overall yield (catalyst C): 82% (104.4 mg); 2o/20o = 20/80.
Compound 2o. Yellow wax; IR (neat): 2982, 1680, 1607, 1556, 1256 cm−1; 1H NMR
(400.13 MHz) (CDCl3):
δ = 8.27 (bs, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.63 (dd, J1 = 8.2 Hz,
J2 = 1.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.22 (t, J = 4.6 Hz, 1H),
4.54 (d, J = 4.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H); 13C NMR (100.6 MHz) (CDCl3):
δ = 197.8 (q), 197.5 (q), 154.0 (q), 143.1 (q), 137.9 (q),
137.5 (q), 136.9 (q), 136.7 (q), 132.7 (q), 129.1 (CH), 128.9 (CH), 127.2 (CH), 126.1 (CH), 124.6
(CH), 124.0 (CH), 62.7 (CH2), 43.3 (CH2), 26.9 (CH3, 2C), 14.7 (CH3); MS (EI ion source):
m/z (%) = 363 (62, [M+]), 333 (12), 290 (83), 248 (70), 43 (100); HRMS: m/z [M + Na]+ calcd.
for C22H21NO4Na: 386.1363; found: 386.1359.
Compound 20o. Yellow wax; IR (neat): 2981, 1682, 1603, 1450, 1376, 1265 cm−1
;
1H NMR (400.13 MHz) (CDCl3):
1H), 7.31–7.27 (m, 3H), 6.28 (t, J = 5.2 Hz, 1H), 4.40 (d, J = 5.2 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H),
2.59 (s, 3H), 2.07 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz) (CDCl3):
= 202.3
δ = 7.89 (d, J = 8.6 Hz, 2H), 7.85 (m, 1H) 7.38 (t, J = 7.7 Hz,
δ
(q), 197.6 (q), 153.7 (q), 145.8 (q), 139.9 (q), 139.6 (q), 138.1 (q), 136.1 (q), 128.8 (CH), 127.7
(CH), 127.39 (CH), 127.34 (q), 126.9 (CH), 124.1 (CH), 62.6 (CH2), 42.5 (CH2), 29.3 (CH3),
26.7 (CH3), 14.6 (CH3); MS (EI ion source): m/z (%) = 363 (26, [M+]), 334 (41), 290 (54),
232 (28), 204 (30), 43 (100); HRMS: m/z [M + Na]+ calcd. for C22H21NO4Na: 386.1363;
found: 386.1361.
3.3.3. Characterization Data of Compounds 3a, 5b, 6b, 7b
Characterization data of the listed compounds are reported in the Supplementary
Materials.
4. Conclusions
The employment of ethyl carbamate N-protecting group represents a viable alterna-
tive to the tosyl N-protecting group, allowing the efficient synthesis of the corresponding
4-substituted-1,2-dihydroquinolines by means of the gold-catalyzed IMHA reaction. The
reaction proceeds with internal alkynes bearing electron-rich and electron-deficient sub-
stituents in the benzenes affording only the 6-endo cyclization product in fair to high yields.
Au(I)- catalyzed regiodivergent intramolecular hydroarylation of the N-ethoxycarbonyl-
N-propargyl-meta-substituted anilines at the ortho- and para-position cyclization could be
successfully established respectively through fine-tuning electronic and steric effects of the
gold complexes ligands.
Supplementary Materials: The following are available online, general information of reagents and
methods, synthetic procedures, and characterization data.
Author Contributions: Project administration, G.F.; Supervision, A.G.; Conceptualization, A.G.
and A.I.; Methodology, A.G. and A.I.; Investigation, A.F., F.M., A.S. and G.M.; Data curation, A.I.;
Writing—original draft preparation, review and editing, A.A.; Writing—review and editing, V.M.,
A.C., A.G. and A.I. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.

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Informed Consent Statement: Not applicable.
Data Availability Statement: Data is contained within the article or supplementary material.
Acknowledgments: We gratefully acknowledge the PRIN project 2017 “Targeting Hedgehog path-
way: virtual screening identification and sustainable synthesis of novel Smo and Gli inhibitors
and their pharmacological drug delivery strategies for improved therapeutic effects in tumors.”
(20175XBSX4) and La Sapienza, University of Rome, for financial support.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.
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