Article | Published:

Unexpected E-stereoselective reductive A3-coupling reaction of terminal alkynes with aldehydes and amines

Nature Communications volume 5, Article number: 3884 (2014) | Download Citation

Abstract

The transition-metal catalysed three-component coupling of an alkyne, an aldehyde and an amine has been became a widely used method for preparing propargylic amines. Here, we report an unexpected copper(I)-catalysed E-stereoselective reduction of propargylic amines in situ formed from readily available terminal alkynes, aldehydes and 3-pyrroline or isoindoline via [1,5]-hydride transfer, affording E-allylic amines. Through mechanistic studies, it is believed that the unsaturated cyclic dialkylamine is acting as hydrogen donor.

  • Compound C23H29D4N

    d4-2-(1-Cyclohexylnon-2-yn-1-yl)isoindoline

  • Compound C23H33N

    2-(1-Cyclohexylnon-2-yn-1-yl)isoindoline

  • Compound C20H23D4NO

    d4-5-Cyclohexyl-5-(isoindolin-2-yl)-2-methylpent-3-yn-2-ol

  • Compound C20H27NO

    5-Cyclohexyl-5-(isoindolin-2-yl)-2-methylpent-3-yn-2-ol

  • Compound C19H29N

    (E)-1-(1,3-Dicyclohexylallyl)-1H-pyrrole

  • Compound C16H25N

    (E)-1-(1-Cyclohexyl-4-methylpent-2-en-1-yl)-1H-pyrrole

  • Compound C21H27N

    (E)-1-(1-Cyclohexyl-5-phenylpent-2-en-1-yl)-1H-pyrrole

  • Compound C18H29N

    (E)-1-(1-Cyclohexyl-6-methylhept-2-en-1-yl)-1H-pyrrole

  • Compound C19H31N

    (E)-1-(1-Cyclohexylnon-2-en-1-yl)-1H-pyrrole

  • Compound C15H23NO

    (2S,5R,E)-5-Cyclohexyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C15H23NO

    (2S,5S,E)-5-Cyclohexyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C15H23NO

    (2R,5R,E)-5-Cyclohexyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C15H23NO

    (2R,5S,E)-5-Cyclohexyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C16H25NO

    (S,E)-5-Cyclohexyl-2-methyl-5-(1H-pyrrolyl)pent-3-en-2-ol

  • Compound C15H23NO

    (E)-1-(1-Cyclohexyl-4-methoxybut-2-en-1-yl)-1H-pyrrole

  • Compound C15H23NO

    1-(1-Cyclohexyl-4-methoxybut-2-yn-1-yl)-2,5-dihydro-1H-pyrrole

  • Compound C20H34N2

    1-(5-((2,5-Dihydro-1H-pyrrol-1-yl)methyl)undecan-6-yl)-1H-pyrrole

  • Compound C14H21NO

    (E)-4-Cyclohexyl-4-(1H-pyrrol-1-yl)but-2-en-1-ol

  • Compound C21H27NO

    (E)-5-Cyclohexyl-1-phenyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C20H31NO

    (E)-1,4-Dicyclohexyl-4-(1H-pyrrol-1-yl)but-2-en-1-ol

  • Compound C20H25NO

    (E)-4-Cyclohexyl-1-phenyl-4-(1H-pyrrol-1-yl)but-2-en-1-ol

  • Compound C15H23NO

    (E)-5-Cyclohexyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C17H27NO

    (E)-6-Cyclohexyl-3-methyl-6-(1H-pyrrol-1-yl)hex-4-en-3-ol

  • Compound C16H25NO

    (E)-1-(3-(1H-Pyrrol-1-yl)oct-1-en-1-yl)cyclobutanol

  • Compound C17H27NO

    (E)-1-(3-(1H-Pyrrol-1-yl)oct-1-en-1-yl)cyclopentanol

  • Compound C16H19NO

    (E)-2-Methyl-7-phenyl-5-(1H-pyrrol-1-yl)hept-3-en-2-ol

  • Compound C18H23NO

    (E)-2-Methyl-7-phenyl-5-(1H-pyrrol-1-yl)hept-3-en-2-ol

  • Compound C15H25NO

    (E)-2-Methyl-5-(1H-pyrrol-1-yl)dec-3-en-2-ol

  • Compound C13H21NO

    (E)-2,6-Dimethyl-5-(1H-pyrrol-1-yl)hept-3-en-2-ol

  • Compound C16H25NO

    (E)-5-Cyclohexyl-2-methyl-5-(1H-pyrrol-1-yl)pent-3-en-2-ol

  • Compound C25H32N2O3

    (3aR,4S,9R,9aS)-10-((E)-1-Cyclohexyl-4-hydroxy-4-methylpent-2-en-1-yl)-2-methyl-3a,4,9,9a-tetrahydro-1H-4,9-epiminobenzo[f]isoindole-1,3(2H)-dione

  • Compound C25H28D4N2O3

    d4-(3aR,4S,9R,9aS)-10-((E)-1-Cyclohexyl-4-hydroxy-4-methylpent-2-en-1-yl)-2-methyl-3a,4,9,9a-tetrahydro-1H-4,9-epiminobenzo[f]isoindole-1,3(2H)-dione

  • Compound C28H38N2O2

    (3aR,4S,9R,9aS)-10-((E)-1-Cyclohexylnon-2-en-1-yl)-2-methyl-3a,4,9,9a-tetrahydro-1H-4,9-epiminobenzo[f]isoindole-1,3(2H)-dione

  • Compound C28H34D4N2O2

    d4-(3aR,4S,9R,9aS)-10-((E)-1-Cyclohexylnon-2-en-1-yl)-2-methyl-3a,4,9,9a-tetrahydro-1H-4,9-epiminobenzo[f]isoindole-1,3(2H)-dione

  • Compound C28H37DN2O2

    d1-(3aR,4S,9R,9aS)-10-((E)-1-Cyclohexylnon-2-en-1-yl)-2-methyl-3a,4,9,9a-tetrahydro-1H-4,9-epiminobenzo[f]isoindole-1,3(2H)-dione

Introduction

Three-component coupling of an alkyne, an aldehyde and an amine (A3-coupling) has been well recognized as a powerful method for the synthesis of propargylic amines (Fig. 1a) (refs 1, 2, 3, 4). During the course of our efforts directed toward the synthesis of functionalized propargylic amines and allenes5,6, we observed unexpectedly that when treating 2-methybut-3-yn-2-ol 1a with cyclohexanaldehyde 2a and 3-pyrroline in the presence of copper(I) bromide, besides the normal propargylic amine 3aa, the N-allyl pyrrole 4aa was unexpectedly obtained in 42% NMR yield with a complete E-stereoselectivity (Table 1, Entry 1).

Figure 1: Unexpected observation in A3-coupling reactions.
Figure 1

(a) A3-coupling for the synthesis of propargylic amines. (b) A3-coupling for the synthesis of allylic amines.

Table 1: Optimization of the reaction conditions for 4aa*.

Considering the fact that high E-stereoselective semireduction of a triple bond is an important goal of contemporary organic chemistry7,8,9,10,11,12,13,14, herein, we wish to report the development of such a highly selective copper(I)-catalysed tandem three-component coupling-semireduction reaction of commercially readily available terminal alkynes, aldehydes and 3-pyrroline or isoindoline affording N-allyl amines with an E-C=C bond (Fig. 1b).

Results

Optimization of the reaction conditions for 4aa

On the basis of these initial observations, we started to work on developing reaction conditions for the exclusive formation of 4aa-type of E-allylic amines (Table 1). When the loading of CuBr was increased to 20 mol%, N-allyl pyrrole 4aa was obtained in 57% NMR yield after 24 h at 25 °C, while the normal A3-coupling product propargylic amine 3aa was also formed in 37% yield as determined by NMR analysis (Table 1, Entry 2). When the reaction was conducted at 40 °C, 4aa was formed in 84% NMR yield together with 9% NMR yield of the propargylic amine 3aa (Table 1, Entry 4). No better result was obtained when further increasing the loading of catalyst at a higher temperature (Table 1, Entry 5). Finally, the use of 1.2 equiv of 3-pyrroline provided 4aa as the only product with a higher yield (Table 1, Entry 6), which has been defined as the standard reaction conditions for further studies.

Substrate scope

We next explored the scope of this three-component reaction with representative examples of aldehydes and propargylic alcohols (Table 2). The reaction is quite general: both aliphatic and aromatic aldehydes may all be used with good yields; furthermore, the reaction is not limited to tertiary propargylic alcohols, primary and secondary propargylic alcohols are also good partners for this transformation. In some cases, the reaction requires the addition of CuCl (20 mol%) to ensure complete transformation (Table 2, Entries 3, 8 and 12). It is interesting to note that when linear aliphatic aldehydes such as n-hexaldehyde 2c was tested under the standard conditions, the reaction afforded the corresponding product in a low yield with the tentatively assigned 1-(5-((2,5-dihydro-1H-pyrrol-1-yl)methyl)undecan-6-yl)-1H-pyrrole 5c being formed as a byproduct (Table 2, Entry 4), which could also be prepared by treating aldehyde 2c with 3-pyrroline in the presence of CuBr in toluene at 40 °C in 82% NMR yield and 7.2/1 dr value. The similar byproduct was also observed using aldehyde 2d. Although side product could not be avoided here, reaction by increasing the loading of aldehyde and 3-pyrroline to 2.0 equivalents can also furnish the desired products in high yield (Table 2, Entries 5, 6, 9 and 10).

Table 2: Substrate scope*.

Control experiments

In order to unveil the role of the hydroxy group, control experiments were conducted. The results in Fig. 2 show a dramatic decrease of reactivity when the hydroxy group was protected as the methyl ether (with 3-methoxyprop-1-yne 1o). Here, the possible coordination of the hydroxy oxygen may be helping by its coordination with Cu (Fig. 2).

Figure 2: Control experiments.
Figure 2

(1) The reaction of 1o with 2a and 3-pyrroline gave a mixture of 3oa and 4oa under standard conditions. (2) The reaction of 1i with 2a and 3-pyrroline gave 4ia as the only product under standard conditions. equiv, equivalent.

Synthesis of chiral N-allyl pyrrole (S)-4aa

On the basis of Carreira’s and our previous studies15,16,17,18, an efficient synthesis of chiral propargylamine intermediates may be realized. Reaction of propargylic alcohol 1a, aldehyde 2a and 3-pyrroline with CuBr/(R,R)-N-Pinap in toluene afforded the corresponding chiral propargylic amine 4aa in 97% ee. Interestingly, it should be noted that the second-step reaction with CuBr was very slow (Table 3, Entries 1 and 2). Subsequent transformation of the crude propargylic amine 4aa was conducted in the same solvent in the presence of CuCl affording the chiral N-allyl pyrrole 4aa with 63% yield and 97% ee (Table 3, Entry 6).

Table 3: Initial efforts to synthesize chiral N-allyl pyrrole (S)-4aa*.

Synthesis of four diastereosiomers of 4ea

When the optically active propargylic alcohols with a central chirality such as (R)-1e and (S)-1e were used, all four isomers (S,R)-4ea, (R,R)-4ea, (S,S)-4ea and (R,S)-4ea were obtained successfully with this protocol using either (R,R)-N-Pinap or (R,S)-N-Pinap as the ligand (Equations 1–4, Fig. 3). The absolute configurations of N-allyl pyrrole were assigned based on our previous report5.

Figure 3: Synthesis of four diastereosiomers of 4ea.
Figure 3

When a chiral propargylic alcohol was used, we got four diastereosiomers of 4ea easily using either (R,R)-N-Pinap or (R,S)-N-Pinap as the ligand with this protocol. equiv, equivalent.

Reaction with normal terminal alkynes

However, the reaction could not be extended to normal terminal alkynes under this set of standard reaction conditions. After numerous trials and errors (Table 4), luckily, we observed that the reaction with alkyne 1j, cyclohexanaldehyde 2a and 3-pyrroline proceeds very efficiently in 1,4-dioxane with the combination of CuBr and CuCl affording N-allyl pyrrole 4ja in 89% yield. Some extra examples are shown in Fig. 4. Here, the reaction of 3-methoxyprop-1-yne 1o could also perform well under this set of conditions.

Table 4: Optimization of the reaction conditions with normal terminal akynes*.
Figure 4: Reaction with simple non-functionalized terminal alkynes.
Figure 4

The reaction of various simple terminal alkynes with 2a and 3-pyrroline gave N-allyl pyrrole 4 in good yields with the combination of CuBr and CuCl in dioxane. equiv, equivalent.

Reaction with isoindoline

Furthermore, isoindoline may also be used with N-allyl isoindole 6 being formed in 91% NMR yield, which was characterized by converting to 7 in 70% combined yield by a Diels–Alder reaction with N-methylmaliemide (Fig. 5).

Figure 5: A reaction with isoindoline.
Figure 5

The reaction of isoindoline with 1a and 2a afforded N-allyl isoindole 6, which was converted to 7 by Diels–Alder reaction with N-methylmaliemide. equiv, equivalent.

Discussion

To provide further insight into the reaction mechanism, deuterium-labeling experiments were performed as depicted in Fig. 6. Deuterium-labeled d4-3b (96% d-incorporation), prepared from o-phthalimide (Equation 1, Fig. 6), was treated with CuCl in toluene at 60 °C for 24 h giving d4-6 in 61% NMR yield. 1H NMR studies of the crude product d4-6 show that the d-incorporation at γ-position of N-allyl isoindole 6 was 92%, indicating an intramolecular 1,5-hydride transfer from the deuterated isoindole unit. The low D-incorporation at the β-position (17%) was obviously caused by the presence of the free OH group in the terminal propargylic alcohol 1a (Equation 2, Fig. 6). The reaction of deuterium-labeled d4-3c(96% d-incorporation) in the presence of CuBr and CuCl in dioxane at 90 °C gave d4-8 in poor NMR yield (32%) with only 17% D-incorporation at the β-position, suggesting the external proton source participated in the protodemetalation (Equation 3, Fig. 6). Compounds 3c and d4-3cwere then treated under similar conditions in the presence of 10.0 equivalents of CH3COOD, affording a 78% NMR yield of d1-8 with 52% D-incorporation at the β-position and a 60% NMR yield of d4-8 with 81% D-incorporation at the β-position (93% D-incorporation at the γ-position), respectively (Equations 4 and 5, Fig. 6), reconfirming that the β-position proton may be from the azacycle and the moisture in ambient environment. The low D-incorporation in the isoindole unit in d4-8 was caused by the facile H/D exchange as confirmed by the results shown in Equation 6.

Figure 6: Deuterium-labeling experiments.
Figure 6

(1) Preparation of deuterium-labeled propargylic amine d4-3b. (2) Reaction of d4-3b gave d4-6. (3) Reaction of d4-3cgiving d4-8. (d) Reaction of 3c employing AcOD giving d1-8. (e) Reaction of d4-3cemploying AcOD giving d4-8. (f) Reaction of 8 with D2O giving d2-8. equiv, equivalent.

On the basis of these results, we propose a mechanism for this unique unexpected A3-coupling-stereodefined reduction reaction as shown in Fig. 7. The reaction of CuBr with the propargylic alcohol generates the copper alkynylide species 10, which would then react with the iminium intermediate 11 formed in situ from the aldehyde and isoindoline to yield the corresponding propargylic amine-CuBr complex 12. This compound would afford, via an anti-1,5-hydride transfer process, the iminium intermediate 13, which would undergo protodemtalation with H+ or D+ readily to afford the N-allyl isoindole product d4-6 and regenerate the copper catalyst due to the aromatization of the azacycle (Fig. 7).

Figure 7: Proposed mechanism for CuBr-catalysed A3-coupling/reduction reaction.
Figure 7

The key step is the formation of propargylic amines followed by 1,5-Hydride transfer, aromatization and protodemtalation.

In conclusion, we have developed a copper(I)-catalysed three-component tandem reaction for the synthesis of N-allyl pyrroles. This novel reaction is simple and atom economic, affording N-allyl pyrroles with exclusive E-stereoselectivity under exceptionally mild conditions. Moreover, it could provide a highly attractive and convergent approach toward optically active N-allyl amines efficiently. Further investigation including the synthetic application is currently ongoing in our laboratory.

Methods

Materials

All reactions have been carried out in oven-dried Schlenk tubes. CuBr (98%) and CuCl were purchased from Acros and kept in glove box; (R,R)-N-Pinap (97%) and (R,S)-N-Pinap (97%) were purchased from Stream Chemicals and kept in glove box; 4 Å molecular sieves was purchased from Alfa Aesar and kept in glove box after activation (heated at 450 °C for 10 h in Muffle furnace, taken out after cooling to 200 °C and then kept in a glove box to allow to cool to room temperature). 3-Pyrroline (96%) was purchased from Alfa. Isoindoline (98%) was purchased from TCI. Aldehydes were distilled right before use. Toluene, 1,4-dioxane and tetrahydrofuran were dried over sodium wire with benzophenone as the indicator and distilled freshly before use. Other reagents were used as received without further treatment. All the temperatures are referred to the oil baths used.

General spectroscopic methods

1H NMR spectra were obtained at 20 °C using a Bruker spectrometer operating at 300 MHz. 13C NMR spectra were obtained at 20 °C using a Bruker spectrometer operating at 75 MHz. 1H NMR, 13C NMR and high-performance liquid chromatography spectra are supplied for all compounds: see Supplementary Figs 1–90. See Supplementary Methods for the characterization data of compounds not listed in this part.

Synthesis of compound 4aa

To a flame-dried Schlenk tube were added CuBr (98% purity, 29.5 mg, 0.2 mmol) and 4 Å molecular sieves (300.7 mg) inside a glove box. 1a (84.5 mg, 1.0 mmol)/toluene (1.0 ml), 2a (122.9 mg, 1.1 mmol)/toluene (1.0 ml) and 3-pyrroline (96% purity, 86.7 mg, 1.2 mmol)/toluene (1.0 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at 40 °C until completion of the reaction as monitored by thin-layer chromatography (TLC; 24 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (30 ml). After evaporation, the residue was purified by chromatography on silica gel to afford 4aa (219.4 mg, 88%; eluent: petroleum ether/ethyl acetate=20/1 to 10/1) as a liquid: 1H NMR (300 MHz, CDCl3) δ=6.66 (t, J=2.0 Hz, 2 H, from pyrrolyl), 6.14 (t, J=2.1 Hz, 2 H, from pyrrolyl), 5.85 (dd, J1=15.6 Hz, J2=8.1 Hz, 1 H, one proton from CH=CH), 5.68 (d, J=15.6 Hz, 1 H, one proton from CH=CH), 4.00 (t, J=8.6 Hz, 1 H, NCHC=C), 1.83–1.58 (m, 5 H, protons from Cy), 1.49 (s, 1 H, OH), 1.35–1.05 (m, 10 H, protons from Cy and OC(CH3)2), 0.99–0.75 (m, 2 H, protons from Cy); 13C NMR (75 MHz, CDCl3) δ=141.0, 125.3, 119.2, 107.4, 70.6, 67.3, 43.0, 30.3, 29.8, 29.6, 26.2, 25.93, 25.87; mass spectrometry (electrospray ionization) (MS (ESI)) m/z=248 (M+H+); infrared (IR; neat): v=3,331, 2,972, 2,930, 2,849, 1,488, 1,447, 1,403, 1,377, 1,359, 1,336, 1,320, 1,264, 1,225, 1,185, 1,143, 1,091, 1,064, 1,054 cm−1; high-resolution mass spectrometry (HRMS) calculated for C16H26NO [M+H+]: 248.2009, found: 248.2006.

Synthesis of compound (S)-4aa

To a flame-dried Schlenk tube were added CuBr (98% purity, 3.6 mg, 0.025 mmol) and (R,R)-N-Pinap (97% purity, 15.8 mg, 0.0275, mmol) inside a glove box. The Schlenk tube was taken out, toluene (1 ml) was then added under Ar atmosphere. The Schlenk tube was then stirred at room temperature for 1 h. 4 Å molecular sieves (150.1 mg), 1a (42.0 mg, 0.5 mmol)/toluene (0.5 ml), 2a (61.8 mg, 0.55 mmol)/toluene (0.5 ml) and 3-pyrroline (96% purity, 39.7 mg, 0.55 mmol)/toluene (0.5 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at room temperature until completion of the reaction as monitored by TLC (22 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (30 ml). After evaporation, the residue was filtered through a short column of silica gel (eluent: petroleum ether/ethyl acetate/Et3N=250/50/0.13 ml) to collect the crude propargylic amine (S)-3aa after evaporation, which was used in the next step directly. To another Schlenk tube was added CuCl (24.8 mg, 0.25 mmol) inside a glove box; the above crude product was then dissolved in toluene (5.0 ml) and transferred to the Schlenk tube under Ar atmosphere. The Schlenk tube was then stirred at 50 °C until completion of the reaction as monitored by TLC (14 h). The crude reaction mixture was filtrated through a short pad of silica gel eluted with ether (30 ml). After evaporation, the residue was purified by chromatography on silica gel to afford (S)-4aa (77.4 mg, 63%; 5% of (S)-3aa was observed by NMR analysis of crude product; eluent: petroleum ether/ethyl acetate=20/1 to 10/1) as a liquid: 97% ee (high-performance liquid chromatography conditions: Chiralcel AD-H column, hexane/i-PrOH=200/1, 1.0 ml min−1, λ=214 nm, tR(major)=41.5 min, tR(minor) =46.1 min); [α]D24=+62.8 (c=1.08, CHCl3); 1H NMR (300 MHz, CDCl3) δ=6.65 (t, J=2.2 Hz, 2 H, from pyrrolyl), 6.13 (t, J=2.1 Hz, 2 H, from pyrrolyl), 5.84 (dd, J1=15.6 Hz, J2=8.1 Hz, 1 H, one proton from CH=CH), 5.68 (d, J=15.6 Hz, 1 H, one proton from CH=CH), 4.00 (t, J=8.6 Hz, 1 H, NCHC=C), 1.82–1.58 (m, 6 H, protons from Cy and OH), 1.35–1.05 (m, 10 H, protons from Cy and OC(CH3)2), 0.97–0.74 (m, 2 H, protons from Cy); 13C NMR (75 MHz, CDCl3) δ=141.0, 125.3, 119.2, 107.4, 70.6, 67.3, 43.0, 30.3, 29.8, 29.6, 26.2, 25.94, 25.88; MS (ESI) m/z=248 (M+H+); IR (neat): v=3,379, 2,971, 2,923, 2,852, 1,487, 1,449, 1,405, 1,362, 1,318, 1,263, 1,230, 1,186, 1,150, 1,088, 1,065 cm−1; HRMS calculated for C16H26NO [M+H+]: 248.2009, found: 248.2010.

Synthesis of compound 4ja

To a flame-dried Schlenk tube were added CuBr (98% purity, 29.8 mg, 0.2 mmol), CuCl (19.8 mg, 0.2 mmol) and 4 Å molecular sieves (300.1 mg) inside a glove box. 1j (98% purity, 112.6 mg, 1.0 mmol)/dioxane (1.0 ml), 2a (124.0 mg, 1.1 mmol)/dioxane (1.0 ml) and 3-pyrroline (96% purity, 87.0 mg, 1.2 mmol)/dioxane (1.0 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at 40 °C until completion of the reaction as monitored by TLC analysis (24 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (30 ml). After evaporation, the residue was purified by chromatography on silica gel to afford 4ja (244.3 mg, 89%; eluent: petroleum ether/ethyl acetate=100/1) as a liquid: 1H NMR (300 MHz, CDCl3) δ=6.65 (t, J=2.2 Hz, 2 H, from pyrrolyl), 6.12 (t, J=2.1 Hz, 2 H, from pyrrolyl), 5.67–5.47 (m, 2 H, CH=CH), 3.97 (t, J=8.2 Hz, 1 H, NCHC=C), 2.06–1.95 (m, 2 H, C=CCH2), 1.83–1.58 (m, 5 H, protons from Cy), 1.41–1.05 (m, 12 H, protons from Cy and four CH2), 0.96–0.74 (m, 5 H, protons from Cy and CH3); 13C NMR (75 MHz, CDCl3) δ=134.1, 128.4, 119.0, 107.2, 67.8, 43.0, 32.3, 31.6, 30.2, 29.7, 29.0, 28.8, 26.3, 26.0, 25.9, 22.6, 14.0; MS (ESI) m/z=274 (M+H+); IR (neat): v=2,924, 2,853, 1,487, 1,449, 1,264, 1,089 cm−1; HRMS calculated for C19H32N [M+H+]: 274.2529, found: 274.2527.

Synthesis of compound 7

To a flame-dried Schlenk tube were added CuBr (98% purity, 29.8 mg, 0.2 mmol), CuCl (19.6 mg, 0.2 mmol) and 4 Å molecular sieves (300.0 mg) inside a glove box. 1a (83.8 mg, 1.0 mmol)/toluene (1.0 ml), 2a (123.7 mg, 1.1 mmol)/toluene (1.0 ml) and isoindoline (98% purity, 146.4 mg, 1.2 mmol)/toluene (1.0 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at 40 °C until completion of the reaction as monitored by TLC (24 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (30 ml). After evaporation, the crude product 6 was used in the next step without further treatment. The crude product 6 was dissolved in 5 ml of CH2Cl2 in a Schlenk tube. A solution of N-methylmaleimide (122.4 mg, 1.1 mmol) in 5 ml of CH2Cl2 was added via a syringe over 5 min at −10 °C. The Schlenk tube was then stirred at this temperature until completion of the reaction as monitored by TLC (3.5 h). After evaporation, the residue was purified by chromatography on silica gel to afford 7 (285.7 mg, 70%; eluent: petroleum ether/ethyl acetate=2/1) as a liquid: 1H NMR (300 MHz, CDCl3) δ=7.27–7.13 (m, 4 H, Ar–H), 5.51–5.44 (m, 2 H, CH=CH), 4.76 (d, J=4.5 Hz, 1 H, NCHAr), 4.69 (d, J=4.8 Hz, 1 H, NCHAr), 3.68–3.57 (m, 2 H, 2 × CHC=O), 2.35 (q, J=3.9 Hz, 1 H, NCH–C=C), 2.25 (s, 3 H, O=C–NCH3), 1.90–1.60 (m, 5 H, protons from Cy and OH), 1.48–0.75 (m, 13 H, protons from Cy and OC(CH3)2); 13C NMR (75 MHz, CDCl3) δ=176.1, 176.0, 141.7, 140.4, 139.8, 127.5, 127.4, 124.4, 122.8, 122.6, 70.5, 65.5, 64.7, 63.4, 47.3, 46.8, 40.4, 30.9, 29.9, 29.7, 26.6, 26.5, 26.4, 23.63, 23.61; MS (ESI) m/z=409 (M+H+); IR (neat): v=3,453, 2,924, 2,852, 1,774, 1,693, 1,433, 1,378, 1,286, 1,235, 1,206, 1,126, 1,064 cm−1; HRMS calculated for C25H33N2O3 [M+H+]: 409.2486, found: 409.2489.

Synthesis of compound d 4-3b

To a flame-dried 250 ml three-necked flask was added o-phthalimide (1.2941, g, 8.8 mmol), tetrahydrofuran (90 ml) and sodium tetradeuteridoborate (3.8513, g, 92.0 mmol) sequentially under Ar atmosphere. After being cooled to −10 °C, BF3·Et2O (12.7 ml, d=1.15 g ml−1, 102.6 mmol) was added slowly via a syringe. Once the addition was complete, the reaction mixture was heated at 70 °C with stirring. After 20 h, the reaction mixture was allowed to cool to 0 °C, quenched slowly with cold water (18 ml), diluted with ethyl acetate (140 ml) and adjusted pH value to 10 using an aqueous solution of NaOH (6.0 M). The organic layer was separated, washed with brine (4 × 70 ml) and dried over anhydrous Na2SO4. Solvent was removed in vacuo. The residual green solid was diluted with diethyl ether (50 ml) and acidified to pH 2 using an aqueous solution of HCl (6.0 M) with stirring at 0 °C. The aqueous layer was separated, adjusted pH value to 10 using an aqueous solution of NaOH (6.0 M) at 0 °C and extracted with ethyl acetate (100 ml). The organic layer was separated, washed with brine (3 × 70 ml), dried over anhydrous Na2SO4 and rotary evaporated to give the crude d4-isoindoline (431.2 mg) as an oil, which was used in the next step without further treatment. To a flame-dried Schlenk tube were added CuBr (98% purity, 103.1 mg, 0.7 mmol) and 4 Å molecular sieves (1.0002, g) inside a glove box. 1a (328.9 mg, 3.9 mmol)/toluene (2.0 ml), 2a (437.7 mg, 3.9 mmol)/toluene (2.0 ml) and the crude d4-isoindoline (431.2 mg, 3.5 mmol)/toluene (6.0 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at room temperature until completion of the reaction as monitored by TLC (13 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (50 ml). After evaporation, the residue was purified by chromatography on silica gel to afford d4-3b (831.3 mg, 79%) as a liquid: 1H NMR (300 MHz, CDCl3) δ=7.21–7.12 (m, 4 H, Ar–H), 3.31 (d, J=9.0 Hz, 1 H, CHC≡C), 2.41 (bs, 1 H, OH), 2.10–1.94 (m, 2 H, protons from Cy), 1.81–1.62 (m, 3 H, protons from Cy), 1.57–1.39 (m, 7 H, protons from Cy and OC(CH3)2), 1.35–0.94 (m, 5 H, protons from Cy); 1H NMR (300 MHz, CDCl3), the following signal is discernible for 3b: δ=3.97 (d, J=11.4 Hz, 0.17 H, two NCH2); 13C NMR (75 MHz, CDCl3) δ=139.7, 126.4, 122.2, 92.4, 79.2, 65.0, 60.1, 54.4 (quint, JC–D=20.7 Hz), 40.9, 31.7, 31.6, 30.3, 30.2, 26.5, 26.02, 25.97; MS (ESI) m/z=302 (M+H+); IR (neat): v=3,395, 2,979, 2,923, 2,851, 2,788, 1,464, 1,449, 1,362, 1,223, 1,165, 1,133, 1,069 cm−1; HRMS calculated for C20H24D4NO [M+H+]: 302.2416, found: 302.2418.

Synthesis of compound d 4-7

To a flame-dried Schlenk tube were added CuCl (77.0 mg, 0.77 mmol) inside a glove box. d4-3b (386.8 mg, 1.28 mmol)/toluene (5 ml) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at 60 °C until completion of the reaction as monitored by TLC (24 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with ether (30 ml). After evaporation, the crude product d4-6 was used in the next step without further treatment. 1H NMR analysis of the crude d4-6 showed occurrence of 92% and 17% deuteration at γ-position and β-position of N-allylisoindole 6. The crude product d4-6 was dissolved in 6 ml of CH2Cl2 in a Schlenk tube. A solution of N-methylmaleimide (97.8 mg, 0.88 mmol) in 4 ml of CH2Cl2 was added via a syringe over 5 min at −10 °C. The Schlenk tube was then stirred at this temperature until completion of the reaction as monitored by TLC (3.5 h). After evaporation, the residue was purified by chromatography on silica gel to afford d4-7 (262.5 mg, 50%; eluent: petroleum ether/ethyl acetate=2/1) as a liquid: 1H NMR (400 MHz, CDCl3) δ=7.27–7.13 (m, 4 H, Ar–H), 3.68–3.58 (m, 2 H, two CHC=O), 2.40–2.30 (m, 1 H, NCH–C=C), 2.25 (s, 3 H, NCH3), 2.05–1.60 (m, 5 H, protons from Cy and OH), 1.48–0.79 (m, 13 H, protons from Cy and OC(CH3)2); 1H NMR (400 MHz, CDCl3), the following signal is discernible for 7: δ=5.51–5.44 (m, 0.9 H, CH=CH), 4.76 (d, J=4.4 Hz, 0.72 H, NCHAr), 4.70 (d, J=4.0 Hz, 0.72 H, NCHAr); MS (ESI) m/z=413 (M+H+).

Synthesis of compound d 4-9

To a flame-dried Schlenk tube were added CuCl (29.5 mg, 0.3 mmol) and CuBr (98% purity, 43.7 mg, 0.3 mmol) inside a glove box. d4-3c(163.0 mg, 0.5 mmol)/dioxane (3 ml) and CH3COOD (288 μl, d=1.059 g ml−1, 5.0 mmol) were then added sequentially under Ar atmosphere. The Schlenk tube was then stirred at 90 °C until completion of the reaction as monitored by TLC (18 h). The crude reaction mixture was filtered through a short pad of silica gel eluted with toluene (30 ml). After evaporation, the crude product d4-8 was used in the next step without further treatment. 1H NMR analysis of the crude d4-8 showed occurrence of 93% and 81% deuteration at γ-position and β-position of N-allylisoindole 8. The crude product d4-8 was dissolved in 2.5 ml of CH2Cl2 in a Schlenk tube. A solution of N-methylmaleimide (37.0 mg, 0.33 mmol) in 2.5 ml of CH2Cl2 was added via a syringe over 5 min at −10 °C. The Schlenk tube was then stirred at this temperature until completion of the reaction as monitored by TLC (10 min). After evaporation, the residue was purified by chromatography on silica gel to afford d4-9 (126.0 mg, 58%; eluent: petroleum ether/ethyl acetate=10/1) as a liquid: 1H NMR (300 MHz, CDCl3) δ=7.26–7.11 (m, 4 H, Ar–H), 3.67–3.57 (m, 2 H, 2 × CHC=O), 2.35-2.27 (m, 1 H, NCH–C=C), 2.24 (s, 3 H, NCH3), 2.08–1.95 (m, 2 H, C=CCH2), 1.90–1.60 (m, 4 H, protons from Cy), 1.46–0.82 (m, 18 H, protons from Cy, 4 × CH2 and CH3); 1H NMR (300 MHz, CDCl3), the following signal is discernible for 9: δ=5.36–5.20 (m, 0.26 H, CH=CH), 4.79–4.69 (m, 1.39 H, 2 × NCHAr).

Additional information

How to cite this article: Fan, W. et al. Unexpected E-stereoselective reductive A3-coupling reaction of terminal alkynes with aldehydes and amines. Nat. Commun. 5:3884 doi: 10.1038/ncomms4884 (2014).

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Acknowledgements

Financial support from the National Natural Science Foundation of China (21232006) and the National Basic Research Program of China (2011CB808700) is greatly appreciated. We thank Mr Xinjun Tang in this group for reproducing the results of the preparation of 4ea in Table 2, (S,R)-4ea in Fig. 3 and 4la in Fig. 4.

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Affiliations

  1. Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

    • Wu Fan
    • , Weiming Yuan
    •  & Shengming Ma
  2. State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China

    • Shengming Ma

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Contributions

S.M. directed the research and W.F. performed the experiments, deuterium-labeled studies and data analysis. W.Y. performed some experiments. The paper was written by S.M. and W.F.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Shengming Ma.

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