Solid-phase synthesis of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.05.138

We have developed an efficient solid-phase synthetic approach for the synthesis of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine derivatives. The methodology is of value for high throughput synthesis of these potentially bioactive molecules.

Full text of DOI:10.1016/j.tetlet.2011.05.138

Tetrahedron Letters 52 (2011) 4112–4113
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid-phase synthesis of 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine
derivatives
⇑
Zhang Liu, Wenteng Chen, Marc A. Giulianotti, Richard A. Houghten
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient solid-phase synthetic approach for the synthesis of 2,3,4,5-tetrahydro-
Received 4 May 2011
Revised 24 May 2011
Accepted 26 May 2011
Available online 2 June 2011
1
H-benzo[e][1,4]diazepine derivatives. The methodology is of value for high throughput synthesis of
these potentially bioactive molecules.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Solid-phase
Diazepine
Heterocycle
R1
O
N
O
HN
NH2
N
H
R1
H
R1
N
H N
O N
2
2
R
approach for the synthesis of 2,3,4,5-tetrahydro-1H-benzo[e]
[
1,4]diazepines.
Solid-phase organic synthesis (SPOS) is a powerful technique
for the rapid generation of structurally diverse compounds for
the drug discovery community.1 A major focus of this field is the
synthesis of bioactive compounds and their derivatives. Specifi-
cally heterocyclic compounds have received special attention be-
cause of their broad range of biological activities.2 As a result, an
increasing number of pharmaceutically useful heterocyclic com-
Starting from p-methylbenzhydrylamine (MBHA) resin 1, 2-
nitrobenzoic acid was tethered to the resin under standard DIC/
HOBt coupling conditions. Reduction of the aromatic nitro group
of the resin-bound 2-nitrobenzamide 2 with tin(II) chloride yielded
the corresponding aniline 3. After coupling with phenylacetyl chlo-
ride, acetyl chloride or cyclohexanecarbonyl chloride, respectively,
the afforded amides 4 were reduced under BH
4
resulting diamines 5 were cyclized with oxalyl diimidazole in
DMF at room temperature overnight to give the corresponding re-
3
–THF conditions for
3
pounds have been prepared using solid-phase methodologies.
days, and then treated with piperidine for another 24 h. The
The 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine is an attrac-
tive drug template because of its extensive biological activities in
4
various drug targets, such as dopamine and serotonin receptor,
3
sin-bound products 6, which were reduced in BH –THF/piperidine
system once again, and then released from the resin by HF cleav-
ing. After purifying by preparative HPLC, pure 2,3,4,5-tetrahydro-
Glycogen Synthase Kinase-3 Inhibitor,5 5-HT
C receptor, etc.
6
2
Therefore, a facile preparation of diverse 2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepines for lead discovery is highly desirable.
Although many solution-phase methods have been explored for
the synthesis of this useful scaffold, to the best of our knowledge,
no solid-phase synthetic approaches have been reported.7 Herein,
we would like to present an efficient solid-phase synthetic
1
H-benzo[e][1,4]diazepine products 8 were obtained in good
8
yields (Scheme 1).
To illustrate the versatility of this chemistry, a library of 12
compounds (8a–i) was prepared (Table 1). Four different 2-nitro-
benzoic acids and three different carbonyl chlorides were em-
ployed in the synthesis of this library.
In summary, we have developed an efficient solid-phase syn-
thetic approach for the synthesis of 2,3,4,5-tetrahydro-1H-
⇑
Corresponding author.
E-mail address: houghten@tpims.org (R.A. Houghten).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.138

Z. Liu et al. / Tetrahedron Letters 52 (2011) 4112–4113
4113
O
O
O
c
a
b
N
H
NH2
N
H
N
H
R1
R
R1
1
HN
O N
H N
2
2
R2
O
N
4
3
1
2
R1
R1
R
1
d, e
f
g, h
i
N
H
HN
N
N
HN
R
1
O
N
N
O
R2
R2
R2
R2
5
6
7
8
Scheme 1. Reagents and conditions: (a) 2-nitrobenzoic acid (6 equiv 0.1 M), HOBt (6 equiv 0.1 M), DIC (6 equiv 0.1 M) in DMF, rt, overnight; (b) SnCl
rt, overnight; (c) phenylacetyl chloride/acetyl chloride/cyclohexanecarbonyl chloride (6 equiv 0.1 M), DIEA (6 equiv 0.1 M) in DCM, rt, overnight; (d) BH
e) piperidine, 65 °C, 24 h; (f) oxalyl diimidazole (6 equiv 0.05 M), DMF, rt, overnight; (g) BH –THF, 65 °C, 4 days; (h) piperidine, 65 °C, 24 h; (i) HF, 0 °C, 7 h.
2
(20 equiv 2 M) in DMF,
3
–THF, 65 °C, 4 days;
(
3
Table 1
2. Franzen, R. G. J. Comb. Chem. 2000, 2, 195–214.
3
.
(a) Krchnak, V.; Holladay, M. W. Chem. Rev. 2002, 102–161; (b) Liu, Z.; Nefzi, A. J.
Comb. Chem. 2010, 12, 566–570; (c) Liu, Z.; Medina-Franco, J. L.; Houghten, R. A.;
Giulianotti, M. A. Tetrahedron Lett. 2010, 51, 5003–5004; (d) Liu, Z.; Ou, L.;
Giulianotti, M. A.; Houghten, R. A. Tetrahedron Lett. 2011, 52, 2627–2628.
Guzzo, P. R.; Molino, B. F.; Cui, W.; Liu, S.; Olson, R. E. PTC Int. Appl., 2008141081,
Entry
R1
R2
Yielda (%)
MWb
8
8
8
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
g
h
i
H
H
H
Benzyl
Methyl
Cyclohexyl
Benzyl
Methyl
Cyclohexyl
Benzyl
Methyl
Cyclohexyl
Benzyl
Methyl
76
68
72
78
71
75
75
62
68
74
66
69
253 (M+1)
177 (M+1)
245 (M+1)
288 (M+1)
212 (M+1)
280 (M+1)
267 (M+1)
191 (M+1)
259 (M+1)
289 (M+1)
213 (M+1)
281 (M+1)
4
5
.
.
2
008.
Magnus, N. A.; Ley, C. P.; Pollock, P. M.; Wepsiec, J. P. Org. Lett. 2010, 12, 3700–
703.
4-Chloro
4-Chloro
4-Chloro
3-Methyl
3-Methyl
3-Methyl
4,5-Difluoro
4,5-Difluoro
4,5-Difluoro
3
6. Sabb, A. L.; Vogel, R. L.; Welmaker, G. S.; Sabalski, J. E.; Coupet, J.; Dunlop, J.;
Resenzweig-Lipson, S.; Harrison, B. Bioorg. Med. Chem. Lett. 2004, 14, 2603–2607.
7. (a) Katritzky, A. R.; Xu, Y.; He, H. J. Chem. Soc., Perkin Trans. I 2002, 589–592; (b)
Lehmann, J.; Kraft, G. Arch. Pharm. 1984, 317, 595–606.
8. General procedure for the synthesis of N-substituted 3,4-dihydroquinazolinone
derivatives: 100 mg of p-methylbenzhydrylamine (MBHA) (loading: 1.1 mmol/g)
was sealed within a polypropylene mesh packet. Reactions were carried out in
polyethylene bottles. Starting from p-methylbenzhydrylamine (MBHA) resin 1,
j
k
l
Cyclohexyl
2-nitrobenzoic acid was tethered to the resin in the presence of DIC (6 equiv)
a
Yields are based on the weight of purified product and relative to the initial
loading of the resin (1.1 mmol/g). A 21.20 mm 5 m phenomenex (C18, Luna)
and HOBt (6 equiv) with DMF as solvent at room temperature overnight. After
washing with DMF (three times), DCM (three times) and air dried, the resin-
bound nitrobenzoic amide was reduced by SnCl (20 equiv 2 M) in DMF at room
2
temperature overnight. The resin was then washed with DMF (10 times), DCM
(three times) and air dried. The afforded resin was reacted respectively with
phenylacetyl chloride, acetyl chloride or cyclohexanecarbonyl chloride (6 equiv
l
2
column was used on a Shimadzu HPLC running a 2–95 (H O:ACN; 0.1% formic acid)
gradient at 15 ml/min over 30 min.
b
Determined by ESI-MS. A 4.60 mm 5
l
m phenomenex (C18, Jupiter) column
O:ACN;
was used on a Shimadzu LCMS20-A in positive mode running a 5–95 (H
.1% formic acid) gradient over 6 min.
2
0
.1 M) in the presence of DIEA (6 equiv 0.1 M) in DCM at room temperature
overnight and then washed with DMF (three times) and DCM (three times). The
afforded resin was reduced with BH –THF at 65 °C for 4 days, washed with THF
once), MeOH (three times) and then treated with piperidine for another 24 h at
0
3
(
benzo[e][1,4]diazepine derivatives. The methodology is of value for
high throughput synthesis of these potentially bioactive molecules.
65 °C. After washing with DMF (three times), DCM (three times), MeOH (once)
and air drying, the resulting diamine resin was cyclized with oxalyl diimidazole
6 equiv 0.05 M) in DMF at room temperature overnight. The resin was washed
with DMF (three times), DCM (three times), and MeOH (three times), and then
repeated BH –THF/piperidine reduction once again. The crude product was
(
Acknowledgments
3
released from the resin by HF at 0 °C for 7 h. The crude product was purified by
1
This work was supported by the State of Florida, Executive Offi-
cer of the Governor’s Office of Tourism, Trade and Economic
Development.
preparative HPLC and characterized by LC–MS under ESI condition and H NMR.
Yield: ESI-MS (m/z) of 8a: 253 (M+H); 1H NMR of 8a: (500 MHz, DMSO-d
): d
.59–2.70 (m, 3H), 2.81–2.98 (m, 6H), 3.87 (s, 2H), 6.86 (d, J = 7.0 Hz, 2H), 7.12–
6
2
7
1
13
.25 (m, 7H). C NMR of 8a: (125 MHz, DMSO-d
6
): d 34.4, 54.0, 56.1, 56.5, 58.9,
15.5, 120.6, 125.9, 127.9, 128.3, 128.6, 130.0, 130.7, 140.3, 152.4.
References and notes
1
.
(a) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147–
69; (b) Kundu, B. Curr. Opin. Drug Disc. Dev. 2003, 6, 815–826; (c) Feliu, L.; Vera-
Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2009, 11, 175–197.
1