Remarkable effect of phosphine on the reactivity of O,P-acetal - Efficient substitution reaction of O,P-acetal

Article abstract of DOI:10.1039/c0cc00170h

The structure and electronic nature of the phosphine have a significant influence on not only the formation, but also the subsequent transformation of O,P-acetals. The O,P-acetals generated from tris(o-tolyl)phosphine [(o-tol) ₃P] underwent efficient substitution reactions with various nucleophiles.

Full text of DOI:10.1039/c0cc00170h

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Remarkable effect of phosphine on the reactivity of O,P-acetal—efficient
substitution reaction of O,P-acetalw
Hiromichi Fujioka,* Akihiro Goto, Kazuki Otake, Ozora Kubo, Kenzo Yahata,
Yoshinari Sawamaz and Tomohiro Maegawa
Received 1st March 2010, Accepted 7th April 2010
First published as an Advance Article on the web 7th May 2010
DOI: 10.1039/c0cc00170h
The structure and electronic nature of the phosphine have a
significant influence on not only the formation, but also the
subsequent transformation of O,P-acetals. The O,P-acetals
generated from tris(o-tolyl)phosphine [(o-tol)3P] underwent
efficient substitution reactions with various nucleophiles.
also developed the nucleophilic substitution of pyridinium
intermediates.2b,c,3 During the course of our study, we found
that the structure and electronic nature of the pyridine derivative
have a significant effect on the formation of the pyridinium salt
as well as the subsequent hydrolysis. The choice of a suitable
pyridine derivative is essential for the successful substitution.
Consequently, we focused on a phosphine as an alternative to
pyridine derivatives because the reactivity of the O,P-acetal is of
interest. Phosphines have advantages, such as a high nucleo-
philicity and lower basicity unlike pyridines.4 In addition, various
types of phosphines are available including chiral phosphines
which may be applicable for an asymmetric reaction.
The O,P-acetals are known as useful substrates for the Wittig
reaction leading to the corresponding vinyl ethers and as
precursors for C–C bond formation with electrophiles
(Scheme 1, eqn (1)). There have been a number of reports
about the generation of O,P-acetals with triphenylphosphine,
trialkyl phosphite, etc.1 However, the reactivity of O,P-acetal
for the substitution reaction with nucleophiles has not been
fully investigated and few examples have been reported.1m,o
Anders and co-workers have reported the substitution
reactions of the O,P-acetals from PPh3 using various nucleo-
philes,1o but the yields of the substituted products were
moderate, which seemed to be due to the lack of leaving
ability of PPh3. In addition, no report of the hydrolysis of
O,P-acetals to aldehydes has been published since H2O is a
weaker nucleophile than other nucleophiles.
In this communication, we describe that (o-tol)3P works as a
good nucleophile for the formation of the O,P-acetals from
O,O-acetals and as a good leaving group for the subsequent
nucleophilic substitution including the hydrolysis of the
O,P-acetal with various nucleophiles (Scheme 1, eqn (2)).
Initially, we investigated the effect of various phosphines on
the formation of O,P-acetals from n-dodecanal dimethyl
acetal (1a) and the following hydrolysis reaction as a substitu-
tion reaction with a weak nucleophile, i.e., H2O. The reaction
of 1a with PPh3 and TESOTf in CH2Cl2 at 0 1C afforded the
corresponding O,P-acetal within 1 h (checked by TLC analysis
and the O,P-acetal appeared as a highly polar compound).
However, its hydrolysis with H2O needed a long reaction time,
and the corresponding aldehyde 2a was obtained in only 47%
yield even after 96 h (Table 1, entry 1). We presumed that the
lower steric bulkiness of PPh3 caused the slow hydrolysis of
the O,P-acetal. We then examined a variety of aryl and
alkyl phosphines. The Me-substituted triphenylphosphines,
(o-, m- and p-tol)3P, afforded different results depending on
their substitution pattern. The O,P-acetals with these phos-
phines were formed in each case, but the subsequent hydrolysis
did not proceed at all in all the cases of (m-tol)3P and (p-tol)3P
after 24 h (entries 2 and 3). On the other hand, (o-tol)3P
immediately underwent the subsequent hydrolysis and the
reaction was completed within 1 h to give 2a in 78% yield
(entry 4). This result showed that an efficient nucleophilic
substitution of the O,P-acetal with H2O was significantly
affected by the structure of the phosphine. The reaction at
lower temperature (ꢀ5 1C) improved the yield of 2a (95%)
(entry 5) since the O,P-acetal from (o-tol)3P is rather unstable
at 0 1C. Although (o-MeOPh)3P was also expected to give a
similar result, the O,P-acetal was stable and no hydrolysis
occurred at all after 24 h (entry 6). (o-CF3Ph)3P could form the
O,P-acetal, however, the yield of 2a was low due to the rapid
decomposition of the O,P-acetal before the hydrolysis
Recently, we developed a novel method for deprotection of
various acetal type protective groups using TESOTf and
2,4,6-collidine or 2,20-bipyridyl followed by H2O treatment.2
The feature of this method is that the deprotection proceeded
via the formation of the pyridinium intermediate followed by
hydrolysis. As a further application of this method, we have
Scheme 1 Transformation of O,P-acetal.
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; Fax: +8166798229;
Tel: +8166798225
w Electronic supplementary information (ESI) available: Experimental
details and the charts of 1H, 13C, 19F and 31P NMR of the O,P-acetal
from (p-tol)3P. See DOI: 10.1039/c0cc00170h
z Present address: Laboratory of Organic Chemistry, Department of
Organic and Medicinal Chemistry, Gifu Pharmaceutical University,
1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan.
ꢁc
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Table 1 Effect of phosphinea
O,P-acetal to give the substituted product 4a (95%) (entry 3).
The successful substitution of the O,P-acetal from (o-tol)3P
with PhMgBr proceeded in 97% yield (entry 4). Similar
substitution reactions of the O,P-acetal from PPh3 were
reported by Anders.1o They used Et4NCN and MeMgI as
nucleophiles and obtained the substituted products in
moderate yields (Et4NCN (CN); 38% and MeMgI (Me);
33%, respectively).5 In our case, the O,P-acetal from (o-tol)3P
reacted with TMSCN as well as MeMgBr to afford the
corresponding substituted products in high yields (entries 3
and 5). Another aliphatic acetal (1b) was also quantitatively
converted to the O,P-acetal and the subsequent substitution
reaction with various nucleophiles proceeded in good to high
yields (entries 6–9). The aromatic acetal (1c) could afford the
O,P-acetal, and the corresponding aldehyde was obtained in
high yield by the successive hydrolysis (entry 10). However, the
reaction with PhSLi afforded the diphenylthioacetal as well
as the methyl phenylthioacetal (3c). The formation of
diphenylthioacetal should be promoted by an additional acetal
exchange of the methyl phenylthioacetal under acidic conditions.
To prevent the generation of diphenylthioacetal, we examined
the addition of bases. Consequently, iPr2EtN effectively
suppressed the generation of diphenylthioacetal and the methyl
phenylthioacetal (3c) was obtained in 86% yield (entry 11). Other
substitution reactions with nucleophiles provided the substituted
products in high yields (entries 12 and 13).
Entry
R
Time A/h
Time B/h
Yield (%)
47
—
1
2
3
4
5b
6
7
8
9
Ph
m-tol
p-tol
o-tol
1
1
96
24
24
1
c
c
0.5
0.5
0.5
3
0.5
5
—
78
95
o-tol
1
c
o-MeOPh
o-CF3Ph
2,4,6-Me3Ph
nBu
24
0.5
—
17
—
—
d
d
—
24
c
1.5
a
The reaction conditions: To a solution of 1a (1.0 equiv.) in CH2Cl2
(0.1 M), PR3 (3.0 equiv.) and TESOTf (2.0 equiv.) were added at 0 1C
and stirred for Time A. H2O was then added and stirred at rt for Time B.
b
c
At ꢀ5 1C. No hydrolysis proceeded although the O,P-acetal was
d
formed. No O,P-acetal was formed.
(entry 7). These results revealed that the reactivity of
O,P-acetal was affected by not only the steric factor, but
also the electronic factor. The bulkier trismesitylphosphine
[(2,4,6-Me3Ph)3P] did not form the corresponding O,P-acetal
(entry 8), and the alkyl phosphine, nBu3P formed the O,P-acetal,
but it was too stable to undergo the hydrolysis (entry 9). We then
chose (o-tol)3P as the suitable phosphine of the component of
O,P-acetal for further study of the substitution reactions.
To reveal the advantage of using a phosphine, we conducted
the separate reactions of n-dodecanal diisopropyl acetal (1d)
having a bulky acetal group with (o-tol)3P and 2,4,6-collidine
in the presence of TESOTf (Scheme 2). The O,P-acetal was
successfully formed using (o-tol)3P and the concomitant
hydrolysis with H2O afforded n-dodecanal in 72% yield. On
the other hand, no pyridinium salt was formed after 24 h when
2,4,6-collidine was used instead of (o-tol)3P. This result may
We next examined other substitution reactions of the
O,P-acetals generated from the O,O-acetals with a variety of
nucleophiles (Table 2). The reaction of the O,P-acetal from 1a
with PhSLi afforded the methyl phenylthioacetal (3a) in high
yield (97%) (entry 2), and TMSCN also reacted with the
Table 2 The substitution reaction of O,P-acetal with nucleophilesa
Entry
Substrate
Reagent
Product (Nu)
Time/h
Yield (%)
1b
2
H2O
PhSLi
TMSCN
PhMgBr
MeMgBr
2a (—)
1
1
4
1
1
95
97
95
97
90
3a (SPh)
4a (CN)
5a (Ph)
6a (Me)
3c
4
5
6b
7
H2O
PhSLi
TMSCN
PhMgBr
2b (—)
2
2
6
1
72
93
99
80
3b (SPh)
4b (CN)
5b (Ph)
8c
9
10b
11d
12c
13
H2O
PhSLi
TMSCN
PhMgBr
2c (—)
0.5
0.5
5
89
86
95
95
3c (SPh)
4c (CN)
5c (Ph)
0.5
a
The reaction conditions: To the solution of 1 (1.0 equiv.) in CH2Cl2 (0.1 M), (o-tol)3P (3.0 equiv.) and TESOTf (2.0 equiv.) were added at ꢀ5 1C
and stirred for 0.5 h. The nucleophile (1.2 equiv.) was then added and stirred at rt. 10 mL mmolꢀ1 of H2O was added. 3.0 equiv. of TMSCN was
d
used. 3.0 equiv. of Pr2EtN was added with the reagent.
b
c
i
ꢁc
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Notes and references
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(i) E. Nakamura, Tetrahedron Lett., 1981, 22, 663; (j) D. Burkhouse
Scheme 2 The reactivity of (o-tol)3P and 2,4,6-collidine toward
diisopropyl acetal 1d.
and H. Zimmer, Synthesis, 1984, 330; (k) W. Tuckmantel,
¨
indicate that (o-tol)3P has higher nucleophilicity than 2,4,6-
collidine and can be utilized in more situations.
K. Oshima and K. Utimoto, Tetrahedron Lett., 1986, 27, 5617;
(l) D. Y. Kim and D. Y. Oh, Synth. Commun., 1986, 16, 859;
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K. Hertlein, A. Stankowiak and E. Irmer, Synthesis, 1992, 577;
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Y. Kita, Adv. Synth. Catal., 2007, 349, 636; (d) H. Fujioka,
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4 We have observed undesirable side reactions caused by the basicity
of the pyridines such as b-elimination from the pyridinium inter-
mediate under certain conditions.
We also attempted to isolate and characterize the O,P-acetal
intermediate for the confirmation of the reaction pathway.
Although similar O,P-acetals from PPh3 have been synthe-
sized and characterized,1a,g,k,m–o the O,P-acetal from (o-tol)3P
was unstable and gradually decomposed during an NMR
measurement at room temperature. We then chose (p-tol)3P
as the stable O,P-acetal component for the characterization of
the intermediate in the reaction. The O,P-acetal from (p-tol)3P
was stable enough to measure the NMR spectra (1H, 13C, 19
F
and 31P NMR) and showed characteristic peaks of an
O,P-acetal, especially the distinctive split peaks were observed
that were caused by 13C–31P coupling in the 13C NMR.6
In conclusion, we demonstrated the reaction of O,P-acetals
from (o-tol)3P with various nucleophiles. This is the first
example of the efficient substitution of various nucleophiles
to O,P-acetals. The structure and electronic nature of phos-
phine significantly affected not only the formation, but also the
reactivity of O,P-acetal, and (o-tol)3P proved to be suitable for
the substitution reactions. The application of this method,
such as the asymmetric introduction of a nucleophile using
chiral phosphines, is underway.
This work was supported by a Grant-in-Aid for Scientific
Research (B) and for Scientific Research for Exploratory
Research from the Japan Society for the Promotion of Science
(JSPS) and Special Coordination Funds for Promoting Science
and Technology of the Ministry of Education, Culture,
Science and Technology, the Japanese Government.
5 We also examined the substitution reaction of the O,P-acetal
from 1a and PPh3 with PhMgBr and a poor result (9%) was
obtained.
6 These NMR spectra agreed with those of the similar O,P-acetal
with PPh3 as reported by others (ref. 1g, n and o). See also
Electronic Supplementary Information. We have also confirmed
the characteristic peaks of the O,P-acetal from (o-tol)3P.
ꢁc
This journal is The Royal Society of Chemistry 2010
3978 | Chem. Commun., 2010, 46, 3976–3978