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DOI: 10.1039/C6CC02272C (Communication) Chem. Commun., 2016, 52, 5840-5843

Rhodium-catalyzed chemo- and regioselective decarboxylative addition of β-ketoacids to alkynes†

Changkun Li , Christian P. Grugel and Bernhard Breit *
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany. E-mail: bernhard.breit@chemie.uni-freiburg.de

Received 16th February 2016 , Accepted 24th March 2016

First published on 29th March 2016

Abstract

A highly efficient rhodium-catalyzed chemo- and regioselective addition of β-ketoacids to alkynes is reported. Applying a Rh(I)/(S,S)-DIOP catalyst system, γ,δ-unsaturated ketones were prepared with exclusively branched selectivity under mild conditions. This demonstrates that readily available alkynes can be an alternative entry to allyl electrophiles in transition-metal catalyzed allylic alkylation reactions.

Transition-metal catalyzed allylic substitution reactions (Tsuji–Trost reaction) have proven to be of fundamental importance in the construction of complex target molecules, since they allow the simultaneous construction of new stereocenters and a versatile alkene function enabling further skeleton expanding operations. Numerous useful organic building blocks could be synthesized in a highly chemo-, regio-, diastereo- and enantioselective manner.1 γ,δ-Unsaturated ketones are important intermediates for the synthesis of many biologically active molecules.2 The preparation of this type of compounds can be achieved from thermal Claisen rearrangement of vinyl allyl ethers,3 which are usually not easy to access. Recently, alternative methods based on transition metal catalyzed allylic alkylation chemistry have emerged. Starting with linear or branched allylic electrophiles and enolates, high regio- and enantioselectivities could be obtained under milder conditions (Scheme 1, eqn (1)).4 The careful selection of leaving groups and bases is generally crucial for the outcome of the allylic substitutions, and in this respect different additives have to be used and inorganic salt waste is generated during the course of this process. From the viewpoint of atom economy,5 greener alternatives to allylic substitutions are still very desirable.
image file: c6cc02272c-s1.tif
Scheme 1 Transition-metal-catalyzed construction of γ,δ-unsaturated ketone.

Recently, we reported a series of rhodium-catalyzed addition reactions of several pronucleophiles to allenes, furnishing branched allylic products in an atom-economic manner, which can be regarded as atom-economic alternatives to the allylic substitution.6 Inspired by the biosynthesis of polyketides and fatty acids,7 we developed a decarboxylative addition of β-ketoacids to allenes as an efficient method to construct tertiary and quaternary carbon centers under mild and neutral reaction conditions (Scheme 1, eqn (2)).8 Although allenes are excellent substrates in these reactions, the use of alkynes as alternative substrates is much more attractive because of the ease of availability. Herin, we report a rhodium-catalyzed chemo- and regioselective decarboxylative9 addition of β-ketoacids10 to alkynes (Scheme 1, eqn (3)) furnishing valuable γ,δ-unsaturated ketones.

The conversion of terminal alkynes by rhodium to branched allylic products via an intermediate allene developed in our group usually requires the help of a substoichiometric amount of a carboxylic acid as cocatalyst, to allow the coupling of stronger nucleophiles under acidic condition.11 On the other hand, internal methyl alkynes can be converted to terminal allenes with the help of a metal-hydride.12 Especially for the Pd- and Rh-catalyzed processes reported by Yamamoto and Dong, the presence of carboxylic acids is mandatory.12a–e,i,j We expected that β-ketoacids might be capable of fulfilling two roles. First they may act as carboxylic acids to enable the generation of a metal hydride species that allows the conversion of internal and terminal alkynes to allenes (Scheme 2). Secondly, they may act as a source for carbon nucleophiles, needed for the desired C–C bond formation. The rhodium/diphosphine catalyst would have to be efficient and selective for both of the isomerization and addition steps, suppressing a premature decarboxylative decomposition of the less stable β-ketoacid.


image file: c6cc02272c-s2.tif
Scheme 2 Alkynes as atom-economic allyl source in carbon–carbon bond formation.

We started the investigation with 1-phenyl-1-propyne 1a and benzoylacetic acid 2a as model substrates (Table 1). In the presence of 5.0 mol% of [Rh(cod)Cl]2 and 10.0 mol% DPEphos ligand in dichloroethane at 35 °C, 35% of the desired branched γ,δ-unsaturated ketone 3aa was isolated as the only regioisomer (entry 1). When (S,S)-DIOP13 was used as the ligand, the yield increased to 61% (entry 2). Cooling down to room temperature gave a similar conversion and yield (59%, entry 3). Switching the solvent from dichloroethane to toluene, dramatically increased the yield to 84% (entry 4), probably due to the lower solubility of 2a in less polar toluene, which decreases the rate of premature decarboxylation of β-ketoacid 2a. The same level of reactivity was obtained when both, the catalyst loading (entry 5) as well as the amount of alkyne substrate was lowered (entry 6). Gratifyingly, no decrease of yield was observed when less alkyne was subjected to the reaction (entry 7). Further reactivity assays, applying different ligands to the indicated reaction conditions revealed a high sensitivity concerning the bite angle of the diphosphine ligand. Smaller angled DPPP gave much lower yield of the product (entry 8). Even though a similar backbone was applied, DPPB showed different reactivity (entry 9). Furthermore, when DPPF, which is the best ligand in the reported addition to allenes,8 was used in this reaction, only moderate yield was obtained (39%, entry 10). This results in the assumption, that DPPF is not efficient in the isomerization step in this dual catalysis. To our delight, in all cases the reaction exhibited high chemo- and regioselectivities, without formation of any allyl benzoylacetate and linear γ,δ-unsaturated ketone.

Table 1 Optimization of the reaction conditionsa

image file: c6cc02272c-u1.tif
Entry Ligand Solvent X[thin space (1/6-em)]:[thin space (1/6-em)]Y Yieldd (%)
a 0.5 mmol scale reactions were carried out in 1.0 ml of solvent. b The reaction was carried out at 35 °C. c 5 mol% [Rh(cod)Cl]2 and 10 mol% ligand were used. d Isolated yield.
1b,c DPEphos DCE 2[thin space (1/6-em)]:[thin space (1/6-em)]1 35
2b,c (S,S)-DIOP DCE 2[thin space (1/6-em)]:[thin space (1/6-em)]1 61
3c (S,S)-DIOP DCE 2[thin space (1/6-em)]:[thin space (1/6-em)]1 59
4c (S,S)-DIOP Toluene 2[thin space (1/6-em)]:[thin space (1/6-em)]1 84
5 (S,S)-DIOP Toluene 2[thin space (1/6-em)]:[thin space (1/6-em)]1 81
6 (S,S)-DIOP Toluene 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 83
7 (S,S)-DIOP Toluene 1[thin space (1/6-em)]:[thin space (1/6-em)]1.5 82
8 DPPP Toluene 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 25
9 DPPB Toluene 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 43
10 DPPF Toluene 1.5[thin space (1/6-em)]:[thin space (1/6-em)]1 39

With the optimized conditions in hand, we examined the scope of β-ketoacids in this decarboxylative addition reaction (Table 2). Benchmarking the results with 1-phenyl-1-propyne 1a, a wide range of different functional groups on the acid side are tolerated. Aromatic substituted β-ketoacids bearing electron-donating groups and halogen at ortho- and meta-positions respectively, reacted smoothly in good yields (3ab and 3ac). Bulkier naphthyl and 2-thiophenyl substituents (3ad and 3ae) as well as β-ketoacids bearing primary, secondary and tertiary aliphatic groups also behaved well in this reaction, and afforded the desired products in good yields (3af to 3ah). Even more challenging substrates such as a highly α-acidic benzyl group may be incorporated into the corresponding γ,δ-unsaturated ketones (3ai). Notably, even alkenyl substituents are well-tolerated furnishing α,β- and γ,δ-double unsaturated ketones, being suitable for ring closing metathesis reactions leading to cyclopentenones (3aj).4g,14 A limitation is an alkynyl substitutent adjacent to the ketone function. To our surprise, only trace amount of 3ak was detected, giving rise for the assumption that competing coordination of two different alkynes suppress the reaction.

Table 2 The scope of β-ketoacids in the rhodium-catalyzed decarboxylative addition to alkynesa

image file: c6cc02272c-u2.tif
a 0.5 mmol scale reactions were carried out in 1.0 ml of solvent.
image file: c6cc02272c-u3.tif

Next, we investigated the scope of the alkyne coupling partner (Table 3). Halogenated 1-phenyl-1-propynes 1b to 1d reacted with benzoylacetic acid 2a to afford the corresponding γ,δ-unsaturated ketones 3ba to 3da in high yields. Lower yield was obtained for the iodo-substituted alkyne 1e, perhaps due to the fact that aryl iodide is easier to undergo an oxidative addition with the rhodium catalyst. Electron-donating groups are also tolerated in this reaction (3fa and 3ga), although electron-withdrawing groups seem to accelerate the reaction leading to a higher yield (3ha). meta-Methylphenyl and 2-naphthyl have no influence on the reactivities of the coupling reaction (3ia and 3ja). However, a chloro substituent in ortho-position of the phenyl ring slows down the reaction significantly. To our delight, subjecting 1.0 equiv. of benzoic acid to the reaction was beneficial and resulted in good yields for 3ka. This suggests, that the role of the additional benzoic acid presumably is the acceleration of the alkyne/allene isomerization step. Besides aryl groups, alkenyl substituents (1-cyclohexenyl and cinnamyl) may also be introduced at the β position of the γ,δ-unsaturated ketones (3la and 3ma), although for the latter case, a 1[thin space (1/6-em)]:[thin space (1/6-em)]0.9 mixture of regioisomers could be isolated. The aliphatic15 methyl alkynes are generally less reactive than the aromatic counterparts and extra benzoic acid is necessary to accelerate this isomerization. Benzoyl and p-methoxybenzyl protected hydroxyl function as well as a phthalimide function were installed into the γ,δ-unsaturated ketone in high yields (3na to 3pa).

Table 3 The scope of alkynes in rhodium-catalyzed decarboxylative additionsa

image file: c6cc02272c-u4.tif
a 0.5 mmol scale reactions were carried out in 1.0 ml of solvent. b 1.0 equiv. benzoic acid was added in this reaction. c A 1.0[thin space (1/6-em)]:[thin space (1/6-em)]0.9 mixture of two isomers.
image file: c6cc02272c-u5.tif

To this end the (S,S)-DIOP exhibited the highest reactivity in this rhodium-catalyzed decarboxylative allylation reaction, but the enantioselectivity being rather low.16 Subjecting (R,R)-DTBM-DIOP to the indicated reaction conditions resulted in first promising results to conduct this reaction in an asymmetric fashion, furnishing the desired γ,δ-unsaturated ketone in promising 64% ee.17

In conclusion, we have developed a highly regioselective decarboxylative addition of β-ketoacids to alkynes under very mild reaction conditions employing a commercially available rhodium catalyst, thus extending the rhodium-catalyzed addition of pronucleophiles to a new C–C bond forming reaction. Readily available alkynes were used as an alternative entry to allyl electrophiles, releasing CO2 as the only byproduct, and furnishing valuable γ,δ-unsaturated ketones building blocks. Further efforts on the ligand design and synthesis for an asymmetric version of this reaction as well as the extension to other C–C, C–N, C–S and C–O bond forming reactions are under investigation in our laboratory.

This work was supported by the DFG. C. L. thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship.

Notes and references

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  15. Terminal alkynes were also examined in the decarboxylative carbon–carbon bond formation reaction, though in general, the isomerization reaction starting from terminal alkynes is slower than emanating from the internal methyl alkynes.
    image file: c6cc02272c-u6.tif
    .
  16. The enantioselectivities of 3aa from (S,S)-DIOP were 5–14%.
  17. For more details about the asymmetric catalysis, see ESI†.

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc02272c
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