Highly anti-selective one-pot multicomponent synthesis of Mannich-type N-acylated β-amino acid derivatives by copper or sodium salt catalysis

Article abstract of DOI:10.1080/00397911.2010.537008

A stereo-defined process has been developed for the synthesis of Mannich-type products using readily available copper sulfate or sodium chloride as catalyst. Good to excellent diastereoselectivity has been achieved for a broad array of substrates. The obs

Full text of DOI:10.1080/00397911.2010.537008

This article was downloaded by: [University of Missouri Columbia]
On: 25 February 2013, At: 07:17
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Highly Anti-Selective One-Pot
Multicomponent Synthesis of Mannich-
Type N-Acylated β-Amino Acid
Derivatives by Copper or Sodium Salt
Catalysis
D. Bahulayan a , V. S. Shinu a , P. Pramitha a , S. Arun a & B. Sheeja b
a Department of Chemistry, University of Calicut, Malappuram,
Kerala, India
b Department of Chemistry, National University of Singapore,
Singapore
Accepted author version posted online: 13 Oct 2011.Version of
record first published: 22 Dec 2011.
To cite this article: D. Bahulayan , V. S. Shinu , P. Pramitha , S. Arun & B. Sheeja (2012): Highly Anti-
Selective One-Pot Multicomponent Synthesis of Mannich-Type N-Acylated β-Amino Acid Derivatives
by Copper or Sodium Salt Catalysis, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:8, 1162-1176
To link to this article: http://dx.doi.org/10.1080/00397911.2010.537008
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 1162–1176, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.537008
HIGHLY ANTI-SELECTIVE ONE-POT
MULTICOMPONENT SYNTHESIS OF MANNICH-TYPE
N-ACYLATED b-AMINO ACID DERIVATIVES BY
COPPER OR SODIUM SALT CATALYSIS
D. Bahulayan,1 V. S. Shinu,1 P. Pramitha,1 S. Arun,1 and
B. Sheeja2
1Department of Chemistry, University of Calicut, Malappuram, Kerala, India
2Department of Chemistry, National University of Singapore, Singapore
GRAPHICAL ABSTRACT
Abstract A stereo-defined process has been developed for the synthesis of Mannich-type
products using readily available copper sulfate or sodium chloride as catalyst. Good to
excellent diastereoselectivity has been achieved for a broad array of substrates. The observed
diastereoselectivity is explained on the basis of the steric interaction between the acyloxy
group of the aldehyde carbon and the more hindered a-substituted enolate anion. This steric
interaction helps the addition to take place through the less-hindered face to produce the
anti-isomers predominantly.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Amido ketone; common salt; Mannich-type; multicomponent reaction;
stereoselectivity
INTRODUCTION
The traditional chemical industry was hazardous and polluting. It generated
stoichiometric amounts of waste, causing much pollution of both air and water.
Today, the escalating costs of petrochemicals and increasing energy and raw material
consumption are forcing a change. As a consequence, the industry demands from
chemists the development of new reaction methodologies to obtain novel compounds
Received October 4, 2010.
Address correspondence to D. Bahulayan, Department of Chemistry, University of Calicut,
Malappuram 673635, Kerala, India. E-mail: bahulayan@yahoo.com
1162

MANNICH-TYPE N-ACYLATED b-AMINO ACID DERIVATIVES
1163
in a fast, clean, and efficient way.[1] In this scenario, multicomponent reactions
(MCRs) offer an alternative to the traditional synthesis mainly because they are
based on available starting materials, operationally simple, easily automatable,
resource effective, atom economical, and ecologically benign.[1b,2] Mannich-type
products, specifically b-amino carbonyl compounds, are useful chiral building blocks
for the synthesis of b-amino acids, b-lactams, b-amino alcohols, and so forth.[3]
These compounds are generally synthesized by chiral Lewis acids–assisted catalytic
asymmetric reactions of imines derived from aldehydes and amines with enolate
compounds. Several efficient Lewis acid–have been reported over the years,[4] and
a recent attraction in this field is the development of the concept of bifunctional
catalysis, wherein both partners of a bimolecular reaction are simultaneously acti-
vated, is very powerful for developing efficient asymmetric catalysts.[5] Even though
these chiral Lewis acids have proven to be efficient for many reactions, a major
drawback is that most Lewis acids are unstable in the presence of water, and some
of them are even moisture sensitive. Also, multistep reactions demand high synthetic
skill. As an efficient alternative to the synthesis of Mannich-type products, we and
other groups have developed a one-pot multicomponent protocol based on the coup-
ling of an aldehyde, an enolizable ketone, and a nitrile molecule in the presence of an
acid chloride and an acid catalyst.[6] Several efficient catalysts have been reported by
various research groups, including copper(II) tetrafluoroborate,[7a] SnCl4=SiO2,
[7b]
Cu(OTf)2 and Sc(OTf)3,[7c] Mn(bpdo)2Cl2=MCM-41,[7d] CeCl3 ꢀ 7H2O,[7e] ZrOCl2 ꢀ
8H2O,[7f] iron(III) chloride.[7g] (For a detailed list, see the supporting information.)
Approaches with stereocontrol are limited. Until recently, the scope of this
three-component process was limited to the synthesis of b-acetamido carbonyl com-
pounds. Recent developments in this area, particularly from our laboratory,[6b]
revealed that this process is highly useful for the one-step synthesis of highly functio-
nalized organic intermediates.
Our continuing interest is in developing this methodology as a novel route to
access highly functionalized structural scaffolds in a cost-effective and environmen-
tally friendly manner, and more importantly, as a process that requires less operational
skill and conditions. We considered the possibility of performing this reaction in very
mild conditions for the incorporation of a large variety of substrates. For this, we
.
decided to follow this reaction in the presence of salts such as NaCl and CuSO4 5H2O.
RESULTS AND DISCUSSION
We initiated our studies with the synthesis of the b-amino carbonyl compound
1a (Table 1). The sequential addition of benzaldehyde, ethyl methyl ketone and acetyl
chloride in the presence of sodium chloride or copper sulphate in acetonitrile resulted
in the rapid formation of 1a. With a very low amount of the salt (50 mg), the reaction
reached 70% conversion (with respect to the consumption of aldehyde and ketone)
within 10 minutes with a diastereoselectivity 90%. An identical reaction with
ammonium chloride afforded 1a in 15–23% yield with moderate stereoselectivity
(35:65). Here the nitrile source acted as both reagent and solvent. Many nitriles are
expensive and their uses in quantities at solvent level are not affordable. To overcome
this problem, we then examined the synthesis of 1a in solvents like chloroform and
dichloromethane with stoichiometric amounts of aldehyde, enolizable ketone, nitrile

1164

MANNICH-TYPE N-ACYLATED b-AMINO ACID DERIVATIVES
1165
source and acid chloride, and successfully isolated the desired b-amino acid deriva-
tives in comparable yield corresponding to that obtained from reactions carried out
with an excess amount of nitriles.
The reaction can be readily followed by Fourier transform—infrared (FT-IR)
spectroscopy by recording the disappearance of the aldehyde peak followed by the
appearance of amide peak at 1650 cmꢁ1. The structure of the product was confirmed
1
via H NMR, 13C NMR, FT-IR, and mass spectral studies. Stereochemistry was
assigned by comparing the J values of the methine proton with reported data.[6a]
The substrate scope of the reaction was demonstrated with various aldehydes
and ketones (Scheme 1, Tables 1–3). The reactions were generally conducted with
50 mg of sodium chloride or copper sulfate for 30 min. In general, variations in the sub-
stitution patterns on aldehyde and ketone units were well tolerated (Table 1). Aliphatic
aldehydes including a,b-unsaturated aldehydes such as crotonaldehyde were not good
substrates for the reaction. On the other hand, aromatic a,b-unsaturated aldehydes
such as cinnamaldehyde afforded the corresponding product in moderate yield
(Table 3, entry 8). We highlight here that the reactions carried out in the presence of
other acid chlorides resulted in the formation of desired products in satisfactory yield
(Table 2, entry 8). The only unmatched result was found in the reaction of cinnamoyl
chloride, which fails to produce the desired product. The outcome of the reaction was
observed to be a bit sensitive to the presence of polar substituent in substrates. Thus,
our studies with electron-withdrawing groups present in substrates such as nitrobenzal-
dehyde gave lower yields but maintained the anti-diastereoselectivity. Interestingly,
reactions of cyclohexanone were found to proceed in a controlled manner and, workup
with solvent mixtures afforded analytically pure products (Table 1, entries 3 and 4).
We subsequently investigated the reaction with various nitriles. Nitriles with
terminal double bonds were highly compatible and afforded a broad verity of amino
ketone derivatives (Table 2, entries 1–4). Use of other nitriles such as benzyl cyanide,
benzonitrile, valeronitrile, and propionitrile resulted in the formation of the title
compounds in moderate to good yields (Table 2, entries 5–10). Control reactions
done in the absence of acid chloride and catalyst failed to produce the b-amino acid
derivatives with all combination of substrates.
A possible catalytic cycle that illustrates formation of anti-selective Mannich-type
product is given in Scheme 2. The reaction is initiated by the complexation of the car-
bonyl oxygen of the ketone to the metal atom of the catalyst to produce a more steri-
cally hindered enolate anion 5 with a more nucleophilic a carbon. Subsequent reactions
of this metal enolate with aldehyde and acid chloride resulted in carbon–carbon bond
formation to produce a b-acyloxy ketone derivative 6. The steric interaction between
Scheme 1. Sodium chloride catalyzed anti-selective formation of b-amino carbonyl compound scaffolds.

1166

1167

1168

1169

1170

MANNICH-TYPE N-ACYLATED b-AMINO ACID DERIVATIVES
1171
Scheme 2. Proposed catalytic cycle for the anti-diastereoselective formation of b-amido carbonyl scaffolds
using sodium chloride or copper sulfate as catalyst.
the acyloxy group present in the aldehyde carbon and the more hindered a -substituted
enolate anion forces the addition to take place through the less hindered face to
produce 6 in the anti form. The acyloxy group in 6 is then displaced by nucleophilic
nitrogen of the nitrile to produce a stable cation intermediate 7. Addition of water
or other reactive species such as HOCl[8] formed during the reaction leads to the
formation of the anti-diastereomer 1 and closes the catalytic cycle.[6b]
CONCLUSIONS
In conclusion, we have developed an efficient multicomponent process to
access stereo-defined b-amino acid derivatives using readily available salts such as
sodium chloride or copper sulfate as catalyst. The new protocol is highly convenient
for the diastereoselective construction of scaffold diversity suitable for organic and
pharmaceutical chemistry. The simplicity, environmental acceptability, and cost-
effectiveness of this one-pot strategy makes it a practical alternative to the synthesis
of Mannich-type N-substituted amino acid derivatives.
EXPERIMENTAL
Typical Experimental Procedure for the Stereoselective One-Pot,
Three-Component Coupling Reactions of Aldehydes with
a-Substituted Ketones and Acetonitrile with Sodium Chloride
or Copper Sulfate as Catalyst (1a)
.
Powdered CuSO4 5H2O (0.050 g, 8 mol% by weight of benzaldehyde) was
added to an acetonitrile (4 mL) solution of benzaldehyde (0.265 g, 2.5 mmol), ethyl

1172
D. BAHULAYAN ET AL.
methyl ketone (0.180 g, 2.5 mmol), and acetyl chloride (1 mL) at room temperature.
The resulting mixture was stirred for 10 min. The reaction mixture was then poured
into distilled water and stirred well. The precipitate obtained was collected by
filtration, washed with distilled water (3 ꢂ 20 mL), and dried under vacuum. The
dried solid was then washed with diethyl ether (3 ꢂ 15 mL) and airdried to yield
1
the pure b-amino acid derivative 1a. H NMR analysis was used to determine the
diastereoselectivity of the reaction. The product was identified by comparing its
NMR and IR values with those for an authentic sample.[6b] Reactions of cyclohex-
anone required solvent workup or chromatography. The crude product obtained
from aqueous workup was purified by flash chromatography on silica gel (EtOAc=
petroleum ether, 1:8) to yield analytically pure products. similar procedure was
adopted for the purification of products obtained from other nitrile reactions.
Spectral Data
N-(1-(2-Bromophenyl)-3-oxo-3-phenylpropyl)acrylamide (2a). 1H NMR,
(400 MHz, DMSO-d6): d 8.00–7.97 (dd, J ¼ 5.6 and 7.6 Hz, 2H), 7.66–7.58 (m, 2H),
7.54–7.48 (m, 3H), 7.40–7.38 (dd, J ¼ 1.2 and 7.2 Hz, 1H), 7.22–7.20 (dd, J ¼ 2 and
8 Hz, 1H), 5.70–5.64 (m, 1H), 3.75–3.72 (t, 2H), 3.53–3.46 (dd, J ¼ 9.6 and 17.2 Hz,
1H), 2.59–2.56 (t, 2H); 13C NMR (100 MHz, DMSO-d6): d 196.27, 168.25, 141.76,
136.29, 133.35, 132.61, 128.91, 128.71, 128.04, 127.80, 122.19, 48.79, 43.29, 40.91,
40.12; FT-IR (KBr) c max 3298.64, 3065.30, 2962.13, 1682.59, 1649.80, 1595.81,
1549.52, 1438.64, 1406.82, 1384.64, 1356.68, 1231.33, 1019.19, 747.28, 689.42 cmꢁ1
MS m=z 358.1 (Mþ), 261.1.
;
N-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)acrylamide (2c). 1H NMR,
(400 MHz, DMSO-d6): d 8.55–8.53 (d, J ¼ 7.20 Hz, 1H), 7.98–7.96 (t, 2H),
7.66–7.62 (t, 1H), 7.54–7.49 (m, 3H), 7.44–7.41 (dd, 1H), 7.36–7.25 (m, 2H), 5.77 (s,
1H), 3.74–3.71 (t, 3H), 3.54–3.48 (t, 1H), 2.58–2.55 (t, 2H); 13C NMR (100 MHz,
DMSO-d6): d 196.40, 168.23, 140.13, 136.31, 133.32, 131.58, 129.31, 128.71, 128.68,
128.58, 128.02, 127.70, 127.29, 46.40, 43.17, 40.90, 40.12, 39.91, 39.71, 39.50, 39.29,
39.08, 38.87, 38.17; FT-IR (KBr) c max 3292.86, 3086.51, 2970.80, 1682.59,
1647.88, 1596.77, 1552.42, 1442.49, 1404.49, 1384.64, 1356.68, 1287.25, 1231.33,
1196.61, 1119.26, 748.24, 690.39, 614.21 cmꢁ1; MS m=z 314.1 (Mþ), 229.1.
N-(1-(2-Chlorophenyl)-3-(4-chlorophenyl)-3-oxopropyl)acrylamide (2d).
1H NMR, (400 MHz, DMSO-d6): d 8.55–8.53 (d, J ¼ 7.2 Hz, 1H), 8.00–7.98 (d,
J ¼ 8.4 Hz, 2H), 7.94–7.60 (d, 2H), 7.51–7.49 (dd, J ¼ 1.6 and 8 Hz, 1H), 7.44–7.41
(dd, J ¼ 1.2 and 8 Hz, 1H), 7.25–7.26 (m, 2H), 5.73–5.68 (m, 1H), 3.74–3.66 (dd,
J ¼ 6 and 12.8 Hz, 2H), 3.53–3.46 (dd, J ¼ 9.6 and 17.6 Hz, 1H), 2.58-2.55 (t, 2H);
13C NMR (100 MHz, DMSO-d6): d 195.54, 168.24, 139.98, 138.24, 134.99, 131.59,
129.98, 129.31, 128.79, 128.63, 127.31, 127.27, 46.37, 43.21, 40.88, 40.12; FT-IR
(KBr) c max 3285.14, 3088.44, 2973.70, 2911.99, 1685.48, 1648.84, 1590.02,
1552.42, 1440.56, 1401.03, 1357.64, 1281.47, 1230.36, 1094.40, 997.98, 813.81,
755.95 cmꢁ1; MS m=z 348.1 (Mþ) 346.1, 350.1, 277.1.
N-(1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl)acrylamide (2f). 1H NMR,
(400 MHz, DMSO-d6): d 8.63–8-61 (d, J ¼ 7.6 Hz, 1H), 8.09–8.07 (d, J ¼ 8 Hz, 1H),

MANNICH-TYPE N-ACYLATED b-AMINO ACID DERIVATIVES
1173
8.00–7.94 (m, 3H), 7.85–7.83 (d, J ¼ 8.4 Hz, 1H), 7.66–7.46 (m, 7H), 6.25–6.23
(d, 6 Hz, 1H), 3.76–3.73 (t, 2H), 3.66–3.60 (dd, J ¼ 8 and 17.6 Hz, 1H), 2.59–2.56
(t, 2H); 13C NMR (100 MHz, DMSO-d6): d 197.17, 168.10, 137.97, 137.95, 136.47,
133.42, 133.40, 133.32, 133.31, 133.30, 128.72, 128.68, 128.08, 128.05, 127.53,
126.36, 125.68, 123.19, 122.88, 45.09, 43.64, 40.94, 40.12, 39.92, 39.71; FT-IR
(KBr) c max 3283.21, 3062.41, 2969.84, 2904.27, 1683.55, 1649.80, 1596.77,
1551.45, 1447.31, 1359.57, 1272.79, 999.91, 801.27, 777.17, 755.95, 688.46 cmꢁ1
MS m=z 331.2 (M þ 1), 330.2 (Mþ), 229.1.
;
N-(1-(2-Bromophenyl)-3-oxo-3-phenylpropyl)-2-phenylacetamide (2i).
1H NMR, (400 MHz, DMSO-d6): d 8.64–8.62 (d, J ¼ 7.6 Hz, 1H), 8.00–7.97 (dd,
J ¼ 1.2 and 9.6 Hz, 2H), 7.67–7.62 (m, 1H), 7.59–7.50 (m, 3H), 7.44–7.36 (m, 1H),
7.35–7.32 (m, 1H), 7.28–7.18 (m, 6H), 5.66–5.63 (m, 1H), 3.54–3.51 (d, 10 Hz,
2H), 3.41 (s, 2H); 13C NMR (100 MHz, DMSO-d6): d 196.43, 169.29, 141.93,
136.32, 136.14, 133.34, 132.60, 128.89, 128.70, 128.08, 128.05, 127.84, 127.64,
126.25, 122.18, 48.80, 42.14, 40.10; FT-IR (KBr) c max 3297.68, 3061.44, 1680.66,
1655.59, 1547.59, 1447.31,1359.57, 1266.04, 1208.18, 1019.19, 752.10, 688.46 cmꢁ1
MS m=z 424.1 (M þ 2), 422.1 (Mþ), 229.1, 227.1.
;
N-(1-(2-Bromophenyl)-3-oxo-3-(4-acetoxyphenyl)propyl)benzamide (2j).
1H NMR, (400 MHz, DMSO-d6): d 8.89–8.87 (d, J ¼ 6.8 Hz, 1H), 8.08–8.06 (dd,
J ¼ 2 and 6.8 Hz, 2H), 7.83–7.81 (dd, J ¼ 1.2 and 8.4 Hz, 2H), 7.63–7.61 (dd,
J ¼ 1.2 and 8.0 Hz, 1H), 7.56–7.51 (m, 2H), 7.47–7.43 (dd, J ¼ 6.4 and 7.6 Hz, 2H),
7.39 (s, 1H), 7.29–7.27 (dd, J ¼ 2 and 6.8 Hz, 2H), 7.23–7.21 (dd, J ¼ 1.6 and
7.6 Hz, 1H), 5.88 (s, 1H), 3.81–3.74 (dd, J ¼ 10.4 and 17.6 Hz, 1H), 3.27–3.26 (d,
J ¼ 2.8 Hz, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 196.04, 169.52,
166.46, 154.92, 143.05, 134.94, 134.67, 133.34, 131.99, 130.48, 129.57, 128.94,
128.69, 128.42, 128.00, 122.86, 122.80, 49.92, 43.74, 40.84, 40.63, 40.42, 40.21,
21.58; FT-IR (KBr) c max 3312.14, 1753.94, 1684.52, 1637.27, 1600.63, 1531.20,
1383.68, 1305.57, 1213.97, 1163.83, 1015.34, 991.23, 748.24, 696.17 cmꢁ1; MS m=z
466.1 (Mþ), 261.1, 227.1.
N-(1-(2-Bromophenyl)-3-oxo-3-phenylpropyl)benzamide (2k). 1H NMR,
(400 MHz, DMSO-d6): d 8.94–8.87 (m, 1H), 8.09–7.90 (m, 2H), 7.82–7.80 (m, 2H),
7.73–7.59 (m, 2H), 7.57–7.49 (m, 4H), 7.45–7.37 (m, 2H), 7.35–7.25 (m, 1H),
7.21–7.17 (m, 1H), 5.90–5.73 (m, 1H), 3.80–3.72 (dd, J ¼ 10.8 and 18.0 Hz, 1H),
3.26–3.25 (d, J ¼ 2.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 197.08, 166.44,
143.09, 137.05, 134.94, 134.03, 133.34, 131.98, 129.57, 129.41, 128.94, 128.75, 128.
69, 128.44, 128.00, 122.80, 49.92, 43.78; FT-IR (KBr) c max 3327.57, 3055.66,
1686.44, 1634.38, 1578.45, 1529.27, 1354.75, 1230.36, 757.88, 693.28 cmꢁ1; MS m=
z 410.1 (Mþ), 409.1 (M-1), 229.1.
N-(1-(2-Chlorophenyl)-3-oxo-3-phenylpropyl)propionamide
(2o). 1H
NMR, (400 MHz, DMSO-d6): d 8.30–8.28 (d, J ¼ 7.6 Hz, 1H), 7.99–7.96 (dd,
J ¼ 0.8 and 8 Hz, 2H), 7.66–7.62 (m, 1H), 7.54–7.46 (m, 3H), 7.43–7.41 (dd,
J ¼ 1.6 and 8 Hz, 1H), 7.36–7.25 (m, 2H), 5.76 (s, 1H), 3.49–3.46 (d, J ¼ 9.6 Hz,
1H), 3.29–3.28 (d, J ¼ 4 Hz, 1H), 2.09–2.04 (dd, J ¼ 7.6 and 15.2 Hz, 2H),
0.96–0.92 (t, 3H); 13C NMR (100 MHz, DMSO-d6): d 196.59, 172.15, 140.58,
136.37, 133.30, 131.59, 129.31, 128.68, 128.49, 128.02, 127.58, 127.34, 46.16, 43.24,

1174
D. BAHULAYAN ET AL.
40.12, 28.32, 9.80; FT-IR (KBr) c max 3296.80, 3067.23, 2977.55, 2938.02, 1681.02,
1649.80, 1595.81, 1549.52, 1445.39, 1354.75, 1248.68, 1199.51, 754.03, 688.46 cmꢁ1
MS m=z 318.2 (M þ 2), 317.2 (M þ 1), 316.2 (Mþ).
;
N-(1-(Naphthalen-1-yl)-3-oxo-3-phenylpropyl)propionamide
(2p). 1H
NMR, (400 MHz, DMSO-d6): d 8.37–8.35 (d, J ¼ 7.6 Hz, 1H), 8.10–8.08 (d,
J ¼ 8.4 Hz, 1H), 8.00–7.97 (m, 2H), 7.96–7.94 (m, 1H), 7.84–7.82 (d, J ¼ 8 Hz, 1H),
7.66–7.62 (m, 1H), 7.59–7.46 (m, 6H); FT-IR (KBr) c max 3281.29, 3060.48,
2978.52, 2938.02, 1685.48, 1645.95, 1595.81, 1545.67, 1447.31, 1358.60, 1271.82,
1245.79, 802.24, 776.20, 755.95, 688.46 cmꢁ1; MS m=z 265.1 (M þ 2), 263.1, 229.1,
227.1, 219.2.
N-(1-Oxo-1,5-diphenylpent-4-en-3-yl)acetamide
(3 m). 1H
NMR,
(300 MHz, CDCl3): d 7.97–7.94 (d, J ¼ 7.5 Hz, 2H), 7.62–7.57 (t, 1H), 7.50–7.45 (t,
2H), 7.34–7.21 (m, 5H), 6.61–6.54 (t, 2H), 6.39–6.31 (dd, J ¼ 6.9 and 15.9 Hz,1H),
3.57–3.50 (dd, J ¼ 3.9 and 17.4 Hz, 1H), 3.39–3.32 (dd, J ¼ 5.1 and 17.4 Hz, 1H),
2.01 (s, 3H); FT-IR (KBr) c max 3286.11, 3059.51, 3027.69, 1686.44, 1644.98,
1541.81, 1447.31, 1371.14, 1290.14, 1225.54, 969.05, 757.88, 691.35 cmꢁ1; MS m=z
294.6 (Mþ), 250.5, 235.2, 176.4, 154.3, 136.3, 105.3.
REFERENCES
1. (a) Rothenberg, G. Catalysis: Concepts and Green Applications; Wiley-VCH: Weinheim,
2008; (b) Zhu, J., Bienayme, H., (Eds.); Multicomponent Reactions; Wiley-VCH: Weinheim,
2005.
2. For selected reviews, see (a) Bonne, D.; Coquerel, Y.; Constantieux, T.; Rodriguez, J.
1,3-Dicarbonyl compounds in stereoselective domino and multicomponent reactions.
Tetrahedron: Asymmetry 2010, 21, 1085–1109; (b) Toure, B. B.; Hall, D. G. Natural
product synthesis using multicomponent reaction strategies. Chem. Rev. 2009, 109, 4439–
4486; (c) Dotz, K. H.; Stendel Jr.J., Fischer carbene complexes in organic synthesis:
Metal-assisted and metal-templated reactions. Chem. Rev. 2009, 109, 3227–3274; (d)
Ganem, B. Strategies for innovation in multicomponent reaction design. Acc. Chem. Res.
2009, 42, 463–472; (e) Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Multiple multicom-
ponent macrocyclizations (mibs): A strategic development toward macrocycle diversity.
Chem. Rev. 2009, 109, 796–814; (f) Domling, A. Recent developments in isocyanide-based
multicomponent reactions in applied chemistry. Chem. Rev. 2006, 106, 17–89; (g) Domling,
A.; Ugi, I. Multicomponent reactions with isocyanides. Angew. Chem., Int. Ed. 2000, 39,
3169–3210; (h) Ramon, D. J.; Yus, M. Asymmetric multicomponent reactions (AMCRs):
The new frontier. Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (i) Orru, R. V. A.; De Greef,
M. Recent advances in solution-phase multicomponent methodology for the synthesis of
heterocyclic compounds. Synthesis 2003, 1471–1499; (j) Burke, M. D.; Schreiber, S. L. A
planning strategy for diversity-oriented synthesis. Angew. Chem., Int. Ed. 2004, 43, 46–58
(k) Hulme, C.; Gore, V. Multicomponent reactions: Emerging chemistry in drug discovery
from xylocain to crixivan. Curr. Med. Chem. 2003, 10, 51–80; (l) Simon, C.; Constantieux,
T.; Rodriguez, J. Utilisation of 1,3-dicarbonyl derivatives in multicomponent reactions.
Eur. J. Org. Chem. 2004, 4957–4980; (m) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathan, J. S.; Balagopal, L. Strategies for heterocyclic construction
via novel multicomponent reactions based on isocyanides and nucleophilic carbenes.
Acc. Chem. Res. 2003, 36, 899–907.

MANNICH-TYPE N-ACYLATED b-AMINO ACID DERIVATIVES
1175
3. (a) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric Catalysis, Supplement I; E. N.
Jacobsen, A. Pfalz, and H. Yamamoto (Eds.); Springer: Berlin, 2003; chapter 29.5 (b)
Kobayashi, S.; Ishitani, H. Catalytic enantioselective addition to imines. Chem. Rev.
1999, 99, 1069–1094; (c) Cordova, A. The direct catalytic asymmetric Mannich reaction.
Acc. Chem. Res. 2004, 37, 102–112.
4. (a) Schinzer, D. (Ed.). Selectivities in Lewis Acid Promoted Reactions; Kluwer Academic:
Dordrecht, the Netherlands, 1989; (b) Yamamoto, H. (Ed.). Lewis Acids in Organic
Synthesis; Wiley-VHC: Weinheim, Germany, 2000; (c) Kobayashi, S.; Salter, M. M.;
Yamazaki, Y.; Yamashita, Y. Chiral zirconium complex as Bronsted base catalyst in asym-
metric direct-type Mannich reactions. Chem. Asian J. 2010, 5, 493–495; (d) Poisson, T.;
Tsubogo, T.; Yamashita, Y.; Kobayashi, S. Asymmetric Mannich reaction of malonates
with imines catalyzed by a chiral calcium complex. J. Org. Chem. 2010, 75, 963–965; (e)
Matsubara, R.; Berthiol, F.; Nguyen, H. V.; Kobayashi, S. Catalytic Mannich-type reac-
tions of sulfonylimidates. Bull. Chem. Soc. Jpn. 2009, 82, 1083–1102; (f) Ishitani, H.; Ueno,
M.; Kobayashi, S. Enantioselective Mannich-type reactions using a novel chiral zirconium
catalyst for the synthesis of optically active b-amino acid derivatives. J. Am. Chem. Soc.
2000, 122, 8180–8186; (g) Ishitani, H.; Ueno, M.; Kobayashi, S. Catalytic enantioselective
Mannich-type reactions using a novel chiral zirconium catalyst. J. Am. Chem. Soc. 1997,
119, 7153–7154; (h) Wenzel, A. G.; Jacobsen, E. N. Asymmetric catalytic Mannich
reactions catalyzed by urea derivatives:/ Enantioselective synthesis of b-aryl-b-amino
acids. J. Am. Chem. Soc. 2002, 124, 12964–12965; (i) Josephsohn, N. S.; Snapper, M. L.;
Hoveyda, A. H. Ag-catalyzed asymmetric Mannich reactions of enol ethers with aryl, alkyl,
alkenyl, and alkynyl imines. J. Am. Chem. Soc. 2004, 126, 3734–3735.
5. For recent reviews, see (a) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Recent
progress in asymmetric bifunctional catalysis using multimetallic systems. Acc. Chem. Res.
2009, 42, 1117–1127; (b) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Power of
cooperativity: Lewis acid–Lewis base bifunctional asymmetric catalysis. Synlett 2005,
1491–1508; (c) Shibasaki, M.; Matsunaga, S. Design and application of linked-BINOL
chiral ligands in bifunctional asymmetric catalysis. Chem. Soc. Rev. 2006, 35, 269–279;
(d) Shibasaki, M.; Kanai, M. Catalytic enantioselective construction of tetrasubstituted
carbons by self-assembled poly-rare-earth-metal complexes. Org. Biomol. Chem. 2007, 5,
2027–2039; (e) Matsunaga, S.; Shibasaki, M. Multimetallic bifunctional asymmetric cataly-
sis based on proximity effect control. Bull. Chem. Soc. Jpn. 2008, 81, 60–75; (f) Shibasaki,
M.; Matsunaga, M.; Kumagai, N. Strategies for constructing diverse chiral environments in
multimetallic bifunctional asymmetric catalysis. Synlett 2008, 1583–1602; (g) Yamamoto,
H.; Futatsugi, K. ‘‘Designer acids’’: Combined acid catalysis for asymmetric synthesis.
Angew. Chem., Int. Ed. 2005, 44, 1924–1942 (h) Ma, J.; Cahard, D. Towards perfect
catalytic asymmetric synthesis: Dual activation of the electrophile and the nucleophile.
Angew. Chem., Int. Ed. 2004, 43, 4566–4583; (i) Taylor, M. S.; Jacobsen, E. N. Asymmetric
catalysis by chiral hydrogen-bond donors. Angew. Chem., Int. Ed. 2006, 45, 1520–1543.
6. (a) Bahulayan, D.; Das, S. K.; Iqbal, J. Montmorillonite K10 clay: An efficient catalyst for
the one-pot stereoselective synthesis of b-acetamido ketones. J. Org. Chem. 2003, 68, 5735–
5738; (b) Shinu, V. S.; Sheeja, B.; Purushothaman, E.; Bahulayan, D. An efficient green
MCR protocol for the stereoselective synthesis of b-acetamido ketones catalyzed by Select-
fluorTM. Tetrahedron Lett. 2009, 50, 4838–4842; (c) Rao, I. N.; Prabhakaran, E. N.; Das, S.
K.; Iqbal, J. Cobalt-catalyzed one-pot three-component coupling route to b-acetamido
carbonyl compounds: A general synthetic protocol for c-lactams. J. Org. Chem. 2003,
68, 4079–4082; (d) Maghsoodlou, M. T.; Hassankhani, A.; Shaterian, H. R.; Habibi-
Khorasani, S. M.; Mosaddegh, E. Zinc oxide as an economical and efficient catalyst for
the one-pot preparation of b-acetamido ketones via a four-component condensation reac-
tion. Tetrahedron Lett. 2007, 48, 1729–1734; (e) Khodaei, M. M.; Khosropour, A. R.;

1176
D. BAHULAYAN ET AL.
Fattahpour, P. A modified procedure for the Dakin–West reaction: An efficient and
convenient method for a one-pot synthesis of b-acetamido ketones using silica sulfuric acid
as catalyst. Tetrahedron Lett. 2005, 46, 2105–2108.
7. (a) Yadav, J. S.; Subba, R. B. V.; Shankar, K. S.; Premalatha, K. Copper(II) tetrafluoro-
borate as mild and versatile catalyst for the rapid synthesis of b-acetamido ketones and
ketoesters via a three-component reaction. Org. Commun. 2008, 1, 76–83; (b) Mirjalili, B.
B. F.; Hashemi, M. M.; Sadeghi, B.; Emtiazi, H. SnCl4=SiO2: An efficient heterogeneous
alternative for one-pot synthesis of b-acetamidoketones. J. Chin. Chem. Soc. 2009, 56,
386–391; (c) Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K. Synthesis of Mannich-type
products via a three-component coupling reaction. Tetrahedron Lett. 2005, 46 2137–
2140; (d) Heravi, M. M.; Daraie, M.; Behbahani, F. K.; Malakooti, R. Green and novel
protocol for one-pot synthesis of b-acetamido carbonyl compounds using Mn(bpdo)2Cl2=
MCM-41 catalyst. Synth. Commun. 2010, 40, 1180–1186; (e) Khan, A. T.; Choudhury, L.
H.; Parvin, T.; Ali, M. D. A. CeCl3 ꢀ 7H2O: An efficient and reusable catalyst for the prep-
aration of b-acetamido carbonyl compounds by multi-component reactions (MCRs).
Tetrahedron Lett. 2006, 47, 8137–8141; (f) Ghosh, R.; Maity, S.; Chakraborty, A.;
Chakraborty, S.; Mukherjee, A. K. ZrOCl2 ꢀ 8H2O: An efficient Lewis acid catalyst for
the one-pot multicomponent synthesis of b-acetamido ketones. Tetrahedron 2006, 62,
4059–4064; (g) Khan, A. T.; Parvin, T.; Choudhury, L. H. Iron(III) chloride–catalyzed
convenient one-pot synthesis of b-acetamido carbonyl compounds. Tetrahedron 2007, 63,
5593–5601
8. Liu, J.; Wong, C. H. An efficient method for the cleavage of p-methoxybenzylidene (PMP),
tetrahydropyranyl (THP), and 1,3-dithiane protecting groups by SelectfluorTM. Tetra-
hedron Lett. 2002, 43, 4037–4039.