Sulfur Compounds in Organic Synthesis

1
Sulfur Compounds in Organic Synthesis
Iain Coldham
Introduction
Divalent sulfur
1.
RSH, RSR', RSBr, RC(S)OR', etc
Divalent sulfur are sulfenyl compounds
Subdivision based on coordination number around
the sulfur atom
Formal oxidation number at the sulfur atom of 2
2
Sulfur Compounds in Organic Synthesis
Iain Coldham
Introduction
Divalent sulfur
1.
RSH, RSR', RSBr, RC(S)OR', etc
Trivalent sulfur
2.
R3SBr, RS(O)R', RS(O)OR', etc
Trivalent sulfur are sulfinyl compounds
Subdivision based on coordination number around
the sulfur atom
Formal oxidation number at the sulfur atom of 4
3
Sulfur Compounds in Organic Synthesis
Iain Coldham
Introduction
Divalent sulfur
1.
RSH, RSR', RSBr, RC(S)OR', etc
Trivalent sulfur
2.
R3SBr, RS(O)R', RS(O)OR', etc
Tetravalent sulfur
3.
RSO2R', RSO2OR', RSO2NHR', etc
Tetravalent sulfur are sulfonyl compounds
Subdivision based on coordination number around
the sulfur atom
Formal oxidation number at the sulfur atom of 6
4
1. Divalent sulfur
RSH, RSR', RSBr, RC(S)OR', etc
a) Thiols
b) Carbon-centred radicals from sulfur compounds
c) Electrophilic sulfur
d) Episulfonium ion chemistry
e) Carbanions ?- to sulfur
f) Sulfurmetal exchange
g) Carbocations ?- to sulfur
h) Thiocarbonyl compounds
i) Sulfur-containing heterocycles
5
1. Divalent sulfur
RSH, RSR', RSBr, RC(S)OR', etc
a) Thiols RSH
Smelly!
Relatively acidic
pKa (in water)
EtOH
16
EtSH
10.5
PhOH
10
PhSH
6.5
AcOH
4.7
AcSH
3.3
Bond strength for
Weak SH bond
SH is 349 kJ/molCH is 418 kJ/mol
High nucleophilicity
Thiols and thiolates are considered to be soft
and highly polarizable
6
Preparation of Thiols
Use an alkyl halide and H2S or AcSH
J. Am. Chem. Soc., 2005, 127, 15668
J. Org. Chem., 1990, 55, 2736
For palladium coupling of AcS and ArX, see
Tetrahedron Lett., 2007, 48, 3033
7
Preparation of Thiols
Displacement of a leaving group (e.g. a sulfoxide
or sulfone)
Org. Proc. Res. Dev., 2007, 11, 389
8
Reaction of Thiols
Good nucleophiles
Tetrahedron Lett., 2005, 46, 8931
Suitable for alkyl-alkyl and aryl-alkyl
thioethers Successful for secondary alkyl iodides
(iPrI) but not tertiary halides No racemization
using L-cysteine methyl ester
9
Reaction of Thiols
Good nucleophiles
Bioorg. Med. Chem. Lett., 2007, 17, 1455
Formation of heteroaryl-thiols from
isothiocyanates Use of KOH as base for
S-alkylation Activity against Nec-1
(necrostatin-1) to prevent cell death
10
Reaction of Thiols
Good nucleophiles
Tetrahedron Lett., 2006, 47, 7375
Tetrahedron Lett., 2006, 47, 1889
For a review on asymmetic sulfa-Michael
additions, see Synthesis, 2007, 959
11
Reaction of Thiols
Good nucleophiles
Tetrahedron, 2006, 62, 2357
Suitable for nitro-aromatics with various
electron-withdrawing groups (CHO, CO2Me, COMe,
CN, NO2) these can be at the 2- or
4-positions Catalytic Cs2CO3 gave poor conversion
12
Reaction of Thiols
Suitable for coupling reactions
J. Am. Chem. Soc., 2006, 128, 2180 Full paper
Chem. Eur. J., 2006, 12, 7782
Suitable for aryl chlorides, bromides, iodides,
sulfonates, even if hindered Need an
electron-rich, hindered, bisphosphine ligand for
the palladium
For polymer-supported thiols as scavengers for
Pd, see Org. Proc. Res. Dev., 2007, 406
13
Reaction of Thiols
Suitable for coupling reactions
Bioorg. Med. Chem. Lett., 2006, 16, 934
The products were converted, via the
2-chloropyridines, to 2-aminopyridines to prepare
corticotropin releasing factor receptor ligands
For a cobalt-catalyzed coupling using 1 mol
CoI2(dppe)/Zn, see Org. Lett., 2006, 8, 5613
For a nickel-catalyzed coupling of PhI and RSSR
to give PhSR, see Tetrahedron Lett., 2006, 47,
5059
14
Reaction of Thiols
Reversible reaction with thiolesters
This gives 25 thiolesters in equilibrium
Addition of the enzyme acetylcholinesterase
(AChE) causes hydrolysis of the best substrates
i.e. the acetate and propionate hydrolysis
products with half-lives of 210310 min
Eur. J. Org. Chem., 2006, 285
Dynamic combinatorial libraries of thiolesters
15
Reaction of Thiols
The weak SH bond can promote RS and disulfide
formation
Thiols are good hydrogen atom donors in radical
reactions
16
Reaction of Thiols
Thiol radical addition to an alkene
Synlett, 2006, 423
Radical cyclization reactions are best carried
out under dilute conditions
17
b) Carbon-centred radicals from sulfur compounds
Reaction of Xanthates
Tetrahedron Lett., 2004, 45, 6017
Inter- then intramolecular radical reaction then
recombination
18
Carbon-centred radicals from sulfur compounds
Barton deoxygenation
Chem. Rev., 1989, 89, 1413
19
Carbon-centred radicals from sulfur compounds
Barton decarboxylation
Tetrahedron, 1985, 41, 3901
20
c) Electrophilic sulfur
Use elemental sulfur (S8) or RSX where X is Cl,
Br, SR, SO2Ph, NPhth
Bioorg. Med. Chem. Lett., 2006, 16, 2260
Disulfide formation then reduction to give the
thiol
21
Electrophilic sulfur
Use elemental sulfur (S8) or RSX where X is Cl,
Br, SR, SO2Ph, NPhth
Org. Lett., 2006, 7, 565
Using the natural nucleophilicity of indoles
22
Electrophilic sulfur
Can use other disulfides
Synlett, 2006, 792
Can use R2Zn or RZnCl or RZnBr
23
d) Episulfonium ion chemistry
Formed from alkenes and electrophilic sulfur, or
from ?-hydroxy-sulfides
J. Chem. Res., Perkin Trans. 1, 1992, 2303
Example of migration of sulfur from a secondary
to a tertiary centre
24
Episulfonium ion chemistry
Formed from alkenes and electrophilic sulfur, or
from ?-hydroxy-sulfides
J. Chem. Res., Perkin Trans. 1, 1992, 2303
Episulfonium ions can be trapped with internal
nucleophiles
Example of migration of sulfur from a tertiary to
a secondary centre
25
e) Carbanions ?- to sulfur
Metallation provides useful carbon nucleophiles
pKa (in DMSO)
PhS(O)Me
33
PhSO2Me
29
PhSMe
39
PhSCH2SPh
31
PhSO2CH2OMe
31
PhS(O)CH2Ph
27
PhSCH2CN
21
PhSO2CH2SPh
21
PhS(O)2CH2
18
PhSCH2NO2
12
PhSO2CH2SO2Ph
12
Me3SOI
18
What stabilizes the carbanion ?- to sulfur?
Probably is due to stereoelectronic effects
Delocalisation of the carbanion into the ?
orbital of the opposite CS bond
26
Carbanions ?- to sulfur
Allyl phenyl sulfides are good substrates for
lithiationsubstitution If regioselective
substitution is poor then use allyl 2-pyridyl
sulfides
27
Carbanions ?- to sulfur
Chiral acyl anion equivalent
J. Org. Chem., 2001, 66, 3059
Lithium coordinates with the carbonyl oxygen atom
to give one stereoisomeric organolithium species
with SMe and i-Pr on opposite sides
28
Carbanions ?- to sulfur
Dithianes are good acyl anion equivalents
For a review, see Tetrahedron, 2003, 59, 6147
Lithiated 1,3-dithianes react with a variety of
electrophiles
29
f) SulfurLithium exchange
Use lithium and naphthalene, dimethylamino-naphtha
lene or di-tert-butylbiphenyl (DBB)
Tetrahedron, 2006, 62, 2264
Alkyl-, allyl-, vinyl- and aryl-sulfides are
amenable to sulfurlithium exchange
30
SulfurMagnesium exchange
Recent example requires intramolecular activation
Angew. Chem. Int. Ed., 2006, 45, 606
31
g) Carbocations ?- to sulfur
Can be generated from thioethers and NCS or from
sulfoxides (see next lecture)
Sulfonium ions react with soft nucleophiles such
as silyl enol ethers
32
Carbocations ?- to sulfur
Double Pummerer methodology for oxazole synthesis
Tetrahedron Lett., 2002, 43, 7393
Cyclization onto the sulfonium ion then further
sulfonium ion formation and elimination
33
h) Thiocarbonyl compounds
Thioaldehydes and dialkylthioketones are too
unstable to exist
Dithioesters and thioamides are stable due to the
extra conjugation
For a review on Lawessons reagent, see
Synthesis, 2003, 1929
34
Thiocarbonyl compounds
Thioamides can be used in coupling reactions
J. Org. Chem., 2007, 72, 4440
35
i) Sulfur-containing heterocycles
e.g. tetrahydrothiophene, thiophene, thiazole
36
Thiophenes
Use a 1,4-dicarbonyl compound and Lawessons
reagent
Or a diyne and H2S or Na2S and hydroxide
37
Benzothiophenes
Cyclization of an aldehyde equivalent
Org. Proc. Res. Dev., 2006, 10, 296
38
Thiazoles
Use a thioamide and an ?-halo-ketone or acetal
Bioorg. Med. Chem. Lett., 2006, 16, 5317
39
Thiazoles
Tetrahedron Lett., 2006, 47, 2361
For a 2-amino-thiazole use thiourea or thiocyanate
J. Chem. Soc., Perkin Trans. 1, 1999, 2425
40
References
Examples in this presentation have been taken
from
The primary literature
there are many articles in most issues of most
journals! examples from the recent literature in
particular are used.
Organosulfur Chemistry by G.H. Whitham, OUP,
Oxford 1995
ISBN 0 19 855899 6
Organic Chemistry by J. Clayden, N. Greeves, S.
Warren and P. Wothers, OUP, Oxford 2001 (See
Chapter 46, pages 12471275)
ISBN 0 19 850346 6
Modern Methods of Organic Synthesis by W.
Carruthers and I. Coldham, 4th ed., Cambridge
University Press, Cambridge 2004 (e.g. pages
5357)
ISBN 0 52 177830 1