Gold(I) catalyzed [1,3] O → C rearrangement of benzylvinyl ethers

Abstract

A simple procedure for the preparation of 3-(hetero)arylpropionaldehydes has been developed employing a gold-catalyzed [1,3]-rearrangement of vinyl ethers. Using this protocol, Canthoxal, an aromatic aldehyde used in perfumery, has been prepared on a gram scale.

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Gold catalysis has received significant attention over the past decade and many novel and efficient methodologies have been developed.¹ Generally, gold complexes act as tunable soft π-acids.² In particular, the selective activation of alkynes^3a and allenes^3b by gold-complexes, followed by the subsequent inter and intramolecular nucleophilic additions and [3,3]-sigmatropic rearrangements (such as Claisen and Cope rearrangements), has received substantial attention.³ Recently, we reported a gold(I) catalyzed [1,3] O → C rearrangement of allenyl ethers leading to α-substituted acryl aldehydes.^4–6 We have proposed a mechanism that proceeds via the initial coordination of the Au-center with the oxygen of the allenyl ether resulting in elongation of the carbinol C–O bond and, if the pendant substituent of the oxygen is sufficiently electrophilic, the cleavage of the carbinol C–O bond, leading to the formation of a contact-ion pair that subsequently undergoes the [1,3]-rearrangement.^6,7 Extending this concept, we were interested in exploring the [1,3]-rearrangement reaction of vinyl ethers to understand the mechanism in general and especially in the context of the synthesis of the fragrance ingredient Canthoxal and related 3-arylpriopionaldehydes.⁸ The generally adopted approaches for the synthesis of Canthoxal include mainly either Pd-based coupling of 4-haloanisole or hydroformylation of 4-allylanisole and subsequent functional group modifications.^9–11 Recently, Nagashima and co-workers revealed the [1,3] O → C rearrangement as a possible alternative while studying the Ru-catalyzed cationic polymerization of vinyl ethers, albeit, in moderate yield (Fig. 1).¹²

Fig. 1 Selected [1,3] O → C rearrangements.

To start in this direction, as a preliminary experiment, we have synthesized a set of three vinyl ethers of alkyl 1a, benzyl 1b and 4-methoxybenzyl 1c groups from the corresponding allyl derivatives by treating with KO^tBu in DMSO for 15 min [ESI†].¹³

All these vinyl ethers are screened for the initial optimization with Au(PPh₃)Cl alone and in combination with several silver salts like AgNTf₂, AgOTf, AgSbF₆, AgOAc and AgBF₄ in different concentrations from 1 mol% to 0.1 mol%. Several gold complexes are also screened for this purpose at different temperatures from 0 °C to rt [ESI†]. After extensive optimization studies, 0.1 mol% Au(PPh₃)Cl in combination with 0.3 mol% AgSbF₆ has been identified as the catalyst of choice and only the rearrangement of 4-methoxybenzylvinyl ether 1c to the corresponding α-methylated aldehyde 2c was observed in 5 min at 0 °C with 92% isolated yield (Table 1). Whereas with the other two vinyl ethers having alkyl 1a and benzyl 1b groups, hydrolysis was the major event. This revealed that, analogous to allenyl ethers, the reaction progress with vinyl ethers was also significantly affected by the stability of the in situ generated benzylic carbocation and the basicity/coordinating ability of the counter anion.⁶

Table 1 Optimization of the catalytic conditions

S. no.	Substrate	Catalyst	Additive	Yield %
1–3	1a or 1b or 1c	Au(PPh3)Cl	—	No reaction
4–5	1a or 1b	Au(PPh3)Cl	AgSbF6	Hydrolysis
6	1c	Au(PPh3)Cl	AgSbF6	92
7–9	1a or 1b or 1c	—	AgSbF6	Hydrolysis

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With the optimal catalytic conditions in hand, the scope of the rearrangement was investigated employing a wide range of vinyl ethers. The 4-methoxybenzylvinyl ethers having methyl 1d and n-butyl 1e substitution at the benzylic position delivered the corresponding aldehydes 2d and 2e in 87% and 86% yield, respectively, as 1 : 1 diastereomeric mixtures (Scheme 1).

Scheme 1 Substrate scope for the gold(I) catalyzed [1,3] O → C rearrangement. Crude vinyl ethers resulting from KO^tBu mediated olefin-migration of the corresponding allyl ethers have been used directly for the [1,3]-rearrangement. Selected vinyl ethers were purified and characterized (see the ESI†).

A similar trend has been noticed in the case of 2,4-dimethoxy and 3,4-dimethoxybenzyl derived vinyl ethers 1f–1l and the corresponding [1,3] O → C rearranged products 2f–2l were procured in excellent yield. Not only the benzylvinyl ethers, but some of the heteroarylmethylvinyl ethers are also facile for this rearrangement purpose. The rearrangement was successfully achieved by the benzofuran derived vinyl ethers 1m–1p and afforded the α-substituted aldehydes 2m–2p in good yield (86–91%). The vinyl ethers 1m and 1o afforded a 1 : 1 diastereomeric mixture of aldehydes 2m (89%) and 2o (88%). On the other hand, the vinyl ethers 1n and 1p gave the substituted C2-homologated benzofuran aldehydes 2n and 2p in 91% and 86%, respectively. Gratifyingly, the benzothiophene derived vinyl ether 1q, having the methyl- substitution at the benzylic position gave a 1 : 1 diastereomeric mixture of the rearranged product 2q in 89% yield and 1r with gem-dimethyl substitution at the benzylic position delivered 2r in 93% yield. The rearrangement was quite clean with the furyl-derived vinyl ether 1s and the C2-homologated aldehyde 2s was obtained in 90% yield.

Coming to the mechanism, in the case of the [1,3] O → C rearrangement of allenyl ethers, with the help of trapping experiments with O-nucleophiles, we have proposed a reaction path comprising an initial gold(I) complexation with the oxygen lone pair that results in the cleavage of the C–O bond with the simultaneous formation of a contact ion pair intermediate depending upon the stability of the benzylic cation.¹⁴ If the resulting contact ion pair is sufficiently stable, the subsequent alkylation of the benzylic cation with gold enolate results in the formation of a new C–C bond with a net [1,3] O → C rearrangement of the allenyl ether unit.^6,15a A similar mechanism is apparent in the present case of vinyl ethers rearrangement (Fig. 2).

Fig. 2 Plausible mechanistic pathway for the gold(I)-catalyzed [1,3] O → C rearrangement.

At this point, in search of conclusive proof for the nature of the contact ion-pair intermediate [either tight contact ion-pair or dispersed in the solvent media] involved in the rearrangement, the following two crossover experiments have been conducted. An equimolar mixture of 4-methoxybenzylallenyl ether 3 and vinyl ether 1f or 1g was subjected to the gold-catalyzed rearrangement at 0 °C for 30 min (Scheme 2). In general, the rearrangement of allenyl ether 3 was facile even with 0.05 mol% catalyst (half of what vinyl ethers need). On the other hand, the hydrolysis of vinyl ethers 1f/1g and the stability of the resulting counter cations are better than that of the PMB group present in the allenyl ether 3. Hence, if the 1,3-rearrangement of these substrates is proceeding via a solvent-dispersed contact ion-pair, the scrambling of these counter cations is expected and thus, a mixture with 4 products is expected. Whereas, if the reaction proceeds through a tight-contact pair, only two separate products are expected without any scrambling. In the case of the reaction employing a mixture of 4-methoxybenzylallenyl ether 3 and vinyl ether 1f, only the rearranged products 4 and 2f were noticed in the LCMS analysis. A similar trend has been noticed in the case of the LCMS analysis of the second cross-over experiment employing a 1 : 1 mixture of 4 and 2g. Thus, these experiments provided a clear evidence of the involvement of a tight contact ion-pair intermediate in these gold-catalyzed [1,3] O → C rearrangements and thus ruled out an operative ion-pairing effect.

Scheme 2 Crossover experiments for the mechanistic support.

Conclusions

In conclusion, gold(I) catalyzed [1,3] O → C rearrangement of benzylvinyl ethers has been developed as a practical method for the preparation of 2-methyl-3-(hetero)arylpropionaldehydes. The rearrangement is facile with the substrates having the benzylic aryl ring substituted with +M groups. The crossover experiments between vinyl- and allenyl ethers provided indirect evidence for the involvement of a tight contact ion-pair intermediate in the reaction path. As an off-shoot, a gram-scale process was established for the synthesis of the fragrance ingredient Canthoxal.

Acknowledgements

We thank the CSIR for funding this project under the 12 FYP NICE Program (CSC0109) and for a research fellowship to CNK.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00397k

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