Late Stage C-H Activation of a Privileged Scaffold; Synthesis of a Library of Benzodiazepines

Article abstract of DOI:10.1002/adsc.201501009

A library of over twenty 5-(2-arylphenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been formed by a microwave-mediated late-stage palladium-catalysed arylation of 1,4-benzodiazepines using diaryliodonium salts. This can also be applied to nordazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one), the active metabolite of diazepam, and subsequent N-alkylation and/or H/D exchange allows further diversification towards elaborated pharmaceuticals and their 3,3′-deuterated analogues.

Full text of DOI:10.1002/adsc.201501009

FULL PAPERS
DOI: 10.1002/adsc.201501009
À
Late Stage C H Activation of a Privileged Scaffold; Synthesis of
a Library of Benzodiazepines
Raysa Khan,a Robert Felix,b Paul D. Kemmitt,c Simon J. Coles,d Iain J. Day,a
Graham J. Tizzard,d and John Spencera,*
a
Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, BN19QJ, U.K.
Fax: (+44)-(0)1273-876-687; phone: (+44)-(0)1273-877-374; e-mail: j.spencer@sussex.ac.uk
Tocris Bioscience, Tocris House, IO Centre, Moorend Farm Avenue, Bristol, BS11 0QL, U.K.
AstraZeneca, Mereside Alderley Park, Macclesfield, SK10 4TG, U.K.
UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton,
b
c
d
SO17 1BJ, U.K.
Received: November 9, 2015; Published online: January 5, 2016
À
This paper is dedicated to Professor Michel Pfeffer (ULP, Strasbourg) for his contributions to C H activation
and palladacycle chemistry.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501009.
ꢀ2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
Abstract: A library of over twenty 5-(2-arylphenyl)- pam, and subsequent N-alkylation and/or H/D ex-
1,3-dihydro-2H-1,4-benzodiazepin-2-ones has been change allows further diversification towards elabo-
formed by a microwave-mediated late-stage palladi- rated pharmaceuticals and their 3,3’-deuterated ana-
um-catalysed arylation of 1,4-benzodiazepines using logues.
diaryliodonium salts. This can also be applied to nor-
dazepam (7-chloro-5-phenyl-1,3-dihydro-2H-1,4-ben- Keywords: C H activation; deuteration; heterocy-
zodiazepin-2-one), the active metabolite of diaze- cles; microwaves; palladium
À
Introduction
this is followed by repetitive coupling/cyclisation
chemistries (Scheme 1).
The need for efficiency in rapidly producing a library
of closely related analogues cannot be understated in
drug discovery where natural product derivatives or
complex molecules, often synthesised by multistep re-
actions, are fine-tuned to respond to inadequacies in
terms of their biological activity, selectivity, pharma-
cokinetics and undesirable toxicity. The ability to add
functionality to a bioactive core at the final or penul-
timate synthetic step to enable SAR (structure–activi-
ty relationship) studies can drive efficiency and speed
up hit-to-lead and lead optimisation strategies.[1]
We have a longstanding interest in benzodiazepines,
which represent an important class of privileged het-
erocycles.[2] Typical routes for the introduction of dif-
ferent R groups at the 5-position are inefficient since
Scheme 1. A classical route to a 5-(2-arylphenyl)-1,3-dihy-
such reactions are early in the synthetic sequence and dro-2H-1,4-benzodiazepin-2-one.
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Late Stage C H Activation of a Privileged Scaffold
Results and Discussion
of reagents led to slightly improved conversions
(entry 9, Table 2).
Our approach sought to vary the 5-substituent via
a late-stage C H activation; in essence, a benzodiaze- a range of benzodiazepines via this last-stage C H ac-
pine building block could be synthesised, once, on tivation protocol. Critically, we were able to confirm
a large scale using the coupling/cyclisation chemistry that the C H activation had occurred in the ortho-po-
Using our “optimised” approach we synthesised
À
À
À
discussed above, then functionalised by introducing sition as anticipated from a chelation controlled pro-
the new functional groups at the last step, adding cess by crystal-structure determinations of a number
atom and step economy[3] to the library generation of products (vide infra)[8] (Figure 1). We synthesised
À
process. Our test case was the chelation-assisted C H a series of fluorinated aromatics 2 due to the advanta-
activation of the valium (diazepam)-like benzodiaze- geous role of fluorine in medicinal chemistry.[9]
pine 1a using palladacycle chemistry to afford 2a
At this stage, we were still somewhat dissatisfied
(Table 1).[4] Notably, Cintrat et al. showed that ortho- with this approach since we were confined to an N-
halogenation[4c] of the aryl group can be achieved 1 methyl substituent in the final product. A broader
under similar conditions, opening up the possibility of diversity would be enabled by having a N-protected
carrying out complementary Pd-mediated couplings. or free amide group, enabling further diversification
A rapid screen of conditions showed that this was after the arylation reaction. To test the more attrac-
À
indeed possible and that the best conversions, by tive latter hypothesis, preliminary studies on the C H
1H NMR, involved acetic acid as solvent, microwave activation process were carried out (Scheme 2) and
conditions,[5] and employed 5 mol% Pd(OAc)2 as cata- established that:
[6]
lyst and Ph2IBF4 as the arylating agent (entry 2).
À
The use of a mesityl-aryliodonium salt gave similar (i) Stoichiometric chelation-assisted C H activation
promising results (entry 4) and will be exploited fur-
ther on (vide infra). Further iterations (Table 2), in-
À
is indeed possible on the unsubstituted N H
amide since the palladacycle 3 can be isolated.
cluding the use of classical, thermal conditions, lower (ii) An attempted interception of the palladacycle in-
Pd loadings, additives such as silver salts,[7] led to no
or little improvement, although higher concentrations
termediate, by a Pd-catalyzed H/D exchange,[10]
did not lead to the expected product 1c. Instead,
[a]
À
Table 1. Optimization of C H activation.
Time [h] Temp. [oC] Conversion by 1H NMR/LC-MS [%] Solvent
À
Entry R X (equiv.)
Catalyst (mol%)
1
2
3
Ph2IBF4 (1.5)
Ph2IBF4 (1.5)
Ph2IBF4 (1.5)
À À
–
1.5
1.5
1.5
1.5
1
125
125
125
125
125
0
55
5
50
0
AcOH
AcOH
EtOAc
AcOH
AcOH
Pd(OAc)2 (5)
Pd(OAc)2 (5)
4
[Mes I Ar] OTf (1.5) Pd(OAc)2 (5)
5[b]
PhBr (1.5)
Pd(OAc)2 (5)
6
Ph2IBF4 (1.5)
1.5
125
22
AcOH
7
8
9
Ph2IBF4 (2.5)
Ph2IBF4 (1.5)
Ph2IBF4 (1.5)
(MeCN)2PdCl2 (10)
(MeCN)2PdCl2 (5)
Pd(OAc)2 (2.5)
1.5
1.5
1.5
125
125
125
0
0
0
AcOH
DCE
AcOH
[a]
All reactions were conducted in a CEM Explorer microwave unless stated otherwise. DCE=1,2-dichloroethane;
EtOAc=ethyl acetate.
Conventional heating.
[b]
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Raysa Khan et al.
Table 2. Further reaction optimization studies.[a]
Entry
Ph2IBF4 [equiv.]
Pd(OAc)2 [mol%]
Time [h]
Temp. [oC]
Conversion by NMR [%]
AcOH [mL]
1[b]
2[c]
3
4
5
6
7
8
9
1.5
1.5
1.5
1.5
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
5
100
5
10
10
10
5
10
5
5
5
64
1.5
0.15+0.5
2
1
1
1.25
1.5
1
1
1
1
1
100
125
150+120
130
130
125
125
125
125
125
125
125
125
44
0
5
5
5
5
5
5
5
5
2.5
2.5
2.5
2.5
2.5
2.5
28
47
51
48
54
55
58
33
20
16
52
30
10[d]
11[e]
12[f]
13[g]
14[h]
5
5
5
1
125
[a]
All reactions were conducted in a CEM Explorer microwave unless stated otherwise.
Conventional heating.
Analysis of the crude mixture, after PPh3 treatment, showed evidence that the palladacycle was formed.
Ag2O added (1.5 equiv.).
Ag2O added (1.5 equiv. at 1008C).
AgOAc added (1.5 equiv. at 1008C).
[b]
[c]
[d]
[e]
[f]
[g]
[h]
AcOH degassed, reaction under N2.
AcOH dry and degassed, reaction under N2.
Figure 1. ortho-Arylated benzodiazepines.
this reaction, furnished uniquely the D2-methyl-
ene compound 1d, which could also be accom-
plished in the absence of the metal catalyst by
merely stirring in deuterated acetic acid in the mi-
crowave, similar to previous findings on H/D ex-
change.[11]
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Late Stage C H Activation of a Privileged Scaffold
porting Information, note: ND tends to revert to NH
when the samples are concentrated in air).
A further illustration of the diversity achievable is
that the resulting elaborated nordazepam derivatives
5 can be N-alkylated to afford substituted diazepam
and pinazepam analogues (Figure 3).
Conclusions
In summary, we have synthesized a library of benzo-
À
diazepines via a late stage C H activation reaction.
Studies are now underway to address the drug-like-
ness of the products by for example, lowering their
clogP, testing their biological activity, as well as apply-
ing this chemistry to other systems related to benzo-
diazepines such as benzotriazepines.[15]
Experimental Section
General Information
Scheme 2. Deuteration and palladation reactions of 1.
All commercially purchased materials and solvents were
used without further purification unless specified otherwise.
NMR spectra were recorded on a Varian VNMRS 500 (1H
Next, we produced a library of benzodiazepines
lacking an N-1 substituent (Figure 2). Of note, we
were also able to produce arylated nordazepam[12] de-
rivatives 5; nordazepam was quickly made by an
adaptation of a microwave protocol.[13] Yields, in gen-
eral, were superior to those for their N-methylated
analogues, mainly with electron-poor arenes, whereas
the electron-rich 4f and 4h were made in moderate
yield (note: the 2-tolyl derivative of 4h did not form,
possibly due to steric effects). We were pleasantly sur-
prised to be able to obtain the hindered 4g, albeit
under more forcing microwave conditions. Analogue
5b was made from a mesityl-containing aryliodonium
salt.
Products were separated initially using a mass-trig-
gered LC-MS protocol[14] but we found that a re-
versed-phase LC-MS method was equally useful and
we were also able to recover traces of unreacted start-
ing material. Moreover, diarylated products were
often observed in the crude reaction mixtures and, in
some cases, were isolated (Scheme 3, for example, 5c’,
5d’). The yields of 5d and 5d’ were rather low, even
when using a higher temperature.
2
500 MHz, 13C 126 MHz) and VNMRS 400 (19F 376 MHz, H
61 MHz and 31P 162 MHz) spectrometers and prepared in
1
deuterated solvents such as CDCl3 and DMSO-d6. H and
13C chemical shifts were recorded in parts per million
1
(ppm). Multiplicity of H 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). Electron spray ionisation-
high resolution mass spectra (ESI-HR-MS) were obtained
using a Bruker Daltonics Apex III where Apollo ESI was
used as the ESI source. All analyses were conducted by Dr.
A. K. Abdul-Sada. The molecular ion peaks [M]+ were re-
corded in mass to charge (m/z) ratio.
LC-mass spectra were acquired using a Shimadzu LC-MS
2020, on a Gemini 5 m C18 110 Š. column. All X-ray analy-
ses were performed at the UK National Crystallography
Services, Southampton. All elemental analyses were carried
out at the Elemental Analysis Service, London Metropolitan
University. Purifications were performed by flash chroma-
tography on silica gel columns or C18 columns using
a Combi flash RF 75 PSI, ISCO unit.
CCDC 1422838, 1422839, 1422840, 1422841, 1422842,
1422843 and CCDC 1422844 contain the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Following our earlier studies (Scheme 2), we pre-
pared a small number of deuterated derivatives 6a–6c
(Scheme 4). Compound 6a, the deuterated analogue
À
1-Methyl-5-biphenyl-2-yl-1,3-dihydro-2D-1,4-
benzodiazepin-2-one (1b)
of 5c, was prepared by a one-pot dual C H activa-
tion/H–D exchange by simply carrying out the catalyt-
ic arylation protocol in CD3CO2D whereas 6b, 6c
(and earlier, 1b) were simply prepared by stirring the
arylated precursors in CD3CO2D in a microwave.
Compound 2a was stirred in acetic acid-d4 at 1258C in the
microwave for 1 hour. Thereafter, the reaction mixture was
cooled and the white product was collected in quantitative
yield by evaporating the solvent. 1H NMR (500 MHz,
Deuterated benzodiazepine products were easily
2
characterized, for example, by H NMR (see the Sup- CDCl3): d=7.81–7.72 (m, 1H), 7.56–7.45 (m, 2H), 7.27 (d,
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Figure 2. Arylation of 1-NH-benzodiazepines.
J=7.6 Hz, 1H), 7.22 (pt, J=7.9 Hz, 1H), 7.09–6.98 (m, 3H),
6.92–6.82 (m, 5H), 3.13 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=173.2, 169.4, 142.9, 142.2, 138.4, 131.2, 130.5,
130.2, 130.0, 129.9, 129.2, 128.7 (2C), 127.7 (2C), 127.5,
126.5, 123.4, 120.1, 55.5 (m), 34.9; 2H NMR (61 MHz.
CH3CO2H): d=4.95 (1H), 3.94 (1H); HR-MS-ESI: m/z=
329.1614, calculated for C21H16D2N2O [+H]+: 329.1617.
under reduced pressure. The residue was dissolved in DCM
(20 mL), washed with saturated sodium bicarbonate and the
organic layer was collected using a (hydrophobic frit) phase
separator. The solution was concentrated under reduced
pressure to yield an orange product. The crude material was
purified by flash chromatography (30 g C18, acetonitrile:
water, 30% to 90%) and the final product was obtained as
1
a white powder; yield: 0.083 g (43%). H NMR (500 MHz,
CDCl3): d=7.78 (d, J=7.9 Hz, 1H), 7.57–7.49 (m, 2H), 7.29
(dd, J=6.7, 1.9 Hz, 1H), 7.26–7.20 (m, 1H), 7.11–7.20 (m,
3H), 6.93 (d, J=6.4 Hz, 2H), 6.91–6.85 (m, 3H), 4.83 (d, J=
11.0 Hz, 1H), 3.73 (d, J=11.0 Hz, 1H), 3.15 (s, 3H);
13C NMR (126 MHz, CDCl3): d=173.0, 169.5, 139.5, 143.0,
142.1, 140.8, 138.6, 131.2, 130.5, 130.1, 130.0, 129.1, 128.7
(2C), 127.7 (2C), 127.5, 126.4, 123.3, 120.0, 56.3, 34.9; HR-
MS-ESI: m/z=327.1492, calculated for C22H18N2O [+H]+:
327.1497; elemental analysis: calculated for C22H18N2O (%):
C 80.96, H 5.56, N 8.58; found: C 80.69, H 5.32, N 8.54.
1-Methyl-5-biphenyl-2-yl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (2a)
1-Methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one
(0.15 g, 0.60 mmol), diphenyliodonium tetrafluoroborate
(0.33 g, 0.90 mmol) and palladium(II) acetate (6.0 mg,
5 mol%) were combined in glacial acetic acid (4 mL) and
stirred for 1 h at 1258C in the microwave. Thereafter the
cooled reaction mixture was filtered over celite, washed
with dichloromethane (DCM, 10 mL) and concentrated
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Late Stage C H Activation of a Privileged Scaffold
Scheme 3. Nordazepam mono- and diarylations.
Scheme 4. Synthesis of deuterated elaborated benzodiazepines.
1-Methyl-5-(2’-fluorobiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (2b)
This was synthesised on a 0.31 mmol scale by the same pro-
cedure as 2a and bis(2-fluorophenyl)iodonium tetrafluoro-
borate (0.18 g, 0.49 mmol) was used instead of diphenyliodo-
nium tetrafluoroborate. The final product was obtained as
1
a white powder; yield: 0.052 g (49%). H NMR (500 MHz,
CDCl3): d=7.78 (dd, J=5.8, 3.4 Hz, 1H), 7.52 (dd, J=5.8,
3.4 Hz, 2H), 7.31 (dd, J=5.5 Hz, 3.5 Hz, 1H), 7.26–7.23 (m,
1H), 7.11–7.05 (m, 1H), 6.98 (dd, J=7.9, 1.7 Hz, 1H), 6.96–
6.92 (m, 2H), 6.91 (d, J=3.1 Hz, 1H), 6.89 (d, J=2.2 Hz,
1H), 6.72 (pt, J=9.0 Hz, 1H), 4.78 (d, J=10.8 Hz, 1H), 3.68
(d, J=10.8 Hz, 1H), 3.14 (s, 3H); 13C NMR (126 MHz,
Figure 3. ortho-Arylated pharmaceuticals.
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CDCl3): d=171.7, 170.3, 158.9 (d, 1JF,C =247.3 Hz), 142.8,
6.74 (dd, J=7.9, 1.6 Hz, 1H), 4.54 (d, J=10.9 Hz, 1H), 3.64
(d, J=10.9 Hz, 1H), 3.04 (s, 3H); 13C NMR (126 MHz,
DMSO-d6): d=171.6, 169.2, 145.0, 143.1, 140.3, 139.2, 131.8,
131.0, 130.4, 130.2, 129.7, 129.5 (2C), 128.9, 128.6, 127.6 (q,
139.7, 135.6, 131.5 (d, 3JF,C =3.1 Hz), 130.8, 130.4, 129.9,
2
129.4, 129.1, 128.6 (d, 3JF,C =8.0 Hz), 128.5 (d, JF,C
=
4
16.1 Hz), 128.4, 128.1, 123.4, 123.3 (d, JF,C =3.8 Hz), 119.9,
115.0 (d, 2JF,C =22.3 Hz), 56.6, 35.0; 19F NMR (376 MHz,
CDCl3): d=À115.1 (1F); HR-MS-ESI: m/z= 345.1390, cal-
culated for C22H17FN2O [+H]+: 345.1398; elemental analy-
sis: calculated for C22H17FN2O (%): C 76.73, H 4.98, N 8.13;
found: C 76.59, H 4.82, N 8.26.
3
1
2JF,C =31.6 Hz), 125.1 (q, JF,C =3.7 Hz, 2C), 124.6 (q, JF,C
=
272 Hz), 123.9, 120.8, 56.9, 34.7; 19F NMR (376 MHz,
CDCl3): d=À61.15 (s, 3F); HR-MS-ESI: m/z=395.1374,
calculated for C23H17F3N2O [+H]+: 395.1366; elemental
analysis: calculated for C23H17F3N2O (%): C 70.04, H 4.34,
N 7.10; found: C 69.95, H 4.38, N 6.98.
1-Methyl-5-(3’-fluorobiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (2c)
Palladacycle (3)
5-Phenyl-1H-1,4-diazepin-2(3H)-one (0.20 g, 0.85 mmol) and
sodium tetrachloropalladate (0.23 g, 0.78 mmol) were com-
bined in ethanol (20 mL) for 48 h at room temperature. The
orange precipitate was filtered and washed with further eth-
anol (10 mL) and chloroform (10 mL). An orange solid
powder was collected after drying under vacuum; yield:
0.25 g (69%). The product was too insoluble for NMR anal-
ysis.
The same procedure as 2a was used but bis(3-fluorophenyl)-
iodonium tetrafluoroborate (0.36 g, 0.90 mmol) was used in-
stead of diphenyliodonium tetrafluoroborate. The final
product was obtained as a white powder; yield: 0.111 g
(54%). 1H NMR (500 MHz, DMSO-d6): d=7.70 (d, J=
7.4 Hz, 1H), 7.64–7.55 (m, 2H), 7.35 (d, JF,H =7.4 Hz, 2H),
7.18–7.13 (m, 2H), 6.96 (pt, J=7.8 Hz, 2H), 6.74 (d, J=
7.8 Hz, 1H), 6.71 (d, JF,H =7.7 Hz, 1H), 6.67 (d, J=10.0 Hz,
1H), 4.55 (d, J=11.0 Hz, 1H), 3.69 (d, J=11.0 Hz, 1H),
3.10 (s, 3H); 13C NMR (126 MHz, DMSO-d6): d=172.3,
168.9, 162.1 (d, 1JF,C =244.9 Hz), 143.1 (d, 3JF,C =11.9 Hz),
The product from above reaction (0.12 g, 0.33 mmol) and
triphenylphosphine (0.08 g, 0.30 mmol) were combined in di-
chloromethane (10 mL) and stirred overnight. The resulting
unwanted precipitate was filtered through celite and the fil-
trate was concentrated under vacuum. Hexane was added to
the concentrated crude product to induce precipitation, the
precipitates was filtered and dried under vacuum. The prod-
uct was obtained as a yellow solid; yield: 0.12 g (63%).
1H NMR (500 MHz, CDCl3): d=9.29 (s, 1H), 7.81–7.75 (m,
6H), 7.72 (d, J=8.4 Hz, 2H), 7.59 (pt, J=7.8 Hz, 1H), 7.44–
7.41 (m, 3H), 7.39–7.34 (m, 5H), 7.30 (d, J=8.4 Hz, 2H),
7.04 (d, J=7.7 Hz, 1H), 6.83 (pt, J=7.3 Hz, 1H), 6.57–6.49
(m, 2H), 6.15 (d, J=12.2 Hz, 1H), 3.81 (d, J=12.2 Hz, 1H);
13C NMR (500 MHz) CDCl3: d=182.3, 171.6, 159.1, 147.8,
138.6, 135.5 (2C), 135.4 (4C), 135.0 (2C), 132.5, 131.4, 131.2,
131.0, 130.9, 130.6 (2C), 130.4, 130.2, 128.0 (4C), 127.9 (2C),
124.3, 123.5, 123.4, 121.9, 53.9; 31P NMR (162 MHz CDCl3):
d=42.4 (s, 1P); HR-MS-ESI: m/z=603.0837, calculated for
C33H26ClN2OPPd [ÀClÀ]+: 603.0812; elemental analysis: cal-
culated for C33H26ClN2OPPd·0.9CH2Cl2 (%): C 56.88, H
3.91, N 3.91; found: C 56.69, H 4.02, N 3.84.
140.5, 138.6, 132.1, 131.1, 130.4, 130.4 (d, 3JF,C =4.3 Hz),
2
130.3, 129.4, 129.1, 128.3, 125.0, 124.0, 121.1, 115.5 (d, JF,C
=
21.8 Hz), 114.0 (d, 2JF,C =20.9 Hz), 114.1, 56.6, 34.8;
19F NMR (376 MHz, DMSO-d6): d=À113.4 (1F); HR-MS-
ESI: m/z=345.1394, calculated for C22H17FN2O [+H]+:
345.1398; LC-MS: purity (UV)=96%, retention time (tR)=
15.13 min.
1-Methyl-5-(3’-trifluoromethylbiphenyl-2-yl)-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (2d)
The same procedure as 2a was used but bis(3-trifluorome-
thylphenyl)iodonium tetrafluoroborate (0.45 g, 0.90 mmol)
was used instead of diphenyliodonium tetrafluoroborate.
The final product was obtained as a white powder; yield:
0.095 g (40%). 1H NMR (500 MHz, CDCl3): d=7.79–7.74
(m, 1H), 7.57–7.53 (m, 2H), 7.36 (d, J=7.7 Hz, 1H), 7.26–
7.23 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.17 (d, J=1.6 Hz,
1H), 7.16–7.14 (m, 1H), 6.94–6.85 (m, 3H), 4.81 (d, J=
10.9 Hz, 1H), 3.69 (d, J=10.9 Hz, 1H), 3.10 (s, 3H);
5-Phenyl-5-biphenyl-2-yl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (4a)
13C NMR (126 MHz, CDCl3): d=172.0, 169.7, 142.8, 141.9,
2
140.6, 139.1, 132.3, 131.2, 130.4, 130.6, 130.0 (q, JF,C
=
=
=
3
5-Phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one
(0.14 g,
29.9 Hz), 129.9, 129.8, 129.1, 128.1, 127.9, 125.2 (q, JF,C
3
3.2 Hz), 123.7 (q, 1JF,C =272.9 Hz), 123.4, 123.1 (q, JF,C
0.59 mmol), diphenyliodonium tetrafluoroborate (0.33 g,
0.90 mmol) and palladium (II) acetate (6.0 mg, 5 mol%)
were combined in degassed glacial acetic acid (4 mL) and
stirred for 1 h at 1258C. Thereafter the cooled reaction mix-
ture was filtered over celite, washed with DCM (10 mL) and
concentrated under reduced pressure. The residue was dis-
solved in DCM (20 mL), washed with saturated sodium bi-
carbonate and the organic layer was collected using a (hydro-
phobic frit) phase separator. The solution was concentrated
under reduced pressure to yield an orange product. The
crude material was purified by flash chromatography (30 g
C18, acetonitrile: water, 30% to 90%). Starting material, 5-
phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was recov-
ered (0.031 g, 0.13 mmol) and the final product was obtained
3.8 Hz), 119.9, 56.7, 34.7; 19F NMR (376 MHz, CDCl3): d=
À63.3 (s, 3F); HR-MS-ESI: m/z=395.1381, calculated for
C23H17F3N2O [+H]+: 395.1366; LC-MS: purity (UV)=95%,
tR=18.14 min.
1-Methyl-5-(4’-trifluoromethylbiphenyl-2-yl)-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (2e)
The same procedure as 2a was used but bis(4-trifluorome-
thylphenyl)iodonium tetrafluoroborate (0.45 g, 0.90 mmol)
was used instead of diphenyliodonium tetrafluoroborate.
The final product was obtained as a white powder; yield:
0.104 g (44%). 1H NMR (500 MHz, DMSO-d6): d=7.72–
7.68 (m, 1H), 7.61–7.58 (m, 2H), 7.48 (d, J=7.9 Hz, 2H),
7.37–7.28 (m, 2H), 7.12–7.05 (m, 3H), 6.97–6.90 (m, 1H),
as
(500 MHz, DMSO-d6): d=10.33 (s, 1H), 7.57 (dd, J=7.1,
a
white powder; yield: 0.079 g (56%). 1H NMR
104
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ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 98 – 109

À
FULL PAPERS
Late Stage C H Activation of a Privileged Scaffold
1.8 Hz, 1H), 7.55 (dd, J=7.5, 1.6 Hz, 1H), 7.52–7.47 (m,
1H), 7.34 (dd, J=7.6, 1.4 Hz, 1H), 7.19–7.14 (m, 1H), 7.12–
7.04 (m, 3H), 6.95–6.90 (m, 2H), 6.79 (dd, J=7.9, 6.4 Hz,
2H), 6.74–6.70 (m, 1H), 4.04 (s, 2H); 13C NMR (126 MHz,
DMSO-d6): d=172.3, 169.7, 141.5, 140.5, 139.8, 139.2, 131.3,
130.9, 130.2, 130.1, 129.4, 128.6 (2C), 128.3, 128.0 (2C),
127.6, 127.1, 122.6, 120.7, 57.3; HR-MS-ESI: m/z=313.1336,
calculated for C21H16N2O [+H]+: 313.1335; elemental analy-
sis: calculated for C21H16N2O (%): C 80.75, H 5.16, N 8.97;
found: C 80.64, H 5.06, N 9.08.
used instead of diphenyliodonium tetrafluoroborate. Starting
material, 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,
was recovered (0.022 g, 0.09 mmol) and the final product
was obtained as a white powder; yield: 0.119 g (63%).
1H NMR (500 MHz, DMSO-d6): d=10.22 (s, 1H), 7.63–7.53
(m, 3H), 7.42 (d, J=7.9 Hz, 1H), 7.38 (dd, J=7.4, 1.5 Hz,
1H), 7.34 (pt, J=7.9 Hz, 1H), 7.20–7.14 (m, 3H), 6.85–6.79
(m, 2H), 6.75 (dd, J=8.2, 1.5 Hz, 1H), 4.03 (s, 2H);
13C NMR (126 MHz, DMSO-d6: d=171.7, 169.8, 141.6,
140.1, 139.9, 139.2, 132.6, 131.5, 130.9, 130.2 (2C), 129.6,
2
3
129.1, 129.0 (q, JF,C =31.8 Hz), 128.4, 128.0, 125.0 (q, JF,C
=
3.7 Hz), 124.3 (q, 1JF,C =272.6 Hz), 123.8 (q, 3JF,C =3.7 Hz),
122.6, 120.6, 57.4; 19F NMR (376 MHz, DMSO-d6): d=
À61.2 (s, 3F): HR-MS-ESI: m/z=381.1211, calculated for
C22H15F3N2O [+H]+: 381.1209; elemental analysis: calculat-
ed for C22H15F3N2O·0.3CH2Cl2 (%): C 66.00, H 3.87, N 6.90;
found: C 66.19, H 3.97, N 6.99.
5-(2’-Fluorobiphenyl-2-yl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (4b)
The same method as 4a was used but bis(2-fluorophenyl)io-
donium tetrafluoroborate (0.36 g, 0.90 mmol) was used in-
stead of diphenyliodonium tetrafluoroborate. Starting mate-
rial, 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, was
recovered (0.021 g, 0.09 mmol) and the final product was ob-
tained as a white powder; yield: 0.114 g (69%). 1H NMR
(500 MHz, DMSO-d6): d=10.25 (s, 1H), 7.59–7.49 (m, 3H),
5-(4’-Trifluoromethylbiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (4e)
3
7.35–7.30 (m, 1H), 7.22 (ddd, J=6.7, 2.0 Hz, JF,H =8.4 Hz,
The same method as 4a was used but bis(4-trifluoromethyl-
phenyl)iodonium tetrafluoroborate (0.45 g, 0.90 mmol) was
used instead of diphenyliodonium tetrafluoroborate. Starting
material, 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,
was recovered (0.036 g, 0.15 mmol) and the final product
was obtained as a white powder; yield: 0.097 g (58%).
1H NMR (500 MHz, DMSO-d6): d=10.46 (s, 1H), 7.62 (pt,
J=6.7 Hz, 2H), 7.59–7.53 (m, 1H), 7.44 (d, J=7.9 Hz, 2H),
7.40 (d, J=7.5 Hz, 1H), 7.18 (pt, J=7.6 Hz, 1H), 7.13 (d,
J=7.8 Hz, 2H), 6.80 (d, J=7.8 Hz, 2H), 6.75 (d, J=7.9 Hz,
1H), 4.05 (s, 2H); 13C NMR (126 MHz, DMSO-d6): d=
1H), 7.16–7.10 (m, 1H), 6.97–6.87 (m, 3H), 6.86–6.85 (m,
2H), 6.83 (d, J=8.2 Hz, 1H), 3.97 (s, 2H); 13C NMR
1
(126 MHz, DMSO-d6): d=175.9, 174.6, 163.4 (d, JF,C
=
4
247.3 Hz), 145.3, 143.8, 140.3, 136.2 (d, JF,C =3.2 Hz), 136.1,
135.8, 135.4, 134.5, 134.4 (t, JF,C =4.1 Hz), 133.1, 132.9 (d,
3
2JF,C =15.6 Hz), 132.7, 128.9 (d, 3JF,C =3.5 Hz), 127.4, 125.5,
120.1, 120.0 (d, 2JF,C =22.1 Hz), 62.1; 19F NMR (376 MHz,
DMSO-d6): d=À113.4 (1F); HR-MS-ESI: m/z=331.1232,
calculated for C21H15FN2O [+H]+: 331.1241; elemental anal-
ysis: calculated for C21H15FN2O (%): C 76.35, H 4.58, N
8.48; found: C 76.23, H 4.68, N 8.47.
171.7, 169.9, 144.6, 140.1, 139.7, 139.3, 131.5, 131.2, 130.4,
2
130.3, 129.5, 129.4 (2C), 128.5, 128.1, 127.7 (q, JF,C
=
=
5-(3’-Fluorobiphenyl-2-yl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (4c)
1
31.6 Hz), 124.9 (q, 3JF,C =4.1 Hz, 2C), 124.6 (q, JF,C
272.8 Hz), 122.8, 120.6, 57.3; 19F NMR (376 MHz, DMSO-
d6): d=À61.0 (s, 3F); HR-MS-ESI: m/z=381.1206, calculat-
ed for C22H15F3N2O [+H]+: 381.1209; elemental analysis:
calculated for C22H15F3N2O (%): C 69.47, H 3.98, N 7.36;
found: C 69.30, H 3.88, N 7.44.
The same method as 4a was used but bis(3-fluorophenyl)io-
donium tetrafluoroborate (0.36 g, 0.90 mmol) was used in-
stead of diphenyliodonium tetrafluoroborate. Starting mate-
rial, 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was
recovered (0.045 g, 0.19 mmol) and the final product was ob-
tained as a white powder; yield: 0.095 g (72%). 1H NMR
(500 MHz, DMSO-d6): d=10.36 (s, 1H), 7.59 (dd, J=1.8,
3JF,H =7.2 Hz, 1H), 7.56 (dd, J=7.4, 1.7 Hz, 1H), 7.54 (dd,
J=7.4, 1.5 Hz, 1H), 7.36 (dd, J=7.5, 1.5 Hz, 1H), 7.21 (ddd,
5-(4’-Methoxybiphenyl-2-yl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (4f)
3
The same method as 4a was used but 5-phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one (0.095 g, 0.40 mmol) and bis(4-
J=8.5, 1.6, JF,H =7.1 Hz, 1H), 7.15–7.10 (m, 1H), 6.92–6.87
(m, 1H), 6.86–6.80 (m, 2H), 6.73 (dd, J=7.7, 1.6 Hz, 2H),
6.70 (d, J=10.0 Hz, 1H), 4.05 (s, 2H); 13C NMR (126 MHz,
methoxyphenyl)iodonium
tetrafluoroborate
(0.26 g,
1
0.60 mmol) were used instead of diphenyliodonium tetra-
fluoroborate. Starting material, 5-phenyl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one was recovered (0.016 g, 0.07 mmol)
and the final product was obtained as a white powder; yield:
DMSO-d6): d=172.0, 169.8, 161.8 (d, JF,C =243.9 Hz), 142.9
(d, 3JF,C =8.0 Hz), 140.2, 139.8, 139.3, 131.5, 130.9, 130.2,
130.1, 129.9 (d, 3JF,C =8.4 Hz), 129.5, 128.2, 128.1, 124.9,
2
122.7, 120.6, 115.3 (d, 2JF,C =21.9 Hz), 113.9 (d, JF,C
=
1
21.0 Hz), 57.3; 19F NMR (376 MHz, DMSO-d6): d=À113.4
C21H15FN2O [+H]+: 331.1241; LC-MS: purity (UV)=100%,
tR=12.19 min.
0.039 g (35%). H NMR (500 MHz, CDCl3): d=8.36 (s, 1H),
7.69 (d, J=7.4 Hz, 1H), 7.53–7.42 (m, 2H), 7.28 (d, J=
7.5 Hz, 1H), 7.16 (pt, J=7.7 Hz, 1H), 6.94–6.80 (m, 4H),
6.70 (d, J=8.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 2H), 4.30 (s,
2H), 3.72 (s, 3H); 13C NMR (126 MHz, CDCl3): d=173.2,
170.5, 158.6, 141.6, 137.3, 133.3, 131.2, 130.0, 130.1, 129.9,
129.8 (2C), 129.7, 129.6, 127.0, 123.2, 120.0, 113.1 (2C),
110.0, 56.3, 55.3; HR-MS-ESI: m/z=343.1447, calculated for
C22H18N2O [+H]+: 343.1441; LC-MS: purity (UV)=99%,
tR=10.49 min.
(1F);
HR-MS-ESI:
m/z=331.1239,
calculated
for
5-(3’-Trifluoromethylbiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (4d)
The same method as 4a was used but bis(3-trifluoromethyl-
phenyl)iodonium tetrafluoroborate (0.45 g, 0.90 mmol) was
Adv. Synth. Catal. 2016, 358, 98 – 109
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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105

FULL PAPERS
Raysa Khan et al.
J=7.5 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.6 Hz,
1H), 4.33 (s, 2H); 13C NMR (126 MHz, CDCl3): d=171.7,
169.8, 138.7, 137.3, 131.8, 130.7, 130.6, 129.6 (2C), 128.9,
128.5, 128.4 (2C), 122.6, 56.5; HR-MS-ESI: m/z=271.0627,
calculated for C15H11ClN2O [+H]+: 271.0633; LC-MS: purity
(UV)=100%, tR=12.40 min.
3-Benzyl-5-(2’-fluorobiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (4g)
The same method as 4a was used but 3-benzyl-5-phenyl-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (0.17 g, 0.52 mmol) in-
stead of 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,
and bis(2-fluorophenyl)iodonium tetrafluoroborate (0.29 g,
0.78 mmol) were used instead of diphenyliodonium tetra-
fluoroborate and the reaction was carried out at 1508C. The
final product was obtained as a white powder; yield: 0.090 g
7-Chloro-5-biphenyl-2-yl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (5a)
1
(41%). H NMR (500 MHz, CDCl3): d=7.83 (s, 1H), 7.57–
The same method as 4a was used but 7-chloro-5-phenyl-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (0.16 g, 0.6 mmol) was
used instead of 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-
2-one. Starting material, 7-chloro-5-phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one, was recovered (0.010 g, 0.04 mmol)
and the final product was obtained as a white powder; yield:
7.43 (m, 3H), 7.37–7.24 (m, 5H), 7.24–6.87 (m, 7H), 6.73
(pt, J=9.1 Hz, 1H), 6.64 (d, J=8.0 Hz, 1H), 3.75–3.54 (m,
2H), 3.35–3.40 (m, 1H); 13C NMR (126 MHz, CDCl3): d=
170.3, 170.1, 158.8 (d, 1JF,C =247.1 Hz), 139.9, 139.2, 136.8,
135.8, 131.7, 131.2, 130.8, 130.5, 129.9, 129.8 (2C), 129.5,
3
3
1
128.9 (d, JF,C =8.2 Hz), 128.5 (d, JF,C =4.0 Hz), 128.4, 128.3,
0.118 g (61%). H NMR (500 MHz, DMSO-d6): d=10.44 (s,
2
128.2 (2C), 128.1, 126.1, 123.3, 120.0, 114.9 (d, JF,C
=
1H), 7.63 (dd, J=7.6, 1.5 Hz, 1H), 7.61–7.57 (m, 1H), 7.54–
7.50 (m, 1H), 7.36 (dd, J=7.6, 1.4 Hz, 1H), 7.21 (dd, J=8.7,
2.5 Hz, 1H), 7.12 (dd, J=8.1, 6.5 Hz, 2H), 7.10–7.05 (m,
1H), 6.91 (dd, J=7.2, 1.7 Hz, 2H), 6.78 (d, J=8.7 Hz, 1H),
6.63 (d, J=2.4 Hz, 1H), 4.09 (s, 2H); 13C NMR (126 MHz,
DMSO-d6): d=170.8, 169.4, 141.6 140.5, 139.0, 138.2, 131.2,
131.1, 130.5, 130.3, 129.6, 128.5 (2C), 128.4, 128.2 (2C),
127.8, 127.2, 126.4, 122.7, 57.4; HR-MS-ESI: m/z=347.0947,
calculated for C21H15ClN2O [+H]+: 347.0946; elemental
analysis: calculated for C21H15ClN2O (%): C 72.73, H 4.36,
N 8.08; found: C 72.63, H 4.26, N 8.15.
21.8 Hz), 64.8, 37.4; 19F NMR (376 MHz, DMSO-d6): d=
À115.9 (s, 1F); HR-MS-ESI: m/z=421.1709, calculated for
C28H21FN2O [+H]+: 421.1711; elemental analysis: calculated
for C28H21FN2O (%): C 79.98, H 5.13, N 6.66; found: C
79.85, H 4.97, N 6.73.
5-(3’-Methylbiphenyl-2-yl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (4h)
The same method as 4a was used but 5-phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one (0.100 g, 0.42 mmol) and (3-
methylphenyl)(2,4,6-trimethylphenyl)iodonium
(0.31 g, 0.62 mmol) were used instead of diphenyliodonium
tetrafluoroborate. Starting material, 5-phenyl-1,3-dihydro-
triflate
7-Chloro-5-(4’-nitrobiphenyl-2-yl)-1,3-dihydro-2H-1,4-
benzodiazepin-2-one (5b)
2H-1,4-benzodiazepin-2-one
0.05 mmol) and the final product was obtained as a white
powder; yield: 0.070 g (58%). H NMR (500 MHz, CDCl3):
was
recovered
(0.012 g,
The same method as for 5a was used but (4-nitrophenyl)-
(2,4,6-trimethylphenyl)iodonium triflate (0.47 g, 0.9 mmol)
was used instead of of diphenylliodonium tetrafluoroborate.
Starting material, 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-ben-
zodiazepin-2-one recovered (0.040 g, 0.15 mmol) and the
final product was obtained as a white powder; yield: 0.099 g
(55%). 1H NMR (500 MHz, DMSO-d6): d=10.51 (s, 1H),
8.08–7.91 (m, 3H), 7.70–7.65 (m, 1H), 7.64–7.61 (m, 1H),
7.44–7.40 (m, 1H), 7.27 (dd, J=8.8, 2.6 Hz, 1H), 7.18–7.13
(m, 2H), 6.76 (d, J=8.8 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H),
4.09 (s, 2H); 13C NMR (126 MHz, DMSO-d6): d=170.1,
169.4, 144.6, 140.1, 139.6, 139.1, 138.1, 131.5, 131.1, 130.7,
130.1, 129.9, 129.7, 129.1, 128.6, 126.7, 125.4, 124.9, 123.8,
122.6, 57.4; HR-MS-ESI: m/z=392.0008, calculated for
C21H14N3O3 [+H]+: 392.0013; LC-MS: purity (UV)=94%,
tR=17.03 min.
1
d=8.41 (s, 1H), 7.71 (dd, J=8.0, 1.9 Hz, 1H), 7.53–7.45 (m,
2H), 7.31–7.28 (m, 1H), 7.17–7.12 (m, 1H), 6.96–6.91 (m,
1H), 6.88–6.81 (m, 3H), 6.78–6.73 (m, 2H), 6.67 (dd, J=8.0,
1.0 Hz, 1H), 4.29 (s, 2H), 2.18 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=173.2, 170.7, 142.2, 140.6, 139.6, 137.4, 137.1,
131.0, 129.9, 129.8, 129.7, 129.6, 129.5, 128.8, 127.4, 127.3,
127.2, 125.8, 123.0, 119.9, 56.4, 21.1; HR-MS-ESI: m/z=
327.1483, calculated for C22H18N2O [+H]+: 327.1492; ele-
mental analysis: calculated for C22H18N2O (%): C 80.96, H
5.56, N 8.5; found: C 80.93, H 5.42, N 8.65.
7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-
2-one (Nordazepam)
5-Chloro-2-aminobenzophenone (0.621 g, 3.15 mmol), N-(3-
7-Chloro-5-(2’-fluorobiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (5c)
dimethylaminpropyl)-N-ethylcarbodiimide
hydrochloride
(0.604 g, 3.15 mmol) and N-Boc-glycine (0.550 g, 3.15 mmol)
were combined in toluene (6 mL) and irradiated in the mi-
crowave for 30 min at 1508C. Trifluoroacetic acid (2 mL)
was then added to the mixture and it was irradiated for a fur-
ther 20 min at 1508C. The cooled solution was neutralized
by an aqueous 3N NaOH solution (50 mL) and extracted
with dichloromethane (3”30 mL). The organic layers were
dried over MgSO4 and evaporated. The crude material was
purified by column chromatography (ethyl acetate:DCM,
10% to 40%) and the final product was obtained as a white
The same method as 5a was used but bis(2-fluoropheny)lio-
donium tetrafluoroborate (0.36 g, 0.9 mmol) was used in-
stead of diphenylliodonium tetrafluoroborate. Starting mate-
rial, 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-
one, was recovered (0.010 g, 0.04 mmol), the final product as
a white powder; yield: 0.13 g (64%) and the diarylated
product 5c’ was collected as a white powder; yield: 0.026 g
(10%). 1H NMR (500 MHz, DMSO-d6: d=10.37 (s, 1H),
7.66–7.61 (m, 1H), 7.59–7.54 (m, 2H), 7.34 (d, J=7.3 Hz,
1H), 7.31–7.23 (m, 1H), 7.21–7.11 (m, 1H), 6.97 (pt, J=
7.5 Hz, 1H), 6.91 (d, J=9.5 Hz, 1H), 6.87 (dd, J=6.8 Hz,
1
powder; 0.29 g (34%). H NMR (500 MHz, CDCl3): d=9.41
(s, 1H), 7.53 (d, J=7.6 Hz, 2H), 7.50–7.44 (m, 2H), 7.41 (pt,
106
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ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 98 – 109

À
FULL PAPERS
Late Stage C H Activation of a Privileged Scaffold
3JF,H =8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.76 (d, J=
2.5 Hz, 1H), 4.03 (s, 2H); 13C NMR (126 MHz, DMSO-d6):
5-(2’-Fluorobiphenyl-2-yl)-1,3-dihydro-2D-1,4-
benzodiazepin-2-one (6a)
d=169.8, 169.5, 158.7 (d, 1JF,C =244.8 Hz), 139.82, 138.1,
3
The same method as for the synthesis of 4b was used but
acetic acid-d4 (4 mL) was used instead of acetic acid as the
solvent. The final product was obtained as a white powder;
135.5, 131.4, 131.2, 131.1, 130.9, 130.2, 129.8 (d, JF,C
=
=
3
2
8.0 Hz), 129.6, 129.2, 128.6 (d, JF,C =9.8 Hz), 128.0 (d, JF,C
15.6 Hz), 126.6, 124.3 (d, 4JF,C =3.5 Hz), 122.7, 115.3 (d,
2JF,C =22.1 Hz), 57.3; 19F NMR (376 MHz, DMSO-d6): d=
À120.4 (1F); HR-MS-ESI: m/z=365.0847, calculated for
C21H14FN2O [+H]+: 365.0851; elemental analysis: calculated
for C21H14FN2O (%): C 69.14, H 3.87, N 7.68; found: C
68.93, H 3.70, N 7.64.
1
yield: 0.09 g (47%). H NMR (500 MHz, CDCl3): d=8.93 (s,
1H), 7.76–7.69 (m, 1H), 7.55–7.47 (m, 2H), 7.36–7.29 (m,
1H), 7.18 (pt, J=7.7 Hz, 1H), 7.05–6.83 (m, 5H), 6.72 (m,
2H); 13C NMR (126 MHz, CDCl3): d=172.3, 171.0, 158.8
3
(1JC,F =246.8 Hz), 140.2, 137.3, 135.7, 131.4 (d, JF,C =3.9 Hz),
131.2, 130.8, 130.0, 129.8, 129.5, 129.1 (d, 3JF,C =7.9 Hz),
7-Chloro-5-(2,2’-difluorobiphenyl-2-yl)-1,3-dihydro-2H-
128.6, 128.1 (d, 2JF,C =15.4 Hz), 127.9, 123.3 (d, JF,C
=
4
1
1,4-benzodiazepin-2-one (5c’): H NMR (500 MHz, CDCl3):
3.6 Hz), 123.2, 120.2, 114.9 (d, 2JF,C =22.2 Hz), 56.0 (m);
2H NMR (61 MHz, CH3CO2H): d=4.27 (s, 2H); HR-MS-
ESI: m/z=333.1362, calculated for C21H13D2FN2O [+H]+:
333.1210; LC-MS: purity (UV)=97%, tR=11.06 min.
d=7.77 (s, 1H), 7.59 (pt, J=7.7 Hz, 1H), 7.44 (d, J=7.7 Hz,
2H), 7.26–7.00 (m, 8H), 6.87 (pt, J=9.2 Hz, 2H), 6.49 (d,
J=8.6 Hz, 1H), 3.85 (s, 2H); 13C NMR (126 MHz, CDCl3):
1
d=168.3, 167.7, 159.0 (d, JF,C =243.8 Hz, 2C), 139.0, 137.9,
3
136.4, 131.9, 131.8, 131.1 (2C), 131.0 (2C), 129.9 (d, JF,C
=
8.1 Hz, 2C), 129.5, 129.3, 128.5, 128.3, 128.2, 126.5, 124.3 (d,
5-Biphenyl-2-yl-1,3-dihydro-2D-1,4-benzodiazepin-2-
one (6b)
2
4JF,C =3.5 Hz, 2C), 122.6, 115.4 (d, JF,C =22.1 Hz, 2C), 56.9;
19F NMR (376 MHz, DMSO-d6): d=À113.7 (2F); HR-MS-
ESI: m/z=415.1072, calculated for C27H17ClF2N2O [+H]+:
459.1070; LC-MS: purity (UV)=97%, tR=20.38 min.
The same method as 1b was used and the product was col-
1
lected in quantitative yield. H NMR (500 MHz, DMSO-d6):
d=10.31 (s, 1H), 7.58–7.52 (m, 2H), 7.48 (d, J=7.4 Hz,
1H), 7.33 (d, J=7.4 Hz, 1H), 7.15 (pt, J=7.4 Hz, 1H), 7.10–
7.03 (m, 3H), 6.91 (d, J=7.1 Hz, 2H), 6.81–6.75 (m, 2H),
6.70 (d, J=7.9 Hz, 1H); 13C NMR (126 MHz DMSO-d6):
d=173.2, 169.6, 141.5, 140.5, 139.8, 139.2, 131.3, 130.9, 130.2,
130.1, 129.4, 128.6 (2C), 128.3, 128.0 (2C), 127.6, 127.1,
122.6, 120.7, 57.0; 2H NMR (61 MHz, CH3CO2H): d=4.44
(2H); HR-MS-ESI: m/z=315.1453, calculated for
C21H14D2N2O [+H]+: 315.1445.
7-Chloro-5-(4’-trifluorobiphenyl-2-yl)-1,3-dihydro-2H-
1,4-benzodiazepin-2-one (5d)
The same method as 5a was used but diphenyliodonium tet-
rafluoroborate (0.45 g, 0.9 mmol) was used instead of diphe-
nyliodonium tetrafluoroborate and the reaction temperature
was 1458C. Starting material, 7-chloro-5-phenyl-1,3-dihydro-
2H-1,4-benzodiazepin-2-one,
was
recovered
(0.020 g,
0.066 mmol) and the final product 5d was obtained as
a white powder; yield: 0.053 g (24%). The diarylated prod-
uct 5d’ was collected as a brown powder; yield: 0.045 g
5-(3’-Trifluorobiphenyl-2-yl)-1,3-dihydro-2D-1,4-
benzodiazepin-2-one (6c)
1
(15%). H NMR (500 MHz, CDCl3): d=8.27 (s, 1H), 7.76
The same method as 1b was used and the product was col-
(d, J=7.0 Hz, 1H), 7.59 (dd, J=6.7, 6.0 Hz, 2H), 7.38 (d,
J=7.8 Hz, 2H), 7.33 (d, J=7.0 Hz, 1H), 7.11 (d, J=7.9 Hz,
3H), 6.82 (s, 1H), 6.59 (d, J=8.6 Hz, 1H), 4.30 (s, 2H);
1
lected in quantitative yield. H NMR (500 MHz, DMSO-d6):
d=10.20 (s, 1H), 7.61–7.51 (m, 3H), 7.43–7.28 (m, 3H),
7.19–7.10 (m, 3H), 6.80 (dd, J=8.4, 5.1 Hz, 2H), 6.72 (d, J=
7.9 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d=171.7,
169.8, 141.6, 140.1, 139.9, 139.2 (2C), 132.6, 131.5, 130.9,
130.2, 129.6, 129.1 (q, 2JF,C =31.7 Hz), 129.0, 128.4, 127.9,
13C NMR (126 MHz, CDCl3): d=171.1, 170.1, 144.5, 140.6,
2
138.9, 136.0, 131.4, 130.4, 130.3, 129.8, 129.2, 129.0 (q, JF,C
=
33.0 Hz), 129.0 (2C), 128.7, 128.4, 124.5 (q, 3JF,C =3.7 Hz,
2C), 124.0 (q, JF,C =272.4 Hz), 121.3, 121.2, 56.4; 19F NMR
1
3
1
124.9 (q, JF,C =3.7 Hz), 124.3 (q, JF,C =273.2 Hz), 123.8 (q,
(376 MHz, DMSO-d6: d=À63.2 (s, 3F); HR-MS-ESI: m/z=
415.0819, calculated for C22H14ClF3N2O [+H]+: 415.0820;
LC-MS: purity (UV)=95%, tR=19.59 min.
3JF,C =3.8 Hz), 122.6, 120.5, 56.5 (CD2); H NMR (61 MHz,
2
CH3CO2H): d=4.40 (2H); HR-MS-ESI: m/z=315.1453, cal-
culated for C22H13D2F3N2O [+H]+: 315.1445.
7-Chloro-5-(4,4’’-trifluorobiphenyl-2,6-yl)-1,3-dihydro-2H-
1
1,4-benzodiazepin-2-one (5d’): H NMR (500 MHz, DMSO-
d6): d=10.43 (s, 1H), 7.69 (pt, J=7.7 Hz, 1H), 7.57 (d, J=
8.0 Hz, 4H), 7.50 (d, J=7.7 Hz, 2H), 7.30 (d, J=8.0 Hz,
4H), 7.26 (d, J=8.8 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.72
(d, J=8.8 Hz, 1H), 3.71 (s, 2H); 13C NMR (126 MHz,
7-Chloro-1-methyl-5-(2’-fluorobiphenyl-2-yl)-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (7a)
7-Chloro-5-(2’-fluorobiphenyl-2-yl)-1,3-dihydro-2H-1,4-ben-
zodiazepin-2-one 5c (0.035 g, 0.096 mmol) was dissolved in
MeOH/THF (1 mL). Potassium carbonate (0.079 g,
0.57 mmol), iodomethane (0.03 mL, 0.48 mmol) were added
and the reaction mixture was stirred overnight at room tem-
perature. Thereafter the reaction mixture was filtered over
celite, washed through with dichloromethane and concen-
trated under reduced pressure. The final product was col-
lected as a white powder; yield: 0.033 g (91%). 1H NMR
(500 MHz, CDCl3): d=7.79–7.73 (m, 1H), 7.54 (dd, J=6.3,
3.1 Hz, 2H), 7.34–7.28 (m, 1H), 7.19 (dd, J=8.9, 2.5 Hz,
1H), 7.12–7.05 (m, 1H), 6.96–6.88 (m, 3H), 6.83 (d, J=
DMSO-d6): d=168.4, 168.3, 145.0, 141.1, 138.3, 137.4, 131.6,
2
130.6 (2C), 130.2, 129.9 (4C), 129.6, 128.4, 127.9 (q, JF,C
=
33.0 Hz, 2C), 126.7, 125.1 (q, 3JF,C =3.7 Hz, 4C), 124.6 (q,
1JF,C =270.4 Hz, 2C), 122.5, 120.0, 118.8, 56.9; 19F NMR
(376 MHz, DMSO-d6): d=À65.2 (s, 6F); HR-MS-ESI: m/
z=559.1003, calculated for C29H17ClF6N2O [+H]+: 559.1006;
LC-MS: purity (UV)=96%, tR=24.92 min.
Adv. Synth. Catal. 2016, 358, 98 – 109
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
107

FULL PAPERS
Raysa Khan et al.
8.9 Hz, 1H), 6.80–6.73 (m, 1H), 4.79 (d, J=10.9 Hz, 1H),
3.66 (d, J=10.9 Hz, 1H), 3.11 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=170.3, 169.3, 158.9 (d, 1JF,C =247.7 Hz), 141.3,
138.9, 135.6, 131.4, 131.3, 131.0 (d, 3JF,C =8.0 Hz), 130.8,
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3
130.4, 129.9, 128.9, 128.8 (d, JF,C =8.0 Hz), 128.7, 128.5 (d,
2JF,C =15.9 Hz), 128.3, 123.4 (d, 4JF,C =3.6 Hz), 121.4, 115.1
2
(d, JF,C =22.2 Hz), 56.7, 35.0; HR-MS-ESI: m/z=379.1012,
calculated for C22H16ClFN2O [+H]+: 379.1008; LC-MS:
purity (UV)=98%, tR=18.09 min.
7-Chloro-1-prop-2-yn-1-yl-5-biphenyl-2-yl-1,3-
dihydro-2H-1,4-benzodiazepin-2-one (7b)
7-Chloro-5-biphenyl-2-yl-1,3-dihydro-2H-1,4-benzodiazepin-
2-one (0.025 g, 0.072 mmol) was dissolved in MeOH/THF
(1 mL). Potassium carbonate (0.060 g, 0.43 mmol), propargyl
bromide (0.027 mL, 0.30 mmol) were added and the reaction
mixture was stirred overnight at room temperature. There-
after the reaction mixture was filtered over celite, washed
through with dichloromethane and concentrated under re-
duced pressure. The final product was collected as a white
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1
powder; yield: 0.024 g (88%). H NMR (500 MHz, DMSO-
d6): d=7.64 (d, J=7.6 Hz, 1H), 7.59 (pt, J=7.6 Hz, 1H),
7.53 (pt, J=7.6 Hz, 1H), 7.41 (dd, J=8.9, 2.3 Hz, 1H), 7.34–
7.27 (m, 2H), 7.19–7.12 (m, 3H), 6.86 (d, J=7.0 Hz, 2H),
6.67 (d, J=2.5 Hz, 1H), 4.81 (d, J=17.5 Hz, 1H), 4.58 (d,
J=10.9 Hz, 1H), 3.74 (d, J=10.9 Hz, 1H), 3.43 (d, J=
17.5 Hz, 1H), 3.37 (s, 1H); 13C NMR (126 MHz, DMSO-d6):
d=170.8, 168.1, 141.7, 140.9, 140.7, 138.2, 131.6, 131.3, 130.1,
130.7, 130.4, 128.6 (2C), 128.4 (2C), 128.3, 128.1, 128.0,
127.3, 121.8, 80.2, 75.2, 56.7, 38.0; HR-MS-ESI: m/z=
385.1108, calculated for C24H17ClN2O [+H]+: 385.1102; LC-
MS: purity (UV)=96%, tR=20.90 min.
Acknowledgements
We thank Dr. Alaa Abdul-Sada (Sussex) and the EPSRC UK
National Mass Spectrometry Facility at Swansea University
for HR-MS measurements. R.K. is funded as an EPSRC
iCASE PhD student (EP/M507568/1) with additional support
from AstraZeneca [14550001 (SME)] and Tocris Biosciences.
The R. M. Phillips Trust is thanked for providing mass-trig-
gered LC-MS facilities.
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