Secondary amine catalyzed retro-aldol reactions of enals and enones: One-pot conversion of enals to α-substituted derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.039

A practical synthetic procedure to hydrolytically cleave the C,C-double bond of α,β-unsaturated aldehydes and ketones has been developed. Secondary amines are employed as organocatalysts for the retro-aldol process under simple and mild reaction conditions. Beside the generation of the parent aromatic aldehydes, the synthetic procedure has been successfully used in a one-pot reaction sequence to convert simple cinnamaldehydes into their α-aryl/alkyl substituted derivatives.

Full text of DOI:10.1016/j.tetlet.2012.02.039

Tetrahedron Letters 53 (2012) 2091–2095
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Secondary amine catalyzed retro-aldol reactions of enals and enones:
one-pot conversion of enals to
a-substituted derivatives
⇑
Dieter Enders , Thanh V. Nguyen
Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, D52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthetic procedure to hydrolytically cleave the C,C-double bond of
a,b-unsaturated alde-
Received 23 December 2011
Revised 4 February 2012
Accepted 8 February 2012
Available online 15 February 2012
hydes and ketones has been developed. Secondary amines are employed as organocatalysts for the
retro-aldol process under simple and mild reaction conditions. Beside the generation of the parent aro-
matic aldehydes, the synthetic procedure has been successfully used in a one-pot reaction sequence to
convert simple cinnamaldehydes into their
a
-aryl/alkyl substituted derivatives.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Retro-aldol
Cinnamaldehyde
Iminium activation
a,b-Unsaturated aldehydes
Organocatalysis
Benzaldehydes, an important class of carbonyl compounds, are
valuable aromas in food, beverages, cosmetics, and pharmaceutical
industries.1,2 More importantly, benzaldehydes are synthetic start-
ing materials for various families of structurally complex com-
pounds. Hence, the production of benzaldehydes from natural
and synthetic resources has always been in high demand.1–4 Re-
cently, the synthesis of benzaldehyde from natural cinnamon oil,
which contains cinnamaldehyde, has drawn widespread attentions
from synthetic chemists and industrial engineers.5–11 Many pro-
duction procedures have been developed to carry out this process,
including critical-water hydrolysis,5,6 alkaline hydrolysis,7–12
hydrolysis on surfactants7–10 or employment of natural catalysts
such as cyclodextrins,3,4 glycerine1 and proline12 to facilitate the
hydrolysis of cinnamaldehyde to benzaldehyde. However, these
processes have several drawbacks,3,4 such as requiring very harsh
conditions, incomplete conversion of cinnamaldehyde and low
yield of benzaldehyde. Hence, it is still desirable to develop a
new mild and simple method for the highly effective conversion
of cinnamaldehyde to benzaldehyde. Herein, we would like to de-
scribe a practical synthetic approach to produce benzaldehydes
from cinnamaldehydes under very mild reaction conditions,
employing an iminium-catalytic process. The method could also
Iminium catalysis is recognized as one of the most efficient
modes of activation in organocatalysis.13 The catalysts, normally
secondary amines, react with the carbonyl compounds lacking a
hydrogen atom at the a-position to form iminium ion species, thus
activating the system for nucleophilic attacks.13 The reversible
formation of the iminium ion lowers the energy of the LUMO asso-
ciated with the
p-electron system and activates it for subsequent
reactions, which include a wide variety of cycloaddition and
conjugate addition reactions.14 During the work in our group on
iminium activation of
a,b-unsaturated aldehydes by secondary
amines, we noticed that conjugated C,C-double bonds were
cleaved in the presence of water. We reasoned that water could
act as a nucleophile to attack and hydrolyze the C,C-double bond
of the iminium-activated species in a retro-aldol fashion. Although
numerous examples of similar transformation have been reported
to occur under harsh conditions using strong Brønsted bases,7–12
a
systematic method for organocatalyzed hydrolysis of the C,C-dou-
ble bond of the
a,b-unsaturated carbonyl compounds has never
been fully developed.15
We started our investigation by screening different secondary
amine catalysts for the retro-aldol reaction (Table 1). Cinnamalde-
hyde (1) was exposed to 0.5 equiv of secondary amine catalysts in
THF solution in the presence of 2.0 equiv of water (Eq. 1, Table 1).
For most of the catalysts tested, the reactions went smoothly at
room temperature, giving benzaldehyde (2) in good yields (entries
1–5, Table 1). However, acyclic amines such as dibenzylamine and
diisopropylamine showed poorer catalytic activity, and the
reactions with these two amines were not complete within 1 day
be applied to other classes of
a,b-unsaturated carbonyl com-
pounds. Preliminary studies to use this synthetic approach in
one-pot reaction sequences are reported.
⇑
Corresponding author. Fax: +49 241 809 2127.
E-mail address: enders@rwth-aachen.de (D. Enders).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.039

2092
D. Enders, T. V. Nguyen / Tetrahedron Letters 53 (2012) 2091–2095
Table 1
Catalyst screening for the retro-aldol hydrolysis
catalyst (0.5 eq)
H2O (2.0 eq)
CHO
CHO
(1)
THF, rt
1
2
Entrya
1d
Catalyst
Reaction time (day)
1
Conversionb (%)
88
Yield 2c (%)
N
H
64
H
N
2d
3
1
1
90
69
73
100
N
H
O
4
1
100
70
N
H
5
1
2
2
100
25
81
5
N
H
6e
7e
N
CF3CO2
H2
17
3
CO2H
N
H
a
b
c
Reaction conditions: 1 M THF solution, cinnamaldehyde (1.0 equiv), catalyst (0.5 equiv), water (2.0 equiv), rt.
Determined by 1H NMR with 1,3,5-triisopropylbenzene as internal standard.
Yield of isolated benzaldehyde after column chromatography.
After 1 day, the reaction was stopped.
d
e
After 2 days, the reaction was stopped.
(entries 2–3, Table 1). Among the cyclic amines that gave complete
conversion after 24 h, pyrrolidine seemed to be the best catalyst for
the currently studied conditions, yielding 81% of benzaldehyde
(entry 5, Table 1).
Table 2
Solvent screening for the retro-aldol hydrolysis
pyrrolidine (0.5 eq)
CHO
CHO
H2O (2.0 eq)
As iminium activation is often carried out with a Brønsted acid
(2)
co-catalyst,13 we also studied the reaction with the trifluoroacetate
solvent, rt
1
2
ammonium salt of pyrrolidine (entry 6, Table 1) and L-proline (en-
Entrya
Solvent
Reaction time (day)
Conversionb (%)
Yield 2c (%)
try 7, Table 1). However, these catalysts gave unsatisfactory results,
with incomplete conversion and low yields of benzaldehyde. We
think that in these cases the pH of the reaction medium is low, dis-
favoring the nucleophilic addition of water to the C,C-double bond.
It should be noted here that acetaldehyde (bp = 21 °C), the other
product of the reaction, is volatile under the reaction conditions.
We continued to investigate the effect of solvents on the reac-
tion (Eq. 2, Table 2). Cinnamaldehyde was again treated with
0.5 equiv of pyrrolidine and 2.0 equiv of water in various solvents.
The initial study without adding any organic solvent to the reaction
mixture gave very poor conversion and yield (entry 1, Table 2), so
we chose several organic solvents that are miscible with water to
facilitate the reaction. Out of the four solvents tested, tetrahydro-
furan, acetonitrile and dimethylsulfoxide gave comparable results
with clean reactions and high yields of benzaldehyde (entries 2,
4, 5, Table 2). The best yield of 2 was obtained in acetonitrile in
89%. On the other hand, methanol led to disappointing results with
complex reaction mixtures and low yields of benzaldehyde (entry
3, Table 2). We presumed that the methanol solvent might inter-
fere with the iminium ion formation process by forming a hemiac-
etal with cinnamaldehyde 1. Although both of these processes are
reversible, it is possible that the abundant nature of methanol lim-
ited the formation of iminium ions.
1d
2
3
4
5
No solvent
THF
MeOH
DMSO
MeCN
2
1
1
1
1
10
100
67
100
100
Trace
81
5
83
89
a
Reaction conditions: 1 M solution, cinnamaldehyde (1.0 equiv), pyrrolidine
(0.5 equiv), water (2.0 equiv), rt.
Determined by 1H NMR with 1,3,5-triisopropylbenzene as internal standard.
b
c
Yield of isolated benzaldehyde after column chromatography.
No other organic solvent was added. After 2 days, the reaction was stopped.
d
After identifying the best catalyst and solvent for the retro-aldol
reaction of cinnamaldehyde 1, we decided to optimize the catalyst
loading and amount of water added to the reaction (Eq. 3, Table 3).
The amount of added pyrrolidine was varied from 0.1 to 1.0 equiv
while keeping the amount of water constant at 2.0 equiv. The reac-
tion time was prolonged more with less pyrrolidine as the catalyst
(entries 1, 2, 4, 7, Table 3). However, 0.3 equiv of pyrrolidine was
sufficient to catalyze the reaction to full conversion after 12 h at
room temperature in a very good yield of benzaldehyde (entry 4,
Table 3). Then, the amount of water added was varied from 1 to
10 equiv at 0.3 equiv catalyst loading (entries 3–6, Table 3). The re-

D. Enders, T. V. Nguyen / Tetrahedron Letters 53 (2012) 2091–2095
2093
Table 3
Table 4
Optimization of catalyst loading and amount of water
Retro-aldol hydrolysis of cinnamaldehydes16
pyrrolidine
pyrrolidine (0.3 eq)
H2O (2.0 eq)
CHO
H2O
CHO
CHO
CHO
(3)
(4)
MeCN, rt
MeCN, rt, 12 h
1
2
3
4
R
R
Entrya Catalyst (equiv) Water (equiv) Reaction timeb (h) Yield 2c (%)
Entrya
3,4
R
Product 4
Yieldb 4 (%)
1
2
3
4
5
6
7
1.0
0.5
0.3
0.3
0.3
0.3
0.1
2
2
1
2
4
6
8
84
91
85
88
86
76
53
CHO
18
12
12
12
84
1
2
a
H
88
CHO
OMe
10
2
b
c
o-MeO
p-MeO
83
77
a
Reaction conditions: 1 M acetonitrile solution, cinnamaldehyde (1.0 equiv),
CHO
pyrrolidine, water, rt.
b
Reaction time for 100% conversion checked by TLC.
Yield of isolated benzaldehyde after column chromatography.
3
4
c
MeO
CHO
NO2
d
e
o-NO2
p-NO2
84
79
sults of these reactions revealed that 2.0 equiv are probably the
optimal amount of water, as yields of 2 started to decrease when
there was more than 4.0 equiv of water in the reaction mixture.
This trend agrees well with the result of entry 1, Table 2 reported
above.
With the optimized reaction conditions for the retro-aldol
hydrolysis of cinnamaldehyde 1 in hand, we then investigated
the scope of this reaction on a series of substituted cinnamaldehy-
des 3a–h (Eq. 4, Table 4). The reaction worked well on all of the
substituted cinnamaldehydes tested (Table 4), giving high yields
of aromatic aldehydes 4a–h.16 The mixture of Z and E (1:9) isomers
of 4-tert-butylcinnamaldehyde and 4-phenylcinnamaldehyde also
gave the related aldehydes in good yield (entries 7,8, Table 4).
Thus, a catalytic amount of pyrrolidine could facilitate the hydroly-
sis of cinnamaldehydes to their corresponding aromatic aldehydes
under mild reaction conditions.
CHO
CHO
5
6
O2N
N
f
p-NMe2
91
83
CHO
7
8
g
p-tBu Z:E = 1:9
CHO
h
p-Ph Z:E = 1:9
86
We then tried to expand the scope of this retro-aldol hydrolysis
further by examining several other classes of a,b-unsaturated car-
a
Reaction conditions: 1 M acetonitrile solution, cinnamaldehyde (3, 1.0 equiv),
bonyl compounds (Eq. 5, Table 5). These included three aliphatic
aldehydes and three chalcones (Table 5). The hydrolysis of the ali-
phatic aldehydes 5a–c worked smoothly using the optimized reac-
tion conditions developed above (entries 1–3, Table 5). However,
pyrrolidine (0.3 equiv), water (2.0 equiv), rt, 12 h.
b
Yield of isolated aldehyde 4 after column chromatography.
the reactions with a,b-unsaturated ketones (chalcones 5d–f, Table
to form 11a–c under pyrrolidine catalysis.19 Three examples,
where R was a methyl or phenyl group, have been carried out
with moderate to good overall yields.20 The final outcome of this
one-pot two-step reaction is equivalent to an alkylation/arylation
5) were sluggish, so a small amount of trifluoroacetic acid was
added and the temperature was elevated to facilitate the iminium
ion formation (entries 4–6, Table 5).17 With the Brønsted acid co-
catalyst, hydrolysis of the chalcones proceeded well, giving a
moderate yield of the products. It is possible that the inverse aldol
at the
a-position of cinnamaldehydes 8. Thus, the developed ret-
condensation had affected the yield of the reaction with
a,b-unsat-
ro-aldol hydrolysis procedure could be utilized to facilitate an
interesting chemical transformation that would be difficult by
other means.21 Work on further synthetic applications of this
procedure is currently in progress.
urated ketones, different to that of ,b-unsaturated aldehydes
a
where the acetaldehyde by-product is volatile. Yields of products
7d–f were generally lower than that of 6e–f, presumably due to
the fact that they formed the homo aldol products under the
reaction conditions.18 In brief, although the retro-aldol hydrolysis
In conclusion, a practical synthetic procedure to hydrolytically
cleave the C,C-double bond of
a,b-unsaturated aldehydes and ke-
did not work perfectly on
a,b-unsaturated ketones, this synthetic
tones has been developed. It employs the secondary amines as
procedure still gave encouraging results.
organocatalysts for a retro-aldol process under simple and mild
At this stage, we wanted to further extend the synthetic
applications of the developed secondary amine catalyzed retro-
reaction conditions. Several classes of
a,b-unsaturated carbonyl
compounds have been successfully transformed using this proce-
dure, including the valuable cinnamaldehydes. This synthetic pro-
cedure has been successfully employed in a one-pot reaction
aldol hydrolysis procedure of
a,b-unsaturated carbonyl com-
pounds. In a preliminary study, this process was successfully
employed in a one-pot two-step reaction where cinnamaldehy-
sequence to convert cinnamaldehydes into
cinnamaldehydes. Future directions to develop the reported chem-
istry will focus on optimizing catalyst/reaction conditions for ,b-
unsaturated ketones and -substituted ,b-unsaturated aldehydes
a-aryl/alkyl substituted
des 8a–c were converted into
a-substituted cinnamaldehydes
11a–c (Scheme 1). First, cinnamaldehydes 8a–c were hydrolyzed
to the aromatic aldehydes 9a–c with pyrrolidine as the catalyst.
a
a
a
Subsequently, aldehydes with two
a-hydrogen atoms (10a–c)
and including this synthetic transformation in further organocata-
were added to the same reaction mixtures to react with 9a–c
lytic cascade sequences.

2094
D. Enders, T. V. Nguyen / Tetrahedron Letters 53 (2012) 2091–2095
Table 5
Scope of the retro-aldol hydrolysis of a
,b-unsaturated carbonyl compounds17
pyrrolidine
H2O
R2
R3
R3
R2
R1
O
H3C
O
(5)
MeCN
R1
O
7
5
H
6
Entry
Substrate
Additive
Reaction time (h)
Product 6
Yield 6a (%)
Yield 7a (%)
Aliphatic
a
,b-unsaturated aldehydes
1b
2b
a
—
—
12
12
a
62c
79
n.d.
n.d.
CHO
CHO
CHO
CHO
CHO
b
b
3b
c
—
12
c
90
n.d.
O
Chalcones
O
CHO
4d
d
e
f
TFA
TFA
TFA
48
48
48
d
e
f
49
53
51
36
41
39
O
CHO
5d
Cl
Cl
O
CHO
6d
a
b
c
Yield of isolated product after column chromatography, unless otherwise noted.
Reaction conditions: 1 M acetonitrile solution, unsaturated carbonyl compound (5, 1.0 equiv), pyrrolidine (0.3 equiv), water (2.0 equiv), rt.
The reaction was performed in d3-acetonitrile; yield determined by crude 1H NMR with 1,3,5-triisopropylbenzene as internal standard
d
Reaction conditions: 1 M acetonitrile solution, unsaturated carbonyl compound (5, 1.0 equiv), pyrrolidine (0.5 equiv), water (3.0 equiv), trifluoroaceticacid
(TFA, 0.1 equiv), 50 °C.
1. Pyrrolidine (0.5 eq)
H2O (2.0 eq)
MeCN, rt, 12 h
5. Gao, F.; Lv, X. Y. J. Chem. Ind. Eng. (China) 2006, 20, 544–547.
6. Dolfini, J. E.; Glinka, J. U.S. Patent 4,709,098, 1987.
7. Chen, L.T.; Huang, T.S.; Zhu, J.Q.; Lai, G.Y. Patent CN1634837A, 2004.
8. Cui, J. G.; Wang, C. S.; Liao, X. H. Chem. World 2002, 6, 315–317.
9. Zhu, F. G.; Zhou, S. H. Fine Chem. 2002, 19, 678–681.
10. Ye, J.D.; Zhou, W.Y. Patent CN1179934C, 2003.
11. Pittet, A.O.; Muralidhara, R.; Liberman, A.L. U.S. Patent 46,833,42A, 1986.
12. Wiener, C.; Pittet, A. O. U.S. Patent 4,617,419, 1986.
CHO
CHO
8
11
R2
R2
rt, 12 h
CHO (2.5 eq)
R1
R1
2.
NH
R2
CHO
13. Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.
14. Brazier, J. B.; Tomkinson, N. C. O. Top. Curr. Chem. 2010, 291, 281–347.
15. See for example Ref. 1,3,4,12 on the hydrolysis using organic compounds such
as cyclodextrin, proline and glycine as reagents or catalysts. However, these
examples either involve the use of inorganic Brønsted bases or are ineffective.
On the other hand, there have been several literature examples describing
organocatalyzed retro-aldol reactions of b-hydroxy carbonyl compounds:
Flock, A. M.; Reucher, C. M. M.; Bolm, C. Chem. Eur. J. 2010, 16, 3918–3921;
Luo, S.; Zhou, P.; Li, J.; Cheng, J. P. Chem. Eur. J. 2010, 16, 4457–4461.
CHO
R1
10
cat.
Retro-Aldol
Aldol
9
: R1 = H, R2 = Me:
54%
: R1 = OMe, R2 = Me: 69%
: R1 = OMe, R2 = Ph: 51%
a
b
c
Yield 11
16. General procedure for the retro-aldol reaction of cinnamaldehydes: To
a
solution of cinnamaldehyde (3, 1 mmol, 1.0 equiv) in acetonitrile (1 mL) were
added water (2 mmol, 2.0 equiv) and pyrrolidine (0.3 mmol, 0.3 equiv). The
reaction mixture was stirred at room temperature for 12 h under argon, after
which it was filtered through a short pad of MgSO4 and washed with dry
dichloromethane. The solvent of the filtrate was removed in vacuo and the
residue was chromatographed on silica gel (dichloromethane/hexane; 7:3) to
give the aromatic aldehyde 4. All aldehydes 3a–h and 4a–h are either
commercially available or have been described previously, and their analytical
data match literature values.
Scheme 1. One-pot retro-aldol/aldol condensation to convert cinnamaldehydes 8
to -substituted cinnamaldehydes 11.
a
Acknowledgments
We thank BASF SE and the former Degussa AG for the donation
of chemicals. Dr. Thanh V. Nguyen thanks the Alexander von Hum-
boldt Foundation for supporting his research stay at RWTH Aachen
with the AvH postdoctoral fellowship.
17. General procedure for the retro-aldol reaction of chalcones: To a solution of
chalcone (5, 1 mmol, 1.0 equiv) in acetonitrile (1 mL) were added water
(3 mmol, 3.0 equiv), pyrrolidine (0.5 mmol, 0.5 equiv) and trifluoroacetic acid
(0.1 mmol, 0.1 equiv). The reaction mixture was stirred at 50 °C for 48 h under
argon, after which it was cooled to rt and quenched with aqueous saturated
NH4Cl solution. The organic products were extracted with dichloromethane
(3 Â 10 mL). The combined organic phases were dried over MgSO4 and
concentrated in vacuo. The residue was chromatographed on silica gel
(dichloromethane/hexane; 7:3) to give the aromatic aldehyde 6 and aromatic
ketone 7. All of the products 6d–f and 7d–f are either commercially available
or have been described previously, and their analytical data match literature
values.
References and notes
1. Wolken, W. A. M.; Tramper, J.; Van Der Werf, M. J. Flavour Frag. J. 2004, 19, 115–
120.
2. Berger, R. G. Flavours and Fragrances; Springer: Berlin Heidelberg, 2007.
3. Chen, H.; Ji, H.; Zhou, X.; Wang, L. Tetrahedron 2010, 66, 9888–9893.
4. Chen, H. Y.; Ji, H. B. AIChE J. 2010, 56, 466–476.
18. Traces of dimerized products of 7 could be found in the reaction mixture.

D. Enders, T. V. Nguyen / Tetrahedron Letters 53 (2012) 2091–2095
2095
19. General procedure for the retro-aldol/aldol one-pot condensation of
cinnamaldehydes: To a solution of cinnamaldehyde (8, 1 mmol, 1.0 equiv) in
acetonitrile (1 mL) were added water (2 mmol, 2.0 equiv) and pyrrolidine
(0.5 mmol, 0.5 equiv). The reaction mixture was stirred at room temperature
for 12 h under argon and aldehyde 10 (2.5 mmol, 2.5 equiv) was subsequently
added. After another 12 h at rt, the reaction mixture was filtered through a
short pad of MgSO4 and washed with dry dichloromethane. The solvent of the
filtrate was removed in vacuo and the residue was chromatographed on silica
11. Compounds 11a–c are either commercially available or have been
described previously, and their analytical data match the literature values.
20. The backward retro-aldol hydrolysis of 11–9 did not seem to occur, probably
because
a-substituted a,b-unsaturated aldehydes are much less activated by
iminium catalysis due to steric hindrance: Yang, J. W.; Fonseca, M. T. H.; List, B.
Angew. Chem., Int. Ed. 2004, 43, 6660–6662.
21. Arylation/alkylation at this position could possibly be carried out via recently
developed Heck-type coupling chemistry, see review: Arpad, M. Chem. Rev.
2011, 111, 2251–2320 and references therein
gel (dichloromethane/hexane; 7:3) to give the a-substituted cinnamaldehyde