Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et2Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented.


Introduction
Nitrogen-containing heterocycles are recognized as privileged scaffolds for pharmaceuticals due to their increased pharmacokinetics and bioavailability [1][2][3]. As such, N-heterocycles are present in nearly 59% of all FDA-approved small molecule drugs and make up a plurality of newly approved drugs each year [4][5][6]. Piperidines and pyrrolidines appear in the top five most common N-heterocycles in FDA-approved drugs [1]. Industrial drug discovery initiatives often approach drug synthesis by creating large molecular libraries that can comprise hundreds of variations of one scaffold [7,8]. The use of neural networks and powerful algorithms to identify better and more specific target compounds has helped narrow the scope of these libraries [8]. However, each of these target compounds and their variants must be synthesized, purified, and assayed, which can take a significant amount of time to achieve for even a single drug candidate. Therefore, a synthetic method that provides stereodefined N-heterocyclic scaffolds with functional groups that can easily be modified would be extremely useful for drug discovery.

Introduction
Nitrogen-containing heterocycles are recognized as privileged scaffolds for p ceuticals due to their increased pharmacokinetics and bioavailability [1][2][3]. As s heterocycles are present in nearly 59% of all FDA-approved small molecule dru make up a plurality of newly approved drugs each year [4][5][6]. Piperidines and dines appear in the top five most common N-heterocycles in FDA-approved dr Industrial drug discovery initiatives often approach drug synthesis by creating lar lecular libraries that can comprise hundreds of variations of one scaffold [7,8]. Th neural networks and powerful algorithms to identify better and more specific targ pounds has helped narrow the scope of these libraries [8]. However, each of thes compounds and their variants must be synthesized, purified, and assayed, which c a significant amount of time to achieve for even a single drug candidate. Therefore thetic method that provides stereodefined N-heterocyclic scaffolds with fun groups that can easily be modified would be extremely useful for drug discovery We have previously reported one such method involving the use of Et2Zn in a mediated metalloamination/cyclization cascade with subsequent electrophilic fun ization (Scheme 1) [9][10][11]. Unlike previously reported methods, the Zn(II)-mediated metalloamination/ tion cascade does not rely on transient intermediates that limit the following func zation to only those electrophiles which react quickly and completely [12][13][14][15][16][17][18][19][20]. Th cascade generates a stable organozinc intermediate that can readily be transmet

Results and Discussion
Our investigation started with N,N-dimethylhydrazinoalkenes 1-3 ( Figure 2) underwent metalloamination/cyclization as reported previously [9,11]. Benzotrif and toluene provided excellent conversion to the organozinc intermediate, with proceeding at slower rate. In contrast, 1,2-dichlorethane, diisopropyl ether, acet and isobutyronitrile were found to provide incomplete conversion. These intermediates were treated with 1-bromo-1-octyne (two equiv.), CuC (5 mol%), and LiBr (one equiv.). The utilization of LiBr as an additive confers a sig stabilizing and accelerating influence, as we have previously reported [9]. Ether vents were necessary, with THF being optimal for Cu(I)-catalyzed electrophilic fu alization. The isolation of the products was straightforward and produced 1a an good yields (Table 1). Product 3a demonstrates that an increased steric bulk on heterocycle still leads to successful coupling. Having found success with these re we moved forward to coupling with the more reactive alkyne, 1-bromo-2-phenyle

Results and Discussion
Our investigation started with N,N-dimethylhydrazinoalkenes 1-3 ( Figure 2), which underwent metalloamination/cyclization as reported previously [9,11]. Benzotriflouride and toluene provided excellent conversion to the organozinc intermediate, with toluene proceeding at slower rate. In contrast, 1,2-dichlorethane, diisopropyl ether, acetonitrile, and isobutyronitrile were found to provide incomplete conversion. resulting in the formation of a diverse repository of scaffolds. Here, we expand of this method to the use of 1-bromoalkynes in Cu(I)-catalyzed functionalizatio The cross-coupling of 1-haloalkynes with organozinc reagents was first r Knochel [21]. This initial report involved the coupling of alkyl organozincs w and iodoalkynes in the presence of catalytic CuCN·2LiCl to produce internal good yields. The copper/zinc reagent RCu(CN)ZnX formed during this reaction characterized, but subsequent studies by Knochel and others have elucidated mechanism of this reaction (Figure 1, adapted from Thapa et al.) [22][23][24]. Th study demonstrated the usefulness of this method by its application to the syn pheromone present in Amathes c-nigram [21].

Results and Discussion
Our investigation started with N,N-dimethylhydrazinoalkenes 1-3 (Figur underwent metalloamination/cyclization as reported previously [9,11]. Benzo and toluene provided excellent conversion to the organozinc intermediate, w proceeding at slower rate. In contrast, 1,2-dichlorethane, diisopropyl ether, a and isobutyronitrile were found to provide incomplete conversion. These intermediates were treated with 1-bromo-1-octyne (two equiv.), C (5 mol%), and LiBr (one equiv.). The utilization of LiBr as an additive confers a stabilizing and accelerating influence, as we have previously reported [9]. Et vents were necessary, with THF being optimal for Cu(I)-catalyzed electrophili alization. The isolation of the products was straightforward and produced 1a good yields (Table 1). Product 3a demonstrates that an increased steric bulk heterocycle still leads to successful coupling. Having found success with these we moved forward to coupling with the more reactive alkyne, 1-bromo-2-phen These intermediates were treated with 1-bromo-1-octyne (two equiv.), CuCN·2LiBr (5 mol%), and LiBr (one equiv.). The utilization of LiBr as an additive confers a significant stabilizing and accelerating influence, as we have previously reported [9]. Ethereal solvents were necessary, with THF being optimal for Cu(I)-catalyzed electrophilic functionalization. The isolation of the products was straightforward and produced 1a and 2a in good yields (Table 1). Product 3a demonstrates that an increased steric bulk on the N-heterocycle still leads to successful coupling. Having found success with these reactions, we moved forward to coupling with the more reactive alkyne, 1-bromo-2-phenylethyne. Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne with N,Ndimethylhydrazinoalkenes 1, 2, and 3.
Molecules 2022, 27, x FOR PEER REVIEW Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yiel Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction temperat to no improvement. In this case, the product mixture contained a homocoupled product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pur from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere glo All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance lecules 2022, 27, x FOR PEER REVIEW Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethy dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-p were difficult to control. Successful reactions with 1-bromo-2-phenylethyne t −76 °C to complete, and increasing the temperature inevitably led to decrease Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA led to a marked decrease in the yield of 2b (25%). Lowering the reaction tem to no improvement. In this case, the product mixture contained a homoco product and the Zn metalloamination intermediate derived from 2. In cons our previously reported conditions [9], the inclusion of one equiv. of LiBr alkynyalation reactions leading to both 2a and 2b to be run at room temp improved yields.

Materials
All materials were either prepared according to previous literature o from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 w sized by previously reported methods [11,27] and stored in an inert atmosphe All solvents were obtained from a JC Meyer solvent dispensing system. In  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yie Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction tempera to no improvement. In this case, the product mixture contained a homocouple product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pu from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere gl All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethy dimethylhydrazinoalkenes 1, 2, and 3. Product obtained as racemic mixture. b 0.1 mmol N,N-dimethylhydrazinoalk CuCN·2LiBr, and 1 equiv. LiBr. c 0.1 mmol N,N-dimethylhydrazinoalkene, 5 mol% C equiv. LiBr, and 1 equiv. TMEDA. d 1.5 mmol N,N-dimethylhydrazinoalkene, 5 mol% and 1 equiv. LiBr.

1-Bromoalkyne
Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-p were difficult to control. Successful reactions with 1-bromo-2-phenylethyne t −76 °C to complete, and increasing the temperature inevitably led to decrease Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA led to a marked decrease in the yield of 2b (25%). Lowering the reaction tem to no improvement. In this case, the product mixture contained a homoco product and the Zn metalloamination intermediate derived from 2. In cons our previously reported conditions [9], the inclusion of one equiv. of LiBr alkynyalation reactions leading to both 2a and 2b to be run at room temp improved yields.

Materials
All materials were either prepared according to previous literature o from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 w  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yie Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction tempera to no improvement. In this case, the product mixture contained a homocouple product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pu from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere gl All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethy dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-p were difficult to control. Successful reactions with 1-bromo-2-phenylethyne t −76 °C to complete, and increasing the temperature inevitably led to decrease Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA led to a marked decrease in the yield of 2b (25%). Lowering the reaction tem to no improvement. In this case, the product mixture contained a homoco product and the Zn metalloamination intermediate derived from 2. In cons our previously reported conditions [9], the inclusion of one equiv. of LiBr alkynyalation reactions leading to both 2a and 2b to be run at room temp improved yields.

Materials
Molecules 2022, 27, x FOR PEER REVIEW Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yie Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction tempera to no improvement. In this case, the product mixture contained a homocouple product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pu from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere gl All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethy dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-p were difficult to control. Successful reactions with 1-bromo-2-phenylethyne t −76 °C to complete, and increasing the temperature inevitably led to decreased Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA led to a marked decrease in the yield of 2b (25%). Lowering the reaction tem to no improvement. In this case, the product mixture contained a homoco product and the Zn metalloamination intermediate derived from 2. In cons our previously reported conditions [9], the inclusion of one equiv. of LiBr alkynyalation reactions leading to both 2a and 2b to be run at room tempe improved yields.

Materials
All materials were either prepared according to previous literature o from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 w sized by previously reported methods [11,27] and stored in an inert atmosphe All solvents were obtained from a JC Meyer solvent dispensing system. Ino were dried by heating under a high vacuum before use. Thin-layer chromatog  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yie Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction tempera to no improvement. In this case, the product mixture contained a homocouple product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pu from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere gl All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethy dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-p were difficult to control. Successful reactions with 1-bromo-2-phenylethyne t −76 °C to complete, and increasing the temperature inevitably led to decreased Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA led to a marked decrease in the yield of 2b (25%). Lowering the reaction tem to no improvement. In this case, the product mixture contained a homoco product and the Zn metalloamination intermediate derived from 2. In cons our previously reported conditions [9], the inclusion of one equiv. of LiBr alkynyalation reactions leading to both 2a and 2b to be run at room tempe improved yields.

Materials
All materials were either prepared according to previous literature o from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 w  Table 1. Results of the cross-coupling of 1-bromo-1-octyne and 1-bromo-2-phenylethyne w dimethylhydrazinoalkenes 1, 2, and 3. Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-pheny were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took −76 °C to complete, and increasing the temperature inevitably led to decreased yie Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligan accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one led to a marked decrease in the yield of 2b (25%). Lowering the reaction tempera to no improvement. In this case, the product mixture contained a homocouple product and the Zn metalloamination intermediate derived from 2. In consonan our previously reported conditions [9], the inclusion of one equiv. of LiBr allow alkynyalation reactions leading to both 2a and 2b to be run at room temperatu improved yields.

Materials
All materials were either prepared according to previous literature or pu from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were sized by previously reported methods [11,27] and stored in an inert atmosphere gl All solvents were obtained from a JC Meyer solvent dispensing system. Inorgan were dried by heating under a high vacuum before use. Thin-layer chromatograph employed 0.25 mm glass silica gel plates with UV indicator and were visualized w light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance 72 b 25 c a Product obtained as racemic mixture. b 0.1 mmol N,N-dimethylhydrazinoalkene, 5 mol% CuCN·2LiBr, and 1 equiv. LiBr. c 0.1 mmol N,N-dimethylhydrazinoalkene, 5 mol% CuCN·2LiBr, 1 equiv. LiBr, and 1 equiv. TMEDA. d 1.5 mmol N,N-dimethylhydrazinoalkene, 5 mol% CuCN·2LiBr, and 1 equiv. LiBr.
Knochel reported that Cu(I)-catalyzed cross-couplings with 1-bromo-2-phenylethyne were difficult to control. Successful reactions with 1-bromo-2-phenylethyne took 1-4 h at −76 • C to complete, and increasing the temperature inevitably led to decreased yields [21]. Diamine ligands can exert a stabilizing effect on copper catalysts [25]. These ligands also accelerate Cu(I)-catalyzed cross-coupling reactions [26,27]. Unfortunately, in our hands, the coupling of 2 with 1-bromo-2-phenylethyne in the presence of TMEDA (one equiv.) led to a marked decrease in the yield of 2b (25%). Lowering the reaction temperature led to no improvement. In this case, the product mixture contained a homocoupled diyne product and the Zn metalloamination intermediate derived from 2. In consonance with our previously reported conditions [9], the inclusion of one equiv. of LiBr allowed the alkynyalation reactions leading to both 2a and 2b to be run at room temperature with improved yields.

Materials
All materials were either prepared according to previous literature or purchased from commercial sources. N,N-dimethylhydrazinoalkene substrates 1-3 were synthesized by previously reported methods [11,27] and stored in an inert atmosphere glovebox. All solvents were obtained from a JC Meyer solvent dispensing system. Inorganic salts were dried by heating under a high vacuum before use. Thin-layer chromatography (TLC) employed 0.25 mm glass silica gel plates with UV indicator and were visualized with UV light (254 nm) or potassium permanganate staining. Nuclear magnetic resonance (NMR) data were obtained from a Bruker AVANCE III HD NMR spectrometer equipped with an Ascend 500 (500 MHz) magnet. High-resolution mass spectra (HRMS) were obtained from a Bruker MicroTOF with a Dart 100-SVP 100 ion source.

General Procedure for the Synthesis of Alkynyl N,N-Dimethylhydrazinoalkenes
In an inert atmosphere glovebox, a 5 mm J. Young NMR tube with a sealed 3 mm NMR calibration tube containing C 6 D 6 was charged with benzotrifluoride (BTF, 0.4 mL), 2 M diethyl zinc in BTF (60 µL, 0.12 mmol, 1.2 equiv.), and the requisite N,N-dimethylhydrazinoalkene (0.1 mmol). The J. Young tube was placed in a 90 • C oil bath and the cyclization reaction was monitored by NMR (indicated by the recession of the alkene peaks), using BTF as an internal standard. Upon completion of the cyclization, the volatiles were removed in vacuo. The J. Young NMR tube was returned to the glovebox and was charged with THF (0.3 mL), the requisite 1-bromoalkyne (0.2 mmol), 0.5 M CuCN·2LiBr solution in THF (10 µL, 5 mol%), and 2 M LiBr in THF (50 µL, 0.1 mmol, 1 equiv.). The reactant mixture was allowed to stand at room temperature overnight. The resulting solution was dispersed in diethyl ether (1 mL) and washed with an aqueous solution of 1:1 sat. NH 4 OH/sat. NH 4 SO 4 (3 × 1 mL). The combined aqueous washes were then back-extracted with diethyl ether (2 × 1 mL) and the combined organic layers were concentrated in vacuo. The resulting crude product was dissolved in CH 2 Cl 2 (1 mL), dispersed onto silica gel (50 mg), and dried in vacuo. This was purified by dry-loading the resulting silica gel onto a silica gel plug and eluting with pentane. The product was then flushed from the silica gel using diethyl ether and concentrated in vacuo. The product could be further purified, if necessary, by column chromatography (15% ether/pentane for elution).
In an inert atmosphere glovebox, a 5 mm J. Young NMR tube was charged with 0.4 mL of benzotrifluoride, 300 µL of 2-(2,2-dimethylpent-4-en-1-yl)-1,1-dimethylhydrazine (1.5 mmol), and 185 µL of Et2Zn (1.8 mmol, 1.2 equiv.). The J. Young tube was placed in a 90 • C oil bath and the cyclization reaction was monitored by No-D NMR (indicated by the recession of the alkene peaks) using BTF as an internal standard. Upon completion of the cyclization, the J. Young tube was returned to the glovebox and the contents were transferred to a 10 mL Schlenk flask equipped with a magnetic stirring bar, and a Schlenk adapter with a septum on the sidearm. The J. Young tube was rinsed with THF (3 × 0.5 mL), which was added to the Schlenk flask, and the flask was then removed from the glovebox. The volatiles were removed in vacuo and the resulting solids were redissolved in a preformed solution of 500 µL of 1-bromo-1-octyne (3.125 mmol, 2.08 equiv.) in 1.5 mL of THF. The resulting solution was cooled to −78 • C and a preformed solution of 130 mg of LiBr (1.5 mmol, 1 equiv.) and 150 µL of 0.5 M CuCN·2LiBr solution in THF (5 mol%) in 3 mL of THF was slowly added. The solution was allowed to warm to RT with stirring overnight. The reactant mixture was then dispersed in 5 mL of diethyl ether and washed with a 1:1 sat. aqueous NH 4 Cl: sat. aqueous NH 4 OH solution (3 × 2 mL). The combined aqueous layers were back-extracted with diethyl ether (2 × 2 mL). The combined organic layers were dried with brine and Na 2 SO 4 , concentrated in vacuo, and the volatile components were removed under a high vacuum. The crude product was further purified by column chromatography using gradient elution (hexane to 20% EtOAc/hexane) to provide 293.1 mg (76%) of the title compound as a yellow oil. 1

General Procedure for the Synthesis of 1-Bromoalkynes
To a 100 mL round bottomed flask equipped with a magnetic stirring bar, acetone (30 mL) and the requisite 1-alkyne (12.5 mmol) were added. To this solution, AgNO 3 (0.213 g, 1.25 mmol) was added and, with vigorous stirring, N-bromosuccinimide (2.5 g, 14 mmol) was added in portions. The mixture was stirred at room temperature for 2 h when confirmed to be completed by TLC. The reactant mixture was diluted in pentane (75 mL) and filtered. The resulting solution was washed with water (2 × 25 mL) and the combined aqueous washes were back-extracted with 1:1 diethyl ether/pentane (2 × 15 mL). The combined organic layers were dried with Na 2 SO 4 , filtered through a plug of silica gel, and concentrated in vacuo. The product could be further purified by vacuum distillation or flash column chromatography. Procedure adapted from Gao et al. [28].

Conclusions
The Cu(I)-catalyzed cross-coupling of 1-bromoalkynes with the aminozincation intermediates derived from N,N-dimethylhydrazinoalkenes is described here. The use of LiBr as an adjuvant led to higher conversions and improved yields in this transformation. The incorporation of TMEDA (1.0 equiv.) was detrimental in the cross-couplings involving 1-bromo-2-phenylethyne. It is significant from a practical standpoint that this method can easily be extended to a preparative scale with no decrease in yield. The present technique provides saturated N-heterocyclic pharmaceutical scaffolds possessing a highly modifiable internal alkyne for further synthetic elaboration. The extension of this method to the utilization of heteroatom-bearing 1-bromoalkynes, as well as alternative N,N-dimethylhydrazinoalkenes, will be the topic of future reports from this laboratory.