Efficient multi-component synthesis of 1,4-benzodiazepine-3,5-diones: a Petasis-based approach

Article abstract of DOI:10.1016/j.tet.2015.06.060

Abstract A new design for the synthesis of 1,2-dihydro-4H-benzo[e][1,4]diazepine-3,5-diones based on Petasis reaction followed by intramolecular amidation in one-pot manner is reported. By employing different primary aromatic and aliphatic amines along with boronic acid derivatives, the desired products have been obtained at ambient temperature in moderate to good yields.

Full text of DOI:10.1016/j.tet.2015.06.060

Accepted Manuscript
Efficient multi-component synthesis of 1,4-benzodiazepine-3,5-diones: a Petasis-
based approach
Saeedeh Noushini, Mohammad Mahdavi, Loghman Firoozpour, Setareh Moghimi,
Abbas Shafiee, Alireza Foroumadi
PII:
S0040-4020(15)00957-6
10.1016/j.tet.2015.06.060
TET 26896
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 March 2015
Revised Date: 31 May 2015
Accepted Date: 16 June 2015
Please cite this article as: Noushini S, Mahdavi M, Firoozpour L, Moghimi S, Shafiee A, Foroumadi
A, Efficient multi-component synthesis of 1,4-benzodiazepine-3,5-diones: a Petasis-based approach,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.060.
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Efficient multi-component synthesis of 1,4-
benzodiazepine-3,5-diones: a Petasis-based
approach
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Saeedeh Noushinia, Mohammad Mahdavia, Loghman Firoozpourb, Setareh Moghimia, Abbas Shafieea, Alireza
Foroumadia,b*
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran, Iran
b Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Efficient multi-component synthesis of 1,4-benzodiazepine-3,5-diones: a Petasis-
based approach
Saeedeh Noushinia, Mohammad Mahdavia, Loghman Firoozpourb, Setareh Moghimia, Abbas Shafieea,
Alireza Foroumadia,b
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
b Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new design for the synthesis of 1,2-dihydro-4H-benzo[e][1,4]diazepine-3,5-diones based on
Petasis reaction followed by intramolecular amidation in one-pot manner is reported. By
employing different primary aromatic and aliphatic amines along with boronic acid derivatives,
the desired products have been obtained at ambient temperature in moderate to good yields.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Petasis reaction
Benzodiazepine-3,5-diones
Primary amines
Multi-component reaction
Molecular sieves
1. Introduction
reported to date regarding this point that every new inserted
structural unit to benzodiazepine core donates new bioactivities
to the molecule.
After the first report on multi-component reaction (MCR) by
Strecker,1 many efforts have been devoted to investigate new
types of this strategic pathway due to their importance in the
synthesis of complex molecules.2 A quick literature survey
enabled us to claim that the vast majority of MCRs were founded
by the reaction between amines and carbonyls. The enhanced
tendency of the third component to the resultant adducts (like
imines) compared to the parent carbonyl despite inherent
electrophilic character kept chemists enthusiasm fresh to create
effective compounds. Accordingly in 1993, the first application
of boronic acids with the key pair of amine and carbonyl in
multi-component reactions was reported by Petasis.3 The boronic
acid building block is mild, air-stable and non-toxic with
reluctant character towards the carbonyl moiety providing the
above mentioned factor.4 Therefore, Petasis reaction known as
the type ӀӀ MCR according to Dömling and Ugi’s classification,5
has emerged as a promising strategy for the construction of
structurally diverse molecules6-8 with biological activities.9
For
instance,
1,4-benzodiazepine-2,5-diones
showed
herbicidal12 properties whereas in the case of pyrrolo-[2,1-c][1,4]
benzodiazepine-5,11-diones additional antitumor, analgesic and
antiphage activities have been reported accompanied by the
primary herbicidal activity.13 Given the high level of activities,
1,4-benzodiazepine-3,5-dione analogues have received less
attention. To date, reported routes have been limited to the
intramolecular amide bond formation employing DCC
(dicyclohexylcarbodiimide) as
a
coupling reagent14 and
Et3N/ethyl chloroformate15 to promote the cyclization. Recently,
our group revealed an intermolecular cyclization of 2-
aminobenzamides by means of dichloro epoxide under the
Bargellini-type condition.16 Therefore, considering the possible
effects of structural variations on biological responses, we
decided to serve 1,4-benzodiazepine-3,5-diones as an interesting
goal to establish innovative synthetic pathway.
Seven-membered heterocyclic rings are amongst the most
appealing fragments owing to their prevalence in molecules with
biological activities. Benzodiazepines, a prominent substructure
in medicinal chemistry since the discovery of chlordiazepoxide
and diazepam in the late 1950s,10 represent a wide range of
2. Results and discussion
In light of our interest in the synthesis of nitrogen-containing
seven-membered rings17 and 2-amino benzamide chemistry,18
herein, we disclose the first multi-component synthesis of 1,2-
bioactivities.11 Various derivatives of benzodiazepines have been
———
Corresponding author. Tel.: +98-21-66954708; fax: +98-21-66461178; e-mail: aforoumadi@yahoo.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
dihydro-4H-benzo[e][1,4]diazepine-3,5-diones starting from
The role of activated molecular sieves in speeding up the
boronic acid derivatives 4a-c, glyoxalic acid 5 and 2-amino-N-
substituted benzamide derivatives 3a-f in the presence of
molecular sieves at ambient temperature (Scheme 1). Different
benzamide derivatives were prepared via the simple reaction
between isatoic anhydride 1 and various amines 2a-f in water at
room temperature.16
reaction was clearly observed by performing the reaction in the
absence of the drying agent (entry 8). The increased rate would
be attributed to the facile formation of imine upon removal of
water from the reaction medium which shifts the equilibrium to
the desired product.
With these results in hand, the scope of the reaction has been
explored for 2-amino-N-substituted benzamide derivatives
synthesized via different primary amines and phenylboronic
acids bearing electron-withdrawing or electron-donating
substituents. The reaction smoothly furnished 6a-h in 60-78%
yields by combining these reagents in three-component fashion.
However, utilizing electron-rich boronic acid led to the better
results compared to unsubstituted derivatives.
Table 2. Investigation of substrate scopea,b
Scheme 1. Synthesis of benzodiazepine-3,5-diones 6a-h.
First, solvent screening (Table 1) for a simple model reaction
between phenylboronic acid, 2-amino-N-phenylbenzamide and
glyoxalic acid revealed dichloromethane as the solvent of choice
and provided the product in 72% at room temperature (entry 6). It
is noteworthy that increasing the temperature to reflux
temperature resulted in reduced yield (entry 7).
Table 1. The optimization of the model reactiona
Entry
Solvent
Temperature Time (h)
Yieldb
(%)
1
2
3
4
5
6
7
8c
CH3CN
DMF
r.t.
36
36
36
36
36
36
48
48
43
39
26
41
14
72
29
35
r.t.
THF
r.t.
EtOH
r.t.
a
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
Reaction condition 3 (1 mmol), 4 (1.2 mmol), 5 (1 mmol) and molecular
sieves 4Å (200 mg) in 4 mL CH2Cl2. b Isolated yields.
r.t.
A mechanistic rationalization according to the previous studies
is depicted in Scheme 2.19,20 2-Aminobenzamide derivatives
formed in situ from isatoic anhydride and amine derivatives
undergo condensation with aldehyde component of glyoxalic acid
to generate imine intermediate 7. The reaction of boronic acid
with 7 leads to the formation of ate complex 8. Based on DFT
reflux
r.t.
a 3a (1.2 mmol), 4a (1 mmol) and 5 (1 mmol) and molecular sieves (200 mg)
in solvent (4 mL). b Isolated yield. c Without molecular sieves.

3
4.2.1.
2,4-diphenyl-1,2-dihydro-3H-benzo[e][1,4]diazepine-
calculation, the irreversible and rate-limiting transfer of boron
substituent occurs through five-membered transition state. Then,
intramolecular amidation affords 6a in 72% yield.
ACCEPTED MANUSCRIPT
3,5(4H)-dione (6a). (236 mg, 72%); white powder; mp: 117-119
°C; IR (KBr): 3309 (NH), 1685, 1635, 1246, 741, 679 cm–1; H
1
NMR (400 MHz, CDCl3): δ = 5.14 (s, 1H), 6.50 (d, J = 8.4 Hz,
1H), 6.71 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.23-7.25
(m, 1H), 7.32-7.40 (m, 4H), 7.52-7.56 (m, 3H), 7.58 (d, J = 8.0
Hz, 2H), 8.27 (dd, J = 8.0, 1.2 Hz, 1H), 8.57 (brs, 1H, NH); 13C
NMR (100 MHz, CDCl3): δ = 60.8, 113.0, 116.4, 120.7, 124.6,
127.3, 127.5, 128.0, 129.0, 132.7, 133.2, 133.3, 133.4, 133.5,
135.6, 167.8, 175.2; MS: m/z (%) = 328 (M+, 23), 251 (100), 174
(45), 146 (33), 104 (51), 77 (84); Anal. Calcd for C21H16N2O2: C,
76.81; H, 4.91; N, 8.53. Found: C, 76.85; H, 4.88; N, 8.54.
CONHPh
OH
N
O
O
O
PhB(OH)2
Ph
+
-H2O
N
OH
H
NH2
O
CONHPh
-
3a
5
+
N
H
O
4.2.2.
2-(4-methoxyphenyl)-4-phenyl-1,2-dihydro-3H-benzo
O
7
[e][1,4]diazepine-3,5(4H)-dione (6b). Yield (279 mg, 78%);
white powder; mp: 110-112 °C; IR (KBr): 3322 (NH), 1698,
1
1645, 856, 745, 687 cm–1; H NMR (500 MHz, DMSO-d6): δ =
OH
O
HO
Ph
3.70 (s, 3H), 5.04 (s, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.60 (t, J =
7.4 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H),
7.17 (t, J = 7.8 Hz, 1H), 7.33-7.37 (m, 4H), 7.66 (d, J = 7.8 Hz,
1H), 7.74 (d, J = 7.6 Hz, 2H), 8.62 (brs, 1H, NH); 13C NMR (125
MHz, DMSO-d6): δ = 55.1, 59.2, 112.4, 113.9, 114.7, 116.5,
120.6, 123.5, 128.2, 128.6, 129.1, 131.3, 132.4, 139.2, 147.1,
158.6, 168.0, 173.2; Anal. Calcd for C22H18N2O3: C, 73.73; H,
5.06; N, 7.82. Found: C, 73.73; H, 5.12; N, 7.81.
B
-
NH Ph
+
O
6a
N
H
O
CONHPh
Ph
OH
O
9
8
Scheme 2. Plausible pathway for the reaction.
4.2.3.
4-(4-methylbenzyl)-2-phenyl-1,2-dihydro-3H-benzo[e]
3. Conclusion
[1,4]diazepine-3,5(4H)-dione (6c). Yield (221 mg, 62%); white
powder; mp: 176-178 °C; IR (KBr): 3213 (NH), 1686, 1654
1306, 862, 764, 657 cm–1; 1H NMR (400 MHz, CDCl3): δ = 2.37
(s, 3H), 4.60 (d, J = 4.0 Hz, 2H), 5.16 (s, 1H), 6.34 (t, J = 5.2 Hz,
1H), 6.47 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 7.2 Hz, 1H), 7.17-7.21
(m, 3H), 7.25-7.27 (m, 2H), 7.33-7.40 (m, 3H), 7.56 (d, J = 7.4
Hz, 2H), 8.78 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3): δ =
21.1, 43.7, 60.6, 112.8, 116.0, 116.2, 127.3, 127.4, 128.0, 128.5,
129.0, 129.5, 132.9, 134.9, 136.9, 137.4, 147.4, 169.3, 175.0;
Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found:
C, 77.45; H, 5.69; N, 7.84.
In summary, our interest in the synthesis of medium-sized
heterocycles led us to discover an unprecedented approach to 1,4-
benzodiazepine-3,5-diones through Petasis reaction followed by
lactamization. Mild condition, simplicity, available reactants and
high yields are considered as the advantageous features of this
novel multi-component reaction. We are completely assured that
this work will inspire researchers seeking for new ways to unique
synthetic fragments.
4. Experimental section
4.1. General
4.2.4.
4-(4-chlorobenzyl)-2-phenyl-1,2-dihydro-3H-benzo[e]
[1,4]diazepine-3,5(4H)-dione (6d). Yield (244 mg, 65%); white
powder; mp: 190–191 °C; IR (KBr): 3319 (NH), 1687, 1631,
Commercially available reagents were used without further
purification. Melting points were measured with a Kofler hot
1
1391, 1235, 846 cm–1; H NMR (400 MHz, CDCl3): δ = 4.74 (d,
1
stage apparatus and are uncorrected. H and 13C NMR spectra
J = 5.6 Hz, 2H), 5.15 (s, 1H), 6.47 (d, J = 8.4 Hz, 1H), 6.58 (t, J
= 5.4 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H),
7.24-7.28 (m, 2H), 7.32-7.34 (m, 2H), 7.37-7.42 (m, 2H), 7.46-
7.49 (m, 1H), 7.54 (d, J = 6.8 Hz, 2H), 8.70 (brs, 1H, NH); 13C
NMR (100 MHz, CDCl3):δ = 41.8, 60.6, 112.9, 116.3, 127.2,
127.3, 127.4, 128.5, 129.0, 129.1, 129.6, 130.4, 133.0, 133.8,
135.5, 147.5, 167.5, 173.9; Anal. Calcd for C22H17ClN2O2: C,
70.12; H, 4.55; N, 7.43. Found: C, 70.13; H, 4.69; N, 7.34.
were recorded with a Bruker FT-400, 500, using TMS as an
internal standard. IR spectra were obtained with a Shimadzu 470
spectrophotometer (KBr disks). MS were recorded with an
Agilent Technology (HP) mass spectrometer operating at an
ionization potential of 70 eV. Elemental analysis was performed
with an Elementar Analysen system GmbH Vario ELCHNS
mode.
4.2.5.
4-(4-fluorobenzyl)-2-phenyl-1,2-dihydro-3H-benzo[e]
4.2. General procedure for the synthesis of 6a
[1,4]diazepine-3,5(4H)-dione (6e). Yield (216 mg, 60%); white
To a magnetically stirred solution of 2-amino-N-phenyl
benzamide (1 mmol), glyoxalic acid (50%, 1 mmol) and 4Å
molecular sieves (200 mg) in CH2Cl2 (4 mL) was added
phenylboronic acid (1.2 mmol). The mixture was stirred at room
temperature for 36 h, then the solvent was removed under
reduced pressure and the residue was purified by silica column
chromatography with gradient solvent system starting from ethyl
acetate to ethyl acetate/ethanol (5:1). The product was
recrystallized from petroleum ether/ethyl acetate (1:1) to afford
6a as a white powder.
powder; mp: 123-125 °C; IR (KBr): 3299 (NH), 1698, 1645,
1
1286, 1145, 764, 855 cm–1; H NMR (400 MHz, CDCl3): δ =
4.58 (s, 2H), 5.12 (s, 1H), 6.39 (m, 1H), 6.46 (d, J = 8.0 Hz, 1H),
6.62 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 8.6 Hz, 2H), 7.20 (t, J = 7.4
Hz, 1H), 7.30-7.36 (m, 5H), 7.54 (d, J = 7.2 Hz, 2H), 8.73 (brs, 1
H, NH); 13C NMR (100 MHz, CDCl3): δ = 43.1, 60.8, 112.9,
115.5, 121.9, 124.2, 125.2, 126.0, 127.3, 128.4, 128.9, 129.5 (d,
JC-F = 8.1 Hz), 131.1, 133.0, 147.7, 159.4 (d, JC-F = 202.2 Hz),
169.8, 171.3; Anal. Calcd for C22H17FN2O2: C, 73.32; H, 4.75; N,
7.77. Found: C, 73.28; H, 4.83; N, 7.76.

4
Tetrahedron
ACCEPTED MANUSCRIPT
6. (a) Morin, M.S.T.; Lu, Y.; Black, D.A.; Arndtsen, B.A. J. Org.
4.2.6. 4-(4-fluorobenzyl)-2-(4-methoxyphenyl)-1,2-dihydro-3H-
Chem. 2012, 77, 2013-2017; (b) Shi, X.; Hebrault, D.; Humora,
M.; Kiesman, W.F.; Peng, H.; Talreja, T.; Wang, Z.; Xin, Z. J.
Org. Chem. 2012, 77, 1154-1160.
benzo[e][1,4]diazepine-3,5(4H)-dione (6f). Yield (265 mg,
68%); white powder; mp: 103-105 °C; IR (KBr): 3359 (NH),
1678, 1665, 1281, 1009, 859 cm–1; H NMR (500 MHz, DMSO-
1
7. For examples in the synthesis of heterocycles: (a) Neogi, S.; Roy,
A.; Naskar, D. J. Comb. Chem. 2010, 12, 617-629; (b) Wang, Y.;
Saha, B.; Li, F.; Frett, B.; Li, H. Tetrahedron Lett. 2014, 55, 1281-
1284; (c) Ayaz, M.; Dietrich, J.; Hulme, C. Tetrahedron Lett.
2011, 52, 4821-4823.
8. For examples of asymmetric Petasis reaction: (a) Yamaoka, Y.;
Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686-
6687; (b) Li, Y.; Xu, M.-H. Org. Lett. 2012, 14, 2062-2065.
9. Sugiyama, S.; Arai, S.; Kiriyama, M.; Ishii, K. Chem. Pharm.
Bull. 2005, 53, 100-102.
d6): δ = 3.67 (s, 3H), 4.44 (s, 2H), 5.09 (s, 1H), 6.33-6.45 (m,
2H), 6.80 (m, 2H), 7.05-7.15 (m, 3H), 7.33-7.37 (m, 2H), 7.56 (s,
1H), 8.27-8.33 (m, 2H), 8.47 (brs, 1H, NH); 13C NMR (125 MHz,
DMSO-d6): δ = 41.6, 55.0, 60.5, 112.4, 113.4, 113.8, 114.9,
115.1, 115.3, 128.1 (d, JC-F = 25.3 Hz), 129.1 (d, JC-F = 7.2 Hz),
132.0, 132.8, 136.3, 147.6, 158.2 (d, JC-F = 246.9 Hz), 162.1,
168.9, 174.5; Anal. Calcd for C23H19FN2O3: C, 70.76; H, 4.91; N,
7.18. Found: C, 70.73; H, 4.87; N, 7.20.
10. Sternbach, L.H. J. Med. Chem. 1979, 22, 1-7.
11. (a) Schimer, J.; Cigler, P.; Vesely, J.; Saskova, K.G.; Lepsik, M.;
Brynda, J.; Rezacova, P.; Kozisek, M.; Cisarova, I.; Oberwinkler,
H.; Kraeusslich, H.G.; Konvalinka, J. J. Med. Chem. 2012, 55,
10130-101-35; (b) Anzini, M.; Valenti, S.; Braile, C.; Cappelli, A.;
Vomero, S.; Alcaro, S.; Ortuso, F.; Marinelli, L.; Limongelli, V.;
Novellino, E.; Betti, L.; Giannaccini, G.; Lucacchini, A.; Daniiele,
S.; Martini, C.; Ghelardini, C.; Mannelli, L.D.C.; Giorgi, G.;
Mascia, M.P.; Biggio, G. J. Med. Chem. 2011, 54, 5694-5711.
12. (a) Boojamra, C.G.; Burow, K.M.; Thompson, L.A.; Ellman, J.A.
J. Org. Chem. 1997, 62, 1240-1256; (b) Horton, D.A.; Bourne,
G.T.; Smythe, M.L. Chem. Rev. 2003, 103, 893-930
13. (a) Kamal, A.; Reddy, G.S.K.; Reddy, K.L. Tetrahedron Lett.
2001, 42, 6969-6971; (b) Boojamra, C.G.; Burow, K.M.; Ellman,
J.A. J. Org. Chem. 1995, 60, 5742-5743.
14. (a) Stavropoulos, G.; Theodoropoulos, D. J. Het. Chem. 1977, 14,
1139-1143; (b) Osman, A.N.; El-Gendy, A.A.; Omar, R.H.;
Wagdy, L.; Omar, A.H. Boll. Chim. Farm. 2002, 141, 8-14.
15. Wiklund, P.; Rogers-Evans, M.; Bergman, J. J. Org. Chem. 2004,
69, 6371-6376.
16. Mahdavi, M.; Asadi, M.; Saeedi, M.; Rezaei, Z.; Moghbel, H.;
Foroumadi, A.; Shafiee, A. Synlett 2012, 23, 2521-2525.
17. (a) Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee, A.
Tetrahedron 2013, 69, 3506-3510; (b) Rasouli, M.A.; Mahdavi,
M.; Ranjbar, P.R.; Saeedi, M.; Shafiee, A.; Foroumadi, A.
Tetrahedron Lett. 2012, 53, 7088-7092; (c) Mahdavi, M.;
Foroughi, N.; Saeedi, M.; Karimi, M.; Alinezhad, H.; Foroumadi,
A.; Shafiee, A.; Akbarzadeh, T. Synlett 2014, 25, 385-388.
18. (a) Shafii, B., Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee,
A. Synth. Commun. 2014, 44, 215-221; (b) Farzipour, S.; Saeedi,
M.; Mahdavi, M.; Yavari, H.; Mirzahekmati, M.; Ghaemi, N.;
Foroumadi, A.; Shafiee, A. Synth. Commun. 2014, 44, 481-487;
(c) Mahdavi, M.; Asadi, M.; Saeedi, M.; Tehrani, M.H.; Mirfazli,
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2392.
4.2.7.
4-(3,4-dimethoxyphenethyl)-2-phenyl-1,2-dihydro-3H-
benzo[e][1,4]diazepine-3,5(4H)-dione (6g). Yield (287 mg,
69%); white powder; mp: 144–146 °C; IR (KBr): 3389 (NH),
1672 1632, 1278, cm–1; H NMR (400 MHz, CDCl3): δ = 2.88
1
(t, J = 6.8 Hz, 2H), 3.71 (dd, J = 12.8, 6.4 Hz, 2H), 3.85 (s, 3H),
3.88 (s, 3H), 5.15 (s, 1H), 6.16 (t, J = 5.4 Hz, 1H), 6.44 (d, J =
8.4 Hz, 1H), 6.58 (t, J = 7.2 Hz, 1H), 6.77-6.85 (m, 2H), 7.15-
7.21 (m, 2H), 7.32-7.39 (m, 3H), 7.55 (d, J = 6.8 Hz, 2H), 8.73
(brs, 1H, NH); 13C NMR (100 MHz, CDCl3): δ = 35.1, 41.0, 55.8,
55.9, 60.6, 111.4, 111.9, 112.8, 115.9, 116.1, 120.7, 127.2, 127.3,
128.4, 129.0, 131.4, 132.8, 137.0, 147.3, 147.7, 149.1, 169.6,
174.6; Anal. Calcd for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73.
Found: C, 72.13; H, 5.82; N, 6.87.
4.2.8.
4-butyl-2-(4-fluorophenyl)-1,2-dihydro-3H-benzo[e]
[1,4]diazepine-3,5(4H)-dione (6h). (202 mg, 62%); white
powder; mp: 151–152 °C; IR (KBr): 3201 (NH), 1671, 1634,
1140, 845 cm–1; 1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.4
Hz, 3H), 1.42 (m, 2H), 1.59 (quint, J = 7.4 Hz, 2H), 3.45 (dd, J =
12.8, 6.8 Hz, 2H), 5.10 (s, 1H), 6.19 (m, 1H), 6.38 (d, J = 8.4 Hz,
1H), 6.63 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 8.6 Hz, 2H), 7.17 (dt, J
= 7.8, 0.4 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.52 (dd, J = 8.4, 5.2
Hz, 1H), 8.82 (brs, 1H, NH); 13C NMR (100 MHz, CDCl3): δ =
13.8, 20.2, 31.6, 39.7, 60.0, 112.8, 115.7, 115.9, 116.2, 116.4,
127.3, 128.9 (d, JC-F = 8.1 Hz), 132.7 (d, JC-F = 22.1 Hz), 147.1,
161.4 (d, JC-F = 245.5 Hz), 169.7, 174.5; Anal. Calcd for
C19H19FN2O2: C, 69.92; H, 5.87; N, 8.58. Found: C, 69.96; H,
5.87; N, 8.65.
Acknowledgments
This work was supported by grants from Tehran University of
Medical Sciences and Iran National Science Foundation (INSF).
19. Candeias, N.R.; Cal, P.M.S.D.; Andre´, V.; Duarte, M.T.; Veiros,
L.F.; Gois, P.M.P. Tetrahedron 2010, 66, 2736-2745.
Supporting information
20. Schlienger, N.; Bryce, M.R.; Hansen, T.K. Tetrahedron 2000, 56,
10023-10030.
1H and 13C NMR spectra were provided as Supplementary data.
References and notes
1. Strecker, S. Justus Liebigs Ann. Chem. 1850, 75, 27-45.
2. For recent examples in multi-component reactions see: (a) Zhou,
J.; Yeung, Y.-Y. J. Org. Chem. 2014, 79, 4644-4649; (b)
Rajaguru, K.; Suresh, R.; Mariappan, A.; Muthusubramanian, S.;
Bhuvanesh, N. Org. Lett. 2014, 16, 744-747; (c) Mercalli, V.;
Giustiniano, M.; Del Grosso, E.; Varese, M.; Cassese, H.;
Massarotti, A.; Novellino, E.; Tron, G.C. ACS Comb. Sci. 2014,
16, 602-605; (d) He, X.; Shang, Y.; Zhou, Y.; Yu, Z.; Han, G.; Jin,
W.; Chen, J. Tetrahedron 2015, 71, 863-868; (e) Gunawan, S.;
Ayaz, M.; De Moliner, F.; Frett, B.; Kaiser, C.; Patrick, N.; Xu,
Z.; Hulme, C. Tetrahedron 2012, 68, 5606-5611.
3. Petasis, N.A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583-
586.
4. Candeias, N.R.; Montalbano, F.; Cal, P.M.S.D.; Gois, P.M.P.
Chem. Rev. 2010, 110, 6169-6193.
5. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.

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Supporting Information
Efficient multi-component synthesis of 1,4-benzodiazepine-3,5-diones: a
Petasis-based approach
Saeedeh Noushinia, Mohammad Mahdavia, Loghman Firoozpourb, Setareh Moghimia, Abbas
Shafieea, Alireza Foroumadia,b*
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran 14176, Iran
b Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
Corresponding author. Alireza Foroumadi
Tel.: +98-21-66954708; fax: +98-21-66461178; e-mail: aforoumadi@yahoo.com
Copies of 1H-NMR and 13C-NMR

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1H and 13C-NMR Spectra of compound 6a (CDCl3, 400 MHz)

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1H and 13C-NMR Spectra of compound 6b (DMSO, 500 MHz)

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1H and 13C-NMR Spectra of compound 6c (CDCl3, 400 MHz)

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1H and 13C-NMR Spectra of compound 6d (CDCl3, 400 MHz)

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1H and 13C-NMR Spectra of compound 6e (CDCl3, 400 MHz)

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1H and 13C-NMR Spectra of compound 6g (CDCl3, 400 MHz)

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1H and 13C-NMR Spectra of compound 6h (CDCl3, 400 MHz)