Gold(i)/Zn(ii) catalyzed tandem hydroamination/annulation reaction of 4-yne-nitriles

Article abstract of DOI:10.1039/c0cc02357d

The tandem hydroamination-annulation reaction of 4-pentyne-nitriles in the presence of amine nucleophiles and a cooperatively operating catalyst system, consisting of Ph₃PAuCl and Zn(ClO₄)₂, provides an efficient route to 2-aminopyrroles. Two regioisomeric 2-aminopyrroles were formed in moderate to good yields.

Full text of DOI:10.1039/c0cc02357d

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Gold(I)/Zn(II) catalyzed tandem hydroamination/annulation reaction
of 4-yne-nitrilesw
Ayhan S. Demir,*a Mustafa Emrullahogluab and Kerem Burana
Received 4th July 2010, Accepted 1st September 2010
DOI: 10.1039/c0cc02357d
The tandem hydroamination–annulation reaction of 4-pentyne-
nitriles in the presence of amine nucleophiles and a cooperatively
operating catalyst system, consisting of Ph3PAuCl and Zn(ClO4)2,
provides an efficient route to 2-aminopyrroles. Two regioisomeric
2-aminopyrroles were formed in moderate to good yields.
In light of our previous investigation wherein nitriles could
be activated by Zn(II) salts towards nucleophilic attacks, we
report herein a conceptually new synthetic approach to
substituted pyrroles via a cooperative Au(I)/Zn(II)-catalyzed
sequential inter/intramolecular hydroamination reaction of
4-yne-nitriles with various amines.
The most notable aspect of the present reaction is the sequential
activation of nitriles as pronucleophiles and alkynes as electro-
philes, which enables the rapid assembly of a range of 2-amino
substituted pyrroles with high efficiency. 2-Aminopyrroles
have been found to show interesting biological properties8,9
or have been used as precursors10 for known drugs, in which they
have found use as synthetic precursors for the acyclic nucleoside
analogs of the pyrrolo[2,3-d]pyrimidine ring system.11
Over the past six years, gold catalysis has shown to be a
powerful tool in organic synthesis. Cationic gold(I) and gold(III)
complexes show unique behavior towards unactivated alkenes,
alkynes, allenes, 1,3-dienes, and enynes promoting the nucleo-
philic addition of a variety of functional groups both inter- and
intramolecularly.1 In that respect, a great number of gold
catalyzed tandem reactions of various systems with external
nucleophiles that enable the formation of cyclic systems are
present in the literature.2 Especially those transformations
including the catalytic addition of N–H bonds across C–C
multiple bonds (hydroamination) that are catalyzed by both
gold(I) and gold(III) complexes have found wide application
for the generation of new C–N bonds3,4 affording nitrogen
containing heterocycles, such as pyrroles and pyridines.
Among the various synthetic strategies, catalytic trans-
formations that use transition-metal catalysts are one of the
modern approaches for forming pyrroles.5 Relatively few
examples of the gold-catalyzed synthesis of highly substituted
pyrroles have been reported, however.4e,6
In this simple one pot assembly, the a-propargyl methyl
nitriles (4-yne-nitriles)12 4 and a series of aliphatic and aro-
matic amines 5, as nucleophiles, are used as starting materials
to produce pyrroles 6 and 7 with high diversity (Scheme 2).
The initial efforts focused on the optimization of an efficient
system starting from 4-yne-nitrile 4a (Ewg = CO2Et) as a
model substrate. In our initial studies, 4a was treated with
aniline (5a) under various conditions (Table 1). Firstly, the
inclusion of Zn(ClO4)2 as a potential catalyst at room
temperature only led to the recovery of a starting material,
in which only traces of the cyclization products 6aa and 7aa
In the course of our research to develop new methodologies
for the synthesis of nitrogen containing heterocycles that are
promoted by transition metal catalysts, we recently demon-
strated Zn(II) salts to be effective catalysts for the activation of
the CQO bond and CN triple bond.7 These principles led us to
the discovery of a novel catalytic one-pot synthesis of
2-aminopyrroles starting from a-cyanomethyl-b-ketoesters.
Zinc perchlorate smoothly catalyzes the amination of nitriles,
and the subsequent cyclocondensation affords five-membered
rings (pyrroles) in good yield, as exemplified in the conversion
of 1 to 2 and 3 (Scheme 1).7a
Scheme
2
Au(I)/Zn(II)-catalyzed sequential inter/intramolecular
hydroamination reaction of 4-yne-nitriles with amines.
Table 1 Efficiency of the transition-metal catalysts for the trans-
formation of 4a with aniline 5a to 6aaa and 7aaa
Entry
Catalysta
Conditions
Yieldc (%)
1
2
3
4
5
6
7
8
Zn(ClO4)2
PTSA
AgSbF6
AuCl3
(PPh3)AuCl
(PPh3)AuCl/AgSbF6
AuCl3/AgSbF6
AuCl3/Zn(ClO4)2
(PPh3)AuCl/Zn(ClO4)2
(PPh3)AuCl/Zn(ClO4)2
(PPh3)AuCl/Zn(ClO4)2
(PPh3)AuCl/Zn(OTf)2
(PPh3)AuCl/AgClO4
80 1C, 12 h
80 1C, 12 h
60 1C, 8 h
60 1C, 8 h
60 1C, 8 h
60 1C, 6 h
60 1C, 8 h
60 1C, 5 h
rt, 12 h
60 1C, 5 h
90 1C, 3 h
60 1C, 5 h
80 1C, 8 h
Trace
—
—
—
—
58
—
—
40
Scheme 1 Zn(II) salt catalyzed formation of pyrroles.
9
10
11
12
13
65, 70b
68
63
a Department of Chemistry, Middle East Technical University,
06531 Ankara, Turkey. E-mail: asdemir@metu.edu.tr;
Tel: 0090 (0)312 210 32 42
61d
b
a
b
10 mol% of each species in DCE. 15 mol% of each species in
˙
The Izmir Institute of Technology Gulbahc¸e Koyu, Urla,
35430 Izmir, Turkey
¨
¨
¨
c
DCE. Total yield (%) of 6aa and 7aa after column chromato-
d
graphy. A pre-formed cationic gold(I) catalyst is used.
w Electronic supplementary information (ESI) available: Tables and
spectral data. See DOI: 10.1039/c0cc02357d
c
8032 Chem. Commun., 2010, 46, 8032–8034
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were observed at higher temperatures (entry 1).13 To rule out
the possible involvement of the conjugate Brønsted acid in
alkyne activation, the reaction of 4a was performed in the
presence of a catalytic amount of PTSA, in which no
cyclization products were obtained (entry 2). Single metals such
as Ag(I), Au(I), and Au(III) did not work as well (entries 3–5). As
was planned beforehand, a combination of Zn(II) and Au(I) or
Au(III) was feasible to catalyze this conversion. Unfortunately,
Au(III) together with Zn(II) or Ag(I) did not induce the reaction
sought (entries 7 and 8). However, the presence of Au(I), instead
of Au(III), together with Zn(II), showed the formation of two
products (6aa, 7aa) (40%) at room temperature (entry 9). An
increase in the reaction temperature was necessary to improve
the conversion of the starting material (5 hours, 60 1C, 65%)
(entry 10). At higher temperatures, however, other unidentified
side products were observed.
Table 2 Scope of the reaction
Yieldb
Entry Ewg-4
R2-(5)
Ph-5a
Ratio 6/7a Time/h (%)
1
6aa/7aa
3/2
5
5
4
65
62
74
3,4-Dimethyl-
Ph-5b
2
3
6ab/7ab
2/1
6ac/7ac
3/1
p-MeO-Ph-5c
4
5
6
7
8
9
4a (R1 = H) p-NO2-Ph-5d
p-Cl-Ph-5e
6ad/7ad
1/0
6ae/7ae
3/2
6af/7af
3/1
7
5
5
3
3
4
13
65
60
81
75
56
The outcome of this experiment unambiguously demon-
strated that the gold-based catalysis was uniquely responsible
for the alkyne activation. Control reactions clearly indicate
that the cationic Au(I) species is required for the reaction to
proceed. In the absence of either Zn(II) or Au(I), no cyclization
products were obtained at all. By far the best catalyst system
was a combination of Ph3PAuCl (10 mol%) and Zn(II)
(10 mol%) carried out in DCE (1,2-dichloroethane) at 60 1C
in order to efficiently afford the pyrroles 6 and 7. The reaction
can be carried out in various solvents, such as DCM, DCE,
toluene, acetonitrile, and ethanol, which gave similar results.
Practical reasons made DCE the solvent of choice. Zinc
perchlorate and zinc triflate salts were used as the Zn(II)
source, which showed similar effects on the reaction yields
and reaction time (entries 10 and 12).
m-Cl-Ph-5f
Benzyl-5g
6ag/7ag
6/1
1-Phenylethyl-5h 6ah/7ah
3/1
Ethyl-5i
6ai/7ai
2/1
6ac
8
—
10
11
12
13
4c (R1 = TMS) p-MeO-Ph-5c
4d (R1 = CH3) p-MeO-Ph-5c
4e (R1 = Ph) Benzyl-5g
Ph-5a
8
9
9
5
o5c
61c,d
nrc
6ba/7ba
3/2
67
3,4-Dimethyl-
Ph-5b
14
15
6bb/6bb
4
4
65
72
1/0
6bc/6bc
MeO-Ph-5c
The product distribution was carefully investigated (Table 2).
The reaction of 4-yne-nitrile (4) with various amines ended up
being regioselective, in turn giving pyrrole 6 as the major and
pyrrole 7 as the minor product. The ratio of pyrrole 6 to 7
increases when carried out with the more nucleophilic in character
aliphatic amines (benzylamine) (entry 7), which runs up (6/1),
whereas the ratio decreases when carried out with comparably less
nucleophilic aromatic amines (aniline, 3/2) (entries 1 and 13).
Except for the products carried out with 1-phenylethyl
amine (entries 8 and 18), we were pleased that all of the
regioisomeric pyrroles could be separated by column chromato-
graphy. The value of the product ratio was determined according
to the isolated product yields. However, for inseparable isomers,
4/1
16
17
18
4b (R1 = H) NO2-Ph-5d
Benzyl-5g
6bd/6bd
1/0
6bg/7bg
1/0
1-Phenylethyl-5h 6bh/7bh
7
3
3
16
73
70
3/1
a
b
Average ratio of at least two experiments. Total yield of compounds
c
d
6 and 7. Reaction carried out at 90 1C. Yield of compound 8.
substitution, the only product that was isolated was a trace
amount of pyrrole 6ac after in situ desilylation (entry 10).
The loading of both catalysts from 10 to 15 mol% slightly
(5%) increased the reaction yield. However, higher amounts
had no dramatic effect on the reaction yields. The Ph3PAuCl/
Ag(I) catalyst system was also proven to catalyze this reaction
(entry 6). In this system, Ag(I) may act in the same way as
Zn(II). However, this combination was less effective than the
Ph3PAuCl/Zn(II) catalyst system. The additional parallel
experiments were carried out with AgSbF6 and Zn(ClO4)2
under the standard conditions described above, in which the
yields with Zn(ClO4)2 were in all cases higher (56–81%) than
with AgSbF6 (41–58%) (Table S3, see ESIw).
1
this ratio was determined by H-NMR.
With optimized reaction conditions in hand, two possible
2-aminopyrroles (6 and 7) were formed. This reaction works for
a range of different amines. A variety of amines, such as aliphatic
or aromatic amines, except for electron poor anilines (entries 4
and 16), reacted smoothly to afford the desired products. Starting
yne-nitriles, possessing both internal and terminal alkynes, were
employed for this cyclization (entries 10–12). For terminal alkynes,
the reaction proceeded through an exo-dig cyclization in order to
afford the corresponding five membered rings (pyrrole). For the
methyl substituted internal alkyne (4d), however, the cyclization
gave a six membered ring (compound 8) through a possible
endo-dig cyclization (entry 11). Despite our great effort, the
cyclization did not tolerate the internal alkynes substituted with
both aryl and TMS groups (entries 10 and 12). In the case of TMS
A plausible mechanism for the Au(I)/Zn(II)-catalyzed cycliza-
tion is shown in Scheme 3. First, Zn(II) enhances the electro-
philicity of the nitrile, which allows the attack of the amine (5) at
the nitrile to give the intermediate I. It seems to be that Zn(II) has
a dual effect of nitrile activation and chloride ligand abstraction
c
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from Ph3PAuCl. This is also supported by the parallel experi-
ments carried out with AgSbF6 and Zn(ClO4)2, in which the
yields with Zn(ClO4)2 were in all cases higher than with AgSbF6,
and where the attack of both nitrogen pronucleophiles of inter-
mediate I at the Au(I) activated alkyne would allow for the
intermediates II and III. Further arrangement leads to the
formation of 2-aminopyrroles 6 and 7 (Scheme 3).
We succeeded in developing an Au(I)/Zn(II) catalyzed tandem
cyclization of 4-pentyne-nitriles with various amines that
provided an efficient and general route to pyrroles with a wide
range of substituents. To our knowledge, this is the only report in
which the cationic Au(I) species has been combined with Zn(II)
salts, which cooperatively catalyze the hydroamination/
annulation reaction of 4-yne-nitriles. Further studies on the
mechanism, elucidating the product distribution of this reaction,
and extending the scope of synthetic utility are currently in
progress in our laboratory.
We gratefully acknowledge the Scientific and Technological
Research Council of Turkey (TUBITAK), the Turkish
Academy of Sciences (TUBA), and the Middle East Technical
University (METU).
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8034 Chem. Commun., 2010, 46, 8032–8034
This journal is The Royal Society of Chemistry 2010