Recent Progress in Pd Catalyzed Direct Arylation

7/26/2019 Recent Progress in Pd Catalyzed Direct Arylation

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Recent progress in Pd catalyzed direct arylation

Tong Zhao Congkai Ma Nicolaj Ma Jianfeng Zhang Xianglei Meng

UCAS 201528004133069 201528004133076 2015B8009408157 201528004133068 Ph.D.DTU s154862 s154857 s103771 s154861

Contents1. Palladium-Catalyzed Direct Arylation of Selenophene ............................................................. 2

2. Direct Arylation of Primary and Secondary sp3C-H Bonds with Diarylhyperiodononium Salts

via Pd Catalysis .............................................................................................................................. 4

2. Palladium catalyzed direct C-2 arylation of indoles .................................................................. 6

4. Direct C-H arylation of 2-hydroxybenzaldehydes with organic halides .................................... 7

5. Palladium-catalyzed direct intramolecular double -C-H arylation of 1,5-diketone................ 8

6. Rapid access to diverse -carbolines through sequential transition metal catalyzed

amination and direct C-H arylation ............................................................................................... 9

7. Synthesis of symmetrical and unsymmetrical 1,3- diheteroarylbenzenes through palladium-

catalyzed direct arylation of benzene-1, ..................................................................................... 10

8. Pd-catalyzed direct arylation of electron-deficient polyfluoroarenes with aryliodine(III)

diacetates .................................................................................................................................... 12

Bibliography ................................................................................................................................ 14


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1. Palladium-Catalyzed Direct Arylation of Selenophene

Introduction

In the recent years palladium catalyzed direct arylations such as this has revolutionized

organic synthesis, since this mechanism eliminates the need to first synthesize one or two

organometallic derivatives. This makes the reaction more atom-economical with less waste

produced. Selenophenes are selenium analogues of furan and until recently, direct arylation

with Pd had only been accomplished for analogues for dye-sensitized photovoltaic cells with

no consideration for the mechanism. A method for the regioselective formation 2-aryl- or 2,5-

diarylselenophenes has been developed that is both efficient and convenient via Pd-catalyzed

direct arylation. It is viable for a wide variety of aryl halides containing different functional

groups. Its mechanism has been described and this is important because one of the limiting

factors regarding transition-metal catalyzed transformation is the poisoning of the catalyst by

the organoselenium.

Previously a promotion of cross-coupling with selenophene ring would be done through an

initial stage of activation as a halide or organometallic has been required. The direct arylation

avoids this prefunctionalization step.

Fig. 1: Direct arylation of selenophere

Results

Initial experiments with the catalytic system was done under the conditions of Fagnou direct

arylation, and was composed of Pd(OAc)2, an alkylphosphine as its

phosphoniumtetrafluoroborate salt (PCy3HBF4), pivalic acid as co-catalyst, and potassium

carbonate in DMA to act as a base. This only yielded poor amounts of product. Further testing

revealed increasing the catalyst did not affect the result. By using an increased amount pivalic

acid of maximum 60 mol% the yield was improved from 18% to 30%. Best results were

achieved with PPh3 phosphine ligand (up to 16%), of which several other were tested including

PCy3HBF4, P(t-Bu)2MeHBF4, P(o-tol)3and XPhos. The observation was that less bulky andelectron-deficient phosphines provided a better result, and may be explained by facilitating

the arene binding either by creating more electron-deficient palladium atoms or providing

vacant sites for arenes that undergo displacement from the metal center. The base and

additive was screened, and a combination of PPh3-Pd(OAc)2with PivOH-K2CO3gave the best

yields of 2-phenylselenophene. Pd(PPh3) and PdCl2(PPh3) were also both found to be effective

as catalysts.

The scope and limitation of the method was investigated for various aryl halides and

selenophene. Regioselectivity provided a good yield of 30-93% of 2-arylation product in each

case. The reactions proved to be compatible with different oxo, nitro, ester, ether and halogensubstituents. Aryl iodides seem especially efficient compared to aryl bromides, which is in


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contrast to earlier studies on similar type of reaction, that had inhibition due to iodide catalyst

poisoning.

To make 2,5-diarylselenophenes, an excess of 2 equivalents of aryl iodide for every

equivalent of selenophene and the reaction time was. Catalyst amounts were also increased.

Using more than 2 equivalents of aryl iodide did not improve yields, though only slight

amounts of direct triarylation was detected which means that the preparation has a high

selectivity for 2,5-diarylselenophenes.

Conclusion

A method for the regioselective formation 2-aryl- or 2,5-diarylselenophenes was developed

was both efficient and convenient via Pd-catalyzed direct arylation and was usable for a variety

of halides containing different functional groups. The versatile method allows the synthesis of

a large variety of 2-aryl or symmetric 2,5-diarylselenophenes in a single step in excellent yields

of up to 90%. The 2-arylated substrates can undergo an additional arylation to furnish

asymmetric 2,5-diarylselenophenes in good yields.[1]


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2. Direct Arylation of Primary and Secondary sp3C-H Bonds with

Diarylhyperiodononium Salts via Pd Catalysis

Introduction

As an alternative to traditional synthetic methods, transition-metal-catalyzed direct C-Harylation is emerging as an attractive alternative. The unreactive sp3C-H is the current most

challenging part as both efficiency and selectivity suffers, whereas formation of C-C and C-

bonds have been achieved. Though, some achievements in direct functionalization of benzylic

and allylic C-H bonds have been made. In recent years, great effort in direct functionalization

of unreactive sp3C-H bonds have been done via Pd catalysis. As a new approach,

arylhyperiodinium salts have been investigated for arylation due to its high reactivity, stability,

availability, electrophilicity and low toxicity. This method can also be used in application for sp2

C-H arylation. Due to the highly electron-deficient properties and hyperleaving group ability, it

has proven to be convenient and efficient for sp3arylation especially for secondary C-H bonds,

which are often more challenging. Many acid derivatives were also successful by this method.

Fig. 2:Reaction scheme for sp3CH arylation with diarylhyperiodonium.

Method & Results

First direct arylation of sterically hindered benzylic sp3C-H bond of N-3-phenylpropyol-8-

aminoquinoline with diarylhyperiodonium salt was tested. 0.10 mmol of 1aalong with 0.12

mmol of 2awas used in presence of 0.005 mmol Pd catalyst and 0.12 mmol of base in 1.0 mL

of solvent. After 24 hours the yield was determined by crude H NMR spectroscopy.

ClCH2CH2Cl seemed to exhibit best overall efficacy. The carbonate sharply promoted the

transformation and good yield was only observed in presence of K2CO3. In absence of base, the

efficacy of arylation was reduced. Phosphates and acetates were tested but the results were

not comparable to carbonates. Initial test of PD(OAC)2 revealed that 1awas not completely

consumed and that the efficiency was not increased simply by lengthening the reaction time. A

screening between different combinations of Pd catalyst, bases and solvents was performed.

Using Pd(SIMes)(OAc)2, with K2CO3base and ClCH2CH2Cl solvent gave the highest yield of 86%

of theoretical. In comparison using the same base and solvent with Pd(OAc)2gave a yield of

72%.

Furthermore the counteranion of diarylhyperiodonium was examined for its effects. Anions

of BF4, PF6, Br or p-toluenesulfonates (OTf) was tested for application. The efficacy was overall

lower (12-37% yield), except for p-toluenesulfonates with a yield of 86%. The low yield could

have been due to low solubility of the salts in the organic solvents, or be due to precipitation

during the proton-abstraction step which happens to be rate-limiting. Investigation of


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derivatives lead to conclusions thatpara-amide substituents in the phenyl displayed a good

reactivity. Other 2-heteroaryl substituted amides like furanyl or thiophenyl also gave great

yields.

Primary aliphatic sp3C-H bonds have generally poor reactivity, so a reaction using propionyl

derivatives was done, and performed well. A 1:1 ratio of mono- and diarylated products were

obtained. Secondary aliphatic sp3C-H bonds have worse reactivity, more so than primary.

Carboxylic amides in 3-5 membered rings were arylated, with fair success. Though, this

reaction only resulted in double arylation in orthoposition. Also protected amino acids were

tested, it was found that a high yield of 69% was obtained.

The reactivity of diarylhyperiodonium salts may be affected differently by various

substituents with certain electronic or steric features. Diarylhyperiodonoim triflates were were

used successfully in the reaction with yields of 60-84%

ConclusionThis method of direct Pd-catalyzed arylation was successfully able to use

diarylhyperiodonium salts as agent for arylation of aliphatic sp3C-H in, both primary and

secondary. Pd(SIMes)(OAc)2catalyst with K2CO3 and ClCH2CH2Cl obtained the best result, with

a yield of 86%. [2]


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2. Palladium catalyzed direct C-2 arylation of indoles

Introduction

Jie Feng et al. [3] have studied the synthesis and catalytic evaluation of palladium complexes

containing NCN Pincer ligand. The pincer palladium complexes as (pre)catalyst showed

efficient catalytic activity for the C-H arylation of N-substituted indoles, allowing the synthesis

of 2-arylindoles with moderate to good yields and excellent regioselectivities. The reaction

could be conducted in relatively mild conditions obtaining good yields and excellent selectivity

with aryl iodides and shows moderate activity with aryl bromides bearing electron-

withdrawing groups.

The reaction formula for the direct arylation of indoles with aryl iodides with pincer

palladium complex can be shown in Fig. 3 as following.

Fig. 3: The direct arylation of indoles with aryl iodides with pincer palladium complex

Method & Results

Reaction conditions: indoles (1 mmol), aryl halides, (1.5 mmol), KOAc (2 mmol), catalyst 1e(1

mmol%), DMAc (3 mL), 80 C, 24h.

A proposed mechanism for the coupling between N-methyl-indole and aryl halides can be

shown in Fig. 4

Fig. 4: Working hypothesis of the coupling between N-methyl-indole and aryl halides

In the first step, the Palladium (0) proceeds to an aryl-palladium halide intermediate via

oxidative addition. Then, the carboxylates and the corresponding carboxylic acid could

increase the rate of the palladation step and enhance the electrophilicity of a cationic

palladium species. Finally, the palladium species could transfer to C-2 product immediately by

direct metalation and reductive elimination.


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4. Direct C-H arylation of 2-hydroxybenzaldehydes with organic

halides

Introduction

Najmeh Nowrouzi et al. [4] have studied the palladium-catalyzed cross-coupling of 2-hydroxybenzaldehydes with organic halides proceeds in the presence of n-Bu4NBr in H2O

producing the corresponding 2-hydroxybenzophenones. They find that the desired products

were obtained in high yields under the optimum reaction condition.

Method and Results

The reaction formula for the cross coupling of salicylaldehyde with organic helides can be

shown in Fig. 5 as following.

Fig. 5: The cross coupling of salicylaldehyde with organic halides where, Z = H, Br; X = I, Br, CH2Br; R = H, CH3, NO2,

CN.

A possible mechanism for the cross-coupling of salicylaldehyde with organic halides can be

shown in Fig 6.

Fig. 6: A possible mechanism for the cross-coupling of

salicylaldehyde with organic halides

The first step involves the oxidative addition of aryl halide to palladium (0) species, followed

by reaction with salicylaldehyde to form an aryl(aryloxy)palladium intermediate I with

liberation of hydrogen halide under the act of added base. In the next step, there are two

paths A and B to form intermediates II and III. The second oxidative addition of the aldehyde C-

H bond to adduct I affords palladium(IV) species II in path A and the subsequent two-fold

reductive elimination from it may occur to produce the corresponding ketone. In the path B,

direct insertion of Pd-Ar into the C-H bond of aldehyde followed by reductive elimination

reaction produces ketone.


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5. Palladium-catalyzed direct intramolecular double-C-H

arylation of 1,5-diketone

Introduction

TB-CO (polycyclic diones) have high potential application in supramolecular chemistry viafurther transformation. However, the traditional synthetic methods need long steps and harsh

reaction conditions. Jia Ju et al. [5] provide a high atom-economic and simple procedure to

synthesis TB-CO.

Method & Results

It is known that palladium-catalyzed intramolecular arylation of ketones is a normal synthetic

method for cyclic compounds. To establish the easy and efficient synthetic method, they

examined the intramolecular double -arylation of 1,5-di(2-chlorophenyl)-3-pheny-1,5-dione

(1) under normal reaction conditions with aryl chloride as reaction partner. Fortunately, the

yield of desired product 9-aryl-1,3:6,7-dibenzobicyclo[3.3.3]-nona-2,6-diene-4,8-dione (2a) is47%.

Fig. 7: A strategy for the synthesis of 2a.

Next, they designed a tandem reaction of easily available ortho-chloroacetophenone andortho-chlorochalcone for the formation of 2a involving the Michael addition and

intramolecular double -C-H arylation in the presence of PdCl2(PCy3)2/Cs2CO3as shown in

Fig. 8.

Fig. 8: A strategy for the synthesis of analogue of 2a based on the easily available reactant.

Additionally, they optimized the reaction conditions and investigated the generality of the

procedure.


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6. Rapid access to diverse -carbolines through sequential

transition metal catalyzed amination and direct C-H arylation

Introduction-Carbolines (pyrido[2,3-b]indoles) is found to exhibit a wide variety of biological properties,

such as anxiolytic. Furthermore, the tricyclic ring system have recently recently received much

interest as phabitrmacophore for kinase inhibitors which are being explored as anticancer and

antidiabetic agents. Hence, there is a trend to develop new synthetic pathways of -

Carbolines.

The protocols used before have drawbacks from a practical perspective, particularly for the

preparation of complex substrates. This cause multi-step syntheses for their preparation and

limits both the availability of the starting materials and the scope for further functionalization

on the a-carboline. The intramolecular biaryl coupling strategy reported by Sakamoto and co-workers needs harsh conditions and the yield for the direct C-H arylation is low. Therefore, a

mild and efficient protocol is desired. Masahiro Mineno et al. [1] studied on a versatile and

practical synthetic protocol for a-carbolines through a sequence of transition metal catalyzed

amination and direct C-H arylation.

Method & Results

Masahiro Mineno etc. developed a versatile and practical synthetic protocol for

pharmacologically important a-carbolines, through a sequence of Pd catalyzed amination and

direct C-H arylation. The outstanding feature in the direct C-H arylation is that a combination

of DBU and DCHPB plays a critical role to not only enhance the reactivity but also suppress

hydrodehalogenation. The reaction system enables the versatile synthesis of a-carbolines in

moderate to excellent yields.

Having established the optimal catalyst systems for both the Pd catalyzed amination and direct

C-H arylation, a versatile synthesis of a-carbolines was addressed (Fig.xx).

Fig. 9: Synthesis of a-carboline 1 by a sequence of Pd catalyzed amination and direct C-H arylation


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7. Synthesis of symmetrical and unsymmetrical 1,3-

diheteroarylbenzenes through palladium-catalyzed direct

arylation of benzene-1,

Introduction1,3-Diheteroarylbenzenes are an important class of molecules in organic chemistry. They are

useful agents in the treatment of diseases, including inflammatory diseases, cancer, and AIDS.

One way to synthesize unsymmetrical 1,3-diheteroarylbenzenes relies on the

desymmetrization of benzene-1,3-disulfonyl dichloride through two successive palladium-

catalyzed direct desulfitative arylations with two different heteroarenes [7].

Method & Results

First in the method, monoarylated product 1 is synthesized.

Fig. 10: Reaction 1

From table 1 we can see that reaction could also be performed in green solvents such as

diethyl carbonate (DEC) or cyclopentyl methyl ether (CPME) with comparable yields. When the

reaction was performed in DEC, the monoarylation product 1 was obtained in 95% selectivity

with a full conversion of 2-n-butylfuran (Table 1, entry 2). The use of 1,4-dioxane at only 110

and a shorter reaction time (18 h) also furnished a high selectivity in favor of the monoarylated

product 1 (Table 1, entry 4), we can choose this condition to proceed reaction.


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Table 1 Effect of the reaction conditions on Pd-catalyzed desulfitative coupling of benzene-

1,3-disulfonyl dichloride with 2-n-butylfuran

Entry x:y Sovent T( t(h) Conv.(%) 1:2

1 1.51 1,4-dioxane 140 48 100 45:552 1.51 DEC 140 48 100 95:5

3 1.51 CPME 140 48 72 87:13

4 1.51 1,4-dioxane 110 18 100 95:5

5 1.51 DMF 110 48 0 -

6 1.51 BuOH 140 48 0 -

7 1.21 DEC 140 48 100 95:5

8 1.21 1,4-dioxane 110 48 100 94:6

9 1.11 1,4-dioxane 140 48 100 90:10

10 1: 3 1,4-dioxane 140 48 100 9:91

Fig. 11: Reaction 2

The synthesis of the unsymmetrical 1,3-diheteroarylbenzene(Product 2) was

achieved in 82% yield from 1 with 1.5 equiv of 1-methylpyrrole using the classical

reaction conditions for desulfitative direct arylation.

Now, we have successfully achieved the synthesis of unsymmetrical 1,3-diheter -

oarylbenzenes through two successive C-H bond desulfitative arylations from benzene-

1,3-disulfonyl dichloride.


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8. Pd-catalyzed direct arylation of electron-deficient

polyfluoroarenes with aryliodine(III) diacetates

Introduction

Electron-deficient polyfluoroarenes are extensively employed in a wide range of areas toprepare corresponding polyfluorobiaryl structural motif, ranging from the elaboration of

pharmaceutical chemistry to materials science. As is reported [1], a Pd-catalyzed direct

arylation of electron-deficient polyfluoroarenes with readily available aryliodine(III) diacetates

was developed with moderate to good yields. Meanwhile, this process exhibits good functional

tolerance for many groups, such as methyl, methoxy and so on. In contrast to arylation

reactions of polyfluoroaromatic CH bond with (hetero)arenes or aromatic carboxylic acids as

aryl source that have recently been attracted great attentions.

Method & Results

Fig. 12: Reaction 1

This reaction equation represents the main way to produce electron-deficient

polyfluoroarenes. Different catalyst, solvent, base will affect the outcome, especially catalyst.

By plenty of experiments, it was also observed that that the reaction was facilitated when a

substituent at the para-position of tetrafluorobenzene derivative has electron-donating effect

or ppi conjugation effect.

Normally, two different Pd(II)/Pd(IV) mechanisms were assumed for the arylation of

pentafluorobenzene with iodobenzene diacetate. As illustrated in Scheme 1, Cycle A involves

the initial formation of aryl-Pd(IV) species III via the oxidative addition of the in situ generated

iodobenzene to original Pd(II), followed by the palladation of pentafluorobenzene via

concerted metalationdeprotonation and subsequent reductive elimination. Cycle B begins

with the formation of pentafluorophenyl-Pd(II)

species I via the activation of the CH bond of pentafluorobenzene, followed by the oxidative

addition of the in situ generated iodobenzene to pentafluorophenyl-Pd(II) species and then

reductive elimination. In this regard, multiple roles were assigned to Ag2CO3as the base and

promoter in transformation. Considering the oxidative addition of the in-situ generated

iodobenzene to original Pd(II) is easier than that to pentafluorophenyl-Pd(II) species I, thus, the

reaction is possible to favor Cycle A as the catalytic cycle in this transformation.


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Fig. 12: Reaction 2


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Recent Progress in Pd Catalyzed Direct Arylation