Microwave-assisted dealkoxycarbonylation of α-mono- and α,α-disubstituted β-keto- and α-cyanoesters mediated by a silica gel bed

Article abstract of DOI:10.1039/c7nj04340f

A new alternative protocol for the classical Krapcho reaction is reported herein, involving a microwave-assisted method, which replaces the typical aprotic polar solvent with a silica gel support along with the addition of only a few μL of DMF to enhance

Full text of DOI:10.1039/c7nj04340f

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

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Microwave-Assisted Dealkoxycarbonylation of α-Mono- and α,α-
Disubstituted β-Keto- and α-Cyanoesters mediated by a Silica Gel
Bed
Received 00th January 20xx,
Accepted 00th January 20xx
‡
‡
Alejandro Guerrero-Caicedo,a Diana M. Soto-Martínez,a
Rodrigo Abonia-Gonzalez,a Luz M.
DOI: 10.1039/x0xx00000x
Jaramillo-Gómeza*
www.rsc.org/
A new and alternative protocol for the classical Krapcho type reaction is reported here, involving a microwave-assisted
method which replaced the typical aprotic polar solvent by a silica gel support with the adding of only few µL of DMF to
improve the effect of the microwave irradiation. Such experimental procedure was successfully applied to several α-mono-
and α,α-disubstituted β-ketoesters and α-cyanoalkylesters allowing the rapid isolation of the corresponding ketones and
nitriles, with moderate to high yields, in short reaction time.
Introduction
researchers have used microwave irradiation (MWI) and other
variants to the original Krapcho reaction in their
dealkoxycarbonylation processes. In this direction, several
Activated esters, among them, malonates, β-ketoesters and α-
cyanoesters have been remarkably important in organic
chemistry due to they are easily alkylated and transformed in
diverse precursors for synthetic applications. The
monoalkylation or dialkylation reactions over the mentioned
substrates are typically followed by dealkoxycarbonylation (or
decarboalkoxylation) processes.1 In the last decade, three
extensive reviews were published enclosing the countless
synthetic applications of dealkoxycarbonylation of β-
ketoesters, malonates, α-cyanoesters, etc. Reactions were
mainly promoted by heating the starting material in wet
(DMSO or DMF), in the presence of diverse salts like NaCN,
NaCl or the more frequently used LiCl, as useful extensions of
the well-known Krapcho reaction. (Scheme 1).2
examples have been reported applying MWI to perform the
dealkoxycarbonylation under the classical Krapcho reaction. All
of them limited to alkylated malonates or β-ketoesters.3
With other variants, Loupy et al.,4 used MWI for
dealkoxycarbonylation
reactions
on
substituted
2-
ethoxycarbonylcyclohexanones in the presence of LiBr and
Bu4NBr as a solid-liquid phase transfer catalyst (PTC) in
solvent-free reaction conditions. In turn, Curran et al.5
developed
the
dealkoxycarbonylation
reaction
of
unsubstituted and α-monosubstituted malonates and β-
ketoesters in MWI conditions, using simply wet DMF and
without adding salts. Nevertheless, these reaction conditions
were not effective for both α, α-disubstituted-β-keto and
malonate esters. More recently, Murphree et al.6 reported a
study on this reaction with several α-monosubstituted
malonate ethyl esters under MWI evaluating several lithium
salts. The best results were obtained when lithium sulfate was
used in the presence of water as solvent.
CO2R3
H
DMSO or DMF/H O
2
Y
R2
Y
R2
R1
R1
NaCN, NaCl or LiCl, heat
Y = CO2R, COR, CN
As part of our current research work on the synthesis of
non-symmetric ketones mediated by β-ketoesters,7 we are
Scheme 1 Experimental conditions previously used for the classical Krapcho
reaction
reporting
here
a
general
microwave-assisted
dealkoxycarbonylation, of both, α-mono- and α,α-
disubstituted methyl(ethyl) acetoacetates and α,α-
disubstituted methyl 2-cyanoacetates by absorption of these
reagents over silica gel.
Although, the above procedures continue being very
useful, the long reaction time (in several cases), high
temperatures, and several aqueous extractions to remove the
aprotic solvent are required, which normally affects the
reaction yields. In order to overcome these drawbacks, some
Recently we required to synthesize several oxime ethers VI
and VII from methyl acetoacetate (
I) to furtherly be subjected
to bicyclization reactions mediated by free radicals. As shown
in Figure 1, a dealkoxycarbonylation process on esters II/IV
was the key step in this retrosynthetic analysis.
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Scheme 2 Comparative dealkoxycarbonylation reaction on the α-monosusbstituted
methyl β-ketoesters 1
Although compound
2 was isolated in relative less yield under
MWI (approach (b)) in comparison with the classical Krapcho
reaction carried out under conventional heating (approach
(a)), this finding led us to reveal an alternative route for this
reaction using silica gel as support material and MWI as
heating source. Moreover, isolation of product
than that from the approach (a) with a significant shorter
reaction time. From this approach ketone was easily isolated
2 was simpler
2
and purified just by pouring the silica gel absorbed crude
directly into the column chromatography containing 15 g of
clean silica gel and using (7-9% ether/hexane, 1% gradient) as
eluent. Hence, the aqueous extraction to eliminate part of the
aprotic solvent was not required, as is usual in the original
Krapcho procedure, as well as, in most of its variants.
Fig. 1 Retrosynthetic analysis for the oxime ethers VI-VII synthetized from methyl
acetoacetate
With the above result in hand, as a further challenge, we
tried to extend our previous MWI assisted method toward,
hard to decarboxylate, α,α-disubstituted β-ketoesters.2-8 In
that sense, we chose the methyl 2-benzyl-2-(2-bromobenzyl)-
Results and Discussion
To start with our purposes, we attempted to obtain ketones
3-oxobutanoate (
polish the reaction conditions. In a first assay (a), a mixture of
ester (0.090 g, 0.25 mmol), LiCl (0.040 g, 1.01 mmol) and
3), as model precursor, to standardize and
type III and
V through the dealkoxycarbonylation reaction of
their corresponding β-ketoesters II and IV, respectively, via the
classical Krapcho procedure. Thus, as a model reaction for α-
monoalkylated β-ketoesters type II, a mixture of the methyl 2-
3
water (75 µL) was absorbed in silica gel (0.01 g) and subjected
to MWI in a CEM reactor. After 45 min of irradiation at 100 oC
and 200 W, the thin layer chromatography (TLC) showed a
complex mixture of products and unreacted starting material
(3-bromoallyl)-3-oxo-7-phenylhept-6-enoate (1) (0.72 g, 2.19
mmol), LiCl (0.18 g, 4.27 mmol), water (38 µL, 2.14 mmol) and
o
DMSO (5 mL) was heated at 180 C during 1 h. After reaction
3
. In a second assay (b), the same reaction was repeated but
adding DMF (25 µL) instead of water, affording the expected 3-
benzyl-4-(2-bromo-phenyl)butan-2-one ( ) in 61% yield, after
finished and the classical work up was performed, the
expected 1-bromo-9-phenylnona-1,8-dien-5-one
obtained in 69% yield, (approach (a), Scheme 2). In general, by
following this procedure the desired ketones III and were
(
2
)
was
4
only 15 min of irradiation (Scheme 3). This ketone was isolated
and purified, by following our easy work up, as described
above.
V
obtained just in low to acceptable yields (40-70%), in a
o
temperature range of 110-180 C, with a reaction time range
of 1-5 h and after long time-consuming work up in all cases.7
Looking for a more expeditious method, a variant of the
classical Krapcho reaction was considered. Thus, based on
previous reports,3-6 the above reaction was repeated by
absorbing on silica gel (70-230 mesh) of the ester
1 (0.35 g,
2.05 mmol), LiCl (0.36 g, 8.50 mmol), water (80 L, 4.40 mmol).
Then, the reaction mixture was subjected to MWI at 70 W
during 9 min leading the ketone
Scheme 2).
2 in 51% yield, (approach (b),
Scheme 3 Dealkoxycarbonylation of the α,α-disubstituted β-ketoester 3 under the
established reaction conditions
Aimed to explore a wider scope of this approach, a variety
α,α-disubstituted-β-ketoesters, α-cyanoesters (Table 1), and α-
monosubstituted β-ketoesters (Table 2) were subjected to our
established MWI/Silica gel assisted reaction conditions in the
range of 120-150 oC, obtaining the expected ketones 6a-c or
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nitriles 6d-e and also the ketones 8a-e, respectively, in good
to excellent isolated yields (50-93%).
It is remarkable the fact that high yields of ketones 6c (74%),
8a (77%), 8b (92%), 8c (60%) were obtained from the
dealkoxycarbonylation
of
their
corresponding
α,α-
disubstituted and α-monosusbstituted methyl β-ketoesters
bearing a cinnamyl moiety in their structures. In contrast, β-
ketoesters with an alkenyl carboethoxy appendix showed
modest yields, i.e. 6b (50%) and 8d (50%) in comparable
reaction time. Besides, the disubstituted α-cyanoesters 5d and
5e afforded their respective nitriles 6d and 6e in very good
85% and 93% yields, respectively.
Table 2 Dealkoxycarbonylation reaction of α-monosusbstituted methyl β-ketoesters 7a-
7e
Table 1 Dealkoxycarbonylation reaction of α,α-disubstituted methyl β-ketoesters 5a-c
and α-cyanoesters 5d,e
In our method, silica gel was chosen as solid support due to its
resistant
to
the
required
temperatures
for
dealkoxycarbonylation reaction (~150 °C) and because of its
high capability to absorb the starting materials.10 It is
presumed that the silanol groups (Si-OH) play an important
role of retaining the required humidity for this process, but
also acting as source of protons and providing a polar surface
not only to change the spatial orientation of the reactants but
also to facilitate the solvation of the lithium chloride and
substrates through hydrogen bonds (Figure 2).
It is relevant to note, that when we tried to perform the
dealkoxycarbonylation reaction of the α,α-disubstituted β-keto
ester
3 absorbed on silica gel with LiCl and water (instead of
DMF) (Scheme 3), such a reaction did not proceed fairly.
Probably because, as it is well-known, the α,α-disubstituted β-
ketoesters takes longer dealkoxycarbonylation time than α-
monosubstituted derivatives.2,8 Hence, in that assay, the
added water probably evaporated rapidly before reaction was
completed. Interestingly, the adding of DMF helped to solve
the problem, which could be associated with both high boiling
point (153 °C) and high dielectric constant (ε = 36.7) exhibited
by this solvent. In consequence, DMF contains low volatile and
polar molecules sensitive to external electric fields required to
develop the microwave phenomenon.9
Fig. 2 Suggested interactions between substrate (S), H2O, LiCl and the silica gel used as
solid support in our established MWI procedure. Oxigen atoms in black color belong to
abosorbed water molecules. Hydrogen atoms in bold and blue color represent
hydrogen-bonding sites to activate both LiCl-catalyst and substrate (S)
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In order to evaluate the effect of the alkoxyl group on the
At this point, it is worth to recall the described mechanisms
alcoholic moiety, we also investigated and compared the for dealkoxycarbonylation of α-monosusbstituted β-keto- and
efficiency of our method toward α-monosubstituted methyl- malonate esters to afford ketones type 21 where the
vs ethyl β-ketoesters. Thereby, methyl and ethyl esters 9a and mechanistic behavior depends on the structure of the
9b respectively, were prepared and subsequently substrate and the reaction conditions. Moreover, it is
,
,
dealkoxycarbonylated under our established reaction recognized the formation of an enol species type 14 as the key
conditions. The ethyl acetoacetate derivative 9b required two- intermediate in β-ketoesters for this process (Scheme 6).5
fold of time than its methyl analogue 9a to afford product 10
The dealkoxycarbonylation performed in wet DMF or
in similar yields (Scheme 4). This finding is consistent with the DMSO (in absence of salts), for α-monosusbstituted β-
literature reports, indicating that methyl esters are ketoesters 13, proceeds through a neutral hydrolysis (or its
dealkoxycarbonylated faster than ethyl esters.8
enolic 14 form), followed by decarboxylation of the acid 16
,
and the subsequent enolic tautomerization process on 19 to
afford the target ketone 21 (i.e. BAC2 (1) pathway in Scheme
6).5
O
O
H
CO2X
However, adding salts like (LiCl, NaCl, KCN, etc.)
a
H3C
H3C
nucleophilic attack occurs of their corresponding anions (i.e. Cl-
, CN-, etc.) on the carbonyl group (i.e. nucleophilic catalysis), to
form tetrahedral species 17. These species breaks down to the
enolate intermediate 20 which is subsequently protonated to
lead ketone 21. Alternatively, a nucleophilic attack of the
corresponding anion (i.e. Cl- when LiCl is used), on the alkyl
LiCl (4.0 equiv)
SiO2, DMF (25 L)
I
I
200 W,135 o
C
9a (X = -CH3)
9b (X = -CH2CH3)
10 (84%, 10 min)
(83%, 20 min)
group R3 of the alcoholic moiety in 14 could occur (i.e. BAL
pathway, Scheme 6), to generate the carboxylate species 18
Subsequently water mediated decarboxylation process
2
Scheme 4 Comparative dealkoxycarbonylation reaction of α-monosubstituted methyl-
vs ethyl β-ketoesters 9a and 9b respectively
.
a
should lead the target ketone 21
.
Although in this research work we did not require
dealkoxycarbonylate malonate methyl esters, we applied our
H
H2O
OR3
O
O
O
OH
O
O
BAC2 (1)
OR3
OH
established protocol to the dialkylated malonate derivative 11
.
R1
OR3
R1
R1
Reaction proceeded in similar way and product methyl 2-
benzyl-3-phenylpropanoate (12) was obtained in an acceptable
42% yield (Scheme 5).
R2
R2
15
R2
14
Cl-
13
LiCl
-R3OH
BAC2 (2)
BAL2
O-
O
O
O
O
O
OR3
R1
OH
R3Cl + R1
O-
R1
R2
16
R2
18
R2
Cl
17
O
R1
20
Scheme 5 Dealkoxycarbonylation reaction of 2,2-dimethyl diester dibenzylmalonate
(11)
R2
OH
H2O
-CO2
R1
- Cl -, - R3OH,
-CO2
-CO2
H2O
19 R2
In a further experiment, the treatment under MWI (200 W,
135 oC, 8 min) of the α-monosubstituted β-ketoester 7b
adsorbed over silica gel, without adding lithium salt afforded
ketone 8b in 68%. As mentioned above, the same reaction
performed under the presence of LiCl afforded 8b in 92% yield
(see Table 2). This finding indicates that LiCl, although, it is not
strictly necessary to make reaction proceed, its presence is
effectively convenient to improve the efficiency of this
reaction. This result agree with the findings of Curran et al.,5 in
the dealkoxycarbonylation reaction of α-monosubstituted β-
ketoesters under MWI in a mixture DMF/water without adding
salts.
O
R1
21
R2
Scheme 6 Competitive mechanisms for dealkoxycarbonylation of α-monosusbstituted
β-ketoesters 13 under uncatalyzed and LiCl/H2O catalyzed reaction conditions
On the other hand, it was mentioned above that the α,α-
disubstituted
β-ketoesters
22
are
resistant
to
dealkoxycarbonylation reactions in absence of salts.8
According to Schemes 6 and 7, this finding could be supported
by the fact that esters 22 cannot be enolized like 13 for that
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their carbonyl groups could not intramolecularly be activated nm). Column
ARTICLE
chromatography and flash column
as 14. In consequence, the concurrence or synergism of the chromatography conducted under silica gel (Merck, 70-230
pathway type BAC2 ( ) is discarded for esters 22, indeed, their and 230-400 Mesh respectively). The chemical structures of
1
ketonic products 24 could only be formed mediated by salts intermediate and final products were elucidated by nuclear
and predominantly via a BAL2 pathway (Scheme 7),8 which is magnetic resonance spectra (1H NMR, 13C NMR) which were
reflected in
a
relatively time-consuming reaction in determined on a Bruker Avance II 400 MHz spectrometer.
comparison with their α-monosusbstituted analogues 13
.
Chemical shifts reported in parts per million (ppm) using
deuterated solvent peak or tetramethylsilane as internal
standard. Infrared spectra were determined on a SHIMADZU
Spectrophotometer IR affinity-1 with ATR miracle pike.
Elemental analysis was determined on a Thermo FlashEA 1112
series with CHN analyzer. High Resolution Mass Spectra
(HRMS) were recorded on a JEOL JMS-AX505HA spectrometer
with PEG-600 like standard. Reagents as methyl acetoacetate,
diethyl malonate, aryl bromides, lithium chloride, potassium
tert-butoxide, magnesium sulfate and solvents as THF (dried
over Na-benzophenone) and DMF were purchased from
commercial suppliers (Sigma-Aldrich Chemical Co., Acros
Organics, etc.).
Scheme
7
Suggested mechanistic sequence for the LiCl/H2O catalyzed
dealkoxycarbonylation reaction of α,α-disubstituted β-keto esters 22
At this stage, it is worth to highlight the versatility and
advisability of our method for the dealkoxycarbonylation not
only of α-monosubstituted β-keto esters but also α,α-
disubstituted β-keto-, α-cyano- and malonate esters. This
approach covers a broader scope of substrates in comparison
with interesting previous MWI methods like reported by
Curran et al.,5 which was basically effective for α-
monosubstituted malonates and β-ketoesters, but examples of
α,α-disubstituted β-keto esters were not mentioned. In turn,
General procedure for the dealkoxycarbonylation reaction of
α,α-disubstituted β-keto, α-cyanoesters, diethylmalonate
and α-monosubstituted β-ketoesters.
A microwave tube was charged with β-ketoester (1.00 mmol),
LiCl (4.00 mmol), silica gel (70-230 mesh, Merck, 0.40 g per
1.00 mmol of substrate), DMF (25-75 µL) and dichloromethane
(3 mL). The mixture was stirred at room temperature until to
get a homogeneous appearance and subsequently the excess
of dichloromethane removed under vacuum. The tube was
sealed with its plastic cup and heated without stirring in a CEM
Discovery Microwave reactor (with dynamic method), until
consumption of the substrate (monitored by TLC). The silica gel
supported reaction mixture was cooled to room temperature
and poured into a partially filled (with silica gel), column
chromatography. Then, the product was isolated by using
gradients of ethyl ether/hexane mixtures.
Murphree et al.6
also
reported
MWI
assisted
dealkoxycarbonylation reactions but only over monoalkylated
malonates. To our knowledge, the current report is the first
systematic and general work on dealkoxycarbonylation
reaction of diversely α-mono- and α,α-disubstituted β-
ketoesters supported over silica gel and mediated by
microwave irradiation that have been made to date.
Conclusions
Ketones α,α-disubstituted
We have adapted the classical Krapcho type reaction to an
alternative microwave-assisted method replacing the solvent
by a silica gel support with the addition of only few µL of DMF.
This experimental procedure was successfully applied to
several α-mono- and α,α-disubstituted β-keto and α-
cyanoalkylesters. Not only the reaction time could be
substantially reduced, but also the purification process of the
obtained products was simplified. Thus, this protocol is
compatible with the green chemistry and potentially could be
extended to synthetic chemistry when this type of reaction
would be required.
3-Benzyl-4-(2-bromophenyl) butan-2-one (
prepared according to the general procedure from β-keto
ester (0.095 g, 0.25 mmol), LiCl (0.044 g, 1.01 mmol), Silica
4). Compound 4 was
3
gel (0.10 g) and DMF (25 µL). The vial was sealed and heated at
135 °C, 200 W by 15 min. The crude product was purified by
column chromatography (Silica gel 70-230 mesh, 7-9%
ether/hexane, 1% gradient) to afford a colorless oil (0.048 g,
61%). Anal. calcd. for C17H17BrO: C, 64.37, H, 5.40; found: C,
64.36, H, 5.43. IR (ATR), (cm-1): 3408; 3061, 2925, 2855, 1711
(C=O), 1601, 1565, 1494, 1445, 1359, 1328, 1161, 1107, 1026,
753, 526. 1H NMR (CDCl3, 400 MHz), δ (ppm): 1.79 (s, 3H), 2.77
(dd, J = 6.0, 13.0 Hz, 1H), 2.89 (dd, J = 6.0, 13.0 Hz, 1H), 2.95–
3.07 (m, 2H), 3.33–3.41 (m, 1H), 7.08–7.12 (td, J = 2.0, 8.0 Hz,
1H,), 7.16–7.25 (m 5H), 7.27–7.31 (m, 2H), 7.56 (d, J = 8.0 Hz,
1H). 13C NMR (CDCl3, 100 MHz), δ (ppm): 31.8, 38.2, 38.4, 53.8,
124.4, 126.4, 127.5, 128.2, 128.5, 128.9, 131.6, 133.0, 138.7,
139.1, 211.8.
Experimental Section
General Methods: Melting points were determined in open
capillary tubes on Stuart SMP10. Reactions were monitored by
thin layer chromatography (TLC) on 0.2 mm silica gel F254
plates (Merck); the spots were visualized under UV light (254
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3-(2-Bromobenzyl)-4-(4-nitrophenyl)butan-2-one
(6a). procedure from β-keto ester 5d (0.086 g, 0.21 mmol), LiCl
Compound 6a was prepared according to the general (0.037 g, 0,86 mmol), Silica gel (0.084 g) and DMF (25 µL). The
procedure from β-keto ester 5a (0.10 g, 0.24 mmol), LiCl (0.042 vial was sealed and heated at 150 °C, 220 W by 12 min. The
g, 1.0 mmol), Silica gel (0.096 g) and DMF (25 µL). The vial was crude product was purified by column chromatography (Silica
sealed and heated at 150 °C, 200 W by 5 min. The crude gel 70-230 mesh, 14-20% ethyl acetate/hexane, 2% gradient)
product was purified by column chromatography (Silica gel 70- to afford a pale yellow solid (0.061g, 85%), Mp = 85-86 °C.
230 mesh, 1-6% ether/hexane, 1% gradient) to afford a yellow Anal. calcd. for C16H13BrN2O2: C, 55.67, H, 3.80, N, 8.12; Found:
solid (0.048 g, 60%), Mp = 70.8-71.2 °C. IR (ATR) (cm-1): 3400, C, 55.38, H, 3.74, N, 8.40. IR (ATR), (cm-1): 3080, 2957, 2868,
3078, 2848, 1705, 1328, 1275, 1020. 1H NMR (CDCl3, 400 2237, 1612, 1537, 1470, 1350, 1024, 852, 762; 1H NMR (CDCl3,
MHz), δ (ppm): 1.87 (s, 3H), 2.78 - 2.89 (m, 2H), 2.08 (m, 2H), 400 MHz), δ (ppm): 2.99 (dd, J= 10.0, 14.0 Hz, 1H), 3.08 (d, J =
3.36 – 3.43 (q, 1H), 7.13 (td, 1H, J = 8.0, 2.0 Hz), 7.17 (dd, 1H, J 8.0 Hz, 2H), 3.11-3.15 (m, 1H), 3.21-3.28 (m, 1H), 7.14-7-19 (m,
= 8.0, 2.0 Hz), 7.25 (td, 1H, J = 8.0, 1.0 Hz), 7.31 (d, 2H, J = 9.0 1H), 7.27-7.33 (m, 2H), 7.44 (d, J = 9.0 Hz, 2H,), 7.56 (d, J = 8.0
Hz), 7.58 (d, 1H, J = 8.0, 1.0 Hz), 8.13 (d, 2H, J = 9.0 Hz); 13C Hz, 1H,), 8.20 (d, J = 8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz), δ
NMR (CDCl3, 100 MHz), δ (ppm): 31.5, 37.2, 38.7, 53.3, 123.7, (ppm): 33.7, 38.0, 38.6, 120.1, 124.0, 124.3, 128.0, 129.4,
124.4, 127.7, 128.6, 129.8, 131.6, 133.2, 137.9, 146.8, 147.1, 130.0, 131.5, 133.2, 135.6, 144.0, 147.4.
210.4. HRMS (DART): calcd for C17H16BrNO3: 362.0392, found: 2-(2-Bromobenzyl)-3-(2-bromophenyl)propanenitrile
(
6e).
Compound 6e was prepared according to the general
(6b). procedure from β-keto ester 5e (0.10 g, 0.24 mmol), LiCl (0.042
362.0394.
Ethyl
(E)-5-(2-bromobenzyl)-6-oxohept-2-enoate
Compound 6b was prepared according to the general g, 0.98 mmol), Silica gel (0.096 g) and DMF (25 µL). The vial
procedure from β-keto ester 5b (0.094 g, 0.23 mmol), LiCl was sealed and heated at 150 °C, 220 W by 30 min. The crude
(0.041 g, 0.95 mmol), Silica gel (0.092 g) and DMF (25 µL). The product was purified by column chromatography (Silica gel 70-
vial was sealed and heated at 120 °C, 200 W by 30 min. The 230 mesh, 1-2% ether/hexane, 1% gradient) to afford a white
crude product was purified by column chromatography (Silica solid (0.083 g, 93%), Mp = 82-83 °C. Anal. calcd. for C16H13Br2N:
gel 70-230 mesh, 1-2% ether/hexane, 1% gradient) to afford a C, 50.69, H, 3.46, N, 3.69; Found: C, 50.89, H, 3.45, N, 3.87. 1H
yellow oil (0.039 g, 50%). Anal. calcd. for C16H19BrO3: C, 56.65, NMR (CDCl3, 400 MHz), δ (ppm): 3.05 (dd, J = 13.9, 9.7 Hz, 2H),
H, 5.65, Found: C, 56.24, H, 5.52. IR (ATR), (cm-1): 3059, 2982, 3.20(dd, J = 13.6, 5.6 Hz, 2H), 3.41(tt, J = 9.8, 5.7 Hz, 1H) 7.16
2953, 1713 (C=O, ketone), 1653, 1470, 1439, 1368, 1263, 1157, (td, J = 7.7, 1.8 Hz, 2H), 7.32(td, J = 7.5, 1.3 Hz, 2H), 7.38(dd, J =
1
1026, 976, 750, 660. H NMR (CDCl3, 400 MHz), δ (ppm): 1.30 7.6, 1.8 Hz, 2H), 7.57(dd, J = 8.0, 1.2 Hz, 2H); 13C NMR (CDCl3,
(t, 3H, J = 7 Hz), 2.07 (s, 3H), 2.30 – 2.37 (m, 1H), 2.55 – 2.63 100 MHz), δ (ppm): 32.6, 38.6, 120.6, 124.5, 127.8, 129.2,
(m, 1H), 2.82 (dd, 1H, J = 14.0 Hz, J = 7 Hz), 3.04 – 3.09 (m, 1H), 131.7, 133.1, 136.1.
3.15 – 3.22 (m, 1H), 4.19 (q, 2H, J = 7.0 Hz), 5.85 (d, 1H, J = 16.0
Hz), 6.82 – 6.90 (m, 1H), 6.82 – 6.90 (m, 1H), 7.14-7.22 (m, 2H), Ester α,α-disubstituted
7.58 (d, 1H, J = 8.0 Hz);13C NMR (CDCl3, 100 MHz), δ (ppm):
14.3, 30.7, 33.5, 38.0, 50.8, 60.3, 123.7, 124.5, 127.6, 128.5, Methyl 2-benzyl-3-phenylpropanoate (12). Compound 12 was
131.6, 133.2, 138.1, 145.1, 166.1, 210.2.
prepared according to the general procedure from malonate
(E)-3-(2-Bromobenzyl)-6-phenylhex-5-en-2-one (6c). Compound 11 (0.090 g, 0.29 mmol), LiCl (0.051 g, 1.19 mmol), Silica gel
6c was prepared according to the general procedure from β- (0.11 g) and DMF (25 µL). The crude product was purified by
keto ester 5c (1.22 g, 3.04 mmol), LiCl (0.54 g, 12.73 mmol), column chromatography (Silica gel 70-230 mesh, (13-15% ethyl
Silica gel (1.22 g) and DMF (75 µL). The vial was sealed and acetate/hexane, 1% gradient) to afford a colorless oil (0.030 g,
1
heated at 150 °C, 200 W by 17.5 min. The crude product was 42%). H NMR (CDCl3, 400 MHz), δ (ppm): 2.83-2.88 (m, 2H),
purified by column chromatography (Silica gel 70-230 mesh, 1- 3.00-3.05 (m, 3H), 3.55 (s, 3H), 7.19-7.34 (m, 10H). Other
2% ether/hexane, 1% gradient) to afford a brown oil (0.77 g, spectroscopic data for 12 were already reported in the
74%). Anal. calcd. for C19H19BrO: C, 66.48, H, 5.58; Found: C, literature.11
66.35, H, 5.50. IR (ATR), (cm-1): 3058; 3026, 2930, 2845, 1711,
966, 745. 1H NMR (CDCl3, 400 MHz), δ (ppm): 2.03 (s, 3H), Ketones α-monosubstituted
2.34–2.41 (m, 1H), 2.52–2.59 (m, 1H), 2.87 (dd, J = 6.0, 14.0
Hz,1H), 3.01–3.07 (m, 1H), 3.15 (ddd, J = 6.0, 8.0, 14.0 Hz, 1H), (E)-7-(4-Chlorophenyl)-1-(2-iodophenyl)hept-6-en-3-one
(8a).
6.08–6.15 (m, 1H), 6.40 (d, J = 16.0 Hz, 1H), 7.07 (t, J = 7.0 Hz, Compound 8a was prepared according to the general
1H), 7.17–7.21 (m, 3H), 7.25–7.32 (m, 4H), 7.54 (d, J = 8.0 procedure from β-keto ester 7a (0.36 g, 0.74 mmol), LiCl (0.13
Hz,1H,); 13C NMR (CDCl3, 100 MHz), δ (ppm): 30.8, 34.9, 37.6, g, 3.01 mmol), Silica gel (0.30 g) and DMF (50 µL). The vial was
52.0, 124.5, 126.1, 126.6, 127.3, 127.5, 128.2, 128.5, 131.7, sealed and heated at 135 °C, 200 W by 11 min. The crude
132.5, 133.0, 137.2, 138.8,211.2.
product was purified by column chromatography (15% ethyl
acetate/hexane) to afford a yellow oil (0.28 g, 90%). Anal.
calcd. for C19H18ClIO: C, 53.73, H, 4.27; Found: C, 53.63, H,
Nitriles α,α-disubstituted
1
4.19. H NMR (CDCl3, 400 MHz), δ (ppm): 2.51-2.55 (m, 2H),
2-(2-Bromobenzyl)-3-(4-nitrophenyl)propanenitrile
(
6d). 2.63 (t, J = 7.0, 7.2 Hz, 2H), 2.78 (t, J = 7.6, 7.8 Hz, 2H), 3.04 (t, J
Compound 6d was prepared according to the general = 7.6 Hz, 2H), 6.19 (dt, J = 6.8 Hz, 1H), 6.38 (d, J= 15.8 Hz, 1H,),
6 | J. Name., 2012, 00, 1-3
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6.89-6.94 (m, 1H), 7.25-7.35 (m, 7H), 7.83 (d, J = 7.8 Hz, 1H); 230 mesh, 10-15% ethyl acetate/hexane, 1% gradient) to
13C NMR (CDCl3, 100 MHz), δ (ppm): 27.1, 34.8, 42.2, 42.9, afford a pale yellow solid (0.16 g, 64%), Mp = 72.7-74.9 °C.
100.2, 127.2, 128.1, 128.5, 128.47, 128.6, 129.5, 129.7, 132.7, Anal. calcd. for C17H16INO3: C, 49.90, H, 3.94, N, 3.42; Found: C,
1
50.24, H, 4.05, N, 3.62. H NMR (CDCl3, 400 MHz), δ (ppm):
135.9, 139.6, 143.5, 208.5.
(E)-1-(2-Iodophenyl)-7-phenylhept-6-en-3-one (8b). Compound 2.74 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.4 Hz, 1H), 2.99 – 3.05 (m,
8b was prepared according to the general procedure from β- 4H), 6.92 (td, J = 7.5 Hz, 1.6 Hz, 1H), 7.16 – 7.29 (m, 2H), 7.35
keto ester 7b (0.90 g, 1.96 mmol), LiCl (0.35 g, 8.04 mmol), 7.80 (d, J = 8.5 Hz, 2H). 7.82 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.8
Silica gel (0.78 g) and DMF (50 µL). The vial was sealed and Hz, 2H); 13C NMR (CDCl3, 100 MHz), δ (ppm): 29.4, 34.7, 42.9,
heated at 135 °C, 200 W by 8 min. The crude product was 43.3, 100.1, 121.7, 128.5, 129.2, 129.7, 139.6, 143.5, 146.5,
purified by column chromatography (12-14% ethyl 148.8, 207.5.
acetate/hexane, 1% gradient) to afford a yellow solid (0.70 g, 4-(2-Bromophenyl)butan-2-one
(10). Compound 10 was
92%), Mp = 62-64 °C. 1H NMR (CDCl3, 400 MHz), δ (ppm): 2.39- prepared according to the general procedure from β-keto
2.44 (m, 2H), 2.50-2.53 (m, 2H), 2.65-2.69 (m, 2H), 2.91-2.95 ester 9a (0.10 g, 0.34 mmol), LiCl (0.061 g, 1.41 mmol), Silica
(m, 2H), 6.06-6.14 (m, 1H), 6.32 (d, J = 15.8 Hz, 1H), 6.78-6.82 gel (0.14 g) and DMF (25 µL) or 9b (0.13 g, 0.45 mmol), LiCl
(m, 1H), 7.05-7.25 (m, 7H), 7.70-7-76 (m, 1H); 13C NMR (CDCl3, (0.084 g, 1.97 mmol), Silica gel (0.18 g) and DMF (25 µL). The
100 MHz), δ (ppm): 27.2, 34.8, 42.4, 42.9, 100.2, 126.0, 127.1, vial was sealed and heated at 135 °C, 200 W by 10 min (from
128.0, 128.5, 128.5, 128.8, 129.7, 130.9, 137.4, 139.6, 143.58, 9a) and 20 min (from 9b). The crude product was purified by
208.61; HRMS (DART): calcd for C19H19IO: 391.0559, found: column chromatography (Silica gel 70-230 mesh, 2-10% ethyl
391.0559.
acetate/hexane, 2% gradient) to afford a colorless oil (0.065 g,
8c). 84% from 9a and 84.4 mg, 83% from 9b); 1H NMR (CDCl3, 400
(E)-1-(2-Iodophenyl)-7-(4-nitrophenyl)hept-6-en-3-one
(
Compound 8c was prepared according to the general MHz), δ (ppm): 2.16 (s, 3H), 2.76-2.80 (m, 2H), 2.99-3.03 (m,
procedure from β-keto ester 7c (0.18 g, 0.36 mmol), LiCl (0.066 2H), 7.05-7.09 (m, 1H), 7.20-7.28 (m, 2H), 7.53 (d, J = 8.3 Hz,
mg, 1.56 mmol), Silica gel (0.14 g) and DMF (25 µL). The vial 1H). Other spectroscopic data were already reported in the
was sealed and heated at 120 °C, 200 W by 9 min. The crude literature.12
was purified by column chromatography (Silica gel 70-230
mesh, 80% dichloromethane/hexane) to afford a yellow solid General procedure for the synthesis of α,α-disubstituted β-
(0.094 g, 60%), Mp = 62-64 °C. Anal. calcd. for C19H18INO3: C, keto-, α-cyanoesters and methyl malonate
52.43, H, 4.17, N, 3.22; Found: C, 52.33, H, 4.21, N, 3.12. IR
(ATR), (cm-1): 3459, 3115, 2936, 1707, 1512, 1344, 757. 1H To a suspension (
̴ 0.33 M) of potassium tert-butoxide (1.00
NMR (CDCl3, 400 MHz), δ (ppm): 2.55-2.58 (m, 2H), 2.63 (d, J = equiv) in anhydrous THF, under inert atmosphere, it was
6.3 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 3.02 (t, J = 7.7 Hz, 2H), 6.39 added the α-monosubstituted β-keto or α-cyano ester (1.00
(dt, J = 6.3 Hz, 1H), 6.47 (d, J = 16.1 Hz, 1H), 6.87-6.91 (m, 1H), equiv) dropwise. The reaction mixture was stirred during 10
7.26 (d, J = 6.3 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.8 min, the alkyl bromide (1.05-2.00 equiv) was then added
Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz), δ slowly and the stirring continued for 12h at room temperature.
(ppm): 27.1, 34.8, 41.8, 42.8, 100.2, 123.6, 124.0, 126.5, 128.1, After this time (monitored by TLC), the reaction mixture was
128.5, 129.1, 129.7, 134.2, 139.6, 143.4, 143.8, 146.6, 208.1.
quenched with brine and extracted with ethyl acetate, the
Ethyl (E)-8-(2-iodophenyl)-6-oxooct-2-enoate (8d). Compound organic phase dried over anhydrous magnesium sulfate,
8d was prepared according to the general procedure from β- filtered and the solvent removed under reduced pressure. The
keto ester 7d (0.075 g, 0.17 mmol), LiCl (0.032 g, 0.74 mmol), product was isolated by column chromatography on silica gel.
Silica gel (0.068 g) and DMF (25 µL). The vial was sealed and
heated at 120 °C, 200 W by 10 min. The crude product was α,α-Disubstituted β-ketoesters
purified by column chromatography (Silica gel 70-230 mesh,
(11-14% ethyl acetate/hexane) to afford a yellow oil (0.038 g, Methyl
2-benzyl-2-(2-bromobenzyl)-3-oxobutanoate
(3).
50%). Anal. calcd. for C16H19IO3: C, 49.76, H, 4.96, Found: C, Compound
3
was prepared according to the general procedure
1
50.11, H, 5.05. H NMR (CDCl3, 400 MHz), δ (ppm): 1.31 (t, J = from methyl 2-(2-bromobenzyl)-3-oxobutanoate (9a) (0.42 g,
7.2 Hz, 3H, CH3), 2.47 – 2.63 ( m, 3H), 2.72 – 2.78 ( m, 2H), 2.86 2.05 mmol), potassium tert-butoxide (0.26 g, 2.25 mmol),
– 3.21 ( m, 3H), 4.21 ( q, J = 2.0 Hz, 2H, CH2), 5.85 ( d, J = 18.6 benzyl bromide (0.57 g, 2.25 mmol) and THF (7 mL). The crude
Hz, 1H, =CH), 6.84 – 6.98 ( m, 2H), 7.24 – 7.31( m, 2H), 7.84 ( d, product was purified by flash column chromatography (1%
J = 7.0 Hz, 1H, CH); 13C NMR (CDCl3, 100 MHz), δ (ppm): 14.3, diethyl ether/hexanes) to afford a pale yellow solid (0.41 g,
1
26.0, 40.8, 42.8, 60.3, 100.2, 122.2, 128.2, 128.6, 129.7, 139.6, 54%), Mp = 52-54 °C; H NMR (CDCl3, 400 MHz), δ (ppm): 1.98
143.4, 147.1, 166.4, 207.4.
(s, 3H), 3.33(dd, J = 14.0, 4.0 Hz, 2H), 3.49 (dd, J = 15.1, 4.3 Hz,
1-(2-Iodophenyl)-5-(4-nitrophenyl)pentan-3-one
(
8e). 2H), 3.67 (s, 3H), 7.07-7.12 (m, 3H), 7.21-7.28 (m, 5H), 7.56 (d,
Compound 8e was prepared according to the general J = 8.3 Hz, 1H); 13C NMR (CDCl3, 100 MHz), δ (ppm): 28.9, 38.7,
procedure from β-keto ester 7e (0.29 g, 0.61 mmol), LiCl (0.11 40.2, 52.2, 65.7, 126.1, 127.0, 127.3, 128.3, 128.3, 130.1,
g, 2.69 mmol), Silica gel (0.24 g) and DMF (25 µL). The vial was 131.2, 133.1, 136.2, 136.5, 172.0, 204.7; HRMS (DART): calcd
sealed and heated at 120 °C, 200 W by 6 min. The crude for C19H19BrO3: 401.0752, found: 401.0753.
product was purified by column chromatography (Silica gel 70-
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Methyl
(E)-2-(3-(2-iodophenyl)propanoyl)-5-(4- cyanopropanoate (0.3 g, 0.78 mmol), potassium tert-butoxide
nitrophenyl)pent-4-enoate (5a). Compound 5a was prepared (0.090 g, 0.83 mmol), p-nitrobenzyl bromide (0.19 g, 0.90
according to the general procedure from methyl 2-(2- mmol) and 2.4 mL THF. The crude product was purified by
bromobenzyl)-3-oxobutanoate
potassium tert-butoxide (0.75 g, 6.33 mmol), p-nitrobenzyl 5% gradient) to afford a yellow solid (0.11 g, 36 %), Mp =129 –
bromide (1.39 g, 6.38 mmol) and 15 mL THF. The crude 131 °C. Anal calcd. for C18H15BrN2O4: C, 53.62, H, 3.75, N, 6.95;
product was recrystallized from ether (5 mL) to afford a white Found: C, 53.87, H, 3.83, N, 6.68. IR (ATR), (cm-1): 3111, 3082,
solid (1.43 g, 56%), Mp = 105.1-106.5 °C. Anal calcd. for 2959, 2924, 2855, 2250, 1748, 1605, 1514, 1346, 1229, 1057,
(9a) (1.73 g, 6.07 mmol), flash column chromatography (10-30% ethyl acetate/hexanes,
.
.
1
C19H18BrNO5: C, 54.30, H, 4.32, N, 3.33; Found: C, 54.59, H, 1045, 1024, 854, 840, 748, 702. H NMR (CDCl3, 400 MHz), δ
4.16, N, 3.40. IR (ATR), (cm-1): 3067, 2952, 2932, 2844, 1741, (ppm): 3.14 (d, J = 13.5 Hz, 1H), 3.48-3.59 (m, 3H), 3.67 (s, 3H),
1707, 1559, 1342, 1242, 967, 745, 526. 1H NMR (CDCl3, 400 3.72 (s, 3H), 7.20 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.42
MHz), δ (ppm): 2.03 (s, 3H), 3.29 (d, J=14.0 Hz, 1H), 3.42–3.56 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.0 Hz,
(m, 3H), 7.13 (t, J = 8.0 Hz, 1H), 7.20 (ddd, J = 8.0, 2.0 Hz, 1H), 1H), 8.17 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz), δ
7.26 (m, 3H), 7.58 (ddd, J = 8.0, 1.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, (ppm): 41.7, 41.8, 51.8, 53.7, 117.5, 123.7, 125.7, 127.8, 129.,
2H); 13C NMR (CDCl3, 100 MHz), δ (ppm): 28.8, 39.0, 39.3, 52.4, 131.1, 131.5, 133.5, 133.5, 141.4, 147.7, 168.0.
65.7, 123.3, 126.15, 127.5, 128.8, 131.0, 131.1, 133.3, 135.6, Methyl
2-(2-bromobenzyl)-3-(2-bromophenyl)-2-
144.3, 147.1, 171.5, 204.0.
1-Ethyl 6-methyl
cyanopropanoate (5e). Compound 5d was prepared according
(E)-5-acetyl-5-(2-bromobenzyl)hex-2- to the general procedure from methyl cyanoacetate (0.42g,
enedioate (5b). Compound 5b was prepared according to the 4.20 mmol), potassium tert-butoxide (0.48 g, 4.20 mmol), p-
general procedure from methyl 2-(2-bromobenzyl)-3- nitrobenzyl bromide (1.00 g, 4.00 mmol) and 16.8 mL THF. The
oxobutanoate (9a) (0.30 g, 1.02 mmol), potassium tert- crude product was purified by flash column chromatography
butoxide (0.12 g, 1.07 mmol), ethyl (E)-4-bromobut-2-enoate (30-80% ethyl methylene chloride/hexanes, 10% gradient) to
(0.29 g, 1.12 mmol) and 3.1 mL THF. The crude product was afford a white solid (0.45 g, 25%), Mp = 95- 96° C. Anal. calcd.
purified by flash column chromatography (18-24% ethyl for C18H15Br2NO2: C, 49.46, H, 3.46, N, 3.20; Found: C, 49.25, H,
1
acetate/hexanes, 2% gradient) to afford a yellow oil (0.23 g, 3.38, N, 3.38. H NMR (CDCl3, 400 MHz), δ (ppm): 3.56 (q, J =
55%). Anal. calcd. for C18H21BrO5: C, 54.42, H, 5.33. Found: C, 14.2 Hz, 4H), 3.76 (s, 3H), 7.17 (t, J = 7.8 Hz, 2H), 7.31 (t, J = 7.6
1
54.71, H, 5.28. H NMR (CDCl3, 400 MHz), δ (ppm): 1.27 (t, J = Hz 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H); 13C NMR
7.02 Hz, 3H), 2.16 (s, 3H), 2.69-2.82 (m, 2H), 3.48 (dd, J = 14.6 (CDCl3, 100 MHz), δ (ppm): 40.9, 51.0, 53.8, 117.8, 125.9,
Hz, 2H), 3.74 (s, 3H), 4.17 (q, J = 7.02 Hz, 2H), 5.82 (d, J = 15.4 127.7, 129.5, 131.3, 133.3, 134.0, 168.5.
Hz, 1H), 6.77-6.85 (m, 1H), 7.07-7.11 (m, 1H), 7.16-7.24 (m,
2H), 7.54 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3,100 MHz), δ α,α-Disubstituted methyl malonate
(ppm): 14.2, 27.7, 35.3, 37.4, 52.6, 60.4, 64.3, 124.9, 126.0,
127.4, 128.7, 131.4, 133.2, 135.7, 142.5, 165.7, 171.5, 203.3.
Methyl (E)-2-acetyl-2-(2-bromobenzyl)-5-phenylpent-4-enoate prepared according to the general procedure using diethyl
5c). Compound 5c was prepared according to the general malonate (0.40 g, 3.03 mmol), potassium tert-butoxide (0.68 g,
procedure from methyl 2-(2-bromobenzyl)-3-oxobutanoate 6.06 mmol), benzyl bromide (1.20 g, 6.67 mmol) and 20.9 mL
9a) (0.62 g, 2.2 mmol), potassium tert-butoxide (0.28 g, 2.4 THF The crude product was purified by column
Dimethyl 2,2-dibenzylmalonate (11). Compound 11 was
(
(
mmol), 3-bromo-1-phenyl-1-propene (0.50 g, 2.4 mmol) and 4 chromatography (1-6% ethyl acetate/hexanes, 1% gradient) to
1
mL THF. The crude product was purified by column afford white solid (0.60 g, 65%). H NMR (CDCl3, 400 MHz), δ
chromatography (1-5% diethyl ether/hexanes, 1% gradient) to (ppm): 3.29 (s, 4H), 3.69 (s, 6H), 7.21 (d, J = 7.4 Hz, 4H), 7.32
afford a yellow solid (0.49 g, 57%), Mp = 78.7 – 79.7 °C. IR (m, 5H). Other spectroscopic data it was reported in
:
(ATR), (cm-1) 3061; 3023, 2950, 2918, 1745 (C=O, ester), 1712 literature.13
(C=O, ketone),1432, 1355, 1275, 1217, 1196, 1180, 1039, 758,
736. 1H NMR (CDCl3, 400 MHz), δ (ppm): 2.15 (s, 3H), 2.73 – General procedure for the synthesis of α-mono- β-ketoesters
2.84 (m, 2H), 3.46 – 3.56 (m, 2H), 3.71 (s, 3H), 6.06 – 6.14 (m,
1H), 6.41 (d, 1H), 7.06 – 7.09 (m, 1H),7.19 – 7.24 (m, 3H), 7.26 Method 1: To a suspension ( ̴ 0.50 M) of sodium hydride (1.05
– 7.32 (m, 4H), 7.54 (d, 1H, J = 8.0 Hz); 13C NMR (CDCl3, 100 equiv) in anhydrous THF, under inert atmosphere, it was
MHz), δ (ppm): 27.9, 36.4, 37.3, 52.4, 64.8, 124.0, 126.0, 126.2, added the β-keto ester (1 equiv) dropwise. The reaction
127.3, 127.4, 128.5, 128.5, 131.4, 133.1, 133.9, 136.3, mixture was stirred by 10 min, next refluxed and then the alkyl
137.0,172.0, 204.1. HRMS (DART): calcd for C21H21BrO3: bromide (1.05 equiv) was added slowly. The reaction mixture
401.0752, found: 401.0753.
was stirred over night at 70° C. After this time, it was
quenched with brine and extracted with ethyl acetate, the
organic phase dried over anhydrous magnesium sulfate,
filtered and the solvent removed under reduced pressure.
α,α-Disubstituted α-cyanoesters
Methyl
2-(2-bromobenzyl)-2-cyano-3-(4-nitrophenyl)- Method 2: In the same way than the Method 1, but in this
propanoate (5d). Compound 5d was prepared according to the case it was used potassium tert-butoxide as base and reaction
general procedure from methyl 3-(2-bromophenyl)-2- mixture was stirred for 12 h at rt.
8 | J. Name., 2012, 00, 1-3
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afforded a yellow oil (0.17 g, 57%). Anal. calcd. for C18H21IO5 :
C, 48.66, H, 4.76, Found: C, 48.84, H, 4.83. 1H NMR (CDCl3, 400
Methyl (E)-5-(4-chlorophenyl)-2-(3-(2-iodophenyl)propanoyl)
pent-4-enoate (7a). Compound 7a was prepared according to MHz), δ (ppm): 1.30 (t, J = 7.2 Hz, 3H), 2.74–2.87 (m, 3H), 2.94
Method from methyl 5-(2-iodophenyl)-3-oxopentanoate – 3.07 ( m, 3H), 3.64 ( t, J = 7.3 Hz, 1H), 3.72 ( s, 3H), 4.20 ( q, J
1
(618.4 mg, 1.84 mmol), sodium hydride (0.08 g, 1.94 mmol), = 7.0 Hz, 2H), 5.88 ( d, J = 15.6 Hz, 1H), 6.80-6.88 ( m, 1H),
(E)-1-chloro-4-(3-chloroprop-1-en-1-yl)benzene (0.37 g, 1.94 6.90–6.94 ( m, 1H), 7.23–7.31 ( m, 2H), 7.83 ( d, J = 7.8 Hz, 1H);
mmol) and 3.7 mL THF in reflux by 18 h. The crude product 13C NMR (CDCl3, 100 MHz), δ (ppm): 14.2, 30.2, 34.5, 42.3,
was purified by column chromatography (10-16% ethyl 52.7, 57.2, 80.4, 100.0, 123.9, 128.2, 128.5, 129.8, 139.6,
acetate/hexanes, 2% gradient), affording a yellow oil (0.46 g, 142.9, 143.8, 165.9, 166.8, 202.2.
52%). Anal
.
calcd. for C12H13BrO3: C, 52.25, H, 4.18; Found: C, Methyl
5-(2-iodophenyl)-2-(4-nitrobenzyl)-3-oxopentanoate
51.88, H, 4.08. 1H NMR (CDCl3, 400 MHz), δ (ppm): 2.79 (td, J =
(
7e). Compound 7e was prepared according to Method 2 from
7.2, 1.0 Hz, 2H), 2.82-2.88 (m, 1H), 2.96 (dd, J = 6.6, 6.4 Hz, methyl 5-(2-iodophenyl)-3-oxopentanoate (0.55 g, 1.67 mmol),
1H), 3.02-3.07 (m, 2H), 3.67 (t, J = 7.3 Hz, 1H), 3.74 (s, 3H), 6.11 potassium tert-butoxide (0.26 g, 2.28 mmol), p-nitrobencyl
(dt, J = 7.4, 7.2 Hz 1H), 6.43 (d, J = 15.8 Hz, 1H), 6.90-6-94 (m, bromide (0.26 g, 2.28 mmol) and 6.3 mL THF. The crude
1H), 7.24-7.31 (m, 6H), 7.83 (d, J = 8.0 Hz, 1H); 13C NMR (100 product was purified by column chromatography (1-5% diethyl
MHz, CDCl3) δ (ppm): 31.5, 34.5, 42.5, 52.5, 58.4, 100.1, 126.3, ether/hexanes, 1% gradient) to afford a yellow oil (0.50 g,
127.5, 128.2, 128.5, 128.7, 129.9, 131.7, 133.1, 133.5, 135.5, 65%). Anal. calcd. for C19H18INO5: C, 48.84, H, 3.88, N, 3.00;
1
139.6, 143.1, 169.4, 203.2.
Methyl
enoate (7b). Compound 7b was prepared according to Method 2H), 3.69 (s, 3H,), 3.85 (t, J = 7.6 Hz, 1H), 6.91 (td, J = 7.5, 1.8
from methyl (E)-3-oxo-7-phenylhept-6-enoate (0.19 g, 0.81 Hz, 1H), 7.19–7.34 (m, 4H), 7.80 (dd, J = 7.8, 1.0 Hz, 1H), 8.11
Found: C, 49.20, H, 4.05, N, 3.11. H NMR (CDCl3, 400 MHz), δ
(E)-2-(3-(2-iodophenyl)propanoyl)-5-phenylpent-4- (ppm): 2.64–2.73 (m, 1H), 2.89–3.01 (m, 3H), 3.23-3.35 (m,
2
mmol), potassium tert-butoxide (0.11g, 0.89 mmol), 2- (d, J = 8.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz), δ (ppm): 33.5,
iodobenzyl bromide (0.27 g, 0.89 mmol) and 4 mL THF. 34.3, 42.8, 52.7, 59.5, 100.0, 123.8, 128.4, 129.7, 129.8, 139.5,
Purification by column chromatography (10-14% ethyl 142.7, 145.7, 146.8, 166.6, 202.3.
acetate/hexanes, 1% gradient), afforded a yellow oil (0.27 g, Methyl 2-(2-bromobenzyl)-3-oxobutanoate (9a). Compound 9a
75%). 1H NMR (400MHz, CDCl3) δ(ppm) 2.43 (q, J = 6.9 Hz, 2H,), was prepared according to Method
2
from methyl
2.45-2.53 (m, 1H), 2.69 (dt, J = 7.3 Hz, 1H), 3.20 (d, J = 7.5 Hz, acetoacetate (1.00 g, 8.44 mmol), potassium tert-butoxide
2H), 3.59 (s, 3H), 3.94 (t, J = 7.5 Hz, 1H), 6.08 (dt, J = 6.8 Hz, (1.00 g, 8.86 mmol), o-bromobenzyl bromide (2.40 g, 9.28
1H), 6.28 (d, J = 15.8 Hz, 1H,), 6.8-6.8 (m, 1H), 7.10-7.21 (m, mmol) and 25 mL THF The crude product was purified by
7H), 7.72 (d, J = 8.0 Hz, 1H,); 13C NMR (CDCl3, 100 MHz), column chromatography (1-15% ethyl acetate/hexanes, 1%
δ(ppm) 26.8, 38.7, 42.6, 52.5, 58.2, 100.0, 126.1, 127.2, 128.3, gradient) to afford yellow oil (2.10 g, 88%). Anal. calcd. for
128.5, 128.6, 128.7, 130.9, 131.1, 137.4, 139.7, 169.1, 203.4; C12H13BrO3: C, 50.55, H, 4.60; Found: C, 50.38, H, 4.42. 1H NMR
HRMS (DART): calcd for C21H21IO3: 449.0614, found: 449.0615.
Methyl (E)-2-(3-(2-iodophenyl)propanoyl)-5-(4- 3H), 4.03 (dd, J = 7.2 Hz, 1H), 7.11-7.15 (m, 1H), 7.23-7.31 (m,
nitrophenyl)pent-4-enoate (7c). Compound 7c was prepared 2H), 7.57 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ
according to Method from methyl 5-(2-iodophenyl)-3- (ppm): 29.8, 34.5, 58.7, 124.4, 127.6, 128.6, 131.7, 133.0,
(CDCl3, 400 MHz), δ (ppm): 2.27 (s, 3H), 2.32 (m, 2H), 3.73 (s,
2
oxopentanoate (0.49 g, 1.48 mmol), (E)-1-(3-bromoprop-1-en- 137.4, 169.3, 202.2.
1-yl)-4-nitrobenzene (0.39 g, 1.62 mmol), potassium tert- Ethyl 2-(2-bromobenzyl)-3-oxobutanoate (9b). Compound 9b
butoxide (0.20 g, 1.62 mmol) and 4.9 mL THF. Purification by was prepared according to Method 2 from ethyl acetoacetate
column chromatography (silica gel 70-230 mesh, 20% ethyl (4.90 g, 39.0 mmol), potassium tert-butoxide (4.60 g, 39.0
1
acetate/hexane) afforded a yellow oil (0.25 g, 34%). H NMR mmol), o-bromobenzyl bromide (9.90 g, 39.0 mmol) and 130
(CDCl3, 400 MHz), δ (ppm): 2.80-2.88 (m, 3H), 2.97 (dd, J = mL THF. Crude product was purified by column
6.02, 8.53 Hz, 1H), 3.02-3.06 (m, 2H), 3.69 (t, 7.4 Hz, 1H), 3.74 chromatography (01-15% ethyl acetate/hexanes, 1% gradient)
(s, 3H), 6.32 (dt, J = 7.37, 15.8, Hz, 1H,), 6.53 (d, J = 15.8 Hz, to afford yellow oil (9.60 g, 82%).); 1H NMR (CDCl3, 400 MHz), δ
1H,), 6.88-6.93 (m, 1H), 7.25-7.26 (m, 1H), 7.44 (d, J = 8.8 Hz, (ppm): 1.19 (t, J = 7.2 Hz, 3H), 2.23 (s, 3H), 3.25 (d, J = 7.4 Hz,
2H,), 7.81 (d, J = 7.5 Hz, 1H,), 8.17 (d, J = 8.8 Hz, 2H,); 13C NMR 2H), 3.96 (t, J = 7.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 7.02-7.05
(CDCl3, 100 MHz), δ (ppm): 31.5, 34.4, 42.4, 52.64, 58.0, 100.1, (m, 2H), 7.24 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H). Other
123.9, 126.7, 128.5, 129.8, 130.9, 131.0, 139.5, 142.9, 143.3, spectroscopic data were already reported in the literature.14
146.8, 169.1, 202.75; HRMS (DART): calcd for C21H20INO5:
494.0464, found: 494.0470.
Acknowledgements
1-Ethyl
enedioate (7d). Compound 7d was prepared according to
method from methyl 5-(2-iodophenyl)-3-oxopentanoate
6-methyl
(E)-5-(3-(2-iodophenyl)propanoyl)hex-2-
2
Authors greatly thank the Universidad del Valle and
COLCIENCIAS for their generous financial support of this
research work through the research projects 7974 and 71005,
respectively. The “Research Group of Heterocyclic Compounds
(0.25 g, 0.75 mmol), potassium tert-butoxide (0.09 g, 0.79
mmol), 3-bromo-1-phenyl-1-propene (0.21 g, 0.82 mmol) and
1.3 mL THF. The crude product purified by column
chromatography (10-30% ethyl acetate/hexanes, 5% gradient)
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ARTICLE
Journal Name
(GICH)” is also acknowledged for providing us the CEM
Microwave Reactor.
Notes and references
1
Z. Wang in Comprehensive organic name reactions and
reagents; Vol. 3 John Wiley & Sons, Hoboken, 2009, pp. 9-12.
a) A. P. Krapcho, E. Ciganek in The Krapcho
Dealkoxycarbonylation Reaction of Esters with α-Electron-
Withdrawing Substituents. In Organic Reactions; (Eds.: S. E.
Denmark), Ed.; John Wiley & Sons, Inc., 2013, Chapter 1, pp.
38–39; 43–44. b) P. S. Poon, K. S. Banerjee, M. S. Laya, J.
Chem. Res. 2011, 35, 67-73. c) A. P. Krapcho, Arkivoc 2007,
(ii), 1-53, d) A. P. Krapcho, Arkivoc 2007, (ii), 54-120.
a) S. S. Murphree, J. D. Mason, T. G. Bean, M. C. Perry, Synth.
Commun. 2012, 42, 1979-1986, b) M. E. Jung, J. J. Chang,
Org. Lett. 2010, 12, 2962-2965, c) J. Magolan, C. A. Carson,
M. A. Kerr, Org. Lett. 2008, 10, 1437-1440, d) C. M. A. Bode,
S. Ting, E. Schaus, Tetrahedron 2006, 62, 11499-11505, e)
Loupy, A. in Microwaves in Organic Synthesis; Wiley-VCH,
Weinheim, 2006, pp. 2-24, f) B. K. Banik, M. S. Manhas, E. W.
Robb, A. K. Bose, Heterocycles 1997, 44, 405-415, g) S.
Caddick, Tetrahedron 1995, 51, 10403-10432.
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3
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a) L. Perreux, A. Loupy, Tetrahedron 2001, 57, 9199-9223, b)
J. P. Barnier, A. Loupy, P. Pigeon, M. Ramdani, P. Jacquault, J.
Chem. Soc., Perkin Trans. 1. 1993, 397-398.
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S. S. Murphree, J. D. Mason, Synlett 2013, 24, 1391-1394.
Manuscript in preparation.
a) A. P. Krapcho, Synthesis 1982, Part I, 805-822, b) A. P.
Krapcho, J. Org. Chem. 1978, 43, 138-147.
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P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron
2001, 57, 9225-9283.
10 A. Penoni, K. L. Ameta in Heterogeneous Catalysis:
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versatile tool for the synthesis of bioactive heterocycles,
CRC-Press:Taylor and Francis Group, Boca Raton, 2015, pp.1-
20.
11 W. Ford, Y. Chang, J. Org. Chem. 1981, 46, 5364-5371.
12 Z. Wu, Y. Liu, Chem. Commun. 2016, 52, 1158-1161.
13 Y. Zhang, X. Cao, Green Chem. 2016, 18, 2638-2641.
14 a) M. Cooke, R. Widener, J. Org. Chem. 1987, 52, 1381-1396,
b) U. Beifuss, C. Malakar, D. Schmidt, J. Conrad, Org. Lett.
2011, 13, 1972-1975.
10 | J. Name., 2012, 00, 1-3
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Table of contents Entry
An alternative microwave-assisted Krapcho type reaction of α-Mono- and α,α-Disubstituted β-
Keto- and α-Cyanoesters was efficiently performed on a Silica Gel Bed.