Multi-catalysis reactions: Direct organocatalytic sequential one-pot synthesis of highly functionalized cyclopenta[b]chromen-1-ones

Article abstract of DOI:10.1039/b812551a

We have developed a new technology called multi-catalysis for the sequential one-pot synthesis of highly functionalized heterocycles. A practical and novel multi-component aniline-, self- and Bronsted acid-catalyzed selective process for the sequential one-pot synthesis of highly substituted 2-(2-hydroxy-aryl)-cyclopentane-1,3-diones, 3,9-dihydro-2H-cyclopenta[b]chromen- 1-ones and 3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-ones is reported. Direct combination of aniline- and self-catalyzed cascade olefination-hydrogenation (O-H) and Bronsted acid-catalyzed cascade oxy-Michael-dehydration (OM-DH) of 1,3-diones, salicylic aldehydes and organic-hydrides is developed in one-pot to furnish the highly functionalized 3,9-dihydro-2H-cyclopenta[b]chromen-1-ones and 3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-ones with high yields.

Full text of DOI:10.1039/b812551a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Multi-catalysis reactions: direct organocatalytic sequential one-pot synthesis
of highly functionalized cyclopenta[b]chromen-1-ones†
Dhevalapally B. Ramachary,* Y. Vijayendar Reddy and Mamillapalli Kishor
Received 25th July 2008, Accepted 27th August 2008
First published as an Advance Article on the web 14th October 2008
DOI: 10.1039/b812551a
We have developed a new technology called multi-catalysis for the sequential one-pot synthesis of
highly functionalized heterocycles. A practical and novel multi-component aniline-, self- and Brønsted
acid-catalyzed selective process for the sequential one-pot synthesis of highly substituted
2-(2-hydroxy-aryl)-cyclopentane-1,3-diones, 3,9-dihydro-2H-cyclopenta[b]chromen-1-ones and
3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-ones is reported. Direct combination of aniline- and
self-catalyzed cascade olefination–hydrogenation (O–H) and Brønsted acid-catalyzed cascade
oxy-Michael–dehydration (OM–DH) of 1,3-diones, salicylic aldehydes and organic-hydrides is
developed in one-pot to furnish the highly functionalized 3,9-dihydro-2H-cyclopenta[b]chromen-1-ones
and 3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-ones with high yields.
Herein, we discovered a metal-free, novel and multi-catalysis
technology for the synthesis of highly substituted 2,3,4,9-tetra-
Introduction
Heterocycles such as chromanes, chromenes, coumarins and
hydro-xanthen-1-ones and 3,9-dihydro-2H-cyclopenta[b]chro-
tetrahydroxanthenones are of considerable importance in a va-
men-1-ones by using direct organocatalytic sequential one-pot
riety of industries. As is well known, these heterocycles are
multi-component olefination–hydrogenation–oxy-Michael–dehy-
widespread elements in natural products and have attracted
dration (O–H–OM–DH) and olefination–hydrogenation–alkyl-
much attention from a wide area of science, including physi-
ation–oxy-Michael–dehydration (O–H–A–OM–DH) reactions
cal chemistry, medicinal chemistry, natural product chemistry,
from commercially available functionalized 2-hydroxy-benzal-
synthetic organic chemistry and polymer science.1 As such, the
dehydes, cyclopentane-1,3-dione or substituted cyclohexane-
development of new and more general catalytic methods for
1,3-dione and Hantzsch ester (organic-hydride) (Scheme 1).
their preparation is of significant interest.2 Recently nucleophilic
Direct combination of amine- or amino acid-catalyzed cas-
amine-catalysis has emerged for the reaction of 2-hydroxy-
cade olefination–hydrogenation (O–H) and Brønsted acid-
benzaldehyde with substituted enones in the presence of secondary
catalyzed cascade oxy-Michael–dehydration (OM–DH) or
and/or tertiary amines to provide general route to a variety
combination of amine- or amino acid-catalyzed cascade
of functionalized 2,3,4,4a-tetrahydro-xanthen-1-ones and 3,3a-
olefination–hydrogenation (O–H) and self-/base-catalyzed cas-
cade alkylation–oxy-Michael–dehydration (A–OM–DH) of 1,3-
dihydro-2H-cyclopenta[b]chromen-1-ones in moderate to good
yields (Scheme 1).2 But interestingly, there is no direct method
diones, salicylic aldehydes, organic-hydride (Hantzsch ester)
for the synthesis of functionalized 2,3,4,9-tetrahydro-xanthen-
and diazomethane is developed in one-pot as shown in
1-ones and 3,9-dihydro-2H-cyclopenta[b]chromen-1-ones from
substituted 2-hydroxy-benzaldehydes and enones, which are highly
useful starting materials in natural product synthesis (Scheme 1).
Scheme 2. 2,3,4,9-Tetrahydro-xanthen-1-ones and 3,9-dihydro-
2H-cyclopenta[b]chromen-1-ones are useful starting materials for
the synthesis of natural products and their analogues.1
In continuation of our recent discovery of bio-mimetic in situ
reduction of novel active olefins with Hantzsch ester 3 through self-
catalysis by decreasing the HOMO–LUMO energy gap between
olefins and Hantzsch ester 3 in cascade reactions,3 we initiated our
studies of the cascade O–H reaction of cyclopentane-1,3-dione
1a with variety of 2-hydroxy-benzaldehydes 2 and Hantzsch ester
3 under amine- or amino acid-catalysis to furnish the reductive
alkylation products 6 and their applications in the synthesis of
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. CCDC reference numbers 682180 (6ad) and 681487
(10aa). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b812551a
Scheme 1 Synthesis of highly substituted 3,9-dihydro-2H-cyclopenta[b]chromen-1-ones.
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Scheme 2 Combining multi-catalysis and multi-component systems for one-pot cascade reactions.
pharmaceutically useful products with good yields in one-pot (see
Scheme 2).
screening a number of known and novel organocatalysts for the
reductive alkylation of cyclopentane-1,3-dione 1a with 2-hydroxy-
benzaldehyde 2a and Hantzsch ester 3 as shown in Table 1. Based
on our previous experience of the amino acid-promoted reductive
alkylation of 1,3-diones with aldehydes and Hantzsch ester via
cascade O–H reactions,3 we chose CH2Cl2 as solvent; and then
we decided to investigate the catalyst 4 effect on the cascade
O–H reaction of 1a, 2a and 3. It is a well established fact that
the self-catalyzed reaction of cyclopentane-1,3-dione 1a with 3
equiv. of 2-hydroxy-benzaldehyde 2a furnished only the unex-
pected bis-adduct 7aa without the expected olefination product
2-(2-hydroxy-benzylidene)-cyclopentane-1,3-dione 5aa (result not
Results and discussion
Reaction optimization for multi-catalysis reactions in one-pot
First we focused on the optimization for a high yield synthesis
of 2-(2-hydroxy-benzyl)-cyclopentane-1,3-dione 6aa from 1a, 2a,
3 and 4 through amine- or amino acid-catalysis, which is a
precursor for our designed cascade O–H–OM–DH reaction. For
that we initiated our studies of the cascade O–H reaction by
Table 1 Effect of catalyst on the direct amino acid or amine-catalyzed reductive alkylation of 1a with 2a and 3a
Yield (%) productc
Entry
Catalyst 4 (5 mol%)
Time/h
Conversion (%)b
6aa
7aa
1
2
3
4
5
6
Proline 4a
28
28
2
>99
75
>99
>99
>95
>95
80
50
80
80
80
80
20
20
15
15
15
15
Glycine 4b
Aniline 4c
Benzylamine 4d
Piperidine 4e
Pyrrolidine 4f
4
24
24
a Reactions were carried out in solvent (0.3 M) with 3.0 equiv. of 2a and 1.0 equiv. of 3 relative to 1a (0.3 mmol) in the presence of 5 mol% of catalyst 4.
b Conversion based on the TLC analysis. c Yield refers to the column purified product.
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shown in Table 1). The same reaction under proline-catalysis also
furnished only the bis-adduct 7aa without product 2-(2-hydroxy-
benzylidene)-cyclopentane-1,3-dione 5aa with a reduced reaction
time (result not shown in Table 1). Interestingly, proline-catalyzed
reaction of cyclopentane-1,3-dione 1a and 3 equiv. of 2-hydroxy-
benzaldehyde 2a with Hantzsch ester 3 furnished the expected
reductive alkylation product 6aa with 80% yield◦accompanied by
bis-adduct 7aa with 20% yield after 28 h at 25 C in CH2Cl2 as
shown in Table 1, entry 1. These preliminary results prompted
us to investigate the catalyst effect on in situ trapping of the
olefination product of cyclopentane-1,3-dione 1a with 2-hydroxy-
benzaldehyde 2a through bio-mimetic hydrogenation as shown in
Table 1. Interestingly, proline-catalyzed cascade O–H reactions of
1a, 2a and 3 are catalyst dependent reactions as shown in Table 1.
Simple amino acid glycine 4b also catalyzed the cascade O–H of
1a, 2a and 3 but the result is not as good as proline-catalysis
(Table 1, entry 2). The cascade O–H reaction of 1a, 2a and 3
catalyzed by simple amines like benzylamine 4d, piperidine 4e and
pyrrolidine 4f in CH2Cl2 are also not as good in comparison to
proline-catalysis with respect to yields as shown in Table 1, entries
4–6. Interestingly, the reaction rate for cascade O–H under primary
amine, benzylamine 4d-catalysis is 7-fold enhanced compared to
other amine catalysts 4e–f or amino acid catalyst 4a as shown in
Table 1.
product 6aa in 80% yield accompanied by a 15% yield of bis-
adduct 7aa within 2 h at 25 ◦C (Table 1, entry 3). Interestingly, the
cascade O–H reaction rate for aniline-catalysis is 14-fold enhanced
compare to proline- or secondary amine-catalysis as shown in
Table 1. We envisioned the optimized condition to be mixing 3
equiv. of 2-hydroxy-benzaldehyde 2a with cyclopentane-1,3-dione
1a and Hantzsch ester 3 at 25 ◦C in CH2Cl2 under 5 mol%
of aniline-catalysis to furnish the hydrogenated product, 2-(2-
hydroxy-benzyl)-cyclopentane-1,3-dione 6aa in 80% yield (Table 1,
entry 3). The mechanistic aspect of this selective cascade O–H
reaction is discussed in the next section.
With an efficient aniline-catalyzed cascade reductive alky-
lation protocol in hand, we continued our investigation of
optimization for the synthesis of functionalized 3,9-dihydro-
2H-cyclopenta[b]chromen-1-one 10aa from 2-(2-hydroxy-benzyl)-
cyclopentane-1,3-dione 6aa under Brønsted acid-catalysis through
cascade oxy-Michael–dehydration (OM–DH) reactions as shown
in Table 2. The results in Table 2 demonstrate that p-TSA 9f
is a suitable Brønsted acid-catalyst for the cascade OM–DH
reaction compared to other Brønsted acid catalysts 9a-h or Lewis
acid catalyst 9b. Treatment of 2-(2-hydroxy-benzyl)-cyclopentane-
1,3-dione 6aa with 30 mol% of HClO4 in CH2Cl2 at 25 ◦C
furnished the expected cascade product 10aa in only 20% yield, but
interestingly there is no cascade reaction under BF3·OEt2 catalysis
even under hot conditions (Table 2, entries 1–2). Cascade OM–
DH reaction of 6aa in CH2Cl2 at 25 ◦C under CH3SO3H-catalysis
furnished the 10aa with only 45% yield, but interestingly there is no
cascade reaction under CF3SO3H-catalysis (Table 2, entries 3–4).
(+)-Camphor sulfonic acid catalyzed the cascade OM–DH re-
action of 6aa to furnish the product 10aa with 70% yield in
CH2Cl2 at 25 ◦C for 48 h (Table 2, entry 5). Interestingly, the same
reaction under p-TSA catalysis furnished the expected product
10aa in 80% yield (Table 2, entry 7). Phosphoric acid-catalysis for
the synthesis of cascade product 10aa is not superior compared
to p-TSA catalysis (Table 2, entries 9–10). We envisioned the
optimized condition to be mixing the 30 mol% of p-TSA 9f
with 2-(2-hydroxy-benzyl)-cyclopentane-1,3-dione 6aa at 45 ◦C
in CH2Cl2 for 10 h to furnish the cascade OM–DH product,
To increase the dynamics of the cascade O–H reaction without
generating the by-product bis-adduct 7aa, a suitable amine catalyst
is required. Recently, Dawson and coworkers from the Scripps
Research Institute found that aniline is a potent nucleophilic
catalyst for imine-type reactions.4 Aniline is a mild nucleophile,
which strongly catalyzes aqueous reactions of aldehydes and
=
ketones with amines to form stable imines (RR¢C NR¢¢) such
=
=
as hydrazones (RR¢C NNHR¢¢) and oximes (RR¢C NOR¢¢). In
a similar fashion, aniline should catalyze the olefination reaction
under non-aqueous conditions. Here we show that the dynamics
of the cascade O–H reaction can be significantly accelerated by
using aniline as a nucleophilic catalyst. Surprisingly, the cascade
O–H reaction of 1a, 2a and 3 in CH2Cl2 under 5 mol% of aniline-
catalysis furnished the expected hydrogenated reductive alkylation
Table 2 Reaction optimization for the Brønsted acid-catalyzed cascade OM–DH reaction of 6aaa
Entry
Catalyst 9 (30 mol%)
Solvent (0.1 M)
Time/h
Temperature/◦C
Yield (%)b10aa
1
2
3
4
5
6
7
8
9
HClO4 9a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3C6H5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
48
48
48
48
48
10
16
10
40
48
25
25
25
25
25
95
25
45
25
25
20
—
45
—
70
80
80
90
73
50
BF3·OEt2 9b
CH3SO3H 9c
CF3SO3H 9d
(+)-CSA 9e
p-TSA 9f
p-TSA 9f
p-TSA 9f
(PhO)2PO2H 9g
10
(R)-BNDHP 9hc
a Reactions were carried out in solvent (0.1 M) with 30 mol% of catalyst 9. b Yield refers to the column purified product. c (R)-1,1¢-Binaphthyl-2,2¢-diyl
hydrogen phosphate 9h and catalyst 9h were taken as 5 mol%.
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Table 3 Reaction optimization for the organo–Brønsted acid-catalyzed cascade one-pot synthesis of 10aaa
Entry
Catalyst 4 (5 mol%)
Time/h
Solvent (0.3 M)
Temperature/◦C
Time/h
Conversion (%)b
Yield (%)c10aa
1
2
3
4
Proline 4a
Proline 4a
Proline 4a
Aniline 4c
28
28
28
2
CH3C6H5
CH3C6H5
CH2Cl2
100
90
45
10
10
48
10
>99
>99
50
50
50
—
50
CH3C6H5
100
>99
a See Experimental section. b Conversion is based on the TLC analysis. c Yield refers to the column purified product.
Table 4 Chemically diverse libraries of 2-(2-hydroxy-benzyl)-cyclopen-
tane-1,3-diones 6a
3,9-dihydro-2H-cyclopenta[b]chromen-1-one 10aa in 90% yield
(Table 2, entry 8).
After successful optimization of the aniline-catalyzed cascade
O–H and Brønsted acid-catalyzed cascade OM–DH reactions,
we decided to investigate the combination of these two cascade
reactions in one-pot as shown in Table 3. The cascade O–
H reaction of three equiv. of 2-hydroxy-benzaldehyde 2a with
cyclopentane-1,3-dione 1a and Hantzsch ester 3 under proline-
catalysis in CH2Cl2 at 25 ◦C for 28 h furnished the expected
cascade product 6aa, which on evaporation of the solvent CH2Cl2
and treatment with 30 mol% of p-TSA 9f at 100 ◦C in toluene
solvent for 10 h furnished the expected sequential one-pot
O–H–OM–DH product 10aa in >99% conversion with 50%
yield as shown in Table 3, entry 1. Combination of two cascade
O–H and OM–DH reactions under aniline- and p-TSA-catalysis
in one-pot also furnished the sequential one-pot product 10aa
in >99% conversion with 50% yield as shown in Table 3, entry
4. Interestingly, combination of two cascade O–H and OM–DH
reactions under proline or aniline- and p-TSA-catalysis in CH2Cl2
solvent did not furnish the sequential one-pot product 10aa with
>99% conversion, but furnished it only with ≤50% conversion at
45 ◦C for 48 h as shown in Table 3, entry 3; this may be due to the
strong acid–base interactions of p-TSA with pyridine byproduct
of 2,6-dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester 8.
Diversity-oriented synthesis of reductive alkylation products
6aa–6ai
With the three cascade optimized reaction conditions in hand, the
scope of the aniline-catalyzed O–H, p-TSA-catalyzed OM–DH
and aniline–p-TSA-catalyzed O–H–OM–DH cascade reactions
was investigated with cyclopentane-1,3-dione 1a, various func-
tionalized 2-hydroxy-benzaldehydes 2a-i and Hantzsch ester 3 as
shown in Tables 4 and 5. A series of functionalized 2-hydroxy-
benzaldehydes 2a-i (3 equiv.) were reacted with cyclopentane-1,3-
dione 1a and Hantzsch ester 3 catalyzed by 5 mol% of aniline
at 25 ◦C in CH2Cl2 (Table 4). The substituted 2-(2-hydroxy-
aryl)-cyclopentane-1,3-diones 6aa–6ai were obtained as single
isomers (tautomer) with excellent yields. The cascade reaction
of cyclopentane-1,3-dione 1a with 2,3-dihydroxy-benzaldehyde 2b
and 3 furnished the reductive alkylation product 6ab as a single
isomer (tautomer), in 85% yield after 5 h at 25 ◦C (Table 4).
Synthesis of functionalized 2-(2-hydroxy-aryl)-cyclopentane-1,3-
a Yield refers to the column purified product.
diones 6aa–6ai from 1a, 2a-i and 3 at 25 ◦C under aniline-
catalysis requires shorter reaction times (1 to 5 h), compared to
proline-catalysis as shown in Tables 1 and 4. Interestingly, the
aniline-catalyzed reductive alkylation reaction of cyclopentane-
1,3-dione 1a with 5-chloro-2-hydroxy-benzaldehyde 2g/5-bromo-
2-hydroxy-benzaldehyde 2h and Hantzsch ester 3 generated the
expected cascade products 6ag/6ah in excellent yields with very
good selectivity (Table 4). Structure and regio-chemistry of
cascade products 6aa–ai were confirmed by NMR analysis and
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Table 5 Chemically diverse libraries of 3,9-dihydro-2H-cyclopenta-
[b]chromen-1-ones 10a
even after 2000 scans on standard sampling. This same kind
of 13C NMR pattern was observed for the other 1,3-diketones
in the literature due to the rapid keto–enol and enol–enol
tautomerism.6
Diversity-oriented synthesis of heterocycles 10aa–10ai
With the success of cascade synthesis of highly functional-
ized 2-(2-hydroxy-aryl)-cyclopentane-1,3-diones 6, we contin-
ued our investigation for the generation of a highly func-
tionalized diversity oriented library of cascade 3,9-dihydro-2H-
cyclopenta[b]chromen-1-ones 10 under acid-catalysis. The re-
sults in Table 5 demonstrate the broad scope of this novel
green methodology covering a structurally diverse group of 2-
(2-hydroxy-aryl)-cyclopentane-1,3-diones 6aa–ai. Cascade OM–
DH reaction of 2-(2-hydroxy-aryl)-cyclopentane-1,3-diones 6aa–
ai under acid-catalysis furnished the expected 3,9-dihydro-2H-
cyclopenta[b]chromen-1-ones 10aa–ai in 75–99% yield with high
selectivity (Table 5). Unexpectedly, cascade product 10ab only
was only produced in moderate yield from 6ab and 9f. Inter-
estingly, all 4- and 5-substituted 2-(2-hydroxy-aryl)-cyclopentane-
1,3-diones 6ac–ai furnished the expected products 10ac–ai with
very good yields as a single isomer in acid-catalyzed OM–DH
cascade reactions as shown in Table 5. Structure and regio-
chemistry of cascade products 10 were confirmed by NMR
analysis and also by X-ray structure analysis on 10aa as shown in
Fig. 2.5
a Yield refers to the column purified product. b Reaction performed at 100
◦C for 8 h in the toluene solvent.
also by X-ray structure analysis on 6ad as shown in Fig. 1.5
Interestingly, these 2-alkyl-cyclopentane-1,3-diones 6 exist as an
enol form in both solid and solution state and this may be due to
the strong intermolecular hydrogen bonding and this same concept
is observed in many other 1,3-diketones.6 The chemical shifts of
the C1 and C3 carbon atoms in the isolated, non-hydrogen-bonded
enol forms of 2-alkyl-cyclopentane-1,3-diones 6 can hardly be
determined in solution, due to the rapid keto–enol and enol–
enol tautomerism.6 Therefore, in 2-alkyl-cyclopentane-1,3-dione
compounds 6aa–ai, we observed that the 13C NMR spectra show
two of the CH2 carbons a to the carbonyls (C=O) including the
two carbonyl carbons [2 ¥ CH2 and 2 ¥ C=O] at poor resolution
Fig. 2 Crystal structure of 3,9-dihydro-2H-cyclopenta[b]chromen-1-one
(10aa).
Diversity-oriented synthesis of 2-alkyl-3-methoxy-cyclopent-2-
enones 11aa–11ai
With synthetic applications in mind, we extended the three-
component cascade O–H reactions into a novel aniline–self-
catalyzed four-component O–H–A reaction of 1a, 2a-i and 3
with ethereal solution of diazomethane in one-pot as shown in
Table 6. One-pot products 11 were constructed in very good yields
with high chemoselectivity as shown in Table 6 and this method
should have a great impact on the synthesis of functionalized
small molecules. The substituted 2-alkyl-3-methoxy-cyclopent-
2-enone unit is a basic building block for a large number
of valuable naturally occurring products.7 Highly substituted
2-alkyl-3-methoxy-cyclopent-2-enones 11 have gained importance
Fig. 1 Crystal structure of 2-(2-hydroxy-5-methyl-benzyl)-cyclopentane-
1,3-dione (6ad).
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Table 6 Chemically diverse libraries of 2-(2-hydroxy-benzyl)-3-methoxy-cyclopent-2-enones 11a,b
a See Experimental section. b Yield refers to the column purified product. c Yield represents only the etherification reaction.
in recent years as starting materials and intermediates for the
synthesis of prostaglandin analogs, which possess a wide range of
physiological and pharmacological properties.7
80% yield and 2-(2-hydroxy-naphthalen-1-ylmethyl)-3-methoxy-
cyclopent-2-enone 11ai in 85% yield, respectively as shown
in Table 6. For the pharmaceutical applications, diversity-
oriented library of enones 11 could be generated by using
our aniline–self–self-catalyzed, chemoselective one-pot O–H–A
reaction.
After successful chemoselective synthesis of 2-(2-hydroxy-
benzyl)-3-methoxy-cyclopent-2-enone 11aa in good yield, we
decided to test the acid–base effect on this cascade product 11aa.
Treatment of 11aa with both acid (p-TSA) or base (K2CO3)
at room temperature furnished the expected 3,9-dihydro-2H-
cyclopenta[b]chromen-1-one 10aa in good yield as shown in
Scheme 3. Interestingly this same reaction performed in one-pot
as a four-component, multi-catalysis (aniline-, self-, self- and base-
catalysis) of 1a, 2a, 3 and CH2N2 furnished the one-pot product
10aa in 68% yield as shown in Scheme 3. The overall yield of
one-pot product 10aa may be less compared to Table 5, but this
multi-component–multi-catalysis strategy will have much effect
on the synthesis of highly functionalized small molecules like 10
and 11.
Cascade O–H reaction of 1a, 2a and 3 under 5 mol% of
aniline-catalysis furnished the substituted 2-(2-hydroxy-benzyl)-
cyclopentane-1,3-dione 6aa in good yield, which on treatment
with ethereal diazomethane at 0 ◦C to 25 ◦C for 2 h furnished
chemoselectively the one-pot O–H–A product 2-(2-hydroxy-
benzyl)-3-methoxy-cyclopent-2-enone 11aa in 85% yield as shown
in Table 6. Interestingly, the phenol group is not methylated
under these conditions. The acidic or highly enolizable nature
of 2-aryl-cyclopentane-1,3-diones 6 is the main driving force to
the observed highly chemoselective O-alkylation reaction with
diazomethane. Generality of the aniline–self-catalyzed chemos-
elective one-pot O–H–A reaction was further confirmed by
three more examples using 2,3-dihydroxy-benzaldehyde 2b, 5-
chloro-2-hydroxy-benzaldehyde 2g and 2-hydroxy-naphthalene-
1-carbaldehyde 2i to furnish the expected 2-(2,3-dihydroxy-
benzyl)-3-methoxy-cyclopent-2-enone 11ab in 65% yield, 2-(5-
chloro-2-hydroxy-benzyl)-3-methoxy-cyclopent-2-enone 11ag in
Scheme 3 Multi-catalysis and multi-component approach to the synthesis of 3,9-dihydro-2H-cyclopenta[b]chromen-1-one 10aa.
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Table 7 Direct organocatalytic synthesis of 2-(2-hydroxy-benzyl)-5,5-dimethyl-cyclohexane-1,3-diones 6 and 3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-
1-ones 10a,b
a See Experimental section. b Yield refers to the column purified product. c 20% of L-152,804; an orally active and selective neuropeptide Y Y5 receptor
antagonist was accompanied as by-product with 6ca in aniline-catalyzed reaction of 1c, 2a and 3. d 23% of 10cb was accompanied as by-product with 6cb
in aniline-catalyzed reaction of 1c, 2b and 3.
Diversity-oriented synthesis of heterocycles 10ca–10ci
dimethyl-2,3,4,9-tetrahydro-xanthen-1-one (L-152,804) in 20%
yield, which is useful compound as an orally active and selective
neuropeptide Y Y5 receptor antagonist.8 But pure product of
L-152,804 was obtained only after two step O–H and OM–
DH reactions, because separation of L-152,804 from 6ca is
tedious job due to the same Rf in TLC plate. In the reac-
tion of 1c, 2a and 3 under 4c-catalysis, the initial byprod-
uct (L-152,804) was unchanged after heating with p-TSA 9f
in CH2Cl2. The generality of the aniline- and acid-catalyzed
chemoselective cascade O–H and OM–DH reactions of 1c with
2 and 3 was further confirmed by three more examples using
2,3-dihydroxy-benzaldehyde 2b, 5-nitro-2-hydroxy-benzaldehyde
2f and 5-bromo-2-hydroxy-benzaldehyde 2h to furnish the
expected 2-(2,3-dihydroxy-benzyl)-5,5-dimethyl-cyclohexane-1,3-
dione 6cb in 70% yield, 2-(2-hydroxy-5-nitro-benzyl)-5,5-dimethyl-
cyclohexane-1,3-dione 6cf in 75% yield, 2-(5-bromo-2-hydroxy-
benzyl)-5,5-dimethyl-cyclohexane-1,3-dione 6ch in 85% yield,
5-hydroxy-3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one 10cb in
After successful demonstration of the cascade O–H, O–H–A, O–
H–OM–DH and O–H–A–OM–DH reactions on cyclopentane-
1,3-dione 1a with 2, 3 and 4, then we decided to test the same
cascade reactions on other 1,3-diones like cyclohexane-1,3-dione
1b and dimedone 1c. Interestingly, cascade O–H reaction of 1b,
2a and 3 under proline 4a- or aniline 4c-catalysis did not furnish
the expected pure product 2-(2-hydroxy-benzyl)-cyclohexane-1,3-
dione 6ba and the reaction itself is not clean. But the same cascade
O–H reaction with 1c, 2a and 3 under proline 4a- or aniline
4c-catalysis furnished the expected product 2-(2-hydroxy-benzyl)-
5,5-dimethyl-cyclohexane-1,3-dione 6ca in only 65% yield, which
on acid-catalysis furnished the expected 3,3-dimethyl-2,3,4,9-
tetrahydro-xanthen-1-one 10ca in very good yield as shown in
Table 7.
Interestingly, cascade product 6ca was accompanied with
byproduct 9-(2-hydroxy-4,4-dimethyl-6-oxo-cyclohex-1-enyl)-3,3-
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98% yield, 3,3-dimethyl-7-nitro-2,3,4,9-tetrahydro-xanthen-1-one
10cf in 99% yield and 7-bromo-3,3-dimethyl-2,3,4,9-tetrahydro-
xanthen-1-one 10ch in 90% yield, respectively as shown in
Table 7. Interestingly, we could not see the formation of un-
expected byproducts like L-152,804 analogs in the above three
reactions. But, cascade product 6cb was accompanied with
byproduct 5-hydroxy-3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-
one 10cb in 23% yield. Recently, 5,5-dimethylcyclohexane-1,3-
dione derivatives 6ca–ci were evaluated to show their biological
activities like anti-ischemic agents, anti-hypertensive and anti-
psychotics.9
explained by using the HOMO–LUMO energy gaps and enthalpy
differences of reactants and products. Recently we published
complete mechanistic information about this type of self-catalyzed
chemoselective reductive alkylation of 1,3-dione 1a with 2 and 3
under 4a-catalysis through PM3 calculations.3h For the reductive
alkylation of 1,3-diones 1 with 2 and 3 under amine/amino acid
4-catalysis, the 2-hydroxy group is not essential as demonstrated
in our previous work.3h
In the subsequent third step, acid-catalyzed oxy-Michael–
dehydration of 6 via the most likely possible intermediate 14 leads
to the formation of one-pot product 10. In the alternative fourth
step, self-catalyzed reaction of 6 with diazomethane leads to the
formation of 11, which on treatment with K2CO3 generates the
expected one-pot product 10 via most likely possible intermediate
15.
Mechanistic insights
A possible reaction mechanism for the aniline-, self-, acid- and
base-catalyzed chemoselective synthesis of cascade products 6,
10 and 11 through the reaction of cyclopentane-1,3-dione 1a, 2-
hydroxy-benzaldehydes 2, Hantzsch ester 3 and diazomethane
is illustrated in Scheme 4. This catalytic sequential one-pot,
double cascade is a four component reaction comprising a
cyclopentane-1,3-dione 1a, 2-hydroxy-benzaldehydes 2, Hantzsch
ester 3, diazomethane and a simple catalyst, aniline 4c. In the
first step (Scheme 4), the catalyst 4c activates component 2 by
most likely imine formation, which then selectively adds to the
cyclopentane-1,3-dione 1a via a Mannich and retro-Mannich type
reaction to generate active olefin 5 (12 → 13 → 5). The following
second step is bio-mimetic hydrogenation of active olefin 5 by
Hantzsch ester 3 to produce 6 through self-catalysis by decreasing
the HOMO–LUMO energy gap between 3 and 5 respectively.
Highly chemoselective synthesis of cascade hydrogenated products
6 over bis-adduct 7 formation from reactants 1a, 3 and 5 can be
Conclusions
In summary, for the first time we have developed multi-
catalysis technology for the synthesis of highly substituted 2-
(2-hydroxy-benzyl)-cyclopentane-1,3-diones 6, 3,9-dihydro-2H-
cyclopenta[b]chromen-1-ones 10 and 2-(2-hydroxy-benzyl)-3-
methoxy-cyclopent-2-enones 11 from simple starting materials via
cascade O–H, OM–DH, O–H–OM–DH, O–H–A and O–H–A–
OM–DH reactions under combinations of aniline-, self-, base-
and Brønsted-acid catalysis. The cascade O–H reaction proceeds
in good yields with high selectivity using only 5 mol% of aniline as
the catalyst. Furthermore, we have for the first time demonstrated
the application of bio-mimetic aniline-catalysis for the olefination
of aldehydes 2 with CH-acids like cyclopentane-1,3-dione 1a.
Further work is in progress to utilize novel O–H, OM–DH,
Scheme 4 Proposed catalytic cycle for the multi-catalysis reactions.
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O–H–OM–DH, O–H–A and O–H–A–OM–DH reactions and
cascade products 6, 10 and 11 in synthetic chemistry.
was extracted with dichloromethane (3 ¥ 15 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated. Pure
products 10 were obtained by column chromatography (silica gel,
mixture of hexane–ethyl acetate).
Experimental
Amino acid– or aniline–p-TSA-catalyzed one-pot double cas-
cade olefination–hydrogenation–oxy-Michael–dehydration reac-
tions. In an ordinary glass vial equipped with a magnetic stirring
bar, to 0.9 mmol of the aldehyde 2, 0.3 mmol of 1,3-dione
1a and 0.3 mmol of Hantzsch ester 3 was added 1.0 mL of
dichloromethane, and then the catalyst amino acid 4a or aniline
4c (0.015 mmol, 5 mol%) was added and the reaction mixture was
stirred at 25 ◦C for the time indicated in Table 3. After evaporation
of the solvent completely, to the crude reaction mixture was
added 1.0 mL of toluene solvent and p-TSA 9f (0.09 mmol,
30 mol%) and the reaction mixture was stirred at 90 ◦C for
10 h. The crude reaction mixture was worked up with aqueous
NaHCO3 solution, and the aqueous layer was extracted with
dichloromethane (3 ¥ 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. Pure one-pot products
10 were obtained by column chromatography (silica gel, mixture
of hexane–ethyl acetate).
General methods
1
The H NMR and 13C NMR spectra were recorded at 400 MHz
and 100 MHz, respectively. The chemical shifts are reported in
ppm downfield to TMS (d = 0) for H NMR and relative to
1
the central CDCl3 resonance (d = 77.0) for 13C NMR. In the
13C NMR spectra, the nature of the carbons (C, CH, CH2 or
CH3) was determined by recording the 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 micromass ESI-TOF MS. GCMS mass
spectrometry 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 on either a VG7070H mass spectrometer using the EI
technique or a Shimadzu-LCMS-2010A mass spectrometer. IR
spectra were recorded on a JASCO FT/IR-5300 and a Thermo
Nicolet FT/IR-5700. The X-ray diffraction measurements were
carried out at 298 K on an automated Enraf-Nonius MACH
3 diffractometer using graphite monochromated, Mo-Ka (l =
General procedure for the direct organocatalytic one-pot synthesis
of 2-(2-hydroxy-benzyl)-3-methoxy-cyclopent-2-enones 11. In an
ordinary glass vial equipped with a magnetic stirring bar, to
0.9 mmol of the aldehyde 2, 0.3 mmol of 1,3-dione 1a and 0.3 mmol
of Hantzsch ester 3 was added 1.0 mL of dichloromethane, and
then the catalyst aniline 4c (0.015 mmol, 5 mol%) was added and
the reaction mixture was stirred at 25 ◦C for the time indicated
in Table 6. After evaporation of the solvent completely, 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 2 h. After evaporation of the solvent
and excess diazomethane completely in fume hood, the crude
reaction mixture was directly loaded onto a silica gel column
with or without aqueous work-up and pure one-pot products 11
were obtained by column chromatography (silica gel, mixture of
hexane–ethyl acetate).
˚
0.71073 A) radiation with CAD4 software or the 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), silica gel plates Merck 60 F254 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.
Materials
All solvents and commercially available chemicals were used as
received.
General procedure for the multi-catalysis synthesis of 3,9-dihydro-
2H-cyclopenta[b]chromen-1-ones 10. In an ordinary glass vial
equipped with a magnetic stirring bar, to 0.9 mmol of the aldehyde
2, 0.3 mmol of 1,3-dione 1a and 0.3 mmol of Hantzsch ester
3 was added 1.0 mL of dichloromethane, and then the catalyst
aniline 4c (0.015 mmol, 5 mol%) was added and the reaction
General experimental procedures for the multi-catalysis reactions
Aniline-catalyzed cascade olefination–hydrogenation reactions.
In an ordinary glass vial equipped with a magnetic stirring bar, to
0.9 mmol of the aldehyde 2, 0.3 mmol of 1,3-dione 1a and 0.3 mmol
of Hantzsch ester 3 was added 1.0 mL of dichloromethane, and
then the catalyst aniline 4c (0.015 mmol, 5 mol%) was added and
the reaction mixture was stirred at 25 ◦C for the time indicated
in Tables 1 to 6. The crude reaction mixture was directly loaded
onto a silica gel column with or without aqueous work-up, and
pure cascade products 6 were obtained by column chromatography
(silica gel, mixture of hexane–ethyl acetate).
◦
mixture was stirred at 25 C for the time indicated in Scheme 3.
After evaporation of the solvent completely, 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 2 h. After evaporation of the solvent and
excess diazomethane completely in a fume hood, to the crude
reaction mixture was added 3 equivalents of K2CO3 and solvent
ethanol and the reaction mixture was stirred at room temperature
for the 18 h. The crude reaction mixture was worked up with
aqueous NH4Cl solution, and the aqueous layer was extracted with
dichloromethane (3 ¥ 20 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. Pure one-pot products
10 were obtained by column chromatography (silica gel, mixture
of hexane–ethyl acetate).
Acid-catalyzed cascade oxy-Michael–dehydration reactions
of 2-(2-hydroxy-benzyl)-cyclopentane-1,3-diones 6. A solution
of substituted 2-(2-hydroxy-benzyl)-cyclopentane-1,3-diones 6
(0.1 mmol) and p-TSA 9f (0.03 mmol, 30 mol%) in dichloro-
methane (1.0 ml) was stirred at 45 ◦C for 9 to 18 h. After cooling,
the reaction mixture was washed with water and the aqueous layer
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Acknowledgements
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi. YVR and MK thank
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.
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