Abstract:
Disclosed herein is single step process for the synthesis of 4-aryl substituted chromanes of compound of formula 2 comprising subjecting 3-aryloxy-1-phenylpropan-1-ol of formula 1 to gold(III) chloride-catalyzed intramolecular Friedel-Crafts reaction to obtain 4-aryl substituted chromanes. The invention further discloses novel 4-substituted Chromane compounds.

Description:
TECHNICAL FIELD OF THE INVENTION 
       [0001]    Present invention relates to synthesis of 4-aryl substituted chromanes by using gold (III) chloride-catalyzed intramolecular Friedel-Crafts reaction of 3-aryloxy benzyl alcohol. The invention further relates to novel 4-substituted Chromane. 
       BACKGROUND AND PRIOR ART OF THE INVENTION 
       [0002]    The structure of chromanes is abundant in natural products that possess a broad array of biological activities such as antimicrobial, antiviral, anti-proliferative and antitumor activity. Since chromanes are found in many natural products, efficient construction of this ring structure has attracted much attention in the recent past. 
         [0003]    Synthesis of Chromane Derivatives via Indium-mediated Intramolecular Allenylation and Allylation to Imines as in scheme 1 is disclosed by Han-Young Kang et al. in Bull. Korean Chem. Soc. 2004, Vol. 25, No. 11, 1627-1628. However, the reported yields are poor in the range of 70-80%. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0004]    Synthesis of Chromane Derivatives by Palladium-Catalyzed Intramolecular Allylation of Aldehydes with Allylic Acetates or Chlorides using Indium and Indium( III) Chloride as in scheme 2 is reported by Van Cuong Nguyen et al. in Bull. Korean Chem. Soc. 2005, Vol. 26, No. 5, page 711-712. However, the yields reported are poor in the range of 40-80%. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0005]    Synthesis of tetralin and chromane derivatives via In-catalyzed intramolecul arhydroarylationas in scheme 3 is reported by by Kai Xie et al., in Tetrahedron Letters Volume 51, Issue 33, 18 Aug. 2010, Pages 4466-4469.According to this study, In(OTf ) 3  was found to be an effective catalyst for the cyclization of ω-aryl- 1 -alkenes to form tetralin and chromane derivatives. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    Though the use of indium provides cost advantage over the use of palladium/platinum catalysts, the cursory review of prior art methods shows that the yields of the chromane obtained are not exceeded 80% and again the purification of the desired product and recycling of unreacted reagents adds additional steps to the synthesis. 
         [0007]    Most of the reported methods for synthesis of chromanes are run under harsh conditions with high concentration of Lewis acids, which can hardly be tolerated by many functional groups. 
         [0008]    In the light of the above, the present inventors have aimed at the alternate provision of efficient method for the synthesis of important chroman structure that possess a broad array of biological activities such as antimicrobial, antiviral, antiproliferative and antitumor activity. 
       OBJECTIVE OF THE INVENTION 
       [0009]    Main object of the present invention is to provide synthesis of 4-aryl substituted chromanes by using gold(III) chloride-catalyzed intramolecular Friedel-Crafts reaction of 3-aryloxy benzyl alcohol. 
         [0010]    Another objective of the present invention is to provide novel 4-substituted Chromanes. 
         [0011]    Yet another objective of the [present invention is to provide an efficient method to synthesize the compounds having this important active moiety in good yields by single catalytic method. 
       SUMMARY OF THE INVENTION 
       [0012]    Accordingly, present invention provides a single step process for the synthesis of 4-aryl substituted chromanes of compound of formula 2 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    comprising subjecting 3-aryloxy-1-phenylpropan-1-ol of formula 1 to gold(III) chloride-catalyzed intramolecular Friedel-Crafts reaction to obtain 4-aryl substituted chromanes 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein ′ ‘Ar’ is selected from the group consisting of α-Naphthyl, 4-Methylphenyl, Phenyl, β-Naphthyl, 4-Chlorophenyl, 4-Bromophenyl, 4-Fluorophenyl, 4-Cyanophenyl, Cesamoyl, 2-Methylphenyl, 2-Chlorophenyl, 2-Brormophenyl. 
         [0013]    In an embodiment of the present invention, the process is carried out at temperature in the range of 20 to 30° C. 
         [0014]    In yet another embodiment of the present invention, the process is carried out in presence of a solvent selected from the group consisting of halogenated hydrocarbons. 
         [0015]    In yet another embodiment of the present invention, the molar ratios of the 3-aryloxy-1-phenylpropan-1-ol with reference to gold(III) chloride is in the range of 1:0.01. 
         [0016]    In yet another embodiment of the present invention, the formula 2 is selected from the group consisting of:
   a) 3,4-Dihydro-4-phenyl-2H-benzo[h]chromene   b) 3,4-Dihydro-(6-methyl-4-phenyl)-2H-chromene   c) 3,4-Dihydro-4-phenyl-2H-chromene   d) 2,3-dihydro-1-phenyl-1H-benzo[f]chromene   e) 6-Chloro-3,4-dihydro-4-phenyl-2H-chromene   f) 3,4-Dihydro-4-phenyl-2H-chromene-6-carbonitrile   g) 7,8-Dihydro-8-phenyl-6H-1,3-dioxalo-4,5-chromene   h) 6-methoxy-3,4-dihydro-4-phenyl-2H-chromene   i) 6-bromo-3,4-dihydro-4-phenyl-2H-chromene and   j) 6-trifluoromethyl)-3,4-dihydro-4-phenyl-2H-chromene.   
 
         [0027]    In yet another embodiment, present invention provides compound of formula 2 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein ‘A’ is selected from the group consisting of α-Naphthyl, 4-Methylphenyl, Phenyl, β-Naphthyl, 4-Chlorophenyl, 4-Bromophenyl, 4-Fluorophenyl, 4-Cyanophenyl, Cesamoyl, 2-Methyphenyl, 2-Bromophenyl, 2-Chlorophenyl. 
         [0028]    In yet another embodiment of the present invention, The compounds of formula 2 comprises:
   a) 3,4-Dihydro-4-phenyl-2H-benzo[h]chromene   b) 3,4-Dihydro-(6-methyl-4-phenyl)-2H-chromene   c) 3,4-Dihydro-4-phenyl-2H-chromene   d) 2,3-dihydro-1-phenyl-1H-benzo[f]chromene   e) 6-Chloro-3,4-dihydro-4-phenyl-2H-chromene   f) 3,4-Dihydro-4-phenyl-2H-chromene-6-carbonitrile   g) 7,8-Dihydro-8-phenyl-6H-1,3-dioxalo-4,5-chromene   
 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0036]    Present invention provides catalytic single step process for the synthesis of 4-aryl substituted chromanes of compound of formula 2 using gold(III) chloride-catalyzed intra-molecular Friedel-Crafts reaction of 3-aryloxy-1-phenylpropan-1-ol of formula 1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein Ar as shown in formula 1 and 2 is selected from the group consisting of α-Naphthyl, 4-Methylphenyl, Phenyl, β-Naphthyl, 4-Chlorophenyl, 4-Bromophenyl, 4-Fluorophenyl, 4-Cyanophenyl, Cesamoyl, 2-Methylphenyl, 2-Chlorophenyl, 2-Brormophenyl. what is this cesamoyl group kindly add structure here etc. 
         [0037]    The advantage of the instant invention is being a single step catalytic process that can be conducted under milder reaction conditions with high yields. The gold(III) chloride-catalyzed intramolecular Friedel-Crafts reaction of 3-aryloxy-1-phenylpropan-1-ol of formula 1 may effectively be carried out at room temperature i.e. at 20 to 30° C. 
         [0038]    The process is carried out in presence of a solvent selected from the group consisting of halogenated hydrocarbons. 
         [0039]    3-aryloxy-1-phenylpropan-1-ol of formula 1 is subjected to gold(III) chloride-catalyzed Friedel-Crafts intramolecular cyclization in dichloromethane as a solvent at room temperature, to yield 4-aryl substituted chromanes of formula 2 in good yields. The molar ratios of the 3-aryloxy-1-phenylpropan-1-ol with reference to gold(III) chloride is in the range of 1:0.01 and the reaction may be accomplished in about 4-8 hrs. 
         [0040]    As mentioned herein the phrase ‘room temperature’ means and includes a temperature range of 20 to 30° C. 
         [0041]    Similarly, the instant invention provides process for preparation of a library of compounds of formula 2 using gold(III) chloride-catalyzed intramolecular Friedel-Crafts reaction of 3-aryloxy-1-phenylpropan-1-ol of formula 1. The formula 2 of the instant invention prepared according to the process of the invention encompasses the following compounds: 
       a) 3,4-Dihydro-4-phenyl-2H-benzo chromene 
       [0042]    
       
                 
         
             
             
         
       
     
       b) 3,4-Dihydro-(6-methyl-4-phenyl)-2H-chromene 
       [0043]    
       
                 
         
             
             
         
       
     
       c) 3,4-Dihydro-4-phenyl-2H-chromene 
       [0044]    
       
                 
         
             
             
         
       
     
       d) 2,3-dihydro-1-phenyl-1H-benzo[f]chromene 
       [0045]    
       
                 
         
             
             
         
       
     
       e) 6-Chloro-3,4-dihydro-4-phenyl-2H-chromene 
       [0046]    
       
                 
         
             
             
         
       
     
       f) 3,4-Dihydro-4-phenyl-2H-chromene-6-carbonitrile 
       [0047]    
       
                 
         
             
             
         
       
     
       g) 7,8-Dihydro-8-phenyl-6H-1,3-dioxalo-4,5-chromene 
       [0048]    
       
                 
         
             
             
         
       
     
         [0049]    The invention provides novel compounds of formula 2 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein ‘Ar’ is selected from the group consisting of α-Naphthyl, Methylphenyl, ethylphenyl, Phenyl, β-Naphthyl, Chlorophenyl, bromophenyl, iodo phenyl, fluorophenyl, Cyanophenyl, methoxyphenyl, trifluromethylphenyl and Cesamoyl. 
       EXAMPLE 
       [0050]    Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention. 
       Example 1 
       [0051]    To a solution of gold(III) chloride (3 mg, 1 mol %), in CH 2 Cl 2  (5 mL) was added 3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol 1a (278 mg, 1 mmol) in (2 mL CH 2 Cl 2 ) at 25° C. The resulting mixture was stirred for 6 h at 25° C. After stirring 6 h reaction mixture was quenched with water and extracted with CH 2 Cl 2  (10 mL×2). The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 . The solvent was concentrated in vacuo and the residue was purified by column chromatography (pet. Ether: ethyl acetate=9:1) to afford the desired cyclized product 3,4-dihydro-4-phenyl-2H-benzo[h]chromene or 4-aryl substituted chromanes (2a) in 98% yields. 
       Example 2 
       [0052]    To study the generality of the reaction, several 3-aryloxy-1-phenylpropan-1-ol (1a-g) were subjected to AuCl 3 -catalyzed Friedel-Crafts intramolecular cyclization the results of which are presented in Table 1. It is observed that 3-phenoxy-1-phenylpropan-1-ol as well as 3-(naphthalen-1-yloxy)-1-phenylpropan-1-ol gave good yields. In the case of both electron-donating (1b) as well as electron-withdrawing (1f) substituted 3-aryloxy-1-phenylpropan-1-ol gave the corresponding chromanes in 98% and 90% yields respectively. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Synthesis of 4-aryl substituted chromanes a   
               
             
          
           
               
                 Entry 
                 Substrate (1a-g) 
                 Product (2a-g) 
                 Yield (%) b   
               
               
                   
               
               
                 a 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98 
               
               
                   
               
               
                 b 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98 
               
               
                   
               
               
                 c 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 d 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 e 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 f 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 90 
               
               
                   
               
               
                 g 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 Reaction conditions: 
               
               
                   a 3-aryloxy benzyl alcohols (1 mmol), AuCl 3  (1 mol %), CH 2 Cl 2  (5 mL) 25° C., 4-8 h; 
               
               
                   b yields refer to isolated yields after column chromatography. 
               
             
          
         
       
     
         3 , 4 -Dihydro-4-phenyl-2H-benzo[h]chromene (2a) 
       [0053]    
       
                 
         
             
             
         
       
     
         [0054]    Yield: 98%; colorless solid m.p.: 82° C.; IR (CHCl 3 , cm −1 ): 701, 768, 1023, 1105, 1216, 1262, 1403, 1404, 1491, 1507, 1576, 2882, 2954, 3019, 3057;  1 H NMR (200 MHz, CDCl 3 ): δ 2.07-2.22 (m, 1H), 2.37-2.53 (m, 1H), 4.26-4.38 (m, 3H), 6.92 (d J=8.1 Hz, 1H), 7.11-7.32 (m, 6H), 7.40-7.50 (m, 2H), 7.68-7.74 (m, 1H), 8.18-8.22 (m, 1H);  13 C NMR (50 MHz, CDCl 3 ): 31.8, 40.9, 63.6, 117.4, 119.7, 121.8, 125.2, 126.0, 126.4, 127.4, 128.2, 128.4, 128.7, 133.5, 145.9, 150.3; Anal. Calcd for C 19 H 16 O requires C, 87.66; H, 6.19; found: C, 87.60; H, 6.25%. 
       3,4-Dihydro-(6-methyl-4-phenyl)-2H-chromene (2b) 
       [0055]    
       
                 
         
             
             
         
       
     
         [0056]    Yield: 98%; colorless gum; IR (CHCl 3 , cm −1 ): 768, 1023, 1107, 1218, 1266, 1403, 1404, 1491, 1508, 1576, 2884, 2954, 3019, 3050;  1 H NMR (200 MHz, CDCl 3 ): δ 1.97-2.12 (m, 1H), 2.16 (s, 3H), 2.22-2.37 (m, 1H), 4.08-4.16 (m, 3H), 6.61-6.62 (m, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.89-6.94 (m, 1H), 7.10-7.33 (m, 5H);  13 C NMR (50 MHz, CDCl 3 ): 20.5, 31.8, 41.0, 63.4, 116.5, 123.8, 126.4, 128.4, 128.5, 128.6, 129.2, 130.7, 145.8, 153.0; Anal. Calcd for C 16 H 16 O requires C, 85.68; H, 7.19; found: C, 85.70; H, 7.25%. 
       3,4-Dihydro-4-phenyl-2H-chromene (2c) 
       [0057]    
       
                 
         
             
             
         
       
     
         [0058]    Yield: 96%; gum; IR (CHCl 3 , cm −1 ): 768, 1030, 1107, 1220, 1266, 1406, 1404, 1491, 1508, 1576, 2882, 2950, 3019, 3051;  1 H NMR (200 MHz, CDCl 3 ): δ 2.04-2.14 (m, 1H), 2.27-2.36 (m, 1H), 4.13-4.20 (m, 3H), 6.73-6.86 (m, 3H), 7.07-7.33 (m, 6H);  13 C NMR (50 MHz, CDCl 3 ): 20.5, 31.8, 41.0, 63.4, 116.5, 123.8, 126.4, 128.4, 128.5, 128.6, 129.2, 130.7, 145.8, 153.0; Anal. Calcd for C 15 H 14 O requires C, 85.68; H, 6.71; found: C, 85.72; H, 6.67%. 
       2,3-dihydro-1-phenyl-1H-benzo[f]chromene (2d) 
       [0059]    
       
                 
         
             
             
         
       
     
         [0060]    Yield: 97%; colorless solid m.p.: 85° C.; IR (CHCl 3 , cm −1 ): 701, 768, 1023, 1105, 1216, 1262, 1403, 1404, 1491, 1507, 1576, 2882, 2954, 3019, 3057;  1 H NMR (200 MHz, CDCl 3 ): δ 2.10 (qd, J=2.2, 6.9 Hz, 1H), 2.43-2.61 (m, 1H), 4.07 (td, J=2.0, 10.4 Hz, 1H), 4.19-4.28 (m, 1H), 5.11 (d, J=5.2 Hz, 1H), 7.08-7.28 (m, 8H), 7.44-7.99(m, 1H), 7.66-7.74 (m, 2H);  13 C NMR (50 MHz, CDCl 3 ): 30.9, 36.8, 61.3, 114.1, 119.0, 123.0, 123.1, 126.3, 126.4, 128.4, 128.5, 128.8, 129.2, 133.0, 145.8, 153.0; Anal. Calcd for C 19 H 16 O requires C, 87.66; H, 6.19; found: C, 87.60; H, 6.25%. 
       6-Chloro-3,4-dihydro-4-phenyl-2H-chromene (2e) 
       [0061]    
       
                 
         
             
             
         
       
     
         [0062]    Yield: 93%; pale yellow gum; IR (CHCl 3 , cm −1 ): 766, 1030, 1100, 1218, 1260, 1403, 1404, 1491, 1508, 1576, 2884, 2952, 3010, 3045;  1 H NMR (200 MHz, CDCl 3 ): δ 1.99-2.14 (m, 1H), 2.21-2.36 (m, 1H), 4.09-4.19 (m, 3H), 6.76-6.82 (m, 1H), 7.03-7.13 (m, 3H), 7.16-7.36 (m, 4H);  13 C NMR (50 MHz, CDCl 3 ): 31.3, 41.0, 63.8, 118.2, 125.1, 126.0, 127.9, 128.5, 128.6, 130.0, 144.8, 153.7; Anal. Calcd for C 15 H 13 ClO requires C, 73.62; H, 5.35; found: C, 73.60; H, 5.40%. 
         3 , 4 -Dihydro-4-phenyl-2H-chromene-6-carbonitrile (2f) 
       [0063]    
       
                 
         
             
             
         
       
     
         [0064]    Yield: 90%; colorless gum; IR (CHCl 3 , cm −1 ): 768, 1023, 1103, 1218, 1266, 1403, 1410, 1491, 1510, 1576, 2210, 2253, 2884, 2954, 3019, 3054;  1 H NMR (200 MHz, CDCl 3 ): δ 2.01-2.14 (m, 1H), 2.21-2.39 (m, 1H), 4.06-4.18 (m, 1H), 4.26 (t, J=5.1 Hz, 2H), 6.90 (d, J=8.3 Hz, 1H), 7.05-7.15 (m, 3H), 7.26-7.43 (m, 4H); Anal. Calcd for C 16 H 13 NO requires C, 81.68; H, 5.57; N, 5.95; found: C, 81.60; H, 5.60; N, 5.91%. 
       7,8-Dihydro-8-phenyl-6H-1,3-dioxalo-4,5-chromene (2g) 
       [0065]    
       
                 
         
             
             
         
       
     
         [0066]    Yield: 93%; colorless gum; IR (CHCl 3 , cm −1 ): 765, 1023, 1107, 1218, 1266, 1403, 1409, 1491, 15108, 1576, 2884, 2954, 3019, 3057;  1 H NMR (200 MHz, CDCl 3 ): δ 1.99-2.09 (m, 1H), 2.23-2.35 (m, 1H), 4.03-4.13 (m, 3H), 5.91 (s, 2H), 6.24 (s, 1H), 6.38 (s, 1H), 7.11-7.33 (m, 5H);  13 C NMR (50 MHz, CDCl 3 ): 38.4, 66.1, 71.7, 98.1, 101.0, 105.7, 108.0, 125.8, 127.6, 128.5, 141.7, 144.3, 148.2, 154.2; Anal. Calcd for C 16 H 14 O 3  requires C, 75.57; H, 5.55; found: C, 75.50; H, 5.65%. 
       ADVANTAGES OF THE INVENTION 
       [0067]    1. Efficient single step process 
         [0068]    2. Harsh conditions and high concentrations of Lewis acid avoided.