Copper-catalyzed etherification of arene C-H bonds

Article abstract of DOI:10.1021/ol402904d

A method for direct, auxiliary-assisted alkoxylation and phenoxylation of β-sp² C-H bonds of benzoic acid derivatives and γ-sp ² C-H bonds of amine derivatives is reported. The reaction employs (CuOH)₂CO₃ catalyst, air as an oxidant, phenol or alcohol coupling partner, DMF, pyridine, or DMPU solvent, and K₂CO ₃, tetramethylguanidine, or K₃PO₄ base at 70-130 C.

Full text of DOI:10.1021/ol402904d

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5842–5845
Copper-Catalyzed Etherification of Arene
CÀH Bonds
James Roane and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003,
United States
olafs@uh.edu
Received October 8, 2013
ABSTRACT
A method for direct, auxiliary-assisted alkoxylation and phenoxylation of β-sp2 CÀH bonds of benzoic acid derivatives and γ-sp2 CÀH bonds of
amine derivatives is reported. The reaction employs (CuOH)2CO3 catalyst, air as an oxidant, phenol or alcohol coupling partner, DMF, pyridine, or
DMPU solvent, and K2CO3, tetramethylguanidine, or K3PO4 base at 70À130 °C.
CarbonÀhydrogen bond functionalization methodol-
ogy is perhaps the most direct way to introduce function-
ality into organic molecules. In the past decade, significant
advances in CÀH activation and functionalization have
been realized.1 However, relatively scarce second- and
third-row transition metals are most commonly used for
these transformations. It would be beneficial if abundant
first-row transition metals could replace their heavier
analogues as catalysts for CÀH bond functionalization.2
Most examples of direct hydroxylation or etherification of
sp2 CÀH bonds have been performed under palladium or ru-
thenium catalysis.3 While copper-promoted oxygenation
of sp2 CÀH bonds has been studied in the context of
evaluating mechanisms of oxidations by enzymes, catalytic
applications of such reactions in synthetically relevant
systems have been rare.4 An early report by Reinaud
showed that copper(II) mediates aromatic hydroxylation
by trimethylamine N-oxide.4a More recently, Yu has
shown that a number of nucleophiles, including water,
can be coupled with 2-phenylpyridine by employing Cu(II)
salts and oxygen oxidant.4b Subsequently, other groups
have reported related copper-catalyzed sp2 CÀH bond
functionalization reactions.4 Martin has shown that
copper-catalyzed hydroxylation of 2-phenylbenzoic acid
is possible.5a This report is especially interesting since
carboxylate functionality remains intact.5b We disclose
here a general method for aminoquinoline and picolinamide-
directed benzoic acid and amine derivative ortho-etherifi-
cation by employing air as an oxidant.
(1) Reviews: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (b) Ackermann, L. Chem. Rev. 2011, 111, 1315. (c)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (d) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074. (e) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174. (f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010,
75, 6061. (g) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (h)
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 677. (i) Li, C.-J.
Acc. Chem. Res. 2009, 42, 335.
In 2005, we introduced picolinic acid and 8-amino-
quinoline auxiliaries for palladium-catalyzed CÀH bond
(2) (a) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087. (b)
Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed.
2011, 50, 11062. (c) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.;
Kozlowski, M. C. Chem. Rev. 2013, 113, 6234. (d) Hickman, A. J.;
Sanford, M. S. Nature 2012, 484, 177.
(3) (a) Liu, W.; Ackermann, L. Org. Lett. 2013, 15, 3484. (b) Shan,
G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem., Int. Ed. 2012, 51, 13070. (c)
Gulevich, A. V.; Melkonyan, F. S.; Sarkar, D.; Gevorgyan, V. J. Am.
Chem. Soc. 2012, 134, 5528. (d) Desai, L. V.; Stowers, K. J.; Sanford,
M. S. J. Am. Chem. Soc. 2008, 130, 13285. (e) Thirunavukkarasu, V. S.;
Ackermann, L. Org. Lett. 2012, 14, 6206. (f) Zhang, Y.-H.; Yu, J.-Q.
J. Am. Chem. Soc. 2009, 131, 14654.
(4) (a) Reinaud, O.; Capdevielle, P.; Maumy, M. J. Chem. Soc.,
Chem. Commun. 1990, 566. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.;
Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (c) Hong, S.; Huber, S. M.;
Gagliardi, L.; Cramer, C. C.; Tolman, W. B. J. Am. Chem. Soc. 2007,
129, 14190. (d) Wang, W.; Luo, F.; Zhang, S.; Cheng, J. J. Org. Chem.
2010, 75, 2415. (e) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi, H.;
Lei, A. Angew. Chem., Int. Ed. 2012, 51, 4666. (f) Xu, R.; Wan, J.-P.;
Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531.
(5) (a) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013, 135,
9350. (b) Bhadra, S.; Dzik, W. I.; Gooßen, L. J. Angew. Chem., Int. Ed.
2013, 52, 2959.
r
10.1021/ol402904d
Published on Web 11/01/2013
2013 American Chemical Society

functionalization.6 Subsequently, these auxiliaries have
been used by a number of groups for palladium-, nickel-,
iron-, and ruthenium-catalyzed sp2 and sp3 CÀH bond
functionalization.7 Recently, we have developed amino-
quinoline- and picolinamide-directed, copper-catalyzed
sulfenylation, amination, and fluorination of arene and
heteroarene CÀH bonds.8 The common feature of these
reactions is the coupling of a nucleophile with a CÀH
bond. We speculated that copper-catalyzed etherification
of sp2 CÀH bonds should be possible if aminoquinoline or
picolinic acid directing groups are employed. Additionally,
in an insightful mechanistic study of Cu(II)-mediated sp2
CÀH bond oxidation, Stahl has reported the methoxyla-
tion of N-(8-quinolinyl)benzamide by employing metha-
nol solvent and 2 equiv of Cu(OAc)2.9a
Table 1. Screening of Reaction Conditionsa
entry
catalyst
base
oxidant
yield (%)
1b
Cu(OAc)2
Ag2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NMO
NMO
NMO/O2
air
21
64
67
68
88
2c
Cu(OAc)2
3c,d
4e
5e,f
Cu(OAc)2
(CuOH)2CO3
(CuOH)2CO3
air
Reaction of 8-aminoquinoline 3-trifluoromethylbenz-
amide 1 was investigated with respect to Cu catalyst,
oxidant, and base (Table 1). The conditions developed
for arene amination8b resulted in a low yield of coupling
product (entry 1). Replacing Ag2CO3 with K2CO3 was
beneficial (entry 2), and the reaction could be run under
an atmosphere of oxygen for additional increase of yield
(entry 3). Interestingly, omission of NMO oxidant and
running the reaction under air in an open flask was
successful (entry 4). Furthermore, the yield could be
increased if reaction time was decreased from 12 to 6 h
(entry 5). Thus, the optimal reaction conditions involve
1 equiv of phenol, K2CO3 base, 11% (22% based on Cu)
of (CuOH)2CO3 catalyst, DMF solvent, 110 °C, and air
as oxidant.
a Amide (0.1 mmol), phenol (0.1 mmol), catalyst (0.02 mmol), base
(0.2 mmol). Yields determined by NMR of crude reaction mixtures.
b NMO (N-methylmorpholine oxide) (0.2 mmol), NMP solvent. c NMO
(0.2 mmol), DMF solvent. d Under 1 atm of O2. e Reaction open to air, 11
mol % catalyst (22% Cu). f Isolated yield, reaction time 6 h.
tolerated (entry 6). Ortho-substituted phenols are reactive
(entry 8). Interestingly, bisphenol A can be used and
double arylation product 2 was isolated in 66% yield
(eq 1). The yields range from good to excellent, and
reaction times are 2À8 h. A 3.2 mmol scale reaction of 1
with 4-tert-butylphenol afforded 73% isolated yield of
product (entry 1).
The reaction scope with respect to phenols is presented
in Table 2 and eq 1. Reactions were run on a 0.5 mmol
scale. Electron-rich (entries 1, 8, and 9) and electron-poor
(entries 3À6) phenols are reactive. The reactions tolerate
most functional groups, such as thioether (entry 2), bro-
mide (entry 4), chloride (entries 7 and 8), amino (entry 9),
and even iodide (entry 5). Ester functionality is also
(6) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965. (c) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 7.
Reaction scope with respect to aliphatic alcohols is
presented in Table 3. Optimal base for alkoxylation is
tetramethylguanidine (TMG), and the best results were
obtained by employing 5 equiv of alcohol in pyridine
solvent. Air was used as an oxidant. Simple primary alkyl
alcohols such as cyclopropylmethanol afford good yields
of the product (entry 1). Trifluoromethanol (entry 2) and
allyl alcohol (entry 3) are reactive, and coupling products
were isolated in 73 and 71% yields. More complex struc-
tures such as carbitol (entry 4), cinchonine (entry 5), and
ethyl lactate (entry 6) gave products in fair to excellent
yields. The latter examples show that aliphatic esters,
amines, esters, and polyethers are tolerated in the reaction.
Reaction with trifluoroethanol was carried out in closed
vessel pressurized with O2 due to volatility of the alcohol.
The reaction scope with respect to aminoquinoline
benzamides is presented in Table 4. Cyano- (entry 1),
trifluoromethyl- (entry 2), nitro- (entry 3), and methoxy-
substituted (entries 4 and 5) amides are reactive, and
(7) (a) He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett.
2012, 14, 2944. (b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am.
Chem. Soc. 2012, 134, 3. (c) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.;
Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313. (d) Gou, F.-
R.; Wang, X.-C.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org.
Lett. 2009, 11, 5726. (e) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S.
Angew. Chem., Int. Ed. 2012, 51, 7507. (f) Ano, Y.; Tobisu, M.; Chatani,
N. J. Am. Chem. Soc. 2011, 133, 12984. (g) Gutekunst, W. R.; Baran,
P. S. J. Am. Chem. Soc. 2011, 133, 19076. (h) Reddy, B. V. S.; Reddy,
L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (i) Aihara, Y.; Chatani, N.
J. Am. Chem. Soc. 2013, 135, 5308. (j) Nishino, M.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, 4457. (k) Shang, R.; Ilies,
L.; Matsumoto, A.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030.
(8) (a) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012,
134, 18237. (b) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int.
Ed. 2013, 52, 6043. (c) Truong, T.; Klimovica, K.; Daugulis, O. J. Am.
Chem. Soc. 2013, 135, 9342.
(9) (a) Suess, A. M.; Ertem, M. Z.; Cramer, C. J.; Stahl, S. S. J. Am.
Chem. Soc. 2013, 135, 9797. (b) Ribas, X.; Jackson, D. A.; Donnadieu,
B.; Mahıa, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.;
Llobet, A.; Stack, T. D. P. Angew. Chem., Int. Ed. 2002, 41, 2991. (c)
Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196. (d) King,
A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S.
J. Am. Chem. Soc. 2010, 132, 12068. (e) Campbell, A. N.; Stahl, S. S. Acc.
Chem. Res. 2012, 45, 851.
Org. Lett., Vol. 15, No. 22, 2013
5843

Table 2. Reaction Scope with Respect to Phenolsa
Table 3. Reaction Scope with Respect to Aliphatic Alcoholsa
a Conditions: scale, 0.5 mmol; time, 12À16 h; 1/5 amide/alcohol ratio,
110 °C, 11% catalyst = 22 mol % Cu. See the SupportingInformation for
details. b Closed vessel pressurized with O2.
monosubstitution products are obtained in moderate to
good yields. Heterocyclic amides are compatible with the
reaction conditions (entires 7 and 8). In contrast with
aminoquinoline benzamide amination where diamination
products were not observed,8b bis-phenoxylation is possi-
ble by employing higher phenol/amide rations and DMPU
solvent (entry 8). The disubstitution product was obtained
in 47% yield.
Picolinamide can also serve as a directing group
(Scheme 1). Thus, R,R-dimethylbenzylamine picolina-
mide can be phenoxylated in moderate yield at 130 °C
by employing (CuOH)2CO3 catalyst, K3PO4 base, and
DMF solvent. 1-Naphthylamine picolinamide phenoxy-
lation occurs at the 8-position, and the product was
a Conditions: scale, 0.5 mmol; time, 2À8 h; 1/1 amide/phenol ratio,
110 °C, 11% catalyst = 22 mol % Cu. See the Supporting Information for
details. b Scale: 3.2 mmol, 5.5 mol % (CuOH)2CO3.c Amide/phenol ratio: 1/2.
5844
Org. Lett., Vol. 15, No. 22, 2013

Table 4. Reaction Scope with Respect to Amidesa
Scheme 1. Picolinic Acid Directing Group
isolated in 70% (0.5 mmol scale reaction) or 73% yield
(5 mmol scale reaction). The reactions can be scaled up at
least 10-fold without loss of yield. The directing group
can be removed by base hydrolysis affording 8-aryloxy-
naphthylamine 5 in high yield. Aminoquinoline auxiliary
can be removed as well (eq 2).
In conclusion, we have developed a method for direct,
auxiliary-assisted alkoxylation and phenoxylation of β-sp2
CÀH bonds of benzoic acid derivatives and γ-sp2 CÀH
bonds of amine derivatives. The reaction employs Cu2-
(OH)2CO3 catalyst, air as an oxidant, phenol or alcohol as
coupling partner, DMF, pyridine, or DMPU solvent, and
K2CO3, tetramethylguanidine, or K3PO4 base at 70À130 °C.
The method is advantageous compared to the existing sp2
CÀH bond etherification procedures due to utilization of
inexpensive copper basic carbonate (malachite) catalyst and
a removable directing group. The method shows high
generality and functional group tolerance, with ester,
amine, nitro, nitrile, and halogen functionalities compat-
ible with the reaction conditions.
Acknowledgment. We thank the Welch Founda-
tion (Grant No. E-1571), the NIGMS (Grant No.
R01GM077635), and the Camille and Henry Dreyfus
Foundation for supporting this research.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Conditions: scale, 0.5 mmol; time, 9À12 h; 1/1 amide/alcohol ratio,
70À110 °C, 11% catalyst = 22 mol % Cu. See the Supporting
Information for details. b Amide/alcohol ratio: 1/3, DMPU solvent.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5845