One-pot synthesis of ω-bromoesters from aromatic aldehydes and diols using pyridinium hydrobromide perbromide

Article abstract of DOI:10.1016/j.tetlet.2005.01.159

A simple and efficient one-pot procedure has been developed for the synthesis of ω-bromoesters from aromatic aldehydes and diols in the presence of pyridinium hydrobromide perbromide (PHPB) and triethoxymethane in which aldehyde reacts first with diol and the product, cyclic acetal, reacts with PHPB to give the final product, ω-bromoesters.

Full text of DOI:10.1016/j.tetlet.2005.01.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1989–1992
One-pot synthesis of x-bromoesters from aromatic aldehydes and
diols using pyridinium hydrobromide perbromide
Tadashi Aoyama,a,* Toshio Takidoa and Mitsuo Kodomarib
aDepartment of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Kanda Surugadai,
Chiyoda-ku, Tokyo 101-8308, Japan
bDepartment of Applied Chemistry, Shibaura Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan
Received 21 December 2004; revised 28 January 2005; accepted 31 January 2005
Abstract—A simple and efficient one-pot procedure has been developed for the synthesis of x-bromoesters from aromatic aldehydes
and diols in the presence of pyridinium hydrobromide perbromide (PHPB) and triethoxymethane in which aldehyde reacts first with
diol and the product, cyclic acetal, reacts with PHPB to give the final product, x-bromoesters.
Ó 2005 Elsevier Ltd. All rights reserved.
In multistep synthesis, acetals, which are generally pre-
pared by acid catalyst such as HCl,1 FeCl3,2 Amber-
two or more transformations in a single operation to
increase the complexity of a product starting from
commercially available, relatively simple precursors.
Herein, we report one-pot synthesis of x-bromoesters
from aromatic aldehydes and diols in the presence of
PHPB as the brominating agent and triethoxymethane
as the dehydrating agent. Quite recently, Sayama et al.
have reported the esterification of aldehydes with alco-
hols in the presence of PHPB in water.14 Using their
conditions, the reaction with diols affords hydroxyesters.
x-Bromoesters are not formed.
7
lyst-15,3 ZrCl4,4 DDQ,5 NBS,6 Bi(NO3)3
and
[Hmim]BF4,8 are well known as a protecting group of
the carbonyl groups. Cyclic acetals are also used for
the synthesis of x-haloesters. For instance, Hanessian
et al. have reported the conversion of cyclic acetals into
the corresponding bromoesters using NBS.9 This reac-
tion is somewhat unique in that it allows a protection
group to be converted into a reactive functionality. Simi-
lar conversions of cyclic acetals are also achieved by
using NBS,10 bromine11 and bromotrichloromethane.12
Ammonium tribromides such as pyridinium hydrobro-
mide perbromide (PHPB) are generally used as an easy
handle and useful brominating reagent instead of bro-
mine. Recently, Patel et al. have reported an acetaliza-
x-Bromoesters (4) were obtained in good yields by the
reaction of aromatic aldehydes (1) with diols (2) in the
presence of PHPB and triethoxymethane (see Table 1).
For instance, a mixture of benzaldehyde (1a) (4 mmol),
ethylene glycol (2a) (16 mmol), PHPB (8 mmol) and tri-
ethoxymethane (4.8 mmol) in dichloroethane (8 mL)
was stirred for 2 h at 50 °C to give 2-bromoethyl benzo-
ate (4aa) in 94% yield.15 Large excess of PHPB and ethyl-
ene glycol were required to obtain the products in high
yields. Among the brominating reagents tested, PHPB
is the best one. NBS also gave 4aa in 73% yield under
the same conditions. Copper(II) bromide did not give
4aa, but benzaldehyde ethylene acetal (3aa) was yielded
in 60%. The reaction with bromotrichloromethane did
not proceed, and 1a was recovered quantitatively.
tion
of
carbonyl
compounds
using
tetra-
butylammonium tribromide (TBATB).13 This procedure
is very efficient and useful for the conversion of carbonyl
compounds into acetals. The key step in this procedure
is a generation of bromine from TBATB. Bromine can
be used instead of TBATB for this reaction, and the ace-
tals are also formed in good yield. However, bromine is
hazardous and difficult to manipulate due to its toxicity
and high vapor pressure. One-pot synthesis has attrac-
ted much interest in recent years because it provides a
simple and efficient entry to compounds by including
Several diols were used for this reaction (Table 2). The
yields of x-bromoesters (4aa–ac) decreased according
to the increase of the alkyl chain length in the diols
(2a–c). The reaction of 1a with 2a in the presence of
Keywords: x-Bromo esters; Pyridinium hydrobromide perbromide.
Corresponding author. Tel./fax: +81 3 3259 0818; e-mail: aoyama@
chem.cst.nihon-u.ac.jp
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.159

1990
T. Aoyama et al. / Tetrahedron Letters 46 (2005) 1989–1992
Table 1. Preparation of x-bromoesters
4da in 81% yield, with m-isomer to give 4ea in 61% yield,
and with o-isomer to give 4fa in 7% yield under similar
conditions. Acetalization of p-nitrobenzaldehyde (1g)
proceeded easily, but the bromoesterification of the
resulting acetal proceeded very slow under the same con-
ditions. However, the reaction of 1g was carried out at
80 °C for 3 h to give 4ga in 78% yield. Reaction of 2a
with terephthalaldehyde (1h) was carried out at 80 °C
for 2 h to give 4ha in 84% yield. 1- and 2-Naphthylalde-
hyde were also converted into the x-bromoesters in
excellent yields. The reaction of 2a with 2-thiophenecar-
boxaldehyde (1k) did not afford the expected bromo-
ester, and 5-bromo-2-formylthiophene (5a) was formed
in 73% yield, in which the bromination of thiophene ring
was prevailed over the acetalization. Resulting product,
5a, was also inactive for acetalization.
O
CH(OEt)3
OH
Ar
+
Ar CHO
Br
HO
Ar
O
1
2
4
O
O
3
Brominating reagent
Yield (%)
None
PHPB
No reaction
94
73
0 (60)a
No reaction
NBS
Copper(II) bromide
Bromotrichloromethane
a Yield of acetal.
PHPB was smoothly proceeded to afford 4aa, whereas
the reaction with 2b gave 4ab in 70% yield along with
a small amount of the corresponding acetal. The reactiv-
ity of 2c was lower than that of 2a under the same con-
ditions, and trace amounts of 4ac and the 3ac were
formed in the reaction with 2c. b-diols (2d–f) also re-
acted with 1a to give the corresponding x-bromoesters
(4ad–af) in good yields. The reactions with 2d and 2f
gave 4ad and 4af along with a small amount of the
regioisomer.
When the reaction of 1k with 2a in the presence of large
excess of PHPB was carried out at 80 °C for 3 h, 5-
bromothiophene-2-carboxylic acid 2-bromoethyl ester
(5b) was obtained in 39% yield. The reaction of aliphatic
aldehyde such as hexanal gave a mixture of the desired
bromoester and the a-brominated cyclic acetal (Scheme
1). These products could not be isolated from the reac-
1
tion mixture, but they were confirmed by GC–MS, H
NMR and the spectral data shown in literature.16
The reaction of 4-methoxybenzaldehyde ethylene acetal
(3ca) with PHPB gave the corresponding bromoester
(4ca) in 52% yield along with 4-methoxybenzaldehyde
(1c). In contrast, the reaction of 1c with 2a using our
conditions afforded 4ca in 92% yield, in which 3ca was
produced first, and then converted into 4ca and starting
A series of aromatic aldehydes were used for this reac-
tion (Table 3). Among monobromobenzaldehydes, the
order of reactivity was p -> m -> o-bromobenzaldehyde;
o-isomer is less reactive than p- and m-isomer. Com-
pound 2a reacted with p-isomer to give the bromoester
Table 2. Preparation of x-bromoesters from diols and benzaldehyde
Diol
Product
Yielda (%)
O
OH
2a
4aa
4ab
4ac
4ad
94
Br
HO
HO
O
O
2b
2c
2d
70
OH
O
O
O
O
Br
O
O
OH
Trace
87b
Br
HO
HO
OH
Br
Br
O
OH
Cl
2e
2f
4ae
4af
89
HO
HO
Cl
O
68b
Br
OH
O
a Isolated yield.
b Contaminated with less than 6% of the regioisomer.

T. Aoyama et al. / Tetrahedron Letters 46 (2005) 1989–1992
Table 3. Preparation of x-bromoesters from ethylene glycol and various aldehydes
1991
Aldehyde
Product
Yielda (%)
O
1b
4ba
4ca
97
92
CHO
Br
O
O
1c
Br
MeO
CHO
O
MeO
Br
O
1d
1e
4da
4ea
81
61
Br
Br
CHO
Br
O
O
CHO
Br
O
Br
O
CHO
Br
7 (45)b
O
1f
4fa
Br
Br
O
1g
4ga
78c
CHO
Br
O2N
O
O2N
Br
O
O
1h
1i
4ha
4ia
84d
95
Br
OHC
CHO
O
O
O
Br
CHO
CHO
O
O
Br
1j
4ja
95
O
1k
5a
5b
73
CHO
CHO
O
Br
Br
S
S
S
O
39e
Br
a Isolated yield.
b Parenthetic numbers indicate the yield of acetal.
c 80 °C/3h.
d 80 °C/2h.
e 80 °C/3h, large excess of PHPB.
2a, PHPB
O
OH
+
2
H
O
O
HO
PHPB
MeO
CHO
MeO
B
3ca
1c
+
P
H
P
O
O
O
Br
Br
MeO
O
+
O
2
2
O
Br
4ca
Scheme 1.
Scheme 2.

1992
T. Aoyama et al. / Tetrahedron Letters 46 (2005) 1989–1992
8. Wu, H. H.; Yang, F.; Cui, P.; Tang, J.; He, M. Y.
Tetrahedron Lett. 2004, 45, 4963.
material, 1c, which was converted to 3ca again (see
Scheme 2). Therefore the reaction completely proceeded
to give 4ca in excellent yield.
9. (a) Hanessian, S. Carbohydr. Res. 1966, 2, 86; (b)
Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035.
10. (a) Hullar, T. L.; Siskin, S. B. J. Org. Chem. 1970, 35, 225;
(b) Anderson, L. C.; Pinnic, H. W. J. Org. Chem. 1978, 43,
3417; (c) Binkley, R. W.; Sivik, M. R. J. Org. Chem. 1986,
51, 2619; (d) Lin, H. X.; Xu, L. H.; Huang, N. J. Synth.
Commun. 1997, 27, 303.
In conclusion, we have achieved an efficient method for
the one-pot synthesis of x-bromoesters from aromatic
aldehydes and diols in the presence of PHPB. This reac-
tion proceeded smoothly under mild conditions to give
x-bromoesters in high yields.
11. Venkataramu, S. D.; Cleveland, J. H.; Pearson, D. E.
J. Org. Chem. 1979, 44, 3082.
12. Collins, P. M.; Manro, A.; Opara-Mottah, E. C.; Ali, M.
H. Chem. Commun. 1988, 272.
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14. Sayama, S.; Onami, T. Synlett 2004, 2739.
15. General procedure: A mixture of aldehydes (4 mmol),
diols (16 mmol), triethoxymethane (4.8 mmol) and pyrid-
inium hydrobromide perbromide (8 mmol) in dichloroeth-
ane (8 mL) was stirred for 2 h at 50 °C. The reaction
mixture was washed with aqueous sodium thiosulfate and
aqueous sodium hydrogensulfite, and removed the solvent
to give the crude product which was purified with column
chromatography on silica gel.
1. Fife, T. H.; Jao, L. K. J. Org. Chem. 1965, 30,
1492.
2. Bornstein, J.; Bedell, S. F.; Drummond, P. E.; Kosloski,
C. L. J. Am. Chem. Soc. 1956, 78, 83.
3. Patwardhan, S. A.; Dev, S. Synthesis 1974, 348.
4. Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999,
321.
5. Karimi, B.; Ashtiani, A. M. Chem. Lett. 1999, 1199.
6. (a) Karimi, B.; Seradj, H.; Ebrahimian, G. R. Synlett
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Org. Lett. 1999, 1, 1737.
7. Srivastava, N.; Dasgupta, S. K.; Banik, B. K. Tetrahedron
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16. Mingotaud, A.-F.; Florentin, D.; Marquet, A. Synth.
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