patrick metzner group
DESCRIPTION
LCMT. Patrick Metzner group. Annie-Claude Gaumont group. Vincent Reboul. Synthesis and reactivity of enantiopur cyclic sulfenamides. Easy access to 1,4-benzothiazepines and 1,3-benzothiazines. Cédric Spitz. 09/11/2010. - PowerPoint PPT PresentationTRANSCRIPT
1
2
3
Patrick Metzner group Annie-Claude Gaumont group
Vincent Reboul
LCMT
4
Synthesis and reactivity of enantiopur cyclic sulfenamides. Easy access to 1,4-benzothiazepines
and 1,3-benzothiazines
Cédric Spitz
Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, ENSICAEN-Université de Caen6 Boulevard du Maréchal Juin, 14050 Caen, France.
Supervisors : M. Patrick Metzner, Directeur de recherche au CNRS, (LCMT-ENSICAEN) M. Vincent Reboul, Maître de conférences, Université de Caen, (LCMT-ENSICAEN)
09/11/2010
5
Introduction
Sulfenamides reviews : (1) Craine, L.; Raban M. Chem. Rev. 1989, 89, 689-712. (2) Davis, F. A. Int. J. Sulfur Chem. 1973, 8, 71-81.Effect : Buncel E.; Um I.-H. Tetrahedron, 2004, 60, 7801-7825.
- Electronegativity difference : S electrophile and N nucleophile
S-N : Supernucleophile?
- Lone pairs of the sulfur atom adjacent to nitrogen (effect)
Sulfenamide Sulfinamide Sulfonamide
R1 SN
R3
R2R1 S
N
OR3
R2
O
R1 SN
O
R3
R2
δ+
δ−
6
Reviews on sulfenamide reactivity : (1) N. E. Heimer, L. Field J. Org. Chem., 1970, 3102-3022. (2) L. Craine, M. Raban Chem. Rev. 1989, 89, 689-712.
R1
S N
R3
R2
H2NOH
O
R
HCl
S
NO2
Cl+
-HCl
Goerdeler, H.; Holst, A. Angew. Chem. 1959, 71, 775-788.
COPd(PPh3)4
S
O
N
R3
R3R1
90%(R1 = Ph; R2,R3 = Et)
Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh, K.; Kurosawa, H. J. Org. Chem. 1999, 64, 7305‑7308.
Ph OH
Ph O
H
NCS (5%)
98%
ClS N
t-Bu
Ph
Matsuo, J.-I.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron 2003, 59, 6739-6750.
(10%)
90% (ee : 98%)(R1 = Bn; R2,R3 = triazole)
NH OTMS
RR
HO
H
O
SR1
R = 3,5-CF3C6H3
Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem. 2005, 117, 804-807.
Sulfenamides reactivity
Caserio, M. C.; Kim, J. K. J. Am. Chem. Soc. 1982, 104, 3231-3233.
Me3OBF4
S
NR3
R2
R1
60%(R1, R2, R3 = Me)
Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett. 2004, 45, 1469-1471.
MeO2C CO2Me
MeO2C
NEt2
CO2Me
PhS[RuCl2(CO)3]2
87%
7
Sulfenamides applications
- Vulcanization
- Action mecanism of « proton pump inhibitors »
Omeprazole (racemic) : Mopral-Losec/Astra-ZenecaEsomeprazole (S) : Inexium/Astra-Zeneca (2001)
Global sales in 2006 : 6700 billions $ !
N
N
O
S
OH
N
O
N
N
O
SO
N Enz–SHHN
N
O
O
N
SS
Enz
Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc. 2004, 126, 7800-7811.
S8
8
- Aims : Synthesis of 1,4-benzothiazepines
Use of sulfenamides
SN
R1 R2
δ+
δ−
Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 2609-2616.
HH
O
S
NHR2R1
H
O
S
NR1 R2
1
2
34
R3
OMe
O
Lewis acid
SN
R1 R2 R3
C
MeO
OS
NR1
R3
OMe
O
R2
R3 = H, CO2Me
1
2
3
4
Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett. 2004, 45, 1469-1471.
Ruthenium complex
S[Ru]
N
R1
R2
S
NR1
R2
12
34
9
- Access to 1,4-benzothiazepines
Heart attack1
S
N
R
O
R = SO2-R1
O
N
Bn
R = K-201JTV-519
(1) (a) Kaneko, N. WO Patent 105793, 2005. (b) Kaneko, N.; Oosawa, T.; Sakai, T.; Oota, H. WO Patent 012148, 1992. (c) Marks, A. R.; Lehnart, S. E. WO Patent 021439, 2008. (d) Marks, A. R.; Landry, D. W.; Deng, S.; Cheng, Z. Z. WO Patent 101496, 2006.
Use of sulfenamides
Atheroma2
(accumulation and swelling in artery walls )
Hyperlipidemia3
(abnormally elevated levels of lipids in the blood)
Obesity3
Diabetes4
Cirrhosis of the liver
S
N
H
RR
O OR2N
NR2
(2) Brieaddy, L. E. WO Patent 016055, 1993.(3) (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. (4) Nagase, T.; Sato, Y.; Eiki, J. WO Patent 053548, 2002.
-1,1-dioxydes
10
Summary
I/ Synthesis of cyclic sulfenamides
II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines
III/ Synthesis of 1,3-benzothiazines
IV/ Synthesis of 2-substituted 1,4-benzothiazepines
SN
R1 R2
R
45
21
3
S
NR2R1
R3
R3
R
21
3
45
S
NR2R1
R3
21
3
4
S
N
R1
R2
R3
R
11
Summary
I/ Synthesis of cyclic sulfenamides SN
R1 R2
R
45
21
3
S
NR2R1
R3
R3
R
21
3
45
S
NR2R1
R3
21
3
4
S
N
R1
R2
R3
R
12
Synthesis of precursors
Synthesis of imines
Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 2609-2616.
Li
St-Bu
O
THF
-78°C, 1h30R = H, 80%, ee > 96%
R
n-BuLi (1 éq.), THF
-78°C, 1 h
Br
R
R
R = OMe, 70%
(R)
Kanazawa, A. M.; Denis, J.-N.; Greene A. E. J. Org. Chem. 1994, 59, 1238-1240.
OHN
SO2PhR
Base N R = alkyle, aryleEWG = Ts, Boc, SESHCOOH/H2OHR
R H
EWG
H2NEWG
PhSO2Na EWG
39-75%SES : O2S
SiMe3
Blum, S. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150-155.
Synthesis of sulfoxides
t-BuS
St-Bu
OH
N OH
t-Bu
t-Bu
H2O2 (1.4 equiv)O
St-Bu
t-BuS
O(0,52 mol %)
0,5 mol %VO(acac)2
, 0°C, 24 h
ee > 96%61% (after recristallization)
Ellman's thiosulfinate
13Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem. 2006, 71, 2609-2616.
a Déterminé par RMN 1H sur le brut réactionnel
Aminosulfoxides
R R1 EWG Rdt(%) r.d.a
H i-Pr Ts 80 >98/2
H Ph Ts 64 80/20
H Cy Ts 74 >98/2
H m-BrC6H4 Ts 63 77/23
H Cy SES 63 >98/2
H Ph Boc 54 80/20
H i-Pr Boc 46 >98/2
OMe i-Pr Ts 60 >98/2
Synthesis of cyclic sulfenamides
Addition of sulfoxides to imines
St-Bu
O
St-Bu
NH
EWG
OR11) n-BuLi (1,2 éq) THF, -78 °C, 1 h
2)N
HR1
EWG
THF, -78°C, 1 h
(1,2 éq)
ouHN
SO2PhR1
Boc
(0,55 éq)
(R) (R)
(R)
R R
99
95
98
Sulfenamides
98
98
99
97
96
Rdt (%)
S
EWG
HR1
H2O
acide sulfénique
ToluèneΔ,30min
SN
R1 EWG(R)
OH
N
R R
Quantitative cyclization of sulfenamides
and cyclization
N. Le FurO
St-Bu
Li
R H
NS
O
TolO
Alkyl imines :Total asymetric induction
Aryl imines : d.r. ≈ 80/20
14
SN
Ts SN
Ts
X-Ray Structure
Jean-François Lohier
15
Conclusion
Synthesis of 8 benzisothiazolines with good yields (from 36 to 62%) over 3 steps from Ellman’s thiosulfinate
- total asymetric induction for alkyl imines
- d.r. = 80/20 for aryl imines
- R2 = EWG (Ts, Boc, SES)
Reactivity of cyclic sulfenamides?
St-Bu
O
(R)S
t-Bu
NH
R2
OR11) n-BuLi (1,2 éq.)
(R)
THF, -78°C, 1 h
THF, -78°C, 1 h
(1,2 éq.)
(0,6 éq.)R
imine
sulfoneou
R
46-80%
2) reflux, 30 min
toluèneS
NR1 R2
95-99%R
R = H, OMeR1 = i-Pr, Cy, Ph, m-BrC6H4
R2 = Ts, Boc, SES
16
Summary
II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines
SN
R1 R2
R
45
21
3
S
NR2R1
R3
R3
R
21
3
4
S
N
R1
R2
R3
R
21
3
45
S
NR2R1
R3
17
Reactivity of sulfenamides
Bibliography
Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett. 2004, 45, 1469-1471.
(DMAD)
MeO2C CO2Me
[RuCl2(CO)3]2 (2 mol%)
MeO2C
PhS NEt2
CO2Me
87%
PhS NEt2
100% Z
DMF, 40°C, 6 h
(2 éq.)
Application to the synthesis of 1,4-benzothiazepines
- 1st step : nucleophilic attack of nitrogen of sulfenamide to alkyne
S N R
MeO O
AL
MeO O
δ+
δ−
SN
R
δ−
δ+
MeOO
SN
R
AL
AL
AL
CO2Me CO2MeCO2Me
MeO2C CO2Me
R' R'R'
Deprotection of sulfenamide
1) TFA (5 éq.), CH2Cl2, ta, 5 h
2) NaHCO3CH2Cl2
SN
SN
Boc
SN
H
52%
SN
Cy SES
SN
Cy H
60%ta, 1 nuit
CsF (5 éq.)DMF
S
NH2O
t-Bu
toluène80°C
72%
18
Reactivity of sulfenamides
Nitrogen nucleophilic despite EWG?
SN
TsMeO2C CO2Me
Δor/andcatalyst S
N
CO2Me
Ts
CO2Me
catalyst=ZnCl2,FeCl2,CuI,PdCl2(PPh3)2,RuCl3.3H2O
19
Use of sulfur electrophilie
Phosphines or amines catalysis
14460CH3CNPPh3 (25)
211460CH3CNDABCO (20)
(R)-19a
(Yield)Time (h)
T (°C)
SolventaCatalyst (mol%)
121420CH2Cl2DPPP (20)
701440CH2Cl2PPh3 (100)
351440CH2Cl2PMe3 (100)
161460CH3CN
ou toluene
DPPP (100)
a All reactions were carried out at 0.1 M concentration using 2 equivalents of DMAD.
01460 ou 100
CH3CN ou DMF
-
121440CH2Cl2PPh3 (25)
MeO2C
CO2Me
CO2MeY
CO2Me
SNTs
CO2Me
CO2MeY
SN
Ts
S
N
Ts
CO2Me
CO2Me
X : PR3, NR3Y : R3P+, R3N+
X(R)-19a
20
- bibliography
Gorgues, A.; Stéphan, D.; Cousseau, J. J. Chem. Soc., Chem. Commun. 1989, 1493-1494.
Fluoride catalysis
810,560CH3CNCsF (25)
370,560CH3CNTBAF (200)
880,560CH3CNCsF (200)
730,560CH3CNCsF (200)
86260CH3CNCsF (10)a
19a (Yield)Time (h)T (°C)SolventCatalyst (mol%)
60420CH3CNCsF (200)
02420CH3CNCsF (10)
A slow addition of DMAD over 30 min.
- optimized conditions
0,02
0,1
0,02
0,1
0,02
Concentration
0,1
0,1
Use of sulfur electrophilie
S
NCO2Me
S
NTs
CO2Me
CO2Me+
Ts
19a
MeO2CCsF
CH3CN(1,1 éq.)
FH
CO2Me
MeO2C
Z majo.
H2OCO2MeF
CO2MeMeO2C CO2Me
M F
DMF
M Rdt (%)
CsRbK
NaLi
67403700
21
Scope of the reaction
R R1 Yielda
H Cy 60
H Ph 79
H 3-Br-C6H4 65
OMe i-Pr 35
a slow addition of DMAD over 30 min
S
N
R1
CO2Me
S
NTsR1
CO2Me
CO2Me+
CsF (10%)
CH3CN(C = 0,02 M)
60°C, 2 h
Ts
19
RMeO2C
R
(1,1 éq.)
Fluoride catalysis
22
X-Ray Structure
2 conformations
Jean-François Lohier
S
N
Ts
CO2Me
CO2Me
i-Pr in « pseudo-axial » position i-Pr in « pseudo-equatorial » position
23
Scope with other alkynes
R1 Alkyne Yield (%)a
i-Pr 73
Cy 55
Ph 51
3-Br-C6H4 85
i-Pr 0
3-Br-C6H4 0
a All reactions were carried out with 10 % of CsF in acetonitrile at 60°C (C = 0,02 M) and slow addition of acetylene (1,1 eq.) over 30 min.
S
N
R1
S
NTsR1
CN
CN+CsF (10%)
CH3CN 60°C, 2 h
Ts
ou
SO2t-But-BuO2S
NC CN
NC CN
NC CN
NC CN
NC CN
SO2t-But-BuO2S
SO2t-But-BuO2S
24
X-Ray Structure
S
NCN
CN
Ts
Jean-François Lohier
S
NCN
CN
Ts
25
Mechanistic study
1st mechanism
2nd mechanism
S
NTs
R2
R2
S
R1
NTs
R1
F S NTs
R1
F
S
R1
NTs
F
R2
R2
R2 R2
H2OS
R1 NH
Ts
R1HN
Ts
S?
R2
R2
R2F
R2SN
TsR2
R2F
SN
Ts
F
R1
R1
S
NTs
R2
R2
R1
FH
R2
R2
H2O
R2 = CO2Me
traces
26
2nd mechanism?
- reversible- formation of a sulfenyl fluoride intermediate
Mechanistic study
S
NH
Ts
HN
Ts
S
S
NTs
NaBH4MeOH
puis H2O/HCl
S
NHTs
H
CsF (1 éq.)H2O (20 éq.)
CH3CN, 60°C, 6 h
20%
74%
Ar SF3
H2OAr SO2H
Literature :
Sheppard, W. A. J. Am. Chem. Soc. 1962, 84, 3058-3063.
Sandrinelli, F.; Perrio, S.; Beslin, P. Org. Lett. 1999, 1, 1177-1180.
CsF (1 éq.) Addition lente
de H2O
SO2H
NHTs
CH3I
S
NHTs
Me
O O
46%n-Bu4NBr (cat.)H2O/toluène/acétone
CH3CN, 60°C, 48 h
71%
SF3
NHTssupposition
27
Conclusion
One step synthesis of nine 1,4-benzothiazepines from benzisothiazolines with good yields (from 35 to 86%)
- 1st use of fluoride as nucleophilic catalyst
- formation of a sulfenyl fluoride intermediate
- limitations : - need of 2 EWG on the alkyne
- no reaction with di‑t‑butylsulfonylacetylene
Spitz, C.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Reboul, V.; Metzner, P. J. Org. Chem. 2009, 74, 3636-3639.
R = H, OMeR1 = alkyle, aryle
S
N
R1
R2R2
S
NTsR1
R2
R2+CsF (10%)
CH3CN 60 °C, 2 h
Ts
R2 = CO2Me, CN 35-86%
R
28
Summary
III/ Synthesis of 1,3-benzothiazines
SN
R1 R2
R
45
21
3
S
NR2R1
R3
R3
R
21
3
4
S
N
R1
R2
R3
R
21
3
45
S
NR2R1
R3
29
1,3-benzothiazines
Application of the previous method with terminal alkyne
S
NTs CsF
(10%)
CH3CNta, 30 min
S
N
Ts
CO2Me
CO2Me
H
- very fast reaction- unexpected formation of 1,3-benzothiazine
S
N
CO2Me
Ts
86%(E/Z : 13/87)
H
30
1,3-benzothiazines
Scope of the reaction with other sulfenamides and terminal alkynes
CsF (10%)
CH3CNta, 30 min
S
NR1
R2
Ts
S
N
R1
Ts R2
+
a Determined by 1H NMR of crude
17/8357CO2Me3-Br-C6H4
13/8785CO2Eti-Pr
14/8684CO2MeCy
E/ZaYield (%)R2R1
13/8773CO2MePh
13/8786CO2Mei-Pr - R2 = ester : diastereoisomer Z
- total diastereoselectivity for R1 = aryl and R2 = Ts
>98/274Ts3-Br-C6H4
92/893TsCy
>98/292TsPh
92/896Tsi-Pr
- R2 = tosyle : diastereoisomer E
-0Phi-Pr
- R2 = EWG needed(no reaction with phenylacetylene)
31
X-Ray Structure
S
NPh Ts
CO2Me
S
Ni-Pr Ts
Ts
Jean-François Lohier
32
Scope with others EWG on nitrogen of sulfenamide
- no deprotection of SES with 0.1 eq. of CsF in MeCN- deprotection with 2 eq. of CsF in DMF
S
N
CySES CsF (10%)
CH3CN ta, 30 min
72%
S
NCy SES
CO2Me
E/Z: 1/9
CsF (2 éq.)
DMF, ta, 2 h94%
CO2Me
S
NCy H
CO2Me
SES
S
N
R1
Boc
S
NHR1 Boc
CO2Me
CsF(10%)
CH3CNta, 30 min
S
N
CO2Me
BocR1
CO2Me
R1 = Ph, 97%R1 = i-Pr, 99%
TFA (12 éq.)
CH2Cl2, ta, 20 hS
NH
R1
CO2Me
R1 = Ph, 23%
Boc
- formation of an open molecule- possible to close it deprotecting the amine moiety
33
Mechanistic study
Deprotonation of methylpropiolate with n-BuLi then addition of sulfenamide
SN
Ts
CO2Me
1) n-BuLi (1.1 éq.)
THF, -100°C, 30 min
85%
THF, -100°C, 30 min
2) S
NTs
CO2Me
r.d. = 65/35
- Formation of 1,3-benzothiazine
S
NC
TsO
OMe S
N
TsS
NTs
CO2Me
HF
F
S
NTs
MeO2CS
N
CO2Me
Ts
CO2Me
MeO2C Hbenzothiazine Proposed mechanism
-Key step : deprotonationof alkyne by CsF
- domino reactions with aliphatic aldehydes
CsF (30%)
DMSO t.a.
O
O
H
O
O OMe
H
4 dias (E/Z, syn/anti)1
98%
H H
O O
55%
O
OCO2Me
(2,1 éq.)
(1,2 éq.)
O
CO2Me
O
34
Use of CsF as base
CsF as catalyst for nucleophilic addition of alkynes to carbonyl compounds?
H
OR
O
O
CsF (10%)DMSOta, 2 h
HO
CO2Et
64%
R = Et ou Me
- expected formation of alcohol by addition to cyclohexanone
- deprotonation confirmed
1 work carried out by Damien Deschamps
Ph
O
Hno reaction
35
Conclusion
One step synthesis of ten 1,3-benzothiazines from benzisothiazolines with good to excellent yields (from 57 to 96%) and moderate to excellent diastereoisomeric excess (from 66 to 96%)
- catalytic use of fluoride as base
- limitations : - no reaction with phenylacetylene
EWG sur l’alcyne
- promising first results with carbonyl compounds
CsF (10%)
CH3CNta, 30 min
S
NR1
R3
R2
S
N
R1
R2
R3+
57-96%R1 = alkyle, aryleR2 = Ts, SES
R3 = CO2Me, Ts, CO2Et r.d. = 66-96%
Spitz, C.; Lohier, J.-F.; Reboul, V.; Metzner, P. Org. Lett. 2009, 11, 2776-2779.
36
Summary
IV/ Synthesis of 2-substituted 1,4-benzothiazepines
SN
R1 R2
R
45
21
3
S
NR2R1
R3
R3
R
21
3
4
S
N
R1
R2
R3
R
21
3
45
S
NR2R1
R3
37
1,4-benzothiazepine vs 1,3-benzothiazine
With terminal alkynes, how could we favour formation of 1,4-benzothiazepine?
CO2Me
Y
CO2Me
SNTs
CO2Me
Y
SN
Ts
S
N
Ts
CO2Me
H X : PR3, NR3Y : R3P+, R3N+
X
H
H
H
C
Y H
OMeO
Promote catalyst nucleophilie (1,4 addition) instead of its basicity
SN
R1 Ts
R2
R2 = CO2Me, Ts
S
NR1
Ts
S
NR1 Ts
R2
H
H
R2
CsF (10%)MeCN
rt, 30 min86%
catalyst?
38
93
24
100
79
90
69100/0/04060DMEPyridine (0,5)
-100/0/07260DMEbPyridine (0,5)
80100/0/02460DMEPyridine (1)
-100/0/07060DMEPyridine (0,2)
-55/37/82460MeCNPyridine (0,2)
100
100
100
100
78
Conversion
-
-
-
-
-
15/65/20
0/84/16
18/71/11
17/72/11
22/58/20
2
0,5
1
0,5
24
80
ta
ta
ta
ta
MeCN
MeCN
MeCN
MeCN
MeCN
DPPP (0,1)
PPh3 (0,2)
DABCO (0,2)
DMAP (0,2)
Pyridine (0,2)
Yield A (%)A/B/CaTime (h)T (°C)Solvent
(C = 0,1 mol.L-1)
Catalyst
(Equiv.)
catalyseur
solvantCO2Me
+
S
NTs
CO2MeB
S
NTs
CO2MeA
SN
Ts
S
NTs
CO2Me
C(2 éq.)
a Determined by 1H NMR of crudeb C = 0,02 mol.L-1
1,4-benzothiazepine vs 1,3-benzothiazine
Optimization of conditions to promote benzothiazepine
39
Scope with others sulfenamides- best conditions to promote 1,4-benzothiazepine :0.5 equiv. of pyridine in DME at 60°C
scope with tosylacetylene using optimized conditions :
Ts
+
S
NTs
TsS
NTs
Ts
SN
Ts
S
NTs
Ts
BA C
pyridine (0,5 éq.)
DME, 60°C, 2 h
50 / 0 / 50
- need to reoptimize conditions
pyridine (0,5 éq.)
DME, 60°C, 24 hCO2Me+
S
N
R1Ts
CO2Me
SN
R1 Ts
(2 éq.)
R1 = Ph, 78%R1 = Cy, 82%R1 = m-BrC6H4, 71%
- only benzothiazepine formation
40
best conditions : sequential addition
With tosylacetylene
Use of pyridine with DMAD?
pyridine (0,1 éq.)
MeCN, 60°C, 1 h 30CO2Me+
S
NTs
CO2Me
SN
Ts
(2 éq.)MeO2C
87%
CO2Me
Application of these new optimized conditions to other sulfenamides
- only formation of benzothiazepine
pyridine (0,25 + 0,25 éq.)
DME, 80°CTs+
S
N
R1Ts
Ts
SN
R1 Ts
(1 + 1 éq.)
R1 = i-Pr, 61%R1 = Ph, 75%R1 = Cy, 51%R1 = m-BrC6H4, 65% 30 min + 30 min
41
Aim : Synthesis of 1,4-benzothiazepines of type A, monosubstituted on C-2 by an alkyl group and structurally close to biologically active compounds of type B
2,3-dihydro-1,4-benzothiazepines
SN
R1 R2 O
HR3
S
R3
O
H
NHR2R1
H
S
N
R1R2
R3
proposed pathway : 2 steps, totally different from previous work
1st step : -sulfanylation of an aldehyde with sulfenamide2nd step : intramolecular reductive amination
Nagase, T.; Sato, Y.; Eiki, J. WO Patent 053548, 2002.
Diabetes
S
NH
A O O
S
N
R1R2
R3
B
NR2
42
O
Hamine(30%)
SN
TsBr
MeCN, ta, 16 h
S
NHTs
H
OBr
(2 éq.)
Amine Yield (%) d.r.a
(S)-proline 22 50/50
piperidine 73 50/50
diethylamine 90 50/50a Determined by 1H NMR of crude
1st step : -sulfanylation
Reaction with isovaleraldehyde catalyzed by amine
- best conditions : 0.3 equiv. of diethylamine at rt in acetonitrile- no diastereoselectivity
43
(2 éq.)
O
H
SN
R2R1
S
NHR2R1
H
O
HNEt2(30%) MeCN
R1 R2 T (°C) Time (h) Yield (%) d.r.a
i-Pr Ts ta 16 77 50/50
Ph Ts 60 6 73 50/50
Cy Ts 60 16 65b 50/50
i-Pr Boc 60 24 64c 50/50a Determined by 1H NMR of crudeb 0,6 eq. of diethylaminec 2 eq. of diethylamine
1st step : -sulfanylation
Scope with other sulfenamides
44
R R’ R1 Yield (%) d.r.a
Me H i-Pr 45 50/50
Me H Ph 34 50/50
Me H Cy 32 50/50
Me H m-BrC6H4 37 50/50
Ph H i-Pr 0 -
H Ph i-Pr 0 -a Determined by 1H NMR of crude
1st step : -sulfanylation
Scope with other carbonyl compounds
(2 éq.)
R
O
R'
SN
TsR1
S
NHTsR1
R
R'
O
HNEt2(0,3 éq.) MeCN, ta, 22 h
- propionaldehyde : low yields- phenylacetaldehyde and acetophenone : no reaction
45
2nd step : cyclization
reductive amination : no cyclization, formation of alcohol
intramolecular Mitsunobu reaction from alcohol
SN
R1 Ts
S
NHTsR1
OH
PPh3 (3 éq.), DEAD (3 éq.)
THF, ta, 24 hS
NTs
R1
40 / 60
R1 = m-BrC6H4
S
NHTsR1
OPPh3
PPh3O
35%
a
b
voie b voie a
- 1,4-benzothiazepine obtained but with a low yield and a 70/30 diastereoisomeric ratio- but major product : sulfenamide!!!
S
R3
O
H
NHR2R1
S
N
R1R2
R3
NaBH3CNou NaBH(OAC)3
46
2nd step : cyclization
Deprotection of nitrogen to enhance its nucleophilie
S
NHR2R1
H
OTsOH.H2O (0,1 éq.)
toluène, 60°C, 2 h S
NR2
R1
Ts
Ts
Ts
Ts
Boc
R2
83Ph
75Cy
m-BrC6H4
i-Pr
i-Pr
R1
80
94
84
Rdt (%)
Optimization of acid conditions and scope
S
NHBoci-Pr
H
O TFA (10 éq.)
CH2Cl2, ta, 5 h
S
NH2i-Pr
H
O
S
Ni-Pr
- acid conditions : small amount of deprotection– cyclic major product
S
NBoc
i-Pr
63%
<20%
S
NBoc
i-Pr
OHH
47
R1 Yield (%)
i-Pr 25
Ph 30
Cy 30
m-BrC6H4 32
« One-pot » synthesis no purification of intermediate
(2 éq.)
O
H
SN
TsR1
S
NHTsR1
H
O
HNEt2(0,3 éq.) MeCN, ta, 22 h
TsOH.H2O (0,5 éq.)
toluène, 60°C, 5 hS
NTs
R1
- low global yields- need to use 0.5 equiv. of TsOH.H2O for 2nd step
48
Conclusion
One step synthesis of eight 1,4-benzothiazepines from benzisothiazolines with moderate to good yields (from 51 to 82%)
- with a terminal alkyne, it is possible to promote formation of 1,4-
benzothiazepines instead of 1,3-benzothiazines using different
reaction conditions
pyridine (0,5 éq.)DME, 60°C, 24 h
+pyridine (0,25 + 0,25 éq.)
DME, 80°C 30 min + 30 min
SN
R1 Ts
R2 ou
S
N
R1Ts
R2
R1 = alkyle, aryleR2 = CO2Me, Ts51-82%
49
Conclusion
Synthesis of nine 1,4-benzothiazepines over 2 steps with low to good global yields (from 25 to 72%)
- 1st step : -sulfanylation of aldehyde with sulfenamide in presence
of a catalytic amount of amine
- 2nd step : p-toluenesulfonic acid-catalyzed cyclization
(2 éq.)
R3
O
H
SN
R2R1
S
NHR2R1
H
O
HNEt2(cat.) MeCN
TsOH.H2O
toluèneS
NR3
R2
R1
(0,1 ou 0,5 éq.)
Rdts globaux = 25-72%
R1 = alkyle, aryleR2 = Ts, BocR3 = i-Pr, Me
R3
50
General conclusion
1,4-benzothiazepines
Nucleophilic fluoride
catalysis
S
NEWG
R1
EWG
EWG
R
Pyridine organo-catalysis
S
NEWG
R1
EWG
H
1,3-benzothiazines
Catalytic fluoride
as baseS
N
R1
EWG
EWG2,3-dihydro-1,4-benzothiazepines
Diethylamine organo-catalysis+Reduction+Mitsunobu
S
NEWG
R1S
N
R1
EWG
R
1,4-benzothiazepines
Diethylamine organo-catalysis+ acid catalyzed
cyclizationS
NR2
EWG
R1
51
52
Perspectives
How could we insert an aryl group in position 2?Solution? Initiate the reaction by a metal insertion in sulfur-nitrogen bond
Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett. 2004, 45, 1469-1471.
SN
R1 R2
δ+
δ−Métaldetransition(Pd,Ru...)
S[M]N
R1
R2
S
NR1 R2
Next steps : reduction of double bond, oxidation of sulfur and deprotection of nitrogen
Sato, A.; Yorimitsu, H.; Oshima, K. Synlett 2009, 28-31.
S
NR3
R2
R1
R1 = alkyle, aryleR3 = i-Pr, Me
S
NR3
R2
R1
S
NR3
R2
R1
OO
DéprotectionS
HN
R3R1
OO
[O]Et3SiH
TFA
53
Perspectives
Formation of sulfenamide from disulfure
SN
Ts
S
NH
Ts
HN
Ts
S
CH3CN 60°C, 6 h
CsF (1 éq.)H2O (20 éq.)
New method of synthesis of sulfenamides or sulfinic acids in mild conditions?
RS
SR Cs F
RS
F
R'NH2R
SNHR' F
RS
air
H2O
RSO2H
54
Introduction
- Pro-drogue
Application des sulfenamides
NH
SHHN
O
glutathion
N
O N
SNH3
+ N
O NH2
Carbamazépine(épilepsie)
NH
SHN
O
SNH3
H+
Hemenway, J. N.; Nti-Addae, K.; Guarino, V. R.; Stella, V. J. Biorg. Med. Chem. Lett. 2007, 6629-6632.
- Fonction protectrice des sites actifs d’enzymes
Protéine Tyrosine Phosphatase 1B
NH
SHHN
O
NH
SHN
O
OH
NS
O
NH
2 RSH
[O]
inactif
actif
Sivaramakrishnan, S.; Keerthi, K.; Gates, K. S. J. Am. Chem. Soc. 2005, 127, 10830-10831. Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc. 2007, 129, 8872–8881.
55
Synthesis des sulfoxydes
Synthesis du thiosulfinate
t-BuS
St-Bu
H2O2 (1,4 éq.)
St-Bu
t-BuS
O
VO(acac)2 (0,5 mol%)
acétone, 0°C, 24 h ee > 96% (CLHP)
61% (après recristallisation)
(0,52 mol%)
OH
N OH
t-Bu
t-Bu
(R)
Blum, S. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150-155.
Addition du sulfoxyde lithié au thiosulfinate
St-Bu
t-BuS
OLi S
t-Bu
O
THF, -78°C, 1h30
R = H, 80%, ee > 96%
R
n-BuLi, THF
-78°C, 1 h
Br
R R
R = OMe, 70%
56
Synthesis des imines
N-Tosylimines
N-Carbamoylimines
Imine aliphatique Boc non isolable
R H
O
t-BuOCONH2
PhSO2Na (2,5 éq.)HCOOH (2 éq.)
H2O/MeOH (2/1)20 h, ta
R SO2Ph
NHBoc
R = i-Pr, 62%R = Ph, 69%
(2 éq.)
K2CO3 (6 éq.)N
Boc
Ph HTHF, reflux,4 h99%
Na2SO4 (7 éq.)
N-SESimine
Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. Organic Syntheses 2004, 70-71.
Me3SiSO2NH2
3) NH3(g)Me3Si
1) NaHSO3, PhCO3t-Bu
2) SOCl2, DMFcat.
1) O
NaHCO3
PhSO2Na (1,1 éq.) HCOOH/H2O (1/1)
ta, 14 h
CH2Cl2ta, 3 h
HCyN
HCy
SES
2)
70%
(1 éq.),
SiMe3O2SSES :
41%
O NHSO2p-Tol
SO2PhR
NaHCO3 NPhSO2Na (1,1 éq.) R = i-Pr, 75%
R = Ph, 51%R = Cy, 72%R = m-BrC6H4, 39%
+ p-TolSO2NH2
HCOOH/H2O (1/1)14 h, ta
CH2Cl22 h, ta
HRR H
Ts
57
1,4-benzothiazépines disubstituées en 2 et 3
Généralisation de la méthode à d’autres alcynes
- Synthesis des alcynes :
- dicyanoacétylène
MeO2C CO2Me
NH3(g)Et2O
-78°C->ta1 nuit
O
H2N NH2
O
67%
P4O10
sable
150°C, 2 hNC CN
11%
(a) Hopf, H.; Witulski, B. In Modern Acetylene Chemistry(b) Stang, P. J.; Diederich, F., Ed.; VCH: Weinheim, 1995, 60.
Cl
Cl ClKH (3,5 éq.)
THFta, 1 h
Cl Clt-BuSH (2 éq.)MeOHcat.
0°C->ta20 h
St-Bu
St-Bu30%
m-CPBA (5 éq.)CHCl3
0°C->ta48 h
SO2t-Bu
SO2t-Bu96%
(a) Riera, A.; Cabré, F.; Moyano, A.; Pericàs, M. A.; Santamaría, J. Tetrahedron Lett. 1990, 31, 2169-2172.(b) Riera, A.; Martí, M.; Moyano, A.; Pericàs, M. A.; Santamaría, J. Tetrahedron Lett. 1990, 31, 2173-2176.
- di-t-butylsulfonylacétylène
58
pyridine
solvantTs
+
S
NTs
TsS
NTs
Ts
SN
Ts
S
NTs
Ts
BA C
Nb éq. pyridine
Nb éq. alcyne
Solvant T (°C)Temps
(h)Conversion A/B/Ca Rdt A
(%)
0,5
0,5
0,5
0,5
0,5
2
2
2
2
2
DME
MeCN
toluène
CH2Cl2DME
60
60
60
40
ta
2
2
2
2
2
78
100
100
100
100
50/0/50
0/13/87
10/15/75
29/30/41
38/17/45
-
-
-
-
-
2 2 DME ta 1 100 28/14/58 -
0,5 2 DME 80 1 75 81/0/19 -
0,25+0,25 1+1 DME 80 0,5+0,5 86 100/0/0 61a Déterminé par RMN 1H du brut réactionnel
Optimisation des conditions avec le tosylacétylène
- Meilleures conditions : d’abord 0,25 éq. de pyridine dans le DME à 80°C pdt 30 min puis à nouveau 0,25 éq. de pyridine dans le DME à 80°C pdt 30 min
Application à un autre alcyne