cs 2 co 3 ‐promoted direct n ‐alkylation: highly ...szolcsanyi/education/files/organicka chemia...

DOI: 10.1002/ejoc.201600549 Full Paper

Selective N-Alkylation

Cs2CO3-Promoted Direct N-Alkylation: Highly ChemoselectiveSynthesis of N-Alkylated Benzylamines and AnilinesJuan-Carlos Castillo,[a] Jessica Orrego-Hernández,[a] and Jaime Portilla*[a]

Abstract: Herein is described an efficient and chemoselectivemethod for the synthesis of diversely substituted secondaryamines in yields up to 98 %. Direct mono-N-alkylation of pri-mary benzylamines and anilines with a wide range of alkyl hal-ides is promoted by a cesium base in the absence of any addi-

IntroductionAmines and their derivatives constitute more than two thirdsof the comprehensive medicinal chemistry database.[1] Due totheir powerful physiological activities, secondary amines areamong the most valuable building blocks in organic chemistrybecause they are crucial precursors in the preparation of a widevariety of pharmacologically relevant therapeutic agents, natu-ral occurring products and agrochemicals.[2] In fact, there isgrowing interest in the development of simple and efficientmethodologies for the synthesis of N-alkylated aliphatic or aro-matic amines via C–N bond formation, since they are used inhigh-throughput synthesis of potential drug-like compound li-braries and as important intermediates in pharmaceutical in-dustries.[3] Different N-alkylated amine moieties are present ina variety of drugs such as Piribedil (an anti-Parkinson's diseasedrug),[4] Indobufen [a reversible inhibitor of platelet cyclooxy-genase (Cox) activity],[5] and a Glycine transporter type 1 (GlyT1)inhibitor which has potential as a schizophrenia drug and ischaracterized by a substituted benzylamine moiety amongother interesting structural features (Figure 1).[6]

General synthetic methods for the synthesis of secondaryamines include: (a) direct N-alkylation of primary amines withalkyl halides,[7] (b) reduction of amides,[8] (c) reductive amina-tion of aldehydes with primary amines in presence of differentreducing agents,[9] (d) N-dealkylation of tertiary amines,[10] (e)palladium-catalyzed Buchwald–Hartwig amination,[11] (f ) cop-per-catalyzed Ullmann–Goldberg amination,[12] and (g) transi-tion metal-catalyzed direct alkylation of amines with alcoholsby the borrowing hydrogen strategy.[13] From a methodologicalstandpoint, the direct mono-N-alkylation of primary amineswith alkyl halides or their equivalents (e.g. dialkyl sulfates orsulfonates) in the presence of stoichiometric amounts of car-

[a] Departamento de Química, Universidad de los Andes,Carrera 1 N° 18A-12, Bogotá, ColombiaE-mail: [email protected]://profesores.uniandes.edu.co/jportill/Supporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/ejoc.201600549.

Eur. J. Org. Chem. 2016, 3824–3835 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim3824

tive or catalyst. The basicity and solubility of cesium carbonatein anhydrous N,N-dimethylformamide not only enables mono-N-alkylation of primary amines but also suppresses undesireddialkylation of the desired amines.

Figure 1. Important biologically active N-alkylated amines.

bonates or hydroxides as bases offers significant advantagesover other conventional approaches to secondary amines; theseinclude wide commercial availability of starting materials, mildreaction conditions, high functional group tolerance, and lackof expensive transition metals, toxic ligands, Lewis acids or re-ducing metal hydride reagents. Due to the inductive effects ofalkyl chains, secondary amines are more nucleophilic than thecorresponding primary amines, leading to over-alkylation thatoften gives rise to mixtures of secondary and tertiary aminesand even quaternary ammonium salts. To overcome this draw-back, well-established methods have been successfully em-ployed in amine alkylation reactions including the use of: (a)ionic liquids as solvent,[14] (b) excess starting amine,[15] and (c)additives such as metal oxides,[16] zeolites,[17] and Celite.[18] Ad-ditionally, there are a few reports of the selective mono-N-alkyl-ation of aromatic amines with alkyl halides using microwaveirradiation.[19] Although these methods prevent over-alkylationproblems, many of them present a number of restrictions likethe use of excess amounts of amines, long reaction times, andexpensive or wasteful procedures. In this context, Jung and co-workers reported a highly chemoselective cesium hydroxidepromoted N-alkylation procedure to efficiently synthesize sec-ondary amines under mild conditions.[20] However, cesiumhydroxide is difficult to handle due to its hygroscopicity, is high-priced compared with other cesium bases, and has a substratescope limited almost entirely to primary aliphatic amines. These

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protocols require the use of a drying agent such as powderedmolecular sieves or additives such as tetrabutylammoniumhydrogen sulfate (TBAHS), tetrabutylammonium iodide (TBAI),and sodium iodide to improve reaction yields at room tempera-ture.[20,21] Accordingly, direct N-alkylation of primary amines isstill considered a competitive methodology for the synthesis ofsecondary amines. In connection with the ongoing develop-ment of efficient protocols for the construction of C–Nbonds,[22] and our continuing interest in the synthesis of sec-ondary amines as versatile intermediates for the design of novelmolecules of biological interest,[23] herein, we report a highlychemoselective methodology for the direct mono-N-alkylationof primary aliphatic and aromatic amines with a broad range ofalkyl halides, using cesium carbonate as base in the absence ofany additive or catalyst.

Results and DiscussionOur initial attempt at the synthesis of N-alkylbenzylamines be-gan with evaluating the effects of different organic and inor-ganic bases in the reaction between p-methoxybenzylamine 1aand benzyl bromide 2a. The results of these tests showed thatsecondary N-alkylbenzylamine 3a was produced with high se-lectivity using 2 equiv. of p-methoxybenzylamine 1a, 1 equiv.benzyl bromide 2a, cesium carbonate as base, anhydrous N,N-dimethylformamide (DMF) as solvent, and a 24 h reaction time(Table 1, Entry 1). If the reaction time was reduced, the yield of3a decreased; the use of 1 equiv. p-methoxybenzylamine 1areduced the chemoselectivity in favor of secondary N-alkylatedbenzylamine 3a (Table 1, Entries 2 and 3, respectively). Whenother bases were used, the formation of 3a was diminished,whereas yield of tertiary amine 4a was increased (Table 1, En-tries 4–7). A similar result was observed when the reaction wascarried out in the absence of base (Table 1, Entry 8). Theseresults demonstrated that a “cesium effect” drives the highchemoselectivity in this reaction.[24] Furthermore, it was ob-served that solvent plays an important role in setting reactionselectivity and secondary amine 3a formation. When dimethylsulfoxide (DMSO) was used as solvent, the yield of 3a was mod-

Table 1. Optimization of the reaction conditions for the synthesis of secondary N-alkylbenzylamine 3a.[a]

Entry Base Solvent Time Yield 3a Yield 4a[h] [%][b] [%][b]

1 Cs2CO3 DMF 24 81 62 Cs2CO3 DMF 12 43 43[c] Cs2CO3 DMF 24 55 174 CsF DMF 24 25 215 K2CO3 DMF 24 40 276 KOH DMF 24 51 167 Et3N DMF 24 68 138[d] – DMF 24 47 249 Cs2CO3 DMSO 24 69 10

[a] Reaction conditions: p-methoxybenzylamine (1.76 mmol), benzyl bromide (0.88 mmol), base (0.88 mmol), anhydrous solvent (4.0 mL). [b] Based on isolatedproduct after silica gel chromatography. [c] 1.0 equiv. of p-methoxybenzylamine. [d] Without base.

Eur. J. Org. Chem. 2016, 3824–3835 www.eurjoc.org © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim3825

erately low (Table 1, Entry 9). Once optimal conditions for gen-erating 3a were identified (Table 1, Entry 1), primary aliphaticamines 1a–i and various alkyl halides 2a–k were employed toproduce a wide range of N-alkylbenzylamine derivatives 3a–uin good yields (Scheme 1).

The general application of this approach was confirmed us-ing not only primary alkyl bromides and chlorides (p-vinyl-benzyl chloride 2j and benzyl chloride 2k), but also unreactivesecondary bromide 2i (isopropyl bromide). This methodologywas successfully applied to the synthesis of secondary N-ben-zylamines containing homoallyl, propargyl and nitrile moieties3g–n in 60–86 % isolated yields; these are important structuralelements in natural products and valuable synthetic buildingblocks in organic synthesis.[25] Notably, ethyl bromoacetate 2hdisplayed an interesting chemoselectivity towards mono-N-alk-ylation instead of amidation, leading to α-N-substituted aminoesters 3o–q in good yields using a one-step procedure fromavailable (hetero)benzylamines. On the other hand, the forma-tion of tertiary amines 4a–h was favored when allylamine 1g, 2-aminoethanol 1h, and cyclohexylamine 1i were used as startingmaterials. These results can be explained by the high reactivityof these aliphatic amines under the optimized conditions andcommensurate formation of over-alkylation products.

This new approach shows a high degree of flexibility andversatility in the synthesis of N-alkylbenzylamines. Interestingly,n-butylamine 1j was selectively alkylated with benzyl chloride2k and benzyl bromide 2a, providing 3v in 75 % and 84 %isolated yields, respectively (Scheme 2). The same monoalk-ylated amine 3v is obtained in 73 % yield from benzylamine 1band 1-bromobutane 2c.

At this stage of our study, we wondered if a similar strategytowards chemoselective synthesis of N-alkylated benzylaminescould be applied to the formation of secondary aromaticamines. In order to test this idea, the model reaction betweenaniline 5a and 1-bromobutane 2c was carried out under severalconditions (Table 2). The first experiment was carried out usingidentical conditions to those employed to generate secondaryN-alkylbenzylamine 3a (Table 2, Entry 1). However, the best re-sult was obtained when using cesium carbonate as the base in

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Scheme 1. Cs2CO3-promoted selective mono-N-alkylation of aliphatic amines with various alkyl halides. [a] Reaction conditions: 1 (2.0 equiv.), 2 (1.0 equiv.),Cs2CO3 (1.0 equiv.), DMF (4.0 mL). [b] The 1H NMR analysis of the crude reaction indicated formation of the secondary amine in minor quantities.

Scheme 2. Modular synthesis of N-benzyl-N-butylamine 3v. Reaction conditions: n-butylamine or benzylamine (2.73 mmol), alkyl halide (1.36 mmol), Cs2CO3

(1.36 mmol), and DMF (4.0 mL).

anhydrous DMF at 60 °C for 5 h. These conditions affordedmono-N-alkylated aniline 6a in 62 % isolated yield togetherwith the tertiary amine side product 7a in 3 % yield (Table 2,Entry 3). Although over-alkylation is often a notorious side reac-tion, 2 equiv. of aniline 5a was necessary to achieve the directmono-N-alkylation efficiently, whereas the use of 1 equiv. 5aafforded anticipated secondary N-arylamine 6a in lower yield(Table 2, Entries 3 and 4, respectively). The use of temperaturesbelow 60 °C led to diminished yields of secondary N-arylamine6a (Table 2, Entries 2 and 3). It is noteworthy that heating thereaction above 60 °C did not increase the yield of 6a (Table 2,Entry 7). When the reaction was stirred at 60 °C for times lessthan and greater than the optimal conditions, N-arylamine 6awas isolated with diminished yields (Table 2, Entries 5 and 6).With respect to base, we found that the nature of the cation


plays the predominant role in the reaction (Table 2, Entries 8–10). As expected, the absence of base correlated to very ineffi-cient N-alkylation processes (Table 2, Entry 11). Despite therebeing a few reports of selective mono-N-alkylation of aromaticamines with alkyl halides using microwave-assisted condi-tions,[19] we found the best conversions of N-arylamine 6a toinvolve conventional heating methods rather than microwaveirradiation (Table 2, Entries 12–14).

As delineated in Scheme 3, the general applicability and limi-tations of this method for selective mono-N-alkylation of aro-matic amines was examined using aniline derivatives 5a–j andvarious primary and secondary alkyl halides 2. On the basis ofpreliminary results (Table 2), the reaction conditions (tempera-tures and times) were modified depending on the substrate inorder to optimize mono-N-alkylation. Although chemoselective

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Table 2. Optimization of reaction conditions for the synthesis of N-butylan-iline 6a.[a]

Entry Base Temp. Time Yield 6a Yield 7a[°C] [h] [%][d] [%][d]

1 Cs2CO3 25[b] 24 23 –2 Cs2CO3 40[b] 5 18 –3 Cs2CO3 60[b] 5 62 34[e] Cs2CO3 60[b] 5 29 –5 Cs2CO3 60[b] 2.5 27 –6 Cs2CO3 60[b] 12 56 47 Cs2CO3 80[b] 5 61 –8 K2CO3 60[b] 5 48 –9 KOH 60[b] 5 34 –10 NaOH 60[b] 5 30 –11 –[f ] 60[b] 5 28 –12 Cs2CO3 60[c] 0.5 12 –13 Cs2CO3 100[c] 0.5 44 –14 Cs2CO3 120[c] 0.5 45 6

[a] Reaction conditions: aniline 5a (1.82 mmol), 1-bromobutane 2c(0.91 mmol), base (0.91 mmol), anhydrous DMF (4.0 mL). [b] Conventionalheating. [c] Run in a microwave vial (10 mL) sealed and placed in a microwavereactor (100 W) in anhydrous DMF (2.0 mL). [d] Based on isolated productafter silica gel chromatography. [e] 1.0 equiv. of aniline 5a. [f ] Without base.

N-alkylation was observed in each case, the acidity and reactiv-ity of aniline derivatives 5 had an important influence on theyields of expected products 6. Para-substituted anilines contain-ing electron-donating groups were more reactive than ortho-or meta-substituted analogues (6c vs. 6d) probably due to acombination of steric effects and nucleophilicity differences.Hence, the best result was obtained with p-methoxyaniline,which was converted to 6b in 91 % isolated yield under stan-dard reaction conditions (reaction time 5 h at 60 °C). As ex-pected, the presence of electron-withdrawing substituents onthe aromatic ring necessitated higher temperatures and pro-longed reaction times (reaction time 12 h at 90 °C), en route todesired products 6f–h generated in moderate to excellentyields (45–98 %). It was furthermore established that the react-ivity and acidity of substituted anilines (5f–h) containing elec-tron-withdrawing groups increased in the order: bromo (5f ) <nitro (5g) < nitro-trifluoromethyl (5h). From these data was de-termined that a marked increase in the acidity of the aminegroup promotes formation of cesium amide B, which is the keyintermediate in the synthesis of secondary amines (Scheme 4).Reactions containing activated alkyl halides such as benzylbromide, p-vinylbenzyl chloride, ethyl bromoacetate, and bro-moacetonitrile afforded desired secondary amines 6i–m ingood yields (59–86 %) under standard conditions. Disappoint-ingly, the introduction of a sterically hindered substituent suchas the isopropyl moiety led to mono-N-alkylated product 6nexclusively but in only 36 % isolated yield after 12 h; the pooryield likely is attributable to detrimental steric effects. The reac-tion was also examined using 1-naphthylamine 5i, which af-forded N-benzylated secondary amine 6o in good yield. Re-markably, o-phenylenediamine 5j was selectively mono-N-alkyl-


ated at just one of the amino groups with 1-bromobutane toafford 6p in 68 % isolated yield. With this protocol, the directC–N bond formation using either electron-deficient anilines orsterically demanding substrates proceeded in moderate togood yields compared to other well-known methods. Such well-known methods typically require (a) ionic liquids as solvent,[14]

(b) the pre-formation of an imine followed by its reduction in asecond step,[26a] or (c) the amination of aryl halides catalyzedby expensive and/or toxic transition metals complexes.[26b,26c]

Scheme 3. Cs2CO3-promoted selective mono-N-alkylation of primary aromaticamines with various alkyl halides. [a] Reaction conditions: primary aromaticamine 5 (2.0 equiv.), alkyl halide 2 (1.0 equiv.), Cs2CO3 (1.0 equiv.), anhydrousDMF (4.0 mL). [b] Reaction time 5 h at 60 °C. [c] Reaction time 12 h at 90 °C.[d] Reaction time 12 h at 55 °C. [e] Tertiary amines 7a and 7c were isolatedin only 3 % and 4 % yields, respectively.

As has been already established, the formation of complexA between primary amines and cesium cation enhances theacidity of primary amines. An N-linked acidic hydrogen can beremoved by carbonate ion leading to cesium amide B.[21a,22d]

The high nucleophilicity of the resulting amide anion favorssubstitution reactions with alkyl halides 2 to give 3 or 6. Theformation of another metal complex C between secondaryamine 3 or 6 and cesium cation generates secondary amide Dwhich, as we have found here, does not react with alkyl halides,likely due to steric hindrance issues (Scheme 4).[21a]

We then examined the synthesis of bioactive N-heterocyclesstarting from secondary amines containing ester and nitrilemoieties; the main objective here was in to demonstrate thepower of the new C–N bond formation. The synthesis was initi-

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Scheme 4. Proposed mechanistic sequence for nucleophilic substitution of primary amines 1 or 5 with alkyl halides 2.

Scheme 5. Examples of functionalization reactions of secondary amines containing ester and nitrile moieties.

ated by an amidation reaction between N-substituted α-aminoesters 3p/6k and bubbling ammonia from a mixture of NH4OH/CH3OH/NaOH to give quantitatively corresponding N-substi-tuted α-aminoamides 8, which could be used as building blocksin the synthesis of more complex structures[27a] and pharma-ceutically active molecules (Scheme 5, a).[27b] With these consid-erations in mind, additional studies are currently underway toexpand the scope of this methodology since α-aminoamidescan be used as 1,4-bis-nucleophiles with trialkylorthoformatesleading to subsequent ring closing reactions. The resulting im-idazolinone derivatives belong to a class of agents that haveshown remarkable inhibitory activities against p38αMAPK andERK1/2 kinases.[28] As a further application, 7-substituted purine11 was synthesized in moderate yield using a one-step micro-wave-assisted reaction starting from 2-(phenylamino)acetoni-trile 6l and 6.0 equiv. of formamidine acetate 9, introduced intwo portions to maximize the formation of 4-aminoimidazoleintermediate 10 (Scheme 5, b).[29] Interestingly, purine deriva-tives have been reported as kinase inhibitors, especially of cy-clin-dependent kinases (CDKs).[30]

ConclusionsIn summary, we have established a highly efficient and chemo-selective Cs2CO3-promoted method for direct mono-N-alkyl-ation of primary aliphatic and aromatic amines with reactive,unreactive and secondary halides in the absence of additives


or catalysts enabling preparation of a wide range of secondaryamines in good yields. The practical advantages of this protocolinclude: (a) mild reaction conditions (ambient temperatures), (b)simple procedure, (c) readily available and inexpensive startingmaterials, and (d) relatively short reaction times (secondary aryl-amines). In addition, this highly chemoselective method toler-ates labile and reactive chemical functionalities generatingmono-N-alkylated amines predominantly or exclusively inhigher yields than most conventional protocols. Interestingly,the direct N-alkylation method was applied to unreactive andsecondary halides and various anilines, including deactivatedones such as p-bromoaniline, p-nitroaniline and 2-nitro-4-triflu-oromethylaniline.[13d] The selective mono-N-alkylation of pri-mary amines highlights the crucial role of the “cesium effect”on the formation of secondary amines as the major products,interpretable on the basis that cesium bases possess strongerbasicity than do inorganic bases. More importantly, such cesiumbases appear to suppress over-alkylation of the produced sec-ondary amines. Finally, the choice of cesium carbonate rests onpractical considerations; its ease of handling and low hygro-scopicity relative to cesium hydroxide are significant advanta-ges. Interestingly, some functionalization reactions of secondaryamines containing nitrile and/or ester moieties have been ex-ploited for the preparation of 7-substituted purine derivativesas potential anticancer agents and also N-substituted α-amino-amides, which can serve as 1,4-bis-nucleophiles in the synthesisof bioactive N-heterocycles (e.g., imidazol-4-one).

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Experimental SectionGeneral: All reagents were purchased from commercial sources andused without further purification, unless otherwise noted. All start-ing materials were weighed and handled in air at room tempera-ture. Anhydrous N,N-dimethylformamide was purchased from Al-drich and used without further purification. The reactions weremonitored by TLC visualized by UV lamp (254 nm or 365 nm) and/or with p-anisaldehyde and H2SO4 in EtOH. Column chromatogra-phy was performed on 70–230 μm silica gel. NMR spectroscopicdata were recorded with a Bruker Avance 400 at 298 K. 1H NMRspectroscopic data were recorded in CDCl3 at 400.13 MHz using theresidual non-deuterated solvent as an internal standard (δH = 7.26ppm). 13C NMR spectra were recorded in CDCl3 at 100.61 MHz usingthe deuterated solvent as an internal standard (δC = 77.16 ppm).Coupling constants (J) are in Hertz (Hz) and the classical abbrevia-tions are used to describe the signal multiplicities. Reactions undermicrowave irradiation were performed in oven-dried 10 mL sealablePyrex tubes equipped with a Teflon-coated stirring bar (obtainedfrom CEM). All reactions under microwave irradiation (ν = 2.45 GHz)were performed in a CEM Discover 1–300W system equipped with abuilt-in pressure measurement sensor. High resolution mass spectra(HRMS) were obtained with an Agilent Technologies Q-TOF 6520spectrometer via an electrospray ionization (ESI). Melting pointswere determined in capillary tubes using a Stuart SMP10 meltingpoint apparatus and are uncorrected. Known secondary N-alkyl-benzylamines 3a–v, N-arylamines 6a–p, α-aminoamides 8a,b and7-substituted purine 11 showed characterization data in full agree-ment with previously reported data.

General Procedure for the Cs2CO3-Promoted Synthesis of N-Alkyl-benzylamines 3a–v: A mixture of cesium carbonate(1.0 equiv.) and primary aliphatic amine 1 (250 mg, 2.0 equiv.) inanhydrous DMF (4.0 mL) was stirred at 25 °C for 30 min. To thiswhite suspension was added the alkyl halide 2 (1.0 equiv.) in oneportion, and the resulting reaction mixture was stirred for 24 h.Then, the reaction mixture was filtered and rinsed with ethyl acetate(2 × 5.0 mL). The filtrate was taken up in 1.0 N NaOH (2.0 mL) andextracted with ethyl acetate (4 × 5.0 mL). The combined organiclayers were washed with brine (2 × 10.0 mL), dried with anhydroussodium sulfate, filtered, and concentrated under vacuum to givethe crude product. Column chromatography on silica gel of thismaterial afforded pure N-alkyl-benzylamines 3a–v. These productswere identified by comparison of its spectroscopic data with thosereported in literature.

N-Benzyl-1-(4-methoxybenzyl)methanamine (3a): Following thegeneral procedure, the reaction of p-methoxybenzylamine (1a,238 μL, 1.82 mmol), benzyl bromide (2a, 108 μL, 0.91 mmol) andcesium carbonate (296 mg, 0.91 mmol) in anhydrous DMF (4.0 mL)at 25 °C for 24 h, afforded compound 3a as a yellow oil (168 mg,81 %)[16a] after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR(400 MHz, CDCl3): δ = 3.75 (s, 2 H), 3.80 (s, 2 H), 3.80 (s, 3 H), 6.87(d, J = 8.7 Hz, 2 H), 7.25–7.34 (m, 7 H) ppm, NH was not detected.13C NMR (100 MHz, CDCl3): δ = 52.5 (CH2), 53.0 (CH2), 55.2 (CH3),113.8 (CH), 126.9 (CH), 128.1 (CH), 128.4 (CH), 129.3 (CH), 132.4 (C),140.3 (C), 158.6 (C) ppm. HRMS (ESI+): calcd. for C15H18NO+

228.1388 [M + H]+, found 228.1379.

N,N-Dibenzyl-1-(4-methoxyphenyl)methanamine (4a): Com-pound 4a was obtained as a yellow oil (9 mg, 6 %)[13e] after silicagel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz, CDCl3): δ =3.51 (s, 2 H), 3.56 (s, 4 H), 3.80 (s, 3 H), 6.88 (d, J = 8.5 Hz, 2 H),7.22–7.42 (m, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 52.2 (CH3),57.2 (CH2), 57.7 (CH2), 113.6 (CH), 126.8 (CH), 128.1 (CH), 128.7 (CH),


129.8 (CH), 131.5 (C), 139.7 (C), 158.5 (C) ppm. HRMS (ESI+): calcd.for C22H24NO+ 318.1858 [M + H]+, found 318.1850.

N-(4-Methoxybenzyl)-1-(4-nitrophenyl)methanamine (3b): Fol-lowing the general procedure, the reaction of p-methoxybenzyl-amine (1a, 228 μL, 1.75 mmol), p-nitrobenzyl bromide (2b, 189 mg,0.87 mmol) and cesium carbonate (285 mg, 0.87 mmol) in anhy-drous DMF (4.0 mL) at 25 °C for 24 h, afforded compound 3b as awhite solid (147 mg, 62 %) after silica gel purification (CH2Cl2/MeOH, 50:1), m.p. 178–179 °C (amorphous).[9c] 1H NMR (400 MHz,CDCl3): δ = 3.75 (s, 2 H), 3.81 (s, 3 H), 3.89 (s, 2 H), 6.88 (d, J = 8.7 Hz,2 H), 7.25 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 8.18 (d, J =8.8 Hz, 2 H) ppm, NH was not detected. 13C NMR (100 MHz, CDCl3):δ = 52.1 (CH2), 52.6 (CH2), 55.3 (CH3), 113.9 (CH), 123.6 (CH), 128.7(CH), 129.4 (CH), 131.8 (C), 147.1 (C), 148.1 (C), 158.9 (C) ppm. HRMS(ESI+): calcd. for C15H17N2O3

+ 273.1239 [M + H]+, found 273.1249.

N-(4-Methoxybenzyl)butan-1-amine (3c): Following the generalprocedure, the reaction of p-methoxybenzylamine (1a, 238 μL,1.82 mmol), 1-bromobutane (2c, 98 μL, 0.91 mmol) and cesiumcarbonate (295 mg, 0.90 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3c as a yellow oil (137 mg, 79 %)[13b]

after silica gel purification (CH2Cl2/MeOH, 25:1). 1H NMR (400 MHz,CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H), 1.29–1.38 (m, 2 H), 1.46–1.53(m, 2 H), 2.14 (br. s, 1 H), 2.61 (t, J = 7.1 Hz, 2 H), 3.72 (s, 2 H), 3.79(s, 3 H), 6.86 (d, J = 8.7 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 2 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 14.0 (CH3), 20.4 (CH2), 32.0 (CH2), 48.9(CH2), 53.3 (CH2), 55.2 (CH3), 113.8 (CH), 129.4 (CH), 132.2 (C), 158.6(C) ppm. HRMS (ESI+): calcd. for C12H20NO+ 194.1545 [M + H]+,found 194.1535.

N-(4-Fluorobenzyl)butan-1-amine (3d): Following the generalprocedure, the reaction of p-fluorobenzylamine (1d, 228 μL,2.00 mmol), 1-bromobutane (2c, 108 μL, 1.00 mmol) and cesiumcarbonate (326 mg, 1.00 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3d as a yellow oil (89 mg, 49 %)[31]

after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.30–1.37 (m, 2 H), 1.46–1.53(m, 2 H), 1.74 (br. s, 1 H), 2.61 (t, J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 7.00(t, J = 8.7 Hz, 2 H), 7.28 (t, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 14.0 (CH3), 20.4 (CH2), 32.1 (CH2), 49.0 (CH2), 53.2 (CH2),115.1 (J = 21.2 Hz, CH), 129.6 (J = 8.1 Hz, CH), 136.0 (J = 3.7 Hz, C),161.9 (J = 244.3 Hz, C) ppm. HRMS (ESI+): calcd. for C11H17FN+

182.1345 [M + H]+, found 182.1334.

N-(4-Methoxybenzyl)octan-1-amine (3e): Following the generalprocedure, the reaction of p-methoxybenzylamine (1a, 238 μL,1.82 mmol), 1-bromooctane (2d, 157 μL, 0.91 mmol) and cesiumcarbonate (296 mg, 0.91 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3e as a colourless oil (127 mg,56 %)[9a] after silica gel purification (CH2Cl2/MeOH, 20:1). 1H NMR(400 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.25–1.28 (m, 10 H),1.47–1.52 (m, 2 H), 2.17 (br. s, 1 H), 2.61 (t, J = 7.3 Hz, 2 H), 3.72 (s,2 H), 3.79 (s, 3 H), 6.86 (d, J = 8.7 Hz, 2 H), 7.24 (d, J = 8.7 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1 (CH3), 22.6 (CH2), 27.3(CH2), 29.2 (CH2), 29.5 (CH2), 29.8 (CH2), 31.8 (CH2), 49.2 (CH2), 53.3(CH2), 55.2 (CH3), 113.7 (CH), 129.4 (CH), 132.2 (C), 158.6 (C) ppm.HRMS (ESI+): calcd. for C16H28NO+ 250.2171 [M + H]+, found250.2154.

N-(4-Chlorobenzyl)octan-1-amine (3f): Following the general pro-cedure, the reaction of p-chlorobenzylamine (1c, 215 μL,1.76 mmol), 1-bromooctane (2d, 152 μL, 0.88 mmol) and cesiumcarbonate (286 mg, 0.88 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3f as a colourless oil (174 mg, 78 %)[32]

after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,

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CDCl3): δ = 0.88 (t, J = 6.4 Hz, 3 H), 1.26–1.29 (m, 10 H), 1.48–1.51(m, 2 H), 2.59 (t, J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 7.24–7.32 (m, 4H) ppm, NH was not detected. 13C NMR (100 MHz, CDCl3): δ = 14.1(CH3), 22.6 (CH2), 27.3 (CH2), 29.2 (CH2), 29.5 (CH2), 30.1 (CH2), 31.8(CH2), 49.4 (CH2), 53.3 (CH2), 128.4 (CH), 129.4 (CH), 132.5 (C), 139.0(C) ppm. HRMS (ESI+): calcd. for C15H25ClN+ 254.1676 [M + H]+,found 254.1656.

N-(4-Methoxybenzyl)but-3-en-1-amine (3g): Following the gen-eral procedure, the reaction of p-methoxybenzylamine (1a, 238 μL,1.82 mmol), 4-bromo-1-butene (2e, 92 μL, 0.91 mmol) and cesiumcarbonate (296 mg, 0.91 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3g as a yellow oil (148 mg, 85 %)[33]

after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,CDCl3): δ = 2.25–2.29 (m, 2 H), 2.68 (t, J = 6.8 Hz, 2 H), 3.72 (s, 2 H),3.78 (s, 3 H), 5.01–5.11 (m, 2 H), 5.74–5.81 (m, 1 H), 6.85 (d, J =8.6 Hz, 2 H), 7.22 (d, J = 8.6 Hz, 2 H) ppm, NH was not detected.13C NMR (100 MHz, CDCl3): δ = 34.2 (CH2), 48.2 (CH2), 53.2 (CH2),55.2 (CH3), 113.7 (CH), 116.3 (CH2), 129.2 (CH), 132.5 (C), 136.5 (CH),158.6 (C) ppm. HRMS (ESI+): calcd. for C12H18NO+ 192.1388 [M +H]+, found 192.1399.

N-Benzylbut-3-en-1-amine (3h): Following the general procedure,the reaction of benzylamine (1b, 255 μL, 2.33 mmol), 4-bromo-1-butene (2e, 118 μL, 1.16 mmol) and cesium carbonate (378 mg,1.16 mmol) in 5.0 mL of anhydrous DMF at 25 °C for 24 h, affordedcompound 3h as a yellow oil (148 mg, 79 %)[34] after silica gel purifi-cation (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz, CDCl3): δ = 2.25–2.31 (m, 2 H), 2.70 (t, J = 6.8 Hz, 2 H), 3.79 (s, 2 H), 5.05–5.11 (m, 2H), 5.73–5.84 (m, 1 H), 7.22–7.32 (m, 5 H) ppm, NH was not detected.13C NMR (100 MHz, CDCl3): δ = 34.2 (CH2), 48.2 (CH2), 53.8 (CH2),116.3 (CH2), 126.9 (CH), 128.1 (CH), 128.3 (CH), 136.4 (CH), 140.4(C) ppm. HRMS (ESI+): calcd. for C11H16N+ 162.1283 [M + H]+, found162.1284.

N-(4-Fluorobenzyl)but-3-en-1-amine (3i): Following the generalprocedure, the reaction of p-fluorobenzylamine (1d, 228 μL,2.00 mmol), 4-bromo-1-butene (2e, 102 μL, 1.00 mmol) and cesiumcarbonate (325 mg, 1.00 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3i as a yellow oil (118 mg, 66 %)[35]

after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,CDCl3): δ = 2.25–2.30 (m, 2 H), 2.69 (t, J = 6.8 Hz, 2 H), 3.75 (s, 2 H),5.03–5.11 (m, 2 H), 5.73–5.78 (m, 1 H), 7.00 (t, J = 8.6 Hz, 2 H), 7.27(t, J = 8.5 Hz, 2 H) ppm, NH was not detected. 13C NMR (100 MHz,CDCl3): δ = 34.2 (CH2), 48.2 (CH2), 53.1 (CH2), 115.1 (J = 21.3 Hz, CH),116.4 (CH2), 129.6 (J = 8.1 Hz, CH), 136.0 (J = 2.9 Hz, C), 136.3(CH), 161.9 (J = 244.3 Hz, C) ppm. HRMS (ESI+): calcd. for C11H15FN+

180.1189 [M + H]+, found 180.1189.

N-(4-Chlorobenzyl)but-3-en-1-amine (3j): Following the generalprocedure, the reaction of p-cholorobenzylamine (1c, 215 μL,1.77 mmol), 4-bromo-1-butene (2e, 89 μL, 0.88 mmol) and cesiumcarbonate (286 mg, 0.88 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3j as a yellow oil (148 mg, 86 %)[33]

after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR (400 MHz,CDCl3): δ = 2.25–2.30 (m, 2 H), 2.68 (t, J = 6.8 Hz, 2 H), 3.76 (s, 2 H),5.06–5.12 (m, 2 H), 5.73–5.81 (m, 1 H), 7.22–7.31 (m, 4 H) ppm, NHwas not detected. 13C NMR (100 MHz, CDCl3): δ = 34.2 (CH2), 48.1(CH2), 53.0 (CH2), 116.4 (CH2), 128.4 (CH), 129.4 (CH), 132.5 (C), 136.3(CH), 138.8 (C) ppm. HRMS (ESI+): calcd. for C11H15ClN+ 196.0893 [M+ H]+, found 196.0895.

N-(4-Methoxybenzyl)prop-2-yn-1-amine (3k): Following the gen-eral procedure, the reaction of p-methoxybenzylamine (1a, 238 μL,1.82 mmol), propargyl bromide solution 80 wt.-% in toluene (2f,101 μL, 0.91 mmol) and cesium carbonate (296 mg, 0.91 mmol) in


anhydrous DMF (4.0 mL) at 25 °C for 24 h, afforded compound 3kas a yellow oil (96 mg, 60 %)[36] after silica gel purification (CH2Cl2).1H NMR (400 MHz, CDCl3): δ = 2.25 (t, J = 2.5 Hz, 1 H), 3.40 (d, J =2.4 Hz, 2 H), 3.79 (s, 3 H), 3.81 (s, 2 H), 6.86 (d, J = 8.7 Hz, 2 H), 7.25(d, J = 8.7 Hz, 2 H) ppm, NH was not detected. 13C NMR (100 MHz,CDCl3): δ = 37.1 (CH2), 51.6 (CH2), 55.2 (CH3), 71.5 (CH), 82.1 (C),113.8 (CH), 129.6 (CH), 131.5 (C), 158.8 (C) ppm. HRMS (ESI+): calcd.for C11H14NO+ 176.1075 [M + H]+, found 176.1079.

N-(4-Methoxybenzyl)-N-(prop-2-yn-1-yl)prop-2-yn-1-amine(4b): Compound 4b was obtained as a colourless oil (17 mg, 18 %)after silica gel purification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =2.26 (t, J = 2.4 Hz, 2 H), 3.40 (d, J = 2.4 Hz, 4 H), 3.62 (s, 2 H), 3.80(s, 3 H), 6.86 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz, 2 H) ppm. 13CNMR (100 MHz, CDCl3): δ = 41.6 (CH2), 55.2 (CH3), 56.4 (CH2), 73.1(CH), 78.9 (C), 113.7 (CH), 129.7 (C), 130.4 (CH), 159.0 (C) ppm. HRMS(ESI+): calcd. for C14H16NO+ 214.1232 [M + H]+, found 214.1239.

N-Benzylprop-2-yn-1-amine (3l): Following the general procedure,the reaction of benzylamine (1b, 255 μL, 2.33 mmol), propargylbromide solution 80 wt.-% in toluene (2f, 129 μL, 1.16 mmol) andcesium carbonate (378 mg, 1.16 mmol) in 5.0 mL of anhydrous DMFat 25 °C for 24 h, afforded compound 3l as a colourless oil (109 mg,65 %)[36] after silica gel purification (CH2Cl2). 1H NMR (400 MHz,CDCl3): δ = 1.55 (br. s, 1 H), 2.26 (t, J = 2.4 Hz, 1 H), 3.42 (d, J =2.4 Hz, 2 H), 3.88 (s, 2 H), 7.25–7.35 (m, 5 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 37.3 (CH2), 52.2 (CH2), 71.5 (CH), 82.0 (C), 127.1 (CH),128.4 (CH), 128.4 (CH), 139.3 (C) ppm. HRMS (ESI+): calcd. forC10H12N+ 146.0970 [M + H]+, found 146.0959.

N-Benzyl-N-(prop-2-yn-1-yl)prop-2-yn-1-amine (4c): Compound4c was obtained as a colourless oil (16 mg, 15 %)[37] after silica gelpurification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 2.27 (t, J =2.4 Hz, 2 H), 3.42 (d, J = 2.3 Hz, 4 H), 3.69 (s, 2 H), 7.25–7.38 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.8 (CH2), 57.1 (CH2), 73.2(CH), 78.8 (C), 127.4 (CH), 128.4 (CH), 129.2 (CH), 137.7 (C) ppm.HRMS (ESI+): calcd. for C13H14N+ 184.1126 [M + H]+, found 184.1131.

2-[(4-Methoxybenzyl)amino]acetonitrile (3m): Following thegeneral procedure, the reaction of p-methoxybenzylamine (1a,238 μL, 1.82 mmol), bromoacetonitrile (2g, 63 μL, 0.91 mmol) andcesium carbonate (296 mg, 0.91 mmol) in anhydrous DMF (4.0 mL)at 25 °C for 24 h, afforded compound 3m as a light-yellow oil(107 mg, 67 %)[38] after silica gel purification (CH2Cl2). 1H NMR(400 MHz, CDCl3): δ = 3.54 (s, 2 H), 3.80 (2, 3 H), 3.86 (s, 2 H), 6.88(d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H) ppm, NH was notdetected. 13C NMR (100 MHz, CDCl3): δ = 36.0 (CH2), 51.7 (CH2), 55.3(CH3), 114.0 (CH), 117.7 (C), 129.7 (CH), 129.8 (C), 159.1 (C) ppm.HRMS (ESI+): calcd. for C10H13N2O+ 177.1028 [M + H]+, found177.1032.

2-[(4-Chlorobenzyl)amino]acetonitrile (3n): Following the gen-eral procedure, the reaction of p-chlorobenzylamine (1c, 215 μL,1.76 mmol), bromoacetonitrile (2g, 61 μL, 0.88 mmol) and cesiumcarbonate (287 mg, 0.88 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3n as a yellow oil (133 mg, 84 %)[39]

after silica gel purification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =3.56 (s, 2 H), 3.90 (s, 2 H), 7.26–7.33 (m, 4 H) ppm, NH was notdetected. 13C NMR (100 MHz, CDCl3): δ = 36.2 (CH2), 51.5 (CH2),117.4 (C), 128.8 (CH), 129.7 (CH), 133.5 (C), 136.2 (C) ppm. HRMS(ESI+): calcd. for C9H10ClN2

+ 181.0533 [M + H]+, found 181.0540.

Ethyl (4-methoxybenzyl)glycinate (3o): Following the generalprocedure, the reaction of p-methoxybenzylamine (1a, 238 μL,1.82 mmol), ethyl bromoacetate (2h, 101 μL, 0.91 mmol) and cesiumcarbonate (296 mg, 0.91 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3o as a colourless oil (116 mg,

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57 %)[40] after silica gel purification (CH2Cl2). 1H NMR (400 MHz,CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.87 (br. s, 1 H), 3.38 (s, 2 H),3.73 (s, 2 H), 3.79 (s, 3 H), 4.18 (q, J = 7.1 Hz, 2 H), 6.86 (d, J = 8.7 Hz,2 H), 7.24 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =14.2 (CH3), 50.0 (CH2), 52.7 (CH2), 55.2 (CH3), 60.7 (CH2), 113.8 (CH),129.5 (CH), 131.6 (C), 158.8 (C), 172.4 (C) ppm. HRMS (ESI+): calcd.for C12H18NO3

+ 224.1287 [M + H]+, found 224.1295.

Diethyl 2,2′-[(4-methoxybenzyl)azanediyl]diacetate (4d): Com-pound 4d was obtained as a colourless oil (27 mg, 19 %)[41] aftersilica gel purification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.26(t, J = 7.1 Hz, 6 H), 3.52 (s, 4 H), 3.79 (s, 3 H), 3.84 (s, 2 H), 4.16 (q,J = 7.1 Hz, 4 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 54.1 (CH2), 55.2(CH3), 57.2 (CH2), 60.4 (CH2), 113.7 (CH), 130.2 (C), 130.3 (CH), 158.9(C), 171.2 (C) ppm. HRMS (ESI+): calcd. for C16H24NO5

+ 310.1654 [M+ H]+, found 310.1665.

Ethyl (4-chlorobenzyl)glycinate (3p): Following the general proce-dure, the reaction of p-chlorobenzylamine (1c, 215 μL, 1.77 mmol),ethyl bromoacetate (2h, 98 μL, 0.88 mmol) and cesium carbonate(287 mg, 0.88 mmol) in anhydrous DMF (4.0 mL) at 25 °C for 24 h,afforded compound 3p as a colourless oil (124 mg, 62 %)[42] aftersilica gel purification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.28(t, J = 7.1 Hz, 3 H), 1.89 (br. s, 1 H), 3.39 (s, 2 H), 3.77 (s, 2 H), 4.19(q, J = 7.1 Hz, 2 H), 7.26–7.31 (m, 4 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 14.2 (CH3), 50.0 (CH2), 52.5 (CH2), 60.8 (CH2), 128.5 (CH),129.6 (CH), 132.8 (C), 138.0 (C), 172.3 (C) ppm. HRMS (ESI+): calcd.for C11H15ClNO2

+ 228.0791 [M + H]+, found 228.0768.

Diethyl 2,2′-[(4-chlorobenzyl)azanediyl]diacetate (4e): Com-pound 4e was obtained as a colourless oil (23 mg, 17 %) after silicagel purification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J =7.1 Hz, 6 H), 3.51 (s, 4 H), 3.87 (s, 2 H), 4.15 (q, J = 7.1 Hz, 4 H), 7.26–7.33 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 54.2(CH2), 57.1 (CH2), 60.5 (CH2), 128.5 (CH), 130.3 (CH), 133.0 (C), 136.9(C), 171.1 (C) ppm. HRMS (ESI+): calcd. for C15H21ClNO4

+ 314.1159[M + H]+, found 314.1131.

Ethyl (Pyridin-4-ylmethyl)glycinate (3q): Following the generalprocedure, the reaction of 4-(aminomethyl)pyridine (1e, 205 μL,2.02 mmol), ethyl bromoacetate (2h, 111 μL, 1.00 mmol) andcesium carbonate (325 mg, 1.00 mmol) in anhydrous DMF (4.0 mL)at 25 °C for 24 h, afforded compound 3q as a yellow oil (114 mg,59 %)[43] after silica gel purification (CH2Cl2/MeOH, 25:1). 1H NMR(400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 3 H), 3.41 (s, 2 H), 3.84 (s,2 H), 4.20 (q, J = 7.2 Hz, 2 H), 7.28 (d, J = 6.1 Hz, 2 H), 8.55 (d, J =6.1 Hz, 2 H) ppm, NH was not detected. 13C NMR (100 MHz, CDCl3):δ = 14.2 (CH3), 50.1 (CH2), 52.0 (CH2), 60.9 (CH2), 123.0 (CH), 148.7(C), 149.9 (CH), 172.2 (C) ppm. HRMS (ESI+): calcd. for C10H15N2O2

+

195.1134 [M + H]+, found 195.1144.

N-(4-Methoxybenzyl)propan-2-amine (3r): Following the generalprocedure, the reaction of p-methoxybenzylamine (1a, 233 μL,1.78 mmol), 2-bromopropane (2i, 84 μL, 0.89 mmol) and cesiumcarbonate (290 mg, 0.89 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3r as a yellow oil (72 mg, 45 %)[13a]

after silica gel purification (CH2Cl2/MeOH, 25:1). 1H NMR (400 MHz,CDCl3): δ = 1.09 (d, J = 6.3 Hz, 6 H), 2.83–2.89 (m, 1 H), 3.71 (s, 2H), 3.78 (s, 3 H), 6.85 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2H) ppm, NH was not detected. 13C NMR (100 MHz, CDCl3): δ = 22.7(CH3), 48.0 (CH), 50.8 (CH2), 55.2 (CH3), 113.8 (CH), 129.3 (CH), 132.5(C), 158.6 (C) ppm. HRMS (ESI+): calcd. for C11H18NO+ 180.1388 [M+ H]+, found 180.1391.

N-(4-Chlorobenzyl)propan-2-amine (3s): Following the generalprocedure, the reaction of p-chlorobenzylamine (1c, 206 μL,


1.69 mmol), 2-bromopropane (2i, 79 μL, 0.84 mmol) and cesiumcarbonate (274 mg, 0.84 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3s as a yellow oil (66 mg, 43 %)[13a]

after silica gel purification (CH2Cl2/MeOH, 25:1). 1H NMR (400 MHz,CDCl3): δ = 1.08 (d, J = 6.3 Hz, 6 H), 1.36 (br. s, 1 H), 2.79–2.85 (m,1 H), 3.73 (s, 2 H), 7.23–7.28 (m, 4 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 22.9 (CH3), 48.1 (CH), 50.8 (CH2), 128.4 (CH), 129.4 (CH),132.5 (C), 139.3 (C) ppm. HRMS (ESI+): calcd. for C10H15ClN+

184.0893 [M + H]+, found 184.0899.

2-Ethyl-N-(4-vinylbenzyl)hexan-1-amine (3t): Following the gen-eral procedure, the reaction of 2-ethyl-1-hexylamine (1f, 253 μL,1.55 mmol), 4-vinylbenzyl chloride (2j, 110 μL, 0.78 mmol) andcesium carbonate (254 mg, 0.78 mmol) in anhydrous DMF (4.0 mL)at 25 °C for 24 h, afforded compound 3t as a colourless oil (138 mg,72 %) after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR(400 MHz, CDCl3): δ = 0.83–0.90 (m, 6 H), 1.20–1.45 (m, 9 H), 1.55(br. s, 1 H), 2.50 (d, J = 6.1 Hz, 2 H), 3.77 (s, 2 H), 5.21 (d, J = 10.9 Hz,1 H), 5.73 (d, J = 17.6 Hz, 1 H), 6.70 (dd, J = 10.9, 17.6 Hz, 1 H), 7.28(d, J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 10.9 (CH3), 14.1 (CH3), 23.1 (CH2), 24.4 (CH2), 29.0 (CH2),31.3 (CH2), 39.4 (CH), 52.5 (CH2), 53.9 (CH2), 113.3 (CH2), 126.1 (CH),128.2 (CH), 136.2 (C), 136.6 (CH), 140.4 (C) ppm. HRMS (ESI+): calcd.for C17H28N+ 246.2222 [M + H]+, found 246.2202.

N-Benzyl-2-ethylhexan-1-amine (3u): Following the general pro-cedure, the reac tion of 2- ethyl-1-hexylamine (1f, 253 μL,1.55 mmol), benzyl bromide (2a, 93 μL, 0.78 mmol) and cesiumcarbonate (254 mg, 0.78 mmol) in anhydrous DMF (4.0 mL) at 25 °Cfor 24 h, afforded compound 3u as a colourless oil (137 mg,80 %)[44] after silica gel purification (CH2Cl2/MeOH, 50:1). 1H NMR(400 MHz, CDCl3): δ = 0.83–0.91 (m, 6 H), 1.20–1.44 (m, 9 H), 1.48(br. s, 1 H), 2.52 (d, J = 6.1 Hz, 2 H), 3.78 (s, 2 H), 7.21–7.32 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.8 (CH3), 14.1 (CH3), 23.1(CH2), 24.5 (CH2), 29.0 (CH2), 31.4 (CH2), 39.4 (CH), 52.5 (CH2), 54.2(CH2), 126.8 (CH), 128.0 (CH), 128.3 (CH), 140.7 (C) ppm. HRMS (ESI+):calcd. for C15H26N+ 220.2065 [M + H]+, found 220.2052.

N-Benzylbutan-1-amine (3v): Synthesized according to generalprocedure. Benzylamine (1b, 298 μL, 2.73 mmol), 1-bromobutane(2c, 147 μL, 1.36 mmol) and cesium carbonate (443 mg, 1.36 mmol)affords 3v (162 mg, 73 %). n-Butylamine (1j, 270 μL, 2.73 mmol),benzyl bromide (2a, 162 μL, 1.36 mmol) and cesium carbonate(443 mg, 1.36 mmol) affords 3v (186 mg, 84 %). n-Butylamine (1j,270 μL, 2.73 mmol), benzyl chloride (2k, 156 μL, 1.36 mmol) andcesium carbonate (443 mg, 1.36 mmol) affords 3v (166 mg, 75 %).Colourless oil[13c] obtained after silica gel purification (CH2Cl2/MeOH, 30:1). 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H),1.30–1.37 (m, 2 H), 1.47–1.55 (m, 2 H), 2.07 (br. s, 1 H), 2.64 (t, J =7.2 Hz, 2 H), 3.80 (s, 2 H), 7.22–7.33 (m, 5 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 14.0 (CH3), 20.4 (CH2), 32.0 (CH2), 49.0 (CH2), 53.9 (CH2),126.9 (CH), 128.2 (CH), 128.4 (CH), 140.0 (C) ppm. HRMS (ESI+): calcd.for C11H18N+ 164.1439 [M + H]+, found 164.1427.

N,N-Dibenzylprop-2-en-1-amine (4f): Following the general pro-cedure, the reaction of allylamine (1g, 75 μL, 1.00 mmol), benzylbromide (2a, 119 μL, 1.00 mmol) and cesium carbonate (325 mg,1.00 mmol) in anhydrous DMF (4.0 mL) at 25 °C for 24 h, affordedcompound 4f as a colourless oil (96 mg, 81 %)[11c] after silica gelpurification (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 3.06 (d, J =5.7 Hz, 2 H), 3.57 (s, 4 H), 5.13–5.27 (m, 2 H), 5.86–5.94 (m, 1 H),7.20–7.39 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 56.3 (CH2),57.8 (CH2), 117.3 (CH2), 126.8 (CH), 128.2 (CH), 128.8 (CH), 136.0 (CH),140.6 (C) ppm. HRMS (ESI+): calcd. for C17H20N+ 238.1596 [M + H]+,found 238.1600.

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2-(Dibenzylamino)ethan-1-ol (4g): Following the general proce-dure, the reaction of 2-aminoethanol (1h, 99 μL, 1.64 mmol), benzylbromide (2a, 195 μL, 1.64 mmol) and cesium carbonate (534 mg,1.64 mmol) in anhydrous DMF (4.0 mL) at 25 °C for 24 h, affordedcompound 4g as a colourless oil (140 mg, 71 %)[8b] after silica gelpurification (CH2Cl2/MeOH, 5:1). 1H NMR (400 MHz, CDCl3): δ = 2.18(br. s, 1 H), 2.67 (t, J = 5.5 Hz, 2 H), 3.58 (t, J = 5.5 Hz, 2 H), 3.63 (s,4 H), 7.24–7.35 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.8(CH2), 58.2 (CH2), 58.5 (CH2), 127.2 (CH), 128.4 (CH), 129.0 (CH), 138.7(C) ppm. HRMS (ESI+): calcd. for C16H20NO+ 242.1545 [M + H]+,found 242.1561.

N,N-Dibenzylcyclohexanamine (4h): Following the general proce-dure, the reaction of cyclohexylamine (1i, 115 μL, 1.00 mmol),benzyl bromide (2a, 119 μL, 1.00 mmol) and cesium carbonate(325 mg, 1.00 mmol) in anhydrous DMF (4.0 mL) at 25 °C for 24 h,afforded compound 4h as a white solid (124 mg, 89 %) after silicagel purification (CH2Cl2), m.p. 56–57 °C (amorphous).[45] 1H NMR(400 MHz, CDCl3): δ = 1.08–1.17 (m, 3 H), 1.28–1.38 (m, 2 H), 1.59–1.63 (m, 1 H), 1.75–1.80 (m, 2 H), 1.88–1.93 (m, 2 H), 2.45–2.53 (m,1 H), 3.65 (s, 4 H), 7.21 (t, J = 7.3 Hz, 2 H), 7.29 (t, J = 7.3 Hz, 4 H),7.39 (d, J = 7.2 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 26.1(CH2), 26.5 (CH2), 28.6 (CH2), 53.8 (CH2), 57.6 (CH), 126.4 (CH), 128.0(CH), 128.4 (CH), 141.2 (C) ppm. HRMS (ESI+): calcd. for C20H26N+

280.2065 [M + H]+, found 280.2037.

General Procedure for the Cs2CO3-Promoted Synthesis of N-Alkyl-Arylamines 6a–p: A mixture of cesium carbonate (1.0 equiv.)and primary aromatic amine 5 (250 mg, 2.0 equiv.) in anhydrousDMF (4.0 mL) was stirred at 25 °C for 30 min. To this white suspen-sion was added the alkyl halide 2 (1.0 equiv.) in one portion, andthe resulting reaction mixture was stirred at 55–90 °C for 5–12 h.Then, the reaction mixture was filtered and rinsed with ethyl acetate(2 × 5.0 mL). The filtrate was taken up in 1.0 N NaOH (2.0 mL) andextracted with ethyl acetate (4 × 5.0 mL). The combined organiclayers were washed with brine (2 × 10.0 mL), dried with anhydroussodium sulfate, filtered, and concentrated under vacuum to givethe crude product. Column chromatography on silica gel of thismaterial afforded pure N-alkyl-arylamines 6a–p. These productswere identified by comparison of its spectroscopic data with thosereported in literature.

N-Butylaniline (6a): Following the general procedure, the reactionof aniline (5a, 196 μL, 2.12 mmol), 1-bromobutane (2c, 114 μL,1.06 mmol) and cesium carbonate (345 mg, 1.06 mmol) in anhy-drous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6a as ayellow oil (98 mg, 62 %)[46] after silica gel purification (CH2Cl2/pent-ane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H),1.38–1.45 (m, 2 H), 1.56–1.63 (m, 2 H), 3.10 (t, J = 7.1 Hz, 2 H), 3.56(br. s, 1 H), 6.59 (d, J = 7.8 Hz, 2 H), 6.68 (t, J = 7.4 Hz, 1 H), 7.16 (t,J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3),20.3 (CH2), 31.6 (CH2), 43.6 (CH2), 112.6 (CH), 117.0 (CH), 129.2 (CH),148.5 (C) ppm. HRMS (ESI+): calcd. for C10H16N+ 150.1283 [M + H]+,found 150.1272.

N-Butyl-4-methoxyaniline (6b): Following the general procedure,the reaction of p-anisidine (5b, 200 mg, 1.62 mmol), 1-bromobutane(2c, 87 μL, 0.81 mmol) and cesium carbonate (264 mg, 0.81 mmol)in anhydrous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6bas a yellow oil (132 mg, 91 %)[19c] after silica gel purification (CH2Cl2/pentane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3H), 1.40–1.46 (m, 2 H), 1.56–1.61 (m, 2 H), 3.07 (t, J = 7.1 Hz, 2 H),3.75 (s, 3 H), 6.58 (d, J = 8.9 Hz, 2 H), 6.79 (d, J = 8.9 Hz, 2 H) ppm,NH was not detected. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3),20.3 (CH2), 31.8 (CH2), 44.7 (CH2), 55.8 (CH3), 114.0 (CH), 114.9 (CH),


142.8 (C), 151.9 (C) ppm. HRMS (ESI+): calcd. for C11H18NO+

180.1388 [M + H]+, found 180.1372.

N-Butyl-4-methylaniline (6c): Following the general procedure,the reaction of p-toluidine (5c, 200 mg, 1.87 mmol), 1-bromobutane(2c, 100 μL, 0.93 mmol) and cesium carbonate (303 mg, 0.93 mmol)in anhydrous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6cas a colourless oil (126 mg, 83 %)[13c] after silica gel purification(CH2Cl2/pentane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.98 (t, J =7.3 Hz, 3 H), 1.42–1.50 (m, 2 H), 1.58–1.65 (m, 2 H), 2.27 (s, 3 H),3.11 (t, J = 7.1 Hz, 2 H), 3.41 (br. s, 1 H), 6.56 (d, J = 8.3 Hz, 2 H),7.01 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9(CH3), 20.3 (CH2), 20.3 (CH3), 31.7 (CH2), 44.0 (CH2), 112.9 (CH), 126.2(C), 129.7 (CH), 146.3 (C) ppm. HRMS (ESI+): calcd. for C11H18N+

164.1439 [M + H]+, found 164.1426.

N,N-Dibutyl-4-methylaniline (7c): Compound 7c was obtained asa yellow oil (4 mg, 4 %)[11b] after silica gel purification (CH2Cl2/pent-ane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.4 Hz, 6 H),1.31–1.51 (m, 4 H), 1.52–1.58 (m, 4 H), 2.24 (s, 3 H), 3.23 (t, J =7.6 Hz, 4 H), 6.58 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H) ppm.13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 20.1 (CH3), 20.4 (CH2),29.4 (CH2), 51.0 (CH2), 112.1 (CH), 124.3 (C), 129.6 (CH), 146.2(C) ppm. HRMS (ESI+): calcd. for C15H26N+ 220.2065 [M + H]+, found220.2056.

N-Butyl-2-methylaniline (6d): Following the general procedure,the reaction of o-toluidine (5d, 200 μL, 1.87 mmol), 1-bromobutane(2c, 100 μL, 0.93 mmol) and cesium carbonate (303 mg, 0.93 mmol)in anhydrous DMF (4.0 mL) at 90 °C for 12 h, afforded compound6d as a light-yellow oil (82 mg, 54 %)[9b] after silica gel purification(CH2Cl2/pentane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.00 (t, J =7.3 Hz, 3 H), 1.43–1.51 (m, 2 H), 1.64–1.71 (m, 2 H), 2.15 (s, 3 H),3.18 (t, J = 7.1 Hz, 2 H), 3.45 (br. s, 1 H), 6.62–6.68 (m, 2 H), 7.05 (d,J = 7.2 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 13.9 (CH3), 17.4 (CH3), 20.3 (CH2), 31.7 (CH2), 43.6 (CH2),109.5 (CH), 116.6 (CH), 121.6 (C), 127.1 (CH), 130.0 (CH), 146.4(C) ppm. HRMS (ESI+): calcd. for C11H18N+ 164.1439 [M + H]+, found164.1433.

N-Butyl-3,5-dimethylaniline (6e): Following the general proce-dure, the reaction of 3,5-dimethylaniline (5e, 206 μL, 1.65 mmol), 1-bromobutane (2c, 88 μL, 0.82 mmol) and cesium carbonate(267 mg, 0.82 mmol) in anhydrous DMF (4.0 mL) at 90 °C for 12 h,afforded compound 6e as a yellow oil (94 mg, 65 %)[11b] after silicagel purification (CH2Cl2/pentane, 1:2). 1H NMR (400 MHz, CDCl3): δ =0.98 (t, J = 7.3 Hz, 3 H), 1.41–1.48 (m, 2 H), 1.59–1.65 (m, 2 H), 2.27(s, 6 H), 3.12 (t, J = 7.1 Hz, 2 H), 3.50 (br. s, 1 H), 6.27 (s, 2 H), 6.38(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 20.3 (CH2),21.5 (CH3), 31.8 (CH2), 43.7 (CH2), 110.7 (CH), 119.1 (CH), 138.8 (C),148.7 (C) ppm. HRMS (ESI+): calcd. for C12H20N+ 178.1596 [M + H]+,found 178.1593.

4-Bromo-N-butylaniline (6f): Following the general procedure, thereaction of p-bromoaniline (5f, 250 mg, 1.45 mmol), 1-bromobutane(2c, 78 μL, 0.72 mmol) and cesium carbonate (234 mg, 0.72 mmol)in anhydrous DMF (4.0 mL) at 90 °C for 12 h, afforded compound6f as a colourless oil (74 mg, 45 %)[12c] after silica gel purification(CH2Cl2/pentane, 1:1). 1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J =7.3 Hz, 3 H), 1.37–1.45 (m, 2 H), 1.55–1.61 (m, 2 H), 3.07 (t, J = 7.1 Hz,2 H), 3.62 (br. s, 1 H), 6.47 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.8 (CH3), 20.2 (CH2), 31.4(CH2), 43.6 (CH2), 108.5 (C), 114.2 (CH), 131.8 (CH), 147.4 (C) ppm.HRMS (ESI+): calcd. for C10H15BrN+ 228.0388 [M + H]+, found228.0363.

N-Butyl-4-nitroaniline (6g): Following the general procedure, thereaction of p-nitroaniline (5g, 200 mg, 1.45 mmol), 1-bromobutane

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(2c, 78 μL, 0.72 mmol) and cesium carbonate (234 mg, 0.72 mmol)in anhydrous DMF (4.0 mL) at 90 °C for 12 h, afforded compound6g as a yellow solid (71 mg, 51 %) after silica gel purification(CH2Cl2/pentane, 1:2), m.p. 55–56 °C (amorphous).[12c] 1H NMR(400 MHz, CDCl3): δ = 0.97 (t, J = 7.4 Hz, 3 H), 1.39–1.47 (m, 2 H),1.60–1.67 (m, 2 H), 3.18–3.23 (m, 2 H), 4.53 (br. s, 1 H), 6.51 (d, J =9.0 Hz, 2 H), 8.07 (d, J = 9.0 Hz, 2 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 13.7 (CH3), 20.1 (CH2), 31.2 (CH2), 43.1 (CH2), 110.9 (CH),126.4 (CH), 137.7 (C), 153.5 (C) ppm. HRMS (ESI+): calcd. forC10H15N2O2

+ 195.1134 [M + H]+, found 195.1116.

N-Butyl-2-nitro-4-(trifluoromethyl)aniline (6h): Following thegeneral procedure, the reaction of 2-nitro-4-(trifluoromethyl)aniline(5h, 300 mg, 1.46 mmol), 1-bromobutane (2c, 79 μL, 0.73 mmol)and cesium carbonate (238 mg, 0.73 mmol) in anhydrous DMF(4.0 mL) at 90 °C for 12 h, afforded compound 6h as a yellow solid(188 mg, 98 %) after silica gel purification (CH2Cl2/pentane, 1:1),m.p. 36–38 °C (amorphous).[47] 1H NMR (400 MHz, CDCl3): δ = 1.00(t, J = 7.4 Hz, 3 H), 1.47–1.52 (m, 2 H), 1.73–1.78 (m, 2 H), 3.33–3.38(m, 2 H), 6.94 (d, J = 9.1 Hz, 1 H), 7.61 (dd, J = 4.0, 9.1 Hz, 1 H), 8.27(br. s, 1 H), 8.46 (d, J = 4.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):δ = 13.7 (CH3), 20.2 (CH2), 30.8 (CH2), 42.9 (CH2), 114.4 (CH), 117.1(J = 34.4 Hz, C), 125.0 (J = 541.6 Hz, CF3), 125.0 (J = 4.3 Hz, CH),130.8 (C), 132.1 (J = 2.0 Hz, CH), 147.0 (C) ppm. HRMS (ESI+): calcd.for C11H14F3N2O2

+ 263.1007 [M + H]+, found 263.0995.

N-Benzylaniline (6i): Following the general procedure, the reactionof aniline (5a, 196 μL, 2.12 mmol), benzyl bromide (2a, 126 μL,1.06 mmol) and cesium carbonate (345 mg, 1.06 mmol) in anhy-drous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6i as awhite solid (146 mg, 75 %) after silica gel purification (CH2Cl2/pent-ane, 1:2), m.p. 36–37 °C (amorphous).[46] 1H NMR (400 MHz, CDCl3):δ = 4.01 (br. s, 1 H), 4.32 (s, 2 H), 6.62–6.73 (m, 3 H), 7.15–7.38 (m,7 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 48.3 (CH2), 112.8 (CH),117.5 (CH), 127.2 (CH), 127.5 (CH), 128.6 (CH), 129.2 (CH), 139.4 (C),148.1 (C) ppm. HRMS (ESI+): calcd. for C13H14N+ 184.1126 [M + H]+,found 184.1110.

N-(4-Vinylbenzyl)aniline (6j): Following the general procedure, thereaction of aniline (5a, 196 μL, 2.12 mmol), 4-vinylbenzyl chloride(2j, 149 μL, 1.06 mmol) and cesium carbonate (345 mg, 1.06 mmol)in anhydrous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6jas a light-yellow solid (131 mg, 59 %) after silica gel purification(CH2Cl2/pentane, 1:1), m.p. 40–41 °C (amorphous). 1H NMR(400 MHz, CDCl3): δ = 4.04 (br. s, 1 H), 4.33 (s, 2 H), 5.23 (d, J =10.9 Hz, 1 H), 5.76 (d, J = 16.8 Hz, 1 H), 6.64–6.77 (m, 4 H), 7.19 (t,J = 7.4 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 8.2 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 48.0 (CH2), 112.8 (CH), 113.7(CH2), 117.6 (CH), 126.4 (CH), 127.6 (CH), 129.2 (CH), 136.4 (CH),136.6 (C), 139.0 (C), 148.0 (C) ppm. HRMS (ESI+): calcd. for C15H16N+

210.1283 [M + H]+, found 210.1296.

Ethyl Phenylglycinate (6k): Following the general procedure, thereaction of aniline (5a, 196 μL, 2.12 mmol), ethyl bromoacetate (2h,118 μL, 1.06 mmol) and cesium carbonate (345 mg, 1.06 mmol) inanhydrous DMF (4.0 mL) at 60 °C for 5 h, afforded compound 6k asa light-brown solid (137 mg, 72 %) after silica gel purification(CH2Cl2/pentane, 3:1), m.p. 56–57 °C (amorphous).[48] 1H NMR(400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H), 3.90 (s, 2 H), 4.25 (q,J = 7.2 Hz, 2 H), 4.28 (br. s, 1 H), 6.62 (d, J = 7.9 Hz, 2 H), 6.76 (t, J =7.3 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):δ = 14.2 (CH3), 45.8 (CH2), 61.3 (CH2), 113.0 (CH), 118.1 (CH), 129.3(CH), 147.0 (C), 171.1 (C) ppm. HRMS (ESI+): calcd. for C10H14NO2

+

180.1025 [M + H]+, found 180.1015.

2-(Phenylamino)acetonitrile (6l): Following the general proce-dure, the reaction of aniline (5a, 184 μL, 2.02 mmol), ethyl bromo-


acetate (2h, 111 μL, 1.00 mmol) and cesium carbonate (329 mg,1.01 mmol) in anhydrous DMF (4.0 mL) at 60 °C for 5 h, affordedcompound 6l as a yellow solid (109 mg, 82 %) after silica gel purifi-cation (CH2Cl2/pentane, 1:2), m.p. 41 °C (amorphous).[49] 1H NMR(400 MHz, CDCl3): δ = 3.98 (br. s, 1 H), 4.08 (d, J = 7.1 Hz, 2 H), 6.71(d, J = 8.6 Hz, 2 H), 6.89 (t, J = 8.5 Hz, 1 H), 7.27 (t, J = 8.6 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.7 (CH2), 113.6 (CH), 116.9(C), 120.1 (CH), 129.6 (CH), 145.0 (C) ppm. HRMS (ESI+): calcd. forC8H9N2

+ 133.0766 [M + H]+, found 133.0763.

2-(p-Tolylamino)acetonitrile (6m): Following the general proce-dure, the reaction of p-toluidine (5c, 250 mg, 2.33 mmol), bromo-acetonitrile (2g, 81 μL, 1.16 mmol) and cesium carbonate (378 mg,1.16 mmol) in anhydrous DMF (4.0 mL) at 60 °C for 5 h, affordedcompound 6m as a yellow solid (146 mg, 86 %) after silica gel purifi-cation (CH2Cl2/pentane, 1:1), m.p. 58–59 °C.[50] 1H NMR (400 MHz,CDCl3): δ = 2.28 (s, 3 H), 3.83 (br. s, 1 H), 4.06 (s, 2 H), 6.64 (d, J =8.4 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz,CDCl3): δ = 20.4 (CH3), 33.0 (CH2), 113.8 (CH), 117.1 (C), 129.5 (C),130.0 (CH), 142.6 (C) ppm. HRMS (ESI+): calcd. for C9H11N2

+ 147.0922[M + H]+, found 147.0918.

N-Isoproyl-4-methylaniline (6n): Following the general procedure,the reaction of p-toluidine (5c, 250 mg, 2.33 mmol), 2-bromopro-pane (2i, 109 μL, 1.16 mmol) and cesium carbonate (378 mg,1.16 mmol) in anhydrous DMF (4.0 mL) at 55 °C for 12 h, affordedcompound 6n as a yellow oil (62 mg, 36 %)[13c] after silica gel purifi-cation (CH2Cl2/pentane, 1:2). 1H NMR (400 MHz, CDCl3): δ = 1.22 (d,J = 6.3 Hz, 6 H), 2.25 (s, 3 H), 3.22 (br. s, 1 H), 3.58–3.65 (m, 1 H),6.54 (d, J = 8.3 Hz, 2 H), 7.00 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 20.3 (CH3), 23.0 (CH3), 44.5 (CH), 113.5 (CH),126.1 (C), 129.7 (CH), 145.2 (C) ppm. HRMS (ESI+): calcd. forC10H16N+ 150.1283 [M + H]+, found 150.1274.

N-Benzylnaphthalen-1-amine (6o): Following the general proce-dure, the reaction of 1-naphthylamine (5i, 289 mg, 2.02 mmol),benzyl bromide (2a, 119 μL, 1.00 mmol) and cesium carbonate(325 mg, 1.00 mmol) in anhydrous DMF (4.0 mL) at 60 °C for 5 h,afforded compound 6o as a white solid (207 mg, 89 %) after silicagel purification (CH2Cl2/pentane, 1:1), m.p. 58–59 °C (amor-phous).[13c] 1H NMR (400 MHz, CDCl3): δ = 4.48 (s, 2 H), 4.68 (br. s,1 H), 6.62 (d, J = 7.3 Hz, 1 H), 7.24–7.46 (m, 9 H), 7.78–7.82 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 48.5 (CH2), 104.7 (CH), 117.6(CH), 119.8 (CH), 123.3 (C), 124.7 (CH), 125.7 (CH), 126.6 (CH), 127.3(CH), 127.7 (CH), 128.6 (CH), 128.7 (CH), 134.2 (C), 139.0 (C), 143.2(C) ppm. HRMS (ESI+): calcd. for C17H16N+ 234.1283 [M + H]+, found234.1274.

N-Butylbenzene-1,2-diamine (6p): Following the general proce-dure, the reaction of o-phenylenediamine (5j, 156 mg, 1.45 mmol),1-bromobutane (2c, 76 μL, 0.70 mmol) and cesium carbonate(228 mg, 0.70 mmol) in anhydrous DMF (4.0 mL) at 60 °C for 5 h,afforded compound 6p as a brown solid (78 mg, 68 %) after silicagel purification (CH2Cl2), m.p. 34 °C (amorphous).[10b] 1H NMR(400 MHz, CDCl3): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.46–1.51 (m, 2 H),1.65–1.71 (m, 2 H), 3.12 (t, J = 7.1 Hz, 2 H), 3.28 (br. s, 3 H), 6.66–6.74 (m, 3 H), 6.85–6.88 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):δ = 13.9 (CH3), 20.4 (CH2), 31.8 (CH2), 43.9 (CH2), 111.5 (CH), 116.4(CH), 118.2 (CH), 120.7 (CH), 134.0 (C), 138.2 (C) ppm. HRMS (ESI+):calcd. for C10H17N2

+ 165.1392 [M + H]+, found 165.1385.

General Procedure for the Synthesis of N-Substituted α-Amino-amides 8: A solution of N-substituted α-amino ester 3p or 6k(1.0 mmol) in methanol (5.0 mL) was bubbled with ammonia gas(2 min, every 8 h) which was generated in situ from a concentratedammonium hydroxide solution mixed with sodium hydroxide, the

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resulting reaction mixture was stirred at 25 °C for 24 h. Then, thereaction mixture was concentrated under vacuum to afford N-sub-stituted α-aminoamide 8 without further purification.

2-(4-Chlorobenzylamino)acetamide (8a): Following the generalprocedure, the reaction of ethyl (4-chlorobenzyl)glycinate (3p,150 mg, 0.66 mmol) with ammonia gas in methanol (5.0 mL) at25 °C for 24 h afforded compound 8a as a white solid (127 mg,97 %), m.p. 103–105 °C (amorphous).[2f ] 1H NMR (400 MHz, CDCl3):δ = 1.85 (br. s, 1 H), 3.29 (s, 2 H), 3.77 (s, 2 H), 5.86 (br. s, 1 H), 6.94 (br.s, 1 H), 7.23–7.32 (m, 4 H) ppm. HRMS (ESI+): calcd. for C9H12ClN2O+

199.0638 [M + H]+, found 199.0625.

2-(Phenylamino)acetamide (8b): Following the general procedure,the reaction of ethyl phenylglycinate (6k, 150 mg, 0.84 mmol) withammonia gas in methanol (5.0 mL) at 25 °C for 24 h afforded com-pound 8b as a light-brown solid (124 mg, 99 %), m.p. 135–136 °C(amorphous).[51] 1H NMR (400 MHz, CDCl3): δ = 3.80 (d, J = 5.6 Hz,2 H), 4.30 (br. s, 1 H), 5.66 (br. s, 1 H), 6.58 (br. s, 1 H), 6.64 (d, J =7.6 Hz, 2 H), 6.82 (t, J = 7.4 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 2 H) ppm.13C NMR (100 MHz, CDCl3): δ = 48.4 (CH2), 113.1 (CH), 119.2 (CH),129.5 (CH), 146.9 (C), 173.5 (C) ppm. HRMS (ESI+): calcd. forC8H11N2O+ 151.0871 [M + H]+, found 151.0853.

General Procedure for the Synthesis of 7-Phenyl-7H-purine 11:A solution of the 2-(phenylamino)acetonitrile 6l (50 mg, 0.38 mmol)and formamidine acetate 9 (236 mg, 2.27 mmol) in n-butanol(2.0 mL) was irradiated with microwaves at 140 °C for 2 × 15 min ina sealed tube containing a teflon-coated magnetic stirring bar. Theformamidine acetate was added in two equal portions involvingtwo heating/cooling cycles. The resulting reaction mixture wascooled to 55 °C, concentrated and the residue taken up in water.This was extracted with CH2Cl2 (2 × 5.0 mL) and the combined or-ganic layers were dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum to give the crude product. Columnchromatography (CH2Cl2/MeOH, 25:1) on silica gel of this materialafforded compound 11 (22 mg, 30 %) as a white solid, m.p. 185–186 °C (amorphous).[29] 1H NMR (400 MHz, CDCl3): δ = 7.53–7.67(m, 5 H), 8.47 (s, 1 H) 9.07 (s, 1 H), 9.22 (s, 1 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 123.5 (CH), 125.2 (C), 129.3 (CH), 130.6 (CH),134.8 (C), 140.7 (CH), 146.8 (CH), 153.8 (CH), 161.1 (C) ppm. HRMS(ESI+): calcd. for C11H9N4

+ 197.0827 [M + H]+, found 197.0809.

AcknowledgmentsThe authors are grateful for the financial support from the Uni-versidad de los Andes and COLCIENCIAS. J. O.-H. also is gratefulto the Department of Chemistry at Universidad de los Andesfor her doctoral scholarship. Edwin Guevara is acknowledgedfor acquiring the mass spectra.

Keywords: Synthetic methods · N-Alkylation ·Chemoselectivity · C–N bond formation · Secondaryamines · Cesium

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Full Paper

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Received: May 2, 2016Published Online: July 8, 2016

cs 2 co 3 ‐promoted direct n ‐alkylation: highly ...szolcsanyi/education/files/organicka chemia...

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