Stereo- and regioselective gold(i)-catalyzed hydroamination of 2-(arylethynyl)pyridines with anilines

Article abstract of DOI:10.1039/c8ob02356e

The gold-catalyzed hydroamination of 2-(arylethynyl)pyridines with anilines affords stereoselectively Z-enamine products with excellent regioselectivity. The reaction proceeds with moderate to excellent yields and accommodates a diverse range of functional groups on alkynes (ether, bromo, trifluoromethyl, acetyl, and carbomethoxy) and anilines (ether, bromo, chloro, and carbethoxy). The stereochemistry of the obtained enamines is complementary to that reported in previous studies. A plausible explanation for the observed selectivity was attained by means of NMR experiments.

Full text of DOI:10.1039/c8ob02356e

Organic &
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Stereo- and regioselective gold(I)-catalyzed
hydroamination of 2-(arylethynyl)pyridines
with anilines†
Cite this: Org. Biomol. Chem., 2019,
17, 527
Sandro Cacchi,a Giancarlo Fabrizi,a Andrea Fochetti, a Francesca Ghirga,b
a
Antonella Goggiamani a and Antonia Iazzetti
*
The gold-catalyzed hydroamination of 2-(arylethynyl)pyridines with anilines affords stereoselectively
Z-enamine products with excellent regioselectivity. The reaction proceeds with moderate to excellent
yields and accommodates a diverse range of functional groups on alkynes (ether, bromo, trifluoromethyl,
acetyl, and carbomethoxy) and anilines (ether, bromo, chloro, and carbethoxy). The stereochemistry of
the obtained enamines is complementary to that reported in previous studies. A plausible explanation for
the observed selectivity was attained by means of NMR experiments.
Received 21st September 2018,
Accepted 11th December 2018
DOI: 10.1039/c8ob02356e
rsc.li/obc
only in a few, particular cases.11 The development of a regio-
and stereoselective addition of primary amines to internal
Introduction
Enamines are versatile nucleophiles and because of their rele- alkynes is still a challenge in the transition metal-catalyzed
vance as synthetic intermediates they have attracted consider- hydroamination route to enamines.
able interest of chemists who developed many distinct meth-
In this context, as part of our interest in gold-catalyzed C–N
odologies for their preparation.1 One of the most appealing, bond-forming reactions12 and given the ubiquity of the pyri-
atom-efficient approaches to this class of compounds is rep- dine core in biologically active compounds13 as well as the
resented by the intermolecular hydroamination of non-acti- importance of pyridine-containing enamines as ligands in
vated alkynes with secondary amines in the presence of suit- coordination chemistry,14 it appeared of interest to us to study
able catalysts. In such a reaction, involving the addition of a a new synthesis of enamines through a hydroamination
N–H bond to a C–C triple bond, no side products are formed process of 2-(arylethynyl)pyridine 1 and aniline 2 partners: in
and this, as well as the utilization of readily available and fact, this kind of chemistry may be in part related to the regio-
usually inexpensive starting materials, makes it a very attractive and stereoselective hydroamination of α-β-inones to Z enam-
transformation, particularly from an industrial point of view. ines, a research topic that has been studied by our group.15a–f
Consequently, extensive studies have been made on this Therefore, hypothesizing a similar behaviour of 2-(arylethynyl)
subject. Initially, they focused on the use of mercury2 and thal- pyridines compared to α-β-inones, our reaction could therefore
lium3 catalysts but their toxicity and poor handling made offer a useful way to obtain enamines (Scheme 1). It is interest-
them unsuitable for broad utilization in organic synthesis. In ing that according to our hypothesis, Z enamines should be
the last fifteen years or so, remarkable progress has been obtained while, as reported by Stradiotto,9c the hydroamina-
made and a number of convenient and general procedures tion of 2-(pent-1-yn-1-yl)pyridine with a secondary amine, mor-
based on zirconium,4 rhodium,5 ruthenium,6 silver,7 copper,8 pholine, is reported to give the E stereoisomer.
and gold9 catalysts have been developed. Clearly, it would be
highly desirable to extend the reaction to primary amines,
which instead tend to produce preferentially imines.10 The for-
mation of enamines as the main products has been observed
Herein we report the results of our study.
Results and discussion
aDipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma,
P.le A. Moro 5, 00185 Rome, Italy. E-mail: antonia.iazzetti@uniroma1.it
bCenter for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia,
Viale Regina Elena 291, 00161 Rome, Italy
The reaction of 2-(phenylethynyl)pyridine 1a with aniline 2a
was used as the model system. A brief screening study revealed
that the corresponding Z-hydroamination product 3a could be
isolated in excellent yield when employing JohnPhos(MeCN)
AuSbF6 in dichloromethane at 80 °C (Table 1, entry 1). The
†Electronic supplementary information (ESI) available: Experimental details,
characterization data of all compounds, and copies of 1H and 13C NMR spectra
(PDF). See DOI: 10.1039/c8ob02356e
1
regiochemistry of 3a was assigned on the basis of the H- and
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Table 1 Synthesis of 3a from 2-(phenylethynyl)pyridine 1a and aniline
2a: optimization studiesa
Catalyst
(mol%)
T
(°C)
Time
(h)
Yield %
Entry
Solvent
of 3a b
1
2
3
4
5
6
7f
8
9
L(MeCN)AuSbF6 c (4)
L(MeCN)AuSbF6 c (4)
L(MeCN)AuSbF6 c (4)
—
NaAuCl4 (10)
AlCl3 (10)
CuI (5)/PPh3 (5)
(CF3CO2)2Pd (5)
(CF3SO3)Ag (5)
CH2Cl2
DMSO
Toluene
CH2Cl2
EtOH
MeOH
DMF
80
80
80
80
100
60
100
100
80
20
24
24
24
8
24
24
48
48
93
19d
92
e
—
e
—
e
—
e
—
CH2Cl2
CH2Cl2
31
19
a Unless otherwise stated, reactions were carried out on a 0.5 mmol
scale using 1 equiv. of 1a, 1.1 equiv. of 2a, and 1.5 mL of solvent.
b Yields refer to isolated products. c L = JohnPhos. d Compounds 4a
and 5a were isolated in 27 and 9% yield, respectively, along with an
18% yield of the recovered 1a. e The starting alkyne was recovered in
almost quantitative yield. f The reaction was carried out in the presence
of 2.0 equiv. of K3PO4.
Scheme 1
13C-NMR spectra of the ketonic derivative 4a (prepared via
acid-catalyzed hydrolysis of 3a), which resulted to be identical
to those of an authentic specimen. Its (Z)-stereochemistry has
been assigned by NOESY experiments, which showed also the
presence of an intra-molecular hydrogen bond (N–H⋯Npy).
Switching to DMSO as the solvent led to the isolation of 3a in
low yield (Table 1, entry 2) along with significant amounts of
4a (27%) and 5a (9%), and the recovery of 1a in 18% yield nucleophilicity of the latter. Our attempts to extend the reac-
(Table 1, entry 2). No hydroamination product was formed, tion to primary and secondary aliphatic amines met with
omitting the gold catalyst (Table 1, entry 3), in the presence of failure. No evidence of enamine products was attained when
NaAuCl4 (Table 1, entry 4), or AlCl3 (Table 1, entry 5), or CuI/ 1a was subjected to benzylamine or morpholine under stan-
PPh3 (Table 1, entry 6). Unsatisfactory results were also dard conditions. In both cases, the starting alkyne was recov-
obtained with (CF3CO2)2Pd (Table 1, entry 7) or (CF3SO3)Ag ered in almost quantitative yields.
(Table 1, entry 8).
The presence of two strong coordinating centers in the
The conditions shown in Table 1, entry 1 have been then starting alkyne, the C–C triple bond and the pyridine nitrogen
used when the reaction was extended to other substrates to atom, required careful analysis to identify the correct role of
probe its synthetic scope. Our preparative results are summar- each of them towards the outcome of this highly regio- and
ized in Tables 2 and 3. Usually, the reaction of 2-(arylethynyl) stereoselective reaction. In fact, two complexes could be
pyridines 1 and 2-(alkylethynyl)pyridines 6 with anilines formed through the reaction between an alkyne and catalyst
afforded the corresponding enamines in moderate-to-excellent (Fig. 1, I and II).
yields with excellent regio- and stereoselectivities. The nitrogen
To this purpose, NMR complexation experiments between
nucleophile was always found to be bound to the carbon far JohnPhos(MeCN)AuSbF6 catalyst, 1c and 1h in CDCl3 have
from the pyridine ring and the stereochemistry of the enamine been performed. In both cases, we observed a remarkable
was invariably found to be Z. A variety of important functional polarization of the carbon–carbon triple bond. The chemical
groups are tolerated both in anilines (ether, bromo, chloro, shifts of C2 and C1 moved from 89.5 and 87.6 ppm (δC2 − δC1
and carbethoxy) and alkynes (ether, bromo, trifluorome-thyl, 1.9 ppm) in the uncoordinated 1c to 94.9 and 82.8 ppm (δC2
=
−
acetyl, and carbomethoxy). Only with 2-[(3-methoxyphenyl) δC1 = 12.1 ppm) in the coordinated 1c and from 88.1 and
ethynyl]pyridine and 4-cyanoaniline compound 3o was isolated 91.5 ppm (δC2 − δC1 = −2.4 ppm) in the uncoordinated 1h to
in poor yield (Table 2, entry 15), possibly because of the low 92.8 and 86.0 ppm (δC2 − δC1 = 6.8 ppm) in the coordinated
528 | Org. Biomol. Chem., 2019, 17, 527–532
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Table 2 Gold-catalyzed hydroamination of 2-(arylethynyl)pyridines 1
with anilines 2 a
Table 3 Gold-catalyzed hydroamination of 2-(phenylethynyl)pyridines
and 2-(pentylethynyl)pyridine 6 with anilines 2 a
Yield %
Entry 1 Ar1
2 Ar2
Time (h) of 3 b,c
Yield %
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
a
a
a
a
a
a
b
b
b
c
Ph
20
48
48
72
96
93
83
35 (63)
75
49 (27)
73 (8)
85
78
94
83
67 (16)
98
90
75
19 (67)
75
79
79
46 (49)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Entry R1
6 R2 R3
2 Ar
Time (h) of 7 b
4-MeOC6H4
2-BrC6H4
4-BrC6H4
4-ClC6H4
3-EtOCOC6H4 120
Ph
4-MeOC6H4
3-MeOC6H4
Ph
4-MeC6H4
3-MeOC6H4
Ph
4-MeOC6H4
4-CNC6H4
Ph
4-MeOC6H4
Ph
1
2
3
CF3
CF3
H
H
H
F
Ph
Ph
Ph
Ph
a
a
b
b
b
c
Ph
4-ClC6H4
Ph
3-MeOC6H4 24
4-MeC6H4 24
4-MeOC6H4 48
Ph 48
20
24
24
97
99
86
96
a
b
c
d
e
f
4
H
H
H
H
F
5
F
H
H
Ph
C5H11
C5H11
89
4-MeC6H4
4-MeC6H4
4-Me C6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
2-BrC6H4
3-CF3C6H4
2-MeOCOC6H4
4-COMeC6H4
48
24
32
20
48
24
24
24
72
48
52
72
48
6c
7c
89d
48d,e
c
g
9
10
11
12
13
14
15
16
17
18
19
a Unless otherwise stated, reactions were carried out on a 0.5 mmol
scale using 1.1 equiv. of aniline 2, 0.04 equiv. of catalyst and 1.5 mL of
CH2Cl2. b Yields are given for isolated products. c Reaction carried out
at 120 °C. d Yields determined by NMR. e Along with 7f, compound 4b
and its tautomer were detected in 41% yield (89/11).
c
c
d
d
d
e
f
g
h
Ph
s
a Unless otherwise stated, reactions were carried out on a 0.5 mmol
scale using 1.1 equiv. of aniline 2, 0.04 equiv. of catalyst and 1.5 mL of
CH2Cl2. b Yields are given for isolated products. c Numbers in parenth-
eses refer to the recovered 1.
1h. As it is known that unfunctionalized alkynes coordinate
symmetrically at gold,16 these data are more consistent with
the trend observed when we treated 2-(arylethynyl)pyridines 1
with DCl in DMSO/D2O in an NMR probe. Indeed, under these
conditions, a large downfield shift of C2 was observed in all
cases with a strong polarization of the carbon–carbon triple
bond as compared to the polarization of the uncoordinated
alkynes. For example, the chemical shifts of C2 and C1 in 1c
moved to 101.8 and 80.3 ppm (δC2 − δC1 = 21.5 ppm) and those
in 1h moved to 98.7 and 83.4 ppm (δC2 − δC1 = 15.3 ppm). This
effect was ascribed to the protonation of the pyridine nitrogen.
Consequently, the related downfield shift of C2 and the polar-
ization of the carbon–carbon triple bond following the
addition of JohnPhos(MeCN)AuSbF6 to 2-(arylethynyl)pyri-
dines were ascribed to the coordination of the pyridine nitro-
gen at gold.
Fig. 1 Nitrogen- and CuC- gold(I) complexes.
derived from the coordination catalyst pyridine nitrogen is not
enough for nucleophilic addition of 2a. Furthermore, no reac-
tion was observed when 3-(phenylethynyl)pyridine 8 and,
more importantly, 4-(phenylethynyl)pyridine 9 were treated
with aniline 2a under standard conditions, even when increas-
ing the reaction temperature up to 110 °C.17 The starting
alkyne was recovered in almost quantitative yield in all of the
reported cases (Scheme 2).
The complex
I could undergo a regioselective inter-
molecular nucleophilic attack of the aniline nitrogen on the
C2 of the acetylenic fragment, the point of lower electron
density. This was found to be the general trend of all of the 2-
(arylethynyl)pyridines listed in Tables 2 and 3, independent of
the nature of the aromatic rings. However, no reaction was
observed when 1a was reacted in the presence of a Brønsted
catalyst. Therefore, the polarization of the C–C triple bond
These experiments suggest that the catalyst is involved in
multiple equilibria,18 with complex I predominant on complex II
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Fig. 2 Possible TS of the aminoauration step.
Scheme 2
(Scheme 3); most probably, the nitrogen–gold coordination in
I is not adequate to promote the amine nucleophilic attack on
the acetylenic moiety that requires the activation of gold
present in complex II.
As an explanation for the observed regiochemistry which is
always the same regardless of the electronic effects of the sub-
stituents on the aryl group, the main factor could be the for-
mation of an intramolecular hydrogen bond between the
amine and pyridine nitrogen atom during the anti nucleophi-
lic attack, according to the classical outer sphere mechanism. A
similar behaviour was found by Nolan and colleagues in their
cooperative gold-catalyzed hydrophenoxylation of unsymmetri-
cal alkynes,19 where the observed regioselectivity was ascribed
to the chelating property of nitrogen towards the gold–phenox-
ide complex.20 In fact, since the hydrogen bond between pyri-
dine nitrogen and amine should involve the C–C triple bond
polarization (vide supra), this factor could account for the
observed regioselectivity as a result of the nucleophilic attack
on the C2 of the acetylenic fragment, the point of lower elec-
tron density. Furthermore, in this scenario the hydroamina-
tion could proceed through an endo-dig-like TS 10 instead of
the exo-dig-like 11 (Fig. 2), with the former often preferred in
gold-catalyzed cycloisomerization.10
Scheme 4
intramolecular hydrogen bond, confirmed by 1H NMR in all of
the reported cases. Therefore, whatever the stereoisomer ratio
was after the aminoauration step, an equilibration during pro-
todeauration or on final enamine21 catalyzed by gold22 cannot
be excluded.
Based on the above, a possible catalytic cycle for the gold-
catalyzed hydroamination of 2-(arylethynyl)pyridines may be
the following (Scheme 4). The gold catalyst in the presence of
1a forms two complexes I and II in rapid equilibrium at the
reaction temperature. The complex II then undergoes a regio-
selective nucleophilic anti attack from 2a due to the formation
of a hydrogen bond between pyridine nitrogen and amine. The
resulting vinyl-gold intermediate III after protodeauration
gives the final Z enamine 3a together with the active catalyst.
Due to the stereoselectivity of the reaction, even if the Z
isomer should be the one formed according to this pathway,
HF calculations on both the 3a isomers (at 6-31** basis set
level) showed that the Z isomer is more stable over the E
isomer of about 7.66 kcal mol−1 by the presence of a strong
Conclusions
In conclusion, we have developed a new and versatile method
for the stereo- and regioselective conversion of 2-(arylethynyl)
pyridines into the corresponding enamines in the presence of
a gold catalyst and anilines. The reaction, which proceeds with
moderate-to-excellent yields, significantly extends the scope of
the hydroamination of unsymmetrical internal alkynes and tol-
erates a range of functional groups on alkynes (ether, bromo,
Scheme 3
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trifluoromethyl, acetyl, and carbomethoxy) and anilines (ether, 2 H), 5.52 (s, 1 H); 13C NMR (100.6 MHz) (CDCl3): δ = 158.8,
bromo, chloro, and carbethoxy).
148.5, 147.5, 142.6, 138.3, 136.1, 128.6, 128.5, 128.4, 128.1,
123.1, 121.1, 121.0, 118.4, 103.7; MS (EI ion source): m/z (%) =
272 (76 [M+]), 256 (16), 207 (13), 194 (26), 180 (55), 92 (18),
77 (100), 51 (23); HRMS: m/z [M + H]+ calcd for C19H17N2:
273.1386; found: 273.1393.
Experimental
A list of chemicals and instruments are provided in the ESI.†
Typical procedure for the preparation of 2-(arylethynyl)
pyridines (1): synthesis of 2-(phenylethynyl)pyridine (1a)
Conflicts of interest
There are no conflicts to declare.
A flask equipped with a magnetic stirring bar was charged
with PdCl2(PPh3)2 (49 mg, 0.07 mmol, 0.02 equiv.) and CuI
(26.5 mg, 0.14 mmol, 0.04 equiv.) dissolved in diisopropyl-
amine (7 mL) and N,N-dimethylformamide (5 mL). The resul-
tant solution was stirred under nitrogen at room temperature
for 10 minutes before adding 2-bromopyridine (553 mg,
3.5 mmol, 1.0 equiv.) in diisopropylamine (3 mL) and phenyl-
acetylene (428.5 mg, 461 μl, 4.2 mmol, 1.2 equiv.). Then, stir-
ring was continued at room temperature for an additional
hour. After this time, the reaction mixture was diluted with
Et2O and washed with a saturated NH4Cl solution and with
brine. The organic layer was separated, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was purified by chromatography on SiO2 (25–40 μm) eluting
with an 85/15 (v/v) n-hexane/AcOEt mixture (Rf = 0.25) to
obtain 608.5 mg (97% yield) of 2-(phenylethynyl)pyridine 1a.
Acknowledgements
We gratefully acknowledge the University “La Sapienza”,
Rome, for financial backing and Flavio Cicconi for the practi-
cal support.
Notes and references
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2 J. Barluenga, F. Aznar, R. Liz and R. Rodes, J. Chem. Soc.,
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3 J. Barluenga and F. Aznar, Synthesis, 1977, 195.
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Brown oil; IR (neat): 3054, 2919, 2222, 1580, 1490 cm−1
;
1H NMR (400.13 MHz) (DMSO d6): δ = 8.62 (ddd, J1 = 4.8 Hz,
J2 = 1.8 Hz, J3 = 1.0, 1 H), 7.86 (td, J1 = 7.7 Hz, J2 = 1.8 Hz, 1 H),
7.66–7.60 (m, 3 H), 7.48–7.45 (m, 3 H), 7.42 (ddd, J1 = 7.7 Hz,
J2 = 4.8 Hz, J3 = 1.0 Hz, 1 H);13C NMR (100.6 MHz) (DMSO d6):
δ = 150.6, 142.7, 137.2, 132.1, 129.0, 129.3, 127.8, 124.0, 121.9,
89.4, 88.8; MS (EI ion source): m/z (%) = 179 (100, [M+]), 151
(14), 126 (12); HRMS: m/z [M + H]+ calcd for C13H10N:
180.0808; found: 180.0808.
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Typical procedure for the preparation of (Z)-N-(1-aryl-2-
(pyridin-2-yl)vinyl)anilines (3): (Z)-N-(1-phenyl-2-(pyridin-2-yl)
vinyl)aniline (3a)
A Carousel Tube Reactor (Radley Discovery Technology) con-
taining a stirring bar was charged with 2-(phenylethynyl)pyri-
dine 1a (89.6 mg, 0.5 mmol, 1.0 equiv.) dissolved in CH2Cl2
(1.5 mL) and (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]
gold(I) hexafluoroantimonate (15.4 mg, 0.02 mmol, 0.04
equiv.). Then, aniline 2a was added (51 mg, 50 μl, 0.55 mmol,
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stirred for 20 hours. After cooling, the volatile materials were
evaporated at reduced pressure and the residue was purified
by flash chromatography on neutral Al2O3 (Brockmann activity 1)
eluting with n-hexane (Rf = 0.21) to obtain 126.5 mg of (Z)-N-(1-
phenyl-2-(pyridin-2-yl)vinyl)aniline 3a (93% yield). Yellow
solid; mp: 83–85 °C; IR (KBr): 3357, 3050, 2923, 1626, 1587,
1374 cm−1; 1H NMR (400.13 MHz) (CDCl3): δ = 11.61 (br s 1 H),
8.40 (br d, J = 4.5 Hz, 1 H), 7.47 (td, J1 = 7.7 Hz, J2 = 1.6 Hz,
1 H), 7.43–7.40 (m, 2 H), 7.24–7.22 (m, 3 H), 7.01–6.97 (m, 3 H),
6.87–6.84 (m, 1 H), 6.73 (t, J = 7.2 Hz, 1 H), 6.61 (d, J = 7.7 Hz,
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=
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532 | Org. Biomol. Chem., 2019, 17, 527–532
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