Facile Synthesis of 3-Arylidene-3H-1,4-benzodiazepines by a Sequential Ugi/Staudinger/Aza-Wittig Reaction

Article abstract of DOI:10.1055/s-0036-1588308

N-[2-(Alkylamino)-1-(2-azidophenyl)-2-oxoethyl]-N-(3-oxoprop-1-en-2-yl)amides, obtained from the Ugi reaction of a vinyliminophosphorane, 2-azidobenzaldehyde, a carboxylic acid, and an alkyl isocyanide, reacted with triphenylphosphine to give various 3-ar

Full text of DOI:10.1055/s-0036-1588308

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
H. Xie et al.
Paper
Synthesis
Facile Synthesis of 3-Arylidene-3H-1,4-benzodiazepines by a
Sequential Ugi/Staudinger/Aza-Wittig Reaction
Hai Xiea,b
Jian-Chao Liua
Ming-Wu Ding*a
O
R1
O
R4HN
O
R3
R2
R2
N=PPh2Me
CHO
N
Ph3P
a Key Laboratory of Pesticide & Chemical Biology of Ministry of
Education, Central China Normal University, Wuhan 430079,
P. R. of China
MeOH
toluene
r.t., 2 h, then
reflux, 2–6 h
77–91%
50 °C, 4–6 h
then r.t., 48 h
43–71%
N
R1
R1, R3 = aryl, alkyl;
2 = aryl; R4 = alkyl
12 examples
N3
mwding@mail.ccnu.edu.cn
b College of Chemistry & Chemical Engineering, Shanxi Datong
University, Shanxi 037009, P. R. of China
R3COOH
R4NC
R
Received: 10.08.2016
Accepted after revision: 12.08.2016
Published online: 14.09.2016
benzodiazepines, 3-arylidene-substituted 3H-1,4-benzodi-
azepines were not easily accessible by currently existing
synthetic methods.
DOI: 10.1055/s-0036-1588308; Art ID: ss-2016-h0042-op
The Ugi reaction is a powerful multicomponent reaction
that has been used widely to prepare α-acylamino amides
starting from an aldehyde, amine, acid, and isocyanide.11
The combination of Ugi reaction with other post-condensa-
tion reactions constitutes an extremely powerful synthetic
method for the preparation of many complex molecules, es-
pecially heterocyclic compounds.10b,12 The aza-Wittig reac-
tions of iminophosphoranes have received considerable at-
tention due to their efficient application in heterocyclic
synthesis.13 Owing to its good stability, vinyliminophos-
phorane may be regarded as an equivalent of the unstable
enamine and it has been used in the synthesis of various
heterocycles, such as isoquinolines, dihydropyrimidines,
and oxazoles.14 Continuing our interests in multicompo-
nent reactions15 and aza-Wittig reactions of vinylimino-
phosphoranes,14c–f we wish to report herein a new facile
synthesis of 3-arylidene-substituted 3H-1,4-benzodiaze-
pines via an Ugi/Staudinger/aza-Wittig sequence by using
vinyliminophosphoranes as an Ugi starting material.
Although many primary amines have been used in the
Ugi reaction, vinylamines have not been utilized for the re-
action due to their instability. We have reported that the
aza-Wittig reactions of some stable diphenyl(methyl)imi-
nophosphoranes 1 with 2-azidobenzaldehyde produced N-
vinylimines 2 at 50 °C in good yields,14f which may be used
in further Ugi reactions. The one-pot reaction of diphen-
yl(methyl)iminophosphorane 1, 2-azidobenzaldehyde, car-
boxylic acid, and isocyanide were then investigated
(Scheme 1): after the aza-Wittig reaction of diphen-
yl(methyl)iminophosphorane 1 with 2-azidobenzaldehyde
was complete at 50 °C, the carboxylic acid and isocyanide
were added to the reaction mixture at room temperature.
Abstract N-[2-(Alkylamino)-1-(2-azidophenyl)-2-oxoethyl]-N-(3-oxo-
prop-1-en-2-yl)amides, obtained from the Ugi reaction of a vinylimino-
phosphorane, 2-azidobenzaldehyde, a carboxylic acid, and an alkyl iso-
cyanide, reacted with triphenylphosphine to give various 3-arylidene-
3H-1,4-benzodiazepine in good yields via sequential Staudinger and in-
tramolecular aza-Wittig reaction.
Key words 3H-1,4-benzodiazepine, Ugi reaction, Staudinger reaction,
aza-Wittig reaction, vinyliminophosphorane, azides
Benzodiazepines have attracted great attention in me-
dicinal chemistry because of their broad spectrum of bio-
logical activities. Some 1,4-benzodiazepine derivatives
have been found recently to exhibit good antiseizure,1 anti-
anxiety,2 antileishmanial,3 antitubulin,4 and antitumor ac-
tivities.5 Much effort has been invested in the synthesis of
benzodiazepine derivatives to deduce structure–activity re-
lationships and discover new analogues with improved
properties. The most frequently employed synthetic ap-
proaches to 1,4-benzodiazepine skeletons include the reac-
tion of 2-aminobenzophenones with α-amino acids,6 cyclo-
condensation of 2-halobenzoic acids or 2-halobenzophe-
nones with some diamines,7 and Pictet–Spengler reaction
of N,N′-dimethyl-N-phenyl-1,2-ethanediamine with alde-
hydes.8 In addition, the preparation of these compounds
can be carried out via an indium-catalyzed multicompo-
nent reaction.9 The sequential Ugi and aza-Wittig reactions
were also used successfully to prepare some 1,4-benzodiaz-
epines by using arylglyoxals, α-amino ketones, or 2-amino-
benzophenones as Ugi starting materials.10 Although much
effort has been directed toward the construction of 1,4-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
H. Xie et al.
Paper
Synthesis
The Ugi reaction took place to give azides 3 in only moder-
ate yields (43–71%, Table 1) probably due to some side reac-
tions.
O
O
N
O
R4HN
R3
R2
O
N
R4HN
R3
R2
Ph3P
toluene
r.t.
N
CHO
O
PPh3
R1
N3
O
R1
O
R2
R1
N3
R1
4
3
N
R2
N=PPh2Me
O
O
MeOH, 50 °C
R4HN
O
R3
R2
N3
1
2
N
toluene
O
O
R4HN
N
R3
R3COOH
R4NC
R1
R2
5
N
MeOH, r.t.
Scheme 2 Preparation of compounds 5 via Staudinger/aza-Wittig re-
action
N3
O
R1
3
Scheme 1 Preparation of azides 3 via Ugi reaction
5.83 as two singlets (2:1). The signals of NH appear at δ =
5.40 and 4.97 as two singlets (2:1). The tert-butyl protons
absorb at δ = 1.20 and 0.92 as two singlets (8:1). Such two
singlets might be due to the different conformation and E/Z
configuration of the 3H-1,4-benzodiazepines 5a. However,
The Staudinger reactions of azides 3 with triphenyl-
phosphine occurred smoothly at room temperature to gen-
erate iminophosphoranes 4 with nitrogen evolution. Intra-
molecular aza-Wittig reactions of 4 took place partially at
room temperature, but completely at refluxing tempera-
ture, to produce 3-arylidene-substituted 3H-1,4-benzodi-
azepines 5 in 77–91% yields (Scheme 2,Table 1). The yields
of the products were always good regardless of the R1, R2,
R3, and R4 substituents.
1
the H NMR spectrum of 5a at higher temperature (50 °C)
shows only one singlet at δ = 1.19 for tert-butyl protons, in-
dicating the former two singlets (8:1) may be resulted from
the different conformation. The two singlets (2:1) of CH and
NH did not change, implying that it may be due to the dif-
ferent E/Z configuration. The 13C NMR spectrum data of 5a
show the signals of two CON and C-2 of the benzodiazepine
at δ =171.0, 166.8, and 166.0. These results indicated that
the products 5 obtained were a mixture of isomers and the
data reported are for major isomer in the mixture of two.
The MS spectrum of 5a shows molecular ion peak at m/z
513 with 5% abundance. Furthermore a single crystal of
The structure of 3-arylidene-substituted 3H-1,4-benzo-
diazepines 5 was confirmed by their spectral data. For ex-
1
ample, the H NMR spectrum of 5a at room temperature
shows multiplets at δ = 8.44–6.43 due to the aromatic and
alkenyl hydrogen. The signal of CH is found at δ = 6.19 and
Table 1 Preparation of Azides 3 and 3-Arylidene-3H-1,4-benzodiazepines 5
Entry
R1
Ph
R2
Ph
R3
Ph
R4
t-Bu
Compd
Yielda (%)
Ratiob Z/E
Compd
Yieldc (%)
Ratiob Z/E
1
2
3a
3b
3c
3d
3e
3f
69
43
58
57
65
51
71
69
64
65
46
52
4.1
3.8
3.8
4.2
4.0
3.3
2.9
3.5
2.8
4.4
2.5
3.6
5a
5b
5c
5d
5e
5f
88
80
77
91
78
84
86
83
81
87
85
82
1.9
1.4
3.3
1.7
2.4
2.3
7.1
1.5
4.3
–
4-ClC6H4
Ph
Ph
Ph
t-Bu
t-Bu
Cy
3
Ph
4-NO2C6H4
Ph
4
Ph
Ph
5
Ph
Ph
4-ClC6H4
Ph
Cy
6
Ph
Ph
n-Bu
Cy
7
Ph
Ph
Me
3g
3h
3i
5g
5h
5i
8
Ph
Ph
4-MeC6H4
Et
Cy
9
Ph
Ph
Cy
10
11
12
Ph
Ph
2-ClC6H4
Me
Cy
3j
5j
Ph
4-FC6H4
Ph
t-Bu
t-Bu
3k
3l
5k
5l
5.5
2.1
Me
Ph
a Isolated yields based on iminophosphoranes 1.
b Determined by 1H NMR but the major isomer of the products not being determined.
c Isolated yields based on azides 3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
H. Xie et al.
Paper
Synthesis
compound 5a was obtained from the CH2Cl2 solution, and
X-ray crystal structure analysis verified the proposed struc-
ture (Figure 1). The carbon–carbon double bond of the vinyl
group was observed to be Z-configuration, showing one of
the E/Z isomers was obtained occasionally after recrystalli-
zation.
N-[1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl]-N-(3-oxo-
1,3-diphenylprop-1-en-2-yl)benzamide (3a)
White crystals; yield: 0.77 g (69%).
IR (KBr): 3441, 2133, 1685, 1658, 1638, 1448, 1290, 1122, 1069 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.80 (s, 0.8 H, 0.8 NH), 8.59 (s, 0.2 H,
0.2 NH), 8.57–6.77 (m, 19 H, Ar-H), 6.57 (s, 1 H, =CH), 6.25 (s, 0.8 H,
0.8 CH), 5.38 (s, 0.2 H, 0.2 CH), 1.52 (s, 7 H, 7/9 × 3 CH3), 1.43 (s, 2 H,
2/9 × 3 CH3).
.
13C NMR (150 MHz, CDCl3): δ = 197.5, 171.5, 168.2, 144.1, 140.8,
136.4, 135.6, 132.7, 132.2, 131.6, 130.9, 130.5, 130.2, 130.0, 129.1,
128.9, 128.7, 128.5, 128.4, 128.0, 127.4, 126.2, 125.0, 124.6, 118.1,
62.0, 51.2, 28.6.
Anal. Calcd for C34H31N5O3: C, 73.23; H, 5.60; N, 12.56. Found: C,
73.38; H, 5.79; N, 12.66.
N-[1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl]-N-[3-(4-
chlorophenyl)-3-oxo-1-phenylprop-1-en-2-yl]benzamide (3b)
White crystals; yield: 0.51 g (43%).
IR (KBr): 3442, 2132, 1685, 1648, 1602, 1490, 1292, 1125, 1069 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.67 (s, 0.8 H, 0.8 NH), 8.54 (s, 0.2 H,
0.2 NH), 8.53–6.77 (m, 18 H, Ar-H), 6.61 (s, 0.2 H, 0.2 =CH), 6.50 (s, 0.8
H, 0.8 =CH), 6.24 (s, 0.8 H, 0.8 CH), 5.38 (s, 0.2 H, 0.2 CH), 1.51 (s, 7 H,
7/9 × 3 CH3), 1.42 (s, 2 H, 2/9 × 3 CH3).
13C NMR (150 MHz, CDCl3): δ = 195.7, 169.3, 167.5, 148.3, 143.4,
141.3, 141.1, 139.8, 135.8, 133.9, 132.4, 131.5, 131.1, 130.6, 130.4,
129.1, 129.0, 128.9, 128.5, 127.3, 125.2, 123.9, 122.6, 122.5, 118.3,
62.3, 51.4, 28.5.
Figure 1 ORTEP diagram of the crystal structure of 5a (30% thermal
ellipsoids)
In conclusion, we report herein a facile synthesis of 3-
arylidene-substituted 3H-1,4-benzodiazepines using the
Ugi reaction followed by Staudinger/aza-Wittig reactions.
The Ugi reaction involving the N-vinylimine was also inves-
tigated first. Due to the easy availability of the synthetic ap-
proach and the neutral ring-closure condition, this new
synthetic approach discussed here has potential for the
synthesis of various benzodiazepines, which are of consid-
erable interest in chemical biology study and drug discov-
ery.
Anal. Calcd for C34H30ClN5O3: C, 68.97; H, 5.11; N, 11.83. Found: C,
69.21; H, 5.24; N, 12.00.
N-[1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl]-4-nitro-N-
(3-oxo-1,3-diphenylprop-1-en-2-yl)benzamide (3c)
White crystals; yield: 0.70 g (58%).
IR (KBr): 3442, 2128, 1687, 1664, 1645, 1490, 1292, 1137, 1070 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.63 (s, 0.8 H, 0.8 NH), 8.48 (s, 0.2 H,
0.2 NH), 7.87–6.66 (m, 18 H, Ar-H), 6.57 (s, 1 H, =CH), 6.25 (s, 0.8 H,
0.8 CH), 5.46 (s, 0.2 H, 0.2 CH), 1.52 (s, 7 H, 7/9 × 3 CH3), 1.42 (s, 2 H,
2/9 × 3 CH3).
13C NMR (150 MHz, CDCl3): δ = 197.0, 169.3, 167.6, 165.7 (minor),
148.3, 143.8, 142.5 (minor), 141.4, 140.9, 138.8 (minor), 137.3 (mi-
nor), 135.9, 135.6, 133.2, 132.3, 131.3, 131.2, 130.6, 130.4, 129.2,
129.1, 128.9, 128.6, 128.1, 127.3, 125.2, 123.9, 122.6, 122.5, 118.3,
62.3, 59.6 (minor), 51.3, 28.5.
Melting points were determined using a X-4 model apparatus and are
uncorrected. MS were measured on a Finnigan Trace MS spectrome-
ter. IR spectra were recorded on a PE-983 infrared spectrophotometer
as KBr pellets. NMR were recorded in CDCl3 or DMSO-d6 on a Varian
Mercury 600 or 400 spectrometer and resonances relative to TMS. El-
emental analyses were taken on a Vario EL III elementary analysis in-
strument. The X-ray diffraction data were collected on a Bruker
SMART AXS CCD diffractometer, MoKα, 2θ = 1.86–27.50°.
Anal. Calcd for C34H30N6O5: C, 67.76; H, 5.02; N, 13.95. Found: C,
67.93; H, 5.27; N, 13.89.
Azides 3a–l via Ugi Reaction; General Procedure
N-[1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl]-N-(3-oxo-
A mixture of diphenyl(methyl)iminophosphoranes 114f (2 mmol) and
2-azidobenzaldehyde (0.29 g, 2 mmol) in MeOH (10 mL) was stirred
at 50 °C for 4–6 h. Then the carboxylic acid (2 mmol) and isocyanide
(2 mmol) were added sequentially to the mixture at r.t. The mixture
was stirred at r.t. for 48 h until the solid had precipitated completely.
After the solvent had been evaporated, the crude mixture was puri-
fied by recrystallization (CH2Cl2/petroleum ether) to give azides 3a–l.
1,3-diphenylprop-1-en-2-yl)benzamide (3d)
White crystals; yield: 0.66 g (57%).
IR (KBr): 3443, 2132, 1687, 1650, 1491, 1287, 1133, 1069 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.88 (d, J = 7.8 Hz, 0.8 H, 0.8 NH), 8.51
(d, J = 7.2 Hz, 0.2 H, 0.2 NH), 7.78–6.72 (m, 19 H, Ar-H), 6.57 (s, 1 H,
=CH), 6.35 (s, 0.8 H, 0.8 CH) , 5.51 (s, 0.2 H, 0.2 CH), 3.95–3.82 (m, 1 H,
NCH), 2.14–1.26 (m, 10 H, 5 CH2).
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
H. Xie et al.
Paper
Synthesis
13C NMR (150 MHz, CDCl3): δ = 197.5, 171.4, 168.2, 166.3 (minor),
144.1, 140.7, 136.4, 135.5, 132.6, 132.2, 131.6, 130.9, 130.5, 130.3,
130.0, 129.8, 129.0, 128.7, 128.4, 128.0, 127.3, 126.3, 126.2, 124.9,
124.4, 118.1, 61.5, 59.7 (minor), 48.0, 32.9, 25.6, 24.7, 24.6.
IR (KBr): 3443, 2131, 1683, 1655, 1641, 1450, 1287, 1125, 1070 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.90 (d, J = 7.8 Hz, 0.8 H, 0.8 NH), 8.52
(d, J = 7.8 Hz, 0.2 H, 0.2 NH), 7.80–6.58 (m, 19 H, Ar-H, =CH), 6.35 (s,
0.8 H, 0.8 CH), 5.48 (s, 0.2 H, 0.2 CH), 3.94–3.82 (m, 1 H, NCH), 2.18 (s,
3 H, CH3), 1.95–1.27 (m, 10 H, 5 CH2).
13C NMR (150 MHz, CDCl3): δ = 197.6, 196.0 (minor), 171.5, 170.7 (mi-
nor), 168.2, 166.3 (minor), 144.1, 142.7 (minor), 140.7, 140.1, 136.5,
132.6, 132.5, 132.2, 131.6, 130.8, 130.5, 130.2, 129.1, 129.0, 128.6,
128.3, 127.9, 126.3, 124.9, 124.5, 118.1, 61.5, 59.6 (minor), 47.9, 32.8,
30.8 (minor), 25.5, 24.6, 24.5, 21.2.
Anal. Calcd for C36H33N5O3: C, 74.08; H, 5.70; N, 12.00. Found: C,
74.06; H, 5.62; N, 12.24.
N-[1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl]-4-chloro-
N-(3-oxo-1,3-diphenylprop-1-en-2-yl)benzamide (3e)
White crystals; yield: 0.80 g (65%).
IR (KBr): 3440, 2131, 1682, 1637, 1490, 1295, 1070 cm–1
.
Anal. Calcd for C37H35N5O3: C, 74.35; H, 5.90; N, 11.72. Found: C,
74.55; H, 5.87; N, 11.91.
1H NMR (600 MHz, CDCl3): δ = 8.79 (d, J = 7.8 Hz, 0.8 H, 0.8 NH), 8.47
(d, J = 7.8 Hz, 0.2 H, 0.2 NH), 7.80–6.74 (m, 18 H, Ar-H), 6.58 (s, 1 H,
=CH), 6.34 (s, 0.8 H, 0.8 CH), 5.53 (s, 0.2 H, 0.2 CH), 3.94–3.81 (m, 1 H,
NCH), 2.18–1.27 (m, 10 H, 5 CH2).
N-[1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl]-N-(3-oxo-
1,3-diphenylprop-1-en-2-yl)propionamide (3i)
White crystals; yield: 0.68 g (64%).
IR (KBr): 3441, 2135, 1686, 1657, 1640, 1449, 1291, 1125, 1069 cm–1
1H NMR (600 MHz, CDCl3): δ = 8.54 (d, J = 5.4 Hz, 0.75 H, 0.75 NH),
7.97 (d, J = 7.2 Hz, 0.25 H, 0.25 NH), 7.84–6.77 (m, 15 H, Ar-H), 6.13 (s,
0.75 H, 0.75 CH), 5.48 (s, 0.25 H, 0.25 CH), 3.89–3.80 (m, 1 H, NCH),
2.28–0.98 (m, 15 H, 5 CH2, CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 197.3, 170.4, 167.9, 143.8, 142.6 (mi-
nor), 140.8, 138.6 (minor), 136.3, 136.1, 136.0, 133.8, 132.9, 132.3,
131.4, 131.0, 130.4, 129.1, 128.8, 128.5, 128.0, 127.7, 127.5, 125.0,
124.1, 118.1, 61.6, 48.0, 32.8, 25.5, 24.6, 24.5.
.
Anal. Calcd for C36H32ClN5O3: C, 69.95; H, 5.22; N, 11.33. Found: C,
70.11; H, 5.43; N, 11.41.
13C NMR (150 MHz, CDCl3): δ = 196.8, 175.2 (minor), 174.5, 168.2,
145.3, 142.7 (minor), 140.4, 138.4 (minor), 136.4, 135.0, 132.6, 132.5,
131.7, 131.1, 130.9, 130.0, 129.8, 129.2, 129.1, 128.9, 128.2, 128.0,
126.2 (minor), 125.4, 124.8, 124.7, 118.2, 60.9, 59.4, 48.2 (minor),
47.9, 32.7, 30.8 (minor), 27.0, 26.3 (minor), 25.6, 24.6, 9.3.
N-[1-(2-Azidophenyl)-2-(butylamino)-2-oxoethyl]-N-(3-oxo-1,3-
diphenylprop-1-en-2-yl)benzamide (3f)
White crystals; yield: 0.57 g (51%).
IR (KBr): 3443, 2109, 1679, 1657, 1633, 1488, 1298, 1134, 1069 cm–1
.
Anal. Calcd for C32H33N5O3: C, 71.75; H, 6.21; N, 13.07. Found: C,
72.02; H, 6.29; N, 13.25.
1H NMR (600 MHz, CDCl3): δ = 8.92 (br, 0.75 H, 0.75 NH), 8.50 (br, 0.25
H, 0.25 NH), 7.78–6.75 (m, 19 H, Ar-H), 6.59 (s, 1 H, =CH), 6.40 (s, 0.8
H, 0.8 CH), 5.55 (s, 0.2 H, 0.2 CH), 3.49–3.26 (m, 2 H, NCH2), 1.70–1.35
(m, 4 H, CH2CH2), 0.94–0.87 (m, 3 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 197.6, 171.4, 169.2, 167.3 (minor),
144.2, 142.8 (minor), 140.6, 138.0 (minor), 136.8 (minor), 136.3,
135.3, 132.7, 132.2, 131.5, 130.9, 130.4, 130.3, 130.0, 129.8, 129.2,
129.0, 128.6, 128.4, 128.0, 127.3, 126.3, 124.9, 124.4, 118.1, 61.5, 59.7
(minor), 39.4, 20.1, 13.7.
N-[1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl]-2-chloro-
N-(3-oxo-1,3-diphenylprop-1-en-2-yl)benzamide (3j)
White crystals; yield: 0.80 g (65%).
IR (KBr): 3442, 21313, 1687, 1659, 1647, 1450, 1290, 1130, 1072 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 9.08 (br, 0.8 H, 0.8 NH), 8.36 (d, J = 7.2
Hz, 0.2 H, 0.2 NH), 7.48–6.65 (m, 19 H, Ar-H, =CH), 6.31 (s, 0.8 H, 0.8
CH), 5.63 (s, 0.2 H, 0.2 CH), 4.13–3.87 (m, 1 H, NCH), 2.18–1.25 (m, 10
H, 5 CH2).
Anal. Calcd for C34H31N5O3: C, 73.23; H, 5.60; N, 12.56. Found: C,
73.47; H, 5.75; N, 12.59.
13C NMR (150 MHz, CDCl3): δ = 197.6, 171.0, 168.8, 144.0, 139.5,
136.8, 135.2, 134.9, 132.4, 131.4, 131.2, 131.1, 130.8, 130.5, 129.6,
128.8, 128.7, 128.3, 128.2, 128.0, 125.4, 125.1, 124.6, 123.8, 117.7,
61.1, 53.4, 51.1, 30.8, 28.5, 19.4.
2-(2-Azidophenyl)-N-cyclohexyl-2-[N-(3-oxo-1,3-diphenylprop-1-
en-2-yl)acetamido]acetamide (3g)
White crystals; yield: 0.74 g (71%).
IR (KBr): 3442, 2137, 1677, 1633, 1489, 1310, 1121, 1070 cm–1
.
Anal. Calcd for C36H32ClN5O3: C, 69.95; H, 5.22; N, 11.33. Found: C,
70.07; H, 5.40; N, 11.36.
1H NMR (600 MHz, CDCl3): δ = 8.55 (d, J = 6.6 Hz, 0.8 H, 0.8 NH), 7.96
(d, J = 7.8 Hz, 0.2 H, 0.2 NH), 7.92–6.77 (m, 15 H, Ar-H, =CH), 6.11 (s,
0.8 H, 0.8 CH), 5.49 (s, 0.2 H, 0.2 CH), 3.89–3.79 (m, 1 H, NCH), 2.42–
1.26 (m, 13 H, 5 CH2, CH3).
2-(2-Azidophenyl)-N-tert-butyl-2-{N-[1-(4-fluorophenyl)-3-oxo-
3-phenylprop-1-en-2-yl]acetamido}acetamide (3k)
White crystals; yield: 0.47 g (46%).
IR (KBr): 3445, 2130, 1678, 1641, 1490, 1306, 1122, 1073 cm–1
13C NMR (150 MHz, CDCl3): δ = 196.6, 193.9 (minor), 172.1 (minor),
171.1, 168.0, 145.2, 142.4 (minor), 140.3, 138.4 (minor), 137.0 (mi-
nor), 136.3, 135.3, 132.7, 131.7, 131.1, 130.8, 130.0, 129.2, 129.1,
128.9, 128.2, 125.3, 124.8, 118.2, 60.8, 59.2 (minor), 47.9, 32.7, 32.6,
30.8 (minor), 25.5, 24.6, 21.9.
.
1H NMR (600 MHz, CDCl3): δ = 8.41 (s, 0.7 H, 0.7 NH), 7.96 (br, 0.3 H,
0.3 NH), 7.78–6.57 (m, 14 H, Ar-H, =CH), 6.01 (s, 0.8 H, 0.8 CH), 5.39 (s,
0.2 H, 0.2 CH), 1.99–1.87 (m, 3 H, CH3), 1.48 (s, 7 H, 7/9 × 3 CH3), 1.37
(s, 2 H, 2/9 × 3 CH3).
13C NMR (150 MHz, CDCl3): δ = 196.3, 194.0 (minor), 171.0, 168.0,
167.5 (minor), 165.0, 163.3, 143.6, 140.1, 138.3, 136.3, 136.0, 134.8,
133.1, 132.6, 131.1, 130.0, 129.1, 128.2, 127.3, 126.2, 125.3, 124.9,
124.8, 118.2, 116.2, 61.2, 50.9, 28.8, 28.2, 27.8, 22.0, 21.6 (minor).
Anal. Calcd for C31H31N5O3: C, 71.38; H, 5.99; N, 13.43. Found: C,
71.62; H, 6.14; N, 13.54.
N-[1-(2-Azidophenyl)-2-(cyclohexylamino)-2-oxoethyl]-4-methyl-
N-(3-oxo-1,3-diphenylprop-1-en-2-yl)benzamide (3h)
White crystals; yield: 0.82 g (69%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Anal. Calcd for C29H28FN5O3: C, 67.82; H, 5.50; N, 13.64. Found: C,
67.96; H, 5.72; N, 13.81.
MS: m/z (%) = 547 (2, M+), 446 (10), 105 (100), 77 (18).
Anal. Calcd for C34H30ClN3O2: C, 74.51; H, 5.52; N, 7.67. Found: C,
74.68; H, 5.41; N, 7.85.
N-[1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl]-N-(3-oxo-
1-phenylbut-1-en-2-yl)benzamide (3l)
3-Benzylidene-N-tert-butyl-4-(4-nitrobenzoyl)-2-phenyl-4,5-di-
hydro-3H-1,4-benzodiazepine-5-carboxamide (5c)
White crystals; yield: 0.51 g (52%).
IR (KBr): 3442, 2137, 1677, 1633, 1489, 1310, 1121, 1070 cm–1
.
Yellow crystals; yield: 0.43 g (77%).
1H NMR (600 MHz, CDCl3): δ = 8.63 (s, 0.7 H, 0.7 NH), 8.46 (br, 0.3 H,
0.3 NH), 7.89–6.71 (m, 15 H, Ar-H, =CH), 6.08 (s, 0.8 H, 0.8 CH), 5.26 (s,
0.2 H, 0.2 CH), 2.49–1.92 (m, 3 H, CH3), 1.48 (s, 7 H, 7/9 × 3 CH3), 1.41
(s, 2 H, 2/9 × 3 CH3).
1H NMR (600 MHz, CDCl3): δ = 8.40–6.36 (m, 19 H, Ar-H, =CH), 6.22 (s,
0.2 H, 0.2 CH), 5.89 (s, 0.8 H, 0.8 CH), 5.39 (s, 0.2 H, 0.2 NH), 4.85 (s,
0.8 H, 0.8 NH), 1.23 (s, 8 H, 8/9 × 3 CH3), 0.95–0.86 (m, 1 H, 1/9 × 3
CH3).
13C NMR (150 MHz, CDCl3): δ = 200.3, 171.1, 170.1 (minor), 168.1,
166.0 (minor), 140.8, 140.4, 139.2 (minor), 137.0, 135.5, 131.6, 131.2,
130.7, 130.6, 130.0, 129.9, 129.2 (minor), 128.5, 127.4, 126.1, 124.4,
124.2, 118.0, 117.9, 61.7, 50.9, 29.4 (minor), 28.9, 28.4, 27.9, 25.6,
25.2 (minor).
13C NMR (150 MHz, CDCl3): δ = 168.7, 166.3, 165.7, 149.1, 148.2,
142.3, 134.5, 133.4, 131.8, 130.6, 130.4, 130.0, 128.9, 128.7, 128.6,
128.4, 128.2, 126.7, 126.2, 125.5, 124.7, 122.2, 122.1, 61.1, 51.7, 28.5.
MS: m/z (%) = 558 (5, M+), 308 (20), 215 (18), 165 (41), 149 (100), 103
(26).
Anal. Calcd for C29H29N5O3: C, 70.28; H, 5.90; N, 14.13. Found: C,
70.47; H, 6.03; N, 14.29.
Anal. Calcd for C34H30N4O4: C, 73.10; H, 5.41; N, 10.03. Found: C,
73.37; H, 5.53; N, 10.18.
3-Arylidene-Substituted 4,5-Dihydro-3H-1,4-benzodiazepines 5a–l;
General Procedure
4-Benzoyl-3-benzylidene-N-cyclohexyl-2-phenyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (5d)
Ph3P (0.26 g, 1 mmol) was added to a stirred solution of azide 3 (1
mmol) in dry toluene (10 mL) at r.t. The mixture was stirred for about
2 h; iminophosphorane 4 was formed (TLC monitoring). Then the
solution was heated to reflux for 2–6 h. The solvent was evaporated
under reduced pressure and the residue was purified by column chro-
matography to give 3-arylidene-substituted 4,5-dihydro-3H-1,4-ben-
zodiazepines 5a–l.
White crystals; yield: 0.49 g (91%).
1H NMR (600 MHz, CDCl3): δ = 8.40–6.47 (m, 20 H, Ar-H, =CH), 6.20 (s,
0.4 H, 0.4 =CH), 5.83 (s, 0.6 H, 0.6 =CH), 5.48 (d, J = 5.4 Hz, 0.4 H, 0.4
NH), 4.98 (d, J = 7.2 Hz, 0.6 H, 0.6 NH), 3.79–3.63 (m, 1 H, NCH), 1.85–
0.84 (m, 10 H, 5 CH2).
13C NMR (150 MHz, CDCl3): δ = 171.2, 166.9, 166.1, 149.3, 136.3,
135.3, 134.7, 133.9, 131.6, 130.7, 130.5, 130.2, 129.7, 129.1, 128.9,
128.6, 128.3, 127.7, 127.0, 126.9, 126.5, 126.1, 125.0, 62.3 (minor),
60.9, 48.8, 32.9, 32.4, 25.3, 24.5, 24.4.
4-Benzoyl-3-benzylidene-N-tert-butyl-2-phenyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (5a)
MS: m/z (%) = 539 (4, M+), 412 (28), 308 (7), 165 (12), 105 (100), 77
(18).
White crystals; yield: 0.45 g (88%).
1H NMR (600 MHz, CDCl3, r.t.): δ = 8.44–6.43 (m, 20 H, Ar-H, =CH),
6.19 (s, 0.3 H, 0.3 CH), 5.83 (s, 0.7 H, 0.7 CH), 5.40 (s, 0.3 H, 0.3 NH),
4.97 (s, 0.7 H, 0.7 NH), 1.20 (s, 8 H, 8/9 × 3 CH3), 0.92 (s, 1 H, 1/9 × 3
CH3).
Anal. Calcd for C36H33N3O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 80.22;
H, 6.41; N, 7.98.
3-Benzylidene-4-(4-chlorobenzoyl)-N-cyclohexyl-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (5e)
1H NMR (600 MHz, CDCl3, 50 °C): δ = 8.02–6.41 (m, 20 H, Ar-H, =CH),
6.19 (s, 0.3 H, 0.3 CH), 5.82 (s, 0.7 H, 0.7 CH), 5.35 (s, 0.3 H, 0.3 NH),
4.97 (s, 0.7 H, 0.7 NH), 1.19 (s, 9 H, 3 CH3).
White crystals; yield: 0.45 g (78%).
1H NMR (600 MHz, CDCl3): δ = 8.40–6.43 (m, 19 H, Ar-H, =CH), 6.22 (s,
0.3 H, 0.3 CH), 5.87 (s, 0.7 H, 0.7 CH), 5.47 (s, 0.3 H, 0.3 NH), 4.93 (s,
0.7 H, 0.7 NH), 3.78–3.63 (m, 1 H, NCH), 1.83–0.86 (m, 10 H, 5 CH2).
13C NMR (150 MHz, CDCl3): δ = 170.0, 168.8 (minor), 166.7, 165.8,
149.1, 144.9 (minor), 140.9 (minor), 136.1 (minor), 135.5, 134.7,
134.5, 133.6, 131.6, 130.6, 130.2, 129.1, 128.9, 128.6, 128.2, 127.8,
127.2, 127.0, 126.5, 126.0, 125.0, 124.6, 62.2 (minor), 60.7, 48.8, 32.6,
32.5, 25.0, 24.3.
13C NMR (150 MHz, CDCl3): δ = 171.0, 166.8, 166.0, 149.1, 136.1,
134.7, 133.8, 131.5, 130.7, 130.5, 130.1, 129.7, 129.3, 129.0, 128.5,
128.2, 128.1, 128.0, 127.7, 126.9, 126.5, 126.0, 125.3, 124.7, 61.1, 51.5,
28.5.
MS: m/z (%) = 513 (5, M+), 413 (10), 165 (10), 105 (100), 77 (21).
Anal. Calcd for C34H31N3O2: C, 79.51; H, 6.08; N, 8.18. Found: C, 79.74;
H, 6.25; N, 8.31.
MS: m/z (%) = 573 (2, M+), 446 (25), 165 (20), 139 (100), 111 (16).
4-Benzoyl-3-benzylidene-N-tert-butyl-2-(4-chlorophenyl)-4,5-di-
hydro-3H-1,4-benzodiazepine-5-carboxamide (5b)
Anal. Calcd for C36H32ClN3O2: C, 75.31; H, 5.62; N, 7.32. Found: C,
75.45; H, 5.82; N, 7.58.
White crystals; yield: 0.44 g (80%).
1H NMR (600 MHz, CDCl3): δ = 8.39–6.41 (m, 19 H, Ar-H, =CH), 6.19–
6.13 (m, 0.4 H, 0.4 CH), 5.78 (s, 0.6 H, 0.6 CH), 5.38–5.28 (m, 0.4 H, 0.4
NH), 4.90 (s, 0.6 H, 0.6 NH), 1.20 (s, 7 H, 7/9 × 3 CH3), 0.94–0.86 (m, 2
H, 2/9 × 3 CH3).
4-Benzoyl-3-benzylidene-N-butyl-2-phenyl-4,5-dihydro-3H-1,4-
benzodiazepine-5-carboxamide (5f)
White crystals; yield: 0.43 g (84%).
1H NMR (600 MHz, CDCl3): δ = 8.40–6.49 (m, 20 H, Ar-H, =CH), 6.20 (s,
0.3 H, 0.3 CH), 5.84 (s, 0.7 H, 0.7 CH), 5.67 (br, 0.3 H, 0.3 NH), 5.16 (s,
0.7 H, 0.7 NH), 3.24–3.05 (m, 2 H, NCH2), 1.36–0.73 (m, 7 H,
CH2CH2CH3).
13C NMR (150 MHz, CDCl3): δ = 171.1, 166.8, 165.0. 149.0, 137.9,
136.3, 133.8, 133.4, 131.1, 130.7, 130.5, 130.4, 130.3, 130.2, 130.1,
129.8, 128.6, 128.5, 128.4, 128.2, 127.7, 127.0, 126.1, 125.5, 124.8,
61.1, 51.6, 28.5.
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13C NMR (150 MHz, CDCl3): δ = 171.1, 169.9 (minor), 167.8, 166.1,
149.2, 145.2 (minor), 141.2 (minor), 136.2, 134.7, 133.8, 131.6, 130.7,
130.4, 130.2, 129.7, 129.5, 129.1, 128.9, 128.8, 128.6, 128.2, 127.7,
126.9, 126.5, 126.1, 124.9, 62.2 (minor), 60.8, 40.0, 31.5, 19.8, 13.6.
3-Benzylidene-4-(2-chlorobenzoyl)-N-cyclohexyl-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (5j)
Yellow crystals; yield: 0.50 g (87%).
1H NMR (600 MHz, CDCl3): δ = 8.29–6.03 (m, 20 H, Ar-H, =CH, CH),
5.51–4.63 (m, 1 H, NH), 3.79–3.28 (m, 1 H, NCH), 2.17–0.70 (m, 10 H,
5 CH2).
13C NMR (150 MHz, CDCl3): δ = 168.9, 167.6 (minor), 166.6, 165.4,
149.1, 146.3 (minor), 137.1 (minor), 136.3 (minor), 135.0, 130.4,
130.1, 130.0, 129.6, 129.4, 129.0, 128.7, 128.5, 128.2, 127.9, 127.8,
127.6, 127.3, 126.9, 126.6, 126.1, 125.8, 125.3, 64.4, 62.2, 48.7, 32.5,
32.3, 25.1, 24.6, 24.3.
MS: m/z (%) = 513 (4, M+), 412 (25), 165 (10), 105 (100), 77 (19).
Anal. Calcd for C34H31N3O2: C, 79.51; H, 6.08; N, 8.18. Found: C, 79.54;
H, 6.35; N, 8.39.
4-Acetyl-3-benzylidene-N-cyclohexyl-2-phenyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (5g)
White crystals; yield: 0.41 g (86%).
MS: m/z (%) = 573 (2, M+), 447 (10), 309 (9), 165 (12), 139 (100), 111
(8).
1H NMR (600 MHz, CDCl3): δ = 8.13 (d, J = 7.2 Hz, 2 H, Ar-H), 7.58–
7.18 (m, 12 H, Ar-H), 6.68 (s, 0.1 H, 0.1 =CH), 6.30 (s, 0.1 H, 0.1 CH),
6.22 (s, 0.9 H, 0.9 =CH), 6.09 (s, 0.9 H, 0.9 CH), 5.41 (d, J = 6.6 Hz, 0.1 H,
0.1 NH), 4.89 (d, J = 7.2 Hz, 0.9 H, 0.9 NH), 3.77–3.50 (m, 1 H, NCH),
2.01 (s, 3 H, CH3), 1.65–0.86 (m, 10 H, 5 CH2).
Anal. Calcd for C36H32ClN3O2: C, 75.31; H, 5.62; N, 7.32. Found: C,
75.48; H, 5.81; N, 7.52.
13C NMR (150 MHz, CDCl3): δ = 169.2, 166.6, 166.0, 149.1, 135.9,
133.9. 132.2, 131.3, 130.7, 130.0, 128.9, 128.6, 128.3, 127.7, 126.3,
125.7, 125.5, 124.8, 61.3, 48.6, 48.5, 32.7, 32.4, 24.7, 21.3.
4-Acetyl-N-tert-butyl-3-(4-fluorobenzylidene)-2-phenyl-4,5-dihy-
dro-3H-1,4-benzodiazepine-5-carboxamide (5k)
White crystals; yield: 0.40 g (85%).
MS: m/z (%) = 477 (4, M+), 350 (30), 308 (6), 231 (11), 165 (21).
1H NMR (600 MHz, CDCl3): δ = 8.29–6.90 (m, 13 H, Ar-H), 6.65 (s, 0.2
H, 0.2 =CH), 6.26 (s, 0.2 H, 0.2 CH), 6.19 (s, 0.8 H, 0.8 =CH), 6.04 (s, 0.8
H, 0.8 CH), 5.34–4.85 (m, 1 H, NH), 2.03 (s, 2.5 H, 2.5/3 × CH3) 1.68 (s,
0.5 H, 0.5/3 × CH3), 1.27–0.87 (m, 9 H, 3 CH3).
Anal. Calcd for C31H31N3O2: C, 77.96; H, 6.54; N, 8.80. Found: C, 78.21;
H, 6.64; N, 8.64.
3-Benzylidene-N-cyclohexyl-4-(4-methylbenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (5h)
13C NMR (150 MHz, CDCl3): δ = 168.8, 166.2, 165.8, 162.7, 161.1,
148.9, 135.5, 131.9, 131.4, 131.2, 130.6, 130.5, 130.0, 129.4, 129.3,
128.5, 128.4, 128.2, 126.2, 126.1, 125.6, 125.4, 123.3, 123.2, 115.9,
61.3, 51.3, 28.4, 22.2.
Light yellow crystals; yield: 0.46 g (83%).
1H NMR (600 MHz, CDCl3): δ = 8.43–6.47 (m, 19 H, Ar-H, =CH), 6.19 (s,
0.4 H, 0.4 CH), 5.83 (s, 0.6 H, 0.6 CH), 5.47 (br, 0.4 H, 0.4 NH), 5.00 (br,
0.6 H, 0.6 NH), 3.79–3.63 (m, 1 H, NCH), 2.31 (s, 2.2 H, CH3), 2.17 (s,
0.8 H, CH3), 1.84–0.86 (m, 10 H, 5 CH2).
MS: m/z (%) = 469 (4, M+), 370 (30), 327 (100), 165 (31), 89 (18).
Anal. Calcd for C29H28FN3O2: C, 74.18; H, 6.01; N, 8.95. Found: C,
74.21; H, 6.24; N, 9.08.
13C NMR (150 MHz, CDCl3): δ = 171.2, 170.0 (minor), 166.9, 166.0,
149.1, 145.0 (minor), 141.1 (minor), 139.6, 136.7 (minor), 136.1 (mi-
nor), 134.6, 133.8, 133.3, 131.4, 130.7, 130.5, 130.0, 129.6, 128.8,
128.4, 128.1, 127.6, 127.4, 126.9, 126.4, 125.9, 125.0, 124.6, 62.2 (mi-
nor), 60.7, 48.7, 32.8, 32.4, 25.0, 24.5, 21.4.
4-Benzoyl-3-benzylidene-N-tert-butyl-2-methyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (5l)
White crystals; yield: 0.37 g (82%).
1H NMR (600 MHz, CDCl3): δ = 7.77–6.34 (m, 15.3 H, Ar-H, =CH, 0.3
CH), 5.57 (s, 0.7 H, 0.7 CH), 5.40 (s, 0.3 H, 0.3 NH), 4.86 (s, 0.7 H, 0.7
NH), 2.64–2.24 (m, 3 H, CH3), 1.25 (s, 9 H, 3 CH3).
13C NMR (150 MHz, CDCl3): δ = 170.0, 169.4 (minor), 166.9, 166.0 (mi-
nor), 162.1 (minor), 148.5, 144.6, 135.9 (minor), 135.4, 135.2, 134.3,
133.7, 132.4 (minor), 130.6, 130.5, 129.9, 129.5, 129.3, 128.9, 128.3,
128.2, 127.6, 127.3, 127.0, 126.7, 126.0, 125.9, 125.0, 120.6 (minor),
62.1 (minor), 60.5, 51.4, 28.6, 27.8, 26.8, 26.0.
MS: m/z (%) = 553 (1, M+), 426 (15), 165 (10), 119 (100), 91 (16).
Anal. Calcd for C37H35N3O2: C, 80.26; H, 6.37; N, 7.59. Found: C, 80.38;
H, 6.51; N, 7.84.
3-Benzylidene-N-cyclohexyl-2-phenyl-4-propionyl-4,5-dihydro-
3H-1,4-benzodiazepine-5-carboxamide (5i)
Light yellow crystals; yield: 0.40 g (81%).
MS: m/z (%) = 451 (3, M+), 351 (13), 247 (5.6), 105 (100), 77 (25).
1H NMR (600 MHz, CDCl3): δ = 8.32–8.13 (m, 2 H, Ar-H), 7.77–7.18
(m, 12 H, Ar-H), 6.26 (s, 1 H, =CH), 6.09 (s, 1 H, CH), 5.40 (br, 0.2 H, 0.2
NH), 4.93 (d, J = 3.0 Hz, 0.8 H, 0.8 NH), 3.77–3.52 (m, 1 H, NCH), 2.65–
2.10 (m, 2 H, CH2), 1.71–0.86 (m, 13 H, CH3, 5 CH2).
Anal. Calcd for C29H29N3O2: C, 77.13; H, 6.47; N, 9.31. Found: C, 77.28;
H, 6.56; N, 9.50.
13C NMR (150 MHz, CDCl3): δ = 172.8, 166.3, 166.1, 149.1, 135.8,
133.7, 131.7, 131.2, 130.7, 129.6, 129.2, 128.7, 128.4, 128.2, 127.7,
127.4, 126.1, 125.6, 124.7, 61.4, 48.2, 32.2, 31.9, 26.5, 25.1, 24.2, 24.0,
9.1.
Crystallographic Data
Compound 5a: formula C34H31N3O2, colorless crystal. The crystal is of
monoclinic, space group P2(1)/c with a = 9.4058(6) Å, b = 19.4857(12)
Å, c = 15.9018(10) Å, α = 90°, β = 101.9670(10)°, γ = 90°, V = 2851.1(3)
Å3, Z = 4, Dc = 1.197 g/cm3, F(000) = 1088, μ = 0.075 mm–1, R = 0.0633,
and wR = 0.1479 for 5598 observed reflections with I > 2σ(I0). CCDC
1447870 contains the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
MS: m/z (%) = 491 (4, M+), 364 (19), 309 (100), 231 (9), 165 (21).
Anal. Calcd for C32H33N3O2: C, 78.18; H, 6.77; N, 8.55. Found: C, 78.32;
H, 6.79; N, 8.77.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
H. Xie et al.
Paper
Synthesis
Acknowledgment
(8) (a) Katritzky, A. R.; Xu, Y.-J.; He, H.-Y. J. Chem. Soc., Perkin Trans.
1 2002, 592. (b) Welmaker, G. S.; Sebalski, J. E. Tetrahedron Lett.
2004, 45, 4851.
(9) Nguyen, H. H.; Palazzo, T. A.; Kurth, M. J. Org. Lett. 2013, 15,
4492.
We gratefully acknowledge financial support of this work by the Na-
tional Natural Science Foundation of China (No. 21572075 and
21172085).
(10) (a) Sañudo, M.; García-Valverde, M.; Marcaccini, S.; Delgado, J.
J.; Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74, 2189. (b) Pertejo, P.;
Corres, N.; Torroba, T.; García-Valverde, M. Org. Lett. 2015, 17,
612. (c) Wang, Y.; Chen, M.; Ding, M. W. Tetrahedron 2013, 69,
9056. (d) Lecinska, P.; Corres, N.; Moreno, D.; García-Valverde,
M.; Marcaccini, S.; Torroba, T. Tetrahedron 2010, 66, 6783.
(11) (a) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev.
2014, 114, 8323. (b) Dömling, A.; Wang, W.; Wang, K. Chem. Rev.
2012, 112, 3083.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588308.
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References
(12) (a) Azuaje, J.; Pérez-Rubio, J. M.; Yaziji, V.; Maatougui, A. E.;
González-Gomez, J. C.; Sańchez-Pedregal, V. M.; Navarro-
Vázquez, A.; Masaguer, C. F.; Teijeira, M.; Sotelo, E. J. Org. Chem.
2015, 80, 1533. (b) Peshkov, A. A.; Peshkov, V. A.; Pereshivko, O.
P.; Van der Eycken, E. V. Tetrahedron 2015, 71, 3863. (c) Patil, P.;
Khoury, K.; Herdtweck, E.; Dömling, A. Org. Lett. 2014, 16, 5736.
(d) Alvarez-Rodríguez, N. V.; Dos Santos, A.; El Kaïm, L.; Gámez-
Montaño, R. Synlett 2015, 26, 2253. (e) Vachhani, D. D.; Kumar,
A.; Modha, S. G.; Sharma, S. K.; Parmar, V. S.; Van der Eycken, E.
V. Synthesis 2015, 47, 1337.
(13) (a) Kumar, R.; Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org.
Chem. 2013, 78, 5737. (b) Fesenko, A. A.; Shutalev, A. D. Tetrahe-
dron 2014, 70, 5398. (c) Okamoto, K.; Shimbayashi, T.; Tamura,
E.; Ohe, K. Chem. Eur. J. 2014, 20, 1490. (d) Hu, Y.; Li, X.; Wan, B.
Tetrahedron 2015, 71, 6935. (e) Liu, Y.; Sun, X.; Zhang, X.; Liu, J.;
Du, Y. Org. Biomol. Chem. 2014, 12, 8453. (f) Qu, F.; Hu, R.-F.;
Gao, L.; Wu, J.; Cheng, X.-H.; Wang, S.; He, P. Synthesis 2015, 47,
3701.
(14) (a) Yang, Y. Y.; Shou, W. G.; Chen, Z. B.; Hong, D.; Wang, Y. G. J.
Org. Chem. 2008, 73, 3928. (b) Nishimura, Y.; Cho, H. Synlett
2015, 26, 233. (c) Wang, L.; Ren, Z. L.; Chen, M.; Ding, M. W.
Synlett 2014, 25, 721. (d) Xie, H.; Yuan, D.; Ding, M. W. J. Org.
Chem. 2012, 77, 2954. (e) Nie, Y. B.; Wang, L.; Ding, M. W. J. Org.
Chem. 2012, 77, 696. (f) Xie, H.; Liu, J. C.; Wu, L.; Ding, M. W. Tet-
rahedron 2012, 68, 7984. (g) Xie, H.; Yu, J. B.; Ding, M. W. Eur. J.
Org. Chem. 2011, 6933.
(15) (a) Yuan, D.; Duan, Z.; Rao, Y.; Ding, M. W. Tetrahedron 2016, 72,
338. (b) Zeng, X. H.; Wang, H. M.; Ding, M. W. Org. Lett. 2015, 17,
2234. (c) Wang, L.; Ren, Z. L.; Ding, M. W. J. Org. Chem. 2015, 80,
641. (d) Duan, Z.; Gao, Y.; Yuan, D.; Ding, M. W. Synlett 2015, 26,
2598.
(1) Rivas, F. M.; Stables, J. P.; Murphree, L.; Edwankar, R. V.;
Edwankar, C. R.; Huang, S.; Jain, H. D.; Zhou, H.; Majumder, S.;
Sankar, S.; Roth, B. L.; Ramerstorfer, J.; Furtmüller, R.; Sieghart,
W.; Cook, J. M. J. Med. Chem. 2009, 52, 1795.
(2) Anzini, M.; Braile, C.; Valenti, S.; Cappelli, A.; Vomero, S.;
Marinelli, L.; Limongelli, V.; Novellino, E.; Betti, L.; Giannaccini,
G.; Lucacchini, A.; Ghelardini, C.; Norcini, M.; Makovec, F.;
Giorgi, G.; Fryer, R. I. J. Med. Chem. 2008, 51, 4730.
(3) Clark, R. L.; Carter, K. C.; Mullen, A. B.; Coxon, G. D.; Owusu-
Dapaah, G.; McFarlane, E.; Thi, M. D. D.; Grant, M. H.; Tettey, J. N.
A.; Mackay, S. P. Bioorg. Med. Chem. Lett. 2007, 17, 624.
(4) Galli, U.; Travelli, C.; Aprile, S.; Arrigoni, E.; Torretta, S.; Grosa,
G.; Massarotti, A.; Sorba, G.; Canonico, P. L.; Genazzani, A. A.;
Tron, G. C. J. Med. Chem. 2015, 58, 1345.
(5) (a) Liu, J.-J.; Higgins, B.; Ju, G.; Kolinsky, K.; Luk, K.-C.; Packman,
K.; Pizzolato, G.; Ren, Y.; Thakkar, K.; Tovar, C.; Zhang, Z.;
Wovkulich, P. M. ACS Med. Chem. Lett. 2013, 4, 259. (b) Hunt, J.
T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.;
Chong, S.; Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y.
F.; Leftheris, K.; Miller, A.; Mitt, T.; Patel, M.; Penhallow, B. A.;
Ricca, C.; Rose, W. C.; Schmidt, R.; Slusarchyk, W. A.; Vite, G.;
Manne, V. J. Med. Chem. 2000, 43, 3587.
(6) Nadin, A.; López, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot, A.
C.; Harrison, T. J. Org. Chem. 2003, 68, 2844.
(7) Breslin, H. J.; Kukla, M. J.; Ludovici, D. W.; Mohrbacher, R.; Ho,
W.; Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G.;
Gauthier, D. A.; Ho, C. Y.; Scott, M. K.; De Clercq, E.; Pauwels, R.;
Andries, K.; Janssen, M. A. C.; Janssen, P. A. J. J. Med. Chem. 1995,
38, 771.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G