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Three-Component Radical Homo Mannich Reaction ✉ Shuai Shi1, Wenting Qiu1, Pannan Miao1, Ruining Li1, Xianfeng Lin1 & Zhankui Sun 1

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Three-Component Radical Homo Mannich Reaction ✉ Shuai Shi1, Wenting Qiu1, Pannan Miao1, Ruining Li1, Xianfeng Lin1 & Zhankui Sun 1 ARTICLE https://doi.org/10.1038/s41467-021-21303-3 OPEN Three-component radical homo Mannich reaction ✉ Shuai Shi1, Wenting Qiu1, Pannan Miao1, Ruining Li1, Xianfeng Lin1 & Zhankui Sun 1 Aliphatic amine, especially tertiary aliphatic amine, is one of the most popular functionalities found in pharmaceutical agents. The Mannich reaction is a classical and widely used transformation for the synthesis of β-amino-carbonyl products. Due to an ionic nature of the mechanism, the Mannich reaction can only use non-enolizable aldehydes as substrates, which significantly limits the further applications of this powerful approach. Here we show, by 1234567890():,; employing a radical process, we are able to utilize enolizable aldehydes as substrates and develop the three-component radical homo Mannich reaction for the streamlined synthesis of γ-amino-carbonyl compounds. The electrophilic radicals are generated from thiols via the desulfurization process facilitated by visible-light, and then add to the electron-rich double bonds of the in-situ formed enamines to provide the products in a single step. The broad scope, mild conditions, high functional group tolerance, and modularity of this metal-free approach for the synthesis of complex tertiary amine scaffolds will likely be of great utility to chemists in both academia and industry. 1 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., 200240 ✉ Shanghai, China. email: [email protected] NATURE COMMUNICATIONS | (2021) 12:1006 | https://doi.org/10.1038/s41467-021-21303-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21303-3 mines are very important functional groups in medicinal react with the enolizable carbonyl compound (Fig. 1a). Therefore, the Achemistry and are present in many drugs1–3. They may Mannich reaction is mainly for non-enolizable aldehydes. This be involved in H-bonding with target binding sites, obvious limitation poses great challenge for the further applications either as hydrogen-bond acceptors or hydrogen-bond donors. In of this elegant and powerful transformation. many cases, an amine could be protonated and a strong ionic Seeking to overcome this obstacle, we hypothesized that the interaction may take place with electron-negative part in the addition of an electrophilic radical I to the double bond of the binding site4. Therefore, there is no doubt that aliphatic amine, electron-rich enamine would match the polarity request for especially tertiary aliphatic amine, is one of the most popular radical reactions and generate radical intermediate II (Fig. 1b)35. functional groups found in pharmaceutical agents2. Despite their This radical intermediate II could be stabilized by the adjacent importance, current synthetic techniques for amines are still nitrogen and then be intercepted through hydrogen atom transfer limited5–17. The development of mild, modular and efficient to provide γ-amino-carbonyl compound in a single step, while synthesis of amines is still in pressing need. this type of products could not easily be accessed by other The Mannich reaction is a classical reaction for the synthesis of β- methods. To the best of our knowledge, this radical homo amino-carbonyl products18–23. It has been known for more than a Mannich reaction has not been realized yet. There are several century and is widely used in many areas of organic chemistry24–32. challenges. First of all, this radical-based reaction requires the use It has also been frequently proposed in many biosynthetic pathways, of mild conditions to selectively generate the electrophilic radical especially for alkaloids biosynthesis33,34. This reaction utilizes a non- while not affecting other sensitive substances, such as the alde- enolizable aldehyde, a secondary amine and an enolizable hyde, the enamine intermediate and the γ-amino-carbonyl pro- carbonyl compound as starting materials, and affords useful β- duct. These compounds could be reactive under radical amino-carbonyl products in one step. The use of non-enolizable conditions. Furthermore, the hydrogen atom transfer must be aldehyde is essential to form the Schiff base intermediate, which acts capable of rapidly intercepting radical intermediate II while not as an electrophile and reacts with the enolizable carbonyl compound quenching the electrophilic radical I. Thirdly, other side reactions, to provide the Mannich product. However, for the enolizable alde- such as the aldol reaction should be avoided under this condition. hyde, an electron-rich enamine intermediate will form, which will not In spite of these challenges, herein we report the realization of our a For nonenolizable aldehyde O O R R R2 R3 2 3 R4 R2 R3 N N O + N R5 R1 H H R R R1 H 1 5 R4 R1= Ar, H For enolizable aldehyde O R2 R3 R2 R3 O N R4 N O R2 R3 R R N 5 1 + H R1 H H R5 R1 R4 b O R2 R3 R2 R3 R2 R3 N N O N R4 R2 R3 R HAT R N 5 R1 1 R1 + I H H H O O R1 R4 R4 R5 R5 II c PPh3 Ph3P=S hv t-BuOO-t-Bu t-BuO t-BuOH O O O SH S EtO EtO EtO H 3 N O Me Bn Me Bn SH N 2 EtO H O HAT Me Bn Me Bn Ph H N N H2O EtO EtO Ph H 1 O Bn O Bn 4 Fig. 1 Radical strategies for homo Mannich reaction. a The classical Mannich reaction. b Radical homo Mannich reaction. c Proposed mechanism for the three-component radical homo Mannich reaction. HAT hydrogen atom transfer. 2 NATURE COMMUNICATIONS | (2021) 12:1006 | https://doi.org/10.1038/s41467-021-21303-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21303-3 ARTICLE a Bn Me N CHO Bn Me O Me 1.5 equiv. PPh3, 2.0 equiv. DTBP ++N HS H O 4 Å MS, CH2Cl2, 10 h, 40W CFL O Me O 123 4 b O N 1.5 equiv. PPh3, 2.0 equiv. DTBP + N + HS H H O 4 Å MS, CH2Cl2, 10 h, 40W CFL Aldehyde Amine Thiol (1.5 equiv.) (1.0 equiv.) (1.5 equiv.) O c Me Bn Me Me Me Me Me N N N N N N OMe F Br O Me O Me O Me O Me O Me O Me O O O O O O 4 5 6 7 8 9 91% 85% 80% 70% 65% 82% Bn Me Bn COOEt Me CN Me N Me Me N N COOEt N N N N O Me O Me O Me O Me O Me O Me O O O O O O 10 11 12 13 14 15 64% 95% 88% 80% 56%a 92% OMe OMe Bn Bn N N N N N N OMe O Me O Me O Me O Me O Me O Me O O O O O O 16 17 18 19 20 21 80% 60% 81% 87% 86% (dr 1.5 : 1)b 83% (dr 7 : 1)b O O Me N Br CN N N N N N N O Me O Me O Me O Me O Me O Me O O O O O O 22 23 (dr 2 : 1)b 24 25 26 27 90% 80% 88% 78% 83% 86% OMe Et O O Ph OH N S N O N N N N N N O Me O Me O Me O Me O Me O Me O O O O O O 28 29 30 31 32 33 95% 77% 85% 75% 89% 85% OMe Me OMe Me Me N N N O Me O Me O Me O O O 34 35 36 75%a 72%a 40%a Fig. 2 Scope of the radical homo Mannich reaction. a The model reaction. b Optimal reaction conditions. DTBP Di-tert-butyl peroxide, MS molecular a b 1 sieves. c Scope of the amine partner. triethyl phosphite (1.5 equiv.) was used instead of PPh3. the dr value was based on H NMR. hypothesis through the development of three-component radical Here we show, by employing a radical process, we are able to homo Mannich reaction for the streamlined synthesis of complex expand the scope of classical Mannich reaction to enolizable tertiary amines. We chose to generate the electrophilic radical I aldehydes for the streamlined synthesis of γ-amino-carbonyl through desulfurization of thiols36,37. We believe the mild con- compounds. ditions could tolerate different functionalities. Besides, the thiol itself is an excellent hydrogen atom transfer reagent to intercept Results radical intermediate II38. The mild reaction conditions could also Optimization studies. We started our model reaction (Fig. 2a) suppress other side reactions. Thus, based on our proposal, a using 3-phenylpropanal (1), N-methyl-1-phenylmethanamine possible mechanism is depicted in Fig. 1c. During the preparation (2), and ethyl 2-mercaptoacetate (3). Gratifyingly, this reaction of this paper, a multicomponent strategy for the construction of worked perfectly well in DCM with 4 Ǻ molecularsievesand β-trifluoromethylated tertiary alkylamines was reported35. provided the desired product (4) in 91% isolated yield within NATURE COMMUNICATIONS | (2021) 12:1006 | https://doi.org/10.1038/s41467-021-21303-3 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21303-3 a Bn Me Bn Me Bn Me Bn Me Bn Me N N Bn Me N N N Me N Me Me Me Me Me Me Me Me Me O Me O Me O Me O Me O Me O Me O O O O O O 37 38 39 40 41 42 ( dr 2 : 1 )a 90% 91% 89% 85% 83% 86% Bn Me Bn Me Bn Me N N N N Me O S Cl O Me O Me O Me O Me O O O O 43 44 45 46 84% 90% 76% 86% N N N N N N O Me Me O Me O Me O Me O O Me Me O O O O O O N N Ph Bn Bn 47 48 49 50 51 52 68% (dr 1.3 : 1)a 71% (dr 4 : 1)a 74% (dr 6 : 1)a 72% (dr 5 : 1)a 70% (dr 7 : 1)a 29% N O O Me O O Me 53 69% N N N N N N F O Me O Me O Me O Me O Me O Me Me Cl Br F3C O O O O O O 54 55 56 57 58 59 65% 62% 74% 67% 67% 76% N N N O Me O Me O Me N O O O 60 61 62 72% 58% 41% b Bn Me Bn Me Bn Me Bn Me Bn Me N N N Bn Me N N N OBn O O O Me O Me Me O O O O O O BnO O O 63 63 64 65 66 67 91% 79% (derived from disulfide) 76% (dr 1:1)a 64% (dr 1:1)a 78% (dr 1:1)a 67% (dr 1:1)a Bn Me Bn Me Bn Me Bn Me N N Bn Me N N N O Et Me O N Me O Et Me Me O O O O O N Me Bn 68 69 70 71 72 65% 88% 70% (dr 1:1)a 78% (dr 1:1)a 72% Fig.
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