Nickel(0)-Catalyzed Denitrogenative Transannulation of

Subscriber access provided by HOWARD UNIV

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 Downloaded from http://pubs.acs.org on April 21, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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*‡ †

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

ACS Paragon Plus Environment

ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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.

KEYWORDS: denitrogenative annulations, density functional theory, heterocycles, axially chiral isoquinolones, nickel


Page 2 of 30

Page 3 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

INTRODUCTION 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 metal-catalyzed 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 carbon-carbon 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 co-workers 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 N-unsubstituted benzotriazinone failed to undergo this reaction even at 100 °C. More recently, our research group has successfully developed the first nickel-catalyzed 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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,6-8 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).


Page 4 of 30

Page 5 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

found in the Supporting Information.17

RESULTS AND DISCUSSIONS

Murakami and co-workers 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 cyclopropylidiene-linked bis(oxazoline) ligand was used for DFT calculations to provide useful insight into the intrinsic atroposelective nature of this transannulation reaction.


Page 6 of 30

Page 7 of 30

tru Ex fN no sio

vect i d u t io n R e in a m E li

2

of on rti nd se bo In i-C N

r bo on Ca talati me

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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

Ph

1, 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 seven-membered 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

Ph

2 via

Ph

TS2 requires

overcoming the reaction barrier of 16.0 kcal/mol in activation free energy to give the five-membered complex

Ph

3. The next step corresponds to the dissociation of either a phosphine ligand or N2

molecule to afford aza−nickelacycle

Ph

3′ and

Ph

3", respectively, with a vacant site available for

subsequent alkyne−coordination. It is worth noting that the formation of aza−nickelacycle endothermic by 8.7 kcal/mol. In contrast, the formation of species

Ph

Ph

3′ is

3" 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 30

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

Ph

3" features an

almost planar arrangement of four-coordinate 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

Ph

2, promoted us to consider the aza−nickelacycle

Ph

exclusively potential species in the following calculations of catalytic reaction mechanism.


3" as the

Page 9 of 30

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 (1,4-dioxane) are

1. 9 2 1 .9

2

28 2.

17

2 1.9

2.

33

given in paretheses).

2.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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

Ph

4 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 30

Ni−C1/Ni−C2 bond of 2.30/2.29 Å in three−membered transition state corresponds to insertion of the Ni−C3 through the transition state kcal/mol above the intermediate

Ph

Ph

TS4. The next step

Ph

TS5a, with a barrier of 22.0

5, to afford a seven-membered nickelacycle complex

(depicted as path a in Figure 3). The formation of

Ph

Ph

6a

6a is significantly exothermic by 23.3 kcal/mol

with respect to the Ph4. Then Ph6a undergoes a ring closure reaction via six-membered transition state Ph

TS6a 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

Ph

7a with the resultant heterocyclic product coordinated

to Ni center and an energy loss of 10.9 kcal/mol. Finally, the reductive elimination of intermediate Ph

7a 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 free energy than

Ph

Ph

TS5a of path a. Furthermore, the isomer

Ph

6b is 20.5 kcal/mol higher in

6a. 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 leads to isomer

Ph

7b being 12.3 kcal/mol less stable in energy than

Ph

TS6a vs.

Ph

TS6b), and

Ph

7a. 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 (A-C, Figure 5), as revealed by the increase of HOMO energies (in eV) along the order:

Ph

TS5a (−4.14)
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


Page 15 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

reactivity of N−aryl−substituted benzotriazinones.

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).


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 30

3.4 3.4 3.3

3.4

Ph

TS5-I A

Ph

4-TOl

TS9-I

TS13-I C

B

Figure 7. RDG analysis of π···π interaction in transition state PhTS5a(A), PhTS9a (B) and 4-TolTS13a(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 phenyl-substituted 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; reversible (slightly exothermic by 1.4–2.1 kcal/mol) and a fast expected due to small reaction barriers (8.4 vs. 7.1 for

Ph

Ph

Ph

8b→Ph9b) is

8a/Ph8b equilibrium can be

TS8a vs.

Ph

TS8b). Therefore, the

regioselectivity of annulation process is exclusively controlled by the following steps: insertion of Ni-C 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


Page 17 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

reaction barriers in activation free energy to give the seven-membered cyclometalated Ni complexes Ph

10a and

Ph

10b (20.7 vs. 23.1 kcal/mol for PhTS9a vs.PhTS9b with respect to the species

the reductive elimination which undergoes ring closure efficiently to generate species

Ph

9b), than

Ph

11a and

Ph

11b (15.1 vs. 18.7 kcal/mol for PhTS10a vs.PhTS10b with respect to the species Ph10a). Therefore, the

former as the rate-determining 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

Ph

10a and

Ph

TS10b is highly exothermic (20-23.5 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

Ph

TS9a and

Ph

annulation reaction was predicted to be 95% for formation of

TS9b, the regioselectivity of the Ph

11a. This is consistent with

experimentally observed major product, in which the Ni-bonded phenyl carbon would preferentially form a C−N bond with nitrogen atom.7 Note that the energy difference in the relative activation energy between

Ph

TS9a and

Ph

TS9b increased to be 3.4 kcal/mol without considering the entropy

penalty of these transformations, thus the lower-energy PhTS9a to give

Ph

10b 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 unoccupied π* orbital accepting the electrons from the occupied Ni dz2 orbital (See Supporting 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 Ph

3" exists in

Ph

TS9b, π···π interaction between two phenyl groups of alkyne and

Ph

TS9a, 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).

Figure 8. Free energy profile of Ni–catalyzed transannulation of phenyl-subsituted benzotriazinone with unsymmetrical alkyne starting from

Ph

8a (Path a) and Ni–catalyzed transannulation of


Page 18 of 30

Page 19 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

phenyl-subsituted 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 Ph

TS9b) in solvent (1,4–dioxane) are given in paretheses). The selected atomic mulliken charges are

given in blue numbers.

Experimental and DFT Studies on Ni–catalyzed asymmetric transannulation of N-substituted 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 30

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*.

Table 1. Ni(0)–catalyzed asymmetric insertion: scope of substituents on nitrogen Ia

Entry

I

II

T (˚C)

Conversionb

eec

1

Ia R=p–MeC6H4

IIa RL=1–Napthyl

rt

100%

94%

2

Ib R=Me

IIa RL=1–Napthyl

rt

23%

30%

3

Ib R=Me

IIb RL=4–Pyrenyl

rt

11%

11%

4

Ic R=i-Pr

IIa RL=1–Napthyl

rt

NR

--

5

Id R=t-Bu

IIa RL=1–Napthyl

rt

NR

--

6

Ic R=i-Pr

IIa RL=1–Napthyl

60

NR

--

7

Id R=t-Bu

IIa RL=1–Napthyl

60

NR

--

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


Page 21 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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 4-Tol

starting from –product

4-Tol

13a to give (aR)-product

4-Tol

15a and Path b starting from

4-Tol

13b to give (sR)

15b, 4-Tol＝p–MeC6H4) were located. As shown in Figure 9a, in both pathways, the

π–complexes (4-Tol13a and

4-Tol

13b) with naphthyl substituent at the different orientations are

converted to the seven-membered nickelacycle intermediates 4-Tol14a and 4-Tol14b via transition state 4-Tol

TS13a and

4-Tol

4-Tol

TS13b, which followed by the reductive elimination to yield the (aR)–product

15a and (aS)–product 4-Tol15b, 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 Ni-C 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

4-Tol

TS13a vs.4-TolTS13b; –1.0 vs. 3.4 kcal/mol in

gas phase and 0.8 vs. 3.4 kcal/mol in 1,4–dioxane for 4-TolTS14a vs.4-TolTS14b); 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 (4-TolTS13a and 4-TolTS14a, 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


Me

TS13a and

ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Me

TS13b in the rate-limiting 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 t-BuTS13a 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.


Page 22 of 30

Page 23 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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 methyl-benzotriazinone, (vaules are given in kcal/mol, the activation free energy in solvent (1,4–dioxane) are given in paretheses).

2.03

1.99

1.93

4-Tol

4-Tol

TS13a

O

TS13b

O N

Rs

Steric hindranc e

2.08

N Rs

Ni

N

N

O

Ni

N

N

O

O

ring ring repulsion

O

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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 rate-determining 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. 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.


Page 24 of 30

Page 25 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

ASSOCIATED CONTENT

Supporting Information Cartesian coordinates, total free energies (Hartree/Particle) of all stationary points calculated at M06L/6-311G(d) level and optimized structures for Ni(0)-catalyzed denitrogenative transannulation of N-substituted 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 [email protected] [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Financial support from the 100-Talent 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


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(JCYJ20150430160022517) and South University of Science and Technology of China (FRG-SUSTC1501A-16).

REFERENCES (1) (a) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597‒606. (b) Greenham, N. C.; Moratti, S. C.; Bradley, D. D. C.; Friend, R. H.; Holmes A. B. Nature 1993, 365, 628‒630. (2) (a) Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2013, 52, 1371‒1373. (b) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757‒4759. (c) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463‒4466. (d) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746‒3749. (e) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394‒5396. (e) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394‒5396. (3) (a) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2013, 52, 1507‒1510. (b) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc. 2013, 135, 4652‒4655. (c) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 14972‒14974. (d) Chuprakov, S.; Kwok, S.W.; Zhang, L.; Lercher, L.; Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034‒18035. (e) Grimster, N.; Zhang, L.; Fokin, V. V. J. Am. Chem. Soc. 2010, 132, 2510‒2511. (f) Chuprakov, S.; Malik, J. A.; Zibinsky, M.; Fokin, V. V. J. Am. Chem. Soc. 2011, 133, 10352‒10355. (g) Selander, N.; Worrell, B.T.; Chuprakov, S.; Velaparthi, S.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 14670‒14673. (4) (a) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Comm. 2009, 1470‒1471.


Page 26 of 30

Page 27 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

(5) For a review, see: (a) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 862‒872. (6) (a) Yamauchi, M.; Morimoto, M.; Miura, T.; Murakami, M. J. Am. Chem. Soc. 2010, 132, 54‒55. (b) Miura, T.; Morimoto, M.; Yamauchi, M.; Murakami, M. J. Org. Chem. 2010, 75, 5359‒5362. (c) Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955‒4957. (d) Miura, T.; Nishida, Y.; Morimoto, M.; Yamauchi, M.; Murakami, M. Org. Lett. 2011, 13, 1429‒1431. (e) Miura, T.; Tanaka, T.; Yada, A.; Murakami, M. Chem. Lett. 2013, 42, 1308‒1310. (f) Miura, T.; Funakoshi, Y.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 2272‒2275. (7) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10, 3085‒3088. (8) Fang, Z.-J.; Zheng, S.-C.; Guo, Z.; Guo, J.-Y.; Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2015, 54, 9528‒9532. (9) (a) Xie, H.; Sun, Q.; Ren, G.; Cao, Z. J. Org. Chem. 2014, 79, 11911−11921. (b) Poater, A.; Vummaleti, S. V. C.; Cavallo, L. Organometallics. 2013, 32, 6330−6336. (c) Guan, W.; Sakaki, S.; Kurahashi, T.; Matsubara, S. Organometallics. 2013, 32, 7564−7574. (d) Meng, Q.; Li, M. J. Mol. Model. 2013, 19, 4545−4554. (10) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G.W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J.


ACS Catalysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian, Inc.: Wallingford, CT, 2013. (11) (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput. Chem. 2011, 32, 1456‒1465. (12) (a) Zhao, Y.; Truhlar, Donald G.; Theor. Chem. Account. 2008, 120, 215‒241. (b) Zhao, Yan;. Truhlar, Donald G. J. Phys. Chem. A. 2006, 110, 13126‒13130. (c) Romain, S.; Bozoglian, F.; Sala, X.; Llobet, A.; J. Am. Chem. Soc. 2009, 131, 2768 –2769. (d) Guan, X.; Chan, S. L. -F.; Che, C. -M. Chem. Asian J. 2013, 8, 2046–2056. (e) Zhang, L.; Wang, Y.; Yao, Z. -J.; Wang, S.; Yu, Z. -X. J. Am. Chem. Soc. 2015, 137, 13290‒13300. (f) Benighaus, T.; DiStasio, R. A.; Lochan, R. C.; Chai, J. D.; Head-Gordon, M. J. Phys. Chem. A. 2009, 112, 2702‒2712. (g) Zhang, W. J.; Truhlar, D. G.; Tang, M. S. J. Chem. Theory. Comput. 2013, 9, 3965‒3977. (13) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B. 2009, 113, 6378‒6396. (14) Legault, C. Y. CYLview, 1.0b; Universite de Sherbrooke, 2009. http://www.cylview.org.


Page 28 of 30

Page 29 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

(15) Johnson, E. R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcíá, J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498−6506. (16) Lu, T.; Chen, F. J. Comput. Chem. 2012, 33, 580−592. (17) (a) For optimized structures, see Figure S1. (b) For optimized structures and energy profiles of denitrogenative process, see Figure S2–S4 of Supporting Information. (c) For optimized structures, see Figure S5. (d) The FMO calculation and the detailed discussion, see Figure S6. (e) For optimized structures and energy profiles, see Figure S7–S11. (18) (a) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127, 3252‒3253. (b) Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634‒12635. (c) Geny, A.; Lebœuf, D.; Rouquié, G.; Vollhardt, K. P. C.; Malacria, M.; Gandon, V.; Aubert, C. Chem. Eur. J. 2007, 13, 5408‒5425.


ACS Catalysis

Table of Contents Graphic:

ec M

Re

rb om

eta

lat

ion

gio

se

se rti o

ti v e

el

in

uc

im

in

nd

ed

Ca

ive at

at

lec ti v ity

bo

R

i

tro

n ge

ac ti v i ty

n

n De

Re

sm ni ha

io n

Ni -C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 30

t an En

ios

c ele

tiv

ity


Nickel(0)-Catalyzed Denitrogenative Transannulation of

Recommend Documents