Kuya Metal-Free Synthesis of Indanes by Iodine ( III )-Mediated Ring Contraction of 1 , 2-Dihydronaphthalenes

A metal-free protocol was developed to synthesize indanes by ring contraction of 1,2-dihydronaphthalenes promoted by PhI(OH)OTs (HTIB or Koser’s reagent). This oxidative rearrangement can be performed in several solvents (MeOH, CH3CN, 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), and a 1:4 mixture of TFE:CH2Cl2) under mild conditions. The ring contraction diastereoselectively gives functionalized trans-1,3-disubstituted indanes, which are difficult to obtain in synthetic organic chemistry.


Introduction
The indane ring system is present in several natural products and in non-natural compounds with remarkable biological activity. 1 Consequently, efforts have continuously been made to develop new routes to obtain molecules with this unit. 2A typical strategy to synthesize a functionalized indane is by selecting an appropriate indanone, which is then elaborated into the target molecule. 2,3As tetralones are usually cheaper than indanones, the preparation of indanes starting from a tetralone (or a derivative) through a ring contraction rearrangement could be advantageous. 4 the last years, hypervalent iodine reagents have become an essential tool in synthetic organic chemistry due to the plethora of reactions that can be performed with them in excellent yield and selectivities. 5Moreover, hypervalent iodine compounds represent in many cases an alternative to toxic heavy metals. 5Although the oxidative rearrangement of alkenes mediated by iodine(III) has been described in some papers, 6 the ring contraction of 1,2-dihydronaphthalenes was reported for a few substrates using only p-Me-C 6 H 4 -IF 2 , 6 which led to fluorinated indanes.
Herein, we describe an efficient metal-free protocol for the synthesis of indanes under mild conditions.In a preliminary communication, we report the ring contraction of 1,2-dihydronaphthalenes (which are obtained from 1-tetralones) mediated by PhI(OH)OTs (HTIB or Koser's reagent) for a few substrates. 7In this article, the oxidation of several additional substrates is presented, better defining the reaction scope.Additionally, other reaction conditions were

Ring contractions in methanol
The required 1,2-dihydronaphthalenes are readily available substrates that can be prepared from 1-tetralones by reduction or Grignard reaction followed by dehydration 7,8 (see Supplementary Information, SI, for details).This work was initiated studying the oxidation of 1a with the readily available iodine(III) reagents HTIB, PhI(OAc) 2 , and PhI(OCOCF 3 ) 2 in methanol.Mixtures of several compounds and/or starting material were obtained using PhI(OAc) 2 or PhI(OCOCF 3 ) 2 .Albeit the addition product 3a was isolated as the major component, the desired indane 2a was isolated using HTIB (Table 1, entry 1).Thus, HTIB was selected for further tests.When the reaction was performed at −10 ºC, the overall isolated yield was lower (2a: 24%, trans-3a: 20%, cis-3a: 15%) than at room temperature.The use of trimethylorthoformate (TMOF) as solvent, instead of MeOH, also decreased the global yield (2a: 14%, trans-3a: 12%, cis-3a: 2%).These two trends are opposite to that observed in analogous thallium(III) promoted oxidation of 1,2-dihydronaphthalenes. 9 Although indane 2a was obtained in only 36%, we decided to study the behavior of the methylsubstituted 1,2-dihydronaphthalene 1b, hoping to obtain a higher yield of the ring contraction product. 9Indeed, when 1b was treated with HTIB, the desired trans-indane 2b was obtained in 55% yield, together with the addition products 3b (entry 2).The ring contraction of 1,2-dihydronaphthalene 1c was performed with 3.6 equiv. of HTIB, which delivered indane 2c in 62% yield, as a single diastereomer, together with the addition product 3c in 35% yield (entry 3).With a lower amount of HTIB, the yield of 2c is smaller.A similar pattern was also observed in Tl(III) reactions, where an excess of the oxidant increased the yield of the indane. 8It is important to note that the diastereoselective synthesis of trans-1,3-disubstituted indanes is a difficult task in synthetic organic chemistry. 10Compound 2c is a synthetic intermediate in the synthesis of (±)-indatraline, which displays several interesting biological activities. 7The presence of donating groups at the aromatic ring may facilitate the rearrangement of 1,2-dihydronaphthalenes by increasing the migratory aptitude of the migrating carbon. 8Indeed, the oxidation of alkene 1d, that bears an amide group para to the migrating carbon, with HTIB gave the desired acetal 2d in much higher yield than the corresponding non-substituted substrate 1a (entry 4).However, the treatment of alkene 1e with HTIB gave indane 2e in comparable yield to that obtained for the substrate 1a (cf.entries 1 and 5).When HTIB was added to a methanol solution of substrates 1f-g, which bear a methoxy group at the aromatic ring, the mixture immediately became black, leading to indanes 2f-g in low yield (entries 6 and 7).Low yields in iodine(III)-mediated oxidation of methoxysubstituted substrates has also been observed by others. 11,12onsidering our experience in the oxidations of alkenes mediated by Tl(III), 9 we expected that the trisubstituted 1,2-dihydronaphthalene 1h would have a different behavior toward HTIB from that of the disubstituted alkene 1a.Indeed, when 1h was treated with HTIB in MeOH only the addition product 3h was isolated (entry 8).It is important to note that the acetal moiety in indanes like 2a-g can be easily transformed without epimerization into the corresponding aldehyde. 2

Ring contractions in acetonitrile
The conditions used by Kirschning and co-workers 6 in the oxidation of carbohydrates were also applied in the oxidation of 1,2-dihydronaphthalenes. Naphthalene (4a) was isolated in 30% yield when 1a was treated with HTIB in CH 3 CN (Table 2, entry 1).NMR analysis of the crude product indicates the presence of indane 5a as a minor component, which decomposed during the purification step. 13Similarly, 4a was obtained in 48% yield when the reaction was performed in CH 2 Cl 2 , as solvent.However, when 1h was treated with HTIB in CH 3 CN indane 5h was isolated in 51% yield (entry 2), which should be compared to exclusive formation of addition products in MeOH reactions (Table 1, entry 8).Ring contractions of epoxides can also be performed by treatment with Brønsted or Lewis acids. 4 However, compound 5h can not be prepared in this manner, as no ring contraction product was obtained from the epoxide prepared from 1h. [14][15][16][17] The oxidative rearrangement of other 4-alkyl-1,2-dihydronaphthalenes was also investigated.The reaction of alkenes 1i and 1g, which bear a methoxy group in the aromatic ring, with HTIB in CH 3 CN furnished indanes 5i and 5g, respectively, in low yield (Table 2, entries 3 and 4), similarly to the disubstituted alkenes (Table 1, entries 6-7).Trisubstituted alkenes 1k-m were transformed into indanes 5k-m 13 in good yield (entries 5-7).Thus, the ring contraction is not precluded by the presence of bulky alkyl groups.The behavior of alkene 1n is slightly different to that observed for other substrates.The reaction of 1n with HTIB in CH 3 CN led mainly to indane 5n and ketone 6n 18 in 26 and 23% yield, respectively.The tetralone 6n is formed by migration of the phenyl group. 6The reaction of 1n with HTIB led to a nearly 1:1 mixture of the rearrangement products 5n and 6n, because the aromatic rings have similar migratory aptitude.In theory, if the migratory aptitude of the aromatic rings was different, the ratio of the rearrangement products could be modified.Indeed, when 1o, which has two Cl atoms in one of the rings, was treated with HTIB, trans-indane 5o was isolated and the product of migration of the C 6 H 3 Cl 2 group was not formed, because of the low migratory aptitude of C 6 H 3 Cl 2 .However, a small amount of the tetralone 7o, which is formed by migration of hydride, 13,16 was isolated (entry 9).Finally, we investigated the ring contraction in a seven-membered ring substrate.When alkene 1p was treated with HTIB in CH 3 CN, the substituted tetralin 5p was obtained in good yield (entry 10).The ring contractions in CH 3 CN were performed under inert atmosphere and in the presence of molecular sieves.When these conditions were  not followed, lower yields were observed.The preparation of indanes analogues to 5 from 1,2-dihydronaphthalenes has been reported in a two-step protocol using NBS/water followed by reaction with Et 2 Zn, which requires anhydrous conditions. 17

Ring contractions in fluorinated solvents
After investigating the oxidation of 1,2-dihydronaphthalenes with HTIB in methanol and in acetonitrile, we focused on the more polar solvents 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) because we envisioned that the formation of by products could be decreased performing the reaction in these high polar low nucleophilic solvents.Since the first report by Kita et al., 19 the fluoroalcohols TFE 20 and HFIP 21 have been used as solvent in several reactions with hypervalent iodine compounds.However, TFE and HFIP have never been used in the oxidative rearrangement of alkenes. 5,6or the alkene 1a, the yield of the desired product jumped from 36% (cf.entry 1, Table 1) to more than the double (73%, Table 3, entry 1).The reaction of 1b with HTIB in TFE led to indane 8b in higher yield than in MeOH (55% vs. 70%), although the diastereoselectivity is lower (entry 2 of Tables 1  and 3, respectively).The ring contraction of 1q in TFE led to 8q in 65% yield, as a 10:1 mixture of trans:cis diastereomers, respectively.Considering our previous work on the synthesis of 3-phenyl-1-indanamines, 7 the indane 8q could be used as an intermediate in the synthesis of (±)-irindalone. 225][26] The oxidation of trisubstituted alkenes 1h and 1p with HTIB in TFE gave indanes 5h and 5p, respectively, in higher yield than using acetonitrile (cf.Table 2, entries 2 and 10 with entries 4 and 7 of Table 3).On the other hand, 1k led to 5k in lower yield and diastereoselectivity than in acetonitrile (entry 5 of Tables 2 and 3).
Although the HTIB-mediated oxidation of 1,2-dihydronaphthalenes in TFE led to the rearrangement products in higher yields than in other solvents, the diastereoselectivity is lower.Thus, several conditions were tested trying to optimize the diastereoselectivity, without decreasing the isolated yields.Eventually, this goal was achieved by performing the reaction in a 4:1 mixture of CH 2 Cl 2 :TFE as solvent.Although CH 2 Cl 2 is the major component of the mixture, TFE must have a crucial role because the reaction of 1a with HTIB in pure CH 2 Cl 2 gave naphthalene (cf.entry 1, Table 2).The indane 8a was obtained from 1a in a yield comparable to the reaction in only TFE (73% vs. 67% yield, entry 1, Table 3).The alkene 1q gave the indane 8q in 69% yield, as a trans:cis   ratio of 17:1, i.e., in better yield and selectivity than using only TFE (entry 3, Table 3).The reaction in CH 2 Cl 2 /TFE is also appropriate for trisubstituted alkenes.Ketones 5k and 5m were obtained in higher yield than in acetonitrile or in TFE.Furthermore, the diastereoselectivity is higher than in TFE and comparable to the reaction in acetonitrile (cf.entries 5 and 7 of Table 2 and entries 5 and 6 of Table 3).In summary, treatment of 1,2-dihydronaphthalenes with HTIB in TFE or in CH 2 Cl 2 /TFE gave the desired indanes in higher yields than using MeOH or CH 3 CN for either di-or trisubstituted double bonds.
Considering the very good results with TFE, the obvious extension would be the study of the reaction in the even more polar solvent HFIP.The oxidation of alkene 1a in HFIP was very fast and led to indane 5a.The yield of the ring contraction product was, however, lower than in TFE (cf.entries 1 and 8, Table 3).In the presence of the bulky and low nucleophilic solvent HFIP an aldehyde (5a) is isolated instead of acetals, as in MeOH or in TFE (2a and 8a).Aldehyde 5a is not very convenient for manipulation and storage because it decomposes.We thus investigated if 5a could be reduced in situ, giving a stable alcohol.The reaction of 1a with HTIB in HFIP followed by addition of NaBH 4 gave the desired alcohol 9a in only 34% yield (entry 9).Changing the solvent to a mixture of CH 2 Cl 2 :HFIP (4:1), the alcohol 9a was isolated in better yield, however together with the gem ditosylate 10a 6 in 17% yield (entry 10).We envisioned that the addition of H 2 O could favor the formation of 9a, avoiding the undesired product 10a.Indeed, a smooth ring contraction/reduction was observed when 1a was treated with HTIB in the presence of H 2 O in CH 2 Cl 2 /HFIP (4:1) as solvent, followed by addition of NaBH 4 , giving 9a in 74% isolated yield (entry 11).

Mechanism discussion
The exclusive formation of trans-1,3-disubstituted indanes in the ring contractions in methanol can be explained by the mechanism detailed below.The electrophilic anti-addition of HTIB to the double bond would lead to 12a, through the cyclic organoiodine intermediate 11.The approach of the electrophile occurs opposite to the remote methyl group, [27][28][29] explaining the stereoselectivity of this ring contraction, as well as of the other reactions discussed below.The adduct 12a would equilibrate to its more stable conformational isomer 12b, on which the required anti-periplanarity for the rearrangement is achieved.Migration of the aryl group (carbon 8a) on 13 would displace PhI giving the oxonium 14, which would furnish the trans-indane 2b after addition of MeOH (Scheme 1).The diastereoselective formation of the trans products in ring contractions in TFE or in CH 2 Cl 2 /TFE can be explained by similar mechanisms.However, considering the anhydrous conditions of the ring contraction in CH 3 CN, the mechanism is probably different, as shown in Scheme 2 for 1n.The stereoselective electrophilic addition of HTIB to the alkene 1n would give the bis-benzylic carbocation 15.The hydroxyl group would attack the C1 position of 15, giving the four-membered ring intermediate 16, 6 which would ring open to form 17. The ring contraction would take place on its conformer (18)  giving trans-5n (path a, Scheme 2).The solvent may have some influence in the stereoselectivity of the electrophilic addition of the iodine(III), explaining the formation of  cis-1,3-disubstituted indanes.Alternatively, the cis indanes can be formed by epimerization of the ketone moiety of the corresponding trans isomers.Starting from trisubstituted double bonds, the ring contraction lead to ketones which are always obtained as a free carbonyl.Aldehydes are formed from disubstituted alkenes.In the presence of a nucleophilic solvent, such as MeOH or TFE, acetals were isolated.On the other hand, free aldehydes were obtained in CH 3 CN or in HFIP.
The formation of the cis-2,4-disubstituted-1-tetralone 6n can be explained by the mechanism shown in path b of Scheme 2. The Ph group would migrate on intermediate 17, with the exit of PhI, leading to cis-6n.trans-6n can be formed either by isomerization of cis-isomer or the addition of I(III) to 1n could take place by the other face.In acetonitrile oxidations, small amounts of naphthalenes were isolated in some reactions, which are formed by addition followed by elimination. 13 plausible mechanism to explain the formation of the products of addition of MeOH is shown in Scheme 3, using substrate 1a as example. 6,8The methoxy group of 19 would intramolecularly displace PhI, giving the oxonium 20.Methanol would attack the C1 benzylic position of 20, furnishing trans-3a (path a).Alternatively, the intermolecular displacement of PhI by MeOH in the intermediate 19 would lead to cis-3a (path b).The preferential formation of the trans isomers (Table 1) indicates that the intramolecular process is favored.The formation of cis-and trans-isomers has also been observed in the reaction of indene with iodosobenzene derivatives in methanol. 30However, the oxidation of cyclohexenes with iodine(III) led to rearrangement products, 6 cis-isomers 6,[31][32][33] or trans-isomers, 31,34 depending mainly on the reaction conditions.

Conclusions
A one-step, fast, mild and metal-free protocol was developed for the synthesis of indanes through ring contraction of readily available 1,2-dihydronaphthalenes mediated by HTIB.This oxidative rearrangement is diastereoselective giving 1,3-trans-disubstituted indanes preferentially or exclusively.The developed methodology facilitates the access to this structural motif, which is difficult to construct.Moreover, indanes bearing different functional groups can be easily obtained by changing the reaction conditions.In summary, the protocol herein presented will be useful in synthetic organic chemistry and in medicinal chemistry to access functionalized indanes in an expeditious manner.The protocol represents a green alternative to the analogous reaction using toxic thallium(III) salts. 8,9,13,35,36

Synthesis of 4-(4-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one
To a dry round bottom flask under nitrogen atmosphere, AlCl 3 (7.8g, 59 mmol) was added followed by the addition of fluorobenzene (10.8 mL, 11.1 g, 115 mmol).After cooling the flask to 0 o C, 1-naftol (3.0 g, 20.8 mmol) was added portion-wise under strong stirring (cake forms).After the addition, the flask was charged with a condenser and stirred at 75 o C for 1.5 h.The reaction was again cooled to 0 o C and quenched by adding ice through the condenser (strongly exothermic), until no gas evolution could be observed.The reaction mixture was extracted with (2 × 20 mL) and brine, dried with Na 2 SO 4 , filtered and concentrated to give a thick brown oil (5.48 g).The crude oil was purified by column chromatography (10% Et 2 O in hexane), where the o-isomer elutes first followed by the m-and p-isomers.As the m-and p-isomers have the same R f value, the mixed fractions were checked by GC to collect fractions with pure p-product 4-(4-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one 37 (1.14 g, 4.75 mmol, 23%).

Reaction of 1,2-dihydro-7-methoxy-4-methylnaphthalene (1i) with HTIB in CH 3 CN
To a solution of 1i (0.178 g, 1.02 mmol) and molecular sieves (3 Å, 0.100 g) in CH 3 CN (10 mL) under N 2 was added HTIB (0.442 g, 1.13 mmol) at 0 °C.The ice bath was removed.The mixture was stirred for 15 min at room temperature.A saturated solution of NaHCO 3 was added until pH 7. The organic phase was washed with H 2 O, with brine and dried over anhydous MgSO 4 .The solvent was removed under reduced pressure.The crude product was purified by column (0-40% EtOAc in hexane), affording 5i 39 (0.0231 g, 0.121 mmol, 12%), as a yellow oil and a mixture 1:1 of 4i 40 and starting material (0.0361 g), as a colorless oil.

a
Yield not determined; b together with 1i, ca.20%.

19 b 3 .
Scheme 3. Mechanism for the formation of addition products 3a.

Table 3 .
Reaction of 1,2-dihydronaphthalenes with HTIB in fluoroalcohols a Mechanism for the ring contraction of 1b in MeOH.