N 1-Arylation of 1,4-Benzodiazepine-2-ones with Diaryliodonium Salts

Article abstract of DOI:10.1055/s-0036-1590920

A library of N 1-arylated 5-phenyl-1,3-dihydro-2 H -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.

Full text of DOI:10.1055/s-0036-1590920

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
R. Khan et al.
Letter
Synlett
N1-Arylation of 1,4-Benzodiazepine-2-ones with Diaryliodonium
Salts
O2N
Raysa Khana
Robert Felixb
Paul D. Kemmittc
Simon J. Colesd
OTf–
I+
Ph
2
O
H
O
N
O2N
N
1.1 equiv
Graham J. Tizzardd
N
25% w/w NH3
DCE, rt, 30 min
John Spencer*a
0
0
0
0
0-
0
0
1
5-
2
3
1
8-
8
3
6
N
a Department of Chemistry, School of Life Sciences, University of Sussex, Falmer,
BN19QJ, UK
78%
j.spencer@sussex.ac.uk
b Tocris, Bio Techne, The Watkins Building, Atlantic Road, Bristol, BS11 9QD, UK
c IMED Oncology, AstraZeneca, 310 Cambridge Science Park, Milton Road, Cambridge
CB4 0WG, UK
Bradykinin antagonist
intermediate
d UK National Crystallography Service, Chemistry, University of Southampton, High-
field, Southampton, SO17 1BJ, UK
Received: 13.07.2017
Accepted after revision: 06.09.2017
Published online: 25.09.2017
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 repur-
DOI: 10.1055/s-0036-1590920; Art ID: st-2017-d0556-l
License terms:
posing privileged scaffolds for new biological targets.24,25
Abstract A library of N1-arylated 5-phenyl-1,3-dihydro-2H-1,4-benzo-
diazepin-2-ones has been synthesized starting with unsymmetrical dia-
ryliodonium salts using aqueous ammonia as a base. This can also be
applied to a similar 1,3,4-benzotriazepin-2-one derivative.
26,27
We have an active interest in benzodiazepines
and
recently reported a method to functionalise 5-phenyl-1,3-
dihydro-2H-1,4-benzodiazepin-2-ones via a late-stage pal-
ladacycle 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.30–35
Novak et al. recently reported a protocol for the N-aryla-
tion 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 (Ta-
ble 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.
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).
Key words benzodiazepines, N-arylation, iodonium salt, privileged
scaffold, benzotriazepine
Compounds containing a 1,4-benzodiazepine scaffold
are often termed as ‘privileged structures’ and are of signif-
icant interest to organic and medicinal chemists.1–18 Many
bioactive 1,4- benzodiazepines include N-arylated benzodi-
azepines; for example, the benzodiazepine derivative A
(Figure 1) is a bradykinin antagonist19 and the related ben-
zotriazepine 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 re-
quires high temperatures and strong bases. 19,21–23
HN
HN
HN
NH2
NH2
HN
O
O
Hence, optimal conditions appeared to use NH3 (aq.),
DCE at room temperature for 30 min. Next, a series of func-
tionalized 1,4-benzodiazepines was N-arylated using (4-ni-
trophenyl)phenyliodonium triflate in good to excellent
yields (Scheme 1). Generally, in transition-metal-free pro-
cesses unsymmetrical diaryliodonium salts give a mixture
of products where both groups are transferred and the
transfer of more sterically hindered and electron-with-
N
N
N
N
N
A
B
Figure 1 Bioactive N-arylated Benzodiazepine and Benzotriazepine
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
R. Khan et al.
Letter
Synlett
Table 2 Optimization of N-Arylation of 1,4-Benzodiazepines – Base
Effects
Table 1 Optimization of N-Arylation of 1,4-Benzodiazepines – Solvent
Effects
O2N
O2N
OTf–
OTf–
I+
O
H
O
H
I+
N
O
N
O
Ph
Ph
N
N
O2N
O2N
N
N
N
N
base
DCE, rt, 30 min
25% w/w NH3
solvent, rt, 30 min
Conversion (%)a
Entry
Base
Conversion (%)a
Entry
Solvent
1
2
3
4
NaOH (sat. aq.)
99
99
80
-
1
2
3
4
5
toluene
DCE
95
99
–
NH3 (25% w/w)
K2CO3
PEG
NaH
AcOH
CHCl3
–
a LC–MS conversion.
85
a LC–MS conversion.
ate towards A. We were also pleased to be able to conduct
N-arylation on a previously ortho-arylated hindered benzo-
diazepine, 3h, in good yield, whose structure was also con-
firmed by X-ray crystallography. Such molecules may be
useful precursors to, e.g., α-helical mimetics in medicinal
chemistry.37,38
drawing 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 benzodiaze-
pines such as 3e, 3f, and 3g. Of note, 3e is a key intermedi-
Scheme 1 N-Arylated 1,4-Benzodiazepines
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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R. Khan et al.
Letter
Synlett
The use of other unsymmetrical diaryliodonium tri-
flates was also explored (Table 3), which required longer re-
action time and led to both aryl groups being transferred to
obtain 3i–l. As expected, the transfer of more sterically hin-
dered or less electron-rich groups was preferred. Further at-
tempts to use unsymmetrical diaryliodonium salts such as
phenyl(3-methylphenyl)iodonium triflate, phenyl(4-meth-
ylphenyl)iodonium triflate, and (2-methylphenyl)(2,4,6-
trimethylphenyl)iodonium triflate gave little or no prod-
ucts. Additionally, attempted N-arylation with symmetrical
diaryliodonium triflates or tetrafluoroborates such as bis(2-
fluorophenyl)iodonium tetrafluoroborate and bis(4-bro-
mophenyl)iodonium triftlate gave, at best, traces of prod-
ucts.
Interestingly, the iodonium salts were observed to un-
dergo reaction with water present in the reaction to give di-
arylether 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 react-
ing diaryliodonium salts with phenols in the presence of
mild bases.39
Table 4 Diaryl Ether Formation
Substrate
Expected product
Observed product
Table 3 Further N-Arylation of 1,4-Benzodiazepinesa
O2N
O
H
Salt
Product (major)
Product (minor)
N
O
N
O
N
O
O2N
NO2
OTf–
I+
Br
N
O
Br
N
10; 43%
O
N
8
9; 0%
4
O2N
3j; 8%
O
H
N
O
CF3
O
N
NH
O2N
NO2
OTf–
I+
O
O
N
O
N
10; 45%
NH
O
F3C
11
N
N
12; 0%
5
3l; 9%
In summary we have presented a mild metal-free route
to N-arylated benzodiazepines, three of which were struc-
turally characterized in the solid state (3a, 3h, 3i).40,41
3k; 42%
a Reaction time = 8 h.
We have briefly explored the N-arylation on a 1,3,4-
benzotriazepine 6, which resulted in diarylation and yield-
ed 7 (Scheme 2).
Funding Information
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
O2N
National Crystallography ServiceAstra
Z
e
n
e
c
a
1(
4
5
5
0
0
0
1
S(
M
E)
OTf–
I+
O
H
N
Ph
2 equiv
2
O2N
O
N
NH
Acknowledgment
N
N
NO2
25% w/w NH3
DCE, rt, 4 h
N
We thank Dr. Alaa Abdul-Sada (Sussex) and the EPSRC UK National
Mass Spectrometry Facility at Swansea University for HRMS measure-
ments.
6
7; 51%
Scheme 2 N-Arylation on a 1,3,4-Benzotriazepine
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
R. Khan et al.
Letter
Synlett
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u
p
p
ortiInfogrmoaitn
S
u
p
p
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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 deu-
terated solvents such as CDCl3 and DMSO-d6. 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 – multi-
plet, 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 detec-
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tography on silica gel columns or C18 columns using a Combi
flash RF 75 PSI, ISCO unit.
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General Procedure
To a stirred solution of the appropriate 1,4-benzodiazepine or
1,3,4-benzotriazepine (0.030–1.00 mmol, 1 equiv) and dia-
ryliodonium 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 other-
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14475.
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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wise). 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 chromatogra-
phy, hexane/ethyl acetate (80:20 to 30:70).
HRMS: m/z calcd for
C
21H15N3O3 [+H]+: 358.1186; found:
358.1187. LC–MS purity (UV) = 95%, tR = 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
1-(4-Nitrophenyl)-5-methyl-1,3-dihydro-2H-1,4-benzodiaz-
epin-2-one (3a)
mg, 78%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2
3
H), 7.67 (d, JHH = 7.5 Hz, ArH, 2 H), 7.52–7.48 (m, 1 H), 7.47–
The product was obtained as white solid (0.60 mmol scale, 170
7.43 (m, ArH, 2 H), 7.41–7.37 (m, ArH, 5 H), 7.36–7.30 (m, ArH, 3
mg, 96%). 1H NMR (500 MHz, CDCl3): δ = 8.27–8.21 (m, ArH, 2
H), 7.25–7.21 (m, ArH, 2 H), 6.90 (d, 3JHH = 8.0 Hz, ArH, 1 H), 4.01
3
2,3
H), 7.62 (dd, JHH = 7.5, 1.5 Hz, ArH, 1 H), 7.40–7.35 (m, ArH, 3
(dd, J = 7.5, 6.0 Hz, COCHCH2, 1 H), 3.68 (dd,
J
= 14.0, 6.0 Hz,
HH
H), 7.34–7.29 (m, ArH, 1 H), 6.82 (d, 3JHH = 8.0 Hz, ArH, 1 H), 4.70
(d, 2JHH = 10.5 Hz, COCH2, 1 H), 3.83 (d, 2JHH = 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-
COCHCH2, 1 H), 3.62 (dd,
J
= 14.0, 7.5 Hz, COCHCH2, 1 H). 13
C
2,3
HH
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
HRMS: m/z calcd for
C
16H13N3O3 [+H]+: 296.1030; found:
296.1033. LC–MS purity (UV) = 100%, tR = 8.10 min.
1-(4-Nitrophenyl)-5-(propan-2-yl)-1,3-dihydro-2H-1,4-ben-
zodiazepin-2-one (3b)
C
28H21N3O3 [+H]+: 448.1656; found: 448.1669. LC–MS purity
(UV) = 99 %, tR = 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
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, 3JHH = 7.5, 2.0 Hz, ArH, 1 H), 7.39–7.35 (m, ArH, 3
1
3
mg, 75%). H NMR (500 MHz, CDCl3): δ = 8.26 (d, JHH = 8.5 Hz,
ArH, 2 H), 7.66 (d, 3JHH = 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),
3
H), 7.34–7.30 (m, ArH, 1 H), 6.83 (dd, JHH = 8.0, 1.5 Hz, ArH, 1
2
2
H), 4.72 (d, JHH = 10.5 Hz, COCH2, 1 H), 3.82 (d, JHH = 10.5 Hz,
3
COCH2, 1 H), 3.34–3.25 (m, 1 H), 1.35 (d, JHH = 7.0 Hz,
CNCHC2CH6, 3 H), 1.11 (d, JHH = 7.0 Hz, CNCHC2CH6, 3 H). 13C
6.85 (d, JHH = 8.5 Hz, ArH, 1 H), 3.99 (dd, J = 7.5, 6.0 Hz,
3
3
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 (CNCHC2H6), 19.2
(CNCHC2H6). ESI-HRMS: m/z calcd for C18H17N3O3 [+H]+:
COCHCH2, 1 H), 3.70–3.57 (m, COCHCH2, 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%, tR = 19.71
min.
324.1270; found: 324.1281. LC–MS purity (UV) = 96 %, tR
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, 3JHH = 8.0, 1.5 Hz, ArH, 1H), 7.39–7.24 (m, ArH, 4 H),
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
3
6.85 (dd, J = 8.0, 1.5 Hz, ArH, 1 H), 3.27 (hept, JHH = 7.0 Hz,
mg, 77%). 1H NMR (500 MHz, CDCl3): δ = 8.67–8.62 (m, ArH, 1
3
3
CNCHCH3CH3, 1 H), 3.12 (d, JHH = 9.5 Hz, COCHCHC2H6, 1 H),
H), 8.15 (d, JHH = 8.0 Hz, ArH, 2 H), 8.18–8.12 (m, ArH, 1 H),
3
2.72–2.61 (m, COCHCHC2H6, 1 H), 1.33 (d, JHH = 7.0 Hz,
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, 3JHH = 8.0 Hz, ArH, 1 H), 4.10 (dd, 3JHH = 8.0, 6.0 Hz, COCHCH2,
3
CNCHC2H6, 3 H), 1.07 (d, JHH = 7.0 Hz, CNCHC2CH6, 3 H), 1.05–
1.02 (m, COCHCHC2H6, 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 (CNCHC2H6), 20.1,
(CNCHC2H6) 19.3 (COCHCHC2H6), 18.7 (COCHCHC2H6). ESI-
2,3
2,3
1 H), 3.70 (dd,
J
= 14.0, 7.0 Hz, COCHCH2, 1 H), 3.62 (dd,
J
HH
HH
= 14.0, 7.5 Hz, COCHCH2, 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%, tR = 20.81 min.
HRMS: m/z calcd for
C
21H23N3O3 [+H]+: 366.1812; found:
366.1816. LC–MS purity (UV) = 95%, tR = 23.47 min.
1-(4-Nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiaz-
epin-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
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
3
1
3
(m, ArH, 3 H), 7.45–7.41 (m, ArH, 3 H), 7.29 (d, JHH = 8.0 Hz,
mg, 70%). H NMR (500 MHz, CDCl3): δ = 8.14 (d, 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, 3JHH = 7.5 Hz, ArH, 1 H), 7.38 (d, 3JHH = 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, 3JHH = 7.5 Hz, ArH, 1 H), 7.00–6.93 (m, ArH, 3 H), 6.65
(d, 3JHH = 8.5 Hz, ArH, 1 H), 3.80 (dd, 3JHH = 8.0, 5.5 Hz, COCHCH2,
1 H), 3.69 (d, 3JHH = 8.0 Hz, COCHCH2, 1 H), 3.66 (d, 3JHH = 8.0 Hz,
ArH, 1 H), 6.94 (d, 3JHH = 8.0 Hz, ArH, 1 H), 4.96 (d, 2JHH = 10.5 Hz,
2
COCH2, 1 H), 4.03 (d, JHH = 10.5 Hz, COCH2, 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-
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
R. Khan et al.
Letter
Synlett
COCHCH2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 169.5 (C=O),
167.9 (C=N), 159.2 (d, JFC = 247.5 Hz, ArC) 147.1 (ArC), 145.7
(C=N), 143.1 (ArC), 141.3 (ArC), 138.6 (ArC), 132.0 (q, 2JFC = 29.9
Hz, ArC), 131.9 (ArC), 131.6 (ArC), 131.4 (ArC), 130.7 (ArC), 130.4
1
(ArC), 141.5 (ArC), 138.8 (ArC), 138.7 (ArC), 135.7 (ArC), 132.0 (d,
3JFC = 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),
(ArC), 129.8 (ArC × 2), 129.5 (ArC), 128.5 (ArC × 2), 125.2 (q, 3JFC
=
1
3.5 Hz, ArC), 124.8 (ArC), 124.8 (ArC), 123.5 (q, JFC = 273.0 Hz,
3
ArC), 124.2 (q, JFC = 3.5 Hz, ArC), 57.3 (COCH2). ESI-HRMS: m/z
3
128.9 (d, JFC = 8.0 Hz, ArC), 128.5 (ArC × 2), 128.3 (ArC × 2),
calcd for C22H15F3N2O [+H]+: 381.1209; found: 381.1208. LC–MS
purity (UV) = 96%, tR = 21.35 min.
128.1 (ArC), 126.3 (ArC), 125.2 (ArC), 124.8 (ArC), 124.5 (d, 4JFC
=
3.5 Hz, ArC), 124.2 (ArC x 2), 115.4 5 (d, 2JFC = 22.0 Hz, ArC) 66.0
(COCHCH2), 37.8 (COCHCH2). ESI-HRMS: m/z calcd for
1-Phenyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-
one (3l)
C
34H24N3O3 [+H]+: 542.1874; found: 542.1881. LC–MS purity
The reaction was run for 8 h. The product was obtained as white
1
(UV) = 93%, tR = 23.27 min.
1-(2,4,6-Trimethylphenyl)-5-phenyl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (3i)
solid (0.50 mmol scale, 14 mg, 9%). H NMR (500 MHz, CDCl3):
δ = 7.72 (d, 3JHH = 7.5 Hz, ArH, 2 H), 7.54–7.49 (m, ArH, 1 H), 7.47
3
(d, JHH = 7.5 Hz, ArH, 2 H), 7.43–7.38 (m, ArH, 2 H), 7.37–7.30
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-d6): δ = 7.60–7.57 (m, ArH, 2 H), 7.54–7.46 (m, ArH, 4 H),
(m, ArH, 2 H), 7.24–7.21 (m, ArH, 3 H), 7.20–7.16 (m, ArH, 1 H),
3
2
6.97 (d, JHH = 8.5 Hz, ArH, 1 H), 4.96 (d, JHH = 10.5 Hz, ArH,
2
COCH2, 1 H), 4.01 (d, JHH = 10.5 Hz, COCH2, 1 H). 13C NMR (126
3
7.32 (d, JHH = 8.0 Hz, ArH, 1 H), 7.27–7.23 (m, ArH, 1 H), 7.10–
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-
3
7.07 (m, ArH, 1 H), 6.88 (s, ArH, 1 H), 6.78 (d, JHH = 8.0, 1.1 Hz,
ArH, 1 H), 4.70 (d, 2JHH = 10.0 Hz, COCH2,1 H), 4.04 (d, 2JHH = 10.0
Hz, COCH2, 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-d6): 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%, tR = 21.13 min.
1-(2-Bromophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodi-
azepin-2-one (3j)
HRMS: m/z calcd for
C
21H16N2O [+H]+: 313.1335; found:
313.1338. LC–MS purity (UV) = 90%, tR = 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%, tR = 18.35 min.
The reaction was run for 8 h. The product was obtained as white
1
solid (1.00 mmol scale, 31 mg, 8%). H NMR (500 MHz, DMSO-
3
3
d6): δ = 7.84 (d, JHH = 8.0 Hz, ArH, 1 H), 7.70 (d, 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, 3JHH = 7.0 Hz, ArH, 1 H), 6.92–6.83 (m, ArH, 1 H), 4.69 (d, 2JHH
2
= 10.5 Hz, COCH2, 1 H), 4.01 (d, JHH = 10.5 Hz, COCH2, 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
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 comple-
tion, 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
C
21H15BrN2O [+H]+: 391.0441; found: 391.0457. LC–MS purity
(UV) = 93%, tR = 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, 3JHH = 7.5 Hz, ArH, 2 H), 7.60–7.55 (m, ArH, 2 H), 7.53
C
12H8N2O5 [+H]+: 261.0511; found: 261.0513.
3
(d, JHH = 8.5 Hz, ArH, 2 H), 7.49–7.45 (m, ArH, 2 H), 7.44–7.38
(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.
(m, ArH, 3 H), 7.25–7.20 (m, ArH, 1 H), 6.92 (d,3JHH = 8.5 Hz, ArH,
1 H), 4.95 (d, 2JHH = 10.5 Hz, COCH2, 1 H), 4.02 (d, 2JHH = 10.5 Hz,
COCH2, 1 H). 13C NMR (126 MHz, CDCl3): δ = 170.3 (C=O), 168.3
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F