LETTER 1355 Room-Temperature Copper-Catalyzed Synthesis of Primary Arylamines from Aryl Halides and Aqueous Ammonia SynthesisChuanzhou of Primary Arylamines Tao,*a Weiwei Liu,a Aifeng Lv,b Mingming Sun,a Ying Tian,a Qi Wang,a Jing Zhao*b a School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, P. R. of China Fax +86(518)85895121; E-mail: [email protected] b State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, P. R. of China Fax +86(25)83592672; E-mail: [email protected] Received 11 February 2010 In the meantime, Fu et al. reported a mild copper-cata- Abstract: Primary arylamines can be prepared via a copper-cata- lyzed cross-coupling between aryl halides and aqueous ammonia lyzed coupling of aryl boronic acids and aqueous ammo- nia (Scheme 1).6 The reaction proceeds at room using K3PO4 as a base and DMF as a solvent at room temperature. temperature without ligands, bases, or other additives, and Key words: copper, catalysis, cross-coupling, room temperature, aqueous ammonia, primary arylamine many functional groups are tolerated under mild condi- tions. However, the cost and availability of the aryl boron- ic acids, particularly the highly functionalized ones, hampers their applications. Usually aryl halides are pre- Primary arylamines are important intermediates in the ferred substrates because these electrophiles tend to be manufacture of agrochemicals, pharmaceuticals, dyes, cheaper and easier to prepare. Thus, we set out to develop pigments, and rubber.1 Their preparation has attracted in- more economical, practical, and efficient protocols for the creasing attention. These compounds were traditionally synthesis of primary arylamines from aryl halides under synthesized through the amination of aryl halides using mild conditions. ammonia as the nucleophile,2 but high pressure and high temperature are necessary to achieve good yields. Several As part of our studies on the copper-catalyzed arylation of groups have recently studied the possibility of using tran- nucleophiles,3j,7 we now report that the synthesis of pri- sition metals to catalyze the synthesis of primary aryl- mary arylamines can be achieved by the copper-catalyzed amines from aryl halides. For instance, palladium- and cross-coupling between aryl halides and aqueous ammo- copper-catalyzed synthesis has been achieved with nia at room temperature (Scheme 1). ammonia surrogates. The nitrogen sources include allylamines,3a benzophenone imines,3b,c tert-butyl car- Fu's work bamates,3d,e Li[N(SiMe ) ],3f,g Zn[N(SiMe ) ] ,3h 3 2 3 2 2 Cu2O, MeOH 3i 3j B(OH) ⋅ amidines, 2,2,2-trifluoroacetamide. However, the use Ar 2 + NH3 H2O r.t. of masked ammonia suffers from low atom economy and NH Ar 2 needs an additional cleavage step to liberate the primary CuI, DMF, K3PO4 X ⋅ arylamine. Recently, Hartwig4a,b and Buchwald4c reported Ar + NH3 H2O this work palladium-catalyzed coupling reactions of aryl halides X = I, Br and free ammonia, in which bulky ferrocene or electron- rich phosphine ligands were used. These methods provide Scheme 1 Room-temperature copper-catalyzed synthesis of prima- a highly efficient route to anilines and can be carried out ry arylamines without the ammonia surrogates. More recently, progress has also been achieved in the copper-catalyzed coupling 1-Chloro-4-iodobenzene was selected as a model sub- Downloaded by: Lu YanBo, University Town of ShenZhen. Copyrighted material. ammonia with aryl halides5, such as CuI/L-proline,5b strate for optimization of the reaction conditions at room CuI/2,4-pentanedione,5c CuI/N,N-dimethylglycine/organ- temperature. As shown in Table 1, using CuI as a catalyst ic base,5d CuBr/2-pyridinyl b-ketone,5e and CuI/4- under ligand-free and base-free conditions, different sol- hydroxy-L-proline5f catalytic systems. Wolf and Xu also vents were screened for arylation of ammonia (entries 1– introduced a copper-catalyzed amination protocol in the 5). Low yields of the desired products were obtained in al- 5g solvent of H2O/NMP at 80 °C. The efficiency of all the cohol, acetone, toluene, and dioxane, while the use of above catalytic reactions using ammonia as the nucleo- DMF led to a fair yield (40%) of the cross-coupling prod- phile is highly dependent on the involvement of suitable uct (entry 5). Generally, in the copper-catalyzed carbon– ligands and elevated temperatures (80–110 °C).4,5 nitrogen bond formation of aryl halides, additional bases were essential.8 Although ammonia itself could play the role of a base in the catalyst system, we speculated that the basicity of reaction system was not strong enough. Then, SYNLETT 2010, No. 9, pp 1355–1358 xx.xx.2010 with DMF as solvent, several bases such as Na2CO3, Advanced online publication: 06.05.2010 K2CO3, K3PO4, Cs2CO3, and NaOH were introduced into DOI: 10.1055/s-0029-1219922; Art ID: W02410ST the reaction mixture. We were delighted to find that the © Georg Thieme Verlag Stuttgart · New York 1356 C. Tao et al. LETTER Table 1 Copper-Catalyzed Coupling of 1-Chloro-4-halobenzene of CuI as the catalyst and aqueous ammonia (6.5 equiv) as with Aqueous Ammonia: Optimization of the Reaction Conditionsa the amino source, relative to the aryl halide, DMF as the 9 X NH 2 solvent and K3PO4 as the base at room temperature. CuI, base + H O NH ⋅ 2 3 Having identified the catalytic system of CuI, K3PO4 and Cl Cl DMF, we next examined whether the same catalytic sys- Entry X Cat. Base Solvent Temp Yield (%)b tem could be applied to the coupling of aqueous ammonia with various aryl iodides and bromides with different 1ICuI– MeOHr.t.6 electronic and steric properties (Table 2). It was found that the coupling of aryl iodides containing electron- 2 I CuI – acetone r.t. 7 donating groups with ammonia afforded anilines in mod- 3ICuI– toluener.t.5 erate yields (entries 1–3). Aryl iodide carrying electron- withdrawing groups could be smoothly converted to the 4 I CuI – dioxane r.t. 10 desired products with good to excellent isolated yields 5ICuI– DMFr.t.40 (83–98%, entries 4–13). It is noteworthy that many func- tional groups including ether, cyano, nitro, keto, ester, and 6ICuINa2CO3 DMF r.t. 57 free carboxylic acid moiety were tolerated under these 7ICuIK2CO3 DMF r.t. 66 mild conditions. However, aryl iodide carrying an ortho substituent was not found to be a good substrate in the re- c 8ICuIK3PO4 DMF r.t. 80 (87 ) action (entry 14, 15). Only when a neighboring carboxylic acid group was present, aryl iodide could be readily con- 9ICuICs2CO3 DMF r.t. 69 verted to aniline in 84% yield (entry 16). This finding was 10 I CuI NaOH DMF r.t. 62 consistent with the well-known accelerating effect of the carboxylate group on copper-catalyzed aryl halide ex- 11 I Free K3PO4 DMF r.t. 0 change reactions.10 Although nonactivated aryl bromide 12 I CuCl K3PO4 DMF r.t. 45 reacted sluggishly with ammonia (entry 17), satisfactory 13 I CuBr K PO DMF r.t. 33 yields (40–89%) of primary arylamines were obtained 3 4 when the electron-deficient aryl bromides (entries 18–23) 14 I Cu2OK3PO4 DMF r.t. 15 were utilized. 15 I CuO K PO DMF r.t. 0 3 4 Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha- lides 1 with Aqueous Ammonia at Room Temperaturea 16 I Cu2SO4 K3PO4 DMF r.t. 0 R R 17 Br CuI K PO DMF r.t. 29 (40c, 5d) CuI + X NH H O 3 4 ⋅ NH 3 2 2 K PO , DMF 4 a Reaction conditions: 1-chloro-4-halobenzene (1.0 mmol), 25% aq 3 12 NH3 (6.5 mmol, 0.5 mL), catalyst (10 mol%), base (2.0 mmol), sol- vent (1 mL), nitrogen atmosphere, 24 h. Entry Aryl halide Product Yield (%)b b Isolated yields. c Reaction time: 48 h. NH d I At 80 °C. 1 2 69 coupling yields can be increased to 60% (entries 6–10). 1a 2a I NH Gratifyingly, the use of K3PO4, an inexpensive base, re- 2 2 61 sulted in the coupled product in 80% yield. At this point we screened the copper sources including CuCl, CuBr, 1b 2b Downloaded by: Lu YanBo, University Town of ShenZhen. Copyrighted material. Cu2O, CuO, and CuSO4 (entries 11–16). The yields indi- MeO NH MeO I cated that CuI was the best catalyst. 3 2 50 When 1-chloro-4-iodobenzene was replaced by 1-bromo- 1c 2c 4-chlorobenzene, however, the reaction was less effective Cl NH Cl I providing 4-chloroaniline in 29% yield (entries 17). Sur- 4 2 87 prisingly, when the reaction temperature was raised to 80 1d 2d °C for the aryl bromide, only 5% yield was obtained. It is Br I Br NH noteworthy that in previous reports, an elevated tempera- 5 2 83 ture (up to 80 °C) was usually necessary for aryl bro- mides. However, in our catalytic system, elevating the 1e 2e MeOC NH MeOC reaction temperature results in a reduction of the product I 6 2 84 yield. We presumed that the low reactivity results from the decreased solubility of ammonia in the solvent. There- 1f 2f fore, our optimal reaction condition for room-temperature synthesis of primary arylamines was as follows: 10 mol% Synlett 2010, No. 9, 1355–1358 © Thieme Stuttgart · New York LETTER Synthesis of Primary Arylamines 1357 Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha- Table 2 Copper(I) Iodide Catalyzed Cross-Coupling of Aryl Ha- lides 1 with Aqueous Ammonia at Room Temperaturea (continued) lides 1 with Aqueous Ammonia at Room Temperaturea (continued) R R R R CuI CuI + + X X NH H O NH H O NH ⋅ NH ⋅ 3 2 3 2 2 2 K K PO , DMF PO , DMF 3 4 3 4 1212 Entry Aryl halide Product Yield (%)b Entry Aryl halide Product Yield (%)b EtOOC I NC Br NC NH EtOOC NH 2 7 2 90 20 76 1g 2g 1t 2h O N NH O N Br NC I NC NH 2 2 2 8 2 92 21 89 1h 2h 1u 2j NC NC HOOC I HOOC NH 9 2 88 22 50 Br NH 1i 2i 2 1v 2r O N I O N NH 2 2 2 O N O N 2 10 98 2 23 66 NH 1j 2j Br 2 Cl Cl 2m 11 85 1w I NH 2 a Reaction conditions: aryl halide (1.0 mmol), 25% aq NH3 (6.5 1k 2k mmol, 0.5 mL), CuI (10 mol%), K3PO4 (2.0 mmol), DMF (1 mL), r.t., nitrogen atmosphere, 36–48 h.