Gallium-catalyzed reductive lactonization of γ-keto acids with a hydrosilane

Abstract

Described herein is the GaCl₃-catalyzed lactonization of γ-keto carboxylic acids in the presence of PhSiH₃ leading to the direct preparation of γ-lactone derivatives. This reducing system showed a relatively wide functional group tolerance.

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Since γ-lactone derivatives constitute a central and ubiquitous structure in valuable natural products and biologically active substances, the development of a facile approach to these skeletons has attracted the interest of a number of organic, pharmaceutical and material chemists.¹ Thus far, a typical approach to the γ-lactone skeleton has been generally achieved through cyclization of a carboxylic acid bonding an alcohol moiety (γ-hydroxy acid) in the presence of a variety of condensation reagents.² Also, the lactonization of ω-hydroxy acid by a sole metal triflate, Hf(OTf)₄, has been reported.³ Moreover, a cyclization of 1,4- or 1,5-keto alcohols using a Noyori hydrogen transfer catalyst led to the asymmetrical synthesis of γ-lactone.⁴

On the other hand, as a recent interesting extension, the preparation of a γ-lactone skeleton through a reductive lactonization from a biomass-derived γ-keto carboxylic acid, such as levulinic acid (LA), to γ-valerolactone (GVL), has been disclosed gradually. For example, as with cases involving a homogenous metal catalyst, a RuCl₃–PPh₃ system⁵ or a Ru(acac)₃ complex,⁶ the Shvo complex,⁷ and an iridium pincer complex⁸ with an additive, these have efficiently reduced LA to GVL in the presence of H₂ or HCO₂H as a reducing reagent (eqn (a) in Scheme 1). Also, the same transformation with heterogeneous complexes such as Ni, RANEY® Ni, Cu, Ru, and Pd supported on either activated carbon, SiO₂, or Al₂O₃, under hydrogen gas has been developed (eqn (b) in Scheme 1).⁹ Moreover, as an alternative reducing reagent, the use of easily-handled hydrosilanes has been reported. For example, Doyle¹⁰ and Rovis¹¹ disclosed that a cyclic γ-keto acid embedded in a ring structure was treated with trifluoroacetic acid (TFA)–Et₃SiH or TFA–PhMe₂SiH to form a trisubstituted γ-lactone (eqn (c) in Scheme 1). Although the reductive cyclization of a γ-keto carboxylic acid derivative with a Lewis acid, BF₃ and Et₃SiH was reported by Nordlander and co-workers, the example reported in this paper is the only one example of its kind, and a systematic investigation has not yet been conducted.¹² In addition, as an example of a two-step transformation, the combination of an initial reduction of 3-benzoylpropanoic acid by either a chiral borane¹³ or ZnCl₂–ⁱBu₂AlH¹⁴ and subsequent cyclization with TFA led to the corresponding γ-lactone.

Scheme 1 Diverse approaches to γ-lactones from γ-keto acids.

In this context, we reported the indium-catalyzed annulation of LA with aromatic/aliphatic amines in the presence of PhSiH₃ leading to the preparation of γ-lactam derivatives,¹⁵ and found that a GaCl₃–TMDS (1,1,3,3-tetrahydrosiloxane)–CuCl₂ system undertook the reductive chlorination of carboxylic acids.¹⁶ We report herein a gallium(III)-catalyzed reductive cyclization of γ-keto carboxylic acids with PhSiH₃ smoothly leading to γ-lactone derivatives (eqn (d) in Scheme 1). This procedure using the novel association of a metallic Lewis acid, GaCl₃, and a hydrosilane, PhSiH₃, presents a new entry to a lactone skeleton from a keto carboxylic acid.¹⁷

To achieve this concept, the reaction conditions were initially examined (Table 1). On the basis of our previous results,¹⁵ when keto acid 1a was treated with In(OAc)₃ (5 mol%) in the presence of PhSiH₃ (3 equiv.) in toluene at 80 °C, the reductive cyclization slightly proceeded to produce 4-phenyl-γ-butyrolactone (2a) in a 23% yield (entry 1). Thus, although the effect of a counter anion on the indium compound was examined, a remarkable improvement in the product yield was not observed (entries 2–5). Interestingly, GaCl₃, instead of an indium compound, efficiently catalyzed the reductive cyclization (entry 6). On the other hand, other Lewis acids, such as AlCl₃, ZnCl₂, and BiCl₃, did not show an effect for this cyclization (entries 7–9). Thus, with a gallium halide in hand, when several examinations for solvents and temperatures were performed,¹⁸ the heating conditions at 60 °C in the presence of GaCl₃ showed the best results (entries 10 and 11). Also, the use of a stronger Lewis acid, GaBr₃ and GaI₃, than GaCl₃ caused a decrease in the chemical yield (entries 12 and 13).

Table 1 Examinations of reaction conditions

Entry	Cat.	Solvent	Temp^a (°C)	Yield^b (%)
a Bath temperature.b NMR (isolated) yield.
1	In(OAc)3	Toluene	80	23
2	In(OTf)3	Toluene	80	28
3	InI3	Toluene	80	31
4	InBr3	Toluene	80	20
5	InCl3	Toluene	80	34
6	GaCl3	Toluene	80	59
7	AlCl3	Toluene	80	0
8	ZnCl2	Toluene	80	0
9	BiCl3	Toluene	80	0
10	GaCl3	Benzene	80	82
11	GaCl3	Benzene	60	99 (94)
12	GaBr3	Benzene	60	74
13	GaI3	Benzene	60	69

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Then, the effect of an aryl group on the keto acid was examined under the optimal conditions (Table 2). Regardless of location and number, the cases with a methyl-substituted aryl group gave lactones 2b–f in relatively good yields. In contrast, keto acid 1g having a para-MeO group did not cyclize, and instead, led to a formation (21%) of the carboxylic acid derivative 2g′, the ketone moiety of which was reduced. This may be due to the fact that the indium compound would prefer to activate the methoxy group than the carbonyl moiety. Also, this result is not in complete agreement with the result shown by Nordlander et al., in which the TFA–Et₃SiH system selectively reduced only the ketone moiety of the keto acid.¹²

Table 2 Scope of an aryl group in keto acids 1

Entry	Product			Yield^a (%)
a Isolated yield.b Reaction time = 7 d.
1		2b (o-Me)		86
2		2c (m-Me)		95
3		2d (p-Me)		90
4		2e		78
5		2f		97
6		2g		0
		2g′		21
7		2h		72
		2h′		4
8		2i		84
9		2j (X = F)		76^b
10		2k (X = Cl)		63^b
11		2l (X = Br)		67^b
12		2m		63
13		2n		72
14		2o		78
15		2p		0

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In contrast, the substrate having a para-PhO group afforded the corresponding lactone 2h in a 72% yield with a by-product, the carboxylic acid 2h′ (4%). Moreover, the keto acid with a meta-MeO group successfully produced lactone 2i in a good yield. Keto acids with a halogen substituent also gave the corresponding lactones 2j–2l in relatively good yields, but a quite longer reaction time (>7 days) was required to complete the cyclization. Consequently, a typical halogen atom in the aromatic ring shows a tolerance to the reducing system. On the other hand, the substrates with a CF₃, a biphenyl, and a 1-naphthyl group were mostly complete after 24 h, affording lactones 2m–2o in 63, 72, and 78% yields. Unfortunately, instead of a benzene ring, the keto acid with a thiophene ring did not produce the expected lactone.

As an extension, the present reducing procedure was applied to the lactonization of various γ-keto acids. For example, when keto acid 3 with an alkyl ketone moiety was treated with the optimal conditions, the expected cyclization proceeded cleanly to produce γ-phenethyl-substituted lactone 4 in a nearly quantitative yield (eqn (a) in Scheme 2). Then, when the cyclization was attempted with 2-benzoylbenzoic acid (5), 3-phenylphthalide (6) was obtained in a 50% isolated yield (eqn (b) in Scheme 2). To expand the ring size of the lactone skeleton, the similar lactonization with δ-keto carboxylic acids 7 was examined with the above optimal conditions. However, contrary to our expectation, the lactonization did not proceed cleanly, and, instead, the result was the production of carboxylic acid 8 with a trans-alkene portion (J = 16 Hz) in a low yield (eqn (c) in Scheme 2) and a complex mixture. Thus, when the same reaction was treated with Et₃SiH, the formation of δ-lactone 9 was isolated in a rather low yield, and an over-reduced 2-phenyltetrahydropyran (9′) was obtained in a 59% NMR yield as a major product (eqn (d) in Scheme 2). Although there is no clear reason for the over-reduction at this stage,¹⁹ the reducing system could be applied to the 6-membered lactone construction.

Scheme 2 Extension to various γ-keto carboxylic acids.

Scheme 3 shows a plausible mechanism for the reductive lactonization from keto acids. As an initial step, the formation of silyl ester A via dehydrogenation between a carboxylic acid moiety activated by the indium catalyst and a hydrosilane occurred.²⁰ The second step is the hydrosilylation of the ketone moiety of the intermediate A to produce the anticipative intermediate B (or C). Subsequent intramolecular cyclization of the intermediate finally leads to the production of the expected γ-lactone.²¹ In the cases with a strong electro-donating group, such as a 4-MeO or a 4-PhO substituent, on the aryl group, it seems that an electron-donating effect of these groups would promote the facile release of the silyl ether moiety activated by the gallium catalyst on B, and then the benzyl position was again reduced to produce the corresponding carboxylic acid.

Scheme 3 Plausible mechanism for the lactonization.

We have developed a novel gallium(III)-catalyzed lactonization of γ-keto acids in the presence of PhSiH₃, which led to the production of γ-lactone derivatives with a variety of substituents, and showed that unlike a GaBr₃–TMDS reducing system^17a and an In(III)–hydrosilane reducing system,²² this reducing system involving GaCl₃ and PhSiH₃ in benzene retained the formed ester moiety. The present lactonization cleanly proceeds under relatively mild and neutral conditions.

Acknowledgements

This work was partially supported by JSPS KAKENHI Grant Number JP25410120. We deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of hydrosilanes.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Spectral data and ¹H- and ¹³C-NMR charts of γ-lactones prepared by the present method. See DOI: 10.1039/c6ra19286f

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