Chelation-assisted palladium-catalyzed high regioselective heckdiarylation reaction of 9-allyl-9H-purine: synthesis of9-(3,3-diaryl-allyl)-9H-purines{

Hai-Ming Guo,*a Wei-Hao Rao,a Hong-Ying Niu,b Li-Li Jiang,a Lei Liang,a Yang Zhanga and Gui-Rong Qu*a

Received 6th July 2011, Accepted 13th August 2011

DOI: 10.1039/c1ra00410g

A Pd-catalyzed high regioselective diarylation of 9-allyl-9H-

purine via chelation-assisted Heck reaction is developed. There

were two different types of b-H in the allyl substrate, while the

two aryl groups are exclusively introduced to the terminal of the

olefins.

The Pd-catalyzed Heck reaction of aryl or alkenyl halides or triflates

with alkenes has been developed into a powerful tool for the forma-

tion of C–C bonds.1 Recently, different versions of directing groups

such as organic phosphine,2 tertiary amine,3 pyridine,4 sulfoxide5 and

sulfone6 have been exploited for directing metal-catalyzed Heck

reactions with varying degrees of success (eqn. (1), Scheme 1).7 Those

vinyl ethers8 bearing a directing group are relatively simple since their

structures bear only one type of b-H except for a few cases.4b As a

consequence, challenges with elaborated olefins bearing two types of

b-H lie ahead with respect to regioselectivity and catalytic efficiency.

Furthermore, all those chelation-assisted Pd-catalyzed Heck reac-

tions are based on the classical Pd(0)/Pd(II) catalyst cycle2–7 in the

presence of organic ligand. As such, chelation-assisted Pd-catalyzed

Heck reaction via Pd(II)/Pd(IV) catalyst cycle under an additional

ligand-free condition has not been previously realized.

In the last decade, directed C–H bond activation has emerged as a

versatile strategy for constructing C–heteroatom bonds with a proper

choice of directing group and catalytic system.9 Purine derivatives are

of great importance in medicinal chemistry since they display a broad

spectrum antiviral activity, antimycobacterial activity and biological

activity.10 Purine contains four nitrogen atoms and belongs to a

special class of aromatic heterocycles. We envisioned that purine

could serve as an efficient directing group for the Pd-catalyzed Heck

reaction. Daugulis’ group has reported a series of directed Pd-

catalyzed arylation reactions with a AgOAc/AcOH system.11 Despite

the reported long reaction time, we considered that this catalytic

system might serve as a good partner of the purine-assisted

Pd-catalyzed Heck reaction. As part of our ongoing course of study

on the modification of purine analogues,12herein, a chelation-assisted

Pd-catalyzed high regioselective diarylation reaction of olefins via a

possible Pd(II)/Pd(IV) catalyst cycle is described (eqn (2), Scheme 1).

In comparison to related chelation-assisted Pd-catalyzed Heck

reactions,2–6 the purine directing group is more challenging for its

fused ring structure and possessing multiple nitrogen atoms, and this

diarylation method presumably occurs by a distinct Pd(II)/Pd(IV)

mechanism, which is quite different from a classical Pd(0)/Pd(II)

catalyst cycle in the presence of an organic ligand. Notably, the high

regioselective diarylation and high catalytic efficiency have been

achieved with the choice of purine as a directing group.

We initially conducted our experiment by treating 9-allyl-6-

methoxyl purine (1) with 5 mol % Pd(OAc)2 in the presence of

3.0 equiv. of PhI and 2.0 equiv. of AgOAc in acetic acid at 120 uC for

4.5 h. To our delight, the desired diarylated product 1aa was isolated

in 93% yield (entry 1, Table 1). Remarkably, lowering the catalyst

loading to 3 mol % could also efficiently catalyze the phenylation of

1 to afford 1aa in 88% isolated yield (entry 2) and lowering the

reaction temperature did not bring about a significant reduction of

1aa (entry 3). Further studies showed that catalytic amount of other

Pd(II) sources such as PdCl2, PdCl2(Ph3P)2 could also efficiently

catalyze the phenylation reaction (entries 4–5). Unfortunately, PhBr

was unsuitable for this transformation (entries 6 and 7), which might

be due to the strong dissociation energy of the Ph–Br bond.

With the optimized conditions in hand, a variety of aryl iodides

were further explored. As shown in Table 2, the non-stepwise one-

pot Heck double arylation reactions proceeded smoothly despite two

aCollege of Chemistry and Environmental Science, Key Laboratory ofGreen Chemical Media and Reactions of Ministry of Education, HenanNormal University, Xinxiang, 453007, Henan, China.E-mail: guohm518@hotmail.com; quguir@sina.com; Fax: 86 373 3329276;Tel: 86 373 3329255bSchool of Chemistry and Chemical Engineering, Henan Institute ofScience and Technology, Xinxiang, 453003, China{ Electronic Supplementary Information (ESI) available: Experimentalprocedures, compound characterizations, and the copies of 1H NMR and13C NMR spectra. See DOI: 10.1039/c1ra00410g/

Scheme 1 Different catalytic cycles for Pd-catalyzed diarylation Heck

reaction of olefins.

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different aryl iodides being simultaneously present in the reaction

mixture (entries 2, 3, 6 and 9). Moreover, aryl iodides bearing

either an electron-withdrawing group (i.e. p-COOEt, o-COOMe)

(entries 8 and 12) or an electron-donating group (i.e. p-Me, p-MeO)

(entries 2–4, 7, and 9–11) could serve as good partners of the purine-

assisted Heck arylation reaction. Although the E/Z selectivity was

very poor in the one-pot competitive reaction, the Heck diarylation

reaction proved to be mild and highly efficient. Notably, the reaction

regiospecifically occurred on the terminal of the olefins even though

there were two different types of b-H in the substrates.

Finally, purine as a directing group for Pd-catalyzed Heck reaction

was further tested under the classical catalytic system (Scheme 2).

We were pleased to find that the corresponding product 1aa was

obtained in acceptable to good yields depending on different ligands.

However, the use of dppp or dppf was not as good as Ph3P, which

might be due to their poor steric flexibility during binding of the

Pd atom.

In summary, a Pd-catalyzed high regioselective diarylation of

9-allyl-9H-purine via chelation-assisted Heck reaction is described.

This method bears four important features: 1) purine as a novel

chelate compound to direct arylation, 2) the additional ligand-free

Pd(II)/Pd(IV) catalyst cycle differing from classical Heck reaction,

3) diarylation reaction does not require an inert atmosphere, and

4) high regioselective diarylation though two different types of b-H

which exist in the allyl substrate. Further efforts directed to the

detailed mechanism are under way in our laboratory.

Acknowledgements

We are grateful for financial support from the National Nature

Science Foundation of China (Grant Nos 20802016, 21172059

and 21072047), the Program for New Century Excellent Talents

in University of Ministry of Education (No. NCET-09-0122),

Excellent Youth Foundation of Henan Scientific Committee

(No. 114100510012), the Program for Changjiang Scholars

and Innovative Research Team in University (IRT1061), the

National Students Innovation Experiment Program, and the

Excellent Youth Program of Henan Normal University.

References

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Table 2 Chelation-assisted Pd-catalyzed Heck diarylation of terminalolefinsa

Entry R Ar1-I Ar2-I Product Yield (%)b

1 OMe Ph Ph 1aa 932 OMe Ph p-Me-Ph 1ab 893c OMe Ph p-MeO-Ph 1ac 664 OMe p-Me-Ph p-Me-Ph 1bb 985 Me Ph Ph 2aa 916d OMe Ph p-EtO2C-Ph 1ad 227 OMe p-MeO-Ph p-MeO-Ph 1cc 878 OMe p-EtO2C-Ph p-EtO2C-Ph 1dd 939 OMe p-Me-Ph p-MeO-Ph 1bc 6810 OMe 3,5-bis(Me)-Ph 3,5-bis(Me)-Ph 1ee 9611 Me p-Me-Ph p-Me-Ph 2bb 8612e OMe o-MeO2C-Ph o-MeO2C-Ph 1ff 74a Reaction conditions: 0.2 mmol 1, 0.25 M 1 in AcOH; for doublearylation: 1.02 equiv. Ar1–I, 1.02 equiv. Ar2–I; for diarylation:3.0 equiv. ArI, and the E/Z isomers ratio was determined by 1H NMRintegration. b Isolated yields based on 9-allyl-6-substituted purine.c 1.5 equiv. PhI was used and 1aa was also obtained in 33% isolatedyield in this reaction. d 1aa and 1dd were also obtained in respective31% and 23% isolated yields. e (E)-monoarylated product 1f was alsoobtained in 20% isolated yield in this reaction.

Scheme 2 Chelation-assisted Pd-catalyzed phenylation of 1 under classical

Heck reaction conditions.

Table 1 Optimization of reaction conditions for the Pd-catalyzeddiphenylation of terminal olefina

Entry X Pd cat. Time (h) Yield (%)b

1 I 5 mol % Pd(OAc)2 4.5 932 I 3 mol % Pd(OAc)2 4.5 883c I 5 mol % Pd(OAc)2 4.5 914 I 5 mol % PdCl2 5 905 I 5 mol % PdCl2(Ph3P)2 5 886 Br 5 mol % Pd(OAc)2 14 trace7 Br 10 mol % Pd(OAc)2 24 24a Reaction conditions: 0.1 mmol 1 and 0.3 mmol PhI or PhBr, 2 equiv.of AgOAc, 0.25 M 1 in AcOH. b Isolated yields based on 1. c Thereaction was carried out at 100 uC

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