An unusual reaction of α-alkoxyphosphonium salts with Grignard reagents under an O2 atmosphere

Article abstract of DOI:10.1039/c1cc13919c

An unusual and novel reaction of α-alkoxyphosphonium salts, generated from O,O-acetals and Ph₃P, with Grignard reagents under an O ₂ atmosphere afforded alcohols in moderate to high yields. It was clarified by isotopic labelling experiments that the reaction proceeded via a novel radical pathway.

Full text of DOI:10.1039/c1cc13919c

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COMMUNICATION
An unusual reaction of a-alkoxyphosphonium salts with Grignard
reagents under an O2 atmospherew
Hiromichi Fujioka,* Akihiro Goto, Kazuki Otake, Ozora Kubo, Yoshinari Sawamaz and
Tomohiro Maegawa
Received 1st July 2011, Accepted 19th July 2011
DOI: 10.1039/c1cc13919c
An unusual and novel reaction of a-alkoxyphosphonium salts,
generated from O,O-acetals and Ph3P, with Grignard reagents
under an O2 atmosphere afforded alcohols in moderate to high
yields. It was clarified by isotopic labelling experiments that the
reaction proceeded via a novel radical pathway.
Scheme 1 An unusual reaction of the a-methoxyphosphonium salt
with PhMgBr.
The a-alkoxyphosphonium salts are good precursors of vinyl
ethers for Wittig reactions, of which there are numerous
For the purpose of revealing the scope and limitation of this
applications in the total synthesis of natural products.1
unusual reaction, we chose the a-methoxyphosphonium salt
Despite the utility of a-alkoxyphosphonium salts in organic
synthesis, a-alkoxyphosphonium salts are seldom used for
other reactions. Only a few groups have reported the nucleo-
philic substitution reaction of a-alkoxyphosphonium salts,2
but this reaction has not been fully investigated.
2b as the starting material, which was generated in situ from
benzaldehyde dimethyl acetal 1b because the a-alkoxyphos-
phonium salts are usually highly polar compounds and not
easily handled. The a-alkoxyphosphonium salt 2b formed
from 1b and Ph3P in situ was treated with 5 equivalents of
3a under a N2 atmosphere. The major product was altered by
the reaction temperature. That is, the benzhydrol methyl ether
5b was obtained as a major product when the reaction was
conducted at room temperature, but benzhydrol 4b was the
major product at 0 1C (Scheme 2).
It was curious that although we repeatedly performed the
same reaction at 0 1C, 4b was obtained in different yields in
each run (30–65%). We could not initially understand why the
reaction afforded such varying results. Since phenol (PhOH)
and triphenylphosphine oxide (Ph3PQO) were obtained as
by-products, we then presumed that the N2 gas contained a
small amount of O2 gas,6 which promoted this reaction as well
as oxidized PhMgBr7 and Ph3P to form these by-products. The
varying results must be due to an inconsistent ratio of O2 gas
in the N2 gas.
Recently, as a part of our studies about the reactivities
of cationic intermediates,3 we have developed the efficient
substitution reactions of the a-alkoxyphosphonium salts with
various nucleophiles.4 The a-alkoxyphosphonium salts prepared
from O,O-acetals and tris(o-tolyl)phosphine [(o-tol)3P] are reactive
to nucleophiles such as H2O, cyanides, thiols, and Grignard
reagents, via the elimination of (o-tol)3P. The progress of these
substitution reactions depends on the type of phosphine. For
example, when we used triphenylphosphine (Ph3P) as the phos-
phine source, the substitution reaction of the a-methoxy-
phosphonium salt 2a, which was obtained in 67% yield by the
reaction of dimethyl acetal 1a and Ph3P, with H2O did not
effectively proceed.5 However, when PhMgBr (3a) was used as
a nucleophile for the substitution reaction of 2a, we encountered
an unexpected phenomenon (Scheme 1). The reaction of 2a
with an excess amount of 3a afforded the alcohol 4a (43%) as
the major product along with the substituted product 5a (17%).
To the best of our knowledge, such a reaction has never been
reported. We now report a novel reaction of a-alkoxyphos-
phonium salts with Grignard reagents and its mechanistic study.
Based on this hypothesis, we carried out the reaction at 0 1C
under an O2 atmosphere. Consequently, 4b was obtained in
a reproducible yield (entry 1, Table 1), and no reaction
proceeded under an argon atmosphere (entry 2). Therefore,
the existence of O2 is essential for the reaction. Dry air was
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: +8168798229;
Tel: +8168798225
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13919c
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
Scheme 2 Preliminary experiments with the aromatic a-methoxyphos-
phonium salt.
c
9894 Chem. Commun., 2011, 47, 9894–9896
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Table 1 Optimization of the reaction conditionsa
Table 3 The reaction of various a-alkoxyphosphonium salts with
PhMgBr under an O2 atmospherea
Entry
Equiv. of 3a
Conditions
Yield (%)
Entry Substrate
Product Temp./1C Yield (%)
1
2
3
4
5
6
5
5
5
5
1
3
O2/0 1C
Ar/0 1C
Dry air/0 1C
Dry air/ꢀ40 1C
Dry air/0 1C
Dry air/0 1C
40
NDb
81
57
Trace
49
1
R = Me (1c)
4c
4d
4h
4i
0
ꢀ40
0
ꢀ40
81
83
78
63
a
Reaction conditions: to a solution of 1b (1 equiv.) in CH2Cl2
(0.2 mol Lꢀ1) under O2, Ar or dry air, Ph3P (3 equiv.) and TESOTf
(2 equiv.) were added at 0 1C, and the mixture was stirred for 0.5 h.
2
R = OMe (1d)
R = Br (1e)
R = CF3 (1f)
3
4b,c
b
Then, 3a was added, and the solution was stirred for 2–4 h. Not
detected.
5
4j
ꢀ40
66
suitable for this reaction as the O2 source (entry 3). When the
reaction was performed at a lower temperature (ꢀ40 1C), the
reaction time was prolonged and no improvement in the yield
was observed (entry 4). The use of 1 or 3 equivalents of 3a
decreased the yields of 4b (entries 5 and 6).
6
4b
4b
0
83
60
7c
ꢀ40
We then examined the reaction with various Grignard reagents
under the optimal conditions (Table 2). Various aromatic
Grignard reagents with electron-donating or electron-
withdrawing groups 3a–d reacted with the a-methoxyphos-
phonium salt 2b under dry air at 0 1C to afford the benzhydrol
derivatives 4b–e (entries 1–4). On the other hand, the alkenyl
and alkyl Grignard reagents 3e and 3f were not effective in this
reaction (entries 5 and 6).
8
4a
4k
4l
0
0
0
56
55
70
9
10
Various a-alkoxyphosphonium salts generated from the
O,O-acetals underwent this reaction (Table 3). Aromatic and
heteroaromatic a-alkoxyphosphonium salts derived from the
O,O-acetals 1c–g were converted into the corresponding diaryl-
methanols 4c,d,h–j in good yields (entries 1–5). Cyclic acetal 1h
and diisopropyl acetal 1i were also transformed into benzhydrol
11c
4m
4n
ꢀ40
56
63
12
0
a
Reaction conditions: to a solution of 1 (1 equiv.) in CH2Cl2
(0.2 mol Lꢀ1) under dry air, Ph3P (3 equiv.) and TESOTf (2 equiv.)
were added at 0 1C, and the mixture was stirred for 0.5 h. Then, 3a
(5 equiv.) was added, and the solution was stirred for 2–4 h at 0 1C.
Table 2 Various Grignard reagentsa
b
The reaction of 1f with Ph3P and TESOTf was performed at rt.
TMSOTf was used instead of TESOTf.
c
4b in good yields (entries 6 and 7). In addition, aliphatic
a-alkoxyphosphonium salts derived from the O,O-acetals
1a,j–m also reacted with 3a to give the corresponding alcohols
4a,k–n in moderate to good yields (entries 8–12). In some cases,
the desired reaction proceeded at ꢀ40 1C, while the reaction
competed with nucleophilic substitution at 0 1C.
The mechanism of this unusual reaction was then studied.
We first synthesized the 18O-labelled dimethyl acetal 7 from
n-decanal and CH318OH and carried out the reaction using
this labelled acetal. However the 18O atom was not included in
the product 9 (Scheme 3).8
Entry
RMgX
Product
Yield (%)
1
2
3
4
R0 = H (3a)
R0 = Me (3b)
R0 = OMe (3c)
R0 = F (3d)
4b
4c
4d
4e
81
86
62
57
5
4f
Trace
NDb
6
EtMgBr (3f)
4g
a
Taking into consideration that O2 promoted this reaction,
the reaction using 18O2 gas was then carried out (Scheme 4).
It was found that the isotopic oxygen atom was introduced
into the product 10 verifying that the O atom was derived from
the O2 gas.
Reaction conditions: to a solution of 1b (1 equiv.) in CH2Cl2
(0.2 mol Lꢀ1) under dry air, Ph3P (3 equiv.) and TESOTf (2 equiv.)
were added at 0 1C, and the mixture was stirred for 0.5 h. Then,
3 (5 equiv.) was added, and the solution was stirred for 2–4 h at 0 1C.
b
Not detected.
c
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oxide was generated in the reaction, suggesting that the
a-alkoxyphosphonium salts react with O2-derived radical
species, resulting in the oxidative elimination of phosphine.
In conclusion, we have investigated an unusual and novel
reaction of a-alkoxyphosphonium salts with aryl Grignard
reagents in the presence of O2. Various a-alkoxyphosphonium
salts and aryl Grignard reagents underwent this reaction to
produce the corresponding alcohols. Furthermore, this reaction
is suggested to proceed via a novel radical pathway. These results
open a new aspect of the reactivity of a-alkoxyphosphonium salts.
This study was financially supported by the Hoansha
Foundation, the Uehara Memorial Foundation, Takeda
Science Foundation, and Grant-in-Aid for scientific research
from the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
Scheme 3 Isotopic labelling experiment using the 18O-labelled dimethyl
acetal 7.
Notes and references
Scheme 4 Isotopic labelling experiment using an 18O2 gas.
1 For recent applications in total synthesis, see: (a) W. T. Lambert
and S. D. Burke, Org. Lett., 2003, 5, 515; (b) G. A. Molander,
K. M. George and L. G. Monovich, J. Org. Chem., 2003, 68, 9533;
(c) E. Queron and R. Lett, Tetrahedron Lett., 2004, 45, 4527;
´
(d) W. T. Lambert, G. H. Hanson, F. Benayoud and S. D. Burke,
J. Org. Chem., 2005, 70, 9382; (e) M. E. Jung, J. Cordova and
M. Murakami, Org. Lett., 2009, 11, 3882; (f) M. T. Crimmins,
M. C. Mans and A. D. Rodrıguez, Org. Lett., 2010, 12, 5028.
´
2 (a) S. Kim and Y. C. Kim, Synlett, 1990, 115; (b) E. Anders,
K. Hertlein, A. Stankowiak and E. Irmer, Synthesis, 1992, 577.
3 (a) H. Fujioka, T. Okitsu, Y. Sawama, N. Murata, R. Li and
Y. Kita, J. Am. Chem. Soc., 2006, 128, 5930; (b) H. Fujioka,
T. Okitsu, Y. Sawama, T. Ohnaka and Y. Kita, Synlett, 2006,
3077; (c) H. Fujioka, T. Okitsu, T. Ohnaka, Y. Sawama, O. Kubo,
K. Okamoto and Y. Kita, Adv. Synth. Catal., 2007, 349, 636;
(d) H. Fujioka, T. Ohnaka, T. Okitsu, O. Kubo, K. Okamoto,
Y. Sawama and Y. Kita, Heterocycles, 2007, 72, 529;
(e) H. Fujioka, T. Okitsu, T. Ohnaka, R. Li, O. Kubo,
K. Okamoto, Y. Sawama and Y. Kita, J. Org. Chem., 2007,
72, 7898; (f) H. Fujioka, O. Kubo, K. Senami, K. Okamoto,
T. Okitsu and Y. Kita, Heterocycles, 2009, 79, 1113.
Scheme 5 Plausible reaction mechanism.
4 H. Fujioka, A. Goto, K. Otake, O. Kubo, K. Yahata, Y. Sawama
and T. Maegawa, Chem. Commun., 2010, 46, 3976.
5 The a-methoxyphosphonium salt 2a was less reactive to H2O, so 2a
was able to be easily isolated. See ESIw for details.
Based on these results, a novel radical pathway was theorized
as depicted in Scheme 5.
A part of the aryl Grignard reagent reacts with O2, then the
superoxide radical anion A and the aryl radical are generated.9
The radical anion species A has a high nucleophilicity,10 and
attacks the cationic phosphorus atom of the a-methoxy-
phosphonium salt 2 leading to the oxidative elimination of
the phosphine-like oxaphosphetanes during the Wittig reaction.
As soon as the aldehyde 6 is produced, the remaining Grignard
reagent reacts with 6 to afford the alcohol 4. Since the aliphatic
Grignard reagents are more reactive to O2 than aromatic
ones,7c all of the Grignard reagents seemed to be consumed
before reacting with the aldehyde resulting in a trace amount
of alcohols 4 (entries 5 and 6, Table 2).
6 We used N2 gas from a nitrogen tank via the N2 gas line. A small
amount of O2 in the air may be present in the N2 gas line.
7 (a) C. W. Porter and C. Steel, J. Am. Chem. Soc., 1920, 42, 2650;
(b) H. Gilman and A. Wood, J. Am. Chem. Soc., 1926, 48, 806;
(c) M. T. Goebel and C. S. Marvel, J. Am. Chem. Soc., 1933,
55, 1693; (d) M. S. Kharasch and W. B. Reynolds, J. Am. Chem.
Soc., 1943, 65, 501; (e) C. Walling and S. A. Buckler, J. Am. Chem.
Soc., 1955, 77, 6032; (f) J. F. Garst, C. D. Smith and A. C. Farrar,
J. Am. Chem. Soc., 1972, 94, 7707. For a review, see:
(g) G. Sosnovsky and J. H. Brown, Chem. Rev., 1966, 66, 529.
8 See ESIw for details.
9 The reaction of O2 and Grignard reagents is known to produce
radical anion species. See: C. Walling and A. Cioffari, J. Am.
Chem. Soc., 1970, 92, 6609. The aryl radical species coupled
to itself to afford a biaryl compound which wasdetected as a
by-product.
10 (a) E. J. Corey, K. C. Nicolaou, M. Shibasaki, Y. Machida and
C. S. Shiner, Tetrahedron Lett., 1975, 16, 3183; (b) D. T. Sawyer
and J. S. Valentine, Acc. Chem. Res., 1981, 14, 393, and references
cited therein.
This mechanism was supported by some experiments. First,
the addition of TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl)
interrupted the reaction, which indicated that the reaction
proceeded via a radical pathway. Second, triphenylphosphine
c
9896 Chem. Commun., 2011, 47, 9894–9896
This journal is The Royal Society of Chemistry 2011