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Mechanism of Rhodium(III)-Catalyzed C-H Activation/Annulation of Aromatic Amide with #-Allenol: A Computational Study Ruixue Tian, Yan Li, and Changhai Liang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03078 • Publication Date (Web): 08 Feb 2019 Downloaded from http://pubs.acs.org on February 9, 2019

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The Journal of Organic Chemistry

Mechanism of Rhodium(III)-Catalyzed C−H Activation/Annulation of Aromatic Amide with α-Allenol: A Computational Study

Ruixue Tian†,||, Yan Li*,‡,||,Changhai Liang†

†School

of Petroleum and Chemical Engineering, Dalian University of Technology, Panjin, 124221, P. R. China

‡School

of Chemical Engineering, University of Science and Technology Liaoning, Anshan, 114051, P. R. China

Corresponding person: Yan Li E-mail: [email protected] Telephone: 86-18741219506 Fax: 86-427-2631111

ACS Paragon Plus Environment

The Journal of Organic Chemistry 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

Table of Contents O

OMe

N

Path a

Rh Cp* O NHOMe H

O

2HOAc

+

N Cp* Rh H

RhCp*(OAc)2 +

O

Ph

O

OMe

OMe

Path b

N H Rh Cp*

RhCp*

O N

Ph

Ph •

H OH

OMe

O

Ph

O

Ph

O O

Path c

OMe N

Cp* Rh H

O

Ph


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Abstract With

the

help

of

DFT

calculations,

the

reaction

mechanisms

of

the

rhodium(III)-catalyzed C−H activation/annulation between aromatic amide and α-allenol leading to the formation of isoindolinone have been theoretically investigated. Our calculated results show that the catalytic cycle consists of four stages: N−H deprotonation and C−H activation (Stage I), allene insertion, rearrangement and isomerization (Stage II), β−H elimination and enol-keto tautomerism (Stage III), and catalyst regeneration resulting in the five-membered ring product (Stage IV). For Stage IV, besides the reaction paths proposed by the experimentalists, i.e., the insertion and reductive elimination (labeled as path a) and the reductive elimination and hydroamination (labeled as path b), an alternative path which involves C−N and C−H reductive eliminations (labeled as path c) was proposed and examined. The computational results show that the newly established path c is more energetically favorable than the reaction paths proposed by the experimentalists (paths a and b). The allene (non-terminal double bond) insertion step contributes to the rate-determining step with an overall activation free energy of 24.6 kcal/mol. Our study is beneficial for a better comprehension of the reaction mechanisms and provides a significant suggestion for further developments of similar reactions. Keywords C−H activation, annulation reaction, density functional theory (DFT), reaction mechanism, rhodium



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1. Introduction The isoindolinone core unit is often presented in many kinds of natural products,1 pharmaceuticals,2 and biologically active molecules.3 It can be used as a crucial synthetic intermediate for various highly useful organic molecules and natural products.4 Therefore, the progress of the effective approaches for preparation of such structure motifs is of particular interest in organic synthesis. Especially, transition metal-catalyzed C−H activation/annulation reflects a step- and atom-economical route for the generation of isoindolinone.5 A wide diversity of transition-metal catalysts, including copper,6 nickel,7 ruthenium,8 rhodium,9 palladium,10 and cobalt11 have been applied in these types of reactions. Among them, rhodium complexes have gained much attention during the last two decades because they are highly efficient and generally only require mild reaction conditions.12 Allenes, a kind of compounds involving two accumulated carbon–carbon double bonds, are vital intermediates in organic synthesis due to their rich structural and reactive properties.13 Allenes have been widely recognized to participate in an extensive range of chemical transformations.14 So far, many experimental research15 have been reported on the rhodium-catalyzed C−H activation/annulation of allenes. For example, Casanova and co-workers explored the synthesis of 2,2-disubstituted 2H-chromenes through rhodium-catalyzed [5+1] annulations of 2-alkenylphenols with allenes.16 Wang and co-workers investigated that rhodium-catalyzed C–H activation/cyclization between α-diazo-β-keto and N-nitroso can form indole skeletons.17

The

intramolecular

[5+2]

cycloaddition

between

allene

and

3-acyloxy-1,4-enyne catalyzed by the rhodium complex has been realized by Song and co-workers.18 Comparison with lots of experimental research, theoretical research19 on this type of reaction have been less studied. Wu and co-workers investigated the mechanisms for the formation of lactams via a rhodium-catalyzed [4+2+2] cycloaddition between 3-acyloxy-1,4-enyne and N-pivaloyloxy benzamides based on DFT calculations, and their results revealed the role of the N−OR (R = Piv or Me) moiety on reaction selectivity.20 Wang and co-workers explored the mechanisms and origins of selectivity in [3+2] annulations between vinylaziridines


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and allenes catalyzed by the rhodium complex using DFT calculations, and their results were in line with the high regio-, E/Z-, and diastereo-selectivity observed by the experimentalists.21 Recently,

Zhou

and

co-workers

reported

a

rhodium(III)-catalyzed

C−H

activation/annulation of aromatic amide with α-allenol leading to isoindolinone in acetonitrile solution (CH3CN) at room temperature (Scheme 1).22 In the light of experimental outcomes, the authors suggested a plausible mechanism (shown in Scheme 2). In the proposed mechanism, an active catalyst Cp*Rh(OAc)2 (A) is initially formed through anion exchange when there is AgOAc in the system. Next, the active catalyst A reacts with amide through a C−H activation process giving allylc rhodium intermediate B and two molecules of HOAc. Subsequently, double bond insertion of allene into the Rh−C bond provides seven-membered rhodacycle intermediate C. Then, β−H elimination from C gives intermediate D, from which enol-keto tautomerism occurs to afford intermediate E. Once intermediate E is generated, there are two plausible mechanistic paths to suppose: (1) double bond insertion into the H−Rh bond provides access to intermediate F, which upon reductive elimination yields the five-membered ring product P together with RhCp* species (labeled as path a, Scheme 2); (2) intermediate E delivers RhCp* species and o-alkenyl benzamide intermediate G via reductive elimination process. Subsequently, intramolecular hydroamination takes place to give the final product P (labeled as path b). Scheme 1. Rhodium(III)-catalyzed C−H activation/annulation between aromatic amide and α-allenol. O O NHOMe

+

•

Ph

[Cp*RhCl2]2 AgOAc

OH

CH3CN, rt

NOMe

O

Ph

Although the mechanisms for rhodium(III)-catalyzed C−H activation/annulation of aromatic amide with α-allenol have been purposed, the details are not yet clear. In particular, unclear issues refer to the following questions: how does the catalytic cycle



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happen detailedly? Which step is the rate-determining step? Why are there no possible six-membered ring products observed experimentally? For the sake of answering these questions, a detailed study for the reaction mechanism is highly desirable. A theoretical understanding of the details of the reaction mechanism is extremely beneficial for efficient experiments. Unfortunately, to the best of our knowledge, theoretical investigation on the mechanism of rhodium(III)-catalyzed C−H activation/annulation reaction proposed by Zhou and co-workers has not been reported by now. Scheme

2.

The

activation/annulation

reaction

mechanism

between

aromatic

for

the


amide

and

α-allenol

proposed

by

C−H the

experimentalists. PhCONHOMe

R1 O

2HOAc

Cp*Rh(OAC)2

AgOAc

A

O

NOMe

NOMe

RhI

P

Ph

P

RhIII

O

B

R2

O NOMe RhIII

O NHOMe

G

NOMe RhIII

Ph

OH

Ph

Path b

Path a

C

Ph

O

O

NOMe RhIIIH

NOMe RhIIIH

OH

O

E

OH

O

O

F

O

Ph

•

Ph

D

Ph

Herein, we present the first computational investigation on the mechanisms involved in rhodium(III)-catalyzed C−H activation/annulation between aromatic amide and α-allenol. We plan to afford the details of the reaction mechanism for the title reaction and make previous experimental observations reasonable. We hope the calculated results will provide helpful implications for the mechanism of rhodium(III)-catalyzed


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C−H activation/annulation between aromatic amide and α-allenol, which may be beneficial for the further advance of this and other related reactions. 2. Computational details The Gaussian 09 program suites23 were utilized for all of the calculations implemented here. The geometries of all complexes were entirely optimized at the density functional theory (DFT)24 level employing M06-2X25 hybrid functional. In the DFT calculations, the Rh atom was treated with the effective core potential (ECP) basis set LanL2DZ26, and added a polarization function (ζf =1.350).27 All remaining atoms were treated with the 6-31G* basis set.28 Vibrational frequency calculations were conducted at the same level of theory to verify all the optimized geometries as minima (no imaginary frequencies) or transition states (only one imaginary frequency), and thermodynamic corrections at 298.15 K and 1 atm. The structures of transition states were verified to correctly connect two relevant minima by the intrinsic reaction coordinate (IRC) calculations.29 For purpose of acquiring better accuracy, the SMD solvation model30 was applied to perform single-point self-consistent reaction field (SCRF) calculations. Corresponding to the experimental conditions, acetonitrile was used as the solvent. To carry out SCRF calculations, we used the same method with a larger basis set in which the basis set for Rh retains unaltered whereas the basis set for remaining atoms is increased to 6-311++G**.31 The calculated solvation-corrected free energies were utilized for discussion over all the paper. 3. Results and discussion In the light of the experimental findings22 and our calculated results, a detailed mechanism explaining the rhodium(III)-catalyzed C−H activation/annulation between aromatic amide and α-allenol for the synthesis of isoindolinone is shown in Scheme 3. In experiment, the reaction was conducted in the existence of excess AgOAc additive and a catalytic amount [RhCp*Cl2]2.22 In our calculations, the acetate-ligated species Cp*Rh(OAc)2 (A), depicted in Scheme 3, was used as the real catalyst, because it can be formed by exchanging the ligand between [RhCp*Cl2]2 and acetates.



Scheme

3.

The

calculated

mechanisms

for

the

Page 8 of 27


C−H

activation/annulation between aromatic amide and α-allenol. O

Stage I

RhCp*(OAc)2 +

A

OMe OAc 1 N Rh Cp* 2 H 1OAc

1 7 NHOMe 2 H1

R1

Ph O OMe 3 4 5 6 • H2 N 5OH3 2 Rh R2 Cp*

1

O 1 2 3

J O

OMe N Rh Cp*

4 5

1 2

6 OH

Ph

3

C1

O

D

1 2

2

4 5 Ph

OMe N Rh Cp*

B O

OMe N 5 Ph 4 6 3 O

1 2

P1

OMe 1 N 2 Rh Cp* 4 5 H2 3 6 Ph OH 5

OH 6 5

C1 O OMe 3 HOAc 1 N Cp* 2 4 RhH2 3 5 H' O'' 6 H O' Ph O 5 3

D2

D1 O

Path a

O

O

OMe N Rh Cp*

O OMe 1 N Cp* 2 4 RhH2 3 5 H' '' O 6 O ' Ph 5 H O 3

OMe 'HOAc N Cp* RhH2 4 5 6 3 OH3 5 Ph

1

K

C

B2

1 2

13 HOAc

O OMe RhCp* 1 N Rh Cp* 2 4 5 3 6 Ph HO

O OMe 1 N 2 Rh Cp* 3 4 5 6 Ph HO

I

Path II

Stage III

2 H1

OMe Cp* N Rh 3O O 4

A3

O OMe 1 N 2 Rh Cp* 3 4 5 6 Ph HO

B

O OMe 1 N 2 Rh Cp* 4 5 H2 3 6 Ph OH 5

O 1

A1

Path I

Stage II

1 HOAc

O

5

O OMe 1 N Cp* 2 4 RhH2 3 5 6 O Ph

E

OMe N Rh Cp*

3 4

RhCp*

5 6 Ph

O

F O

Stage IV

OMe 1 7 N Cp* 2 4 RhH 2 3 5 6 O Ph

Path b

E

O OMe 1 N H2 2 4 Rh 3 Cp* 5 6 Ph O

O

RhCp*

G

Path c

OMe 1 N H2 24 3 5 6 Ph O

G1

O 1 N OMe 24 5 6 Ph 3 O

P2

O OMe 17 N Cp* 24 RhH2 5 O

6

3 Ph

RhCp*

M

As depicted in Scheme 3, the reaction mechanism is composed of four stages: N−H deprotonation and C−H activation (Stage I), allene insertion, rearrangement and isomerization (Stage II) , β−H elimination and enol-keto tautomerism (Stage III) and formation of the five-membered ring product (Stage IV). The corresponding energy profiles are given in Figures 1-4 (Stages I-IV). As described in Figures 1-4, the free energy of Cp*Rh(OAc)2 is set as the reference (0.0 kcal/mol). For simplicity of


Page 9 of 27

presentation, the reactants N-methoxybenzamide and 1-phenylbuta-2,3-dien-1-ol are expressed as R1 and R2, respectively. In the next section, we will explore the details of the title reaction mechanism and discuss it in the light of four stages: 3.1 Stage I: N−H Deprotonation and C−H Activation As depicted in Figure 1, R1 initially coordinates to the Rh center of the active catalyst Cp*Rh(OAc)2 with the N atom to generate intermediate A1, in which both acetate ligands are monodentate. This step is determined to be slightly endergonic by 4.6 kcal/mol. The subsequent step is N−H deprotonation in A1 by one of the acetate ligands through transition state TSA1-A2 to give intermediate A2. The release of one molecule of HOAc affords intermediate A3. For intermediate A3, the distances of the Rh−C2 and Rh−H1 bonds are 3.426 and 2.991 Å, respectively (see Figure 1), indicating that the Rh center has no interaction with the ortho C2−H1 bond.

30.0

O OMe

ΔG kcal/mol

1 O

OMe OAc 1 N Rh Cp* 2 H OAc

10.0

R1 0.0

OMe OAc 1 N Rh Cp* 2 O2 HO 1

O

20.0

0.0 RhCp*(OAc)2 A

O 1

-10.0 O R1 =

O3

A2 5.5

5.2

2

1H

TSA3-A4 20.1

H

OMe OAc HOAc 1 N Rh Cp* O 1

H 1.057 O1 1.623

A1

O OMe N Rh

2

O

1

O2

2 H1

OMe Cp* N Rh 3O

4O

C2

O3 H13.426 2.182 1.085

A3

Cp*

1HOAc O OMe 3

1

N Rh Cp*

1HO 3

Rh 2.197 O4 2.233

B -0.5

A4 -2.3

2

2.149 O2

N

2.256

O 3

A3 0.7

1 7 NHOMe 2 H1

2.071 Rh O4

Rh Cp* O4

1

TSA1-A2

A1 4.6

N

2

2.991

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


2.266

O4

Rh

C2 H1 1.344 1.292 O3

2.271 2.163 O4

TSA3-A4

Figure 1. Free energy profile and critical structures for stage I (N−H deprotonation and C−H activation). The relative free energies are shown in kcal/mol. The lengths are shown in angstrom (Å).



Then intermediate A3 experiences a metalation−deprotonation process via the six-membered ring transition state TSA3-A4. As depicted in Figure 2, the length between C2 and H1 is prolonged from 1.085 Å in A3 to 1.344 Å in TSA3-A4, whereas the length between H1 and O3 is reduced from 2.182 Å in A3 to 1.292 Å in TSA3-A4, in the mean time, the length between Rh and C2 is reduced from 3.426 Å in A3 to 2.266 Å in TSA3-A4. Intrinsic reaction coordinate (IRC) calculations reveal that migration of the hydrogen (H1 atom) is accompanied by the generation of Rh−C2 bond in the process of A3→TSA3-A4→A4. This step affords the five-membered rhodacyclic intermediate A4, in which HOAc is still bound to Rh. The free energy of TSA3-A4 is 20.1 kcal/mol and metalation−deprotonation step is exergonic by 3.0 kcal/mol (see Figure 2). Finally, intermediate A4 releases one HOAc molecule to generate the allylc rhodium intermediate B. 3.2 Stage II: Allene Insertion, Rearrangement and Isomerization As depicted in Scheme 3, either C3=C4 or C4=C5 double bond of allene R2 can insert into Rh−C2 bond of intermediate B, two insertion paths (paths I and II) are therefore explored. As depicted in Figure 2, the coordination of R2 to the Rh center of intermediate B affords intermediates H (path I) and B1 (path II). Subsequently, when allene (C3=C4 bond) inserts into Rh−C2 bond of H through transition state TSH-I forms seven-membered rhodacycle intermediate I (path I). The activation free energy for the C3=C4 bond insertion is 17.6 (TSH-I) kcal/mol with respect to intermediate B. In the other path, the C4=C5 double bond of R2 inserts into Rh−C2 bond of intermediate B1 through transition state TSB1-B2 generates the seven-membered rhodacycle B2 (path II). The activation free energy for the C4=C5 bond insertion is 22.8 (TSB1-B2) kcal/mol with respect to intermediate B. What become clear is that the activation free energy of the C3=C4 bond insertion is 5.2 kcal/mol lower than that of C4=C5 bond insertion. The structure results show intermediates I and B2 have a puckered ring structure with the Rh center being weakly coordinated with the aryl moiety that is part of the metallacycle ring. As depicted in Figure 2, the bond distances of Rh−C1 and Rh−C2 are 2.688 and 2.605 Å in I, and 2.808 and 2.632 Å in B2, respectively. Then, a


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structural rearrangement of metalla-cycle ring in intermediates I and B2 leads to intermediates J and C, respectively through eliminating the weakly coordinated aryl ΔG kcal/mol

Path I Path II

O N

2 O

50.0

1

N

2 40.0

HO

OH

1

Rh Cp*

2

20.0

TSB1-B2 22.3

3

4 5 6 Ph

10.0

R2

OH

B1 6.8

3

1

-10.0 2

HO 3 4 R2 = •

5 6

O 2

3 4 5

Ph H2 5OH 3

HO

6 Ph

1 2

OMe N Rh

4 5 6

3

Cp*

Rh 4 5

6 OH 5

O

C -1.8

O

O

OMe

K -6.1

3

OMe N

1 2

J -10.5

TSI-J -8.0

Cp* H2

Ph

C1 10.0

OH

OMe N

Rh 4 5 HO

Cp*

6 Ph

OMe N Rh Cp* 3 4 5 6 Ph HO

N Rh Cp* 3 4 5 6 Ph HO

1 2

1 2

3.415

2.808 C1 C2

6 Ph

HO

O

TSB2-C -1.0

OMe N Rh Cp*

1

Rh

Rh

Rh C5 3 49

2.632

C4 1. 1.510

C1 C2

2.383 2.970 H2

O5

3.424

B2

TSB1-B2

2.214 1.138 H2

3.730 O5

C1

C

3.426

2.688

C1 C2

Rh C1 C2

O

I -11.4

2.120 C2Rh 2.104 C5 1.975 C4 1.411

Ph

B2 -2.7

6 Ph

5

4

3

C

Ph

5

OH 6 5

TSJ-K 51.9

6 OH

3

Rh Cp* 3 4

Ph

1 2

N

4 5

Cp*

OMe N Rh Cp*

1 2

Rh Cp*

TSH-I 17.1

R2 O OMe

Rh

OMe

4 5

B2

H 3.5

B 0.0 -0.5

N

N

2

N

3

O

1

Ph O OMe

30.0

Cp*

O

OMe

1 2

6 Ph

Rh Cp*

4 5 6

3

Rh 3 4 5

OMe

O

OMe

1

C4

C3 1.529 1.514

I

2.605

Rh

2.150 C2

Rh

3.418

1.980 C4

1.989 C3 1.426

J

TSH-J

Figure 2. Free energy profile and critical structures for stage II (allene insertion, rearrangement and isomerization). The relative free energies are shown in kcal/mol. The lengths are shown in angstrom (Å).



moiety. The activation free energies of TSI-J and TSB2-C are 3.4 and 1.7 kcal/mol, respectively. The bond lengths of Rh−C1 and Rh−C2 are 3.426 and 3.418 Å in J, and 3.415 and 3.424 Å in C (depicted in Figure 2), demonstrating that Rh metal center of intermediates J and C has no coordination with the aryl moiety. Subsequently, intermediate J further isomerizes to the six-membered ring intermediate K via a three-membered ring (C2C3C4) transition state TSJ-K, which has calculated activation free energy of 62.4 kcal/mol. The high activation free energy of TSJ-K (62.4 kcal/mol) demonstrates that this path is kinetically unfeasible. Therefore, we can easily deduce that the six-membered ring product P1 can not be formed under experimental conditions, which is consistent with the experimental observations. As for path II, the O5-coordinated intermediate C will further convert to the H2-coordinated intermediate C1, this transformation is endergonic by 11.8 kcal/mol (see Figure 2). The bond lengths of Rh−O5 and Rh−H2 are 2.383 and 2.970 Å in C, and 3.730 and 2.214 Å in C1. It should be noted that for the transformation of C→C1, we can not locate the corresponding transition state despite lots of attempts. We scanned the changes of Rh–O5 bond at the M06-2X level, and the corresponding pointwise potential curve for different Rh–O5 distances was shown in Figure S1. Taken together, for Stage II, although the activation free energy of the C3=C4 bond insertion (17.6 kcal/mol, path I) is lower than that of the C4=C5 bond (22.8 kcal/mol, path II), the high activation free energy of TSJ-K in path I rules out this path. Therefore, we will only discuss the reaction paths associated with intermediate C1 in the following section. 3.3 Stage III: β−H Elimination and Enol-keto Tautomerism Once intermediate C1 is generated, the next step is β−H elimination and enol-keto tautomerism. Firstly, C1 undergoes the migration of H2 atom from C6 atom to the Rh atom concerted with the cleavage of the Rh−C5 bond to produce intermediate D through four-membered ring (C5C6H2Rh) transition state TSC1-D. The length of C6−H2 bond is prolonged from 1.138 Å in C1 to 1.499 Å in TSC1-D, while the length of Rh−H2 bond is gradually reduced from 2.214 Å in C1 to 1.637 Å in TSC1-D, in the mean time, the length of Rh−C5 bond is prolonged from 2.132 Å in TSC1-D to 2.568 Å


Page 12 of 27

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in D (see Figures 2 and 3). IRC calculations of TSC1-D reveal that the migration of the hydrogen (H2 atom) and the cleavage of Rh−C5 bond occur via a concerted manner. The activation free energy of TSC1-D amounts to 9.9 kcal/mol and β−H elimination step is slightly exergonic by 2.1 kcal/mol. O OMe

ΔG kcal/mol

N

1 2

TSC1-D 19.9

20.0

10.0

0.0

-10.0

C1 10.0

O

Rh

Cp* H2

6 OH3 Ph 5

Cp*

4 5 Ph

H2 6

OH

15.7

D 7.9

'HOAc O

O OMe

N 4 5

OMe N Cp* 1 RhH2 2 4 3 5 H' O'' 6 TSD1-D2 O H O' Ph 5 3

Rh

OMe

1 2 3

3

O

1 2 3

D1 Cp* -2.6

N

4 5 6 Ph

OH3 5

O 1 2 5 6 Ph

Rh C5 2.132 1.439

1.637 H2 1.499 C6

TSC1-D

D2 -7.0

RhH2

H2 C5 2.661 C6

Rh 2.568 1.366

D

O

OMe

N Cp* RhH2 4 3 H' O'' O H O' 5 3

3 HOAc

1 2 5

OMe N Cp* RhH 2 4 3 H' O''

6 Ph

E -18.6

OMe N Cp* 1 RhH2 2 4 3 5 6 Ph 5O

O H O' 5 3

1.235 1.385 H' O'' C5 O' H3 1.202 O5 1.218

TSD1-D2

1.097 C5

H'2 .3

74 O'' O' 1.925 H3 0.984 O5

D2

Figure 3. Free energy profile and critical structures for stage III (β−H elimination and enol-keto tautomerism). The relative free energies are shown in kcal/mol. The lengths are shown in angstrom (Å).

Subsequently, intermediate D experiences an enol-keto tautomerization assisted by a HOAc molecule. As depicted in Figure 3, a HOAc-assisted proton transfer takes place through transition state TSD1-D2 to give the intermediate D2, followed by release of HOAc leading to the generation of the intermediate E. As depicted in Figure 3, the length of O5−H3 bond is gradually prolonged from 1.218 Å in TSD1-D2 to 1.925 Å in D2, and the length of H3−O′ bond is reduced from 1.202 Å in TSD1-D2 to 0.984 Å in D2. In the meantime, the length of O′′−H′ bond is gradually prolonged from 1.235 Å



in TSD1-D2 to 2.374 Å in D2, and the length of H′−C5 bond is reduced from 1.385 Å in TSD1-D2 to 1.097 Å in D2. These results indicate that the transfer of H3 proton from O5 atom to O′ atom and the transfer of H′ proton from O′′ atom to C5 atom occur through a concerted manner. The conversion of D to E has an activation free energy of 18.3 kcal/mol and is exergonic by 26.5 kcal/mol. 3.4 Stage IV: Formation of the Five-Membered Ring Product In this stage, we first evaluate the feasibility of the two reaction paths (paths a and b) proposed by the experimentalists (shown in Scheme 2). As shown in Figure 4, path a (black line) involves the double bond insertion and reductive elimination. First, the C3=C4 double bond in intermediate E inserts into the Rh−H2 bond through transition state TSE-F to afford the intermediate F. The activation free energy of TSE-F is determined to be 17.7 kcal/mol and the double bond insertion step is exergonic by 10.6 kcal/mol. Subsequently, F experiences reductive elimination to yield the five-membered ring product P2 together with RhCp* via the transition state TSF-P2 with an activation free energy of 53.1 kcal/mol. Similar to path a, path b (blue line) also consists of two processes. First, intermediate E experiences reductive elimination through transition state TSE-G to deliver intermediate G, which upon releases of RhCp* generates the o-alkenyl benzamide intermediate G1. The activation free energy of the TSE-G amounts to 23.9 kcal/mol. Subsequently, intermediate G1 undergoes a concerted process involving the proton H2 transfers from N atom to C3 atom and the formation of C4−N bond. The length of N−H2 bond is gradually prolonged from 1.648 Å in TSG1-P2 to 2.714 Å in P2, and the length of H2−C3 bond is reduced from 1.253 Å in TSG1-P2 to 1.093 Å in P2, in the mean time, the length of C4−N bond is reduced from 2.371 Å in TSG1-P2 to 1.464 Å in P2 (see figure 4). According to our calculated results, this step needs to overcome an activation free energy of 52.8 kcal/mol. As discussed above, the activation free energies for the reaction paths a and b proposed by the experimentalists are 53.1 and 75.9 kcal/mol, respectively, which seemed to be so high that the rhodium(III)-catalyzed C−H activation/annulation can


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Page 15 of 27 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


not take place under the experimental conditions (room temperature). Therefore, we propose a new path (labeled as path c) (as shown in Scheme 3). 60.0

ΔG kcal/mol

O N

1 2

50.0

Rh

3 4

1 2

Cp*

O 1 2

20.0

6

O

Path b 0.0

-30.0

O

O

OMe

N Cp* 1 7 RhH2 2 4 3 5 6 Ph O

2.141

1 2 4 5

Rh 3

1.653 H2 1.461 C3 1.432

TSE-F

N C4

3

Ph

O

TSE-M 2.9

RhCp*

OMe

Ph

TSF-P2

N 4 6

H2

Cp*

H2

OMe N Rh

4

3

23.9

3

O

O

OMe 1 N 2 4 5 6 Ph 3 O

TSM-P2 0.6 O

OMe 1 7 N Rh Cp* 2 4 H2 3 5 6 Ph O

Cp*

5 6 Ph

RhCp*

Ph

G1 4.5

M -12.0

RhCp*

P2 -12.3

F -29.2

Ph

Rh

2.155 N

2.131 2.567 2.101

N

Rh H2 1.624

C4

TSE-G

TSF-P2

C4

N 1.648 H2 1.253 C3 C4 1.406

2.371

1.357

TSG1-P2

1.464

2.272 1.529 Rh N 2.038 C3 1.419

6

1 2

G -8.0

Rh

C4

1 2 5

OMe

N

6 O

6

O

TSE-F -0.9

-10.0

-20.0

5

O

H2 3

O

O OMe

Cp* 1 7 N 2 4 RhH2

TSE-G 5.3

1 24 5

Ph

O

OMe N

M

O

Ph

57.3

3

6

OMe

Path c

E -18.6

Ph

O

N H2 Rh 4 3 Cp*

5

Path a

5

O

TSG1-P2

OMe

Cp* 1 7 N 2 4 RhH 2

G

30.0

10.0

N H2 Rh 3 Cp*

6

F

O

OMe

4

5

5 6 Ph

O

40.0

O

OMe

2.286

H2 1.538 2.330 C3

Rh

N

N

1.608 H2

C4

1.446 C3 2.191

2.052

2.714 H2 1.093 C3

1.528

TSE-M

M

TSM-P2

P2

Figure 4. Free energy profile and critical structures for stage IV (formation of the five-membered ring product). The relative free energies are shown in kcal/mol. The lengths are shown in angstrom (Å).



As depicted in path c, intermediate E undergoes successive C−N and C−H reductive eliminations to afford the five-membered ring product P2. As depicted in Figure 4 (red line), intermediate E first undergoes C−N reductive elimination through a five-membered ring (C1C2C4NC7) transition state TSE-M to afford intermediate M. The distance between C4 and N is shortened from 2.038 Å in TSE-M to 1.529 Å in M, whereas the distance between C3 and C4 is elongated from 1.378 Å in E to 1.419 Å in TSE-M, then to 1.528 Å in M. The structural results imply that the C4−N bond is generated and the C3=C4 double bond transforms a single bond in C−N reductive elimination process. The activation free energy of TSE-M amounts to 21.5 kcal/mol and C − N reductive elimination step is endergonic by 6.6 kcal/mol (see figure 4). From intermediate M, the C−H reductive elimination is found to occur via the transition state TSM-P2, in which the H2 atom connected to the Rh center transfers to C3 atom accompanied by the cleavage of Rh−N bond, resulting in the generation of product P2 and regenerating RhCp*. The length of Rh−H2 bond is prolonged from 1.538 Å in M to 1.608 Å in TSM-P2, whereas the length of H2−C3 bond is reduced from 2.330 Å in M to 1.446 Å in TSM-P2, in the mean time, the length of Rh−N bond is prolonged from 2.272 Å in M to 2.286 Å in TSM-P2 (see Figure 4). IRC calculations reveal that the hydrogen (H2 atom) migration is concerted with the liberation of RhCp* resulting in the cycloaddition product P2. The activation free energy of TSM-P2 is 12.6 kcal/mol and the C−H reductive elimination step is slightly exergonic by 0.3 kcal/mol (see figure 4). Taken together, the activation free energies for the reaction paths a and b proposed by the experimentalists are inaccessibly high. Considering that the experiment was performed at room temperature, we can easily deduce that paths a and b are not possible under experimental condition. The newly proposed path c is found to be the most preferred path for Stage IV. As depicted in Figures 1-4, the allene (non-terminal double bond) insertion step contributes to the rate-determining step for the title reaction with an overall activation free energy of 24.6 kcal/mol, which corresponds to the energy difference of TSB1-B2 and intermediate A4. 4. Conclusion


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With the help of DFT calculations, we have investigated and revised mechanism of the rhodium(III)-catalyzed C−H activation/annulation between aromatic amide and α-allenol. Our calculated results show that the title reaction proceeds via four stages (Stage I-IV). Stage I includes N−H deprotonation and C−H activation leading to allylc rhodium intermediate. For Stage II (sequential allene insertion, rearrangement and isomerization), two possible channels are examined considering that each double bond of allene can insert into the Rh−C2 bond. Insertion of the non-terminal double bond into the Rh−C2 bond is found to be more energetically favorable than that of the terminal double bond. Stage III (β−H elimination and enol-keto tautomerism) provides access to the o-alkenyl benzamide intermediate. Stage IV is the formation of the five-membered ring product and regeneration of catalyst. For this stage, two possible channels, i.e. the insertion and reductive elimination (labeled as path a) and the reductive elimination and hydroamination (labeled as path b) have been proposed by the experimentalists. However, our calculated results show that paths a and b are not possible under experimental conditions (room temperature) because of their inaccessibly high activation free energies (53.1 kcal/mol in path a, and 75.9 kcal/mol in path b). We have proposed an alternative channel which includes C−N and C−H reductive eliminations to form the final product. The mechanistic insights gained in the present paper should be beneficial for a better comprehension of the relevant rhodium(III)-catalyzed reactions.

ASSOCIATED CONTENT Supporting Information Figure S1, Cartesian coordinates, and energies of all of the stationary points in the reactions (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Author Contributions [||] Ruixue Tian and Yan Li contributed equally to this work.



Page 18 of 27

ORCID Yan Li: 0000-0002-1071-087X Changhai Liang: 0000-0001-7959-251X Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS This work is supported by the National Natural Science Foundation of China (Nos. 21403024), and National Supercomputing Center in Shenzhen. REFERENCES 1.

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