A straightforward synthesis of 4-substituted 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides

Article abstract of DOI:10.1016/S0040-4039(00)01778-0

4-Substituted 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides 11 have been efficiently prepared in two steps from the suphamide 9 by condensation of anion II, derived from 9 by metal-halogen exchange, with aromatic and aliphatic aldehydes and cyclodehydration of the so-formed alcohols 10 under acidic conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01778-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9819–9823
A straightforward synthesis of 4-substituted
3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides
Javier Agejas,a Jose L. Garc´ıa-Nav´ıoa and Carlos Lamasb,*
aDepartamento de Quimica Organica, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain
bCentro de Investigacion Lilly S.A., Avnda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
Received 15 September 2000; accepted 10 October 2000
Abstract
4-Substituted 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides 11 have been efficiently prepared in
two steps from the suphamide 9 by condensation of anion II, derived from 9 by metal–halogen exchange,
with aromatic and aliphatic aldehydes and cyclodehydration of the so-formed alcohols 10 under acidic
conditions. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: bicyclic heterocyclic compounds; benzothiazines; lithiation; cyclization.
Heterocycles incorporating a sulfamido moiety have been reported to possess a variety of
interesting biological activities.1 For example, aminothiadiazole 1,1-dioxides have shown antihy-
pertensive and vasodilating properties.2 Sedative and mild tranquilizer behaviors have also been
reported for benzothiadiazine dioxides.3 Special mention should be made of bentazone (3-iso-
propyl-1H-2,1,3-benzothiadiazin-4-one 2,2-dioxide) which presents an important herbicidal
activity.4
The usual procedure for the preparation of fused 1H-2,1,3-thiadiazine 2,2-dioxides is a
two-step approach involving sulfamoylation of ortho substituted amino derivatives 1 followed by
ring closure.1 Thus, from o-aminobenzoates, o-aminobenzonitriles or 2-aminobenzophenones
4(3H)-oxo,5 4-amino6 or 4-phenyl7 1H-2,1,3-benzothiadiazines 3 or 4 have been obtained
respectively (Scheme 1).
Catalytic hydrogenation of 4 (X=Ph, CH3), using Adams catalyst, yielded the corresponding
3,4-dihydro derivatives 5. These compounds can be prepared directly by reaction of 2-aminoben-
zylamines 6 (X=H) with either sulfuryl chloride8 or sulfamide.9 More recently, Pews reported
the synthesis of 3-alkyl derivatives 7 by reaction of N-alkyl-N%-arylsufamides 2 (G=H) with
trioxane.10 The scope of these methods is related to the substitution in the benzo moiety and so
the C4 position was unsubstituted in almost all cases.
* Corresponding author. Fax: 34 91 6633411; e-mail: lamas carlos@lilly.com
–
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01778-0

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Scheme 1.
As 4-substituted 1H-2,1,3-benzothiadiazine 2,2-dioxides 11 were required for new drug
candidate synthesis, we decided to explore a more straightforward synthetic approach. A simple
retrosynthetic analysis led us to recognize that o-iodoaniline 8 could be a suitable precursor
(Fig. 1). So we decided to explore this approach by carrying out, as the key step, the
condensation of the corresponding ArLi derived from 9 with aldehydes in order to get alcohols
10, which could subsequently be cyclodehydrated under acidic conditions.
Figure 1.
In this communication, we report the successful transformation of 9 (R3=i-Pr, obtained from
8 by a standard procedure10) into 1111 via this approach, thus allowing different substitution
patterns at C-4.
The synthesis of 10 required the formation of the trianion II, necessitating the removal of the
two acidic protons of 9 before the metal–halogen exchange. For this purpose, we chose
methylmagnesium bromide, a base which would not interfere with the halogen. The deprotona-
tion was performed at 0°C in THF until no further methane evolution was observed. For the
metal–halogen exchange, tert-BuLi was the reagent of choice due to its high iodine affinity, even
in the presence of sensitive groups.12 The process took place at −78°C over 20 min. Finally, the
addition of the electrophile gave the desired alcohol 10 (Scheme 2).
The condensation of II with aromatic and aliphatic aldehydes worked well (Table 1, entries
a–g) giving 10 in good yields. The only exception was aldehyde of entry h, where the tribromoac-

9821
Scheme 2.
etaldehyde acted as a bromine donor, affording 12 (Fig. 2) in 70%. However, when ketones were
used as electrophiles (entries j–l) the condensation did not proceed, with only reduced product
13 (Fig. 2) being isolated in more than 80%. In order to increase the reactivity of the ketones,
Et2O·BF3 was added to the reaction but this only yielded a complex mixture of products.
Table 1
Two-step synthesis of 4-substituted 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides 11

9822
Figure 2.
The one exception was cyclobutanone (entry i), which condensed quite well to yield the
expected alcohol 10i in 73% yield. These results can be explained by the facile enolization of
both cyclopentanone and acetophenone when II is present, while the enolate of cyclobutanone
possesses high skeletal strain and so is less readily formed. In this case the enolization is not
thermodynamically favored and so the reaction with II can occur. Furthermore, the driving
force of the condensation in this case could be associated with a release of strain when
cyclobutanone reacts with II.
The final step was the acid-catalyzed cyclodehydration of the benzylic alcohols 10. Methane-
sulfonic acid was initially used, producing the expected heterocycle 11 in high yield. However,
4-pyridine carbaldehyde required more vigorous conditions (reflux temperature), probably due
to the protonation of the basic nitrogen atom. For the five-membered heterocyclic aldehydes
(Table 1, entries b–d), trifluoroacetic acid, a weaker acid, was used yielding the expected
products in good yields in the case of the thiophene carbaldehydes and a very poor yield (24%)
for the furyl derivative. The sensitivity of the furan ring toward acid media required the
cyclization of 10d to be run at low temperature (−30°C, saturated ethereal solution of hydrogen
chloride) in order to obtain a reasonable (70%) yield of 11d. Finally, in the case of alcohols 10
derived from aliphatic aldehydes (Table 1, entries f and g), the dehydration to the corresponding
alkene was a competing process, this being the sole isolated product in the case of 10g (70%),
while 11f was isolated in 67% yield, with only a 15% yield of the alkene side product.
Representative experimental procedure:
Compound 10: To a solution of the iodo derivative 9 (1.0 g, 2.94 mmol) in dry THF (30 mL)
stirred at 0°C was added a 3 M solution of methyl magnesium bromide (2.15 mL, 6.47 mmol).
The mixture was stirred for 1 h and then cooled to −78°C. A 1.7 M solution of tert-BuLi (3.8
mL, 6.47 mmol) was added and the solution stirred at this temperature for 30 min, then the
carbonyl derivative (1.2 mol) was added at −78°C. The mixture was then heated to room
temperature. After 1 h at this temperature, the reaction mixture was quenched with saturated
ammonium chloride solution and extracted into CH2Cl2 (3×25 mL). The combined organic
phases were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by
flash chromatography using hexane/EtOAc (8:2) as eluent.
Compound 11: To a solution of the benzylic alcohol 10 (1 mmol) in CH2Cl2 (15 mL) was
added the corresponding acid (5 mmol) and the mixture was stirred as described for each case
(see footnotes to Table 1). The reaction mixture was quenched with saturated NaHCO3 solution
and worked-up as indicated above for 10. The crude mixture was purified by flash chromatog-
raphy using hexane/EtOAc (8:2) as eluent. The oily product obtained crystallized as a white
powder on standing with hexane.

9823
Acknowledgements
This research was supported by the Spanish PROFARMA program (Ministerio de Industria).
J.A. is grateful to Lilly S. A. for a fellowship.
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