Computational insights into the mechanisms of Ru-catalyzed cycloisomerization of 2-ethynylaniline and 2-(2-propynyl)tosylanilide: The role of pyridine in assisting the metal-vinylidene formation

Article abstract of DOI:10.1016/j.jorganchem.2018.03.036

Mechanistic studies of ruthenium-catalyzed cycloisomerization of 2-ethynylaniline and 2-(2-propynyl)tosylanilide were carried out using DFT calculations. A pyridine assisted hydrogen transfer pathway was unveiled for the formation of Ru-vinylidene complex. The proposed pathway was applied to rationalize the origin of the regioselectivity, 5-exo vs 6-endo cyclization, in the ruthenium catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide. The cycloisomerization of 2-(2-propynyl)tosylanilide in the presence of pyridine produced a 6-endo cyclized product via the Ru-vinylidene intermediate assisted by pyridine while its absence afforded a 5-exo cyclized product via a direct nucleophilic addition. This study sheds more light on alternative pathways for reactions involving alkyne-vinylidene species.

Full text of DOI:10.1016/j.jorganchem.2018.03.036

Accepted Manuscript
Computational insights into the mechanisms of Ru-catalyzed cycloisomerization of
2-ethynylaniline and 2-(2-propynyl)tosylanilide: The role of pyridine in assisting the
metal-vinylidene formation
Abosede Adejoke Ogunlana, Jianping Zou, Xiaoguang Bao
PII:
S0022-328X(18)30207-9
10.1016/j.jorganchem.2018.03.036
JOM 20386
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 14 November 2017
Revised Date: 15 March 2018
Accepted Date: 24 March 2018
Please cite this article as: A.A. Ogunlana, J. Zou, X. Bao, Computational insights into the mechanisms of
Ru-catalyzed cycloisomerization of 2-ethynylaniline and 2-(2-propynyl)tosylanilide: The role of pyridine
in assisting the metal-vinylidene formation, Journal of Organometallic Chemistry (2018), doi: 10.1016/
j.jorganchem.2018.03.036.
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ACCEPTED MANUSCRIPT
Computational Insights into the Mechanisms of Ru-Catalyzed
Cycloisomerization of 2-Ethynylaniline and
2
-(2-Propynyl)tosylanilide: The Role of Pyridine in Assisting the
Metal-Vinylidene Formation
Abosede Adejoke Ogunlana, Jianping Zou,* and Xiaoguang Bao*
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199
Ren-Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, China.
E-mail: jpzou@suda.edu.cn; xgbao@suda.edu.cn
Abstract
Mechanistic studies of ruthenium-catalyzed cycloisomerization of 2-ethynylaniline and
2
-(2-propynyl)tosylanilide were carried out using DFT calculations. A pyridine assisted hydrogen
transfer pathway was unveiled for the formation of Ru-vinylidene complex. The proposed
pathway was applied to rationalize the origin of the regioselectivity, 5-exo vs 6-endo cyclization,
in the ruthenium catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide. The
cycloisomerization of 2-(2-propynyl)tosylanilide in the presence of pyridine produced a 6-endo
cyclized product via the Ru-vinylidene intermediate assisted by pyridine while its absence
afforded a 5-exo cyclized product via a direct nucleophilic addition. This study sheds more light
on alternative pathways for reactions involving alkyne-vinylidene species.
Keywords: DFT, ruthenium, vinylidenes, regioselectivity, cycloisomerization, pyridine.
1

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1
.
Introduction
Transition-metal-catalyzed intramolecular cyclization of aromatic alkynyl amines/amides has
attracted considerable research attention due to its convenient construction of nitrogen containing
heterocycles [1], such as indole, quinoline and isoquinoline derivatives. This class of organic
compounds is prevalent in manifold of biologically active compounds and synthetic organic
materials. A large number of transition metal-based catalysts, such as Ru [2], Rh [3], Au [4], Ag
[5], Cu [6], Pd [7], Ir [8], Pt [9], Zn [10], Mo, W, Cr [11], In [12], Hg [13] and Fe [14] have been
reported to catalyze the intramolecular cyclization of aromatic alkynyl amines/amides. From a
mechanistic point of view, these reactions can be generally classified into two types. The first type
involves taking advantage of the tethered nucleophilic group of alkynyl amines to undergo the
direct nucleophilic addition to the alkyne moiety after π-alkyne activation by transition metals
(Scheme 1a) [15]. For instance, the group of Sakamoto proposed that a direct nucleophilic
addition of the amine moiety in 2-ethynylaniline to the terminal alkyne carbon occurred in the
Cu-catalyzed cyclization of 2-ethynylamines to form indoles [15a]. Moreover, a combined
experimental and computational study carried out by the group of Gevorgyan [15b] supported the
direct 5-endo-dig cyclization over the metal-vinylidene formation in Au-catalyzed
cycloisomerization of propargylic pyridines. This direct cyclization is also consistent with the
mechanism proposed by the group of Wong [15c, 15d] in Ru-catalyzed cycloisomerization of
propargylic pyridines using DFT calculations. The second type employs the intermediacy of
metal-vinylidene species of terminal alkynylamines which subsequently undergo cyclization
(
Scheme 1b) [16]. In this regard, the Tanaka group [16a] has reported the intermediacy of
Rh-vinylidenes in Rh-catalyzed cycloisomerization of 2-silylethynylphenols and
-silylethynylanilines to give 3-silylbenzofurans and 3-silylindoles, respectively. Meanwhile, a
2
great number of reports have been well documented for the formation of the key metal-vinylidene
intermediate via the direct 1,2-H shift [17]. For example, the direct 1,2-H shift has been
investigated for the formation of metal-vinylidene intermediate by Vastine and Hall [17f] using
DFT calculations. A theoretical study on the isomerization of internal alkynes to vinylidenes via a
direct 1,2-aryl shift has been carried out by Takano and co-workers for group 8 transition-metal
complexes [17g]. More recently, the Saito’s group [17h] has reported the formation of
2

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Ru-vinylidene intermediate by 1,2-carbon migration in ruthenium catalyzed cycloisomerization of
2
-alkynylanilides.
Scheme 1. Two mechanistic pathways for the transition-metal-catalyzed cycloisomerization of
alkynylamines to synthesize nitrogen containing heterocycles.
In particular, the Saá’s group [2c] reported an efficient ruthenium(II) catalyzed
cycloisomerization of 2-ethynylaniline 1 which led to the synthesis of indole using pyridine as
solvent (Scheme 2a). It was interesting that the same ruthenium catalyst catalyze the
cycloisomerization of 2-(2-propynyl)tosylanilide 3 in the presence of pyridine to produce a
dihydroquinoline product 4, while the cycloisomerization of 3 by another Ru(II) catalyst,
[
RuCl (p-cymene)] , afforded an indole product 5 in the absence of pyridine (Scheme 2b).
2
2
Scheme
2. The Ru(II)-catalyzed
cycloisomerizations of 2-ethynylaniline
and
2
-(2-propynyl)tosylanilide.
Based on the intermediacy of Ru-vinylidene complex, the mechanism of the reaction might
follow the commonly proposed direct 1,2-H shift (Scheme 3, path A). [16, 17a-e] Also, studies
17a-e] have shown that the oxidative addition of alkyne C-H bond into Ru center to afford a
[
hydrido-alkynyl complex, followed by 1,3-H shift is another viable pathway (path B). In addition,
we envisaged that pyridine as a solvent could also act as a proton shuttle in assisting the
cycloisomerization reaction. This led us to propose a new mode of Ru-vinylidene formation via
3

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the pyridine assisted hydrogen transfer (PAHT) pathway (path C). On the contrary, the
mechanism could bypass the formation of the Ru-vinylidene complex to undergo a direct
nucleophilic addition after the initial activation of the alkyne moiety by the ruthenium catalyst, to
afford the indole product (path D) [15].
Scheme 3. Possible mechanistic pathways for the Ru-catalyzed cycloisomerization of 1.
In order to better understand the mechanism of the ruthenium catalyzed cycloisomerization
reactions and the reason(s) for the different regioselective products obtained, a comprehensive
mechanistic study of the ruthenium catalyzed cycloisomerization of 2-ethynylaniline and
2
-(2-propynyl)tosylanilide was carried out by DFT calculations. An indirect mode of
Ru-vinylidene formation via the PAHT pathway was proposed in this work. In addition, the
proposed pathway could be applied to explain the origin of the regioselectivity, 5-exo vs 6-endo
cyclization, in the ruthenium catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide.
2
.
Computational Method
All calculations were carried out using Gaussian 09 [18] program package with the ωB97XD
[19] density functional method which includes empirical dispersion and long range correction.
This method among others has been reported to be effective for computations involving ruthenium
metal [20]. The LANL2DZ basis set together with LANL2DZ pseudo potential [21] were utilized
for the ruthenium atom while the 6-31G(d,p) basis set [22] was employed for other atoms in the
geometry optimization. Vibrational frequency analysis was carried out on the optimized geometry
to characterize them as minima (no imaginary frequency) or transition states (one imaginary
4

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frequency). Intrinsic reaction coordinate calculations [23] confirmed that the optimized transition
states connect to their respective reactants and products. The Gibbs free energies were evaluated at
2
98.15 K and 1 atm. To consider solvation effects, single-point energy calculations using the
SMD solvation model [24] were performed based on the optimized gas-phase geometries. Larger
basis set (LANL2TZ(f) for Ru atom and 6-311++G(d,p) for other atoms) were utilized for such
single-point energy calculation. In accordance with the experimental conditions, pyridine and
toluene solvents were employed for reactions involving alkynyl amine and amide respectively. It
is known that DFT calculations could overestimate the entropic effect [25]. The translational
entropy correction in solution was incorporated using the method proposed by Whitesides et al.
[26] Unless specified otherwise, the solvation Gibbs free energy was used for discussion and it
was obtained from the addition of the solvation single-point energy and the thermal correction to
the Gibbs free energy. In order to reduce computational costs, the simplified phosphine ligand
PMe was used to replace the experimentally used PPh /PBu ligand. The CYLview software was
3
3
3
employed to show the 3D structures of the studied species [27].
3
. Results and Discussion
3
.1. Mechanistic study of the Ru-catalyzed cycloisomerization of 1 to form indole product.
The crucial Ru-vinylidene intermediate has been proposed to account for the formation of
indole product via the cycloisomerization of 1. Initially, the formation of the Ru-vinylidene
intermediate via the commonly proposed direct 1,2-H shift was computationally explored. The
coordination of the alkyne moiety in 1 to the ruthenium catalyst forms an initial Ru-ethynylaniline
complex INT1, which is characterized by a π-alkyne binding mode. Subsequently, a direct 1,2-H
1
2
shift from the terminal carbon, C , to the internal carbon, C , would afford the Ru-vinylidene
1
complex INT2. The transition state for this shift was located as TS1, in which the H…C and
2
H…C bond distances are stabilized to 1.20 Å and 1.42 Å respectively. The energy barrier for this
step was calculated to be 23.8 kcal/mol and the formed INT2 is thermodynamically stable, being
exergonic by 2.3 kcal/mol (Fig. 1, path A).
Another pathway leading to the formation of the Ru-vinylidene intermediate is the 1,3-H shift
of a hydride-alkynyl complex [17d-e]. In this pathway, the initial π-bound substrate INT1 may
undergo slippage towards the σ-(C-H)-binding mode with the metal center, forming INT3 via TS2
5

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with a barrier of 14.5 kcal/mol relative to INT1. Next, the C-H bond oxidative addition (OA) onto
the Ru center might proceed via TS3 to offer a hydrido-ruthenium complex, INT4. The free
energy of the OA step was calculated to be 17.4 kcal/mol relative to INT1. Subsequently, 1,3-H
2
shift from Ru center to C might follow to generate the Ru-vinylidene complex. The transition
state for the 1,3-H shift was located as TS4 and the energy barrier was predicted to be 49.4
kcal/mol relative to INT1, implying that this step is kinetically very unfavorable. Similar energy
demanding for 1,3-H shift has previously been reported by Angelis and co-workers (51.1 kcal/mol)
+
[
17d] in the DFT study of alkyne to vinylidene rearrangement of [(Cp)(PMe ) Ru(HC≡CH)] .
3
2
Overall, the 1,3-H shift of the hydride-alkynyl intermediate has much higher energy barrier than
the direct 1,2-H shift pathway.
The third pathway leading to the Ru-vinylidene intermediate could take place via an indirect
1
,2-H shift, assisted by the pyridine solvent. In the presence of pyridine, an initial complex INT5
1
is formed in a slightly exergonic manner. Thereafter, the deprotonation of C by pyridine would
1
occur via TS5 to produce INT6. Featuring in this transition state is that the C …H distance is
lengthened to 1.25 Å while the H…N(pyridine) distance is shortened to 1.50 Å. In addition, the
1
2
C -Ru bond distance is stabilized to 2.10 Å. Subsequent protonation of the C by the pyridinium
ion in INT6 would generate the Ru-vinylidene complex INT2 via TS6. The energy barrier for the
pyridine assisted deprotonation step was calculated to be 14.6 kcal/mol, which is 9.2 kcal/mol
lower than that for the direct 1,2-H shift. These results suggest that the PAHT pathway might be
viable for the cycloisomerization reaction considered.
In addition, some reports have supported the electrophilic cyclization of nucleophile-tethered
alkynes after the C≡C activation [15]. In this regard, the direct nucleophilic addition of the amine
1
functional group in INT1 to the C via TS7 was explored computationally. The results indicate
that the nucleophilic addition (NA) step would require the energy barrier of 27.0 kcal/mol (path D,
Fig. 1). This calculated barrier is 12.4 kcal/mol higher than that along the PAHT. Among the
various possible pathways explored for this reaction, it can be assumed that the mechanism of the
Ru-catalyzed cycloisomerization might proceed along path C owing to the lowest energy barrier
to afford a Ru-vinylidene intermediate in an exergonic manner.
6

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Gsol (kcal/mol)
[Ru] = CpRuLCl L=P(CH3)3
Path A Direct 1,2-H shift
H 1.58
.95
1
Path B 1,3-H shift via hydrido-alkynyl
Path C Pyridine assisted vinylidene formation
Path D Direct nucleophilic attack
[Ru]
C
C
NH2
4
9.4
[Ru]
TS4
C
H
C
2
C 1.42
.09
H
NH2
7.0
TS7
NH2
C 1.20
2
Py
[Ru]
C
1.72
1
.50
NH2
C
H
1.58
23.8
C
Py
H
.25
2.10
C 1.12
2.01
C
NH2
1
.35
TS1
1
H
1.98
C
NH2
H
2.23
17.4
TS3
1
7.1
C 1.35
INT4
14.5
TS2
H N
14.6
TS5
2
C
13.6
INT3
[Ru]
10.6
C
TS6
NH2
C
H
Py
C
Py
0.6
0.0
C
-0.4
NH2
INT6
INT1
-
2.3
INT5
-2.3
INT2
[Ru]
Py
INT2
H
C
C
C2
H N
H N
2
2
C1
H
H
2
.26
C
C
NH2
C
C
H
C
H N
2
H N
2
C
2
.17
[Ru]
H
[Ru]
Py
Paths C and D
Paths A and B
7

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Fig. 1 Energy profiles of the various pathways considered in the Ru-catalyzed cycloisomerization
of 1. Bond distances are shown in Å and the atomic movements associated with the imaginary
frequency are indicated in red arrows.
After the formation of INT2, the presence of an incoming pyridine would afford an
1
intermediate INT7, from which NA of the amine moiety to C could occur in an intramolecular
manner to furnish a 5-endo cyclized intermediate INT8 through a transition state, TS8. The NA
step requires the energy barrier of 6.2 kcal/mol relative to INT2. Subsequently, pyridine assisted
1
proton transfer from the ammonium nitrogen to C would occur from INT8 to afford the product
complex INT10, from which the indole product is released (Fig. 2). This computational result
suggests that the presence of pyridine could assist in lowering the activation barrier of the formed
Ru-vinylidene intermediate. Therefore, the ruthenium catalyzed cycloisomerization of 1 would
follow the stepwise PAHT pathway, with the intermediacy of Ru-vinylidene complex.
8

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Fig. 2 Energy profile from the generated Ru-vinylidene intermediate to the final indole product.
Bond distances are shown in Å and the atomic movements associated with the imaginary
frequency are indicated in red arrows.
3
.2. Origin of the regioselective Ru-catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide
The unveiled role of pyridine in assisting the formation of the Ru-vinylidene complex could be
applied to rationalize the origin of the regioselectivity in the Ru-catalyzed cycloisomerization of
aromatic bis-homopropargylic amide to form dihydroquinoline product [2c]. Computational
1
2
results showed that the direct 1,2-H shift from C to C of INT11 will require the energy barrier of
2
8.3 kcal/mol to generate the key Ru-vinylidene intermediate INT15 via TS11 in a concerted
9

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manner (Fig. 3, path A). In addition, from the initial coordination of the alkyne moiety to the
2
Ru-catalyst, a π-alkyne complex INT11, the direct NA of the amide group to C via TS12 could
generate a 5-exo cyclic INT12 (path D1). The activation barrier was predicted to be 24.8 kcal/mol
and the resulting INT12 was formed in an endergonic manner. Likewise, the formation of a
1
6
-endo cyclic intermediate via the direct NA of the amide group to C was another possible
pathway examined (path D2). The located transition state TS13 would require an activation
barrier of 24.6 kcal/mol to afford 6-endo cyclic INT13. These results suggest that the formation of
the Ru-vinylidene complex intermediate via the direct 1,2-H shift is unfavorable.
1
0

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Fig. 3 Energy profile of the regioselective cycloisomerization of 3 to 4. Bond distances are shown
in Å and the atomic movements associated with the imaginary frequency are indicated in red
arrows.
Alternatively, the key Ru-vinylidene intermediate could be formed via the assistance of
1
2
pyridine solvent. The deprotonation of C by pyridine (TS14) and the protonation of C via TS15
ǂ
would generate INT15. The highest ∆G for this path via TS14 was calculated to be 15.4 kcal/mol
(
Fig. 3, path C), indicating that the pyridine assisted formation of the Ru-vinylidene complex is
1
more favorable than the direct 1,2-H shift pathway. Thereafter, NA of the amide moiety to C in
the presence of pyridine would take place via TS16 to generate a 6-membered ring intermediate
INT16. The predicted barrier for this step was calculated to be 15.7 kcal/mol relative to INT15.
1
1

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1
Subsequently, pyridine assisted proton transfer from the amide group to C would take place via
TS17 and TS18 to generate the product complex INT18, from which the final dihydroquinoline
product is liberated.
Therefore, the mechanism of the cycloisomerization of 3 to 4 would follow the PAHT
pathway to generate the dihydroquinoline product via the intermediacy of a Ru-vinylidene
complex. This is in agreement with the experimental findings reported by Saá’s group [2c].
For the cycloisomerization of 2-(2-propynyl)tosylanilide (3) to 2-methylindole (5) in the
absence of pyridine, the aforementioned routes were analyzed. Initially, the cymene ligand in the
ruthenium catalyst would be displaced by an incoming phosphine ligand to afford a π-alkyne
complex INT19. Next, the direct NA via TS19 to afford a 5-exo cyclic INT20 was investigated
from INT19. Computational result showed that the energy barrier for this route is 17.2 kcal/mol
relative to INT19 and the INT20 formed is thermodynamically stable (Fig. 4). In addition, the
formation of a 6-endo cyclic intermediate via the direct NA was also considered. The transition
state was located as TS20. The energy barrier for the formation of 6-endo cyclic intermediate was
predicted to be 28 kcal/mol, which is ca. 11 kcal/mol higher than that of the formation of 5-exo
cyclic intermediate. Moreover, the formed INT21 is thermodynamically unstable relative to
2
INT19. Thus, for 3, the intramolecular nucleophilic attack to C to afford the 5-exo cyclic
1
intermediate is more likely to occur than attack to C .
In the absence of pyridine, the direct 1,2-H shift pathway was explored to yield the
intermediacy of Ru-vinylidene, from which the 6-endo cyclized INT23 might be produced. The
1
corresponding transition state was located as TS21, in which the H…C distance is lengthened to
2
1
2
.16 Å while the H…C distance is shortened to 1.59 Å. The energy barrier was calculated to be
2.1 kcal/mol, which is ca. 5 kcal/mol higher than the direct NA pathway to form the 5-exo cyclic
intermediate (Fig. 4). Therefore, both the direct 6-endo cyclization and the Ru-vinylidene pathway
are less favorable than the direct NA pathway leading to the 5-exo cyclic intermediate. Hence, in
the absence of pyridine, the mechanism of the Ru-catalyzed cycloisomerization of 3 would
regioselectively afford 2-methyl indole via the direct NA pathway.
1
2

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Fig. 4 Energy profile for the regioselective cycloisomerization of 3 to 5. Bond distances are shown
in Å and the atomic movements associated with the imaginary frequency are indicated in red
arrows.
1
3

ACCEPTED MANUSCRIPT
To elucidate the regioselectivity of 3 to 5, the natural population analysis (NPA) for charge
2
distribution was carried out. The results revealed that the slightly negatively charged C of 3 is
1
readier to undergo the direct NA than the more negatively charged C (-0.01 vs -0.26 e
2
respectively). Also, the C in INT19 was found to be slightly positively charged (0.01 e). This
2
suggests that the C of 3 will be preferably attacked by the nucleophile. In addition, frontier
molecular orbital (FMO) analysis was carried out on the structures transforming from 3 to INT20
2
(
Fig. 5). The LUMO of INT19 is partially located on the C with a small magnitude, and
transiting to TS19 shows that there is an increase in magnitude of the LUMO on the same carbon
2
1
atom. This implies that C is more electrophilic than C thus, readier to undergo the direct NA.
Therefore, in the absence of pyridine, the formation of the Ru-vinylidene complex becomes less
2
favourable in comparison with the direct NA at C , which would make the formation of the 5-exo
cyclic intermediate a feasible process. This also is in consonant with the experimental report [2c].
Fig. 5 FMO analysis for the transformation of INT19 to INT20 (isovalue=0.05).
1
4

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4
. Conclusion
Mechanistic studies of the ruthenium-catalyzed cycloisomerization of 2-ethynylaniline and
-(2-propynyl)tosylanilide were carried out using DFT calculations. For the cycloisomerization of
-ethynylaniline to indole, a new mode of Ru-vinylidene formation via the pyridine assisted
2
2
hydrogen transfer (PAHT) pathway was proposed. Computational results showed that this
pathway is more favorable than the previously reported pathways for the
transition-metal-catalyzed cycloisomerization of alkynylamines/amides. Then, the newly proposed
pathway was applied to explain the origin of the regioselectivity, 5-exo vs 6-endo cyclization, in
the ruthenium catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide. The results revealed
that in the presence of pyridine, the 6-endo product would be formed via the Ru-vinylidene
intermediate generated along the PAHT pathway while the absence of pyridine led to a switch in
the reaction mechanism, allowing the formation of a 5-exo product via the direct nucleophilic
addition pathway. This study not only sheds more light on alternative pathways for reactions
involving alkyne-vinylidene species but also underscores the effect of reaction modifications
towards attaining different regioselectivities in cycloisomerization reactions.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (21642004) and the
Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for the
financial support.
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ò
ò
A pyridine assisted hydrogen transfer pathway to form the Ru-vinylidene complex is
unveiled.
The cycloisomerization of 2-(2-propynyl)tosylanilide in the presence of pyridine prefers a
6
-endo cyclized product via the Ru-vinylidene intermediate generated along the pyridine
assisted hydrogen transfer pathway.
ò
In the absence of pyridine, the direct nucleophilic addition pathway is favourable to afford a
5
-exo cyclized product.