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DOI: 10.1055/s-0036-1590920
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N1-Arylation of 1,4-Benzodiazepine-2-ones with Diaryliodonium Salts

Raysa Khana, Robert Felixb, Paul D. Kemmittc, Simon J. Colesd, Graham J. Tizzardd, John Spencer*a
  • aDepartment of Chemistry, School of Life Sciences, University of Sussex, Falmer, BN19QJ, UK   Email: j.spencer@sussex.ac.uk
  • bTocris, Bio Techne, The Watkins Building, Atlantic Road, Bristol, BS11 9QD, UK
  • cIMED Oncology, AstraZeneca, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK
  • dUK National Crystallography Service, Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK
R.K. is funded by an EPSRC/AZ funded PhD studentship (EP/M507568/1) with additional support from AstraZeneca [14550001 (SME)] and Tocris Biosciences. The EPSRC is also thanked for funding the UK ­National Crystallography Service
Further Information

Publication History

Received: 13 July 2017

Accepted after revision: 06 September 2017

Publication Date:
25 September 2017 (eFirst)

 

Abstract

A library of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been synthesized starting with unsymmetrical diaryliodonium salts using aqueous ammonia as a base. This can also be applied to a similar 1,3,4-benzotriazepin-2-one derivative.


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Compounds containing a 1,4-benzodiazepine scaffold are often termed as ‘privileged structures’ and are of significant interest to organic and medicinal chemists.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] Many bioactive 1,4- benzodiazepines include N-arylated benzodiazepines; for example, the benzodiazepine derivative A (Figure [1]) is a bradykinin antagonist[19] and the related benzotriazepine B is an antagonist at the parathyroid hormone (PTH)-1 receptor.[20] Typically N-arylated benzodiazepines can be prepared by transition-metal- catalysed couplings, often with copper, with various arylating agents. Generally, the reaction scope is limited with these routes and often requires high temperatures and strong bases. [19] , [21] [22] [23]

Zoom Image
Figure 1 Bioactive N-arylated Benzodiazepine and Benzotriazepine

Being able to generate libraries of diverse analogues, in this case by adding N-functionality to a privileged core unit, using mild and efficient methodologies, can substantially improve SAR studies (structure–activity relationship) and optimise the drug development process potentially repurposing privileged scaffolds for new biological targets.[24] [25]

We have an active interest in benzodiazepines [26] [27] and recently reported a method to functionalise 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones via a late-stage palladacycle assisted ortho C–H activation protocol.[28] [29] Herein we present our approach to generate a series of N1-arylated 1,4-benzodiazepines using diaryliodonium salts. The latter react with nucleophiles in the absence of transition-metal catalysts and are commonly used in organic synthesis as electrophilic reagents.[30] [31] [32] [33] [34] [35]

Novak et al. recently reported a protocol for the N-arylation of pyrazoles.[36] A quick screen of conditions, adapting this protocol using diaryliodonium salts with weak bases under mild conditions, showed that it was indeed possible to perform similar arylations on the 1,4-benzodiazepine system. Upon initial screening of a number of solvents, 1,2-dichloroethane (DCE) was found to give the best results (Table [1], entry 2). Solvents such as polypropylene glycol (PEG) and acetic acid (AcOH) gave poor yields. Similar results were observed on pyrazoles by Novak et al. where aprotic solvents, immiscible in water, produced the best results.

Table 1 Optimization of N-Arylation of 1,4-Benzodiazepines – Solvent Effects

Entry

Solvent

Conversion (%)a

1

toluene

95

2

DCE

99

3

PEG

4

AcOH

5

CHCl3

85

a LC–MS conversion.

A number of bases were tested subsequently and both NH3 (25% w/w) and NaOH (sat. aq.) gave similar and the best results (Table [2], entries 1, 2).

Table 2 Optimization of N-Arylation of 1,4-Benzodiazepines – Base ­Effects

Entry

Base

Conversion (%)a

1

NaOH (sat. aq.)

99

2

NH3 (25% w/w)

99

3

K2CO3

80

4

NaH

-

a LC–MS conversion.

Zoom Image
Scheme 1 N-Arylated 1,4-Benzodiazepines

Hence, optimal conditions appeared to use NH3 (aq.), DCE at room temperature for 30 min. Next, a series of functionalized 1,4-benzodiazepines was N-arylated using (4-nitrophenyl)phenyliodonium triflate in good to excellent yields (Scheme [1]). Generally, in transition-metal-free processes unsymmetrical diaryliodonium salts give a mixture of products where both groups are transferred and the transfer of more sterically hindered and electron-withdrawing groups is preferable.[34] However, in this case (Scheme [1]) only the nitrophenyl group was transferred. We were able to N-arylate quite sterically hindered benzodiazepines such as 3e, 3f, and 3g. Of note, 3e is a key intermediate towards A. We were also pleased to be able to conduct N-arylation on a previously ortho-arylated hindered benzodiazepine, 3h, in good yield, whose structure was also confirmed by X-ray crystallography. Such molecules may be useful precursors to, e.g., α-helical mimetics in medicinal chemistry.[37] [38]

The use of other unsymmetrical diaryliodonium triflates was also explored (Table [3]), which required longer reaction time and led to both aryl groups being transferred to obtain 3il. As expected, the transfer of more sterically hindered or less electron-rich groups was preferred. Further attempts to use unsymmetrical diaryliodonium salts such as phenyl(3-methylphenyl)iodonium triflate, phenyl(4-methylphenyl)iodonium triflate, and (2-methylphenyl)(2,4,6-trimethylphenyl)iodonium triflate gave little or no products. Additionally, attempted N-arylation with symmetrical diaryliodonium triflates or tetrafluoroborates such as bis(2-fluorophenyl)iodonium tetrafluoroborate and bis(4-bromophenyl)iodonium triftlate gave, at best, traces of products.

Table 3 Further N-Arylation of 1,4-Benzodiazepinesa

Salt

Product (major)

Product (minor)

a Reaction time = 8 h.

We have briefly explored the N-arylation on a 1,3,4-benzotriazepine 6, which resulted in diarylation and yielded 7 (Scheme [2]).

Zoom Image
Scheme 2 N-Arylation on a 1,3,4-Benzotriazepine

Interestingly, the iodonium salts were observed to undergo reaction with water present in the reaction to give diarylether products. The ether product is only observed in substantial amounts when the benzodiazepine substrates react poorly with the diaryliodonium salts (Table [4]). The ether product 10 was also obtained merely by stirring the iodonium salt with water in DCE with a mild base for 20 min at room temperature with a yield of 43%. Olofsson et al. have reported the synthesis of related diarylethers by reacting diaryliodonium salts with phenols in the presence of mild bases.[39]

Table 4 Diaryl Ether Formation

Substrate

Expected product

Observed product

In summary we have presented a mild metal-free route to N-arylated benzodiazepines, three of which were structurally characterized in the solid state (3a, 3h, 3i).[40] [41]


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Acknowledgment

We thank Dr. Alaa Abdul-Sada (Sussex) and the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS measurements.

Supporting Information

  • References and Notes

  • 1 Filippakopoulos P. Qi J. Picaud S. Shen Y. Smith WB. Fedorov O. Morse EM. Keates T. Hickman TT. Felletar I. Philpott M. Munro S. McKeown MR. Wang Y. Christie AL. West N. Cameron MJ. Schwartz B. Heightman TD. La ThangueN. French CA. Wiest O. Kung AL. Knapp S. Bradner JE. Nature 2010; 468: 1067
  • 2 Field GF. Zally WJ. Sternbach LH. J. Am. Chem. Soc. 1967; 80: 332
  • 3 Ellmann JA. Acc. Chem. Res. 1996; 29: 132
  • 4 Nadin A. Sánchez LópezJ. M. Owens AP. Howells DM. Talbot AC. Harrison T. J. Org. Chem. 2003; 68: 2844
  • 5 Baud MG. Lin-Shiao E. Cardote T. Tallant C. Pschibul A. Chan KH. Zengerle M. Garcia JR. Kwan TT. Ferguson FM. Ciulli A. Science 2014; 346: 638
  • 6 Baud MG. Lin-Shiao E. Zengerle M. Tallant C. Ciulli A. J. Med. Chem. 2016; 59: 1492
  • 7 Mirguet O. Gosmini R. Toum J. Clement CA. Barnathan M. Brusq JM. Mordaunt JE. Grimes RM. Crowe M. Pineau O. Ajakane M. Daugan A. Jeffrey P. Cutler L. Haynes AC. Smithers NN. Chung CW. Bamborough P. Uings IJ. Lewis A. Witherington J. Parr N. Prinjha RK. Nicodeme E. J. Med. Chem. 2013; 56: 7501
  • 8 Liu JJ. Higgins B. Ju G. Kolinsky K. Luk KC. Packman K. Pizzolato G. Ren Y. Thakkar K. Tovar C. Zhang Z. Wovkulich PM. ACS Med. Chem. Lett. 2013; 4: 259
  • 9 Evans B. Rittle K. Bock M. DiPardo R. Freidinger R. Whitter W. Lundell G. Veber D. Anderson P. Chang R. Lotti V. Cerino D. Chen T. Kling P. Kunkel K. Springer J. Hirshfield J. J. Med. Chem. 1988; 31: 2235
  • 10 Filippakopoulos P. Picaud S. Fedorov O. Keller M. Wrobel M. Morgenstern O. Bracher F. Knapp S. Bioorg. Med. Chem. 2012; 20: 1878
  • 11 Smith SG. Sanchez R. Zhou M.-M. Chem. Biol. 2014; 573
  • 12 Filippakopoulos P. Knapp S. Nat. Rev. Drug Discovery 2014; 13: 337
  • 13 Carter MC. Alber DG. Baxter RC. Bithell SK. Budworth J. Chubb A. Cockerill GS. Dowdell VC. L. Henderson EA. Keegan SJ. Kelsey RD. Lockyer MJ. Stables JN. Wilson LJ. Powell KL. J. Med. Chem. 2006; 49: 2311
  • 14 Ghelani SM. Naliapara YT. J. Heterocycl. Chem. 2016; 53: 1795
  • 15 Abdelkafi H. Cintrat JC. Sci. Rep. 2015; 5: 12131
  • 16 Kaur N. Int. J. Pharm. Biol. Sci. 2013; 485
  • 17 Hu X. Dong Y. Liu G. Mol. Diversity 2015; 19: 695
  • 18 Spencer J. Rathnam R. Chowdhry B. Future Med. Chem. 2010; 2: 1441
  • 19 Dzladulewlcz EK. Brown MC. Dunstan AR. Lee W. Said NB. Garratt PJ. Bioorg. Med. Chem. Lett. 1999; 9: 463
  • 20 McDonald I. Austin C. Buck I. Dunstone D. Gaffen J. Griffin E. Harper E. Hull R. Kalindjian S. Linney I. Low C. Patel D. Pether M. Raynor M. Roberts S. Shaxted M. Spencer J. Steel K. Sykes D. Wright P. Xun W. J. Med. Chem. 2007; 50: 4789
  • 21 Cuny G. Bois-Choussy ML. Zhu J. J. Am. Chem. Soc. 2004; 126: 14475
  • 22 Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc. 2001; 123: 7727
  • 23 Talukdar D. Das G. Thakur S. Karak N. Thakur AJ. Catal. Commun. 2015; 59: 238
  • 24 Strittmatter SM. Nat. Med. 2014; 20: 590
  • 25 Corsello SM. Bittker JA. Liu Z. Gould J. McCarren P. Hirschman JE. Johnston SE. Vrcic A. Wong B. Khan M. Asiedu J. Narayan R. Mader CC. Subramanian A. Golub TR. Nat. Med. 2017; 23: 405
  • 26 Spencer J. Rathnam RP. Harvey AL. Clements CJ. Clark RL. Barrett MP. Wong PE. Male L. Coles SJ. Mackay SP. Bioorg. Med. Chem. 2011; 19: 1802
  • 27 Clark RL. Clements CJ. Barrett MP. Mackay SP. Rathnam RP. Owusu-Dapaah G. Spencer J. Huggan JK. Bioorg. Med. Chem. 2012; 20: 6019
  • 28 Spencer J. Chowdhry BZ. Mallet AI. Rathnam RP. Adatia T. Bashall A. Rominger F. Tetrahedron 2008; 64: 6082
  • 29 Khan R. Felix R. Kemmitt PD. Coles SJ. Day IJ. Tizzard GJ. Spencer J. Adv. Synth. Catal. 2016; 358: 98
  • 30 Merritt EA. Olofsson B. Angew. Chem. Int. Ed. 2009; 48: 9052
  • 31 Bielawski M. Aili D. Olofsson B. J. Org. Chem. 2008; 73: 4602
    • 32a Yusubov MS. Maskaev AV. Zhdankin VV. ARKIVOC 2011; 370
  • 33 Ghosh R. Olofsson B. Org. Lett. 2014; 16: 1830
  • 34 Tinnis F. Stridfeldt E. Lundberg H. Adolfsson H. Olofsson B. Org. Lett. 2015; 17: 2688
  • 35 Malmgren J. Santoro S. Jalalian N. Himo F. Olofsson B. Chem. Eur. J. 2013; 19: 10334
  • 36 Gonda Z. Novak Z. Chem. Eur. J. 2015; 21: 16801
  • 37 Lanning M. Fletcher S. Future Med. Chem. 2013; 5: 2157
  • 38 Azzarito V. Long K. Murphy NS. Wilson AJ. Nat. Chem. 2013; 5: 161
  • 39 Jalalian N. Ishikawa EE. Silva LF. Jr. Olofsson B. Org. Lett. 2011; 13: 1552
  • 40 Coles SJ. Gale PA. Chem. Sci. 2012; 3: 683
  • 41 All reactions were conducted under an inert atmosphere unless specified otherwise. All commercially purchased materials and solvents were used without further purification unless specified otherwise. NMR spectra were recorded on a Varian VNMRS 500 (1H: 500 MHz, 13C: 126 MHz) spectrometer and prepared in deuterated solvents such as CDCl3 and DMSO-d 6. 1H and 13C chemical shifts were recorded in parts per million (ppm). Multiplicity of 1H NMR peaks are indicated by s – singlet, d – doublet, dd – doublets of doublets, t – triplet, pt – pseudo triplet, q – quartet, m – multiplet, and coupling constants are given in Hertz (Hz). Electrospray ionisation–high resolution mass spectra (ESI-HRMS) were obtained using a Bruker Daltonics Apex III where Apollo ESI was used as the ESI source. The molecular ion peaks [M]+ were recorded as mass to charge m/z ratio.
  • 42 LC–MS spectra were acquired using a Shimadzu LC-MS 2020, on a Gemini 5 µm C18 110 Å column and percentage purities were run over 30 min in water/acetonitrile with 0.1% formic acid (5 min at 5%, 5–95% over 20 min, 5 min at 95%) with the UV detector at 254 nm. Purifications were performed by flash chromatography on silica gel columns or C18 columns using a Combi flash RF 75 PSI, ISCO unit.General ProcedureTo a stirred solution of the appropriate 1,4-benzodiazepine or 1,3,4-benzotriazepine (0.030–1.00 mmol, 1 equiv) and diaryliodonium salt (0.033–1.10 mmol, 1.1 equiv) in DCE (5–10 mL) was added 25% w/w NH3 solution (aq. 5–10 mL), and the reaction mixture was stirred for 30 min (unless stated otherwise). Upon completion, the reaction mixture was diluted with dichloromethane (3 × 15 mL), and the layers were separated. Combined organic layers were dried (MgSO4), concentrated under reduced pressure, and purified by column chromatography, hexane/ethyl acetate (80:20 to 30:70).1-(4-Nitrophenyl)-5-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3a)The product was obtained as white solid (0.60 mmol scale, 170 mg, 96%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2 H), 7.62 (dd, 3 J HH = 7.5, 1.5 Hz, ArH, 1 H), 7.40–7.35 (m, ArH, 3 H), 7.34–7.29 (m, ArH, 1 H), 6.82 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.70 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.83 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 2.62 (s, CH3, 3 H). 13C NMR (126 MHz, CDCl3): δ = 170.1 (C=O), 168.1 (C=N), 146.7 (ArC), 146.0 (ArC), 140.8 (ArC), 131.4 (ArC), 131.3 (ArC), 128.7 (ArC × 2), 127.8 (ArC), 125.9 (ArC), 125.1 (ArC), 124.5 (ArC × 2), 56.6 (COCH2), 25.5 (CH3). ESI-HRMS: m/z calcd for C16H13N3O3 [+H]+: 296.1030; found: 296.1033. LC–MS purity (UV) = 100%, t R = 8.10 min.1-(4-Nitrophenyl)-5-(propan-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3b)The product was obtained as a white solid (0.52 mmol scale, 166 mg, 99%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.20 (m, ArH, 2 H), 7.59 (dd, 3 JHH = 7.5, 2.0 Hz, ArH, 1 H), 7.39–7.35 (m, ArH, 3 H), 7.34–7.30 (m, ArH, 1 H), 6.83 (dd, 3 JHH = 8.0, 1.5 Hz, ArH, 1 H), 4.72 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.82 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.34–3.25 (m, 1 H), 1.35 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H), 1.11 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H). 13C NMR (126 MHz, CDCl3): δ = 176.9 (C=O), 168.7 (C=N), 146.7 (ArC), 145.9 (ArC), 141.5 (ArC), 131.6 (ArC), 130.9 (ArC), 128.3 (ArC × 2), 127.0 (ArC), 126.0 (ArC), 125.0 (ArC), 124.5 (ArC × 2), 56.5 (COCH2), 35.6 (CNCHC2H6), 22.0 (CNCHC 2H6), 19.2 (CNCHC2H6). ESI-HRMS: m/z calcd for C18H17N3O3 [+H]+: 324.1270; found: 324.1281. LC–MS purity (UV) = 96 %, t R = 18.73 min.1-(4-Nitrophenyl)-3-(propan-2-yl)-5-(propan-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3c)The product was obtained as white solid (0.25 mmol scale, 91 mg, 99%). 1H NMR (500 MHz) CDCl3: δ = 8.25–8.18 (m, ArH, 2 H), 7.61 (dd, 3 JHH = 8.0, 1.5 Hz, ArH, 1H), 7.39–7.24 (m, ArH, 4 H), 6.85 (dd, J = 8.0, 1.5 Hz, ArH, 1 H), 3.27 (hept, 3 JHH = 7.0 Hz, CNCHCH3CH3, 1 H), 3.12 (d, 3 JHH = 9.5 Hz, COCHCHC2H6, 1 H), 2.72–2.61 (m, COCHCHC2H6, 1 H), 1.33 (d, 3 JHH = 7.0 Hz, CNCHC2 H 6, 3 H), 1.07 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H), 1.05–1.02 (m, COCHCHC2 H 6, 6 H). 13C NMR (126 MHz, CDCl3): δ = 173.9 (C=O), 168.3 (C=N), 147.4 (ArC), 145.7 (ArC), 141.1 (ArC), 131.9 (ArC), 130.6 (ArC), 128.4 (ArC × 2), 126.8 (ArC), 125.7 (ArC), 125.1 (ArC), 124.4 (ArC × 2), 69.3 (COCHCHC2H6), 35.5 (CNCHCH3CH3), 22.2 (COCHCHC2H6), 21.9 (CNCHC 2H6), 20.1, (CNCHC 2H6) 19.3 (COCHCHC 2H6), 18.7 (COCHCHC 2H6). ESI-HRMS: m/z calcd for C21H23N3O3 [+H]+: 366.1812; found: 366.1816. LC–MS purity (UV) = 95%, t R = 23.47 min.1-(4-Nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3d)The product was obtained as white solid (0.60 mmol scale, 176 mg, 82%). 1H NMR (500 MHz, CDCl3): δ = 8.30–8.23 (m, ArH, 2 H), 7.77–7.71 (m, ArH, 2 H), 7.55–7.51 (m, ArH, 1 H), 7.49–7.45 (m, ArH, 3 H), 7.45–7.41 (m, ArH, 3 H), 7.29 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 6.94 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.96 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.03 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.3 (C=O), 168.3 (C=N), 146.7 (ArC), 146.0 (ArC), 142.7 (ArC), 138.4 (ArC), 131.4 (ArC), 130.8 (ArC), 130.4 (ArC), 130.3 (ArC), 129.4 (ArC × 2), 128.5 (ArC × 2), 128.4 (ArC × 2), 125.4 (ArC), 125.0 (ArC), 124.5 (ArC × 2), 57.4 (COCH2). ESI-HRMS: m/z calcd for C21H15N3O3 [+H]+: 358.1186; found: 358.1187. LC–MS purity (UV) = 95%, t R = 18.35 min.1-(4-Nitrophenyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3e)The product was obtained as white solid (0.40 mmol scale, 140 mg, 78%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2 H), 7.67 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.52–7.48 (m, 1 H), 7.47–7.43 (m, ArH, 2 H), 7.41–7.37 (m, ArH, 5 H), 7.36–7.30 (m, ArH, 3 H), 7.25–7.21 (m, ArH, 2 H), 6.90 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.01 (dd, J = 7.5, 6.0 Hz, COCHCH2, 1 H), 3.68 (dd, 2,3 JHH = 14.0, 6.0 Hz, COCHCH 2, 1 H), 3.62 (dd, 2,3 JHH = 14.0, 7.5 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 168.8 (C=O), 168.5 (C=N), 147.1 (ArC), 145.9 (ArC), 142.1 (ArC), 138.9 (ArC), 138.4 (ArC), 131.5 (ArC), 130.8 (ArC), 130.5 (ArC), 130.3 (ArC), 130.0 (ArC × 2), 129.5 (ArC × 2), 128.6 (ArC × 2), 128.5 (ArC × 2), 128.3 (ArC × 2), 126.3 (ArC), 125.3 (ArC), 125.1 (ArC), 124.5 (ArC × 2), 65.6 (COCHCH2), 37.9 (COCHCH2). ESI-HRMS: m/z calcd for C28H21N3O3 [+H]+: 448.1656; found: 448.1669. LC–MS purity (UV) = 99 %, t R = 20.81 min.7-Chloro-1-(4-nitrophenyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3f)The product was obtained as white solid (0.15 mmol scale, 54 mg, 75%). 1H NMR (500 MHz, CDCl3): δ = 8.26 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.66 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.57–7.50 (m, ArH, 1 H), 7.51–7.44 (m, ArH, 2 H), 7.42–7.36 (m, ArH, 3 H), 7.34–7.30 (m, ArH, 2 H), 7.26 (s, ArH, 3 H), 7.17 (d, J = 8.7 Hz, ArH, 1 H), 6.85 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 3.99 (dd, J = 7.5, 6.0 Hz, COCHCH2, 1 H), 3.70–3.57 (m, COCHCH 2, 2 H). 13C NMR (126 MHz, CDCl3): δ = 168.4, (C=O), 167.2 (C=N), 146.6 (ArC), 146.1 (ArC), 140.6 (ArC), 138.6 (ArC), 137.7 (ArC), 131.7 (ArC), 131.1 (ArC), 129.9 (ArC × 2), 129.8 (ArC), 129.5 (ArC × 2), 128.7 (ArC × 2), 128.6 (ArC × 2), 128.3 (ArC × 2), 126.5 (ArC), 126.4 (ArC), 126.2 (ArC), 124.6 (ArC × 2), 119.3 (ArC) 65.8 (COCHCH2), 37.9 (COCHCH2). ESI-HRMS: m/z calcd for C28H20ClN3O3 [+H]+: 482.1266; found: 482.1286. LC–MS purity (UV) = 95%, t R = 19.71 min. 1-(4-Nitrophenyl)-3-benzyl-5-(pyridine-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3g)The product was obtained as white solid (0.11 mmol scale, 38 mg, 77%). 1H NMR (500 MHz, CDCl3): δ = 8.67–8.62 (m, ArH, 1 H), 8.15 (d, 3 JHH = 8.0 Hz, ArH, 2 H), 8.18–8.12 (m, ArH, 1 H), 7.88–7.81 (m, ArH, 1 H), 7.44–7.42 (m, ArH, 2 H), 7.42–7.37 (m, ArH, 4 H), 7.35–7.26 (m, ArH, 3 H), 7.25–7.21 (m, ArH, 2 H), 6.89 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.10 (dd, 3 JHH = 8.0, 6.0 Hz, COCHCH2, 1 H), 3.70 (dd, 2,3 JHH = 14.0, 7.0 Hz, COCHCH 2, 1 H), 3.62 (dd, 2,3 JHH = 14.0, 7.5 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 168.6 (C=O), 167.6 (C=N), 155.9 (ArC), 148.7 (ArC), 147.1 (ArC), 145.9 (ArC), 141.9 (ArC), 138.9 (ArC), 136.8 (ArC), 131.4 (ArC), 130.8 (ArC), 129.9 (ArC × 2), 128.8 (ArC × 2), 128.3 (ArC × 2), 126.3 (ArC), 125.2 (ArC), 125.1 (ArC), 124.8 (ArC × 2), 124.4 (ArC × 2), 123.8 (ArC), 65.8 (COCHCH2), 37.8 (COCHCH2). ESI-HRMS: m/z calcd for C27H20N4O3 [+H]+: 449.1608; found: 449.1617. LC–MS purity (UV) = 99%, t R = 20.81 min.1-(4-Nitrophenyl)-3-benzyl-5-(2′-fluorobiphenyl-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3h)The product was obtained as white solid (0.03 mmol scale, 11 mg, 70%). 1H NMR (500 MHz, CDCl3): δ = 8.14 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.57–7.52 (m, ArH, 1 H), 7.51–7.45 (m, ArH, 1 H), 7.42 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.38 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.32–7.27 (m, ArH, 7 H), 7.26–7.19 (m, ArH, 2 H), 7.15–7.09 (m, ArH, 1 H), 7.06 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.00–6.93 (m, ArH, 3 H), 6.65 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 3.80 (dd, 3 JHH = 8.0, 5.5 Hz, COCHCH2, 1 H), 3.69 (d, 3 JHH = 8.0 Hz, COCHCH 2, 1 H), 3.66 (d, 3 JHH = 8.0 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 169.5 (C=O), 167.9 (C=N), 159.2 (d, 1 J FC = 247.5 Hz, ArC) 147.1 (ArC), 145.7 (ArC), 141.5 (ArC), 138.8 (ArC), 138.7 (ArC), 135.7 (ArC), 132.0 (d, 3 J FC = 3.5 Hz, ArC), 131.6 (ArC), 131.4 (ArC), 130.8 (ArC), 130.3 (ArC), 129.9 (ArC x 2), 129.8 (ArC), 129.5 (ArC), 129.2 (ArC), 128.9 (d, 3 J FC = 8.0 Hz, ArC), 128.5 (ArC × 2), 128.3 (ArC × 2), 128.1 (ArC), 126.3 (ArC), 125.2 (ArC), 124.8 (ArC), 124.5 (d, 4 J FC = 3.5 Hz, ArC), 124.2 (ArC x 2), 115.4 5 (d, 2 J FC = 22.0 Hz, ArC) 66.0 (COCHCH2), 37.8 (COCHCH2). ESI-HRMS: m/z calcd for C34H24N3O3 [+H]+: 542.1874; found: 542.1881. LC–MS purity (UV) = 93%, t R = 23.27 min.1-(2,4,6-Trimethylphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3i)The reaction was run for 8 h. The product was obtained as white solid (1.00 mmol scale, 181 mg, 51%). 1H NMR (500 MHz, DMSO-d 6): δ = 7.60–7.57 (m, ArH, 2 H), 7.54–7.46 (m, ArH, 4 H), 7.32 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.27–7.23 (m, ArH, 1 H), 7.10–7.07 (m, ArH, 1 H), 6.88 (s, ArH, 1 H), 6.78 (d, 3 JHH = 8.0, 1.1 Hz, ArH, 1 H), 4.70 (d, 2 JHH = 10.0 Hz, COCH 2,1 H), 4.04 (d, 2 JHH = 10.0 Hz, COCH 2, 1 H), 2.26 (s, CH3, 3 H), 2.24 (s, CH3, 3 H), 1.61 (s, CH3, 3 H). 13C NMR (126 MHz, DMSO-d 6): δ = 170.3 (C=O), 167.5 (C=N), 142.2 (ArC), 138.9 (ArC), 137.9 (ArC), 137.0 (ArC), 136.2 (ArC), 134.7 (ArC), 132.3 (ArC), 130.9 (ArC), 130.0 (ArC × 2), 129.6 (ArC × 2), 129.5 (ArC), 128.9 (ArC × 2), 128.7 (ArC), 124.4 (ArC), 122.1 (ArC), 57.3 (COCH2), 21.0 (CH3), 18.5(CH3), 17.5 (CH3). ESI-HRMS: m/z calcd for C24H22N2O [+H]+: 355.1805; found: 355.1804. LC–MS purity (UV) = 97%, t R = 21.13 min.1-(2-Bromophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3j)The reaction was run for 8 h. The product was obtained as white solid (1.00 mmol scale, 31 mg, 8%). 1H NMR (500 MHz, DMSO-d 6): δ = 7.84 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.70 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.66–7.59 (m, ArH, 4 H), 7.52–7.46 (m, ArH, 3 H), 7.41–7.37 (m, ArH, 1 H), 7.32 (dd, J = 7.8, 1.7 Hz, ArH, 1 H), 7.27 (d, 3 JHH = 7.0 Hz, ArH, 1 H), 6.92–6.83 (m, ArH, 1 H), 4.69 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.01 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.7 (C=O), 168.9 (C=N), 142.0 (ArC), 138.9 (ArC), 138.6 (ArC), 134.3 (ArC), 133.7 (ArC), 132.0 (ArC), 131.0 (ArC), 130.9 (ArC), 130.8 (ArC), 129.9 (ArC × 2), 129.8 (ArC), 129.1 (ArC), 128.8 (ArC × 2), 124.7 (ArC), 123.0 (ArC), 121.5 (ArC), 57.0 (COCH2). ESI-HRMS: m/z calcd for C21H15BrN2O [+H]+: 391.0441; found: 391.0457. LC–MS purity (UV) = 93%, t R = 15.23 min.1-(3′-Trifluoromethylphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3k)The reaction was run for 8 h. The product was obtained as white solid (0.50 mmol scale, 80 mg, 42%). 1H NMR (500 MHz, CDCl3): δ = 7.72 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.60–7.55 (m, ArH, 2 H), 7.53 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.49–7.45 (m, ArH, 2 H), 7.44–7.38 (m, ArH, 3 H), 7.25–7.20 (m, ArH, 1 H), 6.92 (d,3 JHH = 8.5 Hz, ArH, 1 H), 4.95 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.02 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.3 (C=O), 168.3 (C=N), 143.1 (ArC), 141.3 (ArC), 138.6 (ArC), 132.0 (q, 2 J FC = 29.9 Hz, ArC), 131.9 (ArC), 131.6 (ArC), 131.4 (ArC), 130.7 (ArC), 130.4 (ArC), 129.8 (ArC × 2), 129.5 (ArC), 128.5 (ArC × 2), 125.2 (q, 3 J FC = 3.5 Hz, ArC), 124.8 (ArC), 124.8 (ArC), 123.5 (q, 1 J FC = 273.0 Hz, ArC), 124.2 (q, 3 J FC = 3.5 Hz, ArC), 57.3 (COCH2). ESI-HRMS: m/z calcd for C22H15F3N2O [+H]+: 381.1209; found: 381.1208. LC–MS purity (UV) = 96%, t R = 21.35 min.1-Phenyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3l)The reaction was run for 8 h. The product was obtained as white solid (0.50 mmol scale, 14 mg, 9%). 1H NMR (500 MHz, CDCl3): δ = 7.72 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.54–7.49 (m, ArH, 1 H), 7.47 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.43–7.38 (m, ArH, 2 H), 7.37–7.30 (m, ArH, 2 H), 7.24–7.21 (m, ArH, 3 H), 7.20–7.16 (m, ArH, 1 H), 6.97 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 4.96 (d, 2 JHH = 10.5 Hz, ArH, COCH 2, 1 H), 4.01 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.7 (C=O), 168.3 (C=N), 146.5 (ArC), 143.3 (ArC), 140.7 (ArC), 138.6 (ArC), 131.3 (ArC), 130.7 (ArC), 130.3 (ArC), 129.6 (ArC × 2), 129.3 (ArC × 2), 128.4 (ArC × 2), 128.3 (ArC × 2), 127.5 (ArC), 124.7 (ArC), 124.2 (ArC), 57.2 (COCH2). ESI-HRMS: m/z calcd for C21H16N2O [+H]+: 313.1335; found: 313.1338. LC–MS purity (UV) = 90%, t R = 16.10 min.1-(4-Nitrophenyl)-3-(4-nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (7)The product was obtained as white solid (0.60 mmol scale, 2 equiv of diaryliodonium triflate, 146 mg, 51%). 1H NMR (500 MHz, CDCl3): δ = 8.34–8.22 (m, ArH, 4 H), 7.85–7.79 (m, ArH, 2 H), 7.77–7.71 (m, ArH, 2 H), 7.74–7.57 (m, ArH, 3 H), 7.59–7.50 (m, ArH, 3 H), 7.41–7.32 (m, ArH, 2 H), 7.07–7.02 (m, ArH, 1 H). 13C NMR (126 MHz, CDCl3): δ = 166.0 (C=O), 158.3 (C=N), 149.1 (ArC), 146.7 (ArC), 145.6 (ArC), 144.1 (ArC), 143.3 (ArC), 135.0 (ArC), 132.6 (ArC), 131.5 (ArC), 129.9 (ArC), 129.6 (ArC), 129.5 (ArC × 2), 128.9 (ArC × 2), 126.8 (ArC × 2), 126.3 (ArC), 125.4 (ArC) 124.5 (ArC × 2), 124.3 (ArC × 2), 121.3 (ArC × 2). ESI-HRMS: m/z calcd for C26H17N5O5 [+H]+: 480.1230; found: 480.1245. LC–MS purity (UV) = 95%, t R = 18.35 min.1,1′-Oxybis(4-nitrobenzene)To a solution of (4-nitrophenyl)phenyliodonium triflate (30 mg, 0.06 mmol) in DCE (1 mL) was added sodium hydroxide (aq., 1 mL) and stirred for 20 min at room temperature. Upon completion, the reaction was diluted with dichloromethane (5 mL × 3) and the layers were separated. Combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford the product as a white powder (7 mg, 43%). 1H NMR (500 MHz, CDCl3): δ = 8.33–8.27 (m, ArH, 4 H), 7.19–7.14 (m, ArH, 4 H).13C NMR (126 MHz, CDCl3): δ = 160.6 (ArC × 2), 144.2 (ArC × 2), 126.2 (ArC × 4), 119.3 (ArC × 4). ESI-HRMS: m/z calcd for C12H8N2O5 [+H]+: 261.0511; found: 261.0513.
  • 43 CCDC numbers 1560492–1560494 contain the supplementary crystallographic data for compounds 3a, 3h, 3i. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

  • References and Notes

  • 1 Filippakopoulos P. Qi J. Picaud S. Shen Y. Smith WB. Fedorov O. Morse EM. Keates T. Hickman TT. Felletar I. Philpott M. Munro S. McKeown MR. Wang Y. Christie AL. West N. Cameron MJ. Schwartz B. Heightman TD. La ThangueN. French CA. Wiest O. Kung AL. Knapp S. Bradner JE. Nature 2010; 468: 1067
  • 2 Field GF. Zally WJ. Sternbach LH. J. Am. Chem. Soc. 1967; 80: 332
  • 3 Ellmann JA. Acc. Chem. Res. 1996; 29: 132
  • 4 Nadin A. Sánchez LópezJ. M. Owens AP. Howells DM. Talbot AC. Harrison T. J. Org. Chem. 2003; 68: 2844
  • 5 Baud MG. Lin-Shiao E. Cardote T. Tallant C. Pschibul A. Chan KH. Zengerle M. Garcia JR. Kwan TT. Ferguson FM. Ciulli A. Science 2014; 346: 638
  • 6 Baud MG. Lin-Shiao E. Zengerle M. Tallant C. Ciulli A. J. Med. Chem. 2016; 59: 1492
  • 7 Mirguet O. Gosmini R. Toum J. Clement CA. Barnathan M. Brusq JM. Mordaunt JE. Grimes RM. Crowe M. Pineau O. Ajakane M. Daugan A. Jeffrey P. Cutler L. Haynes AC. Smithers NN. Chung CW. Bamborough P. Uings IJ. Lewis A. Witherington J. Parr N. Prinjha RK. Nicodeme E. J. Med. Chem. 2013; 56: 7501
  • 8 Liu JJ. Higgins B. Ju G. Kolinsky K. Luk KC. Packman K. Pizzolato G. Ren Y. Thakkar K. Tovar C. Zhang Z. Wovkulich PM. ACS Med. Chem. Lett. 2013; 4: 259
  • 9 Evans B. Rittle K. Bock M. DiPardo R. Freidinger R. Whitter W. Lundell G. Veber D. Anderson P. Chang R. Lotti V. Cerino D. Chen T. Kling P. Kunkel K. Springer J. Hirshfield J. J. Med. Chem. 1988; 31: 2235
  • 10 Filippakopoulos P. Picaud S. Fedorov O. Keller M. Wrobel M. Morgenstern O. Bracher F. Knapp S. Bioorg. Med. Chem. 2012; 20: 1878
  • 11 Smith SG. Sanchez R. Zhou M.-M. Chem. Biol. 2014; 573
  • 12 Filippakopoulos P. Knapp S. Nat. Rev. Drug Discovery 2014; 13: 337
  • 13 Carter MC. Alber DG. Baxter RC. Bithell SK. Budworth J. Chubb A. Cockerill GS. Dowdell VC. L. Henderson EA. Keegan SJ. Kelsey RD. Lockyer MJ. Stables JN. Wilson LJ. Powell KL. J. Med. Chem. 2006; 49: 2311
  • 14 Ghelani SM. Naliapara YT. J. Heterocycl. Chem. 2016; 53: 1795
  • 15 Abdelkafi H. Cintrat JC. Sci. Rep. 2015; 5: 12131
  • 16 Kaur N. Int. J. Pharm. Biol. Sci. 2013; 485
  • 17 Hu X. Dong Y. Liu G. Mol. Diversity 2015; 19: 695
  • 18 Spencer J. Rathnam R. Chowdhry B. Future Med. Chem. 2010; 2: 1441
  • 19 Dzladulewlcz EK. Brown MC. Dunstan AR. Lee W. Said NB. Garratt PJ. Bioorg. Med. Chem. Lett. 1999; 9: 463
  • 20 McDonald I. Austin C. Buck I. Dunstone D. Gaffen J. Griffin E. Harper E. Hull R. Kalindjian S. Linney I. Low C. Patel D. Pether M. Raynor M. Roberts S. Shaxted M. Spencer J. Steel K. Sykes D. Wright P. Xun W. J. Med. Chem. 2007; 50: 4789
  • 21 Cuny G. Bois-Choussy ML. Zhu J. J. Am. Chem. Soc. 2004; 126: 14475
  • 22 Klapars A. Antilla JC. Huang X. Buchwald SL. J. Am. Chem. Soc. 2001; 123: 7727
  • 23 Talukdar D. Das G. Thakur S. Karak N. Thakur AJ. Catal. Commun. 2015; 59: 238
  • 24 Strittmatter SM. Nat. Med. 2014; 20: 590
  • 25 Corsello SM. Bittker JA. Liu Z. Gould J. McCarren P. Hirschman JE. Johnston SE. Vrcic A. Wong B. Khan M. Asiedu J. Narayan R. Mader CC. Subramanian A. Golub TR. Nat. Med. 2017; 23: 405
  • 26 Spencer J. Rathnam RP. Harvey AL. Clements CJ. Clark RL. Barrett MP. Wong PE. Male L. Coles SJ. Mackay SP. Bioorg. Med. Chem. 2011; 19: 1802
  • 27 Clark RL. Clements CJ. Barrett MP. Mackay SP. Rathnam RP. Owusu-Dapaah G. Spencer J. Huggan JK. Bioorg. Med. Chem. 2012; 20: 6019
  • 28 Spencer J. Chowdhry BZ. Mallet AI. Rathnam RP. Adatia T. Bashall A. Rominger F. Tetrahedron 2008; 64: 6082
  • 29 Khan R. Felix R. Kemmitt PD. Coles SJ. Day IJ. Tizzard GJ. Spencer J. Adv. Synth. Catal. 2016; 358: 98
  • 30 Merritt EA. Olofsson B. Angew. Chem. Int. Ed. 2009; 48: 9052
  • 31 Bielawski M. Aili D. Olofsson B. J. Org. Chem. 2008; 73: 4602
    • 32a Yusubov MS. Maskaev AV. Zhdankin VV. ARKIVOC 2011; 370
  • 33 Ghosh R. Olofsson B. Org. Lett. 2014; 16: 1830
  • 34 Tinnis F. Stridfeldt E. Lundberg H. Adolfsson H. Olofsson B. Org. Lett. 2015; 17: 2688
  • 35 Malmgren J. Santoro S. Jalalian N. Himo F. Olofsson B. Chem. Eur. J. 2013; 19: 10334
  • 36 Gonda Z. Novak Z. Chem. Eur. J. 2015; 21: 16801
  • 37 Lanning M. Fletcher S. Future Med. Chem. 2013; 5: 2157
  • 38 Azzarito V. Long K. Murphy NS. Wilson AJ. Nat. Chem. 2013; 5: 161
  • 39 Jalalian N. Ishikawa EE. Silva LF. Jr. Olofsson B. Org. Lett. 2011; 13: 1552
  • 40 Coles SJ. Gale PA. Chem. Sci. 2012; 3: 683
  • 41 All reactions were conducted under an inert atmosphere unless specified otherwise. All commercially purchased materials and solvents were used without further purification unless specified otherwise. NMR spectra were recorded on a Varian VNMRS 500 (1H: 500 MHz, 13C: 126 MHz) spectrometer and prepared in deuterated solvents such as CDCl3 and DMSO-d 6. 1H and 13C chemical shifts were recorded in parts per million (ppm). Multiplicity of 1H NMR peaks are indicated by s – singlet, d – doublet, dd – doublets of doublets, t – triplet, pt – pseudo triplet, q – quartet, m – multiplet, and coupling constants are given in Hertz (Hz). Electrospray ionisation–high resolution mass spectra (ESI-HRMS) were obtained using a Bruker Daltonics Apex III where Apollo ESI was used as the ESI source. The molecular ion peaks [M]+ were recorded as mass to charge m/z ratio.
  • 42 LC–MS spectra were acquired using a Shimadzu LC-MS 2020, on a Gemini 5 µm C18 110 Å column and percentage purities were run over 30 min in water/acetonitrile with 0.1% formic acid (5 min at 5%, 5–95% over 20 min, 5 min at 95%) with the UV detector at 254 nm. Purifications were performed by flash chromatography on silica gel columns or C18 columns using a Combi flash RF 75 PSI, ISCO unit.General ProcedureTo a stirred solution of the appropriate 1,4-benzodiazepine or 1,3,4-benzotriazepine (0.030–1.00 mmol, 1 equiv) and diaryliodonium salt (0.033–1.10 mmol, 1.1 equiv) in DCE (5–10 mL) was added 25% w/w NH3 solution (aq. 5–10 mL), and the reaction mixture was stirred for 30 min (unless stated otherwise). Upon completion, the reaction mixture was diluted with dichloromethane (3 × 15 mL), and the layers were separated. Combined organic layers were dried (MgSO4), concentrated under reduced pressure, and purified by column chromatography, hexane/ethyl acetate (80:20 to 30:70).1-(4-Nitrophenyl)-5-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3a)The product was obtained as white solid (0.60 mmol scale, 170 mg, 96%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2 H), 7.62 (dd, 3 J HH = 7.5, 1.5 Hz, ArH, 1 H), 7.40–7.35 (m, ArH, 3 H), 7.34–7.29 (m, ArH, 1 H), 6.82 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.70 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.83 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 2.62 (s, CH3, 3 H). 13C NMR (126 MHz, CDCl3): δ = 170.1 (C=O), 168.1 (C=N), 146.7 (ArC), 146.0 (ArC), 140.8 (ArC), 131.4 (ArC), 131.3 (ArC), 128.7 (ArC × 2), 127.8 (ArC), 125.9 (ArC), 125.1 (ArC), 124.5 (ArC × 2), 56.6 (COCH2), 25.5 (CH3). ESI-HRMS: m/z calcd for C16H13N3O3 [+H]+: 296.1030; found: 296.1033. LC–MS purity (UV) = 100%, t R = 8.10 min.1-(4-Nitrophenyl)-5-(propan-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3b)The product was obtained as a white solid (0.52 mmol scale, 166 mg, 99%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.20 (m, ArH, 2 H), 7.59 (dd, 3 JHH = 7.5, 2.0 Hz, ArH, 1 H), 7.39–7.35 (m, ArH, 3 H), 7.34–7.30 (m, ArH, 1 H), 6.83 (dd, 3 JHH = 8.0, 1.5 Hz, ArH, 1 H), 4.72 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.82 (d, 2 JHH = 10.5 Hz, COCH2, 1 H), 3.34–3.25 (m, 1 H), 1.35 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H), 1.11 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H). 13C NMR (126 MHz, CDCl3): δ = 176.9 (C=O), 168.7 (C=N), 146.7 (ArC), 145.9 (ArC), 141.5 (ArC), 131.6 (ArC), 130.9 (ArC), 128.3 (ArC × 2), 127.0 (ArC), 126.0 (ArC), 125.0 (ArC), 124.5 (ArC × 2), 56.5 (COCH2), 35.6 (CNCHC2H6), 22.0 (CNCHC 2H6), 19.2 (CNCHC2H6). ESI-HRMS: m/z calcd for C18H17N3O3 [+H]+: 324.1270; found: 324.1281. LC–MS purity (UV) = 96 %, t R = 18.73 min.1-(4-Nitrophenyl)-3-(propan-2-yl)-5-(propan-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3c)The product was obtained as white solid (0.25 mmol scale, 91 mg, 99%). 1H NMR (500 MHz) CDCl3: δ = 8.25–8.18 (m, ArH, 2 H), 7.61 (dd, 3 JHH = 8.0, 1.5 Hz, ArH, 1H), 7.39–7.24 (m, ArH, 4 H), 6.85 (dd, J = 8.0, 1.5 Hz, ArH, 1 H), 3.27 (hept, 3 JHH = 7.0 Hz, CNCHCH3CH3, 1 H), 3.12 (d, 3 JHH = 9.5 Hz, COCHCHC2H6, 1 H), 2.72–2.61 (m, COCHCHC2H6, 1 H), 1.33 (d, 3 JHH = 7.0 Hz, CNCHC2 H 6, 3 H), 1.07 (d, 3 JHH = 7.0 Hz, CNCHC2CH 6, 3 H), 1.05–1.02 (m, COCHCHC2 H 6, 6 H). 13C NMR (126 MHz, CDCl3): δ = 173.9 (C=O), 168.3 (C=N), 147.4 (ArC), 145.7 (ArC), 141.1 (ArC), 131.9 (ArC), 130.6 (ArC), 128.4 (ArC × 2), 126.8 (ArC), 125.7 (ArC), 125.1 (ArC), 124.4 (ArC × 2), 69.3 (COCHCHC2H6), 35.5 (CNCHCH3CH3), 22.2 (COCHCHC2H6), 21.9 (CNCHC 2H6), 20.1, (CNCHC 2H6) 19.3 (COCHCHC 2H6), 18.7 (COCHCHC 2H6). ESI-HRMS: m/z calcd for C21H23N3O3 [+H]+: 366.1812; found: 366.1816. LC–MS purity (UV) = 95%, t R = 23.47 min.1-(4-Nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3d)The product was obtained as white solid (0.60 mmol scale, 176 mg, 82%). 1H NMR (500 MHz, CDCl3): δ = 8.30–8.23 (m, ArH, 2 H), 7.77–7.71 (m, ArH, 2 H), 7.55–7.51 (m, ArH, 1 H), 7.49–7.45 (m, ArH, 3 H), 7.45–7.41 (m, ArH, 3 H), 7.29 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 6.94 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.96 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.03 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.3 (C=O), 168.3 (C=N), 146.7 (ArC), 146.0 (ArC), 142.7 (ArC), 138.4 (ArC), 131.4 (ArC), 130.8 (ArC), 130.4 (ArC), 130.3 (ArC), 129.4 (ArC × 2), 128.5 (ArC × 2), 128.4 (ArC × 2), 125.4 (ArC), 125.0 (ArC), 124.5 (ArC × 2), 57.4 (COCH2). ESI-HRMS: m/z calcd for C21H15N3O3 [+H]+: 358.1186; found: 358.1187. LC–MS purity (UV) = 95%, t R = 18.35 min.1-(4-Nitrophenyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3e)The product was obtained as white solid (0.40 mmol scale, 140 mg, 78%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2 H), 7.67 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.52–7.48 (m, 1 H), 7.47–7.43 (m, ArH, 2 H), 7.41–7.37 (m, ArH, 5 H), 7.36–7.30 (m, ArH, 3 H), 7.25–7.21 (m, ArH, 2 H), 6.90 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.01 (dd, J = 7.5, 6.0 Hz, COCHCH2, 1 H), 3.68 (dd, 2,3 JHH = 14.0, 6.0 Hz, COCHCH 2, 1 H), 3.62 (dd, 2,3 JHH = 14.0, 7.5 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 168.8 (C=O), 168.5 (C=N), 147.1 (ArC), 145.9 (ArC), 142.1 (ArC), 138.9 (ArC), 138.4 (ArC), 131.5 (ArC), 130.8 (ArC), 130.5 (ArC), 130.3 (ArC), 130.0 (ArC × 2), 129.5 (ArC × 2), 128.6 (ArC × 2), 128.5 (ArC × 2), 128.3 (ArC × 2), 126.3 (ArC), 125.3 (ArC), 125.1 (ArC), 124.5 (ArC × 2), 65.6 (COCHCH2), 37.9 (COCHCH2). ESI-HRMS: m/z calcd for C28H21N3O3 [+H]+: 448.1656; found: 448.1669. LC–MS purity (UV) = 99 %, t R = 20.81 min.7-Chloro-1-(4-nitrophenyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3f)The product was obtained as white solid (0.15 mmol scale, 54 mg, 75%). 1H NMR (500 MHz, CDCl3): δ = 8.26 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.66 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.57–7.50 (m, ArH, 1 H), 7.51–7.44 (m, ArH, 2 H), 7.42–7.36 (m, ArH, 3 H), 7.34–7.30 (m, ArH, 2 H), 7.26 (s, ArH, 3 H), 7.17 (d, J = 8.7 Hz, ArH, 1 H), 6.85 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 3.99 (dd, J = 7.5, 6.0 Hz, COCHCH2, 1 H), 3.70–3.57 (m, COCHCH 2, 2 H). 13C NMR (126 MHz, CDCl3): δ = 168.4, (C=O), 167.2 (C=N), 146.6 (ArC), 146.1 (ArC), 140.6 (ArC), 138.6 (ArC), 137.7 (ArC), 131.7 (ArC), 131.1 (ArC), 129.9 (ArC × 2), 129.8 (ArC), 129.5 (ArC × 2), 128.7 (ArC × 2), 128.6 (ArC × 2), 128.3 (ArC × 2), 126.5 (ArC), 126.4 (ArC), 126.2 (ArC), 124.6 (ArC × 2), 119.3 (ArC) 65.8 (COCHCH2), 37.9 (COCHCH2). ESI-HRMS: m/z calcd for C28H20ClN3O3 [+H]+: 482.1266; found: 482.1286. LC–MS purity (UV) = 95%, t R = 19.71 min. 1-(4-Nitrophenyl)-3-benzyl-5-(pyridine-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3g)The product was obtained as white solid (0.11 mmol scale, 38 mg, 77%). 1H NMR (500 MHz, CDCl3): δ = 8.67–8.62 (m, ArH, 1 H), 8.15 (d, 3 JHH = 8.0 Hz, ArH, 2 H), 8.18–8.12 (m, ArH, 1 H), 7.88–7.81 (m, ArH, 1 H), 7.44–7.42 (m, ArH, 2 H), 7.42–7.37 (m, ArH, 4 H), 7.35–7.26 (m, ArH, 3 H), 7.25–7.21 (m, ArH, 2 H), 6.89 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 4.10 (dd, 3 JHH = 8.0, 6.0 Hz, COCHCH2, 1 H), 3.70 (dd, 2,3 JHH = 14.0, 7.0 Hz, COCHCH 2, 1 H), 3.62 (dd, 2,3 JHH = 14.0, 7.5 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 168.6 (C=O), 167.6 (C=N), 155.9 (ArC), 148.7 (ArC), 147.1 (ArC), 145.9 (ArC), 141.9 (ArC), 138.9 (ArC), 136.8 (ArC), 131.4 (ArC), 130.8 (ArC), 129.9 (ArC × 2), 128.8 (ArC × 2), 128.3 (ArC × 2), 126.3 (ArC), 125.2 (ArC), 125.1 (ArC), 124.8 (ArC × 2), 124.4 (ArC × 2), 123.8 (ArC), 65.8 (COCHCH2), 37.8 (COCHCH2). ESI-HRMS: m/z calcd for C27H20N4O3 [+H]+: 449.1608; found: 449.1617. LC–MS purity (UV) = 99%, t R = 20.81 min.1-(4-Nitrophenyl)-3-benzyl-5-(2′-fluorobiphenyl-2-yl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3h)The product was obtained as white solid (0.03 mmol scale, 11 mg, 70%). 1H NMR (500 MHz, CDCl3): δ = 8.14 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.57–7.52 (m, ArH, 1 H), 7.51–7.45 (m, ArH, 1 H), 7.42 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.38 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.32–7.27 (m, ArH, 7 H), 7.26–7.19 (m, ArH, 2 H), 7.15–7.09 (m, ArH, 1 H), 7.06 (d, 3 JHH = 7.5 Hz, ArH, 1 H), 7.00–6.93 (m, ArH, 3 H), 6.65 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 3.80 (dd, 3 JHH = 8.0, 5.5 Hz, COCHCH2, 1 H), 3.69 (d, 3 JHH = 8.0 Hz, COCHCH 2, 1 H), 3.66 (d, 3 JHH = 8.0 Hz, COCHCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 169.5 (C=O), 167.9 (C=N), 159.2 (d, 1 J FC = 247.5 Hz, ArC) 147.1 (ArC), 145.7 (ArC), 141.5 (ArC), 138.8 (ArC), 138.7 (ArC), 135.7 (ArC), 132.0 (d, 3 J FC = 3.5 Hz, ArC), 131.6 (ArC), 131.4 (ArC), 130.8 (ArC), 130.3 (ArC), 129.9 (ArC x 2), 129.8 (ArC), 129.5 (ArC), 129.2 (ArC), 128.9 (d, 3 J FC = 8.0 Hz, ArC), 128.5 (ArC × 2), 128.3 (ArC × 2), 128.1 (ArC), 126.3 (ArC), 125.2 (ArC), 124.8 (ArC), 124.5 (d, 4 J FC = 3.5 Hz, ArC), 124.2 (ArC x 2), 115.4 5 (d, 2 J FC = 22.0 Hz, ArC) 66.0 (COCHCH2), 37.8 (COCHCH2). ESI-HRMS: m/z calcd for C34H24N3O3 [+H]+: 542.1874; found: 542.1881. LC–MS purity (UV) = 93%, t R = 23.27 min.1-(2,4,6-Trimethylphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3i)The reaction was run for 8 h. The product was obtained as white solid (1.00 mmol scale, 181 mg, 51%). 1H NMR (500 MHz, DMSO-d 6): δ = 7.60–7.57 (m, ArH, 2 H), 7.54–7.46 (m, ArH, 4 H), 7.32 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.27–7.23 (m, ArH, 1 H), 7.10–7.07 (m, ArH, 1 H), 6.88 (s, ArH, 1 H), 6.78 (d, 3 JHH = 8.0, 1.1 Hz, ArH, 1 H), 4.70 (d, 2 JHH = 10.0 Hz, COCH 2,1 H), 4.04 (d, 2 JHH = 10.0 Hz, COCH 2, 1 H), 2.26 (s, CH3, 3 H), 2.24 (s, CH3, 3 H), 1.61 (s, CH3, 3 H). 13C NMR (126 MHz, DMSO-d 6): δ = 170.3 (C=O), 167.5 (C=N), 142.2 (ArC), 138.9 (ArC), 137.9 (ArC), 137.0 (ArC), 136.2 (ArC), 134.7 (ArC), 132.3 (ArC), 130.9 (ArC), 130.0 (ArC × 2), 129.6 (ArC × 2), 129.5 (ArC), 128.9 (ArC × 2), 128.7 (ArC), 124.4 (ArC), 122.1 (ArC), 57.3 (COCH2), 21.0 (CH3), 18.5(CH3), 17.5 (CH3). ESI-HRMS: m/z calcd for C24H22N2O [+H]+: 355.1805; found: 355.1804. LC–MS purity (UV) = 97%, t R = 21.13 min.1-(2-Bromophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3j)The reaction was run for 8 h. The product was obtained as white solid (1.00 mmol scale, 31 mg, 8%). 1H NMR (500 MHz, DMSO-d 6): δ = 7.84 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.70 (d, 3 JHH = 8.0 Hz, ArH, 1 H), 7.66–7.59 (m, ArH, 4 H), 7.52–7.46 (m, ArH, 3 H), 7.41–7.37 (m, ArH, 1 H), 7.32 (dd, J = 7.8, 1.7 Hz, ArH, 1 H), 7.27 (d, 3 JHH = 7.0 Hz, ArH, 1 H), 6.92–6.83 (m, ArH, 1 H), 4.69 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.01 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.7 (C=O), 168.9 (C=N), 142.0 (ArC), 138.9 (ArC), 138.6 (ArC), 134.3 (ArC), 133.7 (ArC), 132.0 (ArC), 131.0 (ArC), 130.9 (ArC), 130.8 (ArC), 129.9 (ArC × 2), 129.8 (ArC), 129.1 (ArC), 128.8 (ArC × 2), 124.7 (ArC), 123.0 (ArC), 121.5 (ArC), 57.0 (COCH2). ESI-HRMS: m/z calcd for C21H15BrN2O [+H]+: 391.0441; found: 391.0457. LC–MS purity (UV) = 93%, t R = 15.23 min.1-(3′-Trifluoromethylphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3k)The reaction was run for 8 h. The product was obtained as white solid (0.50 mmol scale, 80 mg, 42%). 1H NMR (500 MHz, CDCl3): δ = 7.72 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.60–7.55 (m, ArH, 2 H), 7.53 (d, 3 JHH = 8.5 Hz, ArH, 2 H), 7.49–7.45 (m, ArH, 2 H), 7.44–7.38 (m, ArH, 3 H), 7.25–7.20 (m, ArH, 1 H), 6.92 (d,3 JHH = 8.5 Hz, ArH, 1 H), 4.95 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H), 4.02 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.3 (C=O), 168.3 (C=N), 143.1 (ArC), 141.3 (ArC), 138.6 (ArC), 132.0 (q, 2 J FC = 29.9 Hz, ArC), 131.9 (ArC), 131.6 (ArC), 131.4 (ArC), 130.7 (ArC), 130.4 (ArC), 129.8 (ArC × 2), 129.5 (ArC), 128.5 (ArC × 2), 125.2 (q, 3 J FC = 3.5 Hz, ArC), 124.8 (ArC), 124.8 (ArC), 123.5 (q, 1 J FC = 273.0 Hz, ArC), 124.2 (q, 3 J FC = 3.5 Hz, ArC), 57.3 (COCH2). ESI-HRMS: m/z calcd for C22H15F3N2O [+H]+: 381.1209; found: 381.1208. LC–MS purity (UV) = 96%, t R = 21.35 min.1-Phenyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (3l)The reaction was run for 8 h. The product was obtained as white solid (0.50 mmol scale, 14 mg, 9%). 1H NMR (500 MHz, CDCl3): δ = 7.72 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.54–7.49 (m, ArH, 1 H), 7.47 (d, 3 JHH = 7.5 Hz, ArH, 2 H), 7.43–7.38 (m, ArH, 2 H), 7.37–7.30 (m, ArH, 2 H), 7.24–7.21 (m, ArH, 3 H), 7.20–7.16 (m, ArH, 1 H), 6.97 (d, 3 JHH = 8.5 Hz, ArH, 1 H), 4.96 (d, 2 JHH = 10.5 Hz, ArH, COCH 2, 1 H), 4.01 (d, 2 JHH = 10.5 Hz, COCH 2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.7 (C=O), 168.3 (C=N), 146.5 (ArC), 143.3 (ArC), 140.7 (ArC), 138.6 (ArC), 131.3 (ArC), 130.7 (ArC), 130.3 (ArC), 129.6 (ArC × 2), 129.3 (ArC × 2), 128.4 (ArC × 2), 128.3 (ArC × 2), 127.5 (ArC), 124.7 (ArC), 124.2 (ArC), 57.2 (COCH2). ESI-HRMS: m/z calcd for C21H16N2O [+H]+: 313.1335; found: 313.1338. LC–MS purity (UV) = 90%, t R = 16.10 min.1-(4-Nitrophenyl)-3-(4-nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (7)The product was obtained as white solid (0.60 mmol scale, 2 equiv of diaryliodonium triflate, 146 mg, 51%). 1H NMR (500 MHz, CDCl3): δ = 8.34–8.22 (m, ArH, 4 H), 7.85–7.79 (m, ArH, 2 H), 7.77–7.71 (m, ArH, 2 H), 7.74–7.57 (m, ArH, 3 H), 7.59–7.50 (m, ArH, 3 H), 7.41–7.32 (m, ArH, 2 H), 7.07–7.02 (m, ArH, 1 H). 13C NMR (126 MHz, CDCl3): δ = 166.0 (C=O), 158.3 (C=N), 149.1 (ArC), 146.7 (ArC), 145.6 (ArC), 144.1 (ArC), 143.3 (ArC), 135.0 (ArC), 132.6 (ArC), 131.5 (ArC), 129.9 (ArC), 129.6 (ArC), 129.5 (ArC × 2), 128.9 (ArC × 2), 126.8 (ArC × 2), 126.3 (ArC), 125.4 (ArC) 124.5 (ArC × 2), 124.3 (ArC × 2), 121.3 (ArC × 2). ESI-HRMS: m/z calcd for C26H17N5O5 [+H]+: 480.1230; found: 480.1245. LC–MS purity (UV) = 95%, t R = 18.35 min.1,1′-Oxybis(4-nitrobenzene)To a solution of (4-nitrophenyl)phenyliodonium triflate (30 mg, 0.06 mmol) in DCE (1 mL) was added sodium hydroxide (aq., 1 mL) and stirred for 20 min at room temperature. Upon completion, the reaction was diluted with dichloromethane (5 mL × 3) and the layers were separated. Combined organic layers were dried (MgSO4) and concentrated under reduced pressure to afford the product as a white powder (7 mg, 43%). 1H NMR (500 MHz, CDCl3): δ = 8.33–8.27 (m, ArH, 4 H), 7.19–7.14 (m, ArH, 4 H).13C NMR (126 MHz, CDCl3): δ = 160.6 (ArC × 2), 144.2 (ArC × 2), 126.2 (ArC × 4), 119.3 (ArC × 4). ESI-HRMS: m/z calcd for C12H8N2O5 [+H]+: 261.0511; found: 261.0513.
  • 43 CCDC numbers 1560492–1560494 contain the supplementary crystallographic data for compounds 3a, 3h, 3i. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

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Figure 1 Bioactive N-arylated Benzodiazepine and Benzotriazepine
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Scheme 1 N-Arylated 1,4-Benzodiazepines
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Scheme 2 N-Arylation on a 1,3,4-Benzotriazepine