Asymmetric Hydrogenation of Cyclic Imines and Enamines: Access to 1,5-Benzodiazepine Pharmacophores

Article abstract of DOI:10.1055/s-0036-1589401

A new strategy towards the pharmacologically relevant class of dihydro-1,5-benzodiazepines was developed by applying a rhodium-catalyzed asymmetric hydrogenation. The approach represents an efficient protocol providing access to the optically active products in excellent yields (up to 99%) and with high enantioselectivities (up to 92% ee). The versatility of the methodology was demonstrated by a broad substrate scope including alkyl, aryl, and heteroaryl substituents as well as halides. Furthermore, investigations regarding the reaction mechanism were performed and unraveled a preferred reaction of the tautomeric enamine in the rhodium-catalyzed asymmetric hydrogenation.

Full text of DOI:10.1055/s-0036-1589401

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
R. Borrmann et al.
Paper
Synthesis
Asymmetric Hydrogenation of Cyclic Imines and Enamines:
Access to 1,5-Benzodiazepine Pharmacophores
Ruediger Borrmann
asymmetric hydrogenation
O
O
Rene M. Koenigs
Jochen Zoller
H
N
H
N
[Rh(cod)Cl]2 (2.5 mol%)
(R)-DifluoroPhos, NaBArF
15 examples
88–99% yield
65–92% ee
R2
R2
Magnus Rueping*
AcCl, DMAP
N
N
R1
R1
Ac
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
magnus.rueping@rwth-aachen.de
Dedicated to Prof. Dieter Enders on the occasion of his 70th birthday
Received: 18.09.2016
Accepted: 30.09.2016
Published online: 13.10.2016
DOI: 10.1055/s-0036-1589401; Art ID: ss-2016-z0648-op
tral nervous system (CNS) activities (1d and 1e, Figure 1).
Therefore, many groups in industry and academia exam-
ined their synthesis.22–27 However, enantioselective variants
remain challenging and less investigated.28–30
Abstract A new strategy towards the pharmacologically relevant class
of dihydro-1,5-benzodiazepines was developed by applying a rhodium-
catalyzed asymmetric hydrogenation. The approach represents an effi-
cient protocol providing access to the optically active products in excel-
lent yields (up to 99%) and with high enantioselectivities (up to 92% ee).
The versatility of the methodology was demonstrated by a broad sub-
strate scope including alkyl, aryl, and heteroaryl substituents as well as
halides. Furthermore, investigations regarding the reaction mechanism
were performed and unraveled a preferred reaction of the tautomeric
enamine in the rhodium-catalyzed asymmetric hydrogenation.
O
O
H
N
N
F3C
N
1a
N
Cl
diazepam
N
H
(Valium®)
O
H
N
Key words asymmetric hydrogenation, rhodium catalysis, benzodiaz-
epines, reduction, enamine
N
1e
CNS activity
O
N
N
N
Cl
Benzodiazepines are privileged structures in medicinal
chemistry as they possess the ability to bind tightly to spe-
cific receptors.1–21 Not surprisingly, benzodiazepines are
broadly used as anesthetics, muscle relaxants, sedatives,
analgesics, and antiepileptic drugs.7–11 Additionally, benzo-
diazepines have found application as psychotherapeutic
agents in the treatment of depression, insomnia, and anxi-
ety neurosis.3–6 Furthermore, they have been shown to act
as anticancer agents12,13 and as inhibitors of HIV replica-
tion.14,15
O
O
R
1b: lofendazam (R = H)
1c: arfendazam (R = CO2Et)
1d
antitumor activity
Figure 1 Pharmacologically active benzodiazepinones: diazepam (1a,
Valium®), lofendazam (1b), arfendazam (1c) (all sedatives), 1d (antitu-
mor activity), and 1e (CNS activity)
Several biologically active benzodiazepines, including
the best-known diazepam 1a (Valium®, Figure 1), are based
on the 1,4-benzodiazepine scaffold, however, the 1,5-annu-
lated core structure has only recently received significant
interest. For instance, the prominent sedatives and biologi-
cally active benzodiazepines lofendazam16–20 (1b) and
arfendazam19–21 (1c) are both based on the less investigated
4,5-dihydro-1,5-benzodiazepinone structure (Figure 1).
The 4-aryl-substituted analogues are particularly interest-
ing, since they are reported to exhibit antitumor and cen-
Recently, we reported on the first enantioselective
Brønsted acid catalyzed transfer hydrogenation of benzodi-
azepinones.28 However, this reaction is somewhat limited
due to the use of stoichiometric amounts of the Hantzsch
dihydropyridine reductant.
Transition-metal-catalyzed enantioselective hydroge-
nations with molecular hydrogen as reductant are among
the most efficient and economic methods to generate chiral
molecules.31 Asymmetric hydrogenations of imines, enam-
ines, and N-heteroarenes in particular represent a very im-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
R. Borrmann et al.
Paper
Synthesis
portant access towards chiral amines,32,33 not only in aca-
demia, but more importantly in industry34 and drug discov-
ery.35 Thus, we decided to investigate an enantioselective
hydrogenation for the preparation of 4,5-dihydro-1,5-ben-
zodiazepinones. This would allow direct access to this im-
portant class of medicinally relevant products. Herein, we
report on the first transition metal catalyzed asymmetric
hydrogenation of 1,5-benzodiazepinones (Scheme 1).
Table 1 (continued)
Entry Metal precursor
Counterion
Conv. (%)b
ee (%)b
e
13
14
[Rh(cod)Cl]2
SbF6
99
31 (S)
54 (S)
[Rh(cod)Cl]2
BArFd
99 (99)f
a Reaction conditions: 2a (0.08 mmol), metal precursor (5 mol%, half
amount for the dimers [Ir(cod)Cl]2 and [Rh(cod)Cl]2), (R)-BINAP
(5.25 mol%), additive (5.25 mol%), CH2Cl2 (3.2 mL, 25 mM), 60 °C, 80 bar
H2, 20 h.
b Determined by SFC using a chiral stationary phase.
c Not determined.
O
O
H
N
H
N
d Prepared in situ by addition of the corresponding sodium salt.
e Prepared in situ by addition of the corresponding silver salt.
f Isolated yield after column chromatography.
metal
chiral ligand
R2
R2
H2
*
N
N
H
R1
R1
2
3
Typically, the counterion has a significant impact on
both the reactivity and the selectivity in enantioselective
hydrogenation reactions. In particular, the tetrakis-[3,5-
bis(trifluoromethyl)phenyl]borate counterion (BArF) has
been shown to be beneficial in iridium-catalyzed hydroge-
nations.36–38 Thus, a series of iridium and rhodium com-
plexes were prepared bearing a weakly coordinating coun-
terion by addition of the corresponding sodium or silver
salts leading to an in situ counterion exchange. While this
procedure generally resulted in an increased reactivity, only
SbF6 and BArF did additionally improve the enantioselectiv-
ity of the reaction with the latter one showing the best re-
sult (54% ee, Table 1, entry 14).
Scheme 1 Asymmetric hydrogenation of 4-substituted 1H-1,5-benzo-
diazepin-2-(3H)-ones
We commenced our studies with the enantioselective
hydrogenation of benzodiazepinone 2a employing different
metal–(R)-BINAP complexes (Table 1). While palladium and
platinum failed to give satisfying results in the hydrogena-
tion (Table 1, entries 1 and 2), rhodium and iridium showed
high reactivity and gave the desired product 3a in good
yields after acetylation. Therefore, we decided to optimize
the reaction focusing on these two metals and applied vari-
ous precursors.
Typically, the chiral ligand has a tremendous influence
on the enantioinduction. Therefore, different axially, planar
and central chiral phosphine ligands were investigated (Ta-
ble 2). Phospholane-derived ligands exhibited unsatisfacto-
ry selectivities in the hydrogenation of benzodiazepinones
(Table 2, entries 2 and 3). Similarly, planar chiral ligands in-
cluding JosiPhos and WalPhos were less effective (entries 4
and 5). Most of the axially chiral ligands investigated result-
ed in moderate enantioselectivities. However, only P-Phos
and DifluoroPhos gave elevated enantioselectivity of 74% ee
and 80% ee, respectively (entries 8 and 11). Further reaction
optimization consisted of the evaluation of other parame-
ters, such as solvent, temperature, and hydrogen pressure.
No substantial improvement was observed when different
solvents were applied. While aromatic solvents, ethers, and
alcohols failed to give the desired product in acceptable
yields, chlorinated solvents gave similar results with regard
to reactivity and enantioselectivity (CH2Cl2, CHCl3, and 1,2-
dichloroethane gave all 80% ee). Variation of the hydrogen
pressure and reaction temperature showed only a minor
impact on the enantioselectivity. However, the hydrogen
pressure needs to be at least 50 bar, otherwise a complete
loss of reactivity is observed.
Table 1 Survey of Different Metal Precursors and Counterionsa
1. metal precursor
(R)-BINAP, additive
O
O
H
N
H
N
CH2Cl2, 60 °C, 80 bar H2
2. AcCl, DMAP, CH2Cl2
N
N
Ac
Ph
Ph
2a
3a
Entry Metal precursor
Counterion
Conv. (%)b
ee (%)b
1
Pd(OAc)2
OAc
Cl
traces
traces
65
n.d.c
2
Pt(cod)Cl2
Ir(cod)Cp
n.d.c
3
Cp
racemic
12 (R)
8 (S)
4
Ir(cod)acac
[Ir(cod)Cl]2
[Ir(cod)Cl]2
Rh(cod)Cp
Rh(cod)acac
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
acac
Cl
60
5
99
6
BArFd
Cp
99
26 (S)
n.d.
7
<5
8
acac
Cl
95
14 (R)
12 (R)
6 (S)
9
80
e
10
11
12
BF4
99
e
PF6
99
12 (S)
13 (S)
In certain reductions, the concentration has a signifi-
cant influence on the selectivity. Indeed, we observed a
concentration effect and were able to improve the enantio-
selectivity to 84% ee by performing the reaction at 40 °C in
a 50 mM solution (Table 2, entry 13).
e
AsF6
99
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R. Borrmann et al.
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Synthesis
Table 2 Survey of Different Chiral Ligandsa
true for further alkyl substituents and annulated bicycles in
4-position as well as functional groups in the backbone of
the benzodiazepinone structure (both 7- and 8-positions).
1. [Rh(cod)Cl]2
O
H
O
H
N
ligand, NaBArF
N
CH2Cl2, 60 °C, 80 bar H2
1. [Rh(cod)Cl]2
O
O
H
N
H
N
(R)-DifluoroPhos
NaBArF, CH2Cl2
50 °C, 80 bar H2
N
2. AcCl, DMAP, CH2Cl2
N
Ph
Ac
R2
R2
Ph
2a
3a
N
N
a,b,c
R1
2. AcCl, DMAP, CH2Cl2
Ac
R1
Entry
Ligand
BINAP
Conv. (%)b
ee (%)b
2a–o
3a–o
1
99
80
90
99
99
<5
99
99
99
99
54 (S)
O
O
O
H
N
H
N
H
N
2
catASium M
catASium T2
JosiPhos
racemic
32 (S)
3 (R)
3
N
N
N
4
O
O
O
5
WalPhos
28 (S)
16 (R)
44 (S)
74 (S)
46 (S)
48 (S)
80 (S)
82 (S)
84 (S)
3ad
3b
3c
Me
Et
6
DuPhos
99%, 84% ee
99%, 86% ee
98%, 87% ee
7
MeO-Biphep
P-Phos
O
H
O
O
H
N
H
N
N
8
9
SegPhos
N
N
N
10
11
12c
13c,d
SynPhos
O
O
O
DifluoroPhos
DifluoroPhos
DifluoroPhos
99
Ph
3d
3e
3f
99
98%, 82% ee
98%, 85% ee
97%, 78% ee
99 (99)e
O
O
O
H
N
H
N
H
N
a Reaction conditions: 2a (0.08 mmol), [Rh(cod)Cl]2 (2.5 mol%), (R)-BINAP
(5.25 mol%), NaBArF (5.25 mol%), CH2Cl2 (3.2 mL, 25 mM), 60 °C, 80 bar
H2, 20 h.
N
N
N
b Determined by SFC using a chiral stationary phase; absolute configuration
in parentheses.
OMe
F
O
O
O
c Temp = 40 °C.
d CH2Cl2 = 1.6 mL (50 mM).
3ie
97%, 77% ee
OMe
3g
3h
e Isolated yield after column chromatography.
98%, 87% ee
97%, 84% ee
O
O
O
H
N
H
N
H
N
Having established the optimal conditions for the first
metal-catalyzed asymmetric hydrogenation of 1,5-benzodi-
azepinones, we investigated the substrate scope of this re-
action.
Me
N
N
N
Br
O
O
O
O
3jf
3kg
3lg
88%, 84% ee
In general, alkyl-, aryl-, and heteroaryl-substituted ben-
zodiazepinones 2a–o can be employed in the hydrogena-
tion and the corresponding 4,5-dihydro-1H-1,5-benzodiaz-
epin-2(3H)-ones 3a–o are obtained in excellent yields and
with good enantioselectivities (Scheme 2). The benzodiaze-
pinones with para- and meta-substituted aryl residues gave
better enantioselectivities as compared to ortho-aryl- and
alkyl-substituted ones. Surprisingly, the electron-rich thio-
phen-2-yl-substituted substrate 2m could be reduced with
a high degree of enantiocontrol (92% ee). The benzodiaze-
pine core can also be varied as demonstrated by the reduc-
tion of the 7-methyl-substituted derivative 2n. It is note-
worthy to mention that also additional substrates including
a broad variety of halogenated substituents (fluorine, chlo-
rine, bromine, iodine, and trifluoromethyl groups) in vari-
ous positions are tolerated. They provide the desired prod-
ucts in excellent yields without showing dehalogenation,
however, the enantioselectivities are moderate. The same is
93%, 65% ee
92%, 73% ee
O
O
O
H
N
H
N
H
N
Me
N
N
N
Me
O
O
O
S
3mg
3ng
3o
99%, 78% ee
93%, 92% ee
95%, 71% ee
Scheme 2 Substrate scope of the enantioselective hydrogenation of
1,5-benzodiazepinones. a Reagents and conditions: 2a–o (0.2 mmol),
[Rh(cod)Cl]2 (2.5 mol%), (R)-DifluoroPhos (5.25 mol%), NaBArF (5.25
mol%), CH2Cl2 (4 mL, 50 mM), 50 °C, 80 bar H2, 36 h. b Isolated yield af-
ter column chromatography. c Determined by SFC using chiral station-
ary phase. d 40 °C. e 48 h. f 60 h. g 72 h.
In order to gain information about the reaction mecha-
nism, additional experiments were performed. For the hy-
drogenation of 1,5-benzodiazepinones, two different path-
ways are plausible: a) reduction of the imine and b) tau-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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R. Borrmann et al.
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tomerization of the imine to the enamine with subsequent
hydrogenation of the enamine (Scheme 3). From literature
it is known that iridium complexes are highly efficient in
the reduction of cyclic imines, whereas rhodium provides
an excellent level of enantioinduction in the reduction of
enamines and enamides.31–33,39,40 Indeed, the results from
our initial screening of various transition metal precursors
are in agreement with the existing reports from the litera-
ture. On the one hand, iridium complexes were highly reac-
tive but suffered from an unsatisfying enantioinduction,
while on the other hand, rhodium species showed a slightly
decreased reactivity but a higher level of enantiocontrol.
O
O
H
N
H
N
Ac2O
N
N
Ac
Ph
Ph
2a
4a
Rh: 18%
Rh: 99%
Ir: traces
Ir: 97%
O
H
N
N
Ac
Ph
3a
O
O
H
N
H
N
Scheme 4 Investigation of the reaction pathways. Reagents and condi-
tions: 2a or 4a (0.08 mmol), [Rh(cod)Cl]2 or [Ir(cod)Cl]2 (2.5 mol%), (R)-
DifluoroPhos (5.25 mol%), NaBArF (5.25 mol%), CH2Cl2, 40 °C, 50 bar
H2, 1 h.
N
N
H
R1
R1
[Ir]
[Rh]
high reactivity
low selectivity
moderate reactivity
high selectivity
Based on these experimental observations, we postulate
a plausible mechanism (Scheme 5) that is closely related to
previous investigations in the literature.31–33
O
O
H
N
H
N
O
H
N
N
H
N
H
H
P
P
R1
R1
H
Rh
X
*
N
H
H
H
Scheme 3 Possible reaction pathways for the hydrogenation of 1,5-
benzodiazepinones
Ph
H
5a
3a'
To further investigate the mechanistic pathways of the
reaction and detect whether the imine or tautomeric
enamine is reduced, we aimed to react substrates that can-
not undergo the tautomerism. Ideally, two small substitu-
ents (e.g., methyl groups) in α-position to the imine carbon
could prevent the enamine formation. Unfortunately, we
did not succeed in synthesizing such a fixed imine. Howev-
er, we were able to prepare the fixed enamine structure 4a
by trapping it with an acetyl-protecting group (Scheme 4).
Submitting this substrate to our asymmetric hydrogenation
conditions provided a tool to compare the reaction path-
ways for rhodium and iridium catalysts. Interestingly,
whereas enamine 4a was completely hydrogenated by the
rhodium complex in just one hour, it did not react with the
iridium species at all. As a control experiment, to demon-
strate that the low reactivity of iridium is not simply caused
by the lowered temperature und shortened reaction time,
the same conditions were applied for the hydrogenation of
standard substrate 2a. Here, iridium showed a complete re-
action whereas rhodium gave only 18% product. Consider-
ing the results of both experiments, our initial hypothesis is
supported and the reaction most likely undergoes the imine
pathway for iridium complexes whereas in the case of rho-
dium species the tautomeric enamine is hydrogenated.
O
H
N
O
H
N
X
X
H
P
P
P
P
Rh
H
Rh
H
*
*
N
H
N
H
Ph
Ph
H
1a'
H
5d
5b
O
H
N
X
Rh
H
P
P
N
H
Ph
*
H
5c
Scheme 5 Postulated mechanism of the rhodium catalyzed asymmet-
ric hydrogenation of 1,5-benzodiazepinones. P–P = chiral diphosphine
ligand, X = halide.
The chiral rhodium(I)–diphoshine complex 5a under-
goes oxidative addition of dihydrogen, thus forming the
rhodium(III)–dihydride catalyst 5b. After η2-complexation
of the benzodiazepinone enamine tautomer 1a′, the π-com-
plexed C=C bond of 5c inserts into the Rh–H bond and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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R. Borrmann et al.
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Synthesis
forms the rhodium–alkyl species 5d. By reductive elimina-
tion of this complex, the dihydrobenzodiazepinone 3a′ is
released and the rhodium precatalyst 5a is regenerated.
In summary, we have developed the first metal-cata-
lyzed hydrogenation of differently substituted 1,5-benzodi-
azepinones. Given the basic nature of the products and the
resulting difficulties, no metal-catalyzed hydrogenation of
this type of substrates has been reported previously. The
key to our successful development is the combination of the
weakly coordinating BArF anion and a DifluoroPhos ligand
in the rhodium-catalyzed hydrogenation. The resulting cat-
alyst furnishes the desired products in excellent yields (up
to 99%) and with good to high levels of enantioselectivity
(up to 92% ee) for a broad range of differently substituted
products. The method presented here not only builds the
basis for the development of potentially more efficient hy-
drogenation catalysts but, more importantly, provides op-
erationally simple access to valuable and biologically rele-
vant dihydrobenzodiazepinones with molecular hydrogen
as environmentally friendly reductant.
mixture was stirred for 3 h at r.t. The crude mixture was adsorbed on
silica gel and purified by column chromatography using cyclohex-
ane/CH2Cl2/EtOAc (1:1:1) to CH2Cl2/EtOAc (1:1) as the eluent.
(4S)-5-Acetyl-4-phenyl-4,5-dihydro-1H-1,5-benzodiazepin-2(3H)-
one (3a)
Synthesized according to the modified general procedure (40 °C, 50
bar, 36 h); yellowish solid; yield: 55.4 mg (99%); mp 110 °C;
[α]43622 +19.0 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 37.6 °C, λ = 220 nm, τminor = 7.19 min,
τ
major = 17.10 min, 84% ee.
IR (ATR): 3220, 3062, 2921, 2858, 1667, 1496, 1369, 1317, 1278, 1162,
1123, 1032, 911, 759, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.23 (br s, 1 H), 7.37 (dt, J = 7.8, 1.5 Hz,
1 H), 7.26–7.18 (m, 6 H), 7.16 (dd, J = 7.9, 1.4 Hz, 1 H), 7.06 (dd, J = 7.8,
1.4 Hz, 1 H), 6.25 (dd, J = 13.8, 5.0 Hz, 1 H), 2.90 (t, J = 13.5 Hz, 1 H),
2.61 (ddd, J = 13.2, 5.0, 1.8 Hz, 1 H), 1.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 170.1, 140.0, 136.2, 133.1,
131.6, 129.6, 128.6, 128.0, 126.7, 126.4, 123.0, 61.0, 39.2, 23.0.
MS (EI): m/z (%) = 281.1 (17), 280.1 ([M]+, 80), 238.1 (16), 237.1 (45),
223.1 (15), 222.1 (77), 221.1 (16), 195.1 (84), 161.1 (16), 134.1 (64),
133.1 (31), 132.1 (80), 131.1 (73), 119.1 (100), 106.1 (28), 105.2 (15),
104.2 (31), 103.2 (48), 92.2 (39), 91.2 (15), 78.2 (25), 77.2 (36), 65.3
(34), 51.3 (16).
All commercially available chemicals were used as provided by the
suppliers without further purification. The only exception was ortho-
phenylenediamine (used for the preparation of benzodiazepinone
starting materials), which was recrystallized from xylenes. Reactions
were performed in anhydrous solvents dried and distilled following
standard procedures. Solvents for column chromatography were tech-
nical grade and distilled prior to use. Analytical TLC was performed
on Merck silica gel 60 aluminum plates with F-254 fluorescence
marker, visualized by UV irradiation. Merck silica gel 60 (particle size
0.063–0.200 mm) was used for preparative column chromatography.
1H, 13C, and 31F NMR spectra were recorded on Inova 400, VNMRS-
400, or Mercury 300 spectrometer in CDCl3 using the residual solvent
peak as an internal reference (δH = 7.26, δC = 77.0). Chemical shifts (δ)
are reported in ppm; standard abbreviations for multiplicities are
used; coupling constants (J) are in hertz (Hz). Mass spectra (MS-EI, 70
eV) were conducted on a Finnigan MET SSQ 7000 system. IR spectra
(ATR) were recorded on a PerkinElmer FT-IR spectrometer and are re-
ported in terms of frequency of absorption (cm–1). Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. Enantiomeric ra-
tios of the products were determined by analytical supercritical fluid
chromatography (SFC) using chiral stationary phase column Daicel
Chiralcel OD-H with solvent mixtures and temperatures as indicated
in each entry. The methods were calibrated with the corresponding
racemic mixtures.
(4S)-5-Acetyl-4-(4-methylphenyl)-4,5-dihydro-1H-1,5-benzodiaz-
epin-2(3H)-one (3b)
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 58.1 mg (99%); mp 208 °C; [α]D22 +15.1 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 7.20 min,
τ
major = 18.78 min, 86% ee.
IR (ATR): 3218, 2919, 2855, 1666, 1597, 1497, 1432, 1370, 1315, 1281,
1236, 1164, 1118, 1034, 912, 814, 752, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.87 (br s, 1 H), 7.37 (dt, J = 7.7, 1.5 Hz,
1 H), 7.19 (t, J = 7.4 Hz, 2 H), 7.13 (d, J = 8.1 Hz, 2 H), 7.07–7.02 (m, 3
H), 6.22 (dd, J = 13.8, 4.9 Hz, 1 H), 2.89 (t, J = 13.5 Hz, 1 H), 2.58 (ddd,
J = 13.1, 5.0, 1.6 Hz, 1 H), 2.25 (s, 3 H), 1.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 170.1, 137.7, 137.2, 136.4,
133.0, 131.5, 129.5, 129.3, 126.6, 126.3, 123.0, 60.8, 39.3, 23.0, 21.1.
MS (EI): m/z (%) = 295.1 (22), 294.2 ([M]+, 98), 252.2 (15), 251.1 (54),
237.2 (17), 236.1 (70), 235.2 (16), 209.1 (70), 145.1 (100), 134.1 (65),
133.1 (21), 132.1 (363), 119.1 (52), 118.2 (51), 117.1 (53), 115.1 (31),
106.1 (22), 92.2 (28), 91.2 (33), 65.3 (30).
(4S)-5-Acetyl-4-(4-ethylphenyl)-4,5-dihydro-1H-1,5-benzodiaze-
pin-2(3H)-one (3c)
Asymmetric Hydrogenation of 1,5-Benzodiazepinones 2; General
Procedure
Synthesized according to the general procedure (36 h); yellowish solid;
In a glovebox, [Rh(cod)Cl]2 (2.5 mol%), (R)-DifluoroPhos (5.25 mol%),
and NaBArF (5.25 mol%) were dissolved in absolute CH2Cl2 (4 mL). The
reaction mixture was allowed to stir for 60 min for the formation of
the active catalyst. Then the appropriate 1,5-benzodiazepinone 2
(0.2 mmol) was added to the catalyst solution and the mixture was
transferred to an autoclave (preflushed with N2). After purging 3
times with N2 and hydrogen, the autoclave was filled with H2 (80 bar)
and the reaction mixture was stirred at 50 °C for the indicated time.
Subsequently, DMAP (1 equiv) and AcCl (3 equiv) were added and the
yield: 60.3 mg (98%); mp 190 °C; [α]D22 +16.8 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 7.78 min,
τ
major = 19.85 min, 87% ee.
IR (ATR): 3213, 2962, 2924, 2865, 1671, 1498, 1370, 1277, 1123, 1039,
833, 758, 711 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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R. Borrmann et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.14 (br s, 1 H), 7.42 (dt, J = 7.7, 1.4 Hz,
1 H), 7.25 (dt, J = 7.6, 1.4 Hz, 1 H), 7.22–7.18 (m, 3 H), 7.15–7.09 (m, 3
H), 6.27 (dd, J = 13.8, 5.0 Hz, 1 H), 2.93 (d, J = 13.5 Hz, 1 H), 2.68–2.56
(m, 3 H), 1.73 (s, 3 H), 1.20 (t, J = 7.6 Hz, 3 H).
(4S)-5-Acetyl-4-(4-biphenyl)-4,5-dihydro-1H-1,5-benzodiazepin-
2(3H)-one (3f)
Synthesized according to the general procedure (72 h); yellowish sol-
id; yield: 68.8 mg (97%); mp 136 °C; [α]D22 +47.0 (c = 0.1, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 172.3, 170.0, 144.0, 137.3, 136.2,
133.1, 131.6, 129.5, 128.1, 126.6, 126.4, 122.9, 60.8, 39.3, 28.5, 23.0,
15.4.
MS (EI): m/z (%) = 309.2 (26), 308.2 ([M]+, 100), 266.2 (18), 265.1 (61),
251.1 (16), 250.1 (80), 223.2 (58), 208.1 (17), 159.1 (82), 134.1 (64),
133.1 (26), 132.1 (67), 131.2 (32), 119.1 (46), 117.1 (52), 115.1 (21),
106.1 (21), 103.2 (15), 92.2 (18), 91.2 (27), 77.2 (15), 65.3 (19).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
15% MeOH/CO2, 4 mL/min, T = 35.7 °C, λ = 250 nm, τminor = 8.81 min,
τ
major = 21.07 min, 78% ee.
IR (ATR): 3216, 3065, 2916, 2682, 2317, 2107, 1915, 1668, 1492, 1368,
1318, 1160, 1115, 1033, 911, 836, 752, 697 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 9.07 (br s, 1 H), 7.58–7.51 (m, 4 H),
7.48–7.37 (m, 5 H), 7.34 (t, J = 7.3 Hz, 1 H), 7.28 (m, 2 H), 7.17 (d,
J = 7.7 Hz, 1 H), 6.38 (dd, J = 13.7, 4.9 Hz, 1 H), 3.02 (t, J = 13.5 Hz, 1 H),
2.72 (ddd, J = 13.0, 4.8, 1.5 Hz, 1 H), 1.79 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 172.9, 170.3, 140.9, 140.6, 139.1,
136.4, 133.0, 131.5, 129.6, 128.8, 127.4, 127.1, 127.0, 126.4, 123.1,
60.9, 39.3, 23.1.
(4S)-5-Acetyl-4-(4-isopropylphenyl)-4,5-dihydro-1H-1,5-benzodi-
azepin-2(3H)-one (3d)
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 62.9 mg (98%); mp 203 °C; [α]D22 +18.6 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 37.8 °C, λ = 220 nm, τminor = 7.51 min,
MS (EI): m/z (%) = 357.4 (25), 356.4 ([M]+, 86), 314.4 (15), 313.4 (37),
298.4 (50), 271.4 (57), 207.3 (80), 181.3 (19), 180.3 (100), 179.3 (36),
178.2 (51), 165.3 (37), 152.2 (21), 147.3 (18), 134.2 (30), 119.2 (29),
92.3 (15).
τ
major = 19.21 min, 82% ee.
IR (ATR): 3215, 2960, 2925, 2869, 1670, 1598, 1498, 1371, 1316, 1279,
1236, 1163, 1124, 1035, 913, 832, 758 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.14 (br s, 1 H), 7.42 (dt, J = 7.7, 1.5 Hz,
1 H), 7.26 (dt, J = 7.6, 1.4 Hz, 2 H), 7.22–7.18 (m, 3 H), 7.15 (m, 2 H),
7.12 (dd, J = 7.9, 1.4 Hz, 1 H), 6.27 (dd, J = 13.8, 4.9 Hz, 1 H), 2.93 (t,
J = 13.5 Hz, 1 H), 2.86 (m, 1 H), 1.73 (s, 3 H), 1.21 (d, J = 6.9 Hz, 6 H).
(4S)-5-Acetyl-4-(4-methoxyphenyl)-4,5-dihydro-1H-1,5-benzodi-
azepin-2(3H)-one (3g)
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 60.7 mg (98%); mp 89 °C; [α]D22 +27.8 (c = 1.0, CHCl3).
13C NMR (100 MHz, CDCl3): δ = 172.3, 170.0, 148.6, 137.4, 136.2,
133.1, 131.7, 129.5, 126.7, 126.6, 126.4, 122.9, 60.8, 39.3, 33.8, 23.9,
23.0.
MS (EI): m/z (%) = 323.2 (19), 322.2 ([M]+, 86), 280.1 (16), 279.2 (52),
264.2 (59), 237.2 (42), 221.1 (16), 173.1 (40), 147.1 (15), 146.1 (22),
134.1 (45), 133.1 (17), 132.1 (36), 131.1 (100), 119.1 (36), 105.1 (15),
91.2 (20).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 9.12 min,
τ
major = 23.99 min, 87% ee.
IR (ATR): 3222, 2958, 2922, 1667, 1502, 1369, 1315, 1243, 1169, 1118,
1029, 946, 911, 831, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.72 (br s, 1 H), 7.37 (dt, J = 7.7, 1.4 Hz,
1 H), 7.21–7.14 (m, 4 H), 7.01 (d, J = 7.8 Hz, 1 H), 6.80–6.74 (m, 2 H),
6.22 (dd, J = 13.7, 5.0 Hz, 1 H), 3.71 (s, 3 H), 2.88 (t, J = 13.5 Hz, 1 H),
2.57 (ddd, J = 13.1, 5.0, 1.5 Hz, 1 H), 1.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 170.0, 159.2, 136.4, 132.9,
132.3, 131.5, 129.5, 127.9, 126.4, 123.0, 113.9, 60.5, 55.2, 39.3, 23.0.
MS (EI): m/z (%) = 310.1 ([M]+, 36), 267.1 (11), 252.1 (11), 225.1 (13),
161.1 (73), 135.1 (12), 134.1 (100), 133.1 (15), 119.1 (24), 91.2 (14),
65.3 (11).
(4S)-5-Acetyl-4-(4-tert-butylphenyl)-4,5-dihydro-1H-1,5-benzodi-
azepin-2(3H)-one (3e)
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 66.2 mg (98%); mp 107 °C; [α]D22 +22.6 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 7.37 min,
τ
major = 19.63 min, 85% ee.
IR (ATR): 3220, 2959, 2868, 1671, 1498, 1369, 1318, 1276, 1163, 1118,
1034, 833, 759, 709 cm–1
(4S)-5-Acetyl-4-(3-methoxyphenyl)-4,5-dihydro-1H-1,5-benzodi-
azepin-2(3H)-one (3h)
.
1H NMR (400 MHz, CDCl3): δ = 8.73 (br s, 1 H), 7.42 (dt, J = 7.7, 1.5 Hz,
1 H), 7.35–7.29 (m, 2 H), 7.27 (dd, J = 7.7, 1.5 Hz, 1 H), 7.24–7.19 (m, 3
H), 7.13 (dd, J = 7.8, 1.4 Hz, 1 H), 6.27 (dd, J = 13.8, 4.9 Hz, 1 H), 2.94 (t,
J = 13.5 Hz, 1 H), 2.65 (ddd, J = 13.2, 5.0, 1.8 Hz, 1 H), 1.74 (s, 3 H), 1.27
(s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 170.1, 150.8, 137.0, 136.3,
133.1, 131.6, 129.5, 126.4, 126.3, 125.5, 123.0, 60.9, 39.4, 34.5, 31.3,
23.1.
MS (EI): m/z (%) = 337.2 (28), 336.2 ([M]+, 100), 294.2 (22), 293.2 (63),
279.2 (19), 278.2 (79), 251.2 (39), 235.2 (20), 187.2 (35), 147.1 (16),
145.2 (56), 134.1 (48), 133.1 (18), 132.1 (30), 131.2 (40), 119.2 (37),
117.2 (20), 91.2 (16), 57.4 (50).
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 60.0 mg (97%); mp 78 °C; [α]D22 +8.8 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 7.86 min,
τ
major = 21.72 min, 84% ee.
IR (ATR): 3220, 2921, 2849, 1668, 1595, 1493, 1370, 1318, 1260, 1155,
1038, 868, 758, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.30 (br s, 1 H), 7.37 (dt, J = 7.7, 1.3 Hz,
1 H), 7.19 (m, 3 H), 7.10 (dd, J = 7.8, 1.3 Hz, 1 H), 6.83–6.80 (m, 2 H),
6.77–6.73 (m, 1 H), 6.21 (dd, J = 13.7, 4.9 Hz, 1 H), 3.71 (s, 3 H), 2.87 (t,
J = 13.5 Hz, 1 H), 2.60 (ddd, J = 13.1, 4.9, 1.4 Hz, 1 H), 1.70 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 170.1, 159.7, 141.7, 136.2,
133.1, 131.6, 129.6, 129.6, 126.4, 123.0, 118.8, 113.2, 112.6, 61.0, 55.2,
39.3, 23.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

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R. Borrmann et al.
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Synthesis
MS (EI): m/z (%) = 311.2 (24), 310.2 ([M]+, 100), 268.2 (26), 267.1 (88),
252.2 (60), 225.2 (74), 182.1 (16), 161.1 (59), 134.1 (78), 133.1 (31),
132.1 (27), 119.2 (72), 118.1 (17), 92.2 (20), 91.2 (20), 65.3 (24).
1H NMR (400 MHz, CDCl3): δ = 8.33 (br s, 1 H), 7.39 (m, 1 H), 7.30–
7.22 (m, 2 H), 7.16 (d, J = 7.9 Hz, 1 H), 7.11–7.05 (m, 3 H), 7.05–6.99
(m, 1 H), 6.33 (dd, J = 13.7, 4.5 Hz, 1 H), 2.82 (t, J = 13.6 Hz, 1 H), 2.55
(s, 3 H), 2.46 (ddd, J = 13.5, 4.5, 1.8 Hz, 1 H), 1.70 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.2, 170.2, 140.0, 135.9, 135.6,
133.7, 131.9, 130.9, 129.4, 127.7, 126.4, 126.1, 125.0, 123.1, 58.0, 40.2,
23.1, 19.2.
MS (EI): m/z (%) = 295.2 (22), 294.1 ([M]+, 100), 251.1 (29), 236.1 (23),
235.1 (25), 234.1 (21), 209.1 (49), 161.1 (16), 150.1 (25), 145.1 (88),
135.1 (18), 134.1 (76), 133.1 (29), 132.1 (55), 119.1 (76), 118.1 (30),
117.2 (50), 116.1 (22), 115.1 (40), 106.1 (23), 92.2 (26), 91.2 (34), 65.3
(31).
(4S)-5-Acetyl-4-(3-fluorophenyl)-4,5-dihydro-1H-1,5-benzodiaze-
pin-2(3H)-one (3i)
Synthesized according to the general procedure (48 h); yellowish sol-
id; yield: 57.7 mg (97%); mp 88 °C; [α]D22 +13.3 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.2 °C, λ = 220 nm, τminor = 5.92 min,
τ
major = 13.68 min, 77% ee.
IR (ATR): 3206, 3063, 2924, 1661, 1495, 1433, 1369, 1343, 1307, 1256,
1094, 1032, 910, 835, 770, 747, 695 cm–1
.
(4S)-5-Acetyl-4-(furan-2-yl)-4,5-dihydro-1H-1,5-benzodiazepin-
2(3H)-one (3l)
1H NMR (400 MHz, CDCl3): δ = 8.44 (br s, 1 H), 7.44 (dt, J = 7.5, 1.3 Hz,
1 H), 7.31–7.24 (m, 2 H), 7.22 (dd, J = 7.9, 1.4 Hz, 1 H), 7.13 (dd, J = 7.9,
1.3 Hz, 1 H), 7.11–7.08 (m, 1 H), 7.02–6.93 (m, 2 H), 6.27 (dd, J = 13.8,
4.9 Hz, 1 H), 2.90 (t, J = 13.5 Hz, 1 H), 2.66 (ddd, J = 13.1, 5.0, 1.7 Hz, 1
H), 1.76 (s, 3 H).
Synthesized according to the general procedure (72 h); yellowish sol-
id; yield: 47.8 mg (88%); mp 111 °C; [α]D22 +26.0 (c = 0.1, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 36.1 °C, λ = 240 nm, τminor = 5.66min,
13C NMR (100 MHz, CDCl3): δ = 172.0, 170.2, 162.8 (d, J = 246.6 Hz),
142.5, 136.2, 132.8, 131.4, 130.2, 129.7, 126.6, 123.1, 122.4, 114.9 (d,
J = 21.1 Hz), 113.6 (d, J = 22.0 Hz), 60.5, 39.1, 23.0.
τ
major = 9.88 min, 84% ee.
IR (ATR): 3221, 2917, 1666, 1498, 1431, 1369, 1317, 1239, 1154, 1019,
917, 880, 747 cm–1
.
31F NMR (282.3 MHz, CDCl3): δ = –112.1.
1H NMR (400 MHz, CDCl3): δ = 8.93 (br s, 1 H), 7.39 (dt, J = 7.7, 1.3 Hz,
1 H), 7.31–7.26 (m, 1 H), 7.25–7.17 (m, 2 H), 7.06 (d, J = 7.7 Hz, 1 H),
6.42 (dd, J = 13.4, 5.4 Hz, 1 H), 6.28 (dd, J = 3.1, 1.8 Hz, 1 H), 6.23–6.20
(m, 1 H), 2.97 (t, J = 13.3 Hz, 1 H), 2.69 (ddd, J = 13.3, 5.2, 1.1 Hz, 1 H),
1.76 (s, 3 H).
MS (EI): m/z (%) = 299.1 (19), 298.1 ([M]+, 93), 256.1 (20), 255.1 (44),
240.1 (67), 239.2 (23), 214.1 (16), 213.1 (89), 161.1 (17), 149.1 (32),
134.1 (48), 133.1 (32), 132.1 (69), 121.1 (22), 119.1 (100), 108.2 (15),
106.1 (21), 101.2 (22), 92.2 (33), 65.3 (31).
13C NMR (100 MHz, CDCl3): δ = 172.4, 170.1, 152.3, 142.1, 136.3,
132.5, 131.1, 129.6, 126.4, 122.8, 110.2, 107.0, 54.4, 27.0, 22.8.
(4S)-5-Acetyl-4-(3-bromophenyl)-4,5-dihydro-1H-1,5-benzodiaze-
pin-2(3H)-one (3j)
MS (EI): m/z (%) = 271.4 (16), 270.3 ([M]+, 81), 227.3 (24), 212.3 (23),
211.3 (19), 185.3 (50), 147.3 (17), 134.2 (70), 133.2 (15), 132.2 (17),
121.2 (100), 119.2 (20), 106.2 (21), 94.2 (60), 66.3 (18), 65.3 (37), 57.4
(17).
Synthesized according to the general procedure (60 h); yellowish sol-
id; yield: 66.6 mg (93%); mp 97 °C; [α]D22 +11.4 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.2 °C, λ = 220 nm, τminor = 10.24 min,
τ
major = 26.16 min, 65% ee.
IR (ATR): 3218, 3068, 2910, 1665, 1594, 1497, 1429, 1369, 1318, 1279,
1236, 1121, 1036, 885, 760, 692 cm–1
(4S)-5-Acetyl-4-(thiophen-2-yl)-4,5-dihydro-1H-1,5-benzodiaze-
pin-2(3H)-one (3m)
.
Synthesized according to the general procedure (72 h); yellowish sol-
1H NMR (300 MHz, CDCl3): δ = 8.92 (br s, 1 H), 7.45–7.30 (m, 3 H),
7.27–7.19 (m, 2 H), 7.19–7.11 (m, 2 H), 7.07 (dd, J = 7.8, 1.3 Hz, 1 H),
6.18 (dd, J = 13.8, 4.8 Hz, 1 H), 2.86 (t, J = 13.5 Hz, 1 H), 2.58 (ddd,
J = 13.1, 4.9, 1.6 Hz, 1 H), 1.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.2, 170.4, 142.3, 136.2, 132.7,
131.4, 131.2, 130.3, 129.8, 129.7, 126.6, 125.4, 123.1, 122.7, 60.5, 39.1,
23.0.
id; yield: 53.1 mg (93%); mp 77 °C; [α]D22 +22.9 (c = 1.0, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
15% MeOH/CO2, 4 mL/min, T = 36.0 °C, λ = 220 nm, τminor = 3.54 min,
τ
major = 6.71 min, 92% ee.
IR (ATR): 3219, 3080, 2910, 1666, 1598, 1497, 1432, 1367, 1313, 1278,
1234, 1169, 1121, 1035, 911, 844, 761, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.69 (br s, 1 H), 7.40–7.33 (m, 1 H),
7.21–7.12 (m, 3 H), 7.03 (dd, J = 7.0, 1.7 Hz, 1 H), 6.91–6.84 (m, 2 H),
6.55 (dd, J = 13.2, 5.5 Hz, 1 H), 2.87 (t, J = 13.1 Hz, 1 H), 2.75 (ddd,
J = 13.1, 5.5, 1.4 Hz, 1 H), 1.71 (s, 3 H).
MS (EI): m/z (%) = 360.0 (42), 358.0 ([M]+, 48), 317.0 (29), 316.1 (16),
315.0 (29), 302.0 (35), 301.0 (16), 300.0 (36), 275.0 (35), 273.0 (36),
194.1 (15), 161.1 (23), 134.1 (48), 133.1 (31), 132.1 (76), 119.1 (100),
106.1 (19), 103.1 (18), 102.1 (28), 92.1 (21), 77.2 (20), 65.2 (22).
13C NMR (100 MHz, CDCl3): δ = 172.0, 170.0, 142.7, 136.4, 132.0,
131.6, 129.8, 126.6, 126.4, 125.0, 124.8, 122.9, 56.4, 39.7, 22.9.
(4S)-5-Acetyl-4-(2-methylphenyl)-4,5-dihydro-1H-1,5-benzodiaz-
epin-2(3H)-one (3k)
MS (EI): m/z (%) = 287.1 (20), 286.1 ([M]+, 90), 244.1 (18), 243.0 (43),
228.1 (28), 201.1 (50), 147.1 (17), 137.0 (100), 134.1 (74), 133.1 (15),
132.1 (17), 119.1 (24), 110.1 (62), 109.1 (34), 108.1 (16), 106.1 (22),
92.1 (18), 65.2 (30).
Synthesized according to the general procedure (72 h); yellowish sol-
id; yield: 53.9 mg (92%); mp 151 °C; [α]D22 –52.8 (c = 0.1, CHCl3).
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.1 °C, λ = 220 nm, τminor = 7.02 min,
(4S)-5-Acetyl-7-methyl-4-phenyl-4,5-dihydro-1H-1,5-benzodiaze-
pin-2(3H)-one (3n)
τ
major = 27.14 min, 73% ee.
IR (ATR): 3252, 2977, 2919, 1657, 1597, 1497, 1432, 1368, 1330, 1283,
1260, 1167, 1120, 1032, 943, 910, 880, 753, 726 cm–1
Synthesized according to the general procedure (72 h); yellowish sol-
.
id; yield: 55.7 mg (95%); mp 85 °C; [α]D22 +18.1 (c = 1.0, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
R. Borrmann et al.
Paper
Synthesis
Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.0 °C, λ = 220 nm, τminor = 7.22 min,
(4) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.;
Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfeld, J. J. Med. Chem. 1988, 31,
2235.
(5) Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10, 34.
(6) Lancel, M.; Steiger, A. Angew. Chem. Int. Ed. 1999, 38, 2852.
(7) Sternbach, L. H. J. Med. Chem. 1979, 22, 1.
τ
major = 17.68 min, 71% ee.
IR (ATR): 3221, 2925, 1666, 1510, 1370, 1310, 1277, 1240, 1126, 1035,
924, 828, 764, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.36 (br s, 1 H), 7.34–7.25 (m, 5 H),
7.21 (dd, J = 8.1, 1.9 Hz, 1 H), 7.09 (dd, J = 8.0, 4.5 Hz, 1 H), 6.91 (d,
J = 1.3 Hz, 1 H), 6.28 (dd, J = 13.8, 4.9 Hz, 1 H), 2.93 (t, J = 13.5 Hz, 1 H),
2.64 (ddd, J = 13.1, 4.8, 1.4 Hz, 1 H), 2.35 (s, 3 H), 1.75 (s, 3 H).
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13C NMR (100 MHz, CDCl3): δ = 172.5, 170.1, 140.2, 136.6, 133.6,
132.8, 131.7, 130.1, 128.6, 127.9, 126.7, 122.8, 61.0, 39.2, 23.0, 20.9.
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MS (EI): m/z (%) = 294.2 ([M]+, 55), 251.1 (24), 236.1 (43), 209.1 (53),
148.1 (52), 147.2 (42), 146.2 (100), 133.2 (67), 131.1 (58), 106.2 (24),
104.2 (26), 103.2 (38), 79.3 (19), 78.3 (18), 77.3 (45).
(4R)-5-Acetyl-4-methyl-4,5-dihydro-1H-1,5-benzodiazepin-2(3H)-
one (3o)
Synthesized according to the general procedure (36 h); yellowish sol-
id; yield: 43.2 mg (99%); mp 175 °C; [α]D22 –9.1 (c = 1.0, CHCl3).
(12) James, G. L.; Goldstein, J. L.; Brown, M. S.; Rawson, T. E.; Somers,
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Enantiomeric excess was determined by SFC, Chiralcel OD-H column,
8% MeOH/CO2, 4 mL/min, T = 38.1 °C, λ = 220 nm, τminor = 4.41 min,
τ
major = 7.30 min, 78% ee.
IR (ATR): 3220, 2926, 1665, 1509, 1370, 1310, 1278, 1240, 1126, 1034,
924, 830, 750, 698 cm–1
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38, 771.
.
1H NMR (400 MHz, CDCl3): δ = 8.72 (br s, 1 H), 7.34 (dt, J = 7.8, 1.3 Hz,
1 H), 7.23–7.17 (m, 1 H), 7.14–7.09 (m, 2 H), 5.37–5.24 (m, 1 H), 2.36
(ddd, J = 12.9, 5.4, 1.2 Hz, 1 H), 2.27 (t, J = 13.0 Hz, 1 H), 1.68 (s, 3 H),
1.13 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.3, 169.9, 136.4, 132.0, 131.0,
129.5, 126.3, 122.9, 54.2, 40.5, 22.0, 19.2.
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MS (EI): m/z (%) = 218.1 ([M]+, 28), 174.2 (18), 161.1 (46), 160.2 (16),
133.2 (46), 132.2 (96), 119.2 (100), 92.2 (23), 69.3 (15), 65.4 (22).
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Acknowledgment
The authors thank Solvias AG and Evonik Industries AG for donation
of chiral ligands and the Fonds der Chemischen Industrie for a schol-
arship given to R.M.K.
Supporting Information
(24) Nawrocka, W.; Sztuba, B.; Zimecki, M. Arch. Pharm. (Weinheim)
2001, 334, 11.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589401.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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