Factors Governing and Application of the Cope Rearrangement of 3,3

Letter pubs.acs.org/OrgLett

Factors Governing and Application of the Cope Rearrangement of 3,3-Dicyano-1,5-dienes and Related Studies Ehsan Fereyduni and Alexander J. Grenning* University of Florida, Department of Chemistry, P.O. Box 117200, Gainesville, Florida 32611, United States S Supporting Information *

ABSTRACT: Cope and co-workers reported the [3,3] rearrangement of 3,3-dicyano-1,5-dienes in the early 1940s (“The Cope rearrangement”). However, these original substrates have remained largely unstudied until recently. Herein we explore styrene-deconjugating Cope rearrangements, a diastereoselective Cope rearrangement/deconjugative α-allylation sequence, and factors governing α- vs γ-allylation regioselectivity of Knoevenagel adduct allyl anions. Ultimately, these studies result in the synthesis of diverse and functionally dense polycycloalkane frameworks from abundant reagents using simple chemistry.

T

Scheme 1. Literature Examples of [3,3] Rearrangement of 3,3-Di-electron-Withdrawing-Group-1,5-Dienes

he Cope rearrangement is an enabling chemical reaction with a rich history.1 Since its discovery in the early 1940s,2 it continues to be studied in terms of catalysis, asymmetry, unique methodological variation, and application in complex molecule synthesis.1 Well applied versions include the oxyCope rearrangement3 and that of divinylcyclopropanes,4 presumably due to the ease of substrate synthesis and an equilibrium that highly, often exclusively, favors product. The originally reported substrates for Cope rearrangement are 3,3-dielectron-withdrawing-group-1,5-dienes (3,3-di-EWG1,5-dienes).2 A key feature is the ease of synthesis of these 1,5dienes by Knoevenagel condensation5 followed by deconjugative α-allylation.6,7 These substrates commonly undergo thermal rearrangement with an equilibrium that greatly favors the product. This is due to a conjugation driving force. Cope noted that the rate of rearrangement is dependent on the electron-withdrawing group.2a The gem-dinitrile-containing substrates reacted with the greatest ease whereas the malonic ester substrate was less reactive and required higher temperature (Scheme 1A). In a recent study,8 Stoltz noted that related substrates bearing a 4-aryl group underwent self-immolative1a Cope rearrangement at 100 °C in ∼5 h (Scheme 1B). This is a significant change in rate and ease, which can be rationalized in part by the additional styrene conjugation achieved upon rearrangement. This reaction also occurs with high chirality transfer. In previous studies from our group,9 we noted a diastereoselective Cope rearrangement of 1,6-substituted 3,3dicyano-1,5-dienes yielding vicinally stereogenic γ-allyl Knoevenagel adducts (Scheme 1C). There are very few other studies of this rearrangement.10 We are interested in the rearrangement of 3,3-dicyano-1,5dienes, as it is a key step en route to terpenoid scaffolds.9,10 Notable qualities of our devised sequence include the abundance of the starting materials (ketones, malononitrile, and allylic electrophiles) and the operational simplicity of the © 2017 American Chemical Society

key C−C bond forming events. Described herein, we further examine the electronic factors and diastereoselectivity of the historic Cope rearrangement, report a one-pot [3,3] rearrangement/alkylation sequence, the synthesis of various polycycloalkanes, and serendipitous routes to other polycycloalkane frameworks via direct γ-allylation of Knoevenagel adducts. To begin our studies, we wished to explore the Cope rearrangement of 6-aryl-3,3-dicyano-1,5-dienes as a key step en route toward frondosin/liphagal-like natural product scaffolds from highly abundant starting materials (cycloalkanones, malononitrile, cinnamyl electrophiles, and allyl electrophiles) by a potentially simple strategy (Scheme 2).11,12 At the outset, we wondered if malononitrile conjugation could drive an otherwise challenging Cope rearrangement, one that results in styrene deconjugation (Scheme 2). Usually, styrene conjugation is thermodynamically favored.1,8,13 A small Received: June 26, 2017 Published: July 19, 2017 4130

DOI: 10.1021/acs.orglett.7b01951 Org. Lett. 2017, 19, 4130−4133

Letter

Organic Letters Scheme 2. Our Motivation to Examine the Cope Rearrangement of 6-Aryl-3,3-dicyano-1,5-dienes

Scheme 3. A Simple Route to Tropane-Frondosin-Core Hybrids

the complex bicyclo[5.5.0]dodecane 3b containing a bridging amino group, pendant aromatic ring, two unique alkenes, and a gem-dinitrile functional group. The Cope rearrangement of 1e was diastereoselective where the existing stereocenters allow for chirality transfer. We wished to probe to what extent location and group size could influence the chirality transfer of 3,3-dicyano-1,5-dienes (Scheme 4A).

series of 6-phenyl-3,3-dicyano-1,5-dienes 1a−1d were prepared from cyclo-alkanone-derived Knoevenagel adducts and cinnamyl acetate by Pd-catalyzed deconjugative allylation (Table 1).7c Table 1. Styrene-Deconjugating Cope Rearrangements

Scheme 4. (A) Chirality-Transferring [3,3] Rearrangement/ Allylation and then (B) Ring Closing Metathesis

entry

Ar =

time (min)

n

1a−d

conv (%)

crude dr

isolated yield/(dr)

1 2 3 4 5 6 7 8 9 10 11

Ph Ph Ph Ph Ph Ph Ph Ph Ph PMP PMP

5 10 30 5 10 30 5 10 30 5 30

1 1 1 0 0 0 2 2 2 1 1

1b 1b 1b 1a 1a 1a 1c 1c 1c 1d 1d

29 39 42 60 62 68 51 62 72 35 42

20:1 10:1 4:1 7:1 5:1 4:1 20:1 20:1 7:1 6:1 2:1

26% (8:1) − − − 58% (3:1) − − − 68% (2:1) − −

The cyclohexene-containing substrate 1a underwent a clean Cope rearrangement at 150 °C with 29% conversion and ∼20:1 dr after 5 min (entry 1). Continued heating resulted in little additional conversion and erosion of stereoselectivity, either by an epimerization pathway or because the Cope rearrangement is proceeding through multiple unique transition states (entries 2−3). Furthermore, the γ-C−H is epimerizable as determined by the decrease in diastereoselectivity from the crude reaction mixture to the purified product 2a. However, conversion tracks well with the isolated yield. Interestingly the cyclopentene- and heptene-containing substrates 1b and 1c resulted in significantly higher conversions (entries 4−9). Thus, strain release in combination with malononitrile conjugation can produce the desired result. We also examined the nature of an electron-rich benzene ring (1d, entries 10 and 11). Thermal rearrangement resulted in a slight but notable increase in conversion compared to 1a. Styrene-deconjugating Cope rearrangement was most effective with cycloheptenyl 1,5-dienes (Table 1). Using this transformation, tropinone−fondosin core hybrids could be prepared efficiently (Scheme 3).14 Tropinone-derived 1,5-diene 1e was prepared by Knoevenagel condensation and deconjugative allylation with cinnamyl bromide. We were pleased to find that the strained bicyclic 1,5-diene underwent styrenedeconjugating Cope rearrangement with ∼75% conversion by NMR. Without isolation of the Cope product, deconjugative alkylation with allyl bromide produced 3a in 41% isolated yield as a single diastereomer. Ring-closing metathesis then yielded

Based on existing models,1a chirality transfer may occur through a Zimmerman−Traxler transition state where the stereocenter’s largest group projects away from the bondforming event. Furthermore, we studied the application of a diastereoselective Cope rearrangement for the preparation of tris-stereogenic terpenoid scaffolds via deconjugative alkylation and ring-closing metathesis (Scheme 4B). For these studies 1,5dienes 4 were prepared by Pd-catalyzed deconjugative allylation from cyclohexanone derived Knoevenagel adducts and the bisacetate of cis-butene-1,4-diol.7c Diastereoselective Cope rearrangement/deconjugative allylation was observed with 4aliphatic (4a), -ester (4b), and -aryl (4c) substrates with a trend correlated to the A-value.15 Unfortunately, 4-oxygenated substrates 4d−4f displayed little diastereoselectivity through the sequence, but could be prepared in good yields as isomeric mixtures. Next, we examined the proximity of the stereocenter to the bond-forming site. Not surprisingly, the location had a dramatic effect. For example, the tropinone derived substrates 4g displayed high diastereocontrol (>20:1) whereas the 4131

DOI: 10.1021/acs.orglett.7b01951 Org. Lett. 2017, 19, 4130−4133

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Organic Letters

Scheme 6. Direct γ-Allylation Observed with Strained Knoevenagel Adducts via Pd-Catalysis

methylated isomers (4a and 4h) displayed decreasing diastereoselectivity, as the stereocenter became more remote. There were several 1,5-dienes prepared that did not undergo the desired [3,3] Cope rearrangement under the standard conditions (150 °C, toluene, Figure 1). The 1,5-diene 7a

Figure 1. Thermally unreactive substrates examined in this study.

bearing a trisubstituted olefin was thermally stable and did not react (0% conversion). The E and Z substrates 7b and 7c derived from dihydrocarvone and buten-1,4-diol derivatives were similarly unreactive. It appears that the rearrangement step is sensitive to sterics at the termini of the 1,5-dienes. Considering that the dihydrocarvone-derived 1,5-dienes 7a and 7b did not undergo Cope rearrangement, we examined the terminally unsubstituted dihydrocarvone-derived 1,5-diene 8a (Scheme 5). We were pleased to see that thermal reactivity was

We wished to further probe the effect of ring strain on Pdcatalyzed allylation regioselectivity (Scheme 7). We prepared Scheme 7. Ring Strain Can Direct γ-Allylation

Scheme 5. Cope Rearrangement and Cyclization Reactions of a Dihydrocarvone-Derived Substrate

the Knoevenagel adduct of verbenone and reacted it with 2 equiv of allyl acetate and catalytic Pd(PPh3)4. A mixture of mono-γ- (10a), di-γ,ε- (10b), and tri-γ,ε,ε-allylation (10c) resulted. Considering this, we next reacted the Knoevenagel adduct with conjunctive reagents 11a and 11b under analogous conditions and observed the products 12a and 12b of γallylation followed by deconjugative α-allylation. Excitingly, this was an operationally simple and mild annulation reaction to functionally dense polycycloalkanes 12, which could be performed on the gram scale. In conclusion, we have explored various aspects of the Cope rearrangement of 3,3-dicyano-1,5-dienes: (a) Styrene-deconjugating Cope rearrangements are possible with these substrates. The reaction can be utilized to prepare tropane-frondosin hybrid cores. (b) Chirality transferring Cope rearrangement/ deconjugative alkylation is a viable strategy for preparing trisstereogenic terpenoid scaffolds. Finally, (c) strained Knoevenagel adducts can undergo Pd-catalyzed γ-allylation directly, which was harnessed to prepare a functionally dense hydrindane and decalin.

reinstated and a diastereoselective [3,3] Cope rearrangement/ deconjugative α-allylation procedure yielded 8b. By ring-closing metathesis, the 6/7 bicycloalkane 8c was prepared, which bears resemblance to phorbol16 and dictyotetraene.17 During the above studies related to the one-pot [3,3] Cope rearrangement/deconjugative alkylation, an unexpected reaction was observed when utilizing the 1,5-diene 1e. We were expecting deconjugative α-allylation, but direct γ-allylation of [I-b] resulted furnishing 9a in 25% yield over the sequence (Scheme 6). The yield is modest, but this is a noteworthy result as direct γ-allylation has yet to be observed with Knoevenagel adducts. Rather, γ-allylation is achieved indirectly as described herein, by deconjugative allylation/Cope rearrangement. That said, it is well established that certain Michael acceptors react at the γ-position with Knoevenagel adducts.18 Regarding our result, γ-allylation occurred using a combination of allyl tertbutyl carbonate and catalytic Pd(PPh3)4. Our result appears to arise from a combination of both strain and the Pd-π-allyl electrophile (compare Scheme 6 to Schemes 3 and 4). With 9a in hand, we observed an RCM reaction to the amino-bridged bicyclo[4.4.1]undecane 9b. There are relatively few examples of bicyclo[4.4.1]undecane synthesis by RCM.19 Natural products having this core include ingenol and cyclocitrinol.20

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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.7b01951. Experimental procedures; Compound characterization (1H NMR, 13C NMR, and HRMS); 1H and 13C NMR reprints (PDF) 4132

DOI: 10.1021/acs.orglett.7b01951 Org. Lett. 2017, 19, 4130−4133

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Organic Letters

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AUTHOR INFORMATION

Corresponding Author

*E-mail: grenning@ufl.edu. ORCID

Alexander J. Grenning: 0000-0002-8182-9464 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We thank the College of Liberal Arts and Sciences and the Department of Chemistry at the University of Florida for startup funds. We thank Dr. Ion Ghiviriga (UF) for aid with NMRbased stereochemical assignment. We thank Materia for generous donation of metathesis catalysts.

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DOI: 10.1021/acs.orglett.7b01951 Org. Lett. 2017, 19, 4130−4133