Letter Cite This: Org. Lett. 2018, 20, 8030−8034
pubs.acs.org/OrgLett
Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring Expansion to 4‑Tetralones Philipp Natho,† Mia Kapun,‡ Lewis A. T. Allen,† and Philip J. Parsons*,† †
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, U.K. School of Chemistry, University of Edinburgh, EH9 3FJ, Edinburgh, U.K.
‡
Org. Lett. 2018.20:8030-8034. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 12/21/18. For personal use only.
S Supporting Information *
ABSTRACT: A facile and transition-metal-free ring expansion of the cyclobutanol moiety to 4-tetralones fused to heteroaromatic systems is described. The oxidative ring expansion proceeds rapidly and regioselectively through mediation by N-bromosuccinimide and acetonitrile in satisfactory to good yields. The preparation of precursors and the ring expansion have proven to be scalable and are straightforward to carry out. he use of cyclobutanols as precursors to a series of γfunctionalized butanones has recently attracted the interest of the synthetic community. This has led to the development of a vast array of γ-functionalization protocols, including fluorination, chlorination, bromination, cyanation, or selenylation through pioneering work by Zhu.1−8 All current protocols for the introduction of functionality to the cyclobutanol ring require the use of catalytic quantities of transition metals such as silver(I) species or manganese(III) acetate. Interestingly, through the absence of a radical trapping agent the protocol can be modified to achieve an oxidative intramolecular ring opening and closure of cyclobutanol 1 to 1-tetralone 2 in one synthetic operation (Scheme 1).9 This reaction proceeds regioselectively to the 1-tetralone 2 in 40% yield.
T
Figure 1. Natural products containing the 4-tetralone motif.
ate for the formation of the 1-tetralone and 4-tetralone would allow for the derivitization of natural products (e.g., regiomeric Ribisin A) to be submitted for structure−activity relationship studies. Cyclobutanols have been shown to expand under halonium ion mediation to the five-membered rings (Scheme 2). This work had been pioneered by Fukumoto in 1996 (a) in which a Scheme 2. Literature Precedent for Halonium Ion-Mediated Cyclobutanol Ring Expansion
Scheme 1. Oxidative Ring Expansion to the 1-Tetralone by Zhu
The conversion outlined in Scheme 1 has also been shown to be effective under hypervalent iodine catalysis, resulting in the formation of the 1-tetralone 2 in 47% yield.10 In contrast to the two protocols existing for the construction of the 1tetralone 2, synthesis of the regioisomeric 4-tetralone from the same cyclobutanol intermediate 1 has not yet been reported. The formation of this motif would be of synthetic importance due to the presence of this unique scaffold in natural products such as Fortuneanoside K or of the Ribisin family, including Ribisin A (Figure 1). The aforementioned compounds have shown interesting biological properties, particularly tyrosinase inhibition and stimulation of neurite outgrowth of NGFmediated PC12-cells.11,12 A common cyclobutanol intermedi© 2018 American Chemical Society
Received: November 13, 2018 Published: December 6, 2018 8030
DOI: 10.1021/acs.orglett.8b03619 Org. Lett. 2018, 20, 8030−8034
Letter
Organic Letters
employed as the solvent at room temperature (entry 6, Table 1). The superiority of acetonitrile in combination with NBS for certain reactions has previously been observed in the bromocyclization of 3-olefinic alcohols.19 Lowering the reaction temperature to −35 °C (entry 7, Table 1) or an increase to reflux (entry 8, Table 1) still led to formation of the desired tetralone 9, but with decreased yields. We deduced from the initial solvent screen that a solvent containing a nitrile group is of essence for this reaction, which was further confirmed by the successful ring expansion to tetralone 9 in propionitrile (entry 9, Table 1). A change of the electrophile from NBS to NIS, NCS, PhSeCl, or tribromoisocyanuric acid (entries 10−13, Table 1) proved inferior. While no conversion was detected with PhSeCl, reactions with NCS and NIS proved sluggish and were accompanied by a complex mixture of unidentifiable side products. The poor yields of products observed in the NCS- or NIS-mediated cyclizations suggest a difference in reaction mechanism compared to NBS. Variation of the bromine source to tribromo-isocyanuric acid again led to complete cessation of the reaction. Addition of further metalbased oxidants (entries 14−15, Table 1) did not lead to yield improvements of the desired product. With optimal conditions in hand, we explored the scope of substrates, which ring-expand under these conditions (Scheme 3). Our initial aim was to exchange the heteroatom from oxygen to sulfur, and to our delight we isolated the tetralone 11 in 49% yield. In order to investigate our ring-expansion chemistry on indoles, protection of the indolic nitrogen was required. Use of N-methylindole-2-cyclobutanol only led to a complex mixture of unidentifiable products. Our assumption was that the indole was too electron-rich to allow the desired reaction to take place. N-boc indole was then selected as a candidate for these experiments due to the electron-withdrawing nature of the boc group. However, the preparation of the cyclobutanol under the metalation conditions failed to give the desired alcohol, but formation of the cyclobutene 33 was observed as the major product in 35% yield (Scheme 4). At this stage we are uncertain if the ring expansion methodology is sufficiently robust to tolerate the boc-protecting group. In addition to these results, we evaluated the use of the tosyl group in these studies. The desired N-tosyl indole was prepared and exposed to n-butyllithium followed by cyclobutanone. This gave the desired cyclobutanol 12 in 44% yield. The electron-withdrawing nature and stability of the tosyl group finally led to successful conversion of the cyclobutanol to the desired 4-tetralone 13 in 52% yield. This transformation was notable for its rate acceleration compared to the benzofuran and thiophene examples with complete conversion of the starting material observed within 10 min. In this case reaction of the cyclobutanol 12 with NBS in acetonitrile proceeded more quickly than the other cases (1 and 10). This is because the enamine moiety in the indole is highly nucleophilic compared with the sulfur and oxygen analogues. When monosubstituted thiophene or furan examples were exposed to NBS in acetonitrile, bromination of the 5-position was found to be favored over ring expansion. In order to prevent monobromination of the ring, we elected to prepare the bis-cyclobutanol 14 for a potential double ring expansion. The bis-cyclobutanol 14 was prepared under bis-metalation conditions with activation through TMEDA and then subjected to 1 equiv of NBS in acetonitrile. Under these conditions, only one of the cyclobutanol rings was observed to
cyclobutanol in the allylic position of an alkene 3 was expanded to the cyclopentanone 4 with an iodine in the βposition. This methodology was advanced by Paquette (1998) (b), who prepared brominated spirocyclic compounds 6 from dihydrofurans 5. Dake (2004) (c) replaced the dihydrofuran moiety with tetrahydropyridines 7 to form the spirocycle 8 in 96% yield.13−15 Furthermore, modifications to the previous work have recently been developed to include similar 1,2carbon migration sequences with concomitant trifluoromethylation, arylation or arylsulfonylation under visible-light or transition-metal-free induction.16−18 In all examples cited, expansion of the alkene-substituted cyclobutanol to the five-membered ring is observed, with concomitant functionalization of the alkene. Mechanistically, as shown in Scheme 2, the formation of a halonium ion was suggested, which induces an electronic shift of the carbon− carbon σ-bond. We envisioned that a further in situ 1,2-carbon migration with elimination of an equivalent of hydrogen bromide should lead to the formation of the desired sixmembered ring and restore aromaticity in an overall 1,3-carbon migration. In order to investigate the aforementioned possibility and to uncover the optimal reaction conditions, we selected cyclobutanol 1 as our model study and subjected it to a variety of potential ring expansion conditions (Table 1) to generate the desired 4-tetralone 9. Table 1. Optimization of Reaction Conditionsa
entry
conditions
solvent
yield [%]
1 2 3 4 5 6 7b 8c 9 10 11 12 13d 14e 15f
NBS NBS NBS NBS NBS NBS NBS NBS NBS NCS NIS PhSeCl (BrNCO)3 NBS, K2S2O8 NBS, Mn(OAc)3·2H2O
iPrOH, propylene oxide THF DCM DMF Et3N MeCN MeCN MeCN EtCN MeCN MeCN MeCN MeCN MeCN MeCN
− − − − − 63 10 40 27 7 3 − − 48 −
a
Conditions: alcohol (1.0 equiv), electrophile (1.15 equiv), solvent (0.05−0.1 M), 0 °C to rt. b−35 °C. c0 °C to reflux. d0.35 equiv of (BrNCO)3. eAddition of 2.1 equiv of K2S2O8. fAddition of 1.2 equiv of Mn(OAc)3·2H2O.
To test our hypothesis, we decided to subject alcohol 1 to conditions used by Paquette and Dake (entry 1, Table 1). Surprisingly, however, no conversion was detected, and no expansion to the five- or six-membered ring could be observed. Equally, when THF, DCM, DMF, or triethylamine (entries 2− 5, Table 1) were employed as the solvent, only starting material could be isolated. To our delight the desired tetralone 9 could be isolated in 63% yield, when acetonitrile was 8031
DOI: 10.1021/acs.orglett.8b03619 Org. Lett. 2018, 20, 8030−8034
Letter
Organic Letters Scheme 3. Scope Evaluation of NBS-Mediated Ring Expansiona
Conditions: alcohol (1.0 equiv), NBS (1.15 equiv), MeCN (0.05−0.1 M), 0 °C to rt. bThis reaction was also performed at a 1.5 mmol scale to yield the tetralone in 53% yield.
a
the desired diketone. We rationalized that the thiophene ring after the first ring expansion is much less electron-rich due to conjugation with the newly formed ketone in the fused cyclohexanone. The thiophene ring is hence considerably less reactive to bromination followed by ring expansion. After variation of the heteroaromatic moiety, we decided to investigate substituted cyclobutanols. 3-Phenylcyclobutanone was prepared according to conditions developed by Haufe,20 and the corresponding heteroaromatic-containing cyclobutanols were prepared through standard lithiation and addition conditions and subsequently subjected to ring expansion conditions. To our delight it was found that all examples (16, 18, and 20) expanded to the expected tetralones (17, 19, and 21) in notably fast rates. The structure of tetralone 17 was confirmed by X-ray crystallography (Figure 2).
Scheme 4. Cyclobutene Formation after Metalation of 32 and Addition to Cyclobutanone
expand as expected to yield 15 in 48% yield. We then reacted the bis-cyclobutanol 14 with 2 equiv of NBS in acetonitrile. To our initial surprise, again only one of the cyclobutanol groups underwent ring expansion. Addition of 4 equiv of NBS to the diol 14 at room temperature and above (reflux) failed to expand the second cyclobutanol ring. Isolation of the mono ring-expanded cyclobutanol 15, followed by addition of an additional 2 equiv of NBS in acetonitrile, also did not provide 8032
DOI: 10.1021/acs.orglett.8b03619 Org. Lett. 2018, 20, 8030−8034
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Organic Letters
for the aromatic part to be heteroaromatic, potentially due to the stabilizing nature for the tertiary radical. Formation of this radical induces expansion (c) to the five-membered ring forming a spirocyclic intermediate 35, also possessing a tertiary radical. This is easily oxidized to the ketone by single electron transfer (d) to the succinimide and ring-expands further eliminating acetonitrile, as well as a bromide ion (e) generating intermediate 37. Aromaticity is restored by abstraction of a proton by bromide (f) yielding the observed tetralone 9. The progression through a five-membered intermediate could explain the regioselectivity observed in examples with disubstituted cyclobutanol rings, in which the carbon containing the substituent would migrate over the unsubstituted carbon due to the higher migratory aptitude. During review, an alternative mechanism was suggested based on previous proposals in the metal-mediated formation of tetralones (Scheme 6).23−25 This pathway involves the
Figure 2. X-ray crystal structure of tetralone 17.
We then proceeded to investigate fused cyclobutanone systems and prepared bicyclo[3.2.0]heptanone21 and the corresponding alcohols. To our delight, the benzofuran and benzothiophene examples 22 and 24 expanded within 15 min and with good yields. The rapid conversion to the tetracycle can be attributed to the release of ring strain of the fused system when expansion occurs. Notably, only the β,γsubstituted tetracycles 23 and 25 were formed, without the α,β-substituted products. To test our hypothesis that the rate increase of the disubstituted examples 22 and 24 was driven by release of ring strain, we decided to prepare the corresponding heteroaromatic-containing alcohols of trans-3-(benzyloxy)methyl-2-phenylcyclobutanone.22 When the disubstituted cyclobutanol precursors 26, 28, and 30 were used, the same selectivity for the β,γ-substitution pattern was observed to yield tetralones 27, 29, and 31 respectively, however with a concomitant drop in yield. In order to probe the mechanism of these transformations we investigated the addition of the free radical TEMPO to benzofuranyl cyclobutanol 1 reaction with NBS. No reaction was observed under these conditions. In addition, a heteroatom in the aromatic ring system adjacent to the cyclobutanol is an essential requirement for successful ring expansion, since nuclear bromination of the aromatic ring instead of ring expansion was observed in corresponding cyclobutanol derivatives of anisole. Based on initial mechanistic studies we propose the mechanism shown in Scheme 5. As demonstrated from the
Scheme 6. Mechanism for the NBS-Mediated Ring Expansion Involving a Hypobromite Species
formation of a hypobromite 38, followed by homolysis to an oxygen-centered radical 39 and carbon−carbon bond cleavage to a high-energy primary radical 40. This mechanistic proposal would eventually form the same intermediate 37 after single electron transfer. Further investigations on the true nature of the mechanism and the intermediates involved are currently underway. In summary we have developed the first ring expansion of cyclobutanols to 4-tetralones on heteroaromatic systems. NBSacetonitrile has been found to be the reagent combination of choice with mild reaction conditions and commercial availability of the reagents. Due to the facile preparation of the cyclobutanol precursors through metalation and addition conditions, this methodology provides a mild and rapid entry to 4-tetralones omitting the use of transition metals and harsh Lewis acid required for Friedel−Craft protocols. The regioselectivity was confirmed through X-ray crystallography, and preliminary mechanistic studies suggest the involvement of acetonitrile in the reaction and a spirocyclic intermediate. Applications of this novel methodology to natural product synthesis are currently ongoing in our laboratories
Scheme 5. Suggested Mechanism for the NBS-Mediated Ring Expansion
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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.8b03619. Experimental procedures and spectra (PDF)
solvent screen, this reaction is specific to solvents containing a nitrile group. Furthermore, the reaction is believed to have a radical character, which was supported by the cessation of the reaction, following addition of TEMPO to the mixture. It is suggested that the bromine radical adds to acetonitrile forming an iminyl radical (a) which adds to the 3-position generating a stabilized tertiary radical 34 (b). It was found to be essential
Accession Codes
CCDC 1878598 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge 8033
DOI: 10.1021/acs.orglett.8b03619 Org. Lett. 2018, 20, 8030−8034
Letter
Organic Letters
(22) Brown, R. C. D.; Bataille, C. J. R.; Bruton, G.; Hinks, J. D.; Swain, N. A. J. Org. Chem. 2001, 66, 6719−6728. (23) Wang, D.; Mao, J.; Zhu, C. Chem. Sci. 2018, 9, 5805−5809. (24) Wu, X.; Wu, S.; Zhu, C. Tetrahedron Lett. 2018, 59, 1328− 1336. (25) Yu, J.; Wang, D.; Xu, Y.; Wu, Z.; Zhu, C. Adv. Synth. Catal. 2018, 360, 744−750.
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Philip J. Parsons: 0000-0002-9158-4034 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge an Imperial College President’s scholarship (to P.N.). Drs. Alfred and Isabel Bader are gratefully acknowledged for their very generous support of this work. We thank Peter Haycock and Dr. Lisa Haigh (Imperial College London) for NMR and mass spectrometric analysis, respectively. We also thank Dr. Jon Wilden (University College London) for his interest in this work. We sincerely thank Dr. Jeremy Cockcroft (University College London) for the X-ray analysis of compound 17.
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DOI: 10.1021/acs.orglett.8b03619 Org. Lett. 2018, 20, 8030−8034
