Development of drug intermediates by using direct organocatalytic multi-component reactions

Article abstract of DOI:10.1039/b602696f

Development of drug intermediates by using direct amino acid organocatalytic multi-component reaction was investigated. Hydrogenations of double-bond containing compounds including carbonyls, imines and olefins are important for living organisms as well as for the industrial production of chemicals. Amino acid catalysis has emerged as a powerful green synthetic tool for the development of both achiral and chiral catalysis of condensations and cycloadditions and the 1,2- and 1,4-additions of enals, enones and ketones including electrophiles. It was found that the amino acid proline 4a catalyzes the Knoevenagel condenstion of cyclohexanone 1a with the CH-acid ethyl cyanoacetate 2a to furnish the active olefin 9aa. This simple and environmentally friendly approach can be used to construct highly substituted hydrogenated products in a regioselective fashion with good yields.

Full text of DOI:10.1039/b602696f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Development of drug intermediates by using direct organocatalytic
multi-component reactions
Dhevalapally B. Ramachary,* M. Kishor and G. Babul Reddy
Received 22nd February 2006, Accepted 14th March 2006
First published as an Advance Article on the web 23rd March 2006
DOI: 10.1039/b602696f
Novel, economic and environmentally friendly one-pot three-
component Knoevenagel/hydrogenation (K/H) and four-
component Knoevenagel/hydrogenation/alkylation (K/H/A)
reactions of ketones, CH-acids, dihydropyridines and alkyl
halides using proline and proline/metal carbonate catalysis,
respectively, have been developed. Many of the products of
these K/H and K/H/A reactions have direct applications in
pharmaceutical chemistry.
highly chemically activated olefin compounds if a suitable hydride
donor could be identified. Such a process would constitute a one-
pot metal-free green hydrogenation similar to bio-transformations.
As we are interested in the engineering of direct organocat-
alytic green multi-component reactions,5a,6f–i,m–o herein we report
the first organocatalytic chemoselective direct tandem Knoeve-
nagel/hydrogenation (K/H) and Knoevenagel/hydrogenation/
alkylation (K/H/A) reactions that produce highly substituted
tandem products 5 and 8 respectively, from ketones 1a–n, CH-
acids 2a–i, Hantzsch ester 3, alkyl halides 7a–f and amino acids
4a,b, as shown in Scheme 1.† Tandem products 5 and 8 are
attractive intermediates in medicinal chemistry, and analogues
thereof have broad utility in pharmaceutical chemistry7 (as insect
repellents, dental adhesives, CRF antagonists, anti-spasmodics,
antiulcer agents, drugs for skin diseases, as agents against tuber-
culosis and leprosy bacteria, and as agents for wound healing etc.)
and in organic synthesis.
A number of pyridine nucleotide-linked dehydrogenases catalyze
the reversible hydrogenation–dehydrogenation of the double bond
in a,b-unsaturated ketones,1 and nicotinamide nucleotides play a
vital role in biological oxidation–reductions;2 namely, NAD(P)H
reduces carbonyl compounds to alcohols. In certain enzymatic
systems, NAD(P)H also reduces carbon–carbon double bonds in
a-ketoolefins such as crotonyl-CoA and benzalacetone.3 Similar
biomimetic conjugate reductions of a,b-unsaturated aldehydes and
ketones occurs with NAD(P)H models, such as 3,5-dicarboethoxy-
2,6-dimethyl-1,4-dihydropyridine (Hantzsch ester).4 In order to
understand mechanisms of biochemical oxidation–reduction re-
actions and to mimic this completely green approach to synthetic
organic chemistry, it is worthwhile to approach the subject from
the viewpoint of organic chemistry.
Hydrogenations of double-bond-containing compounds such
as carbonyls, imines, and olefins are crucial for living organisms as
well as for the industrial production of chemicals. Recently, metal-
free catalytic hydrogenations of olefins have been an emerging
area in green catalysis.5 Herein, we disclose a highly efficient
and remarkably chemoselective metal-free catalytic transfer hy-
drogenation of in situ generated chemically activated olefins in a
tandem approach. The resulting products have direct applications
to drug discovery process.
We found that the amino acid proline 4a readily catalyzes the
Knoevenagel condensation of cyclohexanone 1a with the CH-
acid ethyl cyanoacetate 2a to furnish the active olefin 9aa, which
on treatment with Hantzsch ester 3 produces the hydrogenated
◦
product 5aa with very good yield after 24 h in MeOH at 25 C
(Ta◦ble 1, entry 1). The same reaction, catalyzed by L-proline 4a at
25 C under tandem conditions, furnished the product 5aa with
90–95% yield in protic solvents (Table 1, entries 1–3). The use of
polar aprotic solvents (DMF and DMSO) gave similar yields to
Table 1 Optimization of in situ generation and reduction of active olefinsa
The hydrogenation of activated olefin compounds is a useful
but challenging transformation. As both 1,2- and 1,4-reductions
readily occur, low selectivity for either of the two pathways is com-
mon, and functional groups that are sensitive to hydrogenation
conditions such as the ester, nitro, and nitrile groups are usually
not tolerated. Clearly, mild, catalytic, one-pot, chemoselective and
green variants of this reaction are highly desirable.
Recently, amino acid catalysis has emerged as a powerful
green synthetic tool for the development of both achiral and
chiral catalysis of condensations and cycloadditions, and the
1,2- and 1,4-additions of enals, enones and ketones with many
electrophiles.6 We reasoned that this catalysis strategy might be
applicable to the in situ generation and conjugate reduction of
Entry
Catalyst
Solvent
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
—
—
—
4b
MeOH
EtOH
EtOH
DMF
DMSO
CHCl3
CH3CN
EtOH
DMSO
H2O
24
24
36
24
24
24
24
48
48
48
48
90
93
95
86
86
48
68
80
75
15
72
10
11
EtOH
a Experimental conditions: All reactants (1a, 2a, 3) and catalyst 4 were
mixed at the same time in solvent and stirred at room temperature. b Yield
refers to the column-purified product.
School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
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Table 2 Knoevenagel reaction of cyclohexanone 1a with 2a and 2c
Entry EWG
Catalyst Solvent
Product Conversion (%)a
1b
2
3
4
5
6
7
8
9
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
4a
6
EtOH
EtOH
DMSO
EtOH
DMSO
H2O
EtOH
DMSO
H2O
9aa
9aa
9aa
9aa
9aa
9aa
9ac
9ac
9ac
66
<3
<3
<3
<3
<4
70
6
—
—
—
—
—
—
CN
CN
70
75
a Determined by 1H NMR analysis. b Reaction time was 24 h.
nucleotide-linked dehydrogenases.1 The proline-catalyzed Kno-
evenagel condensation of cyclohexanone 1a with ethyl cyanoac-
etate 2a in the absence of Hantzsch ester 3 furnished the olefin 9aa
with reduced conversion (Table 2, entry 1). Comparison of this
result with entry 2 in Table 1 gives support for the self-catalysis of
Hantzsch ester 3 in tandem reactions. To understand more about
the self-catalysis of 3 in tandem K/H reactions, we performed a
Knoevenagel reaction of 1a with 2a and 2c in the presence of 6 (and
in the absence of catalysts 3 and 4a) in EtOH, DMSO and H2O,
as shown in Table 2. Starting from 1a and 2a, the Knoevenagel
product 9aa was furnished with very poor conversions after 48 h at
25 ◦C in EtOH, DMSO and H2O, both with and without pyridine
6 (Table 2, entries 2–6). Interestingly, Knoevenagel product 9ac
was furnished from 1a and 2c in moderate yields under catalyst-
free conditions, as shown in Table 2, entries 7–9 .This may be due
to the highly acidic nature of malononitrile 2c compared to ethyl
cyanoacetate 2a. From these results, we have strong support for
the self-catalysis of 3 in tandem K/H reactions.
The two possible reaction mechanisms for tandem K/H reac-
tions of 1a, 2a, 3 and 4a are illustrated in Scheme 2. First, reaction
of proline 4a with cyclohexanone 1a generates the iminium
cation 12a, an excellent electrophile that undergoes Mannich-
type reactions with CH-acid 2a to generate Mannich product 14a.
Retro-Mannich or base-induced elimination reaction of amine
14a would furnish active olefin 9aa.6h The subsequent hydrogen
transfer reactions are dependent upon the electronic nature of
the in situ generated conjugated system or, more precisely, the
HOMO–LUMO gap of the reactants 3 and 9aa.5e Interestingly,
Hantzsch ester 3 also catalyzed the simultaneous formation
and hydrogenation of active olefin 9aa via key intermediate
16a, as shown in mechanism 2, and is thus an ideal mimic of
the hydrogenation–dehydrogenation of pyridine nucleotide-linked
dehydrogenases.1 We are able to propose mechanism 2 based on
the acidic nature of Hantzsch ester 3 (pKa = 3.50 0.70).4e
After this preliminary work, we proceeded to investigate the
scope and limitations of the tandem K/H reaction of cyclohex-
anone 1a with a range of active CH-acids 2a–i and Hantzsch
ester 3 under proline catalysis in DMSO (Table 3).8 As shown
in Table 3, acyclic CH-acids 2a–d furnished tandem products
5aa–ad in lower yields than the cyclic CH-acids 2e–i. This may be
Scheme 1 Direct one-pot organocatalytic K/H and K/H/A reactions.
the reactions in MeOH and EtOH (Table 1, entries 4–7). A simple
amino acid, glycine 4b, also catalyzed the tandem K/H reaction
to furnish tandem product 5aa in 72% yield (Table 1, entry 11).
The optimum conditions (entries 3, 4 and 5) involved the use of
catalyst 4a in the tandem K/H reaction of 1a, 2a and 3 in EtOH,
DMF or DMSO at 25 ◦C.
Interestingly, the tandem K/H reaction of 1a, 2a and 3 in the
absence of catalyst at 25 ◦C furnished, after 48 h, the expected
product 5aa in 80% and 75% yields in EtOH and DMSO,
respectively (Table 1, entries 8 and 9). This is best demonstration
of the self-catalytic nature of reagents in tandem reactions, and
also in mimicking the hydrogenation–dehydrogenation of pyridine
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Table 4 Chemically diverse libraries of tandem K/H products 5
Entry
1
Product
Yield (%)a
95
2b
90
3
4
45
95
5
6
90
90
Scheme 2 Proposed reaction mechanisms.
7
8
99
85
Table 3 Tandem in situ generation and reduction of a variety of activated
olefinsa
9
99
95
Entry
CH-acid
Time/h
Yield (%)b
1
2
3
4
5
6c
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
24
24
19
60
48
12
24
24
24
86
99
90
60
95
90
99
99
93
10
a The reactants (1a, 2, and 3) and the catalyst 4a were mixed at the same
time in the solvent and stirred at room temperature. b Yield refers to the
column-purified product. c Reaction performed at 70 ◦C.
11
93
due to the difference in acid strength and the HOMO–LUMO
gap between Hantzsch ester 3 and the in situ generated olefins
9, respectively. Cyclic CH-acids 2e–i have a higher acid strength
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Table 4 (Cont.)
Table 5 Chemically diverse libraries of tandem K/H/A products 8
Entry
12
Product
Yield (%)a
92
Entry
1
Base/solvent
Product
Yield (%)a
65
K2CO3/EtOH
13
14
15
60
61
92
2
3
4
5
6
K2CO3/EtOH
K2CO3/EtOH
K2CO3/EtOH
K2CO3/EtOH
K2CO3/DMSO
65
80
80
99
80
a Yield refers to the column-purified product. b Ratio determined by 1H
and 13C NMR analysis.
than acyclic CH-acids 2a–d, and the same acidic property also
continues in olefins 9. Tandem products 5aa–ai have applications
in pharmaceutical chemistry.7
We generated a useful library of tandem K/H products 5 under
proline catalysis. The results in Table 4 demonstrate the broad
scope of this reductive green methodology, covering a structurally
diverse group of less reactive ketones 1a–n and CH-acids 2a–i
with many of the yields obtained being very good, or indeed
better, than previously published reactions starting from the
corresponding olefins 9 or ketones 1. The tandem K/H reaction
of 4-methylcyclohexanone 1b, ethyl cyanoacetate 2a and Hantzsch
ester 3 furnished the regioselective hydrogenated ester cis-5ba in
3.4 : 1 ratio in 90% yield (Table 4, entry 2). Tandem K/H reactions
produced hydrogenated products 5ba, 5ca, 5da and 5ma with
good regioselectivities compared to NaBH4 reduction of the cor-
responding olefins,9 as shown in Table 4, entries 2–4 and 9–10.10,11
Hydrogenated ester 5aa and analogues are important interme-
diates for the synthesis of cygerol (a wound treatment ointment),7e
perfumes, anti-ulcer agents and drugs for skin diseases; tandem
ester 5na is used as intermediate in the synthesis of the ophiobolins
(natural products);7f tandem products 5ea, 5ma and analogues are
used in the preparation of active anti-spasmodics;7d and tandem
hydrogenated product 5lb is used as a cockroach repellent7a in
the USA. These applications emphasize the value of this tandem
approach.
7
K2CO3/DMSO
K2CO3/DMSO
90
85
8b
9b
K2CO3/DMSO
85
With pharmaceutical applications in mind, we extended the
three-component tandem K/H reactions into a novel proline/
Cs2CO3- and proline/K2CO3-catalyzed one-pot four-component
K/H/A reaction of ketones 1, CH-acids 2 and Hantzsch ester 3
with various alkyl halides 7a–f (Table 5). Various 2,2-disubstituted
ethyl cyanoacetates and malononitriles 8 were synthesized in good
yields, as shown in Table 5.11 We also demonstrated a direct
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Table 5 (Cont.)
Notes and references
† Representative experimental procedures:
Proline-catalyzed tandem Knoevenagel/hydrogenation reactions: In an
ordinary glass vial equipped with a magnetic stirring bar, solvent (1.0 mL)
was added to the ketone 1 (0.5 mmol), the CH-acid 2 (0.5 mmol) and
the Hantzsch ester 3 (0.5 mmol). The amino acid catalyst 4 (0.1 mmol)
was then added and the reaction mixture stirred at 25 ◦C for the time
indicated in Tables 1–3. The crude reaction mixture was directly loaded
onto a silica gel column with or without aqueous work-up, and pure
tandem products 5 were obtained by column chromatography (silica gel,
hexane–ethyl acetate).
Proline/Cs2CO3 or K2CO3-catalyzed one-pot Knoevenagel/hydrogenation/
alkylation reactions: In an ordinary glass vial equipped with a magnetic
stirring bar, solvent (1.0 mL) was added to the ketone 1 (0.5 mmol), the
CH-acid 2 (0.5 mmol) and the Hantzsch ester 3 (0.5 mmol). The proline
catalyst 4a (0.1 mmol) was added and the reaction mixture stirred at 25 ◦C
for 24–96 h. RCH2I or RCH2Br 7 (2.5 mmol) and K2CO3 or Cs2CO3 (0.4
g) were then added and stirring continued at the same temperature for
7–24 h. The crude reaction mixture was worked up with aqueous NH4Cl
and the aqueous layer extracted with dichloromethane (2 × 20 mL). The
combined organic layers were dried (Na2SO4), filtered and concentrated.
Pure products 8 were obtained by column chromatography (silica gel,
hexane–ethyl acetate).
Entry
10
Base/solvent
Product
Yield (%)a
75
Cs2CO3/DMF
Cs2CO3/DMF
Cs2CO3/DMF
11
12
65
65
Many of the tandem products 5 and 8 are commercially available, or have
been described previously, and their analytical data match literature values.
New compounds were characterized on the basis of IR, 1H and 13C NMR
and analytical data.
1 (a) B. Eckstein and A. Nimrod, Biochim. Biophys. Acta, 1977, 1, 499;
(b) I. A. Watkinson, D. C. Wilton, A. D. Rahimtula and M. M. Akhtar,
Eur. J. Biochem., 1971, 1, 23.
2 H. R. Mahler and E. H. Cordes, Biological Chemistry, Harper & Row,
New York, 1966.
3 I. M. Freser, D. A. Fancher and A. Strother, Pharmacologist, 1968, 10,
203.
a Yield refers to the column-purified product. b Ratio determined by 1H
and 13C NMR analysis.
4 (a) U. K. Pandit, F. R. Mas Cabre, R. A. Gase and M. J. De Nie-
Sarink, J. Chem. Soc., Chem. Commun., 1974, 627; (b) Y. Ohnishi, M.
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organocatalytic approach to the synthesis of key intermediates
of the pharmaceutical drug cygerol 19 in a single step (Table 5,
entries 10–12). Decyanation followed by hydrolysis of 8aaf or 8abf
furnished the cyclohexylgeranylacetic acid 19, useful for wound
healing, as demonstrated by Joseph and George in their patent
(Scheme 3).7e
6 For reviews, see: (a) W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem.
Res., 2004, 37, 580–591; (b) B. List, Acc. Chem. Res., 2004, 37, 548–557;
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Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726–3748;
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Chem., Int. Ed., 2003, 42, 4233 (g) D. B. Ramachary, K. Anebouselvy,
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Scheme 3
In summary, we have developed direct amino acid/metal
carbonate-catalyzed tandem K/H and K/H/A reactions which
have direct application in drug discovery processes. This exper-
imentally simple and environmentally friendly approach can be
used to construct highly substituted hydrogenated products in a
regioselective fashion with very good yields. For the first time
in organocatalysis, pyridine nucleotide-linked dehydrogenases are
mimicked in the laboratory. Further work is in progress to develop
an asymmetric version of this tandem process.
7 (a) M. Schwarz, O. F. Bodenstein and J. H. Fales, J. Econ. Entomol.,
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CODEN: PIXXD2 WO 2000059908 A2 20001012, CAN 133:296443
(in English; 118 pp); (d) R. B. Moffett, C. A. Hart and J. Neil, J. Org.
We thank DST (New Delhi) for financial support. M. K.
and G. B. R. thank CSIR (New Delhi) and UGC (New Delhi)
respectively for their research fellowships.
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Chem., 1950, 15, 343; (e) J. Nichols and G. F. Bulbenko, Ger. Pat.,
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German; 80 pp); (f) T. K. Das and P. C. Dutta, Synth. Commun., 1976, 6,
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8 Due to a solubility problem with EtOH, we used DMSO or DMF as
the solvents for the tandem reactions.
(b) D. Nasipuri, A. Sarkar and S. K. Konar, J. Org. Chem., 1982, 47,
2840.
10 Stereochemistries of the tandem K/H products 5 were established using
NMR analysis, and were also based on X-ray crystallography.
11 We did not measure the enantiomeric purity of the hydrogenated
products 5 and 8, because the hydrogenation reaction of olefin 9 with
Hantzsch ester 3 was uncatalyzed (see ref. 5e).
9 (a) J. A. Marshall and R. D. Carroll, J. Org. Chem., 1965, 30, 2748;
1646 | Org. Biomol. Chem., 2006, 4, 1641–1646
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