704 RESEARCH PAPER
DECEMBER, 704-706
JOURNAL OF CHEMICAL RESEARCH 2008
3,3,9,9- Tetramethyl-1,5,7, 11-tetraoxaspiro[5.5]undecane as a reagent for
protection of carbonyl compounds
Mohammad Rahimizadeh*, Mehdi Bakavoli, Ali Shiri, Hossein Eshghi and Sattar Saberi
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran
3,3,9,9-Tetramethyl-1 ,5,7, 11-tetraoxaspiro[5.5]undecane
is introduced as a new, stable and chemoselective reagent
for the protection of aldehydes and ketones under mild reaction condition in high yield.
Keywords: aldehyde, ketone, protection, spiroorthocarbonate, transacetalisation
The protection of carbonyl groups as acetals or ketals and
their subsequent regenerations is an important strategy in a
multi-stage organic synthesis.l Numerous attempts to improve
the efficiency of this process have been investigated and a
number of strategies, such as the use of protic acids, Lewis
acids, solid acids and ionic liquids as the catalyst, with 1,2-
diols, 1,3-diols, 1,2-dithiols, 1,3-dithiols and orthoesters as
the protecting reagents,2 have been reported. Considering the
importance of this transformation, the search for a new catalyst
and especially a new reagent is still needed. Although some of
these methods are carried out under mild reaction conditions
and have been widely used in organic synthesis, others suffer
from drawbacks such as relatively harsh reaction conditions
and long reaction times. The search for an alternative method
that can overcome these drawbacks is desirable. Most attempts
have been focused on finding new catalysts, rather than new
protecting agents.3-6 In this paper, we wish to introduce
3,3,9,9-tetramethyl-l ,5,7, ll-tetraoxaspiro[5.5]undecane (2) as
a promising, efficient and stable reagent for the protection of
carbonyl compounds. There is only one report in the literature 7
concerning the use of 1,4,6,9-tetraoxaspiro[4.4]nonane in
acetalisation of carbonyl compounds. However, because of
its instability and the tedious procedure for its preparation, its
application has been limited.
The spiroorthocarbonate (2) used in this study was easily
prepared in one step from the reaction of 2,2-dimethyl-l,3-
propandiol with dicWorodiphenoxymethane in the presence
of pyridine in dry CH2C12 in 90% yield.8 The resulted
spiroorthocarbonate (2) is stable enough (m.p. = l44-l46°C, lit 8
= l44-l45°C) to be stored at room tempemture for a long time.
Initially, the reaction of benzaldehyde with the reagent (2)
as a model was studied in different solvent systems. As shown
in Table 1, aprotic solvents gave better results than the protic
ones.
Various carbonyl compounds have been used as substrates
to react with the spiroorthocarbonate (2) in the presence of
catalytic amount of p-toluenesulfonic acid (5 mol%) in
CH2C12to give the protected compounds 3a-s (Scheme 1).
The reaction proceeds at room temperature in relatively short
time and in high yield (Table 2). Although the reactions were
monitored by TLC, visual monitoring was also possible. When
p-toluenesulfonic acid was added to a mixture of aldehyde or
ketone (la-s) and the spiroorthocarbonate (2), the colour of
the mixture turns from colourless to slightly brownish liquid,
indicating acetal or ketal formation. Further on increasing the
reaction time, the reverse reaction did not occur. The results
in Table 2 clearly demonstrate the efficiency of this method.
Aliphatic aldehydes afforded their related 1,3-dioxane with
moderate yields (entries 11and 1m). This method is also useful
for protection of cinnamaldehyde (entry 1k). Ketones can also
be converted to the corresponding ketals but the reaction time
was longer than aldehydes. This method is also applicable for
protecting of relatively unreactive and steric-hindered ketones
Table
1 The solvent effect on yield and time of the typical
protection of benzaldehyde
Entry
Solvent
Time/min
Yield/%
1
2
3
4
5
6
CH2CI2
CH3CN
CHCI3
EtOH
MeOH
DMSO
10
10
60
95
75
80
No reaction
No reaction
30
56
0
0
OJ...O
X
TsOH (5 mol %~
+
+
~Olfi
°X
O
R '
R A R '
rI, CH2CI2
0 0
R
X
1a-s
2
4
3a-s
Scheme
1
such as benzophenone and diisopropylketone (entries 10 and
1p). These ketones failed to react with most of the previous
reported reagents.9-l2
Since the reaction of ketone is slower than aldehyde,
this method can be used for the protection of an aldehyde
in the presence of a ketone. An equimolar concentration of
benzaldehyde, acetophenone and spiroorthocarbonate (2)
yielded only the protected aldehyde.
On the other hand, water is not produced in this method
unlike the other reported procedures which use alcohols.
Thus, the method can be especially useful for protection
water-sensitive aldehydes and ketones. (entry Is)
In summary, the advantages of this method of protection
of carbonyl compounds are chemoselectivity, mild reaction
conditions, stability of the reagent, irreversibility and
suitability for water-sensitive aldehydes and ketones and high
yields.
Experimental
The IH NMR (100 MHz) spectra were recorded on a Broker AC
100 spectrometer. Chemical shifts are reported in ppm downfield
from TMS as internal standard. The mass spectra were obtained on
a Varian Mat CH-7 at 70 eV. Elemental analysis was performed on a
Thermo Finnigan Flash EA microanalyser.
General procedure for the preparation of spiroorthocarbonate (2):
A solution of dichlorodiphenoxymethane (0.01 mol, 2.69 g) in dry
CH2C12(10 ml) was added dropwise in an ice-bath at 0-5°C to a
solution ofneopentyl glycol (0.01 mol, 1.04 g) and pyridine (0.02 mol,
1.58 g) in dry CH2C12(20 ml). After the addition was completed,
the mixture was stirred for 2 h. Then, the solid was filtered off and
the mother-liquor was washed with 5% NaOH solution and water,
respectively. The organic phase was dried over anhydrous Na2S04
and the solvent was removed under reduced pressure. The resulting
solid was recrystallised from ethyl acetate. Yield = 90%, m.p. = 144-
146°C, lit.8 = l44-l45°C.
General procedure for the protection of aldehydes and ketones
(la-s): A solution of anhydrous p-toluenesulfonic acid (5 mol%,
8.6 mg) in CH2C12(1 ml) was added to a magnetically stirred
solution of 3,3,9,9-tetramethyl-l,5, 7,ll-tetraoxaspiro[ 5.5]undecane
Rahimizadeh, Mohammad
