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

Abstract

A Pd-catalyzed high regioselective diarylation of 9-allyl-9H-purinevia chelation-assisted Heck reaction is developed. There were two different types of β-H in the allyl substrate, while the two aryl groups are exclusively introduced to the terminal of the olefins.

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The Pd-catalyzed Heck reaction of aryl or alkenyl halides or triflates with alkenes has been developed into a powerful tool for the formation of C–C bonds.¹ Recently, different versions of directing groups such as organic phosphine,²tertiary amine,³pyridine,⁴sulfoxide⁵ 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 β-H except for a few cases.^4b As a consequence, challenges with elaborated olefins bearing two types of β-H lie ahead with respect to regioselectivity and catalytic efficiency. Furthermore, all those chelation-assisted Pd-catalyzed Heck reactions are based on the classical Pd(0)/Pd(II) catalyst cycle^2–7 in the presence of organic ligand. As such, chelation-assisted Pd-catalyzed Heck reactionviaPd(II)/Pd(IV) catalyst cycle under an additional ligand-free condition has not been previously realized.

Scheme 1 Different catalytic cycles for Pd-catalyzed diarylation Heck reaction of olefins.

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.⁹Purine derivatives are of great importance in medicinal chemistry since they display a broad spectrum antiviral activity, antimycobacterial activity and biological activity.¹⁰Purine 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 olefinsvia 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 °C 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.

Table 1 Optimization of reaction conditions for the Pd-catalyzed diphenylation of terminal olefin^a

Entry	X	Pd cat.	Time (h)	Yield (%)^b
a 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 The reaction was carried out at 100 °C
1	I	5 mol % Pd(OAc) 2	4.5	93
2	I	3 mol % Pd(OAc)2	4.5	88
3^c	I	5 mol % Pd(OAc)2	4.5	91
4	I	5 mol % PdCl2	5	90
5	I	5 mol % PdCl2(Ph3P)2	5	88
6	Br	5 mol % Pd(OAc)2	14	trace
7	Br	10 mol % Pd(OAc)2	24	24

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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 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 β-H in the substrates.

Table 2 Chelation-assisted Pd-catalyzed Heck diarylation of terminal olefins^a

Entry	R	Ar1-I	Ar2-I	Product	Yield (%)^b
a Reaction conditions: 0.2 mmol 1, 0.25 M 1 in AcOH; for double arylation: 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 NMR integration. b Isolated yields based on 9-allyl-6-substituted purine. c 1.5 equiv. PhI was used and 1aa was also obtained in 33% isolated yield in this reaction. d 1aa and 1dd were also obtained in respective 31% and 23% isolated yields. e (E)-monoarylated product 1f was also obtained in 20% isolated yield in this reaction.
1	OMe	Ph	Ph	1aa	93
2	OMe	Ph	p-Me-Ph	1ab	89
3^c	OMe	Ph	p-MeO-Ph	1ac	66
4	OMe	p-Me-Ph	p-Me-Ph	1bb	98
5	Me	Ph	Ph	2aa	91
6^d	OMe	Ph	p-EtO2C-Ph	1ad	22
7	OMe	p-MeO-Ph	p-MeO-Ph	1cc	87
8	OMe	p-EtO2C-Ph	p-EtO2C-Ph	1dd	93
9	OMe	p-Me-Ph	p-MeO-Ph	1bc	68
10	OMe	3,5-bis(Me)-Ph	3,5-bis(Me)-Ph	1ee	96
11	Me	p-Me-Ph	p-Me-Ph	2bb	86
12^e	OMe	o-MeO2C-Ph	o-MeO2C-Ph	1ff	74

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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.

Scheme 2 Chelation-assisted Pd-catalyzed phenylation of 1 under classical Heck reaction conditions.

In summary, a Pd-catalyzed high regioselective diarylation of 9-allyl-9H-purinevia 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 β-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.

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Footnote

† Electronic Supplementary Information (ESI) available: Experimental procedures, compound characterizations, and the copies of ¹H NMR and ¹³C NMR spectra. See DOI: 10.1039/c1ra00410g/

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