Solid-phase synthesis of 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]benzo[d]- [1,3]diazepines via Pd(OAc)2/Cu(OAc)2-cocatalyzed cyclization

Article abstract of DOI:10.1055/s-0030-1261186

An efficient approach for the solid-phase synthesis of 2,3,5,6-tetrahydro- 1H-imidazo[1,2-a]benzo[d][1,3]diazepines has been developed. It was realized by Pd(OAc)₂/Cu(OAc)₂-cocatalyzed intramolecular aryl guanidinylation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261186

LETTER
2259
Solid-Phase Synthesis of 2,3,5,6-Tetrahydro-1H-imidazo[1,2-a]benzo[d]-
[1,3]diazepines via Pd(OAc)2/Cu(OAc)2-Cocatalyzed Cyclization
2
, 3,5, 6-Tetrahy
i
H
l
-imidaz
i
o[1,2-
a
]benz
O
o[
d
][1,3]diazepineu a
s
, Zhanying Shao,a Wenteng Chen,a Marc A. Giulianotti,b Richard A. Houghten,b Yongping Yu*a,b
a
College of Pharmaceutical Science, Zijin Campus, Zhejiang University, Hangzhou 310058, P. R. of China
Fax +86(571)88208452; E-mail: yyu@zju.edu.cn
b
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
Received 17 May 2011
with cyanogen bromide. It was reported that the arylation
of guanidines can be realized by palladium- or copper-
catalyzed intramolecular and intermolecular coupling of
aryl halides with guanidines.11 Following optimization of
the reaction conditions, we found the resin-bound com-
pound 6 could be obtained by treatment of 5 with
Pd(OAc)2 (0.2 equiv), Cu(OAc)2 (1 equiv), and Cs2CO3 (5
equiv) in DMF at 100 °C for 48 hours in good yield and
purity. The reaction did not need any ligands or additives
and was performed under air. The desired product was ob-
tained following cleavage from the resin using HF for 1.5
hours at 0 °C. The results are summarized in Table 1.
Eight Boc-protected amino acids and three 2-bromophe-
nyl acetic acid derivatives were employed to illustrate the
versatility of this approach. It was observed that two Boc-
protected amino acids (R1 = 2-naphthyl-CH2, cyclohexyl-
CH2; entries 11 and 12) gave comparably low yield. In ad-
dition, 2-bromophenyl acetic acid derivatives possessed
5-Cl group at R2 position (entry 2) provided higher yield
when compared to other compounds [R2 = H, 4,5-(MeO)2;
entries 1 and 3].
Abstract: An efficient approach for the solid-phase synthesis of
2,3,5,6-tetrahydro-1H-imidazo[1,2-a]benzo[d][1,3]diazepines has
been developed. It was realized by Pd(OAc)2/Cu(OAc)2-cocata-
lyzed intramolecular aryl guanidinylation.
Key words: solid-phase
synthesis,
1,3-benzodiazepines,
Pd(OAc)2/Cu(OAc)2, cyclization, guanidinylation
Combinatorial chemistry is a powerful tool for the prepa-
ration of large organic compound collections utilized in
the drug discovery process.1 Heterocyclic compounds are
well known for their broad range of biological activities.2
Thus, an ever increasing number of pharmaceutically use-
ful heterocyclic compounds have been prepared using sol-
id-phase approaches.3 1,3-Benzodiazepine derivatives
possess broad pharmacological properties, such as antide-
pressant,4 antihypertensive,5 antitumor activities,6 and
dopamine antagonists.7 In addition, guanidine-containing
moieties are found in many biologically active com-
pounds and are known to have useful therapeutic implica-
tions.8 To this extent, it is plausible that a tricyclic fused
scaffold incorporating the 1,3-benzodiazepine and guani-
dine moiety would possess biologically relevant proper-
ties. As part of our ongoing efforts directed toward the
solid-phase synthesis of small molecules and heterocyclic
compounds for discovering biologically relevant com-
pounds,9 herein, we report an efficient solid-phase syn-
thetic approach for the 2,3,5,6-tetrahydro-1H-
imidazo[1,2-a]benzo[d][1,3]diazepines.
O
R1
O
R1
O Br
a, b
c
NH2
NH
NH2
NH HN
NH
2
1
3
R2
R1
NH HN
Br
Br
e
d
N
N
R2
As outlined in Scheme 1, the parallel solid-phase synthe-
sis of 2,3,5,6-tetrahydro-1H-imidazo[1,2-a] benzo[d]-
[1,3]diazepines was carried out using the ‘tea-bag’ meth-
odology.10 Starting from (p-methylbenzhydrylamine)
MBHA resin 1, a variety of Boc-protected amino acids
were coupled to the resin using standard coupling proce-
dures. The Boc group was removed using 55% TFA in
CH2Cl2. The resulting primary amine 2 was coupled with
2-bromophenyl acetic acid derivatives to provide the res-
in-bound compound 3. Exhaustive reduction of the two
amide bonds by treatment with BH3–THF generated di-
amine 4 which possessed two secondary amines. Then the
resin-bound compound 5 was obtained by cyclization
R2
R1
4
5
R2
R2
g
f
N
N
N
HN
N
N
R1
R1
7
6
Scheme 1 Solid-phase synthesis of 2,3,5,6-tetrahydro-1H-imida-
zo[1,2-a]benzo[d][1,3]diazepines 7. Reagents and conditions: (a)
Boc-L-AA(R1)-OH (6 equiv, 0.1 M), HOBt (6 equiv, 0.1 M), DIC (6
equiv, 0.1 M) in DMF, r.t., 2 h; (b) 55% TFA–CH2Cl2, 0.5 h; (c)
R2ArCH2COOH (10 equiv, 0.1 M), HOBt (10 equiv, 0.1 M), DIC (10
equiv, 0.1 M) in DMF, r.t., overnight; (d) BH3–THF, 65 °C, 4 d; (ii)
piperidine, 65 °C, 20 h; (e) CNBr (10 equiv, 0.1 M) in CH2Cl2, r.t.,
overnight; (f) Pd(OAc)2 (0.2 equiv), Cu(OAc)2 (1 equiv), Cs2CO3 (5
equiv), DMF, 100 °C, 48 h; (g) HF, 0 °C, 1.5 h.
SYNLETT 2011, No. 15, pp 2259–2261
x
x
.x
x
.2
0
1
1
Advanced online publication: 12.08.2011
DOI: 10.1055/s-0030-1261186; Art ID: W11911ST
© Georg Thieme Verlag Stuttgart · New York

2260
L. Ou et al.
LETTER
Table 1 Individual 2,3,5,6-Tetrahydro-1H-imidazo[1,2-a]benzo[d][1,3]diazepines
R2
N
HN
N
R1
Entry
1
Product12
R1
R2
Yield (%)a
Purity (%)b
MW (found)c
7a
7b
7c
7d
7e
7f
Me
H
77
85
77
76
84
81
68
72
73
80
50
58
99
98
90
95
98
98
92
98
97
96
96
99
202.0 [M + 1]+
236.0 [M + 1]+
261.9 [M + 1]+
188.0 [M + 1]+
222.0 [M + 1]+
312.0 [M + 1]+
290.1 [M + 1]+
244.0 [M + 1]+
278.0 [M + 1]+
244.0 [M + 1]+
328.1 [M + 1]+
284.1 [M + 1]+
2
Me
5-Cl
3
Me
4,5-(MeO)2
4
H
H
5
H
5-Cl
6
Bn
5-Cl
7
7g
7h
7i
i-Pr
4,5-(MeO)2
8
s-Bu
H
9
s-Bu
5-Cl
H
10
11
12
7j
i-Bu
7k
2-naphthyl-CH2
cyclohexyl-CH2
H
7l
H
a Yields (%) are based on the weight of crude material and are relative to the initial loading of the resin.
b The purity of the crude material was estimated by the peak area from analytical HPLC traces at l = 254 nm.
c Confirmed by mass spectra (ESI).
(4) Martin, L. L.; Setescak, L. L.; Worm, M.; Crichlow, C. A.;
Geyer, H. M. III.; Wilker, J. C. J. Med. Chem. 1982, 25, 346.
(5) Setescak, L. L.; Dekow, F. W.; Kitzen, J. M.; Martin, L. L.
J. Med. Chem. 1984, 27, 401.
(6) Rotas, G.; Natchkebia, K.; Natsvlishvili, N.; Kekelidze, M.;
Kimbaris, A.; Varvounisa, G.; Mikeladze, D. Bioorg. Med.
Chem. Lett. 2005, 15, 3220.
In summary, we have devoloped an efficient approach for
the synthesis of 2,3,5,6-tetrahydro-1H-imidazo [1,2-a]-
benzo[d][1,3]diazepines on solid phase via Pd(OAc)2/
Cu(OAc)2-cocatalyzed intramolecular aryl guanidinyla-
tion. The screening of these potentially bioactive com-
pounds will be reported in due course.
(7) Zhu, Z.; Sun, Z.-Y.; Ye, Y.; McKittrick, B.; Greenlee, W.;
Czarniecki, M.; Fawzi, A.; Zhang, H.; Lachowicz, J. E.
Bioorg. Med. Chem. Lett. 2009, 19, 5218.
(8) (a) Rodríguez, F.; Rozas, I.; Kaiser, M.; Brun, R.; Nguyen,
B.; Wilson, W. D.; García, R. N.; Dardonville, C. J. Med.
Chem. 2008, 51, 909. (b) Keller, M.; Pop, N.; Hutzler, C.;
Beck-Sickinger, A. G.; Bernhardt, G.; Buschauer, A. J. Med.
Chem. 2008, 51, 8168.
(9) (a) Nefzi, A.; Ostresh, J. M.; Yu, Y.; Houghten, R. A. J. Org.
Chem. 2004, 69, 3603. (b) Yu, Y.; Ostresh, J. M.; Houghten,
R. A. J. Comb. Chem. 2004, 6, 83. (c) Zhang, Y.; Xu, C.;
Houghten, R. A.; Yu, Y. J. Comb. Chem. 2007, 9, 9.
(d) Hu, Z.; Ma, T.; Chen, Z.; Ye, Z.; Zhang, G.; Lou, Y.; Yu,
Y. J. Comb. Chem. 2009, 11, 267.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the National Natural Science Foundation of China (No.
30772652 and 90813026) and Zhejiang Provincial Natural Science
Foundation of China (No. Z2110655).
References and Notes
(1) (a) Gil, C.; Bräse, S. J. Comb. Chem. 2009, 11, 175.
(b) Feliu, L.; Vera-Luque, P.; Albericio, F.; Álvarez, M.
J. Comb. Chem. 2007, 9, 521. (c) Combinatorial Chemistry
and Molecular Diversity in Drug Discovery; Gordon, E. M.;
Kerwin, J. F. Jr., Eds.; John Wiley and Sons: New York,
1998.
(2) Franzén, R. G. J. Comb. Chem. 2000, 2, 195.
(3) (a) Dolle, R. E. J. Comb. Chem. 2005, 7, 739. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
893.
(10) Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82,
5131.
(11) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(b) Huang, X.; Yang, H.; Fu, H.; Qiao, R.; Zhao, Y.
Synthesis 2009, 2679. (c) Cortes-Salva, M.; Nguyen, B.-L.;
Cuevas, J.; Pennypacker, K. R.; Antilla, J. C. Org. Lett.
2010, 12, 1316.
(12) Typical Procedure for the Synthesis of 7
MBHA resin (100 mg, loading: 1.1 mmol/g) was contained
in a polypropylene mesh packet. The resin was washed with
Synlett 2011, No. 15, 2259–2261 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,5,6-Tetrahydro-1H-imidazo[1,2-a]benzo[d][1,3]diazepines
2261
CH2Cl2 (2 × 5 mL) followed by neutralization with 5%
mL), and MeOH (2 × 5 mL) and dried. The resulting resin-
bound diamine was cyclized with cyanogen bromide (10
equiv, 0.1 M in CH2Cl2) at r.t. overnight. The resin was then
washed with CH2Cl2 (3 × 5 mL), IPA (2 × 5 mL),CH2Cl2 (3
× 5 mL) and dried. To each tube was added the resin packet,
Pd(OAc)2 (0.2 equiv), Cu(OAc)2 (1 equiv), and Cs2CO3 (5
equiv), followed by anhyd DMF (10 mL). The tube was
sealed, and the mixture was heated at 100 °C for 48 h.
Following washing with DMF (3 × 5 mL), CH2Cl2 (3 × 5
mL), and MeOH (2 × 5 mL), the resin was cleaved with HF
at 0 °C for 1.5 h. The desired product was extracted with
AcOH–H2O (95:5) and lyophilized. The product was
characterized by electrospray LC-MS under ESI conditions,
1H and 13C NMR.
DIEA in CH2Cl2 (3 × 5 mL) and washed with CH2Cl2 (2 × 5
mL). The first Boc-L-amino acid (6 equiv, 0.1 M in DMF)
was coupled to MBHA resin using DIC (6 equiv) and HOBt
(6 equiv) for 2 h at r.t., then the resin was washed with DMF
(3 × 5 mL) and CH2Cl2 (3 × 5 mL). After that, the Boc group
was removed with 55% TFA in CH2Cl2 (5 mL) for 30 min at
r.t. Then the packet was washed with CH2Cl2 (2 × 5 mL),
neutralized with 5% DIEA in CH2Cl2 (3 × 5 mL) and washed
with CH2Cl2 (2 × 5 mL). The resin-bound amine was then
acylated with a 2-bromo phenyl acetic acid derivative (10
equiv, 0.1 M in DMF) using DIC (10 equiv) and HOBt (10
equiv) as coupling reagents overnight. The resin was washed
with DMF (3 × 5 mL), CH2Cl2 (3 × 5 mL), and MeOH (5
mL × 2) and lyophilized. The afforded resin was reduced
with BH3–THF (40 equiv) at 65 °C for 4 d followed by
decantation of the reaction solution and quenching with
MeOH. After washing with DMF (5 mL) and MeOH (4 × 5
mL), the resin was treated with piperidine at 65 °C overnight
to disproportionate the borane complex. Following
Compound 7a: ESI-MS (m/z): 202.0 [M + H+]. 1H NMR
(500 MHz, DMSO-d6): d = 8.44 (s, 1 H), 7.23–7.18 (m, 2 H),
7.13–7.12 (m, 1 H), 7.02–7.00 (m, 1 H), 4.07–4.03 (m, 1 H),
3.76–3.72 (m, 1 H), 3.55–3.47 (m, 2 H), 3.17 (dd, J = 9.5,
6.5 Hz, 1 H), 3.07 (ddd, J = 15.0, 8.5, 3.0 Hz, 1 H), 2.99
(ddd, J = 15.0, 6.0, 2.5 Hz, 1 H), 1.25 (d, J = 6.0 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 154.8, 137.8, 130.2,
130.1, 127.6, 123.4, 120.3, 58.9, 47.5, 46.3, 32.5, 17.9.
decantation of the piperidine–borane solution, the resin
packet was washed with DMF (4 × 5 mL), CH2Cl2 (4 × 5
Synlett 2011, No. 15, 2259–2261 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.