FeCl3·6H2O/acetaldehyde, a versatile system for the deprotection of ketals and acetals via a transacetalization process

Article abstract of DOI:10.1039/c6nj03439j

Mild and efficient catalytic deprotection of ketals/acetals mediated by FeCl₃·6H₂O/acetaldehyde has been described in this paper. The versatility and high chemoselectivity of the iron(iii)/aldehyde system are demonstrated by a large scope of examples. Deprotected ketones/aldehydes are nearly quantitatively isolated after filtration over a pad of silica gel followed by evaporation of volatile by-products.

Full text of DOI:10.1039/c6nj03439j

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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FeCl3.6H2O/acetaldehyde, a versatile system for the deprotection
of ketals and acetals via a transacetalization process
Received 00th January 20xx,
Accepted 00th January 20xx
Lucie Schiavo,a Loïc Jeanmart,b Steve Lanners,b Sabine Choppin*a and Gilles Hanquet*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Mild and efficient catalytic deprotection of ketals/acetals efficiency and chemoselectivity for this purpose is always
mediated by FeCl3.6H2O/acetaldehyde has been described in this useful.
paper. The versatility and high chemoselectivity of the For example, the presence of a quaternary centre adjacent to
iron(III)/aldehyde system is demonstrated by a large scope of the dioxolane moiety of compounds resulting from chemical
examples.
quantitatively isolated after a filtration over a pad of silica gel uncompleted ketal hydrolysis and subsequently
followed by evaporation of volatile by-products separation step. Thus, in 1999, Marko et al. described a nearly
Deprotected
ketones/aldehydes
are
nearly transformations of
2
or
3
may sometimes cause difficult or
a
tricky
.
quantitative deprotection (91% yield) of the dioxolane part of
the protected ketone type Wieland-Miescher using Cerium
Ammonium Nitrate (CAN) in excess in a biphasic system
CH3CN/H2O.7,8 Some other more classical acidic conditions (HCl
1 to 12M in MeOH9 or 3N to 4N in THF10,2d) were also reported
The Wieland-Miescher Ketone (WMK) and derivatives such as
(figure 1) are particularly useful synthons for the
1
construction of a variety of biologically active compounds
belonging to terpenoids and steroids family.1, 2, 3
in the literature to deprotect WMK or derivative 2 but suffer of
a lack of selectivity depending on the sensitivity of the
substrates to acidic media.
O
OTMS
O
O
4
During our studies, directed towards Mukaiyama-aldolisation
of aliphatic aldehydes or corresponding dimethyl acetals with
4
4
O
O
O
O
O
O
Wieland Miescher
Ketone
3
2
1
the silyl enol ether 3, we applied the FeCl3.6H2O-catalyzed
Rodríguez-Gimeno11 conditions in dichloromethane.
A
Figure 1 : Wieland Miescher Ketone and derivatives
1
,
2
and
3.
quantitative deprotection of the cyclic ketal was observed at
room temperature, affording after filtration over a pad of
The rigid bicyclic structure with functionalities in both cycles
and the availability of the starting WMK in the enantiopure
form makes the latter compound an outstanding synthon for
total synthesis of terpenoids.2a,2d,4 Furthermore, the two
ketone functions do not present the same reactivity and can
be chemically differentiated by selective reduction or
protection as dioxolane 24 of the more electrophilic
unconjugated one (C-4). Ketals and acetals such as dioxolane
group occupy a centered position for the protection of ketones
and aldehydes due to their rather good stability towards
nucleophilic and basic reagents.5 Considerable efforts have
been directed towards developing mild and selective methods
for ketals/acetals deprotection.6 However, search for
silica, a mixture of ketone
1 and the dioxolanes of the
corresponding starting aldehydes or dimethyl acetals (figure
1). We supposed that an iron(III) transacetalization reaction
occurred from
3 to aldehyde/dimethyl acetal reagents of the
Mukaiyama-aldolisation. This equilibrated process should be
driven by the higher electrophilicity of aldehydes compared to
diketone 1. Iron(III) chloride hexahydrate was already known
as a deprotected catalyst of ketals or acetals as well as reagent
of THP or MOM ethers cleavage, but often used in large excess
(3.5 equiv.).12 Iron(III) chloride adsorbed on silica gel was also
known for selective deprotection of ketals or acetals in the
presence of OAc, OBn and OTBDMS.13 Recently, Sakiji’s group
reported an efficient cleavage of methoxyphenylmethyl-
protected alcohols in excellent yields.14 Moreover FeCl3 can
efficiently catalyze Boc deprotection of N,N’-diprotected
amines.15 In this context, we supposed that the use of a low
molecular weight aldehyde as transacetalization partner with
catalytic amount of non-toxic and readily available iron(III) salt
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Table 1. FeCl3.6H2O-catalyzed transacetalization deprotection of enone 2a.
should provide highly pure mother ketones, avoiding silica gel
column chromatography. We describe herein the mild,
efficient and chemoselective deprotection of acetals and ketals
via transacetalization with acetaldehyde or propioanaldehyde
in presence of iron(III) trichloride hexahydrate as the Lewis
acid catalyst.
Our pre-examination indicated that only 10 mol % of iron
trichloride could achieve deprotection of
2 in CH2Cl2.
Therefore, we initially investigated the influence of the Lewis
acid, acetaldehyde 4a or propionaldehyde 4b stoichiometry
and the nature of solvent on the reaction rate using enone 216
as substrate (table 1).
Aldehyde
4a-b
Catalyst (mol %) /
Adjuvant
Entry
Solvent
t (h)b
Yield (%)c
(n= 0 or 1)
(mol %)
This first set of experiments determined that standard
deprotection protocol involved preparing a solution of enone
Complex
mixture
1
2
-
FeCl3.6H2O (10)
FeCl3.6H2O (10)
FeCl3.6H2O (1)
FeCl3 (10)
DCM
DCM
3
1.5
30
2
2
with two equivalents of aldehydes 4a or 4b in
4a (2.0)
4a (2.0)
4a (2.0)
4a (2.0)
4b (2.0)
4b (1.0)
4a (10.0)
4a (2.0)
-
99
99
97
99d
99
94
99
99
97
97e
75
97
99
dichloromethane, to which was added FeCl3.6H2O (10 mol %)
(entries 2 and 6). The resulting crude mixture was filtered over
a pad of silica and concentrated under vacuum to afford pure
3
DCM
diketone 1. The use of one equivalent of aldehyde 4b led also
4
DCM
to a total conversion but the volume of aldehyde to handle
was not adapted to the scale (0.2 to 1 mmol) (entry 7). As
expected from literature,12 a nasty deprotection occurred in
the absence of aldehydes 4a-b (entry 1). The reaction can be
performed without any solvent, using an excess (10 equiv.) of
aldehyde 4a (entry 8) which clearly shows that the
FeCl3.6H2O (10)
/DTBP (10)
5
DCM
8
6
FeCl3.6H2O (10)
FeCl3.6H2O (10)
FeCl3.6H2O (10)
FeCl3.6H2O (10)
FeCl3.6H2O (10)
FeCl3.6H2O (10)
In(OTf)3 (1)
DCM
2
7
DCM
2
deprotection
is
undoubtedly
proceeding
via
a
transacetalization reaction. 1H NMR monitoring of the
reactions revealed the concomitant formation of the
corresponding acetaldehyde dioxolane. Deprotection occurred
quantitatively even with only 1 % mol of catalyst but required
longer reaction time (30h, entry 3). Since aqueous solutions of
8
Neat
8
9
Acetone
Acetone
Acetone
Acetone
Acetone
DCM
2
10
11
12
13
14
24
2
FeCl3 contain
a mixture of the weakly acidic hydrates
-
+
+
[Fe(H2O)6]3 and [Fe(H2O)5(OH)]2 able to catalyze the
reaction,12 we applied our standard conditions in the presence
of 10 mol % of 2,6-ditert-butylpyridine (DTBP) as proton
scavenger or by using anhydrous FeCl3. No change was
observed when anhydrous FeCl3 was used as catalyst (entry 4),
but addition of the proton scavenger to FeCl3.6H2O provided a
weaker deprotecting agent (entry 5), since quantitative
deprotection was observed only after 8 hours.
-
24
24
0.5
-
In(OTf)3 (10)
4a (2.0)
In(OTf)3 (10)
In(OTf)3 (10)
6
15
-
Acetone
0d
/DTBP (1 equiv)
days
Inspired by a paper reporting mild and selective acetals and
ketals deprotection using In(OTf)3 (1 mol %)-catalyzed
transacetalization in acetone,17 we attempted FeCl3.6H2O-
catalyzed deprotections in the same solvent (entries 9, 10,
11).
In(OTf)3 (10)
/DTBP (10)
16
17
4a (2.0)
4a (2.0)
DCM
DCM
4.5
98d
97
-
0.25
/Triflic acid (10)
No significative change was observed in acetone and in the
presence of acetaldehyde 4a (entries 2 and 9). In sharp
contrast, the lack of aldehyde lead to significantly longer
reaction time (entry 10) and higher temperature was required
to complete the reaction within two hours (entry 11). This is
easily explained by the lower electrophilicity of acetone
aGeneral conditions: substrate 2 (1 mmol), aldehyde 4a (2 mmol), FeCl3. H2O (10
mol %), DCM (2 mL) at rt. bReaction time needed to observe complete
disappearance of starting material (monitored by GC or 1H NMR). cIsolated yields.
d DTBP=2,6-ditert-butylpyridine eAt reflux in a sealed-tube.
The latter can be improved to 97% when using 10 % mol of
In(OTf)3 (entry 13). Applying our reaction conditions to In(OTf)3
lead to complete deprotection within 30 min (entry 14).
Addition of 1 equiv. of 2,6-ditert-butylpyridine as proton
scavenger in the conditions described by Gregg et al.17
inhibited the reaction and no deprotection was observed even
after 6 days (entry 15). Finally, 10 mol % of In(OTf)3 in the
compared to acetaldehyde 4a
.
In order to compare the catalytic activity of FeCl3.6H2O and
In(OTf)3, we performed a set of experiments using 1 or 10 %
mol of In(OTf)3). Application of Gregg et al. conditions17, in
acetone using 1 mol % of In(OTf)3 gave rise to 75% of
conversion after 24 h (entry 12).
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presence of 10 mol % of 2,6-ditert-butylpyridine and 2 equiv. conversion was obtained with aliphatic acetal
8, since the
of acetaldehyde in dichloromethane required longer time corresponding aldehyde electrophilicity is close to
(4.5h versus 0.5h) to afford a complete deprotection after 24h acetaldehyde (entry 5). As a consequence an equilibrium
(entry 14 and entry 16). It has to be noted that the use of 10 between the protected and deprotected form is observed with
mol % of triflic acid as sole catalyst in the presence of 2 equiv. time.
acetaldehyde in dichloromethane afforded
deprotection within 15 minutes (entry 17).
a
complete The mild, neutral conditions found when using our FeCl3.6H2O
(10 mol %)/acetaldehyde 4a (2 equiv.) system tolerate a wide
The versatility of this transacetalization protocol18 (FeCl3.6H2O range of functional groups including acid sensitive TBDMS-
(10 mol %)/acetaldehyde 4a (2 equiv.)) was demonstrated by allyl- MOM-, benzyl- THP- and PMB ethers, 22b-g, 23 and 24
the quantitative deprotection of different ketals 5-6 or acetals (table 3). In the case of silyl ether 25e, the reaction had to be
7-13 with electron-rich, electron-poor aromatic substrate, monitored since a Si-O bond cleavage started to appear after
sensitive heteroaromatic or sterically hindered substrates to two hours leading to the corresponding keto-alcohol after 3
the corresponding carbonyl compounds (table 2).
hours. Competitive THP ether cleavage was also observed
during the deprotection of 22g and the ketone 25g was
obtained in 48% isolated yield.
Table 2. Substrate scope for the deprotection of several ketals/acetals 5-13 by
FeCl3.6H2O/acetaldehyde 4aa
Table 3 Chemoselective substrate scope for the deprotection of dioxane 22a-g, 23 and
24 with FeCl3.6H2O/acetaldehyde 4a systema
Entry
1
Substrate
T (°C), t (h)
rt, 0.25
Product
Yield (%)
99b
O
O
O
O
FeCl3.6H2O (10 mol %)
DCM, rt, time
+
R
4a
R
2
3
reflux, 1
rt, 0.25
99b
99b
25a-g
= NHP (26)
= O (27)
R = OH OP (
)
R = OH, OP (22a-g )
23
= NHP (
24
)
= O (
)
HO
25a
O
AllylO
25b
O
BnO
O
b
, 30 min., 91%
, 1h, 91%
25c, 30 min., 93%
5
6
7
rt, 1
76c
95b
90b
TBDMSO
O
MOMO
O
PMBO
O
25e
25f
25d, 15 min., 99%
, 2h, 95%
, 15 min., 99%
rt, 0.25
rt, 0.25
THPO
O
BocHN
26
O
O
O
27, 1h, 77%b
O
O
O
25g, 2h, 48%
, 30 min., 60%
10
aReaction conditions: substrates 22a-g, 23 and 24 (0.5 mmol), acetaldehyde 4a (1
mmol), FeCl3.6H2O (10 mol %), DCM (1 mL) at rt. bConversion are consigned since
compounds 25a and 27 are volatiles.
8
9
rt, 0.25
rt, 0.25
98b
98b
Selective deprotection of the N-Boc-aminoketal 23 was observed
and the corresponding N-Boc-aminoketone 26 was isolated in 60%
yield after 30 minutes at rt. Surprisingly, longer reaction time,
higher temperature or the use of larger amount of catalyst did not
improve the yield, and no further N-Boc deprotection was
observed. Diketone 24, protected with one dioxolane was
efficiently deprotected in a reasonable time (1h) in good yield with
the same amount.
O
O
O
H
OMe
20
10
rt, 0.25
98b
Finally, this protocol tolerates acid sensitive tertiary alcohols as
exemplified by scheme 1, where 28 is quantitatively deprotected at
0 °C to the ketone 29 without any formation of the conjugated
double-bond (scheme 1). It is to note that 28 was however
completely converted to conjugated ketone by raising temperature
to rt.
a
Reaction conditions: substrates 5-13 (0.5 mmol), acetaldehyde 4a (1 mmol),
FeCl3.6H2O (10 mol %), DCM (1 mL) at rt. bIsolated yields. c1H NMR conversion.
The dioxane functionality or pinacol acetals which are typically
difficult to remove under mild conditions,7,19 were effectively
hydrolyzed with FeCl3.6H2O (10 mol %)/acetaldehyde 4a (2
equiv.) as demonstrated by the quantitative deprotection of
the cyclic ketals 5, 6 and 13 (entries 1, 2 and 10). Moderate
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Scheme 1: Chemoselective deprotection of aliphatic ketone 28 with
FeCl3.6H2O/acetaldehyde 4a system.
In summary, FeCl3.6H2O (10 mol %)/acetaldehyde (2 equiv.)
catalyzed ketals/acetals cleavage in DCM or acetone
represents a mild, efficient, environmentally friendly and
cheap deprotection reaction. It relies on the transacetalization
from
ketals/acetals
to
the
volatile
2948–2957; (c) H. Hagiwara and H. Uda, J. Org. Chem., 1988, 53,
acetaldehyde/propionaldehyde acetal which can be easily
removed by evaporation. This reaction is driven by the
2308–2311.
4 A. K. Banerjee and M. Laya-Mimo, Studies in Natural Products
difference of electrophilicity of aldehyde and ketone in favour Chemistry, 2000, 24, 175-213.
5
(a) P. G. M. Wuts and T. W. Greene, in Greene’s Protective
of aldehyde. This very simple procedure do not required
anhydrous solvent nor argon atmosphere, and proceeds at
room temperature. No work up or further purification is
needed; a simple filtration over a pad of silica to remove the
iron salt and evaporation of volatile acetal of acetaldehyde
provides pure deprotected ketone. Considering the high
chemoselectivity towards acido-labile ether protected groups,
and N-Boc protected groups, these conditions can be
efficiently applied to total synthesis.
Groups in Organic Synthesis, Wiley, New York, 4th edn, 2006; (b) F.
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the literature. Nevertheless in our hands these conditions lead
to formation of small amount of bis-protected product or not
complete conversion of starting material which were difficult to
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separate. Strict application of the conditions depicted in the
scheme below afforded quantitatively the ketone
2.
(+/-) CSA (cat.),
O
O
(EtO)3CH (1.0 equiv.)
Ethylene glycol anh.(4.0 equiv.),
O
O
toluene, rt, 5h
O
2
1
95% (isolated yield)
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5890–5893.
18 Typical procedure: Acetal/ketal (1 mmol, 1 equiv.) was dissolved
in DCM (2 mL). Acetaldehyde 4a (2 equiv.) was added followed by
the addition of FeCl3.6H2O (0.1 equiv.). The resulting colored
(yellow to brown) reaction mixture was stirred at r.t. until
completion (1H NMR or GC monitoring), then filtered over a pad of
silica gel (1 cm thick, DCM), eluted with DCM and evaporated to get
the pure product.
19 (a) J. C. Stowell and D. R. Keith, Synthesis 1979, 132-133, (b) Y.
Seeleib, G. Nemecek, D. Pfaff, B. D. Süveges and J. Podlech, Synth.
Commun., 2014, 44, 2966-2973.
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