Shan
Li
a,
Yafen
Yuan
a,
Yajun
Li
ab,
Zhengke
Li
a,
Lisi
Zhang
a and
Yongming
Wu
*a
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: ymwu@sioc.ac.cn; Fax: (+86)-021-54925190
bSchool of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, Hubei 430074, China
First published on 16th October 2012
Catalyzed by ligand free Pd(OAc)2, 2,5-disubstituted imidazole was prepared in good yield by the reaction of fluorinated propargyl amidines with iodoarene. Mechanistic studies indicated that this transformation occurs through a nitropalladation–reductive elimination pathway.
In our initial study, 2-trifluoromethyl N-(p-methoxyphenyl-N-propargyl amidine 1aa was treated with p-methoxyl iodobenzene 2a (1.2 equiv.) in the presence of K2CO3 (1.5 equiv.) and Pd(OAc)2 (10 mol%) in CH3CN at room temperature. The desired product, 5-benzyl imidazole 3aaa was obtained in 26% yield. In an effort to optimize the reaction, reaction conditions were investigated by varying the temperature, base, solvent and catalyst. The outcome, however, was not promising (Table 1 in ESI†). In these reactions, 5-benzyl imidazole as the only product was obtained in low yield, no byproduct such as 5-methyl imidazole or 3-(p-methoxphenyl) prop-2-ynyl amidine was detected. The presence of the fluoroalkyl group increases the acidity of the hydrogen atom on the amidinoyl group, which leads to deprotonation under strong basic conditions, and the increased amount of propargyl amidine anion will promote the reaction. By using a 1.0:0.7:1.2 molar ratio of 1aa:2a:K2CO3, an improved yield of 76% was obtained when the reaction was carried out in CH3CN at 80 °C, in the presence of 10 mol% Pd(OAc)2 (Table 1, entry 1). A similar result was obtained when K3PO4 was used as the base (Table 1, entry 2). The yield of 5-benzyl imidazole 3aaa was increased to 84% when DMF was chosen as the solvent (Table 1, entry 5). The concentration of propargyl amidine was found to affect the yield of 3aaa, a lower yield was obtained with a higher concentration of 1aa (Table 1, entries 12, 13).
Entry | Catalyst | Solvent | Base | Temp/°C | Yield/%a |
---|---|---|---|---|---|
a Isolated yield. b Calculated by 19F NMR. c The molar ratio of 1aa:2a = 1:0.8. d The molar ratio of 1aa:2a = 1:1. | |||||
1 | Pd(OAc)2 | CH3CN | K2CO3 | 80 | 76 |
2 | Pd(OAc)2 | CH3CN | K3PO4 | 80 | 71 |
3 | Pd(OAc)2 | CH3CN | Na2CO3 | 80 | 65b |
4 | Pd(OAc)2 | CH3CN | Py | 80 | 58b |
5 | Pd(OAc)2 | DMF | K2CO3 | 80 | 84 |
6 | Pd(OAc)2 | DMF | K3PO4 | 80 | 75 |
7 | Pd(OAc)2 | DMF | Py | 80 | 46b |
8 | Pd(OAc)2 | DMF | K2CO3 | 60 | 70 |
9 | Pd(PPh3)2Cl2 | CH3CN | K2CO3 | 80 | 68 |
10 | Pd(PPh3)2Cl2 | DMF | K2CO3 | 80 | 77 |
11 | Pd(PPh3)2Cl2 | DMF | K3PO4 | 80 | 62 |
12 | Pd(OAc)2 | DMF | K2CO3 | 80 | 74c |
13 | Pd(OAc)2 | DMF | K2CO3 | 80 | 55b,d |
The scope of the palladium-catalyzed coupling of fluorinated propargyl amidines with aryl iodides by this procedure is summarized in Table 2. To our delight, this reaction shows good compatibility towards aryl iodides containing many functional groups, such as ester and acetyl groups (Table 2, entries 5, 6). Iodoarenes with both electron-donating and electron-withdrawing groups gave moderate to good yields of the corresponding products (Table 2, entries 1–7). Iodoarenes with an electron-withdrawing group give a lower yield (Table 2, entries 5–7). Steric hindrance of iodoarene imposed by ortho-substitution has little impact on the yield except for the substrate with ortho-fluorine (Table 2, entries 8, 9, entry 10). Steric and electronic effects of propargyl amidines were also negligible for the coupling reaction (Table 2, entries 11–13). Substrates with –CF2Br are too unstable under the reaction condition to afford any product (Table 1, entry 14), while good yield was obtained from substrates with –CF2H (Table 1, entry 15).
Entry | Rf | R1 | R2 | Yield/%a |
---|---|---|---|---|
a Isolated yield. | ||||
1 | –CF3 | p-OCH3 | p-OCH3 | 3aaa/84 |
2 | –CF3 | p-OCH3 | H | 3aab/80 |
3 | –CF3 | p-OCH3 | p-Cl | 3aac/85 |
4 | –CF3 | p-OCH3 | m-CH3 | 3aad/74 |
5 | –CF3 | p-OCH3 | p-COOEt | 3aae/61 |
6 | –CF3 | p-OCH3 | p-COCH3 | 3aaf/68 |
7 | –CF3 | p-OCH3 | p-CF3 | 3aag/79 |
8 | –CF3 | p-OCH3 | o-OCH3 | 3aah/81 |
9 | –CF3 | p-OCH3 | o-CF3 | 3aai/75 |
10 | –CF3 | p-OCH3 | o-F | 3aaj/42 |
11 | –CF3 | p-Cl | p-OCH3 | 3aba/72 |
12 | –CF3 | o-OCH3 | p-OCH3 | 3aca/86 |
13 | –CF3 | Naphth | p-OCH3 | 3ada/80 |
14 | –CF2Br | p-OCH3 | p-OCH3 | — |
15 | –CF2H | H | p-OCH3 | 3cea/77 |
This transformation may proceed through two pathways.9 In path I, the C–C triple bond in the propargyl amidine coordinates to the σ-aryl palladium complex. A nitrogen atom attacks the activated C–C triple bond and the propargyl amidine accepts the attack of the nitrogen atom to afford a σ-aryl-σ-(5-imidazolymethyl) palladium intermediate, which then undergoes reductive elimination to form 5-benzyl imidazole (path I). Alternatively, 3-aryl prop-2-yne amidine would be produced first from the σ-aryl palladium complex with a terminal alkyne, and then it undergoes 5-exo-dig cyclization to give the desired product (path II).
With the inductive electron-withdrawing effect of fluoroalkyl, deprotonation of amidinolyl readily takes place under basic conditions, and then undergoes intramolecular nucleophilic reaction with the activated alkyne to give the desired product. In our system, 5-benzyl imidazole was found to be the sole product. To distinguish these two pathways, we prepared N-(3-phenyl) prop-2-ynyl amidine 1aab. Under the same conditions, only a low yield (63%) of 5-benzyl imidazole 3aab was detected by 19F NMR, which was lower than from the reaction of fluorinated proparygyl amidine with iodobenzene (Table 2, entry 2). In the presence of an iodoarene, 1aab underwent a cyclization–arylation to give 5-diarymethyl imidazole 3aaba in very low yield due to large steric hindrance. Judging from these observations, it is very likely that the transformation proceeds through path I. The proposed mechanism is shown in Scheme 1. 5-Benzyl imidazole 3 is most likely generated by reductive elimination from the intermediate B, which is more stable than the σ-vinyl-σ-aryl palladium species A (Scheme 2).10
Scheme 1 Transformations of 1aab catalyzed by Pd(OAc)2. |
Scheme 2 Proposed mechanism for the formation of 2,5-disubstituted imidazoles. |
In conclusion, a convenient protocol to generate 2,5-disubstituted imidazoles has been developed. With ligand free Pd(OAc)2 as the catalyst, 2-fluoroalkyl-5-benzyl imidazoles can be obtained in moderate to good yields from the reaction of fluorinated propargyl amidines with aryl iodides. This transformation is compatible with a wide range of functional groups. Mechanistic investigations revealed that the reaction most likely proceeds via a nitropalladation–reductive elimination pathway.
Footnote |
† Electronic supplementary information (ESI) available: General procedure for 2,5-disubstituted imidazole synthesis; Characterization data and NMR spectra for compounds 3aaa–3cea, 3aaba. See DOI: 10.1039/c2ob26377g |
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