One-pot synthesis of polysubstituted 3-amino-2-oxo-2,7-dihydro-1 H -azepines

Article abstract of DOI:10.1055/s-0033-1340473

A facile and efficient synthesis of novel seven-membered heterocyclic derivatives containing 3-aminoazepan-2-one backbone is described using 1,4-protected piperazine-2,5-diones and alkynes as starting materials. The reaction may undergo Michael? addition,

Full text of DOI:10.1055/s-0033-1340473

PAPER
▌621
pOapnere-Pot Synthesis of Polysubstituted 3-Amino-2-oxo-2,7-dihydro-1H-azepines
Polysubstituted 3-Amino-2-oxo-2,7-dihydro-1H-azepines
Shengrong Liao,a Chun Qin,a Peifen Yao,b Jinsheng Li,a Xuefeng Zhou,a Junfeng Wang,a Zhishu Huang,b
Yonghong Liu*a
a
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica/RNAM,
Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, P. R. of China
Fax +86(20)89023244; E-mail: yonghongliu@scsio.ac.cn
b
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, P. R. of China
Received: 06.10.2013; Accepted after revision: 25.11.2013
and antihelminthic activity, 3d,5 whereas their synthetic an-
Abstract: A facile and efficient synthesis of novel seven-mem-
alogues are more potent and can selectively inhibit tuber-
bered heterocyclic derivatives containing 3-aminoazepan-2-one
culosis and malaria,6 or serve as inhibitors of matrix
backbone is described using 1,4-protected piperazine-2,5-diones
and alkynes as starting materials. The reaction may undergo
metalloproteinase,7 factor Xa,8 γ-secretase,9 HIV,10 etc.
Michael addition, unusual nucleophilic attack to an amide group, Hence the 3-aminoazepan-2-one scaffold is potentially
and keto–enol tautomerization. The reaction showed different reac-
tivity when using substrates with different protecting groups: it had
higher efficiency when using either alkanoyl-protecting group with
important in the design of active small molecules in me-
dicinal chemistry.
General methods for the synthesis of this scaffold include:
(1) Beckmann rearrangement,11 (2) lactamization,12 and
(3) ring-closing metathesis (RCM) (Scheme 1).9b,13 The
first two approaches are traditional, while the last is rela-
tively new. All of these approaches require multiple steps,
or use a heavy metal catalyst. In addition, since most po-
tent 3-aminoazepan-2-ones possess side chains in the 1-
and/or 3-positions, the design and synthesis of analogues
may provide a variety of bioactive compounds. Therefore,
exploring a more convenient, economical approach that
may be used to attach one or more substituents directly on
to the aliphatic ring is necessary. Herein we report a new
and facile method for the construction of a novel 3-amino-
cesium carbonate as the base, or benzoyl-protecting group with tri-
ethylamine as the base, but no reaction when using benzyl or allyl
protecting groups with a variety of bases (Et3N, DBU, K2CO3,
Cs2CO3, KHCO3, CsHCO3, and KOt-Bu).
Key words: alkyne, 3-aminoazepan-2-one, Michael addition, pi-
perazine-2,5-dione, protecting groups
3-Aminoazepan-2-one is not only biologically active,1 but
also an important unit in various natural products, such as
cobactin T, mycobactin, amamistatin A and B, and the
bengamide family (Figure 1). They have cell-growth-
promoting,2 antitumor,3 immune-modulating,4 antibiotic,
O
H2N
O
HO
N
NH
O
O
H
OH
3-aminoazepan-2-one
N
O
N
N
N
H
O
O
O
H
OH
O
N
N
OH
mycobactin
OH
O
O
cobactin T
MeO
HO
N
H
O
HO
R1
R2
R3
H
O
O
N
N
H
N
OH
O
N
O
N
N
H
O
O
OH
OH
O
bengamide family
R
R1 = H or OH
2 = H or OC(=O)(CH2)12Me
3 = H or OH
R
R
amamistatin A R = OMe
amamistatin B R = H
Figure 1 Some bioactive natural products containing the 3-aminoazepan-2-one unit
SYNTHESIS 2014, 46, 0621–0628
Advanced online publication: 02.01.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340473; Art ID: SS-2013-H0664-OP
© Georg Thieme Verlag Stuttgart · New York

622
S. Liao et al.
PAPER
azepan-2-one framework, a 3-amino-2-oxo-2,7-dihydro-
1H-azepine, containing unsaturated carbon–carbon bonds
and/or polysubstituted groups on the aliphatic ring.
previous work:
OH
O
N
H
H
N
PG
N
Beckmann rearrangement
NH
a)
b)
PG
O
H
O
N
H
N
PG
OH
PG
lactamization
NH
NH2
O
O
H
H
N
PG
PG
N
PG
PG
RCM
N
c)
PG
N
this work:
O
O
O
H
N
CO2R
Figure 2 Single-crystal X-ray structure of compound 3aa
PG
RO2C
RO2C
PG
N
base
N
+
N
PG
RO2C
ate/1a was 0.5:1 (entry 13); increasing or decreasing the
amount of base did not improve the yield (entries 11, 12,
14, and 15). Finally, we examined the impact of the sol-
vent (entries 16–19) and found that the results were very
different: the reaction did not take place using toluene as
the solvent (entry 16) even after a long time (24 h), while
no product was formed in methanol although the substrate
was consumed in 30 minutes (entry 18), and the reaction
in dimethyl sulfoxide was complete in 35% yield in 30
minutes (entry 19) but the reaction in tetrahydrofuran re-
quired 17 hours and gave the product in 36% yield (entry
17). Thus, the optimized reaction conditions used cesium
carbonate (0.5 equiv with respect to 1a) as the base and di-
methylformamide as the solvent at room temperature.
OH
Scheme 1 Approaches for the synthesis of 3-aminoazepan-2-one
and its analogues
Initially, we examined the reaction of 1,4-diacetylpipera-
zine-2,5-dione (1a) with dimethyl but-2-ynedioate (2a) in
the presence of triethylamine (2.0 equiv relative to 1a) at
room temperature (Table 1, entry 2). To our surprise, there
was one major spot on the TLC plate and the substrate dis-
appeared in 30 minutes. This interesting observation puz-
zled us and the product was separated using silica gel
chromatography, and characterized by H and 13C NMR,
1
and later X-ray crystallographic analysis. The results
showed that the product had a seven-membered, unsatu-
rated 3-aminoazepan-2-one scaffold, with the amino and
amide moieties protected by two acetyl groups, and one
hydroxy group forming a hydrogen bond with the adjacent
ester group on the ring backbone (Figure 2). Optimization
of the reaction conditions followed. We first performed
this reaction either with no base or with the addition of dif-
ferent bases (2.0 equiv relative to 1a) in dimethylform-
amide under the same conditions (entries 1, 3–8). No
reaction took place when no base was present, but the
presence of base promoted the reaction with cesium car-
bonate giving the highest yield in the shortest reaction
time (entry 4), possibly due to its solubility in dimethyl-
formamide and proton-removing ability.14
After establishing the reaction system, we further studied
the reaction of different alkanoyl-protected piperazine-
2,5-diones 1a–e with alkynes to extend the scope of the
reaction (Table 2). Four alkanoyl-protected piperazine-
2,5-diones 1a–d were employed as nucleophiles in the re-
action with dimethyl but-2-ynedioate (2a), and the corre-
sponding 3-aminoazepan-2-one products 3aa–da were
obtained in moderate yields (entries 1–4). These results
were similar to those with diethyl but-2-ynedioate (2b)
(entries 6–9).
However, when benzoyl, benzyl, and allyl groups were
used as the protective functions, the optimized reaction
system was inefficient. For example, no product was
formed when 1,4-dibenzoylpiperazine-2,5-dione (1e) and
cesium carbonate were used, and the main product was
confirmed to be the enol form 4 of the substrate (com-
pound 1e) (Scheme 2), the same product was obtained
when potassium tert-butoxide was used as the base. Sim-
ilarly, when potassium carbonate, potassium hydrogen
carbonate, cesium hydrogen carbonate, or DBU were
We then investigated the effect of reaction temperature
and molar ratio (from 0.1:1 to 3:1) of cesium carbonate to
substrate 1a, attempting to improve the yield of the prod-
uct. As shown in Table 1, the yield did not increase on
changing the reaction temperature (entries 9 and 10), but
increased to 63% when the molar ratio cesium carbon-
Synthesis 2014, 46, 621–628
© Georg Thieme Verlag Stuttgart · New York

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Polysubstituted 3-Amino-2-oxo-2,7-dihydro-1H-azepines
623
from 0.5:1 to 3:1, and it was found that when the molar ra-
tio was 2:1, the yield was the highest (entries 5 and 10).
Using a greater or lower amount of base resulted in either
lower yields or incomplete reaction. Correspondingly, the
reaction did not occur when 1,4-diallylpiperazine-2,5-di-
one (1f) or 1,4-dibenzylpiperazine-2,5-dione (1g) were
used regardless of the base used (Et3N, DBU, K2CO3,
Cs2CO3, KHCO3, CsHCO3, and KOt-Bu) (entries 11–12).
These results showed that the electron-withdrawing abili-
ties of the acyl groups were beneficial to the activation of
the hydrogen at the α-position of the amide group,15 and
strong base was not conducive to the reaction when the
protected functions had steric hindrance.16
Table 1 Optimization of Reaction Conditions for the Synthesis of
Compound 3aa
O
O
N
N
O
O
O
1a
Ac
H
N
N
Ac
+
MeO2C
MeO2C
O
OH
OMe
3aa
MeO
O
2a
On the basis of experimental results, a possible mecha-
nism for cesium carbonate or triethylamine promoted
Michael-type addition of piperazine-2,5-diones to elec-
tron-deficient alkynes is proposed in Scheme 3. It is rea-
sonable that in the existence of cesium carbonate or
triethylamine, compound 1a will undergo a keto–enol tau-
tomerization to give intermediate A, which was confirmed
by isolating compound 4. Intermediate A attacks the al-
kyne 2a through a Michael addition process to generate B,
which immediately changes into C via an unusual attack
to the amide group; after the cleavage of the amide bond
and keto–enol tautomerization,17 compound 3aa is formed.
Entry
Base (equiv)
Solvent
Temp
(°C)
Time Yielda
(h)
(%)
1
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–10
50
24
0.5
14
0.5
0.5
0.5
4
0
2
Et3N (2.0)
44
20
59
25
22
45
51
44
55
17
43
63
54
61
3
K2CO3 (2.0)
Cs2CO3 (2.0)
DBU (2.0)
4
5
6
KOt-Bu (2.0)
KHCO3 (2.0)
CsHCO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (0.1)
Cs2CO3 (0.25)
Cs2CO3 (0.5)
Cs2CO3 (1.0)
Cs2CO3 (3.0)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
Cs2CO3 (0.5)
In conclusion, we have developed an approach for a one-
pot synthesis of unsaturated, polysubstituted 3-aminoaze-
pan-2-one analogues. It was found that different protected
substrates have different reactivity with alkynes using a
variety of bases. This method provided a novel means for
the construction of various important seven-membered
heterocyclic systems. The products may be polysubstitut-
ed and they serve as versatile building blocks for the syn-
thesis of analogues of some important natural products.
An evaluation of the biological properties of the com-
pounds is underway.
7
8
1
9
2
10
11
12
13
14
15
16
17
18
19
0.5
8.5
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2.5
0.5
0.5
24
17
0.5
0.5
All solvents were analytical grade (Tianjin Fuyu Chem. Ind. Fac.)
and dried with CaH2, except for MeOH which was dried with Mg
and distilled. Petroleum ether = PE. Glycine anhydride was pur-
chased from Alfa Aesar, and others from Aladdin. All chemicals
were used without further purification. Silica gel (200–300 mesh)
and TLC plates (20 × 5 × 0.04 cm) from Qingdao Mar. Chem. Ind.
Co. Ltd were used for chromatography. Melting points were deter-
mined using a SRSO-ptiMelt automated melting point instrument
without correction. IR spectra were recorded on a Shimadzu IR
Affinity-1 FT-IR spectrophotometer. NMR spectra were recorded
with Bruker Avance spectrometer operating at 500 MHz (1H) and
125 MHz (13C) using TMS as an internal standard. Mass spectrom-
etry data were collected with an HRMS-TOF instrument or a low-
resolution MS instrument by using ESI ionization.
b
–
36
c
MeOH
DMSO
–
35
a Yield of isolated product.
b No reaction.
c Not determined.
1,4-Dialkanoylpiperazine-2,5-diones 1a–d; General Procedure
Glycine anhydride (500 mg, 2.5 mmol) and alkanoic anhydride (20
mL) were kept at 150 °C overnight and the excess alkanoic anhy-
dride was removed under reduce pressure. The residue was purified
by chromatography (silica gel) to give 1.
used, the main product was also 4 together with trace
amounts of the target product 3ea. But when triethylamine
was used as the base, the target compound 3ea was ob-
tained in moderate yield (Table 2, entry 5); a similar result
was obtained with diethyl but-2-ynedioate (2b) (entry 10).
Just like the reaction of alkanoyl-protected analogues with
alkynes, efforts were also made to improve the reaction
yield by changing the molar ratio of triethylamine to 1e
1,4-Diacetylpiperazine-2,5-dione (1a)18
Following the general procedure using Ac2O (20 mL) gave 1a as a
white solid; yield: 0.84 g (97%); mp 102–103 °C.
© Georg Thieme Verlag Stuttgart · New York
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S. Liao et al.
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Table 2 Synthesis of 3-Aminoazepan-2-one Derivatives
R1
HN
O
O
O
O
R2
R1
R1
base
O
N
N
+
N
DMF, r.t.
R2O2C
R2O2C
O
R1
R2
O
OH
1
2
3
Entry
Piperidinedione R1
Acetylene
R2
Base
Product
Yielda (%)
1
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1f
Ac
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2a
2a
Me
Me
Me
Me
Me
Et
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
3aa
3ba
3ca
3da
3ea
3ab
3bb
3cb
3db
3eb
–
63
46
42
50
40b
61
59
48
56
42b
2
COEt
COPr
COi-Pr
Bz
3
4
5
6
Ac
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
7
COEt
COPr
COi-Pr
Bz
Et
8
Et
9
Et
10
11
12
Et
c
d
CH2CH=CH2
Bn
Me
Me
–
–
c
d
1g
–
–
–
a Yield of isolated product.
b Molar ratio of Et3N/1e was 2:1; the use of other bases such as K2CO3, Cs2CO3, KHCO3, CsHCO3, DBU, and KOt-Bu was also examined.
c The use of Et3N, DBU, K2CO3, Cs2CO3, KHCO3, CsHCO3, and KOt-Bu was also examined.
d Not determined.
Scheme 2 Formation of the enol form 4 of 1e with cesium carbonate
Synthesis 2014, 46, 621–628
© Georg Thieme Verlag Stuttgart · New York

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Polysubstituted 3-Amino-2-oxo-2,7-dihydro-1H-azepines
625
O
O
MeO2C
O
Ac
H
Ac
N
Ac
Michael addition
N
N
–
N
N
CO2Me
Ac
N
Ac
CO2Me
2a
H
Ac
O
H
–O
A
CO2Me
O
B
1a
base
O
H
O
–
O
OMe
CO2Me
CO2Me
O
CO2Me
H+
CO2Me
keto–enol tautomerization
N
CO2Me
Ac
N
N
NH
Ac
NH
N
Ac
Ac
Ac
Ac
O
O
3aa
O
C
Scheme 3 Possible mechanism of the reaction
1H NMR (500 MHz, CDCl3): δ = 4.56 (s, 4 H), 2.54 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 170.7, 165.8, 47.0, 26.6.
MS (ESI): m/z (%) = 197.2 (100) [M – H]–.
1,4-Diallylpiperazine-2,5-dione (1f) and 1,4-Dibenzylpipera-
zine-2,5-dione (1g); General Procedure
Glycine anhydride (285 mg, 2.5 mmol) and NaH (2.2 equiv, 220
mg, 60% dispersion in oil) were stirred in dried DMF (5 mL) at r.t.
for 0.5 h, then allyl bromide or BnBr were added in portions and the
mixture was stirred continuous for 5 h. Crushed ice (10 g) was slow-
ly added and the mixture was poured into sat. NH4Cl (100 mL) and
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (anhyd Na2SO4), filtered, and purified by chromatogra-
phy (silica gel) to give 1f,g.
1,4-Dipropanoylpiperazine-2,5-dione (1b)
Following the general procedure using propanoic anhydride (20
mL) gave 1b as a white solid; yield: 0.86 g (87%); mp 112–113 °C.
1H NMR (500 MHz, CDCl3): δ = 4.57 (s, 4 H), 2.94 (q, J = 15.0,
10.0 Hz, 4 H), 1.15 (t, J = 10.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 174.8, 165.9, 47.4, 32.4, 8.5.
MS (ESI): m/z (%) = 225.2 (85) [M – H]–, 169.2 (10).
1,4-Diallylpiperazine-2,5-dione (1f)19
Following the general procedure using allyl bromide (2.2 equiv,
0.48 mL) gave 1f as a white solid; yield: 208 mg (43%); mp 93–95
°C.
1,4-Dibutanoylpiperazine-2,5-dione (1c)
Following the general procedure using butanoic anhydride (20 mL)
gave 1c as a white solid; yield: 0.68 g (61%); mp 104–107 °C.
1H NMR (500 MHz, CDCl3): δ = 4.57 (s, 4 H), 2.91 (t, J = 10.0, 4
H), 1.72–1.64 (m, 4 H), 0.96 (t, J = 10.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 173.9, 165.9, 47.4, 40.7, 17.7,
13.6.
1H NMR (500 MHz, CDCl3): δ = 5.77–5.69 (m, 2 H), 5.29–5.22 (m,
4 H), 4.02 (d, J = 5.0 Hz, 4 H), 3.95 (s, 4 H).
13C NMR (125 MHz, CDCl3): δ = 163.2, 130.7, 119.5, 49.0, 48.1.
MS (ESI): m/z (%) = 217.2 (10) [M + Na]+, 193.2 (5) [M – H]–,
153.2 (5).
MS (ESI): m/z (%) = 253.3 (80) [M – H]–, 183.2 (10).
1,4-Dibenzylpiperazine-2,5-dione (1g)
Following the general procedure using BnBr (2.2 equiv, 0.65 mL)
gave 1g as a white solid; yield: 676 mg (92%); mp 176–178 °C.
1,4-Diisobutanoylpiperazine-2,5-dione (1d)
Following the general procedure using isobutanoic anhydride (20
mL) gave 1d as a white solid: yield: 0.83 g (74%); mp 92–94 °C.
1H NMR (500 MHz, CDCl3): δ = 4.55 (s, 4 H), 3.68–3.58 (m, 2 H),
1.18 (t, J = 10.0 Hz, 12 H).
13C NMR (125 MHz, CDCl3): δ = 178.5, 165.7, 47.8, 35.8, 19.0.
MS (ESI): m/z (%) = 253.3 (10) [M – H]–, 183.2 (10).
1H NMR (500 MHz, CDCl3): δ = 7.32–7.27 (m, 6 H), 7.23 (d, J =
10.0 Hz, 4 H), 4.55 (s, 4 H), 3.89 (s, 4 H).
13C NMR (125 MHz, CDCl3): δ = 163.2, 134.9, 128.9, 128.5, 128.1,
49.2, 49.1.
MS (ESI): m/z (%) = 317.2 (100) [M + Na]+, 293.2 (50) [M – H]–.
Dialkyl 6-Hydroxy-2-oxo-2,7-dihydro-1H-azepine-4,5-dicar-
boxylates 3; General Procedure
1,4-Dibenzoylpiperazine-2,5-dione (1e)
Glycine anhydride (285 mg, 2.5 mmol) and Bz2O (2 g, 8.8 mmol)
were heated together at 130 °C (TLC monitoring). When the reac-
tion was complete (~5 h), the mixture was cooled to r.t, EtOAc (100
mL) was added and the solution was stirred continuous for another
1 h. The precipitate was filtered, dried, and 1e was collected as a
white solid; yield: 450 mg (56%); mp 204–206 °C.
Cs2CO3 (0.5 equiv) or Et3N (2.0 equiv) was added into a solution
containing piperazine-2,5-dione 1 (100 mg, 1 equiv) and alkyne 2
(1.2 equiv) in anhyd DMF (3 mL). The resulting mixture was stirred
at r.t. for 0.5 or 2.5 h, and then crushed ice (5 g) and H2O (100 mL)
were added. The pH value was adjusted to 5–6 and the mixture was
extracted with EtOAc (3 × 30 mL). The combined organic layers
were dried (anhyd Na2SO4), filtered, and purified by chromatogra-
phy (silica gel) to give the product.
1H NMR (500 MHz, CDCl3): δ = 7.69 (d, J = 10.0 Hz, 4 H), 7.60 (t,
J = 10.0 Hz, 2 H), 7.48 (t, J = 10.0 Hz, 4 H), 4.59 (s, 4 H).
13C NMR (125 MHz, CDCl3): δ = 170.9, 166.6, 133.7, 133.1, 128.8,
128.4, 48.7.
MS (ESI): m/z (%) = 321.3 (40) [M – H]–.
Dimethyl 3-Acetamido-1-acetyl-6-hydroxy-2-oxo-2,7-dihydro-
1H-azepine-4,5-dicarboxylate (3aa)
Following the general procedure using 1a (100 mg, 0.51 mmol), 2a
(75 μL, 0.61 mmol), and Cs2CO3 (83 mg, 0.26 mmol) gave 3aa as a
© Georg Thieme Verlag Stuttgart · New York
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626
S. Liao et al.
PAPER
white solid; yield: 108 mg (63%); mp 139–142 °C; Rf = 0.2 (PE–
EtOAc, 2:1).
Dimethyl 3-Benzamido-1-benzoyl-6-hydroxy-2-oxo-2,7-di-
hydro-1H-azepine-4,5-dicarboxylate (3ea)
Following the general procedure using 1e (100 mg, 0.31 mmol), 2a
(46 μL, 0.37 mmol), and Et3N (85 μL, 0.62 mmol) gave 3ea as col-
orless crystals; yield: 66 mg (40%); mp 142–144 °C; Rf = 0.85 (PE–
EtOAc, 2:1).
FT-IR (neat): 3321, 1705, 1678, 1589, 1469, 1438, 1361, 1304,
1232, 1155, 1065 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.17 (s, 1 H), 9.90 (s, 1 H), 5.20
(d, J = 15.0 Hz, 1 H), 3.90 (d, J = 15.0 Hz, 1 H), 3.76 (s, 6 H), 2.54
(s, 3 H), 2.17 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 172.3, 171.6, 170.7, 168.7, 167.6,
163.7, 137.8, 111.9, 99.3, 52.7, 52.4, 43.2, 26.0, 23.2.
FT-IR (neat): 3298, 1709, 1678, 1655, 1593, 1508, 1470, 1439,
1312, 1261, 1220, 1176. 1138, 1061 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.39 (s, 1 H), 10.89 (s, 1 H), 7.97
(t, J = 10.0 Hz, 4 H), 7.61 (t, J = 10.0 Hz, 1 H), 7.53–7.48 (m, 3 H),
7.41 (t, J = 10.0 Hz, 2 H), 4.90 (d, J = 15.0 Hz, 1 H), 4.41 (d, J =
15.0 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O8: 341.0979; found:
341.0979.
13C NMR (125 MHz, CDCl3): δ = 172.5, 172.0, 170.8, 168.1, 165.3,
162.9, 138.2, 134.5, 133.0, 132.4, 131.9, 129.1, 128.9, 128.0, 127.8,
112.5, 99.1, 52.7, 52.4, 46.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H21N2O8: 465.1292; found:
465.1301.
Dimethyl 6-Hydroxy-2-oxo-1-propanoyl-3-(propanoylamino)-
2,7-dihydro-1H-azepine-4,5-dicarboxylate (3ba)
Following the general procedure using 1b (100 mg, 0.44 mmol), 2a
(65 μL, 0.53 mmol), and Cs2CO3 (72 mg, 0.22 mmol) gave 3ba as
a white solid; yield: 75 mg (46%); mp 128–130 °C; Rf = 0.45 (PE–
EtOAc, 2:1).
Diethyl 3-Acetamido-1-acetyl-6-hydroxy-2-oxo-2,7-dihydro-
1H-azepine-4,5-dicarboxylate (3ab)
Following the general procedure using 1a (100 mg, 0.51 mmol), 2b
(98 μL, 0.61 mmol), and Cs2CO3 (83 mg, 0.26 mmol) gave 3ab as
a white solid; yield: 113 mg (61%); mp 127–129 °C; Rf = 0.35 (PE–
EtOAc, 2:1).
FT-IR (neat): 3356, 1701, 1678, 1605, 1474, 1439, 1362, 1296,
1200, 1150, 1060 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.15 (s, 1 H), 9.95 (s, 1 H), 5.21
(d, J = 15.0 Hz, 1 H), 3.91 (d, J = 15.0 Hz, 1 H), 3.76 (s, 3 H), 3.75
(s, 3 H), 3.03–2.87 (m, 2 H), 2.51–2.35 (m, 2 H), 1.24–1.15 (m, 6
H).
13C NMR (125 MHz, CDCl3): δ = 175.5, 172.4, 172.36, 170.7,
167.7, 163.6, 138.1, 111.5, 99.2, 52.6, 52.3, 43.3, 31.8, 29.4, 8.9,
8.7.
FT-IR (neat): 3337, 1705, 1686, 1655, 1612, 1466, 1447, 1369,
1311, 1208, 1170, 1064 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.25 (s, 1 H), 9.90 (s, 1 H), 5.18
(d, J = 15.0 Hz, 1 H), 4.18 (t, J = 10.0 Hz, 4 H), 3.90 (d, J = 15.0
Hz, 1 H), 2.53 (s, 3 H), 2.15 (s, 3 H), 1.29–1.22 (m, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H21N2O8: 369.1292; found:
369.1293.
13C NMR (125 MHz, CDCl3): δ = 172.1, 171.5, 170.3, 168.6, 161.1,
163.8, 137.4, 112.5, 99.5, 61.9, 61.5, 43.2, 26.0, 23.1, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C16H21N2O8: 369.1292; found:
Dimethyl 3-(Butanoylamino)-1-butanoyl-6-hydroxy-2-oxo-2,7-
dihydro-1H-azepine-4,5-dicarboxylate (3ca)
Following the general procedure using 1c (100 mg, 0.39 mmol), 2a
(58 μL, 0.47 mmol), and Cs2CO3 (64 mg, 0.20 mmol) gave 3ca as a
white solid; yield: 65 mg (42%); mp 97–100 °C; Rf = 0.75 (PE–
EtOAc, 2:1).
369.1300.
Diethyl 6-Hydroxy-2-oxo-1-propanoyl-3-(propanoylamino)-
2,7-dihydro-1H-azepine-4,5-dicarboxylate (3bb)
Following the general procedure using 1b (100 mg, 0.44 mmol), 2b
(85 μL, 0.53 mmol), and Cs2CO3 (72 mg, 0.22 mmol) gave 3bb as
a white solid; yield: 103 mg (59%); mp 100–102 °C; Rf = 0.72 (PE–
EtOAc, 2:1).
FT-IR (neat): 3329, 1705, 1693, 1605, 1457, 1443, 1366, 1312,
1205, 1160, 1064 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.12 (s, 1 H), 9.88 (s, 1 H), 5.16
(d, J = 10.0 Hz, 1 H), 3.88 (d, J = 10.0 Hz, 1 H), 3.73 (s, 3 H), 3.71
(s, 3 H), 2.93–2.79 (m, 2 H), 2.40–2.47 (m, 2 H), 1.69–1.60 (m, 4
H), 0.97–0.90 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 174.5, 172.4, 171.6, 170.6, 167.5,
163.4, 138.0, 111.6, 99.1, 52.5, 52.2, 43.1, 40.0, 38.0, 18.4, 17.7,
14.49, 14.46.
FT-IR (neat): 3337, 1705, 1693, 1601, 1466, 1369, 1315, 1205,
1160, 1060 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.19 (s, 1 H), 9.92 (s, 1 H), 5.15
(d, J = 15.0 Hz, 1 H), 4.18–4.12 (m, 4 H), 3.88 (d, J = 15.0 Hz, 1 H),
2.96–2.83 (m, 2 H), 2.44–2.32 (m, 2 H), 1.23–1.18 (m, 6 H), 1.14 (t,
J = 10.0 Hz, 3 H), 1.10 (t, J = 10.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O8: 397.1605; found:
397.1608.
13C NMR (125 MHz, CDCl3): δ = 175.3, 172.2, 172.1, 170.2, 167.1,
163.6, 137.5, 112.0, 99.3, 61.7, 61.3, 43.2, 31.7, 29.2, 13.8, 8.8, 8.5.
Dimethyl 6-Hydroxy-1-isobutanoyl-3-(isobutanoylamido)-2-
oxo-2,7-dihydro-1H-azepine-4,5-dicarboxylate (3da)
Following the general procedure using 1d (100 mg, 0.39 mmol), 2a
(58 μL, 0.47 mmol), and Cs2CO3 (64 mg, 0.20 mmol) gave 3da as
a colorless oil; yield: 78 mg (50%); Rf = 0.80 (PE–EtOAc, 2:1).
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O8: 397.1605; found:
397.1601.
Diethyl 1-Butanoyl-3-(butanoylamino)-6-hydroxy-2-oxo-2,7-di-
hydro-1H-azepine-4,5-dicarboxylate (3cb)
Following the general procedure using 1c (100 mg, 0.39 mmol), 2b
(75 μL, 0.47 mmol), and Cs2CO3 (64 mg, 0.20 mmol) gave 3cb as a
white solid; yield: 80 mg (48%); mp 135–137 °C; Rf = 0.85 (PE–
EtOAc, 2:1).
FT-IR (neat): 3340, 1690, 1666, 1601, 1470, 1443, 1367, 1327,
1205, 1145, 1061 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.12 (s, 1 H), 9.96 (s, 1 H), 5.09
(d, J = 10.0 Hz, 1 H), 3.92 (d, J = 15.0 Hz, 1 H), 3.73 (s, 3 H), 3.72
(s, 3 H), 3.63–3.58 (m, 1 H), 2.58–2.53 (m, 1 H), 1.22–1.13 (m, 12
H).
13C NMR (125 MHz, CDCl3): δ = 179.3, 175.5, 172.5, 170.6, 167.7,
163.0, 138.3, 111.8, 99.1, 52.5, 52.2, 43.8, 35.5, 35.2, 19.2, 19.0,
18.84, 18.82.
FT-IR (neat): 3337, 1693, 1666, 1601, 1462, 1369, 1311, 1205,
1150, 1061 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.21 (s, 1 H), 9.88 (s, 1 H), 5.15
(d, J = 15.0 Hz, 1 H), 4.18–4.13 (m, 4 H), 3.88 (d, J = 15.0 Hz, 1 H),
2.93–2.79 (m, 2 H), 2.39–2.25 (m, 2 H), 1.68–1.59 (m, 4 H), 1.25–
1.17 (m, 6 H), 0.95–0.89 (m, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O8: 397.1605; found:
397.1610.
Synthesis 2014, 46, 621–628
© Georg Thieme Verlag Stuttgart · New York

PAPER
Polysubstituted 3-Amino-2-oxo-2,7-dihydro-1H-azepines
627
13C NMR (125 MHz, CDCl3): δ = 174.4, 172.2, 171.5, 170.2, 167.1,
163.5, 137.5, 112.2, 99.3, 61.7, 61.3, 43.2, 40.0, 37.9, 18.4, 17.7,
13.8, 13.5, 13.4.
squares on F2. CCDC-959105 of compound 3aa contains the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O8: 425.1918; found:
425.1920.
Acknowledgment
Diethyl 6-Hydroxy-1-isobutanoyl-3-(isobutanoylamino)-2-oxo-
2,7-dihydro-1H-azepine-4,5-dicarboxylate (3db)
This study was supported by grants from the National Key Basic
Research Program of China (973)’s Project (2010CB833800,
2011CB915503), the National High Technology Research and De-
velopment Program (863 Program, 2012AA092104), National Na-
tural Science Foundation of China (31270402, 21172230,
30973679, 41176148, 21002110), Guangdong Province-CAS Joint
Research Program (2011B090300023 and 2012B091100264), and
Guangdong Marine Economic Development and Innovation of Re-
gional Demonstration Project (GD2012-D01-001 and GD2012-
D01-002).
Following the general procedure using 1d (100 mg, 0.39 mmol), 2b
(75 μL, 0.47 mmol), and Cs2CO3 (64 mg, 0.20 mmol) gave 3db as
a colorless oil; yield: 93 mg (56%); Rf = 0.80 (PE–EtOAc, 2:1).
FT-IR (neat): 3279, 1716, 1686, 1609, 1474, 1447, 1366, 1311,
1208, 1149, 1060 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.20 (s, 1 H), 9.93 (s, 1 H), 5.05
(d, J = 15.0 Hz, 1 H), 4.15–4.12 (m, 4 H), 3.91 (d, J = 15.0 Hz, 1 H),
3.62–3.56 (m, 1 H), 2.55–2.50 (m, 1 H), 1.27–1.07 (m, 18 H).
13C NMR (125 MHz, CDCl3): δ = 179.3, 175.3, 172.3, 170.2, 167.1,
163.1, 137.7, 112.4, 99.2, 61.7, 61.3, 43.7, 35.4, 35.1, 19.2, 18.9,
18.8, 18.7, 13.8.
Supporting Information for this article is available online at
HRMS (ESI): m/z [M + H]+ calcd for C20H29N2O8: 425.1918; found:
425.1912.
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Diethyl 3-Benzamido-1-benzoyl-6-hydroxy-2-oxo-2,7-dihydro-
1H-azepine-4,5-dicarboxylate (3eb)
Following the general procedure using 1e (100 mg, 0.31 mmol), 2b
(59 μL, 0.37 mmol), and Et3N (85 μL, 0.62 mmol) gave 3eb as a
white solid; yield: 64 mg (42%); mp 101–104 °C; Rf = 0.74 (PE–
EtOAc, 2:1).
References
(1) Angelucci, L.; Calvisi, P.; Catini, R.; Cosentino, U.;
Cozzolino, R.; Dewitt, P.; Ghirardi, O.; Giannessi, F.;
Giuliani, A.; Guaraldi, D.; Misiti, D.; Ramacci, M. T.;
Scolastico, C.; Tinti, M. O. J. Med. Chem. 1993, 36, 1511.
(2) (a) Reddy, P. V.; Puri, R. V.; Chauhan, P.; Kar, R.; Rohilla,
A.; Khera, A.; Tyagi, A. K. J. Infect. Dis. 2013, 208, 1255.
(b) Francis, J.; Macturk, H. M.; Madinaveitia, J.; Snow, G.
A. Biochem. J. 1953, 55, 596. (c) Madigan, C. A.; Cheng, T.
Y.; Layre, E.; Young, D. C.; McConnell, M. J.; Debono, C.
A.; Murry, J. P.; Wei, J. R.; Barry, C. E.; Rodriguez, G. M.;
Matsunaga, I.; Rubin, E. J.; Moody, D. B. Proc. Natl. Acad.
Sci. U.S.A. 2012, 109, 1257.
(3) (a) Wu, C. R.; Miller, P. A.; Miller, M. J. Bioorg. Med.
Chem. Lett. 2011, 21, 2611. (b) Yokokawa, F.; Izumi, K.;
Omata, J.; Shioiri, T. Tetrahedron 2000, 56, 3027.
(c) Kokubo, S.; Suenaga, K.; Shinohara, C.; Tsuj, T.;
Uemura, D. Tetrahedron 2000, 56, 6435. (d) Thale, Z.;
Kinder, F. R.; Bair, K. W.; Bontempo, J.; Czuchta, A. M.;
Versace, R. W.; Phillips, P. E.; Sanders, M. L.; Wattanasin,
S.; Crews, P. J. Org. Chem. 2001, 66, 1733.
(4) Johnson, T. A.; Sohn, J.; Vaske, Y. M.; White, K. N.; Cohen,
T. L.; Vervoort, H. C.; Tenney, K.; Valeriote, F. A.;
Bjeldanes, L. F.; Crews, P. Bioorg. Med. Chem. 2012, 20,
4348.
(5) Tai, W. Y.; Zhang, R. T.; Ma, Y. M.; Gu, M.; Liu, G.; Li, J.;
Nan, F. J. ChemMedChem 2011, 6, 1555.
(6) (a) Juarez-Hernandez, R. E.; Franzblau, S. G.; Miller, M. J.
Org. Biomol. Chem. 2012, 10, 7584. (b) Miller, M. J.; Walz,
A. J.; Zhu, H.; Wu, C. R.; Moraski, G.; Mollmann, U.;
Tristani, E. M.; Crumbliss, A. L.; Ferdig, M. T.; Checkley,
L.; Edwards, R. L.; Boshoff, H. I. J. Am. Chem. Soc. 2011,
133, 2076.
FT-IR (neat): 3325, 1702, 1678, 1600, 1462, 1447, 1369, 1311,
1257, 1210, 1142, 1068 cm–1.
1H NMR (500 MHz, CDCl3): δ = 12.48 (s, 1 H), 10.89 (s, 1 H), 7.97
(t, J = 10.0 Hz, 4 H), 7.60 (t, J = 5.0 Hz, 1 H), 7.53–7.48 (m, 3 H),
7.41 (t, J = 10.0 Hz, 2 H), 4.89 (d, J = 15.0 Hz, 1 H), 4.43 (d, J =
15.0 Hz, 1 H), 4.26–4.22 (m, 4 H), 1.31–1.26 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 172.4, 172.1, 170.5, 167.7, 165.3,
163.0, 137.8, 134.5, 132.9, 132.4, 132.0, 129.1, 128.9, 128.0, 127.8,
113.2, 99.4, 62.0, 61.6, 46.2, 14.00, 13.96.
HRMS (ESI): m/z [M + H]+ calcd for C26H25N2O8: 493.1605; found:
493.1610.
5-Hydroxy-2-oxo-2,3-dihydropyrazine-1,4-diylbis(phenylmeth-
anone) (4)
This compound was separated from the reaction of 1e (100 mg, 0.31
mmol) with 2a (46 μL, 0.37 mmol) in the presence of Cs2CO3 (51
mg, 0.16 mmol), together with 3ea, as a slightly yellow solid; yield:
67 mg (67%); mp 68–70 °C.
1H NMR (500 MHz, CDCl3): δ = 12.59 (s, 1 H), 7.99 (s, 1 H), 7.82
(d, J = 10.0 Hz, 2 H), 7.64 (d, J = 5.0 Hz, 2 H), 7.59 (t, J = 10.0 Hz,
1 H), 7.54 (t, J = 10.0 Hz, 1 H), 7.47 (t, J = 10.0 Hz, 2 H), 7.43 (t,
J = 10.0 Hz, 2 H), 4.52 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 168.2, 167.2, 165.2, 156.4, 134.3,
133.2, 131.9, 130.9, 129.0, 128.7, 127.7, 127.3, 104.1, 46.8.
MS (ESI): m/z (%) = 345.2 (45) [M + Na]+, 667.2 (40) [2 M + Na]+,
321.2 (100) [M – H]–.
(7) Wilson, L. J.; Wang, B. B.; Yang, S. M.; Scannevin, R. H.;
Burke, S. L.; Karnachi, P.; Rhodes, K. J.; Murray, W. V.
Bioorg. Med. Chem. Lett. 2011, 21, 6485.
X-ray Crystallographic Analysis of Compound 3aa
Colorless crystal of C14H16N2O8 with M = 340.29, triclinic, space
group P-1, a = 8.3465(3) Å, b = 10.0290(5) Å, c = 18.6781(8) Å,
V = 1502.80(11) Å3, Z = 4, crystal size 0.40 × 0.37 × 0.34 mm3. A
total of 15137 reflections (θ = 4.59–66.95°) were collected, 5300 re-
flections independent (Rint = 0.0237), R1 = 0.0353, wR2 = 0.0885. X-
Ray diffraction experiments were carried out on a Bruker Smart
1000 CCD diffractometer at 150 K using graphite monochromated
MoKα radiation (λ = 1.54184 Å). Absorption corrections were done
by semiempirical from equivalents. The structure was solved using
direct methods (SHELXL-97) and refined with full-matrix least-
(8) Shi, Y.; Zhang, J.; Shi, M. X.; O’Connor, S. P.; Bisaha, S.
N.; Li, C.; Sitkoff, D.; Pudzianowski, A. T.; Chong, S.; Klei,
H. E.; Kish, K.; Yanchunas, J.; Liu, E. C. K.; Hartl, K. S.;
Seiler, S. M.; Steinbacher, T. E.; Schumacher, W. A.; Atwal,
K. S.; Stein, P. D. Bioorg. Med. Chem. Lett. 2009, 19, 4034.
(9) (a) Henley, D. B.; May, P. C.; Dean, R. A.; Siemers, E. R.
Expert Opin. Pharmacother. 2009, 10, 1657. (b) Kitas, E.
A.; Galley, G.; Jakob-Roetne, R.; Flohr, A.; Wostl, W.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 621–628

628
S. Liao et al.
PAPER
(14) Yoshimura, T.; Takuwa, M.; Tomohara, K.; Uyama, M.;
Hayashi, K.; Yang, P.; Hyakutake, R.; Sasamori, T.;
Tokitoh, N.; Kawabata, T. Chem. Eur. J. 2012, 18, 15330.
(15) Borthwick, A. D. Chem. Rev. 2012, 112, 3641.
(16) (a) Swiderek, K.; Pabis, A.; Moliner, V. Org. Biomol. Chem.
2012, 10, 5598. (b) Karppanen, E. J.; Koskinen, A. M. P.
Molecules 2010, 15, 6512.
Mauser, H.; Alker, A. M.; Czech, C.; Ozmen, L.; David-
Pierson, P.; Reinhardt, D.; Jacobsen, H. Bioorg. Med. Chem.
Lett. 2008, 18, 304.
(10) Zaman, S.; Campaner, P.; Abell, A. D. Bioorg. Med. Chem.
2006, 14, 8323.
(11) (a) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y.
J. Org. Chem. 2008, 73, 2894. (b) Boero, M.; Ikeshoji, T.;
Liew, C. C.; Terakura, K.; Parrinello, M. J. Am. Chem. Soc.
2004, 126, 6280.
(17) De Silva, H. I.; Henry, W. P.; Pittman, C. U. Synthesis 2012,
44, 3337.
(12) Rico, I.; Halvorsen, K.; Dubrule, C.; Lattes, A. J. Org.
Chem. 1994, 59, 415.
(13) (a) Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D. J.
J. Am. Chem. Soc. 2012, 134, 17482. (b) Nguyen, T. V.;
Hartmann, J. M.; Enders, D. Synthesis 2013, 45, 845.
(18) The results of the spectroscopic data were similar to:
Marcuccio, S. M.; Elix, J. A. Aust. J. Chem. 1984, 37, 1791.
(19) The results of the spectroscopic data were similar to:
Enholm, J. E.; Low, T.; Cooper, D.; Ghivirija, I.
Tetrahedron 2012, 68, 6920.
Synthesis 2014, 46, 621–628
© Georg Thieme Verlag Stuttgart · New York