Chemoselective and chemospecific protection and deprotection of a carbonyl group using polystyrene divinylbenzene sulfonic acid

Article abstract of DOI:10.1080/00397910903161702

Chemospecific protection of one carbonyl group of two identical carbonyls of 2,2-dialkyl-1,3-cyclohexanedione and chemoselective protection of aliphatic or aromatic carbonyls in the presence of conjugated carbonyl compounds using cross-linked polystyrene divinyl benzene sulfonic acid (SPS) as a heterogeneous catalyst has been demonstrated. Copyright

Full text of DOI:10.1080/00397910903161702

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Chemoselective and Chemospecific
Protection and Deprotection of a
Carbonyl Group Using Polystyrene
Divinylbenzene Sulfonic Acid
Sanjeev K. Verma a , Manisha Sathe a & M. P. Kaushik a
a Discovery Centre, Process Technology Development Division,
Defence Research and Development Establishment , Gwalior, India
Published online: 06 May 2010.
To cite this article: Sanjeev K. Verma , Manisha Sathe & M. P. Kaushik (2010) Chemoselective and
Chemospecific Protection and Deprotection of a Carbonyl Group Using Polystyrene Divinylbenzene
Sulfonic Acid, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:11, 1701-1707, DOI: 10.1080/00397910903161702
To link to this article: http://dx.doi.org/10.1080/00397910903161702
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Synthetic Communications1, 40: 1701–1707, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903161702
CHEMOSELECTIVE AND CHEMOSPECIFIC
PROTECTION AND DEPROTECTION OF A CARBONYL
GROUP USING POLYSTYRENE DIVINYLBENZENE
SULFONIC ACID
Sanjeev K. Verma, Manisha Sathe, and M. P. Kaushik
Discovery Centre, Process Technology Development Division, Defence
Research and Development Establishment, Gwalior, India
Chemospecific protection of one carbonyl group of two identical carbonyls of 2,2-dialkyl-1,
3-cyclohexanedione and chemoselective protection of aliphatic or aromatic carbonyls in the
presence of conjugated carbonyl compounds using cross-linked polystyrene divinyl benzene
sulfonic acid (SPS) as a heterogeneous catalyst has been demonstrated.
Keywords: 2,2-Dialkyl-1,3-cyclohexanedione; chemoselectivity; chemospecificity; polystyrene divinyl
benzene sulfonic acid
INTRODUCTION
Chemoselective and chemospecific protection of carbonyl group is one of the
most intriguing tasks in organic synthesis, essentially because of its application in
various multistep syntheses.[1] In various ketones, the chemospecific protection of
one carbonyl in 1,3-diones has great importance because of its involvement in
various natural product syntheses.[1] Protection of carbonyl groups mainly involves
the formation of acetals or ketals in the presence of an acid.[1,2] A myriad of
catalysts=reagents including ionic liquids,[3] organometallic[4] and silyl reagents,[5]
and inorganic compounds [FeCl3, TiCl4, Bi(NO3)3][6] have been employed for the
protection of carbonyl groups; however, these reagents show a number of disadvan-
tages. One among them is nonchemoselectivity. Therefore, efforts were made to
develop new reagents=catalysts with high activity, selectivity, and generality, which
can lead to practical and efficient protection and deprotection of various carbonyl
groups. Recently, we have initiated work in the field of solid-supported reagents
for various chemical transformations in organic synthesis.[7] Polymeric catalysts have
received much attention because of their stability and reusability.[8,9] Such catalysts
not only simplify purification processes but also are ecofriendly. Considering the
significance of protection of carbonyl groups, and in continuation of our work on
Received April 1, 2009.
Address correspondence to M. P. Kaushik, Discovery Centre, Process Technology Development
Division, Defence Research and Development Establishment, Jhansi Road, Gwalior 474 002, M.P.,
India. E-mail: mpkaushik@rediffmail.com
1701

1702
S. K. VERMA, M. SATHE, AND M. P. KAUSHIK
Scheme 1. Protection of carbonyl with SPS.
solid-supported reagents, we report herein an efficient method for the chemospecific
and chemoselective protection and deprotection of carbonyl groups using cross-
linked polystyrene divinyl benzene sulfonic acid (SPS) as a heterogeneous catalyst
(Scheme 1).
RESULTS AND DISCUSSION
Cross-linked SPS was synthesized by refluxing polystyrene beads with chloro-
sulfonic acid in dicholormethane (DCM)[10] and used as a reagent for chemoselective
and chemospecific protection of a carbonyl group. 2,2-Methyl-1,3-dimethyl-1,3-
cyclohexanone was used as reactant to standardize all other parameters (diol,
solvent, acid source).
Effect of the diol on chemoselective protection of 2,2-dimethyl-1,3-
cyclohexanedione was studied using ethanediol and 2,2-dimethyl-1,3-propanediol.
The more hindered 2,2-dimethyl-1,3-propanediol give the best result with SPS, where
only a monoprotected product was observed (entry 1, Table 1), whereas with 1,2-
ethanediol, the ratio of monoprotected to diprotected product was 9:1 with a lesser
conversion rate (entry 16, Table 1).
The effect of acid source on the chemoselective protection of 2,2-dimethyl-1,3-
cyclohexanedione with 2,2-dimethyl-1,3-propanediol was studied using different acid
sources (Table 2) such as p-toluene sulfonic acid (pTsOH), camphor sulfonic acid
(CSA), and SPS. It was found that with a more hindered acid source (CSA), the
percentage of monoprotected product increased. With SPS, only monoprotected
product was observed. When compared with traditional reagents such as p-TsOH
and CSA, the reagent showed shorter reaction time and no azo-tropical removal
of water was required.
The effect of solvent on reaction rate was observed with different solvents
(Table 3). It was found that SPS gave a better result with only solvent that result
in swelling in the beads. The yield in toluene, benzene, or hexane was very poor.
DCM gave the best swelling and was the best solvent for protection with
2,2-dimethyl-1,3-propanediol. DCM does not give the desired yield with ethanediol
because of its very poor reactivity under the reflux temperature of DCM. Ethanediol
show reactivity with toluene, which has a higher boiling point but also less reactivity.
The reaction in the given case may be only outside the beads. That is clear from the
lesser reactivity.
Chemoselectivity was studied with different cyclohexanediones (Table 1,
entries 1–7). Chemospecificity was observed with 2,2 alkyl-1,3-diones only. In
various 2,2-dialkyl-1,3-diones, reaction yield or overall conversion decreased with

CHEMOSELECTIVE PROTECTION OF CARBONYL GROUP
1703
Table 1. Protection of carbonyl using SPS as catalyst
No.
Aldehyde=ketone
Diol
Time (h) Yield (%)a
1
2
2,2-Dimethyl Cyclohexan-1,3-dione
2-Ethyl-2-methyl cycohexane-1,3-dione
2-Methyl-2-propenyl 1,3-cyclohexanedione 2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2
2
7
7
7
7
2
2
2
2
2
8
7
7
6
6
6
6
6
6
6
85
75
65
0
3
4
2-Benzyl-2-methyl- 1,3-cyclohexanedione
2-Methyl cycohexane-1,3-dione
1,3-Cyclohexanedione
1,4-Cyclohexanedione
Cyclohexanone
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-propanediol
1,2-Ethanediol
5
0
6
0
7
50
95
90
0
8
9
2-Methyl-cyclohexanone
Cyclohex-2-en-1-one
Ethyl vinyl ketone
10
11
12
13
14
15
16
17
18
19
20
21
0
Benzaldehyde
85
92
80
40
36
0
p-Nitrobenzaldeyde
p-Methylbenzadehyde
Cyclohexanone
2,2-Dimethyl-cyclohexane-1,3-dione
Cyclohex-2-en-1-one
Carvone
1,2-Ethanediol
1,2-Ethanediol
1,2-Ethanediol
1,2-Ethanediol
0
Benzaldehyde
p-Methylbenzadehyde
p-Nitrobenzaldeyde
0
1,2-Ethanediol
1,2-Ethanediol
0
0
Note. All the products were compared with authentic sample and gave satisfactory IR, NMR, and MS
data.
aIsolated yields. In the case of dione, yield is only of monoprotected carbonyls.
chain length of alkyl groups (Table 1, entries 1–4). This may be the result of a decrease
in diffusion rate in the beads with an increase in chain length. In the case of 1,3-cyclo-
hexanedione and 2-methyl-1,3-cyclohexanedione, the reaction was not observed
(Table 1, entries 5 and 6). It may be because of their enolic form, which decreases
the reactivity of the carbonyl group toward the nucleophilic addition reaction and
poor diffusibility of the enolic form in polymer beads. 1,4-Cyclohexanedione shows
Table 2. Comparision of chemoselective protection of 2,2-dimethylcylcohexane-1,3-dione between SPS
and other acid sources
a,b
No.
Protective reagent
Time (h)
Yield (%)
Azeotropical removal of water
1
2
CSA
SPS
4
2
70
85
Not required
Not required
aYield is only of monoprotected product.
bGC yield.

1704
S. K. VERMA, M. SATHE, AND M. P. KAUSHIK
Table 3. Comparison of protection of 2,2-dimethylcylcohexane-1,3-dione
with SPS in different solvents
No.
Solvent
Time (h)
Yield (%)
1
2
3
4
DCM
CHCl3
Toluene
Hexane
2
2
6
6
92
78
35
20
the formation of both monoprotected and diprotected products without any chemos-
electivity (Table 1, entry 7), which decreases its overall yield.
Protection using a wide range of reactant was also studied with SPS (Table 1,
entries 8–21). SPS was able to protect only aliphatic and aromatic carbonyl
compounds with 2,2-dimethyl-1,3-propanediol and only the aliphatic carbonyl
compound with 1,2-ethanediol. Protection of the conjugated carbonyl group was
not observed with any diol even after a long time of refluxing.
To examine the chemoselectivity using SPS with other carbonyl compounds, equi-
molar mixtures of different aldehydes and ketones were allowed to react with diol (1:3).
As shown in Scheme 2, very high chemoselectivity was observed in each case. More
active 2,2-dimethyl-1,3-propanediol selectively protected aliphatic or aromatic carbonyl
compounds in the presence of conjugated ketones, whereas less active ethanediol was
able to protect only aliphatic ketones in a mixture of aromatic and conjugated ketones.
Whenever the chemoselectivity is compared with other solid supports (e.g.,
mesoporous aluminosilicate,[11] siliceous mesoporous material,[12] zeolite,[13] silica
gel–supported AlCl3,[14] and SO3H-functionalized silica,[15] only SPS was found to
differentiate between two identical carbonyls, the aliphatic and aromatic carbonyl
compounds, and between conjugated and nonconjugated carbonyl compounds.
The chemoselectivity observed in the SPS may be explained on the basis of a
microenvironmental effect that is observed inside the polymer beads. The polymer
bead only showed the desirable result with greater yield in DCM solvent, which results
Scheme 2. Chemoselective protection of the aliphatic carbonyl groups.

CHEMOSELECTIVE PROTECTION OF CARBONYL GROUP
1705
Table 4. Hydrolysis of acetals to respective carbonyl compounds
No.
Acetal
Time (h)
Yielda (%)
1
2
3
4
5
3,3-Dimethyl-1,5-dioxa-spiro(5,5)undecane
3,3,7-Trimethyl-1,5-dioxa-spiro(5,5)undecane
5,5-Dimethyl-2-(4-nitor-phenyl)-(1,3)dioxane
1,4-Dioxa-spiro(4,5)decane
2
2
2
2
2
90
88
88
80
75
6-Methyl-1,4-dioxa-spiro(4,5)decane
Note. All the products were compared with authentic samples and gave satisfactory IR, NMR, and MS data.
aIsolated yield.
in the swelling of SPS to a greater extent, and the reaction is slow in other solvents
(Table 3). Probably most of the reaction occurs inside the polymer beads, and the poly-
mer beads not only act as a source of acid but also give some secondary interaction
sites inside the polymer beads, where polarity is greater then bulk of the medium.
The monoprotected carbonyl compound shows poor diffusion inside the beads as
compared to 1,3-diones, so it does not compete for the formation of diprotected pro-
duct. This can further be supported by the fact that rate of protection decreases with
the increase in chain length of alkyl groups in 2,2-dialkyl-1,3-diones, and no protection
of carbonyl was observed with conjugated carbonyl compounds and 2-alkyl-1,3-dione.
It is well known that diffusion in SPS beads decreases with increase in chain length and
with conjugation.[16] This is also responsible for lack of protection of aromatic and
conjugated ketones, which show poor or no diffusion in polymer beads.
The corresponding deprotection of acetals was also achieved using SPS
(Table 4), which is superior to conventional methods in terms of reaction conditions,
reaction times, and workup procedures.[17]
CONCLUSION
In conclusion, an efficient and simple method for chemospecific and chemo-
selective protection has been described using SPS as a heterogeneous catalyst. The
main advantage of this method is that it is only method that gives chemospecific
protecton of carbonyl compounds. Further reaction required short reaction time,
takes place at reflux temperature, has operational simplicity and no azeotropical
removal of water, and gives excellent yields.
EXPERIMENTAL
Typical Experimental Procedure for the Synthesis of Acetals with
2,2-Dimethyl-1,3-propanediol
2,2-Dimethyl-1,3-cyclohexandione (1.00 mmol) and 2,2-dimethylpropane-1,3-
diol (6.00 mmol) were dissolved in dichloromethane (DCM, 10 mL) at room tem-

1706
S. K. VERMA, M. SATHE, AND M. P. KAUSHIK
perature (ratio of monocarbonyl to diol taken is 1:3). The catalyst (10% w=w) was
added, and the reaction mixture was stirred at 50 ꢀC for 2 h. The reaction mixture
was cooled to room temperature, and the catalyst was removed by filtration through
a celite plug, which was washed with DCM (5 Â 2.5 mL). Solvent was removed under
reduced pressure. Purification by column chromatography gave the desired product.
Typical Experimental Procedure for the Synthesis of Acetals with
Ethane 1,2-Diol
2,2-Dimethyl-1,3-cyclohexandione (1.00 mmol) and ethane1 2-diol (6.00 mmol)
were dissolved in toluene (5 mL) (mono carbonyl=diol 1:3). The catalyst (10% w=w)
was added, and the reaction mixture was stirred at 65 ꢀC for 8 h. The reaction
mixture was cooled to room temperature. The catalyst was removed by filtration
through a celite plug and washed with hexane (5 Â 2.5 mL). Solvent was removed
under reduced pressure to give the product.
Typical Procedure for the Hydrolysis of Acetals
Acetal (1 mmol) was dissolved in acetone and water (5 mL) at room temperature.
The catalyst (5% w=w) was added, and the reaction mixture was stirred at 55 ꢀC for
2 h. The reaction mixture was cooled to room temperature. The catalyst was removed
by filtration through a celite plug, which was washed with DCM (5 Â 2.5 mL). The
solvent was removed under reduced pressure to get the desired product.
ACKNOWLEDGMENT
We thank Dr. Vijayaraghavan, director of the Defence Research and Develop-
ment Establishment, Gwalior, for his keen interest and encouragement.
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