Ligand relay catalysis for cobalt-catalyzed sequential hydrosilylation and hydrohydrazidation of terminal alkynes

Sequential double hydrofunctionalizationalization of alkynes is a powerful method to construct useful vicinal compounds. Herein, we report a cobalt-catalyzed sequential hydrosilylation/hydrohydrazidation of alkynes to afford 1,2-N,Si compounds via ligand relay catalysis. A phenomenon of ligand relay is found that the tridentate anionic N-ligand (OPAQ) could capture the cobalt ion from bidentate neutral P-ligand (Xantphos) cobalt complex. This protocol uses three abundant chemical feedstocks, alkynes, silanes, and diazo compounds, and also features operationally simple, mild conditions, low catalyst loading (1 mol%), and excellent functional group tolerance. The 1,2-N,Si compounds can be easily further derivatized to afford various substituted silane derivatives via Si-H functionalization, alcohols via Fleming-Tamao oxidation, free amines and amides via N-N bond cleavage and protection. The asymmetric reaction could also be carried out to afford chiral products with up to 86% ee. The ligand relay has been supported by control experiments and absorption spectra.

O rganosilicon compounds have been widely used in materials science 1 as well as agrochemistry and organic synthesis 2,3 , also play a growing role in medicinal chemistry as silasubstitution or bioisosteres of carbon or other moieties due to slight physical and electronic alterations 4,5 . Vicinal amino and silyl (1,Si) compounds as an important subclass of organosilicon compounds simultaneously bearing amino and silyl groups have presented in various biologically active compounds such as sila-haloperidol and sila-venlafaxine ( Fig. 1) [6][7][8] .
Sequential double hydrofunctionalization of readily available alkynes could atom-and pot-economically install two functional groups 9,10 . For two transformations with same catalytic species, one metal catalyst could achieve the sequential reactions [11][12][13][14][15][16][17][18][19][20] . For two mechanistically distinctive transformations, a strategy of bimetallic catalysis in which two different metal catalysts respectively play an individual role has been usually employed, however, compatibility issues of two metal catalysts used to limit their utility (Fig. 2a). Ligand exchange is a well-known fundamental elementary reaction in organometallic chemistry 21 . To avoid compatibility issues and also achieve metal economy, a strategy of ligand exchange by using mono metal and two ligands could be proposed in which the former ligand metal complex for catalyzing the first-step reaction would undergo ligand exchange after adding the latter ligand to catalyze the second-step reaction ( Fig. 2a) [22][23][24][25][26][27][28][29][30][31][32][33] . Two reactions would not or slightly interrupt with each other. This one-way ligand exchange for catalyzing two mechanistically distinctive transformations could be called as ligand relay catalysis. However, to the best of our knowledge, this ligand relay catalysis has not been used in sequential double hydrofunctionalization of alkynes.
Sequential double hydrofunctionalization of alkynes could be potentially used to access 1,2-N,Si compounds. Nevertheless, sequential hydrosilylation/hydrohydrazidation of alkynes to deliver 1-amino-2-silylalkanes has not yet been reported. There are several challenges: (1) inhibiting the side-reactions in sequential transformations, including dihydrosilylation [11][12][13] and hydrogenation 14,15 ; (2) controlling the compatibility of two reactions in one pot as well as one product bearing both N-H bond and Si-H bond; (3) achieving high regioselectivity to reduce the possibility of gem-substituted undesired products [16][17][18] , and improving the efficiency of reactions to make the transformation synthetically useful.

Results
Reaction optimization. We began our investigation on sequential hydrosilylation/hydrohydrazidation of alkynes with selected initial reaction conditions, using ethynyl benzene 1a as a model substrate, diphenyl silane 2a as a silicon source, ethyl 2-diazo-2-phenylacetate 3a as a nitrogen source. Based on our previous studies on the cobaltcatalyzed sequential reaction of alkynes 14 , various cobalt complexes for alkyne hydrosilylation have been tested as a solo catalyst for the sequential reaction, however, reactions were messy and fewer desired products have been obtained. To achieve two reactions in one pot, a combined catalytic system using two different catalysts has been tested. One catalytic system is using Xantphos•CoBr 2 and activator NaBHEt 3 for the first hydrosilylation step 38,39 . The other catalytic system is using N-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-6-methylpicolinamide (OPPA) L1 and Co(OAc) 2 for the second hydrohydrazidation step 36 . The combined catalytic system using PhSiH 3 as a hydrogen donor in a solution of Et 2 O could promote the sequential hydrosilylation/hydrohydrazidation of alkynes to access 1-amino-2-silylalkane 4a in 12% yield (entry 1, Fig. 3). The use of different quinoline amine scaffolds improved the reactivity of reaction drastically (entries 2-6). The optimized ligand was N-oxazolinylphenyl 8-aminoquinoline (OPAQ) L5, delivering 4a in 81% yield. Altering several N-containing classical ligands such as OIP, PDI, PI, and Pybox, only trace amounts of 4a could be observed (entries 7-10). It is worth noting that this transformation in the absence of Co(OAc) 2 could smoothly occur, delivering 4a in 84% yield, which presented a unique phenomenon of ligand relay (entry 11). With 3 equiv. of H 2 O as promotor, the reaction smoothly afforded 4a in 86% isolated yield (entry 12). The standard conditions are as shown in entry 12.
Substrate scope. With the optimized conditions in hand, substrate scope was explored as shown in Fig. 4. Substituents at ortho-and meta-positions on aryl rings can be well accommodated (4b-4h). Various functional groups, such as halo, ether, thiol, ether, free amine, Bpin, amide, acetal, and ester, could be tolerated (4i-4v). Substrates bearing fused rings and heterocycles, such as naphthyl, fluorenyl, indolyl, thiophene, benzothiophene, and pyridine, were also compatible in this system delivering corresponding products in 46-86% yields (4w-4ad). The alkyl substituted 1-amino-2-silylalkanes could hardly be observed in the process of aminosilylation of alkenes 40 or ring-opening C(sp 3 )-Si cross-coupling of aziridines [41][42][43] , and it was challenging to obtain these compounds. Preliminary study found that hex-1- yne could be converted into 4ae in 32% yield (7/1 rr) under modified conditions. Aryl alkynes containing bioactive skeletons like estrone and geraniol could undergo the reaction to afford 4af and 4ag in 57-73% yields, which exhibited the underlying feasibility in late-stage modification of complicated molecules. Various hydrosilane, para-chloride and tert-butyl substituents diphenyl silanes and phenylsilane, could participate in this transformation smoothly to deliver 4ah and 4ai in 69-80% yields and 4aj bearing two silicon-hydrogen bonds in 55% yield. The diazo compounds with benzyl ester and dimethyl phosphate were also suitable for the system under standard conditions, delivering 4ak in 72% yield and 4al bearing three hetero atoms P, N, and Si in 61% yield.
To the best of our knowledge, the sequential hydrosilylation/ hydrohydrazidation of alkynes for the synthesis of chiral vicinal N,Si compounds in an enantioselective manner has scarcely been reported. Thus, We preliminarily conducted asymmetric transformation of alkynes to afford chiral 1,2-N,Si compounds in moderate yields with good ee (Fig. 5). Under the optimized conditions, the standard substrates could be transformed to the chiral product in 52% yield with 86% ee. Both electronwithdrawing and electron-donating groups could be tolerated in the catalytic system, delivering the end-product in moderate yields with good ee. Alkynes bearing 2-naphthyl and benzothiophenyl underwent the reaction smoothly in 51% and 53% yields with 84% and 82% ee, respectively.
Gram-Scale reaction and synthetic applications. The gram-scale reaction could be smoothly conducted to access 4a in 82% yield (Fig. 6). The 1,2-N,Si compounds could be further derivatized via C-Si cleavage, Si-H transformation, and N-N cleavage. Firstly, these compounds could be easily transferred to alcohol 6 in excellent yield via Fleming-Tamao oxidation. Then, 1,2-N,Si compounds could be smoothly transformed to silanol 7, fluorosilane 8, and siloxane 9 via Si-H transformation in 67-84% yields. The product can also be converted into amide silane 10 in 48% yield via mild N-N bond cleavage and benzoyl group protection. These compounds containing both N-H bond and Si-H bond might be interesting and potentially useful, due to that, generally, N-H bond could provide a proton and Si-H bond could afford a hydride as a polar opposite reagent.
Mechanistic studies. To gain insight into the mechanism, two control experiments were conducted to illuminate possible mechanism (Fig. 7). With the existence of TEMPO, no desired product can be observed. The benzyl radical generated from MHAT process was trapped by TEMPO delivering the product in 9% yield, indicating that the reaction may go through radical process. The deuterium-labeling experiment was also conducted using PhSiD 3 as a D source to afford 11 in 81% yield with 90% D in the adjacent methylene of silyl group (dr = 1/1), indicating that radical process may exist in this reaction. To further understand the ligand relay process, the absorption measurement was conducted (Fig. 8). Initially, we added NaBHEt 3 to the solution of Xantphos•CoBr 2 and it did not change the shape of absorption peaks. When adding OPAQ to the mixture, in the first 5 mins, there was no change in absorption peaks. A broad peak was observed at 468 nm in 30 mins (red line) which is cater to the absorption peak of OPAQ•CoBr 2 activated by NaBHEt 3 at 467 nm (blue line) indicating that it takes a period of time for Several control experiments were also conducted. Firstly, the anti-Markovnikov hydrosilylation of alkynes could not successfully occur, delivering the α-adduct as the main product instead. Herein, Xantphos was essential for the first hydrosilylation step (Fig. 9a). Next, hydrohydrazidation of alkenyl silane failed in the absence of OPAQ, indicating that the relay process between Xantphos and OPAQ would promote the second step (Fig. 9b). From Fig. 9c we could know that OPAQ would slightly influence the anti-Markovnikov hydrosilylation step and 2% NMR yield of α-adduct was observed. In the end, Xantphos barely affected the hydrohydrazidation step, affording the 1-amino-2-silylalkanes in good yield (Fig. 9d).
Based on the control experiments and previous studies 38,39,44-49 , we envisioned a possible mechanism shown in Fig. 10

Discussion
In summary, we reported a cobalt-catalyzed sequential hydrosilylation/hydrohydrazidation of readily available terminal alkynes with hydrosilanes and diazo compounds to deliver 1,2-N,Si compounds with good functional group tolerance. These products bearing both N-H bond and Si-H bond can be easily transformed to hydrazino  alcohol, diversified silicon-substituted hydrazino silanes, and amide silane. Two mechanistically distinctive transformations including cobalt-catalyzed alkyne insertion for alkyne hydrosilylation and the HAT process for hydrohydrazidation of alkenyl silane could be conducted using 1 mol% of cobalt as a solo metal in one pot. The asymmetric reaction could also be carried out to afford chiral products with up to 86% ee. A phenomenon of ligand relay is found to deliver cobalt from diphosphine ligand to NNN-tridentate ligand which is also illustrated by absorption measurement. Ligand relay could offer an opportunity as a potentially powerful strategy for metal-catalyzed sequential reactions using a solo metal. Further studies on ligand relay guided sequential reactions and the synthesis of organosilicon compounds will be continuously explored in our laboratory. . The combined filtrates were concentrated in vacuo. NMR yield was monitored by 1 H NMR analysis using TMSPh as internal standard. The crude mixture was purified by short flash column chromatography to give the corresponding product.

Data availability
The authors declare that the data Supplementary the findings of this study are available within the paper and its Supplementary Information file. The experimental procedures  c Investigation of hydrosilylation step using a combination of Xantphos, L5, and CoBr 2 . d Investigation of hydrosilylation step using a combination of Xantphos, L5, and CoBr 2 . Fig. 10 Proposed mechanism. Proposed reaction pathway starts from Xantphos•Co-H species to catalyze the hydrosilylation step, followed by the key ligand relay process to generate the OPAQ•Co-H to catalyze the hydrohydrazidation step.