NCS with thiourea as highly efficient catalysts for acetalization of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.01.006

NCS/thiourea-mediated acetalization of aldehydes and alcohols has rapidly provided acetals in almost quantitative yields.

Full text of DOI:10.1016/j.tetlet.2009.01.006

Tetrahedron Letters 50 (2009) 4199–4200
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NCS with thiourea as highly efficient catalysts for acetalization of aldehydes
*
Y. Mei, P. A. Bentley , J. Du
Department of Chemistry and Chemical Biology, MSC03 2060, University of New Mexico, Albuquerque, NM 87131-0001, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
NCS/thiourea-mediated acetalization of aldehydes and alcohols has rapidly provided acetals in almost
Received 20 October 2008
Revised 21 December 2008
Accepted 6 January 2009
Available online 10 January 2009
quantitative yields.
Ó 2009 Published by Elsevier Ltd.
The selective protection of aldehydes is important for synthetic
strategy and is commonly achieved by the formation of O,O-acetals.1
This acetalization can be promoted with alcohols in the presence of
protic acids,2–6 Lewis acids,7–16 transitional metal complexes as cat-
alysts17,18, and under basic conditions.19,20 Cheaper environmen-
tally benign catalysts, such as clays,21 resins, zeolites,22 polymer-
supported reagents23, and functionalized silica,24 have also been
employed. However, these methods require high catalyst loading,
stoichiometric amounts of acid, long reaction time or high tempera-
ture that may be incompatible with other sensitive functionality.
In recent years, NBS and I2 have been used as catalysts to pro-
mote acetalization reactions under almost neutral conditions and
with good chemoselectivity, but either needed to be handled under
inert atmosphere condition or the substrates were toxic.25–29 We
have recently focused upon thiourea catalysis of chlorohydrins,30
entry 3) were selected to study the variation of the alcohol.
Methanol was replaced with ethanol (Table 2, entry 1) or benzyl
alcohol (Table 2, entry 2) without significant change in reaction
duration or yield. However, the use of the sterically more
Table 1
NCS- and thiourea-catalyzed acetalization of 3-phenylpropionaldehyde with meth-
anol
O
O
Catalyst
MeOH (6 cm3), 23 ºC
Ph
O
Ph
H
2
1
, 2.0 mmol
Entry
Catalyst (mol %)
Time
9 h
<5 min
15 min
1 h
Yield (%)
b-chloroether31, and
optimal solvents. When ketones were replaced with aldehydes
the product isolated was the acetal (not the -chloroaldehyde).
a
-chloroketones32 with NCS and alcohols as
1
2
3
4
5
6
NCS (110)
92
85
92
76
91
94
NCS (110) + thiourea (2)
NCS (5) + thiourea (2)
NCS (2) + thiourea (2)
NCS (110) + thiourea (1)
NCS (5) + thiourea (1)
a
Acetal formation had previously been catalyzed by thiourea, yet
catalysis of acetalization with both NCS and thiourea offered much
faster reactions.
10 min
45 min
Without thiourea aldehyde (1) transformation was slow (Table
1, entry 1), yet the acetalization catalyzed by as little as 2 mol %
thiourea rapidly occurred with good yield of the acetal (2) (Table
1, entry 2), half of this thiourea gave a slightly slower reaction with
a higher yield (Table 1, entry 5). Alternatively less NCS demon-
strated similar trends with duration and yield (Table 1, entry 3)
that ended with 2 mol %, which caused a significant drop in yield
(Table 1, entry 4). If both thiourea and NCS diminished simulta-
neously again the duration of the reaction increased, but high
yields were retained (Table 1, entry 6).
Table 2
NCS/thiourea-catalyzed acetalization of 3-phenylpropionaldehyde with a variety of
alcoholsa
5 mol% NCS
R
O
O
O
O
2 mol% Thiourea
or
R
O
Ph
1
H
Ph
Ph
ROH (6 cm3), 23 ºC
3
4
, 2.0 mmol
Entry
ROH
Product
Time (min)
Yield (%)
Alternative acetal protection groups were then explored.33
Suitably fast, high yielding and economic conditions (Table 1,
1
2
EtOH
BnOH
iPrOH
3, R@Et
3, R@Bn
3, R@iPr
4
15 min
15 min
45 min
168 h
90
89
61
92
3
4a
HOCH2CH2OH
* Corresponding author. Tel.: +1 505 277 0369; fax: +1 505 277 2609.
E-mail address: pabco21@gmail.com (P.A. Bentley).
a
Ethylene glycol (2 mmol) anhydrous THF (6 cm3).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.006

4200
Y. Mei et al. / Tetrahedron Letters 50 (2009) 4199–4200
Table 3
Acknowledgments
NCS/thiourea-catalyzed acetalization of a variety of aldehydes with methanola
Financial support from the Department of Chemistry and Chem-
ical Biology and the Research Allocation Committee, University of
New Mexico is gratefully acknowledged.
5 mol% NCS
2 mol% Thiourea
MeOH (6 cm3), 23 ºC
O
O
R
O
R
H
2.0 mmol
Supplementary data
Entry
Product
Time
Yield (%)
1
2
3
4
5
R@n-C7H15
R@n-C8H17
R@n-C9H19
R@n-C10H21
R@n-C11H23
45 min
45 min
45 min
45 min
45 min
92a
95a
94a
97a
99a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.006.
References and notes
6
7
45 min
45 min
2.5 h
94a
97a
50b
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