Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Strain-Activated Diels−Alder Trapping of 1,2-Cyclohexadienes: Intramolecular Capture by Pendent Furans Verner A. Lofstrand,† Kyle C. McIntosh,† Yaseen A. Almehmadi, and F. G. West* Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, Alberta T6G 2G2, Canada
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ABSTRACT: Intramolecular [4 + 2] cycloaddition reactions of substituted 1,2-cyclohexadienes with pendent furans enables the synthesis of complex tetracyclic scaffolds in a single step under mild conditions. All Diels−Alder cycloadducts were obtained as single diastereomers, assigned as the endo isomer. Substrates were easily assembled via Stork−Danheiser alkylation of 3-ethoxy-2-bromocyclohex2-enone to accommodate a range of tethers and furan traps. Cleavage of enol acetate moieties resulted in room-temperature Diels−Alder cycloreversion to tethered furyl cyclohexenones.
D
Scheme 1. Intermolecular (a) vs Intramolecular (b; This Work) Diels−Alder Trapping of Cyclic Allenes
iels−Alder cycloadditions involving furans as 1,3-diene partners provide access to synthetically versatile oxabicycloheptene scaffolds but are complicated by the energetic costs of breaking aromaticity, which require heating or Lewis acid activation of the dienophile.1 Intramolecular Diels−Alder cycloadditions of furans (IMDAF) have been studied extensively and applied to a number of natural products targets.2 A further challenge is the potential for retrograde cycloaddition to regenerate the heteroaromatic reactant,3 an issue that has been overcome through the use of high-pressure reaction conditions.4 Bond angle strain can provide potent activation of otherwise relatively inert functionalities. Well-known reactive intermediates based on strained unsaturated rings such as arynes and cyclohexynes have been established as valuable synthetic building blocks that undergo Diels−Alder cycloaddition and various ionic processes under mild conditions.5 The corresponding cyclic allenes have recently become attractive alternatives as reactants in strain-driven cycloadditions;6 although less strained than cyclohexynes, 1,2-cyclohexadienes still exhibit a high degree of bond angle strain, estimated at ca. 32 kcal/mol.7 Moreover, the distribution of unsaturation over three contiguous carbon atoms raises interesting regioselectivity issues, and the intrinsic chirality of cyclic allenes suggests their possible mobilization in asymmetric synthesis. Notably, acyclic allenes have proven to be unusually good dienophiles in IMDAF reactions,8 prompting us to explore the corresponding strain-activated cyclic allenes in this process. One challenge associated with methodology employing transient cyclic allenes is their propensity for dimerization to afford tricyclic bis(alkylidene)cyclobutanes (Scheme 1).9 Effective Diels−Alder reaction with furan and related 1,3dienes often requires a large excess of the trapping reagent.10 We have found that some stable 1,3-dipoles can be used in comparatively smaller excesses,6b and Garg and co-workers have made comparable observations.6a,c Another strategy to © XXXX American Chemical Society
enhance trapping efficiency for reactive intermediates is intramolecularity. In this case, a furan linked to one terminus of the cyclic allene by a suitable tether (e.g., 1) would be expected to undergo fast unimolecular Diels−Alder reaction to afford 2.11 Here, we describe a general route to such intermediates and their stereoselective conversion to complex tetracyclic products under mild conditions. Of the various reported methods for generation of 1,2cyclohexadienes, fluoride-induced elimination of allylic silanes bearing leaving groups on the adjacent sp2 carbon was selected for this study due to its mild conditions.12 Installation of the furan-bearing tether could be accomplished via a Stork− Danheiser-type transposition13 using 2-bromo-3-ethoxycycloReceived: June 17, 2019
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DOI: 10.1021/acs.orglett.9b02085 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
solution in THF) in CH3CN at rt), resulting in rapid consumption and formation of cycloadducts 2a−j in moderate to good yields and in all cases as single diastereomers (Table 1;
hexanone 3 and organolithium reagents 4, prepared from the corresponding iodides 5 (Scheme 2). The resulting enones Scheme 2. Construction of Furan-Tethered Substrates via Stork−Danheiser Transposition
Table 1. Allene Generation and Intramolecular Diels−Alder Trappinga
substrate
R1
R2/R3
R4
X
n
yieldb (%)
1a 1b 1c 1d 1e 1f 1gd 1h 1i
Me Ph Me Me Me Me Me Me Me
H/H H/H H/H H/H H/Me Me/H H/H H/H H/H
H H H Me H H Et H H
CH2 CH2 CH2 CH2 CH2 CH2 CH2 NBn N(furfuryl)
1 1 2 1 1 1 1 1 1
65 (46)c,d 49 21 62 62 64 47 40 79
a Standard procedure: compound 1 was dissolved in CH3CN (0.02 M), and a 5 equiv solution of Bu4NF in THF (1 M) was added dropwise. After consumption of 1 (1 h), the reaction mixture was concentrated and purified by flash chromatography to furnish 2. b Yield values are for isolated product after chromatographic purification. cYield for gram-scale reaction. dFor these examples, CsF (5 equiv) was used in place of Bu4NF.
6a−f were subjected to silylcuprate conjugate addition, followed by capping of the enolate oxygen with either an acetyl or a benzoyl group. Through this short sequence, allene precursors 1a−g could be obtained, allowing exploration of the effect of furan substitution pattern, tether length, and enolcapping group. Two additional substrates with nitrogen-containing tethers were also prepared (Scheme 3). In this case, chloromethylScheme 3. Preparation of Additional Furan-Tethered Substrates with an Amine-Containing Tether and Lacking Alkene Oxygenation
eq 1). In accounting for the remaining material, no evidence of [2 + 2] dimerization was seen; however, reactions were typically complicated by the presence of uncharacterizable polar side products, which may result from polar trapping of allene intermediates by trace amounts of water14 or reaction with the THF in which the Bu4NF was dissolved.15 The relative configuration of the cycloadducts was assigned on a preliminary basis to be the endo diastereomers shown, in analogy to the intermolecular examples (e.g., Scheme 1). This assignment is supported by the consistent observation of a single upfield proton in the 1H NMR spectra resulting from anisotropic shielding of the axial cyclohexene proton on C12 by the nearby dihydrofuran π system (Figure 1), a spectral feature that has been observed by others.10,16 Single-crystal Xray diffraction analysis of cycloadduct 2f confirmed this stereochemical assignment, allowing the generalization of this relative configuration to other products due to their close spectral analogy. In addition to the complete diastereoselectivity, the Diels− Alder cycloaddition occurred only between the furan diene and the proximal allene π bond to form the angularly fused skeleton. No evidence was seen for the alternative regiochemical outcome to afford the isomers 7 (see Figure 1). Electronic deactivation of the distal π bond by carboxylate ester substitution may be partially responsible, though observation of the same regiochemistry in the case of substrate 1j (eq 1) shows that other factors such as tether length also
lithium was used in the Stork−Danheiser sequence, followed by displacement of the chloride with either N-benzylfurfurylamine or bis(furfuryl)amine to afford 6g,h. Conjugate addition of PhMe2Si and enolate trapping with Ac2O then furnished 1h,i. Finally, a substrate lacking any oxygen substitution on the allene precursor was prepared. In this short route, cyclohexanone 6a was subjected to Luche reduction and conversion of the alcohol to the corresponding carbonate, followed by direct displacement of the allylic carbonate with silylcuprate,14 to afford 1j. Substrates 1a−j were then subjected to desilylation conditions (5 equiv of tetrabutylammonium fluoride (1 M B
DOI: 10.1021/acs.orglett.9b02085 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 4. Unexpected Retro-Diels−Alder Reaction of Enol Acetate Cleavage Products
Figure 1. Characteristic upfield 1H NMR chemical shift of endo cycloadducts, shown for 2f, ORTEP structure of 2f with H12ax labeled, and alternative regiochemical outcome (7) not observed.
contribute to this selectivity. Indeed, a much lower yield in the case of a four-carbon tether (substrate 1c) indicates the importance of proximity of the furan diene to the transient allene. Replacement of the acetate moiety on the allene with benzoate (substrate 1b) led to reduced yields of cycloadduct, and methyl substitution around the furan ring (substrates 1c− e) had a minimal effect. Incorporation of a nitrogen atom in the tether (substrates 1h,i) was tolerated, although much higher yields were seen in the case of the bis(furfuryl) amine 1i, as expected due to the greater likelihood of one of the furans encountering the allene. Finally, on a gram-scale the yield of the reaction is slightly diminished. Cycloadducts 2a−i possess a masked enolate moiety adjacent to the bridging ether oxygen atom of the dihydrofuran embedded in a strained tetracyclic skeleton, and we wondered whether this relationship could be exploited for the controlled modification of cycloadducts via an elimination process. In the event, treatment of 2g with K2CO3 in MeOH failed to afford tricyclic alcohol 8g (Scheme 4). Instead, we observed clean formation of furan-tethered cyclohexenone 10g. We attribute this surprising result to retroDiels−Alder reaction of intermediate 9g, arising from protonation of the intermediate enolate derived from 2g. To test the generality of this process, we subjected 2f to the same conditions, which once again afforded the retro-[4 + 2] adduct (10f) as the main product. We examined cleavage of the enol acetate to the enolate under anhydrous conditions (excess MeLi/−78 °C) using cycloadduct 2i. In this case, we hypothesized that in the absence of an in situ proton source the originally sought elimination might occur. However, once again we saw exclusive reaction through the retro-[4 + 2] pathway to afford 10i in quantitative yield, presumably via enolate protonation during aqueous workup, followed by rapid cycloreversion. The generality of this outcome indicates a Diels−Alder equilibrium that strongly favors the diene and dienophile reactants. Concerted cycloreversions of oxanorbornenes to furans under mild conditions are sensitive to substituent effects,17 and in this case, the strain resident in the tetracyclic adducts 2 may contribute to a lower activation barrier. At this juncture, however, we cannot rule out alternative mechanistic pathways via stepwise heterolytic cleavage, as shown for 9g. Computational studies currently underway should yield additional insights. Moreover, the distinct reactivity of 9 vs 2 highlights the critical role of the high-energy cyclic allene intermediates in driving the intra-
molecular Diels−Alder reactions to completion with no competing cycloreversion. Here, we have described the first intramolecular trapping of 6-membered cyclic allenes via Diels−Alder cycloaddition using pendent furans. Substrates are available via a short sequence, and allene generation takes place under mild and convenient conditions. In all cases, cycloadducts were isolated as single (endo) diastereomers, and no evidence was seen for alternative regiochemistry in the cycloaddition. The dihydrofuran moiety is subject to regioselective opening with the assistance of the masked enolate remaining after addition to the nonoxygenated bond of the allene. Other intramolecular trapping processes and further synthetic elaboration of the polycyclic scaffolds available through this methodology will be described elsewhere.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02085. Experimental procedures, compound data, crystal structure, 1H and 13C NMR spectra (PDF) Accession Codes
CCDC 1895480 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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DOI: 10.1021/acs.orglett.9b02085 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
F. G. West: 0000-0001-7419-2314 Author Contributions †
V.A.L. and K.C.M. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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REFERENCES
We thank Dr. R. McDonald (University of Alberta X-ray Crystallography Facility) for obtaining the X-ray crystal structure of 2f. Acknowledgment is made to the donors of the American Chemical Society Petroleum Research Fund for support of this work. We also thank the Natural Science and Engineering Research Council of Canada (NSERC) for partial support and King Abdulaziz University (KAU) for a postgraduate scholarship (Y.A.A.).
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DOI: 10.1021/acs.orglett.9b02085 Org. Lett. XXXX, XXX, XXX−XXX
