Zinc chloride as an efficient catalyst for chemoselective dimethyl acetalization

Article abstract of DOI:10.1080/00397910802412859

Commercially available anhydrous zinc chloride has been found to be a highly efficient catalyst for dimethyl acetalization in high yields by treatment of aldehydes and ketones with trimethyl orthoformate in methanol-cyclohexane at reflux temperature. Copyright Taylor & Francis Group, LLC.

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Zinc Chloride as an Efficient
Catalyst for Chemoselective
Dimethyl Acetalization
a
a
a
Anupam Roy , Matiur Rahman , Sudarshan Das
,
a
a
Dhiman Kundu , Shrishnu Kumar Kundu , Adinath
a
a
Majee & Alakananda Hajra
a
Department of Chemistry, Visva-Bharati University,
Santiniketan, India
Version of record first published: 28 Jan 2009
To cite this article: Anupam Roy, Matiur Rahman, Sudarshan Das, Dhiman Kundu,
Shrishnu Kumar Kundu, Adinath Majee & Alakananda Hajra (2009): Zinc Chloride
as an Efficient Catalyst for Chemoselective Dimethyl Acetalization, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:4, 590-595
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1
Synthetic Communications , 39: 590–595, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802412859
Zinc Chloride as an Efficient Catalyst for
Chemoselective Dimethyl Acetalization
Anupam Roy, Matiur Rahman, Sudarshan Das, Dhiman Kundu,
Shrishnu Kumar Kundu, Adinath Majee, and Alakananda Hajra
Department of Chemistry, Visva-Bharati University, Santiniketan, India
Abstract: Commercially available anhydrous zinc chloride has been found to be a
highly efficient catalyst for dimethyl acetalization in high yields by treatment of
aldehydes and ketones with trimethyl orthoformate in methanol-cyclohexane at
reflux temperature.
Keywords: Carbonyl compound, chemoselectivity, dimethyl acetalization,
trimethyl orthoformate, zinc chloride
INTRODUCTION
Selective protection of carbonyl groups as acetals is essential step in mod-
ern organic chemistry as it is often necessary to carry out a reaction on a
[
1]
multifunctional substrate without affecting carbonyl groups. Acetals
are one of the most useful carbonyl protecting groups because of their
stability under both neutral and basic media. In addition, acetals can
[
2]
be converted to a variety of other functional groups. A variety of
reagents have been developed for the dimethyl acetalization of carbonyl
[
3]
compounds, which include mainly protic acids and Lewis acids. How-
ever, many of these methods are associated with expensive and toxic
reagents, strongly acidic conditions, stoichiometric amounts of catalysts,
and incompatibility with other functional groups. Moreover, many of the
Received June 12, 2008.
Address correspondence to Alakananda Hajra or Adinath Majee, Department
of Chemistry, Visva-Bharati University, Santiniketan 7318235, India. E-mail:
alakananda.hajra@visva-bharati.ac.in or adinath.majee@visva-bharati.ac.in
5
90

Chemoselective Dimethyl Acetalization
591
1
2
Scheme 1. R ¼ alkyl=aryl; R ¼ H=alkyl.
procedures are practical for aldehydes only. Efficient methods for the
dimethyl acetalization are very limited. Hence, a practical and more
efficient alternative for dimethyl acetalization using an inexpensive and
environment friendly reagent is still of interest.
Zinc chloride, a very inexpensive and easily available Lewis acid
[
4]
catalyst, has been widely used in organic synthesis, but it has not been
studied as a catalyst for the synthesis of dimethyl acetals from the parent
aldehydes and ketones. As a part of our ongoing studies to test the effec-
[
5]
tiveness of various inexpensive Lewis acid catalysts in organic synthesis,
we decided to investigate the zinc chloride–catalyzed dimethyl acetaliza-
tion of carbonyl compounds (Scheme 1).
RESULTS AND DISCUSSION
Initially to optimize the reaction conditions, we tried to convert benzalde-
hyde to its dimethyl acetal in various reaction conditions. The best result
was obtained when the reaction was carried out by stirring the carbonyl
compounds and trimethyl orthoformate (2.0 equiv) in a mixture of anhy-
drous methanol and cyclohexane (1:3, 0.5 mL per mmol of substrate) in
the presence of a catalytic amount of a anhydrous ZnCl (10 mol%) at
2
reflux temperature. When the reaction was attempted using the catalyst
in cyclohexane only (no methanol), significant acetal formation was
not observed. We examined the dimethyl acetalization of a wide range
of simple aldehydes and ketones. The results are summarized in Table 1.
Aromatic aldehydes with variety of substitutions such as Cl (entry 3),
NO (entry 5), OMe (entries 4, 6, and 7), and methylenedioxy (entry 8)
2
underwent smooth transformation to corresponding acetals in excellent
yields. The acid-sensitive heterocyclic substrate such as 2-thiophenecar-
boxaldehyde was efficiently protected as dimethyl acetal without accom-
panying self-condensation or ring cleavage (entry 9). Cinnamaldehyde
was also acetalized without concomitant double-bond isomerization
(
entry 11). Acetalization of hydroxybenzaldehyde under Lewis acid–
catalyzed conditions is a very difficult process and is usually accompanied
with low yields of the products. Nevertheless, this methodology worked

592
A. Roy et al.
Table 1. Dimethyl acetalization of carbonyl compounds
1
2
R
a
Entry
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Ph
p-MeC H
6 4
p-ClC
p-(MeO)-C
p-NO C H
4
4-(OH)-3-(OMe)-C
4-(OMe)-3-(OMe)-C
H
H
H
H
H
H
H
6
7
5
10
5
14
12
11
88
92
90
84
94
72
78
6
H
4
H
6 4
2
6
6
H
3
6
H
3
H
81
9
8
H
78
1
0
10
H
84
11
12
13
14
PhCH¼CH (t)
H
H
H
9
8
9
8
5
88
89
85
86
CH3-ðCH2Þ -
6
CH3-ðCH2Þ -
8
3
(CH )
2
CHꢀCH
2
Me
15
79
6
1
1
6
7
88
20
Ph
Me
24
a
Yields refer to isolated pure products fully characterized by spectral and
analytical data.
very well on hydroxybenzaldehyde and gave desired protected product in
high yields (entry 6). Aliphatic aldehydes worked equally well (entries 12
and 13). Saturated aliphatic and cyclic ketones afforded excellent results

Chemoselective Dimethyl Acetalization
593
Scheme 2. Chemoselective acetalization of aldehydes.
entries 14–16). However, the reaction of aromatic ketone such as aceto-
(
phenone produced only low yields (ꢁ20%) of the corresponding acetal
under similar reaction conditions after 24 h.
To evaluate the chemoselectivity of this method, we also investigated
competitive reactions for acetalization of benzaldehyde in the presence of
acetophenone under the reaction conditions. Employing this catalytic
system, the highly selective conversion of benzaldehyde in the presence
of acetophenone was observed (Scheme 2). This observation indicates
that aldehydes are more reactive than aromatic ketones. This may be
due to higher electrophilicity of aldehydes in comparison to aromatic
ketones. Thus, this methodology will be useful for chemoselective aceta-
lization of aldehydes in the presence of aromatic ketones.
CONCLUSION
In conclusion, the work presented here demonstrates a straightforward
and mild procedure for the efficient and chemoselective method for the
dimethyl acetalization of aldehydes and ketones catalyzed by zinc chlor-
ide. The reaction possesses the following synthetic features: (a) mild con-
ditions, (b) simple operation, (c) good yields, (d) nontoxic and cheap
metal catalyst, and (e) excellent chemoselectivity. The easy formation
of dimethyl acetals using inexpensive catalyst under mild reaction condi-
tions makes the present methodology a practical alternative.
EXPERIMENTAL
In a typical experimental procedure, a mixture of 4-methylbenzaldehyde
(
240 mg, 2 mmol, 236 mL) and trimethyl orthoformate (425 mg, 4 mmol,

594
A. Roy et al.
4
38 mL) was stirred in the presence of a catalytic amount of ZnCl (27 mg,
2
10mol%) at reflux temperature in anhydrous methanol–cyclohexane mix-
ture (1:3, 1 mL) for 7 h as required for completion (monitored by
thin-layer chromatography, TLC). After completion of the reaction,
the solvent was evaporated, and the reaction mixture was filtered through
a plug of silica gel eluted by Et O (20 mL) and evaporated. Analytically
2
pure 4-(dimethoxy)methylbenzene was obtained by a rapid silica-gel
chromatography using n-hexane–EtOAc (20:1) as a colorless oil (92%,
3
scopic data (IR, H NMR) with those reported.
06 mg) whose identity was established by comparison of its spectro-
1
[3k]
ACKNOWLEDGMENTS
A. H. is pleased to acknowledge the financial support from Department
of Science and Technology (DST) (Grant No. SR=FTP=CS-107=2006).
We are thankful to DST-Funding for Infrastructure in Science and Tech-
nology (FIST) and Special Assistance Program (SAP)-University Grants
Commission (UGC), India. D. K. thanks the Council for Scientific and
Industrial Research (CSIR) for his fellowship. We also express our
sincere thanks to Prof. B. C. Ranu, Department of Chemistry, Indian
Association for the Cultivation of Science, for his advice and constant
encouragement.
REFERENCES
1
. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
rd ed.; John Wiley and Sons: New York, 1999; (b) Hanson, J. R. Protecting
Groups in Organic Synthesis, 1st ed.; Blackwell Science, Inc: Malden, MA,
999; (c) Kocienski, P. J. Protecting Groups, 1st ed.; Georg Thieme Verlag:
3
1
Stuttgart, 1994.
. (a) Bergstrom, R. G. In The Chemistry of Ethers, Crown Ethers, Hydroxyl
Groups, and Their Sulphur Analogues; S. Patai (Ed.); Wiley: New York,
2
3
1980; suppl. E, part 2, chapter 20; (b) Schnitz, E.; Eichorn, I. In The Chemistry
of the Ether Linkage; S. Patai (Ed.); Wiley: New York, 1967; chapter 7.
. (a) Meskens, F. A. J. Methods for the preparation of acetals from alcohols or
oxiranes and carbonyl compounds. Synthesis 1981, 501–522; (b) Tateiwa, J.-I.;
3þ
3þ
Horiuchi, H.; Uemura, S. Ce -exchanged montmorillonite (Ce -Mont) as a
useful substrate-selective acetalization catalyst. J. Org. Chem. 1995, 60, 4039–
4043; (c) Firouzabadi, H.; Iranpoor, N.; Kamiri, B. Zirconium tetrachloride
(
compounds. Synlett 1999, 321; (d) Babak, K.; Ebrhimian, G. R.; Hassa, S.
ZrCl )–catalyzed highly chemoselective and efficient acetalization of carbonyl
4
N-Bromosuccinimide (NBS) as a powerful and chemoselective catalyst for

Chemoselective Dimethyl Acetalization
595
acetalization of carbonyl compounds under almost neutral reaction condi-
tions. Synlett 1999, 1456; (e) Karimi, B.; Ashtian, A. 2,3-Dichloro-5,6-
dicyano-p-benzoquinone (DDQ) as a highly efficient and mild catalyst for
diethyl acetalization of carbonyl compounds. Chem. Lett. 1999, 28, 1199; (f)
Basu, M. K.; Samajdar, S.; Becher, F. F.; Banik, B. K. A new molecular
iodine-catalyzed acetalization of carbonyl compounds. Synlett 2002, 319–
321; (g) Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier, B. A.;
Smith, R. C.; Mohan, R. S. A simple and versatile method for the synthesis
of acetals from aldehydes and ketones using bismuth triflate. J. Org. Chem.
2
002, 67, 5202–5207; (h) Gopinath, R.; Haque, S. J.; Patel, B. K. Tetrabuty-
lammonium tribromide (TBATB) as an efficient generator of HBr for a effi-
cient chemoselective reagent for acetalization of carbonyl compounds. J. Org.
Chem. 2002, 67, 5842–5845; (i) Hamada, N.; Kazahaya, K.; Shimizu, H.;
Satao, T. An efficient and versatile procedure for the synthesis of acetals from
aldehydes and ketones catalyzed by lithium tetrafluoroborate. Synlett 2004,
1074–1076; (j) Ranu, B. C.; Jana, R.; Samanta, S. A simple, efficient, and
general procedure for acetalization of carbonyl compounds and deprotection
of acetals under the catalysis of indium(III) chloride. Adv. Synth. Catal.
2
004, 346, 446–450; (k) Kumar, R.; Chakraborti, A. K. Copper(II) tetrafluor-
oborate as a novel and highly efficient catalyst for acetal formation. Tetrahe-
dron Lett. 2005, 46, 8319–8323; (l) Kumar, D.; Kumar, R.; Chakraborti, A. K.
Tetrafluoroboric acid adsorbed on silica gel as a reusable heterogeneous dual-
purpose catalyst for conversion of aldehydes=ketones into acetals=ketals and
back again. Synthesis 2008, 1249–1256.
4
. Knochel, P.; Singer, R. D. Preparation and reactions of polyfunctional orga-
nozinc reagents in organic synthesis. Chem. Rev. 1993, 93, 2117–2188.
. (a) Ranu, B. C.; Hajra, A. Highly selective one-pot conversion of THP and
MOM ethers to acetates by indium triiodide–catalysed deprotection and sub-
sequent transesterification. J. Chem. Soc., Perkin Trans. 1 2001, 2261–2265; (b)
Islam, S.; Majee, A.; Mandal, T.; Khan, A. T. Selective thioacetalization of
aledehyde catalyzed by aquous tetrafluoroborate. Synth. Commun. 2004, 34,
5
2
911–2916; (c) Islam, S.; Majee, A.; Khan, A. T. Tetrahydropyranylation
and depyranylation of alcohols catalyzed by aqueous zinc tetrafluoroborate.
Synth. Commun. 2005, 35, 1789; (d) Majee, A., Kundu, S. K.; Islam, S. A mild
and efficient method oxathioacetalyzation for carbonyl compounds. Synth.
Commun. 2006, 36, 3637–3640.