Pd-catalyzed direct arylation of tautomerizable heterocycles with aryl boronic acids via C-OH bond activation using phosphonium salts

Article abstract of DOI:10.1021/ja804804p

The first direct arylation via C-OH bond activation of tautomerizable heterocycles has been achieved using phosphonium salts, on the basis of a combination of the phosphonium coupling and Suzuki-Miyaura cross-coupling conditions. Optimal reaction condition is obtained through screening of phosphonium salts, Pd catalysts, and bases. The direct arylation via C-OH bond activation tolerates a variety of tautomerizable heterocycles and aryl boronic acids. The mechanism of the Pd-catalyzed phosphonium coupling is proposed to proceed via a domino seven-step process including the unprecedented heterocycle-Pd(II)-phosphonium species. Application of the Pd-catalyzed direct arylation via C-OH bond activation using PyBroP leads to the most efficient synthesis of the biologically important 6-arylpurine ribonucleoside in a single step from unactivated and unprotected inosine. Copyright

Full text of DOI:10.1021/ja804804p

Published on Web 07/30/2008
Pd-Catalyzed Direct Arylation of Tautomerizable Heterocycles with Aryl
Boronic Acids via C-OH Bond Activation Using Phosphonium Salts
Fu-An Kang,* Zhihua Sui, and William V. Murray
Johnson & Johnson Pharmaceutical Research and DeVelopment, LLC, 665 Stockton DriVe, Exton, PennsylVania 19341
Received July 1, 2008; E-mail: fkang@prdus.jnj.com
Scheme 1. Traditional Cross-Coupling versus Direct Arylation
Biaryl compounds (Ar-Ar) have become increasingly important
building blocks in materials and pharmaceuticals.1 Transition-metal-
catalyzed biaryl cross-coupling of arenes or heterocycles (Ar-H) have
proven to be an exceedingly valuable process in contemporary organic
synthesis developed in the past decades.2 Traditional biaryl synthesis
involves the coupling of activated Ar-H (Ar-X) and metalated Ar-H
(Ar-M) (Scheme 1). Preparation of both coupling partners usually
requires multisteps including protection of the sensitive functional
groups in the substrates if necessary. This generates waste from
reagents, solvents, and purifications. Direct arylation is a new type of
cross-coupling between an unactiVated and unprotected substrate and
one of the traditional coupling partners (Ar-X or Ar-M). In recent
years, direct arylation via C-H bond activation has emerged as an
attractive alternative approach to traditional cross-coupling methods,
and has led to a number of reactions that utilize directing groups,
repulsive steric interactions, electron-rich substrates or C-H bond
acidity, through the coupling of Ar-H with either Ar-X or Ar-M.3
Scheme 2. Pd-Catalyzed Direct Arylation via C-OH Bond
Activation Using Phosphonium Salts
Ar-H and Ar-OH are both synthetic precursors of Ar-X. Like
Ar-H, Ar-OH is also widely available as arenols and tautomerizable
heterocycles. Although direct arylation of Ar-H via C-H bond
activation has enjoyed explosive growth in the past several years, direct
arylation of Ar-OH via C-OH bond activation, either catalytically
or stoichiometrically, has remained largely unknown.4 An advantage
an attractive trend in modern synthetic organic chemistry.10 We realized
that this new phosphonium coupling was actually a combination of
C-OH bond activation using a phosphonium salt and subsequent
functionalization with a nucleophile in one step. We envisioned that
under the Suzuki-Miyaura cross-coupling condition (Pd catalyst and
aryl boronic acid), the resulting heterocycle-phosphonium salt might
chemically behave like some of the known preactivated oxygen-
containing cross-coupling partners, such as sulfonates11 and phos-
phates.12 This would undergo Pd-catalyzed direct arylation of the
heterocycle with an aryl boronic acid to furnish the biaryl product with
new C-C bond formation.
of direct arylation of Ar-OH is that the C-OH bond activation and
functionalization is regiospecific, while direct arylation of Ar-H via
C-H bond activation and functionalization is known to suffer from
overfunctionalization or regioselectivity issues.5
Phosphonium salts (PyBroP, PyBOP, BroP, BOP), uranium salts
(TBTU, TATU) and carbodiimides (DCC, EDC) are well-known
reagents for the coupling of carboxylic acids with amines to form
amides and peptides. In 2004,6 we first disclosed that, while uranium
salts and carbodiimides were not effective, phosphonium salts showed
excellent reactivity in the direct C-N, C-O, C-S, and C-C bond
formations of tautomerizable heterocycles with various nucleophiles
via the new phosphonium salt-mediated-tautomerization-activation-
coupling process (phosphonium coupling). When considering the scope
of this unprecedented, mild, efficient, and chemoselective phosphonium
coupling as a new synthetic methodology,7,8 we had predicted that
these coupling conditions could be potentially applicable to other
electron-deficient heterocyclic or aromatic systems.6 Indeed, the utility
and advantage of this new phosphonium coupling has been well
demonstrated in recent rapidly growing applications along this line.9
As part of our continued interest in this new phosphonium coupling
methodology, herein we report the first Pd-catalyzed direct arylation
via C-OH bond activation of tautomerizable heterocycles with aryl
boronic acids using phosphonium salts.
Table 1. Screening of Phosphonium Salts and Pd Catalystsa
Pd catalyst
phosphonium salt
yield (%)b
Pd(PPh3)4
Pd(PPh3)4
PyBroP
BroP
82
78
Pd(PPh3)4
Pd(PPh3)4
PyBOP
BOP
26
20
Pd(OAc)2
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
35
42
trace
11
79
Pd(dppf)CH2Cl2
Pd(dba)CHCl3
PdCl2(CH3CN)2
Pd(OAc)2(PPh3)2
PdCl2[P(o-Tol)3]2
PdCl2(PPh3)2
66
94
The chemo-selective nature of the phosphonium salts that are bonded
only to the acidic phenolic hydroxyl group in the electron-deficient
tautomerizable heterocycles makes protection and deprotection of the
sensitive functionalities in the substrates, such as the alcoholic hydroxyl
group, unnecessary.6 Synthesis without protecting groups is becoming
a Conditions: 2-quinoxalinone (0.5 mmol), phosphonium salt (1.2
equiv) and Et3N (3 equiv) in 1,4-dioxane (4 mL) at room temp for 2 h;
then, Pd catalyst (5 mol %), p-tolyl boronic acid (2 equiv), Na2CO3 (5
equiv) and water (1 mL) at 100 °C for 4 h. b Isolated yield.
9
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10.1021/ja804804p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Direct Arylation of Tautomerizable
Scheme 3. Multistep versus Single-Step Synthesis of 6-Arylpurine
Ribonucleosides
Heterocycles with Aryl Boronic Acids Using PyBroPa
to be sluggish in the absence of water, and replacement of water with
alkyl alcohols such as MeOH, EtOH, and i-PrOH resulted in slower
reactions as well as formation of the alkyloxy-heterocycle ethers as
side products.
With the optimized direct arylation conditions available, we
embarked on an investigation of the reaction scope. A variety of
tautomerizable heterocycles were examined for the Pd-catalyzed direct
arylation via C-OH bond activation using PyBroP (Table 2). The Pd-
catalyzed phosphonium coupling condition proved to be general for
the direct arylation of these tautomerizable heterocycles with p-tolyl
boronic acid. Complete conversion, and good to excellent isolated
yields were observed for all the heterocycles employed.13 Both
electron-rich and electron-poor aryl boronic acids coupled well with
the heterocycle-phosphonium salt to afford the biaryl products in
excellent yields. Direct arylation using heteroaryl and sterically
hindered aryl boronic acids also efficiently furnished the biaryl products
in high yields. It should be pointed out that the cross-coupling of the
heterocycle-phosphonium salts behaved in contrast to the cross-
coupling of aryl phosphates, which was known to be severely impeded
by both electronic and steric effects of the aryl boronic acids.12
One of the important applications to showcase such a mild, efficient,
and chemo-selective direct arylation via C-OH bond activation is the
cross-coupling of the purine ribonucleosides with aryl boronic acids
to synthesize the biologically important 6-arylpurine ribonucleosides,
which were known to display significant cytostatic and anti-HCV
effects.14 It generally takes four steps to prepare the 6-arylpurine
nucleosides, including protection, activation (halogenation or sulfo-
nylation), cross-coupling, and deprotection (Scheme 3). The preparation
of these ribonucleosides has attracted considerable synthetic attention
in recent years.15 By using the Pd-catalyzed phosphonium coupling,
the synthesis of the 6-arylpurine ribonucleoside can now be efficiently
achieved in a single step in 72% yield from unactiVated and
unprotected inosine and an aryl boronic acid.
a Conditions: Ar-OH (0.5 mmol), PyBroP (1.2 equiv) and Et3N (3
equiv) in 1,4-dioxane (4 mL) at room temp for 2 h; then, PdCl2(PPh3)2
(5 mol%), ArB(OH)2 (2 equiv), Na2CO3 (5 equiv) and water (1 mL) at
100 °C for 4 h. b Isolated yield.
At the outset of the study, we investigated the direct arylation of
2-quinoxalinone with p-tolyl boronic acid by using a combination of
two standard conditions: the phosphonium coupling condition6 (Py-
BroP, Et3N, 1,4-dioxane, room temp) and the Suzuki-Miyaura cross-
coupling condition2 (Pd(PPh3)4, Na2CO3, water, heating) (Scheme 2).
A mixture of 2-quinoxalinone (0.5 mmol), PyBroP (1.2 equiv) and
Et3N (3 equiv) in 1,4-dioxane (4 mL) was stirred at room temp for
2 h. Then, Pd(PPh3)4 (5 mol%), p-tolyl boronic acid (2 equiv), Na2CO3
(5 equiv), and water (1 mL) were added, and the mixture was stirred
in a sealed tube at 100 °C for 4 h. To our delight, the direct arylation
proceeded successfully to produce the biaryl product in 82% yield
(Table 1). For comparison purposes, other common phosphonium salts
(PyBOP, BroP, and BOP) were also tested for the direct arylation
reaction. As shown in Table 1, it was found that the Br-derived reagents
(PyBroP and BroP) were far more effective than the OBt-derived
reagents (PyBOP and BOP), probably because the latter simultaneously
produced the heterocycle-OBt ether as the side product6,8 that virtually
shut down the cross-coupling reaction. With PyBroP as the best reagent
of choice for the direct arylation, we then tried to improve the reaction
condition by screening a variety of Pd catalysts. We soon found out
that PdCl2(PPh3)2 was the best catalyst that led to the biaryl product
in 94% yield. As for the base involved in the direct arylation, it was
observed that carbonates (Na, K, and Cs) were more effective than
other bases such as DIPEA, DBU, DABCO, DMAP, CsF, NaOAc,
K3PO4, NaOH, and NaOBut. In addition, the direct arylation appeared
On the basis of the modified Suzuki-Miyaura catalytic cycle,16
we propose the possible mechanism of the Pd-catalyzed direct arylation
of 2-quinoxalinone that is shown in Scheme 4. It most likely proceeds
through the following seven domino steps: (1) tautomerization of
2-quinoxalinone to 2-quinoxalinol in the presence of Et3N; (2)
activation of 2-quinoxalinol with PyBroP generating the heterocycle-
phosphonium salt; (3) oxidative insertion of Pd(0) catalyst to the C-O
bond of the heterocycle-phosphonium salt forming the heterocycle-
Pd(II)-phosphonium species; (4) reaction with a base (e.g., NaOH)
producing the heterocycle-Pd(II)-OH species; (5) activation of the
aryl boronic acid with the base affording the aryl boron-ate complex;
(6) transmetalation of the heterocycle-Pd(II)-OH species with the aryl
boron-ate complex giving the heterocycle-Pd(II)-aryl species; and (7)
reductive elimination of the biaryl product and regeneration of the Pd(0)
catalyst.
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C O M M U N I C A T I O N S
Scheme 4. Possible Mechanism of the Pd-Catalyzed Direct
Arylation via C-OH Bond Activation Using PyBroP
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products (9 and 10). To confirm their structures, the identical biaryl ethers 9a
and 10a were alternatively prepared via our previous phosphonium coupling
for the direct C-O bond formation by using the corresponding phenols (see
Supporting Information). The reason for the biaryl ether formation on this
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In conclusion, we have developed the first Pd-catalyzed direct
arylation via C-OH bond activation of tautomerizable heterocycles
with aryl boronic acids using phosphonium salts. The scope of the
direct arylation has been shown to tolerate a variety of electron-deficient
tautomerizable heterocycles and aryl boronic acids. The mechanism
of the direct arylation is proposed to proceed via a domino seven-step
process including the unprecedented heterocycle-Pd(II)-phosphonium
species. Application of the Pd-catalyzed phosphonium coupling via
C-OH bond activation leads to the most efficient synthesis of the
biologically important 6-arylpurine ribonucleoside from unactiVated
and unprotected inosine in a single step. This direct arylation via
C-OH bond activation using phosphonium salts could be potentially
applicable to other transition-metal-catalyzed cross-coupling reactions,
such as the Sonogashira and the Heck reactions, which will be reported
in due course.
Acknowledgment. Dedicated to Professor William von E. Doering
on the occasion of his 90th birthday. We thank Professor Daniel L.
Comins for helpful discussions.
Supporting Information Available: Preparation of the biaryl ethers
9a and 10a, hydrogen-deuterium exchange experiment of 11-11a,
characterization data and NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
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