Palladium-catalyzed synthesis of terminal acetals via highly selective anti-Markovnikov nucleophilic attack of pinacol on vinylarenes, allyl ethers, and 1,5-dienes

Article abstract of DOI:10.1039/c2cc16561a

A palladium-catalyzed reaction of vinylarenes, allyl ethers, and 1,5-dienes with pinacol proceeded via a selective anti-Markovnikov nucleophilic attack to afford corresponding terminal acetals as major products. The bulkiness of pinacol was found to be critical in controlling the regioselectivity. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc16561a

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COMMUNICATION
Palladium-catalyzed synthesis of terminal acetals via highly selective
anti-Markovnikov nucleophilic attack of pinacol on vinylarenes, allyl
ethers, and 1,5-dienesw
Mayumi Yamamoto, Sonoe Nakaoka, Yasuyuki Ura* and Yasutaka Kataoka
Received 21st October 2011, Accepted 23rd November 2011
DOI: 10.1039/c2cc16561a
A palladium-catalyzed reaction of vinylarenes, allyl ethers, and
1,5-dienes with pinacol proceeded via a selective anti-Markovnikov
nucleophilic attack to afford corresponding terminal acetals as
major products. The bulkiness of pinacol was found to be critical in
controlling the regioselectivity.
critically influenced the regioselectivity to give terminal acetals.
Herein, we report the palladium-catalyzed reliable synthesis of
terminal acetals from vinylarenes, allyl aryl ethers, and 1,5-dienes,
controlling the selectivity in an anti-Markovnikov manner by
using a bulky tertiary diol, pinacol (eqn (1)).
The achievement of anti-Markovnikov regioselectivity in
Wacker oxidation is challenging, but can enable an attractive,
direct transformation from terminal alkenes to aldehydes.1,2
Although the reaction generally proceeds in a Markovnikov
manner to afford methyl ketones, alkenes bearing a heteroatom
directing group,1–3 as well as vinylarenes,4 often afford aldehydes
preferentially. Even with these substrates, however, the regio-
selectivity appears to still be susceptible to various reaction
conditions.1,2,4 The situation is similar in the palladium-catalyzed
acetalization of terminal alkenes with alcohols. Internal acetals are
usually major products,5 whereas electron-deficient a,b-unsaturated
carbonyl compounds5–10 and alkenes with a directing group7,11,12
afford terminal acetals. Alkenes with two hydroxy groups
(3-methylidene-1,5-diols) also give terminal acetals via intra-
molecular acetalization.13 In the case of vinylarenes, the
regioselectivity is known to be mainly affected by the ligands
on palladium. A PdCl2/CuCl/O2/dimethoxyethane (DME)
system gives terminal acetals,8–10 whereas a PdCl2(sparteine)/
CuCl2/O2/MeOH system affords internal acetals.14
ð1Þ
With styrene as a terminal alkene and several 1,2-diols
having different steric bulkiness as nucleophiles, the regio-
selectivity of the nucleophilic attack was first examined in the
presence of PdCl2(MeCN)2 (10 mol%) and p-benzoquinone
(2.0 eq) in N,N-dimethylformamide (DMF, Table 1). When
ethylene glycol, 2-methyl-1,2-propanediol, and 2,3-butanediol
were employed, the formation ratios of the terminal acetals 2a–c
and the internal acetals 3a–c were close to 1 : 1 (entries 1–3),
Table 1 Steric effect of 1,2-diols on the regioselectivity in palladium-
catalyzed acetalization of styrenea
Another potential factor is a steric demand of nucleophiles.
In the reported Wacker oxidations of terminal alkenes, the use
of t-BuOH as a solvent produced aldehydes selectively,
although the yields were generally low.15–17 In these reactions,
t-BuOH would operate as a nucleophile to afford linear
alkenyl t-butyl ethers and/or terminal acetals via alkoxypalla-
dation, and subsequent hydrolysis gives aldehydes; however,
the ethers and acetals appear to be elusive because of the facile
hydrolysis by a trace of water.1,16–18 In this context, during the
course of our investigation on the reaction of terminal alkenes
with diols, we found that the steric demand of the diols
Total yield
Product of 2 and 3b (%) Ratio of 2 : 3c
Entry Diol
1
2
2a, 3a
2b, 3b
48
66
52 : 48
55 : 45
3
2c, 3c
2d, 3d
50
56 : 44
4
72 (60)d
495 : 5
Department of Chemistry, Faculty of Science, Nara Women’s
University, Kitauoyanishi-machi, Nara 630-8506, Japan.
E-mail: ura@cc.nara-wu.ac.jp; Fax: +81 742 20 3979;
Tel: +81 742 20 3403
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization of products and NMR spectra for new
compounds. See DOI: 10.1039/c2cc16561a
a
Reaction conditions: 1a (0.6 mmol), diol (6.0 mmol), PdCl2(MeCN)2
(0.06 mmol), p-benzoquinone (1.2 mmol), and DMF (0.6 mL).
b
c
d
NMR yield. Determined by 1H NMR. GC yield. Isolated yield
is shown in parentheses.
c
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Chem. Commun., 2012, 48, 1165–1167 1165

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along with the formation of a certain amount of acetophenone
derived from styrene and a trace of contaminated water. It is
noteworthy that the use of pinacol critically influenced the
regioselectivity, giving 2d in preference to 3d in the ratio of
495 : 5 (entry 4). These results indicate that the steric bulkiness
of the diol controls the regioselectivity to the terminal carbon in
the nucleophilic attack of the diol on the coordinated styrene.
The reaction conditions using pinacol were applied to
various vinylarenes (Table 2). Styrenes with an electron-with-
drawing substituent such as chloro, nitro, or trifluoromethyl
groups gave the corresponding terminal acetals 2e–h in good
yield (entries 1–4). On the other hand, styrenes with an
electron-donating substituent such as methyl or methoxy
groups were also applicable but the yields of 2i–m were
relatively low (entries 5–9). The existence of the substituent
at the ortho position did not disturb the reaction in terms of
steric hindrance (entries 2, 6 and 9). 2-Vinylnaphthalene was
suitable as a substrate as well, but a small amount (5%) of
2-naphthylcarboxaldehyde acetal was also obtained (entry 10).
The reaction of 2- and 4-vinylpyridines did not proceed. As an
a-substituted vinylarene, a-methylstyrene was tested; however,
no terminal acetal was observed and a large portion of the
substrate remained unreacted.
Allyl aryl ethers were then examined as substrates (Table 3).
These reactions proceeded in shorter reaction time than those
with vinylarenes. When allyl phenyl ether (4a) was employed,
the desired terminal acetal 5a was obtained along with internal
acetal 6a in 75% total yield in the ratio of 88 : 12 (entry 1). For
comparison, the reaction of 4a with ethylene glycol was also
carried out under the same reaction conditions, and the
formation ratio of terminal to internal acetals was 49 : 51
(88% total yield), once again clearly demonstrating the steric
effect of pinacol. In the reaction shown in entry 1, however,
not only the acetals 5a and 6a but also 3-methylbenzofuran (7)
was formed in 14% yield, which was derived from only 4a. As
a control experiment, we tried the same reaction in the absence
of pinacol, and 7 was obtained in 51% yield. Such a Fujiwara–
Moritani/oxidative Heck cyclization of allyl aryl ethers with
electron-donating groups to afford 3-methylbenzofurans was
previously reported by Stoltz et al.19,20 In order to suppress the
side reaction, allyl aryl ethers having an electron-withdrawing
substituent (entry 2) or methyl groups at ortho positions (entry 3)
were employed. In these cases, the formation of 3-methyl-
benzofurans was suppressed and terminal acetals 5b and 5c
were obtained in good to high yield, along with small amounts
Table 2 Palladium-catalyzed synthesis of terminal acetals from vinyl-
arenes and pinacola
Total yield
of 2 and 3b (%)
Entry
1
Product
2e
73 (69)
2
3
4
2f
79 (75)
76 (72)
83 (58)
2g
2h
Table 3 Palladium-catalyzed synthesis of terminal acetals from allyl
aryl ethers and pinacola
5
2i
64 (59)
6
7
2j
69 (58)
39 (33)
Total yield of 5
and 6b (%)
Ratio of
5 : 6c
2k
Entry Product
1
5a 75 (63)d
88 : 12
8
9
2l
71 (49)
2
5b 84 (78)
5c 68 (67)
94 : 6
2m
2n
61 (51)
50 (46)c
3
89 : 11
10
a
Reaction conditions:
1
(0.6 mmol), pinacol (6.0 mmol),
PdCl2(MeCN)2 (0.06 mmol), p-benzoquinone (1.2 mmol), and DMF
a
Reaction conditions: 4 (1.2 mmol), pinacol (12.0 mmol), PdCl2(MeCN)2
b
(0.12 mmol), p-benzoquinone (2.4 mmol), and DMF (1.2 mL). GC
b
(0.6 mL). GC yields. Isolated yields are shown in parentheses.
yields. Isolated yields are shown in parentheses. c Determined by GC.
d
c
A small amount (5%) of 2-naphthylcarboxaldehyde acetal was
obtained along with 2n.
3-Methylbenzofuran was obtained in 14% as a by-product.
c
1166 Chem. Commun., 2012, 48, 1165–1167
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of internal acetals 6b and 6c, respectively. Allyl n-hexyl ether
was also examined as an alkyl analog under similar reaction
conditions as listed in Table 3. While most of the substrate was
consumed, the yield of the corresponding terminal acetal
appeared to be low, ca. 10–20%.
the formation of Pd(0), which is oxidized by p-benzoquinone
to reproduce the Pd(II) species. The formation of the p-benzyl
intermediate is considered a significant factor in controlling
the regioselectivity in an anti-Markovnikov manner in the
previously reported palladium-catalyzed Wacker oxidation,4
acetalization14 and oxidative amination23 of vinylarenes. On the
other hand, in the reactions of allyl aryl ethers and 1,5-dienes,
the appropriately located oxygen atom or alkene moiety would
operate as a directing group to assist the nucleophilic attack of
pinacol on the terminal carbon.1
The present procedure was also applied to 1,5-hexadiene (8)
because 1,5-diene derivatives are known to afford aldehydes
under Wacker oxidation conditions.21,22 Although the yield
was relatively low, the corresponding terminal acetal 9 along
with cyclized internal acetal 10 were obtained in the ratio of
87 : 13 (eqn (2)). Prolonged reaction time decreased the yield
of 9. The reaction of 8 with ethylene glycol resulted in the ratio
of 68 : 32 for terminal/cyclized internal acetals. In the reaction
of 4-vinylcyclohexene (11), terminal acetal 12 was afforded in
44% yield exclusively (eqn (3)). Other a,o-dienes such as diethyl
diallylmalonate and 1,7-octadiene resulted in no formation of
terminal acetals.
In summary, a reliable, palladium-catalyzed method for
synthesizing terminal acetals from vinylarenes, allyl aryl
ethers, and 1,5-dienes has been established. In the present
reaction, the nature of the substrates and the steric bulkiness of
the pinacol synergistically controlled the regioselectivity in an
anti-Markovnikov manner. Further investigations for oxidative
heterofunctionalization reactions of terminal alkenes based on
the present strategy using bulky nucleophiles are in progress.
This work was supported by a Grant-in-Aid for Young
Scientists (B) (23750112) from the Japan Society for the
Promotion of Science (JSPS). Y.U. acknowledges financial
support from The Society of Synthetic Organic Chemistry,
Japan (Asahi Kasei Pharma Award).
ð2Þ
Notes and references
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ð3Þ
A proposed reaction mechanism for the present acetalization
using styrene is shown in Scheme 1. Styrene first coordinates to the
Pd(II) species in an Z4 manner (13), and then, the first nucleophilic
attack of pinacol on the coordinated styrene occurs in anti-
Markovnikov regioselectivity to form the p-benzyl intermediate
14. At this stage, the nucleophilic attack on the internal carbon
would be unfavorable because the steric repulsion between the
phenyl group and the pinacol is greater. This repulsion is especially
effective when pinacol is used compared with other less bulky
diols, as listed in Table 1. The formed 14 is in equilibrium with
s-benzyl intermediate 15, from which b-hydrogen elimination
occurs to give 16. Either palladium-assisted or acid-promoted
cyclization from 16 would proceed to afford 2d along with
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1
t-butyl ethers were observed by H NMR spectroscopy and GC-MS,
albeit in low yield, as a mixture with an aldehyde. See: G. Dong, P. Teo,
Z. K. Wickens and R. H. Grubbs, Science, 2011, 333, 1609–1612.
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Scheme 1 The proposed reaction mechanism.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1165–1167 1167