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Synlett 2009(6): 937-940  
DOI: 10.1055/s-0028-1088194
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Propargylamines by a Copper-Catalyzed Tandem Anti-Markovnikov Hydroamination and Alkyne Addition

Lei Zhoua,b, D. Scott Bohlea, Huan-Feng Jiang*b, Chao-Jun Li*a
a Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax: +1(514)3983797; e-Mail: cj.li@mcgill.ca;
b College of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. of China

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Publication History

Received 20 November 2008
Publication Date:
16 March 2009 (online)

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Abstract

A highly efficient tandem anti-Markovnikov hydroamination and alkyne addition reaction catalyzed by a Cu(I) or Cu(II) catalyst was developed. Various propargylamines were obtained in moderate to good yields. This tandem process provides a novel and simple approach to propargylamine derivatives from alkynes and amines.

Key words

copper - hydroamination - propargylamine - alkynes - amines

Hydroamination of alkynes is a desirable transformation leading to C-N bond formation. It offers a direct route to the synthesis of nitrogen-containing organics such as enamines or imines which can readily undergo further transformations to generate valuable nitrogen-containing compounds. [¹] The high atom economy makes hydroamination highly attractive, because no intrinsic byproducts are produced. [²]

Catalysts derived from both early and late transition metals have been employed to overcome the high activation-energy barrier for such a process. The ability of copper complexes to catalyze intramolecular hydroaminations of alkynes has been known for decades. As early as in the 1960s, Castro et al. described a high-yielding synthesis of indoles by treating o-iodoanilines with cuprous acetylides in refluxing pyridine. [³] However, compared to intramolecular hydroaminations, [4] there are very few examples on the copper-catalyzed intermolecular hydroamination, [¹j] especially the anti-Markovnikov addition of secondary amines to terminal alkynes. [5]

On the other hand, great progress has been made by our group [6] and others [7] on the Grignard-type reactions of alkynes to aldehydes and imines to generate propargyl alcohols and propargylamines via catalytic C-H activation in water (and in organic media). Because of our continued interest in synthesizing propargylamine via activation of alkynes, we discovered a new copper-catalyzed amine-alkyne-alkyne addition via an enamine intermediate. [8] However, our early success in such three-component additions has been largely limited to the allyl- or benzyl-protected amine and requires alkyne-bearing electron-withdrawing groups. Herein, we wish to report a novel Cu-catalyzed tandem hydroamination and addition of simple terminal alkynes to generate propargylamines without any co-catalyst or additive.

Table 1 Copper-Catalyzed Reaction between Phenylacetylene and Diallylaminea

Entry Catalyst Temp (˚C) Yield (%)b
 1 CuBr  60 25
 2 CuBr  80 55
 3 CuBr 100 79
 4 CuBr 120 77
 5 CuBr r.t.  0 
 6 CuOTf 100 15
 7 CuCN 100 33
 8 CuI 100 62
 9 CuCl 100 41
10 CuBr2 100 70
11 CuCl2 100 73
12 AuI 100 10
13 AuCl3 100  0
14 AgCl 100  0
15 AgBF4/HBF4 100 trace
a Reaction conditions: diallylamine (0.5 mmol), phenylacetylene (2 mmol), catalyst (5 mol%), toluene (2 mL), N2 atmosphere, 24 h.
b Measured by ¹H NMR.

At the beginning of this study, we found that the propargylamine product can be formed in 25% yield by using CuBr as a catalyst at 60 ˚C for 24 hours (Table  [¹] , entry 1). Subsequently, it was found that the reaction gives the best yields at 100 ˚C (Table  [¹] , entries 1-5). Among the various copper catalysts examined, CuBr gave the best result (Table 1, entries 3-11). CuCl2 and CuBr2 are also effective, albeit generating the product with a slightly decreased yield (Table  [¹] , entries 10 and 11). Other catalysts such as AuI, AuCl3, AgCl, and AgBF4/HBF4 were found to be essentially ineffective in this reaction (Table  [¹] , entries 12-15). Different solvents were also tested, and the best result was obtained by using toluene as the solvent.

Having optimized the reaction conditions, we explored the scope of the reaction and the results are summarized in Table  [²] . Treatment of diallylamine with different terminal alkynes 1a-h furnished the corresponding propargyl­amines 3a-h in moderate to good yields (Table  [²] , entries 1-8). The reaction can tolerate a halogen group in substrate 1e (Table  [²] , entry 5). Substrate 1f, bearing two tri­fluoromethyl groups, also reacted with diallylamine 1a smoothly at 100 ˚C to give the product in 84% yield (Table  [²] , entry 6). In the reaction of diallylamine and 1,4-diethynylbenzene, a monoaddition adduct was obtained as the sole product (Table  [²] , entry 7) in 55% yield.

Aliphatic alkyne appeared less reactive. Treatment of 1-octyne with diallyamine afforded the desired product in 40% yield (Table  [²] , entry 9). Subsequently, several secondary amines 2b-e were evaluated, and all were suitable substrates for the reaction with terminal alkynes under the standard conditions (entries 10-16). 4-Phenylpiperidine (2d), for example, reacted with phenylacetylene and 4-ethynyltoluene to afford the corresponding products 3l and 3p in 75% and 77% yields, respectively (Table  [²] , entries 12 and 16). The molecular structure of 3o was further confirmed by its X-ray crystal diffraction (Figure  [¹] ).

Table 2 Copper-Catalyzed Tandem Hydroamination and Addition of Alkynesa (continued)

Entry Alkyne Amine Product [] Yield (%)b
 1

1a 		All2NH 2a 3a 74
 2

1b 		2a 3b 81
 3

1c 		2a 3c 58
 4

1d 		2a 3d 68
 5

1e 		2a 3e 72
 6

1f 		2a 3f 84
 7

1g 		2a 3g 55
 8

1h 		2a 3h 55
 9

1i 		2a 3i 40
10 1a

2b 		3j 68
11 1a

2c 		3k 49
12 1a

2d 		3l 75
13 1a

2e 		3m 52
14 1b 2b 3n 73
15 1d 2b 3o 69
16 1b 2d 3p 77
a Reaction conditions: amine (0.5 mmol), terminal alkyne (2 mmol), CuBr (5 mol%), toluene (2 mL), N2 atmosphere, 24 h.
b Isolated yield.

To understand the mechanism of the reaction, we performed two ‘control experiments’. No enyne product was observed after phenylacetylene and CuBr were stirred at 100 ˚C in toluene for 24 hours under nitrogen, and 80% of phenylacetylene remained unreacted. However, the reaction of phenylacetaldehyde, piperidine, and phenylacetyl­ene gave the compound 3j in 27% yield after stirring at 100 ˚C in toluene for 24 hours (Scheme  [¹] ). This result suggests that the first step of this reaction is the hydroami­nation of alkynes followed by the addition of alkyne to the enamine intermediate, rather than the addition of amine to enyne [9] after the dimerization of alkynes. [¹0] Therefore, a tentative mechanism for this reaction is proposed in Scheme  [²] . Terminal alkyne 1 is activated by CuBr to generate intermediate A. Intermediate A further reacts with a secondary amine to give the hydroamination product B, which is protonated to give an iminium intermediate C. [6d] [7e] [h] [¹¹] Subsequently, an intramolecular transfer of the alkyne moiety to the iminium ion produces propargyl­amine 3 and regenerates the copper catalyst. Alternatively, the hydroamination may proceed through an acetylide intermediate.

Figure 1 X-ray crystal diffraction of 3o as a racemic mixture of R,S-isomers

Scheme 1 Copper(I)-catalyzed alkyne dimerization and aldehyde-amine-alkyne coupling

In conclusion, we have developed a highly efficient tandem hydroamination and addition of terminal alkynes catalyzed by Cu catalysts. This tandem process provides a novel and simple approach to propargylamine derivatives from alkynes and amines. The detailed mechanism, the reason for the regioselelctive anti-Markovnikov addition of amines to alkynes, and the scope of the reaction are currently under investigation.

Scheme 2 Tentative mechanism for the copper-catalyzed hydroamination and addition of alkynes

Acknowledgment

We are grateful to the Canada Research Chair (Tier I) foundation (to D.S.B. and C.J.L.), the CFI, NSERC, and McGill ACS-GCI Pharmaceutical Roundtable for support of our research. L.Z. thanks the China Scholarship Council for a Visiting Scholarship.

12

Representative Experimental Procedure Copper(I) bromide (3.6 mg, 0.025 mmol, 5 mol%) was suspended in toluene (2 mL) in a 10 mL Schlenk tube under nitrogen. Then, diallylamine (49 mg, 0.5 mmol) and phenylacetylene (204 mg, 2 mmol) were added. The resulting solution was stirred at 100 ˚C for 24 h. After cooling to r.t., the resulting mixture was filtered through a short path of SiO2 in a pipette eluting with EtOAc. The volatiles were removed in vacuo, and the residue was purified by column chromatography (SiO2, hexane-EtOAc, 10:1) to give 3a (111.3 mg, 74%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl3): δ = 7.42-7.39 (m, 2 H), 7.31-7.23 (m, 8 H), 5.88-5.79 (m, 2 H), 5.23 (d, J = 17.2 Hz, 2 H), 5.13 (d, J = 10.0 Hz, 2 H), 3.97 (t, J = 7.6 Hz, 1 H), 3.41(dt, J = 14.0, 2.4 Hz, 2 H), 3.11-2.97 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 139.0, 136.6, 131.8, 129.7, 128.4, 128.3, 128.1, 126.5, 123.6, 117.5, 87.7, 86.2, 55.4, 54.3, 40.6. MS (70 eV): m/z (%) = 301 [M+], 274, 242, 215, 210(100), 191, 168, 154, 128, 115, 91. HRMS (EI): m/z calcd for C22H23N [M+]: 301.1831; found: 301.1814.
The experiments in Table  [²] were carried out analogously. All products were purified by column chromatography and characterized by NMR spectroscopy and standard/high-resolution mass spectrometry.

12

Representative Experimental Procedure Copper(I) bromide (3.6 mg, 0.025 mmol, 5 mol%) was suspended in toluene (2 mL) in a 10 mL Schlenk tube under nitrogen. Then, diallylamine (49 mg, 0.5 mmol) and phenylacetylene (204 mg, 2 mmol) were added. The resulting solution was stirred at 100 ˚C for 24 h. After cooling to r.t., the resulting mixture was filtered through a short path of SiO2 in a pipette eluting with EtOAc. The volatiles were removed in vacuo, and the residue was purified by column chromatography (SiO2, hexane-EtOAc, 10:1) to give 3a (111.3 mg, 74%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl3): δ = 7.42-7.39 (m, 2 H), 7.31-7.23 (m, 8 H), 5.88-5.79 (m, 2 H), 5.23 (d, J = 17.2 Hz, 2 H), 5.13 (d, J = 10.0 Hz, 2 H), 3.97 (t, J = 7.6 Hz, 1 H), 3.41(dt, J = 14.0, 2.4 Hz, 2 H), 3.11-2.97 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 139.0, 136.6, 131.8, 129.7, 128.4, 128.3, 128.1, 126.5, 123.6, 117.5, 87.7, 86.2, 55.4, 54.3, 40.6. MS (70 eV): m/z (%) = 301 [M+], 274, 242, 215, 210(100), 191, 168, 154, 128, 115, 91. HRMS (EI): m/z calcd for C22H23N [M+]: 301.1831; found: 301.1814.
The experiments in Table  [²] were carried out analogously. All products were purified by column chromatography and characterized by NMR spectroscopy and standard/high-resolution mass spectrometry.

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Figure 1 X-ray crystal diffraction of 3o as a racemic mixture of R,S-isomers

Scheme 1 Copper(I)-catalyzed alkyne dimerization and aldehyde-amine-alkyne coupling

Scheme 2 Tentative mechanism for the copper-catalyzed hydroamination and addition of alkynes