Synthesis of benzothiadiazines, benzothiadiazepines, and benzothiadiazocines from intramolecular azide reactions and iodocyclisations

Article abstract of DOI:10.1055/s-0029-1218278

N-Homoallyl-substituted (2-aminoaryl)sulfonamides undergo intramolecular iodocyclisation to furnish aziridine-fused 1,2,6-benzothiadiazocines. The identical aziridine-fused 1,2,6-benzothiadiazocines were also available from an intramolecular azide to alke

Full text of DOI:10.1055/s-0029-1218278

LETTER
3043
Synthesis of Benzothiadiazines, Benzothiadiazepines, and Benzothiadiazocines
from Intramolecular Azide Reactions and Iodocyclisations
S
ynthesis of Benz
i
othiadia
l
zines,
e
B
enzothiad
s
iazepines,
h
andBenzothiadiaz
P
ocines atel, Christopher S. Chambers, Karl Hemming*
Department of Chemical and Biological Sciences, University of Huddersfield, Huddersfield, West Yorkshire, HD1 3DH, UK
Fax +44(1484)472182; E-mail: k.hemming@hud.ac.uk
Received 17 July 2009
iodocyclisation11 would then yield the corresponding pyr-
rolidine system 7, which would serve as a useful precursor
for the synthesis of the PBTD nucleus 2, via, for example,
loss of HI, oxidation to the pyrrole,12 N-formylation and
Abstract: N-Homoallyl-substituted
(2-aminoaryl)sulfonamides
undergo intramolecular iodocyclisation to furnish aziridine-fused
1,2,6-benzothiadiazocines. The identical aziridine-fused 1,2,6-ben-
zothiadiazocines were also available from an intramolecular azide
to alkene 1,3-diploar cycloaddition involving the corresponding N- Bischler–Napieralski ring closure. In the event we were
homoallylic (2-azidoaryl)sulfonamides in boiling carbon tetrachlo-
ride. The use of boiling DMF as solvent for the same reaction gave
pyrrolo-fused benzothiadiazines. Intramolecular azide–alkene cy-
membered ring and we report the results of this study
cloadditions also allowed access to aziridine-fused pyrroloben-
zothiadiazepines and pyrrolobenzodiazepines.
surprised to discover that compound 6 underwent an en-
tirely different mode of cyclisation to form an eight-
herein.
The requisite 1,2-thiazine 1-oxide precursors 4 were ac-
cessed via a hetero-Diels–Alder reaction in good overall
yield as described previously.8,9 Hydrolysis of the 1,2-thi-
azine 1-oxide moiety in compound 4 was achieved in boil-
ing THF in the presence of 2 M aqueous hydrochloric acid
to give the requisite homoallylic sulfonamide derivatives
6 in 70–80% yield, as shown in Scheme 1. With the amino
compounds 6 in hand, we subjected them to the standard
iodocyclisation conditions,11,12 namely iodine in the pres-
ence of sodium hydrogencarbonate. The products isolated
from these reactions were not the desired pyrrolidines 7,
nor any deiodo product derived therefrom. Extensive two-
dimensional NMR studies of the products led to the as-
signment of the structures as the distinctive13–16 aziridine-
fused benzothiadiazocines 8. As an example, the 1H NMR
spectrum of compound 8a (R1 = Me, R2 = H)17 showed
the absence of both of the hydrogens of the amino NH2
group but showed the presence of the easily identified sul-
fonamide NH group. The sulfonamide NH was coupled to
a methylene group which was in turn coupled to a second
methylene unit. This was attached to a quaternary but sp3
carbon and this in turn was attached to a methyl group and
also to a further methylene group. This final methylene
had no further carbon or hydrogen couplings, and showed
a clear and distinct singlet for each of its two hydrogens,
typical of such aziridines.13–16 This, together with a ratio-
nal mechanism and alternative synthesis (see below), led
to the assignment of the structure as the aziridine-fused
benzothiadiazocine 8a. NOE studies showed that the two
methyl groups in compound 8b were trans (or anti) to one
another, a feature implied the absence of any signal en-
hancement between the two methyls, and further support-
ed by a strong correlation between the hydrogen on C4 of
the 1,2,6-benzothiadiazocine ring and the C5 methyl sub-
stituent.
Key words: aziridine, azide, benzodiazocine, benzodiazepine
1,4-Benzodiazepines are one of the most studied and suc-
cessful motifs in medicinal chemistry.1 The 1,2,5-ben-
zothiadiazepines 1 (Figure 1) are less well studied but
have, nonetheless, attracted interest2 as inhibitors of met-
alloproteinases and farnesyl protein transferases, as CNS
active compounds, as non-nucleosidic reverse tran-
scriptase inhibitors (NNRTI),3–5 and as TACE inhibitors.6
The pyrrolobenzothiadiazepine (PBTD) nucleus 2 is an
analogue of the well-studied antitumour antibiotic pyr-
rolobenzodiazepines (PBD) 3,7 and has also attracted in-
terest as
a
non-nucleosidic reverse transcriptase
inhibitor.2,3 As part of a series of studies8 utilising 1,2-thia-
zine 1-oxides as precursors to bicyclic 1,2,5-benzothiadi-
azepines 1, we became interested in developing
methodologies that would allow access to the tricyclic
PBTD 2, and have already published one such route.9
O
O2
S
O2
S
Z
Y
N
N
N
N
N
N
1
2
3
Figure 1
In our search for further routes to the PBTD nucleus, we
sought to take advantage of the fact that the 1,2-thiazine-
1-oxide 4 (X = NH2, Scheme 1) should,10 on hydrolysis,
yield a sulfinic acid 5, which, after spontaneous retro-ene-
type loss of sulfur dioxide would furnish a homoallylic
sulfonamide 6. We anticipated that a 5-endo-trig
It seems logical to rationalise a mechanism whereby the
arylamino nitrogen and not the sulfonamido nitrogen in
compound 6 (Scheme 1) is the participating nucleophile
SYNLETT 2009, No. 18, pp 3043–3047
Advanced online publication: 09.10.2009
DOI: 10.1055/s-0029-1218278; Art ID: D18909ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

3044
N. Patel et al.
LETTER
O2
S
O2
S
R2
R1
R2
R1
N
S
THF, HCl (aq)
N
H
HO
X
NH2
O
S
O
4, X = NH2
5
O2
O2
S
R2
R2
R1
S
N
N
H
X
R1
NH2
NH2
I
6
7
I2, NaHCO3
O2
••
H
H
N
O
O
O
N
H
H
S
H
S
H
S
NH
O
H
R2
R1
R1
R2
H
N
N
H
I
R2
N
H
R1
6'
8a: 49%, R1 = Me, R2 = H 8b: 30%, R1 = R2 = Me 8c: 43%, R1 = R2 = H
Scheme 1
in the iodocyclisation, thereby giving the thiadiazocine products, from which the pure aziridines could only be
ring. Formation of the aziridine then follows from cyclisa- isolated in low yield (<10%). Interestingly, heating at re-
tion onto the primary alkyl iodide, paralleling well-known flux in DMF gave a reasonably clean reaction in which the
methods for the synthesis of aziridines.13–16 It is of note azides 9 were converted into single new products that
that homoallylic sulfonamide derivatives 6 can adopt con- were not the aziridines 8, and were found in fact to be the
formations, such as that shown in structures 6¢ in pyrrolo-fused 1,2,4-benzothiadiazines 11, formed in
Scheme 1, that can encourage cyclisation via the arylami- yields of 45–48%, as shown in Scheme 2.18,19
no nitrogen. Scheme 1 also shows a possible explanation
The structures of the products 11 were assigned on the
basis of their COSY, HMBC, and HSQC NMR spectra,
infrared observations (NH), and accurate mass measure-
for the trans relationship of the two methyl groups in com-
pound 8b in that the R1 and R2 groups in intermediate 6¢
occupy the two pseudo-equatorial positions shown in the
ments. All doubt was removed by X-ray crystallographic
six-membered-ring transition state, leading to the ob-
studies (Figure 2), which confirmed19 that the products
served trans stereochemistry.
were indeed the pyrrolobenzothiadiazines 11.
We thought it relevant to devise an alternative synthetic
sequence to the aziridino-fused benzothiadiazocines 8 and
O2
S
O2
S
R2
R1
R2
R1
predicted that the azides 9, shown in Scheme 2, might, on
heating, furnish directly the aziridines 8. Azides 9 were
easily synthesised in yields of 71–82% by treating the 1,2-
thiazine 1-oxides 4 (X = N3) in hot THF in the presence of
2 M aqueous hydrochloric acid. Heating azides 9a–c in
carbon tetrachloride for 7.5 hours allowed the isolation of
the aziridino-fused benzothiadiazocines 8a–c in 49%,
52%, and 34% yields, respectively. The products were
identical in all respects (including the stereochemistry of
compound 8b) to those obtained by iodocyclisation in
Scheme 1.
H2O
N
H
N
S
– SO2
N3
X
O
4, X = N3
9
reflux,
DMF
a: R1 = Me, R2 = H
b: R1 = R2 = Me
c: R1 = R2 = H
reflux,
CCl4
O2
S
H
N
O2
S
8a, 49%
8b, 52%
8c, 34%
N
R2
R2
N
R1
N
R1
H
N
N
This route presumably proceeds via an azide–alkene 1,3-
dipolar cycloaddition reaction to give an intermediate tri-
azoline 10 which, on extrusion of molecular nitrogen, fur-
nishes the desired aziridines 8, a sequence shown to be
successful for other aziridine syntheses based upon in-
tramolecular azide–alkene reactions.13–16 The conversion
of the azides 9a–c into the aziridino-fused benzothiadiazo-
cines 8a–c required exacting conditions by heating in car-
bon tetrachloride at 85 °C for 7.5 hours. Heating at reflux
in acetonitrile, THF, chloroform, or toluene gave complex
mixtures of the azide 9, aziridine 8, and other unidentified
11a, 45%
11b, 45%
11c, 48%
10
Scheme 2
A possible mechanism, which would explain the forma-
tion of compounds 11a–c is shown in Scheme 3, and in-
volves a rearrangement of the carbon backbone. Thus,
nitrene insertion into the alkene gives the primary carbon
radical 12. Hydrogen extrusion by the nitrogen followed
by rearrangement of the resulting primary carbon radical
Synlett 2009, No. 18, 3043–3047 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzothiadiazines, Benzothiadiazepines, and Benzothiadiazocines
3045
methods of installing an aziridine in the place of the usual
imine to give the aziridino-PBD 16 and 17, as outlined in
Scheme 4. The imine behaves as an electrophile in the
presence of nucleophilic residues in DNA and is responsi-
ble for the biological activity of the PBD7 – replacement
with an aziridine is thus of interest. We are aware of only
one other attempt at such a process, in which Broggini28
was able to show that the azides 15 (Z = N3; R1 = H, Cl, F;
R2 = H; X = CO) give stable triazolines 18 in carbon tet-
rachloride or toluene at 80 °C. With the analogous azide
(15, R1, R2 = H, X = CO) we were repeatedly unable to
isolate the triazoline but obtained instead (after heating in
acetonitrile at gentle reflux for 20 h) an ca. 1:1 mixture of
the aziridine (16, R1 = R2 = H) and imine 19 in combined
yields of 51–60%. Imines are common products from
azide–alkene cycloadditions.15,29 Interestingly, the sul-
fonamide (15, Z = N3; R1, R2 = H; X = SO2) gave the aziri-
dine 17 (R1, R2 = H) as the only isolated product in 44%
yield.30 The stereochemical assignment of compounds 16
and 17 was suggested by coupling constants in the range
of 8–9 Hz, by NOESY (aziridine CH2 to pyrrolidine CH
correlation and no CH-to-CH correlation) and by Broggi-
ni’s unequivocal assignment of the stereochemistries of
compounds 18 by X-ray crystallography. These prelimi-
nary results with intramolecular azide cycloadditions of
precursors 15 are most encouraging, and we are currently
exploring the scope of this process in more detail. All at-
tempts to access compounds 16 and 17 by iodination of
precursors 15 (Z = NH2) were unsuccessful due to some
unexpected iodination of the aromatic ring.
Figure 2 X-ray crystal structure for compound 11c
13 gives a rearranged carbon backbone together with the
more stable carbon radical 14. Ring closure then furnishes
the final product.
1,5-Benzodiazocines have attracted attention as ana-
logues of the 1,4-benzodiazepines,20 as novel antibacterial
compounds21 and as positive ionotropic calcium sensitis-
ing agents,22 whilst the corresponding 1,2,6-benzothiadia-
zocines are attractive as sulfur analogues of this system
and have also attracted particular attention as potential
NNRTI.23 Aziridine-fused systems are of general and
widespread utility in synthesis and as DNA alkylating
agents and potential antitumour agents.13,24 The pyr-
rolobenzothiadiazines 11 are a subclass of the larger
1,2,4-benzothiadiazine class that has attracted interest as
hepatitis C virus RNA polymerase inhibitors,25 modula-
tors of AMPA receptors,26 and as potassium ATP channel
activators.27
R1
R2
X
R1
R2
X
N
heat
N
Z = N3
– N2
H
H
Z
N
16, X = CO; R1 = R2 = H
17, X = SO2; R1 = R2 = H
15
R2
O
S
H
O
O
H
N
O
Z = N3 Broggini28
N
+
S
R1
X
N
R2
O
N
••
N
•
R1
R2
N
•
••
R1
CH2
H
N
12
Me
H
H
O
O
O
N
N
O
19, X = CO
S
N
S
R2
•
N
N
•
11
18 R1 = H, Cl, F; R2 = H
R2
•
N
N
•
H
R1
13
R1
Scheme 4
H
CH2
14
In conclusion, we have found that N-(o-arylamino)-sub-
stituted homoallylic sulfonamides undergo iodocyclisa-
tion to furnish aziridino-fused 1,2,6-benzothiadiazocines.
The same aziridino-1,2,6-benzothiadiazocines were also
available from the intramolecular azide–alkene cycload-
dition of the corresponding N-(o-arylazido)-substituted
homoallylic sulfonamides in boiling carbon tetrachloride,
whereas the use of boiling DMF gave pyrrolobenzothiadi-
azines. Intramolecular azide–alkene cycloadditions also
allowed access to aziridinopyrrolobenzothiadiazepines
and pyrrolobenzodiazepines.
Scheme 3
The successful formation of aziridino-fused systems from
the iodocyclisation and intramolecular azide processes led
us to investigate the possibility of accessing aziridino-
fused analogues of the much sought after7–9 antitumour
antibiotic pyrrolobenzodiazepines (PBD) 3, a system in
which we have been interested for some time.2,8,9 We
thought it of interest to explore the possibility of using in-
tramolecular iodocyclisation or azide cycloaddition as
Synlett 2009, No. 18, 3043–3047 © Thieme Stuttgart · New York

3046
N. Patel et al.
LETTER
Terraneo, A.; Zecchi, G. Tetrahedron 1999, 55, 14803.
(d) Broggini, G.; Molteni, G.; Zecchi, G. Synthesis 1995,
647.
Acknowledgment
We thank the University of Huddersfield (NP) and the EPSRC-
DTA (CSS) for funding and the EPSRC National Mass Spectrome-
try Service, University of Wales, Swansea.
(17) Typical Procedure for the Synthesis of Compounds 8a–c
To a stirred solution of the homoallylic 2-aminobenzene-
sulfonamide 6a–c (0.15–0.30 g, 1.0 equiv) and NaHCO3 (3.0
equiv) i n dry MeCN (10 mL) was added portionwise finely
powdered iodine (3.0 equiv). The reaction mixture was
stirred at r.t. until TLC showed no starting material (ca. 4 h)
at which point the reaction mixture was treated with sat. aq
Na2S2O3 until decolourisation occurred. The resulting
solution was extracted with CH2Cl2 (3 × 20 mL), and the
combined organic extracts dried (MgSO4), filtered, and
concentrated by rotary evaporation. The crude product was
purified by gravity column chromatography (SiO2) using
PE–EtOAc (3:2) as the eluent. Compound 8a was obtained
single spot pure [Rf = 0.3 (PE–EtOAc, 2:3)] as a yellow oil
(0.161 g, 49% yield) from the N-(butenyl)-2-
References and Notes
(1) Tucker, H.; LeCount, D. J. In Comprehensive Heterocyclic
Chemistry II, Vol. 9; Rees, C. W.; Katritzky, A. R.; Scriven,
E. F. V., Eds.; Elsevier Science: Oxford, 1996, Chap. 9.06,
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aminobenzenesulfonamide (6a, 0.320 g).
Analytical Data
1H NMR (400 MHz, CDCl3): d = 1.35 (3 H, s, Me), 1.51 (1
H, dd, J = 11.2, 8.4 Hz, CMeCH2CH2NH), 2.02 (1 H, ddd,
J = 8.4, 5.9, 2.5 Hz, CMeCH2CH2NH), 2.11 (1 H, s, aziridino
CH), 2.33 (1 H, s, aziridino CH), 3.36 (1 H, m, CH2CH2NH),
3.79 (1 H, ddd, J = 15.0, 7.5, 6.1 Hz, CH2CH2NH), 5.32 (1
H, t, J = 6.1 Hz, SO2NH), 6.85 (1 H, d, J = 7.9 Hz, ArH), 6.98
(1 H, dt, J = 8.4, 0.8 Hz, ArH), 7.35 (1 H, dt, J = 8.4, 1.4 Hz,
ArH), 7.83 (1 H, dd, J = 7.9, 1.3 Hz, ArH). 13C NMR (100
MHz, CDCl3): d = 20.2 (CH3), 35.8 (CH2), 39.2 (CH2), 40.2
(CH2), 43.9 (q), 121.7 (CH), 122.0 (CH), 128.6 (CH), 129.6
(q), 133.0 (CH), 147.8 (q). IR: nmax = 3101 (br m), 2953 (m),
2896 (m), 1591 (m), 1472 (s), 1439 (m), 1333 (s), 1216 (s),
1158 (s), 866 (m) cm–1. HRMS (ES+): m/z calcd for
C11H14N2O2S: 239.0849; found: 239.0845 (100%) [M + H]+.
(18) Typical Procedure for the Synthesis of Compounds
11a–c
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A solution of the N-(butenyl)-2-azidobenzenesulfonamide
9a–c (ca. 100 mg) in DMF (5 mL) was heated at reflux
temperature until TLC showed no starting material (2–3 h).
The mixture was cooled, the solvent removed by reduced
pressure rotary evaporation, and the residue purified by flash
silica column chromatography (PE–EtOAc = 3:2). As an
example, pyrrolo-1,2,4-benzothiadiazine 11b (76 mg, 45%)
was obtained from azidobenzenesulfonamide 9b (130 mg).
Analytical Data
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1H NMR (400 MHz, CDCl3): d = 1.73 (3 H, s, CH3), 1.78 (3
H, d, J = 7.2 Hz, CH3), 1.88 (1 H, dd, J = 13.0, 10.2 Hz,
CMeCHHCHMe), 2.21 (1 H, dd, J = 13.0, 7.1 Hz,
CMeCHHCHMe), 2.41–2.48 (1 H, m, [(CH2)2CHMe], 3.23
(1 H, dd, J = 10.3, 7.0 Hz, NCHH), 3.58 (1 H, dd, J = 10.0,
7.0 Hz, NCHH), 4.56 (1 H, s, NH), 6.61 (1 H, d, J = 8.4 Hz,
ArH), 6.76 (1 H, t, J = 8.0 Hz, ArH), 7.24 (1 H, td, J = 8.4,
1.3 Hz, ArH), 7.68 (1 H, dd, J = 8.0, 1.3 Hz, ArH). 13C NMR
(100 MHz, CDCl3): d = 18.6 (CH3), 27.2 (CH3), 28.3 (CH),
51.0 (CH2), 57.9 (CH2), 79.8 (q), 115.3 (CH), 117.5 (CH),
129.3 (CH), 133.2 (CH), 142.3 (q), 145.0 (q). IR (thin film):
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n
max = 3366 (s), 2965 (s), 2932 (s), 1677 (m), 1605 (s), 1484
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(s), 1453 (s), 1322 (s), 1157 (s), 751 (s) cm–1. HRMS (ES+):
m/z calcd for C12H16N2O2S + H+: 253.1005; found: 253.1008
[M + H]+.
(19) For full details (including X-ray crystallographic data), see:
Nilesh Patel, PhD Thesis; University of Huddersfield: UK,
2006.
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Synlett 2009, No. 18, 3043–3047 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzothiadiazines, Benzothiadiazepines, and Benzothiadiazocines
3047
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(21) Bremner, J. B.; Sengpracha, W. Tetrahedron 2005, 61, 941.
(22) Herold, P.; Herzig, J. W.; Wenk, P.; Leutert, T.; Zbinden, P.;
Fuhrer, W.; Stutz, S.; Schenker, K.; Meier, M.; Rihs, G.
J. Med. Chem. 1995, 38, 2946.
(23) Di Santo, R.; Costi, R.; Artico, M.; Massa, S. J. Heterocycl.
Chem. 1996, 33, 2019.
(28) (a) Broggini, G.; De Marchi, I.; Martinelli, M.; Paladino, G.;
Pilati, T.; Terraneo, A. Synthesis 2005, 2246. (b) Broggini,
G.; De Marchi, I.; Martinelli, M.; Paladino, G.; Pennoni, A.
Lett. Org. Chem. 2004, 1, 221.
(29) Santagada, V.; Perissutti, E.; Fiorino, F.; Vivenzio, B.;
Caliendo, G. Tetrahedron Lett. 2001, 42, 2397.
(24) (a) Hodgkinson, T. J.; Shipman, M. Tetrahedron 2001, 57,
4467. (b) Zang, H.; Gates, K. S. Biochemistry 2000, 39,
14968. (c) Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner,
D. L.; Li, V. S.; Na, Y.; Kohn, H. J. Am. Chem. Soc. 2003,
125, 15796.
(25) Zhou, Y. F.; Webber, S. E.; Murphy, D. E.; Li, L. S.;
Dragovich, P. S.; Tran, C. V.; Sun, Z. X.; Ruebsam, F.; Shah,
A. M.; Tsan, M.; Showalter, R. E.; Patel, R.; Li, B.; Zhoa, Q.;
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(30) Analytical Data for Compound 16 (X = CO, R1 = R2 = H)
1H NMR (400 MHz, CDCl3): d = 2.00 (1 H, d, J = 3.6 Hz,
aziridine CH2), 2.04–2.16 (3H, m, CH2 + CHH), 2.18–2.26
(1 H, m, CHH), 2.53 (1 H, d, J = 4.3 Hz, aziridine CH2), 2.78
(1 H, ddd, J = 9.5, 4.3, 3.6 Hz, aziridine CH), 3.34 (1 H, ddd,
J = 9.5, 2.9, 1.6 Hz, pyrrolidine CH), 3.62–3.69 (1 H, m,
NCH2), 3.81–3.95 (1 H, m, NCH2), 7.01 (1 H, dt, J = 7.9, 0.7
Hz, ArH), 7.11 (1 H, d, J = 8.1 Hz, ArH), 7.44–7.52 (1 H, m,
ArH), 7.74 (1 H, d, J = 7.9 Hz, ArH). 13C NMR (100 MHz,
CDCl3): d = 23.1 (CH2), 29.4 (CH2), 32.7 (CH2), 44.8 (CH),
46.1 (CH2), 58.1 (CH), 122.0 (CH), 122.9 (CH), 126.8 (q),
129.7 (CH), 131.2 (CH), 145.6 (q), 150.3 (q). IR (thin film):
(26) Francotte, P.; de Tullio, P.; Goffin, E.; Dintilhac, G.;
Graindorge, E.; Fraikin, P.; Lestage, P.; Danober, L.;
Thomas, J.-Y.; Ciagnard, D.-H.; Piroote, B. J. Med. Chem.
2007, 50, 3153.
nmax = 3063 (m), 2979 (m), 1625 (s), 1456 (s), 1405 (s), 1039
(m), 922 (m), 766 (s), 730 (s), 704 (s) cm–1. HRMS (ESI+):
m/z calcd for C13H14N2O + H+: 215.1179; found: 215.1178
[M + H]+.
Synlett 2009, No. 18, 3043–3047 © Thieme Stuttgart · New York

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