Copper-catalyzed C-H alkoxylation of azoles

Article abstract of DOI:10.1021/ol303533z

We achieved copper-catalyzed intramolecular and intermolecular alkoxylation of azoles. This reaction is a rare example of transition-metal-catalyzed C-H alkoxylation of heteroaromatic compounds. In addition, the alkoxylation reaction proceeded well even i

Full text of DOI:10.1021/ol303533z

ORGANIC
LETTERS
2013
Vol. 15, No. 4
844–847
Copper-Catalyzed CÀH Alkoxylation
of Azoles
Noriaki Takemura,† Yoichiro Kuninobu,*,†,‡ and Motomu Kanai*,†,‡
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and ERATO, Japan Science and Technology
Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
kuninobu@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Received December 25, 2012
ABSTRACT
We achieved copper-catalyzed intramolecular and intermolecular alkoxylation of azoles. This reaction is a rare example of transition-metal-
catalyzed CÀH alkoxylation of heteroaromatic compounds. In addition, the alkoxylation reaction proceeded well even in gram scale. In most
intermolecular alkoxylations, the use of an excess amount of alcohols (in some cases, alcohols are used as a solvent) is indispensable to
efficiently promote the alkoxylation reaction, but this alkoxylation reaction proceeded using only 1 equiv of alcohols.
CÀH transformations are attractive, effective, and ideal
reactions because carbonÀcarbon and carbonÀheteroatom
bonds can be constructed directly from stable organic
molecules.1 The development of efficient and useful CÀH
transformations is therefore strongly desired. CarbonÀ
oxygen bond forming reactions using alcohols as sub-
strates via aromatic CÀH bond activation, however, are
rare due to both the high electronegativity of an oxygen
atom and the great bond energy of metalÀoxygen bonds
formed in catalytic intermediates.2 Although a metal-
free oxidative coupling reaction between heterocycles
and alcohols was recently reported,3 CÀC bond forma-
tion at the carbon atom adjacent to a hydroxy group
of alcohols proceeded instead of CÀH alkoxylation. In
addition, oxidation of alcohols to aldehydes or ketones
is generally more facile than carbonÀoxygen bond forma-
tion under oxidative conditions.
As examples of aromatic CÀH aryloxylation/alkoxylation,
palladium- and copper-catalyzed synthesis of dibenzofuran
derivatives through intramolecular aryloxylation,4 iron-
mediated intramolecular alkoxylation,5 palladium-catalyzed
† The University of Tokyo.
‡ Japan Science and Technology Agency (JST).
(1) For reviews, see: (a) Kakiuchi, F.; Murai, S. Top. Organomet.
Chem. 1999, 3, 47. (b) Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J.
Inorg. Chem. 1999, 1047. (c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698. (d) Herrerıas, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107,
´
(3) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011,
13, 5016.
(4) (a) Wei, Y.; Yoshikai, N. Org. Lett. 2011, 13, 5504. (b) Xiao, B.;
Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am.
Chem. Soc. 2011, 133, 9250. (c) Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu,
Q. Org. Lett. 2012, 14, 1078.
(5) Tang, L.; Pang, Y.; Yan, Q.; Shi, L.; Huang, J.; Du, Y.; Zhao, K.
J. Org. Chem. 2011, 76, 2744.
(6) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 12203.
(7) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (b) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 1141. (c) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476.
(d) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2012, 134, 7313. (e) Jiang, T.-S.; Wang, G.-W. J. Org.
Chem. 2012, 77, 9504.
2546. (e) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (f) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (g)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (h) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (i) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (j) Kuninobu, Y.; Takai, K. Chem. Rev. 2011, 111, 1938. (k)
Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. (l)
Borovik, A. S. Chem. Soc. Rev. 2011, 40, 1870. (m) Zhou, M.; Crabtree,
R. H. Chem. Soc. Rev. 2011, 40, 1875. (n) Lu, H.; Zhang, X. P. Chem.
Soc. Rev. 2011, 40, 1899. (o) Collet, F.; Lescot, C.; Dauban, P. Chem.
Soc. Rev. 2011, 40, 1926. (p) Hartwig, J. F. Chem. Soc. Rev. 2011, 40,
1992. (q) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2012, 45, 814. (r) Neufeldt, S. R.; Sanford, M. S. Acc. Chem.
Res. 2012, 45, 936.
(2) (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (b)
Li, W.; Sun, P. J. Org. Chem. 2012, 77, 8362.
r
10.1021/ol303533z
Published on Web 01/31/2013
2013 American Chemical Society

synthesis of dihydrobenzofurans through intramolecular
alkoxylation,6 and palladium-catalyzed directing-group-
assisted intermolecular alkoxylation using alcohols as
solvents (use of excess amounts of alcohols)2b,7 have been
reported. Heteroaromatics, however, have not been reported
as substrates in CÀH alkoxylations. In addition, intermole-
cular CÀH alkoxylations are limited by the need for excess
amounts of alcohol and directing groups.2b,7 Efficient intra-
and intermolecular catalytic alkoxylation of heteroaro-
matics has numerous potential applications to the synthesis
of natural products, drugs, and organic functional materials.
We are specifically interested in CÀH alkoxylation of azoles
for the development of new synthetic routes of delamanid, a
promising drug candidate for the treatment of tuberculosis,
and candesartan, a useful antihypertensive drug (Figure 1).8,9
We report herein a copper-catalyzed intra- and intermolecu-
lar alkoxylation of azoles.
obtained in 98% yield (Table 1, entry 1).11,12 Product
derived from CÀH alkoxylation of the benzene ring was
not detected at all. This reaction was quite sensitive to
reaction parameters (catalysts, oxidants, and solvents:
Table 1). Changing the catalyst, CuCl, to other copper
salts and complexes showed that only CuI was effective for
the intramolecular oxidation (entry 3). Otherwise, 2a was
not formed or was generated in quite low yield (entries 2,
4À6).13 Other first-row transition metal chlorides or their
complexes did not promote the alkoxylation reaction
(entries 7À11). The selection of an oxidant was also
important. Silver carbonate Ag2CO3 provided 2a in mod-
erate yield (entry 12), whereas the use of other oxidants
afforded no 2a (entries 13À17).
Table 1. Investigation of Several Catalysts and Oxidants
entry
catalyst
CuCl
oxidant
(tBuO)2
yielda
1
98 (98)b
2
CuBr
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
(tBuO)2
Ag2CO3
K2S2O8
Phl(OAc)2
TBHP
3
3
Cul
70
0
4
CuCN
Cu(OTf)(NCMe)4
CuCl2
MnCl2
MnBr(CO)5
FeCl2
5
7
6
0
7
0
8
0
9
0
10
11
12
13
14
15
16
17
CoCl2
0
NiCl2
0
Figure 1. Pharmaceuticals that contain 2-alkoxyimidazole
frameworks.
CuCl
42
0
CuCl
CuCl
0
CuCl
0
Transition-metal-catalyzed CÀH functionalization
(amination and CÀC bond formation) of azoles is usually
performed in the presence of a base.10 Intramolecular
alkoxylation of benzimidazole 1a was first studied in the
presence of several transition metal catalysts, oxidants,
and bases, but the desired alkoxylation reaction did not
proceed. Therefore, we next investigated base-free condi-
tions. Treatment of 1a with a catalytic amount of CuCl
and 2.0 equiv of oxidant (tBuO)2 in toluene at 80 °C for
12 h led to an intramolecular alkoxylation reaction at the
C-2 position, and benzoimidazodihydrooxazole 2a was
CuCl
tBuOOBz
O2 (1.0 atm)
0
CuCl
0
a Yield was determined by 1H NMR. b Isolated yield.
Next, we investigatedthe substrate scope and limitations
of this CÀH alkoxylation (Table 2). Various substituents,
including electron-donating and -withdrawing groups
as well as ester and amide functionalities, on the phenyl
ring were tolerated (entries 1À9). Specifically, CÀhalogen
(12) Similar transformations can be achieved via two-step halogena-
tion/nucleophilic addition (or cross-coupling) approaches. For exam-
ples, see: (a) Volpini, R.; Ben, D. D.; Lambertucci, C.; Marucci, G.;
Mishra, R. C.; Ramadori, A. T.; Klotz, K.-N.; Trincavelli, M. L.;
Martini, C.; Cristalli, G. ChemMedChem 2009, 4, 1010. (b) Bookser,
B. C.; Dang, Q.; Gibson, T. S.; Jiang, H.; Chung, D. M.; Bao, J.; Jiang,
J.; Kassick, A.; Kekec, A.; Lan, P.; Lu, H.; Makara, G. M.; Romero,
F. A.; Sebhat, I.; Wilson, D.; Wodka, D. WO 2010/047982, 2010. (c)
Sugimura, H.; Nitta, D. Tetrahedron Lett. 2012, 53, 4460. However, the
CÀH alkoxylation reaction has advantages from the viewpoint of
reduced reaction steps and salt wastes.
(8) Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume,
H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.;
Tsubouchi, H. J. Med. Chem. 2006, 49, 7854.
(9) Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.;
Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36, 2182.
(10) For several recent examples, see: (a) Fukuzawa, S.; Shimizu, E.;
Atsumi, Y.; Haga, M.; Ogata, K. Tetrahedron Lett. 2009, 50, 2374.
(b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (c) Miyasaka,
M.; Hirano, K.; Satoh, T.; Kawalczyk, R.; Bolm, C.; Miura, M. Org.
Lett. 2011, 13, 359. For reviews, see: Daugulis, O. Top. Curr. Chem.
2010, 292, 57.
(13) By adding tetrabutylammonium chloride to the reaction of CuBr
(Table 1, entry 2), the yield of 2a was improved to 67%. This result shows
that the chloride ion is important for high reactivity.
(11) Investigation of reaction temperature: 100 °C, 64%; 80 °C, 98%;
50 °C, 0%.
Org. Lett., Vol. 15, No. 4, 2013
845

bonds were intact (entries 5À7), allowing for further
derivatizations through, for example, cross-coupling reac-
tions. Substrate 1k, possessing a benzylic hydroxy group,
was also competent (entry 10). Intramolecular alkoxyla-
tion, however, did not proceed from primary and secondary
alcohols (e.g., 2-(1H-benzo[d]imidazol-1-yl)ethanol and
1-(1H-benzo[d]imidazol-1-yl)-2-propanol). This method
was also useful for six-membered ring construction (entry 11).
Intramolecular alkoxylation also proceeded using monocyclic
compounds such as imidazoles 1m and 1n (entries 12 and 13).
The reaction can be performed in gram scale. Treatment
of 1.20 g of 1a with a catalytic amount of CuCl and oxidant
(tBuO)2 produced 1.09 g of 2a in 92% yield (eq 1), which is
comparable to the yield in Table 1, entry 1 (48 mg scale).
To gain some insights into the reaction mechanism if any
radicalintermediates are generated, the reaction inTable1,
entry 1 was carried out in the presence of a radical scavenger,
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO: 5.0 mol %).
As a result, the yield of 2a was not affected (87%). This result
suggests that this alkoxylation does not proceed via a radical
pathway. The proposed mechanism for the intramolecular
alkoxylation is as follows (Scheme 1):14 (1) oxidation of CuCl
with (tBuO)2;15 (2) formation of an alkoxycopper intermedi-
Table 2. Investigation of Several Substratesa
t
ate via elimination of BuOH;15 (3) formation of a cyclic
alkoxycopper intermediate via CÀH bond activation;16 (4)
reductive elimination17,18 to give the desired product 2 and
regenerate the copper catalyst (Scheme 1).
Scheme 1. Proposed Mechanism for the Alkoxylated Products 2
Interestingly, the reaction pattern switched dramatically
when a base was added. When LiOtBu was added to the
reaction mixture in Table 1, entry 1, intramolecular
(14) Copper-catalyzed oxidative CÀH bond amidation of aromatic
compounds have been reported. The present proposed mechanism is
based on the following reports, see: Shuai, Q.; Deng, G.; Chua, Z.;
Bohle, D. S.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 632.
(15) For a recent example of oxidation of heteroarylcopper inter-
mediates and formation of copper-heteroatom bonds, see: Chen, L.; Li,
C.; Bi, X.; Liu, H.; Qiao, R. Adv. Synth. Catal. 2012, 354, 1773.
(16) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. See also: Reference 10a.
(17) For an example of formation of alkoxylated products by re-
ductive elimination of a copper catalyst, see: Reference 4c.
(18) For an example of formation of carbonÀheteroatom bonds by
reductive elimination of a copper catalyst, see: Reference 15.
(19) For copper-catalyzed dehydrogenative dimerization of hetero-
aromatic compounds, see: (a) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2009, 131, 17052. (b) Monguchi, D.; Yamamura, A.; Fujiwara, T.;
Somete, T.; Mori, A. Tetrahedron Lett. 2010, 51, 850. (c) Li, Y.; Jin, J.;
Qian, W.; Bao, W. Org. Biomol. Chem. 2010, 8, 326. (d) Zhu, M.; Fujita,
K.-i.; Yamaguchi, R. Chem. Commun. 2011, 47, 12876.
a Reaction temperature and time are reported in the Supporting
Information. b 1,2-Dichloroethane was used as a solvent.
846
Org. Lett., Vol. 15, No. 4, 2013

alkoxylation did not proceed at all. Instead, dehydrogena-
tive dimerization of 1a proceeded, affording dimer 3 in 77%
yield without loss of the hydroxy groups (eq 2).19,20 Increas-
ing the reaction temperature to 100 °C improved the yield of
3 to 92% (eq 2). Thus, two different products (2a and 3) can
be selectively synthesized either in the presence or absence of
a base.
sponding products 6b and 6c were obtained in 57% and
41% yields, respectively.21À23
In summary, we successfully developed copper-catalyzed
intra- and intermolecular alkoxylation of azoles.24 To the
best of our knowledge, this is the first example of transi-
tion-metal-catalyzed direct CÀH alkoxylation of hetero-
aromatic compounds. It is noteworthy that only a
stoichiometric amount (1 equiv) of alcohol is required,
without a directing group. Key to our success was the
identification of base-free conditions. The reaction path-
way dramatically switched to dehydrogenative dimeriza-
tion when a base was added to the reaction system. This
method provides a useful and direct method of heteroaro-
matic CÀH alkoxylation, leading to an efficient synthesis
of drugs, natural products, and organic functional materi-
als. Improvement of yields and substrate scope of inter-
molecular reactions is ongoing.
The present alkoxylation conditions can be extended to
an intermolecular reaction (eq 3). Treatment of benzothia-
zole (4a) with 2-phenylethanol (5a) in the presence of a
catalytic amount of CuCl and 2.0 equiv of oxidant (tBuO)2
in toluene at 115 °C for 12 h gave alkoxylated product 6a
in 16% yield. When 3,4,7,8-tetramethylphenanthroline
(3,4,7,8-Me4phen) was added as a ligand to copper, the
yield of 6a increased to 39%. Intermolecular alkoxylation
also proceeded from benzimidazole (4b), and the corre-
(20) Product 3 exhibited a purple fluorescence by UV (254 nm)
irradiation in a dichloromethane solution. Interestingly, 3 has a purple
fluorescence as a solid state.
(21) The alkoxylation reaction also proceeded when isopropanol
(secondary alcohol) was employed as a substrate; however, the yield of
the alkoxylated benzimidazole was low (8%). The alkoxylation reaction
did not proceed using tert-butanol. In this reaction, a complex mixture
was formed. In the mixture, a dimer of 4b was formed in 27% yield by
dehydrogenative dimerization of 4b as described in eq 2, and 4b was
recovered in 28% yield.
(22) We investigated the intermolecular reactions by increasing the
amount of the alcohols, 5a or 5b. However, the yields of 6a, 6b, and 6c
were not improved.
(23) Tertiary alcohols produced higher yields than primary alcohols
in the intramolecular reaction, but the tendency was opposite in the
intermolecular reaction. The hydroxy group of tertiary alcohols could
easily access to the reactive carbon atom of the heterocyles due to the
ThorpeÀIngold effect in the intramolecular reaction; on the other hand,
steric hindrance would hamper the access of the two substrates to each
other in the case of the intermolecular reaction.
Acknowledgment. This work was supported in part by
ERATO from JST.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(24) For several examples of copper-catalyzed cross-coupling reac-
tions to form CÀO bonds, see: (a) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400. (b) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (c) Monnier, F.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 6954.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
847