Development of pharmaceutical drugs, drug intermediates and ingredients by using direct organo-click reactions

Article abstract of DOI:10.1002/ejoc.200701014

Here we report on our studies of the use of combinations of amino acids, amines, K₂CO₃ or Cs₂CO₃ and CuSO₄/Cu for catalysing green cascade reactions. We aimed to prepare the highly reactive and substituted olefin species 7 and 8, under very mild and environmentally friendly conditions, thus giving the hydrogenated products 10 and 12 through the action of Hantzsch ester (4) by self-catalysis through decreasing the HOMO-LUMO energy gaps between olefins 7/8 and Hantzsch ester (4) through biomimetic reductions. Highly useful compounds 10 to 14 were assembled from simple substrates such as aldehydes 1, ketones 2, CH acids 3, Hantzsch ester (4) and alkyl halides 5 by diversity-oriented green synthesis involving cascade olefination/hydrogenation (O/H), olefination/hydrogenation/alkylation (O/H/A) and hydrogenation/olefination/hydrogenation (H/O/H) reaction sequences in one-pot fashion with stereospecific organo- and organo-/metal-carbonate catalysis. Highly functionalized diverse compounds such as 10 to 14 are biologically active products and have found wide applications as pharmaceutical drugs, drug intermediates and drug ingredients. For the first time in organocatalysis, we report the O/H/A/TE reaction to furnish high yields of transesterification products 11 by simply mixing the reactants under proline/K₂CO₃ catalysis conditions. Additionally, a novel organocatalytic H/O/H reaction sequence for the synthesis of alkyl-substituted aromatics has been developed. Furthermore, for the first time we have developed organocatalysed cascade olefination/hydrogenation/hydrolysis (O/H/H) reactions to furnish highly useful materials such as 2-oxochroman-3-carboxylic acid (14kc) and 2-amino-4H-chromene-3-carbonitrile (14kj) in good yields. Experimentally simple and environmentally friendly organocatalytic two-carbon homologation through cascade O/H/H reactions of aldehydes 1, Meldrum's acid (3c), Hantzsch ester (4) and acetic acid/triethylamine in ethanol has been demonstrated. Additionally, we have developed a green synthesis of the highly substituted 1,2,3-triazole 17 from simple substrates through a two-step combination of olefination/hydrogenation/alkylation and Huisgen cycloaddition reaction sequences under stereospecific organocopper catalysis conditions. In this paper we have found strong support for our hypothesis that, "decreasing the HOMO-LUMO energy gap between olefins 7/8 and Hantzsch ester (4) will drive the biomimetic hydrogenation reaction by self-catalysis". This self-catalysis was further confirmed with many varieties of examples. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701014

FULL PAPER
DOI: 10.1002/ejoc.200701014
Development of Pharmaceutical Drugs, Drug Intermediates and Ingredients by
Using Direct Organo-Click Reactions
Dhevalapally B. Ramachary,*[a] Mamillapalli Kishor,[a] and Y. Vijayendar Reddy[a]
Keywords: Amino acids / Biomimetic reductions / Cascade reactions / Organocatalysis / Organo-click reactions
Here we report on our studies of the use of combinations of
amino acids, amines, K2CO3 or Cs2CO3 and CuSO4/Cu for
catalysing green cascade reactions. We aimed to prepare the
highly reactive and substituted olefin species 7 and 8, under
very mild and environmentally friendly conditions, thus giv-
ing the hydrogenated products 10 and 12 through the action
of Hantzsch ester (4) by self-catalysis through decreasing the
HOMO–LUMO energy gaps between olefins 7/8 and
Hantzsch ester (4) through biomimetic reductions. Highly
useful compounds 10 to 14 were assembled from simple sub-
strates such as aldehydes 1, ketones 2, CH acids 3, Hantzsch
ester (4) and alkyl halides 5 by diversity-oriented green syn-
thesis involving cascade olefination/hydrogenation (O/H),
reaction sequence for the synthesis of alkyl-substituted aro-
matics has been developed. Furthermore, for the first time
we have developed organocatalysed cascade olefination/hy-
drogenation/hydrolysis (O/H/H) reactions to furnish highly
useful materials such as 2-oxochroman-3-carboxylic acid
(14kc) and 2-amino-4H-chromene-3-carbonitrile (14kj) in
good yields. Experimentally simple and environmentally
friendly organocatalytic two-carbon homologation through
cascade O/H/H reactions of aldehydes 1, Meldrum’s acid
(3c), Hantzsch ester (4) and acetic acid/triethylamine in etha-
nol has been demonstrated. Additionally, we have developed
a green synthesis of the highly substituted 1,2,3-triazole 17
from simple substrates through a two-step combination of
olefination/hydrogenation/alkylation (O/H/A) and hydro- olefination/hydrogenation/alkylation and Huisgen cycload-
genation/olefination/hydrogenation (H/O/H) reaction se-
quences in one-pot fashion with stereospecific organo- and
organo-/metal-carbonate catalysis. Highly functionalized di-
verse compounds such as 10 to 14 are biologically active
dition reaction sequences under stereospecific organocopper
catalysis conditions. In this paper we have found strong sup-
port for our hypothesis that, “decreasing the HOMO–LUMO
energy gap between olefins 7/8 and Hantzsch ester (4) will
products and have found wide applications as pharmaceuti- drive the biomimetic hydrogenation reaction by self-cataly-
cal drugs, drug intermediates and drug ingredients. For the
first time in organocatalysis, we report the O/H/A/TE reac-
tion to furnish high yields of transesterification products 11
sis”. This self-catalysis was further confirmed with many
varieties of examples.
by simply mixing the reactants under proline/K2CO3 cataly- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
sis conditions. Additionally, a novel organocatalytic H/O/H
Germany, 2008)
organic chemist’s point of view, ideal reaction strategies for
the preparation of structurally diverse substances would in-
volve sequences in which stereocontrolled formation of
multiple carbon–carbon and carbon–heteroatom bonds oc-
cur in a single step from simple, readily available starting
materials. As a result, great attention has been paid to the
development of cascade or domino reactions, because of
their high degrees of atom economy and their applications
in combinatorial chemistry as well as diversity-oriented syn-
thesis.[1] Despite the intense interest, there are only a few
reports of organocatalysed cascade reactions for the synthe-
sis of stereochemically complex compounds.[1n–1ee] A key to
many interesting cascade reactions is the incorporation of
biomimetic olefination, hydrogenation and alkylation reac-
tion sequences to enable construction of structurally diverse
compounds in a completely stereoselective manner.[2]
Introduction
Development of drug-like small molecules from simple
substrates through cascade reactions is one of the emerging
areas in modern synthetic chemistry, even though there are
already many common organic reactions and reaction stra-
tegies for the construction of C–C, C–N, C–O, C–S and C–
X (X = halogen) bonds in structurally diverse natural and
non-natural products by conventional methods. More typi-
cally, these reactions and reaction strategies are not ideal in
comparison with biochemical reactions in terms of selectiv-
ity (chemo-, regio-, diastereo- and enantioselectivity) or in
the ecology and economy of chemical reactions. From the
[a] School of Chemistry, University of Hyderabad, Central Univer-
sity (PO),
Hyderabad 500046, India
Fax: +91-40-23012460
Recent studies in our laboratory have led to the develop-
ment of novel organocatalytic cascade or domino reactions
of simple substrates in one-pot fashion, such as organocata-
E-mail: ramsc@uohyd.ernet.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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D. B. Ramachary, M. Kishor, Y. V. Reddy
FULL PAPER
lytic Claisen–Schmidt/isoaromatization,[1dd] Knoevenagel/ use as pharmaceutical drugs, drug intermediates and ingre-
hydrogenation,[2a,2b]
Knoevenagel/hydrogenation/alky- dients through organo-/metal carbonate- and organo-/CuI-
lation,[2a,2b] Knoevenagel/Michael/aldol condensation/de- catalysed cascade olefination/hydrogenation, olefination/hy-
carboxylation,[1ee] enamine amination/isoaromatization,[1ee] drogenation/alkylation, hydrogenation/olefination/hydro-
enamine amination/isoaromatization/alkylation,[1ee] and genation, olefination/hydrogenation/hydrolysis and ole-
Knoevenagel/hydrogenation/Robinson annulation[2d] reac- fination/hydrogenation/alkylation/Huisgen
cycloaddition
tion sequences. These reaction conditions use less solvent reaction sequences, an approach we call “organo-click reac-
and less toxic solvents than previously developed schemes tions”. K. B. Sharpless and co-workers recently provided
and are thus significantly more environmentally friendly.
guidelines for click chemistry,[3] while Ramachary and
Taking our cue from nature, here we address the develop- Barbas later combined organocatalytic reactions with click
ment of a set of powerful, reliable and selective cascade re- chemistry (organo-click chemistry).[1r,2c] Ideally, organoca-
actions for the rapid synthesis of combinatorial libraries for talytic cascade reactions can also fulfil all aspects of click
Scheme 1. Direct organometal carbonate-catalysed cascade reactions.
Figure 1. Natural and unnatural products library generated from cascade olefination/hydrogenation and olefination/hydrogenation/alky-
lation products.
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Pharmaceutical Drugs by Direct Organo-Click Reactions
reaction conditions. Among these, the reactions must be chemistry, while compounds 10 and 11 have broad utility
modular, wide in scope and high-yielding, generate only in- in pharmaceutical chemistry and are excellent starting ma-
offensive by-products, and must also be stereospecific terials in natural product synthesis as shown in Figure 1.[4]
(Scheme 1).
Hence, their preparation has continued to attract consider-
As part of our program to engineer direct organocata- able synthetic interest in the form of the development of
lytic cascade or domino reactions, and in an extension of new methods for their syntheses.
our previous work,[2a,2b] here we report one-pot organo-
In our reactions we envisioned that amino acids and
and organometal carbonate-catalysed chemoselective direct amines would catalyse the cascade olefination of CH acids
cascade olefination/hydrogenation, olefination/hydrogena- 3 with aldehydes 1 or ketones 2 to form substituted 2-alk-
tion/alkylation,
hydrogenation/olefination/hydrogenation ylidene CH acids 7 and 8, respectively. These are very reac-
and olefination/hydrogenation/hydrolysis reaction sequen- tive intermediates and further undergo chemoselective bio-
ces that produce very useful pharmaceutical drugs, drug in- mimetic reductions with Hantzsch ester (4) to produce hy-
termediates and ingredients of types 10, 11, 12, 13 and 14 drogenated products 10 and 12, respectively, under appro-
from commercially available aldehydes 1, ketones 2, CH ac- priate reaction conditions. Metal carbonate-catalysed alky-
ids 3, Hantzsch ester (4), alkyl halides 5, amino acids or lation of the in situ generated products 10 and 12 with alkyl
amines 6, K2CO3 and Cs2CO3 as shown in Scheme 1. Struc- halides 5 furnishes the useful products 11 and 13 in very
turally diverse compounds 10–13 are attractive intermedi- good yields with interesting selectivity as shown in
ates in the synthesis of natural products and in medicinal Scheme 1. Organocatalytic two-carbon homologation
Table 1. Optimization of the direct organocatalytic cascade olefination/hydrogenation reactions of 1a, 3a and 4.[a]
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through cascade olefination/hydrogenation/hydrolysis reac- and without catalyst (Table 2 and Table 3). Proline-cata-
tions of aldehydes 1, Meldrum’s acid 3c, Hantzsch ester (4) lysed (6a-catalysed) cascade O/H reactions of benzaldehyde
and acetic acid/triethylamine in ethanol was demonstrated. (1a) and Hantzsch ester (4) with a variety of CH acids 3a–k
Additionally we have developed a green synthesis of the in EtOH at 25 °C for 2–27 h furnished the expected cascade
highly substituted 1,2,3-triazole 17 through organo-click re- reductive alkylation products, the 2-benzyl-CH acids 10aa–
actions.
ak, in very good yields, as shown in Table 2, Entries 1–11.
Table 2. Direct organocatalytic cascade olefination/hydrogenation
Results and Discussion
reactions of 1a and 4 with a variety of CH acids 3a–l.[a]
Cascade Olefination/Hydrogenation Reactions of Aldehydes
1 with 3 and 4 – Reaction Optimization
We were pleased to find that the one-pot reaction of
benzaldehyde (1a), N,N-dimethylbarbituric acid (3a) and
Hantzsch ester (4) in the presence of a catalytic amount of
proline (6a) in EtOH at 25 °C for 2 to 14 h furnished the
hydrogenated product 5-benzyl-1,3-dimethylpyrimidine-
2,4,6-trione (10aa)‡ as a single isomer, with 99% conversion
(Table 1, Entry 1) [‡ In all compounds denoted 7xy, 8xy,
10xy, 11xyz, 12xy, 13xyz and 14xy, x is incorporated from
reactant aldehydes 1 or ketones 2, y is incorporated from
the reactant CH acids 3, and z is incorporated from the
reactant alkyl halides 5]. The same reaction, catalysed by
proline (6a) in EtOH at 25 °C under cascade conditions fur-
nished the product 10aa with 98% conversion in a shorter
reaction time (Table 1, Entry 7), perhaps due to the cata-
lytic nature of the Hantzsch ester (4) in the cascade ole-
fination/hydrogenation (O/H) reaction. Interestingly, there
is little solvent effect on the proline-catalysed cascade O/H
reaction of 1a, 3a and 4 in three different type of solvents
(protic polar, aprotic polar and aprotic nonpolar) as shown
in Table 1, Entries 1–13. The simple amino acid glycine (6b)
also catalysed the cascade O/H reaction to furnish hydroge-
nated product 10aa with 99% conversion as a 1:1 ratio of
keto/enol forms (Table 1, Entry 14). The simple amines pyr-
rolidine (6c), piperidine (6d), morpholine (6e) and benzyl-
amine (6f) also catalysed the cascade O/H reaction to fur-
nish hydrogenated product 10aa with 98–99% conversion
as shown in Table 1, Entries 15–18. Interestingly, the cas-
cade O/H reaction of 1a, 3a and 4 without catalyst at 25 °C
for 5 h also furnished the expected product 10aa with 99%
conversion (Table 1, Entry 19), which is the best demonstra-
tion of the catalytic nature of the reagent in cascade reac-
tions. The solvent-promoted one-pot O/H reaction of 1a,
3a and 4 in H2O without catalyst furnished the expected
hydrogenated product 10aa with very good conversion, and
these are the optimal reaction conditions for the construc-
tion of C–C and C–H bonds under green reaction condi-
tions (Table 1, Entry 21). The optimized conditions for the
cascade O/H reaction of 1a, 3a and 4 in CH3CN, EtOH or
H2O at 25 °C to furnish 10aa with excellent conversions
required the presence of catalytic amounts of amino acid
6a or piperidine (6d) (Entries 7–8 and 16), but not in the
cases of Entries 19 and 21.
Following these promising results, we proceeded to inves-
tigate the scope and limitations of the cascade O/H reaction
with a range of CH acids 3a–l and Hantzsch ester (4) with
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Pharmaceutical Drugs by Direct Organo-Click Reactions
Interestingly, diethyl malonate (3l) did not furnish the ex- Hantzsch ester (4)). The selective solvent-promoted one-pot
pected reductive alkylation product 10al in the proline-cata- O/H reaction of benzaldehyde (1a) and Hantzsch ester (4)
lysed cascade O/H reaction with 1a and 4 in EtOH, and we with a variety of CH acids 3a–l was screened in H2O at
also found that 3l did not undergo olefination reaction 25 °C without catalysis, which furnished the expected hy-
either (Table 2, Entry 12). The same reaction in DMSO un- drogenated products 10aa–ak in yields ranging from very
der proline catalysis conditions furnished only the ole- good to poor as shown in Table 3. Cascade O/H reactions
fination product 7al without the expected hydrogenated with various CH acids 3 and aldehydes 1 promoted by
product 10al (result not shown in Table 2).
Hantzsch ester (4) furnished the expected cascade products
10 with poor to moderate yields (discussion of the results
is in the next section). After testing the autocatalytic nature
of the reactions promoted by Hantzsch ester (4) and H2O
in one-pot O/H reactions with different CH acids 3 and
aldehydes 1 as shown in Table 3, we decided to generate a
pharmaceutically useful library of cascade products 10 un-
der proline or piperidine catalysis conditions.
Table 3. Direct water-promoted cascade olefination/hydrogenation
reactions of 1a and 4 with a variety of CH acids 3a–l.[a]
Diversity-Oriented Green Synthesis of Reductive Alkylation
Products 10af–10mЈf
With an efficient organocatalytic cascade reductive alky-
lation protocol to hand, the scope of the proline-catalysed
cascade O/H reactions was investigated with various alde-
hydes 1a–z, 1aЈ–mЈ and CH acids 3e–j through the genera-
tion of a highly useful diversity-oriented library. A series of
substituted aromatic, heteroaromatic and aliphatic alde-
hydes 1a–mЈ were treated with 1.0 equiv. of methyl cyano-
acetate (3e), ethyl cyanoacetate (3f) or malononitrile (3j)
and Hantzsch ester (4) (1.0 equiv.), with catalysis by 5 to
20 mol-% of proline (6a) at 25 °C in EtOH (Table 4). The
2-aryl-2-cyanoacetic acid ethyl esters 10af–dЈf, ethyl 2-alkyl-
2-cyanoacetates 10eЈf–mЈf and 2-alkylmalononitriles 10ij–
mЈj were obtained as single isomers in excellent yields. Cata-
lyst loading for the cascade O/H reactions can be taken
from 5 to 20 mol-% without affecting reaction yields, but
reaction times vary from 1 to 24 h. Interestingly, both pro-
line- and piperidine-catalysed cascade O/H reactions of
ethyl cyanoacetate (3f) with naphthalene-1-carbaldehyde
(1b) at 25 °C in EtOH furnished the reductive alkylation
product 10bf in poor to moderate yields (not shown in
Table 4), but the same reaction under DMAP (10 mol-%)
catalysis conditions in EtOH at 80 °C furnished the re-
ductive alkylation product 10bf in a very good yield
(Table 4). A similar reaction trend was observed for the syn-
thesis of ethyl 2-cyano-2-(2,4,6-trimethylbenzyl)acetate
(10ff) from a cascade O/H reaction as shown in Table 4.
This may be due to the generation of more steric hindrance
in the transition state of the olefin’s formation from alde-
hydes 1b or 1f with CH acid 3f through enamine/iminium
catalysis.
The results in Table 4[4a–4p] demonstrate the broad scope
of this reductive methodology, covering a structurally di-
verse group of activated aldehydes 1a–mЈ and CH acids 3e–
After successful demonstration of one of the sets of opti- f and 3j, with many of the yields obtained being very good,
mized reaction conditions (Table 1, Entry 7) for the cascade or indeed better than those of previously published alky-
O/H reaction with a variety of CH acids 3a–l, we decided lation reactions starting from the corresponding olefins 7 or
to investigate the same with other two optimized sets of aldehydes 1. Cascade O/H reactions of (E)-cinnamaldehyde
conditions (cascade reactions promoted by H2O and (1eЈ) and 3-(2-nitrophenyl)propenal (1fЈ) with 3f and
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Table 4. Synthesis of chemically diverse libraries of alkyl 2-alkyl-2-cyanoacetates 10 through organocatalysed cascade olefination/hydro-
genation reactions.[a]
Hantzsch ester (4) chemoselectively furnished the hydroge- of potent human renin inhibitors F,[4j] while cascade esters
nated esters 10eЈf and 10fЈf, respectively, in good yields ethyl 2-cyano-3-(2-fluorophenyl)propionate (10uf) and ethyl
(Table 4). The hydrogenated esters ethyl 2-cyano-3-(1-naph- 2-cyano-3-(4-fluorophenyl)propionate (10vf) are important
thyl)propionate (10bf) and ethyl 2-cyano-3-(2-naphthyl)pro- intermediates for the synthesis of chemokine receptor an-
pionate (10cf) are important intermediates for the synthesis tagonists B,[4h] and ethyl and methyl 3-(benzo-1,3-dioxol-5-
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Pharmaceutical Drugs by Direct Organo-Click Reactions
yl)-2-cyanopropionates 10ie and 10if are useful synthons for from simple starting materials. Homologated esters 10ac–
the synthesis of cardiovascular active products H[4m] and nЈc are attractive intermediates in medicinal chemistry, and
for the synthesis of cubebinolide I.[4n] In addition, ethyl 2- their analogues have broad utility in pharmaceutical chem-
cyano-3-(thiophen-2-yl)propionate (10dЈf) and its corre- istry[4a–4p] (herbicidal, antidiabetic, analgesic, antiinflam-
sponding methyl ester are important intermediates for the matory and antithrombotics) and in organic synthesis.
synthesis of anthelmintic and insecticidal active products Hence, new methods for their syntheses have continued to
G,[4k] while ethyl 2-cyano-3-(4-hydroxyphenyl)propionate attract considerable interest.
(10mf) is a useful material for the synthesis of insulin resis-
The results given in Table 5 demonstrate the broad scope
tance products E,[4i] emphasizing the value of this cascade of this reductive green homologation, covering a structur-
approach.
ally diverse group of aldehydes 1a–nЈ and CH acids 3a–c,
with many of the yields obtained being very good, or indeed
better than those of previously published homologation re-
actions starting from the corresponding aldehydes 1a–nЈ or
olefins 7.[5] A series of substituted aromatic, heteroaromatic
Diversity-Oriented Green Synthesis of Reductive Alkylation
Products 10ac–10nЈc
After successful demonstration of the cascade O/H reac- and aliphatic aldehydes 1a–nЈ were treated with 1.0 equiv.
tion for the library generation of ethyl 2-aryl-2-cyanoace- of Meldrum’s acid (3c), N,N-dimethylbarbituric acid (3b) or
tates 10af–dЈf and ethyl 2-alkyl-2-cyanoacetates 10eЈf–mЈf, barbituric acid (3a) and Hantzsch ester (4) (1.0 equiv.), with
we then decided to apply the same synthetic strategy to the catalysis by 5 to 20 mol-% of proline (6a) at 25 °C in EtOH
green synthesis of 5-aryl-2,2-dimethyl-1,3-dioxane-4,6-di- or CH3CN (Table 5). The 5-aryl-2,2-dimethyl-1,3-dioxane-
ones 10ac–dЈc and 5-alkyl-2,2-dimethyl-1,3-dioxane-4,6-di- 4,6-diones 10ac–dЈc, 5-alkyl-2,2-dimethyl-1,3-dioxane-4,6-
ones 10eЈc–nЈc, which are highly useful materials in chemis- diones 10eЈc–nЈc and 5-alkylpyrimidine-2,4,6-triones 10mЈb
try. One of the major application of 5-aryl-2,2-dimethyl-1,3- were obtained as single isomers in excellent yields. Interest-
dioxane-4,6-diones 10ac–dЈc and 5-alkyl-2,2-dimethyl-1,3- ingly, the proline-catalysed cascade O/H reaction of Meld-
dioxane-4,6-diones 10eЈc–nЈc is in the two-carbon homolo- rum’s acid (3c) with 2-hydroxybenzaldehyde (1k) and
gation of the corresponding aldehydes 1a–nЈ. Two-carbon Hantzsch ester (4) at 25 °C in EtOH furnished the unexpec-
homologation is a very important transformation in syn- ted cascade olefination/hydrogenation/hydrolysis (O/H/H)
thetic organic chemistry, and numerous methods are avail- product – monoethyl 2-(2-hydroxybenzyl)malonate (10kn) –
able, although most involve redox functional group trans- in a very good yield [Table 5 and Eq. (1)]. The same reac-
formations rather than carbon–carbon bond formation.[5] tion in MeOH also furnished the unexpected cascade O/H/
In this regard, the development of two-carbon homo-
H
product monomethyl 2-(2-hydroxybenzyl)malonate
logation through carbon–carbon bond formation by the or- (10km) in a very good yield as shown in Table 5 and Eq. (1),
ganocatalytic cascade reductive methodology might provide though the same proline-catalysed cascade O/H reaction of
an expedient access to homologated products 10ac–nЈc Meldrum’s acid (3c) with 3-hydroxybenzaldehyde (1l) or 4-
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Table 5. Synthesis of chemically diverse libraries of 5-alkyl-2,2-dimethyl-1,3-dioxane-4,6-diones 10 through organocatalysed cascade ole-
fination/hydrogenation reactions.[a]
hydroxybenzaldehyde (1m) and Hantzsch ester (4) at 25 °C and Hantzsch ester (4) at 25 °C in water furnished the unex-
in EtOH furnished the expected cascade O/H products 10lc pected cascade O/H/H product 2-oxochroman-3-carboxylic
and 10mc, respectively, in very good yields as shown in acid (14kc) in a good yield [Eq. (2)]. In addition, the water-
Table 5.
promoted cascade O/H reaction of malononitrile (3j) with
Interestingly, the water-promoted cascade O/H reaction 2-hydroxybenzaldehyde (1k) and Hantzsch ester (4) at 70 °C
of Meldrum’s acid (3c) with 2-hydroxybenzaldehyde (1k) in water furnished the unexpected cascade O/H/H product
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Pharmaceutical Drugs by Direct Organo-Click Reactions
2-amino-4H-chromene-3-carbonitrile (14kj) in a very good substituted cyano esters 11kfc–mfc in good yields in a single
yield [Eq. (3)]. Formation of the unexpected cascade O/H/ step (Table 6, Entries 7–9). We have also demonstrated the
H products 10km, 10kn, 14kc and 14kj from 1k, 3c, 3j and double-cascade O/H/A reaction with benzene-1,3-dicarbal-
4 with and without proline catalysis in MeOH, EtOH and dehyde (1t) with 3f, 4 and 5e under proline/K2CO3 catalysis
H2O, respectively, can be explained as shown in Eq. (1)– conditions as shown in Table 6, Entry 15. The one-pot cy-
(3). Inter- and intramolecular hydrolysis of the cascade O/ ano ester products 11 have direct applications in pharma-
H products 10kc and 10kj generated in situ by solvents such ceutical and agricultural chemistry.[4a–4p] As examples,
as MeOH/EtOH or H2O gives the cascade O/H/H products among the cascade O/H/A generated products, ethyl 2-(4-
10km, 10kn, 14kc and 14kj, respectively. These two different chlorobenzyl)-2-cyanopropionate (11yfa) is antiinflamma-
types of hydrolysis might possibly be due to the nucleophilic torily active,[4b] ethyl 2-(2-chlorobenzyl)-2-cyanobutyrate
natures of the alcoholic solvents and the possibility of ad- (11wfb) is analgesically active,[4b] and 2-allyl-2-(4-chlo-
ditional weak interactions in water [see Eq. (1)–(3)].
robenzyl)malononitrile (11yjc, D) is very good pesticide,
5-(4-Cyanobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione which showed 100% control against Musca domestica (Ger-
(10rc) is an important intermediate for herbicidal and man cockroach).[4o]
antithrombotic[4c] chemicals and the cascade ester 5-[(an-
thracen-9-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione
Observation of Transesterification in Cascade O/H/A
Reactions
(10dc) is a very useful intermediate for the preparation of
dienophile scavengers,[4d] while 5-(cyclohexylmethyl)pyrim-
idine-2,4,6-trione (10mЈb) shows narcotizing properties,[4p]
emphasizing the value of this reductive homologation ap-
proach. Interestingly, the cascade O/H product 5-benzyl-
2,2-dimethyl-1,3-dioxane-4,6-dione (10ac) was converted
into the two-carbon homologated ester ethyl 3-phenylpropi-
onate (15ac) by a cascade O/H/H sequence in good yield
with HCO2H/NEt3 in one-pot fashion as shown in
Scheme 2.
As shown in Table 6, Entries 13 and 14, cascade O/H/A
reactions of 1a, 3g, 4 and 5c/5d in DMSO solvent under
proline/K2CO3 catalysis conditions furnished the expected
one-pot products 11agc and 11agd in good yields. Interest-
ingly, the same procedure in EtOH as solvent furnished the
one-pot transesterification products 11afc and 11afd in
good yields, as shown in Scheme 3. This is the best demon-
stration of the biomimetic transesterification[6] of highly
functionalized allyl esters 11agc and 11agd under mild basic
conditions and is also first observation in organocatalysis.
One-Pot Synthesis of Highly Active Herbicidal Products
from Direct Cascade O/H/A Reactions
To show more direct applications of cascade O/H/A reac-
tions to pharmaceutical chemistry, here we present the di-
rect one-step synthesis of highly active herbicidal products
11adf and 11oЈdf in very good yields from simple starting
materials (1a or 1oЈ, 3d, 4 and 5f) under proline/K2CO3
catalysis conditions at room temperature as shown in
Scheme 4. The developed cascade O/H/A methodology can
be utilized to develop the diversity-oriented library of ana-
logues of herbicidal products 11adf in very good yields in
comparison with the two-step synthesis demonstrated by
Mitsubishi Kasei Corporation, Japan in their patent.[4a,4f]
Scheme 2. Direct organocatalytic two-carbon homologation
through a one-pot cascade olefination/hydrogenation/hydrolysis re-
action.
Diversity-Oriented Green Synthesis of Reductive Alkylation
Products 11
In view of the results of the proline-catalysed three- and
four-component O/H and O/H/H reactions with various al-
dehydes 1a–nЈ and CH acids 3a–l, we also engineered a
novel proline/K2CO3-catalysed, one-pot, four-component
Organocatalytic Cascade Hydrogenation/Olefination/
Hydrogenation Reactions
List et al. recently demonstrated the amine/acid-catalysed
O/H/A reaction of aldehydes 1, ethyl cyanoacetate (3f), or hydrogenation of α,β-unsaturated aldehydes 1eЈ and 1fЈ
malononitrile (3j), Hantzsch ester (4) and alkyl halides 5a– with Hantzsch ester (4) to furnish the saturated aldehydes
e (Table 6). Highly substituted cyano esters 11, each con- 1lЈ and 1pЈ, respectively, in good yields.[7] Here we utilized
taining a quaternary carbon, were constructed in good the List technique to obtain the saturated aldehydes 1lЈ and
yields with various substituents as shown in Table 6, this 1pЈ in situ from α,β-unsaturated aldehydes 1eЈ and 1fЈ, and
process being the first example of the utility of the proline/ further allowed them to react with CH acid 3 and Hantzsch
K2CO3 combination in green catalysis.
ester (4) to generate the highly functionalized CH acids 10
Here we have demonstrated a direct organo/K2CO3-cata- in good yields in one-pot fashion. Morpholine/CF3CO2H-
lytic double-alkylation approach to the synthesis of highly catalysed hydrogenation of trans-cinnamaldehyde (1eЈ) in
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Table 6. Synthesis of chemically diverse libraries of analgesic and antiinflammatory cyano esters 11 through organo/metal carbonate-
catalysed cascade olefination/hydrogenation/alkylation reactions.[a]
the presence of 1.0 equiv. of Hantzsch ester (4) in THF at nation of amine/acid- and self-catalysed cascade hydrogena-
25 °C furnished 3-phenylpropionaldehyde (1lЈ), which on tion reactions will surely have much impact on synthetic
treatment with 1.0 equiv. each of Meldrum’s acid (3c) and sequences utilized in the total synthesis of natural products.
Hantzsch ester (4) at 25 °C in the same solvent furnished
Cascade Olefination/Hydrogenation Reactions of Ketones 2
with 3 and 4 – Reaction Optimization
the cascade H/O/H product 10lЈc in 50% yield as shown in
Scheme 5. The same reaction sequence with trans-2-nitro-
cinnamaldehyde (1fЈ) also furnished the cascade H/O/H
After successful demonstration of the amino acid- and
product 10pЈc in 70% yield as shown in Scheme 5. Combi- metal carbonate-promoted cascade O/H, O/H/A, O/H/A/
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Pharmaceutical Drugs by Direct Organo-Click Reactions
Scheme 3. Observation of transesterification in organo-/metal carbonate-catalysed cascade olefination/hydrogenation/alkylation reactions.
Scheme 4. Synthesis of highly active herbicidal products through direct one-pot organo-/metal carbonate-catalysed cascade olefination/
hydrogenation/alkylation reactions.
Scheme 5. Direct organocatalysed one-pot cascade hydrogenation/olefination/hydrogenation reactions.
TE, H/O/H and O/H/H reactions for the library generation both in pharmaceutical chemistry[4q–4z] (insect repellents,
of highly useful products 10 and 11 from aldehydes 1, CH dental adhesives, CRF antagonists, antispasmodics, antiul-
acids 3, Hantzsch ester (4) and alkyl halides 5, we then de- cer agents, drugs for skin diseases, against tuberculosis and
cided to apply the same cascade strategy for the generation leprosy bacteria, and wound healing etc.) and in organic
of cascade products 12 and 13, which are highly useful ma- synthesis.
terials in medicinal chemistry, from the less reactive ketones
We found that the amino acid proline (6a) readily cataly-
2, CH acids 3, Hantzsch ester (4) and alkyl halides 5. Cas- ses the olefination of cyclohexanone (2a) with the CH acid
cade products 12 and 13 are attractive intermediates in me- ethyl cyanoacetate (3f) to furnish the active olefin 8af,
dicinal chemistry, and their analogues have broad utility which on treatment with Hantzsch ester (4) in MeOH at
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25 °C for 24 h produced the hydrogenated product 12af in nases.[8] The optimum conditions (Entries 3–5 and 11–14)
very good yield (Table 7, Entry 1). The same reaction cata- involved the use of catalyst, amino acid 6a or amines 6c–f
lysed by -proline (6a) in protic solvents at 25 °C under cas- in cascade O/H reactions of 2a, 3f and 4 in EtOH, DMF
cade conditions furnished the product 12af in 90 to 95% or DMSO at 25 °C to furnish 12af in very good yields.
yields (Table 7, Entries 1–3). The use of polar aprotic sol-
Having obtained this preliminary understanding, we pro-
vents (DMF and DMSO) gave yields similar to those ob- ceeded to investigate the scope and limitations of the cas-
tained in the reactions in MeOH and EtOH (Table 7, En- cade O/H reaction of cyclohexanone 2a with a range of
tries 4–7). Interestingly, proline-catalysed cascade O/H reac- active CH acids 3a–o and Hantzsch ester (4) under proline
tions with ketones 2 are solvent-dependent (Table 7), unlike catalysis conditions in DMSO (Table 8). Even though cas-
the same reactions with aldehydes 1 (see Tables 1, 2, 3, 4, 5, cade O/H reactions gave good yields in EtOH (Table 7),
and 6), which may be due to the less reactive nature of here we used DMSO or DMF as solvent because of the
ketones 2. The simple amino acid glycine (6b) also catalysed poorer solubilities of the reactants in EtOH. As shown in
the cascade O/H reaction to furnish cascade product 12af in
72% yield (Table 7, Entry 10). The simple amines pyrrolid-
Table 8. Direct organocatalytic cascade olefination/hydrogenation
ine (6c), piperidine (6d), morpholine (6e) and benzylamine reactions of 2a and 4 with a variety of CH acids 3a–o.[a]
(6f) also catalysed the cascade O/H reaction at 25 °C for
48 h to furnish the hydrogenated product 12af in 90% yield
as shown in Table 7, Entries 11–14. Interestingly, the cas-
cade O/H reaction of 2a, 3f and 4 in the absence of catalyst
at 25 °C for 48 h furnished the expected product 12af in
80% and 75% yields in EtOH and DMSO solvents, respec-
tively (Table 7, Entries 15 and 16). This is an excellent dem-
onstration of the self-catalytic nature of reagents in cascade
reactions, and also of mimicking of the hydrogenation/de-
hydrogenation of pyridine nucleotide-linked dehydroge-
Table 7. Optimization of the direct organocatalytic cascade ole-
fination/hydrogenation reactions of 2a, 3f and 4.[a]
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Pharmaceutical Drugs by Direct Organo-Click Reactions
Table 8, acyclic CH acids 3e–j furnished cascade products Diversity-Oriented Green Synthesis of Reductive Alkylation
12ae–aj in smaller yields than cyclic CH acids 3a–d and 3o Products 12af–12tf
in cascade O/H reactions, possibly due to the difference in
acid strength and HOMO–LUMO energy gap between
With an ideal cascade reductive alkylation protocol to
Hantzsch ester (4) and the olefins 8 generated in situ. Cyclic hand, the scope of the proline-catalysed cascade O/H reac-
CH acids 3a–d and 3o have higher acid strengths than acy- tions was investigated with various ketones 2a–t and CH
clic CH acids 3e–j, and the same acidic property also con- acids 3e–j in the generation of the highly useful diversity-
tinues in olefins 8. Cascade products 12aa–ao have many oriented library 12. The results in Table 9 demonstrate the
applications in pharmaceutical chemistry.[4q–4z]
broad scope of this reductive green methodology, covering
Table 9. Synthesis of chemically diverse libraries of 12 through organocatalysed cascade olefination/hydrogenation reactions of 2, 3 and 4.[a]
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D. B. Ramachary, M. Kishor, Y. V. Reddy
FULL PAPER
a structurally diverse group of less reactive ketones 2a–t and than through the axial position, perhaps due to the exis-
CH acids 3e–j, with many of the yields obtained being very tence of more steric hindrance in an axial approach. As
good, or indeed better than those of previously published shown in Figure 3, steric strain control (SSC) is the main
reactions starting from the corresponding olefins 8 or controlling factor rather than product stability control
ketones 2. The cascade O/H reaction of (R)-3-methylcy- (PSC) in biomimetic cascade reductions, as the thermody-
clohexanone (2c), malononitrile (3j) and Hantzsch ester (4) namically stable isomer cis-12if is formed as a minor prod-
furnished the regioselective chiral hydrogenated ester uct. This selectivity trend can be easily understood in terms
(1R,3R)-2-(3-methylcyclohexyl)malononitrile (12cj) in 3.0:1 of the approach of bulk hydride source 4 to olefins 8.
ratio in 86% yield, the cascade O/H reaction of 4-methylcy-
Simple cyclic ketones cyclobutanone (2j), cyclopenta-
clohexanone (2d), ethyl cyanoacetate (3f) and Hantzsch es- none (2k) and cycloheptanone (2l) reacted with 3 and 4
ter (4) furnished the regioselective hydrogenated ester cis- under amino acid catalysis conditions to furnish the ex-
12df in 3.4:1 ratio in 90% yield (Table 9, Entry 4), the cas- pected cascade O/H products 12jc, 12jf, 12kf and 12lf in
cade O/H reaction of cyclohexane-1,4-dione (2g) with CH very good yields as shown in Table 9. Acyclic ketones 2m–
acids 3e or 3f and Hantzsch ester (4) under proline catalysis t also participated in the three-component cascade O/H re-
conditions furnished the double cascade products 12ge and action with 3 and 4 to furnish the cascade products 12mj–
12gf in good yields with high selectivity as shown in 12tf in very good yields as shown in Table 9. The cascade
Table 9, and the cascade O/H reactions of highly substi- O/H reactions produced hydrogenated products 12bf, 12cj,
tuted cyclohexanones 2h or 2i with CH acids 3f or 3j and 12df, 12ef and 12sf with good regioselectivities in compari-
Hantzsch ester (4) under proline catalysis conditions fur- son with NaBH4 reduction of corresponding olefins,[10] as
nished the cascade products 12hf, 12if and 12ij in good shown in Table 9.
yields and with high selectivity as shown in Table 9. The
The hydrogenated ester 12af and its analogues are impor-
structures and regiochemistry of cascade O/H products tant intermediates for the synthesis of cygerol (wound treat-
12bf–ij were confirmed by X-ray structure analysis on 12if ment ointment),[4u] perfumes, anti-ulcer agents and drugs
as shown in Figure 2.[9]
for skin diseases, cascade esters 12ge and 12gf are useful
materials for the synthesis of alignment films for liquid
crystal displays,[4y] cascade esters 12jc and 12jf are useful
intermediates for the synthesis of prostaglandin ana-
logues,[4z] cascade products 12mj–oj are useful intermediates
for the synthesis of the antimicrobial sesquiterpene (S)-ar-
turmerone (L) and analogues,[4w] cascade ester 12tf has
been used as an intermediate in the synthesis of ophiobolin
natural products,[4v] cascade products 12kf, 12sf and ana-
logues have been used for the preparation of active anti-
spasmodics,[4t] and cascade hydrogenated product 12qe has
been used in the USA as a repellent for cockroaches[4q]
emphasizing the value of this cascade approach.
,
Figure 2. Crystal structure of ethyl cyano-(2,4-dimethyl-1,3,5-
trioxo-7,11-diphenyl-2,4-diazaspiro[5.5]undec-9-yl)acetate (12if).
The observed high regioselectivity in cascade 12bf–ij
products can be explained as shown in Figure 3. Here, the
approach of the hydride source [Hantzsch ester (4)] to olefin
8bf–ij is the main controlling factor, rather than thermo-
dynamic stability of the resulting hydrogenated products
Diversity-Oriented Green Synthesis of Reductive Alkylation
Products 13
With pharmaceutical applications in mind, we extended
12bf–ij. The approach of the Hantzsch ester (4) towards the three-component cascade O/H reactions to provide a
olefin 8if through the equatorial position is more favourable novel proline/Cs2CO3- and proline/K2CO3-catalysed four-
Figure 3. Observation of steric strain control (SSC) as dominating factor rather than product stability control (PSC) in biomimetic
cascade reductions.
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Pharmaceutical Drugs by Direct Organo-Click Reactions
component one-pot O/H/A reaction of ketones 2, CH acids Huisgen Cycloaddition Reactions on Cascade O/H/A
3 and Hantzsch ester (4) with various alkyl halides 5a–g Products
(Table 10). 2,2-Disubstituted ethyl cyanoacetates and ma-
Huisgen’s 1,3-dipolar cycloadditions[11a] are important
lononitriles 13 were constructed in good yields with various
ring-fusion processes, the most useful member of this class
substituents as shown in Table 10. Here we have demon-
arguably being the cycloaddition of azides and alkynes to
strated a direct organocatalytic approach to the synthesis
give triazoles. The Huisgen cycloaddition of the propargyl-
of key intermediates of the pharmaceutical drug cygerol
substituted cascade product 13hfd with benzyl azide 16 un-
(M; see Figure 1) in a single step (Table 10, Entries 10–12).
der CuSO4/Cu catalysis conditions furnished the regiospec-
Decyanation followed by hydrolysis of 13aeg or 13afg fur-
ifically 1,4-disubstituted 1,2,3-triazole 17 in very good yield
nished the cyclohexylgeranylacetic acid (M), useful for
as shown in Scheme 6. 1,2,3-Triazoles have found wide
wound healing as demonstrated by Joseph and George in
applications in biology, chemistry and materials sci-
their patent.[4u]
ence,[11b–11d] so it is important to develop new and more
efficient cascade approaches to develop a diverse array of
starting materials 13 and 16 for the library generation of
Table 10. Synthesis of chemically diverse libraries of 13 through
1,2,3-triazoles 17, which can be tested for pharmaceutical
applications. In this respect our cascade O/H/A reactions
can deliver a diversity-oriented library of click-chemistry
precursors.
organocatalysed cascade olefination/hydrogenation/alkylation reac-
tions of 2, 3, 4 and 5.[a]
Scheme 6. Regiospecific synthesis of highly functionalized 1,4-di-
substituted 1,2,3-triazole 17.
Mechanistic Insights
The possible reaction mechanism for proline-, self- and
auto-catalysed regio- and chemoselective synthesis of cas-
cade products 10 and 12 through reactions of aldehyde 1 or
ketone 2, CH acid 3, and Hantzsch ester (4) is illustrated in
Scheme 7. This double catalytic cascade reaction is a three-
component reaction involving aldehyde 1 or ketone 2, CH
acid 3, Hantzsch ester (4) and a simple catalyst amine or
amino acid 6a, which is capable of catalysing each step of
this double catalytic cascade reaction. In the first step
(Scheme 7), the catalyst 6a activates component 1/2, most
probably by iminium ion formation, and this then selec-
tively adds to the CH acid 3 through a Mannich- and a
retro-Mannich-type reaction to generate active olefin 7/8.[2]
The following second step is a biomimetic hydrogenation of
active olefin 7/8 by Hantzsch ester (4) to produce 10/12
through self-catalysis by decreasing the HOMO–LUMO en-
ergy gaps between 4 and 7/8.[2d]
Interestingly, one of the reagents in the cascade reaction
also catalyses the cascade sequence to furnish the products
10/12 in good yields. In the first step (Scheme 7), the
Hantzsch ester (4) activates components 1/2, most probably
by acid/base catalysis, and these then selectively add to the
CH acid 3 in a aldol-type reaction to generate active olefins
7/8.[2] The following second step is biomimetic hydrogena-
tion of active olefins 7/8 by Hantzsch ester (4) to produce
10/12 through self-catalysis. As shown in Scheme 7,
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D. B. Ramachary, M. Kishor, Y. V. Reddy
FULL PAPER
Scheme 7. Proposed catalytic cycle for the organocatalytic olefination/hydrogenation reactions of 1, 2, 3 and 4.
Hantzsch ester (4) simultaneously catalyses the activation conducting controlled experiments on various substrates as
of carbonyls 1/2 to form olefins 7/8 and the reduction of shown in Scheme 8 and Table 11. Cascade O/H reactions of
active olefins 7/8 to generate cascade products 10/12 in a 4-fluorobenzaldehyde (1v), Meldrum’s acid (3c) and
single step.
Hantzsch ester (4) in CH3CN at 25 °C for 5 h and of benz-
The dual role of Hantzsch ester (4) as a catalyst and rea- aldehyde (1a), ethyl cyanoacetate (3f) and Hantzsch ester
gent in the cascade O/H reactions was further confirmed by (4) in EtOH at 25 °C for 5 h furnished the cascade prod-
Scheme 8. Dual role of Hantzsch ester (4) as both catalyst and reagent in the cascade olefination/hydrogenation reactions.
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Pharmaceutical Drugs by Direct Organo-Click Reactions
ucts 5-(4-fluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione cedure provides direct access to functionalized diversity-ori-
(10vc) and ethyl 2-cyano-2-phenylpropionate (10af), respec- ented products 10 to 17, shown to be pharmaceutical drugs,
tively, with 75% conversions. However, the same reactions drug intermediates and ingredients in medicinal chemistry.
under proline catalysis conditions furnished the expected For the first time in organocatalysis, we have reported the
products 10vc and 10af with 99% conversions and in O/H/A/TE reaction, furnishing high yields of transesterifi-
shorter times (Scheme 8). To understand more about the cation products 11 simply on mixing of the reactants under
self-catalysis of 4 in cascade O/H reactions, we performed proline/K2CO3 catalysis conditions. Additionally, a novel
olefination reaction of 2a with 3f and 3j in the presence of organocatalytic H/O/H reaction sequence for the synthesis
9 and in the absence of catalyst 6a and 4 in EtOH, DMSO of alkyl-substituted aromatics has been developed. Further-
and H2O solvents as shown in Table 11. Olefin product 8af more, we have for the first time developed organocatalysed
was furnished in very poor conversions after 48 h at 25 °C, cascade O/H/H reactions to furnish highly useful materials
with and without pyridine (9) catalysis in EtOH, DMSO such as 2-oxochroman-3-carboxylic acid (14kc) and 2-
and H2O solvents starting from 2a and 3f (Table 11, En- amino-4H-chromene-3-carbonitrile (14kj) in good yields.
tries 2–6). Interestingly, olefin product 8aj was furnished We have also demonstrated one-pot two-carbon homologa-
from 2a and 3j in moderate yields under catalyst-free condi- tion of aldehydes in high yields through organocatalysed O/
tions, as shown in Table 11, Entries 7–9; this may be due to H/H reactions. Simple amines 6c–f and amino acids 6a–b
the highly acidic nature of malononitrile (3j) in relation to were used as organocatalysts for catalysis of olefin forma-
ethyl cyanoacetate (3f). From these results we have strong tion in cascade reactions.
support for the self-catalysis of 4 in cascade O/H reactions.
Cascade reactions catalysed by combinations of primitive
biomolecules and metal ions should open new doors for
biomimetic strategies in organic synthesis, and should also
give possible reaction mechanisms in the prebiotic evolution
of the molecular world.[1n–1s,12] These reactions can be per-
formed on multigram scales under operationally simple and
environmentally safe conditions. Further studies aimed at
exploring the scope of cascade reactions of these types are
ongoing.
Table 11. Olefination of cyclohexanone 2a with 3f and 3j under
organo- and self-catalysis conditions.
Experimental Section
General Methods: The 1H NMR and 13C NMR spectra were re-
corded at 400 MHz and 100 MHz, respectively. The chemical shifts
are reported in ppm downfield from TMS (δ = 0 ppm) for 1H NMR
spectra and relative to the central CDCl3 resonance (δ = 77.0 ppm)
for 13C NMR spectra. Coupling constants in 1H NMR measure-
ments are given in Hz. In the 13C NMR spectra, the different sig-
nals of the carbon atoms (for C, CH, CH2 or CH3) were assigned
by recording the DEPT-135 experiment, and are given in parenthe-
ses. Column chromatography was performed on Acme’s silica gel
(particle size 0.063–0.200 mm). High-resolution mass spectra were
recorded on a Micromass ESI-TOF MS instrument. GCMS mass
spectrometry was performed on a Shimadzu GCMS-QP2010 mass
spectrometer. IR spectra were recorded on JASCO FT/IR-5300 and
Thermo Nicolet FT/IR-5700 instruments. Elemental analyses were
recorded on a Thermo Finnigan Flash EA 1112 analyzer. Mass
spectra were recorded either on a VG7070H mass spectrometer by
the EI technique or on a Shimadzu-LCMS-2010 A mass spectrom-
eter. The X-ray diffraction measurements were carried out at 298 K
on an automated Enraf–Nonius MACH 3 diffractometer with use
of graphite-monochromated Mo-Kα (λ = 0.71073 Å) radiation and
CAD4 software, or the X-ray intensity data were measured at
298 K on a Bruker SMART APEX CCD area detector system fit-
ted with a graphite monochromator and a Mo-Kα fine-focus sealed
tube (λ = 0.71073 Å). For thin-layer chromatography (TLC), silica
gel plates (Merck 60 F254) were used, and compounds were visual-
ized by irradiation with UV light and/or by treatment with a solu-
tion of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid
(10 mL), and ethanol (900 mL), followed by heating.
Taking the recent applications of amine-catalysed Knoe-
venagel reactions[1q,1r] into account, and in view of the dif-
ferent experiments performed (Scheme 8 and Table 11), we
propose that this cascade reaction is a double catalytic cas-
cade reaction: catalysis by a combination of amine 4 and
amino acid as shown in Scheme 7.
Conclusions
In conclusion, we have demonstrated the organo-, or-
gano-/metal carbonate- and organo-/CuI-catalysed enzyme-
like assembly of cascade products 10, 11, 12, 13, 14, 15 and
17 from readily available precursors through O/H, O/H/A,
O/H/A/TE, H/O/H, O/H/H and O/H/A/HC reaction se-
quences. The combination of proline/M2CO3 and proline/
CuI ions proved to be the optimal organo-/metal catalysts
Materials: All solvents and commercially available chemicals were
for the one-pot cascade reactions. This simple one-pot pro- used as received. CH-Acids 3g–h[13a] and 3o,[1r] spiro ketones 2h,[1q]
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D. B. Ramachary, M. Kishor, Y. V. Reddy
and 2i[1r] were prepared according to literature procedures. (1-Bro- CuSO4/Cu-Catalysed Huisgen Cycloaddition Reaction: For the syn-
FULL PAPER
momethyl-vinyl)benzene (5f) was synthesized by a literature pro-
thesis of highly functionalized triazole 17, O/H/A cascade product
13hfd (0.22 mmol), benzyl azide 16 (0.44 mmol), CuSO4
(0.22 mmol, 35 mg) and Cu wire (23 mg) in ethanol (1.0 mL) were
placed in an ordinary glass vial containing a magnetic stirring bar
and stirred at 25 °C for the time indicated in Scheme 6. The crude
reaction mixture was directly loaded onto a silica gel column with-
out aqueous workup, and pure triazole 17 was obtained by flash
column chromatography (silica gel, mixture of hexane/ethyl ace-
tate).
cedure.[13b]
General Experimental Procedures for Organo-Click Reactions
Amine- or Amino Acid-Catalysed Cascade Olefination/Hydrogena-
tion Reactions: In an ordinary glass vial containing a magnetic stir-
ring bar, solvent (1.0 mL) was added to the aldehyde 1 or ketone 2
(0.5 mmol), CH acid 3 (0.5 mmol) and Hantzsch ester (4, 0.5
mmol). The catalyst amine or amino acid 6 (0.025 mmol to
0.1 mmol) was then added, and the reaction mixture was stirred at
25 °C for the time indicated in Tables 1, 2, 3, 4, 5, 7, 8 or 9. The
crude reaction mixture was directly loaded onto a silica gel column
with or without aqueous workup, and pure cascade products 10
and 12 were obtained by column chromatography (silica gel, mix-
ture of hexane/ethyl acetate).
Many of the cascade products 10 to 17 are commercially available
or have been described previously; their analytical data match lit-
1
erature values. New compounds were characterized by IR, H and
13C NMR and analytical data (see electronic supporting infor-
mation).
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, compound characterization,
and analytical data (1H NMR, 13C NMR and HRMS) for all new
compounds.
Proline/Cs2CO3- or K2CO3-Catalysed One-Pot Olefination/Hydro-
genation/Alkylation Reactions: In an ordinary glass vial containing
a magnetic stirring bar, solvent (1.0 mL) was added to the aldehyde
1 or ketone 2 (0.5 mmol), CH acid 3 (0.5 mmol) and Hantzsch
ester 4 (0.5 mmol). The catalyst proline (6a, 0.1 mmol) was then
added, and the reaction mixture was stirred at 25 °C for 1–96 h.
R4CH2I or R4CH2Br 5 (2.5 mmol) and K2CO3 or Cs2CO3 (0.4 g)
were then added, and stirring was continued at the same tempera-
ture for 7–24 h. The crude reaction mixture was worked up with
aqueous NH4Cl solution and the aqueous layer was extracted with
dichloromethane (2ϫ20 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated. Pure one-pot products
11 and 13 were obtained by column chromatography (silica gel,
mixtures of hexane/ethyl acetate).
Acknowledgments
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi. M. K. and Y. V. R.
thank the Council of Scientific and Industrial Research (CSIR),
New Delhi for their research fellowships. We thank Prof. M. V. Ra-
jasekharan, Mr. A. R. Biju and Dr. P. Raghavaiah for their help in
X-ray structural analysis.
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Amine/Acid-Catalysed One-Pot Hydrogenation/Olefination/Hydro-
genation Reactions: Morpholine (6e, 0.05 mmol, 5 mol-%) and tri-
fluoroacetic acid (0.05 mmol, 5 mol-%) were placed in an ordinary
glass vial containing a magnetic stirring bar, and the system was
stirred at 25 °C for 10 minutes. THF solvent (4.0 mL), trans-cinna-
maldehyde (1eЈ) or o-nitrocinnamaldehyde (1fЈ) (1.0 mmol) and
Hantzsch ester (4) (1.0 mmol) were then added, and stirring was
continued at the same temperature for the time indicated in
Scheme 5. After completion of the hydrogenation, Meldrum’s acid
(3c, 1.0 equiv.) and Hantzsch ester (4, 1.0 equiv.) were added to
the crude reaction mixture, and stirring was continued at the same
temperature for the time indicated in Scheme 5. The crude reaction
mixture was worked up with aqueous NaHCO3 and NH4Cl solu-
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(2ϫ20 mL). The combined organic layers were dried (Na2SO4),
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by column chromatography (silica gel, mixtures of hexane/ethyl
acetate).
Amino Acid-Catalysed One-Pot Olefination/Hydrogenation/Hydrol-
ysis Reactions: In an ordinary glass vial containing a magnetic stir-
ring bar, EtOH (1.0 mL) was added to the aldehyde 1a (0.5 mmol),
Meldrum’s acid (3c, 0.5 mmol) and Hantzsch ester (4, 0.5 mmol).
The catalyst amino acid 6a (0.1 mmol) was then added, and the
reaction mixture was stirred at 25 °C for the time indicated in
Scheme 2. HCO2H (0.5 mL) and NEt3 (1.8 mL) were added to the
crude reaction mixture, which was stirred at 120 °C for 12 h. The
crude reaction mixture was worked up with aqueous NaHCO3 and
NH4Cl solutions and the aqueous layer was extracted with dichlo-
romethane (2ϫ20 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated. Pure one-pot product 15ac
was obtained by column chromatography (silica gel, mixture of
hexane/ethyl acetate).
992
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 975–993

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Received: October 25, 2007
Published Online: December 19, 2007
Eur. J. Org. Chem. 2008, 975–993
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
993