Synthesis of Propargylamines via Michael Addition Using Methyl Vinyl Ketone Derivatives, 1-Alkynes, and Secondary Amines Catalyzed by Copper (I) Halides.

Propargylamines are synthesized from methyl vinyl ketone derivatives, 1-alkynes, and secondary amines catalyzed by Cu salts involving the Michael addition of amine followed by an unusual C-C bond cleavage and addition of metal acetylides formed in situ to iminium ions. In this approach, the di-, tri-, and tetrasubstituted propargylamines are synthesized in 46-98% yields.

Introduction

Propargylamines are versatile building blocks widely used in the synthesis of natural products and bioactive compounds.[1−4] Conventional methods of synthesis of propargylamines involve amination of propargylic halides, phosphates, or triflates[5−7] and reaction of lithium acetylides or Grignard reagents with imines or their derivatives.[8,9] However, some of these reagents are highly moisture-sensitive and hence require strictly controlled reaction conditions. Later, transition-metal-catalyzed three-component coupling reactions of aldehyde, amine, and alkyne (A3 coupling) were developed to access propargylamines.[10] Methods involving copper(I)-catalyzed addition of alkynes to enamines,[11] microwave-assisted, three-component coupling reaction of a ketone, alkyne, and primary amine (KA2 coupling),[12] using amine, acyclic ketone, and 1-alkyne and the catalytic system with 50 mol % of Ti(OEt)4 and 5 mol % of CuCl2,[13] and a tandem Markovnikov hydroamination–alkynylation sequence of reactions for direct access to tetrasubstituted propargylic amines from an amine and alkyne were also reported (Scheme ).[14]

Scheme 1

Overview of the Methods of Synthesis of Propagylamines

Over the years, several synthetic methods were developed using aldehydes (or) ketones, 1-alkynes, and amines to access propargylamines.[15−19] In continuation of the studies on the synthesis of propargylamines and their conversion to allenes in this laboratory,[20,21] we wish to report herein an unprecedented copper-catalyzed reaction using methyl vinyl ketone derivatives, 1-alkynes, and secondary amines to access di-, tri-, and tetrasubstituted propargylamines.

Results and Discussion

Recently, convenient methods have been developed to access chiral propargylamines and chiral allenes via CuX- and ZnX2-promoted transformations.[20,21] In continuation of these studies, we have explored the synthesis of propargylamines via the Michael addition[22] using readily available methyl vinyl ketone, morpholine, and phenyl acetylene with different metal salts like ZnCl2, ZnBr2, ZnI2, CuCl, CuBr, and CuI in various solvents (Table ).

Table 1

Synthesis of Propargylamine 4a Using Morpholine 1a, Methy Vinyl Ketone 2a and Phenyl Acetylene 3a with Different Metal Saltsa,bab

entry	solvent	temp (°C)	MXn	mol (%)	time (h)	yield (%)b
1	DCM	25	ZnCl2	10	24	NR
2	CH3CN	25	ZnCl2	10	24	NR
3	toluene	25	ZnCl2	10	24	NR
4	dioxane	25	ZnCl2	10	24	NR
5	toluene	100	ZnCl2	10	24	25
6	toluene	100	ZnBr2	10	24	33
7	toluene	100	ZnI2	10	12	60
8	toluene	100	CuCl	10	12	92
9	toluene	100	CuBr	10	12	90
10	toluene	100	CuI	10	12	87

The reactions were carried out by taking morpholine 1a (2.0 mmol), phenyl acetylene 3a (2.2 mmol), and methyl vinyl ketone 2a (2.0 mmol) in toluene (4 mL) at 100 °C for 12 h.

Isolated yield. NR: No reaction.

Initially, we have carried out the reaction with ZnCl2 at 25 °C in dichloromethane (DCM), CH3CN, toluene, and dioxane solvents, but the propargylamine 4a product was not formed (entries 1–4, Table ). In reactions using ZnCl2 and ZnBr2, the corresponding propargylamine 4a was isolated in 25–33% yield in 24 h at 100 °C (entries 5 and 6, Table ). Although ZnI2 gave the desired product 4a in 60% yield in 12 h at 100 °C (entry 7, Table ), use of copper (I) chloride afforded the propargylamine 4a in 92% yield (entry 8, Table ). The propargylamine 4a was also formed in similar yields using the CuBr and CuI under these reaction conditions (entries 9 and 10, Table ).

Under these optimized conditions, various secondary amines were employed in this transformation, and the results are summarized in Table . Although the cyclic amines morpholine (1a), piperidine (1b), pyrrolidine (1c), N-benzylpiperizine (1d), and N-phenylpiperizine (1e) gave the corresponding propargylamines 4a–4e in moderate to good yields (53–92%), diethylamine (1f) gave the desired propargylamine 4f in 52% yield. The reaction of morpholine with aliphatic 1-alkynes also afforded the propargylamines 4g–4l in moderate to good yields (Table ). It is of interest to note here that the use of paraformaldehyde, 1-alkyne, and amines under reflux conditions in dioxane solvent gave the corresponding allenes.[23]

Table 2

CuCl-Promoted Synthesis of Propargylamines 4 Using Secondary Amines 1a–f, Methyl Vinyl Ketone 2a, and 1-Alkynesa,b

The reactions were carried out by taking amine 1 (2.0 mmol), 1-alkyne 3 (2.2 mmol), and methyl vinyl ketone 2a (2.0 mmol) in toluene (4 mL) and heating at 100 °C for 12 h.

Isolated yield.

After developing the method for the preparation of the propargylamine derivatives 4, we turned our attention toward the synthesis of propargylamine derivatives 5 employing 3-pentene-2-one 2b to examine the scope of this method (Table ). Indeed, the corresponding propargylamine derivatives 5 are obtained in 70–98% yield (Table ). The phenyl acetylene gave the desired propargylamine in 98% yield (5a, Table ). The substituted phenylacetylenes like p-fluorophenylacetylene and p-tolylacetylene reacted readily with morpholine and 3-pentene-2-one to give the corresponding propargylamines 5 in 81–98% yield (5b and 5c, Table ). The reaction was also extended to aliphatic alkynes to access the corresponding propargylamines in 70–96% yield (5d–5i, Table ). The 5-cyano-1-pentyne also afforded the corresponding propargylamine in 82% yield (5j, Table ). Interestingly, the reaction of pyrrolidine with 3-pentene-2-one and phenyl acetylene in dichloromethane solvent gave propargylamine in 65% yield at 25 °C (5k, Table ).

Table 3

CuCl-Promoted Synthesis of Propargylamines 5 Using Morpholine 1a, 3-Penten-2-one 2b, and 1-Alkynesa,b,c

The reactions were carried out by taking amine 1 (2.0 mmol), 1-alkyne 3 (2.2 mmol), and 3-penten-2-one 2b (2.0 mmol) in toluene (4 mL) at 100 °C for 12 h.

Isolated yield.

Reaction was carried out by taking pyrrolidine 1c (2.0 mmol), 1-alkyne 3 (2.2 mmol), and 3-penten-2-one 2b (2.0 mmol) in DCM solvent at 25 °C for 12 h.

Finally, we have also examined the reaction of pyrrolidine 1c with mesityl oxide 2c and 1-alkynes in the presence of CuCl (10 mol %) to prepare the propargylamine deivatives 6 with two methyl groups. The corresponding propargylamine deivatives 6 were obtained in 46–77% yield at 25 °C, and the results are summarized in Table .

Table 4

CuCl-Promoted Synthesis of Propargylamines 6 Using Pyrrolidine 1c, Mesityloxide 2c, and 1-Alkynesa,b

The reactions were carried out by taking amine 1c (2.0 mmol), 1-alkyne 3 (2.2 mmol), and mesityloxide 2c (2.0 mmol) in DCM (4 mL) at 25 °C about 6–12 h.

Isolated yield.

The CuCl-catalyzed formation of propargylamines 4a may be rationalized by the tentative mechanism involving intermediates outlined in Scheme . The cyclic secondary amine would first react with methyl vinyl ketone 2a in a Michael fashion. The corresponding Michael adduct 7 would then undergo C–C bond cleavage to give the iminium intermediate 8. A subsequent addition of copper acetylide formed in situ to iminium ion would give the propargylamine 4a with regeneration of the copper catalyst.

Scheme 2

Tentative Mechanism for the CuCl-Catalyzed Synthesis of Propargylamines

We have carried out several experiments to further understand the mechanism, intermediates, scope, and limitations of this transformation. We have observed that when the reaction of morpholine 1a was carried out using methyl vinyl ketone 2a in polyethylene glycol (PEG) solvent at 25 °C,[22b] the corresponding Michael addition product 7 was isolated, which upon reaction with phenyl acetylene 3a and CuCl (10 mol %) at 100 °C gave the propargylamine 4a in 65% yield (Scheme ).

Scheme 3

Reaction of Michael Adduct Intermediate 7 with Phenyl Acetylene 3a and CuCl

Also, the reaction of morpholine 1a with 1-phenylprop-2-en-1-one 2d and phenyl acetylene 3a in toluene solvent at 100 °C gave the propargylamine 4a in 52% yield along with the acetophenone 11 (33% y) byproduct (Scheme ). Clearly, these transformations go through the C–C bond cleavage of the Michael adduct 7 as outlined in Scheme .

Scheme 4

Synthesis of Propargylamine 4a Using Morpholine 1a, 1-Phenylprop-2-en-1-one 2d, and Phenyl Acetylene 3a with CuCl

Interestingly, the reaction of primary amines like benzylamine 12 with methyl vinyl ketone 1a and phenyl acetylene 3a in the presence of CuCl in toluene at 100 °C gave the 3-substituted-N-benzylpiperidine product 13 instead of the expected propargylamine derivative. The product 13 was obtained in 85% yield in the reaction of benzylamine (1 equiv) with methyl vinyl ketone (2 equiv) in a double Michael addition, followed by aldol reaction sequence (Scheme ).

Scheme 5

Synthesis of 1-(1-Benzyl-4-hydroxy-4-methylpiperidin-3-yl) Ethanone 13 Using Benzylamine 12 Methyl Vinyl Ketone 1a with CuCl

In the case of the reaction of trimethylsilyl-substituted terminal acetylene with CuCl, morpholine, and methyl vinyl ketone in toluene at 100 °C, only the corresponding Michael addition product 7 was obtained. These results may illustrate the scope and limitations of the CuCl-catalyzed propargylamine synthesis using terminal alkynes and methyl vinyl ketone derivatives.

Conclusions

In summary, we have developed a CuCl-promoted method for the synthesis of propargylamines using amines, α,β-unsaturated ketones, and 1-alkynes via Michael addition followed by C–C bond cleavage to iminium-ion intermediates and subsequent addition of the in situ formed copper acetylides. This method utilizes the inexpensive CuCl as catalyst, and it is applicable to both aromatic and aliphatic alkynes and also to various secondary amines to produce di-, tri-, tetrasubstituted propargylamines in a single-pot synthetic operation. Propargylamines are one of the important classes of intermediates and attractive starting materials for the synthesis of nitrogen heterocycles, natural products, and biologically active compounds.[24] Hence, the method of synthesis for propargylamines described here has a significant synthetic potential.

Experimental Section

General Information

IR (neat) spectra were recorded with polystyrene as reference. 1H NMR (400 MHz) and 13C{1H} NMR (100 MHz) spectra were recorded with chloroform-d as solvent and TMS as reference (δ = 0 ppm). The chemical shifts are expressed in δ downfield from the signal of internal TMS. High-resolution mass spectroscopy (HRMS) images were recorded on micromass electrospray ionization time-of-flight (ESI-TOF). All of the chemicals used were commercially available. Toluene was freshly distilled over sodium-benzophenone ketyl before use. Analytical thin-layer chromatographic tests were carried out on glass plates (3 × 10 cm2) coated with 250 mμ silica gel-G and GF-254 containing 13% calcium sulfate as binder. The spots were visualized by a short exposure to iodine vapor or UV light. Column chromatography was carried out using silica gel (100–200 mesh).

General Procedure for the Synthesis of Propargylamines

In a 10 mL RB flask, CuCl (0.020 g, 0.2 mmol), amine 1 (2.0 mmol), α,β-unsaturated ketone 2a, b (2.0 mmol), and 1-alkyne 3 (2.2 mmol) were taken in 4 mL of toluene at 25 °C under N2 atmosphere, and the contents were stirred at 100 °C for 12 h. Toluene was removed, and water (5 mL) and DCM (15 mL) were added. The DCM layer was washed with saturated NaCl solution, dried with Na2SO4, and concentrated. The residue was chromatographed on silica gel (100–200 mesh) using hexane and ethylacetate (80:20) as eluent to isolate the propargylamine derivatives 4 and 5.

Procedure for the Synthesis of Propargylamine 4a from the Michael Adduct Intermediate 7

A mixture of amine 1a (2 mmol), methyl vinyl ketone 2a (3 mmol), and PEG 400 (5 g) was placed in 25 mL round-bottom flask. The contents were stirred at room temperature until the reaction was complete. The crude mixture was extracted with ether. The ether layer was concerted and purified on silica gel (100–200 mesh) using hexane and ethylacetate (50:50) as an eluent to obtain the adduct in excellent yield.[22b] To a stirred solution of freshly prepared Michael adduct 7 (0.157 g, 1 mmol) in toluene (3 mL), phenyl acetylene 3a (0.16 mL, 1.5 mmol) and CuCl (0.010 g, 0.1 mmol) were added, and the contents were stirred at 100 °C for 12 h. Toluene was removed, and water (5 mL) and DCM (10 mL) were added. The DCM layer was washed with saturated NaCl solution, dried with Na2SO4, and concentrated. The residue was chromatographed on silica gel (100–200 mesh) using hexane and ethylacetate (80:20) as eluent to isolate 4a.

4-(3-phenylprop-2-yn-1-yl) morpholine (4a)[18]

Yield: 0.369 g (92%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 2755, 1598, 1479, 1453, 1391, 1324, 1288, 1236, 1112, 1066, 1019, 911, 854, 751, 694 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.46–7.44 (m, 2H) 7.32–7.31 (m, 3H), 3.80–3.78 (m, 4H), 3.53 (s, 2H), 2.68–2.67(m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 128.1, 123.0, 85.5, 84.1, 66.9, 52.4, 48.1; HRMS (ESI-TOF): [M + H]+ calcd for C13H15NO m/z 202.1232, found m/z 202.1232.

1-(3-phenylprop-2-yn-1-yl) piperidine (4b)[18]

Yield: 0.238 g (60%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 3054, 3028, 2930, 2858, 2796, 2750, 1644, 1593, 1489, 1433, 1371, 1345, 1298, 1257, 1159, 1007, 1066, 1040, 999, 911, 859, 771, 684 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.46–7.44 (m, 2H) 7.32–7.29 (m, 3H), 3.49 (s, 2H), 2.59 (bs, 4H), 1.66 (qt, J = 6.0 Hz, 4H), 1.46 (bs, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 127.9, 123.3, 85.0, 84.9, 53.4, 48.4, 25.9, 23.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H17N: 200.1439; found: 200.1439.

1-(3-phenylprop-2-yn-1-yl) pyrrolidine (4c)[18]

Yield: 0.196 g (53%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2959, 2910, 2854, 2814, 2761, 1597, 1489, 1449, 1347, 1329, 1289, 1269, 1116, 1071, 1006, 916, 861, 757, 692 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.46–7.44 (m, 2H) 7.32–7.30 (m, 3H), 3.80–3.78 (m, 4H), 3.54–3.52 (m, 2H), 2.67–2.66 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 128.1, 122.9, 85.5, 84.0, 66.9, 52.4, 48.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H15N: 186.1282; found: 186.1284.

1-benzyl-4-(3-phenylprop-2-yn-1-yl) piperizine (4d)[25]

Yield: 0.423 g (73%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 3059, 3028, 2930, 2806, 2765, 2693, 1686, 1598, 1494, 1443, 1329, 1293, 1143, 1071, 1019, 911, 828, 756, 694 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.46–7.44 (m, 2H) 7.35–7.33 (m, 4H), 7.32–7.28 (m, 4H) 3.58 (s, 2H), 3.55 (s, 2H), 2.73 (bs, 4H) 2.60 (bs, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.0, 131.7, 129.2, 128.2, 128.0, 127.0, 123.1, 85.2, 84.6, 63.0, 52.9, 52.1, 47.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22N2: 291.1861; found: 291.1860.

1-phenyl-4-(3-phenylprop-2-yn-1-yl) piperizine (4e)

Yield: 0.353 g (64%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 3028, 2941, 2905, 2817, 1598, 1489, 1448, 1391, 1345, 1226, 1138, 1004, 926, 756, 699 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.48–7.46 (m, 2H) 7.33–7.27 (m, 5H), 6.99–6.97 (m, 2H), 6.91–6.88 (m, 1H), 3.61–3.60 (m, 2H), 3.30–3.28 (m, 4H), 2.85–2.83 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 151.2, 131.7, 129.1, 128.2, 128.1, 123.0, 119.8, 116.1, 85.5, 84.2, 52.1, 49.1, 47.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H20N2: 277.1704; found: 277.1704.

N,N-diethyl-3-phenylprop-2-yn-1-amine (4f)[15c]

Yield: 0.194 g (52%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2967, 2930, 2874, 2812, 1562, 1489, 1458, 1371, 1319, 1200, 1117, 1066, 1030, 983, 761, 684 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.45–7.32 (m, 5H) 3.68 (s, 2H), 2.67–2.60 (m, 4H), 1.15–1.08 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 127.9, 123.3, 84.9, 84.3, 47.3, 41.4, 12.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H17N: 188.1439; found: 188.1435.

4-(hept-2-yn-1-yl) morpholine (4g)[26]

Yield: 0.238 g (66%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 2755, 1448, 1376, 1293, 1241, 1123, 1009, 916, 859, 777 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J = 4.6 Hz, 4H) 3.24 (t, J = 2.25 Hz, 2H), 2.55 (s, 4H) 2.21–2.18 (m, 2H), 1.51–1.46 (m, 2H), 1.42–1.36 (m, 2H), 0.90 (t, J = 7.35 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.8, 74.3, 66.8, 52.3, 47.6, 30.8, 21.9, 18.3, 13.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H19NO: 182.1545; found: 182.1540.

4-(oct-2-yn-1-yl) morpholine (4h)[18]

Yield: 0.273 g (70%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2930, 2858, 2817, 1448, 1329, 1283, 1236, 1112, 1071, 999, 911, 864, 797 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.75 (t, J = 4.48 Hz, 4H), 3.25 (t, J = 2.2 Hz, 2H), 2.57–2.56 (m, 3H), 2.22–2.17 (m, 2H), 1.51 (qt, J = 7.0 Hz, 2H), 1.41–1.26 (m, 5H), 0.90 (t, J = 7.04 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.9, 74.3, 66.8, 52.3, 47.6, 31.0, 28.5, 22.1, 18.6, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H21NO: 196.1701; found: 196.1702.

4-(non-2-yn-1-yl) morpholine (4i)[26]

Yield: 0.342 g (82%) yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2848, 2806, 1448, 1350, 1288, 1241, 1117, 1004, 921, 859, 792 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J = 3.6 Hz, 4H), 3.24 (t, J = 1.76 Hz, 2H), 2.55 (s, 3H), 2.21–2.17 (m, 2H), 1.53–1.47 (m, 2H), 1.41–1.36 (m, 2H), 1.31–1.25 (m, 5H), 0.88 (t, J = 5.48 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.9, 74.3, 66.8, 52.3, 47.7, 31.3, 28.7, 28.5, 22.5, 18.7, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H23NO: 210.1858; found: 210.1858.

4-(dec-2-yn-1-yl) morpholine (4j)

Yield: 0.231 g (52%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2951, 2920, 2853, 2806, 1458, 1329, 1293, 1241, 1112, 1066, 999, 916, 859, 792 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.75 (t, J = 4.65 Hz, 4H) 3.25 (t, J = 2.25 Hz, 2H), 2.57–2.56 (m, 3H), 2.21–2.18 (m, 2H), 1.54–1.48 (m, 2H), 1.41–1.36 (m, 2H), 1.32–1.26 (m, 7H), 0.89 (t, J = 6.75 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.8, 74.3, 66.8, 52.3, 47.6, 31.7, 28.9, 28.8, 28.7, 28.5, 18.6, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H25NO: 224.2014; found: 224.2015.

4-(undec-2-yn-1-yl) morpholine (4k)

Yield: 0.350 g (74%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2961, 2925, 2853, 2812, 2765, 1453, 1329, 1262, 1117, 1066, 1004, 911, 864, 797 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J = 4.60 Hz, 4H) 3.23 (t, J = 2.20 Hz, 2H), 2.56–2.55 (m, 3H), 2.21–2.16 (m, 2H), 1.49 (qt, J = 6.72 Hz, 2H), 1.41-1.35 (m, 2H), 1.33–1.27 (m, 9H), 0.87 (t, J = 6.64 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.9, 74.3, 66.8, 52.3, 47.7, 31.8, 29.1, 29.0, 28.9, 28.8, 22.6, 18.6, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H27NO: 238.2171; found: 238.2172.

4-(tridec-2-yn-1-yl) morpholine (4l)

Yield: 0.243 g (46%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2925, 2848, 1453, 1376, 1288, 1236, 1117, 1014, 911, 870, 797, 720 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J = 4.55 Hz, 4H) 3.24 (t, J = 2.1 Hz, 2H), 2.55 (s, 3H), 2.20–2.17 (m, 2H), 1.49 (qt, J = 6.95 Hz, 2H), 1.38-1.34 (m, 2H), 1.29–1.26 (m, 13H), 0.88 (t, J = 6.75 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.9, 74.3, 66.8, 52.3, 47.7, 31.9, 29.6, 29.5, 29.3, 29.1, 28.9, 28.8, 22.6, 18.7, 14.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H31NO: 266.2484; found: 266.2486.

4-(4-phenylbut-3-yn-2-yl) morpholine (5a)

Yield: 0.421g (98%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2894, 2853, 2822, 2755, 1598, 1489, 1443, 1376, 1324, 1298, 1262, 1179, 1123, 1066, 1035, 957, 911, 849, 766 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.46–7.44 (m, 2H) 7.32–7.28 (m, 3H), 3.83–3.75 (m, 4H), 3.72–3.67 (m, 1H), 2.80–2.76 (m, 2H), 2.62–2.59 (m, 2H), 1.48–1.44 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 128.0, 123.0, 87.7, 85.4,67.1, 52.6, 49.5, 19.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H17NO: 216.1388; found: 216.1387.

1-(4-phenylbut-3-yn-2-yl)pyrrolidine (5k)[27]

Yield: 0.258 g (65%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2959, 2910, 2854, 2814, 2761, 1597, 1489, 1449, 1347, 1329, 1289, 1269, 1116, 1071, 1006, 916, 861, 757, 692 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.44–7.43 (m, 2H), 7.31–7.28 (m, 3H), 3.90–3.85 (m, 1H), 2.87–2.75 (m, 4H), 1.85 (s, 4H) 1.53–1.48 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 127.9, 123.2, 88.6, 84.6, 49.8, 49.7, 23.5, 21.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H17N: 200.1439; found: 200.1441.

4-(4-(4-fiuorophenyl)but-3-yn-2-yl) morpholine (5b)

Yield: 0.377 g (81%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2894, 2853, 2822, 1603, 1505, 1453, 1376, 1324, 1226, 1107, 1071, 1035, 968, 921, 890, 833, 808, 751 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.43–7.38 (m, 2H), 7.02–6.96 (m, 2H), 3.82–3.72 (m, 4H), 3.65 (q, J = 7.04 Hz, 1H), 2.77–2.72 (m, 2H) 2.59–2.54 (m, 2H), 1.45–1.41 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.3 (d, J = 247.7 Hz), 133.5 (d, J = 8 Hz), 119.1 (d, J = 3 Hz), 115.5 (d, J = 21 Hz). 87.4, 84.4, 67.0, 52.6, 49.5, 18.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H16FNO: 234.1294; found: 234.1293.

4-(4-(p-tolyl)but-3-yn-2-yl) morpholine (5c)

Yield: 0.448 g (98%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2951, 2920, 2853, 2812, 1505, 1453, 1371, 1324, 1252, 1185, 1112, 1071, 1030, 968, 916, 859, 818, 761 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.35–7.33 (m, 2H), 7.13–7.11 (m, 2H), 3.83–3.75 (m, 4H), 3.70–3.65 (m, 1H), 2.80–2.76 (m, 2H), 2.62–2.58 (m, 2H), 2.36 (s, 3H), 1.47–1.43 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 138.0, 131.5, 128.9, 120.0, 86.9, 85.5, 67.0, 52.6, 49.5, 21.4, 19.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H19NO: 230.1545; found: 230.1546.

4-(oct-3-yn-2-yl) morpholine (5d)

Yield: 0.308 g (79%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 2817, 1453, 1376, 1324, 1252, 1185, 1112, 1071, 1014, 916, 859, 777, 751 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.79–3.69 (m, 4H), 3.44–3.38 (m, 1H), 2.68–2.62 (m, 2H), 2.50–2.45 (m, 2H), 2.20 (dt, J = 7.04 Hz, 1.9 Hz, 2H), 1.53–1.38 (m, 4H), 1.33–1.29 (m, 3H), 0.91 (t, J = 7.24 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.4, 78.0, 67.0, 52.2, 49.4, 31.1, 21.9, 19.2, 18.2, 13.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H21NO: 196.1701; found: 196.1703.

4-(non-3-yn-2-yl) morpholine (5e)

Yield: 0.401 g (96%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2930, 2853, 2822, 1458, 1376, 1324, 1252, 1190, 1123, 1071, 1045, 1004, 947, 916, 859, 771 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.79–3.70 (m, 4H), 3.44–3.39 (m, 1H), 2.68–2.63 (m, 2H), 2.51–2.46 (m, 2H), 2.23–2.18 (m, 2H), 1.53–1.37 (m, 5H), 1.34–1.26 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.5, 78.1, 67.0, 52.2, 49.4, 31.0, 28.7, 22.1, 19.2, 18.5, 13.9; HRMS (ESI-TOF) m/z: [M + H+] calcd for C13H23NO: 210.1858; found: 210.1859.

4-(dec-3-yn-2-yl) morpholine (5f)

Yield: 0.428 g (96%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 2822, 1458, 1376, 1324, 1252, 1185, 1112, 1071, 1045, 999, 952, 916, 864 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.79–3.71 (m, 4H), 3.45–3.40 (m, 1H), 2.69–2.65 (m, 2H), 2.52–2.48 (m, 2H), 2.206 (dt, J = 7.0 Hz, 2.5 Hz, 2H), 1.54–1.48 (m, 2H), 1.42–1.36 (m, 2H), 1.32–1.30 (m, 5H), 1.28–1.26 (m, 2H), 0.90 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.5, 78.1, 67.0, 52.2, 49.4, 31.3, 28.9, 28.5, 22.5, 19.2, 18.6, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H25NO: 224.2014; found: 224.2016.

4-(undec-3-yn-2-yl) morpholine (5g)

Yield: 0.331 g (70%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 2817, 1448, 1376, 1324, 1252, 1190, 1117, 1076, 1045, 1009, 947, 921, 864 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.78–3.70 (m, 4H), 3.44–3.38 (m, 1H), 2.68–2.63 (m, 2H), 2.51–2.46 (m, 2H), 2.201 (dt, J = 7.2 Hz, 2.0 Hz, 2H), 1.54–1.47 (m, 2H), 1.40–1.36 (m, 2H), 1.32–1.28 (m, 9H), 0.89 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.5, 78.1, 67.0, 52.2, 49.4, 31.7, 29.0, 28.8, 28.7, 22.5, 19.2, 18.6, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H27NO: m/z 238.2171; found: 238.2170.

4-(dodec-3-yn-2-yl) morpholine (5h)

Yield: 0.381 g (76%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2930, 2843, 1458, 1371, 1324, 1257, 1179, 1123, 1071, 1045, 957, 911, 864 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.80–3.70 (m, 4H), 3.45–3.39 (m, 1H), 2.69–2.64 (m, 2H), 2.52–2.47 (m, 2H), 2.201 (dt, J = 7.2 Hz, 2.0 Hz, 2H), 1.54–1.47 (m, 2H), 1.40–1.36 (m, 2H), 1.32–1.28 (m, 11H), 0.88 (t, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.6, 78.0, 67.0, 52.2, 49.3, 31.8, 29.2, 29.1. 29.0, 28.8, 22.6, 19.2, 18.6, 14.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H29NO: 252.2327; found: 252.2328.

4-(tetradec-3-yn-2-yl) morpholine (5i)

Yield: 0.412 g (74%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2925, 2853, 1458, 1376, 1319, 1252, 1185, 1117, 1076, 1045, 999, 957, 911, 849 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.80–3.71 (m, 4H), 3.45–3.40 (m, 1H), 2.70–2.65 (m, 2H), 2.53–2.48 (m, 2H), 2.23–2.19 (m, 2H), 1.55–1.48 (m, 2H), 1.39 (s, 2H), 1.33–1.29 (m, 15H), 0.90–0.88 (t, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 85.5, 78.1, 67.1, 52.2, 49.4, 31.9, 29.6, 29.5, 29.3, 29.1, 29.0, 28.8, 22.6, 19.2, 18.6, 14.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H33NO: 280.2640; found: 280.2641.

7-morpholinooct-5-ynenitrile (5j)

Yield: 0.337 g (82%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2951, 2853, 2822, 2248, 1711, 1453, 1329, 1261, 1184, 1112, 1070, 1013, 967, 910, 858, 760 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.76–3.67 (m, 4H), 3.44–3.39 (m, 1H), 2.65–2.59 (m, 2H), 2.49–2.43 (m, 4H), 2.40–2.36 (m, 2H), 1.84 (qt, J = 6.96, 2H), 1.32–1.28 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 119.1, 82.5, 80.1, 66.8, 52.1, 49.3, 24.7, 19.0, 17.7, 16.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H18N2O: 207.1497; found: 207.1500.

1-(2-methyl-4-phenylbut-3-yn-2-yl)pyrrolidine (6a)

Yield: 0.298 g (70%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2961, 2868, 2806, 1686, 1587, 1484, 1438, 1360, 1257, 1179, 1117, 1071, 1019, 911, 844, 756, 694 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.45–7.42 (m, 2H), 7.31–7.29 (m, 3H), 2.84–2.82 (m, 4H) 1.85–1.84 (m, 4H), 1.53–1.51 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 127.7, 123.4, 91.4, 83.8, 54.2, 48.2, 29.7, 23.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H19N: 214.1595; found: 214.1594.

1-(2-methyloct-3-yn-2-yl)pyrrolidine (6b)

Yield: 0.281 g (73%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2926, 2871, 2802, 1706, 1649, 1597, 1458, 1379, 1354, 1324, 1225, 1181, 1126, 1071, 1007, 868, 792 cm–1; 1H NMR (400 MHz, CDCl3): δ 2.72–2.69 (m, 4H), 2.19 (t, J = 6.84 Hz, 2H), 1.80–1.76 (m, 4H), 1.52–1.40 (m, 4H), 1.37 (s, 6H), 0.91 (t, J = 7.16 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 83.6. 81.2. 53.8. 47.9. 31.3. 29.8. 23.7. 21.8. 18.2. 13.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H23N: 194.1908; found: 194.1909.

1-(2-methylnon-3-yn-2-yl)pyrrolidine (6c)

Yield: 0.190 g (46%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2930, 2874, 2806, 1639, 1556, 1453, 1381, 1221, 1185, 1117, 1019, 916, 859 cm–1; 1H NMR (400 MHz, CDCl3): δ 3.77–3.74 (m, 4H), 2.64–2.63 (m, 4H), 2.23–2.17 (m, 2H), 1.58–1.46 (m, 2H), 1.39–1.32 (m, 10H) 0.92–0.89 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 84.2, 81.3, 67.3, 54.1, 47.2, 31.0, 28.7, 27.6, 22.1, 18.5, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H25N: 208.2065; found: 208.2066.

1-(2-methyldec-3-yn-2-yl)pyrrolidine (6d)

Yield: 0.221 g (50%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2930, 2863, 2811, 1463, 1385, 1354, 1323, 1220, 1184, 1112, 1065, 1013 cm–1; 1H NMR (400 MHz, CDCl3): δ 2.70–2.67 (m, 4H), 2.18 (t, J = 6.8 Hz, 2H), 1.80–1.75 (m, 4H), 1.51–1.45 (m, 2H), 1.44–1.38 (m, 3H), 1.35 (s, 6H), 1.29–1.26 (m, 3H), 0.88 (t, J = 6.68 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 83.6, 81.3, 53.7, 47.9, 31.2, 29.9, 29.1, 28.4, 23.7, 22.5, 18.5, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H27N: 222.2221; found: 222.2222.

1-(2-methylundec-3-yn-2-yl)pyrrolidine (6e)

Yield: 0.263 g (56%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2954, 2925, 2854, 2806, 1454, 1383, 1354, 1321, 1221, 1183, 1116, 1073, 1011 cm–1; 1H NMR (400 MHz, CDCl3): δ 2.72–2.71 (m, 4H), 2.19 (t, J = 6.88 Hz, 2H), 1.80–1.77 (m, 4H), 1.52–1.45 (m, 2H), 1.42–1.39 (m, 2H), 1.37–1.36 (m, 6H), 1.33–1.28 (m, 6H), 0.90–0.87 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 83.6, 81.4, 53.7, 47.9, 31.7, 29.9, 29.1, 28.8, 28.7, 23.7, 22.5, 18.5, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H29N: 236.2378; found: 236.2375.

1-(2-methyldodec-3-yn-2-yl)pyrrolidine (6f)[28]

Yield: 0.383 g (77%); yellow liquid; Rf = 0.5 (silica gel, hexane/EtOAc 80:20); IR (neat): 2956, 2920, 2853, 2806, 1458, 1376, 1360, 1329, 1220, 1181, 1111, 1066, 1007 cm–1; 1H NMR (400 MHz, CDCl3): δ 2.71–2.68 (m, 4H), 2.18 (t, J = 6.9 Hz, 2H), 1.79–1.76 (m, 4H), 1.51–1.45 (m, 2H), 1.41–1.38 (m, 2H), 1.36 (s, 6H), 1.31–1.27 (m, 8H), 0.88 (t, J = 6.75 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 83.6, 81.4, 53.7, 47.9, 31.8, 29.9, 29.2, 29.1, 29.0, 28.7, 23.7, 22.6, 18.5, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H31N: 250.2535; found: 250.2536.

General Procedure for the Synthesis of 1-(1-benzyl-4-hydroxy-4-methylpiperidin-3-yl) Ethanone 13

In a 10 mL RB flask, CuCl (0.010 g, 0.1 mmol), benzylamine 12 (0.1 mL, 1.0 mmol), and methyl vinyl ketone 2a (0.16 mL, 2.0 mmol) were taken in 4 mL of toluene at 25 °C under N2 atmosphere, and the contents were stirred at 100 °C for 3 h. Toluene was removed, and water (5 mL) and DCM (15 mL) were added. The DCM layer was washed with saturated NaCl solution, dried with Na2SO4, and concentrated. The residue was chromatographed on silica gel (100–200 mesh) using hexane and ethylacetate (50:50) as eluent to isolate the product 13.

1-(1-benzyl-4-hydroxy-4-methylpiperidin-3-yl)ethanone 13

Yield: 0.210 g (85%); brown liquid; Rf = 0.3 (silica gel, hexane/EtOAc 50:50); IR (neat): 3375, 2927, 2821, 1695, 1569, 1494, 1453, 1360, 1238, 1185, 1150, 1075, 1011, 922, 802, 738, 699, 653, 617 cm–1; 1H NMR (400 MHz, CDCl3): δ 7.33 (s, 5H), 3.73–3.71 (m, 1H), 3.07–2.99 (m, 2H), 2.81–2.78 (m, 1H), 2.64–2.55 (m, 1H), 2.22 (s, 3H), 2.17–2.05 (m, 2H), 1.67–1.62 (m, 2H); 1.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 213.5, 134.9, 129.9, 128.5, 128.0, 68.0, 61.9, 55.3, 50.1, 48.2, 36.9, 31.6, 28.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H21NO2: 247.1572; found: 247.1577.