Ortho-functionalization of 2-phenoxypyrimidines via palladium-catalyzed C-H bond activation

Article abstract of DOI:10.1021/jo901316b

(Chemical Equation Presented) The palladium-catalyzed direct acetoxylation and a3rylation of 2-aryloxypyrimidine has been described. The aromatic C-H bonds may be functionalized in moderate to excellent yields providing a facile method for the synthesis o

Full text of DOI:10.1021/jo901316b

pubs.acs.org/joc
aminomethyl can be regioselectively functionalized via cyclo-
Ortho-Functionalization of 2-Phenoxypyrimidines
via Palladium-Catalyzed C-H Bond Activation
metalated intermediates under palladium, ruthenium, or rho-
dium catalysis. The direct ortho C-H activation of aromatic
carboxylic acids6 and amilides7 can be similarly realized
because of the functions of the β-positioned oxygen and nitro-
gen, whereas the regioselective ortho functionalization of alde-
hydes and ketones have been achieved via aldehydes and
ketones directly or via their imine derivatives.8 Although mono-
and diarylation reactions of 2-phenylphenols and naphthols
with aryl halides have been known to occur at the second
phenyl ring,9 the direct functionalization of simple phenols is
not accessible because phenols are not able to form 5- or
6-membered metallacycles due to lack of directing groups at
the β- or γ-positions. Introduction of a temporary directing
group would be a possible passway leading to ortho C-H
activation and subsequent functionalization. Actually, this
strategy has been successful by using phosphites or phosphi-
nites through reversible in situ transesterification of phenols.
However, the rhodium-catalyzed protocol was not applicable
to 2-position unsubstituted phenols, and the yields were low for
less sterically hindered 2-alkylphenols.10 This disadvantage
could be partly overcome by using hexamethylphosphorous
triamide.10b,11 Herein, we present the direct ortho-acetoxyla-
tion and ortho-arylation of 2-phenoxypyrimidine derivatives
through Pd(OAc)2-catalyzed ortho C-H bond activation.
Phenols can be easily transformed to 2-phenoxypyridine or
2-phenoxypyrimidine by their copper-catalyzed C-O coupling
reactions with 2-halopyridine or 2-halopyrimidine. The C-H
activation of the resulting ethers could be easily realized due to
formation of six-membered palladacyles.12 Thus, subsequent
functionalization would be possible (Scheme 1). We first tested
Pd(OAc)2-catalyzed acetoxylation of 2-naphthyloxypyrimidine
1a with various oxidants and solvents. When air, K2S2O8, ben-
zoxyl peroxide, and silver salts were employed as oxidants, the
desired functionalized product was not observed, and the
pyrimidyl ether could be recovered. However, the ortho-acet-
oxylated product 2a could be obtained in 87% yield using
PhI(OAc)2 as an oxidant under the conditions adopted by
Sanford et al.13 Then we tested Pd(OAc)2-catalyzed acetoxyla-
tion of 2-phenoxypyridine and 2-phenoxypyrimidine using
Shaojin Gu, Chao Chen, and Wanzhi Chen*
Department of Chemistry, Zhejiang University, Xixi Campus,
Hangzhou 310028, P. R. China
chenwzz@zju.edu.cn
Received June 30, 2009
The palladium-catalyzed direct acetoxylation and aryla-
tion of 2-aryloxypyrimidine has been described. The aro-
matic C-H bonds may be functionalized in moderate to
excellent yields providing a facile method for the synthesis
of phenol derivatives, which show antimycobacterial and
herbicidal activities.
Transition-metal-catalyzed direct C-H bond functionaliza-
tion has emerged as a powerful method to afford valuable
transformations of sp2-hybridized C-H bonds to C-O,1 C-X,2
C-C,3 C-N,4 and C-S bonds.5 In this context, many arenes
containing a directing group such as pyridine, oxazoline, and
(1) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300. (b) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem. 2008, 73,
4717. (c) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 149.
(2) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett.
2006, 8, 2523. (b) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi,
Z. J. Am. Chem. Soc. 2006, 128, 7416. (c) Chen, X.; Hao, X.-S.; Goodhue,
C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (d) Mei, T.-S.; Giri, R.;
Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215.
(3) For selected references, see: (a) Dipannita, K.; Deprez, N. R.; Deprez,
L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (b) Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (c) Deng, G. J.; Zhao, L.;
Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 6278. (d) Zhao, X. D.; Yu, Z. K.
J. Am. Chem. Soc. 2008, 130, 8136. (e) Campeau, L.-C.; Schipper, D. J.;
Fagnou, K. C. J. Am. Chem. Soc. 2008, 130, 3266. (f) Alberico, D.; Scott, M.
E.; Lautens, M. Chem. Rev. 2007, 107, 174. (g) Hachiya, H.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737. (h) Canivet, J.; Yamaguchi,
J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733. (i) Ackermann, L.; Mulzer, M.
Org. Lett. 2008, 10, 5043.
(8) (a) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2008, 47, 9462. (b) Desai, L. V.; Malik, H. A.; Sanford, S. M.
Org. Lett. 2006, 8, 1141. (c) Desai, L. V.; Hull, L. K.; Sanford, S. M. J. Am.
Chem. Soc. 2004, 126, 9542. (d) Satoh, T.; Kametani, Y.; Terao, Y.; Miura,
M.; Nomura, M. Tetrahedron Lett. 1999, 40, 5345. (e) Terao, Y.; Kametani,
Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2001, 57,
5967. (f) Ackermann, L. Org. Lett. 2005, 7, 3123. (g) Yoshikai, N.; Matsu-
moto, A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925.
(9) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1740. (b) Satoh, T.; Inoh, J.; Kawamura, Y.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
2239.
(10) (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. 2003, 42, 112. (b) Bedford, R. B.; Limmert, M. E.
J. Org. Chem. 2003, 68, 8669. (c) Bedford, R. B.; Betham, M.; Caffyn, A. J.
M.; Charmant, J. P. H.; Lewis-Alleyne, L. C.; Long, P. D.; Polo-Ceron, D.;
Prashar, S. Chem. Commun. 2008, 990.
(4) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048.
(5) Zhao, X. D.; Dimitrijevic0, E.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 3466.
(6) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Chiong, H.
A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (c) Miura,
M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63,
5211. (d) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(7) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (b) Li, B.; Tian, S.; Fang, Z.;
Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1115. (c) Yang, S.; Li, B.; Wan, X.;
Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (d) Shabashov, D.; Daugulis, O.
J. Org. Chem. 2007, 72, 7720. (e) Zaitsev, V. G.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 4156. (f) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc.
1984, 106, 5760.
(11) Oi, S.; Watanabe, S.-I.; Fukita, S.; Inoue, Y. Tetrahedron Lett. 2003,
44, 8665.
(12) (a) de Geest, D. J.; O’Keefe, B. J.; Steel, P. J. J. Organomet. Chem.
1999, 579, 97. (b) O’Keefe, B. J.; Steel, P. J. Organometallics 2003, 22, 1281.
(13) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008,
130, 13285.
DOI: 10.1021/jo901316b
r
Published on Web 08/12/2009
J. Org. Chem. 2009, 74, 7203–7206 7203
2009 American Chemical Society

Gu et al.
JOCNote
SCHEME 1. Illustration of Phenol Functionalization via C-H
Activation
TABLE 1. Pd(OAc)2-Catalyzed Acetoxylation of Heteroaryl Ethersa
PhI(OAc)2 as an oxidant in mixed Ac2O/AcOH solvent. The
results showed that pyridine and pyrimidine have the same
directing function; thus, pyrimidine drivatives were chosen for
further studies since they can be more easily obtained by C-O
coupling reactions. In addition, these heteroaryl ethers have
been known to show antimycobacterial and herbicidal activ-
ities.14
The successful functionalization of 1a encouraged us to
explore the possibility of other pyrimidyl ethers. We found
that the pyrimidine group directed C-H bond functionaliza-
tion protocol is broadly applicable to a variety of heteroaryl
ethers affording corresponding acetoxylated products in good
to excellent yields (Table 1). For example, 2-phenoxypyrimi-
dine was converted to 2-(pyrimidin-2-yloxy)phenyl acetate in
a yield of 50% together with a small amount of diacetoxylated
product by using 1.1 equiv of PhI(OAc)2. However, when 3.0
equiv of PhI(OAc)2 was employed for the same reaction, the
yield of the double-acetoxylated product (2d) was increased to
84% (entry 4). All of the substrates bearing either an electron-
donating group or an electron-withdrawing group at the
ortho-, meta-, and para-postions of phenyl groups could be
applied to form the desired products (Table 1, entries 5-17).
However, the efficiency of this transformation was compara-
tively low when an electron-withdrawing substituent is pre-
sent. Probably the low electron density on the phenyl ring
would reduce the tendency of C-H oxidative addition
(Table 1, entries 5-8). For substrates containing two ortho
C-H bonds like 2-(p-tolyloxy)pyrimidine, the reaction gave
monoacetoxylated product in moderate yield when 2% Pd-
(OAc)2 was used (Table 1, entry 9). For the sterically hindered
substrates with substituents at the ortho- and meta-posi-
tions, the reaction yields were reduced (Table 1, entries 11
and 12). The polysubstituted diaryl ethers were also inves-
tigated, and the expected products were obtained in excellent
yields (Table 1, entries 13 and 14). It is worth pointing out
that the regioselectivity of this reaction was controlled by the
steric effect. The acetoxylation always occurred at the less
sterically hindered site (entries 15 and 16). In addition, the
additional functional groups such as halogen, methoxyl, and
carboxylate (entries 5-8 and 17) did not interfere with the
palladium-catalyzed oxidative activation reaction showing
good group tolerance. When two ortho positions are blocked
by two methyl groups, the substrate 1p was inert toward
cyclopalladation, and thus, only the starting material was
recovered. The ether, 1q, was also inert probably because
the coordination of two heteroarene would prevent cycloc-
palladation. It was expected that 1r would be easily double
acetoxylized since double cyclopalladation might happen
simutaneously. Surprisingly, the functionalization of 1r did
not occur.
aConditions: 2 mol % of Pd(OAc)2, 1.1 equiv of PhI(OAc)2, 0.125 M in
AcOH/Ac2O, 100 °C, 2-12 h. bConditions: 5 mol % of Pd(OAc)2, 3.0 equiv
of PhI(OAc)2, 0.125 M in AcOH/Ac2O, 100 °C, 4 h.
The success in the highly regioselective acetoxylation of
2-phenoxypyrimidine derivatives by using the pyrimidine-di-
rected C-H activation approach prompted us to explore the
possibility of direct C-H arylation. The Suzuki-Miyaura-type
(14) (a) am Ende, C. W.; Knudson, S. E.; Liu, N.; Childs, J.; Sullivan,
T. J.; Boyne, M.; Xu, H.; Gegina, Y.; Knudson, D. L.; Johnson, F.; Peloquin,
C. A.; Slayden, R. A.; Tonge, P. J. Bioorg. Med. Chem. Lett. 2008, 18, 3029.
(b) Yu, S.-R.; Cho, J.-H.; Ho, C.-U.; Lee, H.-S.; Hong, S.-M.; Kim, H.-U.;
Im, J.-S.; Kim, J.-S. KR 9,511,418, 1995.
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JOCNote
arylation of 1a was first examined using phenylboronic acid
as arylation reagent and Pd(OAc)2/Cu(OTf)2/Ag2O as cata-
lyst. We were pleased to obtain the arylated product 3a in
51% yield at 120 °C within 24 h. The arylation reaction was
successfully extended to various pyrimidyl ethers bearing
different substituents at the aromatic rings. As shown in
Table 2, the Suzuki-Miyaura type coupling reactions of the
ethers could proceed smoothly giving corresponding ortho
arylated ethers in good yields by using 5 mol % of Pd(OAc)2,
1 equiv of Cu(OTf)2, and 1 equiv of Ag2O. We found that
both Cu(OTf)2 and Ag2O are essential for the catalytic cycle.
Other combinations of copper and silver salts led to much
lower yields of arylation products.
TABLE 2. Suzuki-Miyaura Coupling of Various Ethers with Phenyl-
boronic Acida
The scope of this reaction with respect to the heteroaryl
ether substrates was screened. The results in Table 2 showed
that the coupling reactions of electron-rich arylethers were
more efficiently achieved. This observation is not surprising
because C-H oxidative addition is preferred for substrates
bearing electron-donating groups. Although the aromatic
ethers bearing chloride, aldehyde, and carboxylate groups
could be arylated, the yields are relatively low. In the cases
of unsubstituted and para-substituted ethers that possess
two o-C-H bonds, good yields of the double coupled
products 3e, 3f, and 3j were obtained upon addition of
3.0 equiv of Cu(OTf)2, 3.0 equiv of Ag2O, and 15 mol%
Pd(OAc)2 (Table 2, entries 6, 7, and 11). The coupling
reaction of meta-substituted ether occurred at the less
sterically hindered position (Table 2, entries 2 and 3).
The X-ray crystallographic analysis of the arylation pro-
duct 3b verified the regioselectivity of this coupling reac-
tion. The structure of 3b is given in Figure S1 of the
Supporting Information. In addition, unique functional
group tolerance is observed, and the C-Cl bond on the
substrate is tolerated (Table 2, entry 8), although in this case
the yield is somewhat reduced. The product 3g provides
possibility for further C-C coupling reaction to construct
more complex structure. Under the standard conditions,
the direct arylations reaction could be scaled up to 0.5 mmol
of 1 using 1.0 mmol of phenylboronic acid, and 0.025 mmol
of Pd(OAc)2 in 4 mL of toluene (Table 2, entries 13-15).
The corresponding products 3c, 3d, and 3h were readily
isolated in 50%, 66%, and 58% yields, respectively.
A series of substituted phenylboronic acids as coupling
partners were also investigated under the conditions used
above. For the sake of products isolation, 2-(2,4-
dimethylphenoxy)pyrimidine 1l was chosen for evaluation.
The results of the coupling reactions of 1l with different
phenylboronic acids are summarized in Table 3. Both elec-
tron-rich and electron-deficient arylboronic acids gave mono-
arylated products in good yields under the mild conditions.
However, the relatively hindered boronic acid, 2-tolylboronic
acid, demonstrated only poor reactivity (Table 3, entry 4).
Among these reactants, 4-chlorophenylboronic acid is more
interesting because the resultant products 4d bears additional
halide offering an opportunity for the construction of more
complex compounds (Table 3, entry 5).
In summary, we have successfully developed ortho-acetoxy-
lation and ortho-arylation of phenol derivatives through Pd-
(OAc)2-catalyzed C-H bond activation. This protocol was
convenient, efficient, and applicable to various substituted
phenol and naphthol derivatives. 2-Phenoxypyrimidine deri-
vatives have good herbicidal activities; thus, this route may
aThe reactions were carried out with 1 (0.2 mmol) and phenylboronic
acid (0.4 mmol) in the presence of Pd(OAc)2 (5.0 mol %), Cu(OTf)2 (1.0
equiv), and Ag2O (1.0 equiv). bConditions: Pd(OAc)2 (15 mol %),
Cu(OTf)2 (3.0 equiv), Ag2O (3.0 equiv), and phenylboronic acid
(5 equiv). cThe reactions were carried out with
1 (0.5 mmol)
and phenylboronic acid (1.0 mmol) in the presence of Pd(OAc)2
(5.0 mol %), Cu(OTf)2 (1.0 equiv), and Ag2O (1.0 equiv).
provide a simaple procedure for the preparation of such
herbicides.
J. Org. Chem. Vol. 74, No. 18, 2009 7205

Gu et al.
JOCNote
TABLE 3. Arylation of C-H Bonds of 1l with Various Arylboronic Acidsa
to dryness in vacuo. The residual was separated via thin-layer
chromatography with petroleum ether/ethyl acetate (3/1) as the
eluent to give the desired product (2a-q).
1-(Pyrimidin-2-yloxy)naphthalen-2-yl acetate (2a): pale yel-
low solid; mp 136-137 °C; 1H NMR (400 MHz, CDCl3)
δ 8.56 (d, J = 4.8 Hz, 2H), 7.98-7.95 (m, 1H), 7.92-7.89
(m, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.52-7.49 (m, 2H), 7.39 (d,
J = 8.8 Hz, 1H), 7.07 (t, J=4.8 Hz, 1H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.4, 165.1, 159.9, 139.5, 139.0, 132.5,
128.2, 127.9, 126.8, 126.2, 121.9, 121.7, 116.5, 20.6; HRMS (ESI,
m/z) calcd for C16H12N2O3Na 303.0746 (M þ Na)þ, found
303.0740.
General Procedure for the Direct Ortho-Arylation of 2-Phe-
noxypyrimidine Derivatives. Pd(OAc)2 (2.2 mg, 0.01 mmol),
ether 1 (0.2 mmol), Cu(OTf)2 (72.4 mg, 0.2 mmol), Ag2O
(46.4 mg, 0.2 mmol), arylboronic acid (0.4 mmol), and freshly
distilled toluene (2 mL) were added to a dry Schlenk tube.
The reaction mixture was heated and stirred for 24 h at
120 °C. Upon completion, the solvent was evaporated to dry
in vacuo, the saturated sodium sulfide aqueous solution (20 mL)
was added, and the aqueous phase was extracted with CH2Cl2
(2 ꢀ 20 mL). The combined organic phase was washed twice
with brine. The resulting organic layer was dried over MgSO4
and concentrated. Purification of the crude mixture by thin-
layer chromatography (petroleum ether/ethyl acetate) gave the
desired product.
2-(2-Phenylnaphthalen-1-yloxy)pyrimidine (3a): pale yellow
solid; mp 142-144 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d,
J=4.8 Hz, 2H), 7.96 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H),
7.86 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 8.0 Hz, 3H), 7.53-7.46 (m,
2H), 7.32 (t, J=8.0 Hz, 2H), 7.24-7.20 (m, 1H), 6.83 (t, J=4.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.1, 159.5, 145.1,
137.8, 134.2, 130.7, 129.3, 128.2, 128.1, 127.9, 127.2, 126.7,
126.4, 126.0, 122.1, 115.7; HRMS (ESI, m/z) calcd for C20H14-
N2ONa 321.1004 (MþNa)þ, found 321.0999.
aAll the reactions were carried out with 1l (0.2 mmol) and phenyl-
boronic acid (0.4 mmol) in the presence of Pd(OAc)2 (5.0 mol %),
Cu(OTf)2 (1.0 equiv), and Ag2O (1.0 equiv).
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (20872129), RFDP (20080-
3350011), and Zhejiang University K. P. Chao’s HTD
Foundation (2008RC003) for their financial support.
Experimental Section
General Procedure for the Direct Ortho-Acetoxylation of
2-Phenoxypyrimidine Derivatives. A solution of diaryl ether
(0.5 mmol), Pd(OAc)2 (2.3 mg, 0.01 mmol), and PhI(OAc)2
(178 mg, 0.55 mmol) in AcOH (2.0 mL) and Ac2O (2.0 mL) was
stirred in a 20 mL Schlenk tube at 100 °C. The reaction was
monitored by GC. Upon completion, the solvent was evaporated
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
7206 J. Org. Chem. Vol. 74, No. 18, 2009