Multi-catalysis cascade reactions based on the methoxycarbonylketene platform: Diversity-oriented synthesis of functionalized non-symmetrical malonates for agrochemicals and pharmaceuticals

Article abstract of DOI:10.1039/b901652j

In this paper we describe new multi-catalysis cascade (MCC) reactions for the one-pot synthesis of highly functionalized non-symmetrical malonates. These metal-free reactions are either five-step (olefination/hydrogenation/alkylation/ ketenization/esterif

Full text of DOI:10.1039/b901652j

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Multi-catalysis cascade reactions based on the methoxycarbonylketene
platform: diversity-oriented synthesis of functionalized non-symmetrical
malonates for agrochemicals and pharmaceuticals†
Dhevalapally B. Ramachary,* Chintalapudi Venkaiah, Y. Vijayendar Reddy and Mamillapalli Kishor
Received 26th January 2009, Accepted 18th February 2009
First published as an Advance Article on the web 20th March 2009
DOI: 10.1039/b901652j
In this paper we describe new multi-catalysis cascade (MCC) reactions for the one-pot synthesis of
highly functionalized non-symmetrical malonates. These metal-free reactions are either five-step
(olefination/hydrogenation/alkylation/ketenization/esterification) or six-step (olefination/
hydrogenation/alkylation/ketenization/esterification/alkylation), and employ aldehydes/ketones,
Meldrum’s acid, 1,4-dihydropyridine/o-phenylenediamine, diazomethane, alcohols and active
ethylene/acetylenes, and involve iminium-, self-, self-, self- and base-catalysis, respectively. Many of the
products have direct application in agricultural and pharmaceutical chemistry.
alkyl halides under dry conditions, but this has limited scope with
respect to yield, generality, and experimental simplicity.
Recently, acylketenes (B) have often been employed as reactive
electrophiles to trap alcohols to construct b-ketoesters (C) by con-
Introduction
2-Alkylmalonates are an important class of compounds that
display a large spectrum of biological applications, and are widely
used as intermediates for pharmaceuticals and agrochemicals.1
Compounds containing 2-alkyl- and 2-arylmalonates have also
found pharmaceutical applications as glucocorticoid receptor
modulators, peptide deformylase inhibitors, HIV-1 and HIV-
2 protease inhibitors, potent dual ACE/NEP inhibitors, anti-
diabetic agents, ligands for the neuromodulatory receptor and
in organic synthesis (see Fig. 1).1 As such, the development
of new and more general methods for their diversity-oriented
preparation is of significant interest.2 The conventional route to
2-alkylmalonates is the alkylation of symmetrical malonates with
certed addition of an oxygen nucleophile (Scheme 1).3 Thermolysis
of 6-alkyl-1,3-dioxin-4-one derivatives (A) is the most common
method used for the generation of B, and Boeckman and co-
workers pioneered the application of reactive acylketene species in
the synthesis of complex molecules such as macrocyclic lactones
and lactams.3 In situ generation of alkyloxycarbonylketenes (B¢)
from 6-alkyloxy-1,3-dioxin-4-one (A¢) is hardly known, but the
rate of the cycloreversion reaction of A¢ → B¢ is rapid below
25 ◦C relative to A → B, because of electronic factors (Scheme 1).4
In this paper, we have used a new reactive species – alkyloxy-
carbonylketenes (B¢) – to generate a library of non-symmetrical
2-alkylmalonates (C¢) by in situ generation, cycloreversion and
alcohol addition (A¢ → C¢) in one pot under ambient conditions.
As part of our program to engineer direct multi-catalysis cascade
(MCC) reactions,5 we were exploring the in situ generation and
application of the methoxycarbonylketenes (12), as shown in
Scheme 2. We expected that the reaction of 1 with 2/6, 3, 4,
School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS) for all
new compounds; NMR spectra. CCDC reference number 713797 (18ea).
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b901652j
Fig. 1 Generation of a library of pharmaceutically attractive molecules from 2-alkylmalonates.
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Scheme 1 Synthesis of non-symmetrical malonates via alkyloxycarbonylketenes generated from 6-alkyloxy-[1,3]dioxin-4-one.
Scheme 2 One-pot multi-catalysis cascade (MCC) reactions.
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Table 1 Preliminary optimization of MCC reactions
Time (h)
Entry
1b
Cyclic malonate
Organic hydride
O/H step
A/K/E step
2
Product
Yield (%)a
90
2
2
13aa
2b
2
0.5
1
13aa
89
3b
2
0.5
1.5
1
1
13aa
13aa
65
65
4c
6¢a
a Yield refers to the column-purified product. b All reactants 1a–c, 2, 3a and catalyst 4 were mixed at the same time in the solvent and stirred at 25 ◦C;
15 equiv of ethereal diazomethane was then added and the mixture stirred at 25 ◦C. c All reactants 1a, 6, 3a (2 equiv) and catalyst 4 were mixed at the
same time in the solvent and stirred at 25 ◦C; 15 equiv of ethereal diazomethane was then added and the mixture stirred at 25 ◦C.
and 5 would lead to 5-alkyl-2,2-dialkyl-[1,3]dioxane-4,6-diones
8 via olefin intermediate 7. Further in situ treatment of 8 with
CH2N2 and 5 ought to lead to non-symmetrical malonates 13 via
chemoselective generation of key intermediates 12 from 11. Final
HMPT-mediated alkylation of 13 with active ethylene/acetylenes
14 should give non-symmetrical 2,2-dialkylated malonates 16.
Incidentally, the amino acid-/self-catalyzed olefination/
hydrogenation reaction sequence did not work with dialkyl-
malonates 1¢, instead furnishing only the olefin product 9 in good
yield. This may be because the dialkyl benzylidenemalonates 9
are more than 1010 times less reactive than benzylidene Meldrum’s
acids 7 and their cyclic counterparts 7 with organic hydrides 2
(Scheme 2).6
Considering the main reaction sequence, the in situ gen-
eration of methoxycarbonylketenes 12 – and reaction with
various alcohols 5 – was very fast at ≤25 ◦C compared to
acylketenes B. This unexpectedly high reactivity makes this
route a useful way of preparing 12, and further reaction
to give either (a) 2-alkylmalonates 13 (by olefination/hydro-
genation/alkylation/ketenization/esterification (O/H/A/K/E))
or (b) 2,2-dialkylmalonates 16 (with a final alkylation step (A)).
Overall, the route employs aldehydes/ketones 3, Meldrum’s acid
1, 1,4-dihydropyridine 2/o-phenylenediamine 6, diazomethane,
alcohols 5 and active ethylene/acetylenes 14, and does not involve
any metal catalysts. It also generates a quaternary center, two
carbon–carbon s-bonds and two carbon–oxygen s bonds. We
report herein our findings regarding this new organocatalytic one-
pot cascade sequence.
Results and discussion
Reaction optimization for the one-pot MCC reactions
First we focused on the optimization of the synthesis of ethyl
methyl 2-benzylmalonate 13aa from 1, 2/6 and 3a by amino
acid-catalysis in ethanol 5a, by looking at the effect of the cyclic
nature of 1 and the hydrogen donor ability of 2/6. We therefore
tested three known and novel cyclic Meldrum’s acids 1a–c and
organic hydrides 2 (or in situ-generated 6¢a) for the O/H cascade
followed by the A/K/E cascade with benzaldehyde 3a and ethereal
diazomethane in ethanol 5a, as shown in Table 1. Interestingly,
the proline-catalyzed O/H cascade of Meldrum’s acid 1a and
benzaldehyde 3a with Hantzsch ester 2 in ethanol at 25 ◦C for 2 h
furnished the expected reductive alkylation product 8aa in >99%
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conversion, which on in situ treatment with ethereal diazomethane
at 0 → 25 ◦C for 2 h furnished the expected product 13aa in 90%
yield (entry 1). The O/H/A/K/E reaction of Meldrum’s acid
analogues 1b,c with 2, 3a, 5a and diazomethane catalyzed by 4 in
ethanol at 0 → 25 ◦C for 1 h furnished 13aa in lower yield – 89%
and 65% respectively (entries 2 and 3). However, the reaction rate
with 1b,c was 4-fold higher than for 1a.
Interestingly, proline-catalyzed cascade O/H reaction of Mel-
drum’s acid 1a and two equivalents of benzaldehyde 3a with o-
phenylenediamine 6 in ethanol at 25 ◦C for 1.5 h furnished the
expected reductive alkylation product 8aa in >99% conversion,
which on in situ treatment with ethereal diazomethane at 0 →
25 ◦C for 1 h furnished the expected product 13aa, but in only
65% yield (entry 4). From these preliminary results, it was clear
that 1a or 1b and 2 are suitable for the MCC reactions.
After this preliminary investigation, we proceeded to investigate
the scope and limitations of the O/H/A/K/E cascade reaction
of 1a, 2, 3a and diazomethane with a range of alcoholic solvents
5a–j under catalysis by proline at 25 ◦C (Table 2). Larger alkyl
alcohols 5c–h furnished MCC products 13ac–ah in lower yield
than smaller alkyl alcohols 5a,b in the cascade O/H/A/K/E
reactions. The reason may be due to moderate steric hindrance
with larger alkyl groups. Also we observed that the rate of the
cascade O-methylation reaction of 8aa with CH2N2 in MeOH
appeared to be slow compared to other alcoholic solvents –
unreacted cascade product 8aa was isolated in 15% yield after
6 h (entry 2). However, extension of the reaction time up to
26 h in MeOH furnished the expected product 13ab in 85% yield
(result not shown in Table 2). This may be due to the existence
of more interactions between the intermediates and methanol
compared to other solvents. Interestingly, the MCC reaction of
1a, 2, 3a, 4 and diazomethane in benzyl alcohol 5i furnished the
expected product 13ai along with the unexpected product dimethyl
2-benzylmalonate 13ab in good yield with a 6:1 ratio (entry 9).
Generation of 13ab was also observed in other solvents, such as
(S)-ethyl lactate 5j and CH3CN (entries 10–12). Formation of 13ab
in solvents like 5i, 5j and CH3CN can be explained by the lower
nucleophilicity of 5i and 5j compared to methanol 5b, and a small
amount of methanol being present in the ethereal diazomethane
solution (generated in situ from the reaction of NMU with aqueous
KOH in ether at low temperature7). Unexpected formation of 13ab
from above reactions was confirmed by controlled experiment
as shown in Scheme 3, which proved that significant amount of
methanol 5b is present in the ethereal diazomethane solution.7 The
mixture of compounds 13ai/13ab obtained from benzyl alcohol
could be transformed into the useful diols 17a with good yield, as
shown in Scheme 4.
Scheme 3
Development of product-specific MCC reactions
We then decided to investigate the scope and limitations of
the MCC reaction with a range of aldehydes/ketones 3a–k¢,
Table 2 Optimization of MCC reactions
Time (h)
Entry
Organic hydride
R–OH
O/H step
A/K/E step
Product
Yield (%)a
1
2b
3
4
5
6
7
8
2
EtOH 5a
2
2
2
2
2
2
6
2
2
2
2
1
1
1
13aa
90
75
70
65
65
65
70
70
80
89
90
75
2
MeOH 5b
n-PrOH 5c
i-PrOH 5d
n-BuOH 5e
t-BuOH 5f
13ab
2
13ac
2
13ad
2
13ae
2
2
13af
=
2
H2C CHCH2OH 5g
1.5
1.5
1.5
15
15
3
13ag
∫
2
HC C–CH2OH 5h
13ah
9c
10d
11
12
2
BnOH 5i
13ai + 13ab
13ab
6¢a
6¢a
2
(S)-CH3CH(OH)CO2Et 5j
6
12
6
CH3CN
CH3CN
13ab
13ab
a Yield refers to the column-purified product. b Un-reacted cascade O/H product 8aa were isolated in 15% yield. c Compounds 13ai and 13ab were
furnished in 6:1 ratio. d (S)-Ethyl lactate 5j was taken as 5 equiv in CH3CN (0.5 M).
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2-alkylmalonates 13ya–k¢a were obtained as single products with
excellent yields. To show the applicability of this method, we
carried out the large-scale (10 mmol) synthesis of MCC product
13aa with very good yield. The fact that the MCC reaction of
substrates such as 3g, 3n, 3g¢, 3h¢ and 3j¢ in BnOH furnished only
the desired products 13gi–13j¢i without side products may be due
to the substrate electronic factors and also the amount of methanol
available in the ethereal diazomethane solution, which is proved
by the reaction shown in Scheme 6. Reaction of 1a, 3g (2 equiv),
6, 4 and CH2N2 in CH3CN furnished the expected product 13gb
in lower yield (30%) compared to simple benzaldehyde 3a (see
Scheme 6 and Table 2, entries 11–12).
Scheme 4
Meldrum’s acid analogues 1a–e and alcohols 5 under catalysis by
proline and ambient conditions (Scheme 5 and Table 3). As shown
in Scheme 5, MCC reaction of N,N-dimethylbarbituric acid 1d, 2,
3a, 4, 5a and diazomethane furnished the single uracil derivative
18da with 98% yield. Same MCC reaction with barbituric acid 1e
furnished the 2(1H)-pyrimidinone derivative 18ea as major single
product with 70% yield and 5-benzyl-2,6-dimethoxy-3-methyl-
3H-pyrimidin-4-one 19ea with ≤5% yield out of 24 expected
products from the designed reaction as shown in Scheme 5.
5-Benzylpyrimidine-2,4,6-trione 8ea, which is generated in situ
from the O/H cascade reaction, has many active sites toward
methylation with diazomethane, but the only major product
was 5-benzyl-2,6-dimethoxy-3H-pyrimidin-4-one 18ea, which was
confirmed by X-ray structural analysis (see Fig. 2).† Interestingly,
we did not observe the formation of ketenes from 18. Uracil
and 2(1H)-pyrimidinone derivatives 18 are useful compounds as
agrochemical fungicides and potent HIV-1 and HIV-2 inhibitors,
and they also have good anti-viral and anti-bacterial activity.1
Our product-specific MCC technology may be suitable to develop
a large number of diverse-compounds of 18 to screen and identify
suitable bioactive products.
MCC reactions with active functional groups
Interestingly, proline-catalyzed MCC reaction of Meldrum’s
acid 1a, Hantzsch ester 2, 2-hydroxybenzaldehyde 3h and dia-
zomethane at 25 ◦C in EtOH 5a furnished the MCC product
13ha in 80% yield via an unexpected intermediate of the O/H/H
cascade, 2-(2-hydroxybenzyl)malonic acid mono-ethyl ester 20ha,
instead of the expected ketene intermediate 12ha (Table 3 and
Scheme 7). But the same reaction with 3-hydroxybenzaldehyde 3i
or 4-hydroxybenzaldehyde 3j proceeded via ketene intermediates
12ia and 12ja respectively, furnishing the expected MCC products
13ia and 13ja with good yields, as shown in Table 3. Also, MCC
reaction of Meldrum’s acid 1a with 2-hydroxy-benzaldehyde 3h
and Hantzsch ester 2 at 25 ◦C in water furnished the unexpected
intermediate 2-oxochroman-3-carboxylic acid 21ha, which on in
situ treatment with sodium hydroxide furnished the 2-(2-hydroxy-
benzyl)-malonic acid 22ha with very good yield (Scheme 7).
Reaction of 22ha with diazomethane furnished the unexpected
methylated product 13l¢b along with expected product 13hb in
good yield, may be due to the co-operative catalysis from hydrogen
bonding. Unexpected intermediates 20ha and 21ha were isolated
and characterized by NMR analysis.5f Formation of unexpected
cascade O/H/H intermediates from 1a, 2 and 3h under proline-
and self-catalysis in EtOH and H2O can be explained as shown
in TS-1 and TS-2 respectively (Scheme 7). Inter- and intra-
molecular hydrolysis of in situ generated cascade O/H product
8ha with solvents like EtOH or H2O gives the cascade O/H/H
intermediates as shown in TS-1 and TS-2 respectively. These two
different types of hydrolysis can be possible due to the nucleophilic
nature of alcoholic solvents and possibility of hydrogen bonding
interactions with water.
Fig. 2 Crystal structure of 5-benzyl-2,6-dimethoxy-3H-pyrimidin-4-one
(18ea).
Diversity-oriented synthesis of MCC products 13aa–13k¢a
We then generated a useful library of MCC products 13 un-
der proline-/self-/self-/self-/self-catalysis. The results in Table 3
demonstrate the broad scope of this reductive MCC methodology
covering a structurally diverse group of aldehydes 3a–f¢, less
reactive ketones 3g¢–k¢ and alcohols 5a–i, with many of the
yields obtained being better than previously published reactions
starting from the corresponding symmetric malonates 1¢. A large
number of non-symmetrical 2-alkylmalonates 13 are not known,
and our MCC methodology is first to prepare them with good
yields. A series of substituted aromatic aldehydes 3a–v, hetero-
aromatic aldehydes 3w–x, aliphatic aldehydes 3y–f¢ and ketones
3g¢–k¢ were treated with Meldrum’s acid 1a (1.0 equiv), Hantzsch
ester 2 (1.0 equiv) and diazomethane (15 equiv) catalyzed by 5–20
MCC products 13aa and analogues are important intermediates
for the synthesis of glucocorticoid receptor modulator (E),1b HIV-
1 and HIV-2 protease inhibitors (G and H),1d,e anti-ulcer and
anti-diabetic agents (J),1g and ligands for the neuromodulatory
receptors (K)1h and chiral MCC products 13e¢b and 13f¢b are useful
intermediates for the total synthesis of female sex pheromone of
the German cockroach (D).1a MCC products 13ga and 13gi are
important intermediates for the total synthesis of fasidotril, a po-
tent dual ACE/NEP inhibitor (I);1f and products 13c¢a, 13d¢a and
their analogues are key intermediates for the synthesis of peptide
deformylase inhibitors (F) and for the prostaglandin-H synthase
inhibitors,1c,l products 13h¢a and 13h¢i are key intermediates for the
synthesis of prostaglandin analogues,1m and blood clotting factor
inhibitors1n emphasizing the value of this MCC approach to the
pharmaceuticals.
◦
mol% of proline 4 at 25 C in EtOH 5a, MeOH 5b or BnOH 5i
(Table 3). Ethyl methyl 2-arylmalonates 13aa–xa and ethyl methyl
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Scheme 5 Applications of one-pot product-specific MCC reactions.
Development of the MCC reaction for the one-pot generation of
quaternary carbon centres
self-/HMPT-catalyzed six-component one-pot O/H/A/K/E/A
reaction of benzaldehyde 3a, Meldrum’s acid 1a, Hantzsch ester
2, diazomethane and ethanol 5a with various active olefins and
acetylenes 14a–e (Scheme 8). MCC products 16 were constructed
in very good yields with high selectivity, and this method should
be useful in the synthesis of functionalized small molecules.
Highly substituted non-symmetrical 2,2-dialkylated malonates
As part of our program to engineer direct one-pot MCC reactions
to deliver highly functionalized molecules with quaternary car-
bons relevant to pharmaceutical applications, we extended the five-
component cascade O/H/A/K/E reactions into a novel proline-/
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Table 3 Chemically diverse libraries of MCC products 13 a
a Yield refers to the column-purified product. b In situ-generated benzimidazolines 6¢e–z used as organic hydrides. c Compounds 13a¢i/13a¢b and 13b¢i/13b¢b
were furnished in a 6:1 ratio.
16 have gained importance in recent years as starting mate-
rials and intermediates for the synthesis of biologically active
compounds – for example, new M2-selective muscarinic recep-
tor antagonists and isozyme-selective glutathione S-transferase
inhibitors.1i–k
The O/H cascade reaction of 1a, 2, 3a and 5a under catalysis
by 20 mol% of proline furnished the substituted 5-benzyl-2,2-
dimethyl-[1,3]dioxane-4,6-dione 8aa in good conversion. This,
on in situ treatment with ethereal diazomethane at 0–25 ◦C
for 2 h, furnished ethyl methyl 2-benzylmalonate 13aa in good
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Scheme 6 Applications of one-pot product-specific MCC reactions.
Scheme 7 Applications of MCC reactions with 2-hydroxy-benzaldehyde in one-pot.
conversion, which on treatment with catalytic HMPT and methyl
vinyl ketone 14a in CH3CN at 25 ◦C for 0.5 h furnished the
O/H/A/K/E/A product 16aaa with 75% yield, as shown in
Scheme 8. The generality of the proline-/self-/HMPT-catalyzed
chemoselective one-pot O/H/A/K/E/A reaction was further
confirmed by three more examples using methyl acrylate 14b,
acrylonitrile 14c and methyl propiolate 14d to furnish the expected
products 16aab (70%), 16aac (75%) and 16aad (60%) with >95%
de, respectively (Scheme 8). Interestingly, alkylation reaction of
in situ-generated cascade O/H/A/K/E product 13aa with b-
nitrostyrene 14e under catalysis by HMPT did not furnish the
expected compound 16aae, but the same reaction under catalysis
by chiral cinchonidine/thiourea did give 16aae, albeit in 50% yield
with ≤5% de and ≤5% ee (Scheme 8). To achieve high ee, it will
be necessary to optimise the catalyst conditions.
Conclusions
In summary, we have developed direct amino acid-/self-/
self-/self-/self-/HMPT-catalyzed cascade olefination/hydro-
genation/alkylation/ketenization/esterification and olefination/
hydrogenation/alkylation/ketenization/esterification/alkylation
reactions, which have been shown to have direct application in the
drug discovery process. For the first time we have demonstrated
that multi-component coupling can be a product-specific reaction,
furnishing a single product out of many possible compounds. This
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Scheme 8 Applications of MCC for the one-pot generation of quaternary carbon centres.
experimentally simple and environmentally friendly approach can
be used to construct highly functionalized products in a selective
fashion with very good yields. For the first time in organocatalysis,
methoxycarbonylketenes 12 have been generated in situ and their
application in organic synthesis has been demonstrated. Further
work is now in progress to further utilize the active species 12 in
cascade chemistry.
CAD4 software. X-Ray intensity data were measured at 298 K on a
Bruker SMART APEX CCD area detector system equipped with
a graphite monochromator and a Mo-Ka fine-focus sealed tube
˚
(l = 0.71073 A). For thin-layer chromatography (TLC), Merck 60
F254 silica gel plates were used and compounds were visualized
by irradiation with UV light and/or by treatment with a solution
of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid
(10 mL), and ethanol (900 mL) followed by heating. All solvents
and commercially available chemicals were used as received.
Experimental
General experimental procedures for the MCC reactions
General methods
Proline-catalyzed one-pot cascade O/H/A/K/E reactions. In
an ordinary glass vial equipped with a magnetic stirring bar, to
0.5 mmol of the aldehyde/ketone 3, 0.5 mmol of CH-acid 1 and
0.5 mmol of Hantzsch ester 2 was added 1.7 mL of solvent. The
catalyst amino acid 4 (0.1 mmol) was then added and the reaction
mixture was stirred at 25 ◦C for the time indicated in Tables 1–3. To
the crude reaction mixture was added 15 equivalents of an ethereal
solution of diazomethane, and the reaction mixture was stirred
at room temperature for the time indicated in Tables 1–3. After
complete evaporation of the solvent and excess diazomethane in a
fumehood, the crude reaction mixture was worked up with water
if necessary, and then loaded onto a silica gel column, giving pure
one-pot products 13 after chromatography (solvent: hexane/ethyl
acetate).
1
The H NMR and 13C NMR spectra were recorded at 400 MHz
and100 MHz, respectively. The chemicalshifts are reportedinppm
downfield of TMS (d = 0) for 1H NMR and relative to the central
CDCl3 resonance (d = 77.0) for 13C NMR. In the13C NMR spectra,
the nature of the carbons (C, CH, CH2 or CH3) was determined
by a DEPT-135 experiment, and is given in parentheses. The
coupling constants J are given in Hz. Column chromatography
was performed using Acme’s silica gel (particle size 0.063–
0.200 mm). High-resolution mass spectra were recorded on a
Micromass ESI-TOF mass spectrometer. GCMS was performed
on a Shimadzu GCMS-QP2010 mass spectrometer. Elemental
analyses were recorded on a Thermo Finnigan Flash EA 1112
analyzer. LCMS mass spectra were recorded either on a VG7070H
mass spectrometer using the EI technique or a Shimadzu-LCMS-
2010A mass spectrometer. IR spectra were recorded on JASCO
FT/IR-5300 and Thermo Nicolet FT/IR-5700 instruments. The
X-ray diffraction measurements were carried out at 298 K on
an automated Enraf-Nonious MACH 3 diffractometer using
Proline/HMPT-catalyzed one-pot cascade O/H/A/K/E/A
reactions. In an ordinary glass vial equipped with a magnetic
stirring bar, to 0.5 mmol of the aldehyde/ketone 3, 0.5 mmol
of CH-acid 1 and 0.5 mmol of Hantzsch ester 2 was added
1.7 mL of solvent. The amino acid catalyst 4 (0.1 mmol) was
˚
graphite-monochromated, Mo-Ka (l = 0.71073 A) radiation with
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then added and the reaction mixture was stirred at 25 ◦C for the
time indicated in Tables 1–3. To the crude reaction mixture was
added 15 equivalents of an ethereal solution of diazomethane, and
the reaction mixture was stirred at room temperature for the time
indicated in Tables 1–3. After complete evaporation of the solvent
and excess diazomethane in a fumehood, active olefins/acetylenes
14a–d, hexamethylphosphorous triamide (HMPT) 15 (10 mol%)
and CH3CN (1.0 mL) were added to the crude reaction mixture,
and the mixture stirred at 25 ◦C for 0.5 h. The crude reaction
mixture was worked up with water if necessary, and then loaded
onto a silica gel column, giving pure one-pot products 16 after
chromatography (solvent: hexane/ethyl acetate).
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Many of the MCC products 13 and 16 are commercially
available or have been described previously, and their analytical
data match literature values; new compounds were characterized
1
on the basis of IR, H and 13C NMR and analytical data (see
ESI†).
Acknowledgements
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi. CV, YVR and MK
thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, for their research fellowships. We thank Prof. M. V.
Rajasekharan, Mr. A. R. Biju and Dr. P. Raghavaiah for their help
in X-ray structural analysis.
4 For the generation of a-oxoketenes, see: M. Sato, H. Ban and C. Kaneko,
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