Synthesis, characterization, and nucleophilic substitutions of dimethyl(2-ferrocenoylethyl)sulfonium iodide

Article abstract of DOI:10.1016/j.tetlet.2013.06.130

Dimethyl(2-ferrocenoylethyl)sulfonium iodide was synthesized by reacting 1-ferrocenyl-4-thiapentan-1-one with iodomethane and characterized from spectral data and single crystal X-ray structure analysis. This compound was capable of reacting with different N-, S-, and O-nucleophiles giving the corresponding β-functionalized ferrocene-containing ketones. Furthermore, dimethyl sulfide can be displaced from the dimethyl(2-ferrocenoylethyl)sulfonium ion with cyanide or carbanions derived from 1,3-bifunctional compounds and nitropropane, leading to products with a new carbon-carbon bond.

Full text of DOI:10.1016/j.tetlet.2013.06.130

Accepted Manuscript
Synthesis, characterization and nucleophilic substitutions of dimethyl(2-ferro‐
cenoylethyl)sulfonium iodide
Anka Pejović, Ivan Damljanović, Dragana Stevanović, Danijela Ilić, Mirjana
Vukićević, Goran A. Bogdanović, Rastko D. Vukićević
PII:
S0040-4039(13)01115-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.130
TETL 43183
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 April 2013
13 June 2013
26 June 2013
Please cite this article as: Pejović, A., Damljanović, I., Stevanović, D., Ilić, D., Vukićević, M., Bogdanović, G.A.,
Vukićević, R.D., Synthesis, characterization and nucleophilic substitutions of dimethyl(2-
ferrocenoylethyl)sulfonium iodide, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.06.130
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Graphical Abstract
Synthesis, characterization and nucleophilic
substitutions of dimethyl(2-ferrocenoylethyl)sulfonium
iodide
Anka Pejović, Ivan Damljanović, Dragana Stevanović, Danijela
Ilić, Mirjana Vukićević, Goran A. Bogdanović, Rastko D.
Vukićević
The title salt was synthesized and submitted to reaction with several
N-, S-, and O-nucleophiles (to give the corresponding -
functionalized 1-ferrocenylpropan-1-ones), as well as with
C-nucleophiles (to give products containing a new C-C bond).

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis, characterization and nucleophilic substitutions of dimethyl(2-
ferrocenoylethyl)sulfonium iodide
Anka Pejovića, Ivan Damljanovića, Dragana Stevanovića, Danijela Ilićb, Mirjana Vukićevićc, Goran A.
Bogdanovićd, Rastko D. Vukićevića,*
a Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia
b Technical Faculty Kosovska Mitrovica,University of Priština, Kneza Miloša 7, 38220 Kosovska Mitrovica, Serbia
c Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, S. Markovića 69, 34000 Kragujevac, Serbia
d Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001 Belgrade, Serbia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Dimethyl(2-ferrocenoylethyl)sulfonium iodide was synthesized by reacting 1-ferrocenyl-4-
thiapentan-1-one with iodomethane and characterized from spectral data and single crystal X-ray
structure analysis. This compound was capable of reacting with different N-, S- and O-
nucleophiles giving the corresponding -functionalized ferrocene-containing ketones.
Furthermore, dimethyl sulfide can be displaced from the dimethyl(2-ferrocenoylethyl)sulfonium
ion with cyanide or carbanions derived from 1,3-bifunctional compounds and nitropropane,
leading to products with a new carbon-carbon bond.
Available online
Keywords:
Ferrocene;
Sulfonium salt;
2012 Elsevier Ltd. All rights reserved.
Nucleophilic substitution;
-functionalized ferrocenyl ketones;
1,3-dicarbonyls;
X-ray analysis;
Since its discovery more than sixty years ago, ferrocene has
acquired significant attention as a consequence of its unique
physical and chemical properties which allow for its application
in many fields of science, ranging from materials science and
asymmetric catalysis to analytical chemistry and medicine
(bioorganometallic chemistry).1 Thus, despite the general opinion
that organometallic compounds are extremely sensitive to
moisture, ferrocene does not react with water and can be handled
in air when solid and often in solution. On the other hand,
ferrocene can be easily functionalized, Friedel-Crafts acylation
being the most frequently used.2 The carbonyl group of
acylferrocenes obtained in this way provides a plethora of
possibilities for further transformations, utilizing classical
methods of organic chemistry. Acylation is a particularly suitable
method for the derivatization of ferrocene which allows for
simultaneous introduction of an additional heteroatom into the
newly synthesized acylferrocene. Employing a modified Friedel-
Crafts acylation of ferrocene,3 we reported on the synthesis of
several acylferrocenes containing sulfur in their alkyl chains.4
The synthetic value of these compounds has been recognized in
the synthesis of highly functionalized ferrocene-containing
cyclopropane derivatives using 1-ferrocenyl-3-thiabutan-1-one
via the corresponding sulfonium salt, i.e. via a stabilized sulfur
ylide.5 In the present communication, we outline the first results
on the synthetic applications of 1-ferrocenyl-4-thiapentan-1-one
(1), based on a formal substitution of the methylthio group with
several nucleophiles.
The utilization of 1-ferrocenyl-4-thiapentan-1-one (1) in
organic synthesis has been conceptualized as the transformation
of the methylthio group into a good leaving group [─S(CH3)2],
by reacting this β-(methylthio)ketone with iodomethane (Scheme
1) and further substitution of this group with nucleophiles. An
acetonitrile solution of ketone 1 and twice the amount of
iodomethane was stirred at room temperature, while a yellow
1
precipitate formed. On the basis of spectral data (IR, H and 13C
NMR) this product was identified as dimethyl(2-
ferrocenoylethyl)sulfonium iodide (2). Recrystallization of the
crude product from methanol gave brass-yellow crystals of 2,
which were in the shape of very thin plates with a thickness of
less than 0.01 mm and, therefore, not fully suitable for single-
crystal X-ray structure analysis. Nevertheless X-ray analysis
Scheme 1. Synthesis of salt 2
———
* Corresponding author. Tel.: +381-34-300-268; fax: +381-34-335-040; e-mail: vuk@kg.ac.rs.

2
for an analogue of salt 2, dimethyl(2-benzoylethyl)sulfonium
bromide containing a phenyl group instead of a ferrocene.7
To investigate substitution reactions of salt 2, it was submitted
to reactions with several nucleophiles. Thus, when 2 was
refluxed with two equivalents of aniline in methanol, the
corresponding -(phenylamino)ketone 6a (Scheme 3) was
obtained in a 75% yield. The generality of this reaction was
evaluated using four additional anilines as nucleophiles (5b-e)
and, as shown in Scheme 3 and Table 1, the corresponding
Mannich bases 6b-e were obtained in moderate to very high
yields.
Salt 2 was next treated with thiophenol (7a) under the same
conditions (in refluxing methanol). The expected ketosulfide was
not obtained, but instead the corresponding methoxy derivative
10h (Scheme 3), in a low yield (up to 20%). The remainder of
salt 2 was converted into ketone 1. In order to find optimum
conditions that might provide an approach to ketosulfides
different (but less available) from ketone 1 utilizing this
methodology, we tested several solvents (with or without a base)
as the reaction medium. It was found that 2 reacted with
thiophenol in ethyl acetate in the presence of potassium carbonate
giving the corresponding ketosulfide 8a (Scheme 3) in a 78%
yield. Four additional thiophenols (8b-e), as well as two aliphatic
mercapto derivatives, esters 7f, and 7g, were also used as
nucleophiles with the same success (see Scheme 3 and Table 1).
However, some amounts of ketone 1 (up to 20%) were always
obtained as side products in these reactions (for details see the
Supporting Information).
Figure 1. ORTEP drawing of the molecular structure of compound 2.
Displacement ellipsoids are drawn at the 40% probability level.6
successfully and unambiguously confirmed the structure of 2
(Figure 1).
Salt 2 was submitted to reaction with sodium hydride in
benzene. In contrast to the salt obtained from 1-ferrocenyl-3-
thiabutan-1-one,5 compound 2 did not give the corresponding
ylide (3, Scheme 2). Instead, we isolated acryloylferrocene (4,
Scheme 2) in quantitative yield. A reversible deprotonation of the
dimethyl(2-ferrocenoylethyl)sulfonium cation (I, Scheme 2) is,
certainly, possible at both, the -sulfonium and -keto positions,
but the product obtained through the second process (dipolar ion
II, Scheme 2) undergoes irreversible elimination, giving ketone 4
as the sole product. The same product was obtained by treating 2
with a water solution of sodium hydroxide, as was also reported
Many efforts were made to optimize the substitution of
dimethylsulfide from salt 2 with the phenoxy group, but a solvent
suitable for the successful synthesis of 1-ferrocenyl-3-
phenyloxypropan-1-one (10a) was not found. Treatment of 2
with phenol in methanol, acetonitrile, DMF, DMSO and ethyl
acetate gave either acryloylferrocene (in the presence of a base)
or ketone 1 (without the base). The synthesis of this ether was
achieved by exposing a solid mixture of salt 2 and phenol 9a to
ultrasound irradiation. However, ether 10a was obtained in a low
yield (35%), whereas the main product of this reaction was
acryloylferrocene (4; 60%; see the Supporting Information).
Three additional phenols (9b-d) were used as substrates under
the same conditions giving the corresponding β-aminoketones in
similar yields (10b-d; up to 42%; see Scheme 3 and Table 1). On
the other hand, on refluxing 2 in methanol and ethanol in the
presence of sodium hydroxide, the corresponding methoxy- and
ethoxyketones (10h, and 10i, Scheme 3) were obtained in almost
quantitative yields (Table 1).
Scheme 2. Reaction of salt 2 with bases
Scheme 3. Reaction of salt 2 with N-, S- and O-nucleophiles

3
Table 1. Reactions of salt 2 with N-, S- and O-nucleophilesa
Entry Nucleophile Product
Yield (%)b
75
1
2
5a
5b
6a
6b
88
98
63
45
Scheme 4. Reaction of salt 2 with cyanide
3
4
5
5c
5d
5e
6c
6d
6e
6
7
8
9
7a
7b
7c
7d
8a
8b
8c
8d
78
87
84
84
Figure 2. ORTEP drawing of the molecular structure of compound 11.
Displacement ellipsoids are drawn at the 40% probability level.8
Finally, we decided to examine the possibility of using salt 2
for the formation of a new carbon-carbon bond. This salt reacted
smoothly with potassium cyanide in water giving 4-ferrocenyl-4-
oxobutanenitrile (11) in 77% yield (Scheme 4). The molecular
structure of this compound was also confirmed by X-ray
diffraction (Figure 2).
Table 2. Reactions of salt 2 with some C-nucleophilesa
10
7e
8e
80
11
12
13
14
7f
8f
78
98
7g
9a
9b
8g
Entry Nucleophile
1
Product
Yield (%)b
71
10a 35
10b 31
12a
12b
13a
13b
2
3
57
85
15
16
17
9c
9d
9h
10c 42
10d 32
10h 90
12c
12d
12e
13c
13d
13e
4
5
81
50
18
9i
10i 98
a) For experimental details and spectral data of the new compounds see the
Supporting Information.
a) For experimental details and spectral data of the new compounds see the
Supporting Information.
b) Isolated yields based on salt 2.
b) Isolated yields based on salt 2.
Examinations aimed at utilizing 2 in the alkylation of 1,3-
bifunctional carbonyl compounds9 were begun by the reaction of

4
this salt with the carbanion generated from diethyl malonate
12a (Table 2) in tetrahydrofuran, whereby the corresponding
product 13a was obtained in 71% yield. In order to evaluate the
generality of this reaction, three additional anions obtained from
1,3-bifunctional carbonyl compounds 12b-d as well as from 2-
nitropropane (12e), were submitted to the same reaction
conditions. As depicted in Table 2, these substrates reacted to
give
the
corresponding
5-ferrocenyl-5-oxo-2-substituted
carboxylates 13b-d, and 1-ferrocenyl-4-methyl-4-nitropentan-1-
one (13e) in moderate to high yields.
In conclusion, we have presented new and useful synthetic
manipulations of dimethyl(2-ferrocenoylethyl)sulfonium iodide
(2) as a donor of a 3-ferrocenyl-3-oxopropyl group in the
synthesis of amines, organic sulfides and ethers containing this
group. In addition, we showed that this salt can be used as an
alkylating agent in the synthesis of 5-ferrocenyl-5-oxo-2-
substituted carboxylates from the corresponding 1,3-dicarbonyl
compounds. The products of these reactions represent useful
multifunctional ferrocene derivatives that can serve as starting
materials for the synthesis of more complex derivatives of this
metallocene.
Acknowledgements
We thank the Ministry of Education, Science and
Technological Development of the Republic of Serbia for
financial support (Grant 172034).
Supplementary data
Supplementary data (complete experimental procedures, IR and
NMR spectra of the new compounds and comments on the X-ray
structural analyses of compounds 2 and 11) associated with this
article can be found in the online version, at
References and notes
1. a) Togni, A., Hayashi, T., Eds. Ferrocenes: Homogenous Catalysis,
Organic Synthesis, Materials Science; VCH: Weinheim, Germany, 1995.
b) Seiwert, B.; Karst, U. Anal. Bioanal. Chem. 2008, 390, 181–200. c)
Štĕpnička, P., Ed. Ferrocenes: Ligands, Materials and Biomolecules,
Wiley, Chichester, U.K., 2008. d) Jaouen, G., Ed. Bioorganometallics,
Wiley-VCH, Weinheim, 2006. e) van Staveren, D. R.; Metzler-Nolte, N.
Chem. Rev. 2004, 104, 5931-5985
2. Woodward, R. B.; Rosenblum, M.; Whiting, M. C. J. Am. Chem. Soc.
1952, 74, 3458-3459.
3. a) Vukićević, R. D.; Ratković, Z.; Konstantinović, S. Synlett 1998, 1329-
1330. b) Vukićević, M. D.; Ratković, Z. R; Teodorović, A. V.;
Stojanović, G. S.; Vukićević, R. D. Tetrahedron 2002, 58, 9001-9006.
4. a) Vukićević, R. D.; Ilić, D.; Ratković, Z.; Vukićević, M. Monats. Chem.
2001, 132, 625-631. b) Ilić, D.; Damljanović, I.; Stevanović, D.;
Vukićević, M. D.; Radulović, N.; Kahlenberg, V.; Laus, G.; Vukićević,
R. D. Polyhedron 2010, 29, 1863-1869.
5. Ilić, D.; Damljanović, I.; Vukićević, M.; Kahlenberg, V.; Laus, G.;
Radulović, N.; Vukićević, R. D. Tetrahedron Lett. 2012, 53, 6018-6021.
6. Crystallographic data for the structural analysis have been deposited with
the Cambridge Crystallographic Data Centre, CCDC No. 934348 for
compound 2. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting
Information.
7. Bꢀ hme, H.; Heller, P. Chem. Ber. 1953, 86, 443-450.
8. Crystallographic data for the structural analysis have been deposited with
the Cambridge Crystallographic Data Centre, CCDC No. 934349 for
compound 11. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif. See also the Supporting
Information.
9. To the best of our knowledge, only one literature report on the use of an
analogous ketosulfonium system (4-oxohexahydrothiopyrylium iodide)
in the alkylation of 1,3-dicarbonyl compounds has appeared up to
present. See: Cardwell H. M. E. J. Chem. Soc. 1949, 715-719.