One-pot oxidative bromination – Esterification of aldehydes to 2-bromoesters using cerium (IV) ammonium nitrate and lithium bromide

Article abstract of DOI:10.1016/j.tetlet.2016.12.036

A two-step, one-pot reaction of aldehydes with the CAN/LiBr oxidation system under solvent-free conditions followed by the addition of methanol affords methyl α-bromocarboxylates. The oxidation of aldehydes with methanol using this system gives only methyl esters. A facile method, which does not require special equipment, was developed for the synthesis of 2-bromoesters from aliphatic aldehydes with carbon chain lengths of 5–10 atoms.

Full text of DOI:10.1016/j.tetlet.2016.12.036

Accepted Manuscript
One-pot oxidative bromination - esterification of aldehydes to 2-bromoesters
using cerium(IV) ammonium nitrate and lithium bromide
Gennady I. Nikishin, Nadezhda I. Kapustina, Lyubov' L. Sokova, Oleg V.
Bityukov, Alexander O. Terent'ev
PII:
S0040-4039(16)31671-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.036
TETL 48448
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 October 2016
9 December 2016
13 December 2016
Please cite this article as: Nikishin, G.I., Kapustina, N.I., Sokova, L.L., Bityukov, O.V., Terent'ev, A.O., One-pot
oxidative bromination - esterification of aldehydes to 2-bromoesters using cerium(IV) ammonium nitrate and lithium
bromide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.036
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One-pot Oxidative Bromination-
Esterification of Aldehydes to α-Bromoesters
Using Cerium(IV) Ammonium Nitrate and
Lithium Bromide
Leave this area blank for abstract info.
Gennady I. Nikishin, Nadezhda I. Kapustina, Lubov’ L. Sokova, Oleg V. Bityukov, Alexander O. Terent’ev

1
Tetrahedron Letters
One-pot oxidative bromination - esterification of aldehydes to 2-bromoesters using
cerium(IV) ammonium nitrate and lithium bromide
Gennady I. Nikishin a, Nadezhda I. Kapustina a, Lyubov’ L. Sokova a, Oleg V. Bityukov a and Alexander O.
Terent’ev  a,b
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991, Russian Federation
b D.I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya square, Moscow, 125047, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A two-step, one-pot reaction of aldehydes with the CAN/LiBr oxidation system under solvent-
free conditions followed by the addition of methanol affords methyl α-bromocarboxylates. The
oxidation of aldehydes with methanol using this system gives only methyl esters. A facile
method, which does not require special equipment, was developed for the synthesis of 2-
bromoesters from aliphatic aldehydes with carbon chain lengths of 5 to 10 atoms.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aldehydes
Oxidation
Esterification
Bromination
2-Bromoesters
Cerium(IV) ammonium nitrate (CAN)
1. Introduction
oxone/NaBr,21
H2O2/KBr/PhSO3H,22
PhI(OAc)2/KBr,23
H2O2/ZnBr2,24 and others.9,14
Oxidation of the aldehyde group to the carboxyl group is a
reaction of fundamental importance in organic chemistry. In
recent years the oxidation of aldehydes with alcohols giving
carboxylic acid esters has been extensively developed. These
reactions proceed under mild conditions, often selectively, with a
wide range of oxidants. Initial studies in this area were performed
at the end of the 20th century using oxidation systems including
O3/KOH,1 NaClO/MeCOOH,2 CrO3/pyridine,3 pyridinium
dichromate,4 and N-iodosuccinimide/K2CO3.5 In subsequent
years, oxone,6 S-SnO2/H2O2,7 pyridinium hydrobromide
However, it should be emphasized that the formation of
bromine-containing esters has not been reported in the above
publications, despite the involvement of bromine in the oxidation
process. Thus, the idea of aldehyde oxidation to give 2-
bromoesters has escaped the attention of organic chemists.
The first versatile method for the synthesis of 2-
bromocarboxylic acids and 2-bromoesters, which is still
frequently used, was based on the Hell-Volhard-Zelinsky (HVZ)
reaction – the bromination of carboxylic acids with molecular
bromine in the presence of red phosphorus or phosphorus
tribromide, followed by treatment of the reaction mixture with
water or alcohol.25
11
perbromide,8 CuBr/t-BuOOH,9 PhI(OAc)2,10 and Fe(II)/H2O2
were also used as oxidants. In reactions with alcohols, aromatic
aldehydes have been oxidized to aromatic acid esters in the
presence of Ti(IV)/H2O2,12 V2O3/H2O2,13 TsNBr2/K2CO3,14
CaCl2/H2O2,15 B(C6F5)3/t-BuOOH,16 and LiBr/NaIO4,17 as well as
other oxidation systems.5,8,9,11
2. Results and Discussion
In the present work, we describe a new oxidative
transformation of aldehydes accompanied by additional
functionalization. The one-pot oxidation of aldehydes 1a-f with
the CAN/LiBr system can be used to furnish methyl 2-
bromocarboxylates 2a-f or bromine-free carboxylic acid esters
3a-f depending on the reaction conditions (Scheme 1).
Apart from the oxidative esterification of aldehydes, attention
has been given to the development of original approaches to the
synthesis of esters based on oxidative homo- and cross-
esterification of aliphatic and benzylic alcohols. In the context of
our study, this approach is particularly useful because the
oxidation of alcohols proceeds through the formation of
aldehydes and often with the involvement of bromide ions as the
redox catalyst: PhIO/KBr,18 NaBrO3/HBr,19 H2O2/HBr,20
The reaction was performed under solvent-free conditions in
the “solid-liquid” phase composed of cerium and lithium salts,
———
 Corresponding author. Tel.: +7-916-385-4080; e-mail: terentev@ioc.ac.ru

2
Tetrahedron
the aldehyde, and the esterifying alcohol. An important
advantage of this method over the HVZ synthesis is that it does
not require toxic liquid bromine as the starting reagent.
The reaction conditions for the synthesis of esters 2 were
optimized using the oxidation of heptanal 1c to methyl 2-
bromoheptanoate 2c. The influence of the reagent ratio, the
temperature, and the reaction time on the yields of 2с and 3c
were investigated (Table 1).
Scheme 1. Bromination-oxidation of aldehydes to methyl 2-
bromocarboxylates 2a-f and methyl carboxylates 3a-f.
Table 1. Reaction optimization for the oxidation of heptanal 1с with CAN/LiBr to give methyl 2-bromoheptanoate 2c and methyl
heptanoate 3c.
a
Yield 2c (%)b
Yield 3c (%)b
Entry
Molar ratio 1c:CAN:LiBr:MeOH
Conversion 1c (%)
1
1:1:1:1
1:2:1:1
1:2:1:2
1:3:3:2
1:4:1:2
1:4:2:2
1:4:3:2
1:4:3:2
1:4:4:2
1:5:3:2
1:4:3:2
50
trace
3
45
66
79
40
74
22
11
7
2
80
3
93
trace
48
4
100
97
5
11
6
98
67
7
100
100
95
83
8c
87
9
57
24
19
39
77
10
11d
12e
100
98
63
49
1:4:3:2
99
trace
b
aGeneral reaction conditions: 1c (1 mmol), 20 °C, 20 h. Yield with respect to the starting aldehyde 1c was determined by GC using methyl pentanoate and
methyl decanoate as internal standards. c35-40 °С, 3.5-4 h. dNaBr. eNH4Br.
The best results were obtained using the reagents
1c:CAN:LiBr:MeOH in a ratio of 1:4:3:2 at 20 °С for 20 h or 35-
40 °С for 3.5 h (Table 1, entries 7 and 8). Under these conditions,
ester 2c was obtained in 83% and 87% yield, respectively. A
decrease in the amount of CAN or LiBr led to decreased yields of
ester 2c (Entries 1-6). An increase in the amount of these
reagents also, contrary to expectations, led to decreased yields of
ester 2c and the formation of ester 3c (Entries 9 and 10). The use
of NaBr instead of LiBr had an adverse effect, and esters 2c and
3c were produced in nearly equal yields (Entry 11). The reaction
in the presence of NH4Br instead of LiBr gave only ester 3c
(Entry 12).
In the next step of the work, under the optimized conditions
(Table 1, entries 7 and 8) all aldehydes underwent almost
complete conversion to give the targeted products 2a-f in
moderate to high yields (Table 2). The yields for esters 2a-c with
carbon chain lengths of 5-7 atoms were 80-87% (Entries 1-5),
while the yields for esters 2d-f with increased carbon chain
lengths of 8-10 atoms decreased to 39-71% (Entries 6-11). These
differences can most likely be attributed to steric effects while
electronic effects are not manifested. The yields of esters 3a-f
increased in the series of aldehydes from pentanal to decanal.
Table 2. Oxidation of aldehydes 1a-f with CAN/LiBr to give methyl 2-bromocarboxylate 2a-f.26
a
T (°С)
Time (h)
Conversion 1a-f (%)
Yield 2a-f (%)b
Yield 3a-f (%)b
Entry
1a-f
1
1-pentanal (1a)
20
20
100
100
98
2a, 81 (77)
2b, 80 (78)
2b, 84 (80)
2c, 83 (78)
2c, 87 (82)
2d, 58 (52)
2d, 71 (70)
2e, 39 (35)
2e, 65 (60)
2f, 30 (27)
2f, 59 (53)
3a, 9
2
1-hexanal (1b)
20
20
3b, 11
3b, 10
3c, 11
3c, 7
3
35-40
20
3.5
20
1b
4
1-heptanal (1c)
100
100
98
5
35-40
20
3.5
20
1с
6
1-octanal (1d)
3d, 30
3d, 19
3e, 48
3e, 25
3f, 54
3f, 29
7
35-40
20
3.5
20
100
94
1d
8
1-nonanal (1e)
9
35-40
20
3.5
20
99
1e
10
11
1-decanal (1f)
93
35-40
3.5
98
1f
b
aGeneral reaction conditions: molar ratio 1a-f:CAN:LiBr:MeOH = 1:4:3:2, 1a-f (1 mmol). Yield with respect to the starting aldehyde 1a-f was determined by
GC using methyl pentanoate and methyl decanoate as internal standards. Isolated yield in parenthesis.

3
Based on the results obtained in Table 1, a procedure for the
synthesis of esters 3a-f was developed. The required changes
include altering the sequence for the addition of reagents to the
CAN/LiBr mixture: firstly, methanol was added, followed by the
aldehyde (Table 3).
acid bromides at the α-СН2 group with formation of 2-
bromoalkanoyl bromides (mechanism А). It should be noted that
esters 3a-f cannot be transformed to esters 2a-f under the
experimental conditions given in Table 1. This was exemplified
using methyl heptanoate 3c as starting reagent, which was not
converted into 2-bromocarboxylate 2c (see ESI).
Table 3. Synthesis of methyl esters 3a-f
a
Yield 3a-f (%)b
3. Conclusion
Entry
1a-f
1
2
3
4
5
6
1-pentanal, 1a
1-hexanal, 1b
1-heptanal, 1c
1-octanal, 1d
1-nonanal, 1e
1-decanal, 1f
3a, 78 (70)
3b, 80 (73)
3c, 81 (73)
3d, 81 (70)
3e, 80 (76)
3f, 82 (74)
In summary, a new method was developed for the synthesis
of methyl 2-bromocarboxylates, based on the oxidative
bromination-esterification of aliphatic aldehydes using the
CAN/LiBr system. The reaction proceeds under mild conditions
in the absence of solvent through successive steps: bromination
of the aldehyde to form the carboxylic acid bromide and then to
2-bromocarboxylic acid bromide followed by alcoholysis of the
latter with methanol. Methyl 2-bromoesters were produced in up
to 87% yield. Additionally, a novel procedure was developed for
the synthesis of methyl esters from aldehydes by the oxidation of
the latter together with methanol using the same oxidation
system.
aGeneral reaction conditions: molar ratio 1a-f:CAN:LiBr:MeOH = 1:2:0.3: 2,
1a-f (1 mmol), 35-40 °C, 3.5-4 h. bYield with respect to the starting aldehyde
1a-f was determined by GC using methyl pentanoate and methyl decanoate as
internal standards. Isolated yield in parenthesis.
Under the optimal reaction conditions using the reagents
1:CAN:LiBr:MeOH in a molar ratio of 1:2.1:0.3:2 at 35-40 °C
for 3.5 h, esters 3a-f were obtained in 78-82% yield (Entries 1-6).
The oxidation proceeds without additional solvent, which makes
it convenient for the synthesis of methyl esters.
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (Grant no 16-03-00213 a).
Supplementary Material
Supplementary data (experimental procedures, spectroscopic
data for all of the synthesized compounds) associated with this
article can be found, in the online version, at http://........
References and notes
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2003, 5, 1031-1034.
Scheme 2. Proposed reaction mechanism
Taking into account published data on the oxidative
esterification of aldehydes and the oxidative bromination of
ketones, two alternative mechanisms for the transformation of
aldehydes 1a-f to esters 2a-f can be a priori envisaged (Scheme
2).
7. Qian, G.; Zhao, R.; Ji, D.; Lu, G.; Qi, Y.; Suo, J. Chem. Lett. 2004, 33,
834-835.
Mechanism А involves two key steps: successive bromination
of the aldehyde group and the α-СН2 group followed by
esterification of the resulting 2-bromoalkanoyl bromides with
methanol. This interpretation is consistent with the results of
Minisci and co-wokers.20 It was proposed that the oxidation of
aldehydes to esters in the presence of the H2O2/HBr system
proceeds via bromination of the aldehyde group and alcoholysis
of the resulting acid bromides.
8. Sayama, S.; Onami, T. Synlett 2004, 2739-2745.
9. (a) Yoo, W. -J.; Li, C. -J. J. Org. Chem. 2006, 71, 6266-6268; (b) Yoo,
W. -J.; Li, C. -J. Tetrahedron Lett. 2007, 48, 1033-1035.
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11. Wu, X. -F.; Darcel, C. Eur. J. Org. Chem. 2009, 1144-1147.
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2003, 68, 2944-2947.
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55, 1657-1659.
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S. Bull. Chem. Soc. Jpn. 1986, 59, 747-750.
Mechanism B differs only in the sequence of steps. Thus, the
α-СН2 group is brominated first and is followed by bromination
at the aldehyde group. This could be evidenced by the results for
selective bromination of the α-СН2 group in aliphatic ketones
using the CAN/LiBr system where 2-bromoketones were
produced with high selectivity and high yield.27
That the reaction follows mechanism А is supported by the
results presented in Table 1 (in particular, entries 1 and 2).
According to these results, a decrease in the amount of oxidant
(CAN) from 4 to 1-2 equiv. with respect to heptanal 1c, results in
bromination predominantly occurring at the aldehyde group,
while the α-СН2 group remains virtually intact. Consequently, the
transformation of alkanals to esters 2a-f starts with bromination
of the aldehyde group followed by bromination of the resulting
20. Amati, A.; Dosualdo, G.; Zhao, L.; Bravo, A.; Fontana, F.; Minisci, F.;
Bjørsvik, H.-R. Org. Proc. Res. Dev. 1998, 2, 261-269.
21. Koo, B. -S.; Lee, C. K.; Lee, K. -J. Synth. Commun. 2002, 32, 2115-
2123.

4
Tetrahedron
22.
Moriyama, K.; Takemura, M.; Togo, H. J. Org. Chem. 2014, 79,
6094-6104.
mixture stirred for 20 h at 20 °C (3.5 h at 35-40 °C). The reaction
mixture was cooled, diluted with water (10-15 mL) and extracted with
Et2O (3×10-15 mL). The combined organic phases were washed with
aqueous NaHCO3 (10 mL) and water (10 mL), then dried (MgSO4).
The solvent was removed under reduced pressure (water bath
temperature 25-28 °C). The conversion of 1a-f and the yields of 2a-f
and 3a-f were determined by GLC using methyl pentanoate and methyl
decanoate as internal standards. The isolation of 2-bromoesters 2a-f
was performed using gradient silica gel column chromatography with
petroleum ether (b.p. 40-70 °C):chloroform (10-1:1), as eluent.
Preparative yields of 2a-f were 53-82%.
23. Salvo, A. M. P.; Campisciano, V.; Beejapur, H. A.; Giacalone, F.;
Grutterdauria, M. Synlett 2015, 1179-1184.
24. a) Wu, X. -F. Tetrahedron Lett. 2012, 53, 3397-3399; b) Wu, X.-F.
Chem. Eur. J. 2012, 18, 8912-8915.
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242, 141-163; c) Zelinsky, N. D. J. Russ. Phys. Chem. Soc. 1887, 19,
585; d) Zelinsky, N. D. Ber. 1887, Bd. 20, 2026-2026.
26. Table 2. Oxidation of aldehydes 1a-f with CAN/LiBr to methyl 2-
bromocarboxylate 2a-f. To a pear-shaped two-necked reactor (25
mL) equipped with a thermometer and reflux condenser, CAN (2.2 g,
4.0 mmol) and LiBr (261 mg, 3.0 mmol) were added and stirred. Next,
aldehyde 1a-f (1 mmol) was added and the reaction mixture stirred for
10-15 min. Then MeOH (64 mg, 2.0 mmol) was added and the reaction
27. a) Nikishin, G.I.; Sokova, L.L.; Kapustina, N.I. Russ. Chem. Bull. (Int.
Ed.), 2013, 1214-1217; b) Nikishin, G.I.; Sokova, L.L.; Kapustina, N.I.
Russ. Chem. Bull. (Int. Ed.), 2010, 391-395.

5
Highlights
• Synthesis of α-bromoesters from aldehydes
• Solvent free mild conditions
• One-pot procedure