Iron(III)-catalyzed direct N-alkylation of azoles via oxidative transformation of sp3 ci￡h bonds under solvent-free conditions

Article abstract of DOI:10.1002/cjoc.201200690

A new approach to synthesize N-alkylation of azoles by iron(III)-catalyst under solvent-free conditions was developed. The method is broad in scope and highly efficient. A new approach to synthesize N-alkylation of azoles by iron (III)-catalyst under solv

Full text of DOI:10.1002/cjoc.201200690

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DOI: 10.1002/cjoc. 201200690
Iron(III)-Catalyzed Direct N-Alkylation of Azoles via Oxidative
Transformation of sp3 C—H Bonds under
Solvent-Free Conditions
Liu, Xianga,b(刘湘)
Chen, Yongxina,b(陈永欣)
Li, Kangninga,b(李康宁)
Wang, Donga,b(王东)
Chen, Baohua*,a,b(陈保华)
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou, Gansu
730000, China
A new approach to synthesize N-alkylation of azoles by iron(III)-catalyst under solvent-free conditions was de-
veloped. The method is broad in scope and highly efficient.
Keywords azoles, N-alkylation, solvent-free, iron catalyst, C—H activation
Chen and his co-workers[10] make C—N coupling of
imidazoles and benzylic compounds via iron-catalyzed
oxidative activation of C—H bonds with a high effi-
ciency. This efficient method also required some com-
plex condition like organic solvent, high temperature,
long reaction time, and a nitrogen atmosphere.
In summary, there are many approaches to synthe-
size the N-alkylation azoles, but most of them required
high temperature, prolonged reaction time, toxic oxi-
dants, solvents, and functionalized substrates. In recent
years, solvent-free reactions[11] and organic aqueous
phase reactions[12] have been regarded as a promising
alternative to replace reactions in various solvents. Here
we found a simple and efficient way to make N-alkyla-
tion of azoles in the solvent free system. This solvent
free reaction worked well in the air catalyzed by FeCl3,
and it proceeded in a good yield at relatively lower
temperature within a short time.
Introduction
Azoles[1] and their derivatives[2] are important het-
erocycles in natural products and commercial drugs
(like the antiviral, anticonvulsant, antiulcer, anti-in-
flammatory). They have also been frequently used as
backbones in dyes[3] and high-temperature polymers.[4]
Developing efficient methods for the preparation of
functional azoles has caused a lot of attention.[5] The
most common route is a nucleophilic substitution reac-
tion with an electrophile (RX, X＝halide, OTs, OTf,
etc.), and a following deprotonation step. Although they
are efficient methods for azoles, most of them make use
of strong bases, generating stoichiometric amount of
wasteful organic salts and low secondary/tertiary amine
product selectivity. It is another way to synthesize az-
oles through the functionalization of C—H/N—H di-
rectly, and the direct method provides a possible trans-
formation from azoles into a variety of useful deriva-
tives.[6] The direct way processed well these years.
Hamze, Alami and co-workers[7] realized the synthesis
of azoles from N-tosylhydrazones in the presence of
Cs2CO3. This system showed a wide application poten-
tial and high efficiency under mild conditions. However,
it must prepare substrates in advance, and solvents were
required in the reaction. Very recently, Schnürch and
coworks[8] described the synthesis of diarylmethylamine
by C—H arylation, this proves the utility of such com-
pounds. In recent years, iron is a particularly attractive
catalyst in many reactions because of its sustainability,
easy availability, low price, and environmentally
friendly characteristics.[9] There is also a report that
Experimental
Typical procedure for the preparation of 1-benz-
hydryl-1H-benzo[d]imidaole 3aa
Benzimidazole 1a (58 mg, 0.50 mmol), FeCl3 (20
mmol%), tert-butyl hydroperoxide (171 μL, 2.5 equiv.)
and diphenylmethane 2a (2.0 mmol) were added to a
flask with a magnetic stirring bar. The resulting mixture
was stirred for 10 h at 100 ℃. After cooling to room
temperature, the mixture was diluted with ethyl acetate
and filtered. The filtrate was removed under reduced
pressure to get the crude product, which was further
purified by silica gel chromatography (petroleum/ethyl
* E-mail: chbh@lzu.edu.cn; Tel.: 0086-0139-193-57881; Fax: 0086-0931-891-2582
Received July 8, 2012; accepted July 30, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200690 or from the author.
Chin. J. Chem. 2012, 30, 2285—2291
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Liu et al.
Table 1 Optimization of the reaction conditiona
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acetate＝1/1 as eluent) to give product 3aa as a white
solid. The identity and purity of the products were con-
1
1
firmed by H and 13C NMR spectroscopic analysis. H
NMR (300 MHz, CDCl3) δ: 7.845—7.818 (d, 1H),
7.610 (s, 1H), 7.368—7.267 (m, 6H), 7.245—7.124 (m,
7H), 6.745 (s, 1H); 13C NMR (75 MHz, CDCl3) δ:
144.052, 142.533 138.050, 134.051, 128.976, 128.477,
128.171, 122.925, 122.364, 120.372, 110.719, 63.
H
N
catalyst/oxidant
+
solvent/10 h
N
N
100 ℃
2a
1a
N
3aa
Entry
Oxidant
Catalyst/mmol% Solvent Yeildb/%
Results and Discussion
1
2
DDQ
Ag2CO3
TBHP
O2
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (15)
FeCl3 (20)
FeCl3 (25)
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
PhCl
CH3CN
PhNO2
Neat
0
trace
30
In our initial study, we investigated the reaction of
benzimidazole (1a) with diphenylmethane (2a) in the
presence of FeCl3 (10 mmol%) to optimize the reaction
conditions (Table 1). In this preliminary experiment, the
N-alkylation reaction was carried out with different
oxidants. 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ),
Ag2CO3, O2, benzoyl peroxide (BPO) and t-BuOOBu-t
showed little effectiveness on promoting the reaction;
using aqueous tert-butyl hydroperoxide (TBHP) as the
oxidant afforded N-alkylation product 3aa in 30% yield
(Table 1, Entries 1—6). Then, solvent was conducted.
Among the solvents, DMSO, PhCl, and CH3CN were
harmful to the transformation (Table 1, Entries 7, 8, 9),
but solvent-free and PhNO2 showed good performance
(Table 1, Entries 10, 11). Obviously, choosing solvent
free system is more favorable to develop an economical
and environmentally friendly reaction. Moreover, the
yield of the desired product 3aa could be improved by
increasing the amount of FeCl3 gradually. It is notewor-
thy that the yield of 3aa was enhanced to 90% when the
amount of FeCl3 was 20 mmol%, and the high loading
(＞20 mmol%) resulted in the decrease of the yield (Ta-
ble 1, Entriy 14). However, TBHP (5.0—6.0 mol/L in
decane) used in the reaction gave an inferior product
yield compared with that of aqueous TBHP (Table 1,
Entry 13). It should be noted that this reaction did not
work in the absence of FeCl3 or TBHP. Morever, a trace
amount of 3aa was detected when the reaction tem-
perature was below 80 ℃.
3
4
0
5
t-BuOOBu-t
BPO
0
6
15
7
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
0
8
20
9
trace
38
10
11
12
13
14
50
Neat
64
90 (50c)
Neat
Neat
70
a Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), catalyst (20
mmol%), oxidant (2.5 equiv.), solvent (1 mL), 100 ℃, 10 h.
b Isolated yields. c TBHP (5.0—6.0 mol/L in decane).
on the phenyl ring, which yielded single regioisomers.
In addition, new product 3ma in 99% yield was ob-
served when 3,5-dimethyl-1H-pyrazole reacted with di-
phenylmethane.
The reaction scope was also investigated relating to
other coupling partners (Table 3). As you can see in Ta-
ble 3, the reactions of azoles with benzylic compounds
produced the corresponding cross-coupling products
(Table 3, Entries 1—5) in moderate to good yields. The
reaction was also applicable to ethers, such as 1,4-di-
oxane and tetra-hydrofuran (Table 3, Entries 6—10).
A plausible mechanism for this reaction was pro-
posed in Scheme 1. It may involve a free-radical process.
The reaction started with abstraction of H from 2 by
t-BuOOH, giving R1CHR2 radical (A). Subsequently,
FeCl3 oxidized A to B. FeCl2, produced during trans-
formation of A to B, reacted with HCl under oxidization
of TBHP condition giving FeCl3 and t-BuOH or H2O to
complete iron-catalyst cycle. Finally, nucleophilic reac-
tion of 1 with B produced the target product 3. We will
focus on the systematic investigation in future studies.
The scope of the reaction was investigated under the
optimized reaction conditions described above. The re-
sults were shown in Table 2. The 5-substituted azoles 1
containing electron-withdrawing groups showed slightly
higher yields than electron-donating ones (Table 2, En-
tries 7—12). That steric hindrance at the 2-position of
benzimidazoles had only a slight impact on the yields.
However, 3ba, 3ca, 3ea and 3fa were obtained in mod-
erate yields unless using more TBHP, prolonging the
reaction times or at higher temperature (Table 2, Entries
1—6). Benzitriazole also gave higher yield but they do
not have the same level of selectivity. It is caused
probably by strong steric effect. Substrates substituted
by CH3, Cl, or NO2 groups gave a mixture of regioi-
somers. The combined yields ranged from 71% to 99%,
and the ratio of isomers varied from 1∶1.1 to 1∶1.22,
Conclusions
1
confirmed by H NMR and 13C NMR except benzimi-
In conclusion, we developed an iron-catalyzed, en-
vironmentally friendly, economical and efficient method
dazole and benzitriazole substrates with methyl group
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2285—2291

Iron(III)-Catalyzed Direct N-Alkylation of Azoles via Oxidative Transformation
Table 2 Reactions of diphenylmethane 2a with various azoles
H
N
FeCl3 (20%)
R
X
+
+
N
N
TBHP (2.5 equiv.)
Neat, 100 ℃,10 h
R
N
N
N
X
X
2a
1
R
4
3
Entry
Product
Yeildb/%
1
H
N
1
90
N
N
1a
N
3aa
H
N
2
3
4
5
6
49c
73c
81
N
N
1b
N
3ba
H
N
CF3
N
N
CF3
3ca
1c
N
H
N
Cl
N
N
N
Cl
1d
3da
H
N
47d
53e
99
N
N
1e
N
3ea
H
N
O
N
N
N
O
1f
3fa
H
N
Cl
7
Cl
N
N
N
(3ga∶4ga＝1∶1.1)
1g
N
N
Cl
4ga
3ga
Chin. J. Chem. 2012, 30, 2285—2291
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Liu et al.
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Continued
Entry
Product
Yeildb/%
1
H
N
O2N
99
O2N
8
N
N
N
N
(3ha∶4ha＝1∶1.2)
1h
O2N
N
4ha
3ha
H
N
9
65
N
N
N
N
N
1i
3ia
4ia
H
N
N
10
72
N
N
N
1j
N
3ja
H
N
Cl
78
N
Cl
11
N
N
N
(3ka∶4ka＝1∶1.2)
N
N
1k
N
N
Cl
4ka
3ka
H
N
N
12
71
N
N
N
N
N
1l
N
N
4la
3la
H
N
N
N
13
99
N
1m
3ma
a
b
Reaction conditions: 1 (0.5 mmol), 2 (3.0 mmol), catalyst (20 mmol%), oxidant (171 μL, 2.5 equiv.), 100 ℃, 10 h. Isolated yields.
c TBHP (5.0 equiv.). d At 120 ℃. e 24 h.
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Chin. J. Chem. 2012, 30, 2285—2291

Iron(III)-Catalyzed Direct N-Alkylation of Azoles via Oxidative Transformation
Table 3 Reactions of azoles with various active C—H bond
H
N
FeCl3 (20%)
R1
2a
R2
+
R
X
TBHP (2.5 equiv.)
Neat, 100 ℃, 10 h
N
N
N
X
R
1
3
Entry
1
Product
Yieldb/%
1
2
O
83
1a
N
O
2b
N
3ab
t-Bu
t-Bu
2
3
60
75
1a
1a
t-Bu
t-Bu
N
2c
N
3ac
N
2d
N
3ad
4
5
50
61c
77d
1a
1a
N
N
2e
3ae
N
2f
N
3af
O
O
O
N
N
6
7
1a
1a
O
2g
3ag
O
N
78
O
N
2h
3ah
Chin. J. Chem. 2012, 30, 2285—2291
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Liu et al.
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Continued
Entry
Product
Yieldb/%
1
2
O
O
76d
N
N
8
1b
2g
3bg
O
O
9
55d
1j
2g
2h
N
N
N
3jg
O
N
N
10
74
1j
N
3jh
a Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), catalyst (20 mmol%), oxidant (171 μL, 2.5 equiv.), 100 ℃, 10 h. b Isolated yields. c At
120 ℃. d TBHP (5 equiv.).
Scheme 1 A plausible reaction mechanism
TBHP
R1
R2
2
t-BuO or OH
+
FeCl3
t-BuOH or H2O
FeCl3
+
R1
TBHP, HCl
R2
+ t-BuOH or H2O
A
FeCl2
R2
R1
+ t-BuOH or H2O
+ Cl-
B
H
N
N
N
N
R2
R1
1
3
HCl
for N-alkylation of azoles via iron-catalyst and oxidative
transformation of sp3 C—H bonds under solvent-free
conditions. The most attractive feature of this noval
method is simple. It is just an easy one step reaction
with available substrates. Furthermore, the reaction
conditions were relatively mild.
Acknowledgement
We are grateful for the support of this project from
the Scientific Research Foundation of the State Educa-
tion Ministry (No. 107108) and the National Natural
Science Foundation of China (No. J0730425).
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Chin. J. Chem. 2012, 30, 2285—2291

Iron(III)-Catalyzed Direct N-Alkylation of Azoles via Oxidative Transformation
2009, 11, 5178; (e) Yang, F.; Xu, Z.; Wang, Z.; Yu, Z.; Wang, R.
References
Chem. Eur. J. 2011, 17, 6321; (f) Liang, Y.-M.; Liu, X.-Y.; Gao, P.;
Shen, Y.-W. Org. Lett. 2011, 13, 16; (g) Matsuda, N.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860; (h) Hamada, T.; Ye,
X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833; (i) Chen, L.; Shi,
E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J.
2011, 12, 4085.
[1] (a) Palmer, P. J.; Trigg, R. B.; Warrington, J. V. J. Med. Chem. 1971,
14, 248; (b) Bradshaw, T. D.; Wrigley, S.; Shi, D. F.; Schulz, R. J.;
Paull, K. D.; Stevens, M. F. G. Br. J. Cancer 1998, 77, 745; (c) Gra-
vatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W. A. J. Med.
Chem. 1994, 37, 4338; (d) Denny, W. A.; Rewcastle, G. W.; Baugley,
B. C. J. Med. Chem. 1990, 33, 814; (e) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893; (f) Wexler, R. R.; Green-
lee, W. J.; Irvin, J. D.; Goldberg, M. R.; Prendergast, K.; Smith, R. P.;
Timmermans, P. B. M. W. M. J. Med. Chem. 1996, 39, 625.
[2] (a) Soderlind, K. J.; Gorodetsky, B.; Singh, A. K.; Bachur, N.; Miller,
G. G.; Lown, J. W. Anticancer Drug Des. 1999, 14, 19; (b) Woy-
narowski, J. M.; McHugh, M. M.; Sigmud, R. D.; Beerman, T. A.
Mol. Pharmacol. 1989, 35, 177; (c) Nakano, H.; Inoue, T.; Kawasaki,
N.; Miyataka, H.; Matsumoto, H.; Taguchi, T.; Inagaki, N.; Nagai,
H.; Satoh, T. Bioorg. Med. Chem. 2000, 8, 373; (d) Horton, D. A.;
Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (e) Kosano,
H.; Kayanuma, T.; Nishigori, H. Biochem. Biophys. Acta 2000, 11,
1499.
[7] Hamze, A.; Tréguier, B.; Brion, J.-D.; Alami, M. Org. Biomol. Chem.
2011, 9, 6200.
[8] Dastbaravardeh, N.; Schnürch, M.; Mihovilovic, M. D. Org. Lett.
2012, DOI: 10.1021/ol301680v.
[9] (a) Pan, S. G.; Liu, J. H.; Li, H. R.; Wang, Z. Y.; Guo, X. W.; Li, Z. P.
Org. Lett. 2010, 12, 1932; (b) Liu, W. P.; Liu, G. H.; Ogawa, D.;
Nishihara, Y.; Guo, X. W.; Li, Z. P. Org. Lett. 2011, 13, 6272; (c)
Liang, L. F.; Fang, Q.; Xu, X. B. Chin. J. Org. Chem. 2012, 32, 409;
(d) Li, H. J.; He, Z. H.; Guo, X. W.; Li, W. J.; Zhao, X. H.; Li, Z. P.
Org. Lett. 2009, 11, 4176; (e) Li, Z. P.; Cao, L.; Li, C. J. Angew.
Chem., Int. Ed. 2007, 46, 6505; (f) Li, Z. P.; Yu, R.; Li, H. J. Angew.
Chem., Int. Ed. 2007, 46, 6505; (g) Pan, S. G.; Liu, J. H.; Li, Y. M.;
Li, Z. P. Chin. Sci. Bull. 2012, 57, 2382; (h) Guo, X. W.; Pan, S. G.;
Liu, J. H.; Li, Z. P. J. Org. Chem. 2009, 74, 8848; (i) Guo, X. W.; Yu,
R.; Li, H. J.; Li, Z. P. J. Am. Chem. Soc. 2009, 131, 17387.
[10] Xia, Q.; Chen, W.; Qiu, H. J. Org. Chem. 2011, 76, 7577.
[11] (a) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908; (b)
He, T.; Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011, 11, 112; (c)
Wang, D.; Li, N.; Zhao, M.; Shi, W.; Ma, C.; Chen, B. Green Chem.
2010, 12, 2120; (d) Wang, D.; Li, J.; Li, N.; Gao, T.; Hou, S.; Chen,
B. Green Chem. 2010, 12, 45.
[3] Schwartz, G.; Fehse, K.; Pfeiffer, M.; Walzer, K.; Leo, K. Appl. Phys.
Lett. 2006, 89, 083509.
[4] Asensio, J. A.; Gomez-Romero, P. Fuel Cells 2005, 5, 336.
[5] (a) Al-Azmi, A.; George, P.; El-Dusouqui, O. M. E. J. Heterocycl.
Chem. 2007, 44, 515; (b) Begtrup, M.; Larsen, P. Acta Chem. Scand.
1990, 44, 1050; (c) Jeletic, M. S.; Jan, M. T.; Ghiviriga, I.; Abboud,
K. A.; Veige, A. S. Dalton Trans. 2009, 2764; (d) Chen, W. L.; Yan,
R. L.; Tang, D.; Guo, S. B.; Meng, X.; Chen, B. H. Tetrahedron
2012, DOI: 10.1016/j.tet.2012.07.008; (e) Mu, M. M.; Lu, B. W.; Lu,
J. R.; Xin, C. W.; Ji, D.; Li, J. F.; Bao, X. R. Chin. J. Org. Chem.
2012, 32, 1101 (in Chinese).
[6] (a) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780;
(b) Murru, S.; Patel, B. K.; Bras, J. L.; Muzart, J. J. Org. Chem.
2009, 74, 2217; (c) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori,
A. Org. Lett. 2009, 11, 1607; (d) Wang, Q.; Schreiber, S. L. Org. Lett.
[12] (a) Lindströom, U. M. Chem. Rev. 2002, 102, 2741; (b) Kobayahi, S.;
Manabe, K. Acc. Chem. Res. 2002, 35, 209; (c) Li, C.-J. Chem. Rev.
2005, 105, 3095; (d) Blackmond, D. G.; Armstrong, A.; Coomber, V.;
Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798; (e) Peng, J.; Ye, M.;
Zong, C.; Hu, F.; Feng, L.; Wang, X.; Wang, Y.; Chen, C. J. Org.
Chem. 2011, 76, 716.
(Pan, B.; Qin, X.)
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