Heteroaryl ethers by oxidative palladium catalysis of pyridotriazol-1-yloxy pyrimidines with arylboronic acids

Article abstract of DOI:10.1021/ol900592b

The oxidative palladium-catalyzed cross-coupling of pyrimidines containing pyridotriazol-1-yloxy (OPt) as either a urea or an amide functional group with arylboronic acids in the presence of Cs₂CO₃ in DME containing 0.6-1.0% H_2<

Full text of DOI:10.1021/ol900592b

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2511-2514
Heteroaryl Ethers by Oxidative
Palladium Catalysis of
Pyridotriazol-1-yloxy Pyrimidines with
Arylboronic Acids
Sujata Bardhan, Sumrit Wacharasindhu, Zhao-Kui Wan, and Tarek S. Mansour*
Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl RiVer,
New York 10965 and 200 Cambridge Park DriVe, Cambridge, Massachusetts 02140
mansout@wyeth.com
Received March 25, 2009
ABSTRACT
The oxidative palladium-catalyzed cross-coupling of pyrimidines containing pyridotriazol-1-yloxy (OPt) as either a urea or an amide functional
group with arylboronic acids in the presence of Cs2CO3 in DME containing 0.6-1.0% H2O is described for the preparation of heteroaryl ethers.
The bromo substitution in the case of 3-(5-bromo-pyrimidin-2-yloxy)-3H-[1,2,3]triazolo[4,5-b]pyridine 1 could serve as a handle for further
elaborations such as Suzuki coupling for attaching varied aryl groups.
Aryl ethers are an important class of biologically active
compounds.1 Recent synthetic methods that avoid the use
of harsh conditions and result in better control over the
classical methods have been reported. These methods include
Mitsunobu reactions using immobilized triphenylphosphine
for ease of purification,1,2 reaction of aryl fluorides and silyl
ethers,3 and Ullman-type coupling reactions using CuI and
[(dimethylamino)methyl]phosphonic acid derivatives.4 These
also include a variety of metal-mediated transformations
involving Rh(I)-catalyzed [2 + 2 + 2] cycloaddition reac-
tions,5 Pd(0)-catalyzed enyne-diyne [4 + 2] cycloadditions,6
Buchwald-Hartwig Pd-mediated couplings,7 and Pd-cata-
lyzed Heck reactions.8
Recently, we demonstrated the synthetic versatility of
phosphonium-mediated SNAr reactions with heterocycles9
using benzotriazole-1-yl-oxy-tris(dimethylamino)-phospho-
nium (BOP)10 or (7-azabenzotriazol-1-yloxy)tripyrrolidino-
phosphonium hexafluorophosphate (PyAOP)11 reagents. Phos-
phonium intermediates of pyrimidines could also be intercepted
as partners in Suzuki cross-coupling reactions, resulting in
the formation of C-C bonds.10c In the SNAr reactions
involving BOP reagents, mechanistic studies regarding the
nature of the intermediates are consistent with a pathway
involving stepwise formation of HOBt adducts from the
(1) (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T. Y.; Li,
H.; Brase, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421–3422.
(b) Xu, B.; Xue, J.; Zhu, J.; Li, Y. Chem. Lett. 2008, 37, 202–203. (c)
Hartwig, J. F. Handbook of Organopalladium Chemistry for Organic
Synthesis; In Negishi, E. I., Ed.; Wiley-Interscience: New York, 2002; Vol.
1, pp 1097-1106. (d) Hartwig, J. F. Synlett 2006, 9, 1283–1294.
(6) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. J. Org. Chem. 2000,
65, 568–572.
(7) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 3395–3396. (b) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007,
9, 643–646.
(2) Valeur, E.; Roche, D. Tetrahedron Lett. 2008, 49, 4182–4185
(3) Wang, T.; Love, J. A. Synthesis 2007, 15, 2237–2239.
.
(8) (a) He, T.; Tao, X.; Wu, X.; Cai, L.; Pike, V. W. Synthesis 2008, 6,
887–890. (b) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem.
2001, 66, 4340–4343. (c) Berthiol, F.; Feuerstein, M.; Doucet, H.; Santelli,
M. Tetrahedron Lett. 2002, 43, 5625–5628.
(4) Jin, Y.; Liu, J.; Yin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2006,
10, 1564–1568.
(5) Clayden, J.; Moran, W. J. Org. Biomol. Chem. 2007, 5, 1028–1030.
10.1021/ol900592b CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

phosphonium intermediates.9,12 Indeed, benzotriazol-yloxy
quinazoline readily reacted with various nucleophiles in SNAr
fashion. Further investigations led to the discovery of an
oxidative palladium-catalyzed SNAr reaction of pyridotriazol-
yloxy quinazoline (OPt) adducts involving arylboronic acids
and dioxygen under Pd catalysis without direct involvement of
phenols.13 This reaction is especially valuable when phenols
are not readily available and is distinct compared to the
homocoupling reactions in oxidative palladium reactions.
In this letter, we report that pyrimidines carrying an OPt
functional group12 (Figure 1) are good substrates for the
As in the case with quinazoline OPt,13 Pd(PPh3)4 in DME
proved to be advantageous over Pd(OAc)2. Further screening
of base effects identified Cs2CO3 and Na2CO3 as suitable
bases for this transformation. With Cs2CO3 as the base of
choice, dioxygen proved to be the best oxidant in comparison
14
to H2O2 or anhydrous urea hydrogen peroxide (UHP)
(Table 1). The presence of water 0.6-1.0% in DME was
necessary to achieve good yields of 2a. The OBt analogue
of 1 is also a good substrate for this transformation, although
heteroaryl ethers are formed at a slower reaction rate.
Arylboronic acids containing diverse functional groups
underwent transformation to heteroaryl ethers 2a-l readily
under mild conditions (Scheme 1). The presence of a
Scheme 1. Coupling Reaction of 1 with Arylboronic Acids
Figure 1. Oxidative Pd(0) reaction on representative cyclic OPt
heterocycles.
oxidative Pd-catalyzed reaction resulting in the synthesis of
heteroaryl ethers from pyridotriazol-l-yloxy pyrimidines,
arylboronic acids, and dioxygen.
Optimization studies were initially performed on 3-(5-
bromo-pyrimidin-2-yloxy)-3H-[1,2,3]triazolo[4,5-b]pyri-
dine 1 with phenylboronic acid by evaluating various metals,
ligands, solvents, and bases. The desired 2-phenoxy-5-
bromopyrimidine product 2a (Table 1) was observed without
the detection of 2-phenyl-5-bromopyrimidine as the Suzuki
cross-coupling product.
Table 1. Optimization Conditions of
3-(5-Bromo-pyrimidin-2-yloxy)-3H-[1,2,3]triazolo[4,5-b]pyridine
1 Coupling with Phenylboronic Acids
entry
base
solvent
oxidant
yield (%)a
1
2
3
4
5
6
Cs2CO3
Cs2CO3
No Base DME
Cs2CO3
Cs2CO3
Cs2CO3
DME
DME
UHP
18
0c
0
H2O2 (10%)b
O2
N2
O2
thiomethyl moiety in 2b did not result in any complications
due to potential sulfoxide or sulfone formation. The elec-
tronic and steric effects were evaluated using three arylbo-
ronic acids carrying acetyl, carbomethoxy, and methoxy
substituents at the o, m, and p positions. Boronic acids with
electronic withdrawing (acetyl, carbomethoxy) and donating
groups (methoxy) gave moderate to excellent yields of
DME
DME
35d
25
62
DME-H2O (0.8%) O2
a Isolated yields. b 30% w/w H2O2 c 2a was not observed. Instead a
polar and unidentified compound was formed. d Slightly wet batch of Cs2CO3
used.
2512
Org. Lett., Vol. 11, No. 12, 2009

isolated heteroaryl ethers 2d-i and 2j-l, respectively. It is
unclear why the yield of 2d is low especially in comparison
to 2g and 2j, and this does not suggest electronic reasons
since the latter compounds were formed in good yields.
Boronic acids derived from a variety of heterocycles
produce heteroaryl ethers under the oxidative palladium
coupling conditions (Scheme 2). In the case of 3d no
Scheme 3. Suzuki Cross-Coupling Reaction of
5-Bromo-2-(4-methoxyphenoxy)pyrimidine 2l
Scheme 2
.
Coupling Reaction of 1 with Heteroarylboronic
Acids
pyrimidines 1 and 5 demonstrate good potential and broaden
the scope for an effective O-arylation reaction (Schemes 1
protection of the nitrogen moiety is required. A limitation
of the scope of this reaction was realized with boronic acids
containing a heteroatom in the R position as the reaction
was too slow to form the desired product in a synthetically
useful manner. The use of excess arylboronic acids is
necessary to compensate for the homocoupling products
under the oxidative Pd(0) reaction conditions.15
Scheme 4. Oxidative Palladium Coupling Reaction of 4-(3H-
[1,2,3]Triazolo[4,5-b]pyridin-3-yloxy)-1-methylpyrimidin-2(1H)-
one 5 with Arylboronic Acids
The choice of the 5-bromo substituent in 1 was deliberately
made to evaluate the chemo- and regioselectivity of an
oxidative Pd coupling reaction at C2 with a possible Suzuki-
type reaction at C5. In all cases reported (in Scheme 1),
Suzuki coupling at the C5 position was not observed. This
observation leaves the opportunity to exploit further chem-
istry by using the 5-bromo group as a chemical handle.
Toward this end, a few 5-aryl pyrimidines were synthesized
through Suzuki coupling as shown in Scheme 3. Heteroaryl
ethers such as 2l readily underwent cross-coupling reactions
with a variety of arylboronic acids to provide the desired
products using the Buchwald ligand DTBBP (Scheme 3)
under Pd(II) catalysis.16
Pyrimidine bases are important biologically. Therefore,
extension of this transformation to 4-(3H-[1,2,3]triazolo[4,5-b]-
pyridine-3-yloxy)-1-methylpyrimidin-2(1H)-one 5 was at-
tempted since this heterocycle has an N3 substituent different
from that of 1 or the quinazoline analogue in both basicity
and electronic factors. The oxidative palladium reaction
followed by an SNAr reaction, indeed, proceeded very well
with 5 producing excellent isolated yields of heteroaryl ethers
6a-d (Scheme 4). The excellent yields derived from
and 4). Consistent with our earlier findings on the lack of
reactivity of the 5-bromo moiety in 1,13 the 2-chloro moiety
in 6c did not cause any complications. In conclusion, the
expanded scope of the oxidative palladium coupling reactions
of heterocyclic OPt derivatives17 with arylboronic acids
Org. Lett., Vol. 11, No. 12, 2009
2513

provides an efficient synthesis of heteroaryl ethers of
biologically important pyrimidine heterocycles. This trans-
formation amounts to the SNAr reaction12 of phenols with
the OPt heterocycles but offers the advantage of not using
phenols when they are not readily available or are unstable.
Additionally, the reaction conditions are mild and apply to
OPt derivatives of amides and ureas. The formation of
heteroaryl ethers by this method complements earlier reports
on the potential of using stable OPt adducts of heterocycles
in novel synthetic transformations. Mechanistic studies likely
involving the formation13,18 of (η2-O2)Pd(PPh3)2 and its
reaction with aryl boronic acids are under investigation and
will be reported elsewhere.19
Acknowledgment. The authors wish to thank Elwira
Muszynska and Murthy Damarla of Wyeth Research for
purification of 2j.
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T. Org. Lett. 2006, 8, 2425–2428. (c) Levins, C. G.; Wan, Z.-K. Org. Lett.
2008, 10, 1755–1758.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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OL900592B
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