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.

24. Hartung, J.; Kneuer, R. Tetrahedron:Asymmetry 2003, 14, 3019–3031.

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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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6327–6330.

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.