A mild method for eliminating alkyl ethers to alkenes

Abstract

A method for the conversion of methyl ethers into alkenes is described. In a one-step and mild procedure, both conjugated and isolated cyclic alkenes are accessible in mostly good yields using triflic anhydride in combination with triethylamine. This elimination procedure can also be applied to ethyl and benzyl ethers.

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The creation of double bonds is a chemical transformation which is often required in organic syntheses. Due to the fact that alkyl ethers and especially methyl ethers are easily accessible and therefore frequently used as protecting groups in these syntheses, their elimination is an attractive method for the formation of alkenes.

In general, conversion of alkyl ethers to alkenes is accomplished in two steps – ether cleavage to the corresponding alcohol¹ or bromide² followed by elimination. To date, many procedures have been described for the dehydration of alcohols, most of which include in situ transformations into suitable leaving groups. Among them ester pyrolysis,³ the Chugaev elimination,⁴ Monson's method,⁵ and the use of methyl N-(triethylammoniumsulfonyl)carbamate, also known as Burgess reagent.^6,7 However, only a few individual examples for the direct elimination of alkyl ethers have been described so far. For instance, the elimination of steroid methyl ethers by using BF₃-etherate or chlorotrimethylsilane in combination with acetic anhydride.^8,9 Besides, elimination products are frequently observed (mostly as side products) when alkyl ethers are treated with strong Lewis acids.¹⁰

Nevertheless, to the best of our knowledge, there is no general method available for the mild elimination of alkyl ethers, yet.¹¹ Herein we present a mild and effective one-step procedure for the direct conversion of aliphatic alkyl and particularly methyl ethers into alkenes.

In the initial experiment we intended to convert the hydroxyl function of phenol 1¹² into the triflate using triflic anhydride (1.5 equiv.) along with triethylamine (1.5 equiv.) in dichloromethane at 0 °C. Surprisingly, we also observed the elimination of the methoxy group yielding xanthene 2 in 82% (Scheme 1).

Scheme 1 Initial experiment: conversion of alcohol 1 into triflate 2 accompanied by the elimination of the methyl ether.

While the conversion of alcohols into the corresponding triflates followed by an elimination step is already known under the applied conditions,¹³ it has never been used for the in situ synthesis of alkenes from methyl ethers before. Therefore we started further investigations towards a general one-step elimination protocol allowing the synthesis of different alkenes. Surprisingly, the elimination reaction did not occur using N-phenyl-bis(trifluoromethanesulfonimide) as triflating reagent instead of triflic anhydride and the application of triflic acid resulted in an unidentifiable fluorescing mixture. Besides, when only one reagent, either NEt₃ or Tf₂O, was used, no reaction occurred or decomposition was observed, respectively. Furthermore, changing the solvent from dichloromethane to tetrahydrofuran led to poorer yield (61%). Further investigations were implemented on the related substrate 3-OMe, in which only the elimination can take place (Table 1).

Table 1 Optimisation of the reaction conditions

Entry	Reagents (1.50 equiv.)	Temperature/reaction time	Yield
1	NEt3, Tf2O	0 °C, 1.5 h	84
2	DIPEA, Tf2O	0 °C, 1.5 h	79
3	N,N-Dimethyl-1-phenylethylamine, Tf2O	0 °C, 1.5 h	38
4	NEt3, MsCl	Reflux, 5 h, then r.t., 7 days	49

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If Tf₂O and NEt₃ were used as reagents, xanthene 4 could also be isolated in excellent yield (84%). We also explored the replacement of NEt₃ by other tertiary amine bases like DIPEA (entry 2) or N,N-dimethyl-1-phenylethylamine (entry 3). However, in both cases the yields decreased to 79% and 38%, respectively. Moreover, using mesyl chloride instead of triflic anhydride greatly decelerated the elimination. Thus, a reaction could neither be detected after stirring the mixture at 0 °C for 2 h nor after refluxing for 5 h. Further stirring the reaction mixture for 7 days at room temperature led to the desired xanthene 4 in poorer yield (entry 4). Therefore Tf₂O and NEt₃ proved to be the best combination for the elimination of methyl ethers.

With our reaction conditions in hand, we first tested the elimination reaction on the methoxy tetrahydronaphthalenes 5a and 5b (Table 2, entry 1 and 2), both resulting in the same binaphthalene 6.

Table 2 Scope of the alkyl ether elimination reaction

Entry	Substrate	Product	Equiv. of the reagents (Tf2O and NEt3)	Temperature/reaction time	Yield^a [%]
a Isolated yields.b Yield of the side product 8b in parenthesis.c Ratio of 8a : 8b (determined by ^1H NMR) in parenthesis.d Starting material 9 was used as a mixture of isomers (cis/trans = 1 : 2.5); ratio of reisolated starting material (cis/trans = 1 : 1) showed, that only the trans-isomer had reacted.
1			1.5	0 °C, 1.5 h	73
2			1.5	0 °C, 1.5 h to r.t., 4 h	29
3a			1.5	0 °C, 1.5 h	61 (1)^b
3b			3.0	0 °C, 1.5 h	71 (2)^b
3c			1.5	r.t., 1.5 h	71 (3)^b
4a			1.5	0 °C, 1.5 h	Only traces
4b			3.0	0 °C, 1.5 h to r.t., 1 day	78 (3/1)^c
5			1.5	0 °C, 2 h	58
6			1.5	0 °C, 1.5 h to r.t., 3 days	47 (1.5/1)^c
7			1.5	0 °C, 1.5 h	27
8			1.5	0 °C, 1.5 h to r.t., 3 days	15 (1.9/1)^c
9			1.5	0 °C, 1.5 h	20
			3.0	0 °C, 1.5 h	35 (73 brsm)^d

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Due to the fact that the two substrates, 5a and 5b, led to exactly the same product, the reactions proceed in all likelihood via intermediary occurring 1,2-dihydronaphthalene, which subsequently dimerises under the reaction conditions to the binaphthalene 6, as already reported.^14–16 Thus, the elimination reaction primarily gave the desired elimination product in acceptable yields.

Knowing that the method is efficient in eliminating methoxy groups, resulting in a conjugated π-system, we proceeded to investigate systems leading to isolated double bonds (entry 3 and 4). The conversion of trans-(4-methoxycyclohexyl)benzene (7a-OMe) afforded the alkene 8a in good yield, which could be improved by increasing the equivalents of both reagents (entry 3b) or applying higher reaction temperatures (entry 3c). In addition, isomer 8b was obtained as a side product (<3%), giving indications on the mechanism. Unexpectedly almost no reaction occurred in case of the cis-isomer 7b under the same conditions (entry 4a), but the products 8a and 8b could still be obtained by increasing the amount of the reagents, higher temperature and longer reaction time (entry 4b). In addition, the described method could be successfully used for the elimination of the open-chain substrate (3-methoxybutyl)benzene, but resulted in an inseparable mixture of probably five isomers (according to GC-MS) in moderate yield (37%, see ESI†).

In order to determine whether this reaction is capable of eliminating ethyl and benzyl ethers, we tested the reaction conditions starting from ethyl ethers 3-OEt and 7a-OEt as well as from benzyl ethers 3-OBn and 7a-OBn, respectively (entry 5–8). To our delight both substrates could be converted into the corresponding alkenes. However, full conversion required longer reaction times and sometimes higher temperatures and resulted in poorer yields. Thus, we tested whether methyl ethers can be eliminated selectively in presence of benzyl ethers using test substrate 9 (entry 9). The methyl ether could be converted into the alkene 10 without affecting the benzyl ether function, proofing that under mild conditions the elimination of methyl ethers is selective.

Based on the fact that only the trans-isomer 7a-OMe reacted, as well as the occurrence of the migrated double bond (8b), we propose an E1 mechanism, which is depicted in Scheme 2, using the example of the conversion of methyl ether 7a-OMe. According to this mechanism, initially the methoxy group is triflated leading to the oxonium species 11. We assume that due to steric reasons the generation of the intermediate 11 is preferred when the methoxy group is in equatorial position of the cyclohexane chair. As a consequence of the phenyl substituent acting as an anchor group, the cyclohexane conformation with the phenyl substituent being in equatorial position is favored. Thus the 4-methoxy group is in the equatorial position only in case of the trans-isomer 7a-OMe. Elimination of methyl trifluoromethanesulfonate¹⁷ results in the carbocation 12a which is able to react via a Wagner–Meerwein rearrangement yielding carbenium ion 12b. Ensuing base-induced deprotonation gives the final elimination products 8a and 8b, respectively.

Scheme 2 Proposed mechanism for the elimination reaction using the example of methyl ether 7a-OMe.

Conclusions

In summary, we report that methyl ethers can be easily converted into alkenes by using triflic anhydride in combination with a tertiary amine base. The described method can also be applied for the synthesis of alkenes starting from ethyl and benzyl ethers.

Acknowledgements

We gratefully acknowledge the Landesgraduiertenförderung Baden-Württemberg for funding. We thank Danny Wagner for technical assistance.

Notes and references

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10. For an example see: P. D. Woodgate, S. J. Janssen, P. S. Rutledge, S. D. Woodgate and R. C. Cambie, Synthesis, 1984, 1984, 1017–1020.
11. We were not able to find a related report in the literature. In addition, this reaction has not been mentioned in the comprehensive review about Tf₂O: I. L. Baraznenok, V. G. Nenajdenko and E. S. Balenkova, Tetrahedron, 2000, 56, 3077–3119.
12. All starting materials and products are racemates.
13. X. Wang, Y. Chen, R. Crockett, J. Briones, T. Yan, C. Orihuela, B. Zhi and J. Ng, Tetrahedron Lett., 2004, 45, 8355–8358.
14. T. K. Dobbs, D. V. Hertzler, G. W. Keen, E. J. Eisenbraun, R. Fink, M. B. Hossain and D. Van der Helm, J. Org. Chem., 1980, 45, 4769–4774.
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16. H. Wehage, H. Hintze and A. Heesing, Chem. Ber., 1989, 122, 1919–1924.
17. Methyl triflate is toxic, but highly water sensitive, therefore we suggest a thorough quench of the reaction mixture with water.

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Footnote

† Electronic supplementary information (ESI) available: Full characterisation and spectroscopic data is available. See DOI: 10.1039/c4ra03785e

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