Technical Field

The present invention relates to synthesis of dihydroindenes and related compounds.

Priority

The present application claims priority from Singapore patent application SG2010004889-0, filed 7 July 2010, the entire contents of which are incorporated herein by cross-reference.

Background of the Invention

There are numerous natural products, as well as many bioactive synthetic compounds that possess a dihydroindene ring system. In accordance with the special place in organic and medical chemistry of the compounds possessing this skeleton, its synthesis has also been well documented. There have been a large number of methods developed for dihydroindene synthesis, for example cationic cyclization, organometallic catalytic reactions, cycloaddition/reduction and other miscellaneous routes. However, most of these methods suffered from problems of multiple step synthesis, limited substrate scope, low yields, tedious processes and other drawbacks. It is still a great challenge to synthesise the dihydroindene skeleton in a direct and economical way.

The Friedel-Crafts cyclization reaction is a very important methodology for generating various useful carbocyclic compounds through carbon-carbon bond formation with aromatic substrates. Bimolecular Friedel-Crafts cycloadditions, in which bifunctional electrophiles react intramolecularly with the same aromatic ring, are more of a challenge to perform as competitive intermolecular reactions lead to non-ring products. It is well known that a bifunctional substrate capable of both acylation and alkylation of aromatic compounds is appealing for the formation of important cyclic aromatic ketones. Excess amount of A1C1 ₃ /BF ₃ and/or strong protic acids were typically used to promote these cycloaddition reactions, as shown in Fig. 1. The cyclic aromatic ketones could be further reduced to form dihydroindenes.

There is therefore a need for an efficient synthesis method for dihydroindenes (indanes) and related compounds.

Object

It is an object of the present invention to substantially overcome or at least ameliorate one or more of the above disadvantages. Summary

In a first aspect of the invention there is provided a process for making a product having a five membered ring fused to an aromatic ring, said process comprising exposing a starting material of structure Ar-C(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ^S to an acid in the presence of a copper II salt of a superacid. In the starting material, Ar is an optionally substituted aromatic or heteroaromatic ring system (i.e. Ar may have non-hydrogen substituents or may have no non-hydrogen substituents) having at least one hydrogen attached to an aromatic carbon atom, and R ¹ , R ² , R ³ , R ⁴ and R ³ are independently selected from the group consisting of H, alkyl and aryl.

The following options may be used in conjunction with the first aspect, either individually or in any suitable combination.

The process may comprise the step of producing the starting material by reacting an precursor of structure Ar-H _n with an allyl compound of structure XC(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ in the presence of the copper II salt of the superacid, wherein n is an integer greater than 1 and X is a leaving group. The step of reacting the precursor with the allyl compound may be conducted in situ. In this case, the step of producing the starting material may generate the acid and the starting material, so that the process is a one pot process for making the compound having a five membered ring fused to an aromatic ring from the precursor and the allyl compound.

In a second aspect of the invention there is provided a process- for making a product having a five membered ring fused to an aromatic ring, said process comprising combining a compound of structure Ar-H _n , wherein Ar is an optionally substituted aromatic or heteroaromatic ring system and n is an integer greater than 1, and an allyl compound of structure XC(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ wherein R ^! , R ² , R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of H, alkyl and aryl and X is a leaving group, in the presence of a copper (II) salt of a superacid.

The process may be conducted in the presence of an acid.

The following options may be used in conjunction with either the first or the second aspect of the invention, either individually or in any suitable combination.

The copper (II) salt may be copper (II) trifiate. It may be catalytic. It may be catalytic for the coupling reaction of the precursor to the allyl compound or for the cyclisation reaction to convert the starting material to the product or for both the coupling reaction and the cyclisation reaction. The process may be conducted in a halogenated solvent. In the case of the first aspect being conducted as a two step reaction (the first step being making the starting material and second step being reacting the starting material in the presence of acid), either may be conducted in a halogenated solvent or both may be conducted in a halogenated solvent.

Ar may be a carbocyclic aromatic ring system. Ar may be a monocyclic aromatic ring system. Ar may be both monocyclic and carbocyclic.

Ar may have at least one non-hydrogen substituent (in the starting material it may have at least one non-hydrogen substituent other than -C(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ ). The substituents on Ar (other than -C(R ^! R ² )-C(R ³ )=C(R ⁴ )R ⁵ ) may each, independently, be selected from the group consisting of hydrogen, alkyl, hydroxy and alkoxy substituents. The process (or any one of the steps in the process) may be accompanied by migration of a substituent on the aromatic ring. In this case, the substituent which migrates may be an alkyl substituent or an aryl substituent.

In the event that an allyl compound of formula XC(R}R ² ) ^R ³ )r=C(K )R ^s is used, X may be a halide, an alcohol or an ester.

The process may be conducted with no added base. It may be conducted under acidic conditions. It may be conducted under anhydrous conditions.

In some embodiments, R ¹ , R ² and R ³ are all H. In some embodiments, R ⁴ and R ⁵ are either both alkyl or one is hydrogen and the other is an aryl group.

In an embodiment there is provided a process for making a product having a five membered ring fused to an aromatic ring, said process comprising exposing a starting material of structure Ar-CH ₂ -C(H)=C(R ⁴ )R ^: ' to an acid in the presence of copper II triflate;

wherein Ar is an optionally substituted aromatic or heteroaromatic ring system having at least one hydrogen attached to an aromatic carbon atom, and

R ⁴ and R ⁵ are either both alkyl groups or one is hydrogen and the other is an aryl group.

In another embodiment there is provided a process for making a product having a five membered ring fused to an aromatic ring, said process comprising:

producing a starting material of structure Ar-CH ₂ -C(H)=C(R ⁴ )R ⁵ wherein Ar is an optionally substituted aromatic or heteroaromatic ring system having at least one hydrogen attached to an aromatic carbon atom, and R ⁴ and R ⁵ are either both alkyl groups or one is hydrogen and the other is an aryl group, by reacting a precursor of structure Ar-Hn with an allyl compound of structure X-CH ₂ -C(H)=C(R ⁴ )R ⁵ in the presence of copper II triflate, wherein n is an integer greater than 1 and X is a leaving group; and

exposing the starting material to an acid in the presence of the copper II triflate.

In another embodiment there is provided a process for making a product having a five membered ring fused to an aromatic ring, said process comprising combining a compound of structure Ar-H„, wherein Ar is an optionally substituted aromatic or heteroaromatic ring system and n is an integer greater than 1, and an allyl compound of structure X-CH ₂ -C(H)=C(R ⁴ )R ⁵ wherein R ⁴ and R ⁵ are independently selected from the group consisting of H, alkyl and aryl and X is a leaving group, in the presence of copper (II) triflate, said process being conducted in a halogenated solvent and with no added base.

In a third aspect of the invention there is provided use of a copper (II) salt of a superacid to catalyse the reaction of a precursor of structure Ar-H _n and an allyl compound of structure XC(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ as defined earlier, so as to make a product having a five membered ring fused to an aromatic ring.

In a fourth aspect of the invention there is provided a product having a five membered ring fused to an aromatic ring, said compound being made by the process of the first or second aspect.

Brief Description of the Drawings

A preferred embodiment of the present invention will now be. described, by way of an example only, with reference to the accompanying drawings wherein:

Figure 1 is a scheme illustrating Friedel-Crafts cycloaddition reaction on aromatic ring; Figure 2 is a scheme illustrating Proposed reaction mechanism;

Figure 3 is a scheme illustrating Transformation conditions between 1, 2 and 7;

Figure 4 is a scheme illustrating Blank reaction of cinnamyl chloride in Cu(OTf) ₂ catalyst system; and

Figure 5 is an X-ray crystal structure showing the molecular structure of compound 7. Hydrogen atoms have been omitted for clarity.

Detailed Description

The present invention relates to a process for making a product having a five membered ring fused to an aromatic ring. The product may be an dihydroindene (i.e. an indane) or it may be an indane-like compound. In this process a substituted propene starting material cyclises in the presence of acid and a copper II salt of a superacid to produce the product. In its most general form, the starting material has structure In this structure, Ar is an optionally substituted aromatic or heteroaromatic ring system having at least one hydrogen attached to an aromatic carbon atom, and R ^J , R ² , R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of H, alkyl and aryl. In this case, the product will have structure:

The Ar ring system in the may be substituted, e.g. with one or more alkyl groups, aryl groups, alkoxy groups, aryloxy groups or hydroxy groups. It should be noted that the Ar ring system will not change through this reaction, however the substitution pattern may change, since substituent groups, particularly substituent alkyl groups may migrate. This is particularly the case when there are no hydrogen atoms on the Ar ring system ortho to the group in the starting material, e.g. if both ortho substituents are alkyl groups.

The inventors have found that the starting material described above may be prepared by reacting an aryl compound precursor with a suitable allyl compound having a leaving group in the allyl position, in the presence of a suitable copper II compound. In its most general form, the allyl compound has structure XC(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ , in which X is a leaving group, for example a halide, an ester etc. Furthermore, in reacting the allyl compound with the precursor to produce the starting material, acid is generated. Unless the acid is scavenged (by addition of a base, e.g. carbonate or amine) this acid can convert the starting material in situ into the product in the presence of the copper II compound.

Thus in one form of the reaction the starting material is cyclised in the presence of acid and the copper II salt to provide the product. In another form, the allyl compound and the aryl precursor are reacted in the presence of a suitable copper II compound to form the product. In the latter form of the reaction, it is thought that the starting material is formed as an intermediate, and reacts in situ. In a third form, the allyl compound and the aryl precursor are reacted in the presence of a suitable copper II compound to form the starting material. This may in some cases be conducted in the presence of base in order to suppress further reaction. The starting material may then be cyclised to the product by addition of acid, either with or without separation of the starting material from the reaction mixture. In the event that the starting material is separated, further copper II compound may be added. Various materials used in one or other of the reactions outlined above are described in greater detail below.

precursor: this compound contains an aromatic ring system. The ring system of the precursor may be a monocyclic aromatic ring, e.g. a benzene ring or a heterocyclic ring (e.g. pyridine, pyrazine, pyridazine, thiophene, furan etc.). It may be a 6 membered ring, or may be a 5 membered ring or may be some other ring size. The precursor may contain a bicyclic or polycyclic ring system. This may be a carbocyclic aromatic ring fused with either a second carbocyclic aromatic ring or with a heterocyclic aromatic ring. It may comprise two fused heterocyclic rings, which may be the same or may be different. It may for example be a naphthylene, benzofuran, quinoline, isoquinoline, naphthyridine or benzoxazole ring system or some other ring system. The ring, or ring system, may be substituted. It may be substituted with one or more alkyl groups, aryl groups, ether groups (either aryl or alkyl ether), ester groups, halides or other groups, or by more than one of these. It is not necessary for the ring system to have adjacent CH groups, as substituent groups may migrate during the reaction. However the precursor must have at least two hydrogen substituents, i.e. it has structure ArH _n , wherein n is an integer greater than 1. n may be 2, 3, 4, 5 or more than 5. It will be understood that the number of non-hydrogen substituents in the precursor follows directly from the structure of the ring system and the number of hydrogen atoms n. In some embodiments Ar has no non-hydrogen substituents. In other embodiments Ar has at least one (e.g. 1, 2, 3 or 4 or more than 4) non-hydrogen substituent, e.g. an alkyl substituent. Suitable starting materials include 1,2,4,5- tetraalkylbenzene, 1,2,4- and 1,2,3-trialkylbenzene, ortho- and meta-xylene, alkoxyxylenes (e.g. 2,5- and 2,6-dialkylanisole, 2,3,4-, 2,3,5- and 2,3,6-trialkylphenols etc. In the present specification, the term "alkyl" includes cycloalkyl groups. The alkyl groups may be straight chain or may be branched. They may be CI to C 12 or longer, or may be CI to C6, CI to C3, C2 to C12, C6 to C12 or C2 to C6 (provided that if the alkyl group is cyclic or branched it is greater than C2). The alkyl groups may in some cases be substituted. Suitable alkyl groups include optionally substituted methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, neopentyl, hexyl, octyl, isooctyl, cyclopentyl or cyclohexylmethyl. In some embodments the precursor is not 1,3,5-trimethylbenzene or o- xylene.

allyl compound: in its most general form this has formula XC(R ¹ R ² )-C(R ³ )=C(R ⁴ )R ⁵ . In this formula, each of R ¹ to R ⁵ may, independently be alkyl or aryl or hydrogen. X is a leaving group, e.g. halide, an oxygenated leaving group (e.g. hydroxyl, ester: -0-C(=0)R, sulfonate etc.) or some other leaving group. Most commonly the allyl compound will have structure R ⁴ R ⁵ C=C(H)CH ₂ X. The carbon-carbon double bond may be in the cis- form or the anti- form or there may be a mixture of cis and trans forms. Suitable allyl compounds include cinnamates (in which R ⁵ is phenyl and R ¹ to R ⁴ are all H and the double bond is trans). In other suitable allyl compounds the R ⁴ and R ⁵ are both alkyl (e.g. methyl) and R ¹ to R ³ are all H. Common leaving groups in the allyl compound include chloride, bromide, toxylate, hydroxyl, acetate, benzoate etc. When reacting the allyl compound with the precursor, the allyl compound may be used in approximately equimolar amount to the precursor, or in slight molar excess. It may for example be used in a molar ratio to the substrate of about 1.1 (i.e. about 1.1 mole allyl compound per mole of precursor) or of about 0.7 to about 1.5, or about 0.9 to 1.5 or 1 to 1.5, 1.1 to 1.5, 1.3 to 1.5, 0.7 to 0.9, 0.9 to 1.1, 0.9 to 1.3 or 1 to 1.2, e.g. about 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4 or 1.5. Alkyl groups which may be used for R ¹ to R ⁵ may be linear, branched, cyclic or a combination of any or all of these. They may be as described earlier (under "precursor")- They may optionally be substituted, for example by alkyl groups, aryl groups, halides, esters, hydroxyl groups, ether groups etc. Aryl groups may be carbocyclic or heterocyclic. They may be 5 membered, 6 membered or some other ring size. They may be monocyclic or may be bicyclic or polycyclic, and may be fused or linked.

starting material: in its most general form this has formula ArC(R ^, R ² )-C(R ³ )=C(R ⁴ )R ⁵ , where R ¹ to R ⁵ and Ar are as defined above and Ar has at least one hydrogen atom. The double bond may be cis or it may be trans or there may be a mixture of cis and trans forms. The starting material may have the same structure as described for the allyl compound except that X is replaced by Ar. In the one pot process from precursor and allyl compound to product, the starting material may be regarded as an intermediate.

copper salt: this is a copper (II) salt of a superacid. It may be for example a triflate (trifluoromethanesulfonate). It may be a salt of an acid having pKa of less than about -12, or less than about -13, -14 or -15, or of about -12, -12.5, -13, -13.5, -14, -14.5 or -15. Triflic acid has been estimated to have pKa of about -15. Other suitable superacids include fluoroantimonic acid fluorosulfonic acid. Superacids are considered to be those acids with an acidity greater than that of 100% pure sulfuric acid (which has a Hammett acidity function (H ₀ ) of -12). Thus in a superacid the chemical potential of the proton is higher than in pure sulfuric acid. The Hammett acidity function of the superacid may therefore be less than about -12, or less than about -13, -14 or -15, or may be about -12, -12.5, -13, -13.5, -14, -14.5 or -15. The copper salt may be soluble in the solvent used in the reaction. The copper salt may be a copper catalyst. It may be used in a catalytic amount. It may be used in a molar ratio to the precursor or to the starting material of about 1 to about 10mol%, or about 1 to 5, 5 to 10 or 3 to 7mol%, e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10mole%.

acid: the conversion of the starting material to the product requires the presence of an acid. This may be generated in situ, or may be added discretely. It may have a pKa of less than about 5, or less than about 4.5, 4, 3.5, 3, 2.5, 2, 1.5 or 1. It may be a strong acid It may be an organic acid or may be a mineral acid. It may be derived from, or may be the conjugate acid of, the leaving group on the allyl compound. Thus for example if X in the allyl compound is CI, the acid may be hydrochloric acid and if X is acetate, the acid may be acetic acid. If added discretely to the starting material, it may be added in at least 1 mole equivalent relative to the starting material, or at least about 1.5 or 2 mole equivalents, e.g. about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mole equivalents or more. It may be hydrochloric acid, sulfuric acid, trifluoroacetic acid or some other acid.

solvent: the solvent may be a solvent for the substrate and for the allyl compound in the amounts in which these are used. It may be a solvent for the copper salt. It may be an anhydrous solvent. It may be an aprotic solvent. It may be a polar solvent. It may be a halogenated solvent, e.g. chlorinated or brominated or both. It may be a haloalkane. It may be a dihaloalkane, e.g. a dichloroalkane, or a polyhaloalkane. It may be for example methylene chloride or dichloroethane (1,1- or 1,2-). It may be a mixture of halogenated solvents, or may be a mixture of a halogenated solvent with a non-halogenated solvent, preferably an aprotic non-halogenated solvent. In some embodiments, the reaction involves a homogeneous reaction mixture and in other embodiments it involves a heterogeneous reaction mixture.

The conversion from starting material to product may be conducted with no added base. It may be conducted under acidic conditions. It may be conducted in the presence of an acid. It may be conducted under anhydrous conditions. The conversion from precursor to starting material may be conducted under basic conditions or neutral conditions or acidic conditions. It may be conducted under anhydrous conditions. In the event that it is conducted under basic conditions, it may not proceed all the way to the product and may stop at the starting material. This may be subsequently converted to the product under acidic conditions as described above. In this case the combined process may be conducted as a one pot process by addition of acid to the reaction mixture containing the starting material. Sufficient acid should then be added to neutralise any base present in the reaction mixture and to acidify the reaction mixture. Alternatively, the starting material may be isolated and then converted under acidic conditions to the product, making the overall process a two pot process.

The reaction (or either the cyclisation or the coupling reaction or both) may be conducted in a sealed container. It may be conducted at reflux. It may be conducted at a temperature of about 40 to about 80°C, or about 40 to 60, 60 to 80 or 50 to 70°C, e.g. about 40, 50, 60, 70 or 80°C. It may be conducted in solution, in suspension or both in solution and suspension (i.e. some components may be in solution and others in suspension). The reaction time will depend on the actual reagents, concentrations and reaction temperature used. It may be for example about 12 to about 24 hours, or about 12 to 18, 18 to 24 or 14 to 18 hours, e.g. about 12, 14, 16, 18, 20, 22 or 24 hours. It may be conducted under air or under some other atmosphere, e.g. nitrogen, argon, helium, carbon dioxide or a mixture of these.

In a particular embodiment of the invention there is provided a one pot process for making a compound having an indane nucleus. The process comprises combining a precursor comprising an alkyl and/or alkoxy substituted benzene ring having at least two hydrogen atoms attached to the benzene ring, and an allyl compound having an allylic substituent which is a halide or an ester, in a halogenated solvent and in the presence of copper (II) triflate. In this embodiment, an acid, e.g. a hydrogen halide, may be added.

Thus in particular embodiments the present invention relates to a direct, one-step catalytic synthesis of dihydroindene skeleton from substituted benzenes and haloalkenes. The reaction is thought to involve a [3+2] cycloaddition onto an aromatic ring with Cu(OTf) ₂ catalyst under relatively mild conditions. This simple method can be applied to a variety of indane skeletons or benzo-fused carbbcycles synthesis. This is the only method for direct, one-step catalytic synthesis of dihydroindene skeleton. This new method can be applied to a variety of indane skeletons or benzo-fused carbocycles synthesis.

Allylic halides possess two reactive centers susceptible to Friedel-Crafts alkylation. It is known that haloalkenes generally favor reaction at the double bond with protic acid catalysts. ?-Toluenesulfonic acid can promote cinnamyl halide alkylation on the allylic position, but is not applicable to other simple haloalkenes. Metal catalysts also favor the reaction at the allylic position. When Cu(OTf) ₂ was tested in catalyzing allylation of substituted benzene with allylic halide, an unexpected [3+2] cycloaddition dihydroindene product was produced in high yield. Typically, 1 mmol of 1,2,4,5-tetramethylbenzene (Durene 1) and 1.1 mmol of cinnamyl chloride were added in 5 ml of CH2CI2. The mixture was stirred at 60 °C for 16 hours and 2,3,4 _J 5-tetramethyl-9-phenylindane 7 was isolated in 78 % of yield. Higher yields of 7 could be achieved with excess amount of cinnamyl chloride (Table 1, entry 2). The structure of 7 was confirmed by X-ray single crystal diffraction, see Figure 5.

It appears that this remarkable reaction underwent several challenging steps in one pot with a single catalyst. The proposed mechanism for the observed transformation is as follows. Firstly, copper catalyzed allylation of durene forms non-ring intermediate 2, Fig. 2 A. Although there was no intermediate 2 detected in the final reaction mixture, the formation of 2 was confirmed by quenching the reaction at early stage. In traditional Friedel-Crafts alkylation, allyl halides favors the reaction at the double bond while metal catalysts can control the reaction at the allylic position. In the present instance Cu(OTf)2 activated both durene and cinnamyl chloride at the same time and followed with C-C coupling as shown as in intermediate 4 of Fig. 2. Copper was not inserted into the allyl-Cl bond, otherwise it would be expected that the allylic carbenium ion would rearrange since the durene favored electrophilic addition to the double bond. Following the first allylation step, intermediate 2 underwent double methyl migration under acidic conditions to form intermediate 3, Fig. 2 B. Lewis acid promoted methyl migration is well known as a reversible process and generally the efficiency of this migration is low. In this reaction system, as intermediate 3 underwent fast intramolecular alkylation, the methyl migration was very efficient and all intermediate 2 was converted to 7 via intermediate 3. Finally, intermediate 3 underwent acid induced intramolecular alkylation to form cycloaddition product 7, shown in step C in Fig. 2. Overall, Cu(OTf 2 catalyzed the first step allylation reaction. After that, acid generated in the first step played an important role in the following methyl migration and intramolecular alkylation steps.

The following control experiments further supported this hypothesis. When cinnamyl alcohol was used instead of cinnamyl chloride, only 2 was isolated in low yield in the product mixture (Table 1, entry 1 1). However, when cinnamyl acetate was used as reactant, both 2 and 7 (about 1 :2 ratio) were produced (Table 1, entry 13). This is because no acid by-product and weak acid were generated in the cinnamyl alcohol system and the cinnamyl acetate system respectively. On the other hand, when an excess amount of base, such as triethylamine or sodium carbonate, was added in the durene/cinnamyl chloride reaction system, only 2 was generated, in relatively low yield (Table 1, entries 3, 4). Further investigation showed that 2 can convert to 7 under standard reaction condition with acid additives, such as trifloroacetic acid, HCl or acid generated in situ from the reaction between 1 and cinnamyl chloride (Table 1, entry 12, Fig. 3). If no acidic additives were present, 2 could not convert to 7 with only Cu(OTf)2 catalyst.

As shown in Table 1, other copper catalysts, such as CuCl ₂ and Cul, were also tested in this reaction and ether no reaction or trace amount of single alkylation product 2 was obtained. Various solvents were also used for the reaction and only methylene dichloride or tetrachloroethylene gave good results. No cycloaddition product was observed when THF, DMF or MeCN was used. When the reaction was carried in toluene, 1,3-diarylation product was generated in excellent yield. The reaction of cinnamyl chloride alone with Cu(OTf) ₂ catalyst in CH2CI2 was also investigated. An interesting [3+2] cycloaddition product was isolated as major product 8 with some unidentified byproducts, Fig. 4. However, when arenes existed in the reaction system, no cinnamyl chloride self-cycloaddition product 8 was observed.

This reaction protocol was then extended to other substrates. As expected, most substituted benzenes were active toward this reaction to give related cycloaddition dihydroindene skeletons in moderate to good yields, see Table 2. As shown in table 2, entries 1 to 6, bi-, tri- and tetra-methyl substituted benzenes reacted with cinnamyl chloride to form the desired products in good yield. There are no methyl migration steps involved in the reaction of substrates 9, 11, 13 and 15. However, almost no reaction was observed between 1,3,5-trimethylbenzene or o-xylene and cinnamyl chloride under similar conditions. The same reaction was also carried out on substituted phenols, see Table 2, entries 7 to 9. There must be methyl migration steps in the reaction with substrate 21, and very good yield of cyclic product 22 was produced. 3,3-dimethylallyl bromide was also tested with arenes 1, 9 and 11. Similar cycloaddition products 23, 24 and 25 were obtained.

In conclusion, a direct, one pot catalytic synthesis of dihydroindene skeleton with substituted benzenes and haloalkenes was developed. The reaction was underwent a [3+2] cycloaddition onto an aromatic ring with Cu(OTf)2 catalyst under relatively mild conditions. This simple method can be applied to a variety of indane skeletons or benzo- fused carbocycles synthesis.

Examples General Information. All solvents and chemicals were used as received from commercial suppliers, unless otherwise noted. Dry solvents and glove box (Argon Innovative Technologies, Inc.) were used for the set up of reactions. Gas chromatography-mass spectrometry (GC-MS) analyses were performed on a Shimadzu GCMS QP2010 system, while gas chromatography (GC) analyses were conducted on an Agilent GC6890N system. 1H and ^l3 C nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV-400 instrument (400 MHz).

Synthesis procedure (Table 1, entry 1). 1 mmol of 1 (134 mg) and 1.1 mmol of cinnamyl chloride (151 mg) were added into a reaction vial with 5 ml CH2CI2 in glove box. The reaction vial was capped and taken out of the glove box, heated to 60 °C and kept stirring for 16 hours. Then, the reaction mixture was cooled to room temperature and diluted with CH ₂ Cl ₂ (10 mL) and water (15 mL). The aqueous layer was extracted with CH2CI2 (10 mL x 2). The combined organic layer was dried (MgS0 ₄ ), and concentrated. The pure product was obtained through flash silica gel column chromatography of the residue using hexane as the eluent.

X-ray Structure Determinations. Diffraction-quality crystals were obtained by slowly vaporizing of hexane solution. Crystals were mounted in Infineum® oil on a fiber on a goniometer head which was placed in the dinitrogen cold stream on a Siemens (Bruker®) SMART CCD-based diffractometer at 223 K. Cell parameters were retrieved using SMART software and refined using SAINT on all observed reflections.

Table 1. Cu(OTf) ₂ catalyzed cycloaddition of durene with cinnamyl electrophiles. ^[a)

Yields (%) ^1CJ

Entry X Catalyst Solvent Additives ¹ " ¹

2 7

1 CI Cu(OTf) ₂ CH ₂ CI2 - 0 85

3 CI Cu(OTf) ₂ CH2CI ₂ NEt ₃ 30 0

4 Cl Cu(OTf) ₂ CH2CI ₂ Na ₂ C0 ₃ 15 0

5 Cl CuCl ₂ CH2CI ₂ - <5 0

6 Cl Cul CH CI2 - 0 0

7 Cl Cu(OTf) ₂ THF - <5 0

8 Cl Cu(OTf) ₂ MeCN - <5 0

9 Cl Cu(OTf) ₂ D F - 0 0

10 Cl Cu(OTf) ₂ Tol - ₀ M 0

11 OH Cu(OTf) ₂ CH2CI2 - 3Q 0

12 OH Cu(OTf) ₂ CH CI2 HCI 40 60

13 OAc Cu(OTf) ₂ CH2CI2 — 10 20

¹ Reaction conditions: durene (0.5 mmol), cinnamyl chloride (0.55 mmol), catalyst (5.0 mol %), CH ₂ C1 ₂ (2 mL), 60 °C, 16h. ^m Excess amount of additives were used. ^[c] GC yield. ^ 1, 3 -arylation product was produced. Table 2. Cu(OTf)2 catalyzed cycloaddition of arene with haloalkenes [a]

Entry arene haloalkene Temp(°C) Time(h) Products Yield(%)'

xx ₉ ^100/16

100/16

18

8 ~ό„ ^100/16 ^ O ₂₀

9 ^" V ^60/48 90

T 21 22

11 XX, ^100/16 ^ ₂₄

12 «-„ ^100/16 ^„

^[a] Reaction conditions: arene (1 mmol), haloalkene (1.1 mmol), catalyst (5.0 mol %), CH2CI2 or C2H2CI ₄ (4 mL). ^M GC yield and isolated yield in parentheses, [c] 2 mmol of Cinnamyl chloride was used.