Catalytic generation of cesium acetylide by CsF: Synthesis of 1,3-benzothiazines from cyclic sulfenamide

Article abstract of DOI:10.1021/ol9009333

An efficient synthesis of enantiopure 1,3-benzothiazines has been achieved by reaction of cyclic sulfanamides and alkylpropiolate or tosylacetylene catalyzed by cesium fluoride.

Full text of DOI:10.1021/ol9009333

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2776-2779
Catalytic Generation of Cesium
Acetylide by CsF: Synthesis of
1,3-Benzothiazines from Cyclic
Sulfenamides
Ce´dric Spitz, Jean-Franc¸ois Lohier, Vincent Reboul,* and Patrick Metzner
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, UniVersite´ de Caen
Basse·Normandie, CNRS, 6 bouleVard du Mare´chal Juin, 14050 Caen, France
Vincent.reboul@ensicaen.fr
Received April 29, 2009
ABSTRACT
An efficient synthesis of enantiopure 1,3-benzothiazines has been achieved by reaction of cyclic sulfenamides and alkylpropiolate or tosylacetylene
catalyzed by cesium fluoride.
Recent studies in our laboratory have shown that enantiopure
1,4-benzothiazepines 3 can be prepared, with high efficiency
Scheme 2. Synthesis of 1,3-Benzothiazine 6a
and atom economy, from the cyclic sulfenamides 1 and
dimethyl acetylenedicarboxylate 2, using fluoride ion as a
nucleophilic catalyst (Scheme 1).1
Scheme 1. Synthesis of 1,4-Benzothiazepines 3
6a was isolated as a mixture of two separable isomers E/Z
in 86% yield.
Surprisingly, when methyl propiolate 4 was used in the
presence of CsF as catalyst, the expected 1,4-benzothiazepine
5 was not obtained (Scheme 2). Instead, 1,3-benzothiazine
In this communication, we disclose the efficient domino
process to synthesize these heterocycles, based on in situ
catalytic generation of conjugated acetylides. Traditionally,
acetylides were used for the alkynylation of carbonyl com-
pounds, leading to the corresponding propargylic alcohols.2
(1) Spitz, C.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Reboul, V.;
Metzner, P. J. Org. Chem. 2009, 3936–3939.
10.1021/ol9009333 CCC: $40.75
Published on Web 06/01/2009
 2009 American Chemical Society

However, most studies have focused on the use of
arylacetylene or alkylacetylene3 whereas alkyl propiolates
are generally problematic substrates, requiring specific reac-
tion conditions. Indeed, due to the presence of ester function,
catalytic systems such as potassium tert-butoxide4 or cesium
hydroxide5 cannot be employed. Other methods, involving
the in situ generation of zinc acetylide6 in the presence of
tertiary amine led to the aminoacrylic ester7 instead of the
acetylenic alcohol. Ammonium acetylide promoted the
reaction in moderate to low yield8 but also domino processes
can take place to generate enol-protected propargylic alcohols
or 1,3-dioxolane compounds.9 Moreover, no reaction was
observed with rhodium10 or copper acetylide.11 Conse-
quently, two steps procedures, involving the preparation of
metal acetylide in a separate step are still competitive and
allowed efficient preparation of alkyl 4-hydroxy-2-alkynoates.
Among alkali metal derivatives, lithium acetylide is the most
efficient but required very low temperature reactions (-78
°C and -100 °C for ethyl and methyl propiolate, respec-
tively) and careful addition of n-BuLi.12 Silver acetylide is
more convenient and in the presence of Cp2ZrCl2 (1.2 equiv)
and AgOTf (0.2 equiv) promoted coupling with carbonyl
compounds at room temperature.13
Scheme 3. Proposed Mechanism for the Synthesis of 6a
the starting alkynoate in the terminal position, probably due
to the low pKa value of this proton (pKa ≈ 18.8).15 This
acetylide anion reacts with the electrophilic sulfur atom16,1
of sulfenamide to lead to intermediate 7. The cyclization by
intramolecular Michael addition forms enolate 8, proton-
ation17 of which affords less hindered 1,3-benzothiazine (Z)-
6a as major product and regenerates the fluoride anion.
To probe this mechanism, the lithium acetylide of methyl
propiolate11 (n-BuLi, THF, -100 °C) was prepared in a
separate flask and then added to sulfenamide 1a. Benzothi-
azine 6a was the sole isolated compound, in 85% yield (E/Z
mixture 35:65).
The scope of the reaction was next explored with a range
of aryl- and alkylsulfenamides bearing different protecting
groups on the nitrogen atom (EWG ) Ts, SES or Boc). The
required isothiazolines 1a-d, 13b and 14a,c were prepared
according to our described procedure (Scheme 4):18 ortho-
In our process, we proposed the unprecedented generation
of terminal acetylide by fluoride anion (Scheme 3). Instead
of generating the sulfenyl fluoride by the ring-opening
reaction as expected,1 fluorine anion is able to deprotonate14
(2) Tejedor, D.; Lo´pez-Tosco, S.; Cruz-Acosta, F.; Garcia-Tellado, F.;
Me´ndez-Abt, G.; Garcia-Tellado, F. Angew. Chem., Int. Ed. 2009, 48, 2090–
2098.
(3) For reviews, see: (a) Pu, L. Tetrahedron 2003, 59, 9873–9886. (b)
Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 4095–
4105. (c) Guillarme, S; Ple´, K; Banchet, A.; Liard, A.; Haudrechy, A. Chem.
ReV. 2006, 106, 2355–2403. (d) Hatano, M.; Ishihara, K. Synthesis 2008,
11, 1647–1675.
(4) Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61, 416–
417.
(5) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463–
1465.
(6) Highly enantioselective alkynylations have been described recently
but required the use of a large excess of zinc derivative: (a) Trost, B. M.;
Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8–9. (b)
Gao, G.; Wang, Q.; Yu, X.-Q; Xie, R.-G.; Pu, L. Ang. Chem. Int. Ed. 2006,
45, 122–125. (c) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8, 2019–2021. (d)
Lin, L.; Jiang, X.; Liu, W.; Qiu, L.; Xu, Z.; Xu, J.; Chan, A. S. C.; Wang,
R. Org. Lett. 2007, 9, 2329–2332. (e) Zhong, J.-C.; Hou, S.-C.; Bian, Q.-
H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.; Liu, S.-Z.; Wang, M.
Chem.sEur. J. 2009, 3069–3071. In the absence of chiral ligand, low yield
was obtained: (f) Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.;
Tomasini, C J. Org. Chem. 2005, 70, 5733–5736. Surprisingly, no reaction
occurred when zinc acetylide ester was added on imine: (g) Zani, L.;
Eichhorn, T.; Bolm, C. Chem.sEur. J. 2007, 13, 2587–2600. Recently,
the presence of TMSOTf as Lewis acid allowed to use a catalytic amount
of ZnBr2: (h) Downey, C. W.; Mahoney, B. D.; Lipari, V. R. J. Org. Chem.
2009, 74, 2904–2906.
Scheme 4. Synthesis of Isothiazolines 1a-d, 13b and 14a,c
(7) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525–
2527.
(8) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito,
S. J. Org. Chem. 2003, 68, 3702–3705.
(9) Tejedor, D.; Garcia-Tellado, F.; Marrero-Tellado, J. J.; de Armas,
P. Chem.sEur. J. 2003, 9, 3122–3131.
(10) Dhondi, P. K.; Carberry, P.; Choi, L. B.; Chisholm, J. D. J. Org.
Chem. 2007, 72, 9590–9596.
metalation of enantiopure sulfoxide 9 followed by addition
of imine or sulfone (Table 1).19 New aminosulfoxides 10-12
were obtained with complete diastereocontrol when R1 is
(11) Asano, Y.; Ito, H.; Hara, K.; Sawamura, M. Organometallics 2008,
27, 5984–5996.
(12) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28–29.
(13) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525–
2527.
(15) Kresge, A. J.; Pruszynski, P.; Stang, P. J.; Williamson, B. L. J.
Org. Chem. 1991, 56, 4808–4811.
(14) Clark, J. H. Chem. ReV. 1980, 429–452.
Org. Lett., Vol. 11, No. 13, 2009
2777

The stereochemistry of the CdC double bond of the major
diastereoisomer of benzothiazine 6c was assigned as (Z) by
X-ray analysis (Figure 1) which is in agreement with the
Table 1. Synthesis of Isothiazolines from Aminosulfoxides
aminosulfoxides
% yielda
EWG (compd)
isothiazolines
entry
R1
drb
% yielda (compd)
1
2
3
4
5
6
7
i-Pr
Cy
Ph
Ts
Ts
Ts
80 (10a) >98/2
74 (10b) >98/2
64 (10c) 80/20
63 (10d) 77/23
96 (1a)
99 (1b)
97 (1c)
97 (1d)
98 (13b)
99 (14a)
98 (14c)
m-BrC6H4 Ts
Cy
i-Pr
Ph
SES 60 (11b) >98/2
Boc
Boc
46 (12a) >98/2
54 (12c) 80/20
b
a Isolated yields. Determined by H NMR on the crude product.
1
an alkyl group (entries 1, 2, 5, 6). These observations are in
agreement with the proposed stereochemical course of the
reaction: four-membered transition state involving coordina-
tion of the lithium atom with the oxygen atom of the
protecting group.17 A lower asymmetric induction was
observed (dr 80:20) with an aryl group (entries 3, 4, 7) but
the two diastereoisomers can be easily separated by column
chromatography.
By heating in toluene, aminosulfoxides undergo a [2,3]-
sigmatropic process leading to isobutene and the correspond-
ing sulfenic acid. After elimination of H2O, the isothiazolines
1, 13, 14 were isolated in quantitative yields (Table 1) and
in enantiopure forms.
Figure 1. X-ray crystal structure of major diastereoisomer (50%
thermal ellipsoids) of 6c. Hydrogen atoms are omitted for clarity
except for C*H and CdCH.
proposed mechanism. It was generalized to the other
20
1
compounds 6 according to H NMR.
We next conducted a survey of a range of terminal
acetylenes. Tosyl acetylene21 reacted in very good yields
(Table 2, entries 6-9) to afford 1,3-benzothiazines 16.
Surprisingly, the stereochemistry of the CdC double bond
of the major diastereoisomer of benzothiazine 16a was
assigned as (E) according to X-ray analysis (Figure 2).22 With
Having the expected isothiazolines in hand, the synthesis
of 1,3-benzothiazines was next generalized. We used previ-
ously optimized conditions: CsF (10 mol %) in CH3CN at
rt. With alkyl propiolate, we were able to prepare in good
yields a variety of N-tosyl-1,3-benzothiazines 6-15 bearing
aliphatic or aromatic groups in R1 (Table 2, entries 1-5).
Table 2. Synthesis of 1,3-Benzothiazines 6, 15, 16
Figure 2. X-ray crystal structure of major diastereoisomer (50%
thermal ellipsoids) of 16a. Hydrogen atoms are omitted for clarity
except for C*H and CdCH.
entry
R1
R2
% yielda (compd)
E/Zb
1
2
3
4
5
6
7
8
9
i-Pr (1a)
Cy (1b)
Ph (1c)
m-BrC6H4 (1d)
i-Pr (1a)
i-Pr (1a)
Cy (1b)
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
Ts
Ts
Ts
Ts
Ph
86 (6a)
84 (6b)
73 (6c)
57 (6d)
85 (15a)
96 (16a)
93 (16b)
92 (16c)
74 (16d)
0
13/87
14/86
13/87
17/83
13/87
92/8
aromatic sulfenamides 1c,d (entries 8,9), only the isomer (E)
was formed. On the other hand, no reaction occurred with
phenyl acetylene (entry 10).
The reaction was also conducted with sulfenamide 13b
as starting material (Scheme 5). As expected, benzothiazine
92/8
Ph (1c)
>98/2
>98/2
-
m-BrC6H4 (1d)
i-Pr (1a)
b
(16) Reviews on sulfenamides: (a) Davis, F. A. Int. J. Sulfur Chem.
1973, 8, 71–81. (b) Craine, L.; Raban, M. Chem. ReV. 1989, 89, 689–712.
Reactivity of sulfenamides with acetylides: (c) Busi, E.; Capozzi, G.;
Menichetti, S.; Nativi, C. Synthesis 1992, 643–645. (d) Savarin, C.; Srogl,
J.; Liebeskind, L. S. Org. Lett. 2001, 91–93.
10
a Isolated yields. Determined by H NMR on the crude product.
1
(17) Naito, H.; Hata, T.; Urabe, H. Tetrahedron Lett. 2008, 49, 2298–
2301.
The two isomers can be separated by column chromatogra-
phy.
(18) Le Fur, N.; Mojovic, L.; Ple´, N.; Turck, A.; Reboul, V.; Metzner,
P. J. Org. Chem. 2006, 71, 2609–2616.
2778
Org. Lett., Vol. 11, No. 13, 2009

Scheme 5
.
Deprotection of SES Group by CsF
Scheme 6. Reactivity with N-Boc Isothiazolines 14a-c
other electrophiles, in particular aldehydes and ketones, are
currently underway and will be reported in the due course.
Acknowledgment. We thank the “Crunch” Network
(“Centre de Recherche Universitaire Normand de Chimie”),
the “Re´gion Basse-Normandie”, the “Ministe`re de la Re-
cherche”, CNRS (Centre National de la Recherche Scienti-
fique), and the European Union (FEDER funding) for
financial support.
17b was obtained (72% yield). Moreover, the deprotection
of 2-(trimethylsilyl)ethanesulfonyl (or SES) group by fluoride
anion23 in both compounds was not observed in CH3CN.
On the other hand, benzothiazine (Z)-17b could be depro-
tected when the reaction was performed in DMF. Also, in
the presence of a large excess of CsF (5 equiv), deprotection
of sulfenamide 13b occurred but with aromatization to afford
the corresponding aromatic compound 19 in 60% yield
(Scheme 5).
On the other hand, when we next studied the reactivity of
isothiazolines 14 (bearing a Boc group on the nitrogen atom)
with methyl propiolate, benzothiazines were not obtained.
Instead, the corresponding opened compounds 20a,c were
isolated in quantitative yields (Scheme 6) confirming the
proposed mechanism.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds de-
scribed in this work, crystallographic data for the reported
structures (CIF format). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL9009333
(20) The chemical shift of vinylic proton are consistent for each
diastereoisomer: 6.35-6.44 ppm for major and 5.79-5.93 ppm for minor.
(21) To the best of our knowledge, only corresponding lithium acetylide
has been described: Jones, A. C.; Sanders, A. W.; Bevan, M. J.; Reich,
H. J. J. Am. Chem. Soc. 2007, 129, 3492–3493.
In conclusion, we achieved the synthesis of 1,3-benzothi-
azines24 with high efficiency and atom economy, via a
catalytically generated cesium acetylide. Further studies with
(22) The chemical shift of the vinylic proton are consistent with the
diastereoisomer E as the major isomer: 6.23-6.33 ppm.
(23) Ribiere, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. ReV. 2006,
106, 2249–2269.
(19) Alkyl N-Boc-imines were prepared in-situ from corresponding
sulfones by an excess of ortho-lithiated sulfoxide (2.1 equiv): Grach, G.;
Sopkova-de Oliveira Santos, J.; Lohier, J.-F.; Mojovic, L.; Ple´, N.; Turck,
A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 9572–9579.
(24) These compounds are analogous to benzothiazinone described as
heart muscular cell apoptosis inhibitors and cell death inhibitor: (a) Kimura,
H.; Tanida, S.; Kaneko, T. WO 018356, 2002. (b) Kimura, H.; Sato, Y.;
Takizawa, M.; Horiguchi, T.; Notoya, K. WO Patent 090782, 2003.
Org. Lett., Vol. 11, No. 13, 2009
2779