Silica-supported boric acid with ionic liquid: A novel recyclable catalytic system for one-pot three-component mannich reaction

Article abstract of DOI:10.1248/cpb.59.639

A rapid and efficient silica-supported boric acid/ionic liquid ([β-mim][PF₆]), catalyzed, one-pot three-component Mannich reaction has been carried out to synthesize b-amino carbonyl compounds at room temperature. The reaction afforded desired

Full text of DOI:10.1248/cpb.59.639

May 2011
Regular Article
Chem. Pharm. Bull. 59(5) 639—645 (2011)
639
Silica-Supported Boric Acid with Ionic Liquid: A Novel Recyclable
Catalytic System for One-Pot Three-Component Mannich Reaction
Vishal KUMAR, Upendra SHARMA, Praveen Kumar VERMA, Neeraj KUMAR,* and Bikram SINGH
Natural Plant Products Division, Institute of Himalayan Bioresource Technology (Council of Scientific & Industrial
Research); Palampur, Himachal Pradesh–176 061, India.
Received December 24, 2010; accepted February 8, 2011; published online February 22, 2011
A rapid and efficient silica-supported boric acid/ionic liquid ([bmim][PF6]), catalyzed, one-pot three-compo-
nent Mannich reaction has been carried out to synthesize b-amino carbonyl compounds at room temperature.
The reaction afforded desired products in excellent yields with moderate to good diastereoselectivity. The method
provides a novel modification of three-component Mannich reaction in terms of mild reaction conditions, clean
reaction profiles, low amount of catalyst, recyclability of catalyst and a simple workup procedure. The present
report first time describes the preparation of H3BO3–SiO2 catalyst and its use with [bmim][PF6], to synthesize
Mannich products. The catalyst can be reused at least seven times.
Key words b-amino carbonyl compound; boric acid; ionic liquid; Mannich reaction; solid-supported catalyst
Developing new synthetic methods for the construction of action of 4-methoxybenzaldehyde, 4-nitroaniline and cyclo-
nitrogenous molecules1) has defined the frontiers of organic hexanone is very difficult. Hence, the development of a sim-
synthesis since its very beginning. The Mannich reaction is a ple, efficient, cost effective and nature friendly synthetic pro-
very useful platform for the development of nitrogen con- tocol applicable to a variety of substrates always remains a
taining molecules.2)
challenging task for the synthetic chemists.
Originally, this reaction produces b-amino carbonyl com-
Recently, ionic liquids (ILs), which combine the advan-
pounds from three-components, amine, aldehyde and ketone. tages of both traditional molecular solvents and melt salts,
These b-amino carbonyl compounds are used for the synthe- have been considered as promising new reaction media and
sis of amino alcohols, peptides, lactams and as precursors to have found wide use in catalytic and non-catalytic reactions.
synthesize amino acids. The vital importance of the Mannich Among the different Mannich type reactions reported ruthe-
products as useful precursors of pharmaceutical and natural nium complexes and ytterbium(III) triflate have been used as
products3) always boosted researchers to find out better catalysts in 1-butyl-3-methylimidazolium hexafluorophos-
process for their synthesis. The limitations4) associated with phate ([bmim][PF6]).36,37) Mannich reaction using Bronsted
the classical Mannich type reactions such as drastic reaction acid ionic liquids as catalysts and solvent have also been re-
conditions, long reaction time with low yields and formation ported.38,39) However, low yield, use of toxic metal complexes
of undesired side products, have induced numerous modern and applicability to limited variety of substrates, limit the
versions5) of the reaction. These improved methodologies are scope of these methods.
mainly based on two-component reactions where the imine
In this context, a new rapid and environment friendly
as electrophile was pre-formed and reacted with stable nucle- method has been developed for diastereoselective synthesis
ophiles such as enolates, enol ethers and enamines.6—13) of Mannich products using recyclable heterogeneous
However, the preferable route is the use of a one-pot three- catalytic system, which is applicable to a large variety of
component setup rather than a two step that allows a wide substrates and overcomes the limitations of already reported
range of structure variations.14) Numbers of catalysts have protocols. Silica-supported boric acid (H3BO3–SiO2) has
been employed for classical Mannich reaction of aldehydes, been synthesized for the first time and its use with ionic
ketones and amines mainly involving acids like proline,15—17) liquid, [bmim][PF6] in catalytic amount for Mannich reac-
p-dodecyl benzenesulphonic acid (DBSA)18) and some Lewis tion has been studied. The catalytic system, H3BO3–SiO2ꢀ
acids.19—21) Other catalysts for the reaction include [bmim][PF6] (Silica-BA-IL) can be recycled for at least
Yb(OiPr)3,22) InCl3,23,24) lanthanide triflate25) in solvents like seven times without any considerable effect on the yield. The
dichloromethane and acetonitrile, siloxy serine organocata- catalytic combination showed moderate to good diastereose-
lysts,26) phosphorodiamidic acid,27) bromodimethylsulfonium lectivity.
bromide28) and boric acid/glycerol,29) 4-hydroxypyrroli-
dine,30) Trypsin,31) Yb/K heterobimetallic catalyst.32) Some
Experimental
General Methods Boric acid was purchased from Ranbaxy Chemicals
solid-supported catalysts have also been used such as
Ltd., India, Silica gel (60—120 mesh) used for catalyst preparation and sil-
ica gel (230—400 mesh) for column chromatography was purchased from
Sisco Research Laboratories Pvt. Ltd., India, TLC was performed on silica
gel 60 F254 plates and all other chemicals were purchased from Spectrochem,
Merck, Germany, and Sigma-Aldrich, U.S.A. and were used without further
purification. The IR spectrum of silica-supported boric acid was recorded on
Shimadzu FTIR 8400 S spectrometer. NMR spectra were recorded on a
Bruker Avance-300 spectrometer. Mass spectra were recorded on QTOF-
Micro of Waters Micromass. Melting points were determined on a Barnstead
34)
AlCl3–SiO2,33) HClO4–SiO2 and H2SO4–SiO2.35) However,
they often suffer from the drawbacks of long reaction times,
harsh reaction conditions, toxicity and difficulty in product
separation, which limits their use in the synthesis of complex
molecules. Some of the methods mentioned above are not ca-
pable of giving Mannich products from substrates having
strong electron-withdrawing group e.g. –NO2 on aldehyde or
amine. Also, the synthesis of Mannich products from the re- Electrothermal 9100. X-Ray diffraction (XRD) studies were carried out
∗ To whom correspondence should be addressed. e-mail: neerajnpp@rediffmail.com © 2011 Pharmaceutical Society of Japan

640
Vol. 59, No. 5
using Panalytical, D/Max-2500 X-Ray Diffractometer equipped with CuKa
radiation (lꢁ1.5418) employing a scanning rate of 0.02° sꢂ1. Si was used as
standard to determine the instrumental broadening and the (111) reflection
was analysed.
Preparation of Silica-Supported Boric Acid Boric acid (3.0 g) with
60 ml water was taken in a 250 ml round bottom flask and heated to 60—
80 °C. To this, silica gel (60—120 mesh, 27.0 g) was added gradually with
constant stirring and refluxed for 5 h. Water was evaporated under vacuum
and the residue was stirred at 100 °C for 6—7 h under vacuum to give free
flowing white powder. IR (KBr) cmꢂ1: 3400, 3221, 2260, 1345, 1200, 1100,
960, 875, 800 and 720.
Typical Procedure for the Synthesis of b-Amino Carbonyl Com-
pounds A mixture of aromatic aldehyde (1.0 mmol), aromatic amine
(1.0 mmol), cyclohexanone (3.0 mmol) and H3BO3–SiO2 (7.8 mg, 0.0125
mmol) was stirred in [bmim][PF6] (0.2 ml) at room temperature until the
completion of the reaction (as monitored by TLC). To the crude product,
ethyl acetate (5 ml) was added and washed repeatedly with water (3ꢃ5 ml).
The organic layer was dried over anhydrous Na2SO4 and solvent was evapo-
rated under vacuum. The oily products were subjected to column chromatog-
raphy over silica gel (230—400) with ethyl acetate : hexane (1 : 9) as eluent.
The solid products were crystallized directly from ethanol. The aquous lay-
ers were combined and dried under vacuum to afford catalyst H3BO3–SiO2
(Silica-BA-IL) which was reused without any further purification. The cata-
lyst can be used at least seven times without any considerable effect on
yield.
Recyclability of the Catalyst H3BO3–SiO2 catalyst together with ionic
liquid was recovered by addition of ethyl acetate (5 ml) to products and
washing with four equal volumes of water (5 ml each). The evaporation of
water under vacuum afforded H3BO3–SiO2 with ionic liquid which was
reused without any further purification. The catalyst can be used at least
seven times without any considerable effect on yield.
Spectral Data of Products. 2-[(Phenyl)(phenylamino)methyl]cyclo-
hexanone (4a) Eluent: ethyl acetate : hexane (1 : 9). Yield 95%. White
solid, mp 141—142 °C. Syn : anti (9 : 91); 1H-NMR (CDCl3, 300 MHz) d:
1.72—1.81 (m, 2H), 1.89—1.95 (m, 4H), 2.33—2.50 (m, 2H), 2.78—2.80
(m, 1H), 4.68 (d, 0.91H, Jꢁ6.9 Hz), 4.86 (d, 0.09H, Jꢁ3.7 Hz), 6.58 (d, 2H,
Jꢁ7.7 Hz), 6.67 (t, 1H, Jꢁ7.1 Hz), 7.11 (t, 2H, Jꢁ7.2 Hz), 7.23—7.27 (m,
1H), 7.34 (t, 2H, Jꢁ7.1 Hz), 7.41—7.43 (m, 2H). 13C-NMR (CDCl3,
75 MHz), anti isomer, d: 24.0, 28.2, 31.6, 42.1, 57.7, 58.4, 114.0, 117.9,
127.5, 127.9, 128.7, 129.4, 142.1, 147.6, 213.1. HR-MS (ESI) Calcd for
C19H22NO [MꢀH]ꢀ 280.3841, Found 280.3822.
2-[(4-Methoxyphenyl)(phenylamino)methyl]cyclohexanone (4b) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 94%. White solid, mp 134—136 °C.
100% anti; 1H-NMR (CDCl3, 300 MHz) d: 1.68—1.91 (m, 6H), 2.35—2.44
(m, 2H), 2.72—2.74 (m, 1H), 3.78 (s, 3H), 4.63 (d, 1H, Jꢁ7.1 Hz), 6.56 (d,
2H, Jꢁ7.6 Hz), 6.65—6.67 (m, 1H), 6.85—6.88 (m, 2H), 7.05—7.11 (m,
2H), 7.29—7.33 (m, 2H). 13C-NMR (CDCl3, 75 MHz), d: 27.4, 28.2, 31.5,
42.3, 56.0, 57.8, 58.0, 114.1, 114.3, 117.8, 128.7, 129.4, 134.0, 147.9,
159.1, 213.3. HR-MS (ESI) Calcd for C20H24NO2 [MꢀH]ꢀ 310.4101, Found
310.4102.
2-[(3-Bromophenylamino)(4-methoxyphenyl)methyl]cyclohexanone
(4c) Eluent: ethyl acetate : hexane (1 : 9). Yield 96%. Yellow oil. Syn : anti
(37 : 63); 1H-NMR (CDCl3, 300 MHz) d: 1.57—1.68 (m, 2H), 1.79—1.92
(m, 4H), 2.32—2.39 (m, 2H), 2.73 (m, 1H), 3.76 (s, 3H), 4.56 (d, 0.63H,
Jꢁ6.8 Hz), 4.71 (d, 0.37H, Jꢁ3.9 Hz), 4.86 (br s, 1H), 6.46 (d, 1H,
Jꢁ8.0 Hz), 6.72—6.75 (m, 2H), 6.84—6.87 (m, 2H), 6.90—6.92 (m, 1H),
7.25—7.29 (m, 2H). 13C-NMR (CDCl3, 75 MHz), anti isomer, d: 24.1, 28.3,
31.8, 42.2, 55.5, 56.7, 57.7, 112.6, 114.3, 116.7, 120.5, 123.4, 128.6, 130.7,
133.4, 149.3, 159.0, 213.1. HR-MS (ESI) Calcd for C20H23BrNO2 [MꢀH]ꢀ
389.3062, Found 389.3068.
6.75 (d, 2H, Jꢁ6.3 Hz), 7.07—7.10 (m, 1H), 7.14—7.19 (m, 2H), 7.23—
7.28 (m, 2H). 13C-NMR (CDCl3, 75 MHz), anti isomer, d: 20.3, 23.3, 27.8,
31.1, 41.7, 57.5, 58.2, 113.8, 127.1, 127.3, 127.5, 128.4, 129.5, 141.9,
145.0, 212.7. HR-MS (ESI) Calcd for C20H24NO [MꢀH]ꢀ 294.4107, Found
294.4069.
2-[(4-Nitrophenyl)(phenylamino)methyl]cyclohexanone (4f) Eluent:
1
ethyl acetate : hexane (1 : 9). Yield 98%. Yellow oil. Syn : anti (59 : 41); H-
NMR (CDCl3, 300 MHz) d: 1.52—1.97 (m, 6H), 2.24—2.39 (m, 2H),
2.76—2.79 (m, 1H), 4.53 (br s, 1H), 4.63 (d, 0.41H, Jꢁ5.1 Hz), 4.77 (d,
0.59H, Jꢁ4.0 Hz), 6.42 (d, 2H, Jꢁ7.9 Hz), 6.59—6.63 (m, 1H), 6.98—7.03
(m, 2H), 7.46—7.51 (m, 2H), 8.06—8.08 (m, 2H). 13C-NMR (CDCl3,
75 MHz), syn isomer, d: 25.1, 27.2, 29.3, 42.6, 56.4, 57.4, 114.2, 118.6,
123.8, 128.8, 129.4, 146.8, 147.3, 149.7, 210.7. HR-MS (ESI) Calcd for
C19H21N2O3 [MꢀH]ꢀ 325.3817, Found 325.3820.
2-[(4-Bromophenyl)(phenylamino)methyl]cyclohexanone (4g) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 96%. Yellow oil. Syn : anti (39 : 61);
1H-NMR (CDCl3, 300 MHz) d: 1.51—1.85 (m, 6H), 2.24—2.31 (m, 2H),
2.66—2.71 (m, 1H), 4.50 (d, 0.61H, Jꢁ6.2 Hz), 4.64 (d, 0.39H, Jꢁ3.7 Hz),
6.41—6.44 (m, 2H), 6.54—6.59 (m, 1H), 6.99 (t, 2H, Jꢁ6.8 Hz), 7.18—
7.19 (m, 2H), 7.32—7.35 (m, 2H). 13C-NMR (CDCl3, 75 MHz), anti isomer,
d: 24.6, 28.4, 32.1, 42.6, 57.8, 58.1, 114.2, 118.4, 121.4, 129.6, 129.7,
132.1, 141.5, 147.7, 212.9. HR-MS (ESI) Calcd for C19H21BrNO [MꢀH]ꢀ
359.2802, Found 359.2873.
2-[(4-Methoxyphenyl)(4-nitrophenylamino)methyl]cyclohexanone (4h)
Eluent: ethyl acetate : hexane (1 : 9). Yield 95%. Yellow solid, mp 63—65 °C.
Syn : anti (59 : 41); 1H-NMR (CDCl3, 300 MHz) d: 1.57—1.67 (m, 4H),
1.99—2.07 (m, 2H), 2.24—2.37 (m, 2H), 2.84 (s, 1H), 3.74 (s, 3H), 4.66 (d,
0.41H, Jꢁ5.6 Hz), 4.82 (s, 0.59H), 5.80 (br s, 1H), 6.50 (d, 2H, Jꢁ8.5 Hz),
6.82 (d, 2H, Jꢁ7.5 Hz), 7.24 (d, 2H, Jꢁ7.4 Hz), 7.95 (d, 2H, Jꢁ8.4 Hz). 13C-
NMR (CDCl3, 75 MHz), syn isomer, d: 25.0, 27.0, 29.2, 42.6, 55.5, 56.1,
56.8, 112.5, 114.5, 126.5, 128.9, 132.1, 138.2, 153.3, 159.3, 211.7. HR-MS
(ESI) Calcd for C20H23N2O4 [MꢀH]ꢀ 355.4077, Found 355.4054.
2-[(4-Methylphenylamino)(4-nitrophenyl)methyl]cyclohexanone (4i)
Eluent: ethyl acetate : hexane (1 : 9). Yield 98%. Yellow solid, mp 120—
1
122 °C. Syn : anti (34 : 66); H-NMR (CDCl3, 300 MHz) d: 1.63—1.82 (m,
3H), 1.95—2.06 (m, 3H), 2.19 (s, 3H), 2.34—2.41 (m, 2H), 2.86 (s, 1H),
4.74 (d, 0.66H, Jꢁ5.0 Hz), 4.87 (d, 0.34H, Jꢁ3.1 Hz), 6.46 (d, 2H,
Jꢁ7.0 Hz), 6.91 (d, 2H, Jꢁ7.5 Hz), 7.56—7.61 (m, 2H), 8.14 (d, 2H,
Jꢁ8.4 Hz). 13C-NMR (CDCl3, 75 MHz), anti isomer, d: 20.7, 24.8, 28.1,
32.2, 42.7, 57.4, 58.3, 114.1, 124.0, 127.9, 128.7, 130.0, 144.8, 147.4,
150.5, 212.1. HR-MS (ESI) Calcd for C20H23N2O3 [MꢀH]ꢀ 339.4083,
Found 339.4082.
2-[(3-Chlorophenylamino)(4-methylphenyl)methyl]cyclohexanone (4j)
Eluent: ethyl acetate : hexane (1 : 9). Yield 97%. White solid, mp 120—
122 °C; 1H-NMR (CDCl3, 300 MHz) d 1.62—1.80 (m, 3H), 1.90—2.07 (m,
3H), 2.36 (s, 3H), 2.44—2.48 (m, 2H), 2.80—2.82 (m, 1H), 4.61 (d, 1H,
Jꢁ6.7 Hz), 4.80 (br s, 1H, overlapped with proton signal of syn isomer),
6.48 (d, 1H, Jꢁ8.0 Hz), 6.59—6.68 (m, 2H), 6.98—7.04 (m, 1H), 7.15—
7.17 (m, 2H), 7.26—7.31 (m, 2H). 13C-NMR (CDCl3, 75 MHz), major iso-
mer, d: 21.5, 25.1, 27.3, 29.1, 42.7, 56.8, 57.3, 112.5, 114.1, 117.7, 127.8,
129.6, 130.4, 135.1, 137.1, 138.3, 149.2, 211.7. HR-MS (ESI) Calcd for
C20H23ClNO [MꢀH]ꢀ 328.8555, Found 328.8430.
5-[(4-Bromophenyl)(phenylamino)]pantan-3-one (6a) Eluent: ethyl
1
acetate : hexane (1 : 9). Yield 88%. Yellow oil; H-NMR (CDCl3, 300 MHz)
d: 0.99—1.04 (m, 3H), 2.36—2.40 (m, 2H), 2.90 (d, 2H, Jꢁ6.2 Hz), 4.42
(br s, 1H), 4.83 (t, 1H, Jꢁ6.2 Hz), 6.49—6.56 (m, 2H), 6.68—6.73 (m, 1H),
7.08—7.15 (m, 2H), 7.21—7.28 (m, 2H), 7.45—7.47 (m, 2H). 13C-NMR
(CDCl3, 75 MHz), d: 7.9, 37.4, 50.2, 54.5, 114.3, 118.6, 121.5, 128.6, 129.2,
131.9, 142.3, 147.1, 209.9. HR-MS (ESI) Calcd for C17H19BrNO [MꢀH]ꢀ
333.2429, Found 333.2339.
2-[(4-Chlorophenyl)(phenylamino)methyl]cyclohexanone (4d) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 98%. Yellow solid, mp 133—135 °C.
Syn : anti (26 : 74); 1H-NMR (CDCl3, 300 MHz) d: 1.71—1.81 (m, 3H),
1.92—1.97 (m, 3H), 2.34—2.41 (m, 2H), 2.77—2.82 (m, 1H), 4.63 (d,
0.74H, Jꢁ6.2 Hz), 4.77 (d, 0.26H, Jꢁ4.1 Hz), 6.53 (m, 2H), 6.64—6.69 (m,
1H), 7.09 (t, 2H, Jꢁ7.1 Hz), 7.27—7.36 (m, 4H). 13C-NMR (CDCl3,
75 MHz), anti isomer, d: 24.2, 27.4, 31.8, 42.4, 57.7, 57.8, 114.0, 118.3,
129.0, 129.4, 131.9, 140.7, 147.4, 212.7. HR-MS (ESI) Calcd for
C19H21NOCl [MꢀH]ꢀ 314.8289, Found 314.8299.
3-Methyl-4-[(4-bromophenyl)(phenylamino)]butan-2-one (7a) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 88%. Yellow oil. Syn : anti (37 : 63);
1H-NMR (CDCl3, 300 MHz), d: 1.17 (d, 3H, Jꢁ6.9 Hz), 2.03 (s, 3H), 4.48
(d, 0.63H, Jꢁ6.9 Hz), 4.65 (br s, 1H), 4.73 (d, 0.37H, Jꢁ5.0 Hz), 6.49—6.56
(m, 2H), 6.68—6.73 (m, 1H), 7.08—7.15 (m, 2H), 7.21—7.28 (m, 2H),
7.45—7.47 (m, 2H). 13C-NMR (CDCl3, 75 MHz), anti isomer, d: 15.7, 29.9,
53.7, 60.5, 114.3, 118.6, 121.5, 128.6, 129.2, 131.9, 142,3, 147.1, 212.5.
HR-MS (ESI) Calcd for C17H19BrNO [MꢀH]ꢀ 333.2429, Found 333.2339.
5-[(Phenyl)(phenylamino)]pantan-3-one (6b) Eluent: ethyl acetate :
hexane (1 : 9). Yield 81%. Yellow solid, mp 87—88 °C; 1H-NMR (CDCl3,
300 MHz) d: 1.04 (t, 3H, Jꢁ6.9 Hz), 2.38—2.39 (m, 2H), 2.95 (d, 2H), 4.40
(br s, 1H), 4.92 (t, 1H, Jꢁ5.8 Hz), 6.60—6.64 (m, 2H), 6.67—6.72 (m, 1H),
7.14—7.16 (m, 2H), 7.29—7.31 (m, 1H), 7.38—7.41 (m, 4H). 13C-NMR
(CDCl3, 75 MHz), d: 7.4, 36.9, 49.9, 54.5, 113.6, 117.5, 126.3, 127.3, 128.8,
2-[(4-Methylphenylamino)(phenyl)methyl]cyclohexanone (4e) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 97%. Brownish solid, mp 116—
1
117 °C. Syn : anti (32 : 68); H-NMR (CDCl3, 300 MHz) d: 1.50—1.79 (m,
6H), 2.05 (s, 3H), 2.21—2.27 (m, 2H), 2.72—2.74 (m, 1H), 4.32 (br s, 1H),
4.50 (d, 0.68H, Jꢁ7.1 Hz), 4.68 (d, 0.32H, Jꢁ2.25 Hz), 6.34—6.38 (m, 2H),

May 2011
641
129.1, 141.4, 146.9, 212.4. HR-MS (ESI) Calcd for C17H20NO [MꢀH]ꢀ Results and Discussion
254.3468, Found 254.3446.
Silica-supported heterogeneous catalysts have received
considerable attention as inexpensive and recyclable catalysts
for various organic transformations and in most of these cat-
alysts strong toxic acids are employed. Thus, in order to over-
come the above mentioned problems, we have first time
prepared a non-toxic catalyst, silica-supported boric acid
(H3BO3–SiO2) and it was characterized by X-ray diffraction
(XRD) and IR spectroscopy. The IR spectrum of prepared
H3BO3–SiO2 showed stretching and bending vibration bands
for borosiloxane linkage (Si–O–B) at 875 and 720 cmꢂ1,
respectively, and a band at 1345 cmꢂ1 was observed for
B–O stretching vibration of borosiloxane. The other bands
were observed at 3400 (SiO–Hstr), 3221 (BO–Hstr), 2260
(B–OHcombination), 1200 (B–OHbend), 1100 (Si–Ostr), 960
(Si–OHstr) and 800 (Si–O–Sibend) cmꢂ1. XRD pattern of
H3BO3–SiO2 (Fig. 1) showed only one broad peak at 2q ca.
22° which indicates the amorphous nature of catalyst. The
absence of reflection at 2q ca. 28° for free boric acid40,41) in-
3-Methyl-4-[(phenyl)(phenylamino)]butan-2-one (7b) Eluent: ethyl
acetate : hexane (1 : 9). Yield 81%. Yellow solid, mp 87—88 °C. Syn : anti
1
(46 : 54); H-NMR (CDCl3, 300 MHz) d: 1.15—1.20 (m, 3H), 2.05 (s, 3H),
3.00—3.07 (m, 1H), 4.57 (d, 0.55H, Jꢁ6.9 Hz), 4.74 (br s, 1H), 4.83 (d,
0.45H, Jꢁ3.8 Hz), 6.60—6.64 (m, 2H), 6.67—6.72 (m, 1H), 7.14—7.16 (m,
2H), 7.29—7.31 (m, 1H), 7.38—7.41 (m, 4H). 13C-NMR (CDCl3, 75 MHz),
anti isomer, d: 15.1, 29.3, 53.5, 60.5, 113.5, 117.7, 126.9, 127.3, 128.8,
129.1, 142.7, 146.9, 209.8. HR-MS (ESI) Calcd for C17H20NO [MꢀH]ꢀ
254.3468, Found 254.3446.
5-[(4-Methoxyphenyl)(phenylamino)]pantan-3-one (6c) Eluent: ethyl
acetate : hexane (1 : 9). Yield 84%. Yellow solid, mp 82—83 °C; 1H-NMR
(CDCl3, 300 MHz) d: 1.03 (t, 3H, Jꢁ7.0 Hz), 2.37 (q, 2H, Jꢁ7.0, 6.4 Hz),
2.92 (d, 2H, Jꢁ5.1 Hz), 3.79 (s, 3H), 4.67 (br s, 1H), 4.89 (t, 1H, Jꢁ5.9 Hz),
6.62—6.65 (m, 2H), 6.70—6.77 (m, 1H), 6.91 (d, 2H, Jꢁ7.6 Hz), 7.14—
7.18 (m, 2H), 7.24—7.35 (m, 2H). 13C-NMR (CDCl3, 75 MHz), d: 7.4, 36.8,
49.9, 53.8, 55.1, 113.7, 114.0, 117.6, 127.3, 129.0, 134.6, 146.9, 158.7,
209.8. HR-MS (ESI) Calcd for C18H22NO2 [MꢀH]ꢀ 284.3728, Found
284.3721.
3-Methyl-4-[(4-methoxyphenyl)(phenylamino)]butan-2-one (7c) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 84%. Yellow solid, mp 82—83 °C.
1
Syn : anti (28 : 72); H-NMR (CDCl3, 300 MHz) d: 1.17 (d, 3H, Jꢁ6.6 Hz),
2.07 (s, 3H), 2.98—3.00 (m, 1H), 3.79 (s, 3H), 4.53 (d, 0.72H, Jꢁ7.2 Hz), dicated that boron atoms are mainly engaged in the forma-
4.67 (br s, 1H), 6.62—6.65 (m, 2H), 6.70—6.77 (m, 1H), 6.91 (d, 2H,
tion of borosiloxane bridges in the catalyst. The borosiloxane
Jꢁ7.6 Hz), 7.14—7.18 (m, 2H), 7.24—7.35 (m, 2H). 13C-NMR (CDCl3,
linkage in catalyst was further confirmed by comparison with
75 MHz), anti isomer, d: 15.0, 29.0, 53.5, 59.8, 113.7, 114.0, 117.6, 127.3,
reported XRD pattern.40,41)
129.0, 134.6, 146.9, 158.7, 212.4. HR-MS (ESI) Calcd for C18H22NO2
[MꢀH]ꢀ 284.3728, Found 284.3721.
The catalytic efficiency of H3BO3–SiO2 catalyst was evalu-
ated by conducting a three-component model Mannich reac-
tion of benzaldehyde, aniline and cyclohexanone under dif-
ferent catalytic conditions such as boric acid, silica-gel and
H3BO3–SiO2 and also under catalyst free conditions (Table
1). The progress of reaction was studied by thin layer chro-
matography. The model reaction without catalyst under sol-
vent free condition afforded product in very low yield. When
boric acid, silica gel and boric acidꢀsilica gel were used as
catalysts under solvent free condition, the yield was not in-
creased even after a very long period of time (Table 1, entries
1—4). The reaction with H3BO3–SiO2 in absence of solvent
at room temperature, gave only 35% yield even after 12 h
(Table 1, entry 5). Therefore, in order to find out the effect of
temperature on yield, this reaction was carried out at elevated
temperatures i.e. 50, 80 and 120 °C with conventional as well
as microwave (MW) heating (Table 1, entries 6—11). At
50 °C, the yield was increased to 40% under conventional
heating, while at 80 and 120 °C, the yield was reduced and
other undesired byproducts were formed in all the six heating
conditions. The aldol condensation product was observed as
the major byproduct which was characterized by high resolu-
tion (HR)-MS and NMR analysis.
5-[(3-Bromophenylamino)(4-methoxyphenyl)]pantan-3-one (6d)
Eluent: ethyl acetate : hexane (1 : 9). Yield 82%. White solid, mp 81—82 °C;
1H-NMR (CDCl3, 300 MHz) d: 0.99 (t, 3H, Jꢁ7.2 Hz), 2.30—2.36 (m, 2H),
2.88 (d, 2H, Jꢁ6.0 Hz), 3.79 (s, 3H), 4.70 (br s, 1H), 4.77 (t, 1H, Jꢁ6.0 Hz),
6.47 (d, 1H, Jꢁ7.9 Hz), 6.71—6.72 (m, 1H), 6.78 (d, 1H, Jꢁ7.9 Hz), 6.85—
6.88 (m, 2H), 6.91—6.96 (m, 1H), 7.24—7.27 (m, 2H). 13C-NMR (CDCl3,
75 MHz), d: 7.5, 37.1, 49.7, 53.9, 55.3, 112.1, 114.3, 116.5, 120.5, 123.1,
127.4, 130.7, 134.0, 148.3, 159.0, 209.9. HR-MS (ESI) Calcd for
C18H21BrNO2 [MꢀH]ꢀ 363.2689, Found 363.2795.
1,3-Diphenyl-3-phenylaminopropan-1-one (8a) Eluent: ethyl
1
acetate : hexane (1 : 9). Yield 74%. White solid, mp 162—164 °C; H-NMR
(CDCl3, 300 MHz) d: 3.39—3.56 (m, 2H), 4.57 (br s, 1H), 5.01—5.03 (m,
1H), 6.58 (d, 2H, Jꢁ7.5 Hz), 6.65—6.70 (m, 1H), 7.10 (t, 2H, Jꢁ7.0 Hz),
7.25—7.27 (m, 1H), 7.34 (t, 2H, Jꢁ6.9 Hz), 7.45—7.47 (m, 4H), 7.55—
7.59 (m, 1H), 7.92 (d, 2H, Jꢁ7.3 Hz). 13C-NMR (CDCl3, 75 MHz), d: 46.4,
55.0, 114.0, 117.9, 126.5, 127.5, 128.3, 128.8, 128.9, 129.2, 133.5, 136.9,
143.1, 147.1, 198.4. HR-MS (ESI) Calcd for C21H20NO [MꢀH]ꢀ 302.3896,
Found 302.3883.
3-(4-Nitrophenyl)-1-phenyl-3-phenylaminopropan-1-one (8b) Eluent:
1
ethyl acetate : hexane (1 : 9). Yield 61%. Yellow solid, mp 104—106 °C; H-
NMR (CDCl3, 300 MHz) d: 3.41 (d, 2H, Jꢁ5.9 Hz), 4.59 (br s, 1H), 5.02 (t,
1H, Jꢁ5.8 Hz), 6.43 (d, 2H, Jꢁ7.7 Hz), 6.60 (t, 1H, Jꢁ7.2 Hz), 7.01 (t, 2H,
Jꢁ7.3 Hz), 7.33—7.38 (m, 2H), 7.45—7.54 (m, 3H), 7.81 (d, 2H,
Jꢁ7.6 Hz), 8.05 (d, 2H, Jꢁ8.2 Hz). 13C-NMR (CDCl3, 75 MHz), d: 45.4,
53.9, 113.5, 118.1, 123.7, 127.2, 127.8, 128.5, 128.9, 133.4, 136.1, 146.0,
146.9, 150.5, 196.9. HR-MS (ESI) Calcd for C21H19N2O3 [MꢀH]ꢀ
347.3872, Found 347.3825.
3-(4-Bromophenyl)-1-phenyl-3-phenylaminopropan-1-one (8c) Elu-
ent: ethyl acetate : hexane (1 : 9). Yield 58%. White solid, mp 138—140 °C;
1H-NMR (CDCl3, 300 MHz) d: 3.45—3.47 (m, 2H), 4.59 (br s, 1H), 5.00 (t,
1H, Jꢁ5.8 Hz), 6.57 (d, 2H, Jꢁ7.7 Hz), 6.71 (t, 1H, Jꢁ7.0 Hz), 7.13 (t, 2H,
Jꢁ7.3 Hz), 7.34—7.36 (m, 2H), 7.45—7.49 (m, 4H), 7.57—7.61 (m, 1H),
7.92 (d, 2H, Jꢁ7.5 Hz). 13C-NMR (CDCl3, 75 MHz), d: 46.1, 54.3, 114.0,
118.2, 121.1, 128.2, 128.3, 128.8, 129.3, 132.0, 133.6, 136.7, 142.2, 146.8,
197.9. HR-MS (ESI) Calcd for C21H19BrNO [MꢀH]ꢀ 381.2857, Found
381.2856.
1,3-Diphenyl-3-(4-methylphenylamino)propan-1-one (8d) Eluent:
1
ethyl acetate : hexane (1 : 9). Yield 76%. White solid, mp 164—166 °C; H-
NMR (CDCl3, 300 MHz) d: 2.20 (s, 3H), 3.43—3.50 (m, 2H), 4.43 (br s,
1H), 5.00 (t, 1H, Jꢁ6.0 Hz), 6.51 (d, 2H, Jꢁ7.4 Hz), 6.92 (d, 2H, Jꢁ7.6 Hz),
7.22—7.27 (m, 1H), 7.31—7.36 (m, 2H), 7.45—7.47 (m, 4H), 7.55—7.59
(m, 1H), 7.92 (d, 2H, Jꢁ7.6 Hz). 13C-NMR (CDCl3, 75 MHz), d: 20.5, 46.5,
55.2, 114.2, 126.5, 127.1, 127.4, 128.3, 128.8, 128.9, 129.7, 133.5, 136.9,
143.3, 144.8, 198.4. HR-MS (ESI) Calcd for C22H22NO [MꢀH]ꢀ 316.4162,
Found 316.4172.
Fig. 1. XRD Spectrum of H3BO3–SiO2

642
Vol. 59, No. 5
Table 1. Optimization of Reaction Conditions in Different Catalytic Sys-
temsa)
Table 3. Optimization of the Amount of Catalyst
Entry
Catalyst (mol%)
Yield (%)
Entry
Catalyst
Time (h)
Yield (%)b)
1
2
3
4
5
6
7
0.25
0.50
0.75
1.00
1.25
1.50
1.75
36
44
59
93
95
93
94
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Without catalyst
H3BO3
12
12
12
12
12
12
12
12
2
10
12
10
14
35
40
28
15
30
32
24
38
48
39
50
94
SiO2
H3BO3ꢀSiO2
H3BO3ꢂSiO2c)
H3BO3ꢂSiO2d)
H3BO3ꢂSiO2e)
H3BO3ꢂSiO2c, f )
H3BO3ꢂSiO2d, f )
H3BO3ꢂSiO2e, f )
H3BO3ꢂSiO2
ILg)
H3BO3ꢀIL
SiO2ꢀIL
H3BO3ꢀSiO2ꢀIL
H3BO3ꢂSiO2ꢀIL
anticipated that [bmim][PF6] is synergistically enhancing the
catalytic activity of H3BO3–SiO2.
2
2
Further, the amount of catalyst required for the reaction
was optimized (Table 3) by initially starting with 0.25 mol%
of catalyst and gradually increased the amount up to
1.75 mol%. It was observed that initially the yield increased
with the amount of catalyst and maximum yield was obtained
12
12
12
12
0.5
a) Reaction was carried out with 1.0 mmol each of benzaldehyde and aniline, and with 1.25 mol% of catalyst (Table 3, entry 5). Further in-
3.0 mmol of cyclohexanone. b) Yield of isolated product. c) Reaction was carried
crease in the amount of catalyst neither increased the yield
out at 50 °C. d) Reaction was carried out at 80 °C. e) Reaction was carried out at
nor the rate of the reaction.
120 °C. f ) Reaction was carried out under MW irradiation. g) ILꢁionic liquid.
It should be mentioned here that methods reported earlier
for this model reaction required longer time and use of toxic
Table 2. Optimization of Reaction Conditions in Various Solventsa)
42)
catalytic system such as Zn(OTf)2 and Bi(OTf)3·4H2O43)
Although in some cases non-toxic catalytic system was used
(boric acid/glycerol), a very long reaction time (30—45 h)
and low yield limit the scope of the method.29)
Encouraged by the remarkable results obtained with the
above reaction conditions, and in order to find the generality
and scope of this new protocol, various aldehydes and
amines were used. The results (Table 4) clearly demonstrated
that H3BO3–SiO2 in presence of ionic liquid, [bmim][PF6], is
an excellent catalytic system for Mannich reaction. Gener-
ally, excellent yields of Mannich products were obtained for
a variety of aldehydes including those bearing an electron-
withdrawing group (Table 4, entries 4, 6, 7, 9). Some of the
earlier reported methods were not capable of giving Mannich
products from aldehydes substituted with –NO2 group.28,35)
However, in present case excellent yield of product was ob-
tained with 4-nitrobenzaldehyde (Table 4, entries 6, 9). Fur-
thermore, several electron-rich aromatic aldehydes led to the
Entry
Solvent
Time (h)
Yield (%)b)
1
2
3
4
5
6
7
8
9
Neat
H2O
12
12
12
12
12
12
12
0.5
12
35
52
58
53
60
62
55
94
10
EtOH
EtOH : H2O (1 : 1)
THF
DMSO
MeCN
[bmim][PF6]
Without catalyst and neat
a) Reaction was carried out with 1.0 mmol each of benzaldehyde and aniline, and
3.0 mmol of cyclohexanone. b) Yield of isolated product.
Next, the effect of different solvent media on the model re- desired products in good yield with moderate to good “anti”
action in presence of H3BO3–SiO2 was studied. Solvents diastereoselectivity in most of the cases. Syn : anti ratio was
1
such as water, ethanol, ethanol : water (1 : 1), tetrahydrofuran, determined by H-NMR analysis of product. The scope of
dimethylsulfoxide, acetonitrile proved to be good, but in method was extended to other amines also. In case of amines
these solvents extended periods of time were required and having an electron-donating group, such as 4-methylaniline
also, full conversion of reactants was not achieved (Table 2, the corresponding amino ketones were obtained in good
entries 2—7). Interestingly, in presence of ionic liquid, yields. Amines with electron-withdrawing group, such as, 3-
[bmim][PF6], high yield of the Mannich product was ob- bromo, 4-nitro and 3-chloroaniline, gave the desired product
tained (Table 2, entry 8). Encouraged by these observations, in good yields (Table 4, entries 3, 8, 10). Generally, the Man-
model reaction was carried out with catalytic amount of nich reaction of 4-methoxybenzaldehyde, 4-nitroaniline and
boric acid, silica gel and boric acidꢀsilica gel separately in cyclohexanone is very difficult because of the presence of
[bmim][PF6] (Table 1, entries 13—15). The results clearly electron-donating and electron-withdrawing groups in alde-
demonstrated that H3BO3–SiO2 with ionic liquid, hyde and amine, respectively43) and also, no report exists in
[bmim][PF6], was the best catalytic system for three-compo- literature for the synthesis of Mannich product from these
nent Mannich reaction. From these observations, it has been substrates. However, in present case, excellent yield of prod-

May 2011
643
Table 4. Mannich Reaction of Aromatic Aldehydes, Amines and Cyclohexanonea)
Entry
R1
R2
Product
Time (min)
Yield (%)b)
syn : antic)
mp (°C)
1
2
3
4
5
6
7
8
9
H
H
H
3-Br
H
4-CH3
H
H
4-NO2
4-CH3
3-Cl
4a
4b
4c
4d
4e
4f
4g
4h
4i
30
30
35
25
40
35
20
60
25
30
95
94
96
98
97
98
96
95
98
97
9 : 91
0 : 100
37 : 63
26 : 74
32 : 68
59 : 41
39 : 61
59 : 41
34 : 66
ndd)
141—142
134—136
Oily
133—135
116—117
Oily
4-OCH3
4-OCH3
4-Cl
H
4-NO2
4-Br
4-OCH3
4-NO2
4-CH3
Oily
63—65
120—122
122—123
10
4j
a) Reactions were carried out with 1.0 mmol each of aldehyde and amine, and 3.0 mmol of cyclohexanone. b) Yield of isolated products. c) Syn : anti ratio was deter-
mined by 1H-NMR analysis of product. d) nd: not determined due to overlapping signals in 1H-NMR spectrum.
Table 5. Mannich Reaction of Aromatic Aldehydes, Amines and Ethyl Methyl Ketonea)
Regioselectivity
Entry
R1
R2
Product (6, 7)
Time (h)
Yield (%)b)
syn : antic)
mp (°C)
(6 : 7)
1
2
3
4
4-Br
H
4-OMe
4-OMe
H
H
H
6a, 7a
6b, 7b
6c, 7c
6d, 7d
48 : 52
32 : 68
49 : 51
100 : 0
6
8
7.5
7
88
81
84
82
37 : 63
46 : 54
28 : 72
—
Oily
87—88
82—83
81—82
3-Br
a) Reactions were carried out with 1.0 mmol each of aldehyde and amine, and 3.0 mmol of ethyl methyl ketone. b) Yield of isolated products. c) Syn/anti ratio was deter-
mined by 1H-NMR analysis of product.
Table 6. Mannich Reaction of Aromatic Aldehydes, Amines and Acetophenonea)
Entry
R1
R2
Product (8)
Time (h)
Yield (%)b)
mp (°C)
1
2
3
4
H
4-NO2
4-Br
H
H
H
H
8a
8b
8c
8d
8.5
7.0
8.0
9.0
74
61
58
76
162—164
104—106
138—140
164—166
4-CH3
a) Reactions were carried out with 1.0 mmol each of aldehyde and amine, and 3.0 mmol of acetophenone. b) Yield of isolated product.
uct was obtained from these substrates (Table 4, entry 8).
good yields under these conditions. Acyclic ketones were
The high yield, simple reaction protocol, and originality of less reactive than cyclohexanone and needed much more cat-
this novel process prompted us to investigate the reaction on alyst to afford the desired products. The regioselectivity was
1
other ketones under these conditions (Tables 5, 6). Thus, the determined by H-NMR spectroscopy and by comparison
three component coupling reactions were carried out with with the literature NMR values.44—47) In general, “anti” se-
acyclic ketones such as ethyl methyl ketone and acetophe- lectivity was observed when ethyl methyl ketone was used.
none. The expected products were obtained in moderate to
Another characteristic feature of the present protocol is the

644
Vol. 59, No. 5
Conclusion
In conclusion, a new solid supported environmentally be-
nign catalyst has been developed and used efficiently with
ionic liquid for diastereoselective synthesis of b-amino car-
bonyl compounds. This is the first report for the preparation
of H3BO3–SiO2 catalyst and its use in Mannich reaction. This
procedure offers several advantages including low loading of
catalyst, improved yields, clean reaction and use of unmodi-
fied ketones, which makes it a useful and attractive strategy
for the multi-component reactions of combinatorial chem-
istry. In addition, a very easy workup procedure has been re-
alized. When the products were solid, the pure products were
obtained directly by crystallization from ethanol. Chromato-
graphic separation was not necessary in some cases. Current
efforts in our research group are attempting to expand the ap-
plication of this silica-supported boric acid catalyst for other
reactions.
Chart 1. Reaction of Cyclohexanone with Aldimine in Preference to alde-
hyde
Acknowledgments Authors are grateful to the Director, IHBT, Palam-
pur for providing necessary facilities during the course of the work. Thanks
are also due to UGC and CSIR for awarding research fellowships to V.
Kumar and U. Sharma, respectively.
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