Radical mediated-direct conversion of aldehydes into acid bromides

Article abstract of DOI:10.1016/j.tetlet.2006.11.013

A method of preparing acid bromides directly from aldehydes with Br₃CCO₂Et under radical conditions was developed. Aromatic aldehydes with electron-donating group were found to be more reactive than aromatic aldehydes with electron-w

Full text of DOI:10.1016/j.tetlet.2006.11.013

Tetrahedron Letters 48 (2007) 285–287
Radical mediated-direct conversion of aldehydes into acid bromides
Dong Ho Kang,a Tae Young Joo,a Warinthorn Chavasiric and Doo Ok Janga,b,
*
aDepartment of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
bCenter for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Republic of Korea
cDepartment of Chemistry, Faculty of Science, Chulalongkorn University, 10330, Thailand
Received 7 October 2006; revised 28 October 2006; accepted 2 November 2006
Available online 27 November 2006
Abstract—A method of preparing acid bromides directly from aldehydes with Br3CCO2Et under radical conditions was developed.
Aromatic aldehydes with electron-donating group were found to be more reactive than aromatic aldehydes with electron-withdraw-
ing group and aliphatic aldehydes under reaction conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
Acid halides have been utilized as important inter-
mediates for the synthesis of esters, amides, and other
carboxylic acid derivatives.1 Although a variety of
coupling reagents have also been reported for the forma-
tion of these compounds directly from carboxylic acids,2
there is still a need to utilize acid halides for preparing
various carboxylic acid derivatives because the coupling
reagents failed in forming the desired compounds such
as amides with carboxylic acids and amines with low
nucleophilicity or steric hindrance.3 Accordingly, many
procedures for the preparation of acid halides have been
developed. The general synthetic methods are mainly the
transformation of carboxylic acids into acid halides.3,4
However, the examples of direct conversion of alde-
hydes into acid halides were very rare. Chlorine,5 cesium
fluoroxysulfate,6 and 1-chloromethyl-4-fluoro-1,4-di-
azoniabicyclo[2.2.2]octane bis(tetrafluoroborate)7 were
used for the direct transformation of aldehyde into acid
halides under ionic reaction conditions. Sulfuryl chlo-
ride,8 t-butyl hypochlorite,9 carbon tetrachloride,10 and
NBS11 were utilized for the purpose under radical reac-
tion conditions.12 However, these methods suffered from
disadvantages including the use of corrosive reagents,
strong acidic conditions, or the limitations on substitu-
ents of substrates such as olefinic functions. Accord-
ingly, development of a new and convenient method
for direct conversion of aldehydes into acid halides is
invaluable in organic synthesis. Herein, we report on a
simple procedure of preparing acid bromides from alde-
hydes with ethyl tribromoacetate (Br3CCO2Et) under
radical reaction conditions.
The procedure of the transformation of aldehydes into
acid bromides is quit simple. A mixture of benzaldehyde,
Br3CCO2Et (2.0 equiv), and benzoyl peroxide (BPO) in
chlorobenzene was heated to 110 °C for 24 h. Because
of moisture sensitivity of acid halide, the produced acid
bromide was converted into the amide derivative by
treatment with cyclohexylamine in the presence of
Et3N affording cyclohexyl benzamide in 72% yield (Table
1, entry 2). A small increase of the amide was attained
with 3.0 equiv of Br3CCO2Et (entry 3). The same
reaction was carried out with lauroyl peroxide or Et3B
instead of benzoyl peroxide as radical initiator giving
low to moderate yields of the amide (entries 4 and 5).
We presumed that Br3CNO2 is more reactive than
Br3CCO2Et since a radical intermediate from Br3CNO2
might be more stable and then readily generated. When
the reaction was performed with Br3CNO2, 61% of the
amide was obtained (entry 6). The reactivity of CCl3CN
as a radical halogenating reagent was also examined to
give a moderate yield of the amide (entries 7 and 8).
Among the radical halogenating reagents we have
examined, Br3CCO2Et afforded the highest yield of acid
bromide from aldehyde under the present conditions.
To examine the scope and limitations of the present
process, we then carried out the reaction with various
aromatic and aliphatic aldehydes using Br3CCO2Et/
BPO, which was the most effective condition. These
Keywords: Acid bromide; Aldehyde; Radical; Ethyl tribromoacetate;
Amide.
*
Corresponding author. Tel.: +82 337602261; fax: +82 337602208;
e-mail: dojang@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.013

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D. H. Kang et al. / Tetrahedron Letters 48 (2007) 285–287
Table 1. Conversion of benzaldehyde into N-cyclohexylbenzamide via benzoic acid bromide under various radical reaction conditionsa
O
O
Halogenating reagent/
Initiator
110 oC, 24 h
Cyclohexylamine (1.5 equiv)
Et3N (3.0 equiv), rt, 1 h
H
N
H
Entry
Halogenating agent (equiv)
Initiatorb
Solvent
Isolated yield (%)
c
1
2
3
4
5
6
7
8
Br3CCO2Et (2.0)
Br3CCO2Et (2.0)
Br3CCO2Et (3.0)
Br3CCO2Et (2.0)
Br3CCO2Et (2.0)
Br3CNO2 (2.0)
Cl3CCN (2.0)
—
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Benzene
0
72
77
BPO
BPO
LPO
Et3B
BPO
BPO
AIBN
55
32d
61
Chlorobenzene
Chlorobenzene
41d
48d
e
Cl3CCN (8.0)
—
a The initiator was added portionwise (0.2 equiv).
b BPO = benzoyl peroxide, LPO = lauroyl peroxide, AIBN = 2,20-azobisisobutyronitrile.
c Without initiator.
d The reaction was carried out at 80 °C.
e The reaction was performed at 80 °C without solvent.
results are presented in Table 2. Under these reaction
conditions, aromatic aldehydes with electron-donating
groups such as 3,4-dimethoxybenzaldehyde, p-methoxy-
benzaldehyde, and p-tert-butylbenzaldehyde reacted and
produced the corresponding amides in high yields
(entries 1–3). The treatment of slightly deactivated aro-
matic aldehydes such as p-chlorobenzaldehyde and m-
bromobenzaldehyde under the same conditions gave
the corresponding amides in moderate yileds (entries 4
and 5). On the other hand, the yields of amide decreased
with aromatic aldehydes that have electron-withdrawing
groups (entries 6 and 7). Similarly, we examined the
reactivity of aliphatic aldehydes under these conditions.
When heptanal and stearaldehyde were brought in to
react under these conditions, the corresponding amides
were obtained in moderate yields (entries 8 and 9).
The above results implied that the rate-determining step
for the reaction was very sensitive to the electronic effect
Table 2. Preparation of amides from various aldehydes
Entry
Aldehyde
MeO
Productb
Yield (%)a
75
O
H
CHO
CHO
MeO
MeO
C N
1
MeO
O
H
2
3
4
72
69
69
MeO
tBu
Cl
MeO
tBu
Cl
C N
O
C
H
N
CHO
O
H
N
CHO
C
O
H
CHO
C N
5
6
61
51
Br
Br
O
H
O2N
CHO
O2N
C N
O
H
CHO
C N
7
8
55
52
58
O2N
O2N
O
H
CH3(CH2)5CHO
CH3(CH2)5C N
O
H
9
CH3(CH2)16CHO
CH3(CH2)16C N
a Isolated yield.
b Identification of the products was confirmed by comparison with available physical and spectroscopic data of authentic compounds.

D. H. Kang et al. / Tetrahedron Letters 48 (2007) 285–287
287
although the intermediate of the reaction was presumed
to be a radical.
mixture was cooled to room temperature, and Et3N
(210 lL, 1.5 mmol) and cyclohexylamine (73 lL,
0.75 mmol) were added subsequently. The mixture was
stirred at room temperature for 1 h, and the mixture
was diluted with CH2Cl2, washed with water, and dried
over anhydrous MgSO4. After evaporation, the residue
was purified by column chromatography on silica gel
eluting with hexane/EtOAc (8:2) to give p-methoxy-N-
cyclohexyl benzamide (84 mg, 72%): mp 159–162 °C
(lit.13 159–162 °C); IR (KBr) 3331, 2936, 2853, 1626,
Next, we examined the generality of the present process
by varying the amines at the second step. The results are
presented in Table 3. The reaction of 3,4-dimethoxy-
benzaldehyde with secondary amines under the present
reaction conditions gave high yields of the correspond-
ing amides (entries 1–3), while the reaction with a steri-
t
cally hindered amine, BuNH2, or weakly nucleophilic
amines such as 1-naphthylamine and 1,2,3,4-tetrahydro-
quinoline gave moderate yields of the corresponding
amides.
1608, 1335, 1253, 1029 cmꢀ1 1H NMR (CDCl3) d
;
1.64–2.07 (m, 10H), 3.87 (s, 3H), 3.95–4.00 (m, 1H),
5.91 (br, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.74 (d,
J = 8.8 Hz, 2H); MS m/z (relative intensity) 233 (M+,
26), 151 (39), 135 (100), 92 (8), 77 (11).
In conclusion, we developed a method of preparing acid
bromides directly from aldehydes with readily available
Br3CCO2Et under radical conditions. The present
process is easy to perform, and could be applied to the
preparation of various acid bromides. In addition, the
present method afforded several advantages including
neutral reaction conditions and low toxicity of the
reagents.
Acknowledgments
This work was supported by joint research project under
the KOSEF-NRCT cooperative program (F01-2004-
000-10252-0) and CBMH.
A typical experimental procedure is as follows. A mixture
of p-methoxybenzaldehyde (62 lL, 0.5 mmol) and
Br3CCO2Et (487 mg, 1.5 mmol) in chlorobenzene
(4 mL) under argon was heated to 110 °C for 24 h. Dur-
ing the reflux, benzoyl peroxide (121 mg, 0.5 mmol) was
added portionwise to the mixture four times. The
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