Multi-component, regio-selective aldol addition of β-ketoesters to aldehydes: Scope and applications

Article abstract of DOI:10.1039/c1ob06229h

Simple and effective multi-component one-pot aldol addition/protection reactions of β-ketoesters to a series of aldehydes in the presence Me ₃SiCl and i-Pr₂EtN have been described. The analysis of the scope of the reaction revealed a

Full text of DOI:10.1039/c1ob06229h

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Multi-component, regio-selective aldol addition of b-ketoesters to aldehydes:
scope and applications†
Vijaykumar More,b Antonia Di Mola,b Gianluca Croce,c Consiglia Tedesco,a Carmen Petronzi,a
Antonella Peduto,b Paolo De Caprariis,b Rosanna Filosab and Antonio Massa*a
Received 22nd July 2011, Accepted 27th September 2011
DOI: 10.1039/c1ob06229h
Simple and effective multi-component one-pot aldol addition/protection reactions of b-ketoesters to a
series of aldehydes in the presence Me3SiCl and i-Pr2EtN have been described. The analysis of the scope
of the reaction revealed a dramatic dependence of the reactivity on the substrates used. Thus the effect
of a catalytic amount of DMF and different reaction conditions was widely investigated. Further
transformations of the aldol adducts were particularly useful to give valuable diols and compounds
with quaternary stereocenters, while X-ray structural analysis gave also important stereochemical
information about this challenging reaction.
were reacted with malonates to give protected aldol adducts11a,b
1. Introduction
and a number of novel 3-substituted isoindolinones were obtained
The aldol addition of readily enolizable 1,3-dicarbonyl com-
reacting 2-cyanobenzaldehyde in the presence of several 1,3-
dicarbonyl compounds.11c However, under the MCR conditions,
pounds is still an important challenge in organic chemistry. Even
though the obtained adducts are valuable intermediates in the total
synthesis of natural products,1,2 a general approach is not available
yet. In the past very few effective methods have been developed
with a limited scope3,4 and the literature witnessed a plethora
of unsuccessful attempts under both metal and organocatalysed
conditions.3,5,6 The main difficulties can be attributed to the scarce
stability of the adducts and to the inadequacy of the current
methodologies that favour condensation (Knoevenagel reaction)
or retro-aldol process instead of the aldol reaction. For these
reasons different strategies and multi-step non-flexible syntheses
have been developed in some cases.7–10
b-ketoesters were almost completely unreactive.11b
Since the branched aldol adducts derived from b-ketoesters
have been obtained only in few cases with a very limited aldehyde
scope,3,11b as part of our program toward a general procedure for
the aldol addition of active methylene compounds, in this article we
disclose of our efforts about the development of multi-component
one-pot aldol addition/protection reactions to b-ketoesters. Then
the usefulness of the obtained adducts is explored in the synthesis
of substituted diols and alkylated products; important mechanistic
insights have been obtained performing 1H NMR experiments.
Only very recently a multicomponent one-pot aldol addi-
tion/protection reaction (MCR) of malonates to aldehydes for
the obtaining of a large class of new aldol adducts in the presence
of Me3SiCl and i-Pr2EtN was developed by our group.11 In
these studies it was clearly demonstrated that the success of
this challenging aldol addition is mainly related to the in situ
trapping of the unstable aldol adducts by chlorosilanes reagents11a,b
or by their intramolecular trapping.11c In this way a series of
aromatic, hetero-aromatic and even simple aliphatic aldehydes
2. Results and discussion
2.1 Multi-component one-pot aldol addition/protection reaction
of b-ketoesters
Under the conditions used for the one-pot aldol addi-
tion/protection reaction of malonates at -20 ◦C, b-ketoesters
revealed themselves to be almost completely unreactive. Only p-
nitro benzaldehyde in the presence of t-butyl acetoacetate 2a and
(-)-methyl acetoacetate 2b gave the silylated adducts in about a
30% yield at -20 ◦C (Scheme 1, Table 1 entries 1–3). In order
aDipartimento di Chimica e Biologia, Universita` di Salerno, Via Ponte Don
Melillo, 84084, Fisciano, (SA), Italy. E-mail: amassa@unisa.it; Fax: +39
089 969603; Tel: +39 089 969565
bDipartimento di Scienze Farmaceutiche, Universita` di Salerno, Via Ponte
Don Melillo, 84084, Fisciano, (SA), Italy
cDISTA-Universita’ del Piemonte Orientale Viale T. Michel, 11, 15121,
Alessandria, Italy
† Electronic supplementary information (ESI) available: General reaction
procedures and spectroscopic data. CCDC reference numbers 837214–
837215. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob06229h
Scheme 1 Multicomponent aldol addition of b-ketoesters.
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Table 1 Multicomponent aldol addition/protection reaction t-butyl acetoacetate 2a with aldehydes in the presence of Me3SiCl and i-Pr2EtN at -20 ◦
C
Entry
Aldehyde (R)
DMF (eq.)
3
Yield (%)a
d.r.b
1
Ph
0
0
0
3a
3b
3c
3b
—
3d
3d
3e
3e
3f
No reaction
31
35
75
No reaction
79
55
80
2
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
4-CNC6H4
4-CNC6H4
2-CNC6H4
2-CNC6H4
4-ClC6H4
1/1
3c
4
1/2/1d
2.5/1
0.3
0.3
0.3
—
0.3
—
0.3
0.3
0.3
5
6
7
8
2.5/1
2.5/1
2/1
9
58
20
10
11
12
2/1
4-OMeC6H4
3-Ph proprionaldehyde
—
—
No reaction
No reaction
a Yields refer to chromatographically pure compounds. b Determined by 1H NMR analysis of crude. c Reaction performed in the presence of (-)-menthyl
acetoacetate 2b. d Mixture of 3 diastereomers.
Table 2 Multicomponent aldol addition/protection reaction of tert-butyl acetoacetate with aldehydes in the presence of Me3SiCl and i-Pr2EtN
Entry
Aldehyde (R)
T ◦
C
DMF (eq.)
Time (h)
3
Yield (%)a
d.r.b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
-20 ◦
C
0.3
—
—
0.3
—
0.3
—
0.3
—
0.3
0.3
48
48
72
72
72
72
72
72
72
72
72
3a
3a
3a
3a
—
—
3f
No reaction
No reaction
42%
0 ◦
rt
rt
rt
rt
rt
rt
rt
rt
rt
C
1/1
2/1
51%
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
No reaction
No reaction
60%
72%
45%
66%
10%
1.5/1
1.6/1
1.5/1
1.7/1
1.3/1
4-ClC6H4
3f
9
3-Ph proprionaldehyde
3-Ph proprionaldehyde
Ph
3g
3g
3h
10
11c
1
a Yields refer to chromatographically pure compounds. b Determined by H NMR analysis of crude. c Methyl acetoacetate 2c was used instead of of
tert-butyl acetoacetate.
to overcome this disappointing situation several conditions and
strategies were explored. A significant increase of the reactivity
was observed when a catalytic amount of DMF was used (Table
1, entry 4). Thus, we were pleased to observe high yields of
the silylated aldol adducts in the presence of several aromatic
aldehydes bearing strong electron-withdrawing groups like nitro
and cyano both in para and ortho position (Table 1, entries 4, 6
and 8), while without DMF a significant lower yield was observed
(Table 1, cf entries 7 and 9). The presence of a chlorine substituent,
strongly decreased the reactivity, while benzaldehyde and non-
activated aldehydes did not react at all (Table 1, entries 5, 11
and 12). As could have been expected, this MCR guarantees high
regioselectivity in all the cases for the attack of the aldehydes at
the methylene group only, even if 3 were obtained with rather low
diastereoselectivity.
The use of DMF was suggested by the well-known effect of
activation of trimethylsilyl nucleophiles, like silyl enol ethers, by
Lewis bases in a number of C–C bond forming reactions.12,13 1H
NMR experiments at room temperature in CDCl3 of mixture of
TMS-Cl, t-butyl acetoacetate and iPr2EtN revealed the formation
of silyl enol ether intermediates in 1/1 ratio with unreacted starting
materials after only 2 h, while similar experiments in the presence
of di-t-butyl malonate left the starting materials unreacted.
Probably the improvement of the reaction rate is a consequence of
DMF activation of these silyl enol ether intermediates.
In order to improve the reactivity of less reactive aldehy-
des, different reaction temperature, higher concentrated reaction
medium, different solvents and even in solvent-free conditions,
different amines and bases in combination with Me3SiCl were
tried. The most relevant results are summarized in Table 2 and
3. Starting from the conditions of Scheme 1, it can be seen
that the modification of three parameters leads to a sufficient
reactivity. In the presence of 0.3 eq of DMF, at room temperature
and after 72 h, we obtained a 51% yield for 3a (Table 2,
entries 1–4). In these new conditions, the effect of DMF is
still evident for benzaldehyde (Table 2, cf entries 3 and 4) and
other aldehydes. For example when p-chloro benzaldehyde and
the aliphatic 3-phenyl proprionaldehyde were used, we observed
72% and 66% yields respectively, whereas without the Lewis base
the yields were lower (cf entries 7–8 and 9–10 of Table 2). The
result of the aliphatic aldehyde is particular interesting because
self-condensation products have not been observed, while also
under these conditions, p-methoxy benzaldehyde was not reactive
(Table 2, entries 5–6). Moreover another disappointing result was
observed with methyl acetoacetate 2c for which the aldol adduct
3h was obtained in a 10% yield only (Table 2, entry 11).
Since a positive effect on the reaction rate was exerted by the
increasing of the temperature, we used higher boiling solvents like
1,2-dichloroethane and THF at refluxing conditions (Scheme 2,
Table 3). Focusing on less reactive substrates, a good yield was
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Table 3 Multicomponent aldol addition/protection reaction of tert-butyl acetoacetate with aldehydes in the presence of Me3SiCl and i-Pr2EtN
Entry
Aldehyde (R)
R¢
Solvent
Time (h)
3
Yield (%)a
d.r.b
1
Ph
Ph
Ph
Ph
Me
Me
Me
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
1,2-Dichloroethane
THF
8
8
18
8
8
8
8
8
8
3h
3h
3h
3a
3i
55
50
32
57
42
84
78
68
56
62
35
39
1.3/1
1.5/1
1.3/1
1.2/1
1.3/1
1.4/1
1.5/1
1.6/1
1.3/1
1.3/1
1.2/1
1/1
2c
3
4
5
6
7
8
9
10
11
12
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
p-OMeC6H4
p-ClC6H4
p-BrC6H4
2-Furfural
3-Ph proprionaldehyde
Ph
3f
3l
3m
3g
3a
3i
18
18
18
p-OMeC6H4
Ph
THF
THF
3h
a Yields refer to chromatographically pure compounds. b Determined by 1H NMR analysis of crude. c Reaction performed with 0.3 eq of DMF.
useful for preparative purposes. In fact the adducts 3 show very
interesting functionalities that could be subjected to different sets
of transformations to give valuable compounds. For example,
according to Scheme 3, the versatility and the stability of 3 was
firstly tested treating 3h with NaBH4 and with TBAF for the
deprotection of the resulting crude mixture. This sequence easily
provided the valuable known diols 4,14a,d that otherwise require
longer synthesis with the use of toxic metal reagents, but that can be
readily converted into b-lactams and b-lactones.14 According to 1H
NMR analysis on the crude, all the 4 diastereomers were detected
in comparison with those reported by Fleming et al.14a and the two
major isomers 4a and 4c were easily isolated by chromatography.
From the comparison of the diastereomeric ratios of 3h and 4,
we can confidently attribute the stereochemistry of the isomers of
3h as those described in Scheme 3. This stereochemical outcome
Scheme 2 Multicomponent aldol addition of b-ketoesters.
obtained with methyl acetoacetate and benzaldehyde (entry 1,
Table 3).
However the use of DMF did not give any significant improve-
ment to the reactivity and for this reason all the experiments
of Table 3 were performed without this additive (Table 3, entry
2). Longer reaction time led to the disappearance of the starting
materials with the concomitant decrease of the yield due to the
formation of decomposition products (Table 3, entry 3). Among
the tested aldehydes, we observed a moderate reactivity even
with the poorly reactive p-methoxybenzaldehyde (Table 3, entry
5). Furfural, p-chlorobenzaldehyde and p-bromobenzaldehyde
showed good results (Table 3, entries 6–8), while only in the
presence of 3-phenyl propionaldehyde we observed a lower yield
for the formation of decomposition products (cf entry 9 of Table 3
with entry 11 of Table 2) The use of THF led to an increase of the
yield in the presence of benzaldehyde and t-butyl acetoacetate
(entry 10), while we did not observe any improvement when
methyl acetoacetate and p-methoxybenzaldehyde were used (Table
3, entries 11 and 12).
1
can be generalised to all the adducts 3 for the analogy of H
NMR spectra. All the aldols 3 have usually been obtained as an
inseparable mixture of diastereomers. However the minor isomer
of 3e has been isolated by chromatography and easily crystallised
in CH2Cl2. Fortunately these crystals were suitable for X-ray
structural analysis, the obtained structure is reported in Fig. 1.
As it can be seen, the relative configuration of the minor isomer
of 3e (SR,RS) is in agreement with what was previously supposed
for 3h in Scheme 3 even though with a different ester group.
Moreover, when we submitted a 1.3/1 mixture of the two
diastereomers 3a with the supposed configuration as shown in
Scheme 4, to NaBH4 reduction, we obtained quantitatively a
3/1.5/1 mixture for the three main diastereomers of 5, as observed
2.2 Synthetic applications of aldol adducts
1
by carefully analysis of H NMR spectrum. The major diastere-
omer 5a was isolated by chromatography and treated with TBAF
to give the deprotected diol 6 quantitatively. This compound was
All the developed methods can be easily employed for gram
scale synthesis of the aldol adducts, a feature that is particularly
Scheme 3 Reduction and deprotection reactions of aldol 3h.
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Scheme 4 Reduction and deprotection reactions of aldol 3a.
Scheme 5 Diastereoselective alkylation of aldol 3a.
(Scheme 5). Very interestingly, employing the usual 1.3/1 mixture
of the two diastereomers, we obtained the alkylated product 7 in
the enriched 95/5 ratio in 75% yield in 48 h.
Shorter reaction time (24 h) gave 7 in rather low yield (35%).
However in this case the unreacted 3a was recovered in 35% yield
with an enriched 70/30 diastereomeric ratio. Unfortunately 7 was
obtained as an oil and we were not able to crystallise it for X-
ray analysis for a rationalization of the stereochemical outcome.
Considering the importance in the construction of quaternary
centers in stereoselective manner and the fact that, to the best
of our knowledge, similar diastereoselective alkylations are rare,15
further studies are in course to expand the scope of the aldols in
this field.
Fig. 1 ORTEP structure of 3e.
3. Conclusions
In conclusion we have developed a series of multicomponent one-
pot aldol addition/protection reactions of b-ketoesters with a
wide range of aldehydes to give protected aldol adducts in the
presence of Me3SiCl and i-Pr2EtN. The use of catalytic amounts
of DMF led to an increase in the reactivity with aldehydes
bearing electron-withdrawing groups, while less reactive aldehydes
required different solvents and refluxing conditions. Subsequently,
the investigation of the formation of silyl enol ethers of b-
ketoesters also gave important mechanistic insights into the role
that DMF can play. Finally, as examples of the possibilities of
further functionalization of the obtained aldols, 3a and 3h were
submitted to a sequence of reduction and deprotection reactions to
give valuable diols, while alkylation reactions afforded quaternary
stereocentre with high diastereoselectivity. Considering the variety
of versions and reaction conditions that this MCR of b-ketoesters
can tolerate, we think that this work can give important perspective
for a general approach to the aldol addition of other readily
enolizable active methylene compounds. Since the class of active
Fig. 2 ORTEP structure of 6.
crystallised again by slow evaporation of CH2Cl2 solution and the
X-ray scattering gave the structure reported in Fig. 2. The configu-
ration of the three stereocentres 1¢RS, 2SR, 3SR, confirmed what
was previously supposed by simple analogy. The aldol addition of
ethyl 2-methyl acetoacetate to benzaldehyde so as to give an aldol
adduct with contiguous tertiary and quaternary stereocenters was
unsuccessful under conditions of both Scheme 1 and 2. However, in
order to further expand the range of applications of the obtained
aldols 3, we examined the reactivity of 3a as nucleophile under
alkylation conditions in the presence of CH3I and K2CO3 in DMF
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methylene compounds is very large and presents different struc-
tural motifs, in future studies particular emphasis will be given to
other applications of this methodology and of the obtained aldol
adducts in the synthesis of valuable compounds. Other studies are
also in course for the development of enantioselective versions of
these difficult aldol additions.
the reaction was quenched with saturated aqueous NaHCO3
(5 mL), extracted with 15 ¥ 3 mL of CH2Cl2 and dried over
anhydrous Na2SO4. After removing the solvent under reduced
pressure, the crude oil was purified by flash chromatography with
hexane/AcOEt mixture from 90/10 to 1/1 to afford the pure
products 5.
Experimental
Procedure for conversion of 5a into 6
General remarks
5a was dissolved in THF (1.0 mL) and TBAF (25 ml of 1.0 M
solution in THF) was added at 0 ◦C and reacted for 30 min. Then
the mixture was treated with saturated aqueous NaCl (5 mL),
extracted with 15 ¥ 3 mL of CH2Cl2 and dried over anhydrous
Na2SO4. After removing the solvent under reduced pressure, the
crude oil was purified by flash chromatography with 1/1 mixtures
of hexane and AcOEt to afford the pure product 6.
All reactions were performed in oven-dried (140 ◦C) or flame-
dried glassware under dry N2. Dichloromethane was reagent grade
and was dried and distilled immediately from CaH2 before use.
Column chromatographic purification of products was carried out
using silica gel 60 (230–400 mesh, Merck). The reagents (Aldrich
and Fluka) were used without further purification. The NMR
spectra were recorded on Bruker DRX 400, 300, 250 spectrometers
1
Procedure for alkylation of 3a
(400 MHz, 300 MHz, 250 MHz, H; 100 MHz, 75 MHz, 62,5
MHz 13C). Spectra were referenced to residual CHCl3 (7.26 ppm,
1H, 77.23 ppm, 13C). Coupling constants J are reported in Hz.
Yields are given for isolated products showing one spot on a
TLC plate and no impurities detectable in the NMR spectrum.
Mass spectral analyses were carried out using an electrospray
spectrometer, Waters 4 micro quadrupole. Elemental analyses
were performed with FLASHEA 1112 series-Thermo Scientific
for CHNS-O apparatus.
K2CO3 (0.27 mmol) was added to a solution of 3a (0.11 mmol)
and CH3I (0.33 mmol) in DMF (1.0 mL), at r.t. and reacted for
48 h. Then ethyl acetate (20 mL) was added and the mixture was
extracted with brine (10 ¥ 3 mL) and dried over anhydrous Na2SO4.
After removing the solvent under reduced pressure, the crude
oil was purified by flash chromatography with hexane/AcOEt
mixture from 95/5 to 90/10 to afford the pure products 7.
Acknowledgements
Procedure for one pot aldol-silylation reaction in the presence of
Me3SiCl and i-Pr2EtN (Scheme 1)
The corresponding author wants to thank the University of
Salerno for financial support.
In
a flame-dried, 2-necked, round-bottom flask, aldehyde
(0.40 mmol) was added to a solution of i-Pr2EtN (2.3 eq., 0.92
mmol), b-ketoester (1.5 eq., 0.60 mmol) and Me3SiCl (2.0 eq.,
0.80 mmol) in dry dichloromethane (2.0 mL) under nitrogen at
-20 ◦C. At the end of the reaction, the mixture was quenched with
saturated aqueous NaHCO3 (5 mL), extracted with 15 ¥ 3 mL
of CH2Cl2 and dried over anhydrous Na2SO4. After removing the
solvent under reduced pressure, the crude oil was purified by flash
chromatography from hexane to 95/5 hexane/AcOEt mixture to
afford the pure products 3.
References
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(a) S. Marumoto, H. Kogen and S. Naruto, J. Org. Chem., 1998, 63,
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Procedure for one pot aldol-silylation reaction in the presence of
Me3SiCl and i-Pr2EtN (Scheme 2)
In a flame-dried, 2-necked, round-bottom flask equipped with
a condenser, aldehyde (0.80 mmol) was added to a solution of
i-Pr2EtN (2.0 eq., 1.60 mmol), b-ketoester (1.1 eq., 0.88 mmol)
and Me3SiCl (2.0 eq., 1.60 mmol) in dry 1,2-dichloroethane or
THF (4.0 mL), under nitrogen. The solution was kept refluxing
until the end of the reaction, monitored by TLC; then the
mixture was cooled down at room temperature, quenched with
saturated aqueous NaHCO3 (5 mL), extracted with 15 ¥ 3 mL
of CH2Cl2 and dried over anhydrous Na2SO4. After removing the
solvent under reduced pressure, the crude oil was purified by flash
chromatography from hexane to 95/5 hexane/AcOEt mixture to
afford the pure products 3.
Procedure for conversion of 3a into 5
NaBH4 (0.27 mmol) was added to a solution of 3a (0.25 mmol)
in methanol (1.0 mL), at 0 ◦C and reacted for 20 min. Then
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