Syntheses of Bromo-N-Heterocycles through DBH-Promoted Tandem

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Syntheses of Bromo-N-Heterocycles through DBHPromoted Tandem C-H Amination/Bromination Yan-Na Ma, Yan Gao, Yi Jing, Jiaxin Kang, Jie Zhang, and Xuenian Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01833 • Publication Date (Web): 13 Aug 2019 Downloaded from pubs.acs.org on August 13, 2019

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The Journal of Organic Chemistry

Syntheses of Bromo-N-Heterocycles through DBH-Promoted Tandem C-H Amination/Bromination Yan-Na Ma,†‡ Yan Gao,† Yi Jing,† Jiaxin Kang,† Jie Zhang,*† and Xuenian Chen*†‡ School of Chemistry and Chemical Engineering, Henan Key Laboratory of Boron Chemistry and Advanced Energy Materials, Henan Normal University, Xinxiang, Henan 453007, China. ‡ College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, China. †

ABSTRACT: Herein, we report a metal-free radical tandem C-H amination and bromination reaction with dibromohydantoin (DBH) as both the amination and bromination reagent, water as the main solvent. The reaction involves in intramolecular C-H amination and electrophilic bromination using cheap commercially available DBH. The products represent heterocyclic building blocks, readily modifiable by classical cross-coupling reactions.

INTRODUCTION N-Heterocycles are very important compounds found in pharmaceuticals, bioactive compounds, and agrochemicals. 1 Therefore, the development of novel synthetic methods for Nheterocycles and their derivatives has gained considerable attention of chemists in a wide range. Intramolecular C-H bond amination has attracted much attention as they provide a more concise and efficient pathway for the target compounds.[2] Common approaches toward C-H amination rely on the use of transition-metal catalysts and an impressive body of recent work has demonstrated the usefulness of palladium, rhodium, iridium, and other metals for the aforementioned transformation.[3] Despite the high efficiency and wide functional group tolerance, residual transition metal contamination could adversely affect the biological properties of the final products. Moreover, numerous transition metal catalysts are expensive, require harsh reaction conditions and are unstable at ambient conditions. As a consequence, the development of a transition-metal-free and environmentally benign synthetic protocol for N-heterocycles is highly desirable.[4] Hypervalent iodine reagents have been identified as a useful alternative to common transition metals.[5] Their particular appeal stems from their broad scope in general

oxidation chemistry combined with the fact that their use is not hampered by the occurrence of residual metal contamination. Consequently, hypervalent iodine-mediated CH amination has been widely explored in the synthesis of nitrogen-containing compounds.[6] In particular, Muñiz,[7] Antonchick [8] and Togo [9] have contributed a great deal for the synthesis of N-heterocycles via hypervalent iodine mediated C-N bond annulation. Very recently, Sabitha and Reddy summarized the outstanding reactions mediated by hypervalent iodine reagents in the synthesis of various Nheterocycles and highly functionalized molecules. Aromatic halides have been widely used as starting materials in transition-metal-catalyzed cross-coupling reactions, such as the Heck, Suzuki, Negishi, and Sonogashira reactions.[10] As a result, halogenated N-heterocycles would be ideal strating molecules for the synthesis of various functional N-heterocycles. In 2014, Wu’s group reported the iodine (III)mediated intramolecular C-H amination reactions with stoichiometric amounts of molecular iodine and PhI(OAc)2, affording a series of benzosultams with iodization at the 5’position in good to excellent yields (Scheme 1, eq 1).[11] Recently, Yang’s group developed a metal-free diastereoselective radical tandem oxidative C-H amination and

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iodization to synthesize atropoisomeric P-stereogenic phosphinamides with iodization at the 5’-position (Scheme 1, eq 2).[12] Very recently, our group achieved the synthesis of iodo-dibenzothiazines by one-pot N,O-transfer, C-H amination and iodization with 2-biphenyl sulfides as the substrates (Scheme 1, eq 3).[13] While, to the best of our knowledge, related

tandem C-H amination and bromination to synthesize bromoN-heterocycles virtually remained in its infancy.[14] So we became interested in devising as yet unprecedented synthesis of bromo-N-hetereocycles through intramolecular tandem C-H amination and bromination. Through our endeavor, various bromo-N-hetereocycles were obtained with dibromohydantoin (DBH) as both the amination and bromination reagent,[15] water as the major solvent. Scheme 1. Radical tandem oxidative C-H amination and iodization

conditions: 1a (0.5 mmol), [Br] (x eq) in different solvents (5 mL) at 100 C under air atmosphere for 3 hours. bisolated yields.

a o

Table 2. Substrate scope for the tandem reaction of 2biphenyl sulfamides a,b

RESULTS AND DISCUSSION We started our investigation using N-methyl-[1,1'-biphenyl]-2sulfonamide (1a) as the model substrate and NBS as both the amination and bromine reagent in CH3CN at 100 oC (Table 1, entry 1).[16] To our delight, the desired bromo-N-hetereocylce 3a was obtained in 56% yield. Then different solvents were examined with NBS as the halide promoter, the results indicated that the reaction could also proceed smoothly in CH3NO2, ethyl acetate and water (Table 1, entries 2-8). While, when toluene was used, the major product was the cyclization product 2a. Next, we screened other bromine reagents with water as the solvent and the best result was obtained when 2.0 equivalent DBH was used (entries 8-10). While, when the amount of DBH was decreased to 1.0 equivalent, the yield of 3a was 58% and no cyclization product 2a was obtained (entry 11). We think this result should attribute to that the speed of bromination is faster than the intramolecular C-H amination in water. If the amount of DBH was increased to 3.0 equivalent, the yield of 3a was not significantly improved and no dibromo-N-hetereocylce product was obtained (entry 12). Table 1. Reaction conditions screening a,b a conditions: 1 (0.5 mmol), DBH (1.0 mmol) in water (5 mL) at 100 oC under air atmosphere for 3 hours. bisolated yields.


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With this optimized reaction conditions in hand, we next explored the substrate scope (Table 2). Firstly, different Nprotecting groups were examined. The results indicated that alkyls and benzyl were suitable for this transformation (3a-3d). Substrates with an alkyl group (such as methyl, iso-propyl and tert-butyl) on the 4’ position proceeded very well and all the expected products were obtained in good yields (3e-3g). If the substituent was electron-donating (OMe-), the yield was decreased to 31% (3h). If fluorine atom was introduced to the 4’ position, the yield was increased to 96% (3i). When the substrate with an electron-withdrawing group (CF3) was subjected to the reaction, only intramolecular C-H amination product was gained in 81% yield and no bromination occurred (2j). This result may be attributed to the low reactivity of electron-withdrawing arenes in the electrophilic bromination step. Next, the substrate with a substituent at 2’ position was explored, the corresponding product was obtained in 58% yield (3k). Finally, we examined the substitution effect on the other phenyl, the results revealed that the substituents only have a very little influence on the yields, and all of the expected products were isolated in good yields (3l-3n). Next, we extended this transformation to the tandem intramolecular C-H amination and bromination of 2-biphenyl sulfoximines 4 (Table 3).[17] When the representative substrate 4a was subjected to the above reaction conditions, the dibromothiazine 5a was obtained in 85% yield with excellent diastereoselectivity. We think the formation of 5a should be Table 3. Substrate scope for the tandem reaction of 2biphenyl sulfoximines a,b

a conditions: 4 (0.5 mmol), DBH (1.5 mmol) in water (5 mL) at 100 oC under air atmosphere for 3 hours. b isolated yields.

attributed to the small steric hindrance, because there is no substituent group on the nitrogen atom. Based on this result, some representative substrates including common substitution patterns were investigated and the corresponding dibromothiazine products were obtained in moderate to good yields with excellent diastereoselectivity (5b-5d). Aminophosphine compounds with biaryl backbones as an important type of chelating bidentate ligand (MAP-type ligand) have been widely applied to many transition-metal-catalyzed reactions because of their high reactivities.[18] The dibenzophosphamides are important precursors of MAP-type ligand and noteworthy work has been made to the synthesis of this kind compounds.[19] So we finally tend our attention to the tandem C-H amination and bromination of 2-biphenyl phosphamide.[20] While, under the above reaction conditions, no product was observed. So we further screened different organic solvents with P-([1,1'-biphenyl]-2-yl)-N-methyl-Pphenylphosphinic amide (6a) as the standard substrate. To our delight, The monobromo-phosphamide 7a was obtained in 78% yield with excellent diastereoselectivity when toluene was used and the dibromo-phosphamide 8a was obtained in 68% yield with excellent diastereoselectivity when CH3CN was used. With this optimized reaction conditions in hand, we next explored the substrate scope (Table 4). Firstly, different N-protecting groups were examined. The results indicated that alkyls and benzyl were suitable for this transformation (6a-6d). When toluene was used as the solvent, the monobromophosphamide 7a-7d was obtained in moderate to good yields. While, when CH3CN was used, only 8a and 9a was obtained. Then we examined the substituents at 4’ position. When the substituent was methyl, a mixture cyclization products were obtained when toluene was used as the solvent and the dibromo-phosphamide 8e was obtained in 21% yields when CH3CN was used as the solvent. If the substituent was electron-donating methoxyl, the monobromo-phosphamide 7f was gained in 43% yield when toluene was used as the solvent. While, when CH3CN was used as the solvent, we obtained the tribromo-phosphamide 8f in 60% yield. Next, the substituent was changed to fluorine atom, and the desired monobromophosphamide 7g and dibromo-phosphamide 8g were obtained in 63% and 64% yields. If the substituent was electronwithdrawing -CF3, we obtained the cylization product 7h when toluene was used as the solvent, and the monobromophosphamide 8h when CH3CN was used as the solvent. Finally, the 4-F substituted phosphamide 6i was explored, and the corresponding monobromo-phosphamide 7i and dibromophosphamide 8i were obtained in 68% and 56% yields, respectively.

Table 4. Tandem C-H amination and bromination of 2-biphenyl phosphamide



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a condition A: 6 (0.5 mmol), DBH (1.0 mmol) in toluene (5 mL) at 100 oC under air atmosphere for 3 hours. b condition A: 6 (0.5 mmol), DBH (1.5 mmol) in CH3CN (5 mL) at 100 oC under air atmosphere for 3 hours. c 2.0 mmol DBH was used.


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Finally, the reaction mechanism was studied. When the intramolecular amination compound 2a was subjected to the reaction conditions, and the desired bromo product 3a was obtained in 86% yield (Scheme 2). Thus, we suggest that 2a was initially formed as an intermediate. If free radical scavengers such as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT) were added to the reaction mixture, no product was detected. Consequently, we propose that the reaction proceeds through a radical process. Scheme 2. Study of the mechanism

cleavage initiates a radical chain reaction comprising nitrogen and delocalized cyclohexadienyl radical stages B and C, with immediate dehydro-aromatization under DBH to generate the cyclic product 2a. 2a is an electron-rich arene and can easily undergo bromination under the reaction conditions to afford the desired product 3a. CONCLUSIONS In summary, we have developed a metal-free radical tandem C-H amination and bromination process with DBH as both the amination and bromination reagent. With this method, we achieved the synthesis of various monobromo- and dibromoN-hetereocycles in moderate to good yields and excellent selectivities. The bromination products can be further applied to many cross-coupling reactions to afford various functional N-hetereocycles.

EXPERIMENTAL SECTION

According to the present results and previous reports,[12] a possible mechanism similar to that reported in the earlier work is depicted in Scheme 3 with 1a as the representative substrate. It relies on the formation of the key intermediate A which is generated from the starting material 1a by bromination with DBH under concomitant release of hydantoin. Homolytic Scheme 3. Plausible mechanism

General. 1H, 13C, 19F and 31P NMR spectra were recorded on a Bruker advance Ⅲ400 spectrometer (400 MHz for 1H, 100 MHz for 13C, 162 MHz for 31P and 376 MHz for 19F) and Ⅲ600 spectrometer (600 MHz for 1H, 151 MHz for 13C and 243 MHz for 31P) in CDCl3, DMSO-d6 and DMF-d7. Chemical shifts (δ) were measured in ppm relative to TMS δ = 0 for 1H and to chloroform δ = 77.0 for 13C as the internal standard, to CFCl3 δ = 0 for 19F, to 85% H3PO4 δ = 0 for 31P as external standard. Data are reported as follows: Chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), Coupling constants, J, are reported in hertz. Bromine regents and solvents were commercially available and were used without further purification. Thin-layer chromatography (TLC) was performed using 60 mesh silica gel plates visualized with short-wavelength UV light (254 nm). Preparation of 2-biaryl sulfonamide substrates 1a-1n. Compounds 1a-1n were prepared by literature procedures.[11,12] Preparation of 2-biaryl sulfides substrates 4a-4d. Compounds 4a-4d were prepared according to the literature method with some modification.[21] PhI(OAc)2 (6.44 g, 20.0 mmol, 2.0 equivalent) was slowly added to the solution of [1,1'-biphenyl]-2-yl(methyl)sulfane (2.00 g, 10.0 mmol, 1.0 equivalent) and ammonium hydroxide (4.62 mL, 30 mmol, 3.0 equivalent) in MeOH (50 mL) at 0 oC. Then the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash chromatography on silica gel (eluent: petroleum ether: EtOAc = 1:1) to give substrate 4a (1.29 g, 56%). The synthesis procedure of 4b-4d was similar with 4a. Preparation of 2-biaryl phosphamide substrates 6. Compounds 6a-6i were prepared according to the literature method.[22] BuLi (18.8 mL, 30 mmol, 1.6 M in hexane, 3.0 equivalent) was added to the solution of MeNH2 (15 mL, 30 mmol, 2.0 M in THF, 3.0 equivalent) in THF (30 mL) at -78 oC under argon atmosphere. Then the reaction mixture was allowed to room temperature and stirred for 30 minutes. The ethyl [1,1'-biphenyl]-2yl(phenyl)phosphinate (3.22 g, 10 mmol, 1.0 equivalent) was dissolved into THF (20 mL) and was added to the above reaction mixture at -78 oC. After stirring 2 hours at room temperature, the reaction mixture was quenched with water and extracted with dichloromethane, concentrated and purified on a silica gel plug n



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(EA) to give the product 6a (2.76 g, 90%). The synthesis procedure of 6b-6i was similar with 6a.

123.8, 122.3, 121.3, 44.4, 23.2, 13.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14BrNO2SNa 373.9821; found 373.9817.

General procedure for the synthesis of 3a-3n. To a stirred solution of 1 (0.5 mmol, 1.0 equivalent) in water (5 mL) was added dibromohydantoin (286 mg, 1.0 mmol, 2.0 equivalent). Then the reaction mixture was heated to 100 oC (oil bath) and stirred for 3 hours. The residue was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 8:1 for 3a-3b, 3d-3e, 3h-3n; petroleum ether: EtOAc = 20:1 for 3c, 3f-3g) to give the pure product 3a-3n.

9-bromo-6-ethyl-8-isopropyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3f): white solid, mp 173-175 oC; yield: 142 mg, 75%; 1H NMR (400 MHz, CDCl3) δ: 8.16 (s, 1 H), 7.98 (dd, J = 0.8 Hz, 7.6 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.69 (dt, J = 1.2 Hz, J = 7.6 Hz, 1 H), 7.59-7.55 (m, 1 H), 7.28 (s, 1 H), 3.96 (q, J = 7.2 Hz, 2 H), 3.46-3.39 (m, 1 H), 1.32 (d, J = 6.8 Hz, 6 H), 1.56 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 149.8, 137.9, 135.2, 132.5, 131.3, 129.5, 128.6, 125.4, 125.0, 122.5, 120.8, 120.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H18BrNO2SNa 402.0134; found 402.0123.

9-bromo-6-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3a): white solid, mp 166-167 oC; yield: 132 mg, 82%; 1H NMR (400 MHz, CDCl3) δ: 8.12-8.11 (m, 1 H), 8.01 (d, J = 7.80 Hz, 1 H), 7.92 (d, J = 7.96 Hz, 1 H), 7.74-7.70 (m, 1 H), 7.63-7.58 (m, 2 H), 7.18 (d, J = 8.68 Hz, 1 H), 3.43 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 138.4, 134.2, 133.0, 132.6, 131.0, 128.9, 128.3, 125.6, 125.5, 122.5, 120.9, 117.8, 32.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H10BrNO2SNa 345.9508; found 345.9505. 9-bromo-6-ethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3b): white solid, mp 175-177 oC; yield: 152 mg, 90%; 1H NMR (400 MHz, CDCl3) δ: 8.13 (d, J = 2.08 Hz, 1 H), 7.99 (d, J = 7.76 Hz, 1 H), 7.91 (d, J = 7.96 Hz, 1 H), 7.74-7.70 (m, 1 H), 7.62-7.58 (m, 2 H), 7.27 (d, J = 8.64, 1 H), 3.95 (q, J = 7.12 Hz, 2 H), 1.16 (t, J = 7.12 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 137.4, 135.6, 133.0, 132.4, 131.2, 129.0, 128.5, 127.3, 125.6, 123.3, 122.4, 118.5, 44.2, 13.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H12BrNO2SNa 359.9664; found 359.9661. 9-bromo-6-propyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3c): white solid, mp 117-119 oC; yield: 133 mg, 76%; 1H NMR (400 MHz, CDCl3) δ: 8.11 (d, J = 2.4 Hz, 1 H), 7.98 (dd, J = 1.2 Hz, J = 8.0 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.70 (dt, J = 1.2 Hz, J = 8.0 Hz, 1 H), 7.61-7.55 (m, 2 H), 7.24 (d, J = 8.8 Hz, 1 H), 3.85 (t, J = 7.4 Hz, 2 H), 1.60-1.51 (m, 2 H), 0.76 (t, J = 7.4 Hz, 3 H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 137.3, 135.2, 132.9, 132.4, 131.0, 128.9, 128.4, 127.1, 125.6, 123.0, 122.3, 118.2, 50.0, 21.5, 10.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14BrNO2SNa 373.9821; found 373.9821. HRMS calc. for C15H14BrNO2S [M + Na]+, 373.9821; found, 373.9820. 6-benzyl-9-bromo-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3d): white solid, mp 151-152 oC; yield: 76 mg, 38%; 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 2.0 Hz, 1 H), 8.01 (dd, J = 1.2 Hz, J = 7.6 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.68 (dt, J = 1.2 Hz, J = 8.0 Hz, 1 H), 7.60 (dt, J = 0.8 Hz, J = 7.6 Hz, 1 H), 7.46 (dd. J = 2.0 Hz, 8.8 Hz, 1 H), 7.21-7.18 (m, 3 H), 7.16-7.14 (m, 2 H), 7.10 (d, J = 8.8 Hz, 1 H), 5.03 (s, 2 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 137.5, 135.3, 135.2, 132.9, 132.5, 131.2, 128.9, 128.6, 128.3, 127.8, 127.5, 127.3, 125.7, 123.7, 122.6, 118.7, 52.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H14BrNO2SNa 421.9821; found 421.9815. 9-bromo-6-ethyl-8-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3e): white solid, mp 142-143 oC; yield: 151 mg, 86%; 1H NMR (600 MHz, CDCl3) δ: 8.13 (s, 1H), 7.96 (d, J = 7.8 Hz, 1 H), 7.88(d, J = 7.8 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.25 (s, 1 H), 3.93 (q, J = 6.7 Hz, 2 H), 2.48 (s, 3 H), 1.14 (t, J = 6.9 Hz, 3 H); 13C{1H} NMR (151 MHz, CDCl3) δ: 140.3, 137.4, 135.2, 132.4, 131.2, 129.0, 128.5, 125.3, 125.0,

9-bromo-8-(tert-butyl)-6-ethyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3g): white solid, mp 168-169 oC; yield, 173 mg, 88%; 1H NMR (400 MHz, CDCl3) δ: 8.09 (s, 1 H), 7.88 (dd, J = 1.0 Hz, J = 7.8 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.60 (dt, J = 1.2 Hz, J = 7.6 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.35 (s, 1 H), 3.85 (q, J = 7.2 Hz, 2 H), 1.47 (s, 9 H), 1.06 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 150.2, 137.2, 135.3, 132.4, 132.2, 130.9, 128.6, 125.2, 124.7, 122.4, 121.6, 118.8, 44.7, 36.9, 29.4, 13.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H20BrNO2SNa 416.0290; found 416.0285. 9-bromo-6-ethyl-8-methoxy-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3h): white solid, mp 156-158 oC; yield: 57 mg, 31%; 1H NMR (400 MHz, CDCl3) δ: 8.13 (s, 1 H), 7.93 (dd, J = 0.6 Hz, 8.0 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.68-7.63 (m, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 6.86 (s, 1 H), 3.96-3.91 (m, 5 H), 1.11 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 157.0, 138.9, 134.3, 132.4, 131.3, 130.0, 127.9, 124.9, 122.3, 119.9, 108.9, 105.3, 56.5, 44.7, 13.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14BrNO3SNa 389.9770; found 389.9765. 9-bromo-6-ethyl-8-fluoro-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3i): white solid, mp 161-162 oC; yield: 170 mg, 96%; 1H NMR (600 MHz, CDCl3) δ: 8.17 (d, J = 6.6 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 6.6 Hz, 1 H), 7.71 (t, J = 6.9 H, 1 H), 7.59 (t, 6.6 Hz, 1 H), 7.15 (d, J = 9.9 Hz, 1 H), 3.98 (q, J = 7.2 Hz, 2 H), 1.23 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (151 MHz, CDCl3) δ: 159.5 (d, J = 249.8 Hz), 138.9 (d, J = 8.9 Hz), 134.8, 132.6, 130.6, 130.4, 128.7, 125.4, 122.9 (d, J = 3.5 Hz), 122.3, 108.9 (d, J = 25.4 Hz), 105.3 (d, J = 21.6 Hz), 43.5, 13.9; 19F{1H} NMR (376 MHz, CDCl3): -102.89; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H11BrFNO2SNa 377.9570; found 377.9567. 9-bromo-10-methoxy-6-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3k): white solid, mp 190-191 oC; yield: 102 mg, 58%; 1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1 H), 7.95 (dd, J = 1.2 Hz, J = 7.6 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.67 (dt, J = 1.2 Hz, J = 7.6 Hz, 1 H), 7.52 (dt, J = 0.8 Hz, J = 7.6 Hz, 1 H), 6.76 (s, 1 H), 3.97 (s, 3 H), 3.42 (s, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 157.2, 140.1, 132.9, 132.6, 131.2, 129.9, 127.8, 124.8, 122.5, 118.0, 108.0, 103.0, 56.5, 33.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H12BrNO3SNa 375.9613; found 375.9612. 9-bromo-2,6-dimethyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide (3l): white solid, mp 178-179 oC; yield: 121 mg, 72%; 1H NMR (400 MHz, CDCl3) δ: 8.08 (d, J = 2.4 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.68 (s, 1 H), 7.55 (dd, J = 2.2 Hz, J = 8.6 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 3.91 (q, J = 7.1 Hz, 1 H), 2.50 (s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ: 143.1, 137.4, 132.9, 132.7, 131.0, 129.7, 128.3, 127.3, 125.9, 123.3, 122.3, 118.3, 44.1, 21.8, 13.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H14BrNO2SNa 373.9821; found 373.9815.


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9-bromo-2-fluoro-6-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3m): white solid, mp 205-208 oC; yield: 128 mg, 75%; 1 H NMR (400 MHz, CDCl3) δ: 8.04-8.00 (m, 2 H), 7.62 (dd, J = 2.20 Hz, J = 8.60 Hz, 1 H), 7.58 (dd, J = 2.40 Hz, J = 9.60 Hz, 1 H), 7.32-7.27 (m, 1 H), 7.18 (d, J = 8.80 Hz, 1 H), 3.42 (s, 3 H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 164.9 (d, J = 252.1 Hz), 138.7, 134.0 (d, J = 10.2 Hz), 133.8, 130.6 (d, J = 2.7 Hz), 128.4, 125.5 (d, J = 9.1 Hz), 124.8, 121.1, 117.9, 116.4 (d, J = 23.2 Hz), 112.3 (d, J = 23.8 Hz), 32.7; 19F{1H} NMR (376 MHz, CDCl3): 104.29; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H9BrFNO2SNa 363.9414; found 363.9409. 9-bromo-2,4-difluoro-6-methyl-6H-dibenzo[c,e][1,2]thiazine 5,5dioxide (3n): white solid, mp 165-167 oC; yield: 149 mg, 83%; 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J = 2.16 Hz, 1 H), 7.64 (dd, J = 2.20 Hz, J = 8.68 Hz, 1 H), 7.40 (dt, J = 1.92 Hz, J = 8.92 Hz, 1 H), 7.22 (d, J = 8.68 Hz, 1 H), 7.06-7.01 (m, 1 H), 3.42 (s, 3 H); 13 C{1H} NMR (100 MHz, CDCl3) δ: 164.6 (d, J = 241.9 Hz), 158.4 (dd, J = 13.4 Hz, J = 259.5 Hz), 138.6, 135.7 (d, J = 10.2 Hz), 134.3, 128.9, 124.8, 122.2, 120.1, 118.6, 108.6 (dd, J = 3.9 Hz, J = 23.8 Hz), 105.3 (t, J = 25.3 Hz), 34.1; 19F{1H} NMR (376 MHz, CDCl3): -100.73 (d, J = 11.66 Hz), -106. 59 (d, J = 11.66 Hz); HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H8BrF2NO2SNa 381.9319; found 381.9313. General procedure for the synthesis of 5a-5d. To a stirred solution of 4 (0.5 mmol, 1.0 equivalent) in water (5 mL) was added dibromohydantoin (429 mg, 1.5 mmol, 3.0 equivalent). Then the reaction mixture was heated to 100 oC (oil bath) and stirred for 3 hours. The residue was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 2:1) to give the pure product 5a-5d. 7,9-dibromo-5-methyl-5λ4-dibenzo[c,e][1,2]thiazine 5-oxide (5a): white solid, mp 218-219 oC; yield: 164 mg, 85%; 1H NMR (400 MHz, DMF-d7) δ: 8.61 (d, J = 5.6 Hz, 1 H), 8.52 (d, J = 1.6 Hz, 1 H), 8.43 (dd, J = 0.8 Hz, J = 5.2 Hz, 1 H), 7.96-7.92 (m, 2 H), 7.86-7.83 (m, 1 H), 3.97 (s, 3 H); 13C{1H} NMR (100 MHz, DMF-d7) δ: 140.9, 135.7, 133.6, 131.5, 130.1, 126.6, 126.1, 125.2, 124.7, 121.1, 119.5, 111.9, 43.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H9Br2NOSNa 407.8664; found 407.8661. 7,9-dibromo-5-phenyldibenzo[c,e][1,2]thiazine 5-oxide (5b): white solid, mp 251-252 oC; yield: 103 mg, 46%; 1H NMR (600 MHz, CDCl3) δ: 8.12-8.10 (m, 1 H), 8.05 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.79-7.74 (m, 2 H), 7.64-7.61 (m, 1 H), 3.70-3.59 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (151 MHz, CDCl3) δ: 140.8, 136.0, 133.5, 133.4, 129.1, 125.5, 124.5, 124.1, 122.1, 119.8, 119.6, 112.0, 50.9, 8.1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H11Br2NOSNa 469.8820; found 469.8813. 7,9-dibromo-5,8-dimethyl-5λ4-dibenzo[c,e][1,2]thiazine 5-oxide (5c): white solid, mp 256-257 oC; yield: 144 mg, 72%; 1H NMR (400 MHz, DMSO-d6) δ: 8.48-8.46 (m, 2 H), 8.33 (d, J = 8.0 Hz, 1 H), 7.85 (t, J = 7.4 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H), 3.89 (s, 3 H), 2.62 (s, 3 H); 13C{1H} NMR (151 MHz, DMSO-d6) δ: 140.5, 138.6, 133.4, 130.8, 129.5, 126.4, 125.2, 124.7, 124.2, 121.5, 118.2, 114.8, 42.8, 24.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H11Br2NOSNa 421.8820; found 421.8818. 7,9-dibromo-8-fluoro-5-methyl-5λ4-dibenzo[c,e][1,2]thiazine 5oxide (5d): white solid, mp 232-233 oC; yield: 173 mg, 86%; 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (d, J = 7.6 Hz, 1 H), 8.49 (d, J = 8.4 Hz, 1 H), 8.35 (d, J = 7.6 Hz, 1 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.78 (t, J = 7.6 Hz, 1 H), 3.93 (s, 3 H); 19F{1H} NMR (176

MHz, DMSO-d6) δ: -95.18; 13C{1H} NMR (151 MHz, DMSO-d6) δ: 156.8 (d, J = 242.4Hz), 143.1 (d, J = 3.2 Hz), 134.4, 131.3, 130.4, 128.3, 125.7, 125.5, 125.3, 117.3, 106.5 (d, J = 6.0 Hz), 99.9 (d, J = 23.0 Hz), 43.8; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H8Br2FNOSNa 425.8570; found 425.8570. General procedure for the synthesis of 7a-7i. To a stirred solution of 6 (0.5 mmol, 1.0 equivalent) in toluene (5 mL) was added dibromohydantoin (286 mg, 1.0 mmol, 2.0 equivalent). Then the reaction mixture was heated to 100 oC (oil bath) and stirred for 3 hours. The residue was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 1:1) to give the pure product 7a-7i. 2-bromo-5-methyl-6-phenyl-5H-dibenzo[c,e][1,2]azaphosphinine 6-oxide (7a): white solid, mp 196-198 oC; yield: 149 mg, 78%; 1H NMR (600 MHz, CDCl3) δ: 8.18 (d, J = 2.4 Hz, 1 H), 8.03 (dd, J = 5.1 Hz, J = 8.1 Hz, 1 H), 7.70-7.63 (m, 4 H), 7.52-7.49 (m, 2 H), 7.43-7.40 (m, 3 H), 7.02 (d, J = 9.0 Hz, 1 H), 3.16 (d, J = 7.8 Hz, 3 H); 31P{1H} NMR (243 MHz, CDCl3) δ: 17.75; 13C{1H} NMR (151 MHz, CDCl3) δ: 140.12, 135.5, 132.5, 132.4 (d, J = 7.8 Hz), 132.2 (d, J = 2.0 Hz), 131.9 (d, J = 131.4 Hz), 131.8, 131.7, 131.2 (d, J = 10.5 Hz), 128.6 (d, J = 13.2 Hz), 128.1 (d, J = 13.2 Hz), 128.0, 125.5 (d, J = 124.5 Hz), 123.6 (d, J = 9.8 Hz), 116.9 (d, J = 5.1 Hz), 113.8, 31.3 (d, J = 2.6 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H16BrNOP 384.0147; found 384.0145.[12] 2-bromo-5-ethyl-6-phenyl-5H-dibenzo[c,e][1,2]azaphosphinine 6-oxide (7b): white solid, mp 151-153 oC; yield: 147 mg, 74%; 1H NMR (400 MHz, CDCl3) δ: 8.16 (d, J = 2.4 Hz, 1 H), 7.99 (dd, J = 5.2 Hz, J = 8.0 Hz, 1 H), 7.68-7.60 (m, 4 H), 7.50-7.46 (m, 2 H), 7.41-7.37 (m, 3 H), 7.05 (d, J = 8.8 Hz, 1 H), 3.90-3.79 (m, 1 H), 3.72-3.61 (m, 1 H), 1.16 (t, J = 7.0 Hz, 3 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 17.09; 13C{1H} NMR (100 MHz, CDCl3) δ: 138.4, 135.5 (d, J = 5.4 Hz), 132.4 (d, J = 131.3 Hz), 132.3, 132.3, 132.1 (d, J = 2.8 Hz), 131.8, 131.7, 130.9 (d, J = 10.5 Hz), 128.6, 128.5, 128.4, 127.9 (d, J = 13.5 Hz), 125.9 (d, J = 124.0 Hz), 124.4 (d, J = 8.2 Hz), 123.6 (d, J = 9.4 Hz), 117.6 (d, J = 5.3 Hz), 113.6, 38.4 (d, J = 3.0 Hz), 13.3 (d, J =1.9 Hz); HRMS (ESITOF) m/z: [M + H]+ calcd for C20H18BrNOP 398.0304; found 398.0301. 2-bromo-5-isopropyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (7c): yellow oil; yield: 111 mg, 54%; 1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J = 2.4 Hz, 1 H), 7.93 (dd, J = 7.6 Hz, J = 12.4 Hz, 1 H), 7.86 (dd, J = 5.0 Hz, J = 7.8 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 7.52-7.47 (m, 3 H), 7.41-7.35 (m, 2 H), 7.31-7.27 (m, 2 H), 7.23 (d, J = 8.8 Hz, 1 H), 4.66-4.53 (m, 1 H), 1.48 (d, J = 6.8 Hz, 3 H), 1.43 (d, J = 7.2 Hz, 3 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 19.89; 13C{1H} NMR (100 MHz, CDCl3) δ: 138.9, 136.2 (d, J = 6.4 Hz), 132.4, 132.3 (d, J = 131.4 Hz), 131.8, 131.7 (d, J = 2.5 Hz), 130.6, 130.5, 129.9 (d, J = 8.4 Hz), 128.9, 128.8 (d, J = 9.2 Hz), 128.4, 128.3, 128.2 (d, J = 12.5 Hz), 124.4 (d, J = 9.4 Hz), 123.3 (d, J = 5.9 Hz), 115.3, 49.9, 23.4, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20BrNOP 412.0460; found 412.0439. 5-benzyl-2-bromo-6-phenyl-5H-dibenzo[c,e][1,2]azaphosphinine 6-oxide (7d): white solid, mp 229-231 oC; yield: 126 mg, 55%; 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 2.4 Hz, 1 H), 8.04 (dd, J = 5.0 Hz, J = 8.2 Hz, 1 H), 7.80 (dd, J = 7.6 Hz, J = 13.2 Hz, 1 H), 7.72-7.64 (m, 3 H), 7.50-7.45 (m, 2 H), 7.40-7.35 (m, 2 H), 7.307.15 (m, 6 H), 6.87 (d, J = 8.8 Hz, 1 H), 5.17 (dd, J = 6.4 Hz, J = 16.8 Hz, 1 H), 4.67 (dd, J = 7.2 Hz, J = 16.8 Hz, 1 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 13C{1H} NMR (100 MHz, CDCl3) δ:



18.7; 138.7, 136.1 (d, J = 3.3 Hz), 135.7 (d, J = 5.5 Hz), 132.6, 132.3 (d, J = 2.7 Hz), 132.3, 131.5 (d, J = 10.5 Hz), 131.1 (d, J = 10.1 Hz), 128.6, 128.6, 128.5, 128.2 (d, J = 5.2 Hz), 127.2, 126.7, 124.7 (d, J = 8.2 Hz), 123.9 (d, J = 9.4 Hz), 119.1 (d, J = 5.3 Hz), 114.2, 47.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20BrNOP 460.0460; found 460.0452. 2-bromo-3-methoxy-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (7f): white solid, mp 9294 oC; yield: 89 mg, 43%; 1H NMR (400 MHz, CDCl3) δ: 8.20 (s, 1 H), 7.94 (dd, J = 5.4 Hz, J = 8.2 Hz, 1 H), 7.69-7.59 (m, 4 H), 7.50-7.48 (m, 1 H), 7.44-7.39 (m, 2 H), 7.37-7.32 (m, 1 H), 7.27 (s, 1 H), 3.96 (s, 3 H), 3.19 (d, J = 7.6 Hz, 3 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 25.88; 13C{1H} NMR (100 MHz, CDCl3) δ: 139.1, 136.0, 135.1 (d, J = 6.7 Hz), 134.6 (d, J = 2.0 Hz), 134.0 (d, J = 13.0 Hz), 132.8, 132.6 (d, J = 2.8 Hz), 130.6, 130.4 (d, J = 131.6 Hz), 130.2, 129.6 (d, J = 7.7 Hz), 129.1, 128.4, 128.4, 128.3, 128.3 (d, J = 110.7 Hz), 126.0, 125.3 (d, J = 14.5 Hz), 124.3 (d, J = 6.7 Hz), 119.1, 33.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18BrNO2P 414.0253; found 414.0238. 2-bromo-3-fluoro-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (7g): white solid, mp 192-194 oC; yield: 126 mg, 63%; 1H NMR (600 MHz, CDCl3) δ: 8.22 (d, J = 7.8 Hz, 1 H), 7.97 (dd, J = 5.4 Hz, J = 7.8 Hz, 1 H), 7.70-7.63 (m, 4 H), 7.53-7.51 (m, 1 H), 7.45-7.39 (m, 3 H), 6.92 (d, J = 10.8 Hz, 1 H), 3.14 (d, J = 7.2 Hz, 3 H); 19F{1H} NMR (376 MHz, CDCl3): -104.63; 31P{1H} NMR (162 MHz, CDCl3) δ: 17.97; 13C{1H} NMR (100 MHz, CDCl3) δ: 159.6 (d, J = 247.0 Hz), 142.3 (d, J = 10.5 Hz), 134.9 (d, J = 5.0 Hz), 132.6 (d, J = 2.0 Hz), 132.4 (d, J = 2.8 Hz), 131.7, 131.6, 131.5 (d, J = 132.0 Hz), 131.3, 131.2, 130.2, 128.8, 128.6, 127.9 (d, J = 13.4 Hz), 124.7 (d, J = 124.1 Hz), 123.4 (d, J = 9.4 Hz), 103.8 (d, J = 5.4 Hz), 103.5 (d, J = 5.2 Hz), 100.2 (d, J = 21.4 Hz), 31.5 (d, J = 2.9 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H15BrFNOP 402.0053; found 402.0051.

Page 8 of 11

General procedure for the synthesis of 8a-8i. To a stirred solution of 6 (0.5 mmol, 1.0 equivalent) in toluene (5 mL) was added dibromohydantoin (429 mg, 1.5 mmol, 3.0 equivalent). Then the reaction mixture was heated to 100 oC (oil bath) and stirred for 3 hours. The residue was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on silica gel (petroleum ether: EtOAc = 3:2) to give the pure product 8a-8i. 2,4-dibromo-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8a): white solid, mp 244-246 oC; yield: 157 mg, 68%; 1H NMR (600 MHz, CDCl3) δ: 8.20-8.16 (m, 1 H), 7.80-7.77 (m, 2 H), 7.73 (t, J = 7.8 Hz, 1 H), 7.69-7.66 (m, 1 H), 7.65-7.64 (m, 1 H), 7.55-7.52 (m, 2 H), 7.397.36 (m, 1 H), 7.28-7.25 (m, 2 H); 3.14 (d, J = 9.0 Hz, 3 H); 31 P{1H} NMR (243 MHz, CDCl3) δ: 17.75; 13C{1H} NMR (151 MHz, CDCl3) δ: 139.9, 136.6 (d, J = 7.7 Hz), 136.3, 134.5 (d, J = 11.0 Hz), 132.9 (d, J = 1.8 Hz), 132.3 (d, J = 2.9 Hz), 131.3 (d, J = 130.2 Hz), 131.2 (d, J = 6.6 Hz), 130.4 (d, J = 11.7 Hz), 129.3 (d, J = 11.7 Hz), 128.4, 128.3, 128.2, 127.1 (d, J = 112.1 Hz), 125.8 (d, J = 9.8 Hz), 123.4 (d, J = 7.4 Hz), 119.6, 34.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C19H14Br2NOPNa 483.9072; found 483.9072. 2,4-dibromo-5-ethyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8b): white solid, mp 200-202 oC; yield: 52 mg, 22%; 1H NMR (600 MHz, CDCl3) δ: 8.18 (dd, J = 7.5 Hz, J = 11.7 Hz, 1 H), 7.79-7.77 (m, 2 H), 7.73 (t, J = 7.8 Hz, 1 H), 7.68-7.65 (m, 2 H), 7.52 (dd, J = 7.5 Hz, J = 13.5 Hz, 2 H), 7.38-7.36 (m, 1 H), 7.27-7.24 (m, 2 H), 4.06-3.99 (m, 1 H), 3.88-3.80 (m, 1 H), 0.74 (d, J = 7.2 Hz, 3 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 23.43; 13C{1H} NMR (100 MHz, CDCl3) δ: 137.5, 137.0 (d, J = 7.5 Hz), 136.4, 136.2, 132.8, 132.2 (d, J = 2.9 Hz), 131.7 (d, J = 130.0 Hz), 130.4, 130.3, 130.3, 129.4 (d, J = 112. 2 Hz), 129.3, 129.2, 128.3, 128.2, 125.8 (d, J = 9.4 Hz), 123.3, 119.5, 42.3, 13.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17Br2NOP 475.9409; found 475.9401.

5-methyl-6-phenyl-3-(trifluoromethyl)-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (7h): white solid, mp 148-150 oC; yield: 134 mg, 72%; 1H NMR (600 MHz, CDCl3) δ: 8.21 (d, J = 6.4 Hz, 1 H), 8.13-8.11 (m, 1 H), 8.72-8.66 (m, 4 H), 7.54-7.52 (m, 1 H), 7.47-7.42 (m, 3 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.34 (s, 1 H), 3.23 (d, J = 7.8 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3): -62.70; 31P{1H} NMR (162 MHz, CDCl3) δ: 17.80; 13 C{1H} NMR (100 MHz, CDCl3) δ: 141.4, 135.5, 132.5 (d, J = 2.1 Hz), 132.4 (d, J = 2.9 Hz), 131.9, 131.8, 131.6 (d, J = 122.4 Hz), 131.6 (q, J = 32.2 Hz), 131.3 (d, J = 10.7 Hz), 128.8, 128.6, 128.5 (d, J = 13.3 Hz), 126.1, 125.8 (d, J = 124.2 Hz), 124.0 (d, J = 9.4 Hz), 117.5 (q, J = 3.6 Hz), 112.1-112.0 (m), 31.5 (d, J = 2.9 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H16F3NOP 374.0916; found 374.0907.

2,4-dibromo-3,5-dimethyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8e): white solid, mp 206-208 oC; yield: 50 mg, 21%; 1H NMR (400 MHz, CDCl3) δ: 8.19-8.14 (m, 1 H), 7.86 (s, 1 H), 7.80-7.77 (m, 1 H), 7.74-7.70 (m, 1 H), 7.67-7.63 (m, 1 H), 7.57-7.52 (m, 2 H), 7.39-7.35 (m, 1 H), 7.27-7.23 (m, 2 H), 3.10 (d, J = 9.6 Hz, 3 H), 2.58 (s, 3 H); 31 P{1H} NMR (162 MHz, CDCl3) δ: 25.83; 13C{1H} NMR (100 MHz, CDCl3) δ: 140.4, 139.8, 137.0 (d, J = 7.8 Hz), 132.9, 132.3 (d, J = 2.8 Hz), 131.4 (d, J = 131.1 Hz), 130.5, 130.4, 129.0 (d, J = 11.4 Hz), 128.7, 128.3, 128.2, 126.5 (d, J = 111.8 Hz), 126.4, 126.3, 125.5 (d, J = 9.7 Hz), 122.6, 34.2, 24.8; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17Br2NOP 475.9409; found 475.9403.

2-bromo-8-fluoro-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (7i): white solid, mp 174-176 oC; yield: 136 mg, 68%; 1H NMR (400 MHz, CDCl3) δ: 8.11 (d, J = 2.0 Hz), 8.05-8.01 (m, 1 H), 7.68-7.62 (m, 2 H), 7.567.49 (m, 2 H), 7.46-7.42 (m, 2 H), 7.37-7.32 (m, 2 H), 7.03 (d, J = 8.8 Hz), 3.16 (d, J = 8.0 Hz, 3 H); 19F{1H} NMR (376 MHz, CDCl3): -111.57 (d, J = 6.4 Hz); 31P{1H} NMR (162 MHz, CDCl 3) δ: 16.92 (d, J = 5.8 Hz),; 13C{1H} NMR (100 MHz, CDCl3) δ: 161.9 (dd, J = 1.9 Hz, J = 251.1 Hz), 139.7, 132.6 (d, J = 2.7 Hz), 131.8, 131.7, 131.1 (d, J = 130.4 Hz), 128.8 (d, J = 13.2 Hz), 128.1, 126.5 (d, J = 10.9 Hz), 126.4 (d, J = 11.1 Hz), 123.1 (d, J = 7.9 Hz), 120.3 (d, J = 19.6 Hz), 117.1 (dd, J = 11.0 Hz, J = 22.3 Hz), 114.1, 31.4 (d, J = 2.9 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H15BrFNOP 402.0053; found 402.0048.

1,2,4-tribromo-3-methoxy-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8f): white solid, mp 220-222 oC; yield: 171 mg, 60%; 1H NMR (400 MHz, CDCl3) δ: 8.29 (dd, J = 2.0 Hz, J = 11.6 Hz, 1 H), 7.85-7.82 (m, 2 H), 7.61 (dd, J = 5.2 Hz, J = 8.8 Hz, 1 H), 7.56-7.50 (m, 2 H), 7.42-7.38 (m,1 H), 7.30-7.25 (m,2 H), 3.88 (s, 3 H), 3.15 (d, J = 9.2 Hz, 3 H); 31P{1H} NMR (162 MHz, CDCl3) δ: 23.80; 13C{1H} NMR (151 MHz, CDCl3) δ: 155.7, 141.4, 136.0 (d, J = 1.6 Hz), 135.4 (d, J = 7.5 Hz), 133.8 (d, J = 7.2 Hz), 132.6 (d, J = 2.4 Hz), 130.6 (d, J = 132.9 Hz), 130.4, 130.3, 129.4 (d, J = 11.2 Hz), 129.3, 128.7 (d, J = 109.9 Hz), 128.4, 128.3, 127.4 (d, J = 9.9 Hz), 123.8 (d, J = 14.3 Hz), 119.2 (d, J = 6.9 Hz), 115.7, 60.7, 34.3; HRMS (ESITOF) m/z: [M + H]+ calcd for C20H16Br3NO2P 569.8463; found 569.8471.


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2,4-dibromo-3-fluoro-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8g): white solid, mp 239-240 oC; yield: 153 mg, 64%; 1H NMR (600 MHz, CDCl3) δ: 8.18 (dd, J = 7.2 Hz, J = 12.0 Hz, 1 H), 7.87 (d, J = 7.2 Hz), 7.777.73 (m, 2 H), 7.68-7.66 (m, 1 H), 7.52 (dd, J = 7.8 Hz, J = 8.8 Hz, 2 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.28-7.25 (m, 2 H), 3.18 (d, J = 9.0 Hz, 3 H); 19F{1H} NMR (376 MHz, CDCl3): -92.51; 31P{1H} NMR (162 MHz, CDCl3) δ: 25.05; 13C{1H} NMR (100 MHz, CDCl3) δ: 156.2 (d, J = 247.7 Hz), 141.9, 136.2 (d, J = 8.2 Hz), 133.0 (d, J = 2.2 Hz), 132.5 (d, J = 2.9 Hz), 131.2 (d, J = 6.9 Hz), 131.1 (d, J = 130.0 Hz), 130.3 (d, J = 11.5 Hz), 129.8 (dd, J = 4.0 Hz, J = 11.5 Hz), 129.3, 129.1 (d, J = 11.5 Hz), 128.3 (d, J = 13.6 Hz), 126.5 (d, J = 113.4 Hz), 125.7 (d, J = 9.5 Hz), 110.5 (dd, J = 7.2 Hz, J = 21.7 Hz), 106.9 (d, J = 23.1 Hz), 34.4 (d, J = 1.2 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H15Br2FNOP 479.9158; found 479.9152. 2-bromo-5-methyl-6-phenyl-3-(trifluoromethyl)-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8h): white solid, mp 193-195 oC; yield: 198 mg, 88%; 1H NMR (600 MHz, CDCl3) δ: 8.37 (s, 1 H), 8.09-8.07 (m,1 H), 7.73-7.69 (m, 2 H), 7.65 (dd, J = 7.8 Hz, 13.2 Hz, 2 H), 7.54 (t, J = 7.2 Hz, 1 H), 7.50-7.43 (m, 4 H), 3.21 (d, J = 7.8 Hz, 3 H); 19F{1H} NMR (376 MHz, CDCl3): 62.62; 31P{1H} NMR (162 MHz, CDCl3) δ: 17.65; 13C{1H} NMR (100 MHz, CDCl3) δ: 140.2, 134.1 (d, J = 5.0 Hz), 132.7 (d, J = 2.1 Hz), 132.5 (d, J = 2.8 Hz), 131.8 (d, J = 10.6 Hz), 131.6, 131.4 (d, J = 10.7 Hz), 131.3 (d, J = 132.6 Hz), 130.4 (q, J = 31.2 Hz), 129.1 (d, J = 13.2 Hz), 128.8, 128.7, 126.1 (d, J = 123.5 Hz), 125.8 (d, J = 8.4 Hz), 124.0 (d, J = 9.2 Hz), 121.3, 114.7-114.6 (m), 110.5, 31.4 (d, J = 2.9 Hz); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H15BrF3NOP 452.0021; found 452.0009. 2,4-dibromo-8-fluoro-5-methyl-6-phenyl-5Hdibenzo[c,e][1,2]azaphosphinine 6-oxide (8i): white solid, mp 231-233 oC; yield: 134 mg, 56%; 1H NMR (400 MHz, CDCl3) δ: 7.90-7.85 (m, 1 H), 7.81-7.76 (m, 1 H), 7.73 (d, J = 2.4 H, 1 H), 7.67-7.65 (m, 1 H), 7.56-7.51 (m, 2 H), 7.44-7.38 (m, 2 H), 7.317.26 (m, 2 H), 3.14 (d, J = 9.2 Hz, 3 H); 19F{1H} NMR (376 MHz, CDCl3): -109.95 (d, J = 4.5 Hz); 31P{1H} NMR (162 MHz, CDCl3) δ: 23.84 (d, J = 4.1 Hz); 13C{1H} NMR (151 MHz, CDCl3) δ: 163.2 (dd, J = 15.9 Hz, J = 255.0 Hz), 139.3, 136.3, 133.7 (d, J = 10.7 Hz), 132.8 (dd, J = 3.3 Hz, J = 7.2 Hz), 132.6 (d, J = 2.4 Hz), 130.5 (d, J = 132.7 Hz), 130.4, 130.4, 128.5, 128.4, 128.2, 123.4 (d, J = 7.1 Hz), 120.3 (d, J = 21.9 Hz), 119.8, 117.9 (dd, J = 7.1 Hz, J = 22.2 Hz), 34.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H15Br2FNOP 479.9158; found 479.9157.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, characterization data, and copies of 1 H 19 F, 31P and 13C NMR spectra (PDF)

AUTHOR INFORMATION Corresponding Author *Email: [email protected] *Email: [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

We are grateful for the financial support from the National Natural Science Foundation of China (No. 21801065, U180425, 21571052 and 21601051).

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