Seven-Membered Rings through Metal-Free Rearrangement Mediated by Hypervalent Iodine

A versatile and metal-free approach for the synthesis of carbocycles and of heterocycles bearing seven- and eight-membered rings is described. The strategy is based on ring expansion of 1-vinylcycloalkanols (or the corresponding silyl or methyl ether) mediated by the hypervalent iodine reagent HTIB (PhI(OH)OTs). Reaction conditions can be easily adjusted to give ring expansion products bearing different functional groups. A route to medium-ring lactones was also developed.


Results and Discussion
The substrates required for the ring expansion reactions were prepared in an efficient manner. The reaction of 1-tetralone (1a) with CH2=CHMgBr gave the unsaturated 1-tetralol 2a, in 89% yield [35]. Considering the possible instability of the tertiary benzylic and allylic alcohol 2a, we decided to protect it as the trimethylsilyl (TMS) ether. The protocol using trimethylsilyl chloride/hexamethyldisilazane (TMSCl/HMDS) in reflux of hexane was applied to 2a, giving the desired product 3a in only 11% yield. However, using HMDS in the presence of a catalytic amount of I2, as reported by Karimi and Golshani [36], was possible to obtain cleanly 3a in 99% yield (Scheme 1). The above two-step sequence was applied to several ketones, leading to 3b-l. We were also interested in the behavior of alkyl ethers. Thus, the methyl ether 4a was prepared treating 2a with KOH/MeI ( Figure 2) [37]. We first performed a detailed investigation on the reactivity of the TMS-protected 1-vinylcycloalkanol 3a. Thus, treatment of 3a with HTIB in CH3CN, in trimethylorthoformiate or without solvent [38] led to a complex mixture of compounds. Fortunately, when the unsaturated TMS-ether 3a was treated with HTIB in MeOH [31] in the presence of p-TsOH, thin layer chromatography (TLC) analysis indicated the cleavage of the labile TMS-group. Then, the alcohol 2a formed in the medium reacted with iodine(III), giving the ring expansion product 5a, in 60% yield (Table 1, Entry 1). The methoxy-ketone 5a would be originated from 3a in four steps. The first would be the acid-catalyzed deprotection of the TMS group, giving 2a, on which the electrophilic addition of iodine(III) to the double bond would give the cation 9. Migration of the aryl carbon would lead to 10. A reductive solvolysis on 10 would produce the methoxylated ketone 5a (Scheme 2). On this step occurs the highly favorable transformation of the hypervalent iodine into the normal valency compound PhI. Higher temperatures and longer reaction times promote an acid-catalyzed elimination of MeOH from 5a, furnishing the enone 6a, together with the dimer 7a (entry 2). TLC analysis showed that 7a is formed after the work-up. This result is slightly different from that using Tl(III), which gives only the enone 6a from 3a [22]. On standing, the mixture 6a/7a gave pure crystals of 7a, in 55% yield from 3a (Table 1, entry 3), whose structure was assigned by X-ray analysis [34]. The pentacyclic compound 7a is formed from the 1-vinylcycloalkanol derivative 3a in a single operation through a tandem ring-expansion/ hetero-Diels-Alder reaction [39,40]. We envisioned that 7a could be used to obtain a medium ring lactone [41,42]. Indeed, the oxidative cleavage of the double bond of 7a could be performed with RuCl3/NaIO4, giving the eleven-membered ring keto-lactone 11a (Scheme 3). In summary, the commercially available 1-tetralone (1a) was transformed in only four steps into 11a, which bears a spiro seven-membered ring and a medium-ring lactone. Thus, in this short sequence of steps, the molecular complexity is greatly increased, because several reactions took place in a few operations. Since the double bond of enone 6a is prone to further oxidation, we decided to investigate the reaction of 3a with excess of oxidant. When 3a was treated with 2.5 equiv of HTIB, a tandem ring expansion/addition of MeOH gave the dimethoxy-ketone 8a ( Table 1, entry 4). An iodine(III)-mediated electrophilic addition of MeOH to the enone 6a would give 8a. In summary, different ring expansion products 5a-8a can be obtained from the same substrate (3a) by modification of the reaction conditions.
After exploring the oxidation of 3a with iodine(III) under several conditions, we checked if the protection as a silyl ether was really required. The desired dimethoxy-ketone 8a was also obtained when either 2a or 4a were treated with HTIB (Scheme 4). In conclusion, the presence of the TMS group is not essential for the ring expansion, although higher yields of the desired product were observed from 3a (75%) than from 2a or from 4a (65%-67%). However, the protection of the tertiary benzylic and allylic alcohol 3a as a TMS ether greatly facilitate the storage of the substrate and we decide to do this for all substrates. A substituent in the aromatic ring can alter the migratory aptitude of the migrating carbon, which may influence the yield of the rearrangement product. For example, a correlation between yield of the product and migratory aptitude was noted by us in Tl(III)-mediated ring contraction of 1,2-di-hydronaphthalenes [43]. Thus, we investigated the ring expansion of 3 with different groups in the aromatic ring. Alkyl groups in the aromatic ring can be problematic in reactions with hypervalent iodine [44,45]. Fortunately, the TMS-protected alcohol 3b, which bears methyl groups, gave the dimethoxy ketone 8b ( Table 2, Entry 1) in a similar yield to the non-substituted substrate 3a. A methoxy group at the meta position could decrease the migratory aptitude of the migrating carbon. The value of the Hammett constant ρm for OMe is 0.11. Hence, a lower yield of the ring expansion product could be expected. However, the reaction of 3c-d with HTIB led to the corresponding ring expansion products 8c-d, respectively, in comparable yield (Entries 2 and 3). A methoxy group in the para position of the migrating carbon increases the migratory aptitude, which could accelerate the rearrangement. In our experience, this is usually a beneficial effect [43,46]. However, the reaction with 3e gave the ring expansion product 8e, in only 10% yield (entry 4). After some experimentation, we found that treating 3e with HTIB in a mixture of AcOEt/MeOH gave 8e, in 67% yield (Entry 5).   The same solvent mixture (AcOEt/MeOH) was also used in the reaction of 3f. In this case, a mixture of the seven-membered ring compounds 5f, 8f and 12f were isolated in very good overall yield (Entry 6). Compounds 5f and 8f could not be separated from each other by chromatography column or HPLC. The proposed mechanism for the formation of 12f was based on desaromatization reactions previously described in literature [47,48] (Scheme 5). The first step is the transformation of 3f into the seven-membered ring compound 5f, as shown in (Scheme 2), followed by the formation of the charge transfer complex 16 from 5f and HTIB. A single-electron-transfer (SET) oxidation of 16 yields the cation radical 17. Species 17 suffers a MeOH attack from the less hindered convex face and at less hindered carbon 4a (Figure 3), giving the radical 18. A second SET leads to carbocation 19, which reacts with the solvent yielding 20. The enone 12f is formed after an acid hydrolysis of 20 catalyzed by acid. The relative configuration of 12f was assigned by NMR analysis, including NOESY, HMBC and HSQC (see Supplementary Informationfor details).   The reaction of the bromo-substituted substrate 3 g with HTIB needed heating until 50 °C to furnish the ring expanded product in good yield (Table 2, Entry 7). As expected, a withdrawing group as bromide in meta position to migrating carbon decreases its aptitude to migration and, thus, more energetic conditions were necessary. Substrate 3h was exposure to HTIB giving 8 ha/b in 44 and 16%, respectively (Entry 8). The stereoselectivity is determined in the electrophilic addition of iodine(III) to the enone 22. This step occurs preferentially through the less hindered face (Scheme 6).  23 24 Scheme 6. Mechanism for the Formation of 8ha.
The possibility of using a ring expansion reaction to prepare eight-membered rings was also investigated. Substrate 3i was treated with HTIB, giving the desired eight-membered ring compound 8i in 47% yield, together with the unsaturated ether 13i (entry 9). The relative configuration of 13i was assigned based on NMR data of related compounds [49]. This route can be useful to obtain eight-membered ring derivatives, because only three steps are necessary to obtain 8i from the commercially available benzosuberone. The first step in the formation of 20i (Scheme 7) is a ligand exchange from HTIB with 25, giving 26. A sequence of protonation of 26 and dehydration of 27 lead to 28, that participates in a SN2' reaction with the solvent, yielding 20i. The reactivity of heterocyclic substrates was also examined. When compound 3j was treated with HTIB, the ring expansion reaction also took place. However, an inseparable mixture of seven-membered ring O-heterocycles5j, 8j, and 14j was isolated ( Table 2, Entry 10). The oxygen at the ortho position of the migrating carbon 8j change the reactivity, as observed in other oxidative rearrangements promoted by iodine(III) [50]. Treatment of the sulfur derivative 3k with HTIB gave exclusively the sulfoxide, in 75% yield ( Table 2, entry 11). The first reaction is the oxidation of the sulfide moiety to the corresponding sulfoxide [51]. This electron-withdrawing group would decrease the migratory aptitude of the migrating carbon and the SN2' reaction became the favorable pathway. The reaction of substrate 3l with HTIB furnished the benzazepine 8l in good yield (Table 2, Entry 12). Structures like 8l are present in many natural products [52] and have different biological activities [53][54][55][56], being important building blocks for drugs. Among the methodologies for the preparation of benzazepines [57][58][59][60][61][62], metals are involved in most of them and a metal free approach could be a useful alternative, specially for pharmaceuticals applications.
The antiproliferative activity of seven-membered rings products (5f + 8f, 8d, 8g, 12f and 8l) was evaluated against a panel of nine human tumor cell lines and one immortalized human cell line using a protocol described in the literature [63,64]. This methodology aims to evaluate a group of samples in many different tumor cell lines to find evidence of their antiproliferative profile. In order to prioritize further evaluations, a threshold for mean logTGI (Total Growth Inhibition) values (mean log TGI ≤ 1.50) was assumed [65].
Compounds 5f + 8f, 8g and 8l can be classified as inactive considering the average antiproliferative effect (mean logTGI > 1.50) ( Table 3). The mixture 5f + 8f (1:1) showed a selective growth inhibitory effect against glioma (U251, TGI = 4.8 µg·mL −1 ) and prostate (PC-3, TGI = 3.6 µg·mL −1 ) cell lines. Moreover, compounds 12f and 8d showed, respectively, a moderate (mean logTGI = 1.03) and a weak (mean logTGI = 1.35) citostatic effects. This suggests that the presence of methoxy groups in the ring fused to the seven-membered system can contribute to the antiproliferative activity and the inclusion of a methoxy group on the carbon of the ring fusion can increase this effect.

Experimental Section
General Information HTIB, HMDS and MeOH were used as received. THF (tetrahydrofuran) was freshly distilled from sodium/benzophenone, CH2Cl2 was distilled from CaH2 and stored with molecular sieves 3 Å. Vinyl magnesium bromide was purchased from Aldrich or prepared from vinyl bromide and magnesium turnings [66]. 1-Tetralone was distilled before used (bp: ~155 °C, 32 mmHg). Column chromatography was performed using silica gel 200-400 Mesh. TLC analyses were performed in silica gel 60 F254 plates, using UV, I2, p-anisaldehyde, or phosphomolybdic acid solution for visualization. 1 H-and 13 C-NMR spectra were recorded on Bruker (Billerica, MA, USA) or Varian spectrometers (Palo Alto, CA, USA). IR spectra were measured on a Perkin-Elmer 1750-FT (Waltham, MA, USA). Gas chromatography analyses were performed in a HP-6890 series II (Agilent, Santa Clara, CA, USA) and/or Shimadzu-2010 (Kyoto, Japan). Melting points were done in Büchi Melting Point B-545 (Flawil, Switzerland) and are uncorrected. HRMS analyses were performed on a Bruker Daltonics Microtof Eletrospray (Billerica, MA, USA). CHN analyses were performed with Perkin-Elmer CHN 2400 equipment (Waltham, MA, USA). The percentage of bromine in the organic compounds was determined by volumetric titration using a solution of Hg(NO3)2 and diphenylcarbazone as indicator.

Conclusions
In conclusion, a metal-free approach for the synthesis of seven-and eight-membered rings through an iodine(III)-mediated ring expansion reaction was described. The substrates can be easily obtained from readily available starting materials. The amount of the oxidizer and the reaction conditions can be managed to obtain different products. Moreover, a short route to the synthesis of medium-ring lactones was developed. The antiproliferative activity of new seven-membered ring compounds was evaluated, and the results showed compound 12f as having a moderated citostatic effect. The results herein described have great potential for application in the chemical synthesis of seven-membered rings.