Lithium diisopropylamide (LDA) as an efficient reducing agent for thioketones - Mechanistic consideration

Article abstract of DOI:10.1080/10426507.2015.1012201

Treatment of thiocarbonyl compounds with excess of lithium diisopropylamide (LDA) leads to corresponding thiols or sulfides depending on the work-up procedure. The mechanistic scenario for this unusual reduction pathway is discussed.

Full text of DOI:10.1080/10426507.2015.1012201

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Lithium Diisopropylamide (LDA) as an Efficient
Reducing Agent for Thioketones—Mechanistic
Consideration
Marcin Jasiński, Grzegorz Mlostoń, Andreas Gebert & Heinz Heimgartner
To cite this article: Marcin Jasiński, Grzegorz Mlostoń, Andreas Gebert & Heinz
Heimgartner (2015) Lithium Diisopropylamide (LDA) as an Efficient Reducing Agent for
Thioketones—Mechanistic Consideration, Phosphorus, Sulfur, and Silicon and the Related
Elements, 190:8, 1281-1284, DOI: 10.1080/10426507.2015.1012201
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1012201
Accepted online: 15 Jul 2015.
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Date: 10 October 2015, At: 01:37

Phosphorus, Sulfur, and Silicon, 190:1281–1284, 2015
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2015.1012201
LITHIUM DIISOPROPYLAMIDE (LDA) AS AN EFFICIENT
REDUCING AGENT FOR THIOKETONES—MECHANISTIC
CONSIDERATION
Marcin Jasin´ski,1 Grzegorz Mloston´,1 Andreas Gebert,2
and Heinz Heimgartner2
1Department of Organic and Applied Chemistry, Faculty of Chemistry, University
of Ło´dz´, Ło´dz´, Poland
2Department of Chemistry, University of Zurich, Zurich, Switzerland
GRAPHICAL ABSTRACT
Abstract Treatment of thiocarbonyl compounds with excess of lithium diisopropylamide (LDA)
leads to corresponding thiols or sulfides depending on the work-up procedure. The mechanistic
scenario for this unusual reduction pathway is discussed.
Keywords Thioketones; LDA; hydride transfer; sulfides; reaction mechanisms
INTRODUCTION
Thioketones belong to the class of reactive dipolarophiles (so-called superdipo-
larophiles) widely applied for the synthesis of numerous S-heterocylic systems.1 However,
their behavior toward lithiated agents is by far less well known. As a part of our ongoing
project focused on the exploration of thioketones in organic, materials, coordination, and
biometallo-organic chemistry,2 a series of model compounds of type 1 were recently shown
to be suitable reaction partners in reactions with C-nucleophiles. For example, treatment
of adamantanethione (1a) with lithiated methylphosphonate followed by methyl iodide or
with methoxyallene anion provided the corresponding products, i.e., the phosphonylated
sulfide 23 and vinylthiirane derivative 3,4 respectively, as a result of exclusive carbophilic
attack onto the C S group (Scheme 1).
Received 12 December 2014; accepted 20 January 2015.
Address correspondence to Prof Grzegorz Mloston´, Department of Organic and Applied Chemistry, Univer-
sity of Ło´dz´, Tamka 12 PL 91-403, Ło´dz´, Poland. E-mail: gmloston@uni.lodz.pl
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
1281

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M. JASINSKI ET AL.
Scheme 1 Reactions of adamantanethione (1a) with lithiated C-nucleophiles.
Within the studies on [3 + 2]-cycloadditions of thioketones with azomethine ylides,
1,3-thiazole-5(4H)-thione 4a was selected as a model compound.5 Unexpectedly, the treat-
ment of a mixture of 4a and trimethylamine oxide, used as an anticipated source of the
parent azomethine ylide,6 with lithium diisopropylamide (LDA) at 0◦C provided only the
reduction product 5a. Further experiments with 4a confirmed the unusual potential of
LDA for the reduction of C S groups. Thus, depending on the work-up procedure, the
corresponding thiol 5a or methylsulfide 6a was obtained in high yields7 (Scheme 2).
Scheme 2 Reduction of 1,3-thiazole-5(4H)-thione 4a with LDA.
RESULTS AND DISCUSSION
Following the protocol established for compound 4a, a spirocyclic 1,3-thiazole-
5(4H)-thione of type 4 and a series of thioketones 1 were smoothly reduced with excess
of LDA to give respective thiolates, which after trapping with methyl iodide as an elec-
trophile provided the expected products 6b and 7a–f, respectively, in high yields (Figure 1).
Analytically pure samples of products were obtained after chromatographic purification in
40–80% yields. Hence, as shown in Figure 1, dithioacetals 6a–b as well as cycloaliphatic
(7a–b) and aromatic (7c–f) sulfides, including unique diferrocenyl (7e) and hetaryl (7f)
derivatives, are available by the presented method, although the yields in the latter cases
are rather low.7
Although lithium amides are known in the first line as strong bases, often used for the
deprotonation of CH-acidic compounds, reducing properties of LDA and its analogs have
been also reported.8 For example, LDA-induced conversion of nitroarenes to the corre-
sponding aromatic amines and azoxyarenes via a single electron transfer (SET) mechanism
was described.8a An analogous reaction pathway was postulated for the observed formation
of sulfides from 2,2-diaryl-1,3-dithiolanes via the in situ generated aromatic thioketones.8b
On the other hand, treatment of 4-fluorotoluene with LDA in diethyl ether gave, among other
products, a mixture of meta- and para-ethyl(2-tolylethyl)amine.9a A reaction mechanism
via hydride transfer from LiNEt2 to the intermediate aryne, and subsequent addition of aryl
anion to the formed imine, was proposed. Furthermore, the reduction of benzophenone with
LiNEt2 was interpreted as a hydride-transfer reaction via a six-membered transition state.9b

LDA AS AN EFFICIENT REDUCING AGENT FOR THIOKETONES
1283
Figure 1 Products 6 and 7 prepared by the reduction of respective thiocarbonyl substrates.
A strong evidence for this reaction mechanism is the enantioselective reduction of ketones
with enantiomerically pure lithium alkyl phenyl amides9c and lithium dialkylamides.9d
This pathway resembles that of reactions of Grignard reagents with sterically demanding
carbonyl compounds as well as the Meerwein–Schmidt–Ponndorf–Verley reductions of
ketones.10
Based on the above-discussed reports, we suggest that LDA in the reaction with
non-enolizable thioketones acts as a hydride donor. Hydride transfer via the six-membered
transition state A then leads to thiolate B, which can be protonated or trapped with ap-
propriate electrophiles. The respective imine C is formed as a side-product (Scheme 3). A
small amount of the imine C was identified in the 1H-NMR spectra of crude mixtures ob-
tained with both adamantanethione (1a) and thiobenzophenone (1c); a characteristic septet
attributed to the CHMe2 group was found at 3.77 ppm.11 In addition, no incorporation
of a deuterium atom was observed when the reaction of LDA with 4a was performed in
THF-d8.7 However, the competitive SET mechanism, especially in the case of hetaryl-
substituted thioketone 1f, can not be ruled out.
Scheme 3 Postulated transition state (A), and hydride shift leading to thiolate (B).
ACKNOWLEDGMENTS
Marcin Jasin´ski thanks the University of Ło´dz´ Foundation. Stimulating discussion
with Professor D. Seebach is also acknowledged.

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M. JASINSKI ET AL.
1284
FUNDING
Authors acknowledge financial support given by the National Science Center
(PL-Cracow) Grant Maestro-3 No. 2012/06/A/ST5/00219.
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