Letter Cite This: Org. Lett. 2017, 19, 6256-6259
pubs.acs.org/OrgLett
Gold(I) Catalyzed Dearomative Claisen Rearrangement of Allyl, Allenyl Methyl, and Propargyl Aryl Ethers Michael T. Peruzzi,† Stephen J. Lee,‡ and Michel R. Gagné*,† †
Caudill Laboratories, Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States ‡ U.S. Army Research Office, P.O. Box 12211, Research Triangle Park, North Carolina 27709, United States S Supporting Information *
ABSTRACT: Claisen rearrangements of allyl aryl ethers to generate enones bearing all carbon quaternary centers are accelerated by Ph3PAuNTf2 under mild conditions in good yields. Multiple C−C bond containing variants of the allyl fragment are viable, including alkylidenecyclopropanes, allenes, and alkynes, which generate all-carbon stereogenic centers substituted with vinyl cyclopropanes, 1,3-butadienyl, and allenyl substituents, respectively, for subsequent synthetic manipulation. With allyl phenyl ethers, the product of the [3,3] rearrangements can be trapped by a tandem [4 + 2] cycloaddition to generate complex molecular scaffolds from readily available, achiral starting materials.
A
Scheme 1. Chemical Strategies for Dearomatizing Phenols
romatic compounds can be functionalized through a broad array of traditional electrophilic or nucleophilic substitution methodologies. In each case, the reactions proceed through transiently generated nonaromatic intermediates. Recent years have brought new methods that permanently break the aromaticity and transform achiral scaffolds into stereochemically and functionally rich building blocks that are simultaneously more reactive for complex molecule synthesis.1−8 The major challenge in developing dearomatization reactions is the accompanying enthalpic penalty for the loss of aromatic stabilization (∼36 kcal/mol for C6H6). Despite this formidable barrier, several successful strategies have emerged, principally relying on stoichiometric strong oxidants such as I(III), F+, and Br+ (Scheme 1A).9−13 Alternative electrophilic sources include inter- and intramolecular Tsuji−Trost type allylations (Pd, Ir catalyzed), most of which take advantage of the πnucleophilicity of transient phenolate or naphtholate ions.14−17 Generally speaking, the extant methods rely on highly reactive reagents to overcome the unfavorable thermodynamics of dearomatization. In contrast, we envisioned a strategy focused on a dearomatizing rearrangement,18,19 which occurs under the kinetic control of an electrophilic metal catalyst.20−31 To compensate for the lack of a high energy reagent (F+, I(III), etc.), our strategy utilizes a strain-releasing functional group migration notion, which we have previously used to enable the first asymmetric Cope rearrangement.32,33 Carbonyl formation helps make the Claisen rearrangement of allyl vinyl ethers favorable (by ∼20 kcal/mol). However, the loss of aromaticity in aryl allyl ether variants penalizes the analogous processes, though this can be overcome by a rearomatizing keto−enol © 2017 American Chemical Society
tautomerization. If the ortho positions are substituted to block rearomatization, then a Claisen rearrangement would yield a dieneone with an all-carbon stereocenter α to the ketone (Scheme 1C). We postulated that electrophilic transition metal catalysts (e.g., Au(I)), known to promote sigmatropic rearrangement of 1,5-dienes,24,34−37 would be capable of harnessing ring strain release38−42 in suitable aryl vinyl ethers to yield uniquely modified and reactive dienones, which are then poised for additional functionalization. We additionally reasoned that the mild, chemoselective nature of soft π-acids such as LAu+43 would be more Received: October 23, 2017 Published: November 7, 2017 6256
DOI: 10.1021/acs.orglett.7b03306 Org. Lett. 2017, 19, 6256−6259
Letter
Organic Letters accommodating to reactive functional groups than methods employing strong oxidants.18,19,23 Since Au(I) catalysts also activate several different types of C−C multiple bonds, it may be possible to migrate (from O to C) multiple groups in the target [3,3] rearrangement.34,44 Cyclogeneration of cationic intermediates followed by Grob-like fragmentation is a hallmark of electrophilic metal catalyzed sigmatropic processes.35,37 Based on the viability of the alkylidene cyclopropane to vinyl cyclopropane in mediating Cope rearrangements, this group was chosen for our first experiments. Compound 1a, synthesized from 2-cyclopropylideneethanol and 1,3-Me2-2naphthol under Mitsunobu conditions (Supporting Information (SI)), was thus used for exploratory studies. Combining 1a with 10 mol % Ph3PAuNTf245 in CD2Cl2 at room temperature provided the dearomatized product 1b in a sluggish reaction as assessed by in situ 1H NMR spectroscopy. Under these conditions significant catalyst decomposition to inactive (Ph3P)2AuNTf2 occurs. A change in solvent to 1,2DCE slowed this decomposition and provided 1b in 75% isolated yield (Table 1). The successful migration of this group installs a synthetically versatile vinyl cyclopropane.46−49 adjacent to an all-carbon quaternary center.
Table 2. C−C Migrations for Allyl 1-Naphthyl Ethers
a c
Isolated yields run in duplicate on 0.1 mmol scale. b10 mol % Au(I). 5 mol % Au(I).
Vinylcyclopropanes,46−49 1,3-dienes, and allenes50,51 have well-developed reactivities to further modify these structures. Since these groups would not be expected to survive the strongly oxidizing conditions of a typical dearomatization procedure, the catalyzed Claisen route is particularly efficacious at yielding products that facilitate rapid gains in complexity. In an analogy to oxidative dearomatization of 1- and 2naphthol derivatives, a single regioisomer of the ene−one product52 was obtained in each case. Hypothesizing that the 2naphthol regioselectivities were caused by the avoidance of an ortho-benzoquinodimethane intermediate (i.e., 12), we tested whether 10 might yield a dearomatized product despite having a potential keto−enol tautomerization route to the most preferred naphthol 13 (Scheme 2). In the event, Ph3PAuNTf2
Table 1. C−C Migrations for Allyl 2-Naphthyl Ethers
Scheme 2. Selectivity for Monosubstituted 2-Naphthyl Ethers
a c
Isolated yields run in duplicate on 0.1 mmol scale. b10 mol % Au(I). 5 mol % Au(I).
We rationalized that other allyl-type motifs might be susceptible to electrophilic activation/migration. The O-allenyl methyl naphthol 2a is well behaved and migrates to forge an allcarbon quaternary 1,3-butadienyl-containing center in good yield (2b). With 5 mol % catalyst, the O-propargyl substrate (3a) was considerably more reactive, and while satisfactory yields could be achieved at −78 °C, more convenient reactions were carried out in toluene at rt where product decomposition was inhibited (71%). The substituted allene 4a smoothly provides 4b as a 1:1 mixture of diastereomers. Allyl naphthyl ether 5a was also a suitable Claisen substrate, yielding the rearrangement product in 67% yield. The baseline naphthol to phenyl ene−one rearrangement itself is therefore sufficiently favorable to proceed without the extra driving force that results from a favorable O- to C-migration. As shown in Table 2, 1naphthol-based substrates also yield the expected products.
a
Free energies relative to 10 (M06-2x, 6-31G*).
(10 mol %) exclusively provides the kinetic product 11 in 53% yield (14% 10 recovered), confirming that allenyl methyl group migration to C3 (to form 12) is highly disfavored.53 Thermolysis of 10 (75% conv., 48 h, 120 °C) similarly provided 11 indicating a generic selectivity. The feasibility of a diverse collection of migrating groups generates multiple options for modifying the dearomatized structures (Scheme 3). As expected, styrenone 2b is a suitable diene for Diels−Alder cycloadditions with, for example, dimethylacetylene dicarboxylate (DMAD). Partial auto-oxidation of the resulting 1,4-cyclohexadiene was avoided by treating 6257
DOI: 10.1021/acs.orglett.7b03306 Org. Lett. 2017, 19, 6256−6259
Letter
Organic Letters
diastereomers at the all-carbon vinyl cyclopropane-containing center. The sequential Claisen/Diels−Alder reaction thus generates five contiguous stereocenters (two all carbon), from achiral, readily available starting materials in a single synthetic operation.57 The rapid buildup of molecular complexity is a hallmark of a powerful dearomatization strategy. Based on previous experimental and computational studies, our working hypothesis for the reaction mechanism revolves around a stepwise π-activation of the allyl or allyl like fragment and intramolecular 6-endo trig (or dig) arene addition, followed by Grob-like fragmentation to form product and return the catalyst (Scheme 5).37 An ordered chairlike transition state bodes well for future efforts in asymmetric catalysis.58,59
Scheme 3. Example of Styrenone Derivatization Schemes
Scheme 5. Proposed Mechanism for the Au(I)-Catalyzed Aromatic Claisen Rearrangement the Claisen solution with DDQ to give the net-arylated styrenone 14 in 93% yield (Scheme 3A). Compound 3b can be diastereoselectively reduced to 15 with good diastereoselectivity (13:1) and in excellent yield (92%); bulky borohydrides at reduced temperatures deliver hydride from the same face as the smaller allene group (A-value = 1.5 kcal/mol vs 1.9 for Me)54,55(Scheme 3B). Lastly, the hydration of allene 8b is also well behaved and provides a good yield of the methyl ketone (70%) using 5 mol % (IPr)AuOTf (Scheme 3C). Interestingly, the hydration regioselectivity was opposite that found by Weidenhoefer et al., where allylic alcohols were preferred.50,56 The resulting 1,4-dione also has many avenues available for product diversification. As with the naphthol-based substrates, we initiated these studies with an alkylidene cyclopropane to vinyl cyclopropane rearrangement, which should help the thermodynamics of the reaction. Treating 17 with Ph3PAuNTf2 generates, by NMR spectroscopy, a steady state amount of a species consistent with 18, but all attempts to isolate this compound were unsuccessful. Extended reaction times lead to the eventual formation of phenol 19 (∼32% after 24 h), the apparent product of a [2,3] rearrangement from 18. Catalyst deactivation was problematic during these long reactions; the Ph2P(o-biphenyl)-based analog by contrast was similarly reactive but much more stable to decomposition. Since 18 was susceptible to decomposition, the Claisen reaction was repeated in the presence of a dieneophile trap to provide the extra driving force needed to complete the dearomatization. As shown in Scheme 4, this proved effective, giving a modest yield of the bicyclo 20 as a 5:1 mixture of
In summary, we have developed a framework for a catalyst controlled, dearomative Claisen rearrangement that migrates and transposes a variety of O-allyl-type fragments to substituted ortho positions to forge all-carbon containing stereocenters substituted with synthetically versatile groups (1,3-diene, allene, vinyl cyclopropane). The π-acid Ph3PAuNTf2 is a capable kinetic trigger for the [3,3] reaction and is tolerant of reactive fragments in both the starting material and the product. In a proof-of-principle experiment, a phenyl-based substrate could also be productively dearomatized, provided that a subsequent process can provide an extra driving force to siphon off the ene−one product.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03306. Experimental conditions, characterization data, and calculations (PDF)
Scheme 4. Dearomatization of Phenol-Based Systems
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Michel R. Gagné: 0000-0001-8424-5547 Notes
The authors declare no competing financial interest. 6258
DOI: 10.1021/acs.orglett.7b03306 Org. Lett. 2017, 19, 6256−6259
Letter
Organic Letters
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ACKNOWLEDGMENTS We thank the Army Research Office (ARO) for support (W911NF-15-2-0119). Research reported in this publication was supported in part with funding by the University of North Carolina’s School of Medicine Office of Research. We thank the University of North Carolina’s Department of Chemistry Mass Spectrometry Core Laboratory and Dr. Brandie Ehrmann for assistance with mass spectrometry analysis.
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DOI: 10.1021/acs.orglett.7b03306 Org. Lett. 2017, 19, 6256−6259
