Study on the reactions of azo compounds with acyl halides mediated by Sm/TiCl₄

Study on the reactions of azo compounds with acyl halides mediated by Sm/TiCl 4 1 first-author 1 2 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:yminzhang@mail.hz.zj.cn †E-mail:yminzhang@mail.hz.zj.cn yminzhang@mail.hz.zj.cn Department of Chemistry, Zhejiang University, Hangzhou 310028, China Department of Chemistry, Zhejiang University, Hangzhou 310028, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China Amides can be obtained in good to excellent yield by Sm/TiCl 4 mediated reductive cleavage of N=N bond in azo compounds and successive acylation in one pot. It offers an alternative method for the synthesis of amides from very simple starting materials directly. Azo compounds Reduction Amides Sm/TiCl 4 INTRODUCTION 1 Amides are important commercial and biological compounds. Because amides constitute the backbone of protein molecules, their chemistry is of extreme importance. The penicillin and cephalosporin antibiotics are among the best-known products of the pharmaceutical industry. For this reason, the development of new and simple methods for the synthesis of the peptide bond always constitute an important addition to the field of natural products synthesis. Several general methods are available for the preparation of amides, such as starting amines with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylic salts. All of these methods involve nucleophilic addition-elimination reaction by ammonia or an amine at an acyl carbon. Amides can also be made from Beckmann rearrangement of ketoximes (Donaruma and Heldt, 1960 1960 ; Gawley, 1988 1988 ) and conversion of thioamides into amides (Movassagh et al., 2002 2002 ). Samarium diiodide (SmI 2 ) has played an ever-increasing role in organic synthesis since its introduction by Kagan’s group (Girard et al., 1980 1980 ; Krief and Laval 1999 1999 ; Molander, 1998 1998 ; Molander and Harris, 1996 1996 ; 1998 1998 ). Though SmI 2 is a useful reductive reagent, its application in organic synthesis is limited in some extent. For example, Sm 2+ is very sensitive to air and only gives one electron in the reaction, which restricts its application in large scale. However, metallic samarium is stable in air, and its strong reducing power (Sm 3+ /Sm=−2.41 V), is comparable to that of magnesium (Mg 2+ /Mg=−2.37 V), and superior to that of zinc (Zn 2+ /Zn=−0.71 V). Therefore, the direct use of metallic samarium as a reducing agent in organic transformations has attracted considerable attention in recent years (Banik, 2002 2002 ). In most cases, reactions promoted by samarium are usually carried out in THF, and metallic samarium has to be activated or pretreated by various methods so as to ensure smooth reactions. On the other hand, azo compounds serve as suitable models because they are easy to handle and the products are readily identified. Azo compounds can also be obtained by reductive cleavage of an azo linkage of either symmetric or unsymmetric azoarenes which permits two functional groups to be introduced into the aromatic nuclei and this is one of the easiest methods for the preparation of substituted aminoarenes. As azoarenes are easily accessible, it would be desirable to develop an easier and simpler method for the reduction of the N=N bond without affecting the substituents. Previous reports on the reductive cleavage of azo compounds into aminoarenes have been reviewed (Gilchrist, 1991 1991 ). Souppe et al.( 1983 1983 ) reported that azobenzene can be reduced by SmI 2 to give moderate yields of amines if methanol is present. Our previous work (Li and Zhang, 2000 2000 ) reported the synthesis of amidines from azo compounds and nitriles promoted by SmI 2 in THF. To the best of our knowledge, there data on the synthesis of amides from azo compounds by Sm/TiCl 4 system in one pot without isolating the intermediate are not available. In continuing our research in this area (Chen and Zhang, 2004 2004 ; Zhang et al., 2004 2004 ), we wish to present Sm/TiCl 4 mediated reductive cleavage of N=N bond in azo compounds to form a reactive intermediate aniline anion which was immediately acylated to yield amides (Fig. 1 1 ). This reaction can be completed in one pot with the reaction being mild and neutral. Our first attempt was carried out by using azobenzene 1e and benzoyl chloride 2e as model substrates. Table 1 1 shows that when 1e was treated with 2.2 equiv. Sm/TiCl 4 in THF solution at room temperature, it took two hours to finish the reaction after the addition of 2e , with the yield of 3e being 37%. On the other hand, when the temperature was increased to 65 °C, it took 10 min to yield 87% of 3e . Generally, according to the results of the experiment, the ideal temperature for this reaction was 65 °C. Interestingly, the same products 3e were obtained at a little lower yield while using benzoic anhydride 2d instead of 2e . It was ascribed to the higher reactivity of benzoyl chloride than that of the benzoic anhydride. Isolated yields based on azobenzenes. All products were characterized by IR, 1 H NMR and MS Using benzoic anhydride instead of benzoyl chloride Using phthalic anhydride instead of benzoyl chloride The resulting residue was a complicated mixture which defied further separation and identification Entry Ar R Temperature (°C) Time (min) Yield of 3 a a (%) a Ph p -Me-C 6 H 4 65 15 83 ( 3a ) b Ph p -MeO-C 6 H 4 65 10 85 ( 3b ) c Ph p -Cl-C 6 H 4 65 15 87 ( 3c ) d b b Ph (PhCO) 2 O 65 15 81 ( 3e ) e Ph Ph 65 10 87 ( 3e ) f Ph Ph rt 120 37 ( 3e ) g Ph 2-furoyl 65 10 85 ( 3g ) h p -Me-C 6 H 4 Ph 65 8 89 ( 3h ) i p -Cl-C 6 H 4 Ph 65 8 84 ( 3i ) j Ph PhCH 2 65 6 95 ( 3j ) k c c Ph Phthalic anhydride 65 15 – d d l Ph 2-COCl-C 6 H 4 65 15 – d d m Ph 2-Me-C 6 H 4 65 10 – d d n Ph 2,4-diCl-C 6 H 3 65 10 – d d o Ph CH 3 65 5 74 ( 3o ) p Ph CH 2 CH 3 65 5 82 ( 3p ) q p -MeC 6 H 4 (CH 2 ) 2 CH 3 rt 12 89 ( 3q ) r p -MeC 6 H 4 (CH 2 ) 4 CH 3 rt 15 84 ( 3r ) Accordingly, with a view to further investigate the reaction, a series of aromatic acyl chlorides 2 were subjected to the acylation of 1 under the above optimized reaction conditions. To our delight, most of the reactions yielded smoothly under the same conditions and a variety of amides were obtained in good to excellent yields by Sm/TiCl 4 system, as shown in Table 1 1 . However, the reaction is strongly influenced by the substituent on the o -position of the benzoyl chlorides. When such substrates were used (Entry 2k , 2l , 2m , 2n ), the resulting residue was a complicated mixture that defied further separation and identification. Perhaps it was the steric block that hindered the acylation. In conclusion, amides can be obtained in good to excellent yield by Sm/TiCl 4 mediated reductive cleavage of N=N bond in azobenzene and successive acylation in one pot. It offers an efficient alternative method for the synthesis of amides directly from very simple starting materials. EXPERIMENT DETAILS AND RESULTS 1 Melting points were uncorrected. Infrared spectra were recorded on a Bruker Vector-22 spectrometer in KBr. 1 H NMR spectra were measured in DMSO-d 6 or DCCl 3 solutions on a Bruker AC-400 Spectrometer with TMS as the internal standard. Mass spectra were recorded on a HP 5989B MS spectrometer (70 eV). THF was freshly distilled from sodium-benzophenone before use. Metallic samarium and other reagents were purchased from commercial sources and were used without further purification. General procedure for the synthesis of amides from azo compounds by Sm/TiCl 4 2 Under nitrogen atmosphere, 1 mmol of azo compound ( 1 ) dissolved in dry THF (1 ml) was added to the solution of 2.2 mmol Sm/TiCl 4 in THF (10 ml). The deep blue color of the solution changed to brown gradually. After 4 mmol of aromatic acid anhydride ( 2 ) was added to the mixture, the color of the solution changed slowly to yellow. When the reaction monitored by TLC was completed, the reaction mixture was quenched with 0.1 mol/L hydrochloric acid (2 ml) and extracted with ether (20 ml×3). The organic phase was successively washed with water (20 ml), brine (15 ml), and dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure to give crude products, which were purified by preparative TLC using ethyl acetate and cyclohexane (1:3) as eluent. Compound 3a : m.p. 145~147 °C. 1 H NMR (CDCl 3 ) 2.42 (s, 3H), 7.21~7.47 (m, 10H). IR (KBr) 3445 cm −1 , 1655 cm −1 . MS ( m / z ) 211 (M + ), 107, 93, 51. Compound 3b : m.p. 170~172 °C. 1 H NMR (CDCl 3 ) 3.85 (s, 3H), 6.76~7.54 (m, 10H). IR (KBr) 3395 cm −1 , 1655 cm −1 . MS ( m / z ) 227 (M + ), 135 (100), 107, 92, 77, 51. Compound 3c : m.p. 191~193 °C. 1 H NMR (CDCl 3 ) 7.21~8.05 (m, 9H), 7.76 (s, 1H). IR (KBr) 3389 cm −1 , 1655 cm −1 . MS ( m / z ) 231 (M + ), 139 (100), 93, 77, 51. Compound 3e : m.p. 161~163 °C. 1 H NMR (DMSO-d 6 ) 7.12 (t, 1H, J =7.6 Hz), 7.35 (m, 2H), 7.55 (m, 3H), 7.77 (d, 2H, J =7.2 Hz), 7.94 (m, 2H), 10.24 (s, 1H). IR (KBr) 3445 cm −1 , 1650 cm −1 . MS ( m / z ) 197 (M + ), 105, 93, 77, 65, 51. Compound 3g : m.p. 121~123 °C. 1 H NMR (CDCl 3 ) 5.63 (s, 1H, dispeared in D 2 O), 6.86 (m, 3H), 7.20 (m, 5H); IR (KBr) 3316 cm −1 , 1660 cm −1 . MS ( m / z ) 187 (M + ), 92, 81, 77, 65. Compound 3h : m.p. 158~159 °C. 1 H NMR (CDCl 3 ) 2.35 (s, 3H), 7.10 (d, 2H, J =7.6 Hz), 7.51 (m, 5H), 7.74 (bs, 1H), 7.83 (d, 2H, J =7.6 Hz). IR (KBr) 3330 cm −1 , 1660 cm −1 . MS ( m / z ) 211 (M + ), 105 (100), 77, 51. Compound 3i : m.p. 192~194 °C. 1 H NMR (DMSO-d 6 ) 7.31~8.05 (m, 9H), 9.32 (s, 1H). IR (KBr) 3329 cm −1 , 1655 cm −1 . MS ( m / z ) 231 (M + ), 121, 105 (100), 77, 51. Compound 3j : m.p. 116~118 °C. 1 H NMR (DMSO-d 6 ) 3.63 (s, 2H), 7.05~7.61 (m, 10H), 10.14 (s, 1H). IR (KBr) 3295 cm −1 , 1664 cm −1 . MS ( m / z ) 211 (M + ), 93 (100), 77, 51. Compound 3o : m.p. 113~115 °C. 1 H NMR (DMSO-d 6 ) 2.03 (s, 3H), 7.02~7.56 (m, 5H), 9.90 (s, 1H). IR (KBr) 3295 cm −1 , 1665 cm −1 . MS ( m / z ) 135 (M + ), 93 (100), 43. Compound 3p : m.p. 106~108 °C. 1 H NMR (DMSO-d 6 ) 1.08 (t, 3H, J =6.0 Hz), 2.32 (q, 2H, J =6.0 Hz), 7.01~7.60 (m, 5H), 9.82 (s, 1H). IR (KBr) 3305 cm −1 , 1665 cm −1 . MS ( m / z ) 149 (M + ), 93 (100), 57. Compound 3q : m.p. 74~76 °C. 1 H NMR (DMSO-d 6 ) 0.90 (t, 3H, J =7.6 Hz), 1.60 (m, 2H), 2.23 (s, 3H), 2.26 (t, 2H, J =7.2 Hz), 7.08~7.47 (m, 4H), 9.73 (s, 1H). IR (KBr) 3297 cm −1 , 1665 cm −1 . MS ( m / z ) 177 (M + ), 107 (100), 91, 77, 43. Compound 3r : m.p. 74~75 °C. 1 H NMR (DMSO-d 6 ) 0.87 (t, 3H, J =7.6 Hz), 1.28 (m, 4H), 1.57 (m, 2H), 2.23 (s, 3H), 2.28 (t, 2H, J =7.6 Hz), 7.08~7.47 (m, 4H), 9.73 (s, 1H). IR (KBr) 3305 cm −1 , 1669 cm −1 . MS ( m / z ) 205 (M + ), 107 (100), 91, 77, 43. References BK Banik . Samarium metal in organic synthesis . Eur J Org Chem , 2002 . 2002 ( 15 ): 2431 - 2444 . 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A novel reduction of diketones with i-RMgBr catalyzed by Cp2Ti2Cl2 and deoxygenation of sulfoxides by Cp2Ti2Cl2/Al system 10.1631/jzus.2006.B0198 Project (No. 20072033) supported by the National Natural Science Foundation of China and Specialized Research Fund for the Doctoral Program of Higher Education of China 2005-10-24 2005-11-30 2006-02-27 2022-01-05 Copyright © 2006, Journal of Zhejiang University Science 2006 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 03 07