Fluoride ion and phosphines as nucleophilic catalysts: Synthesis of 1,4-benzothiazepines from cyclic sulfenamides

Article abstract of DOI:10.1021/jo900449a

(Chemical Equation Presented) A new methodology, using fluoride ion as a nucleophilic catalyst, was applied for the synthesis of enantiopure 1,4-benzothiazepine from cyclic sulfenamide and electron-deficient acetylene, with high efficiency and atom econom

Full text of DOI:10.1021/jo900449a

SCHEME 1. Expected Mechanism for the Formation of 3
Fluoride Ion and Phosphines as Nucleophilic
Catalysts: Synthesis of 1,4-Benzothiazepines from
Cyclic Sulfenamides
Ce´dric Spitz,† Jean-Franc¸ois Lohier,†
Jana Sopkova-de Oliveira Santos,‡ 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, and
Laboratoire de Crystallographie, Centre d’Etudes et de
Recherche sur le Me´dicament de Normandie, UniVersite´ de
Caen Basse-Normandie, 14032 Caen, France
aldehydes and aminosulfenylation6 of unsaturated aldehydes;
oxidation reactions in the presence of NCS;7 carbonylation8 or
coupling reactions with boronic acids9 using transition metal.
Also of interest is the medicinal applications of sulfenamides:
the prodrug omeprazole inhibits the acid-secreting gastric (H+/
K+)-ATPase involving a sulfenamide as a key intermediate;10
the water-soluble sulfenamide prodrug carbamazepine;11 the
formation of sulfenamide in enzymes to protect their active site
cysteines.12
Vincent.reboul@ensicaen.fr
ReceiVed February 27, 2009
As part of a program aimed at developing cyclic sulfenamide
reactivity,13 we sought an asymmetric synthesis of 1,4-ben-
zothiazepines,14 precursor to 1,4-benzothiazepine-1,1-dioxides,
which both exhibit a large range of biological activities.15
Our initial proposal (Scheme 1) was triggered by the
conjugate addition of the nitrogen atom of sulfenamide 1a to
the electron-deficient dimethyl acetylenedicarboxylate 2 (DMAD).
A new methodology, using fluoride ion as a nucleophilic
catalyst, was applied for the synthesis of enantiopure 1,4-
benzothiazepine from cyclic sulfenamide and electron-
deficient acetylene, with high efficiency and atom economy.
(6) Zhao, G.-L.; Rios, R.; Vesely, J.; Ericksson, L.; Co´rdova, A. Angew.
Chem., Int. Ed. 2008, 47, 8468.
(7) Matsuo, J.-i.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron 2003,
59, 6739.
(8) (a) Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh, K.;
Kurosawa, H. J. Org. Chem. 1999, 64, 7305. (b) Knapton, D. J.; Meyer, T. Y.
J. Org. Chem. 2005, 70, 785. (c) Knapton, D. J.; Meyer, T. Y. Org. Lett. 2004,
6, 687. (d) Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612.
(9) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.
(10) Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc. 2004, 126, 7800.
(11) Hemenway, J. N.; Nti-Addae, K.; Guarino, V. R.; Stella, V. J. Bioorg.
Med. Chem. Lett. 2007, 17, 6629.
(12) (a) Sivaramakrishnan, S.; Keerthi, K.; Gates, K. S. J. Am. Chem. Soc.
2005, 127, 10830. (b) Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc. 2007, 129,
8872.
(13) Le Fur, N.; Mojovic, L.; Ple´, N.; Turck, A.; Reboul, V.; Metzner, P. J.
Org. Chem. 2006, 71, 2609.
(14) Synthesis of 1,4-benzothiazepine core: (a) Fodor, L.; Szabo, J.; Bernath,
G.; Parkanyi, L; Sohar, P. Tetrahedron Lett. 1981, 22, 5077. (b) Kraus, G. A.;
Yue, S. J. Org. Chem. 1983, 48, 2936. (c) Brewer, M. D.; Burgess, M. N.;
Dorgan, R. J. J.; Elliott, R. L.; Mamalis, P.; Manger, B. R.; Webster, R. A. B.
J. Med. Chem. 1989, 32, 2058. (d) Nefzi, A.; Ong, N. A.; Giulianotti, M. A.;
Ostreh, J. M.; Houghten, R. A. Tetrahedron Lett. 1999, 40, 4939. (e) Katritzky,
A. R.; Xu, Y.-J.; He, H.-Y.; Mehta, S. J. Org. Chem. 2001, 66, 5590. (f) Neo,
A. G.; marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 2005, 46,
7977.
(15) Atherosclerosis: Brieaddy, L. E. WO Patent 016055, 1993. Hyperlipi-
daemia: (a) Brieaddy, L. E. WO Patent 005188, 1996. (b) Sasahara, T.; Mohri,
M. WO Patent 020421, 2004. (c) Starke, I.; Alenfalk, S.; Nordberg, M. P.;
Dahlstrom, M. U. J.; Bostrom, S. J. Lemurell, M. A.; Wallberg, A. C. WO Patent
076430, 2004. (d) Sasahara, T.; Mohri, M.; Kasahara, K. I. WO Patent 082874,
2005. (e) Frick, W.; Glombik, H.; Heuer, H.; Schaefer, H.-L.; Theis, S. WO
Patent 009655, 2007. Muscle relaxation accelerator: (f) Kaneko, N. WO Patent
105793, 2005. Cell death of cardiac muscles: (g) Kaneko, N.; Oosawa, T.; Sakai,
T.; Oota, H. WO Patent 012148, 1992. Diabete: (h) Nagase, T.; Sato, Y.; Eiki,
J. WO Patent 053548, 2002. Cardiac hypertrophy: IMarks, A. R.; Lehnart, S. E.
WO Patent 021439, 2008. Anti-arrythmic and heart failure: (j) Marks, A. R.;
Landry, D. W.; Deng, S.; Cheng, Z. Z. WO Patent 101496, 2006.
Among compounds containing the sulfur-nitrogen bond,
sulfenamides are not very popular compared to sulfinamides or
sulfonamides. Recently, the chemistry of sulfenamides has
received growing attention due to their ease of synthesis1 and
the particular reactivity of this functional group. Indeed, because
of the difference in electronegativity, the sulfur atom is
considered electrophilic. Moreover, because of the presence of
lone electron pairs on both atoms, the nitrogen atom is defined
as a “supernucleophile”2 according to the R-effect.3
Consequently, their potential in organic synthesis4 and their
industrial applications have been recognized. For instance, the
ability of sulfenamides to form radicals was used to accelerate
the vulcanization of rubber. Recently, new reactions involving
sulfenamides have emerged: asymmetric sulfenylation5 of
† Laboratoire de Chimie Moléculaire et Thio-organique.
‡ Centre d’Etudes et de Recherche sur le Me´dicament de Normandie.
(1) (a) Davis, F. A.; Nadir, U. K. Org. Prep. Proced. Int. 1979, 11, 35. (b)
Perrio, S.; Reboul, V.; Metzner, P. In Science of Synthesis: Compounds with
two carbon-heteroatom bonds; Ramsden, C. A., Ed.; Thieme: Stuttgart, 2007;
Vol. 31a, p 1041. (c) Taniguchi, N. Synlett 2007, 12, 1917.
(2) Welch, W. M. J. Org. Chem. 1976, 41, 2220.
(3) Buncel, E.; Um, I.-H. Tetrahedron 2004, 60, 7801.
(4) (a) Heimer, N. E.; Field, L. J. Org. Chem. 1970, 35, 3012. (b) Davis,
F. A. Int. J. Sulfur Chem. 1973, 81, 71. (c) Craine, L.; Raban, M. Chem. ReV.
1989, 89, 689.
(5) Sobhani, S.; Fielenbach, D.; Marigo, M.; Wabnitz, T. C.; Joergensen,
K. A. Chem.-Eur. J. 2005, 11, 5689.
3936 J. Org. Chem. 2009, 74, 3936–3939
10.1021/jo900449a CCC: $40.75 2009 American Chemical Society
Published on Web 04/08/2009

TABLE 1. Optimization of Synthesis of 1,4-Benzothiazepine 3a from 1a
entry
catalyst (mol%)
solventa
Temp (°C)
time (h)
3a (% yield)
1
2
3
4
5
6
7
8
-
CH3CN
DMF
CH2Cl2
CH3CN or toluene
CH2Cl2
20 to 80
40
20
60
40
40
60
60
20
20
60
60
60
60
60
60
14
14
14
14
14
14
4
14
24
4
0.5
0.5
0.5
0.5
0.5
2
0
0
PdCl2(PPh3)2 or RuCl3 ·3H2O (5)
DPPP (20)
12 + 6 (21)
16 + 6 (21)
DPPP (100)
PMe3 (100)
PPh3 (100)
35
70
14
21
0
60
73
79
88
92
81
86
CH2Cl2
PPh3 (25)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CNc
CH3CNc
CH3CNc
CH3CNc
DABCO (20)
9
CsF (10)b
10
11
12
13
14
15
16
CsF (200)b
CsF (200)b
CsF (200)
CsF (200)
CsF (100)
CsF (25)
CsF (10)b d
,
a Unless otherwise indicated, all reactions were performed at 0.1 M concentration using 2 equiv of DMAD. b 1.1 equiv of DMDA. c Concentration )
0.02 M. d Slow addition of DMAD over 30 min.
SCHEME 2. Plausible Mechanisms for the Formation of 3a
obtained in only 12% yield (Table 1, entry 3) in addition to a
21% of noncyclized product 6 (8/2 E/Z mixture).19 A slight
improvement was obtained using a stoichiometric amount of
DPPP (entry 4). Other phosphines were also tested (entries 5-7).
However, only PPh3 (1 equiv) gave satisfactory 70% yield
compared to the dramatically lower yield obtained when using
a catalytic amount.20 An insertion of the phosphine into the S-N
bond, affording a pentavalent phosphorus intermediate, could
explain these poor results.21
The tertiary amine DABCO also initiated the formation of
3a with a low yield of 21% (entry 8).
Our attention was next turned to the possibility of using
fluoride ion as a nucleophilic catalyst (Scheme 2; X ) F-; Y
) F). Indeed, CsF is able to react with DMAD 2, in DMF-
water biphasic medium, to afford adduct 7 (Z major), after
protonation of anion 4 (X ) F-; Y ) F).22 Reaction of 4 with
sulfenamide 1a, followed by an addition-elimination process
of intermediate 5 as reported23 provided 1,4-benzothiazepine
3a with regeneration of the fluoride anion.
Our first attempt using CsF catalytically (Table 1, entry 9)
had disappointing results. The reaction turned black very rapidly
indicating polymerization of DMAD. On the other hand, 2 equiv.
of CsF furnished 3a in 60% yield thus validating our concept
(entry 10).24 At 60 °C, the reaction was found to proceed with
73% yield in only 30 min (entry 11). With an increased amount
of DMAD (entry 12), a good yield of 79% was obtained. A
great improvement was observed when the reaction mixture was
diluted (Concentration ) 0.02 M) which also allowed us to use
a catalytic amount of CsF in the presence of a slight excess of
DMAD. After optimization (entries 13-16), 3a was isolated
in an excellent yield of 86% using 10% CsF with slow addition
of DMAD (1.1 equiv) by syringe pump.
Subsequent intramolecular 1,3-shift of the sulfur atom would
afford the desired seven-membered ring 3a.16
However, no reaction occurred when sulfenamide 1a was
submitted to DMAD in acetonitrile by heating (Table 1, entry
1) or in the presence of Lewis acids (entry 2).
To overcome this problem, we turned to the well-known
reactivity of zwitterions 4 generated by nucleophilic addition
of phosphine or tertiary amines, as catalyst, to activated
unsaturated compounds (Scheme 2; X ) PR3, NR3; Y ) +PR3,
+NR3).17 These zwitterions could be able to attack the electro-
philic sulfur atom of sulfenamide to lead to intermediate 5. After
an addition/elimination reaction, 1,4-benzothiazepine 3 could
be obtained.
The reaction was next generalized to sulfenamide 1b bearing
a cyclohexyl substituent (Table 2, entry 1) or an aromatic
Our initial reaction began with diphenylphosphinopropane
(DPPP) as catalyst.18 The expected 1,4-benzothiazepine 3a was
(19) The molecular structure of 3a was confirmed by X-ray crystallographic
analysis (see Supporting Information). Interestingly, two conformations were
positioned in the unit cell: either the iso-propyl group is in a pseudoequatorial
or is in a pseudoaxial disposition, as in the molecular structures of sulfenamides
1a and 1c.
(20) In CH2Cl2 at 40 °C, less than 10% of conversion was observed.
(21) Henke, A.; Srogl, J. J. Org. Chem. 2008, 73, 7783.
(22) Gorgues, A.; Ste´phan, D.; Cousseau, J. J. Chem. Soc., Chem. Commun.
1989, 1493.
(16) Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T. Tetrahedron Lett. 2004,
45, 1469.
(17) For excellent reviews: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535. (b) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346,
1035. (c) Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.
Acc. Chem. Res. 2006, 520. (d) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. ReV.
2008, 1140.
(18) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12928.
(23) Hudlicky, M. J. Fluorine. Chem. 1988, 40, 99.
(24) 3a was obtained in 99% ee (Chiral HPLC, Daicel AD).
J. Org. Chem. Vol. 74, No. 10, 2009 3937

TABLE 2. Syntheses of 1,4-Benzothiazepines 3, 10 Catalyzed by
CsF
SCHEME 4. Synthesis of Disulfide 14
entry
R1
Cy (1b)
Ph (1c)
3-Br-C6H4 (1d)
i-Pr (1a)
Cy (1b)
Ph (1c)
3-Br-C6H4 (1d)
i-Pr (1a)
R2
product
% yielda
1
2
3
4
5
6
7
8
9
CO2Me (2)
CO2Me (2)
CO2Me (2)
CN (8)
CN (8)
CN (8)
CN (8)
SO2t-Bu (9)
SO2t-Bu (9)
3b
3c
3d
10a
10b
10c
10d
11a
11d
60
79
65
73
55
51
85
0
3-Br-C6H4 (1d)
0
To investigate the proposed mechanism, the reaction between
sulfenamide 1a and a stoichiometric amount of CsF in aceto-
nitrile was performed.28 In the presence of water, unstable
sulfenyl fluoride 12 should be transformed to corresponding
disulfide 14.29 Indeed, this compound was isolated in 20% yield
(precipitation in the reaction mixture) when a large amount of
water was added (Scheme 4).30 The structure of disulfide 14
was confirmed by reduction of sulfenamide 1a with NaBH4 into
sulfide 15, followed by aerial oxidation.
a All reactions were performed with 10% of CsF in CH3CN at 60 °C
(0.02 M concentration) with slow addition of DMAD over 30 min (1.1
equiv) of acetylene derivative.
SCHEME 3. Proposed Mechanism for the Formation of 3,
10
To the best of our knowledge, we have demonstrated for the
first time the use of fluoride ion as a nucleophilic catalyst.31
This new methodology was applied for the synthesis of
enantiopure 1,4-benzothiazepines with high efficiency and atom
economy. Isolation of disulfide provided reasonable evidence
for a sulfenyl fluoride as the key intermediate.32 Further studies
with other electrophiles are currently underway.
Experimental Section
Typical Procedure for the Preparation of Benzothiaze-
pines 3, 10 (Table 1, entry 16, 3a as Example). CsF (4.6 mg,
0.03 mmol) was dried under vacuum in a flame-dried round-bottom
flask. The sulfenamide 1a (100 mg, 0.30 mmol) and acetonitrile
(12 mL) were added. The resulting suspension was heated at 60
°C and a solution of dimethyl acetylenedicarboxylate 2 (41 µL,
0.33 mmol) in acetonitrile (3 mL) was added over a period of 30
min by syringe pump. The reaction mixture was stirred at 60 °C
for 2 h. After filtration of the suspension and evaporation of the
solvent, the crude product was purified by column chromatography
on silica gel using pentane/Et2O (8/2) as eluent to yield the
corresponding benzothiazepine 3a (122 mg, 86%) as yellow crystals.
substituent (Table 2, entries 2-3).25 Dicyanoacetylene26 8 also
were used in this reaction as electron-deficient acetylene and
afforded corresponding benzothiazepines 10a-d (Table 2, entries
4-7) in moderate to good yield. On the other hand, no reaction
occurred with di-t-butylsulfonylacetylene27 9 (Table 2, entries
8-9) and the starting material was recovered.
Although fluoroalkene 7 was always detected in the crude
1
1
product by H NMR (<5%) when CsF was used as catalyst,
Rf: 0.20 (pentane/Et2O: 8/2); Mp 123-125 °C; H NMR (CDCl3,
we could consider another mechanism, leading to the same
compound 3, also involving the fluoride anion as nucleophilic
catalyst (Scheme 3): reaction of fluoride ion with the sulfena-
mide to generate sulfenyl fluoride 12; then conjugate addition
of amide anion to the electron-deficient acetylene to provide
carbanion 13, which cyclizes into 1,4-benzothiazepine with
regeneration of the fluoride anion.
500 MHz) δ 7.19 (d, J ) 8.4 Hz, 2H, Ar of Ts), 6.98-7.07 (m,
3H, H6, H7, H8), 6.90 (d, J ) 8.4 Hz, 2H, Ar of Ts), 6.68 (dd, J )
7.6 Hz, J ) 1.5 Hz, 1H, H9), 4.52 (d, J ) 10.8 Hz, 1H, H5), 3.84
(s, 3H, MeCO2), 3.82 (s, 3H, MeCO2), 2.53-2.58 (m, 1H, CH of
i-Pr), 2.26 (s, 3H, Me of Ts), 1.34 (d, J ) 6.4 Hz, 3H, Me of i-Pr),
0.63 (d, J ) 6.8 Hz, 3H, Me of i-Pr); 13C NMR (CDCl3, 125.7
MHz) δ 165.8 (CdO), 164.5 (CdO), 143.3 (Ar of Ts), 138.8 (C5a),
135.3 (Ar of Ts), 133.6 (C2), 132.4 (C6), 129.2 (C9a), 129.1 (2C,
Ar of Ts), 129.0 (C9), 128.6 (C3), 127.8 (C8), 127.6 (2C, Ar of Ts),
126.6 (C7), 73.7 (C5), 53.7 (MeCO2), 53.2 (MeCO2), 28.5 (CH of
(25) Theringexpansiononthebenzylicpositionwasnotobserved:Voskressensky,
L. G.; Akbulatov, S. V.; Borisova, T. N.; Varlamov, A. V. Tetrahedron 2006,
62, 12392.
(26) This compound was prepared from DMAD in two steps: Hopf, H.;
Witulski, B. In Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Ed.;
VCH: Weinheim, 1995; p 60.
(28) The same reaction in CD3CN was followed by 19F NMR but, due to
problems of solubility, no characteristics signal has been found.
(29) The corresponding thiosulfinate was not observed.
(27) This compound was prepared from dichloroacetylene in two steps: (a)
Riera, A.; Cabre´, F.; Moyano, A.; Perica`s, M. A.; Santamaría, J. Tetrahedron
Lett. 1990, 31, 2169. (b) Riera, A.; Martí, M.; Moyano, A.; Perica`s, M. A.;
Santamaría, J. Tetrahedron Lett. 1990, 31, 2173. Bis(arylsulfonyl)acetylenes were
not used due to their instability at room temperature: (c) Pasquato, L.; De Lucchi,
O.; Krotz, L. Tetrahedron Lett. 1991, 32, 2177.
(30) Fifty-five percent of starting material 1a was recovered.
(31) However, the fluoride ion has been reported as catalyst, in a desilylation-
defluorination sequence: Uneyama, K. J. Fluorine. Chem. 2007, 128, 1087.
(32) It was not possible to trap anion 4 (Y ) F) with another electrophile.
Indeed, no reaction occurred when DMAD and phenyl-N-tosylimine were
submittted to CsF in CH3CN (rt to 80 °C).
3938 J. Org. Chem. Vol. 74, No. 10, 2009

i-Pr), 21.6 (Me of Ts), 20.8 (Me of i-Pr), 20.6 (Me of i-Pr); HRMS
(ESI) Calcd for C23H25NO6S2 (MH+) m/z 476.1202, found 476.1216;
IR (cm-1): 2950, 1727, 1581, 1435, 1362, 1267, 1164; Anal. Calcd
for C23H25NO6S2: C, 58.09; H, 5.30; N, 2.95; S, 13.48, found C,
58.08; H, 5.39; N, 3.26; S, 13.60. The ee was 99% by HPLC (Daicel
AD-H column, 1 mL/min, 90/10 n-heptane/propan-2-ol, λ ) 254
Recherche Scientifique), the European Union (FEDER funding)
for financial support.
Supporting Information Available: Experimental proce-
dures and characterization for all new compounds described 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.
ηm, tR ) 23.2 min, tS ) 30.4 min); [R]20 ) -620 (c 0.0025,
D
CHCl3).
Acknowledgment. We thank the “Re´gion Basse-Normandie”,
the “Ministe`re de la Recherche”, CNRS (Centre National de la
JO900449A
J. Org. Chem. Vol. 74, No. 10, 2009 3939