Towards new imidazole-2-thione-based organocatalysts; Sulfur transfer vs. deoxygenation in the reaction of imidazole N-oxides and cycloaliphatic thioketones

Article abstract of DOI:10.1080/10426507.2012.743148

Sulfuration or deoxygenation? Competitive transformations of the title imidazole N-oxides into respective masked thiourea analogs or into the parent heterocycle in the reaction with 2,2,4,4-tetramethylcyclobutane-1,3-dithione are presented. The influence

Full text of DOI:10.1080/10426507.2012.743148

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Phosphorus, Sulfur, and Silicon and the
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Towards New Imidazole-2-Thione-
Based Organocatalysts; Sulfur Transfer
Vs. Deoxygenation in the Reaction of
Imidazole N-Oxides and Cycloaliphatic
Thioketones
a b
a
a
Dorota Rygielska-Tokarska
, Marcin Jasiński , Grzegorz Mlostoń
c
&
a
Heinz Heimgartner
Department of Organic and Applied Chemistry , University of Łódź
Łódź , Poland
,
b
Bioorganic Chemistry Laboratory , Medical University of Łódź ,
Łódź , Poland
c
Institute of Organic Chemistry , University of Zürich ,
Winterthurerstrasse , Zürich , Switzerland
Accepted author version posted online: 10 Dec 2012.Published
online: 29 May 2013.
To cite this article: Dorota Rygielska-Tokarska , Marcin Jasiński , Grzegorz Mlostoń & Heinz
Heimgartner (2013) Towards New Imidazole-2-Thione-Based Organocatalysts; Sulfur Transfer Vs.
Deoxygenation in the Reaction of Imidazole N-Oxides and Cycloaliphatic Thioketones, Phosphorus,
Sulfur, and Silicon and the Related Elements, 188:4, 469-472, DOI: 10.1080/10426507.2012.743148
To link to this article: http://dx.doi.org/10.1080/10426507.2012.743148
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Phosphorus, Sulfur, and Silicon, 188:469–472, 2013
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.743148
TOWARDS NEW IMIDAZOLE-2-THIONE-BASED
ORGANOCATALYSTS; SULFUR TRANSFER
VS. DEOXYGENATION IN THE REACTION OF IMIDAZOLE
N-OXIDES AND CYCLOALIPHATIC THIOKETONES
1
,2
1
Dorota Rygielska-Tokarska, Marcin Jasi n´ ski,
1
3
Grzegorz Mlosto n´ , and Heinz Heimgartner
1
Department of Organic and Applied Chemistry, University of Ł o´ d z´ , Ł o´ d z´ , Poland
Bioorganic Chemistry Laboratory, Medical University of Ł o´ d z´ , Ł o´ d z´ , Poland
Institute of Organic Chemistry, University of Z u¨ rich, Winterthurerstrasse, Z u¨ rich,
2
3
Switzerland
GRAPHICAL ABSTRACT
Abstract Sulfuration or deoxygenation? Competitive transformations of the title imidazole
N-oxides into respective masked thiourea analogs or into the parent heterocycle in the reaction
with 2,2,4,4-tetramethylcyclobutane-1,3-dithione are presented. The influence of an electron-
withdrawing substituents in combination with the steric hindrance of neighboring groups onto
reaction outcome is discussed.
Keywords trans-1,2-Diaminocyclohexane;imidazoleN-oxides;sulfur transfer;deoxygenation
INTRODUCTION
In a series of recent reports, variously functionalized amino components including
amino alcohols, amino acids, and α,ω-diaminoalkanes have been employed for the con-
1
struction of achiral and chiral 2-unsubstituted imidazole N-oxides. In continuation of our
studies, optically pure enantiomers of trans-1,2-diaminocyclohexane (DACH) served as
2
versatile scaffolds for the synthesis of C2-symmetrical bis-imidazole derivatives 1.
Some of the optically active N,N’-dioxides of type 1 as well as their deoxygenated
analogs were successfully applied as organocatalysts, that is, for the asymmetric allylation
3
of aromatic aldehydes. On the other hand, various thiourea derivatives act efficiently
Received 30 September 2012; accepted 21 October 2012.
Address correspondence to Marcin Jasi n´ ski, Department of Organic and Applied Chemistry, University of
Ł o´ d z´ , Tamka 12, 91-403 Ł o´ d z´ , Poland. E-mail: mjasinski@uni.lodz.pl
4
69

470
D. RYGIELSKA-TOKARSKA ET AL.
Figure 1 Substitution pattern of (R,R)-1,2-DACH-derived bis-imidazole N-oxides 1.
4
as ligands or organocatalysts for asymmetric synthesis. Therefore, our ongoing studies
focus on the preparation of nonracemic imidazole-2-thiones, compounds that should be
considered as masked thiourea derivatives. Since bis-imidazolethiones derived from 1
suffer from limited solubility in most of known organic solvents, we paid our attention to
monoprotected derivatives of (R,R)-trans-DACH.
Scheme 1 Synthesis of imidazole N-oxides 3a-c and their reactions with 5a: a) salicylaldehyde (0.95 equiv.),
◦
CHCl3, 0 C, 5h; b) (CH2O)n (1.1 equiv.), EtOH, r.t., overnight, then a-hydroxyiminoketone (1.1 equiv.), reflux,
8
1
h; c) 5a (1.8 equiv.), CHCl3, r.t., overnight; d) 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1.2 equiv.), toluene, reflux,
6 h; e) NaNO2 (1.3 equiv.), AcOH, 0 C to r.t., 2.5h; f) 2 (0.9 equiv.), (CH2O)n (1.0 equiv.), EtOH, r.t., overnight,
◦
then 4, reflux, 8h.

NEW IMIDAZOLE-2-THIONE-BASED ORGANOCATALYSTS
471
RESULTS
Although several monoprotected derivatives of DACH are readily available, the most
commonly applied ones for organic synthesis, that is, N-monoacetylated and N-Boc-
protected analogs, failed in the preparation of desired materials. Thus, salicylaldehyde-
derived monoimine 2 was studied in more detail, and under optimized reaction conditions
furnished desired imidazole N-oxides 3a-b. In search for a chiral α-hydroxyiminoketone
substrate, in situ generated acetylketene was trapped by (S)-1-phenylethylamine to yield,
after subsequent nitrosation, enantiomerically pure 4, suitable for construction of imidazole
N-oxide 3c (Scheme 1).5
Whereas “hemi-salen derived” imidazole N-oxides 3a–b in the reaction with thioke-
tone 5a smoothly yielded the expected imidazole-2-thiones 6a–b, the presence of the
electron-withdrawing carboxamide group in 3c influenced the reaction course to give,
along with the desired imidazole-2-thione 6c, a small amount of deoxygenated compound
7c. We assumed therefore, that the electron-withdrawing N-(1-phenylethyl)carboxamido
group should be decisive for partial change of the reaction outcome. In order to gain more
detailed information about the observed phenomena, a series of model imidazole N-oxides
6
8
were tested under the applied reaction conditions (Scheme 2).
Scheme 2 Sulfur transfer vs. deoxygenation; a structure relationship analysis.
None of imidazole N-oxides of type 8 bearing an aforementioned carboxamido
group at C(4) and a small (Me) or medium (iPr, Bn) substituent at N(1) gave deoxygenated
products of type 10, and the respective imidazole-2-thiones 9 were isolated as sole products.
In contrast, analogous N-(1-adamantyl) derivative yielded corresponding deoxygenated
imidazole exclusively. Similar results were noticed for the C(4)-acetylated imidazole N-
oxide series. Finally, both 1-adamantyl-4,5-dimethylimidazole N-oxide and its 4,5-diphenyl

472
D. RYGIELSKA-TOKARSKA ET AL.
analog afforded the respective sulfurated products, however, small amounts of imidazoles
could also be found in mother liquor, after filtration of the major product. Thus, influence
of the substitution pattern on the reaction outcome clearly indicated that the presence of an
electron-withdrawing substituent at C(4) together with a bulky group at N(1) are necessary
to change the reaction course. Apparently, the bulky adamantyl group causes a stepwise
mechanism leading to the zwitterionic intermediate A, and via 1,3-cyclisation (route b)
affords imidazole 10 accompanied by extremely reactive oxathiirane derivative 11a, which
in the absence of an intercepting reagent, undergoes desulfurization to yield elemental
sulfur and the corresponding ketone. A convincing proof for the postulated formation
of the oxathiirane derivative was found in a trapping experiment with thiobenzophenone
6
(
C6H5)2C = S. In thecaseof less hinderedderivatives, thereaction occurs via formal [3+2]-
7
cycloaddition and subsequent cycloreversion of the primarily formed bicyclic intermediate.
The presented results summarize our recent efforts in the synthesis of enantiomeri-
cally pure imidazole-2-thiones bearing trans-1,2-DACH scaffold as well as a mechanistic
proposal for the unexpected deoxygenation of the starting imidazole N-oxides.
ACKNOWLEDGMENTS
Financial support by the Rector of the University of Ł o´ d z´ (Grant no. 505/712/R) and
technical assistance in the laboratory work by Mrs Małgorzata Celeda, University of Ł o´ d z´ ,
are gratefully acknowledged.
REFERENCES
1
. (a) Jasi n´ ski, M.; Mlosto n´ , G.; Mucha, P.; Linden, A.; Heimgartner H. Helv. Chim. Acta 2007, 90,
1
765-1780. (b) Jasi n´ ski, M.; Mlosto n´ , G.; Linden, A.; Heimgartner H. Helv. Chim. Acta 2008, 91,
1
916-1933. (c) Mlosto n´ , G.; Roma n´ ski, J.; Jasi n´ ski, M.; Heimgartner, H. Tetrahedron: Asymmetry
2009, 20, 1073-1080.
2
. Mucha, P.; Mlosto n´ , G.; Jasi n´ ski, M.; Linden, A.; Heimgartner H. Tetrahedron: Asymmetry 2008,
9, 1600-1607.
1
3
4
. Kwiatkowski, P.; Mucha, P.; Mlosto n´ , G.; Jurczak, J. Synlett 2009, 1757-1760.
. (a) Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427. (b) Zhang, Z.; Schreiner, P. R. Chem. Soc.
Rev. 2009, 38, 1187-1198. (c) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593-601. (d) Wende,
R. C.; Schreiner, P. R. Green Chem. 2012, 14, 1821-1849.
5
. Mlosto n´ , G.; Rygielska, D.; Jasi n´ ski, M.; Heimgartner, H. Tetrahedron: Asymmetry 2011, 22,
669-674.
6
7
. Mlosto n´ , G.; Jasi n´ ski, M.; Rygielska, D.; Heimgartner, H. Heterocycles 2011, 83, 765-776.
. Mlosto n´ , G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 1585-1595.