Mechanism and Origin of Stereoselectivity of Pd-Catalyzed Cascade

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Mechanism and Origin of Stereoselectivity of Pd-Catalyzed Cascade Annulation of Aryl Halide, Alkene and Carbon Monoxide via C-H Activation Xia Fan, Yuan-Ye Jiang, Ling Zhu, Qi Zhang, and Siwei Bi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00348 • Publication Date (Web): 19 Mar 2019 Downloaded from http://pubs.acs.org on March 20, 2019

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The Journal of Organic Chemistry

Mechanism and Origin of Stereoselectivity of Pd-Catalyzed Cascade Annulation of Aryl Halide, Alkene and Carbon Monoxide via C−H Activation Xia Fan†, Yuan-Ye Jiang*,†, Ling Zhu†, Qi Zhang‡, Siwei Bi*,† †School

of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, People’s Republic of China

‡Institute

of Industry & Equipment Technology, Hefei University of Technology, Hefei 230009, People’s Republic of

China

Table of Contents

1

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

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ABSTRACT: The combination of carbon monoxide with palladium chemistry has being demonstrated to be a promising tool for the synthesis of carbonyl compounds, and relative mechanistic studies are desirable to take this field one step further. In this manuscript, density functional theory (DFT) calculations were performed to investigate the mechanism and origin of stereoselectivity of Pd-catalyzed cascade annulation of aryl iodide, alkene, carbon monoxide to access the core of Cephanolides B and C. It was found that the favorable mechanism proceeds via oxidative addition of Ar−I bond, migratory insertion of C=C bond, CO insertion into Pd−(sp3) bond, Ar−H activation and C(sp2)−C(sp2) reductive elimination. The Ar−H activation is the rate-determining step and goes through I-assisted outer-sphere concerted metallation-deprotonation (CMD) mechanism. The C=C bond insertion is irreversible and controls the stereoselectivity. In contrast, other two pathways involving the direct Ar−H activation after the C=C bond insertion is less favored because of the following difficult CO insertion on palladacycle intermediate. Further calculations well reproduced the experimental results, which supports the rationality of our computation. Meanwhile, the influence of the steric effect of three substitution sites on the stereoselectivity was disclosed, which should be helpful to the further experimental design in the synthesis of analogues.

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1. Introduction Carbon monoxide are being widely applied as a highly atom economic and cheap C1 building block in transition-metal-catalyzed reactions in recent years.1 Insertion of carbon monoxide into metal-carbon bonds is a frequently-utilized strategy in these reactions while metal-carbon bonds are able to be generated from various of processes such as C−H activation,2 oxidative addition of C−X bonds3 and migratory insertion of unsaturated bonds.4 The ingenious combination of CO insertion with other elementary reactions well enriched the synthesis of aldehydes,5 ketones,6 carboxylic acids,7 esters,8 amides9 and alcohols.10 Meanwhile, this strategy was also demonstrated to be operative in the synthesis of complex natural compounds or the core structures.11 As a recent outstanding case, Zhao et al.12 successfully realized the total synthesis of (±)-cephanolides B and C that were isolated by Yue et al.13 lately from Cephalotaxus sinensis. The cyclic skeletons were constructed via Pd-catalyzed coupling of Ar−I bond, Ar−H bond, alkene and carbon monoxide (Scheme 1). It is appealing that the stereoselectivity of the annulation can be regulated by the structures of the cyclic alkenes.

MeO Me

Rn

O + CO (1 atm)

I H O Me

Rn I H

Pd(OAc)2 (10 mol%) PPh3 (20 mol%)

Rn

K2CO3 (2.0 equiv.) toluene, 90 C, 18 h

H

O O

O + CO (1 atm)

Pd(OAc)2 (5 mol%) PPh3 (10 mol%)

Rn

Ag2CO3 (1.05 equiv) K2CO3 (2.0 equiv) toluene, 90 C, 18 h

Scheme 1. Pd-catalyzed cascade annulation involving carbon monoxide11

3


Me OMe

H

H

Me O O

O

H


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The cascade annulation was proposed to start from the oxidative addition of aryl halide followed by the successive insertion of alkene and CO (Scheme 2). CMD and electrophilic aromatic substitution (SEAr) were proposed for the next C−H activation. Finally, Ar−C(sp2) reductive elimination could occur to finish the catalytic cycle. Despite of the previously proposed route (Path A), intermediate B possibly undergoes Ar−H activation to form five-membered palladacycle complex C. Note that five-membered-ring palladacycle intermediates were common in Pd-catalyzed C−H activation reactions.14 After the CO insertion on C, the product can be formed via either F (Path B) or D (Path C). In view of these possibilities, the detailed mechanism as well as the origin of stereoselectivity are still unclear.

3 R4 R5 R

R1

R2 1

R

I

Path A

LnIPd

Pd(0)Ln

O C

CO 4

3

R

5

R R

R1 2

R 1

PdILn

R

LnIPd

O

R3

R1

Path C CO

R3

O

R1 LnPd

PdLn O

O D

R4 R5 R2

possible mechanisms for C-H activation

K O CMD

LnPd

R3

R4 R5 R2

B

A

H

R1

R4 R5 R2

H

I

PdLn

CMD

H

I-

PdLn

R1 R4 R5

R2 R3

CO O Path B

E

R4 R5

R2 R3

R4 R5 R2

Pd 3 R Ln F

SEAr

Scheme 2. Possible mechanisms for the Pd-catalyzed cascade annulation

Recently, extensive efforts have devoted to the mechanisms of Pd-catalyzed C−H activation15 and carbonylative reactions catalyzed by other transition metals.16 Relatively less attention has been paid to 4


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the mechanisms of Pd-catalyzed couplings of carbon monoxide17 via C−H activation, especially for the stereoselective reactions. The favorable pathway as well as the origin of the observed stereoselectivity of Zhao’s reactions, which are of high importance for the further synthesis of other potential physiologically active derivatives, are difficult to be decided based on the previous mechanistic studies. Compared with the other reported cases,11 we are more interested in the Zhao’s reaction because of the switchable stereoselectivity. To gain deeper insights into the Pd-catalyzed couplings with carbon monoxide as carbonyl source, a computational study was performed herein for the cascade annulation to access the cyclic skeleton of Cephanolides B and C. We found that the Path A is more favorable than Path B and Path C because the CO insertion on the palladacycle intermediates E cause extra ring strain and makes the relevant steps kinetically difficult. Meanwhile, migratory insertion of alkenes was found to determine the stereoselectivity and the reported stereoselectivity was well reproduced by our calculation. Eextended calculations further revealed the relationship of the stereoselectivity and the steric effect of three substitution sites on the cyclic alkene. These results are expected to be instructive to the experiment design involving Pd-catalyzed CO insertion and the stereoselectivity control of intramolecular migratory insertion of alkenes. 2. Computational Methods Computational study was performed with G09 program.18 Geometry optimization was conducted in gas-phase with B3LYP method19 and BS1 basis set. BS1 denotes the basis set Lanl2DZ20 with the effective core potential and extra polarization functions21 for Pd [ζ(f) = 1.472] and I [ζ(d) = 0.289] atoms and 6-31G(d) for the rest atoms. At the same level of theory, frequency analysis was performed to gain thermodynamic corrections and to confirm that the optimized structures were correct (minimum has no imaginary frequency and transition states have only one imaginary frequency). Meanwhile, intrinsic 5



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reaction coordinates (IRC) analysis22 was performed to ensure the transition states connect the corresponding intermediates. Based on the optimized structures, solution-phase single-point energies were calculated with M06 method,23 SMD solvation model24 (solvent = toluene), ‘ultrafine’ grid25 and BS2 basis set. BS2 denotes the SDD basis set26 and the effective core potential for Pd and I atoms, and 6-311++G(d,p) for the rest atoms. The thermodynamic corrections were added by the solution-phase single-point energies and 1.9 kcal/mol for each species27 (addressing the standard state change from 1 atm to 1 M at 298.15 K) to get the solution-phase Gibbs free energies referring to 1 M and 298.15 K. The program NCIplot developed by Yang et al. was used to display non-covalent interaction.28 The CYLView program was used to generate the 3D diagrams of optimized structures.29

3. Results and Discussion First, sub1 was chosen as the model reactant to clarify the favorable mechanism (Figure 1) as well as the details of each elementary step. Then the stereoselectivity of different substrates was investigated and compared with experimental results to examine the validity of our computational results. Finally, other designed reactants were considered to expand the insights into the influence of substitutes on stereoselectivity. 3.1 Path A Pd(OAc)2 was used as catalyst precursor in Zhao’s experiment and it is able to be reduced to Pd(0) complex by the excess phosphine ligand.30 Therefore, the Pd(0) complex CP0 was chosen as the starting point for mechanistic study (Figure 1). CP0 releases one of the phosphine ligand and combines with sub1 to generate CP1, from which rapid oxidative addition of Ar−I bond occurs via TS1. TS1 affords T-shaped CP2 in which the aryl ligand is cis to the phosphine ligand due to the stronger trans effect of 6


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aryl ligand relative to iodide ligand. The further coordination of the C=C bond to palladium makes CP2 isomerize to CP3. Then CP3 undergoes migratory insertion of the C=C bond via TS2 with an energy barrier of only 8.2 kcal/mol. The isomer of TS2 in which the aryl ligand is trans to the phosphine ligand (TS2B) was considered but it is less favored than TS2 by 3.4 kcal/mol. CP4 is formed after TS2 with a significant energy decrease of 25.5 kcal/mol. The combination of CP4 with carbon monoxide generates CP5 with a further slightly energy decrease of 1.4 kcal/mol. Thereafter, CO insertion occurs via the three-membered-ring transition state TS3 to give the acyl palladium intermediate CP6. This step is also facile with an elementary energy barrier of 11.5 kcal/mol and thermodynamically favorable with an energy decrease of 12.5 kcal/mol. In next, the Ar−H bond activation should occur and several pathways were considered for it (Figure 2). First, CP6 can undergoes anion exchange with K2CO3 to generate CP7 and KI with an energy increase of 1.6 kcal/mol. Then the Ar−H activation is accomplished via the typical inner-sphere CMD transition state TS4A to afford the six-membered-ring palladacycle CP8. Another pathway starts from the ligand exchange of CP6 with K2CO3 to generate CP9 in which the aryl group is coordinated to the palladium with the  bond. This step is remarkably exergonic by 10.2 kcal/mol. Note that Zhao et al. proposed the SEAr for this reaction and we tried to locate the corresponding Wheland intermediate31 from CP9. Although CP9 contains a form cationic palladium center which is expected to be benefit for the SEAr mechanism, the Wheland intermediate still could not be located as a minimum.32 As an alternative, the concerted process was considered for the Ar−H activation from CP9 and this

7



Gsol (kcal/mol) R I Pd L CP1 11.1

L Pd L CP0 0.0

I Pd L TS1 12.8

H

CP2 -1.8

O

O I Pd L H TS2B 7.8

H

CP3 -3.8

L H

O L Pd I

I H Pd

O O

L CP4 -21.1

sub1 O

H

O

O L Pd H I TS2 4.4

R I Pd L

sub1

I

R=

R

L

O

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I H Pd

O

O O

C O TS3 -11.0

O CO

CP5 -22.5

H

O

I L=

H

P

I H Pd L CO Ar-I oxidative addition

alkene insertion

O O

Pd L

H

O O

O CP6 -35.0

CO insertion

Figure 1. Calculated Gibbs free energy changes of Pd-catalyzed cascade cyclization of sub1 leading to CP6. mechanism goes through TS4B. Because the anion I- does not coordinate to the palladium in TS2B, this pathway is able to be called outer-sphere CMD mechanism.33 We also noticed that the metathesis of Pd−I and Ar−H bonds was proposed by Zhao et al. and this mechanism is somewhat akin to TS4B. Nevetheless, the geometry optimization of the metathesis transition state always leaded to TS4B. We speculate that because the basicity of iodide is very low, and thus the Ar−H activation requires the

8


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Gsol (kcal/mol) I

H H

K O Pd C O O L

O

H

O

O TS4A

H H K2CO3 Pd L O

H

CP6 -35.0

Pd L KI

TS4B -15.5

O

H O

O

O

HI

H

K2CO3

Pd L

H

O

H

O O I

KHCO3 Pd L

H

O O

O

inner-sphere Ar-H activation outer-sphere Ar-H activation

H

O O

TS4E 0.6

O

TS5 -33.5

CP8 -43.9

O

H H L Pd OC O

O

KHCO3 Pd H L O

O

TS4D -3.7 KCO3

KHCO3 O L

H O

O

O

H

K2CO3

H

H

H H OC Pd L O

TS4C -10.8

KI

CP9 -45.2

O

H H K2CO3 Pd L O

O

K2CO3 Pd L O CP10 -22.7

CP7 -33.4

KCO3

H

TS4B TS4A -11.9

KCO3

KCO3

H

O

H

H

O

Pd O CP11 -63.5

O

H

L

KHCO3

O pro + CP0 -67.0

H

Ar-C(sp2) reductive elimination

Figure 2. Calculated Gibbs free energy changes of Pd-catalyzed cascade cyclization from CP6 to ketone pro. promotion of Pd−Ar bond formation while the Pd−I bond cleavage helps to the Pd−Ar bond formation. As a result, a late transition state that does not belong to metathesis mechanism was located when iodide was used to accept the proton. In addition to TS4B, some other inner-sphere CMD transition states were investigated. In TS4C, KCO3- was used as a proton accepter. KCO3- is more basic than I- but TS4C is surprisingly less favored than TS4B by 4.7 kcal/mol. The abnormal result is results from the endergonic 9



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reaction of I- + K2CO3  KI + KCO3- (Gibbs free energy change is 29.1 kcal/mol) that makes the KCO3--assisted pathway less favorable overall. Furthermore, CO was used to replace K2CO3 in the Ar−H activation transition state but the corresponding transition states TS4D and TS4E are even less favored than TS4C by over 7 kcal/mol. CP10 is formed after the Ar−H activation via TS4B and generates CP8 via intramolecular acid-base neutralization. Finally, feasible Ar−C reductive elimination proceeds via TS5 to yield the pro-containing complex CP11 with an energy barrier of only 10.4 kcal/mol. The recombination of PPh3 with the palladium releases pro and KHCO3, and regenerates CP0 to finish the whole catalytic cycle. 3.2 Path B and Path C In this section, Path B and Path C were considered. They are different to Path A from the downstream transformations of CP4. Akin to the discussion of the Ar−H activation in Figure 2, CP4 can generate CP12 through the coordination of K2CO3 and then undergoes Ar−H activation directly via the five-membered-ring transition state TS6. By comparison, the KCO3--assisted inner- and outer-sphere CMD mechanisms were found to be less favored than TS6 by 8.2 and 9.7 kcal/mol, respectively (Scheme S1). TS6 affords the palladacycle intermediate CP14 after acid-base neutralization. CP14 combines with CO to generate 16e complex CP15 in which the CO is cis to the aryl ligand. From CP15, CO insertion into the Pd−Ar bond occurs via TS7 with a high energy barrier of 38.3 kcal/mol. TS7

10


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H I K2CO3

H

O

H Pd

HI

O

K2CO3 Pd L

L CP12

H

H

O KHCO3 Pd L

O

H

Gsol (kcal/mol)

H

I H H Pd K2CO3 L TS6 -7.9

Pd

O

Pd L

O

CO

CP12 -30.7

H OC Pd L

H

CP15

H

O O

H

H Pd

O

L

Pd CP16

Ar-H activation

O

O TS10 -22.1

CP19 -25.6

CP18 -27.6

O

H

H H

TS8 -22.8

CP16 -30.2

O

O O

Pd L

KHCO3 H

O O

TS9b 20.1

O

CP15 -28.1

CP14 -34.5

O

O

H

KI

K2CO3

Pd KHCO3

O

H

TS7 10.2

L CP4 -21.1

OC

TS9 14.1

O

H OC

H

O K TS9a

C O

O

H

O

HO O

O

H

L Pd

O

CP13 -10.7

H OC

CP14

CP13

H

O

H L Pd CO

H

O Pd L

O

CP18

H O CP19

CO insertion into Pd-C(sp3) CO insertion into Pd-Ar

CP17 -54.6

O O

L

O L

H Pd

pro + CP0 -67.0

O

H O Ar-C(sp2) R. E. C(sp3)-C(sp2) R. E.

Figure 3. Calculated Gibbs free energy changes of Pd-catalyzed cascade couplings via the Path B or C.

affords CP16 in which PPh3 moves to the cis position of the acyl ligand spontaneously during geometry optimization possibly due to the stronger trans effect of the acyl ligand. From CP16, rapid C(sp2)−C(sp3) reductive elimination occur via TS8 to afford pro. On the other hand, the combination of CP14 and CO possibly generate the isomer CP18 in which the CO is cis to the aryl ligand. The following CO insertion into the Pd−C(sp3) bond via TS9 is even less favored than TS8 by 3.9 kcal/mol. 11



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This is understandable that the p orbital of aryl ligand can participate the C−C bond formation by which a lower degree of Pd−Ar bond cleavage is required. We also tried to locate the CO insertion into the Pd−Ar bond from the axial position of a trigonal bipyramidal transition state (TS9a) but the starting structure always isomerized to square planar TS9b with a higher energy barrier of 6.0 kcal/mol than TS9. The above results show that the CO insertion after the CP14 is kinetically difficult (energy barriers are over 40 kcal/mol) in no matter Path B or Path C. In contrast, the CO insertion on CP5 is much more feasible (Figure 1). We proposed that the CO insertion into the Pd−C bond of a cyclometal complex should be more difficult than the CO insertion on the Pd−C bond of a noncyclometal complex. This is because the cleavage of the Pd−C bond during CO insertion would expand the ring of the cyclometal complex and causes extra ring strains. To verify this proposal, we calculated the electronic energy gaps between the organic cyclic moieties of the preceding intermediates and transition states in the CO insertion into Pd−C(sp3) bonds (Scheme 3). Indeed, the CO insertion via TS9 causes an electronic energy increase of 6.7 kcal/mol for the fused ring moiety whereas that via TS3 leads to an energetic CP5-org H I H Pd L CO

E = -3.4

TS3-org

H

O O CP5-metal

TS3-metal

L

I H Pd

O C O

TS3

CP5

CP18-org H H L Pd CO

O

E = 6.7

TS9-org

H

O L Pd

O TS9-metal

CP18-metal

CP18

H

O O

C O TS9

Scheme 3 Electronic energy gaps of the organic cyclic moieties of the preceding intermediates and transition states in the CO insertion into Pd−C(sp3) bonds at the level of M06/BS2/SMD (kcal/mol) 12


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decrease of 3.4 kcal/mol. Similar to the results herein, previous computational studies showed that the CO insertion into noncylic Pd−C bonds17 are generally more facile than these into cyclic Pd−C bonds.17d Because of the inert CO insertion in Path B and Path C, Path A is the most likely one among the three. 3.3 Controlling Factors of Stereoselectivity After clarifying the reaction mechanism, we turn to investigate the factors controlling the stereoselectivity. Note that some of the chemical and crystal structures in Zhao’s report are the different to the crystal structures provided in their Supporting Information. In view of this matter, we chose to study the stereoselectivity based on the crystal structures provided in their Supporting Information to check the validity of our DFT study first. As shown in Figures 1 and 2, the migratory insertion of C=C bond is irreversible, and thus it is the stereoselectivity-determining step in Path A. Therefore, the migratory insertion of C=C bond of sub2, sub3 and sub4 were calculated (Figure 4 and see Figure S2 for how to decide the structures of sub2-sub4 based on the crystal structures). Interestingly, diastereoisomers sub2 and sub3 prefer different stereoselectivity. There is a repulsion between the hydrogen atom and Pd atom in TS2-sub2-a while a repulsion between the OMe group and the alkyl chain exists in TS2-sub2-b (see Figure S1 for the plots of non-covalent interaction). By contrast, the Pd···H repulsion still exists in TS2-sub3-a whereas the OMe group locates far from the reaction center and avoids the MeO···H repulsion in TS2-sub3-b. Instead, there is a weak H···H repulsion in TS2-sub3-b. As a result, TS2-sub2-a is more stable than TS2-sub2-b whereas TS2-sub3-b is slightly stable than TS2-sub3-a. These results indicate that sub2 can lead to the stereoselectivity of the crystal structure provided in Zhao’s Supporting Information. According to this result, it is understandable that the enantiomer of sub2, that is, the substrate shown in Zhao’s report produced the enantiomer of the crystal structure in their Supporting Information. Because the ester moiety of sub4 is planar and also locates far from the alkyl chain in TS2-sub4-b while the Pd···H repulsion exists in TS2-sub4-a, sub4 13



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prefers the same selectivity as sub3 does, and is also consistent with the crystal structure in Zhao’s Supporting Information.

O-H: 2.54

R = OMe

MeO

MeO Me

Me

H R L Pd I H

O

Me H

O-H: 2.21 H R

L Pd I H

Pd-H: 2.55

TS2-sub2-a 0.0

O

Me H

TS2-sub2-b 3.5

R = OMe MeO Me

MeO Me

H L Pd I H

R

O

Me H

TS2-sub3-a 0.0

L Pd I H

Pd-H: 2.44

R

O

Me H

TS2-sub3-b -1.3

MeO

MeO Me

H-H: 2.05 H

H L Pd I H

Me O Me H O

TS2-sub4-a 0.0

H L Pd I H

Pd-H: 2.56

O Me H O

O-H: 2.42

TS2-sub4-b -1.9

Figure 4. Calculated relative Gibbs free energies of alkene insertion of different substrates (in kcal/mol) and optimized structures of transition states. Atom-atom distances are given in green text (in angstrom).

14


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(a) R = OMe MeO Me

MeO Me

H Me

L Pd I H

O

R H

L Pd I H

Pd-H: 2.69

H-H: 2.03

H Me

R H

O

TS2-sub5-b 8.0

TS2-sub5-a 0.0

(b) R = OMe

Me

H-H: 2.05

MeO

MeO

Me

H L Pd I H

Me

O

H R

L Pd I H

Pd-O: 2.95

TS2-sub6-a 0.0

H Me

H R

O

TS2-sub6-b 2.0

(c) R = OMe

H-H: 2.03

MeO Me

H-H: 2.27

MeO Me

H L Pd I H

R

O

H Me

H L Pd I H

Pd-H: H-H: 2.67 2.03

R

O

H Me H-H: 2.38

TS2-sub7-b -8.0

TS2-sub7-a 0.0 (d) R = OMe

H-H: 2.06

MeO Me

MeO Me

H L Pd I H

H R

O

TS2-sub8-a 0.0

H H

Me I-H: 3.14

L Pd I H

Pd-H: 2.62

R

O

Me

TS2-sub8-b -6.0

Figure 5. Calculated relative Gibbs free energies of the C=C bond insertion of designed substrates (in kcal/mol) and optimized structures of transition states. Atom-atom distances are given in green text (in angstrom). 15



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In next, we turned to explore the stereoselectivity of other substrates based on the above model to provide some theoretical references to the further synthesis of potential physiologically active derivatives (Figure 5). First, several other diastereoisomers of sub2 were considered. For sub5, the branched Me group (instead of the OMe group of sub2) locates close to the alkyl chain in TS2-sub5-b, by which the energy gap between the two migratory insertion transition states is expanded to 8.0 kcal/mol (Figure 5a). If we change the configuration of the ether moiety of sub5 to get sub6, the larger repulsion between Pd and OMe in TS2-sub6-a (relative to the Pd···H repulsion in TS2-sub5-a) would decrease the selectivity though TS2-sub6-a is still favored over TS2-sub6-b (Figure 5b). The endo isomer of sub3, i.e. sub7 significantly prefers the insertion via TS2-sub7-b by 8.0 kcal/mol because of the larger Pd···Me repulsion (relative to Pd···H repulsion in TS2-sub3-a) in TS2-sub7-a (Figure 5c). Finally, the endo isomer sub8 is also likely to exhibit the similar stereoselectivity as sub7 does mainly due to the Pd···H and I···Me repulsion in TS2-sub8-a (Figure 5d). Taking all of the above results into account, we proposed that the stereoselectivity of the concerned reaction can be controlled by the steric effect of R1, R2 and R3 shown in Scheme 5. When the steric effect of R1 is larger than that of R2 and R3, C=C bond insertion prefers the A model because of the repulsion between R1 and the alkyl chain in the B model. On the contrary, when the steric effect of R1 is smaller than that of R2 and R3, B model is preferred due to the Pd···R1 and I···R2 repulsion in the A model. If the two opposite factors exist at the same time, the stereoselectivity is determined by the greater one but a worse result probably comes out. Rn H 1

L Pd I H

R

R2 XY

A model

3

R

steric effect: R1 > R2, R3

Rn I

R1

R2 XY

[Pd]

steric effect: R1 < R2, R3

3

R

X, Y = O or CH2 L = phosphine ligands 16


[Pd]

Rn H

R2 1

L Pd I H

R

XY

B model

R3

Page 17 of 28 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


Scheme 5. Summarized Controlling Factors of Stereoselectivity of the Pd-Catalyzed Cascade Annulation

4. Conclusion The application of carbon monoxide as a C1 building block in Pd-catalyzed cascade annulation provided a useful tool for the synthesis of fused ring compounds. In this manuscript, a DFT study was performed to elucidate the mechanism and origin of stereoselectivity of Pd-catalyzed cascade annulation of aryl iodide, alkene, carbon monoxide via C−H activation to construct the cyclic skeleton of Cephanolides B and C. We found that this reaction proceeds via oxidative addition of Ar−I bond, migratory insertion of C=C bond, CO insertion, Ar−H activation and C(sp2)−C(sp2) reductive elimination. The Ar−H activation is the rate-determining step and is more likely to occur via the I-assisted outer-sphere CMD mechanism. The migratory insertion of C=C bond is irreversible and is the stereoselectivity-determining step. By comparison, the other two pathways involving the CO insertion on the five-membered-ring palladacycle

intermediate are less kinetically favored because this kind of steps cause extra ring strain

during the Pd−C bond cleavage. Based on the favorable mechanism, the experimentally reported stereoselectivity was further reproduced, which gives a support for the rationality of our calculations. Finally, the stereoselectivity of additional substrates were systematically investigated, by which the relationship of the steric effect of three substitution sites and stereoselectivity was established. These results enriched the knowledge of the Pd-catalyzed transformations of carbon monoxide, and especially shed light on how to optimize the stereoselectivity of the annulation. We hope that this manuscript can inspire the further experimental design in the aspects of the choice of elementary steps and the control of stereoselectivity. 17



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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at Calculation relative Gibbs free energies of less favored transition states, NCIplot of selected transition states, calculated solution-phase Gibbs free energies after corrections and Cartesian coordinates of all species (PDF).

AUTHOR INFORMATION Corresponding Author *Email: [email protected]; [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Nos. 21702119, 21873055, 21702041), Natural Science Foundation of Shandong Province, China (Nos. ZR2017QB001). This work was supported by High Performance Computing Center of Qufu Normal University.

References: 18


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Borggraeve,

Bis(trifluoromethyl)carbinols

from

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Role of the Chemically Non-Innocent Ligand in the Catalytic Formation of Hydrogen and Carbon Dioxide from Methanol and Water with the Metal as the Spectator. J. Am. Chem. Soc. 2015, 137, 12330–12342. (b) Jiang, Y.-Y.; Yan, L.; Yu, H.-Z.; Zhang, Q.; Fu, Y. Mechanism of Vanadium-Catalyzed Selective C−O and C−C Cleavage of Lignin Model Compound. ACS Catal. 2016, 6, 4399–4410. (c) Yu, J.-L.; Zhang, S.-Q.; Hong, X. Mechanisms and Origins of Chemo- and Regioselectivities of Ru(II)-Catalyzed Decarboxylative C–H Alkenylation of Aryl Carboxylic Acids with Alkynes: A Computational Study. J. Am. Chem. Soc. 2017, 139, 7224–7243. (d) Jiang, Y.-Y.; Li, G.; Yang, D.; Zhang, Z.; Zhu, L.; Fan, X.; Bi, S. Mechanism of Cu-Catalyzed Aerobic C(CO)−CH3 Bond Cleavage: A Combined Computational and Experimental Study. ACS Catal. 2019, 9, 1066–1080. 28. Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506. 29. Legault, C. Y. CYLview, version 1.0b; Université de Sherbrooke, 2009 (http://www.cylview.org). 30. For the formation of Pd(0) complexes from Pd(OAc)2 and phosphine ligands, see: (a) Amatore, C.; Jutand, A.; Thuilliez, A. Formation of Palladium(0) Complexes from Pd(OAc)2 and a Bidentate Phosphine Ligand (dppp) and Their Reactivity in Oxidative Addition. Organometallics 2001, 20, 3241– 3249. (b) Amatore, C.; Jutand, A.; M’Barki, M. A. Evidence of the Formation of Zerovalent Palladium from Pd(OAc)2, and Triphenylphosphine. Organometallics 1992, 11, 3009–3013. (c) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A. Rates and Mechanism of the Formation of Zerovalent Palladium Complexes from Mixtures of Pd(OAc)2 and Tertiary Phosphines and Their Reactivity in Oxidative Additions. Organometallics 1995, 14, 1818–1826. 31. For the literatures reporting non-metal Wheland intermediates: (a) Twum, E. A.; Woodman, T. J.; Wang, W.; Threadgill, M. D. Observation by NMR of Cationic Wheland-Like Intermediates in the Deiodination of Protected 1-iodonaphthalene-2,4-diamines in Acidic Media. Org. Biomol. Chem. 2013, 27



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11, 6208–6214. (b) Hadzic, M.; Braïda, B.; Volatron, F. Wheland Intermediates: An ab Initio Valence Bond Study. Org. Lett. 2011, 13, 1960–1963. (c) Rathore, R.; Hecht, J.; Kochi, J. K. Isolation and X-ray Structure of Chloroarenium Cations as Wheland Intermediates in Electrophilic Aromatic Chlorination. J. Am. Chem. Soc. 1998, 120, 13278–13279. 32. For the computational studies failing to locate Wheland intermediates in transition-metal-catalyzed C−H activaton: (a) Zhang, S.; Shi, L.; Ding, Y. Theoretical Analysis of the Mechanism of Palladium(II) Acetate Catalyzed Oxidative Heck Coupling of Electron-Deficient Arenes with Alkenes: Effects of the Pyridine Type Ancillary Ligand and Origins of the meta-Regioselectivity. J. Am. Chem. Soc. 2011, 133, 20218–20229. (b) Zhang, L.; Yu, L.; Zhou, J.; Chen, Y. Meta-Selective C–H Alkylation of 2-Phenylpyridine Catalyzed by Ruthenium: DFT Study on the Mechanism and Regioselectivity. Eur. J. Org. Chem. 2018, 5268–5277. (c) Gray, A.; Tsybizova, A.; Roithova, J. Carboxylate-Assisted C–H Activation of Phenylpyridines with Copper, Palladium and Ruthenium: A Mass Spectrometry and DFT Study. Chem. Sci. 2015, 6, 5544–5553. 33. For some recent examples reporting outer-sphere CMD mechanism: (a) Xie, P.; Guo, W.; Chen, D.; Xia, Y. Multiple Pathways for C–H Cleavage in Cationic Cp*Rh(III)-Catalyzed C–H Activation without Carboxylate Assistance: a Computational Study. Catal. Sci. Technol. 2018, 8, 4005–4009. (b) Hu, X.-X.; Liu, J.-B.; Wang, L.-L.; Huang, F.; Sun, C.-Z.; Chen, D.-Z. The Stabilizing Effect of the Transient Imine Directing Group in the Pd(II)-Catalyzed C(sp3)–H Arylation of Free Primary Amines. Org. Chem. Front. 2018, 5, 1670–1678. (c) Haines, B. E.; Musaev, D. G. Factors Impacting the Mechanism of the Mono-N-Protected Amino Acid Ligand-Assisted and Directing-Group-Mediated C−H Activation Catalyzed by Pd(II) Complex. ACS Catal. 2015, 5, 830−840.

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Mechanism and Origin of Stereoselectivity of Pd-Catalyzed Cascade

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