ARTICLE

https://doi.org/10.1038/s41467-020-15167-2 OPEN Visible-light promoted regioselective amination and of remote C(sp3)-H bonds ✉ Quanping Guo1, Qiang Peng1, Hongli Chai1, Yumei Huo1, Shan Wang1 & Zhaoqing Xu 1

The C-N cross coupling reaction has always been a fundamental task in organic synthesis. However, the direct use of N-H group of aryl to generate N-centered radicals which would couple with radicals to construct C-N bonds is still rare. Here we report a visible 3

1234567890():,; light-promoted C-N radical cross coupling for regioselective amination of remote C(sp )-H bonds. Under visible light irradiation, the N-H groups of aryl amines are converted to N- centered radicals, and are then trapped by alkyl radicals, which are generated from Hofmann- Löffler-Freytag (HLF) type 1,5-hydrogen atom transfer (1,5-HAT). With the same strategy, the regioselective C(sp3)-C(sp3) cross coupling is also realized by using alkyl Hantzsch esters (or nitrile) as radical alkylation reagents. Notably, the α-C(sp3)-H of tertiary amines can be directly alkylated to form the C(sp3)-C(sp3) bonds via C(sp3)-H − C(sp3)-H cross coupling through the same photoredox pathway.

1 Institute of Drug Design & Synthesis, Institute of Pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic ✉ Medical Science, Lanzhou University, 199 West Donggang Road, Lanzhou 730000, China. email: [email protected]

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mines are quintessential moieties in pharmaceuticals, arylation)43,44. So far, using the HLF-type C-center radical for sp3 nature products, and organic materials1,2. In the past few C–NorC(sp3)–C(sp3) couplings is still very rare45, and the direct A 2 – 3 – – decades, transition-metal-catalyzed sp C N couplings of cross-coupling between C(sp ) H and N H is not realized. We aryl halides (and pseudo halides) with nucleophiles have here report an example of sp3 C–N cross-coupling reaction been well developed, such as Buchwald–Hartwig reaction3, Ull- between N-center- and alkyl radicals. Notably, the aryl amines are mann coupling4, and Chan–Lam amination5. However, the directly converted to N-center radicals under visible-light irradia- alkylation of amines using alkyl electrophiles is largely under- tion (Fig. 1c). By using the same photoredox catalytic 1,5-HAT developed due to the β-hydrogen elimination from the metal- strategy, the regioselective C(sp3)–H alkylation can also be realized alkyl intermediate6–8. Recently, significant progress has been when Hantzsch esters are used as alkylation reagents. The primary, made in transition-metal-catalyzed radical sp3 C–N bond for- secondary, and tertiary alkylation are all compatible under stan- mations. Fu and coworkers recently disclosed the photoinduced, dard conditions. It is worth noting that the α-C(sp3)–Hoftertiary Cu-catalyzed intermolecular and intramolecular alkylation of amines can be directly alkylated to form C(sp3)–C(sp3) bonds amides9,10. Very recently, Macmillan11 and Hu12 reported a series without pre-functionalization. of Cu-catalyzed, photoinduced decarboxylative sp3 C–N coupling reactions, respectively. In these approaches, the trapping of alkyl Results radicals by Cu-amine species and the reductive eliminations of Cu Investigation of the sp3 C–N coupling reaction conditions. The intermediates were key steps for the cross-couplings (Fig. 1a). fl In the past few years, the addition reactions of N-center radical investigation was initiated by using N-(tert-butyl)-N- uoro-2- 1a 2a to (or enamine intermediates) have been developed methylbenzamide ( ) and aniline ( ) as model substrates. A (Fig. 1b)13–20. However, the direct cross-coupling between alkyl- series of photocatalysts (Ir and Ru complexes, or organic photo- and N-based radicals in the absence of stabilization by transition- catalysts), light sources, solvents, additives, and the substrate ratios metal complex has been rarely explored. Moreover, in the reac- were tested (see the Supplementary Information for details). The tions, the amine (or amide) compounds need to be converted to results indicated the optimal reaction conditions (condition A): – 1a 2a the corresponding N-radical precursors (e.g., N-halogens and N- under 24-W violet LED (390 410 nm) irradiation, and nitrosoamides) by separated steps. The direct use of the N–H (3 equiv) were dissolved in DMF (0.1 M), Ir(ppy)2(dtbpy)PF6 (1 mol %) was used as the photocatalyst, K2CO3 (3.0 equiv) was group of aryl amines to generate Naryl-center radicals and couple with alkyl radicals is still rare17. used as basic additive, and the reaction was stirred at room The regioselective C–H functionalization is one of the most temperature for 12 h. Under these reaction conditions, the desired 3 – 3a fundamental reactions in organic synthetic chemistry. In recent sp C N coupling product ( ) was isolated in 73% yield. Notably, years, the functionalization of C(sp3)–H bonds has become an to achieve this transformation, a suitable photocatalyst with well- important and intensive task to the organic synthetic community. balanced redox potential was required. The organic photocatalysts A–D In the past decade, great progress has been achieved in C(sp3)–H have relatively strong oxidative properties, whereas the functionalization at unactivated sites, which allows streamlined reductive activities were moderate. In contrast, the Ir- and Ru- synthesis of target compounds and late-stage modification based photocatalysts have good redox abilities, which were com- of complex structures. Recently, the application of Hofmann– patible for the reaction (Table 1). Löffler–Freytag (HLF)-type 1,5-hydrogen atom transfer (1,5-HAT) in C(sp3)–H functionalization reactions received much attention Scope of sp3 C–N coupling reactions. With the optimal reaction due to their unique regioselectivities21,22.Althoughtheamidyl conditions in hand, the substrate scope of carboxylamides radical formation and its subsequent 1,5-HAT process have been and anilines was examined, and the results are summarized in well established, the followed transformations of the C-center Fig. 2. To our delight, the carboxamides and anilines bearing radical are still limited, and the reactions mainly focused on electron-donating and electron-withdrawing groups at o-, m-, or – – cyclization23 29, atom transfer (halogenation)30 33, Giese reac- p-position of the aryl ring were compatible with moderate-to-good 34–37 38,39 40,41 fl 42 – – tion , azidation , cyanation ,tri uoromethylation ,and yields (Fig. 2, 3a 3x). A range of functional groups, such as CH3, a b

SET reductive elimination X NR1R2 (X = halogen, nitrosoamindes, H, and et al.) R + CuNR1R2 RCuNR1R2 R-NR1R2

NR1R2 R 1 2 Y + NR R R Y Y = C or N

c O

NHR1 ArNHCH O O 3 H NAr (direct use of aryl amines) or NHAr 2 R1 NHR1 ArNH2 N alkyl Hantzsch esters R2 F or NHAr R + NHAr R NHAr and Ir R2 and Ir O C–N radical cross-coupling 2 R H NHR1 alkyl sp3C–N cross-coupling C(sp3)-C(sp3) cross-coupling R2

Fig. 1 sp3 C–N bond formations with N-center radicals. a Cu-catalyzed radical sp3 C–N cross-couplings6–8. b Addition reactions between N-center radicals and alkenes (enamines)9. c This work: sp3 C–N cross-coupling between alkyl radical and N-center radical. X = halogen, nitrosoamides, H, and so on. Y = CorN.

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Table 1 Optimization of reaction conditionsa.

“Condition A”

Entry Change to “condition A” Yield (%)b 1 Condition A 73 2 No light 0 3 No photocatalyst 0 4 Without K2CO3 0 5 A,B,C,D instead of G 0 6 E, F, H instead of G 20–64 7 Other bases instead of K2CO3 0–49 8 Other solvents instead of DMF 0–55 aUnless noted, the reactions were carried out using 1a (0.1 mmol), 2a (3 equiv), photocatalyst (1 mol %), base (3.0 equiv), and DMF (1 ml), under Ar, and stirred at rt for 12 h under 24-W violet LED irradiation. bIsolated yields.

–OCH3, –CF3, and halides (–F, –Cl, and –Br) were all tolerated. our initial hypothesis, upon irradiation, the high valent photo- The bulkier amines, such as EtNHPh and i-PrNHPh, were suc- catalyst could accept an electron from amine and simultaneously cessfully converted to the corresponding products 3w and 3x with generate an amino radical cation A through single-electron transfer satisfactory yields, respectively. Notably, the amination of alkyl (SET) process (Fig. 3). The amino radical cation would then form amide was also achieved under standard conditions (3y). How- α-amino alkyl radical B by deprotonation. The intermediate B ever, the alkyl-substituted amines, such as CyNH2 and n-Bu2NH, could be captured by C-center radical D that was generated failed to give the corresponding amination products. through 1,5-HAT, and furnished the C(sp3)–C(sp3) coupling.

α 3 – Alkylation of tertiary amine -C(sp ) H bonds.Tertiaryamine Scope of alkylation of tertiary amine α-C(sp3)–H bonds.With motifs are widely represented in many pharmaceuticals and the above hypothesis in mind, we began our study by using 1a and advanced materials1,2. Direct functionalization of tertiary amine ’ fi fi N,N-dimethylaniline (2a ) as model substrates to optimize the provides an ef cient pathway to synthesize structurally diversi ed reaction conditions (see the Supplementary Information for details). tertiary amines. In 2006, Li and coworkers reported a cross- Under the optimal conditions (condition A), the desired C(sp3)–C dehydrogenative-coupling reaction, which could directly couple (sp3) cross-coupling product (4a) was obtained in 75% yield. The the α-C(sp)3–H of tertiary amines with nucleophiles under oxi- 46–49 α generality of the reaction was examined by using a variety of tertiary dative conditions . Very recently, the photoredox-induced -C 4a–4o 3– amines and carboxamides (Fig. 4, ). To our delight, uniformly (sp) H functionalization of tertiary amines was achieved, which good results were obtained with various substrates bearing sensitive could functionalize the α-C(sp)3–H under mild and external – 50,51 functional groups. The C H functionalization of alkyl amide was oxidant-free conditions . Despite these achievements, the direct also realized with good yield (5). Furthermore, the late-stage C(sp3)–C(sp3) cross-coupling reactions between tertiary amines α- fi 3 – 3 – modi cation of androsterone-derived amine was achieved in 56% C(sp ) H and unactivated C(sp ) Hwerestillnotrealized. yield with the ester group untouched 6. Encouraged by the success of photoredox sp3 C–N coupling, we decided to explore an alternate route to realize regioselective C (sp3)–C(sp3) coupling between tertiary amines α-C(sp3)–Hand C(sp3)–C(sp3) coupling reaction using alkyl Hantzsch ester.In unactivated C(sp3)–H using the photoredox 1,5-HAT strategy. In the past few years, the HLF-type radical cross-coupling reactions

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CONFtBu H CONHtBu N R2 R3 “Condition A” + N 1 3 R H 2 R R 1 1 2 R 3

t t t t t CONH Bu CONH Bu CONH Bu CONHtBu CONH Bu CONH Bu

N N N N N N H H H H H H Cl Br Br CF3 3a, 73% 3b, 69% 3c, 65% 3d, 67% 3e, 75% 3f, 51 %

CF3 t OCH3 F t CONH Bu t CONHtBu CONHtBu CONH Bu CONH Bu CONHtBu N N N N N H H N H H N H 3j, 66% 3g, 40 % 3h, 64% 3i, 63% 3k, 57% yield F 3l, 65%

t t t CONH Bu CONH Bu CONH Bu t CONHtBu CONH Bu CONHtBu N N N N N N

Cl Br 3m, 68% 3n, 61% 3o, 64% 3p, 72% 3q, 74% OMe 3r, 64%

F CONHtBu CF3 t t t CONHtBu CONH Bu CONH Bu CONHtBu CONH Bu N N N N N N

3s, 63% 3t, 69% 3u, 64% CF3 3v, 62 % 3w, 57% 3x, 51%

Amination of alkyl amide: O O NH2 “Condition A” Ph N H Ph N + NH F F3C 3y, 51% 1o F3C

Fig. 2 Substrate scope of sp3 C–N coupling reactions. All reactions were conducted in 0.2 mmol scale. Yields referred to isolated yields.

R2R3N H 2′ base SET R2R3N H R2R3N –H+ A B O Ir(III)* Ir(II) NHtBu R1 O O F tBu tBu NR2R3 N 1,5-HAT N H 1 SET R C(sp3)-C(sp3) 1 hv Ir(III) H R cross-coupling O C D tBu N F R1 H 1

Fig. 3 Design plan for alkylation of tertiary amine α-C(sp3)–H bonds. Hypothesis of the mechanism for photoinduced C(sp3)–C(sp3) coupling reactions. were intensively studied21–44. However, its application in the In the above successful C(sp3)–H alkylation reactions construction of C(sp3)–C(sp3) was still rare45. Hantzsch esters (Fig. 4), the alkyl radicals were generated through 1,2-SET of were first synthesized by A. R. Hantzsch in 1881, and widely used N-center radical, which restricted the scope of alkyl substrates. in pharmaceutical chemistry. With the rapid development of Alkyl Hantzsch ester has the ability to serve both as a single- radical chemistry, various alkylation reactions using 4-substituted electron reductant and alkyl radical precursor. We envisioned Hantzsch esters as alkylation reagent have been developed52–55. that alkyl Hantzsch esters could be used instead of tertiary However, the cross-coupling between alkyl Hantzsch esters and C amine as the alkylation reagents for the direct C(sp3)–C(sp3) (sp3)–H was still not realized. cross-coupling.

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H t CONF Bu tBuHNOC R2 R4 R2 N 4 “Condition A” N + 3 R 1 R 3 R H R 1 2′ R1 4

R2 = H or CH3

CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu

N N N N N N OCH3

Br 4a, 75% 4b, 67% Cl 4c, 74% F 4d, 72% 4e, 68% 4f, 73%

t t CONH Bu CONH Bu t N N CONHtBu CONHtBu CONH Bu N N N N N t CONH Bu H OEt Cl 4g, 67% 4h, 72% 4i, 71% 4j, 66% O 4k, 73% 4l, 71% O

CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu N N N N N N

Br Cl F 4p, 73% 4q, 72% 4m, 69% 4n, 64% OCH3 4o, 69% Br 4r, 68%

t CONH Bu t CONHtBu t t CONH Bu CONHtBu BuHNOC BuHNOC N N F N N N N

Cl 4s, 73% 4t, 67% 4u, 63% 4v, 76% 4w, 59% 4x, 64%

C–H alkylation of alkyl amide:

H O “Condition A” O + Ph Ph Ph N N Ph N N F H Ph Ph 1p 5, 47%

Alkylation of androsterone derivative: O O

t CONF Bu H H O “Condition A” O + H H H H CONHtBu H O O

H N 1h N 6, 56%

Fig. 4 Substrate scope of alkylation of tertiary amine α-C(sp3)–H bonds. All reactions were conducted in 0.2 mmol scale. Yields referred to isolated yields.

Scope of C(sp3)–C(sp3) coupling. Initially, cyclohexyl Hantzsch tertiary alkyl Hantzsch nitrile, all proceeded smoothly in ester (7a) was used as model substrate to optimize the reaction satisfactory results (9a–11b) with the sensitive functional groups conditions. After the screening of reaction parameters, the desired (halogens and alkenes) untouched. The results indicated the C(sp3)–C(sp3) cross-coupling product (8a) could be obtained in general ability of our strategy for the construction of C(sp3)–C 71% yield (condition B, see the Supplementary Information for (sp3) bonds in the synthetic chemistry. Notably, the aryl Hantzsch details). Then, the substrate scope of carboxylamides was exam- esters failed to give any desired products under our standard ined (Fig. 5). To our delight, the carboxamides bearing electron- conditions. It should be noted that our method was suitable not donating and electron-withdrawing groups at o-, m-, or p-posi- only for o-methylbenzamide, but also alkyl amide. As shown in tion of the aryl ring were compatible with moderate-to-good Fig. 6, under the standard reaction conditions, 1o and 1p were – – yields (8a 8l). A range of functional groups, such as CH3, smoothly coupled with alkyl Hantzsch esters in satisfactory yields – – – – – OCH3, and halides ( F, Cl, and Br), were all tolerated (8a (12a–12d). 8k). The thiophene-derived substrate delivered the desired pro- duct with 72% yield (8l). The regioisomers were found in the case of 8m, which might be attributed to the competing 1,6-HAT Synthetic applications. To demonstrate the synthetic application pathway32,56. of our method, the amination and alkylation products were To further explore the substrate scope, a variety of alkyl readily converted to the corresponding lactam (3f’) and acid (4s’ Hantzsch esters were examined (Fig. 6). To our delight, the and 10b’) through simple operations with excellent yields, primary and the secondary alkyl Hantzsch esters, as well as the respectively (Fig. 7).

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t tBuHNOC R2 CONF Bu G (1 mol %) CH3OK (2.5 equiv) MeO2C CO2Me 1 + R R2 18-W blue LED R1 N CH2Cl2 (0.1 M), rt, 12 h 1 H 8 2 “Condition B” R = H or CH3 7a

CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu F

8a, 71% 8b, 56% 8c, 63% 8d, 67% OCH3 8e, 55% F 8f, 73% 8g, 69%

t t ε CONH Bu CONHtBu CONHtBu CONHtBu CONHtBu BuHNOC δ Cl S Cl

8h, 65% Cl 8i, 67% 8j, 59% Br 8k, 70% 8l, 72% 8m, 45% (δ : ε = 3:1)

Fig. 5 Substrate scope of carboxylamides with cyclohexyl Hantzsch ester. All reactions were conducted in 0.2 mmol scale. Yields referred to isolated yields.

t CONF Bu t 2 alkyl BuHNOC R “Condition B” MeO2C CO2Me alkyl 1 + R R2 N 1 1 H R 2 R = H or CH3 7 9, 10, or 11

1o alkyl Hantzsch esters:

CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu

9f, 64% 9a, 65% 9b, 63% 9c, 66% 9d, 65% 9e, 69% 9g, 61%

CONHtBu CONHtBu CONHtBu CONHtBu CONHtBu Cl 9i, 65% 9h, 59% 9j, 72% 9k, 68% 9l, 47%

2o alkyl Hantzsch esters: t t CONH Bu t CONH Bu t t t CONH Bu CONH Bu CONH Bu CONHtBu CONH Bu

Cl 10a, 70% 10b, 75% 10c, 67% 10d, 74% 10e, 68% 10f, 72% 10g, 71%

t t CONH Bu CONH Bu t t t ε CONH Bu CONH Bu CONHtBu CONH Bu tBuHNOC F δ S Br Br OCH3 Br 10h, 69% 10i, 73% 10j, 65% 10k, 55% 10l, 74% 10m, 70% 10n, 47% (δ : ε = 2:1)

3o alkyl Hantzsch nitrile:

CONHtBu CONHtBu

Cl 11a, 52% 11b, 43%

C–H alkylation of alkyl amides (under condition B):

O CH3 O O CH3 O Ph N CH3 H Ph N Ph N CH3 Ph N H H H H3C CH3 12a, 64% 12b, 56% 12c, 60% 12d, 53%

Fig. 6 Substrate scope of alkyl Hantzsch esters and nitrile. All reactions were conducted in 0.2 mmol scale. Yields referred to isolated yields.

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CONHtBu O 20% H2SO4 (1) N N H CONHtBu COOH 3f 3f′, 95% yield Conc. HCl (3) Reflux t CONH Bu Ph COOH Ph 10b 10b′, 98% yield N 20% H SO N (2) Ph 2 4 Ph

4s 4s′, 93% yield

Fig. 7 Synthetic applications. (1) Synthesis of lactam 3f’. (2) and (3) Converted amides to acids.

t (1): CONFtBu CONH Bu CONHtBu NH 2 TEMPO (5 equiv) + N + “Condition A” H O N

1a 2a 3a, 0% Detected by HRMS

(2): CONFtBu NH2 Ph “Condition A” PhHN + + Ph Ph Ph CONHtBu 1a 2a (3 equiv) 13, 45%

(3): CONFtBu t NH CONH Bu 2 “Condition A” tBuHNOC CONHtBu + N + H 1a 2a 14, 5% 3a, 73%

(4): CONHtBu CONHtBu NH2 NFSI or PIFA (3 equiv) + N “Condition A” H

15 2a 3a, not detected

(5): CONCltBu CONHtBu NH2 “Condition A” + N H

2a 3a, 53%

(6):

abPhNH + PC 2 300,000 10 2a 1a 9 250,000 200,000 8 150,000 7 Y = 1.385*X + 1 100,000 2 6 R = 0.9235 50,000 /I

0 0

I 5 4 Intensity –50,000 –100,000 3 –150,000 2 Y = 0.06491*X + 1 –200,000 2 1 R = –0.428 –250,000 0 –300,000 0123456 3250 3300 3350 3400 3450 3500 X [G] Quencher concentration (10–4)

Fig. 8 Mechanistic studies. Equation (1) Radical trapping reaction with TEMPO. (2) Radical trapping reaction with ethane-1,1-diyldibenzene. (3) Homo- coupling product. (4) The results under oxidative conditions. (5) The result with N-chloroamide substrate. (6) (a) Fluorescence quenching of Ir

(ppy)2(dtbpy)PF6 by 2a and 1a.(b) EPR experiment result of PhNH2 (2a, PhNH2 (0.1 mmol) and Ir(ppy)2(dtbpy)PF6 (5 mol%) in hexafluoroisopropanol (1 ml), stirred at room temperature for 1 h under 400-nm irradiation, and directly used for EPR experiments).

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NH2 in MeCN) to generate the amidyl radical B.Thesubsequent 2a 1,5-HAT formed the radical intermediate C along with the O oxidation of Ir(II) to Ir(III) to close the catalytic cycle. Finally, NH – base NHtBu the radical radical cross-coupling between N-center radical A SET R1 radical-radical and C-center radical intermediate C was proposed to provide 3 – A cross-coupling the sp C N cross-coupling product 3. Ir(III)* Ir(II) HN Discussion O O 3 – F tBu tBu In conclusion, we disclosed a visible-light-promoted C N-radical N 1,5-HAT N H cross-coupling to realize the regioselective amination of remote C SET (sp3)–H bonds. In the reactions, the N-center radicals were 1 hv Ir(III) O R R directly generated from aryl amines under visible-light irradia- tBu B C N tion. Using the photoinduced HLF-type 1,5-HAT strategy, the F regioselective C(sp3)–C(sp3) cross-coupling was also achieved by using alkyl Hantzsch esters (or nitrile) as alkylation reagents. R1 1 Notably, the α-C(sp3)–H of tertiary amines was directly alkylated Fig. 9 Proposed mechanism. Proposed mechanism for photoinduced C to form the C(sp3)–C(sp3) bonds via C(sp3)–H–C(sp3)–H cross- (sp3)–N coupling reactions. coupling. All the reactions proceeded at room temperature without the assistance of external oxidants.

Methods Mechanistic investigations. In order to gain some mechanistic General procedure for condition A. In a dry 10-ml glass test tube, substrate N- 3 fl insight of this sp C–N coupling reaction, several control experi- uoroamides (0.2 mmol), amine (0.6 mmol, 3 equiv), Ir(ppy)2(dtbpy)PF6 (1 mol%), ments were carried out (Fig. 8). The reaction was completely shut and K2CO3 (0.6 mmol, 3 equiv) were dissolved in DMF (2.0 mL) under Ar atmosphere. The glass test tube was then transferred to a 24-W violet-light pho- down by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO, Equation toreactor, where it was irradiated for 12 h. The residue was added water (10 mL) (1)). Furthermore, when the radical scavenger ethane-1,1-diyldi- and extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried fi benzene was added to the reaction, the corresponding three- over Na2SO4. The resulting crude residue was puri ed via column chromatography component-type product 13 was obtained in 45% yield (Equation on silica gel to afford the desired products. (2)). When 1a and aniline (2a) were used as substrates, the desired General procedure for condition B. In a dry 10-ml glass test tube, substrate N- product 3a was isolated in 73% yield. Notably, the homo-coupling fl product 14 was also obtained in the reaction system with 5% yield uoroamides (0.2 mmol), Hantzsch esters or Hantzsch nitrile (0.6 mmol, 3 equiv), Ir(ppy)2(dtbpy)PF6 (1 mol%), and MeOK (0.5 mmol, 2.5 equiv) were dissolved in (Equation (3)). These results suggested that a) the radical pathway DCM (2.0 mL) under Ar atmosphere. The glass test tube was then transferred to a might be involved in the reaction; b) the HLF-type 1,5-HAT 18-W blue LED photoreactor, where it was irradiated for 12 h. The residue was proceeded in the system and formed the C-center radical; c) aryl added water (10 mL) and extracted with DCM (5 mL × 3). The combined organic fi phase was dried over Na2SO4. The resulting crude residue was puri ed via column amine possibly converted to the corresponding N-center radical chromatography on silica gel to afford the desired products. under standard conditions; d) the radical–radical coupling route might be responsible for this sp3 C–N bond formation reaction. Data availability We also tried this reaction under oxidative conditions. In fi fl 43,44 The authors declare that the data supporting the ndings of this study are available the presence of N- uorobenzenesulfonimide (NFSI, 3 equiv) within the article and its Supplementary Information. Data are also available from the or [bis(trifluoroacetoxy)iodo]benzene (PIFA, 3 equiv)57,the corresponding author on request. un-fluoride amide substrate 15 failed to produce the amination product under standard conditions (Equation (4)). In addition, the Received: 23 October 2019; Accepted: 21 February 2020; N-chloroamide could also give the desired product with modest yield (Equation (5)). These results indicated that the pre- activation of the substrates is crucial to this coupling reaction. In our initial hypothesis, the step that aryl amine converts to the corresponding N-center radical was crucial for this transforma- References tion. To verify this hypothesis, emission quenching and electron 1. Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences. (Wiley- paramagnetic resonance experiments have been conducted, and VCH, Weinheim, Germany, 2008). the results indicated that the radical species was generated in the 2. Lawrence, S. A. Amines: Synthesis, Properties and Applications. (Cambridge system (Equation (6)), see the Supplementary Information for University Press, Cambridge, 2004). − 3. Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C–N details). The Stern Volmer plot showed strong quenching of Ir – *III/II =+ cross-coupling reactions. Chem. Rev. 116, 12564 12649 (2016). (ppy)2(dtbpy)PF6 (E1/2 0.66 V vs. SCE) by PhNH2 (2a) 4. Sambiagio, C., Marsden, S. P., Blacker, A. J. & McGowan, P. C. Copper red =+ (E1/2 0.94 V vs. SCE), favoring a reductive quenching cycle. catalysed Ullmann type chemistry: from mechanistic aspects to modern – These evidences indicated that the excited-state Ir(ppy)2(dtbpy) development. Chem. Soc. Rev. 43, 3525 3550 (2014). PF might undergo a SET process that furnished the formation of 5. Qiao, J. X. & Lam, P. Y. S. Copper-promoted carbon-heteroatom bond 6 – N -center radical. cross-coupling with boronic acids and derivatives. Synthesis 6, 829 856 aryl (2011). 6. 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