N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1λ 6-benzo[e]1,2-thiazin-4-one, a new and efficient agent for electrophilic fluorination of carbanions

Article abstract of DOI:10.1016/S0022-1139(99)00028-7

N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1λ ⁶-benzo[e]1,2-thiazin-4-one (1) was prepared in good yield by fluorination of the corresponding sultam (3) with FClO₃. The sultam (3) was prepared from saccharin (2) in 3 steps. T

Full text of DOI:10.1016/S0022-1139(99)00028-7

Journal of Fluorine Chemistry 97 (1999) 65±67
Short communication
N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1l6-benzo[e]1,2-
thiazin-4-one, a new and ef®cient agent for electrophilic
¯uorination of carbanions
Yoshio Takeuchia,*, Zhaopeng Liua, Emiko Suzukia, Norio Shibataa, Kenneth L. Kirkb
aFaculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
bLaboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease,
National Institutes of Health, Bethesda, MD 20892, USA
Received 12 November 1998; received in revised form 11 December 1998; accepted 11 December 1998
Dedicated to Professor Emeritus Yoshio Kobayashi on the occasion of his 75th birthday
Abstract
N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1l6-benzo[e]1,2-thiazin-4-one (1) was prepared in good yield by ¯uorination of
the corresponding sultam (3) with FClO3. The sultam (3) was prepared from saccharin (2) in 3 steps. The N-¯uorosultam (1), a very stable
crystalline solid, was found to ¯uorinate carbanions readily in good to excellent yields. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: N-¯uorosultams; Electrophilic ¯uorination; a-¯uoroketones
The replacement of hydrogen or hydroxyl with ¯uorine is
an extensively used strategy for enhancement of biological
activity in the design of analogues of biologically important
molecules [1,2]. Electrophilic ¯uorination of carbanions is
one of the most effective methods for this purpose because it
permits the replacement of a C±H bond by a C±F bond in a
single step [3±11]. Historically, electrophilic ¯uorination
could be accomplished only by using toxic, corrosive, and/or
explosive gaseous materials such as molecular ¯uorine,
FClO3 or CF3OF. Usually, specialized equipment and tech-
niques were required. In an important advance that helped
overcome these limitations, Barnette found that the N-¯uor-
osulfonamides can effectively ¯uorinate carbanions [12,13].
Although several N-¯uorosulfonamides have been devel-
oped as electrophilic ¯uorination agents [14±19] since this
report, there remains a need for additional ¯uorinating
agents that are both readily accessible and give high che-
mical yields of ¯uorination product. In this paper, we wish
to report the synthesis of a stable, crystalline compound,
N-¯uoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1l6-
benzo[e]1,2-thiazin-4-one (1), that effectively transfers
¯uorine to carbanions, exists as a stable crystalline com-
pound, and, moreover, is readily and conveniently prepared
in bulk quantities from inexpensive starting materials.
N-Fluorosultam (1) was readily prepared according to the
route outlined in Scheme 1. Thus, saccharin (2) was con-
verted into 3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-
1l6-benzo[e]1,2-thiazin-4-one (3) in three steps that con-
sisted of sequential alkylation, bromination, and ring expan-
sion according to the procedure of Abramovitch et al. [20].
This sequence was carried out on a 10 g scale in more than
40% over all yield. Fluorination of 3 was ®rst attempted by
*Corresponding author. Tel.: +81-764-34-2281; fax: +81-764-34-5053;
e-mail: takeuchi@ms.toyama-mpu.ac.jp
Scheme 1.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 2 8 - 7

66
Y. Takeuchi et al. / Journal of Fluorine Chemistry 97 (1999) 65±67
passing 10% molecular ¯uorine in nitrogen in a 1:1 solution
of Freon-11 and chloroform in the presence of spray-dried
NaF [21] at various temperatures. However, this procedure
resulted in decomposition of 3, even at 508C. In contrast,
¯uorination of the sodium salt of 3 with FClO3 in THF
[22,23] readily gave 1, obtained in pure form in 71% yield
after silica-gel column chromatography and recrystalliza-
tion from hexane. N-Fluorosultam (1) is a colorless, crystal-
line solid, mp 688C (from hexane), which is stable over
several weeks when stored at room temperature.
The results of electrophilic ¯uorination of a variety of
enolates of ketone using 1 are summarized in Table 1. In
experiments designed to optimize reaction parameters, we
®rst examined ¯uorination of 2-methyl-1-tetralone (4a)
under a variety of conditions. We found that the lithium
enolate was a much more suitable substrate than the sodium
Table 1
Fluorination of ketones with 1a
a Fluorinations were carried out using 1.5 eq. of base and 1.5 eq. of 1. Bn: benzyl; PMB: p-methoxybenzyl.
Conditions: A: LiHMDS/THF/ 788C to 208C; B: NaHMDS/THF/ 788C to 208C; C: NaH/THF/08C.

Y. Takeuchi et al. / Journal of Fluorine Chemistry 97 (1999) 65±67
67
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Acknowledgements
This work was supported by a Grant-in-aid for Scienti®c
Research from the Ministry of Education, Science, Sports
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