A novel heterocyclic atom exchange reaction with Lawesson's reagent: A one-pot synthesis of dithiomaltol

Article abstract of DOI:10.1039/b511966a

A one-pot reaction of maltol with Lawesson's reagent generates dithiomaltol, a thiopyran-4-thione, via an unusual heterocyclic atom exchange (HCAE) reaction; only pyrones with proton or aliphatic substituents undergo the HCAE substitution. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b511966a

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COMMUNICATION
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A novel heterocyclic atom exchange reaction with Lawesson’s reagent: a
one-pot synthesis of dithiomaltol
a
Daniel Brayton, Faith E. Jacobsen, Seth M. Cohen and Patrick J. Farmer*
b
b
a
Received (in Cambridge, UK) 23rd August 2005, Accepted 17th October 2005
First published as an Advance Article on the web 17th November 2005
DOI: 10.1039/b511966a
A one-pot reaction of maltol with Lawesson’s reagent generates
dithiomaltol, a thiopyran-4-thione, via an unusual heterocyclic
atom exchange (HCAE) reaction; only pyrones with proton or
aliphatic substituents undergo the HCAE substitution.
Maltol (Scheme 1) is a condensed sugar by-product, most readily
recognized as the smell of cotton candy (a.k.a. candy floss or fairy
1
floss). It also functions as an excellent metal ion chelator, one of a
family of a-hydroxy ketones that have been studied over the past
two decades for their potential applications in the treatment of
Alzheimer’s, anemia, cancer, use in radio-pharmaceuticals, and an
2–6
oxo-vanadium derivative that is in clinical trials. Structurally-
related compounds such as deferiprone and kojic acid have been
used in chelation treatments for the iron-overload disease
7
hemochromatosis.
Several groups have been investigating the modulation of these
8–13
activities by replacing the oxy-functionalities with sulfur.
Scheme 2
The
1
simplest analogue, thiomaltol, or 3-hydroxy-2-methyl-4-thiopyr-
3 4
The H NMR resonances of the ring protons (R and R ) allow
1
4
one (Htma), was first synthesized in 1969 and used for the
15–19
extraction and determination of a variety of cationic metals.
the direct distinction of the various maltol-derived products due to
the sequential downfield shifts that these protons undergo upon
sulfur substitution. Fig. 1 shows their comparative spectra in
Most recently, thiomaltol and related ligands have been re-
investigated for their biological activity, as metalloprotein protease
8,12,13,20–23
inhibitors and as pro-oxidant cancer drugs.
3
CDCl ; for maltol, two doublets appear at d 6.45 and 7.73, for
thiomaltol, the signals are at d 7.33 and 7.59, and for dithiomaltol,
the resonances are at d 7.52 and 8.16. This downfield shift in the
Thiomaltol and related species may be obtained directly from
24
the parent a-hydroxy ketone by reaction with thionating agents
ring protons for thiopyranthiones is known in the literature.
like P
4
S
10 or Lawesson’s reagent (LR). In one such reaction with
Similar, but smaller downfield shifts are also observed for the
methyl group.
excess LR, we observed a product resulting from an apparent
second substitution of sulfur for oxygen in maltol by LR, route A
in Scheme 2. To our surprise, the second substitution is of the
heterocyclic ring oxygen, not the a-hydroxyl group. We have
subsequently developed a single step synthesis for this new
compound, 3-hydroxy-2-methyl-4H-thiopyran-4-thione (dithio-
maltol or Httma), which has been characterized by a variety of
methods.{
The mass spectra also verified that a second S for O substitution
had occurred, but could not identify the position of substitution.
Substitution of the ring position was confirmed by a crystal-
Ph,Me
lographic analysis of the complex [(Tp
Ph,Me
)Zn(dithiomaltolato)]
(Tp
= hydrotris(3-phenyl-5-methylpyrazolyl)borate), shown
Scheme 1
a
Department of Chemistry, University of California, Irvine, CA,
9
2697-2025, USA. E-mail: pfarmer@uci.edu; Tel: (+1) 949-824-6079
1
Fig. 1 H NMR spectra of (A) dithiomaltol, (B) thiomaltol and (C)
b
Department of Chemistry and Biochemistry, University of California,
San Diego, CA, USA
maltol.
2
06 | Chem. Commun., 2006, 206–208
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Table 1 Pyrones investigated for potential HCAE
a
Substrate
R
1
R
2
R
3
R
4
Thiopyranthione
Maltol, Hma
Ethylmaltol, Hema
Hydroxyflavanone
Xanthone
OH Me
OH Et
H
H
H
H
Isolated
Isolated
OH Ring Ring Ring Not observed
Ring Ring Ring Ring Not observed
Chromone
H
H
H
H
H
Ring Ring Not observed
4
2
a
H-Pyran-4-one
,6 Dimethyl-c-pyrone
H
H
H
Observed
Observed
1
Me Me
Isolated indicates characterization by ESI-MS, H NMR and
elemental analysis (EA) within 0.3%. Observed indicates ESI-MS
and H NMR characterization only.
1
Ph,Me
Fig. 2 Structural diagram of [(Tp
)Zn(dithiomaltolato)] with a
partial atom numbering scheme; hydrogen atoms and solvent have been
omitted for clarity.
Ph,Me
in Fig. 2.{ The Tp framework has previously been used as a
model for the active site of matrix metalloproteinases (MMP) and
in the development of chelating inhibitors for these enzymes,
8,20–23
similar in structure to dithiomaltol.
Scheme 4
In our hands, dithiomaltol is not observable in the reaction of
maltol with P S , but adding a two-fold excess of LR to maltol
4
10
pyrone ring, and which most likely proceeds by ring opening and
closing steps. For the arene substituted species, such an initial
addition would be disfavored by the loss of aromaticity in the
intermediate.
cleanly generates the product in good yield. We were intrigued
with the heterocyclic atom exchange reaction, which is unprece-
dented in the literature of thiopyrones. Previously thiopyran-4-
thiones have been synthesized via thiopyrone intermediates,
obtained by the cyclization of unsaturated ketones and subsequent
In conclusion, the one-pot synthesis gives direct access to the
family of thiopyrone compounds via an unusual heterocyclic atom
exchange, unique to Lawesson’s reagent. Through the use of this
transformation, new biologically-active compounds may be
obtained, potentially allowing significant tuning of their chelating
ability. With dithiomaltol in hand, several metal complexes
have been obtained in a similar fashion to their thiomaltol
25
thionation of the ketone, arrow B in Scheme 2. However,
thiopyran-4-thiones with hydryl or methyl substituents are air
sensitive, and the subsequent anaerobic thionations have been
4
reported using P S10. With the use of LR, a one pot synthesis
directly yields the thiopyran-4-thione from the parent pyrone,
isolable by bench-top chromatography. It is unclear at this point
what structural features of dithiomaltol lead to its enhanced
stability under aerobic conditions.
8–10
analogues,
12
and have been reported elsewhere.
This research was supported by the American Cancer Society
Research Scholar grant (P. J. F., RSG-03-251-01), start-up funds
from the University of California, San Diego (S. C.) and the
American Heart Association (S. C., 0430009N). We thank Prof.
Arnold Rheingold for assistance with crystallographic analysis and
Prof. David Van Vranken for valuable discussions and suggestions
during the course of this work.
To probe this unique substitution, other pyrones were reacted
with excess LR and their products analyzed. The structural
variations and outcomes of these experiments are outlined in
Scheme 3 and Table 1, while Scheme 4 illustrates the specific
substrates used. A distinct structural dependence was observed, in
that only those pyrones with proton or aliphatic substituents
underwent the second substitution to yield thiopyranthione
derivatives. Pyrones with an arene group (e.g., hydroxyflavanone,
xanthone, and chromone, Scheme 4) were not converted to their
corresponding thiopyranthione analogues. The structural selectiv-
ity of this heterocyclic ring atom exchange suggests that the
reaction is initiated by a Michael addition at the 2-position of the
Notes and references
{
General procedures: All other solvents used were reagent grade; 1,4-
dioxane was dried-over and distilled-from calcium hydride. All chemicals
were purchased from Aldrich. Where anaerobic techniques were required, a
1
13
glove box and standard Schlenk techniques were used. H and C NMR
spectra were recorded on either Nicolet Omega 500 or GN 500
spectrometers at ambient temperatures, with chemical shifts (d) measured
in ppm relative to the specified solvent. Elemental analyses were performed
by Atlantic Microlab, Atlanta, GA.
Synthesis of 3-hydroxy-2-methyl-4H-thiopyran-4-thione (Httma) dithio-
maltol: Maltol, 3-hydroxy-2-methyl-4H-pyrone (2.501 g, 19.8 mmol),
Lawesson’s reagent (8.421 g, 20.8 mmol) and 25 mL of dry 1,4-dioxane
were combined in a dry box. The solution turned from lime green to orange
after 2–3 min stirring. As the solution was brought to reflux it turned a
Scheme 3
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Chem. Commun., 2006, 206–208 | 207

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dark reddish-brown color and eventually black. After refluxing for y1 h,
the solution was filtered while it was still hot, the dark brown solid collected
by the filter washed twice with pentane and the filtrate run on silica; the
1 G. Farrar, A. P. Morton and J. A. Blair, Food Chem. Toxicol., 1988, 26,
6, 523–525.
2 P. J. Farmer, D. Brayton, C. Moore, D. Williams, B. Shahandeh,
D. Cen and F. L. Meyskens, in Medicinal Inorganic Chemistry, ACS
Monograph Series 903, ed. J. Sessler, S. R. Doctrow, T. J. McMurry,
and S. J. Lippard, American Chemical Society, Washington DC, 2005,
ch. 22, pp. 400–413.
first yellow band was collected and evaporated to yield 1.218 g (39%) of a
1
brown solid. H NMR (499.93 MHz, CDCl
3
): d 2.49 (s, 3 H, –CH ), 7.52
3
(
d, 1 H, –CH–, J = 9.6 Hz), 8.16 (d, 1 H, –CH–, J = 9.6 Hz) and 9.33 (s, 1
13
H, –OH). C NMR (125.70 MHz, C
58.37 and 184.91. Electrospray MS: 159 ([M + H] ). Anal. calc. for
O: C, 45.45; S, 40.52; H, 3.82. Found: C, 45.53; S, 40.53; H, 3.95%.
Synthesis of dithio pyrone analogs: 0.5 g samples of each substrate were
6 6
D ): d 17.80, 123.29, 129.11, 139.09,
+
1
3 M. Finnegan, S. Rettig and C. Orvig, J. Am. Chem. Soc., 1986, 108, 16,
5033–5035.
6 6 2
C H S
4
5
6
7
8
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987, 26, 13, 2171–2176.
K. Thompson, J. McNeill and C. Orvig, Chem. Rev., 1999, 99, 9,
2561–2571.
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Helm, J. Med. Chem., 1996, 39, 19, 3659–3670.
C. Hershko and A. V. Hoffbrand, Rev. Clin. Exp. Hematol., 2000, 4, 4,
1
added to solutions of toluene and dioxane containing a 2-fold excess of
Lawesson’s reagent. Solutions were refluxed for 1 h and monitored by
1
TLC, ESI-MS and H NMR. For each substrate, the first thionation was
completed readily; the second conversion was observed and the product
isolated for ethylmaltol. For 4H-pyran-4-one and 2,6 dimethyl-c-pyrone,
the products were observed but not isolated. For hydroxyflavanone,
xanthone and chromone no evidence of the second conversion was
337–361.
D. T. Puerta, J. A. Lewis and S. M. Cohen, J. Am. Chem. Soc., 2004,
126, 27, 8388–8389.
observed.
Ph,Me
{
Synthesis of [(Tp
)Zn(dithiomaltolato)]: In a 50 mL round-bottomed
Ph,Me
9 J. A. Lewis, D. T. Puerta and S. M. Cohen, Inorg. Chem., 2003, 42,
455–7459.
flask, [(Tp
CH Cl
.09 mmol) dissolved in 20 mL of MeOH. The mixture was stirred at room
)ZnOH] (50 mg, 0.09 mmol) was added to 10 mL of
7
0 J. A. Lewis, B. L. Tran, D. T. Puerta, E. M. Rumberger,
D. N. Hendrickson and S. M. Cohen, Dalton Trans., 2005, 15, 2588–2596.
2
2
. To this solution was added 1.0 equiv. of dithiomaltol (10.3 mg,
1
0
temperature overnight under a nitrogen atmosphere. After stirring, the
solution was evaporated to dryness on a rotary evaporator to give a yellow
solid. The solid was dissolved in the minimum amount of benzene
1
1 V. Monga, B. O. Patrick and C. Orvig, Inorg. Chem., 2005, 44, 8,
666–2677.
2 V. Monga, K. H. Thompson, V. G. Yuen, V. Sharma, B. O. Patrick,
J. H. McNeill and C. Orvig, Inorg. Chem., 2005, 44, 8, 2678–2688.
3 D. Brayton, J. Ziller and P. Farmer, unpublished work.
4 K. Balzevic, K. Japkopic and V. Hahn, Bull. Sci., Sect. A (Zagreb),
969, 14, 1–2.
5 E. Uhlemann, H. Motzny and G. Wilke, Z. Anorg. Allg. Chem., 1973,
01, 255–262.
6 B. Schuknecht, E. Uhlemann and G. Wilke, Z. Chem., 1975, 15,
85–286.
7 E. Uhlemann, W. Bechmann and E. Ludwig, Anal. Chim. Acta, 1978,
00, 635–642.
8 B. Uhlemann, W. Petzold and M. Raab, Z. Anorg. Allg. Chem., 1984,
08, 191–196.
9 W. Bechmann, E. Uhlemann and M. Raab, Z. Anorg. Allg. Chem.,
985, 530, 213–221.
0 F. E. Faith and S. M. Cohen, Inorg. Chem., 2004, 43, 10, 3038–3047.
2
1
(y3 mL), filtered to remove any insoluble material, and the filtrate
recrystallized by diffusion of the solution with pentane. Yield: 89%
Ph,Me
1
1
X-ray crystallographic analysis of [(Tp
)Zn(dimaltolato)]: Yellow thin
plates were grown out of a solution of the complex in benzene diffused with
pentane. A single crystal suitable for X-ray diffraction structural
determination was mounted on a quartz capillary by using Paratone oil
and cooled in a nitrogen stream on the diffractometer. Data was collected
on a Bruker AXS diffractometer equipped with area detectors. Peak
integrations were performed using the Siemens SAINT software package.
Absorption corrections were applied using the program SADABS. Space
group determination was performed by the program XPREP. The
structure was solved by direct methods and refined with the SHELXTL
software package. All hydrogen atoms were fixed at calculated positions
with isotropic thermal parameters, and all non-hydrogen atoms refined
anisotropically. The hydrogen atom on the boron atom was found in the
difference map and its position refined. The compound co-crystallized with
1
1
4
1
2
1
1
1
5
1
1
2
21 D. Puerta and S. M. Cohen, Inorg. Chem., 2003, 42, 11, 3423–3430.
22 D. T. Puerta, J. R. Schames, R. H. Henchman, A. J. McCammon and
S. M. Cohen, Angew. Chem., Int. Ed., 2003, 42, 32, 3772–3774.
23 D. T. Puerta and S. M. Cohen, Inorg. Chem., 2002, 41, 20, 5075–5082.
24 M. G. Marei, Phosphorus, Sulfur Silicon Relat. Elem., 1993, 81, 1–4,
101–109.
one equivalent of benzene per complex.
Ph,Me
Data for [(Tp
6 2
)Zn(dithiomaltolato)]: C42H39BN OS Zn, M = 784.09,
orthorhombic, space group Pbca, a = 21.3832(18), b = 14.9241(13), c =
4.177(2), V = 7715.5(12) s, T = 100(2) K, Z = 8, m = 0.787, 8784
independent reflections, Rint = 0.0497, R = 0.0383, wR = 0.0913 (for I >
s(I)). CCDC 281752. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b511966a
2
1
2
2
25 S. Faulkner, R. C. Whitehead and R. J. Aarons, Science of Synthesis,
2003, 14, pp. 771–786.
2
08 | Chem. Commun., 2006, 206–208
This journal is ß The Royal Society of Chemistry 2006