Regioselective transition-metal-free oxidative cy-clobutanol ring expansion to 4-tetralonesPhilipp Natho†, Mia Kapun‡, Lewis A. T. Allen† & Philip J. Parsons†*†Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, UK‡School of Chemistry, University of Edinburgh, EH9 3FJ, Edinburgh, UK

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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 regios-electively through mediation by N-bromosuccinimide and acetonitrile in satisfactory to good yields. The preparation of precursors, as well as the ring expansion have proven to be scalable and are straightfor-ward to carry out.

The use of cyclobutanols as precursors to a series of -functionalized butanones has recently attracted the interest of the synthetic community. This has led to the development of a vast array of -functionali-sation protocols, including fluorination, chlorination, bromination, cyanation or selenylation through pio-neering 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 trap-ping 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 re-gioselectively to the 1-tetralone 2 in 40% yield.

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 1-

tetralone 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, in-cluding Ribisin A (Figure 1). The aforementioned compounds have shown interesting biological prop-erties, particularly tyrosinase inhibition and stimula-tion of neurite outgrowth of NGF-mediated PC12-cells. 11, 12 A common cyclobutanol intermediate for the formation of the 1-tetralone and 4-tetralone would allow for the derivitisation of natural products (e.g. regiomeric Ribisin A) to be submitted for struc-ture-activity relationship studies.

Figure 1. Natural products containing the 4-tetralone motif.

Cyclobutanols have been shown to expand under halonium ion mediation to the five-membered rings (Scheme 2). This work had been pioneered by Fuku-moto in 1996 (a) in which a cyclobutanol in the al-lylic position of an alkene 3 was expanded to the cy-clopentanone 4 with an iodine in the -position. 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 1,2-carbon migra-tion sequences with concomitant trifluoromethyla-tion, arylation or arylsulfonylation under visible-light or transition metal-free induction.16-18

Scheme 2. Literature precedent for halonium ion-mediated cyclobutanol ring expansion.

In all examples cited, expansion of the alkene-sub-stituted cyclobutanol to the five-membered ring is observed, with concomitant functionalisation of the alkene. Mechanistically, for examples shown in Scheme 2, the formation of a halonium ion was sug-gested, which induces an electronic shift of the car-bon-carbon -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 six-membered ring and re-store aromaticity in an overall 1,3-carbon migration.In order to investigate the aforementioned possibil-ity 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. Optimisation of reaction conditions. a

entry conditions solvent yield %1 NBS iPrOH, propy-

lene oxide--

2 NBS THF --3 NBS DCM --4 NBS DMF --5 NBS Et3N --6 NBS MeCN 637b NBS MeCN 108 c NBS MeCN 409 NBS EtCN 2710 NCS MeCN 711 NIS MeCN 312 PhSeCl MeCN --13d (BrNCO)3 MeCN --14e NBS, K2S2O8 MeCN 4815f NBS,

Mn(OAcMeCN --

)3.2H2Oa Conditions: alcohol (1.0 equiv.), electrophile (1.15 equiv.), solvent (0.05 – 0.1 M), 0 °C to rt. b 35 °C. c 0 °C to reflux. d 0.35 equiv. of (BrNCO)3. e Addition of 2.1 equiv. of K2S2O8. f Addition 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-mem-bered 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 employed as the solvent at room temperature (Entry 6, Table 1). The superiority of acetonitrile in combination with NBS for certain reac-tions has previously been observed in the bromocy-clization of 3-olefinic alcohols.19 Lowering the reac-tion temperature to 35 °C (Entry 7, Table 1) or an increase to reflux (Entry 8, Table 1) still led to forma-tion 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 propioni-trile (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. Whilst no conversion was detected with PhSeCl, reactions with NCS and NIS proved sluggish and were accom-panied by a complex mixture of unidentifiable side products. The poor yields of products observed in the NCS or NIS-mediated cyclisations suggests a dif-ference in reaction mechanism compared to NBS. Variation of the bromine source to tribromo-isocya-nuric acid again lead to complete cessation of the reaction. Addition of further metal-based oxidants (Entries 14-15, Table 1) did not lead to yield im-provements of the desired product.

With optimal conditions in hand, we explored the scope of substrates, which ring-expand under these conditions (Scheme 3).

Scheme 3. Scope evaluation of NBS-mediated ring ex-pan-sion.a

cyclobutanol tetralone reac-tion time

yield %

3 hrs 63

4 hrs 49b

10 min 52

3.5 hrs 48

15 min 40

15 min 25

15 min 38

10 min 39

10 min 43

2 hrs 12

30 min 19

30 min 29

a 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.

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-methylin-dole-2-cyclobutanol only lead 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 se-lected 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 ob-served as the major product in 35% yield (Scheme 4). At this stage we are uncertain if the ring expan-sion methodology is sufficiently robust to tolerate the boc-protecting group.

Scheme 4. Cyclobutene formation after meta-lation of 32 and addition to cyclobutanone.

Further to these results we evaluated the use of the tosyl group in these studies. The desired N-tosyl in-dole was prepared and exposed to n-butyllithium fol-lowed by cyclobutanone. This gave the desired cy-clobutanol 12 in 44% yield. The electron-withdraw-ing nature and stability of the tosyl group finally lead to successful conversion of the cyclobutanol to the desired 4-tetralone 13 in 52% yield. This transforma-tion was notable for its rate acceleration compared to the benzofuran and thiophene examples with complete conversion of the starting material ob-served within 10 minutes. In this case reaction of the cyclobutanol 12 with NBS in acetonitrile pro-ceeded more quickly than the other cases (1 and 10). This is because the enamine moiety in the in-dole 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 2’-position was found to be favoured 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-cy-clobutanol 14 was prepared under bis-metalation conditions with activation through TMEDA and then subjected to one equivalent of NBS in acetonitrile. Under these conditions, only one of the cyclobutanol rings was observed to expand as expected to yield 15 in 48% yield. We then reacted the bis-cyclobu-

tanol 14 with two equivalents of NBS in acetonitrile. To our initial surprise, again only one of the cyclobu-tanol groups underwent ring expansion. Addition of four equivalents of NBS to the diol 14 at room tem-perature and above (reflux) failed to expand the sec-ond cyclobutanol ring. Isolation of the mono ring-ex-panded cyclobutanol 15, followed by addition of fur-ther two equivalents of NBS in acetonitrile also did not provide 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 cyclohex-anone. The thiophene ring is hence considerably less reactive to bromination followed by ring expan-sion.

After variation of the heteroaromatic moiety, we de-cided to investigate substituted cyclobutanols. 3-Phenylcyclobutanone was prepared according to conditions developed by Haufe20 and the corre-sponding heteroaromatic-containing cyclobutanols were prepared through standard lithiation and addi-tion conditions and subsequently subjected to ring expansion conditions. To our delight it was found that all examples (16, 18 & 20) expanded to the ex-pected tetralones (17, 19 & 21) in notably fast rates. The structure of tetralone 17 was confirmed by X-Ray crystallography.

Figure 2. X-Ray crystal structure of tetralone 17.

We then proceeded to investigate fused cyclobu-tanone systems and prepared bicyclo[3.2.0]hep-tanone21 and the corresponding alcohols. To our de-light, the benzofuran and benzothiophene examples 22 and 24 expanded within 15 minutes 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 ,-substituted tetracycles 23 and 25 were formed, and none of the ,-substituted products.

To test our hypothesis that the rate increase of the disubstituted examples 22 and 24 was driven by re-lease of ring strain, we decided to prepare the corre-sponding 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 ,-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 transfor-mations we investigated the addition of the free rad-

ical 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 es-sential requirement for successful ring expansion, since nuclear bromination of the aromatic ring in-stead of ring expansion was observed in correspond-ing cyclobutanol derivatives of anisole.

Based on initial mechanistic studies we propose the mechanism shown in Scheme 5. As demonstrated from the 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 reac-tion, following addition of TEMPO to the mixture. It is suggested that the bromine radical adds to acetoni-trile forming an iminyl radical a) which adds to the 3-position generating a stabilized tertiary radical 34 b). It was found to be essential for the aromatic part to be heteroaromatic, potentially due to the stabiliz-ing nature for the tertiary radical. Formation of this radical induces expansion c) to the five-membered ring forming a spirocyclic intermediate 35, also pos-sessing a tertiary radical. This is easily oxidized to the ketone by single electron transfer d) to the suc-cinimide, and ring-expands further eliminating ace-tonitrile, as well as a bromide ion e) generating in-termediate 37. Aromaticity is restored by abstrac-tion of a proton by bromide f) yielding the observed tetralone 9. The progression through a five-mem-bered intermediate could explain the regioselectivity observed in examples with disubstituted cyclobu-tanol rings, in which the carbon containing the sub-stituent would migrate over the unsubstituted car-bon due to the higher migratory aptitude.

Scheme 5. Suggested mechanism for the NBS-mediated ring expansion.

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 formation of a hypo-bromite 38, followed by homolysis to an oxygen-centred 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 inves-

tigations on the true nature of the mechanism and the intermedi-ates involved are currently undergoing.

Scheme 6. Mechanism for the NBS-mediated ring expansion involving a hypobromite species.

In summary we have developed the first ring expansion of cy-clobutanols to 4-tetralones on heteroaromatic systems. NBS-ace-tonitrile 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 precur-sors 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 inter-mediate. Applications of this novel methodology to natural prod-uct synthesis are currently ongoing in our laboratories

ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge on the ACS Publications website.

Experimental procedures and spectra (PDF)

X-Ray crystal structure of 17 (CIF)

AUTHOR INFORMATIONCorresponding Author* E-Mail: p.parsons@imperial.ac.ukORCIDPhilip J. Parsons: 0000-0002-9158-4034NotesThe authors declare no competing financial inter-ests.

ACKNOWLEDGMENT The authors gratefully acknowledge an Imperial Col-lege President’s scholarship (to P.N.). We thank Peter Haycock and Dr Lisa Haigh (Imperial College Lon-don) for NMR and mass spectrometric analysis re-spectively. We also thank Dr John Wilden (University College London) for his interest in this work. We sin-cerely thank Dr Jeremy Cockcroft (University College London) for the X-Ray analysis of compound 17.

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