Access to α‑Functionalized Amines via Calcium-Catalyzed Deacetylations

Michael P Cameron; Mark G McLaughlin

doi:10.1021/acs.joc.5c03185

. 2026 Mar 23;91(13):4698–4709. doi: 10.1021/acs.joc.5c03185

Access to α‑Functionalized Amines via Calcium-Catalyzed Deacetylations

Michael P Cameron ¹, Mark G McLaughlin ^1,^*

PMCID: PMC13054857 PMID: 41871318

Abstract

A calcium-catalyzed approach to accessing α-functionalized amines via deacetylation has been developed. Using Ca(NTf₂)₂/nBuNPF₆ as a mild Lewis acid system, a range of α-acetoxy substrates undergo smooth deacetylation and functionalization. The reaction displays excellent substrate tolerance and accommodates diverse nucleophiles, including sulfur, indole, amide, and cyanide derivatives. Furthermore, telescoped deprotection–reprotection protocols enable facile access to a variety of N-protected amines in high yields, providing a simple and practical route to valuable α-functionalized amine scaffolds.

Introduction

Amines are ubiquitous in chemistry, with an almost innumerable array of uses across many sectors including pharmaceutical, agrochemical, bulk, and fine chemicals. , Of particular interest are amines with α-functionalization, as this often plays a key role in determining their behavior such as biological activity. As such, the development of new methods for the construction of α-functionalized amines remains a cornerstone of modern synthetic organic chemistry, with advances in organocatalysis, transition metal catalysis, photoredox catalysis, − and electrosynthesis. , Although these methods all produce the desired product, they each have limitations based on catalyst availability (commercial vs bespoke), complicated and costly reaction setups, or simple functional group tolerance. Furthermore, the requirement for strictly anhydrous and oxygen-free conditions in many of these novel methods somewhat limits their uptake in medicinal chemistry.

As part of an ongoing medicinal chemistry program focused on the development of new covalent modalities, we required ready access to a wide range of α-functionalized amines, with a particular emphasis on installing groups that provide a functional handle for further derivatization or inherent hydrogen bonding ability. Given our continuing interest in the use of calcium as a Lewis acid catalyst, − we reasoned that we could use deoxyfunctionalization to install the aforementioned functionality. As such and based on our previous experience, we began by surveying a range of potential ether functionalities in the α-position; however, many of these were difficult to access reproducibly. Interestingly, many of the published methods installed an α-OAc group before further functionalization, − and we wondered if this would be amenable to our system, Scheme .

Results and Discussion

Subjecting 1a to allyl-TMS under the catalytic Ca(NTf₂)₂/nBuNPF₆ system in DCM at room temperature afforded the desired allylated product in 11%, with the remaining mass balance of unreacted starting material (Entry 1). Increasing the reaction temperature to 40 °C gave a marginal increase in yield, although conversion of the starting material remained low (Entry 2). Switching to higher boiling solvents to facilitate reactions at 80 °C, no improvement in yield was observed in EtOAc (Entry 3), whereas MeCN did give a marked increase in yield (Entry 4). Switching to dimethylcarbonate (DMC), a reported green solvent alternative for MeCN, saw a yield drop again (Entry 5). Trialing the reaction in HFIP, which becomes highly Lewis acidic in the presence of Ca(NTf₂)₂, did give full conversion of the starting material but gave a poor yield of the desired product. Finally, 1,2-DCE was screened as a reaction solvent, reproducibly providing the desired product 2a in excellent yield (Entries 7 and 10). Lowering the catalyst loading was found to be detrimental to the yield, with no reaction occurring in its absence (Table ).

1. Optimization Study.

Entry	Solvent	Cat. loading (mol %)	Temp (°C)	Yield
1	DCM	5	r.t.	11%
2	DCM	5	40	18%
3	EtOAc	5	80	13%
4	MeCN	5	80	58%
5	DMC	5	80	22%
6	HFIP	5	80	19%
7	1,2-DCE	5	80	91%
8	1,2-DCE	0	80	n.r.
9	1,2-DCE	2	80	45%
10	1,2-DCE	5	80	84%

Open in a new tab

NMR yields using nitromethane as an internal standard.

Isolated yield.

With these conditions in hand, we set about characterizing a substrate scope, initially focusing on allylation reactions (Table ). The reaction was tolerant to the majority of substrates that we subjected it to. Aryl rings bearing electron-donating and -withdrawing groups in various substitution patterns all worked well, with the notable exception of strongly electron-donating groups (2e, 2j, 2k), which returned the desired products in moderate yields. Furan was only moderately tolerated (2m), possibly due to undesirable interactions between the oxygen-containing heterocycle and oxophilic Ca catalyst; however, the thiophene and cyclohexyl motifs worked in excellent yields (2n, 2o).

2. Allylation Substrate Scope .

Open in a new tab

Isolated yields.

We next moved onto establishing how heteroatomic nucleophiles behaved in the system (Table ). As shown, sulfur (3a–3f) and indole (3g–k) provided the deacetylated products in high yields (64–99%), with differing electronics and substitution patterns being well tolerated across the board. Electron-poor substrates that had lower yields with allyl-TMS (2j, 2k) gave much higher yields with sulfur (3c) and indole (3j) nucleophiles. Amines were much more challenging, with simple aliphatic/aromatic amines all failing to provide the product, most likely due to premature deprotection of the Phth group by the nucleophilic amines. Moving onto amides proved more successful, with a range of amides synthesized in moderate but synthetically useful yields. Cbz-NH₂ was an excellent nucleophile, providing an orthogonally protected bisamine (3o) in an effectively quantitative yield.

3. Further Nucleophile Screen .

Open in a new tab

Isolated yields.

A final survey of nucleophilic partners was conducted using TMSCN, given the usefulness of the products toward further functionalization. As such, a range of our protected O-acyl-N,O-acetals were subjected to the calcium system in the presence of 2 equiv of TMSCN, which resulted in clean conversion to the product with concomitant high yields in most cases (Table ). Again, the reaction was generally tolerant to electron-withdrawing (4b–4e) and -donating groups (4f–4h), heterocyclic scaffolds (4i, 4j), and aliphatic motifs (4l, 4m)

4. TMSCN as a Nucleophile .

Open in a new tab

Isolated yields.

Although phthalimide is a useful protecting group, , we reasoned that installation of a more well-known and encountered protecting group on nitrogen would render our methodology more valuable to the community. A three-step deoxyfunctionalization–deprotection–reprotection strategy was therefore envisaged. Additionally, we decided that telescoping this series of steps would render the process amenable to a range of amines. As such, after surveying traditional phthalimide deprotections, MeNH₂ in EtOH proved to be the most robust. Taking this into account, the three-step procedure was carried out, producing the Boc protecting amines in good to excellent yields (over three steps) throughout (Table ).

5. N-Boc Substrate Scope .

Open in a new tab

Yield is combined yield over three steps of the isolated N-Boc product.

Given the success of this strategy, we then wanted to install other well-known amine protecting groups using the same telescoped process (Table ). As such, Fmoc (6a), Bz (6b, 6h), Alloc (6c, 6i), Ac (6d, 6g), and Cbz (6e, 6f) protecting groups were all successfully deployed in excellent yields (over three steps) to once again provide a small library of useful protected amines.

6. N-Protecting Group Scope .

Open in a new tab

Yield is combined yield over three steps of the isolated N-protected product.

We hypothesize that the reaction proceeds via the mechanism presented in Scheme . There is evidence to suggest that in a 1:1 mixture of Ca(NTf₂)₂ and nBu₄NPF₆, an anion metathesis occurs to give A, which we postulate is the active catalyst species. The oxophilic Ca²⁺ cation of A then initiates the deacetylation of 1, generating N-acyliminium ion 2, which is subsequently attacked by the desired nucleophile, forming adduct 3. The AcO anion of species B then deprotonates/desilylates 3, yielding the α-functionalized Phth-N amine 4 and regenerating the active catalyst A, with AcOH or AcOTMS as a byproduct.

Conclusions

In summary, we have demonstrated a general and efficient calcium-catalyzed methodology for the preparation of α-functionalized amines through deacetylation. This operationally straightforward process proceeds under mild, moisture-tolerant conditions, offering a broad substrate scope and compatibility with multiple nucleophiles. The telescoped deprotection–reprotection sequence further enhances the synthetic versatility of the approach, enabling the preparation of diverse N-protected amine libraries in excellent overall yields. Given the abundance and low toxicity of calcium catalysts, this strategy provides a practical and sustainable alternative to traditional transition metal-mediated α-functionalization methods with significant potential for applications in medicinal and synthetic chemistry.

Experimental Section

Solvents and Reagents

Solvents and reagents were purchased in the highest purity available from Acros Organics, Alfa Aesar, Fluorochem, TCI, Fisher Scientific, or Merck. All solvents were purchased from commercial sources and used without purification (reagent grade). Metal salts and ligands were stored in a desiccator when not in use. The anhydrous solvent was prepared by storing the solvent over activated 4Å MS for 72 h. Standard vacuum line techniques were used, and glassware was oven-dried prior to use. Organic solvents were dried during workup by using anhydrous MgSO₄. All reactions were performed using DrySyn heating mantles and pressure-regulated vials or round-bottom flasks.

Purification and Chromatography

Thin layer chromatography (TLC) was carried out using aluminum plates coated with 60 F₂₅₄ silica gel. Plates were visualized using UV light (254 or 365 nm) and developed with iodine, basic permanganate solution, or ninhydrin. Flash column chromatography (FCC) was performed on Fluorochem Silica gel 60, 40–63 μm RE as the stationary phase, and the solvents employed were reagent grade.

Characterization

¹H NMR spectroscopic data were obtained at 400 MHz (Bruker Ultrashield 400 Plus) or 600 MHz (Bruker Ultrashield 600 Plus), and ¹³C NMR data were obtained at 100 MHz (Bruker Ultrashield 400 Plus) or 151 MHz (Bruker Ultrashield 600 Plus) at 298 K. Infrared spectra were recorded on an Agilent Technologies Cary 630 FTIR spectrometer. High-resolution mass spectrometry data were recorded using electron spray ionization (ESI) on an Agilent 6560 Ion Mobility LC/Q-TOF mass spectrometer.

2-(1-Phenylbut-3-en-1-yl)isoindoline-1,3-dione (2a)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (100 mg, 0.339 mmol), Ca(NTf₂)₂ (10 mg, 0.017 mmol), nBu₄NPF₆ (6.5 mg, 0.017 mmol), and allyl-TMS (46 μL, 0.406 mmol) in 1,2-DCE (1.69 mL), reacting for 1 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (79 mg, 84%). RF (1:3 EtOAc:Hex): 0.74. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.75 (m, 2H), 7.68–7.63 (m, 2H), 7.57–7.52 (m, 2H), 7.37–7.30 (m, 2H), 7.29–7.23 (m, 1H), 5.77 (dddd, J = 17.1, 10.2, 8.3, 5.6 Hz, 1H), 5.45 (dd, J = 10.6, 5.9 Hz, 1H), 5.14 (ddd, J = 17.1, 2.9, 1.7 Hz, 1H), 5.01 (d, J = 10.1 Hz, 1H), 3.48–3.36 (m, 1H), 3.02–2.91 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.3, 139.2, 134.4, 133.9, 131.8, 128.6, 128.1, 127.9, 123.2, 118.3, 54.4, 35.3. Data in accordance with literature.

2-(1-(4-Methoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione (2b)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-methoxyphenyl)methyl acetate (75 mg, 0.231 mmol), Ca(NTf₂)₂ (6.9 mg, 0.012 mmol), nBu₄NPF₆ (4.5 mg, 0.012 mmol), and allyl-TMS (44 μL, 0.277 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h and then being isolated by FCC (1:9 EtOAc:Hex) as a colorless viscous oil (60 mg, 85%). RF (1:4 EtOAc:Hex): 0.56. ¹H NMR (400 MHz, CDCl₃) δ 7.82–7.74 (m, 2H), 7.71–7.62 (m, 2H), 7.55–7.45 (m, 2H), 6.92–6.82 (m, 2H), 5.76 (dddd, J = 17.0, 10.2, 8.2, 5.7 Hz, 1H), 5.39 (dt, J = 17.1, 8.5 Hz, 1H), 5.13 (dd, J = 17.1, 1.2 Hz, 1H), 5.00 (d, J = 10.1 Hz, 1H), 3.77 (s, 3H), 3.44–3.31 (m, 1H), 3.01–2.89 (m, 1H).¹³C{H} NMR (101 MHz, CDCl₃) δ 168.3, 159.2, 134.5, 133.9, 131.9, 131.4, 129.4, 123.2, 118.1, 113.8, 55.2, 53.9, 35.5. Data in accordance with literature.

2-(1-(P-tolyl)but-3-en-1-yl)isoindoline-1,3-dione (2c)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(p-tolyl)methyl acetate (75 mg, 0.242 mmol), Ca(NTf₂)₂ (7.3 mg, 0.012 mmol), nBu₄NPF₆ (4.7 mg, 0.012 mmol), and allyl-TMS (46 μL, 0.290 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (55 mg, 78%). RF (1:4 EtOAc:Hex): 0.68. ¹H NMR (400 MHz, CDCl₃) δ 7.82–7.75 (m, 2H), 7.69–7.63 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 5.77 (dddd, J = 17.0, 10.2, 8.3, 5.7 Hz, 1H), 5.41 (dd, J = 10.5, 5.9 Hz, 1H), 5.13 (dd, J = 17.1, 1.2 Hz, 1H), 5.00 (d, J = 10.1 Hz, 1H), 3.45–3.33 (m, 1H), 3.01–2.91 (m, 1H), 2.30 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.3, 137.6, 136.2, 134.5, 133.9, 131.9, 129.2, 128.0, 123.2, 118.1, 54.1, 35.4, 21.1. IR ν_max (cm^–1): 2961, 2918, 1766, 1705, 1382, 1351, 1326, 1071, 713. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₉H₁₈NO₂ 292.1338; Found 292.1333.

2-(1-(4-Fluorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2d)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-fluorophenyl)methyl acetate (75 mg, 0.239 mmol), Ca(NTf₂)₂ (7.2 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and allyl-TMS (46 μL, 0.287 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (54 mg, 77%). RF (1:4 EtOAc:Hex): 0.67. ¹H NMR (400 MHz, CDCl₃) δ 7.82–7.77 (m, 2H), 7.71–7.65 (m, 2H), 7.56–7.49 (m, 2H), 7.06–6.96 (m, 2H), 5.75 (dddd, J = 17.1, 10.2, 8.2, 5.7 Hz, 1H), 5.41 (dd, J = 10.4, 6.1 Hz, 1H), 5.13 (ddd, J = 17.1, 2.9, 1.6 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 3.46–3.30 (m, 1H), 3.02–2.89 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 168.6 (s), 162.6 (d, J = 246.6 Hz), 135.3 (d, J = 3.3 Hz), 134.4 (s), 134.3 (s), 132.1 (s), 130.2 (d, J = 8.1 Hz), 123.6 (s), 118.7 (s), 115.7 (d, J = 21.4 Hz), 54.0 (s), 35.8 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −114.22. IR ν_max (cm^–1): 3075, 2922, 1768, 1705, 1507, 1384, 1351, 1328, 1223, 1071, 836, 713. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₁₅FNO₂ 296.1087; Found 296.1078.

2-(1-(4-(Trifluoromethyl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (2e)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-(trifluoromethyl)phenyl)methyl acetate (49 mg, 0.135 mmol), Ca(NTf₂)₂ (4.1 mg, 0.007 mmol), nBu₄NPF₆ (2.6 mg, 0.007 mmol), and allyl-TMS (26 μL, 0.162 mmol) in 1,2-DCE (0.68 mL), reacting overnight and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (26 mg, 56%). RF (1:4 EtOAc:Hex): 0.68. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.78 (m, 2H), 7.74–7.69 (m, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 5.76 (dddd, J = 17.0, 10.1, 8.2, 5.7 Hz, 1H), 5.49 (dd, J = 10.5, 6.0 Hz, 1H), 5.15 (dd, J = 17.1, 1.2 Hz, 1H), 5.04 (d, J = 10.1 Hz, 1H), 3.49–3.32 (m, 1H), 3.06–2.92 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 168.2 (s), 143.0 (d, J = 1.2 Hz), 134.1 (s), 133.7 (s), 131.6 (s), 130.1 (q, J = 32.4 Hz), 128.5 (s), 125.6 (q, J = 3.8 Hz), 124.0 (q, J = 272.2 Hz), 123.4 (s), 118.8 (s), 53.8 (s), 35.1 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −62.64. IR ν_max (cm^–1): 3047, 1769, 1705, 1383, 1323, 1167, 1120, 1067, 922, 716. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₁₅F₃NO₂ 346.1055; Found 346.1046

2-(1-(2-Methoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione (2f)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(2-methoxyphenyl)methyl acetate (78 mg, 0.240 mmol), Ca(NTf₂)₂ (7.2 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and allyl-TMS (46 μL, 0.277 mmol) in 1,2-DCE (1.15 mL), reacting for 1 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (72 mg, 98%). RF (1:4 EtOAc:Hex): 0.54. ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.74 (m, 2H), 7.71–7.62 (m, 3H), 7.33–7.20 (m, 1H), 6.97 (td, J = 7.6, 0.8 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.11 (dd, J = 17.1, 1.1 Hz, 1H), 4.99 (d, J = 10.2 Hz, 1H), 3.78 (s, 3H), 3.39–3.25 (m, 1H), 2.93–2.81 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.3, 156.9, 134.7, 133.7, 131.9, 128.9, 128.9, 126.9, 123.1, 120.2, 118.0, 110.4, 55.5, 48.0, 35.2. IR ν_max (cm^–1): 2978, 2946, 1763, 1699, 1494, 1466, 1436, 1390, 1358, 1254, 1120, 911, 721. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₉H₁₈NO₃ 308.1287; Found 308.1281.

2-(1-(2-Bromophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2g)

To a 22 mL screw top vial were added (2-bromophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.200 mmol), Ca(NTf₂)₂ (6.0 mg, 0.010 mmol), nBu₄NPF₆ (3.9 mg, 0.010 mmol), and allyl-TMS (38 μL, 0.24 mmol) in 1,2-DCE (1.00 mL), reacting for 5 h and and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (69 mg, 97%). RF (1:4 EtOAc:Hex): 0.56. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.77 (m, 3H), 7.72–7.66 (m, 2H), 7.55 (dd, J = 8.0, 1.3 Hz, 1H), 7.33 (td, J = 7.7, 1.2 Hz, 1H), 7.14 (td, J = 7.7, 1.6 Hz, 1H), 5.91–5.74 (m, 2H), 5.13 (ddd, J = 17.1, 2.7, 1.5 Hz, 1H), 5.02 (d, J = 10.1 Hz, 1H), 3.39–3.23 (m, 1H), 2.97–2.84 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.2, 137.9, 134.0, 133.1, 131.7, 130.2, 129.4, 127.4, 124.0, 123.3, 118.6, 53.8, 35.9. IR ν_max (cm^–1): 2916, 1770, 1705, 1381, 1347, 1079, 1008, 915, 880, 714. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₅BrNO₄ 356.0281; Found 356.0275.

2-(1-(3-Chlorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2h)

To a 22 mL screw top vial were added (3-chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.227 mmol), Ca(NTf₂)₂ (6.6 mg, 0.011 mmol), nBu₄NPF₆ (4.3 mg, 0.011 mmol), and allyl-TMS (43 μL, 0.272 mmol) in 1,2-DCE (1.10 mL), reacting for 5 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (61 mg, 86%). RF (1:4 EtOAc:Hex): 0.56 ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.77 (m, 2H), 7.73–7.66 (m, 2H), 7.55–7.51 (m, 1H), 7.46–7.40 (m, 1H), 7.30–7.22 (m, 2H), 5.75 (dddd, J = 17.1, 10.2, 8.2, 5.7 Hz, 1H), 5.40 (dd, J = 10.6, 5.9 Hz, 1H), 5.14 (ddd, J = 17.1, 2.8, 1.6 Hz, 1H), 5.02 (d, J = 9.8 Hz, 1H), 3.44–3.31 (m, 1H), 3.00–2.89 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.1, 141.1, 134.4, 134.1, 133.9, 131.7, 129.8, 128.3, 128.1, 126.2, 123.3, 118.6, 53.8, 35.2. IR ν_max (cm^–1): 3065, 2920, 1770, 1705, 1381, 1349, 1071, 915, 714. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₄BrFNO₂ 312.0786; Found 312.0782.

2-(1-(3-Bromo-2-fluorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2i)

To a 22 mL screw top vial were added (3-bromo-2-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.191 mmol), Ca(NTf₂)₂ (5.7 mg, 0.010 mmol), nBu₄NPF₆ (3.7 mg, 0.010 mmol), and allyl-TMS (36 μL, 0.23 mmol) in 1,2-DCE (0.96 mL), reacting overnight and then being isolated by FCC (1:9 EtOAc:Hex) as a white solid (51 mg, 71%). RF (1:4 EtOAc:Hex): 0.61. ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.78 (m, 2H), 7.74–7.65 (m, 3H), 7.52–7.44 (m, 1H), 7.05 (t, J = 7.9 Hz, 1H), 5.84–5.71 (m, 2H), 5.14 (dd, J = 17.1, 1.0 Hz, 1H), 5.04 (d, J = 10.1 Hz, 1H), 3.39–3.24 (m, 1H), 2.97–2.85 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 167.9 (s), 156.8 (d, J = 248.7 Hz), 134.1 (s), 133.5 (s), 133.1 (s), 131.6 (s), 128.8 (d, J = 2.9 Hz), 127.5 (d, J = 14.7 Hz), 124.9 (d, J = 4.5 Hz), 123.4 (s), 118.8 (d, J = 21.0 Hz), 109.3 (d, J = 21.7 Hz), 47.2 (d, J = 2.6 Hz), 35.0 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −109.65. IR ν_max (cm^–1): 3082, 2924, 1770, 1709, 1450, 1385, 1347, 1064, 928, 714. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₁₄BrFNO₂ 374.0186; Found 374.0180.

2-(1-(3,5-Bis(trifluoromethyl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (2j)

To a 22 mL screw top vial were added (3,5-bis(trifluoromethyl)phenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (100 mg, 0.232 mmol), Ca(NTf₂)₂ (7.0 mg, 0.012 mmol), nBu₄NPF₆ (4.5 mg, 0.012 mmol), and allyl-TMS (44 μL, 0.278 mmol) in 1,2-DCE (1.16 mL), reacting overnight and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (22 mg, 23%). RF (1:4 EtOAc:Hex): 0.61. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 2H), 7.87–7.79 (m, 3H), 7.77–7.70 (m, 2H), 5.81–5.68 (m, 1H), 5.53 (dd, J = 10.4, 6.0 Hz, 1H), 5.17 (d, J = 17.0 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 3.47–3.36 (m, 1H), 3.05–2.94 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 168.0 (s), 141.5 (s), 134.3 (s), 133.1 (s), 131.9 (q, J = 33.4 Hz), 131.5 (s), 128.6 (d, J = 2.6 Hz), 123.6 (s), 127.7–118.6 (m), 122.2–121.9 (m), 119.3 (s), 53.3 (s), 35.2 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −62.80. IR ν_max (cm^–1): 3080, 1765, 1703, 1381, 1351, 1274, 1128, 924, 893, 721, 699. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₀H₁₄F₆NO₂ 414.0915; Found 414.092.

2-(1-(4-Nitrophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2k)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-nitrophenyl)methyl acetate (75 mg, 0.22 mmol), Ca(NTf₂)₂ (6.6 mg, 0.011 mmol), nBu₄NPF₆ (4.3 mg, 0.011 mmol), and allyl-TMS (30 μL, 0.264 mmol) in 1,2-DCE (1.10 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a colorless viscous oil (31 mg, 44%).bRF (1:4 EtOAc:Hex): 0.56. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J = 8.8 Hz, 2H), 7.88–7.77 (m, 2H), 7.78–7.66 (m, 4H), 5.83–5.69 (m, 1H), 5.52 (dd, J = 10.4, 6.1 Hz, 1H), 5.16 (dd, J = 17.1, 0.9 Hz, 1H), 5.05 (d, J = 10.1 Hz, 1H), 3.45–3.32 (m, 1H), 3.07–2.95 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.1, 147.5, 146.1, 134.3, 133.3, 131.5, 129.1, 123.8, 123.5, 119.1, 53.5, 35.1. IR ν_max (cm^–1): 3460, 3080, 1770, 1705, 1599, 1509, 1382, 1345, 1077, 993, 851, 721. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₈H₁₅N₂O₄ 323.1026; Found 323.1022

2-(1-(Naphthalen-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2l)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(naphthalen-2-yl)methyl acetate (100 mg, 0.290 mmol), Ca(NTf₂)₂ (9.0 mg, 0.015 mmol), nBu₄NPF₆ (5.8 mg, 0.015 mmol), and allyl-TMS (55 μL, 0.35 mmol) in 1,2-DCE (1.50 mL), reacting for 1 h and then being isolated by FCC (1:12 EtOAc:Hex) as a colorless viscous oil (66 mg, 70%). RF (1:4 EtOAc:Hex): 0.60. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.88–7.77 (m, 5H), 7.73–7.62 (m, 3H), 7.50–7.42 (m, 2H), 5.84 (dddd, J = 17.1, 10.2, 8.2, 5.7 Hz, 1H), 5.63 (dd, J = 10.5, 6.0 Hz, 1H), 5.20 (dd, J = 17.1, 1.2 Hz, 1H), 5.05 (d, J = 10.1 Hz, 1H), 3.60–3.46 (m, 1H), 3.19–3.05 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.6, 136.8, 134.6, 134.1, 133.4, 133.1, 132.0, 128.6, 128.4, 127.8, 127.3, 126.4, 126.4, 126.2, 123.4, 118.5, 54.8, 35.6. IR ν_max (cm^–1): 3047, 2955, 2909, 1768, 1701, 1382, 1351, 1328, 1077, 923, 713. HRMS (ESI) m/z: [M + H]+ Calcd for C₂₂H₁₈NO₂ 328.1338; Found 328.1328

2-(1-(Furan-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2m)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(furan-2-yl)methyl acetate (75 mg, 0.263 mmol), Ca(NTf₂)₂ (7.8 mg, 0.013 mmol), nBu₄NPF₆ (5.0 mg, 0.013 mmol), and allyl-TMS (50 μL, 0.32 mmol) in 1,2-DCE (1.30 mL), reacting for 1 h and then being isolated by FCC (1:9 EtOAc:Hex) as a colorless viscous oil (34 mg, 48%). RF (1:4 EtOAc:Hex): 0.60. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.79 (m, 2H), 7.73–7.67 (m, 2H), 7.32 (d, J = 1.1 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 6.33 (dd, J = 3.3, 1.8 Hz, 1H), 5.77 (dddd, J = 17.0, 10.2, 8.3, 5.7 Hz, 1H), 5.50 (dd, J = 10.3, 5.8 Hz, 1H), 5.14 (ddd, J = 17.1, 2.8, 1.6 Hz, 1H), 5.03 (d, J = 10.0 Hz, 1H), 3.28–3.17 (m, 1H), 3.03–2.93 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.8, 151.9, 141.9, 134.0, 133.5, 131.8, 123.3, 118.7, 110.4, 107.7, 47.7, 34.4. IR ν_max (cm^–1): 3118, 2924, 1772, 1707, 1377, 1355, 1135, 1084, 1008, 934, 876, 713. HRMS (ESI) m/z: [M + H]+ Calcd for C₁₆H₁₄NO₃ 268.0968; Found 268.0962

2-(1-(Thiophen-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2n)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(thiophen-2-yl)methyl acetate (75 mg, 0.249 mmol), Ca(NTf₂)₂ (7.5 mg, 0.013 mmol), nBu₄NPF₆ (4.8 mg, 0.013 mmol), and allyl-TMS (47 μL, 0.30 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h and then being isolated by FCC (1:9 EtOAc:Hex) as a colorless viscous oil (65 mg, 92%). RF (1:4 EtOAc:Hex): 0.59. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.77 (m, 2H), 7.73–7.65 (m, 2H), 7.22 (dd, J = 5.1, 1.0 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1H), 6.94 (dd, J = 5.1, 3.6 Hz, 1H), 5.81–5.71 (m, 1H), 5.68 (dd, J = 10.4, 6.1 Hz, 1H), 5.14 (dd, J = 17.1, 1.2 Hz, 1H), 5.02 (d, J = 10.1 Hz, 1H), 3.46–3.31 (m, 1H), 3.09–2.93 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.8, 142.0, 134.0, 133.8, 131.7, 126.6, 126.3, 125.3, 123.3, 118.6, 49.6, 37.1. IR ν_max (cm^–1): 3076, 1768, 1701, 1466, 1371, 1347, 1325, 1232, 1067, 916, 708. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₆H₁₄NO₂S 284.0740; Found 284.0735

2-(1-Cyclohexylbut-3-en-1-yl)isoindoline-1,3-dione (2o)

To a 22 mL screw top vial were added cyclohexyl(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.250 mmol), Ca(NTf₂)₂ (7.5 mg, 0.013 mmol), nBu₄NPF₆ (4.8 mg, 0.013 mmol), and allyl-TMS (47 μL, 0.30 mmol) in 1,2-DCE (1.2 mL), reacting overnight and then being isolated by FCC (1:15 EtOAc:Hex) as a colorless viscous oil (68 mg, 96%). RF (1:4 EtOAc:Hex): 0.72. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.77 (m, 2H), 7.74–7.66 (m, 2H), 5.65 (dtd, J = 16.9, 9.6, 5.2 Hz, 1H), 4.98 (d, J = 17.0 Hz, 1H), 4.88 (d, J = 10.1 Hz, 1H), 4.07–3.94 (m, 1H), 2.90–2.74 (m, 1H), 2.66–2.52 (m, 1H), 2.16–2.03 (m, 1H), 1.99–1.89 (m, 1H), 1.82–1.72 (m, 1H), 1.70–1.60 (m, 2H), 1.59–1.51 (m, 1H), 1.36–0.86 (m, 5H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.8, 135.1, 133.8, 131.7, 123.1, 117.6, 56.9, 39.2, 33.8, 30.7, 30.3, 26.2, 25.8, 25.7. Data in accordance with literature.

2-(Phenyl(phenylthio)methyl)isoindoline-1,3-dione (3a)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (50 mg, 0.169 mmol), Ca(NTf₂)₂ (5.1 mg, 0.009 mmol), nBu₄NPF₆ (3.3 mg, 0.009 mmol), and thiophenol (21 μL, 0.203 mmol) in 1,2-DCE (0.85 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a colorless viscous oil (58 mg, 99%). RF (1:4 EtOAc:Hex): 0.46. ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.74 (m, 2H), 7.73–7.64 (m, 4H), 7.50–7.43 (m, 2H), 7.39–7.28 (m, 3H), 7.24–7.19 (m, 3H), 6.74 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.8, 136.8, 134.2, 133.5, 133.1, 131.5, 129.2, 128.6, 128.3, 128.1, 123.5, 61.0. IR ν_max (cm^–1): 3058, 1764, 1712, 1375, 1343, 1310, 1068, 889, 695. HRMS (ESI) m/z: [M–PhS]⁺ Calcd for C₁₅H₁₀N₂O₄ 236.0706; Found 236.0711.

2-((3-Bromo-2-fluorophenyl)(phenylthio)methyl)isoindoline-1,3-dione (3b)

To a 22 mL screw top vial were added (3-bromo-2-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.191 mmol), Ca(NTf₂)₂ (5.7 mg, 0.010 mmol), nBu₄NPF₆ (3.7 mg, 0.010 mmol), and thiophenol (23 μL, 0.229 mmol) in 1,2-DCE (0.96 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a colorless viscous oil (79 mg, 94%). RF (1:4 EtOAc:Hex): 0.63. ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.11 (m, 1H), 7.81–7.75 (m, 2H), 7.72–7.66 (m, 2H), 7.56–7.46 (m, 3H), 7.27–7.22 (m, 3H), 7.11 (td, J = 8.0, 1.0 Hz, 1H), 6.96 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 166.3 (s), 155.9 (d, J = 249.3 Hz), 134.3 (s), 134.0 (s), 133.7 (s), 132.3 (s), 131.4 (s), 130.4 (d, J = 1.8 Hz), 129.3 (s), 128.8 (s), 125.5 (d, J = 14.1 Hz), 125.0 (d, J = 4.6 Hz), 123.6 (s), 109.1 (d, J = 21.4 Hz), 54.2 (d, J = 3.2 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −108.95 (t, J = 6.7 Hz). IR ν_max (cm^–1): 3058, 1763, 1716, 1449, 1373, 1321, 1224, 1067, 889, 713. HRMS (ESI) m/z: [M–SPh]⁺ Calcd for C₁₅H₈NO₂FBr 331.9717; 331.9714

2-((4-Nitrophenyl)(phenylthio)methyl)isoindoline-1,3-dione (3c)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-nitrophenyl)methyl acetate (75 mg, 0.220 mmol), Ca(NTf₂)₂ (6.6 mg, 0.011 mmol), nBu₄NPF₆ (4.3 mg, 0.011 mmol), and thiophenol (27 μL, 0.264 mmol) in 1,2-DCE (1.10 mL), reacting for 15 min and then being isolated by FCC (1:4 EtOAc:Hex) as an off-white solid obtained (79 mg, 92%). RF (1:3 EtOAc:Hex): 0.23. ¹H NMR (400 MHz, CDCl₃) δ 8.25–8.18 (m, 2H), 7.90–7.84 (m, 2H), 7.85–7.79 (m, 2H), 7.78–7.70 (m, 2H), 7.51–7.42 (m, 2H), 7.31–7.20 (m, 3H), 6.75 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.6, 147.8, 143.8, 134.6, 133.5, 132.5, 131.3, 129.5, 129.2, 128.9, 123.8, 123.8, 60.3. IR ν_max (cm^–1): 3106, 3080, 1772, 1714, 1597, 1515, 1343, 1319, 1079, 892, 713. HRMS (ESI) m/z: [M–H]⁻ Calcd for C₂₁H₁₃N₂O₄S 389.0602; Found 389.0592.

2-(((2-Fluorophenyl)thio)(thiophen-2-yl)methyl)isoindoline-1,3-dione (3d)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(thiophen-2-yl)methyl acetate (75 mg, 0.249 mmol), Ca(NTf₂)₂ (7.5 mg, 0.012 mmol), nBu₄NPF₆ (4.8 mg, 0.012 mmol), and 2-fluorothiophenol (32 μL, 0.299 mmol) in 1,2-DCE (1.25 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid obtained (59 mg, 64%). RF (1:4 EtOAc:Hex): 0.43. ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.78 (m, 2H), 7.73–7.68 (m, 2H), 7.46 (td, J = 7.5, 1.7 Hz, 1H), 7.32–7.26 (m, 3H), 7.08–7.01 (m, 1H), 7.00–6.94 (m, 2H), 6.90 (d, J = 0.6 Hz, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 166.3 (s), 162.8 (d, J = 248.0 Hz), 139.1 (s), 136.5 (s), 134.3 (s), 131.6 (d, J = 8.1 Hz), 131.5 (s), 127.7 (s), 126.8 (s), 126.63 (s), 124.7 (d, J = 3.9 Hz), 123.6 (s), 119.8 (d, J = 18.4 Hz), 116.1 (d, J = 23.0 Hz), 55.4 (d, J = 2.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −106.62 (ddd, J = 9.1, 7.3, and 5.1 Hz). IR ν_max (cm^–1): 3067, 2924, 1764, 1714, 1466, 1353, 1325, 1218, 1081, 885, 762, 702. HRMS (ESI) m/z: [M–S(C₆H₅F)]⁺ Calcd for C₁₃H₈NO₂S 242.0270; Found 242.0270.

2-(Cyclopropyl((4-methoxyphenyl)thio)methyl)isoindoline-1,3-dione (3e)

To a 22 mL screw top vial were added cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.289 mmol), Ca(NTf₂)₂ (8.7 mg, 0.015 mmol), nBu₄NPF₆ (5.6 mg, 0.015 mmol), and 4-methoxythiophenol (43 μL, 0.347 mmol) in 1,2-DCE (1.45 mL), reacting for 15 min and then being isolated by FCC (1:8 EtOAc:Hex) as a pale-yellow solid obtained (85 mg, 87%). RF (1:4 EtOAc:Hex): 0.47. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.74 (m, 2H), 7.73–7.66 (m, 2H), 7.36–7.31 (m, 2H), 6.75–6.65 (m, 2H), 4.61 (d, J = 10.5 Hz, 1H), 3.71 (s, 3H), 2.11–1.99 (m, 1H), 0.90–0.78 (m, 1H), 0.64–0.52 (m, 2H), 0.39–0.30 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.0, 160.1, 136.6, 134.0, 131.6, 131.6, 123.3, 114.5, 64.5, 55.2, 14.2, 6.6, 5.7. IR ν_max (cm^–1): 2996, 2927, 2834, 1764, 1712, 1589, 1494, 1371, 1246, 1079, 1030, 837, 710. HRMS (ESI) m/z: [M–S(C₆H₅OCH₃)]⁺ Calcd for C₁₂H₁₀NO₂ 200.0706; Found 200.0706.

2-((Ethylthio)(4-methoxyphenyl)methyl)isoindoline-1,3-dione (3f)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-methoxyphenyl)methyl acetate (50 mg, 0.154 mmol), Ca(NTf₂)₂ (4.6 mg, 0.008 mmol), nBu₄NPF₆ (3.0 mg, 0.008 mmol), and ethanethiol (13 μL, 0.185 mmol) in 1,2-DCE (0.77 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a colorless oil obtained (41 mg, 81%). RF (1:4 EtOAc:Hex): 0.45. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.81 (m, 2H), 7.74–7.68 (m, 2H), 7.61–7.55 (m, 2H), 6.89–6.83 (m, 2H), 6.46 (s, 1H), 3.78 (s, 3H), 2.73–2.54 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.1, 159.5, 134.2, 131.7, 129.4, 129.3, 123.5, 113.7, 56.6, 55.3, 26.6, 14.5. IR ν_max (cm^–1): 2929, 2840, 1754, 1709, 1608, 1511, 1373, 1312, 1250, 1189, 1098, 1021, 891, 829, 710. HRMS (ESI) m/z: [M–SEt]⁺ Calcd for C₁₆H₁₂NO₃ 266.0812; Found 266.0806.

2-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)isoindoline-1,3-dione (3g)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (50 mg, 0.169 mmol), Ca(NTf₂)₂ (5.1 mg, 0.008 mmol), nBu₄NPF₆ (3.3 mg, 0.008 mmol), and 5-bromo-N-methylindole (43 mg, 0.203 mmol) in 1,2-DCE (0.85 mL), reacting for 15 min and then being isolated by FCC (1:8 to 1:6 EtOAc:Hex) as an off-white solid obtained (71 mg, 94%). RF (1:4 EtOAc:Hex): 0.31. ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.78 (m, 2H), 7.71–7.66 (m, 2H), 7.64 (d, J = 1.7 Hz, 1H), 7.50–7.45 (m, 2H), 7.36–7.25 (m, 4H), 7.17–7.10 (m, 2H), 6.95 (s, 1H), 3.72 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.9, 137.6, 134.3, 133.0, 130.8, 130.2, 127.8, 127.4, 126.8, 126.6, 123.7, 122.4, 120.3, 112.0, 110.5, 109.9, 48.9, 32.1. IR ν_max (cm^–1): 3058, 3030, 2920, 165, 1701, 1474, 1382, 1353, 1321, 1070, 894, 792, 714. HRMS (ESI) m/z: [M–C₉H₇NBr]⁺ Calcd for C₁₅H₁₀NO₂ 236.0706 Found 236.0703

2-((5-Bromo-1-methyl-1H-indol-3-yl)(2-methoxyphenyl)methyl)isoindoline-1,3-dione (3h)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(2-methoxyphenyl)methyl acetate (75 mg, 0.231 mmol), Ca(NTf₂)₂ (6.9 mg, 0.012 mmol), nBu₄NPF₆ (4.5 mg, 0.012 mmol), and 5-bromo-N-methylindole (58 mg, 0.277 mmol) in 1,2-DCE (1.16 mL), reacting for 15 min and then being isolated by FCC (1:4 EtOAc:Hex) as an off-white solid obtained (90 mg, 82%). RF (1:4 EtOAc:Hex): 0.24. ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.76 (m, 2H), 7.70–7.63 (m, 2H), 7.58 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 7.6, 1.4 Hz, 1H), 7.30–7.24 (m, 2H), 7.21 (s, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 6.88 (td, J = 8.3, 2.0 Hz, 2H), 3.76 (s, 3H), 3.70 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.1, 156.9, 135.6, 133.9, 132.0, 130.4, 130.3, 129.2, 128.6, 126.4, 124.7, 123.2, 121.6, 120.2, 112.9, 111.6, 110.9, 110.4, 55.7, 45.1, 33.0. IR ν_max (cm^–1): 3052, 2961, 2920, 1772, 1705, 1476, 1354, 1239, 1107, 869, 874, 756, 728, 712. HRMS (ESI) m/z: [M–C₉H₇NBr]⁺ Calcd for C₁₆H₁₂NO₃ 266.0812; Found 266.0811.

2-((5-Bromo-1-methyl-1H-indol-3-yl)(furan-2-yl)methyl)isoindoline-1,3-dione (3i)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(furan-2-yl)methyl acetate (75 mg, 0.263 mmol), Ca(NTf₂)₂ (7.9 mg, 0.013 mmol), nBu₄NPF₆ (5.1 mg, 0.013 mmol), and 5-bromo-N-methylindole (66 mg, 0.316 mmol) in 1,2-DCE (1.32 mL), reacting for 15 min and then being isolated by FCC (1:6 to 1:4 EtOAc:Hex) as a brown solid. (82 mg, 72%). RF (1:4 EtOAc:Hex): 0.29. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (t, J = 3.5 Hz, 1H), 7.78 (td, J = 5.3, 2.1 Hz, 2H), 7.69–7.62 (m, 2H), 7.43 (s, 1H), 7.37 (t, J = 1.1 Hz, 1H), 7.27 (dd, J = 8.7, 1.8 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.92 (s, 1H), 6.35 (t, J = 2.3 Hz, 2H), 3.74 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.5, 151.2, 142.2, 135.2, 134.0, 131.9, 131.4, 128.4, 124.9, 123.4, 121.5, 113.3, 111.0, 110.6, 109.4, 108.9, 43.7, 33.2. IR ν_max (cm^–1): 3119, 2920, 1763, 1705, 1476, 1343, 1317, 1142, 1107, 1008, 790, 728. HRMS (ESI) m/z: [M–C₉H₇NBr]⁺ Calcd for C₁₃H₈NO₃ 226.0499; Found 226.0495.

2-((3,5-Bis(trifluoromethyl)phenyl)(5-bromo-1-methyl-1H-indol-3-yl)methyl) isoindoline-1,3-dione (3j)

To a 22 mL screw top vial were added (3,5-bis(trifluoromethyl)phenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.174 mmol), Ca(NTf₂)₂ (5.2 mg, 0.009 mmol), nBu₄NPF₆ (3.4 mg, 0.009 mmol), and 5-bromo-N-methylindole (44 mg, 0.209 mmol) in 1,2-DCE (0.87 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid. (94 mg, 93%). RF (1:4 EtOAc:Hex): 0.45. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 2H), 7.88–7.81 (m, 3H), 7.76–7.70 (m, 2H), 7.67 (d, J = 1.6 Hz, 1H), 7.32 (dd, J = 8.7, 1.8 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.15 (s, 1H), 7.04 (s, 1H), 3.77 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 167.7 (s), 141.5 (s), 135.4 (s), 134.5 (s), 132.4–131.3 (m), 131.6 (s), 131.1 (s), 128.4 (s), 128.1 (d, J = 2.7 Hz), 125.3 (s), 123.7 (s), 123.2 (q, J = 272.8 Hz), 121.9–121.7 (m), 121.1 (s), 113.5 (s), 111.2 (s), 110.0 (s), 49.1 (s), 33.3 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −62.67. IR ν_max (cm^–1): 3062, 2922, 1774, 1705, 1477, 1354, 1280, 1164, 1108, 921, 794, 712. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₆H₁₆ F₆N₂O₂ 581.0294; Found 581.0283.

2-((5-Bromo-1-methyl-1H-indol-3-yl)(cyclohexyl)methyl)isoindoline-1,3-dione (3k)

To a 22 mL screw top vial were added cyclohexyl(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.242 mmol), Ca(NTf₂)₂ (7.2 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and 5-bromo-N-methylindole (61 mg, 0.290 mmol) in 1,2-DCE (1.21 mL), reacting for 15 min and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid. (97 mg, 89%). RF (1:4 EtOAc:Hex): 0.47. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 1.7 Hz, 1H), 7.78–7.72 (m, 2H), 7.65–7.59 (m, 2H), 7.40 (s, 1H), 7.25 (dd, J = 8.6, 1.8 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 5.26 (d, J = 11.4 Hz, 1H), 3.74 (s, 3H), 2.76 (qt, J = 11.2, 3.2 Hz, 1H), 1.77–1.61 (m, 5H), 1.36–1.14 (m, 3H), 1.13–1.00 (m, 1H), 0.98–0.85 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 168.4, 134.9, 133.8, 131.9, 130.2, 129.6, 124.6, 123.1, 121.6, 113.0, 111.8, 110.7, 51.7, 38.5, 33.1, 31.3, 30.5, 26.3, 25.76, 25.67. IR ν_max (cm^–1): 2926, 2845, 1761, 1697, 1474, 1377, 1326, 1071, 793, 731. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₄H₂₄N₂O₂Br 451.1016; Found 451.1007

N-((1,3-Dioxoisoindolin-2-yl)(phenyl)methyl)benzamide (3l)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and benzamide (37 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h and then being isolated by FCC (1:3 EtOAc:Hex) as a white solid (52 mg, 57%). RF (1:1 EtOAc:Hex): 0.71. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 9.6 Hz, 1H), 7.89–7.83 (m, 4H), 7.76–7.70 (m, 2H), 7.62 (d, J = 9.6 Hz, 1H), 7.55–7.47 (m, 3H), 7.47–7.42 (m, 2H), 7.41–7.30 (m, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.7, 166.3, 137.1, 134.4, 133.3, 132.2, 131.7, 129.0, 128.7, 127.3, 126.1, 123.7, 58.8. IR ν_max (cm^–1): 3369, 3050, 1776, 1710, 1664, 1511, 1312, 1258, 1123, 878, 718. HRMS (ESI) m/z:: [M + H]⁺ Calcd for C₂₂H₁₇N₂O₃ 357.1234; Found 357.1236.

N-((3-Chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)-4-methoxybenzamide (3m)

To a 22 mL screw top vial were added (3-chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.227 mmol), Ca(NTf₂)₂ (6.8 mg, 0.011 mmol), nBu₄NPF₆ (4.4 mg, 0.011 mmol), and 4-methoxybenzamide (41 mg, 0.272 mmol) in 1,2-DCE (1.14 mL), reacting for 1 h and then being isolated by FCC (1:3 EtOAc:Hex) as a white solid. (34 mg, 36%). RF (1:3 EtOAc:Hex): 0.20. ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.86 (m, 2H), 7.86–7.80 (m, 3H), 7.78–7.72 (m, 2H), 7.59 (d, J = 9.7 Hz, 1H), 7.49–7.46 (m, 1H), 7.38–7.33 (m, 1H), 7.33–7.29 (m, 2H), 6.97–6.91 (m, 2H), 3.85 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.6, 165.8, 162.9, 139.4, 135.0, 134.5, 131.6, 130.2, 129.3, 128.9, 126.4, 125.3, 124.4, 123.9, 114.0, 58.1, 55.5. IR ν_max (cm^–1): 3367, 2922, 1774, 1707, 1604, 1489, 1313, 1246, 1172, 1026, 842, 721. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₃H₁₈N₂O₄Cl 421.0950; Found 421.0952.

N-((1,3-Dioxoisoindolin-2-yl)(naphthalen-2-yl)methyl)propionamide (3n)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(naphthalen-2-yl)methyl acetate (75 mg, 0.217 mmol), Ca(NTf₂)₂ (6.5 mg, 0.011 mmol), nBu₄NPF₆ (4.2 mg, 0.011 mmol), and propanamide (19 mg, 0.260 mmol) in 1,2-DCE (1.09 mL), reacting for 1 h and then being isolated by FCC (1:3 to 1:2 EtOAc:Hex) as a white solid. (31 mg, 40%). RF (1:3 EtOAc:Hex): 0.17. ¹H NMR (400 MHz, CDCl₃) δ 7.89–7.77 (m, 6H), 7.76–7.70 (m, 2H), 7.57 (d, J = 9.7 Hz, 1H), 7.53 (dd, J = 8.6, 1.9 Hz, 1H), 7.50–7.44 (m, 2H), 7.31 (d, J = 9.7 Hz, 1H), 2.44–2.28 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 173.0, 167.6, 134.5, 134.4, 133.2, 133.0, 131.7, 129.0, 128.2, 127.6, 126.6, 126.6, 125.2, 123.7, 58.4, 29.5, 9.4. IR ν_max (cm^–1): 3371, 2924, 1774, 1707, 1500, 1351, 1209, 1097, 715. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₂H₁₉N₂O₃ 359.1390; Found 359.1393

Benzyl ((1,3-Dioxoisoindolin-2-yl)(phenyl)methyl)carbamate (3o)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and benzyl carbamate (46 mg, 0.304 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h and then being isolated by FCC (1:4 EtOAc:Hex) as a colorless oil. (98 mg, 99%). RF (1:3 EtOAc:Hex): 0.34. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.79 (m, 2H), 7.74–7.67 (m, 2H), 7.46–7.39 (m, 2H), 7.36–7.27 (m, 7H), 7.22–7.12 (m, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.14 (dd, J = 39.6, 12.2 Hz, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 167.4, 155.3, 136.9, 135.9, 134.4, 131.8, 128.9, 128.6, 128.6, 128.3, 126.0, 123.7, 67.5, 60.5. IR ν_max (cm^–1): 3350, 3062, 3032, 2952, 1774, 1703, 1494, 1381, 1351, 1215, 1116, 1038, 883, 717, 693. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₂₃H₁₈N₂O₄Na 409.1159; Found 409.1181

2-(1,3-Dioxoisoindolin-2-yl)-2-phenylacetonitrile (4a)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (295 mg, 1.00 mmol), Ca(NTf₂)₂ (30 mg, 0.05 mmol), nBu₄NPF₆ (19 mg, 0.05 mmol), and TMSCN (250 μL, 2.00 mmol) in 1,2-DCE (5.0 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (202 mg, 77%). RF (1:4 EtOAc:Hex): 0.42. ¹H NMR (400 MHz, CDCl₃) δ 7.93–7.86 (m, 2H), 7.81–7.74 (m, 2H), 7.66–7.60 (m, 2H), 7.45–7.38 (m, 3H), 6.39 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.7, 134.8, 131.7, 131.3, 129.7, 129.2, 127.8, 124.1, 114.7, 43.0. IR ν_max (cm^–1): 2911, 1712, 1377, 1341, 1099, 885, 712. HRMS (ESI) m/z: [M + K]⁺ Calcd for C₁₆H₁₀N₂O₂K 301.0374; Found 301.0380

2-(1,3-Dioxoisoindolin-2-yl)-2-(4-fluorophenyl)acetonitrile (4b)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-fluorophenyl)methyl acetate (75 mg, 0.239 mmol), Ca(NTf₂)₂ (7.2 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and TMSCN (60 μL, 0.478 mmol) in 1,2-DCE (1.20 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (56 mg, 83%). RF (1:4 EtOAc:Hex): 0.44. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.86 (m, 2H), 7.82–7.76 (m, 2H), 7.67–7.60 (m, 2H), 7.14–7.06 (m, 2H), 6.36 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 165.6 (s), 163.3 (d, J = 250.1 Hz), 134.9 (s), 131.2 (s), 130.1 (d, J = 8.7 Hz), 127.8 (d, J = 3.4 Hz), 124.1 (s), 116.3 (d, J = 22.1 Hz), 114.6 (s), 42.4 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −110.73. IR ν_max (cm^–1): 2912, 1716, 1604, 1507, 1377, 1330, 1220, 1095, 840, 713

HRMS (ESI) m/z: [M–CN]⁺ Calcd for C₁₅H₉NO₂F 254.0612; Found 254.0615.

2-(3-Chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4c)

To a 22 mL screw top vial were added (3-chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (50 mg, 0.152 mmol), Ca(NTf₂)₂ (4.6 mg, 0.0076 mmol), nBu₄NPF₆ (2.9 mg, 0.0076 mmol), and TMSCN (38 μL, 0.303 mmol) in 1,2-DCE (0.76 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (38 mg, 84%). RF (1:4 EtOAc:Hex): 0.32. ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.87 (m, 2H), 7.83–7.77 (m, 2H), 7.61–7.57 (m, 1H), 7.56–7.51 (m, 1H), 7.40–7.35 (m, 2H), 6.36 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.5, 135.2, 135.0, 133.5, 131.2, 130.5, 130.1, 127.9, 126.0, 124.2, 114.2, 42.4. IR ν_max (cm^–1): 2933, 1776, 1722, 1470, 1433, 1381, 1325, 1079, 788, 721, 684. HRMS (ESI) m/z: [M–H]⁻ Calcd for C₁₆H₈N₂O₂Cl 295.0280; Found 295.0280

2-(2-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4d)

To a 22 mL screw top vial were added (2-bromophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.200 mmol), Ca(NTf₂)₂ (6.0 mg, 0.010 mmol), nBu₄NPF₆ (3.9 mg, 0.010 mmol), and TMSCN (50 μL, 0.400 mmol) in 1,2-DCE (1.00 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (50 mg, 73%). RF (1:4 EtOAc:Hex): 0.47. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (dd, J = 7.9, 1.6 Hz, 1H), 7.92–7.85 (m, 2H), 7.83–7.74 (m, 2H), 7.58 (dd, J = 8.0, 1.2 Hz, 1H), 7.47 (td, J = 7.7, 1.2 Hz, 1H), 7.30 (td, J = 7.7, 1.6 Hz, 1H), 6.66 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.5, 134.9, 133.5, 132.2, 131.5, 131.2, 130.0, 127.8, 124.1, 122.7, 114.8, 43.8. IR ν_max (cm^–1): 2916, 1772, 1718, 1466, 1373, 1326, 1082, 1026, 890, 717. HRMS (ESI) m/z: [M + Na]⁺ Calcd for C₁₆H₉N₂O₂BrNa 362.9740; Found 362.9735.

2-(3-Bromo-2-fluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4e)

To a 22 mL screw top vial were added (3-bromo-2-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.191 mmol), Ca(NTf₂)₂ (5.7 mg, 0.010 mmol), nBu₄NPF₆ (3.7 mg, 0.010 mmol), and TMSCN (48 μL, 0.382 mmol) in 1,2-DCE (0.96 mL), reacting overnight and then being isolated by FCC (1:8 EtOAc:Hex) as a white solid (19 mg, 28%). RF (1:4 EtOAc:Hex): 0.43. ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.97 (m, 1H), 7.93–7.87 (m, 2H), 7.82–7.76 (m, 2H), 7.63 (ddd, J = 8.1, 6.6, 1.5 Hz, 1H), 7.18 (td, J = 8.0, 1.0 Hz, 1H), 6.67 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 165.2 (s), 156.2 (d, J = 251.4 Hz), 135.5 (s), 134.9 (s), 131.2 (s), 130.1 (d, J = 1.5 Hz), 125.5 (d, J = 4.7 Hz), 124.2 (s), 120.1 (d, J = 14.3 Hz), 113.8 (s), 109.7 (d, J = 20.4 Hz), 37.8 (d, J = 4.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −109.38. IR ν_max (cm^–1): 2920, 1772, 1729, 1466, 1377, 1328, 1080, 894, 792, 743, 719. HRMS (ESI) m/z: [M–H]⁻ Calcd for C₁₆H₇N₂O₂BrF 356.9680; Found 356.9682

2-(1,3-Dioxoisoindolin-2-yl)-2-(p-tolyl)acetonitrile (4f)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(p-tolyl)methyl acetate (50 mg, 0.162 mmol), Ca(NTf₂)₂ (4.9 mg, 0.008 mmol), nBu₄NPF₆ (3.1 mg, 0.008 mmol), and TMSCN (41 μL, 0.324 mmol) in 1,2-DCE (0.81 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (39 mg, 87%). RF (1:4 EtOAc:Hex): 0.36. ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.83 (m, 2H), 7.80–7.73 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 2.34 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.7, 139.9, 134.8, 131.3, 129.9, 128.8, 127.8, 124.0, 114.9, 42.8, 21.2. IR ν_max (cm^–1): 3069, 2909, 1787, 1716, 1513, 1466, 1369, 1332, 1097, 1082, 939, 885, 820, 713. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₇H₁₃N₂O₂ 277.0972; Found 277.0974.

2-(1,3-Dioxoisoindolin-2-yl)-2-(2-methoxyphenyl)acetonitrile (4g)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(2-methoxyphenyl)methyl acetate (50 mg, 0.154 mmol), Ca(NTf₂)₂ (4.6 mg, 0.008 mmol), nBu₄NPF₆ (3.0 mg, 0.008 mmol), and TMSCN (39 μL, 0.308 mmol) in 1,2-DCE (0.77 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (35 mg, 78%). RF (1:4 EtOAc:Hex): 0.30. ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.90 (m, 1H), 7.91–7.83 (m, 2H), 7.79–7.72 (m, 2H), 7.38 (td, J = 8.1, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.0 Hz, 1H), 6.91–6.84 (m, 1H), 6.71 (s, 1H), 3.80 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.6, 156.3, 134.6, 131.4, 131.3, 130.5, 123.9, 120.7, 119.1, 115.3, 110.7, 55.7, 38.7. IR ν_max (cm^–1): 2914, 2845, 1774, 1720, 1492, 1466, 1375, 1332, 1250, 1108, 1025, 754, 715. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₇H₁₃N₂O₃ 293.0921; Found 293.0924

2-(1,3-Dioxoisoindolin-2-yl)-2-(naphthalen-2-yl)acetonitrile (4h)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(naphthalen-2-yl)methyl acetate (50 mg, 0.145 mmol), Ca(NTf₂)₂ (4.3 mg, 0.007 mmol), nBu₄NPF₆ (2.8 mg, 0.007 mmol), and TMSCN (36 μL, 0.290 mmol) in 1,2-DCE (0.73 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (41 mg, 91%). RF (1:4 EtOAc:Hex): 0.23. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J = 0.9 Hz, 1H), 7.91–7.78 (m, 5H), 7.77–7.71 (m, 2H), 7.60 (dd, J = 8.6, 1.9 Hz, 1H), 7.55–7.48 (m, 2H), 6.55 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.7, 134.8, 133.5, 132.9, 131.3, 129.4, 128.9, 128.4, 127.8, 127.7, 127.3, 127.0, 124.4, 124.1, 114.8, 43.2. IR ν_max (cm^–1): 2901, 1787, 1716, 1602, 1466, 1369, 1328, 1097, 1084, 911, 833, 758, 711. HRMS (ESI) m/z: [M + NH₄]⁺ Calcd for C₂₀H₁₆N₃O₂ 330.1237; Found 330.1243

2-(1,3-Dioxoisoindolin-2-yl)-2-(furan-2-yl)acetonitrile (4i)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(furan-2-yl)methyl acetate (50 mg, 0.175 mmol), Ca(NTf₂)₂ (5.3 mg, 0.009 mmol), nBu₄NPF₆ (3.4 mg, 0.009 mmol), and TMSCN (44 μL, 0.350 mmol) in 1,2-DCE (0.88 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (13 mg, 29%). RF (1:4 EtOAc:Hex): 0.28. ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.89 (m, 2H), 7.82–7.77 (m, 2H), 7.39 (dd, J = 1.8, 0.7 Hz, 1H), 6.78 (dt, J = 3.4, 0.8 Hz, 1H), 6.45–6.40 (m, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.3, 144.0, 143.6, 134.9, 131.2, 124.2, 113.2, 111.4, 111.2, 36.9. IR ν_max (cm^–1): 2918, 2849, 1771, 1720, 1371, 1321, 1108, 1012, 922, 751, 713. HRMS (ESI) m/z: [M–CN]⁺ Calcd for C₁₃H₈NO₃ 226.0499; Found 226.0501

2-(1,3-Dioxoisoindolin-2-yl)-2-(thiophen-2-yl)acetonitrile (4j)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(thiophen-2-yl)methyl acetate (75 mg, 0.249 mmol), Ca(NTf₂)₂ (7.5 mg, 0.012 mmol), nBu₄NPF₆ (4.8 mg, 0.012 mmol), and TMSCN (63 μL, 0.500 mmol) in 1,2-DCE (1.25 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (53 mg, 79%). RF (1:4 EtOAc:Hex): 0.35. ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.88 (m, 2H), 7.82–7.76 (m, 2H), 7.44 (d, J = 3.5 Hz, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.01 (dd, J = 5.1, 3.6 Hz, 1H), 6.55 (s, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 165.3, 134.9, 133.3, 131.2, 129.5, 128.1, 127.2, 124.2, 114.3, 38.2. IR ν_max (cm^–1): 2911, 1776, 1716, 1466, 1377, 1334, 1105, 933, 879, 713. HRMS (ESI) m/z: [M–CN]⁺ Calcd for C₁₃H₈NO₂S 242.0270; Found 242.0274

2-Cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4k)

To a 22 mL screw top vial were added cyclohexyl(1,3-dioxoisoindolin-2-yl)methyl acetate (23 mg, 0.076 mmol), Ca(NTf₂)₂ (2.3 mg, 0.004 mmol), nBu₄NPF₆ (1.5 mg, 0.004 mmol), and TMSCN (19 μL, 0.153 mmol) in 1,2-DCE (0.38 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (18 mg, 88%).

RF (1:4 EtOAc:Hex): 0.43. ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.88 (m, 2H), 7.84–7.76 (m, 2H), 4.86–4.77 (m, 1H), 2.34 (qt, J = 11.3, 3.5 Hz, 1H), 2.24–2.14 (m, 1H), 1.90–1.80 (m, 1H), 1.76–1.64 (m, 2H), 1.62–1.52 (m, 1H), 1.41–1.28 (m, 1H), 1.24–1.11 (m, 3H), 1.02–0.89 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.3, 134.8, 131.2, 124.0, 115.5, 45.4, 38.6, 30.1, 29.0, 25.7, 25.1, 25.0. IR ν_max (cm^–1): 2927, 2849, 1772, 1718, 1466, 1453, 1377, 1080, 916, 862, 793, 713. HRMS (ESI) m/z: [M + NH₄]⁺ Calcd for C₁₆H₂₀N₃O₂ 286.1550; Found 286.1554

2-Cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4l)

To a 22 mL screw top vial were added cyclopropyl(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.289 mmol), Ca(NTf₂)₂ (8.7 mg, 0.015 mmol), nBu₄NPF₆ (5.6 mg, 0.015 mmol), and TMSCN (72 μL, 0.579 mmol) in 1,2-DCE (1.45 mL), reacting overnight and then being isolated by FCC (1:6 EtOAc:Hex) as a white solid (56 mg, 86%). RF (1:4 EtOAc:Hex): 0.38. ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.90 (m, 2H), 7.84–7.80 (m, 2H), 4.45 (d, J = 9.6 Hz, 1H), 1.91–1.82 (m, 1H), 0.94–0.84 (m, 1H), 0.77–0.61 (m, 2H), 0.55–0.44 (m, 1H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.1, 134.8, 131.3, 124.0, 115.3, 44.3, 13.4, 4.8, 4.7. IR ν_max (cm^–1): 3006, 2927, 1770, 1712, 1466, 1381, 1330, 1187, 1095, 1030, 903, 838, 797, 711. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₃H₁₁N₂O₂ 227.0815; Found 227.0814.

tert-Butyl (1-phenylbut-3-en-1-yl)carbamate (5a)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (100 mg, 0.339 mmol), Ca(NTf₂)₂ (10 mg, 0.017 mmol), nBu₄NPF₆ (7 mg, 0.017 mmol), and allyl-TMS (64 μL, 0.406 mmol) in 1,2-DCE (1.7 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (206 μL, 1.695 mmol) in EtOH (3.4 mL) overnight, followed by Boc₂O (156 μL, 0.678 mmol), Et₃N (47 μL, 0.339 mmol), and DMAP (cat.) in dry THF (1.7 mL). Following completion of the Boc protection (1 h), purification by FCC (1:12 EtOAc:Hex) afforded the pure compound as a white solid (56 mg, 67% over 3 steps). RF (1:12 EtOAc:Hex):0.50. ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.20 (m, 5H), 5.75–5.61 (m, 1H), 5.17–5.03 (m, 2H), 4.89 (s, br, 1H), 4.74 (s, br, 1H), 2.51 (s, br, 2H), 1.41 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.2, 142.4, 134.0, 128.5, 127.1, 126.2, 118.2, 79.5, 54.0, 41.3, 28.4. Data in accordance with the literature.

tert-Butyl (1-(4-methoxyphenyl)but-3-en-1-yl)carbamate (5b)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-methoxyphenyl)methyl acetate (75 mg, 0.231 mmol), Ca(NTf₂)₂ (7 mg, 0.012 mmol), nBu₄NPF₆ (4.5 mg, 0.012 mmol), and allyl-TMS (44 μL, 0.277 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (134 μL, 1.014 mmol) in EtOH (2.3 mL) overnight, followed by Boc₂O (105 μL, 0.461 mmol), Et₃N (32 μL, 0.231 mmol), and DMAP (cat.) in dry THF (1.2 mL). Following completion of the Boc protection (1 h), purification by FCC (1:12 EtOAc:Hex) afforded the pure compound as a white solid (49 mg, 77% over 3 steps). RF (1:12 EtOAc:Hex):0.17. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.74–5.61 (m, 1H), 5.14–5.02 (m, 2H), 4.81 (s, br, 1H), 4.67 (s, br, 1H), 3.79 (s, 3H), 2.55–2.45 (m, br, 2H), 1.41 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 158.7, 155.2, 134.6, 134.2, 127.4, 118.0, 113.9, 79.4, 55.3, 53.6, 41.2, 28.4. Data in accordance with the literature.

tert-Butyl (1-(p-tolyl)but-3-en-1-yl)carbamate (5c)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(p-tolyl)methyl acetate (75 mg, 0.242 mmol), Ca(NTf₂)₂ (7 mg, 0.012 mmol), nBu₄NPF₆ (4.7 mg, 0.012 mmol), and allyl-TMS (46 μL, 0.290 mmol) in 1,2-DCE (1.2 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (140 μL, 1.21 mmol) in EtOH (2.3 mL) overnight, followed by Boc₂O (111 μL, 0.484 mmol), Et₃N (34 μL, 0.242 mmol), and DMAP (cat.) in dry THF (1.2 mL). Following completion of the Boc protection (1 h), purification by FCC (1:19 EtOAc:Hex) afforded the pure compound as a white solid (35 mg, 55% over 3 steps). RF (1:12 EtOAc:Hex):0.29. ¹H NMR (400 MHz, CDCl₃) δ 7.20–7.07 (m, 4H), 5.74–5.61 (m, 1H), 5.15–5.02 (m, 2H), 4.84 (s, br, 1H), 4.70 (s, br, 1H), 2.56–2.44 (m, br, 2H), 2.32 (s, 3H), 1.41 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.2, 139.4, 136.7, 134.1, 129.2, 126.2, 118.0, 79.4, 53.8, 41.2, 28.4, 21.1. Data in accordance with the literature.

tert-Butyl (1-(2-methoxyphenyl)but-3-en-1-yl)carbamate (5d)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(2-methoxyphenyl)methyl acetate (40 mg, 0.123 mmol), Ca(NTf₂)₂ (3.7 mg, 0.006 mmol), nBu₄NPF₆ (2.4 mg, 0.006 mmol), and allyl-TMS (23 μL, 0.148 mmol) in 1,2-DCE (0.62 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (71 μL, 0.615 mmol) in EtOH (1.23 mL) overnight, followed by Boc₂O (57 μL, 0.246 mmol), Et₃N (18 μL, 0.123 mmol), and DMAP (cat.) in dry THF (0.62 mL). Following completion of the Boc protection (1 h), purification by FCC (1:15 EtOAc:Hex) afforded the pure compound as a white solid (24 mg, 70% over 3 steps). RF (1:12 EtOAc:Hex):0.37. ¹H NMR (400 MHz, CDCl₃) δ 7.25–7.19 (m, 1H), 7.17–7.13 (m, 1H), 6.94–6.84 (m, 2H), 5.75–5.61 (m, 1H), 5.34 (d, J = 6.6 Hz, 1H), 5.11–4.97 (m, 2H), 4.97–4.85 (m, 1H), 3.85 (s, 3H), 2.58–2.43 (m, 2H), 1.42 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 156.9, 155.2, 135.0, 130.0, 128.2, 128.1, 120.5, 117.2, 110.8, 79.1, 55.3, 51.9, 39.9, 28.4. Data in accordance with the literature.

tert-Butyl (1-(4-fluorophenyl)but-3-en-1-yl)carbamate (5e)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-fluorophenyl)methyl acetate (75 mg, 0.229 mmol), Ca(NTf₂)₂ (7 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and allyl-TMS (46 μL, 0.290 mmol) in 1,2-DCE (1.2 mL), reacting for 2 h, and then MeNH₂ (33 wt % in EtOH) (134 μL, 1.21 mmol) in EtOH (2.3 mL) overnight, followed by Boc₂O (110 μL, 0.484 mmol), Et₃N (33 μL, 0.242 mmol), and DMAP (cat.) in dry THF (1.2 mL). Following completion of the Boc protection (1 h), purification by FCC (1:19 EtOAc:Hex) afforded the pure compound as a white solid (18 mg, 26% over 3 steps). RF (1:12 EtOAc:Hex):0.28. ¹H NMR (400 MHz, CDCl₃) δ 7.23 (dd, J = 8.2, 5.5 Hz, 2H), 7.01 (t, J = 8.6 Hz, 2H), 5.73–5.59 (m, 1H), 5.16–5.05 (m, 2H), 4.84 (s, br, 1H), 4.70 (s, br, 1H), 2.48 (m, br, 2H), 1.35 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ 161.9 (d, J = 244.9 Hz), 155.1 (s), 138.2 (s), 133.7 (s), 127.8 (d, J = 8.0 Hz), 118.5 (s), 115.3 (d, J = 21.4 Hz), 79.7 (s), 53.43 (s), 41.2 (s), 28.3 (s). ¹⁹F NMR (376 MHz, CDCl₃) δ −115.84. Data in accordance with the literature.

tert-Butyl (1-(3-chlorophenyl)but-3-en-1-yl)carbamate (5f)

To a 22 mL screw top vial were added (3-chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.227 mmol), Ca(NTf₂)₂ (6.6 mg, 0.011 mmol), nBu₄NPF₆ (4.3 mg, 0.011 mmol), and allyl-TMS (43 μL, 0.272 mmol) in 1,2-DCE (1.1 mL), reacting for 5 h, and then MeNH₂ (33 wt % in EtOH) (132 μL, 1.14 mmol) in EtOH (2.3 mL) overnight, followed by Boc₂O (104 μL, 0.454 mmol), Et₃N (32 μL, 0.227 mmol), and DMAP (cat.) in dry THF (1.1 mL). Following completion of the Boc protection (1 h), purification by FCC (1:19 EtOAc:Hex) afforded the pure compound as a white solid (21 mg, 30% over 3 steps). RF (1:12 EtOAc:Hex):0.31. ¹H NMR (400 MHz, CDCl₃) δ 7.29–7.19 (m, 3H), 7.17–7.12 (m, 1H), 5.73–5.58 (m, 1H), 5.20–5.06 (m, 2H), 4.87 (s, br, 1H), 4.71 (s, br, 1H), 2.56–2.40 (m, br, 2H), 1.41 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.1, 144.7, 134.4, 133.4, 129.8, 127.3, 126.4, 124.5, 118.7, 79.8, 53.6, 41.1, 28.3. Data in accordance with the literature.

tert-Butyl (1-(2-bromophenyl)but-3-en-1-yl)carbamate (5g)

To a 22 mL screw top vial were added (2-bromophenyl)(1,3-dioxoisoindolin-2-yl)methyl acetate (75 mg, 0.200 mmol), Ca(NTf₂)₂ (6.0 mg, 0.010 mmol), nBu₄NPF₆ (3.9 mg, 0.010 mmol), and allyl-TMS (38 μL, 0.240 mmol) in 1,2-DCE (1.0 mL), reacting for 5 h, and then MeNH₂ (33 wt % in EtOH) (116 μL, 1.00 mmol) in EtOH (2.0 mL) overnight, followed by Boc₂O (92 μL, 0.400 mmol), Et₃N (29 μL, 0.200 mmol), and DMAP (cat.) in dry THF (1.0 mL). Following completion of the Boc protection (1 h), purification by FCC (1:19 EtOAc:Hex) afforded the pure compound as a white solid (22 mg, 31% over 3 steps). RF (1:12 EtOAc:Hex):0.28. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 7.9 Hz, 1H), 7.36–7.21 (m, 2H), 7.16–7.04 (m, 1H), 5.79–5.62 (m, 1H), 5.22–4.79 (m, 4H), 2.56 (s, 1H), 2.50–2.27 (m, 1H), 1.41 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.0, 141.5, 133.6, 133.2, 128.5, 127.5, 127.2, 122.7, 118.6, 79.7, 53.5, 39.5, 28.3. Data in accordance with the literature.

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (5h)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and 5-bromo-N-methylindole (64 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 15 min, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by Boc₂O (117 μL, 0.508 mmol), Et₃N (35 μL, 0.254 mmol), and DMAP (cat.) in dry THF (1.27 mL). Following completion of the Boc protection (1 h), purification by FCC (1:5 EtOAc:Hex) afforded the pure compound as a white solid (41 mg, 39% over 3 steps). RF (1:4 EtOAc:Hex):0.33. ¹H NMR (400 MHz, CDCl₃) δ 7.73–7.60 (m, 1H), 7.39–7.32 (m, 4H), 7.31–7.26 (m, 2H), 7.16–7.10 (m, 1H), 6.57 (s, 1H), 6.14 (s, 1H), 5.15 (s, 1H), 3.64 (s, 3H), 1.46 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.2, 141.8, 136.2, 129.0, 128.5, 128.1, 127.3, 126.8, 124.9, 122.2, 116.3, 112.9, 110.9, 79.8, 51.5, 32.9, 28.4. IR ν_max (cm^–1): 3408, 2976, 2931, 1710, 1495, 1474, 1366, 1237, 1157, 1043, 1012, 881, 799, 754, 705. HRMS (ESI) m/z: [M–BocNH]⁺ Calcd for C₁₆H₁₃N⁸¹Br 300.0205, Found 300.0211

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)(4-methoxyphenyl)methyl)carbamate (5i)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(4-methoxyphenyl)methyl acetate (75 mg, 0.231 mmol), Ca(NTf₂)₂ (6.9 mg, 0.012 mmol), nBu₄NPF₆ (4.5 mg, 0.012 mmol), and 5-bromo-N-methylindole (58 mg, 0.277 mmol) in 1,2-DCE (1.20 mL), reacting for 15 min, and then MeNH₂ (33 wt % in EtOH) (135 μL, 1.16 mmol) in EtOH (2.31 mL) overnight, followed by Boc₂O (106 μL, 0.461 mmol), Et₃N (32 μL, 0.231 mmol), and DMAP (cat.) in dry THF (1.20 mL). Following completion of the Boc protection (1 h), purification by FCC (1:8 to 1:6 EtOAc:Hex) afforded the pure compound as an off-white solid (22 mg, 21% over 3 steps). RF (1:4 EtOAc:Hex):0.28. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (s, 1H), 7.33–7.24 (m, 3H), 7.14 (d, J = 8.7 Hz, 1H), 6.91–6.85 (m, 2H), 6.61 (s, 1H), 6.08 (s, 1H), 5.11 (s, 1H), 3.81 (s, 3H), 3.67 (s, 3H), 1.46 (s, 9H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 158.8, 155.1, 136.2, 128.8, 128.0, 128.0, 124.9, 122.2, 116.5, 113.9, 112.8, 110.9, 79.7, 55.3, 51.0, 32.9, 28.4. IR ν_max (cm^–1): 3330, 2978, 2953, 2924, 1675, 1608, 1511, 1474, 1366, 1159, 1023, 790. HRMS (ESI) m/z: [M + Na]+ Calcd for C₂₂H₂₅N₂O₃Na⁸¹Br 469.0920; Found 469.0927

(9H-Fluoren-9-yl)methyl (1-phenylbut-3-en-1-yl)carbamate (6a)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and allyl-TMS (48 μL, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by FmocCl (79 mg, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Fmoc protection (1 h), purification by FCC (1:19 to 1:6 EtOAc:Hex) afforded the pure compound as a white solid (59 mg, 63% over 3 steps). RF (1:4 EtOAc:Hex):0.83. ¹H NMR (400 MHz, CDCl₃) δ 7.78–7.68 (m, 2H), 7.63–7.10 (m, 11H), 5.76–5.55 (m, 1H), 5.21–5.00 (m, 3H), 4.87–4.58 (m, 1H), 4.49–4.30 (m, 2H), 4.26–4.05 (m, 1H), 2.65–2.34 (m, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.7, 144.0, 141.9, 141.3, 133.9, 128.7, 127.7, 127.4, 127.1, 127.1, 126.3, 125.1, 120.0, 118.4, 66.6, 54.5, 47.3, 41.0. Data in accordance with the literature.

N-(1-Phenylbut-3-en-1-yl)benzamide (6b)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and allyl-TMS (48 μL, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by BzCl (35 μL, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Bz protection (1 h), purification by FCC (1:6 EtOAc:Hex) afforded the pure compound as a white solid (31 mg, 49% over 3 steps). RF (1:4 EtOAc:Hex):0.31. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.72 (m, 2H), 7.52–7.45 (m, 1H), 7.45–7.38 (m, 2H), 7.34 (d, J = 4.4 Hz, 4H), 7.29–7.23 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 5.76 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H), 5.29 (dd, J = 14.4, 6.9 Hz, 1H), 5.22–5.07 (m, 2H), 2.69 (t, J = 6.8 Hz, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 166.8, 141.6, 134.6, 134.1, 131.5, 128.7, 128.6, 127.4, 127.0, 126.5, 118.5, 52.8, 40.6. Data in accordance with the literature.

Allyl (1-Phenylbut-3-en-1-yl)carbamate (6c)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and allyl-TMS (48 μL, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by AllocCl (31 μL, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Alloc protection (1 h), purification by FCC (1:9 EtOAc:Hex) afforded the pure compound as a viscous colorless oil. (34 mg, 58% over 3 steps). RF (1:8 EtOAc:Hex):0.22. ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.22 (m, 5H), 5.99–5.80 (m, 1H), 5.68 (ddt, J = 17.2, 10.1, 7.0 Hz, 1H), 5.37–5.01 (m, 5H), 4.89–4.72 (m, 1H), 4.64–4.45 (m, 2H), 2.55 (t, J = 6.1 Hz, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.5, 142.0, 133.8, 132.8, 128.6, 127.3, 126.2, 118.4, 117.8, 65.6, 54.4, 41.1. Data in accordance with the literature.

N-(1-(Thiophen-2-yl)but-3-en-1-yl)acetamide (6d)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(thiophen-2-yl)methyl acetate (75 mg, 0.249 mmol), Ca(NTf₂)₂ (7.4 mg, 0.012 mmol), nBu₄NPF₆ (4.8 mg, 0.012 mmol), and allyl-TMS (47 μL, 0.299 mmol) in 1,2-DCE (1.25 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (145 μL, 1.27 mmol) in EtOH (2.49 mL) overnight, followed by AcCl (21 μL, 0.299 mmol) and Et₃N (35 μL, 0.249 mmol) in dry DCM (1.25 mL). Following completion of the Ac protection (1 h), purification by FCC (1:4 to 1:2 EtOAc:Hex) afforded the pure compound as a white solid (43 mg, 88% over 3 steps). RF (1:3 EtOAc:Hex):0.19. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (dd, J = 4.2, 2.1 Hz, 1H), 6.98–6.90 (m, 2H), 6.10 (d, J = 7.4 Hz, 1H), 5.75 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.37 (dd, J = 15.3, 6.8 Hz, 1H), 5.19–5.06 (m, 2H), 2.69–2.57 (m, 2H), 1.97 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 169.3, 145.5, 133.6, 126.8, 124.4, 124.2, 118.5, 48.3, 40.7, 23.24. IR ν_max (cm^–1): 3240, 3065, 2953, 2849, 1634, 1554, 1433, 1366, 1291, 1077, 1034, 926, 834, 708. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₀H₁₃NOS 196.0791; Found 196.0784

Benzyl (1-(2-Methoxyphenyl)but-3-en-1-yl)carbamate (6e)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(2-methoxyphenyl)methyl acetate (75 mg, 0.231 mmol), Ca(NTf₂)₂ (7.2 mg, 0.012 mmol), nBu₄NPF₆ (4.6 mg, 0.012 mmol), and allyl-TMS (44 μL, 0.277 mmol) in 1,2-DCE (1.15 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (135 μL, 1.16 mmol) in EtOH (2.31 mL) overnight, followed by CbzCl (40 μL, 0.277 mmol) and Et₃N (34 μL, 0.231 mmol) in dry DCM (1.15 mL). Following completion of the Cbz protection (1 h), purification by FCC (1:12 EtOAc:Hex) afforded the pure compound as a white solid (31 mg, 43% over 3 steps). RF (1:4 EtOAc:Hex):0.56. ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.11 (m, 7H), 6.98–6.82 (m, 2H), 5.79–5.54 (m, 2H), 5.19–4.90 (m, 5H), 3.84 (s, 3H), 2.64–2.47 (m, 2H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 156.9, 155.7, 136.7, 134.8, 129.4, 128.5, 128.5, 128.4, 128.2, 128.1, 120.6, 117.5, 110.9, 66.7, 55.3, 52.9, 39.8. Data in accordance with the literature.

Benzyl ((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (6f)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and 5-bromo-N-methylindole (64 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by CbzCl (79 mg, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Cbz protection (1 h), purification by FCC (1:12 to 1:4 EtOAc:Hex) afforded the pure compound as a viscous pale-yellow oil (36 mg, 32% over 3 steps). RF (1:4 EtOAc:Hex):0.27. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H), 7.42–7.27 (m, 11H), 7.17–7.10 (m, 1H), 6.66–6.55 (m, 1H), 6.19 (d, J = 7.3 Hz, 1H), 5.38 (t, J = 15.8 Hz, 1H), 5.13 (q, J = 12.3 Hz, 2H), 3.68–3.61 (m, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.6, 141.3, 136.5, 136.2, 129.1, 128.6, 128.6, 128.1, 127.9, 127.5, 126.9, 126.4, 125.0, 122.1, 115.6, 113.0, 111.0, 66.9, 52.1, 33.0. IR ν_max (cm^–1): 3403, 3311,3028, 2920, 1686, 1492, 1474, 1213, 1025, 695. HRMS (ESI) m/z: [M + K]⁺ Calcd for C₂₄H₂₁N₂O₂BrK 487.0418; Found 487.0411

N-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)acetamide (6g)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and 5-bromo-N-methylindole (64 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by AcCl (22 μL, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Ac protection (1 h), purification by FCC (1:2 to 1:1 EtOAc:Hex) afforded the pure compound as a white solid (37 mg, 41% over 3 steps). RF (1:1 EtOAc:Hex):0.26. ¹H NMR (400 MHz, DMSO) δ 8.71 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.43–7.32 (m, 5H), 7.30–7.24 (m, 2H), 6.99 (s, 1H), 6.31 (d, J = 8.6 Hz, 1H), 3.72 (s, 3H), 1.91 (s, 3H). ¹³C{H} NMR (101 MHz, DMSO) δ: 168.8, 142.8, 136.1, 129.9, 128.7, 128.2, 127.47, 127.32, 124.27, 121.8, 116.1, 112.5, 112.0, 49.1, 33.0, 23.0. Data in accordance with the literature.

N-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)benzamide (6h)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and 5-bromo-N-methylindole (64 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by BzCl (35 μL, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Bz protection (1 h), purification by FCC (1:4 to 1:2 EtOAc:Hex) afforded the pure compound as a white solid (73 mg, 69% over 3 steps). RF (1:4 EtOAc:Hex):0.15. ¹H NMR (400 MHz, DMSO) δ 9.24 (d, J = 8.6 Hz, 1H), 7.98–7.88 (m, 2H), 7.59–7.54 (m, 1H), 7.54–7.34 (m, 8H), 7.33–7.24 (m, 2H), 6.99 (s, 1H), 6.62 (d, J = 8.6 Hz, 1H), 3.73 (s, 3H). ¹³C{H} NMR (101 MHz, DMSO) δ: 166.2, 142.6, 136.1, 134.9, 131.7, 130.3, 128.8, 128.7, 128.5, 128.0, 127.8, 127.5, 124.3, 121.7, 115.8, 112.5, 112.1, 49.8, 33.0. Data in accordance with the literature.

Allyl ((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (6i)

To a 22 mL screw top vial were added (1,3-dioxoisoindolin-2-yl)(phenyl)methyl acetate (75 mg, 0.254 mmol), Ca(NTf₂)₂ (7.6 mg, 0.013 mmol), nBu₄NPF₆ (4.9 mg, 0.013 mmol), and 5-bromo-N-methylindole (64 mg, 0.305 mmol) in 1,2-DCE (1.27 mL), reacting for 1 h, and then MeNH₂ (33 wt % in EtOH) (148 μL, 1.27 mmol) in EtOH (2.54 mL) overnight, followed by AllocCl (35 μL, 0.305 mmol) and Et₃N (35 μL, 0.254 mmol) in dry DCM (1.27 mL). Following completion of the Alloc protection (1 h), purification by FCC (1:8 to 1:4 EtOAc:Hex) afforded the pure compound as a viscous pale-yellow oil (36 mg, 35% over 3 steps). RF (1:4 EtOAc:Hex):0.35. ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.57 (m, 1H), 7.39–7.28 (m, 6H), 7.16–7.12 (m, 1H), 6.66–6.57 (m, 1H), 6.17 (d, J = 7.7 Hz, 1H), 5.98–5.85 (m, 1H), 5.43–5.08 (m, 3H), 4.67–4.53 (m, 2H), 3.66 (s, 3H). ¹³C{H} NMR (101 MHz, CDCl₃) δ: 155.5, 141.4, 136.2, 132.8, 129.1, 128.6, 127.9, 127.5, 126.8, 125.0, 122.1, 117.8, 115.6, 113.0, 111.0, 65.8, 52.1, 32.9. IR ν_max (cm^–1): 3291, 3060, 2924, 1679, 1533, 1474, 1246, 1034, 767, 701. HRMS (ESI) m/z: [M–AllocNH]⁺ Calcd for C₁₆H₁₃N⁸¹Br 300.0205; Found 300.0214

Supplementary Material

jo5c03185_si_001.pdf^{(4.7MB, pdf)}

Acknowledgments

We thank QUB for financial support.

The data underlying this study are available in the published article and its Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c03185.

General information, experimental details, and NMR spectra and data (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

References

Trowbridge A., Walton S. M., Gaunt M. J.. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020;120(5):2613–2692. doi: 10.1021/acs.chemrev.9b00462. [DOI] [PubMed] [Google Scholar]
Afanasyev O. I., Kuchuk E. A., Muratov K. M., Denisov G. L., Chusov D.. Symmetrical Tertiary Amines: Applications and Synthetic Approaches. Eur. J. Org. Chem. 2021;2021(4):543–586. doi: 10.1002/ejoc.202001171. [DOI] [Google Scholar]
Mitchell E. A., Peschiulli A., Lefevre N., Meerpoel L., Maes B. U. W.. Direct α-Functionalization of Saturated Cyclic Amines. Chem. - Eur. J. 2012;18(33):10092–10142. doi: 10.1002/chem.201201539. [DOI] [PubMed] [Google Scholar]
Vasu D., Fuentes de Arriba A. L., Leitch J. A., de Gombert A., Dixon D. J.. Primary α-tertiary amine synthesis via α-C–H functionalization. Chem. Sci. 2019;10(11):3401–3407. doi: 10.1039/C8SC05164J. [DOI] [PMC free article] [PubMed] [Google Scholar]
Deng T., Han X.-L., Yu Y., Cheng C., Liu X., Gao Y., Wu K., Li Z., Luo J., Deng L.. Organocatalytic asymmetric α-C–H functionalization of alkyl amines. Nat. Catal. 2024;7(10):1076–1085. doi: 10.1038/s41929-024-01230-4. [DOI] [Google Scholar]
Jain P., Verma P., Xia G., Yu J.-Q.. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nat. Chem. 2017;9(2):140–144. doi: 10.1038/nchem.2619. [DOI] [PMC free article] [PubMed] [Google Scholar]
Leng L., Fu Y., Liu P., Ready J. M.. Regioselective, Photocatalytic α-Functionalization of Amines. J. Am. Chem. Soc. 2020;142(28):11972–11977. doi: 10.1021/jacs.0c03758. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ye J., Kalvet I., Schoenebeck F., Rovis T.. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018;10(10):1037–1041. doi: 10.1038/s41557-018-0085-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
Ryder A. S. H., Cunningham W. B., Ballantyne G., Mules T., Kinsella A. G., Turner-Dore J., Turner-Dore J., Alder C. M., Edwards L. J., McKay B. S. J., Grayson M. N.. Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines. Angew. Chem., Int. Ed. 2020;59(35):14986–14991. doi: 10.1002/anie.202005294. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fu Z., Fu Y., Yin J., Hao G., Yi X., Zhong T., Guo S., Cai H.. Electrochemical strategies for N-cyanation of secondary amines and α C-cyanation of tertiary amines under transition metal-free conditions. Green. Chem. 2021;23(23):9422–9427. doi: 10.1039/D1GC02529E. [DOI] [Google Scholar]
Liu Y., Li X., Li J.. Photocatalytic and electrocatalytic α-C–H functionalization of tertiary amines. Tetrahedron. 2024;166:134234. doi: 10.1016/j.tet.2024.134234. [DOI] [Google Scholar]
Brown D. G., Boström J.. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016;59(10):4443–4458. doi: 10.1021/acs.jmedchem.5b01409. [DOI] [PubMed] [Google Scholar]
Basson A. J., Cameron M. P., McLaughlin M. G.. Calcium catalysed Strecker-type reactions towards α-aminonitriles. Chem. Commun. 2025;61(31):5739–5741. doi: 10.1039/D5CC00539F. [DOI] [PubMed] [Google Scholar]
Basson A. J., Halcovitch N. R., McLaughlin M. G.. Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization. Chem. - Eur. J. 2022;28(48):e202201107. doi: 10.1002/chem.202201107. [DOI] [PMC free article] [PubMed] [Google Scholar]
Basson A. J., McLaughlin M. G.. Access to functionalized Mannich scaffolds via a calcium-catalyzed dehydrative aza-Friedel-Crafts reaction. Cell Rep. Phys. Sci. 2023;4(4):101234. doi: 10.1016/j.xcrp.2022.101234. [DOI] [Google Scholar]
Abdallahi S. M., Ewies E. F., El-Shazly M., Ould Elemine B., Hadou A., Moncol J., Lawson A. M., Daich A., Othman M.. Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry. Chem. - Eur. J. 2021;27(62):15440–15449. doi: 10.1002/chem.202102357. [DOI] [PubMed] [Google Scholar]
Vieira A. S., Ferreira F. P., Fiorante P. F., Guadagnin R. C., Stefani H. A.. Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles. Tetrahedron. 2008;64(15):3306–3314. doi: 10.1016/j.tet.2008.02.006. [DOI] [Google Scholar]
Jury J. C., Swamy N. K., Yazici A., Willis A. C., Pyne S. G.. Metal-Catalyzed Cycloisomerization Reactions of cis-4-Hydroxy-5-alkynylpyrrolidinones and cis-5-Hydroxy-6-alkynylpiperidinones: Synthesis of Furo[3,2-b]pyrroles and Furo[3,2-b]pyridines. J. Org. Chem. 2009;74(15):5523–5527. doi: 10.1021/jo9007942. [DOI] [PubMed] [Google Scholar]
Felletti S., Spedicato M., Bozza D., De Luca C., Presini F., Giovannini P. P., Carraro M., Macis M., Cavazzini A., Catani M.. et al. Dimethyl carbonate as a green alternative to acetonitrile in reversed-phase liquid chromatography. Part I: Separation of small molecules. J. Chromatogr. A. 2023;1712:464477. doi: 10.1016/j.chroma.2023.464477. [DOI] [PubMed] [Google Scholar]
Lebœuf D., Marin L., Michelet B., Perez-Luna A., Guillot R., Schulz E., Gandon V.. Harnessing the Lewis Acidity of HFIP through its Cooperation with a Calcium(II) Salt: Application to the Aza-Piancatelli Reaction. Chem. - Eur. J. 2016;22(45):16165–16171. doi: 10.1002/chem.201603592. [DOI] [PubMed] [Google Scholar]
Huang W., He D., Jiang H., Wu W.. Recent advances in the transformation of nitriles into diverse N-heterocycles. Chem. Soc. Rev. 2025;54:10724–10795. doi: 10.1039/D5CS00024F. [DOI] [PubMed] [Google Scholar]
Chen Z., Cai Q., Boni Y. T., Liu W., Fu J., Davies H. M. L.. N-Phthalimide as a Site-Protecting and Stereodirecting Group in Rhodium-Catalyzed C–H Functionalization with Donor/Acceptor Carbenes. Org. Lett. 2023;25(22):3995–3999. doi: 10.1021/acs.orglett.3c00844. [DOI] [PMC free article] [PubMed] [Google Scholar]
Han S., Jones R. A., Quiclet-Sire B., Zard S. Z.. A convergent route to functional protected amines, diamines, and β-amino acids. Tetrahedron. 2014;70(40):7192–7206. doi: 10.1016/j.tet.2014.07.055. [DOI] [Google Scholar]
Haubenreisser S., Niggemann M.. Calcium-Catalyzed Direct Amination of π-Activated Alcohols. Adv. Synth. Catal. 2011;353(2–3):469–474. doi: 10.1002/adsc.201000768. [DOI] [Google Scholar]
Indukuri K., Unnava R., Deka M. J., Saikia A. K.. Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel–Crafts Type Reaction of Endocyclic N-Acyliminium Ions. J. Org. Chem. 2013;78(21):10629–10641. doi: 10.1021/jo401450j. [DOI] [PubMed] [Google Scholar]
Ghosh D., Saravanan S., Gupta N., Abdi S. H. R., Khan N.-u. H., Kureshy R. I., Bajaj H. C.. Phosphotungstic Acid as an Efficient Catalyst for Allylation of Isatins and N-tert-Butyloxycarbonylamido Sulfones Under Solvent-Free Conditions. Asian. J. Org. Chem. 2014;3(11):1173–1181. doi: 10.1002/ajoc.201402130. [DOI] [Google Scholar]
Vilaivan T., Winotapan C., Banphavichit V., Shinada T., Ohfune Y.. Indium-Mediated Asymmetric Barbier-Type Allylation of Aldimines in Alcoholic Solvents: Synthesis of Optically Active Homoallylic Amines. J. Org. Chem. 2005;70(9):3464–3471. doi: 10.1021/jo0477244. [DOI] [PubMed] [Google Scholar]
Delaye P.-O., Ahari Mh., Vasse J.-L., Szymoniak J.. A straightforward access to pyrrolidine-based ligands for asymmetric synthesis. Tetrahedron: Asymmetry. 2010;21(20):2505–2511. doi: 10.1016/j.tetasy.2010.09.015. [DOI] [Google Scholar]
Peng B., Ma J., Guo J., Gong Y., Wang R., Zhang Y., Zeng J., Chen W.-W., Ding K., Zhao B.. A Powerful Chiral Super Brønsted C–H Acid for Asymmetric Catalysis. J. Am. Chem. Soc. 2022;144(7):2853–2860. doi: 10.1021/jacs.1c12723. [DOI] [PubMed] [Google Scholar]
Peng X., Wang K.-H., Huang D., Wang J., Wang Y., Su Y., Hu Y., Fu Y.. Tin powder-promoted diastereoselective allylation of chiral acylhydrazones. Appl. Organomet. Chem. 2017;31(10):e3731. doi: 10.1002/aoc.3731. [DOI] [Google Scholar]
Ollevier T., Li Z.. Bismuth Triflate-Catalyzed Addition of Allylsilanes to N-Alkoxycarbonylamino Sulfones: Convenient Access to 3-Cbz-Protected Cyclohexenylamines. Adv. Synth. Catal. 2009;351(18):3251–3259. doi: 10.1002/adsc.200900710. [DOI] [Google Scholar]
Song Q.-Y., Yang B.-L., Tian S.-K.. FeSO4·7H2O-Catalyzed Four-Component Synthesis of Protected Homoallylic Amines. J. Org. Chem. 2007;72(14):5407–5410. doi: 10.1021/jo0704558. [DOI] [PubMed] [Google Scholar]
Yi Z.-J., Sun J.-T., Yang T.-Y., Yu X.-Y., Han X.-L., Wei B.-G.. Cu(OTf)2-catalyzed C3 aza-Friedel–Crafts alkylation of indoles with N,O-acetals. Org. Biomol. Chem. 2022;20(11):2261–2270. doi: 10.1039/D1OB02383G. [DOI] [PubMed] [Google Scholar]

Associated Data

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

Supplementary Materials

jo5c03185_si_001.pdf^{(4.7MB, pdf)}

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information

[ref1] Trowbridge A., Walton S. M., Gaunt M. J.. New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem. Rev. 2020;120(5):2613–2692. doi: 10.1021/acs.chemrev.9b00462. [DOI] [PubMed] [Google Scholar]

[ref2] Afanasyev O. I., Kuchuk E. A., Muratov K. M., Denisov G. L., Chusov D.. Symmetrical Tertiary Amines: Applications and Synthetic Approaches. Eur. J. Org. Chem. 2021;2021(4):543–586. doi: 10.1002/ejoc.202001171. [DOI] [Google Scholar]

[ref3] Mitchell E. A., Peschiulli A., Lefevre N., Meerpoel L., Maes B. U. W.. Direct α-Functionalization of Saturated Cyclic Amines. Chem. - Eur. J. 2012;18(33):10092–10142. doi: 10.1002/chem.201201539. [DOI] [PubMed] [Google Scholar]

[ref4] Vasu D., Fuentes de Arriba A. L., Leitch J. A., de Gombert A., Dixon D. J.. Primary α-tertiary amine synthesis via α-C–H functionalization. Chem. Sci. 2019;10(11):3401–3407. doi: 10.1039/C8SC05164J. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref5] Deng T., Han X.-L., Yu Y., Cheng C., Liu X., Gao Y., Wu K., Li Z., Luo J., Deng L.. Organocatalytic asymmetric α-C–H functionalization of alkyl amines. Nat. Catal. 2024;7(10):1076–1085. doi: 10.1038/s41929-024-01230-4. [DOI] [Google Scholar]

[ref6] Jain P., Verma P., Xia G., Yu J.-Q.. Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides. Nat. Chem. 2017;9(2):140–144. doi: 10.1038/nchem.2619. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref7] Leng L., Fu Y., Liu P., Ready J. M.. Regioselective, Photocatalytic α-Functionalization of Amines. J. Am. Chem. Soc. 2020;142(28):11972–11977. doi: 10.1021/jacs.0c03758. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref8] Ye J., Kalvet I., Schoenebeck F., Rovis T.. Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics. Nat. Chem. 2018;10(10):1037–1041. doi: 10.1038/s41557-018-0085-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref9] Ryder A. S. H., Cunningham W. B., Ballantyne G., Mules T., Kinsella A. G., Turner-Dore J., Turner-Dore J., Alder C. M., Edwards L. J., McKay B. S. J., Grayson M. N.. Photocatalytic α-Tertiary Amine Synthesis via C–H Alkylation of Unmasked Primary Amines. Angew. Chem., Int. Ed. 2020;59(35):14986–14991. doi: 10.1002/anie.202005294. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref10] Fu Z., Fu Y., Yin J., Hao G., Yi X., Zhong T., Guo S., Cai H.. Electrochemical strategies for N-cyanation of secondary amines and α C-cyanation of tertiary amines under transition metal-free conditions. Green. Chem. 2021;23(23):9422–9427. doi: 10.1039/D1GC02529E. [DOI] [Google Scholar]

[ref11] Liu Y., Li X., Li J.. Photocatalytic and electrocatalytic α-C–H functionalization of tertiary amines. Tetrahedron. 2024;166:134234. doi: 10.1016/j.tet.2024.134234. [DOI] [Google Scholar]

[ref12] Brown D. G., Boström J.. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? J. Med. Chem. 2016;59(10):4443–4458. doi: 10.1021/acs.jmedchem.5b01409. [DOI] [PubMed] [Google Scholar]

[ref13] Basson A. J., Cameron M. P., McLaughlin M. G.. Calcium catalysed Strecker-type reactions towards α-aminonitriles. Chem. Commun. 2025;61(31):5739–5741. doi: 10.1039/D5CC00539F. [DOI] [PubMed] [Google Scholar]

[ref14] Basson A. J., Halcovitch N. R., McLaughlin M. G.. Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization. Chem. - Eur. J. 2022;28(48):e202201107. doi: 10.1002/chem.202201107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref15] Basson A. J., McLaughlin M. G.. Access to functionalized Mannich scaffolds via a calcium-catalyzed dehydrative aza-Friedel-Crafts reaction. Cell Rep. Phys. Sci. 2023;4(4):101234. doi: 10.1016/j.xcrp.2022.101234. [DOI] [Google Scholar]

[ref16] Abdallahi S. M., Ewies E. F., El-Shazly M., Ould Elemine B., Hadou A., Moncol J., Lawson A. M., Daich A., Othman M.. Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry. Chem. - Eur. J. 2021;27(62):15440–15449. doi: 10.1002/chem.202102357. [DOI] [PubMed] [Google Scholar]

[ref17] Vieira A. S., Ferreira F. P., Fiorante P. F., Guadagnin R. C., Stefani H. A.. Nucleophilic addition of potassium organotrifluoroborates to chiral cyclic N-acyliminium ions: stereoselective synthesis of functionalized N-heterocycles. Tetrahedron. 2008;64(15):3306–3314. doi: 10.1016/j.tet.2008.02.006. [DOI] [Google Scholar]

[ref18] Jury J. C., Swamy N. K., Yazici A., Willis A. C., Pyne S. G.. Metal-Catalyzed Cycloisomerization Reactions of cis-4-Hydroxy-5-alkynylpyrrolidinones and cis-5-Hydroxy-6-alkynylpiperidinones: Synthesis of Furo[3,2-b]pyrroles and Furo[3,2-b]pyridines. J. Org. Chem. 2009;74(15):5523–5527. doi: 10.1021/jo9007942. [DOI] [PubMed] [Google Scholar]

[ref19] Felletti S., Spedicato M., Bozza D., De Luca C., Presini F., Giovannini P. P., Carraro M., Macis M., Cavazzini A., Catani M.. et al. Dimethyl carbonate as a green alternative to acetonitrile in reversed-phase liquid chromatography. Part I: Separation of small molecules. J. Chromatogr. A. 2023;1712:464477. doi: 10.1016/j.chroma.2023.464477. [DOI] [PubMed] [Google Scholar]

[ref20] Lebœuf D., Marin L., Michelet B., Perez-Luna A., Guillot R., Schulz E., Gandon V.. Harnessing the Lewis Acidity of HFIP through its Cooperation with a Calcium(II) Salt: Application to the Aza-Piancatelli Reaction. Chem. - Eur. J. 2016;22(45):16165–16171. doi: 10.1002/chem.201603592. [DOI] [PubMed] [Google Scholar]

[ref21] Huang W., He D., Jiang H., Wu W.. Recent advances in the transformation of nitriles into diverse N-heterocycles. Chem. Soc. Rev. 2025;54:10724–10795. doi: 10.1039/D5CS00024F. [DOI] [PubMed] [Google Scholar]

[ref22] Chen Z., Cai Q., Boni Y. T., Liu W., Fu J., Davies H. M. L.. N-Phthalimide as a Site-Protecting and Stereodirecting Group in Rhodium-Catalyzed C–H Functionalization with Donor/Acceptor Carbenes. Org. Lett. 2023;25(22):3995–3999. doi: 10.1021/acs.orglett.3c00844. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref23] Han S., Jones R. A., Quiclet-Sire B., Zard S. Z.. A convergent route to functional protected amines, diamines, and β-amino acids. Tetrahedron. 2014;70(40):7192–7206. doi: 10.1016/j.tet.2014.07.055. [DOI] [Google Scholar]

[ref24] Haubenreisser S., Niggemann M.. Calcium-Catalyzed Direct Amination of π-Activated Alcohols. Adv. Synth. Catal. 2011;353(2–3):469–474. doi: 10.1002/adsc.201000768. [DOI] [Google Scholar]

[ref25] Indukuri K., Unnava R., Deka M. J., Saikia A. K.. Stereoselective Synthesis of Amido and Phenyl Azabicyclic Derivatives via a Tandem Aza Prins-Ritter/Friedel–Crafts Type Reaction of Endocyclic N-Acyliminium Ions. J. Org. Chem. 2013;78(21):10629–10641. doi: 10.1021/jo401450j. [DOI] [PubMed] [Google Scholar]

[ref26] Ghosh D., Saravanan S., Gupta N., Abdi S. H. R., Khan N.-u. H., Kureshy R. I., Bajaj H. C.. Phosphotungstic Acid as an Efficient Catalyst for Allylation of Isatins and N-tert-Butyloxycarbonylamido Sulfones Under Solvent-Free Conditions. Asian. J. Org. Chem. 2014;3(11):1173–1181. doi: 10.1002/ajoc.201402130. [DOI] [Google Scholar]

[ref27] Vilaivan T., Winotapan C., Banphavichit V., Shinada T., Ohfune Y.. Indium-Mediated Asymmetric Barbier-Type Allylation of Aldimines in Alcoholic Solvents: Synthesis of Optically Active Homoallylic Amines. J. Org. Chem. 2005;70(9):3464–3471. doi: 10.1021/jo0477244. [DOI] [PubMed] [Google Scholar]

[ref28] Delaye P.-O., Ahari Mh., Vasse J.-L., Szymoniak J.. A straightforward access to pyrrolidine-based ligands for asymmetric synthesis. Tetrahedron: Asymmetry. 2010;21(20):2505–2511. doi: 10.1016/j.tetasy.2010.09.015. [DOI] [Google Scholar]

[ref29] Peng B., Ma J., Guo J., Gong Y., Wang R., Zhang Y., Zeng J., Chen W.-W., Ding K., Zhao B.. A Powerful Chiral Super Brønsted C–H Acid for Asymmetric Catalysis. J. Am. Chem. Soc. 2022;144(7):2853–2860. doi: 10.1021/jacs.1c12723. [DOI] [PubMed] [Google Scholar]

[ref30] Peng X., Wang K.-H., Huang D., Wang J., Wang Y., Su Y., Hu Y., Fu Y.. Tin powder-promoted diastereoselective allylation of chiral acylhydrazones. Appl. Organomet. Chem. 2017;31(10):e3731. doi: 10.1002/aoc.3731. [DOI] [Google Scholar]

[ref31] Ollevier T., Li Z.. Bismuth Triflate-Catalyzed Addition of Allylsilanes to N-Alkoxycarbonylamino Sulfones: Convenient Access to 3-Cbz-Protected Cyclohexenylamines. Adv. Synth. Catal. 2009;351(18):3251–3259. doi: 10.1002/adsc.200900710. [DOI] [Google Scholar]

[ref32] Song Q.-Y., Yang B.-L., Tian S.-K.. FeSO4·7H2O-Catalyzed Four-Component Synthesis of Protected Homoallylic Amines. J. Org. Chem. 2007;72(14):5407–5410. doi: 10.1021/jo0704558. [DOI] [PubMed] [Google Scholar]

[ref33] Yi Z.-J., Sun J.-T., Yang T.-Y., Yu X.-Y., Han X.-L., Wei B.-G.. Cu(OTf)2-catalyzed C3 aza-Friedel–Crafts alkylation of indoles with N,O-acetals. Org. Biomol. Chem. 2022;20(11):2261–2270. doi: 10.1039/D1OB02383G. [DOI] [PubMed] [Google Scholar]

PERMALINK

Access to α‑Functionalized Amines via Calcium-Catalyzed Deacetylations

Michael P Cameron

Mark G McLaughlin

Abstract

Introduction

1. Strategies toward α-Functionalized Amines.

Results and Discussion

1. Optimization Study.

2. Allylation Substrate Scope .

3. Further Nucleophile Screen .

4. TMSCN as a Nucleophile .

5. N-Boc Substrate Scope .

6. N-Protecting Group Scope .

2. Proposed Mechanism.

Conclusions

Experimental Section

Solvents and Reagents

Purification and Chromatography

Characterization

2-(1-Phenylbut-3-en-1-yl)­isoindoline-1,3-dione (2a)

2-(1-(4-Methoxyphenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2b)

2-(1-(P-tolyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2c)

2-(1-(4-Fluorophenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2d)

2-(1-(4-(Trifluoromethyl)­phenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2e)

2-(1-(2-Methoxyphenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2f)

2-(1-(2-Bromophenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2g)

2-(1-(3-Chlorophenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2h)

2-(1-(3-Bromo-2-fluorophenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2i)

2-(1-(3,5-Bis­(trifluoromethyl)­phenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2j)

2-(1-(4-Nitrophenyl)­but-3-en-1-yl)­isoindoline-1,3-dione (2k)

2-(1-(Naphthalen-2-yl)­but-3-en-1-yl)­isoindoline-1,3-dione (2l)

2-(1-(Furan-2-yl)­but-3-en-1-yl)­isoindoline-1,3-dione (2m)

2-(1-(Thiophen-2-yl)­but-3-en-1-yl)­isoindoline-1,3-dione (2n)

2-(1-Cyclohexylbut-3-en-1-yl)­isoindoline-1,3-dione (2o)

2-(Phenyl­(phenylthio)­methyl)­isoindoline-1,3-dione (3a)

2-((3-Bromo-2-fluorophenyl)­(phenylthio)­methyl)­isoindoline-1,3-dione (3b)

2-((4-Nitrophenyl)­(phenylthio)­methyl)­isoindoline-1,3-dione (3c)

2-(((2-Fluorophenyl)­thio)­(thiophen-2-yl)­methyl)­isoindoline-1,3-dione (3d)

2-(Cyclopropyl­((4-methoxyphenyl)­thio)­methyl)­isoindoline-1,3-dione (3e)

2-((Ethylthio)­(4-methoxyphenyl)­methyl)­isoindoline-1,3-dione (3f)

2-((5-Bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­isoindoline-1,3-dione (3g)

2-((5-Bromo-1-methyl-1H-indol-3-yl)­(2-methoxyphenyl)­methyl)­isoindoline-1,3-dione (3h)

2-((5-Bromo-1-methyl-1H-indol-3-yl)­(furan-2-yl)­methyl)­isoindoline-1,3-dione (3i)

2-((3,5-Bis­(trifluoromethyl)­phenyl)­(5-bromo-1-methyl-1H-indol-3-yl)­methyl) isoindoline-1,3-dione (3j)

2-((5-Bromo-1-methyl-1H-indol-3-yl)­(cyclohexyl)­methyl)­isoindoline-1,3-dione (3k)

N-((1,3-Dioxoisoindolin-2-yl)­(phenyl)­methyl)­benzamide (3l)

N-((3-Chlorophenyl)­(1,3-dioxoisoindolin-2-yl)­methyl)-4-methoxybenzamide (3m)

N-((1,3-Dioxoisoindolin-2-yl)­(naphthalen-2-yl)­methyl)­propionamide (3n)

Benzyl ((1,3-Dioxoisoindolin-2-yl)­(phenyl)­methyl)­carbamate (3o)

2-(1,3-Dioxoisoindolin-2-yl)-2-phenylacetonitrile (4a)

2-(1,3-Dioxoisoindolin-2-yl)-2-(4-fluorophenyl)­acetonitrile (4b)

2-(3-Chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)­acetonitrile (4c)

2-(2-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)­acetonitrile (4d)

2-(3-Bromo-2-fluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)­acetonitrile (4e)

2-(1,3-Dioxoisoindolin-2-yl)-2-(p-tolyl)­acetonitrile (4f)

2-(1,3-Dioxoisoindolin-2-yl)-2-(2-methoxyphenyl)­acetonitrile (4g)

2-(1,3-Dioxoisoindolin-2-yl)-2-(naphthalen-2-yl)­acetonitrile (4h)

2-(1,3-Dioxoisoindolin-2-yl)-2-(furan-2-yl)­acetonitrile (4i)

2-(1,3-Dioxoisoindolin-2-yl)-2-(thiophen-2-yl)­acetonitrile (4j)

2-Cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)­acetonitrile (4k)

2-Cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)­acetonitrile (4l)

tert-Butyl (1-phenylbut-3-en-1-yl)­carbamate (5a)

tert-Butyl (1-(4-methoxyphenyl)­but-3-en-1-yl)­carbamate (5b)

tert-Butyl (1-(p-tolyl)­but-3-en-1-yl)­carbamate (5c)

tert-Butyl (1-(2-methoxyphenyl)­but-3-en-1-yl)­carbamate (5d)

tert-Butyl (1-(4-fluorophenyl)­but-3-en-1-yl)­carbamate (5e)

tert-Butyl (1-(3-chlorophenyl)­but-3-en-1-yl)­carbamate (5f)

tert-Butyl (1-(2-bromophenyl)­but-3-en-1-yl)­carbamate (5g)

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­carbamate (5h)

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)­(4-methoxyphenyl)­methyl)­carbamate (5i)

(9H-Fluoren-9-yl)­methyl (1-phenylbut-3-en-1-yl)­carbamate (6a)

N-(1-Phenylbut-3-en-1-yl)­benzamide (6b)

Allyl (1-Phenylbut-3-en-1-yl)­carbamate (6c)

N-(1-(Thiophen-2-yl)­but-3-en-1-yl)­acetamide (6d)

Benzyl (1-(2-Methoxyphenyl)­but-3-en-1-yl)­carbamate (6e)

Benzyl ((5-Bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­carbamate (6f)

N-((5-Bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­acetamide (6g)

N-((5-Bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­benzamide (6h)

Allyl ((5-Bromo-1-methyl-1H-indol-3-yl)­(phenyl)­methyl)­carbamate (6i)

2-(1-Phenylbut-3-en-1-yl)isoindoline-1,3-dione (2a)

2-(1-(4-Methoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione (2b)

2-(1-(P-tolyl)but-3-en-1-yl)isoindoline-1,3-dione (2c)

2-(1-(4-Fluorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2d)

2-(1-(4-(Trifluoromethyl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (2e)

2-(1-(2-Methoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione (2f)

2-(1-(2-Bromophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2g)

2-(1-(3-Chlorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2h)

2-(1-(3-Bromo-2-fluorophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2i)

2-(1-(3,5-Bis(trifluoromethyl)phenyl)but-3-en-1-yl)isoindoline-1,3-dione (2j)

2-(1-(4-Nitrophenyl)but-3-en-1-yl)isoindoline-1,3-dione (2k)

2-(1-(Naphthalen-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2l)

2-(1-(Furan-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2m)

2-(1-(Thiophen-2-yl)but-3-en-1-yl)isoindoline-1,3-dione (2n)

2-(1-Cyclohexylbut-3-en-1-yl)isoindoline-1,3-dione (2o)

2-(Phenyl(phenylthio)methyl)isoindoline-1,3-dione (3a)

2-((3-Bromo-2-fluorophenyl)(phenylthio)methyl)isoindoline-1,3-dione (3b)

2-((4-Nitrophenyl)(phenylthio)methyl)isoindoline-1,3-dione (3c)

2-(((2-Fluorophenyl)thio)(thiophen-2-yl)methyl)isoindoline-1,3-dione (3d)

2-(Cyclopropyl((4-methoxyphenyl)thio)methyl)isoindoline-1,3-dione (3e)

2-((Ethylthio)(4-methoxyphenyl)methyl)isoindoline-1,3-dione (3f)

2-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)isoindoline-1,3-dione (3g)

2-((5-Bromo-1-methyl-1H-indol-3-yl)(2-methoxyphenyl)methyl)isoindoline-1,3-dione (3h)

2-((5-Bromo-1-methyl-1H-indol-3-yl)(furan-2-yl)methyl)isoindoline-1,3-dione (3i)

2-((3,5-Bis(trifluoromethyl)phenyl)(5-bromo-1-methyl-1H-indol-3-yl)methyl) isoindoline-1,3-dione (3j)

2-((5-Bromo-1-methyl-1H-indol-3-yl)(cyclohexyl)methyl)isoindoline-1,3-dione (3k)

N-((1,3-Dioxoisoindolin-2-yl)(phenyl)methyl)benzamide (3l)

N-((3-Chlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)-4-methoxybenzamide (3m)

N-((1,3-Dioxoisoindolin-2-yl)(naphthalen-2-yl)methyl)propionamide (3n)

Benzyl ((1,3-Dioxoisoindolin-2-yl)(phenyl)methyl)carbamate (3o)

2-(1,3-Dioxoisoindolin-2-yl)-2-(4-fluorophenyl)acetonitrile (4b)

2-(3-Chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4c)

2-(2-Bromophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4d)

2-(3-Bromo-2-fluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4e)

2-(1,3-Dioxoisoindolin-2-yl)-2-(p-tolyl)acetonitrile (4f)

2-(1,3-Dioxoisoindolin-2-yl)-2-(2-methoxyphenyl)acetonitrile (4g)

2-(1,3-Dioxoisoindolin-2-yl)-2-(naphthalen-2-yl)acetonitrile (4h)

2-(1,3-Dioxoisoindolin-2-yl)-2-(furan-2-yl)acetonitrile (4i)

2-(1,3-Dioxoisoindolin-2-yl)-2-(thiophen-2-yl)acetonitrile (4j)

2-Cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4k)

2-Cyclopropyl-2-(1,3-dioxoisoindolin-2-yl)acetonitrile (4l)

tert-Butyl (1-phenylbut-3-en-1-yl)carbamate (5a)

tert-Butyl (1-(4-methoxyphenyl)but-3-en-1-yl)carbamate (5b)

tert-Butyl (1-(p-tolyl)but-3-en-1-yl)carbamate (5c)

tert-Butyl (1-(2-methoxyphenyl)but-3-en-1-yl)carbamate (5d)

tert-Butyl (1-(4-fluorophenyl)but-3-en-1-yl)carbamate (5e)

tert-Butyl (1-(3-chlorophenyl)but-3-en-1-yl)carbamate (5f)

tert-Butyl (1-(2-bromophenyl)but-3-en-1-yl)carbamate (5g)

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (5h)

tert-Butyl ((5-bromo-1-methyl-1H-indol-3-yl)(4-methoxyphenyl)methyl)carbamate (5i)

(9H-Fluoren-9-yl)methyl (1-phenylbut-3-en-1-yl)carbamate (6a)

N-(1-Phenylbut-3-en-1-yl)benzamide (6b)

Allyl (1-Phenylbut-3-en-1-yl)carbamate (6c)

N-(1-(Thiophen-2-yl)but-3-en-1-yl)acetamide (6d)

Benzyl (1-(2-Methoxyphenyl)but-3-en-1-yl)carbamate (6e)

Benzyl ((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (6f)

N-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)acetamide (6g)

N-((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)benzamide (6h)

Allyl ((5-Bromo-1-methyl-1H-indol-3-yl)(phenyl)methyl)carbamate (6i)