Application of flow chemistry to the selective reduction of esters to aldehydes

Article abstract of DOI:10.1002/ejoc.201101458

The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity. Copyright

Full text of DOI:10.1002/ejoc.201101458

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101458
Application of Flow Chemistry to the Selective Reduction
of Esters to Aldehydes
[a]
[a]
[b]
[b]
Juan de M. Muñoz, Jesús Alcázar,* Antonio de la Hoz, and Angel Díaz-Ortiz
Keywords: Reduction / Aluminum / Microreactors / Aldehydes
The reduction of esters to aldehydes is an important transfor-
mation in organic chemistry and several reducing agents
have been described. However, the use of this reaction in
medicinal and natural product chemistry is limited due to the
instability of the intermediates and the high reactivity of the
reaction products. In the current article, the general and se-
lective reduction of esters with diisobutyl-tert-butoxyalumi-
num hydride in flow is reported. This reagent allows esters
to be reduced in the presence of different functional groups,
including those considered to be of similar or higher reactiv-
ity.
Introduction
volume ratio in microchannels and this permits very ef-
ficient heat transfer and, as a consequence, good control of
The partial and chemoselective one-step reduction of es- the reaction temperature, thus avoiding the problems asso-
ters to aldehydes is an important transformation in organic ciated with highly exothermic reactions. Mass transfer is
chemistry and several reducing agents have been described also enhanced and the use of dangerous or air- and moist-
to perform this reaction.[1] Among them, diisobutylalumi- ure-sensitive compounds is improved due to the lower reac-
num hydride (DIBAL-H) has become the most popular rea- tion volume. Optimization of reaction conditions is per-
gent for this transformation, although its use requires very formed by control of residence time and scalability of this
low temperatures and provides moderate yields due to the kind of reaction is simply a matter of pumping, mixing, and
[2]
instability of the intermediates formed. Other reducing quenching the reagents continuously through the microre-
agents have also been reported: lithium tri-tert-butoxyalu- actor. This approach permits rapid experimentation and
[3]
minum hydride (LTBA), bis(4-methyl-1-piperazinyl)alumi- scale-up, thus shortening the time from research to develop-
[
4]
num hydride, lithium tris(diethylamino)aluminum hydride ment and production. From an environmental point of
[
5]
[9]
[
(
(
LiAlH(NEt ) ], sodium diethylpiperidinohydroaluminate view, production of hazardous waste is also reduced.
2
3
[
6]
SDPA), and lithium diisobutylpiperidinohydroaluminate
LDBPA). However, these reagents cannot achieve the re-
[
7]
duction of both aromatic and aliphatic esters. More re-
cently, lithium diisobutyl-tert-butoxyaluminum hydride
Results and Discussion
(
LDBBA) was reported as a more effective and general re-
In order to overcome the limitations in the reduction of
[
8]
ducing agent. Due to the lack of a general procedure, this esters to aldehydes, we envisaged the application of flow
transformation is usually carried out in total syntheses in a chemistry to this transformation. We used the commercially
two-step sequence: complete reduction to the alcohol fol- available cooling module of the R2+R4 Vapourtec reactor.
lowed by reoxidation to the aldehyde.[
2c]
One of the lines was fed with the ester and the other with
In recent years, flow chemistry and microreactors have the reducing agent. Both streams were conditioned in the
appeared as novel technologies that, among other advan- module at the reaction temperature and mixed in a T-mixer.
tages, allow much better control of reactions where unstable The mixture was then matured in a coil. The output of the
intermediates are involved, as these species are produced coil was poured into a quenching solution. Alternatively,
and reacted in line. Microreactors have a high surface-to- the output could be directed to a column containing the
scavenger and then collected (Figure 1). No difference in
the outcome of the reaction was observed between on-line
and off-line workup.
[
a] Janssen, Pharmaceutical Companies of Johnson & Johnson,
C/ Jarama 75, Toledo, Spain
Fax: +34-925245771
To the best of our knowledge, only two examples involv-
ing the use of DIBAL-H in this context have been de-
scribed. In both cases, an aliphatic ester was reduced in
E-mail: jalcazar@its.jnj.com
[b] Facultad de Ciencias Químicas,
Universidad de Castilla-La Mancha, Ciudad Real, Spain
Fax: +34-926295318
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101458.
[
2c,10]
good yields to its corresponding aldehyde.
Following
these initial reports we explored the use of DIBAL-H to
260
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 260–263

Flow Chemistry for the Selective Reduction of Esters to Aldehydes
more unreacted starting material was found in an overall
cleaner reaction mixture (Table 1, Entry 8). On increasing
the flow rate, while using the same number of equivalents,
the optimal conditions were obtained for retention times
between 10 and 20 min (Table 1, Entry 9 vs. Entries 8 and
10).
The conditions reported in Table 1, Entry 9 were selected
to explore the scope of the reaction and they proved to be
very successful for a wide range of compounds (Table 2). In
this way, different functional groups were compatible with
this reagent, regardless of their electron-donating or elec-
tron-withdrawing properties and their position in the aryl
Figure 1. Experimental set up of the flow system.
reduce ethyl benzoate (1a) to benzaldehyde (2a), but the ring (see 1a–h). It is worth noting the selective reduction of
conditions explored proved unsuccessful (Table 1, En- the ester group can occur in the presence of a cyano group
tries 1–4). These results are consistent with the previously (see 1e). Reduction of nitriles has been described with lith-
reported reduction of methyl 4-bromobenzoate to its corre- ium diisobutylisopropoxyaluminum hydride (LDBIPA), a
sponding alcohol in flow with DIBAL-H.[
10]
[11]
reducing agent similar to LDBBA.
This example was
scaled up 20-fold with almost identical yield, thus demon-
strating the value of flow technology.
Table 1. Reaction optimization using ethyl benzoate.
Table 2. Scope of the reaction.
Entry
[H]
Equiv.
T
°C
t
Conversion / %[a]
Compd.
R
Yield / % Compd.
R
Yield / %
/
/ min
1a
2a
3a
1
1
1
a
b
c
C
6
H
5
79
80
83
1j
1k
1l
3-pyridyl
2-pyridyl
4-pyrazolyl
2-Br-5-thi-
enyl
97
94
97
1
2
3
4
5
6
7
8
9
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
LDBBA
LDBBA
LDBBA
LDBBA
LDBBA
LDBBA
1
1
1
1
1.3
1.3
1.3
1.1
1.1
1.1
1.2
–70
–40
–20
0
2.5
0.5
0.5
2.5
20
20
20
20
10
53
50
50
53
1
3
3
7
0
0
0
0
75
72
61
79
77
32
74
39
42
43
39
16
14
27
14
13
8
p-FC
p-ClC
-Cl-4-
FC
6
H
4
6
H
4
2
89[b]
1d
85
1m
6
H
4
0
1
1
1
e
e
f
m-CNC
m-CNC
p-MeOC
o-MeOC
p-MeC
4-pyridyl
6
H
H
H
H
4
97
1n
1o
1p
1q
1r
1s
5-oxazolyl
benzyl
80
87
90
79
80
84
–20
25
0
0
0
96[
85
82
90
76
a]
6
4
6
4
4
n-propyl
cinnamyl
4-Br-butyl
N-Boc-4-
piperidinyl
1
1
g
h
6
10
56
–
H
4
1
0
5
180
6
[b]
1i
1
1
LDBBA
0
–
[
a] Conversion by GC–MS. [b] Batch reaction as described in ref.[8]
[
a] Reaction performed on 18 mmol scale. [b] LDBBA (1.3 equiv.).
According to these results, the selective reduction of aryl
esters is difficult with this reducing agent and, for this
Heteroaromatic esters were also reduced effectively. Pyr-
reason, we considered other reducing agents. As described idyl analogues 1i–k provided the corresponding aldehydes
in the Introduction, LDBBA appears to be the most general in good to excellent yields. Pyrazolyl 1l and thienyl 1m were
and effective alternative to DIBAL-H. Both reagents can also reduced, although the latter required a larger excess of
be handled similarly, having the caution of injecting them the reducing agent. Aliphatic esters, such as benzyl and
under an inert atmosphere. The first conditions tried in flow alkyl esters (i.e., 1o–s) were also examined. These were con-
[
8]
were based on the batch procedure described previously
Table 1, Entry 11). The results were similar (Table 1, En- tions used for aromatic esters. It is remarkable that other
try 5) but the reaction was complete in 20 min instead of reducible groups, such as conjugated double bonds (i.e., 1q)
h. The reaction was optimized by modulating the tem- or alkyl halides (i.e., 1r), were not transformed, proving the
verted into their corresponding aldehydes under the condi-
(
3
perature, time, and equivalents of reducing agent to reduce high selectivity of this reducing agent. As a final example,
the amount of alcohol 3a and to increase the amount of Boc-protected piperidine 1s was selected to check that these
aldehyde 2a (Table 1, Entries 6–10). Decreasing the tem- reaction conditions are compatible with this widely used
perature did not improve the selectivity over 3a (Table 1, protecting group.
Entry 6). When the temperature was increased to 25 °C,
Encouraged by the results obtained, four experiments
more over-reduction product was observed (Table 1, En- were designed to explore further the selectivity of the reac-
try 7). Decreasing the equivalents of reducing agent pro- tion: Selective reduction of one ester group in a diester com-
vided the expected aldehyde in similar yields, although pound, selective reduction of esters in the presence of an
Eur. J. Org. Chem. 2012, 260–263
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
261

J. de M. Muñoz, J. Alcázar, A. de la Hoz, A. Díaz-Ortiz
SHORT COMMUNICATION
aldehyde, selective reduction between alkyl and aryl esters, secondary esters was tested with compounds 9 and 1b. Ac-
and selective reduction between primary and secondary es- cording to the original article, both esters were reduced un-
[
8]
ters (Scheme 1).
der the same conditions. Under flow conditions, the ethyl
ester was reduced selectively in the presence of the isopropyl
one, with a 2b/2a ratio of 5:1. Similar results were achieved
in batch after 3 h of reaction but there was almost no con-
version after 10 min, thus demonstrating the efficiency of
the flow approach.
Conclusions
In summary, the reduction of esters to aldehydes with
LDBBA in flow has proven to be a valuable alternative to
batch procedures. Aromatic, aliphatic, heteroaromatic, and
heteroaliphatic aldehydes were obtained in good to excel-
lent yields under flow conditions. It is important to high-
light the selective reduction of an ester group in the pres-
ence of an aldehyde, the selective reduction of a single ester
group, which cannot be achieved under traditional batch
conditions, and the selective reduction of a primary ester in
the presence of a secondary ester. All of these results offer
new possibilities for the preparation of more complex mole-
cules in medicinal and natural product chemistry.
Experimental Section
General Procedure for the LDBBA Reduction in Flow: The manifold
system (pumps, valves, PFA tubing, and reactor coil) of a Vapour-
tec R2+R4 unit was dried with isopropyl alcohol (2 mL/min,
15 min) and anhydrous THF (0.5 mL/min, 20 min). A solution of
the ester (0.909 mmol, 1 equiv.) in THF was loaded into a sample
[
8]
loop (2 mL) on a Vapourtec R2+R4. A solution of LDBBA
1 mmol, 1.1 equiv.) in THF/hexane was loaded into a second sam-
(
ple loop (2 mL). The two sample loops were switched in-line into
streams of THF, each flowing at 0.250 mL/min, and mixed in the
cold reactor at 0 °C. The mixture was then matured in the cold
reactor by using the 5 mL coil. The output of the coil was then
poured directly into a 1 m HCl solution. The reaction mixture was
extracted with ethyl acetate. The organic layer was separated, dried
Scheme 1. Selectivity of LDBBA reductions.
The first example, selective reduction of one ester group
in diester 4, was achieved easily in flow under the standard
conditions. By contrast, the reaction was not complete in
batch after 3 h of reaction, and dialdehyde 6 was identified.
It is worth noting that in batch conditions, in a comparable
reaction time to that used for flow conditions (10 min), di-
ester 4 remained unaltered in solution. This is a good exam-
ple of an outcome that can only be achieved by flow. As
long as diester 4 is reduced to compound 5 this latter com-
pound does not come into contact with more LDBBA to
be reduced to dialdehyde 6, as is the case in batch mode.
The second example, the selective reduction of an ester
in the presence of an aldehyde, was tested with compound
(
MgSO
Workup On-Line: The output of the coil was directed into a 10 mm
diameter Omnifit column filled with Na SO ·10H (2 g,
.20 mmol) and MgSO (1 g, 8.3 mmol). The solution collected was
evaporated to dryness.
4
), filtered, and concentrated to dryness.
2
4
2
O
6
4
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization of compounds, and
GC–MS of selective LDBBA reductions.
Acknowledgments
The authors acknowledge financial support from the Dirección Ge-
neral de Ciencia y Tecnología (DGCYT) of Spain (project
CTQ2010-14975/BQU) and the Junta de Comunidades de Castilla-
La Mancha (Program HITO 2010-54 and project PII2I09-0100)
and thank Dr. Daniel Oelhrich for his assistance during the prepa-
7. Unexpectedly, the ester was reduced selectively to alde-
hyde 8. To the best of our knowledge this is a unique exam-
ple of ester reduction in the presence of a more reactive
group such as an aldehyde.
Unfortunately, it was not possible to obtain selectivity ration of this article.
between alkyl or aryl esters. When both 1r and 1a were
present in solution, they were reduced almost to the same
extent. Finally, the selective reduction between primary and
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[
Received: October 6, 2011
Published Online: December 1, 2011
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