Synthesis of isochromene derivatives using an intramolecular benzylic C(sp³)–C(sp²) bond forming Heck reaction on vinylogous carbonates

Abstract

An intramolecular, benzylic C(sp³)–C(sp²) bond forming Heck reaction on vinylogous carbonates (or β-alkoxyacrylates) is developed for an efficient synthesis of isochromene derivatives. A competitive Heck reaction between a normal olefin and a vinylogous carbonate moiety led to a dihydronaphthalene product via coupling with olefin exclusively. The method was used in the synthesis of a core of cis-dihydrokalafungin and monocerolide.

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The Heck reaction is a very powerful method for the construction of carbon–carbon bonds. A typical Heck reaction involves Pd(0) catalyzed bond formation between aryl or vinyl halides/pseudohalides with an alkene.¹ The first coupling of methyl acrylate with benzyl chloride was reported by Heck nearly four decades ago.² However, use of benzyl electrophiles as a coupling partner is less explored than their aryl counterparts.³ The problems with benzyl electrophiles as compared to aryl and vinyl electrophiles are slow oxidative addition, slow olefin insertion in a Pd-benzyl bond and formation of mixture of products due to double bond migration.⁴ Further, there are only few examples of the intramolecular version of this reaction.⁵

Isochromene and related moieties like pyranonapthoquinone are commonly found in various biologically active compounds and natural products having pharmaceutical interest (Fig. 1).⁶ As a result, isochromene derivatives have attracted considerable attention from the synthetic community.⁷ Despite various synthetic methods available for the construction of isochromene derivatives, there is still scope for developing new catalytic methods leading to these motifs in an efficient and versatile manner from readily accessible starting materials. In a program directed at synthesis of cyclic ethers using vinylogous carbonates (or β-alkoxyacrylates),⁸ herein we wish to report an efficient approach to the synthesis of isochromenes via a benzylic C(sp³)–C(sp²) bond forming Heck reaction on vinylogous carbonates (or β-alkoxyacrylates).⁹

Fig. 1 Biologically active isochromene and pyranonapthoquinone derivatives.

Utility of this method in the synthesis of the core of cis-dihydrokalafungin and monocerolide is also described.

Our strategy for the synthesis of isochromene relied on the intramolecular benzylic C(sp³)–C(sp²) Heck coupling on vinylogous carbonate (Scheme 1). Towards this end, the known^8a vinylogous carbonate (or β-alkoxyacrylates) 5a was subjected to intramolecular Heck reaction under variety of conditions. The reaction of chloro-vinylogous carbonate (or β-alkoxyacrylates) 5a with Pd(OAc)₂ (10 mol%), PPh₃ (20 mol%) and Et₃N (2 equiv.) in DMF furnished the isochromene derivative 6a in 52% yield, along with acetate 7 as the byproduct in 15% yield. In order to avoid the formation of the acetate byproduct 7, Pd(OAc)₂ was replaced with PdCl₂, but isochromene 6a was obtained in only moderate yield. After some experimentation it was found that reducing the catalyst loading and increasing the amount of base circumvents this problem. Thus, when chloride 5a was subjected to Heck reaction using Pd(OAc)₂ (5 mol%), PPh₃ (10 mol%) and Et₃N (15 equiv.) in DMF as a solvent, isochromene 6a was obtained in 86% as only detectable isomer.

Scheme 1 Heck reaction on vinylogous carbonate (or β-alkoxyacrylates) for synthesis of isochromene.

It is pertinent to mention here that under these conditions, there was complete isomerization of initial Heck product and none of the isochroman derivative 8 could be detected.

The scope of this intramolecular Heck reaction on various vinylogous carbonates (or β-alkoxyacrylates) for the synthesis of various isochromene derivatives was studied next (Scheme 2). Dimethoxy substituted benzyl chloride 5b participated in the intramolecular Heck reaction and furnished the isochromene 6b in good yield. Alkyl substituted isochromenes 6c–e too were formed in good yields and excellent regioselectivities. Benzyl chlorides 5f and 5g having ester functionality underwent Heck reaction and gave isochromenes 6f and 6g in good yields. Aryl substituted chlorides 5i–k were found to be good partners in the reaction and corresponding isochromenes 6i–k were formed, respectively, in excellent yield. Chloro vinylogous carbonate 5l having electron withdrawing nitro group as aryl substituent too participated in Heck reaction smoothly and corresponding isochromene 6l was obtained in good yield. However, when nitrile substituted chloride 5h (R³ = CN) was used, only decomposition was observed.

Scheme 2 Substrate scope for synthesis of isochromenes.^{a,b a}Isolated yield. ^bFor R³ = CN, intractable mixture of products.

In order to further expand the scope, vinylogous esters (or β-alkoxy enones) too were used in this intramolecular Heck reaction (Scheme 3). Interestingly, when the vinylogous ester (or β-alkoxy enone) 9a was subjected to optimized conditions, the isochroman 10a was obtained in moderate yields. On the other hand, the vinylogous ester (or β-alkoxy enones) 9b under similar conditions furnished a 2.5 : 1 mixture of cis-isochroman 10b and isochromene 11b in good yields. In a similar manner, the vinylogous ester 9c gave 2 : 1 mixture of cis-isochroman 10c and isochromene 11c.

Scheme 3 Substrate scope for the synthesis of isochromenes and isochroman.

Formation of the isochroman 10b and 10c is probably the outcome of the conjugate addition (or reductive Heck coupling) reaction being the preferred path for the more electron deficient vinylogous ester (or β-alkoxy enones).¹⁰ On the other hand, in the case of relatively less electron deficient acrylates, typical Heck coupling reaction (involving β-hydride elimination) is favored.

The cis-stereochemistry observed in the isochromans 10b and 10c can be explained based on the transition state structures A and B of the carbopalladation step (Fig. 2). The transition state structure B suffers from 1,3-diaxial-type interaction where as transition state structure A is devoid of any such interaction and hence is more stable. The transition state structure A leads to the oxa-π-allyl intermediate 13, which either undergoes reduction with Et₃N to furnish isochroman 10 or the β-hydride elimination followed by isomerization to give isochromene 6 or 11.

Fig. 2 Mechanistic rationale for the stereoselective formation of isochromans.

At this juncture, we decided to study the reactivity of vinylogous carbonate (or β-alkoxyacrylates) in comparison to olefin in the Heck reaction. Thus, the chloro vinylogous carbonate 5m having allylic group at benzylic position was subjected to the optimized conditions, only olefin underwent Heck reaction and vinylogous carbonate (or β-alkoxyacrylates) remained intact leading to the tetrahydronaphthalene derivative 14 in good yield (Scheme 4). This experiment suggested that the normal olefin undergoes faster carbopalladation as compared to vinylogous carbonate.

Scheme 4 Reactivity study of vinylogous carbonate (or β-alkoxyacrylates) and olefin in the Heck reaction.

Synthesis of isochromene by this strategy involves two steps, namely, formation of vinylogous carbonate (or β-alkoxyacrylates) from the corresponding alcohol and intramolecular Heck reaction on it. It was argued that both these steps could be carried out in a ‘one-pot’ fashion without isolating chloro vinylogous carbonate (or β-alkoxyacrylates). To check this hypothesis, chloro alcohol 15 was subjected to ethyl propiolate addition using N-methyl morpholine (NMM) in Et₃N at room temperature and reaction was monitored by thin layer chromatography (TLC). Once the starting alcohol 15 was consumed; Pd(OAc)₂ (5 mol%) and PPh₃ (10 mol%) were added and heated to 100 °C. It indeed gave the isochromene derivative 6a in good overall yield (Scheme 5).

Scheme 5 One-pot protocol for isochromene synthesis.

Finally, to demonstrate the synthetic utility of the current approach, we turned our attention to the synthesis of core of cis-dihydrokalafungin 2 and monocerolide 3 (Scheme 6). Methyl substituted isochromene derivative 6c was subjected to the hydrogenation to furnish isochroman derivative 16, which is the core of cis-dihydrokalafungin 2, as a single diastereomer in excellent yield. Stereochemistry of isochroman 16 was confirmed using NOESY experiment. The cis stereochemistry of isochroman 16 could be explained based on the delivery of the hydrogen from the least hindered face of the olefin. In another direction, epoxidation of isochromene 6a using m-CPBA followed by tandem epoxide ring opening-reduction–lactonization sequence gave γ-lactone derivative 17 in good yield.¹¹ Further benzylic oxidation of γ-lactone derivative 17 using PCC furnished bis-lactone derivative 18 giving facile entry to monocerolide based natural products.

Scheme 6 Synthesis of core of cis-dihydrokalafungin 2 and monocerolide 3.

Conclusions

In summary, we have disclosed a simple and straightforward synthesis of isochromene using a benzylic C(sp³)–C(sp²) bond forming Heck reaction on vinylogous carbonates (or β-alkoxyacrylates). Normal olefin was found to be more reactive than vinylogous carbonate (or β-alkoxyacrylates) towards this non-trivial Heck reaction. The method was used in the synthesis of core structures of cis-dihydrokalafungin (2) and monocerolide (3). The described strategy should allow for the synthesis of natural products of isochromene and pyranonapthoquinone families.

Acknowledgements

We thank CSIR and DST, New Delhi for financial support. We are grateful to CSIR, New Delhi for the award of research fellowships to YGS and SRBR.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Synthetic procedures and characterization data for all the new compounds. See DOI: 10.1039/c4ra08421g

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