A simple and one-pot synthesis of 2,3,4,5-tetrasubstituted 4,5-dihydro-3H-1,4-benzodiazepines

Article abstract of DOI:10.1016/j.tet.2013.08.034

2,3,4,5-Tetrasubstituted 4,5-dihydro-3H-1,4-benzodiazepines were synthesized in one-pot by a new sequential Ugi 4CC/Staudinger/aza-Wittig reaction, starting from easily accessible o-azidobenzaldehyde, α-amino ketone hydrochloride, isocyanide and carboxylic acid.

Full text of DOI:10.1016/j.tet.2013.08.034

Tetrahedron 69 (2013) 9056e9062
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple and one-pot synthesis of 2,3,4,5-tetrasubstituted
4,5-dihydro-3H-1,4-benzodiazepines
*
Ying Wang, Min Chen, Ming-Wu Ding
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2013
Received in revised form 25 July 2013
Accepted 15 August 2013
Available online 20 August 2013
2,3,4,5-Tetrasubstituted 4,5-dihydro-3H-1,4-benzodiazepines were synthesized in one-pot by a new
sequential Ugi 4CC/Staudinger/aza-Wittig reaction, starting from easily accessible o-azidobenzaldehyde,
a-amino ketone hydrochloride, isocyanide and carboxylic acid.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
4,5-Dihydro-3H-1,4-benzodiazepine
Ugi reaction
Aza-Wittig reaction
One-pot reaction
Staudinger reaction
1. Introduction
components that generates a significantly more complex a-acyla-
mino amide adduct.10 The sequence of Ugi isocyanide multicom-
ponent reaction, followed by post-condensation transformations,
constitutes an extremely powerful synthetic tool for the preparation
of structurally diverse complex molecules, especially heterocyclic
compounds.11 The aza-Wittig reactions of iminophosphoranes have
received increased attention in view of their utility in the synthesis
of N-heterocycles.12 Recently the sequence of Ugi and Passerini re-
action, followed by post-condensation Staudinger and aza-Wittig
reaction, has been utilized in synthesis of a series of biologically
useful heterocycles.13e19 Continuing our interest in the synthesis of
various heterocycles via aza-Wittig reaction,20 we wish to report
herein a one-pot synthetic approach to 2,3,4,5-tetrasubstituted 4,5-
dihydro-3H-1,4-benzodiazepines by a sequential Ugi 4CCeStau-
dingereaza-Wittig reaction, starting from the easily accessible o-
1,4-Benzodiazepines are one of the most important and widely
used scaffolds in medicinal chemistry, especially for the treatment
of anxiety and sleep disorders.1
A large number of 1,4-
benzodiazepine derivatives have also been found to show other
biological activities, such as antiarrhythmic,2 anticonvulsant,3 an-
ticancer4 and anti-HIV activities.5 Several new synthetic ap-
proaches have been reported in literature recently. For example,
some 1,4-benzodiazepines can be prepared either by reaction of
bromoethylsulfonium salt with 1,3-diamines,6 or by a one-pot re-
action of methyl 1-arylaziridine-2-carboxylates with N-[2-
bromomethyl(aryl)]trifluoroacetamides.7 Another 1,4-benzodiaze-
pines were obtained from Pd-catalyzed coupling of N-allyl-2-
aminobenzylamine derivatives with aryl bromides,8 or by the re-
action of 2-aminobenzylamine with 1,2-diaza-1,3-dienes.9 Al-
though much effort has been directed toward the construction of
1,4-benzodiazepines, fewer methods for the synthesis of 4,5-
dihydro-3H-1,4-benzodiazepines have been developed. To further
discover molecules with potent and selective biological activity, it is
of importance to explore new methodology for the synthesis of
novel 4,5-dihydro-3H-1,4-benzodiazepine entities.
azidobenzaldehyde,
carboxylic acid.
a-amino ketone hydrochloride, isocyanide and
2. Results and discussion
It has been reported that a-amino ketone hydrochloride 1a can
be used as one reactant in some Ugi reactions to produce normal
products albeit in low to moderate yields (38%e78%).21 However, 2-
azidobenzaldehyde 2 has not been used previously in the reaction to
prepare corresponding azide 7. Initially, we selected the phenacyl-
amine hydrochloride 1a, 2-azidobenzaldehyde 2, 4-methylbenzoic
acid 3a and tert-butylisocyanide 4a as the reactants (Scheme 1).
The Ugi reaction is a powerful, atom-economical reaction be-
tween isocyanide, amine, aldehyde (or ketone) and carboxylic acid
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041; e-mail
addresses: mwding@mail.ccnu.edu.cn, dmw10@126.com (M.-W. Ding).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.08.034

Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
9057
When the phenacylamine hydrochloride 1a, potassium hydroxide,
O
O
N3
2-azidobenzaldehyde 2, 4-methylbenzoic acid 3a and tert-butyli-
socyanide 4a was stirred in methanol at room temperature, the
reaction solution became red and a white solid precipitated, which
was verified unexpectedly to be the tetrahydroimidazole adduct 5
(42%). The normal Passerini product 6 (16%) and Ugi product 7 (25%)
was also isolated from the reaction mixture. The structure of tet-
rahydroimidazole adduct 5 was confirmed by its spectrum data.
Furthermore a single crystal of 5 was obtained from the CH2Cl2
solution, and X-ray structure analysis verified the proposed struc-
ture (Fig. 1). The formation of the adduct 5 might be rationalized in
terms of an initial condensation of 1a and 2 to give the Schiff base
intermediate 8, which undergoes self-condensation under the re-
action condition to produce tetrahydroimidazole 9 through the
condensation of the methylene group of intermediate 8, further
reaction of 9 with aldehyde 2 and isocyanide 4a give the adduct 522
(Scheme 2).
H
N
N
Ph
Ph
N3
Ph
1a
+
2
N
O
N
N3
Ph
O
N3
8
9
2, 4a
5
Scheme 2. Possible mechanism for formation of adduct 5.
We speculated that the formation of adduct 5 would be
diminished if a -substituted
-amino ketone 1 (R2sH) was
used. The -amino ketone hydrochloride (1 equiv), 2-
a
a
a
1
azidobenzaldehyde 2 (1 equiv), acid 3 (1 equiv) and isocyanide 4
(1 equiv) were then employed for the reaction (Scheme 3). We were
pleased to find that, in these cases, the Ugi reaction proceeds
smoothly and some of the products 10 can be isolated in 67e79%
yields, but the obtained azides 10 were found not stable when
stored. So the best result was obtained when the reaction was
carried out in one-pot fashion: after monitoring the formation of
the azides 10, the formed inorganic salt (KCl) was removed by fil-
tration and the solvent was changed from methanol to toluene,
then triphenylphosphine was added and the resulted solution was
refluxed. The final products obtained were verified to be 4,5-
dihydro-3H-1,4-benzodiazepines 12 (in 65e81% overall yields)
(Table 1). The starting material, which was left over has little af-
fection on the proceeding one-pot reaction.
N3
O
COOH
O
HN
O
NH3+Cl-
Ph
H3C
N
3a
1a
Ph
KOH
CHO
N3
N
O
CH3OH
N3
CN
4a
N3
Ph
2
5
+
O
CH3
+
O
HN
N3
O
H
N
N
O
O
O
N3
Ph
H3C
O
R3
R2
O
NH3+Cl-
6
7
O
O
R1
R3 COOH
Scheme 1. Ugi reaction of phenacylamine hydrochloride 1a.
N
R2
R1
NHR4
N3
KOH/CH3OH
r. t., 2-3d
3
1
CHO
N3
R4 NC
10
4
2
R3
O
O
O
R4HN
O
R2
R4HN
R3
R2
N
toluene
reflux
Ph3P
N
R1
toluene
r.t.
O
N
PPh3
11
N
R1
12
Scheme 3. Synthesis of 4,5-dihydro-3H-1,4-benzodiazepines 12.
The compounds 12aep were confirmed by their spectrum data.
For example, the 1H NMR spectrum of 12b shows the signals of
CONH and COCH at 5.85 and 5.00 ppm as singlet. The signals of NCH
appear at 4.95e4.92 ppm as multiplets. The signals of CH2CH3 and
t-Bu appear at 1.66e0.58 as multiplets. The signals attributable to
the AreHs are found at 7.96e7.24 ppm as multiplets. The 13C NMR
spectrum data in 12b showed the signals of C]O and C]N carbon
at 172.4, 167.8 and 167.7 ppm. The MS spectrum of 12b shows
MþꢀCONHBu-t at m/z 387 with 14% abundance. Furthermore
a single crystal of 2,3,4,5-tetrasubstituted 4,5-dihydro-3H-1,4-
benzodiazepine 12a was obtained from the CH2Cl2/petroleum
Fig. 1. X-ray crystal structure of compound 5.

9058
Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
Table 1
a Vario EL III elementary analysis instrument. The X-ray diffraction
Preparation of compounds 12
data were collected on a Bruker SMART AXS CCD diffractometer,
¼1.86e27.50ꢁ.
R1
R2
R3
R4
Yielda (%)
MoKa, 2q
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
12r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Et
n-Bu
PhCH2
PhCH2
4-CH3C6H4
4-ClC6H4
2-CH3C6H4
Ph
4-FC6H4
2-ClC6H4
2-FC6H4
4-CH3OC6H4
4-ClC6H4
Ph
4-FC6H4
4-CH3C6H4
c-C6H11
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
c-C6H11
c-C6H11
c-C6H11
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
74
68
73
65
68
72
73
78
70
77
71
65
81
65
76
75
78
79
4.2. Synthesis of compounds 5, 6 and 7
Finely powdered 4-methylbenzoic acid
3
(R3¼4-CH3C6H4,
0.68 g, 5 mmol) was added to a well-stirred solution of potassium
hydroxide (0.28 g, 5 mmol) in MeOH (15 mL), the phenacylamine
hydrochloride 1 (R1¼C6H5, R2¼H, 0.86 g, 5 mmol) was added to the
above suspension at 5 ꢁC and stirring was continued for 10 min. The
resulting suspension was treated with 2-azidobenzaldehyde 2
(0.74 g, 5 mmol) and then with tert-butylisocyanide 4 (R4¼t-Bu,
0.42 g, 5 mmol). The reaction solution became red and a white solid
precipitated when the reaction mixture was stirred at room tem-
perature for 5e6 h. After stirring for 24 h, the solid precipitated was
filtered, washed with water (30 mL) and dried to give the adduct 5.
The filtrate was then condensed and the residue was purified by
column chromatography (4:1, petroleum ether/diethyl ether) to
give compounds 6 and 7.
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
Me
a
Isolated yields based on azide 2.
4.2.1. 2-(2-Azidophenyl)-2-(2,4-bis(2-azidophenyl)-5-benzoyl-3-(2-
oxo-2-phenylethyl)imidazolidin-1-yl)-N-(tert-butyl)acetamide
(5). White solid (1.01 g, 42%). Mp 196e197 ꢁC. 1H NMR (CDCl3,
ether solution of 12a, and X-ray structure analysis verified the
proposed structure (Fig. 2).
600 MHz):
d
¼8.85 (s, 1H, NH), 7.54e7.15 (m, 16H, AreH), 6.91e6.83
(m, 2H, AreH), 6.68 (s, 1H, AreH), 6.60 (d, J¼7.2 Hz, 2H, AreH), 6.51
(d, J¼7.8 Hz, 1H, AreH), 5.75 (d, J¼9.6 Hz, 1H, CH), 5.32 (d, J¼9.0 Hz,
1H, CH), 5.28 (s, 1H, CH), 5.00 (s, 1H, CH), 3.68 (d, J¼17.4 Hz, 1H,
CHa2), 3.49 (d, J¼18.0 Hz, 1H, CH2b), 1.12 (s, 9H, t-Bu). 13C NMR
(150 MHz, CDCl3):
d¼201.6, 197.3, 170.1, 140.2, 138.8, 138.3, 136.9,
136.0, 133.1, 132.7, 132.5, 132.4, 130.2, 129.3, 129.2, 129.0, 128.2,
127.6, 127.5, 127.2, 126.7, 126.5, 124.9, 124.5, 123.6, 117.8, 117.7, 117.3,
116.4, 74.7, 71.5, 60.6, 50.8, 50.1, 28.2, 28.1. IR (KBr): 3319, 2972,
2905, 2127, 1695, 1698, 1598, 1583 cmꢀ1. Elemental Anal. Calcd for
C42H38N12O3: C, 66.48; H, 5.05; N, 22.15. Found: C, 66.21; H, 5.24; N,
22.01.
4.2.2. 1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl
4-methylbenzoate (6). Light yellow solid (0.39 g, 16%).
Mp 140e141 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
¼7.98 (d, J¼7.2 Hz, 2H,
AreH), 7.59e7.16 (m, 6H, AreH), 6.41 (s, 1H, CH), 6.16 (s, 1H, NH),
2.40 (s, 3H, CH3), 1.37 (s, 9H, t-Bu). 13C NMR (150 MHz, CDCl3):
Fig. 2. X-ray crystal structure of compound 12a.
d
¼167.0, 165.0, 144.2, 137.9, 129.8, 129.6, 129.2, 129.1, 127.3, 126.4,
125.0, 118.2, 51.5, 28.5, 28.6, 21.6. IR (KBr): 3283, 3086, 2970, 2925,
2129, 1727, 1664, 1612, 1563, 1293, 1274, 1111 cmꢀ1. Elemental Anal.
Calcd for C20H22N4O3: C, 65.56; H, 6.05; N,15.29. Found: C, 65.46; H,
5.83; N, 15.24.
3. Conclusion
We have successfully synthesized a series of 2,3,4,5-tetrasub-
stituted 4,5-dihydro-3H-1,4-benzodiazepines in one-pot fashion by
a sequential Ugi 4CCeStaudingereaza-Wittig reaction, starting
4.2.3. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-4-
from the corresponding a-alkyl a-amino ketone hydrochlorides as
methyl-N-(2-oxo-2-phenylethyl) benzamide (7). Light yellow solid
(0.61 g, 25%). Mp 168e169 ꢁC. 1H NMR (CDCl3, 600 MHz):
d¼8.79 (s,
the amino component. The used aminoketones, isocyanides and
acids can be varied broadly, producing products with three po-
tential points of diversity, in combination to the easy availability of
the synthetic approach and the large scope of the reaction makes it
useful in synthetic and medicinal chemistry.
1H, NH), 7.92 (d, J¼7.8 Hz, 2H, AreH), 7.58e7.10 (m, 11H, AreH),
5.65 (s,1H, CH), 4.88 (d, J¼16.8 Hz,1H, NCHa2), 3.64 (d, J¼16.8 Hz,1H,
NCHb2), 2.40 (s, 2.5H, 0.83CH3), 2.27 (s, 0.5H, 0.17CH3), 1.56 (s, 8H,
0.8t-Bu), 1.45 (s, 1H, 0.1t-Bu). 13C NMR (CDCl3, 150 MHz):
d¼196.7,
173.6, 168.2, 140.7, 139.4, 135.2, 133.8, 132.0, 130.6, 129.9, 129.1,
128.6, 128.2, 127.2, 127.0, 125.0, 118.5, 63.6, 52.0, 50.0, 28.7, 21.4. IR
(KBr): 3314, 3066, 2974, 2129, 1694, 1674, 1614 cmꢀ1. Elemental
Anal. Calcd for C28H29N5O3: C, 69.55; H, 6.04; N, 14.48. Found: C,
69.74; H, 5.97; N, 14.35.
4. Experimental
4.1. General
Melting points were determined using a X-4 model apparatus
and were uncorrected. MS were measured on a Finnigan Trace MS
spectrometer. IR were recorded on a PE-983 infrared spectrometer
as KBr pellets with absorption in cmꢀ1. NMR were recorded in
CDCl3 or DMSO-d6 on a Varian Mercury 600 spectrometer and
resonances relative to TMS. Elementary analyses were taken on
4.3. One-pot synthesis of 2,3,4,5-tetrasubstituted 4,5-
dihydro-3H-1,4-benzodiazepines 12
4.3.1. N-(tert-Butyl)-3-ethyl-4-(4-methylbenzoyl)-2-phenyl-
4,5-[dihydro-3H-1,4-benzodiazepine-5-carboxamide
(12a). Finely

Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
9059
powdered 4-methylbenzoic acid 3 (R3¼4-CH3C6H4, 0.27 g, 2 mmol)
150 MHz):
d
¼173.4, 167.9, 167.7, 149.4, 138.0, 135.4, 130.8, 130.4,
was added to a well-stirred solution of potassium hydroxide (0.11 g,
129.1, 128.5, 128.3, 127.3, 127.2, 125.9, 125.3, 124.3, 124.1, 61.7, 59.8,
51.5, 28.5, 24.2, 11.1. MS: m/z (%)¼353 (13, MþꢀCONHBu-t), 248 (6),
232 (4), 207 (6), 193 (4), 135 (7), 122 (4), 105 (100). Elemental Anal.
Calcd for C29H31N3O2: C, 76.79; H, 6.89; N, 9.26. Found: C, 76.57; H,
7.02; N, 9.23.
2 mmol) in MeOH (10 mL), a-alkyl a-amino ketone hydrochlorides
1 (R1¼C6H5, R2¼Et, 0.33 g, 2 mmol) was added to the above sus-
pension at 5 ꢁC and stirring was continued for 10 min. The resulting
suspension was treated with 2-azidobenzaldehyde 2 (0.29 g,
2 mmol) and then with isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol). The
reaction mixture was stirred at room temperature, monitoring the
reactions by thin-layer chromatography (TLC) until the reactants
disappeared. The formed inorganic salt was removed by filtration.
After removing the solvent under reduced pressure, dry toluene
(5 mL) was added. To the above solution was added dropwise the
solution of triphenylphosphine (0.63 g, 2.4 mmol) in dry toluene
(5 mL) at room temperature. The mixture was then heated to reflux,
monitoring the reactions by thin-layer chromatography (TLC) until
the reaction completed. The solvent was then evaporated under
reduced pressure and the residue was purified by column chro-
matography to give 4,5-dihydro-3H-1,4-benzodiazepines 12a. Light
yellow solid (0.69 g, 74%). Mp 175e176 ꢁC. 1H NMR (CDCl3,
4.3.5. N-(tert-Butyl)-3-ethyl-4-(4-fluorobenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12e). Operation as
above with 4-fluorobenzoic acid 3 (R3¼4-FC6H4, 0.28 g, 2 mmol)
and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol) in the first step, com-
pound 12e (0.64 g, 68%) was isolated as light yellow solid.
Mp 177e178 ꢁC. 1H NMR (CDCl3, 600 MHz):
d¼8.10e7.12 (m, 13H,
AreH), 6.20e6.12 (m, 1H, NH), 5.08e4.78 (m, 2H, 2CH), 1.62e1.60
(m, 1H, CHa2), 1.24e1.20 (m, 1H, CHb2), 1.12 (s, 2H, 0.22t-Bu), 0.94 (s,
7H, 0.78t-Bu), 0.71e0.42 (m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d
¼170.7, 170.3, 167.6, 163.9, 162.3, 147.8, 140.1, 132.7, 130.6, 130.2,
128.7, 128.3, 128.2, 128.0, 125.9, 124.6, 124.3, 115.6, 115.5, 64.7, 59.6,
55.5, 51.4, 28.5, 27.9, 27.3, 10.7. MS: m/z (%)¼471 (1) [M] þ, 371 (53),
343 (3), 309 (7), 247 (4), 232 (8), 218 (8), 193 (3), 165 (2), 123 (100).
Elemental Anal. Calcd for C29H30FN3O2: C, 73.86; H, 6.41; N, 8.91.
Found: C, 73.57; H, 6.33; N, 9.16.
600 MHz):
d
¼8.12e7.11 (m, 13H, AreH), 6.22e6.13 (m, 1H, NH), 5.13
(s, 1H, CH), 5.06 (s, 0.2H, 0.2CH), 4.84 (s, 0.8H, 0.8CH), 2.40 (s, 3H,
CH3), 1.65e0.38 (m, 14H, CH2CH3 and t-Bu). 13C NMR (CDCl3,
150 MHz):
d
¼171.8, 170.0, 167.8, 148.2, 147.8, 140.1, 139.4, 133.6,
133.2, 130.3, 129.2, 129.1, 128.2, 128.0, 126.4, 125.8, 124.7, 64.8, 55.4,
51.4, 28.0, 24.7, 21.3, 10.8. MS: m/z (%)¼367 (13, MþꢀCONHBu-t),
232 (3), 120 (9), 119 (100). Elemental Anal. Calcd for C30H33N3O2: C,
77.06; H, 7.11; N, 8.99. Found: C, 77.21; H, 7.12; N, 9.22.
4.3.6. N-(tert-Butyl)-4-(2-chlorobenzoyl)-3-ethyl-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12f). Operation as
above with 2-chlorobenzoic acid 3 (R3¼2-ClC6H4, 0.31 g, 2 mmol)
and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12f (0.70 g,
72%) was isolated as light yellow solid. Mp 176e177 ꢁC. 1H NMR
4.3.2. N-(tert-Butyl)-4-(4-chlorobenzoyl)-3-ethyl-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12b). Operation as
above with 4-chlorobenzoic acid 3 (R3¼4-ClC6H4, 0.31 g, 2 mmol)
and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12b (0.66 g,
68%) was isolated as light yellow solid. Mp 172e173 ꢁC. 1H NMR
(CDCl3, 600 MHz):
d
¼8.23e7.06 (m, 13H, AreH), 6.22e6.13 (m, 1H,
NH), 5.15e4.74 (m, 2H, 2CH), 1.73e1.69 (m, 1H, CHa2), 1.30e0.92 (m,
10H, CHb2 and t-Bu), 0.72e0.33 (m, 3H, CH3). 13C NMR (CDCl3,
150 MHz):
d
¼169.9, 167.8, 167.1, 147.8, 140.0, 135.6, 131.3, 131.1,
130.4, 130.3, 130.1, 129.5, 129.3, 129.0, 128.2, 128.1, 128.0, 127.7,
126.8, 125.7, 124.2, 64.4, 55.5, 55.2, 51.3, 27.9, 24.3, 24.2, 11.2, 10.7.
MS: m/z (%)¼387 (17, MþꢀCONHBu-t), 232 (6), 193 (2), 165 (5), 141
(33), 139 (100). Elemental Anal. Calcd for C29H30ClN3O2: C, 71.37; H,
6.20; N, 8.61. Found: C, 71.53; H, 6.23; N, 8.44.
(CDCl3, 600 MHz):
d
¼7.96e7.24 (m, 13H, AreH), 5.85 (s, 1H, NH),
5.00 (s, 1H, CH), 4.95e4.92 (m, 1H, CH), 1.66e1.61 (m, 1H, CHa2), 1.39
(s, 8H, 0.88t-Bu), 1.16 (s, 1H, 0.12t-Bu), 0.86e0.84 (m, 1H, CHb2), 0.60
(t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
¼172.4, 167.8,
d
167.7, 149.3, 137.9, 136.6, 133.7, 131.0, 129.4, 128.8, 128.7, 128.6,
128.4, 127.3, 127.2, 126.2, 125.0, 124.0, 61.3, 60.0, 51.7, 29.0, 28.4,
27.9, 24.2, 11.0. MS: m/z (%)¼387 (14, MþꢀCONHBu-t), 232 (6), 207
(3), 193 (6), 165 (8), 139 (100). Elemental Anal. Calcd for
4.3.7. N-(tert-Butyl)-3-ethyl-4-(2-fluorobenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12g). Operation as
above with 2-fluorobenzoic acid 3 (R3¼2-FC6H4, 0.28 g, 2 mmol)
and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12g (1.03 g,
73%) was isolated as light yellow solid. Mp 178e179 ꢁC. 1H NMR
C
29H30ClN3O2: C, 71.37; H, 6.20; N, 8.61. Found: C, 71.32; H, 6.12; N,
8.87.
(CDCl3, 600 MHz):
d
¼7.47e7.06 (m, 11H, AreH), 6.84 (t, J¼7.2 Hz,
4.3.3. N-(tert-Butyl)-3-ethyl-4-(2-methylbenzoyl)-2-phenyl-4,5-
1H, AreH), 6.71 (d, J¼8.4 Hz, 1H, AreH), 6.62 (s, 1H, NH), 5.80e5.58
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12c). Operation as
(m, 2H, 2CH), 2.14e1.81 (m, 2H, CH2), 1.28 (s, 9H, t-Bu), 1.05e0.44
above with 2-methylbenzoic acid
3
(R3¼2-CH3C6H4, 0.27 g,
(m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d¼166.9, 166.3, 159.9,
2 mmol) and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12c
158.3, 140.9, 138.0, 134.9, 131.3, 131.2, 129.2, 128.9, 128.7, 125.7,
125.6, 123.5, 122.5, 119.4, 118.3, 116.7, 115.8, 115.6, 65.9, 65.8, 51.3,
28.8, 28.3, 11.4. MS: m/z (%)¼371 (65, MþꢀCONHBu-t), 343 (7), 232
(9), 193 (2), 165 (2), 123 (100). Elemental Anal. Calcd for
(0.68 g, 73%) was isolated as light yellow solid. Mp 173e174 ꢁC. 1H
NMR (CDCl3, 600 MHz):
d
¼8.11e7.04 (m, 13H, AreH), 6.16e6.12 (m,
1H, NH), 5.16e4.76 (m, 2H, 2CH), 2.55 (s, 1H, 0.33CH3), 2.30 (s, 2H,
0.67CH3), 1.78e0.36 (m, 14H, CH2CH3 and t-Bu). 13C NMR (CDCl3,
C29H30FN3O2: C, 73.86; H, 6.41; N, 8.91. Found: C, 73.94; H, 6.18; N,
150 MHz):
d
¼170.5, 169.6, 167.1, 147.6, 140.0, 136.0, 133.1, 130.4,
8.73.
130.2, 129.7, 128.7, 128.1, 128.0, 127.7, 126.4, 126.3, 125.8, 125.6,
124.6, 64.3, 55.3, 51.2, 27.9, 24.3, 18.7, 10.7. MS: m/z (%)¼367 (11,
MþꢀCONHBu-t), 247 (2), 232 (2), 193 (1), 165 (3), 119 (100). Ele-
mental Anal. Calcd for C30H33N3O2: C, 77.06; H, 7.11; N, 8.99. Found:
C, 77.27; H, 7.32; N, 8.82.
4.3.8. N-(tert-Butyl)-3-ethyl-4-(4-methoxybenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12h). Operation as
above with 4-methoxybenzoic acid 3 (R3¼4-CH3OC6H4, 0.30 g,
2 mmol) and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12g
(0.75 g, 78%) was isolated as light yellow solid. Mp 168e169 ꢁC. 1H
4.3.4. 4-Benzoyl-N-(tert-butyl)-3-ethyl-2-phenyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (12d). Operation as above with
benzoic acid 3 (R3¼C6H5, 0.24 g, 2 mmol), compound 12d (0.59 g,
65%) was isolated as light yellow solid. Mp 225e226 ꢁC. 1H NMR
NMR (CDCl3, 600 MHz):
d
¼8.12e7.76 (m, 2H, AreH), 7.50e7.12 (m,
9H, AreH), 6.94 (d, J¼7.8 Hz, 2H), 6.21e6.13 (m, 1H, CH), 5.17 (s, 1H,
NH), 5.05 (s, 0.2H, 0.2CH), 4.84 (s, 0.8H, 0.8CH), 3.85 (s, 3H, OCH3),
1.98e1.26 (m, 2H, CH2), 1.10 (s, 2H, 0.22t-Bu), 0.93 (s, 7H, 0.78t-Bu),
(CDCl3, 600 MHz):
d
¼7.50e7.23 (m, 14H, AreH), 5.70 (s, 1H, NH),
0.70e0.41 (m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d¼171.6, 170.1,
5.04e5.01 (m, 2H, 2CH), 1.43 (s, 9H, t-Bu), 1.20e1.18 (m, 1H, CHa2),
167.9, 160.4, 147.8, 140.1, 130.5, 130.3, 130.2, 128.7, 128.3, 128.2,
128.0, 125.9, 124.7, 124.6, 113.8, 64.8, 55.4, 55.3, 51.4, 27.9, 24.7, 10.7.
0.93e0.86 (m, 1H, CHb2), 0.59 (t, J¼7.4 Hz, 3H, CH3). 13C NMR (CDCl3,

9060
Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
MS: m/z (%)¼383 (25, MþꢀCONHBu-t), 247 (4), 232 (3), 193 (1), 165
(1), 135 (100). Elemental Anal. Calcd for C30H33N3O3: C, 74.51; H,
6.88; N, 8.69. Found: C, 74.25; H, 6.94; N, 8.76.
for C29H31N3O2: C, 76.79; H, 6.89; N, 9.26. Found: C, 76.64; H, 6.93;
N, 9.47.
4.3.13. N-(tert-Butyl)-4-(cyclohexanecarbonyl)-3-ethyl-2-phenyl-
4 , 5 - d i h y d r o - 3 H - 1, 4 - b e n z o d i a z e p i n e - 5 - c a r b o x a m i d e
(12m). Operation as above with cyclohexanecarboxylic acid 3
4.3.9. 4-(4-Chlorobenzoyl)-N-cyclohexyl-3-ethyl-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12i). Operation as
above with 4-chlorobenzoic acid 3 (R3¼4-ClC6H4, 0.31 g, 2 mmol)
and isocyanocyclohexane 4 (R4¼c-C6H11, 0.22 g, 2 mmol), com-
pound 12i (0.72 g, 70%) was isolated as light yellow solid.
(R3¼c-C6H11, 0.26 g, 2 mmol),
a-alkyl a-amino ketone hydrochlo-
rides 1 (R1¼C6H5, R2¼Et, 0.40 g, 2 mmol) and isocyanide 4 (R4¼t-
Bu, 0.17 g, 2 mmol), compound 12m (0.74 g, 81%) was isolated as
light yellow solid. Mp 163e164 ꢁC. 1H NMR (CDCl3, 600 MHz):
Mp 223e224 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
¼8.06e7.67 (m, 2H,
AreH), 7.49e7.12 (m,11H, AreH), 6.20e6.10 (m,1H, NH), 5.06 (s,1H,
CH), 4.92e4.76 (m, 1H, CH), 3.58e3.35 (m, 1H, NCH), 1.74e0.45 (m,
d
¼8.06e7.94 (m, 2H, AreH), 7.49e7.23 (m, 7H, AreH), 6.12e6.04
(m, 1H, NH), 5.28e5.18 (m, 2H, 2CH), 2.60e2.51 (m, 1H, NCH),
2.01e0.95 (m, 21H, CH2, (CH2)5 and t-Bu), 0.71e0.59 (m, 3H, CH3).
15H, CH2CH3 and (CH2)5). 13C NMR (CDCl3, 150 MHz):
d
¼170.7,
170.5, 167.5, 148.0, 140.1, 135.4, 135.1, 130.7, 130.2, 128.8, 128.4,
128.2, 128.1, 127.8, 127.4, 125.9, 124.7, 124.0, 64.2, 55.5, 48.8, 32.2,
24.8, 24.6, 24.3, 10.3. MS: m/z (%)¼513 (2, Mþ), 387 (85), 359 (5),
249 (2), 248 (3), 232 (7), 193 (3), 165 (3), 139 (100). Elemental Anal.
Calcd for C31H32ClN3O2: C, 72.43; H, 6.27; N, 8.17. Found: C, 72.14; H,
6.47; N, 8.03.
13C NMR (CDCl3, 150 MHz):
d¼175.8, 169.2, 167.8, 148.2, 139.6, 131.0,
130.3, 130.2, 128.5, 128.3, 127.9, 127.6, 126.0, 125.8, 124.9, 124.5,
63.5, 53.8, 51.5, 41.1, 28.8, 27.8, 27.5, 26.0, 24.1, 10.8. MS: m/z (%)¼
359 (24, MþꢀCONHBu-t), 331 (5), 249 (100), 247 (3). Elemental
Anal. Calcd for C29H37N3O2: C, 75.78; H, 8.11; N, 9.14. Found: C,
75.81; H, 7.93; N, 9.33.
4.3.10. 4-Benzoyl-N-cyclohexyl-3-ethyl-2-phenyl-4,5-dihydro-3H-
1,4-benzodiazepine-5-carboxamide (12j). Operation as above with
benzoic acid 3 (R3¼C6H5, 0.22 g, 2 mmol) and isocyanocyclohexane
4 (R4¼c-C6H11, 0.22 g, 2 mmol), compound 12j (0.74 g, 77%) was
isolated as light yellow solid. Mp 171e172 ꢁC. 1H NMR (CDCl3,
4.3.14. N-(tert-Butyl)-2-(4-chlorophenyl)-3-ethyl-4-(4-
methylbenzoyl)-4,5-dihydro-3H-1,4-benzodiazepine-5-carboxamide
(12n). Operation as above with 4-methylbenzoic acid 3 (R3¼4-
CH3C6H4, 0.27 g, 2 mmol), a-alkyl a-amino ketone hydrochlorides
1 (R1¼4-ClC6H5, R2¼Et, 0.40 g, 2 mmol) and isocyanide 4 (R4¼t-Bu,
0.17 g, 2 mmol), compound 12n (0.65 g, 65%) was isolated as light
yellow solid. Mp 202e203 ꢁC. 1H NMR (CDCl3, 600 MHz):
600 MHz):
d
¼7.48e7.20 (m, 14H, AreH), 6.06 (s, 1H, NH), 5.16 (s,1H,
CH), 5.03 (s, 1H, CH), 3.91e3.87 (m, 1H, NCH), 1.98e1.92 (m, 2H,
CH2), 1.66e1.09 (m, 10H, (CH2)5), 0.87e0.59 (m, 3H, CH3). 13C NMR
d
¼8.08e7.70 (m, 2H, AreH), 7.49e7.12 (m, 10H, AreH), 6.21e6.08
(CDCl3, 150 MHz):
d
¼173.3, 167.9, 167.6, 149.1, 137.9, 135.2, 130.8,
(m, 1H, NH), 5.12e5.03 (m, 1H, CH), 4.99e4.75 (m, 1H, CH), 2.39 (s,
3H, CH3), 1.64e1.60 (m, 1H, CH2a), 1.31e1.12 (m, 1H, CHb2), 1.10 (s, 2H,
0.22t-Bu), 0.94 (s, 7H, 0.78t-Bu), 0.68 (t, J¼7.2 Hz, 2.5H, 0.83CH3),
0.37 (t, J¼7.2 Hz, 0.5H, 0.17CH3). 13C NMR (CDCl3, 150 MHz):
130.4, 129.4, 129.1, 128.3, 127.2, 127.1, 126.6, 125.9, 125.0, 124.3, 61.2,
59.7, 48.7, 47.9, 32.6, 25.0, 11.4, 10.4. MS: m/z (%)¼479 (1, Mþ), 353
(76), 325 (5), 247 (2), 232 (6), 193 (2), 165 (2), 105 (100). Elemental
Anal. Calcd for C31H33N3O2: C, 77.63; H, 6.94; N, 8.76. Found: C,
77.69; H, 7.13; N, 8.64.
d
¼171.7, 169.2, 167.7, 147.5, 139.4, 138.6, 136.5, 133.5, 130.4, 130.1,
129.3, 129.0, 128.3, 128.2, 126.4, 126.0, 124.6, 64.5, 55.3, 51.3, 28.5,
28.0, 27.9, 24.6, 21.3, 10.7. MS: m/z (%)¼401 (24, MþꢀCONHBu-t),
373 (3), 266 (3), 227 (2), 119 (100), 91 (16). Elemental Anal. Calcd for
4.3.11. N-Cyclohexyl-3-ethyl-4-(4-fluorobenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12k). Operation as
above with 4-fluorobenzoic acid 3 (R3¼4-FC6H4, 0.28 g, 2 mmol),
and isocyanocyclohexane 4 (R4¼c-C6H11, 0.22 g, 2 mmol), com-
pound 12k (0.70 g, 71%) was isolated as light yellow solid.
C30H32ClN3O2: C, 71.77; H, 6.42; N, 8.37. Found: C, 71.73; H, 6.35; N,
8.61.
4.3.15. N-(tert-Butyl)-2-(4-chlorophenyl)-3-ethyl-4-(4-
methoxybenzoyl)-4,5-dihydro-3H-1,4-benzodiazepine-5-
carboxamide (12o). Operation as above with 4-methoxybenzoic
Mp 223e224 ꢁC. 1H NMR (CDCl3, 600 MHz):
AreH), 7.55e7.13 (m, 11H, AreH), 6.21e6.12 (m, 1H, NH), 5.10 (s,
1H, CH), 4.94e4.78 (m, 1H, CH), 3.59e3.36 (m, 1H, NCH),
1.82e0.44 (m, 15H, CH2CH3 and (CH2)5). 13C NMR (CDCl3,
d
¼8.07e7.65 (m, 2H,
acid 3 (R3¼4-CH3OC6H4, 0.30 g, 2 mmol),
a-alkyl a-amino ketone
hydrochlorides 1 (R1¼4-ClC6H5, R2¼Et, 0.40 g, 2 mmol) and iso-
cyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), compound 12o (0.78 g, 76%)
was isolated as yellow solid. Mp 180e181 ꢁC. 1H NMR (CDCl3,
150 MHz):
d
¼170.8, 170.5, 167.6, 164.0, 162.3, 148.0, 140.2, 132.7,
131.2, 130.7, 130.3, 128.8, 128.3, 128.0, 127.4, 126.3, 126.0, 124.7,
124.1, 115.7, 115.6, 64.4, 59.3, 55.6, 48.8, 32.0, 25.2, 24.8, 24.4,
24.2, 10.7. MS: m/z (%)¼497 (2, Mþ), 371 (63), 353 (3), 343 (5), 247
(3), 232 (8), 218 (4), 123 (100). Elemental Anal. Calcd for
600 MHz):
d
¼8.07e7.70 (m, 2H, AreH), 7.49e7.13 (m, 8H, AreH),
6.94 (d, J¼7.8 Hz, 2H, AreH), 6.20e6.07 (m, 1H, NH), 5.16e5.08 (m,
1H, CH), 4.97 (s, 0.2H, 0.2CH), 4.75 (s, 0.8H, 0.8CH), 3.85 (s, 3H,
OCH3), 1.62e1.60 (m, 1H, CH2a), 1.28e1.27 (m, 1H, CHb2), 1.10 (s, 2H,
0.22t-Bu), 0.94 (s, 7H, 0.78t-Bu), 0.67e0.39 (m, 3H, CH3). 13C NMR
C
31H32FN3O2: C, 74.83; H, 6.48; N, 8.44. Found: C, 74.74; H, 6.33;
N, 8.62.
(CDCl3, 150 MHz):
d
¼171.6, 169.3, 167.9, 160.4, 147.6, 138.7, 136.6,
4.3.12. N-(tert-Butyl)-3-methyl-4-(4-methylbenzoyl)-2-phenyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12l). Operation as
130.5, 130.2, 129.5, 129.4, 128.6, 128.3, 126.1, 126.0, 124.6, 124.5,
113.7, 64.8, 64.6, 55.2, 51.4, 28.0, 24.6, 10.7. MS: m/z (%)¼517 (2, Mþ),
417 (11), 282 (5), 266 (2), 227 (3), 135 (100). Elemental Anal. Calcd
for C30H32ClN3O3: C, 69.55; H, 6.23; N, 8.11. Found: C, 69.74; H, 6.28;
N, 8.23.
above with 4-methylbenzoic acid
3
(R3¼4-CH3C6H4, 0.27 g,
2 mmol),
a
-alkyl
a
-amino ketone hydrochlorides 1 (R1¼C6H5,
R2¼Me, 0.37 g, 2 mmol) and isocyanide 4 (R4¼t-Bu, 0.17 g,
2 mmol), compound 12l (0.59 g, 65%) was isolated as light yellow
solid. Mp 173e174 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
¼8.07e7.77 (m,
4.3.16. N-(tert-Butyl)-3-butyl-4-(4-chlorobenzoyl)-2-(4-
chlorophenyl)-4,5-dihydro-3H-1,4-benzodiazepine-5-carboxamide
(12p). Operation as above with 4-chlorobenzoic acid 3 (R3¼4-
2H, AreH), 7.49e7.08 (m, 11H, AreH), 6.24e6.20 (m, 1H, NH),
5.28e5.12 (m, 1H, CH), 5.03e4.84 (m, 1H, CH), 2.40 (s, 3H, CH3),
1.08e0.83 (m, 12H, CH3 and t-Bu). 13C NMR (CDCl3, 150 MHz):
ClC6H4, 0.31 g, 2 mmol), a-alkyl a-amino ketone hydrochlorides
d
¼171.2, 170.7, 167.7, 147.5, 139.5, 139.0, 133.5, 130.6, 130.2, 129.3,
1 (R1¼4-ClC6H5, R2¼Et, 0.40 g, 2 mmol) and isocyanide 4 (R4¼t-
Bu, 0.17 g, 2 mmol), compound 12p (0.82 g, 75%) was isolated
as yellow solid. Mp 146e147 ꢁC. 1H NMR (CDCl3, 600 MHz):
129.1, 128.2, 128.0, 126.5, 126.4, 125.9, 125.1, 64.9, 64.6, 51.5, 50.8,
50.4, 28.4, 28.0, 21.3. MS: m/z (%)¼453 (4, Mþ), 353 (34), 261 (3),
234 (9), 218 (10), 194 (5), 165 (4), 119 (100). Elemental Anal. Calcd
d
¼8.03 (t, J¼8.4 Hz, 2H, AreH), 7.65e7.10 (m, 10H, AreH),

Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
9061
6.17e6.11 (m, 1H, NH), 4.97 (s, 1H, CH), 4.69 (s, 1H, CH), 1.52e1.26
(m, 2H, CH2), 1.17e0.86 (m, 13H, CH2CH2 and t-Bu), 0.67e0.53
117.8, 62.1, 58.3, 51.2, 28.2, 22.4, 19.7, 18.9, 18.8, 10.3. IR (KBr): 3272,
2968, 2131, 1695, 1678, 1617 cmꢀ1. Elemental Anal. Calcd for
C30H33N5O3: C, 70.43; H, 6.50; N, 13.69. Found: C, 70.47; H, 6.36; N,
(m, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d
¼170.6, 169.5,
167.5, 147.8, 138.4, 136.8, 135.4, 135.0, 130.6, 129.5, 128.8, 128.7,
128.5, 128.4, 128.1, 126.1, 124.3, 64.5, 53.9, 51.5, 28.4, 28.1, 27.9,
22.2, 13.6. MS: m/z (%)¼449 (26, MþꢀCONHBu-t), 392 (3), 308
(2), 267 (3), 141 (27), 139 (100). Elemental Anal. Calcd for
13.93.
4.4.2. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-2-
fluoro-N-(1-oxo-1-phenylbutan-2-yl)benzamide (10g). Operation as
above with 2-fluorobenzoic acid 3 (R3¼2-FC6H4, 0.28 g, 2 mmol),
compound 10g (0.80 g, 78%) was isolated as white solid.
C
31H33Cl2N3O2: C, 67.63; H, 6.04; N, 7.63. Found: C, 67.72; H, 6.21;
N, 7.89.
Mp 188e189 ꢁC. 1H NMR (CDCl3, 600 MHz):
d
¼7.79e7.12 (m, 12H,
4.3.17. 3-Benzyl-N-(tert-butyl)-4-(4-chlorobenzoyl)-2-methyl-4,5-
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12q). Operation as
above with 4-chlorobenzoic acid 3 (R3¼4-ClC6H4, 0.31 g, 2 mmol),
AreH), 6.74 (t, J¼7.2 Hz, 1H, AreH), 5.24 (s, 1H, NCH), 5.22e5.00
(m, 2H, NH and NCH), 2.56e2.34 (m, 1H, CHa2), 2.14e2.07 (m,
1H, CHb2), 1.38 (s, 2H, 3CH3), 1.26 (s, 7H, 3CH3), 1.10e1.08 (m, 1H,
CH3), 0.87 (t, J¼6.6 Hz, 2H, CH3). 13C NMR (CDCl3, 150 MHz):
a
-alkyl
a
-amino ketone hydrochlorides 1 (R1¼CH3, R2¼PhCH2,
0.40 g, 2 mmol) and isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol), com-
d
¼195.6, 167.6, 166.6, 138.2, 135.7, 133.1, 133.0, 131.6, 129.3,
pound 12q (0.76 g, 78%) was isolated as yellow solid.
129.2, 128.2, 128.0, 127.8, 127.6, 127.4, 126.2, 124.9, 124.3, 123.9,
117.4, 116.2, 62.3, 58.7, 51.2, 28.3, 22.9, 22.8, 22.7, 10.7. IR (KBr):
Mp 214e215 ꢁC. 1H NMR (CDCl3, 400 MHz):
d
¼7.55e6.45 (m, 13H,
AreH), 6.20e5.42 (m, 1H, NH), 4.92e4.54 (m, 2H, 2CH), 2.92e2.08
2099, 1710, 1679, 1637 cmꢀ1
.
Elemental Anal. Calcd for
29H30FN5O3: C, 67.56; H, 5.86; N, 13.58. Found: C, 67.44; H, 5.63;
N, 13.59.
(m, 2H, CH2), 1.85e1.82 (m, 3H, CH3), 1.22e1.16 (m, 9H, t-Bu). 13C
C
NMR (CDCl3, 100 MHz):
d
¼173.8, 170.0, 167.9, 147.5, 136.7, 135.5,
134.9, 130.9, 130.2, 129.0, 128.9, 1284, 126.7, 126.0, 125.1, 124.5, 64.6,
59.8, 51.7, 36.2, 30.9, 28.2. MS: m/z (%)¼487 (1, Mþ), 387 (53), 184
(11), 141 (27), 140 (8), 139 (100). Elemental Anal. Calcd for
4.4.3. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-4-
methyl-N-(1-oxo-1-phenylpropan-2-yl)benzamide (10l). Operation
as above with 4-methylbenzoic acid 3 (R3¼4-CH3C6H4, 0.27 g,
C
29H30ClN3O2: C, 71.37; H, 6.20; N, 8.61. Found: C, 71.46; H, 6.21; N,
8.73.
2 mmol) and
a
-alkyl
a
-amino ketone hydrochlorides 1 (R1¼C6H5,
R2¼Me, 0.37 g, 2 mmol), compound 10l (0.67 g, 67%) was isolated as
4.3.18. 3-Benzyl-N-(tert-butyl)-2-methyl-4-(4-methylbenzoyl)-4,5-
white solid. Mp 181e183 ꢁC. 1H NMR (CDCl3, 600 MHz):
dihydro-3H-1,4-benzodiazepine-5-carboxamide (12r). Operation as
d
¼8.67e7.13 (m,13H, AreH), 6.02e4.21 (m, 3H, 2NCH and NH), 2.39
above with 4-chlorobenzoic acid
3
(R3¼4-CH3C6H4, 0.27 g,
(s, 3H, CH3), 1.51e0.84 (m, 12H, 4CH3). 13C NMR (CDCl3, 150 MHz):
2 mmol),
a
-alkyl
a
-amino ketone hydrochlorides 1 (R1¼CH3,
d
¼170.5, 167.6, 163.9, 162.3, 148.0, 140.1, 132.7, 130.7, 130.3, 128.8,
R2¼PhCH2, 0.40 g, 2 mmol) and isocyanide 4 (R4¼t-Bu, 0.17 g,
128.3, 127.9, 127.4, 126.0, 124.7, 124.1, 115.6, 64.4, 55.6, 48.8, 32.0,
25.2, 24.8, 24.2, 10.7. IR (KBr): 2091, 1630, 1562 cmꢀ1. Elemental
Anal. Calcd for C29H31N5O3: C, 70.00; H, 6.28; N, 14.07. Found: C,
70.21; H, 6.02; N, 14.04.
2 mmol), compound 12r (0.74 g, 79%) was isolated as yellow
solid. Mp 209e210 ꢁC. 1H NMR (CDCl3, 400 MHz):
d
¼7.53e6.40
(m, 13H, AreH), 6.24e5.44 (m, 1H, NH), 5.06e4.63 (m, 2H, 2CH),
2.98e2.09 (m, 5H, CH2 and CH3), 1.85e1.77 (m, 3H, CH3),
1.23e1.17 (m, 9H, t-Bu). 13C NMR (CDCl3, 100 MHz):
d
¼173.7,
5. Crystallographic material
171.0, 168.1, 147.5, 139.4, 136.9, 133.4, 130.6, 130.6, 130.1, 129.1,
129.0, 128.3, 126.6, 126.3, 126.0, 125.8, 125.4, 124.3, 64.5, 59.9,
51.5, 36.1, 30.9, 28.1, 21.3. MS: m/z (%)¼367 (37, MþꢀCONHBu-t),
247 (3), 233 (4), 207 (6), 184 (3), 129 (4), 119 (100). Elemental
Anal. Calcd for C31H33N3O2: C, 77.06; H, 7.11; N, 8.99. Found: C,
77.12; H, 7.36; N, 8.87.
Compound 5: formula C42H38N12O3, colourless crystal. The
ꢀ
crystal is of triclinic, space group Pꢀ1 with a¼9.1637 (16) A,
¼97.570 (3)ꢁ,
b
¼94.437 (3)ꢁ,
ꢀ
ꢀ
b¼14.864 (3) A, c¼14.891 (3) A,
a
3
ꢁ
ꢀ
g
¼100.613 (3) , V¼1965.4 (6) A, Z¼2, Dx¼1.282 g/cm , F(000)¼
796.28,
m
¼0.085 mmꢀ1, R¼0.0485 and wR¼0.1411 for 6831 ob-
served reflections with I>2s(I0).
4.4. Isolation of some azides 10
Compound 12a: formula C30H33N3O2, colourless crystal. The
ꢀ
crystal is of triclinic, space group Pꢀ1 with a¼10.323 (2) A,
¼105.404 (4)ꢁ,
b
¼102.235 (4)ꢁ,
ꢀ
ꢀ
4.4.1. N-(1-(2-Azidophenyl)-2-(tert-butylamino)-2-oxoethyl)-2-
methyl-N-(1-oxo-1-phenylbutan-2-yl)benzamide (10c). Finely pow-
dered 2-methylbenzoic acid 3 (R3¼2-CH3C6H4, 0.27 g, 2 mmol) was
added to a well-stirred solution of potassium hydroxide (0.11 g,
b¼12.260 (3) A, c¼12.331 (3) A,
a
3
ꢁ
ꢀ
g
¼110.466 (3) , V¼1326.9 (5) A, Z¼2, Dx¼1.170 g/cm , F(000)¼
500.0,
m
¼0.074 mmꢀ1, R¼0.0480 and wR¼0.1590 for 4889 observed
reflections with I>2s(I0).
2 mmol) in MeOH (10 mL),
a
-alkyl
a
-amino ketone hydrochlorides
Crystallographic datas for 5 and 12a have been deposited in the
Cambridge Crystallographic Data Center as supplementary publi-
cation numbers CCDC 939798, 939799. Copies of the data may be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: þ44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
1 (R1¼C6H5, R2¼Et, 0.33 g, 2 mmol) was added to the above sus-
pension at 5 ꢁC and stirring was continued for 10 min. The resulting
suspension was treated with 2-azidobenzaldehyde 2 (0.29 g,
2 mmol) and then with isocyanide 4 (R4¼t-Bu, 0.17 g, 2 mmol). The
reaction mixture was stirred at room temperature for 24 h, moni-
toring the reactions by thin-layer chromatography (TLC) until the
reactants disappeared. After removing the solvent under reduced
pressure, the residues were purified by column chromatography
(4:1, petroleum ether/diethyl ether) to give the azides 10c (0.81 g,
79%), which was analyzed by spectral method immediately. White
solid (yield 79%). Mp 134e136 ꢁC. 1H NMR (CDCl3, 600 MHz):
Acknowledgements
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (Nos. 21172085,
21032001).
d
¼7.53e6.81 (m, 13H, AreH), 5.38e5.14 (m, 2H, NH and NCH),
5.05e5.03 (m, 1H, NCH), 2.58e2.51 (m, 2H, CH2), 2.34e2.14 (m, 3H,
Supplementary data
CH3), 1.34e1.26 (m, 9H, 3CH3), 0.87e0.83 (m, 3H, CH3). 13C NMR
(CDCl3, 150 MHz):
133.1, 130.9, 129.5, 129.1, 128.3, 128.1, 127.6, 127.5, 127.1, 125.7, 124.9,
d
¼196.4, 172.1, 166.8, 138.5, 136.4, 135.4, 134.9,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.08.034.

9062
Y. Wang et al. / Tetrahedron 69 (2013) 9056e9062
S.; Parchinsky, V.; Bukhryakov, K. J. Org. Chem. 2009, 74, 2627; (e) Tour, B. B.;
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