A Convenient Preparation of 4,4-Dimethoxybutanal by Ozonolysis of 1,5-Cyclooctadiene

Full text of DOI:10.1021/jo980049b

J . Org. Chem. 1998, 63, 3151-3152
3151
Sch em e 1
A Con ven ien t P r ep a r a tion of
4,4-Dim eth oxybu ta n a l by Ozon olysis of
1,5-Cycloocta d ien e
Pan Li, J ianwu Wang,† and Kang Zhao*
Department of Chemistry, 29 Washington Place, New York
University, New York, New York 10003
Received J anuary 9, 1998
4,4-Dialkoxybutanals 1 are versatile starting materials
in organic synthesis.1,2 Its profuse use, therefore, merits
investigation of practical preparations. Synthesis from
commercially available succinic dialdehyde would avert
the handling of large quantities of reagents, but monoac-
etalization of this dialdehyde has not been reported. This
is most likely due to the favorable formation of 2,5-
dihydroxytetrahydrofuran (2) (Scheme 1). Other syn-
thetic methods rely upon oxidation or reduction of
functional groups. In evaluating methodology for the
practical preparation of such a low molecular weight
compound, several factors must be considered: (a) the
number of reaction steps; (b) the amount of reagents for
multigrams of products; (c) water solubility of intermedi-
ates for isolation and purification; and (d) overall yields.
Several approaches to compounds 1 have been devel-
oped.1 The method reported by Griesbaum and co-
workers uses ozone as a readily available reagent to
convert cyclohexadiene 3 to the desired product 1a (R )
Me) among others.1d Rhodium-catalyzed hydroformyla-
tion of olefin 4 (R ) Et) provides a one-step procedure
for the monoprotected dialdehyde 1b (R ) Et), although
the reaction requires high-pressure conditions.1e-h Com-
pound 1c (R ) CH2-) can be prepared, following a simple
five-step procedure, from the readily available γ-butyro-
lactone 5.1c Olefin 6 (R ) Et), which may not easily be
obtained, can be efficiently converted to 1b by the
reported procedure1j or ozonolysis. Perhaps the most
practical method, recently reported by Paquette,1a is the
rapid transformation of 7 (R ) Me) to 1a via sodium
Sch em e 2
cyanide displacement and DIBAL reduction. We rea-
soned that preparation of 1 may be achieved by the
stepwise ozonolysis of cyclcooctadiene 8, a readily avail-
able starting material, and that this transformation can
convert the symmetric diene to two molecules of the
desired monoprotected dialdehyde such as 1a (Scheme
2).
Our strategy, as illustrated in Scheme 2, involves two
steps of ozonolysis.3 First, 1,5-cyclooctadiene 8 was
treated with 1 molar equiv (see the Experimental Section)
of ozone in methylene chloride and methanol (1:1) at -78
°C, following the reduction with dimethyl sulfide,4 to
provide an intermediate cis-4-octene-1,8-dialdehyde that
was protected in situ by methanol to give product 9. The
protected dialdehyde 9, which needed no purification, was
then treated with ozone to produce 4,4-dimethoxybutanal
(1a ) in 82% overall yield.5
In conclusion, this efficient method demonstrated that
diene 8 can be ozonized stepwise to prepare monopro-
tected dialdehyde 1a . Several advantages are conferred
by this method. The symmetry of this diene can afford
rapid preparation of 2 equiv of 4,4-dialkoxybutanal 1a .
The use of reagents is minimized, and those used are
inexpensive and easy to handle. Most importantly, a
large quantity of the desired product (>30 g) can be easily
prepared using this method.
† Present address: Department of Chemistry, Shandong University,
J inan, People’s Republic of China.
(1) For the synthesis of 4,4-dialkoxybutanals 1, see: (a) Paquette,
L. A.; Backhaus, D.; Braun, R.; Underiner, T. L.; Fuchs, K. J . Am.
Chem. Soc. 1997, 119, 9662. (b) Lucchesini, F. Tetrahedron 1992, 48,
9951. (c) Herdewijn, P.; Claes, P. J .; Vanderhaeghe, H. J . Med. Chem.
1986, 29, 661. (d) Griesbaum, K.; J ung, I. C.; Mertens, H. J . Org. Chem.
1990, 55, 6024. (e) Cuny, G. D.; Buchwald, S. L. J . Am. Chem. Soc.
1993, 115, 2066. (f) Andrade, J .; Prescher, G.; Samson, M. Ger. Offen.
DE 3, 403, 427, 01 Aug 1985; Chem. Abstr. 1986, 104, 88120p. (g)
Drauz, K.; Kleemann, A.; Samson, M. Chem.-Ztg. 1984, 108, 391. (h)
Maeda, I.; Yoshida, R. Bull. Chem. Soc. J pn. 1968, 41, 2969. (i)
Traverso, G.; Pirillo, D.; Rescia, G. Farmaco, Ed. Sci. 1979, 34, 229.
(j) Kovalev, B. G.; Vaskan, R. N.; Shamshurin, A. A. Zh. Org. Khim.
1969, 5, 1771.
(2) For the use of 4,4-dialkoxybutanals 1, see ref 1a-c and: (a)
Hoffmann, R. W.; Munster, I. Liebigs Ann./ Recl. 1997, 1143. (b)
Kanehira, K.; Tagawa, H.; Shiono, M. J apan Kokai Tokkyo Koho, J P
97104682, Apr 22, 1997; Chem. Abstr. 1997, 127, 17584g. (c) Ando, Y.;
Oosono, S.; Nakagawa, S. J an. Kokai Tokkyo Koho J P 08 27,138 [96
27,138], 30 J an 1996; Chem. Abstr. 1996, 124, 343097p. (d) Cooper, D.
M.; Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J . Tetrahedron
1995, 51, 7791. (e) Le Gall, T.; de Montarby, L.; Gree, R.; Millet, J .;
Sepulchre, C.; Bellamy, F. Bioorg. Med. Chem. Lett. 1994, 4, 247. (f)
Fuchs, K.; Paquette, L. A. J . Org. Chem. 1994, 59, 528. (g) Enders, D.;
Schankat, J .; Klatt, M. Synlett 1994, 10, 795. (h) Sander, T.; Hoffmann,
R. W. Liebigs Ann. Chem. 1993, 1193. (i) Hoffmann, R. W.; Niel, G.
Liebigs Ann. Chem. 1991, 1195. (j) Suzaka, H.; Tomiyama, T.; Ikegami,
S. J . Labelled Compd. Radiopharm. 1990, 28, 901.
(3) For reviews of ozonolysis, see: (a) Schober, B. D. Chim. Oggi
1995, 13, 21. (b) Odinoknv, V. N. Bashk. Khim. Zh. 1994, 1, 29. (c)
Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79. (d) Xiang, Q. Huaxue
Tongbao 1988, 3, 53. (e) Bailey, P. S. In Ozonation in Organic
Chemistry; Academic Press: New York, 1982; Vol. II.
(4) Dimethyl sulfide (Me2S) has an unpleasant smell; it should be
handled in the hood. Triphenylphosphine (Ph3P) can be used as an
alternative reductant for small-scale reactions. In the case of large-
scale reactions, the combination of Me2S and Ph3P can be used to
minimizes the unpleasant smell of dimethyl sulfide. The initial
reductant Me2S is slightly less than 1 equiv, and a small amount of
PPh3 can then finish the reduction. The byproduct Ph3PO can be
removed by dissolving the crude product in petroleum ether.
(5) The corresponding 4,4-diethoxybutanal can be similarly prepared
in 48% overall yield.
S0022-3263(98)00049-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/08/1998

3152 J . Org. Chem., Vol. 63, No. 9, 1998
Additions and Corrections
was purified by vacuum distillation (69-72 °C, 10 mmHg) to
give 4,4-dimethoxybutanal (1a ) (30 g, 227.0 mmol, 82% overall
yield) as a colorless oil: 1H NMR (200 MHz, CDCl3) δ 9.73 (1H,
t, J ) 1.5 Hz), 4.35 (1H, t, J ) 5.5 Hz), 3.30 (6H, s), 2.48 (2H,
dt, J ) 1.5, 7.2 Hz), 1.91 (2H, dt, J ) 5.5, 7.2 Hz); 13C NMR (50
MHz, CDCl3) δ 202.0, 104.3, 53.9, 39.4, 26.0; MS m/z (intensity)
132 (0.01, M+), 131 (0.6, M+ - 1), 101 (29, M+ - CH3O), 75 (100,
M+ - CH2CH2CHO).
Exp er im en ta l Section
Gen er a l Meth od s. General details are as previously de-
scribed.6
4,4-Dim eth oxybu ta n a l (1a ). The relative rate of ozonolysis
was tested by a small scale diozonolysis. A solution of 1,5-
cyclooctadiene (8) (1.0 g, 9.2 mmol) in 10 mL of methylene
chloride and 10 mL of methanol was ozonized at -78 °C. After
18 min,7 the solution turned blue, indicating the complete
ozonolysis. Under these conditions, a solution of 1,5-cycloocta-
diene (8) (15.0 g, 138.6 mmol) in 150 mL of methylene chloride
and 150 mL of methanol was ozonized at -78 °C. After 135
min of ozonolysis,7 TsOH‚H2O (2 g, 10.5 mmol) was then added.
After the solution was stirred at room temperature for 2 h,
dimethyl sulfide (15 mL) was added, and this mixture was
stirred at room temperature overnight. After workup with
aqueous NaHCO3 and CHCl3, the crude product 9 was treated
with ozone at -78 °C until the solution turned blue. Dissolved
ozone was removed by flushing the solution with argon. Di-
methyl sulfide (15 mL) was then added. After the solution was
stirred at room temperature for 3-4 h, the solvents were
removed in the hood by distillation. The residue was dissolved
in diethyl ether (250 mL) and washed with water (2 × 100 mL).
After the removal of diethyl ether by evaporation, the residue
Ack n ow led gm en t. We thank Mr. Omar Ibrahimi
for his technical assistance. We acknowledge the finan-
cial support from the NSF Faculty Early Career Devel-
opment Program, the New York University Technology
Transfer Fund, and the donors of the Petroleum Re-
search Fund, administered by the American Chemical
Society. P.L. acknowledges the New York University
Dean’s Dissertation Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 1a and 9 (4 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(6) Gi, H.; Xiang, Y.; Schinazi, R.; Zhao, K. J . Org. Chem. 1997, 62,
88.
(7) The reaction time depends on the setup of ozone generator.
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Additions and Corrections
Vol. 63, 1998
Rober t Rein h a r d a n d Br igitte F . Sch m id t. Nitrobenzyl-
Based Photosensitive Phosphoramide Mustards: Synthesis and
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paragraph should be added.
1H and 13C NMR spectra for compounds prepared (48
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