Yasuhiro
Yamashita
,
Yuki
Saito
,
Takaki
Imaizumi
and
Shū
Kobayashi
*
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku Tokyo, Japan. E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
First published on 11th June 2014
While Lewis acids and metal amides are among the most frequently used metal species, they are believed to be incompatible when combined. Here we describe a Lewis acid/metal amide hybrid, which contains electron-withdrawing groups and basic and bulky nitrogen functional groups in the same metal complex, as a novel catalyst. We have synthesized In(N(SiMe3)2)2Cl (In(HMDS)2Cl) and In(HMDS)2OTf as Lewis acid/metal amide hybrids, which showed excellent catalytic activity for the reaction of nitrones with terminal alkynes to give synthetically useful propargyl hydroxylamines. It is noted that neither the Lewis acids (InCl3, In(OTf)3) nor the metal amides (In(HMDS)3) have activity; only the hybrids worked well, and the catalytic activity of the hybrids was shown to be much higher than that of previously reported catalysts for this reaction. The concept of a Lewis acid/metal amide hybrid as a catalyst may be expanded to broad acid/base catalysis.
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Fig. 1 (A) A typical Lewis acid (LA) and metal amide (MA); (B) a Lewis acid/metal amide hybrid (LA/MA hybrid). |
In Lewis acids, the metal parts play key roles, and stronger electron-withdrawing counter anions such as halides and trifluoromethanesulfonate (triflate), which lower the LUMO energy of the metal complexes and thus increase the Lewis acidity of the metals, have been investigated. On the other hand, nitrogen atoms play key roles in metal amides. Indeed, nitrogen atoms have two functions, nucleophilicity and basicity.8 To utilize only the base function, sterically bulky metal amides have been developed.6,7 Here, we report a Lewis acid/metal amide hybrid, which contains electron-withdrawing groups and basic and bulky nitrogen functional groups in the same metal complex (Fig. 1B). The hybrid is expected to work as a Lewis acid as well as a Brønsted base.9,10
Next, to demonstrate the catalytic activity of this In(III) Lewis acid/amide hybrid, a model reaction of nitrones with terminal alkynes was examined.16–19 The catalytic addition of terminal alkynes to nitrones provides an efficient route to propargyl hydroxylamines, which can be further transformed into isoxazolines20 and aziridines21via intramolecular cyclization. In the literature, only a couple of catalyst systems have been reported for this reaction. Carreira et al. are pioneers and have shown that the combination of Zn(OTf)2 (10 mol%) and iPr2NEt (25 mol%) is a suitable catalyst system.16 It was also reported that the combination of InBr3 (15 mol%) and iPr2NEt (20 mol%) is an alternative catalyst system.18 In both cases, however, the combination of a Lewis acid and a tertiary amine was needed. While the reaction also proceeded in the presence of a substoichiometric amount of Et2Zn (20 mol%),18 in all these cases, relatively high loading amounts of Lewis acids (10–20 mol%) and external tertiary amines (20–25 mol%) were required to catalyze the reaction.22 We selected the reaction of nitrone 1a, derived from benzaldehyde and benzylhydroxyamine, with phenylacetylene 2a as a model, and several catalysts were examined (Table 1).
Entry | Catalyst | Yieldb (%) | |
---|---|---|---|
5 mol%, 40 °C (condition A) | 1 mol% 25 °C (condition B) | ||
a The reaction of 1a with 2a was performed for 3 h at 40 °C or 25 °C in THF using the indium catalyst shown in the table following condition A or B. Condition A: 1a (0.50 mmol) and 2a (0.55 mmol) were used in the presence of the indium catalyst (0.025 mmol), and the reaction concentration was 0.2 M. Condition B: 1a (1.0 mmol) and 2a (1.1 mmol) were used in the presence of the indium catalyst (0.010 mmol), and the reaction concentration was 0.4 M.
b Isolated yield.
c NMR yield.
d The In catalyst was prepared in situ by mixing InCl3 and KHMDS (1![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
|||
1 | InCl3 | 0 | — |
2 | In(HMDS)3 | 0 | — |
3 | In(OTf)3 | 0 | — |
4 | In(HMDS)2Cl | 84 | 7 |
5 | In(HMDS)Cl2d | 5 | <5c |
6 | In(HMDS)2OTfe | 88 | 38 (92)i, 35j |
7 | In(HMDS)(OTf)2f | 86 | <5 |
8 | In(TMP)2OTfg | 12 | <5 |
9 | In(OtBu)2OTfh | 0 | — |
10 | In(OiPr)3 | 0 | — |
When 5 mol% of InCl3, In(HMDS)3, or In(OTf)3 was used at 40 °C for 3 h, the reaction did not proceed at all (entries 1–3). On the other hand, in the presence of In(HMDS)2Cl, the reaction proceeded smoothly under identical reaction conditions to give the desired compound in 84% yield (entry 4). We further examined other indium salts. When In(HMDS)Cl2 was used, the product was obtained in 5% yield (entry 5); however, in the presence of In(HMDS)2OTf23 and In(HMDS)(OTf)2, the product yields were 88% and 86%, respectively (entries 6, 7). The use of 2,2,6,6-tetramethylpiperidide (TMP) in place of HMDS (In(TMP)2OTf) gave a 12% yield of the product (entry 8), while the corresponding alkoxide (In(OtBu)2OTf) gave no product (entry 9). In(OiPr)3 was also found to give no product (entry 10). We further examined the catalytic activity of these In(III) Lewis acid–In(III) amide hybrids at a loading of 1 mol% at 25 °C for 3 h (Table 1).
We found that In(HMDS)2OTf showed the highest activity among the hybrids. The order of catalytic activity is as follows: In(HMDS)2OTf > In(HMDS)2Cl ≫ In(HMDS)(OTf)2, In(HMDS)Cl2, In(TMP)2OTf > In(OtBu)2OTf. It is noted that neither the Lewis acid (InCl3, In(OTf)3) nor the metal amide (In(HMDS)3) showed any activity for the reaction, and that only the Lewis acid/metal amide hybrids gave the desired products. Moreover, the order of the catalytic activity among the hybrids is remarkable, and an exquisite balance between Lewis acidity and amide basicity is a key for high catalytic activity.24
Substrate scope of the reaction of nitrones with terminal alkynes using In(HMDS)2OTf as the catalyst was surveyed under the optimized reaction conditions (Fig. 3). In(HMDS)2OTf (1 mol%) worked well with a wide variety of substrates to provide the desired propargyl hydroxylamines. The addition reaction of N-benzylnitrones 1 derived from benzaldehyde derivatives bearing electron-donating substituents (1b–1d) with phenylacetylene 2a proceeded to give the desired adducts (3ba–3da) in good yields. The nitrone bearing electron-withdrawing groups (1e–1h) were more reactive, and high yields were obtained under the same reaction conditions (3ea–3ha). The bulkier nitrones with 1- and 2-naphthyl groups (1i, 1j) were also applicable to the addition reaction (3ia, 3ja), and nitrones prepared from heteroaromatic aldehydes (1k, 1l) gave the desired products (3ka, 3la). The reactions using the nitrones prepared from several primary, secondary, and tertiary aliphatic aldehydes (1m–1p) proceeded smoothly to give the desired adducts in high yields (3ma–3pa). Several terminal alkynes 2 could also be used in this reaction. Phenylacetylene derivatives bearing electron-donating and electron-withdrawing substituents on the phenyl group (2b–2d) gave high yields (3ab–3ad). While a terminal alkyne bearing an alkenyl substituent (2e) was successfully employed in the desired reaction (3ae), alkynes bearing alkyl groups (2f, 2g) and a triethylsilyl group (2h) were less reactive, but high yields were obtained at higher temperature (3af–3ah). The terminal alkyne-bearing oxazolidine moiety (2i) reacted without losing any protecting group (3ai). The p-methoxybenzyl group could also be employed as a protecting group on the nitrogen atom (3qa, 3ra).25
The efficiency of the Lewis acid/metal amide hybrid catalyst was also demonstrated in a gram-scale experiment using 0.1 mol% of the catalyst. In the presence of 0.1 mol% of In(HMDS)2OTf, 1a reacted with 2a in THF at 25 °C for 36 h to give the desired propargyl hydroxylamine 3aa in 90% yield (Fig. 4).
A proposed catalytic cycle of this reaction is shown in Scheme 1. Initially, terminal alkyne 2 is activated by In(HMDS)2X (X = Cl or OTf) to form indium acetylide I. This step was independently confirmed by NMR analysis. It is noted that the Brønsted basicity of In(HMDS)2X enables this process and that this step does not proceed at all using a conventional Lewis acid such as InCl3 and In(OTf)3. Acetylide I then reacts with nitrone 1 to give adduct IIIvia addition step II, in which the Lewis acidity of the indium bearing electron-withdrawing group X is important to activate nitrone 1. Thus, both the Lewis acidity and Brønsted basicity of In(HMDS)2X are crucial for this reaction, and moreover, an exquisite balance between the Lewis acidity and Brønsted basicity of the Lewis acid–metal amide hybrids is also key for this reaction. Finally, adduct III reacts with HN(HMDS)2 to give product 3 along with the regeneration of In(HMDS)2X.26
In addition to being a conceptual advance and having a high catalytic activity, this Lewis acid/metal amide hybrid has another synthetic advantage as a catalyst in tandem-type reactions with other catalysts. In the presence of 5 mol% of In(HMDS)2Cl and 20 mol% of AgOTf, 1a reacted with 2a to give a 4-isoxazoline derivative (4aa) directly in high yield (Fig. 5A).20 Moreover, in the presence of 5 mol% of In(HMDS)2Cl and 20 mol% of CuOTf, 1a reacted with 2a to give an aziridine product (5aa) in high yield (Fig. 5B).21 In these cases, In(HMDS)2X (the Lewis acid/metal amide hybrid) is compatible with Lewis acids such as AgOTf and CuOTf, and the tandem addition/cyclization reactions proceeded smoothly in one pot.27
The concept of a Lewis acid/metal amide hybrid as a catalyst could be expanded to other acid/base catalyses. In preliminary results, In(HMDS)2Cl was found to be effective for the reaction of 2a with aldehyde 7a (Fig. 6A). Moreover, In(HMDS)2F was found to be an effective Lewis acid/metal amide hybrid catalyst for the reactions of 2a with 7b (Fig. 6B) and 2a with 7c (Fig. 6C).
Footnote |
† Electronic supplementary information (ESI) available: NMR study of the In catalyst structure, general experimental procedures, DFT calculations of the LUMO energy levels of the In complexes, and physical data of the products. CCDC 928541. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc01332h |
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