Iron (III)-catalyzed synthesis of 1,2,4-trisubstituted imidazoles through the reactions of amidines and aldehydes in air

Article abstract of DOI:10.1002/adsc.201300590

A novel and efficient iron (III)-catalyzed synthesis of 1,2,4-trisubstituted imidazoles through the reactions of amidines and aldehydes in air has been developed. Five hydrogen dissociations involving C-H and N-H bond activation are realized under mild conditions in this approach. The procedure is sustainable, simple and environmentally friendly.

Full text of DOI:10.1002/adsc.201300590

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DOI: 10.1002/adsc.201300590
Iron(III)-Catalyzed Synthesis of 1,2,4-Trisubstituted Imidazoles
U
through the Reactions of Amidines and Aldehydes in Air
Xiang Liu,a,b Dong Wang,a,b Yongxin Chen,a,b Dong Tang,a,b and Baohua Chena,b,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, Peopleꢀs Republic of
China
b
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, Peopleꢀs
Republic of China
Fax : (+86)-931-891-2582; e-mail: chbh@lzu.edu.cn
Received: July 3, 2013; Revised: July 21, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300590.
Abstract: A novel and efficient iron
G
dines and terminal alkynes. Despite the advances of
these methods for multisubstituted imidazoles, most
of them require strong bases, long reaction times and
an oxygen atmosphere, but only provide low yields.
Therefore, the development of improved ways for the
synthesis of multi-substituted imidazoles continues to
be a challenging goal.
Amidines, as easily available and versatile struc-
tures, play an important role as precursors for the syn-
thesis of N-containing heterocyclic compounds such
as quinazolines, benzimidazoles, pyrimidines or imida-
zoles.[11] Earlier in this year, our group reported
a novel and efficient strategy for the synthesis of tri-
or tetrasubstituted imidazoles via copper-catalyzed
[3+2]cycloaddition reactions of nitroolefins with ami-
synthesis of 1,2,4-trisubstituted imidazoles through
the reactions of amidines and aldehydes in air has
been developed. Five hydrogen dissociations involv-
À
À
ing C H and N H bond activation are realized
under mild conditions in this approach. The proce-
dure is sustainable, simple and environmentally
friendly.
Keywords: aldehydes; amidines; green chemistry;
imidazoles; iron
1,2,4-Trisubstituted imidazoles are one of the most dines.[12] As a part of our current studies on the devel-
important classes of N-containing heterocyclic com- opment of new routes in multisubstituted imidazoles
pounds, they have been found in a lot of biologically synthesis, herein, we first present a new and efficient
active drugs[1] and functional materials.[2] In addition, iron
ACTHNUTRGNE(NUG III)-catalyzed synthesis of 1,2,4-trisubstituted
À
À
they are of interest in the synthesis of organic semi- imidazoles via oxidative activation of C H and N H
conductors,[3] dyes,[4] dehydroannulenes,[5] and electro- bonds from amidines and aldehydes.
luminescent materials.[6] During the last decades,
First, the reaction conditions were optimized using
many methodologies have been developed for the N-phenylbenzamidine 1a and benzaldehyde 2a as
synthesis of multi-substituted imidazoles. Among model substrates. As shown in Table 1, the reaction
them, the general one is the reaction of an a-hydroxy was carried out with N-phenylbenzamidine 1a
ketone/1,2-diketone, a primary amine, an aldehyde (0.24 mmol), benzaldehyde 2a (0.20 mmol) in the
and ammonium acetate in one-pot.[7] A number of presence of FeCl3 (10% mmol) in CH3NO2 (2 mL) at
catalysts for this process have been reported,[8] such 908C under an atmosphere of O2 for 8 h. The desired
as silica gel/NaHSO4, molecular iodine, HClO4·SiO2, product 3aa was obtained in only 5% yield (Table 1,
BF3·SiO2, hetero-polyacids, Wells–Dawson acid, l- entry 1). When the reactions were carried out in dif-
proline, FeCl3·6H2O. Very recently, another way to ferent solvents including THF, DMF and DMSO, they
synthesize multi-substituted imidazoles through the did not give the expected product 3aa (entries 2–4).
À
À
functionalization of C H/N H bonds directly was de- The yield of 3aa was increased to 42% by using a mix-
veloped. For example, Yan and co-workers[9] reported ture of DMF and CH3NO2 as solvent (entry 5). Then,
the copper-catalyzed synthesis of imidazo
[1,2-a] pyri- the cyclization reactions were conducted in different
À
À
dines via oxidative activation of C H and N H bonds solvent mixtures, such as CH3NO2/DMSO, CH3NO2/
from aminopyridines and nitroolefins. Neuville and toluene, CH3NO2/DMA and CH3NO2/1,4-dioxane,
co-workers[10] developed an efficient copper-catalyzed and the reactions did not provide higher yields (en-
synthesis of 1,2,4-trisubstituted imidazoles using ami- tries 6–9). Based on the above-studied results, we
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Solvent
Yield[b]
1
2
3
4
5
6
7
8
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (30%)
FeCl3 (10%)
FeCl3 (20%)
O2
O2
O2
O2
O2
O2
O2
O2
CH3NO2
THF
DMF
DMSO
5%
0%
0%
0%
42%
40%
12%
trace
trace
12%
trace
5%
CH3NO2/DMF
CH3NO2/DMSO
CH3NO2/DMA
CH3NO2/toluene
CH3NO2/dioxane
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
CH3NO2/DMF
9
O2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[c]
25[d]
TBHP
DDQ
Ag2CO3
t-BuOOBu-t
BPO
CO
air
air
air
air
air
air
air
air
air
air
trace
4%
(NH2)2·H2O2
55%
42%
45%
62%
54%
55%
45%
12%
0%
FeCl3 ACTHNUTRGNEUG(N 30%)
FeCl3 (50%)
FeBr3 (30%)
Fe
Fe
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
CuI (30%)
FeCl3 (30%)
FeCl3 (30%)
44%
62%
[a]
Reaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), catalyst, oxidant (2 equiv), solvent (2 mL), CH3NO2:other solvents=
0.5:1.5 mL, 908C, 8 h.
Isolated yield.
The reaction was carried out at 708C.
The reaction was carried out at 1108C
[b]
[c]
[d]
chose the mixture CH3NO2/DMF as the reaction sol- to 1108C did not enhance the yield. At the tempera-
vent. Next, the reactions were carried out with differ- ture of 708C, the yield decreased sharply (entries 24
ent oxidants. Ag2CO3, BPO and t-BuOOBu-t, 6-dicya- and 25). Increasing the reaction time also did not en-
nobenzoquinone (DDQ), COACTHNUGTRNE(UGN NH2)2·H2O2, and TBHP hance the yield. Thus, 30 mol% FeCl3, 908C and
showed no or slight effects to promote the reaction, CH3NO2/DMF are the optimal conditions for this re-
but using air gave the same yield as what was got action.
under O2 (entries 10–16). Then, we investigated the
Under the optimized reaction conditions, various
reactions at different loadings of FeCl3. The yield of aldehydes 2 were found to be suitable reaction part-
3aa was further improved by increasing the amount of ners with N-phenylbenzamidine 1a to provide the cor-
FeCl3 gradually. When the reaction was carried out responding 1,2,4-trisubstituted imidazoles derivatives
with 30 mol% FeCl3, the yield of 3aa was increased to 3 (Table 2). It could be seen that electronic effects
62%, but the higher loading (>30 mol%) resulted in played a significant role: benzaldehydes with elec-
reduced yield (entries 16–19). Finally, the catalysts tron-donating groups such as methyl and methoxy
screening was done. Some generally used catalysts in- proceeded with good yields (entries 1–6), but the di-
cluding CuI, FeBr3, FeACHTUNGRTENNUG(OTf)3, FeCl3 and FeCAHTUNGTREN(NUGN acac)3 methylamino did not give the expected product
were tested, and FeCl3 was found to be the best one (entry 15). Benzaldehydes with electron-withdrawing
(entries 20–23). Besides, increasing the temperature groups such as chloro, fluoro, cyano and trifluoro-
2
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IronACHTUNGTRENNUNG(III)-Catalyzed Synthesis of 1,2,4-Trisubstituted Imidazoles
Table 2. Reactions of N-phenylbenzamidine with various al-
Table 3. Reactions of benzaldehyde with various N-aryl-
benzamidines.[a]
dehydes.[a]
ACHTUNGTRENNUNG
Entry
R2
R3
Product
Yield[b]
b
Entry
R1
Product
Yield
1
2
3
4
5
6
7
8
C6H5
C6H5
4-CH3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
2-ClC6H4
4-CH3C6H4
4-CH3OC6H4
3-pyridinyl
t-Bu
C6H5
4-CH3C6H4
C6H5
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
62%
72%
71%
62%
75%
61%
58%
54%
52%
71%
76%
57%
0%
1
2
3
4
5
6
7
8
C6H5 (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
62%
64%
70%
61%
66%
59%
57%
52%
60%
61%
56%
40%
0%
0%
0%
57%
55%
51%
41%
4-CH3C6H4 (2b)
4-CH3OC6H4 (2c)
2-CH3OC6H4 (2d)
3,4-CH3OC6H3 (2e)
3,4-CH3C6H3 (2f)
4-ClC6H4 (2g)
2-ClC6H4 (2h)
4-F C6H4 (2i)
3-F C6H4 (2j)
4-CF3C6H4 (2k)
4-CN C6H4 (2l)
4-NO2C6H4 (2m)
2-NO2C6H4 (2n)
4-NMe2C6H4 (2o)
n-C3H7 (2p)
n-C5H11 (2q)
n-C11H23 (2r)
2,6-dimethylhept-5-enyl (2s)
3-CH3C6H4
4-CH3OC6H4
2-C2H5C6H4
4-ClC6H4
3-ClC6H4
C6H5
4-CH3C6H4
4-CH3C6H4
C6H5
9
9
10
11
12
13
14
15
10
11
12
13
14
15
16
17
18
19
C6H5
C2H5
4-NO2C6H4
C6H5
C6H5
0%
0%
[a]
Reaction conditions: 1a–o (0.24 mmol), 2a (0.2 mmol),
FeCl3 (30% mmol), CH3NO2:DMF=0.5:1.5 mL, 908C,
8 h.
[b]
Isolated yield
[a]
Reaction conditions: 1a (0.24 mmol), 2a–s (0.2 mmol),
FeCl3 (30% mmol), CH3NO2: DMF=0.5:1.5 mL, 908C,
8 h.
Isolated yield.
(entries 10 and 11). Benzamidines with electron-with-
drawing groups (such as chloro) gave lower but still
acceptable yields (entries 7–9), but the strongly elec-
tron-withdrawing substituted N-arylbenzamidines
[b]
methyl groups gave lower but still acceptable yields [such as N-(4-nitrophenyl)benzamidine, 1o] did not
(entries 7–12). However, the desired product could give the expect product (entry 15). Moreover, the
not be obtained when a strong electron-withdrawing amidines with aliphatic groups, such as N-phenylpival-
group such as nitro was present (entries 13 and 14).
ACHTUNGTRENaNUNG midine 1m and N-ethylbenzamidine 1n did not give
Aliphatic aldehydes were suitable substrates to pro- the expected product (entries 13 and 14). The 4-sub-
duce 1,2,4-trisubstituted imidazoles in good yield stituted benzamidines showed slightly higher yields
(entry 16–19). Besides, the 2-substituted benzalde- than the 3-substituted ones (entries 3, 4, 7 and 8). No-
hydes showed slightly lower yields than the 4-substi- tably, N-phenylnicotinamidine 2l could also be suita-
tuted ones (entries 3, 4, 7 and 8), which was probably ble for the cycloaddition reactions and provided the
caused by steric effects.
corresponding product 3la with 57% yield (entry 12).
To study the scope and generality of the present
The synthesis of 1,2,4,5-tetrasubstituted imidazoles
protocol, various N-arylbenzamidines were studied through the reactions of amidines and aldehydes was
À
À
for the oxidative C H/N H bond cycloaddition reac- performed in CH3CH2NO2/DMF (1:3), with FeCl3
tions with benzaldehyde under the above optimized (30%) as catalyst at 908C for 8 h (Scheme 1). It was
reaction conditions. As shown in Table 3, the most of found that the corresponding 1,2,4,5-tetrasubstituted
investigated N-arylbenzamidines were suitable part- imidazoles 4a, 4b, 4c, 4d, 4e were obtained in only
À
À
ners for the oxidative C H/N H bond cycloaddition 24–34% yield. This was probably due to steric effects.
reactions and provided the corresponding products in To probe the mechanism of the reactions, several
moderate yields. In general, N-arylbenzamidines with control experiments were performed. While the reac-
electron-donating groups (such as methyl, methoxy tion was carried out with N-phenylbenzamidine 1a
and ethyl) on R2 and/or R3 provided higher yields of (0.24 mmol), benzaldehyde 2a (0.20 mmol), CH3NO2
the desired product (entries 1–6). Especially, when the (0.40 mmol) in the presence of FeCl3 (30 mol%) in
N-arylbenzamidines bearing two electron-donating DMF at 908C under an atmosphere of air for 8 h, the
groups were employed, the yields were up to 76% desired product 3aa was obtained in 25% yield. The
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Scheme 1. Synthesis of 1,2,4,5-tetrasubstituted imidazoles.
cycloaddition reaction did not occur without partici- merized into enamine 9 smoothly. Then, iron-cata-
pation of CH3NO2. Therefore, nitromethane could lyzed synthesis of radical cation 10 from 9 occurred
provide a carbon atom for the reaction. Imidazole 3aa via loss of a proton. Finally, the product 3aa was ob-
was also obtained in 62% yield via reaction of 1a with tained via the intramolecular Michael addition with
2a under N2-protected conditions. Thus, we speculate removal of nitroxyl (HNO) and H2O abstraction from
the the NO2 group was the terminal oxidant in this intermediate 11, which was produced from 10.
process. Based on the above observations and the
In conclusion, we have developed an efficient iron-
AHCTUNGTREG(NNUN III)-catalyzed synthesis of 1,2,4-trisubstituted imida-
analogous mechanisms discussed in the literature,[13]
a plausible mechanism was proposed as shown in zoles through the reactions of amidines and aldehydes
À
Scheme 2. First, the intermediate 4 was produced by in air. Five hydrogen dissociations involving C H and
the condensation reaction of N-phenylbenzamidine 1a N H bonds activation are realized under mild condi-
À
with benzaldehyde 2a. Then the intermediate 5 was tions in this approach. The procedure is sustainable,
produced from Michael addition of intermediate 4 simple and economic. This procedure useds FeCl3 as
with CH3NO2. Subsequently, the iron catalyst oxidized the catalyst which is less toxic than the copper cata-
the intermediate 5 into the radical cation 6, and the lyst. Comparing with the literature methods, this
intermediate 7 was obtained from intermediate 6 methodology has several advantages, such as commer-
after subsequent removal of a hydrogen radical. Next, cial starting materials, multicomponent reaction in
the intermediate 7 underwent proton abstraction with one-pot, use of base-free and ligand-free conditions,
the oxidant forming intermediate 8, which further iso- under air.
Scheme 2. A plausible reaction mechanism.
4
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IronACHTUNGTRENNUNG(III)-Catalyzed Synthesis of 1,2,4-Trisubstituted Imidazoles
N. Mizuno, Angew. Chem. 2003, 115, 1518; c) M.
Kotani, T. Koike, K. Yamaguchi, N. Mizuno, Green
Chem. 2006, 8, 735; d) F. Li, J. Chen, Q. Zhang, Y.
Wang, Green Chem. 2008, 10, 553; e) Y. Zhang, K. Xu,
X. Chen, T. Hu, Y. Yu, J. Zhang, J. Hung, Catal.
Commun. 2010, 11, 951.
Experimental Section
Typical Procedure for the Reaction between
Amidines and Benzaldehydes: Synthesis of 1,2,4-
Triphenyl-1H-imidazole (3aa)
All reactions were performed on a 0.20-mmol scale relative
to aldehydes. The N-phenylbenzamidine (1a, 0.24 mmol),
benzaldehyde (2a, 0.2 mmol), FeCl3 (0.060 mmol) and 2 mL
MeNO2/DMF (1:3) were charged in a round-bottom flask
equipped with a stirrer. The resulting mixture was stirred
for 8 h at 908C. After cooling to room temperature, the re-
action mixture was treated with water (2 mL), and extracted
with ethyl acetate (3ꢂ10 mL). The combined organic phases
were washed with brine (2ꢂ5 mL), dried over anhydrous
MgSO4 and concentrated under vacuum. The residue was
subjected to flash column chromatography with hexanes/
EtOAc (20/1) as eluent to obtain the desired 3aa as a light
yellow oil; yield: 62%. 1H NMR (300 MHz, CDCl3): d=
7.87–7.90 (d, J=9.0 Hz, 2H), 7.21–7.45 (m, 14H); 13C NMR
(100 MHz, CDCl3): d=146.9, 141.6, 138.4, 133.8, 130.2,
129.4, 129.1, 128.7, 128.5, 128.4, 128.1, 126.9, 125.7, 125.0,
118.5. ESI HR-MS: m/z=296.1316, calcd. for C21H16N2 [M+
H]+: 296.1313.
´
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Acknowledgements
We are grateful for financial support from the National Sci-
ence Foundation of P. R. of China (No. 21372102) and the
Project of National Science Foundation of Gansu Province P.
R. China (No. 1208RJZA266).
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COMMUNICATIONS
6 IronACHTUNGTRENNUNG(III)-Catalyzed Synthesis of 1,2,4-Trisubstituted
Imidazoles through the Reactions of Amidines and
Aldehydes in Air
Adv. Synth. Catal. 2013, 355, 1 – 6
Xiang Liu, Dong Wang, Yongxin Chen, Dong Tang,
Baohua Chen*
6
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