Dual gold catalysis: A novel synthesis of bicyclic and tricyclic pyrroles from n -propargyl ynamides

Article abstract of DOI:10.1021/ol503623m

Various N-propargyl ynamides were converted to bicylic and tricyclic pyrroles by the use of a cationic dual-activation gold catalyst. This reaction starts with the nucleophilic addition of a gold acetylide onto an ynamide triple bond at the ?2-position of the nitrogen atom. Thus, gold vinylidene is formed, and then a second cyclization takes place. The formation of the gold vinylidene is indicated by the evidence that not only aryl ynamides but also alkyl ynamides undergo C-H activation in these reactions.

Full text of DOI:10.1021/ol503623m

Letter
pubs.acs.org/OrgLett
Dual Gold Catalysis: A Novel Synthesis of Bicyclic and Tricyclic
Pyrroles from N‑Propargyl Ynamides
Yusuke Tokimizu,† Marcel Wieteck,‡ Matthias Rudolph,‡ Shinya Oishi,† Nobutaka Fujii,†
A. Stephen K. Hashmi,*,‡,§ and Hiroaki Ohno*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
‡Organisch-Chemisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
§Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
S
* Supporting Information
ABSTRACT: Various N-propargyl ynamides were converted to bicylic and
tricyclic pyrroles by the use of a cationic dual-activation gold catalyst. This
reaction starts with the nucleophilic addition of a gold acetylide onto an
ynamide triple bond at the β-position of the nitrogen atom. Thus, gold
vinylidene is formed, and then a second cyclization takes place. The
formation of the gold vinylidene is indicated by the evidence that not only
aryl ynamides but also alkyl ynamides undergo C−H activation in these reactions.
namides have attracted growing attention as useful
building blocks for the formation of nitrogen-containing
Scheme 1. Reactivity of Gold Acetylide onto the Other
Alkyne
Y
compounds.1 Recent progress of alkynylation chemistry has
been facilitating the development of synthesis and valuable
transformations of ynamides under mild conditions.2 Since
ynamides are more electrophilic than simple alkynes,
nucleophilic additions occur in a regioselective manner at the
α-position to the nitrogen atom in most cases. This
regioselectivity arises from the lone pair of the nitrogen atom
directly bound to the alkyne, which polarizes the ynamide triple
bond.
Homogenous gold catalysts are well-known as a useful tool
for the activation of alkynes3 including ynamides,4 which
facilitates addition of various types of nucleophiles onto
alkynes. Recently, the groups of Hashmi and Zhang
independently reported the novel and fascinating gold-
catalyzed cascade cyclization of diynes involving a C−H
activation step (Scheme 1).5 In these reactions, a cationic
gold catalyst activates two alkynes; the terminal by σ-
coordination and the internal by π-coordination, thus
promoting the nucleophilic attack of gold acetylide onto the
internal alkyne. The nucleophilic position of gold acetylide
depends on the tether of two alkynes. While 5-endo-dig
cyclization takes place with phenylene-,5a,c,d 3,4-thiophenyle-
ne-,5k or ethylene-tethered5l diynes (pathway a), 6-endo-dig
cyclization takes place with vinylene-5h or 2,3-thiophenylene-
tethered5f diynes (pathway b). Although the computational
studies5j,k suggested that the electronic effect of the tether is
important for the selectivity, additional experimental studies are
needed to clarify the whole picture of diyne reactions. Our
attention was next focused on the reactivity of N-propargyl
ynamides. In this case, 5-exo-dig cyclization (pathway c) would
be another possible reaction course, considering the general
regioselectivity in the ynamide reactions, in addition to the 5-
endo-dig and 6-endo-dig pathways (a and b). Herein we report
the selective synthesis of bicyclic and tricyclic pyrroles based on
gold(I)-catalyzed ynamide cyclization via pathway a.
At the outset of this work, we examined the reaction of N-
propargyl ynamide 1a with 5 mol % of a gold catalyst. The use
of DAC-NTf2 (DAC = dual activation catalyst), which gave
good results in the previous study,5f allowed the formation of
tricyclic pyrrole 2a in 62% yield (Table 1, entry 1). Though
Received: December 16, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503623m
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Letter
Table 1. Optimization of Reaction Conditions
a
entry
catalyst (mol %)
conditions
yield (%)
1
2
3
4
5
6
7
8
9
DAC-NTf2 (5)
80 °C, 1 h
80 °C, 8 h
80 °C, 15 h
80 °C, 7 h
80 °C, 2 h
80 °C, 4 h
80 °C, 1 h
80 °C, 1 h
110 °C, 1 h
62
b
IPrAuNTf2 (5)
<66
PPh3AuNTf2 (5)
SPhosAuNTf2 (5)
BrettPhosAuNTf2 (5)
t-BuXphosAuNTf2 (5)
DAC-PF6 (5)
10
35
46
42
86
74
DAC-PF6 (2.5)
none
dec
a
b
Isolated yield. Produced as an inseparable mixture.
Figure 1. Gold-catalyzed cyclization of aryl-substituted N-propargyl
a
ynamides. Isolated yield.
Scheme 2. Plausible Reaction Mechanism
IPrAuNTf2 showed a similar reactivity, the desired pyrrole 2a
was obtained as an inseparable mixture (entry 2). Several
phosphine ligands were also tested for the reaction (entries 3−
6). While use of PPh3 significantly decreased the reaction rate
and yield (entry 3), other phosphine ligands such as SPhos,
BrettPhos, and t-BuXPhos gave the pyrrole 2a in slightly better
yields (35−46%, entries 4−6). Fortunately, employment of
DAC-PF6 improved the yield to 86% (entry 7). When the
loading of DAC-PF6 was decreased to 2.5 mol %, 74% yield of
2a was produced (entry 8). Without using any catalysts, only
the decomposition of starting material 1a was observed upon
heating at 110 °C (entry 9).
Having established efficient conditions for the synthesis of
pyrrole 2a (Table 1, entry 7), we evaluated the substrate scope
(Figure 1). Both electron-withdrawing and -donating functional
groups were tolerated in the para position of the phenyl group,
including the synthetically useful halogen substituents (2b−f;
72−77% yields). 3,5-Dimethyphenyl-substituted N-propargyl
ynamide 1g showed the most efficient conversion to give
pyrrole 2g in 87% yield. A thiophene-based substrate could also
be used, providing the corresponding pyrrole 2h containing a
5,5,5-fused ring system (68%). Replacement of the tosyl (Ts)
by a 2-nosyl (o-Ns) group was also successful (2i; 81%).
Branched propargyl ynamides (R1 = alkyl) provided the
corresponding pyrroles 2j−l in moderate yields (64−65%).
A plausible6 mechanism for the reaction is shown in Scheme
2. As is the case with the reported reactions,5c,l N-propargyl
ynamide 1 is converted to dual σ/π-activated alkyne
intermediate I by the action of DAC-PF6. The cationic gold
is transferred to the ynamide alkyne (intermediate II), which
facilitates the nucleophilic addition of the gold acetylide,
leading to formation of gold vinylidene III. The subsequent
arylation of the gold vinylidene forms vinylgold complex IV via
nucleophilic addition or C−H insertion pathway. After the
aromatization of intermediate IV (which might also occur after
the protodeauration of IV), the catalytic cycle can be
terminated by a catalyst transfer from intermediate V to N-
propargyl ynamide 1 to produce pyrrole 2. It is worth
mentioning that the electrophilic carbon of ynamide triple
bond in this reaction is not the α- but the β-position to the
nitrogen atom, contrary to the general preference in many gold-
catalyzed reactions of ynamides.7
To confirm the formation of gold vinylidene III (Scheme 2),
we then investigated C(sp3)−H activation reactions using alkyl-
substituted N-propargyl ynamides 3 (Table 2). In the case of
B
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At the end, we checked the reaction of aryl N-propargyl
ynamides bearing a methyl group at the ortho position of the
phenyl group (Scheme 3). In this case, both aryl C−H and
Table 2. Gold-Catalyzed Cyclization of Alkyl-Substituted N-
Propargyl Ynamides
Scheme 3. Reaction of 2-Methylphenyl-Substituted N-
Propargyl Ynamides
benzyl C−H bonds are potentially reactive. The reaction of N-
propargyl ynamide 1m generated a mixture of 2m and 2m′ with
a moderate regioselectivity (2:5; 78% combined yield). On the
other hand, the reaction of N-propargyl ynamide 1n with two
ortho methyl groups led to decomposition without formation of
detectable amount of 2n, presumably due to the steric
hindrance of the ynamide moiety.9
In conclusion, we have developed a novel cyclization reaction
of N-propargyl ynamides for the synthesis of multisubstituted
pyrroles. The first cyclization step selectively proceeded via 5-
endo-dig cyclization on the β-carbon of the ynamide, contrary to
the general preference for the α-carbon in many gold-catalyzed
reactions of ynamides. Both aryl and alkyl C−H bonds can be
used for the second cyclization step, and corresponding
pyrroles are obtained in moderate to good yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
b
The ratio of 4:5 was determined by NMR analysis. Isolated yield.
c
NMR yield.
AUTHOR INFORMATION
■
Corresponding Authors
N-propargyl ynamides 3a and 3b, both 5-membered (4) and 6-
membered ring compounds (5) were formed (52 and 51%
combined yields, entries 1 and 2), the former of which was the
major isomer (4/5 = 93:7). It is notable that a tertiary C−H
bond in a cycloalkyl substituent was more reactive than a
secondary C−H bond; predominantly, the spirocyclic com-
pound 4c with a quaternary carbon atom was produced (entry
3).8 Selective formation of cyclopenta[c]pyrrole derivative 4d
from substrate 3d bearing a benzyl group showed higher
reactivity of the benzylic C(sp3)−H bond than that of the
C(sp2)−H bond of the phenyl group. With N-propargyl
ynamides 3e−g not having an appropriate C−H bond for the 6-
membered ring formation, only the cyclopentane-fused pyrroles
4e−g were obtained (44−60%, entries 5−7) as we expected.
The pyrrole 4g was produced from N-propargyl ynamide 3g via
the elimination of OTBS group (entry 7). In the case using 3h,
bearing a conjugated enynamide moiety, the pyrrole 5h
containing a 6-membered ring was obtained (57%, entry 8)
via the reaction with a C(sp3)−H bond at the allylic position.
*E-mail: hashmi@hashmi.de.
*E-mail: hohno@pharm.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for the Encourage-
ment of Young Scientists (A), and Platform for Drug Design,
Discovery, and Development from the MEXT, Japan. Y.T. is
grateful for the Strategic Young Researcher Overseas Visits
Program for Accelerating Brain Circulation as well as Research
Fellowships for Young Scientists from the Japan Society for the
Promotion of Science (JSPS).
REFERENCES
■
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D
DOI: 10.1021/ol503623m
Org. Lett. XXXX, XXX, XXX−XXX