Thallium Trinitrate-Mediated Ring Contraction of 1,2-Dihydronaphthalenes: The Effect of Electron-donating and Electron-withdrawing Groups

A oxidação de uma série de 1,2-diidronaftalenos, substituídos no anel aromático, foi investigada com trinitrato de tálio (TTN) em metanol ou em trimetilortoformiato (TMOF) como solvente. Em todos os casos, indanos foram formados, embora o rendimento tenha variado de excelente a baixo, dependendo da estrutura do substrato. A presença de um grupo doador de elétrons no substrato favorece o rearranjo, enquanto que uma quantidade significativa de derivados glicólicos, bem como naftalenos, foi obtida na oxidação de 1,2-diidronaftalenos com um grupo retirador de elétrons, tais como Br e NO 2 . Mecanismos para a formação de cada um destes produtos foram propostos.


Introduction
The indan moiety constitutes the core of several molecules with important biological activity. 1 Thus, a great effort has continuously been made toward the synthesis of such a class of compounds. 2A typical approach to obtain functionalized indans is the selection of a suitable 1indanone as starting material, which is then elaborated into the desired target molecule. 35][6][7][8][9] One of these approaches is the thallium(III)-mediated rearrangement of 1,2dihydronaphthalenes, which are easily obtained from 1tetralones by a reduction/dehydration sequence. 6Treatment of olefins, such as 1 (Scheme 1), with thallium trinitrate (TTN) in trimethylorthoformate (TMOF) gave indans in good yields, together with glycolic derivatives as minor components.However, trisubstituted alkenes, such as 4, led only to the addition product 5 (Scheme 1).Remarkably, this ring contraction is diastereoselective, leading exclusively to trans-1,3-disubstituted indans, when a 1methyl-1,2-dihydronaphthalene is used as starting material. 6The efficiency of this selective reaction has recently been demonstrated in a short total synthesis of the sesquiterpene mutisianthol (Scheme 2). 9Furthermore, during our studies toward the synthesis of this natural product, we found that olefins bearing a methoxy group in para to the migrating carbon, such as 6, lead to the ring contraction product in nearly quantitative yield.This effect was rationalized considering that the methoxy group in para increases the migratory aptitude of the migrating carbon (8a in 7) by mesomeric effect, favoring the rearrangement (Scheme 2). 8,9lthough several aspects of the oxidation of 1,2dihydronaphthalenes with thallium trinitrate have been disclosed, the substituents in the aromatic ring have been restricted to methyl and/or methoxy groups (1 and 6, for example). 6,8,9Considering that indans substituted in the aromatic ring by groups such as halogens, [10][11][12][13][14] hydroxy, [15][16][17] nitro, 15,18 acetamido, 19 dimethyl, 20 and dimethoxy 14,17,20,21 are also important building blocks in organic synthesis, we decided to investigate further our approach based on the ring contraction reaction.The present article describes a detailed study of the TTN-mediated oxidation of 1,2dihydronaphthalenes bearing different groups in the aromatic ring (Me, OMe, OH, NH 2 , NHAc, Br and NO 2 ), better defining the scope of this reaction, which will facilitate future applications.In addition, a more clear picture of the mechanism of the thallium(III)-mediated oxidation of olefins could be drawn based on the new results.

Preparation of 1,2-dihydronaphthalenes
The transformation of the 1-tetralones 9 to 15 into the corresponding 1-tetralols was performed using NaBH 4 (Table 1).The tetralols were then dehydrated under acidic conditions, for which two procedures were used.The first was the treatment of the alcohol with H 3 PO 4 in THF, whereas the second was the use of a catalytic amount of p-TsOH in benzene or toluene.Table 1 summarizes the results obtained in the synthesis of 1,2-dihydronaphthalenes 16-22 from 1tetralones 9-15.
The transformation of a tetralol into the corresponding 1,2-dihydronaphthalene may be troublesome.The preparation of 24 exemplifies well this statement, because when the dehydration step was performed with H 3 PO 4 , the reaction was not reproducible, leading in some runs to the desired product 24 and in others to the dimer 25.
Thus, to obtain the necessary amount of the required substrate, it was preferable to use p-TsOH, although under this condition the olefin 24 was obtained together with the dimer 25 (Scheme 3).The dimerization can be rationalized by the formation of the benzylic carbocation 26, which then reacts with the formed olefin leading to the dimer 25, after losing a proton (Scheme 4).The positive charge in 26 is stabilized by the methoxy group of the carbon 6 through a mesomeric effect.Presumably, this stabilization makes the dimerization easier in the formation of 24 than in the other 1,2-dihydronaphthalenes, where a similar mesomeric effect is not present.Nevertheless, this dimerization could be overcome in the preparation of other similar olefins. 8,9

Oxidation of 1,2-dihydronaphthalenes with thallium trinitrate
With a representative number of differently substituted 1,2-dihydronaphthalenes in hands, we were in position to investigate their behavior toward the oxidation with thallium(III).As shown in Table 2, the reaction of the olefins with TTN led in all cases to the ring contraction product, although the yield varied from excellent to poor.Addition and aromatization products were also formed in some cases.The reason for this variation is discussed on the following paragraphs for each substrate, based on the mechanism of the rearrangement of olefins mediated by thallium(III), 22 which is exemplified for the 1,2-dihydronaphthalene (50)  in Scheme 5.The first step in this mechanism is the formation of the thallonium ion 51, which gives the trans oxythallated adduct 52, after a ring-opening in a Markovnikov sense. 23The rearrangement takes place in this intermediate, giving the acetal 54, after addition of methanol to the oxonium 53, followed by deprotonation.
Treatment of the olefin 24, which bears two methoxy groups, with TTN gave the ring contraction product 27, as the only isolated product, in excellent yield (Table 2, entry 1).This result shows that the behavior of 24 is similar to 6, as expected.
The reaction of the olefin 16 with TTN gave the indan 28, in very good yield.However, in this case, the addition product 29 was also obtained as a minor component (entry 2).The high yield of the ring contraction can be explained considering the well-known hyperconjugative effect of the methyl groups, which increases the migratory aptitude of the migrating carbon.
In our previous studies, when a trisubstituted olefin was treated with TTN in methanol, the formation of the ring contraction product has not been observed (see, for example, Scheme 1). 6However, the reaction of the trisubstituted olefin 55 with TTN in TMOF led to the indan 56, together with the addition products 57 and 58 (Scheme 6).This result shows that the presence of an electrondonating group indeed favors the rearrangement, partially changing the course of the oxidation of trisubstituted olefins by thallium(III).Another reason for the different behavior of 4 and 55 could be the modification of the solvent, because higher yields of the ring contraction products have been obtained for similar reactions in TMOF than in MeOH. 6The relative configuration of the compound 58 was assigned by comparison with the NMR data of similar compounds. 24,25The cis relationship of the hydroxy and the methoxy groups in 57 was analogously suggested.
The behavior of the 8-hydroxy-1,2-dihydronaphthalene 17 toward the oxidation with TTN in methanol (Table 2, entry 3) was somewhat similar to that of the olefins bearing a methoxy group in meta to the migrating carbon, such as 1 Scheme 6. (Scheme 1), because the indan 30 was obtained in good yield, together with the product of addition of methanol 31.However, the yield of the ring contraction product was lower from 17, probably due to the instability of 30.An interesting aspect concerning the reaction of 17 with thallium(III) is that the oxidation of the phenol moiety, which has already been described, 26 was not observed.For olefin 17, the ring contraction product was obtained in higher yield using methanol instead of TMOF.Thus, the oxidation of the following substrates was also examined in methanol.
The reaction of the nitrogenated 1,2-dihydro- Next, the TTN-mediated oxidation of the bromo alkenes 20 and 21 (entries 5 and 6, respectively) was performed.For these substrates the ring contraction product was obtained in modest yields (35-37%).Using a substrate with a more powerful electron-withdrawing group, the nitro alkene 22, the indan was obtained in even lower yield (entry 7).These results shows that the yield of the ring contraction products lowers as the electron-withdrawing power of the substituent in meta to the migrating carbon is increased, because its migratory aptitude is decreased. 28ther products formed in the oxidation of olefins 20-22 were those of the addition of two molecules of methanol (38, 42, 43 and 47), of the addition of methanol and nitrate (39, 44 and 48) and of aromatization (40, 45 and 49).
The results shown in Table 2 allowed additional conclusions.First, comparing the reaction times and temperatures (see, for example, entries 1, 5 and 7), it is possible to conclude that the presence of an electronwithdrawing group in the aromatic ring makes the oxidation of the double bond by thallium(III) slower.Presumably, the electron density of the double bond is decreased by the electron-withdrawing group, which would decrease the rate of the electrophilic addition step.There is also a clear correlation between the rate of oxidation and the yield of the ring contraction product.In fast oxidations, the yields are usually high (compare, for example, entries 1 and 7).This trend has also been observed in previous works. 6,7econd, in the formation of the addition products of methanol the trans diastereomer was formed either as the major compound (entries 4 and 6) or exclusively (entries 2, 3, 5 and 7).A similar selectivity has also been observed in the oxidation of cyclohexene with thallium triacetate (TTA) in anhydrous AcOH, 23,29,30 whereas in the presence of water the cis diastereomer predominated. 22Moreover, 3-t-butylcyclohexene gave exclusively a trans diol, when treated with thallium(III) sulfate. 31The cis glycolic derivatives were obtained in the reaction of chromens with TTN 32 and of steroidal olefins with TTA. 33In summary, the diastereoselectivity of the thallium(III)-mediated addition of nucleophilic species to cyclic olefins can not be easily predicted, because it depends on either the structure of the substrate or on the reaction conditions.Based on these previous works, a mechanism for the formation of the cis and trans isomers was proposed, as exemplified for the olefin 21 in Scheme 7. In the formation of the trans isomer, the oxythallated aduct 59 would originate the oxonium ion 60, by a reductive intramolecular displacement of the thallium(III).Addition of a second molecule of the solvent would give the trans-1,2-dimethoxylated isomer 42, after deprotonation.The cis isomer 43 would be produced directly from 59 by an intermolecular displacement of the thallium(III) by the methanol, followed by deprotonation.
The indans and the dimethoxylated addition products have a quite similar 1 H NMR spectrum.However, these compounds can be easily distinguished by 13 C NMR, where the signal around 107 ppm indicates the presence of the acetal unit of the ring contraction product, whereas for the addition products, two signals between 75 and 80 ppm are present.During the development of this work and others, 6,8,9 a large number of indans, as well as cisand trans-addition products, were obtained, which allowed us to find an easy way to differentiate this kind of compounds by 1 H NMR. This was achieved after tabulating the coupling constants corresponding to the doublets of the hydrogen of the benzylic C1 carbon for the addition products and of the acetal for the indans.The coupling constants of the mentioned hydrogens of all these compounds fall in a very restricted and characteristic range.The coupling constant of the hydrogen of the acetal moiety is the highest of the three kinds of products (7.5 Hz).A similar value was found by Antus et al. for structurally related acetals. 34To assign the cis and trans isomers we considered that the coupling constant of the trans isomers should be higher than the cis, based on the well-established Karplus studies.Thus, for the hydrogen of the C1 carbon, the typical value for the cis isomer would be between 2.2 and 3.0 Hz, while for the trans isomer would be between 4.8 and 5.2 Hz (Figure 1).These values agree with that observed for the cis-and trans-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene and other related cis isomers, 35 as well as with the cis-1,2dimethoxychroman 61 (Figure 2). 32However, the values are not in accord to that determined by Ogibin et al. for the cis-and trans-1,2-dimethoxy-1,2,3,4-tetrahydronaphthalenes. 36itrate derivatives are not usually produced in the oxidation of olefins with TTN, although a few papers reported the isolation of these compounds. 37The somewhat unexpected formation of the trans-1-nitrate-2-methoxy derivatives 35, 39, 44 and 48 probably occurs from the oxonium ion 62, which reacts with a nitrate anion.These nitrates have a very characteristic signal in the 1 H NMR spectrum.The hydrogen of the C1 carbon is deshielded when compared to the corresponding methoxy derivative, appearing as a doublet in ca.6.0 ppm.The coupling constants, ranging from 4.0 to 4.4 Hz (Scheme 8), allowed us to suggest a trans-relationship between the two substituents (compare with Figure 1).
Naphthalene derivatives are usually produced in the oxidation of 1,2-dihydronaphthalenes with TTN, when the substrate has a low reactivity (entries 4 to 7, Table 2), as already observed in the oxidation of other 1,2dihydronaphthalenes. 6,7There are two possible mechanisms to explain the formation of this kind of product, as illustrated for the olefin 22 in Scheme 9.The first would be the allylic oxidation of the 1,2dihydronaphthalene, 38  In summary, the reaction of 1,2-dihydronaphthalenes with thallium trinitrate constitutes an efficient entry into indans, providing electron-withdrawing groups are not present in the aromatic ring.Moreover, these indans bear a masked aldehyde moiety, which could be useful for further transformations.

General
Information concerning general experimental methods was recently published. 56-Methoxy-4,7-dimethyl-1,2dihydronaphthalene (55) was prepared according to the procedure described by Zubaidha et al. 39 Preparation of 1-tetralones 5-Hydroxy-1-tetralone (10).Under nitrogen, NaH (0.30 g, 7.5 mmol, 60% in mineral oil) was washed with anhydrous hexanes (2 x 1 mL).After a few minutes under nitrogen, anhydrous DMF (3.5 mL) was added.To this mixture was slowly added a solution of EtSH (3.9 mL, 53 mmol) in anhydrous DMF (3.9 mL) at 0 °C and the resulting solution was stirred for 20 min at room temperature.The 5-methoxy-1-tetralone (0.881 g, 5.00 mmol) was then added and the  resulting mixture was stirred for 5 h at 140 °C, becoming light yellow.The mixture was cooled to the room temperature and a saturated solution of NH 4 Cl was added.The mixture was extracted with Et 2 O and the organic phase was washed with water, with brine, and dried over anhydrous MgSO 4 .The solvent was removed under reduced pressure and the resulting brown solid was purified by flash chromatography (silica gel 200-400 mesh, 30% AcOEt in hexanes) giving starting material (0.103 g, 0.586 mmol, 12%) and 10 40 (0.590 g, 3.64 mmol, 73%), as a yellowbrown solid (mp 208.1-208.2°C).
followed by the acid catalyzed dehydration of 64 (Path a), which is favored by the formation of an aromatic ring.The second possibility would be two consecutives acid-catalyzed eliminations of MeOH in the addition product 47, which would occur through the intermediate 65 (Path b).

Figure 1 .
Figure 1.Selected chemical shifts for addition and ring contraction products.