Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates via [4 + 3]-Annulation of Azaoxyallyl Cations With 2-Aminophenyl α,β-Unsaturated Esters

Article abstract of DOI:10.1002/bkcs.12060

A metal-free [4 + 3]-annulation of α-halohydroxamates with 2-aminophenyl α,β-unsaturated esters has been developed for the construction of seven-membered 1,4-benzodiazepine-3-one-5-acetates in moderate to good yields (up to 82% yield). The annulation invo

Full text of DOI:10.1002/bkcs.12060

Article
DOI: 10.1002/bkcs.12060
BULLETIN OF THE
H. S. Jang et al.
KOREAN CHEMICAL SOCIETY
Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
via [4 + 3]-Annulation of Azaoxyallyl Cations With 2-Aminophenyl
α,β-Unsaturated Esters
*
Hyun Sun Jang, Yong Il Kwon, and Sung-Gon Kim
Department of Chemistry, Kyonggi University, Suwon 16227, Republic of Korea.
*E-mail: sgkim123@kyonggi.ac.kr
Received May 5, 2020, Accepted May 14, 2020
A metal-free [4 + 3]-annulation of α-halohydroxamates with 2-aminophenyl α,β-unsaturated esters has
been developed for the construction of seven-membered 1,4-benzodiazepine-3-one-5-acetates in moderate
to good yields (up to 82% yield). The annulation involved the cascade reaction of an generation of
azaoxyallyl cation, aza-addition to this azaoxyallyl cation, and intramolecular aza-Michael reaction to
yield 1,4-benzodiazepine-3-one-5-acetates.
Keywords: Annulation, Azaoxyallyl cation, Benzodiazepinone, Catalyst-free
Introduction
for the [4 + 3] annulation between in situ generated
azaoxyallyl cations and 2-aminophenyl α,β-unsaturated
esters for the efficient preparation of 1,4-benzodiazepine-
3-ones.
The azaoxyallyl cation, which can be formed in situ from
α-halohydroxamates in the presence of a base, is a versatile
precursor for the synthesis of various heterocycles.8 The
valuable [3 + 1], [3 + 2], and [3 + 3] cycloadditions of
azaoxyallyl cations have delivered biologically important
heterocyclic compounds. In particular, [3 + 4] cycloaddition
of azaoxyallyl cations is an efficient strategy for the con-
struction of seven-membered heterocycles, which are other-
wise difficult to synthesize.9
1,4-Benzodiazepines are quintessential privileged structures
possessing a diverse array of biological activities, and their
drug-like properties make them useful for the discovery of
several pharmaceutical compounds.1 In particular, 1,4-
benzodiazepinone is a predominant structural unit in medic-
inal chemistry and represents the unique bioactivity of large
numbers of drug molecules (Figure 1).2 For example, diaze-
pam is a positive allosteric modulator of the GABA type A
(GABAA) receptors that is mainly used to treat anxiety,
insomnia, seizures, and alcohol withdrawal syndrome.3
Abbeymycin is an anthramycin-type antibiotic isolated
from Streptomyces sp.4 Lotrafiban and its analogs are
potent antagonists of the platelet glycoprotein IIb/IIIa
receptor (GPIIb/IIIa), which represents a significant devel-
opment in interventional cardiology and in the treatment of
acute ischemic syndromes to avoid vascular occlusion.5
1,4-Benzodiazepinone skeleton has also the ability to
mimic β- and γ-turn peptide secondary structures, which
show binding affinity for AT1 and AT2 receptors. In addi-
tion, it can aid in the activation of G-protein-coupled recep-
tors and enhance the catalytic activity of enzymes such as
protein kinases.6
The development of novel methods toward the synthesis
of benzodiazepinones is highly desirable because of their
intriguing molecular skeletons and biological behaviors. To
this end, several synthetic routes to 1,4-benzodiazepinones
have been reported in the past decade. The commonly used
methods are based in intramolecular nucleophilic aromatic
substitution, Ullmann-type aryl amination, retro-Michael
amination, intramolecular 1,3-dipolar reaction, and cycliza-
tion involving an Ugi reaction.7 However, there are very
few examples of one-step protocols to access 1,4-
benzodiazepin-3-ones. Herein, we report our recent results
Results and Discussion
We have recently reported the one-pot synthesis of 1,4-benzo-
diazepine-3-ones through the aza/aza-[4 + 3] reaction of
α-halohydroxamates with 2-aminophenyl α,β-unsaturated phe-
nyl ketones (Scheme 1(a)).9c The reaction of (E)-3-(2-
aminophenyl)-1-phenylprop-2-en-1-one 1 with N-(benzyloxy)-
2-bromo-2-methylpropanamide 2a in toluene (0.1 M), using
Cs2CO3 as the base and hexafluoroisopropanol (HFIP) as an
additive at room temperature, provided corresponding 1,4-ben-
zodiazepine-3-one 3 in good yield (84%). However, the reac-
tion of (E)-ethyl 3-(2-aminophenyl)acrylate 4a under the same
conditions did not generate the desired seven-membered 1,4-
benzodiazepine-3-one and provided only the aza-substituted
product 5 in 81% yield (Scheme 1(b)). Hence, we had to opti-
mize the reaction conditions for the synthesis of 1,4-benzodi-
azepine-3-one-5-acetates by the reaction of 2-aminophenyl
α,β-unsaturated esters with α-halohydroxamates.
Since the cyclization did not proceed at room tempera-
ture, the reaction mixture of 4a with 2a in the presence of
Cs2CO3 and HFIP in toluene allowed by stirring for 1 h at
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KOREAN CHEMICAL SOCIETY
in a slightly reduced yield (69%). The electronic nature of the
substituents on the aromatic ring had little effect on the reac-
tion efficiency. Both electron-donating (−Me) and electron-
withdrawing (─F, ─Cl, ─Br) groups were well tolerated under
the reaction conditions. However, the position of the substitu-
ents influenced the reaction yield to some extent. For instance,
the C4-fluoro-substituted substrate gave a higher yield than its
C5-fluoro-substituted counterpart (6e vs. 6h). We next
explored the scope of α-halohydroxamates 2 in this [4 + 3]
annulation. Hydroxamates with other N-protecting groups
such as methoxy and allyloxy worked well in this reaction,
providing the desired products (6i and 6j) in moderate to good
yields. Dipropyl substituents on the α-halohydroxamate were
also tolerated under the reaction conditions to give the desired
product 6k in 64% yields. However, the methyl propyl-
substituted halohydroxamate gave 6l in only moderate yield.
We also employed cycloalkyl-substituted halohydroxamates in
this annulation, but cyclopentyl- and cyclobutyl-substituted
halohydroxamates afforded the desired products 6m and 6n in
only 40% and 28%, respectively. The low reactivity in these
cases indicated that the steric rigidity of the cycloalkyl group
might hinder the cyclization.
OH
NH
O
OH
Cl
N
N
O
N
H
N
N
O
H
OMe
Diazepam (Valium)
Abbeymycin
Protein kinase C
modulator
Ph
O
N
N
H
O
N
N
O
N
H
HN
O
N
CO2H
H
HN
CO2H
NH2
Lotrafiban
GPIIb/IIIa antagonist
Figure 1. Selected examples of biologically active 1,4-
benzodiazepinones.
room tempeꢀrature. Then, the reaction temperature was
raised to 60 C. Gratifyingly, under these conditions, cycli-
zation occurred to furnish 1,4-benzodiazepine-3-one 6 in
67% yield along with methacrylamide 4, which was formed
by the elimination of hydrogen bromide (Table 1, entry 2).
To further increase the reaction yield, we added an addi-
tional 1 equiv. of 2a and Cs2CO3, but the yield of 6
decreased (55%) and the amount of 4 increased further
(Table 1, entry 3). When the reaction temperature was
To test the practicality of the current method, we carried out
the [4 + 3] annulation of 2-aminophenyl α,β-unsaturated esters
with α-halohydroxamates on a 1-mmol scale (Scheme 2). Meth-
ylesters 4b and 4g worked well with α-bromohydroxamates 2a
on a 1-mmol scale to give the desired products 6b and 6g in
84% and 64% yields, respectively.
ꢀ
raised to 80 C, with subsequent stirring for 24 h, the prod-
uct yield slightly decreased, and the ratio of 6a:7 increased
marginally (Table 1, entry 4). The best results were
obtained when using CF3C6H5 as the solvent, affording
1,4-benzodiazepine-3-one 6 in 82% yield with a 6a:7 ratio
of 1:0.2 (Table 1, entry 6).
With the optimized reaction conditions in hand, we next
explored the substrate scope and generality of the reaction
(Table 2). First, we performed the reactions of various 2-
aminophenyl α,β-unsaturated esters 4a–e with N-
(benzyloxy)-2-bromo-2-methylpropanamide 2a. Irrespective
of the ester type, the reactions proceeded smoothly to give
the corresponding 1,4-benzodiazepine-3-ones 6a–c in good
yield. Furthermore, the reaction of the sterically bulky tert-
butyl ester 4c presented no problems and afforded 6c, albeit
Finally, the practicality of this method was further dem-
onstrated by investigating the follow-up chemistry, though
reactions were not optimized (Scheme 3). When 6b was
treated with Mo(CO)6 in a mixed solvent (H2O/CH3CN)
under refluxing conditions, N-unprotected 7 was formed in
53% yield by cleavage of the N─O bond. Reduction of 6b
using LiAlH4 provided the corresponding diol 8 in 35%
yield. Hydrolysis of 6b produced acid 9 in 25% yield.
On the basis of the experimental results and the previously
reported cycloaddition of azaoxyallyl cations,8,9 we proposed
a plausible reaction mechanism in Scheme 4. Azaoxyallyl cat-
ion intermediate A is generated from α-bromohydroxamate 2a
in the presence of Cs2CO3. Next, the reaction of 2-
aminophenyl α,β-unsaturated ester 4a with intermediate A
provided zwitterionic intermediate B, followed by the proton-
transfer to furnish intermediate C. Then, intramolecular aza-
Michael addition results in [4 + 3]-annulation to afford cyclic
intermediate D. Finally, the tautomerization of D affords 1,4-
benzodiazepine-3-one 6a.
O
Ph
O
Cs2CO3 (2 equiv)
HFIP (1.2 equiv)
O
OBn
N
Br
+
Ph
(a)
NHOBn
O
Me
Toluene, rt
24 h
Me Me
NH2
N
H
Me
3, 84% yield
1
2a
Conclusion
O
O
OEt
Cs2CO3 (2 equiv)
HFIP (1.2 equiv)
O
In conclusion, we have developed a metal-free [4 + 3]-
(b)
Br
OEt +
NH
H
NHOBn
annulation of α-halohydroxamates with 2-aminophenyl
Toluene, rt
24 h
N
Me Me
NH2
OBn
α,β-unsaturated esters, which provided
a series of
O
4a
2a
5, 81% yield
functionalized 1,4-benzodiazepine-3-one-5-acetates in mod-
erate to good yields (up to 82% yield). The annulation
involved the cascade reaction of an generation of
Scheme 1. Reaction of 2-amino α,β-unsaturated carbonyls with
α-bromohydroxamate 2a.
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
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Table 1. Optimization of [4+3]-cyclization 4a with 2a.a
O
Cs2CO3
(2 equiv)
HFIP
OEt
OBn
O
O
O
(1.2 equiv)
N
+
Br
OEt +
NHOBn
O
Me
NHOBn
solvent
Me
Me Me
N
H
6a
NH2
4a
Me
2a
7
Entry
Solvent
Temp (ºC) and Time (h)
Yield of 6a (%)b
Ratio of 6a:7c
1
2
3d
4
5
6
Toluene
Toluene
Toluene
Toluene
CH3CN
CF3C6H5
rt (24 h)
0
Nd
1:0.4
1:1
1:0.3
1:0.4
1:0.2
rt (1 h) then 60 (24 h)
rt (1 h) then 60 (24 h)
rt (1 h) then 80 (24 h)
rt (1 h) then 80 (24 h)
rt (1 h) then 80 (24 h)
67
55
63
21
82
a Unless otherwise noted, the reactions were carried out in solvent (0.1 M) with 4a (0.1 mmol), 2a (0.15 mmol), Ca2CO3 (0.2 mmol), and HFIP
(0.12 mmol).
b Isolated yield.
c Determined by 1H NMR analysis of crude products.
d Added additional 2a (1 equiv) and Ca2CO3 (1 equiv).
azaoxyallyl cation, aza-addition to this azaoxyallyl cation,
and intramolecular aza-Michael reaction to yield 1,4-benzo-
diazepine-3-one-5-acetates.
80ꢀC and the stirring was continued until the reaction no
longer proceeded, as determined by TLC. The reaction mix-
ture was cooled to room temperature, filtered through a
Celite plug, and concentrated in vacuo. The crude residue
was purified by flash column chromatography with EtOAc/
hexanes as the eluent to afford the desired product 6.
Experimental
General Information. Organic solvents were distilled
prior to use. Organic solutions were concentrated under
reduced pressure using a rotary evaporator. Chromato-
graphic purification of products was accomplished using
forced-flow chromatography on ICN 60 32-64 mesh silica
gel 63. Thin-layer chromatography (TLC) was performed
on EM Reagents 0.25 mm silica gel 60-F plates. Developed
chromatograms were visualized by fluorescence quenching
and with anisaldehyde stain. 1H and 13C NMR spectra were
Ethyl
[4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetra-
hydro-1,4-benzodiazepin-5-yl]acetate (6a). Flash chro-
matography (EtOAc:hexane = 1:4 to 3:7, 31 mg, yield
82%), Colorless gum; H NMR (400 MHz, CDCl3) δ 7.49–
1
7.32 (m, 5H), 7.17 (dd, J = 11.0, 4.1 Hz, 1H), 6.90 (t,
J = 7.3 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.77 (d,
J = 7.7 Hz, 1H), 4.95 (q, J = 10.5 Hz, 2H), 4.76 (dd,
J = 9.9, 4.3 Hz, 1H), 4.03–3.84 (m, 2H), 3.43 (dd,
J = 15.1, 10.0 Hz, 1H), 3.07 (s, 1H), 3.05 (dd, J = 15.1,
4.3 Hz, 1H), 1.63 (s, 3H), 1.21 (s, 3H), 1.07 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 170.8, 144.4,
135.4, 130.1 (two peaks overlapping), 130.0, 129.5, 128.8,
128.6, 123.0, 123.0, 76.1, 65.3, 62.9, 60.5, 37.9, 29.8,
28.1, 14.1; IR (neat) 3316, 2976, 2928, 2872, 1729, 1640,
1599, 1492, 1456, 1413, 1371, 1317, 1288, 1251, 1229,
1200, 1155, 1111, 1036 cm−1; HRMS (EI) m/z calcd for
[M]+ C22H26N2O4: 382.1893 Found: 382.1868.
1
recorded (400 MHz for H and 100 MHz for 13C) and were
internally referenced to residual protic solvent signals. Data
for 1H NMR are reported as follows: chemical shift (δ
ppm), multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constant (Hz) and
integration. Data for 13C NMR are reported in terms of
chemical shift. IR spectra were recorded on an FT IR spec-
trometer and are reported in wave numbers. High-resolution
mass spectroscopy (HRMS) was performed by electron
impact (EI). α-Halohydroxamates9a,10 and 2-aminophenyl
α,β-unsaturated carbonyl compounds11 were prepared
according to literature.
Methyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tetra-
hydro-1,4-benzodiazepin-5-yl]acetate (6b). Flash chro-
matography (EtOAc: hexane = 1:4, 26 mg, yield 71%),
White solid; m.p. 115–117 ꢀC; 1H NMR (400 MHz,
CDCl3) δ 7.49–7.33 (m, 5H), 7.17 (t, J = 7.2 Hz, 1H), 6.91
(t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.77 (d,
J = 7.7 Hz, 1H), 4.95 (q, J = 10.4 Hz, 2H), 4.77 (dd,
J = 9.7, 4.4 Hz, 1H), 3.47 (d, J = 11.5 Hz, 3H), 3.43 (dd,
J = 15.3, 9.8 Hz, 1H), 3.10 (s, 1H), 3.07 (dd, J = 15.3,
4.3 Hz, 1H), 1.63 (s, 3H), 1.20 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.9, 171.3, 144.3, 135.3, 130.1
General Procedure for the [4 + 3] Annulation of 2-
aminophenyl α,β-Unsaturated Esters with α-Bromo-
hydroxamates. To a solution of α-bromohydroxamate 2
(0.15 mmol), 2-aminophenyl α,β-unsaturated esters
4
(0.10 mmol), and HFIP (0.12 mmol) in trꢀifluorotoluene
(1 mL) was added Cs2CO3 (0.20 mmol) at 0 C. After stir-
ring at room temperature for 1 h, temperature was raised to
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
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O
Table 2. . Substrate scope of 2-amino α,β-unsaturated esters and
α-bromohydroxamates.a,b
OMe
OBn
Cs2CO3 (2 equiv)
O
N
O
HFIP (1.2 equiv)
O
Cs2CO3
O
OR2
Br
OMe
+
(2 equiv)
NHOBn
CF3C6H5, rt
rt (1 h) then
80 ºC (24 h)
N
H
Me
Me
HFIP
(1.2 equiv)
Me Me
O
OR
NH2
O
N
4
OR2
R1
Br
R'
+
O
4b
2a
1.5 mmol, 0.41 g
6b
R1
NHOR
CF3C6H5
rt then 80 ºC
1.0 mmol, 0.18 g
84% yield, 0.31 g
5
R"
N
R"
NH2
H
R'
4
2
6
O
OMe
O
O
O
O
OBn
N
Cs2CO3 (2 equiv)
HFIP (1.2 equiv)
O
OEt
OMe
OBn
Ot-Bu
OMe
OBn
Br
O
Br
OBn
OBn
N
O
Br
OMe +
Me
N
N
N
NHOBn
CF3C6H5, rt
rt (1 h) then
80 ºC (24 h)
N
Me
Me Me
O
O
O
O
NH2
H
Me
N
H
N
H
N
N
H
Me
O
Me
Me
Me
Me
H
4g
1.0 mmol, 0.26 g
2a
6g
64% yield, 0.29 g
Me
Me
Me
1.5 mmol, 0.41 g
6a: 82%
6b: 71%
6c: 69%
6d: 61%
Scheme 2. 1 mmol scale synthesis.
O
N
O
OMe
OBn
OMe
OBn
OMe
OBn
N
172.8, 169.9, 144.5, 135.5, 130.1 (three peaks overlapped),
129.4, 128.8, 128.6, 122.9, 122.8, 80.7, 76.1, 65.6, 62.9,
39.2, 29.8, 28.1, 28.0; IR (neat) 3318, 2951, 2927, 2872,
1733, 1641, 1599, 1492, 1456, 1436, 1376, 1357, 1320,
1288, 1229, 1200, 1157, 1111, 1048 cm−1; HRMS (EI) m/
z calcd for [M]+ C24H30N2O4: 410.2206 Found: 410.2212.
F
Cl
Br
N
N
O
O
O
N
H
N
Me
Me
Me
Me
H
H
Me
Me
6e: 72%
6f: 65%
6g: 60%
O
O
O
OMe
OMe
OMe
O
OMe
OBn
N
Methyl [4-(benzyloxy)-2,2,7-trimethyl-3-oxo-1,2,4,5-tet-
rahydro-1,4-benzodiazepin-5-yl]acetate (6d). Flash chro-
matography (EtOAc: hexane = 1:7 to 1:4, 23 mg, yield
F
F
N
N
O
O
O
F
N
H
N
N
H
Me
Me
Me
Me
H
Me
Me
1
ꢀ
61%), White solid; m.p. 154–156 C; H NMR (400 MHz,
CDCl3) δ 7.51–7.32 (m, 5H), 6.97 (dd, J = 7.8, 1.3 Hz,
1H), 6.66 (d, J = 7.8 Hz, 1H), 6.61 (d, J = 1.5 Hz, 1H),
4.94 (q, J = 10.4 Hz, 2H), 4.71 (dd, J = 9.5, 4.6 Hz, 1H),
3.51 (s, 3H), 3.42 (dd, J = 15.3, 9.5 Hz, 1H), 3.08 (dd,
J = 15.3, 4.6 Hz, 1H), 2.94 (s, 1H), 2.23 (s, 3H), 1.61 (s,
3H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9,
171.3, 141.5, 135.3, 132.5, 130.4, 130.0 (two peaks over-
lapped), 129.9, 128.7, 128.5, 122.9, 75.9, 65.3, 62.8, 51.6,
37.8, 29.7, 27.9, 20.6; IR (neat) 3305, 2954, 2923, 2852,
1734, 1626, 1509, 1495, 1456, 1437, 1403, 1353, 1321,
1289, 1254, 1200, 1159, 1130, 1040 cm−1; HRMS (EI) m/
z calcd for [M]+ C22H26N2O4: 382.1893 Found: 382.1880.
6i: 56%
6j: 66%
6h: 51%
O
O
O
O
OMe
OBn
N
OMe
OMe
OBn
N
OMe
OBn
OBn
N
N
O
O
O
O
N
H
N
N
N
Et
Pr
H
H
H
Et
Me
6k: 64%
6l: 32%
6m: 40%
6n: 28%
a Unless otherwise noted, the reactions were carried out in CF3C6H5
(0.1 M) with 4 (0.1 mmol), 2 (0.15 mmol), Cs2CO3 (0.2 mmol), and
HFIP (0.12 mmol).
b Isolated yield.
HO
O
O
(two peaks overlapped), 130.0, 129.6, 128.9, 128.7, 123.1,
123.0, 76.1, 65.3, 62.9, 51.7, 37.7, 29.8, 28.1; IR (neat)
1733, 1641, 1599, 1492, 1456, 1436, 1413, 1376, 1357,
1288, 1229, 1200, 1157, 1111, 1082 cm−1; HRMS (EI) m/
z calcd for [M]+ C21H24N2O4: 368.1736 Found: 368.1722.
OMe
NH
O
Me
OMe
OBn
OBn
Mo(CO)6
LiAlH4
THF
N
N
H2O/CH3CN
OH
Me
O
Me
reflux, 15 h
53%
rt, 20 min
35%
N
H
N
H
N
H
Me
Me
Me
7
6b
8
tert-Butyl [4-(benzyloxy)-2,2-dimethyl-3-oxo-1,2,4,5-tet-
rahydro-1,4-benzodiazepin-5-yl]acetate (6c). Flash chro-
matography (EtOAc:hexane = 1:9 to 1:4, 28 mg, yield
KOH
H2O/1,4-Dioxane
rt, 18 h
25%
1
O
69%), Colorless gum; H NMR (400 MHz, CDCl3) δ 7.51–
OH
7.30 (m, 5H), 7.16 (dd, J = 7.4, 6.7 Hz, 1H), 6.89 (t,
J = 7.4 Hz, 1H), 6.80 (d, J = 7.3 Hz, 1H), 6.76 (d,
J = 7.7 Hz, 1H), 4.95 (q, J = 10.5 Hz, 2H), 4.70 (dd,
J = 10.1, 4.4 Hz, 1H), 3.35 (dd, J = 14.5, 10.2 Hz, 1H),
3.08 (s, 1H), 2.97 (dd, J = 14.5, 4.4 Hz, 1H), 1.63 (s, 3H),
1.25 (s, 9H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
OBn
N
O
Me
N
H
Me
9
Scheme 3. Follow-up chemistry.
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
KOREAN CHEMICAL SOCIETY
yield 60%), White solid; m.p. 167–169 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.51–7.34 (m, 5H), 7.31–7.24 (m,
1H), 6.79 (d, J = 2.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H),
5.01–4.84 (m, 2H), 4.60 (dd, J = 9.7, 4.5 Hz, 1H), 3.53 (s,
3H), 3.38 (dd, J = 15.5, 9.7 Hz, 1H), 3.14–2.96 (m, 2H),
1.62 (s, 3H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
172.4, 170.9, 143.2, 135.1, 132.6, 132.2, 131.9, 130.2,
129.0, 128.7, 124.4, 115.4, 76.1, 64.7, 62.9, 51.7, 37.2,
29.5, 28.2; IR (neat) 3301, 2954, 2925, 2852, 1730, 1626,
1586, 1488, 1451, 1415, 1397, 1374, 1318, 1257, 1222,
1266 1138, 1083, 1061 cm−1; HRMS (EI) m/z calcd for
[M]+ C21H23BrN2O4: 446.0841 Found: 446.0863.
O
OEt
4a
NH2
+
O
N
O
O
OEt
Br
OBn
Cs2CO3
-HBr
Me
OBn
N
N
H
Me Me
NH2
Me
OBn
Me
Me
2a
azaoxyallyl cation
A
O
B
-H+ / H+
H
HO
O
N
O
OEt
OEt
Aza-
Michael
addition
OEt
OBn
OBn
N
Methyl
[4-(benzyloxy)-8-fluoro-2,2-dimethyl-3-oxo-
OBn
Tautomerization
N
NH
1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (6h).
O
Me
O
Me
Me
N
Flash chromatography (EtOAc:hexane = 1:7 to 1:4, 20 mg,
Me
N
H
6a
H
Me
O
1
Me
yield 51%), Colorless gum; H NMR (400 MHz, CDCl3) δ
D
C
7.51–7.32 (m, 5H), 6.74 (dd, J = 8.3, 6.2 Hz, 1H), 6.59 (td,
J = 8.4, 2.5 Hz, 1H), 6.50 (dd, J = 9.2, 2.4 Hz, 1H), 4.94
(q, J = 10.6 Hz, 2H), 4.69 (dd, J = 10.0, 4.3 Hz, 1H), 3.50
(s, 3H), 3.39 (dd, J = 15.4, 10.0 Hz, 1H), 3.13 (s, 1H), 3.02
(dd, J = 15.4, 4.3 Hz, 1H), 1.62 (s, 3H), 1.23 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 172.5, 171.1, 163.0 (d,
J = 248.3 Hz), 146.0 (d, J = 9.2 Hz), 135.2, 131.4 (d,
J = 9.7 Hz), 130.0, 128.8, 128.6, 125.8 (d, J = 3.0 Hz),
109.9 (d, J = 22.3 Hz), 109.6 (d, J = 21.4 Hz), 76.1, 64.5,
63.0, 51.6, 37.4, 29.5, 28.1; IR (neat) 3315, 2922, 2852,
1737, 1630, 1518, 1484, 1428, 1408, 1374, 1327, 1293,
1253, 1220, 1164, 1133, 1105, 1058 cm−1; HRMS (EI) m/
Scheme 4. Plausible reaction mechanism.
Methyl
[4-(benzyloxy)-7-fluoro-2,2-dimethyl-3-oxo-
1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (6e).
Flash chromatography (EtOAc:hexane = 1:7 to 1:4, 28 mg,
yield 72%), White solid; m.p. 164–166 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.48–7.31 (m, 5H), 6.87 (td, J = 8.4,
2.9 Hz, 1H), 6.71 (dd, J = 8.5, 4.8 Hz, 1H), 6.49 (dd,
J = 8.6, 2.9 Hz, 1H), 5.03–4.85 (m, 2H), 4.65 (dd, J = 9.9,
4.4 Hz, 1H), 3.53 (s, 3H), 3.46 (dd, J = 15.6, 9.9 Hz, 1H),
3.05 (dd, J = 15.6, 4.4 Hz, 1H), 2.99 (s, 1H), 1.61 (s, 3H),
1.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.8,
171.018, 158.4 (d, J1 = 242.4 Hz), 140.1 (d, J4 = 2.6 Hz),
135.1, 131.8 (d, J3 = 7.7 Hz), 130.1, 128.9, 128.6, 124.1
(d, J3 = 8.0 Hz), 116.6 (d, J2 = 23.3 Hz), 115.9 (d,
J2 = 22.2 Hz), 76.1, 64.9, 64.8, 62.8, 51.7, 37.3, 29.5, 27.8;
IR (neat) 3309, 2955, 2922, 2851, 1730, 1627, 1506, 1495,
1454, 1438, 1419, 1373, 1354, 1319, 1288, 1247, 1204,
1165, 1150, 1112, 1084 cm−1; HRMS (EI) m/z calcd for
[M]+ C21H23FN2O4: 386.1642 Found: 386.1633.
z
calcd for [M]+ C21H23FN2O4: 386.1642 Found:
386.1646.
Methyl (7-fluoro-4-methoxy-2,2-dimethyl-3-oxo-1,2,4,5-
tetrahydro-1,4-benzodiazepin-5-yl)acetate (6i).
Flash
chromatography (EtOAc: hexane = 1:7 to 1:4, 17 mg, yield
1
56%), Colorless gum; H NMR (400 MHz, CDCl3) δ 7.03
(dd, J = 8.5, 2.9 Hz, 1H), 6.93 (td, J = 8.4, 2.9 Hz, 1H),
6.77 (dd, J = 8.5, 4.8 Hz, 1H), 4.94 (dd, J = 9.7, 4.4 Hz,
1H), 3.77 (s, 3H), 3.59 (s, 3H), 3.54 (dd, J = 15.5, 9.8 Hz,
1H), 3.16 (dd, J = 15.5, 4.4 Hz, 1H), 3.03 (s, 1H), 1.60 (s,
3H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5,
171.0, 158.6 (d, J1 = 242.8 Hz), 140.2 (d, J4 = 2.7 Hz),
132.3 (d, J3 = 7.5 Hz), 124.5 (d, J3 = 8.0 Hz), 116.5 (d,
J2 = 23.2 Hz), 116.1 (d, J2 = 22.2 Hz), 63.3, 62.8, 61.6,
51.8, 37.7, 29.7, 27.6; IR (neat) 3309, 2951, 2925, 2854,
1731, 1627, 1507, 1496, 1438, 1403, 1354, 1320, 1248,
1205, 1166, 1113, 1087, 1048 cm−1; HRMS (EI) m/z calcd
for [M]+ C15H19FN2O4: 310.1329 Found: 310.1306.
Methyl
[4-(benzyloxy)-7-chloro-2,2-dimethyl-3-oxo-
(6f).
1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate
Flash chromatography (EtOAc:hexane = 1:7 to 1:4, 26 mg,
yield 65%), White solid; m.p. 181–183 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.49–7.31 (m, 5H), 7.13 (dd, J = 8.3,
2.4 Hz, 1H), 6.69 (t, J = 5.7 Hz, 2H), 4.93 (q, J = 10.7 Hz,
2H), 4.62 (dd, J = 9.8, 4.5 Hz, 1H), 3.53 (s, 3H), 3.40 (dd,
J = 15.5, 9.8 Hz, 1H), 3.05 (dd, J = 15.5, 4.4 Hz, 2H), 1.62
(s, 3H), 1.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
172.5, 170.925, 142.755, 135.1, 131.5, 130.2, 129.7, 129.3,
129.0, 128.6, 127.9, 124.1, 76.1, 64.8, 62.9, 51.7, 37.2,
29.5, 28.1; IR (neat) 3303, 2953, 2925, 2854, 1731, 1627,
1491, 1454, 1416, 1398, 1354, 1319, 1288, 1324, 1197,
1168, 1125, 1092, 1064 cm−1; HRMS (EI) m/z calcd for
[M]+ C21H23ClN2O4: 402.1346 Found: 402.1364.
Methyl [4-(allyloxy)-7-fluoro-2,2-dimethyl-3-oxo-1,2,4,5-
tetrahydro-1,4-benzodiazepin-5-yl]acetate (6j).
Flash
chromatography (EtOAc: hexane = 1:7-1:4, 20 mg, yield
1
66%), Colorless gum; H NMR (400 MHz, CDCl3) δ 7.00
(dd, J = 8.5, 2.9 Hz, 1H), 6.92 (td, J = 8.4, 2.9 Hz, 1H),
6.76 (dd, J = 8.5, 4.8 Hz, 1H), 6.04 (ddt, J = 17.0, 10.2,
6.6 Hz, 1H), 5.38–5.24 (m, 2H), 4.91 (dd, J = 9.9, 4.3 Hz,
1H), 4.53–4.33 (m, 2H), 3.64–3.49 (m, 4H), 3.17 (dd,
J = 15.6, 4.3 Hz, 1H), 3.01 (s, 1H), 1.59 (s, 3H), 1.19 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 172.8, 171.0, 158.6
Methyl
[4-(benzyloxy)-7-bromo-2,2-dimethyl-3-oxo-
1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl]acetate (6g).
Flash chromatography (EtOAc:hexane = 1:7 to 1:4, 27 mg,
Bull. Korean Chem. Soc. 2020, Vol. 41, 727–734
© 2020 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
KOREAN CHEMICAL SOCIETY
(d, J1 = 242.6 Hz), 140.3 (d, J4 = 2.7 Hz), 132.1, 132.0 (d,
J3 = 7.6 Hz), 124.3 (d, J3 = 8.0 Hz), 121.0, 116.7 (d,
J2 = 23.2 Hz), 116.0 (d, J2 = 22.2 Hz), 75.2, 64.5, 62.8,
51.7, 37.4, 29.5, 27.8; IR (neat) 3318, 2970, 2954, 2920,
2870, 1733, 1641, 1502, 1453, 1437, 1406, 1376, 1357,
1306, 1292, 1245, 1207, 1150, 1106, 1044 cm−1; HRMS
(EI) m/z calcd for [M]+ C17H21FN2O4: 336.1485 Found:
336.1495.
129.98, 129.4, 128.7, 128.5, 122.8, 122.6, 76.0, 73.3, 65.1,
51.6, 39.6, 37.8, 37.5, 24.1, 23.9; IR (neat) 3328, 3031,
2951, 2874, 1735, 1635, 1598, 1485, 1454, 1436, 1411,
1352, 1327, 1284, 1251, 1229, 1198, 1158, 1188, 1028,
1015 cm−1; HRMS (EI) m/z calcd for [M]+ C23H26N2O4:
394.1893 Found: 394.1909.
Methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1H-spiro[1,4-
benzodiazepine-2,1’-cyclobutan]-5-yl}acetate (6n). Flash
chromatography (EtOAc:hexane = 1:7 to 1:4, 11 mg, yield
Methyl
[4-(benzyloxy)-2,2-diethyl-3-oxo-1,2,4,5-tetra-
1
hydro-1,4-benzodiazepin-5-yl]acetate (6k). Flash chro-
28%), Colorless gum; H NMR (400 MHz, CDCl3) δ 7.43
matography (EtOAc:hexane = 1:7 to 1:4, 25 mg, yield
(dd, J = 6.6, 3.0 Hz, 2H), 7.40–7.31 (m, 3H), 7.14 (td,
J = 7.7, 1.6 Hz, 1H), 6.94–6.86 (m, 1H), 6.82 (td, J = 7.5,
1.0 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.01 (t, J = 7.1 Hz,
1H), 4.91 (dd, J = 45.4, 10.1 Hz, 2H), 3.74 (s, 1H), 3.58 (s,
3H), 3.32–3.10 (m, 3H), 2.39–2.29 (m, 1H), 2.18 (dd,
J = 17.5, 12.7 Hz, 1H), 2.03–1.90 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.2, 170.9, 144.4, 135.2, 129.8,
129.3, 128.7, 128.5, 128.2, 126.8, 121.2, 120.6, 64.1, 61.2,
51.8, 36.0, 35.0, 34.0, 29.7, 13.8; IR (neat) 3339, 3031,
2950, 2876, 1736, 1656, 1606, 1482, 1454, 1437, 1355,
1322, 1287, 1258, 1195, 1166, 1117, 1081 cm−1; HRMS
(EI) m/z calcd for [M]+ C22H24N2O4: 380.1736 Found:
380.1717.
Procedure for the N─O Bond Cleavage of 6b. To a solu-
tion of compound 6b (37 mg, 0.10 mmol in CH3CN
(0.9 mL) and H2O (0.1 mL) was added Mo(CO)6 (32 mg,
0.12 mmol) at room temperature. After stirring at reflux for
15 h, the resulting mixture was allowed to room tempera-
ture and filtered through the plug of celite and concentrated
in vacuo. The crude residue was purified by flash column
chromatography with EtOAc/hexanes as eluent to afford
desired product 7 (14 mg, 53% yield). Methyl (2,2-
dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-yl)
acetate, White solid; m.p. 166–167 ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7.27–7.19 (m, 1H), 7.16–7.08 (m,
1H), 7.02 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H),
6.41 (d, J = 5.7 Hz, 1H), 4.69 (ddd, J = 9.9, 6.3, 5.0 Hz,
1H), 3.69 (s, 3H), 3.54 (dd, J = 16.5, 9.6 Hz, 1H), 3.07 (s,
1H), 2.79 (dd, J = 16.5, 4.7 Hz, 1H), 1.55 (s, 3H), 1.27 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 177.3, 172.2, 144.9,
133.1, 129.2, 127.8, 123.6, 123.6, 61.8, 53.9, 52.1, 40.0,
29.7, 28.3; IR (neat) 3340, 3272, 3032, 2922, 2852, 1728,
1643, 1606, 1493, 1439, 1414, 1372, 1349, 1302, 1259,
1226, 1195, 1161, 1090, 1035 cm−1; HRMS (EI) m/z calcd
for [M]+ C14H18N2O3: 262.1317 Found: 262.1335.
1
ꢀ
64%), White solid; m.p. 136–138 C; H NMR (400 MHz,
CDCl3) δ 7.47–7.32 (m, 5H), 7.15 (td, J = 7.6, 1.5 Hz,
1H), 6.86 (td, J = 7.4, 1.1 Hz, 1H), 6.82–6.74 (m, 2H),
4.96 (q, J = 10.6 Hz, 2H), 4.75 (dd, J = 9.7, 4.4 Hz, 1H),
3.38 (dd, J = 15.2, 9.8 Hz, 1H), 3.21 (s, 1H), 3.09 (dd,
J = 15.2, 4.4 Hz, 1H), 2.27 (dq, J = 14.6, 7.4 Hz, 1H), 1.65
(dd, J = 14.1, 7.5 Hz, 1H), 1.58–1.41 (m, 2H), 1.11 (t,
J = 7.3 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.0, 171.2, 144.4, 135.3, 130.0,
129.9, 129.6, 129.4, 128.7, 128.6, 122.5, 122.3, 76.3, 69.4,
65.2, 51.6, 38.2, 32.3, 32.2, 9.0, 7.6; IR (neat) 3317, 2954,
2914, 2855, 1734, 1621, 1597, 1486, 1455, 1439, 1373,
1349, 1303, 1273, 1260, 1219, 1166, 1114, 1104,
1037 cm−1; HRMS (EI) m/z calcd for [M]+ C23H28N2O4:
396.2049 Found: 396.2044.
Methyl [4-(benzyloxy)-2-methyl-3-oxo-2-propyl-1,2,4,5-
tetrahydro-1,4-benzodiazepin-5-yl]acetate (6l).
Flash
chromatography (EtOAc:hexane = 1:7 to 1:4, 13 mg, yield
1
ꢀ
32%), White solid; m.p. 117–119 C; H NMR (400 MHz,
CDCl3) δ 7.49–7.42 (m, 2H), 7.40–7.32 (m, 3H), 7.17 (td,
J = 7.5, 1.7 Hz, 1H), 6.88 (dtd, J = 9.1, 7.5, 1.3 Hz, 2H),
6.76 (d, J = 7.0 Hz, 1H), 4.93 (dd, J = 33.5, 10.5 Hz, 2H),
4.78 (dd, J = 9.7, 4.5 Hz, 1H), 3.48 (s, 3H), 3.36 (dd,
J = 15.2, 9.8 Hz, 1H), 3.30 (s, 1H), 3.08 (dd, J = 15.2,
4.5 Hz, 1H), 1.54 (s, 3H), 1.40–1.21 (m, 4H), 0.77 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.2,
171.2, 144.0, 135.3, 129.9, 129.8, 129.7, 129.4, 128.7,
128.5, 122.6, 122.4, 76.16, 65.4, 65.0, 51.6, 41.6, 37.4,
26.1, 16.5, 14.2; IR (neat) 3324, 3065, 2958, 2930, 2874,
1734, 1650, 1626, 1487, 1454, 1436, 1405, 1358, 1327,
1281, 1257, 1192, 1162, 1114, 1025 cm−1; HRMS (EI) m/
z calcd for [M]+ C23H28N2O4: 396.2049 Found: 396.2036.
Methyl {4-(benzyloxy)-3-oxo-4,5-dihydro-1H-spiro[1,4-
benzodiazepine-2,1’-cyclopentan]-5-yl}acetate
(6m).
Flash chromatography (EtOAc:hexane = 1:7 to 1:4, 16 mg,
yield 40%), Colorless gum; H NMR (400 MHz, CDCl3) δ
Procedure for the Synthesis of 8 from 6b. To a solution
of compound 6b (37 mg, 0.10 mmol in THF (0.5 mL) was
added LiALH4 (1 M solution in THF, 0.1 mL, 0.10 mmol)
1
7.48–7.40 (m, 2H), 7.39–7.31 (m, 3H), 7.17 (td, J = 7.6,
1.5 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.88–6.81 (m, 1H),
6.73 (d, J = 7.7 Hz, 1H), 4.95 (dd, J = 24.7, 10.5 Hz, 2H),
4.77 (dd, J = 9.8, 4.4 Hz, 1H), 3.48 (s, 3H), 3.41 (dd,
J = 15.2, 9.8 Hz, 1H), 3.15 (s, 1H), 3.09 (dd, J = 15.2,
4.4 Hz, 1H), 2.78 (ddd, J = 17.4, 10.9, 6.8 Hz, 1H), 1.95
(dd, J = 13.2, 4.5 Hz, 1H), 1.87–1.73 (m, 3H), 1.64 (dt,
J = 12.8, 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.9, 171.3, 144.1, 135.3, 130.01(two peaks overlapped),
ꢀ
at 0 C. After stirring at room temperature for 20 min, the
resulting mixture was quenched with MeOH and diluted
with water. The organic layer was extracted with EtOAc
and was washed with brine, dried over anhydrous MgSO4,
and concentrated in vacuo. The crude residue was purified
by flash column chromatography with EtOAc/hexanes as
eluent to afford desired product 8 (12 mg, 35% yield). 4-
(Benzyloxy)-5-(2-hydroxyethyl)-2,2-dimethyl-1,2,4,5-
Bull. Korean Chem. Soc. 2020, Vol. 41, 727–734
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BULLETIN OF THE
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
KOREAN CHEMICAL SOCIETY
tetrahydro-1,4-benzodiazepin-3-one, Colorless gum; 1H
NMR (400 MHz, CDCl3) δ 7.44–7.26 (m, 5H), 7.04 (td,
J = 7.7, 1.6 Hz, 1H), 6.86 (dd, J = 7.5, 1.5 Hz, 1H), 6.75
(td, J = 7.4, 1.2 Hz, 1H), 6.56 (dd, J = 7.9, 1.1 Hz, 1H),
4.88 (ddd, J = 12.7, 11.0, 3.5 Hz, 1H), 4.72 (q,
J = 11.9 Hz, 2H), 4.34 (s, 1H), 4.16 (d, J = 5.8 Hz, 1H),
3.86–3.75 (m, 1H), 3.23 (s, 1H), 2.79 (tt, J = 12.7, 6.3 Hz,
1H), 1.34 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.6, 138.0, 130.9, 129.4, 129.3, 128.3, 128.2,
127.9, 120.3, 120.1, 91.4, 75.0, 62.6, 60.7, 58.1, 29.4,
27.2, 27.1; IR (neat) 3332, 3029, 2957, 2926, 2853, 1733,
1604, 1587, 1486, 1453, 1383, 1362, 1314, 1274, 1253,
1174, 1143, 1074, 1063, 1036 cm−1; HRMS (EI) m/z calcd
for [M]+ C20H26N2O3: 342.1943 Found: 342.1934.
Procedure for the Synthesis of 9 from 6b. To a solution
of compound 6b (74 mg, 0.20 mmol in 1,4-dioxane
(0.9 mL) and H2O (0.1 mL) was added KOH (34 mg,
0.6 mmol) at room temperature. After stirring at same
temperature for 18 h, the resulting mixture was quenched
with 0.5 M HCl solution and was extracted with EtOAc.
The combined organic layer was washed with brine,
dried over anhydrous MgSO4, and concentrated in vacuo.
The crude residue was purified by flash column chroma-
tography with EtOAc/hexanes as eluent to afford desired
M. Kožíšek, I. Císařová, H. Oberwinkler, H.-G. Kraeusslich,
J. Konvalinka, J. Med. Chem. 2012, 55, 10130. (d)
M. Anzini, S. Valenti, C. Braile, A. Cappelli, S. Vomero,
S. Alcaro, F. Ortuso, L. Marinelli, V. Limongelli,
E. Novellino, L. Betti, G. Giannaccini, A. Lucasshini,
S. Daniele, C. Martini, C. Ghelardini, L. D. C. Mannelli,
G. Giorgi, M. P. Mascia, G. Biggio, J. Med. Chem. 2012, 55,
10130.
3. N. E. Calcaterra, J. C. Barrrow, ACS Chem. Neurosci. 2014,
5, 253.
4. J. E. Hochlowski, W. W. Andres, R. J. Theriault, M. Jackson,
J. B. McAlpine, J. Antibiot. 1987, 40, 145.
5. (a) I. P. Andrew, R. J. Atkins, G. F. Breen, J. S. Carey,
M. A. Forth, D. O. Morgan, A. Shamji, A. C. Share,
S. A. C. Smith, T. C. Walsgrove, A. S. Wells, Org. Process.
Res. Dev. 2003, 7, 655. (b) R. J. Atkins, A. Banks,
R. K. Bellingham, G. F. Breen, J. S. Carey, S. K. Etridge,
J. F. Hayes, N. Hussain, D. O. Morgan, P. Oxley,
S. C. Passey, T. C. Walsgrove, A. S. Wells, Org. Process.
Res. Dev. 2003, 7, 663. (c) F. Liu, R. M. Craft, S. A. Morris,
R. C. Carroll, Expert Opin. Investig. Drugs 2000, 9, 2673.
(d) R. M. Scarborough, D. D. Gretler, J. Med. Chem. 2000,
43, 3453. (e) T. W. Ku, F. E. Ali, L. S. Barton, J. W. Bean,
W. E. Bondinell, J. L. Burgess, J. F. Callahan, R. R. Calvo,
L. Chen, D. S. Eggleston, J. G. Gleason, W. F. Huffman,
S. M. Hwang, D. R. Jakas, C. B. Karash, R. M. Keenan,
K. D. Kopple, W. H. Miller, K. A. Newlander, A. Nichols,
M. F. Parker, C. E. Peishoff, J. M. Samanen, I. Uzinskas,
J. W. Venslavsky, J. Am. Chem. Soc. 1993, 115, 8861.
6. (a) A. A. Dörr, W. D. Lubell, Org. Lett. 2015, 17, 3592. (b)
R. Ettari, N. Micale, T. Schirmeister, C. Gelhaus, M. Leippe,
E. Nizi, M. E. Di Fransesco, S. Grasso, M. M. Zappalà, J.
product
9 (18 mg, 25% yield). 4-(Benzyloxy)-2,2-
dimethyl-3-oxo-1,2,4,5-tetrahydro-1,4-benzodiazepin-5-
yl]acetic acid, White solid; m.p. 141–144ꢀC; 1H NMR
(400 MHz, CDCl3) δ 7 7.59–7.28 (m, 5H), 7.16 (td,
J = 7.6, 1.1 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 6.82 (d,
J = 7.0 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 4.92 (q,
J = 10.5 Hz, 2H), 4.72 (dd, J = 9.7, 4.1 Hz, 1H), 3.45 (dd,
J = 15.8, 9.8 Hz, 1H), 3.05 (dd, J = 15.8, 4.1 Hz, 1H),
1.61 (s, 3H), 1.19 (s, 3H).; 13C NMR (100 MHz, CDCl3)
δ 176.1, 173.1, 144.2, 135.3, 130.11, 130.09, 130.0,
129.6, 128.9, 128.7, 123.2, 123.121, 76.14 65.0, 63.0,
37.7, 29.0, 28.0; IR (neat) 3343, 3031, 2923, 2853, 1725,
1613, 1598, 1492, 1455, 1378, 1360, 1317, 1231, 1202,
1159, 1111, 1046 cm−1; HRMS (EI) m/z calcd for [M]+
C20H22N2O4: 354.1580 Found: 354.1570.
Med. Chem. 2009, 52, 2157.
(c) N. Micale,
A. P. Kozikowski, R. Ettari, S. Grasso, M. Zappalà, J.-
J. Jeong, A. Kummar, M. Hanspal, A. H. Chishti, J. Med.
Chem. 2006, 49, 3064. (d) U. Rosenström, C. Sköld,
G. Lindeberg, M. Botros, F. Nyberg, A. Karlén, A. Hallberg,
J. Med. Chem. 2006, 49, 6133. (e) U. Rosenström, C. Sköld,
G. Lindeberg, M. Botros, F. Nyberg, A. Karlén, A. Hallberg,
J. Med. Chem. 2004, 47, 859. (f) I. Im, T. R. Webb, Y.-
D. Gong, J.-I. Kim, Y.-C. Kim, J. Comb. Chem. 2004, 6, 207.
7. For selected recent examples on synthesis of 1,4-
benzodiazepin-3-ones, see (a) L. D. Sasiambarrena,
I. A. Barri, G. G. Fraga, R. D. Bravo, A. Ponzinibbio, Tetra-
hedron Lett 2019, 60, 264. (b) S. Vézina-Dawod, N. Gerber,
X. Liang, E. Biron, Tetrahedron 2017, 73, 6347. (c)
S. Noushini, M. Mahdavi, L. Firoozpour, S. Moghimi,
A. Shafiee, A. Foroumadi, Tetrahedron 2015, 71, 6272. (d)
M. Mahdavi, M. Asadi, M. Saeedi, Z. Rezaei, H. Moghbel,
A. Foroumadi, A. Shafiee, Synlett 2012, 23, 2521. (e)
H. Wang, Y. Jiang, K. Gao, D. Ma, Tetrahedron 2009, 65,
8956. (f) R. A. De Silva, S. Santra, P. R. Andreana, Org. Lett.
2008, 10, 4541.
Acknowledgments.
This research was supported by
Kyonggi University Research Grant 2019.
Supporting Information
Supplementary data associated with this article can be
found in the online version.
References
8. For review of cycloaddition using azaoxyallyl cation, see (a)
A. E. Bouakher, A. Martel, S. Comesse, Org. Biomol. Chem
2019, 17, 8467. (b) J. Xuan, X. Cao, X. Cheng, Chem.
Commun. 2018, 54, 5154.
9. For examples of [4+3] cycloaddition using azaoxyallyl cat-
ions, see (a) C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff,
C. R. Carson, J. Am. Chem. Soc 2011, 133, 7688. (b) J. Feng,
1. D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003,
103, 893.
2. (a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2014, 57, 10257. (b) S. G. Smith, R. Sanchez, M. M. Zhou,
Chem. Biol. 2014, 21, 573. (c) J. Schimer, P. Cigler,
J. Vesely, K. G. Šašková, M. Lepšik, J. Brynda, P. Řezácˇová,
Bull. Korean Chem. Soc. 2020, Vol. 41, 727–734
© 2020 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Facile Synthesis of Functionalized 1,4-Benzodiazepine-3-One-5-Acetates
KOREAN CHEMICAL SOCIETY
M. Zhou, X. Lin, A. Lu, X. Zhang, M. Zhao, Org. Lett. 2019,
21, 6245. (c) Y. I. Kwon, S. Choi, H. S. Jang, S.-G. Kim,
Org. Lett. 2020, 22, 1420.
2726. (c) F. Mirhashemi, M. A. Amrollahi, Tetrahedron Lett.
2018, 15, 2661.
11. (a) Z.-X. Jia, Y.-C. Luo, Y. Wang, L. Chen, P.-F. Xu, B. Wang,
Chem. Eur. J. 2012, 18, 12958. (b) D. Y. Park, S. Y. Lee,
J. Jeon, C.-H. Cheon, J. Org. Chem. 2018, 83, 12486.
10. (a) M. C. DiPoto, J. Wu, Org. Lett. 2018, 20, 499. (b)
Y. Murata, K. Takeuchi, T. Nishikata, Tetrahedron 2019, 75,
Bull. Korean Chem. Soc. 2020, Vol. 41, 727–734
© 2020 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
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