Understanding Regiodivergence in a Pd(II)-Mediated Site-Selective C

Subscriber access provided by University of Groningen

Understanding Regiodivergence in a Pd(II)Mediated Site-Selective C–H Alkynylation Kenji Usui, Brandon E. Haines, Djamaladdin G Musaev, and Richmond Sarpong ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01116 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 13, 2018

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 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 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.

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 20 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

Understanding Regiodivergence in a Pd(II)-Mediated Site-Selective C–H Alkynylation

Kenji Usui,1,a Brandon E. Haines,2,a Djamaladdin G. Musaev,2* Richmond Sarpong1*

1

Department of Chemistry, University of California, Berkeley, California 94720, United States 2

Cherry L. Emerson Center for Scientific Computation, Emory University, Atlanta, Georgia 30322, United States a

These authors contributed equally to this work.

Abstract Although C–H functionalization is now established as a powerful tool for chemical synthesis, achieving site-selectivity can be challenging, especially in complex systems. Here, we report regiodivergence in a Pd(II)-mediated C(sp2)–H alkynylation of substrates with b-carbolinamide and picolinamide as N,N-bidentate chelating groups based on the identity of the TIPS-alkyne-halide coupling partner: TIPS-alkyne-bromides give d-C(sp2)– H alkynylation products while TIPS-alkyne-iodides give g-C(sp2)–H alkynylation products. Using an integrated experimental and computational approach, we examine the C–H alkynylation mechanism and determine the factors leading to the observed selectivity in great detail. We show that d-palladation is kinetically favored over g-palladation, whereas the latter is thermodynamically favored. However, equilibration of the palladacycles makes them both accessible as reactive intermediates. TIPS-alkyne-bromides react selectively with the six-membered palladacycle (from d-palladation) through a migratory insertion pathway. The observed d-selectivity in this case is attributed to decreased ring strain in the migratory insertion transition state with the six-membered palladacycle. We demonstrated that the g-selectivity observed with TIPS-alkyne-iodides arises from a switch in mechanism, from migratory insertion to Pd(II)/Pd(IV) oxidative addition. Lastly, the in-depth mechanistic study uncovered a b-Pd effect, which is analogous to the well-established bSi effect, that promotes d-C–H alkynylated product formation through an unusual vinyl bhalo elimination.

Keywords: C–H functionalization, Pd catalysis, alkynes, palladacycles, regioselectivity, beffects

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

Introduction Methods for C–H functionalization are now firmly established as a part of the toolbox of synthetic organic chemistry1-3 and are used in complex molecule synthesis where site- and stereo-selectivity are significant challenges.4-5 One prominent approach to overcoming the selectivity challenges in C–H functionalization is to employ a directing group, where a chelating auxiliary on the substrate is used to guide the selectivity of the reaction.6-8 Ultimately, this chelating group must be removed after the desired transformation has been achieved. Therefore, the directing group approach for selective C–H functionalization necessarily leads to additional steps when applied in a synthesis. Recently, we reported a tactic for selective C–H functionalization in complex molecules that uses directing groups that are inherent to the target molecule, obviating the need for their installation and subsequent removal. We have been particularly interested in the use of nitrogen-based directing groups because of their established generality in mediating numerous siteselective C–H functionalizations and the ubiquity of nitrogen in biologically relevant molecules. Specifically, we reported the use of b-carbolines as a component of an N,Nbidentate chelating group to achieve directed C–H functionalization that provided access to derivatives of the natural product alangiobussinine as well as several pharmaceuticallyrelevant compounds (Figure 1A).9 Generally, g-C–H activation arising from five-membered metallacyclic intermediates is thought to be favored in cases where a d-C–H activation arising from six-membered metallacyclic intermediates is also possible. It is largely accepted that the selectivity for five-membered metallacycles is, in most cases, kinetically preferred when both options are available.10-12 However, with the growing scope of C–H functionalization reactions, exceptions to these trends are beginning to emerge.13-17 In one such example, Garcia and Granell reported d-selective Pd(II)-catalyzed C(sp2)–H carbonylation of aromatic a-amino esters.18 Later, Shi and coworkers discovered d-selective Pd(II)-catalyzed C(sp3)–H alkenylation of aliphatic substrates with alkyne coupling partners.19 Experimental18 and computational20 studies in these two cases support more facile migratory insertion of the carbon monoxide or alkyne coupling partner into the six-membered palladacycle, respectively. These studies establish that the d-selectivity arises from greater reactivity of the six-membered palladacycle in the C–H functionalization step, but they leave unanswered the fundamental underlying reasons. A better understanding of the intimate details and governing factors of the g- vs. d-selectivity will improve the broader utilization of these reactions. Here, we build upon this emerging C–H functionalization selectivity trend by demonstrating d-selectivity in Pd(II)-catalyzed C(sp2)–H alkynylation with alkynylbromides (or chlorides) and substrates bearing b-carbolinamides or picolinamides as N,Nbidentate directing groups (Figure 1B). Intriguingly, we observed regiodivergence of the reaction based on the coupling partner: reactions with alkynyl-bromides yield the dfunctionalization products, while a simple switch to the alkynyl-iodide coupling partners


Page 2 of 20

Page 3 of 20 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

makes the g-functionalization products accessible. This finding is synthetically useful, but cannot be explained under our current understanding of the site-selectivity in the Pd(II)catalyzed C(sp2)–H alkynylation with alkynyl-halides. As such, the development of this reaction provides an excellent platform to investigate the mechanism of the Pd(II)catalyzed C–H alkynylation with alkynyl-halides and a better understanding of the emerging g- vs d-site-selectivity paradigm. Herein, we present an integrated experimental and computational study that provides an atomistic level rationalization for the observed site-selectivity and establishes a switch in mechanism (migratory insertion vs oxidative addition) as the major factor leading to regiodivergence with different alkynyl-halide coupling partners. Gratifyingly, these comprehensive studies led us to identify and characterize a stereoelectronic b-effect with Pd, which we call the b-Pd effect in analogy to the b-Si effect. We show that this novel bPd effect is the key to facile vinyl b-halo elimination en route to the C–H alkynylation products.

1A. Previously reported δ-functionalization (Ref. 9) X Pd(OAc)2 (10 mol%) K2CO3 (2 equiv) o-phenylbenzoic acid

N N H

NH

H

O

= aryl, alkynyl, vinyl

N N H

NH O

R

1B. This work: Regiodivergent Pd(II)-catalyzed C(sp2)–H alkynylation

N R

N H

Pd(II) N

δ N H

δ

X , X = Br or Cl NH O

γ

Mechanistic details Switch in site-selectivity

NH O

N

γ R

X, X = I Pd(II)

N H

δ NH

O

γ

R

Figure 1. (A) Previously reported directed C–H alkynylation via a six-membered palladacycle. (B) Illustration of g- versus d-alkynylation of the directed C(sp2)–H functionalization in b-carbolinamides or picolinamides with the various alkynyl-halide coupling partners.

Results and Discussion g- versus d-Selectivity in C–H Activation

Our interest in the unusual preference for d-C–H functionalization under certain scenarios was piqued by the observation of a more facile d-alkynylation of 1 (where n=2; Figure 2) when g-functionalization was also possible (where n=1) under the illustrated conditions


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

(Method A; o-phenylbenzoic acid = o-PBA). This observation led us to investigate the selectivity for C–H alkynylation on carbolinamide substrate 3 where a more direct comparison could be made. Under the conditions listed in Figure 2 (albeit using pivalic acid instead of o-PBA; Method B), a preference for d-alkynylation was observed for 3. This was surprising given the reported selective g-alkynylation of picolinamide substrate 5 using conditions based on Co(II) with TIPS-alkyne-bromide as the coupling partner.21 On the basis of an initial hypothesis that an intramolecular hydrogen bond could lead to a kinetic preference for d-C(sp2)–H palladation, an N-methyl carbolinamide derivative was also subjected to alkynylation using Method B. However, d-C(sp2)–H alkynylation was observed in this case as well, ruling out any influence of intramolecular hydrogen bonding on the observed selectivity, which is in full agreement with our extensive computational analysis (see the SI for more details). Notably, subjecting picolinamide derivative 5 to functionalization using Method B also yielded the products arising from d-alkynylation. Various other reported C–H alkynylation methods based on Co22-23, Ni,24-27 Ru,28 Mn29 and Fe30 were also investigated and in the successful cases led preferentially to the gfunctionalized products – presumably derived from the five-membered metallacycle intermediate.31 R Br (2.1 equiv)

TIPS

Pd(OAc)2 (10 mol%) K2CO3 ( 2 equiv), o-PBA (0.2 equiv)

N N H

NH O

n

DCE, 100 °C, 15 h NMR yields

n

1 (SM)

2 (mono)

2’ (di)

n=1

40

33

25

n=2

0

0

98

carbolinamide 1

2/2’ R

R CA NH

N N H

CA NH

NH O

Pd(OAc)2 (10 mol%) K2CO3 ( 2 equiv), PivOH (0.2 equiv)

Ph

Ph

Br (1.2 equiv)

TIPS

Ph

R 4/4’

3

DCE, 120 °C, 15 h

R

NMR yields N NH

Ph 3

O Ph picolinamide

5 5

3/5 (SM)

4/6 (mono)

4’/6’ (di)

0

33

45

0

30

38

PA NH Ph R 6/6’

Figure 2. Initial observations of preferential d-alkynylation To gain mechanistic insight into the observed preference for d-functionalization for 3 and 5 using TIPS-alkyne-bromide as the coupling partner under the Pd(II) conditions, we sought to prepare and isolate the palladacycles that likely serve as intermediates in these C(sp2)–H alkynylation reactions. Previously, we have isolated d-palladacycle 7 as the tertbutylisonitrile adduct from the corresponding indole carbolinamide precursor (Figure 3).9 However, the palladacycle intermediate derived from carbolinamide derivative 3 has proven difficult to isolate. We have been more successful in isolating and fully characterizing the palladacycle derived from picolinamide 5. As shown in Figure 3, X-ray crystallographic analysis data unambiguously supports the isolation of the five-membered palladacycle (9) as the major product, which was formed via 8 (see the SI for details). In


Page 4 of 20

Page 5 of 20 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

light of our observations that carbolinamide 3 yields the d-alkynylation product (presumably via a six-membered palladacycle), the isolation of 9 implies that the presumably more stable five-membered palladacycles are also present in the reaction mixture. Likewise, Garcia and Granell observed a solution mixture of five- and sixmembered palladacycles with the aromatic a-amino esters in their d-selective Pd(II)catalyzed C(sp2)–H carbonylation reaction.18 Me

Me

Me

Me

C

C

H N

N

Pd

Pd N

N NH

Me

N

N N

Me

O

O 7

9

[x-ray] (Ref. 9)

120 °C, 1 h, PhMe

Me Me AcO Pd(OAc)2 (1 equiv) t-BuNC (1 equiv) 5

C

N

Pd N N

PhMe, 0 °C 15 min

Me

Me

N

Me

C

Me

N

Pd

Ph

N O

O Ph

10

8

Figure 3. X-ray crystal structure representations of metallated palladacycles. Palladacycle 8 and palladacycle 9 have been prepared for the first time. As such, we hypothesized that equilibration between the d- and g-palladacycles under the reaction conditions could be the reason for the observed selectivities. To test the possibility of equilibration, the five-membered palladacycle (9) was heated at 120 °C in either dichloroethane or toluene for 24 h. Minimal conversion to six-membered palladacycle 10 was observed (Table 1). However, the addition of AcOH, which is likely generated under the alkynylation reaction conditions, to the reaction mixture leads to a modest conversion of 9 to 10. This observation indicates that equilibration of the d- and g-palladacycles under our reaction conditions is possible. To understand the effect of palladacycle equilibration on the selectivity for C–H alkynylation, C–H palladation of picolinamide substrate 5 was studied using density functional theory (DFT) calculations. The effect of the ligand environment of the Pd complex was studied with acetate as the counter-ion, potassium carbonate as the added base, and t-butyl isonitrile as an additive to isolate the palladacycle. (See the SI for more details.) Surprisingly, in all cases, C–H activation at the d-position is found to be kinetically favored by 3–5 kcal/mol. The lowest energy barrier is observed when the ligand is acetate, as shown in Figure 4A. To understand the unexpected kinetic preference for C–H activation at the d-position versus the g-position, we closely analyzed the concerted-metalationdeprotonation (CMD)32 transition state (TS) structures, g-TS1 and d-TS1, respectively. Analysis of TSs with acetate is provided here because they gave the lowest barriers. In gTS1, the picolinamide group imposes severe geometric constraints on the substrate arene (a = 41°) that prevent it from adopting the perpendicular orientation (a = 90°) that is ideal for facile cleavage of the C–H bond (Figure 4B).33


ACS Catalysis

Table 1. Equilibration between the 5-membered and 6-membered palladacycles 9 and 10. Me Me Me N C

N

Me Me Me N

Δ

Pd

N

C

N

additive

N

NH

Pd N

solvent

O

O

O

9

10

entry

5

solvent

temp.

time

additive

1

DCE

120ºC

24 h

–

9:10:5 = 5.5:1:0

2

toluene

120ºC

24 h

–

9:10:5 = 8.3:1:trace

3

DCE

120ºC

24 h

AcOH (1.0 eq.)

9:10:5 = 4.7:1:trace

4

DCE

120ºC

24 h

AcOH (2.0 eq.)

9:10:5 = 10:2:1

5

DCE

60ºC

24 h

AcOH (2.0 eq.)

9:10:5 = 14:1:0

6

DCE

23ºC

168 h

AcOH (2.0 eq.)

9:10:5 = 1:0:0

results (NMR ratio)

In d-TS1, the geometric constraints are less imposing and the substrate arene is closer (a = 53°) to the ideal orientation because of the flexibility of the larger ring (Figure 4B). In contrast to the determined kinetic preference for d-(C–H) activation, the five-membered palladacycle, resulting from g-(C–H) activation, is thermodynamically favored by 2–3 kcal/mol (the reaction with acetate as the ligand is shown in Figure 4A). These results are consistent with the isolation of 9 (i.e., g-(C–H) activation product) as the sole product. In the resulting palladacycles, the planar orientation of the substrate (i.e., a = 0°) is preferred, leading to the thermodynamic ordering based on ring size as is observed.34-35

Ideal Substrate Orientation in CMD TS

A.

B. H 3C

O O

Pd

N

N

H 3C

H

O

O O

N Pd

γ γ-TS1 19.5/17.0

γ δ

ΔG/ΔH (kcal/mol)

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 6 of 20

H

H

O

δ

N

Pd

OAc

γ

H 3C

Pd

α = 90°

O γ-C–H activation TS (γ-TS1)

N Pd H N

H O

O

α O

CH3

δ-C–H activation TS (δ-TS1)

AcOH

δ-TS1 17.3/14.4

N Pd

δ

Cα

N

Cα

Pd

Pd

O

O

δ

H

δ-12 7.6/5.8 AcOH

11 0.0/0.0

γ-12 6.0/5.1

N

Pd N

O

γ

H 3C

CH2Ph

O H O

Cα Pd

α = 41°

N

H 3C

Ph

O H O

Pd

N

Cα

α = 53° N

N

Figure 4. A) Free energy surface of C–H activation at the d- and g-positions with acetate as the ligand, B) Geometric rationalization of the d-selectivity in the kinetic palladation step.


Page 7 of 20 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

Our initial experimental and computational analyses suggest that the five-membered palladacycle observed in our experiments with picolinamide substrate 5 occurs via equilibration from a kinetically favored six-membered palladacycle. To further support the validity of this mechanistic picture, we performed an isotopic labeling study. Upon subjecting pentadeutero picolinamide 5-g-d5 (Figure 5A) to our palladacycle-forming conditions, 8-g-d5 is formed in 62% yield. Subsequent heating of 8-g-d5 in toluene at 120 °C for 12 h yields a 10:1 ratio of g- to d-palladacycles. Following trituration with ethyl acetate, mono-deuteration at the d-position of the major g-palladacycle product is observed (70%, see Figure 5A). This strongly indicates competing formation of a d-palladacycle that is presumably deuterated by the AcOD formed in situ from the reversible palladation of the d5-phenyl group of 8-g-d5. The argument can be made that d-palladation of 8-g-d5 is kinetically competitive with gpalladation because of the per-deuteration of the phenyl group, which, by virtue of the lower zero-point energy of the C–D bond, is slower to react. To discount this possibility, we have also studied the palladation of 5-d-d5 (Figure 5B) in which the phenyl ring of the benzyl group is pentadeuterated. In this case, the mono-d-hydrogenated isotopomer forms as the major g-palladacycle product, while the minor product is the doubly-d-hydrogenated isotopomer that is now deuterated at the g-position (see Figure 5B). This finding further supports the competing formation of the d-palladacycle even under circumstances where it should be disfavored on the basis of a kinetic isotope effect. Me

Me

A.

Me Me Me N C D Pd

Me

N

D

D NH

D

O D

D

Pd OAc

Pd(OAc)2 (1.0 equiv) tBuNC (1.0 equiv)

toluene 120 °C, 12 h

10:1 ratio (by crude NMR)

SM:prod

Me

Me

0.5 h

1h

2h

4h

8h

12 h

77:23

60:40

44:56

34:66

18:82

10:90

Pd(OAc)2 (1.0 equiv) tBuNC (1.0 equiv)

NH

Pd OAc

toluene rt, 15 min

D D D D

60% yield

D

O

D

D D

D

5-δ-d5

8-δ-d5

toluene 120 °C, 12 h

5-: 6-membered palladacycle 10:1 ratio (by crude NMR)

washed with AcOEt 62% isolated yield (combined)

H

0.7 H (integrated value)

H

H

(70:30 ratio)

Me Me Me N C H Pd

N

N

O

H H

C

N

D

D

H

Me

N

N

D

H D H

reaction rate at 60 °C (NMR ratio)

8-γ-d5

B.

D

O

H

D

D

5-γ-d5

N

D

O

64% isolated yield (combined)

D

D

N

N

washed with AcOEt

5-: 6-membered palladacycle

N O D

toluene rt, 15 min 62% yield

N

C

N

N

Me Me Me N C D Pd

N

N H

O

N

H

O

H

H

Me Me Me N C H Pd

D

H

H

D

H D

D

D reaction rate at 60 °C (NMR ratio)

SM:prod

0.5 h

1h

2h

4h

8h

12 h

82:18

66:34

51:49

45:55

21:79

11:89

H

D

D D 0.7 (integrated value) (70:30 ratio)

D

Figure 5. Isotopic labelling experiments supporting the mechanistic picture that the observed five-membered palladacycle occurs via equilibration from a kinetically favored six-membered palladacycle. (A) Palladation experiments employing a pentadeutero substrate bearing deuteration at the g-position. (B) Palladation experiments employing a pentadeutero substrate bearing deuteration at the d-position.


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

Taken together, the experimental and computational results strongly support a mechanistic picture for C–H activation of picolinamide substrate 5 in which i) d-palladation occurs faster than, or at least is competitive with, g-palladation, and ii) reversible C–H activation leads to an equilibrium where the g-palladacycle is favored over the d-palladacycle. Thus, as with the previous studies18-20, the site- selectivity (i.e., either proceeding via g- or dpalladacyclic intermediates) is likely to be determined by reaction specific factors including the nature of substrate, directing group, additives, and the coupling partner. With this mechanistic framework for C–H activation as a basis, we next studied the effect of the alkynyl halide coupling partner on the reactivity of the five- and six-membered palladacycles and the subsequent selectivity of the alkynylation. g- versus d-Selectivity in the Alkynylation

We first considered whether the d-alkynylated products could arise from the thermodynamically favored g-palladacycle (9) upon addition of TIPS-alkyne-bromide as the coupling partner (see Table 2). Under stoichiometric conditions, heating a mixture of 9 and TIPS-alkyne-bromide at 60 °C in either DCE or toluene did not lead to a discernable reaction. Increasing the temperature to 90 °C and heating at this temperature for 40 h led to modest conversion to a mixture of g- and d-alkynylated products. Higher conversions to the alkynylated products were observed at 120 °C in both toluene and DCE. Because DCE proved to be marginally superior, the ensuing studies employed this solvent. Ultimately, we found that the addition of AcOH enhanced the selectivity for the formation of the dalkynylated products. Notably, d-functionalization was found to proceed even at 23 °C even though five-membered palladacycle 9 was not observed to undergo equilibration to six-membered palladacycle 10 at 23 °C. (See Table 2.) This observation suggests that even though the six-membered palladacycle may form in concentrations below the NMR detection limit at room temperature, it is reactive enough to generate the d-alkynylated product. The observations also suggest that the barrier to form the g-alkynylated product is significantly higher because it is not observed even though the equilibrium between the palladacycles predominantly favors the five-membered palladacycle. We next employed DFT calculations to gain more insight into the alkynylation reaction between the five- and six-membered palladacycles and TIPS-alkyne-bromide. Although most alkynylations that proceed through C–H activation with alkynyl halide reaction partners are proposed to proceed through Pd(II)/Pd(IV) intermediates,36-37 we posit that migratory insertion of the alkyne into the Pd–C bond of a Pd(II) intermediate is more likely for the cases presented here. Our proposed mechanistic pathway builds on a previous proposal by Tobisu and Chatani38 and an analogous migratory insertion mechanism was recently proposed by Ackermann for Mn- and Fe-catalyzed C(sp2)–H alkynylations29-30 and investigated computationally by Echavarren for a Ru-catalyzed C(sp2)–H alkynylation.39 To compare these mechanistic possibilities for the case of the Pd-catalyzed reaction, we computed both the migratory insertion (MI) and oxidative addition (OA) pathways for the reaction of the five- and six-membered palladacycles with TIPS-alkyne-bromide. Several scenarios with respect to the ligand environment of the Pd center in the alkynylation step were studied for comparision with the available experimental data (see Table 2 and Figure


Page 8 of 20

Page 9 of 20 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

2). For consistency with the stoichiometric conditions reported in Table 2, we studied the reaction in the presence of t-butyl isonitrile (t-BuNC) and AcOH, as well as in the absence of additional ligand (i.e., only TIPS-alkyne-Br). Similarly, we also studied this reaction in the presence of KHCO3, which presumably forms under the catalytic conditions in Figure 2 as a result of carbopalladation. For these four reactions, the computations show dselectivity is preferred (see the SI for more details). However, the calculated difference in the free energy barriers (i.e. DDG‡) for the transition states controlling g- and dalkynylation product formation (see below) is significantly smaller for the cases without additional ligand and with t-BuNC compared to the cases with AcOH and KHCO3. These results are consistent with the experimental data in Table 2 showing d-selectivity is preferred only in the presence of AcOH additive and under catalytic conditions as shown in Figure 2. Furthermore, the free energy profiles in the presence of AcOH and KHCO3 are similar in terms of the site-selectivity. Therefore, we chose to pursue studies starting from the KHCO3-ligated palladacycles (g-13 and d-13) as a general picture of d-selective alkynylation. Table 2. Alkynylation studies with the five-membered palladacycle Me Me Me N C

N

TIPS

TIPS

Pd

N

X

NH

N

Δ, solvent, additive

O

NH

O

O

R

R

9

6/6’

entry

reactant

1

X=Br (1.0 eq.)

DCE

2

X=Br (1.0 eq.)

toluene

3

X=Br (1.0 eq.)

4

R

N

TIPS

R TIPS

TIPS

20/20’

time

additive

results

60ºC

24 h

–

NR

60ºC

24 h

–

NR

DCE

90ºC

40 h

–

mixture of γ- and δ- alkynylated compounds

X=Br (1.0 eq.)

toluene

90ºC

40 h

–


5

X=Br (1.0 eq.)

DCE

120ºC

3h

–


6

X=Br (1.0 eq.)

toluene

120ºC

20 h

–


7

X=Br (1.0 eq.)

DCE

120ºC

1h

AcOH (2.0 eq.)

6:12%, 6’:30%

8

X=Br (1.0 eq.)

DCE

60ºC

20 h

AcOH (2.0 eq.)

6:19%, 6’:18%

9

X=Br (2.0 eq.)

DCE

60ºC

20 h

AcOH (2.0 eq.)

6:trace, 6’:58%

10

X=Br (2.0 eq.)

DCE

23ºC

168 h

AcOH (2.0 eq.)

6:51%, 6’:15%

11

X=I (1.0 eq.)

DCE

60ºC

20 h

_

20:26%, 20’:18%

12

X=I (1.0 eq.)

DCE

60°C

20 h

AcOH (2.0 eq.)

20:28%, 20’:22%

13

X=I (2.0 eq.)

DCE

60ºC

20 h

AcOH (2.0 eq.)

20:22%, 20’:30%

14

X=I (2.0 eq.)

DCE

23ºC

168 h

AcOH (2.0 eq.)

20:46%, 20’:15%

solvent

temp.

The computed free energy barriers (calculated relative to the lowest energy common reactant, g-13) for the MI pathway are 31.5 and 23.1 kcal/mol for the five- and sixmembered palladacycles (g-TSMI and d-TSMI), respectively. For the competing OA


ACS Catalysis

pathway, these barriers at transition states g-TSOA and d-TSOA are 24.3 and 23.8 kcal/mol, respectively (Figure 6A). Thus, the MI pathway for the six-membered palladacycle leading to the d-alkynylated products has the lowest free energy barrier, which is likely to be higher than the barriers associated with equilibration (i.e., d-12 ® d-TS1 and 11 ® g-TS1). This finding reiterates that equilibration of the C–H activation products is likely to occur under the reaction conditions and shows that the d-C–H alkynylation products can form through a lower energy migratory insertion barrier. We also sought to gain insight into the observed selectivity in the MI pathway. Intrinsic reaction coordinate (IRC) calculations, initiated from the five- and six-membered MI transition states (g-TSMI and d-TSMI), respectively, lead to the formation of highly constrained seven- and eight-membered palladacycles g-15 and d-15 (referred to as “constrained-ring” products). The energy difference between the seven- and eightmembered MI products (g-15 and d-15, respectively) is larger (DG = 17.9 kcal/mol) than that for the corresponding five- and six-membered MI reactants (DG = 5.1 kcal/mol) (Figure 6A). This led us to hypothesize that the five-membered MI transition state (gTSMI) and product (g-15) are significantly destabilized by ring strain relative to their sixmembered counterparts. Indeed, the energy released upon “relaxing” the “constrained-ring” structures (g-15 and d-15) to their unconstrained isomers (g-15’ and d-15’) is significantly greater for seven-membered palladacycle g-15’ (DG = –35.6 kcal/mol) than eightmembered palladacycle d-15’ (DG = –15.6 kcal/mol) (Figure 6B). It should be noted that isomeric MI transition states, based on the positions of the TIPS and Br substituents on the alkyne, were also located, but are not likely to be relevant for the reaction pathway because they are higher in energy (see the SI for more details). A.

TIPS

TIPS Br N O

TIPS

KHCO3

Br N

Pd N

O

Pd N

N

KHCO3 O

TIPS Br

N

Pd N

B.

Br

Ring Relaxation TIPS

Pd N

N

δ-TSMI

γ-TSMI

γ-TSOA 24.3/9.4

δ-TSOA 23.8/8.2

N

Br Pd

23.1/20.2

N Pd O

γ-13 0.0/0.0

KHCO3 N

Pd

γ-14 4.4/3.5

O

TIPS

γ

N

O O

Pd N

δ-15’ Br

Br

N

Pd

Br

Pd O

Hyperconjugation across alkenyl-Pd

δ-TSE TIPS

Br

Donor (i): Pd–C σ

TIPS

Acceptor (j): C–Br σ*

N

N

Pd O

Br γ-15

C.

TIPS

Br

N

N

O

5.2/2.3

TIPS N

KHCO3

N

O

Br Pd N

Pd δ-TSE 7.2/2.9

δ-15

δ-13 2.2/2.1

ΔG = –15.6 kcal/mol

N

TIPS

N

TIPS N

δ-15 TIPS

δ-14 9.5/7.1

δ

Pd N

γ-TSE

δ-TSMI 23.1/19.8

γ-15’

Br

N O

Br

KHCO3

Pd

γ-TSE 24.3/20.0

γ-15

N

O

N

O

Br

N

TIPS

N γ-TSMI 31.5/28.7

Pd

O

ΔG = –35.6 kcal/mol

γ-15

TIPS Br

TIPS

Pd

TIPS

N

Br

N

O O

ΔG/ΔH (kcal/mol)

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 20

N

N Pd

δ-15 Br N O

TIPS

Pd

N

N δ-16 –44.4/–48.3 γ-16 –47.0/–48.7


E(2)ij (kcal/mol)

γ-15 32.1

δ-15 28.1

Page 11 of 20 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 6. A) Free energy surface for the reaction of five- and six-membered palladacycles with TIPS-alkyne-bromide through a migratory insertion/b-bromide elimination and oxidative addition pathways, B) Relaxation of the “constrained-ring” migratory insertion products, C) Hyperconjugation in the “constrained-ring” migratory insertion products. Given their significance to the observed selectivity, we next analyzed the factors affecting the stability of the “constrained-ring” products (i.e., g-15 and d-15). We found surprisingly short distances between the Pd and the b-carbon of the newly formed alkenyl-Pd moiety (Pd–Cb = 2.30 and 2.31 Å) leading to a highly distorted double bond with ÐPd–Ca–Cb = 79.7 and 81.2°, respectively. NBO analysis shows that the basis for this interaction is hyperconjugation between the trans Pd–C s and C–Br s* orbitals40 (Figure 6C). Indeed, populating the C–Br s* orbital leads to elongation of the C–Br bond distance in traversing the reaction coordinate from MI reactants to the corresponding “constrained-ring” products: from 1.87 Å in g-14 to 2.12 Å in g-15 and from 1.86 Å in d-14 to 2.08 Å in d-15. The similarity in the strength of the hyperconjugation for the seven- and eight-membered palladacycles (E(2)ij = 32.1 and 28.1 kcal/mol, respectively) suggests that the interaction indirectly leads to the observed selectivity by facilitating the formation of the “constrainedring” products. b-Bromide Elimination Facilitated by the proposed b-Pd Effect

With insight into the factors that govern the regioselectivity of the migratory insertion established, we next sought to understand the mechanism by which the “constrained-ring” MI products (g-15 and d-15) are transformed to the alkynylated products (i.e., g-16 and d16). Our calculations show that this process occurs directly via a vinyl b-bromide elimination pathway indicating that the unconstrained isomers (g-15’ and d-15’) are not intermediates in the reaction. As shown in Figure 6A, the barriers associated with bbromide elimination from the seven- and eight-membered palladacycles (g-TSE and dTSE) are very low: 1.2 and 2.0 kcal/mol, respectively. Concurrent cleavage of the Pd–C bond and relaxation of the “constrained-ring” structure contribute to the large driving force that is calculated for this step (Figure 6A). The vinyl b-bromide elimination that emerged out of our calculations is an elementary organometallic step that has been invoked previously but has not been studied in detail.38, 41 Ackermann suggested that either a b-silicon effect.42 induced by Si substituents on the alkyne or a Lewis acidic additive are required to facilitate this step for Mn- and Fecatalyzed reactions.29-30 In the calculations reported by Echavarren for Ru-catalyzed C(sp2)–H alkynylation, this step was found to have a low barrier facilitated by a potassium acetate additive.39 However, in our case, it is clear that the hyperconjugation resulting from the presence of the Pd in the b-position weakens the C–Br bond and leads to facile elimination. To the best of our knowledge, this is the first characterization of Pd performing this function on an alkenyl system. Due to its analogy with the b-silicon effect, we call this phenomenon the b-Pd effect. Mechanism Summary and Scope


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 12 of 20

On the basis of the computational data, we conclude that the d-alkynylated products arise from the kinetic preference for insertion of the alkynyl bromide coupling partner into the six-membered palladacycle, which is kinetically and thermodynamically accessible. This conclusion is also supported by our experimental observations of the oxidative Heck reaction43-44 of picolinamide 5 (Figure 7A) and carbolinamide 3 (Figure 7B) with methyl acrylate that yield the d-alkenylation product preferentially over the g-alkenylation product. In this case, it is also likely that alkene migratory insertion into the six-membered palladacycle is favored over insertion into the corresponding five-membered palladacycle. These observations support the facility of migratory insertion as a key determinant for the preferred d-selective C(sp2)–H functionalization in these catalytic reactions. A. CO2Me

N

N (2.0 equiv) NH

NH

Pd(OAc)2 (10 mol%) benzoquinone (1.0 equiv) NaHCO3 (2.0 equiv)

O

+

O

Recovered 5 (66% yield)

CO2Me

DCE, O2, 100 °C, 24 h 5

18 (29% yield)

B. CO2Me

N NH

N H

O

N (2.0 equiv)

Pd(OAc)2 (10 mol%) benzoquinone (1.0 equiv) NaHCO3 (2.0 equiv)

N H

NH O

+ CO2Me

Recovered 3 (63% yield)

DCE, O2, 100 °C, 24 h 19 (26% yield)

3

Figure 7. (A) Oxidative Heck reaction of picolinamide 5 and (B) Oxidative Heck reaction of carbolinamide 3 with methyl acrylate lead preferentially to the d-functionalized products. We have also discovered that the d-alkynylations are not limited to TIPS-substituted alkynes, as 1,1-dimethylpropynol derived, t-butyl-, and TMS-substituted alkynes also participate in these functionalization reactions, albeit less efficiently (see the SI for more details). However, the coupling partners are somewhat limited. For example, alkynyl halides bearing n-butyl, TBSOCH2–, and phenyl substituents show poor reactivity as coupling partners in our hands. We note that the unsuccessful coupling partners do not possess sterically large substituents on the alkynyl group. On the basis of our mechanistic analysis, we can speculate that the bulky group is required to control the regioselectivity of the migratory insertion to yield the “constrained ring” isomer from which b-bromide elimination can readily occur through the proposed b-Pd effect. Additional studies of the effects of alkyne substitution on the reactivity and selectivity in the migratory insertion pathway are underway. A competing oxidative addition pathway Using TIPS-alkyne-chloride instead of TIPS-alkyne-bromide as the coupling partner under our optimized conditions with picolinamide 5 also leads to d-selectivity (see the SI for more details). In contrast, in a variation of Method B using TIPS-alkyne-iodide, the Pd(II)catalyzed alkynylation of picolinamide 5 surprisingly yields the mono and di-gfunctionalized products, 20 and 20’ (Figure 8A). In the reaction between the 5-membered


Page 13 of 20 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

palladacycle 9 and TIPS-alkyne-iodide, the g-selectivity showed no dependence on the AcOH additive, which is also in contrast with the results with TIPS-alkyne-bromide (Table 2). Further, we observed that arylation of carbolinamide 3 and picolinamide 5 (Figure 8B) with aryl iodides, as well as alkylation of 5 with alkyl iodides (Figure 8C), all lead to the g-functionalized products. We therefore reasoned that the switch in product selectivity could be explained by a change in mechanism from MI to OA when alkynyl iodide is used as the coupling partner. I (1.2 equiv) TIPS Pd(OAc)2 (10 mol%) K2CO3 (2.0 equiv) PivOH (0.2 equiv)

A.

5

DCE, 120 ºC, 19 h

N

N NH

5

NH

O

yield

O TIPS

TIPS

TIPS

20 (13% yield)

20’ (9% yield) N

B.

N H I

MeO 3

(2.0 equiv)

NH

21 (70% yield)

O

OMe MeO

Pd(OAc)2 (10 mol%) K2CO3 (2.0 equiv) PivOH (0.2 equiv) N

DCE, 120 ºC, 5 h

NH

5

Mono γ-arylated 22 (24% yield) MeO

O OMe

22’ (52% yield)

C.

I (2.0 equiv) Pd(OAc)2 (10 mol%) CuBr2 (20 mol%) K2CO3 (2.0 equiv) 5

H2O, 120 ºC, 36 h

[x-ray] N

N NH

O

NH

+ O

0.25 M

23 (36% yield)

23’ (46% yield)

Figure 8. A) g-Alkynylation with TIPS-alkyne-iodide, B) g-arylation with para-methoxy phenyl iodide, C) g-alkylation with n-butyl iodide In support of this hypothesis, we computationally studied the MI and OA pathways with TIPS-alkyne-iodide (Figure 9). The computed free energy barriers (calculated relative to the lowest energy common reactant, g-13) for the MI pathway are 33.7 and 24.1 kcal/mol for the five- and six-membered palladacycles (g-I-TSMI and d-I-TSMI; I stands for iodide), respectively. With the alkynyl iodide coupling partner, the free energy barriers for the MI pathway increase by ~1 kcal/mol. NBO analysis shows that the hyperconjugation across the alkenyl-Pd moiety is slightly weaker with the C–I s* orbital (E(2)ij = 28.0 and 25.9 kcal/mol for g-I-15 and d-I-15, respectively). This indicates that the hyperconjugation also has an effect on the MI barrier. The competing OA barriers at corresponding transition states g-I-TSOA and d-I-TSOA are 19.9 and 21.4 kcal/mol, respectively. Therefore, the oxidative addition barriers are lower by ~3–4 kcal/mol with the alkynyl iodide. This is in line with the expected reactivity trends for oxidative addition of alkynyl halides.45 Taken together, the calculations indicate that the halide substitution results in a net change in the relative MI and OA barriers of 4–5 kcal/mol. With these changes, the OA pathway


ACS Catalysis

occurs more favorably with the five-membered palladacycle. Thus, our combined experimental and computational studies demonstrate mechanism-dependent siteselectivity for the Pd(II)-catalyzed C–H alkynylation of carbolinamide or picolinamide substrates with different alkynyl halides as coupling partners: TIPS-alkyne-iodide proceeds via a g-selective Pd(II)/Pd(IV) oxidative addition pathway, and TIPS-alkyne-bromide favors a d-selective redox neutral migratory insertion pathway. TIPS

TIPS N

/ N

Pd N

O

TIPS

KHCO3

I

O

δ-I-TSOA

Pd N

N

KHCO3 O

TIPS I

Pd N O

TIPS KHCO3

Δ. 2103 453

O

δ-I-TSOA )

Pd

N γ-I-TSOA )

N

I

Pd N

δ-I-TSMI

I

N

N

γ-I-TSMI

γ-I-TSOA

TIPS

I

TIPS KHCO3

/ N

Pd N

O

O

KHCO3

Pd N

KHCO3 N Pd

δ

I

δ-I-TSRE ) 6(

N O

δ-13

Δ

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 14 of 20

Pd

γ-I-TSRE

6

I

γ

N

N

O

O

TIPS

O

Pd N

Pd

N

KHCO3 TIPS

I N

TIPS

γ-I-18 6( ) 6 (

KHCO3 Pd N

N

δ-I-18 6

TIPS

O

I

6

γ-I-17 6 )

γ-13

KHCO3 N

δ-I-17 6

TIPS

I

KHCO3 N O

KHCO3 6

Pd

I

γ-I-16 6

TIPS

N Pd

N

O 6

N

δ-I-16 6 (

Figure 9. Free energy surface of the reaction of five- and six-membered palladacycles with TIPS-alkyne-iodide through the migratory insertion and oxidative addition pathways. Conclusions In summary, we have demonstrated and provided atomistic level rationalization for the site-selectivity of C(sp2)–H alkynylation of picolinamide and carbolinamide substrates with different alkynyl halide coupling partners. Through a combined experimental and computational study, we have shown that: 1. With picolinamide substrates, the observed d-selective C–H palladation is kinetically favored over g-selective palladation, whereas the palladacycle resulting from the latter is thermodynamically favored. In the absence of a coupling partner, the formation of the fivemembered palladacycle occurs via equilibration from the six-membered palladacycle, a mechanism that is unambiguously supported by experiments utilizing deuterated picolinamide derivatives as well as computations.


Page 15 of 20 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

2. In the presence of TIPS-alkyne-bromide, the Pd(II)-catalyzed d-C–H alkynylation proceeds via migratory insertion of the alkyne into the Pd–C bond that kinetically favors the six-membered palladacycle. The six-membered palladacycle is favored over the fivemembered palladacycle in migratory insertion due to less ring strain in the transition state. The presence of AcOH (or KHCO3) as an additive in the reaction mixture enhances the dselectivity of the alkynylation process. 3. Replacing the TIPS-alkyne-bromide coupling partner with TIPS-alkyne-iodide provides a regiodivergent process leading to the g-functionalization products. The switch in siteselectivity is induced by a mechanistic switch from the aforementioned Pd(II) migratory insertion pathway to a Pd(II)/Pd(IV) oxidative addition pathway that favors the fivemembered palladacycle. 4. The migratory insertion pathway includes the formation of high-energy “constrained ring” intermediates that exhibit hyperconjugation between the trans–disposed Pd–C s and C–Br s* orbitals. This leads to activation of the C–Br bond and facilitates alkyne product formation through a unique vinyl b-bromide elimination step. In analogy to the wellstudied b-Si effect, we have termed this phenomenon as the “b-Pd effect”. The findings of this comprehensive and collaborative experimental and computational study greatly increase our understanding of the factors controlling reactivity and siteselectivity in C–H alkynylation reactions as well as the wider d-/g-site selectivity paradigm in C–H functionalization. It is fully expected that these insights will enable efforts to improve the selectivity and expand the scope of this reaction as well as aid reaction design in the field of catalytic C–H functionalization as a whole. Methods Computational Details The Gaussian 09 suite of programs46 was used for all calculations. Geometry optimizations and frequency calculations for all reported structures were performed at the B3LYPD3/BS1 level of theory, where BS1 = Lanl2dz for Pd, Br, I and K and 6-31G(d,p) for all other atoms, with the corresponding Hay-Wadt effective core potentials (ECP) and Grimme’s empirical dispersion-correction with Becke-Johnson damping for B3LYP.47 Each reported minimum has zero imaginary frequencies and each transition state (TS) structure has only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed for transition state structures to confirm their identity. Bulk solvent effects are incorporated for all calculations using the self-consistent reaction field polarizable continuum model (IEF-PCM)48-50 with dichloromethane as the solvent. Conformational searching of the intermediates and transition states was performed manually to locate the lowest energy structures. Natural bond orbital (NBO) analysis51-52 was performed for selected structures using the NBO program (version 3.1)53, as implemented in G09. Donor-acceptor interactions are analyzed with the second-order perturbation of the natural bond orbitals. This analysis provides a quantitative measure (E(2)ij) of the interaction between an occupied donor NBO (i) and an empty acceptor NBO (j).40 We refined the energies of selected free energy barriers using single point energy calculations at the B3LYP-D3BJ/BS2 level of theory, where BS2 = Lanl08(f) for Pd 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

Lanl08(d) for Br and I with the corresponding ECPs54 and 6-311+g(2d,p) for all other atoms. (See SI for details.) Experimental Details: See the Supporting Information ASSOCIATED CONTENT Supporting Information. Synthetic procedures, Product characterization, NMR spectra, X-ray data, Computational details, Energies and frequency analysis, Cartesian coordinates of all reported structures. This material is available free of charge via the Internet at http://pubs.acs.org AUTHOR INFORMATION Corresponding Authors [email protected], [email protected] NOTES The authors declare no competing financial interests. ACKNOWLEDGMENT This work was supported by the National Science Foundation under the CCI Center for Selective C–H Functionalization (CHE-1700982). K.U. acknowledges the MitsubishiTanabe Pharma Corporation (Japan) for a one-year leave to carry out these studies at UC Berkeley. D.G.M. gratefully acknowledges the NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry Emerson Center for Scientific Computation at Emory University. We are grateful to Ms. Hwisoo Ree (UC Berkeley) for some preliminary experiments on substrate preparation. We thank Dr. Antonio DiPasquale (U.C. Berkeley) and Dr. Nicholas Settineri (U.C. Berkeley) for single crystal X-ray diffraction studies. Xray crystallography instrumentation at U.C. Berkeley is supported by NIH Shared Instrumentation Grant S10-RR027172. The AV-600, AV-500, DRX-500, AVQ-400, and AVB-400 NMR spectrometers are partially supported by NIH grants SRR023679A and 1S10RR016634-01 and NSF grants CHE-9633007 and CHE-0130862.

References 1. Strategies for Palladium-Catalyzed Non-Directed and Directed C-H Bond Functionalization Maiti, D.; Kapdi, A. R., Eds. Elsevier: 2017; p 1-486. 2. C-H Bond Activation and Catalytic Functionalization I Dixneuf, P. H.; Doucet, H., Eds. Springer International Publishing: Switzerland, 2016; Vol. 55. 3. C-H Bond Activation and Catalytic Functionalization Ii Dixneuf, P. H.; Doucet, H., Eds. Springer International Publishing: Switzerland, 2016; Vol. 56. 4. Godula, K.; Sames, D. C-H Bond Functionalization in Complex Organic Synthesis. Science 2006, 312, 67-72.


Page 16 of 20

Page 17 of 20 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. McMurray, L.; O'Hara, F.; Gaunt, M. J. Recent Developments in Natural Product Synthesis Using Metal-Catalysed C-H Bond Functionalisation. Chem. Soc. Rev. 2011, 40, 1885-1898. 6. Ackermann, L. Carboxylate-Assisted Transition-Metal-Catalyzed C-H Bond Functionalizations: Mechanism and Scope. Chem. Rev. 2011, 111, 1315-1345. 7. Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C-C Bond Formation Via Heteroatom-Directed C-H Bond Activation. Chem. Rev. 2010, 110, 624655. 8. Lyons, T. W.; Sanford, M. S. Palladium-Catalyzed Ligand-Directed C-H Functionalization Reactions. Chem. Rev. 2010, 110, 1147-1169. 9. Viart, H. M. F.; Bachmann, A.; Kayitare, W.; Sarpong, R. b-Carboline Amides as Intrinsic Directing Groups for C(sp2)-H Functionalization. J. Am. Chem. Soc. 2017, 139, 1325-1329. 10. He, G.; Chen, G. A Practical Strategy for the Structural Diversification of Aliphatic Scaffolds through the Palladium-Catalyzed Picolinamide-Directed Remote Functionalization of Unactivated C(sp3)-H Bonds. Angew. Chem., Int. Ed. 2011, 50, 5192-5196. 11. Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. Palladium-Catalyzed Transannular C-H Functionalization of Alicyclic Amines. Nature 2016, 531, 220-224. 12. Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regloselective Arylation of 3 sp C-H Bonds Catalyzed by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 1315413155. 13. He, G.; Zhao, Y. S.; Zhang, S. Y.; Lu, C. X.; Chen, G. Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines Via Palladium Catalyzed Intramolecular Amination of C(sp3)-H and C(sp2)-H Bonds at Gamma and Delta Positions. J. Am. Chem. Soc. 2012, 134, 3-6. 14. Nadres, E. T.; Daugulis, O. Heterocycle Synthesis Via Direct C-H/N-H Coupling. J. Am. Chem. Soc. 2012, 134, 7-10. 15. Zhang, S. Y.; He, G.; Nack, W. A.; Zhao, Y. S.; Li, Q.; Chen, G. PalladiumCatalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)-H Bonds with Alkyl Iodides. J. Am. Chem. Soc. 2013, 135, 2124-2127. 16. Deb, A.; Singh, S.; Seth, K.; Pimparkar, S.; Bhaskararao, B.; Guin, S.; Sunoj, R. B.; Maiti, D. Experimental and Computational Studies on Remote Gamma-C(sp3)-H Silylation and Germanylation of Aliphatic Carboxamides. ACS Catal. 2017, 7, 81718175. 17. Ling, P. X.; Fang, S. L.; Yin, X. S.; Chen, K.; Sun, B. Z.; Shi, B. F. PalladiumCatalyzed Arylation of Unactivated g-Methylene C(sp3)–H and d-C–H Bonds with an Oxazoline-Carboxylate Auxiliary. Chem. Eur. J. 2015, 21, 17503-17507. 18. Albert, J.; Ariza, X.; Calvet, T.; Font-Bardia, M.; Garcia, J.; Granell, J.; Lamela, A.; Lopez, B.; Martinez, M.; Ortega, L.; Rodriguez, A.; Santos, D. NH2 as a Directing Group: From the Cyclopalladation of Amino Esters to the Preparation of Benzolactams by Palladium(II)-Catalyzed Carbonylation of N-Unprotected Arylethylamines. Organometallics 2013, 32, 649-659. 19. Xu, J. W.; Zhang, Z. Z.; Rao, W. H.; Shi, B. F. Site-Selective Alkenylation of Delta-C(sp3)-H Bonds with Alkynes Via a Six-Membered Palladacycle. J. Am. Chem. Soc. 2016, 138, 10750-10753.


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

20. Xing, Y. Y.; Liu, J. B.; Sun, C. Z.; Huang, F.; Chen, D. Z. The Underlying Factors Controlling the Pd-Catalyzed Site-Selective Alkenylation of Aliphatic Amines. Dalton Trans. 2017, 46, 9430-9439. 21. Landge, V. G.; Midya, S. P.; Rana, J.; Shinde, D. R.; Balaraman, E. Expedient Cobalt-Catalyzed C-H Alkynylation of (Enantiopure) Benzylamines. Org. Lett. 2016, 18, 5252-5255. 22. Landge, V. G.; Jaiswal, G.; Balaraman, E. Cobalt-Catalyzed Bis-Alkynylation of Amides Via Double C-H Bond Activation. Org. Lett. 2016, 18, 812-815. 23. Sauermann, N.; Gonzalez, M. J.; Ackermann, L. Cobalt(III)-Catalyzed C-H Alkynylation with Bromoalkynes under Mild Conditions. Org. Lett. 2015, 17, 5316-5319. 24. Landge, V. G.; Shewale, C. H.; Jaiswal, G.; Sahoo, M. K.; Midya, S. P.; Balaraman, E. Nickel-Catalyzed Direct Alkynylation of C(sp2)-H Bonds of Amides: An "Inverse Sonogashira Strategy" to Ortho-Alkynylbenzoic Acids. Catal. Sci. Technol. 2016, 6, 1946-1951. 25. Liu, Y. H.; Liu, Y. J.; Yan, S. Y.; Shi, B. F. Ni(II)-Catalyzed Dehydrative Alkynylation of Unactivated (Hetero) Aryl C-H Bonds Using Oxygen: A User-Friendly Approach. Chem. Commun. 2015, 51, 11650-11653. 26. Liu, Y. J.; Liu, Y. H.; Yan, S. Y.; Shi, B. F. A Sustainable and Simple Catalytic System for Direct Alkynylation of C(sp2)-H Bonds with Low Nickel Loadings. Chem. Commun. 2015, 51, 6388-6391. 27. Yi, J.; Yang, L.; Xia, C. G.; Li, F. W. Nickel-Catalyzed Alkynylation of a C(sp2)H Bond Directed by an 8-Aminoquinoline Moiety. J. Org. Chem. 2015, 80, 6213-6221. 28. Ano, Y.; Tobisu, M.; Chatani, N. Ruthenium-Catalyzed Direct OrthoAlkynylation of Arenes with Chelation Assistance. Synlett 2012, 2763-2767. 29. Ruan, Z. X.; Sauermann, N.; Manoni, E.; Ackermann, L. Manganese-Catalyzed C-H Alkynylation: Expedient Peptide Synthesis and Modification. Angew. Chem., Int. Ed. 2017, 56, 3172-3176. 30. Cera, G.; Haven, T.; Ackermann, L. Iron-Catalyzed C-H Alkynylation through Triazole Assistance: Expedient Access to Bioactive Heterocycles. Chem. Eur. J. 2017, 23, 3577-3582. 31. Canty, A. J.; Denney, M. C.; Skelton, B. W.; White, A. H. Carbon-Oxygen Bond Formation at Organopalladium Centers: The Reactions of Pdmer(L-2) (R = Me, 4-Tolyl; L-2= TMEDA, Bpy) with Diaroyl Peroxides and the Involvement of Organopalladium(IV) Species. Organometallics 2004, 23, 1122-1131. 32. Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. Computational Study of the Mechanism of Cyclometalation by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13754-13755. 33. Zhang, L.; Fang, D. C. An Explicit Interpretation of the Directing Group Effect for the Pd(OAc)2-Catalyzed Aromatic C-H Activations. J. Org. Chem. 2016, 81, 74007410. 34. Hancock, R. D. Chelate Ring Size and Metal-Ion Selection - the Basis of Selectivity for Metal-Ions in Open-Chain Ligands and Macrocycles. J. Chem. Educ. 1992, 69, 615-621. 35. Bosque, R.; Maseras, F. A Theoretical Assessment of the Thermodynamic Preferences in the Cyclopalladation of Amines. Eur. J. Inorg. Chem. 2005, 20, 40404047.


Page 18 of 20

Page 19 of 20 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

36. Ye, X. H.; Xu, C.; Wojtas, L.; Akhmedov, N. G.; Chen, H.; Shi, X. D. Silver-Free Palladium-Catalyzed sp3 and sp2 C-H Alkynylation Promoted by a 1,2,3-Triazole Amine Directing Group. Org. Lett. 2016, 18, 2970-2973. 37. Zhao, Y. S.; He, G.; Nack, W. A.; Chen, G. Palladium-Catalyzed Alkenylation and Alkynylation of Ortho-C(sp2)-H Bonds of Benzylamine Picolinamides. Org. Lett. 2012, 14, 2948-2951. 38. Tobisu, M.; Ano, Y.; Chatani, N. Palladium-Catalyzed Direct Alkynylation of CH Bonds in Benzenes. Org. Lett. 2009, 11, 3250-3252. 39. Tan, E.; Konovalov, A. I.; Fernandez, G. A.; Dorel, R.; Echavarren, A. M. Ruthenium-Catalyzed Peri- and Ortho-Alkynylation with Bromoalkynes Via Insertion and Elimination. Org. Lett. 2017, 19, 5561-5564. 40. Alabugin, I. V.; Zeidan, T. A. Stereoelectronic Effects and General Trends in Hyperconjugative Acceptor Ability of Sigma Bonds. J. Am. Chem. Soc. 2002, 124, 31753185. 41. Zanini, M. L.; Meneghetti, M. R.; Ebeling, G.; Livotto, P. R.; Rominger, F.; Dupont, J. The Retro-Chloropalladation Reaction of Heterosubstituted Alkynes. Polyhedron 2003, 22, 1665-1671. 42. Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu, X. Y.; So, J. H.; Chelius, E. C. The Beta Effect of Silicon and Related Manifestations of Sigma Conjugation. Acc. Chem. Res. 1999, 32, 183-190. 43. Deb, A.; Bag, S.; Kancherla, R.; Maiti, D. Palladium-Catalyzed Aryl C-H Olefination with Unactivated, Aliphatic Alkenes. J. Am. Chem. Soc. 2014, 136, 1360213605. 44. Deb, A.; Hazra, A.; Peng, Q.; Paton, R. S.; Maiti, D. Detailed Mechanistic Studies on Palladium-Catalyzed Selective C-H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling. J. Am. Chem. Soc. 2017, 139, 763-775. 45. Jakt, M.; Johannissen, L.; Rzepa, H. S.; Widdowson, D. A.; Wilhelm, R. A Computational Study of the Mechanism of Palladium Insertion into Alkynyl and Aryl Carbon-Fluorine Bonds. J. Chem. Soc., Perkin Trans. 2 2002, 0, 576-581. 46. Gaussian 09, Revision E.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. 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, M. J.; 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, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 47. Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32, 14561465.


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

48. Cances, E.; Mennucci, B.; Tomasi, J. A New Integral Equation Formalism for the Polarizable Continuum Model: Theoretical Background and Applications to Isotropic and Anisotropic Dielectrics. J. Chem. Phys. 1997, 107, 3032-3041. 49. Mennucci, B.; Tomasi, J. Continuum Solvation Models: A New Approach to the Problem of Solute's Charge Distribution and Cavity Boundaries. J. Chem. Phys. 1997, 106, 5151-5158. 50. Scalmani, G.; Frisch, M. J. Continuous Surface Charge Polarizable Continuum Models of Solvation. I. General Formalism. J. Chem. Phys. 2010, 132, 114110-114124. 51. Reed, A. E.; Weinhold, F. Natural Localized Molecular-Orbitals. J. Chem. Phys. 1985, 83, 1736-1740. 52. Reed, A. E.; Weinstock, R. B.; Weinhold, F. Natural-Population Analysis. J. Chem. Phys. 1985, 83, 735-746. 53. Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO, version 3.1; University of Wisconsin: Madison, WI, 1996 54. Roy, L. E.; Hay, P. J.; Martin, R. L. Revised Basis Sets for the Lanl Effective Core Potentials. J. Chem. Theory Comput. 2008, 4, 1029-1031. TOC GRAPHIC:

N N H

L δ N Pd N 6

Hδ NH

Pd(II)

N H

O γ

L

N H

O

H

γ R X X = Br, Cl

H

Migratory Insertion Vinyl β-elimination

N

5

O δ H

R

X

Oxidative Addition Reductive Elimination

X=I

via β-Pd Effect:

R δ

N N H

γ

N Pd

O

N H

N γ

N

Br

R

NH

H

O

Pd

H N

δ

NH R γ


Page 20 of 20

Understanding Regiodivergence in a Pd(II)-Mediated Site-Selective C

Recommend Documents