SciELO - Scientific Electronic Library Online

 
vol.22 issue9Use of Fe3+ ion probe to study intensively weathered soils utilizing electron paramagnetic resonance and optical spectroscopyDansyl-based fluorescent films prepared by chemical and electrochemical methods: cyclic voltammetry, afm and spectrofluorimetry characterization author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Article

Indicators

Related links

  • Have no similar articlesSimilars in SciELO

Share


Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.22 no.9 São Paulo Sept. 2011

http://dx.doi.org/10.1590/S0103-50532011000900024 

ARTICLE

 

Metal-free synthesis of indanes by iodine(III)-mediated ring contraction of 1, 2-dihydronaphthalenes

 

 

Fernanda A. SiqueiraI,#; Eloisa E. IshikawaI; André FogaçaI; Andréa T. FaccioI; Vânia M. T. CarneiroI; Rafael R. S. SoaresI,§; Aline UtakaI; Iris R. M. TébékaI; Marcin BielawskiI, II; Berit OlofssonII; Luiz F. Silva JrI,*,

IDepartamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, CP 26077, 05513-970 São Paulo-SP, Brazil
IIDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden

 

 


ABSTRACT

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.

Keywords: indanes, hypervalent iodine, ring contraction, 1 , 2-dihydronaphthalenes, rearrangements


RESUMO

Um protocolo livre de metais foi desenvolvido para sintetizar indanos através da contração de anel de 1, 2-di-hidronaftalenos promovida por PhI(OH)OTs (HTIB ou reagente de Koser). Este rearranjo oxidativo pode ser realizado em diversos solventes (MeOH, CH3CN, 2 , 2, 2-trifluoroetanol (TFE), 1 , 1, 1, 3, 3, 3-hexafluoroisopropanol (HFIP), e uma mistura 1:4 de TFE:CH2Cl2) em condições brandas. A contração de anel fornece indanos trans-1, 3-dissubstituídos diastereosseletivamente, os quais são difíceis de obter em química orgânica sintética.


 

 

1. 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.2 A typical strategy to synthesize a functionalized indane is by selecting an appropriate indanone, which is then elaborated into the target molecule.2, 3 As 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

In 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.5 Moreover, hypervalent iodine compounds represent in many cases an alternative to toxic heavy metals.5 Although 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-C6H4-IF2, 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.7 In this article, the oxidation of several additional substrates is presented, better defining the reaction scope.Additionally, other reaction conditions were discovered using fluoroalcohols as solvent, which highly improved isolated yields. The best condition employed a 4:1 mixture of CH2Cl2-TFE that led to indanes in very good yield and with high diastereoselectivity.

 

Results and Discussion

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 dehydration7, 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(OCOCF3)2 in methanol. Mixtures of several compounds and/or starting material were obtained using PhI(OAc)2 or PhI(OCOCF3)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.9Although 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.9 Indeed, 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.8 It is important to note that the diastereoselective synthesis of trans-1, 3-disubstituted indanes is a difficult task in synthetic organic chemistry.10 Compound 2c is a synthetic intermediate in the synthesis of (±)-indatraline, which displays several interesting biological activities.7 The 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.8 Indeed, 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, 12 Considering 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-workers6 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 CH3CN (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.13 Similarly, 4 a was obtained in 48% yield when the reaction was performed in CH2Cl2, as solvent. However, when 1h was treated with HTIB in CH3CN 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.14-17 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 CH3CN 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-m13 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 CH3CN led mainly to indane 5n and ketone 6n18 in 26 and 23% yield, respectively. The tetralone 6n is formed by migration of the phenyl group.6 The 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 C6H3Cl2 group was not formed, because of the low migratory aptitude of C6H3Cl2. 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 CH3CN, the substituted tetralin 5p was obtained in good yield (entry 10). The ring contractions in CH3CN 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 Et2Zn, 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 TFE20 and HFIP21 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, 6

For 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.22 Moreover, this new method to obtain fluorinated acetals, which have different applications, 23 is more efficient than the previous described.24-26 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 CH2Cl2:TFE as solvent. Although CH2Cl2 is the major component of the mixture, TFE must have a crucial role because the reaction of 1a with HTIB in pure CH2Cl2 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 CH2Cl2/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 CH2Cl2/TFE gave the desired indanes in higher yields than using MeOH or CH3CN 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 NaBH4 gave the desired alcohol 9a in only 34% yield (entry 9). Changing the solvent to a mixture of CH2Cl2:HFIP (4:1), the alcohol 9a was isolated in better yield, however together with the gem ditosylate 10a6 in 17% yield (entry 10). We envisioned that the addition of H2O 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 H2O in CH2Cl2/HFIP (4:1) as solvent, followed by addition of NaBH4, 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, 27-29 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 CH2Cl2/TFE can be explained by similar mechanisms. However, considering the anhydrous conditions of the ring contraction in CH3CN, 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 CH3CN 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

A plausible mechanism to explain the formation of the products of addition of MeOH is shown in Scheme 3, using substrate 1a as example.6, 8 The 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.30 However, the oxidation of cyclohexenes with iodine(III) led to rearrangement products, 6 cis-isomers6, 31-33 or trans-isomers, 31, 34 depending mainly on the reaction conditions.

 

 

As described above, the solvent has a crucial role in the oxidation of 1, 2-dihydronaphthalenes with HTIB. In methanol, ring contraction is favored toward the addition of solvent for disubstituted double bonds. However, for trisubstituted substrates, the nucleophilic attack of MeOH is faster, probably because the required conformations for the rearrangements are disfavored with an additional methyl group (12b and 13 with Me instead Hª in Scheme 1). In anhydrous acetonitrile, there is no good nucleophile and ring contraction of trisubstituted alkenes occurs through the formation of a tertiary benzylic carbocation (like 15). For disubstituted double bonds, the ring contraction would occur through a less favored secondary benzylic carbocation and, thus, the formation of naphthalenes predominates. In TFE or in CH2Cl2/TFE, ring contraction was observed for either di- or trisubstituted 1, 2-dihydronaphthalenes. The mechanism described for MeOH is the major pathway, as acetals are isolated for disubstituted alkenes. Ring contraction also takes place with trisubstituted substrates, because a less nucleophilic species is present, making the formation of addition products more difficult.

 

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

 

Experimental

General procedure

Synthesis of 4-(4-fluorophenyl)-3, 4-dihydronaphthalen1(2H)-one

To a dry round bottom flask under nitrogen atmosphere, AlCl3 (7.8 g, 59 mmol) was added followed by the addition of fluorobenzene (10.8 mL, 11.1 g, 115 mmol). After cooling the flask to 0 ºC, 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 ºC for 1.5 h. The reaction was again cooled to 0 ºC and quenched by adding ice through the condenser (strongly exothermic), until no gas evolution could be observed. The reaction mixture was extracted with CH2Cl2 (3 × 25 mL), the organics washed with 1 mol L-1 NaOH (2 × 20 mL) and brine, dried with Na2SO4, filtered and concentrated to give a thick brown oil (5.48 g). The crude oil was purified by column chromatography (10% Et2O in hexane), where the o-isomer elutes first followed by the m-and p-isomers. As the m-and p-isomers have the same Rf value, the mixed fractions were checked by GC to collect fractions with pure p-product 4-(4-fluorophenyl)3, 4-dihydronaphthalen-1(2H)-one37 (1.14 g, 4 .75 mmol, 23%).

Synthesis of 1-(4-fluorophenyl)-1, 2-dihydronaphthalene (1c)

4-(4-fluorophenyl)-3, 4-dihydronaphthalen-1(2H)-one (806 µL, 3 .36 mmol) was added to a round bottom flask, diluted with MeOH (25 mL) followed by cooling to 0 ºC and addition of NaBH4 (140 mg, 3 .68 mmol). The reaction was quenched with H2O after 1 h and adjusted to pH 5 with 10% HCl. After evaporation of the MeOH, the aqueous phase was extracted with EtOAc (3 × 15 mL), followed by the washing of the organics with brine, dried with Na2SO4, filtered and concentrated to give a crude yellow oil of 4-(4-fluorophenyl)-1, 2, 3, 4-tetrahydronaphthalen1-ol (928 mg), which was used in the next step without any further purification. The crude tetralol (928 mg) was added to a dry round bottom flask, followed by dry toluene (20 mL) and a few crystals of p-TsOH (cat.). The flask was equipped with a dean-stark trap and refluxed until no alcohol remained according to TLC (ca. 1.5 h). The reaction was quenched with a saturated NaHCO3 solution and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (2 × 15 mL), brine (2 × 15 mL), dried with Na2SO4, filtered and concentrated to give a crude brown oil (761 mg). It was purified by column chromatography (hexane) to afford 1c as colorless oil (728 mg, 3 .25 mmol, 97% over 2 steps); 1H NMR (400 MHz, CDCl3) δ 2.56 (dddd, 1 H, J 13.8, 9.7, 4 .2 and 2.0 Hz), 2 .67 (dddd, 1 H, J 12.1, 7.4, 4 .6 and 1.8 Hz), 4 .12 (dd, 1 H, J 9.3 and 7.7 Hz), 5.99 (dt, 1 H, J 9.6 and 4.4 Hz), 6.55 (dt, 1 H, J 9.6 and 1.5 Hz), 6.81 (d, 1 H, J 7.7 Hz), 7.03-6.95 (m, 2 H), 7.14-7.07 (m, 2 H), 7.22-7.14 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ 32.2, 43.2, 115.3 (d, J 21 Hz), 126.4, 127.1, 127.1, 127.5, 127.9, 128.2, 129.9 (d, J 8 Hz), 134.2, 137.8, 140.3 (d, J 3 Hz), 161.7 (d, J 245 Hz); HRMS (m/z) calcd. for C16 H13F 247.0893 [M + Na]+, found 247.0901.

Reaction of 1, 2-dihydro-6-methoxynaphthalene (1f) with HTIB in MeOH

To a solution of 1f (0.328 g, 2 .05 mmol) in MeOH (8 mL) was added HTIB (0.941 g, 2 .40 mmol) at 0 ºC. Immediately after addition of HTIB the reaction became dark. The mixture was stirred at room temperature for 1 h. The reaction was extracted with EtOAc, washed with H2O, with brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column (0-25% EtOAc in hexane), affording 2f9 (0.0137 g, 0.0616 mmol, 3 %), as colorless oil, trans-3f9 (0.117 g, 0.526 mmol, 26%) and cis-3f (0.0779 g, 0.350 mmol, 17%), both as yellow oils. cis-1, 2, 3, 4-Tetrahydro-1, 2, 7-trimethoxynaphthalene (3f): colorless oil; IR νmax/cm-1 (film) 1101, 1249, 1499, 2834, 2933; 1H NMR (500 MHz, CDCl3) δ 1.91-1.94 (m, 1 H), 2 .16-2.23 (m, 1 H), 2 .67-2.74 (m, 1 H), 2 .92-2.96 (m, 1 H), (s, 3 H), 3 .50 (m, 3 H, ), 3 .61-3.69 (m, 1 H), 3 .79 (s, 3 H), (d, 1 H, J 3.1 Hz), 6.80 (dd, 1 H, J 8.3, 2 .6 Hz), 6.86 (d, 1 H, J 2.6 Hz), 7.04 (d, 1 H, J 8.3 Hz); 13C NMR (75 MHz, CDCl3) δ 22.7, 26.1, 55.3, 56.5, 57.4, 77.9, 78.2, 114.3, 114.4, 128.5, 129.7, 135.7, 157.5; LRMS (m/z, %) 222 (M+• , 17), 191 (7), 190 (52); 189 (9), 164 (100); HRMS (m/z) calcd. for C13 H18O3 [M + Na]+ 245.1148, found 245.1141.

Reaction of 1, 2-dihydro-6, 7-dimethoxynaphthalene (1g) with HTIB in MeOH

As 1f, but using 1g (0.0744 g, 0.391 mmol), HTIB (0.153 g, 0.391 mmol), and MeOH (2.0 mL). The reaction was stirred for 1 h at 0 ºC. The crude product was purified by column (0-30% EtOAc in hexane), affording 2g8 (0.0116 g, 0.0460 mmol, 12%) and trans-3g (0.0080 g, 0.032 mmol, 8%), both as a colorless oil. trans-1, 2, 3, 4-Tetrahydro1, 2, 6, 7-tetramethoxynaphthalene (3g): colorless oil; IR νmax/cm-1 (film) 1121, 1258, 1515, 2830, 2934; 1H NMR (300 MHz, CDCl3) δ 1.88-1.97 (m, 1 H), 2 .05-2.15 (m, 1 H), 2 .62-2.82 (m, 2 H), 3 .44 (s, 3 H), 3 .51 (s, 3 H), 3 .71 (ddd, 1 H, J 7.2, 4 .8, 2 .7 Hz), 3 .84 (s, 3 H), 3 .87 (3H, s), 4.21 (d, 1 H, J 4.8 Hz), 6.58 (1H), 6.83 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 23.4, 25.1, 55.9, 56.0, 56.7, 57.2, 77.2, 79.5, 111.1, 112.4, 126.5, 129.3, 147.5, 148.7; HRMS (m/z) calcd. for C14H20O4 [M + Na]+ 275.1254, found 275.1252.

Synthesis of 1-(dimethoxymethyl)-5-acetamido-indane (2d)

To a stirred mixture of 1d (0.254 g, 1 .36 mmol) and MeOH (27 mL), was added HTIB (0.590 g, 1 .50 mmol) at once at 0 ºC. After 35 min the reaction was quenched with saturated solution of NaHCO3. The aqueous phase was extracted with EtOAc (3 × 10 mL), washed with brine (2 × 10 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column (hexane:EtOAc, 3 :7) giving 2d (72%, 0.244 g, 0.98 mmol) as a yellow solid, trans-3d (10%, 0.035 g, 0.14 mmol) as a solid and cis-3d (7%, 0.025 g, 0.10 mmol) as a solid. 1-(Dimethoxymethyl)5-acetamido-indane (2d): mp 68.4-69.3 ºC; IR νmax/cm-1 (film) 828, 1058, 1124, 1372, 1426, 1492, 1546, 1602, 1667; 1H NMR (200 MHz, CDCl3) δ 1.85-2.28 (m, 3 H), 2.13 (s, 3 H), 2 .70-2.90 (m, 2 H), 3 .37 (s, 3 H), 3 .41 (s, 3 H), 4.27 (d, 1 H, J 7.4 Hz), 7.16 (dd, 1 H, J 1.4, 8.2 Hz), 7.32 (d, 1 H, J 8.0 Hz), 7.46 (s, 1 H), 7.84 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 24.3, 27.5, 31.4, 47.0, 52.9, 54.2, 107.2, 116.4, 118.2, 125.6, 136.8, 138.7, 145.6, 168.6; LRMS (m/z, %) 249 (M+•, 2 .4%), 218 (6), 186 (3), 174 (4), 144 (6), 132 (13), 115 (5), 103 (3), 75 (100); HRMS (m/z) calcd. for C14H19NO3 [M + H]+ 250.1438, found 250.1440. N-(trans-5, 6-dimethoxy-5, 6, 7, 8-tetrahydronaphthalen2-yl)acetamide (trans-3d): mp 108.7-110.5 ºC; IR νmax/cm-1 (film) 830, 915, 1091, 1331, 1372, 1419, 1505, 1544, 1598, 1614, 1671, 2934, 3302, 3507; 1H NMR (200 MHz, CDCl3) δ 1.81-2.18 (m, 2 H), 2 .13 (s, 3 H), 2 .58-2.90 (m, 2 H), 3 .44 (s, 3 H), 3 .48 (s, 3 H), 3 .67-3.74 (m, 1 H) 4.21 (d, 1 H, J 4.8 Hz), 7.21-7.27 (m, 2 H), 7.34 (s, 1 H), 7.56 (s, 1 H). 13C NMR (75 MHz, CDCl3) δ 23.3, 24.5, 25.5, 56.5, 57.3, 77.8, 79.2, 117.5, 119.4, 130.5, 130.6, 137.3, 137.9, 168.3; LRMS (m/z, %) 249 (M+•, 23%), 217 (27), 191 (100); HRMS (m/z) calcd. for C14H19NO3 [M + Na]+ 272.1257, found 272.1262. N-(cis-5, 6-dimethoxy-5, 6, 7, 8-tetrahydronaphthalen-2-yl) acetamide (cis-3d): IR νmax/cm-1 (film) 817, 882, 1081, 1106, 1372, 1419, 1505, 1544, 1602, 1614, 1671, 2933, 3311, 3509; 1H NMR (200 MHz, CDCl3) δ 1.86-2.30 (m, 2 H), 2 .16 (s, 3 H), 2 .68-3.07 (m, 2 H), 3 .45 (s, 3 H), 3 .47 (s, 3 H), 3 .57-3.67 (m, 1 H), 4 .32 (d, 1 H, J 2.8 Hz), 7.25-7.34 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 22.3, 24.6, 27.3, 56.4, 57.1, 77.5, 78.2, 117.1, 119.8, 130.5, 130.6, 137.6, 137.7, 168.3.; LRMS (m/z, %) 249 (M+•, 21%), 217 (28), 191 (100); HRMS (m/z) calcd. for C14H19NO3 [M + Na]+ 272.1257, found 272.1260.

Syntheses of cis and trans-1-(2, 3)-dihydro-1-metyl1H-inden-3-yl)pentan-1-one (5l)

To a solution of 1l (0.129 g, 0.647 mmol) and molecular sieves (3 Å, 0.065 g) in anhydrous CH3CN (6.5 mL) under N2 was added HTIB (0.489 g, 1 .25 mmol) at 0 ºC. The reactionwasstirred for15minat0ºC.Asaturatedsolution of NaHCO3 was added until pH 7. The organic phase was washed with H2O, with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column (0-10% EtOAc in hexane), affording 5l (0.0681 g, 0.315 mmol, 49%) as a trans:cis (10:1) mixture. Naphthalene 4l9 (0.0031 g, 0.016 mmol, 2 %) was also isolated as a colorless oil. cis and trans-5l: yellow oil; IR νmax/cm-1 (film) 755, 1460, 1711, 2870, 2931, 2959; 1H NMR (300 MHz, CDCl3) δ (trans isomer) 0.87 (t, 3 H, J 7.3 Hz), 1 .21-1.25 (m, 1 H), 1 .28 (d, 3 H, J 6.9 Hz), 1 .51-1.56 (m, 2 H), 2 .41-2.62 (m, 3 H), 3 .40 (sext, 1 H, J 6.8 Hz), 4 .08 (dd, 1 H, J 8.7, 3 .4 Hz), 7.14-7.28 (m, 4 H), (cis isomer) 0.91 (t, 3 H, J 7.5 Hz), 1 .35 (d, 3 H, J 6.9 Hz), 1 .81-1.85 (m, 2 H), 3 .21 (sext, 1 H, J 7.2 Hz) (other signals overlap with the trans form); 13C NMR (75 MHz, CDCl3) δ (trans isomer) 13.8, 20.2, 22.3, 25.8, 37.8, 38.5, 40.1, 57.0, 123.8, 124.7, 126.6, 127.6, 140.7, 149.3, 210.8, (cis isomer) 13.9, 19.7, 22.4, 25.9, 38.3, 40.8, 123.5, 124.6, 127.4, 141.0, 148.8, 211.3 (other signals overlap with the trans form); LRMS (m/z, %) 216 (M+•, 5), 131 (100); HRMS (m/z) calcd. for C15O [M + H]+ 217.1587, H20 found 217.1586.

Reaction of 4-isopropyl-1-methyl-1, 2-dihydronaphthalene (1m) with HTIB in CH3CN

The typical procedure for reactions in CH3CN was followed, but using 5m (0.187 g, 1 .00 mmol). The crude product was purified by flash column chromatography (gradient elution, 0-20% EtOAc in hexanes), affording indane 5m (0.0981 g, 0.485 mmol, 48%)13 as a trans:cis (5:1 by 1H NMR after purification) mixture, as yellow oil. Naphthalene 4m (0.0244 g, 0.132 mmol, 13%)38 was also isolated as colorless oil.

Reaction of 1, 2-dihydro-7-methoxy-4-methylnaphthalene (1i) with HTIB in CH3CN

To a solution of 1i (0.178 g, 1 .02 mmol) and molecular sieves (3 Å, 0.100 g) in CH3CN (10 mL) under N2 was added HTIB (0.442 g, 1 .13 mmol) at 0 ºC. The ice bath was removed. The mixture was stirred for 15 min at room temperature. A saturated solution of NaHCO3 was added until pH 7. The organic phase was washed with H2O, with brine and dried over anhydous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column (0-40% EtOAc in hexane), affording 5i39 (0.0231 g, 0.121 mmol, 12%), as a yellow oil and a mixture 1:1 of 4i40 and starting material (0.0361 g), as a colorless oil.

Reaction of 1, 2-dihydro-6-methoxy-4, 7-dimethynaphthalene (1j) with HTIB in CH3CN

As for 1i, but using 1j (0.197 g, 1 .05 mmol), molecular sieves (3 Å, 0.100 g), HTIB (0.489 g, 1 .25 mmol), CH3CN (10 mL). The mixture was stirred for 30 min at room temperature. The crude product was purified by column (0-40% EtOAc in hexane) affording 5j8 (0.0420 g, 0.204 mmol, 20%) and impure 4j (0.0594 g). Impure 4j was purified by column (10% EtOAc in hexane), affording 4j41 (0.0381 g, 0.205 mmol, 20%).

Reaction of 1, 2-dihydro-1-methyl-4-phenylnaphthalene (1n) with HTIB in CH3CN

As for 5l, but using 1n (0.165 g, 0.750 mmol), molecular sieves (3 Å, 0.0750 g), HTIB (0.353 g, 0.901 mmol), and CH3CN (7.5 mL). The mixture was stirred for 20 min at room temperature. The product crude was purified by column (0-10% EtOAc in hexane) affording 5n (0.0452 g, 0.191 mmol, 26%), 13 and 6n (0.0414 g, 0.175 mmol, 23%), 18 as yellow oil and as a cis:trans mixture (6:1). 4n (7.00 mg, 0.0321 mmol, 4 %)42 was isolated, as a colorless oil.

Reaction of 4-(3, 4-dichlorophenyl)-1-methyl-1, 2-dihydronaphthalene (1o) with HTIB in CH3CN

As for 1i, but using 1o (0.118 g, 0.408 mmol), molecular sieves (3 Å, 0.0413 g), HTIB (0.194 g, 0.495 mmol), and CH3CN (4.0 mL). The mixture was stirred for 20 min at room temperature. The product was purified by column (030% EtOAc in hexane) affording 5o (0.0430 g, 0.141 mmol, 35%) and 7o (0.0070 g, 0.023 mmol, 6%), both as a yellow oil. trans-(3, 4-Dichlorophenyl)-2, 3-dihydro-1-methyl1H-inden-3-yl)methanone (5o): IR νmax/cm-1 (film) 755, 1030, 1206, 1687, 2867, 2925, 2958; 1H NMR (500 MHz, CDCl3) δ 1.34 (d, 3 H, J 6.9 Hz), 2 .0.2 (ddd, 1 H, J 12.8, 7.6, 8.7 Hz), 2 .68 (ddd, 1 H, J 12.5, 7.8, 4 .0 Hz), 3 .49 (sext, 1 H, J 7.2 Hz), 4 .95 (dd, 1 H, J 8.8, 3 .9 Hz), 7.04 (d, 1 H, J 7.5 Hz), 7.11-7.14 (m, 1 H), 7.24-7.25 (m, 2 H), 7.59 (d, 1 H, J 8.4 Hz), 7.86 (dd, 1 H, J 8.3, 2 .0 Hz), 8.11 (d, 1 H, J 2.0 Hz); 13C NMR (75 MHz, CDCl3) δ 20.4, 38.4, 38.5, 51.3, 124.0, 124.0, 126.6, 127.9, 127.9, 130.8, 130.8, 133.5, 136.4, 137.7, 140.0, 149.4, 198.2; LRMS (m/z, %) 305 (M+•, 1 %), 131 (100); HRMS (m/z) calcd. for C17H14Cl2O [M + H]+ 305.0494, found 305.0486. 1-(3, 4-Dichlorophenyl)-3, 4-dihydro-4-methylnaphthalen2(1H)-one (7o): IR νmax/cm-1 (film) 755, 1030, 1206, 1687, 2867, 2925, 2958; 760, 1031, 1175, 1380, 1467, 1722, 2928, 2963; 1H NMR (300 MHz, CDCl3) δ 2.31 (dd, 1 H, J 16.8, 7.5 Hz), 2 .98 (dd, 1 H, J 16.8, 6.6 Hz), 3 .12 (sext, 1 H, J 6.9 Hz), 4 .77 (s, 1 H), 6.88 (dd, 1 H, J 8.4, 2 .4 Hz), 7.16 (d, 1 H, J 2.1 Hz), 7.30-7.47 (m, 4 H), 7.62-7.71 (m, 1 H, ); 13C NMR (75 MHz, CDCl3) δ 20.1, 32.5, 41.8, 54.2, 125.5, 126.5, 127.5, 127.8, 128.9, 129.2, 130.6, 132.8, 133.9, 137.2, 140.2, 141.1, 208.8; HRMS (m/z) calcd. for C17H14Cl2O [M + H]+ 305.0494, found 305.0486.

Reaction of 9-methyl-6, 7-dihydro-5H-benzo[7]annulene (1p) with HTIB in CH3CN

The typical procedure for reactions in CH3CN was followed, but using 1p (0.0416 g, 0.263 mmol), molecular sieves (3 Å, 0.0179 g), HTIB (0.118 g, 0.301 mmol) in anhydrous CH3CN (2.5 mL). The mixture was stirred for 15 min at room temperature. The crude product was purified by flash column chromatography (15% EtOAc in hexanes) affording 5p43 (0.0241 g, 0.138 mmol, 52%), as a colorless oil.

Synthesis of 1-[bis(trifluoromethoxy)methyl]-2, 3-dihydro1H-indene (8a)

To a stirred mixture of 1a (0.102 g, 0.78 mmol) and TFE (6 mL), was added HTIB (0.34 g, 0.86 mmol) at once at 0 ºC. After 30 min the reaction was quenched with saturated solution of NaHCO3 until pH 7. The aqueous phase was extracted with EtOAc (3 × 10 mL), washed with brine (2 × 10 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by column (hexane:EtOAc, 9:1) giving 8a (73%, 0.19 g, 0.57 mmol) as a light yellow oil; IR νmax/cm-1 (film) 2949, 2855, 1460, 1281, 1164, 1078; 1H NMR (300 MHz, CDCl3) δ 1.96-2.08 (m, 1 H), 2 .18-2.30 (m, 1 H), 2 .82-3.03 (m, 2 H), 3 .47 (q, 1 H, J 7.9 Hz), 3 .864.07 (m, 4 H), 4 .70 (d, 1 H, J 7.9 Hz), 7.15-7.24 (m, 3 H), 7.38-7.41 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 27.1, 31.2, 47.2, 61.9 (q, J 34.9 Hz), 63.4 (q, J 34.9 Hz), 105.4, 123.7 (q, J 276 Hz), 123.8 (q, J 276 Hz), 124.6, 125.5, 126.5, 127.6, 140.8, 144.6; LRMS (m/z, %) 328 (M, 1 .3%), 211 (70), 129 (21), 117 (100); HRMS (m/z) calcd. for C14H14F6O2 [M + Na]+ 351.0790, found 351.0801.

Synthesis of 1-[bis(trifluoromethoxy)methyl]-2, 3-dihydro3-methyl-1H-indene (8b)

As for 1a, but using 1b (0.146 g, 1 .01 mmol). HTIB was added at once. The reaction was quenched after 7 min. Compound 8b was obtained as a yellow oil (70%, 0.243 g, 0.710 mmol) as a 5:1 trans:cis mixture; IR νmax/cm-1 (film) 2961, 2932, 2872, 1458, 1281, 1174, 1078, 758; 1H NMR (300 MHz, CDCl3) δ (trans isomer) 1.27 (d, 3 H, J 6.9 Hz), 1 .81 (ddd, 1 H, J 13.2, 8.5, 7.3 Hz), 2 .32 (ddd, 1 H, J 13.2, 7.8, 4 .2 Hz), 3 .22-3.34 (m, 1 H), 3 .43-3.50 (m, 1 H), 3 .82-4.06 (m, 4 H), 4 .64 (d, 1 H, J 8.1 Hz), 7.18-7.36 (m, 4 H), (cis isomer) 1.33 (d, 3 H, J 6.9 Hz), 2 .40-2.55 (m, 1 H), 4 .75 (d, 1 H, J 8.4 Hz), 7.08-7.13 (m, 1 H), 7.41-7.44 (m, 1 H), 7.68-7.72 (m, 1 H) (other signals overlap with the trans form); 13C NMR (75 MHz, CDCl3) δ (trans isomer) 20.5, 35.9, 37.6, 46.0, 61.6 (q, J 34.7 Hz), 63.8 (q, J 34.7 Hz), 105.1, 123.5, 123.6 (q, J 276 Hz), 123.8 (q, J 276 Hz), 125.8, 126.6, 127.8, 140.3, 149.2, (cis isomer) 19.7, 36.9, 37.7, 45.6, 105.7, 123.3, 124.8, 126.7, 127.6, 130.2, 137.5 (other signals overlap with the trans form); LRMS (m/z, %) (major diastereomer) 242 (M-CF3CH2OH, 17%), 211 (69), 131 (100), (minor diastereomer) 342 (M, 3 %), 242 (9), 211 (75), 131 (100); HRMS (m/z) calcd. for C15H16F6O2[M + Na]+ 365.0947, found 365.0960.

Synthesis of 1-(2, 3-dihydro-1H-inden-3-yl)ethanone (5h)

As for 1a, but using 1h (0.158 g, 1 .10 mmol). The reaction was quenched after 30 min. The crude product was purified by column (5-10% EtOAc in hexane) affording 5h7 (72%, 0.127 g, 0.791 mmol), as a light yellow oil.

Synthesis of 1-(1, 2, 3, 4-tetrahydronaphthalene-4-yl) ethanone (5p)

As for 1a, but using 1p (0.158 g, 1 .00 mmol). The reaction was quenched after 20 min. The crude product was purified using column (hexane:EtOAc, 9:1) giving 5p13 (62%, 0.107 g, 0.62 mmol), as a light yellow oil.

Synthesis of 1-(bis(2, 2, 2-trifluoroethoxy)methyl)3-(4-fluorophenyl)-2, 3-dihydro-1H-indene (8q)

A dry round bottom flask was charged with 1q (240 mg, 1 .07 mmol), CH2Cl2/TFE (4:1 v/v) followed by HTIB (550 mg, 1 .40 mmol) at room temperature. The reaction color changed towards yellow within a minute. After 10 min at room temperature, the reaction was quenched with H2O, washed with H2O (2 × 20 mL), with 50% NaHCO3 solution (2 × 20 mL), with H2O (20 mL), with brine (2 × 20 mL), dried over anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure to give a brownish oil. The crude product was purified by column (0-25% EtOAc in hexane) giving 8q (312 mg, 0.739 mmol, 69%), as a trans:cis (17:1) mixture as colorless oil; 1H NMR (300 MHz, CDCl3) δ (trans isomer) 2.18 (ddd, 1 H, 13.5, 8.5, 7.7 Hz), 2 .60 (ddd, 1 H, J 13, 5, 8.2, 4 .2 Hz), 3.58 (dt, 1 H, J 8.2, 4 .2 Hz), 4 .11-3.80 (m, 4 H), 4 .43 (t, 1 H, J 8.0 Hz), 4 .74 (d, 1 H, J 7.9 Hz), 7.03-6.93 (m, 3 H), 7.10-7.03 (m, 2 H), 7.29-7.20 (m, 2 H), 7.47-7.39 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ (trans isomer) 38.0, 46.5, 49.2, 62.0 (q, J 35 Hz), 64.1 (q, J 35 Hz), 105.3, 115.5 (d, J 21 Hz), 123.8 (q, J 278 Hz), 123.9 (q, J 278 Hz), 125.4, 126.0, 127.4, 128.3, 129.5 (d, J 8 Hz), 140.8 (d, J 3 Hz), 141.2, 147.2, 161.8 (d, J 245 Hz); HRMS (m/z) calcd. for C20H17F7O2 [M + Na]+ 445.1009, found 445.1017.

Synthesis of 1-(bis(2, 2, 2-trifluoroethoxy)methyl)2, 3-dihydro-1H-indene (8a)

As for 1q, but using 1a (0.130 g, 1 .00 mmol). HTIB (0.510 g, 1 .30 mmol) was added at 0 ºC. The reaction was stirred for 10 min at room temperature. The crude product was purified by column (1-10% EtOAc in hexane) affording 8a (67%, 0.221 g, 0.673 mmol), as a yellow oil.

Synthesis of 1-(2, 3-dihydro-1-methyl-1H-inden-3-yl) ethanone (5k)

As for 1q, but using 1k (0.158 g, 1 .00 mmol). HTIB (1.3 equiv.) was added at 0 ºC. The reaction was stirred for 10 min at room temperature. The crude product was purified by column (1-20% EtOAc in hexane) affording 5k7 (76%, 0.132 g, 0.758 mmol), as a light yellow oil.

Synthesis of 1-(2, 3-dihydro-1-methyl-1H-inden-3-yl)2-methylpropan-1-one (5m)

As for 1q, but using 1m (0.108 g, 0.580 mmol). HTIB (1.3 equiv.) was added at 0 ºC and the reaction was quenched after 2 min at 0 ºC. The crude product was purified by column (2-30% EtOAc in hexane) affording 5m13 (62%, 0.073 g, 0.359 mmol), as a light yellow oil.

Synthesis of 2, 3-dihydro-1H-indene-1-carbaldehyde (5a)

To a stirred solution of 1a (0.122 g, 0.937 mmol) in HFIP (4.0 mL) was added HTIB (0.404 g, 1 .04 mmol) at 0 ºC. After 1 min the reaction was quenched with saturated solution of Na2S2O3 (5.0 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduce pressure and the crude product was purified by column (5-10% EtOAc in hexane) giving 5a13 (58%, 0.080 g, 0.55 mmol) as a light yellow oil.

Reaction of 1, 2-dihydronaphthalene (1a) with HTIB in HFIP/CH2Cl2 followed by in situ reduction with NaBH4

To a stirred solution of 1a (0.050 g, 0.38 mmol) in HFIP (0.8 mL) and CH2Cl2 (3.2 mL) was added at 0 ºC HTIB (0.19 g, 0.49 mmol). The mixture was stirred for 15 min. Then, NaBH4 (0.72 g, 1 .9 mmol) was added and the reaction was allowed to reach room temperature while stirring for 20 min. Alcohol 9a was obtained as a mixture with ditosilate 10a as a yellow oil after column chromatography (AcOEt in hexanes, 1 to 30%). A second column chromatography (20% AcOEt in hexanes) allowed complete separation of the products giving 9a44 (48%, 0.027 g, 0.18 mmol) as a yellow oil and 10a (17%, 0.031 g, 0.066 mmol) as a white solid. (2, 3-dihydro-1H-inden1-yl)methylene bis(4-methylbenzenesulfonate) (10a): IR νmax/cm-1 (film) 1376, 1193, 1178, 750 cm-1; 1H RMN (200 MHz, CDCl3) δ 2.10-2.21 (m, 2 H), 2 .41 (s, 3 H), 2.44 (s, 3 H), 2 .75-2.87 (m, 2 H), 3 .55-3.64 (m, 1 H), 6.50 (d, J 3.8 Hz, 1 , H), 6.99-7.20 (m, 6H), 7.28-7.32 (m, 2 H), 7.44-7.50 (m, 2 H), 7.71-7.77 (m, 2 H); 13C RMN (75 MHz, CDCl3) δ 21.7, 21.7, 25.3, 31.3, 50.2, 100.6, 124.7, 125.2, 126.3, 127.8, 128.1, 129.6, 129.7, 133.2, 133.5; 138.5, 145.0, 145.1, 145.2; HRMS (m/z) calcd. for C24H24O6S2 [M + Na]+ 495.0907, found 495.0910.

Synthesis of (2, 3-dihydro-1H-inden-1-yl)methanol (9a)

To a stirred mixture of 1a (0.13 g, 1 .0 mmol) and H2O (0.40 mL, 22 mmol) was added CH2Cl2/HFIP (16 mL/4 mL) at 0 ºC. HTIB (0.51 g, 1 .3 mmol) was added dropwise. The mixture was stirred for 5 min at the same temperature. NaBH4 was added (0.19 g, 5.0 mmol) at room temperature. The mixture was stirred for 70 min and H2O was added. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduce pressure and the crude product was purified by column (0-20% EtOAc in hexane) giving 9a44 (0.109 g, 0.736 mmol, 74%) as a light yellow oil.

 

Supplementary Information

Supplementary information concerning spectroscopic data, experimental procedures and NMR copies are available free of charge at http://jbcs.sbq.org.br as PDF file.

 

Acknowledgments

The authors wish to thank The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support. We thank F. Y. M. Vieira and E. C. Pedrozo for initial experiments.

 

References

1. For some selected examples, see: Rizzo, S.; Bartolini, M.; Ceccarini, L.; Piazzi, L.; Gobbi, S.; Cavalli, A.; Recanatini, M.; Andrisano, V.; Rampa, A.; Bioorg. Med. Chem. 2010,18,1749;         [ Links ] Li, M.; Xia, L.; Chem. Biol. Drug Des. 2007,70,461;         [ Links ] Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.; Axel, M. G.; Ostovic, D.; Anderson, P. S.; Huff, J. R.; J. Med. Chem. 1994,37,3343;         [ Links ] Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K.; J. Med. Chem. 1995,38,4821;         [ Links ] Kwiatkowska, A.; Sleszynska, M.; Derdowska, I.; Prahl, A.; Sobolewski, D.; Borovicková, L.; Slaninová, J.; Lammek, B.; J. Pept. Sci. 2010,16,15;         [ Links ] Corbett, J. W.; Rauckhorst, M. R.; Qian, F.; Hoffman, R. L.; Knauer, C. S.; Fitzgerald, L. W.; Bioorg. Med. Chem. 2007,17,6250;         [ Links ] Wickens, P.; Zhang, C.; Ma, X.; Zhao, Q.; Amatruda, J.; Bullock, W.; Burns, M.; Cantin, L.-D.; Chuang, C.-Y.; Claus, T.; Dai, M.; Cruz, F. D.; Dickson, D.; Ehrgott, F. J.; Fan, D.; Heald, S.; Hetemann, M.; Iwuagwu, C. I.; Johnson, J. S.; Kumarasinghe, E.; Ladner, D.; Lavoie, R.; Liang, S.; Livingston, J. N.; Lowe, D.; Magnuson, S.; Mannely, G.; Mugge, I.; Ogutu, H.; Williams-Pleasic, S.; Schoenleber, R. W.; Shapiro, J.; Shelekhin, T.; Sweet, L.; Town, C.; Tsutsumi, M.; Bioorg. Med. Chem. 2007,17,4369;         [ Links ] Kato, S.; Tanaka, A.; Watanabe, H.; Sato, Y.; Ikeda, Y.; Böger, P.; Wakabayashi, K.; J. Pestic. Sci. 2005,30,7.         [ Links ]

2. For some recent examples, see: Zhang, L.; Herndon, J. W.; Organometallics 2004,23,1231;         [ Links ] Chen, W.-F.; Lin, H.-Y.; Dai, S. A.; Org. Lett. 2004,6,2341;         [ Links ] Kaim, L. E.; Grimaud, L.; Vieu, E.; Org. Lett. 2007,9,4171;         [ Links ] Kesavan, S.; Panek, J. S.; Porco Jr., J. A.; Org. Lett. 2007,9,5203;         [ Links ] Watson, M. P.; Jacobsen, E. N.; J. Am. Chem. Soc. 2008,130,12594;         [ Links ] Sánchez-Larios, E.; Gravel, M.; J. Org. Chem. 2009,74,7536;         [ Links ] Pi, S. F.;Yang, X. H.; Huang, X. C.; Liang, Y.; Yang, G. N.; Zhang, X. H.; Li, J. H.; J. Org. Chem. 2010,75,3484;         [ Links ] Wilsily, A.; Fillion, E.; J. Org. Chem. 2009,74,8583;         [ Links ] Ferreira, S. B.; Kaiser, C. R.; Ferreira, V. F.; Synlett 2008,2625;         [ Links ] Minatti, A.; Zheng, X. L.; Buchwald, S. L.; J. Org. Chem. 2007,72,9253;         [ Links ] Gharpure, S. J.; Reddy, S. R. B.; Sanyal, U.; Synlett 2007,1889;         [ Links ] Wang,Y.; Wu, J.; Xia, P.; Synth. Commun. 2006,36,2685;         [ Links ] Fillion, E.; Wilsily, A.; J. Am. Chem. Soc. 2006,128,2774;         [ Links ] Bianco, G. G.; Ferraz, H. M. C.; Costa, A. M.; Costa-Lotufo, L.V.; Pessoa, C.; de Moraes, M. O.; Schrems, M. G.; Pfaltz, A.; Silva Jr., L. F.; J. Org. Chem. 2009,74,2561;         [ Links ] Ferraz, H. M. C.; Aguilar, A. M.; Silva Jr., L. F.; Tetrahedron 2003,59,5817;         [ Links ] for a review, see: Ferraz, H. M. C.; Aguilar, A. M.; Silva Jr., L. F.; Craveiro, M. V.; Quim. Nova 2005,28,703.         [ Links ]

3. For some recent examples, see: Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H.; J. Am. Chem. Soc. 1998,120,4550;         [ Links ] Marcus,A. P.; Sarpong, R.; Org. Lett. 2010,12,4560;         [ Links ]Vacher, B.; Funes, P.; Chopin, P.; Cussac, D.; Heusler, P.; Tourette, A.; Marien, M.; J. Med. Chem. 2010,53,6986;         [ Links ] Baur, F.; Beattie, D.; Beer, D.; Bentley, D.; Bradley, M.; Bruce, I.; Charlton, S. J.; Cuenoud, B.; Ernst, R.; Fairhurst, R.A.; Faller, B.; Farr, D.; Keller, T.; Fozard, J. R.; Fullerton, J.; Garman, S.; Hatto, J.; Hayden, C.; He, H. D.; Howes, C.; Janus, D.; Jiang, Z. J.; Lewis, C.; Loeuillet-Ritzler, F.; Moser, H.; Reilly, J.; Steward,A.; Sykes, D.; Tedaldi, L.; Trifilieff, A.; Tweed, M.; Watson, S.; Wissler, E.; Wyss, D.; J. Med. Chem. 2010,53,3675;         [ Links ] Wood, J. L.; Pujanauski, B. G.; Sarpong, R.; Org. Lett. 2009,11,3128;         [ Links ] Dinges, J.; Albert, D. H.; Arnold, L. D.; Ashworth, K. L.; Akritopoulou-Zanze, I.; Bousquet, P. F.; Bouska, J. J.; Cunha, G.A.; Davidsen, S. K.; Diaz, G. J.; Djuric, S. W.; Gasiecki,A. F.; Gintant, G.A.; Gracias,V. J.; Harris,C.M.;Houseman,K.A.;Hutchins,C.W.;Johnson, E.F.;Li, H.; Marcotte, P.A.; Martin, R. L.; Michaelides, M. R.; Nyein, M.; Sowin, T. J.; Su, Z.; Tapang, P. H.; Xia, Z. R.; Zhang, H. Q.; J. Med. Chem. 2007,50,2011.         [ Links ]

4. For a review concerning ring contraction reactions, see: Silva Jr., L. F.; Tetrahedron 2002,58,9137.         [ Links ]

5. For some recent reviews, see: Stang, P. J.; Zhdankin, V. V.; Chem. Rev. 1996,96,1123;         [ Links ] Varvoglis, A.; Hypervalent Iodine in Organic Synthesis; Academic Press: London,1997;         [ Links ] Varvoglis, A.; Tetrahedron 1997,53,1179;         [ Links ] Koser, G. F.; Aldrichim. Acta 2000,34,89;         [ Links ] Stang, P. J.; J. Org. Chem. 2003,68,2997;         [ Links ] Koser, G. F.; Aldrichim. Acta 2001,34,89;         [ Links ] Wirth, T.; Hypervalent Iodine Chemistry; Ed. Springer: Berlin,2003;         [ Links ] Moriarty, R. M.; J. Org. Chem. 2005,70,2893;         [ Links ] Silva Jr., L. F.; Molecules 2006,11,421;         [ Links ] Zhdankin, V. V.; Stang, P. J.; Chem. Rev. 2008,108,5299;         [ Links ] Merritt, E. A.; Olofsson, B.; Angew. Chem. Int. Ed. 2009,48,9052;         [ Links ] Merritt, E. A.; Olofsson, B.; Synthesis 2011,517;         [ Links ] Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D.; Synthesis 2007,24,3759;         [ Links ] Zhdankin, V. V.; ARKIVOC 2009,1;         [ Links ] Pouységu, L.; Deffieux, D.; Quideau, S.; Tetrahedron 2010,66,2235;         [ Links ] Duschek, A.; Kirsch, S. F.; Angew. Chem. Int. Ed. 2011,50,1524;         [ Links ] Satam, V.; Harad, A.; Rajule, R.; Pati, H.; Tetrahedron 2010,66,7659.         [ Links ]

6. Justik, M. W.; Koser, G. F.; Tetrahedron Lett. 2004,45,6159;         [ Links ] Harders, J.; Garming, A.; Jung,A.; Kaiser, V.; Monenschein, H.; Ries, M.; Rose, L. S., K.-U.; Weber, T.; Kirschning, A.; Liebigs Ann. 1997,2125;         [ Links ] Hara, S.; Nakahigashi, J.; Ishi-i, K.; Fukuhara, T.;Yoneda, N.; Tetrahedron Lett. 1998,39,2589;         [ Links ] Justik, M. W.; Koser, G. F.; Molecules 2005,10,217;         [ Links ] Kirschning, A.; Eur. J. Org. Chem. 1998,2267;         [ Links ] Moriarty, R. M.; Pakrash, O.; Duncan, M. P.; Vaid, R. K.; Rani, N.; J. Chem. Res. 1996,432;         [ Links ] Zefirov, N. S.; Caple, R.; Palyulin, V. A.; Berglund, B.; Tykvinskii, R.; Zhdankin, V. V.; Kozmin, A. S.; Bull. Acad. Sci. USSR, Div. Chem. Sci. 1988,37,1289;         [ Links ] Yusubov, M. S.; Zholobova, G. A.; Filimonova, I. L.; Chi, K. W.; Russ. Chem. Bull. 2004,53,1735;         [ Links ] Koser, G. F.; Rebrovic, L.; Wettach, R. H.; J. Org. Chem. 1981,46,4324;         [ Links ] Rebrovic, L.; Koser, G. F.; J. Org. Chem. 1984,49,2462.         [ Links ]

7. For a preliminary communication of part of this work, see: Silva Jr., L. F., Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C.; Org. Lett. 2007,9,1433.         [ Links ]

8. SilvaJr.,L.F.;Sousa,R.M.F.;Ferraz,H.M.C.;Aguilar,A.M.; J. Braz. Chem. Soc. 2005,16,1160.         [ Links ]

9, Ferraz, H. M. C.; Silva Jr., L. F.; Vieira, T. O.; Tetrahedron 2001,57,1709.         [ Links ]

10. For an example, see discussion at Silva Jr., L.F.; Craveiro, M.V.; Org. Lett. 2008,10,5417.         [ Links ]

11. Miyamoto, K.;Sei, Y.; Yamaguchi, K.;Ochiai, M.; J. Am. Chem. Soc. 2009,131,1382.         [ Links ]

12. Ochiai, M.; Yoshimura, A.; Miyamoto, K.; Tetrahedron Lett. 2009,50,4792.         [ Links ]

13. Ferraz, H. M. C.; Carneiro, V. M. T.; Silva Jr., L. F.; Synthesis 2009,385.         [ Links ]

14. Jensen, B. L.; Slobodzian, S. V.; Tetrahedron Lett. 2000,41,6029.         [ Links ]

15. Banks, H.; Ziffer, H.; J. Org. Chem. 1982,47,3743.         [ Links ]

16. Ranu, B. C.; Jana, U.; J. Org. Chem. 1998,63,8212.         [ Links ]

17. Li, L.; Cai, P.; Guo, Q.; Xue, S.; J. Org. Chem. 2008,73,3516.         [ Links ]

18. Ichikawa, J.; Jyono, H.; Kudo, T.; Fujiwara, M.; Yokota, M.; Synthesis 2005,39.         [ Links ]

19. For seminal papers on the use of TFE in hypervalent iodine oxidations, see: Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T.; J. Org. Chem. 1991,56,435;         [ Links ] Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y.; Tetrahedron Lett. 1989,30,1119.         [ Links ]

20. For an excellent discussion about fluoroalcohols as solvent, see: Dohi, T; Yamaoka, N; Kita, Y.; Tetrahedron 2010,66,5775;         [ Links ] for other examples, see: Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y.; Angew. Chem. Int. Ed. 2008,47,3787;         [ Links ] Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R.; J. Org. Chem. 2006,71,8316;         [ Links ] Serna, S.; Tellitu, I.; Dominguez, E.; Moreno, I.; SanMartin, R.; Org. Lett. 2005,7,3073;         [ Links ] Kita,Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T.; J. Am. Chem. Soc. 2009,131,1668;         [ Links ] Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita,Y.; Angew. Chem. Int. Ed. 2010,49,3334;         [ Links ] Ito, M.; Ogawa, C.; Yamaoka, N.; Fujioka, H.; Dohi, T.; Kita, Y.; Molecules 2010,15,1918;         [ Links ] Merritt, E. A.; Carneiro, V. M. T.; Silva Jr., L. F.; Olofsson, B.; J. Org. Chem. 2010,75,7416.         [ Links ]

21. Guérard, K. C.; Chapelle, C.; Giroux, M.-A.; Sabot, C.; Beaulieu, M.-A.; Achache, N.; Canesi, S.; Org. Lett. 2009,11,4756.         [ Links ]

22. For leading references, see: Andersen, K.; Liljefors, T.; Gundertofte, K.; Perregaard, J.; Bogeso, K. P.; J. Med. Chem. 1994,37,950;         [ Links ] Bogeso, K. P.; Arnt, J.; Hyttel, J.; Pedersen, H.; J. Med. Chem. 1993,36,2761.         [ Links ]

23. Biological activity: Richter, J.; Landau, E. M.; Cohen, S.; Mol. Pharmacol. 1977,13,548;         [ Links ] Cohen, S.; Goldshmid, A.; Shtacher, G.; Srebrenik, S.; Gitter, S.; Mol. Pharmacol. 1975,11,379;         [ Links ] polymer chemistry: Tomihashi, N.; Yamana, M.; Araki, T.; Eur. Pat. Appl. 1989, EP0 320981A1;         [ Links ] Wakabayashi, K.; Tamai, R.; Sekiya, A.; Tamura, M.; Jpn. Kokai Tokkyo Koho 2001, JP 2001031613A.         [ Links ]

24. Shipp, K. G.; Hill, M. E.; J. Org. Chem. 1966,31,853.         [ Links ]

25. Kubota, T.; Miyashita, S.; Kitazume, T.; Ishikawa, N.; J. Org. Chem. 1980,45,5052.         [ Links ]

26. Patel, N. R.; Chen, J.; Zhang, Y. F.; Kirchmeier, R. L.; Shreeve, J. M.; Inorg. Chem. 1994,33,5463.         [ Links ]

27. Lucero, M. J.; Houk, K. N.; J. Org. Chem. 1998,63,6973.         [ Links ]

28. Martinelli, M. J.; Peterson, B. C.; Khau, V. V.; Hutchison, D. R.; Leanna, M. R.;Audia, J. E.; Droste, J. J.; Wu,Y. D.; Houk, K. N.; J. Org. Chem. 1994,59,2204.         [ Links ]

29. Maeda, K.; Brown, J. M.; Chem. Commun. 2002,310.         [ Links ]

30. Zhdankin, V. V.; Tykwinski, R.; Berglund, B.; Mullikin, M.; Caple, R.; Zefirov, N. S.; Kozmin, A. S.; J. Org. Chem. 1989,54,2609.         [ Links ]

31. Zefirov, N. S.; Zhdankin, V. V.; Dankov, Y. V.; Sorokin, V. D.; Semerikov, V. N.; Kozmin, A. S.; Caple, R.; Berglund, B. A.; Tetrahedron Lett. 1986,27,3971.         [ Links ]

32. Zefirov, N. S.; Zhdankin, V. V.; Dankov, Y. V.; Kozmin, A. S.; Zh. Org. Khim. 1984,20,446.         [ Links ]

33. Zhdankin, V. V.; Kuehl, C. J.; Simonsen, A. J.; J. Org. Chem. 1996,61,8272.         [ Links ]

34. Muraki, T.; Yokoyama, M.; Togo, H.; J. Org. Chem. 2000,65,4679.         [ Links ]

35. For a recent review, see: Silva Jr., L. F.; Carneiro, V. M. T.; Synthesis 2010,1059.         [ Links ]

36. For a review on thallium(III)-mediated ring contractions, see: Ferraz, H. M. C.; Silva Jr., L. F.; Quim. Nova 2000,23,216;         [ Links ] for examples of Tl(III)-mediated oxidation of 1,2-dihydronaphthalenes, see: Ferraz, H. M. C.; Silva Jr., L. F.; Tetrahedron 2001,57,9939;         [ Links ] Ferraz, H. M. C.; Aguilar, A. M.; Silva Jr., L. F.; Synthesis 2003,1031;         [ Links ] see also references 2,8,9, and 13; for papers comparing Tl(III) to I(III), see: Prakash, O.; Aldrichim. Acta 1995,28,63;         [ Links ] Moriarty, R. M.; Khosrowshahi, J. S.; Prakash, O.; Tetrahedron Lett. 1985,26,2961.         [ Links ]

37. Repinskaya, I.B.; Koryabkin, N.A.; Makarova, Z.S.; Koptyug, V. A.; Zh. Org. Khim. 1982,18,870.         [ Links ]

38. Kraus, G. A.; Jeon, I.; Org. Lett. 2006,8,5315.         [ Links ]

39. Fetizon, M.; Moreau, N.; Bull. Soc. Chim. Fr. 1965,3718.         [ Links ]

40. Kasturi, T. R.; Sattigeri, J. A.; Tetrahedron 1992,48,6439.         [ Links ]

41. Bell, A. A.; Stipanovic, R. D.; Zhang, J.; Mace, M. E.; Phytochemistry 1998,49,431.         [ Links ]

42. Kabalka, G. W.; Ju, Y.; Wu, Z.; J. Org. Chem. 2003,68,7915.         [ Links ]

43. Azemi, T.; Kitamura, M.; Narasaka, K.; Tetrahedron 2004,60,1339.         [ Links ]

44. Goodman, A. L.; Eastman, R. H.; J. Am. Chem. Soc. 1964,86,908.         [ Links ]

 

 

Submitted: March 30,2011
Published online: July 12,2011
FAPESP has sponsored the publication of this article.

 

 

* e-mail: luizfsjr@iq.usp.br
# Present addresses: Universidade Federal de São Paulo, Campus Diadema, Rua Artur Riedel, 275, 09972-270, Diadema-SP, Brazil
§ Instituto Federal de Educação, Ciência e Tecnologia de São Paulo, Rua Pedro Vicente, 625, 01109-010 São Paulo-SP, Brazil
Dedicated with deep respect to Prof. Miuako K. Kuya

 

 

Supplementary Information

Experimental

General information

HTIB was used as received. Methanol and acetonitrile were distilled from magnesium turnings and CaH2, respectively. These solvents were storaged in a bottle containing 4 Å molecular sieves. THF and Et2O were freshly distilled from sodium/benzophenone. Column chromatography was performed using silica gel 200-400 mesh. TLC analyses were performed using silica gel plates, using solutions of phosphomolybdic acid and p-anisaldehyde for visualization. NMR spectra were recorded using CDCl3 as solvent and TMS as internal pattern. The substrates 1a,1 b,1 c,1 e,1 g,1 h,1 j and 1k were prepared as previously described.1-3 See the previous communication for experimental procedures of the HTIB oxidations in MeOH with 1a,1 b,1 c,1 d and 1g, and in MeCN with 1a,1 g and 4l.4

Preparation of 1,2-dihydronaphthalenes

7-Acetamido-1,2-dihydronaphthalene (1d)

In a solution of 6-amino-1-tetralone (1.00 g,6.21 mmol) and DMAP (0.020 g) in Et3N (25 mL) was added Ac2O (2.0 mL). The mixture was stirred for 1 h at room temperature. The reaction was quenched with MeOH (10 mL) and H2O (15 mL), extracted with EtOAc (3 × 15 mL), washed with brine (2 × 10 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (silica gel 200-400 mesh,60% EtOAc in hexanes) giving 6-acetamido-1-tetralone5 (92%,1 .16 g, 5.72 mmol) as a light-yellow solid; mp 124.5-126.7 ºC (124.5-125 ºC)5; 1H NMR (200 MHz, CDCl3) δ 2.02-2.17 (m,2 H), 2 .22 (s,3 H), 2 .62 (t,2 H, J 6.5 Hz), 2 .92 (t,2 H, J 6.0 Hz), 7.27 (dd,1 H, J 2.4 and 8.6 Hz), 7.72 (s,1 H), 7.96 (d,1 H, J 8.4 Hz), 8.31 (1H, s); 13C NMR (75 MHz, CDCl3) δ 23.2, 24.7, 29.9, 38.9, 117.5, 118.5, 128.4,142.7, 146.3, 169.0, 197.7.

To a stirred solution of 6-acetamido-1-tetralone (1.12 g, 5.50 mmol) in anhydrous MeOH (70 mL) was added NaBH4 (0.25 g,6.61 mmol) in portions at 0 ºC. The mixture was stirred for 1 h at room temperature. The reaction was quenched with H2O (20 mL) and a 10% aqueous solution of HCl was added dropwise until pH ca. 7. The resulting solution was extracted with EtOAc (3 × 15 mL), washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure giving 6-acetamido-1-tetralol (78%, 0.882 mg,4 .30 mmol) as a pale-yellow solid. The 1-tetralol (0.841 g,4 .10 mmol) was used without purification in a dehydration reaction using toluene (45 mL), a few crystals of p-TsOH and reaction time of 3 h at 130 ºC, using a Dean-Stark apparatus. The resulting residue was purified by flash chromatography (silica gel 200-400 mesh,80% EtOAc in hexanes) affording 1d6 (95%, 0.728 g,3 .89 mmol) as a pale-yellow solid. Experimental data has not been previously reported: mp: 89.3-90.6 ºC; IR νmax/cm-1 (film) 497,566,684,834,883,1018,1266,1328,1370,1421,1536,1594,1666,2829,2883,2933,3032,3297; 1H NMR (200 MHz, CDCl3) δ 2.14 (s,3 H), 2 .20-2.31 (m,2 H), 2 .72 (t,2 H, J 8.1 Hz), 5.90-5.99 (m,1 H), 6.40 (d,1 H, J 9.6 Hz), 6.92 (d,1 H, J 8.0 Hz), 7.23 (dd,1 H, J 2.2 and 8.0 Hz), 7.31 (s,1 H), 7.89 (s,1 H); 13C NMR (75 MHz, CDCl3) δ 22.9, 24.4, 27.6,117.8, 119.4, 126.1, 127.0,127.6, 130.4, 136.3, 136.5, 168.6; LRMS m/z (%) 187 (M+•,72%), 146 (9), 145 (61), 144 (100), 130 (29), 115 (24), 91 (8), 77 (6), 51 (5), 43 (23); HRMS (m/z) calcd. for C12H13NO [M + H]+ 188.1070, found 188.1067.

1,2-Dihydro-6-methoxynaphthalene (1f)

NaBH4 (0.455 g,12.0 mmol) was added dropwise to a solution of 7-methoxy-1-tetralone (1.52 g,8.63 mmol) in MeOH (50 mL) at 0 ºC. The mixture was stirred at room temperature. After 2 h, the reaction was quenched with H2O and a 10% aqueous solution of HCl was added dropwise until pH ca. 5. The MeOH was removed under reduced pressure and the residue was extracted with EtOAc, washed with brine, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude corresponding 1-tetralol was dissolved in THF (10 mL) and H3PO4 85% (4.5 mL) was added dropwise at room temperature. The mixture was refluxed at 95 ºC for 2 h. The crude product was transferred to an Erlenmeyer and diluted with Et2O. A sat. solution of NaHCO3 was added until ca. pH 7. The solution was extracted with Et2O, washed with sat. solution of NaCl and dried over anhydrous MgSO4. The residue was purified by flash column chromatography (gradient elution, 0-30% EtOAc in hexanes), affording 1f2 (0.885 g,5.52 mmol,64%), as a colorless oil. Starting material was also recovered (0.0089 g, 0.0555 mmol,1 %), as a colorless oil.

1,2-Dihydro-7-methoxy-4-methylnaphthalene (1i)

A solution of 6-methoxy-1-tetralone (1.76 g,10.0 mmol) in Et2O (7.0 mL) was added to a solution of MeMgI [prepared from MeI (1.7 mL,27.0 mmol), Mg (0.673 g, 27.7 mmol) and I2 (some crystals) in anhydrous Et2O (7.0 mL)]. The mixture was refluxed for 4.5 h. After that, a solution of HCl 6 mol L-1 (6 mL) was added dropwise at 0 ºC. The solution was stirred for 15 min at room temperature. The organic layer was extracted with Et2O, washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (gradient elution, 0-30% of EtOAc in hexanes), affording 5j7 (1.08 g,6.20 mmol,62%), as a colorless oil.

4-n-Butyl-1,2-dihydro-1-methylnaphthalene (1l)

The reaction was performed as indicated for 1i.A mixture of 4-methyl-1-tetralone (1.42 g,8.86 mmol) in Et2O (12.0 mL) was added to a solution of n-BuMgI [prepared from 1-bromobutane (1,46 g,10.6 mmol), Mg 0.245 g,10.1 mmol), I2 (some crystals) and anhydrous Et2O

(12.0 mL)]. The mixture was refluxed for 3 h. The crude product was purified by flash column chromatography (gradient elution, 0-5% of EtOAc in hexanes), affording the olefin 1l2 (0.805 g,4 .02 mmol,45%), as a colorless oil. Starting material was recovered (0.214 g,1 .34 mmol,15%).

1,2-Dihydro-4-isopropyl-1-methylnaphthalene (1m)

The reaction was performed as indicated for 1i. A mixture of 4-methyl-1-tetralone (0.961 g,6.00 mmol) in Et2O (4.0 mL), i-PrMgI [prepared from 2-bromopropane (1.93 g,15.7 mmol), Mg (0.321 g,13.2 mmol), I2 (some crystals) in anhydrous Et2O (6.0 mL)] was stirred for 5.5 h. The crude product was purified by flash column chromatography (gradient elution, 0-20% of EtOAc in hexanes), affording 1m8 (0.387 g,2 .08 mmol,35%) as a colorless oil.

1,2-Dihydro-1-methyl-4-phenylnaphthalene (1n)

The reaction was performed as indicated for 1i.A mixture of 4-methyl-1-tetralone (0.641 g,4 .00 mmol) in Et2O (0.5 mL) and PhMgBr [prepared from bromobenzene (0.792 g,5.04 mmol), Mg (0.117 g,4 .81 mmol), I2 (some crystals) in anhydrous Et2O (1.0 mL)] was refluxed for 1.5 h. The crude product was purified by flash column chromatography (gradient elution,10-15% of EtOAc in hexanes), affording the 1,2-dihydronaphthalene 1n9 (0.682 g,3 .10 mmol,78%), as a colorless oil.

4-(3,4-Dichlorophenyl)1,2-dihydro-1-methylnaphthalene (1o)

The reaction was performed as indicated for 1i.A mixture of 4-methyl-1-tetralone (0.645 g,4 .03 mmol) in Et2O (0.5 mL) and 1,2-ClPhMgBr [prepared from 4-bromo1,2-dichlorobenzene (1.15 g,5.09 mmol), Mg (0.117 g, 4.81 mmol), I2 (some crystals) in anhydrous Et2O (1.0 mL)] was refluxed for 2 h. The crude product was purified by flash column chromatography (gradient elution,10-30% of EtOAc in hexanes), affording the 1-(3,4-dichloropheny)1,2,3,4-tetrahydro-4-methylnaphthalen-1-ol (0.870 g, 2.83 mmol,70%), as a colorless oil. The isolated alcohol was dissolved in anhydrous toluene (3.5 mL). Some crystals of p-toluenesulfonic acid were added to that solution. The reaction was refluxed for 6 h. The reaction was extracted with EtOAc. The organic phase was washed with H2O, saturated solution of NaHCO3, saturated solution of NaCl and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography (isocratic elution with hexanes), furnishing the desired alkene 1o (0.385 g,1 .33 mmol,56%), as a colorless oil; IR νmax/cm-1 (film) 1121,1258,1515,2830,2934; 1H NMR (300 MHz, CDCl3) δ 1.30 (d,1 H, J 7,0 Hz), 2 .22 (ddd,1 H, J 16.8, 7.7 and 5.0 Hz), 2 .55 (ddd,1 H, J 16.8,6.5 and 4.4 Hz), 2.98 (sext,1 H, J 7.0 Hz), 6.00 (t,1 H, J 4.7 Hz), 6.93-6.96 (m,1 H), 7.10-7.26 (m,4 H), 7.42-7.46 (m,1 H); 13C NMR (75 MHz, CDCl3) δ 19.8, 31.4, 32.1, 125.3, 126.2, 126.2, 127.4, 127.7, 128.1, 130.2, 130.5, 131.0, 132.3, 133.4, 137.5, 140.9, 141.5; HRMS (m/z) calcd. for C14H20O4 [M + Na]+ 275.1254, found 275.1252.

6,7-Dihydro-9-methyl-5H-benzo[7]annulene (1p)

The reaction was performed as indicated for 1i. A mixture of 1-benzosuberone (0.481 g,3 .00 mmol) in anhydrous Et2O (2.0 mL), MeMgI [prepared from MeI (0.5 mL,8.10 mmol), Mg (0.202 g,8.31 mmol) and I2 (some crystals) in anhydrous Et2O (2.0 mL)] was stirred for 4 h under reflux. The crude product was purified by flash column chromatography (gradient elution, 0-10% of EtOAc in hexanes), affording 1p10 (0.403 g,2 .55 mmol,85%), as a colorless oil.

 

References

1. Ferraz, H. M. C.; Carneiro, V. M. T.; Silva Jr., L. F.; Synthesis 2009,385 (see ref. 13 in the article).         [ Links ]

2. Ferraz, H. M. C.; Silva Jr., L. F.; Vieira, T. O.; Tetrahedron 2001,57,1709 (see ref. 9 in the article).         [ Links ]

3. Silva Jr., L.F.; Sousa, R. M. F.; Ferraz, H. M. C.; Aguilar, A. M.; J. Braz. Chem. Soc. 2005,16,1160 (see ref. 8 in the article).         [ Links ]

4. Silva Jr., L. F.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C.; Org. Lett. 2007,9,1433 (see ref. 7 in the article).         [ Links ]

5. Allinger, N. L.; Jones, E. S.; J. Org. Chem. 1962,27 70.         [ Links ]

6. Kato, K.; Terauchi, J.; Mori, M.; Suzuki, N.; Shimomura, Y.; Takekawa, S.; Ishihara, Y.; PCT Int. Appl. WO 2001021577 2001,363.         [ Links ]

7. Radcliffe, M. M.; Weber, W. P.; J. Org. Chem. 1977,42,297.         [ Links ]

8. Bhonsle, J. B.; Indian J. Chem. B 1995,34B,372.         [ Links ]

9. Newman, M. S.; Anderson, H. V.; Takemura, K. H.; J. Am. Chem. Soc. 1953,75,347.         [ Links ]

10. Russel, M. G. N.; Baker, R.; Billington, D. C.; Knight, A. K.; Middlemiss, D. N.; Noble, A. J.; J. Med. Chem. 1992,35,2025.         [ Links ]

 

 


Figure S1 - Click to enlarge

 

 


Figure S2 - Click to enlarge

 

 


Figure S3 - Click to enlarge

 

 


Figure S4 - Click to enlarge

 

 


Figure S5 - Click to enlarge

 

 


Figure S6 - Click to enlarge

 

 


Figure S7 - Click to enlarge

 

 


Figure S8 - Click to enlarge

 

 


Figure S9 - Click to enlarge

 

 


Figure S10 - Click to enlarge

 

 


Figure S11 - Click to enlarge

 

 


Figure S12 - Click to enlarge

 

 


Figure S13 - Click to enlarge

 

 


Figure S14 - Click to enlarge

 

 


Figure S15 - Click to enlarge

 

 


Figure S16 - Click to enlarge

 

 


Figure S17 - Click to enlarge

 

 


Figure S18 - Click to enlarge

 

 


Figure S19 - Click to enlarge

 

 


Figure S20 - Click to enlarge

 

 


Figure S21 - Click to enlarge

 

 


Figure S22 - Click to enlarge

 

 


Figure S23 - Click to enlarge

 

 


Figure S24 - Click to enlarge

 

 


Figure S25 - Click to enlarge

 

 


Figure S26 - Click to enlarge

 

 


Figure S27 - Click to enlarge

 

 


Figure S28 - Click to enlarge

 

 


Figure S29 - Click to enlarge

 

 


Figure S30 - Click to enlarge

 

 


Figure S31 - Click to enlarge

 

 


Figure S32 - Click to enlarge

 

 


Figure S33 - Click to enlarge

 

 


Figure S34 - Click to enlarge

 

 


Figure S35 - Click to enlarge

 

 


Figure S36 - Click to enlarge

 

 


Figure S37 - Click to enlarge

 

 


Figure S38 - Click to enlarge

 

 


Figure S39 - Click to enlarge

 

 


Figure S40 - Click to enlarge

 

 


Figure S41 - Click to enlarge

 

 


Figure S42 - Click to enlarge

 

 


Figure S43 - Click to enlarge