1278
H. Okada et al. / Tetrahedron Letters 50 (2009) 1276–1278
methoxyoxirane i that is available from oxonium intermediate g
LiX
O
as a possible intermediate.18
PPh3
OMe
R2CHO
n-BuLi
R1
H
Ph3P
LiX
R1
Ph3P
X
In summary, we revealed that additions of some (1-meth-
oxyalkyl)triphenylphosphonium ylides to aldehydes at ꢀ78 °C fol-
lowed by quenching the reaction mixture with aqueous NH4Cl at
R1
– n-BuH
R2
OMe
OMe
b
a
c
ꢀ78 °C afforded
a
-hydroxyketones.19 This is the first example of
phosphonium ylides acting as an acyl anion equivalent. The irreg-
ular Wittig reactions described here are an alternative to 2-lithio-
1,3-dithiane reactions20 with aldehydes.
H
– LiX
OH R1
OH
O
PPh3
OMe
PPh3
– Ph3P
H
H
R2
R1
R1
OMe
OMe
R2
R2
H
Supplementary data
g
d
f
Supplementary data associated with this article can be found, in
– Ph3P
– H
– H
H
H2O
– Ph3PO
R2
– H
– MeOH
R1
OMe
OH
O
H
R2
R1
References and notes
R1
R2
H2O
– MeOH
OMe
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Rev. 1989, 89, 863–927; (b) Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21,
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Ed.; Wiley-VCH: Weinheim, Germany, 2004. Chapter 1.
O
e
i
h
Scheme 3. Plausible mechanism of the irregular Wittig reaction.
2. Coulsen, D. R. Tetrahedron Lett. 1964, 5, 3323–3326.
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Chem. 2007, 2387–2400.
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Fischer, E. O. Chem. Ber. 1973, 106, 1062–1068; See also: (c) Hansen, P.-E. J.
Chem. Soc., Perkin 1 1980, 1627–1634.
The application of this addition reaction to aliphatic aldehyde
912 was also investigated (Table 4). To the ylide, derived from 5a
or 5b, was added aldehyde 9 at ꢀ78 °C, and the mixture was
quenched with saturated aqueous NH4Cl at ꢀ78 °C, affording only
the corresponding a-hydroxyketone, 8c or 8d, in good yield (entry
1 or 3). On the other hand, the normal Wittig reaction predomi-
nantly proceeded (63% yield of 7c, entry 2) or a 1:1 mixture of
7d13 and 8d was obtained (entry 4) when the reaction temperature
was raised to rt.
6. (a) Lambert, W. T.; Burke, S. D. Org. Lett. 2003, 5, 515–518; (b) Lambert, W. T.;
Hanson, G. H.; Benayoud, F.; Burke, S. D. J. Org. Chem. 2005, 70, 9382–9398.
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Groutas, W. C.; Stanga, M. A.; Brubaker, M. J.; Huang, T. L.; Moi, M. K.; Carroll, R.
T. J. Med. Chem. 1985, 28, 1106–1109.
In order to obtain some insight on the mechanism of this irreg-
ular Wittig reaction, we examined the effect of intramolecular lith-
ium chelation between the alkoxide and methoxy groups in the
betaine LiX complex (c in Scheme 3, vide infra). This chelation
might prevent the formation of the oxaphosphetane at low tem-
perature. Along these lines, the trapping reagent (12-crown-4
ether, HMPA, or TMEDA) was added to the ylide solution of 5a at
ꢀ40 °C before addition of benzaldehyde (6) at ꢀ78 °C. The result
remained unchanged compared to entry 3 in Table 2.
8. (a) Katritzky, A. R.; Lang, H.; Wang, Z.; Lie, Z. J. Org. Chem. 1996, 61, 7551–7557;
(b) Mennen, S. M.; Miller, S. J. J. Org. Chem. 2007, 72, 5260–5269.
9. The new salt 5b was prepared by the Oshima’s method: Tückmantel, W.;
Oshima, K.; Utimoto, K. Tetrahedron Lett. 1986, 27, 5617–5618.
10. Zhang, W.; Shi, M. Chem. Commun. 2006, 1218–1220.
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M. J. Am. Chem. Soc. 2001, 123, 3623–3629; (b) Gronheid, R.; Lodder, G.; Ochiai,
M.; Sueda, T.; Okuyama, T. J. Am. Chem. Soc. 2001, 123, 8760–8765.
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14. The adducts, [1-(1-hydroxyalkyl)ethyl]triphenylphosphonium bromide, were
isolated upon workup (ꢀ78 °C) of the reaction (ꢀ78 °C) between unstable salt-
free ylides and aldehydes with aqueous NH4Br. See: Nishizawa, M.; Komatsu,
Y.; García, D. M.; Noguchi, Y.; Imagawa, H.; Yamada, H. Tetrahedron Lett. 1997,
38, 1215–1218.
All these experimental results show that quenching the reaction
mixture of the Wittig ylide and the aldehyde used in this study
with aqueous NH4Cl at low temperature affords the a-hydroxyke-
tone as the major or exclusive product. A plausible mechanism of
this irregular Wittig reaction would be as follows (Scheme 3). Wit-
tig ylide b, derived from Wittig salt a and n-BuLi, adds to the alde-
hyde to afford the betaine LiX complex c.14 According to the
normal Wittig course, c affords enol ether e through oxaphosphe-
tane d. In contrast, addition of aqueous NH4Cl to the reaction mix-
ture at low temperature leads to f, from which elimination of
triphenylphosphine occurs15 which is assisted by the methoxy
15. On entry 1 in Table 2, triphenylphosphine was quantitatively recovered.
16. Aggarwal, V. K.; Harvey, J. N.; Robiette, R. Angew. Chem., Int. Ed. 2005, 44, 5468–
5471.
17. Therefore, direct formation of oxirane i from adduct c would not occur under
the reaction conditions.
18. Methoxyoxirane i has not been detected in the reaction mixture.
19. The
examples
of
the
normal
Wittig
reaction
between
(1-
alkoxyalkyl)triphenylphosphonium ylides and aldehydes show that the
reactions were conducted under the conditions of raising the temperature to
0 °C or rt before workup. See: (a) Anderson, R. J.; Henrick, C. A.; Siddall, J. B.;
Zurflüh, R. J. Am. Chem. Soc. 1972, 94, 5379–5386; (b) Boehm, M. F.; Prestwich,
G. D. J. Org. Chem. 1986, 51, 5447–5450; (c) Mori, K.; Ikunaka, M. Tetrahedron
1987, 43, 45–58; (d) Kim, S.; Kim, Y. C. Tetrahedron Lett. 1990, 31, 2901–2904;
(e) Colinas, P. A.; Lieberknecht, A.; Bravo, R. D. Tetrahedron Lett. 2002, 43, 9065–
9068; (f) Carbery, D. R.; Reignier, S.; Miller, N. D.; Adams, H.; Harrity, J. P. A. J.
Org. Chem. 2003, 68, 4392–4399. See also Refs. 2 and 6.
group. The resulting oxonium intermediate g is hydrolyzed to
a-
hydroxyketone h. The alternative mechanism involving oxirane
formation from f to i might be unlikely according to the computa-
tional calculations16 that show oxirane formation from the betaine
intermediate (nucleophilic displacement of the phosphine) in-
volves a very significant barrier.17 However, we do not discard
20. Nakata, M. In Science of Synthesis; Otera, J., Ed.; Thieme: Stuttgart, Germany,
2007; Vol. 30, pp 351–434.