Copper-catalyzed benzylic C(sp3)-H alkoxylation of heterocyclic compounds

Article abstract of DOI:10.1039/c4ob00215f

We achieved intra- and intermolecular C(sp³)-H alkoxylation of benzylic positions of heteroaromatic compounds using CuBr_n (n = 1, 2)/5,6-dimethylphenanthroline (or 4,7-dimethoxyphenanthroline) and ( ^tBuO)₂ as a

Full text of DOI:10.1039/c4ob00215f

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Copper-catalyzed benzylic C(sp3)–H alkoxylation
of heterocyclic compounds†
Cite this: Org. Biomol. Chem., 2014,
12, 2528
Noriaki Takemura,a Yoichiro Kuninobu*a,b and Motomu Kanai*a,b
Received 27th January 2014,
Accepted 20th February 2014
DOI: 10.1039/c4ob00215f
www.rsc.org/obc
We achieved intra- and intermolecular C(sp3)–H alkoxylation of
benzylic positions of heteroaromatic compounds using CuBrn
(n
= 1, 2)/5,6-dimethylphenanthroline (or 4,7-dimethoxyphen-
anthroline) and (tBuO)2 as a catalyst and an oxidant, respectively.
The reaction proceeded at both terminal and internal benzylic
positions of the alkyl groups. The intramolecular alkoxylation was
performed on a gram scale.
Many bioactive compounds, such as natural products and
drugs, e.g., rivoglitazone,1 balaglitazone,2 PF-2545920,3 and
AMG-208,4 have an ether moiety at the benzylic position of
heterocyclic ring(s) (Fig. 1). The development of practical and
effective synthetic methods of such ethers is therefore in high
demand. Representative reactions for the synthesis of ethers
include Williamson ether synthesis,5 the Ullmann reaction,6
and the Buchwald–Hartwig reaction.7 These reactions have
several drawbacks, however, such as the need for multiple reac-
tion steps, an excess amount of copper powder or salt, and/or
the formation of side products such as metal halides. To
improve the efficiency of ether synthesis, direct C–H alkoxyla-
tion using alcohols as substrates is an ideal strategy. Examples
of C–H alkoxylation, especially C(sp3)–H alkoxylation, however,
are rare.8 The following C(sp3)–H alkoxylation reactions have
been reported: (a) palladium-catalyzed benzylic methoxylation
using a quinoline-type directing group (Fig. 2a);8a (b) palla-
dium-catalyzed tert-butoxylation using an oxazoline-type
directing group (Fig. 2b);9 (c) palladium-catalyzed alkoxylation
using a bidentate directing group (Fig. 2c);10 and (d) copper-
catalyzed butoxylation at the double benzylic position
(Fig. 2d).11 These reactions have similar characteristics: (1)
when palladium-salts are used as catalysts, directing groups
Fig. 1 Drug candidates that contain an ether moiety with a heterocyclic
ring at the α-position.
are indispensable for promoting the reaction, and alkoxylation
proceeds only at the terminal position (Fig. 2a–2c);12 (2) alco-
hols (alkoxylation reagents) are used as a solvent (Fig. 2a, 2c,
and 2d); and, (3) only one substrate example was reported
(Fig. 2a, 2b, and 2d). In this paper, we report copper-catalyzed
intramolecular and intermolecular C–H alkoxylation of
benzylic C(sp3)–H bonds of heteroaromatic compounds
(Fig. 2e). The alkoxylation reaction proceeded regioselectively
at both the terminal and internal benzylic positions of alkyl
chains.
Treatment of 1-hydroxyethyl-2-methylbenzimidazole 1a with
a catalytic amount of CuCl/5,6-dimethylphenanthroline and
(tBuO)2 in chlorobenzene at 100 °C for 4 h led to an intramole-
cular C(sp3)–H alkoxylation reaction, and the desired alkoxy-
lated product 2a was obtained in 47% yield (Table 1, entry 1).
Changing the catalyst to CuBr and extending the reaction time
to 6 h improved the yield of 2a (Table 1, entries 2 and 3).13–15
Although other copper salts showed catalytic activities, the
yield of 2a was lower than that with CuBr (Table 1, entries
4–7). In this reaction, the addition of a ligand was indispens-
able (Table 1, entry 8). Other phenanthroline- and bipyridine-
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: kuninobu@mol.f.u-tokyo.ac.jp,
kanai@mol.f.u-tokyo.ac.jp
bERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis
Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data of substrates (alcohols) and alkoxylated products, and 1H
and 13C NMR charts. See DOI: 10.1039/c4ob00215f
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Table 1 Investigation of several copper catalysts and ligands
Yieldb
(%)
Entry Catalyst
Liganda
1
CuCl
CuBr
CuBr
CuI
5,6-Me2phen
5,6-Me2phen
5,6-Me2phen
5,6-Me2phen
47
70
77 (75)d
62
2
2
3c
4
5
[(CH3CN)4Cu]+(PF6)− 5,6-Me2phen
6
7
8
9
10
11
12
13
14
15
16
CuCl2
CuBr2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
5,6-Me2phen
5,6-Me2phen
None
40
60
0
50
0
18
38
67
50
4
Phen
4,7-Me2phen
3,4,7,8-Me4phen
5,6-(MeO)2phen
4,7-(MeO)2phen
4,7-Ph2-phen
2,2′-Bipyridine
4,4′-di-tert-butyl-2,2′-
bipyridine
7
a Phen = 1,10-phenanthroline. b Yield determined by 1H NMR of the
crude mixture using 1,1,2,2-tetrachloroethane as an internal standard.
c 6 h. d Isolated yield.
Fig. 2 Previous and present C(sp3)–H alkoxylation reactions. (a) Palla-
dium-catalyzed benzylic C(sp3)–H methoxylation using a quinoline-type
directing group. (b) Palladium-catalyzed C(sp3)–H tert-butoxylation
using a oxazoline-type directing group. (c) Palladium-catalyzed C(sp3)–
H alkoxylation using a bidentate directing group. (d) Copper-catalyzed
butoxylation at the double benzylic position. (e) This work.
and a tert-butoxy radical from CuBrn (n = 1 or 2) and (tBuO)2;
(2) formation of an alkoxycopper intermediate8i with a benzyl
radical via the elimination of HX (X
=
Br or OtBu)
t
and BuOH;18 (3) formation of the product 2 by C–O bond
formation between the benzyl radical and the oxygen atom of
the alkoxycopper moiety.18–22
This reaction also proceeded in high yield on the gram
scale. Using 1.64 g of 1a as a substrate, the reaction produced
1.37 g of 2a in 84% yield (eqn (1)). The yield of 2a was slightly
higher than that shown in Table 1, entry 3 (1a: 41.1 mg).
type ligands did not improve the yield of 2a (Table 1, entries
9–16).
We next investigated the substrate scope and limitations
(Table 2). Diaryl-substituted alcohols 1b–1e produced the
corresponding alkoxylated products 2b–2e in 55%–81% yields
(entries 1–4). The yield of the product 2f decreased when
dimethyl-substituted alcohol 1f was used (entry 5).16 A spiro
compound 2g was obtained from 1g (entry 6). The alkoxylation
reaction proceeded with moderate to good yields when using
2-methylbenzimidazoles with a substituent at the aromatic
ring, 1h–1j (entries 7–9). In entry 9, the alkoxylation reaction
proceeded selectively at the 2-methyl group and did not occur
at the 7-methyl group. Alkoxylation reactions are generally
more difficult at the internal positions of alkyl chains than at
the terminal positions. Interestingly, the C(sp3)–H alkoxylation
reaction also proceeded in high yield at the internal position
of the alkyl chains (entries 10–13).17 The conditions were
also applicable to seven-membered ring formation (entry 14),
aryloxylation reaction (entry 15), and heterocyclic substrates
1q–1s other than benzimidazole (entries 16–18).
ð1Þ
Intermolecular C(sp3)–H alkoxylation also proceeded under
the present conditions. Treatment of 1,2-dimethyl-1H-benzo[d]-
imidazole (3) with butanol (4a) or 2-phenylethanol (4b) gave
the corresponding alkoxylated products 5a and 5b in 33% and
37% yields, respectively (eqn (2)). In addition, the intermole-
cular alkoxylation reaction occurred at the benzylic C(sp3)–H
bond of quinazolinone 6 (eqn (3)). Although yields are moder-
ate, these are the first entries to catalytic benzylic C(sp3)–H
alkoxylation using a reagent amount (i.e., not a solvent
amount) of alcohols.
The proposed mechanism for the alkoxylation reaction is
shown in Scheme 1: (1) formation of CuBrX (X = Br or OtBu)
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Table 2 Investigation of several substratesa
Table 2 (Contd.)
Ligandb
(mol%)
Yieldc
(%)
Catalyst
Entry (mol%)
Ligandb
(mol%)
Yieldc
(%)
Catalyst
Entry (mol%)
2
2
16
CuBr2 (10)
B (12)
2q 44%
R1
R2
17
18
CuBr2 (5.0) B (6.0)
CuBr2 (5.0) B (6.0)
2r 49%
2s 50%
1
2
3
4
5
CuBr (5.0)
CuBr (5.0)
CuBr (5.0)
CuBr (5.0)
CuBr (5.0)
A (6.0)
A (6.0)
A (6.0)
A (6.0)
B (6.0)
4-MeOC6H4 Ph
2b 71%
4-MeC6H4
4-FC6H4
4-ClC6H4
Me
4-MeC6H4 2c 55%
4-FC6H4
4-ClC6H4
Me
2d 81%
2e 81%
2f 55%
6
CuBr (5.0)
B (6.0)
2g 52%
a For detailed experimental procedures, see ESI. b A: 5,6-dimethyl-1,10-
phenanthroline; B: 4,7-dimethoxy-1,10-phenanthroline. c Isolated yield.
7
8
9
10
CuBr (5.0)
CuBr (10)
CuBr (5.0)
CuBr (10)
A (6.0)
A (12)
A (6.0)
B (12)
R3 = 5-CF3
6-MeO
7-Me
2h 45%
2i 70%
2j 80%
2k 70%
ð2Þ
11
CuBr (10)
B (12)
2l 67%
12
13
CuBr (10)
CuBr (10)
B (12)
B (12)
2m 71%
2n 41%
ð3Þ
14
15
CuBr (5.0)
CuBr (20)
A (6.0)
A (24)
2o 21%
2p 59%
Conclusions
In summary, we successfully developed a benzylic C(sp3)–H
alkoxylation reaction of heterocyclic compounds using alco-
hols as alkoxylating reagents under copper catalysis. In this
reaction, alkoxylation proceeded selectively at the benzylic
position of heteroaromatics and not at the benzylic position of
a benzene ring. The present reaction is a rare example of
copper-catalyzed C(sp3)–H alkoxylation, and proceeded at both
the terminal and internal positions of the alkyl chains without
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Scheme 1 Proposed mechanism for the catalytic benzylic C(sp3)–H
alkoxylation.
the use of a directing group or an excess amount of the alkoxy-
lating reagents (alcohols). The alkoxylated product was
obtained on the gram scale, and an intermolecular reaction
also occurred. This reaction provides a useful strategy for syn-
thetic organic chemistry.
9 R. Giri, J. Liang, J.-G. Lei, J.-J. Li, D.-H. Wang, X. Chen,
I. C. Naggar, C. Guo, B. M. Foxman and J.-Q. Yu, Angew.
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Acknowledgements
This work was supported in part by ERATO of JST.
11 S. Bhadra, C. Matheis, D. Katayev and L. J. Gooßen, Angew.
Chem., Int. Ed., 2013, 52, 9279.
12 During our investigation, palladium-catalyzed alkoxylation
at the terminal and internal positions of alkyl chains using
an excess amount of alcohols as alkoxylating reagents was
reported. See: F.-J. Chen, S. Zhao, F. Hu, K. Chen,
Q. Zhang, S.-Q. Zhang and B.-F. Shi, Chem. Sci., 2013, 4,
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Notes and references
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following transition metal salts and complexes as a catalyst:
MnCl2, MnBr(CO)5, FeCl2, CoCl2, RhCl(PPh3)3, NiCl2,
NiBr2, NiI2, Ni(OAc)2, Ni(OTf)2, [IrCl(cod)]2, PdCl2, PdBr2,
Pd(OAc)2, Pd(Opiv)2, Pd(acac)2.
3 P. R. Verhoest, D. S. Chapin, M. Corman, K. Fonseca,
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A. A. Boezio, A. Chen, D. Choquette, I. Dussault,
tBuOOBz, tert-butyl hydroperoxide (TBHP), oxone, PhI-
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(OAc)2, K2S2O8, O2 (1.0 atm).
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Me, R2 = H) and 2-(2-methyl-1H-benzo[d]imidazol-1-yl)-
ethanol (1u, R1 = R2 = H) also gave the corresponding intra-
molecular alkoxylated products 2t and 2u in 40% and 24%
yields, respectively.
5 (a) O. C. Dermer, Chem. Rev., 1934, 14, 385; (b) U. Koert, 17 An asymmetric reaction proceeded using a chiral ligand
Synthesis, 1995, 115.
instead of 5,6-dimethylphenanthroline though the yield
and enantiomeric excess were low. Treatment of benzimid-
azole 1l bearing an ethyl group at 2-position with a catalytic
amount of CuBr2/(−)-sparteine and (tBuO)2 gave 2l* in
14% yield and 11% ee. For several examples of asymmetric
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yields, respectively. These results suggest that the reaction
proceeded via intermediary of a benzyl radical derived
from 1a.
18 R. T. Gephart III, C. L. McMullin, N. G. Sapiezynski,
E. S. Jang, M. J. B. Aguila, T. R. Cundari and T. H. Warren,
J. Am. Chem. Soc., 2012, 134, 17350.
21 Another possible pathway is that the reaction proceeds via
alkoxy benzylcopper(III) species. For the details, see the ESI,
Scheme S1.†
19 To elucidate the rate-determining step of the C(sp3)–H
alkoxylation, we investigated a deuterium labeling experi-
ment using 2-methyl group-deuterated 1a. However, the 22 Another possible pathway is that the alkoxylation reaction
kinetic isotope effect (KIE) value could not be determined
because of a scrambling between the deuterium atom of
the 2-methyl group and the hydrogen atom of the hydroxy
group.
proceeds via formation of α-bromomethylheterocyclic inter-
mediates from the starting heterocyclic compounds and
copper bromide catalyst. To validate the possibility, we
investigated reactions between 1,2-dimethyl-1H-benzo[d]-
imidazole (3) and CuBr (1.0 equiv.)/5,6-dimethylphen-
anthroline (1.2 equiv.) (or CuBr2 (1.0 equiv.)/5,6-dimethyl-
phenanthroline (1.2 equiv.)) with or without (tBuO)2
(4.0 equiv.) in chlorobenzene at 100 °C for 4 h. However,
2-(bromomethyl)-1-methyl-1H-benzo[d]imidazole was not
formed at all in the reactions. In addition, such α-bromo-
methylheterocyclic intermediates were not detected in all
entries. Therefore, the pathway through α-bromination is
less likely.
20 The alkoxylation reaction was inhibited by adding a radical
scavenger. Treatment of 1-hydroxyethyl-2-methylbenzimid-
azole 1a with a catalytic amount of CuBr (5.0 mol%)/
5,6-dimethylphenanthroline (6.0 mol%) and (tBuO)2
(1.3 equiv.) in the presence of 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO, 5.0 mol%) in chlorobenzene at 100 °C for
4 h gave the alkoxylated product 2a in 27% yield. By
increasing the amount of TEMPO to 100 mol%, both 2a
and coupling product 8 were formed in 21% and 45%
2532 | Org. Biomol. Chem., 2014, 12, 2528–2532
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