A Mild PPTS-Catalyzed Acetalization of α,β-Unsaturated Aldehydes: The First Single-Step Protocol towards Benzylic Acetals

Article abstract of DOI:10.1055/s-0032-1318169

A mild and convenient procedure for the synthesis of highly sensitive benzylic acetals from α,β-unsaturated aldehydes and the corresponding benzylic alcohols is reported. The new method provides a single-step access to these compounds for the first time.

Full text of DOI:10.1055/s-0032-1318169

PRACTICAL SYNTHETIC PROCEDURES
▌729
pAracMticalislydnthPetiPc pTrocSed-uCresatalyzed Acetalization of α,β-Unsaturated Aldehydes:
The First Single-Step Protocol towards Benzylic Acetals
Synthesis of Benzylic Acetals
Dietrich Böse, Marvin Lübcke, Jörg Pietruszka*
Institut für Bioorganische Chemie der Heinrich-Heine-Universität Düsseldorf am Forschungszentrum Jülich,
Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany
Fax +49(2461)611669; E-mail: j.pietruszka@fz-juelich.de
PSP
Received: 20.11.2012; Accepted after revision: 16.01.2013
No245
Abstract: A mild and convenient procedure for the synthesis of highly sensitive benzylic acetals from α,β-unsaturated aldehydes and the
corresponding benzylic alcohols is reported. The new method provides a single-step access to these compounds for the first time. The ap-
plications of pyridinium p-toluenesulfonate (PPTS) as a very mild Brønsted acid catalyst and 5 Å molecular sieves (MS) as the dehydrating
agent were found to be essential. Furthermore, an application of the acetals in the synthesis of 1-functionalized dienes is exemplified.
Key words: acetals, zeolites, molecular sieves, dienes, aldehydes
R4
O
5 Å MS, PPTS (3 mol%)
R3
R2
O
R3
R2
toluene, r.t.
R3
R4
+
R1, R2, R3 = H, Me
4 = H, p-OMe, p-Br, o-NO2
O
R4
R1
OH
R
R1
2a–c
3a–e
1a–i up to 97%
Scheme 1 PPTS-catalyzed and 5 Å MS mediated synthesis of benzylic acetals from α,β-unsaturated aldehydes
As part of our ongoing research on natural product synthe- by conventional methods failed (Scheme 2). In our hands
sis we aimed to synthesize 1-benzyloxydienes 4 as shown the direct O-alkylation of the correspondent aldehyde 2a
in Scheme 2. A number of 1-oxygenated dienes have been remained unsuccessful, despite the use of different bases
studied as versatile building blocks in various syntheses as KH or NaHMDS and several benzylic electrophiles as
as, for example, in Diels–Alder reactions.1 However, the halides or triflates (Scheme 2).3
synthesis of O-alkyl-substituted dienes is not well docu-
mented in the literature, while the synthesis of O-methyl-
The same results were found when an indirect approach
was chosen. While the TMS protected diene 4a was read-
ily accessible, the transetherification using t-BuOK as a
ated, O-silylated and O-acetylated dienes is well
established.1d,2 Therefore, a general route to this important
base and different electrophiles failed to generate the de-
class of dienes was devised. However, all of our early at-
tempts to synthesize alkyl-(3-methyl)butadienyl ethers 4
sired 1-alkoxydiene 4 (Scheme 2).2 Another approach ex-
amined was based on a Horner–Wadsworth–Emmons
O
OTMS
RX,
R = Bn or PMB
X = Cl, OTf or I
2a
4a
OR
direct O-akylation
acetalization with
benzylic alcohols?
O
P
HWE olefination
RO
OMe
R = MOM, BOM
or PMB
OR
OR
OMe
4a,b
+
O
1a–i
Scheme 2 Attempts towards the synthesis of 1-oxygenated alkyl-substituted dienes 4
SYNTHESIS 2013, 45, 0729–0733
Advanced online publication: 08.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318169; Art ID: SS-2012-T0899-PSP
© Georg Thieme Verlag Stuttgart · New York

730
D. Böse et al.
PRACTICAL SYNTHETIC PROCEDURES
(HWE) olefination. However, despite the fact that a num- led to complete decomposition. In contrast, no decompo-
ber of different bases (NaHMDS, KHMDS, LDA, and sition or bis-PMB ether 5 formation was observed when
s-BuLi) as well as different solvent systems (DME, THF, the weak Brønsted acid pyridinium p-toluenesulfonate
n-Bu2O) were tested, the method could not be successful- (PPTS) was used. Hence the direct acetalization of alde-
ly applied (Scheme 2).4
hyde 2b was reinvestigated (Table 1, entries 7, 8). The
very mild acid PPTS was chosen as the catalyst. After sev-
eral attempts applying MgSO4, 3Å, or 4Å MS as drying
agents, the acetalization took place in the presence of 5 Å
MS (entry 8). The reaction proceeds in toluene at room
temperature as a slow, but very clean reaction with no for-
mation of ether by-product 5 or decomposition. After op-
timizing the equivalents of the benzylic alcohol 3b
(10 equiv were found to be optimal), the 3-methylbut-2-
enal bis(p-methoxybenzyl) acetal (1c) was isolated in
good yield (87%). It is noteworthy that the obtained ace-
tals are very prone to decomposition upon acidic treat-
ment and that therefore an important aspect of the
optimization was to find the right chromatographic condi-
tions. A vacuum distillation must be excluded because po-
lymerization was observed upon heating the acetal 1c.
Addition of Et3N to the mobile phase did not give satisfy-
ing results, but the use of a double-walled, water-cooled
column (ca. 5 °C) led to fast and clean isolation of the
product without considerable decomposition of acetals
1a–i. It was also found that while the NMR spectra of
acetals 1a–i could be recorded in CDCl3, for extended
periods they must be stored in a freezer to avoid decom-
position.
Results thus obtained led us to a different retrosynthetic
approach. Based on the findings from Duhamel’s group,
we decided to synthesize the dienes using an 1,4-elimina-
tion from the corresponding α,β-unsaturated acetals 1a–i
(Scheme 2).5 Hence the first goal was to access to the cor-
responding acetals. To the best of our knowledge there has
been only one published method to synthesize benzylic
acetals; a two-step method, which was developed by
Noyori et al., based on the application of TMS-protected
benzylic alcohols at –78 °C in CH2Cl2 with 10 mol%
TMSOTf as a catalyst.6 The described method was found
to not be applicable to solve our specific problem. Instead
of the desired acetals often only dibenzyl ether 5 forma-
tion and/or decomposition took place (Figure 1).
OMe
MeO
O
O
OMe
2
5
7
Figure 1 Regularly observed by-products 5 and 7
The same results were found when using different known
acetalization conditions including a variety of Brønsted or
Lewis acid catalysts [CSA, PTS, (NH4)2SO4, TPPMS, I2,
or In(OTf)3] (Table 1, entry 5).7 In all cases no improve-
ment could be achieved when different solvents and dry-
ing agents such as MgSO4 or MS 3Å/4Å were applied
(Table 1, entry 6). In fact, in most cases bis-PMB ether 5
was formed as the major product, indicating that the ap-
plied acids were too strong. A transacetalization approach
published by Nakabayashi et al. was also investigated.8
Thus, the aldehyde 2b was converted to its dimethoxy-
acetal 69 with trimethyl orthoformate in MeOH using
1 mol% In(OTf)3 as a catalyst in very high yields (99%).7d
Dimethoxyacetal 6 was used in a consecutive step for the
transacetalization with (NH4)2SO4 as a catalyst (Table 1,
entry 1). This time we were pleased to find that under
these conditions the desired product 1c was formed along
with the bis-PMB ether 5. Another by-product that could
be identified was a mixed methoxy-OPMB acetal 7, an in-
termediate of the reaction (Figure 1). Different experi-
ments were carried out to optimize the obtained result and
it was noticed that with increasing catalyst loading and
reaction time the amount of by-product 7 could be de-
creased. The yield of acetal 1c did not increase since the
formation of bis-PMB ether 5 was rising at the same time.
Another difficulty was the somehow complicated separa-
tion of acetal 1c and ether 5, which made several chro-
matographic steps necessary to obtain the clean product
1c in 36% yield. It could be shown that the use of stronger
acids such as CSA, PTSA, and Amberlyst 15 led to the
formation of bis-PMB ether 5, while the use of In(OTf)3
Table 1 Acetalization/Transacetalization Conditions
O
OMe
OMe
OPMB
OPMB
PMBOH (3b)
or
toluene
1c
2b
6
Entry SMa Catalyst
Additive Result
Yield
(%)
1b
2
3
4
5
6
7
8
6
(NH4)2SO4
H+c
–
mixture of 5, 7, and 1c 36
6
–
(PMB)2O
dec.
–
6
In(OTf)3
PPTS
H+c
–
–
6
–
no reaction
(PMB)2O
(PMB)2O
–
–
2b
2b
2b
2b
–
–
H+c
var.d
var.d
5 Å MS
–
PPTS
PPTS
–
clean reaction
87
a Starting material.
b Reaction was conducted at 120 °C.
c CSA, TSA, and Amberlyst 15 were independently tested.
d MgSO4, 3 Å MS, and 4 Å MS were tested as drying agents.
With the new and convenient protocol in our hand the
scope of the protocol was explored. A number of acetals
1a–i starting from the α,β-unsaturated aldehydes 2a–c and
Synthesis 2013, 45, 729–733
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Benzylic Acetals
731
Table 2 Results of the Direct Acetalization of α,β-Unsaturated Aldehydes Using Benzylic Alcohols
R4
O
R2
R3
R2
O
R3
5 Å MS (1.3 g/1 mmol aldehyde)
PPTS (3 mol%), toluene, r.t.
R3
+
R4
R4
O
R1
OH
R1
10 equiv
3a–e
2a–c
1a–i
Entry
2
R1
R2
3
R3
R4
Time (d)
Product
Yield (%)a
1
2a
2a
2b
2b
2b
2b
2b
2c
2c
H
H
H
H
H
H
H
H
3a
3b
3b
3a
3c
3d
3e
3a
3b
H
H
H
H
Me
H
H
H
H
H
1
1
1a
1b
1c
1d
1e
1f
45
33
87
97
71
28
82
79
76
2
H
p-OMe
p-OMe
H
3b
4
Me
Me
Me
Me
Me
H
1
2
5
H
14
27
27
9
6c
7c
8
o-NO2
p-Br
H
1g
1h
1i
Me
Me
9
H
p-OMe
8
a Isolated yield after column chromatography.
b Conducted on a 30 mmol scale.
c Only 5 equiv of the corresponding alcohol were used.
different benzylic alcohols 3a–e were synthesized ketones, for example, cyclohexenone, were found to be
(Scheme 1, Table 2).
not reactive enough and therefore no conversion was
achieved using the described method. However, surpris-
ingly, cinnamaldehyde was also not converted into its
bis(p-methoxybenzyl) acetal.
We found that high to very high yields (71–97%) could be
obtained using 3-methylbut-2-enal (2b) and different ben-
zylic alcohols 3a, 3b, and 3e (Table 2, entries 3–5 and 7).
Using aldehyde 2b and p-methoxybenzyl alcohol (3b) the With such results in hand our attention was turned to-
reaction was scaled up to 30 mmol without any loss of the wards the synthesis of the p-methoxy-substituted 1-oxy-
yield (entry 3). In the case of the sterically more hindered diene 4b. Applying the protocol published by Duhamel et
aldehyde 2c (R2 = Me) the reaction time needed to be in- al.,5a the desired diene 4b could be isolated in 76% yield
creased from 1 or 2 days to 8 or 9 days to gain good results (Scheme 3). The 1,4-elimination reaction was found to be
(76–79%) (entries 8 and 9). On the other hand, acetals de- highly reproducible even on a large (29 mmol) scale.
rived from sterically less hindered aldehyde 2a (entries 1 Even though diene 4b is highly volatile and very sensitive
and 2) were formed very quickly (full conversion was de- towards acidic conditions, purification could be achieved
termined), but also were very sensitive to decomposition by using a water-cooled column and an n-pentane–Et2O
so that even after several attempts the products could be (95:5) mixture for chromatography.
isolated only in moderate yields (33–45%). Utilization of
OPMB
OPMB
OPMB
chiral alcohol 3c led also to a decreased reaction rate and
the product could be isolated after 14 days in 71% yield
(entry 5). When only 5 equivalents of the corresponding
alcohol were used, the formation of the acetal became
very slow (entries 6 and 7). In the case of o-nitro- and
p-bromobenzyl alcohols (3d and 3e) a high conversion
could only be detected after a prolonged time period (en-
tries 6 and 7). The moderate yield of acetal 1f (entry 6) can
therefore not be explained by a low conversion and is
most probably due to its sensitivity to light. In all cases the
excess of benzylic alcohol 3a–e could be easily recovered
after column chromatography with yields between 74%
and 91% based on the unconverted alcohol. As expected,
t-BuLi, n-pentane
–10 °C, 2 h, 76%
1c
4b
Scheme 3 Synthesis of diene 4b
In conclusion, we have developed a mild and convenient
protocol for the synthesis of otherwise difficult to synthe-
size benzylic acetals 1a–i. The uses of the mild Brønsted
acid PPTS as the catalyst and 5 Å MS as a dehydrating
agent are the key features of the new method. It allows a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 729–733

732
D. Böse et al.
PRACTICAL SYNTHETIC PROCEDURES
with Et2O (400 mL), and washed with H2O (100 mL) and brine
(100 mL). The organic phase was dried (MgSO4) and the solvents
were carefully evaporated at 40 °C/300 mbar (product is volatile).
The crude product was purified using a water-cooled (ca. 5 °C)
chromatographic column (n-pentane–Et2O, 95:5) yielding diene 4b
as colorless crystals (4.55 g, 76%); mp 45–50 °C; Rf = 0.4 (n-pen-
tane–Et2O, 95:5).
simple access to these acetals even on a large scale. Fur-
thermore, the method, combined with the shown 1,4-elim-
ination, opens a new route to the class of alkyl-substituted
1-oxydienes 4, which are important intermediates in a
number of reactions such as Diels–Alder reactions.
FT-IR (film): 2920, 1635, 1515, 1331, 1250, 1175, 1033, 936, 877,
813 cm–1.
Unless otherwise specified the reactions were carried out by using
standard Schlenk techniques under an atmosphere of dry N2 with
magnetic stirring. Glassware was oven-dried at 120 °C overnight.
Solvents were dried and purified by conventional methods prior to
use. All the reagents were used as purchased from commercial sup-
pliers without further purification. Common solvents for chroma-
tography [petroleum ether (PE; 40–60 °C), EtOAc, n-pentane,
Et2O] were distilled prior to use. Flash column chromatography was
performed on silica gel 60, 0.040–0.063 mm (230–400 mesh) using
a water-cooled column. TLC was performed on pre-coated plastic
sheets with detection by UV (254 nm) and/or by staining with ceri-
um molybdenum solution. 1H and 13C NMR spectra were recorded
at r.t.; chemical shifts are given in ppm relative to internal standard
TMS (1H: δ [Si(CH3)4] = 0.00 ppm) or relative to the resonance of
the solvent (13C: δ (CDCl3) = 77.0 ppm). Coupling constants J are
given in Hz. Higher-order δ and J values are not corrected. 13C sig-
nals were assigned by means of C, H, COSY and HSQC or HMBC
spectroscopy. Melting points are uncorrected.
1H NMR (600 MHz, CDCl3): δ = 1.81 (s, 3 H, 3-CH3), 3.81 (s, 3 H,
6′-H), 4.70 (s, 1 H, 4-Ha), 4.74 (s, 2 H, 1′-H), 4.78 (s, 1 H, 4-Hb),
3
3
5.77 (d, J = 12.8 Hz, 1 H, 2-H), 6.60 (d, J = 12.8 Hz, 1 H, 1-H),
6.90 (d, 3J = 8.7 Hz, 2 H, 4′-H), 7.28 (d, 3J = 8.7 Hz, 2 H, 3′-H).
13C NMR (151 MHz, CDCl3): δ = 19.0 (C-3-CH3), 55.3 (C-6′), 71.5
(C-1′), 110.0 (C-2), 111.8 (C-4), 114.0 (C-4′), 128.9 (C-2′), 129.3
(C-3′), 139.7 (C-3), 147.9 (C-1), 159.5 (C-5′).
MS (EI, 70 eV): m/z (%) = 204.0 (10, [(M)+]), 121 (100, C8H9O+).
Acknowledgment
We gratefully acknowledge the Fonds der Chemischen Industrie
(scholarship to D.B.), the Deutsche Bundesstiftung Umwelt, the
Heinrich-Heine-Universität Düsseldorf, and the Forschungszen-
trum Jülich GmbH for their generous support of our projects. Fur-
thermore, we thank the analytical departments of the
Forschungszentrum Jülich as well as Dennis Weidener, Monika
Gehsing, Rainer Goldbaum, Birgit Henßen, Erik Kranz, Vera
Ophoven, Bea Paschold, Truc Pham, Dagmar Drobietz, and Saskia
Schuback for their ongoing support.
Acetals 1a–i; General Procedure
To a solution of aldehyde 2a–c (3.0 mmol) in toluene (10 mL) were
added molecular sieves (5 Å, 4 g), benzylic alcohol 3a–e
(38.6 mmol, 12.7 equiv), and PPTS (20 mg, 0.08 mmol,
0.03 equiv). The suspension was stirred at r.t. until no further con-
version could be observed as judged by 1H NMR analysis. After di-
luting with EtOAc (100 mL) and filtering through a pad of Celite,
the mixture was washed with sat. aq NaHCO3 (30 mL) and brine
(30 mL), and dried (MgSO4). The solvents were removed under re-
duced pressure and the crude product was subjected to column chro-
matography using a double-walled, water-cooled column (PE–
EtOAc) providing the acetals 1a–i as colorless oils.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2013, 45, 729–733
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Benzylic Acetals
733
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Synthesis 2013, 45, 729–733