Three-center-four-electron halogen bond enables non-metallic complex catalysis for Mukaiyama-Mannich-type reaction

Summary The three-center-four-electron halogen bond (3c4e X-bond) presents a fundamental design concept for catalysis. By integrating halogen(I) (X+: I+ or Br+), the bis-pyridyl ligand NN, and a non-nucleophilic counteranion Y, we developed non-metallic complex catalysts, [N···X···N]Ys, that exhibited outstanding activity and facilitated the Mukaiyama-Mannich-type reaction of N-heteroaromatics with parts-per-million-level catalyst loading. The high activity of [N···X···N]SbF6 was clearly demonstrated. NMR titration experiments, CSI-MS, computations, and UV-vis spectroscopic studies suggest that the robust catalytic activity of [N···X···N]Y can be attributed to the unique ability of the 3c4e X-bond for binding chloride: i) the covalent nature transforms the [N···X···N]+ complexation to sp2 CH as a hydrogen-bonding donor site, and ii) the noncovalent property allows for the dissociation of [N···X···N]+ for the formation of [Cl···X···Cl]−. This study introduces the application of 3c4e X-bonds in catalysis via halogen(I) complexes.

INTRODUCTION halogen(I)] + tetrafluoroborate, the so-called Barluenga's reagent, is a representative 3c4e X-bond complex that facilitates iodination, oxidation, and C-H and C-C bond functionalization (Barluenga, 1999;Chalker et al., 2010;Tsuji et al., 2014). Importantly, successful examples have always entailed the use of a stoichiometric amount of 3c4e complexes. Despite the utility of the 3c4e X-bond in synthetic chemistry, its potential for non-metallic complex catalysis has not been thoroughly investigated thus far.
Based on seminal studies (Beckendorf et al., 2012;Zhang and Schreiner, 2009), we have focused on the 3c4e X-bond to strategically design non-metallic complex catalysts, particularly anion-binding catalysts (Figure 2A). We envisaged that the cationic [N$$$X$$$N] + bond-assisted sp 2 -CH-bonding interaction would assemble the chloride at the first stage of catalysis. Subsequently, the electrophilic halogen (X) of the [N$$$X$$$N]Y complex would be subjected to a nucleophilic attack by the chloride to transform the anionic [Cl$$$X$$$Cl]bond through ligand exchange from bis-pyridine to chloride at the second stage, which could serve as a powerful driving force in anion-binding catalysis ( Figure 2B). Specifically, we report the development of bis-pyridine halogen(I) complexes 1 ([N$$$X$$$N]Ys; N is the substituted pyridyl ligand, X is I or Br, and Y is a non-nucleophilic counteranion) as non-metallic complex catalysts for anion-binding catalysis.

Determination of the target reaction
To prove our working hypothesis for the 3c4e X-bond complexes as anion-binding catalysts, we determined the primary target based on scatterplots of the yields (%) vs. catalyst loading (mol%) (see Figure S8). For this purpose, the Mukaiyama-Mannich-type reaction of N-heteroaromatics via chloride-binding was selected, because it provides a variety of useful nitrogen-containing intermediates for pharmaceutical applications (Bull et al., 2012;Sowmiah et al., 2018). To generate the scatterplots, datasets were prepared using 396 reactions employing previously reported anion-binding catalysts, particularly the chloride-binding (see Figure S8) ones, in an asymmetric and racemic manner. The scatterplots of yield (%) vs. catalyst loading (mol%) clearly show that 10 mol% of the catalyst was mainly used, and at A B  iScience Article least 5 mol% of the catalyst was required to achieve high yields. This [N$$$X$$$N]Ys-driven catalysis might solve the inherent limitation of the catalytic activity in previously reported organocatalysis. Among the representative N-heteroaromatics, i.e., isoquinolines, quinolines, and pyridines, the success of this catalytic process for the reaction of pyridines was significantly limited. Therefore, the Mukaiyama-Mannich-type reaction of pyridine compounds 2, chloroformates 3, and silyl enol ethers 4 was examined for our initial study.
Alternatively, N-methylated pyridyl triflate ([2Me$L1]$2OTf) accelerated the reaction (Berkessel et al., 2014) but yielded 10% less 5a than the corresponding iodine(I)complex 1a (entry 11). Overall, these control experiments indicated the potential of catalyst design using halogen(I) complex 1. Next, to establish the utility of 1 as the 3c4e-X-bond-based catalyst system, various counteranions, halogen(I), and pyridyl ligands were examined. Screening of counteranions (entries 12-17) showed that antimonate complex 1e produced the highest yield (90%) of product 5a, even with 0.1 mol% catalyst loading (entry 15). Notably, a similarly high yield (82%) and a satisfactory yield (74%) were obtained even when the 1e loading was reduced to 0.050 mol% (= 500 ppm) and further to 0.025 mol% (= 250 ppm) (entries 16 and 17, respectively), whereas a 100 ppm catalyst loading only produced a moderate yield (entry 18). Bromine(I) antimonate complex 1f  iScience Article and iodine(I) complexes 1g, 1h, and 1i with other pyridyl ligands-L2, L3, and L4-could be used to achieve high yields. Although the handling of these catalysts was complicated owing to the low stability of the complexes, high yields similar to those of 5a were obtained (entries 19-22). Although inorganic compounds, iodine monochloride (ICl), and elemental iodine (I 2 ) accelerated the reaction, the product yields of 5a were lower than that in the case of 1e (entries 16 vs. 23 and 24). To exclude the possibility of hidden acids, resulting from moisture during the manipulations, being the real catalyst species, the reactions were conducted in tetrahydrofuran (THF) with 1 wt % or 5 wt % of H 2 O; no reactions were observed (entries 25 and 26). Finally, the reaction progress at 0 C in the presence of 1e (500 ppm) was compared with those at 0 C, 20 C, and 30 C in the absence of the catalyst to clearly demonstrate the acceleration by 1e ( Figure 3). The reaction profile revealed that the 1e-catalyzed reaction proceeded more than six times faster than those without 1e. These results indicate that [N$$$X$$$N]Ys, composed of the pyridyl ligand,  (1) iScience Article halogen(I), and a non-nucleophilic counteranion, plays a significant role in efficiently promoting the reaction.

Scope of 3c4e X-bond-based anion-binding catalysis
Following the acquisition of the easy-to-handle and optimal complex catalyst 1e, the scope of the Mukaiyama-Mannich-type reaction was examined (Figures 4, see S16 and Table S8). The reactions of 2a with b-disubstituted silyl ketene acetals, 4a, 4b, and 4c, were accelerated in the presence of 500 ppm of 1e, and high yields of products 5a, 5b, and 5c, respectively, were obtained with g-selectivities. In particular, the highly reactive and unstable 4c reacted seamlessly to complete the reaction at À78 C within 15 min. The reaction of 2a with b-unsubstituted silyl ketene acetals 4d and 4e produced remarkable yields of 5d, along with a mixture of the a and g products, regardless of the silyl substituents. However, 1e did not show any catalytic activity in the reaction of silyl enol ether 4f. Other chloroformates such as 3b, 3c, and 3d were also adequately tolerated in this reaction. Although higher catalyst loadings of 0.1-1.0 mol% were required for the 2-, 3-, and 4-substituted pyridines 2b-2i owing to the substitution effect for the reactivity of the pyridinium substrates, moderate to high yields were obtained in the presence of 1e. In the cases that involved a/g selectivity, the product regioselectivities of 5a-5m varied with the electron densities of the nucleophilic carbon in 4; otherwise, 5n-5p depended on the influence of the pyridinium salt. In all cases, 1e affected the reaction acceleration but did not involve a/g selectivity. The 1e catalyst system also tolerated the reaction of quinoline, isoquinoline, and dihydroxyisoquinoline to yield the corresponding products 5q, 5r, and 5s. To clearly demonstrate the robustness of the [N$$$X$$$N]Ys catalyst system, all the experimental data of the primary study and the reaction scope were plotted on 49 previously reported reaction datapoints of the yields (%) vs. catalyst loading (mol%) for the Mukaiyama-Mannich-type reaction of N-heteroaromatics via chloride-binding in a racemic manner ( Figures 5, see S8). The [N$$$X$$$N]Ys catalyst afforded a higher yield with a lower catalyst loading than the previously reported datapoints that were obtained under the best reaction conditions for each system. iScience Article X-Ray diffraction analysis of 3c4e X-bonds As mentioned in previous reports (Turunen and Erdé lyi, 2021), N-I-Cl and Cl-I-Cl bonds were found in the crystal structures of halide complexes; therefore, we preliminarily performed X-ray diffraction analysis to demonstrate the transformation of [N$$$X$$$N] + to [Cl$$$X$$$Cl] À via [NN$$$X] + $$$Cl À . Although co-crystallization was not accomplished with the mixture of any [N$$$X$$$N]Ys and chloride sources such as n-Bu 4 NCl, certain halide complexes were obtained from L1, L2, and ICl (Figures 6, see S9, S10, S11, S12

Mechanistic studies
The X-ray crystal structures indicate the bond formation of Cl$$$I$$$N and [Cl$$$I$$$Cl] À and the further H-bonding of sp 2 -CH$$$Cl À (Figure 7). Based on the aforementioned results, 1 H NMR and CSI-MS measurements were performed using 1e and n-Bu 4 NCl to gain insight into the chloride-binding modes in the solution. Three phases of peak changes were observed during 1 H NMR titration (Figures 8A, see S1, S2, and S3): i) In the cases where 0.1 to 1.0 equiv of n-Bu 4 NCl was added, aromatic peaks of 1e-green-filled dots-shifted downfield owing to the de-shielding effect on the complex triangular structure of 1e. The trend of these shift changes is similar to that reported by Berkessel et al. (2014). These shift changes demonstrate the H-bonding between the chloride and the protons of 1e. Moreover, new sharp aliphatic peaks-red-filled dots-appeared. These peaks clearly explain that the anion exchange from SbF 6 À to Cl À occurs at the initial stage. In addition to these peak changes, new broad aromatic peaks-blue-filled dots-gradually emerged. ii) In cases where 1.0 to 2.0 equiv of n-Bu 4 NCl was added, sharp aromatic peaks of 1e-green-filled dots-decreased in peak size and disappeared when 2 equiv of n-Bu 4 NCl were added. By contrast, broad aromatic peaks-blue-filled dots-as well as sharp aliphatic peaks-red-filled dotsgradually increased in peak size. Particularly, the signals of two aromatic protons of the pyridine ring, H c and H d (indicated in blue), overlapped and appeared downfield as a single broad peak at 0.1 ppm with respect to those of L1. These peak changes demonstrate the formation of [L1$$$I] + $$$Cl À + n-Bu 4 N + % I + $$$Cl À + n-Bu 4 N + $$$L1 in equilibrium by the dissociation of the N$$$I$$$N bond. iii) In cases where more than 2 equiv of n-Bu 4 NCl were added, broad aromatic peaks-purple-filled dots-shifted up-field and were sharpened. Conversely, sharp aliphatic peaks-red-filled dots-shifted downfield and gradually increased in peak size. These observations suggest the formation of [Cl$$$I$$$Cl] À along with the , and [ICl 2 ] À , respectively. The peak intensity of [L1$I] + in the 1:1 mixture was significantly higher than that of L1$n-Bu 4 N + $[ICl 2 ] À following the addition of 0.5 equiv of n-Bu 4 NCl to 1e. By contrast, when a solution with 1e and n-Bu 4 N + in a 1:2 ratio was used, the peak of [L1$I] + disappeared, whereas the peak of L1$n-Bu 4 N + $[ICl 2 ] À was maintained. These spectral changes strongly support the following chloride-binding mode using complex catalyst 1: Considering these experimental studies, we proposed the catalytic cycle shown in Figure 9. In this mechanism, the sp 2 CH of the bis-pyridyl ligand in 1 initially interacts with chloride, and the nucleophilic attack of chloride on halogen(I) subsequently causes the formation of N$$$X + $$$Cl À , followed by [Cl$$$X$$$Cl] À bonds. [N$$$X$$$N] + , the charge-assisted sp 2 -CH-bond and the [Cl$$$X$$$Cl] À anionic 3c4e X-bond should be synergistically involved to generate the electrophilic 2 $ 3 + species. The resulting 2 $ 3 + would be subjected to the nucleophilic attack by silyl enol ether 4 to yield the silylated intermediate, yielding product 5 and R 6 SiCl along with re-generated 1.
To support the proposed mechanism, DFT calculations and UV-vis measurements were performed. The molecular electrostatic potentials (MEPs) of 1e and [N$$$I$$$N] + were mapped on the iso-density surface based on the DFT calculations performed using the SMD18 model (Figures 10A, see S17 and Table S9) (Engelage et al., 2018). The MEP map shows that positive charge is mainly located on the hydrogen atoms of the pyridyl ligand, with some remaining on the iodine atom. An analysis of noncovalent interactions (NCIs) indicated weak attractive interactions: CH$$$Cl À interactions between the a-protons of the pyridine ring in 1e and chloride, N$$$I + $$$N interactions between the pyridyl nitrogen and iodine(I), and C$$$I + interactions between the ethynyl sp carbon and iodine(I) (Figures 10B, see S18 and Table S10). These results suggest that [N$$$X$$$N]Y would promote the reaction via charge-assisted noncovalent interactions, such as hydrogen bonding, in the case of 1e, at the initial stage. Moreover, DFT calculations using the SMD18 model support the formation of the 3c4e X-bond between the pyridyl nitrogen atom and chloride: The transformation of [N$$$I$$$N]Cl to [NN$$$I$$$Cl] resulted in a Gibbs free energy change of À3.2 kcal mol À1 , with a transition-state free energy of 12.9 kcal mol À1 ( Figure 10C, see Table S11). Although the transition state of the [NN$$$I$$$Cl] + Cl À to [NN] + [Cl$$$I$$$Cl] À conversion could not be found, this conversion is also exothermic, with a Gibbs free energy change of À3.7 kcal mol À1 ( Figure 10C, see Table S12). Finally, UV-vis measurements were performed to identify the reformation of [N$$$I$$$N]Ys for the catalytic cycle. The UV-vis spectrum of the crude reaction mixture shows absorption at 307 nm, which was similarly observed in the spectrum of 1e ( Figures 10D, see S6), indicating that [Cl$$$X$$$Cl] À is transformed back to [N$$$X$$$N] + . This can be explained by the robust catalytic activity of [N$$$X$$$N]Ys owing to the distinct feature of the charged 3c4e X-bond: partially covalent and strongly electrostatic interaction derived from halogen(I).

Limitations of the study
This study is limited to the Mukaiyama-Mannich-type reaction of N-heteroaromatics via chloride-binding in a racemic manner. A method based on the current approach could apply to other catalytic reactions, either through Lewis-acid or Brønsted-acid catalysis. The surface was computed on a 0.008 a.u. electron-density contour for visualization. The molecular electrostatic potential maps were created using the GaussView 6 software. Surface potential values are indicated in kJ mol À1 . The color ranges are as follows: red, less than 240 kJ mol À1 ; and blue, greater than 500 kJ mol À1 . (B) The NCI plot between [N$$$I$$$N] + of 1e and Cl À . The isosurface s-value equals 0.3 a.u., green indicates weak attractive interactions.
(D) The UV-vis spectra of the crude reaction mixture, 1e, and L1.

DECLARATION OF INTERESTS
The authors declare no competing interests.

Lead contact
Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Norie Momiyama (momiyama@ims.ac.jp).

Materials availability
All other data supporting the findings of this study are available within the article and the supplemental information, or can be obtained from the lead contact upon reasonable request.
Data and code availability d All original crystal structures have been deposited at CCDC and are publicly available as of the date of publication. CCDC numbers are listed in the key resources table.
d This paper does not report original code.
d Any additional information required to reanalyze the data reported in this paper can be obtained from the lead contact upon request.

General reagent information
Unless otherwise specified, all reactions were carried out under an atmosphere of standard-grade nitrogen gas (oxygen <10 ppm) in flame-dried glassware with magnetic stirring. Commercially available reagents and chemicals were purchased and used without further purification. Dichloromethane (CH 2 Cl 2 ), diethyl ether (Et 2 O), and tetrahydrofuran (THF) were supplied from a ''dehydrated solvent system'' by Kanto Chemical Co., Inc. Other solvents were procured in the dehydrated form from Wako Pure Chemical Industries Ltd. Analytical thin-layer chromatography (TLC) was performed on E. Merck precoated (0.25 mm) silica gel 60-F254 plates. Visualization was accomplished using UV light (wavelength (l) = 254 nm) and a phosphomolybdic acid solution in ethanol with heating. Purification of the reaction products was carried out via flash column chromatography using silica gel 60 N (Merck: 0.040-0.063 mm). The microwave reactions were performed using a Biotage Initiator + model (Biotage Japan Ltd), in which the temperature was monitored via an infrared temperature sensor, and Biotage Microwave Reaction Vials, which were sealed with caps with septa.

Syntheses of halogen(I) complexes
A variety of halogen(I) complex catalysts were synthesized according to the reported procedure (Bedin et al., 2015;Carlsson et al., 2012a). Among them, 1,2-bis(pyridine-2-ylethynyl)benzene iodine(I) triflate (1a), Erdé lyi's complex, was used as the benchmark complex catalyst because it is relatively stable and easy to handle. Moreover, two types of protonated L1 triflates were prepared as references to prevent H + from contaminating 1a (Bedin et al., 2015;Suzaki et al., 2014, see Figure S7). We confirmed that the 1 H NMR spectra of 1a were significantly different from those of protonated L1, which clearly showed our synthesized 1a iodine complex without the contamination of protonated complexes. All complexes 1 were synthesized and characterized accordingly and used as the halogen(I) complex catalysts.

Synthesis of 1,2-diethynylbenzene
To a solution of 1,2-diiodobenzene (0.655 mL; 5.00 mmol; 1.0 equiv) in Et 2 NH (13 mL), trimethylsilylacetylene (1.70 mL; 12.0 mmol; 2.4 equiv), Pd(PPh 3 ) 2 Cl 2 (351 mg; 0.500 mmol; 10 mol%), and CuI (95.2 mg; 0.500 mmol; 10 mol%) were added (Bosch and Barnes, 2001). The mixture was heated to 70 C and stirred for 20 h. It was then allowed to cool to room temperature, diluted with hexane, and washed with water. The organic phase was dried over MgSO 4 and concentrated under reduced pressure after filtration to yield a crude product. The crude product was immediately deprotected as follows: Na 2 CO 3 (250 mg; 2.40 mmol; 0.60 equiv) was added to a solution of the crude product in MeOH (50 mL). The mixture was stirred at room temperature for 2 h, diluted with water, and extracted using hexane (15 mL 3 3). The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure after filtration. The crude product was purified using silica gel column chromatography with hexane as the eluant to yield the desired product as a pale yellow oil (405 mg; 3.20 mmol; 76%, see Scheme S3).

Synthesis of [2Me$L1]$2OTf
Methyl triflate (72 mL; 0.660 mmol; 2.2 equiv) was added to a solution of 1,2-bis(2-pyridylethynyl)benzene (84.1 mg; 0.300 mmol; 1.0 equiv) in CH 2 Cl 2 (2 mL) at 0 C. The mixture was stirred for 14.5 h at room temperature and the solvent was evaporated under reduced pressure. The remaining solid was obtained via filtration and washed with diethyl ether. The residue was dried under reduced pressure to yield the desired compound as a white solid (169 mg; 0.278 mmol; 93%, see Scheme S9.

Synthesis of methyl trimethylsilyl dimethylketene acetal (4a)
To a solution of i-Pr 2 NH (5.26 mL; 38.5 mmol; 1.1 equiv) in THF (50 mL), n-BuLi (1.60 M in n-hexane; 24.1 mL; 38.5 mmol; 1.1 equiv) was added at 0 C. The mixture was stirred for 1 h and cooled to À78 C (Gatzenmeier et al., 2018). Methyl isobutyrate (4.02 mL; 35.0 mmol; 1.0 equiv) was then added to it, and the mixture was stirred for another 1 h. TMSCl (5.31 mL; 42.0 mmol; 1.2 equiv) was added to the reaction mixture, which was stirred for 30 min. It was then slowly warmed to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure, and n-hexane (50 mL) was added. The mixture was filtered through a pad of celite and membrane filter, and n-hexane was evaporated under reduced pressure. Distillation of the crude product (56 C/19 mmHg) yielded the desired product as a colorless oil (3.84 g; 22.0 mmol; 63%, see Scheme S13).

Synthesis of 1-methoxy-1-trimethylsilyloxymethylenecyclohexane (4b)
1-Methoxy-1-trimethylsilyloxymethylenecyclohexane was synthesized according to the reported method (Berkessel et al., 2014). To a solution of diisopropylamine (4.92 mL; 36.0 mmol; 1.2 equiv) in THF (75 mL), n-BuLi (1.60 M in n-hexane; 20.6 mL; 33.0 mmol; 1.1 equiv) was added at 0 C. The mixture was stirred for 20 min and then cooled to À78 C. Methyl cyclohexanecarboxylate (4.29 mL; 30.0 mmol; 1.0 equiv) was then added to it, and the mixture was stirred for another 30 min, after which TMSCl (4.17 mL; 33.0 mmol; 1.2 equiv) was added to it. Then the mixture was slowly warmed to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure and n-hexane (100 mL) was added, which was removed under reduced pressure after filtration. Distillation of the crude product (57 C/6 mmHg) yielded the desired product as a colorless oil (5.59 g; 26.1 mmol; 87%, see Scheme S14).

Synthesis of ((1-methoxyvinyl)oxy)trimethylsilane (4d)
To a solution of dicyclohexylamine (12.0 mL, 60.0 mmol, 1.2 equiv) in THF (50 mL), n-BuLi (1.60 M in n-hexane; 37.5 mL; 60.0 mmol; 1.2 equiv) was added at 0 C. The mixture was stirred for 15 min and cooled to À78 C (Lee et al., 2018). A mixture of methyl acetate (3.98 mL; 50.0 mmol; 1.0 equiv) and TMSCl (7.58 mL; 60.0 mmol; 1.2 equiv) was added to it, and it was stirred for another hour. The mixture was then slowly warmed to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure and n-pentane (20 mL) was added. The mixture was filtered through a pad of celite, and n-pentane ll OPEN ACCESS iScience 25, 105220, October 21, 2022 19 iScience Article was evaporated under reduced pressure. Distillation of the crude product (38 C/40 mm Hg) yielded the desired product as a colorless oil (599 mg; 4.09 mmol; 8%, see Scheme S16).

Synthesis of trimethyl[(1-methylethenyl)oxy]silane (4f)
A mixture of acetone (2.06 mL; 28.0 mmol; 1.0 equiv) and sodium iodide (4.20 g; 28.0 mmol; 1.0 equiv) was dissolved in CH 3 CN (30 mL) and stirred for 5 min at room temperature (Zhang and Lupton, 2017). Et 3 N (3.90 mL; 28.0 mmol; 1.0 equiv) and TMSCl (3.54 mL; 28.0 mmol; 1.0 equiv) were added to the solution, and it was stirred at 40 C for 16 h. The reaction mixture was then cooled to room temperature and quenched with cold pentane (50 mL) and ice water (50 mL), when the two phases separated. The aqueous phase was extracted with n-pentane (30 mL 3 3) and the combined organic phases were dried over MgSO 4 . The solvent was concentrated under reduced pressure after filtration to yield the desired product as a colorless oil (786 mg; 6.03 mmol; 22%, see Scheme S17).
The catalyst (0.20 mmol; 0.05 mol%) was added, and the reaction mixture was stirred for 5 min, following which, methyl trimethylsilyl dimethylketene acetal (120 mL; 0.600 mmol; 1.5 equiv) was added. The mixture was then stirred for 1 h and quenched with saturated aqueous NaHCO 3 (20 mL) for phase separation. The aqueous phase was extracted with diethyl ether (10 mL 3 3) and the combined organic phases were washed with 2M aq. NaOH (10 mL) and brine (10 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure after filtration. The crude product was purified using silica gel column chromatography (ethyl acetate/hexane = 1:8) to yield the desired product as a light yellow oil (99.3 mg; 0.330 mmol; 82%, see Scheme S18).

NMR titration of [N-I-N]SbF 6 with n-Bu 4 NCl
In the NMR tube, [N-I-N]SbF 6 (3.2 mg; 5.0 mmol) was dissolved in THF-d 8 (360 mL) and CD 3 CN (40 mL) and mixed thoroughly using a vortexer. The tube was placed in a 600 MHz NMR spectrometer, in which the prove had been pre-cooled to 0 C, and the 1 H NMR spectrum was obtained. A solution of n-Bu 4 NCl in THF-d 8 /CD 3 CN 9:1 (v/v) was added and mixed thoroughly using a vortexer. The NMR tube was then quickly transferred to the NMR spectrometer. The process was repeated to obtain the 1 H NMR spectra in the presence of varying amounts of n-Bu 4 NCl (0.10-10.0 equiv, see Figures S1, S2 and S3).

5f
The general procedure (Scheme S18) was followed. White solid (117 mg

5h
The general procedure (Scheme S18) was followed.

5n
The general procedure (Scheme S18) was followed.

5o
The general procedure (Scheme S18) was followed. g (minor) and a (major) adducts were obtained as a 16:84 mixture.