Intramolecular 1,3-dipolar cycloaddition as a route to triazolobenzodiazepines and pyrrolobenzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2010.07.050

Intramolecular 1,3-dipolar cycloaddition between an alkyne and an azide leads to a series of 1,2,3-triazolo-fused 1,4-benzodiazepines, 1,2,5-benzothiadiazepines, pyrrolobenzodiazepines and pyrrolobenzothiadiazepines (eight examples). The products are priv

Full text of DOI:10.1016/j.tetlet.2010.07.050

Tetrahedron Letters 51 (2010) 4859–4861
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular 1,3-dipolar cycloaddition as a route to
triazolobenzodiazepines and pyrrolobenzodiazepines
*
Christopher S. Chambers, Nilesh Patel, Karl Hemming
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular 1,3-dipolar cycloaddition between an alkyne and an azide leads to a series of 1,2,3-triazolo-
fused 1,4-benzodiazepines, 1,2,5-benzothiadiazepines, pyrrolobenzodiazepines and pyrrolobenzothiadiaze-
pines (eight examples). The products are privileged structures in medicinal chemistry. The precursor azido
alkynes are obtained, usually as transient intermediates, by treatment of the corresponding aldehydes
Received 28 April 2010
Revised 25 June 2010
Accepted 9 July 2010
Available online 15 July 2010
(derived from a-amino acids) with the Bestmann–Ohira reagent.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzodiazepine
Benzothiadiazepine
Pyrrolobenzodiazepine
Alkyne
Azide
1,3-Dipolar cycloaddition
There is interest in the 1,4-benzodiazepine nucleus as a privi-
leged structure in medicinal chemistry, and hence new properties
and new routes continue to appear.1 Tricyclic benzodiazepines (see
Fig. 1) fused at the a-face such as flumazenil (1)2 and estazolam
(2)3 have achieved clinical success in the treatment of CNS disor-
ders, where the former, when 18F labelled, is also a useful ligand
for positron emission tomography.2e Benzodiazepines with a-fused
1,2,3-triazolo and tetrazolo rings have also attracted attention in
the medicinal chemistry literature.4 The pyrrolobenzodiazepines
(PBDs) such as DC-81 (3) and neothramycin (4) are sequence-spe-
cific DNA interactive antitumour antibiotics.5 The related bretaza-
nil (5) has attracted interest in the treatment of CNS disorders and
for its potential usefulness against neurodegenerative diseases.6
1,2,5-Benzothiadiazepines have attracted less interest than their
carbonyl analogues, but are nonetheless attractive targets with a
range of properties including potential as antiarrhythmic agents,7
between the azide and alkene moieties that are present in compounds
(7) and (8) allow access to aziridinopyrrolobenzodiazepines (9) and
aziridinopyrrolobenzothiadiazepines (10).17 In continuation of this
work, we report the results of our efforts with intramolecular azide
to alkyne cycloadditions and describe herein the synthesis of a series
of eight triazolo-fused 1,4-benzodiazepines, pyrrolobenzodiazepines,
1,2,5-benzothiadiazepines and pyrrolobenzothiadiazepines.
Our previous work with the alkene systems (7) and (8) began by
coupling the proline-derived unstable alkene (11) (Scheme 1) with
O
Ph
X
Me
O
F
N
N
Cl
N
N
MeO
HO
N
N
N
H
CO2Et
N
N
tumour necrosis factor-a
-converting enzyme (TACE) inhibitors8
1
2
3 X = H
4 X = OH
and as hypolipidaemic agents,9 as discussed in a recent review.10
The related pyrrolobenzothiadiazepines such as compound (6)
have attracted interest as PBD analogues,10 as candidates for the
treatment of chronic myelogenous leukaemia11 and as non-nucle-
osidic reverse transcriptase inhibitors.12
As part of a programme of work focusing on new routes to benzodi-
azepines, benzothiadiazepines and pyrrolobenzothiadiazepines,13–16
we have recently shown that intramolecular 1,3-dipolar cycloaddition
O
Br
O2
S
N
N
6
5
H
N
t
H
CO2 Bu
N
N
N
X
X
N
9 X = CO
7 X = CO
8 X = SO2
10 X = SO2
H
H
N3
N
* Corresponding author. Tel.: +44 (0) 1484472188; fax: +44 (0) 1484472182.
E-mail address: k.hemming@hud.ac.uk (K. Hemming).
Figure 1. Important tricyclic and tetracyclic benzodiazepines.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.050

4860
C. S. Chambers et al. / Tetrahedron Letters 51 (2010) 4859–4861
CO2H
N
N
H
N
H
H
12
11
1. (COCl)2, CH2Cl2
2. L-prolinol, K2CO3 (aq),
CH2Cl2, RT
R1
R2
X
R1
R2
X
N
OH
N3
N3
79 - 96%
OH
14 X = CO; R1 = R2 = H
13
15 X = SO2; R1 = R2 = H
23 X = CO; R1 = OMe; R2 = OBn
Figure 3. Crystal structure for compound (29d).
O
P
O
MeO
MeO
(COCl)2, DMSO
Et3N, CH2Cl2, RT
18
Me
R1
R2
X
N2
N
X
X
X
(i)
(ii)
OH
NH
NH
65 - 75%
K2CO3, MeOH, RT
N3
R
R
N3
N3
O
N3
16 X = CO; R1 = R2 = H
O
OH
17 X = SO2; R1 = R2 = H
27
26
O
P
O
R1
R2
X
R1
MeO
MeO
X
N
N
Me
X
X
NH
(iii)
R2
N2
NH
83 - 100%
N3
N
R
R
18
N
N
N3
N
19 X = CO; R1 = R2 = H
N
K2CO3, MeOH
21 X = CO; R1 = R2 = H
N
20 X = SO2; R1 = R2 = H
22 X = SO2; R1 = R2 = H
24 X = CO; R1 = OMe; R2 = OBn
29
28
25 X = CO; R1 = OMe; R2 = OBn
Scheme 2. Synthesis of triazolobenzodiazepine derivatives. Reagents and condi-
tions: (i) (COCl)2, CH2Cl2, rt, then -amino alcohol, K2CO3, CH2Cl2, rt; (ii) (COCl)2,
Scheme 1. Synthesis of tetracyclic PBD analogues.
L
DMSO, Et3N, CH2Cl2, rt; (iii) see Table 1.
2-azidobenzenesulfonic acid or 2-azidobenzoic acid. We found the
corresponding approach with the alkyne derivative (12) tedious and
low yielding when we attempted to access the alkyne (12) from pro-
line (although this approach to a series of triazolopyrrolobenzodiaze-
pines has been reported recently18) and sought instead to access the
desired alkyne precursors (19) and (20), directly from the readily
Table 1
Triazolobenzodiazepines and triazolobenzothiadiazepines (29) produced via Scheme
223
Entry
R/X
% Yield
(26)
% Yield
(27)
% Yield (29)
[from (27)]
available aldehydes (16) and (17). Thus, L-prolinol was coupled to 2-
azidobenzoic acid or 2-azidobenzenesulfonic acid togive the alcohols
(14) (mixture of rotamers) and (15) in yields of 79% and 96%, respec-
tively. Oxidation was best performed via the Swern protocol which
gave yields consistently in the 70–75% range (Dess–Martin oxidation
gavehigheryields, butonlywhenfreshly prepared reagentwasused).
The conversion of the aldehydes into the alkynes (19) and (20) was
achieved via the use of the Bestmann–Ohira reagent (18).19 In fact,
compounds (19) and (20) could not bedetectedand the only products
were the triazoles (21) and (22) which were isolated in83% and quan-
titative yield, respectively. The structures of the final products were
determined by the usual spectroscopic techniques,20 but were con-
firmed by X-ray crystallographic studies (see Fig. 2).21
a
b
c
d
e
i-Pr/SO2
i-Pr/CO
PhCH2/SO2
PhCH2/CO
Indol-3yl-CH2/CO
55
88
81
93
90
72
70
65
72
40
83
77a
73a
80a,b
54
a
Intermediate (28) could be isolated in these cases. Cycloaddition was brought
about by heating the pure alkyne at reflux in chloroform.23
Structure confirmed by X-ray crystallographic studies (see Fig. 3).21
b
We next extended our process to include a pyrrolobenzodiaze-
pine with the substitution pattern present in the natural products
DC-81 (3) and neothramycin (4). Thus, the readily available5 azido-
benzoic acid (13) (R1 = OMe, R2 = OBn, X = CO) was coupled to
L-
prolinol to give the alcohol (23) in 87% yield with subsequent oxi-
dation giving the expected aldehyde in 65% yield. Reaction with
the Bestmann–Ohira reagent again proceeded with concomitant
cyclisation of the presumed intermediate alkyne (24) to form the
desired triazolopyrrolobenzodiazepine (25) in 84% yield.
With a successful protocol in place, we next extended it to ami-
no acids other than proline in order to show that we could provide
access to a short series of triazolobenzodiazepines and tria-
zolobenzothiadiazepines (29), as shown in Scheme 2 and Table 1.
The only similar reported approaches to triazolobenzodiazepines
are limited to the alkyne (12),18 as discussed above, or the use of
propargylamines in the coupling step (including an elegant Ugi se-
quence) rather than amino alcohols.4a,22 It is also noteworthy that
Figure 2. Crystal structure for compound (21).

C. S. Chambers et al. / Tetrahedron Letters 51 (2010) 4859–4861
4861
Alajarín3b has reported a non-alkyne-based approach to tria-
zolobenzodiazepines. We are aware of no other published ap-
proaches to the triazolobenzothiadiazepines such as (22) and (
29a/c) (X = SO2).
We are currently exploring other intramolecular 1,3-dipolar
cycloadditions for the synthesis of tricyclic benzodiazepines and
benzothiadiazepines and tetracyclic pyrrolobenzodiazepines and
pyrrolobenzothiadiazepines.
13. Hemming, K.; Loukou, C. Tetrahedron 2004, 60, 3349.
14. Hemming, K.; Patel, N. Tetrahedron Lett. 2004, 45, 7553.
15. Loukou, C.; Patel, N.; Foucher, V.; Hemming, K. J. Sulfur Chem. 2005, 26, 455.
16. Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou, C. Tetrahedron
Lett. 2000, 41, 10107.
17. Patel, N.; Chambers, C. S.; Hemming, K. Synlett 2009, 3043.
18. Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I. Bioorg. Med. Chem. Lett.
2009, 19, 5241.
19. (a) Ghosh, A. K.; Bischoff, A.; Cappiello, J. Eur. J. Org. Chem. 2003, 821; (b)
Callant, P.; D’Haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14, 155.
20. All new compounds gave satisfactory 1H/13C NMR spectra (including DEPT, COSY,
HSQC and HMBC spectra), mass spectra, HRMS/microanalysis and IR spectra.
Typical procedure: synthesis of 1,2,3-triazolo[1,5-d]pyrrolo[1,2-b][1,2,5]benzothia
diazepine9,9-dioxide(22):Tothealdehyde(17)(300 mg, 1.07 mmol)inanhydrous
MeOH (5 mL) were added K2CO3 (296 mg, 2.14 mmol) and the Bestmann–Ohira
reagent19 (247 mg, 1.29 mmol). The mixture was stirred at room temperature
under an atmosphere of dry N2 for 22 h, whereupon saturated aqueous NH4Cl
(10 mL) was added. The mixture was extracted with CH2Cl2 (4 Â 10 mL), the
combined organic layers were dried (MgSO4), filtered and concentrated by
reduced pressure rotary evaporation. Purification on a column of silica gel (20 g)
using EtOAc and hexane (3:1) as the eluent gave the title compound (295 mg,
100%) as a yellow solid, mp 175–177 °C. Anal. Calcd for C12H12N4O2S: C, 52.16; H,
Acknowledgements
We thank the University of Huddersfield for a Ph.D. studentship
(to N.P.), the EPSRC for a studentship (DTA to C.S.C.), Dr Neil McLay
(University of Huddersfield) for NMR spectroscopy and mass spec-
trometry, Dr Craig Rice (University of Huddersfield) for X-ray crys-
tallography and the EPSRC National Mass Spectrometry Service
Centre at the University of Wales Swansea for mass spectrometry.
4.38; N, 20.28. Found: C, 52.38; H, 4.49; N, 20.37. IR: m
max (neat, cmÀ1): 2924 (w),
1604 (s), 1558 (m), 1541 (m), 1485 (w), 1457 (w), 1356 (m), 1265 (m), 1170 (s),
1119 (m); 1H NMR (400 MHz, CDCl3), dH: 1.63–1.73 (1H, m, CHH), 1.88–2.09 (2H,
m, CH2), 2.27 (1H, dddd, J 2.8, 6.2, 6.6, 12.4, CHCHHCH2), 3.12 (1H, ddd, J 6.6, 9.9,
9.9, NCHH), 3.68 (1H, ddd, J 2.4, 7.5, 9.9, NCHHCH2), 5.19 (1H, dd, J 6.2, 10.2,
NCHCH2), 7.62, (1H, dt, J 1.0, 7.7, ArH), 7.79 (1H, s, triazole-CH), 7.83 (1H, dt, J 1.5,
8.0), 8.10 (1H, dd, J 1.5, 7.7), 8.15 (1H, dd, J 1.0, 8.0, ArH). 13C: dC (100 MHz, CDCl3):
24.4 (CH2), 35.4 (CH2), 50.0 (CH2), 55.1 (CH), 125.4 (CH), 128.7 (CH), 129.3 (CH),
130.9 (q), 133.5 (q), 134.1 (CH), 134.4 (CH), 136.8 (q); m/z (electrospray) HRMS:
calcd for C12H12N4O2S + H+ = 277.0754, found: 277.0752.
References and notes
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(including DEPT, COSY, HSQC and HMBC spectra), mass spectra, HRMS/
microanalysis and IR spectra. As a typical example, in which the alkyne could
be isolated, 3-iso-propyl-1,2,3-triazolo[1,5-a][1,4]benzodiazepin-5-one (29b)
was obtained as follows: To the aldehyde (27b) (118 mg, 0.48 mmol) in
anhydrous MeOH (5 mL) were added K2CO3 (132 mg, 0.96 mmol) and the
Bestmann–Ohira reagent19 (111 mg, 0.58 mmol). The mixture was stirred at
room temperature under an atmosphere of dry N2 for 4 h, whereupon saturated
aqueous NH4Cl (10 mL) was added. The mixture was extracted with CH2Cl2
(4 Â 10 mL), the combined organic layers were dried (MgSO4), filtered and
concentrated by reduced pressure rotary evaporation. Purification on a column
of silica gel (20 g) using EtOAc and hexane (1:3) as the eluent gave the alkyne
(90 mg, 78%). The alkyne (73 mg, 0.30 mmol) was dissolved in anhydrous CHCl3
(10 ml) and heated at reflux for 72 h. The solvent was removed and the residue
was purified on a column of silica gel (10 g) using EtOAc and hexane (1:1) as the
eluent to yield the product as a pale yellow solid (72 mg, 99%), mp 124–126 °C.
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IR:
m
max (neat, cmÀ1): 3174 (m), 3047 (m), 2958, 2860 (w), 1651 (s), 1605 (m),
1580 (m), 1469 (s), 1395 (s), 1350 (m), 1245 (m), 990 (m), 842 (m), 754 (s); 1
H
NMR (400 MHz, CDCl3), dH: 1.00 (3H, d, J 6.0, Me), 1.18 (3H, d, J 6.6, Me), 2.20–2.26
(1H, br m, CHMe2), 4.13 (1H, dd, J 6.4, 9.8, NHCH), 7.59 (1H, dt, J 7.7, 1.1,
NCHHCH2), 7.68, (1H, s, triazole-CH), 7.74 (1H, dt, J 8.0, 1.5, ArH), 8.05 (1H, dd, J
8.0, 0.8, ArH), 8.11 (2H, dd + br s, J 7.7, 1.5, ArH + NH); 13C: dc (100 MHz, CDCl3):
19.2 (Me), 20.3 (Me), 29.3 (CH), 52.2 (CH), 123.0 (CH), 126.2 (q), 129.1 (CH), 130.6
(CH), 131.7 (CH), 133.3 (CH), 133.5 (q), 138.4 (q), 168.1 (q); m/z (electrospray)
HRMS: calcd for C13H14N4O + Na+ = 265.1060, found: 265.1064.
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