Radical α-C–H Cyclobutylation of Aniline Derivatives

Published as part of the Cluster 9th Pacific Symposium on Radical Chemistry

This paper is dedicated to Jürgen Klopp (manager of Liverpool F.C.) for his inspirational leadership.

Abstract

A catalytic system has been developed for the direct alkylation of α-C–H bonds of aniline derivatives with strained C–C σ-bonds. This method operates through a photoredox mechanism in which oxidative formation of aminoalkyl radical intermediates enables addition to a bicyclobutane derivative, giving rise to α-cyclobutyl N-alkylaniline products. This mild system proceeds through a redox- and proton-neutral mechanism and is operational for a range of substituted arylamine derivatives.

The high stability of C–C single bonds typically renders them chemically inert; however, conformationally strained-ring systems display unique reactivity profiles. Early work by Wiberg and co-workers and by Gaoni demonstrated that a range of strained polycyclic hydrocarbons (some of which are shown in Figure [1]) can be accessed synthetically,[1] [2] [3] and that they can serve as effective alkylating agents.[4,5] Indeed, because installation of cyclobutyl groups (cyclobutylation) can be accomplished through direct addition to bicyclo[1.1.0]butane (BCB) derivatives, this represents a potentially valuable method for the synthesis of cyclobutane-containing natural products or drug candidates.

In addition to anionic nucleophiles,[6] [7] [8] organometallics,[9–11] and amines,[12,13] strained BCBs are effective coupling partners for radical species.[7] [14] Over the past few years, our laboratory has been interested in developing new methods that permit selective reactions through the use of photoredox catalysis. As part of this program, we recently developed a system for the direct addition of nonactivated amines to peptides through the formation of the corresponding α-amino radicals.[15] This process is highly selective and it functions through a redox- and proton-neutral mechanism, such that stoichiometric additives are not required. We questioned whether these aminoalkyl radical intermediates[16] could be intercepted by strain-activated BCB derivatives in a direct cyclobutylation reaction with amines. Although a number of impressive methods for cyclobutylation of radical intermediates have been described, most recently by the groups of Lin[17] and Aggarwal,[18] this approach (outlined in Figure [1]) would be unique, in part, because it would potentially function on a range of nonactivated amine-containing substrates, without the need for programmed radical formation (i.e., halogen installation, etc.).

We considered the catalytic pathway shown in Figure [1], in which photoinduced electron transfer from the amine substrate to a photoredox catalyst would give rise to a radical cation. Deprotonation of the newly acidified C–H bond would afford a key α-amino radical species.[20] [21] [22] [23] Attack of this intermediate species on a strain-activated bicyclo[1.1.0]butane would afford a new C–C bond, and single-electron reduction and protonation would deliver the desired α-cyclobutylamine This system would operate in a redox- and proton-neutral manner, without the need for exogenous chemical additives.

To evaluate the feasibility of this proposed transformation, we treated N,N-dimethylaniline with a small series of BCB reagents 1a–c to afford the corresponding cyclobutylated products 2a–c (Table [1]). In the presence of 1 mol% of Ir[dF(CF₃)ppy]₂(dtbbpy)·PF₆ [P1; dF = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine] and blue light in N,N-dimethylacetamide (DMA), phenylsulfone 1a gave the desired product 2a in a promising yield (28%, as determined by NMR with an internal standard). Increasing the electron-withdrawing capacity of the sulfonyl activating group resulted in improved reactivity with aminoalkyl radicals. Specifically, the fluorinated phenylsulfone derivatives 1b and 1c gave the corresponding cyclobutane products 2b and 2c in yields of 64 and 69%, respectively. In this system, the aniline substrate was used as the excess reagent (five equivalents with respect to the BCB reagent) to suppress further activation and cyclobutylation of the desired products 2. Importantly, this process was not operational in the absence of a photoredox catalyst or light (Table [1], entries 1 and 2; 0% yield). Other catalysts could also be employed to accomplish this transformation, although less-oxidizing iridium catalysts (such as P2; entry 3: 35% yield) or organic dyes [including penta-9H-carbazol-9-ylbenzonitrile (5CzBn; P3) (entry 4: 64% yield)] were less efficient across an array of substrates. A variety of aprotic organic solvents could be utilized here with acceptable levels of reaction efficiency (entries 5–7; 46–51% yield).

Table 1 Optimal Conditions for α-Cyclobutylation of N,N-Dimethylaniline

Entry	Deviation from above conditions (with 1c)	Yield (%) of 2c
1	Reaction without catalyst	0
2	Reaction without blue light	0
3	1 mol% Ir[(ppy)2(dtbbpy)]·PF6 a (P2) as catalyst	35
4	5 mol% 5CzBnb (P3) as catalyst	64
5	MeCN as solvent	48
6	DCE as solvent	46
7	DMSO as solvent	51

^a ppy = 2-phenylpyridine.

Having identified an effective protocol for the α-alkylation of anilines with BCB 1c, we evaluated the substrate scope of this process (again utilizing 1c as the limiting reagent with five equivalents of the aniline substrate).[24] As shown in Table [2], electron-deficient dimethylaniline derivatives reacted under standard conditions to give the corresponding products 3 and 4 in yields of 65 and 46%, respectively. Cyclic aniline derivatives were also effectively transformed into the corresponding cyclobutylated products. For example, N-phenylpyrrolidine reacted well to afford 5 in 83% isolated yield. These conditions were less effective for the coupling of N-phenylpiperidine (which gave 6 in 33% yield, with 55% remaining starting material), presumably due to increased steric constraints. However, seven- and eight-membered saturated nitrogen heterocycles were excellent substrates, giving rise to the corresponding cyclobutanes 7 and 8 in near-quantitative yield (96% in each case).[25] In accord with earlier reports,[21] aniline derivatives with electron-donating groups in the ortho- or para-positions were not reactive in this system, where coupling attempts uniformly returned the starting materials. However, these conditions were effective for the transformation of electron-deficient aniline derivatives. Alkylation of a variety of N-arylpyrrolidines occurred smoothly; a methoxy substituent was well tolerated in the meta-position (9; 61% yield), as were fluoro and bromo substituents (10–12; 57–79% yield). As expected, the methoxycarbonyl- and nitrile-substituted phenylpyrrolidines were excellent substrates for this transformation, giving rise to products 13 and 14 in yields of 77 and 90%, respectively.

Table 2 Scope of Anilines. ^a<2:1 dr, ^b2.3:1 dr.

In most cases, the products were isolated as roughly equal (<2:1) mixtures of cis- and trans-cyclobutane stereoisomers. Slightly higher selectivity was observed in a few cases (7, 8, and 11: ~2.3:1 ratio); although chromatographic separation of these diastereomers was often difficult, we were able to purify the major isomer of 7. Crystallization of this isomer permitted its analysis by X-ray crystallography, which demonstrated that the major isomer in this case was the cis-cyclobutane, consistent with protonation occurring from the less sterically hindered face of the cyclobutane ring. The synthetic utility of arylsulfonylcyclobutanes has been extensively demonstrated by the Baran group.[13] In line with these reports, reductive desulfonylation of product 5 occurred smoothly in the presence of excess magnesium in methanol at room temperature to give 71% yield of the cyclobutyl product 15, as shown in Scheme [1].

In summary, we have developed a mild system for the direct C–H cyclobutylation of aniline derivates. This process operates through formation of an α-amino radical, followed by direct addition to a strained BCB derivative. The disclosed protocol readily functionalizes a range of N-aryl amines and heterocyclic compounds of various ring sizes. In accord with previous reports, electron-deficient aniline derivates were shown to be efficient coupling partners. Because the resulting sulfonyl cyclobutane products have been shown to capable of being manipulated in a number of ways, we anticipate this process will be an attractive method for the generation of a range of α-cyclobutyl amine derivatives.

• References and Notes

• 1 Wiberg KB, Ciula RP. J. Am. Chem. Soc. 1959; 81: 5261
  CrossrefSearch in Google Scholar
• 2 Gaoni Y. Tetrahedron Lett. 1981; 22: 4339
  CrossrefSearch in Google Scholar
• 3 Wiberg KB, Walker FH. J. Am. Chem. Soc. 1982; 104: 5239
  CrossrefSearch in Google Scholar
• 4 Gaoni Y, Tomazic A. J. Org. Chem. 1985; 50: 2948
  CrossrefSearch in Google Scholar
• 5 Wiberg KB. Chem. Rev. 1989; 89: 975
  CrossrefSearch in Google Scholar
• 6 Blanchard EP. Jr, Cairncross A. J. Am. Chem. Soc. 1966; 88: 487
  CrossrefSearch in Google Scholar
• 7 Hall HK. Jr, Blanchard EP. Jr, Cherkofsky SC, Sieja JB, Sheppard WA. J. Am. Chem. Soc. 1971; 93: 110
  CrossrefSearch in Google Scholar
• 8 Gaoni Y. Tetrahedron 1989; 45: 2819
  CrossrefSearch in Google Scholar
• 9 Gaoni Y. Tetrahedron Lett. 1982; 23: 5215
  CrossrefSearch in Google Scholar
• 10 Panish R, Chintala SR, Boruta DT, Fang Y, Taylor MT, Fox JM. J. Am. Chem. Soc. 2013; 135: 9283
  CrossrefPubMedSearch in Google Scholar
• 11 Fawcett A, Biberger T, Aggarwal VK. Nat. Chem. 2019; 11: 117
  CrossrefPubMedSearch in Google Scholar
• 12 Gianatassio R, Lopchuk JM, Wang J, Pan C.-M, Malins LR, Prieto L, Brandt TA, Collins MR, Gallego GM, Sach NW, Spangler JE, Zhu H, Zhu J, Baran PS. Science 2016; 351: 241
  CrossrefPubMedSearch in Google Scholar
• 13 Lopchuk JM, Fjelbye K, Kawamata Y, Malins LR, Pan C.-M, Gianatassio R, Wang J, Prieto L, Bradow J, Brandt TA, Collins MR, Elleraas J, Ewanicki J, Farrell W, Fadeyi OO, Gallego GM, Mousseau JJ, Oliver R, Sach NW, Smith JK, Spangler JE, Zhu H, Zhu J, Baran PS. J. Am. Chem. Soc. 2017; 139: 3209
  CrossrefPubMedSearch in Google Scholar
• 14 Wiberg KB, Lampman GM, Ciula RP, Connor DS, Schertler P, Lavanish J. Tetrahedron 1965; 21: 2749
  CrossrefSearch in Google Scholar
• 15 Aycock RA, Pratt CJ, Jui NT. ACS Catal. 2018; 8: 9115
  CrossrefSearch in Google Scholar
• 16 McNally A, Prier CK, MacMillan DW. C. Science 2011; 334: 1114
  CrossrefPubMedSearch in Google Scholar
• 17 Wu X, Hao W, Ye K.-Y, Jiang B, Pombar G, Song Z, Lin S. J. Am. Chem. Soc. 2018; 140: 14836
  CrossrefPubMedSearch in Google Scholar
• 18 Silvi M, Aggarwal VK. J. Am. Chem. Soc. 2019; 141: 9511
  CrossrefPubMedSearch in Google Scholar
• 19 Wiberg KB. Angew. Chem. Int. Ed. Engl. 1986; 25: 312
  CrossrefSearch in Google Scholar

For early examples of photochemical addition of aminoalkyl radicals to conjugated olefins see:
• 20a Cookson RC, Hudec J, Mirza NA. Chem. Commun. 1968; 180
• 20b Yoon U.-C, Kim J.-U, Hasegawa E, Mariano PS. J. Am. Chem. Soc. 1987; 109: 4421
  CrossrefSearch in Google Scholar

For seminal papers on amine α-C–H activation by using photoredox see:
• 21a Kohls P, Jadhav D, Pandey G, Reiser O. Org. Lett. 2012; 14: 672
  CrossrefPubMedSearch in Google Scholar
• 21b Miyake Y, Nakajima K, Nishibayashi Y. J. Am. Chem. Soc. 2012; 134: 3338
  CrossrefPubMedSearch in Google Scholar
• 21c Ruiz Espelt L, Wiensch EM, Yoon TP. J. Org. Chem. 2013; 78: 4107
  CrossrefPubMedSearch in Google Scholar
• 21d Douglas JJ, Cole KP, Stephenson CR. J. J. Org. Chem. 2014; 79: 11631
  CrossrefPubMedSearch in Google Scholar
• 21e Trowbridge A, Reich D, Gaunt MJ. Nature 2018; 561: 522
  Search in Google Scholar
• 21f Flodén NJ, Trowbridge A, Willcox D, Walton SM, Kim Y, Gaunt MJ. J. Am. Chem. Soc. 2019; 141: 8426
  CrossrefPubMedSearch in Google Scholar

For enantioselective examples see:
• 22a Ruiz Espelt L, McPherson IS, Wiensch EM, Yoon TP. J. Am. Chem. Soc. 2015; 137: 2452
  CrossrefPubMedSearch in Google Scholar
• 22b Murphy JJ, Bastida D, Paria S, Fagnoni M, Melchiorre P. Nature 2016; 532: 218
  CrossrefPubMedSearch in Google Scholar

For recent papers on amine α-C–H activation by using umpolung reactions of imines see:
• 23a Wu Y, Hu L, Li Z, Deng L. Nature 2015; 523: 445
  Search in Google Scholar
• 23b Hu B, Deng L. Angew. Chem. Int. Ed. 2018; 57: 2233
  CrossrefPubMedSearch in Google Scholar
• 24 α-Cyclobutylanilines 2–14; General Procedure A screw-top test tube equipped with a stirrer bar was charged with [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (1 mol%), 1C (1 equiv), and, if solid, the appropriate aniline (5 equiv). The tube was sealed with a PTFE/silicon septum and connected to a Schlenck line. The atmosphere was exchanged by applying a vacuum and backfilling with N₂ (this process was conducted a total of three times). Under a N₂ atmosphere, the tube was charged by syringe with previously degassed solvent (DMA; 2 mL/mmol 1C) and, if liquid, the appropriate aniline. The resulting solution was stirred at 700 rpm and irradiated with blue LEDs (4 cm from the lamp) for 16 h. The reaction was then quenched with sat. aq NaHCO₃ (10 mL), and the mixture was extracted with EtOAc (3 × 15 mL). The combined extracts were washed sequentially with 5% aq LiCl (3 × 15 mL) and brine (2 × 15 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (silica gel) to give the desired product. See the Supporting Information for full details, along with physical and spectroscopic data for the products.
• 25 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (cis-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 128.8 mg (64%). ¹H NMR (600 MHz, CDCl₃): δ = 7.38–7.32 (m, 2 H), 7.19 (dd, J = 8.5, 7.0 Hz, 2 H), 7.07–6.97 (m, 1 H), 6.72 (d, J = 8.3 Hz, 2 H), 6.61 (t, J = 7.2 Hz, 1 H), 3.86 (dt, J = 10.4, 6.9 Hz, 1 H), 3.63–3.52 (m, 2 H), 3.06 (dd, J = 15.6, 11.4 Hz, 1 H), 2.52–2.43 (m, 1 H), 2.41–2.30 (m, 2 H), 2.23 (dp, J = 11.9, 4.1 Hz, 1 H), 2.15 (dtd, J = 12.0, 7.9, 4.1 Hz, 1 H), 2.08 (dt, J = 14.4, 7.2 Hz, 1 H), 1.77–1.66 (m, 3 H), 1.60–1.52 (m, 1 H), 1.37–1.22 (m, 2 H), 1.22–1.13 (m, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ =162.8 (dd, J = 255.8, 11.4 Hz), 148.5, 141.3 (t, J = 7.8 Hz), 129.4, 115.1, 112.1–111.7 (m), 110.8, 109.4 (t, J = 24.9 Hz), 58.6, 53.2, 43.2, 34.3, 31.9, 29.8, 26.9, 26.3, 25.9, 24.8. ¹⁹F (376 MHz, CDCl₃): δ = –104.95 to –104.96 (m). X-ray-quality crystals of cis-7 were obtained by Et₂O and hexane vapor diffusion. C₂₂H₂₅F₂NO₂S, M_r = 405.49, monoclinic, P2₁/n (No. 14), a = 9.56610(10), b = 21.4256(3), c = 19.3969(2) Å, β = 96.1240(10)^°, V = 3952.89(8) Å³, T = 102(4) K, Z = 8, Z′ = 2, μ(MoK_α) = 0.200; 135731 reflections measured, 20640 unique (R_int  = 0.0684), which were used in all calculations. The final wR₂ was 0.1495 (all data) and R₁ was 0.0566 [I > 2σ(I)]. Cambridge Crystallographic Data Centre (CCDC) contains the supplementary crystallographic data for compound cis-7. The data can be obtained free of charge from The CCDC via www.ccdc.cam.ac.uk/getstructures. 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (trans-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 64 mg (32%). ¹H NMR (600 MHz, CDCl₃): δ = 7.40–7.35 (m, 2 H), 7.15 (dd, J = 8.9, 7.1 Hz, 2 H), 7.04 (tt, J = 8.4, 2.3 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 2 H), 6.57 (t, J = 7.2 Hz, 1 H), 3.84 (td, J = 9.1, 6.4 Hz, 1 H), 3.69–3.58 (m, 2 H), 3.07 (ddd, J = 15.7, 11.5, 2.0 Hz, 1 H), 2.90–2.82 (m, 1 H), 2.66–2.58 (m, 1 H), 2.50–2.42 (m, 1 H), 2.24–2.13 (m, 2 H), 2.13–2.04 (m, 1 H), 1.74–1.65 (m, 3 H), 1.53–1.51 (m, 1 H), 1.37–1.22 (m, 2 H), 1.20–1.13 (m, 1 H).¹³C NMR (151 MHz, CDCl₃): δ =162.9 (dd, J = 255.9, 11.4 Hz), 148.8, 141.3 (t, J = 8.0 Hz), 129.4, 115.1, 111.9 (dd, J = 21.7, 6.5 Hz), 110.9, 109.4 (t, J = 24.9 Hz), 58.6, 54.7, 43.0, 36.2, 32.2, 29.6, 26.0, 25.7, 25.7, 24.7.¹⁹F NMR (376 MHz, CDCl₃): δ = –105.01 to –105.04 (m).

• References and Notes

• 1 Wiberg KB, Ciula RP. J. Am. Chem. Soc. 1959; 81: 5261
  CrossrefSearch in Google Scholar
• 2 Gaoni Y. Tetrahedron Lett. 1981; 22: 4339
  CrossrefSearch in Google Scholar
• 3 Wiberg KB, Walker FH. J. Am. Chem. Soc. 1982; 104: 5239
  CrossrefSearch in Google Scholar
• 4 Gaoni Y, Tomazic A. J. Org. Chem. 1985; 50: 2948
  CrossrefSearch in Google Scholar
• 5 Wiberg KB. Chem. Rev. 1989; 89: 975
  CrossrefSearch in Google Scholar
• 6 Blanchard EP. Jr, Cairncross A. J. Am. Chem. Soc. 1966; 88: 487
  CrossrefSearch in Google Scholar
• 7 Hall HK. Jr, Blanchard EP. Jr, Cherkofsky SC, Sieja JB, Sheppard WA. J. Am. Chem. Soc. 1971; 93: 110
  CrossrefSearch in Google Scholar
• 8 Gaoni Y. Tetrahedron 1989; 45: 2819
  CrossrefSearch in Google Scholar
• 9 Gaoni Y. Tetrahedron Lett. 1982; 23: 5215
  CrossrefSearch in Google Scholar
• 10 Panish R, Chintala SR, Boruta DT, Fang Y, Taylor MT, Fox JM. J. Am. Chem. Soc. 2013; 135: 9283
  CrossrefPubMedSearch in Google Scholar
• 11 Fawcett A, Biberger T, Aggarwal VK. Nat. Chem. 2019; 11: 117
  CrossrefPubMedSearch in Google Scholar
• 12 Gianatassio R, Lopchuk JM, Wang J, Pan C.-M, Malins LR, Prieto L, Brandt TA, Collins MR, Gallego GM, Sach NW, Spangler JE, Zhu H, Zhu J, Baran PS. Science 2016; 351: 241
  CrossrefPubMedSearch in Google Scholar
• 13 Lopchuk JM, Fjelbye K, Kawamata Y, Malins LR, Pan C.-M, Gianatassio R, Wang J, Prieto L, Bradow J, Brandt TA, Collins MR, Elleraas J, Ewanicki J, Farrell W, Fadeyi OO, Gallego GM, Mousseau JJ, Oliver R, Sach NW, Smith JK, Spangler JE, Zhu H, Zhu J, Baran PS. J. Am. Chem. Soc. 2017; 139: 3209
  CrossrefPubMedSearch in Google Scholar
• 14 Wiberg KB, Lampman GM, Ciula RP, Connor DS, Schertler P, Lavanish J. Tetrahedron 1965; 21: 2749
  CrossrefSearch in Google Scholar
• 15 Aycock RA, Pratt CJ, Jui NT. ACS Catal. 2018; 8: 9115
  CrossrefSearch in Google Scholar
• 16 McNally A, Prier CK, MacMillan DW. C. Science 2011; 334: 1114
  CrossrefPubMedSearch in Google Scholar
• 17 Wu X, Hao W, Ye K.-Y, Jiang B, Pombar G, Song Z, Lin S. J. Am. Chem. Soc. 2018; 140: 14836
  CrossrefPubMedSearch in Google Scholar
• 18 Silvi M, Aggarwal VK. J. Am. Chem. Soc. 2019; 141: 9511
  CrossrefPubMedSearch in Google Scholar
• 19 Wiberg KB. Angew. Chem. Int. Ed. Engl. 1986; 25: 312
  CrossrefSearch in Google Scholar

For early examples of photochemical addition of aminoalkyl radicals to conjugated olefins see:
• 20a Cookson RC, Hudec J, Mirza NA. Chem. Commun. 1968; 180
• 20b Yoon U.-C, Kim J.-U, Hasegawa E, Mariano PS. J. Am. Chem. Soc. 1987; 109: 4421
  CrossrefSearch in Google Scholar

For seminal papers on amine α-C–H activation by using photoredox see:
• 21a Kohls P, Jadhav D, Pandey G, Reiser O. Org. Lett. 2012; 14: 672
  CrossrefPubMedSearch in Google Scholar
• 21b Miyake Y, Nakajima K, Nishibayashi Y. J. Am. Chem. Soc. 2012; 134: 3338
  CrossrefPubMedSearch in Google Scholar
• 21c Ruiz Espelt L, Wiensch EM, Yoon TP. J. Org. Chem. 2013; 78: 4107
  CrossrefPubMedSearch in Google Scholar
• 21d Douglas JJ, Cole KP, Stephenson CR. J. J. Org. Chem. 2014; 79: 11631
  CrossrefPubMedSearch in Google Scholar
• 21e Trowbridge A, Reich D, Gaunt MJ. Nature 2018; 561: 522
  Search in Google Scholar
• 21f Flodén NJ, Trowbridge A, Willcox D, Walton SM, Kim Y, Gaunt MJ. J. Am. Chem. Soc. 2019; 141: 8426
  CrossrefPubMedSearch in Google Scholar

For enantioselective examples see:
• 22a Ruiz Espelt L, McPherson IS, Wiensch EM, Yoon TP. J. Am. Chem. Soc. 2015; 137: 2452
  CrossrefPubMedSearch in Google Scholar
• 22b Murphy JJ, Bastida D, Paria S, Fagnoni M, Melchiorre P. Nature 2016; 532: 218
  CrossrefPubMedSearch in Google Scholar

For recent papers on amine α-C–H activation by using umpolung reactions of imines see:
• 23a Wu Y, Hu L, Li Z, Deng L. Nature 2015; 523: 445
  Search in Google Scholar
• 23b Hu B, Deng L. Angew. Chem. Int. Ed. 2018; 57: 2233
  CrossrefPubMedSearch in Google Scholar
• 24 α-Cyclobutylanilines 2–14; General Procedure A screw-top test tube equipped with a stirrer bar was charged with [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (1 mol%), 1C (1 equiv), and, if solid, the appropriate aniline (5 equiv). The tube was sealed with a PTFE/silicon septum and connected to a Schlenck line. The atmosphere was exchanged by applying a vacuum and backfilling with N₂ (this process was conducted a total of three times). Under a N₂ atmosphere, the tube was charged by syringe with previously degassed solvent (DMA; 2 mL/mmol 1C) and, if liquid, the appropriate aniline. The resulting solution was stirred at 700 rpm and irradiated with blue LEDs (4 cm from the lamp) for 16 h. The reaction was then quenched with sat. aq NaHCO₃ (10 mL), and the mixture was extracted with EtOAc (3 × 15 mL). The combined extracts were washed sequentially with 5% aq LiCl (3 × 15 mL) and brine (2 × 15 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (silica gel) to give the desired product. See the Supporting Information for full details, along with physical and spectroscopic data for the products.
• 25 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (cis-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 128.8 mg (64%). ¹H NMR (600 MHz, CDCl₃): δ = 7.38–7.32 (m, 2 H), 7.19 (dd, J = 8.5, 7.0 Hz, 2 H), 7.07–6.97 (m, 1 H), 6.72 (d, J = 8.3 Hz, 2 H), 6.61 (t, J = 7.2 Hz, 1 H), 3.86 (dt, J = 10.4, 6.9 Hz, 1 H), 3.63–3.52 (m, 2 H), 3.06 (dd, J = 15.6, 11.4 Hz, 1 H), 2.52–2.43 (m, 1 H), 2.41–2.30 (m, 2 H), 2.23 (dp, J = 11.9, 4.1 Hz, 1 H), 2.15 (dtd, J = 12.0, 7.9, 4.1 Hz, 1 H), 2.08 (dt, J = 14.4, 7.2 Hz, 1 H), 1.77–1.66 (m, 3 H), 1.60–1.52 (m, 1 H), 1.37–1.22 (m, 2 H), 1.22–1.13 (m, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ =162.8 (dd, J = 255.8, 11.4 Hz), 148.5, 141.3 (t, J = 7.8 Hz), 129.4, 115.1, 112.1–111.7 (m), 110.8, 109.4 (t, J = 24.9 Hz), 58.6, 53.2, 43.2, 34.3, 31.9, 29.8, 26.9, 26.3, 25.9, 24.8. ¹⁹F (376 MHz, CDCl₃): δ = –104.95 to –104.96 (m). X-ray-quality crystals of cis-7 were obtained by Et₂O and hexane vapor diffusion. C₂₂H₂₅F₂NO₂S, M_r = 405.49, monoclinic, P2₁/n (No. 14), a = 9.56610(10), b = 21.4256(3), c = 19.3969(2) Å, β = 96.1240(10)^°, V = 3952.89(8) Å³, T = 102(4) K, Z = 8, Z′ = 2, μ(MoK_α) = 0.200; 135731 reflections measured, 20640 unique (R_int  = 0.0684), which were used in all calculations. The final wR₂ was 0.1495 (all data) and R₁ was 0.0566 [I > 2σ(I)]. Cambridge Crystallographic Data Centre (CCDC) contains the supplementary crystallographic data for compound cis-7. The data can be obtained free of charge from The CCDC via www.ccdc.cam.ac.uk/getstructures. 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (trans-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 64 mg (32%). ¹H NMR (600 MHz, CDCl₃): δ = 7.40–7.35 (m, 2 H), 7.15 (dd, J = 8.9, 7.1 Hz, 2 H), 7.04 (tt, J = 8.4, 2.3 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 2 H), 6.57 (t, J = 7.2 Hz, 1 H), 3.84 (td, J = 9.1, 6.4 Hz, 1 H), 3.69–3.58 (m, 2 H), 3.07 (ddd, J = 15.7, 11.5, 2.0 Hz, 1 H), 2.90–2.82 (m, 1 H), 2.66–2.58 (m, 1 H), 2.50–2.42 (m, 1 H), 2.24–2.13 (m, 2 H), 2.13–2.04 (m, 1 H), 1.74–1.65 (m, 3 H), 1.53–1.51 (m, 1 H), 1.37–1.22 (m, 2 H), 1.20–1.13 (m, 1 H).¹³C NMR (151 MHz, CDCl₃): δ =162.9 (dd, J = 255.9, 11.4 Hz), 148.8, 141.3 (t, J = 8.0 Hz), 129.4, 115.1, 111.9 (dd, J = 21.7, 6.5 Hz), 110.9, 109.4 (t, J = 24.9 Hz), 58.6, 54.7, 43.0, 36.2, 32.2, 29.6, 26.0, 25.7, 25.7, 24.7.¹⁹F NMR (376 MHz, CDCl₃): δ = –105.01 to –105.04 (m).

• Supplementary Material