Nickel(0)-Catalyzed Denitrogenative Transannulation of Benzotriazinones with Alkynes: Mechanistic Insights of Chemical Reactivity and Regio- and Enantioselectivity from Density Functional Theory and Experiment

Article abstract of DOI:10.1021/acscatal.6b00572

The mechanism of Ni(0)-catalyzed denitrogenative transannulation of 1,2,3-benzotriazin-4(3H)-ones with alkynes to access isoquinolones has been comprehensively studied by a density functional theory (DFT) calculation and control experimental investigation

Full text of DOI:10.1021/acscatal.6b00572

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Article
Nickel(0)-Catalyzed Denitrogenative Transannulation of Benzotriazinones
with Alkynes: Mechanistic Insights of Chemical Reactivity, Regio- and
Enantioselectivity from Density Functional Theory and Experiment
Na Wang, Sheng-Cai Zheng, Lin Lin Zhang, Zhen Guo, and Xin-Yuan Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00572 • Publication Date (Web): 20 Apr 2016
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Nickel(0)
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Catalyzed Denitrogenative
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Transannulation of Benzotriazinones with Alkynes:
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Mechanistic Insights of Chemical Reactivity, Regio
and Enantioselectivity from Density Functional
Theory and Experiment
−
†
‡
†
†
‡
§
§
Na Wang, ShengꢀCai Zheng, Lin−Lin Zhang, Zhen Guo* and Xin−Yuan Liu*
†College of Material Science & Engineering, Taiyuan University of Technology, Shanxi, 030024, P.
R. China
‡Department of Chemistry, South University of Science and Technology, Shenzhen, 518055, P. R.
China
ABSTRACT: The mechanism of Ni(0)−catalyzed denitrogenative transannulation of
1,2,3−benzotriazin−4(3H)−ones with alkynes to access isoquinolones has been comprehensively
studied by density functional theory (DFT) calculation and control experimental investigation. The
results indicate that the transformations proceed via a sequential nitrogen extrusion, carbometalation,
Ni−C bond insertion and reductive elimination process. A frontier molecular orbital (FMO) theory
and natural bond orbital (NBO) analysis reveal that the advantages of substituents on chemical
reactivity and regioselectivity originate from multiple reasons: 1) phenyl groups on N atom of
benzotriazinone and/or unsymmetrical alkynes mainly account for the high reactivity and
regioselectivity via its electronic effect. 2) The π···π interaction between the phenyl substituent on
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the alkyne and triazole ring might partially contribute to the high regioselectivity when
unsymmetrical alkynes were employed as the substrates. Furthermore, DFT calculations successfully
explain the origin of enantioselectivity and discrepancy of reactivities between different
N−substituted benzotriazinones for the asymmetric construction of axially chiral isoquinolones in an
atroposelective manner. The calculated results indicate that high enantioselectivity is mainly
determined by the structural difference between these two transition states of the key annulation step,
which lies in the orientation of naphthyl substituent relative to the chiral ligand.
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KEYWORDS: denitrogenative annulations, density functional theory, heterocycles, axially chiral
isoquinolones, nickel
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INTRODUCTION
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Heterocyclic compounds bearing indole, pyridone and other analogous units are widely
displayed in both naturally occurring and pharmaceutical products.1 Therefore, great synthetic efforts
have been made to develop efficient synthetic approaches for the construction of heterocyclic
compounds. In this context, since the pioneering work from Gevorgyan,2 Fokin,3 and Murakami
groups,4 transition metalꢀcatalyzed annulation reactions of a triazole ring has emerged as an efficient
approach toward diverse azaheterocylic cores,5 particularly those that are based on naturally
abundant Ni(0)ꢀmediated denitrogenative transannulation reactions of benzotriazinones with
unsaturated carbonꢀcarbon bonds have attracted much attention in recent years. For instance, a
series of Ni−catalyzed denitrogenative annulation reactions of benzotriazinones with alkynes, allenes,
alkenes and 1,3−dienes as a unique method for regio– and enantioselective synthesis of plant
alkaloids and bioactive heterocyclic compounds has been reported.6 In this regard, Murakami and
coꢀworkers developed a novel synthetic approach to 1(2H)−isoquinilone via Ni(0)−catalyzed
denitrogenative reaction of 1,2,3−benzotriazin−4(3H)−ones with alkynes.7 The catalytic system
appeared to be very general in scope, excellent yields, high regioselectivity and the tunable reactivity
by changing substituents on the nitrogen of benzotriazinones. For example, N–aryl–substituted
benzotriazinones underwent smooth transannulation reactions at room temperature, whereas the
reaction of N–alkyl–substituted substrates required higher temperatures and Nꢀunsubstituted
benzotriazinone failed to undergo this reaction even at 100 °C. More recently, our research group has
successfully developed the first nickelꢀcatalyzed asymmetric denitrogenative transannulation of
1,2,3−benzotriazin−4(3H)−ones with bulky internal alkynes to construct a novel class of axially
chiral isoquinolones in excellent yields with high enantioselectivity in an atroposelective manner and
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almost complete regioselectivity in the presence of Ni(0)ꢀbisoxazoline catalyst under mild
conditions.8 However, both Ni(0)−catalyzed racemic and asymmetric denitrogenative annulation
reactions have been mainly focused on the scope of alkynes and aryl−substituted benzotriazinones,
but rarely on the other kinds of N−substituted benzotriazinones. As part of our continuous interest in
the development of the axially chiral isoquinolones8 and broadening the application spectrum of
triazole substrates in constructing more structurally diverse axially chiral isoquinolones, herein, we
further investigate Ni(0)−bisoxazoline−catalyzed asymmetric denitrogenative alkyne insertion
reactions of N−substituted benzotriazinones, which bears a variety of alkyl substituents. Furthermore,
although Ni(0)−catalyzed annulation reaction of heterocyclic compounds with unsaturated substrates
have been experimentally well−established,6ꢀ8 only few computational studies have been performed9
and several challenging questions remain to be solved for such type of reactions: (i) What is the
detailed reaction mechanism for Ni(0)−catalyzed denitrogenative transannulation reactions? (ii) How
do the substituents on the nitrogen of benzotriazinone affect chemical reactivity? (iii) What factors
affect the intrinsic regioselectivity? (IV) In particular, for Ni(0)−catalyzed atroposelective
denitrogenative transannulation process, understanding of the discrepancy of reactivity and
enantioselectivity, which were derived from the different N−substituted benzotriazinones, is still
challenging and remains elusive. Here we describe the first computational study of the
Ni(0)−catalyzed denitrogenative transannulation reaction of 1,2,3−benzotriazin−4(3H)−ones with
internal alkynes, with the aim of answering the questions listed above and further confirming or
complementing our experimental findings (Scheme 1).
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Scheme 1. Controlling factors of the Ni(0)−catalyzed denitrogenative transannulation reactions.
COMPUTATIONAL DETAILS
All calculations were carried out using the G09 suite of computational programs.10 The M06L
functional with adding the D3 version of Grimme’s dispersion11 was employed to optimize all
stationary points in gas phase using 6−311G(d) basis sets for all atoms. This computational method
with dispersion correction has been successfully given accurate energies for transition metal
systems.12 Vibrational analysis was performed to confirm that each stationary point is minimal or
transition state. Intrinsic reaction coordination (IRC) calculations were used to verify the connections
among the transition states and its reactant and product. The solvent effect associated with
1,4−dioxane was studied by SMD model13 with full optimization at the M06L/6−311G(d) level.
Unless otherwise specified, all discussed energies in what follows refers to activation free energy
(ꢁG, kcal/mol) values in gas phase. 3D structures for the optimized stationary points were prepared
with CYLview.14 Reduced density gradient (RDG) analyses 15 were performed using Multiwfn16 to
support the existence of π···π interactions in some cases. The additional computational results can be
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found in the Supporting Information.17
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RESULTS AND DISCUSSIONS
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Murakami and coꢀworkers reported Ni(0)−catalyzed 1,2,3−benzotriazin−4(3H)−ones reactions
with alkynes to give a wide range of substituted 1(2H)ꢀisoquinolones via denitrogenative activation
of triazole moiety and the subsequent insertion of alkynes.7 On the basis of these experimental results,
a plausible reaction mechanism was tentatively proposed in Scheme 2. It is commonly assumed that
the reaction involves the formation of a five−membered aza−nickelacyclic complex 3 and the
catalytic cycle consists of four steps: Ni(0)−catalyzed nitrogen extrusion from benzotriazinone
compound, carbometalation process, insertion of Ni−C bonds and reductive elimination to afford the
final isoquinolone products and regenerate the catalyst.
To keep the subsequent computational studies efficient, we chose the simple PMe3 as the ligand,
which has been well established in the Ni−catalyzed transannulation reactions,7 to understand the
detailed reaction mechanism. Furthermore, the real chiral cyclopropylidieneꢀlinked bis(oxazoline)
ligand was used for DFT calculations to provide useful insight into the intrinsic atroposelective
nature of this transannulation reaction.
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Scheme 2. A plausible mechanism of Ni−catalyzed denitrogenative transannunation of
1,2,3−benzotriazin−4(3H)−one with alkyne.
Extrusion of N2. On the basis of the experimental7 and theoretical9b reports, complex Ph1, which is
thermally facile to be generated by the reaction of triazole and neutral Ni(cod)2 in the presence of
excess amount of trimethylphosphine, is chosen as the starting reactant for the nitrogen extrusion
from benzotriazinone (Figure 1 and 2). The catalytic cycle occurs stepwise and involves the
formation of a sevenꢀmembered intermediate Ph2 via PhTS1 with a 0.2 kcal/mol activation free energy.
Then, the cleavage of C−N bond and formation of Ni−C bond of complex Ph2 via PhTS2 requires
overcoming the reaction barrier of 16.0 kcal/mol in activation free energy to give the fiveꢀmembered
complex Ph3. The next step corresponds to the dissociation of either a phosphine ligand or N2
molecule to afford aza−nickelacycle Ph3′ and Ph3", respectively, with a vacant site available for
subsequent alkyne−coordination. It is worth noting that the formation of aza−nickelacycle Ph3′ is
endothermic by 8.7 kcal/mol. In contrast, the formation of species Ph3" via losing the nitrogen
molecule is exothermic by 1.7 kcal/mol. As a result, species Ph3" is 10.4 kcal/mol more stable in free
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energy than species Ph3′. This indicates that the production of species Ph3" with two PMe3 ligands is
more favored thermodynamically in the Ni(0)−catalyzed annulation reaction of triazole with alkyne,
with respect to Ph3′. In addition, the DFT−optimized structure of aza−nickelacycle Ph3" features an
almost planar arrangement of fourꢀcoordinate Ni, like the analogous crystal structure reported by
Murakami.6a The calculated distances of Ni−C bond and Ni−N bond are 1.919 Å and 1.918 Å,
respectively, which are comparable to those found in Murakami’s experimental results (1.905 vs.
1.958 Å for Ni−C vs. Ni−N bond). Together with theoretically reported higher reaction barrier of
monocoordinated phosphine pathway in the analogous Ni(0)−catalyzed decarbonylative addition of
phthalimides to alkynes,9b these relatively large energy difference between the dissociation of PMe3
and N2 ligand from complex Ph2, promoted us to consider the aza−nickelacycle Ph3" as the
exclusively potential species in the following calculations of catalytic reaction mechanism.
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Figure 1. Free energy profile of Ni(0)–catalyzed denitrogenative process of phenyl−substituted
benzotriazinone (vaules are given in kcal/mol, the relative free energy in solvent (1,4ꢀdioxane) are
given in paretheses).
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Figure 2. Optimized structures of stationary points of Ni−catalyzed denitrogenative process of
phenyl−substituted benzotriazinone, along with the key bond lengths (in angstroms). Hydrogen
atoms have been omitted for clarity.
Carbometalation, Ni−C Bond Insertion and Reductive Elimination. With the optimized potential
species Ph3" in hand, we next investigated the subsequent steps, including carbometalation, insertion
of Ni−C bond and reductive elimination (Figure 3 and Figure 4). Our calculations suggest that the
annulation reaction starts with a π−complex Ph4 where the alkyne is coordinated to the Ni atom with
the Ni−C1/Ni−C2 bond distance of 3.56/3.81Å. π−Complex Ph4 underwent the oxidation addition of
alkyne C≡C bond to nickel complex, leading to a carbometalation species Ph5 which lies 3.7 kcal/mol
below Ph4. This step is easy and requires an activation free energy of 10.9 kcal/mol with the forming
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Ni−C1/Ni−C2 bond of 2.30/2.29 Å in three−membered transition state PhTS4. The next step
corresponds to insertion of the Ni−C3 through the transition state PhTS5a, with a barrier of 22.0
kcal/mol above the intermediate Ph5, to afford a sevenꢀmembered nickelacycle complex Ph6a
(depicted as path a in Figure 3). The formation of Ph6a is significantly exothermic by 23.3 kcal/mol
with respect to the Ph4. Then Ph6a undergoes a ring closure reaction via sixꢀmembered transition state
PhTS6a with the forming C2−N bond being 1.81 Å. This is a rather low energy step with a barrier of
only 15.1 kcal/mol, leading to intermediate Ph7a with the resultant heterocyclic product coordinated
to Ni center and an energy loss of 10.9 kcal/mol. Finally, the reductive elimination of intermediate
Ph7a gives the desired product and regenerates the catalyst to enter catalytic cycle. From species Ph5,
an alternative pathway is probably responsible for the formation of the final heterocyclic product.
Additional calculations were conducted by considering the possible initial insertion of alkyne into
the Ni−N bond (depicted as Path b in Figure 3). Calculation indicated that the transition state PhTS5b
of Path b corresponding to the insertion through Ni−N costs 11.3 kcal/mol in activation free energy
more than transition state PhTS5a of path a. Furthermore, the isomer Ph6b is 20.5 kcal/mol higher in
free energy than Ph6a. The next ring closure step (reductive elimination) in path b still costs 15.7
kcal/mol higher in free energy as comparing to path a (−74.3 vs. −58.6 for PhTS6a vs. PhTS6b), and
leads to isomer Ph7b being 12.3 kcal/mol less stable in energy than Ph7a. The reactivity on both
pathways (a and b) could be rationalized by analysis of energies of HOMO orbitals of transition
states in the rate−determining step of insertion of Ni−C3/N bond (AꢀC, Figure 5), as revealed by the
increase of HOMO energies (in eV) along the order: PhTS5a (−4.14) < PhTS5b (−3.66). In addition,
the NBO charge analysis indicates that the HOMOs of Ph5 and PhTS5a have very similar charge
distributions, indicating that small change in charge redistribution is needed to reach the reaction
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barrier in Path a. However, HOMO of PhTS5b features the σNi−N −antibonding orbital which is
conceived to have a higher energy and makes charge redistribution more difficult, and hence the
higher reaction barrier is anticipated. On the other hand, as the Ph5 goes to PhTS5a, the change in their
structures is significantly less than the change that occurs in its counterpart of Path b. For example,
smaller change in the key Ni−C3 and Ni−C1 bond lengths are only about 0.06 Å and 0.03 Å for Ph5 to
PhTS5a, respectively, but those of the key Ni−N and Ni−C2 bond lengths are about 0.30 Å and 0.61 Å
for Ph5 to PhTS5b, respectively.17a Taken together, the calculations revealed that Path a corresponding
to the initial alkyne addition with Ni−C3 bond of Ph5 is more favorable than Path b, both kinetically
and thermodynamically, which is similar to that found in nickel−catalyzed decarbonylative addition
reactions of phthalimides/anhydride to alkyne.9 The transformation of Ph4 to Ph7 is exothermic and
requires overcoming the overall reaction barrier of 22.0 kcal/mol , which is in accordance with the
experimental reaction condition (at room temperature for 3−12 h).
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The solvent effect on the reaction energetics was considered by using the SMD model in
1,4−dioxane with full optimization. The energy profiles in 1,4−dioxane for whole catalytic cycle
were very comparable to those found in gas phase (Figure 1 and 3). In particular, the
rateꢀdetermining step of insertion process (from Ph5 to Ph6a) requires the activation free energy of
22.0 kcal/mol in 1,4−dioxane, which is identical to that in gas phase. Thus, solvent effect does not
change the conclusions drawn from gas phase.
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Figure 3. Free energy profile of Ni(0)−catalyzed denitrogenative transannulation of
phenyl−substituted benzotriazinone with alkyne via insertion of Ni−C bond (Path a) and
Ni(0)−catalyzed denitrogenative transannulation of phenyl−substituted benzotriazinone with alkyne
via insertion of Ni−N bond (Path b) (vaules are given in kcal/mol, the activation free energy in
solvent (1,4−dioxane) are given in paretheses).
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Figure 4. Optimized structures of stationary points of Ni−catalyzed transanulation of
phenyl−substituted benzotriazinone with alkyne via insertion of Ni−C bond (Path a), along with the
key bond lengths (in angstroms). Hydrogen atoms have been omitted for clarity.
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Figure 5. Spatial plots of highest occupied molecular orbitals (HOMOs), together with their energies,
for reactant Ph5(A) and transition state PhTS5b(B),PhTS5a(C), MeTS5a(D) and HTS5a(E).
The Substituent Effect on the Reactivity. Experimental results show that Ni(0)ꢀcatalyzed
transannulation reactions of different N−substituted benzotriazinones with alkynes demonstrated
different reactivities (Scheme 3).7 Our aim in this part is to shed some light on the substituent effect
on the chemical reactivity by DFT calculations. The calculated overall activation free energy profiles
for the annulation reactions of H− and methyl−substituted benzotriazinones to internal alkyne
catalyzed by nickel catalyst were depicted in Figure 6. Calculation shows that H− and
methylꢀsubstituted benzotriazinones have the similar reactivity toward the denitrogenative process
both in gas phase and in the solvent of 1,4−dioxane with a small reaction barrier of 13.2−18.3
kcal/mol in free energy, which are comparable to those found in phenyl−substituted counterpart
(Figure 1).17b However, the reaction initiated by insertion of alkyne into Ni−C bond as the
rate−determining step is less energetically favorable in both cases of H− and methyl−substituted
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benzotriazinones with respect to phenyl−substituted one, as revealed by the higher reaction barriers
of HTS5a(28.5 kcal/mol) and MeTS5a (25.2 kcal/mol) than that of PhTS5a (22.0 kcal/mol) (Figure 3 and
6). This indicates that the reactivity of Ni−catalyzed annulation reaction of triazoles with internal
alkynes was enhanced by replacing substituents on nitrogen of benzotriazinones from hydrogen atom
or methyl group to phenyl groups. It should be noted that the calculated reaction barrier order: 22.0
kcal/mol (PhTS5a) < 25.2 kcal/mol (MeTS5a) < 28.5 kcal/mol (HTS5a), is in accordance with the
experimental findings depicted in Scheme 3, that phenyl−substituted substrate proceeded well at
room temperature to produce isoquinilone and methyl−substituted one gave heterocyclic product at
higher temperatures, while H−substituted one did not react at even 100 °C. The excellent reactivity
for phenyl−substituted benzotriazinone could be attributed to multiple reasons. First, the electronic
factor of phenyl group is important. NBO analysis revealed that σNi−N antibonding orbital characters
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H
were more heavily involved in HOMOs for TS5a and MeTS5a with 40.3% and 39.6%, respectively
(D−E, Figure 5 and Table S1); however, PhTS5a features the mixing of σNi−N antibonding orbital
character of 28.6% with significant π–type orbitals of substituent of phenyl group (C, Figure 5 and
Table S1). This indicates that the presence of phenyl group leads to the delocalization of the
electronic density on the N atom and reduce the antibonding interaction between N atom and Ni
metal. As a result, more stable HOMO in transition state for phenyl−substituted benzotriazinone is
anticipated. Indeed, the calculated energies (eV) of HOMOs of the different transition states decrease
along the order: H (−3.91) > Me (−4.00) > Ph (−4.14) (C−E, Figure 5). On the other hand, the
reduced density gradient (RDG) analysis revealed that phenyl group on N atom has the π···π
interaction with phenyl ring of alkyne in PhTS5a (See green area with blue circle of A in Figure 7).
This weak interaction might be another advantage of phenyl group on N atom for enhancing the
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reactivity of N−aryl−substituted benzotriazinones.
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Scheme 3. Ni(0)−catalyzed annulation reactions of different N−substituted benzotriazinones with
internal alkyne.
Figure 6. Free energy profile of Ni−catalyzed transannulation process of H− and methyl−substituted
benzotriazinones with internal alkyne (vaules are given in kcal/mol, the activation free energy in
solvent (1,4−dioxane) are given in paretheses).
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PhTS5-I
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Figure 7. RDG analysis of π···π interaction in transition state PhTS5a(A), PhTS9a (B) and 4ꢀTolTS13a(C).
Origin of Regioselectivity. Depending on the ligands employed, the regioselectivity of Ni–catalyzed
annulation of triazoles to the unsymmetrical alkynes could reach up to 99%.7 We further selected a
simple PMe3, unsymmetrical internal alkyne (MeC≡CPh) and phenylꢀsubstituted benzotriazinone as
a representative example from the ligands and substrates reported in the literature7 to investigate the
regioselectivity. This also lends the support of the validity of the proposed mechanism. Figure 8
summarizes the calculated reaction profile for the alkyne carbometalation, insertion/reductive
elimination process with Ph3" (only the reaction pathways with the initial alkyne insertion with Ni–C
bond are shown),17c which well reproduces the regioselectivity observed experimentally.7 The
calculation shows that carbometalation process on both pathways (Ph8a→Ph9a; Ph8b→Ph9b) is
reversible (slightly exothermic by 1.4–2.1 kcal/mol) and a fast Ph8a/Ph8b equilibrium can be
expected due to small reaction barriers (8.4 vs. 7.1 for PhTS8a vs. PhTS8b). Therefore, the
regioselectivity of annulation process is exclusively controlled by the following steps: insertion of
NiꢀC bond (Ph9a→Ph10a; Ph9b→Ph10b) and/or reductive elimination (Ph10a→Ph11a; Ph10b→Ph11b).
The calculated results reveal that the insertion of Ni–C bond on both pathways requires much higher
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reaction barriers in activation free energy to give the sevenꢀmembered cyclometalated Ni complexes
Ph10a and Ph10b (20.7 vs. 23.1 kcal/mol for PhTS9a vs.PhTS9b with respect to the species Ph9b), than
the reductive elimination which undergoes ring closure efficiently to generate species Ph11a and
Ph11b (15.1 vs. 18.7 kcal/mol for PhTS10a vs.PhTS10b with respect to the species Ph10a). Therefore, the
former as the rateꢀdetermining step in the whole catalytic cycle plays a crucial role in the
regioselectivity induction. Inspection of Figure 8 demonstrates that the process of Ni–C bond
insertion through path a is more energetically favorable than its counterpart of path b, i.e., PhTS9a has
lower activation free energy than PhTS9b at the amount of 2.4 kcal/mol. In addition, the formation of
their corresponding product of Ph10a and PhTS10b is highly exothermic (20ꢀ23.5 kcal/mol) and
irreversible, indicating the kinetically controlled regioselectivity of annulation process. On the basis
of the energy difference (2.3−2.4 kcal/mol) between PhTS9a and PhTS9b, the regioselectivity of the
annulation reaction was predicted to be 95% for formation of Ph11a. This is consistent with
experimentally observed major product, in which the Niꢀbonded phenyl carbon would preferentially
form a C−N bond with nitrogen atom.7 Note that the energy difference in the relative activation
energy between PhTS9a and PhTS9b increased to be 3.4 kcal/mol without considering the entropy
penalty of these transformations, thus the lowerꢀenergy PhTS9a to give Ph10b might be mainly due to
stereoelectronic effects of unsymmetrical internal alkynes instead of the steric effects. A frontier
molecular orbital [FMO] analysis reveals that in the Ni(0)–catalyzed annulation reaction with
unsymmetrical alkyne, the alkyne participates the insertion step as an electrophile with its
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unoccupied π* orbital accepting the electrons from the occupied Ni dz orbital (See Supporting
2
Information).17d Therefore, the methyl–substituted carbon of MeC≡CPh, which is more π electron
poor, might couple with the Ni–bonded phenyl carbon more easily (See mulliken charges in Figure
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8). Furthermore, consistent with the electronic demand expected in insertion process (Ph9a→Ph10a),
the phenyl substituent of MeC≡CPh is capable of stabilization of a partial negative charge on
carbon next to Ni atom. Such kind of electronic effect is also supported by other experiments, i.e.,
the high regioselectivity observed in boryl–substituted alkynes (possibly due to stabilization of the
carbon negative charge by electron–withdrawing boron group).18 We believed that this explanation
also accounts for the regioselectivity observed in the titled reactions. Interestingly, we disclosed that,
compared with the unfavorable PhTS9b, π···π interaction between two phenyl groups of alkyne and
Ph3" exists in PhTS9a, which might be another positive factor reinforcing the observed
regioselectivity. The existence of the π···π aggregation in PhTS9a is supported by RDG analyses (B,
Figure 7).
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Figure 8. Free energy profile of Ni–catalyzed transannulation of phenylꢀsubsituted benzotriazinone
with unsymmetrical alkyne starting from Ph8a (Path a) and Ni–catalyzed transannulation of
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phenylꢀsubsituted benzotriazinone with unsymmetrical alkyne starting from Ph8b (Path b) (vaules are
given in kcal/mol, the activation free energy (∆G) and relative activation energy {∆E0} for PhTS9a and
PhTS9b) in solvent (1,4–dioxane) are given in paretheses). The selected atomic mulliken charges are
given in blue numbers.
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Experimental and DFT Studies on Ni–catalyzed asymmetric transannulation of Nꢀsubstituted
benzotriazinones in an atroposelective manner. Our previous results showed that Ni(0)–catalyzed
asymmetric denitrogenative transannulation reaction of benzotriazinones bearing a variety of aryl
substituents with bulky internal alkynes furnished a class of novel axially chiral isoquinolones with
63–80% yields and 89–94% ee under mild conditions in an atroposelective manner.8 In this part, the
scope of benzotriazinone (I) with various alkyl substituents on N atom including Me (Ib), i–Pr (Ic)
and t–Bu (Id) were further examined in the reaction with IIa or IIb under the optimal reaction
conditions (Table 1). In the beginning, such reaction of p–MeC6H4–substituted benzotriazinone (Ia)
was repeated, and the result is comparable to previous one (74% yield, 94% ee) (entry 1). However,
substrate Ib with a methyl substituent underwent the reaction with very low conversion and 30% ee
(entry 2) and similar result was also obtained from its reaction with IIb (entry 3). No reaction
occurred for i–Pr (Ic) and t–Bu (Id) substituted benzotriazinones, even at 60 ˚C (entries 4−7). These
results suggested that the nature of the substituent on nitrogen of benzotriazinone have significant
impact on chemical reactivity and enantioselectivity. The experimental observation that mixing of
substrate Ib, Ic, and Id with Ni catalyst all rapidly gave the black solution, implies that Ni–catalyst
could prompt extrusion of a molecular nitrogen smoothly. The observed poor reactivity in the cases
of Ib, Ic, and Id was likely due to the high energy barrier in subsequent insertion of alkyne IIa into
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the nickel–carbon bond. DFT calculations was then conducted to understand discrepancy of chemical
reactivity and enantioselectivity of the reaction of aromatic–substituted benzotriazinone Ia and
alky–substituted ones using Ib and Id with bulky internal alkyne IIa with cyclopropylidiene–linked
chiral ligand L*.
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Table 1. Ni(0)–catalyzed asymmetric insertion: scope of substituents on nitrogen Ia
Entry
T (˚C)
Conversionb
eec
I
II
IIa RL=1–Napthyl
IIa RL=1–Napthyl
IIb RL=4–Pyrenyl
1
2
Ia R=p–MeC6H4
Ib R=Me
rt
rt
100%
23%
94%
30%
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5
Ib R=Me
Ic R=iꢀPr
Id R=t-Bu
rt
rt
rt
11%
NR
NR
11%
ꢀꢀ
IIa RL=1–Napthyl
IIa RL=1–Napthyl
ꢀꢀ
6
7
Ic R=iꢀPr
IIa RL=1–Napthyl
IIa RL=1–Napthyl
60
60
NR
NR
ꢀꢀ
ꢀꢀ
Id R=t-Bu
a All the reactions were conducted on a 0.1 mmol scale. b Yield determined by 1H NMR spectroscopy.
c Determined by HPLC analysis.
For the Ni–catalyzed asymmetric denitrogenative transannulation reaction of Ia with IIa, the
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calculated results indicated that the steps of nitrogen extrusion and carbometalation took place
smoothly with small reaction barriers, similar to those found in the case of PMe3 ligand and thus
does not account for the origin of enantioselectivity in whole catalytic cycle.17e As for the subsequent
steps of Ni–C bond insertion and reductive elimination, two different reaction pathways (Path a
starting from 4ꢀTol13a to give (aR)ꢀproduct 4ꢀTol15a and Path b starting from 4ꢀTol13b to give (sR)
–product 4ꢀTol15b, 4ꢀTol＝p–MeC6H4) were located. As shown in Figure 9a, in both pathways, the
π–complexes (4ꢀTol13a and 4ꢀTol13b) with naphthyl substituent at the different orientations are
converted to the sevenꢀmembered nickelacycle intermediates 4ꢀTol14a and 4ꢀTol14b via transition state
4ꢀTolTS13a and 4ꢀTolTS13b, which followed by the reductive elimination to yield the (aR)–product
4ꢀTol15a and (aS)–product 4ꢀTol15b, respectively. Comparison of calculated potential energy surfaces
on both pathways reveals that：1) Path a was kinetically and thermodynamically more favorable than
path b in both insertion of NiꢀC bond and reductive elimination steps ( 30.1 vs. 30.7 kcal/mol in gas
phase and 27.9 vs. 29.4 kcal/mol in 1,4–dioxane for 4ꢀTolTS13a vs.4ꢀTolTS13b; –1.0 vs. 3.4 kcal/mol in
gas phase and 0.8 vs. 3.4 kcal/mol in 1,4–dioxane for 4ꢀTolTS14a vs.4ꢀTolTS14b); 2) The reaction barrier
for Ni–C bond insertion is 30.1 kcal/mol in gas phase and 27.9 kcal/mol in 1,4–dioxane, respectively,
which is the rate–limiting step for the whole catalytic cycle; 3) Path a to afford (aR)–product was
energetically more favorable than path b by activation free energy of 1.5 kcal/mol in the solvent with
a predicted ee value of 86%, which is comparable to that of 94% found in the experiment; 4)
Evidently, path a renders transition state structures (4ꢀTolTS13a and 4ꢀTolTS14a, Figure 10) with naphthyl
substituent and chiral ligand ring at opposite sites to avoid the repulsive steric interaction, which was
probably responsible for the preferential (aR)–product formation in the reaction of Ia and IIa.
Figure 9b showed that the calculated activation free energy difference between MeTS13a and
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MeTS13b in the rateꢀlimiting step of Ni–C insertion reaction of Ib and IIa is 0.2 kcal/mol in gas phase
and 0.6 kcal/mol in 1,4–dioxane. The calculated lower energy difference leads to a predicted ee value
about 46% in solvent, which is comparable to that found in our experiment (entry 2, Table 1). This
also explained the lower enantioselectivity by switching substituent on the nitrogen of
benzotriazinones from p–MeC6H4 group to methyl group. In the reaction of t–Bu–substituted
benzotriazinone Id, the rate–determining step with transition state tꢀBuTS13a is characterized by a very
high barrier of more than 30 kcal/mol both in gas phase and in 1,4–dioxane,17e which indicated that
such reaction of Id with IIa could not take place. This provides a rationale for no conversion of Id
even at 60 ˚C (entry 7, Table 1). Compared with the HOMO character (C, Figure 5) and RDG
analysis of N– aryl–substituted benzotriazinones (C, Figure 7), the lack of electronic effect of phenyl
group and π···π stacking was probably responsible for the higher reaction barriers and low
enantioselectivity in the cases of N–alkyl–substituted benzotriazinones as discussed previously.
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Figure 9. (a) Free energy profile of Ni–catalyzed asymmetric transannulation of
p–MeC6H4–substituted benzotriazinones with alkyne; (b) the free energy difference between the key
transtion states in the case of methylꢀbenzotriazinone, (vaules are given in kcal/mol, the activation
free energy in solvent (1,4–dioxane) are given in paretheses).
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1.99
1.93
4-TolTS13a
4-TolTS13b
O
O
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N
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ring ring
repulsion
N
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0.0 kcal/mol
G=+1.5 kcal/mol (in 1,4-dioxane)
Figure 10. Optimized structures of key transtion states of Ni–catalyzed asymmetric transannulztion
of p–MeC6H4–substituted benzotriazinone with alkyne, along with the key bond lengths (in
angstroms). Hydrogen atoms have been omitted for clarity. The Ni, Cl, N, and O atoms are set in
dark green, light green, blue and red, respectively. The C atoms of the chiral ligand, benzotriazinone
moiety, and alkyne moiety are set in gray, light blue and pink, respectively.
CONCLUSIONS
In this study, a detailed mechanism study on the Ni(0)–catalyzed denitrogenative transannulation
of 1,2,3–benzotrazin–4(3H)–ones with alkynes has been systematically conducted by DFT
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calculations. The computational results revealed that the transformation is composed of four steps:
nitrogen extrusion, carbometalation, Ni−C bond insertion and reductive elimination. The alkyne
insertion into Ni−C bond was proven to be the rateꢀdetermining step. DFT calculation (FMO and
NBO analysis) revealed: (1) Superior reactivity of N–aryl–substituted benzotriazinones to
N–alkyl–substituted ones is that introduction of conjugated substituents on the N atom of
benzotriazinone will facilitates the insertion step; (2) The intrinsic orbital distribution of MeC≡CPh
mainly accounts for the regioselectivity with asymmetrical alkynes, which favors the bond formation
between methyl substituted alkyne carbon and the Ni–linked phenyl ring carbon; (3) π···π interaction
between the phenyl group of alkyne and the benzotriazinone would benefit the high reactivity and
regioselectivity; (4) The preference of the (aR)–product results from an energetically favorable
transition state with structure of nathpyl substituent and chiral ligand ring at opposite sides in an
atroposelective manner.
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Our results present deeper insights into the reactions involving Ni(0)–catalyzed racemic and
asymmetric transannulation of triazoles with alkynes. The manipulation of stereoelectronic factor
and π···π interaction supported by DFT calculations on how aromatic group impacts the chemical
selectivity, regioselectivity and even enantioselectivity is among the strategies for further
developments in synthesis of more structurally diverse and novel enantiopured heterocyclic
compounds.
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ASSOCIATED CONTENT
Supporting Information
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Cartesian coordinates, total free energies (Hartree/Particle) of all stationary points calculated at
M06L/6ꢀ311G(d) level and optimized structures for Ni(0)ꢀcatalyzed denitrogenative transannulation
of Nꢀsubstituted benzotriazinones with alkynes, experimental procedures, characterization of all new
compounds. This information is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
§N. W and S.C. Z. contributed equally
Corresponding Author
guozhen@tyut.edu.cn
liuxy3@sustc.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the 100ꢀTalent Program in Shanxi Province, and Taiyuan University of
Science and Technology of China is greatly appreciated. X.ꢀY. Liu sincerely thank Financial support
from the National Natural Science Foundation of China (Nos. 215722096, 21302088), the National
Key Basic Research Program of China (973 Program 2013CB834802), Shenzhen overseas high level
talents innovation plan of technical innovation project (KQCX20150331101823702), Shenzhen
special funds for the development of biomedicine, Internet, new energy, and new material industries
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(JCYJ20150430160022517) and South University of Science and Technology of China
(FRGꢀSUSTC1501Aꢀ16).
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