Mechanistic Insights on Orthogonal Selectivity in Heterocycle Synthesis

Article abstract of DOI:10.1021/acscatal.8b02537

Recently, we have developed a method for catalytic regioselective synthesis of 2-substituted and 3-substituted benzofurans starting from phenols. The choice of reacting partner, olefin versus α,β-unsaturated acid, is critical to dictate the isomeric product formation. Instances are known where these olefinic partners did not complement each other and yield a similar outcome. In the current work, we have addressed this paradox with emphasis on (a) the origin of orthogonal selectivity and (b) the key requirements to expect complementary behavior. Experimental and computational studies provided important mechanistic insights. Electrostatic compatibility during migratory insertion and the positioning of the carboxylic acid moiety in catalytic steps are found to exert a paramount impact in determining the regioselectivity. The study offers a predictable single component tuning tool to control the regioselectivity.

Full text of DOI:10.1021/acscatal.8b02537

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Article
Mechanistic Insights on Orthogonal Selectivity in Heterocycle Synthesis
Arun Maji, Yernaidu Reddi, Raghavan B. Sunoj, and Debabrata Maiti
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02537 • Publication Date (Web): 20 Sep 2018
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Mechanistic Insights on Orthogonal Selectivity in
Heterocycle Synthesis
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Arun Maji,†§ Yernaidu Reddi,† Raghavan B. Sunoj†* and Debabrata Maiti†*
†Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076,
India
§ Department of Chemistry; University of Illinois at UrbanaꢀChampaign, Illinois 61801, USA
ABSTRACT: Recently we have developed a method for catalytic regioselective synthesis of 2ꢀ
substituted and 3ꢀsubstituted benzofurans starting from phenols. The choice of reacting partner,
olefin versus α,β−unsaturated acid, is critical to dictate the isomeric product formation. Instances
are known where these olefinic partners did not complement each other and yield a similar
outcome. In the current work, we have addressed this paradox with emphasis on (a) the origin of
orthogonal selectivity, and (b) the key requirements to expect complementary behavior.
Experimental and computational studies provided important mechanistic insights. Electrostatic
compatibility during migratory insertion and the positioning of the carboxylic acid moiety in
catalytic steps are found to exert a paramount impact in determining the regioselectivity. The
study offers a predictable single component tuning tool to control the regioselectivity.
KEYWORDS: Heterocycle • orthogonal selectivity • mechanism• kinetics• computational
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INTRODUCTION
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Achieving site selective transformation on the reactive functional group is a key goal in organic
synthetic chemistry.1 Preferential formation of an isomer in a competitive environment are
largely facilitated by the manipulation of the reaction parameters. In this context, asymmetric
synthesis, chemoselective functionalizations, regioselective transformations are explored in great
details.2ꢀ5 In comparison to the traditional chemical approach, catalytic routes offer a
significantly broader scope of calibration.6ꢀ10 For instance, application of regioselective
functionalization of the unsaturated chemical bonds has largely attributed by the development of
transition metal catalysts.1, 11ꢀ17 The installation of efficient ligands further expands the scope of
fine tuning the selectivity.18ꢀ22 Despite superior selectivity, catalyst dependent selective
functionalization techniques are transformation specific and offers a narrow scope of
generalization. Furthermore, expensive customized ligands make the scalability less affordable.
As an alternative significant amount of effort has been invested to utilize the abundant,
economical olefins as the key component to control the regioselectivity in the product.23ꢀ30 In this
regard our group has demonstrated regioselective synthesis of heterocyclic cores from olefinic
feedstock where the regioselectivity is largely governed by the choice of the olefinic partner.23, 27
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Heterocyclic units with proper positioning of the substituents are extremely important in
the development of functional small molecules and in diversityꢀoriented synthesis. Benzofurans
are one of such prevalent structural motifs found in natural products, pharmaceuticals,
agrochemicals and organic materials.31ꢀ39 Over the last two decades several synthetic methods
have been developed.40ꢀ50 Generally, heteroannulation of alkynylated and olefinated phenols or
arenes are employed to generate functionalized benzofurans.51ꢀ59 Coupling reactions with
appropriate prefunctionalized substrates are also known to be effective.60ꢀ62 Recently direct
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conversion of simple phenols to benzofurans has been explored.23, 27ꢀ28, 63ꢀ68 Our group has
demonstrated the formation of 2ꢀsubstituted benzofurans from phenols by using abundant
olefinic feedstock.23 An orthogonal route for 3ꢀsubstituted benzofuran synthesis was also
developed (Scheme 1).27 Notably, such regioselective synthesis from simple phenol derivatives is
often accompanied by a strained metallacycle formation compounded by a difficult reductive
elimination as well as a competitive oxidative product formation.69ꢀ74 Our methods, however,
offered excellent yield and selectivity. It was observed that the orthogonal selectivity largely
dependents on the choice of the olefinic partners and thus offering a handle to tune a single
reactant to adjust the selectivity.
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Scheme 1. Orthogonal selectivity in benzofuran synthesis
A similar mode of orthogonal selectivity was obtained for 2ꢀ and 3ꢀsubstituted indole
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with aniline as the coupling partner.24,
Interestingly, in FujiwaraꢀMoritani reaction,
replacement of olefins by α, β−unsaturated acids generated isomeric branched olefinated
products, a challenging target for unactivated coupling partners.75ꢀ76 Further, simultaneous
functionalizations at 2ꢀ and 3ꢀpositions of benzofuran were also realized.28 Rovis and coworkers
reported similar selectivity inversion in the synthesis of 2ꢀ and 3ꢀsubstituted pyridines (Scheme
2).29ꢀ30
Seemingly, the selection of olefinic partners is critical to the selectivity inversion and can
be implemented for the generation of diverse core structures.77ꢀ82 Although electronically olefins
and α, β−unsaturated acids are different, instances are known where one acts as an alternative to
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80, 83ꢀ84
other.25,
Therefore understanding the mechanistic intricacies of olefin dependent
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regioselective transformation is essential to gain a predictable control.
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In the current work, we have reasoned the essential characteristics of olefin controlled
regioselective synthesis of benzofuran heterocycle with emphasis on (a) the origin of orthogonal
selectivity, and (b) the essential requirement for such complementary behavior. Experimental and
computational studies are employed to develop deeper understanding and offer predictable
control of regioselectivity.
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Scheme 2. Overview and key mechanistic steps for benzofuran synthesis.
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The key mechanistic features in the formation of benzofuran from phenol can be
considered as follows; palladium acetate can first combine with 1,10ꢀphen (L2) to form the active
catalyst (1). An ortho palladation of phenol in the catalystꢀsubstrate complex can give rise to
intermediates 2 and 3. Subsequent olefin uptake can result in a πꢀadduct 4 which upon migratory
insertion can generate intermediate 5 or 6 depending on the nature of the olefins. Finally, a
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combination of βꢀhydride elimination, cyclization and aromatization completes the regioselective
synthesis of benzofuran. We intend to probe the origin of the mode of migratory insertion
between phenol and olefin in 4 as it can be exploited toward harnessing the product
regioselectivity.
Formation of Palladated Intermediate:
In presence of 1,10ꢀphen ligand, Pd(OAc)2 is likely to form the [Pd(phen)]II species as the active
catalyst (1). The proposition of organometallic intermediates in the catalytic cycle is verified by
trapping the active catalysts with iodide, in the form of Pd(1,10ꢀphen)I2 (Scheme 3i). The
isolated complex is catalytically active, yet kinetically sluggish due to its stability and thus
requires elevated reaction temperature. The active catalyst (1) once formed, trends to interact
with phenol which is likely to go through a Pd−O or Pd−C(ortho) coordination. The formation of
later (Scheme 2; 2 or 3) is confirmed by inserting it to the nitrilic unsaturation of acetonitrile in a
square planar complex (Scheme 3i). The coordinating nature of the nitrile group largely
attributes to the stability of the complex which is likely to resemble the olefin insertion
intermediate (5 or 6) of the catalytic cycle. In addition, control experiments suggest that the
orthoꢀstyrenyl phenol can cyclize to benzofuran whereas vinyl phenyl ether does not (Scheme
3ii).23 Further, failure of sodium phenoxide as a substrate indicates the Pd−C(ortho) species as a
favorable reactive intermediate (Scheme 3ii).23 Moreover, Pd−O connectivity, if formed, can
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switch to Pd−C(ortho) under the reaction condition.85 These observations clearly indicate the
intermediacy of an orthoꢀpalladated species. Arguably phenol is more prone to phenoxide
formation, yet softer nature of orthoꢀcarbon over phenolic oxygen can provide a better anchoring
for palladium. The failure of the phenoxide is largely attributed by the hardꢀsoft mismatch
among the phenoxide and palladium center.
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a reactions were done under respective standard conditions
Scheme 3. (i) Detection of intermediates (ii) substrate dependent control experiments
DFT calculations were performed to compare the energetics of Pd−C (ortho) and Pd−O
bond formation. Calculations suggest that the active catalyst (1,10ꢀPhen)Pd(OAc)2 (1) is likely to
be formed from Pd(OAc)2 and 1,10ꢀphen (Figure 1).85ꢀ86 As shown in path A in Figure 1, the Pdꢀ
bound acetate abstracts the phenolic proton with a concomitant formation of the
Pd−C(ortho) bond (2) via transition state TS(1-2) with a barrier of 8 kcal/mol. On the other hand,
the cleavage of ortho C−H bond (from 2 to 3) involves a higher barrier of 14 kcal/mol (TS(2-3)).
Subsequent migratory insertion of styrene to the Pd−C(ortho) bond of 3 via TS(4-5) leads to the
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formation of orthoꢀolefinated intermediate (5) with a barrier of 14 kcal/mol. The formation of 5
is found to be exoergic by 5 kcal/mol and is also characterized experimentally. Alternatively, in
path B (Pd−O bond formation) a similar deprotonation of phenol by acetate is a barrierless
process forming an intermediate a via TS(1-a). Despite this initial energetic advantage, the
migratory insertion of styrene to form b is found to be highly unfavorable by 30 kcal/mol.
Moreover, the generation of intermediate b is endoergic by 4 kcal/mol. The computed kinetic and
thermodynamic features suggest the involvement of an orthoꢀaryl Cꢀolefinated phenol (path A)
over Oꢀolefination (path B), which is in coherence with the experimental observations.
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Figure 1. Gibbs free energy (kcal/mol) profile for the formation of intermediate 5 at the
SMD(DCE) /B3LYPꢀD3/def2ꢀTZVP//B3LYP/6ꢀ31G**,LanL2DZ(Pd).
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Differential Insertion of Olefin:
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Once the palladium phenol is formed, it reacts with the olefinic partner forming the 5 or 6, the
key intermediate to harness regioselective product formation. Hammett analysis on the phenol
system, with a series of diverse substituents, suggests the formation of negative charge density.
The reaction with electron withdrawing groups are found to be more facile as it favors the
stabilizing the negative charge density and palladation (Scheme 4i). A similar substituent effect is
observed for 3ꢀsubstituted benzofuran synthesis (Scheme 4ii).
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Scheme 4. Hammett analysis for the reaction of phenol with (i) styrene (ii) cinnamic acid
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Hammett analysis on the olefinic partner suggests the formation of partial positive charge
density on the system (Scheme 5), which is stabilized by the presence of electron donating
groups. However, unlike the styrenyl systems, electron deficient cinnamic acids are consumed
without the formation of 3ꢀsubstituted benzofurans.85 Such an observation can be rationalized by
the facile decarboxylation of electron deficient cinnamic acids prior to the binding of Pd besides
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its reduced metal binding ability.87ꢀ89
Hammett Analysis of Styrene
(i)
OH
O2N
standard condition
+
O
(1:2)
R
NO2
R
48-75%
yield
kobs
0.127
0.098
0.081
0.067
0.029
0.027
Groups (R)
OMe
Me
F
Cl
CN
NO2
H
0.083 (k0)
Hammett Analysis of Cinnamic Acid
(ii)
COOH
R
OH
O2N
standard condition
+
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NO2
O
R
kobs
Groups (R)
OMe
0.093
0.089
OEt
Me
F
0.085
0.081
Cl
0.071
0.039 (k0)
H
Scheme 5. Hammett analysis for the reaction of (i) styrene (ii) cinnamic acid
Although both the olefinic partners show the signature of the partial positive charge
accumulation, yet the distribution of charge cannot be concluded from the Hammett analysis.
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The relative distribution of the computed positive charge on the olefinic carbons (C1 and C2;
Figure 2) is found to be different for styrene and cinnamic acid. Relatively more positive charge
on the C2 carbon in the case of styrene and that on C1 carbon of cinnamic acid seem more likely.
Difference in polarization of the olefinic moiety can result in different migratory insertion and
regioselectivity. Notably, a greater slope in Hammett plot for styrene over cinnamic acid aligns
with proposed partial positive charge formation at C1 for styrene and C2 for cinnamic acid.
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In particular, the DFT calculations90 on the regioꢀcontrolling migratory insertion step
provided valuable insights. Different possibilities of the regioꢀcontrolling transition states for
both styrene (S) and cinnamic acid (CA) are considered.85 The calculations suggest that the
transition state (TS) for the nucleophilic addition at C2 carbon of styrene (SC2) is 2.2 kcal/mol
lower than the addition at C1 (SC1) as shown in Figure 2. On the other hand, the TS for the
nucleophilic addition at C1 carbon of cinnamic acid (CAC1) is 5.7 kcal/mol lower than the
addition at C2 carbon (CAC2).
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Figure 2. Olefin binding to orthoꢀpalladated phenol and optimized TS geometries of the
migratory insertion step, TS(4-5). ꢀꢀG‡ (kcal/mol) are in parenthesis. L1=SMD(DCE)/B3LYPꢀ
D3/def2ꢀTZVP//B3LYP/6ꢀ31G**,LanL2DZ(Pd)
31+G**,SDD(Pd)//B3LYP/6ꢀ31G**,LanL2DZ(Pd).
and
L2=SMD(DCE)/M06/6ꢀ
Additional distortionꢀinteraction analysis on these TSs helped us understand the origin of
the computed regioselectivity.49, 91ꢀ92 Higher interaction energy between styrene and orthoꢀ
palladated phenol in SC2 renders C2 addition more favorable in styrene whereas a relatively
lower distortion in both the reacting partners (cinnamic acid and orthoꢀpalladated phenol) in
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CAC1 favors addition at C1 carbon in the case of cinnamic acid.
In the case of styrene, the
difference in Gibbs free energy between the regiocontrolling TSs is found to arise due to higher
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interaction energies in the most favored TS geometry that corresponds to the major isomer.
However, in the case of cinnamic acid, the distortion energy in the TS leading to the major
product is lower, suggesting a prominent role of distortion in regioselectivity (Figure 2).
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Impact of Decarboxylation:
Although it is evident that distinct relative charge distribution on olefin is the key to differential
regioselective insertion, the decarboxylation of cinnamic acid plays a crucial role to maintain
such orthogonality. While studying the interaction of the orthoꢀolefinated phenol (Scheme 6i)
with palladium cis olefin from a cisꢀtrans mixture of 2ꢀpropenyl phenol is found to be consumed
faster than the trans isomer. The interaction of olefinated phenol with palladium can also be
observed based on the change of the UVꢀVis signal of substrate.85 Analogous experiments on
cinnamic acid revealed that the decarboxylation is a critical step. 4ꢀmethyl cinnamic acid when
converted to cinnamate and treated under the standard condition, a mixture of 2ꢀ and 3ꢀ
substituted benzofuran is obtained unlike the parent cinnamic acid that exclusively gave 3ꢀ
substituted benzofuran (Scheme 6ii). In addition, efficient decarboxylation triggers the formation
of styrene and 2ꢀsubstituted product from cinnamic acid.85
Presumably, moderate
decarboxylation rate with catalytic Cuꢀphen system over other decarboxylative condition
reinforced the necessary step sequence. Positioning of decarboxylation following the olefination
step is the key requirement for the selectivity. Retaining such step sequence ensured the
complementary behavior of olefin and α, β ꢀunsaturated acids.82, 93ꢀ95
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Scheme 6. (i) NMR study of olefinꢀPd interaction (ii) Role of Decarboxylation
Kinetics of the reaction:
During the kinetic analysis, unlike styrene, all other components are found to influence the
overall yield of the reaction, but not the regioselectivity (Scheme 7i).85 A similar outcome is also
observed for cinnamic acid. Kinetically, a first order rate dependency is noted for palladium
under both the conditions (Scheme 7ii).27 The reaction followed a first order kinetics with phenol
and a negative order kinetics with styrene.23 Isotope labeling experiment with d2(C2)ꢀ4ꢀ
methoxystyrene shows a product partitioning of 1.27 (PH/PD) whereas 4ꢀmethoxystyrene is
found to be more reactive than d1(C1)ꢀ4ꢀmethoxystyrene [PH/PD = 2.1]. A value of 1.84 (kH/kD)
was observed for the ortho C−H bond cleavage of phenol.23 Such an observation eliminates the
possibility of olefinic and ortho C−H bond cleavage in the rate determining step (RDS).96 It is
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likely that a steady state equilibrium is maintained among the intermediates with no distinct rate
limiting step.85
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Role of Components
(i)
OH
O2N
standard condition
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+
O
(1:2)
NO2
Order of Palladium
(ii)
OH
O2N
Pd(OAc)2 (cat)
standard condition
+
(1:2)
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NO2
Order = 0.96 1.0
deuterated substrate
O2N
D
D
(iii)
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standard condition
+
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O
OMe
OMe
PH/PD = 1.27
(1:1)
OMe
(iv)
OMe
deuterated substrate
D
O2N
4-nitrophenol (2 eq.)
standard condition
or
yield ratio = 2.1
OMe
OMe
Scheme 7. (i) Role of different components (ii) determination of order, and KIE studies with
deuterated olefins (iii) and (iv).
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We have rationalized how the choice of olefinic coupling partner dictates the
regioselective synthesis of 2ꢀ and 3ꢀsubstituted benzofurans starting from a simple phenol
precursor. The change in the fashion of olefin insertion upon moving from styrenyl to
cinnamoyl system is largely responsible for the regioiselectivity. Although both the
olefins develop a partial positive charge during the course of the reaction, their relative
distributions are different and thus the mode of migration. Such distinctions are
maintained only when insertion of cinnamoyl group occurs prior to decarboxylation. A
change in such step sequence leads to the loss of regioselectivity. Thus, under a facile
decarboxylative condition orthogonal behaviour is compromised and both the olefins lead
to similar regioisomeric products. Therefore, maintaining migratory insertion followed by
decarboxylation step is the key requirement for an olefin dependent regioselective
synthesis of benzofurans.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
DM: dmaiti@chem.iitb.ac.in;
RBS: sunoj@chem.iitb.ac.in
Present Addresses
§ Department of Chemistry; University of Illinois at UrbanaꢀChampaign, Illinois 61801, USA
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Notes
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The authors declare no competing financial interest
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Supporting Information
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All the experimental details, procedures, spectroscopic characterizations, crystallographic data
(CIF) are provided in the supporting information.
ACKNOWLEDGMENT
This activity is supported by SERB, India (EMR/2015/000164). Generous computing time from
IIT Bombay supercomputing is acknowledged.
REFERENCES
1.
Aminocarbonylation of Styrenes with Aminophenols. J. Am. Chem. Soc. 2016, 138, 6629ꢀ6635.
2. Bolm, C.; Beller, M., Transition Metals for Organic Synthesis. WileyꢀVCH: Weinheim:
2004; Vol. 1. 2nd Edition.
Xu, T.; Sha, F.; Alper, H., Highly LigandꢀControlled Regioselective PdꢀCatalyzed
3.
Berkessel, A.; Gröger, H., Asymmetric Organocatalysis ꢀFrom Biomimetic Concepts to
Applications in Asymmetric Synthesis. WileyꢀVCH: Weinheim,: 2005.
4.
Applications. WileyꢀVCH: Weinheim: 2013; Vol. 1ꢀ3.
5. Walsh, P. J.; Kozlowski, M. C., Fundamentals of Asymmetric Catalysis;. University
Science Books: Sausalito, CA: 2009.
6. Tsuji, J., Palladium Reagents and Catalysts: New Perspectives for the 21st Century.
WileyꢀVCH: Chichester, U.K.: 2005.
7. Molnár, A., PalladiumꢀCatalyzed Coupling Reactions: Practical Aspects and Future
Developments. WileyꢀVCH: Weinheim, : 2013.
8. Gadge, S. T.; Bhanage, B. M., Recent developments in palladium catalysed carbonylation
reactions. RSC Adv. 2014, 4, 10367ꢀ10389.
9. McDonald, R. I.; Liu, G.; Stahl, S. S., Palladium(II)ꢀCatalyzed Alkene Functionalization
Dalko, P. I., Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and
via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications.
Chem. Rev. 2011, 111, 2981ꢀ3019.
10.
by sp³ CꢀH Activation. Synthesis 2011, 2011, 2590ꢀ2594.
11. Basnet, P.; Dhungana, R. K.; Thapa, S.; Shrestha, B.; Kc, S.; Sears, J. M.; Giri, R., Niꢀ
Wang, C.; Ge, H., PalladiumꢀMediated Olefination of 2ꢀ(tertꢀButyldimethylsilyl)pyridine
Catalyzed Regioselective β,δꢀDiarylation of Unactivated Olefins in Ketimines via Ligandꢀ
ACS Paragon Plus Environment
16

Page 17 of 22
ACS Catalysis
1
2
3
4
5
6
7
8
Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones.
J. Am. Chem. Soc. 2018, 140, 7782ꢀ7786.
12.
Yang, K. S.; Gurak, J. A.; Liu, Z. J.; Engle, K. M., Catalytic, Regioselective
Hydrocarbofunctionalization of Unactivated Alkenes with Diverse C–H Nucleophiles. J. Am.
Chem. Soc. 2016, 138, 14705ꢀ14712.
9
13.
Xu, L.; Hilton, M. J.; Zhang, X.; Norrby, P. O.; Wu, Y. D.; Sigman, M. S.; Wiest, O.,
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
Mechanism, Reactivity, and Selectivity in PalladiumꢀCatalyzed RedoxꢀRelay Heck Arylations of
Alkenyl Alcohols. J. Am. Chem. Soc. 2014, 136, 1960ꢀ1967.
14.
Bartók, M., Unexpected Inversions in Asymmetric Reactions: Reactions with Chiral
Metal Complexes, Chiral Organocatalysts, and Heterogeneous Chiral Catalysts. Chem. Rev.
2010, 110, 1663ꢀ1705.
15.
Guo, J.; Teo, P., AntiꢀMarkovnikov oxidation and hydration of terminal olefins. Dalton
Trans. 2014, 43, 6952ꢀ6964.
16.
Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J., Metalꢀ
catalyzed reductive coupling of olefinꢀderived nucleophiles: Reinventing carbonyl addition.
Science 2016, DOI: 10.1126/science.aah5133
17.
Nguyen, K. D.; Herkommer, D.; Krische, M. J., RutheniumꢀBINAP Catalyzed Alcohol
C–H tertꢀPrenylation via 1,3ꢀEnyne Transfer Hydrogenation: Beyond Stoichiometric Carbanions
in Enantioselective Carbonyl Propargylation. J. Am. Chem. Soc. 2016, 138, 5238ꢀ5241.
18.
Gildner, P. G.; Colacot, T. J., Reactions of the 21st Century: Two Decades of Innovative
Catalyst Design for PalladiumꢀCatalyzed CrossꢀCouplings. Organometallics 2015, 34, 5497ꢀ
5508.
19.
Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J., Development of Preformed Pd
Catalysts for CrossꢀCoupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2,
1147ꢀ1164.
20.
Amination. Angew. Chem. Int. Ed. 2008, 47, 6338ꢀ6361.
21. Martin, R.; Buchwald, S. L., PalladiumꢀCatalyzed Suzuki−Miyaura CrossꢀCoupling
Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41, 1461ꢀ1473.
Surry D. , S.; Buchwald S. , L., Biaryl Phosphane Ligands in Palladium Catalyzed
22.
23.
Zhou, Q. L., Privileged Chiral Ligands and Catalysts. WileyꢀVCH: Weinheim: 2011.
Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D., PalladiumꢀCatalyzed Synthesis
of Benzofurans and Coumarins from Phenols and Olefins. Angew. Chem. Int. Ed. 2013, 52,
12669ꢀ12673.
24.
Sharma, U.; Kancherla, R.; Naveen, T.; Agasti, S.; Maiti, D., PalladiumꢀCatalyzed
Annulation of Diarylamines with Olefins through CꢀH Activation: Direct Access to Nꢀ
Arylindoles. Angew. Chem. Int. Ed 2014, 53, 11895ꢀ11899.
25.
Dihydrofurans from Aryl Ketones and Aromatic Olefins. Org. Lett. 2014, 16, 5446ꢀ5449.
26. Kancherla, R.; Naveen, T.; Maiti, D., Divergent Reactivity in PalladiumꢀCatalyzed
Naveen, T.; Kancherla, R.; Maiti, D., Radical Based Strategy toward the Synthesis of 2,3ꢀ
Annulation with Diarylamines and α,βꢀUnsaturated Acids: Direct Access to Substituted 2ꢀ
Quinolinones and Indoles. Chem. Eur. J. 2015, 21, 8723ꢀ8726.
27.
Agasti, S.; Sharma, U.; Naveen, T.; Maiti, D., Orthogonal selectivity with cinnamic acids
in 3ꢀsubstituted benzofuran synthesis through CꢀH olefination of phenols. Chem. Commun. 2015,
51, 5375ꢀ5378.
ACS Paragon Plus Environment
17

ACS Catalysis
Page 18 of 22
1
2
3
4
5
6
28.
Agasti, S.; Maity, S.; Szabo, K. J.; Maiti, D., PalladiumꢀCatalyzed Synthesis of 2,3ꢀ
Disubstituted Benzofurans: An Approach Towards the Synthesis of Deuterium Labeled
Compounds. Adv. Syn. Catal. 2015, 357, 2331ꢀ2338.
29.
Neely, J. M.; Rovis, T., Rh(III)ꢀCatalyzed Decarboxylative Coupling of Acrylic Acids
7
with Unsaturated Oxime Esters: Carboxylic Acids Serve as Traceless Activators. J. Am. Chem.
Soc. 2014, 136, 2735ꢀ2738.
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
30.
Alkenes and α,βꢀUnsaturated Oxime Esters. J. Am. Chem. Soc. 2013, 135, 66ꢀ69.
31. Lipshutz, B. H., Fiveꢀmembered heteroaromatic rings as intermediates in organic
synthesis. Chem. Rev. 1986, 86, 795ꢀ819.
32. La Clair, J. J.; Rheingold, A. L.; Burkart, M. D., Ganodone, a Bioactive Benzofuran from
the Fruiting Bodies of Ganoderma tsugae. J. Nat. Prod. 2011, 74, 2045ꢀ2051.
33. Nevagi, R. J.; Dighe, S. N.; Dighe, S. N., Biological and medicinal significance of
benzofuran. E. J. Med. Chem. 2015, 97, 561ꢀ581.
34. Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E., Synthesis and Properties of
Neely, J. M.; Rovis, T., Rh(III)ꢀCatalyzed Regioselective Synthesis of Pyridines from
2,3,6,7ꢀTetraarylbenzo[1,2ꢀb:4,5ꢀb‘]difurans as HoleꢀTransporting Material. J. Am. Chem. Soc.
2007, 129, 11902ꢀ11903.
35.
36.
Zareba, K. M., Drugs Today 2006, 42, 75.
Saha, A. K.; Yu, X.; Lin, J.; Lobera, M.; Sharadendu, A.; Chereku, S.; Schutz, N.; Segal,
D.; Marantz, Y.; McCauley, D.; Middleton, S.; Siu, J.; Bürli, R. W.; Buys, J.; Horner, M.;
Salyers, K.; Schrag, M.; Vargas, H. M.; Xu, Y.; McElvain, M.; Xu, H., Benzofuran Derivatives
as Potent, Orally Active S1P1 Receptor Agonists: A Preclinical Lead Molecule for MS. ACS
Med. Chem. Lett. 2011, 2, 97ꢀ101.
37.
Hussain, M.; Thai Hung, N.; Abbas, N.; Khera, R. A.; Malik, I.; Patonay, T.; Kelzhanova,
N.; Abilov, Z. A.; Villinger, A.; Langer, P., Synthesis of Arylated Benzofurans by
RegioselectiveSuzuki–Miyaura CrossꢀCoupling Reactions of 2,3ꢀDibromobenzofuransꢀ and
2,3,5ꢀTribromobenzofurans. J. Hetero. Chem. 2015, 52, 497ꢀ505.
38.
Kim, S.; Evans, T. J.; Mukarakate, C.; Bu, L.; Beckham, G. T.; Nimlos, M. R.; Paton, R.
S.; Robichaud, D. J., Furan Production from Glycoaldehyde over HZSMꢀ5. ACS Sustainable
Chem. Eng. 2016, 4, 2615ꢀ2623.
39.
Christensen, E.; Fioroni, G. M.; Kim, S.; Fouts, L.; Gjersing, E.; Paton, R. S.;
McCormick, R. L., Experimental and theoretical study of oxidative stability of alkylated furans
used as gasoline blend components. Fuel 2018, 212, 576ꢀ585.
40.
Maimone, T. J.; Buchwald, S. L., PdꢀCatalyzed OꢀArylation of Ethyl Acetohydroximate:
Synthesis of OꢀArylhydroxylamines and Substituted Benzofurans. J. Am. Chem. Soc. 2010, 132,
9990ꢀ9991.
41.
Heteroatom−Hydrogen Bonds to Alkynes. Chem. Rev. 2004, 104, 3079ꢀ3160.
42. Bonnamour, J.; Piedrafita, M.; Bolm, C., Iron and Copper Salts in the Synthesis of
Benzo[b]furans. Adv. Syn. Catal. 2010, 352, 1577ꢀ1581.
43. Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.; Koumbis, A. E., Model Studies towards
Alonso, F.; Beletskaya, I. P.; Yus, M., TransitionꢀMetalꢀCatalyzed Addition of
Diazonamide A: Synthesis of the Heterocyclic Core. Angew. Chem. Int. Ed. 2000, 39, 3473ꢀ
3478.
44.
Wang, X.; Lerchen, A.; Daniliuc, C. G.; Glorius, F., Efficient Synthesis of Arylated
Furans by a Sequential RhꢀCatalyzed Arylation and Cycloisomerization of Cyclopropenes.
Angew. Chem. Int. Ed. 2018, 57, 1712ꢀ1716.
ACS Paragon Plus Environment
18

Page 19 of 22
ACS Catalysis
1
2
3
4
5
6
7
8
9
45.
Padmanaban, M.; Biju, A. T.; Glorius, F., Efficient Synthesis of Benzofuranones: Nꢀ
Heterocyclic Carbene (NHC)/BaseꢀCatalyzed Hydroacylation–Stetter–Rearrangement Cascade.
Org. Lett. 2011, 13, 5624ꢀ5627.
46.
Polysubstituted Furans. ANgew. Chem. Int. Ed. 2012, 51, 7562ꢀ7566.
47. Li, Y.; Brand, J. P.; Waser, J., GoldꢀCatalyzed Regioselective Synthesis of 2ꢀ and 3ꢀ
Alkynyl Furans. Angew. Chem. Int. Ed. 2013, 52, 6743ꢀ6747.
48. Li, Y.; Waser, J., Zinc–gold cooperative catalysis for the direct alkynylation of
benzofurans. Beilstein J. Org. Chem. 2013, 9, 1763ꢀ1767.
49. Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N., Distortion/Interaction Analysis Reveals
the Origins of Selectivities in IridiumꢀCatalyzed C–H Borylation of Substituted Arenes and 5ꢀ
Membered Heterocycles. J. Am. Chem. Soc. 2014, 136, 4575ꢀ4583.
50.
Fournier, J.; Arseniyadis, S.; Cossy, J., A Modular and Scalable OneꢀPot Synthesis of
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
Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N., Theoretical
Bond Dissociation Energies of HaloꢀHeterocycles: Trends and Relationships to Regioselectivity
in PalladiumꢀCatalyzed CrossꢀCoupling Reactions. J. Am. Chem. Soc. 2009, 131, 6632ꢀ6639.
51.
Addition. Chem. Rev. 2006, 106, 4644ꢀ4680.
52. Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L., The Selective Reaction of
Aryl Halides with KOH:ꢁ Synthesis of Phenols, Aromatic Ethers, and Benzofurans. J. Am. Chem.
Soc. 2006, 128, 10694ꢀ10695.
53.
Carboalkoxylation or Carboamination of Alkynes. J. Am. Chem. Soc. 2005, 127, 15024ꢀ15025.
54. Fürstner, A.; Stelzer, F.; Szillat, H., PlatinumꢀCatalyzed Cycloisomerization Reactions of
Enynes. J. Am. Chem. Soc 2001, 123, 11863ꢀ11869.
55. Nakamura, I.; Yamamoto, Y., TransitionꢀMetalꢀCatalyzed Reactions in Heterocyclic
Synthesis. Chem. Rev. 2004, 104, 2127ꢀ2198.
56. Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E., 3ꢀZinciobenzofuran and 3ꢀ
Zeni, G.; Larock, R. C., Synthesis of Heterocycles via PalladiumꢀCatalyzed Oxidative
Fürstner, A.; Davies, P. W., Heterocycles by PtCl2ꢀCatalyzed Intramolecular
Zincioindole: Versatile Tools for the Construction of Conjugated Structures Containing Multiple
Benzoheterole Units. Angew. Chem. Int. Ed. 2006, 45, 944ꢀ947.
57.
Alkynes:ꢁ Application to the Synthesis of Benzo[b]furans. J. Org. Chem. 2007, 72, 6149ꢀ6153.
58. Hu, M.; Song, R. J.; Li, J. H., Metal Free Radical 5 exo dig Cyclizations of Phenol
Linked 1,6 Enynes for the Synthesis of Carbonylated Benzofurans. Angew. Chem. Int. Ed.
2014, 54, 608ꢀ612.
Ackermann, L.; Kaspar, L. T., TiCl4ꢀCatalyzed Indirect AntiꢀMarkovnikov Hydration of
59.
Han, Z.; Zhang, L.; Li, Z.; Fan, R., Direct Assembly of 3,4 Difunctionalized
Benzofurans and Polycyclic Benzofurans by Phenol Dearomatization and Palladium Catalyzed
Domino Reaction. Angew. Chem. Int. Ed. 2014, 53, 6805ꢀ6809.
60.
Carbonylations. Chem. Rev. 2013, 113, 1ꢀ35.
61. Colby, D. A.; Bergman, R. G.; Ellman, J. A., RhodiumꢀCatalyzed C−C Bond Formation
via HeteroatomꢀDirected C−H Bond Activation. Chem. Rev. 2010, 110, 624ꢀ655.
62. Yang, Y.; Lan, J.; You, J., Oxidative C–H/C–H Coupling Reactions between Two
(Hetero)arenes. Chem. Rev. 2017, 117, 8787ꢀ8863.
63. Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K., Direct Access to Benzo[b]furans
Wu, X. F.; Neumann, H.; Beller, M., Synthesis of Heterocycles via PalladiumꢀCatalyzed
through PalladiumꢀCatalyzed Oxidative Annulation of Phenols and Unactivated Internal
Alkynes. Angew. Chem. Int. Ed. 2013, 52, 4607ꢀ4612.
ACS Paragon Plus Environment
19

ACS Catalysis
Page 20 of 22
1
2
3
4
5
6
7
8
64.
Agasti, S.; Dey, A.; Maiti, D., Palladiumꢀcatalyzed benzofuran and indole synthesis by
multiple CꢀH functionalizations. Chem. Commun. 2017, 53, 6544ꢀ6556.
65. Guo, X.; Yu, R.; Li, H.; Li, Z., IronꢀCatalyzed Tandem Oxidative Coupling and
Annulation: An Efficient Approach to Construct Polysubstituted Benzofurans. J. Am. Chem. Soc
2009, 131, 17387ꢀ17393.
9
66.
of phenols and unactivated internal alkynes. Chem. Sci. 2013, 4, 3706ꢀ3711.
67. Kobatake, T.; Fujino, D.; Yoshida, S.; Yorimitsu, H.; Oshima, K., Synthesis of 3ꢀ
Zhu, R.; Wei, J.; Shi, Z., Benzofuran synthesis via copperꢀmediated oxidative annulation
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
Trifluoromethylbenzo[b]furans from Phenols via Direct Ortho Functionalization by Extended
Pummerer Reaction. J. Am. Chem. Soc. 2010, 132, 11838ꢀ11840.
68.
Lee, D. H.; Kwon, K. H.; Yi, C. S., Dehydrative C–H Alkylation and Alkenylation of
Phenols with Alcohols: Expedient Synthesis for Substituted Phenols and Benzofurans. J. Am.
Chem. Soc. 2012, 134, 7325ꢀ7328.
69.
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M., PalladiumꢀCatalyzed Regioselective
Monoꢀ and Diarylation Reactions of 2ꢀPhenylphenols and Naphthols with Aryl Halides. Angew.
Chem. Int. Ed. 1997, 3, 1740ꢀ1742.
70.
Intermolecular Orthoarylation of Phenols. Angew. Chem. Int. Ed. 2003, 42, 112ꢀ114.
71. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F., PalladiumꢀCatalyzed C−O
Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E., The Catalytic
Coupling Involving Unactivated Aryl Halides. Sterically Induced Reductive Elimination To
Form the C−O Bond in Diaryl Ethers. J. Am. Chem. Soc. 1999, 121, 3224ꢀ3225.
72.
Intermolecular PdꢀCatalyzed C−O Bond Formation. J. Am. Chem. Soc. 2005, 127, 8146ꢀ8149.
73. Xiao, B.; Gong, T. J.; Liu, Z. J.; Liu, J. H.; Luo, D. F.; Xu, J.; Liu, L., Synthesis of
Vorogushin, A. V.; Huang, X.; Buchwald, S. L., Use of Tunable Ligands Allows for
Dibenzofurans via PalladiumꢀCatalyzed PhenolꢀDirected C–H Activation/C–O Cyclization. J.
Am. Chem. Soc. 2011, 133, 9250ꢀ9253.
74.
OXIDATIVE COUPLING. J. Am. Chem. Soc. 1959, 81, 6335ꢀ6336.
75. Agasti, S.; Dey, A.; Maiti, D., Traceless directing group mediated branched selective
alkenylation of unbiased arenes. Chem. Commun. 2016, 52, 12191ꢀ12194.
76. Tang, J.; Hackenberger, D.; Goossen, L. J., Branched Arylalkenes from Cinnamates:
Hay, A. S.; Blanchard, H. S.; Endres, G. F.; Eustance, J. W., POLYMERIZATION BY
Selectivity Inversion in Heck Reactions by Carboxylates as Deciduous Directing Groups. Angew.
Chem. Int. Ed. 2016, 55, 11296ꢀ11299.
77.
Littke, A. F.; Fu, G. C., A Versatile Catalyst for Heck Reactions of Aryl Chlorides and
Aryl Bromides under Mild Conditions. J. Am. Chem. Soc. 2001, 123, 6989ꢀ7000.
78.
79.
Gurtler, C.; Buchwald, S. L., Chem. Eur. J. 1999, 5, 3107ꢀ3112.
Beletskaya, I. P.; Cheprakov, A. V., The Heck Reaction as a Sharpening Stone of
Palladium Catalysis. Chem. Rev. 2000, 100, 3009ꢀ3066.
80. Lai, S.; Lee, D. G., Heterogeneous Permanganate Oxidation of Styrene and Cinnamic
Acid Derivatives: A Simple and Effective Method for the Preparation of Benzaldehydes.
Synthesis 2001, 2001, 1645ꢀ1648.
81.
Straathof N, J. W.; E., C. S.; Hessel, V.; Noël, T., Practical Photocatalytic
Trifluoromethylation and Hydrotrifluoromethylation of Styrenes in Batch and Flow. Angew.
Chem. Int. Ed. 2016, 55, 15549ꢀ15553.
ACS Paragon Plus Environment
20

Page 21 of 22
ACS Catalysis
1
2
3
4
5
6
7
8
82.
Wei, X. J.; Boon, W.; Hessel, V.; Noël, T., VisibleꢀLight Photocatalytic Decarboxylation
of α,βꢀUnsaturated Carboxylic Acids: Facile Access to Stereoselective Difluoromethylated
Styrenes in Batch and Flow. ACS Catal. 2017, 7, 7136ꢀ7140.
83.
Schwarz, M.; Hofmann, G.; Winterhalter, P., Investigations on Anthocyanins in Wines
from Vitis vinifera cv. Pinotage:ꢁ Factors Influencing the Formation of Pinotin A and Its
9
Correlation with Wine Age. J. Agric. Food Chem 2004, 52, 498ꢀ504.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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84.
Yang, Y.; Yao, J.; Zhang, Y., Synthesis of Polysubstituted Furans via CopperꢀMediated
Annulation of Alkyl Ketones with α,βꢀUnsaturated Carboxylic Acids. Org. Lett. 2013, 15, 3206ꢀ
3209.
85.
86.
S1.
87.
See supporting information for details.
The mechanistic cycles for the formation of intermediates 4 and b are shown in Scheme
Klein, J.; Shekhori, E., The Decarboxylation of αꢀArylcinnamic Acids. Isr. J. Chem.
1968, 6, 701ꢀ712.
88.
Cohen, T.; Berninger, R. W.; Wood, J. T., Products and kinetics of decarboxylation of
activated and unactivated aromatic cuprous carboxylates in pyridine and in quinoline. J. Org.
Chem. 1978, 43, 837ꢀ848.
89.
CꢀCꢀbond formation. Chem. Soc. Rev. 2011, 40, 5030ꢀ5048.
90. Gaussian09, Rev. D.01 is employed for all the computations. 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. Gaussian09, Revision D.01; Gaussian,
Inc.: Wallingford, CT, 2013.
Rodriguez, N.; Goossen, L. J., Decarboxylative coupling reactions: a modern strategy for
91.
Distortion/InteractionꢀActivation Strain Model. Angew. Chem. Int. Ed. 2017, 56, 10070ꢀ10086.
92. Yu, L. Y.; Zhang, S. Q.; Hong, X., Mechanisms and Origins of Chemoꢀ and
Regioselectivities of Ru(II)ꢀCatalyzed Decarboxylative CꢀH Alkenylation of Aryl Carboxylic
Acids with Alkynes: A Computational Study. J. Am. Chem. Soc. 2017, 139, 7224−7243.
Bickelhaupt, F. M.; Houk, K. l. N., Analyzing Reaction Rates with the
93.
Gooßen, L. J.; Rodríguez, N.; Linder, C.; Lange, P. P.; Fromm, A., Comparative Study of
Copperꢀ and SilverꢀCatalyzed Protodecarboxylations of Carboxylic Acids. ChemCatChem 2010,
2, 430ꢀ442.
94.
Synthesis via PdꢀCatalyzed Decarboxylative Coupling of Aromatic Carboxylates with Aryl
Halides. J. Am. Chem. Soc. 2007, 129, 4824ꢀ4833.
Goossen, L. J.; Rodríguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M., Biaryl
95.
Cornella, J.; Sanchez, C.; Banawa, D.; Larrosa, I., Silverꢀcatalysed protodecarboxylation
of orthoꢀsubstituted benzoic acids. Chem. Commun. 2009, 7176ꢀ7178.
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96.
Simmons E., M.; Hartwig J., F., On the Interpretation of Deuterium Kinetic Isotope
Effects in CꢀH Bond Functionalizations by Transition Metal Complexes. Angew. Chem. Int. Ed.
2012, 51, 3066ꢀ3072.
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