23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1145 23.11 SYNTHESIS OF AMINES 1145 CH3 CH3 OA N NH| Cl (23.52) N)| HNO2 HCl ) _ L ++ L L $CH3 $CH3 N,N-dimethylaniline N,N-dimethyl-4-nitrosoanilinium chloride (89–90% yield) PROBLEMS 23.26 Design a synthesis of methyl orange (Eq. 23.49) using aniline as the only aromatic starting material. 23.27 What two compounds would react in a diazo coupling reaction to form FD & C Yellow No. 6? .. .. 23.28 (a) Using the curved-arrow notation, show how the nitrosyl cation, NOA .. , is generated from HNO2 under acidic conditions. (b) Give a curved-arrow mechanism for the electrophilic aromatic substitution reaction shown in Eq. 23.52. 23.11 SYNTHESIS OF AMINES Several reactions discussed in previous sections can be used for the synthesis of amines. In this section, four additional methods will be presented, and, in Sec. 23.7D, all of the methods for preparing amines are summarized. A. Gabriel Synthesis of Primary Amines Recall that direct alkylation of ammonia is generally not a good synthetic method for the preparation of amines because multiple alkylation takes place (Sec. 23.7A). This problem can be avoided by protecting the amine nitrogen so that it can react only once with alkylating reagents. One approach of this sort begins with the imide phthalimide. Because the pKa of phthalimide is 8.3, its conjugate-base anion is easily formed with KOH or NaOH. This anion is a good nucleophile, and is alkylated by alkyl halides or sulfonate esters in SN2 reactions. O O A 1 A KOH CH3CH2CH2CH2 OTs N H N K EtOH _ | L 2 L 2 2 A O A O2 phthalimide O pKa = 8.3 1 A N CH2CH2CH2CH3 K (23.53a) | _ OTs L + 3 2 A O 2 N-butylphthalimide 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1146 1146 CHAPTER 23 • THE CHEMISTRY OF AMINES The alkyl halides and sulfonates used in this reaction are primary or unbranched secondary. Because the N-alkylated phthalimide formed in this reaction is really a double amide, it can be converted into the free amine by amide hydrolysis in either strong acid or base. O O "S A 1 C OH HBr L N CH CH CH CH 2 H O CH CH CH CH N|H Br 2 2 2 3 2 HOAc 3 2 2 2 3 _ L + + butylammonium bromide "C OH A O SL O N-butylphthalimide (23.53b) In this example, acidic hydrolysis gives the ammonium salt, which can be converted into the free amine by neutralization with base. The alkylation of phthalimide anion followed by hydrolysis of the alkylated derivative to the primary amine is called the Gabriel synthesis, after Siegmund Gabriel (1851–1924) a profes- sor at the University of Berlin, who developed the reaction in 1887. Because the nitrogen in phthalimide has only one acidic hydrogen, it can be alkylated only once. Although N-alkyl- phthalimides also have a pair of unshared electrons on nitrogen, they do not alkylate further, because neutral imides are much less basic (why?), and therefore less nucleophilic, than the phthalimide anion. Hence, multiple alkylation, which occurs in the direct alkylation of am- monia, is avoided in the Gabriel synthesis. O O A A R N R RX N| X (23.54) % _ LL+ R 3 alkyl halide % A O A O PROBLEM 23.29 Which one of the following three amines can be prepared by the Gabriel synthesis: 2,2- dimethyl-1-propanamine, 3-methyl-1-pentanamine, or N-butylaniline? Give an alkyl halide starting material for this synthesis, and explain why the other two amines cannot be pre- pared this way. B. Reduction of Nitro Compounds Nitro compounds can be reduced easily to amines by catalytic hydrogenation: NO2 NH2 H , Pd/C % 2 % (23.55) EtOH i i CH O CH O 3 % 3 % "OCH3 "OCH3 1,2-dimethoxy-4-nitrobenzene 3,4-dimethoxyaniline (97% yield) 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1147 23.11 SYNTHESIS OF AMINES 1147 In an older, but nevertheless effective, method, finely divided metal powders and HCl can be used to convert aromatic nitro compounds into aniline derivatives. Iron or tin powder is typ- ically used. Br Br Sn/HCl or $ Fe/HCl OH $ _ 2 3 (23.56) NO2 NH2 Sn | or Fe | salts vL vL + 1-bromo-3-nitrobenzene m-bromoaniline (80% yield) In this reaction, the nitro compound is reduced at nitrogen, and the metal, which is oxidized to a metal salt, is the reducing agent. Although the methods shown in both Eqs. 23.55 and 23.56 also work with aliphatic nitro compounds, they are particularly important with aromatic nitro compounds as methods for introducing an amino group into an aromatic ring. In view of the utility of lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) as reducing agents for other compounds, what happens when nitro compounds are treated with these reagents? Aromatic nitro compounds do react with LiAlH4, but the reduc- tion products are azobenzenes (Sec. 23.10B), not amines: LiAlH4 H3O N | i (23.57) 2 NO2 ether cL % 2 # N % i nitrobenzene 2 azobenzene Nitro groups do not react at all with sodium borohydride under the usual conditions. NO NO the nitro group 2 2 is not reduced $ NaBH $ A 4 CH O EtOH CH2OH (23.58) vL vL m-nitrobenzaldehyde m-nitrobenzyl alcohol Hence, LiAlH4 and NaBH4 are not useful in forming aromatic amines from nitro compounds. PROBLEM 23.30 Outline syntheses of the following compounds from the indicated starting materials. (a) p-iodoanisole from phenol and any other reagents (b) m-bromoiodobenzene from nitrobenzene C. Amination of Aryl Halides and Aryl Triflates Arylamines can be prepared by the direct amination of aryl chlorides and aryl bromides in the presence of a base and a Pd(0) catalyst. 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1148 1148 CHAPTER 23 • THE CHEMISTRY OF AMINES CH3 + HN + Na Ot-Bu Pd(0) catalyst toluene H3C Cl pyrrolidine 1,4-dimethyl- 2-chlorobenzene CH3 ++Na Cl t-BuOH (23.59) H3C N N-(2,5-dimethylphenyl)pyrrolidine (98% yield) The direct amination of aryl halides is sometimes called Buchwald–Hartwig amination to recognize the two chemistry professors who led the research groups that developed these re- actions: Stephen L. Buchwald of MIT, and John F. Hartwig of the University of Illinois. A number of different catalysts have been explored for direct amination. These are typi- cally of the form PdL2, where L is a sterically demanding ligand such as the following: P(Cy)2 P(t-Bu)2 L = or (Cy = cyclohexyl) These catalysts are formed by mixing palladium(II) acetate or other Pd precursors and two equivalents of the ligands. These amination reactions have been shown to operate by more than one mechanism. All of the mechanisms, however, like the mechanisms of the Heck, Suzuki, and Stille reactions (Secs. 18.6A, 18.6B, and 18.10B), involve the key steps of oxidative addition and reductive elimination (Sec. 18.5E). The following scheme summarizes these features. PdL2 PdL + L Base .. R2NH PdL + ArCl oxidative L Pd Ar ligand L Pd Ar reductive PdL + Ar NR2 (23.60) a 12e– complex addition substitution elimination Cl NR2 Pd(0) a 14e– complex + Base H Pd(II) + Cl The amine used as the starting material in the amination reaction must lose a hydrogen in the reaction. Consequently, when a tertiary amine is the amination product, it cannot react further. However, when a primary amine is used as the starting material, the product is a secondary amine. It can in principle serve as the starting material in a competing second amination. Ar RNH2, base, Ar—Cl, base, catalyst catalyst Ar Cl Ar NHR Ar NR (23.61) The product of this second amination becomes an unwanted by-product. Nevertheless, amina- tion with primary amines is practical if the primary amine is itself an arylamine, or if it has a 23_BRCLoudon_pgs5-0.qxd 12/8/08 1:22 PM Page 1149 23.11 SYNTHESIS OF AMINES 1149 large or highly branched alkyl group. In such cases, steric hindrance is used to advantage. The catalyst complex leading to the tertiary amine has significant steric repulsions; as a result, the undesired second amination is relatively slow and does not occur to a significant extent. This is one reason that the catalysts involve sterically demanding ligands. Cl Pd(0) catalyst + H2N CH2(CH2)4CH3 + Na Ot-Bu toluene H3C hexylamine p-chlorotoluene NHCH2(CH2)4CH3 ++Na Cl t-BuOH H3C (23.62) N-hexyl-4-methylaniline (85% yield) As you have learned, reductive amination is another way to prepare tertiary arylamines. (See Eq. 23.23 on p. 1133.) Some tertiary arylamines, however, such those containing nitro- gen heterocycles (Eq. 23.59), would be difficult to prepare by reductive amination. Direct am- ination provides a straightforward route to these amines. Another attractive aspect of direct amination is that it, like other Pd-catalyzed coupling reactions, tolerates a wide variety of other functional groups, as Study Problem 23.5 illustrates. Study Problem 23.5 Outline a synthesis of p-dipropylaminoacetophenone from chlorobenzene. Solution Considering the problem retrosynthetically gives the following synthetic pathway, starting with the target molecule: O O H3C C NPr2 H3C C Cl Cl p-dipropylaminoacetophenone Direct amination of p-chloroacetophenone with dipropylamine and an appropriate Pd(0) catalyst gives the target: O Pd(0) catalyst, base O Pr2NH H3C C Cl H3C C NPr2 Reductive amination would not have worked, because the acetyl group would have been reduced under conditions of reductive amination.