Pd(II)-catalyzed deprotection of acetals and ketals containing acid sensitive functional groups

Article abstract of DOI:10.1016/j.tetlet.2013.12.067

The pincer complex [Pd(C¹,O¹,N¹-L)(NCMe)] ClO₄ (L = monoanionic ligand resulting from deprotonation of the acetyl group of the dimethyl monoketal of 2,6-diacetylpyridine) is used for the high-yield and selective catalytic hydrolysis of aliphatic, aromatic, cyclic, and acyclic dimethyl-acetals, -ketals, and dioxolanes, even in the presence of large substituents. Other protecting groups, such as THP or TBDMS, or very acid-sensitive alcohols were not affected. The catalyst is easily prepared in high yield from Pd(AcO)₂ and 2,6-diacetylpyridinium perchlorate stable to air and moisture, easily and fully recoverable and reusable.

Full text of DOI:10.1016/j.tetlet.2013.12.067

Tetrahedron Letters 55 (2014) 1141–1144
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd(II)-catalyzed deprotection of acetals and ketals containing acid
sensitive functional groups q
⇑
Francisco Juliá-Hernández , Aurelia Arcas, José Vicente
Grupo de Química Organometálica, Departamento de Química Inorgánica, Facultad de Química, Universidad de Murcia, Murcia E-30071, Spain
a r t i c l e i n f o
a b s t r a c t
The pincer complex [Pd(C1,O1,N1-L)(NCMe)]ClO4 (L = monoanionic ligand resulting from deprotonation of
the acetyl group of the dimethyl monoketal of 2,6-diacetylpyridine) is used for the high-yield and selec-
tive catalytic hydrolysis of aliphatic, aromatic, cyclic, and acyclic dimethyl-acetals, -ketals, and dioxol-
anes, even in the presence of large substituents. Other protecting groups, such as THP or TBDMS, or
very acid-sensitive alcohols were not affected. The catalyst is easily prepared in high yield from Pd(AcO)2
and 2,6-diacetylpyridinium perchlorate stable to air and moisture, easily and fully recoverable and
reusable.
Article history:
Received 7 October 2013
Revised 9 December 2013
Accepted 17 December 2013
Available online 25 December 2013
Keywords:
Acetals
Catalysis
Ó 2013 Elsevier Ltd. All rights reserved.
Hydrolysis
Palladium
Acetal deprotection
Introduction
ple of Pd-catalyzed deprotection of acetals and ketals has been re-
ported by Lipshutz et al.16 Low catalyst loading of [PdCl2(NCMe)2]
Protection and deprotection of functional groups are key in
many multi-step organic syntheses. Therefore, the development
of new mild, efficient, and selective reagents to remove established
protecting groups is a valuable endeavor. In particular, the depro-
tection of acetals and ketals1 to give the corresponding carbonyl
compounds has a very important role in total synthesis.2–4
is able to afford the corresponding carbonyl groups in good yields
but competitive reactions are given with the THP alcohol protect-
ing group.
Results and discussion
Many reagents have been developed for this purpose, for exam-
ple, organic acids, metal chlorides, coordination complexes,2 inor-
ganic salts,2,3,5–9 and organic compounds.2,10,11 While these
reagents are useful toward functionally poor organic molecules
they (1) are not efficient to all kinds of acetals and ketals,2,7,8,12
(2) use acidic medium unsuitable for compounds containing acid
sensitive functional groups2,5 or (3) give unwanted side-reactions
with other protecting groups (tetrahydropyranyl (THP), methoxy-
methyl ether (MOM), or silyl ethers).2,9,10 In the last decade, some
methodologies have been highlighted over the rest, such as the use
of triethylsilyl trifluoromethanesulfonate (TESOTf) + base,11,13 that
selectively unmasks acetals in the presence of ketals in good yields,
Bi(III)14 and In(III)3,15 salts that deprotect acetals and ketals in the
presence of THP and silyl ether protecting groups. Only one exam-
We have recently isolated a family of Pd(II) pincer complexes
17
[Pd(C1,O1,N1-L)(L1)]ClO4 (L = monoanionic ligand resulting from
the cyclopalladation of 2,6-diacetylpyridine (Scheme 1), L1 = MeCN
(1), PPh3 (2) and other N-, P-donor ligands) and some containing
C-donor ligands obtained from the hydrolysis of the corresponding
monoketal derivatives [Pd(C1,O1,N1-L0)(L1)]ClO4 (L0, see Scheme 1;
L1 = MeCN (A1), PPh3 (A2). Complex 1 can also be prepared from
Pd(OAc)2 and 2,6-diacetylpyridinium perchlorate.17 The pincer
ligands L and L0 provide palladium complexes with interesting
properties. Thus, L0 is able to stabilize complexes of Pd(IV), which
are, in general, highly unstable; in addition, some Pd(II) and Pd(IV)
derivatives of L or L0 are catalysts.17–19
The above-mentioned hydrolytic process did not occur in neu-
tral homologous complexes of A, for example in [Pd(O1,C1,N1-L0)Cl],
suggesting that it could be caused by increasing the acidic charac-
ter of the Pd(II) center in the cationic complexes A. To test if this
hydrolysis could also occur with an ‘external’ acetal we attempted
to use A1 (L1 = MeCN) or A2 (L1 = PPh3) as the catalyst for the
hydrolysis of decanal dimethylacetal (DDMA). However, although
it occurred, the process was very slow (Table 1) and curiously,
the intramolecular hydrolysis did not take place while there was
q
The patent of this method has been applied for (P201031021).
⇑
Corresponding author. Fax: +34 868 887785.
E-mail addresses: francisco.julia@um.es (F. Juliá-Hernández), aurelia@um.es
(A. Arcas), jvs1@um.es (J. Vicente).
Present address: School of Biological and Chemical Sciences, Queen Mary,
University of London, Joseph Priestley Building, Mile End Road, London E1 4NS,
United Kingdom.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.067

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F. Juliá-Hernández et al. / Tetrahedron Letters 55 (2014) 1141–1144
Table 2
Deprotection of DDMA at different concentrations of 1, temperatures, and reaction
times to reach >90% yield of decanal
Mol % of 1
Temp (°C)
Time
Yielda (%)
1
3
5
10
1
25
25
25
25
50
36 h
12 h
8 h
5.5 h
5 min
92
96
95
97
98
a
Determined by 1H NMR.
added to the mixture (Table 2). Decanal was obtained in quantita-
tive yields after 5.5–36 h depending on the concentration of the
catalyst (1–10%, respectively). When the temperature of the reac-
tion was increased to 50 °C, 98% yield was obtained after 5 min
using 1% mol of 1. Therefore, the latter reaction conditions can be
used for hydrolyzing non-temperature sensitive substrates.
In order to know the potential of our methodology, a number of
aliphatic, aromatic, cyclic, and acyclic dimethylacetals, dim-
ethylketals, and dioxolanes were selected as substrates (Table 3).
The reactions were performed in wet acetonitrile using 1% mol of
1 as the catalyst.22
Scheme 1. Synthesis of complexes 1 and 2.
All deprotection reactions led to the corresponding carbonyl
compounds in more than 95% yield in the range of 1–120 min at
room temperature or by heating at 50 °C. As expected, ketals (entry
4, Table 3) were more easily hydrolyzed than the corresponding
acetals (entry 5). Moreover, dioxolane derivatives were somewhat
more resistant than the corresponding dimethoxy compounds (en-
try 6). This methodology is compatible with the presence of other
protecting groups such as tert-butyldimethylsilylether (TBDMS,
entry 8) or acid-labile tetrahydropyranyl (THP, entry 7). However,
in [PdCl2(NCMe)2]-catalyzed reactions of protected acetal com-
pounds bearing THP groups, both hydrolytic processes are in com-
petition.16 We have also successfully deprotected two ketals
containing really acid-sensitive hydroxy groups (entries 9 and
Table 1
Deprotection of DDMA with various catalysts
Cat.
Time (h)
Yielda (%)
1
A1
A2
8
16
16
16
16
16
95
36
6
30
0
[PdCl2(NCMe)2]16
[Pd(AcO)2]
10% AcOH
0
10)23 that could easily dehydrate, giving the corresponding
a,b-
a
Determined by 1H NMR.
unsaturated carbonyl compounds, if acid deprotecting reagents
were used. Thus, it has been observed dehydration in attempts to
deprotect 1824 and 20.25 These are very remarkable results because
deprotection of compound 18 has only been accomplished with
(NH4)2[Ce(NO3)6] (CAN)9,26 but the hydrolysis of substrates similar
to 20 has failed using TiCl4 as the catalyst or HCl in THF.25,27 We
have found that [PdCl2(NCMe)2] (1%, 50 °C, 1 h) does not deprotect
20. However, neither (MeO)2CH(CH2)3NH2, or its BOC-protected
derivative, nor (MeO)2CHCH2CN were hydrolyzed in the presence
of 1, probably because they N-coordinate to Pd preventing the
coordination of the ketal group.
A large-scale deprotection of DDMA (40 mmol-scale) has been
carried out obtaining 96% isolated yield of the desired aldehyde.
Complex 1 is stable during the hydrolysis reaction and can be
easily recovered (95%) and reused. As complex 1 can also be ob-
tained (and isolated in 94% yield) by reaction of Pd(OAc)2 and
2,6-diacetylpyridinium perchlorate,17 we have also used complex
1 as the catalyst for the deprotection of DDMA preparing it
in situ by successive addition of equimolecular amounts of 2,6-
diacetylpyridinium perchlorate and Pd(OAc)2 to MeCN. We have
proved that palladium acetate or the acetic acid by-product did
not affect the catalytic hydrolysis of DDMA (Table 1). The 1H
NMR of CD3CN solutions of reaction mixtures shows that the for-
mation of the catalyst is quantitative and instantaneous.
DDMA in solution. This suggested us that the intermolecular
hydrolysis occurred by replacement of the ketal group of the ligand
by DDMA, preventing the intramolecular hydrolysis, and not by
replacement of the ligand L1, which, in addition, would be very un-
likely in the case of PPh3 (A2). The greater reaction rate when A1
was used as the catalyst instead of A2 could be attributable to a
higher steric hindrance produced by the bigger phosphine ligand.
Consequently, we thought that complex 1 could be better as cata-
lyst than complexes A because the acetyl group is smaller than the
ketal group, it is electron-withdrawing instead of electron-donat-
ing, making the metal center more acidic, and the Pd–O bond in
1 is weaker than in the A-type complex with L1 = 2,6-Me2C6H3-
NC.17 We selected DDMA for the test because the catalytic depro-
tection of some long chain aliphatic substrates has failed8 and,
particularly, the only reported catalytic hydrolysis of DDMA
reached only 17% yield.20
The deprotection of DDMA using 1 as the catalyst was also com-
pared to that of [PdCl2(NCMe)2], which is the only palladium com-
pound reported for this type of catalytic reactions,16 as well as to
Pd(AcO)2 or 10% of AcOH. The reactions were performed at room
temperature in wet acetonitrile with 5% mol amount of the cata-
lyst.21 Complex 1 was by far the best catalyst for the reaction
(Table 1). We have recently reported that 1 showed also to be a good
precatalyst for some room temperature Pd(II)/Pd(IV) Heck-type
reactions.19
Conclusions
In conclusion, we have developed a new efficient and mild
methodology for the deprotection of cyclic and acyclic acetals
In order to optimize the reaction conditions, we carried out
some experiments at room temperature varying the amount of 1

F. Juliá-Hernández et al. / Tetrahedron Letters 55 (2014) 1141–1144
1143
Table 3
Deprotection of selected acetals and ketalsa
Entry
Substrate
Product
Time (min)
Temp (°C)
Yieldb (%)
1
2
3
Me2C(OMe)2 (3)
MeCH(OMe)2 (5)
C9H19CH(OMe)2 (7)
Me2C(O) (4)
MeCHO (6)
C9H19CHO (8)
10
1
5
25
50
50
99
99
98
4
5
PhC(O)Me (10)
PhCHO (12)
7
50
50
98
98
12
6
120
50
95
7
8
THPO(CH2)2OH (15)
No reaction
960
10
25
25
—
99
9
10
50
50
96
98
10
5
a
Using 1% mol of 1 as the catalyst.
b
Yields determined by 1H NMR.
and ketals using [Pd(O1,C1,N1-L)(NCMe)]ClO4 as the catalyst. We
achieve quickly, in very good yields, and under mild conditions
the corresponding carbonyl compounds without side-reactions,
even in the presence of other protecting groups such as THP or
TBDMS and very acid sensitive alcohols. The hydrolysis without
dehydration of alcohol 20 and the high yield of the dehydration
of DDMA are unprecedented. Viewed as a whole, and having in
mind its hydrolytic properties, the catalyst offers unique proper-
ties: it is easily prepared in high yield from commercial products,
Pd(OAc)2, 2,6-diacetylpyridine and HClO4, fully recoverable, reus-
able, and stable in the solid state and in solution even in the pres-
ence of air and moisture.
References and notes
1. Although current IUPAC terminology classifies ketals as a subset of acetals, in
this work we consider essential to maintain the use of both terms.
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We thank Ministerio de Educación y Ciencia (Spain), FEDER
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13.12.067.

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23. Experimental procedure for the synthesis of compound 21: An NMR tube was
charged with compound 20 (24.80 mg, 0.135 mmols), water (100 L), catalyst 1
(0.53 mg, 0.0013 mmols) and acetonitrile-d3 (500 L). The tube was shaken until
complete dissolution. The sample was heated at 50 °C and NMR spectra was
recorded after 5 min. Compound 21 was detected in 98% conversion. 1H NMR
(300 MHz, acetonitrile-d3): 4.07 (s, 2H, –CH2OH), 2.78 (br, 2H, H2), 2.48–2.37
(m, 4H, H6+H5), 1.69 (s, 3H, Me). 13C{1H} NMR (75.45 MHz, acetonitrile-d3)
212.9 (C1), 131.5 (C4), 128.3 (C3) 61.5 (CH2OH), 46.0 (C2), 39.5 (C6), 28.0 (C5),
18.4 (Me). See Supplementary material for atom numbering of 21. HRMS calc
for C8H13O2 [M+H]+ m/z 141.0910, found m/z 141.0915.
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21. Large-scale hydrolysis of decanal dimethyl acetal catalyzed by complex 1: To
a solution of decanal dimethyl acetal (10 mL, 41.02 mmols) and water (2 mL) in
acetonitrile (50 mL), compound 1 was added (168.1 mg, 0.41 mmols). The
resulting orange solution was heated at 50 °C. After 20 min, the solution was
concentrated (6 mL) and diethyl ether was added (15 mL) to precipitate an
orange solid that was filtered off, washed with diethyl ether, and dried in
vacuo. Yield: 161.3 mg, 0.39 mmols (95%). The filtrate was washed with
saturated aqueous solution of MgSO4 and the solvent was removed in vacuo to
obtain decanal of 98% of purity. Yield: 6.20 g, 39.42 mmols, 96%.
22. Typical procedure for the catalytic deprotection reaction: An NMR tube was
charged with decanal dimethyl acetal (48.3 L, 0.198 mmols), water (100 L),
catalyst 1 (8.07 mg, 0.002 mmols), and acetonitrile-d3 (500 L). The tube was
shaken until complete dissolution. The sample was heated at 50 °C and NMR
spectra were recorded every 5 min. Conversion was calculated integrating the
27. Balme, G.; Gore, J. J. Org. Chem. 1983, 48, 3336–3338.