Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2019 Dec 2;4(25):21587–21595. doi: 10.1021/acsomega.9b03428

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

Bantu Udaykumar 1, Mariappan Periasamy 1,*
PMCID: PMC6921675  PMID: 31867555

Abstract

graphic file with name ao9b03428_0007.jpg

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 triflates5−7 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 1).14

Scheme 1. Overview of the Methods of Synthesis of Propagylamines.

Scheme 1

Open in a new tab

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 addition22 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 1).

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

graphic file with name ao9b03428_0003.jpg

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
Open in a new tab
a

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.

b

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 1). 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 1). Although ZnI2 gave the desired product 4a in 60% yield in 12 h at 100 °C (entry 7, Table 1), use of copper (I) chloride afforded the propargylamine 4a in 92% yield (entry 8, Table 1). The propargylamine 4a was also formed in similar yields using the CuBr and CuI under these reaction conditions (entries 9 and 10, Table 1).

Under these optimized conditions, various secondary amines were employed in this transformation, and the results are summarized in Table 2. 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 2). 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.

graphic file with name ao9b03428_0009.jpg

Open in a new tab
a

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.

b

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 3). Indeed, the corresponding propargylamine derivatives 5 are obtained in 70–98% yield (Table 3). The phenyl acetylene gave the desired propargylamine in 98% yield (5a, Table 3). 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 3). The reaction was also extended to aliphatic alkynes to access the corresponding propargylamines in 70–96% yield (5d–5i, Table 3). The 5-cyano-1-pentyne also afforded the corresponding propargylamine in 82% yield (5j, Table 3). 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 3).

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

graphic file with name ao9b03428_0006.jpg

Open in a new tab
a

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.

b

Isolated yield.

c

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 4.

Table 4. CuCl-Promoted Synthesis of Propargylamines 6 Using Pyrrolidine 1c, Mesityloxide 2c, and 1-Alkynesa,b.

graphic file with name ao9b03428_0004.jpg

Open in a new tab
a

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.

b

Isolated yield.

The CuCl-catalyzed formation of propargylamines 4a may be rationalized by the tentative mechanism involving intermediates outlined in Scheme 2. 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.

Scheme 2

Open in a new tab

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 3).

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

Scheme 3

Open in a new tab

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 4). Clearly, these transformations go through the C–C bond cleavage of the Michael adduct 7 as outlined in Scheme 2.

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

Scheme 4

Open in a new tab

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 5).

Scheme 5. Synthesis of 1-(1-Benzyl-4-hydroxy-4-methylpiperidin-3-yl) Ethanone 13 Using Benzylamine 12 Methyl Vinyl Ketone 1a with CuCl.

Scheme 5

Open in a new tab

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.

Acknowledgments

The authors are thankful to the DST-SERB (New Delhi) for a J.C. Bose National Fellowship (SR/S2/JCB-33/2005) and Green Chemistry (SB/S5/GC-01/2014) research grants and also to the CSIR, New Delhi, for a research grant (02/0176/14/EMR-II). The support of the UGC under UPE and CAS programs is also gratefully acknowledged. B.U. is thankful to the UGC (New Delhi) for a research fellowship.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03428.

  • 1H and 13C NMR spectra of propargylamines (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao9b03428_si_001.pdf (3.5MB, pdf)

References

  1. Nilsson B.; Vargas H. M.; Ringdahl B.; Hacksell U. Phenyl-Substituted Analogues of Oxotremorine as Muscarinic Antagonists. J. Med. Chem. 1992, 35, 285–294. 10.1021/jm00080a013. [DOI] [PubMed] [Google Scholar]
  2. Hattori K.; Miyata M.; Yamamoto H. Highly Selective and Operationally Simple Synthesis of Enantiomerically Pure β-Amino Esters via Double Stereodifferentiation. J. Am. Chem. Soc. 1993, 115, 1151–1152. 10.1021/ja00056a051. [DOI] [Google Scholar]
  3. Huffman M. A.; Yasuda N.; Decamp A. E.; Grabowski E. J. Lithium Alkoxides of Cinchona Alkaloids as Chiral Controllers for Enantioselective Acetylide Addition to Cyclic N-Acyl Ketimines. J. Org. Chem. 1995, 60, 1590–1594. 10.1021/jo00111a016. [DOI] [Google Scholar]
  4. Kauffman G. S.; Harris G. D.; Dorow R. L.; Stone B. R. P.; Parsons R. L.; Pesti J. A.; Magnus N. A.; Fortunak J. M.; Confalone P. N.; Nugent W. A. An Efficient Chiral Moderator Prepared from Inexpensive (+)-3-Carene: Synthesis of the HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor DPC 963. Org. Lett. 2000, 2, 3119–3121. 10.1021/ol006321x. [DOI] [PubMed] [Google Scholar]
  5. Kopka I. E.; Fataftah Z. A.; Rathke M. W. Preparation of a Series of Highly Hindered Secondary Amines, Including Bis(triethylcarbinyl)amine. J. Org. Chem. 1980, 45, 4616–4622. 10.1021/jo01311a014. [DOI] [Google Scholar]
  6. Czernecki S.; Valery J. M. A Stereocontrolled Synthesis of a Lincosamine Precursor. J. Carbohydr. Chem. 1990, 9, 767–770. 10.1080/07328309008543871. [DOI] [Google Scholar]
  7. Imada Y.; Yuassa M.; Nakamura S. I.; Murahashi S. I. Copper(I)-Catalyzed Amination of Propargyl Esters. Selective Synthesis of Propargylamines, l-Alken-3-ylamines, and (Z)-Allylamines. J. Org. Chem. 1994, 59, 2282–2284. 10.1021/jo00088a004. [DOI] [Google Scholar]
  8. a Enders D.; Reinhold U. Asymmetric Synthesis of Amines by Nucleophilic 1,2-Addition of Organometallic Reagents to the CN-double bond. Tetrahedron: Asymmetry 1997, 8, 1895–1946. 10.1016/S0957-4166(97)00208-5. [DOI] [Google Scholar]; b Bloch R. Additions of Organometallic Reagents to C=N Bonds: Reactivity and Selectivity. Chem. Rev. 1998, 98, 1407–1438. 10.1021/cr940474e. [DOI] [PubMed] [Google Scholar]
  9. a Murai T.; Mutoh Y.; Ohta Y.; Murakami M. Synthesis of Tertiary Propargylamines by Sequential Reactions of in Situ Generated Thioiminium Salts with Organolithium and -magnesium Reagents. J. Am. Chem. Soc. 2004, 126, 5968–5969. 10.1021/ja048627v. [DOI] [PubMed] [Google Scholar]; b Ryan C. W.; Ainsworth C. The Synthesis and Anticholinergic Activity of Ester and Amide-Derivatives of 2-Substituted Piperidines. J. Org. Chem. 1961, 26, 1547–1550. 10.1021/jo01064a058. [DOI] [Google Scholar]; c Jung M. E.; Huang A. Use of Optically Active Cyclic N,N-Dialkyl Aminals in Asymmetric Induction. Org. Lett. 2000, 2, 2659–2661. 10.1021/ol0001517. [DOI] [PubMed] [Google Scholar]; d Tubéry F.; Grierson D. S.; Husson H.-P. Simple 4-Acetoxy-5,6-Dihydropyridinium Salts: New Synthons for the Preparation of Functionalized Piperidine Systems. Tetrahedron Lett. 1987, 28, 6457–6460. 10.1016/S0040-4039(00)96887-4. [DOI] [Google Scholar]
  10. Dyatkin A. B.; Rivero R. A. The Solid Phase Synthesis of Complex Propargylamines Using the Combination of Sonogashira and Mannich Reactions. Tetrahedron Lett. 1998, 39, 3647–3650. 10.1016/S0040-4039(98)00639-X. [DOI] [Google Scholar]
  11. Koradin C.; Polborn K.; Knochel P. Enantioselective Synthesis of Propargylamines by Copper-Catalyzed Addition of Alkynes to Enamines. Angew. Chem., Int. Ed. 2002, 41, 2535–2538. . [DOI] [PubMed] [Google Scholar]
  12. Pereshivko O. P.; Peshkov V. A.; Van der Eycken E. V. Unprecedented Cu(I)-Catalyzed Microwave-Assisted Three-Component Coupling of a Ketone, an Alkyne, and a Primary Amine. Org. Lett. 2010, 12, 2638–2641. 10.1021/ol1008312. [DOI] [PubMed] [Google Scholar]
  13. Pierce C. J.; Nguyen M.; Larsen C. H. Copper/Titanium Catalysis Forms Fully Substituted Carbon Centers from the Direct Coupling of Acyclic Ketones, Amines, and Alkynes. Angew. Chem. 2012, 124, 12455–12458. 10.1002/ange.201206674. [DOI] [PubMed] [Google Scholar]
  14. Pierce C. J.; Yoo H.; Larsen C. H. A Unique Route to Tetrasubstituted Propargylic Amines by Catalytic Markovnikov Hydroamination–Alkynylation. Adv. Synth. Catal. 2013, 355, 3586–3590. 10.1002/adsc.201300937. [DOI] [Google Scholar]
  15. a Wei C.; Li C.-J. A Highly Efficient Three-Component Coupling of Aldehyde, Alkyne, and Amines via C-H Activation Catalyzed by Gold in Water. J. Am. Chem. Soc. 2003, 125, 9584–9585. 10.1021/ja0359299. [DOI] [PubMed] [Google Scholar]; b Lo V. K.-R.; Liu Y.; Wong M.-K.; Che C. M. Gold(III) Salen Complex-Catalyzed Synthesis of Propargylamines via a Three-Component Coupling Reaction. Org. Lett. 2006, 8, 1529–1532. 10.1021/ol0528641. [DOI] [PubMed] [Google Scholar]; c Albaladejo M. J.; Alonso F.; Moglie Y.; Yus M. Three-Component Coupling of Aldehydes, Amines, and Alkynes Catalyzed by Oxidized Copper Nanoparticles on Titania. Eur. J. Org. Chem. 2012, 2012, 3093–3104. 10.1002/ejoc.201200090. [DOI] [Google Scholar]; d Yoo W.-J.; Zhao L.; Li C. J. The A3-Coupling (Aldehyde-Alkyne-Amine) reaction: A Versatile Method for the Preparation of Propargylamines. Aldrichim. Acta 2011, 44, 43–51. [Google Scholar]
  16. Blay G.; Monleon A.; Pedro J. R. Recent Developments in Asymmetric Alkynylation of Imines. Curr. Org. Chem. 2009, 13, 1498–1539. 10.2174/138527209789177734. [DOI] [Google Scholar]
  17. a Cheng M.; Zhang Q.; Hu X.-Y.; Li B.-G.; Ji J.-X.; Chan A. S. C. Gold-Catalyzed Direct Intermolecular Coupling of Ketones,Secondary Amines, and Alkynes: A Facile and Versatile Access to Propargylic Amines Containing a Quaternary Carbon Center. Adv. Synth. Catal. 2011, 353, 1274–1278. 10.1002/adsc.201000914. [DOI] [Google Scholar]; b Pierce C. J.; Larsen C. H. Copper(II) Catalysis Provides Cyclohexanone-Derived Propargylamines Free of Solvent or Excess Starting Materials: Sole By-Product is Water. Green Chem. 2012, 14, 2672–2676. 10.1039/c2gc35713e. [DOI] [Google Scholar]
  18. Park K.; Heo Y.; Lee S. Metal-Free Decarboxylative Three-Component Coupling Reaction for the Synthesis of Propargylamines. Org. Lett. 2013, 15, 3322–3325. 10.1021/ol401358t. [DOI] [PubMed] [Google Scholar]
  19. Peshkov V. A.; Pereshivko O. P.; Van der Eycken E. V. A walk around the A3-coupling. Chem. Soc. Rev. 2012, 41, 3790–3807. 10.1039/c2cs15356d. [DOI] [PubMed] [Google Scholar]
  20. a Periasamy M.; Sanjeevakumar N.; Dalai M.; Gurubrahamam R.; Reddy P. O. Highly Enantioselective Synthesis of Chiral Allenes by Sequential Creation of Stereogenic Center and Chirality Transfer in a Single Pot Operation. Org. Lett. 2012, 14, 2932–2935. 10.1021/ol300717e. [DOI] [PubMed] [Google Scholar]; b Periasamy M.; Reddy P. O.; Sanjeevakumar N. Enantioselective Synthesis of Both Enantiomers of Chiral Allenes Using Chiral N-Methylcamphanyl Piperazine Templates. Eur. J. Org. Chem. 2013, 2013, 3866–3875. 10.1002/ejoc.201300231. [DOI] [Google Scholar]; c Gurubrahamam R.; Periasamy M. Copper(I) Halide Promoted Diastereoselective Synthesis of Chiral Propargylamines and Chiral Allenes using 2-Dialkylaminomethylpyrrolidine, Aldehydes, and 1-Alkynes. J. Org. Chem. 2013, 78, 1463–1470. 10.1021/jo302534f. [DOI] [PubMed] [Google Scholar]; d Periasamy M.; Reddy P. O.; Edukondalu A.; Dalai M.; Alakonda L. M.; Udaykumar B. Zinc Salt Promoted Diastereoselective Synthesis of Chiral Propargylamines Using Chiral Piperazines and Their Enantioselective Conversion into Chiral Allenes. Eur. J. Org. Chem. 2014, 2014, 6067–6076. 10.1002/ejoc.201402766. [DOI] [Google Scholar]; e Periasamy M.; Reddy P. O.; Sanjeevakumar N. Convenient Methods for the Synthesis of Highly Functionalized and Naturally Occurring Chiral Allenes. Tetrahedron: Asymmetry 2014, 25, 1634–1646. 10.1016/j.tetasy.2014.11.002. [DOI] [Google Scholar]
  21. a Periasamy M.; Reddy P. O.; Satyanarayana I.; Mohan L.; Edukondalu A. Diastereoselective Synthesis of Tetrasubstituted Propargylamines via Hydroamination and Metalation of 1-Alkynes and Their Enantioselective Conversion to Trisubstituted Chiral Allenes. J. Org. Chem. 2016, 81, 987–999. 10.1021/acs.joc.5b02554. [DOI] [PubMed] [Google Scholar]; b Periasamy M.; Mohan L.; Satyanarayana I.; Reddy P. O. Enantioselective Synthesis of β-Allenoates via Phosphine-Catalyze and ZnI2-Promoted Preparation of Oxazolidines and Propargylamines Using Chiral Amines, 1-Alkynes, and Propiolates. J. Org. Chem. 2018, 83, 267–274. 10.1021/acs.joc.7b02632. [DOI] [PubMed] [Google Scholar]
  22. a Jung M. E. InComprehensive Organic Synthesis; Trost B. M., Fleming I., Eds.; Pergamon: Oxford, 1991, Vol. 4; pp 1–67. [Google Scholar]; b Kumar R.; Chaudhary P.; Surendra N.; Ramesh C. Polyethylene Glycol as a Non-Ionic Liquid Solvent for Michael Addition Reaction of Amines to Conjugated Alkenes. Green Chem. 2006, 8, 356–358. 10.1039/b517397c. [DOI] [Google Scholar]
  23. a Crabbé P.; Fillion H.; Andre D.; Luche J.-L. Efficient Homologation of Acetylenes to Allenes. J. Chem. Soc., Chem. Commun. 1979, 19, 859–860. 10.1039/C39790000859. [DOI] [Google Scholar]; b Kuang J.; Ma S. An Efficient Synthesis of Terminal Allenes from Terminal 1-Alkynes. J. Org. Chem. 2009, 74, 1763–1765. 10.1021/jo802391x. [DOI] [PubMed] [Google Scholar]
  24. Lauder K.; Toscani A.; Scalacci N.; Castagnolo D. Synthesis and Reactivity of Propargylamines in Organic Chemistry. Chem. Rev. 2017, 117, 14091–14200. 10.1021/acs.chemrev.7b00343. [DOI] [PubMed] [Google Scholar]
  25. Chaudhary P.; Kumar R.; Verma A. K.; Singh D.; Yadav V.; Chhillar A. K.; Sharma G. L.; Chandra R. Synthesis and Antimicrobial Activity of N-alkyl and N-aryl Piperazine Derivatives. Bioorg. Med. Chem. 2006, 14, 1819–1826. 10.1016/j.bmc.2005.10.032. [DOI] [PubMed] [Google Scholar]
  26. Shaibakova M. G.; Titova I. G.; Makhmudiyarov G. A.; Ibragimov A. G.; Dzhemilev U. M. Synthesis of 2,3-Acetylenic Amines by Aminomethylation of Acetylenes with Geminal Diamines. Russ. J. Org. Chem. 2010, 46, 43–48. 10.1134/S1070428010010021. [DOI] [Google Scholar]
  27. Hilt G.; Korn J. T.; Smolko K. I. A Short Three-Component Synthesis of Tricyclic Compounds. Synlett 2003, 2, 0241–0243. 10.1055/s-2003-36795. [DOI] [Google Scholar]
  28. Kuang J.; Tanga X.; Ma S. Zinc Diiodide-promoted synthesis of trisubstituted allenes from propargylic amines. Org. Chem. Front. 2015, 2, 470–475. 10.1039/C5QO00047E. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao9b03428_si_001.pdf (3.5MB, pdf)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES