Synthesis of dihydrobenzofurans and dihydroindoles by intramolecular Friedel-Crafts cyclizations of aryloxy-and arylamino-substituted propargylic alcohols

A FeCl3-catalyzed intramolecular Friedel-Crafts cyclization of aryloxyand arylaminosubstituted propargylic alcohols has been studied. This transformation provides a versatile and direct strategy for the construction of dihydrobenzofurans and dihydroindoles from easily accessible starting materials.


Introduction
Both dihydrobenzofuran and dihydroindole moieties are important structural unit frequently found in many natural and synthetic compounds that exhibit a variety of biological properties. 1,2lthough several general methods for their synthesis have been developed, [3][4][5][6][7][8][9][10][11][12] they often suffer from the use of expensive transition-metal catalysts or toxic reagents and multistep preparation of the starting materials.Hence, efficient and general methods for the synthesis of both dihydrobenzofurans and dihydroindoles from easily accessible starting materials using inexpensive and low-toxicity catalysts are still needed.
4][15][16][17][18][19] One of the most important applications of propargylic alcohols is the synthesis of allenes by the coupling of a nucleophiles with allenic carbocation intermediates, which were generated in situ by the Meyer-Schuster rearrangement.1][22][23][24][25][26] In a recent report, the Zhou group have developed an intramolecular Friedel-Crafts (IFC) reaction that provides a facile and versatile method for one-step construction of a variety of six membered ring skeletons from benzylamino-or aryl-substituted propargylic alcohols. 27,28Very recently, our group has reported the application of propargylic alcohols for the construction of substituted fluorenes, in which five-membered rings were constructed by IFC reactions. 29It was envisaged that the similar IFC reaction of propargylic alcohols may also be applied to construct a five-membered heterocyclic skeleton.Herein, we report a concise and versatile route to the synthesis of dihydrobenzofurans and dihydroindoles by FeCl 3 -catalyzed IFC cyclizations of aryloxy-and arylamino-substituted propargylic alcohols.

Results and Discussion
We began our investigation with the IFC reaction of 1a with 1 equiv. of various Lewis acids in the presence of 4Å molecular sieve (MS) in dioxan at 40 o C (Table 1, entries 1-7), FeCl 3 was proven to be optimal, albeit with a low yield (entry 1).Brønsted acids, such as TsOH and TFA were also tested, but no desired product was detected (entries 8 and 9).A series of other desiccants, such as CaH 2 and MgSO 4 , were also tested (entries 10, 11), and they displayed higher efficiency for the reaction.No significant formation of 2a was detected when other solvents, including MeNO 2 , toluene, MeCN and DCM were used (entries 12-15).Decreasing the catalyst from 1 equivalent to 20 mol% had a drastic effect as only 14% of 2a was isolated (entry 16), indicating that stoichiometric catalyst was required for the transformation to occur.However, the yield slightly decreased when the reaction using 1.2 molar equivalent of FeCl 3 (entry 17).In the cases in which the product is not detected or it is obtained in lower yield, the reactions give a large amount of unidentified side-products.
With the optimized reaction conditions in hand, the scope of the FeCl 3 -catalyzed IFC reaction was examined.As shown in Table 2, aryloxy-substituted propargylic alcohols bearing electron-donoring Me and MeO substitution at the phenolic position gave yields of 69% and 36% respectively (Entries 2, 3).Introduction of moderately electron-withdrawing Cl on the paraposition of phenolic position was well tolerated and the product was obtained in 67% yield (entry 4).It is noteworthy that our findings sharply differ from the results reported by the Zhou group, in which benzylamino-substituted propargylic alcohols bearing a chloride group resulted in the isolation of the Meyer-Schuster rearranged ene-ketone as the main product. 27,28It was also found that the substituents of arenes at the propargylic position play a significant role on the reactivity.By using propargylic alcohol bearing p-Me group, the reaction gives only a mixture of unidentified side-products, while the p-Cl substituted propargylic alcohol afforded a yield of 34% (entries 5, 6).When one of the R 2 is an aliphatic substituent, no product was obtained (entry 7).To expand the utility of this methodology, several arylamino-substituted propargylic alcohols were also examined under the optimal conditions (Table 3).Generally, they exhibited higher reactivity than aryloxy-substituted propargylic alcohols.Good to excellent yields were obtained for these substrates with Cl, Me and MeO substituents (entries 2-4).Substrate with Br substituent was also subjected to the process, thus affording the dihydroindole 4e with 82% yield (entry 5).Similar trends in the reactivity were observed with the substituents of arenes at propargylic position.No desired product was isolated in the case of propargylic alcohol with Me substituent, while propargylic alcohol with F substituent can provide the desired product in 52% yields (entries 6-7).

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On the basis of previous reports 5 and our experimental results, a plausible mechanism is outlined in Scheme 1. Propargyl alcohols 1 and 3 are first converted into the allenylic cations I in the presence of Lewis acid via a Meyer-Schuster rearrangement. 4 Then, benzene ring acts as the nucleophile to trap the cation I and form the corresponding dihydrobenzofuran and dihydroindole.

Entry
Products Yield (%) b

Conclusions
In summary, we report a facile and versatile method for synthesis of dihydrobenzofuran and dihydroindole derivatives via FeCl 3 catalyzed intramolecular Friedel-Crafts cyclizations of aryloxy-and arylamino-substituted propargylic alcohols.Further experiments on the derived dihydrobenzofuran and dihydroindole and the construction of other five-membered and sevenmembered ring skeletons using this protocol are in progress.

Experimental Section
General.All organic solvent were pre-dried prior to use.The 1 H NMR and 13 C NMR spectra were recorded at 25 °C in CDCl3 at 500 and 125 MHz, respectively, with TMS as the internal standard.Chemical shifts (δ) are expressed in ppm and coupling constants J are given in Hz.
High resolution mass spectra (HRMS) were obtained on a TOF MS instrument with ESI source.The propargylic alcohols were synthesized according to literature method. 30neral experimental procedure and spectroscopic data.In a Schlenk tube, propargylic alcohols 1 or 3 (0.2 mmol), FeCl 3 (0.2 mmol) and CaH 2 (12 mg) were added and charged with N 2 three times.Anhydrous dioxan (2 mL) was then added.After being stirred at 40 o for 4 h, the mixture was diluted with DCM (20 mL), washed with water and saturated brine, dried over Na 2 SO 4 , and then evaporated under reduced pressure.The residue was purified by column chromatography on silica gel (eluent: light petroleum/ ethyl acetate = 60 : 1) to give the products.2926, 1954, 1597, 1481, 1447, 1357, 1232, 1161, 1102, 695.

Table 1 .
Optimization of reaction conditions for access to 2a a a Reaction conditions: propargylic alcohol 1a (0.2 mmol), Lewis acid (0.2 mmol) and desiccant in solvent (2 mL) at 40 o C for 4 h under N 2 .b Isolated yield, nd = not detected.c 20 mol% of catalyst.d 120 mol% of catalyst.