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Org. Synth. 2012, 89, 409-419 409 Published on the Web 4/6/2012
© 2012 Organic Syntheses, Inc.
Discussion Addendum for:
N-Hydroxy-4-(p-chlorophenyl)thiazole-2(3H)-thione
Cl
O
1. Br2, HOAc
150 °C
2. NH2OH·HCl
EtOH, H2O, 20 °C
Br
NCP
OH
S
NCP
OH
S
OEt
KS OEt
S
acetone, 20 °C
ZnCl
Et2O, 20 °C
N
S
CP S
HO
CPTTOH
CP
Prepared by Christine Schur, Irina Kempter, and Jens Hartung.*1
Original article: Hartung, J.; Schwarz, M. Org. Synth. 2002, 79, 228–235.
O-Alkylation of N-hydroxythiazole-2(3H)-thiones (TTOHs) provides
N-alkoxy derivatives, which are valuable alkoxyl radical precursors for
photobiological, mechanistic, and synthetic purposes.2,3,4
Chemical reactivity
of the N-alkoxythiazole-2(3H)-thiones (TTORs) is controlled by the
thiohydroxamic acid functional group that is embedded in a cross-
conjugated heterocyclic -electron system.5,6,7
Breaking of the
thiohydroxamate nitrogen-oxygen bond in TTORs allows the heterocyclic
fragment to gain aromatic stabilization, which is the reason for the
molecules to liberate oxygen-centered radicals under comparatively mild
conditions.
Systematic exploration of O-alkyl thiohydroxamate-based O-radical
precursors started with the N-alkoxypyridine-2(1H)-thiones.8,9,10
Experimental difficulties associated with synthesis and storage of the
reagents stimulated development of the N-alkoxy-4-(p-
chlorophenyl)thiazole-2(3H)-thiones (CPTTORs). The latter compounds
have shelf-lives from months to years,11,12
but selectively liberate oxygen
radicals if photochemically or thermally excited.4 Problems remaining
unsolved in CPTTOR-chemistry, such as synthesis of tertiary O-alkyl
DOI:10.15227/orgsyn.089.0409
410 Org. Synth. 2012, 89, 409-419
derivatives, were successfully addressed by introducing N-hydroxy-5-(p-
methoxyphenyl)-4-methylthiazole-2(3H)-thione (MAnTTOH) as next
generation alkoxyl radical progenitor.3,13,14
The Chemistry of N-Alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones
CPTTOH is an acid of similar strength to acetic acid and forms primary
and secondary O-esters in 50–70% yield, if converted into the derived
tetraalkylammonium salt and treated with a hard alkylating reagent. The
largest body of chemical reactivity data compiled for the CPTTORs relate to
photochemically or thermally initiated reactions with typical mediators for
conducting radical chain reactions, such as tributylstannane,
tris(trimethylsilyl)silane, O-ethyl cysteine, or bromotrichloromethane.5,15,16,17
In a supplementary project, the propensity of O-acyl- and O-alkyl-
derivatives of CPTTOH to crystallize was used to study the until then
unexplored solid state chemistry of the thiohydroxamates. The results from
this study show that the molecules tolerate a significant degree of steric
congestion at the thiohydroxamate oxygen, because strain effects are
absorbed by structural changes across the whole thiohydroxamte group.18
In addition to radical reactions and solid state chemistry, new ground
state reactivity of CPTTORs was discovered, such as a shift of the methyl
group from oxygen to sulfur, fragmentation of secondary benzylic esters
leading a thiolactam and a ketone, and 4-pentenoxy rearrangements occuring
specifically in the solid state (Figure 1).19,20
S
N
O
SCP
neat, 8 °C
~84 % convn
S
NCP S
CH3
CH3
O
+
–4 years
neat, 8 °C
S
N
O
SCPS
N
H
SCPPh
~37 % conv
+
5 months
S
N
O
SCP
tBu
neat, 8 °C
~43 % convn
S
NCP S
(±)2 years
OH
tBu
H
Ph
O
Figure 1. Background reactivity of neat CPTTORs in the solid state.
Org. Synth. 2012, 89, 409-419 411
5-Substituted N-Hydroxy-4-methylthiazole-2(3H)-thiones
From a structure-reactivity study it became apparent that a substituent
attached in position 5 shifts electronic absorptions of the thiazole-2(3H)-
thione nucleus stronger than the same group does in position 4. Synthesis of
5-substituted N-hydroxy-4-methylthiazole-2(3H)-thiones (Figure 2) starts
from constitutionally dissymmetric ketones. Arylpropanones that are not
commercially available can be prepared from underlying arylcarbaldehydes
and nitroethane via intermediate -nitrostyrenes. Hydrolysis of nitrostyrenes
in acidic aqueous solutions containing iron-powder furnishes the required
ketones, which are chlorinated by sulfuryl chloride at the higher substituted
-carbon. Methods of O-ethyl xanthogenate- and oxime-synthesis follow the
protocol of the original CPTTOH-synthesis (Figure 2). For the final step,
potassium hydroxide in an equimolar volume of dichloromethane and water
is the more efficient reagent to mediate the thiazolethione ring closure
compared to anhydrous zinc chloride in diethyl ether, which is the
recommended reagent for the final step of CPTTOH-synthesis. 3
O
R Cl KS OEt
S
acetone, 20 °C O
R S S
OEt
NH2OH·HCl
MeOH, 20 °C
S
N
OH
S
OEt
R
1. KOH
H2O, CH2Cl2,
20 °C
2. HCl aq., 0 °CN
S
S
OH
R
R total yield / % max / nm
CH3 74 317
C6H5 45 333
4-ClC6H4 (CP) 21 334
4-(AcHN)C6H4 59 335
4-(H3CO)C6H4 (An) 66 334
2,4-(H3CO)2C6H3 54 336
Cl
O3 steps
N
S S
OH
max = 376 nm
16 %
Figure 2. Synthesis of 5-substituted N-hydroxy-4-methylthiazole-2(3H)-
thiones.3
412 Org. Synth. 2012, 89, 409-419
N-Alkoxy-4-methylthiazole-2(3H)-thiones
N-Hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione
(MAnTTOH) was developed as successor of CPTTOR, to improve
photochemical properties of alkoxyl radical progenitors, raise yields of O-
alkylation products, and prepare tert-O-alkyl thiohydroxamates which until
then were not available in yields higher than 5%. MAnTTORs show a
longest wavelength of absorption at around 334 nm that gives some of the
compounds a yellow color and allows photochemical excitation with visible
light or 350 nm-light from a Rayonet®-photoreactor. MAnTTOH-derived
thiohydroxamate salts show an unusual propensity to form products of O-
alkylation (MAnTTORs), if treated with alkyl tosylates, alkyl chlorides, or
even alkyl iodides (top graphic of Figure 3).20
The majority of MAnTTORs
are solids that crystallize by adding an excess of methanol to crude reaction
mixtures. Alkylation at sulfur, which consumes the major fraction of
alkylation reagent in N-alkoxypyridine-2(1H)-thione-synthesis, is restricted
to comparably few instances, such the reaction between the MAnTTOH-
tetraethylammonium salt and methyl iodide (46%; bottom graphic of Figure
3).
N
S
S
OH
An
MAnTTOH
S
N S
O +–
An
M
N
S
S
OR
An
MAnTTOR
MeOH, 20 °C
MOH
DMF, 20 °C
R-X
M R-X yield (MAnTTOR) / %
Na
OTs
OTs
87
57
I 64
I 48
60c-C5H9I
I 47
Ph Cl77
S
N S
O +–
An
NEt4
N
S
SCH3
O
An
DMF, 20 °C
CH3I
+
–
Na
46%
NEt4
NEt4
NEt4
NEt4
NEt4
Figure 3. Preparation of MAnTTORs (top and table; An = p-anisyl) and
selective S-alkylation of a MAnTTOH-derived tetraethyl-
ammonium salt (bottom).20
Org. Synth. 2012, 89, 409-419 413
Alternative methods for thiohydroxamate O-alkylation are the
Mitsunobu-reaction, cyclic sulfate-opening, and O-alkyl isourea-chemistry
(Figure 4). The former two methods proceed via an inversion of
configuration at the attacked carbon,21
and the latter is the only method
available so far to prepare tertiary O-alkyl thiohydroxamates.22
OHH
H
(±)
N
S
S
OH
MTTOH
OMTTH
H
(±)
PPh3, DEAD+
C6H6, 20 °C
S
N
O
S
NEt4+–
+
HO
H9C4
C4H9
H
H
OMTT1. DMF, 22 °C
2. Et2O, H2OOSO2
OH9C4
H9C4
H
H
90%
60 %
H2SO4
N
S
S
OH
+
CH2Cl2, 20 °C
N
N O MAnTTO
58-64%
An
iPr
iPr
H
Figure 4. Synthesis of O-alkyl thiohydroxamates from an alcohol, cyclic
sulfate, or an isourea. 21,22
Scope of the Thiohydroxamate Method
The advantage of N-alkoxythiazole-2(3H)-thiones compared to
alternative alkoxyl radical precursors is their ability to liberate alkoxyl
radicals in a propagating step of a chain reaction. Nitrogen-oxygen bond
homolysis thereby occurs after addition of a chain propagating radical, such
as a carbon-, silicon-, or tin-radical, to the thione-sulfur (Figure 5).14
Alkoxyl radicals are highly reactive intermediates, their selectivities are,
however, predictable in a straightforward manner on the basis of kinetic and
thermochemical data. Additions and hydrogen-atom abstractions, two of the
main alkoxyl radical reactions, are irreversible and therefore controlled by
kinetic effects (Figure 6, top and center). Selectivity of -carbon-carbon
fragmentation for synthesis of carbonyl compounds (Figure 6, bottom), and
alkoxyl radical rearrangements are guided by radical stabilizing effects and
therefore are thermodynamically controlled.2,20,23
414 Org. Synth. 2012, 89, 409-419
O
R
O
O
R
R'
R'
O
RR'
S
NS
An
R'
X
S
NSCCl3
An
3
12
4
5
CCl3
BrCCl3
Figure 5. Radical chain mechanism for synthesis of target compounds
according to the thiohydroxamate method, exemplified by the
use of BrCCl3 as mediator (R = alkyl, phenyl, acyloxy; R’ =
hydrogen, alkyl, phenyl).20,22
•
• homolytic substitution
O
Ph
BrCCl3, AIBN
C6D6, 80 °C
• -carbon-carbon fragmentation
•O O
OAcAcO
AcO HHBu3SnH, h
C6H6, 20 °C
O
OAc
OAcAcO
O
H
• addition
•O BrCCl3, h
C6H6, 20 °C
O
BzO
H
BzO
HO
HBrH
major
H NMe3+
Br–
(+)-allo-muscarine
O PhO
Ph
Br
H
– HBr
HO
2 steps
H
Figure 6. Application of homolytic substitution, addition, and -carbon-
carbon bond fragmentation of alkoxyl radicals in synthesis.24
Org. Synth. 2012, 89, 409-419 415
Since the radical oxygen is electrophilic and the hydroxyl oxygen
nucleophilic, additions of alkoxyl radicals and alcohols to polar carbon-
carbon double bonds occur with complementary selectivity
(Figure 7).7,25,26,27
OCPTTPh BrCCl3, h
C6H6, 20 °C
OPh
cis:trans = 28:72
+N
S
71 %
SCCl3CP
BrCCl3, AIBN
C6H6, 80 °C
OMTT
Ph
OO
+
Ph
Br
58 % 2 %
• alkoxyl radical cyclizations
• ionic cyclizations
OHPhNBS
CH2Cl2, 20 °C
O
Br
Ph
79 %
cis:trans = 6:94
87 %
7 %
cis:trans = 33:67
OH
Ph
O Ph
Br
66 %
CH2Cl2, 20 °C
VOL(OEt) cat.
Br
Ph
Br
py·HBr, TBHP
+OPh
Br
Figure 7. Examples showing complementary selectivity in
bromocyclizations of alkenoxyl radicals (top) and alkenols
(bottom: VOL(OEt) = 2-[(2-oxidophenyl)iminomethyl]
(ethanolato) oxidovanadium(V); py·HBr = pyridinium
hydrobromide; TBHP = tert-butylhydroperoxide}.25,27
Alkoxyl radical generation from N-alkoxythiazolethiones occurs under
pH-neutral, non-oxidative conditions and therefore may be used for
transformations that are not attainable by other alkoxyl radical-generating
methods. Substituted 5-hexenyloxyl radicals, for example, cyclize onto -
bonds having two methyl groups attached at the terminal alkene carbon. The
reaction stereoselectively provides tetrahydropyranylmethyl radicals, which
are trapped by bromotrichlormethane to furnish bromocyclized products
416 Org. Synth. 2012, 89, 409-419
(Figure 8).28,29
Polar bromocyclization of the underlying 5-hexenols provide
oxepans as major products.
OMAnTTPhBrCCl3, AIBN
C6H6, 80 °C
O
Br
Ph
34 %
cis:t rans = 65:35
OPh+
46 %cis:trans = 50:50
OMAnTT O
Br
46 %
cis:t rans = 87:13
O
+
42 %
cis:trans = 12:88
Ph Ph
Ph
BrCCl3, AIBN
C6H6, 80 °C
Figure 8. Synthesis of tetrahydropyrans from MAnTTORs via underlying 5-
hexenoxyl radical cyclization.
The thiohydroxamate method also applies to prepare vicinal
bromohydrin ethers from intermolecular alkoxyl radical addition to alkenes
(Figure 9). O-Alkyl thiohydroxamates thus were used to synthesize
norbornene-derived vicinal bromohydrin ethers, which have interesting
biological properties but are difficult to prepare from ionic reactions due to
complications imposed by non-classical carbocation formation.22,30
MAnTTOR+
BrCCl3 OR
Br
2
3C6H5CF3
conditions
R conditions yield / % 3-exo : 3-endo
H mw / 200 °C 7 13 : 87
CH3 AIBN / 80 °C 64 28 : 72
CH(CH3)2 mw / 150 °C 33 25 : 75
C(CH3)3 h / 20 °C 46 24 : 76
mw = laboratory microwave Figure 9. Synthesis of -bromoethers from intermolecular alkoxyl radical
additions.
Besides adding benefits to organic synthesis, MAnTTORs are excellent
tools for conducting kinetic studies on alkoxyl radical elementary
reactions.22
Kinetic data are the basis for application of alkoxyl radicals in
Org. Synth. 2012, 89, 409-419 417
synthesis of ethers , for complementing selectivity that for more than a
century has been restricted to nucleophilic carbon-oxygen bond formation.
1. Department of Chemistry, Technische Universität Kaiserslautern, D-
67663 Kaiserslautern, Germany. This work was supported by the State
Rheinland-Pfalz (Scholarships for I.K. and C.S.) and the Deutsche
Forschungsgemeinschaft.
2. Adam, W.; Hartung, J.; Okamoto, H.; Marquardt, S.; Nau, W.M.;
Pischel, U.; Saha-Möller C.R.; pehar, K. J. Org. Chem. 2002, 67,
6041–6049.
3. Groß, A.; Schneiders, N.; Daniel, K.; Gottwald, T.; Hartung, J.
Tetrahedron 2008, 64, 10882–10889.
4. Hartung, J.; Daniel, K.; Gottwald, T.; Groß, A.; Schneiders, N. Org.
Biomol. Chem. 2006, 4, 2313–2322.
5. Arnone, M.; Hartung, J.; Engels, B. J. Phys. Chem. A. 2005, 109, 5943–
5950.
6. Hartung, J.; Gottwald, T.; pehar, K. Synthesis 2002, 1469–1498.
7. Greb, M.; Hartung, J. Synlett 2004, 65–68.
8. Beckwith, A.L.J, Hay, B.P. J. Am. Chem. Soc. 1988, 110, 4415–4416.
9. Hartung, J.; Gallou, F. J. Org. Chem. 1995, 60, 6706–6716.
10. Hartung, J.; Hiller, M.; Schwarz, M.; Svoboda, I.; Fuess, H. Liebigs
Ann. Chem. 1996, 2091–2097.
11. Hartung, J.; Schwarz, M.; Svoboda, I.; Fueß, H.; Duarte, M. T. Eur. J.
Org. Chem. 1999, 1275–1290.
12. Hartung, J.; Schwarz, M.; Paulus, E. F.; Svoboda, I.; Fuess, H. Acta
Cryst. 2006, C62, o386–o388.
13. Hartung, J.; Gottwald, T.; pehar, K.; Synlett 2003, 227–229.
14. Hartung, J.; pehar, K.; Svoboda, I.; Fuess, H.; Arnone, M.; Engels, B.
Eur. J. Org. Chem. 2005, 869–881.
15. 4-(4-Chlorophenyl)-3-hydroxy-2(3H)thiazolethione. Hartung J. In
Reagents for Radical Chemistry – Encyclopedia of Reagents in Organic
Chemistry; Crich, D. Ed., John Wiley & Sons, New York, N.Y., 2008,
175–179.
16. Cyclization of Alkoxyl Radicals. Hartung J., In Radicals in Organic
Synthesis; Renaud, P.; Sibi, M.P., Eds.; vol. 2, Wiley-VCH, 2001, 427–
439.
17. Hartung, J. Eur. J. Org. Chem. 2001, 619–632.
418 Org. Synth. 2012, 89, 409-419
18. Hartung, J.; Bergsträßer, U.; Daniel, K.; Schneiders, N.; Svoboda, I.;
Fuess, H. Tetrahedron 2009, 65, 2567–2573.
19. Hartung, J.; Daniel, K.; Bergsträsser, U.; Kempter, I.; Schneiders, N.;
Danner, S.; Schmidt, P.; Svoboda, I.; Fuess, H. Eur. J. Org. Chem.
2009, 4135–4142.
20. Hartung, J.; Schur, C.; Kempter, I.; Gottwald, T. Tetrahedron 2010, 66,
1365–1374.
21. Hartung, J.; Kempter, I.; Gottwald, T.; Kneuer, R.
Tetrahedron:Asymmetry 2009, 20, 2097–2104.
22. Schur, C.; Becker, N.; Bergsträßer, U.; Gottwald, T.; Hartung, J.
Tetrahedron 2011, 67, 2338–2347.
23. Hartung, J.; Kneuer, R.; pehar, K. Chem. Commun. 2001, 799–800.
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Fuess, H. Eur. J. Org. Chem. 2003, 4033–4052.
26. Hartung, J.; Kopf, T.M.; Kneuer, R.; Schmidt, P. C. R. Acad. Sci. Paris,
Chimie/Chemistry 2001, 649–666.
27. Gottwald, T.; Greb, M.; Hartung, J. Synlett 2004, 65–68.
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Jens Hartung was born in Offenbach/Main, Germany in 1961.
He took his diploma degree in 1987 with Klaus Hafner and his
Ph.D. with Bernd Giese in 1990 at the Technische Hochschule
Darmstadt, Germany. That same year, he moved to the MIT to
spent a postdoctoral year with K. Barry Sharpless. In 1992 he
joined the cardiovascular division of Hoechst AG (today
Sanofi-Aventis). In 1994 he moved as lecturer to the
Bayerische Julius-Maximilians-Universität Würzburg, where
he completed his habilitation in 1998. Since 2003 he is full
professor of organic chemistry at the Technische Universität
Kaiserslautern. His research interests include the chemistry of
reactive intermediates, in particular oxygen-centered radicals,
transition metal-catalyzed oxidations, the chemistry of
vanadium-dependent bromoperoxidases, static and dynamic
stereochemistry, synthesis of heterocycles and marine natural
products.
Org. Synth. 2012, 89, 409-419 419
Christine Schur was born in Karassu, Kasachstan in 1983. She
received a Diploma-degree in 2008 from the Technische
Hochschule Kaiserslautern studying selectivity in inter- and
intramolecular alkoxyl radical reactions, working with Jens
Hartung. She continues this project as part of her Ph.D.-thesis.
Irina Kempter was born in Neustadt/Weinstraße, Germany in
1984. She received a Diploma-degree in 2008 from the
Technische Hochschule Kaiserslautern studying stereoselective
O-alkyl thiohydroxamate synthesis, working with Jens
Hartung. Her research interests in a new project as part of her
Ph.D.-thesis are associated with investigation of polar effects in
alkoxyl radical chemistry.