Iron-catalyzed N -alkylation of azoles via oxidation of C-H bond adjacent to an oxygen atom

Article abstract of DOI:10.1021/ol100670m

Figure presented Azole derivatives were synthesized by iron-catalyzed oxidative reactions of azoles and ethers in good to excellent yields. A wide variety of azoles and ethers were selectively transformed into the corresponding oxidative coupling products under neutral reaction conditions.

Full text of DOI:10.1021/ol100670m

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1932-1935
Iron-Catalyzed N-Alkylation of Azoles via
Oxidation of C-H Bond Adjacent to an
Oxygen Atom
Shiguang Pan, Jinhua Liu, Huanrong Li, Zhenyu Wang, Xingwei Guo, and
Zhiping Li*
Department of Chemistry, Renmin UniVersity of China, Beijing 100872, China
zhipingli@ruc.edu.cn
Received January 26, 2010
ABSTRACT
Azole derivatives were synthesized by iron-catalyzed oxidative reactions of azoles and ethers in good to excellent yields. A wide variety of
azoles and ethers were selectively transformed into the corresponding oxidative coupling products under neutral reaction conditions.
Azoles, specifically imidazoles and triazoles, are widely used
as fungicides in agriculture and antifungal agents in phar-
maceuticals.1 Azole derivatives have also been broadly used
as the precursors of N-heterocyclic carbenes (NHC)2 and
ionic liquids.3 Consequently, the development of highly
efficient methods for the synthesis of functional azoles is of
great interest. The N-alkylation and N-arylation of azoles
present the most straightforward method for the synthesis
of azole derivatives with the consideration of a large number
of readily available N-H heterocycles. In recent years,
transition-metal-catalyzed N-arylation of azoles has become
a well-established technique for the synthesis of N-aryla-
zoles.4 Traditionally, the N-alkylation of azoles usually
requires a deprotonation step followed by a nucleophilic
substitution reaction with an electrophile (alkyl halide or
tosylate).5 Drawbacks of these reactions include the follow-
ing: (1) strong base is commonly applied due to low acidity
of the NH group; (2) alkyl or aryl halides are generally used;
and (3) overalkylation of the product gives quaternary salts.
Addition to the CdC bond and substitution with alcohols
present alternative methods for the synthesis of azole
derivatives in modern synthetic chemistry. However, these
methodologies suffer from significant limitations. In the
former case, the CdC bond is generally activated via
conjugation with an electron-withdrawing group.6 In the latter
(1) (a) Sheng, C.; Zhang, W.; Ji, H.; Zhang, M.; Song, Y.; Xu, H.; Zhu,
J.; Miao, Z.; Jiang, Q.; Yao, J.; Zhou, Y.; Zhu, J.; Lu, J. J. Med. Chem.
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(2) For reviews on NHC-organocatalysis, see: (a) Nair, V.; Vellalath,
S.; Babu, B. P. Chem. Soc. ReV. 2008, 37, 2691. (b) Enders, D.; Niemeier,
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Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (d) Zeitler,
K. Angew. Chem., Int. Ed. 2005, 44, 7506. (e) Enders, D.; Balensiefer, T.
Acc. Chem. Res. 2004, 37, 534. For reviews on NHCs as ligands in
transition-metal catalysis, see: (f) Diz-Gonzalez, S.; Marion, N.; Nolan, S. P.
Chem. ReV. 2009, 109, 3612. (g) Marion, N.; Nolan, S. P. Acc. Chem. Res.
2008, 41, 1440. (h) Wurtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523.
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Chem., Int. Ed. 2009, 48, 6954. (b) Corbet, J.-P.; Mignani, G. Chem. ReV.
2006, 106, 2651. (c) Hartwig, J. F. Synlett 2006, 1283. (d) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (e) Jiang, L.;
Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp
699-760.
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R. D. Acc. Chem. Res. 2007, 40, 1182. (b) Rogers, R. D.; Seddon, K. R.
Science 2003, 302, 792. (c) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z.
Chem. ReV. 2002, 102, 3667. (d) Wasserscheid, P., Welton, T., Eds. Ionic
Liquids in Synthesis; Wiley-VCH: Verlag GmbH & Co. KGaA, 2002. (e)
Welton, T. Chem. ReV. 1999, 99, 2071.
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O. M. E. J. Heterocycl. Chem. 2007, 44, 515. (b) Begtrup, M.; Larsen, P.
Acta Chem. Scand. 1990, 44, 1050.
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10.1021/ol100670m  2010 American Chemical Society
Published on Web 04/08/2010

case, only methanol and phenyl methanol are effective
partners.7 Therefore, a selective and efficient method for
N-alkylation of azoles is highly desirable.8
Table 1. Optimization of the Reaction Conditionsa
The readily available and nontoxic iron catalysts are highly
attractive for chemical synthesis from environmental and
economic points of view.9 Therefore, the development of
iron-catalyzed C-N cross-coupling methods is one of the
valuable goals for the preparation of various nitrogen-
containing compounds.10 In conjunction with our recent
results on oxidative functionalization of C-H bonds adjacent
to heteroatoms,11 we herein report a novel protocol of
N-alkylation of azoles via iron-catalyzed oxidative C-N
bond formation.
The reaction of imidazole 1a and tetrahydrofuran (THF)
2a was investigated to examine suitable reaction conditions
(Table 1). Various iron salts were tested for the proposed
reaction using 1,2-dichloroethane (DCE) as a solvent and
tert-butyl hydroperoxide (TBHP) as an oxidant (entries 1-7).
FeCl3·6H2O, which is relatively inexpensive and easy to
handle, showed relative higher catalytic efficiency compared
with other iron salts and thus was chosen as the catalyst for
further optimization. The yields of 3a were further improved
when the amount of 2a and TBHP was increased (entries
8-10). It should be noted that an excess amount of THF 2a
used as a solvent instead of DCE led to almost quantitative
conversion of 1a with 100% selectivity (entry 11). Moderate
yields of the desired oxidative product 3a were obtained
using ethyl acetate or acetonitrile as a solvent (entries 12
and 13). Other solvents resulted in lower yields of 3a, for
example, nitromethane (37%), toluene (48%), and tert-butyl
methyl ether (34%) (entries 14-16). The formation of 3a
was not observed in the absence of a catalyst or an oxidant
(entries 17 and 18). Therefore, both iron catalyst and peroxide
are crucial for this transformation.
2a
(equiv)
TBHP
(equiv)
yieldb
(%)
entry
[Fe]
FeCl2
FeBr2
FeCl3
Fe(OAc)2
Fe2(CO)9
Fe(acac)3
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4
4
4
4
4
4
4
8
8
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
EtOAc
MeCN
MeNO2
PhMe
t-BuOMe
DCE
1
1
1
1
1
1
1
1
3
3
3
3
3
3
3
3
1
31
20
38
20
17
28
42
64
88
10
92
96c
70
8
8
8
8
8
4
4
73
37
48
34
N.D.d
N.D.
FeCl3·6H2O
DCE
a Conditions: 1a (0.5 mmol) and TBHP (5-6 M in decane) under
nitrogen, unless otherwise noted. b Detected by 1H NMR using CH2Br2 as
an internal standard. c THF and 2a (1.0 mL) were used; 3 h. d Not detected
by TLC.
reactions of 4-phenyl-1H-imidazole 1c with THF 2a gave
moderate yields of 3c when 10 equiv of 2a was applied
(entries 6 and 7), a 96% yield of 3c was obtained when 2a
was used as a solvent (entry 8). The regioselectivity of 3c
was confirmed by NOE anaylsis. 4,5-Diphenyl-1H-imidazole
1d reacted with 2a to afford the corresponding product 3d
with moderate to excellent yields (entries 9-11). 2-Substi-
tuted imidazoles 1e and 1f gave moderate yields of the
desired oxidative coupling products 3e and 3f due to the
steric effect (entries 12-15). Moderate yields of azole
derivatives were obtained when 3,5-dimethyl-1H-pyrazole
1g and 1H-1,2,4-triazole 1h were applied (entries 16-19).
Although only 3h was isolated from the reaction mixture, a
trace amount of its regioisomer was observed from crude
NMR analysis (entry 19). When 4-nitro-1H-imidazole was
applied under various reaction conditions, a substantial low
conversion (<8%) of it was observed. We hypothesized that
the low solubility and nucleophilic ability of 4-nitro-1H-
imidazole contributed to the low conversion in this case.
Furthermore, the scope of ether derivatives were also
investigated using benzimidazole 1b as the nucleophile
(Table 3). Benzyl C-H bonds showed high reactivity using
ethyl acetate as a solvent, and the corresponding products
3i-k were obtained in excellent yields (entries 1-3). When
2-methyltetrahydrofuran was used, the C-N bond was
formed at the less substituted carbon in a regiospecific
fashion with a 1:1 ratio of two diastereomers (entry 4). The
reactivity and the regioselectivity of this reaction indicated
Subsequently, the scope of azoles was examined for the
present transformation using THF 2a as a standard substrate
(Table 2). Imidazole 1a and benzimidazole 1b led to the
corresponding products 3a and 3b with good to excellent
yields under various conditions (entries 1-5). Although the
(7) (a) Ono, Y.; Izawa, Y.; Fu, Z.-H. Catal. Lett. 1997, 47, 251. (b)
Tanaka, N.; Hatanaka, M.; Watanabe, Y. Chem. Lett. 1992, 575.
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Angew.Chem., Int. Ed. 2009, 48, 1364. (b) Czaplik, W. M.; Mayer, M.;
Cvengros, J.; Jacobi von Wangelin, A. ChemSusChem 2009, 2, 396. (c)
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Reddy, V. P.; Rao, K. R. J. Org. Chem. 2009, 74, 7514. (b) Lee, H. W.;
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Org. Lett., Vol. 12, No. 9, 2010
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Table 2. Reactions of Azoles with THF 2aa
Table 3. Reactions of Ethers with Benzimidaole 1ba
a Conditions: 1b (0.5 mmol), 2 (5.0 mmol), TBHP (2.5 mmol), and 4
Å MS (200 mg). b NMR yield; the isolated yield was given in the
parentheses. c 2-Methyl-THF (1.0 mL) was used without EtOAc.
a Conditions: 1 (0.5 mmol); 80 °C. b Method A: 2a (5.0 mmol), TBHP
(1.5 mmol), and DCE (1.0 mL) for 1 h. Method B: 2a (5.0 mmol), TBHP
(2.5 mmol), 4 Å MS (200 mg), and EtOAc (1.0 mL) for 1 h. Method C: 2a
(1.0 mL), and TBHP (1.5 mmol) for 3 h. Method D: 2a (1.0 mL), TBHP
(2.5 mmol), and 4 Å MS (200 mg) for 3 h. c NMR yield; the isolated yield
was given in the parentheses.
class of C-O donor ligand.12 Therefore, we investigated the
N-alkylation of 3a leading to the formation of the corresponding
imidazole salts 5 (Table 4). The desired salts 5 were obtained
in near-quantitative yields via the reactions of imidazole 3a with
various alkylating agents.13
In order to explore the possible mechanism of the present
transformation, TEMPO, a radical-trapping reagent, was
added into the reaction (eq 1). The formation of the desired
product 3a was completely suppressed, and the TEMPO-
adduct product 6 was formed as a major product. This result
suggested that a radical process was involved in the initial
steps of the transformation. It should be noted that neither
3a nor 6 was observed in the absence of TBHP.
that the steric effect of ethers plays an important role in the
reactions. Linear dialkyl ethers could also be applied for the
present transformation (entries 5-9). A 97% yield of 3m
was obtained when diethyl ether was used (entry 5). Dibutyl
ether afforded the corresponding product 3n in a slight lower
yield (entry 6). Butyl ethyl ether led to two regioisomers 3o
with a 1:1 ratio (entry 7). Two regioisomers, 3p and 3p′,
were obtained with an excellent combined yield when 1,2-
diethoxyethane was used (entry 8). Importantly, 2-ethoxy-
ethyl acetate gave only one regioisomer product 3q (entry
9). These results indicated that the electronic effect of the
ethers also influences the regioselectivity of ethers.
Imidazole salts continue to attract much attention due to their
widespread applications as precursors to N-heterocyclic carbenes
employed as ligands in metal-catalyzed reactions. With the easy
and efficient synthetic method for the ethereal azole derivatives
in hands, we are interested in their potential applications as a
Moreover, a competition experiment was investigated to
address the influences of the electronic properties of azoles
1934
Org. Lett., Vol. 12, No. 9, 2010

This significant isotopic effect indicates that the C-H bond
cleavage is the rate-determinating step of this transformation.
Table 4. Synthesis of Imidazolium Salts 5a
On the basis of the above results, a plausible mechanism
of the present oxidative C-N bond formation is illustrated
in Scheme 1. TBHP decomposes into tert-butoxyl radical
and hydroxyl anion in the presence of the ferrous catalyst
(step a). Deprotonation of azole gives the anion species A
(step b). On the other side, a hydrogen abstraction of C-H
bond adjacent to an oxygen atom affords B, which could be
trapped by TEMPO, and followed by ferric oxidation to
generate oxonium ion C (step c). Finally, the nucleophilic
addition of A to C provides the desired coupling product 3
(step d). Overall, the Fe2+-Fe3+ redox processes15 play key
roles in the present C-N bond formation, which are the
reductive heterolytic cleavage of O-O bond in the peroxide
(step a) and the oxidation of the carbon radical to oxonium
(step c).
a Conditions: 3a (0.25 mmol), 4 (1.0 mL), room temperature, and 24 h;
unless otherwise noted. b Detected by 1H HMR using CH2Br2 as an internal
standard. c Ethyl acetate (1.0 mL) was added; 40 °C.
Scheme 1. Plausible Pathways for the Formation of 3
In summary, we demonstrated a novel and efficient method
of azole derivative synthesis via iron-catalyzed oxidation of
ethers. The high efficiency of the present transformation and
the wide variety of the functional azoles make the present
methodology attractive for future applications.
in the present C-N bond formation (eq 2). The results
indicated that the reactivity of azoles was related to the
nucleophilicity of the conjugated bases of azoles rather than
the acidity of azoles, which agrees with the regular nucleo-
philic reaction. Moreover, kinetic isotopic effect (KIE)
experiments were carried out under the standard reaction
conditions (eq 3). The reaction shows a kH/kD ) 4.0 ( 0.1.14
Acknowledgment. We thank the NSFC (20832002) for
financial support. H.L. thanks RUC (2009030026) for
financial support. We also thank Prof. Zhenfeng Xi, Peking
University, for helpful discussions.
Supporting Information Available: Representative ex-
perimental procedure, characterization of all new compounds,
and 1H NMR and 13C NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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OL100670M
(15) The combination of an iron catalyst and peroxide is well-known
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and 3a-D.
Org. Lett., Vol. 12, No. 9, 2010
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