Solid-supported odorless reagents for the dithioacetalization of aldehydes and ketones

Article abstract of DOI:10.1021/ol403313h

A solid supported, odorless reagent for the dithioacetalization of aldehydes and ketones has been developed. The new reagent provides the dimercaptoalkane equivalent in combination with stoichiometric amounts of immobilized acid and enables the formation of dithianes and dithiolanes from aldehydes without any additives in good to very good yields with high purities. The reaction is chemoselective for aldehydes, but ketones can be reacted to the corresponding dithioketals if an additional Lewis acid such as BF₃is added.

Full text of DOI:10.1021/ol403313h

Letter
pubs.acs.org/OrgLett
Solid-Supported Odorless Reagents for the Dithioacetalization of
Aldehydes and Ketones
N. Jung,* S. Grassle, D. S. Lutjohann, and S. Brase*
̈
̈
̈
Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
Karlsruhe Institute of Technology, Campus South, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
S
* Supporting Information
ABSTRACT: A solid supported, odorless reagent for the dithioacetali-
zation of aldehydes and ketones has been developed. The new reagent
provides the dimercaptoalkane equivalent in combination with
stoichiometric amounts of immobilized acid and enables the formation
of dithianes and dithiolanes from aldehydes without any additives in good
to very good yields with high purities. The reaction is chemoselective for
aldehydes, but ketones can be reacted to the corresponding dithioketals if
an additional Lewis acid such as BF3 is added.
ethods for the introduction of dithioacetal groups are
Mvery important, as dithiolanes as well as dithianes are
well-known intermediates for some fundamental reactions in
organic chemistry and in natural product synthesis.1 Dithioa-
cetals are important protecting groups that offer various
possibilities for the functionalization of carbonyls.2 Thus they
can be converted into gem-difluorinated compounds3 or they
can be used in the famous Corey−Seebach Umpolung reaction
to allow the reaction of carbonyls with electrophiles. The latter
reaction allows e.g. the synthesis of unsymmetrically substituted
ketones.4 The standard procedure for the formation of
dithianes or dithiolanes from ketones or aldehydes is the
reaction of a carbonyl compound with propane-1,3-dithiol or
ethane-1,2-dithiol in the presence of Lewis acids.5 The reaction
proceeds in good to excellent yields for a large number of
compounds that are stable under the required acidic conditions
but suffers from several disadvantages such as the toxicity of the
reagents, very strong odor of the dithioalkane starting material,
and laborious workup and purification of the target substances.
Within the past decade, alternative strategies have been
developed to overcome some of the above-mentioned draw-
backs. Hitherto, the published procedures provide new catalysts
for the dithioacetalization, e.g. heterogeneous or solid
supported catalysts.6 In addition, solid supported insoluable
dithiane linkers7 and some sulfur-containing compounds that
act as transdithioacetalization reagents have been reported. In
2003, Qun Liu et al. introduced a nonvolatile, odorless
dithiolan-ylidene derivative as a 1,3-propanedithiol equivalent
that could be used to convert carbonyls into the corresponding
dithianes effectively.8 Upon addition of acid, e.g. HCl, the
reagent has been shown to be chemoselective for aldehydes in
both organic solvents and water. As it has known for a long
time that dithiane-ylidene derivatives (such as the ones used by
Liu et al. and others) can be produced by dissolving dithiane
salts, e.g. dithianylium triflates, in appropriate organic solvents
to yield dithiane-ylidenes and the corresponding acid, we
developed a strategy to immobilize these dithiane ylidene
precursors. We have been successful in forming dithianylium
salts 3−8 on solid phases that fulfill all requirements to act as
immobilized reagents for the effective dithioacetalization of
diverse aldehydes and ketones 1 (Scheme 1).
Scheme 1. Resin-Bound Reagents 3−8 for the
Dithioacetalization of Aldehydes and Ketones (1)
The herein described developments combine the benefits of
resin-bound reagents with the advantages of using nonvolatile
dithiols allowing for transformations in very good to excellent
yields with high purity of the target substances. The dithianes
and dithiolanes could be obtained mostly by simple filtration of
the reaction mixtures and evaporation of the solvent or via
filtration over a short pad of silica gel without the need of
chromatographic purification. Searching for the most active
acetalization reagent, we synthesized several dithiolanylium and
dithianylium derivatives on solid supports. All resins have been
shown to be completely odorless and have been, even without
storage under inert atmosphere, stable over several weeks at
Received: November 16, 2013
Published: January 31, 2014
© 2014 American Chemical Society
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Letter
room temperature. In Figure 1, six of our resin-bound
equivalents of ethanedithiol 3, 5, and 7 and propanedithiol 4,
Table 1. Syntheses of Diverse Substituted Aromatic
Dithioacetals via Addition of Resin Bound Reagent 7 or 8
Figure 1. Resin-bound reagents 3−8 for the dithioacetalization of
aldehydes and ketones (1a−t).
starting material
a
b
6, and 8 with varying linker lengths are shown. All resins can be
used to convert aldehydes into the corresponding dithioacetals
in organic solvents such as chloroform or acetonitrile without
the need for further additives and can be used for the formation
of dithioketals in the presence of a Lewis acid such as BF3. It
has been shown that the length of the linker entity unit has only
a slight influence on the result of the dithioacetalization
reaction, as complete conversion of the starting material can be
achieved for all resins. Differences can only be detected with
regards to the purity of the obtained products. While resins 3
and 4 give crude products that are contaminated with
impurities of dithiols, resins 5−8 could be used in many
cases to synthesize the target substances as crude products that
are of high purity even without chromatography. The synthesis
of the two preferably used resins 7−8 is shown in Scheme 2.9
entry
R1
R2
R3
n
solvent
yield [%]
c
1
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
1
1
1
1
0
1
0
1
1
0
1
A
A
A
A
B
A
B
A
A
B
A
quant.
2
OH
H
H
H
H
H
H
H
H
H
H
98
98
98
74
86
81
99
98
70
3
CN
OBn
OBn
OH
OH
Ph
4
5
6
OMe
OMe
H
7
1g
1h
1i
8
9
OMe
OMe
H
10
11
1j
H
1k
C(O)Me
H
92
a
b
c
A = MeCN, B = CHCl3. Isolated yield after chromatography. The
reaction was performed in mmol scale giving an 87% yield.
the starting material at 50−60 °C), but for full conversion
within less than 10 h the temperature of 80 °C is chosen in a
standardized protocol. All compounds have been purified via
chromatography to determine the correlation of full conversion
(TLC control) and isolated yield and to verify the absence of
salt impurities of the filtered reaction mixture (Table 1).
In a standard procedure, 1.6 to 2.4 equiv of the resin are used
for the formation of dithiolanes or dithianes, but it has been
shown that 1.2 equiv of resin 7 or 8 are sufficient for a complete
conversion of aldehydes to the corresponding dithianes. But in
the latter case, prolonged reaction times up to 48 h can be
necessary. Besides the conversion of aromatic aldehydes,
aliphatic and vinylic carbonyls have been dithioacetalizated
via addition of the resins 7 and 8 as well. Whereas the results of
the aromatic aldehydes have been mostly independent of the
substituents on the aromatic ring, the success of the reaction in
giving aliphatic or vinylic dithioacetals depends strongly on the
nature of the given starting carbonyl 1l−q. While the
conversion of phenylacetic aldehyde 1l to its dithiane derivative
2l proceeds very fast and in very good yields, the synthesis of
the compounds 2q and 2r proceeds only in moderate yields.
Interestingly, the yields of the reactions given in Table 2 are not
related to the purity of the crude product. Even compounds 2q
and 2r with an isolated yield of 22% and 26% have been
obtained as crude material with high purity (≥95%, GCMS
results of the crude products). We assume that some aldehydes,
especially α,β-unsubstituted carbonyls, are able to react with the
linker unit giving resin bound side products that may reduce
the yields without affecting the purity of the desired
dithioacetalizated compound.10 Under the given reaction
conditions of Tables 1 and 2 (without any additives), the
herein presented dithioacetalization reagents are chemo-
selective for aldehydes and allow e.g. the conversion of 3-
acetyl benzaldehyde (1k) and the chromenone derivative 1m in
high yields. The dithioactals 2k, 2m, and 2n have been obtained
Scheme 2. Syntheses of Solid-Supported Dithiolanylium and
Dithianylium Tetrafluoroborate Salts 7 and 8
a
a
A: 1,3-propanedithiol, HBF4·Et2O, Et2O. B: 1,2-ethanedithiol, HBF4·
Et2O, Et2O.
As the formation of dithianylium or dithiolanylium tetra-
fluoroborate salts on solid phases requires acidic reaction
conditions, the linker unit has been attached onto the solid
support via an amide bond. The immobilization of the linker
types 7 and 8 onto the solid support was achieved by reacting
aminomethyl resin 9 with with adipoyl dichloride to give resin
10. The acyl chloride 10 has then been converted into the
corresponding dithiolanylium (resin 7) and dithianylium
tetrafluoroborates (resin 8) via refluxing with ethanedithiol or
propanedithiol and HBF4·Et2O in diethyl ether. For the
following thioacetalization protocols, we used resin 7 for
dithiolane and resin 8 for the dithiane formation, as they are
accessible via the shortest synthetic protocol (Scheme 2).
Table 1 summarizes the results of the dithioacetalization
reactions of aldehydes in acetonitrile or chloroform at 80 °C in
crimp cap vials. The reaction tolerates traces of water, and there
is no need to perform the reactions under an inert atmosphere.
The products 2a−k have been isolated in good to excellent
yields, and complete conversion of all substances was achieved
within a few hours (full conversion of compounds 1a and 1b
within 3 h). To reach high yields and purities for all derivatives,
reaction overnight is recommended. The reaction can be
performed successfully at lower temperatures (dependent on
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Letter
Table 2. Syntheses of Aliphatic and Vinylic Dithioacetals via
Addition of Resin Bound Reagent 7 or 8
Table 3. Syntheses of Dithioketals via Addition of the Resin
Bound Reagent 8 and BF·Et2O
ASSOCIATED CONTENT
* Supporting Information
■
S
Supporting Information covering the experimental procedures
for resins 3−8, the syntheses of the dithioacetals 2a−r and
dithioketals 2s−w, and analytical data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nicole.jung@kit.edu.
in high purity without the formation of dithioketal side
products by simply removing the resin bound reagent and the
solvent.11
*E-mail: stefan.braese@kit.edu.
Notes
The herein presented resins are not restricted to the
conversion of aldehydes. They also allow the synthesis of
dithioketals under similar reaction conditions in the presence of
an additional Lewis acid such as BF3·Et2O (Table 3, 2s−2w).
In summary, a solid supported, odorless, easy to handle
reagent for the efficient thioacetalization of aldehydes and
ketones has been developed. The combination of dimercap-
toalkane equivalents and acid immobilized as dithianylium or
dithiolanylium tetrafluoroborate salt on solid supports allows
the conversion of aldehydes into dithianes or dithiolanes with
high yields and purities often without the need for purification.
The reaction of ketones to the corresponding dithioketals has
been shown under similar reaction conditions by using Lewis
acids as additives. The conversion of the carbonyls has been
proven to be complete with only 1.2 equiv of the resin, but for
combinatorial approaches the reaction can be performed with a
2- to 3-fold excess of the reagent to speed up the reaction.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Helmholtz program
Biointerfaces. We thank Pia Lang, Angelika Kernert, and Ingrid
Rossnagel (all Karlsruhe Institute of Technology) for their kind
support.
REFERENCES
■
(1) (a) Yus, M.; Naj
́
era, C.; Foubelo, F. Tetrahedron 2003, 59, 6147−
6212. (b) Melillo, B.; Smith, A. B. Org. Lett. 2013, 15, 2282−2285.
(c) Nicolaou, K. C.; Peng, X.-S.; Sun, Y.-P.; Polet, D.; Zou, B.; Lim, C.
S.; Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 10587−10597.
(d) Brien, M.; Koos, P.; Browne, D. L.; Ley, S. V. Org. Biomol. Chem.
2012, 10, 7031−7036.
(2) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1999; pp 329−344 and 724−727.
1038
dx.doi.org/10.1021/ol403313h | Org. Lett. 2014, 16, 1036−1039

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Letter
(3) (a) Kirsch, P.; Binder, W.; Hahn, A.; Jahrling, K.; Lenges, M.;
̈
Lietzau, L.; Maillard, D.; Meyer, V.; Poetsch, E.; Ruhl, A.; Unger, G.;
Frohlich, R. Eur. J. Org. Chem. 2008, 3479−3487. (b) Shimizu, M.;
̈
Maeda, T.; Fujisawa, T. J. Fluorine Chem. 1995, 71, 9−12. (c) Wiehn,
M. S.; Lindell, S. D.; Brase, S. Angew. Chem., Int. Ed. 2008, 47, 8120−
̈
8122; Angew. Chem. 2008, 120, 8240−8242. (d) Reddy, V. P.; Alleti,
R.; Perambuduru, M. K.; Welz-Biermann, U.; Buchholz, H.; Prakash,
G. K. S. Chem. Commun. 2005, 5, 654−656. (e) Wiehn, M. S.; Furniss,
̈
D.; Brase, S. J. Comb. Chem. 2009, 11, 982−1006.
̈
(4) (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231−237.
(b) Grobel, B.-T.; Seebach, D. Synthesis 1977, 357−402.
̈
(5) (a) Weng, S.-S.; Chang, S.-C.; Chang, T.-H.; Chyn, J.-P.; Lee, S.-
W.; Lin, C.-A.; Chen, F.-k. Synthesis 2010, 1493−1499. (b) Bracher, F.;
Litz, T. Arch. Pharm. 1995, 328, 235−238. (c) Bertini, V.; Lucchesini,
F.; Pocci, M.; Alfei, S.; Idini, B. Synlett 2008, 8, 1141−1144.
(6) (a) Karami, B.; Taei, M.; Khodabakhshi, S.; Jamshidi, M. J. Sulfur
Chem. 2012, 33, 65−74. (b) Shaterian, H. R.; Azizi, K.; Fahimi, N. J.
Sulfur Chem. 2011, 32, 85−91. (c) Weng, S.-S.; Chang, S.-C.; Chang,
T.-H.; Chyn, J.-P.; Lee, S.-W.; Lin, C.-A.; Chen, F.-k Synthesis 2010,
1493−1499. (d) Shaterian, H. R.; Hosseinian, A.; Ghashang, M. Synth.
Commun. 2008, 38, 4097−4106. (e) Rudrawar, S.; Besra, R. C.;
Chakraborti, A. K. Synthesis 2006, 2767−2771. (f) Pore, D. M.; Desai,
U. V.; Mane, R. B.; Wadgaonkar, P. P. Indian J. Chem. 2006, 45B,
1291−1295.
(7) Bertini, V.; Pocci, M.; Lucchesini, F.; Alfei, S.; De Munno, A.
Synlett 2003, 864−866.
(8) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong,
D. J. Org. Chem. 2003, 68, 9148−9150. (b) Yu, H.; Dong, D.; Ouyang,
Y.; Liu, Q. Can. J. Chem. 2005, 83, 1741−1745. (c) Ouyang, Y.; Dong,
D.; Zheng, C.; Yu, H.; Liu, Q.; Fu, Z. Synthesis 2006, 3801−3804.
(d) Dong, D.; Ouyang, Y.; Yu, H.; Liu, Q.; Liu, J.; Wang, M.; Zhu, J. J.
Org. Chem. 2005, 70, 4535−4537.
(9) For a description of the synthesis of resins 3 and 4, see
Supporting Information.
(10) For similar reactions of ketene dithioacetals with Michael
acceptors, see e.g.: Yin, Y.; Zhang, Q.; Li, J.; Sun, S.; Liu, Q.
Tetrahedron Lett. 2006, 47, 6071−6074.
(11) For NMR spectra of the crude and the purified compounds 2m
and 2n, see Supporting Information.
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