Mild Deprotection of Dithioacetals by TMSCl/NaI Association in CH3CN

Article abstract of DOI:10.1002/ejoc.202000979

A mild process using a combination of TMSCl and NaI in acetonitrile is used to regenerate carbonyl compounds from a variety of dithiane and dithiolane derivatives. This easy to handle and inexpensive protocol is also efficient to deprotect oxygenated and mixed acetals as 1,3-dioxanes, 1,3-dioxolanes and 1,3-oxathianes quantitatively. As a possible extension of this method, it was also shown that nitrogenated substrates such as hydrazones, N-tosylhydrazones, and ketimines reacted well under these conditions to give the expected ketones in high yields. The methodology proposed herein is a good alternative to the existing methods since it does not use metals, oxidants, reducing agents, acidic or basic media, and keto-products were obtained in high to excellent yields.

Full text of DOI:10.1002/ejoc.202000979

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Mild Deprotection of Dithioacetals by TMSCl/NaI Association in
CH3CN
Authors: Yunxin Yao, Guangkuan Zhao, Abdallah Hamze, Mouad
Alami, and Olivier Provot
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000979
Link to VoR: https://doi.org/10.1002/ejoc.202000979
01/2020

10.1002/ejoc.202000979
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Mild Deprotection of Dithioacetals by TMSCl/NaI Association
in CH3CN
Yunxin Yao,[a] Guangkuan Zhao,[a] Abdallah Hamze,[a] Mouad Alami,[a] and Olivier
Provot[a]*
[a]
Yunxin Yao, Dr. Guangkuan Zhao, Prof. Abdallah Hamze, Dr. Mouad Alami, Dr. Olivier Provot.
Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France. Phone: +33 (0)146835847.
Email: olivier.provot@universite-paris-saclay.fr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A mild process using a combination of TMSCl and NaI in
acetonitrile is used to regenerate carbonyl compounds from a variety of
dithiane and dithiolane derivatives. This easy to handle and inexpensive
protocol is also efficient to deprotect oxygenated and mixed acetals as
1,3-dioxanes, 1,3-dioxolanes and 1,3-oxathianes quantitatively. As a
possible extension of this method, it was also showed that nitrogenated-
substrates as hydrazones, N-tosylhydrazones and ketimes reacted well
under these conditions to give the expected ketones in high yields. The
methodology proposed herein is a good alternative to the existing
methods since it does not use metals, oxidants, reducing agents, acidic
or basic media, and keto-products were obtained in high to excellent
yields.
Keywords: dithioacetal; deprotection; trimethylsilylchloride; sodium
iodide; ketone
this transformation at room temperature in the
presence of various functional groups. Recently, we
reported the interesting reducing properties of the
TMSCl/NaI association in CH2Cl2 towards various
functional groups as unsymmetrical -diketones,[15] -
ketoesters,[16] and hydrazones[16] derivatives. Under
similar reaction conditions, we next demonstrated that
a variety of dithioacetals were cleanly desulfurized at
rt[17] in CH2Cl2 using this metal-free process in a
Mozingo-type reaction.[18]
Introduction
Dithianes are commonly used in organic chemistry to
mask the electrophilic nature of carbonyl groups[1] in
elaborated molecules and serve as acyl anions in
syntheses according to the Umpolung concept.[2]The
main advantages of dithianes are their easy access
from a carbonyl compound by using propane-1,3-
dithiol and a Lewis acid and their stabilities in alkaline
and acid conditions notably permitting their
purification on a silica column. In counterparts to this
stability, many procedures have been developed for
their deprotection but generally require harsh
conditions.[3] Most of the time, toxic metal salts as
Hg(II),[4] Ag(I),[5] Zn(II),[6] Ga(III),[7] Cu(II),[8] Tl(V)[9]
and others are used in excess in harsh conditions with
some success. The use of hypervalent-iodine reagents
for the removal of dithianes has also been reported as
By replacing CH2Cl2 by CH3CN as the reaction
solvent, we surprisingly observed that dithianes
derivatives were not reduced into methylene substrates
but were totally and cleanly deprotected into ketones.
It seemed interesting to study this method for the
deprotection of thioacetals which does not use metal
salts, oxidants, toxic or expensive reagents (Figure 1).
an efficient process using periodic acid,[10]
diacetoxyiodobenzene,
[11]
bis(trifluoroacetoxy)iodo-
benzene (BTI),[12] Dess-Martin periodinane[13] and N-
halosuccinimides.[14] However, a large variety of the
methods mentioned before require the use of toxic
metals, the need of oxidizing species in large amounts
sometimes accompanied with co-oxidants mainly in
harsh reaction conditions. In this context, we believe
that an alternative milder process is still needed using
for example inexpensive and soft reagents to achieve
Figure 1. Properties of the TMSCl/NaI combination
towards dithioacetals in CH2Cl2 and CH3CN.
1
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
Results and Discussion
needed to complete this transformation in these
solvents. In CH3CN, we were pleased to isolate ketone
2a with a promising yield of 52% (entry 7) with no
trace of the reduced 2-ethylnaphthalene obtained in
CH2Cl2.[17] Under same reaction conditions but
without NaI, 1a was found unchanged showing the
essential role of NaI (entry 8). Addition of water,
NaOHaq or HClaq had a deleterious effect on the
reaction since a large part of 1a was recovered after 24
h of reaction (entries 9-12). The amount of TMSCl/NaI
and the temperature of the reaction were next
examined (entries 13-17) and the best result was
obtained by achieving the deprotection reaction at 60
°C in the presence of 20 eq of TMSCl/NaI leading to
ketone 2a in an excellent yield of 92% (entry 17).
Under the same reaction conditions, the replacement
of CH3CN by PhCN provided 2a but in a low yield of
52% (entry 18). To examine the influence of solvents
(deprotection vs reduction), 1a was reacted with
TMSCl/NaI in CH3CN/CH2Cl2 (1/1) for 24 h at 60 °C
(entry 19). In this mixture of solvents, we have isolated
only ketone 2a (85%) with no trace of the 2-
ethylnaphthalene (reduced compound) showing the
predominant role of CH3CN. Last, the reaction was
also run in CH3CN in the presence of TMSI (10 eq) at
rt (entry 20) for comparison. After only 3 h of reaction,
we observed by TLC the total disappearance of 1a but
2a was isolated, beside a large number of unidentified
by-products, with a low yield of 10%[20] showing the
superiority of the TMSCl/NaI association compared to
TMSI for carrying out these deprotection reactions in
CH3CN. The reasons for this difference in reactivity
between TMSI and TMSCl/NaI in CH3CN remains
unclear.
Table 1. Optimization of reaction conditionsa)
Entry
1
Conditions
Yield %
0b)
TMSCl/NaI (10 eq), EtOH, rt
2
TMSCl/NaI (10 eq), TFE, rt
<10b)
0b)
3
TMSCl/NaI (10 eq), tBuOH, rt
TMSCl/NaI (10 eq), Et2O, rt
4
24b)
25b)
17b)
52
5
TMSCl/NaI (10 eq), THF, rt
6
TMSCl/NaI (10 eq), acetone, rt
TMSCl/NaI (10 eq), MeCN
7
8
TMSCl (10 eq), MeCN, rt
0
9
TMSCl/NaI (10 eq), MeCN/H2O 85/15, rt
TMSCl/NaI (10 eq), wet MeCN, rt
TMSCl/NaI (10 eq), NaOHaq (10 eq.) MeCN, rt
TMSCl/NaI (10 eq), HClaq (10 eq.) MeCN, rt
TMSCl/NaI (15 eq), MeCN, rt
TMSCl/NaI (20 eq), MeCN, rt
TMSCl/NaI (10 eq), MeCN, 60 °C
TMSCl/NaI (15 eq), MeCN, 60 °C
TMSCl/NaI (20 eq), MeCN, 60 °C
TMSCl/NaI (20 eq), PhCN, 60 °C
TMSCl/NaI (20 eq), MeCN/CH2Cl2 (1/1), 60 °C
TMSI (10 eq), MeCN, rt
<10b)
38b)
40b)
36b)
67
10
11
12
13
14
15
16
17
18
19
20
71c)
68
78
92
52
85
10c)
a) All trials were achieved using 100 mg of 1a. b) Most of 1a remained intact.
c) Reaction time: 3 h.
Next, we were interested in evaluating this mild
protocol with 1.3-dioxolane 3, 1,3-dioxane 4, 1,3-
oxathiane 5 and dihydrobenzo[d]thiazole 6 (Scheme
1).
Herein, we wish to report the mild deprotection
conditions of a range of dithianes, dithiolanes and
oxygenated derivatives using the TMSCl/NaI
association in CH3CN.
Scheme 1. Deprotection of cyclic ketals 3,4 and oxathiane
5 by TMSCl/NaI in MeCN
First, we have selected 2-methyl-2-(naphthalen-2-yl)-
1,3-dithiane 1a which was totally reduced into 2-
ethylnaphthalene by TMSCl/NaI combination in
CH2Cl2[17] as our model substrate to herein examine the
dithiane deprotection reaction by the same reagents
under a variety of reaction conditions (Table 1). In
view of using EtOH as a green solvent,[19] we firstly
try to deprotect 1,3-dithiane 1a in EtOH in the
presence of 10 eq of TMSCl/NaI combination.
However, EtOH and other alcohols of different
nucleophilicity as trifluoroethanol (TFE) or tBuOH
were found to be ineffective as 1a was mainly found
unchanged after 24 h of reaction at rt (entries 1-3).
When the deprotection-reactions were done in Et2O,
THF or acetone (entries 4-6), a better trend was
noticed since 2b was isolated in low yields
accompanied by a large part of unreacted 1a. Longer
reaction times or higher temperatures will probably be
2
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
Table 2. Deprotection of 1a-u by TMSCl/NaI in MeCN
As it could be seen in Scheme 1, by using TMSCl/NaI
in CH3CN under the milder conditions A (used in entry
7 of Table 1), we observed a clean and complete
deprotection of ketals 3 and 4 as well as 1.3-oxathiane
5 into ketones (93% to 97%). The deprotection of
benzothiazole 6 was also effective but required
conditions B (entry 17, Table 1) to completely
deprotect 6. For comparison, Jung reported that TMSI
in CHCl3 also deprotected ethylene ketals into ketones
but with meager yields (20 %) and that TMSI was
unable to deprotect thioketals after 24 h of mixing at
75 °C.[21]
Substratea)
TMSCl/NaI(eq)
T
t
Productb)
Yield
(%)
°C (h)
1a 20 60 24
1b 20 60 24
1c 10 rt 24
2a 92
2c 73
2d 89
Encouraged by these results and by the simplicity of
this process, the deprotection of a variety of thioacetals
1a-u was carried out with the TMSCl/NaI association
in CH3CN for 24 h. Table 2 summarizes the results of
this study achieved using 10 eq of TMSCl/NaI at rt
(conditions A) or 20 eq of TMSCl/NaI at 60 °C
(conditions B) for less cooperative substrates. As
observed 1,3-dithianes and 1,2-dithiolanes of
acetophenones 1a-h were deprotected into their parent
ketones with good yields ranging from 54 to 94%. It is
of note that, 1,3-dithianes 1b-d and 1f-h were more
cooperative substrates than our model substrate 1a
since the deprotection reaction required half quantity
of TMSCl/NaI and was achieved at rt under conditions
A. Examination of these results also shows that 1,3-
dithianes seem easier to deprotect using TMSCl/NaI in
CH3CN than their 1,2-dithiolane counterparts
(compare 1d with 1e) and that electron-donating
groups on the aromatic nucleus allowed more efficient
deprotection reactions (compare 1d with 1h). As
expected, 1,3-dithianes prepared from aliphatic aryl
(cyclic or not) ketones 1i-m reacted well with the
TMSCl/NaI combination and furnished ketones 2i-m
in good to excellent isolated yields (64 to 91%). Then
we examined the deprotection reactions with
dialkyldithianes 1n-q. We showed that these
compounds were also cooperative substrates as they
were rapidly and cleanly deprotected to give the
desired ketones 2n-q with satisfactory yields (76% to
95%). Then, the case of diaryldithianes was examined.
Under conditions A (TMSCl/NaI 10 equiv, rt, 24 h),
we observed that 1,3-dithiane 1r having no H,
reacted with TMSCl/NaI to give a mixture composed
in almost equal parts of the expected ketone 2r (43%)
accompanied by the reduction[17] product 1-benzyl-4-
methoxybenzene (40%). To avoid the formation of the
reduction by-product, we successfully replaced NaI by
NaBr, increased the quantity of TMSCl/NaBr and
heated the solution at 60 °C for a prolonged time (TLC
monitoring). Using these conditions, diarylketones 2r
and 2s were then obtained with acceptable yields and
without any traces of the reduced diarylmethane by-
products. Next, 1,3-dithianes of aldehydes were also
studied with compounds 1t and 1u. We noted that
these 1,3-dithianes reacted rapidly using conditions A
to give the corresponding aldehydes in variable yields.
1d 10 rt 24
2e 94
2
2e
1e 20 60 24
1f 10 rt 24
83
2f 86
1g 10 rt 24
1h 20 60 24
2g 76
2h 54
1i 20 rt 48
1j 10 rt 24
2i 90
2j 87
1k 10 rt 24
1l 10 rt 24
2k 83
2l 85
1m 20 60 24
2m 64
2n 90
1n 10 rt 24
10 rt 48
79c)
1o 10 rt 24
1p 10 rt 24
2o 95
2p 76
1q 20 60 24
2q 88
1r 10 rt 24
2r 43d)
30 60 96
87e)
1s 30 60 48
2s 54d)
3
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
nitrogen substrates. In Scheme 3 we present the results
of the regeneration of carbonyl functions of
diphenylhydrazone 7, N-tosylhydrazone 8, N-
benzylimine 9, ketimine 10 and diphenylmethanone
oxime 11, using TMSCl/NaI in CH3CN.
1t 10 rt 24
1u 10 rt 12
2t 93
2u 40
a) Dithioacetals were prepared from the corresponding ketones with dithiols
in the presence of BF3-Et2O.[22] b) All purified ketones had 1H and 13C NMR
Scheme 3. Reaction of 7-11 by TMSCl/NaI in MeCN
c)
data identical to those of authentic samples. 1g of 1n was used. d) 1-
Benzyl-4-methoxybenzene (40%) resulting from the dithioketal reduction
was also isolated. e) NaBr replaced NaI.
For the deprotection of dithioketals of aldehydes, it is
crucial to examine the course of the deprotection
reaction by TLC monitoring because prolonged
reaction times resulted in a severe decrease in yields.
Indeed, it has been reported that, at rt, aldehydes
reacted rapidly with TMSI to give iodosilyl ethers and
diiodoethers.[23] This suggests that, as soon as
aldehydes are formed after thioacetal deprotection,
they add nucleophilic iodides, which may arise from
TMSI slowly generated in the media according to an
exchange Finkelstein reaction.[24]
To show the interest of this process with respect to
other previously reported methods using for examples
HgO associated with BF3-Et2O,[25] 2,6-dicarboxy
[27]
pyridinium chlorochromate (DCPCC)[26] or SbCl5
we have deprotected dithiolanes 1v and 1w by
TMSCl/NaI in CH3CN (Scheme 2).
Scheme 2. Deprotection of dithianes 1v and 1w by
TMSCl/NaI in CH3CN.
We were pleased to observe that the TMSCl/NaI
combination in CH3CN was able to transform imines
and hydrazones into ketones with good yields (90 to
100%) as well as N-tosylhydrazone 8 which required
the use of harsher reaction conditions. On the contrary,
imine 9 and ketimine 10 were easily transformed into
their ketones with high yields using the TMSCl/NaI
association in CH3CN at rt. When diphenylmethanone
oxime 11 was reacted with the TMSCl/NaI association
(10 eq), we isolated, after 24 h of reaction achieved at
rt, 4-methoxy-N-(4-methoxyphenyl)benzamide 12 in
good yield (84%) accompanied by only 4 % of the
bis(4-methoxyphenyl)methanone 2r. The scope of this
interesting Beckmann rearrangement, using the
TMSCl/NaI combination, is currently under
investigation in our lab with a range of oxime
substrates.[29]
The comparison of the yields obtained using the
TMSCl/NaI mild association in CH3CN vs toxic
oxidizing agent as HgO (86 % vs 65%), DCPCC (93%
vs 70%) or SbCl5 (93% vs 77%) supports well that this
novel metal-free process is welcome since the yields
in desired ketones are significantly higher and the
reagents used for the deprotection are inexpensive,
non-toxic and very easy to handle.
A plausible reaction mechanism is proposed in
(Scheme 4).
Next, as dithioacetals, the regeneration of carbonyl
compounds from nitrogen-derivatives as hydrazones,
N-tosylhydrazones, ketimines, and oximes required
most of the time harsh reaction conditions including
oxidative or reducing process, acidic or alkaline
media, expensive reagents or hazardous experimental
protocols.[28] To find a milder process, we next
examined if the TMSCl/NaI combination in CH3CN
process could be applied successfully to these robust
First, TMSCl in the presence of NaI is slowly
transformed by halogen exchange into TMSI which
complexes with CH3CN to give an intermediate of
type I[30] as previously proposed by Olah.[31] Then,
complex I reacts with a sulfur atom of dithiolane 1d to
give a sulfonium species of type II. Further assistance
from the neighboring dithiane sulfur atom possibly
leads to a fragmented sulfonium intermediate III
4
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
Scheme 4. Proposition of mechanism
eq) was stirred in MeCN for 5 min. Then, TMSCl (10
eq) was added to the solution which was stirred for 24
h at rt. The reaction was then hydrolyzed for 5 min.
with H2O (5 mL) and extracted with CH2Cl2. Organic
layers were dried over MgSO4 and concentrated under
reduced pressure to give a residue which was purified
by chromatography on silica gel to give the expected
carbonyl compound which have identical NMR
spectra with starting ketones.
Acknowledgements
Authors gratefully acknowledge support of this project by CNRS
and Univ. Paris-Saclay. Yunxin Yao and Guangkuan Zhao thank
the Chinese Scholarship Council for Ph.D. funding.
which adds H2O (from reagents, CH3CN or during
hydrolysis) to promote hemithioketal IV which is then
activated into a sulfonium intermediate V (having or
not H. With no H as in 1r or 1s, V finally
rearranges into the desired ketone 2e.[32] For
dithiolanes prepared from enolizable ketones as 1d,
the same (a) pathway could be followed, but it is also
reasonable to consider an additional pathway (b) in
which an iodide deprotonates intermediate V to furnish
an enol species which tautomerizes into ketone 2e.
Since dithioacetals having H can evolve according to
two different pathways, this can explain that these
entities are more straightforward to deprotect than
diarylthioketals counterparts. It is noted that Nicolaou
has previously proposed a similar mechanism for the
deprotection of S,S-acetals and ketals using IBX.[33]
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various dithioketals into ketones in CH3CN.
Otherwise, under mild experimental conditions, O,O-
acetals as well as O,S-oxathianes and S,N-acetals were
cleanly deprotected with high yields. It is also possible
to efficiently regenerate the carbonyl function of
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protocol. We believe that this metal-free process is an
excellent alternative to other known methodologies
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[8] T. Mukaiyama, K. Narasaka, M. Furusato, J. Am. Chem.
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Experimental Section
A general experimental procedure is described as
following: a mixture of thioketal (100 mg) and NaI (10
5
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
[15] L. Z. Yuan, D. Renko, I. Khelifi, O. Provot, J.-D. Brion,
[31] G. A. Olah, S. C. Narang, Tetrahedron 1982, 38, 2225-
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[16] L. Z. Yuan, G. Zhao, A. Hamze, M. Alami, O. Provot,
[32] With a dithioketal having no Has 1r,s, an iodide may
attack intermediate IV to give a mixed unstable S,I-ketal
which evolves into the reduction product 1-benzyl-4-
methoxybenzene (footnote c; Table 2). For a possible
mechanism explaining the reduction process, see ref.[17]
Adv. Synth. Catal., 2017, 359, 2682–2691.
[17] G. Zhao, L. Z. Yuan, M. Alami, O. Provot, Adv. Synth.
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[18] For a review see: G. Zhao, L. Z. Yuan, M. Alami, O.
[33] K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, J.
Am. Chem. Soc. 2004, 26, 5192-5201.
Provot, ChemSelect, 2017, 2, 10951–10959.
[19] See for exemple: G. Zhao, C. Roudaut, V. Gandon, M.
Alami, O. Provot, Green Chem., 2019, 21, 4204–4210.
[20] 2-(1-Iodoethyl)naphthalene resulting from the
reduction of 1a was also identified in the crude mixture
(< 10%).
[21] M. E. Jung, W. A. Andrus, P. L. Ornstein, Tetrahedron
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[22] To a solution of ketone or aldehyde (1 mmol) in 20 mL
of DCM was added the thiol derivative (1,2-
ethanedithiol or 1,3-propanedithiol; 5 mmol), followed
by 1 mL of BF3-Et2O. The solution was stirred at rt until
disappearance of starting material (judged by TLC).
Then, H2O (20 mL) and DCM (30 mL) were added to
the solution. The organic layer was separated, washed
with H2O (2 x 10 mL) and saturated NaCl solution (2 x
10 mL), dried over MgSO4, and concentrated under
reduced pressure to give a dithioacetal which was
purified by chromatography on silica gel.
[23] M. E. Jung, A. B. Mossman, Lyster, M. A. J. Org.
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[24] H. Finkelstein, Ber. Dtsch. Chem. Ges. 1910, 43, 1528-
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Ishizuka, A. Harano, H. Tsukiji, R. Takizawa,
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[29] To our knowledge, only one paper reported the use of
TMSCl in CH3CN to achieve at a high temperature of
100 °C, the Beckmann rearrangement of the
cyclododecanone oxime into laurolactam (a single
example having no functional groups was described in
this letter; no isolated yield is mentioned), see: S. Sato,
S. Hoshino, T.; Sugimoto, K. Kashiwagi, Chem. Lett.
2010, 39, 1319•1320.
[30] Analysis of 13C NMR spectra indicates that a complex
of type I may be formed under the conditions used to
deprotect dithioketals. Complex I can be obtained from
the progressive formation of TMSI which complexes
with CH3CN, which is not the case of TMSCl. (see NMR
spectra in SI).
6
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10.1002/ejoc.202000979
European Journal of Organic Chemistry
FULL PAPER
Mild Deprotection of Dithioacetals by TMSCl /
NaI Association in CH3CN
Adv. Synth. Catal. Year, Volume, Page – Page
TMSCl associated with NaI was used to deprotect various
dithioacetals in CH3CN with good to excellent yields.
This metal-free process can also be applied with success
for the regeneration of carbonyl of O,O-acetals, O,S-
oxathianes, S,N-acetals, ketimines and hydrazones.
Yunxin Yao, Guangkuan Zhao, Abdallah Hamze,
Mouad Alami, Olivier Provot*
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