ZHOU Ziyang,YI Ying,ZHANG Fanglin,XU Wengang,LU Zhi,LUO Tian

(School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China)

Abstract: We devoloped an efficient and simple method to synthesize fluorene derivatives via intramolecular Friedel-Crafts alkylation of chalcones.The transform is catalyzed by TfOH in CH3NO2 at 80 ℃and the yield is up to 99%.

Key words: fluorene;intramolecular alkylation;TfOH

1 Introduction

Fluorene is a kind of fundamental and promising material block of thermal stability,high quantum yields,and good charge transport properties[1-3].Fluorene can be applied to organic light emitting diodes,solar cells,thin film transistors,environmentally sensitive fluorescent probes and labels in biology and so on[4-6].They are also used as transition metal ligands in the form of anions,providing effective catalysts for olefin polymerization and other reactions[7].Therefore,it is necessary to develop synthetic methods that can obtain a variety of fluorene and related compounds quickly and efficiently.

Friedel-Crafts reactions have been widely reseached[8-13].In addition to the traditional synthesis methods,such as Friedel crafts cyclization[14]and radical cyclization[15],transition metal catalyzed cyclization involves C-H bond activation[16]and subsequent reaction C-C bond recently[17].

Further,Friedel-Crafts reactions could be applied to construct new C-C bonds via metal-free methodology and synthesize efficiently polycyclic structures involving cycloaddition reactions and intramolecular electrophile-induced cyclization.On the one hand,despite the long history of Friedel-Crafts alkylation,there were little researches in intramolecular Frieldel-Crafts-type alkylation withα,β-unsaturated carbonyl compounds,especially chalcones[18,19].On the other hand,Trifluoromethanesulfonic acid (TfOH),a super acid,plays an important role in Friedel-Craftstype alkylation[20-23].In order to optimize the reaction and subsequent purification,Lewis acid such as AlCl3and FeCl3supported on molecular sieve was also applied.Recently,we prepared 9-aryl fluorenes catalyzed by TfOH[24].Here,an efficient strategy was developed to synthesize 9-alkyl fluorenes.

To the best of our knowledge,no intramole-cular cyclization reaction of chalcones preparing fluorenes has been reported.In 2006,Dirk Trauner’ group reported Friedel-Crafts reaction withα,β-carbonyl compounds generating enol triflates.In 2011,Patrick Dallemagne’ group synthesized 2-(9H-fluoren-9-yl) acetic acid catalyzed by the mixture of 70 equiv TFA and TFA2O.Sanzhong Luo’ group reported an intramolecular conjugate addition of alkenes toα,β-unsaturated carbonyl compounds catalyzed by Cu(OTf)2when we prepared for this manuscript(Scheme 1)[25-27].In this paper,an intramolecular cyclization was built for preparing a variety of fluorene derivatives via Friedel-Crafts alkylation catalyzed by TfOH.

Scheme 1 Intramolecular cyclication of α,β-unsaturated carbonyl compounds

2 Experimental

2.1 General method

1H NMR and13C NMR (400 and 101 MHz,respectively) spectra were recorded in CDCl3and chemical shifts were reported in ppm from internal TMS (δ).All reactions were performed at 80 ℃.Solvents were dried by the standard procedures.Column chromatography was performed with 300-400 mesh silica gel.All of the reagents were used directly.

2.2 Preparation of catalyst

30 g of AlCl3were added to 100 mL of anhydrous ethanol containing 30 g of ZSM-5 molecular sieve,and the mixtures were constantly stirred at 80 °C for 5 h.The catalyst was washed with acetone twice and distilled water three times,and then the catalyst was dried in oven at 110 °C for 2 h and calcined in muffle furnace at 550 °C for 5 h.

2.3 Preparation of 2-arylbenzaldehydes (3)

5.0 mmol of arylboronic acid were added to 15 mL of a 2:1 DMF/H2O solution containing 5.0 mmol of 2-bromobenzaldehyde and 5.0 mmol of Na2CO3and the reaction mixture was stirred for 2 min.Pd(OAc)2(5 mol%) was then added and the flask was flushed with N2,sealed and allowed to stir at 25℃ overnight.Reaction solution was extracted with EtOAc (3 × 50 mL).Combined organic layers were washed with water three times,dried over anhydrous Na2SO4and concentrated under vacuum to yield the crude product,which was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent.

2.4 Preparation of chalcones (5)

2.0 mmol 2-arylbenzaldehyde,2.0 mmol acetophenone and 4.0 mmol K2CO3were added to dry glassware with 15 mL acetone and the reaction mixture was stirred at 60 ℃.Thin layer chromatography(TCL) monitored the reaction until no substrate was detected.Next,reaction solution was neutralized with dilute hydrochloric acid solution and aqueous solution was extracted with EtOAc (3 × 50 mL).Then,combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum to gain crude product.Finally,crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent.

2.5 Intramolecular alkylation for the synthesis of fluorene derivatives (6)

0.5 mmol 3-([1,1’-biphenyl]-2-yl)-1-(4-bromophenyl)prop-2-en-1-one (5a) was added to one reaction tube containing 5 mL CH3NO2and 10% catalyst was added into solution.Next,reaction solution was stirred at 80 ℃.TCL monitored the reaction until no substrate was detected.Next,reaction solution was diluted with 50 mL water and aqueous solution was extracted with EtOAc (3 × 50 mL).Then,combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum to gain crude product.Finally,crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to give fluorene 6a.

3 Results and discussion

The ortho-phenyl chalcone 5a was chosen as a model substrate.Considering in super acid’s property,firstly,TfOH was employed to catalyze the reaction expected.To our delight,the reaction gave intramolecular cyclization product in moderate yield(Table 1,entry 1).Then we checked several weaker acids’ catalytic effect and found thatp-toluene sulfonic acid (p-TSA) can also promote the reaction in lower yield (Table 1,entry 2),CF3COOH and H3PO4only got trace of target product,while preferably yield target product was gained under the catalysis of immobilized Lewis acid FeCl3and AlCl3(Table 1,entries 3-6).In further optimization,different solvents were screened(Table 1,entry 6-11).The product was generated in ethanediol in low yield (Table 1,entry 6) and almost no product was found in acetonitrile (CH3CN) or 1,4-dioxane (Table 1,entries 7 and 8).Further,the reaction proceeded to provide 6a in moderate yield using benzene (PhH) or dichloroethane (DCE) as the solvent (Table 1,entries 9 and 10).However,encouragingly,when nitromethane (CH3NO2) was used as solvent,and TfOH and ZSM-5/AlCl3as catalyst separately,the reaction generated the desired product in good yield (Table 1,entry 11-12).Accordingly,the combination of TfOH as a catalyst and CH3NO2as a solvent was subsequently used as the standard set of conditions.

Table 1 Screening of the reaction conditions for the intramolecular Frieldel-Crafts alkylationa

Having optimized the reaction,we proceeded to explore the substrate scope.For this purpose,Substrates 5a-5u were prepared using Suzuki coupling reaction followed by Aldol condensation and heterocyclic aromatic substrate 5v was obtained similarly.

The results showed that more electron-donating groups produced better yield.Substrates 5b,5c or 5d bearingp-C(CH3)3group,p-Me group orm-Me on the aromatic ring gave good yields and substrate 5f bearing two methyl groups resulted in almost quantitative transformation (Fig.1,6b-6f).In contrast,electronwithdrawing substituents hampered the transformation to proceed.Trace target products were detected of substrates bearingp-Br,p-Cl orp-CF3groups and NMR spectra indicates that the substrates were decomposed(Fig.1,6g-6i).Next,the substituent effect of the aromatic ring ofR2was tested.Compared to 6a,slightly low yields resulted from fluorine substituent (Fig.1,6j and 6k).Finally,the aromatic ring remote to the reacted site was also investigated.Electron-withdrawing substituents were beneficial for preparing target products.Substrates bearing nitro group smoothly converted into corresponding fluorene derivates in excellent yields (Fig.1,6l and 6m).And substrates,which contained electron-withdrawing and conjugated groups,can also generate products in good yields (Fig.1,6n-6p).What’s more,substrates bearing electrondonating groups were tolerated with the intramolecular addition (Fig.1,6q-6t).When no substituent was on substrate,a good yield was gained (Fig.1,6u).Finally,heterocyclic compound was tested and the reaction system was also applicable to the preparation of indeno[2,1-b]thiophene (6v) in moderate yield.

Fig.1 Intramolecular alkylation with chalcones (Yields depicted are of isolated product.Substrates of 6g,6h and 6i were decomposed)

As commonly accepted,Friedel-Crafts alkylation was accomplished by electrophilic attack.To this reaction,proton promoted the conversion to proceed in the manner of Friedel-Crafts alkylation reaction and a plausible mechanism was put forward (Scheme 2).

4 Conclusions

In summary,an efficient methodology has been developed for the synthesis of a kind of fundamental and promising material blocks,fluorene derivatives.This conversion is by catalytic amount of TfOH via intramolecular Friedel-Crafts alkylation,the catalysis of AlCl3also has considerable conversion.Further,we figured out the substituent effect of three aromatic rings of substrates.Above all,this strategy is a highly atom-economic method for the synthesis of various 2-(9H-fluoren-9-yl)-1-phenylethanone derivatives.

Spectroscopic data of new compounds

1-(4-bromophenyl)-2-(9H-fluoren-9-yl)ethanone(6a):1H NMR (400 MHz,CDCl3)δ=7.89– 7.84 (1 H,m),7.81 (1 H,d,J7.6),7.65– 7.60 (1 H,m),7.52 (1 H,dd,J7.5,0.6),7.41 (1 H,t,J7.4),7.31 (1 H,tt,J4.4,1.7),4.79 (1 H,t,J6.7),3.44 (1 H,d,J6.8).13C NMR(101 MHz,CDCl3)δ=197.81,147.00,140.85,135.71,132.00,129.71,128.54,127.41,127.21,124.64,119.95,43.44,42.60.

1-(4-bromophenyl)-2-(2-(tert-butyl)-9H-fluoren-9-yl)ethanone(6b):1H NMR (400 MHz,CDCl3)δ=7.89 (2 H,d,J8.5),7.77 (2 H,dd,J15.2,7.8),7.63(2 H,d,J8.5),7.58 (1 H,d,J8.8),7.54 (1 H,d,J7.5),7.48 (1 H,t,J8.9),7.41 (1 H,t,J7.5),7.29 (1 H,dd,J10.7,4.2),4.81 (1 H,t,J6.8),3.52– 3.35 (2 H,m),1.41(9 H,t,J5.3).13C NMR (101 MHz,CDCl3)δ=198.19,150.62,147.20,146.87,140.88,138.30,135.91,132.02,129.81,128.51,127.41,126.81,124.68,121.51,119.76,119.55,43.57,42.96,34.99,31.64.

1-(4-bromophenyl)-2-(2-methyl-9H-fluoren-9-yl)ethanone(6c):1H NMR (400 MHz,CDCl3)δ=7.91–7.85 (2 H,m),7.77 (1 H,d,J7.6),7.72– 7.67 (1 H,m),7.66– 7.59 (2 H,m),7.51 (1 H,dd,J7.5,0.5),7.40(1 H,t,J7.4),7.35 (1 H,d,J0.5),7.28 (1 H,td,J7.6,1.1),7.24 (1 H,d,J7.7),4.76 (1 H,t,J6.7),3.43 (2 H,t,J9.1),2.44 (3 H,s).13C NMR (101 MHz,CDCl3)δ=197.87,147.31,146.92,140.96,138.24,137.16,135.70,132.00,129.74,128.53,128.28,127.38,126.75,125.37,124.64,119.73,119.65,43.59,42.39,21.75.

1-(4-bromophenyl)-2-(4-methyl-9H-fluoren-9-yl)ethanone(6d):1H NMR (400 MHz,CDCl3)δ=7.96 (1 H,d,J7.7),7.89– 7.84 (2 H,m),7.65– 7.59 (2 H,m),7.56 (1 H,t,J6.3),7.44 (1 H,t,J7.5),7.37 (1 H,t,J6.7),7.32 (1 H,td,J7.5,1.0),7.25– 7.18 (2 H,m),4.80(1 H,t,J6.6),3.51– 3.35 (2 H,m),2.78 (3 H,s).13C NMR (101 MHz,CDCl3)δ=197.94,147.50,147.47,141.84,138.87,135.74,133.17,132.00,129.74,128.53,127.33,126.91,126.55,124.52,123.22,121.99,43.84,42.41,21.15.

1-(4-bromophenyl)-2-(4-methoxy-9H-fluoren-9-yl)ethanone(6e):1H NMR (400 MHz,CDCl3)δ=7.88–7.84 (2 H,m),7.69 (2 H,dd,J8.0,4.5),7.64– 7.59 (2 H,m),7.47 (1 H,dd,J7.5,0.5),7.41– 7.33 (1 H,m),7.24 (1 H,td,J7.5,1.1),7.09 (1 H,d,J2.1),6.96 (1 H,dd,J8.3,2.3),4.74 (1 H,t,J6.7),3.84 (3 H,s),3.50–3.34 (2 H,m).13C NMR (101 MHz,CDCl3)δ=197.82,159.55,148.90,146.57,140.84,135.67,133.79,132.01,129.72,128.55,127.43,126.08,124.48,120.69,119.15,113.36,110.48,55.53,43.64,42.62.

1-(4-bromophenyl)-2-(1,3-dimethyl-9H-fluoren-9-yl)ethanone(6f):1H NMR (400 MHz,CDCl3)δ=7.88– 7.76 (3 H,m),7.64– 7.53 (4 H,m),7.46– 7.38 (1 H,m),7.34– 7.26 (1 H,m),7.05 (1 H,s),4.91 (1 H,d,J9.5),3.83– 3.69 (1 H,m),3.14 (1 H,dd,J18.0,9.7),2.52 (6 H,t,J13.2).13C NMR (101 MHz,CDCl3)δ=197.84,148.30,142.31,141.33,140.91,137.41,135.82,133.62,132.01,130.13,129.74,128.49,127.43,127.17,125.07,120.00,118.46,41.77,41.67,21.58,19.11.

1-(4-bromophenyl)-2-(3-fluoro-9H-fluoren-9-yl)ethanone(6j):1H NMR (400 MHz,CDCl3)δ=7.88–7.83 (2 H,m),7.74– 7.68 (2 H,m),7.64– 7.59 (2 H,m),7.50 (1 H,d,J7.5),7.39 (1 H,dd,J9.4,5.5),7.29(1 H,td,J7.5,0.9),7.24 (1 H,dt,J8.7,4.3),7.09 (1 H,tt,J8.1,4.0),4.74 (1 H,t,J6.7),3.42 (2 H,ddd,J25.3,18.1,6.7),2.08 (1 H,s).13C NMR (101 MHz,CDCl3)δ=197.37,163.77,161.33,149.26,149.18,146.83,146.82,140.04,136.85,136.83,135.46,132.03,129.68,128.67,127.57,126.89,124.54,120.90,120.81,119.65,114.65,114.42,112.42,112.18,43.30,42.58,42.56.

1-(4-bromophenyl)-2-(2-fluoro-9H-fluoren-9-yl)ethanone(6k):1H NMR (400 MHz,CDCl3)δ=7.89–7.84 (2 H,m),7.74 (1 H,d,J7.5),7.66– 7.59 (2 H,m),7.51 (1 H,dd,J7.5,0.7),7.48– 7.38 (3 H,m),7.33 (1 H,td,J7.5,1.2),7.01– 6.93 (1 H,m),4.73 (1 H,t,J6.7),3.42 (2 H,qd,J17.9,6.8),2.07 (1 H,s).13C NMR(101 MHz,CDCl3)δ=197.62,164.10,161.68,147.84,142.89,142.81,142.34,142.31,140.02,139.99,135.55,132.03,129.68,128.65,127.80,127.54,125.84,125.75,124.65,120.21,114.06,113.83,107.03,106.81,43.39,42.04.

2-(9H-fluoren-9-yl)-1-(4-nitrophenyl)ethanone(6l):1H NMR (400 MHz,CDCl3)δ=8.32– 8.23 (2 H,m),8.15– 8.07 (2 H,m),7.79 (2 H,d,J7.6),7.52 (2 H,d,J7.6),7.41 (2 H,t,J7.4),7.31 (2 H,td,J7.5,1.1),4.76 (1 H,t,J6.7),3.51 (2 H,d,J6.7).13C NMR(101 MHz,CDCl3)δ=197.37,150.38,146.64,141.22,140.87,129.18,127.60,127.31,124.60,123.89,120.06,44.05,42.44.

2-(9H-fluoren-9-yl)-1-(3-nitrophenyl)ethanone(6m):1H NMR (400 MHz,CDCl3)δ=8.79 (1 H,dd,J5.6,3.7),8.41 (1 H,ddd,J8.2,2.2,0.9),8.32– 8.27 (1 H,m),7.79 (2 H,d,J7.5),7.66 (1 H,t,J8.0),7.53 (2 H,d,J7.5),7.41 (2 H,t,J7.4),7.32 (2 H,td,J7.5,0.9),4.92– 4.64 (1 H,m),3.53 (2 H,d,J6.7).13C NMR(101 MHz,CDCl3)δ=196.61,148.47,146.65,140.88,138.09,133.61,129.93,127.57,127.48,127.29,124.60,123.04,120.03,43.80,42.41.

1-(3-bromophenyl)-2-(9H-fluoren-9-yl)ethanone(6n):1H NMR (400 MHz,CDCl3)δ=8.17 (1 H,dd,J10.6,9.0),7.91 (1 H,d,J7.8),7.82 (1 H,d,J7.5),7.73– 7.70 (1 H,m),7.54 (1 H,d,J7.5),7.43 (1 H,t,J7.4),7.34 (2 H,q,J7.2),4.81 (1 H,t,J6.7),3.46 (1 H,d,J6.7).13C NMR (101 MHz,CDCl3)δ=197.42,146.99,140.89,138.68,136.14,131.29,130.28,127.47,127.26,126.72,124.68,123.13,120.00,43.64,42.53.

1-(2-chlorophenyl)-2-(9H-fluoren-9-yl)ethanone(6o):1H NMR (400 MHz,CDCl3)δ=7.97– 7.92 (2 H,m),7.81 (2 H,d,J7.5),7.53 (2 H,d,J7.5),7.47–7.44 (2 H,m),7.42 (2 H,t,J7.5),7.32 (2 H,td,J7.5,0.9),4.80 (1 H,t,J6.7),3.45 (2 H,d,J6.8).13C NMR(101 MHz,CDCl3)δ=197.63,147.04,140.86,139.81,135.28,129.63,129.02,127.43,127.23,124.68,119.97,43.46,42.60.

1-(4-chlorophenyl)-2-(9H-fluoren-9-yl)ethanone(6p):1H NMR (400 MHz,CDCl3)δ=7.98– 7.92 (2 H,m),7.82 (2 H,d,J7.5),7.55 (2 H,d,J7.5),7.49–7.39 (4 H,m),7.33 (2 H,dd,J10.8,4.1),4.82 (1 H,t,J6.7),3.45 (2 H,d,J6.8).13C NMR (101 MHz,CDCl3)δ=197.60,147.07,140.89,139.80,135.29,129.65,129.02,127.47,127.27,124.72,120.00,43.45,42.63.

2-(9H-fluoren-9-yl)-1-(4-methoxyphenyl)ethanone(6q):1H NMR (400 MHz,CDCl3)δ=8.03– 7.98 (2 H,m),7.81 (2 H,d,J7.5),7.57– 7.52 (2 H,m),7.41 (2 H,t,J7.4),7.31 (2 H,td,J7.5,1.1),6.98– 6.93 (2 H,m),4.82 (1 H,t,J6.8),3.88 (3 H,d,J5.8),3.43 (2 H,d,J6.8).13C NMR (101 MHz,CDCl3)δ=197.30,163.67,147.38,140.84,130.51,130.18,127.26,127.14,124.74,119.86,113.83,55.48,43.03,42.83.

1-(4-(tert-butyl)phenyl)-2-(9H-fluoren-9-yl)ethanone(6r):1H NMR (400 MHz,CDCl3)δ=8.09–7.98 (2 H,m),7.88 (2 H,d,J7.6),7.65 (2 H,t,J9.2),7.59– 7.52 (2 H,m),7.47 (2 H,t,J7.4),7.37 (2 H,td,J7.5,1.1),4.94 (1 H,t,J6.7),3.51 (2 H,d,J6.8),1.44(9 H,d,J8.0).13C NMR (101 MHz,CDCl3)δ=198.44,157.10,147.49,140.97,134.58,128.33,127.41,127.30,125.72,124.86,119.99,43.41,42.80,35.21,31.20.

2-(9H-fluoren-9-yl)-1-(p-tolyl)ethanone(6s):1H NMR (400 MHz,CDCl3)δ=7.94 (2 H,d,J8.2),7.83(2 H,d,J7.5),7.57 (2 H,dd,J7.5,0.5),7.43 (2 H,t,J7.4),7.33 (2 H,td,J7.2,0.7),7.31– 7.28 (2 H,m),4.85(1 H,t,J6.8),3.48 (2 H,t,J5.9),2.45 (3 H,s).13C NMR (101 MHz,CDCl3)δ=198.46,147.38,144.13,140.89,134.63,129.39,128.37,127.32,127.20,124.77,119.91,43.34,42.78,21.67.

2-(9H-fluoren-9-yl)-1-(o-tolyl)ethanone(6t):1H NMR (400 MHz,CDCl3)δ=7.86 (2 H,d,J7.5),7.66– 7.60 (3 H,m),7.50– 7.32 (6 H,m),7.25 (1 H,t,J7.5),4.88 (1 H,t,J6.7),3.46 (2 H,d,J6.8),2.74 (3 H,s).13C NMR (101 MHz,CDCl3)δ=202.64,147.31,140.96,138.38,137.79,132.18,131.63,128.90,127.41,127.27,125.82,124.74,120.03,46.27,42.96,21.68.

2-(9H-fluoren-9-yl)-1-phenylethanone(6u):1H NMR (400 MHz,CDCl3)δ=8.07– 8.01 (2 H,m),7.83(2 H,d,J7.5),7.64– 7.59 (1 H,m),7.56 (2 H,t,J7.3),7.50 (2 H,t,J7.6),7.43 (2 H,t,J7.5),7.33 (2 H,td,J7.5,1.0),4.85 (1 H,t,J6.7),3.51 (2 H,d,J6.8).13C NMR (101 MHz,CDCl3)δ=198.83,147.28,140.89,137.05,133.31,128.71,128.23,127.36,127.22,124.74,119.93,43.52,42.70.

2-(8H-indeno[2,1-b]thiophen-8-yl)-1-phenylethanone(6v):1H NMR (400 MHz,CDCl3)δ=7.89– 7.85 (2 H,m),7.64– 7.60 (2 H,m),7.56 (1 H,d,J7.4),7.47 (1 H,d,J7.5),7.39– 7.33 (2 H,m),7.28 (1 H,d,J5.1),7.26– 7.21 (1 H,m),4.57 (1 H,dd,J10.3,4.4),3.75– 3.68 (1 H,m),3.13 (1 H,dd,J18.2,10.3).13C NMR (101 MHz,CDCl3)δ=197.42,149.81,148.31,146.03,138.78,135.33,132.01,129.63,129.46,128.66,127.40,124.76,123.91,119.36,118.37,77.38,77.06,76.74,42.95,41.55.

Conflict of interest

All authors declare that there are no competing interests.