Direct amino acid-catalyzed cascade reductive alkylation of arylacetonitriles: High-yielding synthesis of ibuprofen analogs

Article abstract of DOI:10.1016/j.tetlet.2010.07.131

A novel approach for a one-pot, three-component reductive alkylation (TCRA) reaction of arylacetonitriles-containing electron-withdrawing groups with aldehydes/ketones and 1,4-dihydropyridine via iminium-catalysis has been developed. Many TCRA reaction products have direct applications in agricultural and pharmaceutical chemistry.

Full text of DOI:10.1016/j.tetlet.2010.07.131

Tetrahedron Letters 51 (2010) 5246–5251
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Tetrahedron Letters
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Direct amino acid-catalyzed cascade reductive alkylation of
arylacetonitriles: high-yielding synthesis of ibuprofen analogs
*
Dhevalapally B. Ramachary , M. Shiva Prasad
School of Chemistry, University of Hyderabad, Central University (PO), Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach for a one-pot, three-component reductive alkylation (TCRA) reaction of arylacetonitr-
iles-containing electron-withdrawing groups with aldehydes/ketones and 1,4-dihydropyridine via imin-
ium-catalysis has been developed. Many TCRA reaction products have direct applications in agricultural
and pharmaceutical chemistry.
Received 25 April 2010
Revised 14 July 2010
Accepted 22 July 2010
Available online 27 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
Cascade reactions
Ibuprofen analogs
Organocatalysis
TCRA reactions
1. Introduction
organocatalysis approach to the reductive alkylation of less reactive
arylacetonitriles 1 with 2 and 3.5
2-Arylpropionic acids are an important class of compounds,
which are present in a wide variety of biologically active compounds
and are widely used as intermediates in the synthesis of non-steroi-
dal anti-inflammatory drugs (NSAIDs) (Scheme 1).1 Therefore, the
development of new and more general cascade methods for the syn-
thesis of novel NSAIDs is of significant interest.2
First we focused on the optimization for high-yielding synthesis
of 2-(4-nitro-phenyl)-3-phenyl-propionitrile 6aa from 1a, 2a, and
3a–c through amine- or amino acid 4-/self-catalysis, by studying
the effect of catalyst 4, solvent, temperature, and hydrogen donor
ability of 3a–c in the designed TCRA reactions. Interestingly, in
L-proline 4a-/self-catalyzed cascade TCRA reaction of (4-nitro-phe-
As part of our research program to engineer direct multi-catalysis
cascade (MCC) reactions,3,4 we have discovered a metal-free meth-
odology for the reductive alkylation5 of arylacetonitriles 1 contain-
ing an electron-withdrawing groups with aldehydes/ketones 2 and
1,4-dihydropyridines 3 by using amino acid-catalyzed cascade
three-component reductive alkylation (TCRA) reactions via imini-
um- and self-catalysis in one-pot (Scheme 2). We propose that, in
the first step the catalyst (S)-4a activates component 2 by iminium
ion formation, which then selectively adds to arylacetonitriles 1
via a Mannich and retro-Mannich type reaction to generate active
olefin 5. This is followed by bio-mimetic hydrogenation of active ole-
fin 5 by organic-hydrides 3 to produce 6 through self-catalysis by
decreasing HOMO–LUMO energy gap between 3 and 5, respec-
tively.5 Further treatment of 6 with an acid would lead to 2-aryl-3-
aryl-propionic acids or 2-aryl-3-alkyl-propionic acids 7 as shown
in Scheme 2. In this Letter, for the first time we report the soft- or
nyl)-acetonitrile 1a and benzaldehyde 2a with 1.0 equiv of Hantzsch
ester 3a in ethanol at 25 °C for 48 h, neither the expected product
6aa, nor the olefination product 5aa was obtained. But the same
TCRA reaction in ethanol at 70 °C for 12 h furnished the expected
TCRA product 6aa with 75% yield (Table 1, entries 1 and 2). The TCRA
reaction of 1a and 2a with 1.5 equiv of 3a under 4a-/self-catalysis in
ethanol at 70 °C for 12 h furnished the expected product 6aa with
improved (82%) yield (Table 1, entry 3). Interestingly, the TCRA reac-
tion of 1a and 2a with 1.5 equiv of 3a under 4a-/self-catalysis in
DMSO at 25 °C for 20 h furnished the expected product 6aa in 80%
yield (Table 1, entry 5). L-Proline-/self-catalyzed cascade TCRA reac-
tion of 1a and 2a with 1.5 equiv of in situ generated organic hydride
source, 2-phenyl-2,3-dihydro-1H-benzoimidazole 3b in ethanol at
70 °C for 12 h furnished the expected TCRA product 6aa in only
50% yield (Table 1, entry 6). L-Proline-/self-catalyzed cascade TCRA
reaction of 1a and 2a with 1.5 equiv of 2,6-dimethyl-3,5-diacetyl-
1, 4-dihydropyridine 3c in ethanol at 70 °C for 15 h furnished the
expected product 6aa with 75% yield, but the same cascade reaction
in DMSO at 25 °C for 24 h furnished the expected product 6aa with
80% yield (Table 1, entries 7 and 8). To the best of our knowledge, this
is the first time that 3c has been used as organic-hydride in
* Corresponding author. Tel.: +91 40 23134816.
E-mail addresses: ramsc@uohyd.ernet.in, buchiramachary@hotmail.com (D.B.
Ramachary).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.131

D. B. Ramachary, M. Shiva Prasad / Tetrahedron Letters 51 (2010) 5246–5251
5247
Scheme 1. Pharmaceutically attractive NSAIDs generated from 2-arylpropionic acids and 2-aryl-3-alkyl-propionitriles.
ingly we observed that the sequential one-pot reaction of 1a, 2a,
and 3c in DMSO at 25 °C for 24 h furnished the 6aa with reduced
(58%) yield compared to cascade reaction. This may be due to the ab-
sence of self-catalytic nature of 3c in sequential TCRA reaction (entry
9).5a The optimum conditions (Table 1, entries 3, 5, and 8) involved
the use of catalyst 4a in cascade TCRA reaction of 1a, 2a, and 3a or
3c in EtOH or DMSO at 25/70 °C to furnish 6aa in very good yield.6
We then proceeded to investigate the synthesis of 6aa from 1a,
2a, and 3c through amine- or amino acid 4-/self-catalysis, by look-
ing at the structural effect of catalyst 4 in DMSO at 25 °C for 24 h
(Table S1, see Supplementary data). As shown in Table S1, amino
acid glycine 4b furnished the product 6aa in good yield (71%)
compared to amine catalysts.
We then decided to investigate the scope and limitations of the
TCRA reaction of a range of C–H source molecules 1a–h with alde-
hydes/ketones 2a–t and 3c under L-proline 4a-/self-catalysis at 25–
70 °C in EtOH or DMSO (Tables 2 and 3). As shown in Table 2, reac-
tion of (2-nitro-phenyl)-acetonitrile 1b with 2a and 1.5 equiv of 3c
under the 4a-catalysis in EtOH at 70 °C for 48 h furnished the sin-
gle olefin derivative (Z)-5ba in 95% yield instead of the expected
6ba (entry 1). The reaction with 4-cyanomethyl-benzoic acid
methyl ester 1c also furnished the single olefin derivative (Z)-5ca
as major product instead of expected 6ca from the reaction of 1c,
2a, and 3c (entry 2). Similar results were obtained from the reac-
tion of 1b–c, 2a, and 3c under 4a-catalysis in DMSO at 25 °C for
24 h (results not shown in Table 2). The formation of olefins (Z)-
5ba–ca instead of expected alkylation products 6ba–ca from TCRA
reactions could be explained based on the steric/electronic factors
and also based on the HOMO–LUMO energy gap between 5 and
3c.7,5 Interestingly, reaction of 4-cyanomethyl-benzonitrile 1d
with 2a and 1.5 equiv of 3c in EtOH at 70 °C for 24 h furnished
Scheme 2. Cascade TCRA approach to 2-aryl-3-alkyl-propionitriles.
organo-catalytic cascade reactions. 3c has proved to be a better
organic-hydride compared to 3a due to the easy separation of polar
by-product pyridine 3c0 from the crude reaction mixture. Interest-
Table 1
Preliminary optimization of cascade TCRA reactionsa
Entry
Solvent (0.5 M)
Organic-hydride (equiv)
Temperature (T)/°C
Time (h)
Yield 6aab (%)
1
2
3
4
5
6
7
8
9c
EtOH
EtOH
EtOH
DMF
DMSO
EtOH
EtOH
DMSO
DMSO
3a (1)
3a (1)
25
70
70
70
25
70
70
25
25
48
12
12
16
20
12
15
24
24
—
75
82
70
80
50
75
80
58
3a (1.5)
3a (1.5)
3a (1.5)
3b (1.5)
3c (1.5)
3c (1.5)
3c (1.5)
a
b
c
All reactants 1a, 2a, 3a–c, and catalyst 4a were mixed at the same time in solvent and stirred at 25–70 °C.
Yield refers to the column-purified product.
Reaction is performed in sequential manner.

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D. B. Ramachary, M. Shiva Prasad / Tetrahedron Letters 51 (2010) 5246–5251
Table 2
Chemically diverse libraries of cascade TCRA products 6ba–haa
Entry
1
Ar-CH2–CN (0.5 mmol)
Products 5 or 6
Temperature T/°C
Time (h)
48
Yield 5 or 6b (%)
5ba (95)
70
2
3
70
70
24
24
5ca (90)
6da (50)
4
5
70
25
48
5ea (—)
6fa (99)
3
6
7
25
70
5
6ga (98)
6ha (81)
24
a
All reactants 1b–h, 2a, 3c, and catalyst 4a were mixed at the same time in EtOH and stirred at 25–70 °C.
Yield refers to the column-purified product.
b
the expected product 6da in 50% yield (entry 3). Unfortunately, the
reaction of phenylacetonitrile 1e with 2a and 3c did not furnish the
expected 6ea or the olefin 5ea as shown in entry 4, Table 2. Forma-
tion of selective (Z)-olefins 5aa–da from 1a–d and 2a was con-
firmed by conducting two-component reaction of 1a–d and 2a
under proline-catalysis at two different optimized conditions
[EtOH, 70 °C for 11–48 h or DMSO, 25 °C for 11–71 h] to furnish
the (Z)-olefins 5 in very good yields as shown in Table S2 (see Sup-
plementary data). Regiochemistry of (Z)-olefins 5 was confirmed
by X-ray crystal structure analysis on 5aa as shown in Figure S1
(see Supplementary data).8 Reaction of 3-oxo-3-phenyl-propioni-
trile 1f with 2a and 3c under 4a-/self-catalysis in EtOH at 25 °C
for 3 h furnished the product 6fa in 99% yield as shown in entry
5, Table 2. The generality of the TCRA reactions was further con-
firmed by two more examples using different C–H source 1g–h
with 2a and 3c to furnish the expected products 6ga in 98% yield
and product 6ha in 81% yield, respectively as shown in Table 2.
The structure and stereochemistry of substances 5–6 were con-
firmed by NMR analysis and also by mass analysis. This one-pot
TCRA methodology may be suitable for developing a large number
of diverse-compounds of 5 or 6 as intermediates for NSAIDs.
The results in Table 3 demonstrate the broad scope of this
reductive methodology covering a structurally diverse group of
aldehydes 2a–r and less reactive ketones 2s–t.2 Interestingly, a
large number of derivatives of 2-(4-nitro-phenyl)-3-aryl-propioni-
trile 6 are not known and the present methodology gives a protocol

D. B. Ramachary, M. Shiva Prasad / Tetrahedron Letters 51 (2010) 5246–5251
5249
Table 3
Chemically diverse libraries of cascade TCRA products 6aa–ara
80% (6aa)
93% (6ab)
91% (6ac)
70% (6ad)
75% (6ae)
75% (6af)
70% (6ag)b
90% (6ah)
91% (6ai)
90% (6aj)
95% (6ak)
76% (6ao)
70% (6al)
70% (6am)
81% (6an)
50% (6ap)
76% (6aq)
60% (6ar)
85% (5as)
70% (5at)
a
Yield refers to the column-purified product.
Reaction time is 96 h.
b
to prepare them in good yields. A series of substituted aromatic
aldehydes 2a–n, hetero-aromatic aldehyde 2l, aliphatic aldehydes
2o–r, and ketones 2s–t were reacted with 1.0 equiv of (4-nitro-
phenyl)-acetonitrile 1a and organic-hydride 3c (1.5 equiv) cata-
lyzed by 20 mol % of proline 4a in DMSO at 25 °C for 24 h (Table
3). Interestingly, L-proline-/self-catalyzed TCRA reaction of 1a with
2-hydroxy-benzaldehyde 2g and 3c in DMSO at 25 °C took longer
reaction time (96 h) to generate the cascade product 6ag with
confirmed by three more examples using different aldehyde
sources 2p–r with 1a and 3c to furnish the expected TCRA products
6ap in 50% yield, 6aq in 76% yield, and product 6ar in 60% yield,
respectively, as shown in Table 3. Due to the many synthetic and
pharmaceutical applications of 2-(4-nitro-phenyl)-propionitrile
6ar, we further decided to investigate the improvement of the
yield of 6ar with TCRA reaction of 1a with 39% aqueous formalde-
hyde 2r and 3c at different conditions as shown in Table S3 (see
Supplementary data). We screened a TCRA reaction of 1a with
1 equiv of 39% aqueous formaldehyde 2r and 1.5 equiv of 3c under
the amino acid 4a–b-/self- or amine 4c–h-/self-catalysis in various
solvents at 25 °C. But unfortunately none of the conditions gave
better results compared to 4a-/self-catalysis in DMSO at 25 °C for
24 h as shown in Table 3. Interestingly, when we used the 1.5 equiv
of aqueous formaldehyde 2r in TCRA reaction of 1a and 3c with 2r,
we couldn’t find the product formation of 6ar, that may be due to
70% yield (Table 3). But the same L-proline-/self-catalyzed TCRA
reaction of 1a, and 3c with 2-bromo-benzaldehyde 2k at 25 °C in
DMSO furnished the expected TCRA product 6ak within 24 h as
shown in Table 3.
TCRA reaction of 1a with 3-phenylpropionaldehyde 2o and 3c
under 4a-/self-catalysis for 24 h in DMSO furnished the expected
alkylated product 6ao in 76% yield. Generality of the 4a-/self-cata-
lyzed cascade TCRA reactions with aliphatic aldehydes was further

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D. B. Ramachary, M. Shiva Prasad / Tetrahedron Letters 51 (2010) 5246–5251
2. General experimental procedures for the TCRA reactions:
proline-catalyzed cascade TCRA reactions
In a glass vial equipped with a magnetic stirring bar, to
0.5 mmol of arylacetonitrile 1, 0.5 mmol of the aldehyde/ketone
2 and 0.75 mmol of 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine
3c was added 1.0 mL of DMSO, followed by the catalyst amino acid
4a (0.1 mmol). The reaction mixture was stirred at 25 °C for the
time indicated in Tables 1–3. The crude reaction mixture was
worked up with aqueous NH4Cl solution and the aqueous layer
was extracted with dichloromethane (2 ꢀ 20 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated. Pure
TCRA products 6 were obtained by column chromatography [silica
gel, mixture of hexane/ethylacetate (90/10)].
Scheme 3. Applications of cascade TCRA reactions.
3. H2SO4-Catalyzed hydrolysis reactions of 6
A solution of substituted 2-aryl-propionitrile 6 (0.5 mmol) and
H2SO4 (1.5 mL, 50%) in 1, 4-dioxane solvent (1.0 mL) was stirred at
100 °C for 24 h. The reaction mixture was cooled and aqueous layer
was made basic with 1 N aqueous NaOH and then un-reacted start-
ing materials were extracted with CH2Cl2 (2 ꢀ 5 mL). Then the aque-
ous layer was acidified with 10% H2SO4 and the compound was
extracted with CH2Cl2 (3 ꢀ 10 mL). The combined in CH2Cl2 extract
was washed with brine and dried (anhydrous Na2SO4). Evaporation
of the solvent afforded the pure 2-arylpropionic acids 7.
Many of the TCRA products 6 and 7 are commercially available
or have been synthesized previously, and their analytical data
match literature values; and new compounds were characterized
on the basis of IR, 1H and 13C NMR, and analytical data (see Supple-
mentary data).
the presence of more water in the reaction (Table S3, see Supple-
mentary data). TCRA products 6aa–ar and analogs are very impor-
tant intermediates for the synthesis of NSAIDs (A–D) and their
drug-analogs.1 Recently, Jones and co-workers reported the asym-
metric synthesis of (R)-aminoglutethimide C (useful as treatment
for the hormone-dependent breast cancer) from key intermediate
6ap, which was prepared in three-steps starting from 1-chloro-4-
nitrobenzene with <40% overall yield.1d Utilizing the presently
developed TCRA method, we produced the drug intermediate 6ap
in 50% yield in a single step as shown in Table 3 and Scheme 3.
As shown in Table 3, TCRA reaction of (4-nitro-phenyl)-acetoni-
trile 1a with 3.0 equiv of acetone 2s and 1.5 equiv of 3c under the
4a-/self-catalysis in DMSO at 25 °C for 24 h furnished the olefin
derivative 5as in 85% yield instead of expected 6as (entry 19).
Same TCRA reaction of 1a, 3c (1.5 equiv) with 1.5 equiv of cyclo-
hexanone 2t also furnished the olefin derivative 5at as major prod-
uct instead of expected 6at (entry 20). Formation of intermediate
olefins 5as–at instead of expected alkylation products 6as–at from
TCRA reactions could be explained based on the steric and elec-
tronic factors.5
Acknowledgments
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi [Grant No.: DST/SR/S1/
OC-65/2008]. M.S.P. thanks CSIR (New Delhi) for his research
fellowship.
Based on the demand of pharmaceutical applications, we fur-
ther extended the TCRA products 6 into more useful intermediates
7 as shown in Scheme 3. Hydrolysis products 7 were obtained in
very good yields with high selectivity and purity without column
purification through acid-catalysis on 6 as shown in Scheme 3. This
method will be showing much impact on the synthesis of 2-aryl-
propionic acids 7. Compounds 7 have gained importance in recent
years as intermediates for the synthesis of NSAIDs.1 Hydrolysis of
6aa under 30 mol % of H2SO4-catalysis furnished the 2-(4-nitro-
phenyl)-3-phenyl-propionic acid 7aa in 75% yield as shown in
Scheme 3. Generality of the H2SO4-catalyzed hydrolysis of 6 was
further confirmed by two more examples using 6ap and 6ar to fur-
nish the expected 7ap in 95% yield and 7ar in 97% yield, respec-
tively as shown in Scheme 3. For the pharmaceutical
applications, high-yielding synthesis of diversity-oriented library
of substituted 2-arylpropionic acids 7 could be generated by using
our two-step sequence of proline-/self-catalyzed TCRA reaction fol-
lowed by H2SO4-catalyzed hydrolysis reaction.
In summary, we have developed a direct amino acid-/self-cata-
lyzed cascade TCRA reactions of arylacetonitriles 1 containing elec-
tron withdrawing groups with aldehydes 2 and organic-hydride 3c,
which has direct applications in drug discovery process. Also we
have developed the two-step sequence to synthesize 2-arylpropi-
onic acids 7 with very good yields, which are useful as NSAIDs. Fur-
ther work is in progress to utilize novel cascade TCRA products 6 as
starting materials for the development of asymmetric cascade Mi-
chael-aldol reactions.
A. Supplementary data
General experimental procedures, compound characterization,
X-ray crystal structure and analytical data (IR, 1H NMR and 13C
NMR) for all new compounds. Copies of the 1H NMR and 13C
NMR spectra of all new compounds. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.07.131.
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8. CCDC-774736 for 5aa contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336 033; or
mailto:deposit@ccdc.cam.ac.uk.