Recent progress in Pd catalyzed direct arylation

UCAS
DTU

Tong Zhao

Congkai Ma

Nicolaj Ma

Jianfeng Zhang

Xianglei Meng

201528004133069
s154862

201528004133076
s154857

2015B8009408157
s103771

201528004133068
s154861

Ph.D.

Contents
1. Palladium-Catalyzed Direct Arylation of Selenophene ............................................................. 2
2. Direct Arylation of Primary and Secondary sp3 C-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 palladiumcatalyzed direct arylation of benzene-1, ..................................................................................... 10
8. Pd-catalyzed direct arylation of electron-deficient polyfluoroarenes with aryliodine(III)
diacetates .................................................................................................................................... 12
Bibliography ................................................................................................................................ 14

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 2,5diarylselenophenes 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)3 and XPhos. The observation was that less bulky and
electron-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)2 with PivOH-K2CO3 gave 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 halogen
substituents. 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]

2. Direct Arylation of Primary and Secondary sp3 C-H Bonds with

Diarylhyperiodononium Salts via Pd Catalysis
Introduction
As an alternative to traditional synthetic methods, transition-metal-catalyzed direct C-H
arylation is emerging as an attractive alternative. The unreactive sp3 C-H is the current most
challenging part as both efficiency and selectivity suffers, whereas formation of C-C and Cbonds 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 sp3 C-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 sp3 arylation 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 sp3 CH arylation with diarylhyperiodonium.

Method & Results

First direct arylation of sterically hindered benzylic sp3 C-H bond of N-3-phenylpropyol-8aminoquinoline with diarylhyperiodonium salt was tested. 0.10 mmol of 1a along with 0.12
mmol of 2a was 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 1a was 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 K2CO3 base and ClCH2CH2Cl solvent gave the highest yield of 86%
of theoretical. In comparison using the same base and solvent with Pd(OAc)2 gave 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 that para-amide substituents in the phenyl displayed a good
reactivity. Other 2-heteroaryl substituted amides like furanyl or thiophenyl also gave great
yields.
Primary aliphatic sp3 C-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 sp3 C-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 ortho position. 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%

Conclusion
This method of direct Pd-catalyzed arylation was successfully able to use
diarylhyperiodonium salts as agent for arylation of aliphatic sp3 C-H in, both primary and
secondary. Pd(SIMes)(OAc)2 catalyst with K2CO3 and ClCH2CH2Cl obtained the best result, with
a yield of 86%. [2]

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 electronwithdrawing 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.

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 2hydroxybenzaldehydes 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 CH 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.

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 via
further 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) is
47%.

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

Next, they designed a tandem reaction of easily available ortho-chloroacetophenone and

ortho-chlorochalcone for the formation of 2a involving the Michael addition and
intramolecular double -C-H arylation in the presence of PdCl2 (PCy3 )2 /Cs2 CO3 as 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.

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 coworkers 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

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

arylation of benzene-1,
Introduction
1,3-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 palladiumcatalyzed 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 benzene1,3-disulfonyl dichloride with 2-n-butylfuran

Entry

x:y

Sovent

T() t(h)

Conv.(%)

1:2

1
2
3
4
5
6
7
8
9
10

1.51
1.51
1.51
1.51
1.51
1.51
1.21
1.21
1.11
1: 3

1,4-dioxane
DEC
CPME
1,4-dioxane
DMF
BuOH
DEC
1,4-dioxane
1,4-dioxane
1,4-dioxane

140
140
140
110
110
140
140
110
140
140

100
100
72
100
0
0
100
100
100
100

45:55
95:5
87:13
95:5
95:5
94:6
90:10
9:91

48
48
48
18
48
48
48
48
48
48

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 benzene1,3-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 to
prepare 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 Ag2CO3 as 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.

12

Fig. 12: Reaction 2

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H., 2014.
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Secondary sp3 C-H Bonds with Biarylhyperiodononium Salts via Pd Catalysis, ACS
Publications, 2013.
[3] G. L. M. L. C. C. Jie Feng, Palladium catalyzed direct C-2 arylation of indoles, Journal of
Organometallic Chemistry, vol. 761, pp. 28-31, 2014.
[4] N. Nowrouz, S. Motevalli and D. Tarokh, Palladium-catalyzed direct C-H arylation of 2hydroxybenzaldehydes with organic halides in neat water, Journal of Molecular Catalysis
A: Chemical, Vols. 396, J, pp. 224-230, 2015.
[5] J. Ju, L. Zhang and R. Hua, Palladium-catalyzed direct intramolecular double -CH
arylation of 1, 5-diketone: a strategy for synthesis of Trgers base analogues,
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[6] M. Mineno, M. Sera and T. Ueda, Rapid access to diverse -carbolines through sequential
transition metal catalyzed amination and direct CH arylation, Tetrahedron, vol. 70, no.
35, pp. 5550-5557, 2014.
[7] I. Idris, F. Derridj, S. Djebbar, J.-F. Soul and H. Doucet, Synthesis of symmetrical and
unsymmetrical 1,3-diheteroarylbenzenes through palladium-catalyzed direct arylation of
benzene-1,3-disulfonyl dichloride and 3-bromobenzenesulfonyl chlorides, Tetrahedron,
vol. 71, pp. 9617-9625, 2015.
[8] Z. Fu, Q. Xiong, W. Zhang, Z. Li and H. Cai, Pd-catalyzed direct arylation of electrondeficient polyfluoroarenes with aryliodine(III) diacetates, Tetrahedron Letters, vol. 56, pp.
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