Efficient synthesis of 4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides

Article abstract of DOI:10.1016/S0040-4039(00)01779-2

A simple method for the preparation of 4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides is described. Treatment of N-sulfonyl ketimines 2 and 3 with different carbon nucleophiles afforded the corresponding of 4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides 1 in isolated yields of 35-84%. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01779-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9825–9828
Efficient synthesis of
4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine
2,2-dioxides
Esteban Dom´ınguez,a,* Jesu´s de Blas,a Miriam del Prado,b,† M. Teresa Aranda,b
M. Carmen Carren˜ob and Jose´ L. Garc´ıa Ruanob
aCentro de Investigcio´n de Lilly S. A. Avda. de la Industria 30, Alcobendas 28108, Madrid, Spain
bDepartamento Qu´ımica Orga´nica (C-I) Universidad Auto´noma, Cantoblanco 28049, Madrid, Spain
Received 18 September 2000; accepted 10 October 2000
Abstract
A simple method for the preparation of 4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-
dioxides is described. Treatment of N-sulfonyl ketimines 2 and 3 with different carbon nucleophiles
afforded the corresponding of 4,4-disubstituted-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxides 1 in
isolated yields of 35–84%. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: benzothiazines; carbanions.
Among the components of the bicyclic diazine group of heterocyclic compounds,1 benzothia-
diazine-S,S-dioxides are of special interest because of their biological properties. For instance,
diazoxide has been shown to produce muscle relaxation2 and bentazone is a potent herbicide.3
Other members of this family show antihypertensive and vasodilating properties,4 as well as
sedative effects.5 4-Substituted-1H-2,1,3-benzothiadiazine-2,2,-oxides and their 3,4-dihydro ana-
logues are also valuable intermediates in the preparation of disinfectants, bleaching agents and
antiseptics.6 Racemic7 and optically active8 4,4-disubstituted compounds derived quinazolin-
2(1H)-ones, C=O analogues of S,S-dioxides, have been recently reported as a novel group of
non-nucleoside HIV-1 reverse transcriptase inhibitors.
To our knowledge, no 4,4-disubstituted analogue derived from 3,4-dihydro-1H-2,1,3-benzoth-
iadiazine-2,2-dioxides is known, probably as a consequence of the procedures generally applied
to the construction of the heterocyclic moiety. These are mainly based on the transformation of
anilines bearing a carbonyl,9 ester or a nitrile10 group in the ortho position upon treatment with
* Corresponding author. Tel: +34 91 663 34 06; fax: +34 91 663 34 11; e-mail: dominguez esteban@lilly.com
–
†
Present address: Lilly S. A. Avda. de la Industria 30, Alcobendas 28108, Madrid, Spain.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01779-2

9826
sulfamide giving rise to C-4 sp2 derivatives. 3,4-Dihydro benzothiadiazines are available from
2-amino benzylamine and sulfuryl chloride11 or sulfamide12 or by reaction of N-alkyl-N%-arylsul-
famides with trioxane.13
In connection with a program directed towards the synthesis of new drug candidates, we
focused on unknown 4,4-disubstitued-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxides 1
(Table 1). In order to design a versatile and general approach, we chose to use easily available
4-substituted derivatives 2 and 3 as starting materials since an organometallic addition should
provide a direct access to 1. Although the electrophilic character of 2 and 3, cyclic N-sulfonyl
ketimines, was predicted to be low, the method would provide a short access to 1. In this paper
we report the efficient synthesis of 4,4-disubstituted derivatives 1 based on the addition of
different carbon nucleophiles to 2 and 3 previously activated by association with BF3·OEt2. The
generality of this reaction is documented by a wide range of nucleophiles, which allow the
obtention of polyfunctionalized derivatives.
Table 1
Organometallic addition to 4-substituted-1H-2,1,3-benzothiadiazine 2,2-dioxides
Entry
Starting material
R2M
T (°C)
Product14
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
EtMgBr
CH2ꢀCHMgBr
MeLi
0–rt
0–rt
1a
1b
1c
1d
1e
1f
1g
1h
1ia
1j
1k
1l
1m
1n
1o
35
34
65
84
62
75
75
60
45
82
65
55
65
64
48
−78
−78
−78
−78
−78
−78
−78–rt
−78
−78
−78
−78
−78
−78–rt
PhLi
2-Li-1,3 dithiane
LiCH2CO2Et
LiCH2CONMe2
LiCH2SO2Ph
LiCH2SOTol
PhLi
2-Li-1,3 dithiane
LiCH2CO2Et
LiCH2CONMe2
LiCH2SO2Ph
LiCH2SOTol
a It was isolated as a 60:40 mixture of diastereomers as a consequence of the inherent chirality of the sulfoxide,
which results in the formation of a product with two stereogenic centers.
The syntheses utilized the precursors 1-allyl-4-methyl-1H-2,1,3-benzothiadiazine-2,2-dioxide 2
and the analogue 4-phenyl substituted derivative 3, which were prepared as indicated in Scheme
1 from 2-amino acetophenone and 2-amino benzophenone, respectively, following the method

9827
described by Wright9 to generate the thiadiazine ring and further N-allylation of 4 and 5
(LHDMS, DMF, allyl bromide 87% for 2 and 85% for 3). We choose the N-allyl substituent
with the aim of further functionalizing this chain en route to more complex structures.
Scheme 1.
Reaction of EtMgBr with 2 did not give the desired addition product, the starting material
being recovered unchanged after several days. We then tried to increase the electrophilic
character of ketimine 2 by precomplexation with different Lewis acids. Previous treatment of 2
with zinc bromide or ytterbium triflate, followed by addition of the Grignard reagent allowed
the formation of the 4-ethyl-4-methyl substituted derivative 1a in low yield. The best results were
obtained by using BF3·OEt2 as Lewis acid (Table 1, entry 1). When a THF solution of 2 was
sequentially treated with BF3·OEt2 (1 equiv., rt, 30 min) and EtMgBr (3 equiv., 0°C to rt) a 35%
yield of 1a could be isolated pure after flash column chromatography.‡ This reaction was
extended to a series of organometallic derivatives and the results are included in Table 1. Thus,
vinyl magnesium bromide behaved similarly giving rise to 1b in 34% isolated yield (Table 1,
entry 2). The moderate yield which resulted from Grignard reagents could be improved by using
the more nucleophilic MeLi, which gave 4,4-dimethyl substituted compound 1c in a 65% yield
(Table 1, entry 3). Treatment of 2 with PhLi in the conditions indicated in Table 1 (entry 4)
provided an 84% yield of 1d.
To further extend the scope of this 1,2-addition process, we focused on the synthesis of
4,4-disubstitued-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxides 1 bearing a more function-
alized substituent at C-a or C-b. With this aim, the use of stabilized lithium carbanions was
checked. Reaction of 2 with an excess of the lithium salt derived from 1,3-dithiane (n-BuLi,
−78°C) smoothly yielded compound 1e (Table 1, entry 5, 62%), a a-formyl tertiary carbinamine
precursor. Lithium enolates derived from ethyl acetate and N,N-dimethyl acetamide were also
able to give the addition products 1f and 1g upon reaction with 2 in good yields (Table 1, entries
6 and 7). Other stabilized anions such as those resulting from the in situ treatment of methyl
phenyl sulfone with n-BuLi or methyl p-tolyl sulfoxide with LDA reacted with 2 in the presence
of BF3·OEt2 to give the corresponding addition products 1h and 1i (Table 1, entries 8 and 9).
‡ Typical experimental procedure for the preparation of 1a: To a solution of the imine (1 equiv.) in dry
tetrahydrofuran (10 mL) in a dry flask under N2 was added BF3·OEt2 (1 equiv.), the reaction mixture was stirred at
room temperature for 1 h. EtMgBr (3 equiv.) was added at 0°C and then allowed to warm to ambient temperature
and the mixture was stirred for 4 h. It was hydrolyzed with saturated aqueous NH4Cl, extracted with ethyl acetate,
dried over sodium sulfate and evaporated to give the crude product. The crude material was purified by flash
chromatography (AcOEt/Hexane 1:3) to give 1a (34% yield).

9828
Reagents such as Me2CuLi, AlEt2CN, TMSCN or KCN did not react with the mixture
2/BF3·OEt2, even at room temperature and long reaction times, and, in the latter case, in the
presence of 18-crown-6. These results indicate that ketimine addition does not occur when the
nucleophilicity of the organometallic species is low.
The behavior of 1-allyl-4-phenyl-1H-2,1,3-benzothiadiazine-2,2-dioxide 3 in these addition
reactions was also evaluated. When a solution of 3 previously complexed with 3 equiv. of
BF3·OEt was treated with lithium anions, indicated in Table 1 (entries 10–15), the corresponding
1,2-addition products 1j–o were obtained in moderate to good yields. In spite of the presumably
lower reactivity of benzophenone ketimine analogue 3, reaction occurred under similar condi-
tions to 2 being completed at a similar rate in 3 hours. (Table 1). Reactive anions such as PhLi
(entry 10) behaved similarly to the stabilized ones (2-Li-1,3-dithiane, LiCH2CO2Et,
LiCH2CONMe2, LiCH2SOTol and LiCH2SO2Ph, entries 11–15).
The scope of the reaction regarding the N-protecting group variation remains to be evaluated,
but according to the results presented it is likely that little influence will be observed by changing
this group provided the new protecting groups are compatible with the organometallic reagent
to be used.
In summary, we have found conditions for the synthesis of 4,4-disubstituted-3,4-dihydro-1H-
2,1,3-benzothiadiazine 2,2-dioxides based on organometallic addition to 4-substituted-1H-2,1,3-
benzothiadiazine 2,2-dioxides.
Acknowledgements
The Spanish PROFARMA program (Ministerio de Industria y Ministerio de Sanidad)
supported this research. Two of us (M.P. and M.T.A.) thank Lilly S. A. for financial support.
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