Synthesis of a 1,3,5-benzotriazepine-2,4-dione based library

Article abstract of DOI:10.1016/j.tetlet.2012.05.025

A library of benzotriazepines have been synthesised employing microwave-mediated synthesis, supported resins and parallel synthesis methodology.

Full text of DOI:10.1016/j.tetlet.2012.05.025

Tetrahedron Letters 53 (2012) 3607–3611
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a 1,3,5-benzotriazepine-2,4-dione based library
Irina Chuckowree a, , Murtaza Ali Syed a, Giulia Getti a, Asha Parbhu Patel a, Hannah Garner a,
⇑
Graham J. Tizzard b, Simon J. Coles b, John Spencer a,c,
⇑
a School of Science, University of Greenwich at Medway, Chatham ME4 4TB, UK
b UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
c Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, East Sussex BN1 9QJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A library of benzotriazepines has been synthesised employing microwave-mediated synthesis, supported
resins and parallel synthesis methodology.
Received 21 February 2012
Revised 25 April 2012
Accepted 3 May 2012
Available online 10 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Microwaves
Parallel synthesis
Heterocycles
Amides
Cyclisation
Privileged structures are extremely important in drug discovery
and new routes to known or novel scaffolds are desirable since
they can lead to new bioactive drug-like molecules, and can be
incorporated in libraries for fragment-based or high throughput
screening.1 Benzodiazepines (BZDs) are examples of privileged
scaffolds in medicinal chemistry and are found in a number of
known or investigational drugs including those targeting G-protein
coupled receptors (GPCRs).2 In many cases, for example for chole-
cystokinin-2 receptor (CCK2) antagonists, it was found that the
benzodiazepine needs to be enantiomerically pure for receptor
subtype selectivity (over CCK1),3 whereas scaffold-hopping to an
achiral benzotriazepine (BZT) structure led to effective CCK2 antag-
onists, obviating the need for a stereoselective synthesis or resolu-
tion.4 This approach has been extended to the development of
selective BZT-based PTH-1 (parathyroid hormone-1 receptor)
antagonists (Fig. 1).5
previously reported synthesis of BZTs.4a However, we have since
optimised the original chemistry and adapted it using microwave
and supported reagent mediated methods, wherever feasible, to
produce a number of novel BZTs devoid of the structural motifs re-
quired for notably CCK2 binding (i.e. lacking a 3-substituted acet-
amide on the N-3 atom). The compounds hereafter may hence
have interesting applications in medicinal chemistry, e.g. aimed
at GPCR receptors.
N-Alkyl-1,2-diamines 3 were either available commercially or
prepared as described previously.3 Thus, nucleophilic aromatic
substitution of 1-fluoro-2-nitrobenzene (1) with commercially
available primary amines was performed in a microwave reactor
and gave nitroanilines 2 in excellent yields. Reduction of the nitro
group and subsequent alkylation with a-haloketones or a-haloest-
ers gave N,N0-dialkyl-1,2-diamines 4. In our experience, thermal-
mediated synthesis provided a better synthetic route with higher
yields. N,N0-Dialkyl-1,2-diamines 4 were further treated with
freshly prepared phenyl isocyanatoformate (5) under microwave
irradiation to give the N-3 unsubstituted BZTs 6.7 The yields for
this step were comparable or slightly improved compared to the
corresponding step performed under conventional heating. Substi-
tution at the N-3 nitrogen was achieved by base-mediated (NaH or
Given the dearth of 1,3,5-benzotriazepine-2,4-diones (1,3,5-
BZT) in the chemical literature4a and the promising biological
activity of the aforementioned CCK2 antagonists, we report the
synthesis of a novel library based on this scaffold employing
mainly microwave6 and amide coupling reactions.
The synthesis of the 1,3,5-BZT scaffold was achieved as shown
in Scheme 1. The synthetic steps have been largely based on the
PS-BEMP
=
(polymer supported)-2-tert-butylimino-2-diethyl-
amino-1,3-dimethyl-perhydro-1,3,2 diazaphosphorine) alkylation8
to produce the trisubstituted 1,3,5-BZTs 7 (Table 1).
⇑
Corresponding authors. Fax: +44 (0) 2083319805 (I.C.); fax: +44 (0) 1273
876687 (J.S.).
When sodium hydride was used in base-mediated alkylations
on the N-3 nitrogen, transesterification reactions were observed
when the R2 substituent was an alkoxide.9 For example, when
E-mail addresses: I.Chuckowree@greenwich.ac.uk (I. Chuckowree), j.spencer@
sussex.ac.uk (J. Spencer).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.025

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I. Chuckowree et al. / Tetrahedron Letters 53 (2012) 3607–3611
CCK2 ligands
PTH-1 ligand
NH
HN
O
O
O
H2N
N
O
N
O
N
O
O
N
N
N
O
N
N
O
H
N
N
H
N
N
NH
N
N
N
O
N
N
N
NH
O
N
O
N
N
O
O
N
H
H
O
H
N
CO2H
H
BZT
BZTs
BZDs
Figure 1. Bioactive benzodiazepine and benzotriazepine scaffolds.
R1
R1
R1
NH
F
NH
NH
(ii)
5, (iv)
(i)
(iii)
NO2
NO2
NH2
NH
3
4
R2
1
2
O
R1
N
R1
N
O
O
(v)
O
R3
5 =
N
R3
N
O
N
N
O
N
O
C
O
R2
O
O
R2
6
7
(R3 = H)
Scheme 1. Synthesis of 1,3,5-BZTs. Reagents and conditions: (i) H2N-R1, Et3N, MeCN, MW, 90-100%; (ii) 10% Pd/C, H2 (1 atm), EtOH, rt, quant.; (iii) Br-CH2COR2, K2CO3, DMF, rt
or 65 oC, 53-66%; (iv) DMA, MW; (v) NaH or PS-BEMP, X-R3, where X = Cl, Br, I; DMF.
Table 1
Table 2
1,3,5-BZT based library
Synthesis of a 1,3,5-BZT based library
R1
R2
R3
Yielda (%)
Product
R1
R2
R3
Yielda (%)
Substrate
Product
6a
6b
6c
6d
6e
c-C6H11
c-C6H11
Ph
Ph
Ph
OBn
t-Bu
OBn
Ot-Bu
t-Bu
H
H
H
H
H
40
16
59
51
63
6a
6a
6a
6a
6d
6d
6c
6c
6c
6c
6c
7i
c-C6H11
c-C6H11
c-C6H11
c-C6H11
Ph
Ph
Ph
Ph
Ph
OBn
OMe
OBn
CH2-2-Py
Ot-Bu
OMe
OBn
OMe
Me
Me
CH2-2-Py
CH2-2-Py
Me
Me
Bn
Me
56
31
48
n/ib
80
19
92
39
35
84
n/ib
7i0
7j
7j0
7k
7k0
7l
7m
7m0
7n
7n0
6f
t-Bu
H
42b
NH.HCl
NH.HCl
7a
7b
7c
7d
7e
7f
c-C6H11
Ph
Ph
Ph
Ph
t-Bu
OBn
OBn
t-Bu
t-Bu
t-Bu
t-Bu
Me
67c
97c
98c
87c
63c
79c
52c
OMe
O-CH2-2-Py
O-CH2-2-Py
Me
H
O-CH2-2-Py
CH2COt-Bu
CH2-2-Py
Me
Et
Bn
Ph
Ph
The products of the transesterification reactions.
Yields refer to chromatographically isolated products of over 95% purity (NMR)
for the last synthetic step.
Ph
Ph
a
7g
CH2-2-Py
b
99b
Not isolated.
7h
t-Bu
Me
a
Yields refer to chromatographically isolated products of over 95% purity (NMR)
for the last synthetic step.
pounds containing an ester function, and the expected alkylated
products were obtained in 97% (7b, Table 1) and 98% yields (7c, Ta-
ble 1), respectively.
b
Overall yield over two steps.
c
Yields refer to the reactions using PS-BEMP as base.
In examples where N-Boc-protected piperidin-4-ylmethyl was
chosen as an R1 substituent at the N-1 nitrogen, further modifica-
tions on the nitrogen of the piperidine ring were possible after an
initial Boc-deprotection. Compounds 8 (see Supplementary data)
were hence treated with a HCl solution in 1,4-dioxane to afford
quantitative yields of 6f and 7h as hydrochloride salts (Scheme 3).
Compound 7h was then reacted with representative acid chlorides
and sulfonyl chlorides to give compounds 9 and 10, respectively.
Compound 7 (Scheme 4) containing a Bn ester as the R4 substi-
tuent at the N-5 nitrogen were transformed into carboxylic acids
iodomethane was reacted with the sodium salt of 6a, a methyl es-
ter 7i0 (Table 2) was isolated in 31% yield, as well as the Bn ester 7i
in 56% yield (Scheme 2). In one instance, a cross-esterified primary
imide was isolated as the major product of the reaction (7n, Ta-
ble 2), an X-ray structure of which is shown, confirming such a
rearrangement (Scheme 2). These reactions were found, however,
to be somewhat capricious and we are, at present, investigating
the mechanism of this rearrangement. When PS-BEMP was used
as the base, no cross-esterification was observed with the com-

I. Chuckowree et al. / Tetrahedron Letters 53 (2012) 3607–3611
3609
R1
N
R1
N
R1
N
O
O
O
(i)
N
R3
NH
N
R3
N
O
N
N
O
O
R2
O
OR3
O
R2
6
7'
7
O
R2 = OBn or Ot-Bu
O
O
N
N
(ii)
N
N
NH
O
NH
O
O
OBn
O
N
O
6c
7n
Scheme 2. Cross-esterification reactions. Reagents and conditions: (i) NaH, X-R3, where X = Cl, Br, I; DMF; (ii) NaH, 2-Br-CH2-PyꢀHBr; and DMF. The crystal structure of 7n is
shown (CCDC 856222).
O
N
O
O
.
NH HCl
N
O
N
N
N Me
(ii)
O
O
O
N
N
N
N
(i)
R3 = Me
R3
O
N
R3
N
O
N
O
O
O
S
9
(iii)
O
O
R3 = Me
9
8
O
R3 = Me
R3 = H
7h
6f
N
N
N Me
O
O
10
Scheme 3. Modifications of the R1 substituents at the N-1 nitrogen. Reagents and conditions: (i) 4 M HCl in 1,4-dioxane, CH2Cl2, rt, quant.; (ii) AcCl, Et3N, CH2Cl2, rt, 62%; (iii)
MeSO2Cl, Et3N, CH2Cl2, rt, 79%.
R1
N
R1
N
R1
N
O
O
O
(i)
(ii)
N
R3
N
R3
N
R3
R4 = Bn
N
O
N
O
N
O
O
O
OR4
O
NR5R6
OH
11
7
12
(iii) R4 = Me
Scheme 4. Modifications at the N-5 nitrogen. Reagents and conditions: (i) TFA, CH2Cl2, rt, quant. or H2, Pd/C, EtOH, EtOAc, quant.; (ii) HNR5R6, EDCI, HATU, DMAP, and DMF;
(iii) HNR5R6, MW, 150 oC, 30 min.
11 and subsequently converted into secondary or tertiary amides
12. Initial trial reactions indicated that neither EDCI nor HATU
alone gave satisfactory conversion into the product (<50%), nor
did increasing the amount of either reagent; however, combining
the two gave much higher yields. This was, hence, used for the par-
allel coupling sequence without any further optimisation or alter-

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I. Chuckowree et al. / Tetrahedron Letters 53 (2012) 3607–3611
Table 3
Synthesis of amide substituted BZTs
Substrate
Product
R1
R3
NR5R6
Yielda (%)
7b
7k
7i
11a
11b
11c
Ph
Ph
c-C6H11
CH2COt-Bu
Me
Me
—
—
—
100
100
100
11a
7k0
12a
12b
Ph
Ph
CH2COt-Bu
18b
61c
N
N
Me
H
N
11b
11b
12c
12d
Ph
Ph
Me
Me
72d
48d
N
N
N
N
11b
12e
Ph
Me
64d
N
N
N
7i
7i
12f
c-C6H11
c-C6H11
Me
Me
57c
51c
H
N
12g
H
N
11c
12h
c-C6H11
Me
82e
H
N
11c
11c
12i
12j
c-C6H11
c-C6H11
Me
Me
36d
84d
N
N
H
N
11c
11c
12k
12l
c-C6H11
c-C6H11
Me
Me
44d
46d
N
N
H
N
O
a
b
c
Yields refer to chromatographically isolated products of over 95% purity (NMR) for the last synthetic step.
Yields refer to the reactions using PS-CDI as the coupling reagent.
Yields refer to the reactions performed neat in an appropriate amine.
Yields refer to the reactions using HATU/EDCI as the coupling reagent.
Yields refer to the reactions using SOCl2 as a reagent.
d
e
Ph
Ph
Ph
O
O
O
N
N
N
(i)
(ii), (iii)
N
Me
N
Me
N Me
N
N
N
O
O
O
O
O
O
14
13
11b
HO
N
N
BocN
N
R7
14a R7 = H .HCl 100%
14b
14c
R
7 = COMe, 99%
7 = CO-c-C3H5, 92%
R
14d R7 = SO2Me, 86%
Scheme 5. Further modifications at the N-5 nitrogen. Reagents and conditions: (i) Boc-piperazine, EDCI, HATU, DMAP, DMF, 84%; (ii) 4 M HCl in 1,4-dioxane, CH2Cl2, rt,
quant.; (iii) acid chloride or methanesulfonyl chloride, Et3N, CH2Cl2.
ation of the conditions. Moreover, the attempted use of PS-sup-
ported CDI as a coupling agent, gave very low yields (12a, Table 3).
Another versatile method using SOCl2 for acid activation was
employed successfully for the amide synthesis (12h). Methyl esters
70 could also be converted directly into amides 12 using microwave
heating and an appropriate amine as a reagent/solvent (for exam-
ple, compounds 12b, 12f and 12g). Lewis acid mediated amidations
were not attempted although these could represent a useful strat-
egy for the amidation reaction.10
In an attempt to incorporate piperazine-functionalised substit-
uents at N-5, the carboxylic acid 11b was reacted with N-Boc-
piperazine using our previous amide coupling conditions to give

I. Chuckowree et al. / Tetrahedron Letters 53 (2012) 3607–3611
3611
A. L.; Clements, C. J.; Clark, R. L.; Barrett, M. P.; Wong, P. E.; Male, L.; Coles, S. J.;
Mackay, S. P. Bioorg. Med. Chem. 2011, 19, 1802.
13. Deprotection and further modification on the piperazine nitro-
gen yielded target compounds 14 (Scheme 5).
3. Bailey, N.; Box, P. C.; Carr, R. A. E.; Cooke, J. W. B.; Evans, B.; Finch, H.; Head, J. E.;
Pass, M.; Shah, P.; Wheatcroft, J. R. Bioorg. Med. Chem. Lett. 1997, 7, 281.
4. (a) Spencer, J.; Gaffen, J.; Griffin, E.; Harper, E. A.; Linney, I. D.; McDonald, I. M.;
Roberts, S. P.; Shaxted, M. E.; Adatia, T.; Bashall, A. Bioorg. Med. Chem. 2008, 16,
2974; (b) McDonald, I. M.; Black, J. W.; Buck, I. M.; Dunstone, D. J.; Griffin, E. P.;
Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.; Lilley, E. J.; Linney, I. D.; Pether, M.
J.; Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes, D. A.; Walker,
M. K.; Watt, G. F.; Wright, L.; Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50, 3101;
(c) McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Griffin, E.; Harper, E.
A.; Hull, R. A. D.; Kalindjian, S. B.; Linney, I. D.; Low, C. M. R.; Pether, M. J.;
Spencer, J.; Wright, P. T.; Adatia, T.; Bashall, A. J. Med. Chem. 2006, 49, 2253; (d)
Jin, S.; St-Jean, O.; Baltatu, S. I.; Santhakumar, V.; Tomaszewski, M. J.
Tetrahedron Lett. 2012, 53, 1278; (e) Dong, C.; Xie, L.; Mou, X.; Zhong, Y.; Su,
W. Org. Biomol. Chem. 2010, 8, 4827.
In conclusion, a chemically diverse library of 1,3,5-BZTs have
been synthesised using a combination of thermal and microwave
mediated chemistry.
Acknowledgements
This work was supported by a Proof of Concept Fund from the
University of Greenwich. Mass spectra were kindly recorded by
the EPSRC Mass Spectrometry Service at the University of Swansea.
G.J.T. and S.J.C. would like to thank the EPSRC for funding.11
5. McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Gaffen, J.; Griffin, E. P.;
Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.; Linney, I. D.; Low, C. M. R.; Patel, D.;
Pether, M. J.; Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes, D.
A.; Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50, 4789.
Supplementary data
6. For recent microwave-mediated chemistry from our group, see: (a) Spencer, J.;
Nazira, A.; Patel, H.; Rathnam, R. P.; Verma, J. Synlett 2007, 2557; (b) Spencer, J.;
Patel, H.; Rathnam, R. P. Nazira A, Tetrahedron 2008, 64, 10195.
7. Ramirez, F.; Telefus, C. D.; Prasad, V. A. V. Tetrahedron 1975, 31, 2007. Note:
yields drop significantly when using old stock so it is advisable to prepare 5
fresh for each new reaction.
Supplementary data (experimental details and analytical data
for the compounds) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.025.
8. Lausted, L. S.; Sams, C. K. J. Comb. Chem. 2007, 9, 1094.
References and notes
9. For related transesterifcations in the presence of hydrides or strong bases see,
for example: (a) Sereda, G.; Pothula, S.; Dreessen, J. Synth. Commun. 2010, 40,
1312; (b) Stanton, M. G.; Gagné, M. R. J. Org. Chem. 1997, 62, 8240; (c) Otera, J.
Chem. Rev. 1993, 93, 1449.
1. Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein. J. Org. Chem. 2011,
7, 442.
2. (a) Spencer, J.; Rathnam, R. P.; Chowdhry, B. Z. Fut. Med. Chem. 2010, 2, 1441;
For earlier work on benzodiazepines from our group, see for example:. (b)
Spencer, J.; Chowdhry, B. Z.; Mallet, A. I.; Rathnam, R. P.; Adatia, T.; Bashall, A.;
Rominger, F. Tetrahedron 2008, 64, 6082; (c) Spencer, J.; Rathnam, R. P.; Harvey,
10. For a recent example, see: Schwaebe, M. K.; Ryckman, D. M.; Nagasawa, J. Y.;
Pierre, F.; Vialettes, A.; Haddach, M. Tetrahedron Lett. 2011, 52, 1096. And
references cited therein. (Thanks to a reviewer for pointing this out).
11. Coles, S. J.; Gale, P. A. Chem. Sci. 2012, 3, 683.