A Catalytic Construction of Indoles via Formation of Ruthenium Vinylidene Species from N-Arylynamides

Article abstract of DOI:10.1002/adsc.202001342

Treatment of ynamides with a catalytic amount of TpRuCl(PPh₃)₂ resulted in the construction of indole scaffolds known as privileged structure motifs. This reaction involved a cascade of 1,2-rearrangement and cyclization carrying out C?C bond formation via a ruthenium vinylidene intermediate, as revealed by a deuterium-labeling experiments. Furthermore, the transformation of multi-functionalized ynamide, derived from a practical drug molecule, showed a high functional group tolerance of this reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.202001342

UPDATES
DOI: 10.1002/adsc.202001342
A Catalytic Construction of Indoles via Formation of Ruthenium
Vinylidene Species from N-Arylynamides
Masanori Tayu,a Ryuta Watanabe,a Satoshi Isogi,a and Nozomi Saitoa,*
a
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588 Japan
Phone: +81 424958413
E-mail: nozomi-s@my-pharm.ac.jp
Manuscript received: October 30, 2020; Revised manuscript received: December 22, 2020;
Version of record online: December 30, 2020
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001342
benzofuran, which was provided from o-alkynylphenol
Abstract: Treatment of ynamides with a catalytic
by cyclization of hydroxyl group via the vinylidene
amount of TpRuCl(PPh3)2 resulted in the construc-
intermediate.[4b,d,e,g] Syntheses of indole from o-alkyny-
tion of indole scaffolds known as privileged
structure motifs. This reaction involved a cascade of
laniline were realized via CÀ N bond formation
triggered by an intramolecular attack of an amine
1,2-rearrangement and cyclization carrying out CÀ C
bond formation via a ruthenium vinylidene inter-
mediate, as revealed by a deuterium-labeling experi-
ments. Furthermore, the transformation of multi-
functionalized ynamide, derived from a practical
drug molecule, showed a high functional group
tolerance of this reaction.
moiety on vinylidene carbon.[4b,e–i] Tanaka[4g] and
Saito[4h] independently developed a method for the
synthesis of 3-substituted indoles by 1,2-rearrangement
of silyl, aryl, alkyl, and acyl groups (Figure 1, Previous
works).
Ynamide has been investigated intensely as a
versatile building block because it contains a carbon-
carbon triple bond directly substituted to a nitrogen
atom of the amide group.[5] The electron-donating
ability of the nitrogen atom polarizes the triple bond to
give more intriguing reactivity than that of classical
alkynes. The utilization of ynamide as a starting
material for the synthesis of nitrogen-containing
Keywords: Ynamide;
Ruthenium;
Vinylidene;
Indole; Cyclization
Since the indole scaffold is present as a “privileged heterocycles has had a dramatic impact in heterocyclic
structure” in many biologically active compounds chemistry. Various reactions have been developed for
including a large number of natural products and the formation of heterocycles[6–12] such as pyridines,[6]
pharmaceutics, the development of new methods for pyrroles,[7] oxazoles,[8] pyrimidines,[9] carbazoles,[10]
the synthesis of an indole scaffold remains a subject of
considerable interests in the field of organic
chemistry.[1]
Metal vinylidene species are key intermediates in
many synthetically important transformations of
alkynes.[2] In many studies on the reactions of metal
vinylidene species and their applications to synthetic
organic chemistry, significant ring formations have
been developed with a substrate that has a pendant
nucleophilic part in the structure.[3] As an example of
cyclization by the pendant carbon nucleus, the syn-
thesis of naphthalenes and polyaromatics has been
developed by cyclization with an internal alkene
moiety on a vinylidene intermediate generated from o-
alkynylstyrenes and o-alkynylbiphenyls.[3a,d] The use of
Figure 1. Synthetic methods for indole via a metal vinylidene
intermediate by CÀ N bond and CÀ C bond formations.
alkynes bearing a heteroatom nucleus instead of the
carbon nucleus afforded heteroaromatics[4] such as
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and other heterocycles.[11] Furthermore, applications to recovered in 98% yield (entry 6). The use of ethanol
natural product synthesis have also been reported.[12] afforded 6a in 13% yield and resulted in the recovery
We have also developed a number of molecular of 4a in 28% yield accompanying the generation of
transformation of ynamide with a transition metal dealkynylated tosylanilide in 51% yield (entry 7).
catalyst to elaborate valuable molecules.[13]
With the optimized conditions in hand, we then
Although there have been many studies on ynamide studied the application of this reaction to several other
and metal vinylidene chemistries, the investigation of ynamide derivatives (Table 2). In the case of N-
metal vinylidene generated from ynamide has still carbamate ynamides such as N-methoxycarbonyl and
been left as an unexplored area. Following our own N-tert-butoxycarbonylynamides 4b and 4c, the reac-
interests in ynamide chemistry, we envisioned that a tions proceeded smoothly to produce the N-meth-
new method for the synthesis of an indole scaffold oxycarbonyl and N-tert-butoxycarbonylindoles 6b and
would be realized with metal vinylidene generated 6c in 97% and 84% yields, respectively (entries 1 and
from ynamide. Treatment of N-arylynamide 4 with a 2). When N-acetylynamide 4d was used, the corre-
transition metal complex would generate metal sponding N-acetylindole (6d) was obtained in 88%
vinylidene intermediate 5 by a 1,2-rearrangement. yield (entry 3). The reaction of p-methylphenyl, p-
Consecutive cyclization by intramolecular attack of the methoxyphenyl,
and
p-N,N-dimeth-
benzene ring on vinylidene carbon could take place a ylaminophenylynamides 4e–4g afforded the corre-
CÀ C bond formation to provide the indole scaffold 6 sponding 5-substituted indoles 6e–6g in good yields
(Figure 1, This work). Here we describe the expedient (entries 4–6). The structure of 6g was elucidated by X-
synthesis of indoles involving CÀ C bond formation ray crystallographic analysis (Figure 2).[14] The use of
performed by 1,2-rearrangement/cyclization cascade electron-withdrawing groups bearing ynamides 4h and
and the investigation of details of the reaction 4i furnished the corresponding indoles 6h and 6i in
mechanism by deuterium-labeling experiments.
good yields as well (entries 7 and 8). The reaction with
Initially, we studied the reaction of N-arylynamide
and a catalytic amount of a ruthenium complex
(Table 1). The reaction of N-phenyl-N-tosylynamide
4a in THF with 10 mol% [RuCl2(p-cymene)]2 pro-
duced the expected N-tosylindole 6a in 11% yield
(entry 1). Although the use of the cationic complex
[Cp*Ru(MeCN)3]PF6 did not give 6a (entry 2), the
neutral complex CpRuCl(PPh3)2 gave 6a in the yield
of 17% (entry 3). The use of TpRuCl(PPh3)2 afforded
6a in an excellent yield (93%; entry 4). Next, solvent
effects were investigated (entries 5–7). When the
reaction of 4a was carried out in toluene, 6a was
obtained in 72% yield (entry 5). On the other hand, the
reaction did not occur in acetonitrile, and 4a was
Table 2. Ruthenium-catalyzed
cyclization
of
various
ynamides.a)
Table 1. Optimization of the reaction conditions.
a) 96% recovery of 4a.
b) 98% recovery of 4a.
a) The reaction was carried out in the presence of TpRuCl
(PPh3)2 (10 mol%) in THF under reflux conditions for 1 hour.
c) p-tosylanilide was obtained in 51% yield.
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Table 3. Synthesis of indole from complex ynamides.a)
Figure 2. X-Ray crystal structure of 6g (ellipsoids are shown at
50% probability).
meta-substituted ynamides possessing electron-donat-
ing or electron-withdrawing groups 4j–4m gave 6-
substituted indoles 6j–6m in high yields because the
cyclization proceeded with avoiding the steric hin-
drance (entries 9–12). When disubstituted ynamide 4n
was subjected to the same reaction conditions, 5,6-
dimethylindole 6n was obtained in 95% yield (en-
try 13).
We then turned our attention to the challenge of
constructing an indole moiety in more complex
structures to verify the synthetic utility of this reaction
(Table 3). First, ynamides 4o and 4p were used for
this transformation, and the expected methylene-
bridged bisindole 6o and benzoindole 6p were
obtained in good yields (entries 1 and 2). They are the
key structures in a monoamine reuptake inhibitor[15]
a) The reaction was carried out in the presence of TpRuCl
(PPh3)2 (10 mol%) in THF under reflux conditions for 1 hour.
b) 30 mol% of TpRuCl(PPh3)2 was used.
and
a
Keap1-Nrf2 protein-protein interaction
respectively. When meth-
inhibitor,[16]
ylenedioxyphenylynamide 4q was used, the corre-
sponding methylenedioxyindole 6q was obtained in
94% yield, and it had the core structure of an HIV-1
reverse transcriptase inhibitor[17] and oxidative burst position of the indole core. 3-Deuterated indole 6a–d5
inhibitor[18] (entry 3). In the case of fluorenylynamide was obtained in 87% yield with a D-content of more
4r, the corresponding indenoindole 6r, consisting of a than 95%. Therefore, the source of C3 proton was
substantial scaffold of organic transistors,[19] was shown to be derived from the aromatic ring proton of
produced in 89% yield (entry 4). Next, to realize the 4a–d5 (Scheme 1b). In order to determine whether the
synthesis of indole from multi-functionalized ynamide, C3 protonation proceeded by an intramolecular or
the reaction was performed with ynamides 4s and 4t intermolecular reaction, we performed a cross-over
derived from the anesthetic drug procaine and the experiment with 4f and 4a–d5. The C3 protonation
anticancer drug aminoglutethimide, and the desired occurred in an intramolecular manner since the indoles
indoles 6s and 6t were obtained in good yields 6f and 6a–d5 were produced in 82% (H-content
(entries 5 and 6).
>95%) and 93% (D-content >95%) yields without
To gain an insight into the reaction mechanism, we intermolecular scrambling of hydrogen and deuterium
carried out deuterium-labeling experiments and a (Scheme 1c).
cross-over experiment (Scheme 1). The reaction of
The plausible reaction mechanism based on the
deuterated ynamide 4a–d1 was carried out under the observations in these experiments is shown in Figure 3.
same reaction conditions as those shown in Table 1 to First, the coordination of ynamide 4 to the ruthenium
provide 2-deuterated indole 6a–d1 in 86% yield with a complex results in the formation of I, which induces
D-content of more than 95% (Scheme 1a). This result 1,2-rearrangement to generate ruthenium vinylidene
indicated that the reaction proceeded through a intermediate II. Next, consecutive cyclization of II
vinylidene intermediate generated by 1,2-rearrange- produces iminium intermediate III forming a CÀ C
ment. Next, we used deuterated ynamide 4a–d5 as the bond. Finally, intramolecular C3 protonation proceeds
substrate to clarify the proton source on the C3 by aromatization to afford indole 6.
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the detailed mechanism of this reaction. We are
currently applying this methodology to internal yna-
mides and the synthesis of heteroaromatics other than
indoles.
Experimental Section
General Procedure: Ruthenium-catalyzed Construction of
Indole 6. A solution of ynamide 4 in THF was added to
ruthenium catalyst (10 mol% to 4) by cannulation at ambient
temperature. After reflux for 1 h, the reaction mixture was
filtered through a Celite pad. The filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography to give indole 6.
Acknowledgements
We gratefully acknowledge financial support from JSPS
KAKENHI Grant Numbers 17K08226 and 17K15427. We are
grateful to Prof. Kazuhiko Takatori for performing X-ray
spectroscopy. We also thank Tamami Koseki and Shoko Yamada
at the Analytical Center of our university for performing
microanalysis, NMR, and mass spectrometry measurements.
Scheme 1. Deuterium-labeling and cross-over experiments to
reveal the reaction mechanism.
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