An organocatalytic process for the hydrolytic cleavage of dithianes mediated by imidazolium ions: No harsh agents required

Article abstract of DOI:10.1002/ejoc.201402947

A new, organocatalytic approach to the hydrolytic deprotection of dithianes has been developed involving a low-toxicity imidazolium-ion-based catalyst in an aqueous medium. A complimentary solvent-free method without added water and involving a sacrificial aldehyde is also reported. The catalyst does not appear to operate by a specific-acid catalysis mechanism.

Full text of DOI:10.1002/ejoc.201402947

FULL PAPER
DOI: 10.1002/ejoc.201402947
An Organocatalytic Process for the Hydrolytic Cleavage of Dithianes
Mediated by Imidazolium Ions: No Harsh Agents Required
Lauren Myles,[a] Nicholas Gathergood,*[b] and Stephen J. Connon*[a]
Keywords: Organocatalysis / Ionic liquids / Hydrolysis / Dithianes / Thioacetals / Aldehydes
A new, organocatalytic approach to the hydrolytic deprotec-
tion of dithianes has been developed involving a low-toxicity
imidazolium-ion-based catalyst in an aqueous medium. A
complimentary solvent-free method without added water
and involving a sacrificial aldehyde is also reported. The cat-
alyst does not appear to operate by a specific-acid catalysis
mechanism.
the synthesis is therefore obviously key.[3] The deprotection
of these groups has generally proved difficult, particularly
Introduction
The masking of carbonyl groups as dithiane derivatives in cases involving sensitive substrates. Several methods
is well established as a useful and versatile tool. These using metal-based reagents have been developed.[3] These
groups are not only very useful for the protection of carb- include the most widely used mercury(II)-based compounds
[4]
onyl groups against acidic/basic conditions, but also in the [e.g., HgCl2 and Hg(ClO4)2[5]] and AgNO3,[6] but other
reversal of the reactivity of the protected carbonyl group, metal-based compounds have also been used with varying
allowing the formation of new C–C bonds. The umpolung degrees of success, including Tl(NO3),[7] CuCl2,[8] FeCl3,[9]
concept was popularised in seminal work by Corey and See- SbCl5,[10] ZnBr2,[11] and GaCl3.[12] A second commonly
bach.[1] Thus, 1,3-dithiane-protected carbonyl compound 2 used method is based on the halogenative cleavage of the
(derived from aldehyde 1) is first converted into nucleo- dithiane using either N-halosuccinimides [e.g., NBS (N-bro-
philic 2-lithio-1,3-dithiane species 3. This intermediate can mosuccinimide)[13,14] or NCS (N-chlorosuccinimide)[13,15]
]
then react with various types of electrophiles such as alkyl or hypervalent iodine.[16] A variety of other specialised rea-
halides, epoxides, and other carbonyl compounds,[2] to cre- gents have also proved effective in this deprotection reac-
ate a new carbon–carbon bond, e.g., in 4. The regeneration tion, including Oxone,[17] Selectfluor,[18] and Clayfen.[19]
of the carbonyl group through deprotection of the dithiane However, many of the aforementioned methods present
moiety to give 5 then follows (Scheme 1).
challenges associated with toxicity or other concerns related
The ability to regenerate the carbonyl functionality to environmental impact, particularly many of the methods
through hydrolysis of the dithiane at a certain point during based on toxic metal ions (e.g., highly toxic mercury and
Scheme 1. Use of 1,3-dithiane-protected compounds in the formation of new C–C bonds.
[a] Trinity Biomedical Sciences Institute, School of Chemistry,
University of Dublin, Trinity College,
thallium salts). In addition, they also generally require the
use of stoichiometric amounts of the deprotection reagent,
Dublin 2, Ireland
E-mail: connons@tcd.ie
http://chemistry.tcd.ie/staff/people/Connon/index.html
[b] School of Chemical Sciences and National Institute for Cellular
Biotechnology,
harsh reaction conditions, and/or long reaction times to re-
generate the desired carbonyl compounds. Alternative,
more environmentally benign methods are therefore re-
quired.
The use of phosphonium- and imidazolium-ion-based
ionic liquids[20] equipped with a pendant sulfonic acidic
Dublin City University,
Glasnevin, Dublin 9, Ireland
E-mail: Nick.Gathergood@dcu.ie
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402947.
188
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Hydrolytic Cleavage of Dithianes by Imidazolium Ions
moiety in Brønsted-acid-catalysed reactions was first de- Such a process would hold promise as a fundamentally
scribed by Forbes and Davis in 2002 (e.g., 6, Figure 1).[21,22] greener alternative to existing methods.
Later, the use of protonated imidazolium ions[23] (e.g., 7)
and imidazolium ions with acidic counterions[24] (e.g., 8) in
Results and Discussion
various acid-catalysed reactions was reported. An example
of the latter class of ionic liquids has been used in the de-
protection of dithioacetals: Singh et al. used [bmim]HSO4
as a reagent, at stoichiometric loadings, under microwave
conditions.[25] While this potentially represents a step for-
ward, the environmental impact of these strongly Brønsted
acidic materials is currently unknown.
Figure 2B shows the proposed mode of action of 13 in
acetalisation reactions: the equilibrium between 13a and
13b/13c is driven towards the latter pair (which are the
putative acid catalysts in the reaction) through the in-
stallation of electron-withdrawing substituents onto the
imidazolium cation core, which further reduces delocali-
sation and favours nucleophilic attack by the alcohol on the
heterocycle.[29] We envisaged that this electrophilic cation
would also be susceptible to attack by nucleophilic thiol-
based intermediates in a dithiane-hydrolysis reaction.
An initial test of this hypothesis was undertaken using
imidazolium-ion-based catalysts 11 and 13 in the hydrolytic
Figure 1. Classes of imidazolium-ion-based acidic ionic liquids.
deprotection of dithioacetal 14 to give aldehyde
9
We recently reported a generation of aprotic ionic liquid
catalysts that are capable of behaving as Brønsted acids in
an “on-off” fashion, controlled by the use of protic addi-
tives (e.g., imidazolium ion 11[26a] and triazolium ion 12,[26b]
Figure 2A). The optimum catalyst that emerged from this
programme, i.e., 13, could promote ambient-temperature
acetalisation and thioacetalisation reactions of a range of
aldehydes at catalyst loadings of 0.1–1 mol-%, and could
also catalyse the reverse hydrolytic process involving acetals
at low loadings.[27] More importantly, these catalysts were
developed as part of our tandem strategy[26–31] to design
safer chemicals (including organocatalysts and ionic li-
quids[31–33]) based on principles of toxicity, biodegradation,
green catalyst preparation, green chemistry metrics, and
performance.[34] Previous studies had shown that catalysts
11–13 had a low toxicity to a representative range of micro-
organisms (i.e., 8 bacteria and 12 fungi).[28]
(Scheme 2, Table 1) in aqueous THF at 25 °C. Gratifyingly,
imidazolium-ion-based catalyst 13 mediated the cleavage of
the dithioacetal protecting group to regenerate parent
aldehyde 9 in 32% yield at 1 mol-% loading (Table 1, en-
try 1). This result was promising, as despite the low yield,
the use of the conventional strong-acid catalyst pTSA (p-
We were therefore intrigued as to whether these catalysts
could promote the hydrolytic deprotection of dithianes. Scheme 2. Catalytic hydrolysis of dithioacetal 14.
Figure 2. Catalytic imidazolium-ion-based acidic ionic liquids, and the proposed mode of action of catalyst 13.
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189

L. Myles, N. Gathergood, S. J. Connon
FULL PAPER
toluenesulfonic acid), under the same conditions, resulted in these conditions, the yield of 9 increased from 79%
a negligible yield of the desired aldehyde product (Table 1, (Table 1, entry 12) to 90% (Table 1, entry 14).
entry 2), and the use of H2SO4 (Table 1, entry 3) led to a
similarly insignificant product yield.
As 13 was an effective catalyst for the hydrolysis of di-
thioacetal 14, we investigated its ability to promote the
cleavage of the more synthetically relevant dithiolane 16
and dithiane 17 under the optimised conditions. Initial ex-
perimentation was undertaken using dithiane 16, using the
hitherto most advantageous conditions used for the hydrol-
ysis of 14 (i.e., using a THF/H2O solvent mixture). We
found that under these conditions the reaction proceeded
to give a relatively low product yield of 54%. We therefore
decided that a change of solvent may be beneficial, in order
to allow for a further temperature increase to 100 °C.
Therefore THF was replaced with 1,4-dioxane in a 2:1 ratio
with water (Scheme 3, Table 2). We found that in this sol-
vent mixture, catalyst 13 promoted the hydrolysis of dithiol-
ane 16 (Table 2, entry 1) and dithiane 17 (Table 2, entry 2)
to give appreciable yields of the desired aldehyde (i.e., 9).
Furthermore, the addition of two separate portions
(10 mol-%) of the catalyst over 48 h, at 24 h intervals, re-
sulted in the deprotection of these challenging thioacetal
protecting groups, cleanly generating 9 in synthetically use-
ful yields.
Table 1. Catalytic hydrolysis of dithioacetal 14: catalyst evaluation.
Entry
Cat.
Solvent Temp. Time
Loading
[mol-%]
Yield
[%][a]
ratio
[°C]
[h]
1
2
3
4
5
6
7
8
13
pTSA
H2SO4
11
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
2:1
1:1
1:2
1:1
25
25
25
25
25
25
25
35
35
35
35
35
35
35
24
24
24
24
24
24
24
24
24
48
48
48
48
48
1
1
1
1
5
10
20
10
20
10
10
10
32
2
5
0
13
40
59
61
63
63
65
71
79
36
90
13
13
13
9
13
10
11
12
13
14
13
13
13
13
10
13
10 (ϫ2)[b]
[a] Isolated yield after chromatography. [b] Second portion of cata-
lyst added after 24 h.
It is clear that the presence of electron-withdrawing
groups at the C-4 and C-5 positions of the heterocyclic cata-
lytic cation is paramount, as unsubstituted catalyst 11 was
found to be completely ineffective in promoting the reaction
(Table 1, entry 4). Optimisation of the reaction conditions
to improve the product yield was then undertaken. An in-
cremental increase in catalyst loading from 1 to 20 mol-%
was evaluated, and an increase in the amount of aldehyde
generated was observed when the catalyst loading was in-
creased from 1 to 5 mol-% (Table 1, entries 1 and 5) and
again from 5 to 10 mol-% (Table 1, entries 5 and 6). It was
interesting to note that doubling the catalyst loading from
10 to 20 mol-%, at both 25 °C (Table 1, entries 6 and 7) and
35 °C (Table 1, entries 8 and 9), had little effect on the prod-
uct yield. The reaction time was also extended from 24 to
48 h, and a marginal increase in efficacy was observed
(Table 1, entries 8 and 10). The solvent was modified next.
An increase in the amount of H2O relative to THF led to
a smoother hydrolysis (Table 1, entries 10–13), and a 1:1
v/v mixture proved optimal. Since the reaction mixture was
homogeneous in all cases, we would suggest that the re-
Scheme 3. Dithiolane/dithiane deprotection.
Table 2. Dithiolane/dithiane deprotection: effect of catalyst load-
ing.
Entry
Substrate
Loading
[mol-%]
Yield
[%][a]
1
2
3
4
16
17
16
17
10
10
72
76
83
87
10 (ϫ2)[b]
10 (ϫ2)[b]
[a] Isolated yield after chromatography. [b] Second portion of cata-
lyst added after 24 h.
Having established an efficient procedure, we went on to
duced yield observed in a predominantly aqueous medium evaluate the performance of 13 in the deprotection of a
may be due to competitive degradation of the catalyst variety of different dithianes of general type 19 (Scheme 4,
(Table 1, entry 13).
Table 3). Imidazolium salt 13 was found to catalyse the
The plateau in catalytic activity observed when the cata- cleavage of activated (i.e., 20–22, Table 3, entries 1–3), hin-
lyst loading was increased from 10 to 20 mol-% is also note- dered (i.e., 23, entry 4), deactivated (i.e., 24 and 25, entries 5
worthy (Table 1, entries 8 and 9). We questioned whether and 6), heterocyclic (i.e., 26, entry 7), and α,β-unsaturated
this could be due either to the catalyst system reaching (i.e., 27, entry 8) aldehyde-derived dithianes to give the
equilibrium under these conditions, or to degradation of aldehydes in good to excellent isolated yields.
the catalyst by hydrolysis/thiolysis. We therefore tested
The clear superiority of 13 over strong Brønsted acids
whether the yield could be increased by adding further cata- such as pTSA and sulfuric acid cannot be readily explained
lyst 13 during the reaction. Using the hitherto optimum 1:1 using a rationale based on the generation of transient acidic
solvent ratio (THF/H2O), we initially added 10 mol-% of species in the presence of protic media alone. Although a
13 and allowed the reaction to progress for 24 h, after which full mechanistic picture has so far proved elusive (for in-
time further catalyst (also 10 mol-%) was added. Under stance, no intermediates could be detected by 1H NMR
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Hydrolytic Cleavage of Dithianes by Imidazolium Ions
cific-acid catalysis through direct protonation of 29 is also
possible).
The catalytic activity of 13 in the hydrolysis of ketone-
derived dithianes was also investigated. However, under the
conditions described above, the more arduous task of de-
protection of such ketone-derived thioacetals proved im-
possible. However, under the influence of microwave radia-
tion (Scheme 6), we found that acetophenone (31)-derived
dithiane 30 could be deprotected in 48% yield. The o-nitro
analogue (i.e., 33) was generated from 32 in a marginally
higher yet still moderate yield, and the highest yield was
observed for the regeneration of cyclohexanone (35) from
34.
Scheme 4. Organocatalytic hydrolysis of dithianes.
Table 3. Organocatalytic hydrolysis of dithianes: substrate scope.
Scheme 6. Catalytic deprotection of ketone-derived dithianes.
The lower yields (and harsher conditions required) asso-
ciated with the deprotection of these ketone-based di-
thianes, when compared to the aldehyde-derived analogues,
supports the proposed mode of action of the catalyst in
these reactions. If the rate-determining step is attack of the
dithiane at the C-2 position of the imidazolium cation, the
inefficient cleavage of the ketone-derived compounds may
be due their greater steric bulk (Scheme 3, inset). When R4
is H, this will allow a relatively easy addition of the thiol
[a] Isolated yield after chromatography.
spectroscopic analysis of the reaction), at this point it seems to the C-2 position of the heterocycle, but substitution by
plausible that the electrophilic catalyst may serve as a tem- a methyl group (at R4) will contribute to a more sluggish
porary trap for the thiol generated from the cleavage of the addition due to steric hindrance, leading to lower product
first C–S bond of the dithiane/dithioacetal to generate cata- yields due to competitive catalyst degradation over time.
lyst adduct 28 (Scheme 5). If this trapping process retards
Organocatalyst 13, though clearly much less environmen-
reformation of the dithiane enough for attack of solvolytic tally damaging than commonly used mercury-, fluorine-, or
water on alkylated thioketone 28 to compete effectively, iodine-based reagents, is of course not without its draw-
then efficient hydrolysis could occur. Presumably acid catal- backs from a green chemistry standpoint. The solvent used
ysis also plays a role in the regeneration of 13 from 29 (a in the deprotection step must also be considered, especially
general-acid catalysis mechanism is shown, however spe- as dioxane is classed as an “undesirable” solvent by the
Scheme 5. Proposed mode of action of catalyst 13 in the deprotection of dithianes.
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191

L. Myles, N. Gathergood, S. J. Connon
FULL PAPER
pharmaceutical industry.[35] Note that the solvents used typically arduous cleavage of dithianes can be achieved
with mercury- [CH3CN/H2O, 4:1 v/v for HgCl2,[4] and without relying on the use of toxic, environmentally un-
THF/H2O, 5:1 v/v for Hg(ClO4)2[5]], fluorine- (CH3CN for friendly mercury/iodine-based reagents or the use of stoi-
Selectfluor[18]), and iodine-based reagents (DMSO for chiometric amounts of reagents.
IBX[16e]) were defined as “usable” in the same study.[35] Fur-
The catalytic deprotection of various dithiolane- and di-
ther optimisation of our deprotection method was required, thiane-protected aldehydes is possible in good to excellent
with removal of dioxane as the solvent a priority. yields under relatively mild conditions. The hydrolysis of
Therefore, an alternative, solvent-free method was also ketone-based dithianes can also be promoted in the pres-
developed using a “sacrificial” aldehyde, in which an excess ence of 13, albeit to a lesser degree. pTSA and H2SO4 were
of an aliphatic aldehyde Ϫ chosen because dithianes are considerably worse than catalyst 13 as acid catalysts for this
formed more easily from aliphatic aldehydes than from aro- reaction. This observation strongly implies that in the pres-
matic aldehydes[26,27] Ϫ was added to the reaction mixture ence of dithianes, 13 operates by another mechanism than
to sequester the 1,3-propane dithiol as it formed. The re- conventional specific Brønsted acid catalysis.
sults of this study are summarised in Scheme 7 and Table 4.
Experimental Section
General Remarks: 1H NMR spectra were recorded with 400 and
600 MHz spectrometers. Spectra recorded in CDCl3 were refer-
enced relative to residual CHCl3 (δ = 7.26 ppm), those recorded in
[D6]DMSO were referenced relative to residual DMSO (H) (δ =
Scheme 7. Organocatalytic deprotection of dithiane 17 under sol-
2.51 ppm). Chemical shifts are reported in ppm, and coupling con-
vent-free conditions: use of a “sacrificial aldehyde”.
stants in Hertz. 13C NMR spectra were recorded with the same
instruments (100 and 150 MHz) with total proton decoupling. In-
Table 4. Dithiolane/dithiane deprotection under solvent-free condi-
tions.
frared spectra were obtained using neat samples with a Perkin–
Elmer Spectrum 100 FTIR spectrometer equipped with a universal
Entry
Aldehyde
Temperature [°C]
Yield [%][a]
ATR sampling accessory. Flash chromatography was carried out
using silica gel, particle size 0.04–0.063 mm. TLC analysis was car-
ried out on precoated 60F254 slides, which were visualised by UV
irradiation, and staining with KMnO4 or anisaldehyde. All alde-
hydes were sourced commercially, and were either distilled under
vacuum (if liquid) or dissolved in CH2Cl2 and washed with NaOH
(if solid at room temp.) before use. THF was distilled from sodium
and stored under argon.
1
2
3
propanal
butanal
pentanal
45
72
100
81
80
79
[a] Isolated yield after chromatography.
It was particularly pleasing that the reaction proceeded
most efficiently in propanal at a relatively low temperature
(compared to the hydrolyses outlined in Table 3) to give a
synthetically useful yield of the desired aldehyde product
(i.e., 9; Table 4, entry 1). Butanal and pentanal also proved
effective agents, albeit at higher temperatures (Table 4, en-
tries 2 and 3). Only one addition of catalyst was required
in these reactions. Evidently, decomposition of the catalyst
under these milder, drier, conditions is less problematic. It
is noteworthy that this method does not require the use of
aqueous conditions, which may be useful in target-oriented
synthesis applications in cases where removal of a dithiane
moiety from a molecule containing functionality sensitive
to aqueous acidic hydrolysis is necessary. Recovery of the
excess aliphatic aldehyde is easy due to the significant dif-
ference in boiling points of the desired aromatic aldehyde,
the aliphatic aldehyde, and the aliphatic-aldehyde-derived
dithiane.
General Procedure: Hydrolysis of Dithianes (procedure involving
H2O): Compound 13 (8.9 mg, 0.024 mmol) and dithiane
(0.24 mmol) were added to a round-bottomed flask (10 mL)
equipped with a magnetic stirring bar. 1,4-Dioxane (5 mL) and
water (2.5 mL) were added. The flask was fitted with a condenser,
and the reaction mixture was heated under reflux for 24 h, after
which time the solution was cooled, and further 13 (8.9 mg,
0.024 mmol) was added. The reaction mixture was heated under
reflux for 24 h, and the resulting solution was concentrated in
vacuo. The product was then extracted with ethyl acetate (2ϫ
10 mL) and water (20 mL). The organic layers were combined,
dried with MgSO4, and filtered, and the solvent was removed under
reduced pressure. Purification of the crude material by flash
chromatography (hexane/EtOAc, 5:1) gave product 9 (22 mg, 87%)
as a colourless liquid.
General Procedure: Hydrolysis of Ketone-Derived Dithianes: Cata-
lyst 13 (17.9 mg, 0.048 mmol), ketone-derived dithiane 30 (50.0 mg,
0.24 mmol), 1,4-dioxane (2.5 mL), and water (1.25 mL) were added
to a microwave reaction vial (10 mL) equipped with a magnetic
stirring bar. The reaction vessel was fitted with a lid, and placed in
the microwave generator under reduced pressure. The mixture was
stirred for 2 h at 110 °C. Upon completion of the reaction, the sol-
vent was removed in vacuo, and the resulting residue was purified
by flash column chromatography (hexane/EtOAc, 8:1) to give prod-
uct 31 (13 mg, 46%) as a colourless liquid.
Conclusions
A new catalytic protocol for the synthetically useful de-
protection of dithioacetal and dithiolane/dithiane-protected
moieties has been developed. Aqueous and anhydrous
methods have been devised, both using a low-toxicity imid-
azolium-ion-based organocatalyst 13. These are new, more
General Procedure: Hydrolysis of Dithianes (anhydrous procedure):
environmentally benign, catalytic methods by which the Compound 13 (37.2 mg, 0.1 mmol) was added to a reaction vessel
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Hydrolytic Cleavage of Dithianes by Imidazolium Ions
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This mechanism was first proposed as an explanation for the
apparent acidity of N-benzyl pyridinium ions in protic media:
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(10 mL) equipped with a magnetic stirrer, and the reaction vessel
was put under argon. Compound 17 (98 mg, 0.5 mmol) and
aliphatic aldehyde (5 mmol) were added to the reaction vessel by
syringe. The reaction mixture was stirred at the required tempera-
ture for 24 h. Purification of the crude material by flash chromatog-
raphy (hexane/EtOAc, 5:1) gave product 9 (43 mg, 81%) as a
colourless liquid.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and NMR spectra.
Acknowledgments
[21]
[22]
The authors are grateful to the Environmental Protection Agency
for their financial support of this work.
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Received: September 29, 2014
Published Online: Novemer 26, 2014
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