DOI: 10.1002/adsc.201000914

Gold-Catalyzed Direct Intermolecular Coupling of Ketones,Secondary Amines, and Alkynes: A Facile and Versatile Accessto Propargylic Amines Containing a Quaternary Carbon Center

Ming Cheng,a,b Qiang Zhang,a,b Xiao-Yu Hu,a,b Bo-Gang Li,a Jian-Xin Ji,a,*and Albert S. C. Chanc

a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People�s Republic of ChinaFax: (+86)-28-8285-5223; e-mail: jijx@cib.ac.cn

b Graduate University of the Chinese Academy of Sciences, Beijing 100049, People�s Republic of Chinac The president�s office, Hong Kong Baptist University, Kowloon Tong, Hong Kong, People�s Republic of China

Received: December 3, 2010; Revised: February 8, 2011; Published online: May 17, 2011

Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/adsc.201000914.

Abstract: The first gold-catalyzed direct intermolec-ular coupling of ketones, secondary amines, and al-kynes was achieved under mild and solvent-freeconditions. The present methodology provides apromising and versatile tool for the construction ofpropargylic amines with a newly-formed quaternarycarbon center.

Keywords: alkynes; gold salts; ketones; propargylicamines; secondary amines

The addition of carbanions to C=N bonds is an extra-ordinarily useful transformation to access C�C andC�N bond formation in the construction of nitrogen-containing molecules and complex natural products.[1]

For example, the Mannich reaction, first developedby Carl Mannich in 1912,[2] has become a highly sig-nificant method for achieving such conversions. Re-cently, among the well-developed addition reactions,direct coupling reactions have experienced an explo-sive growth, and the nucleophiles for which havebeen extensively extended to various C�H activatedcompounds such as carboxylic acid derivatives, nitro-alkanes, electron-rich aromatic compounds, and ter-minal alkynes (Scheme 1).[3] Notably, in the abovedirect coupling reactions, the A3 (aldehydes, alkynes,and amines) coupling which uses alkynes as carbonnucleophile source is exceptionally attractive, andprovides a fresh avenue for the construction of terti-ary carbon-containing propargylic amines.[4] Com-pared with the indirect coupling reactions,[5] all suchdirect transformations exhibit the following conspicu-ous advantages: (i) it does not require prior prepara-

tion of the sensitive imines or enamines and (ii) thenucleophiles do not need to be preactivated.

Nevertheless, in those direct methodologies, the C=N electrophiles have been restricted to aldimines gen-erated in situ. Ketoimines[6] are generally consideredto be less reactive towards nucleophilic additions thanaldimines, owing to the steric hindrance and electron-ic effects. Therefore, the utilization of ketoimines gen-erated in situ in the direct alkyne addition reactionstill remains a significant challenge for chemists. Upto date, only few methods have been developed inthis field and almost all of them suffer from limita-tions,[7] such as the ketoimine being generated in anintramolecular manner from a preformed precursorcontaining a ketone moiety and amine, specific reac-tion conditions, poor substrate scope, low yields, and/

Scheme 1. Direct and indirect coupling reactions.

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or long reaction times. Recently, Che and co-workersdescribed an Au[P ACHTUNGTRENNUNG(t-Bu)2(o-biphenyl)]Cl/AgSbF6-co-catalyzed addition reaction of phenylacetylene to theketoimine generated in an intramolecular mannerfrom N-(4-methoxyphenyl)-5-aminopentan-2-one.[7a]

Van der Eycken et al. reported a microwave-assistedCuI-catalyzed direct alkyne addition reaction to ke-toimines generated in situ from aliphatic ketones andprimary amines at high temperatures.[7b] Very recently,Yus et al. reported a Cu(OH)x-Fe3O4-catalyzed addi-tion of phenylacetylene to the ketoimine generated insitu from 3-pentanone or acetophenone and piperi-dine with low yield over a long reaction time (7days).[7c] Herein, we report a novel and efficient gold-catalyzed direct alkyne addition reaction to keto-

ACHTUNGTRENNUNGimines generated in an intermolecular manner fromketones and secondary amines for the construction ofquaternary carbon-containing propargylic aminesunder neat conditions without any ligand or additive(Scheme 2).

Propargylic amines represent the core of a series ofbiologically active molecules and can serve as versa-tile building blocks for the synthesis of a variety of ni-trogenous compounds.[8] Traditionally, these com-pounds are synthesized by amination of propargylichalides, propargylic phosphates, and propargylic tri-flates, or through nucleophilic attack of lithium acety-lides, Grignard reagents on imines or their deriva-tives.[9] Convenient and efficient methods to constructpropargylic amines, especially quaternary carbon-con-taining propargylic amines, through direct couplingreactions, are of extraordinary attractiveness.[10] Thepresent methodology provides an effective synthetictool for the direct construction of quaternary carbon-containing propargylic amines in a one-pot procedure.

Initially, the direct coupling reaction of cyclohexa-none (1a), morpholine (2a), and phenylacetylene (3a)was explored as a test reaction in the presence of vari-ous transition metals such as Cu, Zn, In, Ag, and Auin CH2Cl2 (Table 1, entries 1–11). Among those cata-lysts examined, AuBr3 exhibited the best catalytic ac-

Scheme 2. The direct intermolecular coupling of ketones,secondary amines, and alkynes.

Table 1. Optimization of the intermolecular coupling of cyclohexanone, morpholine, and phenylacetylene.[a]

Entry Catalyst Solvent Time [h]/Temperature [8C] Yield [%][b]

1 CuBr CH2Cl2 50/r.t 02 Cu ACHTUNGTRENNUNG(OTf)2 CH2Cl2 50/r.t 03 AgNO3 CH2Cl2 50/r.t 04 AgOTf CH2Cl2 50/r.t 05 Zn ACHTUNGTRENNUNG(OTf)2 CH2Cl2 50/r.t 06 In ACHTUNGTRENNUNG(OTf)3 CH2Cl2 50/r.t 07 InBr3 CH2Cl2 50/r.t 08 AuCN CH2Cl2 50/r.t 89 AuI CH2Cl2 50/r.t 1610 AuCl3 CH2Cl2 50/r.t 4211 AuBr3 CH2Cl2 50/r.t 5112 AuBr3 toluene 50/r.t 1513 AuBr3 toluene 50/60 4414 AuBr3 THF 50/60 4915 AuBr3 CH3CN 50/60 1916 AuBr3 DMF 50/60 017 AuBr3 neat 8/60 89

[a] Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), 3a (1.5 mmol).[b] Isolated yields based on 2a.

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Gold-Catalyzed Direct Intermolecular Coupling of Ketones, Secondary Amines, and Alkynes

Table 2. Intermolecular coupling of ketones, secondary amines, and alkynes cata-lyzed by AuBr3.

[a,b]

[a] Reaction conditions: ketones 1 (1.5 mmol), amines 2 (1.0 mmol), alkynes 3(1.5 mmol).

[b] Isolated yields based on amines 2.[c] The diastereomeric ratio was determined by HPLC analysis.[d] Reaction conditions: acetone (5 mmol), morpholine (1.0 mmol), and phenylacety-

lene (1.5 mmol).

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tivity and afforded the expected product 4a in moder-ate yield (51%, Table 1, entry 11). Further optimiza-tion suggested that solvents had a strong effect onthis process, and the reactions were obviously re-strained when they were performed in toluene, THF,CH3CN, or DMF even at 60 8C (Table 1, entries 12–16). Gratifyingly, the reaction proceeded smoothly inneat conditions (Table 1, entry 17). In summary, thedirect intermolecular coupling of cyclohexanone, mor-pholine, and phenylacetylene could be effectively re-alized employing AuBr3 as catalyst at 60 8C underneat conditions.

With the optimal reaction conditions in hand, thescope and limitation of this reaction were tested withvarious combinations of ketones, secondary amines,and alkynes. As shown in Table 2, aliphatic ketonesincluding cyclic and acyclic ketones exhibited good re-activity (4a–h). However, aromatic ketones, such asacetophenone, 4-methoxyacetophenone, and 4-nitro-ACHTUNGTRENNUNGacetophenone gave none of the desired products (4t–v), which might be explained by the difficulty of thetransformation of an aromatic ketone and an amineto the corresponding enamine 5 or iminium cation in-termediate 6 (Scheme 3) due to the special stability ofconjugated aromatic ketones. With respect to the sec-ondary amines, cyclic amines reacted efficiently underthe standard conditions (4a, 4k, 4l and 4m), whereasacyclic amines, such as dibenzylamines and dibutyl-ACHTUNGTRENNUNGamine, generated the corresponding products in loweryields (4i, 4j). Compared with aliphatic alkynes (4r,4s), aromatic alkynes afforded the target products inmuch higher yields, especially those armed with elec-tron-rich groups (4n, 4o, 4p).

Based on the above observations and previous re-ports, a tentative mechanism was proposed involvingthe complexation of gold, alkyne, and enamine 5 gen-erated in situ from ketone 1 and amine 2, which re-

sults in the intermediate 6. Intermediate 6 underwentintramolecular transfer of the alkyne moiety to afforda gold-complexed intermediate 7. Subsequent decom-plexation produced the corresponding propargylicamine 4 and concomitantly regenerated the gold cata-lyst (Scheme 3).

In conclusion, we have developed an efficientmethod for the synthesis of quaternary carbon-con-taining propargylic amines through a gold-catalyzeddirect intermolecular coupling of ketones, secondaryamines, and alkynes. Taking into account of the fol-lowing conspicuous features, such as the importanceof products, ready availability of the starting materi-als, simple experimental procedures, and mild reac-tion conditions, this catalytic system is expected toprovide an excellent opportunity for the synthesis ofvarious nitrogenous molecules containing a quaterna-ry carbon center. Further studies on the scope and ap-plication of this reaction are underway.

Experimental Section

General Remarks

All chemicals and solvents were used as received withoutfurther purification unless otherwise stated. 1H NMR and13C NMR spectra were recorded in CDCl3 on a BrukerAvance 600 spectrometer with TMS as internal standard(600 MHz 1H, 150 MHz 13C) at room temperature, and thechemical shifts (d) were expressed in ppm and J values weregiven in Hz. Mass analyses and HR-MS were obtained on aFinnigan-LCQDECA mass spectrometer and a Bruker Dalton-ics Bio-TOF-Q mass spectrometer by the ESI method, re-spectively. Column chromatography was performed on silicagel (200–300 mesh).

Scheme 3. Proposed mechanism for direct intermolecular coupling of ketones, secondary amines, and alkynes.

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Gold-Catalyzed Direct Intermolecular Coupling of Ketones, Secondary Amines, and Alkynes

General Procedure for Direct Intermolecular Cou-pling of Ketones, Secondary Amines, and Alkynes

Ketones (1.5 mmol), amines (1.0 mmol), alkynes (1.5 mmol),and AuBr3 (0.04 mmol) were added to a dried 25-mL round-bottomed flask containing a magnetic stirring bar. The reac-tion mixture was stirred for 8 h at 60 8C. Then the catalystwas removed by filtration through silica gel and washedwith EtOAc (10 mL). The filtrate was concentrated undervacuum and the residue was purified by flash chromatogra-phy to give the desired products.

Acknowledgements

We are grateful for the financial support from the NationalScience Foundation of China (20802072).

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