A thiazine-S-oxide, Staudinger/aza-Wittig based synthesis of benzodiazepines and benzothiadiazepines

Article abstract of DOI:10.1016/S0040-4039(00)01797-4

A new approach to the synthesis of imine containing 1,2,5-benzothiadiazepine-1,1-dioxides and 1,4-benzodiazepin-5-ones using iminophosphoranyl thiazine-S-oxides as precursors is reported. Key steps include a Staudinger reaction, an aza-Wittig reaction and

Full text of DOI:10.1016/S0040-4039(00)01797-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10107–10110
A thiazine-S-oxide, Staudinger/aza-Wittig based synthesis of
benzodiazepines and benzothiadiazepines
Balques Anwar,a Paul Grimsey,a Karl Hemming,a,* Matthew Krajniewskib and
Christina Loukoua
aDepartment of Physical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
bSchool of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 10 August 2000; accepted 11 October 2000
Abstract
A new approach to the synthesis of imine containing 1,2,5-benzothiadiazepine-1,1-dioxides and
1,4-benzodiazepin-5-ones using iminophosphoranyl thiazine-S-oxides as precursors is reported. Key steps
include a Staudinger reaction, an aza-Wittig reaction and the conversion of a thiazine-S-oxide into an
amino ketone via a [2,3] sigmatropic rearrangement. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: benzodiazepines; benzothiadiazepines; aza-Wittig reaction; thiazine-S-oxides.
Interest in the chemistry, synthesis and biology of the 1,4-benzodiazepine1 pharmacophore
and related heterocycles, such as the 1,2,5-benzothiadiazepines,2 continues to be fuelled not only
by their activity against a variety of CNS disorders, but also by a range of biological activities
against other disease states. Amongst the imine containing systems of interest are pyrrolobenzo-
diazepine natural products3,4 such as the antitumour antibiotic DC-815 1, and the pyrrolo-1,2,5-
benzothiadiazepine 2, which is representative of a novel class of non-nucleosidic reverse
transcriptase inhibitors.6 Amongst the many1 tricyclic systems of interest are the 1,4-diazepines,
such as nevirapine7 3 and the 1,2,5-thiadiazepines8 such as compound 4, which show activity as
non-nucleosidic inhibitors of reverse transcriptase (Fig. 1).
O
O
H
R1
O2
S
O2
S
MeO
HO
N
N
N
N
N
X
N
N
N
N
N
Y
N
R
1
2
4
3
Figure 1.
* Corresponding author. Tel: +44 1707 284568; fax: +44 1707 484644; e-mail: k.v.hemming@herts.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01797-4

10108
We wish to report herein a four step synthetic protocol, summarised in Scheme 1, by which
the imine containing 1,4-benzodiazepines and 1,2,5-benzothiadiazepines 6 are accessed from
iminophosphoranyl thiazine-S-oxides9 5. As an example, our route allows access to the tricyclic
fused systems 7a and 7b in 49 and 57% yields from the thiazine-S-oxides 5 (X=CO or SO2;
R=n-Bu; R1–R1=ꢀ[CH2]2ꢀ).
R1
X
NH
X
i. - iv.
N
R1
X
N
NH
S
49 - 63%
R1
N
N
O
R1
PR3
5 X = SO2 or CO
6 X = SO2 or CO
R1 = H, Me, or R1-R1 = [-CH2]2-
7a, X = CO;
7b, X = SO2
R = n-Bu, Ph
R1 = H, Me, or R1-R1 = [-CH2]2-
Scheme 1. Reagents and conditions: (i) 2.1 equiv. PhMgBr, THF, −40°C then aqueous work up; (ii) P(OMe)3, MeOH,
60°C; (iii) Dess–Martin oxidation; (iv) toluene or xylene, reflux
The details of the synthesis are summarised in Scheme 2. Thus, the reaction of the
thiazine-S-oxides 5 (R=Bu; X=CO or SO2; R1=H, Me or R1–R1=ꢀ[CH2]2ꢀ) with phenyl
magnesium bromide gave the allylic sulfoxides 8, which were used without further purification.
Treatment of the allylic sulfoxides 8 with hot methanolic trimethyl phosphite under rigorously
dry conditions resulted in the expected9,10 [2,3] sigmatropic rearrangement, which furnished the
alcohols 10 via the intermediate sulfenate esters 9. Alcohols 10 were isolated in good yield, and
were converted into the ketones 11 by Dess–Martin oxidation11 using the sodium thiosulfate
work-up procedure.12 Ketones 11 were heated in boiling toluene or xylene, whereupon intramolec-
ular aza-Wittig reaction13,14 furnished the desired heterocycles 6 (X=CO or SO2; R1=H, Me or
R1–R1=ꢀ[CH2]2ꢀ) in 49–63% overall yield from the thiazine-S-oxides 5. With the triphenyl derived
iminophosphoranyl thiazine-S-oxides 5 (R=Ph; X=CO or SO2; R1=H, Me), we observed
hydrolysis of the iminophosphorane functionality, indicative of the greater reactivity of the P-aryl
iminophosphoranes.13,15 We are currently exploring the use of the polystyryldiphenylphosphine
polymer supported system 5 (R=polystyrene polymer support), which should allow transfer of
the chemistry in Schemes 1 and 2 to the solid phase.16 This offers future potential for the generation
of combinatorial libraries of benzodiazepines, an area of continuing interest.17–22
R1
R1
R1
OH
X
X
N
X
N
N
H
N
H
Ph
N
H
Ph
O
S
57-83%
from 5
S
N
R1
R1
R1
O
PR3
PR3
PR3
R1
8
9
10
O
X
X
N
NH
N
H
+
R1
O PR3
> 90%
R1
N
PR3
R1
11
6
Scheme 2.

10109
The thiazine-S-oxides 5 required for this work were readily available, as shown in Scheme 3.
Thus, the reaction of o-aminobenzamide or o-aminobenzenesulfonamide 12 with HONO,
followed by treatment with sodium azide, furnished the azides 13 in excellent yields. Treatment
of compounds 13 with thionyl chloride23,24 gave the N-sulfinyl dienophiles 14 which underwent
in situ hetero Diels–Alder reaction to give the adducts 15, as single diastereoisomers where
relevant, in 77–95% yield from 13. The stereochemistry of adducts 15 were determined by X-ray
crystallographic studies. Treatment of the azide functionality of adducts 15 with either
triphenylphosphine, tri-n-butylphosphine or polystyrene supported triphenylphosphine25
resulted in near quantitative Staudinger reaction15 to yield the desired iminophosphoranyl
thiazine-S-oxides 5.
O
X
X
X
i.
ii.
NH2
NH2
N S
80-90%
NH2
N3
N3
12 X = CO or SO2
13
14
R1
N
X
iv.
>90%
iii.
5 X = SO2 or CO
S
R = n-Bu, Ph or polymer support
R1 = H, Me, or R1-R1 = [-CH2]2-
77-95%
[2 steps]
N3 O
R1
15
Scheme 3. Reagents and conditions: (i) c.HCl (aq.), NaNO2, 0°C; then NaN3, H2O, NaOAc; (ii) 1.1 equiv. of SOCl2,
6 equiv. of pyridine, CH2Cl2, 25°C, 4 hours; (iii) R1CHꢁCHꢀCHꢁCHR1, CH2Cl2, 25°C, 18 hours; (iv) PR3 (see text),
toluene or THF
In summary, we have developed a reliable synthesis of benzodiazepines and benzothiadi-
azepines 6 starting from readily accessible iminophosphoranyl thiazine-S-oxides. Our synthesis
relies upon the conversion of the thiazine-S-oxide functionality into an amino ketone, followed
by aza-Wittig reaction to furnish the heterocycle. We are currently developing the chemistry of
thiazine-S-oxides to allow an entry into the pyrrolobenzodiazepines and pyrrolobenzothiadi-
azepines, and are also expanding our route to include the synthesis and use of chiral,
non-racemic thiazine-S-oxides.
Acknowledgements
We thank the Nuffield Foundation for the award of an Undergraduate Research Bursary
[URB AT/100/96/0262 to M.K.], the EPSRC for the award of a Standard Research Grant [grant
number GR/M45948] and the Universities of Bath and Hertfordshire for financial and technical
assistance.
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10110
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