Photoredox-Catalyzed Radical Cascade Reaction To Synthesize

Jul 1, 2019 - A new photoredox-catalyzed cascade reaction is described to access fluorinated pyrrolo[1,2-d]benzodiazepine derivatives under mild ...
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Photoredox-Catalyzed Radical Cascade Reaction To Synthesize Fluorinated Pyrrolo[1,2‑d]benzodiazepine Derivatives Guifang Lian, Jingyu Li, Ping Liu, and Peipei Sun* School of Chemistry and Materials Science, Jiangsu Provincial Key Laboratory of Material Cycle Processes and Pollution Control, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing Normal University, Nanjing 210023, China

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S Supporting Information *

ABSTRACT: A new photoredox-catalyzed cascade reaction is described to access fluorinated pyrrolo[1,2-d]benzodiazepine derivatives under mild conditions. In this process, single electron transfer (SET) between the excited state photocatalyst fac-Ir(ppy)3 and ethyl bromodifluoroacetate initiated the regioselective radical addition to a wide range of 2-(1H-pyrrol-1-yl) anilines or indol-substituted anilines, followed by another SET process and intramolecular amidation.

W

nitroaromatics and ketones in the presence of hydrogen, Pt and solid acid catalyst,9 the sequential 1,4-conjugated addition followed by 7-exo cyclization from 1,2-diaza-1,3-dienes (DDs) and 1,3-diamines,10 Cu-catalyzed intramolecular N-arylation of a quinazolinone nucleus,11 or Pd-catalyzed radical cyclization cascade reaction of 2-(1H-pyrrol-1-yl)anilines,12 etc. However, the substrates or catalysts that are not readily available or unstable and toxic phosphorus ligands were needed for these methods. Thus, the development of the convenient and applicable approach for the preparation of benzodiazepines is still a challenge. Visible-light photoredox catalysis provides a new opportunity for organic synthesis not only for its high efficiency and simple operation but also for its diversity of the radical source and the compatibility to most functional groups that typically decorate intricate molecules.13 Fluorine as one of the most important functional groups in pharmaceutical molecules is well-known.14 Thus, the design and synthesis of fluorinefunctionalized molecules are very attractive and challenging tasks for organic chemists. Herein, we are willing to present our preliminary effort on the photoredox-catalyzed radical cascade reaction of o-azacyclic anilines with fluoro-substituted acetate to synthesize fluorinated pyrrolo[1,2-d]benzodiazepine derivatives. In our initial study, 2-(1H-pyrrol-1-yl)aniline (1a) and ethyl 2-bromo-2,2-difluoroacetate (2) were chosen as model substrates (Table 1). Gratifyingly, when the reaction was conducted in CH3CN with fac-Ir(ppy)3 as a photocatalyst, K2CO3 as a base upon 5 W blue LED irradiation under an Ar atmosphere, the desired product 3a was obtained in 49% yield (entry 1). Subsequently, the structure of 3a was further confirmed by an X-ray diffraction analysis (CCDC number

ithout a doubt, heterocyclic compounds are extremely important in pharmaceutical chemistry, as well as in materials science.1 Except for the most common five- and sixmembered heterocycles, seven-membered heterocyclic scaffolds also exist in some drugs and show special biological activities, in which benzodiazepine is such a typical heterocycle.2 Benzodiazepines can act as a GABA (γ-aminobutyric acid) receptor for the treatment of neurological disorders and mental illnesses.3 Clozapine, for example, is an atypical antipsychotic drug. It has a different profile of binding to dopamine receptors compared with the typical antipsychotic drugs.4 Arginine vasopressin (AVP) antagonists, such as VPA985 and VNA-932,5 have a curative effect for the diseases associated with excess renal reabsorption of water (Figure 1). Thus, the development of convenient methods for the construction of this skeleton is desirable.

Figure 1. Examples of biologically active benzodiazepine derivatives.

Numerous strategies for the synthesis of benzodiazepines have been exploited in recent years, in which the reaction of alkynes with azides being the most frequently used.6 Other methods include a Au-catalyzed reaction of o-phenylenediamines with alkynes,7 cascade reaction through a Pictet− Spengler cyclization, aziridine ring formation, skeletal rearrangement and hydroxylation,8 cyclization from substituted © XXXX American Chemical Society

Received: April 5, 2019 Published: June 21, 2019 A

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

entry b

1 2b 3b 4b 5b 6c 7d 8 9 10 11 12 13 14 15 16 17e 18f 19g

photocatalyst fac-Ir(ppy)3 Ir(ppy)2(dtbbpy)PF6 Ru(bpy)3Cl2 eosin Y fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3

base

solvent

yield (%)

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3 K3PO4 Et3N

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DCM THF toluene DMF DCM DCM DCM DCM DCM DCM DCM

49 0 15 trace trace 0 18 72 82 32 52 0 87 31 92 42 75 93 15

Et3N Et3N Et3N

the electron-withdrawing property of the chloro group. The reactant with two halogen atoms on the benzene ring also gave a satisfying result (3n). However, a lower yield of 30% was obtained when a bromo group existed on the 6-position (3o). We were surprised to discover that a pyridine containing substrate showed high reactivity and afforded a high yield of 95% of adduct 3p. If 1-pyrrolyl was replaced by 1-imidazolyl (1q), only substituted product 3q was obtained, and no cyclized compound was found. The optimized reaction conditions were also appropriate for the indole-substituted anilines (Scheme 2). The substitution occurred at the C-2 position of the indole ring and gave the cycloamidation products (5a−5d) in moderate yields whether with electron-donating group (Me, OMe) or electron-withdrawing group (Cl) on the benzene ring. A reactant with a Me group on the C-3 position of the indole ring also gave the product 5e in 62% yield. However, like the product 3r, from the substrate 4f with an imidazole ring, the product 5f was obtained without further cycloamidation. A gram-scale experiment was carried out to show the practicality of this protocol (Scheme 3, eq 1). When 6 mmol of 1a was used, the reaction gave 4.8 mmol (1.12 g) of the desired product 3a in 80% yield. Moreover, to demonstrate the extensibility of the reaction, we treated 3a with NaH and MeI sequentially to obtain the N-methylation product 6 in 82% yield (Scheme 3, eq (2)). In order to further understand the mechanism of this transformation, we added a radical inhibitor TEMPO (2 equiv) into the reaction mixture and found that no product 3a was generated, and the adduct TEMPO−CF2CO2Et (7) could be detected by LC−MS analysis. It revealed that a radical mechanism might be involved in the reaction process (Scheme 4). Furthermore, Et3N was proved to be the most efficient base in this transformation. Our experiment showed that the UV− vis absorption spectrometry of 1a did not observably change in the presence of BrCF2CO2Et or Et3N (see Supporting Information), which indicated that the EDA (electron donor−acceptor) complex mechanism possibly did not exist in this reaction. On the basis of the above experimental results and related reports,15 we proposed a possible mechanism for this transformation (Scheme 5). Initially, the photocatalyst facIr(ppy)3 was changed into an excited state *[Ir(ppy)3] upon irradiation with 23 W CFL. Then, BrCF2CO2Et interacted with Ir*(III) via a single electron transfer (SET) process to form an ethyl difluoroacetate radical (A) and Ir(IV). The selective addition of the radical A to 1a delivered the radical intermediate B. B was oxidized via the subsequent SET process to become the carbocation C, and the photocatalyst Ir(ppy)3 was regenerated so it could be used again the next catalytic cycle. Under the action of a base, the intermediate C is deprotonated to produce D. Subsequently, the intramolecular amidation of D furnished the fluorinated pyrrolo[1,2-d]benzodiazepine derivative 3a. In conclusion, we have demonstrated a simple and efficient protocol for the synthesis of benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one derivatives or benzo[2,3][1,4]diazepino[1,7-a]indol-6(7H)-one derivatives under photoredox catalysis of fac-Ir(ppy)3. This sustainable strategy has many advantages, such as mild reaction conditions, a good functional group tolerance, and ready availability to the starting materials, and is expected to be used in the pharmaceutical industry for the synthesis of functionalized pyrrolo[1,2-d]benzodiazepines.

a

General reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), base (0.4 mmol), photocatalyst (2 mol %), and solvent (2 mL) were irradiated upon 23 W CFL under an Ar atmosphere at room temperature for 24 h. bUsing 5 W blue LEDs. cIn the dark. dUsing 5 W green LEDs. e15 h. f30 h gUnder an air atmosphere.

1902998). In the absence of the photoredox catalyst, the reaction did not occur (entry 2). When the photoredox catalyst was changed to Ir(ppy)2(dtbbpy)PF6, only 15% yield was obtained (entry 3). Other general used catalysts such as Ru(bpy)3Cl2 and eosin Y showed almost no catalytic activity (entries 4 and 5). The visible light was essential. When the reaction was performed in the dark, no product was obtained (entry 6). Several visible light sources were screened, and a 23 W compact fluorescent lamp (CFL) was found to be the most effective (entries 1, 7, and 8). Some commonly used solvents such as dichloromethane (DCM), THF, toluene, and DMF were examined. The results showed that, in DCM, the reaction gave the highest yield of 82% (entries 8−12). Varieties of bases were further tested; a 92% yield was obtained by using Et3N (entries 13−16). The appropriate reaction time was 24 h. In 15 h, a lower yield of 75% was obtained (entry 17). Extending the reaction time to 30 h did not obviously improve the yield (entry 18). Finally, a very poor yield was achieved if the reaction took place under air (entry 19). With the optimized conditions in hand, we turned our attention to determining the generality of this reaction (Scheme 1). Using ethyl 2-bromo-2,2-difluoroacetate as the reaction partner, the reactions of 2-(1H-pyrrol-1-yl) anilines substituted with different types of groups were studied. For most substrates with either electron-donating or electronwithdrawing groups on the 3-, 4-, or 5-position of the benzene ring, the reaction gave the corresponding fluorinated pyrrolo[1,2-d]benzodiazepines in good yields (3a−3l). For a 3-chlorosubstituted reactant (1m), however, only 33% was obtained (3m), which may be due to the effect of steric hindrance and B

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Scheme 1. Substrates Scope of 2-(1H-Pyrrol-1-yl)anilines 1a

a

Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Et3N (0.4 mmol), fac-Ir(ppy)3 (2 mol %), DCM (2 mL), upon irradiation with 23 W CFL under an Ar atmosphere at room temperature for 24 h. bIsolated yields based on 1.

■

(d, J = 8.6 Hz, 1H), 6.42 (t, J = 1.8 Hz, 2H), 3.64 (s, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 139.4, 129.1, 128.0, 127.6, 127.6, 121.8, 116.3, 109.4, 20.3. 4-Methoxy-2-(1H-pyrrol-1-yl)aniline (1c): 16b white solid (1.41 g, 75% yield for two steps); mp 59−61 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 6.90 (t, J = 2.0 Hz, 2H), 6.85−6.78 (m, 3H), 6.39 (t, J = 2.0 Hz, 2H), 3.79 (s, 3H), 3.44 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 152.5, 135.4, 128.2, 121.7, 117.4, 114.8, 112.5, 109.5, 55.9. 4-Chloro-2-(1H-pyrrol-1-yl)aniline (1d): 16a white solid (1.34 g, 70% yield for two steps); mp 85−87 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.20−7.16 (m, 2H), 6.87 (t, J = 2.1 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.41 (t, J = 2.1 Hz, 2H), 3.73 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 140.7, 128.4, 128.1, 127.0, 122. 6, 121.6, 117.0, 109.9. 5-Methyl-2-(1H-pyrrol-1-yl)aniline (1e): 16a white solid (1.27 g, 74% yield for two steps); mp 52−54 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.09 (d, J = 7.7 Hz, 1H), 6.86 (t, J = 2.1 Hz, 2H), 6.68−6.65 (m, 2H), 6.38 (t, J = 2.0 Hz, 2H), 3.66 (s, 2H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 141.7, 138.6, 127.0, 125.3, 121.9, 119.3, 116.7, 109.3, 21.3.

EXPERIMENTAL SECTION

General Information. All reagents and solvents were obtained from chemical suppliers and were used without further purification. The NMR spectra were recorded at 400 MHz (1H), 100 MHz (13C{1H}), and 376 MHz (19F) in CDCl3 or DMSO-d6 using TMS as an internal standard. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, dt = doublet of triplet, m = multiplet. High-resolution mass spectra (HRMS) were obtained by ESI on a TOF mass analyzer. Melting points are uncorrected. General Procedure for the Synthesis of 1 or 4. The starting materials 2-(1H-pyrrol-1-yl)anilines 1 and 2-(1H-indol-1-yl)anilines 4 were synthesized by a known method;16a 10 mmol of substituted 2nitroanilines was used. 2-(1H-pyrrol-1-yl)aniline (1a): 16a white solid (1.14 g, 72% yield for two steps); mp 94−96 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.22 (t, J = 7.9 Hz, 2H), 6.90−6.84 (m, 4H), 6.40 (s, 2H), 3.75 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 142.0, 128.6, 127.5, 127.2, 121.7, 118.5, 116.2, 109.4. 4-Methyl-2-(1H-pyrrol-1-yl)aniline (1b).16b white solid (1.24 g, 72% yield for two steps); mp 51−53 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.06−7.05 (m, 2H), 6.91 (t, J = 1.8 Hz, 2H), 6.78 C

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry Scheme 2. Substrate Scope of 2-(1H-Indol-1-yl)anilines 4a

Scheme 5. Proposed Mechanism

5-Chloro-2-(1H-pyrrol-1-yl)aniline (1g): 16a white solid (1.36 g, 71% yield for two steps); mp 87−89 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.10 (d, J = 8.2 Hz, 1H), 6.85−6.78 (m, 4H), 6.40 (t, J = 2.1 Hz, 2H), 3.81 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 143.2, 134.0, 128.2, 126.0, 121.7, 118.2, 115.7, 109.8. 5-Bromo-2-(1H-pyrrol-1-yl)aniline (1h): 16b white solid (1.65 g, 70% yield for two steps); mp 83−85 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.04−6.78 (m, 5H), 6.36 (d, J = 20.4 Hz, 2H), 3.71 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 143.3, 128.4, 126.4, 121.9, 121.6, 121.2, 118.6, 109.8. 2-(1H-Pyrrol-1-yl)-5-(trifluoromethyl)aniline (1i): 16b white solid (1.47 g, 65% yield for two steps); mp 84−86 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27 (d, J = 8.6 Hz, 1H), 7.08−7.07 (m, 2H), 6.89 (t, J = 1.8 Hz, 2H), 6.42 (t, J = 2 Hz, 2H), 3.93 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 142.2, 130.6 (q, J = 32.2 Hz), 129.9, 127.4, 123.9 (q, J = 270.6 Hz), 121.4, 115.0 (q, J = 3.8 Hz), 112.8 (q, J = 3.8 Hz), 110.1; 19F NMR (376 MHz, CDCl3) δ (ppm) −62.7. Methyl 3-Amino-4-(1H-pyrrol-1-yl)benzoate (1j): 16c white solid (1.32 g, 61% yield for two steps); mp 80−82 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.53 (d, J = 1.5 Hz, 1H), 7.48 (dd, J = 8.1, 1.7 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 2.0 Hz, 2H), 6.39 (t, J = 1.9 Hz, 2H), 3.94 (s, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 166.7, 141.5, 131.0, 129.9, 126.7, 121.3, 119.7, 117.4, 110.0, 52.3. 3-Amino-4-(1H-pyrrol-1-yl)benzonitrile (1k):16d white solid (1.34 g, 73% yield for two steps); mp 95−97 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.22 (d, J = 7.8 Hz, 1H), 7.09−7.07 (m, 2H), 6.88 (t, J = 2.2 Hz, 2H), 6.41 (t, J = 2.0 Hz, 2H), 4.02 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 142.50, 130.76, 127.54, 121.89, 121.18, 119.09, 118.77, 111.66, 110.51. 2-Methyl-6-(1H-pyrrol-1-yl)aniline (1l): 16e yellow oil (1.29 g, 75% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.13 (dd, J = 14.6, 7.6 Hz, 2H), 6.89 (t, J = 2.1 Hz, 2H), 6.79 (t, J = 7.7 Hz, 1H), 6.42 (t, J = 2.1 Hz, 2H), 3.69 (s, 2H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 140.5, 129.7, 127.4, 125.0, 123.4, 121.9, 117.7, 109.4, 17.8.

a Reaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), Et3N (0.4 mmol), fac-Ir(ppy)3 (2 mol %), DCM (2 mL), upon irradiation with 23 W CFL under an Ar atmosphere at room temperature for 24 h. bIsolated yields based on 4.

Scheme 3. Gram-Scale Reaction and Further Transformation of the Product 3a

5-Fluoro-2-(1H-pyrrol-1-yl)aniline (1f): 16a white solid (1.27 g, 72% yield for two steps); mp 73−75 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.12 (dd, J = 8.3, 5.8 Hz, 1H), 6.81 (t, J = 2.1 Hz, 2H), 6.54−6.48 (m, 2H), 6.38 (t, J = 2.1 Hz, 2H), 3.81 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ (ppm) 162.7 (d, J = 243.0 Hz), 143.8 (d, J = 11.6 Hz), 128.6 (d, J = 10.5 Hz), 123.6 (d, J = 2.5 Hz), 121.9, 109.6, 104.8 (d, J = 22.8 Hz), 102.4 (d, J = 25.9 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) −113.3.

Scheme 4. Radical Trapping Experiment

D

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry 2-Chloro-6-(1H-pyrrol-1-yl)aniline (1m)16b: white solid (1.38 g, 72% yield for two steps); mp 93−95 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.15 (t, J = 8.1 Hz, 1H), 6.91 (dd, J = 8.0, 1.1 Hz, 1H), 6.76−6.71 (m, 3H), 6.46 (t, J = 2.1 Hz, 2H), 3.70 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ (ppm) 145.5, 133.3, 129.6, 124.7, 121.7, 118.8, 114.1, 109.8. 4,5-Dichloro-2-(1H-pyrrol-1-yl)aniline (1n): 16b white solid (1.40 g, 62% yield for two steps); mp 51−53 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.26 (s, 1H), 6.91 (s, 1H), 6.82 (t, J = 2.1 Hz, 2H), 6.39 (t, J = 2.1 Hz, 2H), 3.83 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 141.6, 132.0, 128.4, 126.7, 121.5, 120.6, 116.9, 110.2. 3-Bromo-5-methyl-2-(1H-pyrrol-1-yl)aniline (1o): 16g yellow oil (1.65 g, 66% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 6.89 (s, 1H), 6.69 (t, J = 1.8 Hz, 2H), 6.57 (s, 1H), 6.40 (t, J = 1.8 Hz, 2H), 3.50 (br, 2H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 144.9, 140.5, 123.9, 123.0, 122.7, 121.7, 115.2, 109.6, 21.1. 2-(1H-Pyrrol-1-yl)pyridin-3-amine (1p): 16b white solid (1.17 g, 74% yield for two steps); mp 82−84 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (dd, J = 4.4, 1.7 Hz, 1H), 7.18 (t, J = 2.1 Hz, 2H), 7.11 (qd, J = 8.0, 3.1 Hz, 2H), 6.39 (t, J = 2.1 Hz, 2H), 3.88 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 139.6, 138.4, 136.0, 124.3, 123.0, 120.2, 110.0. 2-(1H-Imidazol-1-yl)aniline (1q): 16a white solid (1.18 g, 74% yield for two steps); mp 103−105 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.59 (s, 1H), 7.19 (t, J = 7.8 Hz, 2H), 7.09−7.05 (m, 2H), 6.82−6.74 (m, 2H), 3.89 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 142.1, 137.6, 129.8, 127.1, 123.1, 120.2, 118.3, 116.4. 2-(1H-Indol-1-yl)aniline (4a): 16a yellow oil (1.46 g, 70% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.87−7.85 (m, 1H), 7.39−7.28 (m, 6H), 6.99−6.91 (m, 2H), 6.84 (dd, J = 3.2, 0.8 Hz, 1H), 3.60 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 143.2, 136.5, 129.3, 128.8, 128.8, 128.7, 125.0, 122.4, 121.1, 120.4, 118.7, 116.4, 110.9, 103.4. 2-(1H-Indol-1-yl)-4-methylaniline (4b): 16e yellow oil (1.58 g, 71% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.79 (d, J = 6.3 Hz, 1H), 7.27−7.23 (m, 4H), 7.16 (dd, J = 7.6, 2.1 Hz, 1H), 6.78−6.74 (m, 3H), 3.55 (s, 2H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 142.9, 139.3, 136.6, 128.9, 128.6, 128.5, 122.5, 122.2, 121.0, 120.2, 119.6, 116.9, 110.8, 103.1, 21.4. 4-Chloro-2-(1H-indol-1-yl)aniline (4c): 16e yellow solid (1.64 g, 68% yield for two steps); mp 82−84 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.81−7.79 (m, 1H), 7.30−7.28 (m, 4H), 7.24 (d, J = 3.1 Hz, 2H), 6.81−6.79 (m, 2H), 3.59 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 141.9, 136.2, 129.2, 128.7, 128.5, 128.4, 125.5, 122.6, 122.6, 121.2, 120.6, 117.2, 110.7, 103.9. 2-(1H-Indol-1-yl)-4-methoxyaniline (4d): 16g yellow oil (1.48 g, 62% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.83−7.80 (m, 1H), 7.32−7.28 (m, 4H), 6.97 (dd, J = 8.7, 2.8 Hz, 1H), 6.91−6.85 (m, 2H), 6.80 (d, J = 3.1 Hz, 1H), 3.83 (s, 3H), 3.38 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 152.6, 136.8, 136.4, 128.6, 125.6, 122.4, 121.1, 120.4, 117.6, 115.7, 113.6, 110.9, 103.4, 55.9. 2-(3-Methyl-1H-indol-1-yl)aniline (4e): 16a yellow oil (1.60 g, 72% yield for two steps); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76− 7.74 (m, 1H), 7.33−7.22 (m, 5H), 7.08 (s, 1H), 6.93 (t, J = 7.5 Hz, 2H), 3.64 (s, 2H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 143.1, 136.7, 129.0, 128.9, 128.7, 126.2, 125.2, 122.3, 119.6, 119.1, 118.6, 116.3, 112.5, 110.7, 9.8. 2-(1H-Benzo[d]imidazol-1-yl)aniline (4f):16f white solid (1.36 g, 65% yield for two steps); mp 104−106 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94 (s, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.33−7.23 (m, 4H), 7.14 (d, J = 7.8 Hz, 1H), 6.91−6.83 (m, 2H), 3.82 (s, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ (ppm) 143.4, 143.3, 143.0, 133.9, 130.3, 128.2, 123.6, 122.7, 121.0, 120.4, 118.5, 116.6, 110.9. General Procedure for the Synthesis of 3 or 5. A tube (25 mL) was charged with 2-(1H-pyrrol-1-yl)anilines 1 or 2-(1H-indol-1yl)anilines 4 (0.2 mmol), fac-Ir(ppy)3 (2 mol %). The tube was evacuated and backfilled with argon 3 times, and then ethyl

bromodifluoroacetate (0.4 mmol), Et3N (0.4 mmol), and DCM (2 mL) were added. The tube was sealed and placed approximately 2 cm from a 23 W spiral CFL bulb (Foshan Electrical and Lighting Co., Ltd., 63 lm/W), and then the mixture was stirred under an Ar atmosphere for 24 h. After the reaction was finished as monitored by TLC, the crude production was diluted with water (10 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10:1) to afford the desired products 3 or 5. 7,7-Difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (3a):12 white solid (43.1 mg, 92% yield); mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.95 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.38−7.32 (m, 3H), 7.25−7.24 (m, 1H), 6.76−6.75 (m, 1H), 6.49 (t, J = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 164.0 (t, J = 34.1 Hz), 131.0, 128.1, 127.6, 126.7, 125.7 (t, J = 34.0 Hz), 123.8, 123.4, 123.1, 111.5, 110.9 (t, J = 31.0 Hz), 109.5 (t, J = 244.0 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) −93.9, −119.7. 7,7-Difluoro-2-methyl-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3b):12 white solid (41.7 mg, 84% yield); mp 216−218 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 7.61 (s, 1H), 7.50 (s, 1H), 7.22−7.20 (m, 2H), 6.71 (s, 1H), 6.50 (s, 1H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.9 (t, J = 33.1 Hz), 136.3, 130.4, 128.6, 126.5, 125.2 (t, J = 33.9 Hz), 125.2, 124.3, 123.2, 111.5, 110.5 (t, J = 2.8 Hz), 110.2 (t, J = 242.3 Hz), 20.8; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −93.7, −119.4. 7,7-Difluoro-2-methoxy-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3c): white solid (45.4 mg, 86% yield); mp 222−224 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.04 (s, 1H), 7.70 (s, 1H), 7.27−7.19 (m, 2H), 7.03−7.00 (m, 1H), 6.72 (s, 1H), 6.52− 6.51 (m, 1H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.8 (t, J = 33.0 Hz), 157.5, 131.5, 125.4, 125.3 (t, J = 33.9 Hz), 124.6, 122.0, 114.3, 111.5, 110.6, 110.2, 108.7 (t, J = 242.3 Hz), 56.2; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −93.5, −118.0; HRMS (ESI) m/z calcd for C13H11F2N2O2+ [M + H]+ 265.0783, found 265.0785. 2-Chloro-7,7-difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3d): 12 white solid (33.2 mg, 62% yield); mp 222−224 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.71 (q, J = 1.5 Hz, 1H), 7.50 (dd, J = 8.7, 2.3 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.76−6.75 (m, 1H), 6.54−6.52 (m, 1H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.8 (t, J = 33.3 Hz), 131.6, 130.3, 128.0, 128.0, 125.8, 125.2 (t, J = 33.9 Hz), 124.9, 123.8, 112.0, 111.1 (t, J = 2.9 Hz), 111.0 (t, J = 242.6 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.7, −117.7. 7,7-Difluoro-3-methyl-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3e): 12 white solid (40.7 mg, 82% yield); mp 245−247 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.16 (s, 1H), 7.58−7.54 (m, 2H), 7.17−7.14 (m, 2H), 6.70−6.69 (m, 1H), 6.49 (t, J = 3.2, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 162.1 (t, J = 33.3 Hz), 137.7, 128.6, 128.4, 127.3, 125.2, 125.1 (t, J = 34.0 Hz), 123.9, 123.3, 111.4, 110.4 (t, J = 2.8 Hz), 110.2 (t, J = 242.3 Hz), 20.8; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −93.3, −118.0. 3,7,7-Trifluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)one (3f): 12 white solid (29.2 mg, 58% yield); mp 182−184 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.65 (s, 1H), 7.47 (dd, J = 8.6, 5.2 Hz, 1H), 7.19−7.18 (m, 1H), 7.10−7.05 (m, 2H), 6.76−6.75 (m, 1H), 6.50−6.48 (t, J = 3.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 163.8 (t, J = 34.4 Hz), 160.9 (d, J = 247.2 Hz), 129.4 (d, J = 10.2 Hz), 127.5 (d, J = 3.0 Hz), 125.4 (d, J = 3.0 Hz), 125.0 (d, J = 9.3 Hz), 123.9 (t, J = 2.6 Hz), 113.9 (d, J = 22.6 Hz), 111.6, 111.0 (t, J = 3.0 Hz), 109.9 (d, J = 25.5 Hz), 109.4 (t, J = 244.3 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) −113.0. 3-Chloro-7,7-difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3g): white solid (43.4 mg, 81% yield); mp 202−204 °C; 1 H NMR (400 MHz, CDCl3) δ (ppm) 9.38 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.33−7.31 (m, 2H), 7.20−7.19 (m, 1H), 6.77−6.76 (m, 1H), 6.50 (t, J = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 163.6 (t, J = 34.4 Hz), 133.0, 129.7, 129.0, 126.9, 125.5 (t, J = E

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

259 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.20 (s, 1H), 7.56−7.53 (m, 2H), 7.16 (s, 1H), 6.68 (s, 1H), 6.45 (s, 1H), 2.36 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 162.6 (dd, J = 36.7, 30.0 Hz), 139.9, 132.5 (d, J = 1.6 Hz), 131.7, 128.6 (d, J = 1.7 Hz), 127.5 (d, J = 1.3 Hz), 126.0 (dd, J = 41.5, 28.2 Hz), 123.2, 117.6, 110.5 (dd, J = 247.3, 243.5 Hz), 110.2, 110.0 (d, J = 4.3 Hz), 20.5; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −95.9, −96.6, −118.1, −118.8; HRMS (ESI) m/z calcd for C13H10BrF2N2O+[M + H]+ 326.9939, found 326.9938. 7,7-Difluoro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)one (3p): pale yellow solid (44.7 mg, 95% yield); mp 155−157 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.45 (s, 1H), 8.40 (dd, J = 4.6, 1.3 Hz, 1H), 7.82−7.80 (m, 2H), 7.51 (dd, J = 8.0, 4.6 Hz, 1H), 6.81−6.80 (m, 1H), 6.53 (t, J = 3.3 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.6 (t, J = 33.4 Hz), 145.5, 141.4, 132.4, 124.6 (t, J = 2.4 Hz), 124.5, 124.4 (t, J = 33.7 Hz), 123.6, 111.7 (t, J = 3.0 Hz), 111.6, 109.9 (t, J = 242.2 Hz); 19F NMR (376 MHz, DMSOd6) δ (ppm) −103.7; HRMS (ESI) m/z calcd for C11H8F2N3O+ [M + H]+ 236.0630, found 236.0629. Ethyl 2-(1-(2-Aminophenyl)-1H-imidazol-5-yl)-2,2-difluoroacetate (3q): white solid (26.4 mg, 47% yield); mp 61−63 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.89 (s, 1H), 7.38−7.35 (m, 2H), 7.18 (d, J = 5.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 5.67 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 164.0 (t, J = 35.8 Hz), 146.9, 138.0, 129.7 126.8 (t, J = 5.7 Hz), 124.6 (t, J = 5.9 Hz), 122.1, 120.8, 119.1 (t, J = 26.2 Hz), 116.3, 113.9 (t, J = 248.2 Hz), 63.7, 14.2; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −99.1; HRMS (ESI) m/z calcd for C13H14F2N3O2+ [M + H]+ 282.1049, found 282.1049. 7,7-Difluoro-5H-benzo[2,3][1,4]diazepino[1,7-a]indol-6(7H)-one (5a): pale yellow solid (23.3 mg, 41% yield); mp 158−160 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.44− 7.38 (m, 4H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.8 (dd, J = 33.5, 29.4 Hz), 136.7, 132.1 (dd, J = 39.5, 25.0 Hz), 130.2 (d, J = 1.4 Hz), 129.5 (d, J = 1.8 Hz), 128.2, 128.0 (d, J = 1.3 Hz), 126.6, 125.5, 125.0, 124.0, 122.9, 112.6, 112.0, 110.3 (dd, J = 247.2, 241.2 Hz), 104.2 (dd, J = 5.0, 2.5 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −97.6, −98.3, −116.9, −117.6; HRMS (ESI) m/z calcd for C16H11F2N2O+ [M + H]+ 285.0834, found 285.0837. 7,7-Difluoro-2-methyl-5H-benzo[2,3][1,4]diazepino[1,7-a]indol6(7H)-one (5b): pale yellow solid (27.4 mg, 46% yield); mp 228−230 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.25 (s, 1H), 7.83− 7.72 (m, 3H), 7.40 (t, J = 7.6 Hz, 1H), 7.31−7.18 (m, 4H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.8 (dd, J = 33.5, 29.5 Hz), 137.9, 136.7, 132.0 (dd, J = 39.3, 25.1 Hz), 129.9, 127.9 (d, J = 1.3 Hz), 127.3, 127.1 (d, J = 1.5 Hz), 125.4, 124.8, 124.0, 122.9, 122.5, 112.0, 110.3 (t, J = 243.9 Hz), 103.9, 21.0; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −97.9, −98.6, −116.9, −117.6; HRMS (ESI) m/z calcd for C17H13F2N2O+ [M + H]+ 299.0991, found 299.0992. 2-Chloro-7,7-difluoro-5H-benzo[2,3][1,4]diazepino[1,7-a]indol6(7H)-one (5c): pale yellow solid (31.2 mg, 49% yield); mp 234−236 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.41 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.7, 2.1 Hz, 1H), 7.46−7.42 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 3.7 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.5 (dd, J = 33.5, 29.5 Hz), 136.7, 132.0 (dd, J = 39.7, 25.1 Hz), 130.6 (d, J = 1.8 Hz), 130.3, 129.4 (d, J = 1.2 Hz), 128.2, 128.0 (d, J = 1.4 Hz), 125.8, 125.5, 124.7, 123.0, 122.9, 111.9, 110.1 (dd, J = 241.3, 247.0 Hz), 104.8; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −97.4, −98.1, −117.0, −117.7; HRMS (ESI) m/z calcd for C16H10ClF2N2O+[M + H]+ 319.0444, found 319.0449. 7,7-Difluoro-2-methoxy-5H-benzo[2,3][1,4]diazepino[1,7-a]indol-6(7H)-one (5d): yellow solid (28.3 mg, 45% yield); mp 185− 187 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.15 (s, 1H), 7.79− 7.77 (m, 2H), 7.41−7.29 (m, 4H), 7.10 (s, 1H), 6.96 (d, J = 6.9 Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 163.2 (t, J = 32.3 Hz), 157.8, 136.7, 132.3 (dd, J = 38.5, 24.5 Hz), 131.1,

34.0 Hz), 124.6, 123.8 (t, J = 2.6 Hz), 122.8, 111.8, 111.3 (t, J = 3.1 Hz), 109.3 (t, J = 244.4 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) −94.2, −120.6; HRMS (ESI) m/z calcd for C12H8ClF2N2O+[M + H]+ 269.0288, found 269.0290. 3-Bromo-7,7-difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3h): 12 pale yellow solid (54.9 mg, 88% yield); mp 216− 218 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 7.66−7.62 (m, 2H), 7.56−7.54 (m, 2H), 6.76−6.75 (m, 1H), 6.53 (t, J = 3.4 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.9 (t, J = 33.5 Hz), 130.4, 130.0, 129.2, 126.1, 125.6, 125.5, 125.1 (t, J = 33.9 Hz), 119.9, 112.0, 111.1, 110.0 (t, J = 242.7 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.8, −118.3. 7,7-Difluoro-3-(trifluoromethyl)-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (3i): 12 white solid (53.8 mg, 89% yield); mp 188−190 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.90−7.70 (m, 4H), 7.78−7.56 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.9 (t, J = 33 Hz), 133.5, 130.4, 128.1 (q, J = 32.5 Hz), 125.7, 125.6 (t, J = 33.1 Hz), 125.3, 124.0 (q, J = 270.5 Hz), 122.7 (q, J = 3.5 Hz), 120.5 (q, J = 3.8 Hz), 112.2, 111.2, 110.0 (t, J = 243.0 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −61.2. Methyl 7,7-Difluoro-6-oxo-6,7-dihydro-5H-benzo[b]pyrrolo[1,2d][1,4]diazepine-3-carboxylate (3j): white solid (46.7 mg, 54% yield); mp 220−222 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.42 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.90−7.82 (m, 2H), 7.70 (s, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.57 (t, J = 3.4 Hz, 1H), 3.89 (s, 3H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 165.4, 161.9 (t, J = 33.3 Hz), 134.0, 129.2, 128.9, 127.0, 125.7, 125.4 (t, J = 33.8 Hz), 124.7, 124.3, 112.3, 111.4, 109.9 (t, J = 243.4 Hz), 53.0; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.6, −118.4; HRMS (ESI) m/z calcd for C14H11F2N2O3+[M + H]+ 293.0732, found 293.0736. 7,7-Difluoro-6-oxo-6,7-dihydro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepine-3-carbonitrile (3k): pale yellow solid (44.0 mg, 85% yield); mp 213-215 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.52 (s, 1H), 7.92−7.84 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 6.82 (s, 1H), 6.58 (s, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.8 (t, J = 33.5 Hz), 134.1, 130.2, 129.7, 127.2, 126.0, 125.5, 125.4 (t, J = 33.7 Hz), 118.1, 112.6, 111.8, 110.4, 109.8 (t, J = 242.9 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.1, −119.2; HRMS (ESI) m/z calcd for C13H8F2N3O+ [M + H]+ 260.0630, found 260.0626. 7,7-Difluoro-4-methyl-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3l): white solid (38.7 mg, 78% yield); mp 197−199 °C; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.48 (s, 1H), 7.59 (s, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.32−7.26 (m, 2H), 6.72 (s, 1H), 6.50 (t, J = 3.1 Hz, 1H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, DMSOd6) δ (ppm) 162.2 (t, J = 32.6 Hz), 132.8, 132.1, 129.6, 127.6, 126.7, 125.9 (t, J = 34.0 Hz), 125.4, 122.2, 111.5, 110.7, 110.3 (t, J = 243.2 Hz), 18.8; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −94.5, −95.2, −118.0, −118.6; HRMS (ESI) m/z calcd for C13H11F2N2O+ [M + H]+ 249.0834, found 249.0833. 4-Chloro-7,7-difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (3m): pale yellow solid (17.7 mg, 33% yield); mp 204−206 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.31 (s, 1H), 7.56− 7.54 (m, 2H), 7.46 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 6.71 (s, 1H), 6.48 (t, J = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, DMSOd6) δ (ppm) 162.5 (dd, J = 36.7, 30.0 Hz), 132.8 (d, J = 1.9 Hz), 129.4, 128.6 (d, J = 2.1 Hz), 128.4 (d, J = 1.6 Hz), 128.3, 128.1, 126.1 (dd, J = 40.7, 28.3 Hz), 122.5, 110.5, 110.4 (dd, J = 247.2, 241.1 Hz), 110.2 (d, J = 4.2 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −95.6, −96.3, −118.0, −118.7; HRMS (ESI) m/z calcd for C12H8ClF2N2O+ [M + H]+ 269.0288, found 269.0288. 2,3-Dichloro-7,7-difluoro-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (3n):12 white solid (42.3 mg, 70% yield); mp 254−256 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.39 (s, 1H), 8.06 (s, 1H), 7.71 (dd, J = 2.7, 1.8 Hz, 1H), 7.58 (s, 1H), 6.77− 6.76 (m, 1H), 6.54 (t, J = 3.4 Hz, 1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 161.7 (t, J = 33.6 Hz), 130.4, 130.0, 129.0, 128.4, 126.1, 125.7, 125.0 (t, J = 33.9 Hz), 124.4, 112.1, 111.4, 109.9 (t, J = 243.0 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.1, −118.0. 1-Bromo-7,7-difluoro-3-methyl-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one (3o): white solid (19.6 mg, 30% yield); mp 257− F

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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128.1, 124.8, 124.5, 122.6, 122.3, 122.2, 113.2, 111.5, 110.0, 109.8 (t, J = 245.7 Hz), 104.6, 55.8; 19F NMR (376 MHz, CDCl3) δ (ppm) −98.6, −99.3, −118.6, −119.3; HRMS (ESI) m/z calcd for C17H13F2N2O2+ [M + H]+ 315.0940, found 315.0940. 7,7-Difluoro-8-methyl-5H-benzo[2,3][1,4]diazepino[1,7-a]indol6(7H)-one (5e): pale yellow solid (37.0 mg, 62% yield); mp 264−266 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.25 (s, 1H), 7.83− 7.78 (m, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.46−7.41 (m, 4H), 7.30 (t, J = 7.2 Hz, 1H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 162.44 (dd, J = 33.9, 29.5 Hz), 136.0, 130.6 (d, J = 1.8 Hz), 130.0 (d, J = 2.3 Hz), 129.3, 127.9, 127.4 (dd, J = 35.4, 25.0 Hz), 126.5, 125.8, 125.2, 123.6, 122.0, 121.0, 114.3 (dd, J = 5.9, 1.7 Hz), 112.1 (dd, J = 248.7, 242.7 Hz), 111.7, 9.0 (d, J = 8.7 Hz); 19F NMR (376 MHz, DMSO-d6) δ (ppm) −92.4, −93.2, −116.9, −117.6; HRMS (ESI) m/z calcd for C17H13F2N2O+ [M + H]+ 299.0991, found 299.0994. Ethyl 2-(1-(2-Aminophenyl)-1H-benzo[d]imidazol-2-yl)-2,2-difluoroacetate (5f): pale yellow solid (27.2 mg, 41% yield); mp 80− 82 °C; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.37 (s, 1H), 7.79 (s, 1H), 7.44 (d, J = 6.4 Hz, 1H), 7.29−7.28 (m, 3H), 7.15 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.76 (s, 2H), 4.31 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 164.0 (t, J = 35.9 Hz), 148.0, 144.6, 143.6, 134.4, 127.4 (t, J = 5.5 Hz), 125.9 (t, J = 6.0 Hz), 123.6, 122.6, 120.1, 119.7, 119.0 (t, J = 26.2 Hz), 116.4, 114.0 (t, J = 247.9 Hz), 111.1, 63.7, 14.2; 19F NMR (376 MHz, DMSO-d6) δ (ppm) −99.0; HRMS (ESI) m/z calcd for C17H16F2N3O2+ [M + H]+ 332.1205, found 332.1208. General Procedure for the Synthesis of 6. 17 To a solution of 3a (0.55 mmol) in THF (2.8 mL) were added MeI (0.61 mmol) and NaH (60% dispersion in mineral oil, 0.84 mmol) under an argon atmosphere. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was poured into water (10 mL) and then the product was extracted with DCM (15 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 10:1) to afford the desired product 6. 7,7-Difluoro-5-methyl-5H-benzo[b]pyrrolo[1,2-d][1,4]diazepin6(7H)-one (6): yellow oil (111.9 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45−7.43 (m, 3H), 7.39−7.34 (m, 1H), 7.19 (dt, J = 4.5, 2.3 Hz, 1H), 6.72 (t, J = 3.5 Hz, 1H), 6.47 (t, J = 3.2 Hz, 1H), 3.51 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 162.6 (dd, J = 36.4, 29.6 Hz), 134.2 (d, J = 1.8 Hz), 132.2 (d, J = 2.5 Hz), 127.5, 127.0 (dd, J = 41.4, 26.9 Hz), 126.9, 124.0, 123.8, 122.9 (dd, J = 3.7, 1.6 Hz), 111.5 (d, J = 2.2 Hz), 110.6 (dd, J = 4.2, 1.4 Hz), 109.9 (dd, J = 248.1, 239.8 Hz), 38.0 (d, J = 1.6 Hz); 19F NMR (376 MHz, CDCl3) δ (ppm) −93.6, −94.3, −117.5, −118.2; HRMS (ESI) m/z calcd for C13H11F2N2O+ [M + H]+ 249.0834, found 249.0833.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21672104 and 21502097), the Natural Science Foundation of the Education Department of Jiangsu province (15KJB150015), and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The authors also thank Mr. Hailong Liu for the determination of HRMS.

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REFERENCES

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00937.

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Note

Copies of 1H NMR and 13C{1H} NMR for the substrates 1 and 4, 1H NMR, 13C{1H} NMR, and 19F NMR spectra for the products 3, 5, and 6, and the crystal structure of 3a (PDF) X-ray crystallographic data of 3a (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Peipei Sun: 0000-0002-1716-2343 Notes

The authors declare no competing financial interest. G

DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.joc.9b00937 J. Org. Chem. XXXX, XXX, XXX−XXX