Catalytic Enantioselective Synthesis of Azepine-Fused Planar-Chiral

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Catalytic Enantioselective Synthesis of Azepine-Fused Planar-Chiral Ferrocenes by Pt-Catalyzed Cycloisomerization Mamoru Ito,*,† Moeka Okamura,† Kyalo Stephen Kanyiva,‡ and Takanori Shibata*,† †

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Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan ‡ Global Center for Science and Engineering, School of Advanced Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan S Supporting Information *

ABSTRACT: Enantioselective synthesis of azepine-fused planarchiral ferrocenes was achieved by the chiral cationic Pt-catalyzed intramolecular cycloisomerization of N-propargyl-2-ferrocenylanilines. A mechanistic study using an N-allenyl analogue indicated that the reaction proceeded selectively in a 7-exo-dig manner along with isomerization of the exo-olefin moiety. A methanesulfonylamino tether was crucial for selective cycloisomerization. This is the first example of the enantioselective synthesis of heteropin-fused planarchiral ferrocenes.

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dibenzo[b,f ]azepine derivatives (Scheme 1a).3 Recently, our group developed a synthesis of dibenzo[b,f ]azepine derivatives by the Au-catalyzed 7-endo-dig-selective cycloisomerization of 2-alkynyl-N-arylanilines (Scheme 1b).4 However, to the best of our knowledge, there have been no previous reports of the enantioselective synthesis of dibenzazepine derivatives.5 Cramer and co-workers recently reported an elegant work on Pd-catalyzed intramolecular C−H arylation for the enantioselective synthesis of axially chiral dibenzazepinones (Scheme 1c).6 The geminal substituents adjacent to the amide group are crucial for asymmetric induction. Against this background, we focused on the enantioselective synthesis of planar-chiral dibenzazepine derivatives by replacing one of the two benzene rings of dibenzazepine with ferrocene. We speculated that an intramolecular reaction of N-propargyl-2-ferrocenylanilines would afford planar-chiral azepin-fused ferrocenes via cycloisomerization along with isomerization (Scheme 2a). Hashmi and co-workers reported cationic Au(I)-catalyzed 7-exo-dig-selective cycloisomerization of electron-rich arenes (Scheme 2b).7 In the coexistence of a protic acid, seven-membered carbocycles were obtained along complete double-bond isomerization. We considered that an electron-rich and bulky ferrocenyl group could induce high reactivity and enantioselectivity in the cycloisomerization. In contrast, various strategies have been developed for the catalytic construction of planar-chiral ferrocenes;8 however, most enantioselective syntheses have been limited to five- or

INTRODUCTION Dibenzazepine is an important skeleton among medium-sized N-heterocycles because it is found in many natural products and bioactive compounds.1,2 For example, carbamazepine, which is widely used for the treatment of epilepsy, contains a dibenzo[b,f ]azepine moiety.1 Dimeric erythrivarine B, which was isolated from the flower of E. variegate, contains the dibenzo[b,d]azepine motif.2 While various methodologies have been developed for construction of the dibenzazepine motif, there are few examples of a catalytic approach (Scheme 1). Buchwald and co-workers reported a Pd-catalyzed consecutive Buchwald−Hartwig amination and Heck reaction to provide Scheme 1. Catalytic Construction of Dibenzazepines

Special Issue: Asymmetric Synthesis Enabled by Organometallic Complexes Received: June 24, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

conventional conditions; however, the desired sulfonylated product could not be detected. We considered that steric repulsion between bulky ferrocenyl and tosyl groups hampered sulfonylation. Less bulky mesylation proceeded smoothly to give mesylate 2. Finally, propargylation of 2 gave model substrate 3a in 24% yield in four steps from ferrocene. On the basis of our previous work,9i we started to examine the present cycloisomerization of 3a using cationic Pt(II) complexes (Table 1).14 When (S)-BINAP as a chiral ligand

Scheme 2. Construction of Planar-Chiral Ferrocenes by Cycloisomerization

Table 1. Screening of Reaction Conditionsa

six-membered-ring-fused planar-chiral ferrocenes.9 For example, chiral Au(I)-catalyzed9h and Pt(II)-catalyzed9i enantioselective cycloisomerizations of 1-alkynyl-2-ferrocenylbenzene afforded planar-chiral naphthalene-fused ferrocene derivatives (Scheme 2c). Although there are a few examples of the asymmetric synthesis of seven-membered-ring-fused planarchiral ferrocenes,10 an enantioselective approach has never been reported.

entry

chiral ligandb

X

solvent

yield (%)

ee (%)c

1 2 3d 4d 5d 6d 7d 8d 9d 10d 11d 12d

BINAP none BINAP SEGPHOS SYNPHOS Ph-BPE Ph-BPE Ph-BPE Ph-BPE Ph-BPE Ph-BPE Ph-BPE

SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 SbF6 OTf BF4

DCE DCE DCE DCE DCE DCE PhCl toluene THF dioxane dioxane dioxane

35 5 51 36 27 42 52 NDe 34 60 34 NDe

33 (−) 36 (−) 42 (−) 46 (−) 46 (+) 53 (+) 59 (+) 62 (+) 58 (+)

a

Reaction conditions: 3a (0.05 mmol), PtCl2(cod) (10 mol %), chiral ligand (10 mol %), AgX (20 mol %), solvent (0.5 mL). bS and S,S isomers were used. Definitio ns: SEGPHOS, 5,5′ -bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole; SYNPHOS, 6,6′-bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin; Ph-BPE, bis(2,5-diphenylphospholano)ethane. cThe sign of optical rotation is shown in parentheses. dThe reaction mixture was stirred at room temperature for 1 h before the reaction temperature was raised. e Not detected.

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RESULTS AND DISCUSSION We started the synthesis of 2-(propargylamino)phenylferrocene derivative 3a from 2-bromophenylferrocene, which was prepared from ferrocene and 2-bromoaniline as described in the literature (Scheme 3).11 Copper-mediated reductive amination using trimethylsilyl azide gave 2-aminophenylferrocene 1,12 which was used in the next sulfonylation without isolation.13 First, tosylation of 1 was conducted under

and silver hexafluoroantimonate as a silver salt were used in 1,2-dichloroethane, 3a was completely consumed in 20 h at 60 °C, and the desired product 4a was obtained, albeit in low yield with low enantioselectivity (entry 1). Since the reaction slightly proceeded under ligand-free conditions (entry 2), the reaction mixture was then stirred at room temperature for 1 h before the reaction temperature was raised to complete the ligand exchange from COD to BINAP (entry 3). Although the enantioselectivity did not improve, the yield increased significantly. Under the reaction conditions, various chiral phosphine ligands were examined (entries 4−6). Regarding BINAP derivatives, SYNPHOS gave the best ee, albeit in low yield (entry 5). Ph-BPE achieved a comparable ee along with improved yield (entry 6). On the basis of screening of the solvent (entries 6−10), etherate solvents improved the enantioselectivity and dioxane gave the best results with respect to both yield and ee (entry 10). The counteranion had a significant effect (entries 10−12): triflate resulted in worse yield and cycloadduct 4a could not be detected with tetrafluoroborate. After the recrystallization of 4a in entry 10, a single crystal was obtained and its structure was determined by X-ray structural analysis. The major enantiomer prepared by

Scheme 3. Synthesis of Model Substrate 3a

B

DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Pt(II)-(S,S)-Ph-BPE catalyst was found to be the RP isomer (Figure 1).

Scheme 4. Screening of Tether

Figure 1. X-ray structure of 4a (thermal ellipsoids shown at 50% probability).

Under the conditions of entry 10 in Table 1, substituents on the o-phenylene tether were investigated. When a methyl group was installed at the para position of the ferrocene moiety, the reaction provided the desired cycloadduct 4b in moderate yield with the highest ee of 90% (entry 1 of Table 2).

There are two possible reaction mechanisms for the formation of methyl-substituted azepine (Scheme 5). Path A Scheme 5. Mechanistic Study

Table 2. Substrate Scopea

entry

R1, R2

yield (%)

ee (%)

1 2 3 4 5 6

H, Me (3b) H, i-Pr (3c) H, Cl (3d) H, F (3e) Me, H (3f) Cl, H (3g)

66 (4b) 43 (4c) 55 (4d) 56 (4e) 70 (4f) 52 (4g)

90 39 52 51 71 37

a Reaction conditions: 3 (0.05 mmol), PtCl2(cod) (10 mol %), chiral ligand (10 mol %), AgSbF6 (20 mol %), dioxane (0.5 mL).

In contrast, a bulky isopropyl group drastically decreased both the yield and ee (entry 2). Halogen-substituted substrates also afforded the corresponding products 4d,e in moderate yield and ee (entries 3 and 4). The meta-substituted substrate provided cycloadducts 4f,g in lower ee in comparison to that of their para counterparts (entries 5 and 6).15 We next examined the effect of a tethered moiety for the present cycloisomerization (Scheme 4). When NMe- and NHtethered alkynes 8a,b were subjected to the same reaction conditions, the reactions proceeded sluggishly. While most of the substrates were recovered and ferrocene-fused products 9a,b could not be detected, a small amount of 6-endo-dig product 9′b was obtained in the reaction of 8b (Scheme 4, eq 1). In contrast, the reaction of oxygen-tethered alkyne 10 afforded 6-endo-dig product 11′ as a major product, while ferrocene-fused products 11 could not be detected (Scheme 4, eq 2). These results indicated that the electron-withdrawing and steric effects of a mesyl group were crucial to realize 7-exodig-selective cycloisomerization.

shows 7-exo-dig-selective cycloisomerization and subsequent isomerization of the exo-olefin moiety. In path B, the isomerization of propargyl sulfonamide to allenyl sulfonamide proceeds prior to 7-exo-dig-selective cycloisomerization. We subjected N-allenyl analogue 12 to the above conditions, but 4a could not be detected at all and a trace amount of 6-exo-trig product 13 was obtained16,17 (Scheme 5, eq 3). On the basis of these results, path A would be preferable. Since exo-olefin product could not be detected even in the early stage of the reaction, double-bond isomerization would be facile under these reaction conditions.

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CONCLUSION We achieved a catalytic and enantioselective synthesis of azepine-fused planar-chiral ferrocenes with a chiral cationic Pt C

DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics

2H), 4.87 (br s, 1H), 4.60−4.49 (m, 2H), 4.40−4.30 (m, 2H), 4.11 (s, 5H), 3.75 (br d, J = 19.4 Hz, 1H), 3.12 (s, 3H), 2.41 (t, J = 2.3 Hz, 1H); 13C NMR δ 138.4, 137.1, 132.5, 131.4, 129.4, 129.2, 81.0, 78.0, 74.7, 70.2, 70.0, 69.8, 69.2, 69.1, 41.3, 40.4; HRMS (ESI, positive) m/ z calcd for C20H18ClFeNO2S (M+) 427.0091, found 427.0082. {4-Fluoro-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3e). Isolated by preparative TLC (dichloromethane only, Rf = 0.3). The title compound was obtained as an orange solid in four steps with a total yield of 36% (888.3 mg, 2.2 mmol): mp 113 °C; 1H NMR δ 7.87−7.81 (m, 1H), 7.15−7.08 (m, 2H), 4.83 (br s, 1H), 4.60−4.45 (m, 2H), 4.37−4.28 (m, 2H), 4.11 (s, 5H), 3.84−3.68 (m, 1H), 3.09 (s, 3H), 2.39 (t, J = 2.6 Hz, 1H); 13C NMR δ 160.1 (d, J = 248.0 Hz), 137.1 (d, J = 7.9 Hz), 135.5 (d, J = 3.6 Hz), 132.8 (d, J = 8.6 Hz), 116.4 (d, J = 21.1 Hz), 116.3 (d, J = 21.1 Hz), 81.7, 78.1, 74.6, 69.9, 69.5, 69.2, 69.0 41.3, 40.4 (a pair of ferrocenyl peaks was overlapped); HRMS (ESI, positive) m/z calcd for C20H18FFeNO2S (M+) 411.0378, found 411.0378. {5-Methyl-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3f). Isolated by preparative TLC (dichloromethane only, Rf = 0.3). The title compound was obtained as an orange solid in four steps with a total yield of 7% (87.3 mg, 0.21 mmol): mp 126 °C; 1H NMR δ 7.75−7.71 (m, 1H), 7.20−7.16 (m, 2H), 4.85 (br s, 1H), 4.59−4.49 (m, 2H), 4.37−4.26 (m, 2H), 4.10 (s, 5H), 3.78 (br d, J = 18.9 Hz, 1H), 3.08 (s, 3H), 2.37−2.34 (m, 4H); 13C NMR δ 136.7, 136.2, 136.0, 131.4, 129.9, 129.7, 82.4, 78.6, 74.2, 70.0, 69.9, 69.3, 69.2, 68.8, 41.4, 40.5, 21.1; HRMS (ESI, positive) m/z calcd for C21H21FeNO2S (M+) 407.0637, found 407.0633. {5-Chloro-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3g). Isolated by preparative TLC (dichloromethane only, Rf = 0.3). The title compound was obtained as an orange solid in four steps with a total yield of 24% (615.9 mg, 1.44 mmol): mp 100 °C; 1H NMR δ 7.81 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.21 (dd, J = 8.2, 2.2 Hz, 1H), 4.89 (br s, 1H), 4.63− 4.49 (m, 2H), 4.41−4.33 (m, 2H), 4.14 (s, 5H), 3.75 (br d, J = 19.0 Hz, 1H), 3.09 (s, 3H), 2.37 (t, J = 2.4 Hz, 1H); 13C NMR δ 141.8, 134.8, 134.8, 131.3, 130.7, 126.8, 80.7, 78.2, 74.5, 70.4, 70.1, 70.0, 69.4, 69.3, 41.2, 40.4; HRMS (ESI, positive) m/z calcd for C20H18ClFeNO2S (M+) 427.0091, found 427.0082. General Procedure for the Cycloisomerization. 2-Aminophenylferrocene derivative 3 (0.05 mmol), PtCl2(cod) (0.005 mmol, 10 mol %), and (S,S)-Ph-BPE (0.005 mmol, 10 mol %) were placed in a dried Schlenk tube in air. After the reaction vessel was evacuated and backfilled with argon, it was placed in a glovebox and AgSbF6 (0.01 mmol, 20 mol %) was added. 1,4-Dioxane (0.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h and then at 60 °C for 20 h. After the reaction was finished, the reaction mixture was cooled to room temperature. The crude product was filtered through a short pad of silica gel and purified by PTLC to give desired pure product 4. 4-Methyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5-a]ferrocene (4a). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.6). The title compound was obtained as an orange solid (11.7 mg, 0.030 mmol): mp 170 °C; 1H NMR δ 7.77 (d, J = 7.5 Hz, 1H), 7.40−7.27 (m, 3H), 6.27 (br s, 1H), 4.90 (br s, 1H), 4.48 (br s, 1H), 4.42−4.36 (m, 1H), 4.06 (s, 5H), 2.30 (s, 3H), 2.23 (d, J = 1.4 Hz, 3H); 13C NMR δ 138.2, 137.1, 131.7, 129.6, 128.4, 127.7, 124.1, 83.2, 82.4, 71.4, 71.2, 71.2, 68.7, 68.4, 38.3, 19.4; HRMS (ESI, positive) m/z calcd for C20H19FeNO2S (M+) 393.0480, found 393.0471; [α]34D = 576 (c 0.48, CHCl3, 62% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IB-3 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 3% 2-propanol in hexane, flow rate 1.0 mL/ min, retention time 20.0 min for minor isomer and 21.6 min for major isomer). Crystal data of compound 4a: C20H19FeNO2S, Mr = 393.28, monoclinic, space group P212121 (No. 19), a = 10.4311(5) Å, b = 11.6124(6) Å, c = 14.3412(8) Å, T = 123.2 K, V = 1737.15(16) Å3, Z = 4, μ(Mo Kα) = 10.004 cm−1; number of reflections measured, total 16658 and unique 3942 (Rint = 0.0675), R1 = 0.0401, wR2 = 0.0922,

catalyst. Intramolecular cycloisomerization of N-propargyl-2ferrocenylanilines proceeded to give methyl-substituted benzazepines with planar chirality. The methanesulfonylamino tether was critical for the selective cycloisomerization. This is the first example of an enantioselective synthesis of heteropinfused planar-chiral ferrocenes. Further screening of the asymmetric synthesis of atropisomeric heteropin-fused planar chiral ferrocenes is ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Considerations. 1H NMR spectra were recorded on JEOL ECX-500 (500 MHz) spectrometer. The chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; t, triplet; br s, broad singlet; br d, broad doublet; m, multiplet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were obtained by JEOL ECX-500 (125 MHz) spectrometers and referenced to the internal solvent signals (the central peak is 77.16 ppm in CDCl3). CDCl3 was used as a NMR solvent. High-resolution mass spectra (HRMS) were measured on an ESI (electro spray ionization) instrument. Optical rotations were measured on a JASCO DIP-1000 polarimeter. X-ray structures were obtained by a Rigaku R-AXIS RAPID diffractometer. Preparative thinlayer chromatography (PTLC) was performed with silica gel precoated glass plates prepared in our laboratory. Flash column chromatography was performed over silica gel 200−300. All reagents were weighed and handled in air and backfilled under argon at room temperature. Unless otherwise noted, all reactions were conducted under an argon atmosphere. All reagents were purchased from Wako, Kanto, Aldrich, and TCI and used without further purification. 2-[N-(Prop-2-yn-1-yl)methylsulfonamido]phenylferrocene (3a). Isolated by preparative TLC (dichloromethane only, Rf = 0.3). The title compound was obtained as an orange solid in four steps with a total yield of 24% (288.7 mg, 0.73 mmol): mp 91 °C; 1H NMR δ 7.86 (d, J = 7.7 Hz, 1H), 7.43−7.34 (m, 2H), 7.28−7.21 (m, 1H), 4.89 (br s, 1H), 4.62−4.50 (m, 2H), 4.39−4.28 (m, 2H), 4.11 (s, 5H), 3.77 (br d, J = 17.2 Hz, 1H), 3.10 (s, 3H), 2.36 (t, J = 2.2 Hz, 1H); 13C NMR δ 139.4, 136.4, 131.6, 129.3, 128.9, 126.8, 82.1, 78.5, 74.3, 70.2, 69.9, 69.5, 69.3, 69.0, 41.3, 40.5; HRMS (ESI, positive) m/ z calcd for C20H19FeNO2S (M+) 393.0480, found 393.0475. {4-Methyl-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3b). Isolated by preparative TLC (dichloromethane only, Rf = 0.6). The title compound was obtained as an orange solid (126.8 mg, 0.31 mmol) in four steps with a total yield of 10%: mp 139 °C; 1H NMR δ 7.77−7.20 (m, 1H), 7.21−7.14 (m, 2H), 4.85 (br s, 1H), 4.60−4.48 (m, 2H), 4.36−4.26 (m, 2H), 4.10 (s, 5H), 3.78 (br d, J = 17.5 Hz, 1H), 3.08 (s, 3H), 2.39−2.33 (m, 4H); 13C NMR δ 136.7, 136.2, 136.0, 131.4, 129.9, 129.7, 82.4, 78.6, 74.1, 70.0, 69.9, 69.3, 69.2, 68.8, 41.4, 40.5, 21.1; HRMS (ESI, positive) m/z calcd for C21H21FeNO2S (M+) 407.0637, found 407.0632. {4-Isopropyl-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3c). Isolated by preparative TLC (dichloromethane only, Rf = 0.5). The title compound was obtained as an orange solid in four steps with a total yield of 3% (64.6 mg, 0.15 mmol): mp 129 °C; 1H NMR δ 7.79−7.74 (m, 1H), 7.26−7.22 (m, 2H), 4.85 (br s, 1H), 4.61−4.50 (m, 2H), 4.35−4.26 (m, 2H), 4.11 (s, 5H), 3.76 (br d, J = 18.3 Hz, 1H), 3.10 (s, 3H), 2.96−2.88 (m, 1H), 2.36 (t, J = 2.4 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H); 13C NMR δ 147.6, 136.4, 136.3, 131.5, 127.4, 127.1, 82.5, 78.8, 74.1, 70.0, 69.8, 69.3, 68.8, 41.2, 40.6, 33.6, 24.0, 23.7 (a pair of ferrocenyl peaks was overlapped); HRMS (ESI, positive) m/z calcd for C23H25FeNO2S (M+) 435.0950, found 435.0947. {4-Chloro-2-[N-(prop-2-yn-1-yl)methylsulfonamido]phenyl}ferrocene (3d). Isolated by preparative TLC (dichloromethane only, Rf = 0.4). The title compound was obtained as an orange solid in four steps with a total yield of 12% (308.0 mg, 0.72 mmol): mp 137 °C; 1H NMR δ 7.81−7.76 (m, 1H), 7.37−7.32 (m, D

DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Flack parameter (Parsons quotients = 1255) 0.090(14), CCDC 1919390. 4,8-Dimethyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5a]ferrocene (4b). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.6). The title compound was obtained as an orange solid (13.5 mg, 0.033 mmol): mp 188 °C (decomposed); 1H NMR δ 7.65 (d, J = 7.9 Hz, 1H), 7.20−7.13 (m, 2H), 6.25 (d, J = 1.4 Hz, 1H), 4.88−4.83 (m, 1H), 4.47−4.43 (m, 1H), 4.38−4.34 (m, 1H), 4.05 (s, 5H), 2.35 (s, 3H), 2.29 (s, 3H), 2.22 (d, J = 1.3 Hz, 3H); 13C NMR δ 138.0, 137.8, 137.1, 133.8, 131.9, 129.5, 129.4, 124.0, 83.2, 82.7, 71.1, 70.7, 68.4, 68.2, 38.3, 21.1, 19.4; HRMS (ESI, positive) m/z calcd for C21H21FeNO2S (M+) 407.0637, found 407.0628; [α]34D = 665 (c 0.24, CHCl3, 90% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 3% 2-propanol in hexane, flow rate 1.0 mL/min, retention time 15.0 min for major isomer and 16.7 min for minor isomer). 8-Isopropyl-4-methyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5-a]ferrocene (4c). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.6). The title compound was obtained as an orange solid (9.5 mg, 0.022 mmol): mp 183 °C; 1 H NMR δ 7.77 (d, J = 8.4 Hz, 1H), 7.25−7.16 (m, 2H), 6.27 (d, J = 1.0 Hz, 1H), 4.87−4.83 (m, 1H), 4.47−4.43 (m, 1H), 4.37−4.34 (m, 1H), 4.06 (s, 5H), 3.00−2.88 (m, 1H), 2.29 (s, 3H), 2.22 (d, J = 1.0 Hz, 3H), 1.29 (d, J = 2.4 Hz, 3H), 1.28 (d, J = 2.4 Hz, 3H) 1H; 13C NMR δ 148.7, 138.1, 137.1, 134.0, 129.6, 129.4, 126.8, 124.1, 83.3, 82.7, 71.1, 70.8, 68.4, 68.1, 38.3, 33.7, 24.0, 23.8, 19.5; HRMS (ESI, positive) m/z calcd for C23H25FeNO2S (M+) 435.0950, found 435.0940; [α]34D = 568 (c 0.32, CHCl3, 39% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 3% 2-propanol in hexane, flow rate 1.0 mL/min, retention time 12.0 min for major isomer and 12.8 min for minor isomer). 8-Chloro-4-methyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5-a]ferrocene (4d). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.5). The title compound was obtained as an orange solid (11.7 mg, 0.027 mmol): mp 213 °C (decomposed); 1H NMR δ 7.71−7.66 (m, 1H), 7.36−7.31 (m, 2H), 6.23 (d, J = 1.5 Hz, 1H), 4.89−4.85 (m, 1H), 4.51−4.47 (m, 1H), 4.42−4.39 (m, 1H), 4.06 (s, 5H), 2.31 (s, 3H), 2.22 (d, J = 1.5 Hz, 3H); 13C NMR δ 138.7, 137.3, 136.0, 132.6, 131.5, 130.2, 128.8, 123.6, 83.1, 81.3, 71.3, 71.1, 68.9, 68.6, 38.4, 19.4; HRMS (ESI, positive) m/z calcd for C20H18ClFeNO2S (M+) 427.0091, found 427.0083; [α]34D = 474 (c 0.52, CHCl3, 52% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 3% 2-propanol in hexane, flow rate 0.7 mL/min, retention time 26.3 min for major isomer and 28.9 min for minor isomer). 8-Fluoro-4-methyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5-a]ferrocene (4e). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.5). The title compound was obtained as an orange solid (11.5 mg, 0.028 mmol): mp 182 °C; 1 H NMR δ 7.76−7.70 (m, 1H), 7.15−7.04 (m, 2H), 6.23 (d, J = 1.2 Hz, 1H), 4.87−4.82 (m, 1H), 4.50−4.46 (m, 1H), 4.41−4.36 (m, 1H), 4.06 (s, 5H), 2.31 (s, 3H), 2.23 (d, J = 1.2 Hz, 3H); 13C NMR δ 161.5 (d, J = 248.9 Hz), 139.1 (d, J = 9.5 Hz), 137.4, 133.2 (d, J = 3.6 Hz), 130.2 (d, J = 9.5 Hz), 123.6, 118.4 (d, J = 21.5 Hz), 116.1 (d, J = 21.8 Hz), 83.1, 81.6, 71.2, 70.8, 68.6, 68.4, 38.4, 19.4; HRMS (ESI, positive) m/z calcd for C20H18FFeNO2S (M+) 411.0386, found 411.0382; [α]34D = 478 (c 0.29, CHCl3, 51% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 3% 2-propanol in hexane, flow rate 1.0 mL/min, retention time 17.2 min for major isomer and 19.2 min for minor isomer). 4,9-Dimethyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5a]ferrocene (4f). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.6). The title compound was obtained as an orange solid (14.4 mg, 0.035 mmol): mp 93 °C; 1H NMR δ 7.54 (d, J = 1.7 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.1, 1.8 Hz, 1H), 6.26 (d, J = 1.3 Hz, 1H), 4.89−4.86 (m, 1H), 4.48−4.45 (m,

1H), 4.39−4.36 (m. 1H), 4.06 (s, 5H), 2.43 (s, 3H), 2.28 (s, 3H), 2.21 (d, J = 1.3 Hz, 3H); 13C NMR δ 138.2, 136.9, 136.7, 135.9, 131.3, 129.9, 128.7, 124.2, 83.3, 82.5, 71.4, 71.0, 68.6, 68.3, 38.2, 21.4, 19.4; HRMS (ESI, positive) m/z calcd for C21H21FeNO2S (M+) 407.0637, found 407.0633; [α]34D = 478 (c 0.33, CHCl3, 71% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 1% 2-propanol in hexane, flow rate 1.0 mL/min, retention time 32.7 min for minor isomer and 35.1 min for major isomer). 9-Chloro-4-methyl-6-(methylsulfonyl)-6H-benzo[2,3]azepino[4,5-a]ferrocene (4g). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.6). The title compound was obtained as an orange solid (11.2 mg, 0.026 mmol): mp 198 °C; 1 H NMR δ 7.73−7.69 (m, 1H), 7.25−7.23 (m, 2H), 6.24 (br s, 1H), 4.92−4.89 (m, 1H), 4.52−4.49 (m, 1H), 4.44−4.40 (m, 1H), 4.09 (s, 5H), 2.30 (s, 3H), 2.22 (d, J = 0.92 Hz, 3H) ; 13C NMR δ 139.3, 137.1, 136.7, 134.2, 132.9, 129.1, 127.8, 123.9, 83.2, 80.9, 71.4, 71.3, 69.0, 68.8, 38.3, 19.4; HRMS (ESI, positive) m/z calcd for C20H18ClFeNO2S (M+) 427.0091, found 427.0083; [α]34D = 348 (c 0.41, CHCl3, 37% ee). The ee value was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA 4.6 × 250 mm, 254 nm UV detector, room temperature, eluent 1% 2-propanol in hexane, flow rate 1.0 mL/min, retention time 32.8 min for minor isomer and 35.7 min for major isomer). 2-[N-(Prop-2-yn-1-yl)methyl]phenylferrocene (8a). Isolated by preparative TLC (hexane/ethyl acetate = 10/1, Rf = 0.7). The title compound was obtained as orange oil in four steps with a total yield of 10% (41.5 mg, 0.13 mmol): 1H NMR δ 7.73−7.69 (m, 1H), 7.18− 7.12 (m, 1H), 7.08−7.00 (m, 2H), 4.75−4.71 (m, 2H), 4.28−4.24 (m, 2H), 4.07 (s, 5H), 3.50 (d, J = 2.3 Hz, 2H), 2.70 (s, 3H), 2.12 (t, J = 2.2 Hz, 1H); 13C NMR δ 149.6, 132.4, 131.7, 126.6, 122.8, 120.1, 85.6, 79.8, 72.6, 69.8, 69.8, 68.0, 45.2, 39.7; HRMS (ESI, positive) m/ z calcd for C20H19FeN (M+) 329.0861, found 329.0858. 2-(Propargylamino)phenylferrocene (8b). Isolated by preparative TLC (hexane/ethyl acetate = 5/1, Rf = 0.6). The title compound was obtained as orange oil in three steps with a total yield of 23% (85.2 mg, 0.27 mmol): 1H NMR δ 7.32−7.28 (m, 1H), 7.26− 7.19 (m, 1H, overlap with CDCl3), 6.78−6.70 (m, 2H), 5.67 (br s, 1H), 4.58−4.53 (m, 2H), 4.38−4.33 (m, 2H), 4.22 (s, 5H), 4.11− 4.06 (m, 2H), 2.30−2.27 (m, 1H); 13C NMR δ 144.4, 130.2, 127.8, 122.7, 118.0, 110.9, 85.1, 81.1, 71.7, 69.2, 68.8, 67.8, 33.8; HRMS (ESI, positive) m/z calcd for C19H17FeN (M+) 315.0705, found 315.0701. 2-(Prop-2-yn-1-yloxy)phenylferrocene (10). Isolated by preparative TLC (hexane/dichloromethane = 1/4, Rf = 0.7). The title compound was obtained as an orange oil in three steps with a total yield of 6% (69.0 mg, 0.22 mmol): 1H NMR δ 7.56−7.51 (m, 1H), 7.22−7.17 (m, 1H), 7.00−6.93 (m, 2H), 4.81−4.74 (m, 4H), 4.31− 4.27 (m, 2H), 4.08 (s, 5H), 2.54 (t, J = 2.2 Hz, 1H); 13C NMR δ 154.7, 129.6, 128.2, 127.0, 121.6, 112.8, 82.5, 78.9, 75.6, 69.6, 69.0, 68.6, 56.1; HRMS (ESI, positive) m/z calcd for C19H16FeO (M+) 316.0545, found 316.0542. 8-Ferrocenyl-1,2-dihydrochromene (11′). Isolated by preparative TLC (hexane/dichloromethane = 1/1, Rf = 0.8). The title compound was obtained as orange oil (12.3 mg, 0.039 mmol): 1H NMR δ 7.38−7.33 (m, 1H), 6.87−6.79 (m, 2H), 6.49−6.43 (m, 1H), 5.86−5.80 (m, 1H), 4.89−4.85 (m, 2H), 4.76−4.71 (m, 2H), 4.30− 4.24 (m, 2H), 4.06 (s, 5H); 13C NMR δ 151.1, 129.1, 126.3, 125.3, 124.7, 122.9, 121.9, 121.0, 82.2, 69.5, 68.9, 68.4, 65.4; HRMS (ESI, positive) m/z calcd for C19H16FeO (M+) 316.0545, found 316.0549. N-Methanesulfonyl-2-ferrocenylanilinoallene (12). Isolated by preparative TLC (hexane/ethyl acetate = 6/1, Rf = 0.4). The title compound was obtained as orange oil in five steps with a total yield of 15% (48.5 mg, 0.12 mmol): 1H NMR δ 7.86−7.81 (m, 1H), 7.40− 7.34 (m, 1H), 7.27−7.18 (m, 2H, overlap with CDCl3), 7.06 (t, J = 6.2 Hz, 1H), 5.17 (d, J = 6.3 Hz, 2H), 4.79 (br s, 1H), 4.68 (br s, 1H), 4.33 (br s, 2H), 4.08 (s, 5H), 2.75 (s, 3H); 13C NMR δ 201.3, 140.0, 134.1, 131.3, 131.0, 129.2, 126.8, 103.2, 87.8, 82.7, 70.8, 69.9, 69.3, 68.6, 40.3. (a pair of ferrocenyl peaks was overlapped); HRMS E

DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics (ESI, positive) m/z calcd for C20H19FeNO2S (M+) 393.0480, found 393.0478. N-Methanesulfonyl-4,5-dihydroquinolino-4-vinyl[3,4-b]ferrocene (13). The compound was prepared with an Au catalyst17 and isolated by preparative TLC (hexane/dichloromethane = 1/1, Rf = 0.6). The title compound was obtained as an orange solid (7.9 mg, 0.020 mmol): mp 155 °C; 1H NMR δ 7.43−7.39 (m, 1H), 7.37−7.33 (m, 1H), 7.25−7.19 (m, 1H), 7.09−7.02 (m, 1H), 5.84 (d, J = 7.2 Hz, 1H), 5.73−5.63 (m, 1H), 5.18−5.12 (m, 1H), 5.00−4.96 (m, 1H), 4.65−4.63 (m, 1H), 4.38−4.34 (m, 1H), 4.31−4.28 (m, 1H), 4.16 (s, 5H), 3.29 (s, 3H); 13C NMR δ 136.4, 133.3, 127.8, 126.3, 124.1, 124.0, 120.8, 116.2, 88.4, 76.4, 70.5, 67.6, 66.4, 61.1, 58.5, 42.9; HRMS (ESI, positive) m/z calcd for C20H19FeNO2S (M+) 393.0480, found 393.0479.

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(4) Ito, M.; Kawasaki, R.; Kanyiva, K. S.; Shibata, T. Construction of a Polycyclic Conjugated System Containing a Dibenzazepine Moiety by Cationic Gold(I)-Catalyzed Cycloisomerization. Eur. J. Org. Chem. 2016, 2016, 5234−5237. (5) Liu, J.; Yang, X.; Zuo, Z.; Nan, J.; Wang, Y.; Luan, X. Catalytic Enantioselective Tautomerization of Metastable Enamines. Org. Lett. 2018, 20, 244−247. (6) Newton, C. G.; Braconi, E.; Kuziola, J.; Wodrich, M. D.; Cramer, N. Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C−H Arylation. Angew. Chem., Int. Ed. 2018, 57, 11040−11044. (7) Pflästerer, D.; Rettenmeier, E.; Schneider, S.; Ruiz, E. L. H.; Rudolph, M.; Hashmi, A. S. K. Highly Efficient Gold-Catalyzed Synthesis of Dibenzocycloheptatrienes. Chem. - Eur. J. 2014, 20, 6752−6755. (8) (a) Schaarschmidt, D.; Lang, H. Selective Syntheses of PlanarChiral Ferrocenes. Organometallics 2013, 32, 5668−5704. (b) Arae, S.; Ogasawara, M. Catalytic asymmetric synthesis of planar-chiral transition-metal complexes. Tetrahedron Lett. 2015, 56, 1751−1761. (c) Gao, D.-W.; Gu, Q.; Zheng, C.; You, S.-L. Synthesis of Planar Chiral Ferrocenes via Transition-Metal-Catalyzed Direct C−H Bond Functionalization. Acc. Chem. Res. 2017, 50, 351−365. (9) For the synthesis of five-membered-ring-fused planar-chiral ferrocenes, see: (a) Deng, R.; Huang, Y.; Ma, X.; Li, G.; Zhu, R.; Wang, B.; Kang, Y.-B.; Gu, Z. Palladium-Catalyzed Intramolecular Asymmetric C−H Functionalization/Cyclization Reaction of Metallocenes: An Efficient Approach toward the Synthesis of Planar Chiral Metallocene Compounds. J. Am. Chem. Soc. 2014, 136, 4472−4475. (b) Gao, D.-W.; Yin, Q.; Gu, Q.; You, S.-L. Enantioselective Synthesis of Planar Chiral Ferrocenes via Pd(0)-Catalyzed Intramolecular Direct C−H Bond Arylation. J. Am. Chem. Soc. 2014, 136, 4841− 4484. (c) Shibata, T.; Shizuno, T.; Sasaki, T. Enantioselective synthesis of planar-chiral benzosiloloferrocenes by Rh-catalyzed intramolecular C−H silylation. Chem. Commun. 2015, 51, 7802− 7804. (d) Xu, B.-B.; Ye, J.; Yuan, Y.; Duan, W.-L. Palladium-Catalyzed Asymmetric C−H Arylation for the Synthesis of Planar Chiral Benzothiophene-Fused Ferrocenes. ACS Catal. 2018, 8, 11735− 11740. For the synthesis of six-membered-ring-fused planar-chiral ferrocenes, see: (e) Siegel, S.; Schmalz, H.-G. Insertion of Carbenoids into Cp−H Bonds of Ferrocenes: An Enantioselective-Catalytic Entry to Planar-Chiral Ferrocenes. Angew. Chem., Int. Ed. Engl. 1997, 36, 2456−2458. (f) Ma, X.; Gu, Z. Palladium-catalyzed intramolecular Cp−H bond functionalization/arylation: an enantioselective approach to planar chiral quinilinoferrocenes. RSC Adv. 2014, 4, 36241−36244. (g) Liu, L.; Zhang, A.-A.; Zhao, R.-J.; Li, F.; Meng, T.-J.; Ishida, N.; Murakami, M.; Zhao, W.-X. Asymmetric Synthesis of Planar Chiral Ferrocenes by Enantioselective Intramolecular C−H Arylation of N(2-Haloaryl)ferrocenecarboxamides. Org. Lett. 2014, 16, 5336−5338. (h) Urbano, A.; Hernández-Torres, G.; del Hoyo, A. M.; MartínezCarrión, A.; Carreño, M. C. Mild access to planar-chiral orthocondensed aromatic ferrocenes via gold(I)-catalyzed cycloisomerization of ortho-alkynylaryl ferrocenes. Chem. Commun. 2016, 52, 6419− 6422. (i) Shibata, T.; Uno, N.; Sasaki, T.; Kanyiva, K. S. Pt-Catalyzed Enantioselective Cycloisomerization for the Synthesis of Planar-Chiral Ferrocene Derivatives. J. Org. Chem. 2016, 81, 6266−6272. (j) Liu, Y.; Xu, J.; Zhang, J.; Xu, X.; Jin, Z. Intramolecular Direct C−H Arylation via a Metallocenic Radical Pathway: Stereospecific Approach to Planar-Chiral Ferrocenes. Org. Lett. 2017, 19, 5709−5712. (k) Luo, S.; Xiong, Z.; Lu, Y.; Zhu, Q. Enantioselective Synthesis of Planar Chiral Pyridoferrocenes via Palladium-Catalyzed Imidoylative Cyclization Reactions. Org. Lett. 2018, 20, 1837−1840. (l) Zhao, W.-T.; Lu, Z.-Q.; Zheng, H.; Xue, X.-S.; Zhao, D. Rhodium-Catalyzed 2Arylphenol-Derived Six-Membered Silacyclization: Straightforward Access toward Dibenzooxasilines and Silicon-Containing Planar Chiral Metallocenes. ACS Catal. 2018, 8, 7997−8005. (m) Urbano, A.; del Hoyo, A. M.; Martinez-Carrion, A.; Carreno, M. C. Asymmetric Synthesis and Chiroptical Properties of Enantiopure Helical Ferrocenes. Org. Lett. 2019, 21, 4623−4627.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.9b00422. Synthetic procedure of the starting materials, HPLC charts of products, and NMR spectra of the starting materials and products (PDF) Accession Codes

CCDC 1919390 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for M.I.: [email protected]. *E-mail for T.S.: [email protected]. ORCID

Kyalo Stephen Kanyiva: 0000-0001-9546-8367 Takanori Shibata: 0000-0003-4436-8264 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a Mitsubishi Material Corporation and Waseda University Joint Cooperation Grant. We thank Ms. Ninna Uno (Waseda University) for some initial experiments.

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REFERENCES

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DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX

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Organometallics (10) (a) Metallinos, C.; Szillat, H.; Taylor, N. J.; Snieckus, V. (−)-Sparteine-Mediated Directed ortho-Metalation of N-Cumyl-Nethylferrocenecarboxamide. Versatile Routes to Functionalized Planar Chiral Ferrocenecarboxamides, Amines, Esters and Phosphines. Adv. Synth. Catal. 2003, 345, 370−382. (b) Yasue, R.; Miyauchi, M.; Yoshida, K. Planar Chiral Cyclic (Amino)(ferrocenyl)carbene as Ligand for Transition Metals. Adv. Synth. Catal. 2017, 359, 255−259. (c) Shikata, Y.; Yasue, R.; Yoshida, K. Coordination Behavior of a Planar Chiral Cyclic (Amino)(Ferrocenyl)Carbene Ligand in Iridium Complexes. Chem. - Eur. J. 2017, 23, 16806−16812. (d) Yasue, R.; Yoshida, K. Synthesis and Application of Planar Chiral Cyclic (Amino)(ferrocenyl)carbene Ligands Bearing FeCp* Group. Organometallics 2019, 38, 2211−2217. (11) Panchal, K.; Amin, J.; Roca, F. X.; Motevalli, M.; Horton, P. N.; Coles, S. J.; Richards, C. J. Synthesis of racemic palladacycles from 2ferrocenylphenylphosphines. J. Organomet. Chem. 2015, 775, 12−19. (12) Maejima, T.; Shimoda, Y.; Nozaki, K.; Mori, S.; Sawama, Y.; Monguchi, Y.; Sajiki, H. One-pot aromatic amination based on carbon−nitrogen coupling reaction between aryl halides and azido compounds. Tetrahedron 2012, 68, 1712−1722. (13) Spencer, J.; Amin, J.; Wang, M.; Packham, G.; Alwi, S. S. S.; Tizzard, G. J.; Coles, S. J.; Paranal, R. M.; Bradner, J. E.; Heightman, T. D. Synthesis and Biological Evaluation of JAHAs: Ferrocene-Based Histone Deacetylase Inhibitors. ACS Med. Chem. Lett. 2011, 2, 358− 362. (14) No reaction proceeded by using a chiral cationic Au catalyst (Me2SAuCl (20 mol %), (S)-BINAP (10 mol %), AgSbF6 (20 mol %) in DCE at 60 °C for 20 h). (15) Methyl- and phenyl-substituted alkynes were subjected to the same reaction conditions, but the desired reaction did not proceed. (16) Compound 13 was obtained in 7% yield in the reaction of 3 along with unisolable byproducts. Isomerization of the propargyl to allenyl moiety slightly proceeded under the reaction conditions. (17) A cationic Au-catalyzed reaction of 12 gave 6-exo-trig product 13 in 45% yield.

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DOI: 10.1021/acs.organomet.9b00422 Organometallics XXXX, XXX, XXX−XXX