Ligand-promoted cobalt-catalyzed radical hydroamination of alkenes

ABSTRACT Highly regio- and enantioselective intermolecular hydroamination of alkenes is a challenging process potentially leading to valuable chiral amines. Hydroamination of alkenes via

metal-catalyzed hydrogen atom transfer (HAT) with good regioselectivity and functional group tolerance has been reported, however, high enantioselectivity has not been achieved due to the

lack of suitable ligands. Here we report a ligand-promoted cobalt-catalyzed Markovnikov-type selective radical hydroamination of alkenes with diazo compounds. This operationally simple

protocol uses unsymmetric _NNN-_tridentate (UNT) ligand, readily available alkenes and hydrosilanes to construct hydrazones with good functional group tolerance. The hydrazones can undergo

nitrogen–nitrogen bond cleavage smoothly to deliver valuable amine derivatives. Additionally, asymmetric intermolecular hydroamination of unactivated aliphatic terminal alkenes using chiral

_N_-imidazolinylphenyl 8-aminoquinoline (IPAQ) ligands has also been achieved to afford chiral amine derivatives with good enantioselectivities. SIMILAR CONTENT BEING VIEWED BY OTHERS

NICKEL-CATALYSED ENANTIOSELECTIVE ALKENE DICARBOFUNCTIONALIZATION ENABLED BY PHOTOCHEMICAL ALIPHATIC C–H BOND ACTIVATION Article Open access 29 April 2024 ENANTIOSELECTIVE ALKENE

HYDROALKYLATION OVERCOMING HETEROATOM CONSTRAINTS VIA COBALT CATALYSIS Article 10 July 2024 REGIO‐ AND ENANTIOSELECTIVE NICKEL-ALKYL CATALYZED HYDROALKYLATION OF ALKYNES Article Open access

02 August 2024 INTRODUCTION Amine and its derivatives are significant in natural products and pharmaceutical chemistry (Fig. 1)1,2,3, (https://www.pharmacy-tech-test.com/top-200-drugs.html).

So development of novel methodologies for the synthesis of various amines and their derivatives is highly desirable, particularly from simple and readily available starting materials.

Metal-catalyzed hydrofunctionalization of readily available alkenes with nitrogen sources is one of the most efficient methods for the synthesis of nitrogen-containing molecules; however, to

achieve the high regio- and enantioselectivities of this transformation is still a challenge (Fig. 2a)4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19. Among several activation strategies for

alkene hydroamination, metal-catalyzed hydrogen atom transfer (HAT) reaction exhibits great Markovnikov selectivity and chemoselectivity (Fig. 2b)20. Okamoto and coworkers reported an early

example of cobalt-catalyzed hydronitrosation of styrenes with nitric oxide using a hydroborane salt as a hydrogen source to form oximes21. Since Mukaiyama and coworkers22 reported the

iron-catalyzed hydroamination of unactivated alkenes via HAT, using phenyl silane as a reductant and butyl nitrite as an aminating reagent, various aminating reagents, such as azo

compounds23,24,25,26, nitro compounds27,28, diazo compounds29, azides24,30, and amides31,32 have been explored by many research groups, which offers a great opportunity for retrosynthetic

possibility of new transformations. Although simple 1,3-dicarbonyl metal complexes could promote the reactions, stoichiometric amount or high loading of these complexes used to be

necessary20,33. Additionally, due to the generation of radical intermediates, asymmetric intermolecular hydroamination of alkenes via radical HAT process has not been explored. So the

development of new types of ligands for efficient radical hydroamination of alkenes via a HAT process is still highly desirable. It should be noted that the additional ligands used to

promote the formation of metal hydride species that could undergo classic alkene insertion34,35. Due to the inhibition of generation of the alkyl radical, the reactivity and selectivity of

transformation might decrease dramatically. Otherwise, the tetra- or more dentate ligand-based metal complexes could promote the generation of radical; however, no highly enantioselective

examples have been reported so far due to the weak coordination of alkyl radical with metal complexes. So the discovery of suitable ligand scaffolds for metal-catalyzed radical

hydroamination of alkenes is a challenge and also has great potential (Fig. 2c). Continuing our pursuit of efficient earth-abundant transition metal catalysis via ligand

design36,37,38,39,40,41,42,43,44,45; here, we report the use of unsymmetric _NNN_ tridentate ligands to promote the cobalt-catalyzed radical hydroamination of alkenes via HAT (Fig. 2d).

Meanwhile, asymmetric reaction of unactivated aliphatic terminal alkenes using chiral _N_-imidazolinylphenyl 8-aminoquinoline (IPAQ) ligand has also been achieved to afford chiral amine

derivatives with good enantioselectivities. RESULTS REACTION OPTIMIZATION The reaction of styrene 1A with ethyl 2-diazo-2-phenylacetate 2A in the presence of phenyl silane as a hydrogen

donor in a solution of tetrahydrofura (THF) was selected as a model reaction. The reaction using Co(acac)2 afforded the hydroamination product 3A in a poor yield (entry 1, Table 1). The use

of Co(OAc)2 did not promote this transformation (entry 2). The known ligands for HAT, such as tpp, dmg, dppe, salen, and tridentate half salen L1 have been tested; however, no reactivity or

poor yields were observed (entry 3 and also see in Supplementary Table 1). _NN_-bidentate ligands such as 2,2′-bipyridine (bpy) and 1,10-phenanthroline (phen) could accelerate this reaction

to give 3A in 44 and 37% yields, respectively (entries 4 and 5). The reaction using _NNN_ tridentate _N_-oxazolinylphenyl picolinamide (OPPA) ligands42,46 L2 and L3 afforded 3A in 88 and 92%

yields, respectively (entries 6 and 7). Then, 8-aminoquinoline group was used as a directing group on the ligand instead of 2-picolinamide. The reaction using _N_-oxazolinylphenyl

8-aminoquinoline (OPAQ) L4 as a ligand delivered 3A in 96% yield (entry 8). So, the standard conditions were identified as 0.36 mmol of alkene 1, 0.3 mmol of _α_-diazo ester compound 2, 5 

mol% of Co(OAc)2, 6 mol% of L4, and 1.2 equiv. of PhSiH3 in a solution of THF (0.25 M) at room temperature (r.t.) for 12 h. SUBSTRATE SCOPE With the optimized conditions in hand, the

substrate scope was shown in Table 2. A variety of styrenes bearing electron-donating or electron-withdrawing substituents at _para_-, _meta_-, or _ortho_-position on the phenyl ring

underwent the reactions to afford the corresponding benzylamine derivatives (3B–3T) in 50–95% yields. For more broad synthetic interests, various functional groups, such as halide, ether,

aniline, organoboronate, sulfide, nitrile, aldehyde, ester, and free alcohol were well tolerated. Meanwhile, 2-naphthyl (1U), pyridine derivated alkenes (1V and 1W) could be delivered to the

corresponding products in 71–92% yields. The reaction of alkyl-substituted terminal alkenes could undergo smoothly. Simple alkenes, such as 1-octene and 1-butene could be delivered to

aliphatic amines in 77 and 72% yields, respectively. Alkenes, bearing phenyl, ether, tosyl, free alcohol, amine, amide, as well as nitrogen containing heterocycles, could be converted to the

corresponding products in 49–84% yields. Notably, allylic alcohol and allylic amine derivatives could be reacted to deliver amino alcohol 3AE and diamine 3AF in 49 and 84% yields,

respectively. 1,1- and 1,2-disubstituted alkenes were suitable substrates and provided 3AJ–3AL in 79–86% yields. Natural products, such as amino acid, menthol, uracil, and estrone bearing a

terminal alkene moiety could be employed to deliver products (3AM–3AP) in 59–89% yields, which also demonstrated that this method could be suitable for late-stage functionalization of

complicated molecules. Terminal alkene bearing anti-inflammatory drug naproxen was converted to 3AQ in 61% yield. Configuration was confirmed by the X-ray diffraction of 3M, and the other

products were then assigned by analogy to 3M. FURTHER APPLICATIONS The gram-scale reaction could be smoothly performed to afford 3A in 94% yield (Fig. 3a). The reaction of 3M with

1,3-diketone afforded the pyrazole 4 in 86% yield (Fig. 3b). The three-step reactions containing alkene hydroamination, zinc-promoted reductive cleavage of _N_–_N_ bond, and acyl protection

of amine could be realized smoothly with once flash column chromatography purification process to deliver the corresponding amides 6 and 7 in 53–75% yields (Fig. 3c). The pharmaceutical

substances and biologically active amines 8, such as appetite-suppressant drug clobenzorex, antianginal drug fendiline, and anti-hyperparathyroidism active NPS _R_568, could be efficiently

synthesized in 32–45% yields from simple alkenes using a three-step synthetic protocol (Fig. 3c). SUBSTRATE SCOPE OF ASYMMETRIC HYDROAMINATION It should be noted that metal-catalyzed highly

enantioselective hydroamination of unactivated aliphatic terminal alkenes is still an unsolved problem47. A primary study on asymmetric reaction using chiral unsymmetric _NNN_-tridentate

ligand was explored. A chiral _N_-imidazolinylphenyl 8-aminoquinoline (IPAQ) ligand was designed and synthesized for asymmetric hydroamination of unactivated aliphatic terminal alkenes

followed by cleavage of _N_–_N_ bond and benzyl protection to afford chiral amine derivatives with up to 92.7 : 7.3 _er_ (Table 3)48. The scope of substrate was quite broad. Various

functional groups, such as halide, ether, and indole, could be tolerated. Alkene-bearing free alcohol moiety could underdo this transformation to afford the corresponding amide with a

decreased yield. Chiral products with up to 98.6 : 1.4 _er_ could be obtained after recrystallization. Particularly, the reaction of 1-butene afforded corresponding amide in 67% yield and

89.0 : 11.0 _er_ (97.3 : 2.7 _er_ after recrystallization). The chiral antihypertensive drug labetalol could be obtained from 14 via a known procedure49. MECHANISTIC STUDIES Control

experiments were conducted to illustrate the possible mechanism. The reaction in the presence of TEMPO did not occur, which indicated a possible radical pathway (Fig. 4a). The reaction of

vinyl cyclopropane 28 afforded the ring-opening product 29 in 62% yield (Fig. 4b) via cleavage of the more substituted carbon–carbon bond50, which supported the radical promoted ring-opening

pathway51. A deuterium-labeled experimental reaction of indene using PhSiD3 was conducted to afford 30 in 89% yield with 94% D and 1/1 _dr_ (Fig. 4c) which demonstrated that the hydrogen

came from hydrosilane and the carbon-centered radical formed as an intermediate. Based on the experimental studies and previously reported literatures24,27,52,53,54,55,56, a possible

mechanism was shown in Fig. 5. The cobalt hydride species A obtained from the reaction of Co(OAc)2 with ligand and silane could undergo a metal hydride HAT process to deliver the carbon

radical intermediate and cobalt species B. Due to the possible redox non-innocent property of the ligand, the chemical valence of cobalt was not consistent. The cobalt species B might

coordinate with diazo compound and undergo one electron oxidation with the carbon radical intermediate to afford the cobalt–carbon species C, which could undergo alkyl group migration from

cobalt to nitrogen atom to generate cobalt oxide species D. The possibility that carbon radical directly attacked the cobalt coordinated diazo compound could not be ruled out. The cobalt

species D could react with hydrosilane to regenerate the cobalt hydride species A and afford the vinyl silyl ether intermediate, which could undergo hydrolysis and isomerization to give the

product. Further studies are undergoing in our laboratory to gain an accurate understanding of the mechanism. DISCUSSION In summary, we reported the use of unsymmetric _NNN_-tridentate OPAQ

ligand to promote the cobalt-catalyzed radical hydroamination of alkenes via HAT. The protocol uses simple and commercially available alkenes to deliver the amination products with good

functional group tolerance and high Markovnikov selectivity. The hydrazone compounds could undergo nitrogen–nitrogen bond cleavage smoothly to afford a series of biologically active

molecules. In particularly, asymmetric reaction of unactivated aliphatic terminal alkenes using newly developed chiral IPAQ ligand has also been achieved to afford chiral hydroamination

products with good enantioselectivity. Further studies on asymmetric hydrofunctionalization of simple alkenes are undergoing in our laboratory. METHODS MATERIALS For the optimization of

reaction conditions and control experiments of alkene 1a (Supplementary Table 1), and for the experimental procedures and analytic data of compounds synthesized (Supplementary Methods). For

nuclear magnetic resonance (NMR) spectra of compounds in this manuscript (Supplementary Fig. 1–166). For high-performance liquid chromatography (HPLC) spectra of compounds in this manuscript

(Supplementary Fig. 167–185). GENERAL PROCEDURE A FOR HYDROAMINATION OF ALKENES A 25 mL Schlenk flask equipped with a magnetic stirrer and a flanging rubber plug was dried with flame under

vacuum. When cooled to ambient temperature, it was vacuumed and flushed with N2 and repeated for three times. To the flask, Co(OAc)2 (0.015 mmol), L3 or L4 (0.018 mol), and THF (1.2 mL) were

added. The flask was degassed and stirred for 30 min at r.t. Then, PhSiH3 (0.36 mol), diazo compound (0.3 mmol), and alkene (0.36 mmol) were added in sequence. After 12 h, the reaction was

quenched with 10 ml of petroleum ether (PE) and the mixture was filtered through a pad of silica gel and washed with PE/EtOAc (5/1, 50 mL). The combined filtrates were concentrated and

purified by flash column chromatography using PE/EtOAc as the eluent to afford the corresponding product. GENERAL PROCEDURE B FOR ASYMMETRIC HYDROAMINATION OF ALKENES A 25 mL Schlenk flask

equipped with a magnetic stirrer and a flanging rubber plug was dried with flame under vacuum. When cooled to ambient temperature, it was vacuumed and flushed with N2 and repeated for three

times. To the flask, Co(OAc)2 (0.015 mmol), IPAQ (0.018 mol), ethyl acetate (1.2 mL), and 2-ethylethanol (100 μL, 0.93 g/mL, 0.9 mmol) were added. The flask was degassed and cooled down to

−10 °C and stirred for 30 min. Then, PhSiH3 (0.36 mol), diazo compound (0.3 mmol), and alkene (0.36 mmol) were added in sequence. After 24 h, the reaction was warmed up to r.t. and quenched

with 10 ml of PE. The mixture was filtered through a pad of silica gel and washed with PE/EtOAc (5/1, 50 mL). The combined filtrates were concentrated to afford a yellow oil that was used

for the next step without further purification. CLEAVAGE OF _N_–_N_ BOND To the above suspension, AcOH–THF–H2O (3:1:1 v/v/v, 3 mL) was added, followed by addition of activated Zn powder (0.5

 g, 7.5 mmol) in several portions at r.t. After that, the mixed solution was warmed up to 60 °C and stirred until completion monitored by thin-layer chromatography (usually 3 h). Then, the

reaction mixture was cooled down to r.t. and quenched with water (20 mL). The reaction mixture was basified with a solution of NaOH (6 N) until the solution turned clear (pH > 10) and

then extracted with Et2O (20 mL × 4). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to give a yellow oil that was used for the next step without

further purification. PROTECTION OF FREE AMINES WITH BZ GROUP To the above oil, 3 mL (0.1 M) of THF, 55 μL (1.211 g/mL, 0.45 mmol) of BzCl, and 84 μL (0.728 g/mL, 0.6 mmol) of Et3N were

added, followed by 2 h stirring. The mixture was quenched with water (20 mL) and then extracted with Et2O (20 mL × 4). The combined organic layers were dried over anhydrous Na2SO4, filtered,

concentrated, and purified by flash column chromatography using PE/EtOAc as the eluent to give the corresponding amide. DATA AVAILABILITY The authors declare that the data supporting the

findings of this study are available within the paper and its Supplementary Information file. The X-ray crystallographic coordinates for structures of 3M has been deposited at the Cambridge

Crystallographic Data Centre (CCDC) under deposition numbers CCDC 194446. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via

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(2019). Article  PubMed  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS Financial support was provided by NSFC (21922107 and 21772171), Zhejiang Provincial Natural Science

Foundation of China (LR19B020001), Center of Chemistry for Frontier Technologies, and the Fundamental Research Funds for the Central Universities (2019QNA3008). AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Chemistry, Zhejiang University, Hangzhou, 310058, China Xuzhong Shen, Xu Chen, Jieping Chen, Yufeng Sun, Zhaoyang Cheng & Zhan Lu Authors * Xuzhong Shen

View author publications You can also search for this author inPubMed Google Scholar * Xu Chen View author publications You can also search for this author inPubMed Google Scholar * Jieping

Chen View author publications You can also search for this author inPubMed Google Scholar * Yufeng Sun View author publications You can also search for this author inPubMed Google Scholar *

Zhaoyang Cheng View author publications You can also search for this author inPubMed Google Scholar * Zhan Lu View author publications You can also search for this author inPubMed Google

Scholar CONTRIBUTIONS Z. L. designed the experiments. X. S., J. C. and Y. S. performed the experiments. Z. L. and X. C. designed the racemic ligands. Z. L. and Z. C. designed the chiral

ligands. Z. L. and X. S. prepared this manuscript. X. S., J. C., Y. S. and Z. L. prepared the supplementary information. CORRESPONDING AUTHOR Correspondence to Zhan Lu. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PEER REVIEW INFORMATION _Nature Communications_ thanks the anonymous reviewer(s) for their contribution

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http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Shen, X., Chen, X., Chen, J. _et al._ Ligand-promoted cobalt-catalyzed radical

hydroamination of alkenes. _Nat Commun_ 11, 783 (2020). https://doi.org/10.1038/s41467-020-14459-x Download citation * Received: 28 October 2019 * Accepted: 10 January 2020 * Published: 07

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