Atom-economical construction of a rare 6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2- d ][1,4]benzodiazepine scaffold

Article abstract of DOI:10.1055/s-0034-1378558

We have developed a route towards novel 6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines, in five straightforward steps from commercially available 2-bromobenzaldehydes and 3-(2-aminoethyl)imidazo[4,5-b]pyridines we have described previously, with full control over the three elements of diversity. The route appears to be suitable for systematic exploration of structure-activity relationships around this medicinally relevant tetracyclic scaffold.

Full text of DOI:10.1055/s-0034-1378558

LETTER
▌2323
lAettterom-Economical Construction of a Rare 6,7-Dihydropyrido[3′,2′:4,5]imida-
zo[1,2-d][1,4]benzodiazepine Scaffold
6,7-Dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines
Prashant Mujumdar,a Mikhail Korsakov,b Mikhail Dorogov,b Mikhail Krasavin*a,c
a
Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
b
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
c
Department of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation
Fax +7(812)4286939; E-mail: m.krasavin@hotmail.com
Received: 25.05.2014; Accepted after revision: 29.06.2014
ring-forming process
(for R = 2-HalC6H4)
R
Abstract: We have developed a route towards novel 6,7-dihydro-
pyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines, in five straight-
forward steps from commercially available 2-bromobenzaldehydes
and 3-(2-aminoethyl)imidazo[4,5-b]pyridines we have described
previously, with full control over the three elements of diversity.
The route appears to be suitable for systematic exploration of struc-
ture–activity relationships around this medicinally relevant tetracy-
clic scaffold.
N
N
N
Fe, NH4Cl
R
N
N
N
EtOH–H2O, 70 °C
NH2
NO2
2
1
further
side-chain
diversity
N
Key words: scaffold-oriented synthesis, Buchwald arylation, Be-
champ reduction
N
N
NH
3
Recently, we described a facile transformation of N-(3-ni-
tro-2-pyridyl)imidazolines 1 into 3-(2-aminoethyl)imid-
Scheme 1 Imidazo[4,5-b]pyridines 2 with a 2-aminoethyl side chain
for building further scaffold complexity toward 3
azo[4,5-b]pyridines
2
under Bechamp reduction
conditions.1 The 2-aminoethyl side chain in 2 (derived
from the imidazoline bismethylene moiety in 1) means
that these compounds may be considered as analogues of
tryptamine.2 We reasoned that the primary amine func-
tionality could be viewed not only as a site for introducing
additional side-chain diversity (e.g., via reductive amina-
In contrast, the 7,8,9,10-tetrahydropyrido[3′,2′:4,5]imid-
azo[1,2-a]azepine moiety (shown in the circle) is far less
common and only one report on inverse agonists and an-
tagonists of histamine H3 receptors, exemplified by 10,
was found in the literature.11
tion) but also as providing an opportunity for linking the Prompted by these observations and having access to
imidazo[4,5-b]pyridine moiety to the 2-aryl substituent compound 11 that we had prepared earlier1 and which
(via intramolecular aryl halide amination) and thus form- contained all necessary substitution, we proceeded to test
ing a tetracyclic scaffold 3 (Scheme 1).
out formation of the tetrahydroimidazo[1,2-a]azepine
system under Buchwald conditions.12 Although the for-
mation of a seven-membered ring via intramolecular pal-
ladium-catalyzed amination of haloaromatics (to give
benzazepines) is well documented in the literature,13 there
has been only one report of a similar reaction involving
(benzo)imidazo-bridged amino side chains [realized un-
der copper(I)-catalyzed conditions].14 We were therefore
gratified to observe that compound 11 was converted
cleanly, although somewhat sluggishly, into the desired
6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodi-
azepine (3, Scheme 3) under very similar conditions15 to
those used in the preparation of precursor 11,1 thus alle-
viating a need to screen for alternative ligands and sourc-
es of palladium. Compound 3 turned out to be highly
crystalline (which is consistent with its rigid tetracyclic
structure) and we were able to obtain a single-crystal X-
ray structure for it to confirm the connectivity within the
tetracycle (Figure 1).16
A preliminary review of the literature related to 3 revealed
its novelty. Indeed, only one compound (4) containing this
scaffold in its entirety has been described in the literature
(though no biological data have been reported).3 At the
same time, the two tricyclic moieties contained in 3 ap-
pear as cores for a range of pharmaceuticals (Scheme 2).
The 6,7-dihydroimidazo[1,2-d][1,4]benzodiazepine por-
tion (shown in the box) was featured in Hoffmann-La
Roche’s inverse agonists of GABAA α5 receptors 5,4
Leiden University’s ligands for adenosine receptors 6,5
Acadia Pharmaceuticals’ Mrg receptor agonists for pain
management 76 (also developed at Caltech7), Arqule’s in-
hibitors of Akt1 kinase 8 with antiproliferative activity,8
as well as inhibitors of E. coli RecA ATPase 9 described
by University of North Carolina.9 The latter, along with 7,
appear to stem from a closely related combinatorial li-
brary disclosed by Trega Biosciences.10
We thus envisaged a series of analogues that could be de-
rived from 2-bromobenzaldehydes 12 and 2-chloro-3-nit-
SYNLETT 2014, 25, 2323–2326
Advanced online publication: 26.08.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378558; Art ID: st-2014-d0454-l
© Georg Thieme Verlag Stuttgart · New York

2324
P. Mujumdar et al.
LETTER
O
N
N
N
N
N
Cl
N
N
O
NH
COOEt
O
N
6
5
HN
N
N
N
N
Me
NH
N
N
N
N
O
7
N
N
NH
N
Me
N
N
3
O
4
NH
N
N
H2N
N
N
8
N
H
N
N
N
HN
O
N
N
10
N
H
N
NH
Ph
O
9
Scheme 2 Pharmaceutical relevance of 6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines 3
NH2
Pd(OAc)2/BINAP
NH
Br
Cs2CO3
N
N
N
N
N
toluene, 100 °C
16 h
N
56%
3
11
Scheme 3 Preparation of compound 3 from precursor 11 described
earlier1
ropyridines 14, but we also aimed to introduce a third
point of diversity by performing reductive alkylation of
the 3-(2-aminoethyl)imidazo[4,5-b]pyridines prior to the
Buchwald-type cyclization step. Thus, we sought to
achieve full control over three elements of diversity that
would make our protocol particularly attractive for library
synthesis.
Preparation of 2-imidazolines 13 from the respective
benzaldehydes 12, with subsequent palladium-catalyzed
N-arylation of the former using 14, was achieved in a
straightforward fashion as described previously.17 The re-
ductive rearrangement of the intermediate N-pyridyl im-
idazolines 15 under Bechamp conditions1 turned out to be
high-yielding, tolerating a range of substituents on the
Figure 1 X-ray crystallographic structure of compound 3
Synlett 2014, 25, 2323–2326
© Georg Thieme Verlag Stuttgart · New York

LETTER
6,7-Dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines
2325
amine counterpart 11, the complete conversion was
achieved within 16 hours, providing the target tetracycles
18a–m (Table 1) in good to excellent yields over two
steps from 16 (Scheme 4).19
Table 1 Diversely Substituted 6,7-Dihydropyrido[3′,2′:4,5]imid-
azo[1,2-d][1,4]benzodiazepines 18a–m Prepared in this Work
Entry Product X
Y
R
Yield of Yield of
18
16 (%) 18 (%)
In summary, we have developed a concise, streamlined,
and atom-economical20 route toward novel 6,7-dihydro-
pyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines, in
five steps from commercially available 2-bromobenzalde-
hydes, making use of the primary amine functionality of
the 3-(2-aminoethyl)imidazo[4,5-b]pyridines we have de-
scribed previously, with full control over the three ele-
ments of diversity. The route appears to be distinctly
suitable for systematic library generation within this tetra-
cyclic scaffold.
1
2
18a
18b
18c
18d
18e
18f
4-F
5-F
5-MeO
H
H
H
H
H
Ph
65
73
81
44
63
23
58
61
61
59
82
77
69
33
41
64
Ph
3
c-Pr
4
4-MeOC6H4 711
5
H
6-Me Ph
48
59
6
H
5-Cl
H
Ph
7
18g
18h
18i
H
4-ClC6H4
c-Pr
Ph
711
59
8
H
5-Cl
H
Acknowledgment
9
5-Cl
5-Cl
5-Cl
H
77
M.K. acknowledges support from Griffith University.
10
11
12
13
18j
5-Cl
Ph
78
References and Notes
18k
18l
6-Me c-Hex
58
(1) Mujumdar, P.; Grkovic, T.; Krasavin, M. Tetrahedron Lett.
2013, 54, 3336.
(2) Enzensperger, C.; Lehmann, J.; vonSchroetter, K.; Riyazi,
A.; Verspohl, E. J. Arzneim. Forsch. 2010, 60, 544.
(3) Salomé, C.; Schmitt, M.; Bourguignon, J.-J. Tetrahedron
Lett. 2009, 50, 3798.
H
H
c-Hex
711
711
18m
H
4-ClC6H4
pyridine and the phenyl rings. 3-(2-Aminoethyl)imid-
azo[4,5-b]pyridines 16 were subjected to a stepwise re-
ductive alkylation procedure18 with a range of aromatic as
well as aliphatic aldehydes. The resultant secondary
amines 17 were found to be at least 85% pure by 1H NMR
spectroscopy and, without further purification, were sub-
jected to the same Buchwald arylation conditions as were
used to prepare 3.15 The secondary amines 17 turned out
to be markedly more reactive compared to their primary
(4) Achermann, G.; Ballard, T. M.; Blasco, F.; Broutin, P.-E.;
Büttelmann, B.; Fischer, H.; Graf, M.; Hernandez, M.-C.;
Hilty, P.; Knoflach, F.; Koblet, A.; Knust, H.; Kurt, A.;
Martin, J. R.; Masciadrim, R.; Porter, R. H. P.; Stadler, H.;
Thomas, A. W.; Trube, G.; Wichmann, J. Bioorg. Med.
Chem. Lett. 2009, 19, 5746.
(5) Langemeijer, E. V.; Verzijl, D.; Dekker, S. J.; Ijzerman, A.
P. Purinergic Signalling 2013, 9, 91.
(6) Malik, L.; Kelly, N. M.; Mab, J.-N.; Currier, E. A.; Burstein,
E. S.; Olsson, R. Bioorg. Med. Chem. Lett. 2009, 19, 1729.
NO2
Y
Br
X
Br
X
N
Cl
NH2
N
Br
H2N
X
N
14
O
N
NBS
HN
Pd(OAc)2/BINAP
Cs2CO3
toluene, 100 °C
12–16 h
N
CH2Cl2, 0 °C
H
13
46–87%
NO2
12
Y
15
63–82%
Fe, NH4Cl
EtOH–H2O, 70 °C
16–24 h
R
NH2
R
HN
1. RCHO, MgSO4
CH2Cl2, r.t., overnight
Pd(OAc)2/BINAP
Cs2CO3
Br
N
N
Br
N
N
N
N
N
N
Y
Y
2. NaBH4, MeOH
r.t., 1 h
toluene, 100 °C
12–16 h
Y
N
X
N
X
16
X
17
18a–m
Scheme 4 Synthesis of tetracyclic 6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines 18a–m with three elements of diversity
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2323–2326

2326
P. Mujumdar et al.
LETTER
(7) Anderson, D. J.; Dong, X.; Liu, Q.; Guan, Y. WO
2011017564, 2011; Chem. Abstr. 2011, 154, 225476
(8) Ashwell, M. A.; Eathiraj, S.; Filikov, A.; Koerner, S.;
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Shiina, A.; Yoshida, K.; Yamazaki, T.; Matsuda, A. US
20120108574, 2012; Chem. Abstr. 2012, 156, 613442
(9) Sexton, J. Z.; Wigle, T. J.; He, Q.; Hughes, M. A.; Smith, G.
R.; Singleton, S. F.; Williams, A. L.; Yeh, L.-A. Curr. Chem.
Genom. 2010, 4, 34.
(10) Lang, H.; Pei, Y. WO 2001023392, 2001; Chem. Abstr.
2001, 134, 266334
(11) Chytil, M.; Engel, S. R.; Fang, Q. K.; Spear, K. L. US
20100204214, 2010; Chem. Abstr. 2010, 153, 311281
(12) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 39, 1348.
(13) (a) Sirvent, J. A.; Foubelo, F.; Yus, M. J. Org. Chem. 2014,
79, 1356. (b) Qadir, M.; Priestley, R. E.; Rising, T. W. D. F.;
Gelbrich, N.; Coles, S. J.; Hursthouse, M. B.; Sheldrake, P.
W.; Whittall, N.; Hii, K. K. Tetrahedron Lett. 2003, 44,
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Dominiguez, E. Org. Lett. 2005, 7, 4787.
(14) Mitra, S.; Chattopadhyay, N.; Chattopadhyay, P. RSC Adv.
2013, 3, 1862.
(15) General Procedure for the Intramolecular Buchwald
Arylation (0.1–0.4 mmol Scale)
A thick-glassed, screw-capped pressure tube (50 mL) was
charged with a suspension of the requisite 2-aminoethyl-
substituted imidazo[4,5-b]pyridine intermediate 17 (1.0
equiv) and Cs2CO3 (1.1 equiv) in toluene (3 mL/mmol),
along with a stir bar. Meanwhile, Pd(OAc)2 (0.05 equiv) and
BINAP (0.1 equiv) were weighed into a vial, suspended in
toluene (2–3 mL), and shaken while immersed in a 100 °C
oil bath for 2 min. The resulting clear, purple, or light-brown
catalyst solution was added in one portion to the vigorously
stirred reaction mixture. The tube was filled with argon,
capped and stirred at 100 °C for 16 h (48 h for 3). The
mixture was allowed to cool to ambient temperature, filtered
through a plug of Celite, and the latter was additionally
washed with EtOAc. The filtrate was concentrated under
reduced pressure, and the crude material was purified by
column chromatography on silica gel using a 0–5% gradient
of MeOH in CH2Cl2 to furnish target compounds 3 and 18a–m.
(16) Crystallographic data (excluding structure factors) for
compound 3 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 1004050. Copies of the data can be obtained
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.uk].
(18) General Procedure for the Reductive Alkylation of 16
(0.5 mmol Scale)
Equimolar amounts of 16 and the requisite aldehyde were
combined in CH2Cl2 (5 mL). Anhydrous MgSO4 (500 mg)
was added, and the mixture was stirred at r.t. overnight. The
MgSO4 was filtered off, washed with CH2Cl2 (50 mL), and
the combined filtrate and washings were concentrated in
vacuo. The residue was dissolved in MeOH (5 mL), treated
with NaBH4 (0.3 mmol), and the mixture stirred at r.t. for 1
h, at which point the reaction was complete according to
TLC analysis. The mixture was partitioned between EtOAc
(50 mL) and sat. aq NaHCO3 (25 mL), the organic layer
separated, dried over anhydrous MgSO4, filtered, and
concentrated. The crude product was analyzed by 1H NMR
spectroscopy and used in the next step without further
purification.
(19) Characterization Data for Selected Compounds
Compound 18d: white solid; mp 131–133 °C. 1H NMR (500
MHz, CDCl3): δ = 8.71 (dd, J = 7.9, 1.45 Hz, 1 H), 8.34 (dd,
J = 4.75, 1.25 Hz, 1 H), 8.11 (dd, J = 7.95, 1.25 Hz, 1 H),
7.34–7.37 (m, 1 H), 7.26 (dd, J = 7.95, 4.75 Hz, 1 H), 7.21
(d, J = 8.55 Hz, 2 H), 7.06 (t, J = 7.85 Hz, 2 H), 6.87 (d, J =
8.6 Hz, 2 H), 4.58 (s, 2 H), 4.43–4.45 (m, 2 H), 3.80 (s, 3 H),
3.64–3.66 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 159.3,
153.3, 149.8, 148.7, 143.4, 134.2, 132.1, 131.9, 129.3,
129.0, 126.4, 120.7, 119.1, 118.0, 117.9, 114.4, 56.9, 55.5,
51.7, 45.5. LC–MS (ESI): m/z = 357.40 [M + H]+. Anal.
Calcd for C22H20N4O: C, 74.14; H, 5.66; N, 15.72. Found: C,
73.98; H, 5.57; N, 15.84.
Compound 18g: white solid; mp 170–172 °C. 1H NMR (500
MHz, CDCl3): δ = 8.67 (dd, J = 8.05, 1.5 Hz, 1 H), 8.34 (dd,
J = 4.8, 1.25 Hz, 1 H), 8.11 (dd, J = 7.75, 1.4 Hz, 1 H), 7.26–
7.36 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.07 (t, J = 7.9 Hz,
1 H), 6.98 (d, J = 8.3 Hz, 1 H), 4.60 (s, 2 H), 4.47–4.49 (m,
2 H), 3.65–3.67 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ =
153.2, 149.2, 148.6, 143.6, 136.1, 134.3, 133.5, 132.1,
132.0, 129.2, 129.0, 126.6, 121.1, 119.2, 118.5, 118.1, 57.1,
52.5, 45.0. LC–MS (ESI): m/z = 361.31 [M + H]+. Anal.
Calcd for C21H17ClN4: C, 69.90; H, 4.75; N, 15.53. Found:
C, 70.02; H, 4.67; N, 15.64.
Compound 18k: beige solid, mp 134–136 °C. 1H NMR (500
MHz, CDCl3): δ = 7.83–7.99 (m, 2 H), 7.77 (dd, J = 8.2, 1.7
Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.46 (d, J = 1.7 Hz, 1 H),
4.33–4.38 (m, 2 H), 3.85–3.33 (m, 2 H), 3.33–3.47 (m, 2 H),
2.83 (s, 3 H), 1.38–1.53 (m, 9 H), 1.12–1.28 (m, 3 H). 13
C
NMR (125 MHz, CDCl3): δ = 154.8, 149.6, 147.7, 143.1,
132.3, 130.1, 128.6, 128.5, 126.3, 119.2, 118.7, 114.3, 60.1,
53.4, 40.5, 40.4, 30.1, 27.1, 26.5, 22.8. LC–MS (ESI): m/z =
381.92 [M + H]+. Anal. Calcd for C22H25ClN4: C, 69.16; H,
6.86; N, 14.64. Found: C, 69.07; H, 6.79; N, 14.72.
(17) Krasavin, M. Tetrahedron Lett. 2012, 53, 2876.
(20) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
Synlett 2014, 25, 2323–2326
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