Enantioselective Catalytic Asymmetric A3 Coupling with Phosphino

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Enantioselective Catalytic Asymmetric A3 Coupling with Phosphino-Imidazoline (PHIM) Ligands Balaji Vasantrao Rokade, and Patrick Jerome Guiry J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00728 • Publication Date (Web): 03 Apr 2019 Downloaded from http://pubs.acs.org on April 3, 2019

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The Journal of Organic Chemistry

Enantioselective Catalytic Asymmetric A3 Coupling with PhosphinoImidazoline (PHIM) Ligands Balaji V. Rokade, and Patrick J. Guiry* Centre for Synthesis and Chemical Biology (CSCB), Synthesis and Solid State Pharmaceutical Centre, School of Chemistry, University College Dublin (UCD), Belfield, Dublin 4, Ireland.

ABSTRACT A practical application of the UCD-PHIM ligand in the copper-catalyzed asymmetric A3 coupling is reported for aromatic, alkenylic and alkynylic aldehydes under mild reaction conditions, low catalytic loading and at ambient temperature. A broad range of aldehydes, secondary amines with a cheaper ethyne equivalent, 2-methyl-3-butyn2-ol, was explored and enantioselectivities of up to 99% ee were obtained. The importance of (i) axial chirality and central chirality, (ii) imidazoline moiety over oxazoline moiety and (iii) phosphine unit is investigated for A3 coupling by synthesizing and testing a series of related ligands to UCD-PHIM. INTRODUCTION Chiral amines are highly valuable motifs as they are present in naturally occurring, medicinally useful and synthetically important compounds (Figure 1).1 Chiral propargylic amines are particularly desirable due to the presence of the alkyne motif which is a synthetic handle for further modification. Generally, propargyl amines are synthesized using a multicomponent reaction between an aldehyde, an amine and an alkyne (A3 coupling). 2 The first enantioselective version of A3 coupling between an aldehyde, an alkyne and a secondary amine was developed by Knochel in 2003 using catalytic amounts of CuBr and (R)-Quinap, an axially chiral P,N-ligand developed by Brown.3 In this study, it was observed that aliphatic aldehydes are more suitable substrates compared to aromatic, alkenylic and alkynylic aldehydes which produced the corresponding propargylic amines in poor to moderate ee’s.3,4 Since then there have been many investigation to improve the generality of A3 coupling in terms of its scope and reaction rate.5-9 Most of the axially chiral P,N-ligands developed were investigated in A3 coupling.10 Pinap developed by Carreira was tested in A3 coupling with some success for aromatic aldehydes with cyclic secondary amines but it still suffers from a limited substrate scope.5,6 Stackphos developed by Aponick, provided the best results for aromatic and alkynylic aldehydes, typically poor substrates in A3 coupling, with ees of up to 95% and 96% respectively.7 ACS Paragon Plus Environment

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Figure 1. Medicinally active and synthetically important chiral amines. In continuation of our work on the development and application of axially chiral P,N-ligands in asymmetric catalysis,11 more recently, we and Aponick independently reported the new phosphino-imidazoline ligand (1a) (which we call UCD-PHIM) and its application in copper-catalysed asymmetric A3 coupling.7c,9 During our study, we observed that the various α-branched and non-branched aliphatic aldehydes were effective substrates yielding the corresponding propargylic amines in up to 98% ee. However, the reaction of benzaldehyde (2a) and dibenzylamine (3a) with trimethylsilylacetylene (4a) was very sluggish as it afforded the expected propargylic amine (5a) only in 23% yield with a moderate ee of 65% (Scheme 1). Scheme 1. Our earlier work.9

Herein, we report our investigations into improving the reaction yield and enantioselectivities for aromatic aldehydes with the appropriate secondary amine and alkyne with catalytic amount of CuBr and UCD-PHIM (1a). We also probe the importance of the different chiral elements (axial and central chirality) present in UCD-PHIM and closely related analogues. RESULTS AND DISCUSSION We commenced our study by changing the acetylene surrogate used from trimethylsilylacetylene (4a) to the cheaper 2-methyl-3-butyn-2-ol (4b),12 which resulted in the formation of propargylic amine (5a) in 49% yield with a disappointing ee of 32% (Scheme 2). In related work, Aponick reported the use of propargylic alcohols in an asymmetric alkynylation/cyclisation sequence to generate furan derivatives containing secondary chiral amines.7c Scheme 2. Reactivity of cheaper alkyne equivalent.a-c

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aReaction


conditions: 2a (0.2 mmol), 3a (0.2 mmol), 4b (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol), 4 Å

MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). b Yield after flash column chromatography. cThe ee value was determined by chiral HPLC using IB column.

We suspected that the formation of the iminium intermediate between benzaldehyde and the bulkier dibenzylamine might be the real cause for the low yielding reaction. Hence, we examined different amines and kept benzaldehyde (2a) and alkyne (4b) constant (Scheme 3). Use of less hindered benzylamine (3b) did not furnish the expected propargylic amine product. Similarly, aniline (3c) and tosyl amine (3d) were found to be unreactive. The reaction with diallylamine (3e) resulted in the formation of product 5c in a poor 30% yield but with an encouragingly improved ee of 89%. Finally, pyrrolidine (3f) provided the product 5d in an excellent yield of 94% and ee of 98%. Scheme 3. Reactivity of different types of amines in A3 coupling.a-c

a

Reaction conditions: 2a (0.2 mmol), 3b-3f (0.2 mmol), 4b (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol), 4

Å MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA column. dCorresponding aldimines were isolated.

Having optimized reaction conditions at hand for pyrrolidine (3f), we then extended the scope of the reaction to a focused library of aromatic aldehydes (Scheme 4). We found that an array of aromatic aldehydes with electronwithdrawing and electron-donating substituents at the ortho-, meta- and para- position could be efficiently converted into the corresponding propargylic amines (5e-5s) in a highly enantioselective manner. The presence of methyl (2b), fluoro (2c) and bromo (2d) substituents at the ortho-position of benzaldehyde were well tolerated, furnishing products 5e, 5f and 5g in excellent yields of 85%, 90% and 98% with ees of 98%, 99% and 92%, respectively. Furthermore, benzaldehyde possessing meta-chloro (2e), nitro (2f) and bromo (2g) substituents could be readily converted into the desired products 5h, 5i and 5j in moderate to excellent yields (57-94%) with high enantioselectivities (99, 94 and 99%, respectively). Finally, benzaldehyde possessing para-substituents such as methyl (2h), chloro (2i) and bromo (2j) resulted in the formation of the expected products 5k, 5l and 5m in excellent yields (79-97%) and enantioselectivities (98, 98 and 96%, respectively). Additionally, substrates such as 1napthaldehyde (2k), pentaflurobenzadehyde (2l) and ferrocenaldehyde (2m) smoothly underwent reaction to furnish the corresponding products 5n, 5o and 5p in good yields (53-94%) and ee (88-97%), respectively. Finally, heterocyclic aldehydes such as furan-2-carboxaldehyde (2n), thiophene-3-carboxaldehyde (2o) and 2ACS Paragon Plus Environment


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chloroquinoline-3-carboxaldehyde (2s) furnished the desired products 5q, 5r and 5s in moderate to good yields (70-81%) with high enantioselectivities (93-97%). The absolute configuration of 5s was established as (S) through single-crystal X-ray diffraction analysis. These results offer the best levels of enantioselectivities for a wide range of aromatic aldehydes as substrates in asymmetric A3 coupling. Scheme 4. Substrate scope for different aromatic aldehydes.a-c

aReaction

conditions: 2b-2o (0.2 mmol), 3f (0.2 mmol), 4b (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol), 4

Å MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA or IB columns.

Next, we then sought to examine the possibility of using alkenylic and alkynylic aldehydes (Scheme 5). Cinnamaldehyde (2p) under our optimized reaction conditions, can be smoothly converted into product 5t in 84% yield and an excellent ee of 98%. Interestingly, these are the best results for cinnamaldehyde as a substrate in A3 coupling.4a Similarly, alkynylic aldehyde, 3-(4-methoxyphenyl)propiolaldehyde (2q) furnished desired product 5u ACS Paragon Plus Environment

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in 87% yield and an ee of 93%. This result employing alkynylic aldehyde 2q in A3 coupling is at the high end of the range reported with Stackphos and related alkynylic aldehydes (82-96% ee).7b Scheme 5. Scope of alkenylic and alkynylic aldehydes.a-c

a

Reaction conditions: 2p or 2q (0.2 mmol), 3f (0.2 mmol), 4b (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol),

4 Å MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA or IB columns.

We then turned our attention to a substrate scope in which different cyclic amines were tested under our optimized reaction conditions (Scheme 6). We attempted the reaction of several cyclic amines (3g-3k), with pmethylbenzaldehyde (2n) and 2-methyl-3-butyn-2-ol (4b). It was satisfying to find that, various 4-7 membered cyclic amines such as azetidine (3g), piperidine (3h) and azepane (3i) reacted smoothly to furnish the corresponding propargylic amines 5v, 5w and 5x, respectively, in good to excellent yields (61-99%) with high ees (95-99%). Additionally, morpholine (3j) and tetrahydroisoquinoline (3k) could be reacted to provide the desired products 5y and 5z in excellent yields (99%) and high ees (88 and 95%, respectively). Scheme 6. Substrate scope with different amines.a-c



aReaction

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conditions: 2n (0.2 mmol), 3g-3k (0.2 mmol), 4b (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol), 4

Å MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA column.

Furthermore, changing the alkyne to the less bulky propargylic alcohol 4c, which to date has been investigated only once with maximum ee of 84%, provided product 5aa in 84% yield and an excellent ee of 98% (Scheme 7).6b Scheme 7. Reaction with propargylic alcohol.a-c

aReaction

conditions: 2a (0.2 mmol), 3f (0.2 mmol), 4c (0.21 mmol), CuBr (0.002 mmol), (S,S,Ra)-UCD-PHIM (1a) (0.0024 mmol), 4 Å

MS (100 mg) in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA column.

In order to determine the relative importance of different chiral elements of (S,S,Ra)-UCD-PHIM (1a) in A3 coupling, the closely related ligands 1b-1d were prepared and tested (Scheme 8).13,14,15 Ligand 1b, (S,S)-Diph-PHIM, which lacks the axial chirality element was prepared13 and when applied under optimized reaction conditions (with increased catalytic loading), furnished the desired product 5d in 75% yield with a surprising ee of 99%. It was interesting to know that, both ligands 1a and 1b (one with and without axial chirality) furnished the product 5d with very similar ee (98% and 99%, respectively) but the rate of the reaction was found to be sluggish with ligand 1b. Even with the increased amount of catalytic loading of ligand 1b (5 mol% to the existing 1 mol%), the reaction did not go to completion as some starting benzaldehyde was recovered after 24 h. Unlike our and Aponick’s previous reports, herein we did not observe the preferred formation of the opposite enantiomer when ligand 1b was used instead of ligand 1a when aliphatic aldehyde and dibenzylamine were two of the reactants used.7c,9 Next, we prepared ligand 1c, (S,S)-Diph-PHOX, in which the imidazoline unit of ligand 1b was replaced by an oxazoline unit.14 The copper complex of 1c furnished product 5d in a reduced yield of 32% and ee of 42%. This observation reflects the importance of the extra nitrogen in the imidazoline ring, which also aligns with the higher basicity/donar-ability of the imidazoline nitrogen over oxazoline nitrogen. Finally, ligand 1d, (S,S)-Diph-PyIM, in which the diphenylphosphine unit of ligand 1b has been replaced by a pyridinyl moiety, has also been prepared.15 However, the copper complexes of this ligand did not result in the formation of the desired product after 24 h. Scheme 8. Effect of related chiral ligands in A3 coupling.a-c


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aReaction


conditions: 2a (0.2 mmol), 3f (0.2 mmol), 4b (0.21 mmol), CuBr (0.010 mmol), ligand (1b-1d) (0.012 mmol), 4 Å MS (100 mg)

in toluene (0.2 M) for 24 h at rt (23 ˚C). bYield after flash column chromatography. cThe ee value was determined by chiral HPLC using IA column.

In order to demonstrate the synthetic utility of our chiral propargylic amine products, alkyne deprotection of chirally pure amine 5n (97% ee) was carried out with a catalytic amount of NaH (20 mol%) in toluene to furnish the corresponding terminal alkyne 6 in 89% yield and without erosion of the enantioselectivity (Scheme 9a).12a-c In addition, chirally pure A3 coupling product 5aa (98% ee) was reacted with a stoichiometric amount of silver nitrate to form allene 7 in a stereospecific manner (Scheme 9b).8,16 Scheme 9. Synthetic transformation of A3 coupling product. (a) Deprotection of alkynea,c,d

(b) Stereospecific allene synthesisb-d

aReaction

conditions: a(a) 5n (0.25 mmol), NaH (0.05 mmol) in toluene (0.25 M) for 5 h at 110 ˚C. b(b) 5aa (0.20 mmol), AgNO3 (0.20

mmol) in acetonitrile (0.05 M) for 48 h at 60 ˚C. cYield after flash column chromatography. dThe ee value was determined by chiral SFC using IA column.

In summary, we have presented a practical application of our UCD-PHIM ligand in the copper-catalyzed asymmetric A3 coupling for aromatic, alkenylic and alkynylic aldehydes under mild reaction conditions, low catalytic loading and at ambient temperature. This reaction possesses substantial substrate scope in terms of aldehydes and secondary amines used and the enantioselectivities obtained are excellent (up to 99% ee). Additionally, the cheaper ethyne equivalent, 2-methyl-3-butyn-2-ol, was utilized as an alkyne source. The importance of (i) axial chiraliACS Paragon Plus Environment


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ty and central chirality, (ii) imidazoline over oxazoline moiety and (iii) phosphine unit was studied by synthesizing and testing the related ligands to UCD-PHIM. EXPERIMENTAL SECTION 1.0 General information: Unless otherwise noted, all commercial reagents were used as received without further purification. Toluene and acetonitrile were dried using standard protocol.17 Standard Schlenk technique was employed to carry out all the reactions. Powdered activated 4 Å molecular sieves were purchased from Sigma-Aldrich and were stored in an oven at 120 °C. Thin-layer chromatography (TLC) was performed on aluminium-backed sheets purchased from Merck pre-coated with silica gel 60 F254. Flash column chromatography was performed on Davisil LC60A 4063micron silica gel. 1H and 13C NMR spectra were recorded on Varian-Inova spectrometers (400 and 500 MHz) using tetramethylsilane as an internal standard. HRMS were measured on a Micromass/Waters LCT mass spectrometer. Infrared spectra were recorded on a FT-IR spectrometer and are reported in terms wavenumbers (νmax) with units of reciprocal centimetres (cm-1). Supercritical fluid chromatography (SFC) was performed on a Waters Acquity UPC2 ® instrument with Chiralpak® IA columns. HPLC was performed using Chiralpack® IA and IB columns. Optical rotation measurements were recorded using a Schmidt-Haensch Unipol L2000 polarimeter at 589 nm and are quoted in units of deg dm-1 cm3 g-1 (concentration c is given in g/100 mL). Ligand 1b, 1c and 1d were prepared according to the literature procedure.9,13b,14,15 2.0 Experimental procedures 2.1 General procedure for enantioselective A3 coupling (Scheme 2-7)9 In a flame dry and nitrogen flushed 10 mL Schleck tube, equipped with a magnetic stirrer and a septum, CuBr (0.29 mg, 0.002 mmol, 1 mol%) and (S,S,Ra)-1a (1.71 mg, 0.0024 mmol, 1.2 mol%) were suspended in dry toluene (1 mL, 0.2 M) and solution stirred for 30 min. 4 Å MS (100 mg) were added, followed by the alkyne (0.21 mmol 4b or 4c), the aldehyde 2 (0.20 mmol) and the amine 3 (0.20 mmol). The reaction mixture was stirred at room temperature for 24 h. The crude reaction mixture was directly purified by flash column chromatography on silica gel by using cyclohexane/ethyl acetate/Et3N (90:10:05 to 50:50:0.5) to get 5. 2.2 General procedure for enantioselective A3 coupling (Scheme 8)9 In a flame dry and nitrogen flushed 10 mL Schleck tube, equipped with a magnetic stirrer and a septum, CuBr (1.43 mg, 0.01 mmol, 5 mol%) and chiral ligand 1b or 1c or 1d (0.012 mmol, 6 mol%) were suspended in dry toluene (1 mL, 0.2 M) and solution stirred for 30 min. 4 Å MS (100 mg) were added, followed by the alkyne (0.21 mmol 4b), the aldehyde 2a (0.20 mmol) and the amine 3f (0.20 mmol). The reaction mixture was stirred at room temperature for 24 h. The crude reaction mixture was then directly purified by flash column chromatography on silica gel by using cyclohexane/ethyl acetate/Et3N (90:10:05 to 50:50:0.5) to get chiral amine 5. 2.3 Procedure for deprotection of alkynes12 In a flame dry and nitrogen flushed 5 mL vial, equipped with a magnetic stirrer, alkyne 5n (73.35 mg, 0.25 mmol) in toluene (1 mL, 0.25 M) was added NaH (60% dispersion in mineral oil) (2.0 mg, 0.05 mmol). The reaction mixture was stirred at 110 C for 5 h. The reaction mixture was quenched with a drop of MeOH and then purified by flash column chromatography on silica gel to get terminal alkyne 6. ACS Paragon Plus Environment

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2.4 Procedure for synthesis of chiral allene8,16 In a flame dry and nitrogen flushed 10 mL Schleck tube, equipped with a magnetic stirrer and a septum, alkyne 5aa (43.05 mg, 0.20 mmol) and AgNO3 (33.97 mg, 0.20 mmol) were added followed by dry CH3CN (4 mL). The reaction mixture was stirred at 60 C for 48 h. The reaction mixture was passed through Celite and purified by flash column chromatography on silica gel to get allene 7. Note: The absolute configuration was assigned by comparing the sign of the optical rotation to that of compound 5s. 3. Characterization data (R)-5-(dibenzylamino)-2-methyl-5-phenylpent-3-yn-2-ol (5b): The title compound was prepared according to the general procedure 2.1 Colourless solid. Yield = 36.7 mg, 49%. Rf = 0.25 in 50% ethyl acetate/cyclohexane. [α]20D = +38.34 (C = 1, CHCl3). IR (neat, cm-1): 3374.2, 3084.9, 2979.1, 2807.8, 1602.4, 1452.3, 1362.7, 1117.8, 912.0. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (dt, J = 8.3, 1.2 Hz, 2H), 7.39 (d, J = 7.6 Hz, 4H), 7.35 – 7.27 (m, 8H), 7.27 – 7.17 (m, 3H), 4.72 (s, 1H), 3.71 (d, J = 13.5 Hz, 2H), 3.41 (d, J = 13.5 Hz, 2H), 2.00 (s, 2H), 1.70 (s, 6H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 139.4, 139.0, 128.8, 128.4, 128.3, 128.3, 128.2, 128.12, 128.1, 127.4, 127.0, 127.0, 93.7, 77.0, 65.5, 55.3, 54.5, 32.1. HRMS: (ESI-TOF) calculated for C26H27NO [M + H] 370.2171, found 370.2162. HPLC analysis (Chiralpack IB, heptane/2-propanol:NH4OH (99.8:0.2), 95:5 isocratic, 0.5 mL/min); tR = 6.16 min (minor) and tR = 6.48 min (major). (R)-5-(diallylamino)-2-methyl-5-phenylpent-3-yn-2-ol (5c): The title compound was prepared according to the general procedure 2.1 Colourless gummy oil. Yield = 16.2 mg, 30%. Rf = 0.50 in 20% ethyl acetate/cyclohexane. [α]20D = +251.07 (C = 0.50, CHCl3). IR (neat, cm-1): 3353.7, 3079.3, 2979.3, 1642.4, 1448.9 1164.5, 948.5. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (dd, J = 7.2, 1.1 Hz, 2H), 7.36 – 7.33 (m, 2H), 7.29– 7.26 (m, 1H), 5.87 – 5.79 (m, 2H), 5.27 – 5.23 (m, 2H), 5.14 – 5.12 (m, 2H), 4.90 (s, 1H), 3.23 – 3.18 (m, 2H), 2.96 – 2.91 (m, 2H), 2.03 (s, 1H), 1.64 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 139.1, 136.4, 128.1, 128.0, 127.3, 117.2, 92.8, 77.6, 65.5, 55.8, 55.8, 53.4, 31.9. HRMS: (ESI-TOF) calculated for C18H23NO [M + H] 270.1858, found 270.1866. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 99:1 gradient, 0.5 mL/min, 20 min); tR = 12.65 min (minor) and tR = 13.53 min (major). (R)-2-methyl-5-phenyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5d):6b The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 45.7 mg, 94%. Rf = 0.30 in 50% ethyl acetate/cyclohexane. [α]20D = +31.36 (C = 1, CHCl3). IR (neat, cm-1): 2983.8, 2918.6, 1977.6, 1456.3, 1076.8, 1051.1. 1H NMR (500 MHz, Chloroform-d) δ 7.51 – 7.49 (m, 2H), 7.35 – 7.31 (m, 2H), 7.29 – 7.25 (m, 1H), 4.63 (s, 1H), 2.60 – 2.56 (m, 4H), 2.20 (s, 1H), 1.77 – 1.75 (m, 4H), 1.57 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 139.3, 128.2, 127.5, 91.6, 79.1, 65.3, 58.5, 58.4, 50.2, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C16H22NO [M + H] 244.1701, found 244.1692. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 3.94 min (major) and tR = 4.37 min (minor).



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(S)-2-methyl-5-(pyrrolidin-1-yl)-5-(o-tolyl)pent-3-yn-2-ol (5e): 6b The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 43.7 mg, 85%. Rf = 0.75 in 50% ethyl acetate/cyclohexane. [α]20D = +25.23 (C = 1, CHCl3). IR (neat, cm-1): 3356.1, 3020.1, 2931.1, 1459.7, 1164.9, 1130.9, 948.7. 1H NMR (500 MHz, Chloroform-d) δ 7.57 - 7.54 (m, 1H), 7.18 – 7.12 (m, 3H), 4.78 (s, 1H), 2.62 – 2.49 (m, 4H), 2.40 (s, 3H), 2.08 (bs, 1H), 1.75 – 1.68 (m, 4H), 1.56 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 137.6, 136.6, 130.4, 128.0, 127.3, 125.5, 91.5, 79.1, 65.3, 55.5, 55.4, 50.0, 31.8, 23.5, 19.0. HRMS: (ESI-TOF) calculated for C17H23NO [M + H] 258.1858, found 258.1848. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 99:1 isocratic, 0.5 mL/min, 20 min); tR = 9.96 min (major) and tR = 11.26 min (minor). (S)-5-(2-fluorophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5f): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 47.0 mg, 90%. Rf = 0.60 in 50% ethyl acetate/cyclohexane. [α]20D = +14.80 (C = 1, CHCl3). IR (neat, cm-1): 3351.8, 2974.6, 2808.9, 1488.9, 1455.6, 1268.6, 1231.7, 950.6. 1H NMR (500 MHz, Chloroform-d) δ 7.60 (td, J = 7.6, 1.8 Hz, 1H), 7.28 – 7.23 (m, 1H), 7.13 (td, J = 7.5, 1.2 Hz, 1H), 7.04 7.00 (m, 1H), 4.94 (s, 1H), 2.62 -2.59 (m, 4H), 2.37 (s, 1H), 1.77 – 1.74 (m, 4H), 1.55 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 160.2 (d, J = 247.9 Hz), 130.1 (d, J = 3.5 Hz), 129.3 (d, J = 8.2 Hz), 126.2 (d, J = 13.1 Hz), 123.8 (d, J = 3.7 Hz), 115.3 (d, J = 22.2 Hz), 90.7, 78.8, 65.1, 51.3, 51.3, 50.3, 31.6, 23.2. HRMS: (ESI-TOF) calculated for C16H21NOF [M + H] 262.1607, found 262.1619. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min,10 min); tR = 7.47 min (major) and tR = 7.89 min (minor). (S)-5-(2-bromophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5g): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 63.2 mg, 98%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +7.31 (C = 1, CHCl3). IR (neat, cm-1): 3357.9, 2973.6, 2806.5, 1589.6, 1568.4, 1164.8, 1131.9, 1022.0, 948.9. 1H NMR (500 MHz, Chloroform-d) δ 7.65 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (dd, J = 8.0, 1.3 Hz, 1H), 7.29 (td, J = 7.6, 1.3 Hz, 1H), 7.12 (td, J = 7.7, 1.7 Hz, 1H), 5.02 (s, 1H), 2.67 – 2.57 (m, 4H), 2.25 (s, 1H), 1.76 – 1.73 (m, 4H), 1.55 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 138.7, 132.9, 130.0, 129.0, 127.2, 124.4, 91.4, 78.9, 65.2, 57.4, 50.2, 31.7, 31.6, 23.4. HRMS: (ESI-TOF) calculated for C16H21NOBr [M + H] 322.0807, found 322.0817. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 99:1 gradient, 1 mL/min, 30 min); tR = 5.62 min (major) and tR = 6.12min (minor). (R)-5-(3-chlorophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5h): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 46.7 mg, 84%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +37.44 (C = 1, CHCl3). IR (neat, cm-1): 3353.9, 2973.4, 2810.4, 1595.7, 1573.9, 1166.1, 1131.3, 951.9. 1H NMR (500 MHz, Chloroform-d) δ 7.51 (s, 1H), 7.41 – 7.39 (m, 1H), 7.27 – 7.23 (m, 2H), 4.63 (s, 1H), 2.58 - 2.55 (m, 4H), 2.21 (bs, 1H), 1.79 – 1.74 (m, 4H), 1.57 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 141.5, 134.0, 129.4, 128.2, 127.7, 126.2, 92.2, 78.2, 65.2, 57.8, 57.8, 50.0, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C16H21NOCl ACS Paragon Plus Environment

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[M + H] 278.1312, found 278.1303. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 0.5 mL/min, 20 min); tR = 7.13 min (major) and tR = 7.84 min (minor). (R)-2-methyl-5-(3-nitrophenyl)-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5i): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 32.9 mg, 57%. Rf = 0.50 in 50% ethyl acetate/cyclohexane. [α]20D = +39.57 (C = 1, CHCl3). IR (neat, cm-1): 3368.6. 2972.7, 2821.5, 1529.3, 1348.4. 1H NMR (500 MHz, Chloroform-d) δ 8.42 (t, J = 2,1 Hz, 1H), 8.15 - 8.13 (m, 1H), 7.90 - 7.88 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 4.81 (s, 1H), 2.64 – 2.54 (m, 4H), 2.17 (bs, 1H), 1.81 - 1.76 (m, 4H), 1.61 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 148.2, 141.8, 134.2, 129.1, 123.1, 122.6, 93.2, 77.3, 65.3, 57.4, 49.8, 31.7, 31.7, 23.5. HRMS: (ESI-TOF) calculated for C16H21N2O3 [M + H] 289.1552, found 289.1541. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 6.65 min (major) and tR = 7.36 min (minor). (R)-5-(3-bromophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5j): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 60.6 mg, 94%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +34.14 (C = 1, CHCl3). IR (neat, cm-1): 3365.1, 2972.3, 2810.9, 1593.0, 1569.6. 1H NMR (500 MHz, Chloroform-d) δ 7.66 (t, J = 1.9 Hz, 1H), 7.46 - 7.44 (m, 1H), 7.41 – 7.38 (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 4.62 (s, 1H), 2.58 – 2.55 (m, 4H), 2.33 (bs, 1H), 1.78 – 1.75 (m, 4H), 1.57 (s, 6H).

C{1H} NMR (126 MHz, Chloroform-d) δ

13

141.7, 131.1, 130.6, 129.7, 126.7, 122.3, 92.3, 78.2, 65.2, 57.8, 50.0, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C16H21NOBr [M + H] 322.0807, found 322.0810. HPLC analysis (Chiralpack IA, heptane/2propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 3.72 min (major) and tR = 4.05 min (minor). (R)-2-methyl-5-(pyrrolidin-1-yl)-5-(p-tolyl)pent-3-yn-2-ol (5k): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 49.9 mg, 97%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +32.30 (C = 1, CHCl3). IR (neat, cm-1): 3395.8, 2979.1, 2924.1, 1965.2, 1434.1, 1260.2, 1076.2, 1051.7. 1H NMR (500 MHz, Chloroform-d) δ 7.39 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 4.59 (s, 1H), 2.60 -2.56 (m, 4H), 2.35 (bs, 3H), 1.78 – 1.75 (m, 4H), 1.57 (s, 6H).

C{1H} NMR (126 MHz, Chloroform-d) δ 137.1, 136.3, 128.8,

13

128.1, 91.4, 79.3, 65.2, 58.2, 50.2, 31.7, 23.3, 21.1. HRMS: (ESI-TOF) calculated for C17H24NO [M + H] 258.1858, found 258.1855. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 7 min); tR = 3.56 min (major) and tR = 3.11 min (minor). (R)-5-(4-chlorophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5i): 6b The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 43.9 mg, 79%. Rf = 0.60 in 50% ethyl acetate/cyclohexane. [α]20D = +36.56 (C = 1, CHCl3). IR (neat, cm-1): 3347.6, 2973.9, 2809.8, 1488.4, 1459.1, 1227.5, 1166.8, 1031.2, 1014.9. 1H NMR (500 MHz, Chloroform-d) δ 7.46 – 7.43 (m, 2H), 7.31 – 7.28 (m, 2H), 4.62 (s, 1H), 2.57 – 2.55 (m, 4H), 2.17 (bs, 1H), 1.77 – 1.75 (m, 4H), 1.57 (s, 6H).

C{1H} NMR (126 MHz, Chloroform-d) δ 137.9, 133.2, 129.4,

13

128.3, 92.1, 78.5, 65.3, 57.7, 50.1, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C16H21NOCl [M + H] 278.1312, found 278.1325. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 4.15 min (major) and tR = 4.66 min (minor).



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(R)-5-(4-bromophenyl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5m): 6b The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 58.6 mg, 91%. Rf = 0.60 in 50% ethyl acetate/cyclohexane. [α]20D = +29.30 (C = 1, CHCl3). IR (neat, cm-1): 3358.4, 2972.5, 2809.6, 1589.8, 1485.1, 1167.1, 1010.8. 1H NMR (500 MHz, Chloroform-d) δ 7.46 – 7.43 (m, 2H), 7.40 – 7.38 (m, 2H), 4.60 (s, 1H), 2.57 – 2.54 (m, 4H), 2.39 (bs, 1H), 1.77 – 1.74 (m, 4H), 1.56 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 138.4, 131.2, 129.8, 121.4, 92.1, 78.4, 65.2, 57.8, 50.0, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C16H21NOBr [M + H] 322.0807, found 322.0800. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 7 min); tR = 4.22min (major) and tR = 4.81 min (minor). (S)-2-methyl-5-(naphthalen-1-yl)-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5n): The title compound was prepared according to the general procedure 2.1 Light yellow solid. Yield = 46.9 mg, 80%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +38.47 (C = 1, CHCl3). IR (neat, cm-1): 3356.2, 3048.2, 2972.3, 2806.6, 1598.9, 1509.4, 1165.2, 1131.9, 947.8. 1H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 – 7.76 (m, 2H), 7.52 – 7.41 (m, 3H), 5.33 (s, 1H), 2.70 – 2.65 (m, 2H), 2.58 – 2.54 (m, 2H), 2.10 (bs, 1H), 1.75 – 1.69 (m, 4H), 1.58 (s, 6H). C{1H} NMR (126 MHz, Chloroform-d) δ 135.2, 133.9, 131.4, 128.4, 128.4, 125.8, 125.7, 125.5, 124.9, 124.4,

13

92.1, 79.1, 65.4, 55.9, 55.9, 50.1, 31.8, 31.8, 23.6. HRMS: (ESI-TOF) calculated for C20H23NO [M – NC4H8] 223.1123, found 223.1129. HPLC analysis (Chiralpack IB, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic 0.5 mL/min, 20 min); tR = 6.90 min (minor) and tR = 7.64 min (major). (S)-2-methyl-5-(perfluorophenyl)-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5o): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 35.3 mg, 53%. Rf = 0.10 in 20% ethyl acetate/cyclohexane. [α]20D = +5.29 (C = 1, CHCl3). IR (neat, cm-1): 3354.8, 2976.0, 2818.3, 1652.5, 1520.7, 1123.1, 992.9. 1H NMR (500 MHz, Chloroform-d) δ 4.98 (s, 1H), 2.65 – 2.62 (m, 4H), 2.09 (s, 1H), 1.81 – 1.79 (m, 4H), 1.53 (d, J = 3.0 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 145.1 (d, J = 255.8 Hz), 140.8 (d, J = 255.5 Hz), 137.5 (d, J = 253.3 Hz),112.7, 90.0, 76.6, 65.2, 50.5, 47.7, 31.3, 31.3, 23.3. HRMS: (ESI-TOF) calculated for C16H17NOF5 [M + H] 334.1230, found 334.1227. HPLC analysis (Chiralpack IB, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic 0.5 mL/min, 20 min); tR = 5.09 min (minor) and tR = 5.63 min (major). (S)-2-methyl-5-(ferrocenyl)-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5p): The title compound was prepared according to the general procedure 2.1 Dark brown gummy oil. Yield = 66.0 mg, 94%. Rf = 0.20 in 50% ethyl acetate/cyclohexane. [α]20D = -203.04 (C = 1, CHCl3). IR (neat, cm-1): 3334.5, 3095.2, 2974.9, 2929.9, 2874,9, 1227.5, 1167.6, 952.3. 1H NMR (500 MHz, Chloroform-d) δ 4.47 (s, 1H), 4.38 – 4.37 (m, 1H), 4.24 – 4.23 (m, 1H), 4.18 (s, 5H), 4. 14 - 4.13 (m, 1H), 4.12 – 4.10 (m, 1H), 2.57 – 2.54 (m, 4H), 2.11 (s, 1H), 1.73 – 1.70 (m, 4H), 1.63 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 89.7, 86.0, 79.6, 69.0, 68.9, 68.2, 67.9, 67.7, 65.3, 54.3, 49.9, 31.9, 31.9, 23.2. HRMS: (ESI-TOF) calculated for C20H25NOFe [M – NC4H8] 281.0629, found 281.0632. HPLC analysis (Chiralpack IB, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic 0.5 mL/min, 20 min); tR = 10.41 min (major) and tR = 14.07 min (minor).


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(S)-5-(furan-2-yl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5q): 6b The title compound was prepared according to the general procedure 2.1 Brown gummy oil. Yield = 37.8 mg, 81%. Rf = 0.50 in 50% ethyl acetate/cyclohexane. [α]20D = +24.67 (C = 1, CHCl3). IR (neat, cm-1): 3368.1, 2973.4, 2813.5, 1608.9, 1460.1, 1169.4, 1005.8, 952.9. 1H NMR (500 MHz, Chloroform-d) δ 7.37 – 7.36 (m, 1H), 6.35 – 6.34 (m, 1H), 6.31 – 6.30 (m, 1H), 4.79 (d, J = 1.3 Hz, 1H), 2.67 – 2.57 (m, 4H), 2.43 (d, J = 28.3 Hz, 1H), 1.80 – 1.76 (m, 4H), 1.55 (d, J = 1.9 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 152.3, 142.2, 109.9, 107.9, 90.75, 76.5, 65.1, 51.7, 49.6, 31.6, 23.4. HRMS: (ESI-TOF) calculated for C14H20NO2 [M + H] 234.1494, found 234.1489. HPLC analysis (Chiralpack IB, heptane/2propanol:NH4OH (99.8:0.2), 97:3 isocratic 0.5 mL/min, 20 min); tR = 8.18 min (minor) and tR = 8.85 min (major). (S)-2-methyl-5-(pyrrolidin-1-yl)-5-(thiophen-3-yl)pent-3-yn-2-ol (5r): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 34.9 mg, 70%. Rf = 0.50 in 50% ethyl acetate/cyclohexane. [α]20D = +29.85 (C = 1, CHCl3). IR (neat, cm-1): 3359.8, 3103.4, 2972.1, 2809.4, 1678.7, 1359.2, 1166.3, 952.5. 1H NMR (500 MHz, Chloroform-d) δ 7.30 – 7.29 (m, 1H), 7.26 – 7.24 (m, 1H), 7.18 (dd, J = 5.0, 1.3 Hz, 1H), 4.73 (s, 1H), 2.60 - 2.58 (m, 4H), 2.51 (s, 1H), 1.79 – 1.73 (m, 4H), 1.56 (s, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 140.7, 127.6, 125.4, 122.7, 90.9, 78.9, 65.1, 53.7, 49.8, 31.7, 31.7, 23.4. HRMS: (ESI-TOF) calculated for C14H20NOS [M + H] 250.1266, found 250.1262. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 4.53 min (major) and tR = 4.93 min (minor). (S)-5-(2-chloroquinolin-3-yl)-2-methyl-5-(pyrrolidin-1-yl)pent-3-yn-2-ol (5s): The title compound was prepared according to the general procedure 2.1 White solid. Yield = 50.0 mg, 76%. Rf = 0.50 in 50% ethyl acetate/cyclohexane. [α]20D = +67.19 (C = 1, CHCl3). IR (neat, cm-1): 2999.4, 2923.3, 1670.3, 1382.7, 1057.3. 1H NMR (500 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.04 – 8.02 (m, 1H), 7.87 – 7.85 (m, 1H), 7.75 - 7.72 (m, 1H), 7.59 - 7.56 (m, 1H), 5.18 (s, 1H), 2.76 – 2.71 (m, 2H), 2.63 – 2.59 (m, 2H), 2.02 (s, 1H), 1.82 – 1.76 (m, 4H), 1.61 (d, J = 1.7 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 150.7, 147.0, 137.8, 131.5, 130.4, 128.2, 127.7, 127.1, 127.1, 92.4, 77.7, 65.4, 55.1, 50.2, 31.8, 31.7, 23.5. HRMS: (ESI-TOF) calculated for C19H22N2OCl [M + H] 329.1421, found 329.1409. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 0.5 mL/min, 20 min); tR = 8.18 min (major) and tR = 9.06 min (minor). (R,E)-2-methyl-7-phenyl-5-(pyrrolidin-1-yl)hept-6-en-3-yn-2-ol (5t): The title compound was prepared according to the general procedure 2.1 Brown gummy oil. Yield = 45.2 mg, 84%. Rf = 0.20 in 50% ethyl acetate/cyclohexane. [α]20D = +1.34 (C = 1, CHCl3). IR (neat, cm-1): 3364.8, 3026.7, 2808.5, 1494.9, 1373.3, 1168.6, 1132.3, 966.8. 1H NMR (500 MHz, Chloroform-d) δ 7.40 – 7.37 (m, 2H), 7.32 – 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 6.72 (dd, J = 15.9, 1.4 Hz, 1H), 6.28 (dd, J = 15.8, 6.1 Hz, 1H), 4.26 (dd, J = 6.1, 1.5 Hz, 1H), 2.72 – 2.63 (m, 4H), 2.46 (bs, 1H), 1.81 - 1.79 (m, 4H), 1.57 (d, J = 1.4 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 136.6, 131.8, 128.5, 127.9, 127.6, 126.6, 92.0, 78.0, 65.1, 56.1, 50.0, 31.8, 31.8, 23.4. HRMS: (ESI-TOF) calculated for C18H24NO [M + H] ACS Paragon Plus Environment


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270.1858, found 270.1871. HPLC analysis (Chiralpack IB, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 0.5 mL/min, 20 min); tR = 11.74 min (minor) and tR = 16.54 min (major). (R)-7-(4-methoxyphenyl)-2-methyl-5-(pyrrolidin-1-yl)hepta-3,6-diyn-2-ol (5u): The title compound was prepared according to the general procedure 2.1 Red gummy oil. Yield = 51.7 mg, 87%. Rf = 0.35 in 50% ethyl acetate/cyclohexane. [α]20D = +7.76 (C = 1, CHCl3). IR (neat, cm-1): 3333.5, 2970.4, 2837.6, 1604.3, 1508.4, 1476.9, 1245.4, 1029.1, 746.6. 1H NMR (500 MHz, Chloroform-d) δ 7.39 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.73 (s, 1H), 3.80 (s, 3H), 2.81 – 2.78 (m, 4H), 2.38 (s, 1H), 1.86 – 1.83 (m, 4H), 1.54 (s, 6H).

13

C{1H} NMR (126 MHz, Chloroform-d) δ 159.6,

133.3, 114.7, 113.8, 88.4, 83.7, 82.7, 77.2, 65.0, 55.3, 55.3, 49.5, 45.3, 45.3, 31.4, 23.6. HRMS: (ESI-TOF) calculated for C19H26NO3 [M + HOH + H] 316.1913, found 316.1918. HPLC analysis (Chiralpack IA, heptane/2propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 20 min); tR = 8.53 min (major) and tR = 9.93 min (minor). (R)-5-(azetidin-1-yl)-2-methyl-5-(p-tolyl)pent-3-yn-2-ol (5v): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 29.7 mg, 61%. Rf = 0.25 in 50% ethyl acetate/cyclohexane. [α]20D = +50.50 (C = 1, CHCl3). IR (neat, cm-1): 3373.9, 2976.9, 2925.2, 2851.6, 1511.7, 1166.0, 952.2. 1H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 4.29 (s, 1H), 3.24 (t, J = 7.1 Hz, 4H), 2.59 (s, 1H), 2.33 (s, 3H), 2.02 (p, J = 7.1 Hz, 2H), 1.58 (d, J = 1.6 Hz, 6H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 137.4, 135.1, 129.0, 127.8, 91.6, 79.0, 65.2, 60.9, 51.4, 31., 21.1, 17.0. HRMS: (ESI-TOF) calculated for C16H21NO [M + H] 244.1701, found 244.1691. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 98:2 isocratic, 0.5 mL/min, 20 min); tR = 13.06 min (major) and tR = 14.31 min (minor). (R)-2-methyl-5-(piperidin-1-yl)-5-(p-tolyl)pent-3-yn-2-ol (5w): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 47.2 mg, 87%. Rf = 0.60 in 50% ethyl acetate/cyclohexane. [α]20D = +22.80 (C = 1, CHCl3). IR (neat, cm-1): 3361.7, 2978.9, 2931.2, 1613.0, 1299.2, 1165.8, 988.8. 1H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 4.52 (s, 1H), 2.45 – 2.45 - 2.43 (m, 4H), 2.34 (s, 3H), 1.59 (s, 6H), 1.57 – 1.53 (m, 4H), 1.41 – 1.39 (m, 2H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 137.0, 135.3, 128.6, 128.3, 92.4, 78.5, 65.3, 61.4, 61.3, 50.5, 31.8, 31.8, 26.0, 24.4, 21.0. HRMS: (ESI-TOF) calculated for C18H26NO [M + H] 272.2014, found 272.2018. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 0.5 mL/min, 20 min); tR = 6.81 min (major) and tR = 7.38 min (minor). (R)-5-(azepan-1-yl)-2-methyl-5-(p-tolyl)pent-3-yn-2-ol (5x): The title compound was prepared according to the general procedure 2.1 Light yellow gummy oil. Yield = 56.5 mg, 99%. Rf = 0.70 in 50% ethyl acetate/cyclohexane. [α]20D = +10.33 (C = 1, CHCl3). IR (neat, cm-1): 3356.6, 2927.1, 1611.2, 1452.2, 1173.4. 1H NMR (500 MHz, Chloroform-d) δ 7.48 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 4.68 (s, 1H), 2.64 – 2.61 (m, 4H), 2.36 (s, 3H), 2.04 (s, 1H), 1.66 – 1.54 (m, 14H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 136.9, 136.5, 128.6, 128.1, 91.7, 79.2, 65.4, 61.7, 61.7, 52.5, 31.9, 31.9, 28.9, 26.9, 21.1. HRMS: (ESI-TOF) calculated for C19H27NO [M + H] 286.2171, found 286.2161. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 98:2 isocratic, 0.5 mL/min, 20 min); tR = 8.04 min (major) and tR = 8.69 min (minor).


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(R)-2-methyl-5-morpholino-5-(p-tolyl)pent-3-yn-2-ol (5y): The title compound was prepared according to the general procedure 2.1 White solid. Yield = 54.1 mg, 99%. Rf = 0.50 in 50% ethyl acetate/cyclohexane. [α]20D = +24.68 (C = 1, CHCl3). IR (neat, cm-1): 3404.7, 2978.3, 2858.6, 1614.4, 1110.5, 751.4. 1H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 4.52 (s, 1H), 3.73 – 3.65 (m, 4H), 2.54 – 2.47 (m, 4H), 2.34 (s, 3H), 1.59 (s, 6H), 1.51 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 137.4, 134.6, 128.8, 128.3, 93.2, 77.5, 67.0, 65.2, 61.0, 61.0, 49.6, 31.8, 21.0. HRMS: (ESI-TOF) calculated for C17H23NO2 [M + H] 274.1807, found 274.1809. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 95:5 isocratic, 0.2 mL/min, 20 min); tR = 21.55 min (major) and tR = 23.67 min (minor). (R)-5-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methyl-5-(p-tolyl)pent-3-yn-2-ol (5z): The title compound was prepared according to the general procedure 2.1 Colourless gummy oil. Yield = 63.2 mg, 99%. Rf = 0.75 in 50% ethyl acetate/cyclohexane. [α]20D = +18.90 (C = 1, CHCl3). IR (neat, cm-1): 3368.8, 2979.9, 2929.4, 1632.8, 1603.9, 1454.9, 1374.2, 1168.9, 961.1. 1H NMR (500 MHz, Chloroform-d) δ 7.52 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 7.14 – 7.10 (m, 3H), 7.02 -7.01 (m, 1H), 4.84 (s, 1H), 3.76 (s, 2H), 2.96 – 2.76 (m, 4H), 2.38 (s, 3H), 2.25 (bs, 1H), 1.61 (d, J = 2.4 Hz, 6H). C{1H} NMR (126 MHz, Chloroform-d) δ 137.3, 135.2, 135.0, 134.4, 128.9, 128.6, 128.2, 126.7, 125.9, 125.5,

13

93.2, 77.5, 65.4, 60.5, 52.0, 47.0, 31.8, 29.5, 21.1. HRMS: (ESI-TOF) calculated for C22H25NO [M + H] 320.2014, found 320.2010. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 95:5 isocratic, 0.2 mL/min, 20 min); tR = 18.14 min (major) and tR = 20.82 min (minor). (R)-4-phenyl-4-(pyrrolidin-1-yl)but-2-yn-1-ol (5aa): The title compound was prepared according to the general procedure 2.1 Colourless gummy oil. Yield = 36.2 mg, 84%. Rf = 0.35 in 50% ethyl acetate/cyclohexane. [α]20D = +25.30 (C = 1, CHCl3). IR (neat, cm-1): 2970.9, 2927.1, 1971.1, 1618.4, 1451.8, 1067.7. 1H NMR (500 MHz, Chloroformd) δ 7.51 (d, J = 7.2 Hz, 2H), 7.35 – 7.32 (m, 2H), 7.29 – 7.26 (m, 1H), 4.66 (s, 1H), 4.35 (s, 2H), 2.95 (s, 1H), 2.66 - 2.60 (m, 4H), 1.82 - 1.74 (m, 4H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 138.7, 128.3, 128.2, 127.8, 85.1, 82.7, 58.9, 51.1, 50.4, 23.3. HPLC analysis (Chiralpack IA, heptane/2-propanol:NH4OH (99.8:0.2), 97:3 isocratic, 1 mL/min, 15 min); tR = 6.52 min (major) and tR = 7.41 min (minor). (S)-1-(1-(naphthalen-1-yl)prop-2-yn-1-yl)pyrrolidine (6): The title compound was prepared according to the general procedure 2.2 Colourless oil. Yield = 52.4 mg, 89%. Rf = 0.90 in 20% ethyl acetate/cyclohexane. [α]20D = +70.83 (C = 1, CHCl3). IR (neat, cm-1): 3044.2, 2806.5, 1509.0, 1347.2, 1127.6, 1043.0, 938.6. 1H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.3 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.68 – 7.32 (m, 4H), 5.40 (d, J = 2.2 Hz, 1H), 2.75 (m, 2H), 2.62 (m, 2H), 2.56 (dd, J = 2.3, 0.9 Hz, 1H), 1.86 – 1.69 (m, 4H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 134.8, 133.9, 131.4, 128.53, 128.5, 125.9, 125.8, 125.6, 125.0, 124.3, 80.7, 75.0, 56.0, 50.0, 23.6. HRMS: (ESI-TOF) calculated for C17H17N [M + H] 236.1430, found 236.1439. HPLC analysis (Chiralpack IB, sCO2/Methanol, 100:0 to 95:5 gradient, 2 mL/min, 10 min); tR = 2.62 min (minor) and tR = 2.78 min (major). (S)-4-phenylbuta-2,3-dien-1-ol (7):18



Page 16 of 18

The title compound was prepared according to the general procedure 2.3 Colourless gummy oil. Yield = 17.8 mg, 61%. Rf = 0.30 in 20% ethyl acetate/cyclohexane. [α]20D = +6.09 (C = 0.2, CH3CN). IR (neat, cm-1): 3347.4, 2923.9, 2853.6, 1718.7, 1600.7, 1450.5, 1270.2. 1H NMR (500 MHz, Chloroform-d) δ 7.32 - 7.39 (m, 4H), 7.24 – 7.20 (m, 1H), 6.33 (dt, J = 6.1, 2.9 Hz, 1H), 5.80 (q, J = 6.0 Hz, 1H), 4.27 (dt, J = 5.9, 3.0 Hz, 2H), 1.57 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 204.2, 133.8, 128.7, 127.3, 126.8, 97.3, 95.9, 60.4. HRMS: (ESI-TOF) calculated for C10H10O [M]⸱ 146.0732, found 146.0739. SFC analysis (Chiralpack IA, sCO2/Methanol, 99:1 to 60:40 gradient, 3 mL/min, 5 min); tR = 2.43 min (minor) and tR = 2.51 min (major). ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H and 13C NMR spectra of the products, HPLC chromatographies (PDF) CCDC 1886460 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected] AUTHOR INFORMATION Corresponding Author *Email: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This publication has emanated from research conducted with the financial support of the Synthesis and Solid State Pharmaceutical Centre (SSPC), funded by Science Foundation Ireland (SFI) under grant numbers 12\RC\2275. BVR is grateful for the award of a SSPC Postdoctoral fellowship. BVR also thanks the Irish Research Council (IRC) for the award of a postdoctoral fellowship (GOIPD/2015/453). We acknowledge facilities provided by the Centre for Synthesis and Chemical Biology (CSCB), funded by the Higher Education Authority’s PRTLI. We thank Dr. Helge Müller-Bunz for X-ray crystal structure analysis, Dr. Jimmy Muldoon for mass spectroscopic analysis and Dr. Yannick Ortin for NMR spectroscopic experiments. REFERENCES (1) (a) Lauder, K.; Toscani, A.; Scalacci, N.; Castagnolo, D. Synthesis and Reactivity of Propargylamines in Organic Chemistry. Chem. Rev. 2017, 117, 14091-14200. (b) (b) Blacker, J.; Headley, C. E. Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction. Adv. Synth. Catal. 2010, 352, 753-819. (2) (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. A walk around the A3-coupling. Chem. Soc. Rev. 2012, 41, 3790-3807. (b) Wei, C.; Li, Z.; Li, C.-J. The Development of A3-Coupling (Aldehyde-Alkyne-Amine) ACS Paragon Plus Environment

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Enantioselective Catalytic Asymmetric A3 Coupling with Phosphino

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